From e9fced83ca415f5ce057a31534d10463d8941e6b Mon Sep 17 00:00:00 2001 From: kyleoconnell-NIH <102973993+kyleoconnell-NIH@users.noreply.github.com> Date: Thu, 18 Jan 2024 17:03:15 -0500 Subject: [PATCH] Add files via upload --- .../search_documents/grant_data_sub1.txt | 2500 +++++++++++++++++ .../search_documents/grant_data_sub2.txt | 2499 ++++++++++++++++ 2 files changed, 4999 insertions(+) create mode 100644 tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub1.txt create mode 100644 tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub2.txt diff --git a/tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub1.txt b/tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub1.txt new file mode 100644 index 0000000..542f2c9 --- /dev/null +++ b/tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub1.txt @@ -0,0 +1,2500 @@ +---------------------------------------------------------------------------------------------------------------- +Search Criteria: + Fiscal Year: All FY + Agency/Institute/Center: Nat'l Cancer Institute (NCI) + Admin: Yes +Drilldown filters: +" Fiscal Years: 2024, 2023, 2022" +" Agencies: NIH, NCI" +---------------------------------------------------------------------------------------------------------------- +NIH Spending Categorization Project Terms Project Title Public Health Relevance Administering IC Application ID Award Notice Date Opportunity Number Project Number Type Activity IC Serial Number Support Year Suffix Program Official Information Project Start Date Project End Date Study Section Subproject Number Contact PI Person ID Contact PI / Project Leader Other PI or Project Leader(s) Congressional District Department Primary DUNS Primary UEI DUNS Number UEI FIPS Latitude Longitude Organization ID (IPF) Organization Name Organization City Organization State Organization Type Organization Zip Organization Country ARRA Indicator Budget Start Date Budget End Date CFDA Code Funding Mechanism Fiscal Year Total Cost Total Cost (Sub Projects) Funding IC(s) Direct Cost IC InDirect Cost IC NIH COVID-19 Response Project Abstract Total Cost IC +No NIH Category available Alaska;Area;Biology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Detection;Cancer Etiology;Carcinogenesis Mechanism;Caregivers;Catchment Area;Cause of Death;Cessation of life;Child;Childhood;Clinical;Clinical Research;Collaborations;Communities;Comprehensive Cancer Center;Computational Biology;County;Development;Diagnosis;Diagnostic;Discipline;Disease;Educational process of instructing;Enrollment;Ensure;Equation;Equity;Exposure to;Faculty;Faculty Recruitment;Fostering;Funding;Genomics;Goals;Grant;Health;Health Sciences;Hematopoietic Stem Cell Transplantation;Idaho;Immunology;Immunotherapeutic agent;Individual;Institution;Intervention;Investments;Knowledge;Laboratories;Laboratory Research;Leadership;Malignant Neoplasms;Measures;Mentors;Mission;Molecular;Montana;Outcome;Patients;Peer Review;Population Research;Postdoctoral Fellow;Prevention;Prevention strategy;Primary Prevention;Public Health;Quality of Care;Research;Research Infrastructure;Research Personnel;Resources;Risk Factors;Risk Marker;Science;Secondary Prevention;Students;Therapeutic;Training;Training and Education;Translating;Translational Research;Translations;Transplantation;Underrepresented Populations;United States;Universities;Washington;Work;Wyoming;anticancer research;base;cancer care;cancer diagnosis;cancer therapy;carcinogenesis;clinical care;clinical practice;computer studies;epigenomics;graduate student;host neoplasm interaction;improved;insight;inter-institutional;interdisciplinary collaboration;interest;member;mortality;multidisciplinary;next generation;outreach;pathogen;profiles in patients;programs;synthetic biology;targeted treatment;therapy development;treatment center;treatment trial;tumor;tumor metabolism;tumor progression Cancer Center Support Grant PROJECT NARRATIVE: OVERALLThere were an estimated 1.7 million new cases of cancer in the United States in 2018 and an estimated609000 deaths from the disease. Cancer is the second leading cause of the death in the U.S. The goal of theFred Hutchinson/University of Washington Cancer Consortium is the elimination of cancer as a cause ofsuffering and death through more effective prevention diagnosis and treatment deriving from fundamentalinsights into the biology of the disease. NCI 10992699 12/28/23 0:00 PAR-17-095 3P30CA015704-49S1 3 P30 CA 15704 49 S1 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 397 Research Centers 2024 21867 NCI 21867 0 PROJECT SUMMARY: OVERALLThe Fred Hutchinson/University of Washington Cancer Consortium (the Consortium) brings together morethan 600 members with research interests in basic clinical and public health sciences related to cancer. Thegoal of the Consortium is the elimination of cancer as a cause of suffering and death through more effectiveprevention diagnostics and treatment deriving from fundamental insights into the biology of the disease. Theextensive interdisciplinary collaboration among the partner institutions in the cancer research disciplines ofbasic clinical and public health sciences affords new opportunities to reduce suffering and mortality fromcancer.The Consortium was established in 2002 to build upon the complementary strengths and resources of threepartner institutions: the Fred Hutch which has been an NCI-designated Comprehensive Cancer Center since1976; the University of Washington which has significant strength in cancer research clinical care andteaching; and Seattle Childrens the major pediatric academic center in the region. In 2008 the Seattle CancerCare Alliance the cancer treatment center founded and equally co-owned by the three founding institutionswas formally added to the cancer center designation.The Consortiums total funding base (direct dollars) is $242M of which $117M is peer-reviewed including$50M from the NCI. During the last grant period over 170 new faculty members joined the Consortium addingbreadth and depth to our research and clinical capabilities. In the most recent year we enrolled 1338 patientsonto interventional treatment trials of which more than 50% were investigator-initiated. The ratio of accruals tonewly registered patients was 28%.The Consortium serves a catchment area of 13 counties in western Washington. This equates to the region inwhich 83 percent of our patients reside. As the only NCI-designated comprehensive cancer center in a five-state region (Washington Wyoming Alaska Montana and Idaho) we not only seek to serve the health needsof the catchment area through research training and outreach but also to ensure high impact throughout thelarger region.The Consortium continues to build upon historic strengths in basic cancer biology immunology andtransplantation pathogen associated malignancies tumor specific translational research computationalbiology and studies of cancer etiology prevention and outcomes. The Consortium is well poised to continue itsexceptional level of research in these areas. The CCSG continues to have a high impact on the Consortiumfostering new inter-institutional collaborations strengthening the translational research platform andintensifying research efforts on problems of the catchment area. Partner institutions contributed nearly $1.2billion in institutional support during the last project period including investments in our laboratory and clinicalresearch infrastructure as well as in faculty recruitment and trainee support. 21867 +No NIH Category available Appointment;Arts;Authorization documentation;Award;Basic Cancer Research;Basic Science;Behavioral;Bioinformatics;Biology;Budgets;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Caregivers;Caring;Catchment Area;Chemicals;Clinic;Clinical Data;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Data;Development;Direct Costs;Discipline of Nursing;Disease;Disparity;Early Diagnosis;Education and Outreach;Epidemiology;Epigenetic Process;Evaluation Research;Facility Construction;Faculty;Fostering;Funding;Future;Genetic Research;Genomic approach;Government;Grant;Health;Health Resources;Health Services;Healthcare;Human;Incidence;Information Systems;Infrastructure;Institution;Insurance Carriers;Intervention;Intervention Trial;Investments;Leadership;Malignant Neoplasms;Measures;Medicaid;Medicare;Minority Groups;Mission;Molecular Epidemiology;Monitor;Morbidity - disease rate;Names;North Carolina;Oncology;Outcome;Patient Care;Patients;Performance;Pharmacologic Substance;Pharmacy facility;Policies;Population;Population Heterogeneity;Population Sciences;Prevention;Privatization;Productivity;Protocols documentation;Public Health;Publications;Publishing;Research;Research Personnel;Resource Sharing;Resources;Role;Rural Population;Schools;Science;Scientist;Services;Stretching;System;Talents;Technology;The Cancer Genome Atlas;Therapeutic;Training;Training and Education;Translating;Translations;United States;Universities;Urban Population;anticancer research;authority;cancer care;cancer epidemiology;cancer genetics;cancer research center director;cancer therapy;career;chimeric antigen receptor T cells;college;community based participatory research;community college;community engagement;data management;drug discovery;epidemiology study;imaging detection;innovation;malignant breast neoplasm;medical schools;member;minority disparity;mortality;multidisciplinary;neoplasm registry;operation;outreach;population based;population health;programs;public policy on tobacco;recruit;safety net;screening services;senior faculty;survivorship;undergraduate student Cancer Center Support Grant PROJECT NARRATIVEThe Lineberger Comprehensive Cancer Center (LCCC) forms the nexus for researchers focused onunderstanding and identifying the mechanisms leading to the prevention of and treatments for cancer. LCCCis an integral component of the research mission at The University of North Carolina (UNC) at Chapel Hillcoalescing the cancer research capabilities of the Schools of Medicine Public Health Pharmacy and Nursingand the College of Arts and Sciences. The LCCC strives to reduce cancer incidence morbidity and mortality inNorth Carolina the United States and across the globe through innovative research cutting-edge treatmentsmulti-disciplinary training education and outreach. NCI 10992402 12/6/23 0:00 PAR-20-043 3P30CA016086-48S1 3 P30 CA 16086 48 S1 "SHAFIK, HASNAA" 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6477317 "EARP, HENRY SHELTON" Not Applicable 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 397 Research Centers 2024 189538 NCI 130295 59243 ABSTRACTOver the past 5 years the Center sustained its upward trajectory in cancer research excellence and service toits catchment area the State of North Carolina. With Dr Sharplesss appointment to NCI Director inconsultation with University leadership and the Centers Scientific Advisors Dr Earp was re-appointed UNCLineberger Comprehensive Cancer Center (LCCC) Director for an additional term. The LCCC continued itsexceptional performance of the past decade with respect to all important metrics including state service. Directcost cancer research funding in 2019 increased to $161M of which over $54M comes from NCI; Centerresearch space under the Directors authority increased by ~10000nsf; participation in interventional trials wasover 11000 accruals for the 5 year period; 36% of the more than 6000 cancer related publication werecollaborative; construction of a GMP facility was begun and a CAR T program was initiated with multiple INDsand 8 trials opened; and the Office of Community Outreach Engagement expanded LCCCs traditional strengthin community-based participatory research and implementation .The Centers 324 members span the basic clinical and population sciences organized into 9 programs withsubstantial inter- and intra-programmatic productivity. Faculty additions in the physical and pharmaceuticalsciences created new opportunities in drug discovery delivery imaging and early detection. Substantialinvestment in faculty technology and bioinformatics dramatically expanded cancer genetics research includingleadership in the TCGA and expanded use of sequencing in clinical trials. LCCC population scientists initiatedsignificant new efforts in cancer outcomes with recruitment and infrastructure for analyzing all cancer cases inour catchment area as well as new endeavors in cancer communication health access survivorship andmolecular epidemiology. Groundbreaking observations in breast cancer minority disparity research emergedfrom Center programs. Our basic programs continue to publish high-impact observations that are beingtranslated into human therapeutics. A trans-Center Global Oncology effort received grants in each of the NCIsnew competitions. The Centers continued expansion is driven by remarkable institutional support includingdirect support for cancer research from the state legislature. The UNC Lineberger requests continued fundingfor: 9 scientific programs; 13 shared resources; Clinical Protocol and Data Management; Protocol Review andMonitoring System Developmental Funds Planning Leadership and Evaluation and Cancer Research andCareer Enhancement The CCSG budget supports technological and operational expansion for a talentedfaculty integrated through cancer center mechanisms towards making advancements in the prevention earlydetection and treatment of cancer in North Carolina and the nation. 189538 +No NIH Category available Centromeres and Ovarian Cancer Ovarian cancer the fifth leading cause of cancer deaths among women with the worst prognosis and the highestmortality rate is characterized by changes in centromere and chromosome replication. This project willimplement pioneering technologies to recreate the ovarian cancer-specific DNA changes in healthy cells tounderstand how they affect the stability and replication of chromosomes. This proposal will enhance ourunderstanding of how centromere changes contribute to ovarian cancer development. NCI 10986684 12/8/23 0:00 PA-21-268 7R21CA259630-02 7 R21 CA 259630 2 "RODRIGUEZ, LARITZA MARIA" 12/1/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OBT-J(55)R] 10565289 "CONTRERAS, RAFAEL ALEJANDRO" Not Applicable 7 GENETICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 12/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2022 317649 NCI 213905 103744 The composition organization and function of centromeric DNA remain one of the last frontiers ofgenomics. This proposal Centromeres and Ovarian Cancer will investigate the role centromere DNAsequences play in the correct function of centromeres and chromosome segregation in ovarian cancerand its contribution to ovarian cancer progression. The centromere is the functional unit responsible for thefaithful segregation of chromosomes. Failure to properly partition chromosomes to daughter cells results ingenome instability and aneuploidy (gain or loss of chromosomes) a hallmark of cancers. Functional centromerestructures are made of centromere epigenetic marks that bind to the underlying DNA sequence. During celldivision the microtubules interact with these centromeric structures and pull chromosomes apart. Althoughcentromere identity and function rely on epigenetic mechanisms recent studies suggest that centromeresequences have functional roles as well. However human centromere sequences have not been assembledinto linear contigs due to their high content of repetitive DNA and thus the precise composition organizationand function of centromeric DNA remain to be elucidated. We will investigate the role centromere DNAsequences play in centromere function and chromosome segregation in ovarian cancer. To overcome the virtualabsence of centromere sequence in the Human Genome Project the P.I. has devised rapid quantitative PCR-based methods and innovative Next Generation Sequencing tools to study specifically the centromeric DNAelements of each human chromosome at the molecular level. Using these pioneering technologies wediscovered that the genomes of ovarian cancer cells exhibit severe loss of centromere sequences in specificchromosomes in particular chromosome 17 when compared to healthy matched-tissue. We hypothesize thatthese specific centromere mutations play a key role in centromere formation and function and lead tochromosome 17 missegregation and genome instability seen in ovarian cancer. The proposed research will usemutant ovarian and fallopian tube cell lines with centromere deletions generated using CRISPR Cas9. We willinvestigate whether centromere loss alters the ability of centromeric epigenetic marks to formcentromere/kinetochore structures. We will address whether loss of centromeric material in these mutant cellsaffects genome stability chromosome segregation and transformation. This information will begin to provide abetter understanding of the roles centromere sequences play in cell division and cancer genetics. These studieswill enhance our knowledge of centromeres and chromosomal biology and could potentially result in novelmethodologies to study genetic defects in cancers. 317649 +No NIH Category available ATAC-seq;Acute Lymphocytic Leukemia;Acute leukemia;Adolescent;Adult Acute Lymphocytic Leukemia;Advisory Committees;Apoptosis;Apoptotic;Automobile Driving;B-Cell Acute Lymphoblastic Leukemia;BCL2 gene;Big Data;Bioinformatics;Biological;Biology;Cancer Etiology;Cell Cycle;Cell Cycle Arrest;Cell Line;Cell Proliferation;Cells;Cellular biology;Cessation of life;ChIP-seq;Chemoresistance;Child;Childhood Acute Lymphocytic Leukemia;Chronic;Clinical;Clinical Trials;Clinical Trials Design;Combined Modality Therapy;Complex;Computational Biology;DNA;Dasatinib;Data;Data Set;Dependence;Diagnosis;Drug Targeting;Environment;Epigenetic Process;Evolution;Future;Gene Expression Profile;Genes;Genetic;Genetic Transcription;Genomics;Goals;Growth;Harvest;Heterogeneity;Human;In Vitro;International;K-Series Research Career Programs;Knock-out;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Mentors;Mentorship;Methodology;Modeling;Mutation;Oncogenic;Outcome;Pathway interactions;Patients;Pharmacotherapy;Phenotype;Philadelphia Chromosome;Phosphotransferases;Population;Proliferating;Recurrence;Regulator Genes;Relapse;Research;Research Personnel;Resistance;Resources;Role;Scientist;Signal Transduction;System;Systems Biology;Techniques;Therapeutic;Time;Training;Transcriptional Regulation;Translating;Tyrosine Kinase Inhibitor;Validation;acute lymphoblastic leukemia cell;c-myc Genes;career;childhood cancer mortality;clinical translation;clinically relevant;design;early phase clinical trial;experience;experimental study;gene regulatory network;genetic signature;high risk;improved;in vivo;in vivo Model;inhibitor;inhibitor therapy;insight;knock-down;leukemia;molecular targeted therapies;multidisciplinary;multiple omics;non-genetic;oncogene addiction;overexpression;patient derived xenograft model;pharmacologic;pre-clinical;precision medicine;precision medicine clinical trials;resistance mechanism;risky driving;single cell analysis;skills;synergism;targeted agent;targeted treatment;therapy resistant;transcription factor;transcription regulatory network;transcriptome;transcriptome sequencing;transcriptomics;translational physician;translational scientist;treatment response Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia PROJECT NARRATIVERelapsed acute lymphoblastic leukemia (ALL) is a leading cause of cancer death in children/adolescents andPhiladelphia chromosome-like ALL is a common high-risk subtype characterized by miswired signaling highrelapse rates and extremely poor survival. Our research uses systems biology approaches to identify howchanges in multiple pathways at the single-cell level may lead to leukemia resistance and relapse. Throughthese studies we hope to improve our understanding of the critical biologic mechanisms driving this high-riskleukemia and to develop more effective combination precision medicine therapies to cure patients. NCI 10986579 1/5/24 0:00 PA-21-268 7K08CA273531-02 7 K08 CA 273531 2 "BIAN, YANSONG" 1/5/24 0:00 12/31/27 0:00 Career Development Study Section (J)[NCI-J] 14893488 "DING, YANG-YANG " Not Applicable 7 PEDIATRICS 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 1/5/24 0:00 12/31/24 0:00 398 Other Research-Related 2024 184541 NCI 170871 13670 PROJECT SUMMARY/ABSTRACT This mentored career development award proposal will facilitate my career goal to become anindependent translational researcher using advances in experimental genomics and bioinformatics to developimproved precision medicine therapies for children with difficult-to-cure cancers. During the 5-year training periodI plan to acquire critical skills in computational biology and pursue additional didactic training in transcriptionalregulation death pathways single cell analyses and early-phase clinical trial design. The proposed studies andtraining will be completed under the co-mentorship of Dr. Kai Tan and Dr. Sarah Tasian both internationallyrecognized leaders with complementary expertise in systems and single cell biology and in translational leukemiaresearch respectively. My multi-disciplinary Advisory Committee is composed of world-renowned scientists whohave extensive mentoring experience and diverse expertise including Drs. Chi Dang Nancy Speck John Marisand Xiaolu Yang. The scientific proposal is aimed at elucidating critical dependencies that synergize with kinasepathway oncogene addiction in Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) akinase-driven leukemia with dismal outcomes. Ph-like ALL comprises 15-40% of childhood and adult ALL casesand is associated with extremely high relapse rates and very poor overall survival. We observed in preclinicalPh-like ALL models that treatment with the JAK inhibitor ruxolitinib has incomplete efficacy and also resulted inglobal gene expression changes. Thus combination therapy approaches that effectively target key therapeuticescape mechanisms are needed. Additionally single-cell variability in Ph-like ALL that may drive targetedtherapy resistance is unknown. I hypothesize that ruxolitinib treatment in JAK/STAT pathway-altered Ph-like ALLcells leads to rewiring of the gene regulatory network at transcriptional and epigenetic levels (likely mediated byc-MYC) resulting in cell cycle arrest and apoptotic priming amenable to co-targeting. I propose in Aim 1 to modelpatient leukemia reponse to kinase inhibition in vivo and to identify transcriptional regulatory network changesduring chronic ruxolitinib treatment with subsequent functional validation. This represents an unbiased approachto identifying unknown oncogenic dependencies. In Aim 2 I will use single-cell techniques to examine geneticand non-genetic sub-populational changes during targeted drug perturbation over time then to characterize andtarget resistant cell states. These studies will form the basis for developing rational combinations of molecularlytargeted therapies to improve cure rates for patients with Ph-like ALL. In summary I will benefit from theexceptional interdisciplinary expertise and track-record of my mentors and Advisory Committee as well as therich intellectual environment and scientific resources available at CHOP and Penn which provide an ideal settingin which to conduct cutting-edge omics analyses for eventual clinical translation. These research and trainingefforts will help me realize my ultimate goal to translate big data into clinically relevant cures for children withcancer. 184541 +No NIH Category available Address;Area;Behavioral Risk Factor Surveillance System;Black Populations;Black race;Budgets;Cancer Patient;Caring;Censuses;Characteristics;Clinical Trials;Code;Commuting;Complex;County;Data;Data Set;Databases;Diagnosis;Disparity;Emergency department visit;Evaluation;Excess Mortality;Future;Geographic Factor;Geographic Locations;Geography;Health;Health Information National Trends Survey;Health Insurance;Health Services Accessibility;Health behavior;Healthcare;Hospitalization;Individual;Inferior;Insurance;Intervention;Link;Malignant Neoplasms;Mediating;Mediation;Methodology;Modeling;Nature;Office Management;Outcome;Participant;Play;Policies;Policy Developments;Policy Maker;Population;Poverty;Poverty Areas;Quality of Care;Race;Reasons for Geographic And Racial Differences in Stroke;Reporting;Research Personnel;Role;Rural;Rural Population;SEER Program;Sampling;Social support;Socioeconomic Status;Specialist;Stroke Belt;System;Transportation;Work;cancer health disparity;cohort;comorbidity;contextual factors;data registry;deprivation;evidence base;experience;health literacy;indexing;malignant breast neoplasm;mortality;mortality disparity;multilevel analysis;neoplasm registry;primary outcome;rural area;rural disparities;rural patients;rural poverty;rural residence;rurality;screening;social vulnerability;sociodemographics;statistics;therapy development;urban area;urban disparity;urban residence;virtual Understanding rural mortality disparities in cancer: a multi-level approach Relevance narrativeApproximately 19% of the US population resides in rural areas; for over three decades this population hasexperienced increasingly inferior health outcomes when compared with their urban counterparts. The underlyingcause(s) of the widening rural/urban gap in cancer outcomes is hypothesized to be multifactorial and this studywill provide a comprehensive multi-level evaluation of rural/urban mortality disparities. Findings will provide thecritical evidence needed to inform policy as well as to inform intervention development to address the systemicdisparities in mortality experienced by rural patients with cancer. NCI 10977509 1/3/24 0:00 PA-20-185 3R37CA266193-03S1 3 R37 CA 266193 3 S1 "DELLAVALLE, CURT TAVIS" 1/1/22 0:00 12/31/26 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 11262899 "KENZIK, KELLY " Not Applicable 7 SURGERY 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 200772 NCI 121680 79092 AbstractCancer mortality rates in the US declined by 26% between 1991 and 2015 but the decline has not been equalacross all populations. Approximately 19% of the US population resides in rural areas; for over three decadesthis population has experienced increasingly inferior outcomes when compared with their urban counterparts.The underlying cause(s) of the widening rural/urban gap in cancer outcomes is hypothesized to be multifactorialwith socioeconomic status (SES) both at the individual-level and geographic area-level likely playing a significantrole. Gaps in evidence include the use of multiple rural definitions a lack of evidence on associated geographicfactors and limited evidence based on multi-level approaches to understand the complex nature of ruraldisparities. Therefore the overall objective of this study is to conduct a comprehensive examination of theunderlying causes of rural/urban disparities in mortality among individuals diagnosed with cancer. In the first aimthe Surveillance Epidemiology and End Results (SEER) population-level data will be used to examine mortalityamong individuals diagnosed with cancer across three definitions of rurality providing researchers and policymakers with the magnitude of differences by each definition. In the second aim SEER will be linked via county-indicators to 16 databases (US Census Bureau Area Deprivation Index Bureau of Labor Statistics CountyHealth Rankings and Roadmaps AMA Healthcare Workforce Mapper BRFSS Social Vulnerability Index HealthInformation National Trends Survey etc.). These linkages will allow us to estimate the contribution of specific area-level factors (e.g. area-level SES access to high-quality care) on rural/urban mortality differences using effectdecomposition methodology. In the third aim the Reasons for Geographic and Racial Differences in Stroke(REGARDS) cohort (U01 NS041588) will be linked to state level cancer registry data using the Virtual PooledRegistry Cancer Linkage System (VPR-CLS). REGARDS includes longitudinally collected data for 30239participants (44% blacks) oversampled from stroke belt/buckle states (56% of participants from NC SC GATN AL MS AK LA) with large rural populations experiencing the highest mortality. REGARDS collectsinformation at the individual level on sociodemographics health literacy and distance to healthcaretransportation and risky health behaviors. Multi-level modeling and mediation modeling approaches will allow forthe examination of the contribution of individual-level characteristics and the area-level characteristics simultaneously.Results will provide estimates of how much of the mortality disparity is explained by differences in urban andrural geographic characteristics overall as well estimates that describe the potential impact of hypotheticalinterventions on specific mediating factors. Findings will provide the critical evidence needed to inform policy andintervention development aimed at addressing the systemic disparities in mortality experienced by rural patientswith cancer. 200772 +No NIH Category available Behavior Therapy;Body mass index;Businesses;Carotenoids;Chronic;Cluster randomized trial;Communities;Community Outreach;Computer software;Consumption;Control Groups;Country;Data;Dermal;Diet;Dose;Eating;Education;Effectiveness;Evaluation;Face;Fatty acid glycerol esters;Feedback;Fingers;Food;Food Access;Food Preferences;Funding;Future;Health;Health Food;Healthy Eating;Heart Diseases;Height;Hour;Housing;Improve Access;Income;Individual;Intake;Intervention;Interview;Knowledge;Low Income Population;Low income;Malignant Neoplasms;Marketing;Measurement;Measures;Minority;Minority Groups;Modeling;Neighborhood Health Center;Neighborhoods;Nonprofit Organizations;North Carolina;Obesity;Outcome;Participant;Patient Self-Report;Periodicals;Persons;Population;Preparation;Price;Process;Process Measure;Program Effectiveness;Qualifying;Randomized;Randomized Controlled Trials;Reporting;Request for Proposals;Research;Running;Sales;Scanning;Selection Criteria;Self Efficacy;Site;Socioeconomic Status;Sodium;Surveys;Techniques;Telephone;Testing;Time;Unhealthy Diet;Update;Vulnerable Populations;Weight;cluster randomized design;community college;community engagement;community organizations;cooking;cost;design;dietary;effectiveness measure;effectiveness testing;effectiveness/implementation hybrid;environmental intervention;farmers markets;flexibility;follow-up;food environment;fruits and vegetables;health disparity;hybrid type 1 design;implementation framework;implementation process;improved;informant;intervention participants;member;nutrition education;process evaluation;programs;recruit;research study;saturated fat;skills;social cognitive theory;success;sugar;theories;underserved community Effectiveness and Implementation of a Research Tested Mobile Produce Market Designed to Improve Diet in Underserved Communities NarrativeOur research demonstrated that a mobile produce market can have a significant positive impact on diets ofresidents in lower-income communities. We want to test this program more widely to determine if the effectcan be replicated and develop a best-practices toolkit to help others sustainably implement the program. NCI 10977481 11/28/23 0:00 PA-16-160 3R37CA215232-07S1 3 R37 CA 215232 7 S1 "AGURS-COLLINS, TANYA" 7/1/23 0:00 11/30/24 0:00 10598093 "LEONE, LUCIA A" Not Applicable 26 PUBLIC HEALTH & PREV MEDICINE 38633251 LMCJKRFW5R81 38633251 LMCJKRFW5R81 US 43.003074 -78.785924 5992614 STATE UNIVERSITY OF NEW YORK AT BUFFALO AMHERST NY SCH ALLIED HEALTH PROFESSIONS 142282567 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 40845 NCI 25409 15436 AbstractLower-income and minority groups face significant health disparities with respect to obesity cancer heartdisease and other diet-related chronic conditions. Poor diets low in fruits and vegetables (F&V) and high insaturated fat sodium and sugar contribute to many of the health problems faced by vulnerable groups. Whilesocioeconomic status and other individual level factors (i.e. food preferences time and skills to preparehealthy food etc.) can lead to reduced F&V consumption these must be viewed in an environmental context.Compared with higher-income neighborhoods lower-income and minority neighborhoods are less likely tohave stores that sell a variety of F&V and other healthy foods. And when stores are available produce maynot be affordable high quality or culturally appropriate. Farmers' markets and mobile produce markets (MM)have become increasingly popular strategies to alleviate food access concerns in underserved communities.However it is unclear if these programs have the necessary components to have an appreciable impact ondiet. Our research team recently completed one of the first randomized controlled trials of a MM program calledthe Veggie Van. Veggie Van was run in partnership with our team and a small non-profit organization in NorthCarolina; it delivered boxes of fresh locally grown produce and food-focused education to communities withsignificant barriers to F&V consumption including availability affordability quality and knowledge. In this smallcluster-randomized trial in 12 communities (N=201) we saw impressive changes in F&V intake withintervention participants eating almost 1 more cups per day of F&Vs than the control group. Interventionparticipants also reported increases in perceived access to healthy foods and Veggie Van customers attributedmany dietary changes to the MM program. While these results are very promising we believe it is important totest the effectiveness of the Veggie Van program when implemented by different organizations in multiplecommunities. If shown to be effective we can create a research-tested intervention toolkit which can bedisseminated to communities across the country. For this research we will use a request for proposalsprocess to identify 8 organizations nationwide that are well-qualified to implement the Veggie Van model.Organizations will identify appropriate sites for MM deliveries (32 total) and we will randomize them to either animplementation or planning condition. With the help of our team's technical assistance and provided fundingpartner organizations will engage community members in the process and initiate a MM program. We will usea Type 1 Hybrid Effectiveness-Implementation to measure effectiveness (diet BMI dermal carotenoids) andimplementation (customer reach and sales process measures qualitative interviews with MM staff). We willalso examine sustainability of MM financial models and determine implementation standards (i.e. dose neededto maintain impact) for inclusion in our MM toolkit for future dissemination. 40845 +No NIH Category available Address;Aftercare;Biological Models;Biopsy;Blood Banks;CRISPR library;Cancer Patient;Cancer cell line;Candidate Disease Gene;Cause of Death;Cell Line;Cervical;Chemotherapy and/or radiation;Clinic;Clinical;Clonal Expansion;Custom;DNA Library;DNA Sequence Alteration;Data;Databases;Dimensions;Drug Screening;Evolution;Fistula;Freezing;Fresh Tissue;Future;Gene Pool;Genes;Hemorrhage;Immune;In Vitro;Institution;Laboratories;Libraries;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Modeling;Mutate;Mutation;Organoids;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Population;Precision therapeutics;Prognostic Marker;Publishing;Qualifying;Radiation-Sensitizing Agents;Radiosensitization;Recording of previous events;Relapse;Resistance;Risk;Sampling;Swab;Techniques;Testing;Tissue Banks;Tissues;Translating;Treatment outcome;Woman;biobank;candidate validation;cell bank;chemoradiation;clinical translation;cohort;computational pipelines;driver mutation;exome sequencing;experience;genetic testing;high risk;human tissue;improved;in vitro testing;large-scale database;microbiome;new therapeutic target;novel;patient population;predictive marker;radiation resistance;radiation response;research clinical testing;response;risk variant;screening;single-cell RNA sequencing;standard of care;targeted agent;targeted treatment;therapeutically effective;tumor;tumorigenesis Identifying Novel Radiation Sensitizers in Cervical Cancer Project NarrativeThis project aims to validate potential targets for chemoradiation sensitization in patients with cervical cancerundergoing chemoradiation for cure. This will be accomplished by testing previously identified potential targetsin cervical cancer cell lines and organoid models and by computationally validating mutations that expandduring CRT in patients undergoing treatment. This proposal uses a novel non-invasive swab-based biopsymethod to collect serial data without harm or discomfort to patients which is the first approach in cervicalcancer. NCI 10977475 11/16/23 0:00 PAR-20-292 3R21CA277332-02S1 3 R21 CA 277332 2 S1 "PRASANNA, PAT G" 12/7/22 0:00 11/30/24 0:00 ZCA1-TCRB-9(O1)S 11517691 "COLBERT, LAUREN ELIZABETH" Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 57406 NCI 35436 21970 Project SummaryCervical cancer remains a significant global cause of death in women and 40% of women with cervical cancerwill relapse and die despite chemoradiation treatment. There is an urgent need to identify prognostic andpredictive biomarkers for chemoradiation response. We have developed and optimized a novel non-invasiveswab-based biopsy approach to collect tissue before during and after chemoradiation without patient discomfortor risks of serial biopsies such as bleeding or fistula. Despite low tumor purity we have also developed a customcomputational pipeline to optimize mutation calling and identify clonally expanded mutations duringchemoradiation. Developing a deep understanding of genomic alterations during and after CRT to these findingswill help fast-track clinical translation of targeted therapies. To this end we have used our pipeline in a pilot studyof 70 patients to reconstruct the evolution of mutations during CRT and identify proliferatively advantageousdriver mutations and pathways. This proposal aims to validate the candidate driver mutation lists in multipledimensions and develop a patient-derived organoid platform to test potential targeted therapies. First we willvalidate the preliminary identified clonally expanded genes and pathways in a larger population of alreadycollected but yet-to-be-sequenced samples. Second we will perform a CRISPR/Cas9 library screen of thesepreliminarily identified drivers in available cervical cancer cell lines. Simultaneously we will develop a cervicalcancer organoid biobank to perform single-cell RNA sequencing before and after CRT and validate thesepreliminarily identified genes. This platform will be used in the future to test targeted agents. When we completethe aims of this R21 we will have validated ideal targets developed testing platforms and set the stage fortesting clinically impactful therapies in a future R01. 57406 +No NIH Category available Address;Animal Model;Automation;Cancer Patient;Clinic;Clinical;Clinical Protocols;Clinical Research;Computer software;Coupling;Custom;Data;Data Analyses;Data Collection;Data Reporting;Decision Making;Development;Devices;Diagnostic;Documentation;Electron Spin Resonance Spectroscopy;Engineering;Evaluation;Generations;Good Manufacturing Process;Guidelines;Human;Linear Accelerator Radiotherapy Systems;Magnetic Resonance Imaging;Malignant Neoplasms;Marketing;Measurement;Measures;Medical Device;Medical Technology;Monitor;Morphologic artifacts;Motivation;Movement;National Cancer Institute;Oncology;Oxygen;Oxygen saturation measurement;Patients;Performance;Peripheral Vascular Diseases;Physiologic pulse;Prognosis;Program Research Project Grants;Radiation Oncology;Radiation therapy;Research;Resource-limited setting;Resources;Role;Safety;Site;Speed;System;Technology;Testing;Therapeutic;Time;Tissues;Translating;Treatment outcome;Underserved Population;Work;achievement test;cancer care;cancer therapy;clinical care;clinical research site;cohort;college;commercialization;data acquisition;design;design and construction;diabetic;digital;effective therapy;efficacy evaluation;ergonomics;flexibility;healthy volunteer;heart motion;human subject;image guided;image guided radiation therapy;improved;in vivo;industry partner;innovation;innovative technologies;instrumentation;light weight;manufacture;medical schools;novel;operation;phantom model;prototype;respiratory;response;safety and feasibility;success;therapy outcome;tissue phantom;tool;treatment strategy;tumor;usability;user-friendly EPR scanner for tumor oximetry in the clinic PROJECT NARRATIVEWe propose to build an innovative first-in-clinic easy-to-use oxygen scanner for repeated monitoring of tumoroxygen levels in cancer patients. The scanner will be built using the advanced in vivo electron paramagneticresonance (EPR) technology developed at Dartmouth College and in partnership with ViewRay a pioneer inthe development of MRI image-guided linear accelerator for radiation therapy. The new oxygen scanner canprovide potentially important and previously unavailable information on tumor oxygen status which is importantfor accurate prognosis and development of effective treatment strategies for cancer therapy. NCI 10977456 12/1/23 0:00 PAR-21-166 3R01CA269234-02S1 3 R01 CA 269234 2 S1 "SORG, BRIAN S" 1/1/23 0:00 12/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-S(57)R] 1986495 "KUPPUSAMY, PERIANNAN " Not Applicable 2 ENGINEERING (ALL TYPES) 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH BIOMED ENGR/COL ENGR/ENGR STA 37551421 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 196033 NCI 191443 4590 PROJECT SUMMARYThis academic-industrial partnership (AIP) proposal seeks to develop a robust and easy-to-use clinical scannerfor tumor oxygen measurement (oximetry) in cancer patients. By knowing quantitative tumor oxygen levels inreal time radiotherapy could be better planned and delivered at times when there will be an optimal therapeuticratio thus significantly improving cancer care. The proposed approach seeks to leverage the unique capabilitiesof the in vivo electron paramagnetic resonance (EPR) oximetry technology that we have developed formeasurement in human subjects into a medical device that is ready for routine clinical use. The scanner canmake direct and repeated measurements of tumor oxygen by typical end-users in a clinical setting. The EPRresearch team at the Geisel School of Medicine (Dartmouth College) has successfully demonstrated the clinicalfeasibility and safety of EPR oximetry for measuring tumor oxygen in the clinic and now seeks to expand uponthat success through a collaborative partnership with ViewRay a medical-device company that is engaged inMRI image-guided radiation therapy. The clinical scanner will be designed to make it easier to operate by clinicalstaff and sufficiently robust and reliable for its intended use in a variety of clinical settings. The following specificaims are proposed to achieve the overall objective of developing an advanced EPR scanner for oximetry that isready to be manufactured and used in routine clinical care to enhance cancer therapy: (Aim 1) Design andconstruct a 600-MHz pulse EPR system for clinical oximetry; (Aim 2) Fabricate a new class of compactlightweight and advanced resonator designs specifically optimized for pO2 measurements in human tumors;(Aim 3) Develop hardware and software interface with advanced measurement capabilities and user-friendlyoperation suitable for use in the clinic; (Aim 4) Assemble test and evaluate the scanner for repeatedmeasurements of oxygen concentration using tissue phantoms and animal models of tumor; and (Aim 5)Evaluate the efficacy usability and safety of the oxygen scanner as a medical device and validate its use tomake oxygen measurements in cancer patients and human factors engineering. The EPR scanner fullyintegrated with the hardware and software modules will be evaluated in relation to its ability to meet or exceedregulatory standards and for its practicality as a clinical device. The new first-in-clinical scanner will be a veryvaluable tool in the clinic for accurate prognosis and development of effective treatment strategies for cancertherapy. It can also be a valuable clinical tool for other clinical conditions where tissue oxygen is a critical variablefor decision making e.g. patients with diabetic peripheral vascular disease. 196033 +No NIH Category available Acute Lymphocytic Leukemia;Adherence;Age;Behavior assessment;Behavioral;Biological Markers;Cancer Relapse;Cause of Death;Cessation of life;Child;Child Behavior;Child Rearing;Child health care;Childhood;Classification;Code;Conflict (Psychology);Data;Data Collection;Deglutition;Disease;Dose;Drops;Drug Prescriptions;Education;Educational process of instructing;Electronics;Enrollment;Ensure;Equation;Family;Goals;Health Care Costs;Home;Hospitalization;Ingestion;Intervention;Learning;Life;Malignant Childhood Neoplasm;Measurement;Measures;Medical;Medication Management;Medicine;Methodology;Methods;Modeling;Monitor;Morbidity - disease rate;Nurses;Oral;Parents;Participant;Patient Self-Report;Patients;Pediatric Oncology Group;Pediatrics;Pharmaceutical Preparations;Procedures;Public Health;Randomized Controlled Trials;Research;Resistance;Risk;Schedule;Scheme;Shapes;Specific qualifier value;Stress;Surveys;Techniques;Testing;Time;Treatment Failure;Treatment outcome;United States National Institutes of Health;behavior measurement;biomarker validation;cancer care;cancer risk;caregiving;chemotherapy;clinical care;clinically significant;diaries;efficacy evaluation;experience;health disparity;improved;innovation;medication administration;medication compliance;medication nonadherence;mortality;novel;pharmacologic;pill;programs;recruit;restraint;retention rate;risk prediction;satisfaction;screening;secondary outcome;side effect;skills;translational impact;treatment as usual;usability Behavioral Parenting Skills as a Novel Target for Improving Pediatric Medication Adherence Public Health SignificanceRecent landmark studies from the Childrens Oncology Group (COG) highlight adherence to home-based oralchemotherapy as an enduring problem in pediatric cancer care. Yet little is known about why some familieshave difficulty adhering to their childs home-based oral chemotherapy while others do not. Through the novelexamination of how behavioral parenting skills shape adherence at the episode and daily levels the proposedprogram of research has potential to lead to a paradigm shift in pediatric cancer adherence risk prediction andinterventions moving away from blunt demographic-based risk prediction and identifying behavioral parentingskills that are easily amenable to screening modifiable and may be more precise predictors of non-adherencerisk. NCI 10977392 12/15/23 0:00 PA-18-722 3R01CA258337-03S1 3 R01 CA 258337 3 S1 "NELSON, WENDY" 12/15/21 0:00 11/30/26 0:00 Clinical Management in General Care Settings Study Section[CMGC] 10654598 "BOUCHARD, ELIZABETH " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 210658 NCI 121417 89241 In pediatric health care non-adherence to medications is a significant driver of avoidable suffering and death.Over half of children do not adhere to prescribed medications and non-adherence is the leading cause oftreatment failure in pediatrics. Non-adherence can lead to worsening illness death preventable hospitalizationincreased health care cost and morbidity. Even in pediatric cancer when the consequences of non-adherenceto chemotherapy are potentially life threatening over 40% of patients have clinically significant non-adherence.For the most common pediatric cancer Acute Lymphoblastic Leukemia (ALL) children who miss just 10% ofchemotherapy doses have a nearly 4-fold risk of cancer relapse. Despite decades of research we do not haveeffective strategies to meaningfully increase pediatric medication adherence. The goal of the proposedresearch is to reduce preventable pediatric morbidity and mortality through testing a novel target behavioralparenting skills as a modifiable mechanism to improve medication adherence in young children (ages 3-9).Based upon our preliminary data we have begun to develop CareMeds a parenting skills-focused adherenceintervention. The goal of this project is to use stages 0 and 1 of the NIH Stage Model to further develop andevaluate the feasibility of the CareMeds intervention. Evidence is converging on family functioning andparenting style as critical factors that shape child medication adherence. Yet previous studies typically rely onone-time global measures making it difficult to discern the precise parenting skills that improve medicationadherence. For example we know very little about what exactly supportive or cohesive families are doing topromote medication adherence. In Aim 1 we will use direct observation of medication administration at home tounderstand common episode-level barriers and identify the behavioral parenting skills that are most successfulin achieving medication administration in young children. In Aim 2 we will use daily diary data collection toexamine how daily parenting experiences influence the risk of medication non-adherence. We will use datafrom Aims 1 and 2 and input from diverse parents to refine the final CareMeds intervention package. In Aim 3we will conduct a pilot RCT of the intervention versus usual care with 100 families of young children ages 3-9with ALL within 1 month of initiation of oral chemotherapy prescription. Findings from this program of researchwill make significant conceptual contributions through providing nuanced understanding of the aspects ofparenting at the episode and daily levels that shape medication adherence in young children. It will makeinnovative methodological advances through use of direct observation of medication administration daily diarydata on transient parenting experiences and rigorous measurement of adherence through objective behavioralmeasures (electronic pill bottle monitoring) and pharmacological measures (validated biomarkers of drugmetabolites). Finally it will have significant translational impact through setting the stage for a full-scale multi-center RCT to examine the efficacy of the CareMeds intervention. 210658 +No NIH Category available Acceleration;Address;Alkylating Agents;Animal Model;Animals;Automobile Driving;Behavior;Benchmarking;Biocompatible Materials;Biological Assay;Biophysics;Blood Vessels;Brain;Brain Neoplasms;Cancer Model;Cell Line;Cells;Clinic;Clinical;DNA;DNA Modification Process;DNA Repair;Diffuse;Dimensions;Disparate;Drug resistance;Engineering;Evaluation;Excision;Failure;Gelatin;Generations;Glioblastoma;Glioma;Goals;Human;Hyaluronic Acid;Hydrogels;Imaging Device;Invaded;Libraries;Link;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Meta-Analysis;Metabolic;Methyltransferase;Microfluidics;Modeling;Molecular Weight;Operative Surgical Procedures;Outcome;Patients;Pattern;Pericytes;Physiological;Play;Process;Proliferating;Proteins;Recurrence;Resistance;Resources;Role;Signal Transduction;Specimen;Surgical margins;Survival Rate;Technology;Tissue Engineering;Tissue Model;Variant;Work;Xenograft procedure;anti-cancer;bioinformatics tool;detection limit;drug candidate;in vivo;insight;migration;mimetics;miniaturize;mortality;neurovascular;novel;novel therapeutics;pressure;programs;repaired;response;standard of care;stem;temozolomide;therapeutic evaluation;therapy resistant;tumor Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma NARRATIVEGlioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems fromits diffuse invasion throughout the brain and drug resistance. This project will develop and thoroughlycharacterize a tissue engineering platform to investigate pathophysiological processes responsible for invasivespreading therapeutic resistance and poor survival. NCI 10977384 11/23/23 0:00 PAR-19-113 3R01CA256481-04S2 3 R01 CA 256481 4 S2 "BECKER, STEVEN" 12/1/20 0:00 11/30/25 0:00 Cellular and Molecular Technologies Study Section[CMT] 9109865 "HARLEY, BRENDAN A." Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 68431 NCI 49374 19057 ABSTRACTGlioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgical resectionfollowed by treatment with the alkylating agent temozolomide (TMZ). However two major challenges make GBMcurrently untreatable: 1) its diffuse invasion beyond the surgical margin; and 2) TMZ resistance that is tightlylinked to expression of the DNA damage repair protein MGMT. While perivascular niches (PVNs) extending fromthe tumor into the surrounding parenchyma are believed to regulate invasion recurrence and poor survival themajority of animal glioma models are sensitive to TMZ and most do not express MGMT making it difficult toassess novel therapeutics in animal models that dont display TMZ resistance. This Cancer Tissue EngineeringCollaborative project will develop and thoroughly characterize a multidimensional engineered PVN biomaterialstudy pathophysiological processes driving GBM invasion and TMZ resistance and accelerate the evaluation ofnovel TMZ derivatives created to target diffuse GBM cells regardless of MGMT status. We will use advancedmicrofluidics to create libraries of miniaturized gelatin hydrogels containing margin-mimetic hyaluronic acid (HA)and an embedded perivascular network. We also use a novel synthetic pipeline to create TMZ derivatives thatgenerate alternate DNA modifications that cannot be removed by MGMT that we hypothesize work in an MGMT-independent fashion. Merging these technologies we will benchmark an engineered PVN platform formed usingprimary brain neurovascular cells for rapid evaluation of GBM invasion MGMT expression and TMZ resistanceamenable to analysis of cell lines and patient-derived GBM specimens with disparate MGMT profiles. To do thiswe will first construct and thoroughly characterize an engineered perivascular niche (Aim 1). We will use thisnovel biomaterial to benchmark patterns of invasion and MGMT expression in GBM cell lines (Aim 2). Finallywe will establish predictive efficacy of TMZ variants in an engineered perivascular niche (Aim 3). Together wewill develop characterize and benchmark a tissue engineered PVN to examine the role of microenvironmentalselection pressures in the tumor margin on behaviors related to invasion MGMT-mediated TMZ resistancerecurrence and poor survival. Consistent with score-driving criteria of the CTEC program we will develop andthoroughly characterize an engineered PVN biomaterial show it fits within the continuum of existing cancermodels use it to examine phenomena underlying the failure to achieve durable survival and gain actionableinsight regarding novel TMZ derivatives with potential to effectively target GBM cells in the margins independentof MGMT status. 68431 +No NIH Category available Acceleration;Address;Alkylating Agents;Animal Model;Animals;Automobile Driving;Behavior;Benchmarking;Biocompatible Materials;Biological Assay;Biophysics;Blood Vessels;Brain;Brain Neoplasms;Cancer Model;Cell Line;Cells;Clinic;Clinical;DNA;DNA Modification Process;DNA Repair;Diffuse;Dimensions;Disparate;Drug resistance;Engineering;Evaluation;Excision;Failure;Gelatin;Generations;Glioblastoma;Glioma;Goals;Human;Hyaluronic Acid;Hydrogels;Imaging Device;Invaded;Libraries;Link;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Meta-Analysis;Metabolic;Methyltransferase;Microfluidics;Modeling;Molecular Weight;Operative Surgical Procedures;Outcome;Patients;Pattern;Pericytes;Physiological;Play;Process;Proliferating;Proteins;Recurrence;Resistance;Resources;Role;Signal Transduction;Specimen;Surgical margins;Survival Rate;Technology;Tissue Engineering;Tissue Model;Variant;Work;Xenograft procedure;anti-cancer;bioinformatics tool;detection limit;drug candidate;in vivo;insight;migration;mimetics;miniaturize;mortality;neurovascular;novel;novel therapeutics;pressure;programs;repaired;response;standard of care;stem;temozolomide;therapeutic evaluation;therapy resistant;tumor Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma NARRATIVEGlioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems fromits diffuse invasion throughout the brain and drug resistance. This project will develop and thoroughlycharacterize a tissue engineering platform to investigate pathophysiological processes responsible for invasivespreading therapeutic resistance and poor survival. NCI 10977383 11/22/23 0:00 PAR-19-113 3R01CA256481-04S1 3 R01 CA 256481 4 S1 "BECKER, STEVEN" 12/1/20 0:00 11/30/25 0:00 Cellular and Molecular Technologies Study Section[CMT] 9109865 "HARLEY, BRENDAN A." Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 126652 NCI 79856 46796 ABSTRACTGlioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgical resectionfollowed by treatment with the alkylating agent temozolomide (TMZ). However two major challenges make GBMcurrently untreatable: 1) its diffuse invasion beyond the surgical margin; and 2) TMZ resistance that is tightlylinked to expression of the DNA damage repair protein MGMT. While perivascular niches (PVNs) extending fromthe tumor into the surrounding parenchyma are believed to regulate invasion recurrence and poor survival themajority of animal glioma models are sensitive to TMZ and most do not express MGMT making it difficult toassess novel therapeutics in animal models that dont display TMZ resistance. This Cancer Tissue EngineeringCollaborative project will develop and thoroughly characterize a multidimensional engineered PVN biomaterialstudy pathophysiological processes driving GBM invasion and TMZ resistance and accelerate the evaluation ofnovel TMZ derivatives created to target diffuse GBM cells regardless of MGMT status. We will use advancedmicrofluidics to create libraries of miniaturized gelatin hydrogels containing margin-mimetic hyaluronic acid (HA)and an embedded perivascular network. We also use a novel synthetic pipeline to create TMZ derivatives thatgenerate alternate DNA modifications that cannot be removed by MGMT that we hypothesize work in an MGMT-independent fashion. Merging these technologies we will benchmark an engineered PVN platform formed usingprimary brain neurovascular cells for rapid evaluation of GBM invasion MGMT expression and TMZ resistanceamenable to analysis of cell lines and patient-derived GBM specimens with disparate MGMT profiles. To do thiswe will first construct and thoroughly characterize an engineered perivascular niche (Aim 1). We will use thisnovel biomaterial to benchmark patterns of invasion and MGMT expression in GBM cell lines (Aim 2). Finallywe will establish predictive efficacy of TMZ variants in an engineered perivascular niche (Aim 3). Together wewill develop characterize and benchmark a tissue engineered PVN to examine the role of microenvironmentalselection pressures in the tumor margin on behaviors related to invasion MGMT-mediated TMZ resistancerecurrence and poor survival. Consistent with score-driving criteria of the CTEC program we will develop andthoroughly characterize an engineered PVN biomaterial show it fits within the continuum of existing cancermodels use it to examine phenomena underlying the failure to achieve durable survival and gain actionableinsight regarding novel TMZ derivatives with potential to effectively target GBM cells in the margins independentof MGMT status. 126652 +No NIH Category available African American population;Appearance;B-Lymphocytes;BRCA1 gene;Breast;Breast Cancer Genetics;Breast conservation;Carcinoma;Cells;Chronology;Clonal Expansion;Collaborations;Data;Disease;Dissociation;Duct (organ) structure;Ecosystem;Endowment;Epithelial Cells;Event;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Predisposition to Disease;Genetic Transcription;Genetically Engineered Mouse;Genomics;Germ-Line Mutation;Gland;Goals;Heterogeneity;Human;Immune;Immune system;In Situ;In Situ Lesion;Individual;Intervention;Knock-out;Label;Lesion;Lymphoid Cell;Macrophage;Malignant Neoplasms;Mammary gland;Measures;Mediating;Methods;Mitosis;Molecular;Mus;Myeloid Cells;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Null Lymphocytes;Oncogenic;Organoids;Phenotype;Play;Premalignant Cell;Prevention;Preventive therapy;Prognosis;Puberty;Receptor Protein-Tyrosine Kinases;Role;Route;Signal Transduction;Somatic Mutation;Statistical Data Interpretation;Stress;T-Lymphocyte;TNF gene;TP53 gene;Testing;Tissues;Trees;Tumor Suppressor Proteins;Uncertainty;Variant;Visualization;Woman;Work;breast stem cell;breast tumorigenesis;cancer cell;cancer type;cell type;extracellular;functional loss;immune cell infiltrate;in vivo;innovation;lead candidate;malignant breast neoplasm;mammary;member;mosaic;mosaic analysis;mutant;neoplastic cell;novel;paracrine;pharmacologic;premalignant;progenitor;recruit;success;targeted treatment;tool;transcription factor;transcriptome;transcriptomics;tumor;tumor initiation;tumor progression;tumorigenesis A premalignant chronology of cell-state variability in basal-like breast cancer PROJECT NARRATIVEBasal-like breast cancer has the worst prognosis of all breast cancer types. One of the hurdles to identifyingeffective targeted therapies is the uncertainty about how the disease arises in the first place. By examiningcancer-prone tissues before tumor onset we hope to identify the path(s) that cells take en route to becoming abasal-like cancer. NCI 10977382 1/3/24 0:00 PA-20-185 3R01CA256199-03S1 3 R01 CA 256199 3 S1 "KAI, MIHOKO" 1/1/22 0:00 12/31/26 0:00 Cancer Genetics Study Section[CG] 9677317 "JANES, KEVIN A" "ZONG, HUI " 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA BIOMED ENGR/COL ENGR/ENGR STA 229044195 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 65285 NCI 43234 22051 PROJECT SUMMARY/ABSTRACTBasal-like carcinoma is a rapidly-progressing and highly variable subtype of breast cancer that arisesspontaneously (often in African Americans) or in genetically predisposed women. Such tumors are believed toarise from the functional loss of the BRCA1 and TP53 tumor suppressors in uncommitted basoluminalprogenitors of the breast. However it has been challenging to dissect the origins of the disease for lack ofappropriate tools making it difficult to conceive of how the cell-state variability of premalignant mutants givesrise to basal-like breast cancer. The long-term goal of this work is to identify the critical cellular and moleculartransitions underlying basal-like breast cancer genetics. The current application deploys a novel geneticallyengineered mouse model called mosaic analysis of double markers (MADM) which randomly deletes murineBrca1Trp53 in transit-amplifying progenitors of the mammary gland. In MADM stochastic deletion isgenetically defined by coexpression of GFP allowing locally expanded premalignant lesions to be visualizedwithin the gland before the onset of basal-like disease. We found that premalignant expansion is accompaniedby extensive recruitment of specific immune subsets suggesting they play crucial roles in tumorigenesis. Ourobjective is to combine MADM with innovative methods for dissociation-free transcriptomics that will identifycell-state variabilities within mutant epithelial cells and the infiltrating immune lineages of a premalignancy.The hypothesis is that epithelial-cell plasticity and the stromal microenvironment coordinately diversify mutantlesions revealing premalignant transcriptional states that ultimately progress to basal-like cancer in the breastand mammary gland. The aims of the proposal are: 1) To define shared premalignant trajectories ofbasoluminal diversification triggered by BRCA1TP53 deficiency in mice and humans. 2) To deconvolve theimmune heterogeneities that are locally paired with specific premalignant ecosystems for basal-like breastcancer. 3) To functionally validate cell states important for progression by using genetic pharmacologic andparacrine perturbations that homogenize intrinsic or extrinsic variability of premalignant cells ex vivo. Co-PIsJanes and Zong are thought leaders in their respective fields of intratumor cell-state heterogeneity andgenetically engineered mouse modeling with a multi-year track record of collaboration. Together with a pair ofsenior clinicians the team is poised to have a significant overall impact on our understanding of basal-likebreast tumorigenesis. 65285 +No NIH Category available Acetylation;Adjuvant Therapy;Biological Markers;Biology;Breast;Breast Cancer Cell;Cell physiology;Cells;Cellular Metabolic Process;ChIP-seq;Chemicals;Cisplatin;Clustered Regularly Interspaced Short Palindromic Repeats;Compensation;Complex;Data;Doxorubicin;Drug Metabolic Detoxication;Endocrine;Equilibrium;Estrogen receptor positive;Event;Exhibits;Exposure to;Fatty acid glycerol esters;Fulvestrant;Genes;Grant;Knock-out;Lead;Link;Lysine;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Measurement;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Modeling;Nature;Oncogenic;Pathway interactions;Peroxidases;Phenotype;Physiological;Post-Translational Protein Processing;Property;Publications;Reactive Oxygen Species;Recurrence;Reporter;Resistance;Risk;SOD2 gene;Selective Estrogen Receptor Modulators;Signal Transduction;Sirtuins;Stains;Subgroup;Superoxides;Systemic Therapy;T47D;Tamoxifen;Techniques;Testing;Time;Tissue Microarray;Tumor Promoters;Woman;Work;Xenograft Model;breast malignancies;cancer cell;high risk;hormone therapy;in vivo;knock-down;mammary;mimetics;mitochondrial metabolism;monomer;mouse model;mutant;neoplastic cell;new therapeutic target;novel;patient derived xenograft model;permissiveness;prevent;programs;public database;response;small hairpin RNA;stem;stem cell biomarkers;stem-like cell;stemness;targeted treatment;therapy resistant;tissue culture;transcriptome sequencing;tumor;tumorigenesis;tumorigenic MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies NARRATIVEWe have identified a mitochondrial signaling axis centered on MnSOD-K68 which when its normalacetylation status is altered disrupts cell metabolism leading to aberrant-ROS levels and a tumorpermissive phenotype (Zhu et al 2019). Interestingly emerging data suggests that the disruptionof mitochondrial metabolism including aberrant ROS levels is an increasingly acceptedmechanism of oncogenicity due to an enrichment of stem-like cells. Thus it is proposed that whenMnSOD-Ac exists outside of its normal physiological context it disrupts cellular and mitochondrialmetabolism and promotes lineage plasticity properties (or tumor cell stemness) leading to anoncogenic permissive and TamR phenotype and is a potential target for new therapies. NCI 10977365 11/30/23 0:00 PA-19-056 3R01CA253678-04S1 3 R01 CA 253678 4 S1 "WILLIS, KRISTINE AMALEE" 1/9/21 0:00 12/31/25 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7573491 "GIUS, DAVID " Not Applicable 20 RADIATION-DIAGNOSTIC/ONCOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 136991 NCI 88381 48610 SUMMARYThe dysregulation of mitochondrial networks responsible for maintaining normal metabolism is anestablished hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolismleads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling thatdisrupts metabolic balance which can establish a tumorigenic and/or therapy resistant phenotype.In this regard a subgroup of estrogen receptor-positive (ER+) breast malignancies which exhibitincreased ROS levels and a high risk of recurrence due to endocrine therapy has been identified.We recently found a novel mitochondrial signaling axis centered on manganese superoxidedismutase (MnSOD) which when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered disruptscell metabolism leading to aberrant ROS levels (Zhu Nature Commun. 2019). In addition breastcancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2(known to promote stemness-like properties) increased SOX2 and Oct4 (two established stem cellbiomarkers) leading to oncogenicity and pan resistance phenotype (PanR) to agents commonlyused in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumorsto exhibit a lineage plasticity phenotype. Based on our new data our recent publication (Zhu et alNature Commun. 2019) and work by others it is hypothesized that dysregulated MnSOD biologydue to aberrant/increased MnSOD-K68-Ac levels disrupts normal cellular and mitochondrialmetabolism. This initiates metabolic reprogramming via increased levels of HIF2 leading to a cellstemness-mediated tumor-permissive and/or PanR phenotype. Thus we seek to further explore howMnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype leading tooncogenicity and/or PanR. Finally will GC4419 exposure a chemical SOD detoxification mimicreverse the oncogenic and/or PanR phenotypes? 136991 +No NIH Category available Ablation;Address;Affect;American;Animal Model;Animals;Anti-Inflammatory Agents;Apoptosis;Area;Autoimmune Diseases;Biological Assay;Biomedical Engineering;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Coculture Techniques;Colitis;Colon;Colon Carcinoma;Combined Modality Therapy;Complementary and alternative medicine;Crohn's disease;DNA;DNA Damage;Dangerousness;Disease;Dose;Drug Kinetics;Economic Burden;Effectiveness;Europe;Exposure to;FDA approved;Fractionation;Functional disorder;Genetically Engineered Mouse;Genome;Ginseng Preparation;Goals;Immune;Induction of Apoptosis;Infiltration;Inflammatory;Inflammatory Bowel Diseases;Intestines;Knowledge;Lead;Life Style;LoxP-flanked allele;Macrophage;Malignant Neoplasms;Mediating;Modeling;Molecular;Mus;Myeloid Cells;Natural Compound;Natural Source;Nature;North America;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Plants;Prevalence;Property;Research;Resveratrol;SIRT1 gene;Sepsis;Signal Pathway;Signal Transduction;Standardization;TNF gene;TP53 gene;Testing;Toxic effect;Treatment outcome;Ulcerative Colitis;anti-cancer;anticancer activity;cancer chemoprevention;cell type;cellular targeting;colon cancer prevention;colon cancer risk;conditional knockout;conventional therapy;cost;dextran sulfate sodium induced colitis;efficacy testing;experimental study;improved;in vivo;innovation;microbiota;murine colitis;novel;p53 Signaling Pathway;pharmacologic;replication stress;response;sex;side effect;single molecule;small molecule;sound;treatment strategy Harnessing the power of p53 with Panaxynol from American Ginseng to suppress colitis and prevent colon cancer NARRATIVE The purpose of this project is to address the issue of alternative and impactful options for patients withInflammatory Bowel Disease (IBD) to both treat their disease and prevent colon cancer that can result from long-standing and uncontrolled IBD. In comparing innovative treatment strategies panaxynol (PA; isolated fromAmerican Ginseng) stands out as our most potent molecule tested; and we are exploring a unique mechanismthat might not only elucidate colitis mechanisms and cures but branch into other diseases driven by dysregulatedm function. The results of this project will lead to clinical trials and the standardization of PA as a stand-aloneproduct or as part of a synergistic combination therapy for patients with IBD. NCI 10977338 12/8/23 0:00 PA-19-056 3R01CA246809-05S1 3 R01 CA 246809 5 S1 "PERLOFF, MARJORIE" 1/1/20 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-T(02)M] 7955996 "HOFSETH, LORNE J" "MURPHY, ELIZABETH ANGELA" 6 PHARMACOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF PHARMACY 292080001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 145004 NCI 97318 47686 PROJECT SUMMARY Affecting upwards of 4 million people in North America and Europe with an economic burden of $30 -$45 billion Inflammatory Bowel Diseases (IBDs) are debilitating significantly affect life-style and carry a highcolon cancer risk. Because conventional treatment outcomes are modest with dangerous side effects about halfof IBD patients turn to complementary and alternative medicines (CAMs). Although CAMs have been used forthousands of years there is a gap in our knowledge of the mechanisms supporting their effectiveness.Understanding these mechanisms will lead to standardized treatment for IBD outside of toxic FDA-approveddrugs. This will lower their colon cancer risk. Over the past decade we have shown that American Ginseng (AG)suppresses colitis and prevents colon cancer in mice. Using scientifically rigorous Bioassay-GuidedFractionation we have isolated a polyacetylene called panaxynol (PA) that has anti-inflammatory and anti-cancerproperties. PA (compared to the100's of other CAMs being tested) comes from a natural source and is a singleingredient allowing it to be standardized on its own or in a cocktail. What makes this molecule particularlyinteresting and innovative is the mechanism - it is a single molecule extracted from AG with a unique capacityto target macrophages (m) for apoptosis. Our long-term goal is to identify the primary component(s) of AGresponsible for the robust anti-inflammatory and chemopreventive properties of AG we have observed over thepast decade; and to determine their mechanism of action. The overall objective of this application is to gain adeeper understanding of both: (a) the broad treatment potential of PA (i.e. multiple pharmacologic andbioengineered animal models of colitis and colon cancer); and (b) the underlying mechanism(s) behind theobservation that PA targets m for apoptosis. We focus here on a DNA-damage independent p53 signalingpathway as a mechanism toward m apoptosis. The scientific premise underlying the proposed research isrobust. Comparing nine FDA-approved drugs small molecules and CAMs PA is the most efficacious atsuppressing colitis in a DSS mouse model. Our central hypothesis is that PA isolated after a decade of rigorousbioassay-guided fractionation has anti-inflammatory and anti-cancer activity in the colon because it activatesp53- mediated apoptosis in infiltrating m; mitigating colitis; and preventing colon cancer associated with colitis.Furthermore PA acts as an anti-inflammatory in these models because it induces p53 through a DNA damage-like signaling response in m that is independent of detectable DNA damage. To address this hypothesis wewill test the efficacy of PA in three mouse models of colitis and in genetically engineered mice. Because itappears that PA is taking advantage of a unique p53 mechanism in m we will test PA in mice with p53conditionally knocked out in colonic m. A DNA damage-independent mechanism is explored. Resultsconsistent with our hypothesis would identify an innovative low cost safe specific and natural compound withanti-inflammatory and cancer chemopreventive properties that could quickly be implemented clinically. 145004 +No NIH Category available Address;Adjuvant Chemotherapy;Adult;Aftercare;Award;Beds;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cell Line;Cell Proliferation;Cells;Central Nervous System Diseases;Clinical;Data;Development;Diagnosis;Disease;Drug Delivery Systems;Encapsulated;Engineering;Ensure;Epidermal Growth Factor Receptor;Etiology;Excision;Extracellular Matrix;Flow Cytometry;Ganciclovir;Glioblastoma;Goals;Growth;Immune;Immune response;Immune system;Immunity;Implant;In Vitro;Kinetics;Knowledge;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Mentors;MicroRNAs;Modeling;Molecular;Mus;Operative Surgical Procedures;Pathway interactions;Patients;Phase;Positron-Emission Tomography;Primary Brain Neoplasms;Prognosis;Proliferating;Proto-Oncogene Proteins c-akt;Publishing;Radiation therapy;Regimen;Resected;Role;STAT3 gene;Safety;Signal Transduction;Simplexvirus;Small RNA;Surgically-Created Resection Cavity;Survival Analysis;System;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;Thymidine Kinase;Time;Treatment Efficacy;Tumor Burden;Tumor Debulking;Tumor Volume;Up-Regulation;Validation;cell growth;chemotherapy;clinical care;clinical translation;effective therapy;exosome;fluorescence imaging;image guided;imaging agent;immune activation;immune clearance;implantation;in vivo;induced pluripotent stem cell;migration;mouse model;neoplastic cell;nerve stem cell;novel;promoter;response;restoration;stem cells;success;suicide gene;synergism;therapeutic miRNA;therapy development;treatment strategy;tumor;tumor microenvironment microRNA therapies for advanced brain tumors NARRATIVEThis proposal emphasizes on evaluating the therapeutic potential use of induced pluripotent stem cell derivedneural stem cells to deliver microRNA to advanced brain tumors. Once validated this therapeutic strategy hasa great potential to be integrated into the clinical care regimen for brain tumor therapy. NCI 10977273 12/4/23 0:00 PA-19-130 3R00CA245030-04S1 3 R00 CA 245030 4 S1 "MAAS, STEFAN" 4/1/20 0:00 12/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 11728143 "BHERE, DEEPAK " Not Applicable 6 PATHOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF MEDICINE 292080001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 59728 NCI 43342 16386 ABSTRACTEach year upwards of 14000 patients are diagnosed with Glioblastoma (GBM) the most malignant form ofprimary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options forGBM but patients generally succumb to the disease. MicroRNAs (miR) are emerging as key regulators ofcellular differentiation and proliferation; have been implicated in the etiology of a variety of cancers includingGBM. Our exciting preliminary studies show great promise for exosomes shed from induced pluripotent stemcell derived - neural stem cells (iNSC) expressing miR-124 to target brain tumors. In the mentored (K99)phase of this study I will evaluate the immune effects mediated by miR-124 delivered locally into the tumorbed via encapsulated neural stem cells following tumor debulking. We hypothesize that miR-124 modulation byexosomes enriched in miR-124 from NSC when delivered into the tumor resection cavity will target tumor cellproliferation and enhance T-cell mediated immune clearance of GBM cells. Once these effects are validated inthe R00 phase of the award the potential synergy between the modulation of miR-7 and miR-124 which targetAKT and STAT3 respectively will be studied to develop a sECM encapsulated iNSC delivered miR-7/ miR-124therapeutic approach to target resected GBM. In order to ensure safety of iNSC implantation the herpes simplexvirus thymidine kinase suicide gene system will be incorporated. The efficacy of iNSC-miR-7/miR-124/HSV-TKwill be evaluated in mouse models of GBM resection. We hypothesize that dual modulation of miR-124 and miR-7 will target the AKT-STAT3 signaling that is critical to tumor cell growth and together with the activation of hostimmune system medicated tumor clearance will present therapeutic benefit. Upon validation this microRNAbased therapeutic strategies will pave path to much needed novel treatments to target GBM. 59728 +No NIH Category available DATA ANALYTICS STATISTICAL AND BIOINFORMATIC ANALYSIS AND TOOL DEVELOPMENT Genome wide association studies (GWAS) n/a NCI 10976182 75N91020D00009-0-759102300001-1 N02 9/16/23 0:00 9/15/24 0:00 79361931 "GADDIS, NATHAN " Not Applicable 4 Unavailable 4868105 JJHCMK4NT5N3 4868105 JJHCMK4NT5N3 US 35.9138 -78.848911 6939101 RESEARCH TRIANGLE INSTITUTE RESEARCH TRIANGLE PARK NC Research Institutes 277092194 UNITED STATES N R and D Contracts 2023 126500 NCI TASK AREA C: DATA ANALYTICS STATISTICAL AND BIOINFORMATIC ANALYSIS AND TOOL DEVELOPMENT Genome wide association studies 126500 +No NIH Category available TOPIC 453: A DIGITAL TOOL TO INTEGRATE CANCER PREVENTION WITHIN PRIMARY CARE. n/a NCI 10975542 75N91023C00047-0-9999-2 N43 8/31/23 0:00 8/30/24 0:00 79342294 "CHEN, GRACE " Not Applicable Unavailable MCXNJJ93RDK7 MCXNJJ93RDK7 US -529894 LOS ALTOS CA Other Domestic Non-Profits 940245908 UNITED STATES N R and D Contracts 2023 6571 NCI LucidAct Inc. (LucidAct) is a Digital Health company that offers connected telemedicine and Remote Patient Monitoring (RPM) solutions specifically designed for patients that are non-tech savvy living in rural areas or having cultural and/or language barriers. We provide an end-to-end remote care management solution that combines connected medical devices telehealth and intelligent patient engagement into a single solution for healthcare organizations. LucidAct platform is cost effective responsive and user-friendly for allend-users including patients nurses and physicians. Under this NCI contract LucidAct will develop a digital tool for cancer prevention in which we will identify patients that are at high-risk by assessing all potential risk factors including family history genetics and environmental factors (tobacco use diet obesity etc.). We will offer science- and guideline-based recommendations to patients to engage in lifestyle changes to reduce cancer risk. LucidActs innovative workflow engine is customizable and configurable to manage complex care and to personalize recommendations to each individual patient. We have a team of healthcare and technology professionals that integrate expertise and healthcare data with PCP care and patient expectations to implement smart and usable solutions to complement and extend patient engagement beyond in-person visits. 6571 +No NIH Category available DIVISION OF CANCER CONTROL AND POPULATION SCIENCES (DCCPS) BIOMEDICAL COMPUTING SUPPORT SERVICES_ Moonshot Support n/a NCI 10975530 75N91021D00017-0-759102300002-2 N02 7/3/23 0:00 7/2/24 0:00 79241416 "ANNETT, DAVID " Not Applicable 4 Unavailable 83656892 LGGFBF8YVA71 83656892 LGGFBF8YVA71 US 39.047465 -77.125049 1069201 "INFORMATION MANAGEMENT SERVICES, INC." CALVERTON MD Domestic For-Profits 207053407 UNITED STATES N R and D Contracts 2023 850000 NCI The Division of Cancer Control and Population Sciences (DCCPS) of the National Cancer Institute (NCI) generates new knowledge about the burden of cancer on the US population and seeks to develop strategies in the continuum of cancer care including prevention diagnosis treatment and survivorship strategies. DCCPS also houses the Surveillance Epidemiology and End Results (SEER). The National Cancer Act of 1971 authorizes collection of cancer registry data and mandates that NCI report population-based statistics. The objective of this Task Order (TO) is to obtain non-research and development (non-R&D) information technology and analytic services to the DCCPS NCI. These services occur across several broad areas such as: analytical support systems development data management and maintenance computing infrastructure maintenance and support statistical methodology and programming support and support developing and maintaining websites. 850000 +No NIH Category available THIS PURCHASE ORDER INCLUDES SERVICES TO OBTAIN ANNUAL POPULATION ESTIMATES FOR STATE COUNTIES AND CENSUS TRACTS BASED ON THE COUNTS PRODUCED BY THE US CENSUS BUREAU. THESE SPECIFICALLY-DEVELOPED EST n/a NCI 10974511 75N91023P00771-0-0-1 N02 9/1/23 0:00 8/31/24 0:00 79330185 "HOLDRICH, MARTIN " Not Applicable Unavailable 126551290 WMDKRKNECL24 126551290 WMDKRKNECL24 US 38.922689 -77.042478 -354856 WOODS & POOLE ECONOMICS I WASHINGTON DC Other Domestic Non-Profits 200092808 UNITED STATES N R and D Contracts 2023 160000 NCI THIS PURCHASE ORDER INCLUDES SERVICES TO OBTAIN ANNUAL POPULATION ESTIMATES FOR STATE COUNTIES AND CENSUS TRACTS BASED ON THE COUNTS PRODUCED BY THE US CENSUS BUREAU.SPECIFICALLY-DEVELOPED ESTIMATES 160000 +No NIH Category available SEER RESEARCH SUPPORT REGISTRIES PROGRAM LINKAGES AND DATA MANAGEMENT SUPPORT n/a NCI 10974379 75N91021D00007-0-759102300001-1 N01 9/15/23 0:00 9/14/24 0:00 79365934 "DUNCAN, JEFFREY " Not Applicable 7 Unavailable 113704139 C2AQVDYYUAS7 113704139 C2AQVDYYUAS7 US 42.731083 -84.557095 5234501 MICHIGAN STATE DEPARTMENT OF HEALTH AND HUMAN SERVICES LANSING MI Other Domestic Non-Profits 489331805 UNITED STATES N R and D Contracts 2023 47805 NCI SEER RESEARCH SUPPORT REGISTRIES PROGRAM LINKAGES AND DATA MANAGEMENT SUPPORT 47805 +No NIH Category available SUPPORT FOR THE NCI DCCPS HEALTHCARE DELIVERY RESEARCH PROGRAM FOR THE NCORP ANNUAL MEETING. n/a NCI 10974306 91020A00191023F00006-0-0-1 N02 4/17/23 0:00 10/31/23 0:00 79133844 "EWING, AMY " Not Applicable 8 Unavailable 175358027 ENKBUQ4WXUW7 175358027 ENKBUQ4WXUW7 US 38.99818 -77.025807 2473201 NOVA RESEARCH COMPANY BETHESDA MD Domestic For-Profits 208146900 UNITED STATES N R and D Contracts 2023 61631 NCI THE CONTRACTOR SHALL SUPPORT THE DCCPS HEALTHCARE DELIVERY RESEARCH PROGRAM FOR THE NCORP ANNUAL MEETING. THIS MEETING IS BEING PLANNED AS AN IN-PERSON MEETING; PLANS ARE IN PLACE HOWEVER SHOULD THE NCI NEED TO CONVERT TO VIRTUAL. 61631 +No NIH Category available SUPPORT SERVICES FOR SEER PROGRAM n/a NCI 10974286 75N98022D00027-0-759102300001-1 N02 5/13/23 0:00 5/12/24 0:00 79158773 "FERNANDEZ, ANNA " Not Applicable Unavailable 171830748 VZHBEXPGE6G3 171830748 VZHBEXPGE6G3 US -444345 MCLEAN VA Other Domestic Non-Profits 221023838 UNITED STATES N R and D Contracts 2023 357506 NCI CONSULTING PROFESSIONAL SUPPORT SERVICES FOR SEER PROGRAM CLINICAL DOCUMENTS AND IMAGES (CDI) ACQUISITION ENHANCEMENTS 357506 +No NIH Category available NCI RESEARCH LEVEL NUTRIENT AND FOOD GROUP DATABASE n/a NCI 10974275 75N91023P00775-0-0-1 N02 8/30/23 0:00 8/29/24 0:00 79339165 "DUONG, HUONG " Not Applicable 5 Unavailable 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN Domestic Higher Education 554552070 UNITED STATES N R and D Contracts 2023 29000 NCI INITIAL AWARD TO PROVIDE THE NCI WITH THE RESEARCH LEVEL NUTRIENT AND FOOD GROUP DATABASE TO PROVIDE ITS EXTENSIVE LIST OF NUTRIENTS AND FOOD COMPONENTS ON ITS PUBLIC USE FOOD FREQUENCY QUESTIONNAIRE. 29000 +No NIH Category available SERVICES TO EXTEND METHODS FOR RISK PREDICTION WITH A CONTINUOUS TIME MODEL FOR SURVIVAL UNDER COMPETING RISKS n/a NCI 10974264 75N91023P00730-0-0-1 N02 8/15/23 0:00 8/14/24 0:00 79310248 "FINE, JASON " Not Applicable Unavailable 622781578 E5HLKXD77F77 622781578 E5HLKXD77F77 US 43.087927 -89.504593 -440508 MIDDLETON WI Other Domestic Non-Profits 535623748 UNITED STATES N R and D Contracts 2023 24700 NCI THIS PURCHASE ORDER INCLUDES SERVICES TO EXTEND METHODS FOR RISK PREDICTION WITH A CONTINUOUS TIME MODEL FOR SURVIVAL UNDER COMPETING RISKS USING TWO-TIME SCALES 24700 +No NIH Category available NATIONAL CANCER INSTITUTE (NCI) INFORMATION TECHNOLOGY (IT) BLANKET PURCHASE AGREEMENT (BPA) - DIGITAL SERVICES AND SOLUTIONS (DSS) FOUNDATIONAL SUPPORT n/a NCI 10974263 91023A00391023F00001-P00001-0-1 N02 11/15/22 0:00 5/14/23 0:00 79046580 "KHOO, PETER " Not Applicable n/a Unavailable 187107958 F9KSDU7L9VP6 187107958 F9KSDU7L9VP6 -336869 Other Domestic Non-Profits UNITED STATES N R and D Contracts 2023 1641 NCI C6 NATIONAL CANCER INSTITUTE (NCI) INFORMATION TECHNOLOGY (IT) BLANKET PURCHASE AGREEMENT (BPA) - DIGITAL SERVICES AND SOLUTIONS (DSS) FOUNDATIONAL SUPPORT 1641 +No NIH Category available TO CONTINUE THE COLLECTION AND REPORTING OF CANCER STAGING DATA BY THE SEER REGISTRIES THE NCI/DCCPS SEER PROGRAM REQUIRES ACCESS TO THE MOST CURRENT CANCER STAGING DATA. n/a NCI 10974262 75N91023P00545-0-0-1 N02 6/29/23 0:00 6/28/24 0:00 79245730 "MADERA, MARTIN " Not Applicable 7 Unavailable 68478452 MNSSA5BU44K9 68478452 MNSSA5BU44K9 US 41.893886 -87.62264 245101 AMERICAN COLLEGE OF SURGEONS CHICAGO IL Domestic For-Profits 606113234 UNITED STATES N R and D Contracts 2023 161875 NCI Support to NCI TO CONTINUE THE COLLECTION AND REPORTING OF CANCER STAGING DATA BY THE SEER REGISTRIES THE NCI/DCCPS SEER PROGRAM REQUIRES ACCESS TO THE MOST CURRENT CANCER STAGING DATA. 161875 +No NIH Category available Multi-Modality Imaging-Based Quantitative Pre/During/Post-Treatment Lymph Node Monitoring in Cancers n/a NCI 10973851 75N91023C00023-0-9999-1 N43 8/15/23 0:00 8/14/24 0:00 79309994 "FENG, XUE " Not Applicable 10 Unavailable 81070086 P14BWS94LNM9 81070086 P14BWS94LNM9 US 37.972254 -84.497342 10050207 "CARINA MEDICAL, LLC" Ashburn VA Domestic For-Profits 201484133 UNITED STATES N R and D Contracts 2023 400000 NCI The correct determination of nodal metastatic disease is imperative for patient management in oncology since the patients prognosis and subsequent treatment are inherently linked to the stage of disease. Detection/segmentation of lymph node on imaging is a tedious highly time-consuming process that is inherently subject to intra-/inter-observer variability. Malignancy classification of the lymph node improves both the diagnostic evaluation and treatment planning. An AI software OncoAI was successfully developed in Phase I that automatically detects and segments enlarged lymph nodes from MRI and CT and enables fully automated RECIST measurements. The overall goal of this Phase II proposal is to further enhance the performance of the AI models for lymph node detection segmentation and measurements and develop additional AI models for malignancy classification leveraging multi-modality imaging. Software functionality and usability will be further improved towards seamless incorporation within the clinical workflow. Finally a multi-institutional validation study will be conducted to demonstrate the safety and effectiveness of OncoAI in clinical practice and obtain regulatory approval. The proposed aims will set a strong technical and regulatory foundation for OncoAI and contribute to not only commercial success but also broader impact to the clinical practice of cancer care. 400000 +No NIH Category available Acceleration;Adverse effects;Affect;Aftercare;Attention;Australia;Awareness;Benefits and Risks;Brain;Brain Neoplasms;Canada;Cancer Center;Cancer Patient;Child;Childhood Brain Neoplasm;Childhood Injury;Clinical;Cognitive;Costs and Benefits;Cranial Irradiation;Data;Decision Making;Deposition;Development;Disease;Dose;Education;Exhibits;Face;Family;Fatigue;Goals;Hospitals;Impact evaluation;Impaired cognition;Knowledge;Late Effects;Lead;Life;Longitudinal cohort;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Mediating;Medical;Methodology;Modality;Modeling;Neurocognitive;Neurocognitive Deficit;Normal tissue morphology;North America;Occupational;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Photons;Physicians;Population;Positioning Attribute;Process;Protocols documentation;Protons;Quality of life;Radiation;Radiation Toxicity;Radiation therapy;Research;Research Infrastructure;Risk;Sampling;Short-Term Memory;Site;Social Problems;Socioeconomic Status;Survivors;Symptoms;Texas;Time;Tissues;Toxic effect;Treatment Protocols;Treatment-related toxicity;Work;brain tissue;clinically significant;cognitive function;cohort;contextual factors;cost;daily functioning;design;disability;disorder control;experience;functional independence;functional outcomes;improved;member;multidisciplinary;neurodevelopment;neurotoxicity;predictive modeling;preservation;prospective;proton beam;radiation delivery;recruit;reduce symptoms;social;standard of care;survivorship;theories;treatment group;tumor;x-ray irradiation Comparison of Symptom Burden/Toxicity Neurocognitive Change and Functional Outcomes in Pediatric Brain Tumor Patients Treated with Proton vs. Photon Radiotherapy. PROJECT NARRATIVEMany consider proton beam radiotherapy (PBRT) to be a promising treatment for children with brain tumors asit may preserve cognitive functioning without sacrificing disease control. This will be the first large-scale studyto prospectively compare symptom burden treatment toxicity and neurocognitive change between patientstreated with PBRT vs. conventional photon radiotherapy on comparable treatment protocols and to assessimportant measures of daily functioning that will quantify the clinical significance of any differences identifiedbetween groups in survivorship. Ultimately this line of research is intended to: (1) help physicians and familiesbetter understand the relative effect of PBRT on symptoms and neurocognitive functioning to inform treatmentdecisions and (2) provide functional outcome data to be used toward justifying or reconciling the high cost andaccess limitations currently associated with PBRT. NCI 10973623 12/14/23 0:00 PA-19-056 3R01CA249988-03S1 3 R01 CA 249988 3 S1 "SCHWEPPE, CATHERINE ANN" 3/1/21 0:00 8/31/26 0:00 Nursing and Related Clinical Sciences Study Section[NRCS] 8195518 "KAHALLEY, LISA SCHUM" "HINDS, PAMELA S; MABBOTT, DONALD " 9 PEDIATRICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2024 115672 NCI 72070 43602 PROJECT SUMMARY Most children treated for cancer in the US will achieve long-term survival and survivorship presents uniquechallenges for this growing population. Pediatric brain tumor survivors in particular are at risk forneurocognitive impairments educational difficulties social problems and medical disabilities. Cranial radiationtherapy is an essential lifesaving treatment but is associated with cognitive decline. Proton beam radiationtherapy (PBRT) is one of the most promising recent advances in pediatric brain tumor treatment. The proposedmedical advantage of PBRT lies in the precision of radiation delivery with proton beams depositing maximumdose to clinical targets while minimizing radiation to surrounding tissues. By reducing dose to healthy braintissue PBRT may spare cognitive functioning and reduce symptom burden better than conventional photon orx-ray irradiation (XRT) leading to greater functional independence in survivorship. Using a model-based accelerated longitudinal cohort comparison design we will compare symptomburden/toxicity neurocognitive change and functional outcomes at multiple data points from start of radiationthrough late survivorship in patients treated with PBRT versus XRT. The following aims are proposed: (1) tocompare symptom burden and toxicity by RT type in pediatric brain tumor patients and survivors (2) tocompare change in neurocognitive outcomes over time by RT type (3) to compare functional outcomes inearly and late survivorship by RT type and (4) to examine relations among symptom burden/toxicityneurocognitive function and functional outcomes as a function of RT type. This proposal is consistent with NCIs objective to reduce the long-term adverse effects of cancer and itstreatment in children and to improve the quality of life for cancer patients survivors and their families.Neurocognitive late effects lead to significant educational social and occupational limitations for manysurvivors greatly affecting their quality of life and functional independence long-term. Research is needed todetermine which treatments are best able to limit the suffering associated with symptom burden and post-treatment neurocognitive decline. Our results will have clinical value providing a timely comparison ofsymptoms neurocognitive changes and functional outcomes between PBRT and XRT groups that will guideclinicians and families on the range of outcomes to expect after PBRT. 115672 +No NIH Category available SUPPORT FOR THE NIH SBIR/STTR APPLICANT ASSISTANCE PROGRAM (AAP) IN SUPPORT OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH (NIH) NATIONAL CANCER INSTITUTE (NCI) SMALL n/a NCI 10954081 75N91019P00767-P00008-0-1 N02 9/23/19 0:00 9/22/24 0:00 79299809 "GARLAND, EVA " Not Applicable 2 Unavailable 80270032 XBW5B43MJMR5 80270032 XBW5B43MJMR5 US 35.826783 -78.635729 10042533 "EVA GARLAND CONSULTING, LLC" RALEIGH NC Domestic For-Profits 276097207 UNITED STATES N R and D Contracts 2023 140854 NHLBI SUPPORT FOR THE NIH SBIR/STTR APPLICANT ASSISTANCE PROGRAM (AAP). 98601 +No NIH Category available SUPPORT FOR THE NIH SBIR/STTR APPLICANT ASSISTANCE PROGRAM (AAP) IN SUPPORT OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH (NIH) NATIONAL CANCER INSTITUTE (NCI) SMALL n/a NCI 10954081 75N91019P00767-P00008-0-1 N02 9/23/19 0:00 9/22/24 0:00 79299809 "GARLAND, EVA " Not Applicable 2 Unavailable 80270032 XBW5B43MJMR5 80270032 XBW5B43MJMR5 US 35.826783 -78.635729 10042533 "EVA GARLAND CONSULTING, LLC" RALEIGH NC Domestic For-Profits 276097207 UNITED STATES N R and D Contracts 2023 140854 NIAAA SUPPORT FOR THE NIH SBIR/STTR APPLICANT ASSISTANCE PROGRAM (AAP). 42253 +No NIH Category available NCI-Alliance immune-related Adverse Events (irAE) Biorepository-Cures n/a NCI 10953429 1ZIABC012160-01 1 ZIA BC 12160 1 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 191131 NCI This project will leverage the clinical trials infrastructure of the National Clinical Trials Network (NCTN) to help develop a greater understanding of the mechanisms of immune-related Adverse Events (irAE) through supporting the ongoing development of a novel resource of tissues and gut microbiome samples from patients with irAEs. Analysis of samples will include stool microbiome metagenomics sequencing. Patients experiencing irAEs will have tissue blood and potentially stool collections obtained on an event-driven basis. 191131 +No NIH Category available Center for Cell-based Therapy - Cures n/a NCI 10953428 1ZIABC011855-06 1 ZIA BC 11855 6 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 208597 NCI The mission of the Center for Cell-based Therapy is to facilitate the discovery and development of cellular immunotherapies for patients with cancer. Two important objectives of this work are: (1) developing approaches to successfully target solid tumors with cell-based immunotherapy and (2) facilitating collaborative cell-based therapy projects with strong clinical potential. Four areas currently in development for this project are: (1) developing CAR-T Cells targeting GPC2 as a treatment for Neuroblastoma in collaboration with Mitchell Ho Rosandra Kaplan and Carol Thiele; (2) creating CAR-T Cells targeting mesothelin as a therapy for mesothelioma and lung adenocarcinoma in collaboration with Mitchel Ho and Ira Pastan; (3) developing CAR-T cells to deliver genes of interest into the tumor micro-environment in collaboration with Mitchell Ho; and (4) identification of key genes driving immune suppression and tumor killing in myeloid cells in collaboration with Rosandra Kaplan. This could potentially facilitate the improvement of cell-based therapy strategies. 208597 +No NIH Category available THE COVID 19 SERVICES CATALYZE TRANSLATIONAL RESEARCH FINDINGS INTO PUBLIC HEALTH CHANGES TO ADDRESS THE NOVEL CORONAVIRUS PANDEMIC THROUGH IMPLEMENTATION OF STANDARDIZED SEROLOGY TESTING FOR ITS INTE n/a NCI 10949793 75N91019D00024-P00025-759102000003-61 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1000000 NCATS "The following support shall be provided for Therapeutic Development Branch: Continuation of the ""Integrated Data Resource for Rare Diseases"" working with Advanced Biomedical Computational Science at Leidos Biomedical Research Inc.; Assay validation and non-GMP and GMP manufacturing of batches of drug substance and drug product; Stability studies to support projects with GMP and / or non-GMP products; Biodistribution / imaging and pharmacokinetic studies; Consulting services for development of bioanalytical methods; Regulatory services to support preclinical and / or clinical-stage projects; Electron microscopy studies; Gene expression and proteomic data analyses and cell-based screening studies; Proteomic profiling cell-based efficacy studies and clinical trials for canine comparative oncology; Laboratory animal support." 1000000 +No NIH Category available THE COVID 19 SERVICES CATALYZE TRANSLATIONAL RESEARCH FINDINGS INTO PUBLIC HEALTH CHANGES TO ADDRESS THE NOVEL CORONAVIRUS PANDEMIC THROUGH IMPLEMENTATION OF STANDARDIZED SEROLOGY TESTING FOR ITS INTE n/a NCI 10949789 75N91019D00024-P00025-759102000003-60 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 579629 NCATS "The following support shall be provided for Therapeutic Development Branch: Continuation of the ""Integrated Data Resource for Rare Diseases"" working with Advanced Biomedical Computational Science at Leidos Biomedical Research Inc.; Assay validation and non-GMP and GMP manufacturing of batches of drug substance and drug product; Stability studies to support projects with GMP and / or non-GMP products; Biodistribution / imaging and pharmacokinetic studies; Consulting services for development of bioanalytical methods; Regulatory services to support preclinical and / or clinical-stage projects; Electron microscopy studies; Gene expression and proteomic data analyses and cell-based screening studies; Proteomic profiling cell-based efficacy studies and clinical trials for canine comparative oncology; Laboratory animal support." 579629 +No NIH Category available NExT DTP-23-019 GMP PRODUCTION OF 40MG CAPSULES OF Z-ENDOXIFEN n/a NCI 10948454 75N98019D00058-0-759102300002-1 N02 4/24/23 0:00 7/23/23 0:00 79145963 "GIANNINI, ROBERT " Not Applicable 51 Unavailable 79682716 YRPTVKHDL7Z5 79682716 YRPTVKHDL7Z5 US 32.882508 -117.171157 3452401 "IRISYS, INC." SAN DIEGO CA Domestic For-Profits 921212285 UNITED STATES N R and D Contracts 2023 140000 NCI The Division of Cancer Treatment and Diagnosis (DCTD) National Cancer Institute (NCI) develops cancer therapeutic agents under the Developmental Therapeutics Program (DTP). Part of the DTP services includes formulation and production of clinical dosage forms of the agents selected by DCTD for further development. 140000 +No NIH Category available NEXT DTP-23-017 PRODUCTION OF 0.25MG OF AZATDC AND TDCYD CAPSULES n/a NCI 10948447 75N98019D00058-0-759102300001-1 N02 4/18/23 0:00 7/17/23 0:00 79134030 "GIANNINI, ROBERT " Not Applicable 51 Unavailable 79682716 YRPTVKHDL7Z5 79682716 YRPTVKHDL7Z5 US 32.882508 -117.171157 3452401 "IRISYS, INC." SAN DIEGO CA Domestic For-Profits 921212285 UNITED STATES N R and D Contracts 2023 66182 NCI The Division of Cancer Treatment and Diagnosis (DCTD) National Cancer Institute (NCI) develops cancer therapeutic agents under the Developmental Therapeutics Program (DTP). Part of the DTP services includes formulation and production of clinical dosage forms of the agents selected by DCTD for further development.The Objective of this Task Order is to provide manufacturing of a batch sufficient to deliver 800 capsules containing 0.25 mg Aza-TdC per capsule and 2500 capsules containing 0.25 mg TdCyd per capsule. 66182 +No NIH Category available SBIR PHASE II TOPIC 420: INTEGRATED PLATFORM AND CONSUMABLES FOR ROBUST SENSITIVE AND HIGH-THROUGHPUT SINGLE-CELL PROTEOMICS n/a NCI 10948319 75N91023C00027-0-9999-1 N44 8/25/23 0:00 8/24/25 0:00 79330182 "KELLY, RYAN " Not Applicable Unavailable 117654399 D5MRMU9JKMQ4 117654399 D5MRMU9JKMQ4 US -510574 SPANISH FORK UT Other Domestic Non-Profits 84660 UNITED STATES N R and D Contracts 2023 2000000 NCI Mass spectrometry-based proteomics can now quantify up to thousands of proteins from trace samples including single cells yet such studies require highly specialized custom-built consumables and instrumentation and are thus out of reach of most laboratories. Commercial solutions now exist for cell isolation and reagent dispensing at the beginning of the single-cell proteomics (SCP) workflow and highly sensitive mass spectrometry is available at the end of the workflow but there is a large gap in the middlecomprising sample introduction separations and ionization. Our objective is to provide robust sample-to answer workflows for non-specialist end users for SCP and other trace bioanalyses. We will develop (1) validated sample processing reagents and consumables for streamlined sample preparation; (2) high performance liquid chromatography columns specifically for SCP; (3) a robust multi-column LC platform for high throughput separations. We will achieve a depth of proteome coverage >2500 proteins per cell and athroughput of 96 cells per day (15 min/cell). The platform will also be compatible with multiplexed workflows such as tandem mass tags for an order of magnitude higher throughput. We will thus establish an innovative platform for advancing biomedical research biomarker discovery diagnostics and individualized therapy. 2000000 +No NIH Category available Sphingolipid Signaling and Chemotherapy-Induced Peripheral Neurotoxicity PROJECT NARRATIVEChemotherapy-induced peripheral neuropathy is a dose-limiting toxicity of many drugs used in cancertreatment and can adversely affect patient quality of life for years after therapy. The studies proposed in thisapplication will examine the significance of sphingolipid signaling in this neurotoxicity. A detailed understandingof the mechanisms for chemotherapy-induced peripheral neuropathy will support strategies for its preventionand treatment. NCI 10947162 12/22/23 0:00 PA-21-268 7R01CA261068-04 7 R01 CA 261068 4 "ALTSHULER, RACHEL DINA" 4/1/21 0:00 3/31/26 0:00 Xenobiotic and Nutrient Disposition and Action Study Section[XNDA] 1882790 "KROETZ, DEANNA L" Not Applicable 3 NONE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF PHARMACY 432101016 UNITED STATES N 10/10/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 396776 NCI 251921 144855 PROJECT SUMMARY/ABSTRACTChemotherapy induced peripheral neuropathy is a common dose-limiting toxicity that can reduce therapeuticeffectiveness and impact quality of life for cancer patients. The overarching goal of this research is todetermine the molecular basis of chemotherapy-induced peripheral neuropathy to support the development oftargeted therapies to prevent and treat this toxicity. The proposed studies are based on a reverse translationalpharmacogenetic approach that uses genetic association findings to implicate critical pathways in peripheralneuropathy. Recent genetic association and functional validation findings support a role for sphingosine-1-phosphate (S1P) signaling in chemotherapy-induced neurotoxicity which are consistent with previous studiesin rodent models. The studies proposed in this application will extend these findings and address a significantgap in our knowledge of S1P signaling in target cells for toxicity peripheral sensory neurons. The centralhypothesis that will be tested is that modulation of S1P signaling in peripheral sensory neurons by microtubuletargeting agents plays a critical role in their neurotoxicity. A human induced pluripotent stem cell derivedsensory neuron model of chemotherapy neurotoxicity (iPS-SNs) will be employed for all studies.Pharmacological and genetic approaches will be used to modulate S1P signaling and interrogatechemotherapy toxicity linked to this signaling pathway. The three aims are complementary and addressdiscrete functions of S1P. The first aim will investigate whether microtubule targeting agents alter sphingolipidmetabolism in sensory neurons and will link specific S1P receptors to cytoskeletal changes. The studiesproposed in the second aim will focus on Rho GTPase signaling downstream of S1P receptors and willestablish the S1P signaling axis that is critical for chemotherapy-induced changes in neurite structure and thedevelopment of retraction bulbs. The third aim will use scRNA-seq and sc-ATACseq to elucidate whetherpaclitaxel-induced changes in gene expression in iPS-SNs involve S1P effects on chromatin accessibility. Theability of fingolimod a multiple sclerosis therapy that targets S1P receptor signaling and is currently beingtested for prevention and treatment of paclitaxel-induced peripheral neuropathy to protect againstchemotherapy-induced neurotoxicity will be examined. Collectively these studies will reveal molecularmechanisms underlying the axon degeneration that occurs in sensory neurons in response to microtubuletargeting agents and elucidate novel mechanisms for neuroprotection with fingolimod. 396776 +No NIH Category available Area;Clinical Research;Clinical Trials;Clinical Trials Database;Data;Elements;Human;Performance;Persons;Protocols documentation;Research Personnel;Services;clinical trial protocol;research study PROTOCOL INFORMATION OFFICE (PIO) SUPPORT SERVICES FOR THE PROCESSING OF CLINICAL TRIAL PROTOCOL DOCUMENTS AND TRACKING THE IMPLEMENTATION AND COMPLETION OF HUMAN CLINICAL RESEARCH STUDIES. PERFORMANC n/a NCI 10946185 75N91023C00039-0-9999-1 N02 9/24/23 0:00 9/23/24 0:00 79326538 "BRYANT, WANDA " Not Applicable 11 Unavailable 146014373 LXQRK5BR85F1 146014373 LXQRK5BR85F1 US 38.792695 -77.060392 10027818 "ARSERVICES, LTD" LORTON VA Domestic For-Profits 220791961 UNITED STATES N R and D Contracts 2023 663645 NCI The major objective of this requirement is to provide support which is defined by the five project areas detailed below to the NCI DCP Protocol Information Office (PIO). The five project areas are:Project Area 1. Abstraction of Key Elements from Protocol Related DocumentsProject Area 2. File ManagementProject Area 3. Clinical Trial Review SupportProject Area 4. Manage People (persons such as investigators coordinators reviewers. etc.) and Organizations data in DCP Clinical Trials Database Project Area 5. PIO Operational Support 663645 +No NIH Category available Population Science Data Commons n/a NCI 10944571 75N91019D00024-P00025-759102000003-59 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 232016 NCI The vision for a Cancer Research Data Commons is a virtual expandable infrastructure that will eventually support collaboration among researchers computational scientists and tool developers. It will house multiple cloud-based Commons Nodes for multiple data types initially including genomic imaging proteomics and population sciences data. In the future additional nodes will support other data types. Genomics data in the CRDC is supported by the Genomic Data Commons (GDC) which provides a means of data submission user interfaces and search & visualization tools. The overarching vision for this task order is to develop the Population Sciences Data Commons (PSDC) to make population sciences data more broadly accessible to the cancer research community and to connect investigators with diverse subject matter expertise with cancer research data The PSDC should incorporate data from various NCI population-based sciences programs and awards including the Cancer Epidemiology Cohorts. 232016 +No NIH Category available Authorization documentation;Biological Assay;Biological Availability;Blood;Chemical Structure;Chromatography;Collection;Contractor;Contracts;Data;Data Analyses;Dose;Drug Kinetics;Exercise;Formulation;Hemorrhage;High Pressure Liquid Chromatography;Laboratories;Methods;Modeling;Modification;Molecular Weight;Oral;Plasma;Procedures;Property;Protocols documentation;Rattus;Route;Sampling;Solubility;Testing;Time;Validation;Visual;analytical method;anti-cancer;authority;base;cost estimate;design;drug candidate;drug-like compound PHARMACOKINETIC AND ORAL BIOAVAILABILITY STUDIES IN RATS n/a NCI 10943488 75N91021D00019-0-759102300001-1 N01 9/25/23 0:00 9/24/24 0:00 79376017 "BEUMER, JAN " Not Applicable 12 NONE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA UNIVERSITY-WIDE 152133320 UNITED STATES N R and D Contracts 2023 44968 NCI The purpose of this task order is to identify suitable formulations for administration of potential drug candidates to rats for early pharmacokinetic studies and to characterize the plasma pharmacokinetics (PK) and bioavailability of anticancer compounds in rats. Chemical structures molecular weight (MW) and other available properties of test agents will be provided and should be used to provide guidance on formulation approaches (e.g. pH-adjustment co-solvents). Route and dose level (mg/kg) targets will be provided. There will be a base period and optional tasks included under this task order. The base period will provide for formulation optimization/solubility assessment and one (1) rat pharmacokinetic study with one (1) compound. 44968 +No NIH Category available Address;Administrative Supplement;Administrator;Advisory Committees;Area;Basic Science;Boston;Budgets;Cancer Center;Cell Nucleus;Clinical Sciences;Collaborations;Colon;Color;Communication;Communities;Complex;Dedications;Development;Education;Educational Activities;Electronic Mail;Ensure;Faculty;Foundations;Funding;Goals;Grant;Growth;Infrastructure;Institution;Institutional Review Boards;Joints;Lead;Leadership;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Newsletter;Participant;Population Sciences;Postdoctoral Fellow;Research;Research Personnel;Research Project Grants;Resources;Role;Running;Structure;Training;Universities;Update;cancer health disparity;education research;equity diversity and inclusion;experience;innovation;meetings;member;multidisciplinary;outreach;programs;recruit;social media;success;symposium;synergism;web site Administrative Core n/a NCI 10942896 10/4/23 14:06 PA-20-272 3U54CA156734-13S1 3 U54 CA 156734 13 S1 "WALI, ANIL" 9/1/23 0:00 8/31/26 0:00 ZCA1(A1)-S 8815 8606765 "COLON-CARMONA, ADAN " "MACOSKA, JILL A.; VISWANATH, KASISOMAYAJULA " 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 368125 250000 118125 Summary: The Administrative Core of the University of Massachusetts Boston (UMass Boston) and Dana- Farber/Harvard Cancer Center (DF/HCC) Partnership takes an integrated approach to operational structure to support the growth of broad-based transdisciplinary cancer and cancer disparities research at both institutions. Partnership PIs Drs. K Vish Viswanath and Gregory Goyo Abel from DF/HCC and Drs. Adn Coln- Carmona and Jill Macoska from UMass Boston lead the Administrative Core and provide complementary expertise and abiding dedication to the sustained success of this research program. As the nucleus of the leadership and administrative teams the PIs with the support of effective internal (Internal Advisory Committee (IAC)) external (Program Steering Committee (PSC)) and institutional leaders provide rigorous oversight for the research projects programs and cores to maximize the impact of the Partnership at the institutional level. In addition a single Partnership Program Manager shared by both institutions creates operational synergies in the management of this multi-institutional research collaboration. The aims of the Administrative Core are to: 1) Provide administrative and fiscal oversight for Partnership cores and research projects and ensure responsible stewardship of funds; 2) Coordinate joint Partnership activities at UMass Boston and DF/HCC and facilitate networking opportunities; 3) Ensure proper infrastructural support for funded projects and cores; 4) Manage Partnership communications with all critical stakeholders in greater Boston; 5) Support a new institutionally-funded DEI Manager who will leverage the expertise of the Partnership Cores to begin to investigate reasons for faculty of color attrition train a dedicated group of mentors for before and after hire and develop a new network for diverse post-docs in the Boston metro area; and 6) Track institutional commitment in support of Partnership initiatives particularly toward recruitment efforts for Early Stage Investigators (ESIs) and leverage institutional resources for this effort. +No NIH Category available Achievement;Administrative Supplement;Advisory Committees;Basic Science;Benchmarking;Cancer Patient;Clinical;Cloning;Collaborations;Combined Modality Therapy;Communication;Data;Development;Direct Costs;Doctor of Philosophy;Ensure;Esophageal Adenocarcinoma;Evaluation;Faculty;Funding;Genomics;Goals;Guidelines;Human;Hypoxia;Image;Imaging Device;Immunotherapy;Infrastructure;Institution;Intellectual Property;Iron;Knowledge;Leadership;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Measures;Metabolic;Mus;Myeloid Cells;National Cancer Institute;Office of Administrative Management;Patients;Performance;Policies;Pre-Clinical Model;Principal Investigator;Process;Production;Progress Reports;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Reporter Genes;Research;Research Project Grants;Resistance;Resource Sharing;Resources;Risk;Role;Sampling;Students;Technology;Testing;Therapeutic Agents;Training;Transfection;Transgenic Organisms;Translating;Translational Research;Wages;Work;Xenograft Model;anticancer research;cancer cell;cancer type;chemoradiation;cohort;conflict resolution;data management;data sharing;esophageal cancer patient;interest;meetings;member;molecular imaging;neoplastic cell;novel therapeutics;outreach;peer;programs;radiation resistance;stable cell line;standard of care;therapy resistant;tool;tumor;tumor growth;tumor hypoxia;web site Admin-Core-001 n/a NCI 10942885 10/4/23 14:07 PA-20-272 3U54CA274220-02S1 3 U54 CA 274220 2 S1 "KAI, MIHOKO" 9/1/23 0:00 8/31/27 0:00 ZCA1(M1) 9337 9939858 "GAN, BOYI " "LIN, STEVEN HSESHENG; ROSARIO, SPENCER RAE" 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 182349 135849 46500 ADMINISTRATIVE CORE SUMMARY The proposed Acquired Resistance to Therapy and Iron (ARTI) Center is focused on the role of ferroptosis in acquired resistance to radiation therapy. Radiation therapy is used to treat approximately 50% of cancer patients and is standard of care treatment for lung cancer and esophageal cancer patients. The ARTI Center will focus on these cancer types and comprise three research projects. Project 1 will focus on identifying the mechanisms of ferroptosis in acquired resistance to radiation therapy and testing ferroptosis inducers (FINs) as radiosensitizers. Project 2 will focus on determining whether hypoxia-induced resistance to ferroptosis contributes to acquired tumor resistance to radiation therapy and whether FINs re-sensitize hypoxic tumor cells to radiation treatment. Project 3 will focus on understanding the role of genomic and microenvironment factors in acquired resistance to ferroptosis to chemoradiation in esophageal adenocarcinoma. The three research projects will be supported by one shared Molecular Imaging Core (MIC) which will provide imaging tools and analyses for measuring tumor growth assessing the ability to overcome acquired radiation resistance using combination therapies (e.g. FINs with radiation therapy or immunotherapy) identifying intratumoral hypoxic regions and evaluating myeloid cell expansion in conferring ferroptosis resistance to chemoradiation therapy. To support the MIC and these three projects the Administrative Core (AC) will be established as part of the ARTI Center infrastructure that will support coordinate and facilitate all activities aimed at achieving and evaluating milestones across the projects and core. The AC will establish and maintain engagement and communication among ARTI Center and ARTNet members and program officials in Aim 1. In Aim 2 the AC will facilitate ARTI Center evaluation support the timely and quality development and submission of progress reports and maintain proper and transparent stewardship of funds. The AC will develop and implement an internal solicitation and prioritization process for Pilot and Trans-Network Projects in Aim 3. In Aim 4 the AC will serve as the central infrastructure to build a website and manage data materials resources conflict resolution and issues of intellectual property for technologies and tools. The multiple Principal Investigators (mPIs) of the ARTI Center Boyi Gan PhD and Albert Koong MD PhD will serve as AC Co-Leaders. Under their leadership the AC will be able to leverage institutional and divisional resources; to establish and maintain an ARTI Center Advisory Committee; to encourage the development of junior faculty trainees and students in cancer research; to promote collaborations across ARTNet; and to ensure abidance by the ARTNet governance and resource and data sharing policies. Overall the AC will be the central juncture for the ARTI Center to integrate with other ARTNet centers as well as other National Cancer Institute-funded programs and initiatives. +No NIH Category available Adherence;Administrative Supplement;Adult;Advisory Committees;Arizona;Budgets;Cancer Center;Cancer Control;Certification;Characteristics;Child;Clinical;Collaborations;Colorado;Communication;Communities;Competence;Cost Analysis;Data;Development;Educational workshop;Ensure;Environment;Evaluation;Evidence based program;Expenditure;Funding;Goals;Health;Human Resources;Infrastructure;Institutional Review Boards;Interruption;Intervention;Leadership;Measures;Mentors;Methods;Mission;Modeling;Monitor;NCI-Designated Cancer Center;New Mexico;Outcome;Outcomes Research;Patients;Phase;Policies;Population;Population Sciences;Practical Robust Implementation and Sustainability Model;Primary Care;Printing;Program Development;Progress Reports;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Research;Research Methodology;Research Personnel;Resources;Rural;Safety;Science;Series;Strategic Planning;Structure;Surveys;Testing;Universities;Utah;cancer prevention;career;certificate program;contextual factors;cost;expectation;health equity;human subject;implementation science;implementation study;innovation;interest;lung cancer screening;meetings;member;organizational structure;outreach;pilot test;pragmatic implementation;preference;pressure;primary care setting;programs;research and development;rural area;shared decision making;smoking cessation;success;timeline;underserved area Pragmatic Implementation Science Approaches to Assess and Enhance Value of Cancer Prevention and Control in Rural Primary Care n/a NCI 10942883 10/4/23 14:04 PA-20-272 3P50CA244688-05S1 3 P50 CA 244688 5 S1 "VANDERPOOL, ROBIN CLINE" 9/1/23 0:00 8/31/24 0:00 ZCA1(A1) 7387 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 125000 80386 44614 Project Summary/Abstract Administrative Core The theme of our proposed Implementation Science Center is Pragmatic implementation science approaches to assess and enhance the value of cancer prevention and control in rural primary care. We will apply and advance frameworks pragmatic methods and measures related to cost benefits and value that are rigorous but also generalizable across rural primary care settings that are often struggling with low resources and a high need population. These models and methods will be used to guide selection and implementation of evidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancer screening in rural primary care settings first in Colorado and then nationally through collaboration with a well- established primary care network (i.e. National Research Network). Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadly used Reach Effectiveness Adoption Implementation and Maintenance framework with the addition of contextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It will serve as the basis to develop and test innovative assessments of costs benefits and value from the perspective of different stakeholders to understand and guide implementation. We will meaningfully engage with and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilot Implementation Study will adapt implement and evaluate strategies using stakeholder-engaged approaches to value to guide the implementation of shared decision-making and smoking cessation related to lung cancer screening. Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determine implementation/replication costs from the perspective(s) of patients providers and delivery staff and then develop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIM outcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of different CPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at junior and mid-career investigators and practitioners including online professional development (e.g. graduate certificate program micro-certification) and tailored mentoring and technical assistance approaches; b) dissemination activities to support the packaging and communication of research findings; and c) collaboration activities to facilitate partnerships on CPC and implementation science using multiple channels and including development of shared pragmatic D&I measures and data. +No NIH Category available Adherence;Adult;Advisory Committees;Arizona;Assessment tool;Budgets;Cancer Center;Cancer Control;Certification;Characteristics;Child;Clinical;Collaborations;Colorado;Communication;Communities;Competence;Cost Analysis;Data;Development;Dissemination and Implementation;Educational workshop;Ensure;Environment;Evaluation;Evidence based program;Expenditure;Funding;Goals;Health;Human Resources;Infrastructure;Institutional Review Boards;Interruption;Intervention;Leadership;Measures;Mentors;Methods;Mission;Modeling;Monitor;NCI-Designated Cancer Center;New Mexico;Outcome;Outcomes Research;Patients;Policies;Population;Population Sciences;Practical Robust Implementation and Sustainability Model;Primary Care;Printing;Program Development;Progress Reports;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Research;Research Methodology;Research Personnel;Resources;Rural;Safety;Science;Series;Strategic Planning;Structure;Surveys;Testing;Universities;Utah;cancer prevention;career;certificate program;contextual factors;cost;expectation;human subject;implementation science;implementation study;innovation;interest;lung cancer screening;meetings;member;organizational structure;outreach;pilot test;pragmatic implementation;preference;pressure;primary care setting;programs;research and development;rural area;shared decision making;smoking cessation;success;timeline;underserved area;web-based tool Pragmatic Implementation Science Approaches to Assess and Enhance Value of Cancer Prevention and Control in Rural Primary Care n/a NCI 10942881 10/4/23 14:03 PA-20-272 3P50CA244688-05S2 3 P50 CA 244688 5 S2 "VANDERPOOL, ROBIN CLINE" 9/1/23 0:00 8/31/24 0:00 ZCA1(A1) 7387 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 375995 241798 134197 Project Summary/Abstract Administrative Core The theme of our proposed Implementation Science Center is Pragmatic implementation science approaches to assess and enhance the value of cancer prevention and control in rural primary care. We will apply and advance frameworks pragmatic methods and measures related to cost benefits and value that are rigorous but also generalizable across rural primary care settings that are often struggling with low resources and a high need population. These models and methods will be used to guide selection and implementation of evidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancer screening in rural primary care settings first in Colorado and then nationally through collaboration with a well- established primary care network (i.e. National Research Network). Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadly used Reach Effectiveness Adoption Implementation and Maintenance framework with the addition of contextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It will serve as the basis to develop and test innovative assessments of costs benefits and value from the perspective of different stakeholders to understand and guide implementation. We will meaningfully engage with and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilot Implementation Study will adapt implement and evaluate strategies using stakeholder-engaged approaches to value to guide the implementation of shared decision-making and smoking cessation related to lung cancer screening. Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determine implementation/replication costs from the perspective(s) of patients providers and delivery staff and then develop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIM outcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of different CPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at junior and mid-career investigators and practitioners including online professional development (e.g. graduate certificate program micro-certification) and tailored mentoring and technical assistance approaches; b) dissemination activities to support the packaging and communication of research findings; and c) collaboration activities to facilitate partnerships on CPC and implementation science using multiple channels and including development of shared pragmatic D&I measures and data. +No NIH Category available Advisory Committees;Animals;Cancer Center;Communication;Data;Doctor of Philosophy;Education Projects;Educational workshop;Ensure;Environment;Evaluation;Expenditure;Funding;Future;Goals;Grant;Human Resources;Institution;Institutional Review Boards;Interruption;Leadership;Mission;Modeling;Monitor;Policies;Principal Investigator;Problem Solving;Progress Reports;Publications;Research;Research Project Grants;Resource Allocation;Resources;Safety;Strategic Planning;System;Training;Training Programs;Universities;Virginia;anticancer research;cancer health disparity;education research;human subject;meetings;member;pressure;programs;timeline;tumor progression SUCCEED Administrative Core n/a NCI 10942870 10/4/23 13:59 PAR-18-911 3P20CA264068-03S1 3 P20 CA 264068 3 S1 "RODRIGUEZ, LARITZA MARIA" 9/1/23 0:00 8/31/25 0:00 ZCA1-SRB-2(M2) 7435 1923259 "FAISON, MILTON O" "ROBERTS, DANIEL M." 4 Unavailable 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA Domestic Higher Education 238032520 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 40231 31597 8634 ADMINISTRATIVE CORE: PROJECT SUMMARY The Administrative Core will provide scientific and programmatic leadership to ensure the unifying scientific mission of the Virginia State University (VSU)-Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) PartnErship for CancEr Disparities Research and Training (SUCCEED) program and create an environment in which the scientific and educational projects can flourish without the pressures of routine administrative tasks and interruption. This core will be the hub of SUCCEED. It will support the 2 research projects implement a system for reviewing proposed new pilots during the project funding period support the Cancer Research Education Program (CREP) activities and will be responsible for regulatory oversight fiscal management facilitating communication among the investigative teams and strategic planning. It will also provide a unifying entity for internal and external communication for strategic planning and dissemination. The Administrative Core will be led by a team of multi-principal investigators (MPIs) along with the guidance of an Internal Advisory Committee. The MPI team includes Robert A. Winn MD (VCU MCC Contact MPI) Vanessa Sheppard PhD (VCU MCC) Omar Faison PhD (VSU Contact MPI) and Daniel Roberts EdD (VSU).The aims of the core are to: Aim 1: Provide overall support via close interaction with VSU and MCC leadership the Internal Advisory Committee and the NCI; Aim 2: Provide administrative budgetary and regulatory oversight for SUCCEED; and Aim 3: Organize coordinate and monitor progress toward overall SUCCEED goals. +No NIH Category available BLDG. 1066 FIRST FLOOR REPOSITORYMOD 002 : FINAL INDIRECT FUNDING n/a NCI 10941256 261201500003I-P00002-26100044-1 N01 8/29/17 0:00 9/21/18 0:00 79478801 "BRISCOE, LYNN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 6197 NCI Building 1066 is a two-story 17217 gross sqft steel structure constructed in 1994. Thisproject will refurbish a portion of the first floor to accommodate a new freezer repository.This repository will service anticipated sample needs for the MPACT and MATCHclinical genomics programs. The proposed refurbishment plan will maintain themaximum flexibility for the facility in future by keeping some laboratory infrastructurethat would support sample prep laboratory activities as needed in conjunction to theproposed repository space. The new work will include demolition reconfiguration ofpartitions doors new finishes new plumbing/piping /mechanical/HVAC fire protectionand electrical work. 6197 +No NIH Category available Address;Assessment tool;Automobile Driving;Classification;Computer Vision Systems;Consensus;Data;Development;Dissection;E-learning;Electrocoagulation;Evaluation;Feedback;Future;Gestures;Human;Injury;Interobserver Variability;Knowledge;Link;Machine Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Manuals;Measurable;Methodology;Modeling;Nerve-Sparing Surgery;Operative Surgical Procedures;Outcome;Outcome Measure;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Pattern;Performance;Procedures;Process;Prostatectomy;Questionnaires;Radical Prostatectomy;Recovery;Recovery of Function;Reproducibility;Research;Robotics;Statistical Models;Surgeon;Surgical sutures;System;Technical Expertise;Techniques;Technology;Testing;Tissues;Training;Translating;Treatment Factor;Validation;Variant;Visual Pattern Recognition;Work;deep learning;empowerment;experience;improved;improved outcome;instrument;men;neurovascular;novel;postoperative recovery;preference;preservation;programs;quality assurance;robot assistance;simulation;skills;spared nerve;surgery outcome;tool;virtual reality;virtual reality simulation Preserving Erectile Function by Quantifying the Nerve-Sparing step of the Robotic Prostatectomy NARRATIVEThe proposed work seeks to quantify surgeon performance and build automated assessmentsgrounded in patient-centered outcomes to inform training surgeon on how they can improve.The nerve-sparing (NS) step during robot-assisted radical prostatectomy (RARP) is an ideal testcase as it is a commonly performed procedure with significant surgeon technical variation anddifferences in erectile function outcomes. The knowledge gained from this research will advanceother surgeries by improving the methodology of assessing surgical skill in general objectivelyevaluating surgeon performance through machine learning and developing targeted training toimprove specific post-surgical outcomes. NCI 10940356 12/6/23 0:00 PA-21-268 7R01CA273031-03 7 R01 CA 273031 3 "SONG, MIN-KYUNG H" 7/7/22 0:00 6/30/27 0:00 "Bioengineering, Technology and Surgical Sciences Study Section[BTSS]" 14451658 "HUNG, ANDREW " "HU, JIM " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 7/11/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 646797 NCI 518825 127972 ABSTRACTVariation in performance between surgeons leads to differences in patient outcomes butsurgeons cannot improve if they are not aware of the technical considerations for a surgicalprocedure that will allow them to improve outcomes. As a prime example robot-assistedradical prostatectomy (RARP) for prostate cancer can lead to highly variable rates of patienterectile function (EF) recovery (10-50%). Yet reliable means of objectively assessing surgeonperformance that strongly associate with patient outcomes are generally lacking.In this project as a test case for quantifying surgeon performance to improve a patientoutcome we will focus on assessing a surgeons nerve-sparing (NS) dissection quality duringRARP through the evaluation of surgical video and patient outcomes. The nuanced NS step is agood test case because it is the primary determinant of the quantifiable EF outcome RARP is acommon procedure (~145000 cases/year) and surgical video is readily available for analysis.We will accomplish our objective with three independent yet complementary aims. Aim 1: Weseek to determine through expert consensus the common technical considerationsnecessary to optimally perform the NS step for EF recovery. Aim 2: We will develop anautomated performance assessment pipeline through computer vision analysis of surgicalvideo. Aim 3: We will develop and validate a skills feedback assessment tool for a proof-of-concept NS-specific VR simulation.The primary differentiator of the proposed work is we will quantify the most relevant technicalconsiderations for tissue dissection driving a patient reported outcome. Surgeonsparticipating in this study will not only provide data through surgical videos of them performingthe NS step but they will also contribute real patient EF outcome data from the RARP toestablish the relationship between surgeon skill patient factors and EF outcome.Statistical modeling will delineate the differential impact of surgeon skill and patient factors to EFoutcome. Further we will harness deep learning-based computer vision to holistically capture allthe numerous facets of NS technique and skill to help determine how they contribute to theultimate EF outcome.The proposed work will enable scalable and actionable feedback empowering surgeons withvaluable knowledge to maximize surgical outcome. The NS step and EF recovery after RARPwill serve as our test case for future automated assessments to improve outcomes in anysurgical procedure. 646797 +No NIH Category available Agricultural Health Study;Agriculture;Budgets;Communication;Computers;Contractor;Contracts;Data;Data Linkages;Data Set;Databases;Development;Educational workshop;Information Systems;Institutional Review Boards;Kidney;Licensing;Longitudinal cohort;Maintenance;Medicare;Newsletter;Participant;Phase;Preparation;Records;Reporting;Schedule;Secure;Services;United States;Update;Walking;cohort;data cleaning;data management;follow-up;meetings;member;mortality;neoplasm registry;operation;web site Agricultural Health Study Phase 5 n/a NCI 10937057 261201800029C-P00012-9999-1 N02 9/23/22 0:00 9/22/23 0:00 15713160 "DUNN, MARSHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2023 27048 NIEHS In the fifth phase of the Agricultural Health Study (AHS) contract the Contractor shall serve as the coordinating center for all study activities of cohort maintenance and follow-up. They will be responsible for handling the daily operations of the study scheduling regular and ad hoc meetings maintaining secure data records and updating cohort member contact information. The Contractor shall conduct data linkages to state cancer registries mortality files other types of records as needed (e.g. Medicare United States Renal Data System Internal Revenue Service Drivers Licenses LexisNexis). The Contractor shall conduct communication activities to the cohort and stakeholders maintain and update the studys website and develop the layout of an annual newsletter. They shall also facilitate preparation of compliance documents and manage the studys financial budgets. The overall objective of the contract is to continue to follow and update this longitudinal cohort for the purposes of studying agricultural exposures. 27048 +No NIH Category available Academia;Agreement;Biotechnology;Client;Clinical Research;Clinical Trials;Collaborations;Commercial Sectors;Confidential Information;Contracts;Cooperative Research and Development Agreement;Data;Development;Devices;Disclosure;Employee;Extramural Activities;Industry;Intellectual Property;Laboratories;Laws;Legal patent;Licensing;Marketing;Mediation;Monitor;National Cancer Institute;New Agents;Nonprofit Organizations;Pharmacologic Substance;Policies;Procedures;Recommendation;Regulation;Reporting;Research;Research Personnel;Research Support;Resources;Safety;Services;Technology;Technology Transfer;Transact;Transfer Agreement;United States National Institutes of Health;Universities;data exchange;invention;material transfer agreement;meetings;programs;research and development;symposium;technology development Technology Transfer Center n/a NCI 10936992 1ZIKCO020001-15 1 ZIK CO 20001 15 79381933 "FRISBIE, SUZANNE " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 14646173 NCI Technology Transfer Center (TTC) provides a complete array of services to support the National Cancer Institute's and nine other NIH Institutes technology development and transfer activities. To ensure that these activities comport with Federal statutes regulations and the policies of the National Institutes of Health a large part of TTC's responsibilities includes the day-to-day negotiations of transactional agreements between the NCI and outside parties including universities federal laboratories non-profit organizations as well as pharmaceutical and biotechnology companies. These agreements provide for:The exchange of research materials under the Material Transfer Agreements (MTAs);Collaborative research conducted under Research Collaboration Agreements (RCAs) and Cooperative Research and Development Agreements (CRADAs);Clinical studies to determine the safety and efficacy of new agents and devices under clinical trial agreements (CTAs) and Clinical Trial CRADAS; and exchange of confidential information under confidential disclosure agreements (CDAs) and data under Data Transfer Agreements (DTAs).TTC manages the NCI and its client institutes patent portfolios by reviewing employee invention reports and making recommendations to the institutes concerning filing of domestic and foreign patent applications. Patent prosecution is closely monitored by TTC and managed through contract law firms. TTC negotiates and executes licenses associated with the discoveries coming from the institutes intramural laboratories and programs. In addition TTC assists the institutes in developing strategies for the development marketing and transfer of these technologies into the commercial sector. The NCI TTC staff participate in meetings discussions and conferences with external parties as appropriate to stay apprised of technology transfer best practices and to market our patented technologies. In addition TTC is active in meeting with the institutes program and laboratory staff to monitor the institutes scientific needs which might benefit from the expertise and resources of TTC. 14646173 +No NIH Category available Air Pressure;Cell Therapy;Cells;Cellular immunotherapy;Cyclic GMP;Guidelines;Human;Industry;Infrastructure;Infusion procedures;Manufacturer;Patients;Pharmaceutical Preparations;Phase;Primary Cell Cultures;Primary Neoplasm;Sterility;Tissues;Tumor Expansion;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;design;human subject;manufacture;participant enrollment TIL Rosenberg Modular Processing Facility (T30 building) n/a NCI 10936991 1ZIICO030001-06 1 ZII CO 30001 6 79381930 "KHOSHBIN, JEAN-PATRICE " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3866267 NCI The NIH / NCI TIL cGMP Modular facility project is a state of the art 10 module standalone facility to be constructed at the NIH campus and will be used to aseptically isolate and expand Tumor Infiltrating Lymphocytes (TILs) cell culture from the primary tumors of enrolled patients as well as patient individualized cellular immunotherapy products for safe infusion into human subjects in compliance with FDA cGMP requirements. The facility opened for cellular processing and manufacturing in February 2022 and provides the much needed cGMP and Cell Processing space and support infrastructure that meets the FDA guidelines for manufacturing Phase 1 and early Phase 2 cellular therapies. 3866267 +No NIH Category available Area;Contractor;Contracts;Emergency Situation;Grant;Mission;Monitor;National Cancer Institute;Process;Property;Services;United States National Institutes of Health;cost;cost effective;design;innovation;operation;programs;symposium Space and Facilities Management n/a NCI 10936990 1ZIICO020002-15 1 ZII CO 20002 15 79381930 "KHOSHBIN, JEAN-PATRICE " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 22505621 NCI The National Cancer Institute's (NCI) Office of Space and Facilities Management (OSFM):1. Acquires and manages real property assets in support and furtherance of the NCI mission;2. Coordinates NCI acquisitions for space and facilities;3. Develops and maintains the NCI Space Master Plan;4. Support the NCIs office of Grant Management in managing the NCI Construction Grants Program;5. Manages and monitors all assets and costs associated with NCI facilities leases utilities space and renovations/construction;6. Provides daily support to facilities in the area of operations and function by managing the facilities and space allocated to the Institute to ensure that it is fully utilized and suited to the needs of the occupants; and by acting as the Institute's contact point for space and facilities management activities and coordinates these activities with NIH offices involved in the acquisition renovation and management of space. 22505621 +No NIH Category available Acceleration;Acquired Immunodeficiency Syndrome;Animals;Biomedical Research;Cancer Etiology;Clinical;Communities;Congresses;Development;Diagnostic tests;Disease;Funding;Goals;Government;Healthcare;Home;Investments;Laboratories;Laboratory Research;Lead;Malignant Neoplasms;Nanotechnology;New Drug Approvals;Patients;Persons;Pharmaceutical Preparations;Private Sector;Research;Research Personnel;Scientist;Services;Speed;Technology;Time;Translations;Universities;Vaccines;Washington;animal facility;cancer care;cancer therapy;commercialization;cost;evidence base;flexibility;health care delivery;improved;meetings;nonhuman primate;novel diagnostics;programs;prototype;public-private partnership;research and development;response;technology development;vaccine evaluation NCI-Frederick Support and Technical Services n/a NCI 10936988 1ZICCO020007-15 1 ZIC CO 20007 15 78871689 "KOMSCHLIES MCCONVILLE, KRISTIN " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2653485 NCI NCI-Frederick is designated by Congress as one of 43 Federally Funded Research and Development Centers. These centers provide a rapid response and flexible capability in meeting federal research and development goals that cannot be met effectively by other means.Our campus 50 miles north of Washington D.C. is home to a wealth of expertise including that of our own cancer and AIDS researchers our technology development teams and our regulatory liaisons and commercialization partners. This combination gives us a unique perspective that spans laboratory discovery technology development and healthcare delivery.NCI-Frederick quickly adapts to changing R&D priorities by curtailing or ending programs when necessary to maintain a strategic focus and keep pace with new discoveries development opportunities and healthcare priorities.With our collaborators we are answering the call from Congress and the public to show how taxpayer investments in biomedical research are helping to ease and to end the suffering caused by cancer AIDS and other diseases. The intramural project supports efforts that OSO must fund through the government mechanism on the Bethesda Campus. 2653485 +No NIH Category available Address;Advanced Malignant Neoplasm;Appointments and Schedules;Authorization documentation;Cancer Burden;Cancer Patient;Caring;Censuses;Clinical;Clinical Decision Support Systems;Communication;Communities;Consultations;Data;Development;Electronic Health Record;Environment;Evaluation;Health;Health Resources;Healthcare Systems;Hospitals;Individual;Instruction;Interview;Notification;Oncology;Operative Surgical Procedures;Outcome;Patients;Persons;Phase;Production;Provider;Randomized Controlled Trials;Resources;Schedule;Site;Social Workers;Societies;Software Engineering;Testing;Time;Treatment outcome;Visit;Writing;cancer health disparity;cancer therapy;comparative;digital;disparity reduction;evidence base;evidence based guidelines;health data;hospital readmission;improved;mobile application;patient health information;patient oriented;satisfaction;social epidemiology;social health determinants;treatment adherence TOPIC 423 (PHASE II): AN INTEGRATED MULTI-LEVEL DECISION SUPPORT PLATFORM TO ADDRESS PATIENT-CENTERED AND EVIDENCE-BASED SOCIAL DETERMINANTS OF HEALTH AMONG CANCER PATIENTS. n/a NCI 10936287 75N91023C00056-0-9999-1 N44 9/11/23 0:00 9/10/25 0:00 79356390 "CHAN, CUPID " Not Applicable 11 Unavailable 117520686 E85KNHMS6GM1 117520686 E85KNHMS6GM1 US 38.954213 -77.401925 10060505 PISTEVO DECISION LLC HERNDON VA Domestic For-Profits 201713005 UNITED STATES N R and D Contracts 2023 2047174 NCI A strong body of evidence suggests that addressing Social Determinants of Health (SDH) within healthcare systems advances cancer treatment adherence and reduces disparities in outcomes; however few studies actually intervene and provide resources to meet cancer patients SDH. Integrating SDH with clinical information within operational Clinical Decision Support (CDS) systems built into Electronic Health Records (EHR) is an essential approach for addressing cancer disparities. We propose: (1) Providing a fully functional product with patient-facing and provider-facing interfaces to address SDH needs (2) Testing it in a randomized controlled trial to assess its impact on cancer patient clinical endpoints and user satisfaction and (3) Integrating it into the production environment in both academic and community-based hospitals to evaluate its use in a real-world setting. Our approach combines expertise from software engineering oncology and social epidemiology. Our solution will enhance oncology practice by collecting relevant SDH information from patients and recommending evidence-based clinical actions addressing patient SDH needs resulting in improved cancer treatment outcomes. Our solution will connect patients to actual resources to meet their SDH needs and streamline communication with decision support for patients and their care teams potentially reducing disparities and the burden of cancer on the patient and society. 2047174 +No NIH Category available Adverse effects;Animals;Behavior;Biological;Biological Assay;Cells;Chemicals;Contracts;Data;Development;Drug Kinetics;Enzymes;Excretory function;Human;In Vitro;Metabolism;Methods;Molecular;Permeability;Pharmaceutical Preparations;Phase;Process;Property;Services;Solubility;Standardization;Testing;Time;Tissues;Toxic effect;absorption;analog;behavior prediction;clinical candidate;design;drug candidate;drug development;drug discovery;experimental study;in vitro Assay;in vivo;lead candidate;novel;programs;small molecule SERVICES FOR THE CHARACTERIZATION OF ABSORPTION DISTRIBUTION METABOLISM EXCRETION AND TOXICITY (ADMET) PROPERTIES OF SMALL-MOLECULE DRUG CANDIDATES USING STANDARDIZED IN VITRO METHODS IN SUPPORT O n/a NCI 10936131 75N91023P00713-0-0-1 N02 9/18/23 0:00 9/17/24 0:00 79320481 "GEIBEN LYNN, RALF " Not Applicable Unavailable YNGLSAF57T14 YNGLSAF57T14 US -521234 WATERTOWN MA Other Domestic Non-Profits 24722418 UNITED STATES N R and D Contracts 2023 56313 NCI The purpose of this contract is to determine in vitro ADMET (absorption distribution metabolism excretion toxicity) in two novel compounds using molecular methods. These experiments will help determine the drug-like properties of these novel compounds and their suitability for further development. 56313 +No NIH Category available Area;Cancer Therapy Evaluation Program;Clinical Trials Support Unit;Computer software;Contractor;Contracts;Data;Databases;Development;Ensure;Future;Maintenance;Medidata;Monitoring Clinical Trials;Parents;Production;Services;Standardization;Support System;Systems Integration;Testing;Time;programs HOSTING MAINTENANCE AND PROFESSIONAL SERVICES FOR RAVE AND MEDIDATA RAVE INTEGRATED ANCILLARY SOFTWARE FOR NCI'S CANCER THERAPY EVALUATION PROGRAM (CTEP) n/a NCI 10934067 75N91023D00012-0-759102300001-1 N02 9/1/23 0:00 8/31/24 0:00 79341661 "LEE, WALT " Not Applicable Unavailable 840371087 V25NDJFKMKA1 840371087 V25NDJFKMKA1 US -471915 NEW YORK NY Other Domestic Non-Profits 10014 UNITED STATES N R and D Contracts 2023 9872498 NCI The Contractor shall provide the Parent IDIQ SOW Tasks (Task Areas) 1 2 3 4 and 5 as further described below:a)Hosting (Task 2) and maintenance (Task 3) for Rave-Classic (or RaveEDC) and TSDV for active trials conducted by the NCI multi-center program. Trial activity is based on database action during the prior month (ex. data capture query export). b)Note: NCI is currently using Rave-Classic for majority of its studies and at some time in the future NCI may transition to Rave-EDC. The contractor shall support relevant transition activities and provide professional support for RAVE-EDC as needed under a Task Order. NCI is already using Rave-EDC for some studies. c) Hosting (Task 2) and professional services (Task 4) for approximately 19 production and test URLs identified in Reference #1. The NCI may add new URLs or modify existing ones as needed (Task 5).d)Professional services (Task 4):1.To NCI contractors in support of system integration with NCI CORE applications2.To the following NCI contractors for hosting maintenance and study development/management:(1)Clinical Trials Support Unit (CTSU)(2)Clinical Trials Monitoring Service (CTMS)3.To ensure consistency standardization and best practices across the NCI multi-center URL holders (see reference #1) and the Alliance Network. Note: the Alliance has an independent contract for Rave support services. This NCI contract is limited to support for Medidata ancillary products. 9872498 +No NIH Category available Core-002 n/a NCI 10933745 9/25/23 0:00 PAR-20-077 2U19CA203654-07 2 U19 CA 203654 7 "CARRICK, DANIELLE M" 8/1/17 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 6053 1881790 "AMOS, CHRISTOPHER I." "HUNG, RAYJEAN J.; JOHANSSON, MATTIAS ALEXANDER; LIN, XIHONG " 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 312212 270149 42063 No abstract available +No NIH Category available Abbreviations;Administrative Personnel;Administrator;Advisory Committees;Agreement;Award;Budgets;Cancer Center;Cancer Center Support Grant;Center for Translational Science Activities;Childhood Soft Tissue Sarcoma;Classification;Clinical;Clinical Research;Collaborations;Communication;Computational Science;Coordinating Center Administration;Dedications;Development;Education;Ensure;Evaluation;Faculty;Funding;Funding Agency;Future;Genetic Engineering;Genome;Goals;Grant;Growth;Health Services Research;Histopathology;Image;Institution;Israel;Laboratories;Leadership;Malignant Neoplasms;Medical center;Mentors;Names;Organization administrative structures;Phenotype;Pilot Projects;Policies;Process;Program Development;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Science;Services;Southwest Oncology Group;Strategic vision;Technology;The Jackson Laboratory;Training;Translational Research;Travel;Work;cancer education;cancer research center director;candidate identification;career;cost effective;innovation;meetings;member;microbial genomics;operation;outreach;precision oncology;programs;quality assurance;recruit;single cell technology;symposium;translational cancer research Cancer Center Administration n/a NCI 10933627 9/22/23 0:00 PA-20-272 3P30CA034196-37S1 3 P30 CA 34196 37 S1 "BELIN, PRECILLA L" 8/1/97 0:00 3/31/24 0:00 7968 15361866 "AIRHART, SUSAN " Not Applicable 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 Research Centers 2023 322063 175034 147029 PROJECT SUMMARY CANCER CENTER ADMINISTRATION The Jackson Laboratory Cancer Center (JAXCC) is an organizational unit with dedicated administrative oversight that is strategically integrated with The Jackson Laboratorys (JAX) institutional administration. Dr. Barbara Tennent Associate Director for Research Administration directs the JAXCC Administration and reports to Dr. Edison Liu JAXCC Director and President and CEO of JAX. Mr. Alan Sawyer Associate Director for Shared Resources oversees the JAXCC Shared Resources and reports to Dr. Kenneth Fasman JAX Senior Vice President for Research. The goal of the Administration is to enable cancer-focused research and education and to support the growth of a collaborative and cohesive cancer center membership that drives advances in precision cancer medicine. Interacting closely with the executive governance operational and advisory committees of the Cancer Center the Administration works to ensure that the necessary policies processes financial oversight and reporting are in place to guide the operations and future planning for the JAXCC. The JAXCC Administration coordinates the activities of three committees to support the Cancer Centers operations. The JAXCC Scientific Executive Committee chaired by Dr. Liu is responsible for new initiative planning and alignment with institutional priorities and resources governance inter-campus coordination membership development and evaluation developmental funds priority setting and review. The JAXCC Operations Committee chaired by Deputy Director Dr. Carol Bult brings together inter-campus leaders of the research and education components with JAXCC and institutional administrative personnel to drive the activities necessary to achieve Center goals. The institutional Scientific Services Governance Committee (SSGC) chaired by Dr. Fasman includes several JAXCC senior leaders and has oversight of the institutional Scientific Services many of which are represented in the JAXCC Shared Resources. The JAXCC is strongly supported by institutional administrative offices including Sponsored Research Administration Financial Services Clinical and Translational Research Support and Research Program Development. Funds are requested for partial support of Dr. Tennents responsibilities. She works closely with JAXCC and institutional administrators to coordinate the activities of the JAXCC including External Advisory Board relations developmental funds management collaborative research facilitation and JAXCC record keeping. Kate Macko Research Program Administrator institutionally supported assists in these activities. Institutional funds support dedicated effort for Mr. Sawyer who is responsible for Shared Resources including budget management operations quality assurance technical staffing technology acquisition and implementation and user communications. Mr. Kevin Johnson Shared Resources Project Manager (institutionally funded) and Dr. Mark Adams Director of the JAX Microbial Genomic Services support Shared Resources management. +No NIH Category available Research Education Core n/a NCI 10933161 9/22/23 9:29 PAR-18-767 3U54CA132378-15S1 3 U54 CA 132378 15 S1 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 6697 1922320 "HUBBARD, KAREN " Not Applicable 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 396416 265075 131341 No abstract available +No NIH Category available Admin-Core-001 n/a NCI 10933156 9/22/23 9:21 PA-20-272 3P50CA244431-05S1 3 P50 CA 244431 5 S1 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 ZCA1(A1) 5957 1885266 "BROWNSON, ROSS C" "COLDITZ, GRAHAM A." 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 155498 99999 55499 No abstract available +No NIH Category available Engagement Optimization Unit n/a NCI 10933155 9/22/23 9:17 RFA-CA-19-045 3U2CCA252981-03S1 3 U2C CA 252981 3 S1 "MECHANIC, LEAH E" 9/1/21 0:00 8/31/26 0:00 ZCA1-TCRB-O(M1) 8458 8953837 "DRAKE, BETTINA F." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 4382 2818 1564 No abstract available +No NIH Category available Core A: Administrative n/a NCI 10933148 9/21/23 13:15 PAR-16-457 3U19CA214253-06S1 3 U19 CA 214253 6 S1 "DAEE, DANIELLE L" 7/5/18 0:00 6/30/24 0:00 ZCA1-RPRB-6(O1) 5571 8474689 "HAIMAN, CHRISTOPHER ALAN" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 73392 44480 28912 No abstract available +No NIH Category available Address;Atlases;Automobile Driving;Basic Science;Collaborations;Communication;Communities;DNA Methylation;Data Analyses;Data Collection;Data Coordinating Center;Discipline;Electronic Mail;Evaluation;Evolution;Fibroblasts;Fostering;Funding;GSTP1 gene;Genomics;Grant;Human Resources;Individual;Indolent;Inflammation;Infrastructure;Institution;Joints;Knowledge;Leadership;Lesion;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Mentors;Mission;Modality;Molecular and Cellular Biology;Neoplasms;Peer Review;Postdoctoral Fellow;Procedures;Progress Reports;Prostate;Prostatic;Publications;Research;Research Activity;Research Personnel;Research Project Grants;Role;Site Visit;Students;Summary Reports;Teleconferences;Telephone;Work;anticancer research;carcinogenesis;diverse data;graduate student;interdisciplinary approach;meetings;molecular pathology;mouse model;pre-clinical;programs;support network;synergism;transcriptome sequencing;translational approach;tumor microenvironment;virtual;working group Admin-Core-001 n/a NCI 10933141 9/21/23 13:09 PA-20-272 3U54CA274370-02S1 3 U54 CA 274370 2 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 9/1/23 0:00 8/31/27 0:00 ZCA1(M1) 5956 2146873 "DE MARZO, ANGELO MICHAEL" "YEGNASUBRAMANIAN, SRINIVASAN " 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 82234 50219 32015 Project Summary/Abstract: The mission of the Administration Core is to ensure that the individual Research Projects and the Research Core combine with synergy beyond their individual parts to contribute to the TBEL Program creating strength beyond the individual Centers to integrate with the NCI and the cancer research community. The Administrative Core provides the infrastructure essential for this mission. The Core will supervise a multi-component research program encompassing two basic science and one translational projects and utilizing diverse data collection and analysis modalities. To foster synergy the Core will be the primary contact for internal activities including logistical and organizational activities scientific and administrative activities and collaborative project solicitation review funding and evaluation. To embed our proposed Center within the TBEL Program and the broader cancer research community this Core will also be the primary contact for external interactions with the NCI other TBEL Centers the Coordinating and Data Management Center (CDMC) and external cancer researchers. The Core Leaders Drs. De Marzo and Yegnasubramanian have been active collaborators for 19 years have joint funding on the NCI SPORE grant as well as the NCI MCL grant for the past 6 years and are co-authors on 50 peer-reviewed primary publications and 16 review articles. Drs. De Marzo and Yegnasubramanian are also embedded in internal and external research networks that support their roles. In addition they have co-mentored several graduate students and post-doctoral fellows often serving on their fellow graduate student's thesis committees. They have worked together extensively on the molecular pathology and genomics of prostate cancer over the last 10 years including leading all the RNAseq and whole genomic sequencing efforts for JHU the NCI MCL-U01 projects including the pre-clinical atlas pilot. Also together they have worked extensively on the molecular and cellular biology of prostate precursor lesions together finding partial DNA methylation of GSTP1 in high grade PIN lesions and PIA; a finding directly relevant to the current proposal. Finally they have worked together extensively with Dr. Bieberich on the molecular pathology and genomics of mouse models of prostatic inflammation driven neoplasia and of aggressive versus indolent prostate cancer and with Dr. Pienta in all administrative aspects and tumor microenvironment studies related to the NCI MCL-U01 Program. +No NIH Category available Affect;Affinity;Antisense Oligonucleotides;Base Sequence;Binding Proteins;CRISPR/Cas technology;Cell Line;Cell Proliferation;Cell Survival;Child;Childhood;Chromatin;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Dependence;Disease;Engineering;Epigenetic Process;Evaluation;Genes;Genetic Predisposition to Disease;Genetic Transcription;Goals;Growth;Human;Impairment;In Vitro;Investigation;Knock-out;Libraries;Malignant Neoplasms;Mediating;Methods;Modeling;Oncogenes;Oncogenic;Open Reading Frames;Patients;Pharmaceutical Preparations;Phase;Phosphoproteins;Phosphotransferases;Preclinical Drug Evaluation;Proliferating;Proteins;Proteomics;Sampling;Signal Transduction;Specimen;System;Therapeutic;Therapeutic Uses;Transcript;Translating;Tyrosine Kinase Inhibitor;Validation;Work;Xenograft procedure;functional genomics;fused in sarcoma;gene product;genome-wide;in vivo;in vivo Model;inhibitor;kinase inhibitor;knock-down;novel;patient derived xenograft model;patient subsets;preclinical evaluation;research clinical testing;sarcoma;screening;small hairpin RNA;synovial sarcoma;targeted treatment;therapeutic candidate;therapeutic target;treatment strategy;tumor;young adult Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma NARRATIVE Synovial sarcoma an aggressive cancer that primarily affects children and young adults is characterized by an abnormal protein called SS18-SSX. We hypothesize that SS18-SSX makes synovial sarcomas dependent on specific genes creating an Achilles' heel that could be targeted by specific inhibitors of the function of those genes. We propose to systematically screen synovial sarcoma cells for such dependencies among genes that often function in cancer and genes likely to be related to the function of SS18-SSX with the goal of identifying novel targets or existing drugs that can be clinically evaluated in these patients. NCI 10932624 9/20/23 0:00 PA-20-272 3P50CA217694-05S1 3 P50 CA 217694 5 S1 "UJHAZY, PETER" 9/1/23 0:00 8/31/24 0:00 7792 6879059 "LADANYI, MARC " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 206686 116772 89914 ABSTRACT RP-4 focuses on synovial sarcoma an aggressive pediatric/young adult sarcoma driven by the SS18-SSX fusion oncogene. SS18-SSX has emerged as a multi-faceted disruptor of epigenetic control that mediates genome-wide transcriptional deregulation resulting in proliferation and aberrant or arrested differentiation. Our overall goal is to probe the basic pathobiology of synovial sarcoma so as to nominate potential therapeutic targets. We propose hypothesis-driven screening approaches namely functional genomic screens to uncover vulnerabilities among chromatin/transcriptional regulators and among kinases as well as targeting the oncogenic fusion itself. Based on the hypothesis that SS18-SSX causes synovial sarcoma cells to possess special epigenetic dependencies we will in Aim 1 (a) perform a broad functional genomic screen using a new CRISPR knock-out pooled library against epigenetic modulators; and (b) seek to further validate and understand mechanistically KDM2B a dependency identified in preliminary studies as a vulnerability in human synovial sarcoma cells. Based on the hypothesis that another effect of SS18-SSX is transcriptional deregulation of growth signaling Aim 2 will employ three orthogonal strategies to better define targetable kinase vulnerabilities in this sarcoma. Specifically we will (a) perform a CRISPR-based functional genomic screen against kinases in human synovial sarcoma cell lines; (b) identify activated kinases in synovial sarcoma by phospho-protein profiling of patient-derived xenografts; and (c) define the targets of pazopanib in synovial sarcoma by two complementary methods affinity proteomics and PLATO (parallel analysis of translated ORFs). These two analyses should clarify the critical kinase targets of this multi-targeted kinase inhibitor that is active in a subset of synovial sarcoma patients. The results generated in this Aim will be integrated to form the basis for more rational targeting of critical kinases in this sarcoma. As SS18-SSX is the primary driver oncogene in synovial sarcoma the junction point of the fusion transcript represents an rational and highly specific target for sequence-based therapeutics using new antisense oligonucleotide (ASO) approaches. Building on our promising results using gapmer ASOs to directly target other sarcoma fusions in vitro and in vivo we will optimize and evaluate gapmer ASOs against SS18-SSX. In Aim 4 we will validate the targets identified in Aims 1-3 by confirming on-target effects and expression in human tumors and we will perform preclinical evaluation of their potential as therapeutic targets in vitro and in vivo. The most promising targets will be validated and subjected to extensive preclinical evaluation using multiple orthogonal relevant in vitro and in vivo systems. The ultimate overall goal of this fundamentally translational project is to begin clinical evaluation of at least one agent based on the novel targets and strategies identified through our work in patients with this often lethal sarcoma within five years. +No NIH Category available BRAF gene;Behavior;Biochemical;Biological Models;Biology;Biopsy Specimen;CRISPR interference;CRISPR/Cas technology;Cell Line;Chromatin Remodeling Factor;Citric Acid Cycle;Clinical;Clinical Trials;Clinical Trials Design;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Complex;Custom;DDR1 gene;Defect;Dependence;Development;Disease;Drug resistance;ETV1 gene;Electron Transport;Epigenetic Process;Exhibits;Gastrointestinal Neoplasms;Gastrointestinal Stromal Tumors;Generations;Genes;Genetic;Genomic approach;Goals;Growth;Human;Imatinib;In Vitro;Inter-tumoral heterogeneity;Interstitial Cell of Cajal;Investigation;Knockout Mice;Knowledge;LoxP-flanked allele;MAP Kinase Gene;Maintenance;Malignant Neoplasms;Mediating;Mesenchymal Cell Neoplasm;Mesenchymal Stem Cells;Mitochondria;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mutation;NF1 mutation;Oncogenic;PDGFRA gene;Pathologic;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phase Ib/II Trial;Pilot Projects;Population;Pre-Clinical Model;Proteins;RNA Interference;Receptor Protein-Tyrosine Kinases;Regulation;Resistance;Resistance development;Resources;Role;Sampling;Signal Induction;Signal Pathway;Signal Transduction;Soft tissue sarcoma;Specific qualifier value;Succinate Dehydrogenase;Technology;Therapeutic;Tumor Cell Line;Tumor Subtype;Tyrosine Kinase Inhibitor;cancer genomics;conditional knockout;design;driver mutation;epigenome;epigenomics;exome sequencing;genetic approach;in vitro Model;in vivo;in vivo Model;inhibitor;interdisciplinary approach;loss of function;mouse model;multidisciplinary;mutant;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;pre-clinical;precursor cell;resistance mechanism;response;sarcoma;targeted sequencing;therapeutic development;therapeutic evaluation;therapeutic target;therapy resistant;tumor;tumor initiation;tumorigenesis;ubiquitin-protein ligase Novel therapeutics development and mechanisms of therapeutic resistance in gastrointestinal stromal tumor (GIST) RP-1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GISTNARRATIVEGastrointestinal stromal tumor (GIST) a common subtype of soft tissue sarcoma is difficult to managebecause most tumors eventually develop resistance to imatinib the best available drug. We haveidentified a protein called ETV1 as a novel therapeutic target in both imatinib-sensitive and imatinib-resistant GIST. Here we propose comprehensive collaborative and multidisciplinary studies to betterunderstand the mechanisms of ETV1 biology and therapeutic targeting of ETV1 in GIST as well asdeveloping model systems for investigating a poorly understood GIST subtype (SDH-deficient GIST)with the goal of expedited development of novel therapeutics that will benefit the majority of patientswith advanced GIST. NCI 10932621 9/20/23 0:00 PA-20-272 3P50CA217694-05S1 3 P50 CA 217694 5 S1 "UJHAZY, PETER" 9/1/23 0:00 8/31/24 0:00 7789 6983815 "ANTONESCU, CRISTINA R" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 246736 139399 107337 RP-1: Novel Therapeutics Development and Mechanisms of Therapeutic Resistance in GISTABSTRACTGastrointestinal stromal tumor (GIST) represents one of the most prevalent sarcoma subtypes and isthe most common mesenchymal neoplasm of the GI tract. Most GISTs harbor activating oncogenicdriver mutations in receptor tyrosine kinases e.g. KIT or PDGFRA. Among KIT/PDGFRA wild-typeGISTs the majority harbor loss-of-function defects in the mitochondrial succinate dehydrogenase(SDH) complex a component of the Krebs cycle. KIT/PDGFRA-mutant and SDH-deficient GISTsrepresent molecularly distinct groups with distinct clinical behaviors. We have recently identifiedETV1 as a master regulator for the lineage specification and normal development of the GIST precursorcells the interstitial cells of Cajal. Importantly ETV1 is required for the growth and survival ofimatinib-sensitive and -resistant GISTs in vitro and for tumor initiation and maintenance in vivo. Wehypothesize ETV1 is a novel therapeutic target that is critical for the shared lineage-dependent survivalof both imatinib-sensitive and -resistant GISTs. In this project we propose a comprehensive study tounderstand the regulation of ETV1 protein stability and to develop novel therapeutic strategiestargeting ETV1 protein stability using various pre-clinical GIST models. In parallel we will investigateclinical samples from prior and ongoing clinical trials designed to target ETV1 protein stability to betterunderstand the molecular mechanisms of therapeutic resistance. Moreover targeted sequencing usingcustom IMPACT panels will be used on these matched pre- and post-therapy biopsy samples from theon-going phase Ib/II trials using imatinib in combination with MEK162 to elucidate mechanism ofdrug resistance. This investigation will leverage comprehensive and multidisciplinary approachesincluding biochemical state-of-the-art genomics and genetic approaches in in vitro and in vivo modelsas well as patient tumor samples derived from current GIST clinical trials. The therapeutic strategiesidentified here may benefit other ETV1-dependent malignancies. Lastly since there are no in vitro andin vivo models for focused mechanistic and therapeutic investigation of SDH-deficient GISTs we willgenerate cell line models through novel gene editing technology such as CRISPR and CRISPRi inestablished GIST cell lines as well as in human mesenchymal progenitor cells that are committed to theinterstitial cells of Cajal lineage. We will also develop in vivo murine models of SDH-deficient GISTs forfocused evaluation of therapeutics specifically targeting SDH deficiency that may benefit other SDH-deficient malignancies beyond GIST. +No NIH Category available Animal Model;Animals;Apoptosis;Applied Research;Archives;Basic Science;Bioinformatics;Biological Assay;Biological Specimen Banks;Blood;Cancer Center;Cell Line;Cell Survival;Center Core Grants;Clinical;Clinical Research;Clinical Trials;Collaborations;Collection;Core Facility;Custom;DNA;Data;Database Management Systems;Databases;Diagnosis;Enrollment;Ensure;Evaluation;Fibrosis;Fluorescent in Situ Hybridization;Formalin;Freezing;Generations;Genes;Human;Image;Individual;Induction of Apoptosis;Infrastructure;Institution;Institutional Review Boards;Memorial Sloan-Kettering Cancer Center;Microscopic;Molecular;Morphology;Mus;Mutation;Necrosis;Normal tissue morphology;Nucleic Acids;Office of Administrative Management;Oncogenes;Paraffin Embedding;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phosphorylation;Phosphotransferases;Pilot Projects;Plasma;Play;Proliferating;Protocols documentation;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Scanning;Serum;Services;Soft Tissue Neoplasms;Techniques;Testing;Tissue Embedding;Tissue Microarray;Tissue Sample;Tissues;Translational Research;Xenograft Model;Xenograft procedure;central database;cost effective;design;digital;human tissue;immunohistochemical markers;mouse model;mutation screening;participant enrollment;peripheral blood;programs;response;sarcoma;targeted sequencing;tissue archive;tissue preparation;treatment response;tumor CF 1: Biospecimen Repository Core Core 1: Biospecimen RepositoryNARRATIVEThe Biospecimen Repository Core (CF-A) will play a central role in the collection annotation andstoring of all tumor samples and blood from patients diagnosed with sarcoma and enrolled on researchprotocols at MSKCC. The CF-A will provide expertise with pathology diagnosis and interpretation ofancillary techniques that will assist in the basic and applied research efforts of the SPORE investigatorsand will provide information regarding tumor response to different drug therapies used in variousclinical trials or applied to the animal models of sarcomas. It will also establish a significantinfrastructure for other projects and cores in a cost-effective manner. NCI 10932618 9/20/23 0:00 PA-20-272 3P50CA217694-05S1 3 P50 CA 217694 5 S1 "UJHAZY, PETER" 9/1/23 0:00 8/31/24 0:00 7786 6983815 "ANTONESCU, CRISTINA R" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 103502 58476 45026 CF-1: Biospecimen RepositoryABSTRACTThe Biospecimen Repository Core (CF-1) is designed to provide support to the basic and translationalresearch efforts of the SPORE. The CF-1 will play a central role in collecting annotating storingdistributing and tracking of tissue and blood biospecimens from patients enrolled in research protocols.The Core will provide SPORE investigators with expert histopathological evaluation of tumor samplesboth from patients enrolled on research protocols and from murine and xenograft models. Additionallyit will assist in selecting appropriate formalin-fixed paraffin-embedded tissue and snap-frozen tissue forresearch and pilot projects as well as enable the creation of tissue microarrays (TMAs) for SPOREinvestigator studies. The Core will provide assistance in performing and interpretingimmunohistochemical studies and fluorescence in situ hybridization (FISH) assays. It will providescanning and digital archiving of TMA images and reliable interpretation scoring and archiving of IHCresults from frozen paraffin-embedded sections or TMA sections. The core will also provide systematicassessment of tumor response to therapy in human tissues and in sarcoma murine models includinginterpretation of immunohistochemical markers for drug response such as changes in kinasephosphorylation proliferation inhibition and induction of apoptosis. It also provides a centralizedresource for mutational annotation of sarcoma samples and cell lines using the IMPACT platform.Finally it ensures linkage to the clinical sarcoma database in collaboration with project leaders thebioinformatics core (CF-2 Qin/Socci) and the administrative core (Singer). This establishes a substantialinfrastructure and allows us to provide the required services in a cost-effective manner. The CF-1 istightly integrated with the MSKCC Institutional Pathology Core (supported by the MSKCC CancerCenter Core Grant) and the Clinical Research Database (CRDB) managed by the administrative core. +No NIH Category available Address;Affect;African American;Black Populations;Black race;Cancer Burden;Cancer Center;Cause of Death;Collaborations;Colorectal Cancer;Communities;Comprehensive Cancer Center;Data;Development;Diagnosis;Disease;Disparity;Economics;Education;Elements;Emotional;Evaluation;Faculty;Family;Fostering;Funding;Funding Agency;Goals;Growth;Health;Health Disparities Research;Historically Black Colleges and Universities;Individual;Infrastructure;Institution;Intervention;Journals;K-Series Research Career Programs;Knowledge;Lead;Liver;Localized Malignant Neoplasm;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Massey Cancer Center at the Virginia Commonwealth University;Mentors;Modeling;Nature;Outcome;Output;Pattern;Peer Review;Phase;Pilot Projects;Positioning Attribute;Prevention;Publications;Recording of previous events;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Social Well-Being;Students;Testing;Training;Training Activity;Training Programs;Training and Education;Underrepresented Minority;Universities;Virginia;Vision;Vital Statistics;anticancer research;cancer health disparity;career;career development;community partnership;design;experience;health disparity;health inequalities;malignant breast neoplasm;meetings;member;minority investigator;minority undergraduate;mortality;multidisciplinary;neoplasm registry;programs;research study;rural dwellers;science education;statistics;summer research;survivorship;undergraduate student 2/2 VSU-MCC Partnership for Cancer Disparities Research and Training program (SUCCEED) OVERALL: PROJECT NARRATIVEThe overarching goal of the Virginia State University (VSU)-Virginia Commonwealth University (VCU) MasseyCancer Center (MCC) PartnErship for CancEr Disparities Research and Training (SUCCEED) program is to leadin the transformation of cancer-related outcomes for Virginians and to serve as a model of transdisciplinarydisparities research. The institutions will jointly conduct pilot research projects addressing local cancer-relatedhealth disparities and will develop a training program for VSU faculty and undergraduate students designed toattract and prepare investigators for careers in cancer disparities. NCI 10932453 9/21/23 0:00 PAR-18-911 3P20CA264068-03S1 3 P20 CA 264068 3 S1 "RODRIGUEZ, LARITZA MARIA" 9/20/21 0:00 8/31/25 0:00 ZCA1-SRB-2(M2) 1923259 "FAISON, MILTON O" "ROBERTS, DANIEL M." 4 BIOLOGY 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA SCHOOLS OF ARTS AND SCIENCES 238032520 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 40231 NCI 31597 8634 OVERALL: PROJECT SUMMARYInvestigators from Virginia State University (VSU) a Historically Black College/University and the NCI-designated Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) recognized a need tocollaborate and leverage the expertise and resources of both institutions to educate and train promisingindividuals who will ultimately contribute to diminishing cancer disparities in Virginia. The outcome of thiscollaboration resulted in the formation of the VSU-MCC PartnErship for CancEr Disparities Research andTraining (SUCCEED) program. The overarching goal of SUCCEED is to lead in the transformation of cancer-related outcomes for Virginians and to serve as a model of transdisciplinary disparities research and education.Guided by the NCI framework our preliminary data and the expertise of our multidisciplinary team we willemploy a multilevel approach to develop a robust collaborative infrastructure that will build on the strengths ofthe partnering institutions to enhance their capacity to conduct cancer health inequities research that is drivenby local data and informed by the cancer-related needs of local communities. Specific aims are to: Aim 1:Establish a mutually beneficial collaborative partnership between VSU and MCC in cancer disparities researchand training; Aim 2: Conduct collaborative locally focused liver/gastrointestinal (GI) cancer pilot research studiesby investigators at MCC and VSU; Aim 3: Provide an integrated cancer research training and careerdevelopment experience to VSU faculty; Aim 4: Support underrepresented minority undergraduate studentsfrom VSU to pursue careers in disparities research; Aim 5: Conduct an ongoing evaluation that reflects theprogress of the collaborative partnership in meeting its goals and objectives. To our knowledge this is the firsttargeted effort of this nature to address cancer disparities in the state of Virginia. 40231 +No NIH Category available ANGPT2 gene;Agonist;Angiopoietin-2;Binding;Biological Markers;Blocking Antibodies;Blood Vessels;CD8-Positive T-Lymphocytes;Cell physiology;Clinical Management;Data;Development;Diagnosis;Disease;Endothelium;Excision;Extravasation;Functional disorder;Genetic;Growth;Human;Immune Evasion;Immune checkpoint inhibitor;Immunodeficient Mouse;Immunosuppression;Immunotherapy;Impairment;Incidence;Inflammatory;Islet Cell Tumor;Liver;Mediating;Metastatic Neoplasm to the Liver;Mus;Neoplasm Metastasis;Operative Surgical Procedures;Patients;Perfusion;Plasma;Primary Neoplasm;Prognosis;Prognostic Marker;Receptor Protein-Tyrosine Kinases;Regulation;Resistance;Role;Sampling;Signal Transduction;Signaling Molecule;T cell infiltration;T-Lymphocyte;TIE-2 Receptor;Testing;Therapeutic;Time;Tumor Escape;Tumor Markers;Up-Regulation;Vascular remodeling;Work;antagonist;anti-PD1 therapy;cancer biomarkers;checkpoint therapy;follow-up;high risk;immune cell infiltrate;immunoregulation;improved;insight;liver function;mouse model;objective response rate;potential biomarker;prognostic;receptor;response;therapeutic target;transcriptome sequencing;tumor;tumor diagnosis;tumor growth;tumor progression;tumor-immune system interactions Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pancreatic neuroendocrine tumors PROJECT NARRATIVENearly half of patients with pancreatic neuroendocrine tumors (PanNET) present with liver metastases atdiagnosis which correlates with poor prognosis and the immunosuppressive microenvironment of PanNETlimits the efficacy of immune checkpoint inhibitors (ICI) for metastatic PanNET patients with a less than 10%objective response rate. Emerging evidence suggests that increased vascular leakage and poor vascularperfusion resulting from vascular destabilization impair immune cell infiltration into tumors thus facilitatingtumor immune evasion and consequent tumor progression. In this work we propose to study role ofangiopoietin-2/Tie2 signaling which regulates vascular destabilization and dysfunction in liver metastaticprogression and in ICI therapy resistance of metastatic PanNET as well as the potential of Tie signalingmolecules as sensitive cancer biomarkers for PanNET patients. NCI 10932452 9/21/23 0:00 PA-20-185 3R37CA266270-02S1 3 R37 CA 266270 2 S1 "SNYDERWINE, ELIZABETH G" 7/12/22 0:00 6/30/27 0:00 Tumor Microenvironment Study Section[TME] 11781381 "KIM, MINAH " Not Applicable 13 PATHOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 103971 NCI 66292 37679 Title: Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pancreatic neuroendocrine tumorsPROJECT SUMMARY Liver metastases are found in nearly half of PanNET patients at diagnosis while many others develop livermetastasis after surgical resection of the primary tumor. Though the incidence of pancreatic neuroendocrinetumors (PanNET) has increased steadily over recent decades there are only limited therapeutic options formetastatic PanNET patients. Furthermore immune checkpoint inhibitors (ICI) showed the limited efficacy inpatients with metastatic PanNET due to the immunosuppressive microenvironment. Therefore understandingthe mechanisms underlying liver metastasis immune evasion and their convergence on ICI therapy resistancein PanNET is urgently necessary to improve the clinical management of advanced PanNET. Vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Angiopoietin-2(Ang2) which binds to the receptor tyrosine kinase Tie2 is a potent vascular destabilizing factor. Wedemonstrated that under inflammatory conditions Ang2 suppresses Tie2 signaling and promotes vasculardestabilization and leakage. Importantly emerging evidence suggests that vascular destabilization facilitatestumor immune evasion by impairing immune cell infiltration. In preliminary studies using a spontaneousPanNET mouse model we found that Ang2 inhibition suppresses liver metastatic growth and improves thesurvival. Ang2 inhibition also reduced vascular leakage and increased CD8+ T-cell infiltration in metastases.We previously showed that suppression of Tie2 signaling is accompanied by ectodomain cleavage of the Tie2coreceptor Tie1 resulting in increased circulating levels of soluble Tie1 (sTie1). Our preliminary studies showthat elevated plasma sTie1 levels in PanNET patients have significant prognostic implications. In this project we will elucidate the mechanisms underlying Ang2-mediated liver metastatic progressionimmunosuppression and anti-PD-1 therapy resistance in metastatic PanNET. In Aim 1 we will determine thecontribution of Ang2-mediated vascular destabilization to liver metastatic progression in PanNET by usinghuman liver metastases and function-blocking antibodies or genetic Ang2 deletion in spontaneous andexperimental PanNET mouse models. Mechanistically in Aim 2 we will determine whether Ang2-mediatedvascular leakage impairs CD8+ T-cell infiltration in liver metastases serving as the basis for assessing theeffects of Ang2 inhibition combined with anti-PD-1 therapy in metastatic PanNET. We will determine if Ang2blockade sensitizes PanNET liver metastases to anti-PD-1 therapy by promoting vascular stabilization andCD8+ T-cell infiltration in PanNET mice. Finally Aim 3 will identify circulating levels of sTie1 at diagnosis as apotential biomarker for tumor aggressiveness in PanNET patients. Successful completion of this project whichelucidates the mechanisms underlying vascular regulation of the immune evasion could significantly enhancethe clinical management of metastatic PanNET as well as provide insights for the treatment of metastaticdisease deriving from other tumor types especially those with poor response to ICI therapy. 103971 +No NIH Category available TOPIC 426: ATLASCOPE: COMPOSABLE VISUALIZATION TOOLS FOR MULTISCALE INTEGRATIVE BIOLOGY n/a NCI 10932000 75N91023C00030-0-9999-1 N44 9/15/23 0:00 9/14/25 0:00 79360297 "CHOUDHURY, RONI " Not Applicable 20 Unavailable 10926207 DK6LPWMS5LP5 10926207 DK6LPWMS5LP5 US 42.849889 -73.759124 4014501 "KITWARE, INC." CLIFTON PARK NY Domestic For-Profits 120653104 UNITED STATES N R and D Contracts 2023 1499969 NCI In Phase I we were able to prototype several features for Atlascope and demonstrate that they form a plausible system in which to conduct multiscale biological workflows and visualizations. In Phase II we will aim to scale up our Phase I success in several directions: technologically we will aim to harden the features and the web application we have developed to host our Phase I experiments; biologically we will aim to bring in more production data and reproduce more of our research partners workflows; commercially we will market the new capability to interested parties within and without our network ofcustomers and research partners. 1499969 +No NIH Category available Accountability;Address;Advanced Malignant Neoplasm;Advisory Committees;African;African American;American;Asian;Asian Americans;Asian Pacific American;Black race;Cancer Research Project;Chronic Hepatitis B;Collaborations;Communication;Communities;Community Outreach;Decision Making;Doctor of Philosophy;Education;Education and Outreach;Ensure;Equity;Evaluation;Faculty;Fostering;Foundations;Fox Chase Cancer Center;Goals;Grant;Health Disparities Research;Health Sciences;Health system;Hispanic Americans;Infrastructure;Institution;Joints;Latinx;Leadership;Letters;Localized Malignant Neoplasm;Mentors;Metabolic syndrome;Mission;New Jersey;New York City;Organization administrative structures;Outcome Measure;Patients;Performance;Philadelphia;Productivity;Regional Cancer;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resource Sharing;Role;Science;Services;Structure;Underserved Population;Universities;Vision;Work;anticancer research;cancer health disparity;cancer prevention;career;college;community organizations;design;equity diversity and inclusion;ethnic minority population;experience;implementation outcomes;improved;inter-institutional;medical schools;meetings;member;multidisciplinary;non-alcoholic fatty liver disease;operation;organizational structure;population health;programs;racial minority population;systemic barrier Administrative Core n/a NCI 10931771 9/20/23 0:00 PA-20-272 3U54CA221705-06S1 3 U54 CA 221705 6 S1 "SAN MIGUEL-MAJORS, SANDRA L" 9/19/18 0:00 8/31/28 0:00 ZCA1 5038 6255019 "MA, GRACE X." Not Applicable 2 Unavailable 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA Domestic Higher Education 191226003 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 189986 126075 63911 PROJECT SUMMARYAdministrative CoreTUFCCC: Grace X. Ma PhD (Contact PI) and Camille Ragin PhD MPH (MPI) HC: Olorunseun Ogunwobi MD PhD (Contact PI) and Joel Erblich PhD MPH (MPI)The Administrative Core (AC) of the TUFCCC/HC Regional Comprehensive Cancer Health DisparitiesPartnership 2.0 (aka: SPEECH 2.0) builds on an established effective leadership governance infrastructure andfoundation of productivity and impact. Over the past 5 years the Partnership directly supported 84 investigators56 cancer disparities research projects mentored 180 trainees (61% received career or educationadvancements) and engaged 50 diverse community-based organization partners in cancer prevention activities.The overall goal of the AC for SPEECH 2.0 is to further enhance cancer health disparities research infrastructureand our administrative leadership to provide vigorous scientific/programmatic oversight and integration ofresearch projects education/training and community outreach and engagement activities to be conducted bythe Partnership ensuring high-quality standards of excellence and impact on advancing cancer equity inunderserved Black/African American (AA) Asian Pacific Americans (APA) and Hispanic American/Latinx (HA)communities in the Philadelphia NJ and NYC (PNN) region. The ACs functions include but are not limited toproviding leadership oversight fiscal management coordination integration and communication to support thePartnerships day-to-day operations. The AC will ensure the efficient effective and synergistic performance ofthe proposed Partnerships aims throughout all of the projects cores and shared resources. The aims of theintegrated TUFCCC/HC Administrative Core are as follows: Aim 1. Leverage the established organizationalstructure to enhance operational capacity and provide robust administrative and fiscal support for overallprogram activities of TUFCCC/HC Partnership cores and research projects. Aim 2. Facilitate and enhancecommunication and collaboration opportunities to promote team science among Partnership faculty traineesinvestigators and program coordinators. Aim 3. Strengthen and maintain leadership infrastructure to ensure theintegration of cores projects shared resources as well as inter-institutional initiatives across Partnership andbeyond. Aim 4. Establish and maintain sustainable infrastructure to support and ensure the competitiveness ofthe Partnership's research project portfolio. Aim 5. Direct and support continuous quality improvement usingmultiple metrics to inform decision-making in planning and evaluation across all cores and projects of thePartnership. Both institution leaders have and will continue to provide exceptional commitments to SPEECH 2.0.AC has been well established and integrated and will continue to be jointly led by experienced multidisciplinarycancer research leaders. The AC team demonstrated not only synergistic accomplishments during SPEECH 1.0but also strong long-term commitments to the shared vision of advancing cancer equity among underservedpopulations. Inclusive Excellence will serve as our guiding principle across all cores and projects. In practicethe AC core will be committed to addressing systemic barriers and incorporating diversity equity and inclusionefforts into all aspects of our Partnership for the proposed next U54 grant period. +No NIH Category available NexTGen - DFCI n/a NCI 10931252 9/26/23 0:00 RFA-OT-A2-013 1OT2CA291436-01 1 OT2 CA 291436 1 "SINGH, ANJU" 9/26/23 0:00 5/31/24 0:00 ZCA1-SRC(99) 14980986 "MAJZNER, ROBBIE G." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/26/23 0:00 5/31/24 0:00 393 Other 2023 916494 NCI 517134 399360 No abstract available 916494 +No NIH Category available Cancer Pain Management: A Technology-Based Intervention for Asian American Breast Cancer Survivors This study will provide a prototype of a culturally tailored technology-based program for pain management ofAsian American breast cancer survivors with depressive symptoms. This study will accelerate the translation oftechnology-based programs into health care and will be an important contribution in pain management of cancersurvivors with depressive symptoms. Ultimately this study will contribute to reducing ethnic disparities inhealth/disease experience by providing directions for culturally competent health care services specifically foradequate pain and symptom management of racial/ethnic minority cancer survivors. NCI 10931208 9/21/23 0:00 RFA-NS-22-037 4R33CA280979-02 4 R33 CA 280979 2 "STRECK, BRENNAN PARMELEE" 9/20/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-IFCN-R(50)R] 6800571 "IM, EUN-OK " "CHEE, WONSHIK " 37 NONE 170230239 V6AFQPN18437 170230239 V6AFQPN18437 US 30.291188 -97.737568 578403 UNIVERSITY OF TEXAS AT AUSTIN AUSTIN TX SCHOOLS OF NURSING 787121139 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 853 Non-SBIR/STTR 2023 875844 NINDS 558497 317347 Due to cultural stigma attached to breast cancer cultural stoicism toward pain and symptoms and languagebarriers Asian American breast cancer survivors tend to suffer unnecessarily from pain that could be easilymanaged using existing pharmacologic or non-pharmacologic strategies. Especially Asian American breastcancer survivors with depressive symptoms (ABD) are more likely to have inadequate pain management dueto their depression and pain could further deteriorate depression. Furthermore the recent opioid crisis hasexacerbated their fear of addiction and reluctance to seek help for pain management. The COVID19 pandemic has also placed an additional dimension of stress to this specific population. However survivorship programs at cancer centers lack the staff and time to adequately address these unique needs of this population. A technology-based approach using computers and mobile devices promises to meet this necessity with highflexibility accessibility and anonymity. Based on Preliminary Studies (PSs) the research team developed andpilot-tested an evidence-based Web App-based information and coaching/support program for cancer painmanagement (CAPA) that was culturally tailored to Asian American breast cancer survivors using multipleunique features. However CAPA rarely considered depressive symptoms accompanying pain in its design orcomponents and PSs indicated the necessity of further individualization of the intervention components ofCAPA due to diversities in the needs of ABD. The purpose of the proposed 2-phase study is to furtherdevelop CAPA with additional components for ABD and the individual optimization functionality (CAI) and totest the efficacy of CAI in improving cancer pain experience of ABD. The specific aims are to: a) developand evaluate CAI through an expert review and a usability test (R61 phase); b) determine whether theintervention group (that uses CAI and usual care) will show significantly greater improvements than the activecontrol group (that uses CAPA and usual care) in primary outcomes (cancer pain management and cancerpain experience including depressive symptoms) from baseline to post 1-month and post 3-months; c) identifytheory-based variables (attitudes self-efficacy perceived barriers and social influences) that mediate theintervention effects of CAI on the primary outcomes; and d) determine whether the effects of CAI on theprimary outcomes are moderated by selected background disease genetic and situational factors. This studyis guided by the Banduras Theory and the stress and coping framework by Lazarus and Folkman. The R61phase includes: (a) the intervention development process (b) a usability test among 15 ABD 15 familymembers and 15 community gatekeepers; and (c) an expert review among 10 experts in oncology. The R33phase adopts a randomized repeated measures control group design among 300 ABD. Long-term goals are:(a) to extend and test CAI in various healthcare settings with diverse subgroups of ABD (b) examine the cost-effectiveness sustainability and scalability of CAI in the settings and (c) translate CAI into health care for ABD. 875844 +No NIH Category available Achieving Equity through SocioCulturally-informed Digitally-Enabled Cancer Pain managemeNT (ASCENT) Clinical Trial PROJECT NARRATIVEThe proposed Achieving Equity through SocioCulturally-informed Digitally-Enabled Cancer PainmanagemeNT (ASCENT) clinical trial will test whether a novel digitally enabled collaborative approach toteam based pain management can improve clinical outcomes and reduce longstanding and devastatingdisparities among rural dwelling and Hispanic/Latinx cancer survivors. NCI 10931166 9/21/23 0:00 RFA-NS-22-002 4R33CA278594-02 4 R33 CA 278594 2 "STRECK, BRENNAN PARMELEE" 9/6/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-IFCN-R(50)R] 9459215 "CHEVILLE, ANDREA LYNNE" "AUSTIN, JESSICA DANIELLE" 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 279 Non-SBIR/STTR 2023 1594262 NINDS 1135184 459078 AbstractCancer pain disparities are profound and uniquely harmful among Hispanic/Latinx and rural dwelling survivors as theyundermine their already limited ability to access tolerate and/or receive treatment for their cancer. Disparities are tiedto poor care needlessly persistent and intense pain as well as the over- and under-prescribing of opioids. Multi-modalpain care (MMPC) a robustly validated safer and more effective alternative to a solely medication-based approach hasproven challenging to implement broadly and virtually impossible in resource limited settings. The factors that impededelivery of MMPC; provider bias patients reluctance to report pain and lack of patient-centered MMPC options alsomediate disparities making them key targets for improvement. The Collaborative Care Model (CCM) provides a well-es-tablished and validated framework that can neutralize factors that perpetuate disparities guide MMPC delivery and im-prove pain detection and treatment. However as currently configured the CCMs single symptom emphasis needs to bemodified to address the multi-level drivers of pain disparities. Our team has developed and tested CCM iterations that inte-grate elements of team-based care (TBC) to improve the CCMs monitoring of sociocultural needs as well as to accommo-date MMPCs multi-disciplinary care requirements. In addition we have leveraged electronic health records (EHRs) to en-able care teams to link symptomatic cancer patients with MMPC providers and resources. Our prior research deployingCCM-TBC hybrid interventions with patient-and-care team-centered EHR-reengineering has also significantly improvedpatient symptom reporting and deployment of MMPC. These efforts while fruitful have also shown us that a broaderEHR retrofitting is required to address the breadth of patients needs and the requirements of real-world clinical work-flows. This experience suggests that a flexible modular CCM-TBC hybrid system supported by EHR enablement can de-liver high fidelity MMPC in a manner that improves care and mitigates disparities at multiple levels among Hispanic andrural cancer survivors. We plan to evaluate the effectiveness of this approach in a clinical trial entitled Achieving Equitythrough SocioCulturally-informed Digitally-Enabled Cancer Pain managemeNT (ASCENT ). More specifically we will part-ner with our community stakeholders during an initial 1-year R61 development phase to refine a culturally informedversion of our CCM-TBC hybrid that addresses Hispanic and rural survivors linguistic social and IT needs (Aim 1). Afterconfirming the functionality of the interventions components we plan to transition to a 4-year R33 execution phase witha 2-arm parallel group randomized clinical trial. This trial (Aim 2) will be conducted in 4 semi-autonomous Health Care Sys-tems and is designed to assess whether our culturally informed CCM-TBC hybrid intervention improves pain outcomes rela-tive to usual care among 578 survivors 60% rural and 60% Hispanic assuming 30% overlap. Primary (pain) and secondary(mood sleep physical function work status and healthcare utilization) outcomes will be assessed at 0 3 and 6 months. Alldata excepting patient reported outcome measures will be extracted from the EHR for main effects as well as explora-torymediator and machine learning analyses; the latter to identify characteristics associated with positive responses. Aim 3 willevaluate implementation strategies to support multistakeholder adoption and use of intervention components. 1594262 +No NIH Category available TOPIC 453: THE PERFECT MEDICAL ASSISTANT FOR CANCER PREVENTION WITHIN PRIMARY CARE n/a NCI 10931123 75N91023C00046-0-9999-1 N43 9/18/23 0:00 9/17/24 0:00 79365937 "CHARLAP, STEVEN " Not Applicable 23 Unavailable 117620824 GF2JNND98ER9 117620824 GF2JNND98ER9 US 10073987 "SOAP, INC." BOCA RATON FL Domestic For-Profits 334323973 UNITED STATES N R and D Contracts 2023 400000 NCI Cancer is the second leading and the most expensive cause of death in the United States. With more than 500 million visits a year made to primary care physicians prevention and early detection of cancer by identification of at-risk individuals in the primary care setting can significantly reduce the cancer care and cost burden to individuals and society at large. The Perfect Medical Assistant M (PMA) a patented conversational Al-powered voice and image-based software application that collects and assesses patient data can assist primary care physicians to improve identification of at-risk patients and improve their productivity.In Phase I we will demonstrate that the PM effectively overcomes the two major barriers to widespread adoption by PCPs 1. patient acceptance and usability 2. easy integration into and no-disruption of physician workflows.AIM 1. Demonstrate the feasibility and acceptability of the PMA in a population of potential patient users by testing on up to 400 incentivized but diverse patients.AIM 2. Demonstrate that the PMA and the generated SOAP (Subjective Objective Assessment Plan) formatted clinical note can be integrated into PCPs' electronic health record systems and workflows as the primary patient intake and cancer risk assessment tool by integrating into the HRs of two PCP practices of at least 25 PCPs each. 400000 +No NIH Category available Area;Cancer Control;Caring;Collaborations;Communication;Communities;Data;Development;Discipline;Educational Activities;Ensure;Environment;Evaluation;Funding;Goals;Growth;Interdisciplinary Study;Intranet;Laboratories;Malignant Neoplasms;Manuscripts;Methodology;Methods;Mission;Monitor;Newsletter;Oncology;Pennsylvania;Pilot Projects;Policy Maker;Preparation;Principal Investigator;Problem Solving;Public Health;Publications;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Allocation;Scholars Program;Science;Series;Services;Site;Structure;Sum;Translating;United States National Institutes of Health;Universities;Vision;Vocabulary;anticancer research;behavioral economics;cancer care;care delivery;data sharing;experience;health care delivery;implementation science;improved;meetings;multidisciplinary;novel;outreach;programs;recruit;success;synergism;visiting scholar;web site Administrative Core n/a NCI 10931118 9/21/23 13:41 RFA-CA-19-006 3P50CA244690-04S1 3 P50 CA 244690 4 S1 "VINSON, CYNTHIA" 8/1/20 0:00 7/31/24 0:00 ZCA1-RPRB-L 5125 9176446 "BEIDAS, RINAD SARY" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 125000 76923 48077 This P50 application represents a novel interdisciplinary center at the intersection of behavioral economics and implementation science in pursuit of improving cancer care delivery. The Administrative Core for the University of Pennsylvania Implementation Science Center in Cancer Control (Penn ISC3) will provide overarching operational and scientific oversight. It will be led by the three Penn ISC3 Principal Investigators Drs. Beidas Bekelman and Schnoll in collaboration with an Internal Executive Committee and an External Advisory Board. The Specific Aims of the Administrative Core are as follows: 1) To provide essential management and integration of Penn ISC3 activities (operational structure)which will include administrative support meeting coordination and ensuring the effective use of the Internal Executive Committee and an External Advisory Board; (2) To serve as the hub for implementation science (IS) research in cancer at Penn (IS outreach) which will involve coordination of educational activities drawing upon essential partnerships at Penn engage in activities to ensure communication engaging with other centers funded through this mechanism and coordinating an annual retreat; (3) To coordinate communication and dissemination of the Centers research findings build research capacity and collaboration with other Moonshot awardees and support a national implementation science and cancer research community (network unit); and (4) To support monitor and evaluate Center progress (evaluation unit) which will ensure completion of proposed studies determine the broader impact of the Center and help to translate the results of the proposed studies into subsequent funded research projects. The overarching priority for the Administrative Core is to ensure that the impact of the Penn ISC3 is robust and greater than the sum of its parts. It will do so by coordinating services and maximizing synergies among the Research Program Implementation Laboratory and other center activities. The Administrative Core will interface with the Research Program (Project PIs and Methods Unit) regularly to ensure that each entity is meeting goals and objectives and problem solve as necessary. The proposed Penn ISC3 will bring together junior and senior investigators from multiple disciplines which will create a fertile environment with the long-term goal of improving cancer care delivery and exerting a sustained impact on public health in partnership with key stakeholders. Ultimately the Penn ISC3 Administrative Core will create a culture of exceptional science and ensure the Centers success by stimulating and guiding new conceptual and methodological advancements supporting the growth of IS and cancer research at Penn and nationally and advancing the science of implementation within oncology care. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page +No NIH Category available Award;Basic Science;Cancer Control Research;Clinical;Clinical Research;Collaborations;Development;Disabled Persons;Disparity;Faculty;Fostering;Funding;Future;Goals;Group Meetings;Institution;Laboratories;Mentors;Minority;Minority Recruitment;Operative Surgical Procedures;Peer Review;Program Evaluation;Research;Research Design;Research Personnel;Research Project Grants;Specialized Program of Research Excellence;Translational Research;Wages;Woman;Work;Writing;cancer health disparity;cancer prevention;career;epidemiology study;innovation;leukemia;meetings;mid-career faculty;minority investigator;programs;recruit DRP Project NarrativeThe Developmental Research Program will recruit and support innovative early-stage research in leukemia. NCI 10931080 9/20/23 0:00 PA-20-272 3P50CA171963-10S1 3 P50 CA 171963 10 S1 "KUZMIN, IGOR A" 9/3/13 0:00 6/30/24 0:00 8689 1917511 "LINK, DANIEL C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 Research Centers 2023 29674 19083 10591 ABSTRACT The overall goal of the Leukemia SPORE Developmental Research Program (DRP) is to recruit andsupport developmental research projects in leukemia for future peer-reviewed funding and/or futureindependent SPORE projects. The types of studies to be supported include projects in basic research clinicalresearch epidemiologic studies and cancer prevention and control research in leukemia. Projects supportedunder the DRP will expand the scope of translational research and increase the number of investigatorscommitted to leukemia research. The DRP will work in tandem with the Career Enhancement Program (CEP)to assist in the development of junior investigators and in the recruitment and mentoring of minorityinvestigators. To accomplish these goals the following specific aims are proposed Aim 1. To support developmental research projects in leukemia for future incorporation as fullSPORE projects and for applications for other major peer-reviewed funding. New research projects willbe solicited annually. A total of $300000 has been committed per year to support the combined CEP and DRP(including $50000 per year each for the CEP and DRP from SPORE funds and $200000 per year of matchinginstitutional funds). DRP awards will be for up to $70000 for 1 year with a competitive renewal allowed for asecond year of funding allowed. Funds may be used for salary support or laboratory supplies. Aim 2. To foster collaborations between basic and clinical researchers. The DRP chairs will facilitateinteraction between basic and clinical researchers through shared weekly meetings the annual SPOREretreat and small group meetings. Aim 3. To provide mentoring to junior faculty. All investigators submitting developmental researchprojects will receive a written scientific and statistical review and the DRP chairs will be available to discussthe projects in detail. Where appropriate mentors will be identified to work with junior faculty. All DRPawardees will present their research progress to the SPORE steering committee twice per year. Aim 4. To promote participation of women minorities and disabled investigators in clinicalleukemia research and to promote recruitment of minorities to clinical leukemia trials. +No NIH Category available Acute;Acute Myelocytic Leukemia;Address;Adoptive Cell Transfers;Adoptive Immunotherapy;Agonist;Allogenic;Biology;Blood;Bone Marrow;Cell Count;Cell Therapy;Cells;Cellular biology;Citrus;Clinic;Clinical;Clinical Research;Clinical Trials;Combination immunotherapy;Cyclophosphamide;Cytometry;Data;Disease remission;Disease-Free Survival;Dose;Effectiveness;Engraftment;Environment;Evaluable Disease;Exhibits;Future;Goals;Haptens;Hematopoietic;Human;Immune;Immune system;Immunology;Immunotherapy;Incidence;Interleukin-15;Leukemic Cell;Licensing;Ligands;Longevity;Mediating;Memory;Methods;NK cell therapy;Natural Killer Cell Immunotherapy;Natural Killer Cells;Natural Selections;Outcome;Patients;Phase;Phase II Clinical Trials;Phenotype;Population;Progression-Free Survivals;Property;Receptor Cell;Recurrent disease;Refractory;Regimen;Regulatory T-Lymphocyte;Relapse;Reporting;Research;Residual state;Resistance;Safety;Specialized Program of Research Excellence;Specificity;T-Lymphocyte;Testing;Translating;Transplantation;Virus Diseases;biomarker identification;chronic graft versus host disease;conditioning;cost;cytokine;experimental study;first-in-human;graft vs host disease;graft vs leukemia effect;hematopoietic cell transplantation;high risk;human study;immunotherapy clinical trials;improved;in vivo;leukemia;leukemia relapse;mortality;multidimensional data;novel;older patient;phase 1 study;phase 2 study;primary endpoint;response;response biomarker;safety testing;standard care;success;translational approach;tumor Project 5 - Memory-like NK cell augmented hematopoietic cell transplantation for AML. Project NarrativeOur research will test a new immunotherapy combination in a clinical trial for patients with acute myeloidleukemia utilizing both allogeneic hematopoietic cell (bone marrow) transplantation and same-donor memory-like natural killer cell adoptive therapy. Additional goals of this research are to identify correlates of leukemiaresponse or resistance to this new treatment. We also expect that this research will lead to new combinationimmunotherapy treatments for patients with leukemia in the future. NCI 10931079 9/20/23 0:00 PA-20-272 3P50CA171963-10S1 3 P50 CA 171963 10 S1 "KUZMIN, IGOR A" 9/3/13 0:00 6/30/24 0:00 8688 8417190 "FEHNIGER, TODD A" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 Research Centers 2023 238817 153580 85237 Project Summary/AbstractThe long-term goals of this project are to translate novel findings in the field of immunology into early phaseimmunotherapy clinical trials for patients with leukemia. Allogeneic hematopoietic cell transplantation (HCT) isa standard treatment for high-risk or relapsed AML and is potentially curative. However major barriers tosuccess in older AML patients include 1) an inability to tolerate intensive conditioning 2) disease relapse 3)graft-versus-host disease (GVHD) and 4) the lack of a suitable donor in many cases. One key immune playerin mediating the graft-versus-leukemia (GvL) effect that also potentially limits GVHD is the NK cell. Wehypothesize that new findings in NK cell biology can be translated to the clinic to improve the effectiveness andtolerability of HCT in older AML patients. Recent clinical studies have reported that HCT from an MHC-haploidentical donor (haplo-HCT) withmyeloablative conditioning regimens that incorporate post-HCT cyclophosphamide results in clinical outcomesthat are comparable to HCT from matched unrelated donors. However one major obstacle to treating AMLpatients with haplo-HCT is the large number of older patients that are only candidates for reduced-intensityconditioning (RIC) which results in lower treatment-related mortality but at the cost of a much higher incidenceof AML relapse and thus far poor long-term disease-free survival. To address this important hurdle in the fieldwe will augment HCT with same-donor memory-like NK cell adoptive immunotherapy during the immediatepost-HCT period to enhance GvL while potentially improving engraftment and minimizing GVHD. Reports have recently identified that NK cells exhibit memory-like properties following combined cytokinepre-activation. We and others have established that human memory-like NK cells respond robustly after asecond stimulation and have multiple anti-tumor properties. We have translated this into a cellular therapy forrelapsed/refractory (rel/ref) AML patients and have completed a phase 1 study. However one drawback of thisallogeneic NK cell therapy is its rejection by the recipient's recovering immune system after 2-3 weeksproviding a short window of opportunity for these NK cells to eliminate AML. To address this limitation in theNK immunotherapy field we will incorporate a donor-matched RIC HCT providing an ideal immune-compatibleenvironment for memory-like NK cells to expand and attack residual AML. In this proposal we will 1) test the safety and efficacy of augmenting RIC HCT with same-donor memory-like NK cell adoptive immunotherapy in a phase 2 clinical trial for patients with AML 2) define memory-like NKcell correlates of clinical response and elucidate key mechanisms important for memory-like NK cell anti-AMLresponses. These studies will lead to a new understanding of mechanisms whereby NK cells effectively attackAML and whereby AML resists NK cell therapy and hence strategies to improve memory-like NK cell anti-AML responses in future clinical trials. +No NIH Category available Adverse event;Basic Science;Bioinformatics;Biological Assay;Biometry;Biostatistics Core;Cancer Center;Clinical Research;Clinical Trials;Collaborations;Consult;Consultations;Core Facility;Data;Data Analyses;Databases;Development;Faculty;Genetic;Genomics;Hematopoietic;Individual;Link;Malignant Neoplasms;Methodology;Minority;Monitor;Output;Quality Control;Reporting;Research;Research Design;Research Personnel;Resource Sharing;Resources;Role;Sampling;Specialized Program of Research Excellence;Statistical Methods;Tissue Procurements;Training;Universities;Washington;anticancer research;career;data management;design;epidemiology study;experience;laboratory experiment;leukemia;medical schools;meetings;member;programs;research study;tool;translational clinical trial Core B - Biostatistics PROJECT NARRATIVEDuring recent decades the development and application of new statistical methodology for cancer researchhas resulted in an expanded role for statisticians. The Biostatistics Core provides the statistical bioinformaticsand computational support for all Leukemia SPORE investigators. The Core will support consultation andcollaboration on all aspects of study design database development and quality control and analysisinterpretation and presentation of data. NCI 10931075 9/20/23 0:00 PA-20-272 3P50CA171963-10S1 3 P50 CA 171963 10 S1 "KUZMIN, IGOR A" 9/3/13 0:00 6/30/24 0:00 8683 2110411 "COLDITZ, GRAHAM A." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 Research Centers 2023 137764 88594 49170 Project Summary/AbstractThe Biostatistics Core facility provides the statistical design data management and computational support forall Leukemia SPORE investigators. The Core will support consultation and collaboration on all aspects of studydesign database development and quality control and analysis and interpretation of data. The statisticiansparticipating in the Biostatistics Core bring established collaborations and a broad range of expertise andexperience in clinical trials laboratory experiments genetics and genomics research and epidemiologystudies. Dr. Graham Colditz Katherine Trinkaus and Feng Gao have extensive experience as investigatorsand statisticians within the Hematopoietic Development and Malignancy Program at Siteman. Dr. Petti bringsbioinformatics expertise and a record of collaboration with Drs. Welch and Ley. The team brings expertise inmonitoring minority accrual OnCore REDCap and data management/analysis for clinical studies. Collectivelythese individuals have affiliations at Washington University School of Medicine and the Siteman CancerCenter. The Biostatistics Core members have participated regularly in the investigator meetings for the SPOREprojects over the past 5 years and in design of developmental projects and career enrichment program wherethey provide support and training for junior investigators. The specific aims of this core are to; 1: Providebiostatistical and bioinformatics collaboration for Projects Developmental Research program and Cores in theSPORE to assure robust statistical methods support the projects; 2: Provide biostatistical and bioinformaticssupport and training to junior investigators through the CEP. +No NIH Category available Address;Advocacy;Animals;Clinical Trials;Collaborations;Communication;Contracts;Development;Documentation;Education;Educational workshop;Electronics;Ensure;Faculty;Family;Funding;Goals;Grant;Grant Review;Guidelines;Human;Institution;Journals;Manuscripts;Minority;Minority Participation;Monitor;Newsletter;Participant;Patients;Peer Review;Physicians;Pilot Projects;Preparation;Program Reviews;Progress Reports;Protocols documentation;PubMed;Publications;Publishing;Research;Research Personnel;Research Project Grants;Resource Sharing;Specialized Program of Research Excellence;Talents;Travel;United States National Institutes of Health;Universities;Washington;career;design;leukemia;meetings;member;peer;programs;recruit Administrative Core PROJECT NARRATIVE (2-3 SENTENCES)This shared resource will provide needed administrative support for the translational leukemia researchproposed in this SPORE and facilitate collaboration between other SPORE institutions. NCI 10931073 9/20/23 0:00 PA-20-272 3P50CA171963-10S1 3 P50 CA 171963 10 S1 "KUZMIN, IGOR A" 9/3/13 0:00 6/30/24 0:00 8681 1917511 "LINK, DANIEL C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 Research Centers 2023 103502 66561 36941 PROJECT SUMMARY/ABSTRACTThe Administration Core will provide executive oversight and administrative support for all of the projects andcores that comprise the Leukemia SPORE. The goal of the Administration Core is to monitor the activities of allof the program components to comply with all local and federal guideline for grant administration and tofacilitate communication and collaboration among the program members and with other Leukemia SPOREs.Accordingly the specific aims of the Administration Core are as follows:Aim 1. To facilitate intra- and inter-SPORE communication and collaboration.Aim 2. To provide administrative and fiscal oversight and support for all SPORE components.Aim 3. To coordinate administrative activities of the SPORE Developmental Research Program.Aim 4. To coordinate the SPORE Career Enhancement Program.Aim 5. To assist investigators with the preparation of scholarly presentations publications regulatorydocuments and all other SPORE-related paperwork.Aim 6. To enhance participation of minorities in SPORE activities.Aim 7. To ensure advocacy issues are addressed and included in all aspects of research with patientparticipants. +No NIH Category available Acute Myelocytic Leukemia;Adult;Advanced Malignant Neoplasm;Affect;Apoptotic;BCL-2 Protein;BCL2 gene;Biochemical;Bioinformatics;Biological;Biological Assay;Biology;Biometry;Bone Marrow Cells;CD34 gene;Cancer Center;Cancer Science;Cell Death;Cell Fraction;Cell Line;Cell Respiration;Cell Survival;Clinical;Clinical Trials;Complex;Cytometry;Data;Development;Disease;Doctor of Medicine;Dose;Drug Kinetics;Drug Targeting;Drug usage;Future;Gene Expression Profile;Genetic;Genomics;Genus Hippocampus;Glycolysis;Goals;Growth;Hematologic Neoplasms;Hematopoietic stem cells;Heterogeneity;Human;Idarubicin;In Vitro;Laboratories;Linear Regressions;Maintenance;Malignant Neoplasms;Maximum Tolerated Dose;Measures;Metabolic;Methodology;Methods;Mitochondria;Mitochondrial Proteins;Modality;Modeling;Molecular;Monitor;Mus;Normal Cell;Oncogenic;Oxidative Phosphorylation;Oxygen Consumption;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I Clinical Trials;Phase I/II Clinical Trial;Phenotype;Phosphorylation Inhibition;Population;Proliferating;Property;Proteomics;RNA;Recommendation;Recurrence;Refractory;Regression Analysis;Relapse;Residual state;Respiration;Respiratory Chain;Safety;Sampling;Series;Signal Pathway;Techniques;Testing;Texas;Therapeutic;Time;Toxic effect;Translating;Universities;University of Texas M D Anderson Cancer Center;Xenograft procedure;acute myeloid leukemia cell;arm;chemotherapy;co-clinical trial;cohort;design;drug discovery;experience;first-in-human;genetic profiling;improved;in vivo;inhibitor;leukemia;leukemia initiating cell;leukemic stem cell;metabolic profile;metabolomics;molecular subtypes;nano-string;nanomolar;nonlinear regression;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;preclinical study;response;response biomarker;stem cell population;targeted treatment;tumor;tumor metabolism Project 5: Targeting Oxidative Phosphorylation in AML PROJECT NARRATIVEA leukemia called AML cannot be cured by current treatments in more than half of adult patients. This projectwill test novel experimental drug affecting tumor metabolism alone and in combinations for suppression of AMLdisease development in laboratory models. Phase I/II clinical trial will examine safety and efficacy ofcombinations with standard chemotherapy or with targeted therapies in relapsed/refractory AML. NCI 10931070 9/20/23 0:00 PA-20-272 3P50CA100632-20S1 3 P50 CA 100632 20 S1 "KUZMIN, IGOR A" 9/1/23 0:00 8/31/24 0:00 7428 9974667 "DRAETTA, GIULIO FRANCESCO" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 286452 176822 109630 PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) comprises a genetically and clinically heterogeneous group ofaggressive hematological malignancies. Despite advances in molecular characterization of AML themajority of patients will relapse and die of their disease. In AML oxidative phosphorylation (OxPhos)generates intracellular energy and metabolic intermediates necessary to promote growth and supportsurvival. Unlike normal hematopoietic stem cells AML and leukemia stem cells (LCS) overexpress anti-apoptotic mitochondrial protein Bcl-2 rely on OxPhos and are unable to utilize glycolysis whenmitochondrial respiration is inhibited indicating that the maintenance of mitochondrial function isessential for AML survival. We have identified a novel potent nanomolar inhibitor of OxPhos (OxPhosi) IACS-010759selected from the series of more than 1000 compounds across distinct structural classes. IACS-010759has been found to inhibit complex I of OxPhos respiratory chain and block oxygen consumption. Our datademonstrated profound growth-inhibitory and pro-apoptotic effects of this agent in AML cell lines andprimary AML cells at low nM concentrations with minimal toxicity against normal BM cells. In turncombination of OxPhos inhibitors and Bcl-2 inhibitor venetoclax is synergistic in AML. Daily dosing ofIACS-010759 was well tolerated in mice demonstrated strong efficacy in the in vivo xenograft studiesutilizing the human AML patient-derived xenografts (PDX) and reduced phenotypically defined LSCfractions measured by novel technique of mass cytometry CyTOF. Administration of OxPhosi followingstandard chemotherapy extended survival in primary AML PDX model. A Phase I clinical trial of IACS-010759 in relapsed/refractory AML was recently launched at MDACC. We propose to test the hypothesis that OxPhos inhibition constitutes a novel therapeuticapproach that targets a unique metabolic vulnerability of AML; and that combined blockade ofmitochondrial respiration by OxPhos and Bcl-2 inhibitors will eliminate leukemia-initiating cells andproduce objective responses. We will establish biomarkers of response to OxPhosi in vitro including RNAand metabolomics signatures in a large series of primary AML with known genetic profiling and validatethese in the in vivo AML PDX models. We will further determine mechanisms of synergistic AML celldeath when OxPhos inhibition is primed by Bcl-2 blockade with venetoclax and characterize anti-AMLand anti-LSC efficacy of such combination. We will further metabolically profile AML cells survivingstandard chemotherapy and test the hypothesis that OxPhosi will reduce or eliminate residual survivingAML cells. These concepts will be translated into Phase 1/2 study of standard chemotherapy and of Bcl-2 inhibitor Venetoclax combined with IACS-010759 in patients with relapsed/refractory AML. +No NIH Category available Address;Basic Science;Bioinformatics;Biometry;Cancer Center;Clinical;Clinical Research;Clinical Trials;Collaborations;Collection;Communication;Conduct Clinical Trials;Confidentiality of Patient Information;Consultations;Data;Data Analyses;Data Collection;Data Management Resources;Data Security;Databases;Development;Doctor of Medicine;Ensure;Experimental Designs;Formulation;Futility;Genomics;Human Resources;Laboratory Study;Lateral;Methodology;Monitor;Multi-Institutional Clinical Trial;Patients;Process;Proteomics;Publications;Publishing;Quality Control;Reporting;Research;Research Design;Research Personnel;Resources;Safety;Statistical Data Interpretation;Statistical Models;Techniques;Texas;Translational Research;Universities;Writing;career;cost effective;data acquisition;data integration;data management;data quality;data resource;design;exome sequencing;experimental study;genome sequencing;genomic data;high dimensionality;high throughput analysis;innovation;laboratory experiment;leukemia;meetings;preclinical study;programs;prospective;research study;simulation;sound;symposium;transcriptome sequencing;whole genome Core 3: Biostatistics Data Management and Bioinformatics Project NarrativeThe Biostatistics and Bioinformatics Core provides consultation and collaboration in the design conductanalysis and interpretation of research studies in this SPORE helps them achieve their objectives andensures scientifically valid conclusions will be drawn. Effective formulation and application of efficacy futilityand safety monitoring rules for clinical trials will offer protection to patients. NCI 10931066 9/20/23 0:00 PA-20-272 3P50CA100632-20S1 3 P50 CA 100632 20 S1 "KUZMIN, IGOR A" 9/1/23 0:00 8/31/24 0:00 7423 8617368 "HUANG, XUELIN " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 161394 99626 61768 Project SummaryThe major objective of the Biostatistics and Bioinformatics Core (Core 3) is to provide centralized biostatisticsbioinformatics and database support for all Projects and Cores. Core 3 will provide guidance in the design andconduct of clinical trials and other experiments that arise from the ongoing research of the SPORE facilitateprospective collection entry quality control and integration of data for the basic science pre-clinical andclinical studies and provide bioinformatics data analysis of high-throughput and high-dimensional genomicsdata. We will provide innovative and tailored statistical modeling simulation techniques and data analyses forthe main projects developmental research and career enhancement projects and other cores to achieve theirspecific aims. We will conduct data analyses and prepare statistical reports for all experiments within allprojects ensure that the results of all projects are appropriately interpreted and assist all project investigatorsin the publication of scientific results. Core 3 will also be a resource for intra- and inter-SPORE collaborationsincluding study design and developing databases for multi-center clinical trials. +No NIH Category available Address;Administrator;Advocate;Award;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Caring;Cell Therapy;Clinic;Clinical;Clinical Trials;Collaborations;Communication;Complex;Consultations;Data;Decision Making;Development;Doctor of Medicine;Electronic Mail;Eligibility Determination;Ensure;Fox Chase Cancer Center;Grant;Infrastructure;Institution;Interdisciplinary Study;Laboratories;Leadership;Minority;Monitor;National Cancer Institute;Organ;Outcome;Pathology;Patients;Policies;Preparation;Prognosis;Progress Reports;Protocols documentation;Publications;Quality Control;Regulation;Reporting;Reproduction spores;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Site;Stem cell transplant;Strategic Planning;Supervision;Texas;Tissues;Translational Research;United States National Institutes of Health;Universities;University of Texas M D Anderson Cancer Center;Woman;Work;career;data management;data sharing;design;experience;improved;interdisciplinary collaboration;lectures;leukemia;meetings;novel;programs;quality assurance;recruit;screening;success;symposium;transplantation therapy;web site Administrative Core PROJECT NARRATIVE (Administrative Core)The Administrative Core provides the support and infrastructure for research and financial oversight; clear and open communications among all SPORE investigators patient advocates and developmental awardees; and regulatory monitoring to optimize the successful outcome of the translational research in leukemia. NCI 10931064 9/20/23 0:00 PA-20-272 3P50CA100632-20S1 3 P50 CA 100632 20 S1 "KUZMIN, IGOR A" 9/1/23 0:00 8/31/24 0:00 7421 7847414 "KONOPLEVA, MARINA Y" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 177359 109481 67878 PROJECT SUMMARY (ADMINISTRATIVE CORE) The Administrative Core provides essential support to the MD Anderson Cancer Center and Temple/Fox Chase Cancer Center Leukemia SPORE PIs and investigators to maximize success. It is co-directed by Drs. Hagop Kantarjian and Jean-Pierre Issa who co-chair the Executive Committee and provide overall supervision of five Projects two additional Cores Developmental Research (DRP) and Career Enhancement (CEP) Programs and scientific direction of the SPORE. The Core co-Directors rely on the extensive broad-based scientific research and SPORE experience of the Internal and External Advisory Boards in critical decision- making. Success of the complex interdisciplinary research in the SPORE depends on integration of diverse leukemia research approaches. The Core will overcome barriers to interdisciplinary collaboration and data sharing and will ensure a unified translational research effort. The SPORE is founded on planning integration and translational research efforts supported by this Core. Its leadership and staff will be responsible for monitoring/planning scientific activities; providing scientific direction; ensuring emphasis on translational research; ensuring interdisciplinary and inter-SPORE integration with major leukemia programs within/outside MD Anderson and other broad translational research activities; and providing optimal administrative and fiscal management. Specific responsibilities of the Administrative Core are: Oversee and monitor all SPORE activities; promote integration and communication among the SPORE-related clinical programs; monitor the scientific integrity of all research projects and grant awards; assure compliance with institutional governmental and National Cancer Institute regulations; oversee the fiscal and budgetary activities of the SPORE; coordinate data control quality assurance issues in conjunction with the Internal Advisory Board and the Biostatistics Data Management and Bioinformatics Core (Core 3); coordinate activities associated with clinical trials including design of protocols approval by regulatory bodies implementation and eligibility screening and assignment of patients to different studies; provide oversight and support for Core 3 and the Pathology and Tissue Core (Core 2); coordinate and manage meetings of the SPORE Executive Committee the Internal and External Advisory Boards monthly investigator meetings quarterly research meetings lectures and symposia; administer the DRP and the CEP; coordinate interdisciplinary and inter-SPORE interactions and exchanges/meetings with other Leukemia SPORE programs and investigators and other organ-site SPORE programs; administer the activities of the Patient Advocates; comply with and improve policies addressing recruitment and retention of women and minorities; organize seminars to bring to MD Anderson consultants and speakers with expertise in various clinical and laboratory aspects of leukemia research; maintain a Leukemia SPORE website focused on issues in leukemia translational research. +No NIH Category available Genomics;refractory cancer Refractory Cancers Biospecimen Acquisition and Genomic Characterization n/a NCI 10930763 261201500003I-P00009-26100072-1 N02 9/24/18 0:00 1/31/25 0:00 16231702 "BAVARVA, JASMIN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 258637 NCI Refractory Cancers Biospecimen Acquisition and Genomic Characterization 258637 +No NIH Category available Floor;Infrastructure IGF::OT::IGF Bldg. 469 1st Floor Refurbishment & Infrastructure n/a NCI 10930762 261201500003I-P00002-26100051-1 N01 9/18/17 0:00 5/17/19 0:00 15266031 "DELBRIDGE, MATTHEW " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 49491 NCI Bldg. 469 1st Floor Refurbishment & Infrastructure 49491 +No NIH Category available Core-002 n/a NCI 10930436 9/21/23 0:00 RFA-CA-21-054 7U54CA274375-02 7 U54 CA 274375 2 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 5694 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 4/20/23 0:00 8/31/23 0:00 Research Centers 2023 264891 249516 15375 No abstract available +No NIH Category available Project-006 n/a NCI 10930435 9/21/23 0:00 RFA-CA-21-054 7U54CA274375-02 7 U54 CA 274375 2 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 5693 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 4/20/23 0:00 8/31/23 0:00 Research Centers 2023 373786 358411 15375 No abstract available +No NIH Category available Project-005 n/a NCI 10930434 9/21/23 0:00 RFA-CA-21-054 7U54CA274375-02 7 U54 CA 274375 2 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 5692 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 4/20/23 0:00 8/31/23 0:00 Research Centers 2023 333010 206198 126812 No abstract available +No NIH Category available Project-004 n/a NCI 10930433 9/21/23 0:00 RFA-CA-21-054 7U54CA274375-02 7 U54 CA 274375 2 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 5691 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 4/20/23 0:00 8/31/23 0:00 Research Centers 2023 376087 360712 15375 No abstract available +No NIH Category available Affinity;Antibodies;Antibody Formation;Biological Assay;Clinical;Clinical Trials;Laboratories;Mass Spectrum Analysis;Measurement;Monitor;National Cancer Institute;Proteomics;Reagent;anticancer research;pre-clinical research;programs;tumor Proteomic and Antibody Production and Characterization n/a NCI 10929918 75N91019D00024-P00007-759102000029-1 N01 9/25/20 0:00 9/24/25 0:00 77873750 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 8178103 NCI The National Cancer Institute (NCI)s Clinical Proteomic Tumor Analysis Consortium (CPTAC) comprises of an Antibody Program that comprehensively characterizes affinity reagents for cancer research via its Antibody Characterization Laboratory (ACL) located at the Frederick National Laboratory for Cancer Research (FNLCR) in Frederick MD. Within the ACL a Proteomic Characterization Laboratory (PCL) pilot is to be established for comprehensive Mass Spectrometry (MS)-based proteomic characterization (global- and phospho-proteomes) and targeted (fit-for-purpose) assays. 8178103 +No NIH Category available ConProject-001 n/a NCI 10929913 9/15/23 0:00 PA-20-272 3P30CA014089-47S1 3 P30 CA 14089 47 S1 "HE, MIN" 12/1/96 0:00 11/30/24 0:00 5663 1875698 "LERMAN, CARYN " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2023 500000 500000 0 No abstract available +No NIH Category available Address;American;American Cancer Society;Architecture;Area;Assessment tool;Back;Behavior Therapy;Cancer Center;Cancer Patient;Caring;Categories;Certification;Chicago;Client;Clinic;Clinical;Clinical Management;Code;Communication;Communities;Complement;Complex;Computer software;Consensus;Consent Forms;Consult;Contracts;Data;Data Collection;Data Element;Data Reporting;Databases;Development;Devices;Diet;Education;Eligibility Determination;Ensure;Environment;Environmental Risk Factor;Epidemiology;Family;Family Cancer History;Fast Healthcare Interoperability Resources;Feedback;Funding;General Population;Genetic;Guidelines;Health;Health Insurance Portability and Accountability Act;Health Personnel;Health Technology;Health system;Healthcare;Healthcare Systems;Home;Hospitalization;Hypertension;Infrastructure;Institution;Insurance Carriers;Intelligence;Language;Laws;Life Style;Location;Malignant Neoplasms;Managed Care;Medical;Medical Care Team;Medical Device;Medical center;Monitor;National Comprehensive Cancer Network;Notification;Nurses;Obesity;Oncologist;Patient Care;Patient Self-Report;Patient risk;Patients;Persons;Phase;Physicians;Population;Prevention Guidelines;Prevention program;Preventive;Primary Care;Primary Care Physician;Privacy;Process;Production;Protocols documentation;Provider;Publishing;Recommendation;Recording of previous events;Reporting;Research;Research Personnel;Review Literature;Risk;Risk Assessment;Risk Factors;Running;Sampling;San Francisco;Schedule;Science;Secure;Security;Services;Stream;Surveys;Talents;Telemedicine;Testing;Tobacco use;United States Preventative Services Task Force;Update;Vaccines;Visit;Work;anticancer research;cancer diagnosis;cancer prevention;cancer risk;cancer type;care providers;cloud based;cost effective;data exchange;data integration;data management;design;digital health;digital healthcare;digital platform;digital tool;encryption;experience;feasibility testing;firewall;flexibility;genetic testing;health care service organization;high risk;indexing;individual patient;innovation;interest;malignant breast neoplasm;medical specialties;patient engagement;patient expectation;patient health information;patient navigation;primary care practice;primary care provider;privacy protection;programs;recruit;remote health care;remote patient monitoring;repository;risk prediction;risk stratification;routine screening;rural area;satisfaction;screening;service organization;software development;supplemental screening;systematic review;telehealth;tool;usability;user-friendly;web services TOPIC 453: A DIGITAL TOOL TO INTEGRATE CANCER PREVENTION WITHIN PRIMARY CARE Moonshot support n/a NCI 10929760 75N91023C00047-0-9999-1 N43 8/31/23 0:00 8/30/24 0:00 79342294 "CHEN, GRACE " Not Applicable Unavailable MCXNJJ93RDK7 MCXNJJ93RDK7 US -529894 LOS ALTOS CA Other Domestic Non-Profits 940245908 UNITED STATES N R and D Contracts 2023 392953 NCI LucidAct Inc. (LucidAct) is a Digital Health company that offers connected telemedicine and Remote Patient Monitoring (RPM) solutions specifically designed for patients that are non-tech savvy living in rural areas or having cultural and/or language barriers. We provide an end-to-end remote care management solution that combines connected medical devices telehealth and intelligent patient engagement into a single solution for healthcare organizations. LucidAct platform is cost effective responsive and user-friendly for allend-users including patients nurses and physicians. Under this NCI contract LucidAct will develop a digital tool for cancer prevention in which we will identify patients that are at high-risk by assessing all potential risk factors including family history genetics and environmental factors (tobacco use diet obesity etc.). We will offer science- and guideline-based recommendations to patients to engage in lifestyle changes to reduce cancer risk. LucidActs innovative workflow engine is customizable and configurable to manage complex care and to personalize recommendations to each individual patient. We have a team of healthcare and technology professionals that integrate expertise and healthcare data with PCP care and patient expectations to implement smart and usable solutions to complement and extend patient engagement beyond in-person visits. 392953 +No NIH Category available Active Sites;Binding;Biological;Breast Cancer Cell;CT26;Cancer Model;Cancer cell line;Cells;Clinic;Colon Carcinoma;Combined Modality Therapy;DNA Damage;Data;Development;Dose;Drug Industry;Exhibits;Immune system;Immunotherapeutic agent;Immunotherapy;In Vitro;MCF7 cell;Malignant Neoplasms;Modeling;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Phenotype;Positioning Attribute;Proteomics;RNA-Directed DNA Polymerase;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Resistance;Reverse Transcriptase Inhibitors;Small Business Innovation Research Grant;Stimulator of Interferon Genes;Telomerase;Telomerase Inhibitor;Toxic effect;anti-tumor immune response;cancer therapy;cancer type;conventional therapy;immune activation;immunogenic;improved;in vivo;inhibitor;lung cancer cell;preclinical development;response;senescence;standard of care;tumor SBIR Topic #446 Phase I -Development of Senotherapeutic Agents for Cancer Treatment n/a NCI 10929719 75N91023C00035-0-9999-1 N43 9/25/23 0:00 9/24/24 0:00 14098241 "FROST, GRANT B" Not Applicable 9 Unavailable 118430725 C95RHLDBCVB9 118430725 C95RHLDBCVB9 US 10067707 RIPTIDE THERAPEUTICS LLC EVANSTON IL Domestic For-Profits 602014110 UNITED STATES N R and D Contracts 2023 400000 NCI Cancer therapies that harness the immune system are best positioned to improve long-term survival but current immunotherapeutics suffer from nonresponse resistance and toxicity. Thus conventional therapies such as radiation remain the standard-of-care for most patients. A major drawback of radiation therapy (RT) is the creation of therapy induced senescent (TIS) cells that exhibit a pro-tumor senescence-associated secretory phenotype (SASP) state.However RT could be transformed into anti-tumor targeted immunotherapy using DNA damage response (DDR) inhibitors and/or senotherapeutic drugs. The pharmaceutical industry is pursuing DDR inhibitor + radiation combination therapies. But current DDR inhibitors lack precise cancer targeting and are often too toxic to normal tissue. The drug we will advance with this proposal will be a first-in-class irreversible inhibitor of telomerase reverse transcriptase (TERT) a uniquely cancer-specific DDR target thats in ~90% of tumors but negligible in normal tissue. In a proof-of-concept study the TERT inhibitor will be demonstrated as a potent radiosensitizer and senomorphic agent that induces an anti-tumor immune response in non-small cell lung cancer (NSCLC) in vivo. This should justify the full preclinical development of our TERT inhibitor which may eventually bring cancer-specific therapy sensitizers to the clinic for not just NSCLC but potentially most cancers. 400000 +No NIH Category available Algorithms;Applications Grants;Biological Assay;Cancer Detection;Clinical;Clinical Practice Guideline;Clinical Research;Detection;Development;Distant;Early Diagnosis;Follow-Up Studies;Future;Goals;Head and Neck Cancer;Head and Neck Neoplasms;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Health Care Costs;Incidence;Institution;Intervention;Laboratories;Larynx;Magnetic Resonance Imaging;Malignant Neoplasms;Medical;Medical Imaging;Methods;Methylation;MicroRNAs;National Comprehensive Cancer Network;Nature;Observational Study;Operative Surgical Procedures;Oral cavity;Outcome;PET/CT scan;Patients;Performance;Periodicals;Pharyngeal structure;Phase;Prevalence;Prospective Studies;Publishing;Radiation exposure;Radiation therapy;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Reproducibility;Research;Resource-limited setting;Roentgen Rays;Saliva;Screening for cancer;Specificity;Squamous cell carcinoma;System;Testing;Time;Tissue Sample;Tissues;Tongue;Tumor Burden;Tumor Tissue;Universities;Validation;Washington;biomarker development;biomarker panel;cancer biomarkers;cancer recurrence;clinical application;clinical practice;clinical translation;cohort;cost effective;detection method;experimental study;genomic locus;improved;meetings;microRNA biomarkers;patient population;preclinical study;prediction algorithm;prospective;random forest;rural area;saliva analysis;saliva sample;salivary assay;screening;success;testing access;tool;ultrasound Validation of a saliva test using methylated microRNAs for head and neck cancer recurrence PROJECT NARRATIVEThis application is to develop a robust non-invasive easy to access saliva test that is able to detect head andneck cancer recurrence in a timely and cost-effective way. Success in meeting the objective will enable itsclinical utility into current clinical practice as a Laboratory Developed Test. NCI 10929597 9/19/23 0:00 PAR-18-317 4UH3CA262045-03 4 UH3 CA 262045 3 "BHARTI, SANITA" 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-F(M1) 8518685 "LU, SHI-LONG " Not Applicable 6 OTOLARYNGOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 316128 NCI 203350 112859 PROJECT SUMMARYThe objective of this combined UH2/UH3 application is to develop a non-invasive accurate and cost-effectivesaliva-based test for early detection of squamous cell carcinoma of the head and neck (SCCHN) recurrence.SCCHN includes squamous cell carcinomas derived from oral cavity tongue pharynx and larynx. It is the 7thmost common cancer in US and worldwide by incidence and the 3rd in US and 4th worldwide by 5-yearprevalence. SCCHN is a biologically aggressive cancer in which high rates of recurrence (local locoregional ordistant) contribute significantly to poor patient survival. Current clinical practice methods for detection ofSCCHN recurrence are either subjective invasive hard to access not able to detect recurrence in a timelymanner or expensive. There is an unmet medical need for an objective non-invasive easy to access test thatis able to detect SCCHN recurrence in a timely and a cost-effective way. Our solution is HNKlear a non-invasive saliva-based candidate test for early detection of SCCHN recurrence. HNKlear incorporates a 7-methylated microRNA biomarker panel. The real-time nature of our test will provide more timely and precisedetection of SCCHN recurrence. In our published proof of concept studies HNKlear demonstrated 92%sensitivity and 98% specificity in ~300 SCCHN and control tissue samples and 85% sensitivity and 95% in~200 SCCHN and control saliva samples using continuous variables which supports the clinical translation ofthe test. We propose a combined UH2/UH3 application for the clinical translation of HNKlear. In the UH2phase we will analytically validate the test and algorithm in a pre-clinical study and in a new patient cohort.Success of this phase will let us lock down the test and cut-off when the milestone is met. We will then conducta clinical study in the UH3 phase to demonstrate the clinical validity of HNKlear for SCCHN recurrence in anobservational clinical follow-up study incorporating HNKlear into current clinical practice. Success of this phasewill generate robust evidence of the clinical validity of HNKlear for early detection of SCCHN recurrence andwill further enable clinical application of HNKlear as a Laboratory Developed Test. 316128 +No NIH Category available Investigate and inhibit microglia support of brain metastases n/a NCI 10929588 9/15/23 0:00 PA-20-272 3U54CA261717-03S1 3 U54 CA 261717 3 S1 "GRIL, BRUNILDE M" 9/21/21 0:00 8/31/24 0:00 ZCA1(M1) 6735 10312066 "HAYDEN GEPHART, MELANIE " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 175610 134750 40860 No abstract available +No NIH Category available Advanced Placement;Area;Awareness;Biological Sciences;Biomedical Research;Cancer Center;Cancer Research Project;Career Choice;Career Exploration;Chicago;Clinical;Communication;Communities;Complement;Comprehensive Cancer Center;Coupled;Dedications;Disparity;Diverse Workforce;Education;Educational workshop;Equipment;Face;Faculty;Family;Goals;Healthcare;High School Faculty;High School Student;Incidence;Individual;Industry;Institution;Knowledge;Laboratories;Leadership;Learning;Literature;Maintenance;Malignant Neoplasms;Medicine;Mentors;Population Group;Positioning Attribute;Research;Research Personnel;Research Training;Resources;Science;Series;Side;Students;System;Thinking;Training;Training Programs;Training Support;Underrepresented Populations;Underrepresented Students;Universities;Visit;Youth;anticancer research;cancer health disparity;career;career development;curriculum development;experience;faculty mentor;field trip;hands on research;high school;high school program;innovation;interest;lectures;medically underserved;mortality;next generation;outreach;peer coaching;population based;programs;science museum;skill acquisition;success;summer research;support network;symposium;teacher;undergraduate student;underserved urban area Chicago EYES (Educators and Youth Enjoy Science) on Cancer PROJECT NARRATIVEThe proposed project aims to create and maintain a diverse workforce in cancer research and the biosciencesthrough the creation of an innovative program Chicago EYES on Cancer for underrepresented high schoolstudents and undergraduates and high school educators who serve underrepresented students from theSouth Side of Chicago. Through innovative partnerships with community stakeholders this two-year cancerresearch program centers upon mentored research experiences curriculum development and outreach andwill provide the long-lasting support for trainees throughout their career journeys in cancer-related fields. NCI 10929574 9/15/23 0:00 PAR-17-059 3R25CA221767-05S1 3 R25 CA 221767 5 S1 "LOPEZ, BELEM G" 9/22/17 0:00 8/31/24 0:00 ZCA1-GRB-I(O1) 1891474 "DOLAN, MARY EILEEN" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 9/1/22 0:00 8/31/24 0:00 398 Other Research-Related 2023 150000 NCI 138889 11111 ABSTRACTChicagos South Side is one of the nations most medically underserved urban areas facing significantdisparities in the incidence and mortality of cancer. Eliminating or reducing cancer disparities in this communityrequires the commitment of a health care and biomedical research workforce that reflects the make-up of thelocal community and understands its underlying challenges. The University of Chicago MedicineComprehensive Cancer Center (UCCCC) considered a national leader among cancer centers in supportingthe training and career development of next-generation cancer researchers will serve as the epicenter of theproposed training program Chicago EYES (Educators and Youth Enjoy Science) on Cancer. The overallobjective of the program is to train high school students undergraduates and high school teachers throughresearch experiences and outreach thereby enhancing the diversity of the workforce necessary to meet thenations biomedical population-based and clinical cancer research needs. To accomplish this goal we will:1) Provide mentored research experiences and career/skills development to individuals from underrepresentedbackgrounds at the high school and undergraduate level to inspire and prepare them for research careers incancer and/or cancer disparities; 2) Provide high school teachers of underrepresented students with researchexperiences and curriculum development to prepare them to disseminate knowledge and generate excitementfor science; and 3) Create a strong and long-lasting network of support for students throughout their careerjourneys. In addition to assembling a dedicated mentor team for each individual providing hands-on researchtraining and curriculum development for their teachers and engaging families and communities for support wewill also develop a detailed tracking system to facilitate ongoing communication with program alumni andpersonalized assistance as needed. The experienced leadership team has the scientific educational andadministrative expertise coupled with an established track record of developing and evaluating cancerresearch pipeline programs necessary to successfully deliver the proposed program. Importantly the programwill facilitate strong partnerships with key institutions on Chicagos South Side namely the Museum of Scienceand Industry and diverse local high schools and institutions of higher learning. Together the leadership teamoutstanding mentors and committed partners are well positioned to successfully develop the programevaluate success and support the proposed activities to create and sustain a diverse cancer researchworkforce. Through Chicago EYES on Cancer the UCCCC is committed to positively impacting the scientificcareer development of South Side Chicago youth as well as the education and engagement of the localcommunity. 150000 +No NIH Category available Academic Training;Address;Area;Awareness;Bachelor's Degree;Boston;Cancer Burden;Cancer Center;Cancer Science;Clinical;Communities;Curiosities;Discipline of Nursing;Economically Deprived Population;Education;Educational Curriculum;Educational process of instructing;Ethics;Faculty;Family;Funding;Goals;Health;Health Professional;High School Student;Individual;Institution;Knowledge;Malignant Neoplasms;Measurable;Mentors;NCI Center for Cancer Research;Outcome;Participant;Pathway interactions;Population;Preparation;Process;Professional Competence;Research;Research Project Grants;STEM curriculum;STEM field;STEM research;Science;Science Technology Engineering and Mathematics;Scientist;Students;Supervision;Talents;Thinking;Training;Underrepresented Minority;Underrepresented Populations;United States;Universities;Work;anticancer research;cancer health disparity;career;community engagement;cultural competence;curriculum development;disadvantaged background;economic disparity;empowerment;experience;graduate school;high school;high school program;improved;innovation;interest;outreach;programs;research in practice;skill acquisition;skills;socioeconomic disadvantage;success;summer research;undergraduate student;university student Young Empowered Scientists for ContinUed Research Engagement (YES for CURE) YES for CURE Project NarrativeDana-Farber/Harvard Cancer Center (DF/HCC) requests R25 funding to support a multi-yearcancer and cancer disparities research experience and education program for high schoolstudents and undergraduates in the Boston area. The proposed Young Empowered Scientistsfor ContinUed Research Engagement (YES for CURE) Program aims to engage the scientificcuriosity and promote the academic success and future research careers of promising youngscientists from underrepresented communities. Increasing the engagement and retention ofyoung underrepresented scientists and health professionals in cancer and cancer disparitiesresearch will address the unequal burden of cancer in underrepresented populations. NCI 10929573 9/15/23 0:00 PAR-17-059 3R25CA221738-05S1 3 R25 CA 221738 5 S1 "LOPEZ, BELEM G" 9/19/17 0:00 8/31/24 0:00 ZCA1-GRB-I(O1) 1941096 "DECAPRIO, JAMES A." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/21 0:00 8/31/24 0:00 398 Other Research-Related 2023 200000 NCI 185185 14815 Young Empowered Scientists for ContinUed Research Engagement (YES for CURE) Project Summary Increasing the participation and retention of underrepresented minorities (URMs) in cancer-relatedscience technology engineering and mathematics (STEM) fields is critical for eliminating cancer disparitiesand improving cancer outcomes in the United States. The Dana-Farber/Harvard Cancer Center (DF/HCC)requests funding to address the shortfall of URMs and socioeconomically disadvantaged individuals engagedin cancer research related careers. Our specific goal is to engage the scientific curiosity and promote theacademic success and future research careers of promising young scientists from underrepresentedcommunities. For over 15 years DF/HCC has connected high school and college students fromunderrepresented populations to the world of cancer research by placing them in real research settings atHarvard University-affiliated cancer research institutions through a continuously funded P30 CURESupplement ending this year. More than two thirds of our alumni have gone on to complete STEM degrees andto successfully pursue science and health-related careers. We propose to continue and expand this workthrough the YES for CURE Program which will provide multi-year cancer and cancer disparities researchexperiences and educational programming for high school students and undergraduates in the Boston area.Each year 40 talented high school and college students from the Boston area selected through a competitiveapplication process will engage in a program comprised of three interrelated components: (1) mentored full-time summer research experiences in DF/HCC cancer research labs; (2) a year-round innovative Strategies forScience Success curriculum focused on building scientific and professional competency; and (3) communityand family engagement and outreach geared towards developing a supportive informed and engagednetwork who will nurture and empower program participants to achieve academic success and pursue careersin scientific research. These three components will be woven together into a comprehensive multi-yearexperience that will prime participants for further academic training and careers in scientific research and thepursuit of further program-independent research experiences. Further we will leverage our extensive studenttracking expertise to assess the impact of the YES for CURE Program on student interest in and preparationfor cancer and cancer disparities research careers and their scientific skills and concepts acquisition.By focusing on students at the beginning of their academic career we anticipate that the YES for CUREProgram will spark and nurture participant interest in pursuing science degrees and cancer research careersand increase the retention of underrepresented participants in cancer-related fields. 200000 +No NIH Category available Adoption;Awareness;Behavioral Research;Cancer Control;Communities;Community Health;Development;Electronic Mail;Health Services;Health behavior change;Intervention;Maintenance;National Cancer Institute;Population Group;Public Health;Research;Resources;Services;Testing;behavioral health;digital tool;mHealth;outreach;programs;smoking cessation;social media;usability;virtual;web site;webinar STAKEHOLDER ENGAGEMENT AND OUTREACH SUPPORT FOR HEALTH BEHAVIOR CHANGE AND CANCER CONTROL RESOURCES n/a NCI 10929022 91021A00291023F00001-0-0-1 N02 9/1/23 0:00 8/31/24 0:00 79342334 "KENDRICK, BRANDON " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2023 2038296 NCI The National Cancer Institute (NCI) has created smoking cessation and other behavioral health services for multiple population groups and diverse audiences. NCI needs to provide support for the ongoing development and maturation of these services adoption within the public health community and among target audiences and engagement with research communities to continue to evolve and advance mobile health interventions and the awareness of them. The primary objectives of this task are to provide interactive development and stakeholder engagement support for two initiatives: the SmokefreeVET (SFVET) program and the Behavioral Research program. This support includes web site development and maintenance outreach via social media and email refinement of digital tools through usability testing and stakeholder engagement through virtual webinars and seminars. 2038296 +No NIH Category available Affect;Cancer Control;Cancer Survivor;Cessation of life;Division of Cancer Control and Population Sciences;Grant;Incidence;Malignant Neoplasms;Mission;Morbidity - disease rate;National Cancer Institute;Population Sciences;Qualifying;Quality of life;Recurrence;Research;Risk Reduction;Scientific Advances and Accomplishments;Services;operation;programs;tool PROJECT MANAGEMENT TECHNICAL COMPUTING AND ADMINISTRATIVE SUPPORT SERVICES FOR THE DIVISION OF CANCER CONTROL AND POPULATION SCIENCES (DCCPS) n/a NCI 10929021 75N91021D00022-0-759102300001-1 N02 5/1/23 0:00 4/30/24 0:00 79155173 "LEAHY, ERIN " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2023 2229133 NCI The purpose of this requirement is to procure project management technical computing and administrative services on behalf of the Division of Cancer Control and Population Sciences (DCCPS) at the National Cancer Institute (NCI) to support the execution of its critical mission which aims to reduce the risk incidence morbidity and deaths from cancer and to enhance the quality of life for cancer survivors and others affected by cancer.As part of its recurring ongoing operations and to successfully execute its critical mission the DCCPS requires qualified program management technical computing and administrative services to manage its research portfolios which primarily include grants related to cancer control and population sciences the resulting tools products and scientific advances. 2229133 +No NIH Category available Area;Authorization documentation;Biomedical Computing;Cancer Burden;Collection;Development;Diagnosis;Division of Cancer Control and Population Sciences;Information Technology;Infrastructure;Knowledge;Maintenance;Malignant Neoplasms;Methodology;National Cancer Institute;Population;Prevention;Reporting;SEER Program;Services;Systems Development;authority;cancer care;data management;data registry;neoplasm registry;population based;statistics;survivorship;web site DIVISION OF CANCER CONTROL AND POPULATION SCIENCES (DCCPS) BIOMEDICAL COMPUTING SUPPORT SERVICES n/a NCI 10929019 75N91021D00017-0-759102300002-1 N02 7/3/23 0:00 7/2/24 0:00 79241416 "ANNETT, DAVID " Not Applicable 4 Unavailable 83656892 LGGFBF8YVA71 83656892 LGGFBF8YVA71 US 39.047465 -77.125049 1069201 "INFORMATION MANAGEMENT SERVICES, INC." CALVERTON MD Domestic For-Profits 207053407 UNITED STATES N R and D Contracts 2023 16650000 NCI The Division of Cancer Control and Population Sciences (DCCPS) of the National Cancer Institute (NCI) generates new knowledge about the burden of cancer on the US population and seeks to develop strategies in the continuum of cancer care including prevention diagnosis treatment and survivorship strategies. DCCPS also houses the Surveillance Epidemiology and End Results (SEER). The National Cancer Act of 1971 authorizes collection of cancer registry data and mandates that NCI report population-based statistics. The objective of this Task Order (TO) is to obtain non-research and development (non-R&D) information technology and analytic services to the DCCPS NCI. These services occur across several broad areas such as: analytical support systems development data management and maintenance computing infrastructure maintenance and support statistical methodology and programming support and support developing and maintaining websites. 16650000 +No NIH Category available Adjuvant Therapy;Adopted;Affect;Age;American Cancer Society;Area;Beds;Biological Markers;COVID-19 pandemic;Cancer Patient;Characteristics;Colorectal Cancer;Communities;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Hospitals;Immunotherapy;Incidence;Individual;Inpatients;Insurance Coverage;Knowledge;Laws;Malignant Neoplasms;Medical Records;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Outpatients;Palliative Care;Patients;Pattern;Patterns of Care;Physicians;Physicians' Offices;Race;Radiation therapy;Recommendation;Records;Recurrent Malignant Neoplasm;Reporting;Systemic Therapy;Testing;Time;United States;Update;cancer care;cancer diagnosis;cancer recurrence;cancer therapy;chemotherapy;clinical practice;comorbidity;hormone therapy;malignant breast neoplasm;pandemic potential;sex;targeted treatment;treatment pattern;working group PATTERNS OF CARE STUDY -DIAGNOSIS YEAR 2020 BREAST CANCER AND COLORECTAL CANCER n/a NCI 10928982 75N91023P00126-0-0-1 N02 12/23/22 0:00 12/22/23 0:00 79045974 "MANISCALCO, LAUREN " Not Applicable 2 Unavailable 782627814 M7KCJ79FAVH5 782627814 M7KCJ79FAVH5 US 29.957378 -90.082793 577902 LSU HEALTH SCIENCES CENTER NEW ORLEANS LA Domestic Higher Education 701127021 UNITED STATES N R and D Contracts 2023 90751 NCI NCI Patterns of Care Studies (POC) describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. POC are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To satisfy the directive and to update and enhance the utility of the POC Studies a working group including representatives from the NCIs Divisions of Cancer Control and Population Sciences and Cancer Treatment and Diagnosis and a representative from the American Cancer Society was developed to review knowledge gaps cancer therapy dissemination and to develop priority areas for study. This years Patterns of Care Study shall investigate state-of-the-art therapies for patients diagnosed with breast or colorectal cancer. 90751 +No NIH Category available Adjuvant Therapy;Adopted;Affect;Age;American Cancer Society;Area;Beds;Biological Markers;COVID-19 pandemic;Cancer Patient;Characteristics;Colorectal Cancer;Communities;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Hospitals;Immunotherapy;Incidence;Individual;Inpatients;Insurance Coverage;Knowledge;Laws;Malignant Neoplasms;Medical Records;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Outpatients;Palliative Care;Patients;Pattern;Patterns of Care;Physicians;Physicians' Offices;Race;Radiation therapy;Recommendation;Records;Recurrent Malignant Neoplasm;Reporting;Systemic Therapy;Testing;Time;United States;Update;cancer care;cancer diagnosis;cancer recurrence;cancer therapy;chemotherapy;clinical practice;comorbidity;hormone therapy;malignant breast neoplasm;pandemic potential;sex;targeted treatment;treatment pattern;working group NCI PATTERNS OF CARE STUDY: DIAGNOSIS YEAR (2020 BREAST CANCER AND COLORECTAL CANCER) n/a NCI 10928981 75N91023P00131-0-0-1 N02 12/23/22 0:00 12/22/23 0:00 79045983 "DOHERTY, JENNIFER " Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N R and D Contracts 2023 79740 NCI NCI Patterns of Care Studies (POC) describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. POC are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To satisfy the directive and to update and enhance the utility of the POC Studies a working group including representatives from the NCIs Divisions of Cancer Control and Population Sciences and Cancer Treatment and Diagnosis and a representative from the American Cancer Society was developed to review knowledge gaps cancer therapy dissemination and to develop priority areas for study. This years Patterns of Care Study shall investigate state-of-the-art therapies for patients diagnosed with breast or colorectal cancer. 79740 +No NIH Category available Adjuvant Therapy;Adopted;Affect;Age;American Cancer Society;Area;Beds;Biological Markers;COVID-19 pandemic;Cancer Patient;Characteristics;Colorectal Cancer;Communities;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Hospitals;Immunotherapy;Incidence;Individual;Inpatients;Insurance Coverage;Knowledge;Laws;Malignant Neoplasms;Medical Records;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Outpatients;Palliative Care;Patients;Pattern;Patterns of Care;Physicians;Physicians' Offices;Race;Radiation therapy;Recommendation;Records;Recurrent Malignant Neoplasm;Reporting;Systemic Therapy;Testing;Time;United States;Update;cancer care;cancer diagnosis;cancer recurrence;cancer therapy;chemotherapy;clinical practice;comorbidity;hormone therapy;malignant breast neoplasm;pandemic potential;sex;targeted treatment;treatment pattern;working group PATTERNS OF CARE STUDY: DIAGNOSIS YEAR 2020 (BREAST CANCER AND COLORECTAL CANCER) n/a NCI 10928980 75N91023P00120-0-0-1 N02 12/23/22 0:00 12/22/23 0:00 79045959 "GONSALVES, LOU " Not Applicable 1 Unavailable 807853791 RFZKKT5RU3F8 807853791 RFZKKT5RU3F8 US 41.763931 -72.689473 1854401 CONNECTICUT STATE DEPT OF PUBLIC HEALTH HARTFORD CT Other Domestic Non-Profits 61061367 UNITED STATES N R and D Contracts 2023 97457 NCI NCI Patterns of Care Studies (POC) describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. POC are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To satisfy the directive and to update and enhance the utility of the POC Studies a working group including representatives from the NCIs Divisions of Cancer Control and Population Sciences and Cancer Treatment and Diagnosis and a representative from the American Cancer Society was developed to review knowledge gaps cancer therapy dissemination and to develop priority areas for study. This years Patterns of Care Study shall investigate state-of-the-art therapies for patients diagnosed with breast or colorectal cancer. 97457 +No NIH Category available Adjuvant Therapy;Adopted;Affect;Age;American Cancer Society;Area;Beds;Biological Markers;COVID-19 pandemic;Cancer Patient;Characteristics;Colorectal Cancer;Communities;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Hospitals;Immunotherapy;Incidence;Individual;Inpatients;Insurance Coverage;Knowledge;Laws;Malignant Neoplasms;Medical Records;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Outpatients;Palliative Care;Patients;Pattern;Patterns of Care;Physicians;Physicians' Offices;Race;Radiation therapy;Recommendation;Records;Recurrent Malignant Neoplasm;Reporting;Systemic Therapy;Testing;Time;United States;Update;cancer care;cancer diagnosis;cancer recurrence;cancer therapy;chemotherapy;clinical practice;comorbidity;hormone therapy;malignant breast neoplasm;pandemic potential;sex;targeted treatment;treatment pattern;working group NCI PATTERNS OF CARE STUDIES FOR DIAGNOSIS YEAR 2020 BREAST CANCER AND COLORECTAL CANCER CASES n/a NCI 10928962 75N91023P00127-0-0-1 N02 12/23/22 0:00 12/22/23 0:00 79045977 "DURBIN, ERIC " Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N R and D Contracts 2023 173602 NCI NCI Patterns of Care Studies (POC) describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. POC are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To satisfy the directive and to update and enhance the utility of the POC Studies a working group including representatives from the NCIs Divisions of Cancer Control and Population Sciences and Cancer Treatment and Diagnosis and a representative from the American Cancer Society was developed to review knowledge gaps cancer therapy dissemination and to develop priority areas for study. This years Patterns of Care Study shall investigate state-of-the-art therapies for patients diagnosed with breast or colorectal cancer. 173602 +No NIH Category available Adjuvant Therapy;Adopted;Affect;Age;American Cancer Society;Area;Beds;Biological Markers;COVID-19 pandemic;Cancer Patient;Characteristics;Colorectal Cancer;Communities;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Documentation;Educational process of instructing;Ethnic Origin;Geographic Locations;Hospitals;Immunotherapy;Incidence;Individual;Inpatients;Insurance Coverage;Knowledge;Laws;Malignant Neoplasms;Medical Records;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Outpatients;Palliative Care;Patients;Pattern;Patterns of Care;Physicians;Physicians' Offices;Race;Radiation therapy;Recommendation;Records;Recurrent Malignant Neoplasm;Reporting;Systemic Therapy;Testing;Time;United States;Update;cancer care;cancer diagnosis;cancer recurrence;cancer therapy;chemotherapy;clinical practice;comorbidity;hormone therapy;malignant breast neoplasm;pandemic potential;sex;targeted treatment;treatment pattern;working group NCI PATTERNS OF CARE STUDY - DIAGNOSIS YEAR 2020 BREAST CANCER AND COLORECTAL CANCER n/a NCI 10928954 75N91023P00125-0-0-1 N02 12/23/22 0:00 12/22/23 0:00 79045971 "HERNANDEZ, BRENDA " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N R and D Contracts 2023 71719 NCI NCI Patterns of Care Studies (POC) describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. POC are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To satisfy the directive and to update and enhance the utility of the POC Studies a working group including representatives from the NCIs Divisions of Cancer Control and Population Sciences and Cancer Treatment and Diagnosis and a representative from the American Cancer Society was developed to review knowledge gaps cancer therapy dissemination and to develop priority areas for study. This years Patterns of Care Study shall investigate state-of-the-art therapies for patients diagnosed with breast or colorectal cancer. 71719 +No NIH Category available Academic advising;Area;Awareness;Basic Science;Behavioral;Behavioral Research;Biomedical Engineering;Biomedical Research;Black race;Cancer Biology;Career Choice;Clinical;Communities;Community Outreach;Data Analyses;Doctor of Philosophy;Education;Educational Curriculum;Educational workshop;Engineering;Enrollment;Ensure;Evaluation;Face;Faculty;Family;First Generation College Students;Funding;Future;Goals;Hispanic;Immersion;Immigrant family;Institution;Laboratories;Learning;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Measures;Mentors;Mentorship;Monitor;Nanotechnology;Performance;Postdoctoral Fellow;Preparation;Procedures;Process;Research;Research Design;Research Personnel;Research Training;Resources;Respondent;Series;Services;Socialization;Students;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underrepresented Minority;United States National Institutes of Health;Writing;anticancer research;cancer health disparity;cancer risk;career;career development;community partnership;design;education research;experience;graduate student;hands on research;improved;innovation;member;minority communities;prevent;programs;recruit;skills;social determinants;socioeconomic disadvantage;student mentoring;student participation;success;training opportunity;translational cancer research;undergraduate research;undergraduate student;underrepresented minority student Research Education Core Project NarrativeAs per solicitation PAR-18-767 (U54):Project Narrative: Do not complete. NCI 10928869 9/22/23 9:30 PA-20-272 3U54CA132378-15S2 3 U54 CA 132378 15 S2 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1 6927 1922320 "HUBBARD, KAREN " Not Applicable 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 199999 127388 72611 Research Education CoreSince the inception of the NIH-funded CCNY-MSK U54 in 2008 we have developed and implementedapproaches to engage and mentor students and early stage investigators in cancer research. We haveprovided undergraduate and graduate students with hands-on research experiences developed cancer-relatedcurricula and have provided professional socialization and mentorship for students appropriate to theiracademic level and career interests. Also we have monitored the progress of our early stage investigators andprovided individualized resources to ensure their success. To expand our transdisciplinary research focus wehave hired several faculty members for the Partnership that have been integrated into our training efforts. Inthis competitive renewal we plan to recruit additional faculty who will enhance our translational focus inresearch and training and will broaden opportunities for our students. The majority of students at CCNYespecially those from underrepresented minority communities come from socioeconomically disadvantagedfamilies. Many of our students are also first generation college students and/or from immigrant families. Ourprogram is designed to provide opportunities for them to successfully conduct biomedical and behavioralresearch at CCNY and MSK and to provide mentorship and guidance towards career decisions. Our overallgoals are to: 1) Increase the number of competitively trained underrepresented minority students whoenroll in MD PhD or MD/PhD programs and specifically 2) Increase the numbers of these studentswho pursue cancer-related research careers and 3) Increase the research competitiveness of U54early stage investigators (ESI) (postdoctoral scholars and junior faculty). We will accomplish these goals by:a) Providing experiential activities and opportunities support services and Partnership activities to improve andincrease students' engagement and performance in cancer research related areas and professions; b)Providing academic counseling advisement and mentoring to students to ensure that they are aware of theopportunities and prerequisites for careers in cancer research; c) Providing translational research experiences(basic sciences; engineering; behavioral; clinical; and community-based) for each student prior to graduation;d) Providing resources for the career development of early stage investigators as well as closely monitoringtheir progress; e) Implementing an evaluation plan to measure the results of all program activities and theutilization of all resources; g) Developing and submitting proposals with the goal of providing sustainability ofour educational and training initiatives such as through R25 and IRACDA mechanisms. +No NIH Category available Measuring and manipulating metabolic fluxes in the tumor microenvironment My long-term goal is measuring how metabolism is altered in cancer so we can targetcancer metabolism while sparing healthy tissues. Tumors are made up of a mix of cancerimmune and connective tissue cells which all play a role in supporting tumor growth but thefield has lacked approaches to measure metabolism in these different cell populations. I will usemetabolic flux measurement techniques I have developed to measure the metabolism of each ofthe cell types living within the tumor and to test whether targeting altered fluxes in cancer cellscould slow tumor growth. NCI 10928852 9/20/23 0:00 PA-20-188 4R00CA273517-02 4 R00 CA 273517 2 "WILLIS, KRISTINE AMALEE" 9/1/22 0:00 8/31/26 0:00 Transition to Independence Study Section (I)[NCI-I] 14491664 "BARTMAN, CAROLINE " Not Applicable 3 PHARMACOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 153231 95769 Measuring and manipulating metabolic fluxes in the tumor microenvironment Tumors have altered metabolism compared to normal tissues which suggests that druggingmetabolism could kill tumors while sparing healthy tissues. However tumor metabolism has chiefly beenmeasured in vitro while recent studies have showed that tumor metabolism in the body is distinct from in vitrosystems. Therefore the field needs approaches to measure tumor metabolic fluxes in vivo. During mypostdoctoral fellowship I developed methods to measure glycolytic and tricarboxylic acid cycle (TCA) flux invivo using kinetic infusion of isotope-labeled tracers. These approaches revealed that tumors have much lowerTCA flux than healthy tissues (5 mouse tumor models examined). Though the tumors had higher glycolytic fluxthan healthy tissues the total ATP production rate from glycolysis plus TCA cycle-driven oxidativephosphorylation was significantly lower in tumors than in healthy tissues. Moreover feeding mice a high-fatketogenic diet increased tumor TCA flux and slowed tumor growth synergistically when combined withchemotherapy. These findings raise two key questions. First since tumors in vivo are a mix of cancer cells and otherinfiltrating cells what is the metabolism of cancer cells versus immune cells or fibroblasts in tumors? Secondcan directly upregulating tumor TCA flux slow tumor growth? I propose first to combine my glycolysis and TCAcycle measuring techniques with immunomagnetic and sorting strategies to measure fluxes in cancer cellsimmune cells and fibroblasts (Aim 1). I will apply this strategy to melanoma a tumor type infiltrated by CD8 Tcells which can help control the tumor and to pancreatic adenocarcinoma a tumor type where fibroblasts andmyeloid cells can be even more abundant than cancer cells. Next I will directly upregulate TCA flux in tumorcells by using genetic and pharmacologic approaches: overexpressing the NADH uncoupler protein mito-LbNOX knockout of the TCA suppressor protein PDK and inhibition of PDK with dichloroacetate. I will confirmthat these strategies increase TCA flux using the method I developed and will test whether increased TCA fluxslows tumor growth in primary and metastatic breast tumors. Successful completion of these aims will revealthe metabolism of different cell populations in the tumor microenvironment and will test TCA upregulation as atherapeutic strategy in cancer. 249000 +No NIH Category available Body Regions;Classification;Clinical;Computer software;Consumption;Detection;Diagnostic;Disease;Effectiveness;Enlargement of lymph nodes;Evaluation;Foundations;Goals;Head and Neck Cancer;Image;Institution;Interobserver Variability;Link;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Modeling;Multimodal Imaging;Nodal;Oncology;Patients;Performance;Phase;Process;Safety;Small Business Innovation Research Grant;Time;cancer care;clinical practice;improved;lymph nodes;patient prognosis;success;treatment planning;usability;validation studies FY 2023 SBIR TOPIC 402 PHASE II. ENHANCE THE PERFORMANCE OF THE AI FOR LYMPH NODE DETECTION SEGMENTATION AND MEASUREMENTS AND DEVELOP ADDITIONAL AI MODELS FOR MALIGNANCY CLASSIFICATION LEVERAGING MU n/a NCI 10928777 75N91023C00051-0-9999-1 N44 9/18/23 0:00 9/17/25 0:00 79355872 "FENG, PH.D., XUE " Not Applicable 10 Unavailable 81070086 P14BWS94LNM9 81070086 P14BWS94LNM9 US 37.972254 -84.497342 10050207 "CARINA MEDICAL, LLC" Ashburn VA Domestic For-Profits 201484133 UNITED STATES N R and D Contracts 2023 2000000 NCI The correct determination of nodal metastatic disease is imperative for patient management in oncology since the patients prognosis and subsequent treatment are inherently linked to the stage of disease. Detection/segmentation of lymph node on imaging is a tedious highly time-consuming process that is inherently subject to intra-/inter-observer variability. Malignancy classification of the lymph node improves both the diagnostic evaluation and treatment planning. An AI software OncoAI was successfully developed in Phase I that automatically detects and segments enlarged lymph nodes from MRI and CT and enables fully automated RECIST measurements. The overall goal of this Phase II proposal is to further enhance the performance of the AI models for lymph node detection segmentation and measurements and develop additional AI models for malignancy classification leveraging multi-modality imaging. Software functionality and usability will be further improved towards seamless incorporation within the clinical workflow. Finally a multi-institutional validation study will be conducted to demonstrate the safety and effectiveness of OncoAI in clinical practice and obtain regulatory approval. The proposed aims will set a strong technical and regulatory foundation for OncoAI and contribute to not only commercial success but also broader impact to the clinical practice of cancer care. 2000000 +No NIH Category available Area;Cervical;Costa Rica;Dose;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human papilloma virus infection;Human papillomavirus 16;Immunization;Lesion;Malignant neoplasm of cervix uteri;Participant;Phase;Recommendation;Regimen;Risk;Running;Safety;Schedule;Vaccinated;cervical cancer prevention;cost;follow-up;girls;mortality;premalignant;prevent;prophylactic;vaccine acceptance;vaccine evaluation;vaccine trial Follow-up and Extended Follow-up of Participants - Option 1 n/a NCI 10928690 261201700012I-P00008-26100002-1 N01 4/6/18 0:00 9/15/24 0:00 15726313 "GONZALEZ-MAYA, PAULA " Not Applicable n/a Unavailable 853088008 KDL2VERNRKA5 853088008 KDL2VERNRKA5 CS 9.93333 -84.08333 10011285 FUNDACION INCIENSA SAN JOSE Unavailable 10108 COSTA RICA N R and D Contracts 2023 7761125 NCI This SOW describes activities related to NCIs Human Papillomavirus (HPV) vaccine evaluation efforts required for the next phase of these studies and will cover the follow-up of participants in both the existing trial of the bivalent HPV vaccine (Costa Rica Vaccine Trial or CVT) and the new trial aimed at evaluating the non-inferiority of 1 versus 2 doses of the HPV vaccines. Human papillomavirus (HPV) vaccination successfully prevents targeted HPV infections related precancerous lesions and ultimately has the potential to substantially reduce cervical and other HPV-related cancers. Despite the established efficacy and safety of the HPV vaccine most girls living in areas with the greatest risk for cervical cancer are not being vaccinated. The cost and logistical difficulties of the recommended multiple-dose schedule has been a significant impediment to vaccination uptake and the prevention of cervical cancer and its associated mortality. Task A and Task B will run concurrently. 7761125 +No NIH Category available Anniversary;Contracts;Data;Journal of the National Cancer Institute;Malignant Neoplasms;Monograph;National Cancer Institute;Oncology;Publishing;SEER Program;Universities;Work SUPPLEMENT TO THE JOURNAL OF THE NATIONAL CANCER INSTITUTE (JNCI) MONOGRAPHS 50TH ANNIVERSARY ISSUE OF THE NATIONAL CANCER INSTITUTE'S SEER PROGRAM: A HALF-CENTURY OF TURNING CANCER DATA INTO DISCOVE n/a NCI 10928344 75N91023P00669-0-0-1 N02 7/27/23 0:00 7/26/24 0:00 79286433 "HILL, ANDREW " Not Applicable Unavailable 78625208 KAKBVGTNBZ53 78625208 KAKBVGTNBZ53 US 40.684417 -73.951145 -409350 NEW YORK NY Other Domestic Non-Profits 100164308 UNITED STATES N R and D Contracts 2023 77580 NCI The SEER Program celebrates is 50th anniversary in 2023 and has contracted with the Oxford University Press to publish a special monograph within the Journal for the National Cancer Institute to include multiple articles on SEER current work underway within the SEER Program and how SEER has impacted oncology. 77580 +No NIH Category available Award;Colorado;Data;Data Collection;Data Sources;Malignant Childhood Neoplasm;Registries;Research Support;SEER Program;data management;neoplasm registry;programs;virtual SEER RESEARCH SUPPORT REGISTRIES PROGRAM LINKAGES AND DATA MANAGEMENT SUPPORT n/a NCI 10928342 75N91021D00004-0-759102300001-1 N01 9/15/23 0:00 9/14/24 0:00 79350384 "AREND, JOHN " Not Applicable 1 Unavailable 878208826 Y3WEW9MQ6NH5 878208826 Y3WEW9MQ6NH5 US 39.704841 -104.935864 1719501 COLORADO STATE DEPT/PUB HLTH & ENVIRONMT DENVER CO Other Domestic Non-Profits 802461523 UNITED STATES N R and D Contracts 2023 50099 NCI The SEER Program seeks to enhance the quality and completeness of data collected through the use of various projects and data sources. Colorado is a Research Support Registry and is not contracted to provide data twice annually to the SEER Program. However Research Support Registries are able to receive task order awards to participate in SEER supported projects. This task order award is to enable participation in two SEER supported projects as well as enable the use of SEER*DMS Lite for aspects of the data collection effort. 50099 +No NIH Category available California;Collection;Contracts;Malignant Neoplasms;Registries;SEER Program;Services;System;Testing;migration SUPPORT SERVICES FOR OVERSIGHT OF SEER*DMS MIGRATION FOR ALL THREE (3) CALIFORNIA SEER REGISTRIES TASK ORDER AGAINST IDIQ CONTRACT SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PROGRAM POP: 07/1 n/a NCI 10928339 75N91021D00003-0-759102300001-1 N01 11/15/22 0:00 11/14/24 0:00 79045944 "DAMESYN, MARK " Not Applicable 7 Unavailable 799150615 KD2JSY6LNMW7 799150615 KD2JSY6LNMW7 US 38.57482 -121.486435 10020847 CALIFORNIA DEPARTMENT OF PUBLIC HEALTH SACRAMENTO CA Other Domestic Non-Profits 958145015 UNITED STATES N R and D Contracts 2023 304876 NCI All SEER Core registries are required by contract to migrate to the SEER*DMS system for the collection and abstraction of cancer cases. There are three regional registries in California that are SEER Core registries but have not yet migrated to SEER*DMS. CDPH is the grantholder within the state of California and the regional registries are grantees to CDPH. In order to move forward with DMS migration NCI entered into a contract with CDPH to enable this migration effort to begin. 304876 +No NIH Category available 18 year old;Address;Adult;Affect;Area;Authorization documentation;Behavior;Communication;Competence;Comprehension;Data;Data Set;Decision Making;Demographic Factors;Disease;Disease Outcome;Education;Goals;Health;Health Benefit;Health Campaign;Health Information National Trends Survey;Health Policy;Health behavior;Individual;International;Legal;Literature;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Marketing;Measures;Mediating;Modified Risk Tobacco Product;Moods;Perception;Phase;Population;Population Assessment of Tobacco and Health;Postdoctoral Fellow;Predisposition;Prevention;Public Health;Recommendation;Reporting;Research;Research Project Grants;Risk;Smoking;Smoking Status;Subgroup;Surgeon;Techniques;Tobacco;Tobacco use;United States;Work;authority;cancer prevention;cigarette smoke;demographic disparity;disorder risk;high risk;mathematical ability;population health;prevent;preventable death;programs;risk perception;smoking cessation;tobacco products Use and Impact of Quantitative Information in Tobacco Risk Communications Project NarrativeExamining the relationship between numeracy (the ability to comprehend numerical information) risk perceptionof tobacco-related diseases and tobacco use behaviors has not yet been fully explored especially how theserelationships differ by demographic factors. This project will use nationally representative public data sets thatcontain tobacco use risk perception and numeracy measures to examine these relationships and determinewhich populations have low numeracy do not understand the risks involved with tobacco use and thus cannotmake fully informed decisions on using atobacco product. Identification of these subpopulations will allow tailorededucational campaign recommendations to be formed (involving numeracy-level appropriate risk communication)which will encourage healthy behaviors and decrease tobacco-related disease outcomes (such as cancer).. NCI 10928289 9/20/23 0:00 RFA-CA-21-059 4K00CA274655-03 4 K00 CA 274655 3 "ELJANNE, MARIAM" 9/20/23 0:00 8/31/27 0:00 ZCA1-PCRB-H(M1) 15557177 "DIAZ, DESTINY " Not Applicable 10 PUBLIC HEALTH & PREV MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 114113 NCI 105660 8453 Project Summary/AbstractIn 2019 nearly 14 of every 100 U.S. adults aged 18 years or older (14.0%) currently smoked cigarettes. Currentstrategies of tobacco use risk communication include using quantitative information to explain the likelihood thata consequenceof using aproduct will occur (to prevent initiation/encourage cessation) or to explain the reductionof risk when switching products or quitting. Although increasing numeracy (the ability to comprehend numericalinformation) can increase healthy behaviors there is a critical barrier in research regarding how numeracy isrelated to risk understanding and decision-making around tobacco use. There is also a gap regarding how thisrelationship differs by demographic factors. My overall project goal is to examine the interrelationships amongnumeracy risk perception tobacco product use cessation and product switching. These findings will provideevidence for tailored risk communications for individuals with differing numeracy levels. In the F99 phase wewill analyze cross-sectional and longitudinal data to determine whether or not there are associations amongnumeracy risk comprehension and tobacco use behaviors and if these associations differ by demographicfactors. We will use these findings to determine who should be targeted with public health campaigns and howrisk should be communicated. In the K00 phase we aim to find defend implement evaluate and modify publichealth campaign strategies to disseminate risk information. Risk communication will be tailored forsubpopulations with differing numeracy levels. Numeracy risk perception and tobacco-related behaviorsare expected to be associated providing evidence for tailored risk communication for subpopulationswith differing numeracy. By identifying which segments of the population have low numeracy (F99 phase)these specific subgroups can be targeted with tailored educational campaigns that communicate risk in anumeracy-level appropriate manner (K00 phase). This project will use both objective and subjective numeracymeasures different types of risk perceptionmeasures and will look at familiar (e.g. lung cancer) and less familiar(e.g. bladder cancer) tobacco-related health risks. We will analyze data from nationally representative data sets(The Population Assessment of Tobacco and Health (PATH) the Health information National Trends Survey(HINTS) and the Program for the International Assessment of Adult Competencies (PIAAC)) which containdemographic tobacco use risk perception and numeracy measures. The proposed studies will explorenumeracy and risk perception of tobacco-related diseases and will add to current literature in this area byfocusing on its relationship with specific tobacco-related health behaviors: use cessation and product switching.This research will advance the field of cancer prevention by exploring how tobacco product risk can best becommunicated to groups that need it. These communications will encourage healthy behaviors and decreasetobacco-related disease outcomes (such as cancer). The findings will help to inform who should be targeted withpublic health campaigns how risk should be communicated and whether these campaigns are efficient. 114113 +No NIH Category available Address;Adolescence;Adolescent and Young Adult;Adverse effects;Age;Age Months;Anxiety Disorders;Attention deficit hyperactivity disorder;Behavioral;California;Cannabinoids;Cannabis;Cannabis policy;Characteristics;Chronic;Cigarette;Community Health;Data;Data Sources;Dedications;Dependence;Development;Devices;Disease;Drug abuse;Drug usage;Electronics;Emotional;Expectancy;Flavoring;Friends;Future;Health;High School Student;Impulsivity;Inhalation;Intervention;JUUL;Left;Link;Malignant Neoplasms;Marijuana Smoking;Measures;Mediating;Modeling;Mood Disorders;Nicotine;Oils;Outcome;Participant;Pharmaceutical Preparations;Plants;Play;Policies;Policy Maker;Population;Prevention;Prevention strategy;Problem behavior;Proliferating;Public Health;Research;Rewards;Risk;Risk Factors;Role;Sampling;Schools;Science;Scientist;Self Administration;Smoking;Students;Surveys;THC concentration;Technology;Testing;Tobacco;Tobacco use;Tobacco-Related Carcinoma;Uncertainty;Variant;Waxes;Youth;adverse outcome;aged;biopsychosocial;catalyst;cigarette smoking;cohort;combustible tobacco;design;deviant;digital;distress tolerance;electronic cigarette use;emerging adult;experience;experimental study;flexibility;follow-up;habituation;heated tobacco products;high risk;high school;high-risk adolescents;marijuana use;marijuana vaping;multiple drug use;nicotine exposure;nicotine use;ninth grade;novel;prevent;programs;progression risk;public health priorities;public policy on tobacco;recruit;risk prediction;smoking initiation;social;stem;tobacco products;trait;uptake;vaping;vaping nicotine;young adult Vaping Nicotine and Cannabis Across Adolescence and Young Adulthood !PROJECT NARRATIVEVapingthe inhalation of vaporized substances from electronic deviceshas increased in adolescents andyoung adults (AYAs) including vaping of flavors only nicotine and cannabis products. This study will providenew essential information about whether low-risk AYAs begin nicotine and cannabis use via vaping and whethervaping may lead to adverse consequences including cigarette and cannabis smoking. This study will providepublic health officials with data regarding the potential adverse public health impact of AYA vaping and cleartargets for intervention to reduce AYA vaping and the health consequences that may follow. NCI 10927530 9/20/23 0:00 PA-18-484 3R01CA229617-05S2 3 R01 CA 229617 5 S2 "RODITIS, MARIA LEIA" 9/20/19 0:00 8/31/24 0:00 Addiction Risks and Mechanisms Study Section[ARM] 9227137 "LEVENTHAL, ADAM MATTHEW" "BARRINGTON-TRIMIS, JESSICA LOUISE" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 233333 NCI 141414 91919 !PROJECT SUMMARYIn 2015 evidence that e-cigarette use (vaping) in adolescents and young adults (AYAs) had increased andwas associated with increased risk of cigarette smoking initiation generated concern in the public health community. Subsequent research has left the field with several critical questions including: (1) whether vaping trulyhas a causal effect on smoking or merely reflects a common liability toward deviancy among high-risk AYAswith emotional or behavioral problems (2) whether an emerging wave of new vaping products including newnicotine products such as JUUL and an increasingly diverse class of products dedicated to vaping cannabisplant oils and waxes may increase the appeal and addictive potential of vaping and (3) whether there existparticular characteristics of vaping products and biopsychosocial mechanisms that underlie the risk of AYA vaping initiation progression and transition to other forms of drug use that could be targeted in prevention efforts.The uncertainties regarding the impact of AYA vaping have left policy officials with little evidence to determine ifAYA vaping should be prioritized in public health programs and if so the most effective strategies for prevention.To address the evidence needs and provide a flexible framework for future study of the impact of various vapingproducts on the AYA tobacco product and cannabis use burden we will test a novel catalyst model of AYAvaping. The catalyst model proposes two steps which we will evaluate in Aims 1 and 2 of this proposal. Step 1(AIM 1). To determine whether (a) AYAs with fewer emotional-behavioral risk factors who have been previouslydeterred from drug use in traditional (non-vaporized) forms are at risk of vaping initiation (b) the unique qualitiesand product features of vaping (e.g. concealability flavors appealing technology social acceptability low perceived harm) increase risk of AYA vaping and (c) features of vaping products disproportionately increase therisk of vaping initiation for low-risk AYAs. Step 2 (AIM 2). To determine whether (a) vaping increases the risk ofcross-product transitions involving initiation of other vaping products or combustible nicotine or cannabis aswell as increases risk of progression to problematic drug use outcomes including dependence poly-drug useand chronic drug use through early adulthood (b) rewarding effects from exposure to nicotine cannabinoidsand other product components (e.g. flavorings) increases risk of cross-product transitions and problematic druguse outcomes and (c) product characteristics modify this association. To test the model we will leverage datacollected from participants from age 14-19 (2013-2018) from our existing cohort and follow participants into earlyadulthood (20-23 from 2019-2023; N~2000). We will also recruit a new cohort of 9th grade students at age 14(N=2500) at the same schools as part of a cohort-sequential design that will apply causal inference analyticapproaches to determine whether observed associations are likely causal. Collectively this project will providecritical information regarding the priority and potential targets of public health efforts aimed at reducing the potential adverse public health effects resulting from AYA vaping including tobacco-related cancer. 233333 +No NIH Category available 3-Dimensional;Address;Advanced Malignant Neoplasm;Anti-CD47;Biological;Biological Models;Brain;Brain Neoplasms;Cells;Cellular Tropism;Characteristics;Clinical;Complement;Computer Models;Data;Data Set;Disease Progression;Early Diagnosis;Foundations;Genes;Genomic Instability;Genomics;Goals;Growth;Immune;Immunologic Surveillance;Incidence;Interruption;Link;Macrophage;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Metastatic Neoplasm to the Central Nervous System;Metastatic malignant neoplasm to brain;Microglia;Modeling;Molecular;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Neuroimmune;Neurologic;Operative Surgical Procedures;Organoids;Outcome;Pathway interactions;Patients;Peripheral;Play;Prediction of Response to Therapy;Primary Neoplasm;Prognostic Marker;Radiation;Radiation Tolerance;Radiation therapy;Recording of previous events;Resected;Resources;Risk;Role;Sampling;Selection for Treatments;Statistical Models;Testing;Treatment Efficacy;Treatment outcome;Tropism;biobank;brain cell;cancer genome;cancer type;cell type;differential expression;functional status;genomic biomarker;genomic data;genomic predictors;genomic signature;high risk;imaging modality;in vitro testing;insight;mortality;multiple omics;neuropathology;predictive marker;predictive modeling;pressure;programs;radioresistant;response;screening;standard of care;translational study;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Determine the mechanisms of acquired brain-tropism n/a NCI 10927525 9/18/23 0:00 RFA-CA-20-029 3U54CA261717-03S2 3 U54 CA 261717 3 S2 "GRIL, BRUNILDE M" 9/21/21 0:00 8/31/25 0:00 ZCA1-RTRB-Y 9200 8471415 "JI, HANLEE P" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144234 93416 50818 ABSTRACT PROJECT 1For patients with advanced cancer 30% will be afflicted with brain metastases the cause of devastatingneurologic morbidity and mortality. As a result the incidence of brain metastasis is 170000 new cases per ayear. For screening MRI is the preferred imaging modality for brain metastasis but is prohibitively expensiveand lacks relevant molecular information. We lack predictive models to identify patients at high risk for brainmetastases for screening as treatment efficacy and morbidity are linked to early detection. Treatment involvessurgery and radiotherapy but with a noticeable lack of prognostic or predictive biomarkers for diseaseprogression or treatment. Our central hypothesis is that there are common intrinsic features to the tumor andextrinsic features to the brain microenvironment relevant for cancer brain tropism and response to therapies.We will determine these features association to microglia (Project 2) and peripheral immune surveillance(Project 3) leveraging biological models to test these discoveries. We will identify intrinsic cellular genomicfeatures relevant for brain metastasis that can be generalized across many primary tumor types. Likewise wehypothesize there are extrinsic features of the tumor cellular milieu in the brain that facilitate the seeding andmaintenance of these metastases. (1) For determining extrinsic cellular tropism we will characterize the immunecell types states and function in the brain metastasis tumor microenvironment. Using single cell genomics wewill determine the distribution and functional status of the TME microglia and macrophages across different tumortypes that have CNS metastasis. In parallel using three dimensional organoids we will determine the TME-based macrophage response to anti-CD47 a potent modulator of macrophage function. Our results willdetermine the cellular genomic characteristics and functional status of TME macrophages/microglial cells andtheir regulatory states. (2) For intrinsic tropism factors we will analyze genomic features of the primary tumorand extrinsic features of the brain that indicate increased propensity for brain metastasis. We will conductgenomic sequencing analysis on matched primary and metachronous brain metastasis with complete treatmentexposure patient history. With this data we will determine critical cancer genome features such as the extent ofgenomic instability intratumoral clonal diversity treatment selection pressure and TME immune cell compositionthat are associated with brain metastatic risk. Our results will identify genomic biomarkers indicative of increasedrisk of brain metastasis across different tumor types. (3) Finally we will use the overlapping data set for intrinsicgenomic factors to determine if there are predictive genomic signatures of radioresistant brain metastases. Wehypothesize there are specific genomic features of primary tumors that are radiotherapy predictors. Theseresults may yield potential candidates for increasing sensitivity to this mode of treatment that can be tested invitro. +No NIH Category available Address;Advocate;Biology;Brain;Brain Neoplasms;CRISPR library;Cancer Patient;Clinical;Clinical Trials;Communication;Communities;Data;Dedications;Deterioration;Development;Diagnostic;Disease model;Ensure;Exclusion;Experimental Models;Foundations;Goals;Human;Immune system;Immunotherapy;In Vitro;Incidence;Interruption;Malignant Neoplasms;Mediator;Metastatic malignant neoplasm to brain;Methods;Microglia;Modeling;Molecular;Mus;Neoplasm Metastasis;Neuroimmune;Neurologic;Office of Administrative Management;Organoids;Patient risk;Patients;Physicians;Primary Neoplasm;Production;Productivity;Quality of life;Research;Sampling;Scientist;Site;Specimen;Technology;Testing;Therapeutic;Translating;Translations;Tropism;Tumor Tissue;Work;brain cell;data management;design;experience;glycoproteomics;high throughput screening;human disease;human tissue;improved;in vivo Model;innovation;insight;interest;multidisciplinary;neoplastic cell;neuropathology;new therapeutic target;novel;organizational structure;programs;synergism;therapy resistant;tool;tumor;tumor microenvironment Deconvolution and interruption of the cancer-neuro-immune axis facilitating brain metastases NARRATIVE OVERALL COMPONENTThe Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improvingour understanding and treatment of brain metastases a currently increasing yet underserved subset of cancerpatients. To accomplish the above goal we have developed highly innovative and complementary Projects tounderstand and disrupt the cancer-neuro-immune axis supporting brain metastases and created ResearchCores to make human specimens and cutting-edge technologies readily accessible to participating scientists.We expect to identify and target key mediators of brain metastasis with therapeutic benefit for patients. NCI 10927523 9/18/23 0:00 RFA-CA-20-029 3U54CA261717-03S2 3 U54 CA 261717 3 S2 "GRIL, BRUNILDE M" 9/21/21 0:00 8/31/25 0:00 ZCA1-RTRB-Y(M1) 10312066 "HAYDEN GEPHART, MELANIE " Not Applicable 16 NEUROSURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 144234 NCI 93416 50818 1 ABSTRACT OVERALL COMPONENT 2 3 The development of brain metastases experienced by up to 40% of cancer patients marks a clear inflection 4 point in survival and quality of life. The inaccessibility of brain tumor tissue has stymied progress in our 5 understanding and treatment of brain metastases and patients are regularly excluded from clinical trials. The 6 Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improving our 7 understanding and treatment of brain metastases a currently increasing yet underserved subset of cancer 8 patients. To accomplish the above goal we have: (1) designed an organizational structure that supports 9 scientists in our integrated work; (2) developed highly innovative and complementary Projects to understand10 and disrupt the cancer-neuro-immune axis supporting brain metastases; and (3) created NeuroPathology11 and ToolKit Cores to make human specimens and cutting-edge technologies readily accessible to participating12 scientists. We expect to identify and target key mediators of brain metastasis with therapeutic benefit for13 patients.14 Little is known about the distinct mechanisms that drive tumor cells to the brain and allow them to grow in this15 unique microenvironment supported in part by normal brain cells. Streamlined access to human brain16 specimens combined with innovations in modeling and manipulation of the tumor microenvironment create this17 collaborative opportunity for fundamental advancement. Our expert integrated team of productive collaborators18 aims to understand how the intrinsic features of tumor cells (Project 1) resident microglia (Project 2) and the19 systemic immune system (Project 3) contribute to the onset and progression of brain metastases. These projects20 are facilitated by centralized access to human patient brain metastases samples (NeuroPathology Core) and21 novel multiplexed analyses and disease modeling (ToolKit Core). Our multidisciplinary physician Consultant22 Network provides clinical insight and helps in the rapid translation of our findings into clinical trials for patients23 with brain metastases. The Administrative and Data Management Core will provide the operational support24 necessary to successfully achieve the goals of the program. Our Patient Advocates help to integrate and25 communicate our work to the greater scientific and patient communities.26 We have formed one of the few groups with the expertise interest and capacity to address the underlying27 mechanisms of and therapeutic opportunities for brain metastases. Only through this combined synergy would28 this project be possible. These innovative methods will ensure our findings are reflective of and translatable to29 the human disease enabling our multidisciplinary team to lay the foundation for diagnostic and therapeutic30 advancements. 144234 +No NIH Category available Administrative Core Improving Provider Announcement Communication Training (IMPACT) n/a NCI 10927505 9/12/23 0:00 PA-20-272 3P01CA250989-03S1 3 P01 CA 250989 3 S1 "KOBRIN, SARAH" 9/23/21 0:00 8/31/26 0:00 ZCA1(M1)-P 9944 8226109 "BREWER, NOEL TODD" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 125000 80386 44614 No abstract available +No NIH Category available Biliary;Biological;Chile;Cholelithiasis;Contractor;Data;Data Analyses;Data Collection;Development;Individual;Longitudinal Studies;Malignant neoplasm of gallbladder;Preparation;Procedures;Reporting;Services;Woman;cohort;computerized data processing;epidemiology study;prospective;sample collection SUPPORT SERVICES FOR INTEGRATIVE EPIDEMIOLOGICAL STUDIES n/a NCI 10927167 261201800043C-P00010-9999-1 N02 9/22/23 0:00 3/21/24 0:00 78875686 "GLASSHOFER, SARA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2023 176000 OD Chile Biliary Longitudinal Study (BiLS)The Chile BiLS is a cohort of women with gallstones in Chile which has among the highest rates of gallbladder cancer (GBC) in the world. By providing prospective data taken among individuals with gallstones and extensive biologic sample collection Chile BiLS offers the opportunity to study what drives the development of GBC in the context of gallstones.Contractor Support Activities include:Technical Requirements:Initial TransitionStudy Initiation and LiaisonPreparation of Study Materials and ProceduresSubject ID and Data CollectionData Preparation and Data ProcessingData Analysis QC and Reporting 176000 +No NIH Category available Agreement;Architecture;Authorization documentation;Behavioral;Caliber;Cancer Burden;Cancer Survivor;Cessation of life;Congresses;Contractor;Contracts;Country;Data;Data Analyses;Databases;Decision Making;Development;Diagnosis;Division of Cancer Control and Population Sciences;Epidemiology;Evaluation;Extramural Activities;Fostering;Funding;Grant;Incidence;Informatics;Information Systems;Information Technology;Instruction;Learning;Maintenance;Malignant Neoplasms;Monitor;National Cancer Institute;Population;Prevention;Process;Quality of life;Research;Research Priority;Research Project Grants;Risk Reduction;Services;Statutes and Laws;Strategic Planning;Training;United States;United States Dept. of Health and Human Services;United States National Institutes of Health;anticancer research;authority;cancer genetics;cancer therapy;design;effective intervention;operation;programs;social;trend Department of the Interior: Calibre Database Support Information Technology Services and Support (ITSS) n/a NCI 10926788 APC20006001-1-0-1 Y01 77897581 "COUNTS, ANDREW " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2023 2118562 NCI The National Cancer Institute (NCI) is part of the National Institutes of Health (NIH) and is an operating division within the Department of Health and Human Services (DHHS). The creation of the National Cancer Institute (NCI) was authorized by the U.S. Congress in the National Cancer Act of 1937. In this landmark legislation NCI was given a mandate to engage in certain fundamental activities: conducting and fostering cancer research; reviewing and approving grant-in-aid applications to support promising research projects on the causes prevention diagnosis and treatment of cancer; collecting analyzing and disseminating the results of cancer research conducted in the United States and in other countries; and providing training and instruction in the diagnosis and treatment of cancer. NCI is the world's pre-eminent cancer research organization.The Division of Cancer Control and Population Sciences (DCCPS) of the National Cancer Institute (NCI) National Institutes of Health (NIH) aim to reduce the risk incidence and deaths from cancer as well as to enhance the quality of life for cancer survivors. The Division conducts and supports an integrated program of the highest quality cancer genetic epidemiological behavioral social and surveillance research. The major objective of DCCPS is to fund extramural research. Extramural research is funded via grants contracts and interagency agreements. Under the direction of the Office of the Director the Information Technology Services Group (ITSG) provides Information Technology (IT) services and information systems for tracking and disseminating information relevant to the DCCPS Research Portfolio (grants contracts IAAs). DCCPS information systems provide data for analysis and decision-making that aids in evaluating what has been learned identifying new research priorities and strategies and effectively applying research discoveries to reduce the cancer burden. DCCPS is designed to:understand the causes and distribution of cancer in populationssupport the development and implementation of effective interventions andmonitor and explain cancer trends in all segments of the population.Central to these activities is the process of synthesis and decision-making that aids in:evaluating what has been learnedidentifying new priorities and strategies andeffectively applying research discoveries to reduce the cancer burden.Under the direction of the DCCPS Office of the Director the Information Technology Services Group (ITSG) provides Information Technology (IT) services and information systems for tracking and disseminating information relevant to the DCCPS Research Portfolio. Data and information from the systems are used by management and program staff to aide in analysis evaluation and decision-making regarding the existing research portfolio and to identify new research priorities and strategies that will effectively apply research discoveries to reduce the cancer burden. 2118562 +No NIH Category available Agreement;Area;Bioinformatics;Biological;Biological Assay;Biomedical Research;Biometry;Biotechnology;CCR;Clinical Research;Collaborations;Communities;Computer software;Contracts;Cost Savings;Data;Databases;Dedications;Dideoxy Chain Termination DNA Sequencing;Dissection;Educational workshop;Event;Funding;Funding Mechanisms;Gene Expression Profiling;Genomics;Image;Individual;Investigation;Journals;Laboratories;Licensing;Mammalian Cell;Mediation;Microarray Analysis;Pathway interactions;Principal Investigator;Private Sector;Protein Analysis;Proteins;Proteomics;Publications;Quality Control;Reporting;Research;Research Personnel;Resources;Sampling;Science;Scientist;Services;Signal Transduction;Statistical Data Interpretation;System;Technology;Technology Transfer;Training and Education;Transfer Agreement;Translational Research;United States National Institutes of Health;Work;assay development;bioinformatics tool;biomarker development;clinical application;cost;experimental study;high throughput analysis;high throughput technology;metabolomics;nano-string;nanoscale;new technology;next generation sequencing;programs;protein expression;response;single cell analysis;therapeutic target;transcriptomics Science and Technology Resources n/a NCI 10926727 1ZIKBC010857-17 1 ZIK BC 10857 17 9414524 "GOLDSTEIN, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3754416 NCI The OSTR is supporting a number of protein characterization analyses in mammalian cells for CCR investigators through the Laboratory of Protein Characterization at the Frederick National Lab (FNL). The OSTR continues to evaluate all commercially available platforms for protein and gene expression profiling and other high throughput technologies. To make the latest advances easily accessible to CCR researchers the OSTR has established a number of arrangements with companies providing genomic and metabolomic profiling technologies and services. These agreements have led to far lower cost and an efficient and easy way for CCR investigators to access these technologies. A subsidy program has been established providing subsidies to support CCR investigator access to advanced genomic proteomic metabolomic and bioinformatic technologies. This funding mechanism has helped to extend the limited research dollars available to CCR laboratories and has permitted our researchers to conduct experiments that might otherwise be cost prohibitive. Many of the funded projects have led to important publications in top-tier journals. Most recently the OSTR has been involved in CCR's efforts to access the next generation sequencing technologies including a single cell analysis facility located in building 41 which is available to all CCR investigators. In response to CCR's rapidly growing need to manage and analyze large sets of genomic and proteomic data the OSTR has developed several partnerships with bioinformatics companies. At significant cost savings to NCI OSTR negotiated a variety of license agreements on behalf of all NCI researchers for universal access to sophisticated tools for bioinformatic and statistical analysis of microarray experiments proteomic profiling studies and genomic analysis including next-generation sequencing data. In addition the OSTR has made a number of software applications for the investigation of pathways and biological association networks available to all of NCI. The OSTR continues to assess CCR's requirements in the area of bioinformatics and biostatistics. We continue to work with Leidos Biomedical Research (LBR) to create a CCR dedicated Bioinformatics Program to provide support to CCR investigators. Support for analysis of high throughput genomic and proteomic data is being made available through this new program which is located on the Bethesda campus. Most recently the OSTR has taken on the management of the NanoScale Proteomics section of the Collaborative Protein Technology Resource (reported separately). This Core is an open to all CCR investigators and dedicated to developing and implementing cutting-edge protein-based technologies to facilitate discovery translational and clinical research in CCR/NCI/NIH. This Core offers expertise and provides state-of-the-art technologies to accommodate the demands of CCR/NCI/NIH investigators for: Rapid and precise protein analysis; Comprehensive and quantitative cell signaling event dissection; Nanoscale quantitative proteomics assessment; Biomarker development and therapeutic target identification; and Clinical applicable assay development and applications. Most recently the CPTR is offering spatial proteomics and transcriptomics to the CCR community. The CCR Genomics Core (also reported separately) is also managed under OSTR. This facility is an open core for NGS and Sanger sequencing NanoString assays using the nCounter System and quality control assays for samples to be sequenced at the GC or the CCR Sequencing Facility. 3754416 +No NIH Category available Advocate;Awareness;Benchmarking;CCR;Clinical Research;Clinical Trials;Communication;Communities;Congresses;Development;Division of Cancer Epidemiology and Genetics;Division of Cancer Treatment and Diagnosis;Education and Outreach;Employee;Ensure;Facebook;Government;Instagram;Internet;Interview;Intramural Research;Journals;Malignant Neoplasms;Medical;Mission;Modernization;Multimedia;Paper;Peer Review;Press Releases;Printing;Production;Publications;Research;Research Personnel;Research Training;Scientific Advances and Accomplishments;Taxes;Twitter;United States National Institutes of Health;Visit;Work;Writing;career;clinical center;clinical training;design;interest;migration;news;programs;recruit;research faculty;social media;web site CCR Education and Outreach n/a NCI 10926725 1ZIJBC011285-14 1 ZIJ BC 11285 14 14732225 "BRONEZ, MELISSA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 912369 NCI This project is important because it provides the public Congress and scientific communities with an understanding of the research advances that are being made with U.S. tax dollars and about opportunities to participate in clinical research. The publication and dissemination of research results is a critical component of what the CCR Office of Communications does. Education and outreach are key components to our ability to achieve our mission. Accomplishments this year include: Production of the Milestones publication in print and on line which highlight CCR's most noteworthy research advances. Dozens of summaries of important peer-reviewed journal papers written for the lay public announcements of new clinical trials opening and other activities were shared via the website: https://ccr.cancer.gov/news. The office worked with NCI's Office of Communications and Public Liaison to disseminate press releases and to inform the media about the research progress being made within CCR. CCR also disseminated information to the public through social media including Twitter and NCI's Instagram and Facebook and through video production. The office also worked collaboratively with many other NCI and NIH organizations including the Division of Cancer Treatment and Diagnosis; Division of Cancer Epidemiology and Genetics; Office of Congressional and Government Relations; NCI at Frederick; the NIH Office of Intramural Research; and the NIH Clinical Center. The office supported visits by interested Congressional staff advocates scientific collaborators and dignitaries. A major undertaking this year was the migration of CCR's public website to an upgraded Drupal platform and a redesign that is modern and meets many of the federal website benchmarks. 912369 +No NIH Category available Biology;CCR;Equipment;Goals;Leadership;Modification;Procedures;Professional counselor;Recommendation;Research Personnel;Resources;Services;Strategic Planning;animal facility;square foot CCR New Space Activation n/a NCI 10926722 1ZIIBC011234-15 1 ZII BC 11234 15 10274929 "HENDERSON, DARREN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3220205 NCI On average my office relocates around 100 scientific and administrative staff every year. This number will fluctuate depending on the needs and priorities of the CCR leadership. These relocations involve the planning of new space renovations of existing space procurement and installation of furnishings planning and installation of LAN and telecom equipment and final punch list completion per end user. The renovation projects that occur on a yearly basis range from simple office modifications to complete refurbishment of lab space in the thousands of square feet. This includes basic biology labs computational spaces and in some cases animal facility upgrades. The need for renovations and relocations for the scientific staff is driven by the strategic planning between my office and the CCR leadership as well as recommendations from the Board of Scientific Counselors. 3220205 +No NIH Category available Bioinformatics;Breast Cancer Model;ChIP-seq;Chromatin Interaction Analysis by Paired-End Tag Sequencing;Collaborations;Complex;Computing Methodologies;Data;Data Analyses;Data Set;Epigenetic Process;Gene Expression;Genetic;Genome;Germ-Line Mutation;Goals;Machine Learning;Metastatic Neoplasm to the Lung;Methylation;Modeling;Molecular;Mus;Neoplasm Metastasis;Patients;Post-Transcriptional Regulation;Primary Neoplasm;Proteomics;Public Domains;RNA immunoprecipitation sequencing;Research;Research Personnel;Series;Somatic Mutation;The Cancer Genome Atlas;Tissues;Variant;Work;bisulfite sequencing;deep learning;dynamic system;empowerment;exome sequencing;genetic analysis;genome sequencing;interest;mathematical model;melanoma;metabolomics;transcriptome sequencing;treatment response;tumor progression;whole genome Integrated analyses of genetics epigenetics and gene expression n/a NCI 10926719 1ZIHBC011703-08 1 ZIH BC 11703 8 9692363 "LEE, MAXWELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1112396 NCI We have worked with many high-throughput datasets including the data generated by NCI investigators and those from public domains. In particular we have worked with a series of mouse mammary tumor models and melanoma models with the data generated by many NCI investigators. The data span many platforms including whole genome sequencing exome sequencing RNAseq DHS ChIP-seq bisulfite-sequencing ChIA-PET RIP-seq RPPA metabolomics and involve multiple tissues primary tumors and lung metastasis. We are currently doing integrated analyses including integrating sequence variants with DHS and gene expression; integrating methylation with gene expression and genome sequence features; integrating gene expression with therapeutic response data. Similarly we have also conducted integrated analyses for TCGA data involving collaborations with many NCI investigators. We are also developing bioinformatics machine learning computational methods and mathematical modeling to empower the data analyses. 1112396 +No NIH Category available Animals;Bioinformatics;Budgets;Clinical Research;Clinical Trials;Collaborations;Collection;Computer software;Data;Data Analyses;Data Collection;Data Storage and Retrieval;Databases;Development;Disease;Division of Cancer Epidemiology and Genetics;Documentation;Engineering;Equipment and supply inventories;Funding;Future;Goals;Human;Human Resources;Information Technology;Institutional Review Boards;Iris;Life Cycle Stages;Medical;Methods;NCI Center for Cancer Research;Online Systems;Postdoctoral Fellow;Principal Investigator;Process;Protocols documentation;Qualifying;Research;Research Personnel;Series;Site;Standardization;Study Subject;System;Systems Analysis;Technology;Time;Tissues;United States National Institutes of Health;Validation;cancer type;clinical center;clinical trial participant;clinical trial protocol;design;lectures;prevent;programs;symposium;web app;web site;website development;wiki Support of NCI CCR Clinical Research and Bioinformatics n/a NCI 10926718 1ZIHBC011235-15 1 ZIH BC 11235 15 14732217 "LEVINE, JASON " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 5246178 NCI This program is involved in many aspects of information technology support for the NCI Center for Cancer Research (CCR). Projects which we develop and/or maintain include the following: 1) Labmatrix a tissue research and inventory system for managing both the collection and storage of tissues as well as data resulting from the research analysis of these tissues. Tissues are from numerous types of cancers and other diseases. 2) iRIS a protocol lifecycle management system used for all CCR human and animal protocols as well as DCEG Special Studies IRB-managed protocols. 3) CCR Protocol View a website for NCI and NIH Clinical Center distribution of our clinical trials protocols. 4) Confluence wiki which facilitates standardized documentation collaboration and simple website development for CCR scientific and administrative staff. Confluence acts as an interface to our DB Quick technology allowing ultra fast development of simple web-based database applications. 5) JIRA issue management software used to support those groups in the CCR that need to manage user requests. 6) Future Fellows a web application for the collection and review of C.V.s submitted by potential postdoctoral fellows. 7) Budget Management System used to allocate funds to CCR principal investigators and core research groups. 8) Redesign and reengineering of the CCR website to a Drupal-based site. 9) CCR Referrals. This provides a standardized way to manage potential clinical trial participants and their medical information as it pertains to being qualified to participate in CCR clinical trials. 10) PA Tracker for the tracking of human resource packages through the approval process. 11) Video conference support for scientific presentations including the CCR Grand Rounds Lecture series as well as many smaller scientific collaborations. 11) Section 508 compliance of CCR-managed websites. 12) Scribe a method of collecting study data directly from study subjects and having that data go through real-time validation and entry into a researcher's data collection system. 5246178 +No NIH Category available Address;Adjuvant;Animals;Antineoplastic Agents;Biological;Biotechnology;CCR;Cancer Biology;Canis familiaris;Clinical;Clinical Protocols;Clinical Trials;Collaborations;Common Terminology Criteria for Adverse Events;Communities;Complement;Complement 3d;Conceptions;Contracts;Data;Data Reporting;Development;Development Plans;Drug Industry;Enrollment;Extramural Activities;Foundations;Friends;Goals;Good Clinical Practice;Human;Infrastructure;Institution;Leadership;Lymphoma;Malignant Neoplasms;Multi-Institutional Clinical Trial;Nature;North America;Oncologist;Oncology;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Play;Positioning Attribute;Process;Property;Protocols documentation;Publications;Publishing;Reporting;Research Personnel;Resources;Rewards;Risk;Role;Structure;System;TOP1 gene;Therapeutic;Therapeutic Agents;Time;Translation Process;Update;Veterinary Schools;Work;anticancer research;bridge program;cancer clinical trial;catalyst;comparative;cost;data management;design;drug development;inhibitor;mTOR inhibition;member;novel;novel anticancer drug;novel therapeutics;oncology program;oncology trial;osteosarcoma;pet animal;pharmacokinetics and pharmacodynamics;programs Comparative Oncology Trials Consortium n/a NCI 10926715 1ZIGBC011689-08 1 ZIG BC 11689 8 14280471 "LEBLANC, AMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 113840 NCI "The core component of the COP is the Comparative Oncology Trials Consortium (NCI-COTC) which is an infrastructure uniting study sponsors such as pharmaceutical and biotechnology companies with 24 academic veterinary centers within North America to support multicenter clinical trials of investigational therapeutics wherein centralized trial support and data management is provided by the NCI. This clinical trial infrastructure supports the integration of pet dogs with cancer into the development path of new cancer drugs. The COTC initiates pet animal trials in collaboration with other NCI investigators academic institutions and/or the pharmaceutical industry. These trials are implemented through the collective caseloads of the consortium membership with COTC member institutions united through a single Memorandum of Understanding (MOU). These trials are typically small and focused on relevant biological endpoints associated with drug development. The pet animal trials are intended to answer specific questions regarding the properties of a drug and results are to be rapidly integrated into the development plans for novel therapeutic agents by the sponsor. The data generated through these studies are available to COTC members to facilitate larger investigator-initiated pet animal trials that may further complement this translational process. The COP provides leadership oversight and management of trials. Trial sponsors most often pharmaceutical companies support the clinical costs of studies conducted by the COTC. This support is paid directly to COTC centers by the sponsor through collectively defined contracts and this process has been streamlined so as to not create a barrier to the trial. A requirement is that the scientific question related to human drug development must be explicitly and clearly stated in the protocol. Due to the unique positioning of the COP the framework of these questions is usually guided by the COP as many outside investigators are unfamiliar with this process. Trials conducted by the COTC are designed to include clinical and biological endpoints i.e. pharmacokinetics and pharmacodynamics so as to optimally inform the design of early phase human trials and assist in the difficult transitions between early and later phase human trials. The process of trial initiation and scientific development is led by the COP but involves detailed and iterative discussions with the trial sponsor and COTC investigators. The infrastructure that exists to implement trials within the COTC is leveraged against existing structures within the CCR. For example in collaboration with Jeff Shilling/Pamela Asangong (CCR) we maintain a ""dog friendly"" version of the CCR's C3D (Oracle Clinical) data reporting system. This allows real-time data entry and review under Good Clinical Practice (GCP) by COTC investigators and sponsors exactly analogous to the forms used in human trials. This enables sponsors to quickly assess study results and use them in FDA submissions. The first completed COTC trial was published in 2009 and the 30th trial concept is currently open for enrollment. The detail and scientific rigor mandated for COTC studies is exemplified in our trial protocols. Examples of our open trial protocols are provided under Section V/Clinical Protocol Summary. Despite the progress made in the field of comparative oncology the concept of evaluating new therapeutics in large animals that naturally develop cancer and share strong similarities to human cancers is still considered novel. A significant need in the field is to present this opportunity its risks and potential rewards to various stakeholders not least of which is Pharma. Not all questions should or can be asked through this approach and thus COP plays an important role in providing stewardship over these resources. This expertise has recently been disseminated in the form of a Perspectives piece in Clinical Cancer Research addressing the questions and associated value of comparative oncology studies as well as an invited review in Nature Reviews Cancer. With regard to specific clinical trial activities we recently published the results of a Morris Animal Foundation trial that evaluated adjuvant mTOR inhibition as an anti-metastatic approach in canine osteosarcoma as well as an NCI-sponsored clinical trial of 3 novel TOP1 inhibitors in canine lymphoma. The results of this publication directly impacted and informed the IND submissions for these agents to be assessed in the human Phase 1 setting. Finally we recently worked with our team of extramural COTC investigators to publish an updated version of the Veterinary Common Terminology Criteria for Adverse Events (V-CTCAE) to harmonize standard for AE reporting across comparative oncology studies conducted in our program and across the community." 113840 +No NIH Category available Acquired Immunodeficiency Syndrome;Acute;Animal Experimentation;Animal Model;Animals;B-Cell Lymphomas;Basal Cell;Basic Science;Brain;Breast;Cervical;Clinical;Colon;Communities;Development;Fostering;Future;Genetically Engineered Mouse;HIV;HIV/AIDS;Head and neck structure;Hematopoietic Neoplasms;Image;Intramural Research Program;Kidney;Liver;Lung;Lymphoma;Malignant Neoplasms;Molecular Target;Multiple Myeloma;Myelogenous;NCI Center for Cancer Research;National Cancer Institute;Ovarian;Pancreas;Plasma Cells;Pre-Clinical Model;Preclinical Testing;Principal Investigator;Prostate;Rana;Rattus;Research;Research Personnel;Skin;Skin Neoplasms;Squamous cell carcinoma;Thyroid Gland;Training and Education;Validation;Zebrafish;animal resource;melanoma;nonhuman primate;novel;pre-clinical;pre-clinical research;programs;technology development Basic and Preclinical Animal Models in support of Cancer and HIV-AIDS Research n/a NCI 10926713 1ZIGBC010856-17 1 ZIG BC 10856 17 9414522 "CUSTER, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 17789808 NCI The Center for Cancer Resarch animal program fosters cutting edge basic and preclinical research for creation and use of novel genetically engineered mouse models as well as other animal models including non-human primates rats zebrafish frogs etc. for cancer and HIV/AIDS. The program determines needs of CCR Principal Investigators seeks to fulfill them and facilitates their implementation. The program provides animal resources training and education imaging and technology development in support of moving basic science discoveries to the clinical setting. Keywords: preclinical models molecular targets cancers: including plasma cell myeloma acute myeloid lymphoma B cell lymphoma breast lung kidney prostate pancreas thyroid brain colon head and neck liver melanoma skin cervical ovarian AIDS HIV molecular targets 17789808 +No NIH Category available Address;Area;Basic Science;Beds;Biology;CCR;Cancer Biology;Cancer Model;Chest;Clinical;Clinical Data;Clinical Management;Clinical Research;Clinical Services;Clinical Trials;Communication;Conduct Clinical Trials;Course Content;Data Analyses;Dedications;Diffuse gastric cancer;Disease;Educational Curriculum;Educational process of instructing;Endocrine;Endocrine Surgical Procedures;Epigenetic Process;Evaluation;Exposure to;Fellowship;Foundations;Funding;Future;Gastrointestinal Stromal Tumors;Hepatobiliary;Hospitals;Image;Inherited;International;Laboratories;Literature;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of adrenal cortex;Malignant neoplasm of thorax;Mesothelioma;Methods;Modeling;Modernization;Molecular;National Cancer Institute;Neoplasm Metastasis;Neuroendocrine Carcinoma;Neuroendocrine Tumors;Oncology;Operative Surgical Procedures;Oral;Outpatients;Participant;Patient Care;Patients;Peritoneal;Postoperative Care;Predisposition;Research;Research Project Grants;Rotation;Science;Scientist;Series;Speed;Statistical Data Interpretation;Surface;Surgeon;Surgical Oncologist;Surgical Oncology;Syndrome;Thoracic Surgical Procedures;Tissues;Training;Training Programs;Translational Research;Treatment Protocols;United States National Institutes of Health;Writing;cancer therapy;clinical care;clinical center;clinical training;design;expectation;experience;experimental study;follow-up;gastrointestinal;graduate medical education;interest;laboratory experience;lectures;meetings;molecular oncology;multidisciplinary;next generation;participant enrollment;programs;symposium;therapeutic miRNA;translational study;tumor Surgical Oncology Program Training Program n/a NCI 10926711 1ZIEBC012097-02 1 ZIE BC 12097 2 78858651 "BLAKELY, ANDREW " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4434842 NCI Research Component This includes 18 months of bench laboratory experience in one of the many NCI laboratories with the option to extend for an additional year. In addition Fellows participate in clinical research projects and have first-hand exposure to the design and conduct of clinical trials including statistical analysis of clinical data. Previous Surgical Oncology Research Fellows have gained experiences in the following research tracks among others: - Surgical Oncology: Metastasis biology modeling and analysis hereditary diffuse gastric cancer syndrome wild-type gastrointestinal stromal tumors - Thoracic Surgery: Epigenetics of thoracic malignancies tumor predisposition syndrome microRNA therapeutics for mesothelioma - Endocrine Surgery: Adrenocortical cancer modeling and analysis neuroendocrine tumor and carcinoma imaging and targeting Didactic Component All Fellows participate in a formal didactic lecture and discussion curriculum Foundations of Modern Cancer Biology designed to quickly bring surgical residents up to speed in understanding the current state of molecular oncology. The curriculum covers current and historical breakthroughs in cancer and cancer treatment through a series of lectures and literature-based discussions focusing on experimental methods and data interpretation in tumor types of particular interest to surgical oncologists. A summary of the course content can be found here. Clinical Component This includes operative rotations in the areas of gastrointestinal hepatobiliary endocrine thoracic and peritoneal surface and gynecologic malignancies. Fellows actively participate in all aspects of patient care including conducting the pre-operative evaluation performing the operative procedure and providing post-operative care and subsequent outpatient follow-up. In addition to daily rounds with the attending surgeons clinical training is further enhanced by a series of weekly conferences including multidisciplinary molecular-based tumor boards a weekly clinical service meeting a diverse array of talks on the latest topics in cancer and biomedical science in general by some of the world's most outstanding scientists through lecture series and Grand Rounds held across the entire NIH campus. Expectations At the conclusion of their laboratory clinical and didactic training Fellows will be able to: - Identify critically important questions in surgical oncology - Independently design perform and interpret experiments and their results to directly address these questions - Attain mastery in oral and written communication of both scientific research and clinical patient management. Graduates of the Fellowship are expected to become the next generation of leaders in Surgical Oncology Training at the NIH Clinical Center All CCR residents and clinical fellows train at the 240-bed NIH Clinical Center internationally recognized as the premier hospital dedicated to translational research and clinical care. Clinical rotations offer fellows the opportunity to have direct experience in the care of patients enrolled in investigational oncology-related treatment protocols. Participants will have first-hand exposure to the design conduct and management of clinical trials. All of CCR's clinical training programs are part of Graduate Medical Education at NIH. 4434842 +No NIH Category available Academic Training;Acceleration;Accreditation;Address;Advanced Practice Nurse;Africa;Agreement;Amendment;American;American Nurses' Association;Applied Research;Area;Authorization documentation;Books;Brazil;Categories;Certification;Clinical;Collaborations;Communication;Community of Practice;Competence;Continuing Education;Country;Data Analyses;Delphi Study;Developing Countries;Development;Device or Instrument Development;Discipline of Nursing;Doctor of Philosophy;Education;Educational Curriculum;Educational Intervention;Educational Models;European;European Union;Exclusion;Exhibits;Faculty;Familiarity;Finland;Funding;Genetic;Genomics;Goals;Graduate Degree;Grant;Growth;Guidelines;Health Personnel;Health Surveys;Healthcare;Hospital Planning;Hospitals;Indiana;Institutional Review Boards;Intervention;Interview;Israel;Japan;Journals;Knowledge;Lead;Leadership;Learning;Licensure;Literature;Los Angeles;Malignant Neoplasms;Manuscripts;Measures;Medicine;Methodology;Methods;Midwife;Modeling;Nomenclature;Nurse Practitioners;Nurses;Nursing Education;Nursing Faculty;Nursing Models;Nursing Students;Outcome;Paper;Participant;Pattern;Perception;Pharmacogenomics;Pharmacy facility;Phase;Postdoctoral Fellow;Precision Health;Process;Protocols documentation;Publications;Published Comment;Publishing;Registered nurse;Regulatory Element;Reporting;Research;Research Personnel;Research Priority;Resources;Role;Schools;Science;Services;Site;Strategic Planning;Surveys;Teacher Professional Development;Technology;Testing;Text;United States National Institutes of Health;Universities;Update;Validation;Wales;Work;Workforce Development;Writing;academic preparation;clinical practice;college;design;digital;education planning;electronic book;evidence base;genetic pedigree;genomic data;hospital care;implementation study;instrument;international partnership;medical specialties;meetings;pilot test;recruit;skills;systematic review;tool;translational genomics;web site;webinar Genomic Competency Initiative n/a NCI 10926709 1ZIEBC011912-05 1 ZIE BC 11912 5 16162371 "CALZONE, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 100321 NCI Project 1) Nursing Capacity in Pharmacogenomics: The collaborative national study of advanced practice nurses (APRN) with Dr. Cathy Fulton at Indiana University asseses pharmacogenomic capacity. The exempt protocol is completed with findings prescented at the June 2023 American Association of Nurse Practitioners meeting. The manuscript is being submitted to the Journal of the American Association of Nurse Practitioners but delayed due to the IU statistician who had to repeat the analysis 3 times. The study recruited 266 practicing APRNs with prescriptive privileges. Findings about half N=124 48% reported pharmacogenomic academic training content. Despite that most N=216 86% reported being not at all familiar N=18 7% not very familiar N=80 32% or only somewhat familiar N=118 47% with pharmacogenomics. Most N=209 79% reported never utilizing CPIC Guidelines. Pharmacogenomic usage defined as ordering a pharmacogenomic test within the past year was low N=71 28%. Why APRNs N=162 indicated they do not anticipate ordering a pharmacogenomic test in the next year about half N=76 47% indicated they did not know what test to order. Conclusions are that APRNs reporting pharmacogenomics curricular content did not impact pharmacogenomic familiarity confidence capacity to order a pharmacogenomic test or usage. The protocol to assess APRN pharmacogenomic curricular content is being finalized and the instrument is established. We have permission to recruit through the National Organization of Nurse Practitioner Faculties targeting American Association of Colleges of Nursing Accredited Schools N=910. We will target Deans to identify faculty responsible for pharmacogenomic curricular content a strategy successfully used by phamacy studies PMIDs: 31250730 and 34283786. The study involves a survey and may be amended to include targeted qualitative interviews if indicated. Outcomes will identify curricular gaps and faculty capacity deficits to inform education interventions and convene panel including experts in nursing medicine and pharmacy to develop a model nursing pharmacogenomic curriculum. Project 2) Global Genomics Nursing Alliance (G2NA): G2NA led by the US UK and 23 global nursing leaders has grown to 174 nursing leaders. The G2NA website https://g2na.org/ has funding and support from the University of South Wales; sustains quarterly education webinars; grown the countries represented; established a strategic plan; communicates through a listserv; and is conducting research. Primary efforts are aimed at establishing Global Minimal Genomic Competencies for nurses and midwives. The leadership team includes Emma Tonkin PhD from UK and myself. The steering groups meets monthly and includes representatives from Africa Brazil Israel and Japan. Methods for establishing the competencies have been established. The literature scoping review is in process. G2NA lead by investigators at Tampere University of Applied Sciences in Finland submitted October 2022 a COST Action European Union grant which provides funding for European and global research and capacity building initiatives. This was close to fundable range. With detailed reviewer comments the same team will resubmit with 15 country partners in October 2023. If funded this will facilitate the ability to convene meetings for establishing a research consortium genomic capacity building initiatives and establishing evidence-based best practices with a supporting resource toolkit. This will be the basis for establishing the global genomic communities of practice. Establishing a Global Genomic Nursing Science Blueprint is active but delayed. The systematic review is completed. There were 8532 papers of which: 84 duplicates were eliminated; 8448 abstracts were reviewed with 7833 excluded; 615 underwent full text review and 232 were included in the final analysis. Identified themes were collapsed into categories across five settings (clinical practice nursing education professional development academic research other) and six topical areas (knowledge and perceptions application to practice pre-licensure registered nurse education advanced practice registered nurse education nursing faculty education continuing education other) for more granular reporting. 22.3 percent of articles focused on educating either pre-licensure registered nursing students advanced practice registered nursing students nursing faculty or providing continuing education for practicing nurses. Other articles were on storytelling instrument development/validation and culturally appropriate pedigree nomenclature. 126 articles from 2012-2022 were identified relating to healthcare provider-related clinical and educational outcomes. A median of 12 articles were published each year exhibiting a nearly linear growth pattern in cumulative publications on nursing and genomics. The manuscript describing the findings is being written followed by using these findings to convene a panel to establish the Global Genomic Nursing Science Blueprint to prioritize research where evidence is sparse. 4) The Genomic Nursing Competency (GNC) Update: With collaborators Laurie Badzek and the American Nurses Association (ANA) a national nursing precision health and genomic competency initiative continues. The previously updated but not published Genomic Nursing Competencies were disseminated for public comment in 11/2022. Changes were integrated and ANA digitally produced the competencies and published 6/2023 as a free e-book https://www.nursingworld.org/nurses-books/ana-books/ebook-essentials-of-genomic-nursing-competencies-/. The publication describing the Delphi study and updated competencies is in progress. ANA agreed to integrate the competencies into Scope and Standards of Practice so competencies will no longer be required. ANA is supporting the update to Genetic and Genomic Competencies for Graduate Nurses using the same Delphi methodology. Reviewers have been selected and the list approved by ANA. However these competencies are extensive and pilot testing revealed the Delphi survey was too burdomeson. The survey is being redesigned and the launch is dependent on the next round of testing. Competencies will be revised based on the final Delphi round then disseminated for public comment and digitally published followed by integration into Scope and Standards. Lastly ANA collaborated wtih us to conduct a national precision health and genomics competency assessment to inform whether a national nursing genomic education initiative is required. The Genetic and Genomic Nursing Practice Survey and the newly validated Precision Health Survey were combined and the survey closed on 7/14/2023 having accrued 1066 participants. Data analysis is being planned with the genomic data being compared to the prior national nursing workforce study N=661. Findings will inform capacity building initiatives. The Cedars Sinai genomic implementation built on the MINC study and use the Roadmap and Maturity Matrix Tool is on hold. Cedars collaborator Dr. Bernice Colman worked with me to complete the protocol but is not submitted to the IRB. Cedars has competing demands and despite leadership approval cannot move forward now. The cancer focused MINC-2 with a phased approach beginning with Cedars in Los Angeles followed by all Cedars hospitals with cancer services remains unchanged. If this project moves forward it will measure genomic competency and implementation at baseline and at the conclusion of the intervention and compare usual hospital planned education/competency initiatives to the intervention. Per NIH IRB guidance the protocol will be submitted to Cedars and once approved will have an NIH reliance agreement. I am looking for other sites including Indiana University site of my former post doc Valerie Willis. 100321 +No NIH Category available CCR;Chest;Clinic;Clinical;Clinical Skills;Clinical Trials;Goals;Instruction;Interest Group;Journals;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Malignant neoplasm of thorax;Medical Oncologist;Medical Oncology;Mission;Patients;Primitive foregut structure;Protocols documentation;Research Personnel;Rotation;Surgical Oncology;Training;improved outcome;interest;mesothelin;oncology program;pancreatic cancer patients;symposium;treatment response;tumor Clinical Support n/a NCI 10926708 1ZIEBC011653-09 1 ZIE BC 11653 9 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 17501 NCI The Thoracic and Gastrointestinal Malignancies Branch (TGMB) and Surgical Oncology Program (SOP) have a number of ongoing clinical trials for patients with mesothelin-expressing malignancies. I participate as an Associate Investigator on these trials by seeing trial patients and assessing patient clinical response to therapy. Training new researchers is an important part of the NCI mission. I provide instruction to CCR Medical Oncology fellows that rotate through the GI and Thoracic clinics. I participate in GI Cancer Journal Clubs and also in Foregut Tumor Board which is an interbranch conference for clinicians interested in GI malignancies. I organize an interdisciplinary pancreas cancer journal club monthly for the Pancreatic Cancer Interest Group. 17501 +No NIH Category available 2 year old;Accreditation;Adolescent and Young Adult;Adult;Alveolar;Alveolar Soft Part Sarcoma;Cause of Death;Central Nervous System Melanoma;Central Nervous System Neoplasms;Child;Childhood;Clinical;Clinical Research;Clinical Services;Dasatinib;Disease;Education;Endocrine Gland Neoplasms;Enrollment;Fellowship;Institution;Joints;Late Effects;Lead;Lymphoma;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical;Mentors;Minor;Mission;Neuroblastoma;Nurse Practitioners;Patient Care;Patients;Pediatric Oncology;Play;Publications;Quality of life;Research Personnel;Rhabdomyosarcoma;Role;Soft tissue sarcoma;Softball;Survivors;Training;Training Programs;Translating;Translational Research;United States National Institutes of Health;clinical care;clinical center;graduate medical education;improved;leukemia;osteosarcoma;pediatric patients;phase 1 study;physician-scientist training program;rare cancer;sarcoma;therapy development;tumor Pediatric Oncology Branch Clinical Care and Education n/a NCI 10926707 1ZIEBC011516-11 1 ZIE BC 11516 11 14732189 "GLOD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 6416085 NCI The Clinical Director of the Pediatric Oncology Branch oversees the pediatric oncology clinical service at the NIH Clinical Center and has budgetary and supervisory responsibility for the clinical fellows nurse practitioners and patient care coordinators. The NCI fellowship training program is a joint training program with Johns Hopkins Medical Institutions. The joint training program is accredited by the Accreditation Council for Graduate Medical Education (ACGME). Together we oversee the mentoring and training of 20 fellows. The POB Clinical Core (CC) played a lead role in the study of atezolizumab in patients with alveolar soft part sarcoma (PI A. Chen) enrolling the majority of pediatric patients who participated in this study which was critical to the FDA approval of atezolizumab for adults and pediatric patients age 2 years and older with alveolar softball part sarcoma. The CC also led the publication of a study of guadecitabine for the treatment of SDH-deficient GIST (2023) and an investigator initiated phase 1 study of ganitumab plus dasatinib for patients with rhabdomyosarcoma. 6416085 +No NIH Category available Accreditation;Anatomy;Area;Autopsy;Biological Assay;Case Study;Child;Clinical;Clinical Pathology;Clinical Research;Clinical Services;Clinical Trials;Clonality;Communicable Diseases;Consultations;Cytopathology;DNA Methylation;DNA analysis;Diagnosis;Diagnostic;Digestive System Disorders;Disease;Disease Management;Education;Educational process of instructing;Etiology;Exposure to;Extramural Activities;Flow Cytometry;Fluorescent in Situ Hybridization;Functional disorder;Funding;Gene Fusion;Gene Mutation;Genes;Genetic;Genetic study;Hematopathology;Hospitals;Institution;Kidney Diseases;Laboratories;Learning;Lymphoid;Malignant Neoplasms;Medical Examiners;Medicine;Mission;Molecular Genetics;Mutation;Oncology;Outcome;Pathogenesis;Pathologic;Pathology;Patient Care;Patients;Philosophy;Play;Protocols documentation;Publications;Research;Research Activity;Research Training;Residencies;Role;Rotation;Services;Surgical Pathology;Techniques;Tissue Procurements;Training;Training Programs;United States National Institutes of Health;University Hospitals;Washington;cancer therapy;clinical center;disease diagnosis;epidemiology study;experience;improved;insight;molecular diagnostics;molecular pathology;neoplastic;nervous system disorder;neuropathology;next generation sequencing;novel;participant enrollment;programs;recruit;research clinical testing;soft tissue;urologic Anatomic Pathology Residency Program n/a NCI 10926706 1ZIEBC011384-13 1 ZIE BC 11384 13 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2067992 NCI Residents in the Anatomic Pathology Residency Program contribute to the clinical research program of the NCI and the NIH. Through their efforts as anatomic pathology residents in training they help illuminate the pathological changes associated with initial presentation and therapy of both neoplastic and non-neoplastic diseases and explore new techniques to improve diagnosis of these diseases. These residents are critical to the patient care activities of the NCI and the NIH and contribute to the diagnosis and management of disease. Residents have also contributed to publications dealing with characterization diagnosis and pathogenesis of a number of disease entities. 2067992 +No NIH Category available Academy;Accreditation;American;Appointment;Career Choice;Certification;Child;Clinical;Clinical Research;Communication;Communities;Consultations;Country;Credentialing;Data;Dedications;Diagnosis;Diagnostic;Diagnostic Services;Disease;District of Columbia;Education;Educational Curriculum;Environment;Exposure to;Faculty;Fellowship;Fellowship Program;Flow Cytometry;Functional disorder;Future;Goals;Head;Hematology;Hematopathology;Home;Hospitals;Immune System Diseases;International;Journals;Laboratories;Literature;Lymphoma;Medical;Medical center;Medicine;Mentors;Occupations;Paper;Pathology;Patient Admission;Patient Care;Patients;Peer Review;Philosophy;Positioning Attribute;Procedures;Publishing;Research;Research Project Grants;Review Literature;Rotation;Services;Techniques;Time;Training;Training Programs;Translational Research;United States;United States National Institutes of Health;University Hospitals;Visit;Washington;career;clinical center;clinical training;experience;improved;individual patient;medical specialties;meetings;member;molecular diagnostics;neoplastic;programs;skills;success;symposium Hematopathology Fellowship n/a NCI 10926705 1ZIEBC011241-15 1 ZIE BC 11241 15 9692515 "JAFFE, ELAINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 668263 NCI "All the Clinical Fellows become involved in research projects while their fellowship. Fellows hone their presentation skills through their participation in Journal clubs and Data clubs held on a regular basis. At these meetings fellows discuss recent papers from the published literature and present results of their ongoing projects. These conferences help them transition to their future career path with most of them remaining in the academic sector. In addition to our daily interactions while fellows are on service we have more formal meetings at least twice each year to discuss career goals and job opportunities. More frequent meetings are held to discuss their current research projects at least monthly. We hold regular conferences with clinical branches treating patients with lymphoma and other immune disorders. Mentoring of trainees and Lab members has been a major focus of our group and the success that our trainees have had since leaving the NIH is evidence of our dedication to these goals. Since my appointment as Head of the Hematopathology Section in 1980 we have trained more than 80 Clinical Fellows in Hematopathology and 20 Visiting Fellows seeking to improve their skills prior to return in their home country. Dr. Pittaluga is Program Director a position held since 2005. While the fellowship is sponsored by the Hematopathology Section LP NCI fellows spend a considerable portion of their time in rotations in different units to broaden their educational experience. The ""credentialing year"" of the ACGME accredited program includes rotations in the Hematopathology Section LP (4 months) the Hematology Service of the Department of Laboratory Medicine Clinical Center (DLM CC) (4 months) Flow Cytometry Unit (1 month) Molecular Diagnostics Unit (1 month) Hematopathology Division of the Johns Hopkins Hospital (1 month) with optional rotations at the Children's National Medical Center Washington DC and George Washington University Hospital. In the second year of the program fellows have 8 months of protected research time and enhance their diagnostic skills through an additional fou months of diagnostic service in the Hematopathology Section LP and the Hematology Service DLM CC. Each of the fellows is sponsored to attend the week-long Tutorial in Neoplastic Hematopathology an experience that further rounds out the educational curriculum. 100% of our fellows have passed on the first attempt the examination in Hematology offered by the American Board of Pathology. Since 2015 trainees in the Hematopathology Section have authored more than 60 articles in the peer-reviewed literature. Fellows present at one of the scientific meetings related to our specialty most often the United States and Canadian Academy of Pathology (USCAP)." 668263 +No NIH Category available AIDS related cancer;Acquired Immunodeficiency Syndrome;Adult;Ambulatory Care;American Cancer Society;American Society of Clinical Oncology;Anti-Retroviral Agents;Appointment;Area;Basic Science;Board Certification;Bone Marrow Examination;Cancer Control;Centers for Disease Control and Prevention (U.S.);Clinic;Clinical;Clinical Oncology;Clinical Research;Clinical Sciences;Communities;Comprehensive Cancer Center;Development;Diagnostic Procedure;Disease;Division of Cancer Prevention;Drug Industry;Educational Curriculum;Educational process of instructing;Ensure;Fellowship;Fellowship Program;First Year Experience;Goals;Hematological Disease;Hematologist;Hematology;Hodgkin Disease;Hospitals;Human;Industry;Intramural Research;Investigation;Journals;Laboratories;Laboratory Research;Leadership;Lymphoma;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maryland;Medical;Medical Oncology;Medicine;NCI Center for Cancer Research;National Cancer Institute;National Heart Lung and Blood Institute;Oncologist;Oncology;Outpatients;Paracentesis;Patients;Peer Review;Physicians;Positioning Attribute;Publications;Renal Cell Carcinoma;Research;Research Activity;Research Personnel;Research Project Grants;Rotation;Scientist;Series;Stem cell transplant;Thoracentesis;Time;Training;Translational Research;United States;United States National Institutes of Health;Universities;Washington;Work;anticancer research;cancer therapy;career;chemotherapy;chronic leukemia;clinical care;clinical center;clinical diagnostics;clinical training;design;drug testing;experience;experimental study;inpatient service;interest;lectures;meetings;member;neoplastic;next generation;novel strategies;novel therapeutics;patient oriented;patient population;programs;recruit;skill acquisition;symposium NIH Hematology Oncology Fellowship Program n/a NCI 10926703 1ZIEBC010843-17 1 ZIE BC 10843 17 78858344 "KANAKRY, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 8328218 NCI The NIH Hematology Oncology Fellowship Program provides a unique opportunity for physicians interested in academic careers to develop and integrate both their clinical and basic research interests. This program combines hematology and medical oncology into a series of clinical rotations encompassing 18 months of fellow's training. The clinical portion of the training consists of primary responsibility for the clinical care of inpatients and outpatients with a board spectrum of adult malignancies and hematologic diseases. During the first clinical year there is an emphasis on exposing fellows to the basic science and clinical hematology and oncology. During the research years the fellow will join one of the several hundred available investigators within the NIH to acquire the skills necessary to become an independent biomedical investigator. The NIH works hard to guarantee at least two years of protected research time to all of its fellows. During the first year of training fellows devote 100% of their time to clinical training in inpatient and outpatient care at the NIH Clinical Center (NIH-CC) Georgetown University's Lombardi Comprehensive Cancer Center MedStar Washington Hospital Center. University of Maryland and the Johns Hopkins University. This ensures that fellows undergo comprehensive clinical training and extend their experience with a wide spectrum of human cancers and hematologic diseases. Training in clinical diagnostic procedures such as bone marrow examination thoracentesis and paracentesis is a routine part of the first-year experience. Following completion of this 18-month clinical period the fellow does laboratory or clinical research for up to 4 years of fellowship along with continued outpatient clinical duties. The remaining time in the second and third years is protected time for research in any of the NCI or NHLBI Clinical Teams or any NIH laboratory. Offered throughout the Program are lectures research seminars conferences journal club teaching rounds and conferences relevant to clinical hematology and oncology and cancer research. Most of these are organized specifically for hematology oncology fellows. These include a core curriculum lecture series in clinical hematology and oncology which meets once a week throughout the year and offers lectures by members of the senior staff across the spectrum of issues in neoplastic disease. Fellows are responsible for preparing case presentations and lecture material. In addition there are 10 to 15 research seminars and lectures given per day throughout the NIH; these are advertised in a weekly announcement and are regularly open to the entire NIH community. It is expected that each fellow's research activities will lead to at least one abstract presentation at a national meeting and one or more peer-reviewed publication. All fellows are expected to actively engage in a hypothesis-driven research project(s) in a clinical translational or basic science. The NIH-CC emphasizes the development of new approaches to the treatment of cancer and its complications. Current areas of clinical emphasis include prostate cancer ovarian cancer renal cell carcinoma lymphomas Hodgkin's disease chronic leukemia new drug testing stem cell transplantation and AIDS and its associated malignancies. Patients with AIDS and AIDS associated malignancies constitute approximately 5% of the total patient population; nearly all these patients are involved in studies of experimental antiretroviral compounds and chemotherapy. 8328218 +No NIH Category available Brain Neoplasms;Cancer Diagnostics;Central Nervous System Neoplasms;Classification;Clinical;Clinical Pathology;Collaborations;DNA Methylation;DNA sequencing;Development;Diagnosis;Diagnostic;Europe;Fluorescence;Formalin;Gene Fusion;Goals;Histopathology;Human;Immunohistochemistry;Laboratories;Lead;Malignant Neoplasms;Methods;Methylation;Modality;Molecular;Mutation;New York;North America;Paraffin Embedding;Pathology;Patient Care;Patients;Process;Publishing;RNA;Resources;Series;Solid Neoplasm;Specimen;Techniques;Tissue Sample;United States;Universities;Update;clinical practice;diagnostic accuracy;diagnostic criteria;improved;individual patient;molecular diagnostics;next generation sequencing;personalized diagnostics;precision oncology;programs;standard of care;tumor;tumor diagnosis;virtual;whole genome Classification of tumors using whole-genome methylation profiling n/a NCI 10926697 1ZIDBC012090-02 1 ZID BC 12090 2 78858639 "ABDULLAEV, ZIED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 824537 NCI Given the emphasis at the NCI on precision cancer medicine the NCI-Laboratory of Pathology has implemented methylation-based modality for routine diagnostic on all brain tumor cases. While this technique is being used at several centers in Europe to our knowledge we are one of only 3 centers in North America (in addition to the University of Toronto and New York University) where this has been implemented for brain tumor diagnosis. The goals of the brain tumor diagnosis program at the NCI-Laboratory of Pathology are to serve as a precision diagnostic modality for patients seen at the NCI and as a resource for diagnostic applications for difficult-to diagnose brain tumors throughout the United States. An advantage of this platform in a pathology practice is that it is technically robust on routinely processed formalin-fixed paraffin embedded (FFPE) tissue samples making this applicable to virtually any brain tumor specimen encountered in daily practice. Overall methylation classifier for brain tumors is perhaps the most exciting development in solid tumor cancer diagnostics since the advent of techniques such as immunohistochemistry and fluorescence in-sit hybridization (FISH). Going forward methylation classifiers are being developed for additional tumor types using the same platform increasing its utility and application across the spectrum of human cancer. The NCI Laboratory of Pathology is poised in collaboration with partners in Europe and North America to help lead this effort for a new era in precision cancer diagnostics. 824537 +No NIH Category available Acceleration;Address;Advocacy;Age Years;Basic Science;CCR;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Caring;Classification;Clinical;Clinical Research;Clinical Trials;Common Terminology Criteria for Adverse Events;Conduct Clinical Trials;Data;Data Analyses;Data Collection;Development;Devices;Disease;Doctor of Medicine;Drug Approval;Drug Evaluation;Enhancement Technology;Evaluation;Funding;Future;Glean;Grant;Infrastructure;Label;Lead;Malignant Neoplasms;Measures;Mission;NCI Center for Cancer Research;Outcome;Outcome Measure;Outcomes Research;Palliative Care;Patient Care;Patient Outcomes Assessments;Patient Participation;Patient-Focused Outcomes;Patients;Performance;Persons;Phase;Phase I/II Trial;Population;Positioning Attribute;Process;Protocols documentation;PubMed;Questionnaires;Regimen;Reporting;Research;Symptoms;System;Technology;Testing;Therapeutic;Toxic effect;Translational Research;Treatment Efficacy;anticancer research;associated symptom;cancer therapy;clinical outcome assessment;clinical trial protocol;common symptom;design;drug development;early phase clinical trial;early phase trial;electronic data;experience;improved;infrastructure development;innovation;insight;neglect;novel;novel therapeutic intervention;novel therapeutics;patient oriented;phase I trial;phase II trial;phase III trial;programs;response;success;symptom management;technology platform;timeline;tool development;tumor;virtual reality;wearable device Office of Patient-Centered Outcomes Research (OPCORe) n/a NCI 10926696 1ZIDBC012078-02 1 ZID BC 12078 2 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1296374 NCI The mission of CCR is to improve the lives of all cancer patients by solving important challenging and neglected problems in cancer research and patient care through a world-leading basic translational and clinical research and patient care program. Integral to this is the development and evaluation of novel therapeutic approaches evaluated in early-phase trials. Importantly in these early phase clinical trials toxicity and tolerability are the primary questions being addressed. Standard toxicity assessments provide only limited or inadequate information whereas patient-focused approaches using clinical outcomes assessments (COAs) in which information is gathered on the impact of treatment on the person and not only on tumor response would markedly enhance the understanding of the patient experience in these trials. Patients are uniquely positioned to inform understanding of the therapeutic context for drug development and evaluation of these outcomes. The FDA has noted the need for more systematic ways of gathering patient perspective on their condition and patient experience related to novel therapies on how they feel and function through the use of COAs. COAs can broadly be classified into four distinct groups based on how data is collected including information taken directly from the patient (Patient-reported outcomes or PROs) information gleaned from clinical observation (ClinROs); other observer reported outcomes (ObsROs) and data from performance on a task or test (PerfOs) (http//www.fda.gov/media/104969/download ). In cancer-related clinical trials PROs are increasingly encouraged by regulatory agencies and advocacy groups alike to describe the clinical benefit of a therapeutic regimen. This includes information on disease-associated symptom or functions as a component of determining treatment efficacy and in understanding treatment-associated symptomatic toxicities. These measures which collect information directly from the patient without interpretation by somebody else provides further understanding of the patient perspective about the impact of treatment. The incorporation of PROs in early phase clinical trials is increasingly important as there has be a shift in the clinical trial landscape towards early-phase studies where data from well-designed and pivotal phase I/II trials is leading to accelerated drug approval. Therefore having PROs incorporated in these early phase trials can inform the primary trial objective and provide critical information that can be used to support labeling claims in the future. There are many examples where the value of outcomes measures has been instrumental in assessing treatment efficacy in both Phase II and III trials. Additionally these measures also provide valuable insights about the impact of the disease and its treatment that are critical in improving patient care even when the treatment does not prove to have sufficient activity against the cancer. A recent study of 248 patients participating in Phase I trials at M.D. Anderson Cancer Center revealed that 67% of the patients had seven or more concurrent symptoms and more than half of the patients reported that at least 3 of these symptoms were rated as moderate-to-severe. Surprisingly this was more frequent in the younger patients compared to those over 65 years of age highlighting the need for systematic evaluation (starting before treatment) in order to get an accurate assessment of the impact and tolerability of treatment on patients. https://pubmed.ncbi.nlm.nih.gov/31761957/ . The NCI has a long-standing commitment to patient-centered research. This has included development of tools to measure outcomes such as the development of a PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) with demonstrated validity in early phase trials https://pubmed.ncbi.nlm.nih.gov/33392443/ in addition to supporting development of other PRO questionnaires funded through R Grant and other mechanisms. Inclusion of these outcomes has been encouraged and is considered standard in NCI sponsored cooperative group trials and in CTEP-sponsored Phase III trials. The clinical research program of CCR is uniquely poised to lead efforts in systematic integration of these measures in early phase clinical trials and to align with guidance from the NCI and FDA on the importance of these efforts. The proposed program would systematically integrate COAs into the clinical trials conducted at the CCR provided valuable insight into the patient experience and provide opportunity for evaluation of innovative approaches to data collection and analysis. A centralized CCR program will be created through formation of the Section of Patient Centered Outcomes within the program of the NCI Clnical Director within CCR. As outlined below the program would be instituted in several phases starting first with Core Module development for inclusion in all trials engagement of key stakeholders and agencies and infrastructure development. The use of a core set of symptoms common across cancers in addition to treatment-specific symptomatic toxicities will be foundational for Phase II and III in which novel integration of measures use of technology and integration of care can be incorporated. The proposed plan and timeline is as follows: PHASE I (YEAR 1) Establish Stakeholder Advisory Board set up infrastructure for electronic data capture and reporting develop core construct set of outcomes measures Develop template for incorporation into ongoing and future clinical trial protocols for selected clinical branches and cancers pilot and evaluate system with established metrics of feasibility and success. PHASE II (YEAR 2-3) Expand core construct use throughout CCR clinical research develop process for enhanced core concepts based on population or target launch enhanced core concept development as part of scientific review. PHASE III (YEAR 3-5) Develop enhanced technology platform to enable incorporation of these devices (smart wearables virtual reality as examples) into assessment plan Integrate symptom management into assessment core align CCR Outcomes initiative with early phase protocols (ie integrated palliative care) or across stand-alone studies. 1296374 +No NIH Category available Accreditation;Advisory Committees;Advocacy;Affect;Amendment;American;American Society of Clinical Oncology;Appointment;Bioethics;Budgets;CCR;CDH1 gene;CLIA certified;Charge;Childhood;Classification;Clinical;Clinical Management;Clinical Services;Collection;Communities;Complex;Consent;Consult;Consultations;Continuing Education;Contractor;Contracts;Counseling;Development;Disclosure;Doctor of Philosophy;Education;Education Gap;Educational Curriculum;Educational process of instructing;Electronic Mail;Enrollment;Environment;Ethics;Ethics Consultation;Extramural Activities;Family;Feedback;Funding;Genes;Genetic;Genetic Counseling;Genetic Enhancement;Genetic Research;Genetic Services;Genomics;Germ-Line Mutation;Goals;Guidelines;Healthcare;Hematologic Neoplasms;Hybrids;Incidental Findings;Individual;Infrastructure;Inherited;Interview;Justice;Kidney;Label;Laboratories;Leadership;Learning;Length;Letters;Longterm Follow-up;Lung;Lymphoma;Malignant Neoplasms;Malignant Pleural Mesothelioma;Medical;Medical Genetics;Mentors;Mesothelioma;National Human Genome Research Institute;National Institute of Allergy and Infectious Disease;Needs Assessment;Pathology;Patient Care;Patient Preferences;Patients;Persons;Positioning Attribute;Procedures;Process;Prostate;Protocols documentation;Provider;Public Health Schools;Questionnaires;Recording of previous events;Reporting;Research;Research Personnel;Resources;Role;Rotation;Saliva;Service delivery model;Services;Standardization;Students;Swab;Telemedicine;Telephone;Testing;Time;Training;Training Programs;Tumor Pathology;United States National Institutes of Health;Universities;Variant;Work;Workload;cancer genetics;cancer genomics;career;certificate program;clinical center;clinical infrastructure;clinical sequencing;clinical training;clinically relevant;cost;empowerment;equity diversity and inclusion;evidence base;exome;exome sequencing;experience;genetic counselor;genetic pedigree;genetic testing;genetic variant;instructor;interest;malignant stomach neoplasm;medical schools;meetings;member;multidisciplinary;neuro-oncology;novel;payment;programs;protocol development;racial diversity;research study;simulation;symposium;testing services;tool;tumor;variant of unknown significance;web portal;working group Clinical Cancer Genomics Program n/a NCI 10926692 1ZIDBC011908-05 1 ZID BC 11908 5 16162371 "CALZONE, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1504811 NCI The Genetic Counseling Training Program (GCTP) is staffed by one full-time PhD genetic counselor (GC) who also holds an appointment in the NIH Department of Bioethics. The Clinical Cancer Genetics Service (CCGS) is partially staffed with 1 part-time and 2 full-time clinical GCs and 1 full-time patient care coordinator (PCC) converted from a contactor to a GS position this year. CCR funded a 3rd full-time GC this year and our final candidate is being brought in as a contractor until she can be converted to a GS position given challenges as a direct GS hire. Our geneticist position remains open and continues to be advertised with the American College of Medical Genetics and Genomics and on the CCR Careers page. Dr. Chimene Kesserwan provides support for clinical research and T/N WES germline and somatic variant curation through her NIH Research Collaborator position. Dr. Sheila Rajagopal is available for urgent clinical issues and attends our weekly case conference to discuss complex patients review testing decisions result interpretations. The CCGP has achieved the following: 1) Genetic Counselor Training Program (GCTP): The MOU with the National Human Genome Research Institute (NHGRI) for the NIH GCTP in place through March 31 2025. This year student stipends had a 15% increase and must cover the cost for our 6 students estimated at $16853 for this fiscal year. This is a permanent increase that impacts the MOU annual budget MOU so the AO iworking on paperwork to amend the budget. NCI funded GCTP Assistant Director actively participates in weekly administrative meetings and Executive Committee tasks. This year she participated in a curriculum review with an outside consultant. She is involved in interviewing and ranking GCTP applicants. She is integral in student advising including independent and co-advising student thesis. She was the sole instructor for the Cancer Standardized Patient Rotation and developed and taught the Advanced Topics in Cancer Genomics course. Dr. Jamal received the Johns Hopkins Bloomberg School of Public Health for Excellence in Teaching in 2023 associated with her work on three courses. In 8/2023 Dr. Jamal will complete a certificate program in Justice Equity Diversity and Inclusion for Higher Educators at the UPenn with the aim of influencing the racial diversity of GCTP students. She contributed to the reaccreditation package and Drs. Meltzer and Calzone submitted a letter of support. CCGS GCs accept students for clinical experiences and mentoring. Students are provided a summary of cancer genetic research opportunities to consider for their Research Thesis and CCGS serves on committees as indicated. Dr. Jamal continues 50% effort in the NIH Clinical Center Department of Bioethics. This relationship benefits CCR by enhancing GC education with real ethical cases and facilitating CCR ethics consults. 2) Clinical Cancer Genetics Service (CCGS): CCGS provides investigator support in protocol development; manage genetic incidental findings; provide genetic counseling and testing as clinically or protocol indicated; and perform germline and/or somatic variant interpretation. CCGS continues not to be recognized by the Clinical Center as a formal consult service. We continue to maintain a central email and phone line for consult requests. From 7/10/2022-7/10/2023 CCGS saw 286 new consults up from 216. There were 65 requests for chart and/or genetic test report reviews. Chart reviews decreased as only 1 GC tracked this activity given time constraints. Most CCGS tests are conducted by outside laboratories. We have contracts with 2 laboratories and are establishing a 3rd. GCs complete the test request forms PCC enters POTS information and reconciles when the laboratory invoice comes in to validate the test and charge. CAN 8036225 pays for all tests to avoid payment delinquency which affects laboratory contracts. Quarterly the AO reconciles with the PI CAN.This year CCGS worked with CCR to outline the process and assess need for a central payment mechanism. The final decison was to maintain the existing process and develop a SOP to cover the procedures and streamline the AO workload to reconcile test charges. PIs unable to pay will use the Outside Medical Services mechanism. Dr. Gulley began exploring options with Laboratory of Pathology (LP) to expand their testing platform to include CLIA approved germline testing. Dr. Aldape was provided with CCGS 2022-23 germline test volume/type to inform this effort. CCGS transitioned to a hybrid care delivery model seeing patients in person and telemedicine based on provider/patient preference. GCs are embedded as part of the team in 6 services: Kidney Hematologic Malignancies Mesothelioma; Prostate; Lung; and Inherited Gastric Cancer. DCRI developed a patient online portal family history questionnaire which pre-populates the CRIS Pedigree. DCRI demonstrated the tool to CCGS allowed us to test and provide feedback and on 7/26/2023 the developers demo'd the final product which now moves to the test environment. This may be deployed in CRIS within the next few months which could increase CCGS patient capacity. Tumor/Normal Whole Exome Sequencing (T/N WES) CCGS provides clinical support for the LP T/N WES test. CCGS roles involve: pretest genetic education and counseling; medical and family history collection; consent; germline variant curation presentation of variant evidence at the weekly LP Exome Signout and result disclosure. From 7/10/2022-7/10/2023 there were 182 T/N WES referrals up from 49 in 2022. The CCGS PCC is the central contact for T/N WES consent requests for all NIH including NIAID GC (N=14 referrals) and Pediatric and Neuro Oncology Cases (N=76 referrals). For T/N WES cases not at the Clinical Center saliva or buccal swab kits are mailed to the patient with a pre-paid return Fedex label. CCGS purchases the kits and covers mailing costs. The increase in T/N WES by the CCR Lymphoma team mentioned in last years' report has increased. CCGS supports student education including GCTP students for clinical experiences and research thesis. This year our concept for two post bacs from the Genetics Opportunities Learning Development Empowerment and Networking (GOLDEN) Program was approved. One new post bac was approved with the second Vice slot coming from the existing CCGS CAN. We identified several GOLDEN students interested in pursuing a career in genetic counseling who were not accepted to a GCTP. Many are not local but one is applying and a 2nd is considering the option. 3) Genomic Variant Curation and Clinical Management: Interpreting genomic variants is a challenge. ClinGen built a central resource to define the clinical relevance of genomic variants and convened several Working Groups Task Forces Gene Curation Expert Panels and Variant Curation Expert Panels (VCEP). Grace Fasaye continues as a member on the CDH1 VCEP. Alex Lebensohn serves on the Expert Panel for the American Society of Clinical Oncology's Treatment of Malignant Pleural Mesothelioma Guidelines. She also participated in the FDA Advocacy Panel/Mesothelioma Listening Session. All team members participate in routine clinical work of verifying variant classifications from patients found to harbor a variant of uncertain significance especially if a considerable length of time has passed since the patient was tested. Yi Liu leads the germline variant curation for the NIH T/N WES program with Dr. Calzone performing the Quality review of all variant classifications and accuracy of report content. Dr. Calzone leads the somatic variant curation for Dr. Apolo's protocol Olaparib protocol NCT04858334. Dr. Chimene Kesserwan provides the confirmation of these variant interpretations until a replacement geneticist is hired. 1504811 +No NIH Category available Adult;American Society of Clinical Oncology;Angiogenesis Inhibitors;Antineoplastic Agents;Basic Science;Belief;Biological Response Modifiers;Biology;Biotechnology;Brain;Brain Neoplasms;Cancer Center;Cardiology;Central Nervous System;Central Nervous System Neoplasms;Characteristics;Child;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Complement;Complex;Consultations;Dana-Farber Cancer Institute;Disease;Doctor of Medicine;Double-Blind Method;Endocrinology;Ensure;Environment;Fellowship;Freedom;Genetic;Glioblastoma;Glioma;Group Practice;Health;Health system;Healthcare;Hospitals;Immune checkpoint inhibitor;Immune response;Immunocompetence;Immunologic Monitoring;Infrastructure;Institution;Intramural Research Program;Journals;Kansas;Laboratories;Leadership;Malignant Glioma;Malignant Neoplasms;Measures;Medical;Medical Oncology;Medical center;Medicine;Methodist Church;Microscopic;Mission;Molecular;Monitor;Morphology;National Cancer Institute;National Heart Lung and Blood Institute;National Institute of Mental Health;National Institute of Neurological Disorders and Stroke;Neurocognitive Deficit;Neurology;Neurosurgeon;New England;Newly Diagnosed;Nivolumab;North Carolina;Nurse Practitioners;Nursing Research;Ohio;Oncology;Ophthalmology;Pain;Pathology;Patient Agents;Patient Care;Patient-Focused Outcomes;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Pharmacologic Substance;Physical Medicine;Physicians;Placebo Control;Primary Brain Neoplasms;Privatization;Psychiatry;Publishing;Quality of life;Radiation;Radiation Oncologist;Radiation Oncology;Radiation Therapy Oncology Group;Randomized;Research;Research Personnel;Research Project Grants;Resources;Role;Running;Second Opinions;Services;Site;Social Work;South Carolina;Specialist;Specimen;Spinal Cord Neoplasms;Stratification;Symptoms;Testing;Texas;Therapeutic;Tissues;Training Programs;Translational Research;Treatment Efficacy;Tumor Tissue;United States National Institutes of Health;Universities;Utah;Washington;anti-CTLA4;anti-PD-1;anticancer research;bevacizumab;cancer care;clinical care;clinical center;clinical investigation;cognitive function;design;drug development;effective therapy;improved;individual patient;individualized medicine;innovation;ipilimumab;medical schools;member;multidisciplinary;neuro-oncology;neurosurgery;novel;novel diagnostics;novel therapeutics;palliation;personalized medicine;phase III trial;programs;prototype;safety testing;standard care;survival outcome;tool;translational research program;treatment arm;tumor Brain Tumor Clinical and Clinical Research Program n/a NCI 10926687 1ZIDBC011642-09 1 ZID BC 11642 9 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2237606 NCI "The NOB has made substantial progress towards building an infrastructure necessary for fulfilling its mission of developing new and improved therapies for children and adults with brain and spinal cord tumors. Since Dr. Gilbert's arrival at the NIH in November 2014 he has rebuilt the Brain Tumor Clinical and Clinical Research Program: a highly collaborative robust translational research program centered on finding treatments for brain and other central nervous system tumors. In addition to conducting basic and translational research the NOB has become a nationally recognized resource for patient information and referrals for second opinions. In addition to seeing and treating brain tumor patients Dr. Gilbert currently runs a significant number of national clinical trials and helps organize and administrate over several large national Neuro-Oncology translational science initiatives. Importantly Dr. Gilbert led RTOG 0825 which evaluated the role of the anti-angiogenic agent bevacizumab in patients with newly diagnosed glioblastoma in a double-blind placebo controlled randomized phase III trial. This study accrued 973 patients and successfully incorporated upfront stratification by two molecular parameters as there was 100% compliance with tumor tissue submission. This study which did not demonstrate a survival benefit for bevacizumab demonstrated neurocognitive decline and worsened symptom burden and quality of life in the patients treated with bevacizumab. This study was presented at the Plenary Session at ASCO and published in the New England Journal of Medicine. These efforts have led to his leadership of NRG BN002 a clinical trial that is testing the safety of adding the immune checkpoint inhibitors ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with newly diagnosed glioblastoma. This is the prelude to an NOB study that will help determine whether these immune checkpoint inhibitors have efficacy in glioblastoma by determining if patients who demonstrate a peripheral immune response have improved survival outcomes. A critical component of the trial will be the immunologic monitoring which will comprise testing of tumor tissue for mediators of immune-reactivity and serial monitoring of peripheral blood mononuclear cells as an indicator of the impact of treatment on ""immune competence"". Dr. Gilbert has also transitioned the Brain Tumor Trials Collaborative (BTTC) from M. D. Anderson Cancer Center. This is a national consortium that was founded on philanthropic support. The mission of the BTTC is to rapidly develop and complete innovative clinical trials for patients with primary brain tumors. To date the BTTC has completed a study that used a factorial design (8 treatment arms were evaluated simultaneously) and a trial that used an adaptive randomized design (patient allocation based on treatment efficacy using patient by patient rebalancing). This effort is currently being transferred from the M. D. Anderson Cancer Center to the NCI. There are currently 3 active studies and once relaunched and addition study concepts are anticipated. The list of participating sites is provided below: Aurora Advanced Healthcare National Institutes of Health Baylor University Northwestern University Feinberg School of Medicine Case Western Reserve SOM Ohio State University Cedar-Sinai Medical Center Rush University Cancer Center Cleveland Clinic Texas Oncology Columbia University The Methodist Hospital Dana Farber Cancer Institute University of North Carolina Henry Ford Health System University of Kansas Medical University of South Carolina University of Utah Orlando Health University of Washington Mayo Clinic UT M. D. Anderson Cancer Center Northshore University Health System UT Southwestern Medical Center at Dallas. The NOB has created a vibrant robust and clinically busy center for neuro-oncology excellence that serves as a national resource for patients with CNS malignancies (regardless of their ability to pay) for information consultation clinical trials or referrals to their local centers of excellence for clinical care and NCI-sponsored trials. This was an important accomplishment because: Part of the mission of the NCI is to provide expertise to patients and physicians for a lethal tumor type not frequently seen in the community and for whom standard treatment options are limited. A busy and robust clinical program ensures a steady flow of patients with primary CNS tumors imperative for stimulating clinical and translational research by ensuring rapid patient accrual to clinical trials efficient acquisition of tissue for basic and translational research and for enticing pharmaceutical/biotechnology companies to co-develop novel CNS tumor agents with the NOB and the NCI at large. A multi-disciplinary tumor board convenes every other week and is attended by neuro-oncologists radiation oncologists neurosurgeons neuropathologists and laboratory investigators. Complex and challenging patients are presented and discussed optimizing individual patient care and leading to many collaborative interactions and research projects. This Tumor Board is complemented by a bi-weekly pathology review where NIH neuropathologists prepare specimens from active clinical patients that are examined microscopically and morphologic and genetic features are discussed in conjunction with members of the Brain Tumor Clinical Team. Additionally a Molecular Tumor Board has been incorporated into the Pathology Review that reviews all of the available molecular information from individual patient's tumors so that therapies can be considered in the context of this information. Below are partial lists of accomplishments in the building of an NIH-wide multidisciplinary Brain Tumor Clinic with active participation from three different NCI Branches (ROB MOCRU CCRLP) five different NIH Institutions (NCI NINDS NEI NHLBI NIMH) and six different Clinical Center Programs (Neuroradiology Psychiatry Pain and Palliation Rehabilitation Medicine Social Work). Expertise represented in the clinic includes Medical Oncology Radiation Oncology Neurosurgery Neurology Ophthalmology Cardiology Psychiatry Endocrinology Social Work and Rehabilitation Medicine; Assembled a primary neuro-oncology clinical care/research team which now consists of 5 neuro-oncologists 6 nurse practitioners 5 research nurses 2 clinical fellows 1 clinical collaborator 3 patient coordinators 4 clinical trials specialists; Additionally the NOB provides neuro-oncology services for Walter Reed Medical Center in Bethesda; established close collaborative clinical programs with Johns Hopkins Medical Center George Washington Medical Center Fairfax Inova and Washington Hospital Center and a wide array of private neurosurgical radiation and oncology practice groups locally and nationally; created a neuro-oncology fellowship training program between the NIH and the Johns Hopkins Medical Center. Since the Brain Tumor Clinical and Clinical Research Program re-initiated in 2015 the NOB launched 18 clinical trials." 2237606 +No NIH Category available Antibodies;Antibody-drug conjugates;CCR;Chelating Agents;Chest;Clinical;Clinical Research;Clinical Trials;Conduct Clinical Trials;Drug Targeting;Goals;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotoxins;Label;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Malignant neoplasm of thorax;Malignant neoplasm of thymus;Medical;Non-Small-Cell Lung Carcinoma;Patients;Radiation therapy;Research Personnel;Scientist;Thorium;Tumor Antigens;chimeric antigen receptor T cells;drug development;gastrointestinal;innovation;mesothelin;novel;preclinical study;small cell lung carcinoma;standard care;treatment program Thoracic and Gastrointestinal Malignancies Branch Clinical Core n/a NCI 10926685 1ZIDBC011540-10 1 ZID BC 11540 10 6189074 "HASSAN, RAFFIT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1555914 NCI The medical TGMB has a robust clinical program for treatment of patients with advanced thoracic and GI cancers who have failed standard therapies. The thoracic team is conducting innovative studies for patients with non-small cell lung cancer small cell lung cancer malignant mesothelioma and thymic cancers. These include use of novel treatments developed by scientists at the NCI. A major focus of our team is the development of drugs targeting the tumor antigen mesothelin that is highly expressed in many cancers. We are using an immunotoxin -LMB-100 an antibody drug conjugate- BAY 94-9343 thorium-227 labeled antibody-chelator conjugate-BAY 2287411 and mesothelin targeting CAR-T cells to treat these cancers. In addition we are conducting clinical trials using immunotherapy agents including immune checkpoint inhibitors to treat patients with thoracic cancers who have failed standard treatments. The TGMB is also conducting studies for treatment of gastrointestinal cancers with a special emphasis on liver and pancreatic cancer. Investigators within the TGMB have established a robust program for treatment of patients with liver cancer including use of immunotherapy agents either alone or in combination with radiation therapy or locally ablative therapies for liver cancer. The gastrointestinal group is also conducting clinical trials of novel agents for treatment of pancreatic cancer. 1555914 +No NIH Category available Academic achievement;Acute Myelocytic Leukemia;Adolescent;Adolescent and Young Adult;Adult;Advance Care Planning;Apple;Apple watch;Attitude;Australia;B lymphoid malignancy;Behavioral Sciences;Brain Neoplasms;CAR T cell therapy;CCR;CD19 gene;CD22 gene;CDK4 gene;COVID-19 impact;COVID-19 pandemic;Cancer Patient;Caregivers;Cellular Phone;Central Nervous System Diseases;Characteristics;Child;Child Development;Childhood;Chronic Disease;Clinic;Clinical;Clinical Protocols;Clinical Trials;Cognitive;Country;Cranial Irradiation;Cutaneous;Data;Development;Diagnosis;Discipline;Disease;Distress;Docking;Dysmyelopoietic Syndromes;Education;Electronics;Emotional;Enrollment;Evaluation;Family;Fatigue;Gastrointestinal Stromal Tumors;Hairy Cell Leukemia;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Hydrogen;Imatinib;Immune checkpoint inhibitor;Incidental Findings;Individual;Infusion procedures;Intervention;Interview;Investigation;Leadership;MAP2K1 gene;Malignant Neoplasms;Malignant neoplasm of adrenal cortex;Measures;Medical;Morals;Natural History;Neoplasm Metastasis;Neurocognitive;Neurofibromatosis 1;Neurologic Symptoms;Neuropsychology;Outcome Measure;Pain;Palliative Care;Parents;Patient Outcomes Assessments;Patient Participation;Patient Self-Report;Patients;Pediatric Oncology;Phase;Phase II Clinical Trials;Physical Function;Pilot Projects;Plexiform Neurofibroma;Protocols documentation;Psychosocial Assessment and Care;Psychosocial Factor;Publications;Publishing;Quality of Life Assessment;Quality of life;RUNX1 gene;Reaction Time;Recommendation;Recurrence;Refractory;Relapse;Reporting;Research;Research Support;Services;Siblings;Sickle Cell Anemia;Site;Social Workers;Solid Neoplasm;Stem cell transplant;Sulfate;Symptoms;Technical Expertise;Testing;Transplantation;Treatment Protocols;United States National Institutes of Health;Voice;behavioral health;behavioral health intervention;behavioral outcome;cancer therapy;care providers;checkpoint therapy;chimeric antigen receptor T cells;chronic graft versus host disease;chronic pain patient;cognitive function;cognitive testing;computerized;coping;design;diet and exercise;executive function;flexibility;gut microbiome;high risk;inhibitor;medication compliance;medullary thyroid carcinoma;melanoma;mobile sensor;neurobehavioral;neurocognitive test;neurofibroma;neurotoxicity;next generation sequencing;pain outcome;psychosocial;rare cancer;remote assessment;research study;response;sensor technology;social;stressor;student training;tumor;young adult Pediatric Oncology Branch Behavioral Science Core n/a NCI 10926684 1ZIDBC011517-11 1 ZID BC 11517 11 14732189 "GLOD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1203016 NCI Impact of COVID-19 on the impact of COVID-19 on children undergoing active cancer treatment and their parents (2023) Publication of the impact of COVID-19 on the moral distress of pediatric palliative care providers and social workers(2023). Adapting Voicing My CHOiCES an advance care planning guide for adolescents and young adults in other countries (Australia) developed in the POB. Development and testing of Checking IN a pediatric electronic distress screener Support Intramural PIs: Assessing neurotoxicity using computerized neurocognitive testing and a neurologic symptom checklist that we developed in a phase I/II study of CD33 CAR T-cell infusions in pediatric and adolescent and young adult patients with relapsed/refractory acute myeloid leukemia (PI: Nirali Shah) Assessing neurotoxicity using computerized neurocognitive testing and a neurologic symptom checklist that we developed in a POB phase I CD22 CAR treatment protocol for children with recurrent B-cell malignancies including CNS disease (PI:Shah) Assessing neurotoxicity using computerized neurocognitive testing and a neurologic symptom checklist that we developed and revised based on the CD22 CAR results in the POB phase I CD19/22 CAR treatment protocol for children with recurrent B-cell malignancies (PI:Shah) Assessing neurotoxicity using computerized neurocognitive testing neurologic symptom checklist and patient-reported outcomes on a CD22 CAR trial in adults with Hairy Cell Leukemia (PI:Krietman) Developing a limited-site pilot study to investigate the cognitive aftereffects (subacute and long-term) of neurotoxicity in children and young adults with relapsed/refractory hematologic malignancies who receive CAR T-cell therapy including remote assessments (PI:Shalabi) Assessing patient reported outcomes in children undergoing CAR T therapy and their caregiver through self-report and qualitative interviews (PI: Haneen Shalabi; LAI: Lori Wiener) Collecting subject-reported symptom data prior to infusion of CD33 CAR T-cell infusions and weekly in the month following (PI:Shah) Assessing psychosocial and behavioral outcomes in a longitudinal and natural history study of children and young adults with Medullary Thyroid Carcinoma (MTC) (PI:Widemann) Assessing psychosocial and behavioral outcomes in a longitudinal and natural history study of children and adults with RUNX1 FPD (PI:Liu) Assessing psychosocial and behavioral outcomes in longitudinal and natural history study of children and adults with Adrenal Cortical Cancer (PI:Del Rivero) Assessing psychosocial factors stressors and needs of children and adults with Gastrointestinal Stromal Tumor (GIST) that attend the NIH GIST clinic (PI:Glod) Assessing psychosocial factors stressors and needs of children and adults with Medullary Thyroid Carcinoma (MTC) that attend the NIH MTC clinic (PI:Glod) Investigating the natural history of neuropsychological functioning QOL and pain in children adolescents and young adults with NF1 (PI:Widemann) Analyzing the long-term patient-reported outcome (PRO) data of pain physical function and quality of life in a registration phase II clinical trial of selumetinib in children with NF1 and inoperable plexiform neurofibromas which contributed to FDA approval of selumetib (koselugo) in April 2020 (PI:Widemann) Assessing patient-reported outcomes of pain physical function and quality of life in a phase II clinical trial of selumetinib in adults with NF1 and inoperable plexiform neurofibromas Assessing medication adherence in a phase II clinical trial of selumetinib in children with NF1 and inoperable plexiform neurofibromas (PI:Widemann) Administering the patient-reported outcomes measures for a pilot study of the MEK1/2 inhibitor selumetinib (AZD6244 Hydrogen Sulfate) for adults with neurofibromatosis type 1 and cutaneous neurofibromas (PI:Gross) Assessing patient-reported outcomes measures for a phase I/II study to evaluate the Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas (PI:Gross) Planning the patient-reported outcomes and neurocognitive assessment for a new natural history study of individuals with NF1 and high risk tumors (PI:Gross) Investigating neurocognitive functions pain and quality of life in several protocols of children adolescents and adults with sickle cell anemia undergoing stem cell transplant (PIs: Courtney Fitzhugh John Tisdale) Identifying patient and parent attitudes toward the use of next generation sequencing (NGS) for diagnosing and managing cancer and the return of results and incidental findings (PI: Rosie Kaplan) Evaluating the effects of whole-brain radiation on the neurocognitive functioning of adults with brain tumor metastases (PI: Kevin Camphausen) Assessing psychosocial characteristics of children in a natural history study of clinical factors in children with chronic GVHD (PI: Steven Pavletic) Assessing a core set of patient-reported outcomes to assess children adolescents and adults with rare solid tumors as part of the POB natural history rare tumor initiative (PI: Jaydira Del Rivero) Conducting two cognitive test batteries (low and high functioning) for a natural history study to examine the cognitive social and emotional development of children and young adults with RASopathies (PI: Doug Stewart) Conducted qualitative interviews on order of transplant in siblings undergoing transplant for DOCK8 Deficiency (PI: Nirali Shah) Assessing symptom burden and quality of life in patients undergoing related and unrelated donor Hematopoietic Stem Cell Transplant for Dock 8 Deficiency (PI: Corina Gonzalez) Conducting qualitative interviews pre and 1 year post Hematopoietic Stem Cell Transplant for Dock 8 Deficiency (PI: Corina Gonzalez) Conducting evaluations to investigate the feasibility of mobile sensor technologies using an Apple iPhone and Apple Watch to assess general symptomology (e.g. fatigue pain) and cognitive function (e.g. cognitive flexibility reaction time) of cancer patients (PI: James Gulley) Designing and implementing a behavioral health intervention and patient-reported outcomes in a protocol assessing the effect of diet and exercise on the gut microbiome and response to immune checkpoint inhibitor therapy in patients with melanoma (PI: James Gulley) Assessing quality of life in a natural history protocol for Myelodysplastic Syndromes (PI: Kathy L McGraw). Assessing patient report outcomes and quality of life in a study of Imatinib to increase RUNX1 activity in patients with germline RUNX1 deficiency (PI: Lea Cunningham) Core-Initiated Investigations Establishing and disseminating recommendations on working with patients with chronic pain during the COVID-19 pandemic Explored association between executive function and academic achievement in children with neurofibromatosis type 1 and plexiform neurofibromas published a study of demographic and disease-related predictors of socioemotional development in children with NF1 1203016 +No NIH Category available Acquired Immunodeficiency Syndrome;Adult;Affect;Childhood;Clinical;Collaborations;Consult;Consultations;Emergency Situation;Goals;HIV;Hospitals;Hour;National Cancer Institute;Operative Surgical Procedures;Patients;Play;Research Personnel;Role;Tissue Procurements;Tissues;United States National Institutes of Health;Urologic Oncology;Urologic Surgeon;Urologic Surgical Procedures;Urology;clinical center;coronavirus disease;design;surgical service Urologic Oncology Branch Consult Core n/a NCI 10926681 1ZIDBC011092-16 1 ZID BC 11092 16 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 545075 NCI Investigators in the Urologic Oncology Branch of the National Cancer Institute are the urologic surgeons and general urology consultants to the entire National Institutes of Health. In this role we see patients in consultation for all pediatric and adult urologic surgical problems. The Urologic Oncology Branch answers all emergency as well as elective urologic surgical consultations and provides 24 hour coverage for urologic surgical emergencies that may arise in the Clinical Center Hospital. Increasing surgery in AIDS patients is being performed. The Urologic Oncology Branch also collaborates in the procurement of tissue for studies required by other investigative units. The degree of involvement of the Urologic Oncology Branch in the planning and execution of these studies is variable. The Urologic Oncology Branch often plays an instrumental role in the design of these studies while in other collaborations the Urologic Surgical Service merely provides tissue. Approximately 30% of the clinical surgical effort of the Urologic Oncology Branch is devoted to these consultative and collaborative studies. The Core supports all patients seen at the NIH Clinical Center including HIV+ patients and those affected with COVID. 545075 +No NIH Category available Admission activity;Affect;Amendment;Appointment;Appointments and Schedules;Archives;Bilateral;Blood;Businesses;Cancer-Predisposing Gene;Cardiology;Clinical;Clinical Data;Clinical Management;Clinical Nursing;Clinical Nursing Research;Clinical Oncology;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Complement 3d;Complex;Conduct Clinical Trials;Consent;Consult;Consultations;Contracts;Counseling;DNA;Data;Databases;Dermatology;Diagnosis;Discharge Plannings;Discipline of Nursing;Disease;Education;Educational Materials;Educational process of instructing;Eligibility Determination;Endocrine;Enrollment;Ethics;Evaluation;Family;Family Study;Film;Generations;Genetic;Genetic Counseling;Genetic Predisposition to Disease;Genetic Risk;Genotype;Goals;Good Clinical Practice;Growth;Guidelines;HIV;Health Promotion;Heart;Hereditary Disease;Hereditary Leiomyomatosis and Renal Cell Cancer;Heritability;Human Resources;Humanities;Image;Informed Consent;Inherited;Inpatients;Institutional Review Boards;Intake;Internal Medicine;Kidney Neoplasms;Knowledge;Letters;Location;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measurement;Medical;Medical History;Medical Records;Mentors;Mentorship;Methods;Modality;Natural History;Neurology;Nursing Research;Operating Rooms;Operative Surgical Procedures;PET/CT scan;Paper;Papillary;Patient Appointment;Patient Care;Patient Education;Patient Recruitments;Patient Schedules;Patients;Persons;Physician Assistants;Physicians;Policies;Postoperative Period;Practice Guidelines;Predisposition;Principles of law and justice;Probability;Procedures;Process;Professional Practice;Protocols documentation;Quality of life;Questionnaires;Recommendation;Renal Cell Carcinoma;Renal carcinoma;Reporting;Research;Research Support;Resources;Risk;Schedule;Scientist;Services;Slide;Social Work;Societies;Specialist;Support Groups;Surgeon;Surgical Management;Syndrome;System;Telephone;Test Result;Time;Tissue Procurements;Tissues;Travel;United States National Institutes of Health;Urine;Urologic Cancer;Urologic Oncology;Urology;Visit;Work;Writing;X-Ray Computed Tomography;bone imaging;clinical center;compliance behavior;continuing nursing education;coronavirus disease;data integrity;data management;demographics;diaries;follow-up;genetic counselor;genetic pedigree;genetic testing;human model;human subject protection;imaging study;meetings;member;nephrogenesis;neurosurgery;novel;operation;participant enrollment;patient expectation;programs;psychosocial;recruit;success;surveillance strategy;text searching;tumor Clinical Nursing and Data Management Core n/a NCI 10926680 1ZIDBC011089-16 1 ZID BC 11089 16 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 545075 NCI The heart of the Urologic Oncology Branch is our clinical program- we study the human model of kidney cancer prostate cancer and bladder cancer. The Urologic Oncology Clinical Core is comprised of a genetic counselor / protocol manager clinical research nurses patient care coordinators (PCC) a senior data manager and data managers. RESEARCH NURSES: Clinical trials Research nurse specialists coordinate / manage the operations of our clinical trials in kidney cancer prostate cancer and bladder cancer. Their responsibilities include: kidney cancer prostate cancer and bladder cancer patient recruitment participate in the informed consent process; perform patient education; create patient-specific protocol schedule; schedule blood and urine studies CT scan MRI; PET CT internal medicine neurosurgical ENT consults; register patient with CRO; collect / review diaries with patients; assess patient compliance; rapid and accurate data capture; Q/A data entries in c3D; report AEs to NCI IRB and sponsor according to protocol requirements; submit annual Continuing Reviews to IRB; maintain regulatory binder; participate in clinical trial meetings. Familial Kidney Cancer A key component of the UOB Branch is the study of families who have rare inherited conditions such as von Hippel-Lindau Hereditary Papillary Renal Cell Cancer Birt-Hogg-Dub Syndrome and Hereditary Leiomyomatosis and Renal Cell Carcinoma which predispose to development of kidney cancer. Research nurse specialists and a genetic counselor provide protocol oversight for our natural history protocols in kidney cancer prostate cancer and bladder cancer. Responsibilities include: patient recruitment; telephone intake covering pedigree; initiation of informed consent process to include purpose of study; provide information about NIH the study objectives assess patients expectations; initial medical history; determine appropriate clinical studies; communicate with PCCs re: appointment and indicated studies; assist PCC in obtaining pertinent medical records; tissue slides films; obtain informed consent; assure patient has adequate understanding of information received during visit; prepare/submit annual Continuing Review to NCI IRB. Prostate Cancer and Bladder Cancer The prostate cancer and bladder cancer program is supported by research nurse specialists who have overall oversight of patients with localized prostate or bladder cancer. Responsibilities include: telephone intake to include; purpose of study; information about NIH the study objectives assess patients expectations; initial medical history; initiate informed consent process; determine appropriate clinical studies; communicate with PCCs re: appointment and indicated studies; obtain informed consent in person; patient teaching; follow-up visit; assure Quality of Life questionnaires are submitted /received by patients at multiple time points; work with data managers to assure data is captured and submitted. GENETIC COUNSELING: A Genetic Counselor actively participates in pursuit of the research questions about known genetic syndromes or unknown familial renal cancer. Responsibilities include: family recruitment through professional genetic societies; develop a 3-generation pedigree; complete a personal medical history; determine the genetic test to be performed; perform literature searches contribute to the identification of novel clinical manifestations of rare heritable malignant disorders. Patients with or at risk for an inherited kidney cancer cancer susceptibility disorder undergo an extensive counseling / education session. Topics generally covered during these sessions include: Clinical aspects and natural history of the suspected disorder; if the disorder is unknown the differential clinical and genetic evaluation plan is presented; psychosocial risks of genetic testing; implications of potential genetic test results; clinical management of condition and /or multiple bilateral renal tumors; health promotion strategies; provide supportive counseling at-risk or affected patients; provide written educational material and medical papers if appropriate; provide information about support groups; discuss familial communication. Genetic test results are provided per patient preferred modality; a counseling letter is sent with DNA result and recommended surveillance strategies. PROTOCOL MANAGER: Overall protocol management is the responsibility of our Genetic Counselor. Protocol manager responsibilities include: draft natural history protocols; prepare and submit protocol amendments; submit Continuing Reviews for natural history and tissue procurement protocols; remain informed about the IRB process as well as the ethical / legal aspects of clinical research; serve as a resource/ mentor to the UOB about protocols and the IRB process PHYSICIANS ASSISTANT: The in-patient and Urology consult service is managed by our Physician Assistant (P.A.). Responsibilities include: manage surgical patients upon decision for surgery; determine with surgical Fellows the appropriate pre-operative work-up; arrange in-patient admission; schedule / enter orders for operative admission including imaging studies consultations; refer patients to NIH social service for potential Family Lodge availability; perform H & P upon admission; conduct regular and frequent patient rounds; handle patient concerns while surgeons in operating room; schedule post-operative follow up visit; collaborate with nursing /social service re: discharge plan; see consult patient during post-op visit. The Urology consult service offered to the entire NIH community is managed by our P.A. Responsibilities include: initially see / evaluate all consult patients; assess patient and in concert with UOB Fellows identify probable diagnosis; recommendations to referring service; see all consults at follow-up visits; submit consult note into CRIS system. PATIENT CARE COORDINATORS: The complex task of scheduling multiple appointments and clinical studies is the responsibility of our PCCs. PCC responsibilities include: schedule new and follow- up patient appointments; communicate with patients regarding reimbursement / travel policy; admission procedures; enter patient information into ATV system; schedule all studies such as CT MRI. bone scan PET CT; arrange coordinate consultations with internal medicine neurology endocrine dermatology cardiology consults etc.; develop patient schedule; send letter of invitation; copy of protocol consent appointment schedule; obtain relevant tissue slides imaging studies and medical records; track / oversee recommendation by UOB physicians for follow-up visits and recommended studies for follow-up visits. DATA MANAGEMENT: Senior Data Manager Overall management of UOB data is the responsibility of our senior Data Manager. His responsibilities include: adapt LabMatrix to UOB data needs; maintain extensive UOB database; responsible for data integrity; query requested reports; Q/A entered data; capture and track: demographics; tumor measurements; clinical manifestations; genetic test results / genotype; provide mentorship to contract data personnel. Data management staff: One data management staff is responsible for tracking/ identifying tumor size and location; growth rates of tumors; captures images for UOB archives. Two contract data staff members are responsible for entering / QA data collected from natural history and clinical trials; tracking enrollment; works closely with research nurses and CRO to assure data accuracy. All data from the clinical trials in entered into the LabMatrix database of the UOB. The Core supports all patients seen at the NIH Clinical Center including HIV+ patients and those affected with COVID. 545075 +No NIH Category available Articulation;Brain Neoplasms;Breast;Cancer Patient;Clinic;Clinical;Clinical Research;Collaborations;Consultations;Head and neck structure;Histologic;Intramural Research Program;Journals;Lung;Lymphoma;Malignant Neoplasms;Malignant lymphoid neoplasm;Medical;Medical Oncology;Medical center;Mission;New Agents;Nursing Faculty;Oncology;Operative Surgical Procedures;Patient Admission;Patient Care Management;Patients;Pediatric Oncology;Pediatrics;Physicians;Physics;Private Practice;Prostate;Protocols documentation;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Radiobiology;Research;Residencies;Scientist;Subgroup;Talents;Training;Translational Research;United States National Institutes of Health;Urologic Oncology;Writing;bench to bedside;cancer care;clinical center;clinical training;design;lectures;neuro-oncology;next generation;oncology program;pre-clinical research;programs;success Radiation Oncology Branch - Radiation Clinic n/a NCI 10926678 1ZIDBC010990-16 1 ZID BC 10990 16 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 9227549 NCI The ROB is critical to the overall care of cancer patients in the Intramural Research Program and provides radiation therapy as well as general oncology consultation for patients admitted to the clinical center. This has allowed numerous collaborations and/or interactions with the Surgery Branch Urologic Oncology Branch Pediatric Oncology Branch Medical Oncology Clinical Research Unit (GU GI Head and Neck Breast Gyn cancers) Neuro Oncology Branch Lymphoid Malignancies Branch and the Radiation Biology Branch. These collaborations extend beyond merely treating patients with radiation in that the talented physician/scientists assembled in the ROB are outstanding oncology research scientists who can articulate the latest findings in radiation biology research to the larger oncology paradigm. The ROB maintains a strong radiation oncology residency program in association with radiation oncology departments at Walter Reed Medical Center training the next generation of radiation oncologists/scientists. The residents receive clinical training in a one on one setting with the clinical faculty as well as participate in multiple settings that include lectures didactics journal clubs and formal classes in medical physics and radiobiology. Trainees from the Radiation Oncology Residency Program have enjoyed significant success in both academic and private practices. 9227549 +No NIH Category available Caring;Clinical;Clinical Research;Clinical Trials Design;Collection;Data Analyses;Data Collection;Education;Goals;Hematopoietic Stem Cell Transplantation;Immunology;Individual;Infrastructure;Malignant Neoplasms;Patient Care;Patient Recruitments;Policies;Translational Research;Transplant Recipients;Transplantation;Work;career development;clinical care;design;member;programs;transplantation therapy ETIB Clinical Research Core n/a NCI 10926676 1ZIDBC010963-16 1 ZID BC 10963 16 9692325 "GRESS, RONALD " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 43269 NCI The Experimental Transplantation and Immunology Branch (ETIB) clinical transplantation program has as goals the cure of cancer through hematopoietic stem cell transplant therapies conducting outstanding translational research and providing the highest level of excellence in clinical care. The ETIB Clinical Core provides interactions activities and support across the branch. It represents a collection of individuals each with particular expertise in clinical transplantation and clinical research. While the section functions as a coordinated effort it is also designed for individual career development and professional advancement for members. Specific aims include developing a supportive infrastructure for the conduct of clinical transplantation trials establishing consistent clinical policies and practices in the care of transplantation patients in order to achieve excellence in clinical care and providing and promoting educational opportunities in hematopoietic stem cell transplantation. The work of the ETIB clinical research core concluded in FY23. 43269 +No NIH Category available Accreditation;Address;Adherence;American;Anatomy;Archives;Area;Autopsy;Benchmarking;Biocompatible Materials;Biopsy;CCR;CLIA certified;Childhood;Chromosomes;Clinical;Clinical Laboratory Information Systems;Clinical Management;Clinical Pathology;Clinical Services;Cytology;Cytopathology;Data;Databases;Diagnosis;Diagnostic;Diagnostic Services;Dissection;Elements;Ensure;Ethics;Flow Cytometry;Genomics;Goals;Health care facility;Hematopathology;Histology;Histopathology;Hospital Information Systems;Human Resources;Image;Individual;Institutional Review Boards;Joints;Label;Laboratories;Leadership;Legal;Link;Medical;Mission;Molecular;Monitor;Operative Surgical Procedures;Pathologist;Pathology;Pathology Report;Patient Care;Patients;Performance;Preparation;Process;Protocols documentation;Quality Control;Quality Indicator;Recommendation;Reporting;Research;Research Personnel;Research Support;Resected;Ribonucleases;Scanning;Scientist;Services;Site;Slide;Specialist;Specimen;Stains;Surgical Pathology;System;Telepathology;Testing;Tissue Procurements;Tissues;Training Programs;Training Support;United States National Institutes of Health;clinical center;clinical diagnostics;college;digital;high standard;image archival system;imaging program;improved;meetings;operation;patient safety;process improvement;programs;quality assurance;remote grading;research facility;statistics;surgical research;tissue archive;tissue processing;tissue resource;tool;whole slide imaging Clinical Operations for Laboratory of Pathology n/a NCI 10926674 1ZIDBC010686-19 1 ZID BC 10686 19 14732101 "CHINQUEE, JOSEPH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1042444 NCI The Laboratory of Pathology (LP) supports the clinical and research missions of the NIH and the NCI by providing anatomic pathology and tissue processing services to the Clinical Center and to all of the NIH institutes. LP's clinical sections provide services in surgical pathology autopsy pathology hematopathology cytopathology chromosome pathology pediatric pathology flow cytometry and a dynamic and growing genomic pathology service. Clinical Operations is the administrative and technical core of the clinical component of the Laboratory of Pathology. The Clinical Operations section: oversees the regulatory compliance and accreditation of all clinical sections; manages the Quality Management program; provides core laboratory services in tissue procurement processing and gross analysis of clinical specimens; manages the clinical administrative functions; supports human resource management for clinical and technical staff; supports operations of the Laboratory Information System (LIS); whole slide imaging; and maintains the clinical diagnostic tissue archives of the laboratory. ACCREDITATION AND REGULATORY COMPLIANCE: LP is CLIA-certified and maintains a Certificate of Accreditation. LP is inspected every two years for compliance with regulatory standards by the College of American Pathologists with our last onsite accreditation inspection in March 2022. During that onsite inspection seven laboratory specialists evaluated more than 1200 standards in all of LP's clinical services with minimal recommendations. Continued accreditation is required for CLIA compliance but also demonstrates that the department's quality in patient care is of the highest standards. TISSUE PROCUREMENT HISTOLOGY and SURGICAL PATHOLOGY Support: Clinical Operations' pathologists assistants perform tissue division for clinical and research tissue sections and perform gross analysis dissection and processing of clinical biopsy and resected tissues from NIH patients for anatomic pathology diagnosis. Patients who undergo surgery at the NIH Clinical Center frequently have tissue divided between research and diagnostic purposes as dictated by IRB-approved protocols. For clinical cases the diagnostic material is processed and special stains are performed by the Histopathology section and distributed to LP's pathologists for diagnostic interpretation. After pathology diagnoses are rendered Clinical Operations staff provide pathology reports to requesting clinicians internal and external to the NIH. TISSUE RESOURCE REQUESTS: Clinical Operations staff manage the Tissue Processing and Procurement Facility and have oversight of the Tissue Resource Requests. As a service to investigators throughout the NIH Clinical Operations staff process requests from scientists for tissues to be used for research from the clinical archives while ensuring appropriate ethical approval (from their IRB or from the OHSR). During the fiscal year approximately 16988 individual biospecimens (unstained slides special stains tissue shavings whole mount slides and tissue slides processed with RNAse precautions) were provided to researchers from 2323 blocks our tissue archive. The TRC program facilitated the sendout of $44766 tissue processing requests to support non-LP investigators' TRC requests. The Clinical Operations section also processed approximately 850 medical-legal requests which involved retrieving and processing approximately clinical slides and/or blocks that were forwarded to other healthcare or research facilities at the request of clinicians or patients. LABORATORY INFORMATION SYSTEM (LIS): The LIS is part of the SoftLab system used by the Clinical Center and it interfaces with the hospital information system so that anatomic pathology results are available online. As part of the tissue request process and to support requests for pathology reports from patients and clinicians we conduct searches of the pathology database and provide lists of cases that match the requested criteria. The LIS is used by Clinical Operations to generate benchmark data and quality assurance statistics for managing and continuously improving the clinical diagnostic services. QUALITY MANAGEMENT: The LP Quality Management Program monitors LP's performance with key benchmarks such as: cytology molecular surgical and biopsy turnaround times; specimen adequacy labeling and identification compliance; and quality control performance of special stains. Annual QM reports are provided to LP's leadership to identify areas that have demonstrated improvements but also show areas that need continuous improvement and monitoring. Annual QM reports are provided to the NIH Clinical Center's Office of Patient Safety and Clinical Quality as one element needed to demonstrate an ongoing quality assurance and process improvement program for clinical services that is required for Joint Commission accreditation. In support of the training program the QM program ensures active participating by clinical fellows and residents. Fellows and residents participate with the preparation of monthly QM reports with providing investigative findings to quality outliers; participate in monthly QM meetings and are engaged in discussions about the quality indicators; and participate with six performance improvement projects aimed at addressing administrative processing technical and reporting outliers. WHOLE SLIDE IMAGING: The Clinical Operations staff performed whole slide imaging for more than 1500 clinical cases with 15112 H&E IHC and special stained slides scanned. The whole slide imaging program provides telepathology capability for LP's pathologists and collaborative projects with NCI investigators working with whole slide imaging and analyses. In addition a new file-sharing research image repository Halo-link has been implemented and actively used to manage whole slide images across all NIH Institutes from cases scanned in by the Clinical Operations service. 1042444 +No NIH Category available ABCB1 gene;Agonist;Antineoplastic Agents;Azacitidine;BAY 54-9085;Binding Proteins;Biological;Biological Assay;Biological Availability;Blood;Bortezomib;CCR;Camptothecin;Cancer Cell Growth;Carboplatin;Cells;Child;Chronic Lymphocytic Leukemia;Cisplatin;Clinical;Clinical Pharmacology;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Combined Modality Therapy;Communities;Concentration measurement;Conduct Clinical Trials;Coupled;Cyclophosphamide;Data;Depsipeptides;Detection;Development;Diffuse intrinsic pontine glioma;Disseminated Malignant Neoplasm;Dose;Drug Exposure;Drug Formulations;Drug Interactions;Drug Kinetics;Drug Monitoring;Equation;Erlotinib;Esterification;Esters;Etoposide;Excretory function;Extramural Activities;Finasteride;Fluorescence;Frequencies;Future;Glycolates;Goals;Guidelines;High Pressure Liquid Chromatography;Hydroxyl Radical;Imatinib;Immune checkpoint inhibitor;Immunotoxins;Institution;Interleukin-15;Intervention;Ion Channel;Ketoconazole;Laboratories;Liquid substance;Locally Advanced Malignant Neoplasm;MEKs;MS-275;Mathematics;Measures;Melphalan;Metabolism;Midazolam;Modeling;Modification;Molecular Target;Monoclonal Antibodies;Mus;Mutate;Natural Products;Nelfinavir;Nivolumab;Oncology;Oral;Paclitaxel;Patients;Pharmaceutical Economics;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Phase I Clinical Trials;Phase I/II Trial;Phenylacetates;Phenylbutyrates;Phyllanthus;Physiological Processes;Plants;Plicamycin;Polysaccharides;Population;Pre-Clinical Model;Prodrugs;Program Development;Randomized;Recombinants;Refractory;Regimen;Renal Cell Carcinoma;Reproducibility;Research Personnel;Rhabdoid Tumor;Rhabdomyosarcoma;Route;SU 5416;Sampling;Scheme;Serum;Solid Neoplasm;Stress;Suramin;TNP470;Tamoxifen;Tariquidar;Testing;Thalidomide;Therapeutic;Therapeutic Uses;Time;Tissues;Topoisomerase-I Inhibitor;Topotecan;Toxic effect;United States National Institutes of Health;Valproic Acid;Visit;Xenograft Model;abiraterone;absorption;analog;analytical method;antagonist;anti-PD-1;aurora kinase A;bevacizumab;cancer therapy;canine model;clinical center;clopidogrel;comparative trial;cost;cytotoxicity;detector;docetaxel;drug clearance;drug development;drug disposition;drug metabolism;experimental study;first-in-human;flavopiridol;improved;in silico;inhibitor;instrument;intraperitoneal;intravenous administration;irinotecan;kinase inhibitor;lapatinib;lenalidomide;mass spectrometer;member;method development;mucosal melanoma;nanoparticle drug;nonhuman primate;novel anticancer drug;novel therapeutics;pembrolizumab;personalized approach;pharmacodynamic model;pharmacokinetic model;pharmacokinetics and pharmacodynamics;phase 2 study;phase I trial;pomalidomide;pre-clinical;programs;prospective;randomized clinical trials;response;simulation;temozolomide;trial comparing;tumor;virtual patient Using Clinical Pharmacology Principles to Develop New Anticancer Therapies n/a NCI 10926670 1ZICSC006537-30 1 ZIC SC 6537 30 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1692241 NCI Over the years the CPP has developed analytical methods for a wide range of therapeutics that include the following: depsipeptide TNP-470 phenylacetate phenylbutyrate tamoxifen UCN-01 CAI thalidomide COL-3 suramin melphalan erlotinib perifosine SU5416 2ME MS-275 ketoconazole lenalidomide romidepsin AZD2281 gemicitabine sorafenib finasteride nelfinavir 17-DMAG clopidogrel Hsp90 inhibitor PF-04928473 irinotecan (its active metabolite SN38 and glucuronidated SN38) Trk kinase inhibitor AZD7451 pomalidomide olaparib sorafenib belinostat cediranib abiraterone cabozantinib carfilzomib midazolam lapatinib temozolomide perifosine valproic acid temozolomide cyclophosphamide and its 4-hydroxycyclophosphamide metabolite NLG207 (formerly CRLX-101 nanoparticle-drug conjugate of camptothecin) ONC206 and metarrestin (ML-246). The CPP has provided PK support for various agents in phase I/II trials: suramin TNP-470 CAI UCN-01 docetaxel flavopiridol thalidomide lenalidomide pomalidomide intraperitoneal cisplatin/carboplatin paclitaxel 17-DMAG imatinib sorafenib nelfinavir bevacizumab romidepsin clopidrogrel bortezomib TRC-105 vandetanib olaparib topotecan irinotecan mithramycin durvalumab abiraterone belinostat with cisplatin and etoposide temozolomide seviteronel selumetinib immunotoxin LMB-100 zotiraciclib M6620 (a first-in-class competitive inhibitor of ATR) NIZ985 (a recombinant heterodimeric IL-15 agonist) sorafenib and irinotecan as well as the combo of cabozantinib and docetaxel for mCRPC patients. During the current fiscal year the CPP provided PK support for several phase I/II clinical studies including a phase I trial of panobinostat in children with diffuse intrinsic pontine glioma; a first-in-human phase I clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors; phase II study of duvelisib and ibrutinib combination therapy for chronic lymphocytic leukemia; a phase I trial of sacituzumab govitecan plus berzosertib in advanced solid tumors. Over the years we have conducted population PK (popPK) modeling of the following compounds: depsipeptide romidepsin sorafenib olaparib docetaxel in combination with the p-glycoprotein antagonist tariquidar TRC105 TRC102 belinostat mithramycin seviteronel and NLG207 a nanoparticle-drug conjugate of the potent topoisomerase I inhibitor camptothecin. In collaboration with Drs. Mark Ratain and Daniel Goldstein we're evaluating in silico-based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors. Based on patient-specific estimates for clearance optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels especially as the clearance of the drug decreases over time. We hypothesize that longer dosing intervals than those currently approved (without commensurate dose increases) will maintain efficacy. To this end we are collaborating on a multi-institutional randomized non-inferiority trial to investigate the PK of standard interval dosing compared to extended interval dosing of nivolumab or pembrolizumab in locally advanced or metastatic cancers. The primary objective is to assess the noninferiority of extended interval dosing relative to standard dosing as assessed by drug trough levels above the target concentration of 1.5 ug/ml for both nivolumab and pembrolizumab. Nivolumab and pembrolizumab anti-programmed cell death protein 1 monoclonal antibodies have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated showing that 95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50% thus substantially reducing patient visits (as well as costs) while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing and ultimately an efficacy-driven comparative trial. We performed in silico re-optimization of atezolizumab dosing using PopPK simulation and exposure-response simulation. This in silico study demonstrated the feasibility of extending the dosing interval of atezolizumab 840 mg to every 6 weeks to maintain clinically effective exposures in the vast majority (99%) of virtual patients. We next aim to verify this in a clinical trial seeking to validate extended-interval dosing in a personalized approach using therapeutic drug monitoring. The CPP participates in several preclinical pharmacology projects in order to study drug metabolism PK drug formulation and bioavailability as well as efficacy in preclinical models of drug development to allow for more accurate dosing estimates for future first-in-human studies. The CPP has validated assays and conducted PK analysis for the following compounds: 3-deazaneplanocin (DZ-Nep) PV1162 schweinfurthin G englerin A aza-englerin XZ-419 aurora kinase A/B inhibitor SCH-1473759 and a long-acting prodrug of talazoparib. We have conducted bioavailability studies for schweinfurthin G englerin A and aza-englerin. We collaborate with both intramural and extramural investigators to evaluate the preclinical PK of various novel therapeutics in mouse tumor models and/or non-human primate models including 5-azacytidine pexidartinib photo-activatable paclitaxel prodrug and panobinostat. We evaluated the preclinical PK of sapanisertib (mTORC1/2 inhibitor) and trametinib (MEK inhibitor) in mucosal melanoma xenograft and canine models. We also investigated how dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors. We also evaluated the preclinical PK of trametinib in the presence or absence of ganitumab in RAS-mutated PAX-fusion negative rhabdomyosarcoma models. In collaboration with the Molecular Targets Laboratory and the Natural Products Branch the CPP provided preclinical PK support to study the bioavailability of two new classes of analogs of englerin A (extracted from the Tanzanian plant Phyllanthus engleri Pax on the basis of its high potency and selectivity for inhibiting renal cancer cell growth). The first class of analogs are modified at the esters to improve stability and oral bioavailability while the second class of analogs are modified on the bridgehead of the seven-membered ring within the main englerin body of the compound. Replacement of the isopropyl group by other larger substituents yielded compounds which displayed excellent selectivity and potency comparable to the natural product. Replacement of the glycolate by other functionalities as well as esterification of the glycolate hydroxyl yielded compounds which displayed excellent selectivity and potency compared with the natural product. TRPC4/5 ion channel experiments with five compounds showed delayed or reduced agonism with TRPC5 at much higher concentrations than englerin A. The same compounds were not detectable in mouse serum after a single oral dose of 12.5 mg/kg. At 100 mg/kg p.o. no toxicity was observed and blood levels were barely detectable. Intravenous administration led to toxicity but at substantially lower doses than for englerin A. 1692241 +No NIH Category available Ascites;Bar Codes;Biological;Biological Specimen Banks;Blood;Bone Marrow Aspiration;CCR;COVID-19;Cerebrospinal Fluid;Clinic;Clinical;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;DNA;Data;Data Collection;Databases;Development;Ensure;Extramural Activities;Human;Laboratories;Life Cycle Stages;Methods;Mission;Pleural effusion disorder;Procedures;Process;Protocols documentation;Research;Research Design;Resources;Saliva;Sampling;Services;Specimen;Specimen Handling;Time;Urine;Validation;aspirate;biobank;pandemic disease;pharmacokinetics and pharmacodynamics;repository;sample collection;software systems Biospecimen Processing and Biorepository n/a NCI 10926669 1ZICSC006536-30 1 ZIC SC 6536 30 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1692241 NCI For the current fiscal year the BPC provides support to over 155 clinical trials and receives and processes over 75000 biological samples including blood urine cerebrospinal fluid pleural effusion aspirate ascites saliva and bone marrow aspirate. This Core is responsible for the management and repository of samples from the CCR clinics. Upon arrival all samples are processed according to the clinical protocol (per standard operating procedures) barcoded and entered into a database for sample handling and storage purposes and cataloged into a software system. The BPC handles urgent same-day and routine sample shipments to both intramural and extramural laboratories. The BPC provides a broad range of services including the development and validation of procedures for specimen processing analyses and DNA extraction to establish protocols that optimize specimen integrity and consistency. In addition to laboratory services the Core serves as a resource for clinicians seeking advice on study design including specimen collection and storage methods as well as all protocol-associated study worksheets related to data and sample collection. The BPC provides services related to sample processing barcoding and storage of pharmacokinetic (PK) and pharmacodynamic (PD) biospecimens for all trials. Staff provides support to clinical teams throughout the life cycle of their protocols including assistance with ensuring time-sensitive samples are collected appropriately and with provision of sample data and shipment logs. During the pandemic the BPC provided support and remains involved in processing research bloods for a COVID-19 clinical protocol. 1692241 +No NIH Category available Area;Chemotherapy and/or radiation;Clinical Trials;Development;Genes;Goals;Head and Neck Cancer;Immunotherapeutic agent;In Vitro;Laboratories;Malignant Neoplasms;Nasal cavity;Nose;Olfactory Epithelium;Olfactory Neuroblastoma;Operative Surgical Procedures;Patients;Research Personnel;Series;Sinus;Skull Base Neoplasms;Smell Perception;Translating;Treatment Effectiveness;cancer type;improved;in vivo;interest;programs;skull base;therapeutic target;tumor;tumorigenesis Mechanisms of olfactory neuroblastoma tumorigenesis n/a NCI 10926667 1ZICBC012129-01 1 ZIC BC 12129 1 79355671 "LONDON, NYALL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2173093 NIDCD Our laboratory is focused on understanding how and why head and neck cancers develop in the nasal cavity sinuses and base of the skull. We seek to translate these results into better therapies. We are particularly interested in a type of cancer called olfactory neuroblastoma (also known as esthesioneuroblastoma) which researchers think arises from the olfactory epithelium the area of the nose important for the sense of smell. Our laboratory utilizes a variety of in vitro and in vivo experimental approaches and immunotherapeutic and other treatment platforms to achieve these goals. We are actively developing a series of clinical trials to improve treatment effectiveness and survival in patients with sinonasal and skull base cancers. 803000 +No NIH Category available Area;Chemotherapy and/or radiation;Clinical Trials;Development;Genes;Goals;Head and Neck Cancer;Immunotherapeutic agent;In Vitro;Laboratories;Malignant Neoplasms;Nasal cavity;Nose;Olfactory Epithelium;Olfactory Neuroblastoma;Operative Surgical Procedures;Patients;Research Personnel;Series;Sinus;Skull Base Neoplasms;Smell Perception;Translating;Treatment Effectiveness;cancer type;improved;in vivo;interest;programs;skull base;therapeutic target;tumor;tumorigenesis Mechanisms of olfactory neuroblastoma tumorigenesis n/a NCI 10926667 1ZICBC012129-01 1 ZIC BC 12129 1 79355671 "LONDON, NYALL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2173093 NCI Our laboratory is focused on understanding how and why head and neck cancers develop in the nasal cavity sinuses and base of the skull. We seek to translate these results into better therapies. We are particularly interested in a type of cancer called olfactory neuroblastoma (also known as esthesioneuroblastoma) which researchers think arises from the olfactory epithelium the area of the nose important for the sense of smell. Our laboratory utilizes a variety of in vitro and in vivo experimental approaches and immunotherapeutic and other treatment platforms to achieve these goals. We are actively developing a series of clinical trials to improve treatment effectiveness and survival in patients with sinonasal and skull base cancers. 1370093 +No NIH Category available Basic Science;Bioinformatics;Biological;Biological Assay;Cell Lineage;Cell Surface Proteins;Cells;Chromatin;Clinical Research;Communities;Complex;Consultations;Detection;Disease;Gene Expression Profiling;Genetic;Genetic Transcription;Genomics;Goals;Heterogeneity;Immune;Immune system;Interest Group;Laboratories;Methods;Molecular;NCI Center for Cancer Research;RNA Sequences;Receptor Cell;Research Personnel;Research Project Grants;Resolution;Sampling;Technology;Therapeutic;Tissues;Transcript;United States National Institutes of Health;Work;cell type;experience;insight;multimodality;new technology;programs;response;single cell analysis;tumor microenvironment Single Cell Analysis Facility n/a NCI 10926666 1ZICBC012123-02 1 ZIC BC 12123 2 78858607 "KELLY, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1462132 NCI In the past year SCAF has provided support to over 100 research projects from more than 40 laboratories at the NCI Center for Cancer Research. Collaborative support utilizing cutting edge single cell and spatial technologies provided high resolution insights into biological mechanisms across a range of research projects. This work included the profiling of cellular and tissue heterogeneity using high throughput droplet-based single cell genomics to better understand the tumor microenvironment the immune system and its response to disease and biological response to various therapeutic strategies. The SCAF team also continued to explore new technologies and methods and began collaborative support for new spatial profiling assays which provides a better understanding of the heterogeneity of cell types and transcriptional programs in a native tissue context. SCAF also continued to be committed to sharing its expertise and experience with the greater NIH community and has been active in providing consultations presentations and support for relevant scientific interest groups. 1462132 +No NIH Category available Biological;Computer Simulation;Data;Dependence;Dissection;Entropy;Free Energy;Goals;Hydrogen Bonding;Hydrophobicity;Modeling;Molecular;Nucleic Acids;Paper;Protein Denaturation;Proteins;Publishing;Solvents;Source;Temperature;Testing;Thermodynamics;Water;Work;enthalpy;functional group;hydrophilicity;insight;mechanical force;molecular dynamics;protein complex;protein folding;solute;theories Computer Simulation Studies of Solvation Thermodynamics n/a NCI 10926664 1ZICBC012085-02 1 ZIC BC 12085 2 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 37395 NCI In this period we published a paper that extended our previous work by examining the temperature-dependence of free energies and forces among small model hydrophilic and hydrophobic functional groups of proteins. For the hydrophilic solutes different relative orientations were used to distinguish between direct inter-solute hydrogen bonds and solutes simultaneously hydrogen bonding to a solvent water bridge. Interestingly the temperature dependencies of the hydrophobic and directly hydrogen bonding solutes turned out to be opposite to that of the bridged hydrophilic solutes: with the delta-G becoming more negative for the former and less negative for the latter with increasing temperature. Dissection of the free energy curves into enthalpy and entropy contributions and further separation of the enthalpy term into solute-solute solute-solvent and solvent-solvent components provided insight into the physical molecular causes for the distinctive thermodynamic results. Finally it was reasoned how the opposite temperature dependencies of the two types of hydrophilic interactions provides a rational for the cold denaturation of proteins. 37395 +No NIH Category available Alzheimer's Disease;Amyloid beta-Protein;Atomic Force Microscopy;Data;Dimensions;Electrons;Gamma synuclein;Goals;Image;Ion Channel;Lipoproteins;Modeling;Neurons;Paper;Parkinson Disease;Peptides;Publishing;Side;Synuclein Family;Tubular formation;alpha synuclein;amyloid structure;beta barrel;drug development;monomer;phosphoneuroprotein 14 Modeling Oligomeric Structures of Amyloid forming Peptides n/a NCI 10926663 1ZICBC012084-02 1 ZIC BC 12084 2 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 74791 NCI In this period we published two papers. In the first we proposed a range of concentric beta-barrel models and compare their dimensions to image-averaged electron micrographs of Beta-Amyloid42. The smaller oligomers have 6 8 12 16 and 18 monomers. These beads string together to form necklace-like beaded-annular-protofibrils (bAPFs). These gradually morph into smooth-APFs in which a S3 beta-barrel is shielded on one or both sides by beta-barrels formed from S1 and S2 segments. In the second we extend our beta-amyloid peptide models of oligomers annular protofibrils tubular protofibrils lipoproteins and ion channels to the alpha beta and gamma synuclein family which has been implicated in Parkinson's Disease. 74791 +No NIH Category available Autologous;Cell Count;Cells;Centrifugation;Clinical;Cytomegalovirus;Development;Evaluation;Generations;Goals;Incubated;Intention;Lentivirus;Methods;Muromonab-CD3;Mus;Older Population;Operative Surgical Procedures;Patients;Population;Process;Production;Proliferating;Protocols documentation;Recording of previous events;Retroviral Vector;Retroviridae;System;Systems Development;T-Lymphocyte;Testing;Therapeutic;Time;Training;Transfection;Viral Vector;Virus;cellular transduction;clinically relevant;exhaust;experimental study;gene therapy;improved;individualized medicine;instrumentation;manufacture;manufacturing process;programs;promoter;protocol development;safety testing;success;transgene delivery;vector Use of lentivirus in individualized cell-gene therapy n/a NCI 10926661 1ZICBC012051-03 1 ZIC BC 12051 3 15687510 "BEYER, RACHEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 346606 NCI This was a new project as of January 2021. The initial experiments are centered around establishing a baseline for comparison to the proposed lentiviral system and the development of the system and protocols to generate lentivirus suitable for clinical T-cell transductions. Critical variables of the lentivirus evaluation is the selection of promoter (EF1a CMV or MSCV LTR) lentivirus production method (concentrated vs unconcentrated) transduction protocol (incubation vs spinoculation) and use (or concentration) of OKT3 required for T-cell stimulation and activation. Lentivirus production parameters have been determined and at-scale cell experiments have been performed with the intention of transitioning to a GMP production platform. The newly developed cell production process has reduced the T cell production time to 14 days (from 24 days) and requires only 3 manipulations during that time frame. The T cell repertoire at the end of the new shorter process more closely mimics the starting T cell sub-population ratios with a continued bias towards younger naive T cells. Mouse experiments have been completed with a gamma-retroviral comparator to demonstrate clinical relevance of using lentivirus for TCR transgene delivery. The success of this project has turned the focus to the development of a lentivirus generation strategy appropriate for individualized therapy scale that meets all requirements for GMP and safety testing. Instrumentation has been identified and purchased. Training has been completed and optimization of production and downstream processing initiated. 346606 +No NIH Category available Allogenic;Annual Reports;Antigen-Presenting Cells;Autologous;B-Lymphocytes;Biological Assay;Cells;Clinical;Coculture Techniques;Complex;Contracts;Data;Detection;Development;Disease Progression;Endotoxins;Enrollment;Ensure;Enzyme-Linked Immunosorbent Assay;Failure;Flow Cytometry;Good Manufacturing Process;Human Resources;Individual;Infusion procedures;Lead;Microbiology;Mycoplasma;Operative Surgical Procedures;Patient Schedules;Patients;Plasmids;Production;Qualifying;Quality Control;Reagent;Research;Residual state;Retroviridae;Safety;Specific qualifier value;Specificity;Sterility;Testing;Time;Treatment Protocols;Viral;Virus;cellular transduction;endonuclease;gene therapy;individualized medicine;manufacture;manufacturing organization;mutant;neoantigens;personalized medicine;timeline;transduction efficiency;vector QC and Release Testing of Clinical Vector and Cell Gene Therapy Products n/a NCI 10926660 1ZICBC012049-03 1 ZIC BC 12049 3 15687510 "BEYER, RACHEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 693211 NCI The SBQC team executes multiple assays to demonstrate conformance of viral and cell products manufactured both at the Surgery Branch and from external labs such as Contract Manufacturing Organizations (CMOs). All assays are executed according to specific GMP compliant SOPs and the specifications for product use are captured on the Certificate of Analysis (COA). These assays are complex cell-based multi-day assays that are executed under time constraints to meet clinical patient treatment schedules. As each product (virus or cell) is unique and intended for a single unique patient every vector and cell product must be tested (in contrast to bulk testing for a product administered to multiple patients). Both the vector (encoding a patient specific TCR targeting a mutant neoantigen) and the cells transduced with this vector must conform to the COA specifications. Some reagents such as the antigen presenting cells (APCs) required for co-culture cell based assays are generated and assessed in the SB-QCU for use in release testing. Unique APCs must be generated for each individualized therapy and can take 1 month to generate and test. To date the unit has generated and banked B cells for every vector tested (to 80 banks). Release of Vector: The assays required to demonstrate that a vector produced at the SB or other facility is appropriate safe and meets specification for clinical use are: vector titer TCR specificity and presence (absence) of replication competent retrovirus residual plasmid residual benzonase endonuclease and sterility (microbiology endotoxin and mycoplasma). All assays except the sterility assays are performed by the SB-QCU group. Release of Cell Products: The assays required to demonstrate that cellular products manufactured at the SB is appropriate safe and meets specification for clinical use are: transduction efficiency TCR specificity presence (absence) of replication competent retrovirus residual plasmid residual benzonase endonuclease vector copy number (per cell) and sterility (microbiology endotoxin and mycoplasma). All assays except the sterility assays are performed by the SB-QCU group. The SB-QCU since its inception in 2018 has performed testing on 80 individual vector products (20 since the last annual report) and 50 individual cellular products (15 since the last annual report). An unfortunate consequence of personalized therapies with long lead times from discovery of patient specific TCRs through to a vetted patient treatment is that many vector products are made but not used as the patient becomes ineligible due to disease progression before the treatment is ready. This is the primary cause for the discrepancy in vectors tested for clinical use versus patient products generated for treatment/infusion. Other unique factors of the trials supported by this project are that some vectors are made for allogeneic use (TCR identified in another patient but vector used in manufacturing of patient autologous cells for treatment) as well as some TCRs are transferred to clinical vector production but the data generated by the research team is either incomplete or cannot be replicated using the GMP-qualified assays. The team has recently expanded to begin development of new assays or implementation of existing assays that were not a part of the unit portfolio to support upcoming IND submissions as well as INDs with low or infrequent enrollment (prior to 2018 the SB-QCU did not exist and assays were carried out by manufacturing personnel). The new (4) or resurrected (3) assays include flow cytometry PCR qPCR and cell-based assays (ELISA read-out). 693211 +No NIH Category available ATAC-seq;Algorithms;Antibodies;Area;Bioinformatics;Biological;Biological Assay;Biology;CCR;Cells;ChIP-seq;Classification;Clinical;Communities;Computational Biology;DNA;DNA analysis;DNA sequencing;Data;Data Analyses;Detection;Enhancers;Epigenetic Process;Gene Rearrangement;Genes;Genetic;Genome;Goals;Immunogenomics;Intention;Laboratories;Machine Learning;Malignant Neoplasms;Maps;Mediating;Methods;Micrococcal Nuclease;Molecular Profiling;Molecular Target;Mutation Detection;Oncogenes;Process;Proteomics;Protocols documentation;RNA;Research;Research Personnel;Research Support;Resources;Sequence Analysis;Structure;T-Lymphocyte;Technology;Training;Tumor Antigens;Validation;Work;assay development;biomarker development;clinical biomarkers;collaborative approach;convolutional neural network;epigenetic regulation;exome sequencing;genome sequencing;innovation;mass spectrometric imaging;member;new technology;next generation sequence data;next generation sequencing;response;screening;single-cell RNA sequencing;targeted sequencing;technology development;tool;transcriptome sequencing;tumor;tumor heterogeneity;whole genome Omics Technology facility n/a NCI 10926658 1ZICBC012031-03 1 ZIC BC 12031 3 9692475 "CAO, LIANG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 945320 NCI Core technology development has been the main focus during this fiscal year. We are in the process of establishing NGS-based technologies for the discovery of cancer drivers and for understanding biological mechanisms. Specifically the following technologies are established or near establishment. 1. NGS for cancer mutation detection. We adapted methods for both DNA and RNA Exome sequencing aimed for detection SNV deletion an insertion. 2. NGS for expression and fusion detection. The staff in the lab were trained for RNA Exome seq for the detection of fusions and for expression analysis. 3. Epigenetic regulation. We adapted two different methods for chip-seq including antibody-mediated DNA cutting by micrococcal nucleases and transposes. 4. Targeted sequencing of cancer gene panels 5. Customized assay development and sequencing of genes involved in T-cell mediated responses against tumor antigens 6. Validation of the NGS methods for their intended research or clinical use respectively 7. Refining the analytical pipelines for NGS data analysis. 8. Investigating tumor heterogeneity using FISH RNAScope and other fluorescent based methods. 945320 +No NIH Category available Aftercare;American Association of Cancer Research;American Society of Clinical Oncology;Antibodies;Benign;Biology;Brachyury protein;Brain;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cell Communication;Cell Density;Cell Line;Cell Therapy;Cells;Chordoma;Clinical;Collaborations;Combination immunotherapy;Complex;Cytokeratin;Data;Development;Disease Outcome;Drops;E-Cadherin;Equilibrium;FCGR3B gene;Fluorescent Antibody Technique;Formalin;Frequencies;Funding;Genetic Transcription;Goals;Grant;Granzyme;HLA-DR Antigens;Hospitals;Immune;Immunofluorescence Immunologic;Immunologics;Immunooncology;Immunotherapeutic agent;Interleukin-12;Literature;London;Lymphocyte;Macrophage;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Neoplasm to the Bone;Methods;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;NCAM1 gene;Natural Killer Cells;Nature;Neoadjuvant Therapy;Nivolumab;Olfactory Neuroblastoma;PPBP gene;PTPRC gene;Paraffin Embedding;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Process;Proteins;Quality of life;RNA;Radical Prostatectomy;Regulation;Regulatory T-Lymphocyte;Resistance;Role;Sampling;Scanning;Signal Transduction;Site;Source;Stains;Students;Survival Rate;Synaptophysin;T-Lymphocyte;Tactile;Testing;Tissue Microarray;Tissue Sample;Tissues;Transforming Growth Factor beta;Tumor Tissue;University Hospitals;Validation;Woman;Work;advanced prostate cancer;bone;brain tissue;cancer cell;cancer immunotherapy;castration resistant prostate cancer;chemotherapy;cohort;cytokine;cytotoxic;cytotoxic CD8 T cells;immune cell infiltrate;immunoregulation;indexing;insight;interest;machine learning method;medical schools;meetings;melanoma;mouse model;neoplastic cell;novel;patient response;posters;pre-clinical;programmed cell death ligand 1;prostate biopsy;protein expression;response;targeted treatment;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Tumor Immune MicroEnvironment Facility (Scientific Core) n/a NCI 10926656 1ZICBC012029-03 1 ZIC BC 12029 3 78355765 "LASSOUED, WIEM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 392937 NCI Goals and objectives: The tumor microenvironment plays a critical role in cancer development progression and control. The molecular and cellular nature of the tumor immune microenvironment influences disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Our focus is to study the tumor immune microenvironment (TIME) in preclinical and clinical samples from patients treated with immunotherapeutic agents in solo or in combination with other cures such as Chemotherapy or targeted therapy. In our facility we are developing novel multiplex immunofluorescence techniques to identify immune cells tumor cells cytokines etc. based on their protein expression or RNA transcription. Our studies will provide an immunological signature to provide insight into the complex biology involved immunologically mediated tumor killing or resistance to that killing. These could also be used to predict tumor progression or regression and may reveal new targets for immunotherapies for cancer patients. Project summary: We added 3 more patients to have a total of 13 patients having local advanced prostate cancer and undergoing radical prostatectomy (RP). These patients were treated with neoadjuvant PROSTVAC and Nivolumab (NCT 02933255). We investigated the immune modulation in TIME after treatment using multiplex immunofluorescence (Opal Method). FFPE sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with our validated T cell panel1. Combination immunotherapy significantly increased CD4+ T cells and CD8+ T cells densities in the invasive margin intratumoral and the benign compartments. 91% and 83% patients showed more than 2Xincrease of CD4 and CD8 T cells in the TIME respectively in at least one of the three compartments showing more effect that Prostvac alone. Increased proliferative indices in CD4+ and CD8+ T cells were also seen after treatment. Tregs were present in low frequencies in TIME (average of 10/mm2) with no significant changes. Moreover a significant drop in tumor cell Ki67 after treatment suggests that the combination may control tumor growth. The combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patient. This work was submitted for a poster presentation at SITC 2023 and approval is still pending. Bone metastasis is closely related to the survival rate of cancer patients and their quality of life. In the Bone metastatic site the tumor microenvironment plays a critical role in cancer development and progression by the interaction of immune cells and cancer cells. To characterize the landscape of immune cells infiltrating the prostate cancer Bone metastasis site we applied 3 validated Immunofluorescence multiplex panels (lymphocyte macrophage and Myeloid derived suppressor cell) on 13 tumor tissue samples taken from 9 patients with castration resistant prostate cancer. These samples were provided by Thomas Jefferson University Hospital. We have finished the panels staining and analysis for all samples. The analysis is in the validation process. This work was added in preliminary studies for the PCF tactile grant that was accepted for funding in 2023. In our facility we are continuously developing new multiplex immuno-fluorescence panels to investigate more the tumor microenvironment and study more in depth its components. We have a great interest in studying the role of Natural killer cells in prostate cancer. For this purpose we are developing a new panel that includes CD16 CD56 PDL1 CD8 Granzyme B CK and DAPI. We optimized these antibodies in IHC and single IF and we are at the step of including them in 1 panel. This panel will also serve to look at the cytotoxic CD8 T cells and NKs in other clinical samples. To look at the activation of TGF Beta pathway in clinical tumor samples and at the impact of Bintrafusp alfa on its regulation we are developing a multiplex panel that includes p-smad2 p-smad3 Twist p21 E-cadherin cytokeratin and DAPI. A great progress is made to develop this panel. In collaboration with Dr Nyall London and Riley Larkin (MSRP student) and to look at the HLA classes 1 and 2 and their interaction with CD4 and CD8 T cells in olfactory Neuroblastoma. We developed and validated a multiplex panel that includes: HLA1 HLA-DR CD4 CD8 Ki67 Synaptophysin and DAPI. We applied this panel on an olfactory neuroblastoma Tissue micro array. Data on these cells densities and interaction was generated and presented at the AACR 2023 meeting. in collaborating with Dr Kazusa Ishii and in the context of developing a new cell therapy TCR anti Brachyury. The expression of Brachyury in the brain tissue was to explore since in the literature there is a mixed information about this protein being expressed in the brain and in the Purkinjie cells. We used 3 antibodies anti-Brachyury from 3 different sources. For antibodies optimization we used Formalin fixed paraffin embedded cell lines: a chordoma cell line (UM-chorm1) as positive control and K562A2 as a negative cell line. The 1st and 3rd antibodies we tried showed accurate signal in the cell lines unlike the 2nd Antibody. The Brain tissue was completely negative for Brachyury using these 2 antibodies as well. The next step will be to try these antibodies on more Normal brain samples to confirm that Brachyury is not expressed in the normal brain and therefore a TCR anti Brachyury can be developed. We are developing new IF-multiplex panels for mouse tissues to support the preclinical team at the center or immuno-oncology (CIO). The preclinical team is treating mice bearing different tumor models with different drugs in solo and in combination. To look at the effect of these drugs on TIME and correlate we are developing 6 multiplex panels using IF each of these panels include 6 markers and DAPI. In collaboration with Dr Ling Zhang we looked at the impact of OT1 cells and OT1 cells+IL12 in melanoma murine model using our murine lymphocyte panel that includes: CD4 CD8 Granzyme B CD45 CD98 and DAPI. Additionally this panel was used the look at the effect of Entinostat PDS0101 NHS-Il12 in all combination on TC1 tumors in collaboration with Dr Caroline Jochems. Another aspect of our work is to provide material to AI teams. We are continuing our collaboration with Dr George Zeki from FNL and Dr Faisal Mahmood from Harvard Medical School and the Division of Computational Pathology at the Brigham and Women's Hospital. We started a collaboration with Dr Eytan Ruppin and his team from NCI and we provided scans of H&Es from clinical tumor samples. in this study they tested their machine learning method: ENLIGT-DeepPT on our samples to predict patients response to Bintrafusp alfa. This work was presented in ASCO 2023. 392937 +No NIH Category available AGFG1 gene;Acceleration;Address;Artificial Intelligence;Behavior;Biochemical;Biological Assay;Biological Models;Books;Breeding;CCR;CRISPR/Cas technology;Cardiovascular system;Cell Survival;Cells;Cellular Structures;Cilia;Clinical Research;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Collection;Color;Communication;DUSP6 protein;Data;Data Analyses;Defect;Dependence;Development;Disease;Disease model;Edema;Effectiveness;Embryo;Equipment;Extravasation;Future;Gene Transfer Techniques;Generations;Genes;Genetic;Germ-Line Mutation;Goals;Heart;Hematopoietic stem cells;Human;Hypertrophic Cardiomyopathy;Image;In Situ Hybridization;Injections;Interruption;Knock-out;Label;Laboratories;Letters;MAP Kinase Gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Measurement;Medical Genetics;Membrane;Membrane Fusion;Methods;Mission;Modeling;Molecular;Monitor;Mus;Mutation;Nature;Orthologous Gene;Patients;Pattern;Pediatric Oncology;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Positioning Attribute;Preparation;Process;Production;Productivity;Protein Analysis;Protein Overexpression;Proteins;Publishing;RNA;Rana;Reaction;Regulation;Reporter;Research;Research Personnel;Resources;Retirement;Scholars Program;Severities;Signal Pathway;Signal Transduction;Stains;Structure;Subcellular structure;System;Technical Expertise;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Training;Transgenic Organisms;Transmission Electron Microscopy;United States National Institutes of Health;Validation;Variant;Vascular System;Vertebrates;Visualization;Work;Writing;Xenograft procedure;Zebrafish;Zinc Fingers;cancer cell;cancer genetics;cardiofaciocutaneous syndrome;causal variant;cell motility;ciliopathy;cilium biogenesis;convergent extension;design;developmental disease;egg;experimental study;genetic approach;genetic manipulation;human disease;imaging capabilities;imaging system;in vivo;in vivo imaging;knock-down;knockout gene;melanoma;model organism;mutant;neoplastic cell;novel;novel therapeutics;overexpression;programs;protein expression;protein function;reverse genetics;targeted treatment;tenure track;timeline;tool;trafficking;transcription factor;transgene expression;tumor behavior;tumor microenvironment;tumor progression;variant of interest Zebrafish core n/a NCI 10926654 1ZICBC011956-04 1 ZIC BC 11956 4 77857653 "KETTENHOFEN, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 756150 NCI Project summaries and research accomplishments for the zebrafish Core in 2022/2023 are listed below: 1. The facility is collaborating with Dr. Christopher Westlake's group (LCDS NCI-CCR) on several projects utilizing the zebrafish model system to study primary cilia formation and ciliary signaling. These studies involve the use of morpholino CRISPR transgenic lines and protein overexpression approaches combined with the biochemical analysis of protein expression and imaging of developmental structures by immunofluorescent staining and confocal or transmission electron microscopy. Dr Westlake's group is investigating patient mutations associated with regulation of Rab11 ciliogenesis function. We are using a combination of morpholino and overexpression/rescue approaches in zebrafish to perform functional studies of the human variants and determine whether we could model ciliopathy-related disease. A revised manuscript is being prepared for resubmission to Nature Communication that included several additional zebrafish experiments including the development of a CRIPSR line requested by the reviewers. In a second project the facility is collaborating with Dr. Lu to study the function of a group of proteins involved in membrane fusion and determine whether they function in ciliogenesis. In a third project the facility worked with Dr. Wang and in collaboration with Dr.Daar's group to identify ciliogenesis defects associated with Rab protein functioning in multiciliogenesis. This work was interrupted due to the departure of Dr. Wang but may resume in the future. In a third project with Dr. Saha the facility is developing tools to perform 2-3 color live imaging of membrane tubules using expression of fluorescently labeled proteins in developing zebrafish. Both transient and transgenic (Tg) expression of Rab proteins known to be involved in membrane tubule trafficking and ciliogenesis are monitored overtime using the spinning disk confocal from Dr. Westlake. These novel tools would allow to provide the first evidence of a rab-dependent trafficking cascade important for membrane tubule formation in vivo. This work if successful will be combined with Dr- Saha's work in human cells and included in a manuscript that is currently in preparation. Furthermore the development of transgenic lines and other fluorescent markers amenable for the zebrafish system will be used in the future to perform multicolor live ciliogenesis assays. Finally in collaboration with Dr. Kristen Johnson at UNH Manchester the facility is studying the expression pattern of a transcription factor important for multiciliated cells formation in developing embryos. Overexpression of mutant proteins as well as 2 colors in situ hybridization chain reaction techniques will be used to assess the function of the transcription factor. 2. In collaboration with Dr. Russell Smith in Dr. Deborah Morrison's group (LCDS and the NCI-RASopathy Initiative NCI-CCR) we explored the function and localization of novel B-Raf mutants associated with cardiofaciocutaneous syndrome (CFC) one of a group of developmental disorders known collectively as the RASopathies. In this study we determined whether early cell migration and phenotypical defects induced by overexpression of the B-Raf mutants in zebrafish correlated with the corresponding disease presentation in humans and whether the observed phenotypes were specific to the causative mutation. This work was completed and published at Molecular Cell (Spencer-Smith R. et al. 2022). This recent study was critical to establish standards for a RASopathy-specific phenotypical pipeline that now includes several powerful quantitative assays such as convergent-extension cell movements heart edema formation analysis and measurements of the ceratohyal angles using the Tg(col2a1:GFP) line. This pipeline is currently employed in two separate collaborative projects with Elizabeth Terrel and Dan Ritt from Dr. Deborah Morrison's group to identify the function of other RAF variants and test novel drug treatments. 3. In collaboration with Dr. Marielle Yohe (Pediatric Oncology and the NCI-RASopathy Initiative NCI-CCR) the facility is developing fluorescent reporter transgenic lines (Tg) to assist in the analysis of RASopathy-associated mutant proteins. Collaborative studies with the Yohe group also use the RASopathy phenotypical pipeline developed for the Morrison group and in particular the convergence-extension assay to analyze any previously uncharacterized RASopathy mutants identified through the NCI-RASopathies Initiative. These assays will be important to obtain critical information regarding the severity of the mutations and the effectiveness of various drug treatments. The Tg(Dusp6:GFP) will also be used as a reporter line for RAS/MAPK signaling activation in studies evaluating the effects of specific drug treatments. Additionally a novel assay to identify the presence of hypertrophic cardiomyopathy (HCM) in mutant zebrafish embryos is currently under development. Two transgenic lines Tg(Myl7:GFP) and Tg(cmlc2:GFP) were acquired to characterize heart looping defects. The goal of this collaboration will be to use the zebrafish system to accelerate the development of patient-specific therapeutic approaches. Dr. Yohe invited Dr. Christine Kettenhofen (Insinna) to write the zebrafish models section of a chapter on non-NF1 Rasopathies for an upcoming book edited by Dr. Kate Rauen on Rasopathies. The chapter was submitted. Finally a collaboration with Dr. Michael Sargen from the NCI Clinical Genetics Branch (DCGEG) was proposed in an application for a tenure-track position within the Lasker Clinical Research Scholars Program. A major focus of Dr. Sargens' research will be to identify germline variants contributing to melanoma development. As part of this research Dr. Sargen would be collaborating with Dr. Yohe to perform cell-based functional studies of variants of interest and our facility would perform in vivo experiments using zebrafish models. A letter of support for the Lasker application was written and the proposal submitted. 4. In collaboration with Dr. Orri Gudmundsson in Dr. Jonathan Keller (Mouse Cancer Genetics Program NCI-CCR) the facility is continuing a project started in FY2020 aimed at analyzing the functional requirement of the zinc finger protein Pogz in zebrafish hematopoietic stem cells (HSCs). Embryos lacking pogz were generated using CRISPR/Cas9 and validation of the knockout was confirmed. Once the facility obtains the F2 generation for the double knock-out line the project will be interrupted due to the retirement of Dr. Keller and the line will be transferred to Dr. Gudmundsson to complete the project in his new laboratory. 5. In collaboration with Dr. Esta Sterneck (LCDS NCI-CCR) the facility performed pilot experiments to establish a xenograft assay to study the metastatic behavior of human tumor cells in zebrafish. Several drug treatments that target various cancer-associated signaling pathways were tested. The goal of this research will be to identify classes of drugs that will enhance or reduce tumor cell survival. In the future the behavior of tumor cells will also be studied using a modified xenograft approach to observe whether cells leave the circulatory system and extravasate into surrounding tissues using a transgenic line marking the vascular system. 756150 +No NIH Category available Abdomen;Aftercare;Algorithms;Animals;Bacteria;Biochemical;Biological;Biological Markers;Biopsy;Blood;CCR;Cancer Detection;Cancer Model;Carcinogenesis Mechanism;Cells;Certification;Chemical Shift Imaging;Chemicals;Chills;Chromatography;Clinic;Clinical;Data Collection;Detection;Deuterium;Development;Dose;Electron Spin Resonance Spectroscopy;Glucose;Glycolysis;Goals;Head;Human;Image;Immune system;In Situ;Infusion procedures;Ions;Isotope Labeling;Isotopes;Label;Lipids;Magic;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Malignant neoplasm of brain;Malignant neoplasm of prostate;Mammals;Mass Spectrum Analysis;Metabolic;Metabolism;Methodology;Methods;Monitor;NMR Spectroscopy;Nuclear;Operative Surgical Procedures;Oxygen;PET/CT scan;Pathway interactions;Patients;Physiologic pulse;Plants;Positron-Emission Tomography;Preparation;Procedures;Production;Proliferating;Publications;Pyruvate;Pyruvic Acid;Recurrent Malignant Neoplasm;Renal Cell Carcinoma;Renal carcinoma;Research;Resolution;Resources;Sampling;Scanning;Specimen;Sterility;Succinate Dehydrogenase;TOCSY;Therapeutic Intervention;Time;Tissues;Toxic effect;Tracer;Tumor-Derived;United States National Institutes of Health;Urine;Visualization;cancer biomarkers;cancer diagnosis;cancer imaging;cancer prevention;cancer recurrence;cancer therapy;clinical center;design;experimental study;fluorodeoxyglucose;glucose uptake;imaging capabilities;imaging study;in vivo;inhibitor;instrument;isotope incorporation;mass spectrometer;metabolic imaging;metabolomics;method development;molecular imaging;multimodality;new therapeutic target;novel;novel strategies;novel therapeutics;pre-clinical;small molecule;solid state;spectroscopic imaging;stable isotope;tumor;tumor metabolism;ultra high resolution Metabolomics Core n/a NCI 10926652 1ZICBC011932-04 1 ZIC BC 11932 4 77857650 "CROOKS, DANIEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1632374 NCI This facility is focused on the application of targeted ultra-high resolution stable isotope-resolved metabolomics as well as critical careful sample extraction and preparation methodologies designed to obtain as much information as possible from clinical specimens. The initial mass spectrometer is a Thermo Orbitrap Fusion Lumos capable of 1000000 resolving power. This spectrometer is equipped with an Advion Nanomate direct infusion electrospray module as well as an Ion Chromatography module which together allow for resolution of a wide range of intermediary metabolites. The ultra-high resolution capability of this spectrometer allows for resolution of metabolites that are multiply-labeled with different isotopes (e.g. 13C 15N 2H) in a single specimen. We are currently developing a workflow tailored for targeted quantitation of approximately 120 cellular metabolites with the capability for multiple heavy isotope labels in a single experiment. The facility is also equipped with a powerful 700MHz NMR magnet with with a triple inverse resonance cryoprobe and high-capacity chilled autosampler available for targeted and untargeted isotope-resolved studies of polar and non-polar metabolite and lipid extracts. In situ solid-state tissue metabolite analysis is also available via magic angle spinning (MAS-NMR) Examples include the determination of the global fate of intracellular 13C tracer molecule metabolism in tumor-derived cells such as succinate dehydrogenase-deficient renal cell carcinoma (Saxena et al. 2016) and global assessment of lipid isotope incorporation using 1D and 2D HSQC pulse sequences (Crooks et al. 2018; Lin et al. 2021). In addition positional determination of metabolite isotope labeling can be determined using 1D and 2D NMR pulse sequences such as 1H-1H TOCSY (Kishimoto et al. 2019). Data collection and method development for NMR analysis of metabolite extracts from clinical tissue specimens obtained during surgical and biopsy procedures in the NIH Clinical Center are currently underway analyses performed using this instrument have already resulted in numerous CCR publications. Pre-clinical metabolic imaging resources are available for dynamic small animal metabolic imaging via Dynamic Nuclear Polarization (hyperpolarization) as well as non-hyperpolarized deuterium and 13C metabolic imaging using image deconvolution algorithms developed at CCR. Additionally pre-clinical PET-CT imaging capability will be available in 2021. Recent research highlights include quantitative assessment of the relationship between tumor glycolysis and oxygenation status by multimodal sequential application of electron paramagnetic resonance imaging of tumor oxygen levels hyperpolarized MRI to assess tumor lactate production rates and 18FDG-PET imaging to assess tumor glucose uptake (Yamamoto et al. 2020). In addition a tensor decomposition post-processing algorithm developed at CCR was applied to MRI chemical shift imaging experiments in order to visualize the metabolism of 13C-glucose in tumors in vivo and assess tumor glycolytic propensities without the need for tracer hyperpolarization (Brender et al. 2019). Finally the activity of a novel therapeutic LDH inhibitor molecule developed at CCR was assessed in vivo using hyperpolarized 13C-pyruvate infusion before and after treatment revealing potent on-target efficacy and a rapid rewiring of tumor metabolism following therapy (Oshima et al. 2020). Clinical 13C-hyperpolarized metabolic imaging with the investigational agent 1-13C-pyruvic acid will be conducted at NCI in patients with renal prostate and brain cancers using a SPINLab clinical polarizer and specialized 13C MRI scanner located in the Molecular Imaging Clinic. Clinical head abdominal and endorectal coils are currently under development. Construction of a sterile filling room in the Molecular Imaging Clinic has been completed to facilitate preparation of clinical 13C1-pyruvate doses required for hyperpolarized imaging studies and the sterile filling facility is currently undergoing certification so that an IND can be cross-filed and scanning of patients can begin. 1632374 +No NIH Category available Address;Administrator;Adopted;Affect;Annual Reports;Authorization documentation;Budgets;CCR;Cell Line;Certification;Clinical Protocols;Clinical Research Protocols;Clinical Trials;Code;Communication;Computer software;Counseling;Data;Development;Disease;Education;Electronic Mail;Elements;Ensure;Funding;Gene Expression;Genome;Genomics;Grant;Human;Informed Consent;Infrastructure;Institution;Intramural Research;Intramural Research Program;Laboratory Scientists;Language;Leadership;Legal;Malignant Neoplasms;Manuals;Metagenomics;Names;Notification;Organism;Participant;Pediatric Oncology Group;Persons;Policies;Procedures;Process;Protocols documentation;Published Comment;Rare Diseases;Recommendation;Research;Research Personnel;Resources;Review Committee;SNP array;Science Policy;Services;Specific qualifier value;System;Testing;Time;Transfer Agreement;United States;United States National Institutes of Health;Update;Writing;data management;data portal;data preservation;data sharing;data sharing networks;data standards;data submission;database of Genotypes and Phenotypes;epigenomics;genome wide association study;genomic data;large scale data;meetings;non-genomic;statistics;timeline;tool;transcriptomics;usability;waiver;web site;working group Genomic Data Sharing n/a NCI 10926651 1ZICBC011931-04 1 ZIC BC 11931 4 16162371 "CALZONE, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 902887 NCI This year the NIH Office of Science Policy (OSP) launched the new Data Management and Sharing (DMS) Policy effective January 25 2023. The DMS Policy mandates sharing of scientific data generated from NIH-funded or conducted research and went into effect 1/25/2023 for laboratory scientists and clinical research protocols going in for Scientific Review. For the Intramural Research Program a DMS plan is required for scientific data from research associated with a: ZIA (human and non-human research); Clinical protocol that will undergo IC Initial Scientific Review; Genomic Data Sharing (GDS) project The GDS policy applies to all NIH-funded research generating large-scale human or non-human genomic data. Large-scale data including genome-wide association studies (GWAS) single nucleotide polymorphism (SNP) arrays genome sequence transcriptomic metagenomic epigenomic and gene expression data. The GDS Policy expanded on November 1 2018 to include public access to Genomic Summary Results. At that time the Office of Science Policy (OSP) mandated dbGaP minimal registration for all studies as a means for OSP to communicate with all investigators with policy-applicable studies. OSP has since backed off this mandate so minimal registrations have been discontinued. Guidance issued from the CCR Director also mandates genomic data sharing for rare diseases/cancers with no minimum thresholds. The Trans-NCI Genomic Data Sharing Working Group adopted the definition of rare disease - a disease that affects less than 200000 persons in the United States. The DMS Plan incorporates the requirements of both the DMS and GDS policies and addresses six core elements: Data type; Related Tools Software and/or Code; Data Standards; Data Preservation Access and Associated Timelines; Access Distribution or Reuse Considerations; and Oversight of Data Management and Sharing. There is also an option to include other elements as applicable. Laboratory scientists completed DMS plans by 1/25/2023 using the Annual Report System. Plans that involved genomics were reviewed by K. Calzone in addition to either Brenda Boersma or Kelly Haskins with their focus predominately on non-genomic plan elements. Plans were approved or the investigator was provided with written comments on items to address. DMS plans completed by 1/25/2023 were submitted electronically to OIR in the NIDB. Existing clinical protocols are required to comply at the time of quadrennial review (which CCR does not currently have in place) or as specified by CCR or OIR. New protocols must submit their plan during Scientific Review Committee (SRC). SRC-reviewed plans are revised if applicable finalized and approved during Study Initiation. In contrast to the GDS policy the NCI Office of Data Sharing did not establish a procedure for policy exceptions which can occur because of limitations specified in Tech Transfer agreements. After input from the Office of Science Policy the NCI Office of Data Sharing and legal counsel in the Office of Intramural Research the final determination was that CCR leadership could determine whether to grant a data-sharing waiver. A CCR waiver mechanism has been implemented with the current approver Dr. Misteli or his designee. Investigator Resources Data Sharing Portal: Critical to the infrastructure needed to facilitate investigators is developing and maintaining the CCR Data Sharing Portal (https://service.cancer.gov/gds/). The DMS Policy mandates a DMS Plan (DMSP) and an Institutional Certification (IC) to be completed based on whether the study involves human or non-human organisms or cell lines. DMS plans for new clinical protocols began using the OIR intramural pdf template until the existing Data Sharing portal was modified to create the new DMS plan. Several delays occurred in this process including a delay in receiving the budget from CBIIT and a delay in CCR rendering a budget decision to move forward. Usability testing was completed by the deadline and revisions based on the user testing were completed when one CCR leader submitted changes deemed essential. CBIIT had already reallocated Staff to other projects with budget and staffing implications. After an additional delay the final determination was to launch the portal in its present condition because these items such as the API for ZIA numbers CBIIT was not clear that they could even build in the Service Now platform that houses the portal. The permission to launch the portal as is was shared with me on 6/16/2023. However at that same time NCI ODS notified us that new Institutional Certification memo templates were established and mandated for use effective 7/1/2023. CBIIT immediately began that portal revision and investigating how to update each existing Institutional Certification. At the same time the portal resubmit function was not functioning. As such CBIIT asked that the launch be delayed until that resubmit fix was made and the Institutional Certification update was completed. As of July 21 2023 CBIIT expects to launch the week of August 7 2023. Brenda Boersma has an email prepared for clinical protocol PI distribution once the launch date is finalized. Support Documents: To support the DMS policy and the new portal in addition to the CCR Data Management and Sharing Website we have established the following Standard Operating Procedures (SOPs): 1-RPS 21-Establishing a Data Management Sharing Plan; 2-RPS 22-Requesting a Data Management and Sharing Waiver; 3-RPS 23-Registering a Clinical Trial in dbGaP In addition the Office of Education and Compliance recommended that instead of integrating portal-specific functionality into the SOPs those details be put into a Data Management and Sharing Portal User Manual which could be revised as needed without delays associated with the review/approval process for SOPs. The three SOPs and the Manual are currently on the CCR SOP website. Lastly we have revised the data sharing WIKI page renaming it to Data Management and Sharing and reflecting the current Data Sharing landscape and associated resources. Statistics from July 3 2022-July 4 2023 Tracking Portal: 565 studies are in the GDS Tracking portal. 26 GDSPs were reviewed and 23 were approved. 35 ICs were reviewed and 31 were approved. The GPA Administrator has been auditing the entries for incomplete documents never submitted for review/approval revisions never resubmitted and eliminating duplicates. Waivers: One waiver was submitted and approved IRB001578 ceding data sharing to the Children's Oncology Group. PSO indicates two additional waivers to be submitted: IRB001529-Gulley and IRB01583-Annunziata. Lastly Dr. Aldape has been notified about the new waiver option as he was considering submitting an Exception. New Study Sensitivity Determinations: GSR Sensitivity Determinations: 52 studies were reviewed 19 Sensitive 33 Not Sensitive. Data Sharing: 473 studies are registered in dbGaP 70 complete registrations and 403 minimal registrations (discontinued activity). Data was submitted on 19 studies this year and 3 new versions of existing studies. There are 67 studies with some aspect of data submission: 3 additional studies have complete registrations with no data submission. Specifically 2 are late on submission and one with no target release date. Lastly there are 15 studies with data submitted but late on release. 902887 +No NIH Category available 2019-nCoV;Antibodies;Antibody Therapy;Antibody-drug conjugates;Antigen Targeting;Antigens;Archives;Attention;Award;Bacteriophages;Binding;Binding Proteins;Biological Assay;COVID-19 diagnosis;COVID-19 pandemic;Camels;Cell Surface Receptors;Cells;Clinic;Collaborations;Communicable Diseases;Communication;Communities;Complementarity Determining Regions;Complex;Data;Development;Discipline of Nuclear Medicine;Distant;Engineering;Epitopes;Etiology;Exotoxins;GPC3 gene;Generations;Glypican;Hepatology;Homologous Gene;Human;Immunoglobulin G;Immunoglobulins;Immunotoxins;Intramural Research;Ion Channel;Journals;Laboratories;Laboratory Research;Libraries;Ligand Binding;Malignant Neoplasms;Methodology;Methods;Mus;NCI Center for Cancer Research;Names;National Cancer Institute;National Institute of Allergy and Infectious Disease;Nature;Nurses;Paper;Patients;Phage Display;Property;Proteins;Protocols documentation;Pseudomonas;Publishing;Research;Research Personnel;Resources;SARS-CoV-2 antibody;Scientist;Services;Shark;Signal Transduction;Site;Source;Structure;Technology;Testing;Therapeutic;Therapeutic antibodies;Training;United States National Institutes of Health;Universities;Variant;Virus;Virus Diseases;Work;antibody engineering;antibody libraries;betacoronavirus;cancer therapy;chimeric antigen receptor T cells;clinical efficacy;cross reactivity;feature detection;human disease;immunoengineering;immunogenicity;innovation;interest;mesothelin;molecular imaging;nanobodies;neutralizing antibody;new technology;novel;pathogenic virus;programs;protein data bank;receptor;receptor binding;technology development;therapeutic target;three dimensional structure;variants of concern Antibody Engineering Program n/a NCI 10926650 1ZICBC011891-05 1 ZIC BC 11891 5 9692203 "HO, MITCHELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 502510 NCI While antibody-based therapeutics have emerged as a major component in cancer treatment the generation of antibodies to important targets such as cell surface receptors and ion channels remains difficult. These proteins contain buried functional sites that are often unreachable by classical mouse or human IgG-based antibodies. Single-domain antibodies have shown a promising ability to target difficult antigens and hidden epitopes. Dr. Mitchell Ho at the NCI has demonstrated that single-domain antibodies are capable of targeting buried functional sites in cancer signaling complexes [Feng et al. PNAS 2013; Gao et al Nature Communications 2015; Li et al. PNAS 2017; Li et al. Hepatology 2019]. The Ho lab has constructed large shark and camel single-domain ('nanobody') libraries and isolated binders to a wide range of antigens [Feng et al. 2013; Gao et al 2015; Li et al. 2017; Hong et al. 2022; Li et al. 2023; Buffington et al. 2023] indicating that the phage-displayed single domain antibody libraries can be a valuable source to isolate therapeutic antibodies. In FY23 the AEP published one research article [Buffington et al. FASEB Journal 2023] one method paper [Zhang et al. Current Protocols 2023] and one collaborative paper [Fayn et al. Journal Nuclear Medicine 2023]. SARS-CoV-2 is the etiological agent of the COVID-19 pandemic. Antibody-based therapeutics targeting the spike protein specifically the S1 subunit or the receptor binding domain (RBD) of SARS-CoV-2 have gained attention due to their clinical efficacy in treating patients diagnosed with COVID-19. An alternative to conventional antibody therapeutics is the use of shark new antigen variable receptor domain (VNAR) antibodies. VNAR s are small (15 kDa) and can reach deep into the pockets or grooves of the target antigen. In FY2023 the AEP isolated 53 VNAR s that bind to the S2 subunit by phage panning from a naive nurse shark VNAR phage display library constructed and provided by Dr. Mitchell Ho's laboratory. Among those binders S2A9 showed the best neutralization activity against the original pseudotyped SARS-CoV-2 virus. Several binders including S2A9 showed cross-reactivity against S2 subunits from other beta coronaviruses. Furthermore S2A9 showed neutralization activity against all variants of concern (VOCs) from alpha to omicron (including BA1 BA2 BA4 and BA5) in both pseudovirus and live virus neutralization assays. Our findings suggest that S2A9 could be a promising lead molecule for the development of broadly neutralizing antibodies against SARS-CoV-2 and emerging variants. The nurse shark VNAR phage library created by the Ho lab offers a novel platform that can be used to rapidly isolate single-domain antibodies against emerging viral pathogens. One critical obstacle to getting a shark VNAR single domain to work in the clinic is its potential immunogenicity in humans. The VNAR of shark single domain antibodies is evolutionarily distant from the variable regions (VH) of mammalian immunoglobulins yet we hypothesize that it may still have complementarity-determining regions (CDRs) that are involved in antigen recognition at least for the most part of the antigen recognition therefore making it possible to humanize by grafting these CDRs to the framework of human VH homologs. For testing this hypothesis we show the VNAR CDR based on an analysis of currently available VNAR -antigen structure complexes in the global Protein Data Bank archive of 3D structure data and describe the detailed protocol to humanize VNAR by CDR grafting using B6 (an anti-Pseudomonas exotoxin VNAR) the most common type (Type II) of shark VNAR s as an example. We published the methods in Current Protocols (Buffington J Duan Z Kwon HJ Hong J Li D Feng M Xie H Ho M. Identification of nurse shark VNAR single-domain antibodies targeting the spike S2 subunit of SARS-CoV-2. FASEB J. 2023 Jun;37(6):e22973. doi: 10.1096/fj.202202099RR.) so other scientists can also test our methodology. Ongoing efforts will further optimize the protocol for engineering shark VNARs for treating cancer and other human diseases. In FY2023 the AEP also published one research paper as co-authors in collaboration with Dr. Freddy Escorcia in Molecular Imaging Branch at the NCI CCR [Fayne et al. J Nucl Med 2023]. Ongoing AEP collaborations aim to develop therapeutic antibodies and engineer immune protein and cells with Dr. Ira Pastan Dr. James Gulley (NCI) Dr. Glenn Merlino (NCI) Dr. Peter Kwong (NIAID) Dr. Eytan Ruppin (NCI) and Dr. Christian Hinrichs (Rutgers University). 502510 +No NIH Category available APOCEC3G gene;Affinity;Binding;Catalytic Domain;Cells;Complex;Conflict (Psychology);Cryoelectron Microscopy;Cytosine deaminase;DNA;DNA Sequence Alteration;Deamination;Defense Mechanisms;Epitopes;Evolution;Goals;HIV Genome;HIV-1;HIV/AIDS;Human;Infection;Magnetism;Malignant Neoplasms;Modification;Mutate;Mutation;Nuclear;Nucleotides;Pathway interactions;Prognosis;Proteins;RNA;Reaction;Research;Research Project Grants;Role;Single-Stranded DNA;Source;Spectrum Analysis;Structure;Techniques;Testing;Ubiquitin;Virion;X-Ray Crystallography;Zebularine;analog;cancer therapy;cancer type;inhibitor;multicatalytic endopeptidase complex;novel therapeutics;pathogen;protein structure;response;therapy resistant;tumor;tumor growth;tumor progression;ubiquitin-protein ligase Structural studies of biomolecules related to cancer and HIV-AIDS n/a NCI 10926649 1ZICBC011849-06 1 ZIC BC 11849 6 14732013 "MATSUO, HIROSHI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 654992 NCI APOBEC3G (A3G) and APOBEC3H (A3H) are single-stranded DNA cytosine deaminase that can restrict HIV-1 infection by mutating HIV-1 genome. HIV-1 developed a counter defense mechanism by which virion infectivity factor (Vif) leads the degradation of A3G/A3H through ubiquitin-proteasome pathway. Our ultimate goal is to generate small compounds which inhibit the degradation of A3G/A3H. Previously we had determined NMR and crystal structures of domains of A3 proteins including the VIf-binding domain and the catalytic domain. In addition we had determined co-crystal structures of the A3's catalytic domain-ssDNA complex. We have obtained cryo-EM structure of APOBEC3G:HIV-1 Vif complex which provided unique A3G-RNA and Vif-RNA interaction in addition to A3G-Vif interaction (Kouno et al. Nat. Commun. 2023). We have made progress in determining the structure of the A3H-Vif E3 ubiquitin ligase complex by using cryoEM which will provide epitopes to be targeted by small compounds which inhibit formation of the complex. Dysregulation of APOBEC3A (A3A) and APOBEC3B (A3B) proteins contributes a major endogenous source of DNA mutations traced in approximately 75% of cancer types and 50% of all cancers analyzed. A3A/A3B proteins can cause DNA mutations either alone or as the response to cancer therapies which can drive evolution of cancers and A3A/A3B related mutations maybe associated with poor prognosis and therapeutic resistance in cancers. We have determined co-crystal structure of the A3G-catalytic domain and 2'-deoxy-zebularine DNA and reveal a transition state of deamination. We are developing ssDNA based A3A/A3B inhibitors as ssDNA is the natural substrate for their catalytic reaction. A transition state analogue 2'-deoxy-zebularine was incorporated into the target ssDNA sequence of A3A/A3B and yielded promising affinity and inhibitory effect. We are currently testing modification of nucleotides in order to resist degradation in cells. 654992 +No NIH Category available Accreditation;American;Anatomy;Cancer Center;Clinical;Collaborations;Collection;Complex;Consult;Databases;Diagnosis;Diagnostic;Freezing;Frozen Sections;Genetic Materials;Goals;Histology;Human;Journals;Laboratories;Medical center;Military Personnel;Operating Rooms;Operative Surgical Procedures;Pathologist;Pathology;Patients;Peer Review;Primary Neoplasm;Process;Protocols documentation;Publications;Research;Research Personnel;Research Support;Services;Slide;Specimen;Stains;Standardization;Surgical Pathology;System;Time;Tissue Banks;Tissue Preservation;Tissue Procurements;Tissues;Training;United States National Institutes of Health;Work;biobank;clinical center;college;data resource;demographics;laboratory facility;meetings;operation;preservation;programs;repository;standard of care;tissue processing;tissue resource Tissue Procurement Processing Facility and Biorepository n/a NCI 10926647 1ZICBC011731-08 1 ZIC BC 11731 8 14732101 "CHINQUEE, JOSEPH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 208488 NCI The Tissue Processing and Procurement Facility (TPPF) of the Laboratory of Pathology (LP) is staffed by two Pathologists Assistants (PAs for Pathology) and a Technical Laboratory Manager (TLM) who each also supports the General Surgical Pathology Clinical Operations and Histology services. The TPPF also houses LP's frozen section room and is contiguous to the Clinical Center's Operating Rooms. The connection to the OR allows LP's PAs to support time-sensitive tissue procurement inside the operating room or immediately following collection and delivery to the TPPF. This allows immediate processing and preservation of tissues procured for diagnosis and research. The PAs act as liaisons between OR staff research teams and pathology staff by coordinating tissue procurements in the operating room (OR) which entails facilitation of the complex procurements that often involve multiple investigators and multiple protocols simultaneously. PAs work with investigators identifying what tissues need to be procured how they are to be stabilized and what protocols allow the tissue procurement to occur all while preserving the diagnostic integrity of the tissue. The Pas perform or participate in most research tissue procurements processing and distribution to the research labs. This system allows as many investigators as possible to benefit all while meeting the standard-of-care for anatomic pathology. During the past fiscal year TPPF staff processed more than 3624 specimens to support 1408 tissue procurements during surgery which were distributed to more than 250 NIH investigators in 12 ICs under approximately 250 protocols. PA's also train new clinical residents each year in tissue procurement and frozen sections for intra-operative consults. The WRNMMC tissue bank collection has amassed a repository of frozen and FFPE blocks with associated clinical information that expand upon the research tissue resources available for utilization by NIH investigators. Each request for specimens is reviewed by a Tissue Resource Committee of Pathologists and regulatory administrative staff in LP prior to distribution. Materials acquired from the TRC program were instrumental resources for data comparison and collection leading to publications in peer review journals. 208488 +No NIH Category available Affect;Amino Acid Sequence;Binding;Binding Proteins;Brain;CCAAT-Enhancer-Binding Proteins;Cellular biology;Consensus;CpG dinucleotide;Cyclic AMP-Responsive DNA-Binding Protein;Cytosine;DNA;DNA Binding;DNA Sequence;DNA-Directed DNA Polymerase;Dimerization;Dioxygenases;Epigenetic Process;Family;Family member;Foundations;Gene Expression;Genes;Goals;Helix-Turn-Helix Motifs;Leucine Zippers;Mediating;Methylation;Modification;N-terminal;Property;Response Elements;Single-Stranded DNA;Site;Specificity;Structure;TCF7L2 gene;Thymine DNA Glycosylase;Tissues;USF1 gene;Variant;Work;ZIP protein;activating transcription factor 1;cell type;demethylation;ds-DNA;in vivo;stem cells;structural determinants;transcription factor Effects of Cytosine Modifications on Transcription Factor Binding n/a NCI 10926646 1ZICBC011724-08 1 ZIC BC 11724 8 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 37395 NCI Sequence-specific DNA binding of transcription factors (TFs) is the foundation of regulated gene expression. Two recent observations have broadened the lexicon of sequence-specific DNA binding of mammalian TFs: the first is that methylated cytosines (5mC) are iteratively oxidized by the ten-eleven-translocation family of dioxygenases to 5-hydroxymethylcytosine (5hmC) 5-formylcytosine (5fC) and 5-carboxycytosine (5caC). 5fC and 5caC are removed by thymine DNA glycosylase completing the DNA demethylation cycle. However 5hmC is found accumulatesd in several tissues suggesting it may have a regulatory function. The second finding is that 5mC can occur outside of CG dinucleotides initially being observed in stem cells and later in the brain. 5mC in CG dinucleotides is known to inhibit or enhance the DNA binding of B-ZIP proteins. The cAMP response element-binding protein (CREB1) regulates expression of cellular genes by binding to its consensus CRE sequence (TGAC'GTCA) and its variants including the CRE/CEBP chimeric site (TGAC'GCAA). Double-stranded cytosine methylation of the CG dinucleotide at the center of the CRE motif inhibits CREB1 binding leading to suppression of gene expression. In contrast methylation of the central CG dinucleotide in the C/EBP motif TTGC'GCAA increases DNA binding of C/EBP family members. While the effect of 5mC and 5hmC in CG dinucleotides on sequence-specific DNA binding of transcription factors has been explored their effect outside of CG dinucleotides on DNA binding has not been examined. The B-ZIP family of transcription factors have a bipartite structure with the leucine zipper region mediating dimerization and the N-terminal basic region mediating sequence specific DNA binding. The structural determinants of leucine zipper domain mediated B-ZIP dimerization specificity and stability have been investigated in detail. However the relationship between the amino acid sequence of the B-ZIP basic region and the DNA sequences they bind including those with modified cytosines has not been explored. T7 DNA polymerase can efficiently incorporate 5mC and 5hmC into DNA when double-stranding single-stranded DNA. We exploited this property to double-strand single-stranded DNA 60-mers on an Agilent microarray using 5mC or 5hmC creating double-stranded DNA sequences containing an asymmetric distribution of 5mC and 5hmC that mimics what occurs in several cell types in vivo. Using these protein binding microarrays containing either cytosines on both DNA strands or a combination of cytosines on one strand and 5mC or 5hmC on the second strand we started to examined the sequence specific binding of a number of B-ZIP and helix-loop-helix transcription factors in addition to CREB1: i.e. ATF1 C/EBP JUND TCF4 USF1 and ZTA. 37395 +No NIH Category available Animal Experiments;Animal Model;Animals;Area;Biological;Biological Markers;Biological Process;Biology;Biopsy;Biotechnology;Brain Neoplasms;Breeding;Camptothecin-11;Cancer cell line;Categories;Cell Line;Cells;Central Nervous System Neoplasms;Characteristics;Clinic;Clinical;Clinical Drug Development;Clinical Investigator;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Convection;Cooperative Research and Development Agreement;Cytostatics;Data;Development;Developmental Therapeutics Program;Diagnostic;Dose;Drug Delivery Systems;Drug Screening;Drug Targeting;Evaluation;Extramural Activities;Future;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Generations;Genetic;Genomics;Glioma;Growth;Human;Image;Immunotherapeutic agent;In Vitro;Institution;Intracarotid;Investigational Therapies;Label;Laboratories;Magnetic Resonance Imaging;Magnetism;Metabolic;Methods;Mission;Modeling;Molecular;Mus;National Institute of Neurological Disorders and Stroke;Operative Surgical Procedures;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Program Development;Progression-Free Survivals;Property;Protective Agents;RNA;Radiation-Sensitizing Agents;Reagent;Research;Research Design;Research Personnel;Resources;SN-38;Sampling;Schedule;Serum;Serum Markers;Services;Specimen;Surrogate Markers;Technology;Testing;Therapeutic;Tissues;Translational Research;Tumor Cell Line;Tumor Stem Cells;United States National Institutes of Health;Work;Xenograft procedure;angiogenesis;antitumor agent;antitumor drug;blood-brain barrier disruption;cancer stem cell;clinical center;clinical development;cytotoxic;design;early phase clinical trial;endothelial stem cell;expectation;experimental study;glioma cell line;human disease;imaging science;in vivo;irinotecan;mouse model;neural;novel;novel therapeutics;pre-clinical;precision medicine;preclinical development;programs;protein biomarkers;repository;research facility;response;screening;screening program;stem cell biology;stem cells;subcutaneous;targeted treatment;translational study;tumor;tumor progression;vasculogenesis Pre-clinical Translational Research Facility n/a NCI 10926645 1ZICBC011641-09 1 ZIC BC 11641 9 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2386780 NCI The major mission of the PTRF is to provide services for clinical investigators to evaluate potential new anti-glioma agents in vitro and in vivo. The NOB Lab has collaborated with pharmaceutical companies and academic institutions and the NCI Developmental Therapeutics Program in the preclinical and clinical development of a number of new anti-glioma agents. The first step in the development pipeline is screening of the agent through the PTRF that provides the professional service for screening these agents both in vitro and in vivo using both standard subcutaneous and stereotactic intracranial models. Furthermore PTRF provides experimental and technical support to other investigators both within and outside of the NOB for evaluating newly developed therapeutics. These extended studies involved stereotactic-based intracranial models looking at various dose and administration schedules as well as combination trials of the new drug with other agents. For example the PTRF has helped to generate the RNA for gene expression profiles for given glioma cell lines treated with a specific class of agents. Once characteristic patterns are identified that correspond with anti-tumor activity then clinical trials can/will be devised to administer one of these agents to patients with brain tumors immediately prior to biopsy/surgery in order to attempt and identify a similar genetic profile clinically. In collaboration with the NOB Lab and the Genomic Core team gene expression signatures are being generated in all of glioma cell lines and GIC/GSCs for all compounds tested within the PTRF. In addition a number of newer drug delivery technologies including intra-carotid administration delivery with or without selective or gross blood-brain barrier disruption convection delivery etc. have been evaluated in animal models within the PTRF. Many of the new classes of anti-tumor therapeutics will have cytostatic rather than cytotoxic properties. Evaluating which of these agents will have biologic activity in humans in small early clinical trials is a challenge since the standard response criteria are based on the determination of cytotoxic responses. The only truly valid clinical parameter available for evaluating the activity of a truly cytostatic agent is patient survival or tumor progression-free survival. These however are not useful parameters for screening drug activity in small early phase clinical trials. Thus if surrogate markers of biologic activity could be identified one could utilize these as early endpoints for screening out agents with little or no clinical activity. Toward that end the PTRF is actively working to develop surrogate markers of drug anti-tumor activity that can be utilized and validated in clinical trials which includes three major areas:1) Imaging; 2) Gene expression profiling; 3) Proteinomics/Serum markers. For example in collaboration with investigators in NOB NINDS and the Clinical Centers program of experimental imaging science noninvasive MR imaging has been used to image magnetically labeled endothelial progenitor cells in vivo to directly identify vasculogenesis in a glioma model. Finally the PTRF stores representative tumor tissue and serum samples from animals treated with each new compound tested with the expectations that new candidate tissue and/or serum-based protein markers of drug activity tumor activity and/or some tumor biological process (i.e. angiogenesis) may be found. This will be an invaluable preclinical resource for validating such claims in the future. A major effort of the NOB is to develop human glioma cell lines that more closely model primary human gliomas both biologically and molecularly. The PTRF is actively involved in the generation of primary human glioma cell lines and GIC/GSC lines from fresh surgical specimens for glioma patient operated on at the NIH. Working closely with the cancer stem cell biologists for the growth propagation and characterization of each of these cell lines and animal xenografts the PTRF uses these well-characterized cell lines (described above in the project Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas) as screens for two major categories of drugs; 1) The most promising drugs from the first levels of in vitro and in vivo screens using the more conventional established glioma cell lines; 2) The drugs that target pathways that may not be well represented by the biology of standard glioma cell lines but are reproduced in the GIC/GSCs. The laboratory expertise utilizing these cells and the large resources of different GIC/GSC lines are a potent enticement for potential partnerships between NCI and the pharmaceutical/ biotechnology community given their growing appreciation of the limitation of standard cancer cell lines and the promise of cancer stem cells for better representing the human disease. Since PTRF initiated in 2016 four clinical trials have activated as a direct result of translational work performed within the NOB all of which had preclinical animal studies performed within the facility. Furthermore we have identified 3 compounds solely through the preclinical screening program that have since been brought forward to clinical trials at the NIH (Regadenoson TG02 LB100). One reagent Irinotecan (CPT-11/SN-38) has also been tested on mouse glioma xenografts recently. PTRF is further extending the translational studies such as experimental immunotherapeutics synthetic lethality for the Precision Medicine Program and metabolic targeting therapeutics as well as the experimental therapeutics for rare CNS tumors PTRF is further extending the translational studies such as experimental immunotherapeutics synthetic lethality for the Precision Medicine Program and metabolic targeting therapeutics as well as the experimental therapeutics for rare CNS tumors (Animal Study Proposal: NOB001 005 007 008 021 023 and 024). 2386780 +No NIH Category available 3D Print;COVID-19;Collaborations;DNA;Development;Disease;Experimental Pathology;Fixatives;Freezing;Goals;Histology;Image Analysis;Immunohistochemistry;In Situ Hybridization;Laboratories;Legal patent;Methodology;Microdissection;Pathologist;Pathology;RNA;Reporting;Research;Research Personnel;Research Support;Science;Services;System;Technology;Tissue Microarray;Tissue Preservation;Tissues;cancer type;instrument;invention;laser capture microdissection;member;method development;prevent;tool;whole slide imaging Experimental Pathology Laboratory (EPL) n/a NCI 10926644 1ZICBC011638-09 1 ZIC BC 11638 9 10274463 "HEWITT, STEPHEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1018655 NCI Long-term research efforts in the EPL in support of translational pathology include: developments of new hardware for the construction of tissue microarrays the development of a tissue microarray instrument for frozen tissue refinement of technologies for tissue micro-dissection. Additional efforts in the EPL focus on tissue preservation and storage with efforts in the development of non-formaldehyde containing tissue fixatives refinement to tissue impregnation systems to prevent tissue degradation and development of methods for freezing and storing tissue that prevent degradation. We filed invention reports in this fiscal year both of which will be filed as preliminary patent applications. The research we support involves numerous types of cancers and other diseases including COVID-19. 1018655 +No NIH Category available ATAC-seq;Area;Atlases;Award;Basic Science;Biochemistry;Bioinformatics;Biological;Biological Assay;Businesses;CCR;Cancer Biology;Cells;Cellular biology;ChIP-seq;Collaborations;Color;Communication;Computer software;Computers;Consultations;Core Facility;Custom;DNA;DNA Sequencing Facility;DNA purification;Data;Data Analyses;Data Storage and Retrieval;Detection;Development;Developmental Therapeutics Program;Devices;Dideoxy Chain Termination DNA Sequencing;Discrimination;Endocrine;Enzymes;Experimental Designs;Gene Expression;Generations;Genetic;Genitourinary system;Genomics;Grant;HIV/AIDS;Head;Hour;Human;Immune;Immunology;Immunooncology;Immunotherapy;Individual;Interest Group;Journals;Laboratories;Laboratory Research;Libraries;Malignant Neoplasms;Malignant lymphoid neoplasm;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of thorax;Messenger RNA;Methods;Mission;Molecular;Molecular Biology;Molecular Profiling;Mus;National Center for Advancing Translational Sciences;National Heart Lung and Blood Institute;National Human Genome Research Institute;National Institute of Allergy and Infectious Disease;National Institute of Arthritis and Musculoskeletal and Skin Diseases;National Institute of Child Health and Human Development;National Institute of Dental and Craniofacial Research;National Institute of Diabetes and Digestive and Kidney Diseases;National Institute of Neurological Disorders and Stroke;Nature;Paper;Pathogenesis;Pathology;Plasmids;Policies;Principal Investigator;Procedures;Process;Production;Proteins;Provider;Publishing;Quality Control;RNA;RNA library;Reaction;Reader;Receptor Biology and Gene Expression;Recovery;Reporting;Research;Research Personnel;Resources;Reverse Transcriptase Polymerase Chain Reaction;Running;Sampling;Schedule;Science;Scientist;Secure;Series;Services;Slide;System;Systems Analysis;Technology;Technology Transfer;Thoracic Surgical Procedures;Time;Tissues;Training;Transplantation;United States National Institutes of Health;Urogenital Cancer;Urologic Oncology;Vaccines;Vendor;Woman;Work;cancer genetics;carcinogenesis;cellular oncology;cost;design;digital;genome integrity;innovation;instrument;instrumentation;meetings;member;multiple omics;nano-string;nanopore;next generation sequencing;outreach;programs;proteogenomics;seal;single cell analysis;single cell sequencing;transcriptome;transcriptome sequencing;tumor immunology;webinar CCR Genomics Core n/a NCI 10926643 1ZICBC011623-09 1 ZIC BC 11623 9 14280419 "CONNER, ELIZABETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2859914 NCI CCR Genomics Core lists over 600 registered members in its iLab management and scheduling software. So far in FY23 there are 427 active users; 176 research groups of which 136 are from NCI and the remaining 40 from 11 other NIH institutes. These institutes include NCATS NEI NHGRI NHLBI NIA NIAID NIAMS NICHD NIDCR NIDDK and NINDS. Of the 44 labs/branches/programs listed under the CCR 26 utilized our services in FY23 (60%). These lab/branches include: Basic Research Laboratory Cancer Innovation Laboratory Cancer for Immuno-Oncology Developmental Therapeutics Branch Experimental Immunology Branch Experimental Transplantation and Immunotherapy Branch Genitourinary Malignancies Branch HIV and AIDS Malignancy Branch Laboratory of Biochemistry and Molecular Biology Laboratory of Cancer Biology and Genetics Laboratory of Cell Biology Laboratory of Cellular and Molecular Biology Laboratory of Cellular Oncology Laboratory of Genitourinary Cancer Pathogenesis Laboratory of Genome Integrity Laboratory of Human Carcinogenesis Laboratory of Immune Cell Biology Laboratory of Integrative Cancer Immunology Laboratory of Molecular Biology Laboratory of Pathology Laboratory of Receptor Biology and Gene Expression Lymphoid Malignancies Branch Thoracic and GI Malignancies Branch Thoracic Surgery Branch Urologic Oncology Branch Vaccine Branch and the Women's Malignancies Branch. So far in FY23 the Core has managed over 3200 iLab requests processed over 15000 samples for Sanger sequencing 311 for Nanostring 8816 for ddPCR and 9822 for tapestation. The Core has been involved in 364 different NGS projects featuring the iSeq MiSeq NextSeq 550 and 2000 platforms. Projects included 10X single cell sequencing full plasmid sequencing ChIP-Seq RNA-Seq amplicon sequencing ATAC-seq Cut&Tag NS-Seq END-SEQ custom library and targeted panel sequencing amongst others. A total of 6 NanoString GeoMx DSP spatial profiling projects were performed using both human and mouse Whole Transcriptome Atlas and the Cancer Transcriptome Atlas assays for RNA as well as GeoMx protein assay for NGS and a pilot using spatial proteogenomics assay. The latter workflow enables co-detection of RNA and protein from the same tissue slide with NGS as the readout method. The two Cores are continuing to work on off-instrument data analysis and storage which is an important area for further development. The Core undertook two long-read projects with the M1KC both with direct RNA sequencing and developed a workflow for library prep sequencing and assembly of plasmid constructs. The portfolio for long-read technology will soon be expanded with the addition of the PromethION 2 Solo. This device will allow for higher data generation than the small ONT devices. A single P2 flow cell can generate nearly six times more data than the MinION. Other upgrades will include the addition of QX600 Droplet Reader to our ddPCR service. QX600 device will enable six-color multiplexing allowing discrimination of multiple targets with assays that are cross-compatible with our current QX200 Droplet Digital PCR (ddPCR) System. Outreach efforts of the core facility have included active membership in the NIH Single Cell Interest Group participation in CCR-FYI Colloquium Staff Scientist and Principal Investigator Retreats Genetics Branch Annual Retreat as well as the annual meetings of the ABRF and the AGBT. The Core held its Annual Core Open House in cooperation with CPTR in December of more than 30 cores from both Bethesda and Frederick campuses. Numerous core-sponsored webinars were held in collaboration with Sequencing Facility and the Genomics Technology Lab in Frederick and the Single Cell Analysis Facility to include Illumina seminars on single cell multiomics and spatial analysis uncovering the molecular drivers of cancer with single-cell multiomics Avida Bio (Part of Agilent) on their highly sensitive cfDNA assays and Oxford Nanopore and 10X on single cell sequencing. In addition the Core held Office hours with both Nanostring and Bio-Rad. The core also held a several month demo of Qiagen's QIAcuity Digital PCR System to allow NCI investigators to compare experimental results between the Bio-Rad and Qiagen digital dPCR systems. Presentations on core capabilities were also given to the Bldg. 41 seminar series and to the CCR Staff Scientist group. Other activities include monthly meetings with CPTR Lab of Pathology and NIAID's Rocky Mountain Lab to discuss issues with NIH procured NanoString GeoMx DSP instruments and with NCI CCR sequencing genomics and Single Cell Analysis Facility Core heads. Core members were awarded Federal Technology Transfer Awards and acknowledged in 4 papers reporting on work produced from the Core that have been published in high-impact journals including Cancer Discovery Cell Endocrine and Nature Communications. 2859914 +No NIH Category available Binding;CCR;Cells;Cellular Structures;Computers and Advanced Instrumentation;Custom;Equipment;Fluorescence Microscopy;Fluorescence Recovery After Photobleaching;Fluorescence Resonance Energy Transfer;Light;Maps;Measures;Methods;Microscope;Microscopy;Mission;Molecular;Optics;Proteins;Research Personnel;Resolution;Specimen;Surveys;System;Techniques;Technology;Testing;Time;United States National Institutes of Health;Vision;Work;experimental study;fluorescence imaging;instrument;instrumentation;light microscopy;morphometry;nano;nanomachine;prospective;single molecule;tool;ultra high resolution LRBGE Optical Microscopy Core n/a NCI 10926641 1ZICBC011574-10 1 ZIC BC 11574 10 12448468 "KARPOVA, TATIANA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 794466 NCI The Core mission is to provide state-of-the-art light microscopy instrumentation to anyone in the CCR and NIH who requires assistance with fluorescence imaging. Present work in the Core revolves around several established techniques: structural and morphometrical studies based on colocalization of different fluorescent markers by high-resolution and super-resolution techniques 4D and 5D time-lapse analysis to follow how cellular components change over time and how cellular structures nanomachines and proteins interact fluorescence recovery after photobleaching to measure mobility and binding of cell molecules and fluorescence resonance energy transfer to measure molecular interactions in live or fixed specimens. For that the Core is maintaining and upgrading high-end commercial microscopes. Currently the Core maintains wide-field optical sectioning microscope Delta Vision Elite Carl Zeiss LSM780 and 880 confocal microscopes and Lattice Light Sheet 3I microscope and Carl Zeiss SIM/dSTORM Elyra Super-resolution microscope MINFLUX microscope. The Core develops Single Molecule Tracking technique utilizing custom-built HILO microscopes and MINFLUX. The system adapts MINFLUX nano-resolution technique for molecular maps of proteins in cells. The Core constantly surveys the demands for the state-of-the art technology tests and arranges demonstrations of the new instruments for OMC users and advertises new microscopy methods that may be useful for specific needs of the current and prospective customers. 794466 +No NIH Category available Binding;Biophysics;Cell Nucleus;Cells;Cellular biology;Chromatin;Copper;Custom;DNA;DNA Sequence;Data Analyses;Enhancers;Ensure;Event;Fluorescent in Situ Hybridization;Gene Expression;Genes;Genetic Models;Genetic Transcription;HSF1;Heat-Shock Response;Heavy Metals;Hour;Individual;Mammalian Cell;Measures;Messenger RNA;Methods;Modeling;Molecular;Output;Pharmaceutical Preparations;Process;Publications;Regulatory Element;Reporter Genes;Research;Site;Stress;Techniques;Time;Transcription Process;Transcriptional Regulation;Ultradian Cycle;Visualization;Yeast Model System;Yeasts;chromatin remodeling;circadian;fluorescence imaging;in vivo;instrument;interest;promoter;recruit;residence;response;single molecule;stem;transcription factor Transcription factor mobility n/a NCI 10926640 1ZICBC011571-10 1 ZIC BC 11571 10 12448468 "KARPOVA, TATIANA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 198616 NCI "Expression of many important genes is cyclical and may incorporate multiple cycles at the different time scale such as circadian or ultradian cycles on the scale of hours and fast and short bursts of transcription on the scale of minutes. The mechanisms of this cycling are poorly understood but very important for the correct application of the drugs. At the transcription level gene expression is controlled by the accessibility of the regulatory elements within DNA - promoters and enhancers. Research in yeast and mammalian cells indicates that modulation of chromatin accessibility occurs through interaction of transcription factors (TF) and chromatin remodelers. Binding of certain TF to their target DNA sequences is highly dynamic on the scale of seconds. Also some TF undergo the ""slow"" cycling on the scale of minutes which consist of alternating ""ON"" and ""OFF"" gene states. It is unclear how this TF cycling is related to the transcriptional cycling. We are interested in molecular mechanisms of the TF cycling on promoters and its correlation with transcription cycles. We use as a model yeast gene CUP1 involved in heavy metal stress and HSP104 involved in heat shock stress. CUP1 is activated by copper-bound TF Ace1p. HSP104 is activated by HSF1. We are studying dynamics of these TF factors on specific promoters by Single Molecule Tracking (SMT). Previously we have built a custom instrument for SMT and optimized SMT data interpretation. We have developed methods for SMT in yeast cell nuclei and methods of performing SMT on specific promoters.We constructed reporter genes with promoters of either CUP1 or HSP104. Transcription may be visualized by smFISH (Fluorescence In Situ Hybridization) or by live imaging of the fluorescently tagged mRNA. We correlate the dynamics of the TF at the promoter with transcriptional output. We demonstrated that the transient recruitment of TFs is regulated by fast cyclical chromatin remodeling events to ensure the best dynamic transcriptional response. In our recent publication we demonstrate that the slow cycle of transcription consists of the fast cycles (bursts) of expression on individual genes. This is the first genetic model where the superimposed slow and fast cycles of transcription correlate with superimposed slow and fast cycling of the transcriptional factor. Ultimately these studies will lay the groundwork for the analysis of in vivo interactions of the components of the transcriptional machinery. The technique of correlation of the TF biophysics with transcription modeling that we are in process of developing may be applied to a number of other problems of cellular biology where the information for molecular regulation of transcription is desired." 198616 +No NIH Category available Activated Lymphocyte;Adoptive Cell Transfers;Aftercare;Area;B-Lymphocytes;Back;Biocompatible Materials;Biological;Biopsy;Blood;Blood specimen;Carcinoma;Cell Therapy;Cell physiology;Cells;Characteristics;Cholangiocarcinoma;Clinical;Clinical Protocols;Clinical Trials;Code;Colorectal Cancer;Competence;Core Facility;Cyclic GMP;Disseminated Malignant Neoplasm;Documentation;Effectiveness;Enrollment;Ensure;Environmental Monitoring;Equipment;Equipment and supply inventories;Event;Goals;Human;Human Papillomavirus;Human Resources;Immunologics;Immunotherapy;Infusion procedures;Institution;Laboratories;Location;Lymphocyte;Malignant Neoplasms;Mission;National Cancer Institute;Neoplasms;Operative Surgical Procedures;Patients;Peripheral Blood Lymphocyte;Phase;Production;Protocols documentation;Qualifying;Reagent;Regulation;Report (document);Reporting;Research;Research Personnel;Resected;Running;Sampling;Services;Site;Sterility;Supporting Cell;T-Lymphocyte;Training;Training Programs;Translating;Tumor Antigens;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Vendor;Viral Vector;anti-cancer;biobank;blood product;design;design and construction;follow-up;gene therapy;malignant breast neoplasm;manufacture;manufacturing facility;manufacturing process;manufacturing run;meetings;melanoma;member;neoantigens;novel therapeutics;operation;participant enrollment;programs;quality assurance;square foot;synovial sarcoma;tissue processing;tumor;tumor immunology Cell Production Core Facility n/a NCI 10926639 1ZICBC011569-10 1 ZIC BC 11569 10 78355702 "HALAS, HYUNMI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1933442 NCI The mission of this core laboratory is to provide support to the immunotherapy program established by the Surgery Branch of the National Cancer Institute. Cell Production Facility (CPF) core is overseen by Dr. Hyunmi Halas. The main effort of the laboratory involves the production of large numbers of human anti-cancer T lymphocytes ex vivo to treat patients with advanced metastatic cancer enrolled on Surgery Branch clinical trials. Cancer targeting lymphocytes are either isolated directly from biopsied material or are generated by genetically modifying T lymphocytes from a patient's blood. The Surgery Branch Cell Prep (TIL Lab/CPF) Core receives patient tumors and blood products for processing as outlined in project ZIC BC 010905. These biological materials are used in the by the NCI SB researchers in the discovery of patient specific neoantigens and reactive tumor infiltrating lymphocytes (TILs). Once patient specific neoantigens or TILs are identified a unique patient cellular therapy can be manufactured by the CPF core. 43 treatments were initiated during the reporting period. Four manufacturing runs represent two sets of two products designed for two patients. 4 were terminated due to manufacturing/reagent related issues while 4 runs were terminated due to clinical reasons. 30 treatments were delivered to patients 17 on gene therapy protocols and 13 on TIL related protocols. Each product is a 24-day manufacturing run requiring 2 technicians QA staff supervisory oversight and 4 support staff members. All products are manufactured in the T30 CPF on the NIH Bethesda campus under cGMP conditions as outlined in the Code of Federal Regulations and the FDA for Phase 1 and 2 products. All starting materials are generated by the Surgery Branch Cell Prep (TIL Lab/CPF) Core and moved into manufacturing for the Cell Production Core Facility once patients are enrolled on clinical protocols. All post treatment follow-up samples collected from patients are inventoried by and largely processed by the Cell Production Core Facility. These materials are managed by the Cell Production Core Facility team though the NCI SB Biorepository which contains thousands of samples onsite and many more at offsite locations. All requests for materials for research and tracking needs throughout the branch are received and distributed by Cell Production Core Facility. In addition to manufacturing cellular therapies the Cell Production Core Facility ensure the facility all equipment and materials used in manufacturing are meeting cGMP regulations. This requires constant reporting documentation and review of each processing step and a log of all materials (biological and raw materials). The core lab also performs routine environmental monitoring of the facility (performed with the services from DLM Sterility Lab) and during every aseptic processing event. The Quality Assurance oversight requires a personnel training program that ensures competency and emphasizes the responsibilities and duties of all personnel involved in manufacturing cell therapies in the Surgery Branch. The core lab staff train all new technicians for manufacturing processes under these requirements and undergo annual re-training as well. The facilities staff and QMS is audited minimally on an annual basis by third party vendors through NIH Office of Research and Compliance or through internal NCI SB QA audits. The former primary cell production facility 3W/TIL lab is no longer used for manufacturing as of Dec 2020. New facilities have been qualified and validated for cGMP cellular manufacturing on the NIH campus. These include Trailer 10B which will provide clinical cell supporting capabilities; 1B42 in building 10 which will support viral vector manufacturing; and T30 a 5000 square foot modular building that will serve as the main manufacturing facility for Surgery Branch Cell Therapies which was completed in March 2021. Cell Processing Facility staff were actively involved in the review of all design and construction documents as well as in drafting and reviewing the commissioning documentation that is being generated for these facilities and are responsible for the cGMP operations of these facilities. The facility opened with approve from the NIH and FDA in 2022 and has since been operational for manufacturing and tissue processing. 1933442 +No NIH Category available Area;Bioinformatics;Biological;CCR;Cells;Collaborations;Communities;Computer software;Data Analyses;Data Correlations;Databases;Ecosystem;Fostering;Genomics;Goals;Information Technology;Infrastructure;Laboratories;Maps;Metadata;MicroRNAs;Modeling;Outcome;Pathway interactions;Play;Principal Investigator;Reporting;Research;Research Personnel;Resources;Scientist;Services;Statistical Data Interpretation;System;United States National Institutes of Health;Update;base;bioinformatics resource;biomedical informatics;cancer genomics;comparative genomic hybridization;data integration;data mining;experimental study;forging;improved;mathematical analysis;next generation sequence data;operation;virtual CCR Collaborative Bioinformatics Resource n/a NCI 10926636 1ZICBC011532-11 1 ZIC BC 11532 11 9414524 "GOLDSTEIN, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2584114 NCI "The CCR Collaborative Bioinformatics Resource (CCBR) is an organizational umbrella which provides a mechanism for CCR researchers to obtain many different types of bioinformatics assistance to further their research goals. This entity pulls together many different bioinformatics expertise within NCI with strengths in a broad range of bioinformatics topics. The CCBR currently is providing support to over 80 Principal Investigators within CCR and are working on 120 projects related to several different general areas including support to a wide variety of cancer genomics areas. The newest efforts have been in the area of single-cell genomics. Since its inception in 2011 CCBR has played a progressively key role as an ""ecosystem"" for bioinformatics support in CCR. This conceptual ecosystem has formed relationships for scientific collaborations and for computational logistical and strategic support. This evolving model allows CCBR to strengthen its core service to CCR laboratories while fostering scientific collaborations with other service facilities and embedded bioinformaticians in CCR. The various scientific and operational collaborations create a virtual umbrella under which bioinformatics support is integrated across several logistical pieces of BACS/ABCS operations. These partnerships also act as a conduit for fostering ideas solutions and new opportunities." 2584114 +No NIH Category available Antibodies;Apoptosis;Atlases;Bar Codes;Bioinformatics;Biological Assay;Biological Markers;Biological Sciences;Blood capillaries;CCR;Cancer Detection;Capillary Electrophoresis;Cardiovascular Diseases;Cell Cycle;Cell Death;Cell Proliferation;Cells;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Communities;Complement;Consumption;Data;Data Analyses;Data Storage and Retrieval;Detection;Development;Drug Targeting;Evaluation;Fluorescent Antibody Technique;Freezing;Genes;Genomics;Human;Image;Image Analysis;Immune;Immunoassay;Immunofluorescence Immunologic;Immunologic Monitoring;Immunology;Immunooncology;Individual;Industry Collaboration;Inflammation;Laboratories;Liver;Liver neoplasms;Lymphoid Tissue;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Measurement;Measures;Metabolic Diseases;Metastatic Neoplasm to the Lung;Methods;Molecular;Molecular Profiling;Monitor;Morphology;Mus;Neighborhoods;Neurosciences;Optics;Organ;Pathway interactions;Performance;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Pilot Projects;Plasma;Post-Translational Protein Processing;Preparation;Program Development;Protein Analysis;Proteins;Protocols documentation;Publications;Publishing;RNA;Regulation;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resolution;Resources;Running;Sample Size;Sampling;Science;Serum;Services;Signal Transduction;Signaling Molecule;Site;Slide;Specialist;Specimen;Stains;System;Technology;Tissue Microarray;Tissue imaging;Tissues;Transcript;Tumor Tissue;United States National Institutes of Health;Update;Validation;Vendor;Walking;Work;anticancer research;biomarker validation;cancer therapy;clinical application;clinical practice;cost;cost estimate;cytokine;data analysis pipeline;data infrastructure;data sharing;digital;digital pathology;experience;experimental study;imager;imaging modality;improved;indexing;innovative technologies;instrument;interest;malignant breast neoplasm;melanoma;multidisciplinary;nanoimmunoassay;nanoscale;neoplastic cell;neurofibroma;ovarian neoplasm;pre-clinical;preclinical study;preservation;protein biomarkers;response;technology platform;therapeutic target;tool;transcriptome;treatment response;tumor microenvironment Collaborative Protein Technology Resource - Nano-Scale Protein Analysis Section n/a NCI 10926631 1ZICBC011434-12 1 ZIC BC 11434 12 78355738 "KEDEI, NOEMI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1219494 NCI IIn the past years the core has established 1) the SimpleWesternTM capillary nano-immunoassay (CNIA) system; 2) the bead-based Luminex xMAP multiplexed-immunoassay system for high-performance quantitative protein measurement with small sample consumption; 3) the CO-Detection by Indexing (CODEX) technology for quantitative detection of 40-60 protein markers in tissues at single cell level; 4) GeoMx Digital Spatial Profiler (DSP) enabling detection of 100s of proteins and thousands of RNA targets including cancer transcriptome and whole transcriptome from a single tissue; and 5) CosMx Spatial Molecular Imager (SMI) to image expression of 1000s of RNA transcripts or 64 proteins at single cell level in tissues. 1) The SimpleWesternTM CNIA system is an automated capillary immunoassay system for highly quantitative reproducible detection of target proteins and their post-translational modifications in a format that is applicable to very small sample sizes. The CNIA analysis platform fills a need for high-performance assays for comprehensive and quantitative signaling molecule profiling at the protein level and facilitates transferring those assays from discovery research into preclinical/clinical practice. CPTR is one of the earliest adopters of the CNIA technology. We established assay conditions for more than three hundred signaling molecules covering key pathways including targets in apoptosis/cell death cell cycle and checkpoint control gene and RNA regulation cell proliferation and development. Collaborating with CCR investigators we have successfully developed protocols/strategies supporting multiple clinical trial and drug-development programs including the validation of a panel of 120 CNIA assays in peripheral blood mononuclear cells (PBMCs) allowing analysis of samples collected with non-invasive methods and monitoring of protein levels and state of activation at more frequent intervals. In the 2022-2023 fiscal year we have been working with 5 PIs to support their projects. The data generated facilitated preparation of multiple manuscripts: 1 published 1 accepted for publication. 2) The Luminex xMAP bead-based multiplex-immunoassay system provides a highly-quantitative multiplex-analysis of cytokines metabolites and other serum/plasma biomarkers. The technology has been broadly applied in life-science research including cancer immunology cardiovascular disease metabolic disease and inflammation with clinically applicable assay performance. Using this technology we have been supporting projects on clinical and pre-clinical studies to monitor immune or other treatment responses in cancer therapies. In addition to full support for the technology we also offer walk-up access to the instrument so users do not need to sustain multiple individual instruments at high cost in their laboratories. This fiscal year we have been working with 3 PIs on their research projects. 3) For the last 4 years we offer the CO-Detection by Indexing (CODEX) spatial ultra-highplex immunofluorescence technology to detect expression of tens of protein markers in a tissue as service for CCR/NCI/NIH branches/laboratories. The ability to quantitatively measure 40-60 protein targets from the same tissue at single cell level preserving spatial context allows for deep phenotyping of immune cells in the tumor microenvironment characterize their interaction with tumor cells and identify cellular neighborhoods determining cancer fate and progression as well as response to cancer treatment. CPTR is an early adopter of the CODEX technology and became one of most advanced sites spearheading the development and implementation of improved imaging processing and data analysis workflows. This year we updated one of the two CODEX systems to Phenocycler Fusion that allows for imaging of tissues and tissues microarrays (TMAs) on slides and is reported to be the fastest commercially available imaging modality for multiplex staining. We have assessed CODEX assay performance and feasibility in multiple human/mouse organ and tumor tissues (such as lung and breast cancer ovarian and liver tumors melanoma neurofibroma lung metastasis lymphoid tissues etc.). Previously most of our experience has been with imaging fresh frozen tissues this year we continued to implement assay protocols for the clinically more relevant FFPE tissues and tissue microarrays. Collaborating with CCR/NCI/NIH investigators we customized multiple antibodies to extend the commercially available antibody panel to better support cancer research and therapy. We established a 39-plex antibody panel for fresh frozen human liver tumors and a 41-plex antibody panel for FFPE liver samples to characterize the tumor microenvironment. There is increased interest in using the technology in basic as well as clinical studies. In the 2022-2023 fiscal year we continued to work with 10 PIs to support their research projects. Several manuscripts containing CODEX data generated are in-preparation (n=3) close to be submitted submitted and accepted (n=2) and published (1). We also have been actively working with multi-disciplinary teams of experts involving other CCR technology and bioinformatics specialists and industry collaborators to establish the infrastructure for data storage collaborative data sharing and analysis and implementing image viewing and quantitative analysis tools such as NCI HALO 2D digital pathology image analysis platform. 4) With the help and support from CCR Office of Science and Technology Resource (OSTR) and in collaboration with CCR Genomics Core recently we have established the GeoMx Digital Spatial Profiler (DSP) platform at CPTR. GeoMx DSP combines standard immunofluorescence techniques with the nCounter digital optical barcoding or NGS readout to perform highly-multiplexed spatially-resolved protein and transcript profiling of tissues. Both RNA and protein panels have been developed by the vendor for immune-oncology cancer pathways and neuroscience as well as the 1800-target 'cancer transcriptome atlas' (CTA) and the 18000-target whole transcriptome atlas (WTA) RNA panel. CPTR's unique contribution to this technology is customization of morphology markers based on the project needs to allow for improved selection of regions of interest (ROIs) as well as enabling analysis on the whole slides not only selected ROIs. This fiscal year we have supported 10 intramural investigators for cancer discovery research projects and clinical specimen profiling. The generated results are included in multiple manuscripts in preparation (5) under submission (2) or published (1). 5) Starting September 2022 our laboratory spearheaded the evaluation and implementation of CosMx Spatial Molecular Imager (SMI) to enable high resolution (single cell level) detection of cancer related RNA transcripts (1000) or different protein targets (64). This technology complements the ROI-based GeoMx DSP to detect RNA transcripts and the CODEX multiplex protein detection technology. Imaging of two pilot projects and two early access projects have been finished with the current effort now focusing on establishing data storage and data analysis pipeline. 1219494 +No NIH Category available Acetylation;Affect;Basic Science;Binding Sites;Biochemistry;Biological;Biological Assay;Biotechnology;Bordetella pertussis;C-terminal;CCR;Cancer Biology;Cell Nucleus;Cell membrane;Cells;Cellular biology;Collaborations;Communities;Complex;Cysteine;Cytoplasm;Cytoskeleton;DNA;DNA Structure;Data Analyses;Dermatology;Developmental Therapeutics Program;Escherichia coli;Experimental Designs;Face;Gene Expression;HIV;HIV Infections;Hybrids;Inductively Coupled Plasma Mass Spectrometry;Isotope Labeling;Journals;Keratin;Label;Laboratories;Ligation;Lysine;Manuscripts;Mass Spectrum Analysis;Membrane Proteins;Metals;Methods;Methylation;Molecular Biology;Molecular Chaperones;Molecular Conformation;N-terminal;National Institute of Arthritis and Musculoskeletal and Skin Diseases;National Institute of Diabetes and Digestive and Kidney Diseases;Nuclear;Nuclear Inner Membrane;Nucleic Acids;Oncology;Outcome;Phosphorylation;Phosphorylation Site;Post-Translational Protein Processing;Preparation;Protein Conformation;Proteins;Proteolysis;Proteome;Proteomics;Publications;Publishing;RNA;Regulation;Reporting;Research;Research Personnel;Resolution;Resources;Role;Running;Sampling;Signal Transduction;Single-Stranded DNA;Site-Directed Mutagenesis;System;TP53 gene;Techniques;Technology;Tertiary Protein Structure;Topoisomerase;Translational Research;United States National Institutes of Health;Vaccines;Work;cancer genetics;crosslink;design;experimental study;follow-up;frontier;helicase;inhibitor;loss of function;mechanical signal;mutant;prevent;protein aggregation;response;small molecule inhibitor;thioester;virulence gene;wound healing CPTR - Mass Spectrometry Unit n/a NCI 10926630 1ZICBC011430-12 1 ZIC BC 11430 12 11593641 "JENKINS, LISA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1224498 NCI Overall the expertise of the Mass Spectrometry Unit is being used to further the research of multiple groups within the NIH. In FY23 we collaborated in 65 different projects from 40 different investigators with over 2700 samples run. Among these are projects to characterize the post-translational modifications of target proteins including sites of phosphorylation acetylation and methylation to better understand signal transduction protein regulation and the effects of small molecule inhibitors. The resource is also being used to identify protein interactors of both proteins and nucleic acids. Mass spectrometry is additionally being used extensively for large-scale quantitative proteomics projects using both isotopic labeling and label-free approaches. Structural mass spectrometry applications such as crosslinking and limited proteolysis methods are used to investigate protein conformation. Finally the resource is using inductively-coupled plasma mass spectrometry (ICP-MS) to quantify the level of metals in biological samples. In the past year seven collaborative studies have been published; several other projects are nearing completion or manuscripts are under review. In collaboration with Ettore Appella Laboratory of Cell Biology we investigated the effects and mechanism of action of NSC59984 a small molecule inhibitor of mutant p53. Mass spectrometry analysis revealed that p53 is covalently modified by NSC59984 on specific cysteine residues which likely affects the conformation of p53 R248W and returns it to a more wild-type like state. These findings are reported in one manuscript in Frontiers in Oncology and in a second in preparation. With Maria Morasso NIAMS and adjunct in the Laboratory of Cancer Biology and Genetics mass spectrometry was used to investigate the role of keratin-75 in the wound healing response. Among the interactors was SUN2 an inner nuclear membrane protein and component of the linker of nucleoskeleton and cytoskeleton complex (LINC). LINC transduces mechanical signals from the plasma membrane to the nucleus and influencing gene expression suggesting that this interaction may regulate the wound healing response by regulating gene expression. A proximity ligation assay confirmed the keratin-75-SUN2 interaction and showed that it occurred primarily at the cytoplasmic face of the nuclear periphery. This research was published in the Journal of Investigative Dermatology. Another publication resulted from collaboration with Yves Pommier Developmental Therapeutics Branch. Mass spectrometry was used to characterize the protein interactors of topoisomerase-3B (TOP3B) to help characterize its role in the resolution of R-loops non-B-DNA structures consisting of RNA-DNA hybrids with displaced single-stranded DNA segments. In this work published in Cell Reports mass spectrometry analyses identified the R-loop helicase DDX5 as an interactor of TOP3B and showed that this interaction occurs independently of TDRD3 an auxiliary factor of TOP3B. Further experiments demonstrated that TOP3B and DDX5 function together to resolve R-loops. Thermal proteome profiling mass spectrometry methods were used to examine the targets of the small molecule inhibitor NAV-2729. This project a collaboration with Paul Randazzo Laboratory of Cellular and Molecular Biology focused on the selectivity of NAV-2729 which was originally identified as a specific inhibitor of Arf6. Cell-based experiments showed that Arf6 expression did not correlate with NAV-2729 sensitivity and mass spectrometry approaches identified 48 other possible targets. These results were published in the Journal of Biological Chemistry. Crosslinking mass spectrometry was used to explore the complexes of J-domain proteins with Hsp90 and Hsp70 in collaboration with the group of Sue Wickner Laboratory of Molecular Biology. This study published in the Journal of Molecular Biology explored the role of J-domain proteins in protein reactivation by chaperones. It was found that a J-domain protein CbpA was able to form a ternary complex with E. coli Hsp70 (DnaK) ad E. coli Hsp90. Analysis of crosslinking experiments by mass spectrometry confirmed the ternary complex and identified sites of binding for binary interactions. Collaborative research with the lab of Deborah Hinton NIDDK examined the conformation of the Bordetella pertussis BvgAS system that regulates virulence gene expression. Crosslinking mass spectrometry was used to identify changes in the BvgA conformation when unmodified or phosphorylated. The findings suggest that phosphorylation of BvgA causes a structural rearrangement that relocates its N-terminal domain to allow better interaction of the C-terminal domain with DNA. The findings were published in the Computational and Structural Biotechnology Journal. In addition to the above projects mass spectrometry has been used to investigate the mechanism of action of SAMT-247 a thioester molecule developed to prevent and treat HIV infection. Working with Drs. Genoveffa Franchini Vaccine Branch and Daniel Appella NIDDK mass spectrometry experiments have demonstrated that SAMT-247 covalently modifies cysteine and lysine residues in HIV Gag resulting in protein aggregation and loss of function. Additionally new work has identified a host protein that can also be targeted by SAMT-247 resulting in decreased HIV infection of cells. 1224498 +No NIH Category available Advanced Malignant Neoplasm;Aerosols;Biological Assay;Cell Line;Cell Separation;Cell fusion;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Color;Computer software;Consultations;Containment;Custom;DNA Damage;Data Analyses;Dedications;Development;Drug Targeting;Education;Emergency Situation;Ensure;Epithelium;Equity;Flow Cytometry;Fluorescence-Activated Cell Sorting;Fluorochrome;Future;Generations;Genomics;Goals;Hour;Housing;Image;Immune response;Immunoassay;Immunotherapeutic agent;Interruption;Interview;Laboratories;Laboratory Research;Lasers;Lead;Libraries;Lymphocyte;Lymphoma;Maintenance;Mission;Modeling;NCI Center for Cancer Research;Occupations;Periodicals;Persons;Phagocytosis;Phase;Policies;Positioning Attribute;Procedures;Proteins;Reagent;Reporter;Research Personnel;Resource Sharing;Resources;Rest;Sampling;Schedule;Services;Site;Social Distance;Sorting;Students;Supporting Cell;Technical Expertise;Technology;Thymus Gland;Time;Training;United States National Institutes of Health;Universities;Visit;Work;analytical tool;anticancer research;cancer stem cell;design;dimensional analysis;experience;experimental study;flexibility;follow-up;foot;genome integrity;high dimensionality;innovation;instrument;instrumentation;investigator training;member;mutant;new technology;novel;pre-pandemic;recruit;response;screening;technology development;tool;tumor CCR LGI Flow Cytometry Core n/a NCI 10926629 1ZICBC011428-12 1 ZIC BC 11428 12 14732145 "LIVAK, FERENC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1826105 NCI The mission of the CCR LGI Flow Cytometry Core in Building 37 (FC37) is to offer up-to-date instrumentation and technical expertise to CCR investigators to assist cancer research. The core provides full-scale state-of-the-art flow cytometry services including analytical sample acquisition data analysis imaging flow cytometry fluorescent cell sorting and experimental planning and consultation. The core is committed to the dissemination of novel flow cytometry-based technologies through continuous education of investigators and participating in the NCI-wide flow cytometry training course. The LGI FC37 provides instrumentation for a wide variety of flow cytometry technologies. The core is equipped with seven analytical instruments: a state-of-the-art BD FACSymphony A5 flow cytometer equipped with five lasers and the capacity to identify 27 fluorochromes which is also equipped with a high throughput sampler (HTS) attachment that accommodates 96-well plates to further increase the capacity of the instrument. Two high end BD LSRFortessa cytometers with identical configuration equipped with five lasers and the capacity to identify 18 fluorochromes. One of these instruments LSRFortessa SORP1 also has HTS attachment. The core also operates a three-laser 8-color BD FACSCanto II cytometer. The LGI FC37 was a pioneer in introducing spectral flow cytometry to NCI with the purchase of a 4-laser/32-channel Sony SA3800 analyzer in 2016. Later we purchased a 5-laser/144 channel Sony ID7000 spectral analyzer. At the end of last year we retired the SA3800 instrument once the ID7000 instrument has become a major spectral analyzer of the Core during FY23. In addition the Core operates a dual-camera 4-laser 12-channel Amnis ImageStream MarkII imaging flow cytometer equipped with HTS attachment. To support cell sorting the Core operates two BD FACSAria IIu instruments equipped with 3-4 lasers to simultaneously identify 11-12 fluorochromes. Both of these sorters are enclosed in flexible BioBubble Benchtop Biocontainment units. The Core also has one BD FACSAria Fusion cell sorter housed in a custom-designed Class II type A2 biosafety cabinet which is equipped with five lasers with the capacity to identify 18 fluorochromes. In 2021 the Core acquired a Sony MA900 cell sorter housed in a custom-designed Class II biosafety cabinet. These biosafety cabinets combined with the separate housing in a dedicated laboratory space in Room 6008A allow the LGI FC37 to operate in full compliance with NIH Policy for Biosafety of Cell Sorters (July 28 2012) to perform all sorts at a BSL-2 with enhanced precautions aerosol containment level. Ferenc Livak and Karen Wolcott continued working with James Galentine of NCI Office of Space and Facilities Management to oversee the renovation and expansion of the Core in BG37. The construction has now reached its final phase and the Core is expected to move into the finished expanded space on August 28-29 2023 pending approval. The new expanded space will allow users and staff to maintain minimum 6-foot physical distancing and would give the Core the opportunity to introduce another high-end cell sorter in the coming years in a separate lab space that can continue to operate even in case of future emergency situations. In March 2023 staff member Dr. Caiyi Li announced her desire to leave the Core for a more benchwork-oriented job at another NCI branch. We immediately initiated a search to find a replacement for Dr. Li. After exploring possible candidates within NIH the search was expanded nationwide. A total of 12 candidates were interviewed either online or in some cases in-person. All of these interviews involved the entire staff of FC37 and assessments from all staff members were collected. Finally Ms. Raghad Almofeez a recent masters graduate from George Mason University was offered the position based on her personal qualities and hands-on experience in analytical flow cytometry. Ms. Almofeez began to work as a staff member at the Core in July 31 2023. We have high hopes that she will be soon a fully competent valuable member of our Core service. In FY23 utilization of the LGI FC37 returned to pre-pandemic levels. The Core served 203 users from 79 CCR laboratories as well as from 2 additional laboratories of two other NIH institutes in FY23. Many of these laboratories heavily depend on the services of the Core in conducting high-dimensional analyses aimed at better understanding of lymphocyte development and activation (Bosselut lab [LICB] and Samelson lab (LCMB]) thymus epithelium development (Bhandoola lab [LGI]) and tumor-associated immune responses (Gilbert and Zhuang labs [NOB]). Flow cytometry analyses are used to develop novel immunoassays and immunotherapeutic reagents (Ashwell lab [LICB] Ho and Pastan labs [LMB]). Cell sorting helps with the establishment and maintenance of fluorescent protein reporter-based models (Ruiz Macias lab [LGI] and Wakefield lab [LCBG]). Single cell sorting helps the rapid generation of CRISPR-induced mutant cell lines and is becoming an essential tool in single cell genomic analyses and CRSIPR library screening (Nussenzweig Bhandoola and Lazzerining-Denchi labs [LGI] Bosselut lab [LICB]). The LGI FC37 provides unique support in imaging flow cytometry technology by offering the only Amnis ImageStream instrument on campus to the study of lymphoma drug targeting (Staudt lab [LMBr]) cancer stem cell studies (Yang lab [LCBG]) phagocytosis assays (Appella lab [LCB]) and DNA damage response (Nussenzweig lab [LGI]). The LGI FC37 has trained 57 new users in FY23 on analytical instruments and has also trained one new user for cell sorting. New users are instructed to review instrument and software training tutorials before attending a 4-hour hands-on training session that includes startup and shut down procedures for the cytometers setting up experiments basic instrument troubleshooting and data analysis. Staff member Karen Wolcott introduced and continued with a fully Webex-based remote training schedule. She is also using Webex to provide follow-up support and periodic assistance to inexperienced users which limits the need for the rest of staff to on-site handling of occasional instrument malfunctions. Cell sorter training is offered to select users who need frequent possibly after hour sorting time. The LGI FC37 has designed and maintained policies to ensure safe fair and equitable access of Core resources to all registered users. Despite recent challenges associated with the ongoing renovations and move of the Core the LGI FC37 remains committed to be a leader of flow cytometry services at CCR by offering the highest quality reliable support to the largest number of NCI investigators on campus The LGI FC37 is dedicated to the introduction of innovative flow cytometry-based technologies to further advance the cutting-edge cancer research conducted at NIH. 1826105 +No NIH Category available ADORA2A gene;Affect;Agonist;Amines;Apoptosis;Binding;Biological;Biological Assay;Biomimetics;Cell Adhesion;Cell Surface Receptors;Cell membrane;Cells;Cilengitide;Clinical;Collaborations;Cyclic Peptides;DNA;Development;Drug Targeting;Extracellular Matrix;Extracellular Matrix Proteins;Family;Glioblastoma;Goals;HIV;Human;Hybrids;Infiltration;Integrin alphaVbeta3;Integrins;Investigation;Laboratories;Libraries;Ligands;Malignant Neoplasms;Mediating;Melanoma Cell;Membrane;Metastatic Neoplasm to the Lung;Molecular Conformation;Molecular Target;Nanotechnology;National Institute of Diabetes and Digestive and Kidney Diseases;Nerve Degeneration;Nucleic Acids;Parkinson Disease;Peptide Nucleic Acids;Peptide Synthesis;Peptides;Periodicity;Pharmaceutical Preparations;Phase;Positioning Attribute;Proliferating;RGD (sequence);RNA;Surface;Synthesis Chemistry;Tandem Repeat Sequences;Technology;Vascular Endothelium;Vertebral column;Work;Xanthines;angiogenesis;antagonist;base;cancer cell;cancer therapy;dimer;drug development;echistatin;inhibitor;interest;migration;molecular size;monomer;mouse model;neovascular;overexpression;peptide analog;receptor;scaffold;tumor HIV NCp7 inhibitors and Multivalent Inhibition of Membrane Receptors n/a NCI 10926628 1ZICBC011380-13 1 ZIC BC 11380 13 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 37395 NCI This project is in collaboration with the laboratory of Dr. Daniel Appella (LBC/NIDDK) which specializes in synthetic chemistry of biomimetics. This is an extension of their work developing hybrids of DNA and Peptide Nucleic Acid (PNA) molecules as programmable scaffolds for the multivalent display of biological ligands. PNAs are oligomeric molecules with peptide-like backbones and nucleic acid-type bases i.e. the A G C & T/U of DNA and RNA for sidechains. Thus by adjusting the sequence of the monomers PNAs can be programmed to bind in a helical conformation to a single or tandem repeated complementary sequence in DNA. Specific ligands are positioned anywhere along the PNA/DNA scaffold by the programmed addition of bridging linkers to the synthesized PNA backbone. For a proof of principle we focused on the conserved RGD sequence in extracellular matrix proteins that is a preferential ligand of Integrin alphaVbeta3. We used a 5-residue cyclic-peptide analog of this sequence that is similar to the drug Cilengitide (MerckSerono) which is currently under Phase II investigation for Glioblastoma and other cancers. To determine the optimal configuration the Appella lab generated a library of hybrid molecules with systematically-varied ligand positions and densities and then screened it on a melanoma cell binding assay. Balancing molecular size and potency a construct with 5 PNA segments each presenting three RGD ligands was judged the optimal inhibitor. Using a radiolabled echistatin displacement assay this optimal construct was found to bind 400 times stronger to alphaVbeta3 than the monomeric RGD control. Finally this optimal PNA/DNA inhibitor was also found to outperform monomeric cyclic-RGD in blocking lung metastasis of melanoma cells in a mouse model. Recently we have expanded this project to target the human A2a adenosine receptor for multivalent binding of agonists and antagonists. Recently we expanded the application of this technology to the A2a adenosine receptor a drug target for Parkinson's disease and other neurodegenerative conditions. Using a multivalent library of attached anatagonist ligands (Xanthine Amine Congener) we were able to identify the receptor in both dimer and higher order configurations in the cell membrane. 37395 +No NIH Category available Active Sites;Affinity;Binding;Cancerous;Collaborations;Complex;Computer Models;Cyclic Amino Acids;Cyclic Peptides;DNA Damage;Deuterium;Development;Enzymes;Family;Generations;Genetic Transcription;Goals;Homologous Gene;Laboratories;Lead;Mass Spectrum Analysis;Molecular Conformation;Mutagenesis;National Institute of Diabetes and Digestive and Kidney Diseases;PPP2CA gene;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Process;Proteins;Pyrroles;Role;Series;Serine;Structural Models;Structure;Substrate Specificity;Synthesis Chemistry;TP53 gene;Testing;Threonine;Work;X-Ray Crystallography;ataxia telangiectasia mutated protein;cell growth;cell growth regulation;cell transformation;design;experimental study;inhibitor;magnesium ion;member;p38 Mitogen Activated Protein Kinase;protein phosphatase 2C;scaffold;small molecule;small molecule inhibitor;virtual screening Inhibitor Development Against the Wip1 Phosphatase n/a NCI 10926627 1ZICBC011379-13 1 ZIC BC 11379 13 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 186974 NCI This project is part of a long-standing collaboration with the laboratory of Dr. Ettore Appella (LCB/NCI) in which the Wip1 protein was discovered. Initial characterization resulted in determining two classes of phosphorylated substrates involving many proteins involved in cell growth regulation. The first has a diphosphorylated sequence motif (pT-X-pY) such as in p38 MAP Kinase while the second has a mono-phosphorylated sequence motif (p(S/T)Q) such as in the p53 Chk1/2 and ATM proteins. By development of an atomic-scale computer model of the extended active site of Wip1 and a series of mutagenesis experiments we were able to reveal the structural basis for the range of substrate specificity. This lead to the development of a cyclic peptide molecule that competitively inhibits Wip1 the first inhibitor of any kind for this family of enzymes. We then pursued development of a more drug-like small molecule inhibitor in collaboration with Dr. Daniel Appella (LBC/NIDDK) who specializes in synthetic chemistry. The resultant small molecule is based on a pyrrole ring scaffold with 5 different emanating sidechains to mimic the amino acids of the cyclic peptide. While successful the final inhibition constant was still only in the low micromolar range. To further this effort we returned to optimizing the cyclic peptide inhibitor. By multiple iterations of design and testing we were able to drastically increase the binding affinity resulting in an inhibition constant of 110 nM. The structural modeling involved in this process revealed both important new interactions in the extended active site and the role of the proximal B-loop in binding substrate and regulating activity. Since the B-loop is unique to the Wip1 member of the PP2C family its role was previously unknown. We are now applying these lessons to designing a new generation of pyrrole-based inhibitors. We are also pursuing generating sufficient Wip1 protein to determine the structure by X-ray crystallography which will greatly aid in inhibitor optimization. Recently we have verified the requirement of binding a 3rd magnesium ion for activity of Wip1 and the related PP2Ca homologue and used deuterium exchange mass spectroscopy to study the functional conformational changes. We are currently determining the crystal and NMR structures of PP2Ca/cyclic peptide inhibitor complexes. Recently we used Deuterium Exchange Mass Spectroscopy to study the functional structural changes of Wip1 and the PP2Ca homologue. We have also determine the crystal structure of PP2Ca with a bound substrate. We are using our recently determined crystal structure of Wip1 with the elusive B-loop to perform virtual screening to identify inhibitor leads. 186974 +No NIH Category available Automation;Bioinformatics;Biological Sciences;Communicable Diseases;Communities;DNA;Data;Deoxyribonucleases;Ensure;Failure;Future;Generations;Genomic DNA;High-Throughput Nucleotide Sequencing;Laboratories;Libraries;Liquid substance;Manuals;Messenger RNA;MicroRNAs;Microfluidics;Mission;NCI Center for Cancer Research;Neck;Preparation;Principal Investigator;Process;RNA;Reagent;Resources;Sampling;Stretching;System;Technology;Time;Transcript;anticancer research;bisulfite;cancer type;chromatin immunoprecipitation;coronavirus disease;cost;data quality;exome;genomic variation;instrument;microbial;next generation sequencing;operation;single molecule CCR Sequencing Facility n/a NCI 10926626 1ZICBC011331-14 1 ZIC BC 11331 14 9414524 "GOLDSTEIN, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4976850 NCI Over the last year the CCR-SF has sequenced several hundred samples for dozens of different NCI principal investigators generated Terabases of mappable data and has completed numerous projects. Sample types from various cancer types and infectious diseases including COVID have been successfully sequenced include: whole genomic DNA exome capture DNA Chromatin Immuno-Precipitated DNA (ChIP) DNase HS DNA 4C DNA mRNA short hairpin DNA microRNA and Bisulfite samples. The labor intensive library preparation step is the major workflow bottle neck. To reduce library preparation costs and increase library preparation throughput and the efficiency of laboratory operations the CCR-SF team has implemented Beckmans SPRIworks Fragment Library System (SPRI-TE). The SPRI-TE has the capability to produce three times the number of libraries prepared by a technician uses a tightly controlled micro fluidics system to reduce manual liquid transfer variability and the reagent costs are currently at or below the cost of the Illumina library preparation reagents before optimization. CCR-SF bioinformatics has implemented standard analyses on all applications. These analyses have been incorporated into an automation pipeline providing additional time to bioinformatics staff for optimizing the data quality and automation process. CCR-SF bioinformatics takes all new customers through an Introduction to Illumina session complete with a document for future reference. This course has been given across NCI. The CCR-SF Quality Management team has implemented a robust QC workflow to help identify potential failures as early as possible further conserving resources and increasing overall efficiency. 4976850 +No NIH Category available Adhesions;Agreement;American;Androgens;Antibodies;Antigens;Biology;CCR;Cancer Biology;Carbohydrates;Cell Line;Cell Separation;Cells;Chemicals;Clinical;Clinical Research;Coculture Techniques;Collaborations;Colon;Computer software;Congresses;Consultations;Cytometry;Data Collection;Development;Developmental Biology;Dyes;E-Cadherin;Engineering;Ensure;Epithelium;Equipment;Evaluation;Flow Cytometry;Genomics;Hour;Human;Image;Immune;Immunophenotyping;Individual;Institution;Interferons;International;Investments;Knockout Mice;Laboratories;Lasers;Life Cycle Stages;Literature;Macrophage;Maintenance;Malignant Neoplasms;Manufacturer;Measurement;Measures;Metastatic breast cancer;Methods;Microfluidics;Mitochondria;Molecular Immunology;Molecular Target;Mus;Muscle Cells;National Institute of Allergy and Infectious Disease;Oncogenes;PTGS2 gene;Pathology;Pathway interactions;Price;Publications;Publishing;RNA;Reagent;Reporting;Research;Research Personnel;Resolution;Sampling;Science;Scientist;Secure;Services;Signal Transduction;Societies;Sorting;Stromal Cells;Students;T-Cell Leukemia;Technology;Testing;Training;Training Programs;United States National Institutes of Health;Vaccines;Work;antibody conjugate;assay development;cancer genetics;chromophore;college;cyanine;essays;functional group;glycogen synthase kinase 3 beta;improved;innovation;insight;instrument;instrumentation;investigator training;lectures;multicatalytic endopeptidase complex;programs;quality assurance;sound;structural biology;thymocyte;tool;transcriptome sequencing CCR-Frederick Flow Cytometry Core n/a NCI 10926623 1ZICBC011236-15 1 ZIC BC 11236 15 77857619 "CARRELL, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 334964 NCI To date in FY2023 the Core has performed 230 billable services including 522 individual samples sorted and 1024 hours billed. The core's cytometers were used for 1454 sessions totaling more than 4300 hours. The Core recorded 90 unique users from numerous CCR labs and NIH programs including the Cancer Innovation Laboratory Mouse Cancer Genetics Program Chemical Biology Laboratory RNA Biology Laboratory Cancer & Developmental Biology Laboratory Center for Structural Biology Laboratory of Cell & Developmental Signaling Vaccine Branch FNL Molecular Targets Lab Collaborative Clinical Research Branch (NIAID) and the Office of the Clinical Director. The core trained 14 new users (scientists fellows students and technicians) from 6 different labs to use flow cytometry in their work. To keep up with evolving cytometry technology and ensure uninterrupted service as old instruments become obsolete core staff evaluates new instruments and software and meets regularly with flow facility leaders across NCI to harmonize instrument offerings and secure favorable pricing for equipment and service maintenance agreements. The core organized technology presentations highlighting using cytometry in RNAseq workflows by BioLegend and 10X Genomics (Jun 2023) and advances in spectral cytometry by Thermo (Nov2022) and microfluidic cell sorting by Miltenyi (May 2023). Core staff attended the Congress for the International Society for the Advancement of Cytometry (CYTO May 2023) and Automated Flow Solutions showcase (Montgomery College Oct 2022). The core was acknowledged for technical contributions to these 2022/2023 publications: 1) IL-27 induces an IFN-like signature in murine macrophages which in turn modulate colonic epithelium. Andrews C et al. Front Immunol 14: 1021824 (2023) PMID 37153622 2) Co-Culture and Transduction of Murine Thymocytes on Delta-Like 4-Expressing Stromal Cells to Study Oncogenes in T-Cell Leukemia. Rodrigues et al. J Vis Exp 196 (2023) PMID 37358271 3) Selective Recognition of Carbohydrate Antigens by Germline Antibodies Isolated from AID Knockout Mice. DeLaitsch et al. J. Am. Chem. Soc 144: 4925 (2022) PMID 35282679 4) An engineered cell line with a hRpn1-attached handle to isolate proteasomes. Negi et al. J. Biol. Chem. 299(8): 104948 (2023) PMID 37354974 5) IFN-? and androgens disrupt mitochondrial function in murine myocytes. Fenimore et al. J Pathol 260: 276-288 (2023) PMID 37185821 6) Method To Diversify Cyanine Chromophore Functionality Enables Improved Biomolecule Tracking and Intracellular Imaging. Usama et al. J. Am. Chem. Soc. 145:14647 (2023) PMID 37367935 7) Cyanine Masking: A Strategy to Test Functional Group Effects on Antibody Conjugate Targeting. Thapaliya et al. Bioconjugate Chem. 33: 718 (2022) PMID 35389618 8) Stabilization of E-cadherin adhesions by COX-2/GSK3beta signaling is a targetable pathway in metastatic breast cancer. Balamurugan et al. JCI Insight 8(6):e156057 (2023) PMID 36757813. The core manager presented a flow cytometry lecture as invited speaker to Hood College Molecular Immunology class BMS 539 (Nov2022) and also published an in memorium essay about cytometry pioneer Howard Shapiro in Critical Values (published by American Society of Clin Pathology Sep2022). 334964 +No NIH Category available Affinity;Apoptosis;Architecture;Arginine;Binding;Biochemical Pathway;C-terminal;CREBBP gene;Cancer Biology;Cell Cycle Arrest;Cell Cycle Kinetics;Cellular Stress;Chemicals;Chromatin;Collaborations;Complex;DNA Damage;Development;EP300 gene;Electrostatics;Genes;Genetic Transcription;Histone Acetylation;Homologous Gene;Hydrophobicity;Laboratories;Lead;MDM2 gene;Mediating;Modification;Monitor;Mutation;N-substituted Glycines;N-terminal;Normal Cell;Pattern;Peptides;Peptoids;Phosphorylation;Post-Translational Protein Processing;Proteins;Series;Serine;Signal Pathway;Signal Transduction;Site;Structure;Surface;TP53 gene;Thermodynamics;Threonine;Transactivation;Work;Zinc;alpha helix;design;drug development;histone acetyltransferase;inhibitor;interest;molecular modeling;molecular targeted therapies;novel;promoter;protein protein interaction;recruit;response;scaffold;structural biology;transcription factor;tumor Molecular Modeling of Interactions Regulating the Activity of the p53 Protein n/a NCI 10926617 1ZICBC011077-16 1 ZIC BC 11077 16 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 74791 NCI This project continues a long-standing collaboration with the Laboratory of Dr. Ettore Appella (LCB/NCI). Initially we focused on the inactivation of p53 by the binding of the MDM2 and MDMX proteins to the N-terminal transactivation domain. This work lead to the development of two types of competitive inhibitor molecules. The first based on a poly N-substituted glycine scaffold was the proof of principle that such peptoids could be designed against a protein target. The second easier to produce molecule was based on a novel N-acylpolyamine (NAPA) scaffold. This latter molecule was optimized to have a binding affinity comparable to the well-known MDM2 inhibitor Nutlin (Hoffman-La Roche). However superior to Nutlin our inhibitor is potent against both MDM2 and MDMX. Subsequently we have concentrated on the functional interactions of p53 with the histone acetyltransferase coactivator homologs CREB-binding protein (CBP) and p300. Chromatin-bound p53 recruits these proteins to the gene promoter resulting in localized acetylation of the histones and thus the required unwinding of the chromatin needed for transcription. CBP and p300 are each composed of seven distinct domains arranged in a common architecture. Among these are two transcriptional adaptor zinc-binding domains Taz1 (C/H1) and Taz2 (C/H3) which mediate protein-protein interactions important for transcription. While both these domains were known to interact with both transactivation domains of p53 (TAD1 & TAD2) nothing was known of the structural details. In collaboration with Drs. Hanqiao Feng and Yawen Bai (LBMB/NCI) we were the first to elucidate the structure of the interaction of the TAD1 of p53 with the Taz2 domain of p300. In the complex the p53 peptide forms a short helix and interacts with the Taz2 domain through an extended surface. The specific way in which the helix is bound is different from what has been observed in complexes with other proteins most notably with MDM2 and MDMX. While the complex is primarily stabilized by hydrophobic bonds electrostatic interactions also play a role. Our additional studies involving NMR mutations and thermodynamics indicated how the structure of the complex shifts and is further stabilized upon phosphorylation of p53 at residues Ser15 and Thr18 which was known as post-translational modification signals for the recruitment of CBP and p300. By revealing the specific interactions of the phosphorylated residues of p53 with proximal arginine residues of Taz2 we were able to explain the structural basis for this important signaling pathway. Currently we are pursuing the structure of the complex of the p300 Taz2 domain with TAD2 the second transactivation domain of p53. This is of particular interest because unlike the first the interaction is not altered by phosphorylation of the analogous serine and threonine residues in the p53 sequence. Finally we have at least two new directions we are gearing-up to pursue. One is to evaluate the formation of a putative stabilizing alpha-helix in the C-terminal regulatory domain and to determine the effect of modifications on the stabilization of the p53 tetramer. The other is to monitor directly in cells the kinetics of the site-specific chemical modifications of p53 and the resultant series of molecular interactions that follow different types of cellular stresses. Recently we finished refining and analyzing the NMR structure of the p300-Taz2/p53-TAD2 complex. 74791 +No NIH Category available 3-Dimensional;ABCB1 gene;ATP-Binding Cassette Transporters;Address;Adenosine;Antibodies;Binding;Carrier Proteins;Cells;Chemotherapy-Oncologic Procedure;Computing Methodologies;Crystallography;Data;Effectiveness;Electron Microscopy;Electrons;Environment;Experimental Designs;Exposure to;Family;Genetic Polymorphism;Goals;Homologous Protein;Human;Hydrolysis;Hydrophobicity;Integral Membrane Protein;Knowledge;Label;Lipids;Membrane;Methods;Modeling;Molecular Conformation;Multi-Drug Resistance;Mus;Mutation;Pattern;Proteins;Pump;Roentgen Rays;Sequence Alignment;Site-Directed Mutagenesis;Structural Models;Structure;Substrate Specificity;Transmembrane Domain;X-Ray Crystallography;analog;cancer therapy;chemotherapy;crosslink;design;experimental study;extracellular;flexibility;human model;in vivo;mathematical methods;member;molecular modeling;nucleotide analog;small molecule;small molecule inhibitor;stem;three dimensional structure;tripolyphosphate Molecular Modeling of the Human P-glycoprotein Transporter Protein n/a NCI 10926616 1ZICBC011075-16 1 ZIC BC 11075 16 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 299160 NCI Like many transmembrane proteins determination of the structure of P-gp by X-ray crystallography has proven very difficult. This stems from the problems encountered forming sufficient-quality crystals that maintain the native physiochemical environments for the different parts of the protein and thus the native conformations. After many years of endeavor a structure of the closely-related mouse P-gp protein has become available. However many questions remain as to how close the crystal structure relates to the protein in vivo and how the conformation changes as part of the transport function. To address these questions we are striving to integrate all available X-ray crystal and electron microscopy determined and indirect experimental data with physiochemically-based mathematical methods to produce advanced models of the structures. Fortunately over three decades of study has provided a wealth of information about P-gp from which we can gleam structural information. In addition to mouse P-gp crystallographic structures are available from homologous proteins: especially bacterial Sav1866 and the MsbA lipid flippase. Examples of useful indirect experimental data include the effects of site-directed mutagenesis naturally occurring polymorphisms and residue cross-linking. Examples of theoretical physiochemically-based methods include examining the patterns of residue conservation and polarity/hydrophobicity within the family of closely related MDR proteins and the superfamily of ABC transporters. This information helps predict which residues are exposed to the core and headgroup layers of the membrane which residues line the pore and which are at the interfaces of the two transmembrane domains. To this end we are developing a grand sequence alignment of homologous families and the superfamily. The results of this will also enable the determination of patterns of correlated mutations which help identify groups of residues that are proximal in the 3-dimensional structure of the protein. We have used our 3-D structural modelling of human P-gp to determine where to put electron paramagentic probes to experimentally determine different conformational states over the functional cycle of the protein. Additionally we will use computational methods with our P-gp models to select nucleotide analogs and labeling agents to interact with and further elucidate the structure and functional mechanisms. Most recently we have use the models to explain the experimentally-determined binding-effects of 5'-fluorosulfonylbenzonyl-5'-adenosine (FSBA) an ATP analogue on the functional mechanisms of P-gp. We have also used computational methods to better account for the membrane environment on the protein. Recently the models were used to design and interpret experiments that revealed the functional flexibility of the P-gp binding pocket. That is mutation of known substrate-binding residues identified alternative sub-pockets that allow for functional transport. We have also used computational methods to predict the binding of antibodies to the extracellular loops of human Pgp. 299160 +No NIH Category available Anatomy;Ancillary Study;Breast;Cell Count;Cell Line;Central Nervous System;Clinical;Clinical Protocols;Clinical Research;Cytology;Cytopathology;Diagnosis;Diagnostic;Diagnostic Services;Duct (organ) structure;Evaluation;Fellowship;Fine needle aspiration biopsy;Flow Cytometry;Goals;Gynecologic;Investigation;Irrigation;Malignant Neoplasms;Molecular;Molecular Analysis;Morphology;Nature;Organ;Organism;Pathologic;Pathology;Patients;Pericardial cavity;Peritoneal;Pleural;Prognosis;Protocols documentation;RNA;Research;Research Technics;Residencies;Respiratory System;Sampling;Specimen;System;Techniques;Technology;Testing;Therapeutic;Training;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;coronavirus disease;experience;human disease;immunocytochemistry;immunosuppressed;neoplastic cell;patient population;prognostic;research study;urogenital tract Cytopathology Core n/a NCI 10926615 1ZICBC011052-16 1 ZIC BC 11052 16 9692483 "FILIE, ARMANDO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1867065 NCI Cytopathology provides diagnostic evaluation of cytology specimens that direct patient management and treatment. The Cytopathology Section provides complete diagnostic service in cytopathology for the various clinical protocols at the NIH. We specialize in the application of ancillary techniques (i.e. immunocytochemistry flow cytometry and molecular testing) to patient material for the confirmation of morphologic diagnoses evaluation for protocol entry criteria and collaborative investigations. The Cytopathology Section evaluates cytology specimens from the central nervous system pleural/peritoneal/pericardial cavities respiratory tract genitourinary tract gynecologic system fine needle aspiration (FNA) samples of various organs and other less common cytology specimens. Due to the nature of the specimen material evaluated by our Section often our cases require immunocytochemical and/or other ancillary studies. The immunosuppressed nature of our patient population at the NIH dictates that a significant proportion of our cases require special studies for pathologic organisms. The relatively high rate of pathologic findings combined with the diversity of types of exfoliative and FNA specimens provide a broad experience in diagnostic cytopathology for anatomic pathology residency and cytopathology fellowship training. The Cytopathology Section is involved in numerous clinically related research studies many of which utilize FNA or non-gynecologic exfoliative samples with immunocytochemistry and/or molecular techniques to provide additional ancillary diagnostic prognostic therapeutic or protocol required information. A partial list of such studies includes: (1) morphologic and immunocytochemical evaluation of tumor infiltrating lymphocytes samples for possible tumor cell contamination prior to therapy; (2) FNA material for subsequent analysis by molecular technologies; (3) evaluation of cell lines by morphology and immunocytochemistry; (4) application of RNA-based molecular technique to non-gynecologic and FNA cytology samples to enhance diagnosis prognosis and patient management; and (5) morphologic evaluation of breast ductal lavage samples for diagnosis and cell count needed for protocol research studies. 1867065 +No NIH Category available Amendment;Animal Care and Use Committees;Animal Experimentation;Animal Genetics;Animal Model;Animals;Area;B-Cell Lymphomas;Bioluminescence;Breeding;Cancer Biology;Cancer Model;Communities;Computer software;DNA;Equipment;Foundations;Genetic;Genomics;Genotype;Goals;Image;Laboratories;Malignant neoplasm of prostate;Monitor;Multiple Myeloma;Mus;National Cancer Institute;Neoplasm Metastasis;Pharmaceutical Preparations;Plasma Cell Neoplasm;Plasma Cells;Preclinical Testing;Preparation;Process;Research;Research Personnel;Research Support;Skin Carcinogenesis;Techniques;Technology;Western Blotting;Writing;anticancer research;cancer genetics;cancer initiation;design;experimental study;gel electrophoresis;malignant breast neoplasm;melanoma;mouse model;new technology;tool;tumor;tumor progression;tumorigenesis Animal Model and Genotyping Core Support Facility n/a NCI 10926614 1ZICBC011047-16 1 ZIC BC 11047 16 16162291 "DU BOIS DE VROYLANDE, WENDY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1222900 NCI The mouse model animal and genotyping core provides support to investigators in the Laboratory of Cancer Biology and Genetics in several areas all relating to mouse models of B cell lymphoma myeloma plasma cell tumorigenesis skin carcinogenesis melanoma breast cancer and prostate cancer all of which have been developed by various investigators in the group. In the animal core we maintain the genetic integrity and oversee all of the breeding strategies required to maintain the many different lines of mice. The core staff carries out all genetic monitoring/genotyping. We routinely perform DNA extraction genotyping of all mouse lines by PCR and gel electrophoresis. We are in the process of outfitting the lab so that we can do Western Blot experiments. We actively participate in the planning design execution and analysis of various types of experiments using animal models and in setting up and executing preclinical testing of various drugs for their anti-tumor activity.. We have acquired a Lumina II imaging machine and can now carry out tumor/drug studies using bioluminescence technology. We write many of the original Animal Study Proposals and associated amendments and assure that they are kept up to date and in compliance with the NCI Animal Care and Use Committee. We actively participate in preparation for all inspections by the ACUC and AALAC. The animal core is responsible for coordinating the shipment of mouse lines as well as tumor lines to investigators all over the world thus providing useful research tools to others in the cancer research community. The combination of animal and genomic expertise in the core assists our investigators in their mechanistic studies of cancer initiation cancer progression and cancer metastasis. 1222900 +No NIH Category available Advanced Technology Center;Analysis of Variance;Bacterial Genes;Base Sequence;Basic Science;Bioinformatics;Biometry;Chromosomes;Clinical Research;Collaborations;Communities;Computer Analysis;Computer software;Computing Methodologies;Consultations;Core Facility;Custom;Data;Data Analyses;Data Set;Database Management Systems;Databases;Detection;Development;Educational workshop;Equipment;Experimental Designs;Extramural Activities;Gene Chips;Gene Expression;Gene Expression Profiling;Genes;Housekeeping Gene;Human Resources;Image;Information Centers;Information Management;Information Resources;Information Technology;Internet;Joints;Journals;Label;Literature;Loss of Heterozygosity;Maintenance;Malignant Neoplasms;Maps;Measurement;Meta-Analysis;Methods;Microarray Analysis;Mining;NCI Center for Cancer Research;National Cancer Institute;Odds Ratio;Pathway Analysis;Positioning Attribute;Process;Publications;Quality Control;RNA;Radiation Oncology;Regression Analysis;Research;Research Personnel;Resources;Risk Estimate;Running;Sampling;Services;Signal Transduction;Statistical Data Interpretation;Statistical Methods;Students;Sum;Survival Analysis;Technology;Testing;Tissue-Specific Gene Expression;Training;Validation;Visualization;Work;Writing;advanced analytics;analytical method;beta Actin;cDNA Arrays;comparative;data format;data integration;data mining;data visualization;differential expression;experimental study;gel electrophoresis;genetic profiling;high throughput analysis;in silico;innovation;meetings;member;multidisciplinary;population based;preference;public repository;reference genome;shared database;shared repository;sound;symposium;technology development;tool;tool development;user-friendly Radiation Oncology Branch - Microarray Facility n/a NCI 10926610 1ZICBC010991-16 1 ZIC BC 10991 16 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 912615 NCI "Core services: As an integral component of the ROB research framework the MCF has contributed to the scientific excellence of the ROB investigators. The Core has been utilized by all ROB investigators and a few external collaborators leading to many joint publications. The MCF provides two main services: 1) Affy microarray service and 2) bioinformatics and biostatistics analysis. a. Microarray service. The core specializes in the use and analysis of microarrays for large-scale gene expression profiling and genetic profiling and provides full core lab services for Affymetrix GeneChip arrays. The process begins with a research hypothesis and the development of a sound experimental design in consultation with the primary researcher. Basic gene expression service begins by providing the core with total RNA. The core will first run the samples on gel electrophoresis or on an Agilent 2100 bioanalyzer to assess sample quality. If the samples pass QC the core processes the samples through each step culminating with a comprehensive dataset. Users will be provided with all the array files associated with their runs. In addition the files are uploaded to a shared microarray database (mAdb) system (http://madb.nci.nih.gov) developed by National Cancer Institute's (NCI) Center for Cancer Research (CCR) in collaboration with the Center for Information Technology. b. Data analysis service. Collaborative statistical support on multidisciplinary projects is provided to basic and clinical research investigators. Analysis of high throughput studies involves a wide range of statistical methods begins with consultation regarding experimental design. Microarray results are directly influenced by the experimental design; therefore it is suggested that the researcher control for as many experimental factors as possible. Arrays are initially evaluated for basic quality control. In the case of Affymetrix chips a set of bacterial gene (BioC bioD and cre) spike-in controls are used to evaluate hybridization efficiency. A set of internal housekeeping gene (GAPDH and B-Actin) controls are used to assess the quality of the synthesis of labeled cRNA. The data are normalized by the Lowess (cDNA array) MAS5.0 scaling method Robust Multichip Average (RMA) or other methods depending on attributes of the experiment or the user's preference. The data are formatted to show probe-gene identities aligned with log2 signal intensity measurements and detection p-values for each gene of each array experiment. In the case of sequencing data computational analysis of reference genome alignment quality filtering annotation to map the aberrations to cancer specific and population based sequences and comparative analysis are performed. Whenever possible data are normalized copy number is computed and segmented and loss of heterozygosity is calculated. Data are also visualized to see gains and losses across chromosomes. The primary users are consulted after the initial analysis of the data that may for example include a statistical analysis whereby Student's t-test or Wilcoxon rank-sum may be used to assess the significance of differential expression of genes between two groups or more than two groups (e.g. ANOVA Kruskal-Wallis) followed by false discovery correction (e.g. Benjamini and Hochberg method). After consultation with the primary user advanced analytical objectives such as data visualization and mining differential expression analyses pathway analyses and in silico independent validation of results (meta-analysis using information available in the literature and in expression databases) to draw meaningful conclusions from the ""omic"" technologies. Support for clinical studies involves methods to estimate risk ratios odds ratios survival analysis and cox regression analysis. The analytical methods for the analysis of high throughput data are continuously evolving and to keep abreast of the latest developments and best practices the core works in collaboration with members of CCR bioinformatics core as needed in statistical methods. Personnel also attend scientific conferences and participate in advanced workshops at the meetings. In addition the core organizes weekly journal club discussions of new innovations within the bioinformatics community. c. Information resources and management service Uma you said the core does two things in the intro and now you are introducing a third The core has unique interdisciplinary expertise and is in a good position to generate and maintain information resources including customized technology development projects not found in commercial software. Microarray processes generate large amounts of data. Information including the images image quantitation data and attributes of the samples are quite valuable. Generally only a fraction of the results generated by microarray experiments can be further investigated by a single workgroup. Unlike the research samples generated by the investigators the information generated by these experiments represents a resource that should be widely shared. The maintenance and dissemination of this resource requires specialized equipment and expertise. For the gene expression microarrays processed in the core the results of all array experiments are stored in the mAdb shared repository accessed and used by ROB investigators and their collaborators. In addition accompanying publication the raw and processed data analyzed at the core will be submitted to public repositories as required by the scientific journals (e.g. Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo )) and be available to researchers globally. After publication information and processed data are maintained at the microarray array core. These data along with data from public resources are used to generate user friendly tools with an advantage of: 1) presenting data with common standards and 2) mining the integrated data for added confidence of a particular result and help conserve resources by redirecting investigators research efforts in other directions. This is accomplished using MySQL database components configured with custom software written by bioinformatics staff in the core. The database is maintained locally and backed up remotely by NCI-maintained servers." 912615 +No NIH Category available Autologous;Cell Separation;Clinic;Clinical;Colon Carcinoma;Core Facility;Dedications;Epithelial Cells;Gene Delivery;Generations;Goals;Individual;Lentivirus Vector;Malignant neoplasm of lung;Mediating;Metastatic Melanoma;Mutation;Oncogenes;Operative Surgical Procedures;Patients;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Production;Reagent;Research;Retroviral Vector;Solid Neoplasm;Specific qualifier value;T cell therapy;T-Cell Receptor;T-Lymphocyte;Testing;Time;Tumor-Infiltrating Lymphocytes;Viral;Viral Vector;antigen-specific T cells;cancer cell;cell bank;cellular transduction;chimeric antigen receptor;cost;gene therapy;gene therapy clinical trial;immunogenic;improved;individualized medicine;malignant breast neoplasm;manufacture;meetings;neoantigens;nonsynonymous mutation;novel;novel strategies;programs;tumor;vector Clinical production of viral vectors for cancer gene therapy n/a NCI 10926609 1ZICBC010989-16 1 ZIC BC 10989 16 15687510 "BEYER, RACHEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 693211 NCI The Surgery Branch Vector Production Facility (SBVPF) was established to provide clinical-grade retroviral and lentiviral vectors to support of our gene therapy clinical trials with the goal of providing GMP quality products while reducing production time and cost. These products both retroviral and lentiviral vectors will be used to introduce novel T cell receptors (TCR) or chimeric antigen receptors (CAR) to genetically modify T cells to make them specifically recognize and kill tumor. This lab provides all the clinical viral reagents for our clinical gene therapy program. Our current focus is to isolate T cell receptors targeting nonsynonymous mutations presented by tumors from tumor infiltrating lymphocytes residing within the given tumor and testing the hypothesis that immunogenic mutations (neoantigens) presented on a patient's tumor mediate tumor regression by TIL. In some cases TIL cannot be generated but TCRs can still be cloned. We use a gene therapy approach to treat patients by introducing neoantigen-specific TCRs into autologous PBMC using these viral vectors expanding the transduced cells ex vivo and administering to the patient. We have developed a small scale transient vector production platforms (gammaretroviral) that supports GMP-compliant transient vector production for single individualized patient treatments targeting neoantigens. Since the opening of a dedicated GMP viral vector production space in October 2019 the SB GMP VPF has produced 60 novel individual vectors encoding patient specific TCRs meeting the specifications required for clinical use. Specifically since August of 2022 through August of 2023 the SBVPF has manufactured 20 vector supernatants appropriate for clinical use. 693211 +No NIH Category available Aneuploidy;Antibody-drug conjugates;Biological Assay;Biological Markers;Cancer Gene Mutation;Chromosome abnormality;Chromosomes;Clinical Drug Development;Clinical Management;Clinical Trials;Data;Detection;Development;Disease;Dose;Drug Kinetics;Evaluation;Goals;Human Papillomavirus;Immune response;Investigation;Investigational Therapies;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Monitor;Mutation Analysis;National Institute of Child Health and Human Development;Neoplasms;Pathogenicity;Patient Monitoring;Patient Selection;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Pregnant Women;Process;Publishing;Research Personnel;Screening for cancer;Side;Somatic Mutation;T cell therapy;Technology;Test Result;Testing;Therapeutic;Therapeutic Agents;Time;Tumor Antigens;Tumor Markers;Validation;Work;antigen test;assay development;biomarker driven;cell free DNA;clinical development;clinical investigation;drug development;early detection biomarkers;genotyped patients;mesothelin;new technology;new therapeutic target;novel;novel marker;patient safety;resistance mechanism;response;specific biomarkers;targeted therapy trials;technology development;tumor;tumor DNA Biomarker Investigations for Clinical Trials n/a NCI 10926608 1ZICBC010981-16 1 ZIC BC 10981 16 9692475 "CAO, LIANG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 945320 NCI Related to the specific biomarker goals above we conducted various studies to support biomarker driven early-stage drug development: 1. Application of new or novel biomarkers in early-stage trials of highly unique therapeutic agents. A) We supported correlative marker investigations of Dr. Raffit Hassan on his mesothelin-targeted novel therapies including traditional antibody drug conjugate therapies and T cell therapies using the assay that we have previously developed (JCO Precis Oncol. doi: 10.1200/PO.17.00282 2018). Significant responses were seen in many patients where our tumor antigen tests were performed in near real time to provide investigators with timely information on responses and on progression. According to the new focus of our facility the project was completed from our side and assay capabilities were transferred to Dr. Hassan's lab. B) We provided continues biomarker support of clinical trials by Dr. Andrea Apolo and some of the work was published (Girardi DM Clin Cancer Res doi: 10.1158/1078-0432. 2022). This project has been finalized and is terminated. C) We developed a cell free DNA detection for cervical cancer and use it for treatment monitoring minimum residue disease (MRD) detection cancer genotyping for patient selection. We support HPV-targeted therapy trials by Dr. Scott Norberg. Some of the recent work was focused on using NGS with cell free DNA for resistance mechanisms against T cell therapies. Also this project was completed and terminated. D) Somatic mutation analysis with cell free DNA in pregnant women with abnormal chromosome test results. In working with Christina Annunziata and Dr. Diana Bianchi of NICHD we performed some pioneer work to uncover tumor specific somatic mutation informing on cancer origins on common pathogenic processes and on treatment drug options. Interim results presented some significant novel knowledge in the field which could impact the patient clinical management and inform on the feasibility of using chromosome aneuploidy for cancer screening. We focus on the development of a circulating tumor DNA based technology for predicting the development of cancer in pregnant women and for determining cancer gene mutations associated with cancer. We are currently working on a cell free DNA test for the investigation of potential neoplasia in pregnant women who presented with abnormal NIPT test results in a trial led by Dr. Diana Bianchi of NICHD. 945320 +No NIH Category available 3-Dimensional;Adult;Basic Science;Brain;Brain region;Breast;CCR;Cells;Child;Circulation;Clinical Research;Collaborations;Colorectal;Communities;Computers;Confocal Microscopy;Core Facility;Differentiation Antigens;Distant;Educational process of instructing;Elements;Embryo;Epithelial Cells;Equipment;Genomics;Gleason Grade for Prostate Cancer;Glioblastoma;Goals;Human;Image;Image Analysis;Indolent;Label;Laboratories;Lasers;Lymph;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of thyroid;Manuscripts;Measures;Microdissection;Microscope;Microscopy;Mission;Modeling;Molecular;Motor;Mus;Neoplasm Metastasis;Optics;Organ;Organoids;Ovarian;Pathogenesis;Patients;Postbaccalaureate;Postdoctoral Fellow;Preparation;Process;Prostate;Proteins;Radical Prostatectomy;Research;Research Personnel;Resolution;Role;Scanning;Scientist;Signal Pathway;Signaling Molecule;Slide;Speed;Stains;Stomach;Structure;Surveys;System;TNF gene;Techniques;Time;Tubular formation;Urogenital Cancer;Visualization;Xenograft Model;Zebrafish;anticancer research;cancer cell;castration resistant prostate cancer;cell motility;cohort;empowerment;experimental study;fluorescence imaging;fluorescence microscope;gang;high resolution imaging;imaging capabilities;imaging software;interest;novel therapeutic intervention;patient derived xenograft model;progression marker;prostate cancer metastasis;real time model;residence;stem-like cell;summer student;three dimensional cell culture;trafficking;transcriptomics;tumor progression;virtual imaging;whole slide imaging Laboratory of Genitourinary Cancer Pathogenesis Microscopy Core Facility n/a NCI 10926603 1ZICBC010947-16 1 ZIC BC 10947 16 14732110 "LAKE, ROSS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 521931 NCI The Core Facility houses a Carl Zeiss LSM 780 laser scanning module mounted on an Axio Observer Z1 motorized fluorescent microscope. It also has two Zeiss Axio Observer Z1 fluorescent microscopes with attached computers equipped with Zen software for image acquisition. The Core also has a Nikon TI2E Epiflourescent microscope with attached computer with Nikon Elements software for image acquisition and analysis. Finally the facility has two Carl Zeiss AxioScan Z.1 slide scanning microscope with bright-field and fluorescence imaging capabilities for creating virtual images of whole slides. Researchers from over forty different laboratories (approximately 60 users) in the NCI are currently using the LGCP Microscopy Core Facility. The research focus of the scientists using the facility includes ovarian breast prostate colorectal gastric glioblastoma and thyroid cancer progression and metastasis. In the Laboratory of Genitourinary Cancer Pathogenesis (LGCP) 20 scientists including postdoctoral fellows post baccalaureate fellows and summer students routinely use the Core Facility in their research efforts. In Dr. Kathy Kelly's laboratory postdoctoral and baccalaureate fellows are using microscopy to study the molecular mechanisms and identify differentiation markers and signaling molecules on both primary murine and human prostate cells in order to elucidate the signaling pathways involved in prostate cancer metastasis. They are using whole slide scanning to characterize normal and transformed prostate epithelial cells stained with progression markers and signaling molecules in 2 and 3 dimensional cultures. Confocal microscopy is also being used for observing the localization of these components in the spherical and tubular structures that grow in 3D culture. Dr Adam Sowalsky's lab is comparing the genomic and transcriptomic profiles of high grade prostate cancers (that have progressed to Gleason score 7 or higher) to indolent cancers (Gleason score 6 prostate cancers from an active surveillance cohort). Researchers from the Sowalsky lab use whole slide scanning to process hundreds of immunohistochemically stained radical prostatectomy slides inorder to identify the regions of interest which require further microdissection and analysis. Scientists from several other branches or laboratories are currently using the Core as an integral part of their research. Below are some examples of ongoing projects using the Core Facility. The Tofilin Lab is using the Core slide scanning microscope in their study of glioblastoma (GBM) stem-like cells (GSCs). They are able to obtain high quality images to survey the entire brain from a number of replicate mice at a resolution that allows them to make quantitative measures of the labeled cells in discrete brain regions. The study would have taken a prohibitive amount of time to acquire on any other microscope they had access to. Postdoctoral fellows in Dr. Zheng-Gang Liu's laboratory are using the Core to investigate TNF-induced necroptosis. Confocal microscopy is being used by this group to investigate the role and cellular localization of the necroptosis related proteins MLKL and RARgamma. The Tanner Lab is investigating mechanisms of metastasis using zebrafish models. While the conceptual framework describing cancer cell trafficking through the lymph and circulation systems to colonize distant organs is well accepted actual visualization of this process has proven difficult. Dr. Tanner exploits the use of optically transparent embryonic zebrafish injected with human cancer cells as a xenograft model for real-time visualization of the metastatic cascade. Dr. Tanner uses a variety of equipment within the Core to obtain high-resolution images in which cancer cell migration speeds residence times and interactions with host cells have been characterized to better understand the metastatic spread of cancer. Apart from collaborating on projects involving the microscopy core facility teaching scientists various aspects of microscopy and maintaining the equipment in the core I am conducting research in collaboration with the branch Chief of LGCP Kathy Kelly on castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). 521931 +No NIH Category available Activated Lymphocyte;Address;Adoptive Cell Transfers;Antigens;Area;Authorization documentation;Autologous;B lymphoid malignancy;Back;Biological Response Modifiers;Biopsy;Blood;Blood Component Removal;Blood specimen;Carcinoma;Cell Therapy;Cell physiology;Cells;Characteristics;Cholangiocarcinoma;Clinical;Clinical Treatment;Clinical Trials;Collection;Colorectal Cancer;Computer software;Contracts;Core Facility;Cyclic GMP;Data;Development;Disseminated Malignant Neoplasm;Documentation;Effectiveness;Electronics;Employee;Enrollment;Ensure;Environment;Event;Excision;Extramural Activities;Genes;Goals;Human;Immunologics;Immunotherapy;Industrialization;Industry;Infusion procedures;Institution;Laboratories;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Manufactured Materials;Manufacturer;Mission;Mutation;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Patients;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Phase;Procedures;Process;Production;Protocols documentation;Quality Control;Quarantine;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resected;Sampling;Sanitation;Serum;Services;Somatic Mutation;Source;Specific qualifier value;System;T cell therapy;T-Lymphocyte;Testing;Tissues;Training;Translating;Tumor Antigens;Tumor Tissue;Tumor-Associated Process;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Update;adverse event monitoring;anti-cancer;authority;cancer cell;clinical translation;data curation;design;expiration;gene delivery system;gene therapy;healthy volunteer;improved;interest;malignant breast neoplasm;manufacture;manufacturing facility;melanoma;neoantigens;novel;novel therapeutics;operation;patient safety;prevent;programs;quality assurance;response;screening;success;synovial sarcoma;therapy development;tool;tumor;tumor immunology Surgery Branch Cell Prep Core n/a NCI 10926600 1ZICBC010905-16 1 ZIC BC 10905 16 78355702 "HALAS, HYUNMI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1933442 NCI The mission of the TIL lab/Cell Production Facility (CPF) core services is to provide support to the immunotherapy program established by the Surgery Branch of the National Cancer Institute. The laboratory has been managed by Dr. Hyunmi Halas. The main effort of the laboratory involves the production of large numbers of human anti-cancer T lymphocytes ex vivo to treat patients with advanced metastatic cancer enrolled in Surgery Branch clinical trials. Cancer-targeting lymphocytes are either isolated directly from biopsied cancer metastases or are generated by genetically modifying T lymphocytes from a patient's blood. 59 patients underwent a resection between 01-July-2022 and 01-Aug-2023 with the purpose of generating clinical tumor-infiltrating lymphocyte (TIL) cultures for screening and potential patient treatment. Of the 59 total resections processed under cGMP conditions by CPF to generate tumor-infiltrating lymphocytes (TIL) culture for potential treatments. 17 of the 59 tumors processed yielded positive screens for reactive TIL to be used as potential therapy and 11 are pending screening. In addition to the clinical resections 25 tumors were handled by the TIL lab for research purposes. These samples were documented and transitioned to the SB research team for tumor neoantigen identification. 24 of the 55 patients did not receive TIL treatments due to several reasons including patient ineligibility insufficient reactivity in the patient's TIL fragments or the patient was deceased. During the reporting period 13 patients were treated with final TIL therapies initially grown by the TIL lab/Cell Processing Facility screened by SB researchers for reactivity and manufactured as a final cell product under strict regulation by the TIL lab in the GMP T30 facility. A second critical core function of CPR is to distribute resected tumor tissue leftover after the clinical treatment needs have been fulfilled. These samples are used by investigators in the Surgery Branch cell therapy program to evaluate the progress of each clinical trial as well as to address research questions that identify changes that can be implemented to improve these trials. In addition the samples from these trials facilitate research that generates new patient therapies. These research projects include 1) Transducing patients' T cells with genes whose products will better target tumors or enhance endogenous tumor activity 2) Evaluating the ability of infused anticancer lymphocytes to function and survive in patients 3) Identifying new cancer-associated antigens that can be targeted by anticancer cells 4) Identifying novel patient specific antigens that are created by somatic mutations and selecting cultures that recognize these mutations for use in personalized T cell therapies 5) Identifying characteristics of infused anticancer cells that are associated with objective tumor regression 6) Identifying characteristics of patients who are most likely to respond to anticancer T cell therapies 7) Evaluating selected biological response modifiers tested in Surgery Branch clinical trials 8) Evaluating new gene delivery systems or improvements to the current systems. A third critical function CPF is responsible for is the processing of all starting materials for patient treatments. In addition to the tumor resections for clinical TIL cultures all patient and healthy donor phereses for peripheral blood mononuclear cells are processed under cGMP condition by CPF. During the reporting period 140 pheresis collections and 6 healthy volunteer serum collections (of no fewer than 4 donors) were processed. The processed PBMCs are used for neoantigen screening as starting materials for autologous gene therapy cellular treatments and for research purposes throughout the branch. Finally the core laboratory maintains and curates all source documents data protocols and expertise associated with cGMP manufacturing and the portion of the clinical translation of anticancer cell therapies carried out in the core lab. Due to the success of these therapies developed by the Surgery Branch investigators within the Surgery Branch intramural NCI laboratories extramural regulatory agencies industrial and academic partners and other interested parties increasingly want access to these data protocols and advice. There is a need to develop new tools for curating data from older trials. There is a need to convert existing data into a format that can be read by newer software packages it is essential that existing data generated in the core lab is not lost as older file types become obsolete. In response to two independent audits of the Surgery Branch cell production facility in early 2016 several programs and systems have been developed to comply with NIH FDA and industry guidance/best practices. We have established an independent Quality Assurance (QA) program. This QA program functions independently of the NCI SB and has the authority to stop production or prevent the release of cell-based therapies manufactured by the Surgery Branch cell processing facility when deemed necessary. Additionally the QA program performs internal audits to ensure compliance with SOPs and procedures and approves the new employee and annual training of the facility staff. These programs ensure that patient safety along with generating clinically effective anti-cancer cells is a primary concern of all employees involved in the manufacture of cell-based therapies. A crucial component of the QA program is document control. The document management system used by NCI SB Operations and Quality Assurance group MediaLab is employed to ensure that all staff has access to the most update version of SOPs forms and regulations used by the cell processing facility. MediaLab allows full tracking of all document versions and changes to ensure better compliance and training for all cell processing facility SOPs and regulations. The TIL Lab has been working to assist in the transition to a new electronic management system MasterControl to tie into the system used by the greater NIH cGMP groups including ORSC the NIH GMP oversight office. A cleaning service that specializes in cleanroom sanitation has been contracted by the Office of Research Support and Compliance (ORSC) to clean all NIH aseptic facilities including NCI SB manufacturing facility T30. The final component of efforts to develop a robust GMP environment is the development of a materials management and facility oversight program. Materials management controls the acquisition quarantine acceptance and release of all manufacturing materials while the facility oversight ensure the manufacturing facility operate to the design cleanroom specifications required by the FDA and meet the compliance requirements for cGMP manufacturing of phase 1 and 2 cellular products. The goal of this program is to increase patient safety by improving documentation of source lot number and expiration date and quality control of all materials used to manufacture cell products within the Surgery Branch cell processing facility. This program is crucial in identifying patient's whose past or pending treatments are associated with a manufacturer recall or in the event of a facility issue. The materials management and facility oversight program allows all patients impacted by a recall to be identified and monitored for adverse events. Dr. Xu Zhao is currently the facility manager of the Cell Production Facility at the Surgery Branch of the National Cancer Institute in Bethesda USA where the main interest is to establish successful gene therapies and cell-based treatments for patients with advanced metastatic cancer. 1933442 +No NIH Category available 3-Dimensional;Architecture;Brain;CCR;Cell Differentiation process;Cells;Communities;Core Facility;Educational process of instructing;Elements;Gene Expression;Image;Image Analysis;Imaging Techniques;Interest Group;Licensing;Light;Methodology;Methods;Microscope;Microscopy;Molecular Structure;Monitor;Motion;Mus;Neoplasm Metastasis;Organoids;Positioning Attribute;Protein Dynamics;Publications;Research;Research Personnel;Services;Site;Techniques;Time;Training;Tumor Cell Invasion;United States National Institutes of Health;Visualization;Zebrafish;anticancer research;cancer stem cell;chromatin modification;image processing;imaging software;in vivo imaging;induced pluripotent stem cell;instrument;light microscopy;neoplastic cell;outreach;superresolution imaging;tumor;two-photon;ultra high resolution CCR Microscopy Core n/a NCI 10926599 1ZICBC010858-17 1 ZIC BC 10858 17 9692243 "KRUHLAK, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1145792 NCI The NCI microscopy core is used consistently by a wide range of NCI researchers with 145 users from 30 labs in the past year. Among the techniques now in use within our CCR microscopy core are methods to visualize live cells in three dimensions over time including the tracking of cell motion in three-dimensions in vivo imaging of differentiated induced pluripotent stem cells in 3D spheroids spontaneous fusion and asymmetric division of cancer stem cells super-resolution imaging of chromatin modifications in metastatic tumor cells monitoring protein dynamics in sub-cellular macromolecular structures using FRAP and multi-position time lapse imaging of live iPS cells with induced gene expression upon cell differentiation. Our Zeiss Z.1 lightsheet microscope has been used to study tumor cell invasion in live zebrafish cellular differentiation and organization in tumor organoids and tumor architecture in cleared mice brains. The number of projects supported represents the diversity of cancer research pursued by CCR investigators. 1145792 +No NIH Category available Acquired Immunodeficiency Syndrome;Admission activity;Autopsy;Biopsy;Clinic;Clinical;Consult;Consultations;Cytopathology;Data;Diagnosis;Diagnostic;Diagnostic Services;Dissection;Educational process of instructing;Evaluation;Growth;Hematopathology;Histology;Histopathology;Immunohistochemistry;Infection;Laboratories;Malignant Neoplasms;Microscope;Microscopic;Microscopy;Microtomy;Mission;Operative Surgical Procedures;Pathologist;Pathology;Patients;Preparation;Process;Protocols documentation;Reporting;Research;Research Activity;Research Personnel;Research Support;Rotation;Scanning;Slide;Specimen;Stains;Surgical Pathology;Techniques;Tissue Procurements;Tissues;Training;United States National Institutes of Health;clinical center;coronavirus disease;digital imaging;digital pathology;human tissue;laboratory experience;laboratory experiment;methylation testing;molecular diagnostics;next generation sequencing;novel;tissue processing Histology Core Laboratory n/a NCI 10926598 1ZICBC010687-19 1 ZIC BC 10687 19 14732101 "CHINQUEE, JOSEPH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2918843 NCI The Histopathology (Histology) section of the Laboratory of Pathology (LP) is devoted to supporting the clinical activities of LP which involves tissue procurement processing and distribution of patient reports to inhouse and submitting clinicians. The Histology Lab does not conduct primary research but supports the activities of many investigators. The laboratory processes a large variety of tissue specimens from NIH and non-NIH patients including a wide variety of malignancies AIDS-related diagnostic specimens COVID-related biospecimens infections and surveillance biopsies. This consists of accessioning human tissues removed at surgery or in clinics processing the tissues preparing and staining slides for microscopy by LP's pathologists clinical fellows and residents. Pathology residents are trained by LP's Pathologists Assistants (PAs) in techniques of gross dissection and taught to evaluate large and small specimens in preparation for microscopic evaluation during Histology rotations. The Histology lab serves Immunohistochemistry Surgical Pathology Hematopathology Postmortem Pathology and Cytopathology sections as well as the Specialized / Molecular Diagnostics Unit. During the past fiscal year the Histopathology section processed approximately 28236 tissue blocks prepared microtomy of 162479 slides and more than 10000 H&E and special stains. Total slides prepared doubled from the previous year. During this period LP's Pathologists Assistants performed and trained residents in gross analysis and selection of the most diagnostically relevant sections for tissues collected from over 12718 inhouse biopsy and 12667 surgical tissues. The laboratory processed over 72142 consult slides and 12500 blocks from over 4889 cases that were submitted to LP's pathologists for clinical consultation or review for patients being admitted to the NIH Clinical Center or entry on protocol. There has been a steady increase in consult cases attributed to the growth in volumes of the novel methylation testing and next-generation sequencing cases provided to our NCI COMPASS Molecular Diagnostics services. 2918843 +No NIH Category available Acquired Immunodeficiency Syndrome;Autopsy;Brain Stem Glioma;COVID-19 mortality;Cause of Death;Cessation of life;Chest;Clinical;Clinical Investigator;Clinical Pathology;Clinical Protocols;Clinical Research;Collaborations;Cultured Tumor Cells;Databases;Dementia;Demyelinating Diseases;Disease;Genetic;Glioma;Goals;Hematologic Neoplasms;Hospitals;Hour;Human;Immunologic Deficiency Syndromes;Information Systems;Intramural Research Program;Investigation;Laboratories;Magnetic Resonance Imaging;Malignant Neoplasms;Mission;Multiple Sclerosis;Normal tissue morphology;Pathologic;Pathology;Patient Care;Patients;Procedures;Process;Protocols documentation;Reporting;Research;Research Personnel;Research Project Grants;Research Subjects;Research Support;Science;Services;Specimen;System;Text;Time;Tissues;Training;United States National Institutes of Health;clinical care;clinical center;clinical investigation;graft vs host disease;human tissue;nervous system disorder;quality assurance;quality of death;tool;treatment response;tumor;urologic Postmortem Pathology n/a NCI 10926597 1ZICBC010685-19 1 ZIC BC 10685 19 12499012 "KLEINER, DAVID ERWIN" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1170897 NCI The Postmortem Pathology Section provides a complete 24 hour per day 365 days per year service in autopsy pathology for the Clinical Center. All patients on protocols for any of the Institutes or the Clinical Center may have an autopsy performed by the Laboratory of Pathology at the discretion of the principle investigator. The results from autopsies are used to assess treatment response to answer clinical questions at the time of death to identify pathology that was unknown or misdiagnosed prior to death and to provide for hospital and protocol quality assurance. In addition when the use and study of human pathological material is requested by research staff of any of the categorical institutes the Postmortem Section makes every effort to collaborate with and/or supply the researchers with the human tissues upon approved request. (The Laboratory of Pathology has a standard procedure for tissue requests.) The autopsy material is utilized by NIH staff and fellows for research projects involving clinicopathological correlation and characterization of disease processes. Currently several collaborative projects are on-going: COVID-19 related deaths; clinical-pathological studies in dementia; culture of tumor cells from post-mortem tumor specimens following rapid autopsy; brain stem gliomas; MRI correlations with normal tissue and de-myelinating disease (multiple sclerosis); investigation into non-HIV immunodeficiencies and complications of graft-versus-host disease. A partial database of major autopsy findings from 1953 through the present is available and all findings from March 1999 on are available on-line through the Laboratory of Pathology's Information System. This system contains the full text of all autopsy reports. Texts of final reports are also available in the Clinical Research Information System (CRIS) after sign-out. In addition to its primary clinical responsibilities and research support function the Post-mortem Pathology section is responsible for training pathology residents in the art and science of autopsy pathology. Diseases with deaths investigated in this fiscal year include AIDS hematological malignancies non-heatological malignancies (particularly thoracic and urological tumors) gliomas and non-AIDS immunodeficiencies.. 1170897 +No NIH Category available Animals;Antigen-Presenting Cells;Apoptosis;Area;B cell repertoire;B-Cell Activation;B-Lymphocytes;Basic Science;Biology;Blood Cells;CISH gene;Cancer Research Project;Cell Cycle;Cell Death;Cell Lineage;Cell Separation;Cell Survival;Cell membrane;Cell physiology;Cell surface;Cells;Cellular biology;Color;Computer software;Consultations;Core Facility;Cost Savings;Cultured Cells;Cytokine Signaling;Data;Data Analyses;Defect;Dendritic Cells;Development;Disease;Electronics;Epithelial Cells;Event;Experimental Autoimmune Encephalomyelitis;Experimental Designs;FOXO1A gene;Factor Analysis;Flow Cytometry;Gene Expression Regulation;Generations;Genetic;Genetic Transcription;Goals;Histocompatibility Antigens;Human Resources;Immune;Immune system;Immunobiology;Immunology;In Vitro;Individual;Interleukin 7 Receptor;Investigation;Lasers;Lymphocyte Biology;Lymphoid Cell;MHC Class I Genes;MHC Class II Genes;Manufacturer;Measures;Mediating;Membrane Microdomains;Metabolic;MicroRNAs;Modification;Mucosal Immune Responses;Multiparametric Analysis;NCI Center for Cancer Research;National Cancer Institute;Pathogenesis;Phenotype;Phosphotransferases;Post-Transcriptional Regulation;Problem Solving;Proliferating;Reagent;Regulation;Regulation of Exocytosis;Regulatory T-Lymphocyte;Research Personnel;Research Project Grants;Research Support;Role;Running;Signal Transduction;Signaling Molecule;Source;Specific qualifier value;Sterility;Stimulus;T cell differentiation;T-Cell Development;T-Cell Receptor;T-Lymphocyte;TAF7 gene;Techniques;Technology;Thymic epithelial cell;Thymus Gland;Tissues;Transcription Initiation;cost;cytokine;in vivo;instrument;instrumentation;intestinal barrier;intestinal epithelium;intraepithelial;laser cell sorter;lymphocyte proliferation;member;proteostasis;receptor;receptor expression;release of sequestered calcium ion into cytoplasm;response;single cell analysis;stem cells;thymocyte;trafficking;transcription factor Application of Flow Cytometry to Cell Biology n/a NCI 10926594 1ZICBC009255-49 1 ZIC BC 9255 49 79355596 "CROSSMAN, ASSIATU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1478641 NCI The Experimental Immunology Branch (EIB) Flow Cytometry Core Facility currently supports multiple research projects for more than 50 investigators from within the EIB and elsewhere in the Center for Cancer Research (CCR). These investigations involve multi parametric quantitative single cell analysis of and electronic cell separation of cells based upon parameters associated with cells freshly prepared from different species and/or tissues as well as a spectrum of in vitro cultured cells. Basic research support is provided to members of the EIB and to other investigators within the Center for Cancer Research NCI. Currently supported projects include but are not limited to the following areas of study: a) in vivo and in vitro analyses of intra-cellular signaling via cell surface molecules; b) analyses of cellular processes and/or defects in animals and/or cells with genetic modifications; c) studies of the mechanisms and consequences of immune pathogenesis; d) analyses of the coordinate cell surface expression of a variety of molecules; e) investigations of T cell and B cell repertoire generation; g) analyses of expression of transplantation antigens; h) investigations of mechanisms involved in T cell lineage development; i) mechanisms of cell death; j) stem cell analyses and k) mechanisms of immune gene regulation. The following EIB/NCI/CCR Projects are supported by the core: PI: Alfred Singer; ZIA BC 009273 T Cell Differentiation and Repertoire Selection ZIA BC 011106 Specification of T cell function during development Z1A BC 011111 Cytokine signaling in developing thymocytes and T cells ZIA BC 011112 Development and function of regulatory T cells Z1A BC 011113 T cell Survival Z1A BC 011114 Role of microRNAs in T cell development Z1A BC 011116 MHC-independent T cells Z1A BC 011117 T cell receptor regulation of cytokine signaling. PI: Richard Hodes: Z1A BC 009265; Analysis of the T Cell repertoire Z1A BC 009281 Receptor Mediated T and B Cell Activation Z1A BC 009405; Regulation of Lymphocyte Proliferation and Replicative Capacity. PI: Dinah Singer Z1A BC 009285 Responses of MHC Class I Genes to Exogeneous Stimuli Z1A SC 010375 TAF7: A Check-point Regulator in Transcription Initiation Z1A BC 009279 Regulation of Expression of MHC Class I Genes ZIA BC 011381 Brd4 is an atypical kinase that regulates transcription ZIA BC 011425 Expression of class I in Treg cells. PI: Paul Roche Z1A BC 009404 Regulation of MHC Class II Trafficking in Antigen Presenting Cells Z1A BC 011033 Mechanisms of MHC Class II Association with Plasma Membrane Microdomains Z1A BC 011035 Regulation of Exocytosis from Immune Cells. PI: Hyun Park Z1A BC 011214 Post-Transcriptional Regulation of Interleukin-7 Receptor Expression Z1A BC 011215 Immune Regulatory Roles of Suppressor of Cytokine Signaling (SOCS) Molecules. PI: Vanja Lazarevic ZIA BC 011431 Role of T-bet in the pathogenesis of experimental autoimmune encephalomyelitis ZIA BC 011432 Regulation of T-bet expression in TH17 cells by microRNAs. PI: Chuan Wu ZIA BC 011755 The role of Foxo1 for intestinal epithelial cells during mucosal immune response ZIA BC 011801 CD101 controls intraepithelial cells (IELs) for intestinal barrier integrity. PI: Yousuke Takahama ZIA BC 011806 Thymus Biology. PI: Christian Mayer: ZIA BC 011975 The role of apoptosis in B lymphocyte biology. PI: Stanley Adoro ZIA BC 012135 Proteostasis regulators in blood cell development and function. The facility operates and maintains two operator run multi-laser flow cytometers with cell sorting capabilities including a state-of-the-art 6-laser cell sorter S6 Symphony and 5-laser Fusion. 5 user/operator flow cytometers with analysis only capabilities including 3 state-of-the-art 5/6-laser flow cytometer analyzers (Symphony A5 (6-lasers) 2 5-lasers Fortessa) and two 3-laser analyzers (X-20). Facility staff members provide consultation to investigators in the areas of: experimental design problem-solving reagent selection and data analysis and interpretation. The facility supports a wide variety of flow cytometric applications including: rare event analysis (including but not limited to analysis/cell sorting of subpopulations of stem cells thymic epithelial cells innate lymphoid cells (ilc) T regulatory cells and dendritic cells); analysis and cell sorting of a variety of immune system cells in studies of development activation and response to disease. These various studies employ multi-color phenotypic analyses cell cycle analysis proliferation analysis metabolic analyses including calcium flux analysis sterile cell sorting and intra-cellular cytokine and transcription factor analyses. The facility also as a cost-savings measure maintains a reagent bank of over 150 commonly used flow cytometry reagents that are pre-titered and aliquoted by facility personnel for use by multiple EIB investigators. The reagent bank minimizes costs by buying in bulk and minimizing labor and effort involved in characterizing individual batches of reagents. The facility is developing WINDOWS-based pc software for flow cytometry analysis that will provide capabilities not currently available in software available from instrument manufacturers or 3rd party software source. 1478641 +No NIH Category available Allogenic;Animal Model;Autologous;Bone Marrow;Bone Marrow Cells;Bone Marrow Stem Cell;Canis familiaris;Cells;Child;Clinical Trials;Complication;Defect;Detection;Disease;Dog Diseases;Engraftment;Flow Cytometry;Future;Gene Expression;Gene Modified;Gene Transfer;Generations;Genetic;Genetic Diseases;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homologous Transplantation;Human;ITGB2 gene;Individual;Lentivirus Vector;Leukocyte Adhesion Deficiency;Leukocytes;Membrane;Methods;Modeling;Patients;Pre-Clinical Model;Regimen;Retroviral Vector;Spumavirus;Study models;Surface;Testing;Transgenes;Transplantation;Viral;Viral Genes;Viral Vector;canine model;clinical phenotype;conditioning;disease phenotype;donor stem cell;gene correction;gene replacement;gene therapy;gene transfer vector;genotoxicity;graft vs host disease;immune reconstitution;promoter;receptor;stem cell biology;stem cell gene therapy;success;vector Hematopoietic Stem Cell Gene Therapy for Leukocyte Adhesion Deficiency n/a NCI 10926591 1ZIASC010384-23 1 ZIA SC 10384 23 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 135659 NCI These studies aim to identify new methods of gene transfer into hematopoietic stem cells using the genetic disease canine leukocyte adhesion deficiency (CLAD) as a model. We are using the canine model to identify new vectors for gene transfer and conditioning regimens to enable sufficient numbers of gene modified hematopoietic stem cells to engraft and reverse the disease phenotype. The canine form of this disease is an optimal model for these studies since: 1) the defect involves a membrane receptor on the surface of leukocytes flow cytometry allows fascile detection and analysis of the number of gene corrected cells; 2) low levels of gene-corrected cells result in reversal of the disease phenotype; and 3) studies in the canine model have been predictive of success in humans in the field of hematopoietic stem cell biology. The presence of a human counterpart to the canine disease allows the results from the animal model to be directly extrapolated to humans. The long-term objective of these studies is to develop strategies that will allow levels of expression of CD18 in hematopoietic cells of children with leukocyte adhesion deficiency (LAD) that are sufficient to reverse the clinical phenotype. We have utilized this model to test retroviral and foamy viral gene transfer into the bone marrrow cells of dogs. The foamy viral vector demonstrated greater efficacy and a more favorable integration profile than the conventional retroviral vectors. The foamy viral vector-treated dogs are being followed for the durability of the correction and for any possible genotoxicity from the vector. To date there has been no genotoxicity. These results represent the first successful use of a foamy virus (FV) vector to treat a genetic disease and they suggest that foamy virus vectors will be effective in treating human hematopoietic diseases. We are currently testing third-generation foamy viral vectors and lentiviral vectors with cellular promoters and lentiviral vectors with cellular rather than viral promoters in our canine model. 135659 +No NIH Category available ABCB1 gene;Acute Myelocytic Leukemia;Biological Assay;Biological Models;CCR;CDKN1A gene;Cell Line;Chemoresistance;Chromosomal Rearrangement;Chromosomal translocation;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;DNA Insertion Elements;DNA copy number;Development;Event;Fusion Oncogene Proteins;Genes;Genomic Segment;Goals;Human;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Mediating;Methotrexate;Molecular;Mus;Oncogenes;Oncogenic;PTEN gene;Pathway interactions;Phenotype;Process;Production;Proto-Oncogenes;Publishing;Recurrence;Reproducibility;Resistance;Resistance development;Structure;T-Cell Leukemia;Tumor Suppressor Genes;Vincristine;acute T-cell lymphoblastic leukemia cell;cancer cell;chemotherapy;childhood sarcoma;driver mutation;experimental study;fusion gene;in vivo Model;leukemia;prevent;thyroid neoplasm Mechanisms of Chromosomal Translocation n/a NCI 10926590 1ZIASC010379-23 1 ZIA SC 10379 23 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 205688 NCI "We recently developed an in vivo model in which mice with decreased expression of Mcm2 (Mcm2 hypomorph) develop leukemia with recurrent copy number alterations (CNA) involving known or suspected cancer-related genes. These experiments were done in collaboration with CCR colleagues Drs. Meltzer and Nussenzweig and manuscripts describing these findings were published in FY2020 and FY2023 (PMID: 35920299. As discussed in detail under ""Collaborative Pathways that Lead to Leukemia [ZIA BC 010982]"" mice that are deficient for Mcm2 develop a specific mutator phenotype that involves recurrent acquired DNA copy number losses. These losses can both inactivate tumor suppressor genes (CDKN1A PTEN) as well as activate oncogenes (Notch1) and lead to B and T cell leukemias in mice. Less commonly the leukemias that develop in Mcm2 hypomorphic mice are accompanied by copy number gains; one recurrent gain that we have characterized leads to a fusion between Nup214 and Abl1; of note Nup214-Abl1 fusions are recurrent events associated with B and T-ALL in humans. We are pursuing the mechanisms by which Mcm2 deficiency leads to this mutator/deletor phenotype by using a CRISPR-mediated structure/function assessment of Mcm2. In addition it is well-established that many leukemias are initially sensitive to chemotherapy but ultimately develop resistance. We have a panel of Mcm2 deficient and control Mcm2 proficient T-ALL cell lines. We are in the process of developing derivatives of this panel of cell lines that are chemotherapy resistant. Chemotherapy resistant cell lines will then be assayed for acquired SNV and CNA to determine important events in developing chemotherapy resistance. Preliminary results from this study are encouraging as we have detected focal pronounced (20-fold) copy number gains of Dhfr and Abcb1a (previously designated MDR1) associated with resistance to methotrexate and vincristine respectively. Chromosomal translocations and the mechanisms by which they occur are highly relevant for childhood cancer. In fact one of the cancer moonshot goals ""Fusion Oncoproteins in Childhood Cancers (FusOnC2)"" is focused on fusion oncoproteins. Fusion oncoproteins are well-known critical ""driver"" mutations in a wide spectrum of childhood cancers from leukemias including acute myeloid leukemia to childhood sarcomas to thyroid tumors. The vast majority of fusion oncoproteins are produced by recurrent non-random chromosomal translocations." 205688 +No NIH Category available Acute Myelocytic Leukemia;Aneuploidy;Animal Model;Animals;B-Cell Lymphomas;Cell Line;Cells;Childhood Acute Myeloid Leukemia;Chromosomal translocation;Clinical;Collaborations;Development;FLT3 gene;Generations;Genes;Genetic;Hematologic Neoplasms;Hematopoietic;Lesion;Link;Malignant - descriptor;Malignant Neoplasms;Manuscripts;Mus;Mutate;Mutation;NUP98 gene;Nodal;Oncogenic;Patients;Point Mutation;Process;Proto-Oncogenes;Publishing;Recurrence;Series;T-Lymphocyte;TP53 gene;Testing;Time;Transgenes;Transgenic Mice;Translocation Breakpoint;Yeasts;chemotherapy;chromosome missegregation;experimental study;expression vector;fusion gene;gene cloning;in vivo;leukemia;novel;overexpression;premalignant;response Activation of Proto-Oncogenes by Chromosomal Translocation n/a NCI 10926589 1ZIASC010378-23 1 ZIA SC 10378 23 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 411374 NCI A large series of pediatric acute myeloid leukemia patients has demonstrated that over 5% of patients have a NUP9::NSD1 fusion and that this fusion predicts a poor response to chemotherapy. We have cloned a NUP98::NSD1 fusion into the Vav1 expression vector and generated mice that have incorporated the transgene. Three of the founders developed acute myeloid leukemia. Unexpectedly acute myeloid leukemia is not increased in the F1 generation. However it has been noted that most pediatric AML patients with a NUP98::NSD1 fusion have a concomitant FLT3-ITD mutation. When vav1-NUP98::NSD1 mice were crossed to mice that expressed a Flt3-ITD over 70% of mice developed AML indicating an in vivo collaboration between these two mutations. A manuscript describing these findings was published in FY 2023. In collaboration with Dr. Munira Basrai of the Genetics branch we have generated mice that overexpress CENPA in the hematopoietic compartment. CENPA overexpression in yeast and cultured cell lines leads to chromosomal mis-segregation; the transgenic mice will enable us to determine if the mis-segregation takes place in primary cells as well. Moreover CENPA overexpression has been linked to several malignancies these mice will enable us to determine if CENPA overexpression is oncogenic in vivo. A portion of these results were published in FY2021. Preliminary experiments indicated that T and B cell lymphomas that developed in mice that overexpress CENPA on a TP53 deficient background have increased aneuploidy; we are in the process of confirming these observations using an orthogonal approach. 411374 +No NIH Category available Achievement;Acquired Immunodeficiency Syndrome;Acute;Antineoplastic Agents;Apoptosis;Apoptotic;Arthritis;Autoimmune Diseases;Binding;Biological;Breast Cancer Model;CD8-Positive T-Lymphocytes;COVID-19;Cell Death;Cell Death Induction;Cell Proliferation;Cell Surface Proteins;Cell surface;Cells;Cessation of life;Chronic;Crohn's disease;Data;Development;Diagnosis;Disease;Dose;E-Cadherin;Equilibrium;Event;Future;Glucose;Goals;Human;Immune;Inflammation;Inflammatory;Inflammatory Response;KRAS2 gene;Knowledge;Laboratories;Life;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator;Molecular;Mus;Necrosis;Neoplasm Metastasis;Pathogenesis;Pathology;Pathway interactions;Peptide Hydrolases;Physiological;Play;Production;Proteins;Regulation;Research;Rheumatoid Arthritis;Role;Septic Shock;Signal Pathway;Signal Transduction;Specific qualifier value;T-Lymphocyte;TNF gene;Therapeutic;Tissues;Transforming Growth Factors;Translating;Tumor Promotion;Virus Diseases;Work;anticancer research;apoptosis inducing factor;cancer therapy;cancer type;chronic inflammatory disease;cytokine;cytokine release syndrome;cytotoxicity;deprivation;genetic regulatory protein;improved;inhibitor;malignant breast neoplasm;neoplastic cell;novel;receptor;response;tumor;tumorigenesis TNF Signaling Cell Death and Cancer n/a NCI 10926588 1ZIASC010376-23 1 ZIA SC 10376 23 9417013 "LIU, ZHENG-GANG " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1541254 NCI "The research goal of our laboratory is to understand the molecular mechanism of tumor necrosis factor (TNF) signaling and the regulation of cell death and the role of cell death in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events including cell proliferation differentiation and cell death. TNF is also involved in many types of diseases including cancer. Inappropriate production of TNF plays a critical role in the pathogenesis of both acute and chronic inflammatory diseases such as septic shock acquired immunodeficiency syndrome (AIDS) and arthritis. The development of anti-TNFalpha therapy is arguably the most significant achievement in the treatment of autoimmune-diseases such as rheumatoid arthritis and Crohn's disease. Opposing effects of TNF on cancer have been described: a high dose of TNF (acute inflammation) has anti-neoplastic effects such as direct cytotoxicity on certain types of cancer while an endogenous low-dose of TNF (chronic inflammation) promotes cancer development. Studies from many laboratories have demonstrated that the diverse TNF-mediated biological responses are achieved through activating multiple signaling pathways (see below). Although much information about TNF signaling has been obtained in recent years many molecular aspects of TNF signaling and its role in inflammation and cancer development remain unknown. Therefore uncovering the molecular mechanism of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to understand its role in inflammation and cancer development. In last year we have made several significant contributions to the understanding of the molecular mechanism regulating TNF signaling and the regulation of cell death. In the future we will continue to investigate the regulation of TNF signaling particularly the molecular mechanisms of TNF-induced cell death and to explore the role of cell death in tumorigenesis as specified in the following: Studying the regulation of TNF-induced cell death and the involvement of key cell death regulatory proteins in tumorigenesis Aim1: Investigating the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein ATIA and its potential role in tumorigenesis. a) Understanding the underlying mechanism of the anti-apoptotic effect of ATIA. b) Demonstrating the importance of ATIA in tumorigenesis. Aim 2: Identifying and studying novel players in tumor necroptosis and exploring the role of necroptosis in tumorigenesis. Understand the regulation of tumor necroptosis. a) Investigate the mechanism of MLKL-mediated necroptosis. b) identifying new components of tumor necroptosis. Study the role of tumor necrosis in tumor development and tumor metastasis. Recently we have found that necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis. we found that tumor necroptosis is induced by glucose deprivation but not TNF and that ZBP1 not RIPK1 mediated tumor necroptosis during tumor development in breast cancer models. Most recently we demonstrated that necroptosis-mediated shedding of cell surface proteins promotes tumor metastasis through inhibiting the anti-tumor activities of T cells (Breast Cancer Research). Importantly we showed that tumor necroptosis leads to the activation of cell surface proteases ADAMs which mediate the shedding of tumor cell surface proteins including E-Cadherin. Subsequently the soluble E-Cadherin binds to the immune inhibitory receptor KLRG1 on CD8+ cells resulting in the inhibition of the anti-tumor activity of CD8+ T cells and promoting tumor metastasis. Blocking ADAMs activity with their specific inhibitor or neutralizing KLRG1 will dramatically reduce tumor metastasis in mouse breast caner models. Currently we are translating our findings to cancer treatment by targeting necroptosis blocking ADMAs activity or neutralizing KLRG1. For instance to targeting necroptosis we are generating PROTACs to eliminate ZBP1 or MLKL to block necroptosis. We also explored the role of necroptosis in COVID-19 pathology as necroptosis is involved in viral infection. Our preliminary data indicated that necroptosis plays a key role in ""cytokine storm"" during viral infection and COVID19 pathology. Therefore blocking necroptosis is a potential valuable treatment for cancer metastasis and viral infection. Currently we are developing potential therapeutics PROTACs for treating tumor metastasis by targeting key mediators of necroptosis. We are also exploring the role of necroptosis in the inflammatory response particularly ""cytokine storm"" of COVID-19. For the ATIA project we found that ATIA is a key factor for tumor growth and could serve as a diagnosis marker of multiple types of cancers." 1541254 +No NIH Category available Acute;Address;Adverse event;Agreement;Anticonvulsants;Biological;Biopsy;Blood;Bone Marrow;Brain Neoplasms;Brain Stem;Cancer Therapy Evaluation Program;Clinic;Clinical;Clinical Trials;Collaborations;Combined Modality Therapy;Common Terminology Criteria for Adverse Events;Complication;Computer software;Cooperative Research and Development Agreement;DNA;Data;Databases;Development;Dose;Enrollment;European;European Organization for Research and Treatment of Cancer;Excision;Fractionation;Hepatotoxicity;Image;Industry;Intramural Research Program;Investigation;Laboratories;Location;Long-Term Survivors;Measures;Metabolic;Molecular Target;Morbidity - disease rate;Nature;Necrosis;Neurologic;Neurologic Symptoms;Neurological Models;Newly Diagnosed;Newly Diagnosed Disease;Normal tissue morphology;Optic Nerve;Oral;Organ;Pancreas;Patients;Pattern;Perception;Performance Status;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Probability;Progression-Free Survivals;Protocols documentation;Publications;Publishing;Radiation;Radiation Dose Unit;Radiation Oncologist;Radiation Therapy Oncology Group;Radiation therapy;Radiation-Sensitizing Agents;Recommendation;Recurrence;Recurrent tumor;Regimen;Reporting;Research;Respondent;Retreatment;Risk;Role;Running;Schedule;Scheme;Serum;Structure;Surveys;Systemic Therapy;Time;Toxic effect;Translating;Tumor Volume;United States National Institutes of Health;Valproic Acid;Work;acute toxicity;arm;chemotherapy;clinical care;clinical center;clinical development;clinical practice;clinically relevant;improved;inhibitor;irradiation;mathematical model;novel;novel therapeutics;phase 1 study;phase 3 study;phase II trial;phase III trial;preclinical study;radiological imaging;response;success;synergism;targeted agent;time interval;treatment pattern;treatment planning;tumor The Synergy Between Radiotherapy and Molecularly Targeted Agents n/a NCI 10926586 1ZIASC010373-23 1 ZIA SC 10373 23 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1553938 NCI Recently we reported on our Phase II trial of Valproic Acid/ RT/TMZ in patients with newly diagnosed GBM. Briefly 37 patients with newly diagnosed GBM were enrolled and administered VPA 25 mg/kg orally divided into two daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. We used this one week run in period to escalate the VPA dose as the final VPA dose could have had pancreatic/hepatic toxicity. VPA and TMZ related acute toxicities were evaluated using the Cancer Therapy and Evaluation Program Common Toxicity Criteria (CTC) Version 3.0 for toxicity and adverse event reporting as well as the RTOG/EORTC Radiation Morbidity Scoring Scheme. Although VPA has been used for 40 years as an anti-convulsant often in combination with RT/TMZ it is typically used at a much lower dose (5-10mg/kg). Overall 67% of patients completed the VPA/RT/TMZ according to protocol. The patient's median overall survival (OS) was 29.6 months (21-63.8m) and median progression free survival (PFS) was 10.5m (6.8-51.2m). Additionally the combination was well tolerated; the most common grade 3/4 acute toxicities of VPA/RT/TMZ were blood/bone marrow toxicity (32%) neurological (11%) and metabolic/laboratory (8%). Interestingly the serum VPA levels were not correlated with the measured grade 3/4 toxicities and most of the toxicities could be attributed to the concurrently administered TMZ. Overall there were 16 (43%) acute grade 3-5 toxicities significantly lower than the 6 other Phase II sensitizer/RT/TMZ studies (reviewed in Krauze 2015) which had grade 3-5 toxicities rates ranging from 62-142%. As the pattern of recurrence for GBM is 85% local the use of re-RT is commonly prescribed. However the appropriate features of the tumor patient and previous radiation doses that might impact on the success of re-irradiation are not well understood. To develop this understanding we pursued two lines of investigation: the first was surveying Radiation Oncologists that primarily treat patients with recurrent brain tumors. We asked 13 experts in brain tumor re-irradiation (8 US and 5 European) to rate 11 clinical factors impacting their decision to offer re-RT. From this we found a heterogeneous treatment pattern including the prescribed doses and volumes but the clinical factors used most often to decide on the appropriateness of offering re-irradiation were: time since previous radiation therapy (92%) recurrent tumor volume (85%) previously administered dose to organs at risk (77%) and patient performance status (69%). These factors have been previously mentioned in multiple publications but this is the first time a ranking of the various clinical factors has been published. Additional findings included a split in the fractionation schedules most often recommended with 25% offering SRS or standard fractionation (2Gy) and 50% offering hypo-fractionated regimens. There was also a difference in the clinical practice of these respondents for the time required between the two courses of radiotherapy with 50% requiring 6m and 50% requiring 12m before they would consider offering re-RT. An additional common perception was that if re-RT is given earlier in the re-treatment schema the patients responded better. Our second investigation was a report of the results for the re-irradiation of patients with brain tumors performed within the ROB. To properly evaluate every patient primary treatment plans and re-treatment plans we loaded into the current Eclipse software to create cumulative tumor doses and cumulative doses to the organs at risk (OAR). We found a 15% variance in the OAR volumes when comparing the original treatment plan volumes to those generated from the combination of treatment plans. In the 31 patients that had both plans available the median cumulative Biological Effective Dose 2Gy (BED) combining the two treatments was 96Gy (range 72-112Gy). Using the doses from the combined plans and the mathematical model Normal Tissue Complication Probability (NTCP) we would have expected complication rates of 25% for the chiasm 21% for the right optic nerve and 59% for the brainstem. Thus 25-60% of our patients should have had a long term neurological toxicity. Yet with a median overall survival of 6m (range 0.7-103m) we had no documented grade 3-5 toxicities in any OAR nor evidence of necrosis in the re-RT treatment fields. This included 13 patients that had concurrent chemotherapy with the re-RT course. This underscores the disconnect that we currently have between the mathematical models of neurological toxicity (NTCP or QUANTEC) and the toxicity that is observed in the clinic. Our two publications highlight some of the current issues in GBM re-RT: what is the appropriate total dose and fractionation; the optimal interval between irradiation courses; the role of concomitant therapy with re-RT; and the potential toxicity of the re-RT? 1553938 +No NIH Category available Address;Adjuvant Chemotherapy;Affect;Anticonvulsants;Biological Markers;Biopsy;Blood - brain barrier anatomy;Brain Neoplasms;Bypass;Cells;Characteristics;Chemicals;Clinic;Clinical;Clinical Trials;Collaborations;DNA;Data;Development;Diagnosis;Dose;Drug Kinetics;Drug Screening;Evaluation;Excision;FDA approved;Failure;Foundations;Fractionation;Functional disorder;Future;Glioblastoma;Glioma;Glycolysis;Goals;Histone Deacetylase Inhibitor;Image;In Vitro;Long-Term Survivors;MGMT gene;Megakaryocytes;Metabolism;Modeling;Molecular;Molecular Classification of Tumors;National Center for Advancing Translational Sciences;Newly Diagnosed;Operative Surgical Procedures;Oral;Pathologic;Patients;Penetrance;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pre-Clinical Model;Primary Neoplasm;Publishing;Radiation;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Recurrence;Recurrent tumor;Research;Role;Site Visit;Surrogate Markers;Testing;Therapeutic;Thrombocytopenia;Toxic effect;Toxicology;Translating;Translations;Valproic Acid;Warburg Effect;Work;blood-brain barrier crossing;blood-brain barrier penetration;chemoradiation;clinically relevant;cost;drug development;experience;improved;in vivo;inhibitor;interest;irradiation;metabolic imaging;molecular imaging;neoplastic cell;novel;novel marker;novel therapeutics;pre-clinical;preclinical development;preclinical study;predictive modeling;programs;radiation response;randomized trial;response;temozolomide;tumor Pre-clinical Development of Radiation Sensitizers for Patients with Glioblastoma n/a NCI 10926585 1ZIASC010372-23 1 ZIA SC 10372 23 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 665974 NCI Glioblastoma multiforme (GBM) is the most common and most aggressive type of brain tumor with a median survival of 14 months. Currently the diagnosis of GBM requires surgical resection and pathological examination followed by concurrent chemoradiotherapy then adjuvant chemotherapy using oral temozolomide (TMZ). Despite this treatment most tumors recur within the irradiation field thus GBM continues to represent a significant therapeutic challenge. As such we have focused on the development of drugs that can sensitize GBM to irradiation. We and others have shown that multiple HDACi from diverse chemical backgrounds can sensitize tumor cells to radiation (RT). Our previous work focused on valproic acid (VPA) for several reasons: it is currently used in the clinic as an anti-convulsant; VPA pharmacology including its blood-brain-barrier (BBB) penetrance is well known; and VPA has a low cost per dose. Our group was the first to show that VPA had HDACi activity that could sensitize glioma cells to irradiation both in vitro and in vivo and that maximal radiosensitivity occurred when the HDACi was present both prior to and following irradiation. This preclinical data formed the foundation for our recently published clinical trial of VPA/RT/TMZ in patients with newly diagnosed GBM. The logical next step would be to initiate a randomized trial of VPA/RT/TMZ through one of the cooperative groups. However that trial is currently not planned. It is not planned for several reasons including a lack of understanding of how the tumor molecular classification (i.e. MGMT(+) versus MGMT(-)) from the patients in our study affected VPA-induced radioresponse. Second newer HDAC inhibitors may have improved pharmacokinetics and thus be more effective with less toxicity than VPA. Third there is a question whether VPA and TMZ have a synergistic toxic effect against megakaryocytes leading to thrombocytopenia. My group is addressing these pre-clinical issues in Project 1 Aim 1. There was also a concern that the addition of a radiation sensitizer to the RT/TMZ combination would lead to late CNS effects in long term survivors which will be addressed in Project 2. In addition to HDAC inhibitors there are other classes of molecules that can sensitize GBM to irradiation that will be studied in our preclinical models including two that should progress to clinical trial shortly. The first is the DNA-pK inhibitor from Vertex Pharmaceuticals shown to enhance GBM radiosensitivity both in vitro and in vivo. The second is the XPO1 inhibitor Selinexor. Additionally we are interested in drugs that are known to cross the blood-brain-barrier but are not currently known as radiation sensitizers. We will screen these drugs for an enhancement of radiosensitivity through an off-target effect through a collaboration with NCATS. As most GBM fail within the first year there is a need for the development of models of recurrent GBM to test novel therapies. As re-irradiation (re-RT) is often offered as a therapeutic option additional studies are needed to understand the effects of re-RT in pre-clinical models. The Tofilon lab has recently developed a model of primary GBM RT failure that we will expand to study re-irradiation of recurrent GBM. Questions of dose fractionation and the addition of radiation sensitizers will be addressed in these pre-clinical models and used to guide future clinical trials. As brain tumors are difficult to evaluate through serial biopsy the development of surrogate biomarkers from biofluids or imaging would potentially offer information about the tumor that is currently unavailable. Since the last site visit our evaluation of novel GBM biomarkers has been focused on molecular imaging. As it is assumed that gliomas bypass standard glycolysis through the Warburg effect and that the metabolism of different gliomas contributes to the efficacy of our current therapy our biomarker studies will focus on the use of 13C hyperpolarized molecular imaging in both the primary and recurrent GBM models. Thus my section is focused on the pre-clinical development of radiation sensitizers for both primary and recurrent GBM the use of novel metabolic imaging and the translation of these pre-clinical findings into clinical trials. Specific Research Aims: 1. To continue the development of VPA as a radiation sensitizer. To determine if the molecular characteristics of GBM tumors are predictive of VPA-RT response we will extend our previous pre-clinical studies by exploring the role of VPA as a radiation sensitizer in MGMT(-) GSCs. This will include both in vitro and in vivo studies. As newer HDACi may have improved pharmacology compared to VPA new HDAC inhibitors (128) will be screened in combination with RT in a collaboration with the National Center for Advanced Translational Sciences (NCATS) program using a post-IR ?-H2AX screen. Furthermore additional toxicology including work on megakaryocyte dysfunction will include both TMZ and VPA/TMZ combinations. 2. To test novel radiation sensitizers in models of primary GBM. In order to maximize the potential for Selinexor to be successfully translated to the clinic we will perform additional preclinical work including combination studies with TMZ studies of the timing of Selinexor with irradiation and tumor pharmacokinetic studies using RNAscope. The DNA-pK inhibitor VX-984 will also be studied in our pre-clinical orthotopic models using a clinically relevant combination of RT/TMZ. An additional screen of all FDA approved BBB penetrant drugs will be conducted in collaboration with NCATS to identify agents already known to penetrate the BBB that can act as radiosensitizers. 3. The development of a model for GBM re-irradiation. Questions from our clinical experience that will be tested in the GBM re-RT model include: does more dose of re-RT improve overall survival; is a single or fractionated dose more effective; does the timing of re-RT after failure affect survival (early versus late); and lastly does the addition of TMZ or novel radiation sensitizers in the setting of reirradiation improve overall survival? 665974 +No NIH Category available 1p36;Address;Age;Algorithms;Alveolar Rhabdomyosarcoma;Biologic Characteristic;Cancer Diagnostics;Cessation of life;Child;Classification;Clinical;Clinical Trials Cooperative Group;Collaborations;Companions;Custom;DNA Sequence Alteration;Data;Data Set;Databases;Diagnosis;Disease;Disease-Free Survival;Enrollment;Event;FOXO1A gene;Face;Gene Deletion;Gene Expression Profiling;Genes;Genetic;Genomics;Goals;Hematoxylin and Eosin Staining Method;Histologic;Histology;Image;International;Knowledge;Learning;Link;MYCN gene;Machine Learning;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mesenchymal Cell Neoplasm;Methods;Modeling;Molecular;Mutation;Neural Crest Cell;Neural Network Simulation;Neuroblastoma;Outcome;PAX3 gene;Participant;Pathway interactions;Patients;Pattern;Pattern Recognition;Pediatric Oncology Group;Performance;Phosphorylation;Ploidies;Prevalence;Prognosis;Proteins;Proteomics;Recurrent disease;Reporting;Research;Resistance;Rhabdomyosarcoma;Risk;Sampling;Slide;Soft tissue sarcoma;Somatic Mutation;Survival Analysis;Survival Rate;TP53 gene;Techniques;Testing;Therapeutic;Tissues;Training;Tumor Biology;United Kingdom;aggressive therapy;artificial neural network;biomarker development;cDNA Arrays;cancer diagnosis;cancer genomics;cell type;clinical risk;conventional therapy;convolutional neural network;deep learning;diagnostic biomarker;diagnostic tool;differential expression;digital;driver mutation;effective therapy;exome sequencing;fusion gene;genetic variant;genome sequencing;genomic biomarker;genomic profiles;high risk;innovation;insertion/deletion mutation;insight;molecular subtypes;next generation;next generation sequencing;outcome prediction;personalized approach;phosphoproteomics;predicting response;prognostic;prognostic indicator;prospective;protein expression;risk stratification;targeted treatment;therapeutic target;transcriptome sequencing;treatment group;tumor;tumor diagnostic;whole genome Predicting Response Prognosis in Pediatric Cancers n/a NCI 10926584 1ZIASC010366-23 1 ZIA SC 10366 23 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 184515 NCI Neuroblastomas are cancers that originate from neural crest cells and their prognosis varies based on factors like age at diagnosis stage histology MYCN amplification chromosomal ploidy and the 1p36 deletion status. However the specific molecular mechanisms determining good or poor prognosis in this and other malignancies remain largely unknown. Our groundbreaking research has shown that gene expression profiling using cDNA microarrays and sophisticated pattern recognition algorithms such as Artificial Neural Networks can aid in diagnosing cancers. To further advance this knowledge the Oncogenomics Section has collaborated with the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) group. Together we are conducting extensive genomic analysis employing next-generation whole genome exome and transcriptome sequencing on clinically annotated neuroblastoma samples. Through these cutting-edge techniques we aim to identify somatic mutations and tumor-specific expression patterns that can uniquely pinpoint patients with poor prognoses as well as those linked to specific genetic aberrations including MYCN amplification. Rhabdomyosarcoma (RMS) is the most prevalent soft tissue sarcoma in children. Unfortunately despite aggressive therapy patients with metastatic or recurrent disease face a poor 5-year survival rate and there are currently no genomic markers available for risk stratification. To address this critical gap we launched an international consortium study. The primary objective is to determine the prevalence of driver mutations and their association with clinical outcomes in RMS patients. Tumor samples collected from participants in Children's Oncology Group (COG) and United Kingdom trials (Malignant Mesenchymal Tumour and RMS2005) were subjected to custom capture sequencing. By identifying mutations indels gene deletions and amplifications we plan to perform survival analysis and create a searchable companion database (https://clinomics.ccr.cancer.gov/clinomics/public/). This database will include comprehensive genomic variants and clinical annotations including survival data. The goal is to uncover genomic profiles that correlate with prognosis and to identify the specific genes responsible for these biological characteristics. Following our report that specific genomic alterations in RMS strongly correlated with survival we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS. Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998-2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data. The trained CNN could accurately classify alveolar RMS a high-risk subtype associated with PAX3/7-FOXO1 fusion genes with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67 and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63 respectively. Remarkably CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification. This study demonstrates that high-risk features including those associated with certain mutations can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma which will be tested in prospective COG clinical trials. In parallel we are utilizing advanced proteomic analysis techniques like mass spectroscopy and phospho-proteomic analysis. These methods allow us to quantitatively measure protein expression levels and phosphorylation status in different cell types and tissues. By comparing proteins from samples with poor (death) and good (event-free survival 3 years) outcomes we plan to identify 3000-4000 differentially expressed proteins. This data will help us identify potential targets for therapy diagnostic markers and prognostic indicators for high-risk patients. Additionally it will provide valuable insights into the biology of these tumors which currently show resistance to conventional therapy. In summary our research endeavors are aimed at revolutionizing cancer diagnostics prognostics and treatment by unraveling the molecular complexities that influence prognosis in neuroblastomas and rhabdomyosarcomas. Through innovative genomic proteomic analyses and machine learning we hope to unlock valuable information that will ultimately lead to more effective and personalized approaches for patients facing these challenging diseases. 184515 +No NIH Category available 3T3 Cells;Acute;Affinity;Alleles;Binding;Binding Sites;Biological Assay;Birth;Cell Cycle;Cell Cycle Progression;Cell Differentiation process;Cells;Chimeric Proteins;Chromatin;Chromatin Loop;Chromatin Structure;Collaborations;Complex;DNA;DNA Binding Domain;DNA Sequence;DNA Structure;DNA sequencing;DNA-Binding Proteins;DNA-Directed RNA Polymerase;DNA-Protein Interaction;Dangerousness;Development;Dimensions;Disease;ERCC3 gene;Elements;Embryo;Epigenetic Process;Excision;FUBP3 gene;Family;Family member;Feedback;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomics;Goals;Hematopoietic;Heterogeneous-Nuclear Ribonucleoprotein K;Human;Impairment;In Vitro;KH Domain;Knock-in;Knock-out;Knockout Mice;Laboratories;Lymphocyte Activation;Malignant Neoplasms;Measures;Mechanical Stress;Mechanics;Mediating;Mediator;Modeling;Molecular;Molecular Conformation;Molecular Machines;Monitor;Movement;Mus;Mutate;Mutation;Normal Cell;Nuclear;Nucleosomes;Nucleotide Excision Repair;Oncogenes;Output;Pathologic;Pathology;Pathway interactions;Phenotype;Physiologic pulse;Physiological;Probability;Property;Proteins;RNA;RNA Interference;Regulation;Regulatory Element;Reporter;Repression;SP1 gene;SS DNA BP;Series;Serum;Signal Pathway;Signal Transduction;Single-Stranded DNA;Site;Small Interfering RNA;Stimulus;Stress;System;T7 RNA polymerase;Testing;Time;Torque;Torsion;Transcript;Transcription Coactivator;Transcription Repressor;Variant;Work;X-Ray Crystallography;Xeroderma Pigmentosum;c-myc Genes;c-myc Proto-Oncogenes;cancer cell;cell growth;cell type;chromatin immunoprecipitation;experimental study;flexibility;genetic corepressor;genome-wide;helicase;in vivo;insight;knock-down;melting;nanopore;nuclease;prevent;promoter;prospective;rapid test;response;tool;transcription factor;transcription factor TFIIH;transmission process Mechanisms of transcription factor integration at the c-myc promoter n/a NCI 10926574 1ZIASC009144-39 1 ZIA SC 9144 39 9692465 "LEVENS, DAVID L." Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 638560 NCI "We have been studying regulatory elements that are single-stranded when the human c-myc proto-oncogene is expressed and have been characterizing the conformation and topology sensitive DNA binding proteins that interact with these elements. First a cell type differentiation specific positive cis-element FUSE 1.5 kb upstream of promoter P1 is single stranded when c-myc is expressed in vivo and is devoid of nucleosomes except when c-myc is repressed. This element specifically binds FUBP a sequence specific single strand DNA binding protein. FUBP's amino terminus is a potent transcriptional repressor which interacts with TFIIH while the carboxyl is a powerful transcription activator. The activation domain of FUBP binds directly with the p62 subunit and the p89 helicase subunit of TFIIH. A co-repressor with FUBP FIR binds the central domain of FBP and interacts with TFIIH. FIR increases the affinity of FBP for binding with the FUSE element. FBP activation is defective in xeroderma pigmentosum cells mutated in TFIIH subunits. So endogenous c-myc expression is unresponsive to FUBP in XP cells. In XPB cells we have discovered that tight regulation of c-myc is lost and remarkable cell-to-cell variation in MYC levels occur. The XPB mutation prevents FUSE from looping and interacting with the major P2 promoter as a result both the induction and shutoff of c-myc in response to serum addition and removal are impaired. Thus the same mutation that disables nucleotide excision repair also deregulates a dangerous oncogene. Moreover we have discovered that this mutation also disturbs normal cell cycle progression and leads to an accummulation of cells in G2/M. Knockdown of FIR with siRNA provokes a similar cell cycle alteration and similarly disturbs the serum response of the c-myc gene. Along with FBP two other family members FUBP2 and FUBP3 probably form a basis set to adjust the steady levels of important genes. The central domain of FBP mediates interaction with FUSE. This portion of the protein is composed of repeated ""KH"" motifs which comprise a bi-partite DNA binding domain. Sub-domains constituted of the amino-terminal two KH repeats or the carboxyl pair of KH motifs bind weakly and strongly respectively with upstream and downstream contiguous sequence segments of FUSE. SELEX studies have identified specific DNA sequences interacting with FBP's KH domains and have enabled a genomic analysis of prospective FBP binding sites. Upon binding with FIR the weak binding sub-domain of FUBP recognizes the upstream segment of FUSE with increased affinity. Both FBP and FIR have been shown to control levels of endogenous c-myc expression. FIR repression of c-myc also fails in XP cells. ChIP (chromatin immunoprecipitation)-Seq studies are revealing that the FBP-FIR system is a commonly used molecular machine that controls the output of a large number of genes. NMR studies of a complex between the strong binding sub-domain and the downstream segment of FUSE suggest that FUBP is truly a DNA binding protein as particular features of the complex are unique to DNA-protein interactions. X-ray crystallography in collaboration with Dr. Demetrios Braddock revealed new features of the FUBP-FIR-FUSE system. Recent evidence in collaboration with Leonie Quinn (Melbourne) shows that FUBP is likely to also interact with the Mediator complex. All of these interactions occur both in vivo and in vitro. The mechanism of transcriptional modulation by the FBP/FIR/TFIIH/repressor/co-activator complex reveals that FUBP hastens RNA polymerase movement through earliest stages of transcript elongation. In contrast FIR delays the transition of RNA polymerase into its elongation mode. mechanisms. The relevance of FUBP and FIR to the regulation of c-myc has been established using RNAi. Additional experiments have exposed the presence of multiple signals embedded within FBP targeting the protein to multiple nuclear compartments. We have developed an FUBP knockout mouse that dies just before birth and seems to display hematopoietic abnormalities. MEF and 3T3 cells from FUBP ko embryos have been developed to study the molecular mechanisms targets and cell dynamics that are under the control of FUBP. We have also developed a a c-myc-EGFP knock-in that is the best reporter system yet developed to study the regulation and deregulation of c-myc expression. combined with our studies of FIR and FUBP via DNA topology these studies provide an extra dimension to our understanding of gene regulation. We are using this system to provide new insights for the identification and understanding of MYC targets during lymphocyte activation. Recent studies in the lab have established that FUBP2/KHSRP another FBP family cooperates with FBP/FUBP1 to control MYC levels. The properties of FUBP and hnRNP K that each bind to both single stranded DNA and RNA prompted examination of c-myc regulatory cis-elements in vivo and in vitro to determine how these sites become melted. Using actively transcribing T7 RNA polymerase to generate torque experiments indicate that the dynamic transmission of mechanical stress destabilizes particular elements such as FUSE and CT-elements even in the absence of defined topological boundaries. Recent experiments have been devised to measure the level of superhelical stress transmitted into DNA by ongoing transcription. The level attained is close to the theoretical limit and is suprisingly high high enough to disturb chromatin and DNA structures and so may of regulatory consequence. Recent studies are establishing the the equivalence of our in vitro and in vivo studies. Because single-stranded DNA is much more flexible to torsion and flexion than is duplex interposing CT-elements between genetically interacting sites facilitates these interactions. Therefore one function of regulated single-stranded cis-elements is to serve as protein-DNA hinge. Recent work suggests that competition between hnRNP K and SP1 at the CT element may be mediated by a conformation switch. To explore the interplay between these DNA conformation sensitive factors and the multitude of conventional transcription factors that regulate c-myc we have knocked EGFP as a chimeric protein into the c-myc locus. This knock-in allele is fully functional as homozygous myc-EGFP mice are phenotypically normal. The EGFP allows us to monitor MYC levels in single living cells. This will allow us to describe the distribution of cell-to-cell variation in MYC levels with the quantitative precision necessary to develop a predictive mechanistic model if how the c-myc promoter works. Why is c-myc regulation so complicated? We have determined that even a brief pulse of forced MYC expression can cause cells to undergo several cycles of cell division. Therefore expression must be held to close tolerances. Using a new nuclease assay developed by us we are commencing the the analysis of the differential utilization of cis-reguatory modules that control MYC expression in helath and disease. We demonstrated that MYC levels have precise and epigentically fixed set points in different cells and that these set points are disturbed in cancer. With low level stimulation cells induce MYC while respecting a ceiling that is epigenetically bounded but with high level stimulation this ceiling may be breeched and pathological MYC levels ensue. The high-MYC cells are primed for a rapid response to stimulii. Strategies are beginning developed to use Nanopore long-read sequencing of DNA recovered from cells treated with DNA-confomration sensitive agents in order to study the usage coordination and cooperation of cis-elements distributed throughout the MYC locus that sensitive to DNA topology and dynamic supercoiling. This approach promises to reveal DNA mechanics operating to provide realtime regulation of ongoing transcription." 638560 +No NIH Category available Agonist;Animals;Antibodies;Apoptosis;Binding Proteins;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer cell line;Caspase;Cell Death;Cell Death Induction;Cells;Cessation of life;Clinical Trials;Collaborations;Combined Modality Therapy;Credentialing;Data;Drug Synergism;Drug usage;Endometrial Carcinoma;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epigenetic Process;Family;Genes;Genetic;Induction of Apoptosis;Ligands;Mediating;Mitochondria;National Center for Advancing Translational Sciences;Necrosis;Pathway interactions;Patients;Peptide Hydrolases;Pharmaceutical Preparations;Phase II Clinical Trials;Protein Tyrosine Kinase;Proteins;Resistance;TNF gene;TNFRSF10A gene;TNFRSF10B gene;TNFRSF1A gene;Toxic effect;Trastuzumab;Tumor Necrosis Factor Ligand Superfamily Member 6;Tumor Necrosis Factor Receptor;Work;cancer cell;cancer subtypes;cell killing;chemotherapeutic agent;functional genomics;immunogenicity;malignant breast neoplasm;member;novel;novel drug class;pre-clinical;preclinical study;receptor;recruit;targeted agent;targeted treatment;tumor initiation Activating Cell Death Pathways in Breast Cancer Cells n/a NCI 10926572 1ZIASC007263-31 1 ZIA SC 7263 31 14821366 "LIPKOWITZ, STANLEY " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1045773 NCI Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. TNF family death receptors (e.g. TNFR Fas DR3 TRAIL Receptor 1 and TRAIL Receptor 2) induce apoptosis in cells by recruiting and activating caspases upon activation by their respective ligands (e.g. TNF Fas Ligand and TRAIL). We are investigating the expression and function of TRAIL death receptors (members of the TNFR family) and their ligands (e.g. TRAIL and agonistic antibodies) in breast cancer cells in order to selectively trigger apoptosis in the cancer cells. In our early work we found that most breast cancer cell lines are resistant to the induction of apoptosis by TRAIL. We have demonstrated that a subset of breast cancer cells those with triple-negative/basal-like features are very sensitive to TRAIL-induced apoptosis while other breast cancer subtypes are relatively resistant to TRAIL-induced apoptosis. This subset of breast cancers is particularly aggressive and most in need of targeted therapies. Further we found that TRAIL Receptor 2 and not TRAIL Receptor 1 is required for TRAIL induced apoptosis in the sensitive breast cancer cells. This latter finding will help in the selection of TRAIL agonists for eventual clinical trials in breast cancer patients. In addition we have found that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents targeted agents such as trastuzumab and EGFR inhibitors. More recently we have demonstrated that inhibition or loss of the G2/M checkpoint tyrosine kinase Wee1 enhances TRAIL-mediated apoptosis in basal-like breast cancer cells. Together these studies are beginning to provide clear preclinical rationales for studies of TRAIL ligands alone or in combination with other drugs in patients with breast cancer. Ongoing work is: 1) using functional genomics to identify and characterize the genes and proteins that regulate apoptosis induced by TRAIL receptor agonists in breast cancer cells. 2) characterizing novel TRAIL receptor agonists in breast cancer cells 3) evaluating the effects on the immunogenecity of breast cancer cells. In a spin off projject we are characterizing the mechanism of action of ClpP agonists. The latter drug was described to work via the TRAIL pathway. However our data suggest that it works independent of the TRAIL pathway to kill breast cancer and other cancer cells. Our ongoing work includes 1) characterizing the mchanism of death induced by ClpP agonists on breast cancer cells; 2) in collaboration with NCATS we conducted a screen to identify drugs that synergize with ClpP agonists in breast cancer cells and are validating hits from that screen to credential combination therapies that will be useful with ClpP agonists. 3) investigating the effects of ClpP agonists on breast cancer tumor initiating cells. 1045773 +No NIH Category available 16S ribosomal RNA sequencing;Actinobacteria class;Address;African American;Architecture;Atypia;Autologous;Bacteroidetes;Breast;Breast Cancer Prevention;Breast Cancer Risk Factor;Breast Carcinogenesis;Breast Magnetic Resonance Imaging;CCR;Caucasians;Cells;Characteristics;Chemoprevention;Chronic;Classification;Clinical;Clinical Research;Collecting Cell;Collection;Core Facility;Cytologic Atypia;Cytology;DNA;Development;Disparity;Doctor of Medicine;Duct (organ) structure;Ductal Carcinoma;Ductal Epithelial Cell;Ductal Epithelium;Early identification;Endoscopy;Epithelium;Evaluation;Feasibility Studies;Flow Cytometry;Freezing;Gene Chips;Gene Expression Profile;Gene Expression Profiling;Genes;Genomics;Goals;High Risk Woman;Hispanic Americans;Immune;Immunologic Surveillance;Individual;Inflammation;Institutional Review Boards;Irrigation;Laboratory Study;Lymphocyte;Magnetic Resonance Imaging;Malignant Neoplasms;Mammary Gland Parenchyma;Methods;Molecular;Molecular Profiling;Monitor;Mutation;Pathway interactions;Patients;Pharmaceutical Preparations;Pilot Projects;Play;Population;Proteins;Protocols documentation;Reporting;Risk;Risk Assessment;Role;Saline;Sampling;Sampling Studies;Signal Pathway;Source;Suspensions;Woman;Work;anticancer research;cancer stem cell;carcinogenicity;caucasian American;cell type;clinically significant;design;differential expression;exome sequencing;follow-up;high risk;immune checkpoint;improved;intraepithelial;malignant breast neoplasm;mammary;microbiome;microbiome research;neoplastic;progenitor;prognostic;sample collection;stem cells Molecular Characterization of Breast Duct Epithelium at Risk for Breast Cancer n/a NCI 10926568 1ZIASC006663-34 1 ZIA SC 6663 34 6572190 "DANFORTH, DAVID " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 200422 NCI This project is designed to define the cytologic ductal architectural and molecular characteristics of breast ducts and ductal epithelial cells of women at normal risk and at high risk for breast cancer including Caucasian Hispanic and African American women. This information is needed to define the early changes in the carcinogenic pathway for breast cancer to develop an improved classification and molecular signature of preneoplastic breast tissue for risk assessment to identify new targets and to facilitate selection and monitoring of women for breast cancer prevention and to define the molecular basis for disparities in the development and presentation of breast cancer. This project includes the following clinical and laboratory study: Protocol 02-C-0077 Characterization of High-Risk Breast Duct Epithelium by Cytology Breast Duct Endoscopy and Gene Expression Profile (DN Danforth PI). This protocol examines by ductal lavage and ductal endoscopy the breast ducts and ductal epithelium of women at normal risk and at high risk for breast cancer. The studies conducted under protocol 02-C-0077 have provided important clarification of the clinical and prognostic role of cytologic atypia in women at risk for breast cancer. Chronic inflammation has long been recognized as an important factor promoting the development of cancer as well as promoting expression of immune checkpoint proteins which can inhibit lymphocytes and immunosurveillance. Our studies have further defined the presence of intraductal cytologic atypia. In normal risk subjects cytologic atypia was present in 25.7% but was not associated with altered gene expression by microarray profiling or with abnormalities on ductal endoscopy or on breast MRI or on follow-up providing the important observation that cytologic ductal atypia in normal risk subjects does not appear to be of clinical significance. In high-risk subjects atypia was present in 22.9% and follow-up MRI revealed a ductal carcinoma in 13.7% of patients indicating the importance of ductal evaluation in high-risk subjects. These findings have recently been reported [Danforth DN. et al. Characteristics of breast ducts in normal risk and high-risk women and their relationship to ductal cytologic atypia. Cancer Prev Res 2020;13:1027-36]. An important secondary objective of the study is to determine the presence of mammary stem cells in the ductal microenvironment. Mammary stem cells (MSC) are considered the progenitors of all ductal cell types. Importantly mammary stem cells may also be transformed into cancer stem cells (CSC) the origin of breast cancer. Identification of MSCs or CSCs in the breast ductal cellular compartment could have important implications for understanding early breast carcinogenesis. Recent evidence has also indicated the presence of a microbiome in breast tissue. We recently performed a pilot study in which 8 frozen ductal samples were analyzed by 16s rRNA sequencing through the CCR Microbiome Core Facility. We identified microbia in all samples with the following relative distribution according to phylum: Bacteroidetes Firmacutes Protobacteria Actinobacteria. This confirmed the feasibility of studying the microbiome in our normal risk and high-risk breast ductal samples. Further characterization of the microbiome in our ductal samples will clarify the relation of the intraductal microbiome to breast cancer risk and as a potential cause of chronic intraductal inflammation which we have observed in the high-risk ducts. Work on this project was completed in FY23. 200422 +No NIH Category available 3-Dimensional;Affect;Alkaloids;Angiogenesis Inhibitors;Angiogenesis Pathway;Anti-Bacterial Agents;Anti-Inflammatory Agents;Antifungal Agents;Antineoplastic Agents;Aorta;Benzamides;Binding;Biological;Biological Assay;Biological Markers;Biological Models;C-terminal;Chemical Structure;Chick Embryo;Clinical;Collaborations;Cysteine;Cytochrome P450;Development;Docking;Drug Design;Drug Targeting;EP300 gene;Endothelial Cells;Energy Metabolism;FDA approved;Fluorescence;Histidine;Human;Hypoxia;Hypoxia Inducible Factor;In Vitro;Inflammation;Invaded;Isoenzymes;Laboratories;Lead;Legal patent;Libraries;Ligase;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic Biotransformation;Modeling;Molecular;Molecular Target;Multi-Drug Resistance;Multiple Myeloma;Natural Products;Natural Products Chemistry;New Agents;New Zealand;Pharmacology;Pharmacology Study;Pharmacology and Toxicology;Porifera;Pre-Clinical Model;Preparation;Property;Pyrroloiminoquinones;Rattus;Regimen;Reporting;Research;Saphenous Vein;Series;Solid Neoplasm;Structure;Structure-Activity Relationship;Substrate Specificity;Synthesis Chemistry;Teratogens;Testing;Thalidomide;Therapeutic;Toxic effect;Toxicology;Transactivation;Tube;Tumor Angiogenesis;United States National Institutes of Health;Viral;Xenograft Model;Zebrafish;analog;angiogenesis;anti-cancer;cancer therapy;chemotherapy;cytotoxicity;design;drug development;glutarimide;high throughput screening;hypoxia inducible factor 1;immune modulating agents;immunoregulation;improved;in silico;in vivo;in vivo Model;inhibitor;interest;lenalidomide;marine;migration;novel;pharmacophore;pomalidomide;pre-clinical;preclinical study;protein protein interaction;rational design;repository;research clinical testing;secondary analysis;side effect;small molecule inhibitor;targeted treatment;therapeutically effective;tumor growth Development of Anticancer Agents n/a NCI 10926567 1ZIASC006538-30 1 ZIA SC 6538 30 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 785162 NCI Development of immunomodulatory drugs: The antiangiogenic properties of thalidomide reported by D'Amato and colleagues prompted its clinical evaluation in various solid tumors including prostate cancer. Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort in our laboratory. Previously we showed that one of the products of cytochrome P450 2C19 isozyme biotransformation of thalidomide 5'-OH-thalidomide is responsible for the drug's antiangiogenic activity. Based on the chemical structure of this metabolite we collaborate with Drs. Nigel Greig (NIA NIH) and Michael Gutschow to synthesize novel thalidomide analogs evaluate them using in vitro and in vivo models to assess activity and characterize their structure-activity-relationships for further rational drug design. We have synthesized over 315 novel analogs of thalidomide and screened them for inhibition of inflammation and angiogenesis using various in vitro ex vivo and in vivo drug development models (e.g. rat aorta ring model human saphenous vein model cultured endothelial cells migration and tube formation assays). In collaboration with Dr. Neil Vargesson we conduct an in vivo screen of a library of new analogs to determine which agents demonstrate activity using the in vivo zebrafish and chicken embryo model systems. We identified the most potent of these agents and have patented them. We continue to develop these compounds which appear to have minimal side effects in initial preclinical toxicology studies and may have improved pharmacology over the FDA approved thalidomide and immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide. We have recently completed characterization of the cytotoxicity antiangiogenic and anti-inflammatory properties of polyfluorinated benzamides as well as tested them in IMiD-resistant multiple myeloma models. Studies are ongoing to identify potential leads in three dimensional (3D) myeloma spheroid models which will subsequently be evaluated for in vivo toxicology and pharmacology studies in xenograft models as well as to understand the mechanisms of action since the compounds are structurally similar to thalidomide but lacks the glutarimide moiety that binds to the drug's targetcereblon (CRBN). The binding of these IMiDs to CRBN alters the substrate specificity of the ligase thereby mediating multiple effects that are exploited in cancer therapy. Due to its antiangiogenic and anti-immunomodulatory activity thalidomide continues to be of clinical interest despite its teratogenic actions and efforts to synthesize safer clinically active thalidomide analogs are continually underway. We conducted a structure-activity relationship study to evaluate the antiangiogenic activity and in silico CRBN binding analysis of novel thalidomide analogs. In silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the novel thalidomide analogs. Studies are ongoing for SAR analysis of rationally designed and synthesized IMiD analogs. Development of HIF-1alpha inhibitors: The hypoxia-inducible factor (HIF) is fundamentally involved in tumor angiogenesis invasion and energy metabolism. Inhibition of HIF-1 represents an attractive therapeutic strategy for targeting hypoxia a hallmark of many solid tumors and tumor angiogenesis. One promising approach for directly inhibiting HIF-1 activity is by disrupting the tight binding between HIF-1alpha and p300. Previously our laboratory developed an in vitro fluorescence binding assay that can be used in a high-throughput screen to identify small-molecule inhibitors of HIF-1a through inhibiting the binding interaction between the C-terminal transactivation domain (CTAD) of HIF-1a and the cysteine/histidine-rich 1 (CH1) domain of p300. Using our HIF-1alpha/p300 assay we performed high-throughput screen of NCI's Natural Products Repository in collaboration with the Molecular Targets Laboratory (NCI). This effort led to the discovery of a series of pyrroloiminoquinone alkaloids including discorhabdin and makaluvamine alkaloids originating from a Latrunculia sp. of marine sponge as potential HIF-1a/p300 inhibitors. Efforts are ongoing to extract more discorhabdins from New Zealand sponges in order to continue preclinical studies to further understand the mechanisms of these novel compounds. Epidithiodiketopiperazines (ETPs) possess diverse biological activities including anticancer antifungal antibacterial and antiviral properties. ETPs are known as a class of compounds that have been shown to inhibit HIF-1alpha with the ETP core itself being sufficient to block the HIF-1alpha and p300 interaction in vitro. There is considerable interest in synthetic chemistry of these natural products and preparation of analogs is actively pursued; however they are structurally challenging to synthesize. This study is undertaken to screen synthetic ETP analogs rationally designed and synthesized by our collaborator Dr. Tom Snaddon and to determine the activity of these novel compounds in biological assays. We have recently patented several lead compounds with promising activity and will further evaluate them in preclinical models. 785162 +No NIH Category available Adenoviruses;Adjuvant;Affect;Affinity;Age;Agonist;Allogenic;Antibodies;Antigen Presentation;Antigens;Arylsulfatases;Autologous;Avidity;Binding;Biotechnology;Breeding;CCR;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Vaccines;Cells;Cholesterol;Clinic;Clinical;Clinical Trials;Combined Vaccines;Cooperative Research and Development Agreement;Cytoprotection;Cytotoxic T-Lymphocytes;Data;Dose;ERBB2 gene;Endometrial Carcinoma;Endosomes;Epitopes;Equilibrium;Evaluable Disease;Excision;FOXP3 gene;Failure;Gene Expression Profile;Glycolipids;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;HLA-A2 Antigen;Helper-Inducer T-Lymphocyte;Histocompatibility;Human;IL17 gene;Immune checkpoint inhibitor;Immune response;Immunity;Immunologic Surveillance;Immunology;Immunotherapy;Interleukin-12;Interleukin-13;Interleukin-15;KDR gene;Knock-in Mouse;Knockout Mice;Ligands;Lipids;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Mammary Neoplasms;Mediating;Metastatic Neoplasm to the Lung;Microbe;Modification;Mucosal Immunity;Mucous Membrane;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Omega-3 Fatty Acids;PD-1 blockade;PD-L1 blockade;PPBP gene;Pathway interactions;Patients;Peptides;Phase I Clinical Trials;Phase I/II Trial;Primary Neoplasm;Process;Publishing;Purinergic P1 Receptors;Rattus;Regulation;Regulatory T-Lymphocyte;Research;Role;Safety;Sampling;Skin;Stimulant;Structure;Sulfoglycosphingolipids;T cell response;T-Cell Depletion;T-Lymphocyte;TLR3 gene;Testing;Therapeutic Effect;Tissues;Toll-like receptors;Transforming Growth Factor beta;Transgenic Mice;Translating;Translations;Transmembrane Domain;Trastuzumab;Tropism;Tumor Antigens;Tumor Immunity;Tumor Promotion;Vaccine Adjuvant;Vaccine Design;Vaccinee;Vaccines;Viral Cancer;Virus;Virus Diseases;Work;alpha-galactosylceramide;analog;anergy;anti-PD-1;anti-PD-L1;cancer immunotherapy;cell killing;cytokine;extracellular;gut microbiome;immunoregulation;improved;inhibitor;invention;malignant breast neoplasm;melanoma;microbiome;microbiome alteration;neoplastic cell;novel;novel strategies;phase I trial;preclinical study;prevent;receptor for advanced glycation endproducts;recruit;response;scavenger receptor;synergism;transcriptome sequencing;tumor;tumor growth;vaccine efficacy;vaccine immunogenicity;vaccine strategy;viral transmission Vaccine and immunotherapy strategies for cancer and viruses causing cancer n/a NCI 10926563 1ZIASC004020-46 1 ZIA SC 4020 46 6572144 "BERZOFSKY, JAY A" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2147209 NCI The strategies above involve 5 steps that together comprise a push-pull approach to optimize antigen structure improve quantity and quality of the response and remove regulatory barriers. Regulation of tumor immunity by NKT cells: NKT cells are true T cells recognizing glycolipid antigens presented by CD1d. We discovered a novel immunoregulatory pathway in which NKT cells suppress tumor immunosurveillance using IL-13 to induce myeloid cells to make TGF-b that suppresses immunity. We completed a phase I trial of anti-TGF-b with clinical benefit in melanoma patients. We discovered synergy between TGF-b blockade and cancer vaccines in mice. Blockade of TGF-b1 / 2 (without 3) was sufficient to enhance vaccine efficacy further amplified by PD-1 blockade. Type I (invariant-TCR) NKT cells promote tumor immunity whereas we found that type II (diverse-TCR) NKT cells suppress tumor immunity. We discovered these subsets cross-regulate each other defining a new immunoregulatory axis. We are investigating relationships with other regulatory cells/ molecules. Both type II NKT cells and Treg cells can suppress tumor immunity concurrently but type I inhibit type II NKT cells leaving Tregs as the dominant suppressor unless type I NKT cells are blocked or absent. Thus the balance between 2 regulatory cells is determined by a 3rd cell that regulates the regulators. Moreover we found distinct regulatory cells dominate in the same tumor in the lung and skin. Thus tissue context determines cancer immunity for the same tumor implying that immunotherapy for primary tumors and metastases in different tissues may unexpectedly need to be different. We are performing a structure-function study of sulfatide analogs to activate or inhibit type II NKT cell activities. One sulfatide analog stimulates type II NKT cells when not processed but type I NKT cells when processed by DCs and under that condition can prevent instead of promote cancers. Endosomal processing by arylsulfatase A converts sulfatide to b-GalCer not expected to be active but which turned out to be a strong type I NKT cell stimulant. This is the first case of glycolipid processing that changes cell tropism and reverses function. We identified a new class of agonist for type I NKT cells b-ManCer that inhibits tumors by a mechanism distinct from that of a-GalCer synergizes with a-GalCer is much less anergy-inducing than a-GalCer and stimulates human NKT cells also. Studies using structure-specific antibodies showed that b-ManCer could assume a structure resembling a-GalCer. All of these studies are aimed to remove the roadblocks to allow cancer vaccines to successfully induce tumor regression. Epitope enhancement in cancer vaccine strategies and translation to clinical trials: We first devised and carried out epitope enhancement (sequence modification to improve MHC binding) on an HLA-A2-binding epitope we discovered in a novel prostate and breast cancer antigen TARP. The enhanced epitope induces human T cells that kill human tumor cells. We translated this to a phase I clinical trial of 2 peptides in stage D0 prostate cancer. 74% of vaccinees had a decreased PSA slope and tumor growth rate at 1 year (p = 0.0004). We studied preclinically and published a novel adenovirus-based HER-2 vaccine expressing the extracellular (EC) and transmembrane (TM) domains of rat neu (ErbB2) which prevents tumor growth in the neu-transgenic mice and cures large established TUBO mammary tumors (2 cm) and established lung metastases. The therapeutic effect in mice is purely antibody mediated through inhibiting ErbB-2 function unlike trastuzumab which is FcR dependent so may work in trastuzumab failures. We translated to a clinical autologous DC vaccine transduced with an Ad5f35 expressing the EC and TM domains of human HER2 and have now published a phase I/II trial of this human vaccine. At vaccine doses of 10-40 million DCs 7/21 (33%) evaluable patients showed clinical benefit (CR PR or SD) and complete safety. A new study combining this vaccine with checkpoint inhibitors (anti-PD-1 a VEGFR inhibitor and an enhanced IL-15) in endometrial cancer is under review. We also found preliminary data for synergy among anti-TGFb anti-LAG3 anti-TIGIT and anti-PDL1. Without the vaccine the checkpoint inhibitors don't work without anti-TGFb. We also found vaccine efficacy enhancement by blockade of PD-L1 and TIGIT a combination further enhanced by CD4 T cell depletion. Based on DTR-Foxp3 Knock-in mice the enhancement was due to removal of Foxp3+ CD4 Treg cells. Thus inhibitors of negative regulation amplify the vaccine efficacy. Moreover we are defining signature expression profiles of different tumors that allow prediction of which combination of inhibitors will be most effective for each. We invented a new modified a-GalCer (PLS-a-GalCer) that is more potent in treating mouse tumors and are investigating the mechanism involving targeting a scavenger receptor by PLS. We also carried out a CRADA-collaborative study in mice of an intratumoral therapy that we found induces a T cell response necessary for regression. This has been translated to the clinic by our collaborators. We are examining the effects of cholesterol and omega-3 lipids in regulating tumor growth in mice. Tumor growth is slowed in mice that genetically make more omega-3 lipids and cancer vaccine efficacy is enhanced. Indeed DCs from the transgenic mice are more effective vaccine vehicles and the effect can be mimicked by growing DCs in lipid-containing media. We also initiated a CRADA with BriaCell to test the ability of semi-allogeneic DCs to act as more effective cancer vaccine vehicles by recruiting allogeneic help and have now shown proof of concept. Also we opened a CRADA with Portage Biotech to examine the ability of their agents that block RAGE or adenosine receptors and activate the STING pathway to enhance cancer vaccine efficacy. Cytokines as vaccine adjuvants for induction of high avidity T cells: Our earlier work showed that high avidity T cells were more effective at clearing viral infections and cancers. We discovered ways to induce them with cytokines and TLR ligands and a novel adjuvant CAF09. The quality of response proved more important than the quantity. We also found that IL-1b induces Th17 helper cells that do not help Tc1 CD8 T cells that protect against virus. Rather they skew the T cells to Tc17 that make IL-17 and do not protect. TGF-b blockade can prevent this problem. We also examined combinations of cytokines and TLR ligands as vaccine adjuvants and found greatest efficacy of IL-15 + TLR3 and TLR9 agonists followed by IL-12 + GM-CSF. Mucosal immunity microbiome: We are also examining the effect of the gut microbiome on cancer and of NKT cells on the gut microbiome and the downstream effect on cancer. We have bred Ja18 knockout (KO) mice that lack type I NKT cells only and CD1d KO mice that lack both type I and type II NKT cells along with wild type B6 mice that have both types in the same facility. We collected their gut microbiome samples at ages 14 23 30 60 and 90 days and did 16S RNA sequencing with the CCR Microbiome Core. We cohoused mice pairwise from day 30 to day 90 and examined the ability of microbes to be transferred. We are finding microbes that grow selectively in mice lacking or retaining different subsets of NKT cells. This could provide an indirect mechanism by which the presence or absence of different types of NKT cells can affect cancer growth through altering the microbiome. 2147209 +No NIH Category available Aggressive behavior;American;Award;Awareness;B cell clonality;B-Cell Lymphomas;BCL1 Oncogene;BCL2 gene;Benign;Biology;Birbeck Granule;Bone Marrow Involvement;CREBBP gene;CSF1R gene;Case Series;Case Study;Cell Proliferation;Cells;Centrocyte;Characteristics;Classification;Clinical;Clinical Management;Consensus;Cutaneous;Data;Dendritic Cells;Diagnosis;Disease;Disease remission;ETV3 gene;Eosinophilic Granuloma;Europe;European;Extranodal;Female genitalia;Fluorescent in Situ Hybridization;Follicular Lymphoma;Functional disorder;Gene Rearrangement;General Population;Genes;Genetic;Genetic Heterogeneity;Genomic approach;Genomics;Goals;Heel;Hematologic Neoplasms;Hematopathology;Heterogeneity;Histiocytosis;Immune system;Immunophenotyping;Institution;International;Knowledge;Langerhans cell;Lesion;Localized Disease;Lymphadenitis;Lymphoma;MAP Kinase Gene;MS4A1 gene;Macrophage Colony-Stimulating Factor Receptor;Malignant Neoplasms;Modification;Molecular;Mutate;Mutation;Myeloproliferative disease;NCOA2 gene;Nature;Neoplasms;Nodal;Nomenclature;Paper;Pathogenesis;Pathologic;Pathologist;Pathway interactions;Patients;Pattern;Process;Prognosis;Progressive Disease;Proliferating;Publications;Publishing;Recommendation;Recurrence;Reporting;Research;Risk;S100 Proteins;Scientist;Series;Signal Pathway;Skin;Societies;Terminology;Translating;United States;Update;Variant;Work;clinical practice;diagnostic criteria;diagnostic tool;differential expression;disease classification;follow-up;genetic approach;herpesvirus entry mediator;histiocyte;improved;insight;langerin;large cell Diffuse non-Hodgkin's lymphoma;lymphoid neoplasm;meetings;neoplastic cell;next generation sequencing;novel;novel diagnostics;phenotypic biomarker;reproductive tract;treatment response;tumor Lymphoma Disease Discovery and Definition n/a NCI 10926561 1ZIASC000550-43 1 ZIA SC 550 43 9692515 "JAFFE, ELAINE " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1069221 NCI Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994 subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists geneticists molecular scientists and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years with many new insights provided by genomic studies have changed the definition of some entities and have led to the recognition of other entities. With my collaborators I have led a major international effort to update the classification of lymphoid neoplasms culminating in the publication of the International Consensus Classification in 2022 and a series of follow-up articles in 2023. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition recommended studies and criteria for the diagnosis of many entities have been extensively refined. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma based on genomic and clinical features. The nature of other extranodal follicular lymphomas is not well defined. We reported 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma B-cell clonality fluorescence in situ hybridization for BCL2 gene rearrangement and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15 80%) had a follicular pattern at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6 while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealed TNFRSF14 as the most frequently mutated gene in 6/10 (60%) cases. No case had CREBBP or KMT2D mutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5 y) with a 5-year overall survival of 100%. We concluded that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas. We have been exploring the clinical and genomic heterogeneity of histiocytic neoplasms with new data on phenotypic markers helpful for diagnosis. We recently observed the differential expression of another marker - macrophage colony stimulating factor receptor or colony stimulating factor-1 receptor (CSF1R/CD115) - between the dendritic cells of dermatopathic lymphadenitis and and the lesional cells of Langerhans cell histiocytosis (LCH). In published work we showed its value in the diagnosis of Langerhans cell neoplasms. Indeterminate cell histiocytosis (ICH) is a rare subtype of histiocytic neoplasm first described in 1985. It is characterized by a proliferation of histiocytes which mimic the neoplastic cells of the Langerhans cell histiocytosis) cytologically and immunophenotypically (positive for CD1a and S100 protein) but lack Langerin and Birbeck granules characteristic of LCH. The ICH has been documented in sporadic case reports and small case series and proposed to be a unique entity with recurrent ETV3::NCOA2 fusions. The full clinicopathologic and molecular spectra of ICH remain however poorly characterized. In hopes of clarifying the clinical and molecular features of ICH we assembled ICH patient data across 2 institutions in Europe and the United States with a specific research focus on histiocytosis. We have compiled the largest study of ICH to date with detailed clinicopathologic data of 33 patients. We show major differences between primary and secondary ICH. Primary cases mainly present in the skin and have a mostly benign clinical course whereas secondary cases arising with other lymphoid or myeloid neoplasms have more aggressive behavior. Our findings highlighted genetic heterogeneity with common occurrence of MAPK pathway alterations. This work was presented at the USCAP meeting in 2023 and received an award from the Society for Hematopathology for the best paper presented by a trainee (resident or fellow). 1069221 +No NIH Category available Acute;Acute Myelocytic Leukemia;Antigens;Autologous;Cell Line;Clinical Trials;Collaborations;Dysmyelopoietic Syndromes;Genes;Goals;Hematologic Neoplasms;In Vitro;KRAS2 gene;Multiple Myeloma;Mutate;Mutation;Myeloproliferative disease;Patients;Specificity;T cell therapy;T-Cell Antigen Receptor Specificity;T-Cell Receptor;T-Lymphocyte;TP53 gene;Testing;cellular transduction;chimeric antigen receptor T cells;clinical trial enrollment;genetically modified cells;mouse model;neoantigens;participant enrollment;targeted treatment;therapy development;vector Adoptive T-cell Therapies Targeting Mutations in Hematologic Malignancies n/a NCI 10926547 1ZIABC012158-01 1 ZIA BC 12158 1 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 624367 NCI We are utilizing previously discovered T-cell receptors (TCRs) that target neoepitopes arising from mutations in the p53 NRAS or KRAS. We are testing T cells transduced with vectors encoding these TCRs for functionality and specificity in vitro. We are also testing them in murine models of multiple myeloma and acute myeloid leukemia. We intend to demonstrate specificity of these TCRs and efficacy against hematologic malignancies. If these goals can be completed we will start a clinical trial that will assess treatment of patients with myeloid malignancy. 624367 +No NIH Category available Antibodies;B-Cell Lymphomas;CAR T cell therapy;Cells;Development;Goals;Human;In Vitro;Malignant Neoplasms;Mus;Phase I Clinical Trials;T-Cell Lymphoma;T-Cell Receptor;T-Lymphocyte;Testing;alpha-beta T-Cell Receptor;chimeric antigen receptor T cells;delta receptors;design;mouse model;preclinical study; T cells Development of CAR T cells targeting T-cell malignancies n/a NCI 10926546 1ZIABC012157-01 1 ZIA BC 12157 1 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 624367 NCI T cell lymphomas make up approximately 10% of non--Hodgkin lymphoma. Unlike B-cell lymphomas there are not clearly effective CAR T-cell therapies for T-cell malignancies. The first steps of this project are already underway. We are attempting to find antibodies that specifically recognize the gamma-delta T-cell receptor. The gamma-delta T-cell receptor serves as a specific target for gamma-delta malignancies. The gamma-delta receptor is not expressed on human cells except for gamma-delta T cells which make up 2-10% of total human T cells. After at least 1 specific antibody is identified for the gamma-delta T-cell receptor we will design CARs test the CARs in vitro and then test the CARs in murine models. If an appropriate CAR can be identified it will be tested in a phase I clinical trial. We are also starting preclinical studies to develop CARs against alpha-beta T-cell receptor-expressing malignancies. 624367 +No NIH Category available Adoptive Cell Transfers;Appointment;Carcinoma;Cell physiology;Engineering;Equipment;Failure;Frequencies;Functional disorder;Goals;Human;Immunity;In Vitro;Mediating;NCI Center for Cancer Research;National Cancer Institute;Operative Surgical Procedures;Patients;Phenotype;Postbaccalaureate;Postdoctoral Fellow;Process;Property;Reagent;Research;Research Personnel;Solid;Source;T cell differentiation;T-Lymphocyte;Technology;Tissues;Training;Tumor Expansion;cancer immunotherapy;human model;immune checkpoint blockade;improved;mouse model;recruit;research study;stem;success;tenure track;tumor Studying phenotypic states of antitumor human T cells n/a NCI 10926545 1ZIABC012156-01 1 ZIA BC 12156 1 79355545 "KRISHNA, SRI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 88719 NCI Following my recent appointment as a Stadtman tenure-track Investigator at the National Cancer Institute Center for Cancer Research I am currently in the process of establishing my lab within the Surgery Branch. This includes acquiring key reagents and the necessary equipment and technology for carrying out my research and completing the required training. I am also taking steps to recruit several postdoctoral fellows as well as post-baccalaureate fellows. I anticipate initiating research studies outlined in this project before the end of the fiscal year. 88719 +No NIH Category available Affect;Age;Aging;Alveolar;Bone Marrow Transplantation;Cancer Model;Cells;Chemicals;Computer software;Cutaneous;Development;Disease;Ectoderm;Endoderm;Environment;Gene Expression;Genetic;Immune;Immune response;Immune system;In Vitro;Inflammation;Intervention;Intrinsic factor;Lesion;Lung;Lung Adenocarcinoma;Lung Neoplasms;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Metastatic Neoplasm to the Lung;Modeling;Monitor;Mus;Mutagens;Myeloid Cells;Oncogenes;Oncogenic;Phosphopeptides;Phosphotransferases;Play;Primary Cell Cultures;Process;Ras Signaling Pathway;Role;Signal Transduction;Skin;Skin Cancer;Skin Neoplasms;Testing;Tissues;Transplantation;Tumor Promotion;Tumor Suppressor Genes;Tumor-associated macrophages;Tumorigenicity;age related;alveolar type II cell;cancer initiation;epigenomics;experimental study;human old age (65+);keratinocyte;mouse model;mutant;neoplastic cell;phosphoproteomics;ras Oncogene;self-renewal;single-cell RNA sequencing;stem cells;therapeutic target;transcriptomic profiling;transcriptomics;tumor;tumor behavior;tumor growth;tumor initiation;tumor microenvironment;tumorigenesis;tumorigenic Factors that influence age-dependent Ras mutant cancer development in mice n/a NCI 10926544 1ZIABC012155-01 1 ZIA BC 12155 1 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 327426 NCI This proposal aims to understand how the aging tissue environment can influence tumor initiation and tumor development. We hypothesize that both cell-autonomous mechanisms involving the aging cancer initiating cells and cell non-autonomous mechanisms involving the aging immune system play a role in this process. We plan to contrast two Ras-driven mouse cancer models - cutaneous skin cancer driven by Kras activation that arise from keratinocytes (ectoderm origin) and lung adenocarcinomas driven by Kras activation that arise from alveolar type II cells (endoderm origin) - to understand how their developments differ between young and old mice in identical genetic backgrounds. We believe these models are ideal for examining age-induced change in tumor initiating cells and in macrophages to illuminate distinct differences in tumor development in a young vs. old host. Aim 1. Defining age-dependent tumor initiation by the Ras oncogene and down-stream Ras signaling pathway in mouse tumor models. Aim 1A. Compare skin and lung tumor initiation in young vs. old mice. We will compare the rate of tumor initiation and tumor growth in young (8 weeks) and old (12 months) mice for tumor initiation in the lung and in the skin. Aim 1B. Compare the tumorigenicity of in vitro Ras-transformed young vs. old tumor-initiating cell in young vs. old mice. We will generate short-term in vitro culture of primary skin keratinocytes and lung alveolar type 2 (AT2) cells and activate the Ras oncogenes using adenoviral-Cre. The tumorigenicity of the resulting cells will be assessed by transplanting them into syngeneic young and old recipients orthotopically and then monitoring tumor growth. Aim 1C. Phosphoproteomic and transcriptomic profiling of tumor cells from young and old mice. Using tumors from young and old mice in Aim 1A and primary cell culture from young and old mice in Aim 1B we will conduct phospho-proteomic analysis to profile kinome activity using the software recently developed in the Cantley lab that predicts the kinases that are most activated or inhibited based on phospho-peptide changes between tumors from old vs. young mice. In parallel we will conduct single cell RNA sequencing to profile age-induced changes in the clustering of tumor stroma and immune cells. Aim 2. Define a role of the aging macrophage in Ras tumor development. Aim 2A. Analysis of tumor associated macrophage (TAM) function. Using models described in Aim 1 TAM abundance and localization will be analyzed in tumors from young vs. old mice. We will also carry out single cell RNA sequencing of these TAMs to understand differences in their gene expression profiles. Aim 2B. Impact of macrophage depletion and therapeutic targeting on lung metastasis. We will transiently deplete macrophage in young vs. old mice and test the impact on lung metastasis of syngeneic Kras mutant cells. Aim 2C. Impact of bone marrow transplant on tumor development. We will transplant bone-marrow-derived myeloid cells from young mice to syngeneic old mice and vice versa to test whether tumor development will be altered. 327426 +No NIH Category available Antibodies;Appointment;Bar Codes;Cell Separation;Cell Therapy;Cells;Cellular immunotherapy;Common Neoplasm;DNA;Engineering;Epithelium;Equipment;HLA Antigens;Libraries;Malignant Neoplasms;NCI Center for Cancer Research;National Cancer Institute;Oligonucleotides;Operative Surgical Procedures;Papillomavirus;Patients;Peptides;Phenotype;Postbaccalaureate;Postdoctoral Fellow;Process;Proteomics;Reagent;Research;Research Personnel;Sampling;Source;T cell receptor repertoire sequencing;T-Cell Receptor;T-Lymphocyte;Technology;Tissue Sample;Training;Tumor Antigens;Tumor-Infiltrating Lymphocytes;Virus;driver mutation;peripheral blood;recruit;research study;tenure track;transcriptome sequencing;transcriptomics;tumor Identifying antitumor T cell receptors for cellular immunotherapy n/a NCI 10926543 1ZIABC012154-01 1 ZIA BC 12154 1 79355545 "KRISHNA, SRI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 88719 NCI Following my recent appointment as a Stadtman tenure-track Investigator at the National Cancer Institute Center for Cancer Research I am currently in the process of establishing my lab within the Surgery Branch. This includes acquiring key reagents and the necessary equipment and technology for carrying out my research and completing the required training. I am also taking steps to recruit several postdoctoral fellows as well as post-baccalaureate fellows. I anticipate initiating research studies outlined in this project before the end of the fiscal year. 88719 +No NIH Category available ATM activation;Affect;BRAF gene;BRCA1 gene;Biological Assay;Brain;CRISPR screen;CRISPR/Cas technology;Cancer Histology;Cancer cell line;Cell Death;Cell Survival;Cells;Cessation of life;Clinical;Clinical Data;Clinical Management;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Combined Modality Therapy;Complex;Coupled;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Gene;DNA Repair Pathway;Data;Dependence;Disease;Dose;Drug resistance;Engineering;Epidermal Growth Factor Receptor;Essential Genes;FDA approved;Genes;Genetic Determinism;Genetic Engineering;Genome;Genomic Instability;Goals;Human;Immunocompetent;Immunocompromised Host;Implant;Knock-out;Lead;Libraries;Link;MAP Kinase Gene;MAPK3 gene;MEKs;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thyroid;Mediating;Melanoma Cell;Modeling;Modification;Mus;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Oncogenic;Outcome;Output;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Phosphorylation;Phosphotransferases;Play;Process;Reporting;Resistance;Role;Site;Solid;Solid Neoplasm;System;Therapeutic;Toxic effect;Transcriptional Activation;Tyrosine Kinase Inhibitor;Undifferentiated;Validation;Vascular Endothelial Growth Factors;Xenograft Model;Xenograft procedure;anaplastic thyroid cancer;angiogenesis;ataxia telangiectasia mutated protein;bone;cancer cell;cancer therapy;cell killing;genome-wide;improved;in vivo;inhibitor;insight;mouse model;novel;novel therapeutic intervention;precision oncology;preclinical study;repaired;resistance mechanism;response;targeted agent;targeted treatment;therapeutic target;thyroid neoplasm;treatment duration;tumor;tumor growth;tumor progression Unlocking mechanisms of resistance to targeted therapy in thyroid cancer n/a NCI 10926539 1ZIABC012150-01 1 ZIA BC 12150 1 79355540 "BOUFRAQECH, MYRIEM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 808861 NCI Aim 1: Identify novel genes or essential pathways required for resistance to BRAFV600E inhibition utilizing genome wide and focused CRISPR-based screens. First using BRAFV600E-ATC cell line 8505c we will harness a human CRISPR knockout library of 19050 genes to identify genes whose loss enhances cell death by the BRAF selective inhibitor Dabrafenib. Dabrafenib has a better toxicity profile compared to the canonical inhibitor vemurafenib and was recently approved by the FDA for the treatment of advanced and metastatic thyroid cancer. BRAF activity will be inhibited using 400 nM of Dabrafenib a dose which yielded about 20% of cell death and a complete inhibition of phospho-MEK and phospho-ERK1/2 in a 14-days treatment survival assay. Mechanisms of resistance to targeted therapy including those involving BRAFV600E inhibitors is a complex process which involve various alterations that enable cancer cells to escape death. To more specifically unlock these mechanisms of resistance we engineered a focused CRISPR/cas9 and CRISPR/dCas9 transcriptional activation (SAM system) libraries targeting genes sets selected based on strong correlations with BRAFV600E activation and dependency in collaboration with the Genome modification Core of the NCI-Frederick. We will utilize single sgRNA CRISPR guides targeting top genes identified in our CRISPR screens output to validate the putative synthetic lethality with BRAFV600E inhibition. To further substantiate the significance of essential gene (s) in vivo we will use two models 1) ATC cells 8505c will be depleted for the validated gene(s) and used in an immunocompromised xenograft model for ATC. 2) The murine BRAFV600E-driven ATC cell line will be depleted for the validated gene(s) and implanted orthotopically into immunocompetent mice. In both mouse models tumor growth and metastasis of wild type and target-depleted cells will be evaluated in response to dabrafenib. This study will identify novel genes involved in resistance to BRAFV600E inhibition and will unfold new avenues of therapeutic strategies in patients with anaplastic thyroid cancer. Aim2: Targeting ATM and BRAFV600E in anaplastic thyroid cancer for precision medicine. Preclinical studies in cancer therapy have shown that targeting major genome maintenance genes such as ATM ATR or harnessing deficiency in DNA damage response genes such as BRCA1 may help to overcome drug resistance in multiple solid malignancies. These findings provide insights into targeting DNA repair proteins to sensitize cancer cells to targeted therapies. In line with these observations we found that ATM expression is strongly associated with adverse clinical features and aggressive thyroid cancer histology thereby suggesting that ATM may play a key role in mediating thyroid cancer metastasis particularly in BRAF-driven thyroid tumors. ATM is a major genome maintenance gene involved in the repair of double-stranded DNA breaks. While several reports have demonstrated links between genetic alterations in ATM and DNA repair response genes little is known about how changes in ATM expression level and kinase activity affect cancer progression. We aim to determine the extent to which ATM expression level is associated with key features of thyroid cancer aggressiveness and whether ATM could serve as a druggable therapeutic target in advanced and metastatic thyroid cancer. To elucidate the role of ATM in thyroid cancer progression we performed functional studies and found that ATM is a key regulator of VEGF secretion and angiogenesis in ATC. Furthermore ATM depletion or its inhibition with a highly selective ATM inhibitor reduced tumor metastasis in a model of ATC xenografts. On the other hand little is known about the impact of BRAFV600E inhibition on DNA repair pathways in solid tumors. Our preliminary data show that increasing doses of BRAFV600E inhibitors dabrafenib (FDA approved) and PLX4720 (modified vemurafenib) lead to a robust phosphorylation of ATM on its Serine1981 residue in BRAFV600E driven ATC cells. These observations are consistent with two major recent findings demonstrating an increased phosphorylation of ATM in EGFR and BRAFV600E inhibitors treated NSCLC and melanoma cells respectively. Together these data suggest that therapy targeting oncogenes such as BRAFV600E induces dependency on ATM activation in cancer cells and combination of ATM inhibitor AZD1390 (currently in clinical trial) with specific BRAFV600E inhibitors such as dabrafrenib will unlock acquired resistance to BRAFV600E inhibitors in ATC. Remarkably we found that AZD1390 sensitizes ATC and PDTC BRAFV00E driven cells to dabrafenib. The validation of the clinical benefit of this combination therapy in a genetically engineered ATC mouse model (BRAFV600E; Trp53R270H) with a similar phenotype and disease aggressiveness as in human patients will provide a valuable new therapeutic strategy that may significantly improve the clinical management of patients with undifferentiated thyroid cancer. 808861 +No NIH Category available 18 year old;Alpha Particles;Anatomy;Binding;Biodistribution;Cell membrane;Cells;Characteristics;Chemicals;Clinical;Deposition;Disseminated Malignant Neoplasm;Dose;Eastern Cooperative Oncology Group;Effectiveness;Eligibility Determination;Gamma Rays;Head and Neck Cancer;Human;Image;Ligands;Lung;Magnetic Resonance Imaging;Malignant Neoplasms;Maximum Tolerated Dose;Neuroendocrine Tumors;Paraganglioma;Participant;Patients;Peptides;Performance Status 0;Pharmaceutical Preparations;Phase I Clinical Trials;Phase I/II Clinical Trial;Phase I/II Trial;Pheochromocytoma;Positron-Emission Tomography;Radiation Dose Unit;Radioisotopes;Radionuclide therapy;Renal carcinoma;Retreatment;SSTR2 gene;Safety;Scanning;Somatostatin Receptor;Surface;Therapeutic Agents;Time;comparative efficacy;design;efficacy evaluation;insulinoma;kidney cell;neoplastic cell;overexpression;phase I trial;radioligand;radiological imaging;receptor;receptor expression;response;safety assessment;single photon emission computed tomography;small cell lung carcinoma;success;tumor;uptake Pb212 VMT alpha NET in treatment and re-treatment of SSTR+ tumors n/a NCI 10926534 1ZIABC012138-01 1 ZIA BC 12138 1 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 337122 NCI Background: Somatostatin receptors (SSTR) especially type 2 have been shown to be over-expressed in a number of human tumors including GI neuroendocrine tumors (GI NET) pheochromocytoma/paragangliomas (PPGL) small cell lung cancers (SCLC) kidney cancers (KC) and some head and neck cancers. -Targeted radioligand therapy (TRT) is a class of cancer therapeutic agents formed by attaching a radioactive isotope to a ligand which can target specific surface receptors such as SSTR on a tumor cell membrane. Efficacy is typically determined by the radiation dose deposited onto a tumor which is determined by the radioactive isotope being used as well as binding characteristics of the ligand-receptor/transporter pair. While there have been clinical successes with treating GI NET and PPGL with SSTR-targeting beta-emitting TRTs tumors will invariably start to progress after some time. Re-treatment using the same beta-emitting agents at time of progression can be done but has decreased efficacy compared to the TRT-naive setting. Alpha emitters such as 212Pb emit alpha particles that are more damaging to tumor cells than beta emitters such as Lu-177. TRT agents using alpha emitters are considered to be more potent than beta emitting TRTs. VMT-alpha-NET is a peptide that binds to SSTR which when attached to 212Pb becomes an alpha particle-emitting TRT that can be used to treat tumors that have SSTR surface expression. [203Pb]VMT-alpha-NET is the chemically identical imaging surrogate for [212Pb]VMT-alpha-NET and has the same mechanism of action via binding to SSTR2. The nuclide 203Pb contained in [203Pb]VMT-alpha-NET emits gamma radiation suitable for SPECT imaging. These images can be used to assess drug product biodistribution throughout the body. We are initiating two phase I clinical trials to assess the safety and efficacy of [212]Pb-VMT-alpha-NET in SSTR tumors including GI NET PPGL SCLC KC or HN: 1. a Phase I Trial of [212Pb]VMT-alpha-NET in Metastatic or Inoperable Somatostatin-Receptor Positive GI Neuroendocrine Tumors Pheochromocytoma/Paragangliomas Small Cell Lung Renal Cell and Head and Neck Cancers. The study seeks to evaluate the safety and effectiveness of [212]Pb-VMT-alpha-NET in SSTR tumors including GI NET PPGL SCLC KC or HN. -[203Pb]VMT-alpha-NET will be used in these SSTR tumors to assess biodistribution throughout the body. Objectives: -Determine the MTD of [212Pb]VMT-alpha-NET using a 3+3 dose escalation design in several different SSTR+ tumor types. Eligibility: -Age 18 years. Histopathologically confirmed GI NET PPGL SCLC KC or H&N cancers that are metastatic or inoperable. Evidence of SSTR expression on at least 50% of the radiographically identifiable (i.e. visible on an anatomic scan such as CT or MRI) tumor as indicated by a positive (uptake qualitatively identifiable as above the local background) SSTR PET scan. ECOG Performance Status 0-1. 2. a Phase I/II Trial of [212Pb]VMT-alpha-NET in Metastatic or Inoperable GI Neuroendocrine Tumors and Pheochromocytoma/Paragangliomas Previously Treated with Systemic Radioligand Therapy. The study seeks to evaluate the safety and effectiveness of [212]Pb-VMT-alpha-NET in GI NET and PPGL patients who have been previously treated with at least 1 cycle of beta-emitting systemic radionuclide therapy. [203Pb]VMT-alpha-NET will be used to assess biodistribution throughout the body. 337122 +No NIH Category available Adaptor Signaling Protein;Adult;Affect;Age;Animal Model;Antigen Receptors;Area;Blood Cells;Bone Marrow;Cell Differentiation process;Cell Lineage;Cell Maintenance;Cell physiology;Cells;Cytosol;Defect;Development;Developmental Process;Disease;Dissection;Functional disorder;Genetic;Genomics;Goals;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Homeostasis;Human;Immune;Impairment;In Vitro;Investigation;Longevity;Macrophage;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mammalian Cell;Mammals;Mediating;Molecular;Monitor;Organelles;Outcome;Pathogenesis;Pathway interactions;Proteins;Proteome;Proteomics;Regulation;Research;Role;Rough endoplasmic reticulum;Sampling;Signal Transduction;System;T-Lymphocyte;Testing;Tissues;Translations;Ubiquitin;Work;cytokine;extracellular;genome integrity;hematopoietic differentiation;imprint;improved;in vivo;innovation;mouse model;multicatalytic endopeptidase complex;programs;protein degradation;protein folding;proteostasis;response;stem cells;tool;transcriptomics Proteostasis regulators in blood cell development and function n/a NCI 10926532 1ZIABC012135-01 1 ZIA BC 12135 1 79355532 "ADORO, STANLEY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 927571 NCI "In adult mammals all blood cells arise from bone marrow hematopoietic stem cells (HSCs) through a tightly regulated developmental process involving progressive differentiation of HSCs through progenitor cells and culminating in various terminally differentiated blood cell lineages. During this developmental process and throughout their lifespan blood cells continually integrate both extracellular and cell intrinsic signals (e.g. cytokines antigen receptors and metabolites) into a cellular and molecular program that imprints cell identity and function while promoting their survival. While the importance of maintaining genome integrity to blood cell development and function is now well-established it is less clear if and how maintenance of proteome integrity impacts hematopoietic cell fate during differentiation. Proteome homeostasis (or ""proteostasis"") describes the fate of proteins from translation to their eventual turnover. In mammalian cells this proteostasis is accomplished by the complimentary activity of cytosolic or organelle-specific unfolded protein response pathways that following translation in the cytosol or rough endoplasmic reticulum monitor and promote protein folding and the ubiquitin proteasome system that mediates protein degradation. The goal of my research is to understand mechanisms of proteostasis in blood cells and how proteostasis pathways contribute to normal and malignant blood cell development and function. Our central hypothesis is that proteostasis pathways determine blood cell differentiation outcomes and that decline or defects in the proteostasis machinery contributes to hematopoietic cell dysfunction and malignancy. To this end we utilize state-of-the-art tools in genomics transcriptomics and proteomics to assess how changes in proteostasis pathways affect normal blood cell development and disease pathogenesis in relevant human samples and animal models. In the long term we expect that these studies will uncover vulnerabilities in proteostasis pathways that can be exploited to augment hematopoiesis improve immune cell function and treat blood cancers. Combining relevant human samples with innovative genetic mouse models that allow precise dissection of core mammalian proteostasis pathways in vitro and in vivo our investigation of this hypothesis is currently centered around three areas of research: 1. The unfolded protein response (UPR) in HSC maintenance and malignancy. 2. The role of UPR deficiency in T cell dysfunction 3. Tunable regulation of normal and malignant hematopoietic cells by the adaptor protein CHMP5" 927571 +No NIH Category available Affect;Aging;Alleles;Binding;Biochemical;Bioinformatics;Biological Assay;C-terminal;Cell Cycle;Cell Cycle Inhibition;Cell Cycle Progression;Cell Differentiation process;Cell Line;Cell Proliferation;Cell division;Cells;Chemical Engineering;Complex;Coupled;Cyclin D1;Cyclin Regulation of Cell Cycle Pathway;Cyclin-Dependent Kinases;Cyclins;DNA;Docking;Engineering;Ensure;Equipment;Family;Family member;G1 Arrest;G1/S Transition;Gene Expression;Genetic Screening;Genetic Transcription;Imaging Techniques;In Vitro;Kinetics;Label;Laboratories;Link;Malignant Neoplasms;Mammalian Cell;Mass Spectrum Analysis;Metabolism;Methods;Modeling;Modification;Molecular;Mutation;Normal Cell;Peptides;Phase;Phase Transition;Phospho-Specific Antibodies;Phosphorylation;Phosphotransferases;Play;Postbaccalaureate;Postdoctoral Fellow;Preparation;Process;Protein C;Proteins;Proteome;Proteomics;RNA Polymerase II;Reagent;Regulation;Research;Retinoblastoma Protein;Role;Rotation;S phase;Saccharomycetales;Side;Site;Students;System;Techniques;Testing;Time;Transcriptional Activation;Work;Yeasts;alpha helix;analog;cancer cell;candidate identification;cell growth;cell type;cyclin G1;experimental study;improved;in vivo;novel;phosphoproteomics;pre-doctoral;prevent;promoter;protein protein interaction;reconstitution;recruit;summer student;tool;transcriptomics;tumor;volunteer Biochemical mechanisms cyclin-dependent kinases use to control cell division n/a NCI 10926530 1ZIABC012133-01 1 ZIA BC 12133 1 79355528 "KOIVOMAGI, MARDO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1255805 NCI Determine the substrates and mechanisms of mammalian cyclin-Cdk complexes during the first steps in cell cycle Background: The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk46 is the retinoblastoma protein Rb which inhibits cell-cycle progression until its inactivation by phosphorylation. Recently we have shown that cyclin D-Cdk46 docks one side of an alpha-helix in the Rb C terminus which is not recognized by downstream cell cycle cyclins. This helix-based docking mechanism for cyclin D is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents its phosphorylation promotes G1 arrest and enhances Rb's tumor suppressive function. However because Rb can be phosphorylated by other cyclin-Cdks and cyclin D-Cdk46 may target other substrates involved in cell division identifying novel targets of cyclin-Cdk complexes will deepen our understanding how Rb and cyclin D-Cdk4/6 regulate cell-cycle progression. Proposed aims: Our specific aims are: 1) Utilize novel analog-sensitive Cdk46 to identify cyclin D-Cdk46 substrates across the proteome 2) Identify substrates employing helix-based docking. Experimental systems: I have engineered chemically inhibitable versions of Cdk4 and Cdk6 kinases. While creating analog-sensitive versions of many kinases in the Cdk family has been relatively simple Cdk46 versions have proven more challenging and were considered impossible. Using the developed Cdk46 analog-sensitive alleles we will apply quantitative phosphoproteomic analysis to identify peptides with altered phosphorylation states following specific Cdk46 inhibition in vivo. As an alternative approach we will employ improved proximity-labeling based methods coupled with mass spectrometry to validate the hits from bioinformatic analysis or to characterize entirely new ones in a cellular context. The combined proteomics techniques will allow the identification of proteins interacting with G1 cyclin-Cdk complexes potentially uncovering new docking mechanisms and providing a more comprehensive understanding of the role of G1 cyclin-Cdk complexes. Progress: This work has been started by a special volunteer and a post baccalaureate in the laboratory. In addition we have successfully recruited a postdoctoral fellow who along with the post baccalaureate (CRTA) will begin work on this project later in 2023. Moreover all the essential equipment required for this research has been acquired and set up in the laboratory. Preparation of reagents for the quantitative biochemical assays is now complete enabling us to conduct critical tests on our novel engineered version of Cdk46 kinase. Initial in vitro biochemical assays have already been performed confirming the activity of the novel analog-sensitive Cdk46 kinases and their inhibition by bulky ATP analogs. Next we are creating cell lines with modified Cdk46 kinases to first validate and then perform above proposed experiments to find novel targets G1 cyclin-Cdk complexes. To identify targets phosphorylated through the helix-based docking mechanism we carried out a proteome-wide bioinformatic analysis. Currently we are in the process of purifying the identified candidate proteins to evaluate their interactions with G1 cyclin-Cdk complexes. This will be achieved using quantitative biochemical assays to determine if these proteins are genuine substrates of the G1 cyclin-Cdk complexes. Determine promoter-specific RNA polymerase II regulation by cell cycle cyclin-Cdk complexes. Background: Cyclin dependent kinases (Cdks) and cyclins are the key regulators of proper cell cycle progression phosphorylating their specific target proteins depending on the specific cell cycle phase. Recently my work showed that in yeast cell cycle G1 cyclin-Cdk complex directly phosphorylates and regulates RNA polymerase II activity at specific promoters leading to transcriptional changes critical for the G1 to S phase transition. However our understanding of how cyclin-Cdk complexes directly regulate transcription through modification of RNA polymerase II in cells during different cell cycle phases remains limited. Proposed aims: Our specific aims are: 1) Understand the molecular mechanisms by which cyclin-Cdk complexes regulate transcriptional changes in a promoter-specific manner during cell cycle 2) Study how these changes in transcription affect cell cycle progression in normal and cancer cells. Alternatively should the Cdk-dependent transcription not regulate cell cycle progression we aim to study whether it is needed for other described non-canonical roles of cell cycle Cdks including but not limited to aging cell differentiation metabolism and cell growth. Experimental systems: We will employ a combination of in vitro quantitative biochemical assays state-of-the-art methods to determine protein-DNA and protein-protein interactions transcriptomic methods and genetic screens to determine functional interactions in different cell types. We will also use advanced imaging techniques to study the cyclin-Cdk-RNA polymerase II interactions and the effects of cyclin-Cdk binding on transcription kinetics in live cells. Progress: Work on this has been started by a pre-doctoral IRTA student doing rotation in the laboratory and by a summer student. In addition we have successfully recruited two postdoctoral fellows who are set to join the laboratory in second part of 2023. They will be employing either the budding yeast or the mammalian system as a model to investigate our research questions proposed above. In preparation for their research all the essential equipment required for this project has been procured and properly set up in our laboratory ensuring a fully functional workspace. Moreover we have made substantial progress in preparing the key reagents necessary for conducting quantitative biochemical assays essential for this project. During this we have set up a workflow to biochemically reconstitute a key complex required to test our hypothesis described above. We have also generated a key tool phospho-specific antibody to critically test our ideas in cellular settings. In addition as part of the initial biochemical proof of principle experiments we have performed some crucial assays testing validity of our proposed approach. 1255805 +No NIH Category available Address;Adoptive Transfer;Aftercare;Alcohol abuse;Antigens;Autologous;Basic Science;Biopsy Specimen;Blood specimen;Cell surface;Cells;Chronic;Circulation;Clinical;Clinical Research;Correlative Study;Data;Development;Disease;Epithelial Neoplasms;Excision;Gene Expression;Goals;Head and Neck Neoplasms;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 11;Human papillomavirus 6;Immunity;Immunotherapy;In complete remission;Infiltration;Laboratories;Life;Medical;Mus;Neoadjuvant Study;Neoadjuvant Therapy;Neoplasms;Newly Diagnosed;Operative Surgical Procedures;Papilloma;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Phase;Protocols documentation;Recurrent respiratory papillomatosis;Repeat Surgery;Research;Residencies;Specimen;T cell therapy;T-Cell Receptor;T-Lymphocyte;Therapeutic;Tissues;Transforming Growth Factor beta;Translating;Tumor Debulking;Tumor Immunity;United States National Institutes of Health;Vaccination;Vaccine Design;Vaccine Therapy;Vaccines;Voice;Work;anti-tumor immune response;chimeric antigen receptor T cells;chronic infection;clinical center;design;early phase clinical trial;engineered T cells;immune checkpoint blockade;improved;industry partner;neoplastic cell;novel;novel strategies;novel therapeutics;novel vaccines;phase 2 study;pre-clinical;programs;standard of care;therapeutic evaluation;therapeutic vaccine;tobacco abuse;tumor;vaccination outcome Enhancing anti-tumor immunity in head and neck neoplasms n/a NCI 10926528 1ZIABC012131-01 1 ZIA BC 12131 1 79355524 "ALLEN, CLINT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4097112 NIDCD Major activities of our program include progress in both HNSCC and RRP. Our recent work on HNSCC has focused on the rationale sequencing of immune checkpoint blockade (ICB) immunotherapy and surgery for patients with newly diagnosed HNSCC. Previous mouse work in our laboratory revealed that ICB resulted in the development of durable systemic anti-tumor immunity when administered prior to surgical resection of tumors but not when the ICB was administered after surgery. This observation was striking but the mechanisms underlying this finding were unclear. To study this phenomenon in patients we designed and completed a phase II study of neoadjuvant ICB in patients with HNSCC and studying pre- and post-treatment tumor biopsies and blood samples. We observed that tumor-specific T cells became activated and expanded in the tumor after treatment. Additionally we observed that tumors act as a reservoir for tumor-specific T cells through induction of a tissue residency gene expression program. With ICB treatment a proportion of the tumor-specific T cells were released from the tumor into circulation leading to enhanced systemic anti-tumor immunity. These data indicate that without neoadjuvant ICB treatment most of a patient's anti-tumor immune response would be removed with surgical removal of the tumor. Conversely neoadjuvant ICB induces egress of some T cells from the tumor enhancing the patient's systemic immunity. These findings are the strongest scientific argument to date supporting the use of neoadjuvant ICB in patients with HNSCC. We next explored the mechanistic drivers of this tissue resident gene expression program in tumor-specific T cells in the laboratory and found TGF-b to be a major driver. In pre-clinical mouse studies we observe that the addition of TGF-b blockade to ICB further enhanced the degree of systemic antitumor immunity that develops compared to ICB alone. Our ongoing work aims to determine if other pathways are involved in efforts to uncover more possible therapeutic strategies to enhance systemic anti-tumor immunity in patients with newly diagnosed HNSCC. Our recent work on RRP has focused on identifying non-surgical medical treatment options for this rare hard to treat disease. The standard-of-care treatment for RRP is repeat surgery to debulk disease and maintain a functional voice and airway. Our team has pioneered approaches to address the underlying cause of RRP chronic HPV infection with immunotherapy. Initial trials with immune checkpoint blockade (ICB) resulted in clinical benefit for some patients but no patients were cured. Our correlative analyses on specimens from these trials revealed that ICB was not unleashing the activity of HPV-specific T cells in papillomas due at least in part to the paucity of HPV-specific T cells present in these papillomas at baseline. We next worked with an industry partner to develop a therapeutic vaccine designed to generate new or expand existing HPV-specific T cells in patients with RRP. Phase I clinical study with this new vaccine resulted in robust clinical activity and protocol defined complete responses in 50% of patients. Correlative studies from this trial revealed significant polyclonal expansion of HPV-specific T cells in the periphery after vaccination and the ability of these T cells to traffic and infiltrate into papillomas in responder patients. Ongoing phase II study with this vaccine has led to FDA Breakthrough Designation. These data indicated that enhancement of peripheral HPV-specific T cell immunity can lead to papilloma destruction and clinical benefit in patients with HPV-driven neoplasms. Yet therapeutic vaccination does not result in the expansion peripheral HPV-specific T cell immunity in all patients. Other approaches are needed to enhance systemic HPV-specific immunity in these patients. Adoptive transfer of autologous T cells engineered to express a T cell receptor (TCR) specific for HPV has proven efficacy in HPV-associated malignancies and could be a new approach for life-threatening cases of RRP. Treatment with chimeric antigen receptor (CAR) T cells is not possible currently as no cell surface markers specific for HPV infected papilloma cells are known. A TCR-engineered T cell therapy approach necessitates the discovery of one or more TCRs that recognize antigen derived from HPV 6 or 11. Discovery of novel TCRs that target HPV 6 or 11 antigens is a major research effort currently in our laboratory. 1389968 +No NIH Category available Address;Adoptive Transfer;Aftercare;Alcohol abuse;Antigens;Autologous;Basic Science;Biopsy Specimen;Blood specimen;Cell surface;Cells;Chronic;Circulation;Clinical;Clinical Research;Correlative Study;Data;Development;Disease;Epithelial Neoplasms;Excision;Gene Expression;Goals;Head and Neck Neoplasms;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 11;Human papillomavirus 6;Immunity;Immunotherapy;In complete remission;Infiltration;Laboratories;Life;Medical;Mus;Neoadjuvant Study;Neoadjuvant Therapy;Neoplasms;Newly Diagnosed;Operative Surgical Procedures;Papilloma;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Phase;Protocols documentation;Recurrent respiratory papillomatosis;Repeat Surgery;Research;Residencies;Specimen;T cell therapy;T-Cell Receptor;T-Lymphocyte;Therapeutic;Tissues;Transforming Growth Factor beta;Translating;Tumor Debulking;Tumor Immunity;United States National Institutes of Health;Vaccination;Vaccine Design;Vaccine Therapy;Vaccines;Voice;Work;anti-tumor immune response;chimeric antigen receptor T cells;chronic infection;clinical center;design;early phase clinical trial;engineered T cells;immune checkpoint blockade;improved;industry partner;neoplastic cell;novel;novel strategies;novel therapeutics;novel vaccines;phase 2 study;pre-clinical;programs;standard of care;therapeutic evaluation;therapeutic vaccine;tobacco abuse;tumor;vaccination outcome Enhancing anti-tumor immunity in head and neck neoplasms n/a NCI 10926528 1ZIABC012131-01 1 ZIA BC 12131 1 79355524 "ALLEN, CLINT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4097112 NCI Major activities of our program include progress in both HNSCC and RRP. Our recent work on HNSCC has focused on the rationale sequencing of immune checkpoint blockade (ICB) immunotherapy and surgery for patients with newly diagnosed HNSCC. Previous mouse work in our laboratory revealed that ICB resulted in the development of durable systemic anti-tumor immunity when administered prior to surgical resection of tumors but not when the ICB was administered after surgery. This observation was striking but the mechanisms underlying this finding were unclear. To study this phenomenon in patients we designed and completed a phase II study of neoadjuvant ICB in patients with HNSCC and studying pre- and post-treatment tumor biopsies and blood samples. We observed that tumor-specific T cells became activated and expanded in the tumor after treatment. Additionally we observed that tumors act as a reservoir for tumor-specific T cells through induction of a tissue residency gene expression program. With ICB treatment a proportion of the tumor-specific T cells were released from the tumor into circulation leading to enhanced systemic anti-tumor immunity. These data indicate that without neoadjuvant ICB treatment most of a patient's anti-tumor immune response would be removed with surgical removal of the tumor. Conversely neoadjuvant ICB induces egress of some T cells from the tumor enhancing the patient's systemic immunity. These findings are the strongest scientific argument to date supporting the use of neoadjuvant ICB in patients with HNSCC. We next explored the mechanistic drivers of this tissue resident gene expression program in tumor-specific T cells in the laboratory and found TGF-b to be a major driver. In pre-clinical mouse studies we observe that the addition of TGF-b blockade to ICB further enhanced the degree of systemic antitumor immunity that develops compared to ICB alone. Our ongoing work aims to determine if other pathways are involved in efforts to uncover more possible therapeutic strategies to enhance systemic anti-tumor immunity in patients with newly diagnosed HNSCC. Our recent work on RRP has focused on identifying non-surgical medical treatment options for this rare hard to treat disease. The standard-of-care treatment for RRP is repeat surgery to debulk disease and maintain a functional voice and airway. Our team has pioneered approaches to address the underlying cause of RRP chronic HPV infection with immunotherapy. Initial trials with immune checkpoint blockade (ICB) resulted in clinical benefit for some patients but no patients were cured. Our correlative analyses on specimens from these trials revealed that ICB was not unleashing the activity of HPV-specific T cells in papillomas due at least in part to the paucity of HPV-specific T cells present in these papillomas at baseline. We next worked with an industry partner to develop a therapeutic vaccine designed to generate new or expand existing HPV-specific T cells in patients with RRP. Phase I clinical study with this new vaccine resulted in robust clinical activity and protocol defined complete responses in 50% of patients. Correlative studies from this trial revealed significant polyclonal expansion of HPV-specific T cells in the periphery after vaccination and the ability of these T cells to traffic and infiltrate into papillomas in responder patients. Ongoing phase II study with this vaccine has led to FDA Breakthrough Designation. These data indicated that enhancement of peripheral HPV-specific T cell immunity can lead to papilloma destruction and clinical benefit in patients with HPV-driven neoplasms. Yet therapeutic vaccination does not result in the expansion peripheral HPV-specific T cell immunity in all patients. Other approaches are needed to enhance systemic HPV-specific immunity in these patients. Adoptive transfer of autologous T cells engineered to express a T cell receptor (TCR) specific for HPV has proven efficacy in HPV-associated malignancies and could be a new approach for life-threatening cases of RRP. Treatment with chimeric antigen receptor (CAR) T cells is not possible currently as no cell surface markers specific for HPV infected papilloma cells are known. A TCR-engineered T cell therapy approach necessitates the discovery of one or more TCRs that recognize antigen derived from HPV 6 or 11. Discovery of novel TCRs that target HPV 6 or 11 antigens is a major research effort currently in our laboratory. 2707144 +No NIH Category available Animal Model;Blood;Bone Marrow;Brain;Breast cancer metastasis;Cause of Death;Cessation of life;Clinical;Committee Members;Common carotid artery;Control Groups;DNA;Diagnosis;Event;General Population;Goals;Growth;Heart;Immunocompetent;Incidence;Incidental Findings;Inferior vena cava structure;Inflammation;Injections;Interruption;Investigation;Ischemia;Link;Magnetic Resonance Imaging;Malignant Neoplasms;Metastatic malignant neoplasm to brain;Modeling;Mus;Myocardial Infarction;National Heart Lung and Blood Institute;Natural Immunity;Neoplasm Metastasis;Patients;Phenotype;Play;Prognosis;Reporting;Role;Stroke;Thrombin;Thromboembolism;Thrombosis;Thrombus;United States;Woman;cancer cell;cancer complication;cancer therapy;cancer type;comparison control;extracellular;malignant breast neoplasm;monocyte;mouse model;neutrophil;novel;novel therapeutic intervention;survival outcome;treatment strategy;tumor growth;venous thromboembolism Elucidating the role of thrombosis and inflammation in breast cancer metastasis n/a NCI 10926527 1ZIABC012130-01 1 ZIA BC 12130 1 79355522 "FUJII, TAKEO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 506815 NCI Objective 1; To identify the mechanisms by which asymptomatic small strokes promote breast cancer brain metastasis. Among all the metastasis brain metastasis has the worst survival outcomes. It is reported that 10-20% of general population have asymptomatic small strokes found incidentally by MRI. To mimic this clinical scenario in patients with cancer we have developed a novel stroke-brain metastasis mouse model in which PBS with microthrombi prepared ex vivo by mixing fresh murine blood and thrombin is injected into a common carotid artery (stroke group) on Day 0 followed by intracardiac cancer cell injection on Day 2 in immunocompetent mice. The size and number of the brain metastatic foci were significantly larger in stroke group compared to control group (Injection of PBS without microthrombi). The ASP for further investigation is currently under ACUC review. Objective 2: To determine the mechanisms by which DVT promotes breast cancer growth. DVT is the most common type of venous thromboembolisms in the patients with cancer. In collboration with Dr. Yogen Kanthi from NHLBI who has well-established Electrolytic Inferior Vena Cava Model (EIM) DVT mouse mode we are dveloping a novel DVT-breast cancer mouse model. We hypothesize that DVT promotes breast cancer growth by altering the innate immunity in bone marrow based on a report that myocardial infarction (local ischemia in heart) reprogrammed Ly6Chi monocytes in the bone marrow to an immunosuppressive phenotype leading to tumor growth. The ASP for this study is currently waiting for final signoffs from ACUC committee members. 506815 +No NIH Category available Adolescent;Adult;Affect;Alternative Splicing;Antibody-drug conjugates;Antigens;Award;B-Cell Acute Lymphoblastic Leukemia;B-Lymphocytes;Back;Bone Tissue;Brain Neoplasms;CCR;CD19 gene;CD22 gene;Cancer Patient;Cancer cell line;Cell Line;Childhood;Childhood Leukemia;Clinical Trials;Data;Encyclopedias;Evaluation;Exons;Experimental Models;Extramural Activities;FDA approved;Goals;Hematologic Neoplasms;Human;Immune;Immune Targeting;Immunooncology;Immunotherapeutic agent;Immunotherapy;Laboratories;Libraries;Lymphoid Cell;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Messenger RNA;Methodology;NK cell therapy;Natural Killer Cells;Neuroblastoma;Neuroendocrine Tumors;Neurosecretory Systems;Open Reading Frames;Operative Surgical Procedures;PAX5 gene;Patient-Focused Outcomes;Patients;Pediatric Hospitals;Population Heterogeneity;Pre-Clinical Model;Procedures;Process;RNA Splicing;RNA-Binding Proteins;Recurrence;Refractory Disease;Relapse;Research;Resistance;Resistance development;Role;Sampling;Site;Soft tissue sarcoma;Solid Neoplasm;Source;T-Lymphocyte;Testing;Transcript;Transforming Growth Factor beta;Translating;Translational Research;Tumor Immunity;Untranslated RNA;Variant;Work;chemotherapy;childhood sarcoma;chimeric antigen receptor T cells;early phase clinical trial;effective therapy;experimental study;first-in-human;high throughput analysis;imprint;improved;improved outcome;manufacture;negative affect;novel;novel therapeutic intervention;participant enrollment;patient prognosis;phase I trial;prevent;protein expression;response;transcription factor;tumor;tumor microenvironment;vaccine development;vector;young adult Bench to Beside and Back translational immuno-onocology-Cures n/a NCI 10926526 1ZIABC012128-02 1 ZIA BC 12128 2 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 124779 NCI "Four CCR projects are currently supported by this Cancer Moonshot Bench to Beside and Back award: 1. TME informed NK cell therapy for pediatric sarcomas led by Rosandra Kaplan (CCR) and Timothy Cripe (Nationwide Children's Hospital). The overall goal of this project is to develop natural killer (NK) cell therapy with TGF-beta imprinting that can be augmented through manipulation of the immune suppressive tumor microenvironment (TME) leading to improved NK cell-mediated anti-tumor immunity and serves as a potential effective therapy for patients with relapsed pediatric sarcoma. Bone and soft tissue sarcomas are one of the most common solid tumors in pediatric adolescent/young adult (AYA) patients. Despite improved outcomes due to advances in surgical local control and multi-agent chemotherapy prognosis for patients who develop recurrent metastatic or refractory disease remains poor. For these patients new therapeutic approaches are urgently needed. The team at Nationwide Children's Hospital (NCH) has developed a genetically modified feeder cell line that enables extensive ex vivo propagation of highly-active human NK cells from various sources and this methodology has been evaluated in early-phase clinical trials for hematologic malignancies and brain tumors. 2. Targeting neuroendocrine tumors with DLK1 directed immunotherapy led by Nitin Roper (CCR) and John Maris (CHOP). During the first year of the BtB award we have focused on Aim 1 of our proposal: defining the anti-tumor activity of ADCT-701 a novel antibody drug conjugate targeting DLK1 in neuroendocrine neoplams. In particular the goal of Aim 1 was to assess whether there is activity of ADCT-701 beyond neuroblastoma which has been the focus of Dr. Maris' laboratory our extramural collaborator. The results of our experiments in Year 1 demonstrate evidence of ADCT-701 anti-tumor activity in multiple ACC pre-clinical models. Thus based on these data ACC is an indication in our upcoming clinical trial: ""A First in Human Phase I Trial with ADCT-701 in Neuroendocrine Neoplasms"". The IND for ADCT-701 has been FDA approved and we expect to enroll patients in this clinical trial later this year. 3. B2B and Back: CD22 and CD19/22 CAR immunotherapies for childhood leukemia led by Naomi Taylor (CCR) and Crystal Mackall (Stanford). The Taylor and Mackall teams are carrying out clinical trials with identical CD22 and CD19/CD22-bivalent CAR vectors but the two sites are using different manufacturing procedures to generate the CAR-transduced T cells that are being infused into patients. The current proposal is to test the hypothesis that variability in CAR-T cell immunotherapeutic potential is affected by variations in manufacturing platforms and can be predicted through evaluation of antigen-dependent CAR-T cell activity. High throughput analyses of these parameters will be leveraged to optimize CAR manufacturing evaluate divergent patient outcomes and enhance durable responses in pediatric leukemia patients. 4. Alternative splicing of CD22 following Inotuzumab led by Nirali Shah (CCR) and Andrei Thomas-Tikhonenko (CHOP). Recent work from the Thomas-Tikhonenko lab has shown that CD22 protein expression is highly dependent on the inclusion of exon 2 which is where the open reading frame begins (Zheng et al. 2022). When exon 2 inclusion is negatively affected by aberrant splicing the number of transcripts capable of being translated is significantly decreased resulting in the emergence of CD22-low variants. To identify suitable experimental models for mechanistic studies we quantitated total expression and reads spanning different exon 1 junctions in a panel of lymphoid cell lines from the Cancer Cell Line Encyclopedia (Ghandi et al. 2019). We observed that widely used NALM6 and REH cell lines differ in the relative abundance of the exon 2-skipping/non-coding CD22 mRNA variants which were prominent in the former but not the latter. Using sgRNAs from the well-validated pooled Brunello library (Sanson et al. 2018) in NALM6 and REH cell lines we identified dozens of positive and negative regulators of CD22 expression that passed our stringent false discovery rate (FDR) cut-offs with the CD22 gene predictably being the most significant regulator of its own protein expression. Further up on the list are known B cell-specific transcription factors PAX5 and EBF1 but also several RNA-binding proteins with potential roles in splicing. We are currently in the process of cross-referencing them with top correlates of CD22 exon 2 inclusion in B-ALL samples from the NCI. However we are also prioritizing targets based on their known involvement in mRNA splicing as well as potential druggability." 124779 +No NIH Category available Adaptive Immune System;Adoptive Cell Transfers;Aftercare;Antigens;Biological Assay;Cancer cell line;Cell Proliferation;Cell Therapy;Cell physiology;Cells;Cytotoxic T-Lymphocytes;Exhibits;Flow Cytometry;Gene Expression;Gene Proteins;Genes;Genetic;Growth;HLA-A11;Human;Immune;Immune response;Immunohistochemistry;Implant;In Vitro;Infiltration;Injections;Interleukin-2;KRAS2 gene;KRASG12D;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Metabolism;Mitogen-Activated Protein Kinases;Modeling;Modification;Muromonab-CD3;Mus;Mutation;Oncogenic;Operative Surgical Procedures;PIK3CA gene;PIK3CG gene;PTEN gene;Pancreas;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Phosphoric Monoester Hydrolases;Production;Proliferating;Property;Proto-Oncogene Proteins c-akt;Role;Sampling;Signal Pathway;Signal Transduction;Stains;T cell differentiation;T cell therapy;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;Testing;Transcript;Translations;Tumor Suppressor Proteins;Vertebral column;Viral Vector;Western Blotting;anti-tumor immune response;cancer cell;clinically relevant;comparative efficacy;cytokine;gain of function mutation;genetic approach;immune cell infiltrate;in vivo;inhibitor;knock-down;loss of function mutation;neoplastic cell;pancreatic cancer cells;pharmacologic;pre-clinical;preclinical study;programmed cell death protein 1;protein transport;receptor;small hairpin RNA;small molecule inhibitor;subcutaneous;success;transport inhibitor;tumor;tumor growth;vector Retroviral genetic modification of PBLs to optimize expansion for cell therapy n/a NCI 10926524 1ZIABC012121-02 1 ZIA BC 12121 2 78858404 "KLEMEN, NICHOLAS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1179214 NCI Cytotoxic T cells respond to antigen by reprogramming their metabolism to support cellular proliferation differentiation and effector functions. These changes are induced by changes in gene expression induced by intracellular signaling pathways including the PI3K-AKT pathway and the MAP kinase (MAPK) pathway. These pathways are essential for T cell function but oncogenic alterations in cancers stimulate proliferation through these same networks. Gain of function mutations in PIK3CA or KRAS can drive gastrointestinal cancers; many tumors also exhibit loss of function mutations in PTEN a tumor suppressor and negative regulator of PI3K signaling. Preclinical studies have suggested that combining immune-based approaches with inhibitors of the PI3K or MAPK pathways can promote anti-tumor immune responses and inhibit tumor growth. Despite a substantial body of preclinical evidence supporting this approach there has been little discernible success at translation. Between these studies there are conflicting results and it is not clear whether the effects are specific to T cells cancer cells both or neither. In order to better understand how these shared pathways influence interactions between the adaptive immune system and cancer cells we propose to investigate phosphatases that regulate the PI3K and MAPK pathways in a clinically relevant adoptive cell transfer model. 1179214 +No NIH Category available Adult;Anatomy;Atlases;Biological Assay;Cell Lineage;Cell Ontogeny;Cell Transplantation;Cells;Clover;Coupling;Development;Embryo;Embryonic Development;Future;Gene Expression;Goals;Homeostasis;Human Resources;Individual;Mediating;Modeling;Molecular;Natural regeneration;Organism;Planarians;Platyhelminths;Pluripotent Stem Cells;Population;Postdoctoral Fellow;Process;Property;Regulation;Research Personnel;Source;Tissues;cell behavior;comparative;experimental study;in silico;innovation;irradiation;member;pluripotency;postnatal;programs;regenerative;single-cell RNA sequencing;stem cell fate specification;transcriptomics Adult pluripotent stem cell specification during planarian embryogenesis n/a NCI 10926523 1ZIABC012120-02 1 ZIA BC 12120 2 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 364075 NCI This project began as a team-driven effort led by NCI iCURE Postdoctoral Researcher Dr. Kayla Titialii-Torres with the assistance of postbaccalaurate researcher Clover Stubbert and bioinformaticist Laura Paez Baena. With the departure of these three team members I am now restructuring the project to accommodate a change in model species and personnel. Our working hypothesis is that cycling piwi-1+ cells in early embryos are the cellular antecedents of adult pluripotent stem cells (aPSCs). We posit that stage-dependent changes in gene expression correlate and are potentially causative in effecting the embryonic to adult pluripotency transition. We collected single cell RNA-Seq whole-embryo atlases for nine developmental stages encompassing this key cell fate transition and construction of the adult anatomy. In the future we will characterize the changing lineage repertoire for the piwi-1+ cells during embryogenesis and in performing trajectory analysis to generate testable hypothesis about key regulators of this process. In tandem we have been developing functional assays that will answer key questions about piwi-1+ cell behavior during embryogenesis including whether cells at different stages are clonogenic and multipotent and whether pluripotency is an individual or collective property of piwi-1+ cells at different stages. These studies will also shed light on the contribution and regulation of nascent aPSCs to the establishment of livelong whole-body regenerative abilities late in embryogenesis. 364075 +No NIH Category available Adult;Amputation;Anatomy;Area;Atlases;Biological Markers;Biological Models;Candidate Disease Gene;Cells;Embryonic Development;Female;Future;Genetic;Germ Cells;Gonadal structure;Homeostasis;Homologous Gene;Imaging Techniques;Morphogenesis;Natural regeneration;Organ;Outcome;Platyhelminths;Postembryonic;Process;Protocols documentation;Reaction;Regulation;Reproductive system;Resources;Signal Transduction;Source;Specific qualifier value;Starvation;Structure;Techniques;Time;Tissues;Transgenic Organisms;Visualization;cell type;falls;germline stem cells;gonad development;imaging modality;male;marine;nano;postnatal;programs;reproductive;screening;segregation;self assembly;self organization;sexual dimorphism;single-cell RNA sequencing;stem cell fate;stem cells;tissue fixing;transcriptomics Inductive germ cell specification and self-assembly of sexually dimorphic gonads n/a NCI 10926522 1ZIABC012119-02 1 ZIA BC 12119 2 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 242716 NCI Dr. Xintao Fan has made steady progress since the initiation of this project in Fall 2021 and has brought new techniques to bear in this emerging model system. He developed hybridization chain reaction protocols to visualize candidate aPSC and early germ cell biomarkers including nanos and vasa homologs. He has characterized both postnatal and de novo gonad formation following amputation or starvation using cell type-specific markers on fixed tissue. He has identified conditions critical to the capture of biologically impactful time points for single cell RNA-Seq transcriptomic analysis as part of a collaborative atlas-building project to identify cellular constituents of the reproductive system and candidate genes for future functional perturbation. A key area of focus in the upcoming fiscal year will be generating transgenic lines that allow us to visualize and track the dynamics of adult PSCs and the outcome of asymmetric divisions giving rise to germline stem cells. We will develop live imaging methods to observe gonad morphogenesis in different adult contexts and will begin functional screening of candidate genes implicated in the establishment of germline stem cell fate(s). 242716 +No NIH Category available Biochemical;Biological Markers;Cancer Patient;Collaborations;Data;Developmental Therapeutics Program;Disease Progression;Enrollment;FOLH1 gene;Goals;Image;Malignant neoplasm of prostate;Natural History;Patients;Pharmacodynamics;Population;Positron-Emission Tomography;Process;Protocols documentation;Recurrence;Research;Scanning;Toxic effect;men;molecular imaging;new technology;overtreatment Natural History of Biochemically Recurrent Prostate Cancer n/a NCI 10926521 1ZIABC012118-02 1 ZIA BC 12118 2 10687105 "MADAN, RAVI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 364304 NCI This protocol (000628) is a collaboration with the Molecular Imaging Branch and the Developmental Therapeutics Branch (Translational Pharmacodynamics Research Group). This protocol will enroll men with recurrent prostate cancer and track their imaging including CT Tc99 and PSMA PET imaging. We will also track PSA and evaluate biomarkers as well. This study is approved by the scientific review process and will hopefully open later in 2022. Even though PSMA PET imaging was approved in prostate caner in recent years there is no natural history data to accompany this new technology. This likely leads to over-treatment of patients. Data is needed to better understand who requires therapy in this population and who can be spared the toxicity of such therapies. 364304 +No NIH Category available AML/MDS;Acute Myelocytic Leukemia;Adoptive Cell Transfers;Adoptive Transfer;Amendment;Binding;Blood;Bone Marrow;Cells;Characteristics;Clinical Protocols;Collection;Development;Dysmyelopoietic Syndromes;Growth;Hematologic Neoplasms;Hematology;Immunotherapy;In Vitro;Laboratories;Malignant Neoplasms;Mutation;Myelogenous;Myeloproliferative disease;Natural History;Patient Transfer;Patients;Peptides;Peripheral Blood Mononuclear Cell;Postbaccalaureate;Prevalence;Process;Research;Research Project Grants;Sampling;Solid;T cell response;T-Cell Receptor;T-Lymphocyte;Testing;Training;Validation;Work;cancer immunotherapy;cohort;driver mutation;leukemia;neoantigens;next generation sequencing;personalized screening;translational goal;tumor Targeting cancer neoantigens in patients with myeloid malignancies n/a NCI 10926519 1ZIABC012116-02 1 ZIA BC 12116 2 78858397 "LEKO, VID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 570422 NCI General: 1. Established an independent laboratory in a new space (in which I moved in April 2023) 2. Hired and am training one post-baccalaureate fellow (since April 2023) Personalized screening: 1. Expanded T cells from three patients with MDS-precursor conditions and two patients with MDS/AML using patient-specific mutations. Expansion for another patient with leukemia is in progress. Currently optimizing conditions for growth and preparing for final testing. 2. Amended two clinical protocols (natural history studies for MDS and GVHD) to allow collection of additional samples for research. Isolation of TCRs recognizing common driver mutations and fusions: 1. Prepared and created an extensive list of candidate mutations/fusions that may serve as valuable immunotherapy targets. Generated lists of peptides representing these mutations that are predicted to bind to common class I HLA molecules. Peptide ordering initiated and will be completed before the end of the fiscal year. 2. Processed and banked PBMCs from several healthy donors with common class I HLA molecules; collection of additional samples in in progress. 3. Experimental work on isolating TCRs against these peptides will begin in August 2023. 570422 +No NIH Category available ASCL1 gene;Adenocarcinoma;Adrenal Glands;Androgen Receptor;Androgens;Animal Model;Biology;Bone Marrow;Bone Tissue;Bromodeoxyuridine;CDH1 gene;CDKN1A gene;Cardiac;Castration;Cell Lineage;Cell Survival;Cells;Clinical;Communication;Computer software;Cytokeratin-8 Staining Method;Development;Dimensions;Euthanasia;Goals;Heterogeneity;Histologic;Human;Image;Image Analysis;Incidence;Injections;Interferons;Investigation;Kidney;Liver;Malignant neoplasm of prostate;Marrow;Metastatic Neoplasm to the Bone;Metastatic Neoplasm to the Liver;Minority;Modeling;Mus;NF-kappa B;NR3C1 gene;Neoplasm Metastasis;Organoids;Osteoblasts;Osteoid;Osteolytic;Paralysed;Pathway Analysis;Pathway interactions;Patients;Phenotype;Physiology;Preclinical Testing;Primary Neoplasm;Proliferating;Proliferation Marker;RB1 gene;Receptor Signaling;Recovery;Resistance;Role;Sampling;Scanning;Signal Transduction;Stains;TP53 gene;Tissue-Specific Gene Expression;Tissues;Tumor Burden;Variant;Visualization;advanced prostate cancer;bioluminescence imaging;bone;clinical phenotype;deprivation;experience;gastrointestinal;in vivo;inhibitor;interest;metastatic process;molecular phenotype;neoplastic cell;novel therapeutic intervention;prostate cancer metastasis;quantitative imaging;receptor expression;single-cell RNA sequencing;soft tissue;spine bone structure;therapeutic evaluation;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor heterogeneity Biology of AR+ prostate cancer metastases and the role of the microenvironment n/a NCI 10926515 1ZIABC012111-02 1 ZIA BC 12111 2 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 556681 NCI LuCaP 136 model establishment and initial characterization: Following intracardiac injection of single cells bone metastasis can be visualized using bioluminescence imaging (BLI) by 3 weeks after inoculation and tumors grow exponentially with mice requiring euthanasia between 6-7 weeks. A large percentage of mice are paralyzed due to the outgrowth of metastasis in vertebrae. Metastasis also can be found in liver adrenal and kidney but the predominant burden is in bone. Castration results in a dramatic slowing in tumor burden accumulation and importantly a general shift to heterogeneous tumor phenotypes. Of particular interest we determined that soft tissue liver metastases are enriched for the NE phenotype compared to bone following castration (see below) and similar to human mPC. Tumor phenotypes: Serial sections of tissues containing metastasis were stained for eight markers including BrdU and pHH3 proliferation markers. One form of analysis co-registered sections using HALO quantitative image analysis software where 70 micron bins from the image scans were aggregated to analyze co-expression of markers. Bins containing multidimensional marker quantifications were subsequently clustered by similarity and projected in 2D space as UMAPs. There is a dramatic phenotypic shift and gain in heterogeneity from the intact to late castration tumors with relatively few marker positive cells at the early castration stage. Intact tumor cells lose AR and proliferation markers while small clusters of NR3C1(GR) positive cells are either maintained or newly gained. Late castration metastases diffusely express SOX2 as expected and in addition we discovered CDKN1A (p21) is frequently observed in SOX2+ metastases. Of interest ASCL1 and SYP are expressed predominantly in non-identical or non-adjacent cells within SOX2+ tumors and proliferation is more associated with the ASCL1 subpopulation suggesting SYP+ differentiation-associated quiescence. Molecular phenotypes: Molecular phenotyping of metastases are ongoing using bulk and single cell transcriptomic analyses. To gain sufficiently in-depth sequences for tumor cells we determined that depletion of mouse cells from tumor-bearing bone marrows is the optimal approach. We have analyzed intact and early and late castrated samples as well as orthotopic tumors via RNAseq. Because of the quality and depth of sequencing in bulk samples differential gene expression (DGE) in even small subpopulations are observable. DGE and pathway analysis revealed loss of AR signaling in castrated samples as expected. IFN and NFkB signaling was induced with castration and neuro as well as gastrointestinal pathways became prominent in late vs early castration demonstrating lineage plasticity. We have begun single cell (sc) RNAseq analyses in order to associate transcriptomic and pathway analyses with specific subpopulations of heterogeneous tumor cells. Of particular interest is the finding that the MYC pathway is overrepresented in most bone metastasis cellular phenotypic clusters as compared to matched adrenal clusters. Importantly MYC pathway enrichment has been demonstrated previously in human and mouse bone metastases relative to primary tumors In the second model of interest LuCaP23.1 have altered TP53 (TP53-/mut) and WNT (APC-/mut) pathways. LuCaP23.1 is a relatively slow growing model with bone metastasis detected two months after tumor cell inoculation in about 30% of mice. Tumor bearing mice can survive up to 6 months. Histologically osteoblastic bone metastases occur mainly in vertebrae with extensive osteoid matrix surrounding marrow spaces that contain tumor cells. ARPC LuCaP23.1 tumors (CK8+CDH1+) maintain strong AR expression in the bone microenvironment. Because clonally-derived osteoblastic metastases have not been investigated previously our initial goal is to determine the cross-communication between tumor cells and the osteoblast lineage cells in the bone marrow. LuCaP167 is a PDX-derived CRPC model that expresses AR-V7. Following cardiac injection the model localizes mainly to the bone to form both clonal-separated osteoblastic and osteolytic metastases. A minority of tumors form in the adrenal glands. This model shows no sensitivity to castration as anticipated. The model will serve as a good preclinical test for therapeutics directed to the AR-V7 variant. 556681 +No NIH Category available Acute;Brain;Cell division;Chromatin;DNA Methylation;Development;Disease;Epigenetic Process;Face;Genetic Transcription;Genome;Genomic approach;Goals;Impairment;Lead;Learning;Longevity;Malignant Neoplasms;Memory;Methyl-CpG-Binding Protein 2;Modification;Molecular;Mus;Mutation;Neurodevelopmental Disorder;Neurologic;Neurons;Organism;Proteins;Reader;Regulation;Research;Research Project Grants;Rett Syndrome;Role;Syndrome;cell type;experimental study;genome integrity;insight;nervous system disorder;postnatal Chromatin Regulation in Brain Development and Disease n/a NCI 10926514 1ZIABC012110-02 1 ZIA BC 12110 2 78858390 "BOXER, LISA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1287241 NCI In one research project we are using molecular and genomic approaches to understand the function of these neuron-specific forms of DNA methylation. We are investigating why these modifications accumulate in neurons what proteins associate with these modifications how these modifications regulate transcription and genome integrity and how mutations in regulators of DNA methylation lead to neurodevelopmental disorders and cancer. Another project is focused on a specific methyl-DNA-binding protein MeCP2 mutations in which cause the neurodevelopmental disorder Rett syndrome. To investigate the function of MeCP2 we have developed an approach to rapidly degrade the MeCP2 protein in the mouse brain. We are using this approach to distinguish the immediate molecular consequences of acute MeCP2 loss from the secondary consequences of neurological impairment. These experiments will lend insight into the primary function of MeCP2 and this approach can be broadly applied to other proteins implicated in neurological disease. 1287241 +No NIH Category available Address;Biomass;Brain;Collaborations;Data;Databases;Development;Dryness;Gene Cluster;Genome;Human;Human Genome;Human Microbiome;Hybrids;Malignant Neoplasms;Metagenomics;Methods;Natural Products;Play;Population;Protocols documentation;Resolution;Role;Running;Sampling;Time;United States National Institutes of Health;Variant;cost;detection method;experimental study;genome sequencing;improved;microorganism;molecular sequence database;nanopore;pan-genome;tool;treatment response;tumor;whole genome Population-scale long-read characterization of human genome and microbiome n/a NCI 10926513 1ZIABC012109-02 1 ZIA BC 12109 2 78858383 "KOLMOGOROV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 191819 NCI In Aim 3.1 as a part of the NIH CARD collaboration we are aiming to sequence 4000+ human brain genomes to study structural variation which will be the largest long-read based SV database to date. We have optimized nanopore sequencing protocol capable of producing 30x whole-genome sequencing from a single experiment. At the same time we are developing new assembly-based methods for detecting the variation at all scales that runs within a day for each sample. In Aim 3.2 we are developing long-read assembly methods for improving the resolution of the human microbiome. Microorganisms may play an important role in cancer development and treatment response; and their role may be understudied in part because of our incomplete understanding of the human microbiome diversity and function. Here we are developing a tool for strain-level metagenomic deconvolution using long reads which addresses the limitation of the current methods that fail to distinguish genomes of closely-related strains or species. Finally in Aim 3.3 we develop new hybrid long-read and short-read approaches as the vast majority of the current whole-genome sequencing databases contain Illumina data. We will first explore the pangenome approach to improve somatic SV calling using short reads. Then we aim to develop a hybrid long- and short-read approach for low biomass tumors when generating deep long-read whole-genome sequencing is impractical. cilitate discovery of known and new biosynthetic gene clusters that encode important natural products. 191819 +No NIH Category available Canis familiaris;Collaborations;Complex;Data;Detection;Diagnostic;Event;Evolution;Extramural Activities;Genomic Instability;Genomics;Goals;Human Papillomavirus;Karyotype;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Missouri;Modeling;Multiomic Data;Mus;Mutation;Pediatric Neoplasm;Prevalence;Prevalence Study;Process;Research Personnel;Role;Site;Variant;cancer genome;cancer genomics;cancer initiation;cancer type;chromothripsis;clinical application;insertion/deletion mutation;insight;melanoma;nanopore;osteosarcoma;tumor;tumor initiation;tumor progression Complex rearrangement detection in cancer genomes using long reads n/a NCI 10926512 1ZIABC012108-02 1 ZIA BC 12108 2 78858383 "KOLMOGOROV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 383639 NCI Structural variation is a key mutational process that contributes to cancer initiation and progression. In contrast to SNVs and small indels SVs vary greatly in size and complexity and are known to be difficult to profile using the current state-of-the-art short-read sequencing. Here we will apply the methods developed in sub-project 1 to study SV prevalence evolution and effects in several different tumor types. In Aim 2.1 in collaboration with Dr. Michael Dean (DCEG) we will study the prevalence and mechanisms of Breakage-Fusion-Bridge and chromothripsis events in cervical cancer. Our preliminary data suggests that in some cancers genomic instability is caused by HPV integrations which may also form ecDNA amplicons. In Aim 2.2 we study the revolve of structural variants in tumor evolution. In collaboration with Drs. Cenk Sahinalp and Chi-Ping Day (CCR) study mouse melanoma models in which multiple sublines propagate from the original tumor (multi-omics data for each sublime is available). Further in collaboration with Dr. Paul Meltzer (CCR) will apply multi-site nanopore sequencing of dog osteosarcoma to gain insights into complex karyotype changes associated with this type of cancer. In Aim 2.3 we collaborate with Dr. Midhat Farooqi (U Missouri) to explore clinical applications of long-read structural variant analysis. In particular we perform PacBio HiFi sequencing of various pediatric tumors with the goal to develop a long-read based genomic diagnostics workflow. 383639 +No NIH Category available Biogenesis;Biological;Biology;Biomedical Research;Categories;Cell surface;Cells;Classification;Communities;Development;Diagnostic;Disease;International;Knowledge;Language;Macromolecular Complexes;Methodology;Nomenclature;Ontology;Pathway interactions;Process;Research;Research Personnel;Societies;Structure;Terminology;Therapeutic;design;exosome;extracellular;extracellular vesicles;improved;liquid biopsy;metrology;molecular diagnostics;response;tool Classification and Ontology of Macromolecular Complexes in Liquid Biopsies n/a NCI 10926511 1ZIABC012107-02 1 ZIA BC 12107 2 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 86642 NCI "This is a continuing project started in 2021-2022 in response to ongoing requests from researchers across the biomedical research space to provide input on the design and interpretation of ""exosome"" studies pertaining to various diseases. Although the International Society for Extracellular Vesicles the largest society of EV and ""exosome"" researchers defines ""exosomes"" in terms of how these structures are produced by cells researchers studying EVs and ""exosomes"" in liquid biopsies generally have no tools with which to determine whether an extracellular vesicle in a biofluid arose from an intraluminal body and released (via a pathway for exosome biogenesis) or whether an extracellular vesicle was shed from the surface of the cell. Moreover several additional categories of extracellular macromolecular complexes such as exomeres and supermeres have been identified for which researchers encounter similar challenges of ontologic clarity. The first steps for this project will be to assess the state of the field and delineate potential next steps towards harmonized terminologies. This will be a large collaborative initiative encompassing the EV biology and Liquid Biopsy/Molecular Diagnostics communities and will engage with regulatory communities working with ""exosome"" metrology diagnostics and therapeutics." 86642 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;Apical;Area;B-Lymphocytes;Biology;Blood;Bone Marrow;Breast Cancer Cell;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCL13 gene;Cancer Model;Cancer Patient;Cells;Characteristics;Clinical;Clinical Trials;Collaborations;DNA Vaccines;Data;Dendritic Cells;Development;Disease;Disseminated Malignant Neoplasm;Dose;Effector Cell;Exclusion;FLT3 ligand;Family;Frequencies;Gene Expression;Gene Expression Profile;Goals;Growth Factor;HIV;HIV Infections;HIV therapy;Helper-Inducer T-Lymphocyte;Human;IL7 gene;ITGAM gene;Immune;Immune response;Immune system;Immunity;Immunologic Memory;Immunotherapeutic agent;Immunotherapy;Interferons;Interleukin-15;Intervention;Link;Location;Lymphocyte;Lymphocyte Activation;Lymphocyte Function;Lymphocytic Infiltrate;Lymphoid;Lymphoid Cell;Lymphopoiesis;Macaca;Macaca mulatta;Maintenance;Malignant Neoplasms;Mediating;Methods;Modeling;Mus;Myelogenous;Myeloid Cells;Natural Killer Cells;Neoplasm Metastasis;Pathway interactions;Phenotype;Plasma;Play;Population;Production;Proliferating;Property;Proteomics;Protocols documentation;Regimen;Regulation;Regulatory T-Lymphocyte;Reporting;Role;SIV;SIV Vaccines;Shapes;Site;Structure of germinal center of lymph node;T-Cell Proliferation;T-Lymphocyte;Technology;Testing;Therapeutic Agents;Treatment Protocols;Up-Regulation;Viral;Viral reservoir;Viremia;Virus;Work;adaptive immune response;adaptive immunity;anti-PD-1;arm;cancer immunotherapy;chemokine;clinical application;combinatorial;cytokine;cytotoxic;design;first-in-human;gene therapy;genetic signature;glycosylation;immunological intervention;immunoregulation;improved;inhibitor;interest;interleukin-21;lymph nodes;migration;monocyte;mouse model;orthotopic breast cancer;pre-clinical;prevent;recruit;response;simian human immunodeficiency virus;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor eradication;tumor microenvironment;vaccine strategy;viral RNA Examining IL-15 and IL-7 as an immunotherapy agent in cancer and AIDS n/a NCI 10926509 1ZIABC012105-02 1 ZIA BC 12105 2 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1121375 NCI Understanding of the cellular mechanisms controlling expression shed new light in the biology and regulation of IL-15 led to the identification of the bioactive heterodimeric form of IL-15 and provided methods for the efficient production and clinical application of this cytokine (Bergamaschi J. Biol. Chem. 283: 4189 2008; Bergamaschi Blood 120: e1-8 2012; Bergamaschi Cancers 13 2021). We have shown that hetIL-15 greatly increases lymphocyte infiltration in several tumors in mouse models and in macaques suggesting a general method to increase lymphocyte infiltration which is associated with anti-tumor activity. We have performed first-in-human clinical trials of hetIL-15 in metastatic cancers (Conlon JITC:e003388. 2021) and also in combination with anti-PD-1 check point inhibitor (NCT02452268; collaboration with Novartis). hetIL-15 is extensively studied in mouse tumor models where we demonstrated the rapid interaction of lymphoid and myeloid cell networks resulting in changes in numbers and migration of different cell populations. Extensive transcriptomics and proteomics analysis has revealed additional pathways affected by hetIL-15 (Bergamaschi J. Immunother. Cancer: 8:e000599 2020; Bergamaschi Cancers 13 2021). We have studied the effects of hetIL-15 in the number and properties of Dendritic Cells (DC) in tumors. DC participate in a network of cells that are induced during hetIL-15 treatment and in turn support more recruitment of effector cells in tumor sites. We showed that locoregional monotherapy with hetIL-15 in a triple-negative breast cancer (TNBC) orthotopic mouse model resulted in tumor eradication in 40% of treated mice reduction of metastasis and induction of immunological memory against breast cancer cells (Stellas Cell Reports 42:112501 2023). hetIL-15 reshaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes conventional type 1 dendritic cells (cDC1s) and a DC population expressing both CD103 and CD11b markers. These CD103intCD11b+DCs share phenotypic and gene expression characteristics with both cDC1s and cDC2s have transcriptomic profiles more similar to monocyte derived DCs (moDCs) and correlate with tumor regression. Therefore hetIL-15 a cytokine directly affecting lymphocytes and inducing cytotoxic cells has also an indirect rapid and significant effect on the recruitment of myeloid cells initiating a cascade for tumor elimination through innate and adoptive immune mechanisms. The intratumoral CD103intCD11b+DC population induced by hetIL-15 may be the target for the development of additional cancer immunotherapy approaches. Together our studies in mouse orthotopic models showed that DC populations correlate with tumor regression and reveal additional beneficial effects of hetIL-15 in inducing or enhancing long term protective immune response against tumors. In addition to cancer immunotherapy IL-15 has generated strong interest for clinical use to treat HIV infection especially in protocols targeting viral eradication or a functional cure. The use of IL-15 as an immune therapeutic agent against HIV infection is based on its effects as a growth factor and key regulator of cytotoxic responses mediated by both the innate (NK cells) and the adaptive (CTL) arms of the immune system. Importantly hetIL-15 treatment promotes the entrance of cytotoxic (GrzB+) CD8+ T cells in the B cell follicles areas within the LN where CTL are typically excluded and where SIV/HIV infected follicular helper CD4+ T cells reside. hetIL-15 treatment led to significant decrease in cell-associated viral RNA within the LN as well as in plasma viremia in SHIV infected macaques (Watson PLoS Pathog. 14: e1006902 2018). In a collaborative effort we further reported that a IL-15 transcriptional signature response to a viral RhCMV/SIV vaccine strongly correlated with protection (Barrenas PLoS Pathog 17:e1009278; 2021). We have expanded this concept and are testing the contribution of a combinatorial treatment including hetIL-15 in reducing reservoir in the SIV infected ART-treated macaques. We found that a combinatorial treatment including anti-PD-1 and NAb led to reduction of the viral reservoir. Detailed underlying mechanisms are being investigated and treatment regimens are being improved in on-going study. These pre-clinical data demonstrate that harnessing the immune system using different immunological interventions during ART-treatment can play a critical role the reduction of the reservoir and the control of viremia. We continue to work on optimizing this proof-of-concept study. IL-7 is another homeostatic cytokine like IL-15 belonging to the gamma-chain family. Like for IL-15 we employed a dose-escalation regimen in rhesus macaques to deliver human-cell produced glycosylated IL-7 a cytokine critical for development and maintenance of T lymphocytes (Pandit iScience 26: 105929 2023). We showed that IL-7 increased proliferation and survival of T cells and triggered several chemokines and cytokines. Induction of CXCL13 in lymph nodes (LN) led to a remarkable increase of B cells in LN proliferation of germinal center follicular T helper cells and elevated IL-21 levels indicting an increase in follicle activity. Transcriptomics analysis showed induction of IRF-7 and Flt3L which was linked to increased frequency of circulating plasmacytoid dendritic cells (pDC) on IL-7 treatment. These pDC expressed higher levels of CCR7 homed to LNs and were associated with upregulation of type-1 interferon gene signature and increased production of IFN-a2a on TLR stimulation. Superior effects and dose-sparing advantage was observed by the step-dose regimen. Taken together our results indicate that IL-7 therapy acts at different levels in the immune system involving both lymphoid and myeloid compartments. T cell immunity could be strengthened by promoting redistribution survival and proliferation of T cells whereas the influx of B cells and Tfh activation can result in improved humoral immune responses. The role of IL-7 at the interface of cell and humoral adaptive immunity can be exploited in vaccine strategies and in immunotherapeutic regimen. Because IL-7 functions at the apex of lymphopoiesis in the bone marrow and is crucial for lymph node development our findings demonstrate the importance of delineating the systemic effects of IL-7 beyond its direct targets which is part of on-going work. Together IL-7 treatment promoted proliferation of T cells and increase of B lymphocytes in LN together with activated Tfh cells and pDC producing type-1 interferon an immune landscape that is the potential to enhance cellular and humoral adaptive immune responses. 851991 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;Apical;Area;B-Lymphocytes;Biology;Blood;Bone Marrow;Breast Cancer Cell;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCL13 gene;Cancer Model;Cancer Patient;Cells;Characteristics;Clinical;Clinical Trials;Collaborations;DNA Vaccines;Data;Dendritic Cells;Development;Disease;Disseminated Malignant Neoplasm;Dose;Effector Cell;Exclusion;FLT3 ligand;Family;Frequencies;Gene Expression;Gene Expression Profile;Goals;Growth Factor;HIV;HIV Infections;HIV therapy;Helper-Inducer T-Lymphocyte;Human;IL7 gene;ITGAM gene;Immune;Immune response;Immune system;Immunity;Immunologic Memory;Immunotherapeutic agent;Immunotherapy;Interferons;Interleukin-15;Intervention;Link;Location;Lymphocyte;Lymphocyte Activation;Lymphocyte Function;Lymphocytic Infiltrate;Lymphoid;Lymphoid Cell;Lymphopoiesis;Macaca;Macaca mulatta;Maintenance;Malignant Neoplasms;Mediating;Methods;Modeling;Mus;Myelogenous;Myeloid Cells;Natural Killer Cells;Neoplasm Metastasis;Pathway interactions;Phenotype;Plasma;Play;Population;Production;Proliferating;Property;Proteomics;Protocols documentation;Regimen;Regulation;Regulatory T-Lymphocyte;Reporting;Role;SIV;SIV Vaccines;Shapes;Site;Structure of germinal center of lymph node;T-Cell Proliferation;T-Lymphocyte;Technology;Testing;Therapeutic Agents;Treatment Protocols;Up-Regulation;Viral;Viral reservoir;Viremia;Virus;Work;adaptive immune response;adaptive immunity;anti-PD-1;arm;cancer immunotherapy;chemokine;clinical application;combinatorial;cytokine;cytotoxic;design;first-in-human;gene therapy;genetic signature;glycosylation;immunological intervention;immunoregulation;improved;inhibitor;interest;interleukin-21;lymph nodes;migration;monocyte;mouse model;orthotopic breast cancer;pre-clinical;prevent;recruit;response;simian human immunodeficiency virus;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor eradication;tumor microenvironment;vaccine strategy;viral RNA Examining IL-15 and IL-7 as an immunotherapy agent in cancer and AIDS n/a NCI 10926509 1ZIABC012105-02 1 ZIA BC 12105 2 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1121375 OD Understanding of the cellular mechanisms controlling expression shed new light in the biology and regulation of IL-15 led to the identification of the bioactive heterodimeric form of IL-15 and provided methods for the efficient production and clinical application of this cytokine (Bergamaschi J. Biol. Chem. 283: 4189 2008; Bergamaschi Blood 120: e1-8 2012; Bergamaschi Cancers 13 2021). We have shown that hetIL-15 greatly increases lymphocyte infiltration in several tumors in mouse models and in macaques suggesting a general method to increase lymphocyte infiltration which is associated with anti-tumor activity. We have performed first-in-human clinical trials of hetIL-15 in metastatic cancers (Conlon JITC:e003388. 2021) and also in combination with anti-PD-1 check point inhibitor (NCT02452268; collaboration with Novartis). hetIL-15 is extensively studied in mouse tumor models where we demonstrated the rapid interaction of lymphoid and myeloid cell networks resulting in changes in numbers and migration of different cell populations. Extensive transcriptomics and proteomics analysis has revealed additional pathways affected by hetIL-15 (Bergamaschi J. Immunother. Cancer: 8:e000599 2020; Bergamaschi Cancers 13 2021). We have studied the effects of hetIL-15 in the number and properties of Dendritic Cells (DC) in tumors. DC participate in a network of cells that are induced during hetIL-15 treatment and in turn support more recruitment of effector cells in tumor sites. We showed that locoregional monotherapy with hetIL-15 in a triple-negative breast cancer (TNBC) orthotopic mouse model resulted in tumor eradication in 40% of treated mice reduction of metastasis and induction of immunological memory against breast cancer cells (Stellas Cell Reports 42:112501 2023). hetIL-15 reshaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes conventional type 1 dendritic cells (cDC1s) and a DC population expressing both CD103 and CD11b markers. These CD103intCD11b+DCs share phenotypic and gene expression characteristics with both cDC1s and cDC2s have transcriptomic profiles more similar to monocyte derived DCs (moDCs) and correlate with tumor regression. Therefore hetIL-15 a cytokine directly affecting lymphocytes and inducing cytotoxic cells has also an indirect rapid and significant effect on the recruitment of myeloid cells initiating a cascade for tumor elimination through innate and adoptive immune mechanisms. The intratumoral CD103intCD11b+DC population induced by hetIL-15 may be the target for the development of additional cancer immunotherapy approaches. Together our studies in mouse orthotopic models showed that DC populations correlate with tumor regression and reveal additional beneficial effects of hetIL-15 in inducing or enhancing long term protective immune response against tumors. In addition to cancer immunotherapy IL-15 has generated strong interest for clinical use to treat HIV infection especially in protocols targeting viral eradication or a functional cure. The use of IL-15 as an immune therapeutic agent against HIV infection is based on its effects as a growth factor and key regulator of cytotoxic responses mediated by both the innate (NK cells) and the adaptive (CTL) arms of the immune system. Importantly hetIL-15 treatment promotes the entrance of cytotoxic (GrzB+) CD8+ T cells in the B cell follicles areas within the LN where CTL are typically excluded and where SIV/HIV infected follicular helper CD4+ T cells reside. hetIL-15 treatment led to significant decrease in cell-associated viral RNA within the LN as well as in plasma viremia in SHIV infected macaques (Watson PLoS Pathog. 14: e1006902 2018). In a collaborative effort we further reported that a IL-15 transcriptional signature response to a viral RhCMV/SIV vaccine strongly correlated with protection (Barrenas PLoS Pathog 17:e1009278; 2021). We have expanded this concept and are testing the contribution of a combinatorial treatment including hetIL-15 in reducing reservoir in the SIV infected ART-treated macaques. We found that a combinatorial treatment including anti-PD-1 and NAb led to reduction of the viral reservoir. Detailed underlying mechanisms are being investigated and treatment regimens are being improved in on-going study. These pre-clinical data demonstrate that harnessing the immune system using different immunological interventions during ART-treatment can play a critical role the reduction of the reservoir and the control of viremia. We continue to work on optimizing this proof-of-concept study. IL-7 is another homeostatic cytokine like IL-15 belonging to the gamma-chain family. Like for IL-15 we employed a dose-escalation regimen in rhesus macaques to deliver human-cell produced glycosylated IL-7 a cytokine critical for development and maintenance of T lymphocytes (Pandit iScience 26: 105929 2023). We showed that IL-7 increased proliferation and survival of T cells and triggered several chemokines and cytokines. Induction of CXCL13 in lymph nodes (LN) led to a remarkable increase of B cells in LN proliferation of germinal center follicular T helper cells and elevated IL-21 levels indicting an increase in follicle activity. Transcriptomics analysis showed induction of IRF-7 and Flt3L which was linked to increased frequency of circulating plasmacytoid dendritic cells (pDC) on IL-7 treatment. These pDC expressed higher levels of CCR7 homed to LNs and were associated with upregulation of type-1 interferon gene signature and increased production of IFN-a2a on TLR stimulation. Superior effects and dose-sparing advantage was observed by the step-dose regimen. Taken together our results indicate that IL-7 therapy acts at different levels in the immune system involving both lymphoid and myeloid compartments. T cell immunity could be strengthened by promoting redistribution survival and proliferation of T cells whereas the influx of B cells and Tfh activation can result in improved humoral immune responses. The role of IL-7 at the interface of cell and humoral adaptive immunity can be exploited in vaccine strategies and in immunotherapeutic regimen. Because IL-7 functions at the apex of lymphopoiesis in the bone marrow and is crucial for lymph node development our findings demonstrate the importance of delineating the systemic effects of IL-7 beyond its direct targets which is part of on-going work. Together IL-7 treatment promoted proliferation of T cells and increase of B lymphocytes in LN together with activated Tfh cells and pDC producing type-1 interferon an immune landscape that is the potential to enhance cellular and humoral adaptive immune responses. 269384 +No NIH Category available Address;Algorithms;Aneuploidy;Basic Science;Biological;Cell Line;Childhood Leukemia;Clinical Research;Clonality;Collaborations;Communities;Complex;DNA Sequencing Facility;Data;Data Set;Detection;Event;Evolution;Extramural Activities;Genome;Genomics;Goals;Graph;Haplotypes;Head and Neck Cancer;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Minisatellite Repeats;Modeling;Normal Cell;Phase;Research Personnel;Role;Sampling;Series;Site;Statistical Models;Time;Variant;algorithm development;cancer genome;cancer type;chromothripsis;insertion/deletion mutation;markov model;melanoma;open source tool;osteosarcoma;tool;tumor;variant detection New methods for structural variation analysis of rearranged cancer genomes using n/a NCI 10926508 1ZIABC012104-02 1 ZIA BC 12104 2 78858383 "KOLMOGOROV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 383639 NCI Most of the current long-read analysis tools for genome assembly and variant detection were not designed for tumor genomes and fail to distinguish somatic variants and complex rearrangements in cancer genomes. In this sub-project we aim to develop new fundamental algorithms and tools for long-read analysis of tumor genomes that specifically address the issues of somatic variation calling clonality aneuploidy and complex rearrangements. We expect this project to result in multiple open source tools freely available to the basic and clinical research community. The algorithmic developments will be informed by the analysis of specific biological collaborations described in sub-project 2. Access to high-quality long-read tumor sequencing data is critical for new algorithmic developments. In Aim 1.1 we will collaborate with multiple intramural and extramural researchers and sequencing cores to generate various different sequencing datasets spanning different cancer and sample types. The current plans include sequencing of matching tumor/normal cell lines head and neck and cervical cancers osteosarcoma melanoma and pediatric leukemia tumors. In Aim 1.2 we will develop a new algorithm for detecting somatic rearrangements in matching tumor-normal long-read sequencing as well as multi-site and time series samples. We use a genomic graph approach to cluster breakpoints from complex events such as chromothripsis or breakage-fusion-bridge. Other algorithmic challenges include matching VNTR indels and detection of collapsed segmental duplications. Further in Aim 1.3 we will develop a method for reconstructing cancer kariotypes in presence of aneuploidy large copy number alterations (CNAs). Importantly the algorithm will reconstruct haplotype-specific coverage profiles taking advantage of the direct variant phasing using long reads. The implementation will rely on various unsupervised probabilistic models such as Hidden Markov Models (HMM) or Gaussian Mixture Models. 383639 +No NIH Category available Algorithm Design;Cancer cell line;Cell Line;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Databases;Direct Repeats;Exons;Genes;Genetic;Genetic Screening;Genomics;Guide RNA;Human Genome;Hybrids;Individual;Libraries;Maps;Modification;Property;Resources;Signal Transduction;Site;System;Testing;Time;Variant;Work;combinatorial;design;experimental study;fitness;genetic element;genome editing;genome-wide;improved;knockout gene;mouse genome;nuclease;online resource;paralogous gene;promoter;scaffold;screening;searchable database;tool Improving editing efficiency and guide design of CHyMErA screening platform n/a NCI 10926507 1ZIABC012102-02 1 ZIA BC 12102 2 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 315172 NCI We have cloned and established multiple cell lines for various Cas12a variants in the context of our CHyMErA screening Cas9/Cas12a screening platform. We have screened the different CHyMErA variants in multiple cell lines with a hgRNA library allowing us to compare editing efficiency as well as precision of the Cas12a variants in the context of our screening system. Our results revealed editing improvements with new Cas12a variants which were confirmed with focused experiments. Genome-scale screens have been performed with the enhanced screening platform to map fitness exons and genes across various cancer cell lines. In addition to optimizing Cas nucleases we have also performed guide optimization screens in order to improve both the Cas12a direct repeat scaffold as well as to improve our guide design algorithms allowing us to achieve higher genome editing efficiency and precision. This screening data is currently being analyzed. In parallel we have been collecting all possible Cas9 and Cas12a target sites in the human and mouse genome have scored guide sequences for on- and off-target properties and have uploaded guide sequences genomic features and scores to an online data base. Current work focuses on making those data bases searchable in a time-effective fashion. The online tool will eventually allow for facile and efficient design of individual or large-scale guide design for Cas9 and Cas12a nuclease for numerous genome editing applications. 315172 +No NIH Category available Ablation;Binding Sites;Biological Process;Biomedical Research;CRISPR screen;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Coupled;DNA cassette;Data;Disease;Engineering;Genes;Genetic;Genetic Screening;Genomics;Guide RNA;Hybrids;Link;Phenotype;Poly A;Polyadenylation;Process;Proteins;Protocols documentation;Reagent;Role;System;Technology;Therapeutic Intervention;Transcript;combinatorial;cost;cost effective;design;experimental study;expression vector;gene function;genetic element;genome-wide;genomic platform;improved;indexing;insight;loss of function;novel;prevent;response;screening;single cell analysis;single-cell RNA sequencing;therapeutic candidate;transcriptome;transcriptomics Establishing combinatorial screening platform coupled to single-cell analysis n/a NCI 10926506 1ZIABC012101-02 1 ZIA BC 12101 2 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 105058 NCI Hybrid guide RNA cassettes have been engineered to harbor capture sequences within Cas9 and Cas12a guide RNAs which make them amenable to capture using 10x Genomics protocols and reagents during single-cell analysis. Pilot experiments have been performed to assess capture efficiency of hgRNAs along with polyadenylated transcripts. Following those results we have further modified the hgRNA expression cassettes to improve the simultaneous capture of Cas9 and Cas12a guides while retaining efficient editing efficiency of our combinatorial system. The guide design has now been fully optimized and we are in the process of perform genetic screening with single-cell transcriptomic readouts thereby allowing us to gain mechanistic insights into the cellular rewiring in response to single or combined genetic perturbations. 105058 +No NIH Category available Bees;Cell Line;Cell surface;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNA Damage;Flow Cytometry;Gene Expression;Gene Targeting;Genes;Genetic Transcription;Individual;Malignant Neoplasms;Pathway interactions;Quantitative Reverse Transcriptase PCR;Repression;System;Testing;Tissues;Transcription Coactivator;Transcription Repressor;Variant;Western Blotting;cell type;combinatorial;expression vector;genome editing;knockout gene;nuclease;promoter;recruit;response;screening Combinatorial CRISPR transcriptional perturbation screening platform n/a NCI 10926505 1ZIABC012100-02 1 ZIA BC 12100 2 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 210114 NCI Transcriptional repressor domains have been cloned into lentiviral expression vectors carrying various CRISPR-Cas nucleases (Cas9 and Cas12a variants). HAP1 and RPE1 cells have been transduced with CRISPRi constructs (single and Cas9/Cas12a pairs) and nuclease expression has been verified by western blotting. Editing efficiency of individual CRISPRi effectors have been verified by assessing expression of cell surface markers by flow cytometry. Transcriptional activator domains are also beeing cloned into lentiviral expression vectors carrying various CRISPR-Cas nucleases (Cas9 and Cas12a variants) and will be tested in HAP1 cells by flow cytometry and qRT-PCR. After observing strong cell line editing and nuclease expression variation we are currently focusing on modifying the CRISPRa effectors to enhance nuclease expression and hence genome editing efficiency. 210114 +No NIH Category available CCR;Cell Line;Cells;Chromosome Mapping;Clustered Regularly Interspaced Short Palindromic Repeats;Dependence;Genes;Genetic;Genome;Goals;Libraries;Malignant Epithelial Cell;Metabolic;Metabolism;Patients;Regulation;Renal Cell Carcinoma;Somatic Mutation;Therapeutic;Translations;Validation;Western Blotting;combinatorial;fitness;functional genomics;genome-wide;insight;knockout gene;novel;nuclease;screening Genetic interaction screening in renal cell carcinoma n/a NCI 10926504 1ZIABC012099-02 1 ZIA BC 12099 2 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 420229 NCI We have obtained 6 patient-derived renal cell carcinoma (RCC) cell lines harboring somatic mutations in metabolic genes from the lab of Marston Linehan (UOB/CCR/NCI). We have transduced those RCC lines with CRISPR-Cas nucleases amenable to our CHyMErA combinatorial genome perturbation platform. Expression of Cas nucleases have been verified by western blotting and editing efficiency of the cell lines has been confirmed. Screens with genome-scale gene knockout libraries are currently in progress to identify fitness genes across the various environmental and genetic backgrounds. In a second project we have generated a metabolism-focused genetic interaction library and are currently performing a pilot screen with this library. 420229 +No NIH Category available 3' Untranslated Regions;Adaptor Signaling Protein;Adenocarcinoma;Affect;Alleles;Animals;Antineoplastic Agents;Apoptosis;BRAF gene;Benign;Binding Proteins;Binding Sites;Biogenesis;Cancer cell line;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complex;Cytoplasm;Cytostatics;DNA Damage;Dependence;Development;Disabled Persons;Disease;Docking;Elements;Endosomes;Exclusion;Exhibits;Exposure to;Future;Genes;Genetic Transcription;Genotype;Goals;Human;Individual;Inflammatory;Investigation;KRAS2 gene;KRASG12D;KSR gene;Laboratories;Lesion;Lung Neoplasms;MAPK3 gene;Malignant - descriptor;Malignant Neoplasms;Mediating;Messenger RNA;Modeling;Molecular and Cellular Biology;Mus;Mutate;Mutation;Neoplastic Cell Transformation;Normal Cell;Nuclear;Nuclear Translocation;Oncogenes;Oncogenic;Pathway interactions;Phenotype;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Population;Post-Translational Protein Processing;Probability;Proliferating;Protein Phosphorylation Inhibition;Proteins;RAS genes;RAS inhibition;RNA Decay;Regulation;Repression;Research;Ribosomal RNA;Ribosomes;Series;Signal Transduction;Site;Substrate Specificity;TOLLIP gene;TP53 gene;Testing;Transcript;Translating;Translational Activation;Translations;Tumor Burden;Tumor Cell Line;Tumor Tissue;Work;adenoma;cancer cell;cell transformation;experimental study;factor C;high resolution imaging;in vivo;insight;lung tumorigenesis;mRNA Decay;mutant;neoplastic cell;novel;novel anticancer drug;phosphoproteomics;prevent;ras Oncogene;recruit;refractory cancer;response;scaffold;senescence;small molecule;therapeutic DNA;therapeutic target;transcription factor;transcriptome;transcriptome sequencing;transmission process;tumor;tumor progression Control of Oncogenic Signaling Through Spatial Organization of Kinases and mRNAs n/a NCI 10926503 1ZIABC012098-02 1 ZIA BC 12098 2 8777578 "JOHNSON, PETER F" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1472076 NCI "Our research is organized into two inter-related subprojects. The first focuses on how 3'UTR sequences in mRNAs encoding substrates of oncogenic kinases such as ERK and CK2 regulate access of these proteins to their kinases in tumor cells. The 3'UTR mechanism involves subcellular mRNA localization which can either inhibit or stimulate phosphorylation of the encoded protein by controlling access to kinases. The kinases in turn display different localization in normal and transformed cells. The second subproject involves investigating how oncogenic kinases partition to the perinuclear cytoplasm in tumor cells to form perinuclear signaling centers or PSCs. PSCs serve as critical signaling engines that drive malignant transformation and cancer. 1. 3'UTR regulation of protein activity (UPA) and its underlying mechanisms. 3'UTR regulation of protein activity was discovered through our earlier observation that the CEBPB 3'UTR inhibits RAS-induced post-translational activation of the C/EBPb protein in tumor cells. Thus the 3'UTR uncouples C/EBPb from RAS signaling thereby constraining its pro-senescence activity. UPA also represses the ability of C/EBPb to activate transcription of pro-inflammatory senescence-associated secretory phenotype (SASP) genes. UPA requires a long G/U-rich element (GRE) motif in the 3'UTR and its cognate binding protein HuR/ELAV1. These components exclude CEBPB mRNAs from a perinuclear cytoplasmic compartment where ERK1/2 and CK2 are present on signaling endosomes embedded within the ER network. Hence newly translated C/EBPb is prevented from accessing its kinases. We later found that the RNA decay proteins UPF1 and Staufen (STAU1/2) are also essential UPA factors and are enriched within the perinuclear cytoplasm. Together with HuR these proteins promote perinuclear mRNA decay (PMD) of CEBPB transcripts. Depletion of UPF1 or STAU in tumor cells increased the nuclear-proximal population of CEBPB transcripts leading to C/EBPb phosphorylation on its CK2 site and senescence. High resolution imaging showed that the perinuclear CEBPB mRNAs frequently colocalize with CK2 foci. These observations suggest that when UPA is disabled C/EBPb undergoes phosphorylation by CK2 which is contingent on close proximity of CEBPB transcripts (and thus newly translated CEBPb) with activating kinases. We identified a STAU binding site (SBS) adjacent to the GRE which when deleted activates the pro-senescence functions of C/EBPb and phosphorylation by CK2 but not its ability to induce SASP genes. Furthermore deletion of the GRE alone also leads to C/EBPb-induced senescence but not phosphorylation by CK2. These and other observations imply that distinct 3'UTR sequences repress different C/EBPb functions likely by differential inhibition of PTMs. We propose that various mRNA decay factors (e.g. STAU) which recognize discrete 3'UTR sequences are tethered to different types of signaling endosomes; e.g. those carrying ERK CK2 or other kinases. Hence individual 3'UTR elements may promote mRNA decay in the vicinity of particular kinases and thereby inhibit protein phosphorylation on specific sites. Future work will expand upon this novel relationship between modular 3'UTR motifs localized mRNA decay and inhibition of specific PTMs on the encoded protein. To examine the in vivo relevance of UPA we generated mice with a deletion that removes the Cebpb GRE and part of the adjacent SBS. This mutant strain was tested in a Kras model of lung tumorigenesis. Although overall lung tumor burdens in deltaGRE mice were similar to WT animals regions of malignant adenocarcinoma were significantly reduced. Benign lesions such as adenomas were unaffected. These findings provide the first in vivo evidence that UPA constrains C/EBPb activity to facilitate tumor progression to carcinomatous lesions. We are currently performing senescent cell analysis and RNA-seq studies on tumors of different stages in the two genotypes to assess whether the delGRE mutation increases senescence and how this allele alters the C/EBPb transcriptome. A key goal of our work is to determine whether UPA is a general mechanism that regulates many proteins. We are using CRISPR-mediated deletion of 3'UTRs and 3'UTR swap strategies to identify other UPA-regulated genes. p53 is one such candidate. Its3'UTR suppresses the cytostatic activity of a p53 in RAS tumor cells without affecting p53 protein levels and excludes TP53 mRNAs from the kinase-rich perinuclear region inhibiting phosphorylation on its CK2 site Ser392. TP53 transcripts partition away from the nuclear-proximal region in tumor cells. However TP53 mRNAs undergo perinuclear translocation in exposed to chemotherapeutic DNA damaging agents that induce p53-dependent senescence or apoptosis coinciding with increased Ser392 phosphorylation. In summary our findings demonstrate that 3'UTR-dependent changes in mRNA localization control the activity of p53 C/EBPb and probably many other proteins. 2. Mechanisms and function of perinuclear signaling centers (PSCs) as key signaling engines in cancer cells. Oncogenic RAS induces perinuclear translocation of p-ERK and CK2 and the signaling scaffold KSR1. These proteins form signaling hubs on endosomes tethered to the ER network. These PSCs are critical to the 3'UTR (UPA) mechanism and are observed in all cancer cell lines and tumor tissues tested. PSCs are key signaling engines that drive cancer allowing oncogenic kinases to access targets that are important for neoplastic transformation. We found that the endosomal adaptor TOLLIP is required for perinuclear localization of RAB11A+ endosomes harboring CK2 and KSR1 but not ERK. ERK resides on a different class of signaling endosomes. TOLLIP is perinuclear in human cancer cells and KRasG12D-driven mouse tumors but is pan-cytoplasmic in non-transformed cells and thus coincides with the presence of PSCs. A conserved ""linker"" region in TOLLIP mediates interactions with KSR1 pseudo-kinase domain. This association recruits CK2 signaling complexes to endosomes. A series of phosphoproteomic experiments showed that perinuclear CK2 phosphorylates selective substrates including proteins involved in ribosome biogenesis and translation. One such target is the atypical kinase RIOK1 which regulates 18S rRNA processing and 40S subunit maturation. Mutant analysis suggests that phosphorylation on RIOK1 Ser22 by perinuclear CK2 is essential for RIOK1 function in tumor cells. KRasG12D-driven lung tumors in Tollip-/- mice progress less efficiently to the malignant adenocarcinoma stage. Furthermore tumor cell lines carrying mutant KRAS or NRAS but not HRAS or BRAF mutations require TOLLIP for proliferation/survival. TOLLIP is therefore a key signaling adaptor in K/NRAS tumor cells whose inhibition is a potential vulnerability of these aggressive treatment-resistant cancers. in collaboration with Dr. Nadya Tarasova (CIL) we are identifying small molecules that are projected to dock in TOLLIP pockets. One such candidate shows potent inhibition of proliferation/survival in KRAS mutant cancer cells. This and other compounds that that block PSC formation in tumor cells will be considered for further development as anti-cancer agents. As cancer cells driven by mutant HRAS BRAF and other oncogenes display reduced dependence on TOLLIP but nevertheless exhibit perinuclear CK2 we believe that an alternative adaptor protein(s) provides a redundant perinuclear tethering function in these cells. Furthermore ERK PSCs remain perinuclear in the absence of TOLLIP. Therefore our future research will include identifying and characterizing additional endosomal adaptors involved in PSC formation by ERK CK2 and other components of the RAS pathway." 1472076 +No NIH Category available Address;Algorithms;Area;Biological;Biological Markers;Blood;Clinical;Collaborations;Data;Data Collection;Data Set;Dose;Ecosystem;Failure;Future;Goals;Histology;Image;Infrastructure;Link;Location;Methodology;Methods;Modeling;Normal tissue morphology;Oncology;Outcome;Patient imaging;Patient-Focused Outcomes;Patients;Pilot Projects;Proteomics;Protocols documentation;Radiation Oncology;Radiation therapy;Radiometry;Resources;Site;Testing;Tumor Biology;Tumor Tissue;United States National Institutes of Health;Urine;Validation;Work;artificial intelligence algorithm;data cleaning;data framework;data harmonization;data-driven model;design;improved;improved outcome;prognostic;response;standard of care;tissue biomarkers;treatment optimization;tumor Advancing clinically meaningful AI algorithms to improve oncologic outcomes n/a NCI 10926502 1ZIABC012096-02 1 ZIA BC 12096 2 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 248771 NCI "The goals are to: 1) generate a ""toolkit"" of algorithms that directly link RT biology tumor response/failure to clinical areas of need to improve patient outcomes 2) define and create optimal methodology linking RT dose/volumes to AI to outcomes and 3) identify surrogates for response/failure as pertaining to radiation oncology ie. biomarkers. Current work involves building connections and collaboration with AI resources using existing data to pilot projects to generate a gap analysis and build data framework and create a functional query ready radiation oncology study platform in the NIH AI ecosystem to allow for streamlining of analysis. Algorithms are being developed at the clinical imaging and proteomic level for future aggregation. Future protocol will be aimed at validating promising algorithms." 248771 +No NIH Category available Aftercare;Artificial Intelligence;Biological Markers;Clinical Data;Data;Data Aggregation;Data Analyses;Data Collection;Dose;Genomics;Goals;Image;Infrastructure;Laboratories;Location;Maintenance;Methods;Oncology;Pathology;Patients;Pattern;Proteomics;Radiation;Radiation therapy;Resistance;Testing;Time;Tissues;Work;data cleaning;data framework;data harmonization;data streams;large scale data;response;usability Generating a multi-channel data framework for AI analysis in Radiation therapy n/a NCI 10926501 1ZIABC012095-02 1 ZIA BC 12095 2 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 248771 NCI Following exhaustive data gap analysis of location extent and usability of data streams several have now been successfully aggregated and work is ongoing in particular with respect to imaging and radiation therapy data which are particularly siloed. The current goal is to gather data in robust manner that allows for a queriable and scalable format and then to develop AI methods for the curation and cleaning of data to create buildable infrastructure for robust data collection and harmonization of oncology patients. 248771 +No NIH Category available Adjuvant;Agreement;Behavior;Biological;Biological Markers;Brain;Brain Neoplasms;Classification;Clinic;Clinical;Clinical Data;Data;Dose;Excision;Fractionation;Glioblastoma;Glioma;Image;Immunotherapy;Magnetic Resonance Imaging;Managed Care;Methodology;Neurologic;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Predictive Value;Proteins;Proteome;Proteomics;Protocols documentation;Radiation therapy;Recurrence;Signal Transduction;Staging;Steroids;Stratification;Systemic Therapy;The Cancer Genome Atlas;Time;Valproic Acid;biomarker discovery;clinical application;clinical predictors;follow-up;improved;improved outcome;large scale data;novel;predictive signature;prognostic;prognostic signature;prognostic value;response;standard of care;temozolomide;tumor Prognostic and predictive clinical and proteomic biomarker discovery in GBM n/a NCI 10926500 1ZIABC012094-02 1 ZIA BC 12094 2 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 248771 NCI The objectives are to define biological behaviors survival and response in glioma through clinical data features and proteome driven stratification in order to optimize radiation therapy management and patient outcomes. 1) Exploring differential biomarker expression post-radiation therapy in relationship to recurrence and survival and existing data on proteins associated with predictive and/or prognostic value; 2) Replicating and extending possible differential proteomic biomarker expression pre- vs post-radiation therapy across large scale data sets (TCGA CGGA); 3) Explore existing and novel statistical methodology in as pertaining to proteomic signals and merging these with clinical data. 248771 +No NIH Category available Adjuvant;Age;Agreement;Algorithms;Artificial Intelligence;Biological;Biological Assay;Biological Markers;Blood;Brain;Brain Neoplasms;Classification;Clinic;Clinical;Clinical Data;Data;Data Set;Diagnosis;Dose;Early treatment;Eligibility Determination;Enrollment;Excision;Fostering;Fractionation;Gender;Genomics;Glioblastoma;Glioma;Image;Immunotherapy;Institutional Review Boards;Ionizing radiation;Literature;Magnetic Resonance Imaging;Malignant Neoplasms;Managed Care;Metabolism;Methods;Neurologic;Operative Surgical Procedures;Outcome;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Predictive Value;Prognosis;Proteins;Proteomics;Protocols documentation;Radiation therapy;Recurrence;Resources;Serum;Steroids;Systemic Therapy;Technology;The Cancer Genome Atlas;The Cancer Imaging Archive;Time;Treatment Failure;Urine;Validation;Work;angiogenesis;aptamer;biomarker discovery;clinical application;clinical predictors;clinically relevant;follow-up;improved;irradiation;predictive signature;prognostic;prognostic signature;prognostic value;proteogenomics;proteomic signature;radiation resistance;radiation response;radiological imaging;response;standard of care;stemness;temozolomide;tumor Proteogenomic characterization and biomarker discovery in glioblastoma n/a NCI 10926499 1ZIABC012093-02 1 ZIA BC 12093 2 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 248771 NCI Methods: 82 pts diagnosed with pathology proven glioblastoma (2005-2013) were enrolled on IRB approved protocol 04-C-0020 and treated with concurrent chemoirradiation with blood and urine biospecimens obtained prior to and following completion of radiation therapy. Serum was then screened using the aptamer-based SOMAscan proteomic assay technology for changes in expression of 7000 protein analytes. Employing each patient as their own control biomarker expression was initially analysed using Graphpad and IPA to identify preliminary proteomic signatures representative of biological mechanisms involved in ionizing radiation and hallmarks of cancer including angiogenesis stemness and metabolism. These were then correlated using clinical data (pt age gender) tumor related factors (extent of resection) radiation therapy volumes (GTV PTV) outcomes (PFS OS). Further work will be aimed at: 1) Replicating and extending possible differential proteomic biomarker expression pre vs post radiation therapy. 2) Connecting large scale proteomic data to upstream pathways and genomic analysis to identify proteogenomic clusters defining radiation resistance and response and prognosis. 3) Validation with large scale public data sets (eg TCGA/TCIA and others). 4) Exploring differential biomarker expression prior to radiation therapy as compared to glioma subtypes described in the literature. 5) Exploring differential biomarker expression post radiation therapy in relationship to recurrence and survival and existing data on proteins associated with predictive and/or prognostic value. 6) Aggregating proteomic and proteogenomic results with AI driven progression criteria in glioma (currently subject of imaging analysis with Artificial Intelligence Resource (AIR)) and validation with large scale public data sets. 248771 +No NIH Category available Address;Adjuvant;Agreement;Algorithms;Artificial Intelligence;Brain;Brain Neoplasms;Classification;Clinic;Clinical;Data Set;Diagnosis;Ensure;Excision;Fostering;Glioblastoma;Glioma;Image;Immunotherapy;In complete remission;Institutional Review Boards;Magnetic Resonance Imaging;Managed Care;Maps;Methodology;Neurologic;Operative Surgical Procedures;Patient imaging;Patient-Focused Outcomes;Patients;Prediction of Response to Therapy;Protocols documentation;Radiation therapy;Resources;Secondary to;Selection for Treatments;Stable Disease;Steroids;Testing;Time;Toxic effect;Treatment Efficacy;Treatment Failure;United States National Institutes of Health;cohort;follow-up;improved outcome;neuro-oncology;novel;partial response;response;standard of care;temozolomide;treatment optimization;tumor progression Using artificial intelligence and MRI to address limitations in glioblastoma n/a NCI 10926498 1ZIABC012092-02 1 ZIA BC 12092 2 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 248771 NCI We hypothesize that MRI images of patients with glioma when subjected to change over time analysis (at diagnosis prior to and post radiation therapy) can identify features predictive of treatment failure helping guide patient management in the clinic. Successful algorithms can be validated using large scale publicly available data sets fostering the secondary advancement of currently lacking ground truth data sets for glioma progression. Our methodology will include MRI (Magnetic Resonance Imaging) of the brain using standard of care sequences generally carried out at most centers will initially be employed to ensure transferrable findings. However we would like to identify and test additional features including ADC and CBV maps that may enhance the predictive ability of algorithms to identify true progression vs. pseudoprogression acknowledging that these may not be consistently carried out outside of centers of excellence secondary to limitations in resources and expertise. The patient cohort initially employed consists of glioblastoma patients treated on IRB approved ROB protocols at NCI NIH for whom biospecimens for correlative omic analysis are available. 248771 +No NIH Category available Address;African American population;Bladder;Bladder Neoplasm;Cell Line;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Computer Analysis;DNA;DNA Sequence Alteration;Data;Deaminase;Disease Outcome;Disparity;Enzymes;Genes;Goals;In Vitro;Intrinsic factor;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Modeling;Molecular;Multiomic Data;Mus;Mutagenesis;Mutation;Natural Immunity;Neoadjuvant Therapy;Neoplasm Metastasis;Organoids;Outcome;Pathway interactions;Patients;Phenotype;Process;Prognosis;RNA;Role;Sequence Read Archive;Testing;The Cancer Genome Atlas;Therapeutic;Tumor Subtype;Untranslated RNA;Viral;Woman;cancer cell;cancer therapy;cell transformation;database of Genotypes and Phenotypes;epithelial to mesenchymal transition;genetic manipulation;improved;in vivo;mouse model;multiple omics;new therapeutic target;prevent;response biomarker;sensor;therapy resistant;tool;transcriptome sequencing;translational research program;tumor;tumor microenvironment;tumor-immune system interactions;tumorigenesis;whole genome Investigating mechanisms of bladder tumorigenesis and therapeutic resistance n/a NCI 10926497 1ZIABC012091-02 1 ZIA BC 12091 2 78858369 "BANDAY, ABDUL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1459602 NCI Our lab mines multi-omics data of bladder cancer available through The Cancer Genome Atlas Sequence Read Archive dbGAP etc. We are in the process of performing whole-genome and whole-transcriptome sequencing of bladder tumors - treatment-naive and neoadjuvant from diverse ancestries through collaborations. Through these studies we also aim to address disparities associated with prognosis and disease outcomes of bladder cancer in African Americans and women. We have begun functional testing of some specific hypotheses based on computational analysis of tumor -omics data. We are using cell lines and are planning to generate organoids mouse models and ex vivo tumor cultures for further explorations. Specially we are performing CRISPR-I screen to identify target genes of non-coding mutations found in bladder tumors and are establishing syngeneic mouse tumor models for exploring role of APOBECs and RNA sensors in modulating tumor micro-environment. Our ultimate goal is to identify new druggable targets and biomarkers for response and resistance to therapies and survival in patients with cancer. 1459602 +No NIH Category available 3-Dimensional;Address;Algorithms;Biological;Catalysis;Cells;Computer software;Cryoelectron Microscopy;Crystal Formation;Data;Development;Electron Beam;Electron Microscopy;Electrons;Growth;Heterogeneity;Image;Image Analysis;Individual;Investigation;Ligands;Liquid substance;Maps;Methodology;Methods;Microscope;Morphology;Performance;Population;Positioning Attribute;Property;Reaction;Research;Resolution;Rotation;Route;Sampling;Science;Series;Shapes;Structure;Substrate Interaction;Surface;Thermodynamics;Time;Time Series Analysis;Variant;automated segmentation;density;detector;expectation;experimental study;graphene;improved;insight;invention;nanocrystal;nanoparticle;nanoscale;particle;quantitative imaging;reconstruction Algorithms for atomic-resolution structure identification of nanocrystals n/a NCI 10926495 1ZIABC012088-02 1 ZIA BC 12088 2 78858365 "ELMLUND, HANS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 804049 NCI "Ensembles of synthesized ligand-protected nanocrystals each with a unique atomic structure can be imaged tumbling in solution using Graphene-Liquid Cell Electron Microscopy (GLC-EM). Projection images of differently rotated nanocrystals are acquired using a direct electron detector with high temporal ( 2.5 ms) resolution. The analysis of time-series data of nanocrystals imaged in solution to obtain 3D structural information is an emerging field of research with great potential for improving our understanding of the physiochemical properties of nanocrystals which thermodynamically deviate from the expectations derived from the bulk material. We previously developed a ""one-particle 3D reconstruction method"" based on imaging of individual Pt nanocrystals rotating in solution and the use of Single-Particle Analysis (SPA) to obtain an ensemble of 3D reconstructions (Science 2015 & 2020). However the standard SPA workflow cannot straightforwardly be applied to reconstruct atomic- resolution 3D density maps of the nanocrystals. A number of critical steps need to be addressed: (1) the individual nanocrystals need to be accurately tracked throughout the time-series and robust tracking algorithms have proven difficult to develop (2) the strong interfering background of the GLC needs to be subtracted (3) low-quality images that result from the nanocrystals moving vertically out of the narrow depth of focus of the aberration-corrected microscope need to be identified and rejected and (4) tailored strategies for 2D and 3D alignment and averaging that differ from those used in biological cryo-EM are needed." 804049 +No NIH Category available Algorithm Design;Cells;Cryo-electron tomography;Cryoelectron Microscopy;Data;Data Analyses;Data Collection;Data Set;Electron Microscopy;Feedback;Future;Goals;Image;Image Analysis;Intelligence;Liquid substance;Manuals;Methods;Microscope;Preparation;Procedures;Research Personnel;Robotics;Sampling;Stream;Time;Tissues;computational platform;computerized tools;computing resources;data acquisition;data quality;experimental study;image processing;image reconstruction;imaging modality;improved;instrument;movie;nanocrystal;particle;statistics;success Unsupervised image processing methods for cryoEM analysis in real time n/a NCI 10926494 1ZIABC012087-02 1 ZIA BC 12087 2 78858365 "ELMLUND, HANS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 804049 NCI Traditionally imaging experiments involve a linear workflow with sample preparation followed by data acquisition and analysis. In this workflow data acquisition is often conducted manually-a researcher sits at a microscope and decides which particle cell or tissue section to image. These procedures not only make imaging experiments incredibly time and labour intensive they also limit the volume of data that can be acquired and can create biased data sets. With the advent of robotics for sample preparation and completely automated microscopes it is now time to upscale imaging experiments to generate larger and better data sets through integration of analysis during data acquisition. 804049 +No NIH Category available Active Sites;Aspartate;Biochemical;Camptothecin;Cells;DNA;DNA Damage;DNA Repair;DNA biosynthesis;DNA replication fork;DNA-protein crosslink;Data;Development;Dimerization;Disease;Goals;Hydrophobic Interactions;In Vitro;Movement;Peptide Hydrolases;Pharmaceutical Preparations;Protease Domain;Proteins;Regulation;Roentgen Rays;Serine Protease;Structure;Therapeutic;Topoisomerase Inhibitors;Valine;anti-cancer therapeutic;cancer cell;crosslink;dimer;improved;inhibitor;monomer;mutant DNA Replication and Repair n/a NCI 10926493 1ZIABC012086-02 1 ZIA BC 12086 2 78858363 "MACHIDA, YUICHI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1485953 NCI In our previous study we have solved X-ray crystal structures of the FAM111A serine protease domain (SPD). Our biochemical and structural studies suggested that FAM111A SPD forms a homodimer through the alpha-1 helix at the N-terminus where two subunits are held together through hydrophobic interactions. Substitution of the valine residue on the dimerization interface with aspartate diminished dimer formation and protease activity of the SPD in vitro as well as the ability to protect replication forks from DPCs induced by a topoisomerase inhibitor camptothecin in cells. To understand how dimerization of the SPD promotes the protease activity we have solved X-ray crystal structures of an SPD mutant that lacks a part of the dimerization interface. Interestingly not only the dimerization interface but also the oxyanion hole an active site structure critical for protease activity is disordered in the monomeric mutants. These new data reveal a mechanism of the dimerization-dependent activity of the FAM111A SPD in which dimerization triggers a cascade of disorder-to-order transitions that leads to the stabilization of the oxyanion hole. These structural studies will help us determine potential mechanisms that regulate the protease activity of FAM111A at replication forks stalled at DPCs and facilitate the development of FAM111A inhibitors as a sensitizers of anti-cancer therapeutics including topoisomerase inhibitors. 1485953 +No NIH Category available Aftercare;Automobile Driving;Cells;Evolution;Goals;Immunologic Surveillance;Immunotherapy;Methods;Molecular;Monitor;Mucous Membrane;Patients;Play;Process;Role;T-Lymphocyte;Time;Treatment Failure;liver cancer patient;neoplastic cell;novel;patient prognosis;patient response;response;transcriptomics;treatment response;tumor;tumor heterogeneity;tumor microenvironment;tumorigenesis Tumor evolution in response to treatment n/a NCI 10926492 1ZIABC012083-02 1 ZIA BC 12083 2 78858358 "MA, LICHUN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 370354 NCI Tumor evolution is a dynamic process with continuous changes of tumor cells and the interactions with the tumor microenvironment. Based on single-cell transcriptomic profiles from liver cancer patients before and after treatment we developed a novel CASCADE method to monitor tumor evolution. We demonstrated that a tumor's evolutionary trajectory may change over time in response to immunotherapy. We suggest mucosal-associated invariant T (MAIT) cells may contribute to patient response to immunotherapy. 370354 +No NIH Category available Biological Assay;Cancer Intervention;Cells;Early Diagnosis;Failure;Goals;Heterogeneity;Malignant Neoplasms;Malignant neoplasm of liver;Methods;Nature;Neoplasm Metastasis;Outcome;Patient-Focused Outcomes;Patients;Secondary to;Solid;Technology;Therapeutic;cancer cell;cancer therapy;improved;novel strategies;single cell analysis;transcriptome;transcriptomics;tumor;tumor heterogeneity Tumor heterogeneity in liver cancer n/a NCI 10926491 1ZIABC012079-02 1 ZIA BC 12079 2 78858358 "MA, LICHUN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 370354 NCI Tumor heterogeneity is a key factor in therapeutic failures and lethal outcomes of solid malignancies. Uncovering the nature behind the phenomenon of heterogeneity is critical for developing effective cancer treatments. We demonstrated that vast transcriptomic heterogeneity occurs both intertumor and intratumor in liver cancer using single-cell analysis. We developed a method to determine transcriptomic clusters of malignant cells as functionally unique states within a tumor using single-cell transcriptomes and found that tumors with a higher number of functional states are associated with worse patient outcomes. 370354 +No NIH Category available Acute;Age;Allogenic;Anemia;Blood Platelets;Bone Marrow;Bone Marrow Cells;Bone marrow failure;Busulfan;Cessation of life;Characteristics;Classification;Clinical;Cutaneous;Cyclophosphamide;Development;Disease;Dose;Drug Kinetics;Dysmyelopoietic Syndromes;Dysplasia;Ear;Eligibility Determination;Engraftment;Enzymes;Erythroid Progenitor Cells;Fever;Genes;Genetic;Glucocorticoids;Hematologic Neoplasms;Hematology;Hematopoietic Stem Cell Transplantation;Infiltration;Inflammatory;Link;Lung;Marrow;Methionine;Morbidity - disease rate;Mosaicism;Musculoskeletal;Mutation;Myelogenous;Myeloproliferative disease;Names;Neutropenia;Nose;Participant;Patients;Plasma Cell Neoplasm;Polyarteritis Nodosa;Prednisone;Prophylactic treatment;Recurrence;Refractory;Regimen;Relapsing polychondritis;Research;Research Personnel;Secondary to;Sirolimus;Somatic Mutation;Steroids;Sweet's Syndrome;Syndrome;Temporal Arteritis;Testing;Thrombocytopenia;Time;Transfusion;Ubiquitin-Activating Enzymes;United States National Institutes of Health;Vacuole;Whole-Body Irradiation;autoinflammatory;clinical phenotype;conditioning;cytopenia;design;fludarabine;graft vs host disease;inflammatory marker;mortality;mycophenolate mofetil;novel;patient population;phase 2 study;post-transplant;skin lesion;systemic inflammatory response Hematopoietic Stem Cell Transplant for VEXAS n/a NCI 10926490 1ZIABC012075-02 1 ZIA BC 12075 2 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 271318 NCI "We opened a trial ""A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS Syndrome"" NCT05027945 in August 2021. Our research objectives are: To determine whether allogeneic hematopoietic stem cell transplantation (HSCT) results in sustained donor engraftment at day 100 and one-year post-HSCT. To determine whether allogeneic HSCT results in reversal of the clinical phenotype of VEXAS at one year and two years post-HSCT without requiring interval prednisone at greater than 0.5 mg/kg per day for reasons other than graft-versus-host disease (GVHD). Eligibility: Recipients ages 18-75 year-old with or without a somatic mutation in UBA1 who have: 1) the clinical phenotype for VEXAS with refractory cutaneous pulmonary musculoskeletal and/or other recurrent acute inflammatory manifestations and 2) require greater than 0.5 mg/kg per day of prednisone for inflammatory manifestations OR have cytopenia (transfusion dependent anemia transfusion dependent thrombocytopenia/platelets less than 75000 neutropenia less than 1000/uL) or myeloid neoplasm (by WHO criteria) or being intolerant or refractory to use steroids. Have an 8/8 or 7/8 HLA-matched related or unrelated donor or a haploidentical related donor. Design: For Recipients with 8/8 HLA Matched Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 40 mg/m2 IV once daily for four days on days -6 -5 -4 -3 and Busulfan IV for three days on days -6 -5 -and -4 followed by HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (3.2 mg/kg IV per day will be the default dose). For Recipients with 7/8 HLA Matched Donors or Haploidentical Related Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 30 mg/m2 IV once daily for five days on days -6 -5 -4 -3 and -2 cyclophosphamide 14.5 mg/kg for two days on days -6 and -5 200 cGy total body irradiation (TBI) on day -1 busulfan IV once daily for two days on days -4 and -3 and HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (3.2 mg/kg IV per day will be the default dose). For Post-Transplant GVHD Prophylaxis: Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4 along with mycophenolate mofetil from day +5 to approximately day +35 and sirolimus from day +5 to approximately day +180." 271318 +No NIH Category available Acute;Adrenal Cortex Hormones;Affect;Anxiety;Brain Neoplasms;Central Nervous System Neoplasms;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical Trials;Collection;Diagnosis;Distress;Electronics;Emotional;Environment;Equipment and supply inventories;Feeling;Health;Health Technology;Heart Rate;Home;Individual;Intervention;Learning;Measurement;Measures;Mental Depression;Mental disorders;Moods;National Comprehensive Cancer Network;Participant;Patient Recruitments;Patient Self-Report;Patient-Focused Outcomes;Patients;Personal Satisfaction;Persons;Phase;Population;Primary Brain Neoplasms;Questionnaires;Reporting;Sleep;Sleep disturbances;Surveys;Symptoms;Technology;Thermometers;affective disturbance;anxiety states;computer generated;death anxiety;depressive symptoms;diaries;emotional symptom;experience;falls;fitbit;improved;indexing;participant enrollment;physical symptom;preference;research clinical testing;sleep health;sleep quality;stress reduction;telehealth;tumor;tumor diagnosis;virtual assessment;virtual reality;virtual reality headset;virtual reality intervention;wearable device Implementation of telehealth and health technology to improve patient outcomes n/a NCI 10926488 1ZIABC012073-02 1 ZIA BC 12073 2 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 635228 NCI We have recently initiated three clinical trials using telehealth and health related technologies to improve patient experience for those with primary brain tumors (PBTs) or primary central nervous system tumors (PCNSTs): The first trial will use describe sleep disturbances and circadian disruption in people with PBT using Fitbits to learn more about sleep disruptions caused by tumors. Participants in this trial will receive a Fitbit which they will wear for one month to track sleep heart rate and activity they will keep a sleep diary for one week and complete 4 surveys with questions about the patient's quality of sleep their ability to fall asleep and stay asleep how the quality of their sleep affects their daily activities and their sleep hygiene and preferences. We will assess the feasibility of using smart wearable devices to measure the impact of oncologic therapy on sleep and circadian rhythms in the PBT population. We will also assess if reported quality of sleep collected with the PROMIS Sleep Indices are comparable between clinical evaluation and collection at-home if patient chronotype as measured by the Morningness-Eveningness Questionnaire (MEQ) are more pronounced in individuals with circadian disruption or sleep disturbances as measured by smart wearables or if circadian rhythm variables (Amplitude and Phase onset/offset) are dampened or phase shifted in patients with moderate to severe levels of sleep disturbances (as measured by the MDASI-BT score of =5). This trial has begun enrolling participants by invitation. The second trial will assess whether a type of therapy called CALM can help patients with PCNST manage distress symptoms and the emotional challenges experienced with a tumor diagnosis. Participants will fill out 7 electronic surveys asking about physical and emotional symptoms depression feelings about death and dying feelings about close relationships and general well-being. Participants will be assigned to a CALM therapist and will have 3 to 6 individual therapy sessions in 6 months. To assess the effects of the CALM intervention in reduction of depressive symptoms we will compare PROMIS-Depression scale results in PCNST participants from baseline to 6 months. We will also assess the effects of CALM intervention on death anxiety at both 3 and 6 months using the Death and Dying Distress Scale (DADDS) and the feasibility of implementing CALM remotely in a PCNST population. This trial has begun enrolling participants by invitation. The third trial will assess if virtual reality (VR) technology can help reduce stress and improve mood in people with PBTs. Participants will receive a VR headset by mail which they will use to view computer-generated environments and they will complete questionnaires at 4 timepoints during the study. At the end of the study we will assess the number of participants who completed the study the effects of a VR intervention on self-reported mood disturbance (as measured by PROMIS -Anxiety PROMIS -Depression Short Forms) and symptom burden and interference (as measured by the MD Anderson Symptom Inventory Brain Tumor [MDASI-BT]) if the effects VR has on distress and anxiety are more pronounced in those with high distress (based on DT cut-off score of greater than or equal to 5) compared those with to low distress (based on DT scores of 0 4) Measurement of Distress the effects of a VR intervention on self-reported acute and subacute distress (as measured by the NCCN Distress Thermometer [DT]) and anxiety (as measured by the State Anxiety Inventory [STAI-6]) in PBT patients and if the effects VR has on distress and anxiety are more pronounced in those individuals not on systemic corticosteroids (CS) compared to those who are not. This trial has begun recruiting participants. 635228 +No NIH Category available Adult;Agarose Chromatography;Age;Algorithms;Biological Assay;Cancer Patient;Cancer Personalized Profiling by Deep Sequencing;Caring;Catecholamines;Cells;Child;Citric Acid Cycle;Classification;Cluster Analysis;Collaborations;Collection;DNA;DNA Methylation;Data;Data Science;Data Set;Detection;Dioxygenases;Disease;Early Diagnosis;Enrollment;Enzyme Inhibition;Enzymes;Excision;Family;Freezing;Fumarates;Gastrointestinal Stromal Tumors;Gender;Genes;Genome;Glycolysis;Goals;High Pressure Liquid Chromatography;High-Risk Cancer;Hour;Hybrids;Hypermethylation;Kidney;Laboratories;Literature;Localized Disease;Magnetic Resonance Imaging;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Methods;Methylation;Modeling;Molecular;Mutation;Natural History;Paraganglioma;Patient Care;Patients;Pediatric Oncology;Pentosephosphate Pathway;Pheochromocytoma;Plasma;Predictive Value;Proteins;Protocols documentation;Publishing;Renal Cell Carcinoma;Reporting;Research;Sampling;Screening for cancer;Serum;Solid Neoplasm;Somatic Mutation;Succinate Dehydrogenase;Succinates;TP53 gene;Technology;Testing;Time;Training;Urine;alpha ketoglutarate;cancer type;cell free DNA;cohort;demethylation;detection limit;digital;genetic variant;indexing;inhibitor;metabolic profile;metabolomics;methylation pattern;model building;model development;mutant;objective response rate;participant enrollment;patient population;patient screening;peripheral blood;predictive signature;programmed cell death ligand 1;prospective test;rare cancer;rare variant;screening;screening guidelines;small molecule;tumor;tumor DNA;tumor behavior Early Detection of Cancer Patients with Germline SDH Deficiency n/a NCI 10926487 1ZIABC012072-02 1 ZIA BC 12072 2 14732189 "GLOD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 401005 NCI The initial training set will include 40 patients with SDH-deficient GIST 40 patients with SDH-deficient paraganglioma and 40 patients matched for gender and SDH subunit mutation enrolled on the Rare Tumor Natural History Study. Peripheral blood and urine samples will be collected at the second void of the day at three separate time points separated by at least one month for each patient to minimize the impact of normal variability in the metabolic profiling. All patients will continue to be followed using the current standard screening recommendations. Cell free DNA will be isolated from plasma. Urine cfDNA will be isolated using a Q-Sepharose chromatography protocol which has been shown in the literature to outperform other published and commercial urine cfDNA isolation methods for trans-renal cfDNA yield. PDL-1 methylation has been demonstrated to regulate PDL-1 expression and DNA methylation patterns have been shown to match or exceed TMBs predictive value for PDL-1 inhibition. When sufficient cfDNA is isolated PDL-1 methylation status will be assessed using previously published probes and digital PCR enhanced Methylight technology. This technology's minimal DNA input is 3ng with limits of detection approaching 0.03%. PDL-1 methylation status would be compared to objective response rates for predictive value as a stand-alone assay as well as when integrated with cfDNA derived TMB using a synergistic index. While the genome of SDH-deficient GIST typically contain very few somatic mutations other cancer-associated genes including p53 and RB have been observed particularly in patients with more aggressive tumor behavior. In addition to methylation analysis cfDNA variant allele detection and copy number alterations will also be assessed using a CAPP-seq approach. Previously validated and optimized probe sequences will be incorporated into a targeted hybrid capture NGS panel (cancer personalized profiling by deep sequencing (CAPP-Seq)). Using integrated digital error suppression CAPP-seq limit of detections for rare variants approaches 0.0025% (2.5 in 105 molecules). Metabolomic analysis will be performed in collaboration with the laboratory of Dr. Naomi Taylor through the Mass Spectrometry (Protein and Small Molecule) core at NCI at Frederick. Paired serum and urine samples will be collected and frozen within 2 hours of collection. Metabolic profiling of batched samples will be performed via HPLC-Mass spectrometry including quantitation of TCA cycle pentose phosphate shunt and glycolysis metabolites. AIM 2: Model building will be performed in collaboration with the NCI's Cancer Data Science Laboratory. The combination of DNA methylation and metabolomic data will provide a robust data set for model development using standard algorithms for unsupervised cluster analysis. If possible the model will be refined and simplified to use only better-discriminating features. AIM 3: A testing data set will be generated through ongoing enrollment of patients with germline SDH deficiency on the Rare Tumor Natural History Study. Metabolomic and cfDNA methylation data will be collected from newly enrolled patients with GIST PHEO/PGL and without evidence of cancer (20 in each group). The model will be tested and refined using this dataset. 401005 +No NIH Category available Biological Process;Cellular Membrane;Collaborations;Complex;Cryoelectron Microscopy;Genetic Transcription;Membrane;Molecular;Molecular Conformation;Nucleic Acid Folding;Proteins;RNA;RNA Folding;Signal Transduction;Structure;T-Cell Development;Technology;Translations;structural biology Structural biology collaborations n/a NCI 10926485 1ZIABC012070-02 1 ZIA BC 12070 2 78355629 "LEA, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 565383 NCI We are using the expertise and the state of the art cryoEM technology in the Center of Structural Biology to assist our intramural collaborators on a number of projects. Specific projects include: 1) trying better to understand how the complexes formed under the cellular membrane drive T-cell development; 2) how protein-RNA complexes regulate translation and transcription and 3) how folded RNAs regulate activity by shifting conformational space. We anticipate additional projects over the coming year. 565383 +No NIH Category available Anti-Bacterial Agents;Binding;Cells;Disease;Ensure;Goals;Health;Human;Huntington Disease;Infection;Malignant Neoplasms;Membrane Proteins;Pharmaceutical Preparations;Proteins;Publishing;Signal Transduction;Structure;Therapeutic Agents;Work;anti-cancer;design;improved;novel;protein folding;small molecule;structural biology;therapy design Eukaryotic Protein Maturation and Transport n/a NCI 10926484 1ZIABC012069-02 1 ZIA BC 12069 2 78355629 "LEA, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 848074 NCI Control of entry of molecules to the cell is fundamental to cellular health as is ensuring that proteins are correctly folded and incorporated in the right cellular compartment. We are using structural biology to dissect the membrane proteins that achieve these goals. This year we have published structures that now form the start point for larger studies of drug-bound forms that will enable redesign of therapies for both cancer and novel anti-bacterial agents. Additionally we have extended our work to delineate the structural basis for the association with disease of expansions of the HTT protein in Huntington's Disease. 848074 +No NIH Category available Abbreviations;Allogenic;American;American Society of Clinical Oncology;Antithymoglobulin;Award;Cell Therapy;Cells;Clinical Trials;Correlative Study;Disease;Distal;Engraftment;Enrollment;Equus caballus;Goals;Grant;HIV;Hematologic Neoplasms;Infection;Infection Control;Infection prevention;Institutional Review Boards;Kinetics;Malignant Neoplasms;Oral;Organ;Patients;Peripheral;Process;Prophylactic treatment;Publications;Radiation;Regimen;Research Personnel;Societies;Survivors;T-Cell Lymphoma;Toxic effect;Transplant Recipients;Writing;arm;conditioning;data submission;disorder control;efficacy evaluation;expectation;follow-up;graft vs host disease;hematopoietic cell transplantation;immune reconstitution;novel;novel strategies;participant enrollment;pharmacokinetics and pharmacodynamics;transplantation therapy Reduced toxicity allogeneic hematopoietic cell transplantation in malignancies n/a NCI 10926482 1ZIABC012065-02 1 ZIA BC 12065 2 78858344 "KANAKRY, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 884663 NCI In this fiscal year a study of reduced-intensity transplant for patients with peripheral T cell lymphoma has enrolled an arm of the study with 1 year of follow-up of survivors and is in the process of being written for publication. The study results have been presented in oral form at the American Society for Transplantation and Cell Therapy. The correlative studies of the project including the study of horse ATG pharmacokinetics and pharmacodynamics have begun with preliminary data submitted in a successful ASCO Young Investigator Award grant earned by Dr. Kamil Rechache. The peripheral T cell lymphoma study has expanded to enroll patients on a new arm to further study and optimize this novel reduced intensity approach. A new study for patients with hematologic malignancies requiring allogeneic hematopoietic cell transplantation and who are living with HIV has been written and is in the process of IRB review with the expectation of being open to enrollment by the end of the fiscal year. 884663 +No NIH Category available Address;Adult;Agreement;Algorithms;Anatomy;Animals;Atlases;Behavior;Bioinformatics;CCR;Cell Lineage;Cells;Data;Data Set;Development;Dissociation;Dyes;Embryonic Development;Female;Fluorescence-Activated Cell Sorting;Gene Expression;Genes;Genetic Transcription;Germ Cells;Heterogeneity;Homeostasis;In Situ Hybridization;Internships;Laboratories;Lead;Morphology;Natural regeneration;Nuclear;Oregon;Platyhelminths;Pluripotent Stem Cells;Postdoctoral Fellow;Postembryonic;Preparation;Protocols documentation;Regulation;Reporting;Reproductive system;Resources;Sampling;Scientist;Sexual Maturation;Specific qualifier value;Stains;System;Technology;Time;Tissue-Specific Gene Expression;Tissues;Treatment Protocols;Universities;Work;analysis pipeline;cell fate specification;cell type;comparative;differential expression;digital;germline stem cells;irradiation;male;marine;programs;regenerative;research facility;single-cell RNA sequencing;statistical service;transcriptome sequencing Anatomical and gene expression resource for Macrostomum lignano n/a NCI 10926476 1ZIABC012055-03 1 ZIA BC 12055 3 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 364075 NCI The Macrostomum lignano (Mlig) postembryonic anatomical atlas is a collaborative team effort. Dr. Matthew Voas has optimized cell dissociation vital nuclear dye staining and fluorescence activated cell sorting protocols required for sample preparation and he is producing pilot 10x scRNA-Seq data sets in conjunction with Dr. Sevilay Turan and Dr. Bao Tran's team at the CCR Sequencing Facility at the NCI-Frederick Advanced Technology Research Facility. Postdoctoral Scientist Dr. Xintao Fan has determined the developmental time points from hatchling to sexually mature adult that are most biologically impactful for sequencing and he determined the irradiation treatment regimen necessary for complete elimination of adult pluripotent stem cells and germ cells. University of Oregon Masters intern Laura Paez Baena developed a scRNA-Seq analysis pipeline tailored to Mlig expression data. Laura was the lead bioinformatic analyst for the project but her May 2023 departure means we are now working out new collaborative agreements with NCI Statistical Services staff for our analysis needs. Data sets have been acquired and we are moving on to analysis of our data. In We will work to create an interactive Shiny app that integrates digital and spatial gene expression data for differentially expressed genes defining anatomical entities captured in our analysis. 364075 +No NIH Category available ALVAC;Acute;Adjuvant;Affect;Affinity;Agonist;Animals;Antibiotics;Antibodies;Antigens;Avidity;Back;Binding;Blood Platelets;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Vaccines;Cell Aggregation;Cell Line;Cells;Citrobacter;Clinical Trials;Colitis;Collaborations;Colon;Cross Presentation;Cytoprotection;Cytotoxic T-Lymphocytes;DNA;Data;Dose;Endosomes;Epigenetic Process;Epitopes;Exclusion;Fertilization;Funding;Genes;Genetic Transcription;Glycocalyx;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Gut Mucosa;HIV;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;HIV/SIV vaccine;Helper-Inducer T-Lymphocyte;Histocompatibility;Home;Homing;Human;IL17 gene;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunization;Immunodominant Epitopes;Immunoglobulin A;Immunology;Immunotherapy;Infection;Interferon Type II;Interferons;Interleukin-12;Interleukin-15;Large Intestinal Mucosa;Large Intestine;Ligands;Macaca;Malignant Neoplasms;Memory;Modeling;Modification;Mucosal Immunity;Mucous Membrane;Mus;Myeloid-derived suppressor cells;Natural Immunity;OVA-8;Oral;PF4 Gene;PPBP gene;Patients;Phase;Plasma Cells;Plasmablast;Predisposition;Production;Proteins;Rectum;Regulation;Research;Risk;Role;SIV;SIV Vaccines;STAT1 gene;Safety;Site;Small Intestines;Stomach;Structure;Surface;T cell response;T-Cell Depletion;T-Lymphocyte;TLR3 gene;Testing;Textbooks;Time;Toll-like receptors;Training;Transforming Growth Factor beta;Transgenic Mice;Translating;Translations;Tretinoin;Vaccine Adjuvant;Vaccine Design;Vaccines;Vaccinia virus;Vagina;Viral;Viral Antigens;Viral Load result;Virus;Virus Diseases;Work;aluminum sulfate;anti-PD-L1;base;cancer immunotherapy;carboxypeptidase C;chemokine receptor;cytokine;design;gp160;gut microbiota;immune activation;imprint;improved;in vivo;interleukin-21;invention;knock-down;lymphoid structures;melanoma;microbicide;microbiome;monocyte;mucosal vaccine;nanoparticle;nanoparticle delivery;novel;novel strategies;prevent;receptor expression;rectal;response;simian human immunodeficiency virus;single-cell RNA sequencing;synergism;trafficking;transcriptome sequencing;transmission process;vaccine delivery;vaccine efficacy;vaccine immunogenicity;vaccine strategy;vaginal mucosa;viral detection;viral transmission Vaccine strategies for HIVAIDS n/a NCI 10926475 1ZIABC012054-03 1 ZIA BC 12054 3 6572144 "BERZOFSKY, JAY A" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1073604 NCI "The strategies above involve several steps that together comprise a push-pull approach to optimize antigen structure improve quantity and quality of the response and remove regulatory barriers. Blocking negative regulation in HIV and vaccine strategies: We carried out epitope enhancement (sequence modification to improve MHC binding) to increase MHC binding of epitopes from several viral antigens including HIV and showed these improved vaccine efficacy. We have pioneered the use of anti-TGFb as a novel checkpoint inhibitor given that TGFb is one of the most immunosuppressive cytokines known. We even showed preliminary evidence of efficacy and safety in a clinical trial in melanoma patients. We have also compared combinations of checkpoint inhibitors and anti-TGF-b in enhancing vaccine efficacy in mice and found preliminary data for synergy among anti-TGFb anti-LAG3 anti-TIGIT and anti-PDL1. These strategies are applicable to both HIV and cancer. Cytokines as vaccine adjuvants for HIV and induction of high avidity T cells: Our earlier work first showed that high avidity T cells were more effective at clearing viral infections. We found ways to induce them with cytokines and TLR ligands including expressing IL-15 in the vaccine and inclusion of costimulatory molecules in collaborations with Tom Waldmann and with Jeff Schlom respectively. The quality of response proved more important than the quantity. We recently found using a novel adjuvant CAF09 that we could lower the vaccine dose sufficiently to induce higher avidity CD4 T cells to better clear HIV-gp160-expressing virus infection in mice. We also found that IL-1b induces Th17 helper cells that do not help Tc1 CD8 T cells that protect against vaccinia virus expressing HIV gp160. Rather they skew the CD8 response to Tc17 cells that make IL-17 and do not protect. TGF-b blockade can prevent this problem as TGF-b is involved in Th17 induction. We are examining the epigenetic and transcriptional mechanisms behind high avidity T cells by carrying out a single-cell RNAseq study of high vs low avidity T cell lines generated against the same antigen. T cells from OT-I TCR-transgenic mice were grown with high or low concentrations of antigen to produce low or high avidity lines respectively with the identical TCR to exclude effects of intrinsic TCR affinity. These were stimulated with the same SIINFEKL peptide and subjected to RNAseq. Also T cells were generated against the same SIINFEKL peptide and subjected to concurrent TCR and RNAseq analysis and high and low avidity lines with the same clonotype were compared. Promising genes are being tested in knock-down studies. We also found that IL-21 synergizes with IFN-g to induce IFN-stimulated genes and clear Citrobacter colitis through an effect on STAT1. We also examined combinations of cytokines and TLR ligands as vaccine adjuvants and found greatest efficacy of IL-15 + TLR3 and TLR9 agonists but also some efficacy of IL-12 + GM-CSF. We are comparing these for qualitative differences in the immune response as well as quantity. Mucosal immunity microbiome and HIV/SIV vaccines: About 85% of HIV transmission is mucosal. We found that a mucosal T cell vaccine can impact the initial mucosal nidus of infection. We are studying induction and trafficking of T cells DCs and MDSCs among mucosal compartments to optimize mucosal vaccine efficacy. In mice we found that T cells could be directly primed in the vaginal mucosa despite lack of organized lymphoid structures contrary to textbook dogma. We also discovered that colonic DCs can imprint CD8 T cells to home back to the colon preferentially based on differential retinoic acid expression vs. small intestine DCs. We are currently examining the mechanism of this effect in terms of chemokine receptor expression and homing activity and by using an RNAseq comparison of clonal OT-1 T cells stimulated by DCs from the small vs large intestines. We discovered that altering a cathepsin S cleavage site could protect an immunodominant epitope of HIV gp120 from degradation in endosomes during cross-presentation providing proof of concept for a novel mechanism of virus escape for HIV that infects mostly non-APCs. Using NHP models we found that activated mucosal T cells determine susceptibility to SIV/HIV infection (transmission) eclipse time prior to systemic viral detection and acute viral load. We found that even in naive animals gut microbiota can strongly affect susceptibility to transmission by immune activation and also affect vaccine efficacy. We are exploring the mechanisms by testing the effect of antibiotics on multiple cell subsets in the large compared to the small intestine. Further we found that vaccines can induce MDSCs that counteract vaccine protection and also infection can affect trafficking of MDSCs. We also demonstrated for the first time that MDSCs could be infected by SHIV in vivo. As most HIV transmission is through mucosal surfaces and HIV homes to the gut mucosa we have designed and invented a nanoparticle vaccine delivered orally in mice but coated to pass through the stomach intact and to be released selectively in the large intestine where it induces CTL responses in the large intestine and vaginal mucosa and protects against rectal or vaginal challenge with a virus. We translated our oral nanoparticle (NP) approach to macaque SIV vaccines finding reduced risk against SHIV rectal acquisition in 2 studies. Surprisingly we discovered that protection against SIV acquisition in 3 studies can occur without anti-envelope antibodies. While T cell immunity was induced it did not correlate with protection and protection was not abrogated by CD8 T cell depletion. Rather protection correlated with trained innate immunity involving monocyte ""memory"" for SIV in induction of cytokines maintained by epigenetic changes. We have carried out RNAseq to determine what changes occur in monocytes after immunization leading to new mechanistic hypotheses including an unexpected role for platelets and their production of platelet factor 4 (PF4) also known as CXCL4. This is manifested by platelet-cell aggregates in which platelets actually coat cells. Also we are combining an SIV vaccine and mucosal NP boost to increase mucosal immunity with a microbicide to reduce the viral inoculum in an OAR-funded study. Our hypothesis is that priming and boosting with mucosally delivered nanoparticles containing V2 loop antigens will both increase mucosal immunity to protect against intrarectal SIV challenge and selectively expand immune responses against the V2 loop that have been shown to correlate with protection in the RV144 phase III human trial. Initial results show that priming and boosting orally with NPs containing a V2-loop pentamer can increase protection compared to the base vaccine alone consisting of SIV gag and env DNA ALVAC expressing gp120 and deltaV1 gp120 protein in alum. Immune correlates are under study including some evidence for mucosal IgA ADCC mucosal plasma cells and plasmablasts and T cell responses." 1073604 +No NIH Category available ABCB1 gene;ABCC1 gene;ABCG2 gene;ATP-Binding Cassette Transporters;Adult;Astrocytes;Biological Assay;Biological Models;Blood;Blood - brain barrier anatomy;Brain;Caring;Categories;Cells;Cerebrovascular system;Collaborations;Consumption;Data;Drug Delivery Systems;Drug or chemical Tissue Distribution;Drug resistance;Firefly Luciferases;Fishes;Generations;Glial Fibrillary Acidic Protein;Goals;Homologous Gene;Human;In Situ Hybridization;Kidney;Knockout Mice;Light;Liver;Luciferases;Malignant Neoplasms;Measures;Modeling;Monitor;Mus;National Center for Advancing Translational Sciences;Nature;Orthologous Gene;Penetration;Permeability;Play;Promega;Property;Reaction;Resistance;Role;Shrimp;Signal Transduction;Site;Spinal Cord;Study models;Substrate Specificity;System;Testing;Time;Transgenic Organisms;Variant;Water;Zebrafish;blood-brain barrier crossing;blood-brain barrier penetration;blood-brain barrier permeabilization;brain tissue;coelenterazine;cytotoxicity;deep ocean;high throughput analysis;high throughput screening;improved;inhibitor;luciferin;model organism;mouse model;nanoluciferase;novel;prevent;promoter Zebrafish model of blood-brain barrier to improve drug delivery to the brain n/a NCI 10926473 1ZIABC012052-03 1 ZIA BC 12052 3 9414470 "GOTTESMAN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 852096 NCI Not only are ABC transporters responsible for drug resistance in cancer but they are a major component of the blood-brain barrier (BBB) and blood-placental barrier. The three most prominent transporters at the blood-brain barrier are ABCB1 ABCC1 and ABCG2. We previously developed a murine model for analysis of ABCG2 expression at the blood-brain barrier based on the fact that luciferin is an ABCG2 substrate and its entry into the brain is prevented by transporter expression. In this model firefly luciferase is under the expression of the GFAP promoter leading to its expression in the astrocytes. When mice are injected with luciferin no light signal from the brain is detected due to ABCG2 preventing luciferin from crossing the blood-brain barrier. However when luciferin is coadministered with an ABCG2 inhibitor it can cross the blood-brain barrier and react with luciferase expressed in the astrocytes to produce light which can be quantitatively measured. Because studies of the BBB in mice are time-consuming and expensive we are developing homologous models in the zebrafish as components of the zebrafish BBB appear to be very similar to those of the mammalian BBB. We have developed and characterized a transgenic zebrafish line with NanoLuciferase derived by Promega from a deep sea shrimp under the control of the GFAP promoter. In this model NanoLuc is expressed in the developing zebrafish brain and spinal cord. Coelenterazine is one of the substrates for NanoLuc and is transported by both ABCB1 and ABCG2. Furimazine a coelenterazine derivative with very high yield of light is an ABCG2 substrate. Thus this model can be used to study the role of transporters at the blood-brain barrier but could also be used to screen compounds that might increase permeability of the barrier irregardless of the mechanism. We have shown that addition of a substrate such as furimazine and an Abcg2 inhibitor to the water containing larval zebrafish result in light generation consistent with penetration of furimazine across the BBB. If zebrafish are to be considered an appropriate model for study of transporters at the blood-brain barrier the zebrafish homologs of human transporters must be carefully characterized. Zebrafish do not have a direct homolog of human ABCB1 but instead have 2 similar variants-Abcb4 and Abcb5. Expression of these transporters in heterologous systems has enabled their detailed characterization and inhibition properties. In collaboration with Matthew Hall at NCATS we have found that zebrafish Abcb4 is nearly identical to human ABCB1 in conferring resistance to 90 known ABCB1 substrates. Abcb5 is also a functional transporter and confers resistance to many ABCB1 substrates but has a slightly narrower substrate specificity. While zebrafish Abcb4 is the only homolog that localizes to the BBB Abcb4 and Abcb5 are expressed at other barrier and excretory sites in zebrafish such as the gut liver and kidneys. Zebrafish also have 4 homologs of human ABCG2-Abcg2a Abcg2b Abcg2c and Abcg2d. We have functionally categorized these zebrafish ABCG2 orthologs and determined the brain tissue distribution of zebrafish ABCG2 homologs. To determine substrates of the transporters we stably expressed each in HEK-293 cells and performed cytotoxicity and fluorescent efflux assays with known ABCG2 substrates. We found Abcg2a had the greatest substrate overlap with ABCG2 and Abcg2d appeared to be the least functionally similar. Using RNAscope in situ hybridization we identified abcg2a as the only homolog expressed at the adult and larval zebrafish BBB based on its localization to claudin-5 positive brain vasculature. These results demonstrate the conserved function of zebrafish Abcg2a and suggest that zebrafish may be an appropriate model organism for the studying the role of ABCG2 at the BBB. Having identified zebrafish Abcb4 and Abcg2a as the homologous transporters at the zebrafish BBB we characterized the ability of NanoLuc substrates to be transported by zebrafish and human transporters at the BBB. We examined several coelenterazine derivatives as well as some furimazine derivatives and found that furimazine was the brightest NanoLuc substrate tested and was transported by human ABCG2 and zebrafish Abcg2a. Coelenterazine h was the brightest coelenterazine derivative and was also transported by human ABCG2 and zebrafish Abcg2a. Thus these compounds could be used to study the role of ABCG2 at the BBB. We also received more furimazine derivatives from Promega Corporation that were not found to penetrate the BBB in their studies in hopes of finding other NanoLuc substrates that might be transported by Abcb4 or Abcg2a in the zebrafish. 852096 +No NIH Category available ABL1 gene;AML/MDS;Acute Lymphocytic Leukemia;Address;Alleles;Antigen Targeting;Antigen-Presenting Cells;Antigens;B lymphoid malignancy;Biological Assay;Brachyury protein;CD22 gene;CD8B1 gene;Categories;Cell Line;Cells;Chordoma;Clinic;Collaborations;Data;Databases;Disease;Dose;Engineering;Epitopes;Evaluation;Frequencies;Fusion Oncogene Proteins;Goals;HLA-A gene;HLA-A2 Antigen;HLA-B Antigens;HLA-C Antigens;Hematologic Neoplasms;Hematological Disease;Human;Immunology;Immunotherapeutic agent;In Vitro;Inflammatory;International;Legal patent;Love;Lymphoma;MS4A1 gene;Mass Spectrum Analysis;Mature B-Lymphocyte;Mediating;Methods;Modeling;Molecular Abnormality;Mus;Mutation;Myeloproliferative disease;National Institute of Child Health and Human Development;Normal tissue morphology;Oncogenic Viruses;Pathway interactions;Patients;Peptide/MHC Complex;Peptides;Peripheral Blood Mononuclear Cell;Population;Pre-Clinical Model;Process;Proteins;Publishing;Rare Diseases;Receptor Signaling;Recurrence;Research;Safety;Science;Somatic Mutation;T cell therapy;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Translating;United States National Institutes of Health;Virus;Xenograft Model;cancer cell;chimeric antigen receptor T cells;clinical translation;clinically relevant;cross reactivity;cytokine;cytokine release syndrome;cytotoxicity;early phase clinical trial;engineered T cells;expression vector;improved;interest;leukemia;leukemia/lymphoma;manufacture;neoantigens;novel;pre-clinical;preclinical development;preclinical safety;programs;prospective;receptor expression;screening;technology development;therapy development;vector TCR engineered T cell therapies for hematologic malignancies n/a NCI 10926470 1ZIABC012045-03 1 ZIA BC 12045 3 78355631 "ISHII, KAZUSA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 628503 NCI Activity 1: TCR class I and II epitope discovery for myeloid malignancies (AML/MDS/MPN): The objective of this activity is to discover epitopes that can be targeted with T cell receptors. The project is pursued in collaboration with Dr. Josh Elias (Stanford/Chan Zuckerberg Biohub). Recurrent somatic mutations or chromosomal breakpoints shared across patients with frequencies of at least 2% in a given disease category were curated using the publicly accessible COSMIC database. A total of 47 such genetic abnormalities were chosen and expression vectors for tandem minigenes (as described by Tran E et al. Science 2014) encoding these genetic abnormalities were manufactured. Then a panel of artificial antigen presenting cells expressing tandem minigene with one or two HLA class I or II alleles were engineered. A total of sixty cell lines were established which cover 12 most frequent HLA class I and II alleles in the US population. These artificial cell lines were lysed peptide-MHCs were pulled down and the lysates are currently being analyzed by mass spectrometry by Dr. Elias' team. The initial assay identified multiple new epitopes derive from PRAME restricted by HLA-A*02:01 HLA-B*08:01 HLA-C*07:02 HLA-B*07:02 an BCR-ABL1 fusion onco-protein-derived epitope restricted by HLA-B*08:01 and several TMG-encoded neoantigen-derived epitopes. Top candidate epitopes identified in this project will be used for TCR discovery using reverse immunology approaches. ------Activity 2: Pre-clinical development of HLA-A*02:01-restricted CD22TCR: We have discovered T cell receptor that recognizes HLA-A*02:01-restricted epitope of CD22 which is an antigen expressed broadly by mature B-cell malignancies and a portion of acute lymphoblastic leukemia. The CD22TCR demonstrates promising pre-clinical anti-leukemia/lymphoma activity against multiple cell lines in both CD22- and HLA-A2-restricted manner. Furthermore the CD22TCR does not demonstrate severe cross-reactivity that would cause off-target toxicities on normal tissues. The CD22 TCR is patented (International Patent Application No. PCT/US2022/016561 filed February 16 2022). Extensive pre-clinical safety evaluation was completed which confirmed that the CD22 TCR-T cells do not cross-react with peptides derived from other human proteins. In NSG xenograft models CD22 TCR-T cells mediated anti-leukemia/lymphoma cytotoxicity at clinically relevant cell doses. Leukemia clearance by CD22 TCR-T cells was not associated with systemic cytokine elevation. In contrast CD22 CAR-T was not able to control leukemia at its clinically relevant dose. The CD22 CAR-T cells at higher cell dose (500-fold higher than the dose feasible/safe in humans) cleared leukemia but the treatment was associated with systemic proinflammatory cytokine elevation reminiscent of cytokine release syndrome. These data support that the CD22 TCR-T cells is an active and potentially safer alternative cell-based treatment for B-cell malignancies and the data warrant clinical translation of the TCR. Through the NCI DCTD NExT Program we are currently in the process of GMP-grade vector manufacturing which will be used in the early-phase clinical trial of the CD22 TCR-T cells. ------Activity 3: Establishment of TCR cross-reactivity screening strategy: Using a panel of murine TCRs recognizing HLA-A*02:01-restricted epitope of CD20 we established a method of prospectively identifying the cross-reactivity that could cause prohibitive toxicities if translated into clinic. The method was patented (Patent Application No. 63/481757 filed January 26 2023) and published (Ishii K et al. Science Advances. 2023 In Press). ------Activity 4: Discovery of TCRs against HLA class I-restricted epitopes of brachyury and PRAME: Using in vitro stimulation of human PBMCs we have isolated multiple TCRs against HLA class I-restricted epitopes of brachyury and PRAME. We are currently vetting the antigens and these TCRs for further clinical translation. ------Activity 5: Development of technologies to safely enhance the potency of TCR-T cell therapies: In this activity we are evaluating various methods of improving the therapeutic potency of TCR-engineered T-cell therapies developed in activity #2 and #4. Methods being developed and evaluated include 1) Augmentation of CD8 co-receptor expression and modulation of CD8 intracellular sequences and 2) modulation of CD22 TCR signaling by introducing CD3z mutation (collaboration with Dr. Paul Love NICHD NIH). 628503 +No NIH Category available Antibiotics;Bacteria;Bacteriophages;Cryoelectron Microscopy;Disease;Environment;Future;Goals;Health;Human;Infection;Medical;Methods;Molecular;Multiprotein Complexes;Pathogenesis;Pathway interactions;Protein Secretion;Proteins;Research;Resistance;System;Work;X-Ray Crystallography;cell motility;genetic information;human pathogen;novel;pathogen;structural biology;uptake Structural biology of host-pathogen interactions n/a NCI 10926469 1ZIABC012043-03 1 ZIA BC 12043 3 78355629 "LEA, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1413457 NCI We are studying Bacterial systems required for pathogenesis chiefly secretion and motility systems. These two functions are often achieved via a single large apparatus such as in the bacterial flagellar system which is also a protein secretion system. We are using structural biology and functional studies to dissect systems relevant for infection by a variety of human pathogens. Another range of systems we are starting to investigate include protein assemblies associated with uptake of genetic information from the environment and resistance to phages 1413457 +No NIH Category available Acinar Cell Carcinoma;Affect;Area;CCR;Clinical;Clinical Research;Clinical Trials;Collaborations;Correlative Study;Disease model;Engineering;Exocrine pancreas;Extramural Activities;Goals;Histologic;Histology;Immune;Intervention;Malignant neoplasm of pancreas;Molecular;Molecular Profiling;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Exocrine Neoplasm;Pancreatic carcinoma;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Reporting;Research;Sampling;Site;Testing;Therapeutic;Variant;Work;cancer diagnosis;improved outcome;inhibitor;overexpression;phase II trial;prospective;rare cancer;small molecule;tumor Rare Exocrine Tumors of the Pancreas n/a NCI 10926467 1ZIABC012041-03 1 ZIA BC 12041 3 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 350012 NCI GOAL#1) Improving outcomes for patients with adenosquamous carcinoma of the pancreas (ASCP). ASCP is a highly aggressive variant of PDAC that consists of at least 30% squamous component on a background of typical glandular PDAC component. Recent work by extramural collaborators (Von Hoff & Han) demonstrated that myc overexpression drives ASCP and that the small molecule drug Minnelide (Minneamrita Therapeutics LLC) is a superenhancer inhibitor that suppresses myc expression in ASCP. Based on these results we have initiated a Phase 2 single-site CCR-sponsored study to test the anti-tumor activity of Minnelide in patients with advanced previously treated ASCP (PI Alewine). Correlative studies examining drug bioactivity affect on immune components and ASCP molecular fingerprint will be performed by collaborators with expertise in these areas. Accrual is in progress. GOAL#2) Improving outcomes for patients with pancreatic acinar cell carcinoma (PACC). PACC is an ultra-rare tumor type that is histologically and genetically distinct from PDAC. Aim 1: Develop pre-clinical models of PACC. We have initiated a collaboration with CAPR Frederick (S. Kozlov) to engineer a PACC GEMM. Aim 2: Identify new treatments for PACC. We have initiated a Phase 2 trial to test olaparib in patients with PACC based on research by us and others suggesting that PACC is an ID3 deficient tumor and that deficiency of ID3 leads to PARP inhibitor sensitivity. 350012 +No NIH Category available Antibodies;Antibody Response;Cells;Cloning;Goals;Human;Knowledge;Laboratories;Patients;Research;SARS coronavirus;SARS-CoV-2 B.1.1.529;SARS-CoV-2 infection history;SARS-CoV-2 variant;Sarbecovirus;Serum;Somatic Mutation;Techniques;Therapeutic;Vaccines;Virus;cross reactivity;design;improved;neutralizing antibody Antibody responses to viruses n/a NCI 10926464 1ZIABC012038-03 1 ZIA BC 12038 3 77857435 "MAYER, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 12016 NCI This research was primarily carried out by a cooperating laboratory. Through the use of single-cell BCR cloning and other techniques antibody responses were characterized in a patient with a history of SARS-CoV2 infection and elite serum neutralization activity. One study identified broadly neutralizing antibodies that can neutralize all SARS-CoV2 variants and dissected the importance of somatic mutations for neutralization breadth and potency. Another study focused on those antibodies that are cross-reactive to SARS-CoV1 and to SARS-CoV2 variants. One key finding was that SARS-CoV1 cross-reactive antibodies evaded the SARS-CoV2 Omicron lineage and the escape mechanism was documented through structural analyses. Collectively these studies improve our understanding of human antibody responses to sarbecoviruses. 12016 +No NIH Category available Address;Affect;Alternative Splicing;Biological;Biomedical Research;CRISPR screen;Cells;Code;Complex;Coupled;Coupling;Cues;Data;Development;Dimensions;Disease;Essential Genes;Event;Exons;Follow-Up Studies;Gene Expression;Gene Expression Alteration;Gene Expression Profile;Genes;Genetic;Genetic Screening;Genetic Transcription;Genome;Goals;High-Throughput Nucleotide Sequencing;Human;Human Genome;Individual;Introns;Knowledge;Libraries;Link;Malignant Neoplasms;Manuscripts;Maps;Molecular Analysis;Mutation;Names;Neurodevelopmental Disorder;Nonsense Codon;Nuclear;Outcome;Output;Pathogenicity;Peptide Initiation Factors;Phenotype;Physiology;Poly A;Poly(A)+ RNA;Polyadenylation;Post-Translational Modification Site;Process;Proliferating;Protein Binding Domain;Protein Isoforms;Proteins;Proteomics;RNA Splicing;RNA library;RNA-Binding Proteins;Research;Resolution;Role;Series;Site;Splice-Site Mutation;TAF1 gene;TAF5 gene;TATA-Box Binding Protein;Tertiary Protein Structure;Tissues;Transcript;Transcription Initiation;Transcription Initiation Site;Translating;Translations;Vertebrates;Work;biological adaptation to stress;cell type;combinatorial;exome;experimental study;fitness;functional genomics;genome-wide;high dimensionality;insight;interest;mRNA Precursor;mutation screening;new technology;novel;preservation;programs;recruit;respiratory;screening;single-cell RNA sequencing;tool;transcription factor;transcriptome;transcriptome sequencing;transcriptomics High-throughput phenotypic screening for functionally characterizing alt. exons n/a NCI 10926461 1ZIABC012033-03 1 ZIA BC 12033 3 77857482 "GONATOPOULOS-POURNATZIS, THOMAS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 614769 NCI Alterative pre-mRNA splicing greatly diversifies the human transcriptome expanding the coding potential of the genome. RNA sequencing profiling studies have revealed that almost all multi-exon human genes are subject to alternative splicing. Networks of timely coordinated alternative exons and introns are under elaborate regulatory control in different cell and tissue types and upon altering environmental cues generating diverse transcriptomic and proteomic landscapes that can support different cell fates or stress responses. It is estimated that over 10% of pathogenic mutations impact alternative splice site activation and dysregulation of alternative splicing has been associated with complex diseases such as cancer and neurodevelopmental disorders. Major challenges in the alternative splicing field include i) the functional characterization of alternative exons the overwhelming majority of which remain uncharacterized and ii) understanding how splicing programs are remodeled in various cell types or environmental conditions. My research group is using a combination of functional genomics and focused molecular analyses to address these challenges as elaborated below. Project 1: High-throughput identification and characterization of phenotypically critical alternative exons Frame-preserving alternatively spliced exons that overlap coding sequences and are devoid of premature stop codons are translated and contribute to protein diversity. The functional consequences of such splice isoforms are difficult to predict and it has been a matter of debate to what extent they represent stochastic differences in splice site selection during transcription with little biological repercussions910. Accordingly a major challenge in the splicing field is to identify the full repertoire of biologically relevant alternative exons that contribute to phenotypic outcomes. Such knowledge will facilitate the prioritization of alternative splicing events for focused studies and will also provide predictive phenotypic insights of disease or disorder states characterized by widespread splicing alterations. To enable exon-resolution functional genomics we have developed orthogonal ultra-efficient exon deletion and splice site mutation screening platforms and we have shown that can be used for the high-throughput interrogation phenotypically relevant exons in the human genome. Aim 1: Systematic identification of the human exons underlying cell fitness & proliferation. The first aim of our group has been to systematically profile the human exome to identify individual exons that can impact cell fitness and proliferation a very important and quantitative cellular phenotype. To achieve this we took advantage of the tools we have developed and generated guide (g)RNA libraries for exon deletion and splice site mutation screening to profile 15000 frame-preserving exons from 2500 genes in human HAP1 and RPE1 cells in total. Reassuringly both screening strategies result in a significant overlap and positive correlation of exons that affect cell fitness. Our screens revealed that 20% of the interrogated exons affect cell fitness and these exons are more frequently found in highly expressed and essential genes. The cell fitness-affecting exons tend to be conserved in vertebrates and frequently overlap post-translation modification sites. Furthermore we have shown that the fitness exons are enriched for overlapping modular protein domains and protein-protein interaction interfaces while being devoid of low complexity regions. A manuscript describing these data is under revision. Aim 2: Development and application of exon-resolution genetic screening coupled to high-dimensional single-cell transcriptomic read-out. The transcriptome represents a very powerful and information-rich phenotype of cellular state and thus the coupling of CRISPR screens with single-cell RNA-Sequencing (scRNA-Seq) has been harnessed for examining high-dimensional phenotypic landscapes. To enable exon deletion screens with high-dimensional phenotypic profiling we applied a series of optimization steps to have been able to combine exon deletion screens with single-cell RNA-Seq phenotypic readouts (an approach dubbed as scCHyMErA-Seq). We are currently performing a large-scale exon perturbation screen targeting 500 exons for deletion coupled to scRNA-Seq readouts. In these experiments we built on our previously performed proliferation screens (see Aim 1) which identified 1000 exons that affect cell fitness in human cells. We have generated CHyMErA libraries to excise a subset of these exons (with a focus on exons residing in gene expression regulators) and assess the gene expression changes in individual cells using scCHyMErA-Seq. This study represents the first large scale exon perturbation screening strategy with dimensional phenotypic read out and is fundamental novel insights of the exons in the human genome that affect gene expression signatures. Aim 3: In depth mechanistic characterization of alternative exons in transcription factors that control gene expression outputs. A major interest of our group is to functionally characterize alternative exons that can impact transcription pre-mRNA processing or translation as demonstrated by our previous work. Both the cell fitness as well as the scCHyMErA screens have identified dozens of frame-preserving alternative exons in transcription factors. Focused follow-up studies of an alternative exon in the TFIID general transcription initiation factor component TAF5 uncovers that the inclusion levels of this single exon can control the overall assembly of the TFIID complex. Forced skipping of this alternatively spliced exon results in widespread gene expression alterations suggesting that this exon functions as a regulatory switch to tune TFIID formation and activity by controlling TATA-binding protein recruitment to transcription start sites. This study highlights the power of applying exon perturbation screens to interrogate phenotypically important exons at genome-scale as a means for uncovering novel mechanisms that control gene expression and cell fitness. Preliminary analysis of our exon deletion single-cell RNA-Sequencing screens has revealed that among other exons an alternative exon in NRF1 nuclear respiratory transcription factor 1 affects gene expression signatures. Based on these observations we hypothesize that this exon is important at least partially for NRF1 function and currently performing focused studies to understand the role of this exon in regulating NRF1 activity and gene expression outputs. 614769 +No NIH Category available ALVAC;Adjuvant;Antibodies;Antigens;Binding;CD4 Positive T Lymphocytes;Communicable Diseases;DNA;DNA Vaccines;Development;Engineering;Epidemic;Epigenetic Process;Exposure to;Goals;Government;Grant;HIV;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Human;Hydroxides;Immune response;Immune system;Immunity;Inflammatory;Intellectual Property;Invertebrates;Investigation;Lead;Legal patent;Licensing;Macaca;Malignant Neoplasms;Mediating;Memory;Modeling;Natural Immunity;Natural Killer Cells;Phase;Preparation;Private Sector;Production;Proteins;Recombinants;Risk;SIV;T cell response;Testing;Thailand;Training;Translating;Vaccination;Vaccines;Virus;aluminum sulfate;antibody-dependent cell cytotoxicity;design;efficacy trial;gp160;monocyte;nonhuman primate;novel;pathogen;programs;trait;vaccine efficacy;vaccine platform;vaccine trial Phase I HIV vaccine trial with DNAALVAC-HIV gp120 delta V1 vaccines n/a NCI 10926460 1ZIABC012025-03 1 ZIA BC 12025 3 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4110031 OD The project will exploit the DNA/ALVAC-HIV vaccine platform's ability to induce lasting trained monocyte memory in combination with a clade AE (A244 strain) V1-deleted HIV-gp160 prime and a novel V1-deleted HIV gp120/alum protein boost. The deletion of V1 from the gp120 envelope will be specially engineered to minimize antibody interference and elicit a high level of antibodies to V2 the primary correlate of risk in RV144. Alum hydroxide will be used as adjuvant for its ability to maximize the induction of trained immunity (through its ability to induce IL-1B) and CD4+ T-cell responses that constituted the secondary correlate of decreased risk of HIV acquisition in RV144. The overall objective of this proposal is to design and produce both a novel HIV V1-deleted A244 gp160 (A244 DeltaV1 gp160) DNA vaccine and a novel HIV V1-deleted A244 gp120 (A244 DeltaV1 gp120) in GMP conditions for testing in a phase I human HIV vaccine trial. These immunogens will first be tested in macaques to assess whether this approach also induces long-lasting non-interfering antibodies innate monocyte memory and adaptive CD4+ T-cells with a low inflammatory profile in humans. The investigation of protective monocyte or NK memory trained immunity will prove beneficial in combatting additional infectious diseases and cancer. Evolutionary conserved from invertebrates trained immunity is an ancient trait of the human immune system that is defined by durable epigenetic reprogramming of monocytes providing the first line of defense against pathogens .This will lead not only to the production and testing of a novel HIV vaccine but also to the thorough investigation of unexplored host protective immune responses in non-human primates (NHP) whose immune system mirrors that of humans. 450000 +No NIH Category available ALVAC;Adjuvant;Antibodies;Antigens;Binding;CD4 Positive T Lymphocytes;Communicable Diseases;DNA;DNA Vaccines;Development;Engineering;Epidemic;Epigenetic Process;Exposure to;Goals;Government;Grant;HIV;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Human;Hydroxides;Immune response;Immune system;Immunity;Inflammatory;Intellectual Property;Invertebrates;Investigation;Lead;Legal patent;Licensing;Macaca;Malignant Neoplasms;Mediating;Memory;Modeling;Natural Immunity;Natural Killer Cells;Phase;Preparation;Private Sector;Production;Proteins;Recombinants;Risk;SIV;T cell response;Testing;Thailand;Training;Translating;Vaccination;Vaccines;Virus;aluminum sulfate;antibody-dependent cell cytotoxicity;design;efficacy trial;gp160;monocyte;nonhuman primate;novel;pathogen;programs;trait;vaccine efficacy;vaccine platform;vaccine trial Phase I HIV vaccine trial with DNAALVAC-HIV gp120 delta V1 vaccines n/a NCI 10926460 1ZIABC012025-03 1 ZIA BC 12025 3 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4110031 NCI The project will exploit the DNA/ALVAC-HIV vaccine platform's ability to induce lasting trained monocyte memory in combination with a clade AE (A244 strain) V1-deleted HIV-gp160 prime and a novel V1-deleted HIV gp120/alum protein boost. The deletion of V1 from the gp120 envelope will be specially engineered to minimize antibody interference and elicit a high level of antibodies to V2 the primary correlate of risk in RV144. Alum hydroxide will be used as adjuvant for its ability to maximize the induction of trained immunity (through its ability to induce IL-1B) and CD4+ T-cell responses that constituted the secondary correlate of decreased risk of HIV acquisition in RV144. The overall objective of this proposal is to design and produce both a novel HIV V1-deleted A244 gp160 (A244 DeltaV1 gp160) DNA vaccine and a novel HIV V1-deleted A244 gp120 (A244 DeltaV1 gp120) in GMP conditions for testing in a phase I human HIV vaccine trial. These immunogens will first be tested in macaques to assess whether this approach also induces long-lasting non-interfering antibodies innate monocyte memory and adaptive CD4+ T-cells with a low inflammatory profile in humans. The investigation of protective monocyte or NK memory trained immunity will prove beneficial in combatting additional infectious diseases and cancer. Evolutionary conserved from invertebrates trained immunity is an ancient trait of the human immune system that is defined by durable epigenetic reprogramming of monocytes providing the first line of defense against pathogens .This will lead not only to the production and testing of a novel HIV vaccine but also to the thorough investigation of unexplored host protective immune responses in non-human primates (NHP) whose immune system mirrors that of humans. 3660031 +No NIH Category available Acidic Region;Acquired Immunodeficiency Syndrome;Address;Aneuploidy;Animal Model;Binding;Biochemical;Biological;Biological Assay;Blood;C-terminal;CD4 Positive T Lymphocytes;Cell Cycle;Cell model;Cell physiology;Cells;Centrioles;Centrosome;Complex;Cryoelectron Microscopy;Cultured Cells;Data;Development;Disease;Etiology;Event;Genome Stability;Goals;HIV;HIV-1;HIV-2;HIV/AIDS;Human;Immune system;Incidence;Infection;Investigation;Light;Link;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Molecular;Nature;Organelles;PLK1 gene;Pathogenesis;Persons;Phosphotransferases;Physiological;Predisposition;Process;Proteins;Proteomics;Research;Research Priority;Risk;Role;Scaffolding Protein;Shapes;Specificity;Structure;T-Lymphocyte;Tail;Tissues;United States National Institutes of Health;WD Repeat;Work;X-Ray Crystallography;antiretroviral therapy;cancer risk;carcinogenesis;cellular targeting;chromosome missegregation;comorbidity;design;experience;high risk;inhibitor;interest;novel strategies;prevent;scaffold;tumorigenesis Unraveling the molecular link between HIVAIDS and cancer n/a NCI 10926459 1ZIABC012024-03 1 ZIA BC 12024 3 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 518342 NCI Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein VprBP via its C-terminal cryptic polo-box. Strikingly HIV-1 Vpr which binds to the WD40 domain (1003-1400) of VprBP greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the ternary complex formation appeared to augment Plk4-mediated centriole duplication. Consistent with these findings VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that when cells are infected with HIV-1 Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4 indicating the specificity of HIV-1 Vpr-induced events. Based on these observations we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore it may offer a new paradigm in understanding the increased cancer risk in people with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Furthermore our efforts to determine the quaternary structure of the Vpr-VprBP-Plk4 complex have been moving along well. Once the quaternary structure is determined we will be interested in designing inhibitors that could disrupt the complex and thus help prevent HIV-1-induced centrosomal abnormalities and their associated human disorders such as cancer. The data that we obtained from various cultured cells revealed that disrupting the Vpr-VprBP-Plk4 complex by either deleting the Vpr's C-terminal tail or the VprBP's acidic region was sufficient to abolish Vpr-dependent centrosome amplification and aneuploidy in multiple CD4+ cells including primary T cells. Given the tight association of aneuploidy and cancer these findings suggest that the HIV-1-induced Vpr-VprBP-Plk4 complex can directly promote oncogenesis in HIV-1-susceptible T cells or other blood Vpr-transducible cells by hijacking the host machinery for Plk4-mediated centriole duplication. In light of the finding that the risk of developing NHL remains high even during the combination antiretroviral therapy this work may offer a new direction for investigating underlying mechanisms that give rise to HIV-1-associated cancers. 368342 +No NIH Category available Acidic Region;Acquired Immunodeficiency Syndrome;Address;Aneuploidy;Animal Model;Binding;Biochemical;Biological;Biological Assay;Blood;C-terminal;CD4 Positive T Lymphocytes;Cell Cycle;Cell model;Cell physiology;Cells;Centrioles;Centrosome;Complex;Cryoelectron Microscopy;Cultured Cells;Data;Development;Disease;Etiology;Event;Genome Stability;Goals;HIV;HIV-1;HIV-2;HIV/AIDS;Human;Immune system;Incidence;Infection;Investigation;Light;Link;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Molecular;Nature;Organelles;PLK1 gene;Pathogenesis;Persons;Phosphotransferases;Physiological;Predisposition;Process;Proteins;Proteomics;Research;Research Priority;Risk;Role;Scaffolding Protein;Shapes;Specificity;Structure;T-Lymphocyte;Tail;Tissues;United States National Institutes of Health;WD Repeat;Work;X-Ray Crystallography;antiretroviral therapy;cancer risk;carcinogenesis;cellular targeting;chromosome missegregation;comorbidity;design;experience;high risk;inhibitor;interest;novel strategies;prevent;scaffold;tumorigenesis Unraveling the molecular link between HIVAIDS and cancer n/a NCI 10926459 1ZIABC012024-03 1 ZIA BC 12024 3 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 518342 OD Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein VprBP via its C-terminal cryptic polo-box. Strikingly HIV-1 Vpr which binds to the WD40 domain (1003-1400) of VprBP greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the ternary complex formation appeared to augment Plk4-mediated centriole duplication. Consistent with these findings VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that when cells are infected with HIV-1 Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4 indicating the specificity of HIV-1 Vpr-induced events. Based on these observations we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore it may offer a new paradigm in understanding the increased cancer risk in people with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Furthermore our efforts to determine the quaternary structure of the Vpr-VprBP-Plk4 complex have been moving along well. Once the quaternary structure is determined we will be interested in designing inhibitors that could disrupt the complex and thus help prevent HIV-1-induced centrosomal abnormalities and their associated human disorders such as cancer. The data that we obtained from various cultured cells revealed that disrupting the Vpr-VprBP-Plk4 complex by either deleting the Vpr's C-terminal tail or the VprBP's acidic region was sufficient to abolish Vpr-dependent centrosome amplification and aneuploidy in multiple CD4+ cells including primary T cells. Given the tight association of aneuploidy and cancer these findings suggest that the HIV-1-induced Vpr-VprBP-Plk4 complex can directly promote oncogenesis in HIV-1-susceptible T cells or other blood Vpr-transducible cells by hijacking the host machinery for Plk4-mediated centriole duplication. In light of the finding that the risk of developing NHL remains high even during the combination antiretroviral therapy this work may offer a new direction for investigating underlying mechanisms that give rise to HIV-1-associated cancers. 150000 +No NIH Category available Address;Affinity Chromatography;Alternative Splicing;Biogenesis;CRISPR screen;Candidate Disease Gene;Cells;Cellular Stress;Chromosome Mapping;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Complementary DNA;Complex;Coupled;Cues;DNA cassette;Databases;Detection;Development;Disease;Doxycycline;Exons;Genes;Genetic;Genetic Transcription;Genome;Guide RNA;Heat-Shock Response;Human;Immunoprecipitation;Introns;Libraries;Link;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Messenger RNA;Methodology;Molecular;Molecular Analysis;Mutation;Neurodevelopmental Disorder;Nuclear;Osmolar Concentration;Pathogenicity;Pathway interactions;Phenotype;Protein Isoforms;Proteins;Proteomics;RNA;RNA Processing;RNA Splicing;RNA-Binding Proteins;Regulation;Regulator Genes;Regulatory Pathway;Reporter;Research;Role;Signal Transduction;Site;Spliceosomes;Stress;Temperature;Testing;Time;Tissues;Transcript;Transcriptional Regulation;biological adaptation to stress;cancer cell;cell type;combinatorial;crosslink;deep sequencing;environmental change;experimental study;functional genomics;gene regulatory network;genome editing;genome wide screen;genome-wide;insight;mRNA Precursor;novel;nuclease;programs;response;transcriptome;transcriptome sequencing;transcriptomics;tumor growth;vector Investigating the regulation of alternative splicing and its role in disease n/a NCI 10926457 1ZIABC012019-04 1 ZIA BC 12019 4 77857482 "GONATOPOULOS-POURNATZIS, THOMAS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 614769 NCI Project 2: Mapping gene regulatory networks that control alternative splicing Our understanding of transcriptomic complexity has advanced in parallel with the development of large-scale methodological approaches enabling the detection and mapping of RNA binding proteins (RBPs) across the transcriptome. Such studies have provided mechanistic insights into RNA processing regulation and its contribution to disease-states. Despite this remarkable progress we are still lacking a complete understanding of the regulatory networks that control alternative splicing. These is particularly prevalent in the context of stress-related pathways that are exploited from cancer cells to generate transcript isoform with advantageous effects on tumor growth. It is thus crucial to elucidate the molecular pathways that enable stress signaling to converge on remodeling alternative splicing programs. Aim 1: Development and application of a massively parallel and quantitative CRISPR screening platform for mapping splicing regulatory networks. To enable large-scale combinatorial CRISPR perturbations coupled with alternative pre-mRNA splicing readouts we have developed a novel methodology combining CHyMErA combinatorial genetic perturbations with deep-sequencing readouts of splicing reporters to quantitatively measure splicing phenotypes and associate them with each perturbation. To achieve this we modified our lentiviral combinatorial CRISPR screening vector to enable the expression of splicing minigene reporters in an inducible manner while harboring gRNA expression cassette within the 3' end of the reporter. Lentiviral delivery of these constructs in cells expressing Cas nucleases results in programable genome editing as determined by the constitutively expressed gRNAs which is followed by the doxycycline-dependent activation of reporter expression at the desired time. mRNA from these cells is purified and Illumina sequencing libraries are generated from splicing reporter cDNA. Paired-end sequencing is used to quantify splicing reporter phenotypes and link them with the corresponding genetic perturbations determined by the gRNA sequences thus enabling genome-wide interrogation of splicing regulators. By applying different splicing reporters we have identified several hundred genes that can impact alternative splicing genes that are highly enriched for RNA splicing and spliceosome biogenesis functional terms. This demonstrates the feasibility and the power of our approach to identify bona-fide splicing regulatory genes. Aim 2: Identification and characterization of novel regulators of alternative splicing programs. Our genome-wide splicing reporter screens have identified several genes to impact the splicing of multiple reporters that have not been previously associated with splicing regulation. Some of these genes also display evidence of interacting with splicing related proteins based on BIOGRID and/or STRING databases. These include genes such as PAXBP1 ZNF41 ZNF207 and KBTBD2 all of which are nuclear and rather understudied genes that have been mostly implicated with transcription regulation. We hypothesize that these factors can directly impact alternative splicing of specific genes. To test this hypothesis we will rapidly deplete these genes in human cells using degrons and assess their impact on newly transcribed RNA using Nascent-Seq. We will also apply affinity purification coupled to mass spectrometry as well as crosslinking and immunoprecipitation experiments to identify the direct protein and RNA interactions of these factors and gain mechanistic insights on how they can regulate alternative splicing decisions. These studies are expected to provide novel insights of alternative splicing regulation in human cells. Aim 3: Which are the molecular pathways that control alternative splicing responses to cellular stress? An important challenge in the splicing field is to understand how splicing regulatory pathways respond to environmental changes including stresses imposed by alterations in osmolarity or temperature. Indeed hyperosmotic stress and heat shock both result in widespread splicing alterations. We have generated splicing reporters that are responsive to these stresses and we have performed genome-wide screens as described above in cells subjected to the corresponding stress condition. These screens have identified several candidate genes critical for stress-dependent splicing changes. 614769 +No NIH Category available Apoptosis;Cell Cycle Arrest;Cells;Chromosomes;DNA Damage;Data;Defect;Development;Functional disorder;Genomic Instability;Goals;Knowledge;Malignant Neoplasms;Pathway interactions;Pluripotent Stem Cells;Process;Proliferating;Research Project Grants;Work;cancer cell;cell type;embryonic stem cell;genetic manipulation;response;stem cells;telomere;tumor;tumor initiation Mechanism of end protection in stem cells n/a NCI 10926453 1ZIABC012015-04 1 ZIA BC 12015 4 10105415 "LAZZERINI DENCHI, EROS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 714153 NCI When telomeres become critically short they become dysfunctional and elicit activation of the DNA damage response pathway at chromosome ends. Cells with dysfunctional telomeres can either undergo programmed cell death enter into an irreversible cell cycle arrest or accumulate genome instability and eventually transform into an aggressive cancer cell. Using conditional deletion of shelterin components we have shown that the differentiation status has a major impact on the cellular response to telomere dysfunction (Lazzerini Denchi et al. 2006; Lobanova et al. 2017; Pinzaru et al. 2016). We have demonstrated that in response to the same type of genetic manipulation certain cell types accumulate genome instability and eventually develop into aggressive tumors. In contrast others never overcome the proliferation barrier imposed by telomere dysfunction (Lobanova et al. 2017; Pinzaru et al. 2016). Given the importance of telomere-driven genome instability in the development of cancer these data highlight a significant gap in knowledge in a critical tumor-initiating process. Our ongoing work aimed at understanding the connection between telomere dysfunction and the differentiation status revealed that unexpectantly pluripotent embryonic stem cells (ESCs) could survive in the absence of essential shelterin components. This unexpected finding opens a set of outstanding questions regarding the mechanism of telomere protection in pluripotent stem cells 714153 +No NIH Category available AIDS related cancer;Acute;B cell repertoire;B-Cell Lymphomas;B-Lymphocytes;Cancer Burden;Cancer Etiology;Cause of Death;Cells;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Codon Nucleotides;Complex;Development;Disease;EBV reactivation from latency;Elements;Engineering;Enrollment;Epithelial Cells;Flow Cytometry;Genes;Genome;Goals;Guide RNA;HIV;HIV/AIDS;Herpesviridae;Herpesvirus Vaccines;Human Herpesvirus 4;Human Herpesvirus 8;Immune;Immune response;Immunotherapy;Individual;Infection;Infection prevention;Innate Immune Response;Intervention;Kaposi Sarcoma;Lymphoma;Lymphoproliferative Disorders;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Methods;Molecular;Morbidity - disease rate;Mus;Mutate;Mutation;Oncogenic;Patients;Peripheral Blood Mononuclear Cell;Persons;Pre-Clinical Model;Process;Repetitive Sequence;Research;Risk;Sampling;Site;System;T cell response;T-Lymphocyte;Technology;Therapeutic Intervention;United States;Vaccination;Vaccines;Viral Genes;Viral Genome;Viral Load result;Virus;Virus Replication;adaptive immune response;antiretroviral therapy;chemotherapy;design;effective therapy;gammaherpesvirus;gene complementation;gene product;high risk population;immune modulating agents;lytic gene expression;malignant stomach neoplasm;mortality;next generation sequencing;novel;novel vaccines;pathogen;patient response;post-transplant;prevent;primary effusion lymphoma;programs;recombinant virus;response;success;therapeutic gene;tumorigenesis;vaccine candidate;vaccine strategy;viral genomics Novel interventions for gammaherpesvirus infection and AIDS-Related Malignancies n/a NCI 10926452 1ZIABC012014-04 1 ZIA BC 12014 4 9786523 "KRUG, LAURIE T" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 552560 OD (1) To overcome current challenges in the development of herpesvirus vaccines my collaborators and I devised a codon-shuffled complementing gene method to grow high titer replication-dead virus stocks. This replication-dead virus is mutated in a critical gene common to KSHV that is essential for lytic gene expression. We determined that two administrations of this vaccine candidate generate virus-specific B and T cell responses. We also found that vaccination is protective against acute virus replication upon wild-type virus challenge. Building upon the success of this initial approach we have designed new recombinant viruses that inactivate other viral genes essential to replication and latency of gammaherpesvirus including KSHV. This is a novel vaccine strategy to generate a wide repertoire of B and T cells against structural and non-structural gene products. Our goal is to reduce oncogenic viral loads and associated-cancer burdens in infected individuals especially high-risk individuals with HIV/AIDS. (2) In a second project CRISPR is a gene-editing system that we are developing to neutralize gammaherpesviruses in the cells they infect. This system must be engineered for precision to prevent off-target damage to the host for efficiency to inactivate multiple copies of herpesvirus genomes. We successfully reduced murine gammaherpesvirus replication by CRISPR editing of viral genomic elements. We next applied a modified strategy to deliver guide RNAs that target viral genes and repetitive elements in the multiple sites of the EBV genome. Next generation sequencing is being used to characterize the types of mutations generated and we are examining how this CRISPR system impacts latency and reactivation of EBV in a broad array of B cells and epithelial cells that EBV is known to infect and transform. (3) I am analyzing the host immune response in the peripheral blood mononuclear cells of patients in HAMB clinical trials. We are using flow cytometry to examine if the innate and adaptive immune response differs between HIV+ and HIV- patients. We also study if the immune response changes with the chemotherapies and immunotherapies that are used to treat these patients in the clinical trials. The goal is to identify immune correlates of the clinical response for non-responders and responders to find effective therapies for AIDS associated malignancies. 212916 +No NIH Category available AIDS related cancer;Acute;B cell repertoire;B-Cell Lymphomas;B-Lymphocytes;Cancer Burden;Cancer Etiology;Cause of Death;Cells;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Codon Nucleotides;Complex;Development;Disease;EBV reactivation from latency;Elements;Engineering;Enrollment;Epithelial Cells;Flow Cytometry;Genes;Genome;Goals;Guide RNA;HIV;HIV/AIDS;Herpesviridae;Herpesvirus Vaccines;Human Herpesvirus 4;Human Herpesvirus 8;Immune;Immune response;Immunotherapy;Individual;Infection;Infection prevention;Innate Immune Response;Intervention;Kaposi Sarcoma;Lymphoma;Lymphoproliferative Disorders;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Methods;Molecular;Morbidity - disease rate;Mus;Mutate;Mutation;Oncogenic;Patients;Peripheral Blood Mononuclear Cell;Persons;Pre-Clinical Model;Process;Repetitive Sequence;Research;Risk;Sampling;Site;System;T cell response;T-Lymphocyte;Technology;Therapeutic Intervention;United States;Vaccination;Vaccines;Viral Genes;Viral Genome;Viral Load result;Virus;Virus Replication;adaptive immune response;antiretroviral therapy;chemotherapy;design;effective therapy;gammaherpesvirus;gene complementation;gene product;high risk population;immune modulating agents;lytic gene expression;malignant stomach neoplasm;mortality;next generation sequencing;novel;novel vaccines;pathogen;patient response;post-transplant;prevent;primary effusion lymphoma;programs;recombinant virus;response;success;therapeutic gene;tumorigenesis;vaccine candidate;vaccine strategy;viral genomics Novel interventions for gammaherpesvirus infection and AIDS-Related Malignancies n/a NCI 10926452 1ZIABC012014-04 1 ZIA BC 12014 4 9786523 "KRUG, LAURIE T" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 552560 NCI (1) To overcome current challenges in the development of herpesvirus vaccines my collaborators and I devised a codon-shuffled complementing gene method to grow high titer replication-dead virus stocks. This replication-dead virus is mutated in a critical gene common to KSHV that is essential for lytic gene expression. We determined that two administrations of this vaccine candidate generate virus-specific B and T cell responses. We also found that vaccination is protective against acute virus replication upon wild-type virus challenge. Building upon the success of this initial approach we have designed new recombinant viruses that inactivate other viral genes essential to replication and latency of gammaherpesvirus including KSHV. This is a novel vaccine strategy to generate a wide repertoire of B and T cells against structural and non-structural gene products. Our goal is to reduce oncogenic viral loads and associated-cancer burdens in infected individuals especially high-risk individuals with HIV/AIDS. (2) In a second project CRISPR is a gene-editing system that we are developing to neutralize gammaherpesviruses in the cells they infect. This system must be engineered for precision to prevent off-target damage to the host for efficiency to inactivate multiple copies of herpesvirus genomes. We successfully reduced murine gammaherpesvirus replication by CRISPR editing of viral genomic elements. We next applied a modified strategy to deliver guide RNAs that target viral genes and repetitive elements in the multiple sites of the EBV genome. Next generation sequencing is being used to characterize the types of mutations generated and we are examining how this CRISPR system impacts latency and reactivation of EBV in a broad array of B cells and epithelial cells that EBV is known to infect and transform. (3) I am analyzing the host immune response in the peripheral blood mononuclear cells of patients in HAMB clinical trials. We are using flow cytometry to examine if the innate and adaptive immune response differs between HIV+ and HIV- patients. We also study if the immune response changes with the chemotherapies and immunotherapies that are used to treat these patients in the clinical trials. The goal is to identify immune correlates of the clinical response for non-responders and responders to find effective therapies for AIDS associated malignancies. 339644 +No NIH Category available Adult;Anatomy;Animal Model;Animals;Anterior;Competence;Cues;Defect;Development;Embryo;Embryonic Development;Failure;Genetic;Genetic Transcription;Genomics;Head;Injury;Natural regeneration;Organogenesis;Pathway interactions;Pattern;Planarians;Platyhelminths;Pluripotent Stem Cells;Positioning Attribute;Production;Property;RNA Interference;Regenerative engineering;Regulation;Reverse engineering;Signal Pathway;Source;Structure;System;Tissues;Work;adult stem cell;beta catenin;blastema;cell type;hatching;inhibitor;knock-down;regenerative;stem cell fate specification;stem cells;wound Mechanisms underlying establishment of regeneration competence n/a NCI 10926448 1ZIABC012009-04 1 ZIA BC 12009 4 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 242716 NCI Planarian regeneration requires adult pluripotent stem cells the source of all new tissues and instructive cues from pre-existing tissues to re-establish polarity patterning and orchestrate differentiation of missing cell types. When and how embryos acquire regenerative abilities was not known. We discovered that regeneration competence emerges gradually during embryogenesis and that development of somatic tissue(s) necessary for context-dependent regulation of stem cell dynamics after injury is rate-limiting establishment of regenerative abilities. We observe stage- and axial position-dependent effects on regenerative abilities late in embryogenesis culminating in the production of a fully regeneration-competent animal immediately after hatching. Regeneration-incompetent animals while able to regenerate posterior body structures were incapable of regenerating new anterior (head) tissue. Ongoing work suggests that stem cell specification is not rate-limiting for establishment of regeneration competence: stem cells were present cycling and capable of producing differentiating progeny for pre-existing tissues in regeneration-incompetent animals. We discovered that failure to reset the anterior-posterior axis underlies the head regeneration defect. RNAi knock-down of the Wnt pathway effector Beta-catenin-1 induced precocious head formation in regeneration-incompetent embryos suggesting that high Wnt pathway activity inhibits anterior regeneration. Consistent with this result and in contrast to what was observed in regeneration-competent embryos regeneration-incompetent embryos did not express Wnt pathway inhibitors like notum in anterior-facing blastemas. We are currently investigating how development of tissues that are transcriptionally responsive to wounding including the body wall musculature impinge on axial polarity re-establishment and acquisition of regeneration competence. Our results suggest that regeneration is regulated hierarchically with master regulators of axial polarity governing regional patterning and organogenesis. 242716 +No NIH Category available 2019-nCoV;Antigen Presentation;Antigen Presentation Pathway;Antigens;Cells;Coronavirus;Coronavirus Infections;Cross Presentation;Defect;Family;Goals;Human;Image;Immune;Immune response;Immunologics;Immunology;Life Cycle Stages;Lysosomes;Methodology;Modality;Monitor;Monomeric GTP-Binding Proteins;Natural Killer Cells;Pathway interactions;Patients;RNA Viruses;Reporter;Severe Acute Respiratory Syndrome;T-Cell Activation;Virus;Virus Diseases;betacoronavirus;inhibitor;insight;interest;novel therapeutics;trafficking Dynamics of viral infection n/a NCI 10926446 1ZIABC012007-04 1 ZIA BC 12007 4 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 217669 NCI Beta-Coronaviruses are a family of positive-strand enveloped RNA viruses that include the severe acute respiratory syndrome-CoV2 (SARS-CoV2). While much is known regarding their cellular entry and replication pathways their mode of egress remains uncertain; however this is assumed to be via the biosynthetic secretory pathway by analogy to other enveloped viruses. Using imaging methodologies in combination with virus-specific reporters we demonstrated that beta-Coronaviruses utilize lysosomal trafficking for egress from cells. This pathway is regulated by the Arf-like small GTPase Arl8b; thus virus egress is insensitive to inhibitors of the biosynthetic secretory pathway. Coronavirus infection results in lysosome deacidification inactivation of lysosomal degradation and disruption of antigen presentation pathways. This coronavirus-induced exploitation of lysosomes provides insights into the cellular and immunological abnormalities observed in patients and suggests new therapeutic modalities. 217669 +No NIH Category available AIDS related cancer;Adverse effects;African;Animal Disease Models;Anti-Retroviral Agents;Antibodies;Antineoplastic Agents;Antiviral Agents;BAY 54-9085;CDK4 gene;CYP3A4 gene;Cell Cycle;Clinical;Clinical Pharmacology;Cyclin D1;Cyclin-Dependent Kinase Inhibitor;Cyclins;Cytotoxic Chemotherapy;Development;Disease remission;Dose;Drug Exposure;Drug Interactions;Drug Kinetics;Endothelial Cells;Endothelium;Future;Gastrointestinal tract structure;Generations;Goals;HIV;HIV Seronegativity;HIV diagnosis;HIV therapy;HIV-1;Human;Human Herpesvirus 8;Individual;Interleukin 6 Receptor;Kaposi Sarcoma;Laboratories;Liposomal Doxorubicin;Long-Term Care;Lung;Lymph Node Involvement;Malignant Neoplasms;Metastatic breast cancer;Modeling;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Oral;Parents;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Phase;Phosphorylation;Phosphotransferases;Play;Polypharmacy;Prognosis;Proliferating;Proteins;Recurrence;Refractory;Relapse;Resistance;Retinoblastoma;Retinoblastoma Protein;Ritonavir;Role;Safety;Series;Signal Pathway;Skin;Therapeutic;Therapeutic Agents;Treatment Protocols;Umbilical vein;analog;antiretroviral therapy;bone;comorbidity;cyclin D3;improved;inhibitor;interest;novel;pomalidomide;preclinical development;therapeutic target;tocilizumab;tumor Clinical Pharmacology and Drug-Drug Interactions in HIV-Associated Malignancy n/a NCI 10926441 1ZIABC011996-04 1 ZIA BC 11996 4 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 683497 OD Our laboratory is interested in studying the pharmacokinetics (PK) of therapeutic agents in the absence and presence of concomitant HIV drugs to better understand if there are clinically meaningful changes in drug exposure of either the HIV or non-HIV therapeutic such that dose adjustments would be warranted. We have previously evaluated the safety and drug-drug interactions between sorafenib and ritonavir an HIV medication with strong CYP3A4 inhibitory activity. We also evaluated the PK of tocilizumab a humanized anti-IL-6 receptor (gp80) antibody in patients with Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease. In a separate study the PK of pomalidomide and liposomal doxorubicin were analyzed to assess for any potential drug interactions in patients with KSHV. Furthermore we have investigated the role of polypharmacy in Sub-Saharan African to understand drug-drug interactions between antiretroviral and anti-cancer drugs. Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor caused by Kaposi sarcoma-associated herpesvirus that most frequently involves the skin but may also involve lymph nodes lungs bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV associated KS have worse survival than HIV-infected patients without KS. As it is a relapsing and remitting condition patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS. Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins including cyclin D kinases (CDKs) cyclins and retinoblastoma (Rb)-E2F signaling pathway. Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. KS is an endothelial tumor and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 uM. The CPP will be involved in determining the PK of abemaciclib in a phase I/II study of patients with HIV-associated and HIV-negative KS. In addition current antiretroviral therapy (ART) has greatly improved the prognosis for HIV-infected individuals. However because ART is not curative life-long therapy is required. This long-term therapy is associated with a variety of adverse effects and resistance to available drugs is likely to limit future treatment options for many patients. New antiviral drugs targeting novel steps in the HIV replication cycle are therefore required for the long-term care of HIV-infected individuals. We have played a key role in the development of a new class of anti-HIV compounds known as maturation inhibitors (MIs). With our collaborators we are involved in the preclinical development of second-generation bevirimat and analogs that are active against the strains of HIV-1 that are insensitive to the parent compound. We have identified a series of compounds that are highly potent against a wide range of HIV-1 isolates across multiple subtypes. 200000 +No NIH Category available AIDS related cancer;Adverse effects;African;Animal Disease Models;Anti-Retroviral Agents;Antibodies;Antineoplastic Agents;Antiviral Agents;BAY 54-9085;CDK4 gene;CYP3A4 gene;Cell Cycle;Clinical;Clinical Pharmacology;Cyclin D1;Cyclin-Dependent Kinase Inhibitor;Cyclins;Cytotoxic Chemotherapy;Development;Disease remission;Dose;Drug Exposure;Drug Interactions;Drug Kinetics;Endothelial Cells;Endothelium;Future;Gastrointestinal tract structure;Generations;Goals;HIV;HIV Seronegativity;HIV diagnosis;HIV therapy;HIV-1;Human;Human Herpesvirus 8;Individual;Interleukin 6 Receptor;Kaposi Sarcoma;Laboratories;Liposomal Doxorubicin;Long-Term Care;Lung;Lymph Node Involvement;Malignant Neoplasms;Metastatic breast cancer;Modeling;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Oral;Parents;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Phase;Phosphorylation;Phosphotransferases;Play;Polypharmacy;Prognosis;Proliferating;Proteins;Recurrence;Refractory;Relapse;Resistance;Retinoblastoma;Retinoblastoma Protein;Ritonavir;Role;Safety;Series;Signal Pathway;Skin;Therapeutic;Therapeutic Agents;Treatment Protocols;Umbilical vein;analog;antiretroviral therapy;bone;comorbidity;cyclin D3;improved;inhibitor;interest;novel;pomalidomide;preclinical development;therapeutic target;tocilizumab;tumor Clinical Pharmacology and Drug-Drug Interactions in HIV-Associated Malignancy n/a NCI 10926441 1ZIABC011996-04 1 ZIA BC 11996 4 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 683497 NCI Our laboratory is interested in studying the pharmacokinetics (PK) of therapeutic agents in the absence and presence of concomitant HIV drugs to better understand if there are clinically meaningful changes in drug exposure of either the HIV or non-HIV therapeutic such that dose adjustments would be warranted. We have previously evaluated the safety and drug-drug interactions between sorafenib and ritonavir an HIV medication with strong CYP3A4 inhibitory activity. We also evaluated the PK of tocilizumab a humanized anti-IL-6 receptor (gp80) antibody in patients with Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease. In a separate study the PK of pomalidomide and liposomal doxorubicin were analyzed to assess for any potential drug interactions in patients with KSHV. Furthermore we have investigated the role of polypharmacy in Sub-Saharan African to understand drug-drug interactions between antiretroviral and anti-cancer drugs. Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor caused by Kaposi sarcoma-associated herpesvirus that most frequently involves the skin but may also involve lymph nodes lungs bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV associated KS have worse survival than HIV-infected patients without KS. As it is a relapsing and remitting condition patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS. Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins including cyclin D kinases (CDKs) cyclins and retinoblastoma (Rb)-E2F signaling pathway. Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. KS is an endothelial tumor and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 uM. The CPP will be involved in determining the PK of abemaciclib in a phase I/II study of patients with HIV-associated and HIV-negative KS. In addition current antiretroviral therapy (ART) has greatly improved the prognosis for HIV-infected individuals. However because ART is not curative life-long therapy is required. This long-term therapy is associated with a variety of adverse effects and resistance to available drugs is likely to limit future treatment options for many patients. New antiviral drugs targeting novel steps in the HIV replication cycle are therefore required for the long-term care of HIV-infected individuals. We have played a key role in the development of a new class of anti-HIV compounds known as maturation inhibitors (MIs). With our collaborators we are involved in the preclinical development of second-generation bevirimat and analogs that are active against the strains of HIV-1 that are insensitive to the parent compound. We have identified a series of compounds that are highly potent against a wide range of HIV-1 isolates across multiple subtypes. 483497 +No NIH Category available Age;Alkylating Agents;Allogenic;Busulfan;Chimerism;Clinical;Cyclophosphamide;Defect;Disease;Donor Selection;Dose;Eligibility Determination;Engraftment;HLA-A gene;Hematological Disease;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Immune;Infection;Life;Marrow;Myeloid Cells;Organism;Participant;Patients;Prophylactic treatment;Recording of previous events;Recovery;Regimen;Resolution;Safety;Source;T-Lymphocyte;Tacrolimus;Transplantation Conditioning;Whole-Body Irradiation;alemtuzumab;cohort;conditioning;congenital immunodeficiency;curative treatments;design;disease phenotype;donor stem cell;efficacy evaluation;exome sequencing;fludarabine;gain of function mutation;genome sequencing;hematopoietic transplantation;immune function;loss of function;mycophenolate mofetil;neutrophil;post-transplant;programs;reconstitution;response;whole genome Allogeneic Hematopoietic Transplantation for Primary Immunodeficiency Diseases n/a NCI 10926440 1ZIABC011994-04 1 ZIA BC 11994 4 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1085274 NCI Background: With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected immune deficiency the number of recognized PID has increased in recent years to over 400 distinct immune defects. Allogeneic hematopoietic stem cell transplantation represents a potentially curative therapy for many hematologic diseases. Hematopoietic stem cell transplant is now an accepted standard or an appropriate experimental approach for treatment of an increasing number of PID The use of conditioning regimens containing high doses of alkylating agents often in combination with total body irradiation are considered myeloablative and are essential and for suppression of the host-versus-graft response to the donor stem cells (i.e. rejection) We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with primary immunodeficiency diseases. 1085274 +No NIH Category available Biological Process;Cancer Patient;Cells;Clinical;Collaborations;Cytotoxic T-Lymphocytes;DNA Damage;DNA Methylation;DNA Repair;Data;Epigenetic Process;Genes;Genetic;Genetic Epistasis;Goals;Individual;Malignant Neoplasms;Mediating;Mesenchymal;MicroRNAs;Modification;Oncogenic;Outcome;Paper;Phenotype;Process;Proliferating;Proteins;Publishing;Reporting;Therapeutic;Tissues;biological systems;cancer cell;cancer type;cell type;clinically relevant;computerized tools;gene function;gene interaction;genetic signature;prognostic of survival;programs;stemness;transcriptomics Gene interactions in cancer n/a NCI 10926434 1ZIABC011984-04 1 ZIA BC 11984 4 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 157745 NCI 1. We have previous published a paper in Cell Reports where where we generalize the concept of synthetic lethality and comprehensively identify clinically relevant gene interactions of 12 distinct types (SL being one of them). In collaboration with Aldape lab are now extending the notion of gene interactions to interactions between specific states of specific cell types (for instance cytotoxic T cells and mesenchymal malignant cells) with goal of specifically identifying functional interactions between specific processes/states across cell types. The project is ongoing. 2. Gene signature refers to a set of genes whose expression characterizes the activity of a specific biological process or a cell state e.g. EMT proliferation stemness etc. Gene signatures are widely used to infer the state of a biological system based on transcriptomic data. However the available gene signatures lack tissue or cellular context. For instance a stemness signature derived from one tissue context may not be perfectly applicable to another tissue context. Across tissues overlapping yet distinct sets of genes are likely to mediate a specific biological process. In a new project we aim to derive cancer type-specific gene signatures initially for 14 oncogenic hallmark processes across 23 cancer types by integrating the available context-agnostic gene signatures with the protein interaction network and cancer-specific transcriptomic data. Our preliminary results suggest that for several hallmarks most notably DNA Damage DNA Repair and EMT the derived tissue-specific gene signatures are significantly more prognostic of survival in the corresponding cancer than the context-agnostic signatures. 157745 +No NIH Category available Biology;Breast;Cell Line;Cells;Chemoresistance;Collaborations;Data;Data Set;Gene Expression;Gene Expression Regulation;Genes;Hematologic Neoplasms;Hematopoietic;Human;Immunotherapy;Kidney;Length;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Measures;Mediating;Mediator;Messenger RNA;Methods;MicroRNAs;Mining;Modeling;Mus;Network-based;Noise;Nucleotides;Pathogenesis;Performance;Play;Poly(A) Tail;Post-Transcriptional Regulation;Protocols documentation;Publishing;RNA Interference;RNA Sequences;Reporting;Resistance;Resolution;Reverse Transcription;Role;SARS-CoV-2 infection;Sampling;Skin;Testing;Tissues;Training;Untranslated RNA;Work;biological systems;cancer heterogeneity;cell type;design;differential expression;gene network;gene regulatory network;human disease;improved;malignant breast neoplasm;melanoma;new technology;novel;response;single-cell RNA sequencing;tool;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;triple-negative invasive breast carcinoma;tumor Machine learning network-based models for gene expression activity function n/a NCI 10926433 1ZIABC011981-04 1 ZIA BC 11981 4 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 315490 NCI We have several subprojects to report on here: 1. We have developed a machine learning tool -- miRSCAPE -- to infer miRNA expression in a sample from its RNA-seq profile. We establish miRSCAPE's accuracy separately in 10 tissues comprising 10000 tumor and normal bulk samples and demonstrate that miRSCAPE accurately infers cell type-specific miRNA activities (predicted vs observed fold-difference correlation 0.81) in two independent datasets where miRNA profiles of specific cell types are available (HEK-GBM Kidney-Breast-Skin). When trained on human hematopoietic cancers miRSCAPE can identify active miRNAs in 8 hematopoietic cell lines in mouse with a reasonable accuracy (auROC = 0.67). Finally we apply miRSCAPE to infer miRNA activities in scRNA clusters in Pancreatic and Lung cancers as well as in 56 cell types in the Human Cell Landscape (HCL). Across the board miRSCAPE recapitulates and provides a refined view of known miRNA biology. miRSCAPE is freely available and promises to substantially expand our understanding of gene regulatory networks at cellular resolution. This work is now published at iScience. We are collaborating with Dr. Chi-Ping Day to apply miRSCAPE to single cell data in mouse melanoma model derived cells to investigate the miRNAs mediating the resistance to immunotherapy. 2. We have been extending miRSCAPE to infer transcription factor (TF) activity in single cells and our preliminary results show substantial improved over widely used tools. 3. We have applied our Network-based transcriptome mining tool PathExt to understanding breast cancer heterogeneity and TNBS therapy resistance. Our study shows greater commonality among BRCA subtype than what the conventional transcriptome-based approach may suggest. We also identify FOXA1 as a key mediator of neo-adjuvent chemotherapy resistance in triple negative breast cancer. This work has now been submitted. 4. We are extending our PathExt tool (originally designed for bulk transcriptomic data) to single cell transcriptomic data as an alternative tool to identify cell type/state markers. 315490 +No NIH Category available Affect;Binding;Binding Sites;Biological Process;Cell Line;Cell Nucleus;Cells;Central Nervous System Diseases;ChIP-seq;Code;Cognition;Collaborations;Complex;Computer Analysis;Data;Data Set;Developmental Process;Effectiveness;Embryo;Enhancers;Evolution;Exhibits;Gene Expression;Gene Expression Regulation;Genes;Genetic Polymorphism;Genetic Transcription;Genome;Genomics;Glean;Goals;Housekeeping;Human;Incidence;Interneurons;Journals;Macaca;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Mutation;Neocortex;Nucleotides;Pattern;Pongidae;Prefrontal Cortex;Process;Property;Publications;Publishing;Race;Sampling;Science;Single Nucleotide Polymorphism;Somatic Mutation;Untranslated RNA;Variant;Work;cancer initiation;cancer type;deep learning model;driver mutation;experimental study;genome sequencing;neocortical;neural;novel;racial disparity;stem cells;tool;trait;transcription factor;trend;tumor;tumor progression;whole genome Identifying non-coding drivers of cancer n/a NCI 10926432 1ZIABC011979-04 1 ZIA BC 11979 4 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 236617 NCI "We have made major progress in the developing the methods and tools and showing its efficacy in identifying mutations in the non-coding regions of the genome during human diversification from other great apes that presumably have created novel regulatory enhancers active in the developing prefrontal cortex. Using deep learning model of embryonic neocortical enhancers and human and macaque embryonic neocortex H3K27ac data we identified 4000 enhancers gained de novo in the human largely attributable to single-nucleotide essential mutations. The genes near de novo gained enhancers exhibit increased expression in human embryonic neocortex relative to macaque are involved in critical neural developmental processes and are expressed specifically in the progenitor cells and interneurons. The gained enhancers especially the essential mutations are associated with central nervous system disorders/traits. Integrative computational analyses suggest that the essential mutations establish enhancer activities through affecting binding of key transcription factors of embryonic neocortex. Overall our results suggest that non-coding mutations may have led to de novo enhancer gains in the embryonic human neocortex that orchestrate the expression of genes involved in critical developmental processes associated with human cognition. This work is published in Science Advances. Encouraged by the effectiveness of the method in prioritizing non-coding mutations during evolution we are now in the process of evaluating the non-coding mutations in cancer. The challenge has been identifying matched healthy and tumor whole genome sequence data in sufficient numbers. We have now identified 10 such matched datasets in Esophaegeal cancer. Also for lack of whole genome sequencing data we have utilized the H3K27AC ChIP-seq data in these samples to identify non-coding mutations. We have also initiated a new collaboration to prioritize race-specific polymorphisms in the enhancer regions to understand the racial disparity in prostate cancer incidence. These efforts are still in the early stages. Additional activity under this projects involves a collaboration where we analyze the spatial organization ofTranscription factor (TF) binding in the nucleus. We find that in multiple cell line contexts TFs form two groups such that TFs within a group 'attract' each other and those across the groups 'repel'. The same trend is also seen in the linear organization of the TF binding on the genome suggesting a co-evolution of the linear genome with the spatial organization. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties as well in their function-while one group regulates housekeeping function the other potentially regulates lineage-specific functions that are disrupted in cancer. We also show that weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest a complex pattern of spatial cooperativity of TFs that has evolved along with the genome to support housekeeping and lineage-specific functions. This work is accepted for publication in Cell journal ""Heliyon""." 236617 +No NIH Category available Alternative Splicing;Antineoplastic Agents;Brain;Cancer Patient;Cancer cell line;Cells;Collaborations;Communication;Data;Deposition;Development;Embryo;Embryonic Development;Event;Exhibits;Exons;FDA approved;FOXM1 gene;Foundations;Gene Expression;Genes;Genetic Transcription;Goals;HepG2;Human;Intracellular Transport;Link;Liver;Logic;Malignant Neoplasms;Manuscripts;Mediating;Mesenchymal;Mus;Mutation;Natural regeneration;Neoplasm Metastasis;Oncogenic;Organ;Organogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Process;Proliferating;Proteins;Publishing;RNA Splicing;Reporting;Resistance;Role;Schwann Cells;Side;Spliced Genes;Tissue Differentiation;Transmembrane Domain;Work;Writing;biological adaptation to stress;cancer cell;cancer type;experimental study;glycosylation;knock-down;melanoblast;melanoma;novel;response;small hairpin RNA;stem cells;theories;transcription factor;transcriptomics;tumor;tumor microenvironment;tumor progression;tumorigenesis;wound healing Developmental origins of cancer n/a NCI 10926431 1ZIABC011978-04 1 ZIA BC 11978 4 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 394362 NCI We have three subprojects to report. 1. Leveraging temporal transcriptomic data during development in multiple human organs we demonstrate that the 'embryonic positive (EP)' alternative splicing events specifically active during human organogenesis are broadly reactivated in the organ-specific tumor. EP events are associated with key oncogenic processes and their reactivation predicts proliferation rates in cancer cell lines as well as patient survival. EP exons are significantly enriched for nitrosylation and transmembrane domains coordinately regulating splicing in multiple genes involved in intracellular transport and N-linked glycosylation respectively known critical players in cancer. We infer critical splicing factors (CSF) potentially regulating these EP events and show that CSFs exhibit copy number amplifications in cancer are mutational hotspots and somatic drivers in multiple cancer types and upregulated specifically in malignant cells in the tumor microenvironment. Mutational inactivation of CSFs in cancer patients and shRNA knockdown in HepG2 cell line results in decreased EP splicing supporting their causal role. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of CSFs in brain and liver which can be potentially targeted using FDA approved drugs. Our study provides the first comprehensive demonstration of a splicing-mediated link between development and cancer and suggest novel targets including splicing events splicing factors and transcription factors. This work was published in Nat Communications. 2. In collaboration with Merlino lab@NCI we have analyzed the in-house single cell transcriptomics data of developing melanoblasts in mouse at 2 developmental timepoints - E11.5 and E15.5. We have identified several cellular states among the developing melanoblasts and show that some of the Schwann cell progenitor and Mesenchymal states are recapitulated in the melanoma metastasis. Through an extensive analysis of publicly available data we show that these states are associated with patient survival in human melanoma and are associated with vemurafenib and ICB resistance. The manuscript was deposited in BioRXiv and . 3. As a side project we have also started analyzing the links between oncogenesis and three key homeostatic processes namely Stress response Wound Healing and Regeneration. We have compiled genes associated with these processes from original perturbation experiments in multiple species. We show that indeed known human cancer drivers highly overlap with these processes are proximal to these processes in the protein-interaction network and very interestingly we show that based simply on the proximity from these processes in the protein interaction network we can predict known cancer drivers from other genes. We are currently writing a manuscript reporting this work. 4. Following up on our Nat Comm work (#1 above) we are launched a new project exploring the rolw of alternative splicing in cancer drug response and resistance. 394362 +No NIH Category available 2019-nCoV;Adopted;Adoptive Transfer;Animals;Ankylosing spondylitis;Antigen-Presenting Cells;Apoptotic;Autoimmune;Autoimmune encephalitis;Blocking Antibodies;CD4 Positive T Lymphocytes;CXCL3 gene;Cell Surface Receptors;Cells;Colitis;Couples;Death Domain;Disease;Evaluation;Granulocyte-Macrophage Colony-Stimulating Factor;IL17 gene;Immune response;Inflammation;Inflammatory;Innate Immune Response;Interferon Type II;Interleukin-10;Interleukin-4;Knockout Mice;Macrophage;Malignant Neoplasms;Minor;Modeling;Mus;Pancreatic Ductal Adenocarcinoma;Pathogenicity;Pathologic;Pathway interactions;Psoriasis;Regulation;Regulatory T-Lymphocyte;Rheumatoid Arthritis;Role;Shapes;Signal Transduction;T-Cell Activation;T-Cell Depletion;T-Lymphocyte;TNF gene;TNFRSF1A gene;Tumor Immunity;Tumor Necrosis Factor Receptor;Virus Diseases;adaptive immune response;anti-tumor immune response;cytokine;immune cell infiltrate;in vivo;migration;response;single-cell RNA sequencing;transcription factor;transcriptome sequencing;transcriptomics;tumor;tumor microenvironment TNF and inflammation n/a NCI 10926429 1ZIABC011976-04 1 ZIA BC 11976 4 9692263 "ASHWELL, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 457987 NCI "CD4+ T cells are ""skewed"" to different ""T helper"" (Th) fates by activating them in the presence of certain cytokine cocktails. Among the best studied Th subsets are Th1 (master transcription factor: T-bet signature cytokine: IFN-gamma) Th2 (GATA-3 and IL-4) and Th17 (RORgt and IL-17). Th17 cells can be further roughly divided into non-pathogenic and pathogenic cells. The former express immunosuppressive IL-10 whereas the latter express inflammatory products such as GM-CSF and CXCL3. We have found that when naive CD4+ murine T cells are skewed in the presence of TNF as the primary cytokine they adopt an inflammatory Th17 state. We have used both antibody-blocking and the analysis of knockout mice to determine that TNFR2 (the minor TNF receptor) is responsible for this. In addition in vivo studies of various autoimmune inflammatory models (e.g. experimental autoimmune encephalopathy (EAE) and colitis due to adoptive transfer of Treg-depleted T cells) with the corresponding TNFR knockout mice have demonstrated a role for TNF signaling in pathological Th skewing. Evaluation of the composition of immune cell infiltrates as well as transcriptomic analysis both bulk RNA sequencing (RNA-seq) and single cell RNA sequencing (scRNA-seq) has provided a precise picture of how TNF regulation of Th skewing and how it alters the adaptive and innate immune responses. These studies have shown that TNF signaling is upstream of inflammatory Th responses and exacerbates autoimmune/inflammatory diseases. The major and best-studied TNF receptor is TNFR1. We have found that mice deficient in TNFR1 are better able to deal with inflammatory tumors such as pancreatic ductal adenocarcinoma (PDAC). This is due to an enhanced anti-tumor immune response. We are exploring this phenomenon in vivo using mice that spontaneously develop PDAC and are characterizing the innate and adaptive immune response in these animals. Our results indicate that signaling via TNFR1 suppresses the migration and function of antigen-presenting cells in the tumor microenvironment and its abrogation results in enhanced tumor immunity and survival." 457987 +No NIH Category available Address;Affinity;Antibody Affinity;Antigen Receptors;Apoptosis;Autoantigens;Autoimmune Diseases;B cell differentiation;B-Cell Antigen Receptor;B-Lymphocytes;Biology;Bone Marrow;Cell Death;Cells;Cellular biology;Complex Mixtures;Cues;Dangerousness;Dendritic Cells;Dendritic cell activation;Development;Disease;Experimental Autoimmune Encephalomyelitis;Genes;Goals;Guidelines;Human;IgG autoantibodies;Immune;Immune response;Immunize;Immunologist;Informal Social Control;Memory B-Lymphocyte;Methods;Multiple Sclerosis;Mus;Mutation;Pathogenicity;Plasma Cells;Play;Process;Production;Proliferating;Publications;Reaction;Regulation;Research;Role;Self Tolerance;Serum;Structure of germinal center of lymph node;T-Cell Activation;T-Lymphocyte;TNFRSF5 gene;Tissues;adaptive immune response;adaptive immunity;antigen binding;autoreactivity;cell type;experimental study;human disease;immunoregulation;improved;mouse model;protocol development;reconstitution Regulation of self-tolerance and adaptive immunity by cell death and other cues n/a NCI 10926428 1ZIABC011975-04 1 ZIA BC 11975 4 77857435 "MAYER, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1189648 NCI B lymphocytes assemble the genes encoding for the antigen receptor (B cell receptor BCR) during their development in the bone marrow. Once a diverse repertoire of naive B cells has been generated only those B cells that can best respond to an antigenic challenge become activated start to proliferate and some of those clones may also seed a germinal center (GC) reaction. GC B cells introduce mutations into the BCR-encoding genes and select for cells with increased antigen binding affinity. During these dynamic processes memory B cells and high-affinity antibody producing plasma cells are also generated. B cell affinity maturation requires help from specialized T cells which are activated by dendritic cells (DCs). BCR assembly in the bone marrow and BCR mutation in GCs both result in the production of self-reactive B cells. How these potentially dangerous cells are controlled is a long-standing question that has puzzled immunologists. Our lab studies apoptosis as one proposed mechanism to delete self-reactive B cells. We have made progress in developing improved methods to detect autoreactivity and established new mouse models that will allow addressing these questions. Another potential mechanism to control self-reactive B cells is to inhibit their activity directly or indirectly for example by altering T cell activation by dendritic cells. Co-stimulatory molecules such as CD40 are expressed by both DCs and B cells but the role CD40 plays in each cell type during autoimmune disease is not well understood. We contributed to a collaborative study dissecting the role of CD40 in DCs and B cells in experimental autoimmune encephalomyelitis resembling the human autoimmune disease multiple sclerosis. CD40 in dendritic cells was crucial for priming pathogenic T cells whereas CD40 in B cells made an independent contribution to the disease. Disease could be reconstituted in autoantigen-immunized mice lacking CD40 in B cells by transferring serum from diseased mice. We helped to trace this pathogenic contribution of B cells to IgG autoantibodies. Harnessing DCs for modulating immune responses first requires a basic understanding of DC biology. DCs have been difficult to study because they are extremely rare immune cells and come in different subsets. These include conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Among cDCs we further distinguish cDC1 and cDC2 subsets that differ in development and function. DC research has been greatly facilitated by the development of protocols to culture bone marrow precursors and differentiate them into DCs. Existing culture methods produce large numbers of DCs that allow experiments to dissect their biology. However these DCs often do not correspond well to the DCs found in tissues or they are complex mixtures of cDC1 cDC2 and pDCs and thus require further purification steps. I have previously developed a new culture method called iCD103 that allows differentiating large numbers selectively of the cDC1 subset. This greatly facilitated research on this DC subset without the need for further purification and is now widely used in the field. I have contributed to a study highlighting current guidelines on the methods used for studying DC biology. A section on the iCD103 method is included in this publication. 1189648 +No NIH Category available 2019-nCoV;Affect;Antiviral Agents;Biological Assay;COVID-19;Cells;Chymase;Containment;Coronavirus;Development;Enzymes;FDA approved;Genes;Genome;Goals;Human;Nonstructural Protein;Open Reading Frames;Papain;Peptide Hydrolases;Pharmaceutical Preparations;Polyproteins;Population;Protease Inhibitor;Proteins;RNA;RNA Viruses;RNA replication;RNA-Directed RNA Polymerase;SARS coronavirus;SARS-CoV-2 inhibitor;SARS-CoV-2 protease;Site;Structural Protein;Toxic effect;Translating;Viral;Viral Genome;Virus;Virus Replication;absorption;high throughput screening;improved;in vitro Assay;mRNA Translation;novel coronavirus;small molecule Development of Cell-based Assays to Identify SARS-CoV-2 Protease Inhibitor n/a NCI 10926424 1ZIABC011969-04 1 ZIA BC 11969 4 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 66890 NCI Coronaviruses are positive-strand RNA viruses with exceptionally large genomes (27-32 kb). All coronaviruses encode the enzymes required for their replication in genes 1a and 1b. Genes 1a and 1b are translated as polyproteins; 1b is expressed by -1 frameshifting at the end of the 1a open reading frame. In both SARS-CoV and SARS-CoV-2 the 1a polyprotein contains two proteases a papain-like (PL) protease and a 3-chymotrypsin-like (3CL) protease. Together these proteases cleave polyprotein at 14 sites (3 for PL protease 11 for 3CL protease) generating 16 nonstructural proteins (nsps). These proteins include viral enzymes required for RNA replication including RNA-dependent RNA polymerase. The RNA replication machinery not only generates more copies of the viral genome but also generates subgenomic RNAs that act as mRNAs for the translation of structural proteins. Thus the PL and 3CL proteases are critical for viral replication which make them excellent targets for antivirals. ___We have developed a human cell-based assay that can be used to identify inhibitors of the SARS-CoV-2 3CL protease. This assay has advantages over other protein-based assays that are often affected by in vitro assay conditions and do not account for compound absorption and toxicity issues. Furthermore this assay can be used in BSL-2 containment making it far more accessible than the existing BSL-3 replication-competent virus assays which are not amenable to high-throughput platforms. We are currently modifying the assay to make it suitable to determine the 3CL protease activity of multiple coronaviruses that can infect the human population. The main goal is to have an assay that can be quickly adapted to screen for antivirals against emerging coronaviruses. 66890 +No NIH Category available 2019-nCoV;ATP phosphohydrolase;Address;Binding;Binding Proteins;Biogenesis;Cell Surface Receptors;Cells;Cellular Membrane;Collaborations;Coronavirus;Coronavirus spike protein;Cryo-electron tomography;Development;Endothelial Cells;Epithelial Cells;Family;Genes;Goals;HIV;HIV envelope protein;HIV-1;Human;Immune;Immune response;Infection;Innate Immune Response;Integration Host Factors;Interferon Type II;Interferons;L-Selectin;Measures;Mediating;Membrane;Membrane Glycoproteins;Middle East Respiratory Syndrome Coronavirus;National Institute of Environmental Health Sciences;Natural Immunity;P-selectin ligand protein;Play;Proteins;Publishing;Role;SARS coronavirus;SARS-CoV-2 spike protein;Structure;Surface;Tertiary Protein Structure;Therapeutic Intervention;Tissues;Vaccine Design;Vaccines;Viral;Viral Physiology;Virion;Virus;Virus Diseases;Virus Replication;Virus-like particle;Work;adaptive immunity;airway epithelium;antagonist;antiviral drug development;cell motility;cell type;experience;guanylate;insight;mutant;neutralizing antibody;particle;protein transport;trafficking;ubiquitin-protein ligase;viral entry inhibitor;viral transmission Antagonism of Coronavirus Spike Proteins by Cellular Host Factors n/a NCI 10926423 1ZIABC011968-04 1 ZIA BC 11968 4 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 54403 NCI In a structural and functional analysis of the SARS-CoV-2 S protein that we recently started we have determined that MARCH8 but not a catalytically inactive MARCH8 mutant targets the S proteins of SARS-CoV MERS-CoV and SARS-CoV-2 for degradation. We also showed that human airway epithelial cells express MARCH8 upon treatment with IFN. The work on MARCH protein-mediated antagonism may reveal new opportunities for therapeutic intervention with S protein trafficking and incorporation into virus particles. This work was recently published (mBio 12: e00219-21 2021). _____In a separate study we showed that virion incorporation of PSGL-1 on SARS-CoV and SARS-CoV-2 pseudovirions blocks S protein-mediated virus attachment and infection of target cells. These results demonstrate that PSGL-1 can serve as an IFN-regulated host factor that restricts CoV infectivity. This work was recently published (Viruses 13: 46 2020). _____We are now focusing on defining the mechanism by which MARCH E3 ubiquitin ligases antagonize the SARS-CoV-2 S protein evaluating the antiviral activity of GBP ATPases against the SARS-CoV-2 S protein and measuring the expression of host cell anti-SARS-CoV-2 S protein antagonists in relevant cell types. 54403 +No NIH Category available 2019-nCoV;ACE2;Binding;Cell Culture Techniques;Cell Line;Cell membrane;Cell surface;Cells;Cholesterol;Collaborations;Complement;Coronavirus Infections;Data;Endosomes;Exhibits;Goals;HIV;Human;IFITM1 gene;Immune;Infection;Influenza A virus;Journals;Mediating;Ohio;Pathway interactions;Peptide Hydrolases;Play;Proteins;Protocols documentation;Publishing;Research;Role;Route;SARS coronavirus;SARS-CoV-2 infection;SARS-CoV-2 spike protein;SARS-CoV-2 variant;Severity of illness;TMPRSS2 gene;Transfection;Universities;Vesicular stomatitis Indiana virus;Virus;Work;human coronavirus;in vivo;mutant;novel coronavirus;permissiveness;protein function;receptor;respiratory virus;variants of concern Deciphering the Double-Edged Role of IFITM3 during SARS-CoV-2 Infection n/a NCI 10926422 1ZIABC011967-04 1 ZIA BC 11967 4 15201721 "COMPTON, ALEX " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 111969 NCI We have successfully produced HIV-based and VSV-based pseudovirus bearing the spike protein of SARS-CoV-1 and SARS-CoV-2 variants and produced cell lines that are permissive to these pseudoviruses. We have developed a protocol for transiently transfecting human ACE2 (the receptor for SARS-CoV-1 and SARS-CoV-2) and TMPRSS2 (a protease that activates the fusion potential of SARS-CoV-1 and SARS-CoV-2 spike proteins) into HEK293T cells stably expressing human IFITM1 IFITM2 IFITM3 and mutants thereof. We then challenged these cells with the pseudoviruses and found that the human IFITM proteins inhibit both SARS-CoV-1- and SARS-CoV-2-mediated entry into cells albeit to different extents. Whereas IFITM3 strongly inhibits SARS-CoV-1-mediated entry it only slightly inhibits that driven by SARS-CoV-2. Furthermore if target cells express TMPRSS2 the inhibitory effect of IFITM3 is negligible. These results suggest that viruses utilizing TMPRSS2 have decreased sensitivity to IFITM proteins indicating that TMPRSS2 usage may alter the virus entry route into the cell and may be a means for the virus to evade intrinsic immune barriers. To complement our studies we are collaborating with Jacob Yount at Ohio State University where infections with replication-competent SARS-CoV-2 can be performed. The first chapter of our collaborative work was published in the EMBO Journal (Shi et al. EMBO J. 2021). Interestingly we found that IFITM3 localized to endosomes restricts SARS-CoV-2 infection while IFITM3 at the plasma membrane promotes SARS-CoV-2 infection. This finding demonstrated that SARS-CoV-2 may coopt IFITM3 at the cell surface for its own benefit and provides yet another explanation for why SARS-CoV-2 exploits a cell entry pathway at the cell surface while SARS-CoV-1 does not. Currently we are investigating the mechanisms by which IFITM3 promotes SARS-CoV-2 fusion at the plasma membrane and we are assessing whether the recently evolved variants of concern including Omicron exhibit the same capacity to use IFITM3 for its own benefit. We will explore how the amphipathic helix and its cholesterol binding activity contribute to the promotion of SARS-CoV-2 infection by IFITM3. 111969 +No NIH Category available Adrenocortical carcinoma;Biology;Blood;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer cell line;Cells;Chromatin;Collaborations;Data;Data Set;Drug resistance;Endothelial Cells;Engineering;Environment;Future;Gene Expression;Genes;Genetic Transcription;Goals;Immune;Individual;Interleukin-12;Learning;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Mus;Myeloid Cells;Neoplasm Metastasis;Patients;Pharmaceutical Preparations;Pharmacotherapy;Population;Primary Neoplasm;Property;Publishing;Relapse;Repression;Specific qualifier value;T-Cell Development;T-Lymphocyte;The Cancer Genome Atlas;Thymus Gland;Tissues;Work;cell type;cohort;computational pipelines;differential expression;exhaust;overexpression;prognostic;single-cell RNA sequencing;therapy resistant;transcriptome;transcriptomics;tumor Transcriptomic origins of cancer n/a NCI 10926419 1ZIABC011964-04 1 ZIA BC 11964 4 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 473235 NCI 1. We are currently developing a computational pipeline to do so. We learn each drugs effect on the global transcriptome in a specific cell types (from public datasets like CCLE and CytoSig) and by comparing that with the transcriptional difference between two cell states (say exhausted T cells versus active T cell states) we attempt to prioritize individual drugs by their potential to reverse cell state. This approach recovers for instance IL12 as a potential therapy to alter pre-metastatic niche in lung cancer (previously identified by our collaborator Dr Rosie Kaplan). The work is under progress. 2. We have made substantial progress in analyzing and characterizing the tumor and adjacent normal micro-environment of lung and liver metastasized Adrenal Cortical Carcinoma (ACC) tumors in the NCI cohort. This work is done in collaboration with Dr. Rosie Kaplan. Bulk (80%) of the work is completed and we have found several cell type-specific states in the metastasis and adjacent normal microenvironment (for example Tip and Stalk endothelial cells Exhausted T cell etc) uniquely found in met and adjacent environments that are prognostic of patient survival in TCGA. Intriguingly our analysis has identified 5 lncRNAs that are broadly over expressed in metastasis and the adjacent tissues across all cellular compartments and are strongly associated with survival in TCGA data. 3. We have launched a new project to characterize cellular states emerging in cancer cell lines after drug treatment as a way to characterize drug-resistant states and study their properties regulators and implication in understanding therapeutic resistance and relapse. 473235 +No NIH Category available Acquired Immunodeficiency Syndrome;Animal Model;Animals;Area;B cell repertoire;B-Lymphocytes;Basic Science;Binding Proteins;Biochemical;Biological;Biopsy;Bypass;Cancer Burden;Cause of Death;Cell Culture System;Cell Culture Techniques;Cell Line;Cell Nucleus;Cell Proliferation;Cells;Clinical;Clinical Trials;Clonal Expansion;Clonality;Collaborations;Complex;DNA biosynthesis;Data;Data Set;Development;Disease;Endothelial Cells;Epstein-Barr pathogenesis;Etiology;Event;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Recombination;Genetic Risk;Genome Stability;HIV;HIV/AIDS;Herpesviridae;Herpesviridae Infections;Host Defense;Human;Human Herpesvirus 4;Human Herpesvirus 8;Immunoglobulins;Immunologic Deficiency Syndromes;Implant;Individual;Infection;Interferons;Interphase Cell;Intervention;Investigation;Kaposi Sarcoma;Knock-out;Knowledge;Laboratories;Learning;Lytic;Malignant - descriptor;Malignant Neoplasms;Molecular;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Mus;Nuclear;Nucleotides;Oncogenic;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Process;Productivity;Proliferating;Property;RRM1 gene;Reporting;Research;Research Personnel;Risk;Role;STAT1 gene;STAT3 gene;Sampling;Series;Signal Transduction;Source;Structure;Structure of germinal center of lymph node;System;T-Lymphocyte;Therapeutic;Trans-Activators;Transgenic Mice;Viral;Viral Genome;Viral Physiology;Viral Proteins;Virus;Xenograft procedure;antiretroviral therapy;cell transformation;cohort;conditional knockout;cytokine;dUTP pyrophosphatase;differential expression;gammaherpesvirus;infected B cell;lymph nodes;mortality;mouse model;next generation sequencing;novel;nucleotide metabolism;participant enrollment;pathogen;patient derived xenograft model;pre-clinical;pre-clinical research;primary effusion lymphoma;programs;protein metabolism;rational design;receptor;response;synergism;transcriptome sequencing;tumor;uracil-DNA glycosylase;viral DNA;virus host interaction Investigation of viral and host determinants of gammaherpesvirus pathogenesis n/a NCI 10926414 1ZIABC011953-04 1 ZIA BC 11953 4 9786523 "KRUG, LAURIE T" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1358576 NCI (1) STAT3 activation is associated with gammaherpesvirus latency and cancer in cell culture systems but the target genes that drive latency proliferation and transformation are not well-defined. As a prelude to studying the effects of STAT3 activation in KSHV itself we used transgenic mice with a B cell-specific knock-out of STAT3 to determine that STAT3 signaling is critical for the establishment of gammaherpesvirus latency in primary B cells of the host. We also determined that the viral lytic gene transactivator RTA interacts with STAT3 in a cytokine-dependent manner. Our central hypothesis is that gammaherpesviruses require STAT3 to promote B cell latency. To define the STAT3-dependent gene expression program of infected B cells we performed RNAseq to compare the gene expression profile in infected cells with and without STAT3. Thus far we have identified a pro-viral role of STAT3 in dampening the interferon response in B cells via STAT3 inhibition of STAT1/2 and numerous antiviral interferon-stimulated genes. We will merge differentially expressed genes from all available gammaherpesvirus datasets to identify and prioritize common STAT3-regulated pathways and target genes. These will lead to further investigations of latency reactivation and transformation in KSHV and murine cell culture systems using conditional knock-out approaches. (2a) The numerous herpesvirus genes involved in nucleotide metabolism indicate that the nucleotide pool is a major restriction point in non-dividing cells. We recently reported that the enzymatic properties of the viral uracil DNA glycosylase (UNG) synergize with the viral nucleotide metabolism protein dUTPase to promote pathogenesis and counter recombination-based deletions in the viral genome. We are currently exploring protein binding partners of the viral UNG. In collaboration with Kevin McBride we are examining the differential biochemical properties of the viral and host UNG. (2b) Also in collaboration with the McBride lab we analyzed the immunoglobulin repertoire of infected and uninfected B cells from infected mice using next generation sequencing. This analysis revealed that gamamherpesvirus-infected cells undergo clonal expansion yet only a few clones were shared between the infected and uninfected germinal center B cells. There is also evidence for receptor editing and clear bias for specific IghV genes in the infected B cells. These novel data indicate the gammaherpesviruses occupy a distinct niche in the infected host and takes an active role in subverting the immunoglobulin repertoire in the B cells that it infects. This supports the existence of a critical strategy that is shared with KSHV and EBV namely that these viruses bypass normal selection processes placing the B cells at risk for genetic instability and for producing immunoglobulins with pathologic potential. I am also collaborating with other NCI investigators and clinicians in HAMB to analyze the B cell repertoire of KSHV-infected cells in HIV-associated primary effusion lymphoma and lymph node material of HIV-infected KSHV-multicentric Castleman disease patients enrolled in HAMB clinical trials. This will enable us to examine the clonality and source of the B cell transformation. Importantly this might inform the possible etiology of these diseases which often occur in a concurrent or sequential manner in people living with HIV. (3) We are examining the mechanism by which the viral ribonucleotide reductase large subunit relocalizes host nuclear defense factors termed PML-NB into track-like structures. We hypothesize that this relocalization by the virus neutralizes their antiviral functions and promotes productive infection. (4) With regard to the development of direct animal models of Kaposi sarcoma a hallmark tumor of AIDS I am collaborating with clinicians in the HIV and AIDS Malignancy Branch and in the Center for Advanced Preclinical Research (CAPR) of NCI Frederick in more translational projects towards the establishment of a patient-derived xenograft model. KS biopsy material from HIV infected patients in the HAMB clinical cohorts is being implanted into immunodeficient animals. Thus far we observe KSHV-infected endothelial cell proliferation and expansion in the xenografts. Cell lines derived from this system that maintain KSHV infection and drive tumors in mice will be a tremendous advancement for the field since there is no way to maintain KSHV+ endothelial cells upon explant and there is no pre-clinical animal model of Kaposi sarcoma to screen for effective drug interventions of this AIDS-defining cancer. 1358576 +No NIH Category available Acute;Antibody Formation;Antigens;B-Lymphocytes;COVID-19 pandemic;COVID-19 patient;Clone Cells;Collaborations;Data;Genes;Immune;Immune response;Immune system;Immunoglobulins;Lymphoma;Malignant Neoplasms;Maryland;Mutate;Outcome;Patients;Pattern;Persons;Population;Publications;Publishing;SARS-CoV-2 antibody;Sampling;Symptoms;Testing;Time;Universities;Vaccination;Variant;Work;chemotherapy;coronavirus disease;experience;rituximab Patterns of immune response in COVID-19 patients n/a NCI 10926413 1ZIABC011952-04 1 ZIA BC 11952 4 6212020 "KREITMAN, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 185073 NCI The 1st project involving patients without active malignancy who are acutely infected with COVID has been completed and submitted for publication. we found a broad distribution of responding B-cell clones without noticeable skewing of IGHV gene usage. Some patients demonstrated monoclonal populations carrying highly mutated IGHV rearrangements indicating antigen experience at a few or all of the time points tested including even before anti-SARS-CoV2 antibodies were detected. We did not find a particular pattern of immune response correlating with outcome. Data from the latter 2 projects are still being collected as we receive samples drawn mainly to follow HCL. For the 2nd project a total of 253 HCL patients with COVID19 have been tested including 238 with HCL 15 with HCL variant (HCLv). We found striking differences in the immune response to COVID with respect to antibody production with respect to recent treatment and presence of normal B-cells. This work has been submitted for publication. Data for the 3rd project is currently being analyzed. A patient with lymphoma who had multiple vaccinations after rituximab-containing chemotherapy was recently published in collaboration with Dr. Rappaport at University of Maryland. 185073 +No NIH Category available 2019-nCoV;Address;Antibodies;Antibody Response;Binding;Binding Proteins;Biological;C Type Lectin Receptors;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;COVID-19;COVID-19 pandemic;COVID-19 patient;Cell Degranulation;Cell physiology;Cells;Cellular Stress;Classification;Collaborations;Coronavirus;Data;Diagnosis;Disease Outcome;Down-Regulation;Family;Genes;Genetic;Genetic Transcription;Hepatitis Viruses;Herpesviridae;Human;Immune;Immune Response Genes;Immune response;Immunity;Immunoglobulins;Immunotherapy;Impairment;In Vitro;Individual;Infection;Killer Cells;Ligands;Lymphocyte;MMP9 gene;Major Histocompatibility Complex;Malignant - descriptor;Mediating;Messenger RNA;Molecular;Monoclonal Antibodies;Mutation;Natural Killer Cells;Pathogenesis;Prevention;Proteins;Receptor Down-Regulation;Research;Research Personnel;Role;SARS-CoV-2 infection;Sarbecovirus;Severity of illness;Signal Transduction;Surface;T cell response;T-Lymphocyte Subsets;Testing;Transfection;Vaccination;Variant;Viral;Viral Proteins;Virus;Virus Diseases;cancer cell;cancer therapy;cell killing;cytotoxic;cytotoxicity;genetic association;genetic resistance;influenzavirus;lung xenograft;neutralizing antibody;novel;novel strategies;pandemic impact;preclinical study;receptor;receptor downregulation;response;severe COVID-19;tumorigenesis;variants of concern;virtual Host genetic resistance to COVID-19 n/a NCI 10926412 1ZIABC011949-04 1 ZIA BC 11949 4 9414396 "CARRINGTON, MARY N." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 127700 NCI Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing COVID-19 pandemic. The pandemic's impact has spurred research into the pathogenesis diagnosis treatment and prevention of SARS-CoV-2 and its emerging variants of concern. Prior studies have elucidated the role of neutralizing antibody responses to SARS-CoV-2 and the emergence of viral variants that escape these responses via mutations in spike protein. In addition the critical role of T-cell responses against SARS-CoV-2 has also been well-established. However research addressing the role of natural killer (NK) cells in SARS-CoV-2 infection is limited. NK cells and some CD8+ T-cell subsets express a variety of germline-encoded activating and inhibitory receptors which are broadly classified into three families: natural cytotoxicity receptors (e.g. NKp46) killer-cell immunoglobulin-like receptors (KIRs) and C-type lectin NK group 2 (NKG2) receptors. Activating receptors such as NKG2D can bind a variety of ligands expressed in the context of cellular stress. NKG2D is a potent activating receptor expressed on virtually all cytotoxic lymphocytes both NK cells and CD8+ T cells. NKG2D uniquely signals through the adaptor molecule DAP10 and binds to eight known ligands: major histocompatibility complex class I chain-related proteins A (MIC-A) and B (MIC-B) and UL16-binding proteins 1-6 (ULBP-1-6). These ligands are expressed in response to cellular stress induced by infection or tumorigenesis facilitating NK and CD8 T-cell recognition and killing via NKG2D. These ligands are targeted and downmodulated by many viruses including herpesviruses hepatitis viruses and influenza virus as well as by cancer cells to escape immune recognition and killing. Previous data have also shown that in several infectious and malignant contexts NKG2D ligand shedding increases systemic levels of soluble ligands which induces NKG2D receptor downregulation and impairs responsiveness and activity of both NK cells and CD8+ T cells. Studies analyzing immune responses in severe COVID-19 patients have revealed downregulation of NKG2D on circulating NK and CD8+ T cells as well as impaired function of these cells. As such given the involvement of NKG2D in cytotoxic immune cells it is important to study if and how this axis is modulated by SARS-CoV-2 and other coronaviruses. In collaboration with investigators at the Ragon Institute the effect of SARS-CoV-2 infection on NKG2D ligand modulation was investigated and it was found that SARS-CoV-2 and its variants downregulate NKG2D ligands including MIC-A/B from the surface of infected cells. Further this surface downregulation is the result of proteolytic cleavage mediated by endogenous sheddases which were found to be transcriptionally induced by SARS-CoV-2 infection. This occurs despite transcriptional induction of MICB mRNA and increased overall MIC-A/B whole-cell protein levels. It was confirmed that SARS-CoV-2 infection transcriptionally induces MICB and the sheddase MMP9 in human lung xenografts and sera from COVID-19 patients showed significantly increased levels of soluble MIC-A and MIC-B with MIC-A levels associating with disease severity. To identify viral protein responsible for this effect all 32 SARS-CoV-2 proteins in their native form were individually expressed (i.e. no tags) via mRNA transfection. Only ORF6 an accessory protein specific to mammalian sarbecoviruses was capable of downregulating MIC-A/B via shedding similar to live virus infection. Despite evasion from NKG2D recognition NK cells were still able to efficiently recognize and kill SARS-CoV-2-infected cells and also protect bystander cells from SARS-CoV-2 infection in vitro indicating protective NK cell mechanisms against the virus beyond NKG2D alone. Remarkably inhibition of MIC-A/B shedding in SARS-CoV-2-infected cells with 7C6 a monoclonal antibody in pre-clinical studies for the treatment of cancer resulted in further increased NK-cell killing and degranulation highlighting its potential role as a novel immunotherapy for COVID-19. Altogether the data demonstrate a novel strategy that SARS-CoV-2 employs to evade NK-cell immunity mediated by ORF6 accessory protein that is shared among sarbecoviruses and suggest a potential target for immunotherapy to subvert the immunevasive tactic of the virus. 127700 +No NIH Category available 2019-nCoV;ACE2;Affinity;Antibodies;Antibody Therapy;Antigen Targeting;Antigens;Attention;Bacteriophages;Binding;Binding Proteins;Biological;Biological Assay;CCR;COVID-19;COVID-19 diagnosis;COVID-19 pandemic;Camels;Cells;Complex;Cross Reactions;Cryoelectron Microscopy;Data;Development;Dose;Dromedaries;Etiology;Future;Human;Infection;Journals;K-18 conjugate;Laboratories;Libraries;Molecular Conformation;Nurses;Patients;Phage Display;Protein Engineering;Proteins;Publishing;Receptor Inhibition;Research;SARS coronavirus;SARS-CoV-2 B.1.351;SARS-CoV-2 B.1.617.2;SARS-CoV-2 antibody;SARS-CoV-2 spike protein;SARS-CoV-2 variant;Shark;Site;Structure;Surface;Therapeutic;Therapeutic antibodies;Transgenic Mice;Variant;Viral;Virus;Work;Writing;betacoronavirus;clinical efficacy;cross reactivity;global health;improved;nanobodies;neutralizing antibody;novel;pandemic disease;pathogenic virus;receptor;receptor binding;therapeutic target;variants of concern Development of neutralizing nanobodies against SARS-CoV-2 n/a NCI 10926408 1ZIABC011943-04 1 ZIA BC 11943 4 9692203 "HO, MITCHELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 290927 NCI During the pandemic Dr Ho has evaluated the challenges for developing antibody therapeutics targeting SARS-Cov-2 and wrote a review/perspective article [Ho Antibody Therapeutics 2020; PMID: 32566896]. SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore the S protein is the primary target for neutralizing antibodies. In FY2022 we summarized our work on isolation of dromedary camel nanobodies against SARS-CoV-2 and published the data in PNAS [Hong et al. PNAS. 2022]. We isolated two VHH nanobodies (7A3 and 8A2) from dromedary camels by phage display which have high affinity for the receptor-binding domain (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants. Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike regardless of the RBD conformational state. 7A3 at a dose of 5 mg/kg efficiently protects K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2 suggesting that the nanobody has promising therapeutic potentials to curb the COVID-19 surge with emerging SARS-CoV-2 variants. SARS-CoV-2 is the etiological agent of the COVID-19 pandemic. Antibody-based therapeutics targeting the spike protein specifically the S1 subunit or the receptor binding domain (RBD) of SARS-CoV-2 have gained attention due to their clinical efficacy in treating patients diagnosed with COVID-19. An alternative to conventional antibody therapeutics is the use of shark new antigen variable receptor domain (VNAR ) antibodies. VNAR s are small (15 kDa) and can reach deep into the pockets or grooves of the target antigen. In FY2023 we isolated 53 VNAR s that bind to the S2 subunit by phage panning from a naive nurse shark VNAR phage display library constructed in our laboratory. Among those binders S2A9 showed the best neutralization activity against the original pseudotyped SARS-CoV-2 virus. Several binders including S2A9 showed cross-reactivity against S2 subunits from other beta coronaviruses. Furthermore S2A9 showed neutralization activity against all variants of concern (VOCs) from alpha to omicron (including BA1 BA2 BA4 and BA5) in both pseudovirus and live virus neutralization assays. Our findings suggest that S2A9 could be a promising lead molecule for the development of broadly neutralizing antibodies against SARS-CoV-2 and emerging variants. The nurse shark VNAR phage library offers a novel platform that can be used to rapidly isolate single-domain antibodies against emerging viral pathogens. We published this work in FASEB Journal in FY2023 [Jesse Buffington Zhijian Duan Hyung Joon Kwon Jessica Hong Dan Li Mingqian Feng Hang Xie Mitchell Ho. Identification of nurse shark VNAR single-domain antibodies targeting the spike S2 subunit of SARS-CoV-2 FASEB J. 2023 Jun;37(6):e22973. doi: 10.1096/fj.202202099RR.] Ongoing studies aim to improve the potency and coverage of SARS-CoV variants by using protein engineering and combining both S1 and S2 neutralizing nanobodies isolated in the Ho laboratory at the CCR NCI. This work may also be helpful for future battles against SARS-CoV-like infections. 290927 +No NIH Category available 2019-nCoV;CCR;COVID-19;COVID-19 pandemic;COVID-19 treatment;Collaborations;Communities;Computer software;Detection;Disease;Flow Cytometry;HIV;Laboratories;Malignant Neoplasms;Manuscripts;Measurement;Methods;Molecular Analysis;Monitor;Physiologic pulse;Protocols documentation;Research;Resources;SARS-CoV-2 infection;Technology;Update;Viral;Virus;Virus Diseases;exosome;extracellular vesicles;nano;nanobiologic;nanobiology;open source;particle;programs;tool;web site Translational Nanobiology Approaches to Viral Diseases (HIV HTLV SARS-CoV2) n/a NCI 10926407 1ZIABC011942-04 1 ZIA BC 11942 4 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 86642 NCI We established and are maintaining an open-access resource at nano.ccr.cancer.gov wherein protocols and methods for virus and extracellular vesicle (EV) detection or characterization that is developed in this program are shared with the worldwide research community. Since launch of the website we have been posting updates on a near-weekly basis. Additional open source software relating to extracellular vesicles particles research has been added in 2022 and will be presented in upcoming manuscripts. New 2023 software includes 1) an updated FCMpass package for single EV flow cytometry and 2) updated post acquisition analysis software for resistive pulse sensing measurements. 86642 +No NIH Category available 2019-nCoV;ACE2;Adjuvant;Affect;Air Movements;Animal Model;Animals;Antibodies;Antibody Specificity;Antibody titer measurement;Antigens;Appearance;B-Lymphocyte Epitopes;Binding;Bioinformatics;Body Weight decreased;Bronchoalveolar Lavage Fluid;CD8-Positive T-Lymphocytes;COVID-19;COVID-19 prevention;COVID-19 susceptibility;COVID-19 vaccine;Cancer cell line;Cell Line;Cells;Cholesterol;Collaborations;Coupled;DNA Vaccines;Data;Dendritic Cells;Diet;Disease;Dose;Electroporation;Engineering;Epithelial Cells;FDA Emergency Use Authorization;Female;Formulation;Gender;Granulocyte-Macrophage Colony-Stimulating Factor;HIV vaccine;Hamsters;Human;Human Cell Line;Immune;Immune response;Immunity;Immunize;Immunoglobulin A;Immunoglobulin G;In Vitro;Industrialization;Infection;Infection prevention;Interferon Type I;Interleukin-12;Interleukin-15;Licensing;Ligands;Lung;Macaca;Macaca mulatta;Malignant neoplasm of lung;Medical center;Messenger RNA;Methods;Modeling;Monitor;Morbidity - disease rate;Mucosal Immunity;Mucous Membrane;Mus;Myeloid Cells;Nasal cavity;Natural Immunity;Non-Small-Cell Lung Carcinoma;Nose;Obesity;Omega-3 Fatty Acids;Oropharyngeal;Persons;Production;Proteins;Public Health;Publishing;RNA vaccine;Reagent;Recombinants;Respiratory Mucosa;Risk Reduction;Role;Route;SARS-CoV-2 B.1.1.529;SARS-CoV-2 B.1.617.2;SARS-CoV-2 infection;SARS-CoV-2 spike protein;SARS-CoV-2 variant;SIV Vaccines;Serum;Site;South African;T cell response;T-Lymphocyte;TLR3 gene;TMPRSS2 gene;Testing;Texas;Time;Touch sensation;Transgenic Mice;Universities;Vaccinated;Vaccination;Vaccines;Variant;Vascular Endothelial Cell;Viral;Viral Vaccines;Virion;Virus;Work;airway epithelium;aluminum sulfate;chemokine;comparison control;coronavirus disease;dimer;disorder control;disorder prevention;experience;gender difference;health goals;immunogenicity;immunopathology;improved;in vivo;indicated prevention;lung cancer cell;male;mucosal vaccine;nanoparticle;neutralizing antibody;nonhuman primate;preclinical study;prevent;receptor;receptor binding;respiratory challenge;response;transmission process;vaccine candidate;vaccine trial;variants of concern;viral transmission Studies of the SARS-CoV-2 Spike Protein n/a NCI 10926406 1ZIABC011941-04 1 ZIA BC 11941 4 6572144 "BERZOFSKY, JAY A" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2147209 NCI In vivo vaccine studies in macaques and hamsters: Rhesus macaques have been primed IM with S1 spike protein in different adjuvants and boosted systemically with spike in alum or mucosally intranasally with spike in nanoparticles with IL-15 and TLR ligand adjuvants. We have found and published that nanoparticles containing S1 spike protein delivered intranasally can boost macaques primed IM with S1 in alum and result in better protection against respiratory challenge with SARS-CoV-2 than can the IM vaccine alone even though the S1-binding and neutralizing antibody levels are lower. Other mechanisms must play a role and we have found correlations with mucosal IgA dimeric IgA and type I interferon production in the lung and certain types of myeloid cells. We then tested a mucosal nanoparticle boost with the B1.351 (South African) variant S1 protein to protect against this SARS-CoV-2 variant in macaques. The beta variant was the most difficult to neutralize before the appearance of the omicron variant which had not been identified at the time we started this second study. The beta variant mucosal nanoparticle vaccine given 1 full year after the animals had last been boosted systemically or mucosally with the original Wuhan strain induced a 3-log increase in both IgG binding antibody in both the serum and bronchoalveolar lavage fluid (BAL representing response in the lung). Further it boosted the titer to the original Wuhan strain as much as to the beta variant. Neutralizing antibody titers were also similar against both virus variants. IgA and dimeric IgA to both strains were also increased. This suggests a role for original antigenic sin in determining the fine specificity of antibodies at the time of first primary vaccination. When challenged the animals were well protected against intranasal challenge with the beta variant SARS-CoV-2. Thus a variant intranasal vaccine can induce strong protective immunity in the lungs and nasal cavity and eliminate virus from these sites. These studies suggest that a human intranasal nanoparticle COVID-19 vaccine given to people who had been previously immunized systemically with one of the approved vaccines could improve protection against infection and reduce the risk of forward transmission to others by reducing intranasal virus which is especially a problem with the delta and omicron variants This second NHP study was also published. In addition three more studies have been carried out in a hamster model as hamsters get COVID disease more like humans. The intranasal vaccine was able to markedly reduce weight loss in the immunized animals compared to controls implying the prevention of disease and reduce virus particles in the lungs. It could also more effectively reduce virus in the oropharynx of hamsters than the S1 protein in alum an important accomplishment that would be expected to reduce forward transmission. To test this hypothesis we have now done a forward transmission study in hamsters. In this study we also examined priming with one of the licensed mRNA vaccines to compare. Groups of hamsters were vaccinated first IM with the Moderna mRNA spike protein vaccine. Then half of them were boosted with the same mRNA vaccine IM but the other half were boosted with the nasal nanoparticle S1 vaccine incorporating the CpG/PolyI:C & IL15 adjuvants. All the animals were challenged with SARS-CoV-2 including a group that was not immunized at all. Then they were cohoused with naive hamsters separated only by a screen that allowed air flow between them but did not allow touching. The naive hamsters were then monitored for infection. The intranasal nanoparticle vaccine boost was substantially superior to a second IM dose of the mRNA vaccine in preventing forward transmission to the co-housed naive hamsters! This finding is critical as it demonstrates that an intranasal boost with an effective vaccine such as the one we have developed is needed to prevent COVID-19 infections from spreading the key public health goal. Gender effects: In the hamsters we observed that female hamsters were better protected against SARS-CoV-2 infection and disease than males but reagents are not available to study the hamster immune response in detail. To determine the mechanism we carried out similar studies in mice and confirmed the gender difference in mice as well. Studies are in progress to identify the mechanistic differences in immune response between the male and female mice which could be important in optimizing efficacy of human vaccines. In vivo studies in mice: In wild type B6 mice we have immunized with recombinant spike protein S1 S1+S2 or RBD in several different adjuvants to determine the best formulation. The best combination so far is S1 antigen with IL-15 + ligands for TLR3 and 9 for both antibody and T cell responses but the runner up was S1 with GM-CSF and IL-12. Studies are in progress to determine which components contribute the most to protection and whether they induce qualitatively different types of immune responses. The DNA vaccine with spike protein coupled to a chemokine has been constructed and initial results show that it can induce a strong CD8 T cell response. Human cell lines: We have received the immortalized human lung epithelial cell lines which express ACE2 from John Minna at UTSW as well as some of his non-small-cell lung cancer cell lines that also express ACE2. We have obtained an antibody to ACE2 to verify expression. Initial results show that omega-3 fatty acids and cholesterol differentially affect ACE2 expression on lung cancer cells as well as TMPRSS2 expression and may help explain how diet and obesity as well as lung cancer can affect susceptibility to SARS-CoV-2. 2147209 +No NIH Category available 2019-nCoV;Anti-Inflammatory Agents;Antibodies;Antigens;B-Lymphocytes;Binding;Biological Markers;Biology;CCL2 gene;CCL22 gene;CCL3 gene;CCL4 gene;CCL8 gene;COVID-19;COVID-19 vaccination;COVID-19 vaccine;CXCL10 gene;CXCL13 gene;CXCR3 gene;Cancer Patient;Cells;Data;Development;Disease;Early identification;Effectiveness;Goals;HIV vaccine;Hematologic Neoplasms;Humoral Immunities;IL16 gene;IL8 gene;Immune;Immune response;Immunity;Immunocompromised Host;Immunologic Markers;Individual;Infection;Inflammatory;Innate Immune Response;Interferon Type II;Interleukin-15;Interleukin-16;Interleukin-6;Internships;Longevity;Longitudinal cohort;Messenger RNA;Nature;Participant;Patients;Persons;Pfizer-BioNTech COVID-19 vaccine;Population;RNA vaccination;RNA vaccine;Regimen;Role;SARS-CoV-2 immune response;SARS-CoV-2 infection;Shapes;Structure of germinal center of lymph node;TNF gene;Vaccinated;Vaccination;Vaccine Design;Vaccinee;Virus;adaptive immune response;adaptive immunity;anakinra;chemokine;cohort;cytokine;frontier;high risk;individual patient;microorganism;neutralizing antibody;novel;prognostic;research and development;response;vaccine development;vaccine efficacy;vaccine platform;vaccine strategy COVID-19 vaccine in naive individuals and cancer patients n/a NCI 10926405 1ZIABC011940-04 1 ZIA BC 11940 4 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 851991 NCI We have been studying the immune response of COVID-19 cohorts longitudinally to characterize the nature and longevity of immune response (Rosati M Am J Hematol: 97:E3 2022; Rosati Frontiers Immunol 12: 793953 2021; Thomopoulos Viruses 1:1844; 2021; Terpos Eur J Intern Med 89:872021; Pappa Microorganisms 9 806 2021; Terpos Microorganisms. 8:1885 2020). The analysis of natural infection is providing important information for the design of vaccine strategies. To characterize adaptive and innate immune responses in SARS-CoV2 vaccinated persons we identified early responses to vaccination that are important in shaping both humoral and cellular protective immunity (Bergamaschi Cell Rep 36:109504; 2021; Bergamaschi Frontiers Immunol 3:899972 2022). We characterized the cytokine and chemokine responses to BNT162b2 mRNA (Pfizer/BioNtech) vaccinations in antigen-naive and in previously COVID-19-infected individuals and in patients with hematological malignancies (NCT04743388). We identified a systemic signature including IL-15 IFN-gamma IP-10/CXCL10 TNF-alpha and IL-6 (Bergamaschi Cell Rep 36:109504; 2021). Transient increases in IL-15 and IFN-gamma levels early after boost correlated with Spike antibody levels supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We expanded our studies to immunocompromised individuals including patients with hematological malignancies a population at high risk of developing severe disease upon SARS-CoV-2 infection (Bergamaschi Frontiers Immunol 3:899972 2022). Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. Overall the patients showed heterogeneous adaptive immune responses with lower humoral (binding and neutralizing antibodies) levels. In contrast to vaccination of a cohort of healthy participants patients with hematological malignancies who had a lower anti-Spike response also had a diminished systemic cytokine response (IFN-g IL-15 and CXCL10/IP-10) and this correlated with the lower anti-Spike antibody levels. On the other hand in patients who failed to develop antibodies the innate systemic response showed a lack of the IL-15/IFN-g signature with responses dominated by CCL8/IL-8 and CCL3/MIP-1alpha. Thus we concluded that successful development of an anti-Spike immune response was associated with a robust transient activation of the IL-15 signature serving as a novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination. We have been expanding our research of the development of adaptive and innate immune responses upon the third COVID-19 mRNA vaccination. In addition to the previously identified cytokine/chemokine responses we detected induction of CXCL13 a biomarker for germinal center activation and a key regulator of B cells found only after the 3rd vaccination. In contrast to the transient increase of the IL-15 signature cytokines a set of pro-inflammatory cytokines (CCL3/MIP-1alpha CCL4/MIP-1beta MCP-1 CCL22/MDC CXCL8/IL-8 IL-16) and the anti-inflammatory factor IL-1Ra remained at higher levels for up to one month post the 2nd and the 3rd vaccination indicative of a state of longer-lasting innate immune change. Importantly changes of the IL-15 signature and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses. Together these data revealed that repeated BNT162b2 mRNA vaccination induced both rapid/transient as well as longer-lasting cytokine/chemokine changes. These results highlight the important role of innate responses to the BNT162b2 mRNA vaccination in shaping adaptive immunity. Together our results show coordinated responses to the BNT162b2 mRNA vaccine and highlight the important role of a network of innate responses centering on IL-15 in shaping adaptive immunity after vaccination. This study suggests that understanding the role of these biomarkers could also help the refinement of regimens to increase efficacy of other vaccine platforms including HIV vaccines. 851991 +No NIH Category available Adenocarcinoma;Affect;Bladder;Bladder Adenocarcinoma;Bladder Squamous Cell Carcinoma;Carcinoma;Caring;Clinical;Clinical Research;Clinical Trials;Collecting Ducts of Bellini Carcinoma;Country;Data;Data Pooling;Disease;Duct (organ) structure;Genitourinary system;Histologic;Histology;Human;Immune;Incidence;Individual;Literature;Malignant Neoplasms;Malignant neoplasm of penis;Malignant neoplasm of testis;Malignant neoplasm of urinary bladder;Mutation;Nivolumab;Patients;Penis carcinoma;Peripheral Blood Mononuclear Cell;Persons;Pharmaceutical Preparations;Phase;Rare Diseases;Renal carcinoma;Resources;Science;Skin Appendage Carcinoma;Small Cell Carcinoma;Squamous cell carcinoma;Transitional Cell Carcinoma;Tumor Expansion;United States National Institutes of Health;Urethra;Urogenital Cancer;Variant;bladder Carcinoma;bone;cancer type;cohort;exome sequencing;ipilimumab;phase 1 study;phase 2 study;rare cancer;recruit;response;transcriptome sequencing;tumor;urogenital tract Rare genitourinary tumors projects n/a NCI 10926403 1ZIABC011928-05 1 ZIA BC 11928 5 10687150 "APOLO, ANDREA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 978735 NCI A phase 2 study of Ipilimumab CabOzantinib and NIvolumab in rare genitourinary (GU) cancers (ICONIC) The phase 1 study of combination CaboNivo and CaboNivoIpi included patients with rare GU histologies. Objective responses were seen in patients with adenocarcinoma of the bladder/urachal squamous cell carcinoma of the bladder small cell carcinoma of the bladder penile cancer sarcomatoid RCC chromophobe RCC and renal medullary carcinoma leading to multiple rare tumor expansion cohorts. The final data for these rare tumors and the pooled data from the phase 1 and expansion cohorts are currently being analyzed. Based on these data I initiated a phase 2 study through the Alliance cooperative group of CaboNivoIpi in patients with rare GU tumors which includes 12 cohorts: bladder squamous cell carcinoma bladder small cell carcinoma bladder adenocarcinoma bladder plasmacytoid bladder sarcomatoid urethra (all histologies) penile cancer sarcomatoid RCC collecting duct RCC renal medullary carcinoma bone-only non-prostate GU tumor and miscellaneous rare GU tumors. As of September 2020 the trial has accrued 100 patients (44% accrued). Preliminarily in this study we have seen confirmed responses in the bladder squamous cell carcinoma bladder small cell carcinoma bladder adenocarcinoma urethra penile cancer sarcomatoid RCC renal medullary carcinoma and testicular adnexal carcinoma. An extensive number of translational correlatives are being conducted in this study with baseline and serial subsequent cycles of therapy. We will analyze the immune subsets of circulating PBMCs and ctDNA and use whole-exome sequencing to define the relationship between tumor mutational burden in each histologic subtype and response to the trial drugs. We will also use RNA sequencing to define the relationship between expression-based subtypes the immune context of the tumors and response to study drugs. Having a rare tumor clinical trial developed through the NIH and available nationally through a cooperative such as the Alliance builds on our center's recruitment strength and on our collaborative science. If this trial shows clinical activity it may provide a potential new treatment option for patients with rare GU tumors. 978735 +No NIH Category available Adenocarcinoma;CRISPR library;CRISPR/Cas technology;Castration;Epigenetic Process;Gene Silencing;Genes;Genetic Predisposition to Disease;Genotype;Growth;Guide RNA;Individual;LNCaP;Malignant Neoplasms;Mediating;Mediator;Metastatic Prostate Cancer;Modeling;Neuroendocrine Prostate Cancer;Neurosecretory Systems;Organoids;Process;Prostate;RB1 gene;Resistance;Role;Screening Result;TP53 gene;Work;design;genetic manipulation;neuroendocrine phenotype;screening;therapeutic target;transcription factor;transdifferentiation Identifying genetic vulnerabilities in neuroendocrine prostate cancer n/a NCI 10926398 1ZIABC011919-05 1 ZIA BC 11919 5 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 334009 NCI We will utilize CRISPR/CAS9 mediated gene inactivation to identify viability factors required for the growth of NEPC. We are screening PDX-derived organoid models using CRISPR/CAS9 libraries directed against transcription factors or epigenetic modulators. By screening in various metastatic prostate cancer classes we are determining lineage-specific and genotype specific viability factors. Our main focus has been on RB1 deficient models which express lineage plasticity encompassing adenocarcinoma double negative and neuroendocrine phenotypes. We also have produced and characterized genetically-manipulated models to produce RB1 deficiencies in adenocarcinomas (LNCaP and LuCAP 167). We have identified transcription factors that selectively are required for viability in double negative prostate carrying RB1/TP53 loss genotypes. We are currently validating screen results with individual guide RNAs. Current work is directed at determining the role of PROX1 in lineage plasticity and commitment to the neuroendocrine lineage. 334009 +No NIH Category available APC gene;Address;Adult;Animals;Apoptosis;Binding;Biochemical;Biochemical Reaction;Biological;Biological Process;Cardiovascular Diseases;Cell Communication;Cell Compartmentation;Cell Cycle Arrest;Cell Surface Receptors;Cell membrane;Cell physiology;Cell surface;Cells;Chemosensitization;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Communication;Complex;Cues;Defect;Dental;Development;Diabetes Mellitus;Disease;Down-Regulation;Embryo;Embryonic Development;Endowment;Epithelium;Evolution;FDA approved;Family;Family member;Gene Amplification;Gene Family;Genetic Screening;Goals;Growth Factor;Haploidy;Helix-Turn-Helix Motifs;Heparan Sulfate Proteoglycan;Homeostasis;Human;Hyperactivity;Inhibition of Cell Proliferation;Instruction;Language;Leucine Zippers;Life;Ligand Binding;Ligands;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Mediator;Membrane;Mesenchymal;Modeling;Molecular;Morphogenesis;Mutate;Natural regeneration;Neoplasm Metastasis;Neurodegenerative Disorders;Oncogenic;Organ;Organism;Organoids;Outcome;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Physiological;Process;Property;Proteins;Regulator Genes;Regulatory Element;Reporter;Research;Research Project Grants;Role;Signal Induction;Signal Pathway;Signal Transduction;Site;Therapeutic;Tissues;Transcription Coactivator;Transcriptional Activation;Transgenic Mice;Ubiquitin;Ubiquitination;Vertebrates;WNT Signaling Pathway;Xenopus laevis;beta catenin;cancer type;casein kinase;comparative;fascinate;forward genetics;gastric cancer cell;genetic analysis;genome wide screen;malformation;member;migration;mouse model;prevent;programs;receptor;response;self-renewal;skeletal;stem cells;therapeutic target;tissue regeneration;tissue stem cells;transcription factor;tumor;ubiquitin ligase;zygote New regulatory mechanisms of WNT signaling in development stem cells and cancer n/a NCI 10926389 1ZIABC011901-05 1 ZIA BC 11901 5 16162143 "LEBENSOHN, ANDRES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1291943 NCI New regulatory mechanisms in WNT signaling: Through forward genetics screens in haploid human cells harboring a fluorescent reporter of WNT signaling we discovered new regulators of ligand-induced signaling and regulators selectively required to sustain hyperactive oncogenic signaling. This study (Lebensohn et al. eLife 2016) comprised seven genome-wide screens systematically interrogating the pathway including screens for positive negative and attenuating regulators of ligand-induced signaling as well as suppressor screens following disruption of key regulators commonly mutated in WNT-driven tumors such as the tumor suppressor APC. A comparative analysis of the screens revealed new regulatory mechanisms for ligand reception signal transduction and transcriptional activation as well as new gene regulatory elements (Patel Lebensohn et al. PLoS One 2019). Our current goal is to elucidate the molecular underpinnings of these new regulatory mechanisms understand their physiological functions and evaluate their potential as therapeutic targets. The following research projects are aimed at elucidating some of these new regulatory mechanisms and evaluating their therapeutic potential. 1) The transcription factor TFAP4 is a new limiting component of the WNT signaling pathway. Our genetic screens uncovered a basic helix-loop-helix leucine zipper transcription factor called TFAP4 as a potential regulator of WNT signaling (Lebensohn et al. eLife 2016). We have shown that TFAP4 acts downstream of b-catenin the principal transcriptional co-activator in the WNT pathway and is a limiting component for signaling activity. Furthermore excess TFAP4 can promote ectopic activation of WNT signaling during Xenopus laevis development causing the formation of a secondary body axis. Interestingly TFAP4 expression is tightly linked to malignancy in gastrointestinal cancers: TFAP4 is upregulated in colorectal cancer where it mediates epithelial-mesenchymal transition (EMT) and metastasis and its down-regulation in gastric cancer cells inhibits proliferation induces cell cycle arrest and promotes apoptosis. We are dissecting the molecular mechanism by which TFAP4 regulates WNT signaling and evaluating its potential as a therapeutic target. 2) A new function of the b-catenin destruction complex regulating WNT signaling through the ubiquitin ligase HUWE1. HUWE1 is a HECT-domain ubiquitin ligase involved in dozens of cellular processes through the ubiquitination of diverse substrates. Both oncogenic and tumor suppressive functions have been ascribed to HUWE1. HUWE1 has been postulated as a negative regulator of WNT signaling through at least two distinct mechanisms. However in our unbiased forward genetic screen for mediators of hyperactive WNT signaling induced by loss of the b-catenin destruction complex kinase casein kinase 1a we identified HUWE1 as a positive regulator of the WNT pathway (Lebensohn et al. eLife 2016). We also demonstrated that HUWE1 potentiates WNT signaling in cells and in Xenopus laevis embryos. We have now found that HUWE1 promotes WNT/b-catenin signaling by regulating b-catenin sub-cellular localization. This mechanism is independent of the control of b-catenin protein stability. Potentiation of WNT signaling by HUWE1 requires its ubiquitin ligase activity and a subset of b-catenin destruction complex components. These results reveal a new role for some destruction complex components in regulating b-catenin sub-cellular localization and WNT signaling downstream of HUWE1 distinct from their established activity in controlling b-catenin stability. New regulatory mechanisms in R-spondin signaling: Some WNT responses during embryonic development and in stem cell compartments depend on a second signal provided by the R-spondin family of secreted growth factors only present in vertebrates. R-spondins are key regulators of WNT signaling strength but the mechanisms by which they transduce signals are not fully understood and how the four different members of the family control distinct physiological functions is unknown. We discovered that R-spondins 2 and 3 can uniquely potentiate WNT signaling in cells lacking their only known cell-surface receptors LGRs 4-6 through an alternative interaction with heparan sulfate proteoglycans (HSPGs) (Lebensohn & Rohatgi eLife 2018; Dubey et al. eLife 2020 reviewed in Lebensohn et al. Curr Top Dev Biol 2022). This finding is transformative because LGRs were thought to be required to transduce all R-spondin signals and hence determine their site of action but now we know that R-spondins can also signal in tissues where LGRs are not expressed. The following research projects are aimed at elucidating the molecular mechanisms and physiological functions of HSPG-dependent signaling by R-spondins. 3) Molecular mechanisms of LGR-independent signaling by R-spondins. A central question regarding any signal transduction mechanism is how binding of the ligand to the receptor communicates the signal across the plasma membrane and into the cell. In the prevailing model simultaneous binding of R-spondins to their LGR receptors and to the transmembrane ubiquitin ligases ZNRF3 or RNF43 triggers their internalization. This prevents ZNRF3 and RNF43 from targeting WNT receptors for ubiquitin-mediated degradation thus increasing their abundance on the cell surface and enhancing sensitivity to WNT ligands. We are investigating the molecular mechanisms whereby R-spondins transduce signals in the absence of LGRs through their alternative HSPG receptors to potentiate WNT signaling. 4) Physiological roles for LGR-dependent and LGR-independent signaling by R-spondins during embryonic development and in stem cells. Gene amplifications followed by neo- or sub-functionalization of different gene family members underlie much of the functional diversification generated during evolution. Yet paralogues are often deemed to be redundant and drastically different phenotypes resulting from their loss are simply attributed to tissue-specific patterns of expression. This is the prevailing view regarding the four members of the R-spondin family which potentiate WNT signaling during embryonic development and in adult tissue stem cells. However the markedly distinct phenotypes caused by the loss of different R-spondins or their LGR receptors could also be due to intrinsic differences in the capacity of these R-spondins to signal through LGR-dependent and HSPG-dependent mechanisms. We are using transgenic mouse models to investigating in what contexts these two modes of signaling are used during development tissue homeostasis and regeneration. We are also trying to understand what unique properties make LGR-dependent and HSPG-dependent R-spondin signaling specifically suited to their physiological functions. 1291943 +No NIH Category available Cancer Vaccines;Cell Line;Cells;Chemotherapy and/or radiation;Clinical;Collaborations;Combination immunotherapy;Combined Modality Therapy;DNA;Development;Dose;Evaluation;Goals;Histones;Immune;Immune checkpoint inhibitor;Immune response;Immunotherapy;Interleukin-12;Malignant neoplasm of prostate;Metastatic/Recurrent;Mutation;Necrosis Induction;Newly Diagnosed;Patients;Phase;Phenotype;Population;Pre-Clinical Model;Progression-Free Survivals;Prostate Cancer therapy;Protocols documentation;Radiation;Radiation Oncology;Recurrence;Renal carcinoma;Research;T cell infiltration;Toxic effect;castration resistant prostate cancer;chemotherapy;clinical efficacy;cytokine;docetaxel;melanoma;necrotic tissue;programs;standard of care;synergism;systemic toxicity;therapeutic evaluation;tumor;tumor microenvironment;tumor-immune system interactions Evaluation of Immune-based Combinations in Prostate Cancer n/a NCI 10926386 1ZIABC011897-05 1 ZIA BC 11897 5 10687105 "MADAN, RAVI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 485739 NCI Current studies are exploring a combination of standard of care chemotherapy with an immunocytokine combination treatment. Unlike checkpoint inhibitors which may require T-cell infiltration or high tumor mutational burden to be effective cytokines provide an opportunity to impact multiple immune cell lines within the prostate cancer microenvironment and convert them broadly from immune suppressive to a more anti-tumor phenotype. Indeed cytokines have been a key part of immune treatments for kidney cancer and melanoma before the development of checkpoint inhibitors but the potential systemic toxicity of high doses of cytokines often limited treatment delivery and thus efficacy. Immunocytokines are able to deliver smaller doses of cytokines in a targeted fashion to the tumor microenvironment thereby limiting systemic toxicity and perhaps enhancing clinical efficacy. NHS-IL12 (M9241) has been developed clinically within the GMB Immunotherapy Section and specifically targets histones of exposed DNA in necrotic tissue. This capability forms the basis of a key strategy within my research program. By using standard therapies for prostate cancer such as radiation and chemotherapy to induce necrosis the goal is to use NHS-IL12 to alter the pleiotropic immune microenvironment including multiple immune cell populations shifting it to a more anti-tumor phenotype. We have completed the phase 1 portion of 21-c-0001 which has established a safe dose of docetaxel with M9241. We will now explore immune responses in this study as we move into the phase 2 portion of the study that will focus on metastatic castration resistant prostate cancer. We also recently opened a new study combining NHS-IL12 and radiation in patients with newly diagnosed and localized prostate cancer in a collaboration with the Radiation Oncology Branch (protocol 000114). This is based on the potential synergy of radiation and M9241 established in preclinical models. Immunotherapy combinaton studies are also being done in recurrent prostate cancer (18-c-0005) 485739 +No NIH Category available Agreement;Androgen Antagonists;Area;Biochemical;COVID-19 pandemic;Cancer Patient;Castrate sensitive prostate cancer;Cells;Clinical;Clinical Trials;Collaborations;Combination immunotherapy;Data;Data Analyses;Development;Evaluation;FDA approved;Future;Goals;Image;Immune;Immunologics;Immunotherapy;Industry;Investigational Therapies;Kinetics;Malignant neoplasm of prostate;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Nonmetastatic;Outcome;Patients;Phase;Population;Positron-Emission Tomography;Prostate;Protocols documentation;Publications;Quality of Life Assessment;Quality of life;Radiation;Radiopharmaceuticals;Radium;Recurrence;Safety;Science;Surveys;androgen deprivation therapy;castration resistant prostate cancer;cohort;enzalutamide;follow-up;microbiome;novel;phase II trial Evaluation of novel treatments in biochemically recurrent prostate n/a NCI 10926385 1ZIABC011896-05 1 ZIA BC 11896 5 10687105 "MADAN, RAVI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 364304 NCI Two protocols have been completed. 13-c-0153: Enzalutamide in Combination With PSA-TRICOM in Patients With Non-Metastatic Castration Sensitive Prostate Cancer has completed the data analysis phase and is pending publication. Enzalutamide alone extends PSA suppression in patients with non-metastatic castration resistant prostate cancer and future studies are planned ti further evaluate this. Furthermore immune changes were noted after enzalutamide therapy as well. 16-c-0035: Prostvac in Patients With Biochemically Recurrent Prostate Cancer: This study has completed accrual at the NCI Dana Farber and Sloan Kettering and is now being prepared for publications. Of note late PSA declines were seen in 15-20% of patients. 18-c-0005: Phase II Trial of Combination Immunotherapy in Biochemically Recurrent Prostate Cancer: This study has completed the safety phase of the trial and now is in the main cohort of non-metastatic castration resistant prostate cancer patients and is accruing at the NCI. We are approximately 2/3 of the way through accrual and expect to compete accrual in the next 6-10 months. 20-c-0010 Radium 233 in biochemically recurrent prostate cancer is evaluating the immune impact of an FDA-approved radiopharmaceutical in patients with micro-metastatic (only PET scan positive) prostate cancer. This study had its accrual held through much of the COVID pandemic but is now approximately 1/3 of the way through accrual with rapid accrual in recent months. Additional studies are being planned with other non-toxic immunotherapy strategies. The uniform use of PET imaging is part of the GMB's programmatic approach to developing clinical trials in BCRpc. All current and future BCRpc studies are evaluating the impact of PSA kinetics on these patients using validated quality of life survey. In addition the immunologic impact of these treatments on circulating immune cell subsets. And in a collaboration with Dr. Heidi Kong of NIAMS we are evaluating the microbiome to better understand how baseline the microbiome may be associated with clinical outcomes while also evaluating the influence of experimental therapies on the microbiome in BCRpc. 364304 +No NIH Category available FOLH1 gene;Future;Human;Pharmaceutical Preparations;Radiation Dose Unit;Radiopharmaceuticals;Testing;improved;prostate cancer cell;radioligand;side effect;tumor Improving PSMA-based radioligand therapy via combination radioligand therapy n/a NCI 10926384 1ZIABC011895-05 1 ZIA BC 11895 5 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 168560 NCI The approach taken by this proposal is to combine the PSMA drug with other radioactive drugs that also selectively target prostate cancer cells. If this approach is proven to be successful we will be able to increase the radiation dose give to tumors without causing additive worsening of side effects. Furthermore this combinational approach could become the new paradigm for which all radioactive drugs are given in the future. We expect this approach to be ready for testing in humans in about 5 years. 168560 +No NIH Category available Animals;Behavior;Behavioral;Behavioral Model;Biological;Blood;C57BL/6 Mouse;Central Nervous System;Central Nervous System Neoplasms;Cognition;Computer software;Cranial Irradiation;Darkness;Data;Data Analyses;Dose;Eating;Exposure to;Foundations;Genes;Genetic Polymorphism;Goals;Graph;Grooming;Hour;Human;Hypersomnias;Hypersomnolence;Individual;Light;Low Dose Radiation;Monitor;Mus;Natural History;Patients;Phase;Pre-Clinical Model;Procedures;Quality of life;Radiation;Radiation Dose Unit;Radiation therapy;Rest;Rodent;Sleep;Symptoms;System;Testing;Time;Translations;Travel;Walking;Work;behavior measurement;early onset;experience;experimental study;irradiation;male;mouse model;radiation effect;sleep behavior;standard of care;tumor Behavioral Correlates in Mouse Model of CNS radiation-induced hypersomnia n/a NCI 10926382 1ZIABC011893-05 1 ZIA BC 11893 5 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 423485 NCI Radiation therapy is the standard of care for both primary and secondary central nervous system tumors tumors. A majority of patients experience radiation induced hypersomnia (RIH) which may impact life quality and treatment tolerance. Currently there is no mouse model of RIH that measures behavioral sleep and activity. Previously we demonstrated that Ethovison software can be used to effectively monitor differences in the sleep behavior of mice. Here we test the dose effect of radiation in mice using our system prior to introducing tumor. Aims: Establish the optimal radiation dose to recapitulate symptoms experienced by patients who receive cranial irradiation such as heightened daytime sleep and reduced activity. Experimental Procedure: Animals: Male young (6wk) C57BL/6 mice were individually housed in Phenotyper cages Monitored for 10 days pre-irradiation and 11 days post irradiation under 12:12 light dark conditions. 24 non-tumor bearing C57BL/6 mice received whole brain radiation at one of 4 doses (sham 2Gy 5Gy and 15Gy) using a single fraction Ethovision XT Software automatically generate general activity data as total distance travelled over time. Mouse Behavior recognition module scored Sleep/Rest Walking Grooming and Eating. Data Analysis: General activity was examined for total activity across 24 hours for 11 days between doses.Behaviors were compared between doses for three days (Day 8-10). Groups were analyzed between high (5&15Gy) and low (0&2Gy) doses. Baseline Analysis: Baseline activity was not significantly different between groups (F(3.23) = 0.649 p=0.593). As expected activity levels are higher during the dark period (active period) while sleep is higher during the light period (inactive period). Post-Irradiation Activity Analysis: Activity levels were unchanged less than 5% difference for sham and 2Gy however high doses 5Gy and 15Gy were suppressed by 10% Suppression of activity started after 2 days in 15Gy and 5 days in 5Gy mice. Data was corrected to baseline which is represented by zero in the graph Post-Irradiation Behavioral Analysis: Across three days (8-10) 5Gy and 15Gy (1987sec) had more sleep during their active phase (t=2.27 p=0.03) than sham or 2Gy (17618 sec). Grooming was significantly higher (t=2.588 p=0.017) for low radiation dose during the active phase. There are no effects on amount of time spent eating or the amount of time spent walking Animals had no significant difference in baseline activity or sleep between groups. Shams and 2Gy had activity levels similar to baseline while 5 and 15Gy had decreased activity levels post-radiation. Mice exposed to 15Gy radiation had an earlier onset of radiation induced hypersomnolence with decreases starting three days before 5Gy mice. Significant effects for sleep and grooming were observed during the active phase with animals exposed to high radiation doses having more sleep and less grooming. No changes were observed for eating or total walking time between groups. Our study demonstrates that cranial irradiation causes a clear increase in sleep during the active period and decrease in activity both factors that recapitulate the human RIH experience. Activity and sleep are impacted by irradiation in patients. A good behavioral model to observe these changes has not yet been developed in rodents. Here we demonstrate a reliable system to collect and analyze activity and sleep parameters in mice exposed to irradiation that will serve as the foundation for ongoing experiments. 423485 +No NIH Category available Categories;Cells;Characteristics;Clinical;Clinical Research;Colorectal Cancer;Data;Databases;Diagnosis;Head and Neck Cancer;Image;Imaging technology;Individual;Label;Learning;Location;Lung Adenocarcinoma;Malignant Neoplasms;Maps;Methodology;Methods;Outcome;Patients;Phase;Prognosis;Protein Analysis;Proteins;Proteomics;Sampling;Structure;Technology;Tissue imaging;Tissues;Training;Tumor Escape;cancer type;clinical predictors;convolutional neural network;high dimensionality;image visualization;imaging Segmentation;information organization;machine learning method;malignant breast neoplasm;protein biomarkers;survival outcome Computational approaches for the analyses of spatial profiling technologies n/a NCI 10926380 1ZIABC011890-05 1 ZIA BC 11890 5 16162128 "JIANG, PENG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 792649 NCI Aim 1: Unsupervised training of image region encoder for highly-multiplexed spatial proteomics data. We will first identify the optimal encoder to obtain image region representations. This encoding will be learned in a completely unsupervised approach to use all the available regions in the spatial imaging data without requiring any clinical labels or any individual cell location information from any preprocessing step. The learned encoding will be used in Aim 2. Aim 2: Interpretable differential analysis across cancer types to identify spatial topological features associated with clinical characteristics like survival outcomes. We will use interpretable machine learning methods to predict clinical characteristics from images represented in terms of learned image region encodings. The interpretability of the prediction method will help in visualizing image regions associated with different clinical categories like good and poor prognosis. The commonality or differences of important image regions in the encoded space will identify underlying key similarities or differences across clinical outcomes which could be used to identify tumor immune evasion mechanisms and help in diagnosis and therapy. Preliminary Data. We have collected spatial proteomics images and corresponding patient survival from external databases for colorectal cancer (432 samples) head and neck cancer (308 samples) and breast cancer (681 samples) for spatial imaging technologies like CODEX and IMC. We also have Lung adenocarcinoma CODEX images collected internally at NCI. 792649 +No NIH Category available Algorithms;Atlases;Cells;Clinical;Code;Computing Methodologies;Data;Detection;Gene Expression;Genes;Human;Immunooncology;Knowledge;Ligands;Mediating;Mus;Outcome;Patients;Pattern;Protein Secretion;Proteins;Resistance;Role;Signal Transduction;Signaling Protein;Tumor Escape;Tumor Promotion;Tumor-Secreted Protein;anti-tumor immune response;cancer immunotherapy;cohort;cytokine;genomic data;in vivo;in vivo Model;overexpression;protein function;receptor;transcriptomics;treatment response;tumor;tumor progression Data-driven inference of regulators for cytokine-mediated tumor killing n/a NCI 10926379 1ZIABC011889-05 1 ZIA BC 11889 5 16162128 "JIANG, PENG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 792649 NCI Aim 1 Discover new cytokines promoting tumor progression through data-integrative analysis. We will comprehensively integrate clinical genomics data from cancer immunotherapy studies to identify new soluble proteins whose gene expression levels are significantly associated with patient clinical outcomes in many cohorts. Then we will validate the top candidates' in-vivo impact on tumor progression using gene over-expression in mouse tumors. For validated secreted proteins we will generate treatment response profiles to enrich the CytoSig framework. Aim 2. Develop an algorithm to identify secreted protein signaling in ST data. Many computational methods exist for studying ligand-receptor interactions from bulk or single-cell transcriptomics data. However the receptors for most secreted proteins (1903 by estimation) are unknown. Also many non-receptor proteins may serve the essential regulators or indicators of secreted protein functions. To study signaling activities for a broad set of secreted proteins we will develop spatial pattern detection algorithms to identify functional-relevant genes whose expression patterns have positive or negative spatial correlations with the coding gene of secreted proteins. Then top predicted regulators will be validated using the in-vivo models established in Aim 1. 792649 +No NIH Category available Affect;Amendment;American Association of Cancer Research;Angiogenesis Inhibitors;Animal Model;Biopsy Specimen;Blood Vessels;Cells;Clinical Research;Collaborations;Combined Modality Therapy;Correlative Study;Cytotoxin;Data;Dose;Drug Kinetics;Elements;Endothelial Cells;Extramural Activities;Fibroblasts;Growth;Human;Infusion procedures;Integrin alphaVbeta3;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mus;Neoplasm Metastasis;Pancreatic Ductal Adenocarcinoma;Patients;Penetration;Pharmaceutical Preparations;Phase;Protein Engineering;Recommendation;Safety;Sampling;Schedule;Solid Neoplasm;Structure;Testing;Therapeutic;Time;Toxic effect;United States National Institutes of Health;cell killing;clinical center;density;first-in-human;improved outcome;mesothelin;mouse model;novel;pancreatic ductal adenocarcinoma model;participant enrollment;preclinical study;rational design;safety testing;symposium;therapy resistant;tumor;tumor growth First in Human Trials of ProAgio a Cytotoxin n/a NCI 10926377 1ZIABC011886-05 1 ZIA BC 11886 5 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 700025 NCI AIM1 (ongoing): Test safety and pharmacokinetics (PK) of ProAgio in patients. A Phase I clinical study at the NIH Clinical Center was initiated in previously treated patients with advanced solid tumor malignancies (PI Alewine). Patient accrual began in 12/2021 and is ongoing to the dose expansion study. Patients receiving dose levels (DL) 1-3 received ProAgio infusion every 2 weeks. No significant toxicity or efficacy was observed. Pharmacokinetic studies suggested the ProAgio trough levels were insufficient to maintain activity and the study was amended in 2022 to a weekly dosing schedule for DLs 4-6. Once accrual of the dose escalation phase is completed and the recommended phase 2 dose is identified then enrollment of patients to the dose expansion phase will begin. AIM 2 (ongoing): Identify the specific cell subsets in the PDAC TME that are targeted by ProAgio and characterize its effect on TME structure over time. Our current data indicate that short-course ProAgio treatment does not deplete PDAC TME cell subsets that express integrin alphaV-beta3 despite causing significant retardation of tumor growth in an autochthonous mouse model of PDAC. These data have been presented at the AACR Special Conference on Pancreatic Cancer. We are continuing to study the affect of ProAgio on the murine PDAC TME after longer courses of treatment. AIM 3 (ongoing): Assess bioactivity of ProAgio in patients. Tumor biopsy samples are being collected from patients on the ProAgio study. Correlative studies to assess ProAgio effect on stromal density blood vessels and tumor cellular components will begin when all samples are collected. AIM4 (ongoing): Determine whether ProAgio co-administration can increase penetration of large molecule therapeutics. The anti-fibrotic activity of ProAgio is predicted to increase ability of large molecule therapeutics to penetrate PDAC tumors. Combination of ProAgio with the mesothelin-targeted iTox LMB-100 is being tested in novel humanized mesothelin mouse models developed in collaboration with Serguei Kozlov (NCI/ CAPR). 700025 +No NIH Category available 3-Dimensional;Address;Biological Assay;Biological Process;Cells;Cellular Assay;Chromatin;Chromatin Structure;DNA;DNA analysis;DNA biosynthesis;Detection;Genetic Transcription;Goals;Histones;Human;Lead;Pattern;Population;Regulation;Signal Transduction;Superhelical DNA;Topoisomerase;Transcriptional Regulation;Variant;cohesin;experimental study;genome-wide The dynamics of chromatin topology in human cells n/a NCI 10926376 1ZIABC011884-05 1 ZIA BC 11884 5 16162122 "CHEN, CHONGYI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1581115 NCI In FY 2023 we quantitatively characterized genome-wide DNA supercoiling patterns in human cells. We then analyzed DNA supercoiling patterns in correlation with the 3D chromatin structure and histone marks studied the potential players in establishing and maintaining such supercoiling patterns by perturbation experiments probing transcription cohesin and topoisomerase activities. The final goal is to elucidate the regulation mechanism and the biological function of DNA supercoiling in human cells. On the other hand the fast dynamics of DNA supercoiling in living cells lead to a significant cell-to-cell variation averaging out a significant portion of the meaningful signal. To address this challenge we are synchronizing cell populations by a variety of approaches to allow better and more sensitive detection. We are also developing single-cell assays for DNA supercoiling utilizing the principle of linear amplification derived from my previously developed LIANTI assay. 1581115 +No NIH Category available Affinity;Antibodies;Antigens;Chromosomal translocation;Clinical Trials;Common Neoplasm;Engraftment;Epitopes;Goals;Human;Human Papilloma Virus-Related Malignant Neoplasm;Infusion procedures;Malignant Neoplasms;Mutate;Oncology;Proto-Oncogenes;Signal Transduction;T cell therapy;T-Cell Development;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;T-Lymphocyte Epitopes;Therapeutic;Tumor Antigens;Viral Oncogene;cancer therapy;chimeric antigen receptor;conditioning;gene therapy;genetically modified cells;melanoma;safety assessment;synovial sarcoma;targeted treatment;therapeutic target;treatment strategy;tumor T-Cell Receptor Gene Therapy for Human Cancers-Cures n/a NCI 10926370 1ZIABC011871-05 1 ZIA BC 11871 5 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 33240 NCI T cell receptor (TCR) gene therapy is a personalized cancer treatment strategy that can precisely and potently target a wide variety of tumor antigens. It is based on the infusion of T cells that are genetically engineered ex vivo to express a TCR directed against a tumor antigen. This strategy enables tumor targeting with a large number of T cells that express a high affinity TCR. It also permits pretreatment host conditioning to enhance anti-tumor T cell engraftment and function. TCR gene therapy has shown encouraging results in melanoma synovial cell sarcoma and human papillomavirus-associated cancers. In contrast to antibody and chimeric antigen receptor (CAR) therapy TCR gene therapy can target intracellular antigens which is important because many of attractive oncological therapeutic targets (e.g. mutated protooncogenes viral oncogenes driver chromosomal translocations and cancer germline antigens) localize to the intracellular compartment. The goal of this NCI Moonshot Project is to catalyze the discovery and development of TCR gene therapy for a wide-array of cancers. 33240 +No NIH Category available 3-Dimensional;Affect;Area;Artificial Intelligence;BAY 54-9085;Bioinformatics;Biological Markers;Biological Products;Biopsy Specimen;Blood;CCR;Carcinoma;Cells;Cholangiocarcinoma;Clinical;Clinical Data;Clinical Trials;Collaborations;Communities;Computational Biology;DNA sequencing;Data;Development;Diagnosis;Early Diagnosis;Elements;Environment;Extramural Activities;Fellowship;Formalin;Foundations;Funding;Future;Genomics;Goals;Heterogeneity;Image Analysis;Immune checkpoint inhibitor;Immunophenotyping;Immunotherapy;Individual;Infrastructure;Institution;Intramural Research;Laboratories;Lead;Liver neoplasms;Machine Learning;Malignant Neoplasms;Malignant neoplasm of liver;Medical;Medicine;Microscopy;Mission;Molecular;Molecular Profiling;Multimodal Imaging;Mutation;Nature;Oncologist;Optics;Outcome;Paraffin Embedding;Patient Care;Patient Monitoring;Patient-Focused Outcomes;Patients;Pilot Projects;Positioning Attribute;Prevention;Prevention approach;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Publishing;Radiogenomics;Refractory;Relapse;Reporting;Research;Research Activity;Research Personnel;Resistance development;Resources;Retrospective Studies;Role;Sampling;Site;Subgroup;Testing;Tissue Embedding;Tissues;Training;Training and Education;Transcript;Translational Research;Treatment outcome;United States National Institutes of Health;Universities;Urine;Validation;Variant;Vision;anticancer research;arm;biliary tract;cancer clinical trial;capecitabine;clinical center;clinical efficacy;effective therapy;exome sequencing;immune cell infiltrate;improved;insight;liver cancer patient;liver development;metabolomics;microbiome;molecular targeted therapies;multidisciplinary;multiplexed imaging;neoplastic cell;new therapeutic target;novel;novel therapeutics;optimism;oxaliplatin;participant enrollment;patient response;patient subsets;pembrolizumab;phase 2 study;phase 3 study;precision medicine;predictive signature;prevent;programs;prospective;responders and non-responders;response;single cell sequencing;standard of care;statistical and machine learning;success;synergism;transcriptome;transcriptome sequencing;transcriptomics;treatment responders;treatment response;tumor Liver Cancer Program n/a NCI 10926369 1ZIABC011870-05 1 ZIA BC 11870 5 16162108 "BUDHU, ANURADHA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 989424 NCI One of main reasons why survival for patients with primary liver cancer (PLC) including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) has not improved in the past twenty years is the lack of approved novel therapies with the exception of the limited success of sorafenib. Multiple phase III studies have failed to demonstrate any survival advantage for patients with liver cancer. We believe that this situation will change dramatically with the advent of immunotherapy and biologicals and by the implementation of precision cancer management strategy. Our optimism is supported by recent findings in the field of HCC. CCR is in a unique position to utilize its expertise in the area of immunotherapy and biologics to test these novel treatment options in patients with liver cancer. Molecular subgrouping and biomarker-guided molecularly-targeted therapies are promising approaches that are being implemented in our ongoing and future studies. One of the key elements of the NCI-LCP is to build an infrastructure which allows intramural investigators to expand on their research and not only collaborate with each other but also with extramural investigators. Our first effort is to build an NCI IRP-based collaborative translational science network of liver cancer clinical trial data with accompanying biospecimens and correlative laboratory data to determine why immunotherapy is effective in certain patients but not in others. This goal is encompassed in our funded Liver Cancer Study (NCI-CLARITY). In this study we are building a national clinical network in liver cancer to 1) define at the molecular level which group of PLC patients respond to immunotherapy and which do not and why some patients develop resistance/tumor relapse and 2) to determine whether any similarities or differences in response to immunotherapy are observed in HCC versus CCA patients. This program is based on the creation of a unique and robust national information commons comprised of comprehensive clinical and molecular data which can be utilized by the cancer research community for future studies of PLC. To accomplish these aims the NCI IRP is serving as the lead and coordinating hub to leverage ongoing immunotherapy-based clinical trials at major institutions treating PLC patients. We have partnered with clinical extramural collaborators across the U.S. to obtain biospecimens (biospy blood urine and fecal) and clinical data (medical chart data treatment outcome and survival) from PLC patients in their ongoing clinical trials and/or standard of care patients treated with immune checkpoint inhibitors. We aim to collect biospecimens and clinical data from 500 PLC patients over a 5-year period across study sites. Comprehensive correlative data will be performed at NCI and NCI Frederick National Laboratory along with our collaborators including molecular (DNA and RNA-Seq) single-cell sequencing metabolomics microbiome immunophenotyping by CODEX 3D-multiplex imaging (Optical Microscopy and Image Analysis Laboratory) and SNP/variant analysis. Radiogenomics pairing data mined from comprehensive multi-modality imaging with genomics by artificial intelligence/machine learning will also be used to screen and predict patient response to immunotherapy. Comprehensive statistical machine learning and bioinformatics analysis will be used to integrate correlative data and clinical data to molecularly characterize and define predictive signatures of treatment responders and nonresponders to immunotherapy in all cases or in the stratified analyses. In concert with this effort we also initiated a pilot retrospective study of archival biopsy specimens collected before and after immunotherapy treatment (IO) from liver cancer patients from the NIH Clinical Center and Georgetown University. Samples from 89 patients undergoing immunotherapy treatment were assessed by DNA and RNA sequencing to identify mutations transcripts and molecular signatures associated with patient outcome following IO treatment. A total of 230 primary HCC and CCA tumors and adjacent non-tumor tissues largely stored as formalin-fixed paraffin-embedded (FFPE) and attained before and following immunotherapy treatment using total RNA sequencing and whole exome sequencing were analyzed. We established a SOP and show feasibility to conduct molecular analytics to monitor patient response to immune therapy utilizing FFPE tissue. We identified four stable survival-related molecular subgroups defined by orthogonal axes of tumor aggressiveness and immune infiltration the latter associated with immunotherapy response. Furthermore although the underlying molecular status of tumors prior to immunotherapy treatment was largely maintained following treatment some molecular responses tracked with patient outcome. Thus outcome-related and intersecting molecular axes are apparent in FFPE liver tumors prior to immunotherapy treatment components of which could serve as indicators of treatment response. The pilot arm of the study was recently published (Budhu et al Cell reports Medicine 2023). Additional samples from these and other collaborating sites will be incorporated and integrated with these analyses to further assess these data. The pilot data are also being utilized as validation samples or additional samples for several ongoing and published studies. This includes a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. We found that capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC (Monge et al Oncologist 2022). Other studies from this program include an assessment of genomic changes at the single-cell level at baseline and in response to therapy which have provided insight into tumor cell heterogeneity and the foundations of alterations which affect outcome in certain patient subgroups (Ma et al Nature Comm 2022). Another example includes the comparison of the bulk transcriptome data of the pilot study with single-cell transcriptomics conducted from samples of the same patient The prospective arm of NCI-CLARITY is underway with 70 patients enrolled and 1900 biospecimens collected. Overall we anticipate that these data will define specific subgroups of patients who are more likely to benefit from immune checkpoint inhibitor treatment. In addition biomarkers and novel druggable targets may be identified to better determine or affect treatment response. 989424 +No NIH Category available Basic Science;Bile fluid;CA-19-9 Antigen;Cessation of life;Cholangiocarcinoma;Clinical;Disease;Epitopes;Evaluation;Excision;Goals;Innovative Therapy;Laboratory Research;Liver neoplasms;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mission;Operative Surgical Procedures;Patient Care;Patient-Focused Outcomes;Patients;Perioperative;Recurrence;Surgeon;Surgical Oncologist;Time;Translational Research;United States;human monoclonal antibodies;metastatic colorectal;neoplasm therapy;novel;pancreatic neoplasm;prevent;tumor Evaluating outcomes for patients with primary-metastatic gastrointestinal cancer n/a NCI 10926367 1ZIABC011861-05 1 ZIA BC 11861 5 15201727 "HERNANDEZ, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 24456 NCI As a surgical oncologist and hepatopancreatobiliary surgeon I specialize in the treatment of pancreatic tumors and tumors of the liver and bile ductsoal and I provide patients undergoing resection of localized tumor(s) with novel adjunctive therapies to prevent recurrence of their disease at a later time. The goal of this project is to bridge clinical and translational evaluation of GI cancers which often forms the basis of hypothesis-driven basic research. I opened a new trial this year NCT03801915 Perioperative MVT-5873 a Fully Human Monoclonal Antibody Against a CA19-9 Epitope for Operable CA 19-9 Producing Pancreatic Cancers Cholangiocarcinomas and Metastatic Colorectal Cancers. 24456 +No NIH Category available Adult;Advocacy;Advocate;Agreement;Anxiety;Apple;Argentina;Award;Awareness;Biological Markers;Biological Specimen Banks;Blood;Books;Brain Neoplasms;CCR;COVID-19;Caregivers;Caring;Central Nervous System Diseases;Central Nervous System Neoplasms;Clinic;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Collection;Communities;Comprehensive Cancer Center;Country;Data;Dedications;Diagnosis;Education;Educational Activities;Educational workshop;Ependymoma;Event;Exhibits;Extramural Activities;Facebook;Fostering;Genetic Counseling;Glioblastoma;Glioma;Goals;Group Meetings;Growth;Guidelines;Health;Health Services Accessibility;Immune checkpoint inhibitor;Immune response;Immunologic Monitoring;Immunologic Tests;Immunotherapy;Individual;Information Technology;Infrastructure;Institution;International;Intervention;Journals;Laboratories;Language;Lead;Leadership;MYCN gene;Malignant Neoplasms;Malignant neoplasm of central nervous system;Medical;Methods;Mexico;Molecular;Monitor;Multi-Institutional Clinical Trial;National Comprehensive Cancer Network;Natural History;Neurology;Newsletter;Nivolumab;Observational Study;Oncology;Operative Surgical Procedures;Oral;Outcome;Paper;Participant;Pathology;Patient advocacy;Patient-Focused Outcomes;Patients;Pediatric Oncology;Persons;Peru;Pharmaceutical Preparations;Physicians;Play;Pregnancy;Primary Brain Neoplasms;Privatization;Professional counselor;Provider;Publishing;Quality of life;Radiation;Radiation Oncology;Recurrence;Reporting;Research;Research Personnel;Research Project Grants;Retrospective Studies;Risk;SKIL gene;Science;Self Care;Self Management;Services;Site;Sleep;Societies;Spain;Support Groups;Surveys;Symptoms;Telemedicine;Testing;Time;Tissues;Topoisomerase Inhibitors;Translations;Twitter;United States;United States National Institutes of Health;Update;Visit;acceptability and feasibility;cancer care;cancer type;clinical center;cohort;data sharing;first-in-human;genetic testing;gliosarcoma;human study;immune checkpoint;improved;improved outcome;individual patient;inhibitor;lectures;medulloblastoma;meetings;member;meningioma;molecular subtypes;multidisciplinary;mutant;neuro-oncology;novel;novel therapeutics;oligodendroglioma;participant enrollment;patient advocacy group;patient oriented;patient population;programs;psychological distress;psychological symptom;research clinical testing;sharing platform;survivorship;symposium;tool;translational immunology;treatment response;treatment trial;tumor;virtual;virtual reality environment;visiting scholar;web site;webinar CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors - Cures n/a NCI 10926364 1ZIABC011853-06 1 ZIA BC 11853 6 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3012837 NCI Our NCI-CONNECT program includes a network of 33 institutions across the nation that help us enroll patients for clinical trials and studies. Our network was instrumental to the launch of two first-of-their-kind multi-center clinical trials after a landmark agreement with Medical Science & Computing that provides unprecedented opportunity for intramural and extramural collaboration on clinical trials for the network. We have formal partnership under an NCI Memorandum of Understanding with 9 patient advocacy groups to share educational content and raise awareness to improve outcomes for people with rare CNS tumors. We collaboratively host workshops meetings and webinars with partners to help share the patient perspective and have collaborated on seven events in the past three years including a Survivorship Care in Neuro-Oncology Symposium virtually in June 2021 with over 200 attendees. NCI-CONNECT leadership also participates in advocacy lead events like the National Brain Tumor Society Quality of Life Research project convened in 2022 with the first workshop held in May 2023. The project brings together patient partners and stakeholders to establish a patient-centered brain tumor QoL research agenda. We host scientific workshops that bring together neuro-oncology experts and patient advocates worldwide to discuss the scientific progress and challenges of a selected specific rare CNS cancer type and find ways to improve therapies and develop new clinical trials. We have published papers from these workshops - four proceedings papers and one supplement - and changed cancer care guidelines; notably in November 2020 the NCCN guidelines for medulloblastoma were updated due to our scientific workshop report. Our NCI-CONNECT website is an educational tool for patients caregivers and professionals. From May 2022 to May 2023 the website exceeded 1 million page views and had 818122 visits. NCI-CONNECT launched a Spanish-language version of its website in 2020 to reach a broader and underserved audience and it averages 21795 monthly visits. The top 10 countries by visits in 2022 included Mexico Spain Columbia Argentina and Peru. In March 2020 we published a new Managing Self-Care section and saw a 58 percent growth in page views to our Living with a Tumor content in 2021. Our monthly NCI-CONNECT e-newsletter is delivered to over 16000 subscribers. Our private Facebook group NCI-CONNECT Community - the first ever for NCI - has 633 members; our YouTube Playlist has 35 videos accumulating 31416 views; and our Twitter account has 6957 followers. All these platforms share educational and scientific information. We also developed a symptom-burden app called My STORI in 2021 (available in the Apple Store and Google Play Store) to facilitate patient symptom monitoring and tracking. Our NCI-CONNECT Clinic is dedicated to bringing together patients with similar rare CNS tumor types for special services. We have seen 421 patients as of January 2022 which is 49 percent of our entire NOB patient population. These patients receive genetic testing and counseling a review of their diagnosis with advanced molecular testing and participate in a support group meeting called CARES with a dedicated Health and Wellness Counselor. During COVID-19 NCI-CONNECT has added partnerships with local physicians to provide study drug and telemedicine to expand access to care for our patients. Clinical studies launched and their progress through NCI-CONNECT include these treatment trials: a basket trial testing the immune checkpoint inhibitor nivolumab for adults with rare CNS cancers (17C0102) progress includes a positive interim analysis in the heavily pre-treated patient cohort and the presentation on these results won an abstract Award for Excellence in Rare CNS Disease at the 2021 SNO Annual Meeting; a first-in-human study of oral ONC206 in recurrent and rare primary CNS neoplasms (20C0069); a study of nivolumab for patients with recurrent IDH mutant gliomas including oligodendrogliomas (19C0006); and an immune monitoring study for patients with gliosarcoma and glioblastoma (21C0015). Clinical and observational studies include one retrospective study of Tissue Outcomes and Pregnancy Sub Study (P194734); two Natural History Studies a natural history and specimen banking study for adults with rare central nervous system (CNS) cancers (16C0151) research using data from our Natural History Study received an Abstract Award for Excellence in Survivorship at the 2021 SNO Annual Meeting and based on study data the 2021 WHO diagnosis book for ependymoma was updated; an online survey of outcomes and risk for patients with adult CNS cancers (17CN141); a trial using immersive Virtual Reality (VR) at the time of clinical evaluation to improve psychological distress and anxiety (20C0065) which the interim results were published in March 2023 and support feasibility and acceptability of the intervention to target psychological symptoms for primary brain tumor patients; a study on managing Cancer And Living Meaningfully (CALM) therapy in individuals diagnosed with a primary brain tumor; and a Sleep Observation Study. NCI-CONNECT is conducting extensive biomarker research as a part of the ongoing immunotherapy basket clinical trial using the immune checkpoint nivolumab for rare CNS cancers. Collaborating with the Translational Immunology Program in the Neuro-Oncology Branch extensive monitoring of individual patient's immune response treatment is underway using serial blood collections. NCI-CONNECT is further advancing science through the identification of new molecular subtypes of CNS tumors. For example through intramural collaborations with the CCR Laboratory of Pathology team led by Dr. Kenneth Aldape NCI-CONNECT importantly uncovered a new subtype of ependymoma characterized by MYCN amplification. Collaborations with other investigators in CCR led to the hypothesis that these cancers may be selectively sensitive to topoisomerase inhibitors and a novel inhibitor PLX-038 will be tested for these and other tumors harboring MYCN amplification in a clinical trial. NCI-CONNECT established a new collaboration with the Pediatric Oncology Branch Radiation Oncology Branch and the Surgical Neurology Branch to develop novel therapies for high-grade and radiation-induced meningioma. The NCI-CONNECT consortium has allowed us to expand our research efforts across the United States and provides a network for patient referrals to our NCI-CONNECT Clinics. We have led educational activities for NCI-CONNECT members several times per year including virtual journal club sessions and live tumor board sessions that we videocast to NCI-CONNECT investigators in conjunction with our scientific workshops. In April 2020 we expanded our weekly multidisciplinary NIH Neuro-Oncology Tumor Board to include investigators and cases from participating NCI-CONNECT consortium sites including 16 Comprehensive Cancer Centers. These educational efforts have been well-attended and engaging as exhibited by our data: 154 providers have presented 154 cases to participants from 47 external sites. In addition NCI-CONNECT holds weekly lectures from visiting scholars and in May 2023 held its first in-person visiting scholar lecture on Survivorship in Neuro-Oncology with a Patient and Caregiver. Further MyPART and NCI-CONNECT networks are collaborating on developing a neuro-oncology clinic for AYAs at the NIH Clinical Center. They held a collaborative workshop October 14 2022 and since are holding regular meetings on clinical research ideas and survivorship care with plans for several clinical trials to be modified to expand to AYAs. With the information technology team led by Dr. Jason Levine NCI-CONNECT is analyzing data from its patient outcomes surveys to dynamically display it publicly online. 3012837 +No NIH Category available DNA Methylation;DNA copy number;Data;Data Set;Epigenetic Process;Gene Expression;Genomics;Goals;Human;Malignant Neoplasms;MicroRNAs;Modeling;Pattern;The Cancer Genome Atlas;Tissue-Specific Gene Expression;Variant;cancer biomarkers;cancer subtypes;cancer type;genome wide methylation;genomic biomarker;genomic data Genomic Biomarkers of Cancer n/a NCI 10926362 1ZIABC011850-05 1 ZIA BC 11850 5 15687397 "ALDAPE, KENNETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 695923 NCI We will study existing genomic data sets from multi-platform analysis to find existing patterns and relationships between epigenetics and genomics. In particular we will study the relationship between changes in DNA methylation compared to changes in gene expression to account for the variation in gene expression among cancer types. In addition we will construct models that take into account epigenetics as well as changes in DNA copy number and microRNA expression that may account for differential gene expression in human cancer subtypes. We will utilize publicly available data sets such as TCGA for this purpose. 695923 +No NIH Category available Adjuvant;Adjuvant Radiotherapy;Adjuvant Therapy;Behavior;Biological Markers;Cessation of life;Clinical;DNA;DNA Methylation;Data;Decision Making;Development;Excision;Genomics;Goals;Histology;Intracranial Neoplasms;Learning;Methylation;Molecular;Mutation;Nomograms;Operative Surgical Procedures;Patient Selection;Patients;Radiation;Recurrence;Recurrent tumor;Subgroup;Therapeutic;Validation;clinical predictors;clinically relevant;epigenome;experience;individual patient;meningioma;methylome;personalized decision;personalized medicine;prevent;standard of care;tumor;tumor progression Development and validation of a predictor of meningioma recurrence n/a NCI 10926360 1ZIABC011847-06 1 ZIA BC 11847 6 15687397 "ALDAPE, KENNETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 675454 NCI An important clinical problem in the management of patients with meningiomas is the difficulty in predicting recurrence at the individual patient level limiting appropriate selection of patients who would benefit from adjuvant therapy to delay recurrence. Grading of tumors is based entirely on histology without molecular considerations but recent data suggest the utility of DNA methylation profile as a clinically relevant biomarker. We therefore aimed to develop and validate a combined molecular and clinical predictor of meningioma recurrence in individual patients to help personalize decision making regarding adjuvant treatment. Results indicate that a molecular definition of meningioma may yield clinically relevant subtypes that can be used to optimize therapeutic decisions. 675454 +No NIH Category available Brain;Brain Neoplasms;Cells;Classification;Computing Methodologies;DNA Methylation;DNA analysis;Data;Diagnosis;Goals;Heterogeneity;Histologic;Human;Immunotherapy;Individual;Malignant Neoplasms;Methods;Methylation;Modality;Pathologic;Pathologist;Sampling;Work;cell determination;cell type;information classification;neoplastic cell;new technology;novel therapeutics;single cell analysis;tumor;tumor microenvironment;virtual Single-cell DNA methylation analysis of human cancer n/a NCI 10926359 1ZIABC011846-06 1 ZIA BC 11846 6 15687397 "ALDAPE, KENNETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 675454 NCI DNA methylation provides a signature to identify cell type. Previous data shows that DNA methylation signature of bulk tumors reveals important classification information that is not available using current standard pathological methods (histologic interpretation by a pathologist). In this project we will extend this concept by analyzing the DNA methylation signatures of individual cells within the tumor. The analysis of single-cell methylation will then enable a cell-by-cell determination of differentiation and heterogeneity within the tumor. It will also allow characterization of the tumor microenvironment which is emerging as a critically important component for new therapeutic modalities including immunotherapy. We have expanded this work to include deconvolution of bulk methylation data in tumors to continue the goals of this project. 675454 +No NIH Category available Adult;Brain Neoplasms;Cells;Central Nervous System Neoplasms;Characteristics;Clinical;Data Reporting;Disease;Early Diagnosis;Environmental Risk Factor;Exposure to;Genes;Genomics;Glioma;Health Status;Incidence;Knowledge;Malignant Neoplasms;Malignant neoplasm of central nervous system;Mutation;Outcome;Participant;Patient Self-Report;Persons;Physicians;Population;Predisposition;Primary Prevention;Process;Quality of life;Reporting;Risk;Risk Factors;Scientist;Symptoms;clinical predictors;cohort;functional status;rare cancer;tumor Outcomes and Risk of Rare Tumors n/a NCI 10926354 1ZIABC011837-06 1 ZIA BC 11837 6 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 423485 NCI Rare cancers are defined as those with 40000 cases per year. There are over 130 separate types of primary CNS tumors all of which meet the definition of a rare cancer. However some CNS cancers have incidences of less than 1000 cases per year. Because of its relative rarity limited reports of the presentation and clinical course have been completed. An additional consequence of the relative rarity of these CNS tumors studies to evaluate risk factors for the occurrence of these rare CNS tumors or predicting the clinical course of these rare CNS tumors are also limited. Rare CNS tumors like other cancers occur when there are changes to genes that control the way cells grow and divide often as a result of exposure to other environmental risk factors. Therefore exploring genetic changes in persons with rare CNS tumors will allow us to begin to understand what changes are associated specifically with these tumors. To date these participants are often included as part of larger cohorts which include other types of brain tumors. We now understand that even among gliomas the risk factors differ]. Therefore identifying the risk factors specifically associated with rare CNS tumors is critical for primary prevention and early detection. This knowledge would allow scientists and physicians to eventually screen for these changes or target the genes or the processes they control for treatment purposes. 423485 +No NIH Category available Acute;Alleles;Allografting;Amplifiers;Cells;Compensation;DNA Sequence Alteration;Dependence;Development;Endothelium;Future;Gene Dosage;Genetic Models;Genetic Predisposition to Disease;Genetic Recombination;Genetic Transcription;Genome;Genomics;Genotype;Germ-Line Mutation;Growth;Hemangiosarcoma;Immunohistochemistry;Induction of Apoptosis;Knockout Mice;Li-Fraumeni Syndrome;LoxP-flanked allele;MYC Family Protein;MYC gene;Malignant Neoplasms;Modeling;Monitor;Mus;Neoplasms;Oncogenic;Outcome;Pathologic;Pathway interactions;Patients;Pharmaceutical Preparations;Physiological;RNA;Recovery;Reporter;Role;Siblings;Spectral Karyotyping;TP53 gene;Tamoxifen;Testing;Therapeutic;Thymic Lymphoma;Tissues;Tumor Promoters;c-myc Genes;cancer cell;cell type;conditional knockout;design;dosage;effective therapy;genetic testing;mouse genetics;mutant;postnatal;programs;therapeutic target;tumor;tumor growth;tumor progression;tumorigenesis;tumorigenic Minimal Myc functional threshold for tumorigenesis n/a NCI 10926353 1ZIABC011835-06 1 ZIA BC 11835 6 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 147693 NCI "We have designed a genetic test of the hypothesis that a minimum level of Myc function is required to ""amplify"" the transcriptional programs necessary for promoting and sustaining tumor formation. We employed the mouse p53 null mutant (p53 KO) as a robust tumor model to test for Myc-dependency by introducing modest changes in the endogenous c-Myc level (c-Myc+/-). Tumor-free survival times were compared in genetically similar p53 KO sibling mice that were either c-Myc+/+ (Myc WT; p53 KO) or c-Myc+/- (Myc-Het; p53 KO). Median tumor-free survival times doubled in the Myc-Het; p53 KO relative to Myc-WT (significant at P 0.0001). This difference was independent of the tumor type with hemangiosarcoma and thymic lymphoma being the most common (83%) tumor types in both groups. Analyses of c-Myc genomic alterations and expression levels in p53 KO tumors using Spectral Karyotyping (SKY) FISH and quantitative RNA ISH and immunohistochemistry revealed that compensation for the initially reduced endogenous c-Myc dosage had occurred in tumors arising in Myc-Het;p53 KO mice. Notably in hemangiosarcomas genome amplification achieved by several rounds of genome tetraploidization was consistently higher in the Myc-Het;p53 KO than in the Myc-WT;p53 KO tumors. Although thymic lymphomas of either genotype showed no genomic amplification expression of Myc RNA and Myc protein were nevertheless comparably elevated in both the Myc-WT and Myc-Het tumors suggesting that compensation for reduced Myc gene dosage had occurred at the transcriptional level. These results indicate that reduced endogenous c-Myc dosage substantially delays tumor development in mice that are genetically predisposed to neoplasia and that in order for Myc-Het;p53 KO mice to develop tumors a compensatory increase in expression of Myc which can occur by multiple mechanisms is required. We have also used allografts using of thymic lymphomas from p53 KO mice carrying conditional c-Myc-floxed and tamoxifen-dependent Cre alleles and a dual-fluorescent reporter to monitor recombination efficacy in order to test whether reducing c-Myc will adversely impact established tumors (i.e. growth progression) and found that after recovery from recombination induced apoptosis tumor growth rate is substantially slowed when endogenous Myc dosage is acutely reduced. Our results strongly suggest that a modest reduction in Myc can curtail cancer growth and has important implications particularly for extending tumor-free survival in patients with Li-Fraumeni syndrome (germline mutations in p53) as well as sporadic cancers. This study provides a framework and model for future analyses of c-Myc role in tumorigenesis and tumor progression and can be readily extended to other tumor types using analogous strategies and other tumor promoters such as oncogenic Ras. We are also exploring whether p53 tumors can arise at all in the context of severely reduced or absent c-Myc expression levels using a conditional knock-out approach to model hemangiosarcomas by removing both p53 and c-Myc selectively from endothelial tissues (Cdh5CreER) in post-natal young mice." 147693 +No NIH Category available Aging;Biosensor;CDK2 gene;CDK4 gene;Cell Cycle;Cell Cycle Regulation;Cells;DNA Damage;Data;Decision Making;Event;Future;G1 Phase;G1/S Transition;G2 Phase;Goals;Image;MEKs;Malignant Neoplasms;Molecular;Play;Role;Stimulus;imaging capabilities;inhibitor;neoplastic cell;response;senescence Study cell cycle regulation in dormant tumor cells n/a NCI 10926352 1ZIABC011832-06 1 ZIA BC 11832 6 15687383 "CAPPELL, STEVEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 573763 NCI The overall goal of this project is to investigate mechanisms underlying irreversible cell cycle exit. We recently uncovered the molecular mechanism underlying APC/C inactivation at the G1/S transition and showed how this molecular switch controls irreversible cell cycle entry. However several studies have recently shown that APC/C re-activation in G2 phase after DNA damage also plays a critical role in the decision to undergo senescence which is defined as an irreversible cell cycle exit. The molecular mechanism underlying this APC/C re-activation is not currently known. Using our APC/C and CDK2 biosensors our data shows that APC/C only re-activates in response to DNA damage when CDK2 activity is suppressed to lower levels than is needed in G1 phase to inactivate APC/C. This critical observation indicates APC/C re-activation demonstrates hysteresis a key feature in irreversible fate transitions and could therefore be the critical event underlying senescence entry. We are currently investigating the mechanism underlying Emi1 suppression in response to DNA damage. In addition we are investigating additional mechanisms that may maintain senescence. Using our time-lapse imaging capabilities we can induce senescence with a combination of MEK and CDK4/6 inhibitors and follow cells as they undergo senescence. By removing the initiating stimulus at various points we will identify the point of irreversibility in senescence. Once identified this mechanism will be an important target for future cancer and possibly aging therapies. 573763 +No NIH Category available Biology;Biosensor;Cell Cycle;Cell Cycle Regulation;Cells;DNA Damage;Decision Making;Engineering;Future;G1 Phase;Genotoxic Stress;Goals;Image;Inflammation;Knowledge;Mitogens;Molecular;Nature;Patients;Play;Role;Science;Screening procedure;Signal Pathway;Signal Transduction;Source;Stress;Work;beta-Transducin Repeat-Containing Proteins;cancer cell;overexpression;prevent;small molecule inhibitor;synthetic peptide;tool;ubiquitin ligase Control of cell cycle commitment by APC-C-Cdh1 n/a NCI 10926350 1ZIABC011830-06 1 ZIA BC 11830 6 15687383 "CAPPELL, STEVEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 573763 NCI The overall goal of this project is to investigate how stress and mitogen signaling pathways regulate the cell's decision to either enter or exit the cell cycle and to investigate the source of single-cell variability in this fate choice. It has been proposed that the decision to enter the cell cycle is made at a discreet point during G1 phase called the restriction point. However we have shown that if cells encounter genotoxic stress even after they have passed the restriction point they can still exit the cell cycle and return to quiescence indicating cells have not yet committed to the cell cycle at the restriction point (Nathans et al Science Advances 2021). These results call into question the concept that cells make the decision to divide at a single point in the cell cycle and also demonstrate that the DNA damage-regulated G1/S checkpoint is highly ineffective. In FY2023 we now show that cells never actually irreversibly commit to the cell cycle. Using time-lapse imaging single-cell tracking and fluorescent biosensors we show that the cell cycle remains fully reversible at any point if mitogen signaling is blocked (Cornwell et al Nature 2023). This finding has major implications for our basic knowledge of how the cell cycle works as well for how cancer cells may be targeted in patients. Future studies with this project will further investigate the implications of this new understanding of cell cycle commitment. Also in FY2023 we have made an important advance in building new tools for studying the cell cycle. We engineered a new biosensor to study the cell cycle-regulated ubiquitin ligase SCFbeta-TRCP. This ubiquitin ligase is often overexpressed in cancer cells and plays an important role in regulating stress signaling and inflammation but little is known about how this ubiquitin ligase is regulated. We engineered a synthetic peptide that is degraded by SCF beta-TrCP and used this tool to both study beta-TrCP biology as well as use it as a screening tool to identify small molecule inhibitors of SCF beta-TrCP (Paul et al. Nature Commmunications 2022). 573763 +No NIH Category available Combined Modality Therapy;DNA Damage;DNA Single Strand Break;Lutetium;Malignant Neoplasms;Names;Neuroendocrine Tumors;Phase;Phase I/II Clinical Trial;Poly(ADP-ribose) Polymerase Inhibitor;Radioisotopes;repaired;stem Phase 1-2 study of Lu177-DOTATATE and olaparib in neuroendocrine tumors n/a NCI 10926348 1ZIABC011827-06 1 ZIA BC 11827 6 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 84281 NCI The rationale behind using combination therapies in cancer stems from the potential of synergistic mechanisms of action of the involved agents. Olaparib is a PARP-inhibitor which blocks the repair of single-stranded DNA breaks and is especially effective when combined with other agents which induces DNA damage. We are proposing a Phase I/II clinical trial to look at the combination of olaparib with the targeted radionuclide agent Lutetium-177-DOTATATE (trade name: Lutathera Novartis/Advanced Accelerator Appliations) in inoperable gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). 84281 +No NIH Category available Affect;Clinical Trials;Collaborations;Dental;FOLH1 gene;Future;Goals;Human;Methods;Pre-Clinical Model;Rodent;Salivary Glands;Translating;Update;pre-clinical;radioligand;tumor;uptake Protection of Salivary Gland in PSMA-targeted radioligand therapy n/a NCI 10926347 1ZIABC011826-06 1 ZIA BC 11826 6 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 84281 NCI The goal of this project is to see if salivary gland uptake of PSMA injected systemically can be blocked selectively blocked by using local blocking methods at the salivary gland level. The desired end point would be blocking salivary gland uptake of PSMA without affected the tumor update. This is a collaboration with Dr. Blake Warner of the Dental Institute and involves the use of rodents as the pre-clinical model. If the pre-clinical approach is successful the approach will be translated to humans in a future clinical trial. 84281 +No NIH Category available Affect;Antibiotic Resistance;Antibiotics;Cessation of life;Environmental Risk Factor;Evolution;Fluoroquinolones;Frequencies;Genes;Genetic Determinism;Genomics;Goals;Health;Lead;Methicillin;Multi-Drug Resistance;Mutation;Pathway interactions;Population;Resistance;Staphylococcus aureus;United States;antimicrobial;efflux pump;healthcare-associated infections;methicillin resistant Staphylococcus aureus;novel;novel therapeutics Evolution of antibiotic resistance n/a NCI 10926345 1ZIABC011821-06 1 ZIA BC 11821 6 15687374 "KHARE, ANUPAMA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 218337 NCI We have evolved several independent populations of methicillin-sensitive as well as methicillin-resistant S. aureus (MRSA) to multiple fluoroquinolones and identified the adaptive trajectories leading to antibiotic resistance. We found that mutations in and genomic amplifications of a less-well characterized efflux pump lead to antibiotic resistance. The presence of the efflux pump increases the frequency of antibiotic resistance and hitchhiking of additional efflux pumps in the amplification also leads to cross-resistance. We are currently characterizing the pathways required for the genomic amplifications as well as the environmental factors that affect the selection of genomic amplifications upon antibiotic exposure. 218337 +No NIH Category available Affect;Antibiotic Resistance;Antibiotics;Bacteria;Behavior;Cells;Clinical;Communities;Cystic Fibrosis;Disease;Escherichia coli;Genes;Health;Human;Infection;Lung infections;Microbial Biofilms;Modeling;Molecular;Mutation;Oxidation-Reduction;Pathway interactions;Patients;Phenazines;Population;Postdoctoral Fellow;Production;Pseudomonas aeruginosa;Pulmonary Cystic Fibrosis;Pyocyanine;Research;Resistance;Staphylococcus aureus;System;Testing;Wound Infection;antimicrobial;cell motility;chronic wound;co-infection;emerging adult;fitness;genome-wide;interest;lung pathogen;microbiome;microorganism;novel;response;small molecule Mechanisms of multi-species bacterial interactions n/a NCI 10926344 1ZIABC011819-06 1 ZIA BC 11819 6 15687374 "KHARE, ANUPAMA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 873351 NCI Our research over the last year had two main directions as described below. I) P. aeruginosa response to sensing S. aureus. Interactions between species can affect multiple bacterial behaviors including antibiotic resistance production of antibiotics biofilm formation and motility. We are interested in studying how S. aureus secreted molecules can affect P. aeruginosa behaviors. specifically focusing on antimicrobial production and motility. II) Characterize the adaptation of S. aureus to P. aeruginosa secreted antimicrobials. P. aeruginosa produces multiple molecules with antimicrobial activity against several other species but their mode of action and the pathways by which other bacteria can adapt to them are not well-defined. We are interested in delineating the effect these molecules have on S. aureus cells and identifying the adaptive trajectories of S. aureus in their presence. We have evolved multiple populations of S. aureus against the P. aeruginosa redox-active phenazine molecule pyocyanin and have identified mutations in several genes that have not been previously implicated in pyocyanin resistance. We aim to characterize how these mutations confer pyocyanin resistance test their relevance in clinical isolates and better describe the cellular effects of pyocyanin on S. aureus. 873351 +No NIH Category available Address;Adult;Affect;Anatomy;Anxiety;Architecture;Biological Models;Biology;Bone marrow failure;Brain;Cells;Central Nervous System;Child;Clinical;Clinical Research;Cutaneous;DNA Damage;Development;Disease;Dyskeratosis Congenita;Functional disorder;Genes;Genetic Diseases;Genetic Models;Growth;Health;Hereditary Disease;Human;Immunologic Deficiency Syndromes;Impairment;Intellectual functioning disability;Knock-out;Learning;Length;Lesion;Leukoplakia;Longevity;Malignant Neoplasms;Memory Loss;Molecular;Molecular Biology;Mus;Mutation;Nail plate;Neuronal Differentiation;Neurons;Nonhomologous DNA End Joining;Pathway interactions;Phase;Play;Process;Psychoses;Role;Seizures;Syndrome;System;TP53 gene;Telomere Maintenance;Testing;Work;chromosome fusion;cognitive capacity;conditional knockout;dentate gyrus;embryonic stem cell;experimental study;genetic approach;granule cell;insight;mouse genetics;mouse model;nestin protein;neurogenesis;neuron loss;novel;postmitotic;progenitor;response;telomere Determine how telomere dysfunction impacts neuronal function n/a NCI 10926343 1ZIABC011816-06 1 ZIA BC 11816 6 10105415 "LAZZERINI DENCHI, EROS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 693148 NCI Here we will: i) define why telomere dysfunction selectively affects neurogenesis in the dentate gyrus (DG) and ii) we will define the mechanism of neuronal loss upon telomere dysfunction in the DG. To define why telomere dysfunction selectively affects neurogenesis in the dentate gyrus we will test the hypothesis that telomere dysfunction selectively affects adult-born granule cells GCs due to their prolonged maturation phase. To this end we generated conditional knockout TRF2 mouse embryonic stem cells that can be differentiated into neuronal cells. This system will allow us to test the hypothesis that the timing of differentiation plays a major role in response to telomere dysfunction. In parallel we will employ mouse genetics models with alteration in the process of DG differentiation. To define the mechanism of neuronal loss upon telomere dysfunction in the DG we will assess the role of the DNA damage activation and onset of end-to-end chromosome fusions taking advantage of our previous work aimed at dissecting the cellular response to TRF2 depletion. In this system activation of the DNA damage response can be abolished by depletion of ATM and to a lesser extent by depletion of p53. Suppression of the NHEJ-pathway completely abolishes the onset of end-to-end chromosome fusions. Collectively these experiments will provide a better understanding of the role of telomeres in the CNS as well as a deeper understanding of the molecular mechanism that leads to neuronal loss upon DNA damage activation in neurons. 693148 +No NIH Category available Alleles;Animals;Binding;Cell Death;Cells;Cohort Analysis;Complex;Data;Data Analyses;Future;Genes;Germ Cells;Growth;Guide RNA;Homeostasis;Individual;Knockout Mice;Laboratories;Length;Names;Play;Population;Process;Proteins;Research Institute;Role;TERF1 gene;Time;Work;Zinc Fingers;cancer cell;experimental study;genome-wide;in vivo;insight;next generation sequencing;novel;stem cells;telomere;telomere loss Investigate the mechanism of action of the novel telomere length regulator TZAP n/a NCI 10926342 1ZIABC011815-06 1 ZIA BC 11815 6 10105415 "LAZZERINI DENCHI, EROS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 693148 NCI Having started my laboratory at NCI in late May 2018 I have been mainly involved in setting up my laboratory. My future work at NCI will be to validate and characterize positive hits identified in the genome-wide gRNA screen described above. These experiments are expected to provide us with mechanistic insights into the role of TZAP and telomere trimming in telomere length homeostasis. In addition we will analysis of cohorts of TZAP null mice will allow us to establish whether TZAP depletion in vivo leads to progressive telomere elongation and the consequences of critically long telomeres in vivo. I am currently waiting for the transfer of animals to start this project here at NCI. 693148 +No NIH Category available Antibodies;Antigens;Biological;Biological Process;Blood;Blood Vessels;Bone Marrow;Boston;Cell Differentiation process;Cell Proliferation;Cells;Chronic;Classification;Clinical;Clinical Trials;Coin;Collaborations;Communication;Custom;Cytokine Signaling;Data;Data Analyses;Defect;Disease;Epitopes;Epstein-Barr Virus Infections;Equilibrium;Experimental Designs;Explosion;Foundations;Frequencies;Functional disorder;Funding;Genomics;Goals;Grant;Homeostasis;Hospitals;Immune;Immunologic Deficiency Syndromes;Immunologics;Immunologist;Immunology;Immunophenotyping;Inflammation;Interferons;Label;Leukocytes;Link;Machine Learning;Magnesium;Measurement;Measures;Methodology;Methods;Modeling;Mus;National Institute of Allergy and Infectious Disease;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Neoplasms;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Physics;Physiologic pulse;Population;Process;Regulation;Research;Research Project Grants;Resolution;Sampling;Signal Pathway;Site;Systemic Lupus Erythematosus;T-Lymphocyte;Time;United States National Institutes of Health;Universities;Validation;Variant;Whole Blood;Work;autoimmune lymphoproliferative syndrome;bioinformatics pipeline;cell type;clinical application;computational pipelines;congenital immunodeficiency;cytokine;density;design;granulocyte;high dimensionality;immunoregulation;machine learning pipeline;monocyte;neutrophil;response;single-cell RNA sequencing;synergism;tool;tumor;vector Immunophenotyping by CyTOF and machine learning n/a NCI 10926336 1ZIABC011807-06 1 ZIA BC 11807 6 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 544173 NCI "Our application of high-dimensional immune-phenotyping using CyTOF finds natural applications in clinical settings. There has been an explosion of experimental methodologies for measurement multiplexing in immunology (e.g. cytokine arrays by SomaLogic single-cell RNAseq) and we are focusing on CyTOF for its close connection to biological function in immunological problem. Our main project has been to develop new machine-learning derived tools to automatically analyze CyTOF data (collaboration with Pankaj Mehta's theoretical physics group at Boston University). This collaboration (funded in part by a seed grant from the Moore foundation) synergizes Pankaj Mehta's expertise in machine learning and the Altan-Bonnet lab's expertise in quantitative immunology to optimize new methods in CyTOF data analysis. We emphasize interpretability of immunological classifier to allow immunologists to leverage the results of our machine learning pipeline into testable hypotheses and experimental validation. We are collaborating with clinical labs at the NIH to apply our experimental/theoretical pipeline to analyze clinical samples from ongoing clinical trials. Our collaboration with Mike Lenardo's group at NIAID led to the design and validation of a CyTOF panel that provides general immunophenotyping for peripheral blood mononuclear cell (PBMC) samples for the clinical genomics group at NIAID. This 35-label panel covers all the main leukocyte cell types of the blood and leaves open channels for augmentation with antibodies against disease-specific epitopes. We are profiling the PBMC of patients afflicted with XMEN (""X-linked immunodeficiency with magnesium defect EBV infection and neoplasia"") and ALPS (""Autoimmune lymphoproliferative syndrome"") under study within the Lenardo lab. Preliminary measurements demonstrate how the large number of available samples within the clinical genomics branch at NIH can be leveraged with our high-dimensional phenotyping to generate immunological classifier that best correlates with disease status. We will apply support-vector classifiers to identify the leukocyte populations whose variation in frequency and/or change in differentiation status best correlates with clinical scores. Moving forward we will further this collaboration to build a custom-designed experimental and computational pipeline that robustly classifies patients from multiple primary immunological deficiencies. Hence our goal is to fine-tune our machine learning tools to clinical applications while probing the global disruption of immunological homeostasis (as studied in project I) with access to rare samples of patients with primary immunodeficiencies. Similar collaborative work is ongoing with Mariana Kaplan's lab within NIAMS. This collaboration aims at deepening our understanding of the dysregulation of neutrophils in Systemic Lupus Erythematosus (SLE) patients. The Kaplan lab has identified a new population of low-density granulocytes that trigger enhanced formation of neutrophil entrapment traps (""NETosis"") IFN secretion and vascular damage. Our working hypothesis for this collaboration is that such neutrophilic dysfunction in SLE globally displaces homeostasis by maintaining chronic inflammation. Here we expanded our general immune-phenotyping CyTOF panel with antibodies specific to neutrophils. Analysis of neutrophils requires the processing of fresh whole blood and the Kaplan lab receive fresh samples biweekly from patients at the NIH hospital. For this reason our CyTOF-based immune-phenotyping pipeline is particularly well suited to identify large-scale disruption of immune homeostasis in the blood of SLE patients as we have validated the robustness of the pipeline when fresh samples are being accrued processed and analyzed over a large period of time (1 month). Hence we will accrue samples (n100) with varied clinical presentations in order to focus our understanding of altered homeostasis in the blood of SLE patients. As in the collaboration with the Lenardo lab we are taking the opportunity of collaborating with the Kaplan lab to fine-tune our CyTOF pipeline in clinical settings as well as to further probe how global immunological disruption can be set in the context of chronic inflammation." 544173 +No NIH Category available Ablation;Biological;Cessation of life;Death Rate;Detection;Development;Diagnosis;Disease;Engineering;Excision;Goals;Image;Immunotherapy;Incidence;Intravenous;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Modality;Molecular;Patient Selection;Patients;Phase;Positron-Emission Tomography;Primary carcinoma of the liver cells;Radiation therapy;Radioembolization;Survival Rate;Transplantation;United States;X-Ray Computed Tomography;cancer type;falls;high risk;imaging agent;improved;intrahepatic;novel;palliative;screening;treatment planning;tumor Engineering HCC-selective PET agent n/a NCI 10926330 1ZIABC011800-06 1 ZIA BC 11800 6 15687349 "ESCORCIA, FREDDY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1744239 NCI Liver cancer is ranked second in cancer-related deaths worldwide. Unlike many other cancer types the incidence and death rate of liver cancers is rising in the United States with a 5-year survival of 18% (all stages). Treatment of hepatocellular carcinoma the most common type of liver cancer transplant and resection offer curative potential and have 5 year overall survival (OS) rates of 70% and 40% respectively. For palliative local treatments 5 year OS rates fall to 20-35%. Classic imaging of HCC includes Tri-phasic CT scan and MRI however these modalities provide little biological information of the tumors especially after local ablative therapies compromising our ability to discern active from treated disease. Our goal is to engineer HCC-selective PET agents that will allow us to define the extent of disease to facilitate screening of in patients at high risk of HCC development aide in treatment planning once HCC has been diagnosed and help in selecting patients who may benefit from tumor-selective therapies (e.g. immunotherapy molecular radiotherapy). 1744239 +No NIH Category available Categories;Cell Lineage;Cells;Chromatin;DNA;DNA Sequence;Development;Diabetes Mellitus;Elements;Enhancers;Exocrine pancreas;Gene Expression;Genome Mappings;Genomics;Goals;Islets of Langerhans;Link;Logic;Malignant neoplasm of pancreas;Maps;Pancreas;Pancreatic Diseases;Regenerative Medicine;Regulatory Element;Research;Technology;Work;body system;cell type;diabetes risk;interest;programs;reference genome;risk variant Identification of genomic regulatory elements in pancreas cells n/a NCI 10926329 1ZIABC011798-06 1 ZIA BC 11798 6 15687347 "ARDA, HATICE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1558428 NCI Using cutting-edge genomic technologies we have mapped and categorized thousands of genomic elements that might be putative regulators of pancreas cell lineages. We identified chromatin regions that are associated with cell type-specific gene expression. Our work has revealed an enhancer logic that suggests a mechanism for the diversification of pancreas cell lineages during development. Our results also revealed previously unrecognized links between endocrine and exocrine pancreas in diabetes risk. 1558428 +No NIH Category available Goals;Literature;Metastatic Pheochromocytoma;National Institute of Child Health and Human Development;Paraganglioma;Patients;Progression-Free Survivals;early phase clinical trial;improved;phase 2 study;rare cancer;safety assessment Phase 2 study of Lu-177-DOTATATE in inoperable paraganglioma - pheochromocytoa n/a NCI 10926326 1ZIABC011789-07 1 ZIA BC 11789 7 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 168560 NCI The goal of this project it to assess the safety and to evaluate the ability of Lu-177-DOTATATE to improve upon progression-free survival (PFS) at 6 months in patients with inoperable SSTR positive PHEO/PGL by comparing PFS of patients treated with Lu-177-DOTATATE to historical controls from existing literature. This will be an early phase clinical trial of 90 patients which will seek to determine whether Lu-177-DOTATATE can be used to improved the PFS in the rare tumor metastatic pheochromocytoma and paraganglioma. This is a collaborative project with Dr. Karel Pacak of NICHD. 168560 +No NIH Category available Acceleration;Animals;Area;Belief;Big Data;Biochemical Pathway;Bioinformatics;Biological;Biological Process;Biology;Biomedical Research;Blood specimen;Brain Neoplasms;Cancer Genome Anatomy Project;Cancer Research Project;Cell Line;Cells;Central Nervous System Neoplasms;Chordoma;Classification;Clinical Data;Clinical Trials;Collaborations;Collection;Complex;Computer Analysis;DNA;DNA Sequence;DNA biosynthesis;Data;Data Analyses;Databases;Decision Making;Development;Disease;Enrollment;Evolution;Explosion;Formalin;Freezing;Functional disorder;Funding;Gene Expression Profile;Gene Expression Profiling;Generations;Genes;Genetic;Genomic Data Commons;Genomics;Glioma;Human;Human Genome Project;Hybrids;Impact evaluation;In Vitro;Information Storage;Laboratories;Link;Mainstreaming;Malignant Neoplasms;Malignant neoplasm of central nervous system;Maps;MicroRNAs;Microarray Analysis;Mining;Modality;Molecular;Molecular Analysis;Monitor;Morphology;Natural History;Nature;Nucleic Acids;Paraffin Embedding;Patients;Pattern;Pharmacotherapy;Phenotype;Process;Proteins;Proteomics;RNA;RNA chemical synthesis;Research;Research Personnel;Resolution;Resources;Sampling;Science;Signal Transduction Pathway;Source;System;Techniques;Technology;The Cancer Genome Atlas;Therapeutic;Time;Tissue Sample;Tissues;Translating;Treatment Efficacy;Tumor Biology;Tumor Tissue;Variant;Work;analytical tool;bioinformatics tool;cDNA Arrays;cell behavior;clinical care;clinical practice;companion diagnostics;data acquisition;data streams;data warehouse;design;differential expression;driving force;drug development;genome wide methylation;genome-wide;histone methylation;improved;in vivo;laboratory experiment;mRNA Translation;metabolomics;methylation pattern;molecular diagnostics;molecular targeted therapies;neuro-oncology;novel;novel therapeutics;older patient;participant enrollment;patient prognosis;patient stratification;peripheral blood;precision medicine;programs;prospective;protein aminoacid sequence;protein distribution;sample collection;small molecule;stem cells;therapeutic biomarker;therapeutic target;three dimensional structure;transcriptomics;treatment response;treatment stratification;user-friendly;whole genome Bioinformatics: Characterizing Brain Tumor Data n/a NCI 10926324 1ZIABC011784-07 1 ZIA BC 11784 7 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 895043 NCI As a hybrid science that links biological data with techniques for information storage distribution and analysis to support multiple areas of scientific research including biomedicine Bioinformatics has been driven by the great acceleration in data-generation processes in biology. The NOB for the past years has enrolled over 1000 patients on the Natural History study which mandates the collection of tumor tissue as well as peripheral blood samples for germline DNA. This includes an unprecedented number of patients with rare CNS cancers. Moreover the sample collection is accompanied by careful and prospective clinical data acquisition allowing an unprecedented wealth of matched molecular and clinical data permitting a wide variety of analyses. Advances in the molecular analysis of genes proteins and metabolites have greatly improved our understanding of biological processes and disease and have increased our ability to monitor treatment response and stratify patients to improve treatment efficacy. Precision medicine facilitated by companion diagnostics is one of the driving forces accelerating the drug development process and improving therapeutic management. Launched in 2016 the NCI Genomic Data Commons (GDC) provides a single source for data from NCI initiatives and cancer research projects including TCGA and TARGET and the analytical tools needed to mine them. The new initiated NOB Bioinformatics has extended our bioinformatics and computational analyses efforts to utilize the GDC databases. For example using the TCGA data effectively doubles the number of GBMs we have to work with and affords us the advantage of formulating computationally derived hypothesis based on one database with the ability to validate those hypotheses on a totally different database. For example a significant amount of time has been spent by NOB Bioinformatics on the databases to try and understand the biologically basis for the more aggressive phenotype and thus shorter survival of GBMs from older patients compared to those of younger GBMs. To date we have found a very interesting set of differentially expressed genes and miRNAs as well as specific genome wide methylation patterns and specific chromosomal number variants that differentiate older versus younger GBMs. We are in the process of using some of these findings to perform wet lab experiments to better annotate the significance of these findings. Furthermore in collaborated with NCI ClinOmics (now COMPASS) program we analyzed and created genomic profiling data from the rare CNS tumors such as chordomas and dissected signal transduction pathways and aided in the design of novel therapeutics. In addition to characterizing the samples from patients enrolled the NOB Bioinformatics has generated genomic-scale analyses of the many human glioma initiating cells/glioma stem cells (GIC/GSC) lines produced in laboratory. This characterization is both at the primary cell level (including evolution through passages) as well as evaluation of the impact of different treatments (differentiation animal passages drug treatment etc) on the biological behavior of the cells. 895043 +No NIH Category available 3-Dimensional;Address;Adenocarcinoma;Antibody-drug conjugates;Apoptosis;Apoptotic;Area Under Curve;Automobile Driving;Biological Assay;Biological Markers;Biology;Biopsy;Biopsy Specimen;Bypass;CCR;CD276 gene;CHD1 gene;Castration;Categories;Cell Count;Cell Cycle;Cell Line;Cell Proliferation;Cell surface;Cells;Characteristics;Chronic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Complementary therapies;Coupled;Development;Disease;Dose;Double Strand Break Repair;Dropout;Drug Targeting;Drug resistance;Epithelium;Evolution;Future;Generations;Genes;Genomics;Genotype;Goals;Growth;Histologic;In Vitro;Interferons;Libraries;Malignant neoplasm of prostate;Manuscripts;Metastatic Prostate Cancer;Methodology;Modeling;Molecular;Mutagens;Neoplasm Metastasis;Neurosecretory Systems;Normal tissue morphology;Organoids;Pathogenesis;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Physiological;Population;Pre-Clinical Model;Principal Component Analysis;Procedures;Proteins;Publications;RB1 gene;Recurrence;Refractory;Regimen;Reporting;Research;Resistance;Resolution;Sampling;Signal Transduction;Site;Solid;Solid Neoplasm;System;TP53 gene;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;Tumor Antigens;Tumor Biology;Tumor Escape;Work;antibody conjugate;anticancer research;aurora kinase A;biomarker discovery;bone;cancer stem cell;cohort;comparative;coronavirus disease;disease heterogeneity;docetaxel;experimental analysis;genotoxicity;high throughput screening;high-throughput drug screening;immunoregulation;improved;in vitro Model;in vivo;inhibitor;loss of function;matrigel;molecular phenotype;neuroendocrine phenotype;novel;overexpression;patient derived xenograft model;patient population;patient prognosis;patient stratification;preclinical trial;predictive marker;progenitor;programs;prostate cancer model;protein expression;pyrrolobenzodiazepine;replication stress;resistance mechanism;responders and non-responders;response;response biomarker;screening;specific biomarkers;stem;stem cell population;stem cells;subcutaneous;success;targeted treatment;therapeutic target;transcription factor;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor growth;tumor xenograft Mechanisms of pathogenesis in patient derived organoid models of prostate cancer n/a NCI 10926323 1ZIABC011782-07 1 ZIA BC 11782 7 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1336035 NCI I. A cancer stem cell population underlies a multi-lineage phenotype and drug resistance in prostate cancer: We have performed an in-depth analysis on an organoid culture established from a CCR patient biopsy sample exemplifying a resistance mechanism that bypasses an AR requirement via lineage plasticity resulting in the emergence of phenotypes spanning luminal epithelial and neuroendocrine phenotypes (NEPC). This work addresses the molecular phenotypes and lineage relationships as well as the therapeutic sensitivity of cells within a mixed lineage mPC tumor population. Some key accomplishments include: 1) The definition of multiple states of differentiation and their developmental hierarchy originating from bipotential and clonal stem/progenitor subpopulations. 2) A determination that the program driving the multi-lineage phenotype of the organoids included concurrently active luminal epithelial NE and stem cell-determining transcription factors. 3) The identification of specific molecular vulnerabilities in the stem/progenitor subpopulations to block tumor growth. The AURKA inhibitor alisertib caused a selective depletion of the stem/progenitors and combined inhibition of AURKA and AR blocked the growth of xenograft tumors. This work contributes significantly to our understanding of treatment-induced lineage plasticity in mPC by illuminating underlying cellular and molecular drivers of the phenomenon in near patient models. Importantly it demonstrates a potential treatment for certain types of CRPC. This work has been submitted for publication. II. A genotoxic antibody drug conjugate targeting CD276/B7H3 demonstrates efficacy across multiple biomarker defined classes of treatment refractory metastatic prostate cancer: We have analyzed the therapeutic response by our extensive organoid/PDX library of models to an antibody-drug conjugate that targets a tumor-specific antigen B7H3. B7H3 is a cell surface immunomodulatory protein often correlated with higher tumor grade and poor patient prognosis in several solid tumors. It is an attractive therapeutic target due to its frequent upregulated protein expression relative to normal tissue. We interrogated response to an anti-B7H3 targeted antibody conjugated to the pyrrolobenzodiazepine (PBD) genotoxic agent and identified predictive biomarkers of response. This analysis exemplifies the utility of comprehensively evaluating a large heterogeneous cohort. In addition to demonstrating broad efficacy for treatment-resistant forms of mPC we have identified multiple partially-overlapping specific biomarker classes of responsiveness which contribute to both a mechanistic understanding and also provide in-depth information for patient stratification. RB1-deficiency/ replication stress SLFN11 expression and chronic tumor intrinsic interferon (IFN) signaling are partially-overlapping significant predictors of B7H3-PBD response independent of tumor lineage. In addition models compromised in specific aspects of double-stranded break repair CHD1 and ATR loss of function were responsive even in the absence of the other biomarkers. We performed preclinical trials using four PDX models based on their RB1 SLFN11 and IFN signature status. B7H3-PBD eradicated large established subcutaneous tumors and metastasis and improved long-term overall survival in RB1-deficient tumors with or without SLFN11 expression but showed no response in an RB1+/SLFN11NEG tumor model. Collectively these findings support the potential of B7H3-PBD-targeted therapeutics for mPC. Of note at least one of the multiple above biomarkers is expressed in about 70% of CRPC clinical samples suggesting broad potential for mechanistically complementary treatment of tumors escaping current regimens. This work has been submitted for publication. III. High throughput drug screening: Because mPC/CRPC is a highly phenotypically and genotypically heterogenous disease our hypothesis has been that the effective translation of novel treatments requires a representative cohort of models in order to discover rational response classes and to effectively predict efficacy in treatment-resistant mPC patient populations. We have implemented a high throughput screening (HTS) approach in order to efficiently uniformly and comparatively assay a large number of drugs encompassing various mechanisms of action. Several conclusions from the HTS are summarized below. Unfortunately in vivo confirmatory studies were delayed due to COVID which has postponed the submission of a manuscript. High-throughput drug screening on a cohort of 30 patient-derived organoid models covering 5 histological phenotypes and 6 sites of metastasis has been completed (Fig. 1). Full transcriptomic sequencing of generation 1 organoids was conducted on the entire model cohort to aid in future biomarker discovery based on baseline transcriptomics shown in a principal component analysis plot (PCA) in Fig. 2. Adenocarcinoma (ARPC) models cluster together and with their matched recurrence ARPC models that were previously experimentally castrated (designated EXP-CR). Neuroendocrine models (NE) cluster together; amphicrine models (AMP) expressing both ARPC and NE markers reside in the space between ARPC and NE clusters and the single double negative (DNPC) model shows no overlap with any other histological phenotype. An important feature of this HTS was the screening in 3D solid Matrigel which enables a closer resemblance to physiological tumor biology. Each of the 80 compounds was tested at 10 doses resulting in the ability to generate entire drug response curves and enabling the use of Area Under Curve (AUC) as a continuous variable of response in organoid-drug pairs which maximized resolution in assigning responder and non-responder categorizations accurately. The drug response patterns demonstrated that the majority of compounds tested showed either single model-specific responses or a general lack of efficacy. However roughly 20 compounds demonstrated a range of responses providing opportunity for further analysis into characteristics governing resistance and sensitivity. Docetaxel (DTX) is a relatively widely used and proven efficacious drug for mPC and provided the largest observed range in AUC responses. Strikingly for a proportion of drugs including DTX we observed significant correlations between and among particular drugs targeting cell cycle apoptosis and cell replication pathways. This cluster of therapeutics demonstrated common response and nonresponse patterns across multiple models suggesting a similarity in the biology governing resistance and sensitivity among these correlated response patterns. Importantly removing RB1/TP53 null models largely conserved this cluster of co-efficacious compounds suggesting this observation holds true for ADPC and is not driven by replication stress or RB1-loss-dependent lineage/phenotypic differences. Because DTX responses overlapped with the majority of correlated compounds in the cluster of co-efficacious compounds it was used as the basis for building transcriptomic contrasts from sensitive versus resistant models in order to investigate the underlying mechanisms of vulnerability. Overrepresentation of differential gene analysis between responsive and nonresponsive RB1/TP53- intact models revealed strong enrichment in nonresponsive models for glucuronidation and HNF1A transcription factor driven activity. Further experimental analysis of HNF1A-dependent mechanisms have included 1) ectopic over expression associated DTX resistance 2) in vivo PDX responses determined by HNF1A expression in related tumors (LuCaP 170.2 and 170.3) correlated with HNF1A expression and 3) cIAP2 expression correlated with HNF1A and modulating apoptotic responses. 1336035 +No NIH Category available Animals;Antibodies;Autoimmune;Biological Phenomena;Blood;Bone Marrow;Bromodeoxyuridine;Cancer Burden;Cell Differentiation process;Cell Proliferation;Cells;Choristoma;Collaborations;Cytometry;Cytotoxic T-Lymphocytes;DNA biosynthesis;Detection;Development;Disease;Erythrocytes;Experimental Models;Genetic;Goals;Heavy Metals;Hematopoiesis;Homeostasis;Human;Immune;Immune system;Immunologics;Immunology;Inflammatory;Kinetics;Lymphoid Cell;Mathematics;Metals;Methodology;Mus;Myeloid Cells;Noise;Nucleotides;Organ;Organism;Physiologic pulse;Resolution;Rest;Signal Transduction;Source;System;T-Lymphocyte;Thymus Gland;Tissues;United States National Institutes of Health;Vascular blood supply;animation;equipment acquisition;experimental study;flexibility;hematopoietic differentiation;interest;lymphoid organ;mathematical model;monocyte;stem;tool;tumor;tumor immunology;tumorigenesis Dynamics of hematopoietic differentiation n/a NCI 10926322 1ZIABC011781-07 1 ZIA BC 11781 7 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 435338 NCI "We have introduced a new methodology using a combination of CyTOF immune profiling IdU pulse-chasing and mathematical modeling to derive a systemic understanding of immune homeostasis. CyTOF is a recently-acquired instrument (within the NIH-wide Center for Human Immunology) that performs mass cytometry: it is similar to the classical flow cytometer except that its detection capacity relies on the mass-cytometric resolution of heavy metals tagging antibodies. We have implemented CyTOF within NIH and demonstrated its capacity to achieve immune profiling with a 40+ panel of antibodies (e.g. targeted against key markers of hematopoietic differentiation). We have also implemented IdU Pulse-chasing to mark proliferating cells (by incorporation of the metal-tagged nucleotide during DNA replication) and to detect its dilution by cell proliferation or differentiation (by relying on the mass-cytometric capacity of CyTOF): IdU pulse-chasing combines the non-perturbative high-signal noise of BrdU pulse-chasing with the deep immunological profiling of CyTOF. Finally we developed a mathematical framework to model the experimental results obtained from CyTOF IdU pulse-chasing: our quantitative analysis enables us to ""animate"" our network of immune cells and to quantitate the rates at which cells differentiate We have applied our methodology to delineate the differentiation of NK T cells in the thymus (in collaboration with Dr. Hyun Park from EIB-NCI) of monocytes (in collaboration with Dr. Frederic Geissmann from Memorial Sloan-Kettering) and other systems are under consideration. We are demonstrating the flexibility and resolution power of our new methodology to better analyze the systemic perturbation of hematopoiesis occurring during tumor development (in collaboration with Dr. Romina Goldzmid from CIP-NCI). One major finding so far has been that monocytes of the mouse immune system do not differentiate only in the blood of these animals but follow a parallel dynamic of differentiation in the bone marrow and in the lymphoid organs. This implies that the main source of blood monocytes may not reside in the blood itself but rather come from the bone marrow. Such result (obtained without perturbation at homeostasis) challenges the common understanding of blood monocyte differentiation as obtained from genetic perturbations. A second finding was that NKT2 cells (i.e. Type 2 natural-killer T cells) do not derive from NKT1 cells but rather have a direct (yet inefficient) path of differentiation from immature NK T cells. Again our kinetic analysis of pulse-chase experiments revealed an alternative path of differentiation that was partially uncovered by genetic perturbation. All in all this project offers new tools to dissect the dynamics of differentiation and homeostasis in the immune system." 435338 +No NIH Category available 2019-nCoV;Affect;Amphipathic Alpha Helix;Antiviral Therapy;Binding;Cell membrane;Cell physiology;Cells;Cellular Membrane;Cellular Structures;Cholesterol;Development;Ensure;Exhibits;Glean;HIV-1;Half-Life;Human;IFITM1 gene;Immune response;Immunologic Factors;Immunology;Influenza A virus;Integral Membrane Protein;Interferons;Journals;Learning;Lipid Binding;Membrane;Membrane Fusion;Membrane Microdomains;Molecular;Molecular Biology;Nature;Play;Population;Printing;Process;Protein Family;Proteins;Publishing;Receptor Signaling;Reporting;Role;Therapeutic Intervention;Viral;Viral Physiology;Virus;Work;Zika Virus;biophysical properties;gene therapy;human pathogen;in silico;insight;molecular dynamics;new therapeutic target;novel;pathogenic virus;receptor;response;scaffold;therapeutic target;trafficking;tumorigenesis;tumorigenic;tyrosine receptor;viral transmission Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry n/a NCI 10926320 1ZIABC011779-07 1 ZIA BC 11779 7 15201721 "COMPTON, ALEX " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 847772 NCI We published two articles pertaining to this project in 2020 (Ahi et al. mBio 2020; Rahman et al. eLife 2020) two articles in 2022 (Rahman et al. Journal of Molecular Biology 2022; Majdoul et al. Nature Reviews Immunology 2022) and one preprint so far in 2023 (Shi et al. bioRxiv 2023). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. Notably we identified an amphipathic alpha helix that is required for the antiviral activity of IFITM3 against multiple viruses including HIV-1 Zika virus and Influenza A virus (Chesarino Compton et al. EMBO Reports 2017). Subsequently we showed that the amphipathic helix is required for the ability of IFITM3 to alter the biophysical properties of cellular membranes (membrane rigidity and curvature) (Rahman et al. eLife 2020). Most recently we demonstrated that the amphipathic helix exhibits direct cholesterol binding activity providing a possible explanation for its impacts on membranes and a plausible mechanism for how IFITM3 restricts membrane fusion pore formation (Rahman et al. Journal of Molecular Biology 2022). We now plan to examine how cholesterol binding by IFITM3 directly contributes to its antiviral activities by incorporating in silico analyses using molecular dynamics simulations. We will also assess how lipid binding by IFITM3 affects its trafficking through the cell and protein half-life. In addition our findings will allow us to better understand the cellular roles played by IFITM3 and related proteins including its ability to act as a scaffold for receptor tyrosine receptor signaling at lipid rafts in the plasma membrane. Our findings will provide insight into the poorly characterized tumorigenic roles played by this family of proteins and provide therapeutic targets for inactivation. 847772 +No NIH Category available Antibodies;Antigen Targeting;Antigens;Antineoplastic Agents;Autologous;Breast;CEA Family Protein;Cancer Control;Cancer Patient;Cancer Vaccines;Carcinomatosis;Categories;Cells;Cellular immunotherapy;Cervical;Chemical Models;Clinic;Clinical;Clinical Research;Clinical Trials;Colorectal Cancer;Combined Modality Therapy;Disease Resistance;Endometrial;Endometrial Carcinoma;Engineering;Generations;Genes;Genetic;Goals;Greater sac of peritoneum;HLA Antigens;Half-Life;Head and Neck Cancer;Hour;Human;Immune;Immune response;Immune system;Immunize;Immunohistochemistry;Immunologic Surveillance;Immunotherapeutic agent;In Vitro;Interferon Type II;Interferon alpha;Interferons;Intravenous;Location;Longevity;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Membrane Glycoproteins;Membrane Proteins;Mesothelioma;Messenger RNA;Methods;Modification;Monoclonal Antibodies;Mucinous;Natural Immunity;Natural Killer Cells;Normal Cell;Ovarian Serous Adenocarcinoma;Pancreatic Adenocarcinoma;Pathology;Pathway interactions;Patients;Peritoneal;Peritoneal Fluid;Phase;Phase I Clinical Trials;Play;Preparation;Process;Prognosis;Proliferating;Property;Proteins;Reaction;Recombinants;Relapse;Risk;Role;Route;Safety;Sampling;Series;Serous;Signal Transduction;Site;Solid Neoplasm;Specimen;Stains;T cell therapy;T-Lymphocyte;TNF gene;TNFSF10 gene;Testing;Therapeutic;Therapeutic antibodies;Tissue Microarray;Tissue Sample;Tissues;Tumor Antigens;Tumor Cell Line;Viral;Woman;adaptive immunity;antigen binding;cancer cell;cancer initiation;cancer type;carcinogenesis;cell growth;chimeric antigen receptor T cells;cytokine;design;extracellular;fighting;human tissue;immune activation;improved;innovation;intraperitoneal;malignant breast neoplasm;member;mesothelin;monocyte;mouse model;neoantigens;neoplastic cell;novel;pembrolizumab;peripheral blood;phase I trial;preclinical study;receptor;safety testing;side effect;synergism;triple-negative invasive breast carcinoma;tumor Immune cell control of ovarian cancer n/a NCI 10926319 1ZIABC011775-07 1 ZIA BC 11775 7 9692487 "ANNUNZIATA, CHRISTINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 587759 NCI Goal 1: Monocytes It has been shown in mouse models of chemically induced cancer that Interferons (IFNs) are important in the immune-surveillance and immune-editing of tumors. While IFNs alpha (IFNa) and gamma (IFNg) have been shown to have potent anti-neoplastic and anti-proliferative properties in vitro they have shown little efficacy in the clinic. Our observations that IFNs play an important role in killing tumor cells in the presence of monocytes suggests that combination therapy of monocytes and IFNs may have a more potent effect than IFNs alone. We and others have shown that IFNs are more potent anti-cancer agents when used in combination with monocytes isolated from the peripheral blood. Based on these studies we have completed a Phase 1 clinical trial of immune cell therapy using autologous transfer of ex vivo monocytes stimulated with IFNs into the peritoneal cavity of patients who have resistant disease. We are now in the process of defining the mechanism of IFN-induced monocyte killing of ovarian cancer cells. we found that IFNs induce a unique set of genes regulated in monocytes that occurs only with the combination of IFNa and IFNg and this signature may be driven by the TNF/TRAIL pathway. I have the ability to examine tissue and peritoneal fluid samples from women on our phase 1 trial receiving intraperitoneal autologous monocytes stimulated with IFNs providing another platform for defining dual-IFN induced mechanisms of monocyte activity in the context of the complete immune response. Goal 2: ADCC A monoclonal antibody was developed against a semi-purified human membrane protein preparation derived from cancer tissues. The protein preparation was used in previous clinical trials for use as a cancer vaccine where it was demonstrated to be safe and efficacious. The antibody NEO201 was shown to react with the immunizing antigen preparation as well as several human tumor cell lines and tissues from colorectal pancreas lung and ovarian cancer patients. NEO201did not cross-react significantly with normal human tissues thus representing a potential therapeutic product. The target of NEO201was studied and shown to be related to CEACAM-5/6 a member of the carcinoembryonic antigen family of proteins which has been shown to be associated with several cancer types. Endometrial breast and ovarian cancer have specifically been found to have increased expression in human tumor samples. In endometrial cancer 45/88 (51%) of tissue samples show reactivity through immunohistochemistry 38/72 (53%) of breast and although 16/129 (12%) of ovarian cancer specimens stain positive in this series two subtypes mucinous 15/22 (68%)and signet cell 2/2 (100%) ovarian cancers shows significant reactivity (50%) in an IHC of ovarian cancer tissue arrays representing over 600 samples. Our phase 1 clinical trial is completed demonstrating safety and preliminary activity of the NEO201 in patients with solid tumors likely to express the target. The phase 2A expansion is ongoing testing NEO201 in combination with pembrolizumab in cervical endometrial lung and head/neck cancers. Goal 3: T cells Mesothelin (MESO) is a 41-kD cell surface glycoprotein that is highly expressed in many human cancers including high grade serous adenocarcinoma of the ovary (75%) pancreatic adenocarcinoma (85%) triple negative breast cancer (66%) epitheliod mesothelioma (95%) of patients with MESO-expressing malignancies. While the function of MESO on normal cells is non-essential the expression of MESO on cancer cells may contribute to the pathology of cancer with higher expression associated with poorer prognosis increased metastatic spread and activation of cell growth pathways. A tremendously innovative immunotherapeutic approach is the use of chimeric antigen receptor-modified T cells (CAR). CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that allows the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When expressed in T cells CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. The most widely used method for T-cell modification is viral transduction integration and expression of a genetic construct that expresses the chimeric receptor. Another approach to the generation of CAR T-cell therapies that may provide potent anti-tumor activity and improve safety and product preparation involves the use of mRNA to modify T-cells. Using mRNA to re-engineer a patient's T-cells to express a tumor-antigen targeted CAR T-cell can be accomplished in a few hours allowing on-site preparation and deployment to multiple treatment locations. mRNA CAR T-cells have the safety factor of a limited lifespan with half-life times similar to antibody therapeutics and lack of rapid immune activation and proliferation limiting the risk for severe cytokine release side effects. Meso-targeted CAR T-cells using mRNA have demonstrated significant promise in preclinical studies and clinical studies by intratumoral intraperitoneal and intravenous of routes of administration. We completed a phase 1 clinical trial testing the safety of intraperitoneal administration of the CARMA MCY-M11 in women with ovarian cancer and peritoneal carcinomatosis. 587759 +No NIH Category available Adult;Cells;Childhood;Childhood Solid Neoplasm;Clinic;Clinical;Clinical Research;Collaborations;DNA Damage;DNA Repair;Data;Development;Developmental Therapeutics Program;Disease;Enzymes;Ewings sarcoma;Extramural Activities;Genetic Screening;Goals;Heat-Shock Proteins 90;Hematologic Neoplasms;Lead;Malignant Childhood Neoplasm;Metabolic;Metabolism;Modeling;Molecular;National Center for Advancing Translational Sciences;New Agents;Oncogenes;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Population;Pre-Clinical Model;Process;Research Personnel;Rhabdomyosarcoma;Role;Screening procedure;Site;Testing;Topoisomerase;Translating;Translations;Urologic Oncology;Work;cancer cell;chemotherapy;childhood sarcoma;cohort;combinatorial;experience;first-in-human;human study;in vivo;inhibitor;interest;lactate dehydrogenase A;metabolic abnormality assessment;neoplastic cell;nicotinamide phosphoribosyltransferase;novel;novel therapeutics;patient population;pharmacologic;phase 1 testing;pre-clinical;preclinical study;resistance mechanism;sarcoma;standard of care;tumor DNA;tumor metabolism Development and translation of novel therapies for pediatric sarcoma n/a NCI 10926318 1ZIABC011774-07 1 ZIA BC 11774 7 15201715 "HESKE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1852868 NCI Tumor Metabolism Studies: Our lab is interested in identifying specific metabolic vulnerabilities in pediatric sarcomas. We have previously identified lactate dehydrogenase A (LDHA) as an oncogene-driven vulnerability in Ewing sarcoma as well as PHGDH as an additional metabolic vulnerability in Ewing sarcoma. Our group has continued to study the mechanisms behind NAD metabolism in cancer cells. Specifically we are using inhibitors of the rate-limiting enzyme in the NAD salvage pathway nicotinamide phosphoribosyltransferase (NAMPT) in preclinical models of pediatric solid tumors. We initially identified the exquisite sensitivity of Ewing sarcoma cells to these inhibitors as part of a collaboration with The National Center for Advancing Translational Science (NCATS). Based on this work we have continued our preclinical studies to better understand role of NAD and NAMPT in Ewing sarcoma and in other pediatric solid tumors. We have formed a collaboration with investigators in the Urologic Oncology Branch who also have an interest in targeting this pathway. To date there have been no clinical studies of NAMPT inhibitors in any pediatric cancers. We are in the process of developing a pediatric trial for this patient population using OT-82 a clinical NAMPT inhibitor currently undergoing phase 1 evaluation in an extramural first-in-human study for hematologic malignancies. DNA Damage and Repair Studies: Project 1. In FY2021 the first-in-human trial of PEN-866 a novel HSP90 inhibitor-SN38 drug conjugate which acts as to inhibit topoisomerase 1 and cause prolonged DNA damage in tumor cells accrued additional patients. The rationale for this study for which NCI was a lead site was based in part on preclinical work done in our lab demonstrating superior activity and durability of PEN-866 as compared to other standard of care chemotherapy in models of pediatric sarcoma. The study was conducted in collaboration with the Developmental Therapeutics Branch at NCI to target an adult population for the first-in-human experience. Based on our preclinical data in sarcoma and the available phase 1 data generated by the study we developed a combination study using PEN-866 with chemotherapy which was approved in FY2022 but is currently on hold due to issue with drug availability. This study incorporates disease-specific expansion cohorts for rhabdomyosarcoma and Ewing sarcoma. In the lab we have continued to study PEN-866 in Ewing sarcoma and rhabdomyosarcoma with a focus on identifying and overcoming potential mechanisms of resistance as part of a collaboration with the Developmental Therapeutics Branch and the Urologic Oncology Branch. Project 2. Related to our work with the topoisomerase 1 inhibitor PEN-866 we are evaluating several novel topoisomerase 1 inhibitors (the indenoisoquinolines) in our pediatric sarcoma models against the current standard of care topoisomerase agents for these diseases. This project is part of a collaboration with the Molecular Pharmacology Group in the Developmental Therapeutics Branch. Project 3. Our group has identified several potential new agents and combinations of agents that impact the DNA-repair machinery of cancer cells and are particularly effective in preclinical models of Ewing sarcoma. We are in the process of completing the in vivo studies to further describe the effects of these inhibitors. 1852868 +No NIH Category available Biological Specimen Banks;Central Nervous System Neoplasms;Clinical;Disease;Education;Future;Genetic;Malignant neoplasm of central nervous system;Natural History;Patients;Phase;Probability;Protocols documentation;Syndrome;design;high risk;interest;neuro-oncology;tumor Natural History and Specimen Banking for Patients with CNS Tumors n/a NCI 10926315 1ZIABC011768-07 1 ZIA BC 11768 7 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 635228 NCI This protocol is designed to meet an unmet need in neuro-oncology by evaluating patients with CNS tumors throughout their disease course. The protocol will evaluate patients with tumors of the central nervous system (CNS) who appear to be probable candidates for future protocol entry have disease manifestations that are of unique scientific interest importance and/or educational value or who have understudied tumors with unknown or unclear natural history. Patients with known genetic syndromes at high risk of developing CNS cancers will also be evaluated. 635228 +No NIH Category available ADD-1 protein;AKT1 gene;Animals;Body fat;Brain;Cancer Biology;Cell physiology;Cessation of life;Cholesterol;DNA Binding;Data;Gene Expression;Genes;Genetic Transcription;Goals;Growth;HSF1;Heat-Shock Response;Hepatomegaly;Human;Investigation;Laboratories;Lipids;Liver;Malignant Neoplasms;Mediating;Megalencephaly;Membrane;Messenger RNA;Metabolic;Modeling;Modification;Molecular;Mus;Oncogenic;Outcome;PI3K/AKT;PIK3CG gene;PTEN gene;Phosphorylation;Physiological;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Renal carcinoma;Research;Research Project Grants;Role;SHH gene;STK11 gene;Sampling;Signal Transduction;Small Interfering RNA;Stress;Tissues;Tumor Suppressor Proteins;Xenograft procedure;amyloidogenesis;cancer addiction;cancer cell;cancer therapy;constitutive expression;experimental study;in vivo;inhibitor;knock-down;lipid biosynthesis;lipid metabolism;malignant breast neoplasm;melanoma;novel;novel therapeutic intervention;postnatal;preservation;promoter;protein complex;proteostasis;proteotoxicity;sensor;smoothened signaling pathway;steroid hormone;transcription factor;tumor Preservation of Proteomic Stability and Promotion of Protein Lipidation by HSF1 n/a NCI 10926314 1ZIABC011767-07 1 ZIA BC 11767 7 15201738 "DAI, CHENGKAI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1036451 NCI Aim1: To examine the role of HSF1 in sustaining tissue overgrowth driven by oncogenic PI3K/AKT signaling. Our preliminary results show that the PI3K/AKT signaling cascade is required for activation of the HSR/PSR by heat shock (HS) in MEFs and for constitutive HSF1 activation in malignant cells. Importantly AKT physically interacts with HSF1. Furthermore AKT phosphorylates HSF1 at Ser230 and expression of the constitutively active AKT1 or loss of the tumor suppressor PTEN is sufficient to activate HSF1. By contrast AKT inhibitors block HSF1 Ser230 phosphorylation and its DNA binding to HSP gene promoters. Furthermore constitutively active PI3K/AKT signaling causes overgrowth or enlargement of both brains and livers in mice conditions similar to megalencephaly and hepatomegaly in humans respectively leading to rapid postnatal death. Importantly simultaneous deletion of Hsf1 in both tissues impedes overgrowth and prolongs animal survival. Moreover Hsf1 deletion also markedly impedes the liver overgrowth in mice deficient for Pten a tumor suppressor negatively regulating PI3K activity prolonging their survival. Our results further show that constitutively active PI3K/AKT disrupts proteostasis and induces proteotoxic stress which is markedly heightened by Hsf1 deficiency. Based on these preliminary results we plan to interrogate: 1) whether HSF1 is a new physiological substrate for AKT; 2) whether and how HSF1 suppresses proteotoxic stress induced by constitutive activation of PI3K/AKT signaling and thereby promotes tissue overgrowth in vivo; and 3) the molecular mechanisms underlying disrupted proteostasis in overgrown tissues. Aim 2: To examine the role of HSF1 in promoting lipid metabolism and protein lipidation. Our previous studies revealed that HSF1 is a physiological substrate for AMPK a key cellular metabolic sensor and that the AMPK-mediated Ser121 phosphorylation negatively regulates HSF1 activation. Now our preliminary results using HSF1 deletion constructs deficient for transcriptional activity show that just like the wild-type HSF1 they interact with AMPK and suppress AMPK Thr172 phosphorylation a modification key to its activation indicating a transcription-independent mechanism of action of HSF1. Conversely Hsf1 deficiency causes AMPK activation which is blocked by the AMPK inhibitor. Interestingly our results show that HSF1 can be co-precipitated with both AMPK and LKB1 revealing a LKB1-AMPK-HSF1 protein complex. Furthermore in human kidney and breast cancer samples higher HSF1 mRNA levels are inversely correlated with AMPK Thr172 phosphorylation congruent with the results of our mechanistic studies. Our preliminary data show that Hsf1 deficiency and enhanced HSF1 expression result in diminished and heightened cellular lipid content respectively suggesting that HSF1 promotes lipogenesis to support malignancy. Strikingly Hsf1-deficient mice display markedly reduced whole-body fat mass. Importantly these effects of HSF1 on cellular lipid content and body fat mass can be markedly rescued by either AMPK inhibitors or siRNA-mediated AMPK knockdown suggesting that the lipogenic effect of HSF1 is largely mediated via AMPK suppression. At the molecular level HSF1 deficiency causes inactivation of SREBP1c a key transcription factor controlling lipogenic gene expression in addition to inactivation of ACC. Cholesterol is an important lipid implicated in many key cellular processes including membrane composition signaling transduction and synthesis of steroid hormones. Congruent with diminished cellular lipid content our results reveal a markedly reduced cellular cholesterol level caused by HSF1 deficiency which is rescued by AMPK inhibition. Based on these preliminary results we plan to investigate: 1) the molecular mechanisms underlying AMPK suppression by HSF1; 2) whether HSF1 promotes cholesteroylation of sonic hedgehog (SHH) proteins and supports SHH signaling; and 3) whether HSF1 promotes lipid metabolism and SHH cholesteroylation in xenografted human melanoma models. 1036451 +No NIH Category available Acute;Bacteria;Binding;Biogenesis;Cancer cell line;Cell Fate Control;Cell Proliferation;Cells;Chemistry;Chronic;Comparative Study;Development;Dioxygenases;Disease;Energy Metabolism;Environment;Enzymes;Family;Follow-Up Studies;Fumarates;Gene Expression;Genome;Goals;Growth;Health;Homeostasis;Human;Isocitrate Dehydrogenase;Malignant Neoplasms;Maps;Measures;Metabolic;Metabolism;Methods;Modeling;Modification;Molecular;Mutate;Pathway interactions;Phenotype;Play;Positioning Attribute;Proliferating;Protocols documentation;RNA;RNA methylation;Regulation;Regulator Genes;Role;Succinate Dehydrogenase;Succinates;Surveys;Tissues;Transfer RNA;Translations;alpha ketoglutarate;cancer cell;cancer type;cellular engineering;epigenome;experimental study;improved;inducible gene expression Regulation of RNA biogenesis and function by RNA modifications n/a NCI 10926313 1ZIABC011766-07 1 ZIA BC 11766 7 15201736 "DE OLIVEIRA RODRIGUES BATISTA, PEDRO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1218469 NCI Uncontrolled cell proliferation is a hallmark of cancer and is often accompanied by reprogramming of energy metabolism. In addition to providing the building blocks required for uncontrolled proliferation metabolic reprograming interferes with gene expression enabling cancer cells to evade mechanisms that maintain tissue homeostasis. Imbalances in the metabolite pool driven by metabolic rewiring create an environment that inhibits activity of regulators of gene expression such as the alpha ketoglutarate (aKG)-dependent dioxygenase family. This family of enzymes includes the RNA demethylases FTO ALKBH1 and ALKBH5 important regulators of RNA methylation. Recent studies have demonstrated that RNA methylation plays an important role in cell identity and is implicated in cancer establishment and progression. Fumarate Succinate and (R)-2-hydroxyglutarate known to accumulate in multiple types of cancer are examples of metabolites known to inhibit 2-oxoglutarate (2OG)-dependent dioxygenase enzymes. To understand how energy reprograming remodels gene expression through modulation of RNA methylation dependent pathways we are performing comparative studies between established cancer cell lines (with chronic accumulation of these metabolites) with cells engineered to allow for acute inactivation of Fumarate Hydrogenase (FH) and Succinate Dehydrogenase (SDH) or inducible expression of mutated isocitrate dehydrogenase 1 (IDH1). This approach will allow us to understand how accumulation of fumarate (loss of FH) succinate (loss of SHD) or 2-HG (expression of mutated IDH1) contribute to the establishment and progression of cancer phenotype. Metabolite analysis shows similar metabolite accumulation in both groups of cells. Preliminary experiments suggest that changes in gene expression induced by chronic or acute accumulation of oncometabolites are distinct. For follow up studies we have established protocols to measure and map multiple types of RNA methylation including m6A m6Am 5mC m1A and Am. Modifications in tRNAs are critical to maintain fidelity in translation. The modification 4SU at position 8 of prokaryotic tRNA has been shown to respond to change in growth rate. In order to understand how the 4SU modification is regulated and determine if a similar modification is present in eukaryotic RNAs we develop a method that relies on orthogonal chemistry to capture 4SU modified tRNAs. With this method we are able to identify 4SU modified tRNAs at a genome level and easily survey multiple growth conditions greatly improving our ability to study this modification. Moving forward we will use this method to identify 4SU modified tRNAs in bacteria with a negative impact on human health. 1218469 +No NIH Category available Autoimmune Diseases;Autoimmune Responses;Autoimmunity;CD4 Positive T Lymphocytes;Cell Differentiation process;Cells;Cessation of life;Clinical;Combined Modality Therapy;Cytokine Receptors;Development;Disease;FOXP3 gene;Family;Future;Gene Expression Profiling;Genes;Genetic Transcription;Goals;IL17 gene;Immune;Infection;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Mediating;Multiple Sclerosis;Mus;Organ;Pathogenesis;Pathogenicity;Pathway interactions;Peripheral;Pharmaceutical Preparations;Psoriasis;Resolution;Rheumatoid Arthritis;Role;T-Lymphocyte;Testing;Therapeutic;Transcriptional Regulation;Treatment Efficacy;cytokine;genetic signature;immunoregulation;improved;novel;overexpression;pharmacologic;premature;programs;transcription factor Transcriptional regulation of inflammatory and autoimmune responses n/a NCI 10926312 1ZIABC011765-07 1 ZIA BC 11765 7 11592667 "LAZAREVIC, VANJA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1333998 NCI TH17 cells have been implicated in the pathogenesis of most common autoimmune and inflammatory diseases. However not all TH17 cells are pathogenic. The goal of this project is to identify novel transcriptional regulators that regulate differentiation of TH17 cells with immunoregulatory versus pathogenic effector functions. We have focused on the role of Egr family of transcription factors in TH17 differentiation because high resolution transcriptional profiling predicted that Egr1 and Egr2 could function as positive regulators of TH17 differentiation program. Our studies have shown that the transcription factor Egr2 but not Egr1 is a positive regulator of TH17 cell differentiation. Egr2 augmented the expression of the TH17 lineage-signature genes: Rorc Il17a Il17f and Il22. Interestingly over-expression of Egr2 in non-pathogenic TH17 cells induced the expression of pathogenicity-associated genes (e.g. Il22 Tbx21 Ccl3) and augmented the expression of immunoregulatory genes (e.g. Foxp3 Il9 Il10). To determine whether Egr2 was required for the development of immunoregulatory or pathogenic TH17 cells we have generated mice with peripheral T cell-specific deletion of Egr2 (Egr2f/f hCD2-Cre+). In our future studies we investigate the effects of T cell-specific Egr2-deficiency on the differentiation and effector function CD4+ T cells in the context of infections and autoimmunity. 1333998 +No NIH Category available Adult;Aging;Alternative Therapies;Basal Cell;Basal cell carcinoma;Biological Models;Cancer Cell Growth;Cell Differentiation process;Cell Fate Control;Cell Proliferation;Cell Surface Receptors;Cells;Coupling;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Development;Diagnosis;Disease;Epithelial Cell Proliferation;Epithelial Cells;Epithelium;Equilibrium;Erinaceidae;Excision;Family;G-Protein-Coupled Receptors;GTP-Binding Proteins;Genes;Genetic Transcription;Growth;Healthcare Systems;High Prevalence;Homeostasis;Human;Immunotherapy;Impairment;Intervention;Laboratory Study;Local Tumor Spread;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Mus;Mutation;Neoplasm Metastasis;Oncogenic;Organ;Pathology;Pathway interactions;Production;Proliferating;Protein Kinase A Inhibitor;Proteins;Regulation;Research;Role;Second Messenger Systems;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Carcinoma;Tissues;cancer initiation;cell regeneration;inhibitor;insight;interest;keratinocyte;novel;novel therapeutics;pharmacologic;prostate cancer cell;side effect;smoothened signaling pathway;stem;stem cells;therapy resistant;tissue regeneration;tumor;tumor growth Regulation of epithelial cell fate decisions in tissue homeostasis and cancer n/a NCI 10926311 1ZIABC011763-07 1 ZIA BC 11763 7 15201732 "IGLESIAS-BARTOLOME, RAMIRO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1113209 NCI Non-melanoma skin cancers including Basal Cell Carcinoma (BCC) are the most frequently diagnosed human cancers. BCC is caused by dysregulated Hedgehog signaling stemming from mutations that over-activate the G-protein coupled receptor (GPCR) Smoothened (SMO). SMO causes uncontrolled basal cell proliferation and blockage of differentiation leading to tumor formation. More than 3 million cases of BCC are diagnosed each year in the US alone causing a significant burden to the healthcare system. Most BCCs are easily treated by surgical removal although some can be difficult due to their high numbers location or localized tumor spread. Alternative therapies in these cases involve using SMO inhibitors or immunotherapy although side effects and therapeutic resistance undermine their use. The deficiency of additional therapies for BCC and the fact that Hedgehog signaling is an oncogenic pathway in other tumor types makes it a priority to find novel therapeutic options for targeting Hedgehog-driven tumors. BCC is a prototypical GPCR-driven cancer. GPCRs are the most diverse family of cell-surface receptors relaying their signaling by coupling to heterotrimeric Galpha beta and gamma subunits or by G-protein independent pathways. Classic stem cell regulatory signals like Hedgehog and WNT rely on G protein-independent pathways to regulate cell proliferation and differentiation. Nevertheless I found a novel Galpha protein-dependent pathway vital to coordinating epithelial cell fate and Hedgehog signaling. Gs and Gi heterotrimeric Galpha proteins either stimulate (Gs) or inhibit (Gi) production of the second-messenger cyclic AMP (cAMP). In mouse skin inactivating Gs or its downstream target protein kinase A (PKA) blocks basal cell differentiation and triggers BCC formation. Gs or PKA disruption alone can activate Hedgehog GLI and Hippo YAP1 revealing a high degree of overlap between these signaling pathways. Understanding how Gs and PKA signaling regulate Hedgehog and BCC formation could reveal new targets for the pharmacological intervention of somatic stem cell activity to reduce cancer growth. Hence my current research plan focuses on dissecting the crosstalk between Gs-PKA and Hedgehog signaling and characterizing cell fate regulation by the downstream signals of these pathways. Beyond BCC we are exploring the role of PKA inactivation by protein kinase A inhibitor proteins (PKIs) in tumor growth and metastasis in other organs particularly in prostate cancer. Prostate cancer shows amplifications on the PKIalpha gene and we have demonstrated that PKIalpha is involved in prostate cancer cell growth. We are characterizing the molecular mechanisms regulated by PKI in this tumor type. 1113209 +No NIH Category available 3-Dimensional;Adjuvant;Amino Acids;Back;Binding;Biological Models;Biology;Cell Line;Cells;Cholangiocarcinoma;Clinical Trials;Cooperative Research and Development Agreement;Custom;Cytoplasm;DNA Binding;Data;Development;Distant;Drug Evaluation;Excision;Exportins;Gene Expression;Genes;Genetic Screening;Genetic Transcription;Human;Immune;Immune system;KRASG12D;Literature;Liver;Malignant Neoplasms;Mediating;Mediator;Mesothelium;Metastatic Neoplasm to the Liver;Modeling;Molecular;Morphology;Mus;Mutation;Neoplasm Metastasis;Nuclear Export;Nutrient;Oncogenic;Oncology;Operative Surgical Procedures;Organ;Outcome;PIK3CG gene;Pathway interactions;Patients;Pattern;Perfusion;Pharmaceutical Preparations;Phase;Phase I/II Trial;Phosphotransferases;Process;Protein Export Pathway;Proto-Oncogene Proteins c-akt;Rare Diseases;Recurrence;Resected;Sampling;Secure;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Specificity;Structure;System;Techniques;Therapeutic;Time;Transplantation;Tumor Biology;Xenograft procedure;aminoacid biosynthesis;animation;cancer care;cancer imaging;cell killing;clinical efficacy;clinical predictors;cytokine;drug mechanism;ex vivo perfusion;imaging modality;in vivo;inhibitor;insight;kinase inhibitor;knock-down;mortality;multi-photon;neoplastic cell;next generation sequencing;novel;patient response;patient subsets;programs;promoter;quadruplex DNA;response;sensor;stem;targeted agent;transcription factor;transcriptomics;tumor;tumor microenvironment;tumor progression;tumorigenesis Interrogating the molecular underpinnings of metastatic colonization n/a NCI 10926309 1ZIABC011759-07 1 ZIA BC 11759 7 15201727 "HERNANDEZ, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2421179 NCI Sub-Project 1. I used 318 patient samples to demonstrate specific cytoplasmic accumulation of XPO7 within tumor cells in a subset of patients with CCA and further verified this localization pattern in a panel of CCA cell lines. I then used the cells lines to show that XPO7 binds to and stabilizes Ste20-like kinase (SLK) which in turn activates downstream oncogenic signaling pathways including the PI 3-Kinase-AKT pathway and subsequently reverted back to tumor samples to verify this relationship. Given the absence of specific SLK inhibitors we next profiled the kinome-specificity of 250 inhibitors to identify those with activity against SLK. Based on that data I selected one of those agents tivozanib for further study. Using murine xenografts and CCA tumor from a patient in the SMART system (see Project #3) I demonstrated that tivozanib treatment resulted in tumor shrinkage/tumor cell killing and substantial morphologic alterations similar to those observed with XPO7 or SLK knockdown. Based upon these results I have successful secured tivozanib from Aveo Oncology through a CRADA mechanism and have opened a Phase I/II trial (NCT 04645160) for patients with CCA. Sub-Project 2. Genetic screening identified the amino acid sensor GCN1 as a driver of metastatic outgrowth in the liver by activating a dual translational and a transcriptional gene expression program. While the translational program activates genes involved in nutrient acquisition and intrinsic amino acid biosynthesis in an ATF4-dependent manner the transcriptional function sustains oncogenic drive by interacting with DNA binding transcription factor HNRNPK which activates the expression of KRASG12D through DNA quadruplex (G4) unwinding in its promoter. Intriguingly the GCN1-dependent translational and transcriptional program is negatively regulated by IMPACT which binds and inhibits GCN1 function. The expression of IMPACT is lost in highly aggressive and metastatic cell lines and inversely correlates with GCN1 pathway activation. Our data suggest that GCN1 signaling is indispensable for in vivo liver metastasis and agents targeting GCN1 and downstream signaling pathway may have clinical efficacy in the adjuvant setting. Sub-Project 3. I utilized tumor-bearing mesothelium and created an oxygenated perfusion circuit termed the SMART System (Surgically-resected Mesothelium ContAining UnalteRed Tumor Microenvironment) which I demonstrated maintains tumor with minimal alterations in structure cellular composition and transcriptomics. Importantly cells remain functional and respond to cytokines and drugs. The SMART System is the subject of an EIR. I developed hardware to perform live imaging of the tumor repurposing our advanced confocal and multiphoton scopes. This technique gives unprecedented insight into tumor biology dynamics. To compliment the SMART system I conceived and implemented ex vivo perfusion of tumor-bearing liver segments. We initially sought to repurpose commercially available transplant machines but these lacked real-time adjustment capabilities required for prolonged ex-vivo animation. To circumvent the limitations I have assembled a team and built a custom liver perfusion system. 2421179 +No NIH Category available 2019-nCoV;Address;Anti-Inflammatory Agents;Autophagocytosis;Benefits and Risks;Biogenesis;CCI-779;Cell Line;Cell Survival;Cells;Cellular Metabolic Process;Clinical;Endocytosis;Endosomes;Epithelial Cells;FRAP1 gene;Gene Modified;Goals;Growth;Hamsters;Human;Immune response;Immunosuppressive Agents;Infection;Influenza A virus;Innate Immune Response;Journals;Lentivirus Vector;Link;Lysosomes;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Multivesicular Body;Mus;Oncogenic;PIK3CG gene;Pathway interactions;Patients;Pharmaceutical Preparations;Predisposition;Property;Proteins;Publications;Publishing;Regimen;SARS-CoV-2 infection;Signal Transduction;Sirolimus;TSG101 gene;Therapeutic;Tissues;Ubiquitination;Viral;Virus;Virus Diseases;Work;antiviral immunity;cell growth;cellular targeting;clinical investigation;gene therapy;improved;in vivo;inhibitor;mTOR inhibition;member;mutant;permissiveness;scaffold;severe COVID-19;therapeutic gene;trafficking;transcription factor;tumorigenesis;vacuolar H+-ATPase An Intrinsic Link between the Metabolic and Antiviral States of the Cell n/a NCI 10926307 1ZIABC011756-07 1 ZIA BC 11756 7 15201721 "COMPTON, ALEX " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 639828 NCI Since work on this project began in February 2017 we have made a number of key advancements. Our initial work using rapamycin on transformed epithelial cell lines revealed that mTOR inhibition confers a 4- to 20-fold enhancement of infection by lentiviral vectors and by Influenza A virus. Furthermore we found that the rapamycin-dependent enhancement of infection is reversed by inhibitors of endosomal acidification (v-ATPase) revealing that the enhancement requires active degradation of cellular factors via the lysosomal pathway. Through a number of approaches we show that mTOR inhibition by multiple drugs leads to lysosomal degradation of IFITM3 in an autophagy-independent manner. Instead endocytic trafficking through multivesicular bodies is necessary to delivery of IFITM3 to lysosomes as confirmed by a functional requirement of ESCRT member TSG101 and by inhibition of multivesicular body formation by the compound U18666A. By studying mutant IFITM3 constructs we found that mTOR inhibition leads to clearance of IFITM2 and IFITM3 from endosomes in a manner that is dependent on endocytosis ubiquitination and lysosomal acidification. This work is the first instance to describe an interrelationship between mTOR cell-intrinsic antiviral immunity and virus entry into cells. These results have been published in 2018 (Shi et al. PNAS 115: E10069 2018). More recently we have compared the ability of rapamycin analogs (rapalogs) to downmodulate IFITM proteins and to enhance other virus infections including SARS-CoV-2. Rapamycin is currently being investigated as a therapeutic anti-inflammatory compound to treat severe COVID-19. We found that some rapalogs downmodulate IFITM proteins and enhance SARS-CoV-2 infection while others do not laying the groundwork for a mechanistic understanding of the cellular pathways involved. Speficially we found that some rapalogs promote IFITM downmodulate by activating TFEB a transcription factor controlling lysosome biogenesis and function. TFEB is also required for the SARS-CoV-2 infection-enhancing effects of rapalogs and together with our previous publication we found TFEB triggers IFITM degradation and SARS-CoV-2 enhancement through microautophagy an endosomal remodeling pathway. We also showed that rapalog administration in hamsters and mice increases susceptibility to experimental SARS-CoV-2 infection and viral disease in vivo. These results were published in the Journal of Clinical Investigation in 2022 (Shi et al.). We now plan to study how rapalogs which are already used clinically to inhibit cancer growth influence the oncogenic functions of IFITM3. IFITM3 is commonly upregulated in a variety of cancers and may act as a scaffold for PI3K/Akt/mTOR signaling to favor cell survival and growth. Thus this project has provided an opportunity for my lab to explore new avenues with relevance to the basic and clinical understanding of tumorigenesis. 639828 +No NIH Category available Alveolar Rhabdomyosarcoma;Antibodies;Antibody Therapy;Biologic Development;Biological;Bypass;Childhood;Clinic;Clinical;Clinical Data;Clinical Trials;Combined Modality Therapy;Dasatinib;Dose;Embryonal Rhabdomyosarcoma;IGF1R gene;Insulin-Like-Growth Factor I Receptor;Pathway interactions;Patients;Phase;Phase I/II Clinical Trial;Pre-Clinical Model;Publishing;Refractory;Relapse;Resistance;Rhabdomyosarcoma;Role;Testing;Time;Work;cell growth;efficacy evaluation;industry partner;kinase inhibitor;neoplastic cell;novel;pre-clinical;preclinical study;premature;research clinical testing;response;src-Family Kinases;stability testing Development of biologic based therapies for rhabdomyosarcoma n/a NCI 10926303 1ZIABC011745-07 1 ZIA BC 11745 7 15201715 "HESKE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 326976 NCI Our phase I/II clinical trial testing the combination of the IGF-1R antibody ganitumab with dasatinib a multi-kinase inhibitor targeting the SRC-family kinase YES in patients with relapsed and refractory rhabdomyosarcoma was developed based upon preclinical work in our lab that identified YES activation as a bypass pathway for resistance to IGF-1R inhibition. Dual blockade of YES and IGF-1R demonstrated enhanced tumor cell growth inhibition in a number of preclinical models of both embryonal and alveolar rhabdomyosarcoma. In FY2022 the trial was prematurely closed due to a decision by our industry partner to discontinue stability testing and restrict our access to the investigational product ganitumab. At that time we had accrued 13 patients onto the phase 1 part of this study which was complete and had begin accrual onto the phase 2 part of this trial. This trial had several aims including identification of the highest safe dose for this combination (complete) evaluation of efficacy of this combination in patients with relapsed and refractory rhabdomyosarcoma (incomplete) and correlative biologic studies of response and resistance which were completed in FY2023. We have recently published the findings. 326976 +No NIH Category available 3-Dimensional;Adoption;Affect;Alveolar;Alveolar Cell;Biology;Cancer cell line;Carcinoma;Cell Culture Techniques;Cell Survival;Cell model;Cells;Development;Dissection;Epithelial Cells;Epithelium;Exhibits;Gene Expression;Genetic;Goals;Growth;Human;In Vitro;KRAS2 gene;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Methods;Microscope;Modeling;Molecular;Mus;Oncogenes;Oncogenic;Organoids;Outcome;Phenotype;Signal Transduction;Surface;System;Xenograft procedure;cancer cell;cell behavior;cell growth;cost;in vitro Model;in vivo;lung cancer cell;metaplastic cell transformation;monolayer;mutant;neoplastic cell;scale up;stem cells;stemness;targeted treatment;transplant model;tumor;tumor behavior Organoid models of KRAS mutant cancer n/a NCI 10926295 1ZIABC011733-08 1 ZIA BC 11733 8 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 545711 NCI BACKGROUND. Traditional cell culture method of growing epithelial cancer cells as a 2D monolayer on a stiff adherent surface fails to capture the transformed phenotype of these cells. Indeed a key hallmark that distinguishes cancer from normal epithelial cells is their ability to grow under anchorage-independent conditions. Alternatively cancer cells that can be cultured under 3D anchorage-independent conditions and under such conditions they often form a spheroid that mimic a microscope tumor. Such tumor spheroid culture has been difficult to scale up in the past thus limiting their utility. A method to grow tumor spheroids on a larger scale with lower cost will enable the wider adoption of this model for in vitro studies. Recent development in organoid culture has made it possible to grow primary epithelial cells and maintain their lineage identify in vitro. In the lung evidence suggests that alveolar type 2 (AT2) cells which are the resident stem cells of the alveolar space are also the cell of origin for lung adenocarcinoma. A scalable murine lung organoid model of normal and KRAS mutant AT2 cells will provide better resemblance of lung cancer cell in vivo. These advanced cell models will be valuable for dissecting the function of the KRAS oncogene in the context of anchorage-independent cell growth. OBJECTIVES. 1) Develop a scalable tumor spheroid culture method for human cancer cells and elucidate the function of the KRAS oncogene in anchorage-independent cell growth and survival; 2) Develop a scalable murine lung organoid model of KRAS mutant cells and investigate the function of the KRAS oncogene in the oncogenic transformation of lung epithelial cells; and 3) Use mouse xenograft and orthotopic transplant models to validate discoveries from organoid models. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Elucidating KRAS oncogene function under anchorage-independent conditions. We have developed a tumor spheroid culture method that can be applied to many epithelial KRAS mutant cancer cell lines. Importantly this culture method is scalable and it is amenable to molecular and genetic dissection of cellular phenotypes. Using this system we have identified features of KRAS oncogene signaling that is distinct from those in 2D cell culture. We are investigating the functional impact of these 3D-specific signaling from the KRAS oncogene and dissecting how they contribute to cellular transformation. 2) Using murine AT2 organoid to model lung adenocarcinoma in vitro. We have established organoid culture of KRAS mutant murine AT2 cells to study the biology of KRAS mutant lung adenocarcinoma. These organoids stably maintain their AT2 lineage markers exhibit features of transformation and are addicted to the KRAS oncogene for their growth. We are using this system to understand how mutant KRAS impact signaling gene expression and stemness in AT2 cells. We are developing organoid culture of normal AT2 cells to understand how targeted therapies affect their viability. 545711 +No NIH Category available Anchorage-Independent Growth;Attention;CRISPR/Cas technology;Cancer Patient;Cancer cell line;Cells;Clinical Trials;Colorectal;Colorectal Cancer;Combined Modality Therapy;Dependence;Development;Drug Combinations;Drug Targeting;Drug resistance;Drug toxicity;Epithelial Cells;Genes;Genetic;Genetic Screening;Genetic Transcription;Goals;KRAS2 gene;Libraries;Lung;MAP Kinase Gene;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Modality;Modeling;Multiple Myeloma;Mus;Oncogenes;Oncogenic;Outcome;PIK3CG gene;Pancreas;Pathway interactions;Patients;Pre-Clinical Model;Resistance;Signal Transduction;Stress;Therapeutic;Xenograft procedure;cancer cell;driver mutation;functional genomics;high-throughput drug screening;improved;in vivo;inhibitor;kinase inhibitor;loss of function;mutant;new therapeutic target;novel drug combination;novel therapeutics;oncogene addiction;pharmacologic;posttranscriptional;prevent;ras Oncogene;resistance mechanism;response;small molecule inhibitor;targeted treatment;tool;treatment response;tumor Target discovery and combination therapy in KRAS mutant cancer n/a NCI 10926294 1ZIABC011732-08 1 ZIA BC 11732 8 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 545711 NCI BACKGROUND. The KRAS oncogene is a driver mutation in a significant fraction of lung pancreatic and colorectal cancers. Recently breakthroughs with inhibitors targeting the KRAS-G12C mutant is the first Ras targeted therapies in decades. For other KRAS mutant tumors there are no effective targeted therapies. Resistance to KRAS inhibitors develop rapidly in cancer patients and drug combination that can prevent or delay drug resistant are needed to extend the durability of response in patients. In addition to Ras kinases inhibitors against Ras effector pathways have been developed to target the MAPK and PI3K pathways. However these agents have not demonstrated efficacy in clinical trials against KRAS mutant tumors. Thus far targeted therapies have primarily focused on blocking OA and less attention have been devoted to blocking NOA in KRAS mutant cells. Co-targeting NOA and OA together could lead to better drug combinations with orthogonal therapeutic modalities improved therapeutic window and more durable response in KRAS mutant tumors. OBJECTIVES. 1) Using functional genomic screens to identify genetic dependencies resulting from oncogene addiction (OA) and non-oncogene addiction (NOA) in KRAS mutant cancer cells; 2) Evaluating the mechanism selectivity of targeted therapies in KRAS mutant cells and the mechanisms leading to drug resistance; and 3) Identify drug combinations that orthogonally target distinct aspects of OA and NOA in KRAS mutant cells to achieve better therapeutic window. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Genetic screens to identify functional vulnerabilities in KRAS mutant cancer cells. Using pooled CRISPR/Cas9 gene KO libraries we have carried out loss-of-function screens in KRAS mutant cancer cells under different culture conditions. We have identified a candidate druggable gene that is critical for the anchorage-independent growth of KRAS mutant cells and we are currently investigating the mechanism of this genetic dependency and exploring small molecule inhibitors of this target. 2) Mechanisms of drug resistant to Ras pathway inhibitors. Using different KRAS mutant cancer cell lines including colorectal pancreatic lung and multiple myeloma cells we have evaluated genetic and post-transcriptional mechanisms that contribute to resistance to KRAS inhibitors and MEK inhibitors. We are currently elucidating how these resistance mechanisms can be reversed to improve therapeutic response in pre-clinical models. 3) Identification of novel drug combinations for KRAS mutant cancer. Using high-throughput drug screen and hypothesis-driven approach we are evaluating drug combinations that involve inhibitors targeting Ras OA to block oncogenic Ras signaling and inhibitors targeting NOA pathways to exacerbate oncogenic stress in KRAS mutant cancer cells. We contrast the toxicity of drug combinations in KRAS mutant cancer cells against that in normal epithelial cells to assess the therapeutic window and we use mouse xenograft and autochthonous tumor models to evaluate the drug combination's efficacy against KRAS-driven tumors in vivo. 545711 +No NIH Category available Address;Antigens;Antitumor Response;Autoantigens;CD8-Positive T-Lymphocytes;Cell Communication;Cell model;Cells;Cessation of life;Collaborations;Communication;Cues;Development;Feedback;Frequencies;Goals;Heterogeneity;Immune response;Immunity;Individual;Interleukin-2;Laws;Leukocytes;Macrophage;Microfluidics;Output;Pathway interactions;Population;Predisposition;Production;Proliferating;Property;Reaction;Recovery;Signal Transduction;Stimulus;T cell response;T-Cell Activation;T-Lymphocyte;Time;Tissues;Translating;Tumor Antigens;Work;analog;anti-tumor immune response;antigen-specific T cells;cytokine;design;exhaustion;immunoreaction;neoplastic cell;paracrine;response;self organization;tool;tumor Cytokine coordination of collective immune responses against tumors n/a NCI 10926293 1ZIABC011728-08 1 ZIA BC 11728 8 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 544173 NCI We developed quantitative models of the cell-to-cell communications via cytokines amongst population of T lymphocytes. Our goal is to understand how leukocytes self-organize to decide their cell fate (e.g. between quiescence -tolerance- and death/proliferation -responses). At a fundamental level we developed theoretical tools to analyze the heterogeneity and synchronicity of T cell responses in dense tissues. In the context of responses to tumor we found that a critical mass of T cells existed to drive tumor rejection. Additional work is being carried out to dissect quantitatively how T cell decide collectively between tumor rejection and tumor tolerance. We also made progress in the development of a microfluidic platform (collaboration with Don DeVoe within the NI/UMD partnership) to address spatial aspects of cell-to-cell communications. This platform allows the assembly of micro-immune reactions with tumor cells T cell and macrophages and the observation of the ensued immune responses. The platform is also designed to allow cell recovery towards off-chip analysis (e.g. scRNAseq and FACS). 544173 +No NIH Category available Address;Antibodies;Antigens;Artificial Intelligence;B-Lymphocytes;Biochemical;Biological;Biology;Bone Marrow;Bypass;CCR;CD8B1 gene;Calibration;Cell Proliferation;Cell model;Cells;Classification;Clinical;Clinical Investigator;Collaborations;Communication;Computer Models;Custom;Cytokine Signaling;Cytometry;Data;Differential Equation;Discrimination;Distal;Down-Regulation;Feedback;Flow Cytometry;Fluorescence;Goals;Heterogeneity;Human;IL7 gene;Immune;Immune response;Immune system;Immunological Models;Individual;Interleukin-2;Kinetics;Lead;Leukocytes;Ligands;Lupus;Lymphocyte;MEKs;Malignant Neoplasms;Maps;Measurement;Memory;Methodology;Methods;Modeling;Monitor;Mus;Names;Nature;Outcome;PTPN6 gene;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiologic pulse;Population;Preparation;Proteins;Provider;Reagent;Regulation;Robotics;Sampling;Science;Signal Transduction;Sorting;Specificity;Speed;System;T-Cell Activation;T-Lymphocyte;Testing;Theoretical model;Therapeutic;Time;Transgenic Mice;United States National Institutes of Health;Vaccines;Validation;antagonist;biochemical model;chimeric antigen receptor T cells;combinatorial;computer program;cytokine;digital;disease classification;inhibitor;machine learning method;melanoma;neutrophil;phenomenological models;pre-clinical;profiles in patients;receptor;response;single cell analysis;small molecule inhibitor;tissue culture;tool;transcription factor;tumor Phenotypic variability within isogenic population of lymphocytes n/a NCI 10926292 1ZIABC011726-08 1 ZIA BC 11726 8 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 435338 NCI "We found that phenotypic variability can be driven by the heterogenous expression of key components within signal transduction cascade. Such variability has practical importance when modeling how cells vary in their drug response. In particular we found that the topology of signal transduction cascades explain why small-drug inhibitors of proximal signaling components (e.g. Src) acted digitally (i.e. in an all-or-none manner) while inhibitors against distal signaling components (e.g. Mek) acted analogously (i.e. in a continuous manner) We expanded our findings on the phenotypic variability of cell signaling with a new methodology (termed ""cell-to-cell variability analysis): such method relies on single-cell phospho-profiling of primary cells in preclinical and clinical settings to identify which biological components (receptor kinase phosphatase transcription factor) is quantitatively limiting in terms of functional consequences. We illustrated the strength of this approach by showing how response to IL-2 and IL-7 are mutually exclusive within individual primary T cells. A computational model based on biochemical modeling and Bayesian optimization was introduced to test how sequestration of a shared but limited receptor chain could generate such flip-flop in cytokine signaling. This study provided a mechanistic explanation for the transition between effector and memory cells within an isogenic population of T cells (Cotari et al. Science Signaling 2013). Concomitantly we introduced and distributed a computer program (named ScatterSlice) that enables experimenters to analyze the cell-to-cell variability in their Flow Cytometry data (Cotari et al. Science Signaling 2013). Such methodology has found applications in many clinical settings (Palomba et al. PLoS One 2014; Kitano et al. Cancer Immunol Res 2014). In parallel we have been implementing mass cytometry (so-called CyTOF) at the NIH. CyTOF enables the multiplexing of large sets of antibodies (typically 40 at once) while bypassing issues of spectral overlap of classical fluorescence-based cytometry. We validated and optimized multiple antibody panels to profile multiple immunological systems: general profile of bone marrow in mouse and human deepvprofile of T cell populations in mouse and human human neutrophils and human B cells. We collaborated with clinical investigators at the NIH to profile patients' samples in the context of XMEN ALPS Lupus (PBMC) and melanoma (TIL). Moreover we developed a method to pulse-chase IdU (a reagent that gets picked up and inserted in proliferating cells) and monitor the kinetics of differentiation of leukocytes in mice. We have expanded our robotic platform with higher multiplexing of sample preparation of measurements (bulk cytokine and single-cell measurements) and used our well calibrated in mouse transgenic T cell model in order to map out the phenotypic diversity of human TILs and CAR-T cells (collaboration with Naomie Taylor and Nirali Shah in the CCR-POB). Finally we introduced a machine-learning-based method to automatically identify clusters of differentiation amongst leukocytes under consideration: this method was applied to define a new T cell population whose phenotype correlates with positive clinical outcomes. We are pursuing our goal to better characterize the cellular complexity of immune responses towards better classification of disease and therapeutic states and better modeling. Finally we are developing a platform to address leukocyte diversity (its origins and its functional significance). We built a custom-made robotic tissue culture system to systematically assemble immune responses ex vivo (using primary samples from mouse or human) and to monitor its time dynamics. Our system generates typically 500 conditions (as a convolution of cell contents activation conditions drug perturbations and time points) that get characterized for their soluble content (cytokine secretion) and cell composition (single-cell profiling by CyTOF and FACS). We then apply tools from the field of artificial intelligence to deconvolve the combinatorial complexity of these immune responses. Our goal is to identify new immune signatures & features that best classify immune responses then to validate these signatures in models of immune responses (against vaccines and/or tumors)." 435338 +No NIH Category available Antiretroviral drug resistance;Biology;Cell Line;Cells;Cellular biology;Complex;Cytoplasmic Tail;Data;Defect;Development;Drug resistance;Elements;Future;Glycoproteins;Goals;HIV;HIV-1;Hela Cells;Human;Integrase;Integration Host Factors;Lentivirus;Maps;Maryland;Mediating;Modification;Molecular;Monkeys;Mutation;NMR Spectroscopy;Natural Immunity;Nature;Pathway interactions;Peripheral Blood Mononuclear Cell;Play;Point Mutation;Primates;Process;Proteins;RNA Interference;Research;Retroviridae;Rhesus;Role;SIV;Signal Transduction;Structure;Surface Plasmon Resonance;T-Lymphocyte;Tail;Terminator Codon;Titrations;Universities;Viral;Virion;Virus;Virus Replication;Work;antagonist;antiretroviral therapy;cell type;experimental study;in vivo;inhibitor;insight;interest;mutant;novel;overexpression;particle;recruit;trafficking;ubiquitin-protein ligase Envelope Glycoprotein Incorporation and Function n/a NCI 10926290 1ZIABC011721-08 1 ZIA BC 11721 8 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 870446 NCI We have been actively engaged in defining the molecular mechanism by which retroviral Env glycoproteins are incorporated into virus particles during the assembly process. A complete understanding of this process has been stymied by a lack of structural information about the matrix domain of Gag (MA) and the cytoplasmic tail (CT) of gp41 in virions cell-type-specific differences in the requirement for the gp41 CT in Env incorporation clear differences in the roles of the gp41 CT between HIV-1 and the SIVmac strain of simian immunodeficiency virus in human vs. monkey cells and the plethora of trafficking and signaling motifs present in the CTs of retroviral Env proteins. Recently we have made significant progress in understanding the structural requirements for Env incorporation from the perspective of MA and will build on these advances to elucidate the role of the gp41 CT in Env incorporation. ___Several lines of evidence suggest that HIV 1 Env glycoproteins are recruited into virions via direct interactions between Env and MA; for example mutations in both MA and the gp41 CT can block HIV 1 Env incorporation. Our recent findings strongly support the hypothesis that trimerization of the MA domain plays an important role in Env recruitment: a mutation at the putative MA trimer interface is able to rescue the Env-incorporation defect imposed by a large panel of MA mutations and a small deletion in the gp41 CT and mutations that disrupt MA trimer formation block Env incorporation. In this project we aim to further elucidate the structural requirements for Env incorporation focusing first on HIV-1 and then extending our analysis to other lentiviruses and more broadly other retroviruses. ___We showed a number of years ago that HIV-1 Env is likely to interact in a cell-type-dependent manner with host cell factors that promote Env incorporation. More recent studies suggested that Env incorporation is mediated by interactions between MA and the host factor tail-interacting protein of 47 kDa (TIP47). As part of our ongoing efforts to understand the host cell machinery required for HIV-1 Env incorporation we reevaluated the role of TIP47 in this process. A direct interaction between MA and TIP47 was confirmed by NMR spectroscopy titration experiments and surface plasmon resonance [performed in the labs of our collaborators Drs. Michael Summers (University of Maryland) and Simon Cocklin (Drexel University)]. However in HeLa cells TIP47 overexpression or RNAi-mediated depletion had no significant effect on HIV-1 Env incorporation virus release or particle infectivity. Similarly depletion of TIP47 in the Jurkat T-cell line did not impair HIV-1 Env incorporation virus release infectivity or replication. Our results thus do not support a role for TIP47 in HIV-1 Env incorporation or virion infectivity. ___More recently the Spearman lab demonstrated that another host protein Rab11-FIP1c plays an important role in Env trafficking and incorporation into virions. The retromer complex was also suggested to function in Env trafficking. An intriguing aspect of the cell-type-specific nature of lentiviral Env incorporation is that while in most relevant human cell types truncation of the gp41 CT blocks HIV-1 replication SIVmac acquires gp41 CT stop codons when propagated in human cells. These stop codons revert to the wild-type sequence when the mutant viruses are propagated in monkey cells (e.g. rhesus PBMCs). Thus the HIV-1 gp41 CT plays a positive role in virus replication whereas the SIVmac gp41 CT plays a negative role in human cells but a positive role in monkey cells. Understanding the basis for these observations is likely to provide novel insights into the role of gp41 in lentiviral biology. We will evaluate the role of host factors in primate lentiviral Env glycoprotein incorporation and the determinants in MA and gp41 required for Env incorporation. ___Although a trimeric MA crystal structure has been available since 1996 evidence for functional MA trimers has been elusive. The mechanism of HIV-1 Env recruitment into virions likewise has been unclear. We identified a point mutation in MA (62QR) that rescues the Env-incorporation defects imposed by an extensive panel of MA and Env mutations. Mapping the mutations onto the putative MA trimer reveals that the incorporation-defective mutations cluster at the tips of the trimer at the perimeter of a putative gap in the MA lattice into which the gp41 CT could insert. By contrast the rescue mutation is located at the trimer interface suggesting that it confers rescue of Env incorporation via modification of MA trimer interactions. These data strongly support the existence of MA trimers in the immature Gag lattice and demonstrate that rescue of Env-incorporation defects is mediated by modified interactions at the MA trimer interface. The importance of the trimer interface in rescuing HIV-1 Env incorporation suggests that the trimeric arrangement of MA plays a critical role in permitting incorporation of Env into the Gag lattice. Inhibitors could be developed to block HIV-1 Env incorporation by disrupting this essential structural element in MA trimerization. Future work could also yield strategies to block HIV-1 Env incorporation by disrupting the function of host factors or the interactions between host factors and either Env or Gag. We have also demonstrated that the cellular E3 ubiquitin ligase MARCH8 restricts a number of viral envelope glycoproteins including that of HIV-1. Our findings indicate that MARCH8-mediated antagonism of HIV-1 Env does not require the cytoplasmic tail of gp41. We have shown that mutations in Env can confer broad resistance to antiretroviral drugs by enhancing the efficiency of cell-cell transfer. This effect is particularly pronounced for integrase strand transfer inhibitors. Current efforts are aimed at deciperhing the mechanism by which Env mutations confer drug resistance and determining whether this phenomenon occurs in vivo. 870446 +No NIH Category available Binding;Binding Proteins;Biochemistry;Capsid Proteins;Cell membrane;Cell surface;Cells;Cellular biology;Collaborations;Complex;Destinations;Development;Family;Glycoproteins;Goals;HIV;HIV-1;HIV-2;Imaging Techniques;Immunoglobulins;Inositol;Integration Host Factors;Interferons;Membrane;Molecular;Mucins;Natural Immunity;Ohio;P-selectin ligand protein;Pathway interactions;Phosphatidylinositols;Phosphatidylserines;Play;Production;Protein Family;Proteins;Reporting;Research;Role;SIV;Site;Sphingomyelinase;T-Lymphocyte;Universities;Viral;Virion;Virus;Virus Assembly;Work;antiretroviral therapy;env Gene Products;gene product;inhibitor;insight;interest;nef Protein;novel;particle;polyanion;protein function;structural determinants;trafficking;virology;vpu Protein Gag Trafficking Assembly and Release n/a NCI 10926289 1ZIABC011720-08 1 ZIA BC 11720 8 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 870446 NCI While it is clear that HIV-1 assembly occurs predominantly on the plasma membrane (PM) the itinerary that the HIV-1 Gag precursor follows to reach this destination remains ill defined. Likewise the host cell machinery that promotes Gag trafficking to the PM is incompletely understood. We and others have demonstrated that the matrix (MA) domain of Gag regulates targeting to the site of virus assembly and we discovered that the phosphoinositide PI(45)P2 is a key player in directing Gag to the PM. We hypothesize that host factors in addition to PI(45)P2 play a vital role in the trafficking of Gag to the PM. In this project we are defining the role of host cell machinery in Gag trafficking to the PM and in subsequent steps of particle assembly and release. This effort combines virology biochemistry cell biology and imaging techniques. Our overarching goal is to establish a unified view of the mechanism and pathway(s) involved in the late stages of the HIV-1 replication cycle and to develop inhibitors of HIV-1 Gag trafficking assembly and release. ___ Most of our efforts and those of our colleagues with regard to late-acting host factors have focused on factors that promote HIV-1 particle assembly and release. However we have become increasingly interested in cellular factors that interfere with the late stages of HIV-1 replication. The best-characterized example of a late-acting negative factor is tetherin (BST-2) an interferon-stimulated gene product that restricts viral particle release at the cell surface. Tetherin is counteracted by the HIV-1 Vpu protein and the Nef or Env proteins of certain strains of HIV-2 and simian immunodeficiency virus. Apart from tetherin however little is known about the host cell factors that interfere with HIV 1 assembly or release. We are engaged in studying these host proteins with an initial focus on the T-cell immunoglobulin and mucin domain (TIM) family of phosphatidylserine-binding proteins. We recently reported in collaboration with Dr. Shan-Lu Liu's lab (Ohio State University) that the TIM-family proteins strongly inhibit HIV-1 release by retaining HIV-1 particles on the cell surface through binding to phosphatidylserine on the viral membrane. We will further characterize the mechanism of action by which such host factors restrict HIV-1 particle production resulting in diminished viral production and replication. We have been involved with studies examining the effect of the host factor PSGL-1 on the binding of virus particles to target cells and the incorporation of viral envelope glycoproteins into virions. We are also examining the role of neutral sphingomyelinase 2 on HIV assembly release and maturation. Finally we have several major projects focused on the role of the small cellular polyanion inositol hexkisphosphate (IP6) in HIV-1 assembly and maturation. 870446 +No NIH Category available Acute Graft Versus Host Disease;Adhesions;Affect;Affinity;Antigens;Autoimmune Diseases;Binding;Biochemical;Blood;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Calcineurin;Cell Adhesion;Cell Proliferation;Cells;Co-Immunoprecipitations;Complex;Confocal Microscopy;Cyclosporine;Defect;Disease;Disease Progression;Dissociation;Distal;Event;FK506;Family;Follow-Up Studies;Graft Rejection;ICAM1 gene;Image;Immunity;Immunosuppression;Immunosuppressive Agents;Intercellular adhesion molecule 1;LCP2 gene;Ligands;Liver;Lymphocyte-Specific p56LCK Tyrosine Protein Kinase;MAP Kinase Gene;MAP Kinase Modules;Mediating;Molecular;Mus;Mutate;Peptides;Phosphorylation;Phosphotransferases;Physiologic pulse;Process;Production;Protein Dephosphorylation;Protein Isoforms;Protein Tyrosine Kinase;Proteins;Receptor Signaling;Reporting;Role;Series;Signal Transduction;Signaling Molecule;Small Interfering RNA;Stress;T cell infiltration;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Tissues;Treatment Efficacy;Uncertainty;Work;ZAP-70 Gene;adaptive immune response;calcineurin phosphatase;cytokine;in vivo;knock-down;lymph nodes;member;mimetics;mutant;novel;nuclear factors of activated T-cells;p38 Mitogen Activated Protein Kinase;perforin;recruit;response;standard care;transcription factor;transplantation therapy;two-photon T cell receptor proximal signaling n/a NCI 10926287 1ZIABC011715-08 1 ZIA BC 11715 8 9692263 "ASHWELL, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 457987 NCI Cyclosporin A (CsA) and FK506 are widely used immunosuppressive drugs that inhibit the Ca2+-activated phosphatase calcineurin. Calcineurin's major activity in T cells is thought to be dephosphorylation (and thus activation) of the NFAT family of transcription factors which are important for cytokine production and cell proliferation. It inhibition of this process that is thought to underlie the therapeutic efficacy of CsA in the treatment of transplant rejection and autoimmune diseases. It has been reported that CsA also inhibits the classic MAP kinase cascade and therefore the stress-induced activation of p38. Signaling via the TCR results in the activation of the MAP kinase p38 by a MAPK cascade-independent mechanism: phosphorylation of p38 Y323 by ZAP-70. Therefore we were surprised to observe that CsA also inhibited p38 activation downstream of TCR signaling. This led us to explore the molecular mechanism for this inhibition and we have made the following observations: 1. Remarkably CsA and FK506 inhibited a number of key events in proximal T cell signaling. These include phosphorylation of ZAP-70 on Y493 LAT and SLP76 whereas phosphorylation of ZAP-70 Y319 PLCgamma1 and ERK were intact. 2. Calcineurin itself is recruited to the TCR signalosome within two minutes of activation and then slowly dissociates over the next 30-60 minutes. This was confirmed both by co-immunoprecipitation studies as well as imaging of TCR micro clusters by confocal microscopy. 3. Calcineurin recruitment requires Lck signaling and ZAP-70 but not ZAP-70 signaling. Therefore we believe that it is binding phosphorylated ZAP-70. 4. siRNA-mediated knockdown of calcineurin recapitulates inhibition of ZAP-70 493 and introduction of ZAP-70 Y493R (which cannot be phosphorylated on residue 493) results in signaling defects similar to those described above (point 1). 5. The calcineurin target in the TCR signalosome is Lck S59 whose phosphorylation has been reported to inhibit TCR signaling. Consistent with this introduction of Lck mutants (Lck S59A which can not be phosphorylated and Lck S59E a phospho-mimetic) resulted in enhanced and inhibited signaling respectively. 6. To determine if inhibition of proximal TCR signaling could be a novel mechanism for its immunosuppressive effects we looked for important NFAT-independent events downstream of TCR signaling. LFA-1-dependent adhesion to ICAM-1 is a very rapid and essential step in T cell activation and egress from the blood to tissue. We found that CsA inhibited conversion of LFA-1 from the inactive to the active state and blocked cell adhesion to ICAM-1-coated wells. Studies with T cells expressing the Lck-mutants confirmed that the phosphorylation status of S59 was responsible. Followup studies have shown that the addition of CsA to T cells already activated and bound to ICAM-1-coated plates or antigen-pulsed APC results in rapid (minutes) reversal of adhesion. These results have shown that unexpectedly calcineurin is an integral member of the TCR signaling complex. We have performed in vivo studies to assess the affect of cyclosporin A on T cell activation. We have B6 mice in which LckS59A (unable to be phosphorylated and thus not a calcineurin target) has been knocked into the WT locus. We used these mice to study acute graft-vs-host disease (aGVHD) in which H-2b T cells are injected into irradiated (H-2b X H-2a)F1 mice. CsA is a standard treatment for this disease and it is accepted that it works by inhibiting NF-AT-dependent cytokine production. By comparing the effect of CsA on disease caused by WT or LckS59A T cells we can determine if NF-AT TCR signaling or a combination of the two is responsible for CsA efficacy. We found that despite effective inhibition of NFAT-dependent cytokine production aGVHD progression was largely unaffected by CsA when LckS59A T cells were the transferred effectors. There was less CD8 T cell infiltration in the liver and the cells that were there expressed very little of the cytolytic protein perforin. Moreover 2-photon imaging of antigen-specific T:DC interactions in lymph nodes in WT or LckS59A mice treated with CsA found that the former but not the latter had markedly decreased T:DC interations and fewer T cell clusters consistent with the effect of CsA on LFA-1/ICAM1 binding. These results demonstrate that the current paradigm that CsA ameliorates aGVHD by inhibiting NFAT activation is incorrect. Rather it does so by inhibiting TCR signaling that otherwise increases in LFA-1-affinity and perforin expression and no doubt other not-yet-characterized responses. In addition to these we have found that siRNA-mediated knockdown of calcineuring alpha and beta results in a more profound loss of TCR signaling than inhibition of calcineurin enzymatic activity. We have generated CRISPR/Cas9 KO of the calcineurin alpha and beta forms of the A chain in Jurkat T cells with the same deficits. We are performing biochemical analysis and confocal microscopy to characterize the ability of these cells to form signaling TCR microclusters and propagate downstream events. Reintroduction of the A chain isoforms wt or mutated are planned to try to understand the structural basis of calcineurin's non-enzymatic role in TCR signaling. 457987 +No NIH Category available Adrenal Cortex Hormones;Adult;Basic Science;Biology;Blood;Blood - brain barrier anatomy;Blood specimen;Brain Neoplasms;Cells;Clinical Trials;Collaborations;Complex;Epigenetic Process;Exhibits;Face;Foundations;Functional disorder;Future;Glioblastoma;Goals;Heat shock proteins;Hematologic Neoplasms;Hypoxia;Iatrogenesis;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Monitoring;Immunologics;Immunology;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;Laboratories;Lymphocyte;Lymphocyte Function;Lymphopenia;Malignant Neoplasms;Malignant neoplasm of central nervous system;Metabolic;Molecular;Multi-Institutional Clinical Trial;Natural Immunity;Newly Diagnosed;Nivolumab;Oncology;Patients;Peptides;Persons;Play;Predisposition;Primary Brain Neoplasms;Process;Proteins;Radiation therapy;Randomized;Regimen;Regulatory T-Lymphocyte;Role;Running;Sampling;Seminal;Silent Mutation;Solid;T-Lymphocyte;Tissues;Toxic effect;Translational Research;Tumor-associated macrophages;United States National Institutes of Health;Vaccines;brain based;cancer immunotherapy;cancer therapy;clinical center;design;efficacy evaluation;fighting;immune function;immunoregulation;improved;improved outcome;in vivo;interest;ipilimumab;neoantigens;neoplastic cell;novel;participant enrollment;pembrolizumab;peripheral blood;phase II trial;prevent;programmed cell death ligand 1;programmed cell death protein 1;programs;randomized clinical trials;response;temozolomide;trafficking;translational immunology;tumor;tumor microenvironment Translational Immunology n/a NCI 10926286 1ZIABC011714-08 1 ZIA BC 11714 8 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 522109 NCI Although there have been advances in ways of how to overcome tumor related immunosuppression many factors such as T cell lymphopenia T cell dysfunction disproportionately high numbers of circulating suppressive regulatory T-lymphocytes tumor cell expression of PD-L1 and a suppressive tumor-associated macrophage (TAM) orientation as well as impaired immune effector trafficking across the BBB present challenges for effective immunotherapy in glioblastoma. Our basic and translational research focuses on the immunologic interactions between brain tumors the local tissue microenvironment and the systemic immune response. We aim to enhancing immune therapies by 1) improving lymphocyte function and 2) making the tumor more susceptible to immune attack. We are interrogating components of the tumor microenvironment such as immune modulating cells hypoxia and metabolic factors for their impact on immune function. We are also examining the mechanisms of immune depletion induced by corticosteroids and anti-cancer therapies. Finally we are examining the epigenetic and molecular mechanisms employed by tumor cells to evade immune attack. The Immunology Program has two major components: Immunologic monitoring for immune-based brain tumor clinical trials and elucidating the mechanisms of immunosuppression in brain tumor patients focusing on iatrogenic causes such as corticosteroid use lack of neoantigens and the impact of the tumor microenvironment. The immunologic monitoring will be performed as correlative biology for seminal brain tumor clinical trials whereas the modulation of the immunosuppression in brain tumors will serve as the foundation for future hypothesis-based clinical trials. In collaborate with NOB PTRF and Clinical Center we are further investigating the experimental immunotherapeutics in vivo. Two clinical trials are then open recently (17C0102 Immune Checkpoint Inhibitor Nivolumab in People with Select Rare CNS Cancers; and 17C0034 Phase II trial of Radiation Therapy plus Temozolomide and Pembrolizumab with and without SPPC-6 in newly diagnosed Glioblastoma). One OSTR/STARS supported project on T cell trafficking into the brain tumor has been on-going. 522109 +No NIH Category available Biological;Brain Neoplasms;Cell Line;Cells;Databases;Exposure to;Goals;Incubators;Maps;Metabolism;Methods;Noise;Nuclear;Pharmaceutical Preparations;Pharmacotherapy;Raman Spectrum Analysis;Signal Transduction;Slide;Tissues;Visualization;improved;in vivo;instrument;new technology;tumor Develop RAMAN imaging to visualize metabolism in cell lines and tissue n/a NCI 10926285 1ZIABC011711-08 1 ZIA BC 11711 8 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 427539 NCI We have developed conditions to record RAMAN spectra with high signal/noise ratio while maintaining the cells alive. We have recorded cells after exposure to different treatments and are satisfied with the results of the instrument. Our result pinpoint to certain classes of metabolites that are altered upon drug treatment and we will use these to further investigate via mass spec. We can also map the nuclear or cytosolic localization of different drugs. In addition the method can establish a line between the normal and tumor in tissue slides. 427539 +No NIH Category available Brain;Clinical;Disease Progression;Glucose;Glutamine;Image;In Vitro;Injections;Label;Laboratories;Magnetic Resonance Imaging;Measures;Metabolic;Mus;Normal Cell;Pathway interactions;Protocols documentation;Source;cohort;experimental study;in vivo;mouse model;pre-clinical;tumor In vivo and in vitro metabolic flux analysis in preclinical mouse models n/a NCI 10926284 1ZIABC011710-08 1 ZIA BC 11710 8 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 285026 NCI Our mice protocol has been approved for the next 3 years. We plan to use a cohort of mice for the metabolic flux analysis and correlate with in in vitro studies. We are in the initial stages of this project and therefore do not have significant result yet. Mice that developed mature tumors will be transported from building 37 to building 10 MIF initially for different field imaging using 1H-MRS and 13C-MRS then to Dr. Murali Cherukuri's laboratory where the injection of precursors will take place right before the hyperpolarized MRI experiment. In between experiments we will keep the mice in the allocated cage in building 10. We will inject the mice with the 13C precursors in order to probe different pathways then immediately start the imaging experiment. 285026 +No NIH Category available Animal Model;Biological Markers;Blood;Cerebrospinal Fluid;Correlation Studies;Data;Diagnosis;Disease remission;Future;Human;Hydrophobicity;Measures;Metabolic;Metabolism;Methods;Modeling;Mus;Mutate;Patient Monitoring;Patients;Prognosis;Reporting;Sampling;Serum;Statistical Data Interpretation;Time;Tissues;Urine;Xenograft procedure;hydrophilicity;mutant;treatment response;tumor Metabolite profiling of patients blood urine cerebrospinal fluid and tissue n/a NCI 10926283 1ZIABC011709-08 1 ZIA BC 11709 8 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 142514 NCI We have developed methods to separate and quantify D-2HG from IDH-mutant patients. We have robust methods to extract and manipulate hydrophobic and hydrophilic metabolites from urine serum cerebrospinal fluid and tissue. In order to provide significance to our animal models in the future we plan to correlate these studies with the mice xenografts. This will help establish whether mice metabolism is similar enough to human to constitute viable future models. In addition the extraction of metabolites from biofluids is easy and represents a non-invasive approach to the identification of metabolic signatures specific to IDH1-mutated tumors. 142514 +No NIH Category available DNA sequencing;Defect;Goals;Human;Lead;Mass Spectrum Analysis;Metabolic;Metabolism;Mus;Mutate;Mutation;NMR Spectroscopy;Pathway interactions;Running;Time;Tissue Sample;Xenograft procedure;cohort;established cell line;experimental study;metabolomics;novel;targeted treatment;tumor Targeted and untargeted metabolomics in IDH1 mutated xenografts in mice n/a NCI 10926282 1ZIABC011708-08 1 ZIA BC 11708 8 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 285026 NCI We have been approved to start the studies in mice for the next 3 years. Our pilot experiments has provided with a time frame for mice developing tumors and their survival. We have confirmed the presence of IDH1 mutation via WB and DNA sequencing. Our next goal is to start a larger cohort of mice and to use them for global metabolic profiling. We will use NMR spectroscopy and mass spectrometry to profile metabolites. This study will uncover novel pathways altered by IDH mutations which can be targeted for therapies. 285026 +No NIH Category available Animal Model;Biological Assay;Biological Models;Cell Culture Techniques;Cell Death;Cell Line;Cells;Cessation of life;DNA Methylation;Diet;Drug Combinations;Future;Glioma;Goals;In Vitro;Investigation;Mass Spectrum Analysis;Metabolic;Methods;Modeling;Mus;Mutate;Mutation;Pharmaceutical Preparations;Phenotype;Production;Research;Testing;Therapeutic;Therapeutic Effect;Western Blotting;established cell line;histone methylation;in vivo;mouse model;protein expression;response;tumor The effect of therapeutics on mutated IDH1 cell lines and mice tumor models n/a NCI 10926281 1ZIABC011707-08 1 ZIA BC 11707 8 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 285026 NCI Using the methods described above we have identified 2 IDH-mutated cell lines that are producing the expected phenotype and will be used for further investigations. The cells behave as expected in terms of D-2HG production and the response to different therapeutics will be determined in the future. We are evaluating different metabolic drugs as well as diets. The goal is to establish a combination of drugs or drug/diets that causes cellular death. once we understand the mechanism of cell death we plan to test these in animal models. 285026 +No NIH Category available Affinity;Alternative Splicing;Anabolism;Apoptosis;Binding;Biochemical;Biogenesis;Biological Assay;Biological Models;Bone Tissue;CCR;Cancer Biology;Carbon;Carcinoma;Cell Line;Cell Survival;Cell physiology;Cells;Chimeric Proteins;Chromosomal Rearrangement;Chromosome 11;Chromosome 22;Chromosomes;DNA;DNA Damage;Data;Dependence;Detection;Development;Dimensions;Disease;Dissociation;Distant;Dreams;EWSR1 gene;Enzymes;Evaluation;Event;Ewings sarcoma;Exclusion;Exhibits;Exons;Exposure to;FLI1 Transcription Factor;FLI1 gene;Follow-Up Studies;Fusion Oncogene Proteins;G-Quartets;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Glutamine;Glycine;Growth;Guanine;Image;Individual;Interferometry;Introns;Investigational Drugs;Laboratories;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Messenger RNA;Meta-Analysis;Molecular;Molecular Carcinogenesis;Molecular Conformation;Molecular Target;Mutation;National Center for Advancing Translational Sciences;Neoplasm Metastasis;Neoplasms;Nucleic Acids;Nutrient;Oncogene Deregulation;Oncogenes;Oncogenic;Oncoproteins;Oxidation-Reduction;Pathology;Pathway interactions;Pediatric Oncology;Pharmacotherapy;Post-Transcriptional Regulation;Post-Translational Regulation;Primary Neoplasm;Process;Proliferating;Proteins;Publishing;RNA;RNA Binding;RNA Interference;RNA Splicing;RNA interference screen;Reactive Oxygen Species;Regulation;Reporting;Research;Research Personnel;Reverse Transcription;Series;Serine;Signal Transduction;Site;Small RNA;Source;Spliceosomes;Stimulus;Structure;Technology;Therapeutic;Tissues;Transcript;Translations;Translocation Breakpoint;Tumor Cell Invasion;United States National Institutes of Health;Work;cancer cell;cancer therapy;combinatorial;design;functional genomics;fusion gene;gene discovery;genome-wide;genome-wide analysis;insight;leukemia;loss of function;mRNA Precursor;migration;neoplastic cell;new therapeutic target;novel therapeutic intervention;nucleic acid binding protein;posttranscriptional;protein complex;protein expression;protein function;recruit;response;soft tissue;transcription factor;transcriptome;tumor;tumorigenesis;uptake Discovery of genes required for expression or activity of fusion oncogenes n/a NCI 10926280 1ZIABC011704-08 1 ZIA BC 11704 8 9692277 "CAPLEN, NATASHA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1739029 NCI We began our work to discover genes required for the expression or function of fusion oncogenes by using the results of a genome-wide RNAi screen designed to identify genes needed for the activity of the fusion oncoprotein EWSR1::FLI1. The development of this RNAi screen was a collaborative effort involving the Caplen laboratory and researchers from CCR's Pediatric Oncology Branch and the trans-NIH RNAi screening facility at the National Center for Advancing Translational Sciences (NCATS). EWSR::FLI1 is an oncogenic transcription factor that results from a chromosomal rearrangement involving chromosomes 11 and 22. Chromosome 11:22 translocation is the most frequent primary genetic event observed in Ewing sarcoma (EWS) a cancer of the bone and soft tissues. The genome-wide RNAi screen revealed that EWSR1::FLI1 fusion transcript expression is sensitive to inhibiting the activity of specific splicing factors. We identified that expression of the EWSR1::FLI1 transcripts expressed in EWS cells harboring translocations where the breakpoint in chromosome 22 occurs within a region of DNA (intron 8 of the EWSR1 gene) requires the splicing factor HNRNPH1 to generate an in-frame mRNA (Grohar Kim ... Caplen Cell Reports 2016). The depletion of HNRNPH1 in EWS cells that harbor a chromosome 22 breakpoint in EWSR1-intron 8 disrupts the expression and the activity of the EWSR::FLI1 protein and reduces cell survival. A follow-up study (Neckles ... Caplen RNA 2019) demonstrated that guanine-rich sequences within EWSR1-exon 8 that can fold into RNA G-quadruplex structures influence the recruitment of HNRNPH1. Critically we showed that EWSR1-exon 8 fusion-positive cell lines are more sensitive to treatment with the pan-quadruplex binding molecule pyridostatin (PDS) than EWSR1-exon 8 fusion-negative lines. Also the treatment of EWSR1-exon 8 fusion-positive cells with PDS decreases EWSR::FLI1 transcriptional activity and reverses the transcriptional deregulation driven by EWSR1::FLI1. Most recently (Vo et al. Nucleic Acids Research 2022) we performed a meta-analysis of studies reporting Chr. 22 breakpoints and determined that about 35% of EWSR::FLI1-positive Ewing sarcomas harbor EWSR1-intron 8 breakpoints. Using long-read sequencing we have determined that the exclusion of EWSR1-exon 8 is the dominant HNRNPH1-dependent event observed in the processing of EWSR1::FLI1 in EWS cell lines harboring EWSR1-intron 8 breakpoints. Though the HNRNPH1/H2 and F proteins are highly homologous (90 and 70% respectively) minigenes focused on EWSR1-exon 8 confirmed our previous findings that only HNRNPH1 is responsible for excluding EWSR1-exon 8. Furthermore a series of minigenes in which we included G-A substitutions to disrupt G-tracts to which HNRNHP1 could bind demonstrated a shift in splicing from detection of both exon inclusion and exclusion events to only exon inclusion. Analysis of HNRNPH1's binding of RNA oligomers corresponding to G-rich regions of the EWSR1-exon 8 3' end using Bio-layer Interferometry demonstrated its binding of these G-rich sequences. HNRNPH1 binds these G-rich sequences with low nM affinities irrespective of structural state - unfolded or folded as parallel G4 structures but exhibits faster association and dissociation rates when these RNAs are in a folded state. Critically using spectroscopic assays we showed that the binding of HNRNPH1 to EWSR1-exon 8 G-rich sequences in a folded state results in a concentration-dependent change in RNA structure to that of one that more resembles an unfolded state. Our results indicate that HNRNPH1's binding of G-rich sequences can destabilize rG4 structures in a non-catalytic fashion. In summary our results provide the first evidence that HNRNPH1's binding of G-rich sequences in a quadruplex state can alter this structural conformation provides insights into the function of HNRNPH1 as a regulator of alternative splicing and suggest means for inhibiting EWSR1::FLI1 expression through disruption of EWSR1::FLI1 mRNA biogenesis. Our current research aims are as follows (1) Determination of cis-regulatory sequences defining EWSR1-exon 8 exclusion in the context of the EWSR1::FLI1 transcript as the basis of a strategy for inhibition of fusion oncoprotein expression in a subset of Ewing sarcomas. (2) Exploration of the adaption of mechanisms that regulate the processing of the pre-mRNAs expressed by EWSR1 or its partner genes to express the translatable product of a fusion gene. (3) The evaluation of splicing regulation by HNRNPH1 to define its functions further and inform the study of disease states associated with mutations in HNRNPF/H genes or sequences they bind. We discussed the importance of understanding the function of the HNRNPF/H proteins in further detail in a recently published review - Brownmiller and Caplen WIREs RNA 2023 doi: 10.1002/wrna.1788. Our follow-up studies of the genome-wide RNAi screen of EWSR1::FLI1 activity also identified SF3B1 the catalytic component of the spliceosome a protein complex required for splicing as a protein that EWS cells are dependent upon for cell survival. We discovered that the biogenesis of the EWSR1::FLI1 mRNA is sensitive to disruption of spliceosome function and that canonical splicing is a potential vulnerability in EWS. In 2020 we published an opinion piece that discussed the rationale for studying the biology of cancer-associated fusion transcripts in further detail which included discussion of several other fusion driven cancers including subtypes of leukemia lung and prostate cancer and NUT-midline carcinoma (Neckles Sundara Rajan Caplen Wiley Interdiscip Rev RNA 2020). Building on these previous studies we have recently initiated studies that use multi-dimensional assays (quantitative and image-based) to identify additional proteins that regulate the expression or activity of EWSR1 and/or the fusion oncoprotein EWSR1::FLI1 and the respective functions of these proteins. Our research also involves evaluating the hypothesis that mechanisms contributing to and resulting from the EWSR1-fusion oncoprotein's deregulation of gene expression represent potential tumor-specific dependencies with therapeutic potential. We are investigating how gene expression regulatory mechanisms contribute to the pathology of an EWSR1-fusion driven cancer with an initial focus on EWSR1 and the study of pathways EWSR1::FLI1 deregulates. For example we have demonstrated that EWSR1::FLI1 positively regulates the expression of proteins required for serine-glycine biosynthesis and uptake of the alternative nutrient source glutamine (Sen .. Caplen Molecular Carcinogenesis 2018). Specifically we show that EWSR1::FLI1 can alter the expression of PHGDH PSAT1 PSPH and SHMT2 genes encoding enzymes required for serine-glycine biosynthesis. Using cell-based studies we also established that EWS cells are dependent on glutamine for cell survival and that EWSR1::FLI1 positively regulates the expression of the glutamine transporter SLC1A5 and two enzymes involved in the one-carbon cycle MTHFD2 and MTHFD1L. Inhibition of serine-glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species DNA damage and apoptosis. Importantly analysis of EWS primary tumor transcriptome data confirmed that most of the genes identified by our cell-based studies also exhibit increased expression compared with non-diseased tissues including PHGDH and SHMT2. Current studies aim to examine other cellular processes EWSR1::FLI1 regulates to promote EWS tumorigenesis in particular processes that have the potential to favor dissemination of tumor cells and thus metastasis. 1739029 +No NIH Category available AIDS clinical trial group;Acquired Immunodeficiency Syndrome;Acute;Adherence;Affect;Anti-Retroviral Agents;Antiretroviral resistance;Binding;Biological Assay;Cells;Clinical;Collaborations;Data;Data Set;Drug resistance;Enrollment;Evolution;Failure;Far East;Frequencies;Genes;Genetic;Genetic Recombination;Genome;Genotype;HIV;HIV Envelope Protein gp120;HIV Genome;HIV Infections;HIV drug resistance;Hawaii;In Vitro;Individual;Infection;Integrase;Interruption;Length;Libraries;Link;Manuscripts;Medical;Minority;Multi-Drug Resistance;Mutation;Opportunistic Infections;Participant;Pattern;Pharmaceutical Preparations;Phylogenetic Analysis;Plasma;Population;Population Dynamics;Proviruses;Publications;Recombinants;Red Cross;Regimen;Reporting;Research;Research Institute;Resistance;Rest;Retroviridae Infections;Retrovirology;Role;Sampling;Science;Structure;Techniques;Technology;Thailand;Variant;Viral;Viral Genome;Viremia;Virion;Virus;acute infection;antiretroviral therapy;bioinformatics pipeline;cost;design;drug resistance development;env Genes;experimental study;genome sequencing;high risk population;improved;in vivo;insight;integration site;nanopore;next generation;next generation sequencing;off-target mutation;pre-exposure prophylaxis;pressure;prevent;programs;rare variant;resistance mutation;response;symposium;transmission process;virtual Ultrasensitive Single-Genome Sequencing to Study HIV Transmission and Evolution n/a NCI 10926279 1ZIABC011699-08 1 ZIA BC 11699 8 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1144522 OD "BACKGROUND: In this project we developed a new method for NGS library construction of viral genomes that reduces PCR bias and error eliminates PCR recombinants from the final datasets and generates thousands of single-genome HIV sequences of the same quality as standard sequencing but with 100-fold more variants (Boltz et al. Retrovirology 13:87 2016). This new ultrasensitive SGS (uSGS) assay has been used not only for detecting linkage of rare alleles including drug-resistance mutations (Boltz et al. JCI Insight 2021) but also for in-depth phylogenetic analyses of viral populations. We are also pursuing next generation of uSGS using Oxford Nanopore Technologies (ONT). We have begun these studies by demonstrating that ONT can be used to generate accurate near full-length HIV sequencing (Wright et al. Cells 2021) and by developing a pipeline to annotate the sequences generated (Wright et al. Retrovirology 2021). Moving forward we will improve our current ONT assays and pipeline to capture the HIV integration sites as well as the full-length HIV sequences in samples collected from donors on ART. This advancement will contribute significantly to our understanding of HIV persistence. Dr. Freed recently reported that HIV can develop drug resistance in vitro to multiple classes of antiretroviral drugs by acquiring Env mutations. However it is not known if these mutations confer multidrug resistance in vivo as they do in vitro. To investigate the possible contribution of Env mutations to drug resistance in vivo we obtained plasma samples from five donors failing INSTI [raltegravir (RAL)]-containing regimens without mutations in the integrase gene by standard HIV genotyping and with plasma drug levels confirming adherence. Using samples obtained from the ACTG study A5273 we performed sequencing on donor samples from pre-ART early RAL failure and during late RAL failure. Sequences obtained were analyzed for known drug resistance mutations in IN and for newly emergent Env mutations. Several Env mutations emerged upon drug failure in the highly conserved gp120/gp41 interface similar to those confirmed to confer drug resistance in vitro (Hikichi et al. mBio 2021). These findings suggest that Env mutations might contribute to HIV drug resistance in vivo. If Env mutations are demonstrated to confer resistance to ART we will initiate evolutionary studies to determine the origin and selection pressures on the newly identified drug resistance mutations (e.g. if they existed prior to ART and if so at what frequencies if they are found in donors failing other ART regimens and if they are selected in donors without ART). Understanding the role of Env in ART resistance will have significant clinical impact if mutations are found to confer drug resistance alone or to be a ""stepping stone"" toward virologic failure. ____ACCOMPLISHMENTS: ___Using our SGS assays we demonstrated that pre-exposure prophylaxis can fail to prevent HIV transmission when drug-resistance mutations are present in the donor population of viral variants (Spinelli et al. Clin. Infect. Dis. 72:2025-2028 2021). ___In collaboration with the lab of Dr. Eric Freed (HIV Dynamics and Replication Program) we investigated the role of off-target mutations in the failure of ART to control HIV replication in vivo. We identified several mutations in the gp120-gp41 interface of the HIV env gene that are capable of conferring low- to medium-level resistance to multiple ARVs (Hikichi et al. mBio12:e03134-20 2021). ___We developed new near full-length HIV single-genome sequencing assay using Oxford Nanopore Technologies and demonstrated it's accuracy to be equivalent to other approaches at a reduce cost and higher throughput. This assay will be used to characterize HIV proviruses that persist on ART (Wright et al. Cells. 10 2021). ___We developed a new bioinformatic pipeline to annotate near full-length HIV sequences and determine if they are intact and likely capable of fueling rebound viremia if ART is interrupted (Wright et al. Retrovirology. 18: 16 2021.). __ Although it is generally believed that most HIV infections are initiated with a single virion this conclusion rests on experiments in which the number of viral genomes analyzed was relatively small (about 10-100 HIV genomes). Using uSGS we performed an in-depth study of HIV genetics in acute infection to answer the question of whether in some of the individuals that appear to have been infected with a single virus there were also minority variants that were missed due to shallow sampling. We were able to obtain plasma samples from 15 donors enrolled in the RV254/South East Asia Research Collaboration with Hawaii 010 Trial (101). The trial was conducted by the Thai Red Cross AIDS Research Centre and the Department of Retrovirology U.S. Army Medical Component Armed Forces Research Institute of Medical Sciences. The study was designed to identify acute HIV infection in high-risk populations in Thailand and offer immediate initiation of ART. Fifteen samples were collected from participants during acute HIV infection. Ten of the donors were previously reported to have a single founder virus in acute infection by standard SGS and five donors were shown to have two to five founders using the same approach. Using our uSGS approach we confirmed that no minority variants were detected in the 10 donors that were previously reported to have infection resulting from the transmission of a single viral variant. We are now analyzing the data to understand patterns of HIV evolution in early infection. Results from this aim will inform studies using bNAbs in acute infection to target founder viruses and will contribute to our understanding of HIV transmission evolution and population dynamics were presented at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) and are being assembled into a manuscript for publication in the coming year." 310000 +No NIH Category available AIDS clinical trial group;Acquired Immunodeficiency Syndrome;Acute;Adherence;Affect;Anti-Retroviral Agents;Antiretroviral resistance;Binding;Biological Assay;Cells;Clinical;Collaborations;Data;Data Set;Drug resistance;Enrollment;Evolution;Failure;Far East;Frequencies;Genes;Genetic;Genetic Recombination;Genome;Genotype;HIV;HIV Envelope Protein gp120;HIV Genome;HIV Infections;HIV drug resistance;Hawaii;In Vitro;Individual;Infection;Integrase;Interruption;Length;Libraries;Link;Manuscripts;Medical;Minority;Multi-Drug Resistance;Mutation;Opportunistic Infections;Participant;Pattern;Pharmaceutical Preparations;Phylogenetic Analysis;Plasma;Population;Population Dynamics;Proviruses;Publications;Recombinants;Red Cross;Regimen;Reporting;Research;Research Institute;Resistance;Rest;Retroviridae Infections;Retrovirology;Role;Sampling;Science;Structure;Techniques;Technology;Thailand;Variant;Viral;Viral Genome;Viremia;Virion;Virus;acute infection;antiretroviral therapy;bioinformatics pipeline;cost;design;drug resistance development;env Genes;experimental study;genome sequencing;high risk population;improved;in vivo;insight;integration site;nanopore;next generation;next generation sequencing;off-target mutation;pre-exposure prophylaxis;pressure;prevent;programs;rare variant;resistance mutation;response;symposium;transmission process;virtual Ultrasensitive Single-Genome Sequencing to Study HIV Transmission and Evolution n/a NCI 10926279 1ZIABC011699-08 1 ZIA BC 11699 8 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1144522 NCI "BACKGROUND: In this project we developed a new method for NGS library construction of viral genomes that reduces PCR bias and error eliminates PCR recombinants from the final datasets and generates thousands of single-genome HIV sequences of the same quality as standard sequencing but with 100-fold more variants (Boltz et al. Retrovirology 13:87 2016). This new ultrasensitive SGS (uSGS) assay has been used not only for detecting linkage of rare alleles including drug-resistance mutations (Boltz et al. JCI Insight 2021) but also for in-depth phylogenetic analyses of viral populations. We are also pursuing next generation of uSGS using Oxford Nanopore Technologies (ONT). We have begun these studies by demonstrating that ONT can be used to generate accurate near full-length HIV sequencing (Wright et al. Cells 2021) and by developing a pipeline to annotate the sequences generated (Wright et al. Retrovirology 2021). Moving forward we will improve our current ONT assays and pipeline to capture the HIV integration sites as well as the full-length HIV sequences in samples collected from donors on ART. This advancement will contribute significantly to our understanding of HIV persistence. Dr. Freed recently reported that HIV can develop drug resistance in vitro to multiple classes of antiretroviral drugs by acquiring Env mutations. However it is not known if these mutations confer multidrug resistance in vivo as they do in vitro. To investigate the possible contribution of Env mutations to drug resistance in vivo we obtained plasma samples from five donors failing INSTI [raltegravir (RAL)]-containing regimens without mutations in the integrase gene by standard HIV genotyping and with plasma drug levels confirming adherence. Using samples obtained from the ACTG study A5273 we performed sequencing on donor samples from pre-ART early RAL failure and during late RAL failure. Sequences obtained were analyzed for known drug resistance mutations in IN and for newly emergent Env mutations. Several Env mutations emerged upon drug failure in the highly conserved gp120/gp41 interface similar to those confirmed to confer drug resistance in vitro (Hikichi et al. mBio 2021). These findings suggest that Env mutations might contribute to HIV drug resistance in vivo. If Env mutations are demonstrated to confer resistance to ART we will initiate evolutionary studies to determine the origin and selection pressures on the newly identified drug resistance mutations (e.g. if they existed prior to ART and if so at what frequencies if they are found in donors failing other ART regimens and if they are selected in donors without ART). Understanding the role of Env in ART resistance will have significant clinical impact if mutations are found to confer drug resistance alone or to be a ""stepping stone"" toward virologic failure. ____ACCOMPLISHMENTS: ___Using our SGS assays we demonstrated that pre-exposure prophylaxis can fail to prevent HIV transmission when drug-resistance mutations are present in the donor population of viral variants (Spinelli et al. Clin. Infect. Dis. 72:2025-2028 2021). ___In collaboration with the lab of Dr. Eric Freed (HIV Dynamics and Replication Program) we investigated the role of off-target mutations in the failure of ART to control HIV replication in vivo. We identified several mutations in the gp120-gp41 interface of the HIV env gene that are capable of conferring low- to medium-level resistance to multiple ARVs (Hikichi et al. mBio12:e03134-20 2021). ___We developed new near full-length HIV single-genome sequencing assay using Oxford Nanopore Technologies and demonstrated it's accuracy to be equivalent to other approaches at a reduce cost and higher throughput. This assay will be used to characterize HIV proviruses that persist on ART (Wright et al. Cells. 10 2021). ___We developed a new bioinformatic pipeline to annotate near full-length HIV sequences and determine if they are intact and likely capable of fueling rebound viremia if ART is interrupted (Wright et al. Retrovirology. 18: 16 2021.). __ Although it is generally believed that most HIV infections are initiated with a single virion this conclusion rests on experiments in which the number of viral genomes analyzed was relatively small (about 10-100 HIV genomes). Using uSGS we performed an in-depth study of HIV genetics in acute infection to answer the question of whether in some of the individuals that appear to have been infected with a single virus there were also minority variants that were missed due to shallow sampling. We were able to obtain plasma samples from 15 donors enrolled in the RV254/South East Asia Research Collaboration with Hawaii 010 Trial (101). The trial was conducted by the Thai Red Cross AIDS Research Centre and the Department of Retrovirology U.S. Army Medical Component Armed Forces Research Institute of Medical Sciences. The study was designed to identify acute HIV infection in high-risk populations in Thailand and offer immediate initiation of ART. Fifteen samples were collected from participants during acute HIV infection. Ten of the donors were previously reported to have a single founder virus in acute infection by standard SGS and five donors were shown to have two to five founders using the same approach. Using our uSGS approach we confirmed that no minority variants were detected in the 10 donors that were previously reported to have infection resulting from the transmission of a single viral variant. We are now analyzing the data to understand patterns of HIV evolution in early infection. Results from this aim will inform studies using bNAbs in acute infection to target founder viruses and will contribute to our understanding of HIV transmission evolution and population dynamics were presented at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) and are being assembled into a manuscript for publication in the coming year." 834522 +No NIH Category available Address;Aftercare;Biological Assay;Cell Fraction;Cell Proliferation;Cells;Child;Clonal Expansion;Clone Cells;Collaborations;Cytotoxic T-Lymphocytes;Data;Disease remission;Dose;Emodin;Event;Future;Genes;Genetic;Genetic Transcription;Genome;HIV;HIV Infections;HIV-1;Heterogeneity;Histone Deacetylase Inhibitor;Immune;Immune checkpoint inhibitor;In Vitro;Individual;Infection;Infusion procedures;Intervention;Investments;Maintenance;Manuscripts;Measures;Methods;Minor;Modification;National Institute of Allergy and Infectious Disease;Nature;North Carolina;Oncogenes;Opportunistic Infections;Participant;Patients;Peripheral Blood Mononuclear Cell;Population;Production;Proliferating;Proviruses;Publications;RNA;Reporting;Research;Resistance;Retroviridae Infections;Sampling;Structure;T memory cell;T-Lymphocyte;Technology;Tissues;Universities;Viral;Virus;Vorinostat;Zinc Fingers;acute infection;anti-PD-1;antiretroviral therapy;cell killing;curative treatments;cytotoxicity;efficacy evaluation;improved;in vivo;inhibitor;insight;integration site;lymph nodes;neutralizing antibody;neutralizing monoclonal antibodies;new technology;peripheral blood;pressure;response;symposium Impact of Interventions on Clonally Expanded Proviruses and Their RNA Expression n/a NCI 10926278 1ZIABC011698-08 1 ZIA BC 11698 8 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 667617 NCI BACKGROUND: The persistence of HIV during antiretroviral therapy (ART) has been shown to be driven by the proliferation of cells that were infected prior to initiating treatment and not from ongoing cycles of HIV replication in the peripheral blood or in tissues such as lymph nodes or gut (McManus et al. J. Clin. Invest. 129:4629-4642 2019; Bozzi et al. Sci. Adv. 5:eaav5045 2019). However little is known about the drivers of cellular proliferation or about their selective maintenance during ART or during treatment with new interventions aimed at controlling HIV without ART. New interventions aimed at achieving HIV remission without ART include latency-reversing agents broadly neutralizing antibodies genetic modifications of HIV proviruses enhancement of immune recognition of infected cells and more. Our current studies are aimed at understanding the selection and persistence of cell clones during ART the drivers of clonal proliferation before and during ART and the effect of new interventions on clonal expansion of infected cells and on the expression of proviruses that persist during ART. Previously we investigated the distribution of HIV integration sites in cell clones prior to ART and compared it to the distribution of cell clones after years on ART to identify the selection pressures that allow HIV to persist despite treatment (Coffin et al. JCI Insight 4:e128432 2019; Coffin et al. PLoS Pathog. 17:e1009141 2021; Bale Katusiime et al. mBio 12:e00568-21 2021). We found that HIV proviruses that persist on ART are more frequently integrated in regions of the host genome that are not highly expressed and that they are often integrated in the opposite orientation of the host gene. We also found that infected cell clones arise in acute infection and persist for at least 9 years on ART. We are now investigating the effect of the latency-reserving agents on the persistence and dynamics of infected cell clones and on the expression of HIV within infected cell clones. _____One proposed new intervention for HIV has included treating with agents such as HDAC inhibitors that activate latent proviruses inducing expression of intracellular RNA in the hopes that such expression will result in viral production and killing of infected cells by viral cytotoxicity or targeted cytotoxic T-lymphocyte (CTL) response. However previous studies in which we collaborated with Dr. David Margolis (University of North Carolina) showed only a limited effect on reservoir reduction in participants treated with single or multiple doses of the HDAC inhibitor vorinostat (Archin et al. Nature 487:482-485 2012; Archin et al. J. Infect. Dis. 210:728-735 2014) including a lack of increased viral production in vivo measured by the HIV single-copy assay (SCA). More promising data have been obtained from more potent inhibitors and from combinations of HDAC inhibitors in in vitro studies some of which were conducted by the University of Pittsburgh directed by Dr. John Mellors (Cillo et al. PNAS 111:7078-7083 2014; Wei et al. PLoS Pathog. 10:e1004071 2014). Although these potent inhibitors are believed to be more effective at inducing proviral expression it is not currently known what levels of proviral expression are necessary to induce cell killing. By comparing uninduced and induced PBMCs from the same individuals we will determine which inhibitors are capable of reactivating latent proviruses (those that are not expressing HIV RNA prior to induction) in expanded cell clones and which only increase expression of proviruses that were already expressing at low levels prior to the induction and the heterogeneity of these effects among proviruses. While conducting the in vitro studies on the HDAC inhibitors we also plan to assess the efficacy of curative interventions on expanded clones in vivo. We are using samples accessible through our collaboration with Dr. Eli Boritz at NIAID from before and after a single-dose infusion of anti-PD-1 to measure the effects on clonal proliferation of infected and uninfected cell clones. ____ACCOMPLISHMENTS: Our current research is focused on the effect of anti-PD-1 on the HIV reservoir in vivo. In collaboration with Dr. Boritz we obtained samples from HIV-1-infected patients who received anti-PD-1 infusions to determine the effect of this checkpoint inhibitor on levels of HIV-infected cells during ART (Perez-Rodrigo et al. Conference on Retroviruses and Opportunistic Infections 2021). Using our MDA-SGS assay (described in Project ZIA BC 011681) we characterized the sites of integration into the host genome and the proviral structure in infected cells obtained before and after treatment with anti-PD-1. We demonstrated the expansion of infected cells in response to anti-PD-1. We are currently drafting these findings into a manuscript for publication.____ Naive T cells that have been reported to be more resistant to HIV infection we investigated the number of infected cells clones in children the timing of their emergence and their persistence on ART (Bale Katusiime et al. mBio 12:e00568-21 2021). We found that infected cell clones in children arise in early infection and persist for at least 9 years on ART. We also found that there is a selection for proviruses that are in the opposite orientation of the host gene and are in genes that are not highly expressed. We recently completed a study investigating the levels of infected naive and memory T cells in children and the degree to which they form cell clones. We found that 8/8 children studied carry populations of infected naive cells and that some infected naive cells can form cell clones. We presented our results at the 2023 Conference on Retroviruses and Opportunistic Infections and are preparing a manuscript for submission. ____To investigate the drivers of clonal expansion of infected cells before and during ART we compared the integration site profile in ex vivo infected PBMCs to in vivo infected PBMCs collected from donors on short- and long-term ART (Coffin et al. PLoS Pathog. 17:e1009141 2021). We found that integration into oncogenes is only a minor driver of clonal expansion of infected cells suggesting that homeostatic and/or antigenic-driven clonal expansion are the main drivers for persistence of HIV during ART. We are now expanding these findings to determine if integration events into other classes of genes (i.e. zinc-finger genes) are drivers of clonal expansion and persistence of infected T cells. To investigate this question we developed a new technology to investigate the dynamics of infected cell clones before and during ART with higher accuracy and sensitivity than the integration sites assay (Brandt et al. Viruses 13:1235 2021). Using this technology we showed that clones with intact or defective proviruses can increase or decrease in size during treatment. We will apply this method and an improved higher-throughput MDA-SGS methods to address the questions in this project. 667617 +No NIH Category available 5' Untranslated Regions;Address;Binding;Biological Assay;Biological Process;Blood;Case Study;Cell Fraction;Cell Proliferation;Cell Separation;Cells;Clonal Expansion;Clone Cells;Code;Collecting Cell;CpG Islands;DNA;DNA Methylation;Data;Deamination;EZH2 gene;Epigenetic Process;Frequencies;Future;Genes;Genetic Transcription;Genome;Guanine;HIV;HIV Infections;HIV-1;Histone H3;Immune;Immune response;In Vitro;Individual;Interruption;Intervention;Investments;Laboratories;Lysine;Manuscripts;Measures;Methods;Methylation;Multi-Drug Resistance;Natural Killer Cells;Nucleosomes;Opportunistic Infections;Patients;Peer Review;Peripheral Blood Mononuclear Cell;Persons;Plasma;Population;Preparation;Proliferating;Provirus Integration;Proviruses;Publications;Publishing;RNA;RNA Splicing;Reporting;Repressor Proteins;Research;Rest;Retroviridae Infections;Reverse Transcription;Role;Sampling;Science;Site;Sorting;Source;Sulfate;T memory cell;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;Technology;Testing;Time;Tissues;Transcription Initiation Site;Variant;Viremia;Virus;Virus Latency;Work;animation;antiretroviral therapy;digital;env Genes;epigenetic silencing;follow-up;genome sequencing;in vivo;innovation;lymph nodes;member;prevent;promoter;recruit;resistance mutation;response;symposium;transcription factor;viral fitness Effects of Antiretroviral Therapy on Transcriptional Activity of HIV Proviruses n/a NCI 10926277 1ZIABC011697-08 1 ZIA BC 11697 8 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 834522 NCI BACKGROUND: We and others discovered that HIV infection can be maintained during antiretroviral therapy (ART) by the proliferation of cells that were infected prior to initiating ART. However it was not known how commonly such clones express HIV RNA during ART. The findings that expanded clones can be the source of persistent viremia (Maldarelli et al. Science 345:179-183 2014; Simonetti et al. PNAS 113:1883-1888 2016) indicated that at least some members of clonal populations can express HIV unspliced RNA during ART and may therefore result in rebound viremia if ART is interrupted. We hypothesized that the majority of infected cells that persist in individuals on ART have undergone clonal expansion and are composed of members that express HIV RNA. To test this hypothesis we examined HIV expression levels in single cells in both treated and untreated individuals using our single-cell HIV cell-associated RNA and DNA single-genome sequencing (CARD-SGS) method (Wiegand et al. PNAS 114:E3659-E3668 2017). We determined the fraction of HIV proviruses within infected cell clones that express HIV unspliced RNA during ART (Musick et al. Front. Microbiol. 10:2204 2019). In total 34 different clones carrying either intact or defective proviruses were assessed. We found that about 3% of cells within clones contained HIV unspliced RNA. Highest levels of HIV RNA were found in the effector memory T-cell subset. The fraction of cells within clones that contained HIV RNA was not different in clones with intact (median 2.3%) vs. defective (median 3.5%) proviruses (p=0.2). However higher fractions and levels of RNA were found in cells with proviruses containing multiple drug resistance mutations including those contributing to rebound viremia. These findings show that the vast majority of HIV-1 proviruses within expanded T-cell clones including intact proviruses may be transcriptionally silent at any given time implying that infected T cells may be able to be activated to proliferate without inducing the expression of the integrated provirus or alternatively may be able to proliferate without cellular activation. ____ACCOMPLISHMENTS: We previously reported a replication-competent HIV variant that is produced by a highly expanded cell clone and persists in the plasma of an HIV-infected donor treated with ART (Simonetti et al. PNAS 113:1883-1888 2016). In 2020 we expanded this case study to 5 additional donors with their viremia suppressed on ART and demonstrated that clones carrying and expressing replication-competent HIV are common among donors (Halvas et al. J. Clin. Invest. 130:5847-5857 2020). To follow up on the hypothesis that cells may differentiate and proliferate without inducing the expression of the integrated provirus we sorted PBMCs collected from patients with viremia fully suppressed on ART into resting (DR-) and activated (DR+) subsets. We isolated single infected cells from the subsets and measured the fraction that have HIV RNA and the levels of HIV RNA in each of the single cells. Our data show that the fraction and levels of HIV RNA are not different in the resting and activated cells indicating that infected cells that persist on ART are able to maintain proviral latency despite proliferation and activation (Groebner et al. Conference on Retroviruses and Opportunistic Infections 2021). The results of this study are currently being assembled into a manuscript. _____Because our previous studies showed that only a small fraction of infected cells that persist on ART have proviruses that are transcriptionally active we hypothesized that the HIV promotor in the 5' untranslated region may contain CpG islands that are DNA methylated. Such methylation may prevent the expression of the HIV provirus by inhibiting the binding of the HIV transcription factors. To test this hypothesis we isolated single HIV proviruses that were previously shown to be transcriptionally silent in vivo treated them with bisulfate to deaminate unmethylated CpG islands and quantified the number of guanines that retained their animation (indicating that they were methylated). Although we found CpG islands within HIV coding regions that were methylated we rarely identified methylated guanines within the HIV promotor of transcriptionally silent proviruses. Our findings show that methylation of the HIV promotor is not a mechanism for HIV persistence. We published these findings in Viruses in 2021 (Boltz et al. Viruses 13:799. 2021). ___Since methylation of the HIV promoter was not found to be a mechanism for HIV latency in donors on ART we investigated the expression of an antisense gene (Ast) encoded within the HIV env gene (Sklutuis et al. Conference on Retroviruses and Opportunistic Infections 2022). In vitro studies showed that HIV encodes an antisense gene that recruits and retains EZH2 a component of the polychrome repressor complex-2 (PRC2) to the HIV-1 5'LTR. EZH2 catalyzes the trimethylation of lysine 27 on histone H3 a suppressive epigenetic mark that promotes nucleosome assembly and suppresses of HIV-1 transcription. This mechanism suggests that Ast acts as a lncRNA in promoting epigenetic silencing of the HIV-1 5'LTR to induce and maintain viral latency in HIV infected cells. To address these findings our laboratory explored the expression levels of Ast in single infected cells isolated from donors with viremia suppressed on ART using digital reverse transcription PCR. We found a median of 26 copies of HIV Ast per 100 PBMCs at a given point in time. This finding confirmed the presence of detectable Ast levels in donors with their viremia suppressed on ART and suggests its potential role as a regulatory RNA. The results of our Ast study are being prepared for publication. ____ In the absence of ART levels of plasma viremia vary in people living with HIV (PLWH). What determines levels of plasma viremia within individuals is not fully understood but is likely associated with levels of proviral expression immune-control and viral fitness. More than 90% of PLWH have limited natural control of HIV-1 replication without ART (non-controllers); however a small fraction of PLWH (5%) naturally control levels of HIV-1 replication which is reflected by lower levels of plasma viremia (controllers). However using the CARD-SGS assay (described above) our data reveal that there is not a higher fraction of infected cells with transcriptionally active proviruses in non-controllers compared to viremic controllers (determined by measuring levels of unspliced HIV-1 RNA in single infected cells). Rather there are fewer total infected cells in viremic controllers. These findings suggest that natural control of HIV replication is not due to a higher fraction of latently infected cells in these individuals but is due to more potent immune responses (i.e. NK cell and/or CTL responses) that efficiently recognize and kill infected cells that express HIV RNA. This work was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) and a manuscript was submitted and is currently under peer review. Our future studies will characterize the immune responses in HIV controllers and non-controllers. 834522 +No NIH Category available Adult;Adult Glioma;Affect;Ally;American;Apoptosis;Area;Astrocytoma;Basic Science;Biopsy;Brain Neoplasms;Breeding;CCR;California;Canis familiaris;Catalogs;Cell Line;Central Nervous System;Characteristics;Childhood Glioma;Classification;Classification Scheme;Clinical;Clinical Trials;Collaborations;Companions;Comparative Pathology;Consensus;Data;Data Commons;Development;Diagnosis;Discipline;Disease;Early Diagnosis;Enrollment;Event;Excision;Expression Profiling;Extramural Activities;Face;Freezing;Funding;Future;Genomics;Glass;Glioma;Goals;Grant;Group Structure;Hematoxylin and Eosin Staining Method;Histologic;Histology;Histopathology;Human;Illinois;Image;Immunotherapeutic agent;Incidence;Income;Informatics;Infrastructure;Institution;Internal Medicine;Joints;Journals;Knowledge;Link;Magnetic Resonance Imaging;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Manuscripts;Medicine;Methylation;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;National Center for Advancing Translational Sciences;National Heart Lung and Blood Institute;Nature;Neurologist;Neurology;Oncology;Operative Surgical Procedures;Outcome;PAC1 phosphatase;Paper;Pathologic;Pathology;Patient Care;Patients;Physicians;Pituitary Neoplasms;Play;Positron-Emission Tomography;Pre-Clinical Model;Prevention;Procedures;Process;Publications;Publishing;Radiology Specialty;Reporting;Research;Research Personnel;Role;Slide;Specialist;Stains;Surveys;TP53 gene;Texas;The Jackson Laboratory;Time;Tissues;Training;United States National Institutes of Health;Universities;University of Minnesota Cancer Center;Update;Veterinarians;Veterinary Medicine;cancer cell;college;comparative;disease natural history;drug development;drug discovery;exome sequencing;experience;glioma cell line;high-throughput drug screening;human disease;human model;imaging agent;improved;improved outcome;interest;irradiation;meetings;member;meningioma;neuro-oncology;neuropathology;novel;oligodendroglioma;oncology program;pharmacologic;prospective;small molecule;statistics;stem cells;transcriptome sequencing;tumor;ultrasound;working group Comparative Brain Tumor Consortium n/a NCI 10926276 1ZIABC011696-08 1 ZIA BC 11696 8 14280471 "LEBLANC, AMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 113840 NCI The COP has made significant progress on the inaugural comparative pathology effort for this new initiative in 2018 with a publication currently in review at the Journal of Neuropathology and Experimental Neurology. The pathology board consisting of a joint veterinary/physician neuropathology commission of 14 members developed an updated grading and classification scheme for canine gliomas to promote uniformity in diagnosis across institutions and improve making comparisons with human adult and childhood gliomas. A retrospective pathologic assessment of approximately 200 hematoxylin and eosin stained glass slides + a panel of 5 IHC markers treatment-naive canine gliomas of all subtypes and grades has been conducted. The CBTC membership has also proposed genomic analyses and expression profiling of a minimum of 50 canine high-grade gliomas meeting these newly revised classification criteria to allow for comparison with human adult and childhood gliomas and to generate potential pharmacologic targets for canine patients. This project will be both retrospective and prospective in nature. For the retrospective portion snap-frozen tissue from institutions with paired banked FFPE tissue from histopathology-confirmed glial tumors that have been confirmed within the newly proposed grading and classification scheme will be subjected to whole-exome sequencing and RNA-seq. For the prospective portion CBTC members (Texas A&M University/MD Anderson Cancer Center University of Minnesota and University of Califnornia @ Davis) have partnered with Roel Verhaak at the Jackson laboratory. Dr Verhaak is working with these CBTC members whom have received NCI funding through a P30 CC supplemental mechanism to generate molecular profiles from an overlapping set of canine gliomas which will include WGS/WES/RNAseq and methylation profiling data. Sequence information was subjected to informatics processed and shared publicly through the NCI Integrated Canine Data Commons (ICDC) and published in Cancer Cell. We have also initiated several other projects in this area which are listed here: 1. Whole-exome and RNA sequencing of n = 100 canine meningiomas (in collaboration with Peter Dickinson at UC-Davis M. Renee Chambers at UAB and Greg Tawa/NIH/NCATS 2. Survey instrument to veterinary neurologists in the US to capture the clinical landscape of canine brain tumor management 3. High-throughput drug screening of P53 w/t canine and childhood glioma cell lines 4. A clinical trial of a novel capsize-3 activating small molecule (PAC-1) in dogs with meningioma which is linked to assessment of a novel apoptosis-reporting PET imaging agent (in collaboration with NHLBI/IPDC NCI/CCR/MIP and University of Illinois. 5. MRI consensus statement on harmonization of imaging parameters for dogs enrolled in brain tumor clinical trials (manuscript published in Veterinary Radiology and Ultrasound). New projects proposed for 2018- beyond include: a companion comparative histologic and molecular characterization project in canine meningioma; extension of the HTS project with NCATS to include 5 new canine glioma stem cell lines generated at Univ of CA-Davis and a bi-monthly WebEx to offer continuing exchange of ideas and projects among interested CBTC members. 113840 +No NIH Category available Address;Adjuvant;Adolescent;Adult;Adverse event;Age;Agonist;Aliquot;Amputation;Animal Testing;Antineoplastic Agents;Area;Back;Biological;Biological Assay;Biological Markers;Biological Models;Biological Specimen Banks;Biology;Brain Neoplasms;Breeding;Cancer Biology;Cancer Model;Cancer Patient;Canis familiaris;Carboplatin;Cell Line;Characteristics;Child;Childhood;Childhood Osteosarcoma;Clinical;Clinical Data;Clinical Trials;Collaborations;Collection;Companions;Complex;Conduct Clinical Trials;DNA;DNA Resequencing;DNA Sequence Alteration;DNA copy number;DNA sequencing;Data;Databases;Decision Making;Development;Disease;Drug Combinations;Drug Targeting;Early treatment;Engraftment;Event;Extramural Activities;Formalin;Freezing;Future;Gene Expression;Genes;Genome;Genomics;Goals;Growth;Health;Human;Human Cell Line;In Vitro;Infrastructure;Inherited;Investigation;Knowledge;Laboratories;Libraries;Link;Malignant Bone Neoplasm;Malignant Neoplasms;Metastatic Neoplasm to the Lung;Mission;Modeling;Molecular;Multi-Institutional Clinical Trial;Mus;National Center for Advancing Translational Sciences;Natural History;Neoplasm Metastasis;Normal tissue morphology;Oncogenes;Outcome;Pathologist;Pathology;Pathway interactions;Patients;Pediatric Neoplasm;Pharmaceutical Preparations;Phase;Physicians;Planet Mars;Positioning Attribute;Pre-Clinical Model;Preclinical Drug Development;Preclinical Testing;Primary Neoplasm;Process;Progression-Free Survivals;Proteomics;Publishing;Puma;RNA;Rapid screening;Reagent;Research Design;Resource Development;SNP array;Sampling;Single Nucleotide Polymorphism;Sirolimus;Specimen;Techniques;Testing;Toxicity Tests;Toxicogenomics;Translating;Treatment Failure;Treatment Protocols;Tumor stage;Work;Xenograft procedure;anticancer research;arm;assay development;cancer clinical trial;cancer type;central database;chemotherapy;clinical application;cohort;comparative;comparative genomic hybridization;demographics;design;dog genome;drug development;drug efficacy;exome;exome sequencing;experimental study;genome-wide;improved;improved outcome;in vivo;in vivo Model;inhibitor;innovation;laboratory experiment;mouse model;neglect;new therapeutic target;novel therapeutic intervention;novel therapeutics;oncology program;osteosarcoma;pre-clinical;preservation;programs;repository;sarcoma;screening;standard of care;success;transcriptome sequencing;translation to humans;treatment response;tumor Comparative Oncology Program Laboratory n/a NCI 10926275 1ZIABC011692-08 1 ZIA BC 11692 8 14280471 "LEBLANC, AMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2049125 NCI Laboratory activities and projects carried out by the COP laboratory have the specific goal of improving the understanding of the impact of anti-cancer agents on comparative aspects of metastasis biology by virtue of parallel study of murine canine and human cell lines in a variety of in vitro ex vivo/in vivo (Pulmonary Metastasis Assay or PuMA) model systems. Data generated in this manner improves understanding of naturally-occurring canine osteosarcoma (OS) models and could be employed to answer unique in vivo questions regarding the anti-metastatic potential of agents via the COTC clinical trial mechanism. To extend our investigations into the comparative aspects of naturally-occurring OS in dogs to humans we have recently initiated the DOG2 project: Decoding the Osteosarcoma Genome of the Dog. The DOG2 project fulfills the main mission of the NCI-COP which is to strategically position the canine cancer patient in studies of cancer biology and drug development in order to improve outcome for both dogs and humans. The COP has a longstanding focus in osteosarcoma (OS) biology and clinical trials. OS is an aggressive pediatric/AYA malignancy and the most common malignant bone tumor in children and adolescents. OS is also a common naturally-occurring canine cancer with strikingly similar clinical presentation and natural history; preliminary studies suggest a shared molecular landscape. While dogs largely develop OS in adulthood the similar genomic features and clinical disease characteristics underscore the notion that age does not distinguish canine OS from the disease in children. We recognize that osteosarcoma is a complex disease and success is unlikely with a single approach. Therefore to expand this work it is necessary to identify additional targets and drugs. Collectively this work is designed to address the following strategic priorities: 1. Improved knowledge of comparative OS cancer biology to enhance dog to human translation 2. Discovery of new targets and companion biomarkers in support of drug development 3. Assessment and prioritization of new therapeutic strategies in preclinical models 4. Harmonization of comparative canine and human oncology clinical trials to advance new therapeutic concepts Biospecimens. We will utilize an existing high-quality clinically-annotated biospecimen repository of 400 canine OS patient sample sets unique to the NCI gathered from ongoing and completed canine OS clinical trials. This repository contains multiple aliquots of both tumor and matched normal tissues preserved as frozen RNAlater and formalin-fixed specimens. Samples have been derived from treatment-naive dogs that all underwent the same treatment protocol (amputation + 4 cycles of carboplatin chemotherapy). We have full clinical data on every patient including demographics treatment details/adverse events and event-free and overall survival. We propose beginning with a subset of n = 100 patient samples selected from the ends of a Kaplan-Meier curve that represent early treatment failures (progression-free survival less than 90 days) vs. elite responders (progression-free survival greater than 360 days). We will also query n = 25 matched pairs of tumors with their metastases that developed despite therapy. We have not attempted to perform viability testing for PDX engraftment in NSG mice due to the technical challenges and low rate of metastasis associated with PDXs; rather we use 4 unique canine OS cell lines developed in our lab for dog-in-mouse preclinical testing and are in the process of creating and curating a collection of over 25 additional canine OS cell lines from extramural collaborators. All specimens will be subjected to pathology review by an expert board of veterinary and physician sarcoma pathologists to verify adequate sample quality for further genomic study. For genomic profiling we will employ the following platforms to execute a combination of experiments to understand relationships between genomic complexity and integrity (CGH and WES to identify structural rearrangements single nucleotide variants copy number gain/loss) and gene expression (through RNAseq). The specific breed of dog will be verified through use of a germline SNP array recently made available through MARS/Wisdom Health. Samples for genomic profiling will be sent to our collaborator at NCSU (Matthew Breen) for DNA and RNA isolation library prep CGH for genome-wide DNA copy number profiling (Agilent CGH array) and for DNA whole exome sequencing (150b paired end reads at 100x for tumors/30x for normal NovaSeq6000 platform with Roche dog exome kit) methyl-DNA resequencing as well as RNA sequencing (125b paired end reads Illumina HiSeq2500 platform). Computational approach. This project is an extension of an existing collaboration with NCSU and the NCATS Division or Preclinical Innovation (DPI) and Therapy for Rare and Neglected Diseases (TRND) program. Through experiments we have already conducted in n = 12 canine OS sample sets similar to those described above as a discovery cohort the TRND bioinformaticians have developed a strategy that identifies distinct gene co-expression models between and specific to a set of 5 selected canine cancer types of which OS is one from which they derive cancer-specific gene panels. A similar analysis is performed on existing RNAseq data publicly available from human tumor samples from the same tumor types to produce cancer-specific human gene panels. These cancer-specific shared gene panels are compared and genes common to both are retained to facilitate dog-to-human translation of genomic alterations. The RNAseq data after alignment to reference is then compared back to CGH and whole-exome DNA sequencing carried out in the same tumor sample to identify genomic changes (CNV SNV) that are linked to expression changes and that may represent new druggable targets. These oncogenes or other drug targets in given pathway(s) were used to identify inhibitors suppressors or agonists utilizing Pharos which interfaces to a central database containing information about the targets collected by the Illuminating the Druggable Genome (IDG) program and the Comparative Toxicogenomic Database (CTD). This combined experimental/computational approach has already been tested using both proteomic and RNAseq data generated from the first n = 12 OS tumor/normal pairs. The data has been analyzed at NCATS to match changes in gene expression to drugs known to modulate the pathways associated with the associated genes. Canine OS cell line screening is already underway through NCATS to determine the in vitro impact of 40 drugs including 30 synergistic combinations based on the respective drugs' pathway modulation profile. These data serve as a proving ground for additional work carried out in a larger outcome-linked collection of tumor samples proposed herein. Single agents or combinations of drugs identified in Phase I will be tested in our existing panel of human and canine OS cell lines and screened rapidly through available xenograft human-in-mouse and canine-in-mouse models within the COP laboratory. This preclinical animal testing is critical to ranking and advancing appropriate candidates for further study and to understand the comparative features of how drugs behave in our in vivo models. We have expertise in both primary tumor and metastasis modelling to evaluate drug impact at several stages of tumor development and progression. These results will be the basis (go/no go decision making) for canine comparative oncology clinical trials to test the toxicity and efficacy of the drug combinations in vivo. Drug combination candidates that perform well in canine clinical trials would then be considered for human trials. 2049125 +No NIH Category available Antibodies;Antibody-drug conjugates;Bioinformatics;Colorectal Cancer;Critical Pathways;Dependence;Development;Drug Targeting;Enzymes;Genetic;Genomic approach;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;KRAS2 gene;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of ovary;Modality;Molecular;Oncogenic;Phosphotransferases;Play;Role;Small Interfering RNA;Squamous cell carcinoma;Structural Models;Therapeutic Intervention;anticancer research;functional genomics;genome editing;inhibitor;lung tumorigenesis;malignant breast neoplasm;mutant;novel;novel therapeutics;precision drugs;screening;targeted treatment;tumorigenesis Oncogenic Kinases in Cancer n/a NCI 10926274 1ZIABC011691-08 1 ZIA BC 11691 8 14731989 "BROGNARD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1809446 NCI The lab utilizes a multitude of strategies to identify critical pathways required to promote tumorigenesis. These include high-throughput bioinformatics and structural modelling siRNA screening and precision genome editing to establish various functional genomic approaches to identify novel drivers. Utilizing bioinformatics we identify novel kinases enriched for copy number alterations to hone in on activated enzymes that can serve as drug targets. We are focused on novel drivers of the 3q amplicon that play a critical role in promoting tumorigenesis in lung squamous cell carcinoma head and neck cancer and ovarian cancer (Torres-Ayuso et. al. Cancer Discovery Edwards et al. Cancer Research). These novel drivers can serve as targets of therapeutic intervention and an intense effort will be focused on the mechanisms by which these amplified kinases promote tumorigenesis. In addition we are studying a novel kinase target that represent a genetic dependency in KRAS mutant lung adenocarcinomas (Hoang et al. JBC). Lastly we are developing novel antibody-precision drug conjugates (APDCs) to co-target multiple kinase drivers in head and neck Breast Esophageal and colorectal cancer. 1809446 +No NIH Category available Alleles;BRAF gene;Biochemical;Bioinformatics;Biological Assay;Communities;Critical Pathways;Cultured Cells;Dependence;Development;Genetic;Genomic approach;Goals;Human;Knowledge;Malignant Neoplasms;Molecular;Monitor;Mutation;Oncogenic;Pathway interactions;Patients;Phenotype;Phosphotransferases;Pongidae;Process;Research;Small Interfering RNA;Somatic Mutation;Structural Models;cancer genomics;driver mutation;drug development;functional genomics;functional restoration;genome editing;in vivo;loss of function;loss of function mutation;mutant;novel;response;screening;targeted treatment;tumor;tumorigenesis Novel Tumor Suppressing Kinases in Cancer n/a NCI 10926273 1ZIABC011690-08 1 ZIA BC 11690 8 14731989 "BROGNARD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 95235 NCI Cancer genomic sequencing has significantly impacted our understanding of the temporal and spatial genetic alterations that lead to tumorigenesis. This information enables the development of targeted therapies that result in durable and less toxic responses in patients. In regard to kinases the biomedical community has focused research efforts on approximately 200 kinases among the 538 kinases present in the human kinome yet siRNA screens and cancer genomic studies indicate that the vast majority of these unexplored kinases (approximately 300) are implicated in cancer and harbour putative driver mutations. The major focus of my research will be to elucidate novel cancer-associated kinases in the unexplored kinome guided by bioinformatics and functional genomic approaches with an overarching aim of understanding the molecular mechanisms utilized by these kinases to promote tumorigenesis. The lab utilities a multitude of strategies to identify critical pathways required to promote tumorigeneis. These include high-throughput bioinformatics and structural modeling siRNA screening and precision genome editing to establish various functional genomic approaches to identify novel drivers. A completed focus for this project was to perform a motif driven pan-cancer analysis to elucidate the tumour suppressing kinome. This strategy utilities our knowledge of kinases and the requirement for certain kinase motifs to maintain activity (DFG HRD APE for example) and our screen has identified several novel kinases enriched for functional mutations. We will take these kinases further such as MYO3A to assess if this is a novel tumor suppressing kinase. We will study the kinases identified in these screens as follows: general strategy - to determine the functional consequences of somatic mutations in candidate cancer-associated kinases we will carry out a focused logical and stepwise process. We will begin with biochemical kinase assays and functional analysis by expression of WT (wild type) and mutant kinases in cultured cells progressing to utilize genome editing to correct mutant alleles and monitoring phenotypic impacts of restoring function of a tumor suppressing kinase moving on to in vivo tumorigenesis studies and finally investigating the mechanisms of action. Analysis of somatic mutations in a given kinase will only be continued if promising results are observed at each step. When this is not the case we will terminate studies on that kinase and proceed to the next top-tier kinase from our bioinformatic analysis. 95235 +No NIH Category available Acceleration;Affect;Anatomy;Binding;Biological Assay;CD4 Positive T Lymphocytes;Cell Survival;Cells;Cellular biology;Child;Clonal Expansion;Clone Cells;Collecting Cell;Data;Family;Frequencies;Genes;Genetic;Genetic Recombination;Genome;HIV;HIV Genome;HIV Infections;Interruption;Investigation;Length;Location;Malignant Neoplasms;Manuscripts;Memory;Meta-Analysis;Methods;Mutation;Patients;Play;Population;Preparation;Proliferating;Proteins;Provirus Integration;Proviruses;Publishing;Research;Role;Sampling;Science;Site;Source;Structure;T memory cell;T-Lymphocyte;T-Lymphocyte Subsets;Time;Tissues;Update;Viral;Viremia;Virion;Virus Replication;Zinc Fingers;antiretroviral therapy;cell type;coping;detection assay;follow-up;genome sequencing;homologous recombination;in vivo;integration site;lymph nodes;novel;pressure;public database;self-renewal;web page Dynamics and Genetics of HIV Proviruses before and during Antiretroviral Therapy n/a NCI 10926268 1ZIABC011681-08 1 ZIA BC 11681 8 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1001426 NCI BACKGROUND: We and others showed that HIV-infected cells can clonally expand and persist despite ART and that the proviral integration site may influence this phenomenon (Maldarelli et al. Science 345:179-183 2014; Wagner et al. Science 345:570-573 2014). A major focus of this project is to determine how commonly such clonally expanded infected cells that persist during ART carry replication-competent proviruses and in which tissues and cell types they persist. To answer this question we developed a novel method called the multiple-displacement amplification single-genome sequencing (MDA-SGS) assay which allows us to analyze the proviruses in highly expanded clones (Patro et al. PNAS 116:25891-25899 2019). The MDA-SGS assay will determine if HIV proviruses in expanded cell clones that persist during ART have intact sequences or contain lethal mutations or deletions. We will further determine if when activated such clones are capable of producing infectious virions. If we show that latent intact proviruses in infected cells commonly undergo clonal expansion it will mean that strategies intended to cure patients will have to not only block viral replication but also cope with the proliferation of these latently infected cells. ____ACCOMPLISHMENTS: We began our investigations of the HIV reservoir in children more than 4 years ago initially focusing on whether expanded infected cell clones were present in children born with HIV infection and if these cell clones persisted during ART (Bale Katusiime et al. mBio 12:e00568-21 2021). We found that infected T cell clones arose early in children (less than 2 months old) and that they persisted for at least 9 years during treatment. These findings demonstrated that the HIV reservoir in children is maintained by clonal expansion of cells that were infected prior to initiating treatment. We followed up on these efforts by investigating the proviral structures in the largest infected T cell clones in children on ART for more than 6 years and found them all to be solo LTRs (Botha et al. mBio in press). These findings are important because they suggest that homologous recombination of the HIV LTRs after integration may lead to the deletion of HIV genes leaving only an inactive remnant of what might have been a replication competent provirus contributing to the HIV reservoir. These findings suggest that LTR recombination may significantly contribute to reservoir decay over time on ART suggesting that a new curative strategy might be devised that exploits or accelerates LTR recombination. In a related ongoing study we have determined that naive T cells collected from children with HIV can harbor integrated proviruses sometimes in clonal populations and that in one instance the harbored provirus was sequence-intact. These findings change our understanding of both T cell biology and HIV persistence since the proliferation of infected naive cells may lead to a self-renewing pool of infected central and effector memory T cells. A manuscript describing these findings is in preparation. Another ongoing multifaceted effort toward genetically characterizing provirus populations utilizes samples from donors who have high levels of viremia on ART despite full suppression of viral. Notable findings produced in this ongoing in-depth analysis of these samples include the observation that sequence-intact proviruses are disproportionately found integrated into the intronic regions of genes encoding the KRAB family of zinc-finger proteins and that of the 10 largest infected T cell clones identified in these samples 6 are solo LTRs - supporting analysis of samples obtained from children with HIV. To facilitate these efforts we have recently devised and published a new combination provirus sequencing and integration site detection assay that permits more comprehensive provirus characterization that was previously possible (Joseph et al. J. Virol. e0012222 2022). 1001426 +No NIH Category available Address;Affect;Animals;Anorexia;Antibiotics;Antitumor Response;Autoimmunity;Blood;Bone Marrow;Cell Differentiation process;Cell physiology;Cells;Characteristics;Chronic;Cues;Dendritic Cells;Development;Diet;Distant;Embryonic Development;Epithelium;Experimental Neoplasms;Germ-Free;Goals;Homeostasis;Immune;Immune Evasion;Immune response;Immunity;Immunotherapy;Individual;Infection;Infiltration;Inflammation;Inflammatory;Innate Immune Response;Invaded;Lymphoid;Lymphoid Tissue;Macrophage;Maintenance;Malignant Neoplasms;Mammals;Metabolic;Metabolism;Modeling;Molecular;Mononuclear;Mus;Myelogenous;Myeloid Cells;Natural Immunity;Nature;Neoplasm Metastasis;Neutrophil Infiltration;Obesity;Outcome;Pathologic;Pathway interactions;Peripheral;Phagocytes;Phenotype;Play;Population;Population Control;Predisposition;Regulation;Resistance;Resolution;Role;Science;Signal Transduction;Surface;System;T-Lymphocyte;Tissues;Transcriptional Regulation;Tumor Immunity;Tumor Promotion;Virus Diseases;adaptive immune response;adaptive immunity;angiogenesis;anti-cancer;cancer cachexia;cancer therapy;chemotherapy;clinically relevant;commensal bacteria;commensal microbes;comorbidity;dietary manipulation;gut microbiota;improved;microbiota;monocyte;neutrophil;novel;novel therapeutic intervention;pathogen;response;subcutaneous;systemic inflammatory response;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression Role of the microbiota in regulating the mononuclear phagocyte system n/a NCI 10926265 1ZIABC011670-09 1 ZIA BC 11670 9 78355387 "GOLDSZMID, ROMINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1307792 NCI Mononuclear phagocytes MPs play crucial roles in the initiation of innate and adaptive immune responses and in the maintenance of tissue homeostasis. Although MPs share several phenotypic and functional characteristics it has recently become clear that dendritic cells (DC) macrophages (Mac) and monocytes (Mo) are not homogeneous populations and instead they represent developmentally and functionally distinct populations that differentially regulate T cell function. MPs are major components of the tumor microenvironment where they play a dual role inducing adaptive anti-tumor responses but also sustaining immune evasion tumor progression and metastasis formation. Despite major advances in the identification of the MPs developmental pathways and their transcriptional regulation the individual contribution of these distinct cell subsets to the induction and resolution of immunity against invading pathogens or to anti-tumor responses or immune evasion as well as the environmental signals involved in their regulation remain unclear. In this project we will use murine experimental tumor models to investigate the mechanisms regulating MP differentiation and function with particular emphasis on the role of the commensal microbiota. Local and systemic inflammation modulates cancer susceptibility (e.g. in obesity) cancer progression response to therapy and co-morbidity (e.g. cancer cachexia/anorexia). The microbiota influences both immune and metabolic function beyond the gut including peripheral innate cell responses autoimmunity and response to viral infections. In recent studies we have shown that gut commensals control the response of subcutaneous tumors to immunotherapy and chemotherapy by modulating tumor infiltrating MP function (Science 2013 342:967-970). This study demonstrates the novel finding that and intact gut microbiota is needed for optimal response to cancer therapy and underscores the potential to improve cancer treatment by manipulating the gut microbiota. However the exact molecular mechanisms by which commensal bacteria modulate systemic inflammation are still unknown. We use several approaches to address this question performing parallel studies in cancer and infection models. We utilize the germ-free (GF) facility at NCI-Frederick to compare conventionally reared GF animals or animals treated with different antibiotics or given different diets to modulate the microbiota composition either under steady state or different inflammatory settings. We have characterized the innate myeloid and lymphoid infiltrate in several tumor models in the presence or absence of intact microbiota. Our results showed that in the absence of an intact microbiota there is a skewing of myeloid cell differentiation towards a pro-tumoral phenotype. We have shown that these changes occur specifically in the tumor and are not observed in the bone marrow blood or peripheral lymphoid tissues. Importantly we have identified the cellular and molecular pathways involved and we have shown that dietary manipulation of the microbiota can trigger the same pathways to improve anti-cancer immunity. We are currently extending these studies to interrogate the role of microbiota in metastasis formation. In parallel studies we are dissecting the role that individual myeloid cell population play in response to cancer therapy. We demonstrated that neutrophils are required for the optimal response to chemotherapy showed that tumor-infiltrating neutrophils are highly heterogeneous and phenotypically and functionally distinct from circulating neutrophils. We have also shown that microbiota-derived signals regulate neutrophil dynamics in the TME and we have identified a clinically relevant bacterial-derived molecule capable of restoring neutrophils function in microbiota-depleted animals. In a different set of studies we are addressing the role of different myeloid cell populations in tumor progression. In particular we are studying the dynamics of the monocyte/macrophage compartment during chronic inflammatory conditions and how they impact tumor growth. 1307792 +No NIH Category available Antigens;CAR T cell therapy;CD28 gene;Cell Culture Techniques;Chimeric Proteins;Clinical;Clinical Protocols;Clinical Trials;Development;Generations;Goals;Hodgkin Disease;Human;Immune response;In Vitro;Ki-1 Large-Cell Lymphoma;Large-Cell Lymphomas;Lentivirus Vector;Lymphoma;Manuscripts;Methods;Modeling;Mus;Patients;Phase I Clinical Trials;Proteins;Reporting;Risk;Series;T-Cell Activation;T-Lymphocyte;TNFRSF8 gene;Testing;Toxic effect;Transmembrane Domain;Work;chimeric antigen receptor;chimeric antigen receptor T cells;design;human tissue;improved;large cell Diffuse non-Hodgkin's lymphoma;novel therapeutics;pre-clinical;receptor;response;tumor Development of fully-human anti-CD30 chimeric antigen receptors n/a NCI 10926262 1ZIABC011660-09 1 ZIA BC 11660 9 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 156091 NCI We designed 4 different single chain Fv molecules as antigen-recognition domains for anti-CD30 CARs and compared CARs with these different scFvs in vitro. We selected the optimal scFv and tested it in different CAR designs in vitro and in mouse tumor models. We have identified an optimal scFv and CAR design for further development. This work led to 2 CARs that are both highly effective in mice. We have selected one of these CARs for a phase I clinical trial. Simultaneous work has been completed that has led to generation of a clinical-grade lentiviral vector encoding this CAR. We completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR. We have completed preclinical work to improve anti-CD30 CAR design and T-cell culture methods with an emphasis on comparing different hinge and transmembrane domains as well as comparing CD28 versus 4-1BB costimulatory domains . A clinical trial of T cells expressing an anti-CD30 CAR has opened and we have treated 21 patients on this trial. Unfortunately the longest objective duration of response in these patients has been only 3 months. We have ended this clinical trial of anti-CD30 CAR T cells due to toxicity plus lack of efficacy and now we are preparing a manuscript to report the results. 156091 +No NIH Category available Acceleration;Acute Graft Versus Host Disease;Allogeneic Bone Marrow Transplantation;Antigens;Bone Marrow Transplantation;Cell Therapy;Clinical;Clinical Research;Clinical Trials;Communities;Cyclophosphamide;Development;Dose;Engineering;Engraftment;Enrollment;Ensure;Funding;Goals;HLA Antigens;Hematologic Neoplasms;Hematology;Hematopoietic;Human;Immune;Immunologics;Institution;Laboratories;Laboratory Research;Major Histocompatibility Complex;Mixed Lymphocyte Culture Test;Modeling;Modification;Mus;Non-Malignant;Outcome;Patient-Focused Outcomes;Patients;Phase;Prevention;Process;Protocols documentation;Publishing;Recovery;Relapse;Risk Reduction;Siblings;Study models;T-Lymphocyte;Time;Toxic effect;Translating;Translations;Transplant-Related Disorder;Transplantation;Work;clinical efficacy;clinical translation;cohort;conditioning;graft vs host disease;improved;improved outcome;interest;mouse model;novel strategies;pharmacokinetic model;post-transplant;prevent;standard of care;stem;transplant model Deciphering the efficacy of posttransplant cyclophosphamide in BMT n/a NCI 10926261 1ZIABC011659-09 1 ZIA BC 11659 9 14280085 "KANAKRY, CHRISTOPHER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2301775 NCI Over the past several years we have been using our murine transplant models to dissect the mechanisms underlying the efficacy of PTCy and have found that these diverge widely from the prior dogma in the field. We are actively working across several projects to better define a new mechanistic model which will inform rational translation of new approaches or modifications to improve outcomes for patients. Indeed in the course of these studies we have determined that the optimal dose of PTCy is an intermediate dose rather than a very high dose. We have now completed enrollment of the primary cohort of a phase I/II study that has shown that reduced dosing PTCy allows for excellent prevention of acute GVHD while allowing lower early transplant-associated toxicity and better hematopoietic and immune recovery and function. Pharmacokinetic modeling studies accompanying this trial are funded by an R01. We have three other clinical trials that are accruing that are stemming from the work performed in the laboratory with two of these studies being multi-institutional to accelerate the development and execution of these studies and draw on the interest in this work within the broader transplant community. Our goals with these clinical studies and ongoing laboratory research are to use our developing understanding as a basis to explore how to refine this BMT approach clinically towards the clinical goals of further reducing graft-versus-host disease ensuring reliable engraftment with minimal conditioning and serving as a platform for other therapies to reduce relapse. We also are exploring the impact of PTCy on human T cells in mixed lymphocyte cultures with the goal of improving our understanding of the immunologic impact of PTCy in order to improve clinical outcomes. Lastly we have been working over the past 6 years on a way of integrating engineered antigen-specific cellular therapies safely and effectively with haplo BMT using PTCy in our murine models whcih was published in 2023. We are now developing a protocol to clinically translate this approach and expect within the next 12 months to have this clinical study open. 2301775 +No NIH Category available 3-Dimensional;Antineoplastic Agents;Bioinformatics;Biology;Biopsy;Cell model;Cells;Characteristics;Chemicals;Chemistry;Chest;Clinical;Collaborations;Complex;Databases;Development;Diagnosis;Drug Targeting;Epigenetic Process;Evaluation;Feedback;Film;Future;Genes;Genomics;Goals;Human;Hydrogels;In Vitro;Induction of Apoptosis;Interdisciplinary Study;Investigation;Legal patent;Malignant Neoplasms;Malignant Pleural Mesothelioma;Malignant neoplasm of thorax;Membrane;Mesothelial Cell;Mesothelioma;Methods;MicroRNAs;Modeling;Molecular;Non-Small-Cell Lung Carcinoma;Nucleic Acids;Organ;Outcome;Pathogenicity;Pathway interactions;Patients;Peptides;Performance;Pharmaceutical Preparations;Phenotype;Pleura;Pleural;Prognosis;Regimen;Reporting;Research;Research Project Grants;Surface;Surveys;System;Systems Biology;TP53 gene;Techniques;Testing;Therapeutic;Thinness;Thymus Epithelial Neoplasm;Time;Tissues;Translating;Translational Research;Untranslated RNA;Xenograft procedure;anti-cancer;biomarker discovery;bioprinting;cancer cell;cancer type;cell type;combinatorial;human tissue;in vivo;innovation;insight;interest;knowledge base;manufacturing scale-up;materials science;method development;nanoparticle;nanoscale;neoplastic cell;next generation;novel;novel drug class;preclinical development;preclinical study;response;small molecule;therapeutic candidate;therapeutic miRNA;transcription factor;tumor;tumor initiation;tumorigenesis microRNA-based and novel molecular therapeutics in thoracic cancers n/a NCI 10926260 1ZIABC011657-09 1 ZIA BC 11657 9 14280083 "HOANG, CHUONG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1867997 NCI "This project continues to be developed. We are performing bioinformatic analyses to survey genomic databases of mesothelioma to infer microRNA and transcription factors regulatory pairings (in a feedback loop circuit or other relevant motif) of high significance. We are systematically testing the functional relevance of such circuits in vitro and validating phenotypic consequences in vivo. Several candidate microRNA associated with and biologically active in mesothelioma have been reported from our lab with several more in the pipeline. To translate this body of work we have developed a clinical delivery platform based on peptide nanoparticle-hydrogel composite material that can effectively deliver microRNA to tumor cells (in vivo mesothelioma models). Refinements are being made to optimize efficacy and performance characteristics (e.g. scale-up manufacturing) of this hydrogel-based system. We are branching out application of this delivery system to test other nucleic acids-type cargos (non miRNA). New groundwork is established to create the next generation mesothelial cell model for mesothelioma oncogenesis investigation using 3D bioprinting techniques. In this new model construct we are using multiple cell types derived from human tissues to reconstruct the equivalent of ex-vivo pleural membrane ""organs""." 1867997 +No NIH Category available Abdominal Cavity;Affinity;Agonist;Antibodies;Antibody Therapy;Bacterial Toxins;Binding;Blood;Blood Vessels;Blood specimen;Camels;Cancer Patient;Capillary Leak Syndrome;Cell Line;Cell surface;Cells;Cholangiocarcinoma;Clinical Research;Clinical Trials;Collaborations;Correlative Study;Data Analyses;Deposition;Development;Disease;Dose Limiting;Engineering;Goals;Heart;Hour;Human;Immune;Immune response;Immune system;Immunocompetent;Immunotoxins;Impairment;Interleukin-15;Journals;Lung;Lymphocyte;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Manuscripts;Mediating;Medical;Medicine;Membrane;Modeling;Mus;Neoplasm Metastasis;Normal Cell;Paclitaxel;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Participant;Pathway interactions;Patients;Penetration;Peritoneum;Persons;Pharmaceutical Preparations;Phase;Phase I/II Clinical Trial;Physiology;Precision therapeutics;Proteins;Publications;Publishing;Reaction;Recombinants;Role;Shark;Solid Neoplasm;Testing;Therapeutic;Therapeutic Uses;Toxic effect;Transforming Growth Factor beta;Tumor Antigens;Work;advanced disease;antagonist;cancer cell;cell killing;chemotherapy;cytokine;design;fighting;first-in-human;inhibitor;meetings;mesothelin;mouse model;nanobodies;novel;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;participant enrollment;patient response;peripheral blood;phase 1 study;research clinical testing;response;safety testing;therapy resistant;treatment response;tumor;tumor microenvironment;wound healing Precision Therapy to Target Pancreatic Ductal Adenocarcinoma n/a NCI 10926259 1ZIABC011652-09 1 ZIA BC 11652 9 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 682524 NCI "GOAL A (ongoing)- Role of MSLN in PDAC. MSLN is the target of many therapeutics being tested in clinical trials including LMB-100 but little is understood about the effect of MSLN on PDAC aggressiveness and therapeutic resistance. We have previously found that loss of MSLN impairs the ability of PDAC to colonize the peritoneum and cause metastasis there. MSLN loss from cancer cells impaired the establishment of blood vessels to the new tumor deposits. In FY23 we are specifically investigating whether shed MSLN is responsible for increased metastatic efficiency or whether membrane-bound MSLN is more important in metastasis promotion. Importantly our previous work has been performed with human PDAC cell lines using immune-suppressed mice as hosts. However MSLN has previously been shown to interact with macrophages in the immune system and can be recognized by tumor-fighting lymphocytes in the peripheral blood of PDAC patients. In collaboration with Serguei Kozlov (NCI/CAPR) we developed new immune-competent PDAC models with MSLN loss to better understand the role of MSLN in this context. During FY23 we have continued to investigate the pathways contributing to PDAC metastasis in these models. We hope to submit our work for publication during FY24. GOAL B (clinical trial complete data analysis ongoing)- LMB-100/ tofacitinib clinical testing. The clinical study ""A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with Tofacitinib in Persons with Previously Treated Pancreatic Adenocarcinoma Cholangiocarcinoma and other Mesothelin Expressing Solid Tumors"" (PI Alewine) was closed to accrual in 1/2021 due to toxicity and our results have been published in abstract form at national meetings. We are continuing to analyze the results of correlative studies examining the patient immune response to treatment. Manuscript submission is anticipated late FY23 or FY24. GOAL C (complete)- Patient immune response to LMB-100 treatment. We analyzed patient blood samples collected during accrual of ""A Phase Ib/II Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with Nab-Paclitaxel in Participants with Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma"" (PI Alewine) to identify cytokine and immune cell changes that accompany 1) patient response to treatment and 2) significant capillary leak syndrome (the dose-limiting toxicity of LMB-100/ nab-paclitaxel combination). We found that the patient who achieved an objective response to iTox treatment had large increases in immune cells that can fight cancer following the treatment while other patients did not. Moreover patients who would go on to develop significant capillary leak syndrome had increases in specific cytokines within hours of LMB-100 administration suggesting that this toxicity was caused by immune response to the iTox. These findings were published in the journal Cancer Medicine in 2023. GOAL D (newly initiated)- Developing a MSLN-targeted nanoboady drug conjugate (NDC). Mitchell Ho (NCI/ LMB) has recently engineered a high affinity nanobody against MSLN that is much smaller than traditional antibodies. We are collaborating with chemist Goncalo Bernardes (Cambridge) to conjugate this nanobody with a payload for therapeutic use against PDAC. GOAL E (newly initiated)- TGF-beta modulation to remodel the PDAC tumor microenvironment. We are collaborating with HCW Therapeutics to test the safety of HCW9218 a novel protein drug with dual TGF-beta antagonist activity and IL-15 agonist activity. We are actively enrolling patients on this first-in-human clinical trial." 682524 +No NIH Category available African American;Age;Blood coagulation;Breast Cancer Patient;Characteristics;Classification;Clinical;Clinical Trials;DNA;Data;Databases;Development;Diagnosis;ERBB2 gene;Enrollment;Estrogen receptor negative;Genomics;Germ Lines;Mammary Neoplasms;Metaplastic carcinoma of the breast;Multivariate Analysis;Mutation;Nature;Outcome;Patients;Prognosis;Proteomics;Research;Research Institute;Sampling;The Cancer Genome Atlas;Tissue Banks;Woman;biobank;cohort;exome sequencing;high risk;human old age (65+);malignant breast neoplasm;older women;participant enrollment;patient population;public database;transcriptome sequencing;tumor;young woman Genomic characterization of breast cancer in high risk subsets of breast cancer n/a NCI 10926257 1ZIABC011650-09 1 ZIA BC 11650 9 14821366 "LIPKOWITZ, STANLEY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 190141 NCI Women under the age of 40 account for approximately 5% percent of breast cancer patients but numerous studies have shown that they have a worse prognosis and poorer outcome than women diagnosed at older ages. Breast tumors from young women are often ER-negative from African-American patients and have other indicators of high risk: yet multivariate analyses demonstrated that young age in and of itself is an independent predictor of poor outcome. At least partially due to the unique nature of the patient population served by DOD a disproportionate number of breast cancer cases in young women are seen at WRNMMC. Thus CBCP has enrolled a good number of invasive breast cancer patients under 40 making it possible for us to propose this study. The CBCP Tissue Bank hosted at the Windber Research Institute has 40 tumors in OCT with germ line DNA available from blood clots for these sample. Thus there are sufficient numbers to get meaningful data. The tumors from young patients will be directly compared to those in the biobank from older women using the same platforms. The tumors will undergo whole exome sequencing RNAseq and proteomic analysis. These analyses will allow us to determine the spectrum of mutations seen in tumors from young women. All of these samples are clinically annotated into groups based on the clinical classification of the tumors (Luminal A Luminal B HER2+ and triple negative). For patients enrolled from the WRNMMC most of the cases have outcome data and more outcome data is being collected. These analyses will be compared to the publicly available databases for breast cancer (e.g. TCGA) in order to validate differences between the younger and older cohort in our data. Despite the poor prognosis of young women with breast cancer little research and no clinical specific clinical trials are available. This project and its further development could represent a major advance in the field. 190141 +No NIH Category available 10q;11p;11q;12q13;13q;14q13;19q;1p34;1q32;20p;20q;22q;3q26;8q24;Animals;Apoptosis;Area;Astrocytoma;Automobile Driving;Binding Proteins;Bioinformatics;Biological Assay;Biology;Biotechnology;Brain;Brain Neoplasms;CDKN2A gene;Cancer Genome Anatomy Project;Candidate Disease Gene;Cell Line;Cellular biology;Central Nervous System Neoplasms;Chromatin;Chromosome abnormality;Classification;Clinical;Collaborations;Complex;DNA;DNase I hypersensitive sites sequencing;Data;Data Analyses;Decarboxylation;Deoxyribonuclease I;Development;Dioxygenases;Disease;Disparity;Enzymes;Epidermal Growth Factor Receptor;Epigenetic Process;Exhibits;Gene Chips;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Gene Expression Regulation;Gene Silencing;Genes;Genetic;Genetic Transcription;Genome;Genomics;Glioblastoma;Glioma;Gliomagenesis;Goals;Heterogeneity;Human;Human Genome Project;In Vitro;Isocitrate Dehydrogenase;Isocitrates;Laboratories;Learning;Link;Location;Loss of Heterozygosity;Malignant - descriptor;Methods;Methylation;Microarray Analysis;Molecular;Molecular Target;Morphology;Mutation;Neuroglia;Neurons;Nuclear;Nucleic Acid Regulatory Sequences;Oncogenes;Operative Surgical Procedures;PTEN gene;Pathologic;Patients;Process;Proliferating;Protocols documentation;Receptor Biology and Gene Expression;Recurrence;Reproducibility;Role;SNP array;Sampling;Signal Transduction Pathway;Site;Specimen;Structure;TP53 gene;Testing;Therapeutic Intervention;Tissues;Transplantation;Tumor Biology;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;Work;Xenograft procedure;alpha ketoglutarate;cDNA Arrays;chromosome 5q loss;enzyme activity;experimental study;expression vector;falls;gene cloning;gene discovery;genome-wide;immunosuppressed;in vivo;insight;malignant phenotype;new technology;new therapeutic target;next generation sequencing;novel;permissiveness;postmitotic;self-renewal;stem cells;transcription factor;transcriptome;tumor;tumorigenesis;tumorigenic Identifying New Glioma-Associated Tumor Suppressors and Oncogenes n/a NCI 10926255 1ZIABC011647-09 1 ZIA BC 11647 9 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 522109 NCI "Previously we have initiated a large cDNA microarray effort in collaboration with the Human Genome Project and the Cancer Genome Anatomy Project (CGAP) to develop a comprehensive and novel molecular classification schema for human gliomas based on a gene expression profile using cDNA microarray technology. We have constructed our own cDNA microarray ""chips"" which will be enhanced for new and selective genes thought to be important in glioma biology. This project will include hundreds of tumor specimens and offer an unprecedented opportunity for gene discovery dissecting signal transduction pathways and learning this exciting new technology. Glioma stem cell is a tumor subpopulation that can self-renew in culture perpetuate a tumor in orthotopic transplant in vivo and generate diversified neuron-like and glia-like postmitotic progeny in vivo and in vitro. Recently conventional and array-based CGH (aCGH) profiling of human gliomas have shown a significant number of copy number alterations (CNAs) including gain/amplification (1p34-36 1q32 3q26-28 5q 7q31 8q24 11q 12q13 13q 15p15 17q22- 2519q 20p and 20q) and deletion/loss (3q25-26 4q 6q26-27 9p10p 10q 11p 12q22 13q 14q13 14q23-31 15q13-21 17p11-13 18q22-23 19q and 22q) (Kotliarov et al. 2006; Nigro et al. 2005; Phillips et al. 2006). The large number of chromosomal aberrations and the large number of genes contained therein have to date made it impossible to identify which genes are in part responsible for driving the biology of these tumors. We have analyzed a large number glioma samples for genetic characterization of recurring CNAs using Affymetrix 100K single-nucleotide polymorphism (SNP) array chips and Genechip HumanGenome U133 Plus 2.0 Expression array (Kotliarov et al. 2006). Based on our bioinformatics data from these array and gene expression profiling experiments we have found novel genes frequently altered in gliomas. Furthermore we have explored the new biotechnology such as next generation sequencing for this project. We have generated sequence-verified gene Gateway entry clones of these genes and cloned them into pLenti/UbC/V5 expression vectors for transduction of various target cell lines. With our candidate gene constructs we will identify whether candidate genes change the biology of these cells in such a way that may be consistent with a role in tumorigenesis (i.e. clonogenecity proliferation apoptosis tumorigenic potential in immunosuppressed animals). The NOB Laboratory recently began collaborating with Dr. Gordon Hager and the Laboratory of Receptor Biology and Gene Expression. Dr. Hager's work has focused on the reorganization of the nuclear chromatin and the impact of these changes on gene regulation. In the context of brain tumor biology there are a variety of primary central nervous system tumors that despite a malignant phenotype have few mutations. Therefore it is possible that alterations in the transcriptional profile may help explain this apparent disparity. The NOB laboratory is using the DHS-seq method to profile genome-wide transcriptional changes in glioma patient samples. As described above the DHS-seq will reveal dynamic changes in the chromatin which are important in the development and progression of brain tumors and allow us to identify novel molecular targets to treat this disease. We have tested the DHS-seq protocol on two glioma stem cell lines (827P12 and 923P9) and corresponding xenograft tissues. Preliminary analyses of these data suggest that in combination with gene expression and copy number data we will obtain novel insights into the genomics underlying brain tumor biology. To this end the NOB laboratory has begun testing this method on patient samples using tumor tissues and adjacent normal brain directly from surgical specimens. The plan is to continue processing additional patient samples as they become available with the ultimate goal of incorporating the ""transcriptome"" analysis into the comprehensive genomic analysis that is being planned as a component of the molecular tumor board described in the Clinical Project." 522109 +No NIH Category available Attention;Binding;Biology;CRISPR/Cas technology;Cell Cycle Arrest;Cell Line;Cell Survival;Cell physiology;Colorectal;Colorectal Cancer;DNA Damage;Gene Expression;Gene Expression Profiling;Genes;Genetic Transcription;Genome;Goals;Human;Investigation;Laboratories;Malignant Neoplasms;Mediating;Messenger RNA;MicroRNAs;Modeling;Mus;Mutate;Pathogenesis;Pathway interactions;Phenotype;Play;Post-Transcriptional Regulation;Proliferating;RNA Splicing;RNA-Binding Proteins;Research;Role;Sampling;Signal Transduction;TP53 gene;Untranslated RNA;colon cancer patients;epigenetic regulation;experimental study;gene repression;human disease;mRNA Stability;mRNA Translation;novel;protein function;response;transcription factor;transcriptome;translational potential Role of long non-coding RNAs and RNA-binding proteins in p53 signaling n/a NCI 10926254 1ZIABC011646-09 1 ZIA BC 11646 9 11142391 "LAL, ASHISH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1857668 NCI Our research is focused on investigating the function and mechanism of novel lncRNAs and RNA-binding proteins (RBPs) in p53 signaling using colorectal cancer as a model. We hypothesize that in response to DNA damage select p53-regulated lncRNAs and RBPs play a critical role in regulating a subset of the p53-regulated transcriptome to control cell survival and/or cell cycle arrest. As a first step towards achieving our goal we have identified novel lncRNAs transactivated by p53 in multiple p53-proficient colorectal cell lines. To examine their function we use CRISPR/Cas9 to abolish their expression and for phenotypic studies. To determine their role in regulating the transcriptome we employ gene expression profiling from candidate lncRNA-proficient and lncRNA-deficient isogenic cell lines in the presence or absence of DNA damage. In parallel we perform lncRNA pulldowns to identify the factors bound by the candidate lncRNA. To examine the role of these lncRNAs in cancer pathogenesis we conduct experiments in colorectal cancer patient samples and in mice. These investigations will further our understanding of the function and mechanism of action of novel p53-regulated lncRNAs in the DNA damage response and their involvement in colorectal cancer. In addition to lncRNAs we are also investigating the roles of RBPs in the p53 pathway. Our recent study on ZMAT3 a p53-induced RBP has uncovered a function of ZMAT3 in regulating mRNA splicing. Currently we are investigating how other p53-induced RBPs function in mediating the effects of p53. 1857668 +No NIH Category available Astrocytoma;Caregivers;Caring;Categories;Central Nervous System Neoplasms;Chordoma;Choroid Plexus Carcinoma;Classification;Clinical;Clinical Trials;Collaborations;Consensus;Data Management Resources;Development;Disease;Education;Ependymoma;Evaluation;Fostering;Funding;Gene Amplification;Gene Fusion;Genomic DNA;Genomics;Glioblastoma;Glioma;Gliomatosis cerebri;Goals;Histones;Imaging technology;Immune checkpoint inhibitor;Immunologic Monitoring;Incidence;Infrastructure;International;Investigation;Joints;Knowledge;Laboratories;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of central nervous system;Molecular;Molecular Analysis;Monitor;Monograph;Mutate;Mutation;National Cancer Institute;Natural History;Neoplasms;Nivolumab;Normal tissue morphology;Oncology;Pathogenesis;Pathology;Patient Participation;Patient advocacy;Patients;Pediatric Oncology;Persons;Phenotype;Primary Brain Neoplasms;Primary Neoplasm;Proteomics;Provider;Publishing;Qualifying;Rare Diseases;Recruitment Activity;Regimen;Research;Research Personnel;Resources;Rhabdoid Tumor;Sampling;Testing;Therapeutic;Tissue Banks;Tumor Biology;Tumor Tissue;United States;United States National Institutes of Health;clinical infrastructure;imaging biomarker;immunotherapy trials;improved;medulloblastoma;member;metabolomics;methylome;molecular pathology;mutant;oligodendroglioma;outreach;participant enrollment;patient advocacy group;patient engagement;phase II trial;pineoblastoma;predicting response;predictive marker;prognostic;programs;rare cancer;routine imaging;treatment response;tumor;tumor diagnosis Rare Central Nervous System Cancers Initiative n/a NCI 10926253 1ZIABC011643-09 1 ZIA BC 11643 9 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 522109 NCI The NIH is uniquely suited to create a rare CNS cancer initiative. This effort utilizes the following specific resources of the NIH. This has required developing a clinical trial infrastructure including data management system to oversee the disease specific therapeutic and natural history studies. Collaborations with experts in imaging technologies to create imaging biomarkers and routine imaging for monitoring response to therapies are planned. A tissue repository has been established to store both tumor and normal tissue for molecular analyses including genomics metabolomics and proteomics with the intent of advancing the understanding of tumor biology and pathogenesis leading to better prognostic information sub-classification and ultimately markers predictive of response to specific treatments. Additionally specific testing capabilities have been developed such as the CNS Molecular Panel described above and additional tests are under development. For example an immunotherapy trial is underway and actively recruiting. This study includes immunologic monitoring that are being performed in Dr. Gilbert's laboratory. NIH-based outreach efforts will be utilized to interact with patient advocacy groups to enhance patient participation in these efforts and provide a venue for educational programs to improve patient and caregiver understanding of their uncommon disease. Two clinical trials are recently open (17C0102 Immune Checkpoint Inhibitor Nivolumab in People with Select Rare CNS Cancers;19-C-0006 Phase II Trial Evaluating Nivolumab in Patients with IDH-Mutant Gliomas with and without Hypermutator Phenotype). The NCI-CONNECT: Comprehensive Oncology Network Evaluating. Rare CNS Tumors for fostering patient-advocacy-provider partnerships and networks to improve approaches to care and treatment is very active with clinical trial participation among the members of the network. 522109 +No NIH Category available Bioinformatics;Biological Models;Biology;Brain Neoplasms;Cancer cell line;Cell Culture Techniques;Cell Line;Cells;Cellular biology;Characteristics;Ciliary Neurotrophic Factor;Clinic;Clinical;Collaborations;Computer Analysis;Cytostatics;Data;Database Management Systems;Embryo;Equilibrium;Gene Expression;Gene Expression Profiling;Genes;Genetic;Genomics;Genotype;Glioblastoma;Glioma;Homeostasis;Human;In Vitro;Laboratories;Messenger RNA;Metabolic;Modeling;Molecular;Mus;Mutate;Normal tissue morphology;Oncogenes;Pathway interactions;Patients;Phenotype;Primary Neoplasm;Research;Resources;Serum;Signal Pathway;Signal Transduction;Study models;System;Technical Expertise;Therapeutic;Therapeutic Agents;Tretinoin;Tumor Stem Cells;Tumor Suppressor Proteins;Tumor-Derived;exome sequencing;experimental study;gene function;genome-wide;glioma cell line;immunoreaction;improved;in vivo;material transfer agreement;methylome;miRNA expression profiling;neoplastic cell;nerve stem cell;new therapeutic target;novel therapeutics;personalized medicine;pre-clinical;preclinical study;screening;stem cell biology;stem cell self renewal;stem cells;tool;transcriptome;transcriptome sequencing;translational study;tumor;tumor initiation;tumor xenograft;tumorigenesis Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas n/a NCI 10926252 1ZIABC011640-09 1 ZIA BC 11640 9 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 372935 NCI We have performed experiments to improve our understanding of the molecular mechanisms of deregulated differentiation pathways in TSCs: The delicate balance between stem cell self-renewal and differentiation is controlled by various cell intrinsic and extrinsic factors that are critical for normal tissue homeostasis. Despite extensive phenotypic and functional similarities between GSCs and normal stem cells the differentiation potentials of GSCs are not entirely normal. Elucidation of the differentiation pathways that are operative in both normal stem cells and GSCs will be critical for fully understanding tumorigenesis and will likely lead to novel therapeutic targets. We have also identified a set of deregulated differentiation pathways in GSCs derived from human primary GBM. Elucidation of underlying molecular mechanism will provide important clues for predicting sensitivity of differentiation therapeutic approach. Characterization of TSCs in aspect of differentiation-inducing agents further revealed the limitations of traditional glioma cell lines grown in serum. For example retinoic acid treatment and CNTF exposure potently induce differentiation in most GBM tumor initiate cells (TICs) but not of traditional cell lines. This prompted us to question whether many of potential tumor suppressors and/or cytostatic genes previously studied in cell lines were not recognized. Given the ever-increasing number of potential GSGs and oncogenes in glioblastoma TSCs identified from bioinformatics approaches and technical expertise of stem cell culture accumulated in the laboratories we have set up screening systems to study the function of these genes in stem cell cultures. In addition we have made significant progress on one of keystone projects that is to understand the genomic and molecular signaling similarities and differences between our glioma TSCs and normal neural stem cells (NSC). We have performed a very large scale study of 7 different GBM-derived TSCs and normal embryonic NSC lines under both proliferative and differentiating conditions and derived high-throughput mRNA and microRNAs profiling. Since November of 2014 when Dr Gilbert initiated the new glioma stem cell translational study project we have created 6 more glioma-derived TSCs introduced 3 IDH- mutated TSCs and subsequently performed the computational analyses for characterization of the genetics and signaling pathways in these GSCs enabling these cell lines to be used to explore the therapeutic potential of glioma stem cell biology such as metabolic changes and immunological reactions. Additionally we have through collaborations and Material Transfer Agreements obtained important cell lines that provide an outstanding resource for the laboratory. In total there are now 70 human tumor lines in the NOB Laboratory. As part of this project each of these cell lines has been extensively molecularly characterized including whole exome sequencing analysis of the methylome and RNA sequencing. These data are being uploaded into a database system (CellMinerDB) to enable analysis and selection of optimal model systems for preclinical studies for all of the research groups in the NOB. 372935 +No NIH Category available Bone Marrow;Cell Lineage;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Defect;Development;Epithelial Cells;Gene Expression Profiling;Genetic Transcription;Growth;Hematopoietic;Immune;Immunity;Infection;Influenza;Laboratories;Lymphocyte;Lymphoid Cell;Maintenance;Malignant Neoplasms;Modeling;Mutagenesis;Natural regeneration;Organ;Role;Signal Transduction;System;T cell response;T-Cell Development;T-Lymphocyte;Technology;Thymic epithelial cell;Thymus Gland;Tissues;Work;age related;cell type;epigenomics;fetal;insight;mouse model;notch protein;progenitor;programs;single-cell RNA sequencing;thymic regeneration;transcription factor T cell Development and Regeneration n/a NCI 10926251 1ZIABC011633-09 1 ZIA BC 11633 9 14280065 "BHANDOOLA, AVINASH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2116341 NCI There are two major ongoing projects in our laboratory: 1. The development and function of innate lymphoid cells. Innate lymphoid cells have transcriptional programs that appear to mirror those of T cells. The comparison of innate lymphocyte cell development with T cell development provides an opportunity to understand the factors that underlie the shared as well as the unique features and functions of these apparently closely related cell lineages. We have identified the earliest known precursors committed to innate cell lineages and are characterizing the functions of transcription factors expressed in these early innate lymphocyte precursors. 2. Transcription factors in thymic epithelial cells. Distinct transcription factors are expressed in fetal thymic epithelial cells and in different subtypes of thymic epithelial cells. We are combining models of CRISPR mutagenesis to generate appropriate mouse models with single-cell RNA sequencing and single-cell epigenomics. These technologies will provide unprecedented insight into the mechanisms that support the development and maintenance of adaptive and innate immune lymphocytes. 2116341 +No NIH Category available Adverse event;Angiogenesis Inhibition;Angiogenesis Inhibitors;Anorexia;Avidity;Binding;Bladder Adenocarcinoma;Blood;Body Weight decreased;CCR;CD8-Positive T-Lymphocytes;Cancer Patient;Cancer cell line;Carboplatin;Carcinoid Tumor;Cell surface;Cells;Cisplatin;Clear cell renal cell carcinoma;Clinical;Clinical Treatment;Data;Data Pooling;Databases;Dehydration;Diarrhea;Dose;Dose Limiting;ENG gene;Endoglin;Endometrial Carcinoma;Enzymes;Equilibrium;Evaluable Disease;Fatigue;Flow Cytometry;Functional disorder;Goals;HGF gene;Human;Immune;Immune checkpoint inhibitor;Immunotherapeutic agent;Innate Immune Response;International;Journals;KDR gene;Literature;Liver;MAP Kinase Gene;Malignant neoplasm of penis;Malignant neoplasm of urinary bladder;Manuscripts;Mediating;Medicine;Metastatic Renal Cell Cancer;Monoclonal Antibodies;Mononuclear;Mucositis;Myelogenous;Myeloid-derived suppressor cells;Nausea;Neuroendocrine Tumors;New England;Nivolumab;Non-Small-Cell Lung Carcinoma;PIK3CG gene;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Phase;Phase II Clinical Trials;Placebos;Platinum;Population;Primary carcinoma of the liver cells;Progressive Disease;Property;Protein Tyrosine Kinase;Proteins;Randomized;Receptor Protein-Tyrosine Kinases;Recommendation;Recurrence;Regulatory T-Lymphocyte;Renal Cell Carcinoma;Reporting;Risk;Running;Safety;Sarcomatoid Features;Sarcomatoid Renal Cell Carcinoma;Series;Signal Pathway;Signal Transduction;Squamous cell carcinoma;T-Lymphocyte;Testing;Therapeutic;Therapeutic Trials;Thyroid Gland;Toxic effect;Transitional Cell Carcinoma;Triplet Multiple Birth;Unresectable;Urine;Urothelium;Uterine Corpus Carcinosarcoma;Vomiting;adaptive immunity;advanced disease;angiogenesis;bevacizumab;checkpoint inhibition;chemotherapy;cohort;effector T cell;exhaust;gemcitabine;granulocyte;immunoregulation;improved;ipilimumab;kidney cell;lenalidomide;melanoma;monocyte;mortality risk;neoplastic cell;neuroendocrine differentiation;peripheral blood;phase 1 study;phase 2 study;phase 3 study;phase III trial;programmed cell death protein 1;rare cancer;response;safety assessment;small molecule inhibitor;standard care;symposium;targeted agent;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression Targeting the MET Pathway in Urothelial Carcinoma n/a NCI 10926249 1ZIABC011594-10 1 ZIA BC 11594 10 10687150 "APOLO, ANDREA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 326245 NCI Effect of cabozantinib on peripheral blood immune subsets in urothelial carcinoma and other GU tumors We conducted a study to assess the impact of cabozantinib on systemic innate and adaptive immune cells. TKIs against VEGFR and other receptor tyrosine kinases may have antitumor immune mediated mechanisms. MET is expressed in tumor cells and in immunosuppressive myeloid cells including human monocytes and granulocytic MDSCs. Signaling downstream of HGF MET interaction in monocytes may shift the Th1/Th2 balance and expand MDSCs and Tregs. We hypothesized that cabozantinib can modify the tumor microenvironment by modulating immunosuppressive Tregs and MDSCs. We assessed peripheral blood mononuclear cell (PBMC) immune subsets including effector T cells exhausted T cells Tregs MDSCs and the functional markers PD 1 and TIM 3 using flow cytometry in metastatic urothelial carcinoma patients undergoing treatment with cabozantinib at baseline and after 2 cycles of continuous cabozantinib treatment and correlated our findings with clinical response to therapy PFS and OS. In summary our study showed that cabozantinib has innate and adaptive immunomodulatory properties that provide a rationale for combining cabozantinib with immunotherapeutic strategies. Cabozantinib modulated peripheral blood myeloid populations including decreasing classical monocytes increasing non classical monocytes and decreasing MDSCs. Cabozantinib also favorably impacted CD4 polarization to decrease Tregs increase the ratio of CD8 T cells to Tregs and upregulate PD 1 expression on Tregs. We plan to validate these findings in 155 patients treated with CaboNivo or CaboNivoIpi with a larger immune subset panel and additional functional markers with the goal to further understand the immune response of innate mononuclear cells that may serve as a targetable nexus for therapeutic engagement of adaptive immunity. Combining cabozantinib with checkpoint inhibition with nivolumab and ipilimumab Based on the immunomodulation seen with cabozantinib I initiated a multicenter phase 1 study where I combined CaboNivo or CaboNivoIpi. The study included a phase 1 study with 8 dose levels (n = 54) and 7 expansion cohorts including urothelial carcinoma renal cell carcinoma urothelial carcinoma patients previously treated with checkpoint inhibitors adenocarcinoma of the bladder/urachal penile cancer squamous cell carcinoma and other rare tumors (n = 155). The phase 1 portion is complete but we are still running the expansion cohorts. Safety of the combination of CaboNivo and CaboNivoIpi: In a phase 1 study I assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) with or without ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma and other GU malignances. Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase 2 dose (RP2D). Overlapping toxicities with the use of TKIs and checkpoint inhibitors included thyroid dysfunction diarrhea and elevated liver enzymes. Cabozantinib 60 mg/day led to higher rates of clinical treatment related adverse events of all grades including fatigue diarrhea anorexia weight loss nausea vomiting mucositis and dehydration. Although the study did not have any dose limiting toxicities the RP2D was cabozantinib 40 mg/day plus nivolumab 3 mg/kg for the doublet and cabozantinib 40 mg/day nivolumab 3 mg/kg and ipilimumab 1 mg/kg for the triplet based on better clinical tolerability and similar efficacy of cabozantinib at 40 mg/day vs. 60 mg/day. These data established the safety of the combinations and the RP2D for larger trials. Activity of CaboNivo and CaboNivoIpi: In the phase 1 study of CaboNivo and CaboNivoIpi (n = 54) we reported an ORR of 30.6% for all patients and 38.5% for urothelial carcinoma patients.23 Median duration of response was 21.0 months for all patients and not reached for metastatic urothelial carcinoma patients. Median PFS was 5.1 months for all patients and 12.8 months for urothelial carcinoma patients. Median OS was 12.6 months for all patients and 25.4 months for metastatic urothelial carcinoma patients. Based on the initial efficacy seen in the phase 1 patients additional expansion cohorts were added to the study. Expansion cohorts of CaboNivo and CaboNivoIpi in patients naive to checkpoint inhibition: The pooled data from the phase 1 and expansion cohorts in patients naive to immune checkpoint inhibition (n = 120) are currently being analyzed. For all currently evaluable patients (n = 109) the ORR = 37.6% CR = 9.2% PR = 28.4% and SD = 43.1%. The urothelial carcinoma expansion cohort included 24 patients treated with CaboNivo (n = 12) and CaboNivoIpi (n = 12). Similar to the phase 1 study where the ORR was 38.5% in the urothelial carcinoma expansion cohort the ORR = 42.9% for the 24 urothelial carcinoma patients and for the phase 1+ expansion cohort (n = 40) the ORR = 41.2% CR = 20.6% PR = 20.6% SD = 38.2% and progressive disease = 23.5%. The clear cell renal cell carcinoma (RCC) patients included patients with sarcomatoid features. In phase 1 all 3 RCC patients had a PR the RCC expansion cohort included 12 patients treated with CaboNivo (n = 6) and CaboNivoIpi (n = 6) and an additional RCC sarcomatoid patient from the rare tumor cohort. The phase 1 + RCC expansion cohort (n = 16) had an ORR = 62.5% CR = 12.5% PR = 50% SD = 37.5% and progressive disease = 0%. The promising activity seen in this phase 1 study has led to additional expansion cohorts within this study including cohorts for urothelial carcinoma RCC and other rare GU tumors with no standard treatment options and has also led to larger trials in GU tumors including CheckMate 9ER a randomized phase 3 trial of CaboNivo vs. sunitinib in the first line treatment of mRCC PDIGREE an adaptive phase 3 trial of CaboNivoIpi in untreated mRCC COSMIC 313 a phase 3 trial of CaboNivoIpi vs. NivoIpi plus placebo in mRCC and the Alliance ICONIC study of CaboNivoIpi for rare GU tumors. Several other trials are testing CaboNivo in non clear cell RCC carcinoid tumors metastatic triple negative breast cancer locally advanced hepatocellular carcinoma advanced endometrial cancer recurrent uterine carcinosarcoma poorly differentiated neuroendocrine tumors and non small cell lung cancer. A study of CaboNivoIpi in unresectable advanced melanoma is also underway. I am on the steering committee for CheckMate 9ER. The first results from the randomized phase 3 study n = 651 were presented in the presidential symposium at ESMO 2020 showing first line CaboNivo vs. sunitinib improves PFS 16.6 vs. 8.3 months OS 40% decrease in risk of death and ORR 55.7 vs. 27.1% with benefit in all International Metastatic RCC Database Consortium risk groups. CaboNivo has potential as first line therapy for metastatic RCC patients. I am an author of the manuscript which was submitted to the New England Journal of Medicine. I am currently working on a subset analysis for patients with sarcomatoid RCC within the 9ER study. For bladder cancer patients I am working on developing a phase 3 study for the second line treatment of patients post platinum based therapy. 326245 +No NIH Category available BAY 54-9085;BRCA mutations;Blood;Clinic;Clinical Data;Clinical Trials;Collaborations;Dasatinib;Development;Enrollment;Goals;Growth Factor;Hereditary Breast and Ovarian Cancer Syndrome;Induction of Apoptosis;Institutional Review Boards;International;Karyotype;Li-Fraumeni Syndrome;Malignant Neoplasms;Malignant neoplasm of ovary;Metabolic;Metformin;Patients;Peritoneal;Phase;Pleural;Pregnant Women;Process;Protein Family;Protocols documentation;Research Personnel;Source;Specimen;Testing;Therapeutic;Woman;angiogenesis;bevacizumab;drug testing;effusion;fetal;inhibitor-of-apoptosis protein;phase 1 study;prevent Clinical trials in womens cancers n/a NCI 10926247 1ZIABC011584-10 1 ZIA BC 11584 10 9692487 "ANNUNZIATA, CHRISTINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 391839 NCI We are currently in the process of analyzing specimens and data from clinical trials 07C0058 - Bevacizumab and Sorafenib phase 2 in ovarian cancer; and 09-C-0019 phase 1 study of bevacizumab and dasatinib. As a Branch we opened 19-C-0025 to collect blood and effusions (pleural and peritoneal) from patients with cancer enrolled on other protocols at the NCI. Additional clinical trials are under development at the concept stage or are under review by IRB. Within the WMB I collaborate with Jung-min Lee and Stan Lipkowitz as Associate Investigator on several other clinical trials. I also collaborate with Diana Bianchi on a clinical trial to investigate the source of abnormal cfDNA in pregnant women with normal fetal karyotype. Another collaboration tested the metabolic effects of metformin in patients with Li Fraumeni Syndrome and a larger international clinical trial is under development to test this drug as a strategy to prevent cancer in LFS patients. 391839 +No NIH Category available Advanced Development;Age Years;Biochemical;Biochemistry;Biological;Biological Assay;Biology;CCR;Cancer Biology;Cell Line;Cell physiology;Cellular biology;Characteristics;Chemicals;Chemistry;Chimeric Proteins;Collaborations;Collection;Competitive Binding;Complement;Computational Science;Computer Models;Crystallization;DNA;DNA Topoisomerases;Data;Data Analyses;Development;Digit structure;Disease;Enzyme-Linked Immunosorbent Assay;Evaluation;Exhibits;Extramural Activities;Family;Fibrolamellar Hepatocellular Carcinoma;Fingerprint;Fractionation;Gene Fusion;Genes;Genetic;Goals;HCT116 Cells;HIV;Human;Immune checkpoint inhibitor;Immunology;Immunotherapeutic agent;Individual;Industrialization;Intervention;Journals;Large Intestine Carcinoma;Lead;Legal patent;Letters;Libraries;Link;Malignant Neoplasms;Malignant neoplasm of liver;Manuscripts;Merkel cell carcinoma;Mesothelioma;Methodology;Microbe;Modification;Molecular;Molecular Biology;Molecular Probes;Molecular Target;Natural Products;Natural Products Chemistry;Natural Source;Neurosecretory Systems;New Agents;Oncogenic;Organic Synthesis;PRKCA gene;Pathway interactions;Patients;Penicillium;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacology;Phosphotransferases;Photosensitizing Agents;Plakortis;Plants;Play;Porifera;Positioning Attribute;Process;Proliferating;Protein Chemistry;Protein-Serine-Threonine Kinases;Publications;Publishing;RNA;RNA Virus Infections;Reporting;Research;Resources;Role;Route;Scientist;Serine;Skin Cancer;Source;Specificity;Structure;Survival Rate;Synthesis Chemistry;Techniques;Technology;Topoisomerase;Translational Research;United States National Institutes of Health;Urochordata;X ray diffraction analysis;alternative treatment;analog;anti-cancer;assay development;bioactive natural products;cancer cell;cancer type;cytotoxic;cytotoxicity;design;diketopiperazine;experience;experimental study;fluorophore;high throughput screening;improved;inhibitor;insight;interdisciplinary approach;kinase inhibitor;marine;marine organism;monomer;nanomolar;novel;novel therapeutics;patient population;pembrolizumab;pharmacologic;preclinical development;programs;proto-oncogene protein c-cbl;response;scaffold;screening;screening panel;secondary metabolite;skills;structural biology;therapeutic development;tumor;tumorigenesis;ubiquitin ligase Natural Products Discovery and Characterization Through Network Collaborations n/a NCI 10926246 1ZIABC011568-10 1 ZIA BC 11568 10 78355366 "DU, LIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1304841 NCI The NPCS utilized high throughput screening technologies to help identify compounds and extracts that can specifically interact with or modulate the function of selected biochemical targets or processes. Bioassay-guided chemical fractionation of natural products extracts is employed to isolate and purify the individual bioactive compounds. Identification and structural characterization of these compounds provides new structural classes or molecular scaffolds for the development of potential drug leads or biological probes that can interact with the desired molecular target. In addition to extensive NMR and mass spectroscopic analyses our efforts include rigorous evaluation of a new compound's potency molecular target specificity and mode of action. In FY 2023 we have been continuing our research campaign to identify bioactive natural products that interact with a wide variety of molecular targets including the ubiquitin ligase Cbl-b the Merkel cell carcinoma the J-PKAc alpha kinase fusion protein the topoisomerase-3B the NCI60 cell line screening panel and mesothelioma (MPM). Totally the NPCS has completed 98 isolation projects leading to the identification of 267 natural products including 91 new compounds. Among all compounds 151 of them including 47 new compounds exhibited bioactivities against the selected targets. (1) Cbl-b: The E3 ubiquitin-protein ligase Cbl-b represents an attractive target for immunotherapeutic intervention in cancer. In FY 2022 we reported the identification of two novel Cbl-b inhibitors (+)-plakoramine A and (-)-plakoramine A from a marine sponge Plakortis sp. We continued to reveal a previously undescribed nonenzymatic route to form plakoramine A via photochemical conversion of its naturally occurring monomeric counterpart plakinidine B which stands for a new functional fluorophore with potential utility as both a photosensitizer and a photochemically triggered electrophilic agent. The plakoramine story has been successfully published on the ACS journal Organic Letters. (2) Merkel cell carcinoma: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer. The treatment of advanced MCC often utilizes immune checkpoint inhibitors such as avelumab or pembrolizumab. Despite relatively high response rates to these agents less than half of patients achieve durable benefit; thus alternative treatments are urgently needed. Two new cytotoxic oxygenated diketopiperazines brevianamides E1 and E2 were identified from a Penicillium brevicompactum. Both compounds showed selective cytotoxicity against the Merkel cell carcinoma cell line MCC13 cell line with IC50 values at 2.6 and 2.5 mM respectively. (3) The J-PKAc alpha kinase fusion protein (PKADJ): Fibrolamellar Hepatocellular Carcinoma (FLHCC) is a rare liver cancer with a young patient population ( 35 years of age) and a 5-year survival rate of only 30-35%. The DNAJB1-PRKCA oncogenic gene fusion is specifically expressed in the tumor and exclusively detected in FLHCC patients. The DNAJB1-PRKCA gene fusion produces an enzymatically active chimeric protein J-PKAc alpha that is a key driver in the oncogenesis of FLHCC. A high-throughput modified sandwich ELISA assay was developed by PCMBS to identify selective modulators of the J-PKAc alpha catalytic activity by screening the prefractionated natural product library recently created by the NCI Program for Natural Product Discovery (NPNPD). In FY 2023 the NPCS has been engaged in the bioassay-guided fractionations of 36 PKADJ-active extracts. The NPCS assisted PCMBS in the publication of the first PKADJ HTS manuscript on ACS Pharmacology & Translational Science by providing several bioactive natural products. Last year we reported the identification of a novel PKADJ lead molecule aplithianine A (1) from a marine Aplidium sp. tunicate. Aplithianine A (1) showed potent inhibition against both J-PKAc alpha and wild-type PKAc alpha with an IC50 value 1 uM in the primary assay. Further mechanistic studies including co-crystallization and X-ray diffraction experiments revealed that 1 inhibited PKAc alpha catalytic activity by competitively binding to the ATP pocket. Human kinome profiling of 1 against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK DYRK and PKG families with IC50 values ranging from 11-90 nM. An efficient four-step total synthesis of 1 has been accomplished enabling further development of aplithianines as biologically relevant kinase inhibitors. Through the collaboration with the CCR medicinal chemistry accelerator we have designed and synthesized more than 400 aplithianine analogs and successfully improved the biochemical potency to single digit nanomolar range. Based on data from the initial discovery and following optimization of alithianines a manuscript and two provisional patent applications have been submitted and a following PCT application was also filed after one of the provisional applications. (4) Topoisomerase-3B: DNA Topoisomerase-3B (TOP3B) stands out among all mammalian topoisomerases due to its distinctive capability to resolve topological entanglements in both DNA and RNA. Deletion of the topoisomerase-3B (TOP3B) gene has been linked to various cancer types. This unique characteristic has made TOP3B a promising target for the development of new therapeutics for both cancer and RNA virus infections. The paired colorectal carcinoma HCT116 cell lines with (TOP3B-WT) and without TOP3B (TOP3B-KO) were developed for discovering TOP3B-specific proliferation modulators. In this high-throughput screening campaign the NPCS has been engaged in the bioassay-guided fractionations of 38 TOP3B-active extracts leading to the identification of 76 active natural products including 20 new compounds. In FY2024 the NPCS will continue to improve the efficiency of our HTS-based bioassay-guided fractionation platform by optimizing the analytical-fingerprint-based dereplication and project selection pipelines. We will also incorporate new computational modeling and organic synthesis techniques/methodologies to establish our expertise in structure modification target identification and activity optimization. The long-term focus of this project is to exploit the vast spectrum of chemical diversity within the NPR for potential anticancer and anti-HIV applications. It relies on close integration with the MTP Assay Development and Screening Section Chemical Diversity Development Section and the Protein Chemistry and Molecular Biology Section for extract screening data analysis bioassay support and functional analysis of isolated compounds. Our CCR collaborators who study aspects of cancer biology genetics and immunology provide expertise for target selection and subsequent compound evaluation. We have assembled a broad consortium of intramural and extramural partners with expertise in organic synthesis chemical biology molecular pharmacology computational sciences and spectroscopic analysis to help characterize and advance our natural product discoveries. The Natural Products Chemistry Section is uniquely positioned within the NCI to combine molecular target-based discovery with natural products chemistry. Natural products are a source of structural complexity and biological activity that can provide insight on the function of new targets pathways or cellular processes. They play an important role in dissecting and understanding the intricacies of cancer development and progression so continued natural products discovery efforts can complement the goals of the CCR and NCI. 1304841 +No NIH Category available Biochemical;Biogenesis;Biological;Biological Process;Cell Nucleus;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;DNA Polymerase II;DNA Polymerase III;Data Analyses;Databases;Development;Disease;Enzymes;Focus Groups;Foundations;Future;Genes;Genetic;Genetic Screening;Goals;Health;Hemostatic function;Hour;Isomerism;Malignant Neoplasms;Mammals;Methods;MicroRNAs;Modification;Monitor;Nucleotides;Pathway interactions;Physiology;Plasmids;Play;Proteins;RNA Interference;Regulation;Role;Safety;Shapes;Small Interfering RNA;Specificity;System;Tail;Testing;The Cancer Genome Atlas;Therapeutic;Transcript;Untranslated RNA;Variant;cancer cell;cancer therapy;design;gene therapy;genome-wide;improved;in vivo;insight;knock-down;next generation sequencing;novel;novel strategies;overexpression;small hairpin RNA;tool;tumor progression;tumorigenesis Mechanism Regulation and Application of miRNA pathway in cancer n/a NCI 10926245 1ZIABC011566-10 1 ZIA BC 11566 10 12448167 "GU, SHUO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1500359 NCI "We focus on the first step of miRNA biogenesis where most of the regulations take place. Drosha initiates miRNA biogenesis by chopping hairpin-shaped miRNA precursors (pre-miRNA) off the primary transcripts (pri-miRNA) in the nucleus. Reduced enzymatic activity of Drosha has been described in various malignancies. We have created a powerful genome-wide genetic screen approach based on CRISPR. Applying this method in addition to data-analysis of the TCGA database we plan to identify novel cellular regulators of Drosha activity and investigate why and how these are regulated in physiology and in cancer. Their impacts on the efficiency and accuracy of miRNA biogenesis will then be tested by in the corresponding KO cells. DNA-directed RNAi (shRNA expressed from plasmids) is more desirable than traditional synthetic siRNAs in setting of gene therapy. However unsatisfactory knockdown efficacy and off-target effects hamper its applications often due to inefficient low fidelity of processing. Our previous finding on Dicer processing has established a ""loop-counting"" rule which laid the groundwork in designing Pol III-driven pre-miRNA-like shRNAs free of the off-target effects resulting from heterogeneous processing. We are currently working on transferring such a design into the Pol II system in which more complicated manipulation of shRNA function is possible. In particular we are developing conditionally activated shRNAs whose function can be specifically turned on in cancer cells. This approach will dramatically increase shRNA specificity and safety. Given the long half-lives of mature miRNAs (ranging from hours to days) biogenesis control by itself is inadequate in situations that require rapid changes in miRNA function. Post-maturation regulation is an important component of how miRNAs function. Thus in alignment with our goal of understanding miRNA regulation we study the biogenesis and function of 3' isomiRs which are miRNA variants generated by post-maturation tailing (adding nucleotides) and/or trimming (removing nucleotides). Interestingly the alteration in isomiR profile rather than in overall miRNA abundance correlates with cancer progression which suggests a unique role of isomiRs in tumorigenesis. These observations highlight the importance of isomiR study. To investigate the function of 3' isomiR we checked the status of 3' sequence modifications during miRNA overexpression and decay. We found that isomiR profiles are not random but rather tightly regulated. This suggests that the 3' end modification is not merely a consequence of miRNA overexpression but rather plays an active role in maintaining the miRNA hemostasis. To establish a causative relation we are working on identifying the enzymes that are responsible for producing certain isomeric forms. We also aim to develop novel strategies to monitor the function specific to certain isomiRs. Overall these studies seek to significantly advance our basic understanding of isomiRs and provide a foundation for future mechanistic study of their functions in cancer." 1500359 +No NIH Category available Biochemical;Biological;Biological Markers;Biopsy;Cancer Patient;Cancer Therapy Evaluation Program;Characteristics;Chemotherapy and/or radiation;Clinical;Clinical Trials;Data;Evolution;Failure;Genetic;Goals;In Vitro;Laboratories;Laboratory Study;Local Therapy;Localized Malignant Neoplasm;MEK inhibition;MEKs;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Neoadjuvant Therapy;Outcome;Pathway interactions;Patients;Phase I Clinical Trials;Prostate;Protocols documentation;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Rectal Cancer;Recurrence;Recurrent disease;Recurrent tumor;Research;Resistance;Risk Factors;Therapeutic;Time;Tissues;Tumor Tissue;Work;biomarker identification;chemoradiation;chemotherapy;clinical translation;imaging modality;in vivo;inhibitor;irradiation;novel;participant enrollment;phase I trial;prospective;radiation resistance;radiation response;radiological imaging;resistance factors;targeted radiotherapeutic;tumor;tumor specificity Targeting mechanisms of radiation resistance n/a NCI 10926242 1ZIABC011552-10 1 ZIA BC 11552 10 9414510 "CITRIN, DEBORAH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1829924 NCI An example of this approach is my laboratory's work with AZD6244 a MEK inhibitor. My laboratory demonstrated the therapeutic potential of MEK inhibition as a radiation sensitizer in several cancers both in vitro and in vivo(12) evaluated the impact of concurrent chemotherapy on the radiosensitizing effect of MEK inhibition(13) identified biomarkers that may predict efficacy of this approach and highlighted the mechanisms of radiation sensitization when this pathway is targeted.(12-14) This work culminated in the initiation of a CTEP sponsored Phase I trial at the NCI investigating MEK inhibition combined with the current standard chemoradiotherapy in the neoadjuvant setting in patients with locally advanced rectal cancer. There are currently three open and two completed Phase I clinical trials evaluating MEK inhibition combined with radiation and chemotherapy for the treatment of localized cancers. We have recently identified additional compounds that show preliminary efficacy in vitro as radiation sensitizers. The approach we have used in the past to select agents for study has been effective in identifying radiation sensitizers. This approach is evolving as we collect tumor tissue and clinical outcomes data from prostate cancer patients on my protocol 13-C-0119. This clinical trial will allow us to evaluate multiple biologic clinical and radiographic predictors of local failure in patients treated with radiotherapy for localized prostate cancer. Patients enrolled in this study undergo a pretreatment multiparametric MRI and MRI-guided research biopsy of all tumors within their prostate. Following radiation therapy patients with a rising PSA who meet biochemical failure criteria undergo repeat multiparametric MRI of the prostate and repeat MRI-guided research biopsy of persistent tumor. The molecular characteristics of tumor are analyzed to evaluate for predictors of failure and to study tumor evolution after radiation. Data from the tissue studies described above will be mined to generate a list of candidate pathway responsible for radiation resistance in prostate cancer. These data will inform laboratory studies aimed at determining the importance of these pathways in radiation response. 1829924 +No NIH Category available AKT1 gene;Antibody-drug conjugates;BRCA mutations;Binding;Biological Markers;Biology;Biopsy;Biopsy Specimen;Blood;Blood specimen;CCR;CHEK1 gene;Cancer Patient;Cancer Therapy Evaluation Program;Cancer cell line;Cause of Death;Cell Cycle;Cell Cycle Arrest;Cell Cycle Checkpoint;Cell Death;Cell Proliferation;Cessation of life;Characteristics;Chemoresistance;Clinic;Clinical;Clinical Research;Clinical Trials;Collaborations;Collection;Combined Modality Therapy;Complement;Congresses;Cooperative Research and Development Agreement;Core Facility;Correlative Study;DNA;DNA Damage;DNA Repair;DNA sequencing;Data;Data Analyses;Development;Disease;Drug Combinations;Drug Targeting;Drug resistance;Effectiveness;Endothelium;Enrollment;Gene Expression;Gene Mutation;Genomic Instability;Goals;Gynecologic Oncology Group;Hybrids;Immune;In Vitro;Interferon Type II;Interferons;International;Interruption;Intramural Research Program;Investigation;KDR gene;Laboratories;Letters;M cell;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Manuscripts;Mediating;Mediator;Membrane Glycoproteins;Molecular;Molecular Profiling;Mus;Mutation;Mutation Analysis;NCI Center for Cancer Research;National Center for Advancing Translational Sciences;Oncology;Operative Surgical Procedures;Outcome;Ovarian Carcinoma;PI3K/AKT;Pathway interactions;Patient observation;Patients;Pharmaceutical Preparations;Phase;Phase 1/1b Clinical Trial;Phosphotransferases;Physicians;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Prognosis;Proteins;Proto-Oncogene Proteins c-akt;RNA;Recurrence;Reporting;Research;Research Personnel;Resistance;Resolution;Role;Science;Scientist;Serous;Signal Transduction;Single-Stranded DNA;Site;Subgroup;TACSTD2 gene;TP53 gene;Testing;Therapeutic;Tissue Sample;Translational Research;Tumor Debulking;Tyrosine Kinase Inhibitor;United States;United States National Institutes of Health;Woman;Work;anti-PD-L1;arm;bench to bedside;bevacizumab;cell growth;chemokine;chemotherapy;clinical development;cytokine;cytotoxicity;design;effective therapy;exceptional responders;experimental study;first-in-human;helicase;high risk;human study;immune checkpoint blockade;improved;in vivo;inhibitor;insight;investigator-initiated trial;mouse model;new therapeutic target;next generation;novel;novel drug combination;novel therapeutics;phase 2 study;phase I trial;phase II trial;pre-clinical;pre-clinical research;preclinical study;predictive marker;primary endpoint;programmed cell death ligand 1;programs;prospective;recruit;replication stress;research clinical testing;response;response biomarker;standard of care;stem;tenure track;therapeutic target;transcriptome sequencing;translational approach;translational medicine;translational research program;translational scientist;translational study;tumor;tumor growth Leveraging DNA damage repair pathways as therapeutic targets in womens cancers n/a NCI 10926240 1ZIABC011525-11 1 ZIA BC 11525 11 12032154 "LEE, JUNG-MIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1729738 NCI Project 1. Therapeutic modulation of cell cycle checkpoint pathways in HGSOC. Cell cycle checkpoints e.g. ATR and CHK1 are the major regulators of DNA damage response (DDR) pathways. ATR and CHK1 function as primary mediators of G2/M cell cycle arrest due to universal TP53 mutation and consequent G1/S cell cycle dysregulation in HGSOC making them important therapeutic targets. My investigator-initiated phase II trial of the CHK1 inhibitor (CHK1i) prexasertib (prex) (NCI 14-C-0156; NCT02203513) is the first demonstration of monotherapy activity of the ATR/CHK1 pathway inhibitor in recurrent HGSOC with comprehensive translational studies (Lancet Oncology 2018 and Science Translational Medicine 2023). In this proof-of-concept trial of CHK1i I separately examined the role of CHK1i in the background of BRCA mutation (BRCAm) and BRCA wild-type (BRCAwt) HGSOC and have characterized the possible subsets of HGSOC patients (pts) who most likely benefit from CHK1i. My current and future research is focusing on the clinical development of novel drugs and/or novel drug combinations targeting of DDR pathways in recurrent HGSOC complemented by the mechanistic translational studies. SA 1. Clinical development of CHK1i in molecularly selected platinum-resistant (PR) HGSOC pts. I initiated a collaboration with Acrivon Therapeutics and participated in the development of molecular signature which identifies the subset of HGSOC pts for CHK1i response. Based on our findings a multi-center registration-intent phase II trial of ACR-368 (a.k.a. prex) was launched for PR-HGSOC and I am the Study Chair (GOG-3082; NCT055482962). The trial requires pretreatment fresh biopsies to provide the first prospective evidence of replication stress (RS)-related biomarker subgroups. If positive this aim will identify the predictive biomarker for CHK1i and change the standard of care therapy (SOC) for PR-HGSOC pts. SA 2. Development of ATR/CHK1 pathway blockade combination therapy in HGSOC. I conducted a quantitative high throughput drug combination screen for CHK1i with NCATS/NIH. Several compounds targeting the PI3K/AKT pathway were found to be synergistic with CHK1i. Mechanistically my lab identified combined inhibition of the PI3K/AKT pathway and CHK1 resulted in lethal RS and cell death in BRCAwt PR-HGSOC preclinical models. My lab also performed another drug combination screen using a ATR inhibitor (ATRi). In this screen ATRi (ceralasertib) was found to be synergistic with drugs targeting the cell cycle the PI3K/AKT pathway and other pathways important in cell growth and proliferation. We chose to combine PI3K/AKT pathway inhibitors with ATRi given that PI3K/AKT signaling is associated with chemoresistance and poor prognosis in HGSOC. a. Mechanistic investigation of the ATRi and AKT inhibitor (AKTi) combination. Recent data suggest aberrant R-loops which consist of a DNA:RNA hybrid and a displaced ssDNA induce genomic instability and RS. I hypothesize that R-loop-mediated RS may contribute to cell death caused by dual inhibition of ATR/CHK1 and PI3K/AKT pathways in PARPi-resistant HGSOC. My lab identified the novel function of AKT1 which directly binds to the sites of R-loops in concert with the DHX9 helicase via its kinase domain for R-loop resolution. AKTi thus interrupts DHX9 recruitment to R-loops leading to R-loop accumulation and consequent RS (manuscript submitted). b. Clinical evaluation of the ATRi and PI3K/AKT pathway inhibitor combination. While conducting mechanistic in vitro studies my lab also performed mouse experiments which showed the combination significantly reduced tumor growth and prolonged survival compared to monotherapy. My letter of intent (LOI) for a new investigator-initiated phase I/Ib clinical trial of ATRi and PI3K/AKT pathway inhibitor combination was approved by NCI/CTEP (LOI#10591). Discussions are ongoing with the drug companies. c. Investigation of novel combination with antibody drug conjugates (ADCs). I initiated a collaboration with Gilead Sciences (CRADA#3391) to develop preclinical models of the Trop2-targeting ADC sacituzumab govitecan [SG] and cell cycle checkpoint blockade combination. Trop2 is a 36 kDa transmembrane glycoprotein encoded by the TACSTD2 gene and is expressed ubiquitously in many cancers including 80-90% of OC. My lab is now investigating cytotoxicity of SG and cell cycle checkpoint blockade combination in a panel of HGSOC cell lines and characterize key modulators of DDR pathways. My lab is also evaluating the combination therapy effectiveness in drug-resistant OC mouse models. Discussions are ongoing with the company for the development of new investigator-initiated clinical trials. Project 2: Immune checkpoint blockade (ICB) with PARPi olaparib (O) and VEGFR tyrosine kinase inhibitor (TKI) cediranib (C) combination in PR-OC. Another project includes the development of O and C combination for PR-HGSOC. I serve as a Study Chair on the multi-center phase II/III NRG-GY005 trial (NCT02502266) of O+C combination vs SOC chemotherapy in PR-HGSOC. This international trial has enrolled 540 pts and data will be reported in 1Q 2024. Building on my work with O+C combination I am exploring anti-PDL1 durvalumab (D) with O+C in PR-OC. My phase I trial (15-C-0145; NCT02484404) is the first-in-human study of D in combination with O and/or C. My group also reported the clinical and translational study results from the phase II study of D+O in recurrent OC and demonstrated that the activity of ICB and PARPi combination may vary depending on the clinical and molecular characteristics. My current and future research is focusing on the clinical development of ICB-based combination therapies in recurrent PR-OC and to investigate molecular correlates to find predictive biomarkers of response and/or resistance to ICB-based combination therapies. SA 1. Investigation of molecular correlates of response to O+C combination therapy with anti-PDL1 a. NRG GY023 multi-center phase II study. I designed and chair a multi-center phase II trial (NRG-GY023; NCT04739800) testing the D+O+C combination versus SOC in PR-OC pts who had prior bevacizumab. The primary end point was PFS with planned accrual of 164 pts. Interim analysis data will be reported at the 2023 ESMO congress. The NRG-GY023 study required mandatory submission of archival tissue samples for further correlative studies. We will identify the exceptional responders and investigate their molecular and clinical characteristics in collaboration with NRG Oncology. b. NCI 15-C-0145 single center phase II study. My NCI phase II study of D+O+C arm (15-C-0145) is near completion of accrual. This study requires baseline and on-treatment fresh tumor biopsies and serial blood collections for comprehensive correlative study endpoints. Correlative studies include (1) DNA-seq for specific DDR genes mutational analysis and BRCA reversion mutations (2) RNA-seq to identify molecular characteristics and correlate them with clinical outcome (3) to evaluate the expression of genes involved in IFN response and their interactions with other pathways and study an IFN gamma-related DNA damage resistance signature 4) IHC for immune subsets endothelial markers and PD-L1 expression in tissue samples and STING expression by multiplex IHC 5) blood samples to evaluate immune subsets and cytokines/chemokines. Insights gained from these studies are also expected to inform the development of rational combination strategies and complement the correlative study findings from NRG-GY023. Collectively this focused clinical and translational approach will make CCR a recognized center focusing on the treatment of women with high-risk OC with a strong translational research program. 1729738 +No NIH Category available 3-Dimensional;Abnormal Cell;Aneuploidy;Animals;Architecture;Binding;Biogenesis;Biological Process;C-terminal;Catalogs;Cell Cycle;Cell Cycle Progression;Cell division;Cell physiology;Cells;Cellular biology;Centrioles;Centrosome;Chromosome Segregation;Client;Complex;Data;Defect;Development;Disease;Ensure;Etiology;Eukaryotic Cell;Event;Exhibits;Fluorescence Recovery After Photobleaching;Future;Goals;Human;In Vitro;Life;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Microtubule-Organizing Center;Mitotic spindle;Molecular;Molecular Sieve Chromatography;Mutation;Names;Nanoscopy;Organelles;Organism;PLK1 gene;Phase;Physical condensation;Play;Polo-Box Domain;Procentriole;Process;Property;Protein Dynamics;Proteins;Research;Role;Scaffolding Protein;Shapes;Site;Somatic Mutation;Structure;Subcellular structure;Tissues;Ultracentrifugation;Variant;Work;X-Ray Crystallography;biophysical techniques;density;genome integrity;human disease;in vivo;insight;macromolecular assembly;mutant;nanoscale;novel;scaffold;sedimentation equilibrium;self assembly;self organization;single molecule Molecular basis of centriole duplication n/a NCI 10926238 1ZIABC011518-11 1 ZIA BC 11518 11 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1105026 NCI "The centrosome a unique membrane-less multiprotein organelle that serves as the main microtubule-organizing center in animal cells plays a pivotal role in the orderly progression of the cell cycle. Since faulty assembly and duplication of the centrosome results in abnormal cell division which then leads to various human disorders elucidating the molecular mechanisms underlying centrosome assembly and function is likely a key step to understanding the etiology of centrosome-associated human diseases. By combining cell biology with biophysical methods and X-ray crystallography we demonstrated that two pericentriolar scaffolds Cep152 and Cep63 possess intrinsic activity of co-phase-separating into condensates and form a heterotetrameric complex that serves as a building block for generating a nanoscale cylindrical self-assembly around a centriole. Remarkably two short uncharacterized regions named Self-Assembly Motifs (one each from Cep63 and Cep152) cooperatively conferred physicochemical properties that allowed them to undergo density transition and self-assemble into a cylindrical architecture. Interestingly the Cep152-Cep63 condensates exhibited a rapid turnover underwent fusion with other assemblies and carried out a significant degree of internal rearrangement within a condensate. A Cep152-Cep63 cylindrical architecture that self-assembled on a flat substrate displayed a decreased but still detectable level of dynamic turnover. Interestingly Polo-like kinase 4 (Plk4) a key regulator of centriole biogenesis also dynamically phase-separated from a Cep152-bound state around a centriole (i.e. ring state) into a dot-like low-nanoscale spherical condensate (i.e. dot state) upon autophosphorylating its C-terminal cryptic polo-box domain. Additional in vitro and in vivo data suggest that the Plk4 condensate serves as an assembling body at the future procentriole assembly site by amassing downstream procentriole assembly components such as STIL and Sas6 and facilitating Plk4-mediated centriole biogenesis. Thus the formation of biomolecular condensates appears to be a fundamental step that not only promotes the self-assembly of a pericentriolar architecture but also triggers the process of centriole duplication. Along with this progress we have been focusing on examining the mechanism underlying pericentriolar material (PCM) organization self-assembling activity of pericentriolar scaffold proteins molecular basis of building higher-order PCM architectures. To this end we performed size-exclusion chromatography sedimentation equilibrium ultracentrifugation and interferometric scattering mass spectrometry and showed that the heterotetrameric building block generates octameric and hexadecameric complexes in a concentration-dependent manner suggesting that the cylindrical self-assembly is formed through stepwise processes. By using MINFLUX nanoscopy which offers low-nanometer-scale localization precision in a three-dimensional space we further showed that mutants defective in forming the Cep63-Cep152 heterotetramer exhibited crippled pericentriolar Cep152 organization consequently failing to promote polo-like kinase 4 (Plk4)'s dynamic relocalization from around the centriole to the future procentriole assembly site as well as Plk4-mediated centriole duplication. Remarkably the entire self-assembly process could be driven by two short uncharacterized regions (which we named ""self-assembly modules"") in Cep63 and Cep152 capable of cophase-separating and generating cylindrical self-assemblies in vitro. Fluorescence recovery after photobleaching revealed that the self-assembled architecture is highly dynamic undergoing internal rearrangement within the assembly while exchanging its components with those in the surroundings. Dynamic turnover of pericentriolar Cep63 and Cep152 has also been observed in human centrosomes. Intriguingly multiple cancer-associated Cep63 and Cep152 mutations are found in human cancer tissues (Catalogue of Somatic Mutations in Cancer; https://cancer.sanger.ac.uk/cosmic) but not in the gnomAD (https://gnomad.broadinstitute.org) which generally represents wildtype variants. Several of these mutations are present within the regions forming the heterotetrameric Cep63-Cep152 complex. Thus investigating the mutations' significance could offer a deeper understanding about the architecture-function relationship of the Cep63-Cep152 complex. It may also help uncover new principles of building the Cep63-Cep152 self-assembly and provide valuable insights into the causes of PCM-associated human disorders. Given the evolutionarily conserved organization of PCM this work could serve as a paradigm for investigating the structure and function of centrosomal scaffolds in other organisms." 1105026 +No NIH Category available Antibodies;Appearance;Area;Cancer Center;Cell Death;Cell membrane;Cell surface;Cells;Clinical Trials;Collaborations;Development;Diagnosis;ERBB2 gene;Epidermal Growth Factor Receptor;Exposure to;FOLH1 gene;GPC3 gene;Goals;Head and neck structure;IL2RA gene;Image;Light;Liposomes;Malignant Neoplasms;Membrane;Mucin 1 protein;Names;Necrosis;Normal Cell;Penetration;Photosensitizing Agents;Process;Proteins;Reagent;Sensitivity and Specificity;Singapore;Site;Surgeon;Therapeutic Effect;Tissues;cancer cell;cancer therapy;cell injury;cell killing;cell type;chemotherapy;effective therapy;esophageal squamous cell cancer;hydrophilicity;imaging modality;imaging probe;improved;manufacturing scale-up;mesothelin;nanoparticle;nanoparticle delivery;nanosized;non-invasive imaging;novel;photoimmunotherapy;targeted cancer therapy;tumor Cancer-cell specific therapy: photo-immunotherapy n/a NCI 10926237 1ZIABC011513-11 1 ZIA BC 11513 11 12032143 "KOBAYASHI, HISATAKA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1611216 NCI Photoimmunotherapy has been established as a potential and highly selective cancer therapy against EGFR HER2 PSMA and CD25 postive tumors. All targeted cells are killed by necrotic cell death after irreversible damage to the cell membrane immediately after exposure to near infrared light at 690 nm. We are currently investigating precise mechanisms of membrane damage. We are also expanding the repertoire of potential target molecules to include MUC1 CEA laminine GPC3 mesothelin etc. by obtaining new antibodies for covering wider varieties of cancer. Additionally we are also establishing novel non-invasive imaging methods to diagnose the therapeutic effects of PIT because necrotic cell killing induced by PIT is a very rapid process and cells die well in advance of changes of physical appearance on conventional images. We have recently discovered that PIT dramatically increases (20-fold) the delivery of nanoparticle sized therapies (e.g. liposomal chemotherapy) to PIT-treated cancer tissue. Therefore the combination of PIT with nano-sized cancer reagents holds potential for even more effective therapy. Finally we are now preparing clinical trials in head and neck and esophageal squamous cell cancer at NCI/Hopkins National Cancer Center Singapore and Netherland/Groningen Univ in collaboration with surgeons at these sites. We are working with the Image Probe Development Center (IPDC) to scale up production of IR700 and antibody-IR700 conjugates for eventual use in these trials. 1611216 +No NIH Category available Angiography;Antibodies;Binding;Biodistribution;Biological;Cells;Clinical;Contrast Media;Detection;Diagnostic;Disease;Electron Transport;Fluorescence;Fluorescence Resonance Energy Transfer;Gadolinium;Gamma-glutamyl transferase;Homo;Indocyanine Green;Iodine;Label;Lesion;Magnetic Resonance Imaging;Malignant Neoplasms;Molecular;Operative Surgical Procedures;Optics;Photons;Procedures;Property;Published Comment;Radioisotopes;Radionuclide Imaging;Sensitivity and Specificity;Signal Transduction;Specificity;Testing;Tissues;X-Ray Computed Tomography;cancer imaging;clinical application;design;dimer;flexibility;fluorescence imaging;imaging modality;imaging probe;in vivo;molecular imaging;pharmacologic;rational design Activatable molecular cancer imaging probe n/a NCI 10926236 1ZIABC011512-11 1 ZIA BC 11512 11 12032143 "KOBAYASHI, HISATAKA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 179024 NCI We have been investigating the rational design and in vivo applications of target-cell specific activatable probes. Designing these probes based on their photo-chemical (e.g. activation strategy) pharmacological (e.g. biodistribution) and biological (e.g. target specificity) properties has recently allowed the rational design and synthesis of target-cell specific activatable fluorescence imaging probes which can be conjugated to a wide variety of targeting molecules. Several different photo-chemical mechanisms have been utilized each of which offers a unique capability for probe design. These include: self-quenching homo- and hetero-fluorescence resonance energy transfer (FRET) H-dimer formation and photon-induced electron transfer (PeT). In addition the repertoire is further expanded by the option for reversibility or irreversibility of the signal emitted using the aforementioned mechanisms. Given the wide range of photochemical mechanisms and properties target-cell specific activatable probes possess considerable flexibility and can be adapted to specific diagnostic needs. From a translational viewpoint including considerations of both the clinical value and regulatory approval requirements several clinically applicable candidates including indocyanine green labeled antibodies or a small molecular gamma-glutamyltransferase activatable probe which are designed to be used during surgical or endoscopic procedures have been tested. 179024 +No NIH Category available Autophagocytosis;Breast;Breast Cancer Cell;CBFB gene;Cancer Etiology;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Cytoplasm;Defect;Etiology;Event;FDA approved;Future;Gene Expression;Gene Expression Regulation;Genetic Transcription;Genomics;Goals;Human;Malignant Neoplasms;Mammary Neoplasms;Mediating;Mesenchymal Stem Cells;Metabolic;Modeling;Molecular;Mutate;Oncogenes;Pathway interactions;Ramp;Reporting;Repression;Research;Role;Signal Transduction;TP53 gene;Translational Regulation;Translations;malignant breast neoplasm;mortality;novel;novel therapeutic intervention;osteoblast differentiation;osteosarcoma;pediatric patients;programs;sarcoma;targeted treatment;transcription factor;tumor Vulnerabilities in osteosarcoma and breast cancer n/a NCI 10926234 1ZIABC011504-11 1 ZIA BC 11504 11 10270570 "HUANG, JING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1777187 NCI Osteosarcoma (OS) is a leading cause of cancer-related death in pediatric patients. Mortality rates for this cancer have not changed substantially during the last three decades partly due to the lack of an FDA-approved targeted therapy. Understanding the etiology of OS is a critical need for developing new treatment options. Genomic sequencing studies did not find any dominant actionable targets. Our strategy is to identify OS cells' survival signals related to the p53 pathway. In addition to human OS cell lines we have been using mesenchymal stem cells (MSCs) as a model since they are the putative cell-of-origin of OS cells. During this review period we have made several critical advances. First we showed that p53 represses RUNX2 expression in MSCs and p53 loss predisposes these cells to osteoblast differentiation providing an explanation for the clinical observation that OS is tightly associated with p53 loss. Second we identified the CBFB/RUNX2 axis as a survival signal in OS cells. Third we uncovered that in the context of p53 loss oncogenes determine the types of sarcomas originating from MSCs. For example the cFos-Sox9 axis promotes chondroblastic OS from p53 null MSCs. Future studies are focused on further investigating the pro-survival function of RUNX2 in OS. We hope that we will find vulnerabilities of OS in RUNX2-regulation gene expression that can be exploited for developing a novel treatment of OS. We have recently ramped up our efforts to study translation dysregulation in breast cancer based on our discovery of a new function for CBFB in the translational regulation of breast cancer. The CBFB gene is mutated in about 5 percent of breast tumors; however its function in breast cancer had not been known. We were the first to report that CBFB has a tumor-suppressive role in breast cancer. The underlying molecular mechanism was completely unexpected. In contrast to the well-accepted view that CBFB is a transcription factor we found that cytoplasmic CBFB directly regulates translation in breast cancer cells. Because transcriptional events are difficult to target translation represents a vital step in gene expression for identifying cancer vulnerabilities. Indeed our preliminary studies suggested that downstream events caused by the deregulation of CBFB-mediated translation could be further exploited to identify vulnerabilities in breast cancer. Therefore understanding CBFB-regulated translation in breast cancer has become a major focus of my research program. Ongoing efforts are concentrated on investigating the metabolic shift and autophagy dysregulation caused by the CBFB defect in breast cells. 1777187 +No NIH Category available Blood Vessels;CCR;Cells;Cephalic;Cessation of life;Clinical;Clinical Protocols;Collaborations;Disease;Disseminated Malignant Neoplasm;Elements;Goals;Immune;Immune response;Immunosuppression;Laboratories;Laboratory Research;Malignant Neoplasms;Medical Oncology;Patient Care;Patient Monitoring;Patients;Protocols documentation;Quality of life;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Research;Role;Sampling;Stromal Cells;Stromal Neoplasm;Study Section;Surgical Oncology;System;Translational Research;Tumor Markers;United States National Institutes of Health;Unresectable;Work;clinical practice;clinical translation;curative treatments;design;extracellular vesicles;immune activation;immunoregulation;improved;improved outcome;irradiation;liquid biopsy;nanobiology;neoplastic cell;particle;patient population;phosphatidylserine receptor;response to injury;tissue injury;tool;translational goal;translational research program;treatment response;tumor;tumor progression Discovery of Tumor Treatment Response and Systems-based EVP Signatures n/a NCI 10926233 1ZIABC011503-11 1 ZIA BC 11503 11 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 866419 NCI As a practicing radiation oncologist seeking to integrate my laboratory and clinical efforts into a cohesive translational research program I have focused my clinical practice on the care of patients with metastatic cancers for whom radiation may be beneficial. In the past year I created the Treatment of Extra-cranial Advanced Malignancies (TEAM) group in the NCI Radiation Oncology Branch and we are developing protocols designed to improve the assessment and treatment of patients with advanced malignancies. A major focus of my work with the TEAM group is liquid biopsies and a major research aim currently is to determine what liquid biopsy or biofluid EVP profiles correlate with responses to treatment. The translational research efforts of this project are following a two-pronged approach: 1) collaborating with medical and surgical oncology colleagues at NIH to investigate EVPs as biomarkers for tumor status as part of those collaborators' existing protocols and 2) developing new clinical protocols to capture information and samples from this patient population in a more cohesive and informative manner. Both of these approaches are supported by and provide support to the CCR's clinical translational mission and the basic scientific work ongoing in the Translational Nanobiology Section for the study of EVP repertoires. 866419 +No NIH Category available Acceleration;Area;Biological;Biology;Biomedical Research;Biophysics;Blood Tests;Blood Vessels;CCR;Cancer Patient;Cells;Collaborations;Communities;Computer software;Detection;Disease;Foundations;Future;Goals;Immune;Immune Evasion;Immune response;Immunobiology;Knowledge;Malignant Neoplasms;Measures;Medicine;Methods;Mission;Molecular;Monitor;Neoplasm Circulating Cells;Nucleic Acids;Patient Care;Protocols documentation;Radiation;Reproducibility;Research;Resolution;System;Translational Research;Tumor Biology;Vision;Work;anticancer research;biological systems;biophysical properties;clinical translation;exosome;extracellular vesicles;frontier;improved;interest;liquid biopsy;macromolecular assembly;microvesicles;multiple omics;nano;nanobiology;nanoparticle;nanoscale;neglect;novel;particle;programs;submicron;tool;treatment response;treatment strategy;tumor;tumor progression Biophysical Characterization of EVPs and other Macromolecular Nanoparticles n/a NCI 10926232 1ZIABC011502-11 1 ZIA BC 11502 11 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 750015 NCI Liquid biopsies are part of this emerging frontier in biomedical research. This frontier is of interest to all areas of biology and medicine and is of particular interest to the cancer research community. Circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) are two types of liquid biopsies where clear progress has been made in the past decade towards understanding these CTC and cfNA tumor-related and systems-based biological information. Systematic accurate and reproducible studies of sub-micron extracellular vesicles (EVs) and other nanoscale macromolecular assemblies (collectively referred to hereafter as extracellular vesicles and particles or EVPs) are difficult to perform due to a lack of robust and reliable tools for correctly measuring these submicron and nanoscale materials. CCR's mission is to improve the lives of all cancer patients by solving important challenging and neglected problems in cancer research and patient care. The Translational Nanobiology Section's particular expertise perspective collaborations and vision within CCR is building bridges to span the existing gaps between basic biophysical and metrological first principles advanced molecular multi-omics strategies and clinical translational investigation in order to develop systematic robust and accurate ways to study EVPs tumor- immune- and stromal-/vascular- EVP compositions as they relate to tumor progression and treatment response in our cancer patients. Although the specific focus of my lab pertains most immediately to cancer and cancer-related immunobiology we intend for our work to be a general asset to the biomedical research community. As such my Section is committed to sharing our tools for general research use so that they can accelerate studies in other diseases as well. The ultimate goal of my program is to leverage the information content in EVPs to interrogate biological systems in a systematic manner that is by identification and characterization of specific sub-sets of EVPs to 'read' the status of compartments represented by those sub-sets. The purpose of Projects 1 and 2 in the Translational Nanobiology Lab is to develop and demonstrate the use of new tools for the field to use that will enable us to monitor tumor immune and vascular/stromal systems in a manner that we hope will enable us to perform blood tests to detect relevant changes in those systems early in the course of radiation or other therapies and we hope that this will more broadly serve as a foundation for enabling selectively (system-specific) adaptive treatment strategies in the future. Project 1 is focused on spanning the gap in available tools and knowledge to accurately characterize the liquid biopsy components EVPs and their cargo for Project 2. 693135 +No NIH Category available Acceleration;Area;Biological;Biology;Biomedical Research;Biophysics;Blood Tests;Blood Vessels;CCR;Cancer Patient;Cells;Collaborations;Communities;Computer software;Detection;Disease;Foundations;Future;Goals;Immune;Immune Evasion;Immune response;Immunobiology;Knowledge;Malignant Neoplasms;Measures;Medicine;Methods;Mission;Molecular;Monitor;Neoplasm Circulating Cells;Nucleic Acids;Patient Care;Protocols documentation;Radiation;Reproducibility;Research;Resolution;System;Translational Research;Tumor Biology;Vision;Work;anticancer research;biological systems;biophysical properties;clinical translation;exosome;extracellular vesicles;frontier;improved;interest;liquid biopsy;macromolecular assembly;microvesicles;multiple omics;nano;nanobiology;nanoparticle;nanoscale;neglect;novel;particle;programs;submicron;tool;treatment response;treatment strategy;tumor;tumor progression Biophysical Characterization of EVPs and other Macromolecular Nanoparticles n/a NCI 10926232 1ZIABC011502-11 1 ZIA BC 11502 11 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 750015 RMOD Liquid biopsies are part of this emerging frontier in biomedical research. This frontier is of interest to all areas of biology and medicine and is of particular interest to the cancer research community. Circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) are two types of liquid biopsies where clear progress has been made in the past decade towards understanding these CTC and cfNA tumor-related and systems-based biological information. Systematic accurate and reproducible studies of sub-micron extracellular vesicles (EVs) and other nanoscale macromolecular assemblies (collectively referred to hereafter as extracellular vesicles and particles or EVPs) are difficult to perform due to a lack of robust and reliable tools for correctly measuring these submicron and nanoscale materials. CCR's mission is to improve the lives of all cancer patients by solving important challenging and neglected problems in cancer research and patient care. The Translational Nanobiology Section's particular expertise perspective collaborations and vision within CCR is building bridges to span the existing gaps between basic biophysical and metrological first principles advanced molecular multi-omics strategies and clinical translational investigation in order to develop systematic robust and accurate ways to study EVPs tumor- immune- and stromal-/vascular- EVP compositions as they relate to tumor progression and treatment response in our cancer patients. Although the specific focus of my lab pertains most immediately to cancer and cancer-related immunobiology we intend for our work to be a general asset to the biomedical research community. As such my Section is committed to sharing our tools for general research use so that they can accelerate studies in other diseases as well. The ultimate goal of my program is to leverage the information content in EVPs to interrogate biological systems in a systematic manner that is by identification and characterization of specific sub-sets of EVPs to 'read' the status of compartments represented by those sub-sets. The purpose of Projects 1 and 2 in the Translational Nanobiology Lab is to develop and demonstrate the use of new tools for the field to use that will enable us to monitor tumor immune and vascular/stromal systems in a manner that we hope will enable us to perform blood tests to detect relevant changes in those systems early in the course of radiation or other therapies and we hope that this will more broadly serve as a foundation for enabling selectively (system-specific) adaptive treatment strategies in the future. Project 1 is focused on spanning the gap in available tools and knowledge to accurately characterize the liquid biopsy components EVPs and their cargo for Project 2. 56880 +No NIH Category available Acceleration;Adverse effects;Aging;Alternative Splicing;Alzheimer's disease model;Apoptosis;Area;Astrocytes;Biogenesis;Biological Assay;Brain;Breeding;CAR T cell therapy;CD19 gene;CD8-Positive T-Lymphocytes;Cancer Survivor;Cell Aging;Cell Proliferation;Cells;Chronic Lymphocytic Leukemia;Clinic;Clinical;Clinical Trials;Coculture Techniques;Cranial Irradiation;Craniocerebral Trauma;DNA Repair;DNA cassette;Data;Development;Disease;Drug Screening;Fibroblasts;Generations;Glioblastoma;Human;Impaired cognition;Impairment;In Vitro;Incidence;Injections;Invaded;Investigation;Knock-in Mouse;Laboratory Finding;Length;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;Methods;Mitochondria;Mitotic spindle;Modeling;Mus;Mutation;Natural Products;Nature;Neurodegenerative Disorders;Normal Cell;Oncogenic;Organ;Oxidative Phosphorylation;Pathology;Pathway interactions;Patients;Phenotype;Physiological;Prevention;Primates;Process;Progeria;Proliferating;Protein Isoforms;Protocols documentation;Publications;RNA Splicing;Radiation therapy;Regulation;Research;Ribosomes;Safety;Small Interfering RNA;Solid Neoplasm;Syndrome;System;T-Lymphocyte;TP53 gene;Tamoxifen;Therapeutic;Therapeutic Effect;Transgenic Mice;Translations;Tumor Suppression;cancer cell;cancer immunotherapy;cancer type;cell type;chimeric antigen receptor T cells;chronic traumatic encephalopathy;clinical application;contact sports;drug candidate;drug repurposing;experimental study;functional improvement;high throughput screening;humanized mouse;improved;in vivo;in vivo Model;knock-down;leukemia;lung cancer cell;military veteran;mouse model;mutant;non-oncogenic;novel;promoter;senescence;small molecule libraries;stemness;therapeutic target;tumor p53 Aging and Cancer n/a NCI 10926230 1ZIABC011496-11 1 ZIA BC 11496 11 9692183 "HARRIS, CURTIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1713400 NCI The CAR-T cells with the delta133p53alpha expression cassette have been examined for anti-tumor activity in an established CD19+ leukemia model. The delta133p53alpha-CAR-T cells showed superior tumor killing activity compared with the control CAR-T cells both in a co-culture experiment in vitro and in a mouse injection experiment in vivo. This superior activity was revealed to be associated with inhibition of p53-mediated senescence and apoptosis (while p53-mediated DNA repair was maintained) and metabolic shifts such as increased mitochondrial oxidative phosphorylation and ribosome biogenesis which both favor T cell stemness proliferation and sustained activity. Importantly we observed the delta133p53alpha-induced functional improvement not only in CAR-T cells derived from normal donors but also in those derived from CLL (chronic lymphocytic leukemia) patients who did not respond to the current CAR-T cell therapy supporting its clinical therapeutic value. These data warrant further investigation of this novel CAR-T cell strategy toward treatment of current non-responders and patients with currently hard-to-treat solid tumors. To investigate in vivo therapeutic effects of delta133p53alpha we have generated multiple mouse models that express the human/primate-specific delta133p53alpha isoform. Since modest expression of delta133p53alpha in human p53-knocked-in mice (hupki) did not show any effects on accelerated aging phenotypes in progeria model mice we generated the safe-harbor transgenic mice in which delta133p53alpha under the control of the synthetic CAG promoter (strong) or the endogenous ROSA26 promoter (intermediate) can be induced via a Cre/ERT2-loxP system. These transgenic mice were confirmed to express delta133p53alpha in various organs upon tamoxifen treatment. They are currently under the aging study to examine physiological aging processes and spontaneous tumor incidence and spectrum and also being bred with the progeria model mice to examine an effect on accelerated aging phenotypes. These mice are also an essential material for our study on neurodegenerative diseases through breeding with Alzheimer's disease model mice and applying disease-causing protocols such as cranial irradiation (mimicking radiotherapy-induced late cognitive impairment in cancer survivors) and head trauma (mimicking chronic traumatic encephalopathy in contact sports athletes and military veterans). We have performed high-throughput screening of small molecule libraries repurposed drugs and natural products to identify drug candidates that can enhance the expression of delta133p53alpha leading to the two candidates (compound 'A' and compound 'C' whose identities cannot be disclosed here). They were confirmed to increase the delta133p53alpha expression and inhibit senescence-associated secretory phenotype in otherwise senescent astrocytes and progeria-derived fibroblasts. Other human cell types we previously used (e.g. CAR-T cells and endogenous CD8+ T cells) and the delta133p53alpha-humanized mouse models as mentioned above are being treated with these compounds to further confirm their activity and therapeutic potential. Since these compounds have already been used in clinical trials for safety and other diseases they could significantly facilitate the translation of our laboratory findings to the clinic. We have pioneered a new area of p53 research by investigating cancer-associated mutant versions of the p53 isoforms p53beta and delta133p53alpha. While siRNA knockdown of a splicing factor SRSF3 was previously shown to induce p53beta (via alternative splicing switching from full-length p53 to p53beta) and cellular senescence in p53-wild-type normal human cells we have recently discovered that also in p53-mutant GBM and lung cancer cells SRSF3 knockdown induces p53beta (with a cancer-associated mutation) and causes cellular senescence and apoptosis. These data suggest that SRSF3 knockdown can convert the oncogenic mutant full-length p53 to the tumor-suppressive mutant p53beta isoform prompting us to develop a method of cancer-specific delivery of SRSF3 siRNA that aims at cancer-specific senescence and apoptosis with no or minimal adverse effect on normal cells. We have also revealed that wild-type and mutant delta133p53alpha isoforms are functionally distinct in GBM cells. Mutant delta133p53alpha functions oncogenic through increased cell proliferation and invasion impaired DNA repair and activated IL4I1/IDO1/AHR pathway which can be a therapeutic target in p53-mutant GBM. [Publications] Muys BR Shrestha RL Anastasakis DG Pongor L Li XL Grammatikakis I Polash A Chari R Gorospe M Harris CC Aladjem MI Basrai MA Hafner M Lal A. Matrin3 regulates mitotic spindle dynamics by controlling alternative splicing of CDC14B. Cell Rep. 42: 112260 2023. 1713400 +No NIH Category available 16S ribosomal RNA sequencing;Acceleration;Acids;Adenocarcinoma;African;Algorithms;Annual Reports;Anti-Inflammatory Agents;Antigen Presentation Pathway;Anus;Bioinformatics;Biological Assay;Biological Factors;Biological Markers;Blood Platelets;CA-19-9 Antigen;CD4 Positive T Lymphocytes;Campylobacter;Cancer Patient;Cancer Prognosis;Case/Control Studies;Cells;Cholestanes;Classification;Clinical;Collaborations;Colorectal Cancer;Contracts;Creatine;DNA Methylation;Data;Data Set;Detection;Development;Diagnosis;Diagnostic;Disease;Environmental Exposure;Esophageal carcinoma;Esophagus;Evaluation;Exposure to;Fusobacterium;Genets;Glucuronides;Goals;Human;Hydrocortisone;Immunotherapy;In Vitro;Infection;Infiltration;Inflammatory;Intrahepatic Cholangiocarcinoma;Investigation;Ions;Laboratories;Lactobacillus;Large Intestine Carcinoma;Length;Leptotrichia;Liquid Chromatography;Location;Lung;Lung Adenocarcinoma;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Measures;Medical;Messenger RNA;Metagenomics;MicroRNAs;Mitochondria;Modality;Modeling;Molecular;Molecular Analysis;Molecular Carcinogenesis;Molecular Genetics;Mus;Mutation;Myeloid Cells;N-Acetylneuraminic Acid;NF-kappa B;Neoplasm Metastasis;Neutrophil Infiltration;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Plasma;Play;Population;Prevotella;Probiotics;Prognosis;Property;Proteome;Recurrence;Reporting;Research;Residencies;Resources;Risk;Role;Sampling;Science;Serum;Signal Transduction;Smoking;Statistical Data Interpretation;Streptococcus;Sulfate;TLR4 gene;TP53 gene;Taxonomy;The Cancer Genome Atlas;Therapeutic;Tissue Sample;Tissues;Tumor Tissue;Urine;Validation;Veillonella;Work;algorithm training;analytical method;anticancer research;bench to bedside;cancer biomarkers;cancer cell;cancer diagnosis;cancer risk;cancer therapy;carcinogenesis;cohort;cytokine;diagnostic value;dysbiosis;genome wide association study;gut microbiome;health disparity;high risk;immune cell infiltrate;improved;individual patient;interleukin-23;liquid biopsy;lung carcinogenesis;machine learning algorithm;metabolome;microbial;microbiome;mouse model;neoplastic cell;neutrophil;novel;patient subsets;precision medicine;precision oncology;prevent;prognostic;prognostic tool;programs;recruit;riboside;screening;single-cell RNA sequencing;tandem mass spectrometry;targeted treatment;therapeutic target;therapy outcome;tool;transcriptome sequencing;tumor;tumor microenvironment;tumorigenesis;tumorigenic;urea cycle;urinary;validation studies Precision Medicine of Cancer n/a NCI 10926229 1ZIABC011492-11 1 ZIA BC 11492 11 9692183 "HARRIS, CURTIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2570099 NCI Precision medicine in cancer is multifaceted and the lab's research has led to significant discoveries that will advance the diagnostic and prognostic utilization of biomarkers including elucidating the role and mechanism the microbiome plays in lung carcinogenesis. Cancer Microbiome: To identify additional diagnostic targets for precision medicine we previously demonstrated that the microbiome is altered in lung cancer and identified the Acidovorax genus as enriched in lung cancer and associated with TP53 mutations and smoking. Full-length 16S sequencing identified the species Acidovorax temperans which lead us to ask if microbial dysbiosis as modeled by A. temperans instillation played a passenger or driver role in tumor development. In a lung adenocarcinoma mouse model we found repeated exposure to A. temperans dramatically accelerated tumor development and reduced survival indicating a driver role. In contrast instillation of the lung commensal species Lactobacillus gasseri had no effect on tumor development. By FACS and scRNA-seq analyses we identified a pro-inflammatory pathway specifically increased in A. temperans mice where TLR4/NF-kB signaling was activated in macrophages which upregulated MHC II to activate effector CD4+ T cells polarizing them to TH17 states. These TH17 cells recruited neutrophils to the lungs which acquired tissue residency and pro-tumorigenic phenotypes. The neutrophils then increased IL-23 signaling to recruit additional TH17 cells. In contrast L. gasseri-treated mice upregulated anti-inflammatory cytokines to inhibit neutrophils and prevent CD4+ T activation. The scRNA-seq portion of this work is currently Under Review at Oncogenesis. We are now working to identify strategies to ameliorate the tumor development accelerated by A. temperans including addition of probiotic bacterial strains. As the rates of esophageal carcinoma (ESCA) are increasing globally particularly adenocarcinoma in the West we also asked if the esophageal microbiome could reveal targets for precision medicine in this disease as well. In collaboration with Leigh Greathouse we performed 16S sequencing on 229 tissue samples from the NCI-MD case control study (126 NT 98 T) and also performed metagenomic analyses of the non-human aligned reads in the RNA-seq (11 NT 162 T) and WGS datasets (61 NT 62 T) for TCGA ESCA. We identified four genera co-enriched in ESCA tumor tissue across datasets: Campylobacter Fusobacterium Prevotella and Streptococcus the first such description of these four taxa. We identified further bacterial co-occurrences enriched in colorectal cancer (Fusobacterium Prevotella Leptotrichia Veillonella) another gut malignancy. Predicted immune cell infiltration identified these taxa with an increase in platelet infiltration which occurs prior to ESCA metastasis. This work is currently Under Review at Scientific Reports. In collaboration with Eytan Ruppin we continued our investigations into the gut microbiome developing an algorithm for identifying microbial reads within scRNA-seq data. We first showed newer droplet-based sequencing modalities return fewer microbial reads than plate-based but are far more specific in in vitro infection models. Colorectal and ESCA patient datasets revealed most bacterial reads are present in myeloid cells within the tumor microenvironment and not tumor cells as previously thought. Bacterial-positive myeloid cells upregulated pro-inflammatory cytokines while bacterial-positive tumor cells upregulated antigen presentation pathways which suggests potential roles for intratumoral bacterial burden and location in immunotherapy. This work is currently Under Review at Science Advances. Cancer Metabolome: Correlation of identified metabolites with specific cancers created biomarker profiles that can be utilized for non-invasion diagnostic and prognostic evaluation of many types of human cancer and could pave the way for targeted therapies. Liquid biopsy of urine serum and plasma are used to measure four biomarkers (creatine riboside (CR) N-acetylneuminic acid (NANA) cortisol sulfate (CS) and 27alpha-nor-5beta-cholestane-3alpha 7alpha 12alpha 24alpha 25alpha Pentol glucuronide (NCPG) of lung cancer by mass spectrometry (Haznadar M. et al. Cancer Epidemiol. Biomarker Prev. 25:978-86 2016). CR paired with other identified urinary metabolite biomarkers such as (NANA) improve diagnostic capability and reliability (Mathe Ewy A et al. Cancer research vol. 7412 (2014): 3259-70). We have shown that creatine riboside (CR) is a cancer cell-derived metabolite that at high levels is associated with mitochondrial urea cycle dysregulation and it an indicator of poor prognosis for cancer patients (Parker A. et al. JNCI 132(14)2022). These foundational studies validated the use of urinary metabolite screening leading to further investigation into biomarker association with human cancer as well as the analytical method using liquid chromatography-tandem mass spectrometry (Patel DP. et al. J Pharm Biomed Anal. 191: 113596 2020). And as mentioned in the 2020 and 2021 annual report urinary metabolite biomarker profiling could offer diagnostic and prognostic evaluation of intrahepatic cholangiocarcinoma (ICC). Employing UPLC-MS/MS four metabolites for the quantitation of metabolites CR N-acetylneuraminic acid (NANA) cortisol sulfate and a glucuronide fragmented ion designated as 561+ are significantly increased in HCC and ICC and are robust at classifying ICC in combination with a clinically utilized marker CA19-9. The NCI-MD cohort were studied and observations verified by the TIGER-LC cohort. By conducting rigorous analytical validations and mechanistic studies our aim is to gain a comprehensive understanding of the significance and potential implications of these novel metabolites in human cancer development. This research paved the way for prognostic tools such as an accurate risk score calculator developed in the lab utilizing the described biomarkers with additional clinical factors. The calculator is built using sophisticated machine learning algorithms trained on the NCI-MD lung cancer cohort. Using this tool both a R_score as a cancer risk predicator and predication of recurrence risk can be generated for a specific patient with a high degree of accuracy. Through this research the lab has determined properties that are significant for a biomarker to its use in CLIA lab-based assays of biomarkers in liquid biopsy which ultimately will benefit patients' outcomes. 2570099 +No NIH Category available Affect;Aneuploidy;Binding;Biochemical;Cell Cycle Progression;Cell division;Cells;Centromere;Chemicals;Chromatin;Chromatin Structure;Chromosome Segregation;Chromosomes;Complex;Defect;Detection;Ensure;Enzymes;Event;Genome;Genomic Instability;Geometry;Histones;Human;In Vitro;Kinetochores;Maintenance;Microtubules;Mitosis;Mitotic;Phosphorylation;Poison;Post-Translational Protein Processing;Process;Proteins;Research;Role;Signal Pathway;Signal Transduction;Sister Chromatid;Somatic Cell;System;Work;Xenopus;aurora B kinase;blastomere structure;cancer cell;chromatin modification;daughter cell;egg;embryo cell;histone modification;interdisciplinary approach;interest;prevent;protein purification;reconstitution;repaired;response;scaffold;technique development;vertebrate embryos Role of kinetochore proteins in chromosome segregation n/a NCI 10926228 1ZIABC011491-11 1 ZIA BC 11491 11 12032122 "KELLY, ALEXANDER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1496919 NCI The faithful segregation of chromosomes is the key event of mitosis and its dysregulation can lead to aneuploidy and genomic instability both hallmarks of cancer cells. A fundamental component in genome distribution during cell division is the centromere. Proteinaceous complexes known as kinetochores that form on centromeric chromatin generate a dynamic interface with spindle microtubules to segregate chromosomes to each daughter cell. Signalling pathways emanating from centromeric chromatin detect and correct errors in the geometry of chromosome-spindle microtubule attachments and prevent cell cycle progression until all chromosomes are properly connected. A key player in this process is the kinase Aurora B which is part of the Chromosomal Passenger Complex (CPC) and resides at the centromeric chromatin between two joined sister chromatids. Histone modification and chromatin structure control the localization abundance and activity of Aurora B at the centromere. Aurora B phosphorylates targets that regulate kinetochore-microtubule attachment to release erroneous geometries. However Aurora B also controls kinetochore assembly and we are interested in understanding the interplay between Aurora B's roles in assembly and error sensing. The proposed work will focus on defining the mechanisms by which centromeric chromatin functions as a scaffold to coordinate kinetochore assembly microtubule attachment and the detection and repair of erroneous attachments. The impact of mitotic histone modifications on chromatin structure and their roles in centromeric identity will be analyzed through in vitro reconstitution with purified proteins and in Xenopus egg extracts. The mechanism of chromatin binding by the CPC and its role in Aurora B kinase activation at the centromere will also be analyzed using a combination of structural and biochemical approaches. The mechanism by which the CPC responds to and senses tension applied by spindle microtubules to kinetochores will be examined in the Xenopus extract system and genetically defined human cells and elucidated with the development of techniques to globally define Aurora B substrates in response to microtubule poisons. 1496919 +No NIH Category available Actins;Address;African;Algorithms;Allografting;Animal Model;Antineoplastic Agents;Benzene;Bioinformatics;Biological Assay;Biological Testing;Breast Cancer cell line;Cancer Cell Growth;Cancer cell line;Cell Line;Cells;Cellular Assay;Central Nervous System;Central Nervous System Neoplasms;Child;Collaborations;Collection;Cytoskeleton;Data;Defect;Deoxyglucose;Dependence;Development;Dryness;Electronics;Esters;Euphorbiaceae;Ewings sarcoma;F-Actin;Formulation;Foundations;Fractionation;Glioblastoma;Glucose;Glycolates;Grant;HSF1;Investigation;Iowa;Isomerism;Link;Location;Macaranga;Malignant Neoplasms;Miniature Swine;Modeling;Molecular Target;Natural Compound;Natural Products;Natural Source;Nature;Neurofibromatosis 1;Optical Rotation;Pathway interactions;Pattern Recognition;Peripheral Nerve Sheath Neoplasm;Pharmacologic Substance;Pharmacotherapy;Phyllanthus;Plants;Play;Province;Renal Cell Carcinoma;Renal carcinoma;Reporting;Role;Sampling;Series;Sesquiterpenes;Small Interfering RNA;Source;Starvation;Structure;Synthesis Chemistry;Tanzania;Testing;Toxic effect;Trees;Tumor Cell Line;Universities;Variant;Xenograft Model;addiction;analog;anti-cancer therapeutic;anticancer activity;cell growth;cellular imaging;drug candidate;enantiomer;in vitro activity;in vivo Model;inhibitor;methyl group;novel;oxysterol binding protein;pi bond;preclinical development;renal toxin;schweinfurthin A;stem;tumor Development of Natural Product Leads as Anticancer Therapeutics n/a NCI 10926222 1ZIABC011470-12 1 ZIA BC 11470 12 11592706 "BEUTLER, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 798286 NCI ENGLERINS: Englerin A was isolated based on the activity of the organic extract of the bark of Phyllanthus engleri Pax in the NCI 60 cell screen. The extract was identified in a retrospective bioinformatic analysis of testing data for 68000 extracts which sought to identify samples with the most selectivity against renal cancer cell lines. Bioassay guided fractionation of the extract led to isolation of the novel sesquiterpene diester englerin A. Englerin A was isolated in high yield (1-4 g/kg dry wt.) from stem bark and root bark of the Tanzanian tree Phyllanthus engleri Pax (Euphorbiaceae). Isolation required three purification steps. Other plant parts from the initial collection did not contain appreciable amounts of englerins and were devoid of anticancer activity. Three collections of bark collected from the original location in Iringa Province Tanzania have all yielded similar amounts of englerin A showing that natural collections are a viable source for preclinical development. The NCI currently possesses 6 g of pure englerin A which is available for development activities isolated from Tanzanian bark. I recently reported a series of chlorinated analogues derived from englerin A one of which has activity only 2.5-fold weaker than the natural product. Structure-activity studies have established several important points: a) Cell growth inhibition is not simply due to release of glycolate a well-known but low-potency renal toxin since a reverse ester analogue which cannot generate glycolate is active. b) The cinnamate moiety tolerates substantial variation without loss of activity. The cinnamate double bond plays a rigidifying role but its electronic contributions are not important. c) The isopropyl group plays an important role in activity since its simplification to ethyl and methyl groups rapidly decreases potency. d) The cinnamate benzene ring is not required to be aromatic. Our current hypothesis is that the net effect of englerin A is to simultaneously starve the cells of glucose while creating an addiction to glucose. We believe that the selectivity depends on cells expressing both PKC-theta and HSF1 and/or being highly glucose dependent. Sensitivity to englerin A also correlates directly with sensitivity to 2-deoxyglucose further highlighting the link between englerin A sensitivity glucose dependence and PKC-theta activation. Englerin A was shown to be active in two different xenograft models. Pharmaceutical formulation and other preclinical development is ongoing. Collaborations with three synthetic chemistry groups have resulted in a number of active analogues which are being evaluated in tandem with the natural product. In addition we have discovered that englerin A has excellent in vitro activity in a large panel of Ewing's sarcoma cell lines. SCHWEINFURTHINS: I isolated schweinfurthins A and B from the African plant Macaranga schweinfurthii Pax. The compounds displayed potent and selective activity against central nervous system renal and breast cancer cell lines in the NCI 60 cell assay with GI50 values for four sensitive CNS tumor cell lines in the 10-25 nM range. The spectrum of anticancer activity did not match that of any currently used agent indicating that these compounds might be acting at a previously unrecognized target or through a novel mechanism. Thus far a total of 11 schweinfurthins have been isolated from nature. Synthetic strategies have been developed by the Wiemer lab (University of Iowa) to provide a reliable source of natural schweinfurthins and synthetic analogues for further biological testing. In the case of schweinfurthin F total synthesis of the (RRR) and (SSS) enantiomers and comparisons of spectral data optical rotations and bioassay data with those reported for the natural product have resulted in assignment of the natural compounds as the (RRR) isomers. These synthetic efforts have continued and most of the naturally occurring schweinfurthins have now been obtained by total synthesis. Investigations into the mechanism of action of schweinfurthins have yet to identify a proximate molecular target; however in glioblastoma cell lines it appears that a defective neurofibromatosis type 1 (NF1) pathway confers sensitivity. With a grant from the Children's Tumor Foundation we are conducting a massive siRNA screen for potential targets at a CRO. My collaboration with the Lockett lab (FNLCR) focused on the clear effect of natural schweinfurthins on the cellular actin cytoskeleton in sensitive cell lines. Development of pattern recognition algorithms for cellular images has enabled quantitation of changes in F-actin distribution with drug treatment. A synthetic analogue of schweinfurthin A has shown activity in an allograft model of peripheral nerve sheath tumor driven by an NF1 defect. Pharmaceutical development is ongoing with planned studies in genetically altered mini-pigs to examine three promising compounds for efficacy and toxicity. Further mechanism of action studies are planned to dissect the role of oxysterol binding proteins. 798286 +No NIH Category available Actinobacteria class;Agreement;Biological Assay;Boston;Cells;Chemicals;Collaborations;Collection;Data;Development;Funding;Future;Goals;Industrialization;Information Systems;International;Kansas;Kazakhstan;Laboratories;Libraries;Methodology;Microbiology;Molecular Target;National Institute of General Medical Sciences;Natural Products;Online Systems;Pharmaceutical Chemistry;Plant Extracts;Plants;Process;Research Personnel;Rome;Sampling;Science;Scientist;Series;Soil;Source;Specimen;Structure;System;Technology;Testing;Traditional Medicine;Travel;Tube;US State;Universities;analog;bioweapon;design;gang;improved;material transfer agreement;programs;repository;screening;screening program;virology Building Libraries with Chemical Diversity for Screening n/a NCI 10926221 1ZIABC011469-12 1 ZIA BC 11469 12 11592706 "BEUTLER, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 798286 NCI We established MTAs with three of the four NIGMS-funded Chemical Methodologies & Library Developments (CMLD) (Boston University University of Kansas and University of Pittsburgh). These three centers alone have provided over 15000 samples of known structure. Each CMLD has a distinct approach to library design thus there is negligible overlap between their libraries. The MTP has subsequently entered into numerous agreements with other academic and industrial partners to increase the breadth of our libraries. Notable collaborations with traditional medicinal chemistry groups are with Prof. Gang Liu of Tsinghua University and Prof. Roberto DiSanto of the University of Rome. Furthermore we have obtained a number of focused compound sets including LOPAC BioMol Natural Products ICCB Known Bioactives as well as a large series of synthetic compounds from DCTD NCI. As part of a US State Department-funded threat reduction program scientists at the former bioweapons (BW) facility in Stepnogorsk Kazakhstan have been encouraged to explore non-BW scientific horizons. The program is conducted under the umbrella of the International Science and Technology Center (ISTC) in Astana Kazakhstan. MTP staff traveled to Kazakhstan on five occasions to develop this collaboration. We have organized plant collections focused on the 800 species endemic to Kazakhstan. To date we have collected over 227 plant specimens; the plant extracts have been tested in the NCI 60 cell screen and prefractionated for testing in MTP screens. We have also collaborated with the Institute of Virology and Microbiology in Kazakhstan to screen 300 extracts of extremophilic actinomycetes from hypersaline and basic soils. Another library is a collection of 700 plant extracts from the Brazilian cerrado with Dr. Espindola of the University of Brasilia. Our ongoing collaboration with these laboratories has enabled us to receive a large collection of purified plant natural products as well. New samples have also been received from a collaboration with the University of Istanbul as well as hosting several Turkish scientists in the MTP. We recently began to add prefractionated samples from the DTP to our screening set replacing our in-house set. 503000 samples have been added so far with a similar number expected each year in the near future. Currently our storage system holds 65893 tubes and 1831 plates. Over the past 13 years the Chemical Diversity Development Section in the MTP has developed a customized web based assay and sample management system which allows our researchers to manage sample libraries design assay plates and store and analyze bioassay data. This system is currently undergoing a complete renovation to improve its functionality and to add new capabilities. 798286 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;Anatomy;Anti-Retroviral Agents;Autopsy;BACH2 gene;Biological Assay;Biopsy;Blood;Bronchoalveolar Lavage Fluid;CCR;CD4 Positive T Lymphocytes;Cells;Chronic;Clinical Protocols;Clonal Expansion;Collaborations;Colon;Colonoscopy;Complement;Containment;Data;Development;Evaluation;Event;Evolution;Fluorescence-Activated Cell Sorting;Funding;Future;Gammaretrovirus;Gastrointestinal tract structure;Gene Expression;Genes;Genetic;Goals;Grant;HIV;HIV Drug Resistance Program;HIV-1;Immunologics;Individual;Infection;Infrastructure;Interruption;Intestines;Investigation;Learning;Location;Lung;Lymphocyte;Lymphoid Tissue;Measures;Memory;Methodology;Mutation;National Institute of Allergy and Infectious Disease;National Institute of Neurological Disorders and Stroke;Natural History;Participant;Pathology;Pathway interactions;Patients;Penetration;Peripheral Blood Mononuclear Cell;Persons;Pharmaceutical Preparations;Plasma;Population;Process;Proliferating;Protocols documentation;Provirus Integration;Proviruses;Reporting;Research Personnel;STAT5B gene;Sampling;Sampling Studies;Shapes;Site;Sorting;Source;Structure;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Tonsil;United States National Institutes of Health;Universities;Viral;Viremia;Virus;Work;antiretroviral therapy;clinical center;cohort;digital;driving force;follow-up;homologous recombination;ileum;in vivo;innovation;insight;integration site;lymph nodes;next generation sequencing;novel strategies;programs;repository;tool;virus host interaction HIV Persistence During Suppressive Antiretroviral Therapy n/a NCI 10926220 1ZIABC011466-12 1 ZIA BC 11466 12 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1436333 OD These studies and others revealed no decrease in persistent viremia after drug intensification suggesting that persistent viremia may be the product of long-lived reservoirs of chronically infected cells. Others however suggested ongoing replication of HIV is the source of persistent viremia. In the last year we conducted a critical test of the question of whether ongoing HIV replication persists in sanctuary locations by analyzing HIV populations in blood and tissues from individuals after prolonged cART (8-16 y). In untreated individuals HIV replication is rapid and error prone leading to the accumulation of genetic changes that are readily detectable in the proviruses. Here we found that infected cells persist and clonally expand but there was no detectable evidence of HIV evolution nor was there any evidence of compartmentalization of the HIV proviruses in blood or tissues in six individuals who were studied during effective combination ART for prolonged periods cumulatively totaling over 60 patient-years of follow-up. These studies did not reveal any evidence for ongoing replication as a mechanism for HIV persistence during ART. Instead we found that HIV is maintained during therapy through long-lived cells that persist and can undergo clonal expansion. We are now building on these studies to quantify and genetically characterize virus in plasma to investigate HIV reservoirs in cellular compartments and expanding the range of our analyses by applying new single-cell methodologies and isolating specific cell subsets in blood and tissue from infected individuals. We are investigating HIV in plasma PBMC and cells derived from ileum and colon in infected individuals taking combination ART with suppressed less than 50 copies who are undergoing colonoscopy at the NIH Clinical Center. We have performed these colonoscopies in collaboration with J. Kovacs (CCMD) in the protocol Virologic and Immunologic Evaluation of Lymph Node Tonsillar and Intestinal Biopsies and Bronchoalveolar Lavage Fluid and have used a new sampling strategy that will yield useful information regarding the distribution of HIV-infected cells in the gastrointestinal tract. In collaboration with S. Hughes (HIV DRP) X. Wu (Leidos) J. Coffin (Tufts) M. Kearney (HIV DRP) and J. Mellors (University of Pittsburgh) we have investigated HIV integration sites in vivo in these individuals. We are expanding these analyses to investigate HIV-infected cells in CD4 cell subsets in individuals undergoing long-term combination ART (supported by Intramural AIDS Targeted Antiviral Program funding). It is critical to learn how clonal expansion shapes the overall population of HIV-infected cells. It is also important to understand how HIV proviruses are expressed in these subsets. We began these studies using blood-derived T cells but we also need to understand the dynamics of HIV-infected T cells as they traffic through lymphoid tissue where 98% of all lymphocytes are located. We also need to know whether clonal expansion of HIV-infected cells in blood and tissues reflects global T-cell expansion. We will therefore complement our studies of clonal expansions of HIV-infected cells by investigating the diversity and clonal expansion of the T-cell repertoire using next-generation sequencing to quantify the T-cell receptor diversity in these subsets (collaboration with E. Boritz and D. Douek). In this collaboration we will study HIV-infected individuals undergoing combination ART for prolonged periods in our natural history study. We are working with Dr. Boritz to obtain highly purified subsets of CD4 cells such as central and transitional naive and effector memory populations by fluorescence-activated cell sorting (FACS) of PBMC from these participants and will determine T-cell receptor diversity and quantify the extent of T-cell clonal expansion in these T-cell subsets. We will accomplish this using new sorting facilities that we have established with Drs Lifson and Trubey; these are new state of the art capabilities with appropriate containment for infectious material on the Frederick campus greatly facilitating our work. In these studies we will quantify the levels of HIV proviruses in these highly purified subsets as well as characterize the genetic composition of HIV populations. We are will investigating the distribution of integration sites of the proviruses in these subsets and investigate the extent of clonal expansion. These studies will determine whether clonal expansion of HIV-infected cells reflects overall T-cell clonal expansion or represents a distinct process that takes place whether generalized T-cell clonal expansion occurs or not. In support of these studies we recently reported new droplet digital PCR techniques to accurately measure relative amounts of defective proviruses and found that defective proviruses are enriched over time in most patients undergoing ART. The enrichment was progressive and took place only after several years on therapy suggesting the enrichment was due either to selective elimination of intact proviruses or to increases in defective proviruses perhaps by clonal expansion. These new techniques will greatly assist the field in understanding the dynamics of HIV-infected cells during ART. We have also initiated several new studies of HIV persistence. Previously in collaboration with Dr. Hughes we identified relatively rare examples in which integration of a provirus in specific portions of particular genes (e.g. BACH2 MKL2 STAT5B) was implicated in persistence and clonal expansion. We suggested that the provirus affects the expression of these host genes making it important to determine the structure of these proviruses. Most (over 98%) proviruses are defective and it is not known whether the proviruses in these three genes are intact or highly defective. To resolve this issue we are determining the structure of proviruses integrated in BACH2 and MKL2. Preliminary data suggest that proviruses integrated in these genes have large deletions indicating that they are not infectious. By determining the structure of the proviruses we will better understand how they affect gene expression and drive replication and persistence. In addition we previously demonstrated infected cells may contain proviruses consisting of HIV solo LTRs. Although such structures have been previously identified in gammaretroviruses they had never been demonstrated in HIV infected individuals. Solo LTR forms are generated after integration by homologous recombination and understanding the development of these proviruses will provide new insights on persistence of infected cells We are also investigating the persistence of HIV infected cells in anatomic compartments. In collaboration with NIH CC/CCMD investigators Drs. J. Kovacs and B. Chimukangara we have initiated new studies to characterize HIV infected cell populations in pulmonary tissue (supported by OAR Innovation Program Grant) have now developed robust infrastructure to investigate the distribution of HIV infected cells in anatomic compartments. In collaboration with investigators in NCI Pathology ( Drs. S. Hewitt and D. Kleiner) CCR (Drs. R. Yarchoan K. Lurain R. Ramaswami J. Kanakry) NIH CC/CCMD (Dr. D. Chertow J. Kovacs) and NINDS (Dr. Avi Nath) we have conducted autopsies of HIV infected individuals (N=10) and have now established a repository of samples for study. We are quantifying the levels characterizing the composition and determining the integration sites of populations of proviruses in these tissues. These studies will shed light on specific pathways necessary for HIV persistence and identify testable strategies to interrupt expansion and persistence driven by specific integration events. 248000 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;Anatomy;Anti-Retroviral Agents;Autopsy;BACH2 gene;Biological Assay;Biopsy;Blood;Bronchoalveolar Lavage Fluid;CCR;CD4 Positive T Lymphocytes;Cells;Chronic;Clinical Protocols;Clonal Expansion;Collaborations;Colon;Colonoscopy;Complement;Containment;Data;Development;Evaluation;Event;Evolution;Fluorescence-Activated Cell Sorting;Funding;Future;Gammaretrovirus;Gastrointestinal tract structure;Gene Expression;Genes;Genetic;Goals;Grant;HIV;HIV Drug Resistance Program;HIV-1;Immunologics;Individual;Infection;Infrastructure;Interruption;Intestines;Investigation;Learning;Location;Lung;Lymphocyte;Lymphoid Tissue;Measures;Memory;Methodology;Mutation;National Institute of Allergy and Infectious Disease;National Institute of Neurological Disorders and Stroke;Natural History;Participant;Pathology;Pathway interactions;Patients;Penetration;Peripheral Blood Mononuclear Cell;Persons;Pharmaceutical Preparations;Plasma;Population;Process;Proliferating;Protocols documentation;Provirus Integration;Proviruses;Reporting;Research Personnel;STAT5B gene;Sampling;Sampling Studies;Shapes;Site;Sorting;Source;Structure;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Tonsil;United States National Institutes of Health;Universities;Viral;Viremia;Virus;Work;antiretroviral therapy;clinical center;cohort;digital;driving force;follow-up;homologous recombination;ileum;in vivo;innovation;insight;integration site;lymph nodes;next generation sequencing;novel strategies;programs;repository;tool;virus host interaction HIV Persistence During Suppressive Antiretroviral Therapy n/a NCI 10926220 1ZIABC011466-12 1 ZIA BC 11466 12 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1436333 NCI These studies and others revealed no decrease in persistent viremia after drug intensification suggesting that persistent viremia may be the product of long-lived reservoirs of chronically infected cells. Others however suggested ongoing replication of HIV is the source of persistent viremia. In the last year we conducted a critical test of the question of whether ongoing HIV replication persists in sanctuary locations by analyzing HIV populations in blood and tissues from individuals after prolonged cART (8-16 y). In untreated individuals HIV replication is rapid and error prone leading to the accumulation of genetic changes that are readily detectable in the proviruses. Here we found that infected cells persist and clonally expand but there was no detectable evidence of HIV evolution nor was there any evidence of compartmentalization of the HIV proviruses in blood or tissues in six individuals who were studied during effective combination ART for prolonged periods cumulatively totaling over 60 patient-years of follow-up. These studies did not reveal any evidence for ongoing replication as a mechanism for HIV persistence during ART. Instead we found that HIV is maintained during therapy through long-lived cells that persist and can undergo clonal expansion. We are now building on these studies to quantify and genetically characterize virus in plasma to investigate HIV reservoirs in cellular compartments and expanding the range of our analyses by applying new single-cell methodologies and isolating specific cell subsets in blood and tissue from infected individuals. We are investigating HIV in plasma PBMC and cells derived from ileum and colon in infected individuals taking combination ART with suppressed less than 50 copies who are undergoing colonoscopy at the NIH Clinical Center. We have performed these colonoscopies in collaboration with J. Kovacs (CCMD) in the protocol Virologic and Immunologic Evaluation of Lymph Node Tonsillar and Intestinal Biopsies and Bronchoalveolar Lavage Fluid and have used a new sampling strategy that will yield useful information regarding the distribution of HIV-infected cells in the gastrointestinal tract. In collaboration with S. Hughes (HIV DRP) X. Wu (Leidos) J. Coffin (Tufts) M. Kearney (HIV DRP) and J. Mellors (University of Pittsburgh) we have investigated HIV integration sites in vivo in these individuals. We are expanding these analyses to investigate HIV-infected cells in CD4 cell subsets in individuals undergoing long-term combination ART (supported by Intramural AIDS Targeted Antiviral Program funding). It is critical to learn how clonal expansion shapes the overall population of HIV-infected cells. It is also important to understand how HIV proviruses are expressed in these subsets. We began these studies using blood-derived T cells but we also need to understand the dynamics of HIV-infected T cells as they traffic through lymphoid tissue where 98% of all lymphocytes are located. We also need to know whether clonal expansion of HIV-infected cells in blood and tissues reflects global T-cell expansion. We will therefore complement our studies of clonal expansions of HIV-infected cells by investigating the diversity and clonal expansion of the T-cell repertoire using next-generation sequencing to quantify the T-cell receptor diversity in these subsets (collaboration with E. Boritz and D. Douek). In this collaboration we will study HIV-infected individuals undergoing combination ART for prolonged periods in our natural history study. We are working with Dr. Boritz to obtain highly purified subsets of CD4 cells such as central and transitional naive and effector memory populations by fluorescence-activated cell sorting (FACS) of PBMC from these participants and will determine T-cell receptor diversity and quantify the extent of T-cell clonal expansion in these T-cell subsets. We will accomplish this using new sorting facilities that we have established with Drs Lifson and Trubey; these are new state of the art capabilities with appropriate containment for infectious material on the Frederick campus greatly facilitating our work. In these studies we will quantify the levels of HIV proviruses in these highly purified subsets as well as characterize the genetic composition of HIV populations. We are will investigating the distribution of integration sites of the proviruses in these subsets and investigate the extent of clonal expansion. These studies will determine whether clonal expansion of HIV-infected cells reflects overall T-cell clonal expansion or represents a distinct process that takes place whether generalized T-cell clonal expansion occurs or not. In support of these studies we recently reported new droplet digital PCR techniques to accurately measure relative amounts of defective proviruses and found that defective proviruses are enriched over time in most patients undergoing ART. The enrichment was progressive and took place only after several years on therapy suggesting the enrichment was due either to selective elimination of intact proviruses or to increases in defective proviruses perhaps by clonal expansion. These new techniques will greatly assist the field in understanding the dynamics of HIV-infected cells during ART. We have also initiated several new studies of HIV persistence. Previously in collaboration with Dr. Hughes we identified relatively rare examples in which integration of a provirus in specific portions of particular genes (e.g. BACH2 MKL2 STAT5B) was implicated in persistence and clonal expansion. We suggested that the provirus affects the expression of these host genes making it important to determine the structure of these proviruses. Most (over 98%) proviruses are defective and it is not known whether the proviruses in these three genes are intact or highly defective. To resolve this issue we are determining the structure of proviruses integrated in BACH2 and MKL2. Preliminary data suggest that proviruses integrated in these genes have large deletions indicating that they are not infectious. By determining the structure of the proviruses we will better understand how they affect gene expression and drive replication and persistence. In addition we previously demonstrated infected cells may contain proviruses consisting of HIV solo LTRs. Although such structures have been previously identified in gammaretroviruses they had never been demonstrated in HIV infected individuals. Solo LTR forms are generated after integration by homologous recombination and understanding the development of these proviruses will provide new insights on persistence of infected cells We are also investigating the persistence of HIV infected cells in anatomic compartments. In collaboration with NIH CC/CCMD investigators Drs. J. Kovacs and B. Chimukangara we have initiated new studies to characterize HIV infected cell populations in pulmonary tissue (supported by OAR Innovation Program Grant) have now developed robust infrastructure to investigate the distribution of HIV infected cells in anatomic compartments. In collaboration with investigators in NCI Pathology ( Drs. S. Hewitt and D. Kleiner) CCR (Drs. R. Yarchoan K. Lurain R. Ramaswami J. Kanakry) NIH CC/CCMD (Dr. D. Chertow J. Kovacs) and NINDS (Dr. Avi Nath) we have conducted autopsies of HIV infected individuals (N=10) and have now established a repository of samples for study. We are quantifying the levels characterizing the composition and determining the integration sites of populations of proviruses in these tissues. These studies will shed light on specific pathways necessary for HIV persistence and identify testable strategies to interrupt expansion and persistence driven by specific integration events. 1188333 +No NIH Category available Accounting;Acute;Affect;Amplifiers;Apoptosis;Binding;Binding Sites;Biochemical;Biology;CRISPR screen;Cells;Chromatin;Code;Complex;Coupled;DNA;DNA Damage;DNA-Directed RNA Polymerase;Equipment and supply inventories;Event;Gene Expression;Genes;Genetic;Genetic Processes;Genetic Transcription;Genome;Growth;Human;Immediate-Early Genes;In Vitro;Intercept;Investigation;Knock-in Mouse;Literature;Lymphocyte Activation;MYC gene;MYCN gene;Malignant Neoplasms;Maps;Mechanical Stress;Metabolism;Methods;Modeling;Molecular;Mutation;Normal Cell;Nuclear;Oncogenes;Oncogenic;Output;Pathologic;Pathway interactions;Physiologic pulse;Physiological;Proliferating;Proteins;Proto-Oncogenes;RNA Polymerase II;Regulation;System;TOP1 gene;TOP2A gene;TP53 gene;Testing;Therapeutic;Tissues;Topoisomerase;Transcription Coactivator;Transcriptional Activation;Transfection;Variant;Work;ZIP protein;c-myc Genes;cancer cell;carcinogenesis;chromatin modification;coping;design;embryonic stem cell;experimental study;genome integrity;genome-wide;genome-wide analysis;in vitro activity;in vivo;neoplastic cell;preservation;promoter;protein function;recruit;synthetic biology;theories;transcriptome;tumor c-Myc Function n/a NCI 10926219 1ZIABC011465-12 1 ZIA BC 11465 12 9692465 "LEVENS, DAVID L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 766271 NCI The c-Myc bHLH-ZIP protein has been implicated in physiological or pathological growth proliferation apoptosis metabolism and differentiation at the cellular tissue or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc?s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated the transcriptomes and the genome-wide distributions of Myc RNA polymerase II and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity but is a non-linear amplifier of expression acting universally at active genes except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. Current investigations are exploring the molecular mechanisms exploited by MYC to augment gene expression and to demonstrate how small changes in MYC levels or short pulses of MYC activity may modify the growth of normal and neoplastic cells. The theory that MYC is an amplifier was derived from genome-wide studies of MYC and RNA polymerase binding to chromatin in vivo and RNA expression. We are now testing this theory with an orthogonal set of methods and experiments based on transfections and synthetic biology that thus far fully confirm the predictions of the amplifier model. We are exploring a possible a biochemical mechanism that unifies MYC's diverse activities and that has therapeutic implications. We have recently found that MYC forms a complex with both top1 and top2 simultaneously and stimulates both of their activities in vitro and in vivo. Because DNA topology is an issue for all DNA transactions via topoisomerases MYC can contribute directly to all genetic processes. We have mapped the sites of binding and activity of this complex (the topoisome) across the genome and have determined that two related complexes form: one includes MYC TOP1 and TOP2A while the other includes MYCN TOP1 and TOP2B. We have found that excessive MYC topoisome activity leads to its replacement by a p53-assembled topoisome that acutely and effectively guards against too much MYC. We have also devised a CRISPR screen to identify the cellular components that contribute to MYC amplifier action and an in vitro transcription system responsive to MYC recruited factors. This screen is designed to be conducted in almost any cell system. 766271 +No NIH Category available Adverse effects;Affect;Anatomy;Angiolymphoid hyperplasia;Anti-Inflammatory Agents;Antibiotics;Antigens;Antineoplastic Agents;Award;Bacterial Translocation;Binding;Biopsy;Blood;CCR;CD4 Positive T Lymphocytes;Cells;Clinical;Clinical Protocols;Clinical Research;Clonal Expansion;Collaborations;Cryptococcal Meningitis;Data;Defect;Disease;Event;Goals;HIV;HIV Infections;HIV therapy;HIV vaccine;HIV/AIDS;Human;Immune response;Immune system;Immunologics;Immunomodulators;Individual;Infection;Inflammatory;Integration Host Factors;Interferon Alfa-2b;Interferons;Interruption;Intervention;Intervention Studies;Interventional radiology;Kaposi Sarcoma;Location;Long-Term Effects;Lymphoid Tissue;Lymphoma;Malignant Neoplasms;Metabolic;Modality;National Institute of Allergy and Infectious Disease;Natural Immunity;Patients;Peripheral Blood Lymphocyte;Phylogenetic Analysis;Plasma;Population;Positron-Emission Tomography;Primates;Production;Progressive Multifocal Leukoencephalopathy;Protocols documentation;Regimen;Research Personnel;Resistance;Retrovirology;Role;SARS-CoV-2 infection;Sampling;Series;Site;Source;Squamous cell carcinoma;Structure;Syndrome;Therapeutic;Tuberculosis;United States National Institutes of Health;Vaccination;Vaccines;Viral;Viremia;antiretroviral therapy;candidate identification;chemotherapy;chimeric antigen receptor T cells;clinical center;clinical effect;co-infection;comorbidity;cytotoxic;design;driving force;experience;fluorodeoxyglucose;gastrointestinal;gut microbiome;immune activation;immune reconstitution;in vivo;interferon therapy;microbiome;multidisciplinary;neoplastic;response;rifaximin;therapeutic vaccine;vaccine trial Clinical Interventional Studies of HIV Reservoirs n/a NCI 10926218 1ZIABC011464-12 1 ZIA BC 11464 12 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 713000 NCI Fundamental gaps in our understanding of HIV reservoirs preclude a precisely targeted approach to eradication. HIV is neither eliminated nor often controlled by the human immune system and the immunologic defect(s) responsible for this lack of control are unknown. We are conducting several studies to investigate the effects of clinical events on HIV reservoirs. We have established useful collaborations to investigate the effects of clinical interventions on HIV reservoirs. We are collaborating with R. Yarchoan (HIV and AIDS Malignancy Branch NCI) to study individuals with HIV infection and comorbid cancer treated at the NIH Clinical Center. These study patients receive antineoplastic cytotoxic and immune modulator therapy to treat cancers treatment modalities that may also have significant effects on HIV-infected cells and we are studying the effects of these therapies on HIV reservoirs. In collaboration with I. Sereti (NIAID) we are studying patients with advanced HIV/AIDS who initiate antiretroviral therapy (ART) and experience immune reconstitution inflammatory syndrome (IRIS) in response to coinfections such as tuberculosis cryptococcal meningitis and progressive multifocal leukoencephalopathy (PML). IRIS results in a vigorous immune response to the comorbid infection with significant increases in CD4 T cells; as such IRIS may have profound effects on HIV reservoirs. We have been studying individuals with IRIS and TB and found that HIV-infected cells are part of the robust immune response that occurs during IRIS. In fact HIV-infected cells can specifically respond to TB antigens. We have also found that IRIS has long-term effects on the structure of HIV populations during therapy suggesting IRIS may alter HIV reservoirs. In collaborations with Irini Sereti (NIAID) we have recently demonstrated the effects of PML-IRIS on HIV populations. In addition we demonstrated that treating IRIS with anti-inflammatory agents can reduce the production of HIV from reservoirs over 100-fold. These studies point to new studies to manipulate the composition and production of HIV populations during therapy. Understanding additional forces that can affect HIV reservoirs have also been initiated. Antineoplastic chemotherapy may have profound effects on HIV populations and we are working with CCR investigators (Drs. K. Lurain R. Ramaswami R. Yarchoan) to investigate the effects of new chemotherapeutic regimens for Kaposi Sarcoma Primary effucsion lymphoma and Castlemans disease on HIV populations. In addition we are now investigating the effects of the SARS-CoV-2 infection and vaccination. We have also initiated a new analytic treatment interruption study to determine the sources of rebound viremia when HIV therapy is interrupted (NIH protocol 000277). For these studies we are conducting a multidisciplinary analysis of HIV reactivation. We use state of the art 18FDG positron emission tomography to characterize metabolic activity of lymphoid tissue followed by site directed biopsy approach pioneered by our collaborators in NIH interventional radiology. We are quantifying the size and composition of HIV populations in biopsies and blood derived samples prior to and following a short (10 day) treatment interruptionand analyze these data in the context of detailed immunologic studies. As a result we will obtain a comprehensive analysis of the earliest steps in HIV reactivation. We are also completing a clinical study (NIH protocol 13-I-0062) investigating generalized immune activation in the gastrointestinal-associated lymphoid tissue (GALT) on persistent HIV in individuals undergoing ART. We have been studying the effects of the nonabsorbable antibiotic rifaximin to specifically alter the gut microbiome and affect translocation of bacterial cell products and the consequent levels of generalized immune activation and low-level HIV viremia. Although we identified changes in the gut microbiome these changes did not result in downstream effects on levels of HIV viremia or levels of immune activation. These studies will further our understanding of the role of modifying the microbiome in immune activation. We are also investigating the role of innate immunity in HIV persistence by studying the effects of the innate immune modulator interferon alpha 2b. We have characterized the effects of exogenous interferon therapy in a series of HIV-infected individuals undergoing ART (NIH protocol 11-I-0057). We found no effect of interferon on levels of HIV in plasma or in peripheral blood lymphocytes and are now characterizing interferon effects on the phylogenetic structure of the HIV populations. Our studies of HIV reservoirs indicate a critical role of anatomic locations particularly lymphoid tissues in HIV persistence. In a new studies we are collaborating with Dr. S. Norberg in his CAR-T studies which now have been expanded to include therapy for squamous cell carcinoma in HIV infected individuals. Dr. Norborg studies have been awarded additional support through CCR Flex award. Finally we have initiated new collaboration with Dr. Genoveffa Franchini from NCI Vaccine Branch to evaluate new HIV vaccines based on highly successful candidates identified in primate studies. These studies are also expected to generate new studies of the effects of such agents in therapeutic vaccine studies as well. 713000 +No NIH Category available Affect;Antiviral Therapy;Biology;Capsid;Cells;Chimeric Proteins;Chromatin;Cyclophilin A;Gene Transduction Agent;Genome;HIV-1;Infection;Integration Host Factors;Lentivirus Vector;Maps;Mediating;Nuclear;Nuclear Pore Complex;Nuclear Pore Complex Proteins;Play;Process;Protein Analysis;Protein Isoforms;Proteins;Regulation;Role;Surface;TRIM5 gene;Virus;anti-cancer;chimeric antigen receptor T cells;gene therapy;improved;migration The role of POM121 in HIV-1 infection n/a NCI 10926217 1ZIABC011461-12 1 ZIA BC 11461 12 8123034 "KEWALRAMANI, VINEET N" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 295847 NCI The HIV-1 core composed as a lattice of CA hexamers and pentamers engages FG-nucleoporins to enable transport of the virus through nuclear pore complexes to access host cell chromatin. The choreography of this interaction specifically which nucleoporins are engaged in what order and the multivalency of this interaction specifically which interactions are overlapping and which might be displaced are key issues that need to be resolved to better understand the mechanism of HIV-1 nuclear entry. HIV-1 CA mediates these interactions and is highly vulnerable to antiviral therapy because of the central role that CA plays in engaging possibly a dozen or more host factors through the same interface. How HIV-1 migrates through the nuclear pore complex also affects where it integrates its genome in host cell chromatin. Given the use of HIV-1 derived lentiviral vectors in gene therapy including the establishment of anticancer CAR T cells the elucidation of this biology could be beneficial in developing improved vectors for gene therapy. The interaction of HIV-1 CA with POM121 appears to be one of the strongest ones in the cell based on TRIM5 fusion protein analysis. We thus want to define more precisely the interaction surfaces. Based on the subcellular localization of POM121 we expect this interaction to be early in the nuclear entry process. This is also consistent with regulation by CypA. We will use the domain interaction studies as a basis to help understand how CypA governs use of POM121 and what role POM121 plays in HIV-1 migration through the nuclear pore complex. Finally there are other isoforms of POM121 - POM121C and soluble POM121. We are examining whether they affect HIV-1 infection and whether conserved domains are contributing to interactions with HIV-1 CA. 295847 +No NIH Category available Acquired Immunodeficiency Syndrome;Acute;Adult;Animal Model;Antibodies;Antibody Response;Antigens;BK Virus;Brain Diseases;Capsid Proteins;Chronic;Clinical;Colorectal Cancer;Development;Disease;Genotype;Goals;Human;Human Papillomavirus;Humoral Immunities;Immunocompromised Host;Immunosuppressive Agents;India;Individual;Industry;Infection;Injection product;JC Virus;Kidney Diseases;Kidney Transplantation;Legal patent;Lesion;Licensing;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Mediating;Mus;Oral;Pathology;Patients;Phase I/II Clinical Trial;Play;Polyomavirus;Polyomavirus Infections;Preventive vaccine;Progressive Multifocal Leukoencephalopathy;Resistance;Risk;Role;Route;Serotyping;Serum;Symptoms;System;Therapeutic immunosuppression;Transplant Recipients;Urinary tract;Urine;Vaccination;Vaccines;Variant;Viral;Virion;Virus;Virus-like particle;Viviparous-1 protein;Work;human monoclonal antibodies;industry partner;invention;neutralizing antibody;novel;pressure;prevent;recombinant virus;renal damage;tool;vaccine development;virus development BKV and JCV vaccine development n/a NCI 10926216 1ZIABC011460-12 1 ZIA BC 11460 12 9692553 "BUCK, CHRISTOPHER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 771566 NCI "Two distinct polyomaviruses called BKV and JCV chronically infect the human urinary tract. Most healthy adults are stably infected with both viruses and occasionally shed infectious virions in the urine. Although BKV and JCV aren't known to cause overt symptoms in healthy individuals each of the two viruses can cause severe pathology in immunocompromised individuals. Most notably BKV causes acute kidney damage in up to 10% of kidney transplant recipients. In AIDS patients and patients taking certain immunosuppressive drugs JCV can cause a fatal brain disease called progressive multifocal leukoencephalopathy (PML). A further concern is that a controversial body of evidence has linked both BKV and JCV to various forms of cancer including prostate and colorectal cancer respectively. Our goal for this project is to develop preventive vaccines that might protect at-risk patients against BKV associated nephropathy (BKVN) or PML. The vaccines would draw on the same approach that led to the current highly successful vaccines against human papillomaviruses - specifically the BKV or JCV vaccine would be composed of recombinant virus-like particles (VLPs) composed solely of the viral major capsid protein VP1. The VLP vaccine would be aimed at eliciting antibody responses capable of neutralizing the infectivity of BKV or JCV virions. To be successful viruses must avoid being recognized by neutralizing antibodies elicited by previous infections. This evolutionary pressure drives the development of distinct viral ""serotypes"" that are not cross-recognized by serum antibodies. For example it is well established that BKVs are not generally recognized by antibodies elicited during JCV infection. Although it has long been recognized that different BKV isolates are genetically distinct no prior work has investigated the possibility that some BKV genotypes are resistant to neutralization by antibodies elicited by other other BKV genotypes. In other words it is unclear whether distinct serotypes exist within the viral species BKV. This question is also unresolved for JCV. Our lab's work in FY2011 revealed that BKV genotype I (BKV-I) and BKV-IV are distinct serotypes that are reciprocally resistant to antibody-mediated cross-neutralization. Work in FY2012 has revealed that BKV genotypes can be divided into as many as five distinct serotypes. Encouragingly administration of a multivalent VLP-based vaccine to mice elicits highly potent neutralizing antibody responses capable of neutralizing all five BKV serotypes. This suggests that a multivalent BKV VLP vaccine might be effective for protecting kidney transplant recipients against BKVN. We have recently begun extending our BKV findings to JCV. Specifically we hypothesize that JCV VP1 variants found in PML lesions may allow the virus to escape from antibody-mediated neutralization. If this hypothesis is true it would suggest that administering patients a VLP-based vaccine containing PML-variant VP1 might protect patients who are candidates for immunosuppressive therapy against PML. This work is the subject of an NCI patent application submitted in FY12. In FY15 we have began building industry partnerships to develop BKV and JCV vaccines. In FY16 we have developed industry and academic partnerships to investigate BKV- and JCV-neutralizing human monoclonal antibodies. Such antibodies could be of clinical utility for patients and would also provide a practical demonstration that the humoral immunity we seek to stimulate through vaccination will be effective. During FY20 these discoveries were licensed to an industry partner in India. We have been supporting the partner's development of VLP immunogens. During FY22 we began a new project exploring the possibility that vaccination can be achieved by non-injection routes (for example oral or intranasal delivery). We anticipate development of a Phase 1/2 clinical trial for the original injection product in FY24." 771566 +No NIH Category available Affect;Animals;Architecture;Biogenesis;Biology;Cell Cycle;Cell division;Cell physiology;Cells;Centrioles;Centrosome;Cilia;Continuous Positive Airway Pressure;Defect;Development;Diagnostic;Disease;Ensure;Event;Genetic Diseases;Goals;Homeostasis;Human;Individual;Investigation;Knowledge;Malignant Neoplasms;Manuscripts;Maps;Membrane;Microcephaly;Microtubules;Mitotic spindle;Molecular;Multiprotein Complexes;Organelles;PLK1 gene;Pathologic;Phosphotransferases;Preparation;Process;Proteins;Publications;Publishing;Research;Resolution;Sensory;Signal Transduction;Site;Structure;Therapeutic;Tissues;Tumor Promotion;cell motility;ciliopathy;cilium motility;nanoscale;receptor;tumor;tumorigenesis Control of centrosome biogenesis n/a NCI 10926215 1ZIABC011459-12 1 ZIA BC 11459 12 11592694 "LONCAREK, JADRANKA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1025462 NCI Centrosomes are minute multifunctional membrane-less organelles present in only two copies in a typical cycling animal cell. In the core of a centrosome is a nine-fold symmetrical cylindrical microtubule-based structure called a centriole. The centriole organizes the second major part of the centrosome called pericentriolar material which is a large and dynamic multiprotein complex and the site of most centrosomal functions. Centrosomes perform vital cellular functions such as microtubule nucleation organization of the bipolar mitotic spindle pole during cell division and cellular signaling and they influence tissue architecture and cell motility. Centrioles also organize sensory and motile cilia which are critically important for development and tissue homeostasis. Supernumerary and/or structurally aberrant centrioles and centrosomes can initiate tumorigenesis promote tumor invasiveness and are present in almost all types of tumors. Centriolar or ciliary defects are in addition an underlying cause of genetic disorders known as ciliopathies. Our current research focuses on understanding the molecular mechanisms that regulate centriole and centrosome numbers in healthy and pathological conditions and on deciphering their architecture at high resolution. Recently we focused on elucidating the dynamics of a centrosomal protein CPAP (also known as CENPJ). We have characterized centriolar defects that occur under suboptimal levels of CPAP protein which include the lack of complete centriole walls structural instability and breakage. We have also demonstrated that CPAP is highly dynamic within the centriole but may not directly participate in the formation of mitotic spindles and cell division as previously suggested. In another line of investigation we dissected centrosomal localization of centrosome-forming kinase Plk4 at nano-scale resolution. We build a precise distribution map of Plk4 and its receptor Cep152 and Cep44 Cep192 and Cep152-anchoring factors Cep57 and Cep63. Centriole duplication is a highly regulated process driven by Polo-like kinase 4 (Plk4) and a few conserved initiators. Dissecting how Plk4 and its receptors organize within centrosomes is critical to understand centriole biogenesis. We have also explored how various cell cycle kinases (Plk1 Cdk2 Plk4) which are frequently upregulated in cancer regulate centriole and centrosome number ensure centriole and centrosome homeostasis and how their dysregulation leads to their aberrant amplification and reduplication. Finally we studied the basic principles of centriole elongation in human cells. Proper centriole structuring is a prerequisite for proper centrosome and cilia functioning. However strikingly little is still known about the mechanisms that regulate centriole assembly. Specifically we are exploring how individual cell cycle regulators affect centriole elongation during specific parts of the cell cycle. The final goal of this study is to understand how healthy cells maintain relatively uniform centriole and centrosome size and to identify how structurally defective centrioles and centrosomes occur in tumors. Manuscripts describing our recent findings are being published or are in preparation for publication. 1025462 +No NIH Category available Antigen Targeting;Antigens;Apoptosis;Area;B-Lymphocytes;Binding;Blood;CAR T cell therapy;CASP9 gene;Cell Line;Cell Maturation;Cells;Clinical Trials;Development;Dimerization;Disease remission;Enrollment;Family member;Genetic Engineering;Goals;Human;Immunohistochemistry;In Vitro;Industry;Journals;Laboratories;Licensing;Malignant - descriptor;Malignant Neoplasms;Measurable;Medicine;Multicenter Trials;Multiple Myeloma;Mus;New England;Normal tissue morphology;Organ;Paper;Patients;Pattern;Phase;Phenotype;Plasma Cells;Publications;Publishing;Remission Induction;Research;Research Personnel;SLAM protein;Site;T-Lymphocyte;Testing;Time;Work;cancer cell;chimeric antigen receptor;chimeric antigen receptor T cells;design;design and construction;human tissue;immunogenic;improved;novel;phase I trial;preclinical development;response;suicide gene;tumor Development of Chimeric Antigen Receptors Targeting Multiple Myeloma n/a NCI 10926214 1ZIABC011439-12 1 ZIA BC 11439 12 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 624367 NCI An important focus of my work is development of chimeric antigen receptor T cell therapies for multiple myeloma which is a usually incurable malignancy of plasma cells. My group was the first to design and construct CARs that specifically recognize B-cell maturation antigen (BCMA). BCMA has a very restricted expression pattern in normal tissues but BCMA is expressed on the malignant plasma cells of multiple myeloma. The BCMA specific CARs that we have constructed specifically recognize multiple myeloma cell lines and primary myeloma cells in vitro and eradicate myeloma tumors in mice. An extensive analysis of BCMA expression in normal human tissues by immunohistochemistry and quantitative PCR has been conducted. Except for expression by normal plasma cells BCMA expression was not detected in nomal human organs by immunohistochemistry. The first clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma was opened for enrollment in September 2014. James Kochenderfer was Principle Investigator of this trial. Twenty -six patients were treated on this trial. There have been impressive responses on this trial which were the first demonstrated examples of elimination of measurable multiple myeloma by CAR T cells. This work led to a publication in the journal Blood in 2016. In conjunction with Bluebird Bio Inc. We have developed a new anti-BCMA CAR that Bluebird licensed from the NCI. This new CAR was developed in my laboratory and modified by bluebird bio. This new CAR is being tested in a world-wide phase I and II multicenter trials conducted by Celgene Inc. I am a site PI of the phase I trial of this CAR. The longest ongoing complete remission from this trial is 3 years in duration. Results from his trial were published in the New England Journal of Medicine in May 2019; James Kochenderfer was senior author of this paper. Another general area of research on CAR T-cell therapies for multiple myeloma is improving the design of CARs. We have designed novel CARs with fully-human heavy-chain-only antigen-recognition domains and a clinical trial testing one of these CARs designated FHVH33-CD8BBZ is underway. We hypothesize that fully-human heavy-chain-only anti-BCMA CAR T cells will be less immunogenic than traditional CARs with single-chain variable fragment antigen-recognition domains. 25 patients have been treated on this clinical trial and 92% of patients have had objective responses. We are also designing CARs against antigens other than BCMA because multiple myeloma is a phenotypically heterogeneous malignancy in many cases so targeting more than one antigen might be necessary to effectively induce long progression-free intervals of multiple myeloma. We have designed CAR constructs containing a CAR targeting signaling lymphocyte activation molecule family member 7 (SLAMF7). We have completed preclinical development of a construct that encodes an anti-SLAMF7 CAR and a suicide gene. The suicide gene allows on-demand elimination of the CAR-expressing T cells. The suicide gene is activated by a dimerizer agent called Rimiducid. After dimerization caspase 9 is activated which leads to apoptosis of the CAR-expressing T cells. The anti-SLAMF7 p;lus suicide gene construct is designated IC9-Luc90-CD828Z. We have initiated a clinical trial of IC9-Luc90-CD828Z T cells. The clinical trial of SLAMF7 CAR T cells did not yield any responses. We are focused on finding new anti-SLAMF7 CAR strategies. 624367 +No NIH Category available Affect;Animal Model;Autoimmune Diseases;CD4 Positive T Lymphocytes;CNS autoimmune disease;Candidate Disease Gene;Cell Differentiation process;Cells;Central Nervous System;Central Nervous System Diseases;Complex;Demyelinations;Development;Disease;Disease remission;Encephalomyelitis;Etiology;Exhibits;Experimental Autoimmune Encephalomyelitis;Genes;Genetic;Genetic Predisposition to Disease;Goals;Immune;Immunity;Immunologics;Impairment;Individual;Inflammatory;Intervention;Investigation;Laboratories;Lead;Mediating;Modeling;Multiple Sclerosis;Nature;Nervous System Trauma;Neurologic Deficit;Pathogenesis;Pathogenicity;Pathologic;Patients;Predisposition;Primary Progressive Multiple Sclerosis;Process;Progressive Disease;Relapse;Research;Role;Secondary Progressive Multiple Sclerosis;Signal Transduction;T-bet protein;Th1 Cells;axon injury;environmental agent;gene product;genome-wide;interleukin-23;multiple sclerosis patient;multiple sclerosis treatment;neuroinflammation;new therapeutic target;novel therapeutics;programs;response;transcription factor;treatment strategy Role of T-bet in the pathogenesis of experimental autoimmune encephalomyelitis n/a NCI 10926211 1ZIABC011431-12 1 ZIA BC 11431 12 11592667 "LAZAREVIC, VANJA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1333998 NCI Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) of uncertain etiology. It is a complex disease in which one or more environmental agents predispose genetically susceptible individuals to develop immunologically mediated CNS demyelination and axonal injury. In 80-90% of cases MS starts with a relapsing-remitting course (RR-MS) but most patients develop progressive neurological deficits (i.e. secondary progressive MS; SP-MS). In 10-20% of cases MS patients exhibit a more progressive disease without remission namely primary progressive MS (PP-MS). Despite intense investigation into the pathological changes of MS many questions regarding the nature of immunological dysregulation that lead to the development of MS remain unanswered. Most of our understanding of the pathogenesis of multiple sclerosis comes from investigations using experimental autoimmune encephalomyelitis animal model. In this model both CD4+ T helper type 1 (TH1) and T helper type 17 (TH17) cells contribute to the pathogenesis of the disease. The transcription factor T-bet (encoded by the Tbx21 gene) drives the development of TH1 cells and inhibits the differentiation of TH17 cells. Interestingly despite its role as a negative regulator of TH17 differentiation program in naive CD4+ T cells T-bet is critical for the function of mature TH17 cells. T-bet is re-expressed in TH17 cells in response to IL-23 which drives the pathogenesis of several autoimmune diseases. T-bet deficient TH17 cells treated with IL-23 are not pathogenic in the setting of neuroinflammation. This observation raised important questions: (a) What makes TH17 cells pathogenic? (b) Is it the genetic program regulated by T-bet in response to IL-23 signaling? To answer these questions we have performed genome-wide profiling of wild-type and T-bet deficient TH17 cells. In the process an intriguing panel of candidate genes has been uncovered. Identifying the T-bet target genes in CD4+ T cells responsible for conferring pathogenicity and understanding how these gene products lead to CNS damage will lead to novel therapeutic targets. Treatment strategies directed at a specific subset of T-bet target genes rather than T-bet itself will provide selective intervention without causing global impairment of Type 1 immunity. Ultimately the goal of this research is to lead to the development of new therapies for multiple sclerosis. 1333998 +No NIH Category available Architecture;Biological;Body Regions;Categories;Cells;Child;Childhood;Chromatin;Chromatin Structure;Clinical;Cluster Analysis;Collaborations;Cre-LoxP;DNA;DNA Methylation;DNA analysis;Data;Databases;Development;Elements;Engineering;Epigenetic Process;Etiology;Event;FOXO1A gene;Family;Gene Expression;Gene Fusion;Genes;Genetic Transcription;Genomic DNA;Goals;Human;Hypermethylation;Malignant Neoplasms;Methodology;Methylation;Molecular;Mouse Strains;Mus;Mutation;Oncogenic;Other Genetics;Outcome;PAX3 gene;PAX7 gene;PTCH gene;Pattern;Point Mutation;Principal Component Analysis;Promoter Regions;Publishing;Recurrence;Regulatory Element;Rhabdomyosarcoma;Sampling;Series;Skeletal Muscle;Soft Tissue Neoplasms;Testing;Tissue-Specific Gene Expression;Tissues;Tumor-Derived;bead chip;cancer therapy;density;driver mutation;genome wide methylation;genome-wide;methylation pattern;mouse model;overexpression;promoter;sarcoma;soft tissue;therapy development;tumor Epigenetic studies in rhabdomyosarcoma n/a NCI 10926209 1ZIABC011423-12 1 ZIA BC 11423 12 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 537679 NCI During the last year we continued our studies of the DNA methylation patterns in mouse models of rhabdomyosarcoma (RMS). In particular my collaborator Dr. Charles Keller (Children's Cancer Therapy Development Institute) used Cre-LoxP methodology to generate a series of mouse strains in which one or more driver mutations (Pax3-Foxo1 [P3F] fusion and deletions of Tp53 Rb1 or Ptch) is introduced into one of four myogenic lineages (as defined by activity of the Pax3 Pax7 Myf5 or Myf6 expression regulatory elements). These mice containing a germline Tp53 deletion with or without other germline driver mutations frequently develop soft tissue tumors resembling RMS or related sarcomas. The DNA methylation patterns of tumors from these mouse studies were then profiled to explore the biological basis for the DNA methylation differences previously described in comparisons of human fusion-negative (FN) and fusion-positive (FP) RMS tumors. In particular we hypothesized that these DNA methylation differences may be due to differences in the genetic changes (driver mutation) that occur in these tumors or due to differences in the underlying cell of origin (lineage) of these tumors. For these studies we selected 31 mouse tumors corresponding to a variety of lineages and driver mutations and then utilized the Infinium Mouse Methylation BeadChip (Illumina) to analyze the genome-wide methylation patterns in DNA isolated from these tumors. We performed unsupervised analysis of the resulting DNA methylation patterns by hierarchical clustering and t-Distributed Stochastic Neighbor Embedding (t-SNE). Both methodologies identified two distinct clusters. In one cluster the driver was always P3F and the targeted lineages were those defined by the Pax3 Myf5 or Myf6 expression elements. In the other cluster the driver/lineage was either P3F in a Pax7-associated lineage or other driver mutations (Tp53 Rb1 or Ptch deletions without P3F) in any of the four lineages. Previous published studies demonstrated that P3F targeted into the Pax7-associated lineage has very low expression whereas P3F targeted to the other three lineages has much higher expression and thus the two dominant clusters can be defined by high P3F vs low or no P3F expression. This finding supports the premise that high expression of the P3F driver mutation is a major determinant of the DNA methylation pattern. However the finding that the Pax7-associated lineage is always associated with the opposite DNA methylation pattern regardless of whether the driver mutation is P3F indicates that lineage also is a major determinant of DNA methylation pattern. In addition further analysis of the cluster with low/no P3F expression demonstrates two distinct subclusters. Although both subclusters contain tumors in which a Tp53 or PTC1 mutation is targeted to the Pax3 or Myf6 lineage one of these subclusters contains all tumors in which a Tp53 or PTC1 mutation is targeted to the Pax7 lineage and the other subcluster contains all tumors in which a Tp53 or PTC1 mutation is targed to the Myf5 lineage. These DNA methylation differences further support the premise that the lineage also makes a major contribution to the DNA methylation pattern. As the presence of a highly expressed P3F gene is associated with a distinct DNA methylation in both human and mouse tumors we investigated whether there are genes with common DNA methylation changes in human and mouse tumors. For promoter methylation changes there were 41 genes with promoter hypermethylation in FP compared to FN tumors (6.9% of hypermethylated genes in mouse tumors and 7.4% in human tumors) and 108 genes with promoter hypomethylation in FP compared to FN tumors (16.3% of hypomethylated genes in mouse tumors and 6.9% in human tumors). Similarly for body methylation changes there were 143 genes with body hypermethylation in FP compared to FN tumors (15.4% of hypermethylated genes in mouse tumors and 17.3% in human tumors) and 283 genes with body hypomethylation in FP compared to FN tumors (25.0% in mouse tumors and 16.6% in human tumors). There was a significant association (P0.01 Fisher test) for all four comparisons of mouse and human tumors and thus it appears that that there are numerous commonalities between the DNA methylation patterns in mouse and human RMS tumors. Despite these commonalities comparison of mouse and human tumors by unsupervised analyses of the DNA methylation data demonstrated distinct species-specific clustering of these tumors and thus the differences between the two species appears to be more dominant than any similarities associated with fusion status. Finally we used both RNA expression and DNA methylation databases to identify genes demonstrating changes in DNA methylation and RNA expression in fusion-positive compared to fusion-negative tumors in both human and mouse. Our findings reveal 44 genes that fit these criteria; these genes break down into the following categories: 5 promoter hypermethylated/underexpressed 2 promoter hypermethylated/overexpressed 3 promoter hypomethylated/underexpressed 1 promoter hypomethylated/overexpressed 5 body hypermethylated/underexpressed 4 body hypermethylated / overexpressed 14 body hypomethylated/underexpressed 10 body hypomethylated/overexpressed. Therefore only a subset of the DNA methylation changes are associated with changes into gene expression; these findings support the premise that many of these DNA methylation changes are associated with lineage-specific chromatin structure. 537679 +No NIH Category available Antifungal Agents;Autoimmune Diseases;B-Cell Development;B-Lymphocytes;CD4 Positive T Lymphocytes;Cells;Chronic;Development;Epidermal Growth Factor Receptor;Esophageal Squamous Cell Carcinoma;Fostering;Human;IKK alpha;Immunity;Impairment;Infection;Inflammation;Knock-in Mouse;Link;Modeling;Mycoses;NF-kappa B;Pathway interactions;Patients;Phenotype;Phosphotransferases;Polyglandular Autoimmune Syndrome Type I;Predisposition;Role;Spleen;T-Cell Depletion;T-Lymphocyte;Thymic epithelial cell;autoreactive T cell;autoreactivity;carcinogenesis;cell type;central tolerance;epithelial injury;lymphoid organ;oral fungal;organ growth;tissue injury Role of IKK alpha in lymphoid organ development n/a NCI 10926208 1ZIABC011422-12 1 ZIA BC 11422 12 10270679 "HU, YINLING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 357603 NCI Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) a T cell-driven autoimmune disease caused by impaired central tolerance are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikka knockin mice develop APECED-like phenotypes including impaired central tolerance autoreactive T cells chronic fungal infection and ESCCs expressing specific human ESCC markers. Using this model we investigated the link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or autoreactive CD4 T cell depletion rescues whereas oral fungal administration promotes ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore autoreactive T cells and chronic fungal infection fostered by inflammation and epithelial injury promote ESCC development. 357603 +No NIH Category available 3-Dimensional;ADP-Ribosylation Factors;Binding;Biophysics;Collaborations;Complex;Data;Development;Environment;Family;GTP-Binding Proteins;GTPase-Activating Proteins;Investigation;Isotope Labeling;Lipids;Mass Spectrum Analysis;Membrane;Methodology;Methods;Molecular;Molecular Conformation;Multiprotein Complexes;Mutation;NMR Spectroscopy;Neutrons;PH Domain;Pathway interactions;Phosphatidylinositol 45-Diphosphate;Process;Protein Family;Proteins;Publications;Publishing;Roentgen Rays;Role;Science;Signal Transduction;Structural Models;Structure;Surface;System;Uveal Melanoma;Variant;Work;cofactor;collaborative approach;crosslink;experimental study;insight;interest;member;mimetics;molecular dynamics;multidisciplinary;myristoylation;nanodisk;novel;spectroscopic survey;stable isotope;structural biology;tool Structural Biology of GTPase Activating Proteins n/a NCI 10926207 1ZIABC011419-13 1 ZIA BC 11419 13 15201459 "BYRD, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 787255 NCI In collaboration with Dr. Paul Randazzo we are studying the structure and interactions between Arf proteins and a member of the ASAP family of Arf-GAP proteins. We have produced a variety of stable-isotope variants of these proteins and established conditions for NMR spectroscopic studies. Studies are underway to provide resonance assignments structure confirmation based on existing known structures and to determine structures which are unknown binding studies of cofactors and to examine the assembly of larger multi-domain and multi-component systems. New findings emerged on the role of the PH domain within ASAP1 and an integrated multi-disciplinary study was published in Science Advances in 2020. We have developed methods to examine these proteins in a membrane environment. We will also combine the use of Neutron Reflectometry (NR) data with novel NMR and EPR methods to develop three-dimensional structural models of these complexes. We have utilized unique methodology in the NMR spectroscopy structure calculation and isotopic labeling to obtain new structural information about ASAP1. These data are combined with binding information to activating lipids and membrane mimetics to pursue functional understanding of these important proteins. Previous developments include structural elucidation by X-ray and NMR of the PH domain from ASAP1 interacting with PIP2 lipid head groups. Our current work demonstrates binding to nano disk membrane mimetics the equivalence of the mimetic and large unilamellar membrane standards and we have described a unique cooperative binding mechanism of the ASAP1 PH domain with membrane surfaces. We have demonstrated that we can assemble functional and isotopic labeled (for NMR) myristoylated-Arf1 into membrane nano disks. This systems shows functional complexation with ASAP1 functional domains at the membrane surface. Current work in submission for publication describes the distribution of and conformational selection process involved in Arf1 recognition of ASAP1. New mass-spectrometry cross-linking experiments are assisting a combined NMR/MD analysis of the Arf1:PH complex on the surface of the membrane. Understanding the mechanism of interaction between Arf1 and ASAP1-PZA is progressing extremely well with publications and molecular insight. 787255 +No NIH Category available Adoptive Transfer;Adrenal Cortex Hormones;Antigens;B cell therapy;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Biological;CD19 gene;Chronic Lymphocytic Leukemia;Clinical Trials;Clone Cells;DNA Sequence;Effectiveness;Enrollment;Event;FDA approved;Gammaretrovirus;Gene Transduction Agent;Human;Infusion procedures;Lymphoma;MS4A1 gene;Membrane;Patients;Principal Investigator;Role;T-Lymphocyte;Testing;Time;Toxic effect;anti-CD20;cell bank;chimeric antigen receptor;chimeric antigen receptor T cells;chronic T-cell leukemia;curative treatments;cytokine;design;experimental study;genetically modified cells;improved;large cell Diffuse non-Hodgkin's lymphoma;leukemia/lymphoma;novel therapeutics;pre-clinical;vector Improved Chimeric Antigen Receptor Therapies B-cell Malignancies n/a NCI 10926205 1ZIABC011417-13 1 ZIA BC 11417 13 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 936552 NCI In the past year we have designed and selected an optimal bicistronic CAR construct that targets both CD19 and CD20. The bicistronic construct encodes 2 CARs one of the CARs is the previously -described Hu19-CD828Z CAR. The second CAR is an anti-CD20 CAR designated Hu20-CD8BBZ. The entire bicistronic construct is designated Hu19-CD828-Hu20BB and the construct is encoded by a gammaretroviral vector. We plan to start a clinical trial with bicistronic CAR designs targeting CD19 and CD20 in late 2022. We have spent extensive time optimizing the DNA sequence of the bicistronic vector to eliminate deletion events driven by homologous DNA sequences. We have an optimized gene therapy vector that has been produced under GMP conditions. An IND will be submitted to the FDA very soon. We have also prepared a producer cell clone that generates a gamma-retrovirus encoding the Hu19-CD828Z anti-CD19 CAR. GMP-grade vector has been produced from this master cell bank. We plan to use this vector in a clinical trial that will enroll CLL patients. Substantial time and effort has been expended in the past year to prepare required regulatory documents for the two upcoming clinical trials. We have also carried out experiments to examine the impact of cytokines on CAR toxicity including the role of corticosteroids which are used to treat CAR T-cell toxicity on CAR T cells. 936552 +No NIH Category available Acute Lymphocytic Leukemia;Allogenic;B lymphoid malignancy;B-Cell Leukemia;Blood;CD19 gene;Cell Transplantation;Cells;Clinical Oncology;Clinical Trials;Collaborations;Disease remission;Donor person;Enrollment;Goals;Hematopoietic Stem Cell Transplantation;Homologous Transplantation;Immunology;Infusion procedures;Journals;Learning;Lymphoma;Malignant Neoplasms;Manuscripts;Paper;Partial Remission;Patients;Preparation;Process;Proliferating;Proteins;Publishing;Relapse;Reporting;Research Personnel;Stem cell transplant;T cell differentiation;T cell therapy;T memory cell;T-Lymphocyte;Testing;Toxic effect;Work;cellular transduction;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;experimental study;genetically modified cells;leukemia/lymphoma;recruit;stem Allogeneic T cells Transduced with an Anti-CD19 Chimeric Antigen Receptor n/a NCI 10926204 1ZIABC011415-13 1 ZIA BC 11415 13 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 156091 NCI This trial is one of few CAR trials exclusively focused on applying anti-CD19 CAR T cells to the allogeneic transplantation setting. This trial is significant because unlike most trials of anti-CD19 chimeric antigen receptors it does not include chemotherapy so it gives a pure assessment of the activity of the anti-CD19 CAR T cells. We continue recruit more patients for this trial. We have obtained important information on toxicity and predictors of successful therapy with each patient. A paper covering this trial (Brudno et al.) was published in the Journal of Clinical Oncology in 2016. The project is now focused on testing less-differentiated T cells called stem memory T cells (Ttscm) transduced with an anti-CD19 CAR. In this effort we are currently collaborating with another Investigator Luca Gattinoni in developing a process for administering allogeneic anti-CD19 CAR stem memory T cells. We have treated 11 patients with anti-CD19 CAR Tscm cells on this clinical trial. A patient with acute lymphoid leukemia obtained a complete remission after infusion of Tscm anti-CD19 CAR T cells that is ongoing. Another patient with lymphoma obtained a partial remission. This trial has now ended enrollment and a manuscript reporting the results is in preparation. Many correlative immunology experiments are in progress. 156091 +No NIH Category available Adenocarcinoma;Adenocarcinoma Cell;Affect;Attenuated;Bone Marrow;CCL22 gene;CD4 Positive T Lymphocytes;CSF1 gene;Cancer Etiology;Cells;Cessation of life;Code;Development;Disease;Epidermal Growth Factor Receptor;Epithelial Cells;Epithelium;Generations;Genetic Transcription;Human;IKK alpha;Immunity;Inflammation;Inflammatory;KRAS2 gene;KRASG12D;Knock-in Mouse;Knock-out;Link;Lung;Lung Adenocarcinoma;Macrophage;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mesenchymal;Metastatic Neoplasm to the Lung;Modeling;Mus;Mutant Strains Mice;Oncogenic;Pathway interactions;Patients;Phosphotransferases;Physiological;Prevention;Receptors Tumor Necrosis Factor Type II;Regulatory T-Lymphocyte;Reporting;Role;Sampling;Signal Transduction;Smoker;Spindle-Cell Carcinomas;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;TNF gene;TNFRSF1A gene;TNFRSF1B gene;TP53 gene;Tail;Transducers;Transgenic Organisms;Ubiquitin-Conjugating Enzymes;United States;Veins;c-myc Genes;cancer cell;carcinogenesis;cell dedifferentiation;cytokine;keratin 5;lung carcinogenesis;lung tumorigenesis;monocyte;mouse model;overexpression;recruit;targeted cancer therapy;therapeutic target;tumor;tumor microenvironment;tumorigenic Role of IKK alpha in lung cancer development n/a NCI 10926200 1ZIABC011391-13 1 ZIA BC 11391 13 10270679 "HU, YINLING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 715207 NCI The tumor microenvironment (TME) provides potential targets for cancer therapy. However how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus coding for IkB kinase a (IKKa) correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice but it is unknown how reduced IKKa expression affects the TME. Here we report that low IKKa expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cells (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1 CCL22 TNF and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation these cytokines promote lung ADC progression. Depletion of TNFR2 c-Rel or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion reduced cancer cell IKKa activity enhances formation of a pro-tumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC. Tumor necrosis factor receptor 1 (TNFR1) encoded by TNFRSF1A is a critical transducer of inflammatory pathways but its physiological role in human cancer is not completely understood. Here we observed high expression of TNFR1 in many human lung squamous cell carcinoma (SCCs) samples and in spontaneous lung SCCs derived from kinase-dead Ikka knock-in (KA/KA) mice. Knocking out Tnfrf1a in KA/KA mice blocked lung SCC formation. When injected via tail vein KALLU+ lung SCC cells that highly expressed TNFR1 Sox2 c-Myc Twist1 Bcl2 and UBCH10 generated dedifferentiated spindle cell carcinomas with epithelial-mesenchymal transition markers in mouse lungs. In contrast KALLU+ cells with silenced TNFR1 and KALLU- cells that expressed low levels of TNFR1 generated well-differentiated lung SCCs and were less tumorigenic and metastatic. We identified a downstream effector of TNFR1: oncogenic UBCH10 an E2 ubiquitin-conjugating enzyme with targets including Twist1 c-Myc and Sox2 which enhanced SCC cell dedifferentiation. Furthermore Tg-K5.TNFR1;KA/KA mice which expressed transgenic TNFR1 in keratin 5-positve epithelial cells developed more poorly-differentiated and metastatic lung SCCs than those found in KA/KA mice. These findings demonstrate that an overexpressed TNFR1-UBCH10 axis advances lung carcinogenesis and metastasis through a dedifferentiation mechanism. Constituents in this pathway may form the development of differentiation-related therapies for lung SCC. 715207 +No NIH Category available Animals;Biological Assay;Biological Models;CRISPR/Cas technology;Candidate Disease Gene;Cell Culture System;Cell Culture Techniques;Cell Line;Cells;Childhood;Chimeric Proteins;Collaborations;Development;Down-Regulation;Doxycycline;Event;Excision;FGF8 gene;FGFR1 gene;FGFR2 gene;FGFR3 gene;FGFR4 gene;FOXO1A gene;Fibroblast Growth Factor;Fibroblast Growth Factor Receptors;Gene Fusion;Genes;Genetic Transcription;Genetic study;Goals;Growth Factor;Human;In Vitro;Knock-out;Laboratories;Laboratory mice;MYCN gene;Maintenance;Malignant Neoplasms;Modeling;Molecular;Myoblasts;Neoplasm Metastasis;Oncogenes;Oncogenic;Oncoproteins;PAX3 gene;Pathogenicity;Pathway interactions;Patients;Pharmacology Study;Phenotype;Point Mutation;Population;Population Growth;Primary Neoplasm;Proliferating;Publishing;Recurrence;Recurrent tumor;Rhabdomyosarcoma;Role;Signal Transduction;System;Testing;Time;Tumor-Derived;Tumorigenicity;Up-Regulation;Variant;Work;cDNA Expression;comparison control;drug sensitivity;experimental study;genetic analysis;genome-wide;in vivo;inhibitor;neoplastic cell;novel;receptor;resistance mechanism;soft tissue;targeted treatment;therapeutic target;transcription factor;translational approach;tumor;tumor progression;tumorigenesis;tumorigenic Studies of gene fusions in rhabdomyosarcoma n/a NCI 10926199 1ZIABC011387-13 1 ZIA BC 11387 13 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 785837 NCI In our recently published work we demonstrated that FGF8 influences proliferation and transformation of fusion-positive (FP) rhabdomyosarcoma (RMS) cells as well as tumorigenicity of primary and recurrent tumors in our myoblast model system. My laboratory and other laboratories previously determined that PAX3-FOXO1 (P3F) induces upregulation of both FGF8 and FGFR4 and thus P3F is able to activate expression of both a growth factor and its receptor in FP RMS. To further understand fibroblast growth factor (FGF) signaling in RMS tumors we analyzed expression of the FGF's and FGF receptors (FGFR1 FGFR2 FGFR3 FGFR4) in human primary RMS tumors and cell lines. Of the four receptors FGFR1 and FGFR4 are highly expressed in both FP and fusion-negative (FN) RMS tumors and of the FGFs FGF8 is most highly expressed in FP tumors. Whereas FGFR1 and FGFR4 expression levels are relatively consistent among FP RMS tumors there is substantial variability in FGF8 expression in FP RMS tumors. In the human Dbt myoblast model system FGF8 is induced by P3F in parental and primary tumor-derived (TD) cells and is expressed at very high levels in a P3F-independent manner in several recurrent TD clones. For the FGF receptors FGFR1 was uniformly present in primary and recurrent TD cells whereas FGFR4 was higher in P3F-induced parental and primary TD cells but very low to absent in the recurrent TD cells. To study the functional significance of these growth factors and receptors we selected FGF receptor inhibitors that are specific for FGFR1 (PD173074) and FGFR4 (H3B6527) in addition to a potent pan inhibitor (Erdafitinib). In real-time population growth and colony assays FP RMS cells with high FGF8 expression are more sensitive to the FGFR4 and pan-FGFR inhibitors than FP RMS cells with low FGF8 whereas there was no consistent difference between the two groups in the effect of the FGFR1 inhibitor. To investigate the relationship of FGF8 to these inhibitors we knocked out FGF8 in the high FGF8-expressing FP RMS cell line RH30. Comparison of control to knockout subclones revealed a lower sensitivity to the FGFR4 and pan-FGFR inhibitors in the knockout subclones but no difference in FGFR1 inhibitor sensitivity. These findings suggest that FGF8 expression in FP RMS cells is necessary for the sensitivity to FGFR inhibitors. We then assessed the effect of P3F on these effects in three different systems. First comparison of drug sensitivity between high FGF8-expressing RH30 cells and a spontaneous non-transformed variant expressing very low levels of P3F (as well as FGF8 and FGFR4) revealed a substantial loss in sensitivity to the FGFR4 and pan-FGFR inhibitors in the low P3F variant and only a small change in FGFR1 inhibitor sensitivity. Second after P3F knockout in two FP RMS lines these lines demonstrated FGF8 and FGFR4 downregulation and a large loss in sensitivity to the FGFR4 and pan-FGFR inhibitors but only a small change in FGFR1 inhibitor sensitivity. Third after inducing P3F expression in our Dbt myoblast system we found the expected increase in FGF8 and FGFR4 expression along with augmented sensitivity to the FGFR4 and pan-FGFR inhibitors but not to the FGFR1 inhibitor. To determine the effect of FGF8 on inhibitor sensitivity in the absence of P3F we introduced FGF8 into the MYCN-expressing Dbt cells and found increased sensitivity to the FGFR1 and pan-FGFR inhibitors but not the FGFR4 inhibitor. These results suggest that FGF8 is sufficient to activate the FGF pathway and thus sensitize the cells to the FGF receptor inhibitors. In addition these results suggest that in the presence of P3F FGF8 signals through FGFR4 but in the absence of P3F such as in the P3F independent recurrences FGF8 signals through FGFR1. 785837 +No NIH Category available Acute;Acute Myelocytic Leukemia;Area;Behavior;Biophysics;Blood;Cells;Cellular biology;Clinical;Clonal Hematopoietic Stem Cell;Complement;Computer Analysis;Computer Models;Coupled;Coupling;DNA-Directed RNA Polymerase;Development;Disease;Disease Progression;Dysmyelopoietic Syndromes;Dysplasia;Eukaryotic Cell;Fluorescent Probes;Gene Expression;Gene Expression Alteration;Gene Expression Process;Gene Expression Profiling;Gene Expression Regulation;Genes;Genetic Transcription;Genomic approach;Goals;Health;Hematopoiesis;Hematopoietic stem cells;Heterogeneity;Human;In Vitro;Individual;Ineffective Hematopoiesis;Laboratories;Malignant - descriptor;Marrow;Methods;Microscopy;Modeling;Molecular;Molecular Machines;Mutation;Myeloproliferative disease;Nuclear Structure;Nucleotides;Patients;Play;Population;Process;Prognosis;Proliferating;Proteins;RNA;RNA Splicing;Regulation;Research;Resolution;Ribosomes;Role;Sampling;Site;Spliceosome Assembly Pathway;Spliceosomes;Sum;Time;Tissues;Translations;Variant;Visualization;Work;bench to bedside;cytopenia;hematopoietic differentiation;live cell imaging;macromolecule;peripheral blood;posttranscriptional;programs;reconstitution;single molecule;stem cells;structural biology;transcriptome sequencing Transcription and Splicing Dynamics in Single Cells n/a NCI 10926198 1ZIABC011383-13 1 ZIA BC 11383 13 11142375 "LARSON, DANIEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2567555 NCI "Gene Expression in Single Cells: Gene expression refers to the sum of processes that enable cells to control their complement of RNA and protein. Megadalton molecular machines such as RNA polymerase the spliceosome and the ribosome carry out the synthesis processing and translation of RNA. Advances in structural biology have revealed the atomic details of these machines and the revolution in sequencing has engendered an understanding of their respective enzymatic activities with nucleotide resolution. A central challenge in cell biology is to understand how these processes are coupled and regulated in time and space in single living cells. In recent years through parallel advances in microscopy fluorescent probe development computational modeling and gene editing it is now possible to directly observe the processes of gene expression (transcription splicing translation) in living cells. The Larson lab has played an essential role in this development for example by being the first lab to visualize transcription and splicing of single human genes in real time. The view that has emerged from these studies is that gene regulation is an extremely dynamic process where the random behavior of individual molecules plays an important role in determining how a cell controls expression. Coupling live-cell imaging with RNA-sequencing based methods is an exciting approach for understanding gene expression in health and disease. Gene Expression in Myeloid Malignancy: The differentiation of hematopoietic stem cells into committed lineages in the blood is the result of concerted regulation between transcription splicing and translation and a goal of the laboratory is to understand the dynamic interplay between these processes in single cells. Moreover mutations in the gene expression machinery drive the development of clonal stem cell disorders termed 'myeloid malignancies.' Specifically the Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are a heterogeneous group of malignant clonal hematopoietic stem cell disorders with poor prognosis and few treatment options. MDS is characterized by ineffective hematopoiesis marrow dysplasia peripheral blood cytopenia and a high propensity for transformation into AML which is an acute proliferative disease. Simply stated MDS is a disease of differentiation while AML is a disease of differentiation plus proliferation. Over 60% of MDS patients carry a mutation in the spliceosome and the Larson lab has proposed a non-canonical role for the splicing machinery in disease progression. Overall gene regulation in this tissue is exceptionally dependent on post-transcriptional mechanisms opening new avenues of research for understanding hematopoiesis. Analysis of primary human samples and close coupling with the newly-established Myeloid Malignancies clinical program - ""bench-to-bedside-to-bench"" - makes this area a vibrant and impactful area of study where basic concepts in gene regulation can be immediately applied to human health. Thus the projects in the laboratory are loosely divided into several areas: 1) Visualizing spliceosome assembly and splice site selection 2) Deciphering the role of nuclear structure in modulating gene expression 3) Determining the causes and consequences of transcriptional heterogeneity 4) Developing in vitro reconstituted models for examining the coupling between transcription splicing translation 5) Computational analysis of gene expression 6) Understanding gene expression alteration in myeloid malignancy." 2567555 +No NIH Category available 12q13;13q14;1p36;Behavior;Biological;Biological Assay;CRISPR/Cas technology;Candidate Disease Gene;Cell Culture System;Cell Culture Techniques;Cell Line;Cells;Chemicals;Childhood;Complementary DNA;Engineering;Event;FOXO1A gene;Family;Gene Amplification;Gene Chips;Genes;Genetic Complementation Test;Genetic Heterogeneity;Genetic Transcription;Genomics;Goals;Growth;Guide RNA;Human;Human Engineering;Immunohistochemistry;Knock-out;Laboratories;Link;MYC Family Protein;MYCN gene;Malignant Neoplasms;Maps;Methyl-CpG-Binding Protein 2;MicroRNAs;Molecular;Mus;Myoblasts;Nucleic Acid Regulatory Sequences;Oncogenic;Oncoproteins;PAX3 gene;PAX7 gene;Pathogenesis;Pathway interactions;Phenotype;Process;Proteins;Publishing;RNA Interference;Reagent;Recurrence;Resistance;Rhabdomyosarcoma;Role;System;Therapeutic Intervention;Tissue Microarray;Transcription Repressor;Untranslated RNA;Up-Regulation;Western Blotting;candidate identification;directed attention;experimental study;fusion gene;gene interaction;genome-wide;interest;lentivirally transduced;loss of function;member;overexpression;research study;soft tissue;targeted treatment;therapeutic target;transcription factor;transcriptome sequencing;tumor;tumorigenesis Studies of amplification in rhabdomyosarcoma n/a NCI 10926196 1ZIABC011378-13 1 ZIA BC 11378 13 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 744477 NCI In past studies of gene amplification in fusion-positive (FP) rhabdomyosarcoma (RMS) we identified MYCN and MIR17HG as key targets of the 2p24 and 13q31 amplicons respectively. MYCN encodes a member of the Myc family of transcription factors and MIR17HG generates six microRNA's (miRNA's). In our recent studies we investigated the relationship of the PAX3-FOXO1 (P3F) fusion with MYCN and MIR17HG. To link these genes in a common pathway we note that previous studies in my laboratory showed that MYCN is a transcriptional target upregulated by P3F and other published studies revealed that Myc family proteins such as MYCN contribute to the upregulation of MIR17HG. Based on these findings we hypothesized a scenario in which P3F upregulates MYCN which in turn upregulates MIR17HG. To investigate the validity of this scenario we used two cell culture-based systems. In the first system we engineered two FP RMS cell lines (RH30 and RH41) with an inducible Cas9 and constitutively expressing PAX3-directed gRNA's thereby permitting inducible knockout of P3F. In each RMS line P3F knockout resulted in a substantial decrease in MYCN expression. Analysis of the six mature miRNA's of the miR-17-92 cluster (miR-17 miR-18 miR-19a miR-19b miR-20 and miR-92) processed from MIR17HG also demonstrated a substantial decrease in expression of these miRNA's following P3F knockout. In rescue experiments lentiviral transduction of a P3F construct (modified to be resistant to knockout) into these P3F knockout cells increased expression of MYCN and the miRNA's of the miR-17-92 cluster. Of interest recent experiments with lentiviral transduction of MYCN into the P3F knockout cells suggests that MYCN may only restore a lower level of miR-17-92 expression than the level restored by P3F rescue. These findings suggest that P3F may have regulatory effects on MIR17HG (and the miR-17-92 cluster) that are not fully recapitulated by MYCN. In a second system we used the human myoblast line Dbt along with inducible P3F and constitutive MYCN constructs to assess the effects of P3F and/or MYCN on this miRNA cluster. It should be noted that P3F only induces a small increase in MYCN expression in these myoblasts so that this system permits P3F and MYCN to be independently assessed without significant effects on each other's expression. In these experiments P3F alone does not significantly upregulate miRNA expression in the myoblasts whereas MYCN expression induces a small increase in expression of each of the six miRNA's. In contrast the combination of P3F and MYCN results in a substantial increase in expression of each of the six miRNA's. Therefore there appears to be a synergistic effect between P3F and MYCN so that P3F does not entirely act through upregulation of MYCN. Although MYCN may be necessary for P3F to upregulate the six microRNA's MYCN is not sufficient to fully upregulate these targets. To assess the phenotypic effects of high versus low level miR-17-92 expression we developed two experimental systems. In one system we transduced a lentiviral construct constitutively expressing the miR-17-92 cluster into derivatives of the human Dbt myoblast system resulting in increased expression of the six corresponding miRNA's with or without increased expression of MYCN or P3F. For loss of function studies we engineered human RMS cell lines to express an inducible Cas9-KRAB-MeCP2 construct and a construct constitutively expressing six gRNA's targeting the MIR17HG 5' regulatory region. In these cells the modified Cas9 protein acts as a transcriptional repressor and down-regulates MIR17HG expression resulting in very low levels of the six miRNA's of the miR-17-92 cluster. Now that these two systems have been fully developed and implemented we will assay the phenotypic changes associated with increased miR-17-92 expression in Dbt myoblasts and decreased miR-17-92 expression in human RMS cells. 744477 +No NIH Category available Adjuvant Study;Area;Cancer Etiology;Cessation of life;Clinical;Cystectomy;Disease;High Prevalence;Human;IgG1;Immune checkpoint inhibitor;Immunotherapy;Ligands;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Modality;Muscle;PD-1/PD-L1;Pathway interactions;Patients;Phase III Clinical Trials;Principal Investigator;Randomized;Reporting;Research;Somatic Mutation;Testing;Transitional Cell Carcinoma;Treatment outcome;Tumor-Infiltrating Lymphocytes;United States;United States Food and Drug Administration;Urothelium;Woman;anti-PD-L1;bladder transitional cell carcinoma;first-in-human;high risk;improved;improved outcome;inhibiting antibody;men;novel therapeutics;pembrolizumab;programmed cell death ligand 1;programmed cell death protein 1;programs;response;targeted agent;treatment choice;tumor;tumor microenvironment Bladder Cancer Program n/a NCI 10926192 1ZIABC011351-14 1 ZIA BC 11351 14 10687150 "APOLO, ANDREA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 869986 NCI Immunotherapy with immune checkpoint inhibitors particularly agents targeting the axis of programmed cell death protein 1 and its ligand (PD-1/PD-L1) has improved treatment outcomes in many tumor types. The rationale for assessing immune checkpoint inhibitors in advanced urothelial cancer is supported by a high prevalence of tumor somatic mutations and the presence of PD-L1 expression on tumors and tumor-infiltrating lymphocytes in the tumor microenvironment. Avelumab is a fully human anti-PD-L1 IgG1 antibody that inhibits PD-1/PD-L1 interactions but leaves the PD-1/PD-L2 pathway intact. The first-in-human trial of avelumab was led at the intramural NCI and I led the clinical effort for avelumab in advanced/metastatic urothelial carcinoma which showed clinical benefit leading to approval by the U.S. Food and Drug Administration (FDA) for this indication. Given the activity of several immune checkpoint inhibitors in this setting I was eager to test these agents in an earlier disease setting in patients with high-risk muscle-invasive disease. I initiated a phase 3 clinical trial of adjuvant pembrolizumab post-cystectomy in patients with high-risk muscle-invasive urothelial carcinoma of the bladder and upper tract. I am the principal investigator on this Alliance/NCI-sponsored study. The trial is accrued with 702 patients randomized. If positive would provide a treatment choice for patients with urothelial carcinoma in this setting. 869986 +No NIH Category available Affect;CSF1R gene;Cell Communication;Cells;Cirrhosis;Coculture Techniques;Detection;Environment;Flow Cytometry;Functional disorder;Genetic;Heterogeneity;Human;Image;Immune;Immunity;Immunologic Surveillance;Immunosuppressive Agents;Infection;Infiltration;Inflammation;Liver;Liver diseases;Liver neoplasms;Machine Learning;Malignant Neoplasms;Malignant neoplasm of liver;Mucous Membrane;Mus;Neighborhoods;Patients;Primary carcinoma of the liver cells;Regulatory Element;Role;Sampling;T-Lymphocyte;Tumor Escape;Tumor-associated macrophages;anti-PD-1;anti-PD-L1 therapy;cytotoxicity;fatty liver disease;indexing;microbiome;mouse model;novel;programmed cell death ligand 1;single-cell RNA sequencing;targeted treatment;tool;tumor growth Analysis of cancer-related immune suppressor mechanisms in mice n/a NCI 10926191 1ZIABC011345-14 1 ZIA BC 11345 14 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1906828 NCI This year placed a specific focus on innate immune cells in the liver and studied Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAITs are assigned crucial roles in regulating immunity and inflammation yet their role in liver cancer remains elusive. Here we present a MAIT- centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq flow cytometry and 37-plex co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAITs in HCC and their defective capacity to infiltrate liver tumors. Novel machine learning tools were used to dissect the spatial cellular interaction network within the MAIT neighborhood. Co- localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages and MAITs was identified as key regulatory element of MAIT dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and in murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAITs in HCC patients. 1906828 +No NIH Category available Affect;Cells;Correlative Study;Disease;Future;Goals;Immune;Immune checkpoint inhibitor;Liver;Liver neoplasms;Malignant neoplasm of gastrointestinal tract;Oncolytic viruses;Patient-Focused Outcomes;Patients;Primary Neoplasm;Publishing;Sampling;Vancomycin;bevacizumab;novel;participant enrollment;therapy outcome;tumor;tumor microenvironment Immune suppressor mechanisms in patients with GI cancer n/a NCI 10926190 1ZIABC011344-14 1 ZIA BC 11344 14 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 127122 NCI We performed correlative studies using samples from patients enrolled in our trials. This includes patients with HCC and CCC treated with immune checkpoint inhibitors +/- anti-VEGF patients with CRC treated with immune checkpoint inhibitors plus oncolytic virus and patients with liver tumors treated with vancomycin. Some of the studies have been concluded and have been published (CRC: PexaVec) other have been submitted and should appear in the near future (CCC plus immune checkpoint inhibitors) Vancomycin treatment of patients with liver dominant diease 127122 +No NIH Category available Autophagocytosis;CAR T cell therapy;Carcinoma;Cessation of life;Chemoembolization;Clinical Protocols;Colorectal Cancer;Combined Modality Therapy;Conduct Clinical Trials;GPC3 gene;Gastrointestinal Neoplasms;Hydroxychloroquine;Immunotherapy;KRAS2 gene;Liver;MEKs;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mutation;Nivolumab;Oncolytic viruses;Operative Surgical Procedures;Oral;Patient-Focused Outcomes;Patients;Phase;Pilot Projects;Primary carcinoma of the liver cells;Protocols documentation;Radiation therapy;Refractory;Treatment Protocols;United States;Vancomycin;anti-PD-1;bevacizumab;biliary tract;checkpoint inhibition;chemotherapy;experience;hepatobiliary cancer;improved;improved outcome;inhibitor;metastatic colorectal;molecular targeted therapies;novel therapeutic intervention;participant enrollment;phase 1 study;phase 2 study;phase II trial;tadalafil;tumor Clinical protocols for the treatment of gastrointestinal cancer n/a NCI 10926189 1ZIABC011343-14 1 ZIA BC 11343 14 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 508487 NCI Gastrointestinal cancer represents one of the major reasons for tumor related death in the United States. Current treatment options are limited to surgery chemotherapy radiation therapy and molecular targeted therapy and new treatment options are urgently needed. We have completed and closed the following protocols:NCI-20-C-0022: NCI-20-C-0152: Phase II Study of combination of Trametinib (MEK inhibitor) and Hydroxychloroquine (HCQ) (autophagy inhibitor) in Patients with KRAS Mutation Refractory Bile Tract Carcinoma (BTC)Phase II trial of VB-111 in Combination with Nivolumab in Patients with Metastatic Colorectal Cancer (mCRC). NCI-19-C-0033:Phase II Study of Nivolumab (anti-PD1) Tadalafil and Oral Vancomycin in Patients with Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer from Colorectal or Pancreatic Cancers; NCI-17-C-0092: A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination with Immune Checkpoint Inhibition in Refractory Colorectal Cancer; NCI-16-C-0135: A Pilot Study of Combined Immune Checkpoint Inhibition in combination with ablative therapies in Subjects with Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC). We have enrolled patients on the following protocols: 19C0094 A: A Phase II Study of Combined Treatment of Durvalumab Bevacizumab Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects with Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinoma (BTC).NCI-21-C-0030: Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC) 508487 +No NIH Category available Adjuvant;Adjuvant Therapy;Adult;Aging;Area;Biological;Biological Assay;Biological Markers;Blood;Blood Vessels;Bone Marrow;CD8-Positive T-Lymphocytes;CSF1R gene;Cell Communication;Cell Line;Cell Lineage;Cell Therapy;Cell physiology;Cells;Chemotherapy and/or radiation;Childhood;Childhood Solid Neoplasm;Chronic Disease;Clinical;Clinical Trials;Collaborations;Colony-Stimulating Factors;Cytometry;Cytotoxic T-Lymphocytes;Data;Development;Disease;Disseminated Malignant Neoplasm;Distant;Effectiveness;Endothelial Cells;Endothelium;Engineering;Enrollment;Epigenetic Process;Ewings sarcoma;Excision;Extracellular Matrix;FLT3 gene;Fibrinogen;Fibroblasts;Flow Cytometry;Gene Expression Profile;Genetic;Genetic Engineering;Genetic Transcription;Giant Cell Tumors;Growth;Growth and Development function;Heart Diseases;Hematopoietic;Hematopoietic stem cells;Human;Image;Immune;Immune Targeting;Immune response;Immune system;Immunofluorescence Immunologic;Immunosuppression;Immunotherapy;Individual;Inflammatory;Institutional Review Boards;Investigation;Laboratories;Longevity;Longitudinal Studies;Luciferases;Macrophage;Macrophage Colony-Stimulating Factor;Malignant Neoplasms;Measures;Mediating;Mediator;Mesenchymal;Metabolic;Modeling;Molecular;Monitor;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Neuroblastoma;Normal tissue morphology;Organ Transplantation;Patients;Pericytes;Phagocytosis;Phase;Play;Population;Pre-Clinical Model;Primary Neoplasm;Process;Recurrent Malignant Neoplasm;Recurrent disease;Relapse;Rhabdomyosarcoma;Risk;Role;Shapes;Signal Transduction;Site;Solid Neoplasm;Stromal Cells;Supporting Cell;System;T cell response;T cell therapy;T-Lymphocyte;Testing;Therapeutic;Tissues;Translating;Translational Research;Transplant-Related Disorder;Treatment Efficacy;Tumor Cell Line;Tumor Immunity;Tumor Markers;Universities;Vascular Diseases;Work;bone circulation;cancer recurrence;cell behavior;cell type;chimeric antigen receptor T cells;conventional therapy;cytotoxicity;delivery vehicle;endothelial stem cell;experimental study;fighting;hematopoietic stem cell niche;high risk;immune phagocytosis;immunoregulation;improved;in vitro Model;in vivo;individualized medicine;inhibitor;insight;microvesicles;monocyte;myeloid cell development;neoplastic cell;non-genetic;novel;osteosarcoma;pediatric patients;pre-clinical;preclinical study;predictive tools;progenitor;prognostic tool;programs;rare cancer;receptor;recruit;repository;response;single cell sequencing;specific biomarkers;standard care;stem cells;targeted treatment;therapeutic target;therapy design;therapy development;tissue regeneration;tissue repair;transcriptomics;tumor;tumor microenvironment;tumor progression;tumor xenograft;tumorigenesis;vesicular release Biomarkers and Therapeutic Targets in Tumor Microenvironment and Metastasis n/a NCI 10926187 1ZIABC011334-14 1 ZIA BC 11334 14 10712506 "KAPLAN, ROSANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1190749 NCI As one of the crucial steps in metastatic progression requires tumor to successfully interact with its local microenvironment it follows that targeting this cross-talk may be an attractive adjuvant to standard treatment approaches. We are focused on developing therapies that can target and modulate the associated tumor recruited host immune and stromal cells. We have an IRB approved biological repository study to obtain blood bone marrow tumor and adjacent normal tissue when available from patients with malignancy and healthy donors. In addition to on-going studies of measuring and characterizing the circulating bone marrow-derived progenitor immune endothelial and mesenchymal cells that may be altered in the setting of cancer and other chronic diseases we have more recently been developing functional assays for human circulating monocytes. Utilizing both quantification and functional assays including flow cytometry and immune suppression and phagocytosis assays we are assessing the circulating bone marrow-derived myeloid cell populations in pediatric and adult patients with malignancies. We have broadened our investigations to better understand the changes in the hematopoietic stem cell niche that results in alterations in immune milieu in response to a growing primary tumor. These studies now include in addition to monitoring hematopoietic and endothelial progenitor cells but also CD4 and CD8 T cells and myeloid cells including classical intermediate and non-classical monocytes MDSCs and M1 and M2 macrophages and stromal cell populations. Furthermore we measure circulating microvesicles released by tumor cells and tumor associated myeloid and stromal cells that may impact important cell behavior and are known to be critical to cell-cell communication. We have on-going investigations to explore circulating monocytes and monocyte function and the impact on metastatic risk. Our recent studies have determined host cell plasticity and cell state determine the microvesicles released from these cells and this plasticity in perivascular cells play key roles in regulating metastasis. We are currently investigating markers of this perivascular cell plasticity as a predictor of metastasis and response to conventional therapies and immune based therapies. We have on-going studies and a collaboration with Lynn Hedrick at University of Georgia examining monocyte subpopulations and functions in metastasis and as a biomarker of metastasis. We have established multiple pre-clinical models for testing microenvironment-targeting therapy in pediatric solid tumors. Utilizing a Ewings sarcoma (EWS) xenograft tumor cell line and two syngeneic models- rhabdomyosarcoma (RMS) cell line and an osteosarcoma (OS) cell line we have performed flow cytometry and immunofluorescence to demonstrate the influx of myeloid cells and alterations in stromal cell populations in the tumor and pre-metastatic tissues. We also monitor metastatic progression in a resection model using luciferase imaging. In this fashion pre-metastatic metastatic colonization and progression to visible metastasis can be followed and compared in treated and untreated groups without requiring multiple terminal end points. We are conducting pre-clinical investigations utilizing inhibitors targeting stromal cell plasticity specifically to assess impact on metastatic progression. We also now have a marker of tumor associated fibroblast activation and stromal cell lineage tracing mice in order to monitor activation of these cells in this process. We have performed serial in vivo mouse experiments examining modulation of myeloid cells and stromal cells to determine their impact on metastatic progression. We are using different investigational agents to determine their specific impact on each microenvironmental cell. These pre-clinical studies will answer whether this approach to treatment may likely be a good window for targeting the recruitment of these microenvironment tumor-associated cells that support tumor progression. Our studies using a colony stimulating factor -one receptor (csf1-R) inhibitor revealed that these models of RMS and Ewings sarcoma secrete a good deal of CSF-1 and lead to the recruitment of CSF-1R expressing cells. These cells are found in early metastatic sites and are immune suppressive and can protect disseminated tumor cells from cytotoxic T cell activity. We are working on developing approaches to reversing myeloid mediated immunosuppression and promote myeloid mediated anti-tumor T cell responses. We are performing studies to determine the critical effectors of this cytotoxicity. We have also established a good in vitro model to understand the role of tumor-secreted factors on myeloid cell development and stromal cell plasticity and function and investigating different approaches to modulating this process. We have studies examining myeloid cell function and exploring activators and inhibitors of these functions including the myeloid polarization process and phagocytosis. We also have studies exploring the activation and expansion of stromal cell populations that promote metastasis. We completed the Phase I portion of Pexidartinib which inihibits FLT3 Kit and CSF1R. We are now enrolling on the expanded Phase I in pediatric patients with tenosynovial giant cell tumor for open access approval for this agent for pediatric patients as it is approved for this tumor in adults. We are also actively planning a new trial to target immune suppressive myeloid cells. We have developed a new cell therapy based on genetically engineering myeloid cells (GEMys) that can be novel delivery vehicles given their propensity to accumulate in tumor and metastatic sites. These cells can be engineered to deliver Il12 into the tumor milieu and reprogram multiple cell types change gene transcriptional signatures and reverse immune suppression and enhance anti-tumor immunity. We have developed humanized murine systems to examine human cell therapy with advanced human tumors. On going work to bring this to clinical setting is on-going and harnessing myeloid cells for introduction of signaling in tumor microenvironment. These investigations also include stromal cells and extracellular matrix remodeling. Single cell sequencing can provide exquisite detail of individual cell cluster transcriptional programs. Our laboratory has begun performing single cell sequencing of rare tumors to investigate tumor and microenvironmental interactions. Such studies can be invaluable for tumor and microenvironment genetic and non genetic interactions that provide insights to targeting cross talk and unique aspects of both tumor and associated microenvironment. We have recently leveraged the data we have generated from our first clinical trial of chimeric antigen receptor T cells targeting GD2 in patients with osteosarcoma and neuroblastoma. This collaboration with Dr. Lynn Hedrick and team now at University of Georgia and Dr. Mackall and team at Stanford has allowed deep transcriptomic mass cytometry and epigenetic investigations into immune response in patients on CART trial. We found that myeloid cells are key regulators of the CART cells. We have that myeloid cells depending on the subpopulations and their receptors can be helpful in promoting effective anti-tumor immunity and conversely myeloid subpopulations can also limit CART expansion. These studies speak to the diversity of myeloid populations and their functions and importance of studying these aspects. These investigations are shaping a new understanding of myeloid mediators of CART expansion and may ultimately impact efficacy and serve as a path to combine myeloid and T cell based therapies. Furthermore myeloid markers of CAR efficacy will be further explored in other clinical trials to more completely evaluate the markers across solid tumor trials. 1190749 +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Adhesions;Adjuvant;Adrenocortical carcinoma;Adult;Area;Blood Vessels;Bone Marrow;Breast;Breast Carcinoma;CSF1R gene;Cell Communication;Cell Compartmentation;Cell Line;Cell Survival;Cell Therapy;Cells;Cellular Assay;Cessation of life;Characteristics;Childhood;Childhood Lymphoma;Childhood Rhabdomyosarcoma;Circulation;Clinic;Clinical;Colon;Cyclophosphamide;Data;Development;Disease;Distant;Dose;Dysmyelopoietic Syndromes;Endothelial Cells;Environment;Equilibrium;Event;Ewings sarcoma;Extracellular Matrix;FLT3 gene;Fibroblasts;Genes;Genetic Engineering;Glioma;Goals;Growth;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;High-Risk Cancer;Human;ITGAM gene;Immune;Immune Evasion;Immunosuppression;Immunotherapy;In Vitro;Individual;Inflammation;Interleukin-12;Investigation;Lead;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of adrenal cortex;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Mediating;Mesenchymal;Metalloproteases;Metastatic Neoplasm to the Bone;Modeling;Molecular;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Natural Killer Cells;Neoplasm Metastasis;Nerve;Neuroblastoma;Organ;Pathway interactions;Patients;Pediatric Neoplasm;Pericytes;Pharmaceutical Preparations;Phase;Phenotype;Physiological;Play;Population;Pre-Clinical Model;Primary Neoplasm;Proliferating;Proteins;Recurrence;Refractory;Reproducibility;Rhabdomyosarcoma;Role;Sampling;Signal Transduction;Site;Soil;Solid Neoplasm;Stromal Cells;Supporting Cell;T cell response;T-Lymphocyte;Tissues;Translating;Tumor Immunity;Tumor Promotion;Tumor-Derived;Tumor-infiltrating immune cells;Vascular Endothelial Growth Factor Receptor-1;Vascular Endothelial Growth Factors;Work;adolescent patient;angiogenesis;anticancer research;arginase;bone;bone scaffold;cancer therapy;cancer type;cellular engineering;combinatorial;design;exosome;fludarabine;genetic manipulation;hematopoietic stem cell niche;human tissue;in vivo;insight;lung Carcinoma;melanoma;metastatic process;mouse model;neoplastic cell;neurofibroma;novel;novel strategies;novel therapeutic intervention;osteosarcoma;pediatric patients;pre-clinical;prevent;programs;recruit;response;response to injury;sarcoma;small molecular inhibitor;stem cell biology;stem cell niche;stem cells;therapy design;therapy development;tissue injury;tissue repair;transcription factor;translational study;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Tumor Microenvironment in Cancer Progression n/a NCI 10926185 1ZIABC011332-14 1 ZIA BC 11332 14 10712506 "KAPLAN, ROSANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1190749 NCI We have established that during primary tumor growth there is a formation of a niche environment in distant tissue sites during metastatic initiation. This pre-metastatic tissue has an influx of bone marrow-derived cells including populations of myeloid cells and overall expansion in myeloid cells that induce immunosuppressive of T and NK cell mediated anti-tumor immunity. These myeloid cells also provide factors such as matrix metalloproteases to remodel extracellular matrix and pro-growth and survival signals such as VEGF and arginase to support the colonizing disseminated tumor cells and allow for immune evasion. These sites are created as a systemic response to tumor progression and may be organ specific and activate tissue injury response programs in specific microenvironments. Using syngeneic cells lines that have a high spontaneous metastatic rate we have identified unique changes within the bone marrow microenvironment that lead to mobilization of bone marrow-derived cells that are recruited to the pre-metastatic niche in multiple tumor models including E0771 breast carcinoma F4 osteosarcoma 76-9 and M3-9M pediatric rhabdomyosarcomas and B16 melanoma. Previously we have shown that CD11b myeloid cells expressed VEGFR1 in the pre-metastatic tissue. We have now discovered these cells are hematopoietic progenitor cells that become an immune suppressive myeloid population that alter the local immune environment favoring immune evasion similar to sanctuary sites in stem cell niches (Giles et al Cancer Research 2016). We have also identified the central role of immune suppression in creation of pre-metastatic and early metastatic niche and the means of reprogramming this immune suppression to limit metastasis (Kaczanowska et al Cell 2021). These cells are immune suppressive myeloid cells derived from mobilized bone marrow-derived hematopoietic stem and progenitor cells which play an integral role in regulating T cell responses (Giles et al Cancer Research 2016; Kaczanowska et al Cell 2021). We are able to manipulate metastatic progression by altering these unique bone marrow-derived cell enriched areas. We have new data demonstrating that the pre-metastatic niche has similar features to physiological stem cell niches in order to promote distant tumor cell survival. We have found that the localized tumor prior to established metastasis is activating the hematopoietic stem cell niche within the bone marrow and inducing proliferation of hematopoietic stem cells and mobilization of these cells into the circulation. We have found that there are changes that occur in the bone marrow microenvironment in response to tumor secreted factors that induce the myeloid skewing and expansion of hematopoietic progenitor cells that we have seen during tumor progression (Giles et al Cancer Research 2016). Targeting the skewing to prevent the expansion in hematopoietic progenitor cells and myeloid cells may be a way to reset this maladaptive response to a growing tumor and prevent metastatic progression. We have on-going investigations examining the small molecular inhibitor PLX3397 that targets CSF1R found on myeloid cells cKit and FLT3-ITD which we have determined that when the drug is given in the adjuvant setting can limit metastatic progression in tumor bearing hosts. We have initiated and completed the Phase I dose escalation of PLX3397 in pediatric and adolescent patients with recurrent or refractory tumors (Boal et al Clinical Cancer Research). We have also developed a new cell therapy approach platform to reprogram these recruited immune suppressive myeloid cells by introducing genetically engineered myeloid cells (GEMys) that express IL12. These IL12 GEMys can reverse the immune suppression program in the pre-metastatic niche and lead to inhibition of metastatic progression and significantly prolong overall survival in highly metastatic murine models (Kaczanowska et al Cell 2021). IL12 GEMys when given following fludarabine and cyclophosphamide tumor bearing hosts lead to long term cures in these metastatic pre-clinical models (Kaczanowska et al Cell 2021). In addition to investigations into the recruited hematopoietic progenitor bone marrow derived cell populations that become immune suppressive cells in pre-metastatic sites we continue to investigate the essential changes in stromal cells including pericytes vascular cells and fibroblasts as well as the extracellular matrix in the pre-metastatic and metastatic niche. We have established several lineage tracing models to better track and characterize these stromal cell populations as well as genetically manipulate key genes within specific cell populations. Using these models we can interrogate the function of specific proteins to these cells and their role in the metastatic process. A specific transcription factor KLF4 we have discovered is critical to mediating this stromal cell plasticity. These stromal cells that become activated create a distinct extracellular matrix that support disseminated tumor cell survival. We are currently investigating the role of tumor conditioned media and tumor derived exosomes in making local changes in the stromal cell compartment and matrix that provides the scaffolding for bone marrow-derived cells and are essential component of the pre-metastatic niche (Murgai et al Nat Med 2017). We have identified two critical cellular pathways in pre-metastatic niche formation related to inflammation and stem cell biology involving myeloid and stromal cells. Understanding the activation of these tissue repair pathways and inflammation- related pathways in the metastatic process are an active area of investigation. In addition to our existing stromal models we have developed a new lineage tracing model to track mesenchymal cells that support nerves. These models are robust and show a new phenotype of mesenchymal nerve support cells that are found in bone and other sites and we have preliminary data to suggest a function in the pre-metastatic niche in bone during bone metastasis. Our current investigations reveal important components of the dysregulated microenvironments that occur during metastatic progression. Our novel cell therapy approach can provide a platform to locally rebalance these altered microenvironments and a potential new therapeutic approach to limit metastatic progression in pediatric and adult patients at high risk for cancer progression. We are developing multiple approaches to translate this new cell therapy platform into the clinic setting. We are also actively exploring which cargo are most effective to rebalance dysregulated microenvironments that occur during metastasis. As many cancers have a dense extracellular matrix and we determined that extracellular matrix remodeling is occurring in an enhanced fashion from stromal cell expansion. We are investigating modulation of extracellular matrix through cell therapy delivery of extracellular matrix remodeling proteins. More dense matrix is associated with malignant tissue. We aim to explore the impact of matrix remodeling on metastatic progression. We have developed robust cell engineering strategies culture conditions and reproducible assays for cell therapy development. We continue to develop functional studies that help demonstrate human genetically engineered myeloid cell therapy (GEMys) can effectively deliver the cargo and that the cargo has the anticipated response in vitro and in preclinical in vivo studies. We are preforming extensive IND enabling studies. We are also developing correlative markers to explore response and microenvironmental changes in immunotherapy in solid tumors. These studies can not only provide insights into response but also development of potential combinatorial approaches to target diverse aspects of the tumor microenvironment. 1190749 +No NIH Category available Address;Anatomy;Apoptotic;Behavior Control;Cardiac;Cell Communication;Cell Death;Cells;Chronic Kidney Failure;Cis-Acting Sequence;Compensation;Connective Tissue;Data;Defect;Dermis;Development;Disease;Dorsal;Embryo;Embryonic Development;Family member;Fibroblast Growth Factor;Future;GBX1 gene;Gene Expression;Gene Expression Profiling;Gene Family;Gene Targeting;Genes;Genetic;Goals;Growth Factor Gene;Human;Interneurons;Knowledge;Label;Malignant Neoplasms;Mantle Zone;Mesoderm;Messenger RNA;Modeling;Molecular;Motor Neurons;Muscle;Mutant Strains Mice;Pathology;Pathway interactions;Periodicity;Play;Proliferating;Reaction;Regulation;Regulatory Element;Role;Segmentation Clock Pathway;Signal Pathway;Signal Transduction;Somites;Spinal Cord;Trans-Activators;Transcription Repressor;Vertebral column;Work;angiogenesis;bone;cell behavior;combinatorial;insight;member;migration;mutant;neurogenesis;notch protein;novel;prevent;somitogenesis;spine bone structure;synergism;transcription factor Identification and characterization of FGF target genes n/a NCI 10926182 1ZIABC011321-14 1 ZIA BC 11321 14 8123123 "LEWANDOSKI, MARK B" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 395696 NCI To address the deficiency in our knowledge of what genes respond to FGF signaling we have an ongoing project to molecularly define FGF targets genes as well as their function and regulation. In past work we and others have identified the transcription factors encoded by Gbx1 and Gbx2 as FGF targets. Recently we investigated the functional relationship between Gbx family members in the developing spinal cord using combinatorial Gbx mouse mutants. We showed that each Gbx gene is upregulated if the other is absent. Additionally Gbx genes regulate development of a subset of PAX2+ dorsal inhibitory interneurons. Also expansion of proliferative cells into the anatomically defined mantle zone occurs in Gbx mutants. Lastly our data shows a marked increase in apoptotic cell death in the ventral spinal cord of Gbx mutants during mid-embryonic stages. While our studies reveal that both members of the Gbx gene family are involved in development of subsets of PAX2+ dorsal interneurons and survival of ventral motor neurons Gbx1 and Gbx2 are not sufficient to genetically compensate for the loss of one another. Thus our studies provide novel insight to the relationship harbored between Gbx1 and Gbx2 in spinal cord development (J Dev Biol. 2020. PMID: 32244588). In current work we demonstrate that the Hes7 transcriptional repressor is apparently a direct target of Fgf4 signaling. During vertebrate development the presomitic mesoderm (PSM) is periodically segmented into somites which will form the segmented vertebral column and associated muscle connective tissue and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. We examined mouse mutants lacking only Fgf4 or Fgf8 which we previously demonstrated act redundantly to prevent PSM differentiation. Fgf8 is not required for somitogenesis but Fgf4 mutants display a range of vertebral defects. Analyzing gene expression with spatial model-based quantification of mRNAs fluorescently labeled by hybridization chain reaction we show that FGF4 controls Notch pathway oscillations through the transcriptional repressor HES7. We support this hypothesis by demonstrating a genetic synergy between Hes7 and Fgf4 but not with Fgf8. Thus we establish Fgf4 as an essential Notch oscillation regulator and potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. (eLife 2020 Nov 19;9:e55608. doi: 10.7554/eLife.55608.) Future work focuses on what regulatory elements within the Hes7 gene are responsive to Fgf4 signals. 395696 +No NIH Category available Acceleration;CRISPR library;CRISPR/Cas technology;Cancer Model;Cells;Collection;Complex;Dependence;Development;Gene Expression;Gene Mutation;Genes;Genetic;Genetic Screening;Genotype;Guide RNA;Human;Libraries;Mammalian Cell;Mammalian Genetics;Methods;Modeling;Mus;Mutation;Outcome;Pattern;Proteins;Publishing;RNA Interference;Reagent;Small Interfering RNA;Somatic Mutation;Technology;Work;anticancer research;cancer cell;cancer genome;cell behavior;combinatorial;flexibility;genetic analysis;genetic manipulation;genetic testing;genome editing;genome-wide;genomic locus;knock-down;knockout gene;neoplastic cell;paralogous gene;preclinical study;tool;tumor Methods for mammalian genetic analysis n/a NCI 10926177 1ZIABC011304-14 1 ZIA BC 11304 14 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 218285 NCI BACKGROUND. Cancer research requires our ability to accurately model the pattern of gene mutation and gene expression observed in human tumors. Gene expression can be downregulated with RNAi. More recently CRISPR/Cas9 has become a major genome-editing tool for introducing mutations and for altering gene expression in mammalian cells. A major challenge in modeling the cancer genome is that we can currently recapitulate only a fraction of the complex changes observed in a tumor cell. Thus developing methods that enable genome editing on a more complex scale will be critical for the modeling of cancer cell behavior in pre-clinical studies. OBJECTIVES. 1.) To develop combinatorial RNAi method and reagents for downregulating the expression of multiple genes simultaneously in human and mouse cells; 2) To develop combinatorial CRISPR/Cas9 gene knockout method and reagent for deleting multiple genes simultaneously in human and mouse cells; and 3) to develop method and reagent for gene editing in human and mouse cells to introduce mutations and to regulate gene expression. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1). Multiplexed RNAi for combinatorial gene knockdown. We have developed a multiplexed gene knockdown method using high potency siRNAs. This method enables the simultaneous knockdown of up to 7 genes in the same cell. This level of complexity allows us to interrogate gene paralog redundancy and the function interaction of multiple genetic nodes in human cancer cells. This work was published. 2). Multiplexed CRISPR/Cas9 for combinatorial gene knockout. We have developed a multiplexed CIRSPR/Cas9 gene knockout method using pre-validated synthetic guide RNAs. This method enables the simultaneous knockdown of up to 3 genes in human cancer cells. This approach enables rapid genome editing at multiple gene loci. This work was published. 3). Development of modular CRISPR libraries for genetic screens. We have developed a curated collection of pooled sgRNAs library modules. Genes in each module were curated by their functional annotation. This enables the construction of sub-genome scale focused CRISPR libraries of flexible size for specialized genetic screen purposes. 218285 +No NIH Category available Antineoplastic Agents;Autophagocytosis;Biological Models;CHD1 gene;Cancer Biology;Categories;Cells;Chromosomal Stability;DNA Damage;Dependence;Development;Drug Targeting;Equilibrium;Evolution;Genes;Genetic;Genetic Screening;Goals;Growth;Immunologic Surveillance;Inflammatory;KRAS oncogenesis;KRAS2 gene;Knowledge;Ligase;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic stress;Mitotic;Molecular;Mutate;Neoplasm Metastasis;Normal Cell;Oncogenes;Oncogenic;Outcome;Pathway interactions;Phenotype;Play;Pre-Clinical Model;Proteins;Publishing;RAF1 gene;RNA Interference;RNA Splicing;RNA interference screen;Role;Signal Transduction;Spliceosomes;Stress;Sumoylation Pathway;Therapeutic;Work;biological adaptation to stress;cancer cell;cancer genome;cancer therapy;combinatorial;effective therapy;experience;inhibitor;malignant state;mutant;novel therapeutics;oncogene addiction;proteotoxicity;small molecule;targeted treatment;tumor Non-oncogene addiction in cancer cells n/a NCI 10926176 1ZIABC011303-14 1 ZIA BC 11303 14 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 545711 NCI BACKGROUND. We define NOA as increased dependency of cancer cells on stress-response pathways for survival. The malignant state of the cancer cell is associated with a unique set of oncogenic stress phenotypes involving DNA damage metabolic stress proteotoxic stress inflammatory microenvironment and immune surveillance. Oncogenic stress renders cancer cells more dependent on stress-response pathways for survival and consequently more sensitive to the disruption of these stress-response pathways. In contrast normal cells in the body do no experience oncogenic stress therefore normal cells are much less sensitive to the perturbation of stress-response pathways. This fundamental difference in cancer vs. normal cell's dependency on stress-response pathways forms the theoretical basis of NOA. NOA is distinct from oncogene dependency because stress response pathway genes are rarely mutated in the cancer genome. NOA represents a broad category of synthetic lethal and collateral dependency mechanisms in cancer cells and targeting NOA could offer orthogonal therapeutic approaches to current targeted treatment of tumors. OBJECTIVES: The objectives of this project are 1.) Identify NOA genes and genetic pathways in cancer cells using genetic screen and hypothesis-based approaches; 2) Investigate the molecular mechanism that underly a NOA phenomenon and understand its essentiality to the oncogenic state; and 3) Explore the therapeutic implication of NOA as potential cancer drug targets. We will carry out these objectives primarily using cancer cells harboring the KRAS oncogene as our model system as KRAS mutant tumors have generally lacked effective therapies. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1.) NOA of KRAS mutant cells to the RNA splicing factor ERH. Through a synthetic lethal RNAi screen in KRAS mutant cells we have identified the ERH gene as a synthetic lethal partner in KRAS mutant cells. ERH is an evolutionarily conserved protein with poorly understood function. Using mass-spectrometry we identified ERH associates with the spliceosome protein SNRPD3 and is therefore a component of the RNA splicing machinery. We showed that ERH is required for the proper splicing and expression of a subset of mitotic genes including CENPE that are critical for maintaining chromosomal stability in KRAS mutant cells. This work defined a new function for the ERH protein uncovered a previously unknown NOA in KRAS mutant cells to the RNA splicing machinery. This work suggests that selective perturbation of RNA splicing to disrupt the balance of mitotic proteins could be a potential approach to target KRAS mutant cancer cells. This work has been completed and published. 2.) NOA of KRAS mutant cells to the SUMO pathway for transformed growth. Through a synthetic lethal RNAi screen in KRAS mutant cells we have identified the SUMO pathway particularly the SUMO E2 ligase UBE2 to play an important role in supporting the viability and transformation growth of KRAS mutant cancer cells. Using mass-spectrometry we identified multiple proteins whose SUMOylation are disrupted in a KRAS-dependent manner. Using gene rescue approaches we showed that several SUMO target proteins including KAP1 CHD1 and EIF3L are critical for the viability of KRAS mutant cells under anchorage independent conditions. This work identifies a new role of the SUMO pathway in KRAS-driven oncogenesis and suggests the SUMO pathway as a potential drug target for KRAS mutant tumors. This work has been published. We are currently exploring the effect of small-molecule SUMO inhibitors in preclinical models of KRAS mutant cancer. 3) NOA of KRAS mutant cells to autophagy. Through a combinatorial RNAi analysis of the gene dependency landscape in KRAS mutant cells we identified critical OA and NOA that components in the Ras signaling network and in stress-response pathways respectively. We found CRAF/RAF1 as the major onco-effector of mutant KRAS and the autophagy E1 ligase ATG7 as a major NOA. This work identifies the autophagy pathway as a co-target with CRAF as a rational combination for KRAS mutant cells. This work has been published. We are currently investigating the mechanism by which autophagy contributes to the growth and survival of KRAS mutant tumors. 545711 +No NIH Category available Ablation;Affect;Affinity;Alloantigen;Animals;Antibodies;Antigens;Autoantigens;Autoimmune Responses;Avidity;Biological;Biological Assay;Biosensor;CD3 Antigens;Cell Membrane Permeability;Cell physiology;Cells;Cessation of life;Chimeric Proteins;Chromatin;Clinical;Corticosterone;Cytochrome P450;Deoxycorticosterone;Detection;Detergents;Ensure;Environment;Enzymes;Epithelium;Event;Exposure to;Fixatives;Generations;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gonadal Steroid Hormones;Hormones;Immune response;Immunization;Immunosuppressive Agents;In Vitro;Infection;Knock-in Mouse;Knock-out;Knockout Mice;Laboratories;Life;Ligand Binding;Ligands;LoxP-flanked allele;Lymphocytic choriomeningitis virus;Major Histocompatibility Complex;Mature T-Lymphocyte;Mitogens;Mixed Function Oxygenases;Mus;Names;Nuclear Receptors;Pathologic;Pathway interactions;Peptides;Production;Progestins;Proliferating;Receptor Signaling;Regenerative pathway;Series;Shapes;Specificity;Steroids;T cell response;T-Cell Antigen Receptor Specificity;T-Cell Development;T-Cell Receptor;T-Lymphocyte;T-cell receptor repertoire;Techniques;Testing;Thymic epithelial cell;Thymocyte Development;Thymus Gland;Time;Tissues;Transcriptional Regulation;Transgenes;Transgenic Organisms;Virus;Work;alpha-beta T-Cell Receptor;anti-tumor immune response;beta Chain Antigen T Cell Receptor;cross reactivity;crosslink;deep sequencing;in vivo;mouse model;neoplastic;neoplastic cell;paracrine;pathogen;receptor;receptor expression;response;thymocyte;transcription factor;tumor;tumor growth Glucocorticoids and T cell development and function n/a NCI 10926172 1ZIABC011264-14 1 ZIA BC 11264 14 9692263 "ASHWELL, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 915975 NCI "We have previously generated conditional glucocorticoid receptor (GR) knockout mice which were crossed with lck-Cre animals to produce mice that lack GR expression in thymocytes and T cells (GRlck-Cre). These mice have a modest reduction (about 40%) in the number of double positive (DP) and single positive (SP) thymocytes. Introduction of a transgenic T cell receptor (TCR) that has differing affinities for different MHC-encoded class II molecules revealed that the higher the avidity for self the greater the reduction in thymocyte number in the GR KO mice indicating that the thymocytes are undergoing increased negative selection in the absence of GR signaling. If the TCR repertoire the range of receptors expressed after selection is indeed affected by glucocorticoids there should be changes in the specificity of immune responses. We have found that mature T cells from the conditional GR-null mice proliferate normally to mitogens or to TCR cross-linking but poorly to alloantigen. Moreover immunization with peptide antigens results in a poor T cell recall response. Strikingly if the TCR repertoire is ""fixed"" by introducing alpha/beta TCR transgenes the proliferative response of GRlci-Cre T cells to antigen in normal in vitro and in vivo. Deep sequencing of TCRbeta CD3 regions which have the largest contribution to TCR specificity found that there was a significant difference between but not within groups of wild type and GRlci-Cre naive T cells. These results demonstrate that exposure to glucocorticoids in the thymus is a critical event in shaping the T cell repertoire and thus the ability to respond to foreign pathogens. We have also made mice in which the enzyme responsible for corticosterone production Cyp11b1 encoding steroid 11beta-hydroxylase is floxed. We have crossed these mice onto Cre-expressing animals to knockout glucocorticoid production in thymic epithelial cells (TEC) allowing us to test the hypothesis that local glucocorticoid production is important for thymocyte development. We have found that the T cell response to alloantigen is blunted just as it is in the GRlck-Cre mice. Furthermore the response to infection with the virus LCMV show changes in the fine-specificity of the TCRs used. In another series of studies we found that if one uses a cell fixative plus a detergent (to permeabilize the membrane) glucocorticoid receptors that are ligand bound and chromatin-associated will be cross linked to adjacent chromatin. As a result the GR (and other nuclear receptors) can be used as biosensors that can quantitate ambient ligand concentration. Use this ""perm-fix"" technique we have been able to identify for the first time the effects of paracrine hormone production in the thymus. We have found that DP thymocytes that have been triggered by self antigen are in a high glucocorticoid environment (approximately threefold higher than other thymocytes) due to corticosterone production by thymic epithelial cells. This assay allows the detection and quantification of hormone exposure in tissues at the single cell level. Because antibodies against Cyp11b1 are highly cross-reactive with other P450 enzymes involved in steroid synthesis we have created a ""knockin"" mouse that expresses a fluorescent Cyp11b1 fusion protein. We have found that Cyp11b1 is exclusively made by medullary thymic epithelial cells under the control of the transcription factor Aire. In fact we identified Aire-regulated production of sex steroids and progestins by medullary thymic epithelial cells. This represents the first example of Aire controlling expression of entire enzymatic pathways that result in the production of non-protein (in this case steroid) biologically active products. In another facet of our studies we have found that some neoplastic tumor cells produce glucocorticoids by a regeneration pathway in which the enzyme 11b-HSD1 (gene name 11HSD1b1) produces deoxycorticosterone from the inactive metabolite dehydrocorticosterone. Genetic ablation of 11HSDb1 in the tumors enhances the anti-tumor immune response and reduces tumor growth. Current studies are aimed at understanding the biological mechanism." 915975 +No NIH Category available Adjuvant Chemotherapy;American;Bioinformatics;Biological Models;Biology;Breast cancer metastasis;Cancer Etiology;Cell physiology;Cessation of life;Clinical;Copy Number Polymorphism;Critical Pathways;Data;Data Set;Diagnosis;Discipline;Disease;Distant;Environment;Etiology;Experimental Models;Future;Genes;Genetic;Genetic Transcription;Genetic study;Genomic Instability;Genotype;Goals;Human;Human Genetics;Inherited;Intervention;Invaded;Investigation;Localized Disease;Malignant Neoplasms;Mammary Neoplasms;Mechanics;Mediating;Modeling;Molecular;Morbidity - disease rate;Mouse Mammary Tumor Virus;Multiprotein Complexes;Mutate;Mutation;Neoplasm Metastasis;Nuclear Pore;Patients;Penetrance;Point Mutation;Pore Proteins;Predisposition;Primary Lesion;Primary Neoplasm;Proteomics;Public Health;Publishing;Recurrence;Relapse;Role;Sampling;Single Nucleotide Polymorphism;Somatic Mutation;Survival Rate;Susceptibility Gene;System;Therapeutic;United States;Variant;Woman;advanced breast cancer;anticancer research;burden of illness;design;driver mutation;epigenomics;extracellular;genetic approach;genome-wide;improved;malignant breast neoplasm;mechanical signal;mechanotransduction;metastatic process;migration;mortality;mouse genetics;mouse model;multidisciplinary;polyoma middle tumor antigen;precision medicine;prevent;promoter;response;transcriptome sequencing;tumor;tumor progression Genetic Modifiers of Initiation and Progression of Mammary Cancer n/a NCI 10926171 1ZIABC011255-14 1 ZIA BC 11255 14 1867359 "HUNTER, KENT WILLIAM" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2981137 NCI Breast cancer remains the most commonly diagnosed malignancy and is the second leading cause of cancer-related death in American women. It is estimated that there were more than 266000 new cases of breast cancer in the United States in 2018 with 41000 patients succumbing to the disease. Although the 5-year survival approaches 100% for those patients diagnosed with localized disease the 5-year survival rate for patients diagnosed with distant metastatic disease in only 27% highlighting the critical importance of the metastatic process in patient mortality. For those patients diagnosed with localized disease the widespread application of adjuvant chemotherapy has reduced late relapse and long-term mortality by an estimated 19%. However despite these efforts 25% of patients receiving adjuvant chemotherapy still progress to metastatic disease. Despite changes in therapeutic strategies little improvement in the survival of these patients has been observed . At present it is estimated that 155000 women are currently living with metastatic disease in the United States highlighting the significant public health burden of this disease. It is therefore critically important to obtain a comprehensive understanding of the etiology and biology of metastases to develop more effective clinical interventions to further reduce the morbidity and mortality of advanced breast cancer. In FY22 we have performed two parallel strategies for further investigations into the etiology of breast cancer metastasis. The first strategy investigated the acquisition of somatic mutations and copy number variations that might function as driver mutations for metastatic progression. Extending our previous analysis in the MMTV-PyMT mouse model we have added additional primary-metastasis pairs to our data set as well as analyzing three additional models of metastatic mammary cancer MMTV-Myc MMTV-Her2 and C3(1)-TAg. Surprisingly unlike the in primary tumor transformation activation mutations enriched in metastases induced by single nucleotide variants (SNVs) were relatively rare suggesting that point mutations are not a major driver of tumor progression. In contrast recurrent copy number variations (CNVs) were frequently enriched metastases compared to primary tumors in a genotype-specific manner suggesting that genomic instability may be the primary somatic driver of metastatic disease. Despite these recurrent CNVs however RNAseq revealed little transcriptional variation between matched primary and metastatic lesions. These data imply that transient interactions and cellular responses may be more important in metastatic progression than the stable differences and that genomic instability may be required to enable cellular plasticity during the multiple cellular insults and challenges faced during the metastatic cascade. The second strategy pursued is the continuation of our genetic studies into the etiology of metastasis susceptibility. In FY2022 we published the results of a study of the role of the nuclear pore protein NUP210 in metastatic progression. These studies demonstrated that NUP210 mediates mechanical signaling from the extracellular environment to poised promoters of migration and invasion genes inducing tumor dissemination from the primary tumor mass. Intriguingly proteomics analysis has revealed that additional previously identified metastasis susceptibility genes also participate in this mechanical response mechanism. The convergence of these independently identified metastasis-associated factors on a single multiprotein complex suggests that our genetic strategy is interrogating a critical component of the metastatic cascade. Importantly these genes are not frequently mutated in either experimental model systems of metastasis nor in human clinical samples. Thus our gene susceptibility screen appears to be highlighting important cellular and molecular mechanisms that would be difficult to access by conventional cancer research strategies. Current efforts are focused on more detailed analysis of the mechanisms and potential integration of additional metastasis susceptibility genes that may contribute to the tumor dissemination mechanotransduction response. 2981137 +No NIH Category available Amino Acids;Anabolism;Annual Reports;Baltimore;Binding;Binding Proteins;Biological Assay;Bladder;Bladder Diseases;Bladder Neoplasm;Cancer cell line;Cells;Characteristics;Chemicals;Chronic Disease;Collaborations;Data;Data Analyses;Disaccharides;Down-Regulation;Drug Design;Epidermal Growth Factor;Epithelial Cells;Epithelium;Fluorine;Frizzled Domain;Glycobiology;Glycopeptides;Goals;Growth Factor;Heparin Binding;Increased frequency of micturition;Interstitial Cystitis;Investigational Drugs;Journals;Lead;Location;Manuscripts;Maps;Maryland;Methods;Modeling;Molecular Conformation;Morphology;National Institute of Dental and Craniofacial Research;Natural Products;Pain;Paper;Pathologic;Patients;Peptides;Permeability;Pharmaceutical Preparations;Play;Proliferating;Protein Fragment;Proteins;Publishing;Receptor Signaling;Reporting;Role;Seminal;Series;Stretching;Structural Models;Structure;Therapeutic Agents;Thinness;Tight Junctions;Translating;Transmembrane Domain;Tumor Cell Line;Tumor-Associated Carbohydrate Antigens;Ulcer;Universities;Urine;Vaccine Design;WNT Signaling Pathway;Work;analog;anti-cancer;anticancer activity;antiproliferative agents;biophysical techniques;cancer cell;cancer immunotherapy;carbohydrate analog;cell transformation;design;glycosyltransferase;hydroxyl group;inhibitor;micturition urgency;molecular modeling;nanomolar;neoplastic cell;novel;novel anticancer drug;receptor;scaffold;sialylation;sugar A Glycopeptide from Interstitial Cystitis Patients as a Novel Anticancer Lead n/a NCI 10926170 1ZIABC011232-15 1 ZIA BC 11232 15 8777873 "BARCHI, JOSEPH JOHN" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 305407 NCI Interstitial cystitis/painful bladder disease (IC/PBS) is a chronic disease of the bladder characterized by thinning and ulceration of the bladder epithelial layer causing severe pain urinary frequency and urgency. Seminal work at the University of Maryland Baltimore showed that a specific factor was responsible for many of the characteristic pathological changes that occur in IC/PBS. This factor called APF was shown to have antiproliferative activity toward bladder epithelial cells at sub-nanomolar concentrations. APF caused an increase in paracellular permeability the down regulation of several proteins involved in tight junctions formation and reduced the levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF). In addition APF was also a potent antiproliferative agent against bladder tumor cells at equally low concentrations and has subsequently been shown to inhibit proliferation of other tumor cell lines. The peptide portion of APF has 100% sequence identity to a stretch of amino acids in the 6th trans-membrane domain of Frizzled 8 a Wnt signaling receptor. Whereas the sugar portion Neu5Ac(alpha)2-3Gal(beta)1-3GalNAc(alpha)-O-Thr is the sialylated form of the well-known Thomsen Friedenreich disaccharide a tumor associated carbohydrate antigen used in vaccine design and in the immunotherapy of cancer. In 2006 synthesis began on a series of analogues of the asialo derivative of APF (as-APF equipotent to the natural sialylated compound) to define the structure-activity profile of the natural glycopeptide. In the last annual report we outlined the extensive structure-activity studies we had done with this molecule and reported in the minimal requirements for full activity of the molecule as an antiproliferative agent. We published this year on the two inhibitors we identified and the normalization of IC/PBS-like bladder cells when treated with these drugs. They are being developed as therapeutic agents for IC/PBS. We are continuing with the SAR work by preparing carbohydrate analogues where specific hydroxyl groups are removed or replaced with isosteres like fluorine to map the important interactions of the sugar. Several of these have been prepared and two have been incorporated into the peptide. Our work with the CKAP protein was stalled since the construct we prepared as unstable and aggregated very rapidly under standard conditions. Thus we were not able to develop and assay for all our analogues. This is being revised and modified protein fragments will be explored. We have made a lot of progress on the structural front with our collaborators at the University of Maryland. By NMR and molecular modeling methods we have identified specific motifs in various analogues that are important for dictating the conformational bias of those structures. These data have helped in elucidation the manner in which the sugar portion of the glycopeptides interacts with the peptide portion: this could be highly relevant to its interactions with specific cellular receptors and thus aid in actual drug design of particular analogues that may have selective anticancer activity. A manuscript on this work was published in the Journal of Chemical Information and Modeling. We are also working with collaborators now at the National Institute of Dental and Craniofacial Research to determine the specific glycosyltransferases that are involved in the biosynthesis of APF and to explore whether or not the sugar portion is relevant to binding with specific receptors on cancer cells. The major accomplishments were: 1) Analysis of data on all 8-mer analogues as well as 4 of the most important 9-mer analogues by NMR and modeling defined the important interactions of the molecule with itself and now expanding to protein binding; 2) Anticancer activity of two of the analogues in 11 different cancer cell lines with our collaborators and publishing a full paper in Investigational New Drugs; and 3) Exploration of the two inhibitor molecules on APF-transformed cells; and 4) Synthesis of the carbohydrate analogues and compilation of all these data for another manuscript. We have now prepared several synthetically challenging fluorinated carbohydrate analogues of APF and found that one of them is almost as active as the natural material. A fruitful collaboration with Dr. Alex Mackerell of the University of Maryland has yielded a structural model of APF where we can now perform pharmacaphore searches and try to design a non-peptidic APF anlogue that is as active as the natural product. We can also attempt to design analogues that will selectively target cancer cells. 305407 +No NIH Category available Acceleration;Affect;Carcinogens;Cells;Chemicals;Cladosporium;Databases;Development;Disease;Distal;Environment;Event;Firmicutes;Genetic;Genomic Instability;Genomics;Growth;Head and Neck Squamous Cell Carcinoma;Homeostasis;Human;IKK alpha;IL17 gene;Immune;Infection;Inflammation;Inflammatory;Investigation;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Microbe;Molecular;Mus;Mutation;Mycoses;Oral;Organ;Patients;Population;Reporting;Role;STAT3 gene;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;The Cancer Genome Atlas;Therapeutic;Time;Tissues;Tumor Suppressor Proteins;Ultraviolet B Radiation;Wild Type Mouse;carcinogenesis;fungus;microorganism;mouth squamous cell carcinoma;neutrophil;oral fungal;prevent;skin squamous cell carcinoma;trait;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis Functions of IKK alpha in Skin Homeostasis and Skin Tumorigenesis n/a NCI 10926166 1ZIABC011212-15 1 ZIA BC 11212 15 10270679 "HU, YINLING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 715207 NCI It is yet unknown how the interaction of fungus tumors and immune cells affects tumorigenesis. We uncovered that the enhanced STAT3-dependent oral squamous cell carcinoma (SCC) development by oral Cladosporium cladosporioides infection promoted the fungal growth whereas infection was cleaned up in wild-type mice suggesting a synergic tumor-fungus loop involved in this accelerated carcinogenesis. Oral acidic metabolites elicited by C. cladosporioides infection were found to convert protective neutrophils to inflammatory neutrophils characterized by elevated IL-1b and decreased ROS that failed to kill fungi. Such a neutrophil population expressing IL1B associated with fungi was identified in human head and neck SCCs (HNSCCs). Importantly fungal counts were much greater in HNSCCs and SCC-adjacent tissues than in healthy controls and the advanced HNSCCs had significantly increased fungal signals. A Firmicutes to Protobacteria change and enhanced bacterial numbers which were also mediated by a C. cladosporioides-dependent oral acidic tumor milieu in mice were detected in HNSCC patients showing poor survival. C. cladosporioides and induced IL-1b/IL-17A augmented STAT3 activity in SCC cells contributing to local and distal skin tumorigenesis. Collectively these traits shared between fungus-associated HNSCCs in humans and mice highlight that oral fungal infection constitutes the tumor microenvironment for tumor progression. 715207 +No NIH Category available Address;Binding Proteins;Biochemical;Biological Models;Cell Cycle;Cells;Centromere;Chromatin;Chromatin Structure;Collaborations;Complex;Computer Models;Cryoelectron Microscopy;Data;Epigenetic Process;Funding;Genome;Goals;Human;Kinetochores;Manuscripts;Mitotic;Modification;Molecular Chaperones;Nucleosomes;Paper;Postdoctoral Fellow;Proteins;Publishing;Structure;Technology;Untranslated RNA;Work;centromere protein A;centromere protein C;complex data;daughter cell;graduate student;in vivo;nuclear division;protein complex;segregation;unpublished works Formation of Centromeres in vivo n/a NCI 10926164 1ZIABC011209-15 1 ZIA BC 11209 15 8630576 "DALAL, YAMINI P" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 201619 NCI Our goal is to dissect the mechanism by which kinetochore proteins binds the centromeric chromatin in the genome and creates the basis for a functional centromere. We have published a few papers on this work and have 2 more manuscripts that detail more cenRNAs involved in centromere function. We also have unpublished work with EM and biochemical data demonstrating how CENP-A nucleosomes can be altered in the presence or absence of various proteins. These data demonstrate how various epigenetic factors namely lncRNAs and kinetochore proteins can modulate CENP-A structure to uniquely define how functional centromere domains are formed and maintained. 201619 +No NIH Category available Acetylation;Amino Acids;Antineoplastic Agents;Binding;Binding Proteins;Biochemical;Biological Assay;Cancer Biology;Cell physiology;Centromere;Chromatin;Chromatin Modeling;Chromatin Remodeling Factor;Chromatin Structure;Chromosome Segregation;Chromosome Structures;Complex;Coupled;Cullin Proteins;DNA;DNA Binding;DNA Damage;DNA biosynthesis;Defect;Development;Elements;Enzymes;Epigenetic Process;Euchromatin;Eukaryota;Eukaryotic Cell;Event;Family;Fission Yeast;Gene Expression Profile;Gene Expression Regulation;Gene Silencing;Genes;Genetic Screening;Genetic Transcription;Genome;Heterochromatin;Higher Order Chromatin Structure;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone Deacetylation;Histone H3;Histones;Homologous Gene;Human;Link;Lysine;Maintenance;Malignant Neoplasms;Measures;Mediating;Methylation;Modification;Molecular;Mutagens;Nucleosomes;Pathway interactions;Pattern;Phosphorylation;Positioning Attribute;Post-Translational Protein Processing;Process;Proteins;RNA Interference;RNA Polymerase I;RNA Polymerase II;Repression;Research;Retrotransposon;Role;Sister Chromatid;Site;Structure;Tail;Transcript;Transposase;Variant;Work;cancer therapy;cell type;centromere autoantigen 80K;centromere protein A;chromatin remodeling;cohesin;cohesion;genome integrity;histone methylation;histone methyltransferase;histone modification;human disease;insight;malignant breast neoplasm;methylation pattern;mutant;novel;posttranscriptional;prevent;promoter;recruit;scaffold;therapeutically effective;ubiquitin ligase Roles of Chromatin-modifying Factors in Epigenetic Control of the Genome n/a NCI 10926163 1ZIABC011208-15 1 ZIA BC 11208 15 8777973 "GREWAL, SHIVINDER S" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1849078 NCI The involvement of histone modifications in higher-order chromatin assembly has been highlighted by our studies in S. pombe showing that several factors identified in genetic screen for mutants defective in heterochromatic silencing (such as Clr3 Clr4 and Clr6) are involved in modification of histone tails. Among these Clr4 belongs to a highly conserved Suv39 family of histone methyltransferases which specifically methylate histone H3 at lysine 9 (H3-K9) across heterochromatic domains associated with repetitive DNA elements. Biochemical analysis has shown that Clr4 is a component of multisubunit complex containing a cullin family protein Cul4 that serves as scaffold to assemble ubiquitin ligases and a WD protein Rik1 which mediates recruitment of Clr4 activity to the target repeat loci via a RNA polymerase II transcription coupled process. Clr3 and Clr6 are histone decaetylases with strong homologies to class II and class I HDACs from humans. We have shown that Clr6 exists in at least two distinct core complexes. One of these complexes (Clr6-C1) predominantly targets gene promoters and is responsible for regulation of gene expression through local deacetylation of histones. The second Clr6 complex (Clr6-CII) that targets transcribed chromosomal regions and centromeric loci is responsible for global deacetylation of histones. Our analyses suggest that defects in Clr6-CII abrogate global protective functions of chromatin such as suppression of antisense transcripts strand-specific repression of heterochromatic repeats and protection of DNA from damage by genotoxic agents. We have also performed biochemical characterization of Clr3. Clr3 exists in a multienzyme effector complex termed SHREC that in addition to histone decaetylase activity associated with Clr3 contains a Snf2 family chromatin remodeling factor Mit1. We have shown that SHREC is targeted across all major heterochromatic domains and its activities are essential for proper positioning of nucleosomes to assemble higher-order chromatin structures critical for heterochromatin functions. We are continuing to investigate the functions of these and other histone modifying activities. Given that histone modifiers are conserved among species and control fundamental chromosomal processes including stable maintenance of gene expression patterns during development and maintenance of genomic integrity their deeper understanding is important for the development of effective therapeutic measures for treatment of cancer and other human diseases. Heterochromatin nucleated at specific sites spread in a manner that depends upon the activities of histone decaetylases heterochromatin proteins and the ability of Clr4 to both methylate H3-K9 as well as bind to methylated H3 tail via its chromodomain. Moreover methylation of H3-K9 is essential for recruitment of HP1 proteins such as Swi6 Chp2 and Chp1. Our research has unraveled a new theme wherein HP1 proteins bound to methylated H3-K9 provide a dynamic platform for factors involved in many cellular processes including proteins involved in cell-type switching and proper segregation of chromosomes. Chp1 a component of the RITS complex tethers RNAi machinery to heterochromatic loci facilitating post-transcriptional silencing of repeats in cis. However the exact functions of Chp2 and Swi6 in heterochromatin assembly and their associations with other factors were poorly understood. We recently showed that Swi6 and Chp2 associate with Clr6 and SHREC histone deacetylase complexes which are critical for transcriptional silencing of the heterochromatic centromeric repeats. This work further revealed that Swi6 and Chp2 proteins and their associated HDAC complexes have overlapping functions in limiting RNA polymerase II occupancy across pericentromeric heterochromatin domains. Interestingly purified Swi6 fraction also contains factors involved in a variety of chromosomal processes such as chromatin remodeling and DNA replication. In addition Swi6 co-purifies a cohesin loading factor essential for sister chromatid cohesion and with centromere-specific histone H3 variant CENP-A which is incorporated into chromatin in a heterochromatin-dependent manner. These analyses suggest that HP1 proteins associate with a variety of factors including histone-modifying factors essential for the assembly of repressive chromatin. Identification of HP1 associated factors and their role in chromatin assembly may help us understand the causes of breast cancer associated with altered HP1 expression. Although HP1 proteins are critical for the preferential recruitment of histone deacetylases to repeat elements within heterochromatin domains alternative mechanisms exist to target these activities to repeats dispersed across the genome. Specifically we have uncovered a novel genome surveillance mechanism for retrotransposons by a family of transposase-derived CENP-B homologs. We found that CENP-Bs localize at and recruit histone deacetylases to silence retrotransposons. This mechanism also represses retrotransposon relics scattered throughout the S. pombe genome. CENP-B-mediated surveillance is proactive capable of preventing an extinct retrotransposon from reentering the host genome. These results reveal a likely ancient retrotransposon surveillance pathway and suggest that eukaryotic cells have a toolkit of repressor activities that are either targeted across large domains via HP1 proteins or in a site-specific manner by CENP-B and other DNA binding factors. We also gained insight into the significance of the role of HDAC in regulating histone turnover. By using a newly developed assay we were able to detect differential turnover rates at heterochromatin and euchromatin domains. Interestingly we found that defects in RNAi machinery which is required to establish the H3K9me mark for HP1 recruitment cause increased histone turnover. Similarly we found that defects in HP1 or the associated histone deacetylase (HDAC) activity also cause increased histone turnover. This work has yielded a novel insight into the role of HDACs which are recruited by HP1 or other factors in precluding histone turnover to promote silencing and inheritance of heterochromatin. These findings have implications for our understanding of heterochromatin assembly in higher eukaryotes as the machinery and activities that operate in fission yeast are often conserved. 1849078 +No NIH Category available 3-Dimensional;Address;Affect;Aging;Atomic Force Microscopy;Biochemical;Biological Assay;Biology;Biomechanics;Biophysics;Cell Nucleus;Cells;Centromere;Chromatin;Chromosomes;Complex;Crowding;Disease;Endothelium;Epigenetic Process;Eukaryota;Genetic Transcription;Genome;Genomics;Glioblastoma;Goals;Growth;Histones;Immunofluorescence Immunologic;In Vitro;Malignant - descriptor;Malignant Neoplasms;Mechanics;Mitosis;Modeling;Normal Cell;Nuclear;Oncogenic;Outcome;Paper;Pathway interactions;Pharmaceutical Preparations;Phenotype;Polymers;Process;Property;Publishing;Seminal;Stains;Stress;Stretching;Therapeutic Agents;Tissues;Variant;Work;bioprinting;cancer cell;chemotherapy;daughter cell;epigenome;field study;fighting;in vivo;mechanical force;mechanical properties;novel therapeutics;response;segregation;sensor;temozolomide;therapy development;tumor;tumor microenvironment Biomechanical properties of chromatin in cancer and normal cells n/a NCI 10926162 1ZIABC011207-15 1 ZIA BC 11207 15 8630576 "DALAL, YAMINI P" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 806473 NCI Chromatin composition and organization define genome function in eukaryotes. Aside from its transcriptional influences chromatin also contributes to the mechanical stiffness of the nucleus a sensor governing cellular mechanoresponses critical for tumor adaptation to the microenvironment. A fundamental question remains: how does chromatin respond to mechanical forces in the context of tumor-stroma interactions? Glioblastoma is one of the most malignant and lethal cancers with less than two years of median survival and highly deregulated chromatin composition. Moreover recapitulating the complex tumor microenvironment in vitro poses a major challenge for novel therapy development. Here we utilize 3D bio-printed glioblastoma tissues mimicking the tumor microenvironment in vivo and traditional 2D culture to study the mechanical properties and chromatin mechanoresponses using atomic force microscopy immunofluorescence staining and other biochemical assays. Over the last fiscal year we found that treatment of specific chemotherapy drugs differentially alters tissue stiffness potentially leading to altered chromatin composition and affecting tumor killing outcomes. Specifically the only approved first-line chemotherapy drug for glioblastoma temozolomide surprisingly promotes endothelial network growth and stiffens tumor stroma leading to increased proliferative subpopulation of glioblastoma cells in the tumor. On the contrary another promising chemotherapy drug regorafenib softens tumor stroma leading to decreased proliferative subpopulation of glioblastoma cells in the tumor. Our study aims to provide the first model of the interactions between chromatin mechanoresponses tumor microenvironment and drug response in glioblastoma. Targeting chromatin mechanoresponse pathways may lead to new therapeutic agents in the fight against the currently incurable glioblastoma. 806473 +No NIH Category available Address;Affect;Aging;Area;Automobile Driving;Brain;Cell Aging;Cell Cycle Arrest;Cell Separation;Cells;Centromere;Chromatin;Chromatin Structure;Chromosomal Instability;Collaborations;Complex;Computer Models;Defect;Down-Regulation;Epigenetic Process;Euchromatin;Failure;Fibroblasts;Genes;Genetic Transcription;Genome;Glioblastoma;Heterochromatin;Histone H3;Histones;Human;Individual;Invaded;Kinetochores;Location;Malignant Neoplasms;Manuscripts;Maps;Mediating;Mitotic;Molecular;Nuclear Accidents;Nucleoproteins;Organ;Organism;Organoids;Outcome;Pathway interactions;Pattern;Predisposition;Process;Property;Proteins;Proteomics;Publishing;Research Personnel;Role;Skin;Solid;Specificity;Tissues;Untranslated RNA;Variant;Work;aged;cancer cell;cell age;cell growth;centromere protein A;differential expression;follow-up;genome-wide;insight;knock-down;new technology;tumor;tumorigenesis Role of histone variants in aging and cancer n/a NCI 10926161 1ZIABC011206-15 1 ZIA BC 11206 15 8630576 "DALAL, YAMINI P" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1008091 NCI Aging is a universal process that affects all living organisms. While the cellular and organ-level disruptions caused by aging are well-documented the specific nuclear events responsible for this phenomenon remain largely unknown. Cell growth and its division is tightly regulated by the nucleoprotein complex chromatin which undergoes various structural and functional changes during cellular aging. The factors mediating these alterations in chromatin structure during cellular senescence however is yet to be explored. In this project we focus on the centromeric chromatin which is responsible for the kinetochore formation and faithful cell segregation. The centromere is epigenetically marked by histone H3 variant CENP-A which unlike the canonical histones are expressed in a replication independent manner. As cells cease to divide we observe an increasing loss of the canonical histones along with the redistribution of repressive and accessible chromatin domains in aged cells. Through a proteomic analysis of heterochromatin and euchromatin fractions isolated from young and old human skin fibroblasts we found that aging not only led to the differential expression of several histone variants and chromatin associated proteins but also a change in their distribution pattern across the chromatin fractions. Interestingly we also found that CENP-A is reduced in the chromatin fractions of aged human cells which possibly contribute to the observed cell cycle arrest. This reduction of CENP-A in aged cells is accompanied by inactivation of centromeres epigenetically which results in mitotic defects. Furthermore CENP-A reduction was also observed in aged fibroblasts obtained from otherwise healthy individuals. We also observed a substantial reduction in centromere transcription prompting us to delve into the underlying molecular mechanism responsible for this downregulation. Through various cross-disciplinary approaches we elucidate an epigenetic pathway by which centromeric transcription is regulated. To further investigate this phenomenon and shed light on its implications for aging we employed knockdown strategies targeting specific epigenetic regulators to reactivate centromeres in aged cells successfully. This study offers valuable insights into the mechanistic basis by which chromatin structure governs and influences the aging process through histone variants particularly that of centromeric histone variant. By expanding our understanding of these intricate processes including why chromosome instability occurs during aging. 1008091 +No NIH Category available ATP phosphohydrolase;ATP-Dependent Proteases;ATPase Domain;Adaptor Signaling Protein;Affect;Amino Acids;Bacteria;Bacteria sigma factor KatF protein;Biochemical;Biological;Cell division;Cells;Codon Nucleotides;Collaborations;Complex;Cues;Cytoplasm;DNA Damage;DNA-Directed RNA Polymerase;Defect;Dissection;Ensure;Escherichia coli;Feedback;Gammaproteobacteria;Gene Expression;Gene Expression Regulation;Gene Proteins;Genes;Genetic;Growth;Hyperactivity;In Vitro;Investigation;Magnesium;Mutate;Mutation;Mutation Analysis;N-terminal;Names;National Institute of Diabetes and Digestive and Kidney Diseases;Organism;Peptide Hydrolases;Play;Polyamines;Polymerase;Polysaccharides;Process;Protease Domain;Proteins;Proteolysis;Pseudomonas aeruginosa;Quality Control;Recovery;Regulation;Resistance;Ribosomes;Role;Sigma Factor;Signal Transduction;Silent Mutation;Small RNA;Starvation;Stress;Structure;System;Translations;Universities;Work;biological adaptation to stress;cell growth;endopeptidase Clp;environmental change;extreme temperature;falls;feeding;flexibility;in vivo;inhibitor;inorganic phosphate;insight;misfolded protein;multicatalytic endopeptidase complex;mutant;novel;programs;promoter;protein degradation;reconstitution;response;small molecule;transmission process Proteolysis and Regulation of Bacterial Cell Growth Control n/a NCI 10926159 1ZIABC011203-15 1 ZIA BC 11203 15 2402881 "GOTTESMAN, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 635817 NCI "For many years our lab has investigated the role of energy-dependent proteolysis in regulation of gene expression in bacteria. The ATP-dependent cytoplasmic proteases akin to the eukaryotic proteasome contain ATPase domains or subunits that recognize substrates and unfold them feeding them to the proteolytic domains. Bacteria contain multiple ATP-dependent proteases; five of them have been characterized in E. coli. Abnormal or misfolded proteins are degraded by these proteases. In addition to this quality control role the proteases degrade proteins that are naturally unstable; for these proteins degradation is likely to play an important biological role. Such protease substrates fall into two general classes: proteins that are always degraded so that regulation of their abundance depends primarily on changes in synthesis and proteins that show regulated proteolysis. In all cases identifying how the substrate is recognized by the protease and how recognition is affected by growth conditions is important in understanding how and when regulation is carried out. Our lab showed that the Lon ATP-dependent protease regulated capsular polysaccharide synthesis and cell division by degrading the RcsA and SulA proteins discovered and characterized the two-component Clp proteases ClpAP and ClpXP and investigated the roles of these proteases in vivo and in vitro. In recent years our focus has been on the regulated degradation of the RpoS sigma factor a subunit of RNA polymerase that directs the polymerase to specific promoters. RpoS is important for cells to switch to a stationary or stress response gene expression program; the expressed genes provide resistance to starvation temperature extremes and other stresses. However RpoS and its expressed genes are detrimental when the bacteria is under optimal growth conditions. The cell regulates RpoS accumulation in a variety of ways including at the level of translation via small RNA activators of translation and by regulated proteolysis. We have been studying this proteolysis one of the best examples of regulated protein turnover in E. coli. RpoS is rapidly degraded during active growth in a process that requires the energy-dependent ClpXP protease and the adaptor protein RssB a phosphorylatable protein that presents RpoS to the protease. RpoS becomes stable after various stress or starvation treatments; the mode of stabilization was a mystery until work from our lab led to discovery of a small previously uncharacterized protein that acts as an anti-adaptor blocking the ability of RssB to deliver RpoS to the protease. Mutants in the gene for that protein now named IraP (inhibitor of RssB activity after phosphate starvation) abolish the stabilization of RpoS after phosphate starvation. IraP blocks RpoS turnover in a purified in vitro system and directly interacts with RssB. In E. coli phosphate starvation leads to IraP induction due to an increase in the levels of the small molecule alarmone ppGpp; the iraP promoter has become the best example of how ppGpp positively regulates promoters. Two other small proteins also stabilize RpoS in a purified in vitro system IraM and IraD. These proteins are not similar in predicted structure to IraP. IraM is made in response to magnesium starvation dependent on the PhoP and PhoQ regulators; IraD is important after DNA damage. The anti-adaptors define a new level of regulatory control interacting with the RssB adaptor protein and blocking its ability to act; environmental signals regulate RpoS turnover by regulating expression of different anti-adaptors. In continuing collaborative studies with Sue Wickner (NCI) on the structure and function of RssB and its anti-adaptors we use in vivo genetics and in vitro reconstitution to understand how the antiadaptors and adaptor protein work. A collaboration with A. Deaconescu (Brown University) has led to a structure of an IraD/RssB complex providing valuable new insight into how IraD inactivates RssB and fully supporting our earlier genetic and biochemical studies. We are further defining how RssB interacts with ClpX the ATPase subunit of the ClpXP protease. The N-terminal domain of ClpX known to interact with some other adaptors and substrates interacts with the RssB C-terminus. Continued dissection of this system is providing insight into how this process is balanced in the cell. A long-standing question has been how the cell recovers from stress in particular from the antiadaptors. We have investigated this process for recovery from phosphate starvation. During starvation IraP is induced and stabilizes RpoS. We find that degradation of RpoS is restored rapidly after phosphate is returned to cells and that this rapid recovery implying active inactivation of IraP is dependent on a feedback loop in which RpoS increases the synthesis of RssB. Another regulator of RpoS Crl plays a critical and unexpected role in the recovery from starvation. Crl promotes the association of RpoS with the core RNA polymerase thus favoring expression of RpoS-dependent promoters including the promoter for the rssB gene encoding the adaptor. Mutational analysis of IraP demonstrates that the C-terminus of this anti-adaptor is critically necessary for rapid recovery suggesting that it modulates the interaction of IraP with RssB. In vitro and in vivo IraP lacking or mutated for critical residues in the C-terminus are unexpectedly hyperactive. Therefore the C-terminus acts as a critical negative regulator of IraP ensuring that it is active only when required. In another aspect of RpoS regulation H. Tabor's lab (NIDDK; deceased in 2020) had observed that cells devoid of polyamines have very low levels of RpoS. In a collaboration with them we have confirmed and extended this work. We find that the lack of polyamines allows rapid co-translational degradation of RpoS. Ribosomal mutations that increase translational proofreading have a similar if not as drastic effect. In both cases changing codon usage within the rpoS gene is sufficient to overcome much of the defect. These results suggest that previously unrecognized aspects of codon usage poise some genes including rpoS to be particularly sensitive to translational stress and reinforce the importance of so-called ""silent"" mutations that change codon usage within a protein without changing the encoded amino acids. While our work focuses on RpoS and its adaptor in RssB in E. coli both proteins are found in a range of other gammaproteobacteria. In a recent project comparisons of RssB from selected other species shows that the role of RssB in regulating RpoS is widespread but that in some organisms for instance P. aeruginosa RssB may act as an anti-sigma rather than as an adaptor for proteolysis. The basis of this difference is under investigation. Overall our proteolysis studies continue to provide novel insights into regulatory mechanisms used by bacteria." 635817 +No NIH Category available Ablation;Antigen Presentation;Binding;Binding Sites;Biochemical;Biological Assay;Biophysics;CD8B1 gene;Catalytic Domain;Cell Proliferation;Cells;Characteristics;Chemotherapy-Oncologic Procedure;Clear cell carcinoma;Collaborations;Crystallization;DNA Damage;Detection;Deuterium;Development;Drug Kinetics;Family;Family member;Fluorescence;France;Gene Expression;Genetic;Genetic Transcription;Goals;Growth;Human;Hydrogen;Immune;Immune system;Infiltration;Investigation;Ionizing radiation;Ions;Lewis lung carcinoma cell;Libraries;Ligands;Lymphocyte;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Metabolic;Metals;Methods;Modeling;Molecular;Molecular Conformation;Mus;Mutate;Myelogenous;National Center for Advancing Translational Sciences;Neuroblastoma;Neutrophil Infiltration;Normal Cell;Outcome;Ovarian Clear Cell Tumor;PPM1D gene;Pancreatic Adenocarcinoma;Phenotype;Phosphopeptides;Phosphoric Monoester Hydrolases;Physiological;Protein Serine/Threonine Phosphatase;Proteins;Radiation therapy;Recombinants;Regulation;Research;Resistance;Resolution;Role;Route;Series;Solid Neoplasm;Specificity;Stress;Structure;Structure-Activity Relationship;TNFSF4 gene;TP53 gene;Testing;Tumor Immunity;Tumor Suppressor Proteins;Ultraviolet Rays;Universities;Work;X-Ray Crystallography;cancer cell;cancer therapy;cytotoxic;granulocyte;high throughput screening;improved;inhibitor;malignant breast neoplasm;malignant stomach neoplasm;medulloblastoma;melanoma;member;neoplastic cell;neutrophil;overexpression;p38 Mitogen Activated Protein Kinase;phosphatase inhibitor;precision medicine;protein phosphatase 2C;scaffold;screening;small molecule libraries;transcriptome sequencing;trend;tumor;tumor progression;tumorigenesis Regulation and Function of WIP1 Phosphatase and its Role in Tumor Cells n/a NCI 10926158 1ZIABC011197-15 1 ZIA BC 11197 15 6568841 "APPELLA, ETTORE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 697267 NCI The wild-type p53-induced phosphatase Wip1 (PP2Cdelta or PPM1D) is a member of the serine/threonine protein phosphatase 2C (PP2C) family. Although Wip1 is expressed at low levels in most normal cells its transcription is induced by p53 after exposure of cells to DNA damage-inducing agents such as ionizing radiation (IR) or ultraviolet (UV) light. The Wip1 protein is frequently overexpressed or the PPM1D gene is amplified in several human cancers and this increased expression is associated with worse outcomes. Studies of human cells have shown that overexpression of Wip1 compromises tumor suppressor functions and studies of mice that lack Wip1 show that they are resistant to tumorigenesis. The current research on Wip1 is focused on understanding its regulation and functions identifying its functional targets and performing high-throughput screens (HTS) of small molecule libraries to identify specific modulators of Wip1 phosphatase activity. Recently we characterized the effects of the binding of the labile metal ion and the phospho-peptide substrate on the conformation of human PPM1A a family member of Wip1 by both hydrogen/deuterium exchange mass spectrometry and x-ray crystallography. Together these structural studies have allowed us to better understand substrate binding in this family of phosphatases and characterize the labile third metal ion that is essential for catalytic activity both critical aspects that could be abrogated by the binding of a specific inhibitor. In collaboration with Dr. Oleg Demidov (University of Burgundy Dijon France) we have used syngeneic tumor models to investigate the effects of ablating Wip1 in the immune system on tumor progression. We found that myeloid-specific deletion of Wip1 delayed the growth of both B10 melanoma tumors and LLC1 lung cancer tumors confirming an important role of Wip1-deficient innate immune cells in anti-tumor immunity. The loss of Wip1 expression significantly increased the infiltration of solid tumors by myeloid granulocytes and neutrophils. Genetic depletion of Ppm1d in neutrophils transformed them into efficient activators of CD8 + cytotoxic lymphocytes in part through p53-dependent induction of lymphocyte co-stimulating ligands 4-1BBL and OX-40L. Recently we have used RNA Seq and found that tumor-infiltrated neutrophils induce profound phenotypic changes resulting in an anti-tumor phenotype characterized by increased expression of genes involved in antigen presentation and a metabolic switch. Determination of a high-resolution structure of the Wip1 catalytic domain that includes the conformation of the B-loop would greatly aid further development of specific inhibitors of Wip1 phosphatase activity. Additionally high-resolution structural information for the Wip1 catalytic site would be useful for further optimization of known inhibitors and activators and to guide structure-activity investigations. To that end we have continued optimizing the expression of recombinant Wip1 and screening for crystallization conditions. These systematic efforts have provided the first structure of Wip1 that will help to better understand the specificity and potential for Wip1 inhibition and activation. As Wip1 is amplified or overexpressed in numerous human cancers including breast cancer ovarian clear cell carcinoma gastric cancer pancreatic adenocarcinoma medulloblastoma and neuroblastoma developing inhibitors of Wip1 activity may be beneficial in the treatment of several human cancers. Wip1 though can function as a tumor suppressor in cancer cells bearing inactive mutated p53. Therefore developing activators of Wip1 is as important as characterizing inhibitors of this phosphatase. We have developed and validated two orthogonal plate-based Wip1 activity assays for high-throughput screens (HTS). The two assays have high sensitivity and broad dynamic range enabled by either fluorescence detection or mass spectrometry and are suitable for screening compound libraries for modulators of Wip1 activity. In collaboration with the National Center for Advancing Translational Sciences (NCATS) we have used the above-mentioned HTS method to screen 102277 compounds at a single concentration from the NCATS Genesis library using physiologically relevant substrates to identify Wip1 modulators. Hits were evaluated over a range of 11 concentrations with both the Rapid-Fire MS assay and the orthogonal fluorescence-based assay. Further biophysical biochemical and cell-based studies of confirmed hits revealed a Wip1 activator and two inhibitors one competitive and one uncompetitive. These new scaffolds are prime candidates for optimization which might enable inhibitors with improved pharmacokinetics and a first-in-class Wip1 activator. Characterizing new Wip1 inhibitor and activator scaffolds represents a means to control the phosphatase activity using a precision medicine approach for cancer treatment. We have also identified a series of alkyl-substituted N-methylaryl-N'-aryl-4-aminobenzamides and tested their Wip1 inhibitory activity. A straightforward synthetic route was developed to synthesize the target compounds from commercially available starting materials. Three different portions of the core scaffold were extensively modified to examine structure-activity relationships. This study revealed interesting trends about a new molecular scaffold to inhibit Wip1. Additional work may lead to more potent inhibitors that interact with a larger portion of the Wip1 binding site and increase its specificity. 697267 +No NIH Category available ABCG2 gene;Apoptosis;Apoptotic;Attenuated;BRAF gene;Breast;CASP3 gene;CD44 gene;Cancer Patient;Cancer cell line;Cell Death;Cell Proliferation;Cells;Decitabine;Development;Diagnosis;Disease;Endocrine Gland Neoplasms;Evaluation;Follicular thyroid carcinoma;Genes;Genetic Transcription;Glioma;Human;In Vitro;Inhibition of Cell Proliferation;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thyroid;Mediating;Mesenchymal Stem Cells;Mutate;Oncogenes;Operative Surgical Procedures;Papillary thyroid carcinoma;Patients;Phase II Clinical Trials;Population Sizes;Publishing;Renal carcinoma;Resistance;S phase;Solid;THRB gene;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Thyroid Gland;Thyroid Hormone Receptor Beta;Tumor Suppressor Proteins;Tyrosine Kinase Inhibitor;United States Food and Drug Administration;Up-Regulation;Variant;Western Blotting;Xenograft Model;aldehyde dehydrogenases;anaplastic thyroid cancer;beta catenin;c-myc Genes;cancer cell;cancer stem cell;chemotherapy;clinically relevant;clinically significant;improved;in vitro activity;in vivo;inhibitor;mouse model;novel;novel therapeutic intervention;pre-clinical;radioiodine therapy;recruit;self-renewal;stem cell population;stem cells;therapy resistant;transcriptome;transcriptomics;treatment strategy;tumor;tumor growth;tumor initiation;tumor microenvironment;tumor progression;tumor xenograft Preclinical Mouse Models of Thyroid Cancer n/a NCI 10926157 1ZIABC011191-15 1 ZIA BC 11191 15 6569140 "CHENG, SHEUE-YANN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 930012 NCI TRbeta acts as a tumor suppressor by regulating CSC activity. We showed that TRbeta functions as a potent inhibitor of CSC activity by blocking tumor-sphere formation in vitro and by reducing CSCs and their self-renewal capacity in vivo to block tumor initiation and progression. The inhibition of CSC activity by TRbeta is mediated by suppressing key stem-cell regulators including ALDHs KLF2 ABCG2 SOX2 beta-catenin and CD44. T3 in particular potentiates the CSC-suppressing activity of TRbeta suggesting that TRbeta directly regulates transcription of CSC-related genes. Remarkably our single-cell transcriptomic analysis of tumors induced by ATC patient-derived cells showed that TRbeta significantly reduces total CSC population size blocks recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment and ultimately shifts the cell landscape toward a tumor-free milieu through re-differentiation. This CSC-suppressing action of TRbeta has clinical significance. Our integrative transcriptome analysis of The Cancer Genome Atlas (TCGA) reveals inverse relationships of the THRB gene with many essential CSC-related genes in diverse human cancers including thyroid breast glioma kidney and lung cancer. The present findings have important clinical relevance in developing novel treatment strategy for ATC patients. Our novel findings were published (Doolittle et al. Oncogene 2022). 2. Reactivated Thyroid Hormone Receptor beta Attenuates ATC Stem Cell Activity. Our findings shown above prompted us to test the hypothesis that re-activation of the silenced THRB gene could mitigate the CSC activity to block ATA tumor growth. We therefore treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRbeta on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRbeta as evidenced by western blot and immunohistochemical analyses. The expressed TRbeta inhibited cell proliferation by arresting cells at the S phase increased apoptotic cell death by upregulation of cleaved caspase-3 and markedly suppressed the expression of CSC regulators including cMYC ALDH SOX2 CD44 and beta-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity inhibiting cancer cell proliferation and increasing apoptosis. Our findings indicate that re-expression of the endogenous TRbeta is a novel therapeutic approach for ATC via suppression of CSC activity. These clinically relevant findings have been published (Zhu et al Endocr Relat Cancer 2023) 930012 +No NIH Category available Affect;Apoptosis;Apoptotic;Area;Behavior Disorders;Biological;Biology;Cell Cycle;Cell Death;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell membrane;Cell physiology;Cells;Cellular Structures;Ceramides;Coupling;Diabetes Mellitus;Disease;Drosophila genus;Embryo;Embryo Deaths;Endocrine;Endocytosis;Enzymes;Essential Genes;Exocytosis;Genes;Genetic Screening;Glucosylceramides;Heart Abnormalities;Human;Impairment;Inborn Errors of Metabolism;Individual;Lipids;Mammals;Membrane;Metabolic;Metabolism;Mitochondria;Movement;Mus;Mutant Strains Mice;Neoplasm Metastasis;Niemann-Pick Diseases;Organogenesis;Pathway interactions;Phagocytosis;Phenotype;Phospholipids;Play;Process;Proteins;Research;Research Personnel;Response to stimulus physiology;Role;Second Messenger Systems;Signal Transduction;Sphingolipids;acquired drug resistance;clinically relevant;fly;gastrointestinal system;heart function;human disease;model organism;mouse development;mutant;tumor Sphingolipid Signaling in Mammals n/a NCI 10926155 1ZIABC011187-15 1 ZIA BC 11187 15 6802050 "ACHARYA, JAIRAJ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 919175 NCI We have also extended to study the role of CERT protein in mammalian biology. CERT is an essential gene for mouse development and embryonic survival and quite strikingly is critical for mitochondrial integrity. CERT mutant embryos accumulate ceramide in the ER but also mislocalize ceramide to the mitochondria compromising their function. Cells in mutant embryos show abnormal dilation of the ER and degenerating mitochondria. These subcellular changes manifest as heart defects and cause severely compromised cardiac function and embryonic death around embryonic day 11.5. In spite of ceramide accumulation CERT mutant mice do not die as a result of enhanced apoptosis. Instead cell proliferation is impaired and expression levels of cell cycle-associated proteins are altered. Individual cells survive perhaps because cell survival mechanisms are activated. Thus global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways. PL and SL at the plasma membrane play an important role in stimulus-response coupling cell differentiation movement and exo- and endocytosis. They are asymmetrically distributed in biological membranes and different proteins catalyzing uni- and bi-directional movements of lipids perpetuate asymmetry. Our current efforts focus on scramblase a protein proposed to be involved in bi-directional transbilayer movement of phospholipids. We have recently completed two genetic screens and obtained Drosophila flies lacking two of the identified scramblase proteins. We have also generated flies lacking both genes (double mutants). Phenotypic analysis of the double mutants indicates that surprisingly scramblases do not have a determining role in the scrambling of phospholipids that accompany apoptosis phagocytosis and fusion. Instead scramblases play a regulatory role in regulated exocytosis. This has implications for a wide range of cellular processes involving digestive system and endocrine and exocrine secretions with clinical relevance for a wide range of diseases such as diabetes behavior disorders and even tumor metastasis. 919175 +No NIH Category available Ablation;Antibodies;Biological Process;Biological Response Modifiers;Biology;CCL2 gene;CCR;Cause of Death;Cell Separation;Clinical Trials;Collaborations;Complex;DNA;Data;Data Set;Development;Diagnosis;Disease;Division of Cancer Epidemiology and Genetics;E-Cadherin;Elements;Excision;Free Radicals;Generations;Genes;Genetic;Genetically Engineered Mouse;Goals;Growth;Host Defense;Human;Human Characteristics;Immune;Immune signaling;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Innate Immune Response;Investigation;KPC model;KRASG12D;Knockout Mice;Lesion;Ligands;Literature;Liver;Lymphomagenesis;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mediator;Messenger RNA;Microsatellite Repeats;Migration Inhibitory Factor;Molecular;Mus;Mutation;N-Cadherin;NOS2A gene;NOS3 gene;Nature;Neoplasm Metastasis;Nitric Oxide;Nitric Oxide Synthase;Nitrogen;Operative Surgical Procedures;Organoids;Oxygen;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic duct;Patients;Pharmaceutical Preparations;Physiological Processes;Play;Pre-Clinical Model;Primary Neoplasm;Production;Prognosis;Prognostic Marker;Proteins;Quantitative Reverse Transcriptase PCR;Refractory;Regression Analysis;Regulation;Reporting;Research;Resected;Role;Sampling;Severities;Signal Pathway;Signal Transduction;Stains;TP53 gene;Testing;Therapeutic;Therapeutic Effect;Tumor Promotion;United States;Vasodilation;Vimentin;attenuation;cancer statistics;cancer type;chemokine;chronic inflammatory disease;clinical center;clinically relevant;cohort;cytokine;gemcitabine;genetic approach;hazard;human disease;immunoregulation;in vivo;inducible gene expression;inhibitor;mouse model;neoplastic cell;neurotransmission;novel;pancreatic cancer model;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;pancreatic tumorigenesis;pharmacologic;pre-clinical;preclinical study;promoter;protein expression;small molecule;standard of care;therapeutic candidate;therapeutic target;therapy resistant;tumor;tumor progression;tumor xenograft Role of Immune and Inflammation Mediators in Progression of Pancreatic Cancer n/a NCI 10926154 1ZIABC011185-15 1 ZIA BC 11185 15 15201469 "HUSSAIN, SYED PERWEZ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 565875 NCI We reported that a higher expression of MIF in tumors is associated with poorer survival in PDAC patients. Furthermore we validated these findings in 3 additional cohorts including in publicly available data sets. We hypothesized that MIF is a potential therapeutic target in PDAC. To test this hypothesis we used a genetic strategy by deleting MIF gene in LSL-KrasG12D/+;LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice a genetically engineered mouse model of PDAC which mirrors the development progression and molecular and histopathological characteristics of human disease. Kaplan-Meier analysis showed that MIF-deficient KPC (MKPC) mice survived significantly longer than that of KPC mice with wild-type MIF (P 0.0001). Additionally MKPC mice showed a significant reduction in metastatic burden (P 0.01). Most of the metastasis occurred in liver of both KPC and MKPC mice. Furthermore primary tumor cells isolated from MKPC mice showed an enhanced expression of E-cadherin and reduced expression of vimentin zeb1 and N-cadherin at both the protein and mRNA levels as compared with primary tumor cells from KPC mice suggesting an attenuation of EMT in MKPC tumors. These findings provided in vivo proof-of-concept that MIF is a potential therapeutic target in PDAC. We are currently using pharmacological MIF inhibitors and anti-MIF antibodies to examine the effect of MIF inhibition on pancreatic cancer growth progression and survival using several pre-clinical models including KPC mice PDTX and human pancreatic cancer organoids. Additionally we assessed the clinical relevance of NOS2/NO signaling in the patients with PDAC and examined the NOS2 expression by qRT-PCR in tumors from 107 early stage resected cases. Patients were then divided into NOS2-high and NOS2-low groups based on the median value of NOS2 expression. Patients with the tumor NOS2 expression above the median value were defined as NOS2-high group and the patients with the NOS2 expression lower than the median value constituted NOS2-low group. Kaplan-Meier analysis showed that patients with a higher NOS2 had significantly poorer survival as compared to the patients with lower NOS2 expression in resected tumors (Log-rank test p=0.012). Furthermore a higher NOS2 in tumors predicted poor prognosis by both univariable (hazard ratio=1.73 95 percent CI=1.09-2.75 p=0.020) and multivariable (hazard ratio=1.75 95 percent CI=1.10-2.79 p=0.018) Cox-regression analyses. Additionally immunohistochemical staining showed a significantly higher NOS2 protein expression in tumors as compared to nontumor pancreatic ducts. These findings showed that NOS2 is a candidate prognostic marker in early stage PDAC patients undergoing surgical resection and NOS2/NO signaling may play a role in pancreatic cancer progression. To examine the role of NOS2/NO signaling in pancreatic cancer progression we used a genetic strategy by deleting the NOS2 gene in KPC mouse model of PDAC and generating NOS2-deficient NKPC mice. Pancreatic tumors in KPC mice expressed a high level of NOS2 protein which as expected was undetectable in tumors from NKPC mice. Kaplan-Meier analysis showed that NKPC mice survived significantly longer than KPC mice (Log Rank test p 0.01). Compared to tumors in KPC mice NKPC tumors showed significantly reduced macrophages infiltration as determined by immunohistochemical analysis of F4/80 a murine macrophage marker and a marked decrease in the expression of chemokine ligand 2 (CCL2) also known as monocyte chemoattractant protein-1 (MCP1). Furthermore qRT/PCR analysis revealed a significant decrease in the expression of mir-21 in NKPC tumors as compared to tumors from KPC mice. These findings using a genetic strategy provided in vivo proof-of-concept that targeting NOS2 may have potential therapeutic benefits. Furthermore NOS2/NO signaling may enhance inflammation and miR-21 expression in PDAC. We are currently pursuing pharmacological inhibition of NOS2 using a small molecule NOS2-specific inhibitor in multiple preclinical models of PDAC to assess the therapeutic effect of NOS2 inhibition on PDAC. Furthermore based on our observation of a lower expression of miR-21 in pancreatic tumors from NOS2-deficient mice we are extending our investigation on the mechanistic role of NOS2 signaling by investigating the interactive role of NO and miR-21 in pancreatic cancer progression and disease aggressiveness. Our ongoing research builds upon our current findings on the role of MIF and NO in pancreatic cancer. As described we have recently shown that a higher ( median) expression of MIF and NOS2 are associated with poor survival in pancreatic cancer. Furthermore genetic ablation of either MIF or NOS2 in a genetically engineered mouse model of PDAC prolonged survival. We hypothesize that MIF and NOS2 are candidate therapeutic targets in PDAC. Based on the genetic proof-of-concept as described above that MIF and NOS2 may be potential targets for PDAC we are pursuing several preclinical studies using KPC mice patient-derived tumor xenografts and patient organoids. These preclinical studies involve pharmacological inhibition of MIF and NOS2 as single agents or in combination of the standard of care drug gemcitabine to evaluate their effects on the pancreatic cancer growth progression and survival. Our major goal is to establish strong preclinical evidence providing key support to initiate a clinical trial at CCR/NCI clinical center. Furthermore we have extended our investigation on the regulation of MIF- and NO-mediated signaling pathways in pancreatic cancer progression which includes the interactive role of NO and miR-21 in pancreatic cancer progression and genetic regulation of MIF activity in disease aggressiveness in PDAC patients. These investigations are being pursued by the generation of NOS2 and mir-21 double knockout mice in the background of pancreas specific p53 and Kras mutation. To examine the genetic regulation of MIF we have focused on the presence of a higher number of CATT microsatellite repeat in MIF promoter. A higher than 5 CATT repeat enhances the MIF production and severity of several inflammatory diseases. We are testing the hypothesis that a higher than 5 CATT repeats in MIF promoter is associated with poorer survival in pancreatic cancer patients. To test this hypothesis DNA of patients from PLCO cohorts have been examined in collaboration with the DCEG NCI. 565875 +No NIH Category available 3' Untranslated Regions;Automobile Driving;Baltimore;Binding;Biochemical;Biological;Biological Markers;Biology;Cell Line;Cell physiology;Characteristics;Clinical;Code;Collaborations;Critical Pathways;Development;Diagnosis;Disease;Disease Outcome;Disease Progression;Endothelium;Evaluation;Event;Excision;Future;Gene Expression;Gene Expression Profiling;Genes;Genetically Engineered Mouse;Genomics;Growth;Human;Immune signaling;Impairment;Inflammation;Inflammatory;Institution;Investigation;Kynurenine;Link;Lipase;Maintenance;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Maryland;Mediating;Medical;Metabolic;Metabolic Pathway;Mineralocorticoid Receptor;Molecular;Molecular Profiling;Molecular Target;Nitric Oxide;Nonesterified Fatty Acids;Nuclear Receptors;Operative Surgical Procedures;Outcome;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Pathologic;Pathway interactions;Patients;Play;Precision Medicine Initiative;Precision therapeutics;Prevention;Primary Neoplasm;Production;Prognosis;Protocols documentation;RUNX3 gene;Receptor Gene;Regulation;Regulatory Pathway;Reporting;Resected;Role;Sampling;Signal Induction;Signal Pathway;Signal Transduction;Subgroup;Surveys;System;Testing;Therapeutic;Therapeutic Intervention;Tumor Suppressor Proteins;United States;Universities;Untranslated RNA;Validation;cancer subtypes;candidate identification;cohort;design;differential expression;gene network;improved;inhibitor;insight;malignant breast neoplasm;member;metabolic profile;metabolome;metabolomics;miRNA expression profiling;molecular subtypes;novel;novel strategies;pancreatic cancer patients;pancreatic neoplasm;patient subsets;profiles in patients;screening;targeted treatment;therapeutic target;therapy resistant;transcriptomics;translational potential;treatment response;treatment strategy;tumor;tumor growth;tumor progression Integrative Molecular Profiling of Human Pancreatic Cancer n/a NCI 10926147 1ZIABC011162-15 1 ZIA BC 11162 15 15201469 "HUSSAIN, SYED PERWEZ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 565875 NCI This project utilizes a combination of omics-based and targeted strategies for investigating the underlying mechanisms of pancreatic cancer progression and disease aggressiveness to identify candidate therapeutic targets. During the course of our investigation several cross-talks have developed with the first project described earlier. In one of our studies we tried to attain a comprehensive molecular insight into tumors with high- and low-MIF expression and to identify key MIF-signaling pathways that drive tumor progression we analyzed the expression of coding and non-coding genes in high (above median) and low (below medianmedian) MIF-expressing tumors in multiple cohorts of PDAC patients. The identified key genes and pathways were linked to patients' survival and were mechanistically functionally and clinically characterized using cell lines genetically engineered mouse model and PDAC patient cohorts. We reported mechanistic functional and clinical evidence of a novel MIF-driven signaling pathway that inhibits a previously undescribed potential tumor suppressor nuclear-receptor-subfamily-3 group-C member-2 (NR3C2) leading to enhanced disease aggressiveness and poorer survival in PDAC. Mechanistically MIF upregulated miR-301b which then targeted and suppressed NR3C2 expression. Tumors with a higher MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally patients with a lower NR3C2 expression in tumors showed poorer survival in multiple independent cohorts of PDAC patients. These findings discovered a key MIF-induced signaling pathway which enhances tumor progression and disease aggressiveness in PDAC. This study also identified NR3C2 a mineralocorticoid receptor gene as a putative inhibitor of disease progression. We are currently investigating the mechanistic role of NR3C2 in PDAC which involves it potential function in regulating the metabolic pathway genes. Furthermore in our initial effort to characterize tumors from early stage resected PDAC patients with markedly different survival we compared gene expression profiles in tumors from early stage PDAC cases with extremely poor survival (6 months) and those surviving 2 years or more following surgical resection. Inflammatory gene network dominated among 1820 differentially expressed genes between the two groups. A lower expression of NOSTRIN was associated with significantly poor survival indicating its potential tumor inhibitory role in disease progression. NOSTRIN inactivated endothelial NOS (eNOS/NOS3) and inhibited the production of nitric oxide (NO). Furthermore miR-221 bound to the 3'UTR of NOSTRIN and suppressed its expression and an increased miR-221 expression associated with poor survival in PDAC. Our findings are consistent with the hypothesis that NOSTRIN is a potential negative regulator of disease aggressiveness which may be targeted for designing improved treatment strategy in PDAC. We are investigating the NO-dependent and NO-independent mechanistic role of NOSTRIN in PDAC. By using a similar strategy to characterize the patients tumor with markedly different survival as described above we conducted an untargeted micro-RNA profiling and identified a novel miR-331-3p/ADAMTSL3 axis which enhances disease aggressiveness in resected pancreatic cancer patients As mentioned earlier molecular subgroups of pancreatic ductal adenocarcinoma have been reported based on the differences in genomic transcriptomics and metabolic profiling however specific molecular targets with therapeutic significance in these subgroups are yet to be clearly defined. Our ongoing study is investigating a highly aggressive subgroup to define key mechanisms driving tumor progression and disease aggressiveness that may be targeted with potential therapeutic significance. In our metabolomic studies we have shown that impairment in a lipolytic pathway involving lipases and a unique set of free fatty acids may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention. We are currently investigating the role of inflammatory signaling pathways in the regulation of metabolic reprogramming in pancreatic cancer. Our effort also includes the investigation of an interactive role of MIF-miR-301b-NR3C2 signaling axis in the regulation of metabolic reprogramming in pancreatic cancer. Additionally we have defined a novel NO/RUNX3/kynurenine metabolic signaling pathway which enhances disease aggressiveness in human pancreatic cancer and may have potential translational significance in improving disease outcome. Furthermore we are conducting and in-depth analysis of the most aggressive molecular subtype to get an insight into the disease aggressiveness and identify potential therapeutic target. With this approach we have investigated how the difference in metabolic adaptation in different molecular subtypes of cancer mediates the disease aggressiveness in one subtype versus another. 565875 +No NIH Category available Apoptosis;Binding;Biological Models;CHARGE syndrome;CRISPR/Cas technology;Cell Differentiation process;Cells;ChIP-seq;Code;DNA;DNA Damage;DNA Sequence Alteration;Data Set;Development;Down-Regulation;Embryo;Embryonic Development;Enhancers;Feedback;Foundations;Gene Expression Profile;Genes;Genetic Transcription;Genome;Genome Stability;Glioblastoma;Goals;Human;Hypersensitivity;Induction of Apoptosis;Inherited;Inner Cell Mass;Knock-out;Malignant Neoplasms;Mammary Neoplasms;Mandibulofacial Dysostosis;Maps;Mediating;Metabolism;Modeling;Molecular;Mus;Mutate;Mutation;Normal Cell;Nuclear;Organism;Outcome;Peptides;Play;Prognosis;Proliferating;Prostatic Neoplasms;Proteins;RNA;Regulation;Repression;Role;Signal Transduction;Stress;Syndrome;TP53 gene;Technology;Testing;Transcript;biological adaptation to stress;blastocyst;cancer genome;cell motility;cell type;clinical practice;coping;daughter cell;embryonic stem cell;genetic signature;genome-wide;in vivo;insight;interest;knock-down;mutational status;neoplastic cell;novel;programs;receptor;response;stem;stem cell differentiation;tissue regeneration;transcriptome sequencing;tumor;tumor progression;tumorigenesis;tumorigenic Stress responses in embryonic stem cells n/a NCI 10926146 1ZIABC011158-15 1 ZIA BC 11158 15 10270570 "HUANG, JING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 93536 NCI Compared to differentiated cells ES cells are hypersensitive to DNA damage-induced apoptosis. It is thought that this hypersensitivity to DNA damage-induced apoptosis contributes to the low mutation burden of ES cells because ES cells with mutated DNA caused by DNA damage are removed by apoptosis. We have hypothesized that ES cell-specific factors contribute to this ES cell-specific hypersensitivity to DNA damage-induced apoptosis. During fiscal year (FY) of 2015 we have made significant progress of identifying these ES cell-specific factors that could potentially regulate the hypersensitivity of mES cells to DNA damage. We have previously mapped a global p53 signaling in ES cells (Li M et al. Molecular Cell 2012). Based on the datasets generated by this earlier study we have identified ES cell-enriched factors that may be involved in p53 signaling in ES cells. We have decided to focus on one transcript called Apela for further study because Apela is repressed by p53 and encodes a putative secretory peptide Apela. Apela peptide binds to its receptor Aplnr to regulate cell movement in differentiated cells. We found that Apela positive regulates p53-regulated apoptosis in mouse ES cells as knockdown of Apela compromised p53-mediated apoptosis in the cells. Surprisingly the coding ability of Apela is dispensable for its role in p53-mediated apoptosis. Instead Apela binds and antagonizes the function of heterogeneous nuclear ribonuclear protein L (hnRNPL). hnRNPL interacts with p53 and inhibits p53 activation. Therefore we have discovered an Apela RNA-mediated negative feedback loop in mouse ES cells that regulates apoptosis. Given that Apela is specifically expressed in ES cells our findings provide an explanation to the hypersensitivity of ES cells to DNA damage. Our study on Apela also establishes foundations for investigating two aspects of the regulation of p53 signaling in ES cells. First under unstressed condition p53 activity needs to be controlled to allow ES cells to proliferate. However the factor(s) inhibits p53 activity under unstressed condition is(are) unknown. Here we identified hnRNPL as one of such inhibitory factors that control p53 activities in ES cells. Interestingly hnRNPL knockout embryos die at the blastocyst stage. We plan to test whether hnRNPL is the inhibitory factor for p53 activity in vivo. A second aspect of the regulation of p53 signaling concerns about the mechanisms underlying the enhancer interference by activated p53. We have previously found that p53 represses ES cell-specific genes such as Nanog Oct4 and Sox2 by interfering with their enhancer activities. However the mechanisms of enhancer interference are unclear. We were not able to use Nanog Oct4 or Sox2 as our model genes to study the mechanisms because prolonged down-regulation of either of these genes will lead to ES cell differentiation. Apela down-regulation however does not cause ES cell differentiation. Therefore Apela serves as a good model gene to study enhancer interference. We plan to use Apela and CRISPR technology to investigate the molecular mechanism of p53-directed enhancer interference in ES cells. In the next several years our main interest is to study the role of p53 in metabolism regulation in ESCs. 93536 +No NIH Category available Address;Affect;Aging;Alpha Cell;Architecture;Beta Cell;Binding;Binding Proteins;Biological;Biological Models;Biological Process;Biology;Birth;Blood;Carcinogens;Cell Nucleus;Cell model;Cell physiology;Cell-Free System;Cells;Cellular Structures;Child;Childhood Leukemia;Chromatin;Chromatin Fiber;Chromatin Remodeling Factor;Chromatin Structure;Chromosome 21;Code;Communities;Congenital Abnormality;DNA;DNA Methylation;DNA Repair;Defect;Development;Developmental Process;Disease;Down Syndrome;Drug Targeting;Embryo;Embryonic Development;Endocrine;Etiology;Eukaryota;Event;Experimental Models;Gene Expression;Gene Expression Profile;Generations;Genes;Genetic Diseases;Genetic Transcription;Germ Cells;Glucagon;Glucose;Goals;HMGN Proteins;HMGN1 gene;HMGN2 gene;HMGN3 gene;High Mobility Group Proteins;Histone H1;Human;Immunity;Impairment;Insulin;Islets of Langerhans;Knock-out;Knockout Mice;Laboratories;Link;Literature;Maintenance;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of prostate;Mental Retardation;Mesoderm;Molecular;Molecular Target;Mus;Muscle;Myocardium;Neoplasm Metastasis;Newborn Infant;Nuclear Protein;Nucleosome Core Particle;Organism;Pharmaceutical Preparations;Phenotype;Physiological Processes;Placenta;Play;Property;Protein Family;Proteins;Protocols documentation;Reporting;Research;Role;Structural Protein;Structure;Structure of beta Cell of islet;System;Testing;Therapeutic;Transgenic Mice;Variant;biological systems;blastocyst;blood glucose regulation;cancer therapy;carcinogenesis;cell motility;diabetic;embryo tissue;gamma irradiation;histone modification;implantation;insight;insulin secretion;lead-binding proteins;link protein;liver development;malignant breast neoplasm;member;migration;overexpression;practical application;promoter;protein expression;protein function;repaired;tissue culture;tissue repair;tissue/cell culture;tool;transcription factor;trophoblast;tumorigenesis;tumorigenic Biological Functions of Chromosomal Proteins n/a NCI 10926145 1ZIABC011154-15 1 ZIA BC 11154 15 6568847 "BUSTIN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 197210 NCI Chromatin regulates gene expression and therefore plays a key role in developmental processes and in the etiology of various diseases including cancer. Nuclear protein such as histone H1 and HMGs have been shown to bind to and alter the properties of the chromatin fiber. Changes in the expression of these architectural proteins are linked to various developmental defects and to various diseases including cancer. It is significant that in higher eukaryotes every cell contains H1 and HMGs. The ubiquitous presence of these proteins in numerous cells and their relative conserved structure is a strong argument that their biological function is important for the generation or maintenance of the cellular phenotype. However in spite of numerous studies the mechanism of action and the exact cellular function of these proteins remains one of the most perplexing aspects of chromatin biology. Towards understanding the biological function and mechanism of action of HMGNs and other chromosomal proteins we have generated genetically modified mice that either lack or overexpress all the HMGN protein variants. An early and very important general finding of these studies is the realization that previous observations with cell free systems or even with cells grown in tissue culture do not fully explain the possible biological functions of the various proteins in the context of the entire organism. HMGN5/NSBPB1 a new member of the HMG protein family which we discovered is highly expressed in preimplantation embryos but after implantation it is not expressed in embryonic tissues but it is highly expressed in the placenta and in trophoblast cells. At later developmental stages the protein is re-expressed in most cells albeit at low levels. The migration of trophoblast cells during and after implantation has been used as a model for cell migration during metastasis. The high expression of HMGN5 in trophoblast cells together with recent reports in the literature that the levels of HMGN5 are elevated in prostate and breast cancer implicate the protein in tumorigenesis. Using transgenic mice in which we specifically targeted HMGN5 expression to embryonic tissues we found that aberrant expression of HMGN5 affects the viability and phenotype of the born mice. A significant number of newborn mice are either very small or die immediately after birth. Further analysis revealed abnormalities in the heart muscles. The muscle contained numerous abnormal nuclei in which the chromatin structure seems significantly perturbed. These studies demonstrate the biological consequences of structural alterations in the chromatin fiber. We have elicited conditional HMGN5-/- knock out mouse and are studying its phenotype. We found that HMGN3 a member of the HMGN protein family is highly and specifically expressed in all the endocrine cells of Langernas pancreatic islets. Knock-out mice lacking HMGN3 protein are diabetic. In the blood of these mice the glucose levels are elevated and both glucagon and insulin levels are lower than those of normal mice. Detailed studies on alpha cells indicated that HMGN3 does not affect the synthesis or secretion of glucagon from alpha cells. On the other hand HMGN3 has significant effect of the transcription profile of the insulin-secreting beta cells. but both their We elucidated the molecular mechanism leading to this phenotype and demonstrated that in pancreatic beta cells HMGN3 enhances the binding of the transcription factor PDX1 to the promoter of the Glut2 transporter. Loss of HMGN3 decreases the levels of Glut2 thereby impairing glucose import into beta cells insulin secretion from these cells and glucose homeostasis of the mice. These studies demonstrate directly that the interaction of HMGN protein with chromatin has significant biological consequences. Our previous studies suggest that loss of HMGN1 protein may affect the tumorigenic potential of mice. HMGN1-/- mice cannot properly repair the damage induced in their DNA either by UV or by gamma irradiation. The impaired DNA repair of these mice can be linked directly to the interaction of HMGN1 protein with chromatin and to the effect of HMGN protein on the properties of the chromatin fiber. To address directly whether loss of HMGN could affect carcinogenesis we have initiated a study in which we treat wild type and HMGN1-/- mice with N-nitrosodiehylamine a potent carcinogen leading to liver cancer. We are using standard protocols developed and extensively used by other laboratories at NCI to test whether loss of HMGN1 affects the development of liver cancer. The gene coding for human HMGN1 is located in located on chromosome 21 in a region that contains only 33 genes which are known to be critical for the development of Downs syndrome one of the most prevalent genetic disease. We have generated a transgenic mice overexpressing HMGN1 at levels similar to those found in humans containing 3 copies of chromosome 21. Using these mice and also mice lacking HMGN1 we find that HMGN1 modulates the expression of genes known to lead to significant mental retardation and to other biological abnormalities. Potentially these studies may provide new insights into molecular mechanisms underlying the generation of the Downs syndrome phenotype. Studies with a conditional HMGN2 knock-out moue which we have recently generated reveal that proper expression of this protein during development is crucial for embryonic survival. Loss of the protein leads to embryonic lethality at E8.5 just before full mesoderm induction. The results suggest that HMGN2 may play a crucial role in the induction of this germ cell layer. These studies also serve as a classical example that studies with tissue culture cells may not always help elucidate the true biological function of a protein. Tissue culture cells lacking HMGN2 do survive but mouse embryos do not. Studies with these mice will lead to an understanding of the mechanisms whereby HMGN regulate the orderly progression of gene expression that is needed for proper development and differentiation. Cell migration is essential for various physiological processes such as embryonic development immunity and tissue repair. The metastasis of tumor cells involves gain of migration capabilities. Thus elucidating the fundamental mechanisms regulating cell migration has important implication to the understanding of a wide range of biological processes and may have practical applications to the development of better cancer therapies. We have discovered that cell migration involves and is contingent on major reorganization in the structure of the chromatin fiber. This pioneering study which is the first to report that cell migration involves changes in the structure chromatin fiber points out to an additional cellular structure that can be targeted by drugs aimed at interfering with cell migration. In summary we have developed new model systems for studies on the role of chromatin and chromosomal-binding proteins in various biological processes. These experimental systems provide necessary tools and experimental models for detailed studies on the role of chromatin and chromatin modifiers in a wide range of biological systems. We intend to share these mice with the entire scientific community thereby expanding the scope of our research efforts and contribute to the understanding of the molecular mechanisms whereby events occurring in chromatin ultimately impact the entire organism.An important resent finding is that HMGN1 plays a major role in the childhood leukemia seen in Downs syndrome children. 197210 +No NIH Category available Bacteria;Cells;Cessation of life;Chronic;Colon;Colon Carcinoma;Color;Disease;Engineering;Experimental Models;Food;Goals;Human;IL17 gene;IL7 gene;Immune;Immune response;Immunologics;Immunosuppression;Inflammation;Inflammation Process;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Intestines;Knock-in;Lactococcus lactis;Lymphocyte;Macrophage;Mus;Oral;Organoids;Process;Reporter;T-Lymphocyte;Therapeutic;Tissues;Visualization;carcinogenesis;cytokine;design;gut inflammation;insight;interleukin-22 Chronic Inflammation and Carcinogenesis n/a NCI 10926142 1ZIABC011150-15 1 ZIA BC 11150 15 6569217 "DURUM, SCOTT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 378549 NCI We have two projects in colon cancer that emerged from our previous focus on IL-7. One project involves IL-17A IL-17 F and IL-22. These are cytokines that are produced by cells that strongly promote the intestinal inflammation that leads to colon cancer. It had not been determined where IL-17 or IL-22 is produced during this inflammatory response. We developed knockin reporter mice for the two IL-17 genes using two colors and for IL-22. This enabled us to visualize T cells and innate lymphocytes producing these critical inflammatory cytokines during bowel inflammation leading to colon cancer. These reporter mice have been sent to numerous labs around the world and are in use for investigating many immunological processes. A second project aims to inhibit the bowel inflammation leading to colon cancer. IL-27 is a suppressive cytokines that we have cloned into the food bacterium Lactococcus lactis. These engineered bacteria were given orally to mice with three different models of experimentally-induced inflammatory bowel disease. IL-27 rescued all mice from disease and death and therefore is an extremely promising therapeutic. To investigate the mechanism of IL-27 therapy we have also developed murine organoids derived from colon. Using cultures of organoids and inflammatory cells we find that IL-27 acts on inflammatory macrophages suppressing their ability to damage colon tissues. Currently we are characterizing a new L.lactis-IL-27 construct that is designed for human therapy. 378549 +No NIH Category available Annual Reports;Area;Binding;Biophysics;Chemistry;Collaborations;Complex;Data;Development;Disease;Dissection;Engineering;Equilibrium;Event;Isotope Labeling;Label;Measurement;Measures;Membrane;Membrane Proteins;Methods;Modification;Molecular Conformation;Molecular Structure;Monitor;Multidimensional NMR Techniques;NMR Spectroscopy;National Heart Lung and Blood Institute;Neutrons;Physiologic pulse;Protein Engineering;Proteins;Publications;Publishing;Relaxation;Reporting;Roentgen Rays;Sampling;Scheme;Site;Speed;Structure;Sulfur;Surface;System;Techniques;Work;biophysical techniques;data acquisition;experimental study;improved;in vivo;intermolecular interaction;macromolecule;method development;mimetics;molecular dynamics;nanodisk;novel;novel strategies;protein complex;protein protein interaction;small molecule inhibitor;structural biology;tool Methods Development n/a NCI 10926141 1ZIABC011132-16 1 ZIA BC 11132 16 15201459 "BYRD, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 393628 NCI We devote our efforts in this project to the development of improved NMR techniques and hardware and to new approaches to protein engineering and isotopic labeling. We are continuing and expanding our efforts to develop new approaches to tagging macromolecules with paramagnetic centers and obtaining unique structural information about intermolecular interactions and structures of multi-component complexes. In addition new approaches are developed when traditional methods require augmentation with new experiments or data. These methods include novel isotopic labeling schemes pulse sequence development automated methods and novel methods in relaxation NMR of proteins. This effort is continuing as a subset of the various structural biology projects described in other parts of the annual report. Specific developments have included the use of non-uniform sampling to speed up data acquisition of multi-dimensional NMR data tagging with a range of molecules to facilitate paramagnetic relaxation enhancement to measure long-range distances in multi-component complexes. We have reported new and optimized approaches to engineering systems for deuteration segmental labeling lipidation and construction of multi-domain systems that include intrinsically disordered regions. These tools enable the strength of NMR spectroscopy to be applied to more complex systems much more similar to in vivo settings. Ongoing work in membrane mimetics is expected to impact both major projects in the lab in the coming year and beyond. New approaches to characterizing nano disk membrane mimetics have been developed and will be published in this year. Our recent work includes the development of new methods for examining fast conformational dynamics in proteins and the application of this to E2:E3 interactions. A new aspect within this project is the development of NMR pulse sequence methods combined with novel isotopic labeling and the unique modification of NMR probe hardware to explore the use of triple resonance NMR to monitor sulfur sites in proteins. Through collaboration with the NHLBI Chemistry and Synthesis Center we have developed double labeled 13C and 77Se compounds for incorporation into proteins. In our lab we re-engineered a conventional H/C/N triple resonance probe to perform H/C/Se triple resonance experiments. The first publication describing these efforts is submitted and under review. 393628 +No NIH Category available Affinity;Binding;Binding Sites;Biological;Biology;Biophysics;CCR;Cells;Collaborations;Complex;Crystallography;Data;Development;Disease;Endoplasmic Reticulum;Engineering;Enzymes;Family;Human;Intervention;Investigation;Label;Laboratories;Ligation;Link;Malignant Neoplasms;Membrane;Methods;Molecular;Molecular Biology;Molecular Conformation;Motion;Nature;Neoplasm Metastasis;Pathway interactions;Positioning Attribute;Process;Proteins;Publications;Publishing;Reaction;Regulation;Reporting;Research;Ring Finger Domain;Roentgen Rays;Role;Series;Specificity;Structure;Substrate Specificity;Surface;System;Therapeutic;UBD protein;UBE2G2 gene;Ubiquitin;Ubiquitin-Conjugating Enzymes;Ubiquitination;Work;insight;interest;member;method development;mimetics;molecular dynamics;multidisciplinary;protein complex;protein degradation;protein protein interaction;receptor;sarcoma;structural biology;tumor;ubiquitin-protein ligase Investigation of Protein-Protein Interactions in the ERAD Ubiquitylation Pathway n/a NCI 10926140 1ZIABC011131-16 1 ZIA BC 11131 16 15201459 "BYRD, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 787255 NCI Our studies of the ubiquitin-ligase E3 called gp78 are conducted in collaboration with Dr. Allan Weissman CCR. The gp78 protein has a role in sarcoma metastasis and it is an excellent target for a combined structural and molecular biological investigation of mechanism and intervention. We have reported major findings from this project in a series of publications. The effort is an interdisciplinary effort involving molecular biology in the Weissman lab NMR structural biology and biophysics in the Byrd lab and X-ray crystallograpny in the Ji lab. These studies uncovered a new aspect of the E2:E3 interaction wherein the action of a newly identified E2-binding site in gp78 results in an allosteric effect on the E2 Ube2g2 increasing the affinity for the gp78-RING finger domain by 50-fold. We also showed that the effect of the binding region (G2BR) is effective for other RING finger containing E3s (Mol. Cell). The generalization of this phenomenon is leading to a broader understanding of ubiquitination and shifting in the paradigm for the molecular mechanism of ubiquitin transfer. These studies have been extended in both the Weissman and Byrd labs. We published structural information on the ternary complex of the gp78-RING:Ube2g2:G2BR system from both NMR and crystallographic studies (EMBO J) and a related approach was undertaken for a different E2:E3 pair and published in Molecular Cell. We have examined the solution structure of the CUE domain which is a distinct functional domain within gp78 and its interactions with ubiquitin and di-ubiquitin. These results were published in Structure. We are continuing our examination of the detailed interactions and mechanism of ubiquitin transfer. Another aspect of this system is the role of dynamics in determining chain linking specificity. We are employing NMR methods to directly correlate molecular motions/dynamics of regions of the Ube2g2 enzyme with the pertinent interactions to domains of gp78. These data will be critical to developing an overview of the reaction cycle for ubiquitin loading transfer and chain specificity. We have added the use of small-angle X-ray scattering (SAXS) conducted on protein complexes in solution to enable us to examine larger constructs of the ubiquitination machinery. We have also developed a membrane mimetic which will enable the extension of these studies to the membrane surface. These efforts will continue for the next year. Current efforts also involve understanding the role of conformational dynamics via both experimental NMR and computational (molecular dynamics) methods to provide molecular insight to the allosteric mechanisms (published in Structure 2017 and methods developments in 2016-2020). We are also investigating the positioning and dynamics of the ligated ubiquitin in the context of E2Ub and E3:E2Ub complexes. Our efforts are expanding to include the use of NMR-derived conformational dynamics to understand allosteric mechanisms. Current developments are enabling us to examine the complete gp78C system in complex with the E2 Ube2g2 using our developed segmental engineering and labeling approaches. We are also examining further specificity identified in the Weissman laboratory regarding E2 recognition by complimentary E3 proteins. In 2021 an extension of the concepts found in this work led to a publication in PLoS Biology that illustrates a related allosteric binding partner for E2 enzymes. This new protein AUP1 provides the means to dissect the allosteric selection and activation of E2:E3 pairs and will lead to further understanding of recognition and specificity in ERAD. New aspects of this work involve examining dynamic processes in the recognition and positioning of the ligated ubiquitin on an E2Ub conjugate for transfer. The approach uses enhanced molecular dynamics simulations and NMR methods to examine the nature of these dynamics. A comparison of the dynamics will be made for E2's that catalyze different Ub-linkages to determine the relative role of dynamics in linkage construction. 787255 +No NIH Category available AIDS prevention;Acquired Immunodeficiency Syndrome;Adjuvant;Affect;Age;Animal Model;Animals;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Blood;CD14 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Canarypox Vectors;Cells;Chinese;Collaborations;Combined Vaccines;Communities;DNA;Data;Dependence;Development;Epigenetic Process;FCGR3B gene;Female;Frequencies;Futility;Future;Genes;Genetic Transcription;HIV;HIV Envelope Protein gp120;HIV Vaccine Trials Network;HIV vaccine;Homing;Human;Hypoxia;IL8 gene;Immune;Immune response;Immune system;Immunity;Immunize;Immunoglobulin G;Infection;Infection prevention;Infectious Agent;Inflammasome;Innate Immune Response;Insulin-Like Growth Factor I;Integrin Binding;Interleukin-10;Interleukin-6;Intervention;Intramuscular;Joints;Knowledge;Legal patent;Liposomes;Lung;Lymphoid Cell;MF59;Macaca;Macaca mulatta;Macrophage;Malignant Neoplasms;Mediating;Memory;Metabolic;MicroRNAs;Modality;Modeling;Monoclonal Antibodies;Mucositis;Mucous Membrane;Myeloid Cells;National Institute of Allergy and Infectious Disease;Natural Immunity;Pathway interactions;Peripheral Blood Mononuclear Cell;Phase;Plasma;Political Factor;Population Genetics;Preventive;Proteins;Recombinant Vaccines;Rectum;Regimen;Research;Research Personnel;Risk;Role;SARS-CoV-2 infection;SIV;SIV Vaccines;STAT3 gene;South Africa;Specificity;T cell response;T-Lymphocyte;Testing;Th2 Cells;Thailand;Training;Uncertainty;United States National Institutes of Health;Universities;Vaccinated;Vaccines;Viral;Virus;Virus Diseases;Work;adaptive immune response;age related;aluminum sulfate;animal facility;animal model development;antiretroviral therapy;arm;cytotoxic CD8 T cells;design;efficacy testing;exosome;expectation;extracellular vesicles;gender difference;immunogenic;immunogenicity;insight;lymph nodes;male;microbiome research;monocyte;monomer;natural killer cell protein 44-kDa;neonate;neutralizing antibody;neutrophil;next generation;novel;novel vaccines;nutrition;pathogen;predictive modeling;rational design;rectal;response;risk minimization;sex;simian human immunodeficiency virus;simian immunodeficiency virus gp120;vaccine candidate;vaccine efficacy;vaccine evaluation;vaccine platform;vaccine strategy;vaccine trial;volunteer Development of rationally designed HIV vaccines n/a NCI 10926139 1ZIABC011126-16 1 ZIA BC 11126 16 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2689105 NCI "Accomplishments 1: Assess which macaque model better predicts or recapitulates the efficacy of HIV vaccine candidates in humans. The SIVmac251 model has predicted and recapitulated RV144: In 2005 a collaborative study in neonates predicted the results of RV144. More recently we recapitulated the efficacy of the RV144 vaccine regimen in young (2-3 years) male and female macaques. The latter study has provided more value than just the evaluation of vaccine efficacy. Our integrated study of RNA expression in PBMCs and exosomes together with comprehensive analyses of innate and adaptive immune responses in blood lymph nodes and mucosa uncovered unexpected correlates of risk of virus acquisition such as mucosal innate lymphoid cells (ILCs) and the expression of 12 genes ten of which are part of the RAS pathway. The usefulness of this model was validated by similar observations in another protective vaccine regimen that I developed in collaboration with Dr. Strbo and the late Dr. Eckhart Podack of Miami University. This approach was the subject of a joint patent. We have also performed a confirmatory study entirely supported by the Division of AIDS NIAID in other animal facilities wherein we compared the immunogenicity and efficacy of the ALVAC and NYVAC SIV-based vaccine regimens. The ALVAC-SIV based vaccine was also protective in Chinese macaques whereas the ""more immunogenic"" NYVAC-based SIV recombinant vaccine was not. Of note the NYVAC-based vaccine did not induce an early burst of IL-1B as was the case in the non-protective Ad26 prime regimen. Will the SIVmac251 model predict the results of HVTN-702? We tested the efficacy of the ALVAC-based SIV vaccines in the SIVmac251 model using the alum in parallel with the MF59 adjuvant in the gp120 boost. To our surprise the MF59 based regimen in the SIV model was not efficacious despite its higher immunogenicity. While this observation stirred debate in the scientific community our findings did not influence the decision by the P5 Partnership to use MF59 as an adjuvant in the HVTN-702 study in South Africa. Instead logistical and political factors likely influenced the decision to proceed as originally planned. Given the current uncertainty of how accurately the SIVmac251 animal model will predict human results our study will provide crucial information to define the model's utility since we observed no efficacy in macaques. The preliminary analysis of futility in HVTN-702 will be made public in 2018 and will address this issue. SHIV-clade C Tier 1 in female Chinese rhesus macaques: In another study supported mostly by NIAID macaques were immunized with the identical ALVAC-HIV-based vaccines used in HVTN702 combined with either the MF59 or the alum (Novartis) in the gp120 boost and challenged with a SHIV clade C Tier 1 virus. The MF59 based regimen was protective whereas the alumN was not. Protection was associated with neutralizing antibodies to the SHIV clade C Tier 1 virus. In its current state I don't believe that this SHIV model will predict the results of HVTN-702 because only 1% of HIV clade C viruses in South Africa are sensitive to neutralization. However the interim analysis of HVTN-702 for futility will further our knowledge of animal model predictability and will guide the choice and refinement of faithful animal models for the development of fully effective vaccines for HIV. 2. HIV vaccine candidate activation of hypoxia and inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition. This study demonstrated that CD14+ and CD16+ monocytes have a role in the risk of SIVmac251 acquisition and has contributed to the mechanistic insight on the role of IL-1B and IL-10 in the DNA/ALVAC/alum vaccine platform. We compared ALVAC-SIV DNA-SIV and Ad26-SIV prime modalities in combination with two ALVAC-SIV + gp120 protein boosts in young male macaques. We used the intramuscular DNA-SIV prime with the intent of increasing CD4+ T cells and antibody responses since we demonstrated in prior work that the CD4+ T cells elicited by the DNA prime influence the anti-envelope titers. The Ad26-SIV prime was chosen with the intent of increasing mucosal antibodies to Env and CD8+ T cell responses. The DNA prime protected against infection in the DNA prime regimen and VE correlated with hypoxia and inflammasome activation in classical CD14+ CD16negative monocytes that in turn directly correlated with the gut-homing CCR5negative Th2 cell responses and with mucosal NKp44+ cells and IgG to V2. In the same group the frequency of differentiated CD16+ monocytes correlated with reduced vaccine efficacy via STAT3 activation. The Ad26 prime regimen did not protect against SIV acquisition despite its higher immunogenicity and it was associated with a decrease in total CD14+ DR+ monocytes in blood accumulation of de novo differentiated CX3CR1+ CD163+ macrophages in lymph nodes mucosal inflammation and skewing of CD4+ T cells toward Th17 cells in the rectal mucosa and lungs. Th17 cells are preferentially infected by HIV/SIV and negatively regulate NKp44+ cells. It is possible that vaccine-generated target cells for virus infection may have decreased the efficacy of the Ad26 prime regimen as was observed in other vaccine studies in macaques and humans. 3. A simplified vaccine regimen based on DNA/ALVAC-SIV / ALVAC-SIV + gp120 / alum affords 69% vaccine efficacy. With the intent of confirming the importance of monocyte-mediated innate immunity and investigating whether the DNA/ALVAC/gp120/alum approach was also effective in female macaques we designed a study in young and old females. We tested a simplified version of the DNA prime ALVAC/gp120/alum vaccine approach using two intramuscular DNA primes (weeks 0 and 4) one ALVAC-SIV boost (week 8) and a single final boost with the combination ALVAC-SIV and gp120 in alum at week 13. Challenge exposure was started at week 17 and continued for 11 weeks. We found that this vaccine had 69% VE in young female macaques (average age 2.7 years) but failed to protect old female macaques (average age 7.5 years). Protection in young females correlated with the frequency of CD14+ classical monocytes confirming the results of the previous study in young males. In old vaccinated females however we observed a correlation with the plasma level of IL-6 and IL-8 and increased virus acquisition. These data further support a role for monocytes in protection of both female and male macaques and uncovered an age-dependent factor. No difference in SIVmac251 acquisition was observed in young or old naive controls (data not shown). Current Research and Future Plans 1. Define the epigenetic signatures of CD14+ monocytes neutrophils and Th2 CCR5negative T cells and study the miRNA signatures in extracellular vesicles (EV) that track with protective immunity. 2. Define the specificity and mechanistic intersection between protective vaccine-induced V2-targeted humoral responses and innate immunity 3. Development of the next generation of ALVAC based HIV vaccine candidate leveraging innate immunity to elicit durable protective immune profiles 4. Investigate whether monoclonal antibodies to V2 that inhibit a4B7 integrin binding protect against SIVmac251 acquisition alone or in combination with innate monocyte memory immunity 5. Durability 6. Investigate the basis for the age bias vaccine efficacy and test adjuvants that may overcome it such as IGF-1 and an alum-based liposome ALFA adjuvant with respect to innate immunity. 7: Design an HIV clade B based optimal DNA/ALVAC/gp120/alum vaccine regimen and test it in a phase I HIV vaccine trial in young volunteers. We will also seek to understand the role of monocytes in SARS-CoV-2 infection." 1719105 +No NIH Category available AIDS prevention;Acquired Immunodeficiency Syndrome;Adjuvant;Affect;Age;Animal Model;Animals;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Blood;CD14 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Canarypox Vectors;Cells;Chinese;Collaborations;Combined Vaccines;Communities;DNA;Data;Dependence;Development;Epigenetic Process;FCGR3B gene;Female;Frequencies;Futility;Future;Genes;Genetic Transcription;HIV;HIV Envelope Protein gp120;HIV Vaccine Trials Network;HIV vaccine;Homing;Human;Hypoxia;IL8 gene;Immune;Immune response;Immune system;Immunity;Immunize;Immunoglobulin G;Infection;Infection prevention;Infectious Agent;Inflammasome;Innate Immune Response;Insulin-Like Growth Factor I;Integrin Binding;Interleukin-10;Interleukin-6;Intervention;Intramuscular;Joints;Knowledge;Legal patent;Liposomes;Lung;Lymphoid Cell;MF59;Macaca;Macaca mulatta;Macrophage;Malignant Neoplasms;Mediating;Memory;Metabolic;MicroRNAs;Modality;Modeling;Monoclonal Antibodies;Mucositis;Mucous Membrane;Myeloid Cells;National Institute of Allergy and Infectious Disease;Natural Immunity;Pathway interactions;Peripheral Blood Mononuclear Cell;Phase;Plasma;Political Factor;Population Genetics;Preventive;Proteins;Recombinant Vaccines;Rectum;Regimen;Research;Research Personnel;Risk;Role;SARS-CoV-2 infection;SIV;SIV Vaccines;STAT3 gene;South Africa;Specificity;T cell response;T-Lymphocyte;Testing;Th2 Cells;Thailand;Training;Uncertainty;United States National Institutes of Health;Universities;Vaccinated;Vaccines;Viral;Virus;Virus Diseases;Work;adaptive immune response;age related;aluminum sulfate;animal facility;animal model development;antiretroviral therapy;arm;cytotoxic CD8 T cells;design;efficacy testing;exosome;expectation;extracellular vesicles;gender difference;immunogenic;immunogenicity;insight;lymph nodes;male;microbiome research;monocyte;monomer;natural killer cell protein 44-kDa;neonate;neutralizing antibody;neutrophil;next generation;novel;novel vaccines;nutrition;pathogen;predictive modeling;rational design;rectal;response;risk minimization;sex;simian human immunodeficiency virus;simian immunodeficiency virus gp120;vaccine candidate;vaccine efficacy;vaccine evaluation;vaccine platform;vaccine strategy;vaccine trial;volunteer Development of rationally designed HIV vaccines n/a NCI 10926139 1ZIABC011126-16 1 ZIA BC 11126 16 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2689105 OD "Accomplishments 1: Assess which macaque model better predicts or recapitulates the efficacy of HIV vaccine candidates in humans. The SIVmac251 model has predicted and recapitulated RV144: In 2005 a collaborative study in neonates predicted the results of RV144. More recently we recapitulated the efficacy of the RV144 vaccine regimen in young (2-3 years) male and female macaques. The latter study has provided more value than just the evaluation of vaccine efficacy. Our integrated study of RNA expression in PBMCs and exosomes together with comprehensive analyses of innate and adaptive immune responses in blood lymph nodes and mucosa uncovered unexpected correlates of risk of virus acquisition such as mucosal innate lymphoid cells (ILCs) and the expression of 12 genes ten of which are part of the RAS pathway. The usefulness of this model was validated by similar observations in another protective vaccine regimen that I developed in collaboration with Dr. Strbo and the late Dr. Eckhart Podack of Miami University. This approach was the subject of a joint patent. We have also performed a confirmatory study entirely supported by the Division of AIDS NIAID in other animal facilities wherein we compared the immunogenicity and efficacy of the ALVAC and NYVAC SIV-based vaccine regimens. The ALVAC-SIV based vaccine was also protective in Chinese macaques whereas the ""more immunogenic"" NYVAC-based SIV recombinant vaccine was not. Of note the NYVAC-based vaccine did not induce an early burst of IL-1B as was the case in the non-protective Ad26 prime regimen. Will the SIVmac251 model predict the results of HVTN-702? We tested the efficacy of the ALVAC-based SIV vaccines in the SIVmac251 model using the alum in parallel with the MF59 adjuvant in the gp120 boost. To our surprise the MF59 based regimen in the SIV model was not efficacious despite its higher immunogenicity. While this observation stirred debate in the scientific community our findings did not influence the decision by the P5 Partnership to use MF59 as an adjuvant in the HVTN-702 study in South Africa. Instead logistical and political factors likely influenced the decision to proceed as originally planned. Given the current uncertainty of how accurately the SIVmac251 animal model will predict human results our study will provide crucial information to define the model's utility since we observed no efficacy in macaques. The preliminary analysis of futility in HVTN-702 will be made public in 2018 and will address this issue. SHIV-clade C Tier 1 in female Chinese rhesus macaques: In another study supported mostly by NIAID macaques were immunized with the identical ALVAC-HIV-based vaccines used in HVTN702 combined with either the MF59 or the alum (Novartis) in the gp120 boost and challenged with a SHIV clade C Tier 1 virus. The MF59 based regimen was protective whereas the alumN was not. Protection was associated with neutralizing antibodies to the SHIV clade C Tier 1 virus. In its current state I don't believe that this SHIV model will predict the results of HVTN-702 because only 1% of HIV clade C viruses in South Africa are sensitive to neutralization. However the interim analysis of HVTN-702 for futility will further our knowledge of animal model predictability and will guide the choice and refinement of faithful animal models for the development of fully effective vaccines for HIV. 2. HIV vaccine candidate activation of hypoxia and inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition. This study demonstrated that CD14+ and CD16+ monocytes have a role in the risk of SIVmac251 acquisition and has contributed to the mechanistic insight on the role of IL-1B and IL-10 in the DNA/ALVAC/alum vaccine platform. We compared ALVAC-SIV DNA-SIV and Ad26-SIV prime modalities in combination with two ALVAC-SIV + gp120 protein boosts in young male macaques. We used the intramuscular DNA-SIV prime with the intent of increasing CD4+ T cells and antibody responses since we demonstrated in prior work that the CD4+ T cells elicited by the DNA prime influence the anti-envelope titers. The Ad26-SIV prime was chosen with the intent of increasing mucosal antibodies to Env and CD8+ T cell responses. The DNA prime protected against infection in the DNA prime regimen and VE correlated with hypoxia and inflammasome activation in classical CD14+ CD16negative monocytes that in turn directly correlated with the gut-homing CCR5negative Th2 cell responses and with mucosal NKp44+ cells and IgG to V2. In the same group the frequency of differentiated CD16+ monocytes correlated with reduced vaccine efficacy via STAT3 activation. The Ad26 prime regimen did not protect against SIV acquisition despite its higher immunogenicity and it was associated with a decrease in total CD14+ DR+ monocytes in blood accumulation of de novo differentiated CX3CR1+ CD163+ macrophages in lymph nodes mucosal inflammation and skewing of CD4+ T cells toward Th17 cells in the rectal mucosa and lungs. Th17 cells are preferentially infected by HIV/SIV and negatively regulate NKp44+ cells. It is possible that vaccine-generated target cells for virus infection may have decreased the efficacy of the Ad26 prime regimen as was observed in other vaccine studies in macaques and humans. 3. A simplified vaccine regimen based on DNA/ALVAC-SIV / ALVAC-SIV + gp120 / alum affords 69% vaccine efficacy. With the intent of confirming the importance of monocyte-mediated innate immunity and investigating whether the DNA/ALVAC/gp120/alum approach was also effective in female macaques we designed a study in young and old females. We tested a simplified version of the DNA prime ALVAC/gp120/alum vaccine approach using two intramuscular DNA primes (weeks 0 and 4) one ALVAC-SIV boost (week 8) and a single final boost with the combination ALVAC-SIV and gp120 in alum at week 13. Challenge exposure was started at week 17 and continued for 11 weeks. We found that this vaccine had 69% VE in young female macaques (average age 2.7 years) but failed to protect old female macaques (average age 7.5 years). Protection in young females correlated with the frequency of CD14+ classical monocytes confirming the results of the previous study in young males. In old vaccinated females however we observed a correlation with the plasma level of IL-6 and IL-8 and increased virus acquisition. These data further support a role for monocytes in protection of both female and male macaques and uncovered an age-dependent factor. No difference in SIVmac251 acquisition was observed in young or old naive controls (data not shown). Current Research and Future Plans 1. Define the epigenetic signatures of CD14+ monocytes neutrophils and Th2 CCR5negative T cells and study the miRNA signatures in extracellular vesicles (EV) that track with protective immunity. 2. Define the specificity and mechanistic intersection between protective vaccine-induced V2-targeted humoral responses and innate immunity 3. Development of the next generation of ALVAC based HIV vaccine candidate leveraging innate immunity to elicit durable protective immune profiles 4. Investigate whether monoclonal antibodies to V2 that inhibit a4B7 integrin binding protect against SIVmac251 acquisition alone or in combination with innate monocyte memory immunity 5. Durability 6. Investigate the basis for the age bias vaccine efficacy and test adjuvants that may overcome it such as IGF-1 and an alum-based liposome ALFA adjuvant with respect to innate immunity. 7: Design an HIV clade B based optimal DNA/ALVAC/gp120/alum vaccine regimen and test it in a phase I HIV vaccine trial in young volunteers. We will also seek to understand the role of monocytes in SARS-CoV-2 infection." 970000 +No NIH Category available Adult;Apoptotic;Binding Proteins;Biochemical;Biotin;Bypass;Cell Adhesion;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;ChIP-seq;Chick;Complex;Data;Development;Developmental Biology;Digit structure;ERG gene;Elements;Embryo;Ensure;Equilibrium;Erinaceidae;Event;Feedback;Fibroblast Growth Factor;Fingers;Foundations;GLI gene;GLI3 gene;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Diseases;Genetic Transcription;Genetic study;Genomics;Goals;Growth;HOX protein;Homeobox Genes;Homeostasis;Human;Intercept;Internet;Joints;Knock-out;Label;Learning;Length;Limb Bud;Limb Development;Limb structure;Link;Malignant Neoplasms;Mammals;Mass Spectrum Analysis;Mission;Modeling;Modification;Molecular;Molecular Genetics;Morphogenesis;Morphology;Mus;Mutant Strains Mice;Mutate;Neoplasm Metastasis;Neoplasms;Organ;Organogenesis;Pathogenesis;Pathologic;Pathology;Pathway interactions;Pattern;Phalanx;Phase;Physical condensation;Physiological Processes;Play;Process;Proliferating;Proteins;Proteomics;Regulation;Research;Role;SHH gene;Secondary to;Shapes;Signal Pathway;Signal Transduction;Skeleton;Skin;Specific qualifier value;Structure;Study models;Supporting Cell;System;Systems Biology;Thumb structure;Tissues;Tumor Biology;Vertebrates;Work;beta catenin;cell behavior;cell motility;cellular targeting;chromatin immunoprecipitation;design;genetic approach;genome-wide;insight;model building;morphogens;mutant;neoplastic cell;osteoprogenitor cell;progenitor;programs;protein protein interaction;regeneration potential;response;self-renewal;single-cell RNA sequencing;stem cells;three dimensional structure;transcription factor;transcriptome;transcriptome sequencing;transcriptomic profiling;tumorigenesis Genome-wide target analysis of Shh-activated transcription network in limb bud n/a NCI 10926138 1ZIABC011120-16 1 ZIA BC 11120 16 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 443079 NCI "Our long term goal is to unravel the steps linking early patterns of gene regulation and expression with the ultimate realization of structure to serve as a paradigm for how signaling networks orchestrate the formation of a complex tissue. To accomplish this we are using combined genetic genomic and proteomic approaches to study transcription factors and regulatory cascades operating during limb development with the ultimate aim of elucidating the regulatory hierarchy between early induction of antero-posterior pattern (thumb to pinky) and the final morphogenesis of distinct digits. Learning how this 3-dimensional structure forms will be generally relevant for understanding how organogenesis is achieved and insights on how growth and morphogenesis are orchestrated will advance our understanding of how to treat genetic diseases and cancers that arise when such regulatory components are either mutated or expressed abnormally............................................................................................................................................................... 1) Early events downstream of Shh: Our analyses of temporal requirements for Shh signals in mutant mouse limb buds suggests that Shh acts at early stages to specify digits through an indirect signal relay rather than acting as a classical morphogen and more likely acts to divide the limb field into discrete domains with differing potential to respond to secondary downstream signals than to specify 'final' distinct digit identities. To determine the initial differences established during early signaling we will perform single cell transcriptome analysis from normal limb buds at and shortly after Shh activation to identify expression signatures and characterize immediate-early response zones. This will provide a foundation for subsequent studies using mouse mutants in which early Shh activity is altered. Furthermore our genetic studies indicate that there are 2 classes of Shh responsive target genes with very different regulatory features: those that respond to a transient signal and become stably expressed and those that require continuous signaling to maintain their expression. From our analysis the former class would include targets critical for organizing a basic pattern of limb elements that can form and the latter would include regulators of growth and survival necessary for the later expansion and morphogenesis of these elements. We are using transcriptome profiling of Shh mutant limb buds to begin to characterize the genes in these two distinct target classes and determine the basis of their differential regulation. Transcriptome profiles of Shh mutant vs. Shh mutant rescued by a transient Shh exposure (early ""trigger"" function) and bypassing the need for Shh to support cell survival (Bax/Bak knockout see also Project ZIA BC 011118) will be compared to identify expression signatures in the transient Shh signaling phase and characterize immediate-early response genes. Similar comparisons of Shh-null with control embryos will identify all targets including those dependent on sustained Shh signaling that play important roles in cell survival. Understanding the proliferative and anti-apoptotic roles of Shh in the context of these differentially regulated target classes will provide a reference for deciphering and intercepting Shh roles in cancer as well as normal development..................................... 2) Feedback circuits between Shh and Fgf signaling: Reciprocal positive and negative feedback loops between the mesodermal Shh-expressing and ectodermal Fibroblast growth factor (Fgf)-expressing signaling centers in the limb bud act to both maintain and restrict each other's activity in regulating digit pattern and outgrowth and eventually to terminate activity when limb organogenesis is complete. We are using genetic strategies to manipulate Shh and Fgf levels at different limb bud stages to begin to unravel the positive and negative regulatory inputs controlling their expression. These results will be incorporated into the analysis of the regulatory networks operating at different stages of limb morphogenesis to arrive at a more complete model of how these circuits are integrated. 3) Gli3-Hox interactions and regulation of morphogenesis: Gli3-Hox protein-protein interactions govern multiple processes in limb morphogenesis including the rate of proliferation and timing of cell adhesion during formation of progenitor skeletal condensations and the control of distinct final digit morphologies by late signals from interdigital tissues (webbing) adjacent to each of the digit primordia. We previously identified a highly conserved domain in Gli3 that interacts with Hox factors and also several other key developmental regulators (Smad1 beta-catenin). We will use mass spectrometry (with BioID-biotin tag proximity labeling to capture and enrich interaction partners) to elucidate the range of partners that can modulate Gli3 activity in the limb and may also compete Hox protein binding which will be validated using other biochemical and genetic strategies. In parallel to gain insight into the mechanisms by which Gli3 and Hoxd proteins act antagonistically we are comparing the normal limb transcriptome with 5'Hoxd Gli3 and compound mutants to identify expression changes in potential gene targets. Our results will be compared with known direct transcriptional targets of Hoxd13 and of Gli3 (from available ChIPseq data) and supplemented with ChIPseq in our lab for later limb stages if needed. Identifying late-stage Hoxd and Gli3 targets will provide insight into co-regulated genes and Gli3-Hoxd roles as well as illuminating late effectors of Hoxd genes in limb morphogenesis. The transcriptional network regulated by Hoxd and Gli3 in the limb will also be analyzed in relation to Shh-pathway targets that form two distinct classes requiring either transient or sustained signaling for their stable activation. ......................... 3) Finally single cell expression profiling will be used to characterize the digit progenitor regions (digit tips) that are instructed to form phalangeal segments and joints by the interdigit signaling network that is controlled by Gli3-Hox balance (see also Project ZIA BC 011119). This region behaves as a stem cell pool for the digit skeleton and has some limited regenerative potential even in mammals. Using this combination of approaches we hope to uncover the regulatory cascade leading to formation of defined digit morphologies with distinct numbers of segments and joints. Gli3 and Hox genes are also aberrantly co-expressed in some cancers and may contribute to their pathogenesis and these studies will also shed light on their possible roles in these contexts. ........................................................................................................................ 4) Insights on regulatory network from adaptive limb modifications: The basic regulatory network instructing formation of the limb skeleton is largely conserved throughout vertebrates. Uncovering regulatory changes that underlie evolutionary adaptations can illuminate critical network parameters and basis for robustness. Previous work in chick and in mouse from our lab have shown that digit morphology (identity) is regulated at late stages by interdigit signals. Our genetic evidence indicates that 5'Hoxd and Gli3 are part of an interdigit signaling center that regulates final digit identity. Elucidating signaling pathway differences between different interdigits will provide new insights on how digit identity is regulated at late stages and potential mechanisms by which Hoxd and Gli3 genes act." 443079 +No NIH Category available Adult;Ambystoma;Amphibia;Amputation;Anterior;Appearance;Cartilage;Cell Adhesion;Cell Aggregation;Cell Death;Cell physiology;Cessation of life;Collaborations;Complex;Congenital Abnormality;Development;Developmental Biology;Digit structure;Disease;Distal;Elements;Embryo;Ensure;Equilibrium;Erinaceidae;Evolution;Excision;Failure;Feedback;Fibroblast Growth Factor;Finger joint structure;Fingers;GLI3 gene;Gene Dosage;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomics;Goals;Growth;Homeobox;Homeostasis;Human;Intercept;Joints;Learning;Length;Limb Bud;Limb Development;Limb structure;Link;Maintenance;Malignant Neoplasms;Mammals;Mesenchyme;Methods;Mission;Morphogenesis;Morphology;Mus;Neoplasm Metastasis;Neoplasms;Organ;Organ Culture Techniques;Output;Pathologic;Pathology;Pathway interactions;Pattern;Periodicals;Phalanx;Phalanx of hand;Phase;Physical condensation;Physiological Processes;Play;Population;Positioning Attribute;Process;Proliferating;Proteins;Proteomics;Radial;Regenerative capacity;Regulation;Replication Licensing;Research;Role;Running;SHH gene;Shapes;Signal Induction;Signal Transduction;Site;Skeleton;Skin;Structure;Study models;System;Systems Biology;Testing;Thumb structure;Tissues;Tumor Biology;Vertebrates;Work;beta catenin;cell behavior;cell motility;cellular targeting;design;digit regeneration;gastrointestinal epithelium;genetic approach;genome-wide;in vivo;insight;joint formation;limb regeneration;model building;mutant;neoplastic;neoplastic cell;postnatal;progenitor;programs;regeneration potential;single-cell RNA sequencing;skeletal;skeletal regeneration;smoothened signaling pathway;transcription factor;transcriptome;tumorigenesis;ulna Hoxd and Gli3-Hoxd interaction roles in Hedgehog regulated digit morphogenesis n/a NCI 10926137 1ZIABC011119-16 1 ZIA BC 11119 16 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 443079 NCI 5'Hoxd genes play many roles during limb development and may control the effectors of morphogenesis at late stages. How Hoxd genes guide digit morphogenesis and their downstream targets remain enigmatic. Using genetic approaches in mice we find that in addition to a role in initiating Sonic hedgehog (Shh) expression 5'Hoxd genes determine the polarity of the primary limb axis early and regulate digit pattern and morphogenesis at late stages after digit condensations have already formed including joint formation and positioning; a major mechanism by which Hoxd genes regulate digit identity. We previously discovered genetic and physical interactions between 5Hoxd and Gli3 that modify Gli3 repressor (Gli3R) function (and hence Shh output) antagonizing Gli3R and potentially converting it to an activator. We find that Gli3-Hox interactions both modulate the polarity of limb axis formation and regulate the pacing of cartilage vs joint formation in digits which may have relevance for skeletal homeostasis and disease as well as skeletal birth defects. ....................................................................................................................................................................................................................................................................................................................Role of 5'Hoxd genes and Hoxd-Gli3 interaction in determining polarity of primary limb axis formation: In most vertebrates the primary limb axis runs through the posterior limb with the ulna/digit4 (d4) condensing first. In urodele amphibians such as axolotl which retain the ability to regenerate limbs as adults the anterior limb axis is dominant (radius/d2 appear first). Based on altered expression patterns it has been proposed that the axis shift in Urodeles results from a failure to expand 5'Hoxd gene expression in the late distal limb. We have analyzed limb axis formation in the 5'Hoxd mutant (Hoxd11-13 deleted) and found that the anterior axis forms first as in urodeles. Furthermore we find that in compound 5'Hoxd;Gli3 mutants posterior axial dominance is restored. The 5'Hoxd homeobox transcription factors play roles in replication licensing and cell adhesion. Gli3R expressed anteriorly also regulates proliferation and condensation and antagonizes 5'Hoxd function. We are analyzing how changes in the relative timing and rate of proliferation and of cell aggregation/condensation in different zones of the limb bud are altered in these mutants and if they correlate with anterior vs posterior axial dominance. We propose that the balance between antagonistic 5'Hoxd-Gli3 functions governs the polarity of primary limb axis formation and are investigating the potential relation between altered axis polarity and regenerative capacity. ....................................................................................................................................................................................................................................................................................................................Role of Hoxd genes and Hoxd-Gli3 interaction in cartilage differentiation and joint formation to determine distinct digit identities: Digit identity remains plastic even after the formation of the digit primordial chondrogenic condensations and is regulated by interdigit zones which are also late sites of 5'Hoxd and Gli3 expression. We found that genetic removal of several Hoxd genes (d11-d13) results in abnormal joint formation both loss of digit joints and/or abnormal joint position as well as short biphalangeal digits. Collaborating with Marian Ros (Univ. Cantabria) we are also examining the role of Hoxa13 in digit formation. Hoxa13 acts upstream of and induces the late phase of Hoxd13 expression and plays a distinct role in regulating the formation of a normal thumb acting hierarchically upstream of and together with Hoxd13. The canonical Wnt pathway plays an essential role in joint formation and we find that activated beta-catenin restores normal joint formation in the 5'Hoxd mutant digits. But surprisingly selective activation of stabilized beta-catenin in the interdigital tissues is required for rescue indicating that at least some aspects of beta-catenin and 5'Hoxd function in joint formation occur indirectly via interdigit signaling. Gli3 (the transcriptional effector of Shh and Hoxd protein interactor) also has striking effects on cartilage differentiation and joint formation in digits. During joint formation in digit precursors Gli3 mutants form abnormal segments with excessive joint formation extending into the cartilage elements. Genetically the balance between total 5'Hoxd and Gli3 gene dosage regulates the periodic formation of normal joints and the normal 3 bony segments typical of mammalian digits. Our genetic evidence indicates that the Hoxd-Gli3 balance acts indirectly from interdigital mesenchyme to modulate Bmp activity and thereby regulate the periodic appearance of digit elements (phalanges) and joints from a digit tip progenitor pool. We are extending our analysis to determine: 1) targets regulated by Gli3-Hoxd interaction and 2) other signaling inputs that regulate the digit tip progenitor pool to determine phalanx number and size including signals induced by beta-catenin activation in interdigits. We are also generating transcriptome profiles of digit tip tissues using single cell RNAseq to better characterize the progenitor population that gives rise to successive digit elements (repeating phalanges/joints) (see also Project: Genome-wide target analysis of Shh-activated transcription network in limb bud; ZIA BC 0111120). Even in mammals distal digit tips retain a limited capacity for regeneration and understanding the regulation of this distal digit progenitor pool and its maintenance will provide new and testable insights relevant to skeletal regeneration potential in adults. With this goal in mind we are developing organ culture techniques to reproduce digit-like structures from limb mesenchyme in culture to interrogate regulation by signaling factors active in vivo as well as methods to genetically mark embryonic digit tip progenitors and test their ability to contribute to digit regeneration post-natally following digit tip amputation. 443079 +No NIH Category available Adult;Affect;Anterior;Apoptosis;Apoptotic;Autocrine Communication;Basal Cell Nevus Syndrome;Biological Assay;Brain;Bypass;Cell Death;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cessation of life;Child;Code;Communities;Complement component C5;Complementary DNA;Complex;Coupled;Development;Developmental Biology;Digit structure;ERG gene;Elements;Embryo;Ensure;Enterobacteria phage P1 Cre recombinase;Exons;Family member;Feedback;Fibroblast Growth Factor;Fingers;Gene Deletion;Gene Expression Profile;Gene Expression Regulation;Genes;Genetic;Genetic Diseases;Genetic Transcription;Genomics;Goals;Growth;Holoprosencephaly;Hour;Human;Infant;Intercept;Joints;Learning;Length;Ligands;Limb Bud;Limb Development;Limb structure;Link;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mesoderm;Mission;Mitogens;Modeling;Morbidity - disease rate;Morphogenesis;Mus;Mutant Strains Mice;Mutate;Mutation;Neoplasm Metastasis;Neoplasms;Neural Crest;Normal tissue morphology;Nucleic Acid Regulatory Sequences;Organ;Pancreas;Pathologic;Pathology;Pathway interactions;Pattern;Phalanx;Phase;Physiological Processes;Play;Population;Process;Production;Proliferating;Prostate;Proteomics;Refractory;Regulation;Research;Role;SHH gene;Shapes;Signal Pathway;Signal Transduction;Skeleton;Skin;Sonic Hedgehog Pathway;Specific qualifier value;Stomach;Structure;Study models;System;Systems Biology;Tamoxifen;Testing;Therapeutic Intervention;Thumb structure;Time;Tissues;Tumor Biology;body system;cancer type;cell behavior;cell motility;cellular targeting;design;developmental genetics;genome-wide;insight;model building;morphogens;mortality;mutant;neoplastic cell;novel;paracrine;progenitor;programs;response;selective expression;smoothened signaling pathway;stem cell population;tissue culture;tissue regeneration;tool;transcription factor;transcriptome;transcriptomic profiling;transcriptomics;tumor;tumorigenesis Role of Shh in developmental patterning and growth of digit skeleton n/a NCI 10926136 1ZIABC011118-16 1 ZIA BC 11118 16 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 443079 NCI Sonic hedgehog (Shh) acts as a mitogen and cell survival factor in many adult processes during normal tissue renewal and in many types of cancer but acts as a morphogen in several developmental contexts. How the mitogenic role of Shh is integrated with the morphogenetic role in developmental contexts is still poorly understood. In the limb Shh regulates both digit number and identity of different digits (A-to-Pthumb to pinky). Shh is thought to act as a morphogen forming a gradient along the limb AP axis with higher concentrations specifying more posterior digit types. We have determined the time-requirements for Shh function in limb (using a tamoxifen-regulated Cre to remove Shh at different times in mice). To perform this analysis we generated and characterized a novel conditional Cre recombinase line selectively expressed in early limb mesoderm neural crest gut and tailbud. This line provides an excellent tool available to the scientific community to illuminate different temporal roles of key developmental regulators in several important developmental models using mouse mutants as well as for genetic lineage tracing studies in mice. Our results deleting Shh function at different time points are most consistent with a model in which Shh activity is required only very transiently (several hours) to specify the complete complement of 5 different digit types but is required for a prolonged time (about 2 days) to maintain cell survival and proliferation enabling 5 normal digits to form. To further test this model for Shh function we have assessed whether restoring cell survival can rescue normal digit formation in mutant embryos after a transient period of Shh activity that is terminated by Shh gene deletion. To rescue cell survival the compound mutant for the pro-apoptotic Bcl2 family members Bax/Bak (which play roles in normal interdigital apoptosis) has been introduced to inactivate the intrinsic death pathway. Our results indicate that both normal digit number and pattern (morphogenesis) can be rescued by simply restoring cell survival and proliferation in Shh mutant embryos. In addition genetic lineage tracing of cells in the limb that have responded to Shh signals at different time points indicates that Shh only signals directly to the very posterior part of the limb bud at the time when all 5 digit progenitors have been specified. This result indicates that Shh acts indirectly in the early limb bud via a system of relay signals to specify digits. We developed a genetic assay to test for relay signaling by artificially enforcing Shh-response in the posterior limb bud in embryos lacking all Shh function (Shh KO). This partly rescues anterior digit formation and strongly suggests the presence of relay signals acting downstream of Shh. Our results are incompatible with Shh acting as a classic morphogen in the limb and suggest that Shh acts as a trigger to activate a relay mechanism. Furthermore our results indicate that there are 2 classes of Shh responsive target genes those that respond to a transient signal and become stably expressed and those that require continuous signaling to maintain expression. We are comparing the transcriptomes of Shh mutant and rescued limb buds to characterize the types of genes in these two differentially regulated target classes (see also Project : Genome-wide target analysis of Shh-activated transcription network in limb bud; ZIA BC 0111120). ......................................................................................................................................................................... Our results also indicate that both Shh-expression and response are highly dynamic and we are characterizing these features using several approaches. Our lineage tracing results of Shh production and response indicate that Shh producing cells arise from a renewing progenitor pool in the proximal limb bud margin providing a high level of robustness to Shh signaling in the limb. In parallel we performed single cell transcriptome profiling from normal limb buds to identify expression signatures in the transient Shh signaling phase and characterize immediate-early response genes. These studies have revealed a potential renewing progenitor population by trajectory analysis and identified progenitor-specific markers. We are following up on these observations using a conditional Cre driven by marker regulatory regions to genetically mark and further characterize the progenitor lineage. Understanding the basis for robustness and renewal capacity in Shh-expressing progenitors may be valuable in devising therapeutic intervention for Shh-driven cancers. ......................................................................................................................................................................... The lineage analysis of Shh-production and -response also suggest that Shh-producing cells are completely refractory to autocrine signaling response which is a feature shared by many Shh-driven tumors in humans (signaling is often paracrine and regulates a supportive tumor niche). Our genetic and transcriptomic studies suggest that non-responsiveness to Shh signaling is tightly coupled to functional Shh-ligand production but occurs in a cell autonomous manner in the producing cells. We are dissecting the requirements for ligand production in a tissue culture model using comparison of the endogenous Shh locus vs Shh cDNA with only coding exon sequences to assess the basis for this autonomous non-responsiveness. Understanding the underlying mechanisms for this strict inhibition of autonomous response will also provide insights on how this inhibition is bypassed in some Shh-driven cancers. 443079 +No NIH Category available Adenoviruses;Affect;Animals;Antibodies;Arachnida;BK Virus;Basic Science;Bioinformatics;Collaborations;DNA Viruses;Data Set;Deposition;Distant;Division of Cancer Epidemiology and Genetics;Exanthema;Family;Goals;Human;Human Biology;Immunity;Individual;Investigation;JC Virus;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mission;Molecular Biology;Names;Papillomavirus;Parvovirus;Peer Review;Perception;Play;Polyomavirus;Process;Proteins;Pruritus;Recombinants;Recording of previous events;Retroviridae;Risk;Role;Testing;United States National Institutes of Health;Virion;Virus;Work;clinical center;deep sequencing;immunosuppressed;neutralizing monoclonal antibodies;organ transplant recipient;precursor cell;prevent;public database;receptor;tumor;vaccine development Molecular biology of human polyomaviruses n/a NCI 10926125 1ZIABC011090-16 1 ZIA BC 11090 16 9692553 "BUCK, CHRISTOPHER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 771566 NCI "We have developed bioinformatics approaches to discovering divergent new families of viruses in our deep sequencing datasets. The work led to the deposit of several thousand highly diverse previously virus species into public databases. In a parallel set of studies we discovered several previously unrecognized families of animal viruses. We have suggested the names adomavirus adintovirus and ahomavirus. The names denote the distant relationships of the new families to known families including adenoviruses parvoviruses and retroviruses. These lines of investigation are presently in press or under peer review. A related study involving the molecular biology of the virion proteins of a new group of arachnid-associated polyomaviruses we discovered promises to draw further evolutionary ties between multiple families of non-enveloped animal DNA viruses. We have been collaborating with NIH Clinical Center colleagues to investigate cases of human polyomavirus 7 (HPyV7) associated pruritic rashes. The project led to the discovery of a previously unknown HPyV7 protein that we dub ""Agnoprotein."" We are testing the hypothesis that Agnoprotein is involved in assembly of the HPyV7 and we are exploring the possibility that the protein directly triggers receptors involved in itch perception. A related project seeks to develop recombinant HPyV7-neutralizing monoclonal antibodies that could be used for treatment of HPyV7 pruritis. In collaboration with colleagues at NCI DCEG we have performed deep sequencing of bladder cancers affecting organ transplant recipients who are known to be at increased risk of developing bladder cancer. The work shows that bladder cancers from immunosuppressed individuals often harbor polyomaviruses or papillomaviruses. The results suggest a possible causal role for these viruses and raise the possibility that the vaccine we are developing against BK and JC polyomaviruses might prevent bladder cancer." 771566 +No NIH Category available Biological Assay;Biopsy;CCR;Clinical Trials;Collaborations;Combination immunotherapy;DNA Damage;DNA Double Strand Break;Development;Developmental Therapeutics Program;Division of Cancer Treatment and Diagnosis;Enzyme-Linked Immunosorbent Assay;Gamma-H2AX;Goals;Immunofluorescence Immunologic;MEKs;Molecular;New Agents;Pediatric Oncology;Pharmacodynamics;Pharmacology;Phase;Poly(ADP-ribose) Polymerases;Protein Isoforms;Proto-Oncogene Proteins c-akt;Series;System;Therapeutic Agents;Tumor Tissue;Type I DNA Topoisomerases;United States National Institutes of Health;clinical center;clinical development;detector;first-in-human;inhibitor;insight;novel;novel anticancer drug;novel therapeutics;pharmacologic;rapid diagnosis;rare cancer Phase 0-1 Clinical Trials n/a NCI 10926123 1ZIABC011078-16 1 ZIA BC 11078 16 9692531 "DOROSHOW, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 627868 NCI The collaboration between the DTB and DCTD has been responsible for the development of several new pharmacodynamic assays including an ultrasensitive immunofluorescence assay for gamma H2AX (DNA double strand break detector) in tumor tissue biopsies and ELISAs for topoisomerase I and poly ADP-ribose polymerase (PARP) as well as assays for other DNA damage markers (pNBS1) all of the isoforms of MEK ERK and AKT DNMTs as well as a series of immuno-PD markers. These assays have been essential for first in human clinical trials of novel non-camptothecin topoismerase I inhibitors DNMT1 inibitors and immunotherapy combinations that have been activated in the NIH Clinical Center. In addition collaborations with the Pediatric Oncology Branch have facilitated the development of new agents used for rare tumors. Additional collaborations have developed around our use of the NCI 60 for systems pharmacology. 627868 +No NIH Category available Acquired Immunodeficiency Syndrome;Adopted;Adult;Area;Autoimmune Diseases;B-Cell Lymphomas;B-Lymphocytes;Basic Science;Cell Differentiation process;Cell physiology;Childhood;Classification;Clinical;Clinical Protocols;Clinical Research;Communities;Consultations;Development;Diagnosis;Diagnostic;Diagnostic Services;Disease;Education;Extranodal;Genes;Goals;Growth;Hematologic Neoplasms;Hematopathology;Histiocytosis;Hodgkin Disease;Human Herpesvirus 4;Human Herpesvirus 8;Hyperplasia;Immunohistochemistry;Immunologic Deficiency Syndromes;In Situ Hybridization;Institution;International;Knowledge;Laboratories;Lesion;Lymphoblastic Leukemia;Lymphocyte Function;Lymphoid;Lymphoid Cell;Lymphoma;Lymphoproliferative Disorders;Malignant lymphoid neoplasm;Mission;Molecular;Multicentric Angiofollicular Lymphoid Hyperplasia;National Heart Lung and Blood Institute;National Human Genome Research Institute;National Institute of Allergy and Infectious Disease;Neoplasms;Nodal;Pathogenesis;Pathologic;Pathologist;Pathology;Patients;Phenotype;Physicians;Physiology;Proliferating;Publications;Rare Diseases;Reproducibility;Research;Second Opinions;Services;Standardization;T-Cell Lymphoma;T-Cell and NK-Cell Neoplasm;Training;Uncertainty;United States National Institutes of Health;Work;age group;clinical diagnosis;clinical practice;disease classification;histiocyte;improved;in vivo;leukemia/lymphoma;lymphoid neoplasm;molecular diagnostics;neoplastic;novel;programs;promoter;symposium;synergism;tool;translational study Hematopathology Diagnosis n/a NCI 10926122 1ZIABC011070-16 1 ZIA BC 11070 16 9692515 "JAFFE, ELAINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 935568 NCI "Dr. Pittaluga and I aid in the diagnosis and classification of reactive and neoplastic lymphoproliferative disorders immunodeficiency states and diverse hematological malignancies. We provide consultative and collaborative services to physicians in the NCI as well as to physicians studying patients with hematolymphoid disorders in other institutes in particular NIAID NHLBI NHGRI and NIAMSD. We regularly present at conferences sponsored by clinical branches in the NCI and other Institutes (NIAID NHLBI and NHGRI.) We receive more than 2000 cases in consultation each year. We try to restrict consultations to difficult or challenging cases and do not accept cases for ""routine second opinions"". A significant proportion (approximately 20%) of the cases are submitted by other academic institutions based on diagnostic uncertainty or because of differences of opinion among several institutions. We are often the final arbiter on challenging diagnostic problems. Additionally we have made novel observations based on our clinical practice and a number of publications have emanated from case material originally reviewed in consultation. Our clinical consultation practice also synergizes with other NIH clinical groups enhancing referral to NIH clinical protocols. Our work has led to improvement in the diagnosis and classification of several rare diseases including multicentric Castleman disease KSHV- and EBV-associated proliferations novel forms of both B-cell and T-cell lymphoma and expanding spectrum of histiocytic neoplasms. We have helped to define the differences between lymphomas occurring in adults from those in the pediatric age group. We have studied the difference between nodal and extranodal lymphomas. This work has advanced our knowledge regarding the classification of lymphoid and histiocytic neoplasms." 935568 +No NIH Category available Antibodies;Antibody Response;Antigens;Area;Binding;Biological Assay;Biological Markers;Blood typing procedure;Cancer Vaccines;Carbohydrates;Collaborations;Detection;Disease;Forssman Antigen;GVAX Cancer Vaccine;Goals;Human;Immune response;Immunoglobulin M;Malignant Neoplasms;Measures;Monitor;Pancreas;Patients;Play;Polysaccharides;Prognosis;Prostate Cancer Vaccine;Proteins;Research;Role;SARS-CoV-2 infection;Serum;Technology;Trisaccharides;Vaccination;Vaccines;Whole Cell Vaccine;blood group;cancer biomarkers;cancer diagnosis;cancer therapy;carcinogenesis;improved;response;treatment response Serum Antibody Profiling with a Carbohydrate Microarray n/a NCI 10926119 1ZIABC011055-16 1 ZIA BC 11055 16 15201322 "GILDERSLEEVE, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 177499 NCI Biomarkers play a critical role in cancer diagnosis and treatment. Serum antibodies represent an important class of biomarkers with many advantageous features such as good stability accessibility in biofluids and easy detection. There has been extensive research on identifying changes in antibody levels to protein antigens; however analysis of antibodies that binding carbohydrate antigens have been largely underutilized. Our carbohydrate microarray is well-suited to monitor the repertoire of anti-glycan antibodies in human serum and to study changes in their levels in response to disease or treatment of disease. The high-throughput approach can be used to identify new single biomarkers or to identify combinations of changes or profiles that are useful as biomarkers. Over the last few years we have developed and validated a carbohydrate microarray assay for measuring antibody levels in human serum. We are now applying this technology in a variety of areas. In collaboration with Dr. Schlom and colleagues we have been using the array to evaluate immune responses to the PSA-TRICOM prostate cancer vaccine (PROSTVAC-VF). We have found the pre-vaccination IgM antibody levels to blood group A trisaccharide correlate with survival on PROSTVAC-VF. In addition we have found that antibody response to the Forssman antigen correlate with overall survival. Both correlations are consistent in two independent patient groups encompassing over 100 patients. These are promising new biomarkers for determining which patients should receive PROSTVAC-VF and which patients on PROSTVAC-VF are having a favorable immune response. Finally in collaboration with Elizabeth Jaffee we have profiled immune responses induced by GVAX Pancreas whole cell vaccine. We also began studying antibody responses to carbohydrate antigens induced by SARS-CoV-2 infection. 177499 +No NIH Category available Adhesions;Affect;Aggressive behavior;Apoptosis;Biological;Biological Markers;Biology;Bypass;CASP8 gene;Cancer cell line;Cell Nucleus;Cell physiology;Cells;Chemoresistance;Chemotherapy-Oncologic Procedure;Classification;Clinic;Clinical;Clinical Trials;Collaborations;Complex;Cytoprotection;Databases;Dependence;Diagnosis;Disease;Drug Screening;Family;Gene Expression;Gene Expression Profile;Genes;Goals;Growth;Heterogeneity;Histone Deacetylase Inhibitor;I-kappa B Proteins;IKKepsilon;Immunofluorescence Immunologic;In Vitro;Invaded;Laboratories;Libraries;Lymphoid;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Mammary Neoplasms;Mediating;Molecular Structure;Multiple Myeloma;Mutation;NF-kappa B;NF-kappaB-inducing kinase;Neoplasm Metastasis;Nuclear;Outcome;Output;Pathogenesis;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phase II Clinical Trials;Phenotype;Phosphorylation;Population;Predisposition;Process;Proliferating;Property;Proteins;Refractory;Relapse;Research;Resistance;Role;Signal Pathway;Signal Transduction;Solid Neoplasm;Specificity;TNFRSF5 gene;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Woman;Work;cancer cell;cancer survival;chemotherapy;cytokine;design;development of lymphoid malignancy;effective therapy;extracellular;genetic manipulation;genetic signature;improved;inhibitor;insight;malignant breast neoplasm;mimetics;mouse model;multicatalytic endopeptidase complex;neoplastic cell;novel;ovarian neoplasm;overexpression;p65;pharmacologic;preclinical development;prognostic;prostate cancer cell;relapse prevention;response;small hairpin RNA;synergism;taxane;therapeutic target;transcription factor;translational approach;tumor;tumor initiation Nuclear Factor-kappaB in Ovarian Cancer n/a NCI 10926118 1ZIABC011054-16 1 ZIA BC 11054 16 9692487 "ANNUNZIATA, CHRISTINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 979598 NCI The NF-kB pathway promotes survival of cancer cells. My research in ovarian cancer began with characterizing the activation state and biological relevance of NF-kB in this disease. The NF-kB family of transcription factors is ubiquitously expressed. NF-kB signaling has been implicated in ovarian cancer but the significance and mechanism of NF-kB signaling in ovarian cancer is unknown. There is precedent to propose that NF-kB is a critical signaling mechanism in cancer. I initially hypothesized that the NF-kB pathway is over-activated in ovarian cancers with more aggressive behavior. The NF-kB pathway was implicated in ovarian cancer proliferation and cytokine secretion in vitro and contributed to chemoresistance of ovarian cancer cell lines. I therefore sought to determine the expression patterns and prognostic associations of NF-kB pathway proteins in primary ovarian cancer tissues. I demonstrated that overexpression of the NF-kB subunit p50 at diagnosis conveyed poor outcome in these patients. The biological relevance of NF-kB in ovarian cancer was established in my laboratory. Having demonstrated the coordinate presence of NF-kB machinery in ovarian cancers I sought to modulate its activity. Inhibitors of NF-kB (IkBs) are tagged for degradation through the proteasome upon specific inducible phosphorylation by IkB kinases (IKKs). Therefore targeted inhibition of IKKs could isolate NF-kB as a mechanism for ovarian cancer pathogenesis. A subset of ovarian cancer cell lines was affected by inhibition of IKKb in properties of growth adhesion invasion and cytokine secretion. I developed a gene expression signature of IKKb signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKKb. This signature gave insight into the results of NF-kB in ovarian cancer based on known functions of the ovarian cancer-specific target genes and allowed me to probe established ovarian cancer databases in order to estimate the relative impact of NF-kB signaling on the survival of women with ovarian cancer. Higher NF-kB activity conveyed a worse outcome suggesting that modulation of IKKb might benefit patients whose tumors showed elevated target gene expression. A key discovery from this work was the tissue specificity of NF-kB signaling. The 9-gene signature experimentally defined in ovarian cancer was completely different from the 11 genes I previously identified in multiple myeloma. The overall goal of this project is to dissect the molecular structure of NF-kB signaling in ovarian cancer with the intent to develop biomarkers of dependence on NF-kB and novel points of therapeutic intervention. We completed two shRNA library screens one in combination with an inhibitor of IKKbeta and another in combination with shRNA against IKKepsilon. These studies identified novel interactions between the NF-kB pathway in ovarian cancer. In combination with IKKbeta we found caspase 8 to be cooperative in protecting the cells from necroptosis. This work continues with designing a translational strategy for improving clinical outcome of women with caspase 8-deficient cancers. We plan to target the necroptosis pathway therapeutically to bypass the defective apoptosis that mediates resistance to standard chemotherapy regimens. In a related avenue we continue to study NF-kB signaling in ovarian cancer tumor-initiating cells. We observed by immunofluorescence that classical NF-kB appeared to be active in only a sub-population of the cultures at any given time based on the presence of NF-kB p65 in the nucleus. Elevated classical NF-kB signaling has been observed in tumor-initiating cells (TICs) of prostate breast and ovarian tumors but there are limited studies examining alternative NF-kB signaling. Both classical and alternative signaling cascades are required for maintenance and promotion of breast cancer TICs. The classical and alternative NF-kB pathways can regulate each other and integrate with other signaling pathways for fine-tuning functional outputs. Thus the diverse and complex roles of NF-kB suggest this transcription factor family regulates cellular functions in a context dependent manner and may be a key factor in maintaining heterogeneity. We are currently testing the hypothesis that classical and alternative NF-kB pathways support distinct subpopulations of ovarian cancer tumor-initiating spheroids that collaborate to populate secondary tumors following chemotherapy. Our recent results suggest that NF-kB supports the TIC phenotype and functional outputs of NF-kB are responsible for proliferation chemoresistance differentiation multipotency. A better understanding of the biology underlying NF-kB signaling in TIC and non-TIC populations of tumor cells will guide the design of more effective therapies to overcome chemoresistance prevent relapse and improve survival of women with ovarian cancer. From a therapeutic standpoint we previously completed a phase 2 clinical trial using the SMAC mimetic birinapant - that can target NF-kB signaling via inhibition of IAP proteins - in women with relapsed and refractory ovarian cancer. There were no clinical responses. Therefore we completed a matrix drug screen testing 2000 compounds in combination with birinapant in order to identify synergistic combinations to move to the clinic. We identified drug classes that met the criteria for synergy and are in the process of testing these in mouse models. Ongoing work is testing the combination of SMAC mimetic with either HDAC inhibitor or Taxane chemotherapy in vitro and in mouse models. Three clinical trials are currently under development from this preclinical work. 979598 +No NIH Category available Affect;American;Animal Model;Animals;Area;Binding;Binding Proteins;Cancer Etiology;Cancer cell line;Cell Surface Receptors;Cells;Clear Cell;Clear cell renal cell carcinoma;Clinical;Code;Cutaneous;Cyst;Cystic kidney;Cytoplasm;Development;Disease;Evaluation;Family;Folliculin;Foundations;Frameshift Mutation;Genes;Germ-Line Mutation;Growth Factor;HGF gene;Hereditary Neoplastic Syndromes;Hereditary Papillary Renal Carcinoma;Histology;Human;Hybrids;Hyperplasia;In Vitro;Inherited;Kidney;Kidney Neoplasms;Knockout Mice;Loss of Heterozygosity;Lung;MET Gene Mutation;MET Oncogene;MET gene;Modeling;Molecular;Mus;Mutation;New Agents;Nonsense Mutation;Oncogenes;Oxyphil Cells;Papillary;Pathway interactions;Patients;Phenotype;Phosphorylation;Protein Truncation;Proteins;Renal Cell Carcinoma;Renal carcinoma;Risk;Role;Sampling;Sirolimus;Somatic Mutation;Specimen;Syndrome;Testing;Therapeutic;Tissues;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tyrosine Kinase Domain;VHL gene;Work;cancer type;in vitro Model;in vivo;kindred;loss of function;novel;patient subsets;receptor;targeted agent;targeted treatment;tumor Molecular Therapeutics of Kidney Cancer: MET Gene and BHD Gene n/a NCI 10926117 1ZIABC011043-16 1 ZIA BC 11043 16 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 953880 NCI Molecular Therapeutics of Kidney Cancer-MET Gene and BHD Gene: Understanding the genes that cause kidney cancer provides the opportunity to develop approaches for molecular therapeutics for this disease. We have identified 3 genes that cause cancer of the kidney: the VHL gene (clear cell renal cell carcinoma); the c-Met gene (papillary type 1 renal carcinoma); and the BHD gene (chromophobe renal carcinoma). Targeting the MET Gene - Type 1 Papillary Kidney Cancer: We have found activating mutations of the MET gene in the germline of patients with Hereditary Papillary Renal Cell Carcinoma (HPRC) as well as in a subset of tumors from patients with sporadic type 1 papillary kidney cnacer Studies are underway to target the c-Met type 1 papillary kidney cancer gene pathway in papillary kidney cancer. The Met gene codes for a cell surface receptor for a systemically circulating growth factor hepatocyte growth factor (HGF). The germline mutations identified in the HPRC kindreds and somatic mutations of the c-Met oncogene in sporadic type 1 papillary renal carcinoma are located in the tyrosine kinase domain of the MET gene and are predicted to activate this receptor. In-vitro and in-vivo studies are underway to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of type 1 papillary renal carcinoma. Targeting the BHD Gene - Chromophobe Kidney Cancer: The BHD gene is the gene for the inherited form of chromophobe kidney cancer associated with Birt-Hogg-Dub syndrome. When we found the BHD gene it was a novel gene with no known function. Studies are currently underway to determine what type cancer gene the BHD gene how it functions normally and how damage to this gene leads to chromophobe renal carcinoma. We have identified mutations of the BHD gene in 94% of the BHD families tested. In order to determine what type of gene the BHD gene is we searched for mutation of the second copy of the gene in kidney tumor specimens from BHD patients. We found mutation (or loss of heterozygosity) of the second copy (the wild type copy) of the BHD gene in 70% of the tumor samples evaluated. These findings provided the evidence that the BHD gene is a loss of function tumor suppressor gene. When we found the BHD gene it was a novel gene with unknown function. In order to determine what the function of the BHD gene is we performed studies to determine which proteins bind to the BHD protein (called folliculin). We found that folliculin binds to a novel protein called FNIP1 (folliculin interacting protein) that FNIP1 binds to AMPK which is the cells main energy sensing protein. AMPK phosphorylates both FNIP1 and AMPK and FNIP phosphorylate folliculin. AMPK inhibits the function of MTOR through the TS pathway. We found that MTOR phosphorylates folliculin and that this phosphorylation is inhibited in-vitro by treatment with rapamycin. We have subsequently found that folliculin binds to a second protein FNIP2 which also binds AMPK and which is also phosphorylated by AMPK and that AMPK/FNIP2 phosphorylate folliculin. Folliculin and FNIP1 and FNIP2 co-localize in the cytoplasm and the binding of folliculin to FNIP1 and FNIP2 is in the carboxy terminus of the protein. The finding that the germline BHD mutations are predominantly mutations that are predicted to truncate the protein (frameshift or nonsense mutations) suggests that folliculin binding to FNIP1/FNIP2 is critical to folliculins tumor suppressor function. In order to develop a BHD animal model to further understand the effect of mutation of the BHD gene and to provide a model for evaluation of targeted therapeutics we developed a kidney specific BHD knockout mouse. In this model BHD -/- mice developed large cystic kidneys with areas of hyperplastic tissues. These animals develop renal insufficience and survive for only 30 days. In order to evaluate the effect of a targeted therapeutic approach for the BHD gene pathway the BHD -/- animals were treated with rapamycin. The rapamycin treated animals had a significant diminution in the kidney phenotype and their survival was doubled. We have developed a unique in-vitro model of a human kidney cancer cell line from a BHD patient and are evaluating multiple agents with target the BHD pathway in our in-vivo and in-vitro models. These studies provide the basis for the development of a targeted therapeutic approach for BHD-associated kidney cancer and for a subset of patients with sporadic non-inherited chromophobe kidney cancer. 953880 +No NIH Category available 2019-nCoV;Affect;American;Binding;COVID-19 treatment;Cancer Etiology;Cancer Model;Catalytic Domain;Cell Culture Techniques;Cell Line;Citric Acid Cycle;Clear Cell;Clear cell renal cell carcinoma;Clinical;Clinical Trials;Complex;Conventional (Clear Cell) Renal Cell Carcinoma;Cryoelectron Microscopy;Cutaneous Leiomyoma;Development;Disease;Enzymes;Family;Foundations;Fumarate Hydratase;Fumarates;Geldanamycin Analogue;Genes;Genetic Transcription;Genome;Goals;Growth;Heat-Shock Proteins 90;Hereditary Leiomyomatosis and Renal Cell Cancer;Hereditary Neoplastic Syndromes;Histology;Human;Hypoxia;Hypoxia Inducible Factor;In Vitro;Individual;Inherited;Iron;Kidney Neoplasms;Ligation;Loss of Heterozygosity;MET gene;Malignant Neoplasms;Mediating;Metal Binding Site;Metals;Modeling;Molecular;Mutate;Mutation;New Agents;Oncogenes;Papillary;Pathway interactions;Patients;Platelet-Derived Growth Factor;Process;Procollagen-Proline Dioxygenase;Proteins;RNA-Directed RNA Polymerase;Renal Cell Carcinoma;Renal carcinoma;Risk;Role;SARS-CoV-2 antiviral;SARS-CoV-2 inhibitor;Scientist;Site;Small Interfering RNA;Stains;Structure;Sulfur;System;Therapeutic;Transforming Growth Factor alpha;Translations;Tumor Tissue;Ubiquitin;Urologic Oncology;Uterine Fibroids;VHL gene;VHL protein;Vascular Endothelial Growth Factors;Viral;Von Hippel-Lindau Syndrome;Work;Zinc;beta catenin;cancer type;cofactor;elongin B;elongin C;helicase;in vitro Model;in vivo;novel;oxidation;prevent;receptor;targeted agent;targeted treatment;tempol;transcription factor;tumor Molecular Therapeutics of Kidney Cancer: VHL Gene and Fumarate Hydratase Gene n/a NCI 10926116 1ZIABC011038-16 1 ZIA BC 11038 16 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2861642 NCI Molecular Therapeutics of Kidney Cancer-VHL Gene and Fumarate Hydratase Gene: Understanding the genes that cause kidney cancer provides the opportunity to develop approaches for molecular therapeutics for this disease. We have identified 3 genes that cause cancer of the kidney: the VHL gene (clear cell renal cell carcinoma); the c-Met gene (papillary type 1 renal carcinoma); and the BHD gene (chromophobe renal carcinoma). Targeting the VHL Clear Cell Kidney Cancer Gene Pathway: Urologic Oncology Branch scientists are studying intensively how damage (mutation) to the VHL gene leads to the manifestations in VHL and sporadic renal carcinoma patients. Recently it is has been shown that the VHL protein forms a complex with other proteins including elongin C and B and the CUL-2 protein and this complex targets the alpha subunit of hypoxia inducible factors (HIF1-alpha and HIF2-alpha) for ubiquitin-mediated degradation. This is a hypoxia-mediated process normally i.e. under hypoxic conditions HIF is not degraded by the VHL complex. HIF is a transcription factor that regulates the transcription of a number of downstream genes important for cancer such as VEGF Glut 1 TGF-alpha and PDGF. When the VHL gene is mutated in the germline of VHL patients or in tumor tissue from patients with clear cell renal carcinoma the HIFs cannot be degraded and the result is the over-transcription of VEGF Glut1 TGF-alpha and PDGF. One approach to evaluating the role of agents targeting the VHL pathway in VHL and clear cell renal carcinoma is to determine the activity of agents which block the VEGF and TGF-alpha/EGFr pathways in-vitro and in-vivo. Another approach for molecular therapeutics of clear cell RCC is by use of agents such as geldanamycin analogues which disrupt the binding of HIF to HSP-90. In-vitro studies have shown that the 17AAG geldanamycin analogues can degrade HIF even in VHL -/- cell lines. In-vitro and in-vivo studies are underway in kidney cancer models that we have developed from human material to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of clear cell kidney cancer. Clinical trials evaluating the role of geldanamycin analogues as well as agents which target the VEGF/EGFr receptors and other parts of the VHL pathway are currently in progress. Targeting the Fumarate Hydratase Gene - Type 2 Papillary Kidney Cancer: The Krebs cycle enzyme fumarate hydratase (FH) is the gene for Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). HLRCC patients are at risk for the development of cutaneous and uterine leiomyomas as well as a very aggressive form of type 2 papillary kidney cancer. We have found mutations of the FH gene in the germline of 95% of our HLRCC families and loss of heterozygosity of the FH gene in HLRCC-associated kidney cancer. In order to understand how mutation of a Krebs cycle enzyme could cause kidney cancer we stained HLRCC-associated kidney tumors for the presence of hypoxia induced factor 1-alpha (HIF1-alpha) and hypoxia induced factor 2-alpha (HIF2-alpha). We found both HIF1-alpha and HIF2-alpha to be elevated in the HLRCC kidney tumors. We are developing novel in-vitro models from human tumors and evaluating growth in in-vitro and in-vivo systems. In in-vitro models we found that when fumarate hydratase was inactivated (with SiRNA) fumarate increased and the increase in fumarate inhibited prolyl hydroxylase. The inhibition of prolyl hydroxylase prevented normoxic VHL-mediated HIF degradation providing a VHL-independent mechanism for dysregulation of HIF degradation in HLRCC kidney cancer. These studies provided the rationale for the development of a targeted therapeutic approach for the treatment of HLRCC-associated kidney cancer. In-vitro and in-vivo studies are underway to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of HLRCC-associated as well as sporadic type 2 papillary kidney cancer. Based on our work targeting iron sulfur clusters in order to inhibit HIF2 translation in VHL-deficient renal cell carcinoma we began to examine Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase with T. Rouault. SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp nsp12 ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly potently inhibited the RdRp and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19. We have shown that tempol will be an excellent anti-viral for SARS-CoV-2. 2861642 +No NIH Category available Adrenal Gland Neoplasms;Adrenal Glands;Affect;American;Bilateral;Blood Tests;Brain Neoplasms;Chromosome 17;Chromosome 3;Chromosome 7;Chromosome Arm;Chromosome Mapping;Clear Cell;Clinical;Clinical Management;Clinical Research;Clinical Trials;Complex;Conventional (Clear Cell) Renal Cell Carcinoma;Cytogenetics;Defect;Detection;Development;Diagnosis;Disease;Ear Neoplasms;Event;Eye;Family;Family Study;Foundations;Fumarate Hydratase;Gene Mutation;Genes;Genetic;Genetic study;Genomics;Genotype;Germ-Line Mutation;Hereditary Leiomyomatosis and Renal Cell Cancer;Hereditary Papillary Renal Carcinoma;Histology;Hybrids;Iceland;Individual;Inherited;Kidney;Kidney Neoplasms;Laboratories;Labyrinth;Leiomyomatosis;MET gene;Malignant Neoplasms;Methods;Methylation;Molecular Genetics;Mutation;Mutation Detection;New Agents;Oncogenes;Oxyphil Cells;Pancreas;Papillary;Pathology;Pathway interactions;Patients;Pattern;Phenotype;Pheochromocytoma;Proto-Oncogenes;Renal carcinoma;Reporting;Research Personnel;Risk;Running;Series;Somatic Mutation;Spinal Neoplasms;Surgical Management;Syndrome;Tumor Suppressor Genes;Tyrosine Kinase Domain;United States National Institutes of Health;VHL gene;VHL mutation;Vertebral column;Von Hippel-Lindau Syndrome;Work;cancer type;clinical diagnosis;design;genetic linkage analysis;genetic testing;improved;kindred;member;minimally invasive;new therapeutic target;novel;pancreatic neoplasm;preclinical study;targeted treatment;tumor;working group Clinical Studies of the Molecular Genetic Basis of Kidney Cancer n/a NCI 10926113 1ZIABC011028-16 1 ZIA BC 11028 16 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1907762 NCI Our work has shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer each with a different histology a different clinical course responding differently to therapy and each caused by a different gene. Our approach has been to identify the genes that cause kidney cancer in order to provide the foundation targeted therapeutic approaches to this disease. In order to identify the genes that cause kidney cancer we have studied the inherited forms of cancer of the kidney. Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are a number of different types of inherited kidney cancer including: 1) von Hippel Lindau (VHL) the inherited form of clear cell renal carcinoma; 2) Hereditary Papillary Renal Carcinoma (HPRC) hereditary Type 1 kidney cancer 3) Birt Hogg Dub (BHD) the inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC) type 2 papillary renal carcinoma. In order to develop new methods for treatment of patients with sporadic as well as familial kidney cancer we established an NIH kidney cancer working group involving clinicians and investigators from 29 different laboratories and branch from 9 different NIH Institutes. Individuals affected with von Hippel Lindau (VHL) are at risk for the development of bilateral multifocal clear cell kidney cancer as well as tumors in the brain spine eyes pancreas adrenal gland and inner ear. By studying VHL families we were able to perform genetic linkage analysis to localize and subsequently identify the VHL gene on chromosome 3. We have identified the VHL gene mutation in the germline of 246/246 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating novel minimally invasive forms of therapy for kidney and adrenal tumors in VHL. We have described the surgical management of VHL kidney cancers as well as VHL pheochromocytoma pancreas tumors ear tumors and brain and spine tumors. We currently have two clinical trials in progress targeting the VHL gene pathway in patients affected with VHL. We have shown that the VHL gene is also the gene for the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). In a series of studies we have identified mutation/methylation of the VHL gene in up to 92% of tumors from patients with sporadic (non-inherited) clear cell kidney cancer. Study of the VHL gene pathway has provided the foundation for the development of targeted therapeutics for patients with both clear cell kidney cancer as well as von Hippel-Lindau. We currently are conducting a clinical trial of an agent which targets the VHL pathway in patients with advanced clear cell kidney cancer. In 1994 we described a novel form of inherited kidney cancer Hereditary Papillary Renal Carcinoma (HPRC). HPRC is an inherited cancer syndrome in which affected individuals are at risk for the formation of multifocal bilateral type 1 papillary kidney cancer. In order to identify the gene for HPRC we studied families with this rare inherited cancer syndrome to determine which individuals had the kidney cancers and which did not. Linkage analysis performed in the families to localized the gene to the long arm of chromosome 7. The proto-oncogene MET was subsequently identified as the HPRC gene. We have identified activating mutations in the tyrosine kinase domain of the MET gene in the germline of the HPRC families as well as in a subset of tumors from patients with sporadic non-inherited type 1 papillary kidney cancer. These findings provided the foundation for the development of a targeted therapeutic approach to the treatment of patients affected with HPRC as well as for patients with sporadic non-hereditary papillary kidney cancer. We are currently conducting a clinical trial with an agent which targets the MET gene pathway in patients with Hereditary Papillary Renal Carcinoma and sporadic papillary kidney cancer. We also described another novel type of inherited kidney cancer associated with Birt Hogg Dub (BHD). Birt-Hogg-Dub patients are at risk for the development of bilateral multifocal chromophobe and hybrid/oncocytic kidney cancer. By studying BHD families and we were able to localize and subsequently identify the BHD gene on chromosome 17. We have detected BHD gene mutations in over 95% of BHD families and are now able to 1) make the clinical diagnose of BHD with a blood test as well as determine which at-risk members of BHD families are affected with BHD. We have defined the kidney cancer phenotype of BHD and have described the surgical management of BHD-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the BHD pathway in patients with BHD-associated kidney cancer. In addition we have described another inherited form of papillary kidney cancer which is now called Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). Affected individuals in HLRCC families are at risk for the development of a very aggressive form of type 2 papillary renal carcinoma. We have reported the identification of germline mutations of the fumarate hydratase gene (FH) in the germline of over 90% of North American HLRCC kindreds. We have described the HLRCC kidney cancer phenotype and the method of clinical management of HLRCC-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the FH pathway in patients with HLRCC-associated kidney cancer. Kidney Cancer Genetic Testing The identification of germline VHL c-Met BHD and FH mutations makes possible pre-symptomatic genetic testing for at-risk individuals in VHL HPRC BHD and HLRCC families and paves the way for additional studies to understand the pathology of these diseases and for the design of effective new therapies targeted to the specific defects brought about by mutation of the these disease genes. We have recently demonstrated improved detection of germline mutations in the von Hippel Lindau disease tumor suppressor gene. We can now detect mutations in nearly 100% of families. We have additionally detected a new phenotype associated with complete deletion of the VHL gene. We are intensively studying the somatic events (genomic cytogenetic) associated with the development of tumors in patients with different types of germline mutations. The ability to detect germline as well as somatic mutations of the VHL Met BHD and FH gene may provide substantial opportunity for improvements in the diagnosis of both hereditary as well as sporadic forms of kidney cancer. Finally we are studying the genetic basis of Familial Renal Carcinoma (FRC). FRC is a term that describes the kidney that runs in families that are not part of previously described hereditary kidney cancer syndromes. Studies in Iceland have suggested that nearly 60% of kidney cancer may be genetic. We suspect that there is a complex genetic pattern to FRC and we are currently evaluating FRC kindreds in order to 1) describe this clinical syndrome and 2) to identify its genetic basis. 1907762 +No NIH Category available Binding;Biological;Biological Models;Cells;Chemicals;Chromatin;Chromatin Structure;Computing Methodologies;Coupling;DNA;DNA Structure;DNA-Directed RNA Polymerase;Elements;Enhancers;Enterobacteria phage P1 Cre recombinase;Enzymes;Episome;Excision;Exposure to;Fiber;Gene Expression;Gene Expression Regulation;Generations;Genes;Genetic;Genetic Processes;Genetic Transcription;Genome;Genome Mappings;Genomics;Human Herpesvirus 4;In Vitro;Knowledge;Left;Literature;Malignant Neoplasms;Maps;Measures;Mechanics;Medical;Metallothionein;Methods;Molecular Conformation;Molecular Machines;Monitor;Nucleic Acid Binding;Oncogenes;Output;Pathologic;Pathologic Processes;Penetration;Physics;Physiologic pulse;Physiological;Physiological Processes;Potassium Permanganate;Process;Pyrimidines;RNA Binding;Reaction;Regulator Genes;Regulatory Element;Replication Origin;Resolution;Role;SS DNA BP;Site;Solvents;Specificity;Stress;Structure;Superhelical DNA;Testing;Topoisomerase;Topoisomerase II;Topoisomerase Inhibitors;Torque;Transcription Initiation Site;Ultraviolet Rays;Variant;Work;Z-Form DNA;Zinc;base;c-myc Genes;chemotherapeutic agent;crosslink;density;druggable target;endonuclease;enzyme activity;experimental study;genome-wide;improved;in vivo;intercalation;nanopore;novel;novel strategies;permanganate;preference;preservation;programs;promoter;recruit;single molecule;transcription factor;transmission process;virtual;whole genome The genome-wide function of supercoiling and alternative DNA conformations n/a NCI 10926112 1ZIABC011011-16 1 ZIA BC 11011 16 9692465 "LEVENS, DAVID L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1149408 NCI First to establish that our hypothesis that transcriptionally generated DNA supercoiling regulates the activity of particular elements we prepared a model system comprised of an EBV-based episome where the FUSE element was sandwiched between divergent metallothionein promoters. By adding zinc to defined levels we could adjust the level of ongoing transcription and control the forces propagated onto FUSE. Upon exceeding a key threshold the FUSE element would become single-stranded recruit the specific single stranded DNA binding protein FBP and reprogram the output of the metallothionein promoters. Using Cre-recombinase to excise precisely defined DNA circles allowed us to monitor directly the accompanying changes in DNA topology validating this novel mechanism as potentially general principle to confer precise control on activated promoters. We are now developing experimental and analytical approaches to map the level and distribution of supercoiling forces on a genome-wide basis. to accomplish this we are exploiting the known preference for psoralen to intercalate into negatively supercoiled DNA. Because psoralen readily penetrates living cells and can be cross-linked to DNA by a pulse of UV light by comparing the relative hybridization of cross-linked to uncross-linked DNA to high density genomic tiling arrays we can map the genome-wide distribution of psoralen. By including proper controls to account for ongoing transcription chromatin structure and by eliminating the influence of replication (by using properly synchronized cells) we can infer the distribution of supercoils. Because high levels of supercoiling promotes the formation of non-B DNA structures we have also devised a method to map the distribution of non-B DNA across the genome. Virtually any of the non-B DNA structures formed in vitro result in the exposure of DNA bases to the local solvent (at least the the junctions between B and non-B DNA) potassium permanganate can be used as a chemical probe of unpaired bases. Because permanganate rapidly permeates cells following a short exposure to this chemical when DNA is extracted the permanganate oxidized pyrimidines in stabilize foci of non-B DNA and preserve sensitivity to cleavage by single strand specific endonucleases. Following cleavage with such endonucleases these ends can be marked and recovered and analyzed by sequencing. Application of this approach reveals enrichment for permanganate sensitive sites in sequences computationally predicted to 1)be sensitive to supercoil induced duplex destabilization (SIDD); 2) to be Z-DNA (left handed double helix; or 3) to form G-quadraplex structures. Application of the methods that we have developed reveals the genome to be extraordinarily dynamic with changes in structure associated with particular gene sets and particular physiological and pathological processes. The same methods will allow us to associate topoisomerase activity with changes in DNA structure and gene activity. We exploring variations on this method that should improve its efficiency and approach the examination of DNA structure and topology at the single cell level. We are currently developing a high-resolution method that concurrently interrogates DNA structure and topology across a whole genome to illustrate the interplay between genetic transactions and DNA physics.These studies will likely shed new light on how chemotherapeutic agents that alter DNA conformation and topology may be improved to increase efficacy and improve specificity. Topoisomerases are enzymes that control the distribution and level of supercoiling and torsional stress in DNA fibers. We have recently commenced the combination of Oxford Nanopore long read sequencing with the in vivo use of permanganate and other agents that react with non-B DNAs to map alternative structures on chromosomal DNA strands without the need for strand fragmentation or PCR. These results will allow us to study the linkage of non-B DNA structure with associating promoters and enhancers or replication origins to get a better perspective on the mechanics of genomic processes. We have begun to analyze where type I and type II topoisomerase act across the genome to assess their relationship to gene activity and DNA structure. We are using ChIP to map sites of topoisomerase 1 binding across the genome to overlay the sites of top 1 binding on top maps of supercoiling and alternative DNA structures. We have discovered that there is tight coupling between RNA polymerase recruitment and topoisomerase action at the promoters of active genes. Moreover topoisomerase 1 is used as a component of the transcription machinery independently of its enzymatic activity. In fact topoisomerase 1 activity is held in check until the topoisomerase is recruited beyond 1 kilobase downstream of the transcription start site. Now we are exploring the ability of other specific or general transcription factors to activate or inhibit topoisomerase activity. Because MYC activity serves to sustain the expression of all genes but especially those that are highly expressed the best MYC targets are also those most dependent on topoisomerase. Because of this MYC was tested to see if it interacted with and/or activates topoisomerases. Focusing on top 1 we found that MYC both binds and activates top 1. Current experiments are determining which features of each molecule support this interaction and how top 1 activity is augmented. Additional studies are testing the hypothesis that FUBP1 has intrinsic or augments other toposiomerase activities. Because the FUBP's bind nucleic acids through KH-motifs that are often associated with RNA-binding we are exploring whether the FUBPs influence the generation or removal of R-loops and if so the relationship between R-loops and gene expression at FUBP targets. Computational methods are being developed to enable the study in single molecules in vivo of the relationship between DNA topology and conformation with ongoing transcription and replication. 1149408 +No NIH Category available Age;Behavior;Bioinformatics;Biological;Biology;Cancer Biology;Cells;Clinical;Complex;DNA;DNA copy number;Diagnosis;Genes;Genetic Transcription;Genome;Genomics;Goals;Image;Individual;Investigation;Lead;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Messenger RNA;Modeling;Morbidity - disease rate;Multiomic Data;Mutation;Outcome;Pathway interactions;Patients;Phenotype;Proteins;Proteome;Proteomics;Rhabdomyosarcoma;Systems Biology;Transcriptional Regulation;biological systems;cell growth;convolutional neural network;deep learning;dynamic system;epigenetic profiling;genome wide methylation;genome-wide;high risk;improved;mathematical model;methylation pattern;precision medicine;protein expression;single-cell RNA sequencing;transcriptomics;tumor Bioinformatics Machine Learning Systems Biology of Cancers n/a NCI 10926108 1ZIABC011002-16 1 ZIA BC 11002 16 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 922580 NCI The goals of this project are: 1) Integration of mathematical modeling and bioinformatics to decipher the complex biology of pediatric cancers; 2) Model how DNA copy number alters expression of RNA; 3) Model how global methylation profiles alter expression of RNA; 4) Model how DNA copy number alters expression of protein; 5) Model how global methylation profiles alter expression of protein; 6) Model interactions of DNA copy number messenger RNA (mRNA) and protein with the cancer phenotype; 7) Investigate pathways activated or suppressed in pediatric cancers; 8) Model and predict how can mutations lead to alteration of function and pathways; 9) Epigenetic profiling of rhabdomyosarcoma; 10) single-cell RNAseq and spatial proteomics and transcriptomics; 11) Perform machine learning and convolutional neural networks of H&E images to predict mutations and biological behavior of cancer. It has become increasingly clear that individual genes do not act in isolation within a cell but acts in concert with other genes within pathways. In addition many genes within a pathway are redundant such that many genes can perform a particular function and conversely a single gene can have many functions depending on its cellular context. High throughput genome wide approaches allow the investigation of the complexity of cell as a whole. The integration of genomics and proteomics with functional analysis will be referred to as systems biology. My lab has utilized these systematic approaches to understand more clearly the biology of high-risk pediatric cancers. Systems biology seeks to integrate high-throughput biological studies to understand how the whole biological systems function. By studying the relationships and interactions between various parts of the biological system (NB in our case) including DNA copy number methylation patterns mRNA and protein levels cell growth clinical parameters (age stage and outcome (survival)) it is hoped that eventually this will enable a more complete understanding of pediatric cancers which will lead to improved survival of patients with minimal long term morbidity. The genome and proteome of a cell is a complex interrelated dynamic system. DNA copy number can impact the mRNA mRNA is transcribed into proteins and proteins control transcription by its action on DNA and mRNA and proteins. We are using deep learning with convolutional neural networks to identify tumor features in H&E images that are associated with multi-omic data including DNA mRNA and protein alterations to increase the understanding of the behavior of cancers predict diagnosis and outcome and facilitate precision medicine. 922580 +No NIH Category available Age;Alveolar;Amino Acids;Antibodies;Antibody-drug conjugates;Apert-Crouzon syndrome;Biology;Cancer Biology;Childhood Soft Tissue Sarcoma;Chromosomal translocation;Chromosome 13;Classification;Clinical Trials Design;Code;Colon Carcinoma;Dedications;Development;Diagnosis;Disease;Embryonal Rhabdomyosarcoma;Endometrial Carcinoma;Epigenetic Process;Event;FGFR1 gene;FGFR2 gene;FGFR3 gene;FGFR4 gene;FOXO1A gene;Fibroblast Growth Factor Receptor Family Gene;Fibroblast Growth Factor Receptors;Gene Expression Profiling;Gene Family;Genes;Genetic Polymorphism;Genome;Genomic Imprinting;Genomics;Germ-Line Mutation;Glioblastoma;Goals;Growth;Growth Factor Receptor Genes;Histologic;Human;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Molecular;Monoclonal Antibodies;Mutate;Mutation;Natural Products;Oncogenes;Oncogenic;Outcome;PAX3 gene;Pathway interactions;Patients;Pattern;Pfeiffer Syndrome;Phenotype;Process;Prognosis;Proteins;Publishing;Reagent;Receptor Protein-Tyrosine Kinases;Reporting;Rhabdomyosarcoma;Site;Somatic Mutation;Testing;Tumor Biology;angiogenesis;cell motility;chimeric antigen receptor T cells;diagnostic biomarker;efficacy testing;epigenome;fusion gene;hypochondroplasia;improved;in vivo;inhibiting antibody;inhibitor;insight;interest;mRNA Expression;malignant breast neoplasm;member;mouse model;neoplastic cell;new therapeutic target;novel strategies;older patient;overexpression;paralogous gene;sarcoma;small molecule inhibitor;targeted treatment;tumor;tumor progression Targeting FGFR4 RAS and PAX3-FOXO1 gene in Rhabdomyosarcoma n/a NCI 10926107 1ZIABC010999-16 1 ZIA BC 10999 16 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1107095 NCI Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma typically classified as either alveolar (ARMS) or embryonal histological subtypes. ARMS is observed in older patients and is associated with a chromosomal translocation creating a fusion gene involving FOXO1A on chromosome 13 and members of the PAX gene family. Embryonal RMS is characterized by a younger age at diagnosis loss of heterozygosity and altered patterns of genomic imprinting1. An important determinant of poor long term survival for all RMS histological subtypes is the presence of metastatic disease. Factors contributing to tumor progression and metastatic disease are not well understood. Analysis of gene expression patterns have led to improved accuracy of tumor identification and advances in sarcoma biology particularly new insights into possible mechanisms of metastatic regulators. We and others have previously reported that FGFR4 a receptor tyrosine kinase (RTK) member of the fibroblast growth factor receptor (FGFR) gene family is highly expressed in RMS and mRNA expression correlates with protein levels. These observations suggest that FGFR4 could be a tumor specific diagnostic marker and/or a determinant of tumor biology. In other human cancers the presence of a common polymorphism in the coding region (FGFR4 G388R) is associated with increased tumor cell motility and prognosis in patients with sarcomas colon or breast cancer. The FGFR genes are of great interest in cancer biology because they regulate essential processes including cellular survival motility development and angiogenesis. Comparison of the FGFR coding regions indicates segments of high amino acid conservation in FGFR1 FGFR2 FGFR3 and FGFR4. Germline mutations in these paralogs have been described for several rare highly penetrant Medelian disorders including Crouzon syndrome Pfeiffer syndrome and hypochondroplasia. Somatic mutations at the same sites of paralologs have been observed within the FGFR TK domains in glioblastoma multiforme breast cancer lung cancer and endometrial carcinoma. These observations lead us to hypothesize that FGFR4 activation perhaps by somatic mutational events could be critical to the oncogenic process in RMS sarcomas or other cancers. Furthermore FGFR4 over activity could be associated with advanced stage disease and poor outcome. We have now published a manuscript that confirms that activating FGFR4 mutations occur in 7.5% or RMS and that over expression is associated with a more aggressive phenotype. Our group has also recently performed a comprehensive genomic analysis of the rhabdomyosarcoma genome and found that RAS pathway genes are mutated in 50% of fusion negative rhabdomyosarcoma. Finally we are dedicating considerable efforts in characterizing the molecular epigentic and functional effects of the PAX3/7- FOXO1 fusion oncogene and developing novel strategies to target the epigenome of fusion positive rhabdomyosarcoma including a natural product screen. We are therefore developing new therapies targeting FGFR4 RAS and the fusion gene in rhabdomyosarcoma. 1107095 +No NIH Category available Adoptive Cell Transfers;Antigen Targeting;Antigens;BAY 54-9085;Biological Assay;CAR T cell therapy;CD276 gene;Calcitonin;Cell secretion;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Clinical Trials;Disease;Drug resistance;Epidermal Growth Factor Receptor;Epigenetic Process;European;Gefitinib;Glypican;Goals;Imatinib;Immunotherapy;Inherited;KDR gene;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of thyroid;Medicine;Methods;Modeling;Mutation;Neoplasm Metastasis;Neuroblastoma;Operative Surgical Procedures;Patients;Pharmacotherapy;Phase III Clinical Trials;Phosphotransferases;Protein Tyrosine Kinase;Proteins;Proto-Oncogenes;Resistance;Resistance development;Rhabdomyosarcoma;Signal Transduction;Solid Neoplasm;Survival Rate;T-Lymphocyte;Testing;Thyroidectomy;Tumor Antigens;Tyrosine Kinase Inhibitor;United States Food and Drug Administration;advanced disease;chimeric antigen receptor;chimeric antigen receptor T cells;clinically relevant;cytotoxicity;drug resistance development;exhaustion;exome;inhibitor;medullary thyroid carcinoma;neuroendocrine cancer;next generation sequencing;novel therapeutics;patient subsets;prevent;resistance mechanism;side effect;single-cell RNA sequencing;small molecule inhibitor;standard care;targeted treatment;therapy resistant;transcriptome;transcriptome sequencing Therapy Resistance Mechanisms for Cancer n/a NCI 10926106 1ZIABC010998-16 1 ZIA BC 10998 16 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 553548 NCI "We use a variety of next-generation sequencing methods including exome bulk RNAseq and single cell RNAseq as well as epigenetic analysis to identify mechanisms of resistance to small molecules inhibitors and adoptive cell therapies. Currently the gold standard treatment for these patients is thyroidectomy. The efficacy of surgery as a standalone treatment option is limited by the fact that many patients have been found to have metastatic disease upon initial presentation. Just under half of patients initially present with stage III or IV disease and are associated with 10-year survival rates of 71% and 21% respectively. Despite the availability of RET inhibitors 10% of patients develop metastases . Several tyrosine kinase inhibitors (TKIs) that target RET tyrosine kinase signaling have been evaluated for treatment of advanced MTC in recent years. Of the TKIs that reached phase III clinical trials (axitinib cabozantinib gefitinib imatinib motesanib sorafenib sunitinib and vandetanib) vandetanib and cabozantinib have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of advanced MTC. Along with targeting RET kinases vandetanib also targets EGFR and VEGFR kinases. Meanwhile cabozantinib targets RET c-MET and VEGFR kinases. However despite the promising results of vandetanib and cabozantinib in patients with advanced disease there are a subset of patients who develop drug resistance accompanied by adverse side effects and poor tolerability. This project aims to identify the genetic and epigenetic changes in MTC cells which results in development of resistance to different RET inhibitors. We will develop new therapies that may be synergistic and prevent or treat therapy resistance to small molecule inhibitors of RET. For mechanisms of resistance to adoptive cell therapies we focus on Chimeric antigen receptor (CAR) T cell therapies targeting single antigens. These have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs) limited T cell persistence and T cell exhaustion. We aim to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3) which were highly but heterogeneously expressed in neuroblastoma (NB). We use pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) termed P-COCC to simultaneously analyze protein and transcriptome expression of CAR T cells to identify high-activity CARs. We perform cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic ""OR"" CAR (BiCisCAR). We test if the BiCisCAR T cells demonstrate prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study aims to show that targeting multiple TAAs with BiCisCAR may overcome resistance to therapy due to heterogenous expression of target antigens in solid tumors to identify potent clinically relevant CARs against NB." 553548 +No NIH Category available Angiogenesis Inhibitors;Apoptosis Inhibitor;Azacitidine;Bone Marrow;Bone Marrow Transplantation;Cell Line;Cell Therapy;Cells;Collaborations;Cooperative Research and Development Agreement;DNA;DNA Methyltransferase Inhibitor;Disease;Division of Cancer Treatment and Diagnosis;Dysmyelopoietic Syndromes;Engraftment;Funding;Genome;Graft-Versus-Tumor Induction;Hematopoietic;Hematopoietic stem cells;Histocompatibility;Histone Deacetylase Inhibitor;In Vitro;Industry;Institution;Ionizing radiation;Licensing;MCL1 gene;Manuscripts;Minor;Modeling;Mus;NUP98 gene;Patients;Pharmacologic Substance;Phase I Clinical Trials;Pre-Clinical Model;Prediction of Response to Therapy;Preparation;Proteins;Publishing;Research Personnel;Role;Transgenes;Transgenic Mice;Transgenic Organisms;Transplantation;Xenograft Model;conditioning;cytopenia;effective therapy;efficacy evaluation;experimental study;human disease;improved;in vivo;inhibitor;mouse model;myelodysplastic anemia;novel;novel therapeutics;peripheral blood;pre-clinical;preclinical study;small molecule Pre-clinical Studies of Therapy for Myelodysplastic Syndrome n/a NCI 10926103 1ZIABC010983-16 1 ZIA BC 10983 16 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 617062 NCI Our initial studies used the DNA-methyltransferase inhibitor 5-azacytidine; some of these results have been published (Genome Res. 4:580-91 2014).However since our initial studies used transgenic mice effective treatment with 5-azacytidine could not replace the MDS bone marrow with completely normal (ie wildtype or WT) bone marrow since all of the bone marrow was transgenic. Therefore in order to distinguish improvement in peripheral blood cytopenia due to differentiation of the MDS clone from elimination of the MDS clone we have repeated the experiments using chimeric mice that have both WT and NHD13 bone marrow. Drs. Difillipantonio Doroshow and colleagues from the Division of Cancer Treatment and Diagnosis (DCTD) have developed two novel DNMT1 inhibitors both of which are in phase I clinical trials. In collaboration with Dr. Difillipantonio and colleagues we are now treating chimeric NHD13/WT mice with these compounds to assess efficacy in treatment of MDS. In addition we have refined our model to enable transplant of NHD13 MDS hematopoietic cells without using ionizing radiation as a conditioning agent. We have successfully engrafted WT mice with NHD13 BM by pre-treating the recipient mice with the Cdc42 inhibitor CASIN which leads to egress of the WT hematopoietic stem cells. A manuscript describing these studies as well as an unexpected finding that one of the two novel DNMT1 inhibitors was associated with specific CG transversions has recently been submitted. In addition to the experiments outlined above we have transferred NHD13 mice to colleagues at many academic institutions and have licensed NHD13 mice to industry for pre-clinical studies. These colleagues have treated NHD13 mice with a variety of agents including histone deacetylase inhibitors apoptosis inhibitors and angiogenesis inhibitors. One of these compounds (ACE-536 or luspatercept) was recently approved for treatment of anemic MDS patients by the FDA. We previously executed a CRADA with Tolero Pharmaceuticals who have provided us with funding to study the effects of alvocidib (a Cdk9/Mcl1 inhibitor) and DNMTi on NHD13 mice and cell lines. A manuscript describing the in vitro and in vivo results of these studies is now in preparation. 617062 +No NIH Category available 3' Untranslated Regions;ABCB1 gene;ABL1 gene;Acute leukemia;Age Months;Alleles;Animal Model;Apoptosis;B cell differentiation;B-Cell Acute Lymphoblastic Leukemia;B-Cell Leukemia;B-Lymphocytes;Binding;Blood;CRISPR screen;Candidate Disease Gene;Cell Line;Cells;Chemoresistance;Clinical;Collaborations;Complex;DHFR gene;DNA Resequencing;DNA biosynthesis;DNA replication fork;DNMT3a;Development;Epigenetic Process;Gene Dosage;Gene Expression Profile;Generations;Genes;Genetic;Genetically Engineered Mouse;Genets;Genomic DNA;Growth;Hematopoietic stem cells;Human;Hunger;Immunophenotyping;Impairment;In Vitro;Insertional Mutagenesis;Knock-in;Knock-out;Length;Leukemic Cell;Licensing Factor;Ligands;Loss of Heterozygosity;Lymphoblastic Leukemia;Lymphoma;Maintenance;Malignant Neoplasms;Manuscripts;Methotrexate;Methylation;Modeling;Molecular;Mouse Strains;Mus;Mutant Strains Mice;Mutate;Mutation;Myelogenous;NOTCH1 gene;NU/NU Mouse;NUP214 gene;NUP98 gene;Nature;PTPN1 gene;Pathway interactions;Patients;Pattern;Phenotype;Phosphotransferases;Preparation;Production;Proliferating;Proteins;Publishing;Recurrence;Reporting;Resistance;Sampling;T-Cell Leukemia;T-Lymphocyte;TAL1 gene;TCF3 gene;TOP1 gene;Thymocyte Development;Transgenes;Transgenic Mice;Tumor Suppressor Genes;Vincristine;acute T-cell lymphoblastic leukemia cell;cancer cell;cell type;exome sequencing;experimental study;follow-up;fusion gene;helicase;human disease;inhibitor;leukemia;leukemia/lymphoma;leukemic transformation;mutant;novel strategies;offspring;precursor cell;retroviral transduction;small hairpin RNA;stem cell self renewal;theories;thymocyte;whole genome Collaborative Pathways that Lead to Leukemia n/a NCI 10926102 1ZIABC010982-16 1 ZIA BC 10982 16 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 822748 NCI We crossed transgenic mice that express a IDH2 R140Q mutation with mice that express an NHD13 fusion; the offspring develop a form of early T cell precursor (ETP) leukemia that resembles the human disease in terms of clinical presentation immunophenotype gene expression profile and collaborative mutations. In terms of molecular mechanism the IDH2R140Q mutant mice produce the oncometabolite 2HG; consistent with overproduction of 2HG the leukemic cells show aberrant methylation of genes required for normal thymocyte development. Finally a specific inhibitor of mutant IDH2 (AG-221) inhibits the growth of these ETP cells in vitro. A manuscript describing these findings was published in FY2021 (PMID: 34321240) and a follow-up manuscript was published in FY2023 (PMID: 36330381). Mini-chromosome maintenance component 2 (Mcm2) is a DNA replication licensing factor that is part of the Mcm2-7 complex which functions as a DNA helicase unwinding genomic DNA at the replication fork. Not surprisingly homozygous deletion of Mcm2 is lethal. However insertion of a cre cassette into the 3' UTR of Mcm2 leads to 50% reduction in Mcm2 protein and cells with two copies of the cre knock-in allele express only 20-30% as much Mcm2 protein compared to wild-type cells. Despite the diminished Mcm2 protein levels mice with two copies of the Mcm2cre allele are born at normal Mendelian ratios are not growth-retarded and are indistinguishable from wild-type littermates at two months of age. Beginning at 2-3 months of age the mice become ill and invariably die from pre-T lymphoblastic leukemia/lymphoma (pre-T LBL). Copy number alteration (CNA) analysis reveals a pattern of gains and losses predominantly losses 10-1000 kb in length. Notably there is a recurrent constellation of losses including biallelic deletions of Pten Tcf3 (E2a) and Dnmt3a and mono-allelic deletions of the amino-terminus of Notch1. This constellation of cooperative deletions fits a model (supported by published experiments with Pten Tcf3 Dnmt3a) in which Dnmt3a deletion leads to increased stem cell self-renewal Tcf3 deletion blocks thymocyte differentiation Pten deletion leads to hyperproliferation and deletion of the amino terminus of Notch1 leads to ligand independent growth. All of these genes except TCF3 are frequently mutated in human T-ALL; NOTCH1 being the single gene most commonly mutated in human T-ALL. Although TCF3 is not frequently deleted in human T-ALL TCF3 is functionally inactivated by inappropriate expression of TAL1/SCL and LMO1/2 proteins (EMBO J 16:2408-19; Nature Immunol 1:138-44) in 25-50% of human T-ALL patients (Cancer Cell 1:75-87) underscoring the relevance of TCF3 inactivation in human T-ALL. Mice that express a NUP98::HOXD13 (NHD13) transgene develop myeloid T-cell and B-cell leukemia. Crossing the NHD13 transgene onto an Mcm2cre/cre background led to B-cell precursor (BCP) ALL in a subset of Mcm2cre/creNHD13+ mice. CNA analysis of these BCP-ALL revealed consistent deletions in Pax5 gains of a region bounded by Nup214 and Abl1 and bi-allelic loss of Ptpn1. The gains of Nup214 and Abl1 led to generation of a Nup214-Abl1 fusion gene similar to that seen in some human T-ALL and BCP-ALL patients. PTPN1 deletions have not been reported in human BCP-ALL however deletions of the closely related PTPN2 co-occur with NUP214-ABL1 fusions and PTPN2 was identified as a negative regulator of the NUP214-ABL1 kinase (Nat Genet 42:530-5 2010). This constellation of cooperative losses and gains fits a model in which the NHD13 transgene leads to increased stem cell self-renewal the Pax5 deletion leads to a block in B cell differentiation the Nup214-Abl1 fusion leads to hyperproliferation and the Ptpn1 deletion enforces hyperproliferation. Similar to the findings for T-ALL these genes and pathways have been highlighted as being important for human BCP-ALL (see review by Mullighan and Hunger Blood 125:3977-87). Overall this Mcm2 deficiency leads to a unique mutator phenotype characterized by copy number gains/losses of 50-1000 kb. A manuscript describing these findings was published in FY2020 (PMID: 31622281). In theory this mutator phenotype could be used to identify constellations of mutations in other forms of cancer if they lived for 3 months. if Mcm2cre/cre mice could be protected from the highly penetrant pre-T LBL we might uncover additional malignancies triggered by the Mcm2 deficiency. Therefore we crossed Mcm2cre/cre mice onto a nu/nu background and demonstrated that these mice are indeed protected from development of pre-T LBL living a median of 8 months as opposed to 3 months. However the vast majority of Mcm2cre/cre:nu/nu mice develop B cell ALL beginning at approximately 9 months of age; a manuscript describing these findings was published in FY 2023 (PMID: 35920299). Given the frequent focal homozygous deletions of Ptpn1 in mice that developed BCP-ALL in the context of an NHD13 fusion we the NHD13 transgene onto a Ptpn1 knockout background. Over half of the NHD13+/Ptpn1-/- mice developed BCP-ALL demonstrating a strong genetic collaboration between these two mutations. A manuscript describing these findings is currently in preparation. As a final component to this project we have generated a panel of Mcm2cre/cre T-ALL cell lines that display the CNA mutator phenotype. Although CRISPR screens are an excellent mechanism to detect phenotypes produced by gene loss they will not detect phenotypes produced by gene copy number gains. Therefore we have begun a study to identify copy number loss and gains associated with chemotherapy resistance. Initial results are encouraging as we have detected methotrexate resistance associated with specific copy number gains of the Dhfr gene and vincristine resistance associated with focal gains of the Abcb1a (previously known as MDR1) gene. 822748 +No NIH Category available Biochemical;Breast Cancer Model;CBL Protein;Carcinoma;Cells;Collaborations;Complex;Down-Regulation;ERBB2 gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelium;Human;In Vitro;Investigation;Laboratories;Malignant Neoplasms;Mammalian Cell;Mediating;Molecular Target;Mus;Mutation;Natural Killer Cells;Outcome;PIK3CA gene;PIK3CG gene;Pathogenesis;Pathway interactions;Protein Family;Protein Tyrosine Kinase;Proteins;Receptor Protein-Tyrosine Kinases;Regulation;Research Personnel;Ring Finger Domain;Role;Signal Pathway;Signal Transduction;Structure;T-Lymphocyte;Tumor Immunity;Ubiquitination;Work;cancer cell;cell killing;in vivo;inhibitor;malignant breast neoplasm;member;mutant;overexpression;patient subsets;programs;trafficking;triple-negative invasive breast carcinoma;tumor;tumor initiation;ubiquitin-protein ligase Cbl Proteins as Regulators of Tyrosine Kinase Signaling n/a NCI 10926101 1ZIABC010977-16 1 ZIA BC 10977 16 14821366 "LIPKOWITZ, STANLEY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 665492 NCI RTKs such as EGFR HER2 MET and RET are often inappropriately active (due to mutation or overexpression) in a wide array of epithelial malignancies. My laboratory cloned two of the three members of the mammalian Cbl protein family and demonstrated that they are negative regulators of the EGFR in mammalian cells. We have shown that Cbl proteins are RING finger E3s and that all mammalian Cbl proteins mediate ubiquitination of the activated EGFR resulting in the degradation of the activated EGFR signaling complex. Work in my lab in collaborations with other laboratories and by other investigators has shown the Cbl proteins regulate many RTKs and signaling pathways. In addition my lab has contributed to the structure function analysis of the Cbl proteins. More recently my laboratory has identified and characterized proteins which interact with and modify the function of Cblc the least well characterized Cbl protein identified and are characterizing E2 proteins that interact with the Cbl proteins and identified mutant forms of Cbl proteins in human and mouse epithelial tumors. Ongoing work: 1) i investigates the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. 2) a screen to identify Cblb E3 inhibitors; 3) Investigations on the function of TROP2 in TNBC and the mechanisms of downregualtion of TROP2. In a translational project we have found that EGFR is amplified in 2% of breast cancer tumors and that this protends a poor outcome. Further we have found that the EGFR amplified tumors frequently have activating mutations in the PI3K pathway (40-70%). Ongoing work is 1) characterizing the ability of EGFR inhibitors +/- PIK3CA inhibitors to kill cells with mutations in these pathways in vitro and in vivo; and 2) evaluating the effects of these inhibitors on tumor initiating cells. 665492 +No NIH Category available Abscopal effect;Antigens;Antitumor Response;Brachytherapy;CD8-Positive T-Lymphocytes;Cancer Vaccines;Carcinoembryonic Antigen;Clinical;Colorectal Cancer;Combined Modality Therapy;Coupling;Cytolysis;Distal;Environment;External Beam Radiation Therapy;Gamma Rays;Goals;Human;Immune system;Immunotherapy;In Vitro;Label;Laboratory Finding;Low Dose Radiation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mediating;Modality;Modeling;Monoclonal Antibodies;Neoplasm Metastasis;Patients;Phenotype;Poxviridae;Primary Neoplasm;Process;Prostate Cancer therapy;Radiation;Radiation therapy;Radio;Radioisotopes;Radiolabeled;Regimen;Role;Site;Source;System;Systemic disease;T cell response;T-Lymphocyte;Therapeutic;Transcend;Transgenic Mice;Translating;Tumor Antigens;Vaccination;Vaccine Antigen;Vaccine Therapy;Vaccines;bone;cancer cell;cancer therapy;cancer vaccination;cell killing;chelation;immunoregulation;improved;interest;neoplastic cell;preclinical study;prevent;radiation effect;radio frequency;subcutaneous;synergism;thermal stress;tumor;tumor growth;tumor microenvironment;vaccine response Vaccine and radiation for the therapy of human cancers n/a NCI 10926100 1ZIABC010975-16 1 ZIA BC 10975 16 9692343 "HODGE, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 806457 NCI Radiation is a primary modality in cancer treatment. Radiation can also reduce tumor growth outside the treatment field often referred to as the abscopal effect. The mechanisms and therapeutic potential of the abscopal effect have not been fully elucidated. Here we evaluated the role of vaccination directed against a tumor-associated antigen (TAA) in the induction and amplification of radiation induced abscopal effects. Active-specific immunotherapy with a TAA- specific vaccine regimen was used to induce and potentiate T-cell responses against carcinoembryonic antigen (CEA) in combination with local radiation of subcutaneous tumors. We examined the potential synergy of a poxvirus-based CEA vaccine regimen in CEA-transgenic (Tg) mice in combination with either external beam radiation or brachytherapy of local tumors. The induction of CD8+ T-cells specific for multiple TAAs not encoded by the vaccine were observed after the combination therapy. In two tumor models the antigen cascade responses induced by vaccine and local radiation mediated the regression of antigen negative metastases at distal subcutaneous or pulmonary sites. Clinically local control of the primary tumor is necessary and can sometimes prevent metastases radiation generally fails to control pre-existing metastases. By The studies here suggest that by coupling tumor radiation with immunotherapy the abscopal effect can transcend from anecdotal observation to a defined mechanism that can be exploited for the treatment of systemic disease. As our understanding of the immunomodulatory effects of radiation has improved interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further more robust immune system activation. We have now focused preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy including external beam radiation radiolabeled monoclonal antibodies bone-seeking radionuclides and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination. 806457 +No NIH Category available Adult;Autologous;Bronchiolitis Obliterans;Clinical;Clinical Trials;Disease remission;Failure;Frequencies;Graft Rejection;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Immune system;Interferons;Joints;Laboratory Finding;Logistic Regressions;Modeling;Musculoskeletal;Nature;Patients;Phase;Publishing;Refractory;Relapse;Serology;Symptoms;Syndrome;Systemic Lupus Erythematosus;Work;barrier to care;chronic graft versus host disease;cohort;genetic signature;graft vs host disease;hematopoietic cell transplantation;immune reconstitution;montelukast;tumor ETIB Clinical Trials n/a NCI 10926099 1ZIABC010960-16 1 ZIA BC 10960 16 9692325 "GRESS, RONALD " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 110336 NCI We previously published our phase II results that suggest montelukast may safely halt the progression of bronchiolitis obliterans syndrome which is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation. In a collaborative study we found a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study. In addition we found durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory systemic lupus erythematosus (SLE) following lymphodepleting autologous haematopoietic cell transplantation (AHSCT). Work on this project was completed in FY23 110336 +No NIH Category available Adhesions;Affect;Apical;Binding;Biochemical;Biological Models;Breast;Cancer cell line;Cell Adhesion;Cell Fate Control;Cell Line;Cell Lineage;Cell membrane;Cell physiology;Cell-Cell Adhesion;Cells;Cephalic;Colon;Complex;Contact Inhibition;Data;Defect;Development;Developmental Process;Disease;Disseminated Malignant Neoplasm;Distal;E-Cadherin;Embryo;Embryonic Development;Endosomes;Environment;Eph Family Receptors;Ephrins;Epithelial Cells;Event;Family;Family member;GTPase-Activating Proteins;Histologic;Human;Intercellular Junctions;Invaded;Investigation;Laboratories;Ligands;Locomotion;Lung;Malignant Neoplasms;Maps;Mediating;Membrane;Metalloproteases;Morphogenesis;Morphology;Movement;Neoplasm Metastasis;Neural Crest;Neural Crest Cell;Neural Tube Closure;Neural tube;Neuroblastoma;Ovarian;Pathway interactions;Play;Predisposition;Process;Prosencephalon;Prostate;Proteins;Rana;Receptor Protein-Tyrosine Kinases;Recycling;Research;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;System;Telencephalon;Tissues;Tyrosine Phosphorylation;Visual Fields;Xenopus;Xenopus oocyte;angiogenesis;autism spectrum disorder;cell motility;experimental study;flotillin;gene product;improved;insight;interest;loss of function;melanoma;member;migration;mutant;neoplastic;novel;planar cell polarity;rab11 protein;receptor;retinal progenitor cell;scaffold;tumorigenesis Signaling Mechanisms of EphrinB1 in Cell Adhesion Migration and Invasion n/a NCI 10926097 1ZIABC010958-16 1 ZIA BC 10958 16 9692315 "DAAR, IRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 750182 NCI Our current research interests are aimed toward examining the mechanism by which Eph receptor tyrosine kinases and their ephrin ligands signal events affecting cell-cell adhesion and morphogenetic movements. From the elucidation of these signal transduction pathways we may improve our understanding of oncogenesis. The cell-cell adhesion system plays a major role in normal development and morphogenesis. Inactivation of this adhesion system is thought to play a critical role in cancer invasion and metastasis. The Xenopus embryo is well suited for investigations of these processes because the frog has a well characterized and invariant cell fate map and cell lineage can be easily traced during experiments. Mutant receptors ligands and other proteins can be ectopically expressed in embryos. Thus their effects on signal transduction motility and differentiation can be assessed morphologically and histologically as well as biochemically in a developing vertebrate. Our laboratory is currently investigating the role of the Xenopus Eph receptor tyrosine kinases and ephrinB transmembrane ligands in cell signaling and function using the Xenopus oocyte and embryo systems as well as human cultured cell lines. At present our emphasis is placed upon the mechanism by which these Eph family members send signals affecting morphogenetic movements. Members of the Eph family have been implicated in regulating numerous developmental processes and have been found to be deregulated in metastatic cancers for example prostate ovarian breast colon neuroblastoma lung and melanoma. Our laboratory has continued these studies examining proximal and distal signaling from ephrinB1 that controls cell adhesion and cell movement. We found evidence that ephrinB1 signals via its intracellular domain to control retinal progenitor movement into the eye field by interacting with Dishevelled (dsh) and co-opting the Wnt/planar cell polarity (PCP) pathway. Using biochemical analysis and gain or loss of function experiments our data suggest that dsh associates with ephrinB1 and mediates ephrinB1 signaling via downstream members of the PCP pathway during eye field formation. Thus we have used the eye field as a model system for understanding how ephrinB1 controls cell movement. Recently we have examined the mechanisms by which ephrinB1 affects cell-cell junctions. A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells and the formation of cell and tissue boundaries. These processes are dependent on the cell cell adhesion system which plays a crucial role in normal morphogenetic processes during development as well as in invasion and metastasis. Although ephrinB ligands are bi- directional signaling molecules the precise mechanism by which ephrinB1 signals through its intracellular domain to regulate cell-cell adhesion in epithelial cells remains unclear. We also have shown that a decrease in a highly related Eph ligand ephrinB2 protein causes neural tube closure defects during Xenopus embryogenesis. Such a decrease in ephrinB2 protein levels is observed on the loss of flotillin-1scaffold protein a newly identified ephrinB2-binding partner. This dramatic decline in ephrinB2 protein levels on the absence of flotillin-1 expression is specific and is partly the result of an increased susceptibility to cleavage by the metalloprotease ADAM10. These findings indicate that flotillin-1 regulates ephrinB2 protein levels through ADAM10 and is required for appropriate neural tube morphogenesis in the Xenopus embryo. Although Eph-ephrin signaling has been implicated in the migration of cranial neural crest (CNC) cells it is still unclear how ephrinB transduces signals affecting this event. We provide evidence that TBC1d24 a putative Rab35-GTPase activating protein (Rab35 GAP) complexes with ephrinB2 via the scaffold Dishevelled (Dsh) and mediates a signal affecting contact inhibition of locomotion (CIL) in CNC cells. Moreover we found that in migrating CNC ephrinB2 interacts with TBC1d24 which in turn negatively regulates E-Cadherin recycling in these cells via Rab35. Upon engagement of the cognate Eph receptor ephrinB2 is tyrosine phosphorylated which disrupts the ephrinB2/Dsh/TBC1d24 complex. The dissolution of this complex leads to increasing E-Cadherin levels at the plasma membrane resulting in loss of CIL and inhibition of CNC migration. Our results indicate that TBC1d24 is a critical player in ephrinB2 control of CNC cell migration via CIL. We have also completed a study that pertains to our previous focus on mechanisms that regulate ephrinB protein levels and the resulting effects on development. Rab11Fip5 is a target of the non-canonical Wnt/PCP signaling pathway and regulates recycling of proteins to the membrane through its interaction with Rab11. Rab11 and its role in neural tube closure has been shown to be under the control of PCP signaling which is required for the apical accumulation of the recycling Rab11-associated endosomes. We were able to determine that Rab11Fip5 plays a critical role in cycling ephrinB1 to the membrane in the developing forebrain. Moreover the interaction between ephrinB1 and Rab11Fip5 is mediated by Rab11 protein and is key to maintaining ephrinB1 at the membrane and maintaining the proliferative capacity of these telencephalic cells. These results provide a novel mechanistic connection between the candidate autism spectrum disorder gene product Rab11fip5 and ephrinB1 and indicate that proper recycling of ephrinB1 through the Rab11/Rab11fip5 complex controls proper telencephalon formation. 750182 +No NIH Category available Affect;Animal Model;Antibodies;Antigen Targeting;Antigens;Automobile Driving;CAR T cell therapy;CCR;CD28 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Camels;Cancer Biology;Cancer Family;Cancer Patient;Cell Surface Proteins;Cell Therapy;Cell physiology;Cell surface;Cells;Child;Clinical;Clinical Trials;Collaborations;Communication;Development;Dimerization;Disease;Distal;Dromedaries;Elements;Engineering;Epitopes;Event;Exhibits;Fc domain;Female;Funding;GPC3 gene;GPI Membrane Anchors;Gastroenterology;Generations;Genes;Glypican;HMGB1 gene;HMGN2 gene;Heparan Sulfate Proteoglycan;Hepatology;Human;IgG4;Immunization;Immunodeficient Mouse;Immunotherapeutic agent;Journals;Laboratories;Malignant Childhood Neoplasm;Malignant Epithelial Cell;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Membrane;Memory;Mesothelioma;Molecular Biology;Mus;National Cancer Institute;Nature;Neuroblastoma;Patients;Pediatric Neoplasm;Pediatric Oncology;Phage Display;Pre-Clinical Model;Primary carcinoma of the liver cells;Proteomics;Publishing;Reporting;Role;Signal Transduction;Signal Transduction Pathway;Site;Solid Neoplasm;Structure;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic antibodies;Transmembrane Domain;Tumor Antigens;United States National Institutes of Health;Up-Regulation;Work;antibody engineering;beta catenin;cancer immunotherapy;cancer therapy;chimeric antigen receptor T cells;clinic ready;clinical center;clinical development;cytotoxic;density;effector T cell;extracellular;granulysin;immunogenic;improved;liver cancer model;mesothelin;nanobodies;novel;nuclear factors of activated T-cells;oncofetal antigen;pancreatic cancer model;pre-clinical;programs;research clinical testing;syndecan;therapeutic target;transcriptomics;tumor;tumor eradication;tumor microenvironment;vector Development of antibody engineering-based cancer therapies n/a NCI 10926091 1ZIABC010891-16 1 ZIA BC 10891 16 9692203 "HO, MITCHELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1851352 NCI Heparan sulfate proteoglycans (HSPGs) regulate numerous cell surface signaling events. They are extracellular modulators of signal transduction pathways during development and diseases such as cancer. HSPGs are cell-surface proteins that mainly consist of glycosylphosphatidylinositol (GPI)-anchored glypicans and transmembrane syndecans. In the last over 15 years Dr Mitchell Ho's laboratory at the National Cancer Institute (NCI) has developed GPC3 and other glypicans such as GPC1 and GPC2 as a new family of cancer therapeutic targets and generated novel antibody and cell-based immunotherapeutic technologies for treating solid tumors including liver cancer pediatric cancers and other solid tumors. In FY2023 we continued to optimize the CAR-T cells targeting GPC3 for treating hepatocellular carcinoma (HCC) a major form of liver cancer. In our previous study (Li et al. Gastroenterology 2020) we found CAR-T cells targeting a membrane-proximal site recognized by YP7 antibody were more potent than the CAR-T cells targeting a membrane distal site recognized by HN3 indicating current CAR formats are not tailored toward targeting membrane distal epitopes. In FY2023 using hYP7 Fv (membrane proximal) and HN3 VH nanobody (membrane distal) as GPC3 targeting elements we sought to determine how hinges and transmembrane portions of varying structures and sizes affect CAR T-cell function. We generated multiple permutations of CAR T cells containing CD8 CD28 IgG4 and Fc domains. We show that engineered HN3 CAR T cells can be improved by 2 independent synergistic changes in the hinge and transmembrane domains. The T cells expressing the HN3 CAR which contains the hinge region of IgG4 and the CD28 transmembrane domain (HN3-IgG4H-CD28TM) exhibited high cytotoxic activity and caused complete HCC tumor eradication in immunodeficient mice. HN3-IgG4H-CD28TM CAR T cells were enriched for cytotoxic-memory CD8+ T cells and NFAT signals and reduced beta-catenin levels in HCC cells. Our findings indicate that altering the hinge and transmembrane domains of a nanobody-based CAR targeting a distal GPC3 epitope in contrast to a membrane-proximal epitope leads to robust T-cell signaling and induces swift and durable eradication of HCC tumors. We published this work in FY2023 in Hepatology Communications (Aarti Kolluri Dan Li Nan Li Zhijian Duan Lewis R Roberts Mitchell Ho. Human VH-based chimeric antigen receptor T cells targeting glypican 3 eliminate tumors in preclinical models of HCC. Hepatol Commun. 2023 Jan 18;7(2):e0022. doi: 10.1097/HC9.0000000000000022. eCollection 2023 Feb 1.). In addition to GPC3 and GPC2 in FY2023 Dr. Mitchell Ho's lab developed novel CAR T cells targeting GPC1 an oncofetal antigen expressed in pancreatic cancer. We reported the generation of dromedary camel VHH nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We found that a structurally rigid IgG4H and CD28TM domain brought the two D4 fragments in proximity driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells revealed specific genes (e.g. HMGB1) associated with high T-cell polyfunctionality. Our study demonstrates the potential of VHH-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes. This work was published in Nature Communications in April 2023 (Nan Li Alex Quan Dan Li Jiajia Pan Hua Ren Gerard Hoeltzel Natalia de Val Dana Ashworth Weiming Ni Jing Zhou Sean Mackay Stephen M Hewitt Raul Cachau Mitchell Ho. The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer. Nat Commun. 2023 Apr 8;14(1):1986. doi: 10.1038/s41467-023-37616-4. To pursue the clinical development of CAR-T cell therapy we have collaborated with Carol Thiele Rosandra Kaplan and Rosa Nguyen in the Pediatric Oncology Branch at the CCR NCI to produce clinical-ready CAR-T cells for an upcoming clinical trial treating neuroblastoma in the NIH Clinical Center. In a major effort through our collaboration we demonstrated that our single-chain variable fragment targeting GPC2 CT3 integrated into a CAR vector with a CD28 hinge CD28 transmembrane and 4-1BB co-stimulatory domain (CT3.28H) elicited the best preclinical anti-tumor activity compared with other tested CAR constructs. This enhanced activity was associated with an enrichment of CD8+ effector T cells in the tumor-microenvironment and upregulation of several effector molecules such as GNLY GZMB ZNF683 and HMGN2. We concluded that given the robust preclinical activity of CT3.28H these results form a promising basis for further clinical testing in children with neuroblastoma. The work was published in the Journal of Immunotherapy of Cancer in FY2023 (Sun et al. 2023). We have developed GPC3 (hYP7) GPC2 (CT3) and mesothelin (hYP218) CAR T cells for clinical trials at the NIH for treating liver cancer mesothelioma and neuroblastoma. Dr. Mitchell Ho has obtained funds from the Cancer Moonshot program and the NCI CCR to support these clinical trials for treating cancer patients at the NIH. 1851352 +No NIH Category available ATAC-seq;Affect;African;African American;African ancestry;Age;Alcohol dehydrogenase;American;Architecture;Autopsy;Award;Bile Acids;Biological;Biology;Blood specimen;Body mass index;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;CCR;Cancer Biology;Cancer Research Project;Cancerous;Cell Nucleus;Cell Proliferation;Cells;Characteristics;Chromatin;Clinical Research;Collaborations;Consent;Contracts;Crowns;DNA Damage;DNA Methylation;DNA Repair;DNA Repair Disorder;Data;Data Set;Development;Diabetes Mellitus;Diagnosis;Disease;Disease Outcome;Disease Progression;Division of Cancer Epidemiology and Genetics;Environment;Environmental Exposure;Estrogen receptor negative;Ethnic Origin;European;European ancestry;Excess Mortality;Exposure to;Follow-Up Studies;Food;Freezing;Gene Expression;Gene Proteins;Genetic;Glutamine;Heterogeneity;Hormonal;Human;Hyperglycemia;Immune;Immunologics;Inflammation;Insulin-Dependent Diabetes Mellitus;Investigation;Iron;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mammary Gland Parenchyma;Mammary Neoplasms;Marker Discovery;Maryland;Measures;Medical Records;Mesenchymal;Messenger RNA;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Mutation;Neighborhoods;Neoplasm Metastasis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncoproteins;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Pathology;Pathway interactions;Patient Self-Report;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Pilot Projects;Population;Population Group;Premenopause;Process;Proliferating;Proteins;Proteome;Publishing;Race;Reactive Oxygen Species;Reproductive History;Research;Research Personnel;Resources;Risk Factors;Role;Schedule;Signal Transduction;Social Environment;Social isolation;Stress;Stressful Event;Structure;Surveys;System;Technology;Therapeutic;Tissue Banks;Tissue Sample;Tissues;Transcript;Tumor Biology;Tumor Markers;Validation;Woman;aggressive breast cancer;biomarker discovery;biomarker identification;breast cancer progression;breast density;c-myc Genes;cancer surgery;clinically significant;cohort;comorbidity;deprivation;design;digital;digital pathology;epigenome;exome sequencing;experience;genome-wide;health disparity;improved;indexing;inflammatory marker;inhibitor;insight;interest;malignant breast neoplasm;metabolome;metabolomics;methylation pattern;microbiome;neoplastic cell;novel marker;patient biomarkers;perceived stress;prognosis biomarker;response;single nucleus RNA-sequencing;stem-like cell;survival outcome;targeted treatment;transcriptome;transcriptomic profiling;transcriptomics;tumor;tumor xenograft;tumor-immune system interactions Novel Markers for Disease Outcome in Breast Cancer n/a NCI 10926089 1ZIABC010887-16 1 ZIA BC 10887 16 9692197 "AMBS, STEFAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1159062 NCI Project 1: We continued to comprehensively examine the metabolome proteome and transcriptome of breast tumors from African American and European-American patients for biomarker discovery. The promise of this approach is the discovery of markers for prognosis and of mechanisms that may drive the aggressiveness of breast cancer in African American women. We characterized the metabolomic profile of breast tumors and adjacent non-cancerous tissue from 67 patients and described the differential abundance of more than 200 metabolites. One of them was 2-hydroxyglutarate which was elevated up to 100-fold in tumors that were primarily estrogen receptor-negative. This accumulation of 2-hydroxyglutarate was closely associated with the co-occurrence of a c-Myc signaling signature in the tumors (PMID: 24316975). In a follow up study we could show that breast tumors predominately accumulate D-2-hydroxyglutarate and describe the D-2-hydroxyglutarate-producing alcohol dehydrogenase iron-containing protein 1 (ADHFE1) as a breast cancer oncoprotein that is associated with disease survival. Our data show that ADHFE1 promotes a reductive glutamine metabolism with increased D-2-hydroxyglutarate and mitochondrial reactive oxygen species formation (PMID: 29202474). In an extension to these metabolome studies we analyzed breast tumors for presence of bile acids and how their accumulation may relate to breast cancer biology. This exploratory analysis revealed that a subset of breast tumors accumulates bile acids and show a distinct tumor biology. Tumors with a high bile acid content showed a decreased proliferation rate and associated with improved survival (PMID: 31296531). In a different study focusing on the breast cancer proteome we performed an integrated proteotranscriptomic characterization of breast tumors. We measured global proteome and transcriptome expression in 118 human breast tumors and adjacent non-cancerous tissues. Comparing proteome with transcriptome data we found that the proteome describes differences between cancerous and non-cancerous tissue that are not captured by the transcriptome. Moreover the proteome and transcriptome highlighted partially different tumor biologies. When we applied an integrated analysis of both technologies the approach revealed a global increase in protein-mRNA concordance in tumors. Highly correlated protein-gene pairs were enriched in protein processing and disease metabolic pathways and occurred more commonly in tumors of African American patients. The increased concordance between transcript and protein levels was further associated with aggressive disease including basal-like/triple-negative tumors and decreased patient survival. Our study indicates that an integrated analysis of the proteome and transcriptome in cancer can uncover disease characteristics beyond the ability of a single technology. These data have been published in 2018 (PMID: 30501643). Project 2: Environmental exposures and obesity can modify DNA methylation patterns and alter the tumor epigenome as shown for prostate and breast cancer. Our current research investigates genome-wide DNA methylation in human breast tissues in association with age body mass index tissue inflammation population group and neighborhood deprivation measures. Here we are combining the resources from the NCI-Maryland contract resource with a complementary resource acquired by the Gierach laboratory (DCEG/NCI) from the Komen tissue bank. This partnership will encompass genome-wide DNA methylation data from about one thousand women. It is the unique aspect of the NCI-Maryland cohort that we can link DNA methylation pattern to the neighborhood deprivation index breast cancer and the diagnosis of diabetes in this population. The Komen tissue bank cohort consists of African American and European American age-matched pre-menopausal donors without breast cancer. These women provided non-cancerous breast tissue from breast reduction surgery. We will study DNA methylation and tissue inflammation markers in these tissues additional breast reduction tissues from the NCI-Maryland cohort and in normal breast tissues obtained from autopsy cases. This study will be supplemented with DNA methylation data from breast tumor-adjacent non-cancerous tissue pairs from African American and European American patients. It is the main aim of this collaboration to evaluate patterns of genome-wide DNA methylation in association with tissue inflammation markers like crown-like structures and other risk factors differences between African American and European-American women the impact of diabetes and neighborhood deprivation measures on DNA methylation and to study differences between cancerous and non-cancerous tissues in African American and European-American women. The DNA methylation data can also be integrated with existing gene expression data sets for many of these tissues. Project 3: This project evaluates the role of environmentally induced stress signaling and co-morbidities in breast cancer progression. We started projects studying the impact of stressful life events and diabetes on tumor biology. In a clinical study we will give breast cancer patients who are scheduled for breast cancer surgery a short survey evaluating their perceived stress and social isolation. We will also collect frozen tumor and adjacent normal breast tissue and blood samples from these patients and evaluate whether the breast tissue or the blood samples have a biological signature related to their perceived stress and social isolation status. We hypothesize that patients with a high perceived stress exposure have a biological signature consistent with a more aggressive disease and poorer survival. The pilot study is designed to collect 100 tumor/normal pairs from consented patients with a completed survey. In a second study we are evaluating the relationship between self-reported diabetes and tumor biology and breast cancer aggressiveness. Here a patient's diabetes status based on survey and medical record data will be correlated with global gene expression metabolite patterns and mutational signatures in their tumors to identify cancer-related pathway that are impacted by diabetes. This study is ongoing and will assess whether type 1 and 2 diabetes induce changes to tumor biology that enhance the odds of disease progression. We are particularly interested in changes to metabolic pathways and how they can be targeted to decrease the negative impact that a diabetes diagnosis may have on breast cancer outcomes. More specifically we are investigating the influence of diabetes on breast cancer biology using a three-pronged approach that includes analysis of orthotopic human tumor xenografts patient tumors and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. Current findings are as follows: Diabetes did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. It also promoted oxyradical formation and both transcriptome and mutational signatures of DNA repair deficiency. Moreover food- and microbiome-derived metabolites tended to accumulate in breast tumors in presence of diabetes potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors that are cancer therapeutics. 1159062 +No NIH Category available Acute;Adolescence;Allogenic;B-Lymphocytes;Biological;Chimerism;Clinical;Clinical Protocols;Disease;Disease-Free Survival;Dysmyelopoietic Syndromes;Engraftment;Flow Cytometry;Hematology;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Immunologic Deficiency Syndromes;Incidence;Individual;Infection;Kinetics;Leukocytes;Mutation;Mycobacterium avium Complex;Natural Killer Cells;Opportunistic Infections;Patients;Pattern;Phenotype;Population;Recording of previous events;Residual state;Safety;Syndrome;T cell reconstitution;T-Cell Depletion;T-Lymphocyte;Therapeutic;Time;Toxic effect;Transplantation;chronic graft versus host disease;curative treatments;emerging adult;immune reconstitution;leukemia;monocyte;patient population;peripheral blood;primary endpoint;reconstitution Hematopoietic Stem Cell Transplant for GATA2 Deficiency n/a NCI 10926084 1ZIABC010870-16 1 ZIA BC 10870 16 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1220934 NCI The primary aim of this clinical protocol is to evaluate whether allogeneic hematopoietic stem cell transplant (HSCT) reverses the hematological abnormalities in a recently described syndrome known as MonoMAC which is characterized by: 1) onset in late adolescence or early adulthood; 2) clinical history of opportunistic infection frequently with mycobacterium avium complex (MAC); 3) a distinct peripheral blood leukocyte subset pattern with the presence of T-lymphocytes but a severe deficiency of B-lymphocytes natural killer (NK) cells and the lack of monocytes; 4) dominant inheritance; and 5) frequent progression to myelodysplastic syndrome (MDS). We propose to evaluate whether allogeneic hematopoietic stem cell transplantation (HSCT) can reconstitute normal hematopoiesis in MonoMAC and reverse the hematological abnormalities in myelodysplastic syndrome (MDS) if MDS is present at the time of transplant. While allogeneic HSCT is the conventional curative treatment for immunodeficiency and MDS patients with MonoMAC because of an intact T-cell population and co-existing infection represent a profile not generally encountered in the setting of allogeneic HSCT. The biological questions with MonoMAC center around whether the individual leukocyte compartments that are lost in MonoMAC (B-lymphocytes natural killer cells and monocytes) will be constituted with HSCT and whether the residual recipient T-lymphocytes will represent an impediment to engraftment. We will also evaluate whether we achieve sufficient donor chimerism to reverse the myelodysplastic syndrome. Our specific aims are: 1) To determine whether allogeneic HSCT reconstitutes normal hematopoiesis and reverses the MonoMAC flow cytometry phenotype in patients with MonoMAC by day +100; 2) To determine whether HSCT demonstrates potential as a pre-emptive anti-leukemia strategy in this patient population; 3) To characterize the engraftment kinetics of specific leukocyte subsets (monocytes B-lymphocytes and natural killer cells) deficient in MonoMAC as well as reconstitution of T-cells that are depleted in the course of therapy and the kinetics and extent of reversal of the abnormalities in MDS; 4) To determine the safety of this therapeutic HSCT approach including transplant-related toxicity the incidence of acute and chronic graft-versus-host disease (GVHD) immune reconstitution overall survival and disease-free survival. The primary end-points are to determine whether allogeneic HSCT reconstitutes normal hematopoiesis and reverses the MonoMAC flow cytometry phenotype in patients with MonoMAC by day +100 and to determine whether HSCT demonstrates potential as a pre-emptive anti-leukemia strategy in this patient population. We have now transplanted 15 patients with this syndrome with excellent results. 1220934 +No NIH Category available Accidents;Acute;Animals;Biological Markers;Cell Culture Techniques;Clinic;Clinical Trials;Collaborations;Collection;Complex;Development;Dose;Environment;Extensive Radiation;Goals;Injury;Intervention;Intestines;Knowledge;Laboratories;Lung;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of prostate;Methods;Normal tissue morphology;Organ;Pathway interactions;Patients;Peripheral;Phenotype;Play;Process;Program Evaluation;Protocols documentation;Radiation Dose Unit;Radiation Injuries;Radiation Protection;Radiation Toxicity;Radiation exposure;Radiation therapy;Radiobiology;Radiodermatitis;Reproducibility of Results;Role;Sampling;Skin;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Translating;Work;candidate marker;design;experience;experimental study;in vivo Model;interest;irradiation;malignant breast neoplasm;prevent;radiation delivery;radiation mitigation;radiation mitigator;senescence;targeted agent;tissue injury;tissue stem cells Mechanisms of Normal Tissue Toxicity From Irradiation n/a NCI 10926083 1ZIABC010850-17 1 ZIA BC 10850 17 9414510 "CITRIN, DEBORAH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1829924 NCI In order to evaluate mechanisms of normal tissue injury adequate in vivo models must be developed. Cell culture does not provide the complex environment that is found in tissues thought to be responsible for the initiation of radiation injury. In addition experiments assessing late toxicity often require 6 months to determine if the expected injury has occurred. The delivery of radiation with these experiments must be precisely localized to the tissue of interest to prevent possible peripheral effects to confound results. Our laboratory has established a program for evaluation of late normal tissue toxicity through initiation of a number of animal protocols designed to develop and further study acute and late toxicity in the skin lung and intestine. This has involved the development of specialized radiation treatment immobilizers and shields to deliver the intended dose accurately. Animals have been treated with doses of radiation that we found could reproducibly result in toxicity and samples have been collected for additional high-throughput and hypothesis-driven work to determine the temporal activation of known and yet undescribed pathways in the process of radiation toxicity. In addition two clinical trials were conducted NCI 07-C-0111 and NCI 09-C-0120 that included the collection of various biospecimens in patients receiving radiotherapy for gastrointestinal malignancies breast cancer and prostate cancer. A number of candidate biomarkers of radiation toxicity are being tested in the context of this clinical trial. An additional trial was completed testing a topical nitroxide as a possible method to reduce radiation dermatitis. This nitroxide has been studied extensively by the radiation biology branch who is collaborating in this trial. The major goal of this project is to describe pathways associated with radiation injury target them and translate these findings to the clinic. Several pathways important in radiation injury have already been identified in this project and agents targeting these pathways have been shown to be effective radiation mitigators. We hope to translate these findings into the clinic. 1829924 +No NIH Category available 3-Dimensional;ABCB1 gene;ABCC1 gene;ABCG2 gene;ATAC-seq;Affect;Agreement;Amino Acid Transporter;Animal Model;Antineoplastic Agents;Binding;Bioreactors;Blood capillaries;Breast Cancer Cell;CRISPR screen;Cancer Cell Growth;Cataloging;Cell Death;Cell Line;Cell Survival;Cell physiology;Cell surface;Cells;Chickens;Childhood Rhabdomyosarcoma;Cisplatin;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Collaborations;Colon Carcinoma;Complex;Cultured Cells;Cutaneous;Cytoplasm;Cytotoxic agent;Development;Diffusion;Disease;Drug resistance;Exposure to;FDA approved;Fishes;Gene Expression;Gene Expression Profile;Genes;Genomics;Goals;Growth;Guide RNA;HDAC3 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;Homologous Gene;Hydrogels;In Vitro;KB Cells;Knock-out;Length;MAP Kinase Gene;MCF7 cell;Malignant Neoplasms;Malignant neoplasm of ovary;Methylation;Methyltransferase;Microtubule Stabilization;Microtubules;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Molecular;Multi-Drug Resistance;Multidrug Resistance-Associated Proteins;Mus;Mutation;Oxygen;PIK3CG gene;Paclitaxel;Patients;Pattern;Peripheral;Pharmaceutical Preparations;Phenotype;Physiological;Platinum Compounds;Play;Polymers;Probability;Protein Isoforms;Proteins;Rattus;Resistance;Rhabdomyosarcoma;Role;Signal Pathway;Silicon;Solid Neoplasm;Specificity;Specimen;Sulfhydryl Compounds;Suspensions;System;T-Cell Lymphoma;Technology;Testing;Transfection;Transgenic Organisms;Tubulin;Validation;Verapamil;Vertebrates;Vorinostat;Zebrafish;Zinc;cancer cell;cancer drug resistance;clinically relevant;drug resistance development;efficacy evaluation;efflux pump;in vivo;inhibitor;mutant;neurotoxicity;overexpression;oxaliplatin;paralogous gene;patient derived xenograft model;polymerization;pre-clinical research;prevent;receptor;resistance mechanism;scale up;transcriptome sequencing;tumor;uptake Mechanisms of non-classical multidrug resistance in cancer n/a NCI 10926078 1ZIABC010830-17 1 ZIA BC 10830 17 9414470 "GOTTESMAN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1704193 NCI Three major approaches have been taken to define non-classical multidrug resistance in cancer. In the first we isolate KB cells and ovarian cancer cells resistant to increasing levels of cisplatin (CP-r) and demonstrate multidrug resistance to many other cytotoxic agents. In some cases this cross-resistance pattern is due to reduced uptake of each of these agents because their receptors have been relocalized from the cell surface into the cytoplasm of the cell. We have undertaken a complete genomic analysis using RNA-seq ATAC-seq and Pro-seq technologies to define the alterations in gene expression that accompany the development of drug resistance in cisplatin-selected cell lines and one cataloguing alterations in cisplatin-resistant cells that contribute to drug resistance. Comparing gene expression in cisplatin-sensitive 1A9 ovarian cancer cells cisplatin-resistant 1A9CP80 cells and partially revertant 1A9CP80R cells we noted increased expression of TPPP3 (tubulin polymerization promoting protein 3) in the resistant cells with lower levels in the revertant cells and no expression observed in the parental line. Additionally we noted that cisplatin treatment destabilizes microtubule ends and reduces microtubule length and hypothesized that TPPP3 might mitigate these effects. Interestingly the ability of TPPP3 to counteract the effects of cisplatin treatment were most effective in tubulin purified from 1A9CP80 cells and least effective in 1A9 cells and appeared to correlate with changes in expression of tubulin isoforms in the cell lines. Deletion of TPPP3 via CRISPR knockout partially resensitized the 1A9CP80 cells to cisplatin. High expression of TPPP3 in tumors from patients treated with cisplatin correlated with worse survival probability suggesting a possible clinical role for this protein. In addition cells exposed to cisplatin (which we have shown destabilizes microtubules) are more resistant to paclitaxel an antimicrobule drug that stabilizes microtubules. These results have implications both for the neurotoxicity of cisplatin and for strategies that employ combinations of cisplatin and paclitaxel to treat ovarian cancer and other cancers. To understand more about non-classical mechanisms of multidrug resistance in cancer we are undertaking CRISPR screens in cells exposed to various drugs including cisplatin and oxaliplatin. These screens involve using gRNAs in combination with CRISPR-cas constructs that can activate inhibit or knock out target genes. Cells exposed to platinum compounds or other drugs undergo cell death and surviving cells overexpress gRNAs which turn on genes which can independently confer resistance or underexpress genes whose expression is needed for sensitivity to cisplatin. We are identifying genes whose over- or under-expression affects drug resistance with the goal of defining clinically relevant molecular changes. Recent studies using CRISPR screens to determine the basis of oxaliplatin resistance in colon cancer cells has identified amino acid transporters as playing an important role in sensitivity to this drug. Histone deacetylase inhibitors (HDIs) are used clinically to treat cutaneous and peripheral T-cell lymphomas diseases for which 3 HDIs have been FDA approved as single-agent therapies. In the case of solid tumors the HDIs have not been effective suggesting intrinsic resistance mechanisms to these drugs. We found that synergistic killing can be achieved with HDIs and inhibitors of the MAPK and PI3K signaling pathways in cells that harbor Ras mutations. We also found that a dual ERK/PI3K inhibitor could take the place of separate MAPK and PI3K inhibitors when combined with an HDI. Further studies have shown that the dual BRD4/PI3K inhibitor SF2523 is synergistically toxic to Ras mutant cells when combined with an HDI. In collaboration with Dr. Mari Yohe we demonstrated that SF2523 alone is particularly effective in childhood rhabdomyosarcoma cell line models and its efficacy can be increased by the addition of the HDI romidepsin. The Center for Advanced Preclinical Research (CAPR) has agreed to examine the efficacy of the SF2523/romidepsin combination in patient-derived xenograft models of rhabdomyosarcoma. Resistance to HDI's such as romidepsin can occur in cultured cells owing to overexpression of P-glycoprotein but in clinical cancers resistance does not appear to be due to this mechanism. To identify non-P-gp mechanisms of resistance we selected MCF-7 breast cancer cells with romidepsin and verapamil to yield the MCF-7 DpVp300 line which is about 200-fold more resistant to romidepsin than the parental cells. The cells are uniquely resistant to romidepsin as the resistant line was only 3- to 5-fold more resistant to other HDIs such as vorinostat belinostat or panobinostat. RNA Seq analysis comparing the parental and resistant line identified the gene METTL7A which codes for a poorly-described methyltransferase as a potential resistance mechanism. METTL7B a paralog of METTL7A was recently determined to be an alkly thiol methyltransferase that is capable of methylating thiol groups. As the active form of romidepsin has a thiol in its active form and as methylation of the thiol group would prevent coordination of the molecule with zinc in the HDAC binding pocket we hypothesized that METTL7A might be able to inactivate romidepsin or other HDIs with a thiol as the zinc-binding group. In support of this hypothesis knockout of METTL7A from DpVp300 cells resensitized the cells to romidepsin as well as other thiol-based HDIs such as KD5170 and largazole. Interestingly HEK293 cells transfected with METTL7A were resistant to all of the thiol-based HDIs but METTL7B overexpression conferred less resistance to largazole and KD5170 than METTL7A and no resistance to romidepsin. METTL7A and METTL7B thus appear to be methyltransferases with somewhat different specificity that confer resistance to thiol-based HDIs by inactivating these drugs. To determine if animal models could be used to elucidate the normal function of these methyltransferases we examined homologs of METTL7A from different species. We found that METTL7A is conserved across vertebrates while METTL7B is not. To determine if the ability of METTL7A to methylate thiols is conserved we transfected HEK293 cells to express mouse rat chicken or zebrafish METTL7A. We found that expression of any of the METTL7A isoforms could confer resistance to all of the thiol-containing HDACis tested suggesting that the function of METTL7A is conserved across species. These results have led us to create a transgenic zebrafish where METTL7A is deleted. We will characterize the knockout fish in hopes of finding a physiological role for METTL7A. Validation of these results indicating that MDR is complex and multifactorial in clinical cancers will require the development of reliable in vitro culture models. Towards this goal we have developed a bioreactor that mimics capillary delivery (through silicon hydrogels and the polymer PTMS) of oxygen to cells grown in 3D suspension. We have demonstrated physiological oxygen gradients and altered growth of cancer cells more closely approximating in vivo phenotypes. Evidence that oxygen gradients substantially change gene expression patterns has been obtained by detailed RNAseq analysis. Delivery of physiological concentrations of 3% oxygen directly to cells via artificial capillaries mimics the gene expression patterns of 20% oxygen delivered via diffusion. The bioreactor can be scaled up for growth of multiple cultures of primary cancer cells or cultured cancer cells to determine whether growth conditions and mode of oxygen delivery play a primary role in affecting patterns of drug resistance. 1704193 +No NIH Category available Acetylation;Address;Affect;Aneuploidy;Area;Basic Science;Biochemical;Biological Assay;Cell Cycle;Cell Cycle Regulation;Cell Line;Cell model;Cells;Cellular biology;Centromere;Chromatin;Chromosomal Instability;Chromosomal Stability;Chromosome Segregation;Chromosomes;Clinic;Clinical Trials;Complement;DAXX gene;DNA;DNA Sequence;Defect;Diagnosis;Diploidy;Dose;Drosophila polo protein;Ensure;Euchromatin;Excision;F-Box Proteins;Future;Gene Dosage;Genes;Genetic;Genetic Screening;Genome;Hela Cells;Heterogeneity;Histone Acetylation;Histone Deacetylase Inhibitor;Histone H3;Histone H4;Histones;Homologous Gene;Human;In Vitro;Incidence;Kinetochores;Length;Link;Lysine;Malignant Neoplasms;Mediating;Methylation;Microtubules;Mitosis;Mitotic;Molecular;Molecular Chaperones;Mus;Nucleosomes;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Post Translational Modification Analysis;Post-Translational Protein Processing;Process;Prognosis;Proliferating;Proteins;Proteolysis;Regulation;Reporting;Research;Role;Saccharomyces cerevisiae;Saccharomycetales;Sister Chromatid;Site;Solid Neoplasm;Sumoylation Pathway;Topoisomerase II;Translating;Ubiquitin-mediated Proteolysis Pathway;Ubiquitination;Variant;Xenograft procedure;Yeast Model System;Yeasts;anticancer research;cancer cell;cancer therapy;centromere protein A;chromosome loss;chromosome missegregation;cohesin;cohesion;constitutive expression;daughter cell;dosage;established cell line;fly;genome wide screen;genome-wide;human model;in vivo;inducible gene expression;insight;interdisciplinary approach;micronucleus;mouse model;multidisciplinary;mutant;novel;overexpression;prevent;segregation;stoichiometry;targeted treatment;tool;transmission process;tumorigenesis Molecular Determinants of Chromosome Transmission and Cell Cycle Regulation n/a NCI 10926077 1ZIABC010822-17 1 ZIA BC 10822 17 9414472 "BASRAI, MUNIRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2343563 NCI We use multi-organismal (yeast mouse and human cells) and multi-disciplinary (genetic cell biology biochemical and genome-wide) approaches to study faithful chromosome segregation a fundamental process of every living cell. Genetic screens served as a starting point and in-depth mechanistic studies have provided evidence for new roles for kinetochore genes and the identification of new kinetochore genes. We have identified and defined roles for post-translational modifications (acetylation methylation phosphorylation sumoylation and ubiquitination) of Cse4 in chromosome segregation. Our research is focused on understanding the role of Cse4-associated proteins in chromosome segregation and defining pathways that prevent mislocalization of Cse4 to non-centromeric regions. In the first project we defined roles for Scm3 Pat1 Cdc5 and Sgo1 for the assembly of centromeric chromatin and characterized role of post-translational modifications of centromeric histones in faithful chromosome segregation. We determined that imbalanced stoichiometry of a Cse4 chaperone Scm3 (HJURP in humans) leads to chromosome mis-segregation in both human and yeast cells thereby providing a link between HJURP overexpression and mitotic defects in cancers (Mishra et al. 2011). Scm3 interacts with Pat1 (Protein associated with topoisomerase II) and Pat1 regulates the topology of centromeric chromatin (Mishra et al. 2013). We used a pat1 deletion strain to define the number of Cse4 molecules at the yeast kinetochore (Hasse Mishra 2013 Mishra et al. 2015) and provided evidence for a structural role for Pat1 in the structural integrity of centromeric chromatin and localization of Cse4 for faithful chromosome segregation. In addition to kinetochore proteins association of cohesins with centromeres and along the length of the chromosomes ensures faithful segregation of sister chromatids during mitosis. We reported that evolutionarily conserved polo kinase Cdc5 associates with centromeric chromatin to facilitate the removal of centromeric cohesins (Mishra et al. 2016) and Cdc5-mediated phosphorylation of Cse4 regulates faithful chromosome segregation (Mishra et al. 2019). Furthermore evolutionarily conserved Sgo1 which protects centromeric cohesion interacts with Cse4 and this is required for faithful chromosome segregation (Mishra et al. 2018). We recently reported that evolutionarily conserved Hpr1 prevents the accumulation of R-loops at centromeric chromatin affects the assembly of kinetochore and leads to chromosomal instability (Mishra et al. 2021). We have done a comprehensive analysis of Post-translational modifications (PTMs) of Cse4 and identified conserved sites for acetylation methylation and phosphorylation (Boeckmann et al. 2013). We determined that evolutionarily conserved Aurora B/Ipl1 kinase phosphorylates Cse4 in vivo and in vitro for faithful chromosome segregation (Boeckmann et al. 2013) and that cell cycle regulated methylation of Cse4 prevents CIN (Mishra et al. 2023). Using budding yeast with a single nucleosome we provided the first evidence that yeast centromeres contain hypoacetylated histone H4 and that increased acetylation of histone H4 on lysine 16 (H4K16) leads to chromosome mis-segregation (Choy et al. 2011). Even though HDAC inhibitors (HDACi) are used in clinical trials we do not fully understand their mode of action. A genome-wide screen with an HDACi was used to identify pathways that are vulnerable to altered histone acetylation. Our results showed that chromosome segregation mutants are more sensitive to HDACi (Choy et al. 2015). Future studies will allow us to understand the molecular role of PTMs of Cse4 in chromosome segregation and determine if these PTMs are conserved in human CENP-A. In the second project we have focused on the identification of pathways that prevent mislocalization of Cse4 and CIN. We showed previously that S. cerevisiae spt4 mutants show mislocalization of Cse4 and chromosome segregation defects that are complemented by human SPT4 (Basrai et al 1996 and Crotti and Basrai 2004). We established the cause and effect of Cse4 mislocalization by showing that altered histone dosage and mislocalization of Cse4 to non-centromeric chromatin correlate with chromosome loss (Au et al. 2008). We identified a novel role for the N terminus of Cse4 in ubiquitin (Ub)-mediated proteolysis for faithful chromosome segregation (Au et al. 2013) and showed that Cse4 is sumoylated and ubiquitination of sumoylated Cse4 by Slx5 regulates its proteolysis to prevent mislocalization to euchromatin (Ohkuni et al. 2016 2018 2020). Genome-wide approaches have been used to identify regulators that prevent mislocalization of Cse4 to euchromatin and these studies revealed a role for histone chaperones (Ciftci-Yilmaz et al. 2018). F-box proteins Cdc4 and Met30 in Cse4 proteolysis (Au et al. 2020) Dbf4 dependent kinase (DDK) (Eisenstatt et al. 2020) and Cdc48 (Ohkuni et al. 2022). Furthermore reduced dosage of histone H4 prevents mislocalization of Cse4 (Eisenstatt et al. 2021). In the third project we have focused on causes and consequences of mislocalization of CENP-A in human cells and xenograft mouse model. Mislocalization of CENP-A has been observed in many cancers and this correlates with poor prognosis. Hence it is critical to understand how CENP-A overexpression contributes to tumorigenesis and whether CENP-A expression can be exploited for prognosis diagnosis and targeted treatment of CENP-A overexpressing cancers. We established cell lines and optimized cell biology-based assays to address a long-standing question of whether mislocalization of overexpressed CENP-A contributes to CIN. We determined that constitutive or inducible expression of CENP-A in HeLa and stable diploid RPE1 cells results in mislocalization of CENP-A to non-centromeric regions. Comprehensive analysis for mitotic effects showed a dose-dependent effect of CENP-A overexpression on chromosome segregation defects and higher incidence of micronuclei. Altered localization of kinetochore proteins contributes to a weakening of the native kinetochore in CENP-A overexpressing cells. Depletion of the histone chaperone DAXX prevents CENP-A mislocalization and rescues the CIN phenotype in CENP-A overexpressing cells. These results show that mislocalization of CENP-A is one of the major contributors for CIN in CENP-A overexpressing cells. Our studies provide the first evidence for how mislocalization of CENP-A to non-centromeric chromatin contributes to CIN in human cells and provide mechanistic insights into how CENP-A overexpression may contribute to aneuploidy in CENP-A overexpressing cancers (Shrestha et al. 2017). We recently reported that mislocalization of overexpressed CENP-A in pseudodiploid DLD1 cell line and xenograft mouse model contribute to CIN aneuploidy with karyotypic heterogeneity (Shrestha et al. 2021). We are pursuing studies with human homologs of the yeast genes identified in genome wide screens and using genome-wide approaches to identify and characterize pathways that prevent mislocalization of CENP-A and CIN. We recently reported that histone H3 chaperone CHAF1B prevents mislocalization of CENP-A and CIN in human cells (Shrestha et al. 2023). n summary our studies using multi-organismal and multi-disciplinary approaches have provided mechanistic insights for how defects in kinetochore function contribute to aneuploidy in human cancers. We are optimistic that our studies will help translate basic science research to the clinic and aid in the diagnosis prognosis and treatment of cancers that show overexpression of CENP-A. 2343563 +No NIH Category available Acute;Africa South of the Sahara;Algorithms;Award;Binding;Bioinformatics;Blood Cells;Cells;Chronic;Clinic;Collaborations;Country;Data;Diagnosis;Drug resistance;Early identification;Enrollment;Epidemic;Genetic;Genetic Polymorphism;Genetic Population Study;Genetic Recombination;Genetic Transcription;Genetic Variation;Genotype;Goals;HIV;HIV Drug Resistance Program;HIV Infections;HIV drug resistance;HIV risk;HIV-1;High Prevalence;Incidence;Individual;Indonesia;Infection;Integrase Inhibitors;Israel;Lamivudine;Link;Mediating;Molds;Mutation;Nature;Newly Diagnosed;Nucleosides;Patients;Pattern;Peripheral;Plasma;Population;Population Dynamics;Population Genetics;Population Heterogeneity;Population Sizes;Positioning Attribute;Prevention approach;Procedures;Protocols documentation;Public Health;Reporting;Research;Research Personnel;Resistance;Resistance development;Reverse Transcriptase Inhibitors;Risk;Role;Sampling;Source;Structure;Technology;United States National Institutes of Health;Universities;Variant;Viremia;Virus;Washington;Zidovudine;abacavir;algorithm development;antiretroviral therapy;assay development;bench to bedside;cathinone;genetic analysis;genetic approach;genome sequencing;in vivo;inhibitor;insight;intravenous drug user;invention;next generation sequencing;non-nucleoside reverse transcriptase inhibitors;participant enrollment;population based;resistance mutation;technique development HIV-1 Genetic Variation in Infected Individuals n/a NCI 10926076 1ZIABC010819-17 1 ZIA BC 10819 17 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 475333 NCI HIV replication in vivo is rapid and error prone and results in large and genetically diverse populations of HIV-infected cells. We are using population-based sequencing as well as the single-genome sequencing (SGS) technology we developed previously. In addition with M. Kearney's group (HIV DRP) we have investigated the use of next-generation sequencing (NGS) approaches (Illumina sequencing) to study HIV population genetics. We have utilized these approaches to analyze and understand the accumulation of genetic variation in gag/pol and env. We have made significant advances in additional assay development and have extended studies to a number of different patient groups including chronically infected patients both naive and on therapy as well as in primary and early HIV infection. As a result we are obtaining a more comprehensive picture of HIV genetic variation in vivo in the presence or absence of drug resistance. We have previously reported that replicating population size is substantial prior to initiating antiretroviral therapy (ART). We have applied NGS approaches to refine the estimates of HIV and found that 1X107 infected cells may be replicating in infected individuals daily. In our new studies we have been able to investigate rates of recombination in vivo and found that recombination occurs at a high rate in vivo such that there are very few linked polymorphisms in any virus population and that recombination represents a potentially important mechanism for spread of HIV mutations. As resistance to integrase inhibitors increases and NIH clinics are enrolling more such patients we are studying the development of resistance to this important class of HIV inhibitors. We have recently reported the emergence of high-level resistance to dolutegravir with the addition of a single secondary mutation at position T97A. We have now completed a detailed analysis of the emergence of resistance and found that the T97A variant emerged from a limited number (3-4) of variants that arose rapidly by replication and as predicted by our population genetics studies through recombination. The development of these techniques has led to new insights in HIV population dynamics in understanding the effects of ART the nature of replication in natural suppression of HIV and population dynamics of non-subtype B HIV populations.We have initiated new collaborations with Drs. W.s. Hu and E. Nicolaitchik to understand transcriptional patterns of HIV infection in peripheral blood cells from HIV infected individuals which we provide new insights on the populations of expressed HIV in vivo. We also collaborated with Drs. S. Hughes and P. Boyer to understand the mechanisms of drug resistance to nucleoside reverse transcriptase inhibitors. The dynamics of HIV-1 populations in patients undergoing ART remain uncertain and we are conducting an extensive genetic analysis of HIV-1 before and after initiation of ART (completed Protocol 97-I-0082 new Protocol 08-I-0221). These results will yield new information regarding the nature and timing of genetic bottlenecks occurring during ART. Analysis of HIV-1 sequences at relatively low viremia has been limited by technical issues in amplifying the relatively few HIV-1 sequences present in plasma during therapy. We have successfully adapted the SGS procedure to obtain acceptable numbers of sequences from patients suppressed on ART. In collaboration with M. Polis and D. Persaud (NIH Bench to Bedside Award 2006) we are analyzing genetic variation in patients enrolled in Protocol 97-I-0082 (now 08-I-0221; F. Maldarelli PI) who have been suppressed on ART for prolonged (greater than 8 y) periods. Initial analyses demonstrate that HIV does not undergo a genetic bottleneck upon initiation of ART; despite a 100- to 10000-fold decline in levels of peripheral viremia no significant decreases in genetic diversity were detected in the first 1-2 y of therapy. These data indicate a common source of virus infecting short-lived cells (responsible for greater than 90-99% of virus produced prior to therapy) and longer-lived cells (responsible for virus produced 1-2 years after therapy is initiated). After prolonged therapy emergence of predominant clones (as previously noted by Bailey et al.) was detected in the majority (7/8) patients. We are also applying population genetics approaches to quantify the emergence of drug-resistance mutations in rebound viremia in patients undergoing ART. We are specifically investigating the relative roles of mutation and selection in development of resistance to AZT and NNRTI as well as quantifying the role of APOBEC-mediated mutations in the emergence of the M184I mutation conferring resistance to 3TC FTC and to a degree abacavir. We are using these approaches to investigate the spread of HIV in the US and in selected populations in the world. We have demonstrated clear evidence of early spread of drug-resistant HIV in the HIV epidemic in Washington DC which has the highest prevalence of HIV in the US. We are now investigating the spread of HIV in DC using samples stored early in the epidemic. We have demonstrated that subtype C HIV the most common subtype in the world had entered the US years before previously thought and prior to the rapid expansion of this subtype in sub-Saharan Africa. These studies provide important insights on the early spread of HIV and on the spread on epidemics in general They have also yielded information and new sequences that are critical to understanding the current spread of HIV in DC and will inform public health strategies to eliminate the spread of HIV in DC. In addition we reported analysis of a mini-epidemic spread of a specific subtype A HIV variant among intravenous drug users (IVDU) associated with cathinone abuse in Israel. Despite public health efforts to halt the spread we found this variant was continuing to spread in IVDU and could also be detected in other HIV risk groups. Understanding the expansion of genetic diversity following infection from a genetically limited to a highly diverse population has useful implications for applicability in understanding the HIV epidemic. Based on our understanding of genetic variation in acute and chronically infected individuals we developed a new bioinformatics algorithm to discriminate between recently and chronically infected individuals based exclusively on population-based commercial genotyping data. Development of this algorithm has yielded the invention report EIR #238-2009. This approach has been used in a variety of settings and we have used it to investigate spread of HIV in DC and more recently in analysis of the subtype A mini-epidemic in Tel Aviv Israel. In new studies we have extended our expertise to understanding the spread of HIV in Indonesia the fourth most populous country in the world with substantial ongoing HIV spread. In collaboration with investigators at the University of Indonesia (Nawang Wulan and Dr. Pritiwi Sudarmono) we have used our expertise in identifying early infection and in characterizing spread to develop the first empiric estimates of HIV incidence in Indonsia. In these studies currently in revision at iScience we have found 12.5% of all newly diagnosed individuals are likely to have been infected in the year prior to diagnosis. We are currently completing a new analysis of spread of HIV in Indonesia from earliest introduction in the 1980's; current patterns of spread indicate substantial bridging across risk groups demonstrating that a broad approach to prevention will be essential to public health efforts to reduce and eliminate HIV infection. These studies have shed new light on the spread of HIV in populations and inform the public health efforts to eradicate HIV worldwide. 475333 +No NIH Category available Adoptive Cell Transfers;Affinity;Animal Model;Antibodies;Ascites;Bacterial Toxins;Binding;Biopsy;C-terminal;CAR T cell therapy;CTLA4 gene;Cancer Patient;Categories;Cell Line;Cell surface;Cells;Characteristics;Clinic;Clinical;Clinical Trials;Complex;Conduct Clinical Trials;DNA Repair Gene;Development;Differentiation Antigens;Distal;Drug Targeting;Epidermal Growth Factor Receptor;Epitopes;Follow-Up Studies;Genetic;Germ-Line Mutation;Goals;Human;Immune checkpoint inhibitor;Immunocompetent;Immunocompromised Host;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Immunotoxins;In Vitro;Inflammation;Injections;KRAS2 gene;Laboratories;Laboratory Research;Laboratory Study;Large Intestine Carcinoma;Link;Liquid substance;Longterm Follow-up;Lung Adenocarcinoma;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of thorax;Maximum Tolerated Dose;Mediating;Medicine;Membrane;Mesothelial Cell;Mesothelioma;Modeling;Monoclonal Antibodies;Morphology;Mus;Mutation;Nature;Non-Small-Cell Lung Carcinoma;Oryctolagus cuniculus;Outcome;PD-1/PD-L1;Pancreatic Adenocarcinoma;Pathway interactions;Patient Recruitments;Patients;Peripheral Blood Mononuclear Cell;Peritoneum;Pharmaceutical Preparations;Phase I Clinical Trials;Phase I/II Clinical Trial;Platinum;Pleura;Pleural;Pleural Mesothelioma;Pre-Clinical Model;Prior Therapy;Prognosis;Pseudomonas aeruginosa toxA protein;Publishing;Regulation;Research;Role;Safety;Screening for cancer;Side;Signal Transduction;Solid Neoplasm;Stomach Carcinoma;Surface;T cell therapy;T memory cell;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Therapeutic Agents;Toxic effect;Transfection;Translating;Translational Research;Tumor Cell Line;Vaccines;Work;anti-PD-L1 antibodies;anti-PD1 antibodies;antitumor effect;cancer prevention;cancer therapy;cell killing;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;cytotoxicity test;de-immunization;differential expression;drug sensitivity;effective therapy;efficacy study;exhaustion;falls;graft vs host disease;human model;humanized mouse;immune cell infiltrate;immune checkpoint;immunotherapy clinical trials;improved;in vivo;in vivo Model;ipilimumab;mesothelin;mouse model;mutant;neoplastic cell;novel;novel strategies;novel therapeutics;participant enrollment;pembrolizumab;pericardial sac;phase 1 study;phase 2 study;phase I trial;phase II trial;preclinical study;programmed cell death ligand 1;programs;receptor;stem cells;systemic inflammatory response;targeted agent;translational medicine;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions;vector Immunotherapy for Malignant Mesothelioma and Lung Cancer n/a NCI 10926075 1ZIABC010816-17 1 ZIA BC 10816 17 6189074 "HASSAN, RAFFIT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2148642 NCI 1. Exploiting mesothelin for mesothelioma therapy and related translational research Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin which is expressed on normal mesothelial cells lining the pleura pericardium and peritoneum but is highly expressed in several human tumors especially mesothelioma ovarian cancer lung cancer and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. These include anti mesothelin immunotoxin (LMB-100) an anti-mesothelin drug conjugate (BAY 94-9343) mesothelin vaccine (CRS-207) and adoptive T-cell therapy (TC-210 TC-510). We are currently developing mesothelin-targeting adoptive cellular therapy using chimeric antigen receptor (CAR)-T cells. Majority of the anti-mesothelin antibodies in clinical development target the membrane distal region of mesothelin that could partly account for the lack of activity of anti-mesothelin CAR-T cell therapy in the clinic. To improve CAR-T cell anti-tumor activity we propose a new approach i.e. developing anti-mesothelin CAR-T cells that target an epitope close to the surface of tumor cells. My collaborator Dr. Mitchell Ho has identified a high affinity rabbit monoclonal antibody (YP218) specific for region III which is located at the C-terminal end of mesothelin close to the tumor cell surface. We have tested the cytotoxicity of the hYP218 CAR-T construct on several mesothelin expressing cell lines and anti-tumor effect in animal models. The pre-clinical studies have shown increased tumor killing (1). This construct is now under clinical development. We are studying the efficacy of hYP218 CAR T cells in colorectal and gastric carcinoma pre-clinical models so that we can translate it to clinical trials of these malignancies. Along side we are working on further improving the efficacy of CAR-T cell therapy. We have shown that naive or stem cell memory T cells have better persistence than bulk T cells in pre-clinical models. We are studying the role of tumor microenvironment in CAR T-cell efficacy and persistence. Most studies so far have been done in immunocompromised hosts. We are developing immunocompetent mice tumor models to accomplish these goals. Parallelly we are conducting a clinical trial of a T-cell receptor fusion construct (TRuCs). Unlike other constructs TRuCs are naturally incorporated into the native TCR complex thus exploiting the full potential of TCR-driven T cell activation effector function and regulation. The phase 1 trial of TC-210 (also known as gavocabtagene autoleucel or gavo-cel) has recently been completed. Gavo-cel has shown promising efficacy in solid tumor with manageable toxicity (Hassan et al. Nature Medicine in press). We are now conducting the phase 2 trial of gavo-cel. T-cell exhaustion is a major reason for limited activity of adoptive cellular therapies. To overcome PD-1/PD-L1 mediated T-cell exhaustion a new TRuC construct TC-510 has been developed. This is a mesothelin directed TRuC that contains a PD-1xCD28 receptor switch. It has cell intrinsic mechanism to overcome PD-L1/PD-L2 mediated immunosuppression and turns this inhibitory function into a costimulatory signal. We are treating patients on Phase 1 study of TC-510. LMB-100 is an immunotoxin consisting of the anti-mesothelin Fv linked to a truncated form of the potent bacterial toxin Pseudomonas exotoxin A which has been de-immunized to decrease its antigenicity. We have recently completed the phase I trial of LMB-100 and established its safety and maximum tolerated dose (MTD) published in Cancer (2). Currently we are evaluating the results of a recently concluded a phase II study of LMB-100 in patients with mesothelioma in combination with immune checkpoint inhibitor Pembrolizumab. Since LMB-100 causes systemic inflammation and increase in immune cell infiltration in patient tumors we hypothesized that intra- tumoral injection of LMB-100 would lead to increased inflammation and immune cell infiltration. Administering checkpoint inhibitors would further increase tumor-cell killing. We are presently conducting a phase 1 clinical trial in patients with mesothelioma where they are intratumorally administered LMB-100 on days 1 and 4 followed by CTLA-4 checkpoint inhibitor ipilimumab given i.v. on day 2 of a 21-day cycle. Patients will receive 2 cycles of LMB-100 plus ipilimumab followed by 2 cycles of ipilimumab alone. Tumor biopsies will be performed prior to each administration of LMB-100 to evaluate changes in the tumor immune microenvironment. The trial is recruiting patients. We have previously shown that germline mutations in DNA repair genes increases sensitivity to platinum therapy and improves overall survival in patients with pleural mesothelioma (3). Currently my laboratory is studying germline mutations in DNA repair genes that could predispose to mesothelioma and influence clinical outcome. We are enrolling patients and their relatives harboring such mutations for a long term follow up study for early cancer detection and prevention. In the laboratory we have focused on developing in-vitro and in-vivo models of human mesothelioma. We have established several early passage tumor cell lines from ascites and pleural fluid of patients. We have evaluated the morphological and genetic characteristics of these cell lines and are using them to study in-vitro drug sensitivity. Additionally we have established a humanized mesothelioma xenograft tumor model with patient derived tumor cells and human PBMCs from healthy donor for in-vivo studies. As the development of Graft Versus Host Disease (GVHD) in the PBMC-humanized mouse model limits assessment of duration of anti-tumor efficacy we have developed a syngeneic immunocompetent mouse model. Because the immunotoxin LMB-100 can target human mesothelin specifically we established a human mesothelin expressing immunocompetent syngeneic mouse tumor model by transfecting PD-L1 positive mouse lung adenocarcinoma cell line with a hMSLN expressing vector encoding the membrane bound fragment of hMSLN. These cell lines were used to develop tumor. We have studied the effect of LMB-100 in combination with anti-PD1 antibody in both the models and have seen tumor regression. We have published our findings in Science Translational Medicine (4). These models are essential to evaluate novel therapeutic agents for mesothelioma and for the mechanistic studies of anti-tumor efficacy. Other ongoing laboratory studies are focused on understanding the mesothelioma tumor immune micro-environment and changes following treatment with anti-mesothelin targeted agents. 2. Immunotherapy to treat lung cancers. We are currently conducting clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C in patients with lung adenocarcinoma who have failed prior therapies. Our laboratory has recently shown that about 25% of patients with metastatic lung adenocarcinoma highly express mesothelin. Mesothelin expression in these tumors is highly associated with KRAS mutations and wild type EGFR status and is independently associated with poor prognosis. Our hypothesis is that patients with K-RAS mutant lung cancer can benefit from mesothelin directed therapies. Clinical trials of mesothelin directed therapies for treating lung cancer are about to open. Our laboratory is also studying the role of immune checkpoints in malignant mesothelioma so that drugs targeting this pathway can be exploited for treating mesothelioma. We are currently conducting a Phase II trial of NSCLC patients treated with LMB-100 in combination with pembrolizumab. 2148642 +No NIH Category available Adopted;Affect;Binding;Biochemical;Biological Assay;Bypass;Cell Nucleus;Cells;Characteristics;Complex;Cytoplasm;Defect;Dimerization;Elements;Epidemic;Evolution;Exhibits;Gatekeeping;Genome;Goals;Guanosine;HIV;HIV-1;HIV-2;Image;Integration Host Factors;Knowledge;Length;Molecular Cloning;Nucleotides;Pathway interactions;Primate Lentiviruses;Production;Proteins;Proviruses;RNA;RNA Folding;RNA Splicing;RNA Transport;Regulation;Replication Origin;Role;SIV;Site;Structure;TATA Box;Transcript;Transcription Initiation;Transcription Initiation Site;Translations;Treatment Protocols;Vaccines;Viral;Viral Genome;Viral Proteins;Virion;Virus;Virus Latency;Virus Replication;design;exportin 1 protein;fitness;improved;insight;mutant;novel;pathogen;pol Gene Products;progenitor;rev Protein;rev-Responsive Elements;transmission process Elucidating the Regulation of HIV RNA Functions: Translation Genome Packaging n/a NCI 10926074 1ZIABC010814-17 1 ZIA BC 10814 17 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 958753 NCI Retroviral full-length RNA serves two important roles in viral replication: the template for Gag/Gag-Pol translation and the genome in the virion. Recent studies from our group and others demonstrated that HIV-1 transcription initiates from multiple neighboring sites generating RNA species that only differ by a few nucleotides at the 5' end including those with one (1G) or three (3G) 5' guanosines. Strikingly 1G RNA is preferentially packaged into virions over 3G RNA. We used biochemical and virological assays to investigate how HIV-1 distinguishes between these two nearly identical HIV-1 RNAs. We found that 1G RNA but not 3G RNA mainly folds into structures that expose elements important for RNA:RNA and RNA:Gag interactions. Additionally we have identified mutants in which 1G and 3G RNAs fold into similar structures resulting in efficient packaging of 3G RNA. Thus HIV-1 selects its viral genome based on its capacity to adopt structures that facilitate RNA dimerization and Gag binding. Unspliced HIV-1 RNA serves two important roles during viral replication: as the virion genome and as the template for translation of Gag/Gag-Pol. Previous studies of two HIV-1 molecular clones have concluded that the TSS usage affects unspliced HIV-1 RNA structures and functions. To investigate the evolutionary origin of this replication strategy we determined transcription start sites (TSS) of HIV-1 RNA in infected cells and virions for 15 primate lentiviruses. All the HIV-1 isolates examined including several transmitted founder viruses utilized multiple TSS and selected a particular RNA species for packaging. Furthermore these features were observed in SIVs related to the progenitors of HIV-1 suggesting that these characteristics originated from the ancestral viruses. HIV-2 SIVs related to HIV-2 and other SIVs also exhibited multiple TSS and preferential packaging of specific unspliced RNA species. These findings indicate that multiple TSS usage and selective packaging of a particular unspliced RNA species predate the emergence of HIV-1. We have determined that transcription initiation is regulated by the distance between the CATA/TATA box and the three guanosines as well as the sequence context of the initiation sites. We have constructed two HIV-1 mutants each with two-nucleotide substitution that predominantly express 3G or 1G RNA. We found that both mutants can replicate; however both exhibited defects during stages of replication cycle; furthermore neither virus can replicate as well as the wildtype virus indicating defects in replication fitness. These results indicate that HIV-1 optimizes its replication fitness by using multiple transcription start sites to generate RNAs that serve different functions. We are currently studying how the 5' context of the HIV-1 RNA affects RNA translation and protein production as well as RNA splicing. As an unspliced RNA HIV-1 RNA needs to bypass the cellular gatekeepers to be exported from the nucleus and reach the cytoplasm. HIV-1 RNA contains an RNA structure the Rev responsive element (RRE). The viral protein Rev binds to the RRE and interacts with the host protein CRM1 to allow for the export of HIV-1 RNA. Recent studies revealed that the regulation of RNA export may be more complex than previously envisioned and may involve multiple host factors other than CRM1 and RanGTP. We are studying how export pathways affect cytoplasmic HIV-1 RNA transport and proteins associated with the RNA. In summary we seek to gain a better understanding of how HIV-1 RNA serves its critical roles in generating infectious viruses and how latent viruses can be activated. This knowledge can potentially help us design novel antiviral or cure strategies. 958753 +No NIH Category available Binding;Chromatin;Chromatin Structure;Cryoelectron Microscopy;DNA;DNA Binding Domain;DNA Sequence;Eukaryota;GATA4 gene;Genome;High Mobility Group Proteins;Histones;Kinetochores;Molecular Chaperones;Nucleosomes;Play;Proteins;Role;Structural Models;Structure;TAF1 gene;Time;gene function;insight;interest;residence;transcription factor Chromatin structure and dynamics n/a NCI 10926073 1ZIABC010808-17 1 ZIA BC 10808 17 8778148 "BAI, YAWEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2195922 NCI For FY22/23 we used cryo-EM to determine the structures of the nucleosomes containing native-DNA sequences bound to various pioneer transcription factors including OCT4 Pu.1 FoxA1/GATA4 and Ascl1. Our studies provide structural insights into the hypothesis of pioneer transcription factors (PTF) by showing: (i) PTFs help evict H1 by direct blocking and by an allosteric effect; (ii) the DNA binding domain can serve as a wedge to unwrap the nucleosomal DNA; (iii) multiple PTFs can bind to the nucleosome which may increase the overall residence time. In addition we found surprisingly that PTFs may use non-canonical motifs instead of canonical motifs to bind the nucleosome. We also established a structural model of H1 bound to its chaperone TAF1-beta using NMR. We showed that TAF1-beta binds to the linker histone and functions as a chaperone by blocking H1 interactions with DNA. 2195922 +No NIH Category available ALK gene;Ablation;Affinity;Amino Acids;Animal Model;Antigens;Apoptosis;Biological Assay;Biological Products;Biology;Bromodomain;CD276 gene;CD3 Antigens;CD8B1 gene;CMV promoter;CRISPR screen;CRISPR/Cas technology;Cell Death;Cell Line;Cell Therapy;Cell physiology;Cell surface;Cells;Childhood;Childhood Solid Neoplasm;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complement;Detection;Development;Dimensions;Down-Regulation;Drug Compounding;Drug Screening;Enhancers;Ensure;Epidermal Growth Factor Receptor;Epigenetic Process;Evaluation;Extracellular Domain;FDA approved;FGFR4 gene;FOXO1A gene;Family member;Firefly Luciferases;Generations;Genes;Genetic;Genetic Transcription;Goals;Green Fluorescent Proteins;Growth;Human;Immune Targeting;Immunotherapeutic agent;Immunotherapy;In Vitro;Injury;Institution;Investigation;Knock-in;Laboratories;Lead;Libraries;Luciferases;Malignant Childhood Neoplasm;Mediating;Methods;Molecular;Monitor;Monoclonal Antibodies;Mus;Mutate;Mutation;Myoblasts;National Center for Advancing Translational Sciences;Neuroblastoma;Normal tissue morphology;Oncogenes;Organ;PAX3 gene;Pathogenesis;Patient-Focused Outcomes;Patients;Peptides;Pharmaceutical Preparations;Phase;Play;Post-Translational Protein Processing;Process;Prognostic Marker;Proteins;RNA Interference;Receptor Protein-Tyrosine Kinases;Renilla Luciferases;Reporter;Research;Rhabdomyosarcoma;Role;Safety;Signal Transduction;System;T-Cell Receptor;Technology;Tertiary Protein Structure;Therapeutic Intervention;Toxic effect;Translating;Transmembrane Domain;Xenograft procedure;cancer therapy;chimeric antigen receptor;chimeric antigen receptor T cells;design;diagnostic biomarker;differential expression;fusion gene;gene repression;genome-wide;high risk;high throughput screening;improved outcome;in vivo;inhibitor;knockout gene;luminescence;muscle regeneration;novel;novel therapeutics;patient derived xenograft model;peripheral blood;pharmacologic;programs;protein protein interaction;proteostasis;receptor;response;small molecule;synergism;targeted treatment;therapeutic target;trafficking Developing Novel Therapies for High Risk Pediatric Cancers n/a NCI 10926072 1ZIABC010806-17 1 ZIA BC 10806 17 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 922580 NCI The goal of this project is to identify potential therapeutic targets for PAX3-FOXO1 funsion gene driven Rhabdomyosarcoma (FP-RMS) and Neuroblastoma (NB). We employ various assays including the Incutyte and iCELLigence System. Furthermore we conduct CRISPR screens using genome-wide and epigenetic-focused libraries to uncover critical genetic and epigenetic factors involved in RMS pathogenesis. For the drug screening phase we conduct extensive analyses of single agent and combination responses to a panel of over 2000 drugs. This panel known as the Mechanism Interrogation Plate has been developed by NCATS. The library includes FDA-approved compounds some of which are already used in cancer therapy as well as those currently in clinical trials (phase 1 2 or 3. The targets or mechanisms of action are known for these compounds. Our strategy revolves around identifying the most promising targets which will undergo further evaluation using patient-derived xenograft animal models. In collaboration with NCATS we are also conducting targeted efforts to identify inhibitors of the PAX3-FOXO1 fusion gene which plays a pivotal role in RMS pathogenesis. To accomplish this we utilize a PAX3-FOXO1 activity reporter cell line that we developed in our laboratory. This reporter line utilizes the super-enhancer region within the ALK gene cloned upstream of a minimal CMV promoter that drives a Green Fluorescent Protein (GFP)-Luciferase reporter. This setup allows us to efficiently monitor PAX3-FOXO1 activity and assess its responses to different treatments. Additionally we have now developed a more direct and accurate approach by using assay readouts of tagged endogenous proteins. To achieve this we decided to fuse the pro-luminescent HiBiT peptide to the endogenous PAX3-FOXO1 using CRISPR/Cas9-mediated knockin. The HiBiT peptide is a small 11-amino acid peptide capable of producing a luminescence signal that is approximately 100-fold brighter than traditional firefly or Renilla luciferases. This high-affinity complementation with LgBiT an 18 kDa subunit derived from the NanoLuc luciferase enables detection with exceptional sensitivity. With the HiBiT signal readily detectable we were able to monitor HiBiT-tagged PAX3-FOXO1 levels at the protein level upon treatment with the BRD4 inhibitors JQ1 and CPI-0610 which have demonstrated promising effects on FP-RMS xenograft growth suppression. The results from our previous studies have been quite promising revealing that PAX3-FOXO1 reprograms the cis-regulatory epigenetic landscape by inducing de novo super-enhancers. This phenomenon occurs in collaboration with the bromodomain and extra-terminal domain protein family member BRD4 effectively locking the RMS cells in a myoblast-like state. These findings demonstrate the feasibility of using unbiased high-throughput screening approaches to identify small molecules that can effectively disrupt the PAX3-FOXO1 core regulatory circuitry. Of particular significance we have observed that the transcriptional activity of PAX3-FOXO1 relies heavily on its physical interaction with BRD4. To this end we utilized the BRD4 inhibitor JQ1 which effectively ablates this interaction and subsequently reduces PAX3-FOXO1 protein levels. This reduction correlates with the suppression of FP-RMS xenograft growth in mice making it a promising avenue for potential therapeutic intervention. Beyond protein-protein interactions we recognize that protein homeostasis which encompasses processes such as synthesis folding trafficking and degradation plays a crucial role in cellular function. Consequently we are exploring strategies to selectively target specific post-translational modifications that could lead to decreased stability or activity of PAX3-FOXO1 offering an attractive approach to developing novel FP-RMS therapies. Our research efforts extend beyond PAX3-FOXO1 as we recognize the significance of other potential therapeutic targets. In this regard we have identified FGFR4 as a rational target for RMS due to its essential role in myogenic differentiation and muscle regeneration after injury. Moreover FGFR4 is highly expressed in all RMS and has been identified as a diagnostic and prognostic biomarker. In addition to this we have noted that approximately 10% of FN-RMS have activating mutations in FGFR4 and cells harboring these mutations are oncogene-addicted and sensitive to pharmacological inhibition by small molecules. These findings solidify FGFR4 as a key cell surface tyrosine kinase receptor for RMS biology growth and survival. Our focus on FGFR4 has led us to develop monoclonal antibodies and human scFv binders to target this receptor. We are diligently examining FGFR4 expression levels in normal human organs to mitigate potential organ toxicity concerns. Furthermore we are actively pursuing the development of FGFR4 GPC2 and CD276 chimeric antigen receptors (CARs) as potential therapies for RMS and NB. For RMS we have designed a second-generation lentiviral construct for the FGFR4 CAR that contains the CD8 transmembrane region 41BB CD3zeta intracellular domains and a human EGFR extracellular domain. This design has proven effective in clinical trials showing CAR T cell persistence in patients' peripheral blood for several months after therapy. Our anti-FGFR4 CART cells have shown promising results in vitro and in vivo. Our research endeavors also extend to the development of novel TCRs (T-cell receptors) as potential therapies for pediatric solid tumors. The successful development of potent immunotherapeutic biologics and cell-based therapies for aggressive pediatric cancers is a key objective of our ongoing efforts. In conclusion our research efforts for NB and RMS are multidimensional and encompass various cutting-edge technologies and approaches. We aim to identify and validate promising therapeutic targets while ensuring the safety and efficacy of potential treatment options. Through extensive drug screening molecular investigations and collaboration with leading institutions we strive to advance novel therapies that will make a significant impact on improving outcomes for patients with RMS and other aggressive pediatric cancers. 922580 +No NIH Category available Alternative Splicing;Area;Bacillus subtilis;Bacteria;Base Pairing;Biochemical;Biochemistry;Bioinformatics;Biological;Biological Assay;Biological Models;Breast Cancer Cell;Breast Cancer cell line;Cells;Clinical;Codon Nucleotides;Collaborations;Communication;Coupled;Coupling;Cues;DNA;DNA Repair;DNA lesion;DNA sequencing;DNA-Directed RNA Polymerase;Data;Disease;Distal;ERBB2 gene;Elongation Factor;Energy-Generating Resources;Environment;Epigenetic Process;Escherichia coli;Estrogen receptor negative;Eukaryota;Eukaryotic Cell;Evaluation;Event;Failure;Foundations;Frequencies;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomic Instability;Goals;Growth;Human;Hypoxia;In Vitro;Intervention;Laboratories;Malignant Neoplasms;Manuscripts;Maps;Metabolic;Methodology;Methods;Modeling;Modernization;Molecular;Molecular Biology;Nature;Neoplasm Metastasis;Nonsense Mutation;Nucleosomes;Organism;Outcome;Oxidative Phosphorylation;Paper;Pathway interactions;Play;Polymerase;Preparation;Progesterone Receptors;Prognosis;Prokaryotic Cells;Protein Isoforms;Proteins;Publishing;RNA;RNA Caps;RNA Polymerase II;RNA Processing;RNA Splicing;Reaction;Recurrent Malignant Neoplasm;Regulation;Reporter Genes;Research;Resolution;Ribonucleases;Role;Saccharomyces cerevisiae;Signal Transduction;Site;Solid;Solid Neoplasm;Stress;Structure;Targeted Research;Techniques;Technology;Testing;Transcript;Transcriptional Elongation Factors;Transcriptional Regulation;Translations;Woman;Work;Yeasts;attenuation;biological adaptation to stress;cancer cell;cancer recurrence;cancer type;cleavage factor;court;environmental change;genetic approach;genetic manipulation;genome-wide;hormone therapy;in vivo;knock-down;knockout gene;malignant breast neoplasm;mutant;next generation sequencing;novel;promoter;response;rho;termination factor;transcription factor;transcription factor S-II;transcription termination;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor progression;tumorigenesis Mechanisms of transcription pausing and fidelity in prokaryotes and eukaryotes n/a NCI 10926071 1ZIABC010795-17 1 ZIA BC 10795 17 6802163 "KASHLEV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1724328 NCI In this project my lab published 2 research papers (PNAS and Nature Communications) and a review article in Critical Reviews in Biochemistry and Molecular Biology. We also have one collaborative manuscript published in 2021 in eLife that describes the role of elongation factor NusG in transcription termination in B. subtilis. We completed developed a new powerful NGS method involving a combination of ribonuclease-coupled NET-seq (RNET-seq) and DNA-seq that allows genome-wide mapping of pause sites for E. coli B. subtilis and human RNA polymerase II (Pol II) with a single base pair resolution. This methodology allowed us to determine translocation register of RNA polymerase at each pause site and identify the underlying causes of pausing. This method enabled direct examination of the role of ALL general and specialized transcription elongation and termination factors NusA NusG NusB Rho RfaH SuhB RpoD (sigma70) GreA GreB mfd and UvrD in pausing and promoter escape in vivo. This goal was achieved by applying RNET-seq/DNA-seq to the genetically modified bacterial strains carrying the systematic gene knockouts and conditional knockdowns (using inducible dCas9 transcription roadblocks) of the corresponding target gene followed by biochemical evaluation of the mechanism of pausing at the representative pause sites in vitro. By using RNET-seq we were first to demonstrate the crucial role of sigma70 subunit and Gre transcript cleavage factors in regulation of promoter escape at a striking large number of E. coli promoters primarily involved in regulation of stress response and cellular responses to changing environmental cues (Nature Communications). We also elucidated the role of elongation factors NusA and NusG in regulation of transcription pausing and termination in E. coli and B. subtilis (PNAS eLife and manuscript in preparation). Transcription fidelity: In our approach to study transcription fidelity we combine the efficiency and high-sensitivity of the novel cre/lox-based genetic assay developed for the yeast and E. coli cells in our group as a team effort with three other RBL groups with the power and precision of biochemical analysis of RNAP mutants transcription factors and reaction conditions promoting transcription errors in these organisms. We also study in vitro the mechanisms of transcription fidelity in higher eukaryotes. For genetic assay we create site-directed chromosomal mutants and gene constructs using advanced high-precision methods of gene manipulations based on recombineering developed in collaboration with Don Court's group. Application of the modern NGS RNA sequencing techniques brings our analysis of transcription errors to a genome-wide scale. The use of four biological models namely E. coli B. subtilis S. cerevisiae and human triple negative breast cancer (TNBC) cells under normal and stress conditions allows us to do the cross-species and cross-kingdom study of transcription fidelity helping to unravel conserved and unique features of strategies that various organisms implement to control transcription fidelity. We believe that the experimental strategy and techniques that we use in the current work lay a solid foundation for our future studies on transcription fidelity. In 2020-21 my lab continued active intervention to the new area of transcription research targeting the role of pausing of human Pol II in transcription-coupled events of 5' RNA capping co-transcriptional splicing and transcription termination in triple negative breast cancer cells (TNBCs). This study will help us in identifying the novel splicing isoforms genome-wide which are deregulated in TNBC cells. Since hypoxic stress is an emerging hallmark of TNBCs we aim to determine how the RNA capping co-transcriptional splicing and transcription termination downstream from polyA sites are deregulated during hypoxic stress. Our preliminary data strongly indicate that co-transcriptional splicing and transcription termination downstream from the polyA sites are significantly altered in TNBC cells compared to their non-TNBC counterparts including these events in hypoxia-induced genes. 1724328 +No NIH Category available 3-Dimensional;Accounting;Adopted;Affect;Affinity;Alleles;Amino Acids;Area;Binding;Bioinformatics;CD94 Antigen;Cell surface;Cells;Clinical;Competence;Complex;Computer Models;Copy Number Polymorphism;Cytomegalovirus;Data;Dependence;Development;Dimensions;Disease;Disease Outcome;Disease model;Education;Effector Cell;Elements;Ensure;Epitopes;Foundations;Frequencies;GEM gene;Gene Frequency;Genes;Genetic Polymorphism;Genetic Transcription;Genetic study;Genotype;HLA Class I Genes;HLA-A gene;HLA-B Antigens;HLA-C Antigens;Immune;Immune response;Immunogenetics;Individual;Innate Immune Response;Investigation;KLRD1 gene;Ligands;Maps;Measures;Mediating;Messenger RNA;Methods;Molecular Conformation;Molecular Genetics;Motion;Natural Immunity;Natural Killer Cells;Pathogenesis;Pattern;Peptide Signal Sequences;Peptides;Population;Population Study;Positioning Attribute;Process;Property;Protein Isoforms;Proteins;Protocols documentation;RNA;Regulation;Resolution;Role;Sampling;Structure;T-Lymphocyte;Time;Transcript;Variant;Viral;Virus;acquired immunity;adaptive immune response;antigenic peptide transporter;cell type;cohort;differential expression;disorder risk;genome wide association study;human disease;improved;insight;interest;molecular dynamics;novel;preference;pressure;receptor;receptor binding;reference genome;single-cell RNA sequencing;tapasin;tool;transcriptome;transcriptome sequencing Molecular genetics and population studies of the KIR and HLA gene complexes n/a NCI 10926069 1ZIABC010792-17 1 ZIA BC 10792 17 9414396 "CARRINGTON, MARY N." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 510799 NCI HLA-E is expressed at low levels by most cell types and is loaded primarily with nonamer peptides called VL9 derived from the signal peptides (SPs) of HLA-A -B -C and -G. HLA-E is the ligand for the inhibitory CD94/NKG2A and activating CD94/NKG2C receptors expressed on subsets of NK and T cells. HLA-E-mediated inhibition dominates over activation because CD94/NKG2A is expressed on a much greater fraction of effector cells and has higher affinity for HLA-E than does CD94/NKG2C. Like KIR CD94/NKG2A plays a role in NK cell education which results in functional competence of cells expressing inhibitory receptors that bind self-HLA class I. Functionally competent CD94/NKG2A positive NK cells can eliminate target cells in the periphery that have downregulated levels of HLA-E on their cell surface. HLA class I SPs are moderately polymorphic but not all allotypes can generate peptides suitable for HLA-E loading. We systematically characterized the degree to which all common HLA-A- HL-B and -C derived SPs facilitate cell surface expression of HLA-E and recognition by CD94/NKG2. We found that among 16 common classical HLA class I SP variants only 6 can be efficiently processed to generate epitopes that enable CD94/NKG2 engagement which we term 'functional SPs'. The single functional HLA-B SP known as HLA-B-21M induced high HLA-E expression but conferred the lowest receptor recognition. Consequently HLA-B-21M SP competes with other SPs for providing epitope to HLA-E and reduces overall recognition of target cells by CD94/NKG2A calling for reassessment of previous disease models involving HLA-B/-21M. The combined frequencies of functional SPs at each individual HLA locus are remarkably similar across populations despite well-described differences in HLA allele frequencies across these same populations suggesting that selection pressure may maintain prescribed frequencies of functional SPs at each locus. The frequency patterns indicate a dominant role for HLA-A and HLA-C loci in HLA-E-mediated regulation of effector cells at the population level particularly given that the single 'functional' HLA-B SP (SP-6B) confers poor CD94/NKG2 recognition. The major contribution of HLA-A and HLA-C is also supported by the frequencies of HCMV VL9 variants which mimic HLA-A and HLA-C (but not HLA-B) functional SPs with frequencies that correlate between the virus and the host. This correlation suggests viral adaptation to mimic host. Interestingly VMAPRTLIL the most frequent HCMV VL9 variant is a derivative of an HLA-C SP which induced relatively high levels of HLA-E expression and receptor recognition in our study suggesting that HCMV has adapted not only to the most common host classical HLA VL9 variant but also to the most optimal in terms of binding to HLA-E and engaging CD94/NKG2A. Differential CD94/NKG2 recognition of HLA-E-VL9 is likely to impact immune responses in disease/clinical settings. Our comprehensive characterization of HLA class I SP polymorphism and its influence on HLA-E-mediated regulation of effector cells expressing CD94/NKG2 provide the foundation for building computational models to predict strength of immune responses based on HLA class I genotypes affording more accurate interpretation of disease association data and understanding of disease pathogenesis. HLA class I and II loci are essential elements of innate and acquired immunity. Their exceptional influence on disease outcome has now been made clear by genome-wide association studies. HLA polymorphism has been the main focus for determining HLA effects on disease. However HLA expression levels have also been implicated in disease outcome adding another dimension to the extreme diversity of HLA that impacts variability in immune responses across individuals. To estimate HLA expression immunogenetic studies traditionally rely on qPCR. Recently however multiple bioinformatic methods have been developed to accurately estimate HLA expression from RNA-seq data. We analyzed three types of expression data for HLA class I genes for a matched set of individuals: RNA-seq qPCR and cell surface HLA-C expression. We observed a moderate correlation between expression estimates from qPCR and RNA-seq for HLA-A -B and -C. However our study suggests areas that require improvement in the determination of HLA transcript expression. Comparisons between RNA-seq and qPCR for example should employ uniform processing of samples across methods (e.g. same RNA isolation protocol storage/thawing time RNA integrity) to limit artefactual differences associated with these methods. Mapping short reads to single reference genomes or transcriptomes clearly generates biases and strategies that map reads accounting for HLA polymorphism are necessary. There is also a need to develop methods that adequately account for isoform variation. In this context long-read data which directly generates full transcript information can be a powerful tool. Finally copy number variation should also be considered when quantifying expression levels. HLA class I is loaded with peptide by the multiprotein peptide loading complex (PLC) within the ER. Tapasin a key protein of the PLC bridges HLA class I molecules and the transporter associated with antigen processing TAP. It also stabilizes HLA class I in a peptide-receptive conformation promoting peptide exchange to ensure binding of sufficiently high affinity peptides and stability on the cell surface. HLA class I allotypes vary in their dependence on tapasin for peptide loading and expression on the cell surface which may confer selective immune advantages for CTL recognition depending on disease type ultimately affecting the quality of immune responses. We have quantified tapasin dependence (TD) values for 250 HLA allotypes commonly present across worldwide populations. The data show a continuum of TD values for these allotypes. Among these 250 allotypes 106 pairs differed by only a single amino acid showing a range of differences in TD level between allotypes of each pair. Single amino acid changes within some regions such as positions 60-80 of the HLA-A molecule consistently showed no effect on TD level. Other positions such as 97-116 of HLA-B (within/near the F pocket) either strongly affected TD level (resulting in high log delta TD values) for certain pairs of allotypes or had very little impact on TD level (low log delta TD). Overall the data suggest that variation in certain regions of the HLA peptide binding groove (hotspots) are more important than others in determining TD level but complexities of the peptide binding region (PBR) structure in general can impact whether variation within the hotspot will or will not impact TD level. Given the global contribution of the PBR in determining TD level we have considered structural and conformational changes that may potentially impact the interactions between tapasin and HLA class I allotypes and influence TD. Molecular dynamic (MD) simulations which provide an estimate of the motion (and thus stability) of a molecule in 3D can reveal differences in stability between proteins as measured by the root mean square deviation (RMSD). We have begun to explore RMSD for pairs of alleles that differ by only a single amino acid. The structure of the more tapasin-dependent allele of a given pair generally appeared less conformationally stable (higher RMSD) compared to that of the tapasin-independent allele (lower RMSD). Overall these data suggest that tapasin-dependent allotypes are generally less capable of adopting a peptide receptive conformation on their own perhaps explaining their greater dependence on tapasin for optimal peptide loading. 510799 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;Affinity;African;African American population;Alleles;Amino Acids;Antibody Response;Antigens;Autoimmune Diseases;Binding;Binding Sites;Biological;Biological Process;Black Populations;Black race;CD8-Positive T-Lymphocytes;CD8B1 gene;CD94 Antigen;Categories;Cell surface;Cells;Characteristics;Clinical;Communicable Diseases;Complex;Data;Data Set;Databases;Dependence;Disease;Disease Outcome;Entropy;Enzyme-Linked Immunosorbent Assay;Family;Freedom;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;HIV;HIV Antigens;HIV vaccine;HIV-1;HLA-A gene;HLA-B Antigens;HLA-C Antigens;Heterozygote;Homozygote;Immune;Immune Response Genes;Immune response;Immunogenetics;Immunoglobulins;Immunologic Receptors;Immunologic Surveillance;Incidence;Individual;Innate Immune Response;Interruption;KLRD1 gene;Killer Cells;Knowledge;Leukocytes;Ligands;Link;Macaca;Malaria;Malignant Neoplasms;Measures;Messenger RNA;MicroRNAs;Minor;Molecular;Mutation;Natural History;Natural Killer Cells;Noise;Outcome;Parasites;Pathogenesis;Peptide Signal Sequences;Peptides;Phase II Clinical Trials;Plasmodium falciparum;Population;Positioning Attribute;Predisposition;Prevalence;Principal Component Analysis;Process;Property;Proteins;Reporting;Resistance;Resources;Risk;Role;Shapes;Signal Pathway;Stains;T cell response;T-Lymphocyte;Testing;Time;Transcription Factor AP-2 Alpha;Transplantation;Uganda;Vaccination;Vaccine Antigen;Vaccines;Variant;Viral Load result;Virus;antigen test;cancer immunotherapy;cohort;env Gene Products;gag Gene Products;genetic association;human disease;human leukocyte antigen testing;improved;interest;mRNA Expression;mosaic;novel;peptide I;pol Gene Products;receptor;response;tapasin;tool;vaccine efficacy;vaccine response;vaccine trial Effects of genetic polymorphism in MHC KIR and related loci on human disease n/a NCI 10926068 1ZIABC010791-17 1 ZIA BC 10791 17 9414396 "CARRINGTON, MARY N." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 638498 NCI "HLA class I (HLA-I) allotypes vary widely in their dependence on tapasin (TAPBP) an integral component of the peptide loading complex to present peptides on the cell surface. We have determined tapasin dependence (TD) values for common HLA-I allotypes across worldwide populations (N = 250) which show a continuum of values for HLA-A HLA-B and HLA-C. This variation is functionally relevant as tapasin-independent allotypes were shown to present a broader array of peptides than tapasin-dependent allotypes and tapasin independence conferred protection in HIV-1 disease. Given the role of tapasin in shaping the HLA-I peptide repertoire and its impact on disease outcome we hypothesized that natural variation in its expression level could also affect disease pathogenesis and susceptibility. We have studied a large longitudinal malaria cohort collected in Uganda to estimate immunogenetic effects of variation on malarial disease outcome. One of these studies identified two SNPs rs111686073 (G or C) and rs59097151 (A or G) that regulate TAPBP mRNA expression levels by altering AP-2alpha transcription factor and microRNA-4486 binding sites respectively. The variants conferring high TAPBP mRNA level rs111686073G and rs59097151A associated with lower Plasmodium falciparum parasite prevalence and lower incidence of clinical malaria specifically among individuals carrying tapasin-dependent HLA class I allotypes. Tapasin-independent allotypes associated with relative protection regardless of the genotype at these two SNPs. These data suggest that higher tapasin expression levels can enhance peptide loading of tapasin-dependent allotypes to a similar extent displayed by tapasin-independent allotypes resulting in better control of P. falciparum. Associations between HLA Class I alleles and HIV disease have long been known. Established associations in Blacks include protective associations for B5702 B5703 B5801 and B8101 and susceptible associations for B1801 B1802 B4501 and B5802. The Janssen vaccine phase 2 clinical trial studied many aspects of the immune response to a mosaic antigen vaccine; ELISA and ELISpot response to HIV antigens were predictive of protection against HIV challenge in the parallel macaque vaccine trial. Trial data with vaccine response reported includes 306 subjects of which 172 are African Americans or Black Africans thus we focused our analyses on this group. We investigated whether the association of HLA with HIV control also associated with differential gag/env response after vaccination. Response measures included the strength of ELISA responses which measured antibody responses to five variant Env proteins and ELISpot count which measured T-cell responses to 11 Env Gag and Pol protein pools. In addition we considered intra-cellular staining (ICS) antigen response levels elicited by both CD4 and CD8 T cells for 10 Env Gag and Pol protein pools as these assess T cell functionality distinctly from ELISpot and ICS responses were previously linked to protection in previous vaccine trials. A principal components analysis (PCA) was performed to reduce the degrees of freedom for the multiple HIV antigens tested in the ELISA and ELISpot analysis; the first principal component (PC) captured the strength of overall response while the second PC captured differential response to different antigens. There were no significant associations for HLA class I or II in the first PC for ELISA or ELISpot responses but the second PC for ELISpot response approached statistical significance for some class I alleles after correction for the number of comparisons tested (FDR less than 0.1). The second PC of the ELISpot data was primarily driven by the difference between the T cell responses to Gag vs. Env antigens. Responses to Gag are known to confer HIV control in natural history studies whereas those to Env are less protective because of the extreme mutation rate of the gene encoding Env. Thus we hypothesized that the HLA associations identified in the second PC reflected a differential response to Gag vs. Env by those alleles that showed significance. We therefore defined a ""Gag - Env"" variable for ELISpot and ICS by subtracting the mean Env response from the mean Gag response and tested for HLA class I associations with this variable. Several significant associations were observed. The strongest association was that of HLA-B5703 with the CD8 ICS Gag - Env response (FDR of 5E-07). Of note HLA-B shows the strongest effects for control of HIV. We also observed a significant correlation between the effects of HLA-B alleles on HIV viral load control (measured as mean HIV viral load over time) and the Gag - Env variable. Thus HLA-B alleles that confer protection in untreated HIV-1 infected subjects may also confer protective CD8 T cell responses to HIV vaccines that contain HIV Gag inserts as antigens. These data suggest that vaccine efficacy may apply to a proportion of subjects receiving the vaccine. HLA allelic diversity is thought to be maintained through overdominance a selective advantage determined by allelic heterozygosity. Heterozygous advantage may be the result of a broader variety of peptides presented by HLA resulting in a better immune surveillance than for homozygous individuals whose universe of peptides is determined by one allele only. We have previously reported this detrimental effect on HIV progression. A limitation of this analysis emanates from the blunt distinction between genetically homozygous vs. heterozygous individuals. A genotype composed of two alleles that are very closely related may for example bind as limited a peptide repertoire as do true genetic homozygotes. Calculation of genetic distances between the pair of alleles composing a given genotype is one means for estimating the degree of functional similarity between pairs of alleles assuming that as the genetic distance between alleles increases so should the distinctiveness of the peptide repertoire. However genetic distance analyzed as a continuous variable showed no effect on AIDS progression in our seroconverter cohort. Detailed studies of peptides eluted from various common HLA class I allotypes have been performed and made publicly available. These data provide the means to more directly quantitate the impact of allelic heterozygosity on the breadth of the HLA peptide repertoire. We focused on aggregate properties of the peptides presented by a given allotype rather than minor differences across peptides. We retained only those amino acids with a positional entropy lower than 0.1 (i.e. high selectivity for one amino acid at a given position) in order to reduce noise contributed at positions with high entropy. The resulting simplified logograms termed submotifs allow compact representation of the different families of peptides that a given allotype can present. This approach condensed a universe of 111898 nonamer peptides presented by 95 different HLA class I allotypes into 382 distinct submotifs. We compared submotifs of the allotype pairs encoded by a given genotype at each locus and calculated the proportion of submotifs that are not shared between that pair of allotypes in order to quantify the functional divergence between allotypes. Using the novel submotif metric we compared for each locus individuals with the most functionally divergent genotypes to those with the least functionally divergent genotypes. This categorization at each locus improved the association with AIDS progression far beyond that observed for genetic zygosity at both HLA-A (HR 2.63 p 3.5E-05) and HLA-B (HR 2.68 p 2.5E-05). We plan to apply the metric or related metrics to other human diseases including other infectious diseases cancer and outcome to cancer immunotherapy and autoimmune diseases." 638498 +No NIH Category available Achievement;Acquired Immunodeficiency Syndrome;Acute;Affect;Animal Cancer Model;Anti-Tumor Necrosis Factor Therapy;Antigen-Antibody Complex;Antigens;Antineoplastic Agents;Apoptotic;Arthritis;Autoimmune;Autoimmune Diseases;Biological;Blood Vessels;COVID-19;Cell Proliferation;Chronic;Collaborations;Crohn's disease;Development;Disease;Dose;Emigrations;Exhibits;Genes;Glucocorticoids;Growth;Helicobacter Infections;Hepatitis C;Immature Monocyte;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Innate Immune Response;Innate Immune System;Interferons;Interleukin-1;Interleukin-10;Interleukin-13;Interleukin-4;Invaded;Knock-out;Laboratories;Lipopolysaccharides;Lymphangiogenesis;Macrophage;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Mediator;Modeling;Molecular;Multiple Sclerosis;Mus;NF-kappa B;Necrosis;Neoplasm Metastasis;Nitric Oxide;Parasites;Participant;Pathogenesis;Pathologic;Pathology;Pathway interactions;Peripheral;Phenotype;Play;Primary carcinoma of the liver cells;Process;Production;Proteins;Regulation;Research;Rheumatoid Arthritis;Role;SARS-CoV-2 infection;Septic Shock;Signal Pathway;Site;T-Lymphocyte;TNF gene;TNFR1 Signaling Pathway;Testing;Therapeutic;Tissue Differentiation;Tissues;Transforming Growth Factors;Tumor Promotion;Tumor-associated macrophages;Virus Diseases;Whole Organism;adaptive immune response;angiogenesis;antagonist;arginase;cancer therapy;cancer type;chronic inflammatory disease;colon carcinogenesis;cytokine release syndrome;cytotoxicity;extracellular;leukemia/lymphoma;malignant breast neoplasm;malignant stomach neoplasm;monocyte;neoplastic cell;neutralizing antibody;pathogen;response;transcription factor;tumor;tumor growth;tumor initiation;tumorigenesis Inflammation Macrophage Differentiation and Cancer n/a NCI 10926065 1ZIABC010783-17 1 ZIA BC 10783 17 9417013 "LIU, ZHENG-GANG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 660538 NCI "Inflammation plays a critical role in tumorigenesis and it is known that many cancers are associated with sites of chronic inflammation. For instance colon carcinogenesis is associated with inflammatory bowel diseases (IBD) Helicobacter pylori infection is the cause of stomach cancer and hepatitis C viral infection correlates with liver carcinoma. Opposing effects of TNF on cancer have been described: high dose of TNF (acute inflammation) has antineoplastic effects such as direct cytotoxicity on certain types of cancer while endogenous low-dose of TNF (chronic inflammation) promotes cancer development. As a potent inducer of NF-kB activation the tumor promoting effect of TNF is believed to be through activating this transcription factor. The constitutive activation of NF-kB is associated with many autoimmune inflammatory diseases such as rheumatoid arthritis multiple sclerosis and inflammatory bowel disease as well as certain cancers such as leukemia and lymphomas breast cancer and gastrointestinal cancers. NF-kB promotes tumorigenesis both by enhancing cell proliferation and by induction of anti-apoptotic genes. Inhibition of NF-kB is a potential anti-cancer therapy. However one of the caveats in inhibiting NF-kB systemically is that NF-kB is indispensable for both innate and adaptive immune responses. Tissue-specific knock-out models allow to study the effects of selective targeting of the NF-kB pathway on tumorigenesis without affecting NF-kB in the whole organism. Due to the tumor promoting effect of TNF TNF antagonists have been suggested as potential cancer treatment agents. Alternatively targeting various molecules involved in TNFR1 signaling pathway upstream of NF-kB is another possible therapeutic strategy against cancer-promoting inflammatory responses. Macrophages are chief participants in host inflammatory responses of the innate immune system. Deregulation of macrophage differentiation and function may lead to diseases including cancer Following antigen stimulation immature monocytes emigrate from blood vessels into peripheral tissues where they differentiate into mature macrophages. Macrophages are considered classically activated (M1) when stimulated by interferon (IFN) or lipopolysaccharide (LPS) to release nitric oxide (NO) important for killing intracellular pathogens and alternatively activated (M2) when stimulated by interleukin (IL)-4 or IL-13 (M2a) to produce IL-10 transforming growth factor (TGF) and arginase-1 (Arg1) important for killing extracellular parasites. M2 can be further subdivided to those induced by immune complexes (ICs) and LPS or IL-1 (M2b) or those induced by IL-10 TGF or glucocorticoids (GC) (M2c) (51). The molecular processes that occur during monocyte/macrophage differentiation and polarization particularly in the differentiation of M2 type macrophage are not completely understood. The capability of macrophages to express distinct functional phenotypes is typically manifested in pathological conditions including cancer. Tumor-associated macrophages (TAMs) which represent the major inflammatory component of the stroma of many tumors are critical mediators of tumor initiation progression and metastasis. In contrast with normal macrophages TAMs exhibit pro-tumoral functions including the growth survival invasion and metastasis of tumor cells as well as angiogenesis and lymphangiogenesis in tumors. TAMs have been shown to display an alternative M2 like activation phenotype and play a detrimental pro-tumoral role. Blocking TAMs functions has been shown to have great inhibitory effect on tumorigenesis. We also study the regulation of monocyte/macrophage differentiation. Particularly how tumor cells regulates macrophages to become tumor associated macrophages. Recently we found that tumor necrosis/necroptosis-induced inflammation is critical for tumorigenesis. tumor cells secret certain proteins to mediate the differentiation of TAMs which in turn promote tumor growth. we are evaluating the roles of these proteins on TAMs function in animal cancer models. Eventually we will test if using neutralizing antibodies against these proteins will help to control tumor metastasis. We also collaborated with others to study the inflammation-promoting effect on tumor development. We are currently using mouse macrophages to study macrophage-mediated response to SARS-Cov-2 infection in vitro. We found that macrophages play a critical role in host ""cytokine storm response"" and pathology caused by infection." 660538 +No NIH Category available Adverse effects;Anti-Retroviral Agents;Antiviral Agents;Betulinic Acid;Binding;Biochemical;Capsid;Cells;Clinical Trials;Collaborations;Conduct Clinical Trials;Development;Generations;Genetic Polymorphism;Goals;HIV-1;Link;Maps;Molecular;Mutation;Pathway interactions;Patients;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phytic Acid;Play;Polyproteins;Preclinical Testing;Property;Protein Biosynthesis;Research;Resistance;Role;SP1 gene;Site;Structural Biologist;Structure;Structure-Activity Relationship;Techniques;Time;Toxic effect;Viral;Viral Load result;Virus;Work;analog;antiretroviral therapy;forging;gag Gene Products;inhibitor;insight;multidisciplinary;mutant;novel;resistance mutation;response;structural biology;viral resistance HIV-1 Maturation n/a NCI 10926063 1ZIABC010778-17 1 ZIA BC 10778 17 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1001849 OD "While currently available antiretroviral therapies are highly effective in suppressing HIV-1 replication in treated patients these drugs are not curative. Patients are thus required to remain on continuous lifelong therapy which has been associated with a variety of toxicities and adverse effects. Also over time viral resistance is likely to pose an increasingly serious problem for patients on therapy. The development of novel classes of inhibitors that block steps in the replication cycle distinct from those targeted by currently available drugs is therefore a high priority. We have played a leading role in the development of one such novel class of HIV-1 antiviral drugs the maturation inhibitors (MIs). _____In the HIV-1 replication cycle Gag proteins are synthesized as a polyprotein precursor (Pr55Gag) that is cleaved by the viral protease (PR) during virus release from the infected cell. Completion of the Gag processing cascade is essential for virus maturation and infectivity. In collaboration with Panacos Pharmaceuticals we found that 3-0-(3'-3'-dimethylsuccinyl) betulinic acid (PA-457 now known primarily as bevirimat or BVM) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag-processing pathway the conversion of the capsid-spacer peptide 1 (CA-SP1) region of HIV-1 Gag to mature CA. Clinical trials conducted with BVM produced mixed results; in some patients significant reductions in viral loads were achieved whereas in other patients no benefit of BVM therapy was observed. We and others demonstrated that this lack of response was linked to polymorphisms in SP1. We have also studied in detail the target mechanism of action and resistance pathways of a second structurally distinct MI discovered by Pfizer (PF-46396 or PF96). We found that resistance to PF96 was conferred by mutations not only in the vicinity of the CA-SP1 cleavage site [where resistance to BVM maps] but also upstream in the CA major homology region (MHR). Notably the MHR mutants that arose during selection for PF96 resistance were markedly PF96 dependent. The MHR mutants which on their own are highly deficient in assembly and replication could also revert by acquiring a second-site mutation in SP1 residue 8 (T8I). The study of the PF96-dependent MHR mutants and the T8I compensatory mutant is providing a wealth of information about the role of CA and SP1 in assembly and maturation and will advance our understanding of the structural properties of SP1. Our research on BVM and PF96 has provided novel insights into the structure-function relationship between CA and SP1 as well as a framework for increased structural understanding of HIV-1 MI activity. _____We have now forged a multidisciplinary collaborative effort together with chemists at DFH Pharmaceuticals to develop ""second-generation"" BVM analogs that are significantly more potent and broadly active against polymorphic isolates of HIV-1 than BVM or PF96. The best of these analogs are undergoing preclinical testing in anticipation of clinical trials. More long term we hypothesize that defining the structure of the MI-binding pocket in HIV-1 Gag will greatly facilitate the development of novel and more potent inhibitors; to this end we are collaborating with several structural biology labs to define the structure of the CA-SP1 region in the immature Gag lattice in both the presence and the absence of bound inhibitor. Our working hypothesis is that MIs block CA-SP1 processing by stabilizing a six-helix bundle that extends from the C-terminus of CA into SP1. Resistance mutations confer escape by stabilizing this helical bundle. We are collaborating with structural biologists to define the structure of MI-bound Gag by NMR techniques. We are also studying the effect of inositol hexakisphosphate (IP6) on MI activity. We believe that our work in this project will be transformative both in understanding the structure and function of the CA-SP1 region of Gag which plays critical roles in HIV-1 assembly and maturation and in developing MIs as a novel class of antiretroviral agents." 77000 +No NIH Category available Adverse effects;Anti-Retroviral Agents;Antiviral Agents;Betulinic Acid;Binding;Biochemical;Capsid;Cells;Clinical Trials;Collaborations;Conduct Clinical Trials;Development;Generations;Genetic Polymorphism;Goals;HIV-1;Link;Maps;Molecular;Mutation;Pathway interactions;Patients;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phytic Acid;Play;Polyproteins;Preclinical Testing;Property;Protein Biosynthesis;Research;Resistance;Role;SP1 gene;Site;Structural Biologist;Structure;Structure-Activity Relationship;Techniques;Time;Toxic effect;Viral;Viral Load result;Virus;Work;analog;antiretroviral therapy;forging;gag Gene Products;inhibitor;insight;multidisciplinary;mutant;novel;resistance mutation;response;structural biology;viral resistance HIV-1 Maturation n/a NCI 10926063 1ZIABC010778-17 1 ZIA BC 10778 17 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1001849 NCI "While currently available antiretroviral therapies are highly effective in suppressing HIV-1 replication in treated patients these drugs are not curative. Patients are thus required to remain on continuous lifelong therapy which has been associated with a variety of toxicities and adverse effects. Also over time viral resistance is likely to pose an increasingly serious problem for patients on therapy. The development of novel classes of inhibitors that block steps in the replication cycle distinct from those targeted by currently available drugs is therefore a high priority. We have played a leading role in the development of one such novel class of HIV-1 antiviral drugs the maturation inhibitors (MIs). _____In the HIV-1 replication cycle Gag proteins are synthesized as a polyprotein precursor (Pr55Gag) that is cleaved by the viral protease (PR) during virus release from the infected cell. Completion of the Gag processing cascade is essential for virus maturation and infectivity. In collaboration with Panacos Pharmaceuticals we found that 3-0-(3'-3'-dimethylsuccinyl) betulinic acid (PA-457 now known primarily as bevirimat or BVM) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag-processing pathway the conversion of the capsid-spacer peptide 1 (CA-SP1) region of HIV-1 Gag to mature CA. Clinical trials conducted with BVM produced mixed results; in some patients significant reductions in viral loads were achieved whereas in other patients no benefit of BVM therapy was observed. We and others demonstrated that this lack of response was linked to polymorphisms in SP1. We have also studied in detail the target mechanism of action and resistance pathways of a second structurally distinct MI discovered by Pfizer (PF-46396 or PF96). We found that resistance to PF96 was conferred by mutations not only in the vicinity of the CA-SP1 cleavage site [where resistance to BVM maps] but also upstream in the CA major homology region (MHR). Notably the MHR mutants that arose during selection for PF96 resistance were markedly PF96 dependent. The MHR mutants which on their own are highly deficient in assembly and replication could also revert by acquiring a second-site mutation in SP1 residue 8 (T8I). The study of the PF96-dependent MHR mutants and the T8I compensatory mutant is providing a wealth of information about the role of CA and SP1 in assembly and maturation and will advance our understanding of the structural properties of SP1. Our research on BVM and PF96 has provided novel insights into the structure-function relationship between CA and SP1 as well as a framework for increased structural understanding of HIV-1 MI activity. _____We have now forged a multidisciplinary collaborative effort together with chemists at DFH Pharmaceuticals to develop ""second-generation"" BVM analogs that are significantly more potent and broadly active against polymorphic isolates of HIV-1 than BVM or PF96. The best of these analogs are undergoing preclinical testing in anticipation of clinical trials. More long term we hypothesize that defining the structure of the MI-binding pocket in HIV-1 Gag will greatly facilitate the development of novel and more potent inhibitors; to this end we are collaborating with several structural biology labs to define the structure of the CA-SP1 region in the immature Gag lattice in both the presence and the absence of bound inhibitor. Our working hypothesis is that MIs block CA-SP1 processing by stabilizing a six-helix bundle that extends from the C-terminus of CA into SP1. Resistance mutations confer escape by stabilizing this helical bundle. We are collaborating with structural biologists to define the structure of MI-bound Gag by NMR techniques. We are also studying the effect of inositol hexakisphosphate (IP6) on MI activity. We believe that our work in this project will be transformative both in understanding the structure and function of the CA-SP1 region of Gag which plays critical roles in HIV-1 assembly and maturation and in developing MIs as a novel class of antiretroviral agents." 924849 +No NIH Category available Agonist;Antibodies;Basic Science;Binding;Carbohydrates;Child;Clinical;Databases;Diagnostic;Disease;Disease Progression;Engineering;Evaluation;FDA approved;Goals;Lectin;Malignant Neoplasms;Mammals;Microarray Analysis;Monoclonal Antibodies;Neuroblastoma;Polysaccharides;Protein-Carbohydrate Interaction;Proteins;Reagent;Research;Therapeutic Agents;antagonist;cancer cell;carbohydrate binding protein;carbohydrate receptor;design;high throughput technology;interest;tool;tumor;tumor progression Carbohydrate Microarray Profiling of Glycan-Binding Antibodies and Lectins n/a NCI 10926061 1ZIABC010740-18 1 ZIA BC 10740 18 15201322 "GILDERSLEEVE, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1242490 NCI Carbohydrate-binding antibodies are used extensively for basic research and are useful as diagnostic and therapeutic agents. They are especially useful in the field of cancer. Cancer cells undergo dramatic changes in carbohydrate expression during the onset and progression of disease. As a result there has been considerable interest in understanding why these changes occur how they contribute to the disease and exploiting these changes for clinical use. For example Unituxin (dinituximab) is an FDA approved monoclonal antibody that targets the tumor associated carbohydrate GD2 and is used to treat children with neuroblastoma. Unfortunately there are very few good monoclonal antibodies to carbohydrates. The lack of high quality antibodies is a major barrier for the field. We are taking a multi-pronged approach to help alleviate this problem. First we use our glycan microarray to evaluate the selectivities of existing antibodies to carbohydrates. This information is crucial for selecting the right antibody for a particular application and interpreting results. Second we have developed a database of antibodies to carbohydrates (Database of Anti-Glycan Reagents; DAGR) that can be used to find antibodies and information about those antibodies. Third we are studying the mechanisms by which antibodies to carbohydrates are produced in mammals. Fourth we are using our glycan microarray to discover and engineer new antibodies to carbohydrates 1242490 +No NIH Category available Abnormal Cell;Accounting;Antimitotic Agents;Binding;Binding Sites;Biological Assay;Biological Availability;Catalytic Domain;Cause of Death;Cell Cycle;Cell Proliferation;Cell division;Cell physiology;Cells;Cessation of life;Characteristics;Charge;Chemicals;Collaborations;Derivation procedure;Development;Docking;Dose Limiting;Enzyme-Linked Immunosorbent Assay;Epithelial Cells;Exhibits;Generations;Goals;Human;In Vitro;Investigation;Laboratories;Lead;Legal patent;Ligand Binding Domain;Ligands;Lymphocyte;Malignant Neoplasms;Mediating;Microtubules;Mission;Mitosis;Mitotic;Modeling;Mus;National Center for Advancing Translational Sciences;National Institute of Diabetes and Digestive and Kidney Diseases;Nature;Normal Cell;Outcomes Research;PLK1 gene;Paper;Parents;Permeability;Pharmaceutical Preparations;Phosphotransferases;Play;Polo-Box Domain;Process;Prodrugs;Property;Protein Kinase;Proteins;Role;Series;Specificity;Structural Models;Structure;Structure-Activity Relationship;Therapeutic Agents;Toxic effect;United States National Institutes of Health;Vinca Alkaloids;Water;Work;anti-cancer therapeutic;cancer addiction;cancer cell;cancer therapy;cell type;cross reactivity;drug discovery;follow-up;high throughput screening;histone H1 kinase;improved;in silico;in vitro Assay;inhibitor;intestinal epithelium;lead optimization;molecular modeling;novel;novel strategies;overexpression;screening;small molecule;targeted agent;taxane;therapeutic target;tumor;tumorigenesis Development of inhibitors targeting Plk1 polo-box domain n/a NCI 10926056 1ZIABC010681-19 1 ZIA BC 10681 19 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 368342 NCI Anti-mitotic drugs such as taxanes and vinca alkaloids that are directed at inhibiting the dynamic function of microtubules (MTs) have proved effective in treating cancer. However the use of these conventional MT-targeting agents is severely constrained by their dose-limiting toxicities due to the widespread functions of MTs in mediating both mitotic and non-mitotic cellular processes in many cell types notably intestinal epithelial cells and lymphocytes. Therefore developing a new class of anti-cancer therapeutics by targeting mitosis-specific proteins critical for cancer cell proliferation is an important line of investigation. Polo-like kinase 1 (Plk1) is one of the most attractive targets for anti-cancer therapy. Efforts to generate Plk1-specific inhibitors by targeting the catalytic activity of Plk1 have proven difficult due to similarities with the catalytic domains of other structurally related kinases. Here we propose to develop a new class of mono-specific Plk1 inhibitors by employing a novel approach to target the non-catalytic but functionally essential PBD of Plk1. To this end we have carried out a high throughput screen in collaboration with NCATS Bethesda MD. From this screen we have identified 3000 compounds from a primary screen which were narrowed down to the final two compounds (1S and B7) through secondary medium throughput and tertiary cell-based assays. Through systematic molecular modeling/docking of these parent compounds we obtained six significantly improved compounds which showed Plk1 PBD inhibition activity at levels similar to that of one of the previously characterized PBD-binding ligands PLHSpT (Kd = 450 nM) in an in vitro ELISA. Since the original HTS leads may belong to a class known as pan-assay interference compounds or PAINS we will further incorporate many drug-like characteristics during the hit-to-lead optimization in order to obtain a high-impact chemical probe that ultimately exhibits the desired efficacy against the Plk1 PBD in proof-of-concept mouse tumor models. As the first step of drug discovery we generated the co-crystal structure of Plk1 PBD with one of the lead compounds. This structural model will be used to conduct structure-activity relationship studies and further optimize the compounds. As a result of this effort we obtained several initial hits subjected to several rounds of in silico derivatization and ELISA-based Plk1 PBD inhibition analysis. These efforts led to discovery of seven compounds (NC21 to NC27) with distinct chemotypes. In vitro FP and ELISA assays with purified compounds confirmed their anti-PBD specificity with Kd values in the 100-200 nM range. For the past two years we have carried out hit-to-lead optimizations (in collaboration with Dr. Ken Jacobson NIDDK NIH) and developed 20 inhibitors that appear to potently inhibit Plk1 PBD inhibitors in vitro assays. However the efficacy and bioavailability of these inhibitors exhibit less than expected. Now the effort is focused on improving potency and permeability. This work has resulted in a paper (Alverez CN et al. J. Med. Chem. 2020) that describes several novel triazoloquinazoline-derived small-molecule prodrugs specific against Plk1 PBD. To follow up on this initial research outcome we generated various derivatives to increase the potency and specificity against Plk1 PBD. This effort resulted in two subsequent papers (Park JE et al. ACS Pharm. & Transl. Sci. 2023 and Park JE et al. PNAS 2023 in press) a US patent application (No. 18/028463; filed on March 24 2023) and a US provisional patent application (No. 63/455608; filed on March 30 2023) that covers the first allosteric Plk1 PBD inhibitor called Allopole with a unique mode of binding to Plk1 PBD1. The mode of Allopole binding to Plk1 PBD revealed an allosteric binding site that could selectively disrupt the canonical interactions between the PBD and its phospho-binding targets. Given the structural uniqueness and occluded nature of the Allopole-binding pocket it could be advantageous to target this pocket over the canonical phosphoepitope-binding site which requires a negatively charged ligand capable of mediating multiple water-mediated interactions. We are taking advantage of the unique properties of the Allopole-binding site to develop Plk1 PBD-specific inhibitors. 368342 +No NIH Category available Angiogenesis Inhibitors;Cancer Cell Growth;Cell Cycle;Cell Proliferation;Colon Carcinoma;Colorectal Cancer;Down-Regulation;Drug Targeting;EGF gene;Epithelium;Flavoproteins;Future;G1/S Transition;Genes;Goals;Growth;Growth Factor;HT29 Cells;Human;Induction of Apoptosis;Inflammatory;Knock-out;Laboratories;Ligand Binding;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Membrane;Modification;NADP;NADPH Oxidase;NADPH Oxidase 1;Oxidants;Oxidases;Oxidation-Reduction;Oxidative Stress;Oxygen;Pathogenesis;Pharmaceutical Preparations;Platelet-Derived Growth Factor;Play;Production;Protein Isoforms;Protein Kinase;Protein Tyrosine Phosphatase;Proteins;Reactive Inhibition;Reactive Oxygen Species;Receptor Protein-Tyrosine Kinases;Regulation;Role;Series;Serine;Signal Transduction;Signal Transduction Pathway;Superoxides;Therapeutic;Therapeutic Agents;Threonine;Vascular Endothelial Growth Factors;Xenograft Model;Xenograft procedure;angiogenesis;cell growth;colon cancer cell line;cytokine;in vivo;inhibitor;interest;member;neoplastic cell;novel;novel therapeutic intervention;receptor;small hairpin RNA;targeted cancer therapy NADPH Oxidases as Novel Targets for Cancer Therapy n/a NCI 10926055 1ZIABC010677-19 1 ZIA BC 10677 19 9692531 "DOROSHOW, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1166042 NCI Epithelial NADPH oxidases are flavoproteins that catalyze the NADPH-dependent reduction of oxygen to superoxide following binding of ligands for receptor tyrosine kinases (including EGF PDGF VEGF). Current evidence suggests that NADPH-dependent reactive oxygen species play a critical role in growth factor-mediated signal transduction and that the NADPH oxidase 1 isoform is abundantly expressed in human colon cancers. Because inhibition of constitutive oxidant production and cell growth of human colon cancer cell lines as well as induction of apoptosis and blockade of the G1/S transition and induction of p27 occurred over the same concentration range for a series of iodonium-based flavoprotein inhibitors Dr. Doroshows studies suggest that the therapeutic potential of iodonium NADPH oxidase inhibitors may be related to modification of redox-related signal transduction pathways essential for colorectal cancer cell growth. Iodonium derivatives have also been found to be active in two human colon cancer xenograft models. In future studies Dr. Doroshow plans to develop additional novel members of the iodonium drug class as potential therapeutic agents. Dr. Doroshow has also employed stable shRNA constructs developed in his laboratory (that are capable of downregulating NADPH oxidase 1 expression by >80%) to specifically investigate the role of this protein in colorectal cancer cell proliferation. These recent studies demonstrate that downregulation of NADPH Oxidase 1 leads to a significant decrease in reactive oxygen production in HT-29 cells a G1 cell cycle block down regulation of a large number of antiangiogenic genes and inhibition of reactive oxygen-mediated signaling through several receptor protein kinases. In addition we have found that the activity of several serine threonine and tyrosine phosphatases are increased when NADPH oxidase is knocked out. In vivo downregulation of NADPH oxidase 1 dramatically decreases the growth of HT-29 xenografts in part due to diminished angiogenesis. We have also found that pro-inflammatory cytokines involved in the pathogenesis of colon cancer strongly upregulate NADPH Oxidase 1. These studies strongly suggest that NADPH oxidase 1 is an important potential drug target in colon cancer. 1166042 +No NIH Category available Adhesions;Antibodies;Antigens;Avidity;Basic Science;Binding;Binding Sites;Biological Assay;Biological Process;Bovine Serum Albumin;Carbohydrates;Carrier Proteins;Cells;Complex;Development;Diagnostic;Enzyme-Linked Immunosorbent Assay;Epoxy Compounds;Glycopeptides;Glycoproteins;Immobilization;Inflammation;Lectin;Libraries;Ligands;Methodology;Methods;Microarray Analysis;Microscope;Neoglycoproteins;Neoplasm Metastasis;Play;Polysaccharides;Printing;Protein-Carbohydrate Interaction;Proteins;Reagent;Robotics;Role;Slide;Solid;Translational Research;Tumor Antigens;Vaccines;Viral;Virus;carbohydrate binding protein;carbohydrate receptor;high throughput analysis;improved;inhibitor;interest;macromolecule;miniaturize;novel;tool Development of a Carbohydrate Microarray n/a NCI 10926054 1ZIABC010675-19 1 ZIA BC 10675 19 15201322 "GILDERSLEEVE, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 354998 NCI Carbohydrate-protein interactions are essential for a wide range of biological processes such as inflammation bacterial and viral adhesion and metastasis. As a result there has been significant interest in identifying carbohydrate binding proteins and developing ligands to modulate their activity. Analysis of carbohydrate-protein interactions is complicated by a number of factors. First carbohydrates are extremely difficult to isolate or synthesize. Therefore only small amounts can be obtained in many cases. Second traditional methods for studying binding are not high-throughput and require large amounts of material. Third monovalent interactions between carbohydrates and proteins are notoriously weak. To achieve a high avidity carbohydrate-binding proteins contain multiple binding sites and form multivalent complexes. As a result carbohydrates must be presented in a multivalent fashion and the spacing and orientation of the carbohydrates play a critical role in recognition. Carbohydrate microarrays or glycan arrays contain many different carbohydrates or glycans immobilized on a solid support in a spatially-defined arrangement. Using an array one can evaluate binding of a lectin antibody cell or virus to all the carbohydrates on the array simultaneously. The array provides a multivalent presentation of carbohydrates and the miniaturized format requires only picogram amounts of each carbohydrate for an assay. We have developed a novel glycan array format utilizing neoglycoproteins. Neoglycoproteins are multivalent conjugates wherein carbohydrates are covalently attached to a carrier protein such as bovine serum albumin. These neoglycoproteins as well as natural glycoproteins are printed onto epoxide coated microscope slides using a robotic microarrayer to produce microarrays. Neoglycoproteins can be used as multivalent reagents for other assays such as ELISAs as multivalent inhibitors and as multivalent immunogens. We currently have one of the largest and most unique glycan arrays in the world. Recently we have focused on expanding and improving the carbohydrate microarray. One objective is to increase the number of glycans on the array. We have been developing improved synthetic methods for preparing glycopeptides. The methodology will be used to prepare a large library of glycopeptides for addition to the array. in addition we are optimizing methods to conjugate carbohydrates to proteins to produce neoglycoproteins. 354998 +No NIH Category available ATAC-seq;Address;Adoptive Transfer;Affinity;Aging;Agonist;Antigen Presentation;Antigen Receptors;Antigen Targeting;Antigens;Binding;Binding Sites;Biochemical;Biological Assay;Bone Marrow Transplantation;CD4 Antigens;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CRISPR/Cas technology;Cancer Patient;Cause of Death;Cell Communication;Cells;Cessation of life;Chromatin;Colitis;Complex;Computer Analysis;DNA-Binding Proteins;Deacetylase;Development;Experimental Models;Experimental Neoplasms;Gene Expression;Gene Expression Profiling;Generations;Genes;Genetic Transcription;HIV;Homing;Immune response;Immune system;Immunologic Deficiency Syndromes;Immunology;In Situ;In Vitro;Infection;Inflammation;Integrin beta Chains;Intestines;Laboratories;Laboratory Research;Leukocytes;Life;Ligands;Major Histocompatibility Complex;Maps;Mediating;Membrane Glycoproteins;Modeling;Molecular;Morbidity - disease rate;Mutant Strains Mice;Myeloablative Chemotherapy;Nucleosomes;Peptides;Population;Prevention;Property;Protein Analysis;Puberty;RUNX3 gene;Reporting;Repression;Research;Shapes;Signal Transduction;Small Intestines;Surface;T cell differentiation;T cell response;T-Cell Depletion;T-Cell Development;T-Lymphocyte;Thymocyte Development;Thymus Gland;Transcriptional Regulation;Tumor Antigens;Virus Diseases;Work;Zinc Fingers;cell mediated immune response;chronic infection;cytotoxic;gene regulatory network;genetic analysis;genetic approach;genome editing;genome-wide;high throughput analysis;in vivo;interest;intestinal homeostasis;intraepithelial;laboratory experiment;migration;mortality;novel;programs;protein function;recruit;recurrent infection;response;single cell analysis;single-cell RNA sequencing;thymocyte;transcription factor;transcriptomics;tumor Genetic Analysis of T-cell Differentiation n/a NCI 10926053 1ZIABC010671-19 1 ZIA BC 10671 19 8778182 "BOSSELUT, REMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2375018 NCI "We study T cell development and function. T cells are essential for immune responses. Most express an antigen receptor (TCR) made of an alpha and a beta chain (ab T cells) and recognize peptide antigens presented by class I (MHC-I) or class II (MHC-II) classical Major Histocompatibility Complex molecules and express either of two surface glycoproteins that contribute to antigen recognition: CD4 which binds MHC-II or CD8 which binds MHC-I. Consistent with such binding properties MHC I-specific T cells generally are CD4-CD8 (CD8 T cells) whereas MHC II-specific T cells generally are CD4+CD8- (CD4 T cells). CD4 T cells are essential for life: CD4 T cell deficiency whether innate or acquired leads to recurrent or chronic infections and death. Studies of ab T cell development in the thymus have remained at the forefront of the laboratory activity in the past few years. We implemented single cell (sc) analyses of gene expression: single-cell RNA sequencing (scRNAseq for gene expression itself) and single cell ATAC sequencing (scATACseq) to map chromatin accessibility. In addition to T cell development studies summarized below we used these approaches to study T cell responses to viral infection and tumor antigens (Ciucci et al. 2019; Vacchio et al. 2019; Magen et al. 2019; Ciucci et al. 2022). A recent report from the laboratory (Chopp et al. 2020) combined scRNAseq and scATACseq to identify developmental trajectories during the intrathymic differentiation of ab T cell precursors. In parallel studies we showed that the zinc finger transcription factor LRF (encoded by Zbtb7a) is necessary for the proper development of thymic precursors of ""CD8alpha-alpha"" intestinal intraepithelial T cells (CD8aa IEL) a major subset of gut T cells whose functions remain enigmatic (Nie et al 2022). Using scRNAseq and a variety of adoptive transfer assays we showed that LRF is necessary for the expression of the intestine-homing integrin beta7 for the migration of IEL precursors to the small intestine and for their contribution to intestinal homeostasis and prevention of inflammation in an experimental model of colitis. Building on these recent findings ongoing studies focus on two directions. First we are exploring the mechanisms that promote the development of thymocytes carrying antigen receptors with high affinity for self-ligands (called ""agonist-selected"") including CD8aa IEL precursors. We are notably investigating how in situ transcriptomics can shed light on cell interactions along intrathymic developmental trajectories of agonist signaled thymocytes. Second we are leveraging our recent gene regulatory network inference studies (Chopp et al. 2020) to identify factors needed for CD4 T cell development and to study their actual functions using genetic approaches. The long-term objective of these studies is to build in vitro strategies for the differentiation of CD4 T cells. Among the factors needed for CD4 T cell development in the thymus is the zinc finger transcription factor Thpok encoded by Zbtb7b. Understanding Thpok functions has been a key objective of the laboratory research over the past 5-10 years. We reported the genome-wide distribution of Thpok binding sites in CD4 T cells and differentiating CD4-lineage thymocytes (Ciucci et al. 2019; Chopp et al. 2020). More recently we showed that Thpok binds the nucleosome remodeling and deacetylase (NuRD) complex and we identified the domain of Thpok involved in this binding (Gao et al. 2022). We also found that such binding mediates critical functions of Thpok in intrathymic CD4 T cell differentiation. Specifically recruitment of NuRD is essential for Thpok repression of CD8-lineage genes including the transcription factor Runx3 that controls CD8 T cell differentiation; in contrast NuRD recruitment is dispensable for Thpok to promote Cd4 expression. We are currently examining whether NuRD recruitment is involved in the repression of cytotoxic genes by Thpok in post-thymic CD4 T cells and whether such mechanisms could control acquisition of cytotoxic gene expression in recently described cytotoxic CD4 T cell populations." 2375018 +No NIH Category available Abscopal effect;Aftercare;Biological;Biological Markers;Cell Survival;Cells;Clinic;Clinical;Combined Modality Therapy;Complex;Data;Dose;Drug Design;Drug usage;Endothelial Cells;Epigenetic Process;Fractionation;Genes;Growth;Health;Heat-Shock Proteins 90;Human;Immune;Immune response;Immunotherapy;In Vitro;Intensity-Modulated Radiotherapy;Laboratories;Magnetic Resonance Imaging;MicroRNAs;Miniature Swine;Molecular;Molecular Target;Normal tissue morphology;Ontology;Pathway interactions;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Predisposition;Proteomics;Radiation;Radiation Dose Unit;Radiation Injuries;Radiation Oncology;Radiation therapy;Readiness;Services;Systems Analysis;Techniques;Technology;Testing;Update;Work;biodosimetry;biological adaptation to stress;biomarker identification;cancer care;cell killing;chemoradiation;drug-sensitive;fractionated radiation;image guided radiation therapy;immunoregulation;in vivo;inhibitor;interest;mass casualty;metabolic abnormality assessment;metabolomics;molecular targeted therapies;programs;response;survival prediction;targeted agent;tissue injury;tumor Radiation-induced molecular targets n/a NCI 10926052 1ZIABC010670-19 1 ZIA BC 10670 19 15686950 "COLEMAN, NORMAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1968826 NCI "The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on ""radiation inducible targets"" that is exploring the use of multi-fractionated (MF) radiation as well as higher single doses (SD) to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy and immunotherapy. In essence radiation would set up the tumor for enhanced drug killing and enhanced immune response. This project has now demonstrated that different dose sizes of radiation- MF and SD - (10 Gy x1 2 Gy x5 1 Gy x10 and down to 0.5 Gy x 10) produce different phenotypes. We have demonstrated that the cells post-radiation are more drug sensitive to a drug post-radiation than before at 1 week and up to 3 months later indicating stable adaptation. This is applicable to drugs available for clinical use. We are now working with experts in complex systems analysis to identify pathways to target and working on timing of radiation and drug(s). With the major interest in immune modulation our work has significant bearing on the dose and fractionation of radiation that can be exploited for immune enhancement for tumor control including direct and abscopal effects. We are working with Jim Mitchell of RBB and Murali Cherukuri of RBB who has hyperpolarized MRI techniques to study metabolic adaptation. Closely related to this work are efforts being done on identifying biomarkers and machanisms of radiation injury. This relates to work I do in the Administration for Strategic Preparedness and Response in Health and Human Services (HHS). We are working on the potential of bringing these mitigators into cancer care." 1968826 +No NIH Category available Animals;Architecture;Area;Basic Science;Biodistribution;Charge;Chemicals;Clinical Trials;Code;Computer software;Coupled;Custom;Data Analyses;Detection;Development;Devices;Disease;Electronics;Evaluation;Event;Future;Gamma Cameras;Gamma Rays;Goals;Growth;Human;Image;Imaging Device;Imaging technology;Label;Laboratory Animals;Light;Magnetic Resonance Imaging;Measurement;Mission;Mus;Names;National Cancer Institute;Nuclear;Pathway interactions;Photons;Positioning Attribute;Positron;Positron-Emission Tomography;Radioisotopes;Radionuclide Imaging;Research;Research Personnel;Scanning;Scientist;Side;Speed;Structure;Support Groups;System;Systems Development;Technology;Testing;Time;Tube;United States National Institutes of Health;Validation;Work;animal imaging;cancer therapy;clinical diagnostics;computerized data processing;cost;design;detector;drug development;flexibility;human subject;image reconstruction;imaging system;improved;instrumentation;magnetic field;microPET;microSPECT;molecular imaging;news;novel;nuclear imaging;optical imaging;photomultiplier;portability;programs;simulation software;single photon emission computed tomography;thallium-doped sodium iodide;tomography Instrumentation for microSPECT and microPET imaging n/a NCI 10926051 1ZIABC010668-19 1 ZIA BC 10668 19 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1973242 NCI In 2008 as a first step towards a novel flat panel microPET device the Nuclear Camera Team produced a new dual flat panel projection imaging device for mouse imaging. It consists of two flat panel detectors side-by-side with the ability to rapidly obtain projection image in mice on a portable device. This system is now operational and plans are being put in place to further develop devices that allow tomorgraphic imaging. In 2010 work began on leveraging the first device code named MONICA for Mobile Nuclear Imaging Camera into a low cost projection microPET employing two parallel detectors (rather than side by side). The design incorporates coincidence scanning between the two plates but also the capability for depth of interaction (DOI) measurement allowing some tomographic abilities. Also in 2010 work began on adapting this device to a projection microPET MR compatible device. Testing is ongoing to determine the ability of new crystals to withstand the effects of a strong magnetic field. Development work carried out by the nucelar camera group and its (essential) collaborators is based on the notion of directed exploration where technological opportunities are examined at the research level but with a particular systems level goal in mind (A): Research areas in imaging system development: (B): current focused systems level development project: dual gamma camera planar projection imaging system for single photon high-speed dynamic whole body bio-distribution studies in mice. To illustrate this parallelism work is now underway in each of the areas shown in LaBr3 slab and NaI(Tl) pixelated detector modules and support electronics development (CIT-NIH/RIG); evaluation of a new modular DAQ system (Thomas Jefferson National Accelerator Facility (JLAB) Newport News VA/RIG); creation of a high speed data processing interface using both centroid event positioning and advanced Maximum Likelihood (ML) positioning (RIG/CIT); and evaluation of a commercial system (Nuclear Mac) for image display and analysis (RIG/CIT). Each of these sub-system projects are evaluated in light of the current systems level goal of creating a dual planar gamma camera device for imaging mice while at the same time providing information in each technical area for potential use in our next systems level development project. For example one of the detector modules will be comprised of a rectangular pixelated NaI(Tl) array coupled to two side-by-side Hamamatsu H8500 position-sensitive photomultiplier tubes Initial imaging results obtained with this combination required full use of the JLAB DAQ CIT developed electronics and RIG-developed data processing software for acquisition and analysis of these data. Thus considerable progress is being made in the development of novel microSPECT and microPET cameras that could result in much less costly imaging cameras in the future. Moreover because of their larger coverage the sensitivity for such devices might be considerably higher leading to the possibility of detecting disease with ever greater sensitivity. Clearly improved camera design could have a significant impact on molecular imaging research in the future. Our latest camera design if for direct time of flight imagingi which will eliminate the need for image reconstruction. This will relieve design constraints based on the torus PMT architecture. With TOF PET imaging flat panel arrays will be possible enabling portable PET scans (for instance in the ICU). We plan to continue this exploratory work with the goal of turning over the completed dual gamma camera system to MIP scientists followed by a review of accrued technical findings and designation of the next systems level project. 1973242 +No NIH Category available Acceleration;Advisory Committees;Antibodies;Antigen Targeting;Area;Biliary Tract Cancer;Brachyury protein;CCR;Cancer Patient;Cancer Vaccines;Cell physiology;Cells;Clinic;Clinical;Clinical Data;Clinical Trials;Cohort Studies;Collaborations;Colorectal Cancer;Combination immunotherapy;Combined Modality Therapy;Combined Vaccines;Conduct Clinical Trials;Data;Disease;Enrollment;Epithelium;European;FDA approved;Goals;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;IL8 gene;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunologics;Immunooncology;Immunotherapy;Industry Collaboration;Infiltration;Interleukin-12;International;Intervention;Intravenous;Laboratories;Laboratory Finding;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measures;Mediating;Medicine;Merkel cell carcinoma;Modality;Mucin 1 protein;Natural Killer Cells;Neoadjuvant Study;Orphan Drugs;Pathologist;Pathway interactions;Patient Selection;Patients;Phase;Phase III Clinical Trials;Play;Process;Prostate Cancer Vaccine;Proteins;Radiation Oncologist;Randomized;Recombinant Vaccines;Recombinants;Renal Cell Carcinoma;Research;Research Personnel;Role;Route;Running;Safety;Scientist;Signal Transduction;Surgeon;T cell response;T-Lymphocyte;T-cell inflamed;Testing;Tissues;Transforming Growth Factor beta;Tumor Antigens;Vaccines;Yeasts;advanced disease;anti-PD-L1;anti-PD-L1 antibodies;antibody-dependent cell cytotoxicity;cancer cell;cancer immunotherapy;castration resistant prostate cancer;checkpoint modulation;clinical development;clinical translation;cohort;design;first-in-human;immune checkpoint;immune stimulatory agent;immunogenic;immunoregulation;improved;innovation;interest;novel;objective response rate;peripheral blood;phase 2 study;phase 3 study;phase II trial;programmed cell death ligand 1;programmed cell death protein 1;radiologist;refractory cancer;research clinical testing;response;safety study;side effect;subcutaneous;targeted agent;therapy design;trend;trial design;tumor;tumor microenvironment;vaccine strategy;vaccine trial Cancer Immunotherapy n/a NCI 10926050 1ZIABC010666-19 1 ZIA BC 10666 19 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 4037445 NCI Dr. Gulley is interested in immunotherapy for epithelial malignancies with a focus on prostate cancer. As the co-Director of the Center for Immuno-Oncology he designs and conducts clinical trials based on promising laboratory findings. These innovative investigator-initiated studies involve the use of cancer vaccines and other immunostimulatory agents to modulate the immune response in cancer patients and the addition of other strategies to enhance vaccine-mediated tumor killing. Dr. Gulley played a pivotal role in the clinical development of the prostate cancer vaccine Prostvac. Working with scientists in the laboratory he developed the data needed to bring this logistically simple but immunologically sophisticated vaccine strategy developed within the CCR into phase I (first-in-human safety studies) and phase II (first test for clinical activity) clinical trials in prostate cancer. A multicenter randomized phase II trial designed in collaboration with Dr. Gulley provided evidence of enhanced median overall survival (OS) (P = 0.0061) in patients with metastatic castration-resistant prostate cancer. A concurrent study ran by Dr. Gulley at the CCR demonstrated that patients with greater PSA-specific T-cell responses showed a trend (P = 0.055) toward enhanced survival. Median OS was 26.6 months with a greater apparent treatment benefit in patients with less aggressive or less advanced disease. Dr. Gulley and colleagues then met with the FDA and designed a phase III clinical trial that he subsequently shepherded through the process of gaining approvals from the Recombinant Advisory Committee the FDA and European Medicines Agency. This randomized controlled phase III study which he led enrolled 1297 patients and disappointingly showed no improvement in overall survival. A neoadjuvant study of this vaccine demonstrated that not only could vaccine specific immune cells be generated in the peripheral blood but that increase infiltrates following vaccine could be seen in or around the tumors of these patients compared with pre-vaccine (Sater JITC 2020). This has led to combination immunotherapy efforts described in detail in Dr. Gulley's other project. Other vaccines that Dr. Gulley has helped bring into the clinic in phase I or II studies include pox-viral platforms targeting CEA MUC-1 and Brachyury; yeast platforms targeting CEA and Brachyury and adenoviral vaccines targeting CEA MUC-1 PSA and Brachyury. He has also been involved in the clinical translation of several vaccines targeting HPV specific targets which are more immunogenic than most off the shelf tumor associated antigen targets. Dr. Gulley has also been involved in the clinical evaluation of different routes of administration of vaccines (intradermal subcutaneous intratumoral and intravenous). Immunotherapy remains the most active area of research in cancer based in part on the rapid profound and durable responses seen with immune checkpoint inhibitors targeting PD-1 or PD-L1 proteins. (Immune checkpoints are molecules that modulate immune system signals. Many cancers use them to evade immune attack.) Dr. Gulley served as the coordinating PI of an international trial of avelumab an anti-PD-L1 antibody. This trial is a CCR collaboration with EMD Serono (who also partnered with Pfizer). Early data suggest robust activity for avelumab with a side-effect profile similar to other agents. However unlike other anti-PDL1 agents avelumab is also capable of antibody-dependent cellular cytotoxicity (ADCC). Thus this antibody in addition to directly enhancing the activity of T cells can mediate ADCC which involves Natural Killer Cell-mediated killing of the tumors and immune cells that block T-cell function. Recent findings suggest that anti-PD-L1 agents that can mediate ADCC have improved activity over agents that cannot do so. Dr. Gulley's study enrolled over 1700 patients (about 130 at the CCR) providing the initial safety and efficacy data that have led to multiple phase III clinical trials of avelumab. In 2017 the FDA approved avelumab for 2nd line bladder cancer and Merkel Cell cancer (both based in part on clinical data from Dr. Gulley's group) and in 2019 for Renal Cell Carcinoma and in 2020 for an expansion indication in bladder cancer. While the clinical response with immune checkpoint modulators has been profound it is limited to patients who have an underlying T-cell inflamed tumor. The importance of determining the immune relevant cells and pathways operational within the tumor microenvironment is thus crucial to selecting patients who may benefit from immune checkpoint modulating therapies alone but more importantly the impact of therapies designed to generate a T-cell inflamed tumor and to guide rationale for potential combination studies. To further explore this we have established multiple strong collaborations with several groups (including surgeons radiation oncologists interventional radiologists pathologists and various industry collaborations) who can assist us with obtaining and analyzing tissue before and after immunotherapy in various different disease settings. Furthermore we are investigating a range of different modalities to induce T-cell inflammation which are in active clinical trials including vaccines immunocytokines (e.g. NHL-IL12) and planned clinical trials (NK cells). As an extension of the importance of overcoming negative immune regulatory influences within the tumor microenvironment we also have brought into the clinic a first-in-class agent (M7824 or bintrafusp alfa) that targets both cell intrinsic (PDL-1) and cell extrinsic (TGF-beta) pathways and have seen that this is well tolerated and has preliminary evidence of activity. This initial study performed at the NCI now has multiple expansion cohorts with promising levels of activity seen in a number of different tumors including biliary tract cancer (for which it received FDA orphan drug designation) lung cancer (objective response rate 28%) and HPV associated malignancies (objective response rate 30% Strauss et al. JITC 2021). This has led to a number of phase 2 studies. Internationally over 700 patients have been treated with M7824. We have multiple ongoing studies combining vaccines with immunocytokines and with agents designed to facilitate activity in the tumor microenvironment (including immune checkpoint inhibitors). These studies have led to responses in cancers that don't typically respond to immunotherapy (prostate cancer colorectal cancer and immune checkpoint inhibitor refractory cancers). Dr. Gulley is also leading efforts to bring in other novel agents such a agents targeting IL8 (Humax) Lair-1 (NC-410) and tumor targeted IL-12 (NHS-IL12) with the goal to bring these from first-in-human studies into combination clinical trials. 4037445 +No NIH Category available ABCB1 gene;Aftercare;Apoptosis;Apoptotic;BCL1 Oncogene;CXCL5 gene;Cell Death;Cell Line;Cell Maturation;Cell surface;Cells;Cisplatin;Clinical;Colorectal Cancer;Combination Drug Therapy;Combined Vaccines;Complex;Cytolysis;Cytostatics;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Dose;Drug Modulation;Exposure to;Gene Expression Profile;Genes;Goals;Granzyme;Growth;HMGB1 gene;Human;Human Biology;IL8 gene;Immune response;Immunotherapy;In Vitro;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mediating;Membrane;Modeling;Molecular;Molecular Profiling;Mucin 1 protein;Non-Small-Cell Lung Carcinoma;Peptides;Phenotype;Platinum;Pre-Clinical Model;Predisposition;Prostate Cancer therapy;Protein Secretion;Regimen;Resistance;Signal Transduction;T cell response;T-Lymphocyte;TNF gene;Therapeutic;Transcript;Transforming Growth Factor beta;Tumor Cell Line;Vaccines;Vinorelbine;anti-tumor immune response;antigen processing;calreticulin;cancer cell;chemokine;chemotherapeutic agent;chemotherapy;cytokine;cytotoxic CD8 T cells;cytotoxicity;docetaxel;exposed human population;genetic signature;immunogenic;immunogenic cell death;knock-down;lung Carcinoma;neoplastic cell;perforin;predicting response;response;small molecule inhibitor;standard of care;tumor;vector Vaccine and Drug Combination Therapy for Human Cancers n/a NCI 10926049 1ZIABC010661-19 1 ZIA BC 10661 19 9692343 "HODGE, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 806457 NCI "Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast several chemotherapeutic drugs modulate antitumor immune responses despite not inducing classic ICD. In addition in many cases tumor cells do not die after treatment. Here using docetaxel one of the most widely used cancer chemotherapeutic agents as a model we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion or cell death. However calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA MUC-1 or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery and mediated largely by calreticulin membrane translocation as determined by functional knockdown of calreticulin PERK or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+ CD133+) by continuous exposure to docetaxel. These cells while resistant to direct cytostatic effects of docetaxel were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. We provided an operational definition of ""immunogenic modulation"" where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy. Chemotherapy with platinum doublets including cisplatin plus vinorelbine is standard of care for non-small cell lung cancer (NSCLC). Sublethal exposure to certain chemotherapeutic agents has been demonstrated to alter the phenotype or biology of human tumor cells rendering them more susceptible to cytotoxic T lymphocyte (CTL)-mediated lysis. However the effects of cisplatin/vinorelbine on tumor sensitivity to T-cell cytotoxicity and its molecular mechanisms have not been fully elucidated. Here we examined the effect of this chemotherapy on growth cell-surface phenotype and CTL-mediated lysis of five distinct human lung carcinoma cell lines in vitro and examined the molecular mechanisms associated with enhanced CTL sensitivity. These studies demonstrate that sublethal exposure of human lung tumor cells to the platinum doublet modulates tumor cell phenotype and increases sensitivity to MHC-restricted perforin/granzyme-mediated CTL killing. These studies also demonstrate that exposure to chemotherapy markedly decreased the protein secretion ratio of TGF-beta/IL-8. We examined the gene expression profile of two lung tumor cell lines in order to identify a shared gene signature in response to sublethal cisplatin/vinorelbine and found coordinate expression of only 16 transcripts including those for cytokine/chemokine expression and apoptosis such as TNF-alpha IL8 CXCL5 and BCL-2 like genes. Overall these results suggest that sublethal exposure to cisplatin/vinorelbine increases sensitivity to perforin/granzyme-mediated CTL killing by modulation of a) tumor phenotype b) cytokine/chemokine milieu and c) the pro-apoptotic/anti-apoptotic gene ratio. The data presented here propose a complex mechanism that is distinct from and complementary to that of immunogenic cell death. This molecular signature may be useful in predicting responses to immunotherapy as well as provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine regimens." 806457 +No NIH Category available Affect;Affinity;Albumins;Antibodies;Area;BODIPY;Binding;Biomaterials Research;Biomedical Engineering;Biotechnology;Bone Marrow Transplantation;Cell Therapy;Cell membrane;Cell surface;Cells;Cetuximab;Chemistry;Clinical;Clinical Research;Collaborations;Color;Colorectal Cancer;Combined Modality Therapy;Cytoplasm;Data;Dendritic Cells;Development;Dimerization;Dose;Dyes;Elements;Endocytosis;FDA approved;Fiber;Fiber Optics;Fluorescence;Future;Galactose;Gastrointestinal tract structure;Goals;Human;Image;In Situ;Indocyanine Green;Injections;Kinetics;Label;Lesion;Ligands;Light;Magnetic Resonance Imaging;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Methods;Molecular;Molecular Probes;Monitor;Multimodal Imaging;Mus;Nanotechnology;Natural Killer Cells;Normal Cell;Normal tissue morphology;Optics;Oxyquinoline;Positron-Emission Tomography;Primates;Radioisotopes;Reporter Genes;Reporting;Research;Resolution;Rhodamine;Route;Series;Site;Synthesis Chemistry;Techniques;Testing;Therapeutic Agents;Time;Tokyo;Toxic effect;Translating;Trastuzumab;Universities;Vertebral column;Work;adult stem cell;biomaterial compatibility;bone;cancer cell;cancer cell differentiation;cancer site;cell killing;cell type;cellular engineering;clinical application;design;dimer;fluorophore;galactose receptor;imaging agent;improved;in vivo;in vivo imaging;malignant stomach neoplasm;method development;molecular imaging;nanocrystal;near infrared dye;neoplastic cell;optical fiber;optical imaging;photoimmunotherapy;receptor;single photon emission computed tomography;stem cells;success;targeted imaging;theories;tumor Cellular In vivo Imaging n/a NCI 10926048 1ZIABC010657-19 1 ZIA BC 10657 19 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1183945 NCI Cell tracking studies are vital to the development of new cell based therapies. For instance we are using PET labeled adult stem cells to track the intrabone injection of cells for possible bone marrow transplants. Similarly we exploring the kinetics of NK cell injections by PET labeling these cells and injecting them. We are conducting studies to see whether dendritic cells can be induced to traffic to tumors to which they are sensitized. In vivo molecular imaging agents specifically target the cell surface or microenvironment. However most of the highly specific changes of cancer cells that differentiate cancers cells from normal cells occur intracellularly. The challenge therefore is to develop agents that report intracytoplasmic changes yet still are capable of being imaged in vivo. The first step in achieving this goal is to target the imaging agent to the cell surface which requires affinity for a cell surface marker. The ligand must then be internalized by endocytosis and then bind to the appropriate site whereupon it activates. Endocytosis can also be used without specific cell surface binding but internal binding. These requirements place large demands on synthetic chemistry since the molecular construct must have multiple functionalities. We are developing activatable optical constructs which only fluoresce when they are internalized to the cytoplasm. Using a series of commercially available dyes that are bound to targeting compounds and then modified to fluoresce under specific intracellular conditions such as lower pH and in the presence of specific enzymatic activity we are making progress toward the goal of intracellular in vivo imaging. This work is being performed in collaboration with Prof. Urano from the University of Tokyo Chemistry Department. We have made considerable advances in this area by proving that it is possible to create highly activatable optical imaging agents based on the BODIPY and Rhodamine backbones. We are also pioneering efforts to create multimodal imaging agents; agents that can be seen on both optical cameras as well as PET MR or radionuclide cameras. The agents being designed are highly biocompatible and elements have already been used in humans. For instance the agent Galactosylserum Albumin (GSA) which we have labeled with Rhodamine Green (GSA-RhG) is internalized rapidly within cancer cells and may be viable as an agent for human use. We are developing activated fluorescent molecular imaging agents and have a number of successes over the year. However we continue to pursue a solution that will activate only within cancer cells and not within other normal cells. In addition to GSA as a targeting ligand we are employing commercially available antibodies such as trastuzumab and cetuximab that will enable targeting binding and internalization. Specifically we have used trastuzumab in combination with a self quenched indocyanine green ICG an FDA approved Near InfraRed (NIR) dye to target in situ tumors. When the antibody binds its cognate receptor it is internalized releasing the ICG which then begins to fluoresce. Both components of this construct are FDA-approved so in theory this technique could be translated clinically fairly easily. The ability to image multiple targets simulanteously led us to explore multiexcitation and multiemission cameras. We had hoped that a single excitation light would be able to activate multiple fluorophores at differing wavelengths but this proved to be unrealistic. Instead we use multiple wavelength excitation light using a new Maestro camera. This has allowed us to simultaneously image up to 4 targets in the near infrared and is very promising for clinical application. Additionally we are developing fiberoptic scopes with fluorescence receptors to allow very small areas to be examined percutaneously using small fiber-based scopes. Recently we have demonstrated that is possible to image live unanesthetized mice by using a highly tuned real time camera. It may be possible in the near future to develop multi-targeted multi color imaging to better characterize tumors. Most recently we have developed highly specific activatable probes based on H dimer formation. For instance Rhodamine dimerizes when bound to the Fc portion of an antibody leading to a quenching of fluorescence. pH activatable probes have been developed as well as upconverting nanocrystals that are excited at higher wavelengths than they emit at. Finally uniquely targeted near infrared probes have been developed that appear to have specific cell membrane toxicity suitable for photoimmunotherapy therapy that is highly targeted. Relevant cancer sites: Ovarian Cancer Stomach Cancer Colorectal Cancer Gastrointestinal Tract Pancreatic Cancer. Relevant Research Areas: Bioengineering Nanotechnology Biomaterials Research Biotechnology Clinical Research. More recently MIP has been developing new methods of tracking cells using Zr89 oxine labeling. Hematopoetic cells of all types have been labeled and tracked. We intend to try tracking cells in vivo using PET imaging and have demonstrated feasibility in a variety of cell types and conditions both in mice and primates as preliminary data prior to human testing. Reporter gene strategies are being developed to monitor cells over longer duration. Cellular engineering that combines therapies and cell tracking is also currently undergoing study. 1183945 +No NIH Category available Adrenal Gland Neoplasms;Amino Acids;Animal Model;Antibodies;Binding;Biopsy;CD276 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCL9 gene;CXCR4 gene;Cell surface;Cells;Clinic;Clinical Trials;Collaborations;Detection;Diagnosis;Disease;Dyes;Early Diagnosis;Endocrine Gland Neoplasms;Exposure to;FOLH1 gene;Fibroblasts;Growth Factor;Head and Neck Cancer;Human;IL2RA gene;Image;Immune response;Immunotherapy;Isotopes;Japan;Label;Leucine;Licensing;Ligand Binding;Light;Logic;Long-Term Survivors;Lutetium;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Membrane;Microscopic;Multiple Myeloma;Neoadjuvant Therapy;Operative Surgical Procedures;Pancreas;Patient Selection;Patients;Pattern;Phase;Photons;Pituitary Gland;Positron-Emission Tomography;Prior Therapy;Radioimmunoconjugate;Recurrence;Regulatory T-Lymphocyte;Risk;Scanning;Serum;Solid Neoplasm;T memory cell;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Translating;United States National Institutes of Health;Universities;Work;X-Ray Computed Tomography;absorption;analog;antibody conjugate;bone imaging;cancer cell;cell killing;chemokine;fibroblast-activating factor;imaging agent;imaging probe;imaging program;immune activation;immunogenic;implantation;interest;invention;manufacture;molecular imaging;mouse model;neoplastic cell;novel therapeutics;objective response rate;phase 2 study;phase 3 testing;photoimmunotherapy;pre-clinical;prevent;programs;prostate cancer cell;receptor;response;small molecule;targeted agent;theranostics;treatment effect;tumor;tumor diagnosis;tumor microenvironment Growth Factor Imaging and Photoimmunotherapy n/a NCI 10926047 1ZIABC010656-19 1 ZIA BC 10656 19 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1578593 NCI This project spans many parts of the molecular imaging program. We have been and continue to be focused on developing membrane receptor targeted agents in order to diagnose stage and select patients for therapy. In addition to the agents described above one other class of imaging agents is based on antibodies. We have developed multiple radiolabeled antibodies and have completed several clinical trials involving them. In addition we have developed a novel therapy called photoimmunotherapy (PIT) that conjugates a specific photon absorbing dye IR700 to an antibody. This antibody photon absorber conjugate (APC) is then injected and binds to the cognate receptor on the tumor cell surface. Exposure to near infrared light (NIR) produces a rapid and selective cancer cell killing. PIT was discovered by our team in 2010 and multiple animal models were undertaken. By 2013 the invention was licensed to Aspyrian which is now Rakuten. Over the past several years Phase 1 and Phase II studies in head and neck cancers have been performed with a 44% objective response rate in recurrent head and neck cancers. Several long term survivors have been seen. PIT is now in global Phase 3 testing and was approved in Japan in late 2020. Meanwhile we are developing PIT that targets immunosuppressive cells in the hopes of promoting an even stronger immune response than is evoked by PIT of the tumor. When for instance Treg PIT is combined with anti tumor PIT in mouse models strong immunogenic responses are seen with induction of memory T cells preventing further implantation of the tumor. We are studying this phenomenon in mouse models at the microscopic level to better understand how removing T reg cells from the tumor microenvironment specifically causes T cell mediated cell killing. At the same time we continue as a program to develop targeted small molecule and antibody conjugates for PET imaging. We are initiating a clinical trial in the CC NIH to use PIT as a neoadjuvant therapy prior to surgery in patients with operable head and neck cancers. A CD25 antibody for killing Treg cells has been developed and is currently being manufactured for use in human trials. This agent when combined with a tumor targeted PIT will cause a substantial increase in the immune response to PIT leading to more profound treatment effects. 1578593 +No NIH Category available Ablation;Acetates;Adenocarcinoma;Affect;Aftercare;Age;Algorithms;American;Amino Acids;Animal Model;Antibodies;Antigen Targeting;Arachidonic Acids;Area;Artificial Intelligence;Basic Science;Biological Markers;Biopsy;Biopsy Specimen;Bombesin;CXCR4 gene;Cancer Etiology;Canis familiaris;Cessation of life;Circumscribed Lesion;Clinical Trials;Cognitive;Collaborations;Computer-Assisted Diagnosis;Cooperative Research and Development Agreement;Coupled;DNA Sequence Alteration;Data;Devices;Diagnosis;Diagnostic;Disease;FOLH1 gene;Focused Ultrasound Therapy;Generations;Genes;Genomics;Gleason Grade for Prostate Cancer;Glutamine;Goals;Grant;Human;Image;Image Guided Biopsy;Immunoglobulin Fragments;Implant;Intervention;J591 Monoclonal Antibody;Joints;Lamivudine;Lasers;Lutetium;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Medical;Medical center;Metabolism;Metastatic Neoplasm to the Bone;Methods;Military Personnel;Molds;Molecular;Molecular Weight;Morbidity - disease rate;Names;Natural History;Neoplasm Metastasis;Operative Surgical Procedures;PSA level;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Physicians;Positron-Emission Tomography;Procedures;Prostate;Prostate Cancer therapy;Prostatectomy;Protocols documentation;Pyruvate;Quality of life;RB1 gene;Radiation;Radiation therapy;Recurrence;Recurrent Malignant Neoplasm;Regulation;Research;Role;Sales;Salivary;Salivary Glands;Salivary duct structure;Screening Result;Screening for Prostate Cancer;Sensitivity and Specificity;Serum;Skin Cancer;Sodium Fluoride;Specificity;Specimen;Staging;System;TP53 gene;Techniques;Testing;Time;Tracer;Treatment Side Effects;Ultrasonography;Urologic Oncology;analytical tool;androgen deprivation therapy;androgen sensitive;artificial intelligence algorithm;artificial intelligence method;blind;bone imaging;cancer cell;cancer imaging;cancer recurrence;castration resistant prostate cancer;clinically significant;cofactor;computer generated;design;digital;digital pathology;high risk;histological specimens;imaging agent;imaging modality;improved;male;men;metabolic abnormality assessment;minimally invasive;non-invasive monitor;novel;overtreatment;photoimmunotherapy;preclinical study;preservation;prognostic;programs;prostate biopsy;prostate cancer model;prostate lesions;radiologist;screening;serum PSA;small molecule;standard care;standard of care;success;targeted agent;targeted imaging;tumor;ultrasound;uptake Prostate Cancer Imaging n/a NCI 10926046 1ZIABC010655-19 1 ZIA BC 10655 19 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3157187 NCI Prostate cancer is the 2nd leading cause of cancer death in males. As a result of screening with serum prostate specific antigen (PSA) there has been a dramatic increase in the number of men diagnosed with prostate cancer. The diagnosis is being made at a younger age yet the morbidity of the standard treatment such as surgery and radiation---remain unchanged. Thus men with the diagnosis of prostate cancer are often overtreated for their disease and will live with the consequences of this treatment for many years greatly affecting the Quality of Life Years (QALY). The ultimate answer to this dilemma is serum biomarkers that identify lethal cancers but not incidental cancers but this is unlikely to occur soon. In the meantime methods of localizing prostate cancer and treating them with minimally invasive therapy would dramatically lessen the morbidity associated with widespread screening and the overdiagnosis/overtreatment of prostate cancer. A variety of imaging methods have been developed and we are exploring their role in localizing early prostate cancer. The MIP has partnered with the Urologic Oncology Branch to develop new imaging methods to be coupled with minimally invasive treatment methods which include RF/laser ablation targeted radiation and photoimmunotherapy. The MIP is engaged in a number of pre-clinical studies in prostate cancer. We have been investigating a variety of targeted imaging agents. Initially we have evaluated several antibodies and antibody fragments against PSMA (3TC J591) in animal models of prostate cancer. Recently we began using PSMA PET based on small molecules that target PSMA. We are seeking to understand at a molecular level what controls the expression of PSMA in a cancer cell. Metabolic studies of prostate cancer may have implications for therapy. We are investigating PET in animal models of prostate cancer to detect differences in metabolism between the androgen-sensitive and insensitive state. Moreover we are launching a program in C13 hyperpolarization of pyruvate which will enable non invasive monitoring of metabolism Clinical Trials The MIP has been studying prostate cancer imaging in humans since its inception. We have developed analytic tools in conjunction with a CRADA with Philips Medical Systems. We have demonstrated that a multiparametric approach improves the specificity of 3T MRI for prostate cancer. However there remain significant limitations in the sensitivity and specificity of 3T MRI. After patients undergo prostatectomy and their specimens are available for review it is clear that less than 40% would be amenable for focal therapy based on being single well circumscribed lesions that are visible on MRI. We have designed a customized prostate mold which is in use in all patients undergoing surgery at NCI. It enables the imaging to be directly correlated with the pathologic specimen. Therefore working with Philips Medical Systems we have designed an US-MR fusion system that takes the data from the 3T MRI and fuses it to the real time ultrasound image. This product was released for sale in 2013 under the name UroNav. Biopsy and interventional procedures can then be performed under MR guidance using the ultrasound. This device has been used successfully in over 2000 patients at NCI. A dog study showed the accuracy was about 3-4mm but was much better than cognitive biopsies. We are currently using a similar platform to direct focal laser ablation (FLA) of suitable prostate lesions (i.e. ones that are well demarcated low Gleason score and could otherwise be watched. We are also testing HIFU in animal models. Computer aided diagnosis and machine learning are new areas of research for the MIP. Significant progress has been made in designing new AI algorithms to help radiologists identify cancers and characterize them. We have extended these AI algorithms to encompass pathologic analysis of biopsy specimens in the hopes of better predicting high risk patients. We are developing novel PET agents that might be more specific for prostate cancer especially in detecting metastases. For instance we completed a PET study using 11C-Acetate and 18F-ACBC an agent associated with amino acid transport which has shown success in localizing recurrent prostate cancer. Ultimately we wish to combine PET-MR studies and conduct minimally invasive therapies after US fusion. We completed a trial of the agent F18-DCFBC which is a first generation low molecular weight tracer directed at PSMA. We are performing PET studies with a PSMA targeted PET agent. We are conducting trials using F18 DCFPyl a second generation agent directed at PSMA. This agent has already shown great potential to characterize the disease status even when post treatment PSA levels are quite low. We are hoping to use cold PSMA injected retrograde in the salivary ducts to block uptake in the salivary glands. This will be useful in preserving salivary function when PSMA-directed therapies such as lutetium 177 PSMA are used to treat metastatic castrate resistant prostate cancer. We are also generating computer aided diagnosis (CAD) devices and algorithms that could automate the diagnosis of prostate cancer. As part of a FLEX grant we have tested numerous other PET agents including F-DHT arachidonic acid CXCR4 FDG and F Glutamine and F Bombesin in order to select better agents for imaging prostate cancer. Moreover since PSMA is so important we have begun basic research to evaluate the expression of PSMA and what controls it. For instance we found PSMA is one a small group of genes that is regulated by numerous co-factors. We have improved the understanding of FOLH1 regulation which is responsible for PSMA expression. Also we have demonstrated alterations in metabolism related to specific genetic mutations (RB1 TP53) in adenocarcinomas. ADT slow release implants are also introduced into tumors to reduce need for systemic ADT especially during radiation therapy. Artificial intelligence methods are being used to improve diagnostics with imaging and digital pathology. A major project is underway with the Joint Pathology Center at Walter Reed Military Medical Center to evaluate 30 years of digital pathologic specimens of prostatectomy specimens using AI. 3157187 +No NIH Category available ABCB1 gene;ABCG2 gene;Age;Alleles;Angiogenesis Inhibitors;Anti-Retroviral Agents;Antiepileptic Agents;Antimetabolites;Antineoplastic Agents;Azathioprine;Biological;CYP1B1 gene;CYP2C19 gene;CYP2D6 gene;CYP3A4 gene;CYP3A5 gene;Candidate Disease Gene;Carboplatin;Central Nervous System;Chemotherapy-Oncologic Procedure;Clinical;Clinical Trials;Development;Differentiation Antigens;Disease;Drug Kinetics;Drug Targeting;Drug Transport;Enzymes;Etiology;Future;GNRH2 gene;Gender;Genes;Genetic;Genetic Determinism;Genetic Markers;Genetic Polymorphism;Genetic Variation;Genotype;Gleason Grade for Prostate Cancer;Goals;HLA Antigens;Hyperplasia;Immunofluorescence Immunologic;Immunoglobulins;Immunosuppressive Agents;Individual Differences;Inherited;Killer Cells;Knowledge;Laboratories;Link;Local Therapy;Malignant Neoplasms;Malignant neoplasm of prostate;Mammals;Mediating;Membrane;Molecular;Movement;Multivariate Analysis;Mutation;Normal tissue morphology;Oncology;Organ;Outcome;Paclitaxel;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Pharmacogenetics;Pharmacogenomics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Phenotype;Physiology;Plicamycin;Population;Prior Therapy;Process;Progression-Free Survivals;Prostate;Prostatic hypertrophy;Publishing;Race;Research;Research Design;Scanning;Serum;Statistical Data Interpretation;Testosterone;Therapeutic;Therapeutic Index;Tissue Microarray;Tissues;Topoisomerase Inhibitors;Toxic effect;Treatment outcome;UGT1A1 gene;United States National Institutes of Health;Update;Variant;Work;Xenobiotics;abiraterone;androgen deprivation therapy;bevacizumab;cancer therapy;chemotherapy;clinical center;comorbidity;docetaxel;drug development;drug disposition;drug metabolism;experimental study;genetic association;genetic variant;genotyped patients;improved;inter-individual variation;interest;lenalidomide;neoplastic;novel;patient response;patient stratification;peptide hormone;pharmacodynamic biomarker;phase 1 study;precision medicine;predicting response;programs;receptor;response;side effect;success;therapeutic protein;therapy outcome;treatment response Clinical Pharmacogenetics n/a NCI 10926045 1ZIABC010627-20 1 ZIA BC 10627 20 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 966995 NCI Our laboratory has a strong interest in clinical pharmacogenetics. We have integrated pharmacogenetics and pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism pharmacokinetics (PK) response and toxicity as well as to understand the contribution of inter-individual variation in clinical outcomes in therapies with an already narrow therapeutic window. Given the importance of pharmacogenomics in precision medicine we are actively involved with implementing the pharmacogenomics program at the NIH Clinical Center. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein MDR1) ABCG2 (BCRP) SLCO1B3 (OATP1B3 OATP8) CYP3A4 CYP3A5 CYP1B1 CYP2C19 CYP2D6 UGT1A1 UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such they are involved in physiology development of disease drug PK and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. Thus we are interested in studying how inherited variants in transporters are associated with disease etiology disease state and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. While many studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. In the past we have genotyped patients with the Drug Metabolizing Enzymes and Transporters (DMET) platform (which ascertains 1931 genotypes in 235 genes) to explore potential links between these genes and outcomes from several cancer therapies. In the current fiscal year we have transitioned over to the updated Pharmacoscan platform which interrogates 4627 variants in 1191 ADME genes. It also detects 4389 ancestry informative markers 239 gender markers 7116 human leukocyte antigen markers and 1484 killer cell immunoglobulin-like receptor markers. We have studied the PG assessments of many anticancer agents including recently mithramycin belinostat docetaxel/lenalidomide/bevacizumab combination olaparib/carboplatin combination carfilzomib azathioprine abiraterone paclitaxel cabozantinib and zotiraciclib. While over ten-thousand phase I studies are published in oncology fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84) evaluating toxicity (n = 42) response or PFS (n = 32) and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors antimetabolites and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities prior therapies racial backgrounds and other factors that confound statistical analysis of pharmacogenetics. Taken together phase I studies analyzed herein treated small numbers of patients (median 95% CI = 28 24-31) evaluated few variants that are known to change phenotype and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions. Gonadotropin-releasing hormone 2 (GNRH2) is a poorly-studied peptide hormone that is widely distributed in the central nervous system and expressed in peripheral tissues of mammals. The non-synonymous rs6051545 variant in GNRH2 (A16V) has been linked to higher serum testosterone concentrations. This study investigated whether the A16V variant is associated with altered androgen-deprivation therapy (ADT) progression-free survival (PFS) and overall survival (OS). We examined the expression of GNRH2 in prostate tissue microarrays comprising normal tissue prostatic hyperplasia and prostate cancer using immunofluorescence. We also evaluated the GNRH2 genotype in 131 patients with prostate cancer who received ADT and compared PFS and OS between the variant and wild-type genotypes. GNRH2 was detected in all prostate tissues although expression did not vary with Gleason grade or disease stage (p=0.71). The GNRH2 A16V genotype was not associated with PFS or OS; however univariate and multivariate analyses revealed Gleason score and definitive local therapy were each associated with PFS whereas age and Gleason score were associated with OS. GNRH2 is expressed in normal hyperplastic and neoplastic prostate tissues; the A16V variant is not related to treatment outcome or survival. 966995 +No NIH Category available ATAC-seq;Address;Affect;African;African American;African American population;African ancestry;Alleles;American;Anti-Inflammatory Agents;Antigen Presentation;Arachidonic Acids;Area;Aspirin;Award;Biological Assay;Blood Platelets;Blood specimen;Cancer Patient;Case/Control Studies;Chemotaxis;Chemotherapy and/or radiation;Chromatin;Chromatin Structure;Chromosomes;Clinical;Cohort Studies;Collaborations;Communities;DNA;DNA Damage;DNA Methylation;Data;Development;Disease;Disease Progression;Eicosanoids;Environment;Environmental Risk Factor;Epigenetic Process;Ethnic Population;European;Fatty Acids;Future;Gene Expression;Genes;Genetic;Genotype;Ghana;Goals;Herpesviridae;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;Immunobiology;Immunomodulators;Immunosuppression;Immunotherapy;Incidence;Indigenous;Infection;Inflammation;Inflammatory;Integration Host Factors;Interferons;Knowledge;Link;Malignant neoplasm of prostate;Maps;Maryland;Measures;Medical History;Mesenchymal;Metastatic Prostate Cancer;Mission;Modeling;Molecular Profiling;Neighborhoods;Neoplasm Metastasis;PTGS1 gene;Participant;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Platelet aggregation;Pollution;Population;Prevention;Prostatic Neoplasms;Proteins;Publishing;Recording of previous events;Recurrent disease;Reduce health disparities;Reporting;Research;Resected;Residencies;Resistance;Resources;Risk;Risk Factors;Risk Reduction;Role;Seroprevalences;Serum;Sex Behavior;Signal Pathway;Signal Transduction;Socioeconomic Status;Surveys;Technology;Testing;Therapeutic;Thromboxane A2;Thromboxane B2;Tobago;Transposase;Tumor Biology;Tumor Immunity;Tumor Suppression;Tumor-Derived;Up-Regulation;Viral;Virus;Virus Diseases;West Indies;Work;anticancer research;cancer cell;cancer health disparity;chemokine;cohort;cooking;cytokine;deprivation;disease disparity;environmental agent;genetic signature;genetic variant;genome wide association study;genome-wide;high risk population;immune function;indexing;inflammatory marker;lifestyle factors;malignant breast neoplasm;men;men's group;metastatic process;mimicry;mortality;neoantigens;new technology;novel;pathogen;precision medicine;predictive signature;prevent;programs;prostate cancer progression;prostate cancer risk;proteomic signature;racial population;recruit;research study;response;trait;tumor;tumor microenvironment;urinary The Molecular Profile of Prostate Tumors in African-American Men n/a NCI 10926044 1ZIABC010624-20 1 ZIA BC 10624 20 9692197 "AMBS, STEFAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 869296 NCI "We made progress in several research areas as part of completed and ongoing research studies. Specifically we a) further strengthened the NCI-Maryland Prostate Cancer study; b) corroborated that aspirin use inversely associates with lethal prostate cancer; c) demonstrated the presence of an interferon signature in African American tumors and established a relationship with disease recurrence and a genetic ancestral marker d) showed that thromboxane A2/B2 signaling associates with lethal prostate cancer in African American men and inversely correlates with aspirin use and e) discovered a serum proteomics signature that links suppression of tumor immunity to African ancestry and lethal prostate cancer. In 2023 we further reported that neighborhood deprivation is associated with prostate cancer risk and mortality among exposed men affecting African American men more so than European American men. A deprived neighborhood residency may increase the risk of African American men for prostate cancer and a related mortality through its association with systemic immune function and inflammation (PMID: 36662526). Previously we generated gene expression profiles of primary prostate tumors resected from African American and European American men. Many of the differently expressed genes were immune-regulatory and pro-inflammatory (PMID: 18245496). Unexpected was the presence of an interferon signature in many of the African American tumors. This signature is related to an ""interferon-related DNA damage resistance signature (IRDS)"" that predicts resistance to chemotherapy and radiation in breast cancer. IRDS has also been linked to the pro-metastatic mesenchymal transition of cancer cells. Thus IRDS may promote the metastatic process and is as we found associated with early disease recurrence in prostate cancer (PMID:30012562). Furthermore we observed that aspirin use significantly reduces the risk of aggressive prostate cancer in African American men (PMID: 2829292333293340) suggesting inflammation as a driver of disease progression. Because of these findings we will test if the tumor biology of prostate cancer patients who are regular aspirin users is different from patients who do not take aspirin showing less inflammation. The presence of an interferon gene signature in prostate tumors also suggested a possible involvement of either a viral infection in disease pathology or the reactivation of endogenous retroviral sequences in the tumor microenvironment which occurs commonly (PMID: 22247020). This hypothesis was supported by our data showing that the interferon signature in prostate tumors coincides with a gene signature of retroviral activation. Moreover men with interferon lambda 4-encoding IFNL4-dG a genetic variant enhancing the risk of viral infections (PMID: 23291588) may have an increased risk of herpesvirus 8 (HHV-8)-associated prostate cancer as we showed (PMID: 35468990). Patients with the IFNL4-dG allele which is significantly more common in African than European populations have increased occurrence of IRDS connecting this allele to both an increased risk of viral infections and an increased risk of prostate cancer (PMID: 30456312). This finding has been published in Clinical Cancer Research (PMID: 30012562). Because viral infection-related host factors are associated with prostate cancer in African American men as we showed we begun to study the relationship between viral infection history and the disease using a novel technology termed VirScan (PMID: 32526205). VirScan can detect an infection history of all human viruses analyzing blood samples. We will examine the viral infection history in men of African descent and how it relates to prostate cancer analyzing men from the NCI-Maryland and NCI-Ghana studies and a cohort from Tobago West Indies. We will also further investigate the relationship between the IFNL4 dG genotype and viral infections and whether there is an interaction between them in prostate cancer development and progression. A completed study linking sexual activity to prostate cancer supports the hypothesis that a viral infection may contribute to the risk of prostate cancer among carriers of the IFNL4 dG genotype (PMID:30456312). An alternative pathway that may lead to an interferon signature in prostate tumors is the aberrant expression of tumor-derived neo-antigens which can elicit an immune response. For example it was shown that therapy-induced alterations in DNA methylation can cause the expression of otherwise silenced endogenous retroviral sequences resulting in an interferon response in tumors and enhanced sensitivity to immune therapy. The observation supports the hypothesis that changes in DNA accessibility can lead to increased neo-antigen presentation linking DNA accessibility to neo-antigen expression and an immune response. DNA accessibility is largely controlled by the chromatin structure (e.g. open vs. condensed). We hypothesize that distinct chromatin accessibility signatures could be the underlying cause for the increased expression of endogenous retroviral sequences in tumors of African American men and the common occurrence of an interferon signature in them. To test this hypothesis we will use the Assay for Transposase Accessible Chromatin with high throughput sequencing termed ATAC-seq which is a technology for fast and sensitive profiling of chromatin accessibility. Lastly we are completing work in support of the DoD Impact award W81XWH1810588 (PI Ambs Yates Cook) ""A Precision Medicine Study of How Inflammation May Underlie the Excessive Burden of Prostate Cancer in Men of African Ancestry"". Here 82 immune-inflammation marker and the fatty acid profile (n=24) of blood samples will be analyzed in NCI-Maryland (see ZIA BC 010499) and NCI-Ghana study participants and will be linked to GWAS and survey data. The aim is to examine associations of these proteins and metabolites with lethal prostate cancer African ancestry lifestyle factors socioeconomic status and neighborhood deprivation index and medical history. Data from this ongoing project show that circulating chemokines and cytokines related to immune suppression and chemotaxis are generally higher in men of African ancestry (African American and Ghanaian men). When we link the markers to survival up-regulation of markers that comprise the ""suppression of tumor immunity"" pathway associated with lethal prostate cancer in fully adjusted models (PMID:35365620). The preventative benefits of aspirin in the development of lethal prostate cancer have been attributed to inhibition of the arachidonic acid signaling pathway. Thromboxane A2 (TXA2) an eicosanoid produced primarily via COX1 in activated platelets orchestrates platelet aggregation. TXA2 elevated during inflammation contributes to metastasis. Hence we assessed the role of TXA2 levels in the development of lethal prostate cancer. Measuring levels of urinary 11-dehydrothromboxane B2 (TXB2) a stable metabolite and marker for TXA2 we observed a distinct elevation of urinary TXB2 in African American men and an inverse association between TXB2 levels and aspirin use. Moreover high TXB2 was positively associated with metastatic prostate cancer. High TXB2 was also associated with all-cause and prostate cancer-specific mortality in African American men. The data are consistent with our previous findings of a prevalent immune-inflammation signature and an inverse association of aspirin use with lethal prostate cancer in these patients. Our study highlights the potential benefit of aspirin for prevention of lethal prostate cancer in this high-risk group of men through inhibition of TXA2 synthesis (PMID: 34264335)." 869296 +No NIH Category available Animal Model;Animals;Antibodies;Antigen Targeting;B-Lymphocytes;Basement membrane;Benign;Binding;Biological Assay;Biology;Blocking Antibodies;C-terminal;CD8-Positive T-Lymphocytes;Capsid;Carrageenan;Cell Culture Techniques;Cervical;Clinical Trials;Communicable Diseases;Controlled Clinical Trials;Cosmetics;Costa Rica;Data;Development;Disease;Dose;Epithelial Cells;Epithelium;Epitopes;Exposure to;FDA approved;Female genitalia;Food;Genes;Genital;Genitalia;Goals;HIV Infections;Herpes Simplex Infections;Hour;Human;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immune;Immune response;In Vitro;Infection;Intervention;Legal patent;Lesion;Life Cycle Stages;Lubricants;Macaca mulatta;Malignant - descriptor;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular Conformation;Mucous Membrane;Mus;Nonoxynol 9;Oropharyngeal;Papillomavirus;Papillomavirus Infections;Persons;Pharmaceutical Preparations;Plasmids;Polysaccharides;Prevention;Process;Proliferating;Proteins;Regimen;Research;Serum;Site;Stains;Surface;T-Lymphocyte;Technology;Testing;Therapeutic Agents;Translational Research;Vaccination;Vaccines;Vagina;Virion;Virus;Virus-like particle;Woman;cervicovaginal;chronic infection;efficacy testing;gene transfer vector;genetic vaccine;immunogenicity;improved;in vivo;intraepithelial;keratinocyte;manufacture;microbicide;mouse model;neutralizing antibody;particle;prevent;reproductive tract;response;technology development;therapeutic effectiveness;therapeutic vaccine;vaccination strategy;vaccine development;vaccine evaluation;vector;young woman Papillomavirus Virion Proteins and Vaccines n/a NCI 10926040 1ZIABC010579-20 1 ZIA BC 10579 20 2093670 "LOWY, DOUGLAS R." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 686183 NCI Papillomaviruses (PVs) infect the epithelia of animals and humans where they generally induce benign proliferations at sites of infection. In addition persistent infection by some human papillomaviruses (HPV) especially HPV16 can induce malignant progression of human genital and oropharynx lesions. Our research is mainly concerned with the biology of papillomavirus infection elucidation of the PV life cycle and development of vaccines and other strategies to inhibit HPV infection. We previously developed a simple and efficient strategy for generating high titers of infectious papillomavirus particles that transduce encapsidated marker plasmids i.e. pseudovirions. We have exploited this technology in our basic virologic and translational research efforts leading to developing a mouse cervicovaginal challenge model for HPVs. Using this model we determined that transient disruption of epithelial integrity is required for HPV infection that the first step in the virus life cycle involves binding of the virus to the basement membrane and that the virus transfers to target epithelial cells only after the L2 protein in the capsid has undergone an enzymatic cleavage while the virus is on the basement membrane. The cleavage of L2 is associated with a conformational change in the capsid leading to exposure of highly conserved L2 cross-neutralization epitopes that lie C-terminal to the cleavage site. In a process that takes several hours the virions transfer from the basement membrane to the surface of keratinocytes that are re-epithelializing the exposed basement membrane and the virions are then internalized. The mouse model also enabled us to determine that antibodies induced by L1 VLP (virus-like particle) vaccines and L2 vaccines block in vivo infection by distinct mechanisms. At high concentrations L1 VLP-induced antibodies block virion binding to the basement membrane while at low concentrations they permit basement membrane binding but prevent binding to target keratinocytes. Since the L2 cross-neutralization epitopes are cryptic and are not exposed until after the virions have been bound to the basement membrane L2 antibodies that broadly cross-neutralize HPV types do not interfere with initial basement membrane binding. Once the L2 epitopes are exposed however while the virions remain on the basement membrane the L2 antibodies can bind to the virions and abrogate the infectious process by preventing transfer of the virions to target keratinocytes. Both in the mouse model and in an analogous model developed for the rhesus macaque infection is prevented by local application of carrageenan which is an algal polysaccharide widely used in processed food and cosmetics and is the main gelling agent in some over-the-counter lubricants. Based on our data clinical trials of carrageenan as a microbicide to prevent genital HPV infection in young women are underway. Using HPV pseudoviruses we previously developed a high throughput in vitro HPV neutralization assay that has become the gold standard for the field. Based on the improved understanding of the in vivo infectious process and the mechanism by which L2 vaccines confer protection we developed an alternative in vitro neutralization assay that is approximately three orders of magnitude more sensitive than the standard assay in detecting L2 neutralizing antibodies. The alternative assay has considerable potential for determining the immunogenicity of candidate L2 vaccines and for clinical trials of L2 vaccines. Our development of a method to induce efficient HPV pseudovirus infection of the female genital tract after transient epithelial disruption with nonoxynol-9 (N-9) proved to be the key to our development of an effective intravaginal vaccination strategy. In patent pending studies we found that intravaginal pseudovirus vaccination of N-9-treated mice induces strong systemic and mucosal T and B cell responses to target antigens transduced by the pseudovirions. Systemic responses rival those induced by previously optimized Ad5 vectors. Intravaginal responses are remarkably strong with up to 80% of intravaginal CD8 T cells staining tetramer positive for the targeted antigen. Most of the induced T cells appear to be intraepithelial and are maintained in the vaginal tract at least 100 days after vaccination. Intravaginal pseudovirus vaccination is a promising approach for focusing immune responses to the female genital tract that may increase the effectiveness of therapeutic vaccines directed at herpes simplex virus infection HIV infection and HPV infection. We have also organized and participated in NCI human clinical trials of the virus-like particle vaccines following our earlier development of the technology that underlies the commercial HPV vaccines. We initially tested the bivalent HPV vaccine (manufactured by GlaxoSmithKline) in Costa Rica where post-hoc analyses of women who received fewer than the standard 3 dose regimen indicated they were as protected during 7 years of study against infection by the HPV types targeted by the vaccine (HPV16/18) as the women who received all 3 doses. In addition the women who received only one dose had stable serum HPV16/18 antibody levels between years 1 and 7 suggesting the strong protection may be durable. This surprising result raised the possibility that a single vaccine dose might confer long-term protection. A rigorously controlled clinical trial that tests the efficacy of one vaccine dose vs. two doses with two FDA-approved vaccines has now started in Costa Rica. 686183 +No NIH Category available Algorithms;Androgen Receptor;Androgens;Animal Testing;Biology;Camptothecin;Clinic;Clinical;Clinical Pharmacology;Combined Modality Therapy;Cystitis;Development;Disease;Disease Progression;Dose;Drug Design;Drug Screening;Evaluable Disease;Evaluation;Gene Targeting;Goals;Hypoxia;Hypoxia Inducible Factor;In Vitro;Intravenous infusion procedures;Laboratories;Lead;Malignant neoplasm of prostate;Modeling;Molecular;Monitor;Myelosuppression;Neoplasm Metastasis;Oral;Pathway interactions;Patient Selection;Patients;Pharmacology and Toxicology;Phase;Pre-Clinical Model;Prediction of Response to Therapy;Process;Prognostic Marker;Provenge;Recommendation;Regimen;Research;Resistance;System;Testing;Therapeutic;Treatment Failure;Treatment outcome;Up-Regulation;Validation;Work;advanced prostate cancer;androgen biosynthesis;angiogenesis;arm;bench to bedside;cancer therapy;castration resistant prostate cancer;chemotherapy;clinical development;clinical efficacy;design;docetaxel;drug candidate;drug development;drug discovery;effective therapy;efficacy evaluation;enzalutamide;experience;hormone therapy;inhibitor;interest;metastatic process;nanoparticle drug;neoplastic cell;new therapeutic target;next generation;next generation sequencing;novel;novel therapeutics;phase 2 study;potential biomarker;pre-clinical;precision medicine;preclinical development;prostate cancer model;research clinical testing;resistance mechanism;screening;standard of care;targeted treatment;therapy resistant;tool;treatment response;tumor;tumor hypoxia Drug Development for Prostate Cancer and other Metastatic Processes n/a NCI 10926038 1ZIABC010547-21 1 ZIA BC 10547 21 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1046884 NCI Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of novel therapeutics with efforts on characterizing their molecular and clinical pharmacology as well as evaluating for potential biomarkers of treatment response and resistance. We are also interested in understanding the mechanisms of resistance of prostate cancer regimens. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Effective treatments for patients with mCRPC following disease progression on enzalutamide are currently an unmet clinical need. We previously demonstrated that simultaneous inhibition of the HIF-1and androgen receptor (AR) pathways can overcome enzalutamide resistance in vitro. Combination treatment with NLG207 a nanoparticle-drug conjugate of camptothecin and inhibitor of HIF-1a and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer therapeutic resistance and disease progression are inevitable. We next investigated NLG207 in combination with enzalutamide in patients with mCRPC following progression on enzalutamide. This was a single-arm optimal two-stage phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide (NCT03531827). A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily. Between March 2019 and June 2021 four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients. NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy. We are currently developing novel targeted therapies against metastatic CRPC. We have embarked upon a new drug screening project to identify novel drug targets and develop rationale combination therapies using next-generation sequencing and a matrix combination screening platform that is designed to identify novel drug targets/pathways for CRPC. We are currently testing promising combinations in various preclinical prostate cancer models with the goal of selecting the best treatment combination to move towards clinical development. 1046884 +No NIH Category available Affect;Aging;Allogenic;Biology;CAR T cell therapy;CCR9 gene;CD3 Antigens;CD4 Positive T Lymphocytes;Cells;Chronic Lymphocytic Leukemia;Down-Regulation;Goals;Hematopoietic Stem Cell Transplantation;Homeostasis;IL7 gene;Immune;Immunotherapy;Malignant Neoplasms;Natural Killer Cells;Peripheral;Role;T cell reconstitution;T-Lymphocyte;Tissues;Work;cancer therapy;cell regeneration;cytokine;immune reconstitution;improved;in vivo;novel;senescence;sialic acid binding Ig-like lectin Immune Reconstitution n/a NCI 10926036 1ZIABC010525-21 1 ZIA BC 10525 21 9692325 "GRESS, RONALD " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 62741 NCI Previously we have: 1) identified a novel CAR-T cell therapy for chronic lymphocytic leukemia (CLL) and establish Siglec-6 as a possible target for immunotherapy; 2) shown that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies as dynamic downregulation of target expression may affect in vivo efficacy; 3) revealed a previously unappreciated role for CCR9 in the tissue homeostasis and effector function of CD4 T cells in the gut; and 4) demonstrated that the abundance of IL-7 and not IL-15 limits the size of the peripheral iNKT cell pool. These results redefine the cytokine requirement for iNKT cells and indicate competition for IL-7 between iNKT and conventional alpha-beta T cells. Work on this project was concluded in FY23. 62741 +No NIH Category available Affect;Antisense RNA;Biochemical;Cell Cycle;Cell physiology;Cells;Chromatin;Chromatin Modeling;Chromosome Structures;Complex;Coupled;Cues;Development;Double-Stranded RNA;Elements;Ensure;Epigenetic Process;Eukaryota;Fission Yeast;Foundations;Gametogenesis;Gene Expression Profile;Gene Silencing;Genes;Genetic;Genetic Recombination;Genetic Transcription;Genome;Heterochromatin;Histone H2A;Histone H3;Introns;Investigation;Large-Scale Sequencing;Link;Location;Lysine;Maintenance;Maps;Measures;Mediating;Messenger RNA;Methylation;Modeling;Modification;Pathway interactions;Play;Poly A;Polyadenylation;Polycomb;Process;Proteins;RNA;RNA Degradation;RNA Interference;RNA Polymerase II;RNA Splicing;Regulation;Repression;Resolution;Role;S phase;Signal Induction;Site;Small Interfering RNA;Small RNA;Structure;Transcript;Variant;Work;cancer therapy;exosome;genome integrity;genome-wide;human disease;insight;novel;posttranscriptional;preservation;prevent;protein complex;recruit;response;therapeutically effective RNAi and Epigenetic Control of Higher-Order Chromatin Assembly n/a NCI 10926034 1ZIABC010523-21 1 ZIA BC 10523 21 8777973 "GREWAL, SHIVINDER S" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1849078 NCI The dynamic regulation of higher-order chromosome structure governs diverse cellular processes ranging from stable inheritance of gene expression patterns to other aspects of global chromosome structure essential for preserving genomic integrity. Our earlier studies revealed that RNA interference (RNAi) whereby double-stranded RNAs silence cognate genes plays a critical role in targeting of heterochromatin a specialized form of chromatin that can inhibit transcription and recombination across large chromosomal domains to specific locations in the fission yeast Schizosaccharomyces pombe genome. Subsequent genetic and biochemical investigations identified the RNAi-induced transcriptional gene silencing (RITS) complex that provides a direct link between small RNAs and heterochromatin formation. These studies also uncovered surprising interdependency between heterochromatin and RNAi mechanism and led to the discovery of an elegant self-reinforcing RNAi loop mechanism that ensures both transcriptional and post-transcriptional silencing in cis. In this loop mechanism RNAi machinery operates as a stable component of the heterochromatic domains via tethering of RNAi complexes (such as RITS) to heterochromatin marks (including histone H3 methylated at lysine 9) to destroy repeat transcripts that escape heterochromatin-mediated transcriptional silencing. The processing of transcripts by RNAi machinery generates small interfering RNAs (siRNAs) that are utilized for further targeting of heterochromatin complexes so the mechanism continues. We have extended these analyses to gain insights into the full spectrum of target sequences affected by the RNAi and heterochromatin machineries. In a comprehensive study we developed a high-resolution map of heterochromatin distribution across the entire S. pombe genome. These analyses together with mapping of RNAi components and large scale sequencing of siRNAs associated with an RNAi effector RITS complex involved in heterochromatic silencing have yielded novel insights into the epigenetic profile of this model eukaryotic genome. In an interesting new development our recent work suggests that heterochromatic structures are dynamically regulated during the cell cycle. In particular heterochromatic repeat elements are transcribed during a brief window during the S-phase. Importantly we have discovered that the transcription of repeats by RNA polymerase II is coupled to the recruitment of heterochromatin complexes supporting a prominent role for transcriptional machinery in determining the epigenetic makeup of the genome. In another surprising finding we have discovered that low levels of heterochromatin factors localize broadly across euchromatic regions containing genes and cooperate with RNAi machinery to regulate expression of RNA polymerase II transcripts across large portions of the genome. In particular we have found that heterochromatin/RNAi factors prevent accumulation of potentially deleterious antisense RNAs. Heterochromatin and RNAi factors are partially redundant in this regard with a histone H2A variant H2A.Z. Loss of Clr4/Suv39h-containing heterochromatin silencing complex or an Argonaute protein alone has little effect on antisense transcript levels but cells lacking either of these factors and H2A.Z show markedly increased levels of antisense RNAs that are normally degraded by the exosome. These analyses suggest that in addition to performing other functions heterochromatin and RNAi factors cooperate with H2A.Z to suppress antisense transcripts which has important implications for diverse chromosomal processes. In another important finding we have discovered a novel heterochromatin assembly pathway that relies on transcription and RNAs but does not require RNAi machinery. We have discovered that facultative heterochromatin is established at genes required for gametogenesis (which are repressed in vegetative cells) and that its formation is dependent on conserved RNA degradation factors including a protein complex involved in polyadenylation of transcripts and the exosome that degrade gene transcripts. Importantly heterochromatin formation by this pathway is modulated in response to signals that induce gametogenesis. Most recently we have investigated how the cell distinguishes different types of RNA molecules and links their processing to heterochromatin establishment. We discovered core machinery that associates with different factors (including splicing factors) to mediate targeting of mRNA ncRNA and introns to assemble heterochromatin domains at specific sites throughout the genome. These groundbreaking studies have paved the way for understanding the more complex regulatory networks at work in higher eukaryotes including that involve polycomb silencing and has provided a foundation for understanding the large scale reprogramming of the genome in response to developmental and environmental cues that occur through modifications of heterochromatin. 1849078 +No NIH Category available Address;Adult;Affect;Apoptosis;Behavior;Biology;Bone Morphogenetic Proteins;Cell Death;Cells;Cellular biology;Data;Development;Disease;Distal;Down-Regulation;Effector Cell;Elements;Embryo;Embryonic Development;Family;Fibroblast Growth Factor;Gastrointestinal Neoplasms;Gene Expression;Gene Silencing;Generations;Genetic;Goals;Growth;Heart;Hindlimb;Imagery;Induction of Apoptosis;Limb Bud;Limb Development;Limb structure;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mesenchyme;Metastatic Neoplasm to the Bone;Modeling;Molecular;Mus;Normal Cell;Pathway interactions;Pattern;Pelvis;Phocomelia;Protein Family;Role;Shapes;Signal Transduction;Signaling Molecule;Signaling Protein;Surface Ectoderm;Testing;Work;bone morphogenetic protein receptors;breast cancer progression;homeodomain;insight;novel;premature;transcription factor;tumor Role of BMP and FGF signaling during limb development n/a NCI 10926033 1ZIABC010518-21 1 ZIA BC 10518 21 8123123 "LEWANDOSKI, MARK B" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 474836 NCI In previous work we produced genetic evidence for a novel model in which the surface ectoderm must receive a BMP signal resulting in down regulation of Fgfs which in turn induces apoptosis of the underlying mesenchyme. Thus we demonstrated that BMPs control programmed cell death indirectly by regulating FGF signaling. However it is important to emphasize that this insight does not exclude a direct role for BMP signaling in controlling cell death in the developing limb. Therefore we extended these studies by studying the role of BMP and FGF signaling in various aspects of limb development using mouse lines that express Cre in specific region of the developing limb. For example the only way to test the hypothesis that BMPs act as direct effectors of cell death is to inactivate BMPs receptors only in the lineage that undergoes cells death without affecting FGF expression in nearby cells. We have achieved this using new Cre lines that allow Cre-mediated gene inactivation in these lineages. With these lines we have determined that BMPs are direct effectors of cell death (Dev Biol. 411: 266-76). In current work we showed that a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal FGF signals. Elimination of Meis results in premature limb distalization and proximalization of PD segmental borders and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning (Sci Adv 2020 PMID: 32537491) . In ongoing work we are defining the role of distal FGF signals in generating the pattern and differentiation of the pelvis in the hindlimb. We had previously demonstrated that these FGF signals are downstream of the BMP receptor 1a (Development 2007 PMID: 17537800) . We are now using sophisticated genetics and cutting-edge imagery of gene expression to define which FGFs are responsible for forming this most proximal element and initiating limb formation. 474836 +No NIH Category available Affect;Cell Nucleus;Cell membrane;Cells;Cytoplasm;Dimerization;Ensure;Epidemic;Event;Evolution;Family;Fluorescence Microscopy;Frequencies;Genome;Goals;HIV;HIV-1;Human;Infection;Kinetics;Knowledge;Length;Location;Minor;Parents;Process;Production;Proteins;Proviruses;RNA;Regulation;Research;Retroviridae;Role;Signal Transduction;Site;Structure;T-Lymphocyte;Testing;Time;Travel;Treatment Protocols;Vaccines;Viral;Viral Genome;Viral Packaging;Viral Proteins;Virion;Virus Assembly;Virus Replication;dimer;gag Gene Products;genetic information;imaging study;improved;insight;live cell imaging;macromolecule;particle;pathogen;protein complex;trafficking;viral RNA;virus genetics Defining Mechanisms of HIV-1 Gag:RNA Interactions and Virus Assembly n/a NCI 10926029 1ZIABC010506-21 1 ZIA BC 10506 21 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 958753 NCI We are studying the trafficking of HIV-1 macromolecules and assembly. Once it has exited the nucleus HIV-1 RNA needs to travel to various subcellular locations to carry out its functions including dimerizing with another viral RNA and assembling into a viral particle. To generate infectious particles HIV-1 RNA and proteins traffic to the plasma membrane the major virus assembly site. The Gag protein drives HIV-1 assembly and interacts with viral RNA and proteins to ensure the packaging of the viral genome and replication machinery. Additionally Gag interacts with host proteins for virus egress. We have studied the assembly of HIV-1 Gag containing heterologous NC domain that does not recognize HIV-1 RNA and the adaptation of HIV-1 to improve Gag:RNA interactions. These studies revealed the minor changes in the NC domain can alter Gag:RNA interactions and improve RNA packaging and viral replication. It has often been suggested that the interactions of HIV-1 RNA and Gag leading to assembly are initiated in the cytoplasm. To better understand the regulation of virus assembly we are examining cytoplasmic HIV-1 Gag:RNA and RNA:RNA interactions. We are also studying HIV-1 RNA trafficking in T cells and exploring the role of the RNA genome in HIV assembly. We have examined the dynamics of viral RNA and Gag-RNA interactions near the plasma membrane by total internal reflection fluorescence (TIRF) microscopy. We found that in the absence of Gag most of the HIV-1 RNAs stayed near the plasma membrane transiently. The presence of Gag significantly increased the time RNAs stay near the plasma membrane. We observed that the frequency of HIV-1 RNA packaging was dependent on the Gag expression level. Our results showed that only a small proportion of the HIV-1 RNAs (approximately one tenth to one third) that reached the plasma membrane was incorporated into viral protein complexes. These studies determined the dynamics of HIV-1 RNA on the plasma membrane and obtained the temporal information of RNA-Gag interactions that lead to RNA encapsidation. We will continue these live-cell imaging studies to determine the kinetics of HIV-1 and nonviral RNA on the plasma membrane and examine the factors that affect their retention on the plasma membrane. We have studied the role of HIV-1 RNA during virus assembly. We hypothesize that HIV-1 full-length RNA facilitates the formation of viral particles. To test our hypothesis we examined the efficiencies of particle formation with and without RNA containing HIV-1 packaging signal. We found that although viral particles can be generated without the presence of RNA genome the HIV-1 RNA genome facilitates the production of HIV-1 particles. Furthermore the effects of the RNA genome are dependent on the level of Gag expressed in the cells. These observations are consistent with our hypothesis that packaging a dimeric RNA is the nucleation process of HIV-1 assembly. We will continue these studies to examine the role of viral RNA in facilitating HIV particle assembly. 958753 +No NIH Category available Cells;Chromosomes;Complex;DNA;Defect;Epidemic;Event;Evolution;Exhibits;Family;Generations;Genetic Recombination;Genome;Goals;Guanosine;HIV;HIV Genome;HIV-1;HIV-2;Infection;Innate Immune Response;Knowledge;Laboratories;Length;Modification;Nucleotides;Parents;Primate Lentiviruses;Process;Proviruses;RNA;Regulation;Research;Retroviridae;Reverse Transcription;Role;SIV;Signal Transduction;T-Lymphocyte;Transcription Initiation Site;Treatment Protocols;Vaccines;Viral;Virus;Virus Replication;dimer;fitness;genetic information;genome integrity;insight;mutant;pandemic pathogen;particle;pathogen;preservation;progenitor;transmission process;viral DNA;viral RNA;virus genetics Understanding Retroviral Reverse Transcription Recombination and Replication n/a NCI 10926028 1ZIABC010504-21 1 ZIA BC 10504 21 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 245263 NCI During replication HIV-1 converts its packaged dimeric RNA genomes into DNA and generates one provirus in an infection event. In this process HIV-1 needs to preserve its genetic information while the host innate immune response attempts to abolish the generation of proviruses capable of producing infectious progeny. HIV-1 uses several transcription start sites to generate several unspliced RNAs including those containing three or one guanosine at the 5 ft end referred to as 3G and 1G RNA respectively. The 1G RNA is preferentially selected for packaging indicating that these 99.9% identical RNAs exhibit functional differences. To determine whether heterogenous transcription start site usage is unique to laboratory adapted HIV-1 strains we examined 15 primate lentiviruses including transmitted founder viruses of HIV-1 HIV-2 and several simian immunodeficiency viruses (SIVs). We found that all 15 viruses used multiple transcription start sites to some extent. Most viruses also exhibited selective packaging of specific full-length viral RNA species into particles. These findings demonstrate that using multiple transcription start sites and selective packaging of certain full-length viral RNA species are conserved features of primate lentiviruses. In addition an SIV strain closely related to the progenitor virus that gave rise to HIV-1 group M the pandemic pathogen exhibited transcription start site usage similar to some HIV-1 strains and preferentially packaged 1G RNA. These findings indicate that multiple transcription start site usage and selective packaging of a particular unspliced RNA species predate the emergence of HIV-1. To better understand the importance of using multiple transcription start sites we have generated two HIV-1 mutants with distinct 2-nucleotide modifications that predominantly express 3G RNA or 1G RNA. Both mutants can generate infectious viruses and undergo multiple rounds of replication in T cells. However both mutants exhibit replication defects compared to the wild-type virus. Our findings demonstrate that HIV-1 maximizes its replication fitness by using multiple transcription start sites to generate unspliced RNAs with different specialized roles in viral replication. The three consecutive guanosines at the junction of U3 and R may also maintain HIV-1 genome integrity during reverse transcription. These studies reveal the intricate regulation of HIV-1 RNA and complex replication strategy. Additionally we have examined the adaptation of a HIV-1 that contained a NC domain that does not interact properly with packaging signals. These studies provide understanding to the HIV-1 replication. 245263 +No NIH Category available Affect;African;African American;African American population;African ancestry;Age;American;Area;Aspirin;Award;Baltimore;Biological;Blood;Cancer Etiology;Cancer Patient;Case/Control Studies;Cessation of life;Chemotaxis;Child;Chronic;Cities;Classification;Clinical;Cohort Studies;Collaborations;Collection;Communities;Control Groups;DNA Methylation;Data;Databases;Development;Diabetes Mellitus;Diagnosis;Diet;Dietary Factors;Disease;Disease Marker;Disease Outcome;Disease Progression;Enrollment;Environmental Risk Factor;European;European ancestry;Female;Freezing;Frequencies;Gene Expression;Genotype;Ghana;Gleason Grade for Prostate Cancer;Goals;Guidelines;Hereditary Malignant Neoplasm;Hospitals;Household;Household Heads;Immune;Immune response;Immunooncology;Individual;Infection;Inflammation;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Maryland;Measures;Mediating;Medical;Medical History;Medical Records;Medical center;Minor;Molecular;Molecular Profiling;Motor Vehicles;Mutation Spectra;National Comprehensive Cancer Network;Native American Ancestry;Neighborhoods;Nigerian;Occupational;Operative Surgical Procedures;Outcome;PSA level;Paraffin Embedding;Participant;Pathologic;Pathology;Pathway interactions;Patients;Pattern;Penetrance;Pharmaceutical Preparations;Phase;Pilot Projects;Poverty;Procedures;Prospective Studies;Prostatectomy;Prostatic Neoplasms;Proteins;Protocols documentation;Public Assistance;Race;Recording of previous events;Records;Recurrent disease;Reporting;Research;Risk;Risk Factors;Risk Reduction;Role;Secure;Sexually Transmitted Diseases;Signal Pathway;Socioeconomic Status;Specimen;Study Subject;Surveys;Susceptibility Gene;TNM;Time;Tissue Sample;Tissues;Tobacco use;Tobago;Tumor Biology;Tumor Immunity;Tumor Markers;Tumor Suppression;Unemployment;United States Department of Veterans Affairs;Universities;Update;Urine;Virus Diseases;West Indies;Work;advanced disease;bead chip;cancer diagnosis;cancer health disparity;cohort;cooking;database of Genotypes and Phenotypes;deprivation;design;disease diagnosis;disorder risk;ethnic difference;follow-up;gene environment interaction;genetic risk factor;genetic signature;genetic variant;high risk;immune function;indexing;inflammatory marker;male;men;metabolome;mortality;population based;precision medicine;prospective;prostate cancer risk;protective effect;protein activation;protein expression;racial difference;recruit;smoking exposure;socioeconomics;survival disparity;systemic inflammatory response;tumor Maryland Prostate Cancer Case-Control Study n/a NCI 10926027 1ZIABC010499-21 1 ZIA BC 10499 21 9692197 "AMBS, STEFAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 869296 NCI Our study was implemented in two phases. The first phase which started in April of 2005 constituted a pilot study to evaluate recruitment procedures. This phase was successful and the full study was initiated with minor changes to the protocol in April of 2006. The full study was completed in 2015 [976 cases (489 African American and 487 European American) and 1034 population-based controls (486 African American and 548 European American)]. We collected blood and urine from all individuals and paraffin-embedded and fresh-frozen tissue specimens form 135 prostatectomy surgeries. Cases are from two Baltimore hospitals the Veterans Affairs Medical Center and the University of Maryland Medical Center. Cases have pathologically confirmed prostate cancer. They had a disease diagnosis within the last two years prior to recruitment and presented with prostate cancer at all stages of the disease. One-hundred and thirty-eight cases had advanced stage disease (n = 79 with T3 and n = 59 with T4 disease). Cases were also assigned to National Comprehensive Cancer Network risk groups based on the patients' TNM stage Gleason score Gleason pattern and PSA level at diagnosis according to the guidelines for prostate cancer version 2.2021. They were classified into low intermediate high and very high risk based on the likelihood of their disease to progress to lethal prostate cancer. Lastly we have secured current information on overall and disease-specific survival from National Death Index records for the cases. A recent update brought the number to 247 deaths from all causes with 66 of them being reported as a prostate cancer-specific mortality. The median survival follow-up time for the cohort is now 9.7 years (NDI follow up through December 31 2020). We will continue to collect this information for both cases and controls. More recently we were able to determine PSA values at recruitment for 888 men from the control group. Only 16 of them had PSA 4 at time of recruitment ( 2%). Furthermore we defined 823 patients as incident cases (422 African American 401 European American) when they were recruited into the study within one year after the disease diagnosis having an average interval between diagnosis and enrollment into our study of 4.8 months (4.4 months for African American and 5.2 months for European-American men). The population-based controls were identified through the Maryland Department of Motor Vehicles database and were frequency-matched by age and race to cases. The study involved the administration of a survey and collection of blood and urine from all study subjects. Tumor specimens were obtained from cancer patients if they were available after prostatectomy. Our survey evaluates tobacco use medication use occupational history diet medical and sexual history familial cancer history and socioeconomic status. Current activities in this study include the collection of additional data from pathology and medical records to have clinicopathology for all cases and information on disease recurrence as available. We continue to characterize the study participants and performed ancestry-typing in collaboration with the Kittles laboratory (City of Hope). Participants were evaluated for their West African European and Native American ancestry using 105 ancestry informative markers. The genotyping data showed that self-identified African American participants have an average West African ancestry of 75.5% among cases and 72.1% among controls whereas the European ancestry in the self-identified European American participants ranged from an average 85.8% among cases to 89.9% among the controls. For a subset (83%) of the cases and controls we obtained additional West African ancestry estimates using the Infinium HumanOmni5-Quad BeadChip array (genotyping data for 706 cases and 744 controls were submitted to dbGaP). West African ancestry estimates using the two approaches were highly similar (r=0.98). In 2021 we completed a multi-year effort to link neighborhood measures of poverty to participants in our studies. We have completed analyses using neighborhood deprivation and gentrification as exposures. A neighborhood deprivation index was generated following the guidelines by Messer at al. Our index contains the following variables: percent (%) households in poverty % female headed households with dependent children % households on public assistance % households earning under $30000/year % households with no car and % males and females unemployed. Our study is aimed at identifying differences in risk factor exposure and tumor biology between African American and European American men. Molecular work will be used to examine race/ethnic differences in tumor biology. Our research is also aimed at identifying environmental and inherited factors (e.g. infections and immune response smoking exposure ancestry-related factors low penetrance susceptibility loci) that promote the development of an aggressive disease and specifically contribute to the survival disparity between African American and European American men. A major research focus is the role of tumor and systemic inflammation in disease progression because of our previous observation that tumors of African American patients contain a prominent immune-inflammation gene signature. We also investigated the link between regular use of aspirin and prostate cancer. This study shows that aspirin use significantly reduces the risk of aggressive prostate cancer in African American men (PMID: 28292923). Moreover regular aspirin use reduced disease recurrence in these men. We did not find the same strong protective effects of aspirin among the European American men. Thus regular aspirin use before and after a prostate cancer diagnosis may reduce the development of an aggressive disease in African American men who are at high risk of a lethal malignancy. This finding was corroborated with an analysis of the Southern Community Cohort Study (SCCS) a large prospective study to investigate the causes of cancer health disparities. Here we found that regular aspirin use at baseline protects against a prostate cancer mortality on follow-up among the African American men in SCCS (PMID:33293340). We think these are significant observations indicating that regular aspirin use protects against lethal prostate cancer. More recently we studied if men of African descent harbor a unique systemic immune-oncological signature and measured 82 circulating proteins in almost 3000 Ghanaian African American and European American men from the NCI-Maryland and NCI-Ghana studies. Protein signatures for suppression of tumor immunity and chemotaxis were distinctively elevated in men of West African ancestry. Importantly the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer pointing to clinical importance particularly for men of African descent (PMID:35365620). Lastly we begun to investigate the impact of neighborhood deprivation and gentrification on prostate cancer outcomes. These studies are designed to further define the relative contribution of ancestral versus neighborhood factors to aggressive disease in African American men. Assigning neighborhood deprivation as the exposure we reported that neighborhood socioeconomic deprivation was associated with a prostate cancer diagnosis and mortality independent of individual SES and having different effects on African American and European American men. The association between neighborhood deprivation and prostate cancer might be partly mediated through effects that poverty may have on systemic immune-oncology protein expression and activation of signaling pathways related to systemic immune function and inflammation (PMID: 36662526). 869296 +No NIH Category available Affect;Affinity;Antiviral Agents;Attenuated;Binding;C-terminal;Cell Line;Cell Nucleus;Cell membrane;Cells;Complex;Cyclosporine;Cytoplasm;Dependence;Diameter;Diffusion;Dipeptides;Docking;Exhibits;Filament;Genes;Genome;Glycine;HIV-1;Hela Cells;Host Factor 1 Protein;Human;Human Cell Line;Human immunodeficiency virus test;Impairment;Infection;Integration Host Factors;Interphase Cell;Jurkat Cells;Karyopherins;Mediating;Membrane;Membrane Fusion;Modeling;Mutation;N-terminal;Night Monkey;Nuclear;Nuclear Envelope;Nuclear Import;Nuclear Pore;Nuclear Pore Complex;Nuclear Pore Complex Proteins;Nucleoplasm;Pathway interactions;Phenotype;Play;Pore Proteins;Process;Proline;Property;Proteins;RNA;Reporter;Resistance;Retroviridae;Reverse Transcription;Role;Route;Series;Side;Site;Small Interfering RNA;TRIM5 gene;Testing;Variant;Vesicular stomatitis Indiana virus;Viral;Virus;Virus Replication;cell type;experimental study;genome wide screen;heterokaryon;inhibitor;knock-down;macromolecule;molecular mass;mutant;nucleocytoplasmic transport;particle;prevent;receptor;trafficking HIV-1 passage through the nuclear pore complex n/a NCI 10926026 1ZIABC010488-21 1 ZIA BC 10488 21 8123034 "KEWALRAMANI, VINEET N" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 295847 NCI In the mature viral particle two plus sense copies of the HIV-1 RNA genome and viral enzymatic proteins are enclosed in a conical core which is composed of a lattice of CA hexamers and pentamers. After the HIV-1 Envelope fuses with the target-cell membrane the viral core is released into the cytoplasm. Although previous models suggested that the core immediately disassembled after membrane fusion the persisting integrity of the core in the cytoplasm and the presence of CA at the NPC indicate that CA is not an immediate castaway during early steps of replication and is instead functionally associated with the PIC facilitating critical steps in infection. HIV-1 infects dividing and nondividing cells equally well due to efficient utilization of NPCs . NPCs are transport channels that span the nuclear envelope and regulate bidirectional transport of macromolecules between the nucleus and cytoplasm. With an estimated molecular mass of more than 100 MDa NPCs are composed of multiple copies of 30 different proteins called nucleoporins (Nups); including transmembrane Nups (Poms) structural Nups and FG (phenyalanine-glycine) Nups. FG Nups are essential components of the nuclear diffusion barrier and provide docking sites for transport receptors. NPCs allow the passive diffusion of molecules with a diameter of up to 9 nm and active translocation of large cargoes with a diameter of up to 39 nm. Structural analysis suggests that the NPC can dilate up to 50 nm in diameter. How the PIC traverses the NPC has been a subject of great inquiry. Early experiments with HIV-1/MLV chimeric viruses revealed that replacement of HIV-1 CA with MLV CA impairs the ability of HIV-1 to infect nondividing cells. These findings were supported by studies showing specific mutations in CA also prevented HIV-1 infection of nondividing cells. Studies with host factors that regulate nuclear transport solidified a role for CA in this process. Genome-wide screens for HIV-1 host factors exhibited significant overlap in identifying karyopherins as well as nuclear pore protein components. In particular transportin-3 (TNPO3 or TRN-SR2) Nup358 (also known as RNABP2) and Nup153 emerged as potent regulators of HIV-1 infection. Nup358 the largest FG Nup is the main component of NPC filaments that extend towards the cytoplasmic side of the pore and plays an essential role in regulating cargo trafficking by forming a physical meshwork of FG repeats. Another FG Nup Nup153 is anchored in the nuclear side of the NPC and its FG enriched filaments extend into the nucleoplasm. Depletion of Nup358 or Nup153 impairs HIV-1 infection and reduces 2-LTR circle formation but does not affect reverse transcription. Parallel studies from our group on CPSF6 had revealed that mutation forms of the protein blocked HIV-1 nuclear entry. Notably we selected for a virus resistant to this nuclear entry block and obtained N74D HIV-1 again implicating a role of CA in regulating HIV-1 nuclear entry. However unlike previous HIV-1 CA mutants that were impaired for nuclear entry the N74D mutant virus efficiently infected nondividing cells. We exploited this property to test if N74D HIV-1 had different nuclear pore requirements relative to WT HIV-1. Indeed we soon discovered that TNPO3 Nup358 and Nup153 depletion impaired WT HIV-1 but not N74D HIV-1 infection. WT HIV-1 and N74D HIV-1 do overlap in utilization of some Nups and N74D HIV-1 appears to be more dependent on Nup85 and Nup155 relative to WT HIV-1. With this finding we and others more carefully investigated the relationship between CA and NPC components. Nup358 and Nup153 are thought to have distinct interactions with CA. One group has shown that Nup358 interacts with CA through a CypA-homology domain in C-terminal domain of Nup358 while other studies have found that three FG repeats in the N-terminal domain are sufficient to support HIV-1 infection. In contrast Nup153 has been shown to bind to a conserved pocket in CA also targeted by CPSF6 and the antiviral compounds PF-74 and BI-2. Interestingly both Nup153 and CPSF6 possess 'FG' dipeptides that are necessary for binding CA. Notably HIV-1 with CA mutations that prevent CypA-interaction also appeared to exhibit reduced sensitivity to Nup153 depletion. CypA is a highly abundant cellular protein and binds to the HIV-1 CA residues glycine 89 and proline 90 on the proline-rich loop between helices 4 and 5. Disruption of this interaction by CA mutation (such as G89V or P90A) by cyclosporine A (CsA a competitive inhibitor of CypA) by CypA knockdown or by homozygous deletion of the CypA gene impairs HIV-1 replication in most human cells. Although CypA is incorporated into HIV-1 particles CypA-CA interaction in the target cell rather than in the producer cell is necessary to enhance viral replication. CypA can also have deleterious effects on HIV-1 replication. Passage of HIV-1 in a CD4+ HeLa cells in the presence of CsA selected two mutants (A92E and G94D) in the CypA-binding loop of CA although neither mutation affected the affinity of CA for CypA. Viruses bearing either A92E or G94D show attenuated HIV-1 infectivity in some human cell lines such as HeLa and H9 cells; however reducing the CypA-CA interaction by CsA treatment or by introducing an additional mutation at proline 90 rescued HIV-1 infectivity in these cells. In contrast the A92E and G94D mutants are able to replicate in the presence or absence of CsA in other cell lines such as Jurkat cells. How these CA mutants behave very differently following CsA treatment in different target cells is still a puzzle. One possible explanation for these phenotypes is that differential effects of CypA mutants on HIV-1 replication in different cell types might be due to variations in CypA expression levels. In support of this idea some studies have shown that there is correlation between different CypA expression levels and CsA effects in different cell lines. Another possibility to explain the CsA-dependency of these mutants in some cell types is a CypA-dependent restriction factor activity. In owl monkey cells TRIMCyp blocked HIV-1 infection but restriction was released by CA mutants that disrupt the interaction with CypA and by CsA treatment. Since A92E HIV-1 infection was also rescued by CA mutants or CsA it was hypothesized that a CypA-dependent restriction factor was inhibiting A92E replication in these cells. Use of heterokaryons has shown that CsA-dependent infection by A92E and G94D mutants is due to a dominant cellular restriction factor but the restriction is not by retrovirus restriction factor TRIM5alpha. Because A92E HIV-1 and G94D HIV-1 are impaired at the level of nuclear entry in nonpersmissive cell types we sought to understand whether CypA interaction with the WT HIV-1 PIC also had the potential to restrict nuclear transport - but HIV-1 had adapted in use of the NPC to overcome the impediment. To investigate the role of nuclear pore subcomplexes in HIV-1 infection we systematically depleted all thirty-two human nuclear pore proteins in HeLa cells with siRNA and then infected with VSV-G pseudotyped reporter viruses. In this effort we have identified HIV-1 dependency on nucleoporins that are regulated by CA interactions with CypA. Strikingly CypA dictates the nuclear import route utilized by HIV-1 favoring an FG-receptor mediated pathway. We hypothesize that CypA regulates access the N74 pocket of HIV-1 CA and facilitates subsequent interaction with FG-nucleoporins. 295847 +No NIH Category available Affect;Antiviral Therapy;C-terminal;Cell Nucleus;Cells;Chromatin;Companions;Complex;Cytoplasm;Data;Dependence;Equine Infectious Anemia Virus;Feline Immunodeficiency Virus;Genetic;Genetic Transcription;HIV;HIV-1;HIV-2;Infection;Integration Host Factors;Karyopherins;Mutation;Nuclear;Nuclear Pore;Pore Proteins;Role;Route;SIV;Viral Physiology;Virus;experimental study;trafficking;viral resistance The role of CPSF6 in HIV-1 infection n/a NCI 10926025 1ZIABC010487-21 1 ZIA BC 10487 21 8123034 "KEWALRAMANI, VINEET N" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 591692 NCI We have previously described a C-terminally truncated form of CPSF6 (CPSF6-358) that has potent antiviral activity against different HIV-1 HIV-2 and SIV isolates but no activity against EIAV FIV or MLV. CPSF6-358 interferes with the nuclear entry of HIV-1. We selected for HIV-1 replication in cells expressing CPSF6-358 and identified a mutation of N74D of CA as sufficient to confer viral resistance. We examined the nuclear pore dependencies for wild-type (WT) and N74D HIV-1 and found that the isolates require some of the same pore proteins but differ in requirements for others. In particular N74D HIV-1 was less sensitive to depletion of TNPO3 (a karyopherin) NUP153 and NUP358/RanBP2 than WT HIV-1. These experiments established a genetic interaction between HIV-1 CA and the nuclear pore. We are now attempting to define the route that HIV-1 takes to the nucleus: the cell factors it interacts with and how it interacts with these factors. Our data suggest a direct interaction of WT CPSF6 with CA. We have also discovered that TNPO3 regulates CPSF6 nuclear localization. We are examining whether CPSF6 normally interacts with HIV-1 CA in the cytoplasm and whether this interaction is important for nuclear entry of the virus. Within the nucleus we find that the HIV-1 pre-integration complex interacts with CPSF6 and this interaction regulates HIV-1 integration in the host cell chromatin. Notably we find that by interacting with CPSF6 HIV-1 is first directed to speckles after entering the nucleus and prior to integration. Nuclear speckles colocalize with regions of chromatin that HIV-1 preferentially integrates. Thus we hypothesize that HIV-1 co-opted CPSF6 to access regions of chromatin that are broadly transcriptionally active due to their proximity to nuclear speckles. A companion effort has identified cytoplasmic and nuclear host factors that affect CPSF6-trafficking of the HIV-1 to nuclear speckles. 591692 +No NIH Category available Aftercare;Androgen Receptor;Androgens;Bathing;Binding;Biochemical;Brain imaging;Carbon;Cell Nucleus;Cell Respiration;Chemicals;Citric Acid Cycle;Communities;Complex;Contrast Media;Data;Dependence;Drug Targeting;Electron Transport;Evaluation;Future;Goals;Heat-Shock Proteins 70;Image;Isotope Labeling;Label;Link;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Monitor;Nature;Nuclear;Pharmaceutical Preparations;Physiological;Physiology;Prostate Cancer therapy;Protons;Pyruvate;Rationalization;Relaxation;Reporting;Research;Ribosomes;Role;Sampling;Signal Transduction;Sodium Chloride;Source;Techniques;Terminal Disease;Theophylline;Time;Tracer;Translations;Water;aerobic glycolysis;alpha ketoglutarate;androgen deprivation therapy;castration resistant prostate cancer;catalyst;chemical bond;density;deprivation;detection limit;in vivo;inhibitor;metabolic imaging;molecular imaging;novel therapeutics;treatment effect;treatment response;tumor Overhauser Enhanced Magnetic Resonance Imaging (OMRI) n/a NCI 10926023 1ZIABC010477-21 1 ZIA BC 10477 21 8778758 "CHERUKURI, MURALI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1064634 NCI "Evaluation of JG-98 inhibitor of HSP70 by metabolic MRI: The androgen receptor is a key regulator of prostate cancer and the principal target of current prostate cancer therapies collectively termed androgen deprivation therapies. Insensitivity to these drugs is a hallmark of progression to a terminal disease state termed castration-resistant prostate cancer. Therefore novel therapeutic options that slow progression of castration-resistant prostate cancer and combine effectively with existing agents are in urgent need. We show that JG-98 an allosteric inhibitor of HSP70 re-sensitizes castration-resistant prostate cancer to androgen deprivation drugs by targeting mitochondrial HSP70 (HSPA9) to suppress aerobic respiration. Rather than impacting androgen receptor stability as previously described JG-98's primary effect is inhibition of mitochondrial translation leading to disruption of electron transport chain activity as shown by 13C MRI using hyperpolarized 133C labeled pyruvate. Although functionally distinct from HSPA9 inhibition direct inhibition of the electron transport chain with a complex I or II inhibitor creates a similar physiological state capable of re-sensitizing castration-resistant prostate cancer to androgen deprivation therapies. These data identify a significant role for HspA9 in mitochondrial ribosome function and highlight an actionable metabolic vulnerability of castration-resistant prostate cancer. a-Ketoglutarate is a key biomolecule involved in a number of metabolic pathways horizontal line most notably the TCA cycle. Abnormal alpha-ketoglutarate metabolism has also been linked with cancer. Here isotopic labeling was employed to synthesize [1-(13)C5-(12)CD(4)]alpha-ketoglutarate with the future goal of utilizing its [1-(13)C]-hyperpolarized state for real-time metabolic imaging of alpha-ketoglutarate analytes and its downstream metabolites in vivo. The signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH) hyperpolarization technique was used to create 9.7% [1-(13)C] polarization in 1 minute in this isotopologue. The efficient (13)C hyperpolarization which utilizes parahydrogen as the source of nuclear spin order is also supported by favorable relaxation dynamics at 0.4 muT field (the optimal polarization transfer field): the exponential (13)C polarization buildup constant T(b) is 11.0 +/- 0.4 s whereas the (13)C polarization decay constant T(1) is 18.5 +/- 0.7 s. An even higher (13)C polarization value of 17.3% was achieved using natural-abundance alpha-ketoglutarate disodium salt with overall similar relaxation dynamics at 0.4 muT field indicating that substrate deuteration leads only to a slight increase ( approximately 1.2-fold) in the relaxation rates for (13)C nuclei separated by three chemical bonds. Instead the gain in polarization (natural abundance versus [1-(13)C]-labeled) is rationalized through the smaller heat capacity of the ""spin bath"" comprising available (13)C spins that must be hyperpolarized by the same number of parahydrogen present in each sample in line with previous (15)N SABRE-SHEATH studies. Remarkably the C-2 carbon was not hyperpolarized in both alpha-ketoglutarate isotopologues studied; this observation is in sharp contrast with previously reported SABRE-SHEATH pyruvate studies indicating that the catalyst-binding dynamics of C-2 in alpha-ketoglutarate differ from that in pyruvate. We also demonstrate that (13)C spectroscopic characterization of alpha-ketoglutarate and pyruvate analytes can be performed at natural (13)C abundance with an estimated detection limit of 80 micromolar concentration x *%P(13C). All in all the fundamental studies reported here enable a wide range of research communities with a new hyperpolarized contrast agent potentially useful for metabolic imaging of brain function cancer and other metabolically challenging diseases" 1064634 +No NIH Category available 3-Dimensional;Acceleration;Aftercare;Algorithms;Angiogenesis Inhibitors;Area;Biochemical;Blood Vessels;Blood flow;Cell Nucleus;Chemicals;Citric Acid Cycle;Collaborations;Combined Modality Therapy;Complex;Computer software;Consumption;Data;Data Analyses;Dependence;Electron Spin Resonance Spectroscopy;Enzymes;Fourier Transform;Frequencies;Fumarate Hydratase;Goals;Hereditary Leiomyomatosis and Renal Cell Cancer;Human;Image;In Vitro;Information Centers;Ionizing radiation;Kidney Neoplasms;Label;Laboratories;Literature;Magnetic Resonance Imaging;Magnetism;Measures;Mechanics;Mediating;Metabolic;Metabolism;Methods;Modality;Monitor;Mutation;NQO1 gene;Nature;Neoplasms in Vascular Tissue;Nuclear Magnetic Resonance;Oxygen;Oxygen Consumption;Partial Pressure;Patients;Pattern;Pharmacotherapy;Phase;Physics;Physiological;Physiology;Process;Property;Protons;Pyruvate;Quinone Reductases;Radiation therapy;Reactive Oxygen Species;Reporting;Research;Resolution;Risk;Running;Sampling;Scanning;Scheme;Series;Signal Transduction;Slice;Specific qualifier value;Speed;Techniques;Therapeutic Agents;Time;Tissue imaging;Toxic effect;Tracer;Treatment Efficacy;Tumor Oxygenation;Urologic Oncology;Water;Xenograft Model;aerobic glycolysis;anatomic imaging;animal imaging;beta-Lapachone;cancer imaging;chemotherapeutic agent;chemotherapy;data acquisition;data space;data visualization;density;experimental study;image reconstruction;image registration;imager;imaging capabilities;imaging modality;imaging properties;imaging study;improved;in vivo;in vivo evaluation;instrumentation;interest;metabolic imaging;metabolic profile;molecular imaging;neoplastic cell;non-invasive imaging;response;routine imaging;scale up;temporal measurement;treatment effect;treatment optimization;treatment response;tumor;tumor growth;tumor hypoxia;tumor metabolism;tumor xenograft;two-dimensional Time Domian Electron Paramagnetic Resonance Imaging n/a NCI 10926022 1ZIABC010476-21 1 ZIA BC 10476 21 8778758 "CHERUKURI, MURALI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1064634 NCI Goals and Summary: The goals of this project are to develop instrumentation concepts in imaging physics and image reconstruction to provide the ability to non-invasively image properties associated tumor physiology such as tumor oxygenation tumor microvessel density and tumor blood flow. Using such capabilities we propose to use them to longitudinally monitor changes in tumor physiology in response to tumor growth treatment with chemotherapeutic agents and ionizing radiation and the combination. Such capabilities will make it possible to identify temporal profiles of changes in these factors to optimize treatment. Of the various imaging modalities available to determine these properties pertaining to tumor physiology Electron Paramagnetic Resonance Imaging (EPRI) using paramagnetic tracers has a unique ability to quantitatively provide such information and can be used serially during the tumor growth and also treatment phase. This capability enables monitoring changes in tumor oxygen status in response to treatments such as chemotherapy anti-angiogenic drug therapy and radiotherapy and correlate such information with anatomic images and information pertaining to blood vessel density and blood flow. The specific goals of this project are summarized below: 1) Develop and optimize EPR Imaging instrumentation for small animal imaging with capabilities to image tissue oxygen concentration with a spatial resolution of 2 mm in an imaging time of 2 minutes with a pO2 discriminating capability of +/- 3 mm Hg. 2) Develop imaging algorithms improving temporal spectral (Physiologic) and spatial resolution and co-register the images with those from MRI and also additional physiologic information such as tumor blood vessel density blood flow and metabolic profile. 3) Develop image formation methods capable of serially monitoring changes in tumor oxygen status physiology and metabolic status in response to treatment. 4) Evaluate strategies to scale up this modality for human applications. Implementation of Slice Selection in EPR Imaging: Imaging two-dimensional (2D) slices of a 3-d object instead of imaging three-dimensional (3D) volume has its own benefits. The scan time of 2D slice is faster by orders of magnitude data visualization and interpretation is easier with 2D images and there are several software readily available to process 2D images. In MRI the 3D volume is routinely imaged by collecting a series of 2D slices using slice selecting gradient to confine the signal to only desired slice. After the slice selecting gradient is turned off the phase-encoding and frequency read out gradients are turned on sequentially to generate the 2D image of desired object. This approach is not practical for EPR imaging because the gradient settling times are much longer than the EPR echo time. Since EPR imaging uses static field gradients we proposed using modulated field gradient (MFG) to obtain image information from the center area of MFG the so-called sensitive zero crossover point of the subject. A series of slices of the object are scanned by mechanically shifting the resonator using a high precision slider attached to it. All the images were scanned by FT-EPRI in single point imaging (SPI). This capability in EPR imaging greatly enhances the spatial and temporal resolutions and presents EPR imaging data to the end user in exactly the same format as conventional MRI. Increasing Temporal Resolution of FT-EPRI: The principles of the FT-EPR imager developed in our laboratory are similar to MRI though fundamentally it deals with electron paramagnetic resonance instead of nuclear magnetic resonance. Increasing the scan speed is an active research area in MRI and numerous methods to improve the scan speed and temporal resolution were reported in MRI literature. The similarity between the imaging methods of single point imaging FT-EPRI and MRI allows application of many of those techniques in FTEPRI. Time domain signals are acquired in both FT-EPRI and MRI defining the k-space matrix from which image reconstruction is done by Fourier transformation. The k-space has Hermitian symmetry in which the complex conjugates are equivalent. These properties offer a variety of options to optimize the scan speed. In case of imaging a static object partial k-space acquisition exploitation of conjugate symmetry or compressed sensing methods using sparse sampling can speed up data acquisition. In the case of imaging a dynamically changing object the temporal resolution may be improved by considering static and dynamic regions of the image. The key-hole method is an ancient simple dynamic data acquisition scheme where the central k-space region alone is acquired at each time point (t) in dynamic run. The remaining k space data are substituted from a reference of full k-space acquired either before or after the dynamic acquisition. More comprehensive methods such as k-t BLAST and k-t SENSE allow accelerated data acquisition of k-t space in a specified pattern using single or multiple receiver coils. Further quality improvement of reconstructed image can be accomplished by k-t FOCUSS method using compressed sensing. Incorporating these methods to enhance the temporal resolution of EPR imaging allows probing the dynamics of tumor physiology which is an active area of interest to probe the phenomenon of cycling tumor hypoxia. Imaging tumor physiology changes with NQO1-mediated cycling in HLRCC: In Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) patients are at risk for aggressive renal tumors caused by the mutation of the TCA cycle enzyme fumarate hydratase. In collaboration with the Urologic Oncology Branch we identified a therapeutic agentb-lapachone that exploits the high level of expression of quinone reductase NQO1 in HLRCC tumors. We found that b-lapachone significantly increased the rate of non-mitochondrial oxygen consumption in cultured HLRCC tumor cells and showed selective toxicity in vitro by the induction of futile NQO1-mediated cycling which consumes both cytosolic NAD(P)H and oxygen and produces reactive oxygen species (ROS). A pilot experiment demonstrated a reduction in partial pressure of oxygen in an HLRCC tumor xenograft following b-lapachone treatment. We are presently exploring the in vivo therapeutic efficacy and mechanisms of b-lapachone using metabolic imaging. Current efforts include expansion of in vivo metabolic imaging studies to include additional RCC subtypes and imaging modalities such as hyperpolarized 13C MRI to interrogate altered tumor metabolism induced by b-lapachone treatment as well as testing the in vivo therapeutic efficacy of b-lapachone with rationally chosen combination therapies (i.e. evofosamide) in HLRCC xenograft models. The dynamics of pO2 changes will be probed in tumor xenografts with the imaging capabilities of EPR with enhanced spatial and temporal resolution. 1064634 +No NIH Category available Affect;Androgens;Asian;Automobile Driving;Benign;Biological;Biological Assay;Biology;Black race;Body mass index;Cancer Biology;Candidate Disease Gene;Castration;Chemopreventive Agent;Clinical;Collaborations;Complex;DNA Sequence Alteration;Data;Data Set;Development;Diffusion;Disease;Disease Management;Disease Progression;Drug Interactions;Finasteride;Frequencies;Future;GENIE;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genetic Transcription;Genetic Variation;Genomics;Germ-Line Mutation;Goals;Gonadal Steroid Hormones;Haplotypes;Hereditary Malignant Neoplasm;Heritability;Hormones;Hyperplasia;IGFBP2 gene;Impairment;Incidence;Individual;Institution;Insulin;Insulin-Like Growth Factor I;Insulin-Like Growth-Factor-Binding Proteins;Investigation;Kinetics;Knowledge;Laboratories;Link;Logistic Regressions;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;MicroRNAs;Molecular;Molecular Biology;Molecular Genetics;Mutation;Nested Case-Control Study;Obesity;Odds Ratio;Organic Anion Transporters;Outcome;Pathway interactions;Patients;Pharmacogenetics;Pharmacogenomics;Prevention strategy;Prostate Cancer Prevention Trial;Race;Regulator Genes;Regulatory Element;Research;Research Personnel;Resistance;Risk;Risk Assessment;Role;Sample Size;Sampling;Screening for cancer;Serum;Serum Markers;Single Nucleotide Polymorphism;Specimen;Steroids;Testing;Testosterone;The Cancer Genome Atlas;Therapeutic;Time;Tissues;Transcript;Translational Research;Tumor Markers;abiraterone;advanced prostate cancer;ancestry analysis;androgen deprivation therapy;biomarker discovery;black men;cancer genomics;cancer risk;candidate identification;castration resistant prostate cancer;clinically relevant;cohort;differential expression;drug development;extracellular vesicles;health disparity;improved;interest;liquid biopsy;men;microRNA biomarkers;mortality;new therapeutic target;novel;overexpression;precision medicine;precision oncology;predictive marker;promoter;prostate biopsy;prostate cancer prevention;prostate cancer risk;racial difference;randomized placebo controlled trial;resistance mechanism;steroid hormone;targeted treatment;therapy resistant;transcription factor;transcriptomics;treatment response;trend;tumor;uptake Genetics and Molecular Mechanisms of Prostate Cancer n/a NCI 10926021 1ZIABC010453-22 1 ZIA BC 10453 22 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 785162 NCI We have conducted translational research to understand the genetic and molecular mechanism that govern prostate cancer development and progression to identify novel pathways for drug development and investigate mechanisms of resistance to treatment paradigms. Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer and germline testing is increasingly important in cancer screening risk assessment and the overall treatment and management of the disease. We are interested in understanding germline variants associated with inherited predisposition prostate cancer risk and outcomes. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. We have a longstanding collaboration with the Prostate Cancer Prevention Trial (PCPT) investigators to elucidate the molecular and genetic mechanisms that may help explain the trial outcomes of the PCPT. The overall goals of this project are: a) to better understand associations between important androgen regulatory gene polymorphisms and PCa risk; and b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for PCa. Studies are ongoing examining the effects of obesity-related serum markers on modulating the association of obesity with prostate cancer risk. Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor 1 (IGF1) pathways. We investigated the association of circulating serum markers (e.g. androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial a randomized placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF1 axis analytes. Logistic regression estimated odds ratio and 95% CIs for risk of overall low-grade (Gleason 2-6) and high-grade (Gleason 7-10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF1 axis was significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI only the IGF1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments. As the era of cancer genomics expands disproportionate rates of prostate cancer incidence and mortality by race have demonstrated increasing relevance in clinical settings. While Black men are most particularly affected as data has historically shown the opposite is observed for Asian men thus creating a basis for exploring genomic pathways potentially involved in mediating these opposing trends. Studies on racial differences are limited by sample size but recent expanding collaborations between research institutions may improve these imbalances to enhance investigations on health disparities from the genomics front. In this study we performed a race genomics analysis using the GENIE dataset to investigate mutation and copy number frequencies of select genes in both primary and metastatic patient tumor samples. Further we investigated the TCGA race cohort to conduct an ancestry analysis and performed transcriptomics analysis to identify differentially expressed genes highly upregulated in one race and subsequently downregulated in another. Our findings highlight pathway-oriented genetic mutation frequencies characterized by race and further we identify candidate gene transcripts that have differential expression between Black and Asian men. We are also interested in understanding the molecular genetics of androgen transport. The organic anion transporter OATP1B3 encoded by SLCO1B3 is involved in the transport of steroid hormones. We have shown that prostate cancer overexpresses OATP1B3 compared to normal or benign hyperplastic tissue and the common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with CaP. We found that a polymorphism in this transporter increases testosterone import is associated with a shorter time to androgen independence in patients with CaP who are treated with ADT. Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. We recently conducted studies to ascertain the androgen uptake kinetics functional and clinical relevance of de novo expression of OATP1B3. We found that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Studies are ongoing to characterize the molecular mechanisms of SLCO1B3 transcription including transcription factor complexes that assemble at distinct regulatory elements in the SLCO1B3 promoter for driving tissue-specific expression of OATP1B3 in prostate cancer. We recently demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will also assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics. We are also currently investigating the role of extracellular vesicles (EV)-based liquid biopsy tumor markers for CRPC disease progression. 785162 +No NIH Category available Acetates;Adhesives;Affinity;Amines;Amino Acids;Anabolism;Antibodies;Antibody titer measurement;Antibody-drug conjugates;Antigen-Presenting Cells;Antigens;Antitumor Response;Apoptotic;Binding;Biological Assay;Biological Markers;C-Type Lectins;CD4 Positive T Lymphocytes;Cancer Vaccines;Carbohydrates;Cell surface;Cells;Collaborations;Dendritic Cells;Development;Diagnostic;Drug Delivery Systems;Enzymes;Epitopes;Event;Extramural Activities;Galectin 3;Glucans;Glucose;Glycopeptides;Glycosides;Gold;Human;Hybrids;Image;Immune response;Immunization;In Vitro;Keyhole Limpet Hemocyanin;Macrophage;Magnetism;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Medical Research;Metals;Methods;Monoclonal Antibodies;Mucins;Mus;N-terminal;Neoplasm Metastasis;Organic Synthesis;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Pharmaceutical Preparations;Phenotype;Play;Polysaccharides;Proteins;Publishing;Reaction;Reagent;Reproducibility;Research Personnel;Role;Serine;Serum;Specificity;T-Lymphocyte;Tandem Repeat Sequences;Technology;Therapeutic;Therapeutic Agents;Therapeutic Uses;Thompson-Friedenreich Antigen;Threonine;Tissue Microarray;Toxic effect;Tumor Cell Line;Tumor Tissue;Tumor-Associated Carbohydrate Antigens;Vaccinated;Vaccination;Vaccines;Work;analog;biophysical techniques;cancer cell;cell motility;chimeric antigen receptor T cells;cytokine;cytotoxicity;dectin 1;design;in vivo;interest;macromolecule;mimetics;monomer;nanoGold;nanoparticle;neoplastic cell;novel;novel therapeutics;novel vaccines;overexpression;pancreatic ductal adenocarcinoma cell;particle;physical property;process optimization;receptor;tumor;tumorigenesis Carbohydrate Antigen-bearing Nanoparticles for Antitumor Therapy n/a NCI 10926020 1ZIABC010451-22 1 ZIA BC 10451 22 8777873 "BARCHI, JOSEPH JOHN" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 712618 NCI An established hallmark of tumorigenesis is the biosynthesis of aberrant glycan chains due to changes in the expression of glycoprocessing enzymes in tumor tissue. These aberrations become more marked as the tumor acquires a more aggressive phenotype. Tumor cell-surface carbohydrates play important roles in the motility and metastasis of many different cancer cells. In addition many of these aberrant glycans are tumor-associated carbohydrate antigens (TACA) and have been used in the development of tumor vaccines. Since most of the cellular interactions with TACAs are not well understood there is an urgent need to better characterize the specific molecular interactions that occur during these events. One feature of carbohydrate binding to macromolecules that is well understood is the concept of multivalency: Monomer carbohydrates bind to proteins very weakly while clustering of a monomer raises this affinity as much as a million-fold. We have prepared the important Thomsen-Friedenreich (Tf) antigen (Gal(beta)1-3GalNAc(alpha)-O-Ser/Thr) on very specific templates to take advantage of this so-called cluster glycoside effect. Over the years we have prepared many optimized gold nanoparticles bearing the TF antigen attached to both threonine and serine amino acid residues with a capping acetate at the N-terminal amine group. Examination of these particles in various tumor cell lines for cytotoxicity has been performed and compared against each construct. These cells were chose to be either positive or negative for expression of the anti-apoptotic protein Galectin-3 an in vivo receptor for the TF antigen. Cells that are negative for Gal-3 do not respond to our particles which suggest that cytotoxicity does go through a Gal-3 mediated pathway. Our latest iteration utilized a novel and more stable linker that imparts incredible stability to the particles in human serum and was published in this cycle. Our initial vaccine construct was previously described and this 3-component vaccine gave a good immune response to glycopeptides bearing the TF antigen that were derived from a tandem repeat sequence from Mucin-4 (MUC4) a large protein which is overexpressed on Pancreatic Ductal Adenocarcinoma (PDAC) Cells and is a biomarker for PDAC-based tumors. This study identified a best construct called MUC4-5TF and this specific antigen was conjugated to KLH and polyclonal sera showed high specificity for the glycopeptide used for immunization. We subsequently collaborated with Rockland Immunochemicals to prepare a monoclonal antibody (mAb) which was found to be highly useful as a diagnostic and possibly a therapeutic agent against PDACS. We have shown this reagent to be 1) specific for tumor in tissue arrays 2) Bind only to the sequence we vaccinated with 3) Not cross react with a commercial antibody raised to an unglycosylated sequence and to not react at all with our linker technology. The reagent is now a commercial product with Rockland. In addition we have re-tooled our vaccine construct and prepared gold nanoparticles with a coating of beta-13 glucans. These are glucose polysaccharides that bind to a specific C-type lectin on antigen presenting cells (APCs) such as macrophages and dendritic cells called Dectin-1. This facilitates entry into the APC and presentation of the attached antigen to T-cells. We showed after vaccination of mice that antibody titers to the antigen were very high cytokine profiles were relevant to an antitumor response and CD4+ T-cells that react with the antigen are generated. We are in the process of optimizing this construct for therapeutic use. In addition the mAb we produced with Rockland has been shown to distribute selectively to MUC4 positive tumors in vivo. An antibody drug conjugate *ADC) was also prepared and it shows high toxicity to MUC4 positive tumors in vitro. We have prepared a single chain fragment (ScFv) and are now developing a novel CAR-T cell is from this antibody. 712618 +No NIH Category available Acrolein;Adenocarcinoma;Aging;Anti-Inflammatory Agents;Asthma;Binding;Binding Sites;Biological Assay;Biological Process;CASP4 gene;Caspase;Cell Culture Techniques;Cell Death;Cell Surface Receptors;Cells;Characteristics;Chronic Obstructive Pulmonary Disease;Cigarette smoke-induced emphysema;Complex;Cytosol;Development;Disease;Embryo;Epithelium;Event;Family member;Fibroblasts;Genes;Genetic Transcription;Goals;Growth Factor;Heparan Sulfate Proteoglycan;Homeostasis;Homo;Human;Immune;In Vitro;Induction of Apoptosis;Inflammasome;Inflammatory;Knockout Mice;Lacrimal gland structure;Lesion;Lipopolysaccharides;Lung;Lung diseases;Malignant neoplasm of lung;Membrane;Molecular Chaperones;Molecular Weight;Mus;Nuclear;Organ Culture Techniques;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Physical condensation;Physiology;Pregnancy;Premature Infant;Prostate;Protein Family;Proteins;Pulmonary Emphysema;Pulmonary Fibrosis;Recombinants;Reporter;Research Project Grants;Risk;Role;STAT1 gene;STAT3 gene;Salivary Glands;Serine Proteinase Inhibitors;Signal Transduction;Site;Smoke;Structure;Structure of parenchyma of lung;TP53 gene;Therapeutic;Tissues;Trypsin;Uterus;airway epithelium;alveolar destruction;anticancer activity;cancer cell;chromatin immunoprecipitation;cigarette smoke;cigarette smoke-induced COPD;cytokine;diagnostic biomarker;exposure to cigarette smoke;immunocytochemistry;immunoregulation;in vitro activity;in vivo;knock-down;lipopolysaccharide-binding protein;member;mouse model;novel;overexpression;syndecan;tumor Role of Novel Cytokine-like Molecule Secretoglobin (SCGB) 3A2 in Lung n/a NCI 10926019 1ZIABC010449-22 1 ZIA BC 10449 22 6568943 "KIMURA, SHIOKO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 750711 NCI We previously demonstrated that SCGB3A2 inhibits acrolein-induced apoptosis through decreased P53 phosphorylation. Acrolein is abundant in cigarette smoke and is thought to be the most important component of smoke condensate leading to chronic obstructive pulmonary disease (COPD) a multifactorial disease with both airway and emphysematous lesions. We further demonstrated that SCGB3A2 may be required for maintaining homeostasis and immune activity in the lungs during aging and SCGB3A2 deficiency might increase the risk of emphysema of the lung. Based on these results we hypothesized that SCGB3A2 may play a role in the development of cigarette smoke (CS)-induced COPD. Accordingly Scgb3a2-KO Scgb3a2-lung-specific overexpressing (TG) and WT mice were subjected to the COPD mouse model by exposing them to cigarette smoke (CS) for 6 months. At the end of 6 months their lungs were analyzed. As compared with WT mouse lungs the KO mice showed loss of lung structure under control condition and CS exposure resulted in more expansion of airspace and destruction of alveolar structure. In contrast TG mouse lungs showed no significant changes after CS exposure. SCGB3A2 increased the expression and phosphorylation of STAT1 and STAT3 and the expression of alpha1-antitrypsin (A1AT) in mouse lung fibroblast-derived MLg cells and mouse lung epithelial-derived MLE-15 cells. A1AT is a serine proteinase inhibitor and its deficiency is known to cause emphysema. In MLg cells A1AT expression was decreased in Stat3-knockdown cells and increased upon Stat3 overexpression. STAT3 formed a homodimer when cells were stimulated with SCGB3A2. Chromatin immunoprecipitation and reporter assays demonstrated that STAT3 binds to specific binding sites on the Serpina1a gene encoding A1AT and upregulates its transcription in lung tissues of mice. Furthermore nuclear localization of phosphorylated STAT3 was detected upon SCGB3A2 stimulation by immunocytochemistry. These findings demonstrate that SCGB3A2 protects the lungs from developing CS-induced emphysema by regulating A1AT expression through STAT3 signaling. This anti-emphysematous activity adds to the expanding list of biological functions of SCGB3A2 and as a potential therapeutic to treat lung diseases. 750711 +No NIH Category available Address;Aging;Aneuploidy;Antineoplastic Agents;Artificial Human Chromosomes;Bacterial Artificial Chromosomes;Binding;Biogenesis;Bioinformatics;Biological Assay;Candidate Disease Gene;Catalogs;Cell Cycle Progression;Cell Death;Cell division;Cells;Centromere;Chromosomal Instability;Chromosome Segregation;Chromosomes;Cloning;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Consensus Sequence;DNA;DNA sequencing;Development;Disease;Distal;Epigenetic Process;Equilibrium;Etoposide;Event;Evolution;Foundations;Gene Dosage;Gene Duplication;Generations;Genes;Genetic;Genetically Engineered Mouse;Genome;Genomics;Glioma;Goals;Growth;Heterogeneity;Human;Human Chromosomes;Human Genome;Individual;Kinetochores;Knock-out;Knowledge;Lead;Maintenance;Malignant Glioma;Malignant Neoplasms;Measures;Methods;Microtubules;Missense Mutation;Mitosis;Molecular;Mouse Strains;Mus;Mutation;National Center for Advancing Translational Sciences;Nucleolar Organizer Region;Ontology;Paclitaxel;Pharmaceutical Preparations;Phenotype;Plant Extracts;Plasmids;Play;Poison;Polyploidy;Positioning Attribute;Primates;Process;Productivity;Proliferating;Publishing;Radial;Repetitive Sequence;Research;Ribosomal DNA;Ribosomal RNA;Ribosomes;Role;Screening procedure;Small Interfering RNA;Solid Neoplasm;Structure;System;TP53 gene;Tandem Repeat Sequences;Technology;Testing;Therapeutic;Variant;Vincristine;Work;Yeasts;anticancer research;arm;biological adaptation to stress;cancer cell;carcinogenesis;cell growth;centromere autoantigen 80K;chromosome number abnormality;cytotoxic;experimental study;functional genomics;gene function;gene therapy;genetic variant;high throughput screening;human model;in vivo;innovation;insertion/deletion mutation;live cell microscopy;mouse genome;novel;novel therapeutic intervention;plasmid DNA;rRNA Genes;segregation;synthetic biology;targeted cancer therapy;temozolomide;transmission process;tumor;tumor progression;vector Human Artificial Chromosomes for Cancer Research and Functional Genomics n/a NCI 10926013 1ZIABC010413-23 1 ZIA BC 10413 23 6808478 "LARIONOV, VLADIMIR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2078937 NCI "The organization and the degree of divergence of the human rDNA units within an individual NOR are only partially known. To address this lacuna we applied the TAR cloning technology to isolate individual rDNA units from chromosomes 21 and 22. This approach revealed an unexpectedly high level of heterogeneity in mature 18S/28S rRNA sequences raising the possibility of corresponding variations in ribosome dynamics. A functional analysis of these variants in vivo i.e. in the presence of many copies of rRNA genes in acrocentric chromosomes is impossible. To overcome this obstacle we are using a yeast rDNA assay developed by Dr. Susan Liebman's lab. They constructed the yeast strain in which the chromosomal rDNA repeats were completely deleted and cell growth was supported by the presence of a single kind of rDNA repeat units on a 2-micron DNA plasmid. Using plasmid shuffling this system can be used to examine the effects of any mutational changes of rDNA on growth of yeast cells on translational accuracy and on rRNA structures involved in the ribosome assembly and/or function. Using this system we are testing dozen sequence variants identified in 18S and 28S regions that are conservative between human and yeast. Specifically each variant in the conservative segments is introduced to the corresponding position of yeast rDNA and a modified complete yeast rDNA unit 9 kb in size was used for plasmid shuffling. We have now applied the TAR cloning strategy to characterize the structure and variations of rDNA in the mouse genome. Mice were chosen because genetically engineered mouse models (GEMMs) of human disorders including cancer and aging have been created. Although rDNA heterogeneity and instability in mice are well documented until now only one mouse rDNA unit has been assembled based on the 45S rRNA sequence and one available BAC carrying the IGS region. Such a non-representative reference sequence precludes employing computational and bioinformatic methods to identify rDNA variants. To isolate mouse rDNA units the TAR vector carrying YAC and BAC cassettes was used. Unexpectedly the size of the isolated clones did not correspond to the published 45 kb mouse rDNA reference sequence BK000946. 24 independent TAR-isolated rDNA-containing clones are represented by three-size classes (35-40 kb 40-45 kb and 45-50 kb). DNA sequencing confirmed the size of inserts in each BAC clone. Their sequence comparison revealed that size difference is determined by different size of the IGS region. Note that such size variations in the IGS region have never been observed for human and primate rDNA units. Because the observed size heterogeneity of rDNA units makes it difficult to assemble a reference sequence we assembled three consensus sequences i.e. 1 (38954 bp) 2 (42007 bp) and 3 (46251 bp) corresponding to three types of rDNA units. Comparison of these consensus sequences revealed both insertions and deletions of SINE and other repetitive elements within the IGS region. In contrast the region encoding 45S rRNA is relatively stable. Analysis of this region revealed 206 variations between TAR-isolated rDNA units and the published ""standard"" 45S rRNA sequence. We plan to continue the characterization of mouse rDNA. rDNA units will be TAR-cloned from three different mouse strains to clarify if these IGS size variants are common in mice. Finally we will employ radial TAR cloning developed in our lab to identify sequences flanking the rDNA clusters in the mouse chromosomes [distal (DJ) and proximal (PJ) regions]. Information about these sequences is critical to analyze the dynamics of mouse NORs during aging and carcinogenesis. Mammalian centromeres direct faithful genetic inheritance and are typically characterized by regions of highly repetitive and rapidly evolving DNA. In the recent collaborative work we described centromere innovations within a mouse species. We focused on a mouse species Mus pahari that we found has one chromosome with a massive expansion of a newly evolved repeat array that houses 20000 functional CENP-B boxes: 100-fold more than on the other M. pahari centromeres. The balance of pro- and anti-microtubule-binding by the new centromere permits it to segregate during cell division with high fidelity alongside the older ones whose sequence creates a markedly different molecular composition. We previously constructed a synthetic HAC vector (tetO-HAC) that has a great potential for the study of assembly and maintenance of human kinetochore as well as for gene therapy and synthetic biology. To extend the utility of the tetO-HAC we have developed two assays for measuring chromosome instability (CIN). These assays allow: i) ranking different anticancer drugs and cytotoxic plant extracts with respect to their effects on chromosome transmission fidelity and ii) identifying new CIN genes that may be targets for cancer therapy. Using HAC-based assays we were able to rank different anticancer drugs with respect to their effects on CIN. Drugs with various mechanisms of action were included in the analysis. New and potentially less toxic compounds that selectively elevate CIN in cancer cells identified by the HAC-based screening tool could lay the foundation for new treatment strategies for cancer. Recently the HAC-based assay was used to evaluate contribution of the most common glioma missense mutations in IDH1 and TP53 genes on chromosome transmission. Based on this analysis IDH1R132H and TP53R248Q missense mutations result in a high level of CIN in cancer cells. We also investigated the sensitivity of malignant glioma cells carrying these mutations to CIN-inducing drugs - paclitaxel vincristine and etoposide - compared to conventional temozolomide. New and potentially less toxic agents that selectively elevate CIN to promote cancer cell death identified in this study could lay the foundation for new treatment strategies of gliomas. An abnormal chromosome number is a feature of most solid tumors and is often accompanied by an elevated rate of chromosome instability (CIN). Gain or loss of entire chromosomes leads to large-scale changes in gene copy number and expression levels. Mutations in CIN genes are thought to be an early event in tumor development. At present approximately 400 human genes that control proper chromosome transmission have been annotated with gene ontology terms while systematic CIN gene screens in yeast have revealed more than 900 genes. Therefore it may be supposed that many human CIN genes remain unidentified. In our previous work we developed a high-throughput assay for identification of new human CIN genes using the tetO-HAC expressing a degron-destabilized EGFP. In the current study we have been used an available at NCATS Ambion collection of 19000 siRNAs covering the whole human genome for identification of new CIN genes. As a result 250 new CIN candidate genes have been identified. The experiments on reconfirmation of 250 CIN candidate genes have been performed using newly developed siRNAs and CRISPR knock-out experiments and live-cell microscopy. As a result 44 new CIN genes were identified. The experiments are in progress to clarify a function of these genes in proper chromosome transmission. Identification of new CIN genes should create opportunities for the development of new therapeutic strategies to target the CIN phenotype of cancer cells." 2078937 +No NIH Category available Address;Affect;Anaphase;Back;Binding;Biochemical;Bioinformatics;Cell Cycle;Cell Proliferation;Cell division;Cells;Chromatin;Chromosome abnormality;Chromosomes;Clinical;Collaborations;Complex;Consensus;DNA;DNA Damage;DNA Repair Pathway;DNA Sequence;DNA biosynthesis;DNA replication fork;DNA-Protein Interaction;Development;Developmental Therapeutics Program;Distal;Elements;Energy Metabolism;Ensure;Epigenetic Process;Event;Exhibits;Exposure to;Fiber;Future;Genetic;Genome;Genome Stability;Genomic Instability;Health;Human;Image;Learning;Link;Location;Malignant Neoplasms;Mammalian Cell;Maps;Mediating;Metabolic;Metaphase;Mitosis;Molecular;Molecular Machines;Nature;Oncogenes;Pathway interactions;Phosphotransferases;Play;Property;Protein Family;Proteins;Regulation;Replication Initiation;Replication Origin;Replication-Associated Process;Research Personnel;Role;SIRT1 gene;Set protein;Signal Pathway;Signal Transduction;Site;Specificity;TOPBP1 Gene;Techniques;Testing;Translating;Work;anti-cancer therapeutic;biochemical tools;cancer cell;cancer therapy;cell growth;cell type;chemotherapeutic agent;chromatin modification;chromosome replication;cis acting element;computerized tools;genome integrity;genome-wide;histone modification;inhibitor;insight;member;novel;prevent;programs;protein complex;protein protein interaction;recruit;replication stress;response;segregation;tool;translational potential;treatment response;tumorigenesis;ubiquitin ligase;whole genome Initiation of DNA Replication in Mammalian Cells n/a NCI 10926012 1ZIABC010411-24 1 ZIA BC 10411 24 8314239 "ALADJEM, MIRIT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1909382 NCI "Our studies focus on cellular signaling pathways that regulate the location timing and progression of DNA synthesis. We have identified cis-acting elements that facilitate the initiation of DNA replication generated whole-genome-scale maps of replication initiation sites in human cells and detected novel protein-DNA interactions at replication initiation sites (replication origins). These discoveries were enabled by novel bioinformatics and biochemical approaches that we developed and implemented. Mapping replication origin activity and characterizing replication fork progression have demonstrated strong links between replication histone modifications and chromatin packaging. The observed highly orchestrated order of the DNA replication program however contrasts with the low sequence-specificity exhibited by the molecular machines that catalyze DNA synthesis and the absence of a ""consensus"" DNA sequence that identifies all replication origins. We address this challenge by proposing and testing the hypothesis that genome duplication is guided by nuanced selective protein-DNA interactions at discrete groups of replication origins that share distinct features. In the recent review period we used a combination of genetic biochemical bioinformatics imaging and functional analyses to study DNA-protein interactions and chromatin transactions that govern the initiation of DNA replication. We identified protein complexes that selectively assemble on groups of replication origins and modify their initiation capacity providing the first example of site-specific interactions that modulate the initiation of DNA replication. The approach exemplified in our studies can pave a path towards a complete understanding of the interactions that spatially and temporally orchestrate chromosome duplication. Our current studies focus on two sets of protein-DNA interactions at replication origins. First we found that the RepID protein a member of the DDB1-Cul4-associated-factor (DCAF) protein family preferentially interacts with replication origins. We have shown that RepID is required for initiation of DNA replication at the origins that bind it. We have further shown that RepID controls the replication program by recruiting the ubiquitin ligase complex CRL4 to chromatin. In turn RepID-recruited CRL4 prevents aberrant chromosome re-replication ensuring that genome duplication occurs only once per cell division. We also discovered another function of RepID and CRL4 in regulating the metaphase-anaphase transition during mitosis. These observations have provided new insights into the mechanisms by which the fidelity of chromosome duplication and segregation can be compromised in cancer cells. Our current studies probe into the question of how cells orchestrate the activity of RepID and CRL4 with other ubiquitin ligases on chromatin to regulate cell proliferation and characterize in detail the consequences of dysregulation of CRL4 chromatin recruitment and activity at replication origins. Given the mounting evidence that chromosomal re-replication and mis-segregation can be triggered by oncogenes at the onset of tumorigenesis and the recent development of CRL4 inhibitors (e.g. NEDDylation inhibitors) as anti-cancer therapeutics these studies have potential translational implications. Second we identified an interaction between replication origins and the NAD+-dependent protein deacylase SIRT1. Unlike RepID SIRT1 is not required for DNA replication but instead restricts the initiation of DNA replication to a particular group of origins (""baseline"" origins) while preventing replication from initiating at other (""dormant"") origins. This observation points to a mechanistic link between cellular energy metabolism epigenetic marks and the regulation of replication origin activation which play critical roles in maintaining genome integrity. Using SIRT1 activity as a molecular switch to turn dormant origins on and off we have begun to characterize origin dormancy in detail mapping the locations of dormant origins and identifying chromatin modifications that distinguish dormant from baseline origins. This work led us to identify components of a signaling network involving the ATR kinase and the replication accessory protein TOPBP1 that relieves SIRT1-mediated origin dormancy when the baseline origins are stalled as it occurs when cells are under replication stress. Pointing to the critical role in SIRT1 in maintaining origin dormancy and genome stability cells with activated dormant origins harbor extrachromosomal elements and exhibit DNA breaks. Our current studies are focused on proteins that associate with dormant origins the mechanism(s) by which SIRT1 suppresses initiation. We also study molecular pathways including the abovementioned ATR pathway that counter SIRT1-mediated suppression to activate dormant origins in cells exposed to stressful conditions. Because ATR inhibitors are explored at the DTB and elsewhere as promising therapy agents these analyses also have a translational potential. The responses of the replication machinery to perturbations are pertinent to human health and the specific cell-cycle regulatory deficiencies in distinct cancer cell types are likely to provide clues to their sensitivity to therapy. Our studies demonstrate that deregulation of the early stages of DNA replication leads to excess replication and subsequent genomic instability through two distinct paths: one that involves activation of dormant origins and another involving over-activation of baseline origins. We are currently characterizing genetic and epigenetic properties of the replication origins activated by each pathway as well as protein-DNA interactions modulated by each pathway. Using a combination of single-fiber analyses and sequencing-based techniques we analyze replication dynamics following exposure to chemotherapeutic agents and chromatin modulators. These studies are expected to identify chromatin targets that are normally involved in preventing excess replication and uncover signaling pathways that convey metabolic status to chromatin. As we learn more about local and distal interactions that promote DNA replication we will explore pathways that signal back from chromatin to the cell cycle machinery to affect the replication landscape and the cellular responses to anticancer therapy. Our studies rely on tools we have developed to map replication initiation sites throughout the genome and compare replication initiation sites with distinct chromatin features. We are also collaborating with other investigators within and outside NCI to characterize genetic and epigenetic features of cancer cells and participate in collaborative efforts that link genetic and epigenetic signatures with responses to therapy. In future studies we plan to further dissect the molecular interactions that regulate chromosome duplication. Specifically using a combination of single-fiber analyses biochemical and computational tools we will systematically characterize protein-DNA and protein-protein interactions that mediate the effects of RepID SIRT1 and DNA damage signaling pathways on the chromosome replication program." 1909382 +No NIH Category available 2019-nCoV;AIDS prevention;Adjuvant;Adverse effects;Anatomy;Animals;Antibodies;Antibody titer measurement;Antigens;B-Lymphocytes;Binding;Biological Markers;Biology;Blood;COVID-19;CXCL10 gene;CXCL13 gene;CXCR3 gene;Cells;Codon Nucleotides;Combined Vaccines;DNA;DNA Vaccines;DNA delivery;Data;Development;Disease;Electroporation;Epitopes;FCGR3A gene;Gene Expression;Genes;HIV;HIV Antigens;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Human;Immune;Immune response;Immunity;Immunization;Immunologics;Infection;Infection prevention;Interferon Type II;Interleukin-12;Interleukin-15;Interleukin-6;Intramuscular;Liposomes;Longevity;Lower respiratory tract structure;Macaca;Maintenance;Measurement;Mediating;Messenger RNA;Methodology;Methods;Modality;Modeling;Molecular;Mucosal Immune Responses;Nucleic Acid Amplification Tests;Nucleic Acid Vaccines;Nucleic Acids;Pfizer-BioNTech COVID-19 vaccine;Play;Production;Proteins;Proteomics;Protocols documentation;RNA;RNA vaccination;RNA vaccine;Rectum;Regimen;Relative Risks;Reporting;Research;Risk;Role;SARS-CoV-2 infection;SIV;Secondary Immunization;Shapes;Site;Structure of germinal center of lymph node;Structure of mucous membrane of nose;T cell response;TNF gene;Testing;Translating;Vaccinated;Vaccination;Vaccines;Viral reservoir;Virus;adaptive immunity;antibody-dependent cell cytotoxicity;antibody-dependent cellular phagocytosis;cytokine;design;draining lymph node;efficacy testing;env Gene Products;experience;expression vector;immunogenicity;improved;in vivo;lymph nodes;mRNA Expression;mucosal site;nanoparticle;nanoparticle delivery;neutralizing antibody;novel;plasmid DNA;predictive marker;proteomic signature;recombinant viral vector;rectal;response;scaffold;simian human immunodeficiency virus;transmission process;treatment strategy;vaccine delivery;vaccine development;vaccine efficacy;vaccine formulation;vaccine platform;vaccine strategy;vaccine-induced immunity;vaginal mucosa;vector;vector vaccine Development testing of nucleic acid-based vaccine for HIV other indications n/a NCI 10926007 1ZIABC010350-24 1 ZIA BC 10350 24 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1950208 NCI The development of a safe and effective vaccine and to improve treatment strategies aiming to reduce/eliminate the virus reservoir are currently at the forefront of our research. Based on our recognition of the fundamental mechanisms of mRNA expression exemplified by the regulated expression of HIV we developed the key methodology to express HIV antigens at high level from RNA/codon-optimized genes which allows efficient antigen production when expressed from simple DNA plasmids or as part of recombinant viral vectors (Schwartz J. Virol. 66: 150-159 1992; Schwartz J. Virol. 66: 7176-7182 1992; Nasioulas J. Virol. 68: 2986-2993 1994; Schneider J. Virol. 71: 4892-4903 1997). Attractive features of the nucleic acid (DNA mRNA) platform lie in its simplicity versatility stability with repeated administration without vector immunity being a non-replicating vaccine and not association with adverse effects. Immunogenicity is augmented in the presence of cytokines i.e. IL-12 DNA co-administration. We optimized DNA delivery with the result of achieving systemic and mucosal immune responses. Importantly we reported the dissemination of the DNA vaccine induced T cell responses to mucosal sites including rectal and vaginal mucosa the portal of entry of HIV. We also found that DNA induced immune responses show extraordinary longevity in vaccinated macaques detectable for several years after the last vaccination. Using DNA+Protein combination vaccines the magnitude breadth and longevity of the immune responses increased resulting in significant improved protection from infection in the SIV/SHIV macaque model (Patel PNAS 110: 2975 2013; Jalah PLoS One 9: e91550 2014 Felber Cell Reports 31:107624 2020). The vaccine platform combines the delivery of both vaccine components into the same anatomical site targeting the same draining lymph node. We recently reported that co-administration in the same site showed a 67% reduction in per exposure acquisition risk relative to the controls whereas neither animals vaccinated with DNA and protein in separate sites nor the controls were protected from an intravaginal SHIV CH505 virus challenge (Felber Cell Reports 31:107624 2020). Non-neutralizing Env antibodies antibodies mediating cellular cytotoxicity (ADCC) and antibodies with high binding to Fc-gamma RIIIa were associated with decreased transmission risk. These data suggest that simultaneous recognition processing and presentation of DNA + Env protein in the same draining lymph nodes play a critical role in the development of protective immunity. These data have important implications for other vaccine modalities because combination vaccines are typically administered in separate anatomical sites. We hypothesize that optimization of immunogens to better target the rare B cell precursor combined with the co-administration of vaccine vector and protein in same draining lymph nodes could provide an immunological advantage over current protocols resulting in significantly improved protection and we are exploring this mechanism in the macaque model. Our aim has been to design and test a vaccine regimen focusing the immune response to targets associated with infection prevention i.e. the V2 domain of the HIV gp120 Env. In the VR144 trial non-neutralizing antibodies targeting V2 were found to correlate with reduced risk of HIV infection suggesting this region as a target for vaccine development. To favor induction of V2-specific Ab we developed novel molecules to direct and focus humoral immune responses to V2 domain of the HIV gp120 Env. We showed that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region in the absence of immune interference by other epitopes. We reported that priming with this DNA altered the hierarchy of humoral immune responses to V2 region epitopes providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection (Devasundaram J Virol 95:e01193 2020). We are testing the hypothesis whether these responses translate to better protection in the macaque model. We applied our experience in developing HIV vaccines towards SARS-CoV-2 (Rosati PLoS Pathog 17:e1009701; 2021). The different Spike DNA-based vaccine regimens induced robust antibody and T cell responses able to effectively mediate protection and to control SARS-CoV-2 infection in macaques. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly a vaccine regimen comprising simultaneous co-immunization of DNA and protein at the same anatomical site showed was more effective than DNA alone in inducing protective immune responses and controlling SARS-CoV-2 infection. We are now exploring novel nucleic acid-based vaccines and delivery methods to achieve better immunity of DNA-only vaccine to simplify the vaccine platform. Early responses to vaccination are important for shaping protective immunity. Dissecting innate vaccine signatures may provide biomarkers predicting immunogenicity and assist optimization of vaccine strategies. We have previously reported a proteomic signature after BNT162b2 mRNA vaccination (NCT04743388; PMID: 34352226). These results were compared with the proteomic analysis of different RNA or DNA vaccines in macaques which allowed frequent blood and lymph nodes measurements and in-depth Flow analysis and comparing different vaccine formulations. Our studies show a rapid innate response within 4-24 hrs with liposome or nanoparticle delivery and a delay in response (day 6) after electroporation. We identified a systemic transient signature upon BNT162b2 mRNA vaccination including IL-15 IFN-g IP-10/CXCL10 TNF-alpha and IL-6 in humans. Importantly we found correlations of IL-15 and IFN-g responses and binding and neutralizing Spike antibody (0.5-3 months after booster vaccination). Using different vaccine platforms in macaque model a unifying finding has been the transient increase of IL-15 IFN-gamma IP-10. Platforms including LNP and nanoparticles also induced CXCL13 a biomarker for Germinal Center (GC) activation. Together these data indicated a coordinated cytokine responses to the mRNA/DNA vaccines and highlight the important role of innate responses to vaccination in modulating adaptive immunity. 1022388 +No NIH Category available 2019-nCoV;AIDS prevention;Adjuvant;Adverse effects;Anatomy;Animals;Antibodies;Antibody titer measurement;Antigens;B-Lymphocytes;Binding;Biological Markers;Biology;Blood;COVID-19;CXCL10 gene;CXCL13 gene;CXCR3 gene;Cells;Codon Nucleotides;Combined Vaccines;DNA;DNA Vaccines;DNA delivery;Data;Development;Disease;Electroporation;Epitopes;FCGR3A gene;Gene Expression;Genes;HIV;HIV Antigens;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Human;Immune;Immune response;Immunity;Immunization;Immunologics;Infection;Infection prevention;Interferon Type II;Interleukin-12;Interleukin-15;Interleukin-6;Intramuscular;Liposomes;Longevity;Lower respiratory tract structure;Macaca;Maintenance;Measurement;Mediating;Messenger RNA;Methodology;Methods;Modality;Modeling;Molecular;Mucosal Immune Responses;Nucleic Acid Amplification Tests;Nucleic Acid Vaccines;Nucleic Acids;Pfizer-BioNTech COVID-19 vaccine;Play;Production;Proteins;Proteomics;Protocols documentation;RNA;RNA vaccination;RNA vaccine;Rectum;Regimen;Relative Risks;Reporting;Research;Risk;Role;SARS-CoV-2 infection;SIV;Secondary Immunization;Shapes;Site;Structure of germinal center of lymph node;Structure of mucous membrane of nose;T cell response;TNF gene;Testing;Translating;Vaccinated;Vaccination;Vaccines;Viral reservoir;Virus;adaptive immunity;antibody-dependent cell cytotoxicity;antibody-dependent cellular phagocytosis;cytokine;design;draining lymph node;efficacy testing;env Gene Products;experience;expression vector;immunogenicity;improved;in vivo;lymph nodes;mRNA Expression;mucosal site;nanoparticle;nanoparticle delivery;neutralizing antibody;novel;plasmid DNA;predictive marker;proteomic signature;recombinant viral vector;rectal;response;scaffold;simian human immunodeficiency virus;transmission process;treatment strategy;vaccine delivery;vaccine development;vaccine efficacy;vaccine formulation;vaccine platform;vaccine strategy;vaccine-induced immunity;vaginal mucosa;vector;vector vaccine Development testing of nucleic acid-based vaccine for HIV other indications n/a NCI 10926007 1ZIABC010350-24 1 ZIA BC 10350 24 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1950208 OD The development of a safe and effective vaccine and to improve treatment strategies aiming to reduce/eliminate the virus reservoir are currently at the forefront of our research. Based on our recognition of the fundamental mechanisms of mRNA expression exemplified by the regulated expression of HIV we developed the key methodology to express HIV antigens at high level from RNA/codon-optimized genes which allows efficient antigen production when expressed from simple DNA plasmids or as part of recombinant viral vectors (Schwartz J. Virol. 66: 150-159 1992; Schwartz J. Virol. 66: 7176-7182 1992; Nasioulas J. Virol. 68: 2986-2993 1994; Schneider J. Virol. 71: 4892-4903 1997). Attractive features of the nucleic acid (DNA mRNA) platform lie in its simplicity versatility stability with repeated administration without vector immunity being a non-replicating vaccine and not association with adverse effects. Immunogenicity is augmented in the presence of cytokines i.e. IL-12 DNA co-administration. We optimized DNA delivery with the result of achieving systemic and mucosal immune responses. Importantly we reported the dissemination of the DNA vaccine induced T cell responses to mucosal sites including rectal and vaginal mucosa the portal of entry of HIV. We also found that DNA induced immune responses show extraordinary longevity in vaccinated macaques detectable for several years after the last vaccination. Using DNA+Protein combination vaccines the magnitude breadth and longevity of the immune responses increased resulting in significant improved protection from infection in the SIV/SHIV macaque model (Patel PNAS 110: 2975 2013; Jalah PLoS One 9: e91550 2014 Felber Cell Reports 31:107624 2020). The vaccine platform combines the delivery of both vaccine components into the same anatomical site targeting the same draining lymph node. We recently reported that co-administration in the same site showed a 67% reduction in per exposure acquisition risk relative to the controls whereas neither animals vaccinated with DNA and protein in separate sites nor the controls were protected from an intravaginal SHIV CH505 virus challenge (Felber Cell Reports 31:107624 2020). Non-neutralizing Env antibodies antibodies mediating cellular cytotoxicity (ADCC) and antibodies with high binding to Fc-gamma RIIIa were associated with decreased transmission risk. These data suggest that simultaneous recognition processing and presentation of DNA + Env protein in the same draining lymph nodes play a critical role in the development of protective immunity. These data have important implications for other vaccine modalities because combination vaccines are typically administered in separate anatomical sites. We hypothesize that optimization of immunogens to better target the rare B cell precursor combined with the co-administration of vaccine vector and protein in same draining lymph nodes could provide an immunological advantage over current protocols resulting in significantly improved protection and we are exploring this mechanism in the macaque model. Our aim has been to design and test a vaccine regimen focusing the immune response to targets associated with infection prevention i.e. the V2 domain of the HIV gp120 Env. In the VR144 trial non-neutralizing antibodies targeting V2 were found to correlate with reduced risk of HIV infection suggesting this region as a target for vaccine development. To favor induction of V2-specific Ab we developed novel molecules to direct and focus humoral immune responses to V2 domain of the HIV gp120 Env. We showed that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region in the absence of immune interference by other epitopes. We reported that priming with this DNA altered the hierarchy of humoral immune responses to V2 region epitopes providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection (Devasundaram J Virol 95:e01193 2020). We are testing the hypothesis whether these responses translate to better protection in the macaque model. We applied our experience in developing HIV vaccines towards SARS-CoV-2 (Rosati PLoS Pathog 17:e1009701; 2021). The different Spike DNA-based vaccine regimens induced robust antibody and T cell responses able to effectively mediate protection and to control SARS-CoV-2 infection in macaques. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly a vaccine regimen comprising simultaneous co-immunization of DNA and protein at the same anatomical site showed was more effective than DNA alone in inducing protective immune responses and controlling SARS-CoV-2 infection. We are now exploring novel nucleic acid-based vaccines and delivery methods to achieve better immunity of DNA-only vaccine to simplify the vaccine platform. Early responses to vaccination are important for shaping protective immunity. Dissecting innate vaccine signatures may provide biomarkers predicting immunogenicity and assist optimization of vaccine strategies. We have previously reported a proteomic signature after BNT162b2 mRNA vaccination (NCT04743388; PMID: 34352226). These results were compared with the proteomic analysis of different RNA or DNA vaccines in macaques which allowed frequent blood and lymph nodes measurements and in-depth Flow analysis and comparing different vaccine formulations. Our studies show a rapid innate response within 4-24 hrs with liposome or nanoparticle delivery and a delay in response (day 6) after electroporation. We identified a systemic transient signature upon BNT162b2 mRNA vaccination including IL-15 IFN-g IP-10/CXCL10 TNF-alpha and IL-6 in humans. Importantly we found correlations of IL-15 and IFN-g responses and binding and neutralizing Spike antibody (0.5-3 months after booster vaccination). Using different vaccine platforms in macaque model a unifying finding has been the transient increase of IL-15 IFN-gamma IP-10. Platforms including LNP and nanoparticles also induced CXCL13 a biomarker for Germinal Center (GC) activation. Together these data indicated a coordinated cytokine responses to the mRNA/DNA vaccines and highlight the important role of innate responses to vaccination in modulating adaptive immunity. 927820 +No NIH Category available Affect;Apoptotic;Behavior;Biological;Biology;Cell Death;Cell Maintenance;Cell Survival;Cells;Collaborations;Communities;Complex;Computer Models;Congenital Abnormality;Defect;Dermis;Development;Disease;Embryo;Embryonic Development;FGF17 gene;Family;Fibroblast Growth Factor;Gene Expression;Generations;Genes;Genetic;Genetic Models;Genetic study;Genets;Goals;Growth Factor Gene;Health;Hindlimb;Human;Intermediate Mesoderm;Kidney;Knowledge;Ligands;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Mesoderm;Messenger RNA;Modeling;Molecular;Morphogenesis;Mus;Muscle;Paper;Pathway interactions;Play;Positioning Attribute;Process;Proliferating;Publications;Publishing;Role;Series;Signal Transduction;Somites;Technology;Testicular Neoplasms;Tissues;Undifferentiated;WNT Signaling Pathway;Work;allantois;bone;cancer therapy;cardiogenesis;cell behavior;external genitalia;fibroblast growth factor 18;genetic manipulation;innovation;insight;male;malignant breast neoplasm;medical schools;migration;mouse genetics;mutant;nephrogenesis;notch protein;novel;reproductive tract;somitogenesis;spine bone structure;stem cells;tool;tumorigenesis;vertebra body;vertebrate embryos The Role of Fgf Signaling in Vertebrate Development n/a NCI 10926004 1ZIABC010338-24 1 ZIA BC 10338 24 8123123 "LEWANDOSKI, MARK B" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 712253 NCI The long term goal of this project is to understand how an important family of signaling ligands called Fibroblast Growth Factors (FGFs) control a wide spectrum of cell biological behaviors such as proliferation cell death migration stem cell maintenance and gene expression. In particular we use complex mouse genetics to understand the role of FGF signaling in mesodermal lineages with a special emphasis on extension of the body axis and formation of somites (segmented mesodermal segments that are the building blocks of vertebrate muscle dermis and vertebral bodies). Our work has made clear that genetic redundancy is an important aspect of this biology; therefore all work in this project emerges from an effort to comprehensively characterize the genetic redundancy of FGF signaling in the mesodermal lineage. Such work is relevant to many cases of cancer where more than one FGF gene may be damaged. To achieve this we have generated and characterized important Cre mouse lines which are tools that allow the control of gene expression in the early embryo. These include TCre (expressed in the early emerging nascent mesoderm; see Development. 132: 3859-71. ) TCreERT2 (active in emerging nascent mesoderm at all embryonic stages; see PLoS ONE. 8: e62479) and Tbx4-Cre (expressed in a posterior mesodermal domain that includes the allantois hindlimb and external genitalia; see Dev Dyn. 240: 2290-300. doi: 10.1002/dvdy.22731). TCre in particular has had a major impact on the field being essential in over 50 publications. For example both TCre and TCreERT2 have important in a collaborative effort to demonstrate that Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension (Hum Mol Genet. 2014 Jul 31. pii: ddu397). Besides providing the mouse genetics community with valuable mouse lines this project has yielded papers that document our major insights regarding FGF signaling in the early embryo. We published that Fgf8 not required for somitogenesis although a body of high-profile work had placed it in a central position in current models. However in collaboration with NCI colleague Alan Perantoni we demonstrated that Fgf8 was essential for development of the kidney and male reproductive tract (Development. 132: 3859-71 Development. 138: 5369-78). A feature of these mutants was aberrant cell death due to loss of Fgf8 signaling. This past year we published a study showing we can restore cell survival to such mutants by removing the pro-apoptotic genes Bax and Bak. This genetic manipulation restores some measure of kidney development but nephrogenesis is not normal revealing new insights into Fgf8 function in this process (Differentiation 2023 130:7-15). We showed that Fgf8 together with Fgf4 are required for essential aspects of somitogenesis: expression of oscillating gene domains WNT pathway genes and markers of undifferentiated presomitic mesoderm (Proc Natl Acad Sci U S A. 108: 4018-23). By examining FGF mutants in which we genetically restored WNT signaling we demonstrated that FGF signaling operates independently of WNT signaling in this process. The functional redundancy that we uncovered has implications for cancer as both FGFs have been found to be aberrantly active in testicular tumors. In recent studies we have delved deeper into this work and have shown that Fgf4 mutants (but not Fgf8 mutants) display a range of vertebral defects that model a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. A key innovation in this work is our adaption of computational modeling to generate embryonic volumetric subsets of the embryo. We then quantify mRNA levels of key target genes affected by the loss of Fgf4 signaling within these volumes (eLife 2020;9:e55608. DOI: https://doi.org/10.7554/eLife.55608). We applied this technical innovation in a collaborative study published with the Kwon lab at Johns Hopkins Medical School on the role of WNT signaling in heart development (Proc Natl Acad Sci U S A. 2023 120(4):e2217687120). In another recent publication we demonstrated that the Fgf8 subfamily (Fgf8 Fgf17 and Fgf18) are required for closing the ventral body wall in the vertebrate embryo. Defects in this process are a major class of human birth defect and a significant health burden (Development (2020) 147 dev189506. doi:10.1242/dev.189506). We are continuing to study genetic redundancy in FGF signaling in several aspects of embryonic development. We are currently focusing on two aspects of development: generation of the promitive streak which generates all embryonic mesoderm and differentiation of the somite into its derivative lineages (muscle and bone). 712253 +No NIH Category available 2019-nCoV;AIDS clinical trial group;Achievement;Address;Adjuvant;Antibody Response;Antigens;COVID-19;Chronic;Clinic;Clinical Trials;Collaborations;Combination immunotherapy;Cytotoxic T-Lymphocytes;DNA;DNA Vaccines;DNA delivery;Data;Data Analyses;Development;Disease remission;Electroporation;Elements;Epitopes;Exclusion;Exhibits;Formulation;Genes;Goals;HIV;HIV Infections;HIV Vaccine Trials Network;HIV vaccine;HIV-1;Highly Active Antiretroviral Therapy;Homologous Gene;Human;Immune checkpoint inhibitor;Immune response;Immunization;Immunologics;Immunotherapeutic agent;Immunotherapy;Individual;Infection;Interleukin-12;Length;Macaca;Mediating;Memory;Messenger RNA;Methodology;Methods;Modality;Modeling;Molecular;Mus;National Institute of Allergy and Infectious Disease;Nucleic Acid Vaccines;Pathway interactions;Persons;Phase;Preventive vaccine;Process;Proteins;Proteome;Publications;RNA vaccine;Regimen;Research;SIV;Secondary Immunization;T cell response;T-Lymphocyte;Testing;Translating;Translations;Vaccination;Vaccines;Variant;Viral;Viral reservoir;Virus;Virus Diseases;clinical development;cohort;combinatorial;cytokine;expression vector;frontier;human disease;immunogenic;in vivo;insight;lipid nanoparticle;novel;novel strategies;novel vaccines;preclinical trial;prevent;response;therapeutic vaccine;tool;treatment strategy;vaccin protein;vaccine development;vaccine evaluation;vaccine platform;vaccine strategy;vaccine trial Conserved Element DNA Vaccine n/a NCI 10926003 1ZIABC010334-24 1 ZIA BC 10334 24 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 681593 NCI "An ideal HIV vaccine should provide protection against all HIV-1 variants. Thus an important aspect of HIV vaccine development is the selection of immunogens which has to take into consideration the diversity of the different HIV clades and the identification of the critical epitopes able to induce relevant immune responses avoiding potential immunodominant ""decoy"" epitopes. Considering the diversity of the different HIV clades we are focusing on highly conserved regions of HIV to induce immune responses to nearly invariable proteome segments essential for the function of the virus while excluding responses to variable and potentially immunodominant ""decoy"" epitopes (Kulkarni PLoS One 9: e86254 2014; Kulkarni PLoS One 9: e111085 2014; Hu Hum. Vaccin. Immunother. 14: 2163 2018). In proof-of-concept studies in mice and macaques we demonstrated that immunization with Gag CE DNA elicits robust cellular and humoral immune responses including robust cytotoxic T cell responses targeting subdominant epitopes against CE which cannot be achieved by vaccination with the full-length p55gag DNA and induces Priming with CE DNA and boosting with CE+gag DNA maximizes both magnitude and breadth (Kulkarni PLoS One 9: e86254. 2014; Kulkarni PLoS One 9: e111085 2014; Hu J. Immunol. 197: 3999 2016). This DNA vaccine regimen induces potent memory responses that can be rapidly recalled 2 years later by CE DNA booster vaccinations (Hu Hum. Gene Ther. 29: 1029-1043 2018). Thus we identified a novel and effective strategy to maximize responses against Gag and provide a novel strategy to shift the immunodominance hierarchy and to induce robust immune responses to subdominant epitopes effectively targeting the Achilles' heel of the virus. We are currently expanding this concept to SARS-Co-V2. We further developed an SIV homolog of the CE and demonstrated that priming with CE DNA followed by CE+gag DNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth (Hu J. Immunol. 197: 3999 2016). These data mirror our findings from the HIV p24CE vaccine and provide us with a tool to explore the functional applications of the Gag CE DNA vaccine in the macaque model. SIV Gag CE-specific T cells are able to reduce viral infection (Hu Hum. Vaccin. Immunother. 14: 2163-2177 2018) and application of this CE DNA vaccine is expanded to our on-going therapeutic vaccine trials in the macaque model. We have translated the HIV CE DNA vaccine concept to the clinic in the HIV Vaccine Trial Network (HVTN)/DAIDS/NIAID-supported clinical trial (HVTN 119; NCT03181789) with the aim to test whether our p24CE DNA vaccine concept elicits superior breath and magnitude of Gag responses compared to the optimized immunogen comprising the complete p55Gag protein. This vaccine includes Profectus' GENEVAX IL-12 DNA as molecular adjuvant and in vivo electroporation as DNA delivery method two vaccine components our research had shown to be of importance to induce potent T cell responses in macaques. HVTN 119 combines several of milestones (DNA expression vectors adjuvants and delivery) we have achieved over many years in vaccine development. This trial is now closed and we are finalizing data analysis for publication. In another on-going study we have translated the Gag CE DNA vaccine in a phase I/IIb trial (ACTG A5369; NCT03560258) supported by the AIDS Clinical Trial Group to be tested in HIV-infected persons under HAART. This trial is now closed and we are finalizing data analysis for publication. Together HVTN119 and A5369 allowed us to explore the translation of our data from mice and macaques to humans and initial data analysis supports our achievement of this goal. Both trails have demonstrated that the p24CE DNA vaccine is safe and immunogenic in humans. We achieved our goal to translate results from pre-clinical trials to humans and found that iclusion fo the CE immunogen contributesd significantly to direct to immune response to these highly conserved regions. These two trials offer further another unique opportunity to directly compare the same vaccines in two different cohorts naive and HIV-infected on ART using the same methodology and will provide novel insight in the development in immune responses comparing the two cohorts. In addition the CE DNA vaccine regimen is being tested in a third trial NCT04357821 supported by amfAR and UCSF as part of a combinatorial therapy to induce an HIV remission. Importantly this trial showed that the majority of individuals who received combination immunotherapy exhibited evidence of virologic control post-ART indicating that the treatment mediated immunological and virological control. We are in the process of dissecting thiese machanisms. These data are in support of our goal is to develop and test immunotherapeutic methods that can lead to virus reservoir reduction or elimination. We have further expanded the CE vaccine regimen in collaboration with CureVac Inc. as an mRNA/lipid nanoparticle (LNP) formulation in the macaque model (Valentin Frontiers Immunol 2022). The mRNA/LNP formulation induced robust durable antibody responses but lower adaptive T-cell responses a feature also shared with the current COVID-19 mRNA vaccine. On the other hand the mRNA/LNP vaccine was able to strongly boost pre-existing cellular response suggesting that it could be useful in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases. Our studies have provided useful information about different nucleic acid vaccine platforms and guide further clinical development." 681593 +No NIH Category available Acceleration;Active Biological Transport;Aging;Anabolism;Antineoplastic Agents;Apoptosis;Biochemical;Cell Death;Cell membrane;Cell physiology;Cells;Ceramidase;Ceramides;Cessation of life;Chemotherapy-Oncologic Procedure;Clinical;Complex;Deterioration;Development;Disease;Drosophila genus;Drosophila inturned protein;Endocytosis;Endoplasmic Reticulum;Environment;Enzymes;Epinephrine;Etiology;Failure;G-Protein-Coupled Receptors;Generations;Genetic;Golgi Apparatus;Growth Factor;Homologous Gene;Inhibition of Apoptosis;Investigation;Lead;Link;Lipid Peroxides;Lipids;Longevity;Malignant Neoplasms;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Molecular;Multi-Drug Resistance;Pathway interactions;Phospholipid Metabolism;Phospholipids;Photoreceptors;Physiological;Physiology;Predisposition;Process;Production;Proliferating;Property;Protein Secretion;Proteins;Reactive Oxygen Species;Receptor Protein-Tyrosine Kinases;Regulation;Research;Research Personnel;Rhodopsin;Role;Second Messenger Systems;Signal Transduction;Sphingolipids;Sphingomyelins;Sphingosine;Structure;Thrombin;Transgenic Organisms;base;cancer cell;cancer therapy;cell growth;ceramide 1-phosphate;chemotherapy;drug resistance development;experimental study;fly;in vivo;mutant;oxidative damage;phosphoethanolamine;response;sphingosine 1-phosphate;success;therapeutically effective Phospholipid and Sphingolipid Signaling in Drosophila n/a NCI 10926002 1ZIABC010331-24 1 ZIA BC 10331 24 6802050 "ACHARYA, JAIRAJ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 919175 NCI Intermediates of sphingolipid (SL) and phospholipid (PL) metabolism serve as second messengers for a number of signaling cascades including activation of G-protein-coupled receptors such as adrenaline thrombin etc. as well as receptor tyrosine kinases by growth factors. These intermediates mediate a number of processes ranging from protein secretion to activation of apoptosis. We have initiated studies to understand different aspects of lipid signaling in Drosophila. Sphingomyelin (or phosphorylethanolamine ceramide CPE in Drosophila) could serve as a reservoir for several lipid messengers such as ceramide ceramide 1-phosphate sphingosine and sphingosine 1-phosphate. We have initiated studies to delineate the in vivo role of some of the enzymes of the putative 'Sphingomyelin Cycle'. We have begun by identifying homologous genes in Drosophila. We are using transgenic and mutagenic studies to analyze the importance of such a pathway in Drosophila. We have recently demonstrated that modulation of the sphingolipid biosynthetic pathway such as targeted expression of ceramidase rescues degeneration in certain photoreceptor mutants. We have also demonstrated that ceramidase facilitates membrane turnover and rhodopsin endocytosis in Drosophila photoreceptors. Sphingolipids are synthesized vectorially. While the steps that lead up to the generation of ceramide occur in the endoplasmic reticulum (ER) the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids occurs mostly outside of the ER either in the Golgi complex or in the plasma membrane. This necessitates the active transport of ceramide from ER to the Golgi complex. This transport is mediated by a protein called ceramide transfer protein (CERT). We have now demonstrated that CERT-mediated transfer of ceramide is critical for the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids. Lack of CERT in Drosophila leads to decreased CPE and complex sphingolipids and plasma membranes with altered physical and physiological properties. These changes render them susceptible to normal loads of reactive oxygen species encountered by the cell. The ensuing oxidative damage to the plasma membrane leads to production of lipid peroxides that will further oxidize the membrane and cellular constituents leading to a rapid deterioration in the metabolic function of the cell. All these changes manifest as accelerated aging in Drosophila and thus result in a very short life span for these flies. We anticipate that a combination of genetic molecular and biochemical approaches in Drosophila will define the important players involved in PL SL signaling in their normal cellular environment. 919175 +No NIH Category available Acquired Immunodeficiency Syndrome;Amino Acids;Anti-Bacterial Agents;Anti-HIV Agents;Basic Science;Binding;Biochemical;Biogenesis;Biological;Biological Assay;Biological Models;Biophysics;Catalysis;Cell division;Complex;Couples;DNA-Directed RNA Polymerase;Data;Development;Dimerization;Double-Stranded RNA;Drug Design;Endoribonucleases;Eukaryota;Exhibits;Family;Folic Acid;Goals;Guanosine Triphosphate Phosphohydrolases;Hydrolysis;Ions;Magnesium;Malignant Neoplasms;Mammals;Maps;Modeling;Molecular Conformation;Nucleotides;Orthologous Gene;Play;Prokaryotic Cells;Proteins;RNA;RNA Interference;RNA Processing;RNA metabolism;Reaction;Research;Ribonuclease III;Ribonucleases;Role;Side;Site;Site-Directed Mutagenesis;Structure;System;Virus Diseases;Yeasts;anti-cancer;antimicrobial;antimicrobial drug;cell growth;design;drug development;endonuclease;enzyme pathway;helicase;inhibitor;macromolecule;magnesium ion;member;microorganism;novel;phosphodiester;structural biology;targeted agent;therapeutic development;transcription factor Biomolecular Structure and Mechanism Structure-Based Drug Design n/a NCI 10926000 1ZIABC010326-24 1 ZIA BC 10326 24 6801952 "JI, XINHUA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1732356 NCI By structural analysis we map the reaction trajectory or functional cycle of selected biological macromolecules. By structure-based development we design synthesize and characterize novel anticancer and antimicrobial agents. We carry out structure-based drug development as a continuation of our basic research on the structure and mechanism of biomolecular systems with anticancer and antimicrobial significance. To date we have described the reaction trajectory or functional cycle of HPPK (a folate pathway enzyme essential for microorganisms but absent in mammals) Era (an essential GTPase that couples cell growth with cell division) RapA (a Swi2/Snf2 protein that recycles RNA polymerase) two members of the RNase III family (a family of dsRNA-specific endoribonucleases) and DDX3X (a DEAD-box helicase that unwinds short RNA duplexes). Among these biomolecules HPPK is a target for novel antibacterial agents and DDX3X is a target for novel anticancer and anti-HIV agents. Structure-based drug development is in progress. We have made significant progress toward novel antibacterial agents targeting HPPK closely mimicking the reaction intermediate and thereby exhibiting high potency. Representative members of the RNase III family include prokaryotic RNase III and eukaryotic Rnt1p Drosha and Dicer. They play important roles in RNA processing and maturation post-transcriptional gene silencing and defense against viral infection. For structural and mechanistic studies bacterial RNase III and yeast Rnt1p are valuable model systems for prokaryotes and eukaryotes respectively. For both RNase III and Rnt1p we have shown how the dimerization of their endonuclease domain (RIIID) creates a catalytic valley where two cleavage sites are located how the catalytic valley accommodates a dsRNA substrate in a manner such that each of the two RNA strands is aligned with one of the two cleavage sites how the hydrolysis of each strand involves both RIIIDs and how RNase III uses the two cleavage sites to create 2-nucleotide (2-nt) 3' overhangs in its products. We have also shown how magnesium is essential for the formation of a catalytically competent protein-RNA complex and how the use of magnesium ions can drive the hydrolysis of each phosphodiester bond. Moreover we have described a stepwise model by which RNase III and Rnt1p execute the phosphoryl transfer reaction. All members of the RNase III family propel RNA hydrolysis by two-Mg2+-ion catalysis which exhibits distinct features however by prokaryotes and eukaryotes. As revealed by our structures prokaryotic RNase IIIs require a third magnesium ion in catalysis whereas eukaryotic RNase IIIs employ two additional amino acid side chains. DDX3X belongs to the family of DEAD-box helicases that regulate RNA processing and metabolism by unwinding short RNA duplexes. Sharing a helicase core composed of two RecA-like domains (D1D2) DDXs function in an ATP-dependent non-processive manner. As an attractive target for cancer and AIDS treatment DDX3X and its orthologs are extensively studied yielding a wealth of biochemical and biophysical data including structures of apo-D1D2 and post-unwound D1D2:ssRNA complex. However the structure of a pre-unwound D1D2:dsRNA complex was not available until we have recently determined the crystal structure of a D1D2 core in complex with a 2-turn RNA duplex at the pre-unwound state showing that two DDXs recognize the RNA duplex. Each DDX mainly recognizes a single strand and conformational changes induced by ATP binding unwinds the RNA duplex in a cooperative manner. Our structure has significantly altered a previous model of three-molecule cooperativity. To validate our new model we are currently elucidating the functional cycle of DDX3X using site-directed mutagenesis RNA-unwinding assay ATP-hydrolyzing assay Hill cooperativity analysis and structural studies. We are also developing DDX3X inhibitors based on available structural and mechanistic information. 1732356 +No NIH Category available Address;Adopted;Adrenal Cortex Hormones;Antiinflammatory Effect;Biochemical;Biological Assay;Cells;Characteristics;DNA Binding;Endocrine Disruptors;Endocrine system;Environment;Exposure to;Genes;Genomics;Glucocorticoid Receptor;Glucocorticoids;Health;Higher Order Chromatin Structure;Human;Mammalian Cell;Methods;Modeling;Molecular Conformation;Mutation;Nuclear;Nuclear Receptors;Physiological;Population;Privatization;Public Health;Reporting;Response Elements;Risk;Risk Management;Role;Sampling;Seasons;Signal Transduction;Source;Steroid Receptors;Steroids;Structure;Thyroid Gland;Water;Water Supply;androgenic;aryl hydrocarbons;dimer;estrogenic;health data;in vivo imaging;novel;receptor binding;receptor function;response;screening In vivo Imaging Analysis of Steroid-Nuclear Receptor Function n/a NCI 10925996 1ZIABC010308-25 1 ZIA BC 10308 25 8777551 "HAGER, GORDON L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 542665 NCI 1 Globally contaminant exposure in unregulated water sources is a recognized public-health data gap and an obstacle to both risk-management. To address contaminant exposures in hydrologically-vulnerable aquifers rivers and tap water samples were collected from multiple sources. We assessed EDCs activity (aryl hydrocarbon [AhR] androgenic [AR] thyroid [Ty] estrogenic [ER] corticosteroid [CS]) with novel mammalian cell-based assays that express nuclear steroid receptors. Results demonstrate that AR and AhR activities are commonly detected in water supplies and that bioactivity varies by season and utility/sample characteristics. Screening EDCs with bioassays holds promise for characterizing population exposure to diverse EDCs mixtures. Continued assessment of unmonitored and unregulated private supply TW is needed to model contaminant exposures and human-health risks. 2. The glucocorticoid receptor (GR) is widely believed to bind DNA as a dimer to regulate gene responses related to its anti-inflammatory effects. This model has been built upon widely reported studies that focus on dead cell genomics. We reported earlier that GR adopts a tetramers conformation on response elements in living cells. Recent reports from the Barcelona group identified crystal structures for AR GR consistent with tetramer formation. We analyzed a variety of GR DBD and LBD mutations and their effect on multimerization. We report preliminary evidence that the GR can also form crystal structures with tetrameric conformations. Results do support a physiological role for tetrameric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids. 542665 +No NIH Category available Affinity;American Society of Clinical Oncology;Anti-CD22;B lymphoid malignancy;BCL1 Oncogene;BL22 immunotoxin;BRAF gene;Behavior;Biological Assay;Biology;Blood;Bone Marrow Cytometry;CD22 Immunotoxin;CD22 gene;Cancer Therapy Evaluation Program;Capillary Leak Syndrome;Cells;Characteristics;Chemoresistance;Cladribine;Clinical;Combination Drug Therapy;Data;Development;Disease;Dose;Enrollment;Evaluable Disease;Exotoxins;FDA approved;Follicular Lymphoma;Genes;Guidelines;Hairy Cell Leukemia;Hairy Cell Leukemia Variant;Hematologic Neoplasms;Hemolytic-Uremic Syndrome;Histology;Immunoglobulins;Immunohistochemistry;Immunotoxins;Indolent;Kidney Failure;Laboratory Research;Licensing;Life;Lymphoma;Lymphoma cell;MEK inhibition;MEKs;MS4A1 gene;Mantle Cell Lymphoma;Measures;Mediation;Methods;Molecular;Multicenter Trials;Mutation;National Comprehensive Cancer Network;Newly Diagnosed;Nodal;Non-Hodgkin's Lymphoma;Ohio;Outpatients;Pathogenesis;Pathway interactions;Patients;Pentostatin;Pharmaceutical Preparations;Phase;Prognosis;Progression-Free Survivals;Pseudomonas;Publishing;RNA;Randomized;Recombinants;Refractory;Regimen;Relapse;Reporting;Residual Neoplasm;Retreatment;Running;Safety;Sampling;Side;Testing;Thrombocytopenia;Time;Toxic effect;Toxicity due to chemotherapy;Toxin;Treatment Efficacy;Treatment-related toxicity;Tumor Markers;United States National Institutes of Health;Universities;Variant;Waldenstrom Macroglobulinemia;Work;anaplastic thyroid cancer;chimeric antigen receptor T cells;clinical development;cohort;cytotoxicity;exome sequencing;follow-up;genetic profiling;hairy cell leukemia cell;immunogenicity;improved;inhibitor;leukemia treatment;next generation sequencing;novel therapeutic intervention;novel therapeutics;optimal treatments;participant enrollment;primary endpoint;prospective;purine analog;randomized trial;response;rituximab;small molecule;standard of care;targeted agent;targeted treatment;transcriptome Development of Recombinant Toxins to Treat Hematologic Malignancies n/a NCI 10925993 1ZIABC010301-26 1 ZIA BC 10301 26 6212020 "KREITMAN, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1665659 NCI Overview. We focus on targeted therapy for hematologic malignancies particularly hairy cell leukemia (HCL) and other new therapies for HCL. Moxetumomab pasudotox (Moxe) contains truncated Pseudomonas exotoxin (PE) fused to an anti-CD22 Fv fragment. Previously called HA22 or CAT-8015 it is an affinity-matured form of a previous molecule BL22 for targeting hematologic malignancies particularly HCL. We test combinations of chemotherapy and rituximab to help determine the optimal therapy of newly diagnosed and multiply relapsed HCL and to better understand the behavior of HCL in immunotoxin-treated patients. We also test small molecules as targeted therapy for HCL and poor-prognosis variants like HCLv. In the lab we use clinical samples from patients to investigate treatment efficacy and toxicity and to better understand the biology and pathogenesis of HCL/HCLv. Development of anti-CD22 recombinant immunotoxins for CD22+ B-cell malignancies. Based on published phase 1 and 3 results for Moxe the FDA approved Moxe for relapsed/refractory HCL in September of 2018. The most important toxicities reported earlier with BL22 included reversible capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS) the latter a combination of transient thrombocytopenia and renal insufficiency resolving without treatment. To improve efficacy in HCL we began a trial at NIH testing Moxe with rituximab (MoxeR) the latter to decrease immunogenicity and to help kill HCL cells and to hasten MRD-free CR. We presented the first 9 patients at ASCO 2021 reporting an MRD-free CR rate of 78%. The primary endpoint of the MoxeR trial was safety which was met after 13 patients were enrolled. To determine whether MoxeR was more effective than Moxe in achieving MRD-free CR AstraZeneca (AZ) allowed additional patients to be enrolled with the NIH supplying the Rituximab biosimilar Ruxience. After enrolling a total of 18 patients the MRD-free CR rate (defined by negative bone marrow flow cytometry and immunohistochemistry) was 72% for MoxeR compared to 47% (30 of 64 evaluable patients) after Moxe alone which was a significant difference (1-sided p=0.05 Fisher's exact). We proposed testing MoxeR as a method to eliminate MRD after therapy for indolent Non-Hodgkin's lymphoma (NHL) including follicular lymphoma (FL) marginal zone lymphoma (MZL) mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma (LPL). We found that MCL and MZL cells were sensitive to the cytotoxicity of Moxe like HCL cells. To make Moxe easier and safer to administer as an outpatient we proposed testing MoxeR in HCL every 2 weeks rather than every other day for 3 doses on 4-week cycles. Unfortunately AZ was not interested in developing Moxe further returned the license to the NIH and at this time another company is considering taking over development of this lifesaving therapy. Development of MAb-chemotherapy combinations for early and relapsed/refractory HCL. For the past 30-35 years cladribine alone or less commonly pentostatin alone was the standard 1st and 2nd line treatment of HCL but without cure in most patients. To determine the value of rituximab added to cladribine newly diagnosed or once-relapsed HCL patients were randomized to cladribine with either immediate or 6-month delayed rituximab and MRD at 6 months and other time points measured. As published in 2020 1st line concurrent cladribine-rituximab (CDAR) eradicates MRD in 97% vs 32% of patients with cladribine alone (CDA) (p0.0001). Delayed rituximab was given when MRD was detected in blood and eradicates MRD in 2/3 of patients with most MRD-free CRs persisting at a median follow-up of 6.5 years. Of 68 patients treated with either approach only 1 progressed to the point of needing next treatment vs 28% of 90 historical patients treated with CDA alone and followed until retreatment was needed for relapse (p0.0001). Thus while CDAR is superior with respect to long-term MRD-free CR CDA alone with delayed rituximab is also established as a new standard of care for treatment of newly diagnosed HCL. Cladribne with rituximab is a new option for 1st line HCL treatment in the NCCN guidelines. Once-relapsed HCL patients are continuing to be enrolled on the trial. In the poor prognosis HCL variant (HCLv) concurrent rituximab + cladribine was highly effective establishing CDAR as a new standard of care for early HCLv. Long-term data from the 20 patient-cohort of HCLv showed a 95% CR rate and 80% MRD-free CR rate. To study pentostatin-rituximab and bendamustine-rituximab (BR) combinations in HCL prospectively a randomized trial which recently complete accrual showed both regimens as highly effective particularly in eradicating MRD albeit with chemotherapy toxicities. Targeted therapy for HCL. The BRAF V600E mutation is present in 80-90% of classic HCL. Those lacking V600E include those with unmutated IGHV4-34 immunoglobulin rearrangement first described by our group in 2009. For the first time in HCL we treated BRAF V600E+ HCL patients by inhibiting both BRAF with Dabrafenib and its downstream pathway MEK with Trametinib. This trial was part of a Novartis-sponsored multicenter registration trial in many different BRAF V600E+ histologies and the HCL results were recently published. We also treated several patients with anaplastic thyroid cancer (ATC) a rapidly fatal disease also expressing BRAF V600E leading to the approval of Dabrafenib and Trametinib by the FDA for the treatment of ATC. To continue development of BRAF/MEK inhibition for HCL we initiated a trial of BRAF inhibitor Encorafenib and MEK inhibitor Binimetinib in HCL. For HCLv which is BRAF WT and HCL cases which are also BRAF WT we began a trial of Binimetinib alone. As part of this trial we are determining if response to Binimetinib depends on the presence of MEK mutations which we have reported in about half of BRAF WT HCL/HCLv. We treated 20 of the 37 patients enrolled on the multicenter BTK inhibitor Ibrutinib study run by Ohio State University and the published report showed low response rates but excellent progression-free survival (PFS). While agents targeting BRAF MEK and BTK generally do not eliminate MRD they can achieve regression of nodal disease and may be useful as a bridge to Moxe or Moxe-R which can then eliminate MRD. In our trials patients may receive rituximab or other CD20 Mab combined with of Binimetinib +/- Encorafenib if patients achieve MRD+ CR with Binimetinib +/- Encorafenib alone. Finally the BCL-2 inhibitor Venetoclax was recently published by others to achieve responses in a few patients with relapsed/refractory HCL/HCLv and after several years of negotiating with the Cancer Therapy Evaluation Program (CTEP) and recently with Abbvie-Genentech we have been given approval to lead a multicenter trial of Venetoclax in HCL/HCLv. Laboratory research to study HCL/HCLv biology and treatment. To better target HCL/HCLv new potential drugs are also being tested in cytotoxicity assays including BRAF MEK BTK and BCL-2 inhibitors. Using clinical samples from HCL/HCLv patients we are sequencing immunoglobulin rearrangements (IgH) unique to each HCL patient to study HCL biology and test MRD by RQ-PCR and next-gen sequencing (NGS). We are performing whole exome sequencing and RNA transcriptome analysis for HCLv and BRAF WT HCL samples to determine what causes disease in these variant cells. We have found and are studying genes which are characteristic of patients with HCL and/or HCLv including Myf6 which as we published is the most common gene expressed in HCL compared to HCLv and is expressed in 100% of HCL patients. Our work with this and other genes may shed light on pathogenesis of HCL/HCLv and possible new treatments for these disorders. 1665659 +No NIH Category available ABCB1 gene;ABCG2 gene;ATP Hydrolysis;ATP phosphohydrolase;ATP-binding cassette transport;Address;Adenosine A3 Receptor;Affinity;Alanine;Antineoplastic Agents;Area;Binding;Biochemical;Biological Assay;Biological Availability;Biophysics;Breast Cancer Cell;CCR;Cancer Patient;Carrier Proteins;Cells;Charge;Chemicals;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinic;Collaborations;Cryoelectron Microscopy;Data;Development;Drug Efflux;Drug Interactions;Drug Kinetics;Drug Transport;Drug resistance;Energy Metabolism;Exhibits;Extramural Activities;FDA approved;Formulation;Genus Hippocampus;Goals;Hela Cells;Human;Hydrophobicity;Knowledge;Ligands;Light;Link;Lipids;Malignant Neoplasms;Maryland;Mediating;Membrane;Molecular;Molecular Conformation;Monoclonal Antibodies;Multi-Drug Resistance;Mus;Mutagenesis;Mutate;Mutation;Names;Natural Products;Nature;PUVA Photochemotherapy;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phosphatidylinositide 3-Kinase Inhibitor;Photochemistry;Photosensitizing Agents;Play;Poly(ADP-ribose) Polymerase Inhibitor;Production;Proteins;Pump;Reactive Oxygen Species;Regulation;Resistance;Resolution;Rhodamine 123;Role;Series;Site;Structure;Structure-Activity Relationship;Substrate Specificity;Tariquidar;Testing;Time;Transmembrane Domain;Tyrosine Kinase Inhibitor;Universities;Work;cancer cell;cancer drug resistance;cancer type;design;drug repurposing;flexibility;glycoprotein structure;improved;in silico;in vivo;inhibitor;insight;interdisciplinary approach;kinase inhibitor;member;molecular dynamics;molecular modeling;multidrug resistant cancer;mutant;nanodisk;nanomedicine;novel strategies;novel therapeutic intervention;programs;reconstitution;refractory cancer;screening;small molecule;small molecule libraries;tool;triple-negative invasive breast carcinoma;uptake Biochemical Analysis of Multidrug Resistance-linked Transport Proteins n/a NCI 10925988 1ZIABC010030-28 1 ZIA BC 10030 28 6569320 "AMBUDKAR, SURESH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1762305 NCI "We have designed a coordinated strategy using multidisciplinary approaches to understand the molecular basis of the polyspecificity exhibited by the ATP-binding cassette (ABC) drug transporter P-glycoprotein (P-gp) and the mechanism of P-gp-mediated drug transport. Our approaches include several biochemical and biophysical assays cell-based transport assays purification and reconstitution in lipid nanodiscs for structural studies using cryo-EM medicinal chemistry to synthesize a large number of compounds to assess structure-activity relationships in silico molecular modeling and MD simulations to extend our understanding of the mechanistic aspects and structure-function relationships. In addition we are employing a novel approach of substituting multiple conserved residues with alanine in homologous transmembrane helices (TMHs) to elucidate the transport mechanism of P-gp. Furthermore we are devoting considerable effort to the screening of repurposed drugs dual inhibitors tyrosine kinase inhibitors (TKIs) and small molecule modulators of both P-gp and ABCG2 that are used in the clinic for treatment of various types of cancers. 1. Elucidation of the catalytic cycle of ATP hydrolysis and transport pathway of P-gp: We continue to study the catalytic cycle of P-gp specifically the mechanism of ATP hydrolysis by inhibitors. Cryo-EM analysis of P-gp structures has revealed that two molecules of inhibitors such as zosuquidar tariquidar elacridar and encequidar are bound in the transmembrane region. One of the molecules of the inhibitor is bound in the substrate-binding pocket (SBP) and another in a cavity referred to as an ""access tunnel"" extending from the SBP to the gate formed by TMHs 4 and 10. It was hypothesized that inhibitor occupancy of the access tunnel would impede substrate transport. To test this hypothesis residues lining the access tunnel that interact with four inhibitors were substituted with alanine to generate mutants named L-site-5A L-site-8A and L-site-9A. These mutants along with the wild-type (WT) P-gp were expressed in HeLa cells. The mutants showed expression levels similar to those of WT P-gp. In addition the L-site-5A mutant showed normal transport activity for eight of the ten fluorescent substrates tested and partial transport for two of them whereas the L-site-8A and L-site- 9A mutants exhibited progressive loss of transport function. When compared to the L-site-5A mutant L-site-8A and L-site-9A have residues N296/I299/F770/V991 substituted by Ala. These residues or at least some of them may be essential for transport of the tested fluorescent substrates even though they are located at some distance from the SBP. Surprisingly all four inhibitors partially inhibited or completely inhibited (70%) the drug efflux activity of the L-site mutants. The inhibition of Rhod-2 AM efflux was further characterized obtaining IC50 values for tariquidar inhibition for the three L-site mutants not significantly different from WT (13 nM). However there were significant differences observed in the case of inhibition by zosuquidar with the mutants displaying values up to 200-fold higher compared to WT-P-gp indicating decreased affinity. 2. Mechanism of the reversal of the direction of P-gp-mediated drug transport from efflux to uptake: Previously we generated the 14A mutant of human P-gp in which seven conserved residues each from TMH6 and TMH12 were mutated to alanine and found that this mutant could not efflux most of the substrates tested. But surprisingly it was able to import four of the tested substrates including Rh123 and Flutax-1. We continue to study the mechanism of how the direction of transport from efflux to uptake is changed. We focused on these three sub-aims. (a) Determination of the minimum number of mutations in TMHs 6 and 12 necessary for the uptake function: We generated a series of mutants with mutations ranging from 4 to 16 in TMH6 and TMH12 based on their possible interaction with substrates. We found that a minimum of 7 residues (3 from TMH 6 and 4 from TMH 12 a mutant named 7AII) are required for complete loss of efflux of tested substrates and to gain the ability to mediate uptake of 5 substrates. These findings are consistent with the presence of a switch region comprised of residues present in the upper halves of both TMH6 and TMH12 which determines the direction of substrate transport. We plan to test whether the substitution of 2 to 4 residues in this region of TMH6 and 12 with positively (Arg) or negatively (Asp) charged residues changes the direction of transport. (b) Conversion of mouse P-gp into drug uptake pumps for structural and in vivo functional studies: Human P-gp is a highly conserved transporter and shares 87% identity with mouse P-gp Abcb1a. We substituted the same residues in TMH6 and 12 of mouse P-gp forming the human P-gp 7A-II mutant to determine whether the murine transporter can be converted to a drug uptake pump. We found that indeed mouse P-gp 7A mutant also lost efflux function but could mediate uptake of 5 substrates. Furthermore rhodamine 123 uptake by the mouse P-gp-7A mutant was inhibited by substrates and inhibitors similar to the human 7A-II mutant. 3. The molecular basis of the polyspecificity of human P-gp: To understand the molecular basis of the broad substrate specificity of P-gp we substituted seven residues with Ala in both homologous transmembrane helices (TMHs) 4 and 10 which undergo significant conformational changes during the catalytic cycle of P-gp. We found that the transport function of the mutants containing seven Ala substitutions either in TMH4 or 10 alone is almost the same as that of WT P-gp. However when the same seven residues are mutated in both TMHs 4 and 10 the TMH410-14A mutant lost the ability to transport most tested substrates. These data consistent with the flexible nature of the TMDs indicate that multiple mutations in a single TMH are well tolerated. Additional data including molecular dynamics (MD) simulations suggest that residues in TMHs 4 and 10 function cooperatively to generate conformational changes necessary for the translocation of substrate drugs out of cells. Thus our findings provide a functional correlation with the observed structural changes in TMHs 4 and 10 in the inward-open and -closed states of P-gp. 4. Mechanism of photodynamic regulation of P-gp and ABCG2: We have begun to elucidate the molecular mechanism of photo dynamic therapy (PDT)-mediated regulation of ABC drug transporters. These studies are carried out in collaboration with Dr. Huang-Chiao Huang (partnership program between CCR NCI and the University of Maryland). PDT is a photochemistry-based tool that involves light activation of photosensitizers to generate reactive oxygen species. PDT using the photosensitizer benzoporphyrin (BPD which is a substrate of P-gp and ABCG2) inhibits both transporters by modulating their ATPase activity and protein integrity. To improve the efficiency of PDT for drug-resistant cancer we devised a photoimmunoconjugate formulation combining hydrophobic BPD photosensitizers and a conformation-sensitive UIC2 monoclonal antibody to identify P-gp expression on triple negative breast cancer (TNBC) cells. We plan to use Seahorse-based assays to assess the effect of PDT on the energy metabolism and ATP production in P-gp or ABCG2 expressing drug-resistant cancer cells. 5. Screening of non-toxic natural products small molecules and repurposed drugs as modulators to overcome resistance mediated by P-gp and ABCG2: We continue to characterize natural products recently developed tyrosine kinase inhibitors repurposed drugs and small molecules for their effect on the function of P-gp and ABCG2. These studies are carried out in collaboration with intramural and extramural collaborators." 1762305 +No NIH Category available Androgen Receptor;Architecture;Cell Nucleus;Chromatin;Chromatin Loop;Complex;Enhancers;Gene Expression Regulation;Gene Structure;Genes;Genomics;Glucocorticoid Receptor;Interphase;Nature;Nuclear;Play;Role;Steroid Receptors;Transcriptional Regulation;cancer initiation;cohesin;experimental study;follow-up;interest;transcription factor Function of Steroid Receptors in Subcellular Compartments n/a NCI 10925987 1ZIABC010027-29 1 ZIA BC 10027 29 8777551 "HAGER, GORDON L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 542665 NCI The cohesin complex is central to chromatin looping but mechanisms by which these long-range chromatin interactions are formed and persist remain unclear. We discovered that interactions between a transcription factor (GR) and a multimeric complex including the cohesin loader NIPBL and cohesin regulate enhancer dependent gene activity. We demonstrated that the glucocorticoid receptor stabilizes the cohesin complex at GR enhancers promoting loop extrusion and long-range gene regulation. Follow up experiments suggest that the androgen receptor (AR) also interacts with a similar complex for long range gene regulation. Structural studies are underway to probe the nature of the steroid receptor interactions with the cohesin complex. 542665 +No NIH Category available 2019-nCoV;Animals;Anti-Bacterial Agents;Antibiotics;Antigen Presentation;Antigens;Bacterial Infections;Bacteriophage T7;Bacteriophage lambda;Bacteriophages;Biotechnology;COVID-19 vaccine;Caring;Communicable Diseases;Data;Diagnosis;Disease;Drug resistance;Engineering;Future;Genes;Glioblastoma;Goals;Infection;Investigation;Investments;Klebsiella;Libraries;Link;Malaria;Malignant Neoplasms;Mutation;Peptide Antibiotics;Peptides;Phage Display;Process;Production;Prophages;Proteins;Publishing;Resistance;SARS-CoV-2 immunity;SARS-CoV-2 spike protein;Tail;Technology;Testing;Time;Vaccines;developmental genetics;epidermal growth factor receptor VIII;experimental study;human disease;immunogenicity;leukemia;mouse model;mutant;prevent;screening Use of Bacteriophages to Prevent Diagnose and Treat Diseases n/a NCI 10925986 1ZIABC010017-28 1 ZIA BC 10017 28 6129912 "ADHYA, SANKAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1110488 NCI Part A. Three lines of investigations are being pursued currently. 1. Use of bacteriophages in treating human diseases because of bacterial infections. We are currently dealing with infections caused by Klebsiella. We have succeeded in defining bacteriophage cocktails that take care of bacteriophage resistance that arises during infection processes. 2. We have succeeded in engineering Klebsiella phages to have multiple tails to increase the host range of a phage to be capable of infecting and killing multiple hosts species. 3. We have succeeded to construct a T7 bacteriophage derivative in which we cloned a peptide antibiotic gene (AMP) which when infects a given host also produces vast amount of the antibiotic. This enables the phage to kill by the action of AMP any mutant bacterial host which becomes resistant to phage. However the expression of AMP has been poor which does not kill phage resistant hosts. But when the AMP expression is covalently linked to a soluble protein the expression was reasonable. Currently we have made a library of phage carrying random mutations in the peptide anti biotic and screening them for one with more effective anti-bacterial activity. These findings encourage us to pursue the process further. Part B. We are using our previously developed phage display technology using bacteriophage Lambda to make vaccines against infectious diseases as well as against cancer. We already constructed displaying potential antigenic peptides and proteins of CLL leukemia malaria and Covid 19 virus. We invested a lot of time in engineering purifying validating and testing the authenticity of multiple phage constructs that could potentially be developed as a phage-based vaccine for COVID-19 CLL and malaria. Currently we are performing several experiments and analyzing data on testing phage-based vaccines in a mouse model to generate immunity against COVID-19 and glioblastoma. We are currently working in the future experimental plan to demonstrate the efficacy of phage-based COVID-19 vaccine. The goal is the same in both cases: to prepare purified engineered lambda for animal immunogenecity study. In the first branch of the project we engineered a phage with the EGFRvIII antigen present in glioblastoma and attached to the D protein of the lambda phage. The other branch of the project involved the same process but the antigen was a fragment of the covid-19 spike protein. These constructions were made as prophages. The prophages were then induced phage production and phages purified and concentrated. The respective phages are now being tested for immunogenecity in animals. 1110488 +No NIH Category available Alleles;Base Pairing;Binding Sites;Bone Marrow Transplantation;CRISPR/Cas technology;Cell Communication;Cell physiology;Cell-Mediated Cytolysis;Cells;Clinical;Collaborations;Complex;Data;Development;Distal;Education;Elements;Family;Frequencies;Future;Genes;Genetic Polymorphism;Genetic Variation;Goals;HLA-A gene;HLA-B Antigens;HLA-C Antigens;Hematopoietic stem cells;Human;Immune;Inflammation;Investigation;Ligands;Major Histocompatibility Complex;Malignant Neoplasms;Messenger RNA;Minnesota;Molecular;Mus;Mutation;Natural Killer Cells;Nature;Outcome;Peripheral Blood Lymphocyte;Population;Process;Program Research Project Grants;RNA Splicing;Receptor Cell;Regulation;Regulatory Element;Research;Role;System;T-Cell Receptor;Tissues;Transcriptional Regulation;Universities;Variant;Virus;Work;donor stem cell;interest;man;novel;programs;promoter;receptor;receptor expression;stem cells;transcription factor;trophoblast;tumor Molecular Studies of Cellular Cytotoxicity n/a NCI 10925983 1ZIABC010013-28 1 ZIA BC 10013 28 6569288 "ANDERSON, STEPHEN K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 917478 NCI "Our group has been studying the regulation of class I major histocompatibility complex (MHC) receptors in mouse (Ly49) and man (KIR) for many years and we are pioneers in the identification of molecular mechanisms underlying the variegated expression of these receptors by NK cells. We have discovered many instances of genetic variation in KIR and Ly49 genes that can change the responsiveness of NK cells to MHC on target cells. However our long-standing collaboration with the Carrington lab in the Cancer and Inflammation Program (CIP) has stimulated our interest in studying the expression of the KIR ligands and the HLA-C gene in particular. Dr. Carrington's lab has demonstrated significant allelic variation in HLA-C expression suggesting that both the receptors and ligands are involved in an evolutionary ""tuning"" process to produce optimal NK:target cell interactions. We have therefore conducted an extensive characterization of polymorphisms in HLA-C regulatory elements. In the past year significant progress has been made in the investigation of the transcriptional control of HLA-C expression -a major ligand for the KIR family of human class I MHC receptors expressed by natural killer (NK) cells. We have identified and characterized a novel distal NK cell-specific HLA-C promoter. This discovery has important implications for the study of NK cell education by self MHC molecules. NK cell education has been a major focus in the field and recent data has suggested a role for MHC expression by the NK cell itself in this process. Our work has defined a novel paradigm for cell-intrinsic regulation of NK cells by HLA-C and we have discovered a complex system of tissue-specific alternative mRNA splicing that controls HLA-C expression by NK cells in different tissues. Furthermore we have identified specific HLA-C alleles that have a single base pair polymorphism that inactivates the NK-specific promoter resulting in reduced HLA-C expression by NK cells. We have found that this polymorphism has a significant effect on NK cell activity and we are in the process of determining if hematopoietic stem cells donors that have low HLA-C expression on NK cells are associated with a distinct clinical outcome. This study is a component of our participation in a program project grant led by Dr. Jeffery Miller at the University of Minnesota. In addition we have conducted a thorough analysis of allelic variation of transcription factor binding sites in the HLA-C gene and identified multiple polymorphisms that account for the variation of HLA-C expression levels in peripheral blood lymphocytes that has been observed by the Carrington lab. Our detailed study of HLA-C has also revealed the presence of trophoblast-specific elements in the HLA-C gene that are not present in HLA-A or HLA-B genes providing an explanation for the specific expression of HLA-C by trophoblasts. Future plans include: investigating the mechanism of NK cell-intrinsic tuning by HLA-C; using CRISPR technology to confirm functional role of the multiple KIR and HLA-C elements identified; studying clinical correlations of polymorphisms in the KIR and HLA genes. Preliminary data obtained from the study of bidirectional promoters in lineage-defining transcription factors has revealed an abundance of both divergent and opposing promoter pairs in human transcription factors. Future studies in this project will investigate the effect of mutations in these elements on the frequency of specific immune cell subsets generated from progenitor cells." 917478 +No NIH Category available Actins;Adaptor Signaling Protein;Adhesions;Affect;Antigen-Antibody Complex;Apical;Axon;Benign;Binding;Biochemistry;Biological Models;Breast;Cancer cell line;Cell Adhesion;Cell Cycle Progression;Cell Line;Cell Shape;Cell-Cell Adhesion;Cell-Matrix Junction;Cells;Colon;Complex;Congenital Abnormality;Cues;Cytoplasmic Tail;Development;Dsh protein;Embryo;Embryonic Development;Eph Family Receptors;Ephrins;Event;Fibroblast Growth Factor;Fibroblast Growth Factor Receptors;Frequencies;Human;Human Cell Line;Invaded;Laboratories;Ligand Binding;Ligands;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mass Spectrum Analysis;Mediating;Membrane;Modification;Morphogenesis;Movement;Myosin ATPase;Neoplasm Metastasis;Neural Crest Cell;Neural Tube Closure;Neural tube;Neuroblastoma;Pathway interactions;Pattern;Phenotype;Play;Positioning Attribute;Proliferating;Prostate;Proteins;Receptor Protein-Tyrosine Kinases;Regulation;Repression;Research;Retina;Rho-associated kinase;Robinow syndrome;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Stem Cell Development;System;Tissues;Tumor Angiogenesis;Tumor Cell Invasion;Tumor Cell Line;Tumor Stem Cells;Vertebrates;Visual Fields;WNT Signaling Pathway;Xenopus;angiogenesis;cell fixing;cell motility;cellular imaging;constriction;driving force;embryonic stem cell;epithelial to mesenchymal transition;experimental study;gain of function;hindbrain;human disease;in vivo;insight;loss of function;melanoma;member;migration;mutant;neoplastic cell;overexpression;pluripotency;receptor;recruit;retinal progenitor cell;scaffold;skeletal;small cell lung carcinoma;stem cell fate specification;stem cells;tumor;tumorigenesis Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways n/a NCI 10925981 1ZIABC010006-28 1 ZIA BC 10006 28 9692315 "DAAR, IRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 750182 NCI During normal development progenitor cells of many tissues undergo progressive restriction of pluripotency epithelial-to- mesenchymal transition proliferation migration and differentiation. Most if not all of these events involve modifications of cell-cell and cell-matrix adhesion and abnormal modifications of these adhesion systems are often associated with the formation of tumors. The Eph family of receptor tyrosine kinases and their ligands the ephrins are frequently over-expressed in a wide variety of cancers including breast small-cell lung and gastrointestinal cancers melanomas and neuroblastomas. Using the Xenopus embryonic system we have demonstrated that signaling mediated by the intracellular domain of ephrinB affects cell-cell adhesion and that this activity can be modulated by interaction with an activated FGF receptor. The transmembrane ephrinB1 protein is a bi-directional signaling molecule that signals through its cytoplasmic domain to promote cellular movements into the eye field whereas activation of the fibroblast growth factor receptor (FGFR) represses these movements and retinal fate. In Xenopus embryos ephrinB plays a role in retinal progenitor cell movement into the eye field through an interaction with the scaffold protein Dishevelled (Dsh). We recently identified a signaling complex that includes ephrinB2 a transmembrane ligand for Eph receptors and non-canonical Wnt signaling molecules that we term the WERDS complex consisting of Wnt4 EphrinB2 Ror2 Dsh2 and Shroom3. This signaling complex instructs a critical cell shape change known as apical constriction that is a driving force for neural tube closure during development. We used mass spectrometry of immune-complexes to identify proteins associated with ephrinB2 in the neural tube due to our previous finding that the regulation of ephrinB2 protein levels is necessary for normal neural tube closure (Ji et al Nat Comm 2014). In our current study we use a blend of biochemistry live and fixed cell imaging gain-of-function and loss-of-function along with rescue experiments using wild-type and mutant constructs in vivo to provide mechanistic insight into the instructive cue responsible for proper neural tube closure. These experiments led us to the discovery of the WERDS signaling complex that is responsible for this major morphogenetic process. Briefly we found that Wnt4 binds to Ror2 a non-canonical Wnt receptor that plays a substantive role in Robinow syndrome and enhances the interaction of ephrinB2 with this forming complex through Dishevelled the main scaffold of Wnt signaling. These interactions in turn recruit Shroom3 an adaptor protein critical for neural tube formation which activates Rho-associated kinase (Rock) to cause contraction of the actin-myosin networks required for neural tube closure. We believe that these findings provide the profound understanding of how cross-talk occurs between two seemingly separate major signal transduction pathways Eph/ephrin and Wnt to coordinate an important morphogenetic event neural tube formation. 750182 +No NIH Category available Aging;Apoptosis;Binding;Binding Proteins;Blood Cells;Cell Cycle;Cell Line;Cell Lineage;Cell Transplantation;Cells;Chronic stress;Clonal Expansion;Cytarabine;DNA;Development;Developmental Process;Differentiation Inhibitor;Enzymes;Erythroid Cells;Event;Exhibits;Family member;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Genomic Instability;Goals;Helix-Turn-Helix Motifs;Hematopoiesis;Hematopoietic Neoplasms;Hematopoietic Stem Cell Specification;Hematopoietic stem cells;Histones;Human;Hypoxia Inducible Factor;ID2 gene;Incidence;Inflammatory;Lymphoid;MB02;Mediator;Membrane;Mitochondria;Modeling;Molecular;Monitor;Mus;Mutate;Mutation;Myelogenous;Myeloid Cells;Patients;Phase;Play;Population;Predisposition;Preleukemia;Process;Proteins;Reactive Oxygen Species;Resistance;Role;Signal Transduction;Specific qualifier value;Stress;Transplantation;cell growth;cell growth regulation;clinically relevant;comparison control;exhaustion;experimental study;genotoxicity;hematopoietic stem cell quiescence;in vivo;knock-down;leukemia;leukemia/lymphoma;mouse model;myeloid cell development;overexpression;preservation;programs;recruit;self-renewal;senescence;stem cell biology;stem cells;therapeutic target;transcription factor Molecular-Cellular Regulation of Hematopoietic Stem Cells n/a NCI 10925980 1ZIABC010001-28 1 ZIA BC 10001 28 6569266 "KELLER, JONATHAN R" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1082718 NCI During the last year we continued to define the molecular events that regulate hematopoietic stem and progenitor cell (HSPC) quiescence survival self-renewal and myeloid cell lineage commitment and differentiation. We have found that the helix loop helix (HLH) transcription factor inhibitor of differentiation 1 (Id1) is induced during the early stages of myeloid development and can instruct hematopoietic stem cells toward a myeloid versus lymphoid/erythroid cell fates suggesting that this gene and other family members including Id2 and Id3 may regulate cell specification of HSPC. We found that HSCs require Id2 for HSC quiescence and survival using an Id2 conditional (Id2F/F) mouse model to delete Id2 in vivo by regulating hypoxia inducible factor (HIF) -1a and downstream targets. In more recent studies we found that ID2-KD in AML cell lines (UT-7 MB-02 and M-07e) significantly reduced their leukemogenic potential in NSG mice indicating that ID2 is essential for AML cell growth in vivo. Conversely overexpressing ID2 in the human AML cell line M-07e enhanced their leukemic potential and burden in NSG mice supporting the notion that ID2 may preserve LSC quiescence. Experiments with primary AML-PDX cells which are more clinically relevant also showed reduced leukemic potential in transplanted NSG mice upon ID2 knockdown. Additionally ID2-KD cells displayed significantly lower levels of reactive oxygen species (ROS) and mitochondrial activity compared to control cells in both AML cell lines and PDX cells. As ROS-low cells are more susceptible to cytarabine (AraC) we investigated whether ID2-KD renders AML cells more susceptible to AraC. Indeed MB-02-ID2-KD and UT7-ID2-KD cells showed increased sensitivity to AraC while M-07e cells overexpressing ID2 exhibited resistance to AraC. Furthermore AraC effectively eliminated ROS-low cells but ROS-high cells remained resistant supporting previous findings. To further investigate the effect of ID2-KD in AraC resistance in vivo UT7-ID-KD and MB-02-ID2-KD transplanted NSG mice were treated with AraC and monitored for their overall survival and it was observed that ID2-KD transplanted mice have significantly higher overall survival compared to the control cell transplanted mice. Thus we found that ID2 plays a critical role in maintaining human AML cells. In other studies we discovered that mice that lack Id1 show increased quiescence during BMT and are protected from exhaustion during serial BMT and in other models of chronic stress including genotoxic and inflammatory stress and aging. These studies laid the foundation for our current and future goals to determine if Id1 promotes clonal hematopoiesis a preleukemic phase that proceeds leukemia and if reducing Id1 expression can reduce hematopoietic stem and progenitor (HSPC) cell cycling and clonal expansion and reduce the incidence of hematopoietic malignancies. We found that Id gene expression is increased in HSPC progenitor cells from Tet2-/- mice a murine model of clonal hematopoiesis. Furthermore we have determined that reducing Id1 levels in Tet2-/- mice rescues enhanced donor repopulation during BMT reduces HSPC expansion and myeloid skewing of Tet2-/- HSPCs. These results suggest we are reducing clonal expansion in Tet2-/- mice. We have shown that reducing Id1 levels in Tet2-/- mice delays the onset of leukemia. Finally we have found that reducing reducing Id1 gene expression reduces the mutational load and genomic instability of in Tet2-/- in HSPCs in vivo. We have found that reducing Id1 levels in Tet2-/- mice increases apoptosis and senescence which could account for the reduced growth of these cells. Mechanistically we found that Tet2-/- HSPCs show low levels of p16 that are increased by reducing Id1 levels in Tet2-/- mice. KD of p16 expression in Tet2-/-Id1-/- HSPCs reduces senescence and apoptosis and suggest that Id1 reduces p16 levels and apoptosis in Tet2-/- HSPCs. 1082718 +No NIH Category available ATM deficient;Acceleration;Affect;Age;Aggressive Clinical Course;Aplastic Anemia;B lymphoid malignancy;B-Cell Development;B-Cell Lymphomas;B-Lymphoma Development;BCL10 gene;Biology;Breeding;Buffers;CD3E gene;CRISPR/Cas technology;Categories;Cell Aging;Cell Lineage;Cell Proliferation;Cell Survival;Cell division;Cells;Chromosomal Instability;Chromosome 18;Chromosome Structures;Clinical;Collaborations;Complex;Defect;Dependence;Development;Disease;Disease model;Down-Regulation;Dyskeratosis Congenita;Enzymes;Epigenetic Process;Excision;Exhibits;Family;Fibroblasts;Frequencies;Gene Expression;Gene Expression Profiling;Generations;Genes;Genetic;Genetic Engineering;Genetic study;Germ Cells;Heterozygote;Histologic;Human;Immunoglobulin M;Immunologic Surveillance;In Vitro;Incidence;Knock-out;Knockout Mice;Laboratories;Length;Link;Lymphocyte;Lymphoma;Lymphomagenesis;Malignant - descriptor;Malignant Neoplasms;Malignant lymphoid neoplasm;Mediating;Modeling;Mucosa- associated lymphoid tissue lymphoma translocation protein-1;Mus;Mutation;NF-kappa B;National Heart Lung and Blood Institute;Oncogenic;Outcome Study;PTEN gene;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Play;Predisposition;Proliferating;Proto-Oncogene Proteins c-akt;Pulmonary Fibrosis;RNA;RNA-Directed DNA Polymerase;Recurrence;Regulation;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Ribonucleoproteins;Role;Signal Pathway;Signal Transduction;Skin;Small Interfering RNA;Somatic Cell;Stress;Study models;T-Cell Lymphoma;T-Cell Receptor Genes;T-Cell Transformation;T-Lymphocyte;TP53 gene;Telomerase;Telomere Length Maintenance;Telomere Maintenance;Telomere Shortening;Testing;Therapeutic Intervention;Thymic Lymphoma;Thymus Gland;Time;Translations;Up-Regulation;activated B cell like;ataxia telangiectasia mutated protein;cancer cell;early onset;embryonic stem cell;gene product;genome integrity;human model;in vivo;inhibitor;insight;knock-down;large cell Diffuse non-Hodgkin's lymphoma;lymphocyte proliferation;mouse model;neoplastic cell;non-genetic;offspring;overexpression;prevent;prototype;recombinase;senescence;small hairpin RNA;telomere;tumor;tumorigenesis Regulation of Lymphocyte Proliferation and Replicative Capacity n/a NCI 10925979 1ZIABC009405-29 1 ZIA BC 9405 29 2405210 "HODES, RICHARD J." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 38993 NCI Telomeres are unique terminal chromosomal structures that shorten with cell division in vitro and with increased age in vivo in human somatic cells. Telomerase a ribonucleoprotein enzyme that is capable of synthesizing telomeric repeats is expressed in germline and malignant cells and is absent in most normal human somatic cells.We demonstrated that telomerase is in fact highly regulated during development and activation of mouse and human lymphocytes. Expression of the two genes encoding the necessary and sufficient components of telomerase RNA template (TR) and reverse transcriptase catalytic component (TERT) was found to be regulated during lymphocyte development and activation. Our studies of genetically engineered knockout mice have demonstrated that in addition to the defect in telomere length maintenance observed in complete homozygous knockouts for either of the telomerase components there is a deficiency in telomere maintenance in mice that are heterozygous for inactivation of one copy of either telomerase component. This phenomenon termed haplo-insufficiency has recently been observed in an increasing number of clinical entities including dyskeratosis congenita aplastic anemia and pulmonary fibrosis resulting from mutation and inactivation of telomerase components or related genes. In collaboration with the laboratory of Dr. Neal Young (NHLBI) we have assessed the impact of parental haplo-insufficiency for telomere maintenance on the telomere length and function of genetically normal or abnormal offspring in these affected families. The outcome of studies in mice and humans demonstrated that inheritance of telomere length is not determined by species-specific homeostatic mechanisms but by stochastic factors. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells but its role in somatic cells remains to be understood. In recent studies we have identified an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed Tert heterozygous knockout mice (mTert +/-) for 26 generations during which time there was progressive shortening of telomeres and obtained primary skin fibroblasts from mTert +/+ and mTert -/- progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations both mTert +/+ and mTert -/- fibroblasts showed comparable and extremely short telomere length. However mTert -/- cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than mTert +/+ cells. Furthermore an evident upregulation of TERT expression was detected in mTert +/+ cells at the pre-senescence stage. Moreover removal or downregulation of TERT expression in mTert +/+ and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated mTert -/- phenotypes of accelerated senescence and transformation and overexpression of TERT in mTert -/- cells rescued these phenotypes. Together this study suggests that TERT has a previously under-appreciated protective role in buffering senescence stresses due to short dysfunctional telomeres and preventing malignant transformation. Cell survival and proliferation are also regulated by the p53 tumor suppressor molecule. Ataxia-telangiectasia mutated (ATM) is a kinase that plays a central role in maintaining genomic integrity. In both humans and mice ATM deficiency is associated with an increased incidence of lymphoid cancers. We asked if ATM plays a more general role in preventing non-T cell malignancies by breeding mice that were both ATM-and T cell-deficient. This model removes T cells as targets for lymphomagenesis as well as eliminating T cell-dependent immune surveillance. These mice exclusively develop early onset IgM+ B cell lymphomas that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B cell lymphomas (DLBCL). Tumors express clonal as well as emerging IghV hypermutation and express AID but B lymphoma development is independent of AID occurring at equal frequency in AID knockout mice. These ATM-deficient lymphomas show considerable chromosomal instability with a recurrent amplification of a 4.48Mb region on chromosome 18 (MMU18) orthologous to a region amplified in some cases of human ABC-DLBCL and containing Malt1 in the region of highest amplification. Importantly these lymphomas also depend on NF-kB MALT1 and BCR signaling for survival. Gene expression analysis revealed strong similarities between these mouse lymphomas and human ABC-DLBCL. This study reveals that ATM is required to prevent the development of B cell lymphomas that model human ABC-DLBCL and identifies an unappreciated role of T cells in preventing the emergence of these tumors. Studies now in progress are characterizing the pathways that mediate transformation of the T cell thymic lymphomas in ATM-deficient mice. We had previously reported that thymic T cell lymphomas develop in mice that are deficient in RAG-1 or RAG-2 recombinase in addition to ATM deficiency. These findings contrast to the absence of T cell lymphomas in mice double deficient in ATM and CD3e. This suggests the possibility that CD3e-containing complex independent of rearranged TCR gene products is required for lymphomagenesis. Additional studies now in progress are testing the requirement for components of the prototypic TCR/pre-TCR signal pathways such as LAT in development of lymphomas. The requirements for survival and proliferation of ATM-deficient T cell lymphomas have in fact not been fully elucidated. We have therefore initiated studies of the genetic and epigenetic changes in these lymphomas and their dependence on defined signaling pathways. Initial findings have included a universal defect in the phosphatase PTEN through genetic/non-genetic mechanisms that vary from tumor to tumor. Consistent with loss of PTEN activity we have observed activation of the AKT pathway and concomitant susceptibility of lymphomas to inhibitors of AKT activity. These findings will inform the underlying biology of T cell transformation with potential relevance to clinical approaches to human T cell malignancies. Lentiviral shRNA knockdown of targets including CD3e and LAT are in progress to test the requirements for TCR signaling pathways in survival of ATM-deficient T cell lymphomas. Initial results have demonstrated that thymic lymphomas which develop in ATM-deficient mice comprise two distinct subsets which differ in expression of TCR/pre-TCR components in gene expression assessed by RT-PCR and in susceptibility to in vitro survival by inhibition and shRNA knockdown of CD3e. These findings provide a basis for translation to categorization and treatment of subsets of human T cell lymphomas. 38993 +No NIH Category available Asthma;Autoimmune Diseases;Autoimmunity;CCR;Cell Transplantation;Cell division;Cells;Childhood;Clinical;Clinical Trials;Code;Dermatitis;Diabetes Mellitus;Disease;Drug Combinations;Genetic Polymorphism;Goals;Health;Human;Hydrogels;IL7 gene;IgG1;Immune;Immune system;Immunologic Deficiency Syndromes;Immunologic Stimulation;Immunotherapy;In Vitro;Interleukin 7 Receptor;Leukemic Cell;Lymphoblastic Leukemia;Lymphocyte Count;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Methods;Monoclonal Antibodies;Multiple Sclerosis;Mus;Mutate;Neoplasms;Pathway interactions;Patients;Pharmaceutical Preparations;Reaction;Receptor Signaling;Reporting;Sepsis;Signal Transduction;Stem cell transplant;T-Cell Development;Texas;Therapeutic;antagonist;antibody-dependent cell cytotoxicity;chemotherapy;cytokine;improved;leukemia;mortality;mutant;receptor;relapse patients;secondary infection;septic patients Cytokines and T Cell Development n/a NCI 10925976 1ZIABC009287-39 1 ZIA BC 9287 39 6569217 "DURUM, SCOTT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1514192 NCI The IL-7 pathway is critical for regulating the number of lymphocytes as has been shown in humans as well as in mice. We and our collaborators recently showed that the IL-7 receptor is mutated in pediatric lymphocytic leukemia and the mutant receptors drive cell division. We developed a panel of monoclonal antibodies against mutant receptors all of which also react with normal receptors. These mouse monoclonals have been chimerized with human IgG1 to optimize antibody-dependent cell-mediated cytotoxicity. These monoclonals are effective as single agents in treating human leukemia cells transplanted into mice. A clinical trial is being developed together with the Fannin Group and Baylor Medical Center in Houston Texas and will also involve CCR. Pediatric lymphocytic leukemia patients that relapsed following chemotherapy will be treated with our monoclonal antibodies. This clinical trial is expected to begin within one year. In addition to leukemias the IL-7 pathway has also been implicated in other neoplasias including lung cancer and we aim to explore treatment of these other cancers with our monoclonal antibodies. Using a different approach we recently reported that drugs which block signaling from the IL-7 receptor combined with drugs that block the Ras pathway are effective in killing leukemia cells in vitro and in mice. These drug combinations will be evaluated for treating patients. The same monoclonal antibodies and drugs will also be evaluated in autoimmune diseases. It was previously found by others that a polymorphism in the coding region of IL-7 receptor predisposes to autoimmune diseases. We recently found that this polymorphism regulates the strength of signal by the receptor offering promise for inhibiting these signals in autoimmunity. Therefore antagonists of the IL-7 pathway may be effective in autoimmunity and we are exploring this possibility. While blocking the IL-7 pathway has promise in autoimmunity and cancer IL-7 itself has therapeutic potential in clinical settings that could benefit from its potent activities in stimulating the immune system. Together with collaborators we recently reported results of a small clinical trial in sepsis patients showing that IL-7 effectively rescues immune cells that are severely suppressed. A larger trial in sepsis patients is planned. There is a great need for improved treatment of these patients who suffer high mortality from secondary infections. In another project together with collaborators at NCI we developed a new method for delivering IL-7 that is incorporated in a slow-release hydrogel. We are evaluating this material for improving immunotherapy because it greatly improves transfer of immune cells. 1514192 +No NIH Category available Affect;Affinity;Antibody Affinity;Antibody Formation;Antibody Response;Antigen Presentation;Antigen-Presenting Cells;Antigens;Appearance;Autoimmune Diseases;Autoimmunity;B-Cell Activation;B-Lymphocytes;Binding Sites;CD28 gene;CD4 Positive T Lymphocytes;CD8B1 gene;CRISPR/Cas technology;Cell Communication;Cell surface;Cells;Critical Pathways;Cytoplasmic Tail;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Dependence;Development;Disease;Disease model;Event;Experimental Autoimmune Encephalomyelitis;General Population;Generations;Genetic Models;Helper-Inducer T-Lymphocyte;Human;Humoral Immunities;Immune Sera;Immunoglobulin Class Switching;Intervention;Ligands;Lymphoid Cell;Mediating;Modeling;Molecular;Mouse Strains;Mucous Membrane;Multiple Sclerosis;Mus;Myeloid Cells;Pathogenesis;Pathogenicity;Pathway interactions;Peripheral;Phase;Play;Population;Predisposition;Process;Productivity;Proliferating;Recombinants;Regulation;Reporting;Role;Severities;Signal Transduction;Specificity;Structure of germinal center of lymph node;T memory cell;T-Cell Activation;T-Cell Development;T-Cell Proliferation;T-Lymphocyte;TNFRSF5 gene;TNFSF5 gene;TP53 gene;Thymic epithelial cell;Thymus Gland;antigen-specific T cells;conditional knockout;cytokine;draining lymph node;experimental study;human model;in vivo;insight;mouse genetics;mouse model;mutant;novel;receptor;response;thymocyte;vaccine response Receptor Mediated T and B Cell Activation n/a NCI 10925974 1ZIABC009281-37 1 ZIA BC 9281 37 2405210 "HODES, RICHARD J." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 623877 NCI We investigated the function of tumor suppressor p53 in regulating proliferation and function of T lymphocytes. These studies elucidate a critical role of p53 as a negative regulator of T cell proliferation. It is the termination of p53 elevation by TCR signaling that allows proliferative responses to occur enforcing antigen specificity. Preliminary studies of p53 effect on antigen-inexperienced and memory T cell repertoire have strongly suggested that p53 affects the threshold of TCR signaling required for activation of unprimed T cells by specific antigen and their subsequent differentiation into memory T cells. p53 thus appears to be an important regulator of antigen-specific T cell activation and in vivo response proliferation and differentiation. T cell-dependent germinal center (GC) responses require coordinated interactions of T cells with two distinct antigen-presenting cell populations (APCs) B cells and dendritic cells (DCs) in the presence of B7- and CD40-dependent costimulatory pathways. Conventional models describe the expression of both of these costimulatory molecules on the same APC both for T cell presentation and for cross-regulation of B7 and CD40 expression. Here we report that contrary to the conventional paradigm cellular requirements for B7 and CD40 expression were distinct for GC TFH GC B cell and high affinity antibody responses. B7 expression was required on DCs but not on B cells while CD40 was required on B cells but not DCs; and there was in fact no requirement for co-expression of B7 and CD40 on the same cell for GC responses. Our findings thus identify a much revised model for costimulatory function in the GC response with crucial and distinct contributions of B7- and CD40-dependent pathways expressed by distinct APC populations. T cell-dependent germinal center (GC) responses require coordinated interactions of T cells with two distinct antigen-presenting cell populations (APCs)-B cells and dendritic cells (DCs)-in the presence of B7- and CD40-dependent costimulatory pathways. T-APC interactions with both populations are generally considered to depend on similar molecular mechanisms including the involvement of these two costimulatory receptor-ligand pairs but direct assessment of the role of each pathway in germinal center-dependent adaptive responses has not been conducted. Here we have utilized models that enable the selective elimination of CD28-B7 and CD40-CD40L signaling during T-DC vs. T-B antigen-driven interactions to probe this issue. In contrast to prevailing views that both pathways are critical for productive T-dependent humoral immunity at both the early (T-DC) and late (T-B) phases of the response we found that the cellular requirements for B7 and CD40 expression were distinct. B7 expression was required on DCs but not on B cells while CD40 was required on B cells but not DCs. These data emphasize the emerging evidence that distinct molecular rules apply to CD4+ T cell-myeloid cell and CD4+ T cell-lymphoid cell interactions with important implications for understanding how to optimize or inhibit these events to promote vaccine responses or limit autoimmunity To further elucidate the role of CD40-CD40L interactions in multiple T cell-developmental and functional events we have generated unique mouse genetic models. To analyze the role of signaling through CD40 on diverse cell populations we have produced by CRISPR-Cas9 a set of CD40 cytoplasmic domain mutants that disrupt putative binding sites for TRAFs 23 and 6 and have generated initial data indicating differential dependence of these cytoplasmic domains for diverse functions including B cell germinal center responses Ig class switching and affinity maturation; susceptibility to experimental autoimmune encephalomyelitis (EAE); in vivo T cell cytokine responses; and iNKT cell selection. Costimulatory CD40 plays an essential role in autoimmune disease models including EAE a murine model of human multiple sclerosis (MS). However the mechanism underlying CD40 function are not well defined in these processes. Conditional knockout of CD40 on either dendritic cells (DCs) or B cells led to profoundly reduced severity of EAE induced by recombinant human MOG (rhMOG). CD40 expression on DCs but not on B cells was required for priming of pathogenic T helper (Th) cells in peripheral draining lymph nodes and for appearance of these pathogenic T cells in the CNS. In marked contrast CD40 on B cells but not on DCs was essential for class-switched MOG-specific antibody production. The distinct function of CD40 on B cells and DC was confirmed by the ability of transferred MOG-immune serum to restore sensitivity to EAE in mice lacking CD40 on B cells but not in mice lacking CD40 on DC. Thus CD40 expressed on B cells and on DC provides distinct and complementary pathways essential for EAE pathogenesis providing multiple targets for intervention in EAE and potentially for MS and other autoimmune diseases. Our studies of EAE have identified requirements for CD40 expression by B cells and DC for distinct functions in disease induction. They have further identified requirements for distinct cytoplasmic domains of CD40 in EAE. To determine CD40L function we are in the process of generating mutants that express only cell surface or only secreted forms of CD40L. Invariant natural killer T (iNKT) cells develop in the thymus where iNKT cell development depends on TCR recognition of CD1d ligand on CD4/CD8 double positive thymocytes. We previously reported that B7-CD28 co-stimulation is required for thymic iNKT cell development while underlying cellular and molecular mechanisms are largely not understood. Here we report the unexpected finding that CD28 expression on CD1d expressing antigen presenting T cells is required for thymic iNKT cell development. Mechanistically antigen-presenting T cells provide costimulation through a novel mechanism acquiring B7 molecule via CD28-dependent trogocytosis from B7-expressing thymic epithelial cell DC and B cells and providing critical B7 co-stimulation to developing iNKT cells. Thus these studies demonstrate a previously unappreciated mechanism of B7 co-stimulation in thymic T cell development by antigen-presenting T cells. We have most recently identified an additional mechanism of iNKT regulation demonstrating a role for p53 selectively in generation of the iNKT17 subset. We have in addition initiated studies of generation of mucosal-associated invariant (MAIT) cells another non-conventional T cell population with semi-invariant TCR expression. Initial findings include a functional role of B7 costimulation in thymic MAIT cell generation. 623877 +No NIH Category available Address;Affect;Algorithms;Amino Acids;Antigen-Presenting Cells;Antigens;Autoantigens;Autoimmunity;B-Lymphocytes;CD28 gene;CD4 Positive T Lymphocytes;CD40 Ligand;CD80 gene;CD86 gene;CD8B1 gene;Cell physiology;Cells;Characteristics;Classification;Clonal Deletion;Dangerousness;Defect;Dendritic Cells;Development;Epithelial Cells;Generations;High-Throughput Nucleotide Sequencing;Immunity;Knockout Mice;Machine Learning;Maintenance;Mature Thymocyte;Mediating;Mediator;Methods;Molecular;Mouse Strains;Mus;NF-kappa B;Organogenesis;Pathway interactions;Peptide/MHC Complex;Peripheral;Play;Population;Prevention;Process;Property;Regulatory T-Lymphocyte;Repression;Role;Self Tolerance;Shapes;Signal Transduction;Specificity;T cell regulation;T cell response;T-Lymphocyte;TNFRSF5 gene;TNFSF5 gene;Testing;Thymic epithelial cell;Thymus Gland;Time;Tissues;Transgenic Mice;antigen-specific T cells;autoreactive T cell;autoreactivity;cancer cell;cell type;central tolerance;conditional knockout;cytokine;differential expression;machine learning algorithm;novel;pathogen;receptor;response;thymocyte;transcriptome sequencing Analysis of the T Cell Repertoire n/a NCI 10925972 1ZIABC009265-41 1 ZIA BC 9265 41 2405210 "HODES, RICHARD J." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 116976 NCI "Mice with genetically altered expression of costimulatory molecules CD80 (B7-1) CD86 (B7-2) and CD40 or of the costimulatory receptors CD28 and CD154 (CD40 ligand) have been analyzed for thymic development and T cell repertoire. Our findings identify a previously unappreciated role of redundant costimulatory pathways mediating an essential function in thymic development. The effect of these costimulatory pathways on selection of the T cell repertoire was studied in parallel. Two pathways of negative selection have been identified. One pathway is CD40L-dependent and acts at a relatively early stage in intra-thymic development and is mediated by a non-cell-autonomous mechanism. The second is CD40L-independent and occurs later in intra-thymic or post-thymic development. Interestingly we have observed that when negative selection is abrogated by inactivation of the CD40L pathway functional self tolerance is maintained by a non-deletional mechanism. This non-deletional tolerance is mediated by a CD28-dependent pathway. Thus redundant pathways exist to protect against self reactivity in the thymus and disruption of both C40L (deletional) and CD28 (non-deletional) mechanisms of self tolerance results in a population of highly self-reactive thymic T cells. We have analyzed the signals that mediate T cell-epithelial cell cross-talk during thymic development. We have observed that CD28 costimulation is essential for optimal induction of TNFab in single-positive (SP) thymocytes and that combined defects in CD40-CD40L and TNFab pathways result in defects in medullary thymic eipthelial cell (mTEC) development that are similar to those in combined CD40-CD40L and CD28-B7 disruption and are in fact as profound as those seen in complete absence of mature SP TCRab thymocytes. These findings indicate a novel role for CD28-B7 in addition to other mediators of T cell-TEC cross-talk and demonstrate that any and all signals provided by mature thymocytes for mTEC development are provided by activation of RelB-dependent alternative NFkB signaling. Generation of the T cell repertoire requires positive selection of cells expressing TCR capable of recognizing foreign antigens but negatively selected to eliminate cells with potentially dangerous specificity against normal self antigens. The function of costimulatory CD28-B7 and CD40-CD40L pathways in this repertoire selection has not been fully elucidated. We have initiated studies using peptide-MHC tetramers to identify antigen-specific T cells and have generated the first conditional knockouts for B7 and CD40 to analyze cell type-specific function of these costimulatory pathways in repertoire selection. Generation of the T cell repertoire requires positive selection of cells expressing TCR capable of recognizing foreign antigens but negatively selected to eliminate cells with potentially dangerous specificity against normal self antigens. The function of costimulatory CD28-B7 and CD40-CD40L pathways in this repertoire selection has not been fully elucidated. We have used peptide-MHC tetramers to identify antigen-specific T cells and have generated the first conditional knockouts for B7 and CD40 to analyze cell type-specific function of these costimulatory pathways in repertoire selection.Thymic central tolerance is critical for the prevention of autoimmunity. However the underlying molecular and cellular mechanisms mediating this tolerance are not fully understood. We have analyzed the requirements for B7-CD28 co-stimulation and for B7 expression by specific antigen-presenting cell (APC) types for thymic clonal deletion and Treg cell generation of endogenous tissue-restricted-antigen (TRA)-specific thymocytes. We have employed p-MHC tetramers to identify and track T cells with specificity for specific endogenous tissue-restricted antigens and our recently generated conditional B7 knockout mouse strains to identify APC requirements for Treg generation and for clonal deletion of TRA-reactive cells. Our findings determined that: 1) both clonal deletion and Treg cell generation of TRA-specific thymocytes are B7-CD28-dependent; 2) clonal deletion and Treg cell generation differ in their CD28 signaling domain requirements ; and 3) the role of B7-expressing dendritic cells (DC) B cells and thymic epithelial cells (TEC) can differ in B7-dependent clonal deletion versus Treg cell generation. In the absence of B7-CD28 co-stimulation mature TRA-specific Tconv cells populated the periphery in increased numbers and were capable of mediating destructive autoimmunity. Our findings reveal a previously unappreciated role of B7-CD28 co-stimulation in shaping the T cell repertoire through thymic clonal deletion and Treg cell generation with distinct requirements of CD28 signaling and B7-expressing APC. The ability to generate a rapid and sustained T cell response to external pathogens and transformed cancer cells is essential for protection of the host. At the same time deletion of autoreactive T cells during development and repression of excessive or autoreactive responses in peripheral tissues is essential to proper T cell protective function. This duality in regulation of T cell function is accomplished by two types of T cells: conventional T cells (Tconv) that provide ""helper"" (CD4+) and ""killer"" (CD8+) functions and regulatory T cells (Treg) that control Tconv T cell-dependent responses. Treg cells have been assigned to two subsets based on the origin of their generation: thymic (or natural) Treg (tTreg) that develop in the thymus and peripheral Treg (pTreg) generated in periphery from Tconv cells under specific conditions. The development of tTreg appears to require both TCR and other factors such as costimulatory receptors and cytokines but the precise mechanisms of tTreg generation have not been fully elucidated. We addressed the role of TCR sequence in determining whether T cells develop into tTreg or Tconv lineages. We carried out a comprehensive comparison of both TCRa and TCRb sequences of thymic tTreg and Tconv cells using a UMI based 5' smart switch method. This comparison revealed that although many sequences were unique to either Treg or Tconv a substantial proportion of TCaR (14-20%) and TCRb (8-22%) sequences from tTreg were also found in Tconv cells of two normal mouse strains. TCRa analysis of a TCRb transgenic mouse line revealed an even higher proportion (71%) of sequences found in tTreg that were also found in Tconv cells. Interestingly these shared TCRa clonotypes that were common to tTreg and Tconv cells were significantly more abundant than non-shared TCRa sequences of tTreg and Tconv cells. Finally we used machine learning to develop an algorithm that was capable of distinguishing non-shared TCRa and TCRb sequences expressed by tTreg from those of Tconv cells and in addition found that specific amino acid trimers were differentially expressed in either tTreg or Tconv cells. Taken together our findings identify TCR sequence characteristics that bias to tTreg or Tconv fate in addition to factors that can drive cells with identical TCR sequence into either Tconv or tTreg lineages. These findings identify two populations of tTreg one in which Treg fate is determined by unique properties of the TCR and another with TCR properties characteristic of Tconv cells with tTreg determined by TCR-independent factors. Ongoing studies combining single cell TCR expression and RNAseq will characterize in detail the effect of costimulation on repertoire selection." 116976 +No NIH Category available Affect;Alleles;Amino Acid Motifs;Anchorage-Independent Growth;Attenuated;Binding;Binding Sites;Biological;Biological Process;CDK5 gene;Cells;Code;Cytoplasm;DLC1 gene;DLEC1 gene;Data;EZH2 gene;Epigenetic Process;Focal Adhesion Kinase 1;Gene Deletion;Gene Expression;Genes;Goals;Growth;Guanosine Triphosphate;Half-Life;Histone H3;In Vitro;Intervention;Lesion;Ligands;Lipids;Malignant Neoplasms;Methylation;Missense Mutation;Molecular Biology;Molecular Conformation;Mutate;N-terminal;Neoplasms;Nuclear Protein;Oncogenes;Pathogenesis;Phosphorylation;Phosphotransferases;Physiological;Point Mutation;Post-Translational Protein Processing;Process;Protein Methyltransferases;Proteins;Proto-Oncogene Proteins c-akt;Receptor Protein-Tyrosine Kinases;Regulation;Research;Role;Serine;Signaling Molecule;Talin;The Cancer Genome Atlas;Therapeutic;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tyrosine;antitumor effect;attenuation;cancer type;caveolin 1;cell motility;experimental analysis;histone methylation;in vivo;inhibitor;kinase inhibitor;mRNA Expression;multicatalytic endopeptidase complex;mutant;non-genetic;overexpression;rho;rho GTPase-activating protein;src-Family Kinases;tensin;tumor;tumor xenograft;validation studies Tumor gene expression in vitro and in vivo n/a NCI 10925970 1ZIABC008905-42 1 ZIA BC 8905 42 2093670 "LOWY, DOUGLAS R." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1274339 NCI Our growth regulation research has been concerned with oncogenes as positive regulators and tumor suppressor genes as negative regulators of normal and neoplastic growth. The main current project is focused on the molecular biology of the tumor suppressor gene DLC1 including the targets that regulate it and the targets that it regulates. DLC1 is inactivated frequently in a wide range of tumors but many aspects of its mechanism of action remain incompletely understood. DLC1 negatively regulates Rho via its Rho-GAP activity and also encodes other activities. A major hypothesis is that DLC1 is frequently inactivated in cancer because it encodes a biologically important multifunctional protein. In support of this possibility we have previously determined that DLC1 interacts with: 1) the tensin proteins via an N-terminal region of DLC1 for which no function had been previously identified; 2) focal adhesion kinase (FAK) and talin via a shared 8 amino acid motif; and 3) caveolin-1 (CAV-1) via the StAR-related lipid transfer (START) domain near the C-terminus of DLC1. DLC1 mutant analysis indicated that the binding sites for each of these interactions contributed to the growth suppressor function of DLC1 but that reduced binding seen with the mutants did not affect in vivo Rho-GAP activity of DLC1. These studies validate the hypothesis that DLC1 is a multifunctional protein whose biological activity depends both on its Rho-GAP activity and its ability to bind a variety of signaling molecules. We have also evaluated 12 cancer types in TCGA for the presence of point mutations in DLC1 and 9 other Rho-GAPs. The results indicate that DLC1 is the Rho-GAP that is mutated most frequently with 5-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore 20-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated seven of nine mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Point mutations in DLC1 were scattered throughout the coding sequences of the gene implying that important biological functions are present throughout the protein. These results indicate that point mutation in DLC1 is an important mechanism for its decreased function in cancer in addition to gene deletion and epigenetic or other non-genetic changes. We have characterized how post-translational modifications of DLC1 especially phosphorylations may affect its activity. We first identified CDK5 a cytoplasmic kinase whose physiologic role promotes differentiation as a major activator of DLC1 which occurs via CDK5 phosphorylation of 4 serines in DLC1. When these serines which are located N-terminal to the RHO-GAP domain of DLC1 are not phosphorylated the N-terminus binds to the Rho-GAP domain which places DLC1 in a closed inactive conformation. When the serines are phosphorylated it decreases the interaction of the N-terminus with the Rho-GAP domain which places DLC1 in an open active conformation. AKT is another kinase that directly phosphorylates DLC1 on 3 serines located N-terminal to the Rho-GAP domain. The effects of AKT antagonize those of CDK5 in that the AKT phosphorylations attenuate the Rho-GAP and tumor suppressor activities of DLC1 by changing DLC1 from an open active configuration to a closed inactive configuration. AKT lies downstream from receptor tyrosine kinases (RTKs) and our data indicate that increased Rho-GTP following stimulation of cells with RTK ligands is attributable to the activation of AKT and its attenuation of DLC1. We also identified SRC family kinases (SFKs) as direct targets for phosphorylating DLC1 on two tyrosines which attenuate the RHO-GAP and tumor suppressor activities of DLC1. One tyrosine is located in the RHO-GAP domain and its phosphorylation by SFKs reduces the RHO-GAP function of DLC1. The other tyrosine is located near the sequence required for binding tensin and its phosphorylation reduces tensin binding. The findings with AKT and SFKs may have therapeutic potential as treatment of tumor xenografts with AKT and/or SFK inhibitors has much greater antitumor activity against tumors that express DLC1 compared with isogenic tumors that do not express DLC1. The high antitumor activity from AKT and/or SFK inhibition is associated with loss of phosphorylation of the DLC1 by AKT and/or SFK together with reactivation of the RHO-GAP and tumor suppressor activities of DLC1. We have identified methylation of DLC1 as yet another biologically important post-translational modification. The methylation is attributable to cytoplasmic EZH2 a protein methylase that is overexpressed in many cancers and known mainly as a nuclear protein that regulates mRNA expression because it methylates Histone-H3. DLC1 methylation enables ubiquitnation of the methylated residue and proteasome-dependent degradation of DLC1. This multistep process means DLC1 has a shortened half-life in many tumors and is even absent in some. This process is reversible and inhibition of EZH2 ubiqutination or the proteasome can stabilize the protein. For EZH2 this is conceptually distinct from using its inhibition to change mRNA expression. By itself increasing DLC1 protein levels does not have a major effect on growth regulation but adding an AKT inhibitor and/or SRC inhibitor strongly reduces growth. This effect depends on DLC1 protein and is more than a correlation as disrupting the DLC1 alleles abolishes most of the antitumor effect. 1274339 +No NIH Category available ADP ribosylation;Antibodies;Antibody Specificity;Antibody-drug conjugates;Antineoplastic Agents;Apoptosis;Apoptotic;BCL-2 Protein;Bacteria;Bacterial Toxins;Binding;Biological Response Modifier Therapy;Cancer Model;Cells;Cessation of life;Cholera Toxin;Clinic;Complement;Cytosol;Cytotoxic agent;Data;Drug Screening;Drug resistance;Effectiveness;Enzymes;Epidermal Growth Factor Receptor;Eukaryotic Cell;Exhibits;Exotoxins;Genes;Goals;Human;Immunoglobulin Fragments;Immunotoxins;Inflammatory;Investigation;KDR gene;Link;Malignant Neoplasms;Mammalian Cell;Molecular Weight;Monoclonal Antibodies;Nature;Normal Cell;Pathway interactions;Peptide Elongation Factor 2;Pharmaceutical Preparations;Population;Protein Synthesis Inhibition;Proteins;Pseudomonas;RNA Interference;Recombinants;Reporting;Resistance;Toxin;Vibrio cholerae;Xenograft Model;cancer cell;cancer therapy;cell growth;cell killing;chemotherapy;colon cancer cell line;cytotoxic;density;design;experimental study;gene product;in vivo;inhibitor;mimetics;mutant;neutralizing antibody;pre-clinical;preclinical development;programs;receptor;response;screening;targeted agent;targeted treatment;therapy development;tissue culture;toxin V;whole genome Bio-Therapies for the Treatment of Cancer n/a NCI 10925969 1ZIABC008757-36 1 ZIA BC 8757 36 6569148 "FITZGERALD, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1415385 NCI We use bacterial toxins as killing agents to eliminate cancer cells. To accomplish this we modify the toxin so it no longer binds via its own cell-binding domain and substitute in place of the binding domain a monoclonal antibody. The antibody is chosen to bind cancer cells preferentially over normal cells. These toxin-antibody molecules are called immunotoxins. Immunotoxins are promising but imperfect anticancer agents. Our goal is to understand the interaction of various toxins with eukaryotic cells and use this information to design better agents for treating cancer. To study interactions we add toxins to mammalian cells and study the pathway of death. In tracking the killing of cancer cells by immunotoxins we made the observation that cells grown to high density are resistant to killing. We wish to understand this phenomenon and determine its relevance for cancer therapy in general. A convenient and potentially useful way to study cell-killing pathways is to use RNA interference to identify pathways that participate in toxin delivery to the cytosol - where it acts. Recently we initiated studies with a newly described toxin from V cholera called Vibrio Cholera Exotoxin (CET). This toxin is related to the exotoxin from Pseudomonas exhibiting about 50% identity in selected domains (domains II and III). However antibodies that neutralize the exotoxin from Pseudomonas do not neutralize CET despite the close similarity. Truncated versions of Pseudomonas Exotoxin (PE) have been fused with antibody fragments to produce potent cytotoxic agents termed recombinant immunotoxins. These agents are targeted to kill cancer cells based on the binding specificity of the antibody fragment. Potency is derived from the enzymatic nature of the toxin as it translocates to the cytosol ADP-ribosylates elongation factor 2 and terminates the synthesis of new cellular protein. Most prior investigations reported that PE and PE-immunotoxins kill cells via apoptosis. Here we report that PE and PE immunotoxin inhibit protein synthesis and cell growth of colon cancer cell lines but do not provoke an apoptotic response. However the addition of the BH3-only mimetic ABT-737 in combination with the immunotoxin produces a profound apoptotic response in these cells that neither agent alone can achieve. Tissue culture data for ABT-737 activity has now been confirmed in xenograft models confirming this approach as a viable approach for overcoming resistance to immunotoxin action. We are conducting whole genome screens using RNAi agents to silence all human genes. Immunotoxin is then added to RNAi-treated cells with the goal of identifying genes that inhibit immunotoxin action. These inhibitory genes are identified because when silenced cells display greater sensitivity to immunotoxin action. Likewise we conduct large scale drug screens: again to identify and inhibit gene products that reduce the effectiveness of immunotoxin action. These are likely to include gene products that interfere with cell killing and might also be useful in reversing some forms of drug resistance to chemotherapy. Our overarching goal is to make our immunotoxin program more effective by eliminating the cellular barriers to targeted therapy. Recently we have investigated the utility of using JAK/STAT inhibitors to enhance immunotoxin activity in vivo. The use of tofacitinib has produced promising results with several immunotoxins and an antibody-drug conjugate. The mechanism of enhancement is currently linked to changes in the population of inflammatory cells. We have also identified VEGFR inhibitors as agents that routinely enhance immunotoxin killing in several cancer models. Here the mechanism is less clear but we continue to study the problem with a view to establishing optimal combinations for enhancing immunotoxin activity. We produced seven monoclonal antibodies to EGFR. One of these has proved particularly useful and is now being used to generate antibody drug conjugates. 1415385 +No NIH Category available Address;Anemia;Apoptosis;Atrophic;Attention deficit hyperactivity disorder;Attenuated;Binding;Biological;Biological Assay;Biology;Bone Development;Calmodulin;Caveolae;Clinical;Colon;Communication;Complex;Constipation;Defect;Development;Disease;Electrolytes;Epithelial Cells;Exhibits;Feces;Female;Fibrosis;Gap Junctions;Gene Expression;Gene Expression Regulation;Genes;Genomics;Gland;Growth;Health;Histologic;Homeostasis;Human;Infertility;Interstitial Cell of Cajal;Laboratories;Learning;Lymphocyte Function;Maintenance;Mediating;Metabolic;Molecular;Morphology;Mus;Muscle Cells;Muscle Fibers;Mutant Strains Mice;Mutation;Myosin Light Chain Kinase;Myosin Light Chains;Nuclear;Nuclear Hormone Receptors;Patients;Phosphorylation;Proliferating;Protein Isoforms;Proto-Oncogene Protein c-kit;Publishing;Rectum;Regulation;Reporting;Reproduction;Research;Resistance;Role;Serum;Signal Transduction;Smooth Muscle;Symptoms;THRA gene;THRB gene;Thyroid Gland;Thyroid Hormone Receptor;Thyroid Hormone Receptor Gene;Thyroid Hormones;Thyroid hormone receptor alpha;Thyrotropin;Time;Tissues;Transcriptional Regulation;Transmission Electron Microscopy;Uterus;Water;Western Blotting;fluorescence imaging;genetic corepressor;hearing impairment;hormone response element;human disease;in vivo;insight;lucifer yellow;mouse model;mutant;overexpression;recruit;rectal;small molecule;transcriptome sequencing Thyroid Hormone Nuclear Receptors in Health and Disease n/a NCI 10925966 1ZIABC008752-43 1 ZIA BC 8752 43 6569140 "CHENG, SHEUE-YANN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 930012 NCI 1.TRalpha1 mutants cause morphological and functional defects in mouse model of RTHalpha (Thra1PV/+ mice): We used histopathological analysis confocal fluorescence imaging transmission electron microscopy (TEM) and gene expression profiles to comprehensively analyze the colonic abnormalities of Thra1PV/+ mouse. We found a significant increase in colonic transit time and decrease stool water content in Thra1PV/+ mouse mimicking constipation as found in patients. TEM analysis revealed shorter muscle fibers with wider gap junctions between muscle cells fewer caveolae and hypoplastic interstitial cells of Cajal (ICC) in the rectal smooth muscles of Thra1PV/+ mice. These abnormal histological manifestations suggested defective intercellular transfer of small molecules electrolytes and signals for communication among muscles cells validated by Lucifer Yellow transferring assays. Expression of key smooth muscle contractility regulators such as calmodulin myosin light-chain kinase and phosphorylated myosin light chain was markedly lower and c-KIT signaling in ICC was attenuated resulting in decreased contractility of the rectal smooth muscles of Thra1PV/+ mice. Collectively these abnormal histopathological alterations and diminished contractility regulators led to the constipation exhibited in patients. This is the first demonstration that TRalpha mutants could act to cause abnormal rectum smooth muscle organization defects in intercellular exchange of small molecules and decreased expression of contractility regulators to weaken the contractility of rectal smooth muscles. These findings provide new insights into the molecular basis underlying constipation found in RTHalpha patients. These findings have been published in Thyroid (Kim et.al. 2023). 2.Defining the role of TRalpha mutants in uterus functions. Using Thra1PV/+ mice we found degenerated uterus with fibrosis in the mutant mice. The mutant uterus was atrophied with decreased proliferation increased apoptosis and reduction in the number of glands. RNA-seq analysis of the uterus showed major alterations in lymphocyte functions and signaling. RNA-seq analysis revealed IL-33 was highly elevated subsequently validated by RT/qPCR and western blot analysis. Immunohistochemical analysis showed that IL-33 was highly over-expressed in the epithelial cells. The findings that TRalpha mutants could cause degenerated uterus has broadened the scope of the biological impact of mutant actions. Elucidation of how TRalpha mutants cause uterus abnormalities will pave the way for further understanding of the important role of TRalpha in female reproduction biology. 930012 +No NIH Category available 3-Dimensional;Affect;Affinity;Architecture;Bacterial Chromosomes;Bacterial Physiology;Bacteriophage lambda;Bacteriophages;Base Pairing;Binding;Biochemical;Biological Models;Biology;Bundling;Cell Cycle;Cells;Chromatin Loop;Chromosome Structures;Chromosomes;Color;Complex;Computer Models;Cruciform DNA;Crystallography;DNA;DNA Binding;DNA Structure;DNA-Directed RNA Polymerase;Data;Development;Dissociation;Electrostatics;Environment;Escherichia coli;Eubacterium;Exhibits;Fluorescence Microscopy;Future;Gene Activation;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genetic;Genetic Transcription;Goals;Grain;HU Protein;Histones;Homeostasis;Image;In Vitro;Investigation;Ionic Strengths;K-18 conjugate;Kinetics;Label;Laboratories;Lysine;Lytic;Maintenance;Manuscripts;Maps;Measurement;Mediating;Microscopy;Modeling;Molecular;Molecular Biology;Mutate;Mutation;Operon;Pattern;Physiological;Physiological Processes;Play;Positioning Attribute;Proline;Property;Prophages;Proteins;Regulation;Repression;Research;Role;Site;Structure;Superhelical DNA;Surface;System;Systems Biology;Techniques;Therapeutic;Transcriptional Regulation;Visualization;Work;X-Ray Tomography;antimicrobial;antimicrobial drug;biophysical techniques;cancer cell;cell growth;design;developmental genetics;environmental adaptation;experimental study;fluidity;gene repression;inhibitor;inorganic phosphate;ionic bond;kinked DNA;mathematical methods;microbial;model organism;mutant;novel;pathogen;prevent;promoter;response;single molecule;small molecule;three dimensional structure;transcriptome;viscoelasticity Regulation of Gene Transcription n/a NCI 10925965 1ZIABC008751-43 1 ZIA BC 8751 43 6129912 "ADHYA, SANKAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1110488 NCI "Part A. Chromosome structure and function. From our studies of mechanisms of gene regulation we have previously proposed that the bacterial chromosome (nucleoid) has a condition dependent defined structure that dictates gene expression. HU is the most conserved nucleoid-associated protein in eubacteria but how it impacts global chromosome organization and gene expression is poorly understood. (i) Using single-molecule tracking we demonstrate that HU exhibits nonspecific weak and transitory interactions with the chromosomal DNA. These interactions are largely mediated by three conserved surface-exposed lysine residues (triK) which were previously shown to be responsible for nonspecific binding to DNA. The loss of these weak transitory interactions in a HUa(triKA) mutant results in an over-condensed and mis-segregated nucleoid. Mutating a conserved proline residue (P63A) in the HUa subunit deleting the HUb subunit or deleting nucleoid-associated naRNAs each previously implicated in HU's high-affinity binding to kinked or cruciform DNA leads to less dramatically altered interacting dynamics of HU compared to the HUa(triKA) mutant but highly expanded nucleoids. Our results suggest HU plays a dual role in maintaining proper nucleoid volume through its differential interactions with chromosomal DNA. On the one hand HU compacts the nucleoid through specific DNA structure-binding interactions. On the other hand it decondenses the nucleoid through many nonspecific weak and transitory interactions with the bulk chromosome. Such dynamic interactions may contribute to the viscoelastic properties and fluidity of the bacterial nucleoid to facilitate proper chromosome functions. (ii) By imaging of near-native unlabeled E. coli cells by soft X-ray tomography we showed that HU remodels nucleoids by promoting the formation of a dense condensed core surrounded by less condensed isolated domains. Nucleoid remodeling during cell growth and environmental adaptation correlate with pH and ionic strength controlled molecular switch that regulated HUaa dependent intermolecular DNA bundling. Through crystallographic and solution-based studies we show that these effects mechanistically rely on HUaa promiscuity in forming multiple electrostatically driven multimerization interfaces. Changes in DNA bundling consequently affects gene expression globally likely by constrained DNA supercoiling. Taken together our findings unveil a critical function of HU-DNA interaction in nucleoid remodeling that may serve as a general microbial mechanism for transcriptional regulation to synchronize genetic responses during the cell cycle and adapt to changing environments. (iii) We strived to elucidate how the chromosome's three-dimensional architecture is organized and maintained in bacterial cells. Using fluorescence microscopy techniques we are probing the organization of the E. coli chromosome by directly visualizing the positions of specifically labeled DNA sites within living cells. Using two orthogonal ParB - parS systems we were able to simultaneously label two DNA sites in two colors in the same E. coli strain. Our labeling strategy had a fixed locus as a control point in all strains and additionally had a 'moving' locus that maps the entire chromosome in coarse-grain. Data from our experiments preliminarily suggested that there is a correlation between the linear (genetic) distance separation between DNA sites and their spatial separation. Eventually with the help of computational modeling we hope to simulate the three-dimensional organization of the chromosome from a wealth of carefully conducted distance measurements between different DNA loci in living cells. (iv) We have additionally demonstrated separate physiological roles of specific and non-specific DNA binding of the histone-like protein HU in E. coli. A manuscript is being prepared. in bacterial physiology from maintenance of chromosome structure to regulation of gene transcription. HU is essential in many pathogens making it an attractive target for developing anti-microbial therapeutics. A mechanistic understanding of HU DNA binding and its regulation of physiological processes will aid in the design and development of small molecule HU inhibitors. We have used Escherichia coli as a model organism to investigate how HU interacts with chromosomal DNA and regulates various physiological processes. In E. coli HU binds to DNA in two ways: (i) with low affinity to any DNA (non-specific) through three surface-exposed lysine residues (K3 K18 and K83) that make ionic bonds with DNA phosphates; (ii) with high affinity to contorted DNA of given structures containing a pair of kinks (structure-specific) through conserved proline residues (P63) that mediate specific binding by inducing and/or stabilizing the kinks. We recently demonstrated that HU interacts with chromosomal DNA with rapid association/dissociation kinetics largely through its non-specific binding mediated by the lysine residues. This provides evidence that the overall association of HU to the chromosome is through non-specific binding. Incidentally HU is essential in many pathogens making it a target for developing anti-microbial drugs. A mechanistic understanding of HU DNA binding will aid in the design and development of HU inhibitors. Part B. Gene regulation in Bacteriophage Lambda and Gal operon: The current year we have made more progress in our work with phage Lambda. Investigation of RNA Polymerase & CI repressor Interactions . One of the best understood systems in genetic regulatory biology is the so called ""genetic switch"". This determines the choice the phage-encoded CI repressor makes by binding cooperatively to two tripartite operators OL (OL1 OL2 & OL3) and OR (OR1 OR2 & OR3) in a defined pattern. Transcription at two lytic promoters PL and PR is blocked while transcription at lysogenic promoter PRM is activated and repressed at low CI and high CI concentrations respectively. The autoregulation of PRM is dependent on the interaction of RNA polymerase (RNAP) binding to the PRM promoter and CI binding to OR2. By using a purified in vitro transcription system we analyzed the activation complex between RNAP at PRM and CI at OR2 by DNA and protein mutations. We inserted 5-bp or deleted 1-bp DNA between OR2 & OR3 to change the angular orientation and distance between RNAP and CI. We also mutated E34K of CI which interacts with RNAP during the activation of PRM. We obtained unexpected findings. First a 1-bp DNA deletion of -34A of PRM resulted in the repression of PRM at the same CI concentration for the repression of PL and PR. This repression is depending on DNA looping and the binding of CI to OR2. Second a 5-bp DNA insertion between the PRM promoter site and OR2 site resulted in the repression of PRM at the same CI concentration for the repression of PL and PR. Third mutating E34K of CI which is involved in the activation complex resulted in the repression of PRM at the same CI concentration for the repression of PL and PR. Finally DNA looping enhances PRM activation and repression. Conclusion: Disruption of the activation complex between RNAP at PRM and CI at OR2 by mutating CI or inserting or deleting base pair to change the angular orientation and distance between RNAP and CI led to the repression of PRM. These unexpected results suggest that maybe RNAP is creating negative contacts with CI at OR2 preventing RNAP from escaping and repressing PRM. Future studies are being conducted to understand the molecular mechanisms how these changes result in the repression of PRM. One attempt currently being pursued is to model the structure of a Prm-Ci-RNA polymerase ternary complex with wild type and different mutants DNA/proteins and inspect the feasibility of 'negative' contact between CI and RNA polymerase." 1110488 +No NIH Category available Acetylation;Affect;Alleles;Antibiotics;Area;Bacteria;Bacteria sigma factor KatF protein;Behavior;Binding;Biological Assay;C-terminal;Cell Communication;Cells;Collaborations;Complex;Development;Dissection;Distal;Equilibrium;Escherichia coli;Eukaryotic Cell;Face;Family;Genetic Screening;Goals;Growth;In Vitro;Investigation;Klebsiella;Laboratories;Mediating;Membrane;Messenger RNA;Metabolism;Molecular Chaperones;Mutation;Names;National Institute of Child Health and Human Development;Organism;Pathway interactions;Physiological;Play;Polyribonucleotide Nucleotidyltransferase;Porifera;Process;Protein Family;Proteins;Quality Control;RNA;RNA Binding;RNA Degradation;RNA Stability;Regulation;Regulon;Reporter;Resistance;Role;Series;Sigma Factor;Signal Transduction;Site;Small RNA;Stress;System;Translation Initiation;Untranslated RNA;Virulence Factors;Visit;Work;biological adaptation to stress;capsule;cell behavior;cell growth;endonuclease;falls;genetic regulatory protein;in vivo;insight;interest;mRNA Translation;member;mutant;novel;pathogenic bacteria;posttranscriptional;response;screening;small molecule;symbiont;tool;transcription factor Bacterial Functions Involved in Cell Growth Control n/a NCI 10925964 1ZIABC008714-46 1 ZIA BC 8714 46 2402881 "GOTTESMAN, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1180805 NCI Complex and rapidly adaptable regulatory networks allow bacteria such as E. coli to change metabolism to optimize growth and survival in mammalian hosts and outside of the host and in response to a variety of stresses. In the last twenty years the important roles of small non-coding RNAs in regulation in all organisms have been recognized. Our laboratory in collaboration with others undertook two global searches for non-coding RNAs in E. coli contributing significantly to the 100-200 regulatory RNAs that are now known. The majority of these small RNAs (sRNAs) bind tightly to the RNA chaperone Hfq. We and others have shown that sRNAs that bind tightly to Hfq act by pairing with multiple target mRNAs regulating stability and translation of the mRNA either positively or negatively although some of these sRNAs also have additional roles. Our lab has studied many of these sRNAs in detail. Each sRNA is regulated by different stress conditions suggesting that the sRNA plays an important role in adapting to stress. We have also examined the mechanism by which Hfq operates to allow sRNAs to act using in vivo studies of mutations in the RNA binding faces of Hfq. In a series of studies in collaboration with G. Storz (NICHD) and with S. Woodson (JHU) we have carried out in vivo and in vitro dissection of Hfq that has changed our understanding of how this protein acts with sRNAs. This work demonstrated that Hfq-dependent sRNAs fall into two classes defined by their behavior in different Hfq mutants. Class I sRNAs are rapidly degraded when used most likely dependent upon pairing; their targets bind to the distal face. Class II sRNAs are generally more stable than Class I sRNAs and their targets bind to rim sites in Hfq. These results help to explain previously observed competition between sRNAs differential effects of different hfq alleles on different sRNA:mRNA pairs and provide insights into regulatory networks. The C-terminus of E. coli Hfq (CTD) is unstructured and its role has been unclear. In collaboration with S. Woodson we defined in vivo and in vitro roles for the CTD in stabilization and release of Class II sRNAs. In collaboration with the lab of G. Storz we have examined the global effect of deleting the CTD of Hfq and find only subtle effects on RNA accumulation. However in combination with mutations on the RNA binding faces of Hfq loss of the CTD can have synergistic effects. Our results define two independent roles for the CTD one involved in reinforcing the distal face RNA binding activity of Hfq and the second defined by mutations at the C-terminal tip of Hfq. These different roles help to explain why previous studies came to conflicting conclusions about the role of the CTD. In a genetic screen using a recently developed bifunctional fluorescent reporter we have identified novel regulators of sRNA stability and function including a new RNA sponge and two previously uncharacterized proteins. One of the new proteins the founding member of a family of proteins highly conserved in bacteria specifically targets a subset of sRNAs for degradation. It requires polynucleotide phosphorylase (PNPase) to do this suggesting that it may work in a complex with the PNPase. Work by others demonstrated a novel endonuclease activity for this family of proteins. The other new protein has global rather than sRNA-specific effects on sRNA-based regulation when overproduced.. Unexpectedly this protein a member of the broad transacetylase family. Our results show that this protein now named HqbA directly interacts with the distal face of Hfqhelping in the quality control of RNA binding. Because this effect is independent of acetylation the results suggest this is a bifunctional protein and its discovery suggests that yet other such previously unknown regulators may exist. Overall we have developed highly efficient in vivo tools for studying sRNAs and the networks they reside in. Our focus is increasingly on the role of the sRNAs in complex bacterial behavior investigations into the mechanism of sRNA function and dissecting of novel mechanisms for regulating translation initiation. We have also returned to our interest in the regulatory cascade affecting capsule synthesis in a collaboration with S. Buchanan and NCATs. The proteins in this cascade also regulate aspects of the bacterial response to membrane stress are needed for in vivo establishment of commensal growth and are important virulence factors in Klebsiella. Studies on the Interactions of the components of the regulatory cascade have changed our understanding of signal transduction through this system demonstrating that a critical negative regulator of signaling acts by interaction with a phosphorelay protein leading to a major revision in our understanding of signaling in this system and providing new insight into the general principles affecting related and widespread signaling systems. Recent work has demonstrated that signaling to this cascade can also take place independently of the best-characterized pathway. We have developed an efficient assay for screening for small molecules that activate or inactivate the cascade and have found evidence for effects of a variety of antibiotics in inducing the system. The long-term goal of this is to investigate the development of novel antibiotics that act by perturbing this important regulon. 1180805 +No NIH Category available Acquired Immunodeficiency Syndrome;Adenosine;Amino Acids;Anti-HIV Agents;Binding;Binding Proteins;Biological Assay;Cell Culture Techniques;Chemicals;Chromatin;Clinical;Collaborations;Complex;Contracts;Cryoelectron Microscopy;DNA;Data;Drug Targeting;Drug resistance;Enzymes;Excision;Exhibits;FDA approved;Fasting;Formulation;Gel;Generations;Genes;Genetic Transcription;Goals;HIV;HIV Integrase;HIV therapy;HIV-1;HIV-1 integrase;Histone H3.3;Histones;Individual;Integrase;Integrase Inhibitors;Intestines;Laboratories;Ligation;Liquid substance;Lysine;Macaca;Malignant Neoplasms;Microscopy;Microsomes;Modification;Mutate;Mutation;Nanotechnology;Naphthyridines;National Institute of Diabetes and Digestive and Kidney Diseases;Nucleosomes;PWWP Domain;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Plasma;Plasma Proteins;Polymers;Positioning Attribute;Process;Prodrugs;Program Development;Proteins;Protocols documentation;Reaction;Recommendation;Resistance;Reverse Transcriptase Inhibitors;Salvage Therapy;Side;Solubility;Stomach;Structure;Testing;Thermodynamics;Variant;Viral;Virus;Work;anti-viral efficacy;anticancer research;design;desulfurization;histone modification;improved;inhibitor;invention;lens epithelium-derived growth factor;mutant;next generation;novel;novel therapeutics;nucleoside analog;programs;resistance mechanism;response;treatment response Design and Synthesis of HIV Integrase as Potential Anti-AIDS Drugs n/a NCI 10925961 1ZIABC007363-29 1 ZIA BC 7363 29 6569096 "BURKE, TERRENCE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1491988 NCI Goal One. FDA-approved HIV-1 IN inhibitors belong to a class of drugs called integrase strand transfer inhibitors (INSTIs) due to their ability to preferentially block the enzymes strand transfer (ST) reaction as related to the enzymes 3-processing (3-P) reaction. The current recommended front-line therapy for HIV-1 infected patients is an INSTI either Dolutegravir (DTG) or Bictegravir (BIC) in combination with two nucleoside analog reverse transcriptase inhibitors. Both DTG and BIC potently inhibit most of the first generation INSTI-resistant IN mutants. Although little resistance has been selected by either BIC or DTG in treatment-naive patients patients who have preexisting first-generation INSTI-resistant mutants and have switched to a salvage therapy featuring DTG respond poorly emphasizing the importance of developing new and improved IN inhibitors. This adds impetus to a continuing need to develop next-generation agents that can retain high antiviral efficacy against emerging strains of INSTI-resistant virus. We optimized synthetic protocols for the synthesis of our best in-house developed INSTI designated as 4d or XZ426 and these were employed in the contract synthesis of a multi-gram quantity of XZ426 for use in IDP-sponsored PK studies. The PK studies include 1. Stability in plasma fasted state simulated gastric fluid and simulated intestinal fluid 2. Thermodynamic solubility in fasted state simulated gastric fluid and simulated intestinal fluid 3. Caco-2 permeability 4. Metabolite profiling in microsomes 5. Plasma protein binding. Under sponsorship of the NCI Invention Development Program (IDP) we are partnering with the Frederick National Laboratory for Cancer Research (FNLCR) NCI Alliance for Nanotechnology in Cancer a slow-release polymer prodrug formulation of X426 was generated. This prodrug formulation is currently undergoing testing in macaques in collaboration with Dr. Jeff Lifson director AIDS and Cancer Virus Program (FNLCR). We have partnered with Dr. Lyumkis of the Salk Institute and Dr. Robert Craigie NIDDK to employ cryo-EM to determine how INSTIs interact with their natural drug target the HIV intasome (both WT and mutant) and to elucidate the mechanisms by which resistance to these drugs emerges. Our work is extending and building upon efforts to provide a mechanistic understanding of both why and how select viral resistant variants arise in response to the clinically used DTG as well as XZ426. Based on preliminary Cryo-EM data we have designed new inhibitors that are intended to interrogate the significance of differences observed between the binding of our inhibitors and the best clinical agents. My laboratory is using single round replication assays that employ resistant mutant forms of IN. There are four primary pathways through which IN resistance occurs in response to therapy with the potent INSTI DTG which involve these changes: Q148H/K/R N155H G118R and R263K. Substitutions at one of these positions usually arise first both in patients and in cell culture and can cause a major loss of INSTI potency. There are more than 20 additional positions where a residue can be mutated to give rise to more complex IN mutants. This collectively amounts to hundreds of possible combinations. We have determined antiviral EC50 values against viral constructs having the triple mutant E138K/G140A/Q148K and found that our XZ426 has an EC50 that is 20-fold lower than that of DTG. To understand the basis of this increased potency Dr. Craigie has prepared HIV intasomes bearing these three triple mutations. Dr. Lyumkis has determined structures of Dr. Craigies triple mutant intasomes bound to either to DTG or to our current best INSTI. Although the binding modes of both INSTIs and the configuration of individual protein residues are similar the terminal adenosine of vDNA exhibits a stacked configuration in the context of our INSTI but an unstacked configuration in the context of DTG. These data suggest that adenosine stacking is a real phenomenon that specifically enhances the binding of our naphthyridine-based INSTIs which may contribute to the improved ability of our INSTI to retain antiviral efficacy against this (and perhaps other) mutant(s). We are currently using this to synthesize next generation inhibitor that are designed to retain greater antiviral potencies against resistant mutant forms of IN. Goal Two.The focus of this goal is to prepare H3.3 histone variants for use in the construction of modified intasomes. We have focused on the 135 amino acid residue H3K36Me3 in which the K36 residue has been replaced by a lysine bearing a NMe3-modified side chain. Initially we employed a semisynthetic strategy using an expressed 47-135C110A. However the inherent low solubility of this fragment rendered final TEV tag removal and gel separation to be difficult. Accordingly we investigated a three segment N to C total synthesis approach using native chemical ligations (NCL) strategies. We optimized the total synthesis and purification of 1-135 H3K36Me3 with an overall yield (22%). We are currently optimizing the desulfurization of Cys residues which will yield the desired final histone product. 1491988 +No NIH Category available Affinity;Aldehydes;Alkynes;Amines;Antineoplastic Agents;Azides;Benzoic Acids;Binding;Biological;Biological Assay;C-terminal;Cancerous;Carcinoma;Catalytic Domain;Cell Surface Receptors;Cells;Chemistry;Collaborations;Colon Carcinoma;Colorectal Cancer;Complex;DNA;DNA Repair Enzymes;DNA Topoisomerases;Data;Derivation procedure;Disease remission;Disulfides;Docking;Evaluation;Excision;Extracellular Domain;Fluorescent Dyes;Fluorides;G-Protein-Coupled Receptors;Goals;LGR5 gene;Label;Laboratories;Left;Leucine-Rich Repeat;Libraries;Ligand Binding;Ligands;Light;Mediating;Molecular;N-terminal;Nature;Operative Surgical Procedures;Oximes;Parents;Peptide Synthesis;Peptides;Phase;Phthalic Acids;Positioning Attribute;Process;Proteins;Quinolones;Reaction;Reagent;Reporting;Ring Finger Domain;Side;Signal Transduction;Site;Solid;Stains;Structure;Sulfur;Surgeon;Synthesis Chemistry;Tissues;Topoisomerase;Topoisomerase Inhibitors;Topoisomerase-I Inhibitor;Type I DNA Topoisomerases;Tyrosine;Tyrosine Kinase Inhibitor;Universities;Variant;Work;X-Ray Crystallography;adenoma;anti-cancer;beta catenin;biomaterial compatibility;cancer cell;chemical stability;covalent bond;design;drug-like compound;image translation;inhibitor;inorganic phosphate;knock-down;mimetics;nanomolar;near infrared dye;overexpression;peptidomimetics;phosphodiester;quinoline;relapse prevention;repaired;small molecule;therapeutic target;tumor;tyrosyl-DNA phosphodiesterase Inhibitors of Tyrosine Kinase-Dependent Signaling as Anti-Cancer Agents n/a NCI 10925960 1ZIABC006198-34 1 ZIA BC 6198 34 6569096 "BURKE, TERRENCE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 497330 NCI "Objective One: Tyrosyl-DNA phosphodiesterase 1 (TDP1) it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. Although there have been reports of TDP1 inhibitors there is a pressing need for the discovery of effective and specific TDP1 inhibitors for which there is validated binding and a defined mechanism of actions. We began this work by using an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. More recently we performed a TDP1 small molecule microarray screen of over 21000 drug-like molecules in a small molecules microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified 109 hits from 21000 compounds (0.5% hit rate) and arrived at a preferred TDP1-binding motif. Among the hits were structurally similar N2-diphenylimidazo[12-a]pyrazin-3-amines which we demonstrated functioned as TDP1 binders and catalytic inhibitors. The biological aspects of this work are being done in collaboration with the NCI laboratory of Dr. Yves Pommier. X-ray crystallographic studies were initially conducted in the NCI laboratory of Dr. Dave Waugh but more recently this work has shifted to the FNLCR laboratory of Dr. George Lountos. The SMM work was done in collaboration with the NCI laboratory of Dr. Jay Schneekloth. During the reporting period we have elaborated the structure of the parent SMM-derived platform by adding functionality that extends into the peptide and DNA substrate binding regions. We employed a ""click""-based oxime diversification strategy that we have used successfully in several applications to optimize the binding interactions of parent ligands. A key to this approach is its ability to take a single synthetic parent construct and easily diversity using a library of readily obtainable aldehyde reagents. This involved modifying our SMM-derived platforms by adding aminooxy handles to yield two parent aminooxy-containing constructs. The benzoic acid moieties of these constructs are intended to bind within the catalytic site phosphoryl-binding pocket while the aminooxy groups are situated so that the resulting oxime derivatives would access the DNA or peptide substrate-binding channels. In this way we were able to rapidly interrogate the structures of approximately 500 oxime derivatives. The most promising compounds (low micromolar IC50 values) were further derivatized to increase the chemical stability of the parent oxime linkages. Through this process we were able to achieve TDP1 inhibitors with nanomolar potencies. We obtained the crystal structure of oxime-derived inhibitors bound to the TDP1 catalytic site and observed that they bind in a fashion that is similar to what was predicted by our molecular docking studies. Our current work is using sulfur (VI) fluoride exchange (SuFEx) biocompatible click chemistry reactions to prepare sulfonyl fluoride and fluorosulfate-containing covalent ligands designed to site-specifically target the Tyr204 residue in the catalytic site of TDP1. We have prepared and screened a small library of substituted quinolines with sulfonyl fluorides and fluorosulfate-containing tethers at the 8-position of a parent quinolone platform. Importantly our cocrystal structures of TDP1 bound to these quinolones suggest covalent bond to the Tyr204 at the catalytic site of TDP1. Work is progressing to advance these agents. Object Two: The LGR5 potentiates canonical Wnt/B-catenin signaling. The well characterized deregulation of Wnt/B-catenin signaling that occurs during the adenoma-carcinoma sequence in CRC and further that specific subpopulations or molecules within a tumor may be therapeutically targeted to prevent relapse and induce long-term remissions. This renders LGR5 as a potential therapeutic target. The protein R-spondin-1 (RSPO1) serves as a ligand that binds to the extracellular domain of LGR5. RSPO1 mimetics could potentially serve as affinity tags for targeting cancerous tissues during surgical resection of colon cancers. My laboratory is participating in a multi-party collaboration with Dr. Chris Albanese (Center for Translational Imaging Georgetown University) to develop first-in-class RSPO1 peptide mimetics that can serve as vehicles to deliver near IR (NIR) dyes to light up cancerous tissues during surgical resection of colon cancers. My laboratory is designing and syntgesizing fluorescently tagged LGR5-binding peptide mimetics. Our initial design of RSPO-1 mimetics is based on the crystal structure of RSPO1 bound to LGR5 in a ternary complex with Ring Finger 43 (RNF43). This shows that the major binding interactions between RSPO1 and LGR5 occur via residues F106 and F110 within the bis-disulfide containing sequence K96-K113 located in its C-terminal Furin 2 Domain (FU2). We term this the ""Right Side."" Secondary binding is mediated by the R87 residue contained within residues P77-I95 in its mono-disulfide N-terminal Furin 1 Domain (FU1). We term this the ""Left Side."" Binding interactions of the ""Right Side"" 18-mer are particularly important and emphasis will be placed on optimizing synthesis of the right side by several approaches. The ""Left Side"" will be synthetically explored. Following optimization of the Right and Left Side peptides these mimetics were connected to form bivalent constructs using tethering moieties. We have already developed solid-phase peptide synthesis (SPPS) chemistries to synthesize both the bis-disulfide containing 18-mer Right Side and mono-disulfide containing Left Side. We are using azide-alkyne click chemistry to join the constructs to form the entire ""37-mer"" RSPO1 mimetic which contains the major RSPO1 binding interactions. Binding interactions of the 37-mer may be viewed as being ""bivalent"" in nature with the Left and Right Sides representing independent binding moieties that are connected by a bridging segment. The affinity of bivalent ligands can be significantly higher than the affinities of the isolated components. Specific binding of my RSPO1 mimetics to LGR5 is being confirmed by cell staining knockdown and competition assays." 497330 +No NIH Category available Acceleration;Antitumor Response;Bacteroides;Bacteroides fragilis;Bile Acids;Carcinogens;Cells;Chemicals;Colon;Colonic Neoplasms;Colorectal Cancer;Coupled;Deoxycholic Acid;Drug Targeting;FOXP3 gene;Feces;GTP-Binding Proteins;Genes;Goals;High Fat Diet;Hydrolase;IL2RA gene;Immunosuppression;Ligands;Lipids;Lithocholic Acid;Mass Spectrum Analysis;Metabolic Diseases;Metabolic Pathway;Obesity;Overweight;Pathway interactions;Pharmaceutical Preparations;Publications;Publishing;Recombinants;Regulatory T-Lymphocyte;Role;Xenobiotic Metabolism;beta catenin;bile salts;cancer biomarkers;cancer chemoprevention;cancer therapy;chemokine;colon cancer patients;colon tumorigenesis;colorectal cancer prevention;colorectal cancer progression;insight;lipidomics;metabolomics;mouse model;overexpression;pharmacologic;programs;receptor;toxicant Xenobiotic metabolism cancer chemoprevention and cancer biomarkers n/a NCI 10925955 1ZIABC005708-32 1 ZIA BC 5708 32 6568962 "GONZALEZ, FRANK J" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1048134 NCI Bile salt hydrolase (BSH) in Bacteroides is considered a potential drug target for obesity-related metabolic diseases but its involvement in colon tumorigenesis has not been explored. BSH-expressing Bacteroides is found at high abundance in the stools of colorectal cancer (CRC) patients with overweight and in the feces of a high-fat diet (HFD)-induced CRC mouse model. Colonization of B. fragilis 638R a strain with low BSH activity overexpressing a recombinant bsh gene from B. fragilis NCTC9343 strain results in increased unconjugated bile acids in the colon and accelerated progression of CRC under HFD treatment. In the presence of high BSH activity the resultant elevation of unconjugated deoxycholic acid and lithocholic acid activates the G-protein-coupled bile acid receptor resulting in increased beta-catenin-regulated chemokine (C-C motif) ligand 28 (CCL28) expression in colon tumors. Activation of the beta-catenin/CCL28 axis leads to elevated intra-tumoral immunosuppressive CD25+FOXP3+ Treg cells. Blockade of the beta-catenin/CCL28 axis releases the immunosuppression to enhance the intra-tumoral anti-tumor response which decreases CRC progression under HFD treatment. Pharmacological inhibition of BSH reduces HFD-accelerated CRC progression coincident with suppression of the beta-catenin/CCL28 pathway. These findings provide insights into the pro-carcinogenetic role of Bacteroides in obesity-related CRC progression and characterize BSH as a potential target for CRC prevention and treatment. 1048134 +No NIH Category available Aborigine;Affect;Alveolar;Animal Model;Animal Testing;Animals;Anti-Inflammatory Agents;Australia;Autophagocytosis;B-Lymphocytes;Biopsy;Blood;Body Weight decreased;Bronchiectasis;CD4 Positive T Lymphocytes;CD8B1 gene;Caring;Cell Line;Cell physiology;Cells;Cerebrospinal Fluid;Cessation of life;Clonality;Collaborations;Communities;Complementary DNA;Coupled;Cytarabine;Data;Disease;Engraftment;Exons;Future;Genetic Polymorphism;HTLV-1 Infection;High-Throughput Nucleotide Sequencing;Hospitals;Human;Human Genome;Human T-lymphotropic virus 1;IL2RA gene;IL8 gene;Immune;Immunocompetent;In Vitro;Indigenous;Individual;Infection;Infiltration;Inflammasome;Inflammatory;Initiator Codon;Interleukin-6;Irrigation;Knock-out;Knowledge;Lentivirus;Link;Lung;MHC Class I Genes;Macaca;Macrophage;Maps;Measures;Melanesia;Messenger RNA;Methods;Microbial Biofilms;Modeling;Molecular Cloning;Mus;Nanotubes;Natural Killer Cells;Northern Territory;Open Reading Frames;Organ;Pathway interactions;Peripheral Blood Mononuclear Cell;Persons;Pharmacotherapy;Physicians;Plasma;Population;Productivity;Proliferating;Proteins;Protocols documentation;Pulmonary Inflammation;RNA Splicing;Reagent;Research;Research Personnel;Resistance;Role;Sampling;Seroprevalences;Signal Transduction;Spleen;T-Cell Proliferation;T-Lymphocyte;Taxes;Testing;Tokyo;United States National Institutes of Health;Vertebral column;Viral;Viral Load result;Virus;Virus Integration;Virus Replication;animal data;chemokine;chronic infection;cytokine;cytotoxic;hospital care;human data;humanized mouse;in vivo;inflammatory lung disease;integration site;leukemia;lymph nodes;monocyte;mortality;mutant;nonhuman primate;nucleoside analog;pathogen;response;transmission process;viral DNA;viral transmission;virological synapse;virtual Role of the HTLV-1A and HTLV1-C inflammatory profile in disease n/a NCI 10925954 1ZIABC005645-34 1 ZIA BC 5645 34 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 166365 NCI Accomplishments 1. By performing integrated studies on orf-I sequence in 160 HTLV-1A infected individuals and animal testing on the infectivity of molecular clones carrying polymorphism that result in preferential expression of p8 or p12 we established that efficient HTLV-1A persistence and spread in vivo requires the combined functions of the orf-I proteins. We also found that p8 is essential for productive infection of monocytes and that the expression of both proteins renders infected cells completely resistant to the MHC-class I restricted cytotoxic CD8 killing. 2. Cell-associated HTLV-1 can be transmitted by at least three different mechanisms: virological synapse cellular conduits including Tunneling Nano Tubes and biofilm. However the contribution of each of these mechanisms to viral transmission remains unknown. We have demonstrated that the HTLV-1 p8 increases viral transmission by increasing both cellular conduits and Tunneling Nano Tubes. More recently we found that inhibition of p8-medaited TNT formations by the nucleoside analog cytarabine (cytosine arabinoside AraC) decreases viral transmission by 30% thereby providing a treatment to partly curb the spread of HTLV-1 in vivo. Current Research & Future Plans 1. Functional studies with HTLV-1A and HTLV-1A/C viruses and orf-I cDNAs. We have synthesized the cDNAs derived from the doubly spliced rex-orf-I mRNAs of HTLV-1C that juxtapose the first exon of Rex in frame with orf-I and demonstrated that it produces p16 a protein that increases autophagy. We constructed a chimeric virus by swapping the Cla-1-Sal-1 fragment which contains both the entire orf-I and most of the orf-II of HTLV-1A with that of HTLV-1C. The resultant molecular clone is a replicating virus designated as HTLV-1A/CDF. We plan to create a second HTLV-1A/C by substituting the entire 3' end (HTLV-1A/C) and generating mutants of both chimeric viruses to inhibit the splicing of the rex-orf-I mRNA (HTLV-1A/CDFd16 and HTLV-1A/CDFd16) as a control. The viral DNA clones will be transduced in the 729 B cell line that supports HTLV-1 replication and will be used to infect primary CD4+ T cells. We plan to perform functional studies on monocytes with lentiviruses that express p8 or p16 on primary monocytes and are infected by HTLV-1A WT and the orf-I knockout mutant the chimeric HTLV-1A/CDF WT or rex-orf-I knock-out virus (HTLV-1A/CDFd16). We will assess inflammasome activation autophagy and the level and type of inflammatory cytokines and chemokines produced by primary monocytes and T cells in vitro. 2. HTLV-1A and HTLV-1A/C infection of humanized mice. We have preliminary data that demonstrate that our HTLV-1A molecular clone can be transmitted to humanized NOD/SCID-yc-/- mice using infected irradiated CD4+ T cells. We observed proliferation of human CD25+ CD4+ T cells engrafted in the humanized mice that causes extensive infiltration of these CD4+ T cells in vital organs such as the spleen high viral burden weight loss and death. To explore HTLV-1 clonality in hu-Mice we applied an optimized high-throughput sequencing (HTS) method to map viral integration sites in the human genome and simultaneously measure the abundance of the corresponding clones. The CD4+ T cell proliferation is polyclonal as expected. We do not anticipate differences in the ability of HTLV-1A and HTLV-1A/C to cause this proliferative disease in mice since the Tax is virtually identical in the two viruses. However these studies will be prerequisite to demonstrate viral infectivity of the chimeric HTLV-1A/C in vivo before they can be used in studies in non-human primates. In addition this small animal model may be foundational in testing the extent of inhibition of viral transmission by cytarabine in vivo. 3. Study the inflammatory profile of HTLV-1A and HTLV-1A/C infected macaques and humans. We have demonstrated that HTLV-1A WT and the HTLV-1 orf-I knockout viruses infect monocytes in vitro and macaques in vivo but the HTLV-1 orf-I knockout does not appear to persist. We obtained PBMCs infected with HTLV-1A WT or the HTLV-1A orf-I knockout virus cultured them for 3 days and measured the ability of adherent cells (macrophages) to produce cytokines. The blood was collected at a timepoint when both animals were positive for viral DNA in PBMCs (weeks 8-10). We found higher levels of IL-1B IL-6 and IL-8 in the animal infected with the HTLV-1A orf-I knockout than that with the HTLV-1A WT demonstrating that the absence of orf-I results in a qualitatively different inflammatory profile in vivo as also demonstrated in vitro. We plan to extend this study by infecting 4 macaques with HTLV-1A and 4 with HTLV-1A orf-I knockout viruses to follow the inflammatory profiles caused by the two viruses in detail. We also plan to infect additional macaques with the HTLV-1A/CCS and the HTLV-1A/CCSd16 if warranted by the data. In all the animal studies we will collect lung biopsies bronchial alveolar lavage blood lymph nodes gut biopsies and spinal fluid to quantitate viral burden and differences in systemic inflammatory profiles. To compare the inflammatory profiles of ex vivo monocytes from macaques and humans infected by HTLV-1A and HTLV-1C we have established collaborative efforts with Australian physicians at the Alice Springs Hospital that care for HTLV-1C infected Aborigines and with the IMSUT Hospital in Tokyo and Steve Jacobson at the NIH who both care for HTLV-1A infected people to study their inflammatory profiles directly in plasma or by short term cultures of PBMCs. Our collaboration with Australian researchers is a large pan-Australian consortium to share PBMCs culture protocol Luminex data and reagents for the comparison of human and animal data. 166365 +No NIH Category available Acetylation;Adenocarcinoma Cell;Affect;Amyloidosis;Apoptosis;Apoptotic;B-Lymphocytes;BRCA1 gene;Binding;Biochemical;Biological;Biotin;Biotinylation;C-terminal;CCL2 gene;CD6 antigen;CD8B1 gene;Carbon;Cell Cycle Arrest;Cell Line;Cell Proliferation;Cells;Chemicals;Chronic;Collaborations;Colon Carcinoma;Critical Pathways;DNA;DNA Damage;DNA Repair;Data;Down-Regulation;EP300 gene;Enzymes;Epigenetic Process;Esophageal Adenocarcinoma;Etoposide;Exhibits;Generations;Genes;Genetic;Genetic Transcription;Goals;Growth;Heat-Shock Response;Human;Hydroxylation;Hypoxia;Image;In Vitro;Inflammatory;Interleukin-6;Lower Gastrointestinal Tract;Lysine;MCF7 cell;MS4A1 gene;Macrophage;Mass Spectrum Analysis;Mediating;Metabolic;Metabolism;Methylation;Mitochondria;Modification;Molecular Conformation;Monocyte Chemoattractant Proteins;Mucous Membrane;Mutation;N-terminal;Neoplasm Metastasis;Nuclear Extract;Nuclear Proteins;Oncogenic;Outcome;Pathway interactions;Peptides;Permeability;Phosphorylation;Point Mutation;Population;Post-Translational Protein Processing;Prognosis;Protein Isoforms;Proteins;Proteome;Reaction;Regulation;Reporting;Repression;Research;Role;Signal Transduction;Site;Small Interfering RNA;Stimulus;Stress;Sulfhydryl Compounds;Sumoylation Pathway;T-Lymphocyte;TP53 gene;Transactivation;Transcription Coactivator;Transcriptional Activation;Tumor Promotion;Tumor Suppressor Proteins;Ubiquitination;Work;anticancer treatment;cancer cell;cancer stem cell;cofactor;experimental study;gain of function;high throughput screening;immune cell infiltrate;improved;in vivo;inhibitor;knock-down;metabolic profile;mutant;neuroblastoma cell;neutrophil;novel;peptidomimetics;pharmacologic;preference;prevent;response;senescence;small molecule;stem cell migration;transcription factor;tumor;tumor growth;tumor microenvironment;tumor progression;tumorigenesis Tumor Suppressor Protein p53 n/a NCI 10925953 1ZIABC005599-33 1 ZIA BC 5599 33 6568841 "APPELLA, ETTORE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 464845 NCI "The p53 tumor suppressor protein is a key component of the cellular response to stress. It is a homo-tetrameric sequence-specific transcription factor activated by DNA damage hypoxia heat shock and other types of stress and regulates DNA repair cell cycle arrest senescence metabolism and apoptosis. It is maintained at low levels in unstressed cells but becomes stabilized and activated following DNA damage through extensive post-translational modification (PTM). Our research has focused on identifying and exploring the biological roles of p53 PTMs to better understand how they modulate p53 functions. The tandem N-terminal transactivation domains (TADs) of p53 are crucial for p53 activity as a transcription factor. The two subdomains TAD1 (residues 1-40) and TAD2 (residues 35-59) interact with several domains of the transcriptional coactivator p300. However the two subdomains can function independently of one another suggesting the participation of distinguishing transcriptional cofactors in transcriptional activation by TAD1 and TAD2 in which interactions may be differentially regulated by p53 phosphorylation. To identify distinct interacting partners for TAD1 and TAD2 peptides comprising TAD1 (residues 9-33) or TAD2 (residues 35-59) with and without phosphorylation at Thr 18 or Ser 46 respectively were synthesized and covalently attached to biotin at the N-termini. We used these peptides as a bait for pulldown of interacting proteins from nuclear extracts prepared from MCF7 cells treated with etoposide; mass spectrometry analysis was used to identify and quantitatively compare the interactors to discriminate between those preferentially interacting with the TAD1 or TAD2 subdomains. Our experiments using biological triplicate pulldowns have identified a list of potential interactors that show a preference for either unmodified or modified p53 in untreated cells or following etoposide treatment. In addition to known binding partners of p53 TAD1 and TAD2 we identified several new interactors. We have validated one of the new interactors BRAT1 (BRCA1 Associated ATM Activator 1) as a direct binding partner of p53 and have shown its levels change following induction of stress with etoposide. Current work aims to knockdown BRAT1 isoforms to identify which isoform is directly regulating p53 and affects mitochondrial function and cell proliferation. The C-terminus of p53 exhibits a diverse array of PTMs including phosphorylation methylation acetylation ubiquitination sumoylation neddylation and hydroxylation that are primarily localized to the terminal thirty residues of the protein. We have shown that p53 can be both mono- and dimethylated on Lys382 with the former modification repressing p53 transcriptional activity and the latter promoting DNA repair in addition to demonstrated acetylation and ubiquitination of the same site. SETD8 monomethylates p53 on lysine 382 attenuating p53 pro-apoptotic and growth arrest functions. Using a high-content imaging siRNA screen and a chemical screen in a collaboration with Drs. Veschi and Thiele we identified SETD8 as a suppressor of p53 activity in neuroblastoma cell lines. Genetic or pharmacological inhibition of SETD8 activity resulted in activation of the p53 wild-type pathway by decreasing p53K382me1. We have initiated a collaboration with Drs. Veschi and Stassi and recently showed that SETD8 is highly expressed in colon cancer stem cells (CSCs) with commensurate increased levels of p53K382me1. Interestingly p53K382me1 expression is undetectable in the healthy mucosa while it is highly expressed in the tumor leading edge region together with the CD44v6+ marker which is required for the CSC migration and generation of metastasis. It is known that chronic inflammatory stimuli may promote tumor progression and metastasis. In inflammatory conditions of the lower gastrointestinal tract p53 inactivation represents an early step of tumorigenesis. We detected high levels of p53K382me1 in immune cell infiltrates in CRCs which were significantly associated with worse prognosis. 50% of macrophages (CD163+ CD6 8+) expressed p53K382me1 whereas T lymphocytes (CD4+or CD8+) neutrophils (CD15+) and B cells (CD20+) expressed low levels. Cross talk between cancer cells and macrophages in the tumor microenvironment may lead to functional inactivation of p53; therefore p53K382me1 could represent the first known mechanism of p53 inactivation mediated by an epigenetic regulator in the M2 macrophage population. Preliminary data showed that treatment with conditioned media collected upon direct interaction between CR-CSCs and macrophages high levels of IL-6 and monocyte-chemoattractant-protein (MCP-1) were detected accompanied with down-regulation of p53 target genes suggesting that this may be an early mechanism of p53 functional inactivation during CRC tumorigenesis. Currently there are few available substrate-competitive cell-permeable inhibitors targeting SETD8. The identification of a compound specific for the SETD8-p53 interaction is urgently needed. We are using a high-throughput assay to identify novel inhibitors of SETD8 with an improved activity and tolerability in vivo. P53 point mutations have been reported to occur in approximately half of all human tumors with marked over-representation of specific ""hot-spot"" residues. These mutations abolish the ability of p53 to function as a transcription factor and tumor suppressor. Moreover many mutant forms of p53 have acquired novel oncogenic activities through gain-of-function mechanisms. p53 mutations generally either affect DNA contact or cause structural instability with partial unfolding and aggregate formation similar to that seen in amyloid diseases. We are examining a small molecule NSC59984 in esophageal adenocarcinoma cells and investigating its mechanism of action and effects on the onco-metabolic profile. The findings will help elucidate pathways critical for preventing tumor growth by inhibiting gain-of-function mutant p53 activities and restoring wild-type p53 activity. NSC59984 first identified from a high-throughput screen induces wildtype p53 signaling and anti-proliferative effects while inhibiting mutant p53 gain-of-function activities. Recently we have investigated its specific mechanism of action against p53. We found that NSC59984 reacts with thiols via an unusual Michael addition at the alpha-carbon. Covalent modification of p53 Cys124 and Cys229 was observed both following in vitro reaction and upon treatment of cells. We also used a biotinylated form of NSC59984 and separately thermal proteome profiling to examine off-target effects identifying several proteins involved in cellular metabolism as potential targets. These results demonstrate that covalent modification of p53 by NSC59984 leads to increased wildtype activity and suggest that potential reaction with metabolic enzymes may contribute to antiproliferative function." 464845 +No NIH Category available ABCB1 gene;ABCB6 gene;ABCC1 gene;ABCG2 gene;ATP-Binding Cassette Transporters;Amino Acids;Belgium;Binding;Biological Availability;Blood - brain barrier anatomy;Brain;Cause of Death;Cell Death;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Cytotoxic agent;Dimerization;Doxorubicin;Drug Efflux;Drug Interactions;Failure;Family;Fluorescence;Goals;Histone Deacetylase Inhibitor;Imidazole;Ketones;Knock-out;Laboratories;Length;Lipid Peroxidation;Malignant Neoplasms;Mediating;Molecular;Multi-Drug Resistance;Mutate;Natural Product Drug;Natural Products;Oral;Paclitaxel;Penetration;Pharmaceutical Preparations;Phenotype;Physiological;Piperazines;Process;Proteins;Renal Cell Carcinoma;Reporting;Resistance;Rhodamine;Rhodamine 123;Role;Site;System;Transcript;Transmembrane Domain;Universities;Vinca Alkaloids;Work;cancer cell;cancer drug resistance;chemotherapeutic agent;chemotherapy;erastin;genetic analysis;human tissue;inhibitor;insight;kinase inhibitor;malignant phenotype;melanoma;member;multi drug transporter;multidrug resistant cancer;neoplastic cell;overexpression;prevent;promoter;resistance mechanism;small molecule;tool;uptake Genetic Analysis of the Multidrug Resistance Phenotype in Tumor Cells n/a NCI 10925952 1ZIABC005598-34 1 ZIA BC 5598 34 9414470 "GOTTESMAN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 284032 NCI Resistance to chemotherapy occurs in cancer cells because of intrinsic or acquired changes in expression of specific proteins. We have studied resistance to natural product chemotherapeutic agents such as doxorubicin Vinca alkaloids and taxol and more recently histone deacetylase inhibitors and targeted kinase inhibitors. In most cases cells become simultaneously resistant to multiple drugs because of reductions in intracellular drug concentrations. For the natural product drugs this cross-resistance is frequently due to expression of an energy-dependent drug efflux system (ABC transporter) known as P-glycoprotein (P-gp) the product of the MDR1 or ABCB1 gene or to other members of the ABC transporter family including ABCG2 and ABCB5. In collaboration with the group of Suresh Ambudkar we have examined the basis of directional transport of compounds out of cells by P-glycoprotein. These studies have revealed a set of amino acid residues in the transmembrane regions of P-glycoprotein which can be altered to change the direction of transport of certain rhodamine compounds from out of the cell to into the cell. This process is concentration- and ATP-dependent and gives important insight into how directionality of transport is determined in P-glycoprotein. Further studies are underway in the Ambudkar laboratory to clarify the role of specific residues and the mechanism by which the direction of transport is reversed. In collaboration with Jean-Pierre Gillet (University of Nemours Belgium) we have further explored the role of ABCB5 in cancer drug resistance in the malignant phenotype in melanoma (where it is frequently mutated) and as a partner as a heterodimer with other ABC B-type transporters. In pigmented cells that express ABCB5 there are both full-length and partial transcripts generated from different promoters. The partial transcripts encode a half-transporter which appears to be able to dimerize with other half transporters (notably ABCB6 and ABCB9). The localization and potential function of these heterodimeric transporters is under study. Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported yet little information is available regarding their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp ABCB1) and ABCG2. We thus sought to characterize the interactions of FINS with P-gp and ABCG2 which may provide information regarding oral bioavailability and brain penetration and predict drug-drug interactions. P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1. The FINs ML-162 GPX inhibitor 26a and PACMA31 at 10 micromolar were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells. GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. We conclude that expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions. 284032 +No NIH Category available Agonist;Binding;Carcinogenesis Mechanism;Ceramides;Classification;Clinical Trials;Collagen;Colon Carcinoma;Cytokeratin;Deposition;Diagnosis;Disease;Drug Targeting;ERBB2 gene;Elements;Epithelial Cells;Epithelium;Exclusion;Exons;Family;Fasting;Fenofibrate;Genes;Glycine;Goals;HNF4A gene;Hair;Hepatic;High Fat Diet;Human;Inflammatory;Inflammatory Response;Insulin Resistance;Intestines;Keratin;Knockout Mice;Lipids;Liver;Liver diseases;Low-Density Lipoproteins;Malignant Neoplasms;Malignant neoplasm of liver;Metabolic;Metabolic Diseases;Modeling;Molecular;Morphogenesis;Mus;Natural regeneration;Obesity;Pathogenesis;Pathology;Prevention;Production;Pruritus;Receptor Signaling;Reporting;Role;Severities;Skin;Stress;Structural Protein;Tissues;Xenobiotics;antagonist;bile acid metabolism;cell injury;cytokine;diagnostic biomarker;endoplasmic reticulum stress;fatty liver disease;human disease;improved;liver injury;muricholic acid;nonalcoholic steatohepatitis;novel;programs;receptor;side effect;therapeutic target;transcription factor Xenobiotic receptors n/a NCI 10925951 1ZIABC005562-36 1 ZIA BC 5562 36 6568962 "GONZALEZ, FRANK J" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2445645 NCI Project 2: Keratins are key structural proteins found in skin and other epithelial tissues. Keratins also protect epithelial cells from damage or stress. Fifty-four human keratins were identified and classified into two families type I and type II. Accumulating studies showed that keratin expression is highly tissue-specific and used as a diagnostic marker for human diseases. Notably keratin 79 (KRT79) is type II cytokeratin that was identified as regulator of hair canal morphogenesis and regeneration in skin but its role in liver remains unclear. KRT79 is undetectable in normal mouse but its expression is significantly increased by the PPARA agonist WY-14643 and fenofibrate and completely abolished in Ppara-null mice. The Krt79 gene has functional PPARA binding element between exon 1 and exon 2. Hepatic Krt79 is regulated by HNF4A and HER2. Moreover hepatic KRT79 is also significantly elevated by fasting- and high-fat diet-induced stress and these increases are completely abolished in Ppara-null mice. These findings suggest that hepatic KRT79 is controlled by PPARA and is highly associated with liver damage. Thus KRT79 may be considered as a diagnostic marker for human liver diseases. Project 2: Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH but side effects such as pruritus and low-density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine-beta-muricholic acid (Gly-MCA) is an intestine-specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein we identify a role for Gly-MCA in the pathogenesis of NASH and explore the underlying molecular mechanism. Gly-MCA improved lipid accumulation inflammatory response and collagen deposition in two different NASH models. Mechanistically Gly-MCA decreased intestine-derived ceramides by suppressing ceramide synthesis-related genes via decreasing intestinal FXR signaling leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly-MCA and a correlation was found between intestine-derived ceramides and NASH severity. This study revealed that Gly-MCA an intestine-specific FXR antagonist has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling and ceramide production followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly-MCA a novel agent for the prevention and treatment of NASH. 2445645 +No NIH Category available Acute;Address;Adult;Age;Agreement;Amitrole;Area;Azoles;Benign;Bone Marrow Cells;Bone Marrow Transplantation;Cartilage;Cell Line;Cell Shape;Cell surface;Cells;Characteristics;Development;Diet;Differentiation Antigens;Disease;E-Cadherin;Epithelium;Equilibrium;Gene Mutation;Genes;Genotype;Goals;Growth Factor;Herbicides;Homeostasis;Human;Immune;Immunocompromised Host;Immunohistochemistry;In Situ Hybridization;Injury;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;Iodide Peroxidase;Malignant Neoplasms;Malignant neoplasm of thyroid;Maps;Measures;Mesenchymal;Messenger RNA;Microbial Collagenase;Missense Mutation;Modeling;Mus;Muscle;Names;Natural regeneration;Nature;Nodule;Organ;Pattern;Physiology;Play;Process;Proliferating;RNA;Role;Shapes;Signal Transduction;Signaling Molecule;Stromal Cell-Derived Factor 1;Structure;Subcutaneous Injections;Thinness;Thyroid Diseases;Thyroid Function Tests;Thyroid Gland;Thyroidectomy;Thyrotropin Receptor;Tissues;Trachea;Transgenic Mice;Tumor Suppressor Genes;Vimentin;Wild Type Mouse;adenoma;cancer stem cell;carcinogenesis;differential expression;genome sequencing;homeodomain;hormone receptor-negative;inhibitor;laser capture microdissection;mRNA Expression;nano-string;novel;overexpression;receptor;stem cells;thyroid neoplasm;tool;transcription factor;transcriptome sequencing;tumor;whole genome Thyroid regeneration and carcinogenesis n/a NCI 10925950 1ZIABC005522-36 1 ZIA BC 5522 36 6568943 "KIMURA, SHIOKO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 750711 NCI To understand whether TSH signaling plays a role in thyroid regeneration Tshr (TSH receptor)-null and littermate wild-type mice were subjected to partial thyroidectomy (acute thyroid injury model) that activates thyroid regeneration. A cluster of thin and elongated shaped cells different from round shaped thyroid follicular cells were found near the tracheal cartilage and muscle in both Tshr-null and wild-type mouse thyroids that were positive for NKX2-1 with some cells also positive for Pax8. The cluster of elongated cells were found connected to a newly formed follicle-like structure with NKX2-1 positive cells at the end or in the middle of the cluster. NXK2-1 and PAX8 are the transcription factors critical for development differentiation and function of the thyroid and are considered thyroid differentiation markers. These results suggested that a cluster of thin elongated cells may be a precursor to thyroid follicular cells. These clusters of thin elongated cells were present in both Tshr-null and wild-type mouse thyroids which may become more visible after partial thyroidectomy particularly in wild-type thyroids. When the levels of mRNAs for various thyroid-specific genes growth factors their receptors and related signaling molecules were measured using control Tshr-null and wild-type mice different expression levels were found in some of these genes between the two genotypes however changes in their expression after partial thyroidectomy followed similar pattern in both genotypes. These results suggested that at least this type of thyroid regeneration does not require TSH signaling. In order to address questions whether the thin elongated cells can be considered as thyroid stem/progenitor cells and what are the origin of these cells we carried out Nanostring GeoMX analysis where cells from the area of a cluster of thin elongated cells the surrounding tissues and normal thyroid tissues were captured by laser microdissection followed by RNAseq analysis of each area of cells. Fifty-one differentially expressed genes were obtained in the NKX2-1 cell cluster vs normal thyroid that overlapped between two separate sets of RNAs. Heat maps of these differentially expressed genes showed that many immune-related genes such as Igha Igkc H2-Aa H2-Ab1 H2-Eb1 Cd74 and Cxcl12 were highly expressed in the NKX2-1 cell cluster. This suggests that immune cells may be the origin of thyroid follicular cells at least in the regeneration process taking place after partial thyroidectomy. This is in agreement with our previously obtained results using bone marrow transplantation studies with GFP transgenic mice; GFP-positive cells were found in the elongated cluster of cells suggesting that this cell cluster could be at least partly derived from bone marrow cells. We are currently carrying out in situ hybridization using RNAscope (Bio-Techne) and immunohistochemistry to validate the results we obtained by GeoMx. If indeed validated the results demonstrate that immune cells may be the origin of thyroid follicular cells at least in the regeneration process taking place after partial thyroidectomy. This is a completely unexpected new finding. The results will provide a different way to look at the physiology and diseases of the thyroid and to restore thyroid functions in humans after thyroidectomy due to various thyroid diseases including cancer. The results will help in the development of novel treatment options for thyroid diseases. Carcinogenesis occurs in multi-steps in many tissues including the thyroid. In order to understand multi-step carcinogenesis and its relation to NKX2-1 expression we have established mouse thyroid adenomatous nodule-derived cell lines. Nkx2-1fl/fl mice were fed a diet containing amitrole (3-amino-124-triazole) starting at the age of 5 weeks. Amitrole is a non-food herbicide known to induce thyroid tumors by inhibiting thyroid peroxidase activity. Adenomatous nodules developed within 6-12 months in their thyroids which were dissected digested with collagenase I and displace I and cultured for 5 passages. Five cell lines were eventually successfully established which were named CAT (cells from amitrole treated thyroids). Among them two cell lines CAT458 and 459 showed epithelial characteristics with E-cadherin expression while other cell lines CAT411 413 and 427 expressed vimentin a mesenchymal marker. CAT459 cells expressed NKX2-1 while CAT458 cells had almost no expression of NKX2-1. NKX2-1-positive CAT459 cells showed higher mRNA expression of some thyroid differentiation markers than did NKX2-1-negative CAT458s (sub-line of CAT458) cells and NKX2-1 overexpression increased and/or induced their expression. IGF-I signaling was transduced in thyroid stimulating hormone receptor (TSHR)-negative CAT458s and 459 cells and NVP-ADW72 a selective IGF-I receptor (IGF-IR) inhibitor suppressed their proliferation. No tumors developed in immunocompromised mice after subcutaneous injection of CAT458s or 459 cells. Whole Genome Sequencing analysis revealed that there were no prominent gene mutations involved in thyroid cancers such as Braf Trp53 and Tert but several missense mutations were found in tumor suppressor genes in these cell lines consistent with their being benign adenoma cells. CAT458s and 459 cells provide a tool to further clarify the process of thyroid multi-step carcinogenesis and differentiation. 750711 +No NIH Category available Address;Behavior;Binding;Biological Assay;Biological Models;Breast Cancer Cell;Cell Nucleus;Cells;Characteristics;Chromatin;Chromatin Structure;Complex;Coupling;Crowding;DNA;Disease;Enhancers;Environment;Epigenetic Process;Estrogens;Failure;Gene Activation;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genetic Enhancer Element;Genetic Transcription;Goals;Gonadal Steroid Hormones;Growth;Imaging technology;Internet;Kinetics;Laws;Ligands;Malignant Neoplasms;Mammalian Cell;Modeling;Modification;Motion;Mutate;Neoplasm Metastasis;Nuclear;Nuclear Receptors;Pathway interactions;Patients;Pattern;Photobleaching;Process;Progesterone;Proliferating;Property;Proteins;Regulatory Element;Relapse;Repression;Response Elements;Signal Transduction;Steroid Receptors;Time;Treatment Failure;Work;cancer cell;cancer initiation;chromatin modification;drug development;gene product;genome-wide;in vivo;interest;live cell imaging;malignant breast neoplasm;mutant;neoplastic cell;population based;predictive signature;programs;prostate cancer cell;recruit;response;single molecule;targeted treatment;theories;transcription factor;transcriptome;tumor;tumor progression Chromatin Structure and Gene Expression n/a NCI 10925949 1ZIABC005450-40 1 ZIA BC 5450 40 8777551 "HAGER, GORDON L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2532437 NCI "1 Reprogramming of the chromatin landscape is a critical component to the transcriptional response in breast cancer. Effects of sex hormones such as estrogens and progesterone have been well described to have a critical impact on breast cancer proliferation. However the complex network of the chromatin landscape enhancer regions and mode of function of steroid receptors (SRs) and other transcription factors (TFs) is an intricate web of signaling and functional processes that is still largely misunderstood at the mechanistic level. We are exploring the dynamic interplay between TFs with chromatin and the reprogramming of enhancer elements. We characterize the different modes of action of TFs in regulating enhancer activity specifically how different SRs target enhancer regions to reprogram chromatin. 2 We are adapting recent advances in live cell imaging technology to study the function of T factors in single cells in real time. Single Molecule Tracking (SMT) allows the study of TF dynamics in the nucleus giving important information regarding the search and binding behavior of these proteins with chromatin in vivo. However how TFs navigate within the intricate nuclear environment to find and bind their response elements on chromatin recruit the transcription machinery and ultimately regulate gene expression remains largely unknown. By the implementation of proper photobleaching kinetics theory-based models and an unbiased model selection approach we revealed a new model of TF dynamics where TFs binding times are power-law distributed. Previous models suggested that TFs bound either non-specifically or specifically with each mode of binding having their own distribution that was largely discrete from the other. The power-law model on the other hand indicates that TFs bind not discretely in these two modes but with a continuous distribution from fast to very slow kinetics. These results are aligned with the theoretical underpinnings of TF motions in the crowded nuclear space and exploration of a complex DNA space. Our approaches enable the coupling of population based assays with real time studies to address many unsolved questions about SRs and chromatin dynamics in normal mammalian cells in breast cancer cells and prostate cancer cells. 3 Cancer discovery has been focused primarily on the identification of critical mutated pathways and the development of drugs to target the gene products of these so called ""driver"" mutants. Critical driver mutants are not commonly identified and therapies targeting these pathways are frequently followed by relapse. In fact the regulatory networks that control global gene expression are massively transformed during cancer initiation and progression. The failure to normalize gene regulation and return cells to normal growth control is likely a major factor in treatment failure. To treat cancer effectively a key issue is to identify the regulatory elements that create this abnormal expression pattern rather than simply describing the gene expression pattern in tumor cells. Our primary goal is to analyze the status of enhancer networks in cancer cells and identify enhancer ""signatures"" characteristic of progression and metastasis. Enhancer signatures predictive of cancer progression can then inform threat level for a specific tumor appropriate patient therapy and treatment progress for favorable response in enhancer status." 2532437 +No NIH Category available Biochemical;Biological Models;Biological Process;Chromosome Structures;Chromosomes;Complex;Congenital Abnormality;Cruciform DNA;DNA Damage;DNA Double Strand Break;DNA Repair;Development;Double Strand Break Repair;Ensure;Event;Failure;Genetic;Genetic Crossing Over;Genetic Recombination;Genome;Growth;High-Throughput Nucleotide Sequencing;Homologous Gene;Human;Infertility;Invaded;Location;Malignant Neoplasms;Maps;Meiosis;Meiotic Recombination;Methods;Mitosis;Mitotic Cell Cycle;Molecular;Molecular Chaperones;Pathway interactions;Population;Process;Proteins;Recombinants;Regulation;Research;Saccharomyces cerevisiae;Saccharomycetales;Sister Chromatid;Somatic Cell;Testing;Topoisomerase;Work;Yeasts;helicase;homologous recombination;insight;member;migration;mosaic;novel;prevent;recruit;repaired;tool;topoisomerase IIIalpha;transmission process Mechanism of Meiotic Recombination n/a NCI 10925948 1ZIABC005268-36 1 ZIA BC 5268 36 2068571 "LICHTEN, MICHAEL J" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 288047 NCI Meiotic double-strand DNA break (DSB) repair by homologous recombination occurs via multiple processes defined by distinct decisions points. One important decision involves partner choice between recombining with the sister chromatid (the dominant repair partner during mitosis) or with the homolog (the homologous chromosome of different parental origin the preferred partner during meiosis). Another important decision involves recombination pathway choice between producing crossovers where flanking chromosome sequences are exchanged or noncrossovers. A signature contribution of our group was the demonstration that crossover and noncrossover recombination proceed via different mechanisms that diverge after initial stages of strand invasion and that feature different biochemical activities and genetic requirements. Work during previous review periods had shown that the conserved Sgs1-Top3-Rmi1 helicase-topoisomerase complex (STR) is responsible for partitioning early recombination events between noncrossover and crossover pathways. Sgs1-Top3-Rmi1 is the yeast homolog of the mammalian BLM helicase-Top3alpha-BLAP75 complex implicated in cancer avoidance and recombination control in humans. We showed that all three members of the yeast complex are essential for normal recombination partner choice and for population of regulated meiotic crossover and noncrossover recombination pathways. Based on these findings we hypothesized that STR by promoting frequent disassembly of early strand invasion intermediates acts as a chaperone for early recombination intermediates. We hypothesized that these repeated cycles of strand invasion and disassembly would result in template switching which in turn would lead to recombinants with mosaic parental strand contributions. This hypothesis has now been confirmed by high-throughput sequencing of recombinants that occur in a highly polymorphic test interval; more than 2/3 of recombinants display clear evidence for template switching multiple strand invasions or both. In addition we uncovered evidence for activities specific to the crossover pathway including branch migration (2/3 of crossovers) and exonucleolytic gap-formation (1/3 of crossovers). Current work is aimed at determining the proteins responsible for these activities. Other work is aimed at confirming branch migration by mapping the location of Holliday junctions in recombination using a novel method we have developed to specifically purify Holliday junction-containing intermediates. Finally we are studying how chromosome structure specifically the meiotic chromosome axis contributes to the regulation of recombination. A meiosis-specific subset of chromosome axis components the Hop1 and Red1 proteins are important for meiotic DSB formation and partner choice and are enriched in some regions of the genome relative to others. Using a novel method to recruit axis proteins to regions that are normally depleted of these proteins we have shown that high concentrations of the Hop1 protein are necessary and sufficient for meiotic DSB formation but the recombination events initiated by these DSBs do not follow canonical meiotic recombination pathways. We are currently determining the mechanism by which Hop1 promotes DSB formation and what additional factors are needed for Hop1-dependent DSBs to be repaired by canonical meiotic recombination mechanisms. 288047 +No NIH Category available 20 year old;Adult;Affect;Age;Alleles;Aminoglycosides;Autopsy;B-Lymphocytes;BRAF gene;Big Data;Biological Assay;Cataract;Cell Line;Cells;Cessation of life;Child;Clinical;Cockayne Syndrome;Collaborations;Collection;Communities;DNA;DNA Damage;DNA Repair;DNA Repair Gene;Databases;Defect;Development;Disease;ERCC1 gene;ERCC3 gene;Enrollment;Epidemiologist;Eye;Eye Abnormalities;Family;Family member;Fetal Development;Follow-Up Studies;Frequencies;Functional disorder;Gene Modified;General Population;Genes;Genetic Diseases;Genetic Transcription;Goals;Growth;Gynecologic;Gynecologist;Health;Hematologic Neoplasms;Heterogeneity;Heterozygote;Histologic;Human;Human Development;Hypersensitivity;Individual;Infant;International;Investigation;Italy;Laboratories;Link;Longterm Follow-up;Malignant Neoplasms;Messenger RNA;Methods;Molecular;Mothers;Mutation;Natural History;Necrosis;Nerve Degeneration;Nevi and Melanomas;Nonsense Codon;Nucleotide Excision Repair;Operative Surgical Procedures;Ophthalmologist;PTEN gene;Patient Selection;Patients;Peripheral Nervous System Diseases;Phenotype;Point Mutation;Polymerase;Postoperative Complications;Preclinical Testing;Predisposition;Pregnancy;Pregnancy Complications;Premature Menopause;Process;Proteins;Protocols documentation;Publishing;RNA Splicing;Radiation induced damage;Rare Diseases;Reporting;Research Personnel;Risk;Role;Series;Site;Skin Cancer;Skin Carcinoma;Sun Exposure;System;Testing;Thyroid Nodule;Translational Research;Trichothiodystrophy;Tumor Suppressor Genes;Ultraviolet Rays;United States National Institutes of Health;Variant;Walking;Woman;XPA gene;Xeroderma Pigmentosum;brain size;cancer prevention;cancer risk;cell bank;cohort;exome sequencing;femur head;gene repair;hearing impairment;improved;infancy;insight;melanoma;offspring;radiologist;rare genetic disorder;systemic toxicity;targeted treatment DNA Repair in Human Cancer-Prone Genetic Diseases n/a NCI 10925947 1ZIABC004517-47 1 ZIA BC 4517 47 6568851 "KRAEMER, KENNETH H" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1676630 NCI 1. XERODERMA PIGMENTOSUM We have been examining XP patients at NIH since 1971. We performed long term follow-up studies of cancer hearing lossof eye abnormalities and gynecological health in XP patients. We found that the XP patients under age 20 years had a 10000-fold increased risk of non-melanoma skin cancer (NMSK) and a 2000-fold increased risk of melanoma. In our natural history protocol we ascertained and intensively examined more than 100 XP or Cockayne Syndrome (CS) patients and more than 200 family members at NIH and are collaborating with international researchers to study additional patients. We published detailed autopsy reports of 4 XP patients - including the first autopsy of an XP-D patient. The XP-A and XP-D patients were adults with severe neurological degeneration and were found to have infant sized brains. We found that peripheral neuropathy types differed between the XP-A and XP-D patients. We have now identified mutations in all of the 9 currently known DNA nucleotide excision repair (NER) genes (XPA XPB XPC XPD XPE XPF XPG ERCC1 and TTDA) in the error-prone polymerase pol eta and in TTDN1 in nearly 200 XP or TTD patients. We have established several hundred carefully documented cell lines and contributed them to cell banks for use of the general scientific community. We are using targeted and whole exome sequencing to look for mutations in other genes in cells from XP and TTD patients who do not have mutations in these genes. Our laboratory is the major center in the US for basic clinical and translational expertise concerning DNA repair related disorders. We are actively seeking and have developed the expertise to recognize unusual patients who have unique disease features that provide insights into the functioning of DNA repair genes. These studies have enabled us to identify some remarkable XP patients and better characterize different mechanisms of DNA repair. For example we found XPC patients with splice lariat branch point mutations who had 3 to 5% of XPC mRNA but mild disease indicating that only a small amount of XPC is sufficient for some cancer protection. We found that NER proteins accumulate and persist at sites of DNA damage in XP-B cells. In contrast these NER proteins rapidly accumulate but fail to persist in UV damaged XP-E cells. We found that the melanomas and nevi in the XP patients were different from those in the general population both clinically and histologically. They had a high proportion of mutations in the PTEN tumor suppressor gene (90% UV type) a lower frequency of mutations in BRAF NRAS or KIT and rarely had the BRAF V600E mutation found in the general population. About 12% of genetic diseases involve premature stop codons (PTC). We developed sensitive assay systems to detect readthrough of premature stop codons using cells from our collection with PTC in the XPC DNA repair gene. We found the aminoglycoside gentamycin can improve DNA repair in selected patients permitting precise targeting of therapy to responsive individual cell lines. We are plan to perform pre-clinical tests to determine if topical aminoglycosides can increase DNA repair without systemic toxicity. We are collaborating with NCI epidemiologists to study clinically normal family members of XP patients to determine if XP heterozygotes who are much more frequent than XP patients have increased cancer risk. We have more than 250 XP patients and family members in 54 families enrolled in this protocol. Our investigation of Big Data in the gnomAD database of more than 200000 alleles revealed an unexpectedly high frequency of 2 XP causing missense variants suggesting that there may be thousands of patients who are homozygous for these XP causing mutations in the US. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population. It is possible that variants in other genes modify the phenotype so that the usual features of XP are not apparent. We found that many of the women with mutations in the XPC gene have premature menopause. We found hematologic malignancies in 4 young (18 to 36 years) XP patients with mutations in the XPC gene. XP patients have increased frequency of thyroid nodules at a early age. 2. TRICHOTHIODYSTROPHY In contrast to the profound environmental influence of sun exposure on XP TTD is a disease of altered development. In our current natural history protocol we have ascertained and intensively examined more than 50 TTD or XP/TTD patients and more than110 TTD family members. This is the largest cohort of patients with this rare disorder in the world. We found that TTD patients with mutations in the TTDN1 gene had a distinct phenotype. In collaboration with gynecologists and epidemiologists we published 3 studies on pregnancy abnormalities in TTD. There was a high frequency of gestational abnormalities in pregnancies resulting in TTD affected offspring compared to pregnancies resulting in unaffected offspring from the same mothers or to the general population. These pregnancy complications were present only in pregnancies that had XP-D mutations that resulted in TTD offspring but not in XP-D mutations resulting in XP offspring. These observations provide important insights into the role of DNA repair genes in human pregnancy and fetal development. In collaboration with the ophthalmologists we published a detailed report of the eye findings of 32 TTD patients we studied from 2001 to 2010. Infantile cataracts were present in more than half of these patients. We documented the severe growth retardation in children with TTD. Several young children with TTD have lost the ability to walk due to aseptic necrosis of the femoral head. Unfortunately surgical treatment was followed by a series of post-operative complications leading to death. We are collaborating with radiologists to attempt to determine early signs of this problem and guide management. We have also found patients with features of more than one disease. Thus we identified 12 XP/TTD patients who have features of both XP and TTD and increased cancer risk. We are attempting to further define this entity by use of laboratory testing of DNA repair. In collaboration with colleagues in Italy we identified mutations in a transcription associated gene (GTF2E2) as causing TTD in two patients. This closely links TTD to transcription defects rather than DNA repair defects. 1676630 +No NIH Category available ATM activation;Ablation;Acetylation;Affect;Aging;Architecture;Binding;Binding Proteins;Biochemical;Bioinformatics;Biological Process;Biology;Bypass;C-terminal;Cell physiology;Cells;Chondrocytes;Chromatin;Chromatin Fiber;Chromatin Structure;Collaborations;Congenital Abnormality;Cytology;DNA;DNA Damage;DNA Double Strand Break;DNA Methylation;DNA Repair;Defect;Development;Developmental Process;Diagnosis;Disease;Down-Regulation;Epithelium;Etiology;Euchromatin;Event;Family;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genomic Instability;Genomic Segment;Global Change;Goals;HDAC4 gene;HMGN Proteins;HMGN1 gene;Hair;Hepatocarcinogenesis;Higher Order Chromatin Structure;Histone Deacetylase Inhibitor;Histone H1;Histone H3;Histones;Hypersensitivity;Image;Impairment;In Vitro;Investigation;Kinetics;Link;Malignant Neoplasms;Mediating;Mediator;Molecular;Molecular Target;Mus;Names;Nuclear Protein;Nuclear Proteins;Nucleic Acid Regulatory Sequences;Nucleosome Core Particle;Nucleosomes;Nucleotide Excision Repair;Organism;Pathway interactions;Pharmaceutical Preparations;Phenotype;Photobleaching;Play;Post-Translational Protein Processing;Predisposition;Property;Proteins;Research;Role;SOX9 protein;Site;Stratum Basale;Stress;Structural Protein;Structure of beta Cell of islet;System;TP53 gene;Therapeutic;Up-Regulation;ataxia telangiectasia mutated protein;blastomere structure;cancer therapy;corneal epithelium;ds-DNA;embryo cell;epigenetic marker;epigenetic regulation;gamma irradiation;genome-wide;histone modification;insight;interdisciplinary approach;lead-binding proteins;link protein;novel;protein expression;protein function;reconstitution;repaired;targeted treatment;tissue culture;tumorigenesis;tumorigenic;ultraviolet irradiation Chromosomal Proteins and Chromosomal Functions n/a NCI 10925946 1ZIABC004496-46 1 ZIA BC 4496 46 6568847 "BUSTIN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 197210 NCI Chromatin regulates gene expression and therefore plays a key role in developmental processes and in the etiology of various diseases including cancer. Nuclear protein such as histone H1 and HMGs have been shown to bind to and alter the properties of the chromatin fiber. Changes in the expression of these architectural proteins are linked to various developmental defects and to various diseases including cancer. However in spite of numerous studies the mechanism of action and the exact cellular function of these proteins remains one of the most perplexing aspects of chromatin biology. We are using a multidisciplinary approach including analyses of genetically modified mice to gain a comprehensive understanding of the biological function and mechanism of action of the HMGN proteins the only nuclear proteins that bind specifically to the nucleosome core particle the building block of the chromatin fiber. Biochemical and cytological approaches were used to demonstrate that the binding of these proteins to chromatin alters the higher-order chromatin structure and affect the cellular transcription profile. Using immunochemical analysis and fluorescent photobleaching imaging of living cells we demonstrated that the binding of HMGNs and H1 to chromatin is dynamic rather than static a finding that led to new insights into the kinetics of the intranuclear organization of most nuclear proteins. By microinjecting proteins into living cells expressing tagged proteins we demonstrated that H1 and HMGs form a network of competitive interactions on nucleosomes a novel concept that is relevant to understanding functional redundancy among related proteins and cellular homeostatic mechanisms. We have discovered a new chromatin binding protein named HMGN5/NSBP1 which we show that it binds specifically to euchromatin the genomic region containing transcriptionally active genes. We observed that this protein changes the global structure of chromatin and demonstrated that the C-terminal region of HMGN5 specifically interacts with the C-terminal region of H1. These studies provide fundamental insights into the molecular mechanisms governing chromatin dynamics. By analyzing Hmgn1-/- cells and by studying in vitro nucleosome reconstitution systems we found that H1 and HMGNs affect the levels of histone posttranslational modifications thereby identifying an additional mechanism that regulates the levels of these epigenetic markers. Indeed mice and cells lacking HMGN1 are more susceptible to various stresses such as heat ahock and DNA damage. The hypersensitivity to stress can be directly related to HMGN-dependent changes in histone modifications. Alterations in the levels of posttranslational modifications of histones have been linked to multiple biological processes including genetic instability and cancer. Our analyses of genetically modified mice and cells derived from these mice indicate that HMGN proteins play a role in the repair of damaged DNA and in the etiology of certain cancers. We find that loss of HMGN1 impairs the repair of both single stranded and double stranded DNA damage. The repair of the single stranded damage is impaired because the nucleotide excision repair (NER) cannot effectively access the damage sites. The repair of double stranded DNA breaks (DSB) is largely dependent on the action of the nuclear protein kinase ataxia-telangiectasia mutated (ATM). ATM regulates the activity of key molecules that affect tumorigenesis including p53. We found that loss of HMGN1 or ablation of its ability to bind to chromatin reduces the levels of DSB-induced ATM autophosphorylation and the activation of several ATM targets. HMGN1 alters the interaction of ATM with chromatin both prior to and following the induction of DNA damage and also enhances the DSB-induced acetylation of Lys14 of histone H3 (H3K14). Treatment of cells with a histone deacetylase inhibitor bypasses the HMGN1 requirement for ATM activation. Thus HMGN1 mediate the efficient activation of ATM by optimizing its chromatin interactions both prior to and after DSBs formation. Our studies identify a new mediator of ATM activation and demonstrate a direct link between the steady-state intranuclear organization of ATM and the kinetics of its activation following DNA damage. As chromatin binding proteins HMGNs affect developmental processes. We found that the expression of HMGN proteins is developmentally regulated and that during development the expression of these proteins is severely down regulated. Loss of HMGN1 affects the in vitro differentiation of chondrocytes. This effect is due to misexpression of Sox-9 a key regulator of chondrocyte differentiation. HMGNs bind to the chromatin of Sox 9 gene and affect its expression. Likewise we find that HMGN1 is expressed in the hair bulge region and loss of HMGN1 protein alters the hair cycle. We also found that HMGN1 is highly expressed in the basal layer of the epithelium including the corneal epithelium. Loss of HMGN1 affects the organization of the corneal epithelium. In mouse embryonic cells misexpression of HMGN affects several differentiation pathways. The results suggest that HMGNs regulate transcription levels of specific genes. Indeed our recent unpublished studies indicate that either down regulation or upregulation of HMGN in cells alters the cellular transcription profile. Towards further understanding the molecular mechanisms whereby HMGNs affect the cellular transcription profile we have initiated several collaborations aimed at elucidating the genome wide global organization of HMGNs. The results indicate that genome-wide HMGNs are associated with chromatin regulatory regions.A major new finding is that redundant and compensatory binding of HMGN proteins to nucleosomes maintain DNaseI hypersensitive regions in chromatin. This finding suggests that HMGN proteins maintain or establish regulatory sites in chromatin. Taken together our findings with genetically engineered mice and cells and our previous biochemical findings indicate that HMGNs are fine tuners of chromatin function and that proper differentiation and proper cellular function requires regulated expression of HMGN. 197210 +No NIH Category available Address;Artificial Intelligence;Cancer Patient;Caring;Clinical;Cranial Irradiation;Detection;Early Diagnosis;Evolution;Feedback;Future;Incidence;Metastatic malignant neoplasm to brain;Patients;Performance;Phase;Small Business Innovation Research Grant;Software Tools;Time;Treatment outcome;brain size;cancer diagnosis;cancer therapy;commercialization;deep learning;experience;improved;outcome prediction;prototype;quantitative imaging;tool;treatment planning SBIR TOPIC 417: QUANTITATIVE IMAGING SOFTWARE TOOLS FOR CANCER DIAGNOSIS AND TREATMENT PLANNING n/a NCI 10924835 75N91023C00032-0-9999-1 N44 8/28/23 0:00 8/27/25 0:00 79324354 "JIANG, HAO " Not Applicable 2 Unavailable 92852291 DCWKBA5KJVY1 92852291 DCWKBA5KJVY1 US 43.078163 -89.539926 10061870 NEURALRAD LLC MADISON WI Domestic For-Profits 537172728 UNITED STATES N R and D Contracts 2023 1990308 NCI With brain metastases (BMs) incidences rapidly increasing due to improved systemic treatment and cancer patients survival the BMs management strategies have evolved substantially from whole brain irradiation to localized multisession SRS. The evolution requires contouring and distributed SRS planning for multiple BMs and treatment followups and has put a high demand on care teams time efforts and experience creating a heavy burden on clinicians. Automated effective and efficient tools are unmet clinical needs. 1990308 +No NIH Category available Businesses;Cancer Center Support Grant;Clinical Research;Collaborations;Communication;Community Outreach;Comprehensive Cancer Center;Computers;Consultations;Databases;Decision Making;Dedications;Development;Documentation;Education and Outreach;Educational workshop;Ensure;Equipment;Evaluation;Faculty Recruitment;Film;Fostering;Funding;Funding Opportunities;Future;Goals;Grant;Health;Humanities;Indigenous;Information Systems;Information Technology;Infrastructure;Investments;Leadership;Maintenance;Malignant Neoplasms;Marketing;Mission;Monitor;Process;Recommendation;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Resource Allocation;Resource Sharing;Resources;Science;Services;Strategic Planning;Teacher Professional Development;Training and Education;community engagement;flexibility;grasp;healing;health communication;meetings;member;personalized approach;programs;tool ADMINISTRATION n/a NCI 10924238 9/15/23 0:00 PA-20-272 3P30CA016056-46S2 3 P30 CA 16056 46 S2 "HE, MIN" 6/16/97 0:00 4/30/24 0:00 8050 15303874 "HENRY, DALE " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 200000 116482 83518 The Roswell Park Comprehensive Cancer Center Administration provides the resources guidance processesand expertise to enable Roswell Park to achieve its mission to eliminate cancer's grip on humanity byunlocking its secrets through personalized approaches and unleashing the healing power of hope.Administration infrastructure identifies strategic priorities oversees programmatic activities and ensuresefficient execution of governance planning evaluation space and resource allocation. Administration benefitsfrom a large and robust infrastructure which includes teams focused on research Information Technologymarketing and grant fiscal management.During the current grant period Administration successfully facilitated new faculty recruitment and facultydevelopment; administrative leadership of the planning and evaluation process; administrative oversight ofCCSG Programs and Shared Resources; development and management of computer databases and otherinformation systems tools; fiscal management and consultation; space and equipment management; supportfor selection and monitoring of pilot research funding; administration of the CCSG membership and reviewprocess; coordination of research seminars workshops and retreats; leadership and assistance in developingcollaborations between and among investigators for new research and team science initiatives; planningcoordination and execution of multi-project research grants (e.g. SPOREs PPGs); and targetedcommunication of cancer-related funding opportunities to CCSG members.Administration facilitates the mission of Roswell Park by ensuring efficient and strategic use of funds spaceand Shared Resources. Administration provides the organizational support for CCSG members' research andfacilitating translational collaborations. Administration adds value by supporting five research programs 15Shared Resources and other key components including education and training clinical research andcommunity outreach and engagement. Administration ensures that CCSG members have access to state-of-the-art equipment and services in support of their research. Administration will enhance its support of CCSGmembers and Programs through sophisticated reporting mechanisms to allow Senior Leadership to align betterstrategic plans and informed decision-making and increase the value of Shared Resource use to CCSGmembers. +No NIH Category available Area;Cancer Patient;Cause of Death;Consent;Data;Dose;Electronics;Guidelines;Health Personnel;Hospitals;Individual;Laws;Life;Malignant Neoplasms;Medical;National Cancer Institute;Oncologist;Oncology;Patients;Physicians' Offices;Provider;Recurrence;Reporting;SEER Program;Series;Source;System;Systemic Therapy;cancer care;data registry;demographics;follow-up;interest;neoplasm registry;surveillance data;transmission process ELECTRONIC CAPTURE OF CANCER CLAIMS DATA FOR THE SEER PROGRAM n/a NCI 10923772 75N91021P00809-P00003-0-1 N02 9/7/21 0:00 9/6/24 0:00 78346133 "GOCKERMAN, BRIAN " Not Applicable Unavailable 57900426 T669R8JHHBG7 57900426 T669R8JHHBG7 US -472194 CINCINNATI OH Other Domestic Non-Profits 452361670 UNITED STATES N R and D Contracts 2023 306000 NCI Healthcare providers in all 50 states are required by law to report new cases of cancer to their states cancer registries. The National Cancer Institutes (NCIs) Surveillance Epidemiology and End Results (SEER) Program collects data on eachand every cancer patient in SEER covered areas. This data includes demographics a description of their cancer limited initial treatment information and patient follow-up including cause of death for deceased patients. In the past the main source of registry data came from Hospitals. With the increasing complexity of cancer care and delivery systems patients are being increasingly treated exclusively at physicians offices. Thus for SEER to continue capturing all cancer casesand their treatment information SEER is interested in obtaining other sources of data such as claims data from oncology practices. Oncology practice claims has proven to be a rich source of information on detailed systemic therapy includingagents doses administration dates etc. 306000 +No NIH Category available Adoption;Awareness;Communication;Communities;Community Health;Contractor;Development;Division of Cancer Control and Population Sciences;Equipment;Future;Government;Government Agencies;Health Services;Human Resources;Intervention;Measures;National Cancer Institute;Population Group;Public Health;Qualifying;Research;Research Institute;Research Support;Services;Work;behavioral health;improved;insight;mHealth;outreach;smoking cessation;tool INTERNAL AND EXTERNAL COMMUNICATIONS AND DISSEMINATION SUPPORT FOR DCCPS n/a NCI 10923771 91021A00291022F00001-P00001-0-1 N02 9/15/22 0:00 9/14/24 0:00 78859097 "KILGORE, ELIZABETH " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2023 2980107 NCI The National Cancer Institute (NCI) has created smoking cessation and other behavioral health services for multiple population groups and diverse audiences. NCI needs to provide support for the ongoing development and maturation of these services adoption within the public health community and among target audiences and engagement with research communities to continue to evolve and advance mobile health interventions and the awareness of them. Independently and not as an agent of the Government the Contractor shall furnish all the necessary services qualified personnel material equipment and facilities not otherwise provided by the Government as needed to perform the Statement of Work.The primary objectives of this task are to provide engagement and outreach support to internal and external audiences to help set and refine research agendas improve awareness of NCI research and availability of NCI-developed tools to support research efforts by grantees and other partners; reach target audiences through partnerships as well as earned paid and other outreach efforts; measure the impact of these efforts and provide analysis and insights that may be used in similar future efforts. 2980107 +No NIH Category available 3-Dimensional;Anatomy;Brain;Brain imaging;Breast;Clinical Trials;Development;Diagnostic;Ensure;Health;Investigation;Life;Methods;Organ;Patient Recruitments;Patients;Performance;Phase;Prostate;Radiation therapy;Risk Reduction;Safety;Shapes;Small Business Innovation Research Grant;Speed;Technology;X-Ray Computed Tomography;breast imaging;cancer imaging;commercialization;design;fabrication;improved;large datasets;lung imaging;malignant breast neoplasm;novel strategies;validation studies SBIR TOPIC 401 PHASE II: n/a NCI 10923637 75N91023C00043-0-9999-1 N44 9/18/23 0:00 9/17/25 0:00 79342291 "GHAZI, PH.D., PEYMON " Not Applicable 17 Unavailable GSB6L7B1FB13 GSB6L7B1FB13 US 10073221 MALCOVA INC NEWARK CA Domestic For-Profits 94560 UNITED STATES N R and D Contracts 2023 1998128 NCI As long as breast cancer remains a pervasive health concern the need for ever-improving breast cancer imaging and radiation therapy technologies will exist. Design changes to incorporate new hardware technologies or methods - may trigger the need for clinical trials to ensure safety and assess performance. Conducting a clinical trial is not only expensive but often takes years for patient recruitment and study. Utilizing physical phantoms rather than patients would be faster far less expensive reduces risk to patients and potentially increases the speed with which life-saving technological advances are made available to the public. Currently commercially available compressed and uncompressed breast phantoms do not produce realistic breast images; rather they provide basic breast shapes with no anatomical information. Utilizing access to a large data set (over 200) of three-dimensional real patient breast CT images at UC Davis and a novel approach to phantom development we propose to fill this need. In this Phase II SBIR project we will develop and commercialize patient-derived anthropomorphic phantoms for use in diagnostic and radiation therapy applications. We will also investigate the utility of our core technology in developing anthropomorphic phantoms for prostate brain and lung imaging applications. 1998128 +No NIH Category available Genome Characterization Unit n/a NCI 10923429 9/11/23 0:00 RFA-CA-19-045 5U2CCA252979-03 5 U2C CA 252979 3 "FILIPSKI, KELLY" 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-O(M1) 5450 1934123 "CLAUS, ELIZABETH B." "KWAN, BETHANY MATTHEWS; VERHAAK, ROEL GW" 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 472803 515509 347968 No abstract available +No NIH Category available Address;Adopted;Aerobic Exercise;Agreement;Behavior;Cancer Intervention;Cancer Survivor;Classification;Clinic;Communities;Community Practice;Data;Development;Enrollment;Exercise;Focus Groups;Goals;Guidelines;Health;Individual;Intervention;Interview;Leisures;Location;Maintenance;Malignant Neoplasms;Manuals;Measures;Modality;Modeling;Needs Assessment;Outcome;Participant;Partnership Practice;Phase;Physical activity;Procedures;Protocols documentation;Public Health;Randomized;Recommendation;Research;Resources;Sequential Multiple Assignment Randomized Trial;Site;Structure;Subgroup;Surveys;Survivors;Testing;Time;Training;active lifestyle;adaptive intervention;behavior change;cancer diagnosis;cancer therapy;evidence base;exercise intervention;exercise program;fitness;follow-up;improved;intervention delivery;moderate-to-vigorous physical activity;mortality;personalized approach;pilot trial;primary outcome;programs;psychosocial;resistance exercise;response;social cognitive theory;success;theories;therapy design;videoconference An adaptive physical activity maintenance intervention for cancer survivors Despite the success of interventions for increasing physical activity among cancer survivors many survivorsreturn to inactive or insufficiently active behaviors after the intervention ends. To facilitate long-termmaintenance of physical activity we propose to test an adaptive intervention approach which allocatesadditional support and resources to those who are having difficulty maintaining physical activity following thecompletion of an exercise program. The results from this study will inform the development and implementationof strategies to help cancer survivors maintain sufficient levels of physical activity. NCI 10923121 9/19/23 0:00 PAR-18-307 4R33CA256656-03 4 R33 CA 256656 3 "PERNA, FRANK" 9/1/21 0:00 8/31/26 0:00 Lifestyle Change and Behavioral Health Study Section[LCBH] 14430691 "LEACH, HEATHER JEAN" Not Applicable 2 NONE 785979618 LT9CXX8L19G1 785979618 LT9CXX8L19G1 US 40.57951 -105.081267 1725201 COLORADO STATE UNIVERSITY FORT COLLINS CO UNIVERSITY-WIDE 805232002 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 320970 NCI 221328 99642 It is well established that structured moderate to vigorous physical activity (i.e. aerobic and resistanceexercise) improves many physical and psychosocial health outcomes for cancer survivors. However it isestimated that less than half of cancer survivors are achieving the cancer-specific exercise guidelines.Interventions that are supervised and include theory-based behavior change strategies are effective forincreasing moderate to vigorous physical activity (MVPA) among cancer survivors; but following anintervention many survivors return to previously inactive or insufficiently active lifestyles. To achieve the manybenefits associated with MVPA or exercise cancer survivors must not only adopt or begin a program but alsobe able to maintain these PA levels long-term. In addition to individual behavior change strategiesinterpersonal and environmental support for PA can extend the success of PA interventions. This can beachieved by increasing the accessibility of tailored evidence-informed cancer-specific exercise programs atcommunity-based locations. Thus we propose to engage in a research-practice partnership to deliver anadaptive PA maintenance intervention for cancer survivors. In the R21 phase we will examine acceptability ofmaintenance intervention components and conduct a needs assessment for intervention delivery at three-community partner locations. In the R33 phase we will utilize an adaptive intervention design to determine theoptimal level of support needed to maintain PA following a community-based exercise program. We will enrollcancer survivors who are not currently achieving aerobic and resistance exercise guidelines in a three-monthsupervised group-based exercise and PA behavior change program at one of three community fitnessfacilities. Upon completion of the program participants will be encouraged to continue exercising during athree-month free-living follow-up period during which time there will be no active intervention. After this follow-up period exercise levels will be assessed. Those who are not achieving aerobic and resistance exerciseguidelines for cancer survivors will be classified as incomplete responders and randomized to one of twosubsequent interventions: (a) monthly PA behavior change discussion sessions or (b) monthly PA behaviorchange discussion sessions plus bi-weekly exercise sessions. Responders will be randomized to either: (c) nofurther intervention or (d) monthly PA behavior change discussion sessions. After three-months of thesubsequent PA maintenance intervention exercise levels will be assessed again (i.e. 6-months aftercompletion of the initial exercise program). This project is significant because it aims to develop a tailoredapproach to enhancing PA maintenance by identifying non-responders and providing them with the additionalsupport necessary to engage in MVPA long-term. Delivering the intervention in community-based facilities willincrease potential for scalability and widespread dissemination. Findings from this study will prepare our teamto test this intervention in a full-scale adaptive trial powered for efficacy. 320970 +No NIH Category available Area;Automobile Driving;Awareness;Basic Science;Biological;California;Cancer Center Support Grant;Caring;Catchment Area;Characteristics;Clinical;Clinical Research;Communities;Comprehensive Cancer Center;Data;Dedications;Development;Diagnosis;Disease;Dissemination and Implementation;Early Diagnosis;Ensure;Environment;Family;Funding;Health;Individual;Inequity;Infrastructure;Intervention;Location;Malignant Neoplasms;Mission;Outcome;Patient-Focused Outcomes;Population;Population Heterogeneity;Population Research;Population Sciences;Prevention;Process;Research;Research Support;Resource Sharing;Risk;San Francisco;Science;Strategic Planning;Training and Education;Translating;Translations;Treatment outcome;Universities;anticancer research;community engagement;equity diversity and inclusion;improved;improved outcome;innovation;insight;member;programs;screening;treatment center Cancer Center Support Grant UCSF Helen Diller Family Comprehensive Cancer Center: NarrativeThe UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) seeks to drive scientific discoveryand develop tailored interventions to improve cancer outcomes in the catchment area and beyond. Thismission established through a unique strategic planning process encompasses three Center-wide themesthat are integrated throughout the HDFCCC and will drive research into the next decade and thereafter:Impactful Discovery Effective Translation and Implementation and Dissemination. NCI 10922953 9/21/23 0:00 PAR-21-321 3P30CA082103-24S1 3 P30 CA 82103 24 S1 "SHAFIK, HASNAA" 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 10746885 "ASHWORTH, ALAN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/21/23 0:00 5/31/24 0:00 397 Research Centers 2023 295695 NCI 190048 105647 UCSF Helen Diller Family Comprehensive Cancer Center: Summary/AbstractThe UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) seeks to drive scientific discoveryand develop tailored interventions to improve cancer outcomes in the catchment area and beyond. Thismission established through a unique strategic planning process encompasses three Center-wide themesthat are integrated throughout the HDFCCC and will drive research into the next decade and thereafter. Theme 1 (Impactful Discovery): Advance innovative basic clinical and population research focused on unique characteristics of the individual disease population and community. Theme 2 (Effective Translation): Translate research to define risk emphasize prevention optimize diagnosis tailor screening and treatment and improve outcomes. Theme 3 (Implementation and Dissemination): Reduce inequities in cancer awareness prevention early detection and diagnosis care treatment and patient-centered outcomes through data-driven science and community engagement.The environment of the HDFCCC allows transdisciplinary connections between each theme thus ensuringcontinuity of support for research across the cancer continuum from basic discovery science to populationscience. This is accomplished through seven research programs supported by seven shared resourcesdevelopmental funds and robust clinical and administrative infrastructure. The HDFCCC defines threeFoundational Principles that are integrated throughout the Center and inform every aspect of cancer research:Community Engagement; Education and Training; and Diversity Equity Inclusion and Accessibility.The HDFCCC builds on the richness of the basic biological insights and the extensive and exceptional clinicalresearch and facilities at UCSF a university dedicated to health research. Moreover its location in the SanFrancisco Bay Area of Northern California allows the HDFCCC to leverage one of the most culturally diversepopulations and highly innovative and intellectually vibrant environments in the world. This environment helpssupport the translational transdisciplinary research of HDFCCC members in alignment with the Centersresearch mission of driving scientific discovery and developing tailored interventions to improve canceroutcomes. 295695 +No NIH Category available Development of polymeric synthetic biomaterial IP-001 to potentiate asystemic immunotherapy of hepatocellular carcinoma via thermal ablation PROJECT NARRATIVEImmunophotonics proposes this IND-enabling research project for the development of a polymeric syntheticbiomaterial IP-001 to potentiate a systemic immunotherapy via microwave thermal tumor ablation fortreatment of hepatocellular carcinoma. IP-001 aims to reduce recurrence post ablation and prolong overallsurvival in patients by eliciting immune control over systemic micro-metastases. It revolutionizes the field ofinterventional radiology by transforming it into a means of early immunotherapy that can be applied broadly toother solid cancers without disruption to the standard of care. NCI 10921633 9/15/23 0:00 PA-20-260 4R44CA257683-02 4 R44 CA 257683 2 "ZHAO, MING" 8/16/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-R(11)B] 15451922 "LAM, SIU KIT " Not Applicable 1 Unavailable 962754201 TKECQDEX4LA9 962754201 TKECQDEX4LA9 US 38.636981 -90.252702 10027754 "IMMUNOPHOTONICS, INC." St. Louis MO Domestic For-Profits 63110 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1219852 NCI 815238 324903 Abstract: Immunophotonics is a biotech company developing a synthetic biopolymer IP-001 to potentiate asystemic immunotherapy via microwave (MWA) thermal tumor ablation for treatment of Hepatocellularcarcinoma (HCC). The goal of this SBIR Fast Track is to complete preclinical safety and efficacy testing tosupport an investigational new drug (IND) application based on the feedback from a meeting with the FDA.Significance: HCC is the fourth most common cause of cancer-related death worldwide with 42030 newcases in the U.S. in 2019. This rise is partly due to an increase in hepatitis-induced cirrhosis and non-alcoholicsteatohepatitis (NASH) associated with obesity and diabetes. Currently hepatic transplant and surgicalresection provide the best opportunity for long term remission but less than 20% of patients are eligible. Non-surgical candidates with regional disease only have a 10.8% five-year survival rate. Thermal liver ablativetherapies like MWA are a standard of care alternative to surgeries for BCLC stage 0 A and a subset of stage BHCC patients. However ablation targets only local tumors and systemic tumoricidal effects on micro-metastasisare rare leading to recurrence rate of around 70% after two years. Better therapies for HCC are needed.Product: IP-001 is intended for intratumoral injection immediately after thermal ablation (MWA). It acts by 1)localizing tumor antigens liberated by ablation and prolonging their availability to the immune system and 2)activating immune cells such as antigen-presenting cells. This results in a stronger systemic T cell responsethat can reduce local recurrence eliminate metastases and elicit long-term memory. Investigator-driven trialsin advanced breast cancer show a favorable toxicity profile and early signs of systemic efficacy with somecomplete responders achieving long-term remission. The company has received clinical trial application (CTA)approval in Switzerland to begin a Phase 1/2 clinical trial in melanoma and soft tissue sarcoma.Impact: In HCC patients who receive MWA ablation IP-001 aims to lower recurrence by 50% in stage 0 A & Bpatients and prolong progression-free survival by 50% and overall survival in stage B & C patients with regionaldisease. IP-001 could revolutionize the field of interventional oncology by transforming it into a means of earlyimmunotherapy that is broadly applicable to other solid cancers without disruption to the standard of care.Approach and Specific Aims: In the Phase I Immunophotonics will generate feasibility data of MWA+ IP-001in orthotopic rat HCC model H-4-II-E (in collaboration with Dr. Rob Martin at the University of Louisville) to 1)establish efficacy and generate data demonstrating heightened systemic immune stimulation against cancer2) explore potential synergism with systemic immunotherapy i.e. checkpoint inhibitor anti-PD-1 in mouse HCCmodel Hepa1-6. In the Phase II segment Immunophotonics will further determine 1) maximum tolerated doseof IP-001 for liver injection 2) impacts of common comorbidity NASH/cirrhosis on treatment efficacy and 3)will develop CMC methods for scaling up and analysis of the drug product. 1219852 +No NIH Category available Address;Administrator;Atlas of Cancer Mortality in the United States;Award;Bioethics;Biomedical Research;Cessation of life;Child;Childhood;Childhood Leukemia;Clinical Trials;Clinical Trials Design;Comprehension;Consolidated Framework for Implementation Research;Data;Decision Making;Disease;Dissemination and Implementation;Education;Effectiveness;Equity;Ethnic Origin;Feedback;Future;Goals;Hispanic;Hispanic Populations;Hybrids;Incidence;Inequity;Informed Consent;Institute of Medicine (U.S.);Intervention;Knowledge;Limited English Proficiency;Linguistics;Longevity;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Methods;Minority Participation;Modeling;Newly Diagnosed;Not Hispanic or Latino;Outcome;Parents;Patient Participation;Pediatric Oncologist;Physicians;Population;Population Heterogeneity;Provider;Qualitative Methods;Randomized;Research;Sampling;Scientist;Site;Survival Rate;Testing;Training;Translating;Work;acceptability and feasibility;anticancer research;behavioral clinical trial;cancer health disparity;cancer therapy;clinical care;compare effectiveness;cost;design;effectiveness/implementation design;ethnic disparity;hybrid type 1 trial;implementation intervention;implementation science;improved;infancy;leukemia;literacy;patient navigation;peer;pilot test;post intervention;primary outcome;racial disparity;randomized clinical trials;recruit;satisfaction;secondary outcome;survival disparity;treatment as usual COMPRENDO: Adaptation and Implementation of a Peer-Navigation Intervention to Improve Research Literacy and Diversity in Pediatric Leukemia Clinical Trials NARRATIVEWhereas Hispanic children will comprise 33% of the U.S. population and have higher incidence of certaincancers their participation in biomedical research is critically low and they have poorer survival rates than non-Hispanic Whites. Interventions to improve research literacy and clinical trial participation particularly forHispanics are lacking. The objective of this proposal is to improve research literacy in parents of children withleukemia by adapting (from the patient-navigation model) and implementing a tailored peer-navigationintervention. NCI 10921490 9/13/23 0:00 PAR-16-400 3K08CA230306-05S1 3 K08 CA 230306 5 S1 "RODRIGUEZ, LARITZA MARIA" 7/17/18 0:00 6/30/24 0:00 Career Development Study Section (J)[NCI-J] 12571768 "ARISTIZABAL, PAULA " Not Applicable 50 PEDIATRICS 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 7/1/22 0:00 6/30/24 0:00 398 Other Research-Related 2023 148614 NCI 137606 11008 ABSTRACTChildhood cancer is the leading cause of child death by disease past infancy in the US. While survival hasimproved mainly due to patient participation in clinical trials critical racial/ethnic disparities remain. Comparedto non-Hispanic White (NHW) children Hispanics have higher incidence of leukemia and poorer survival rates.Although Hispanics will comprise 33% of the U.S. childhood population by 2060 their participation inbiomedical research is critically low and as shown in our prior work Hispanics are underrepresented inpediatric cancer research. As a result outcomes data are obtained mostly from NHW. Our preliminary dataand research from others suggest that adequate informed consent and low research literacy (capacity tounderstand and act on information to make decisions about research) are barriers to minority participation inclinical trials. Interventions to improve research literacy and clinical trial participation particularly for Hispanicsare lacking. There is an urgent need to fill this gap in knowledge as tailored interventions guided byimplementation science can improve research literacy and minority participation in clinical trials. The objectiveof this K08 is to improve research literacy in parents of children with leukemia by adapting (from the patient-navigation model) and implementing COMPRENDO (ChildhOod Malignancy Peer REsearch NavigatiOn) atailored peer-navigation intervention (PNI). Our hypothesis and rationale are that PNIs guided byimplementation science in which trained peers deliver culturally and linguistically concordant education toparents during informed consent can identify and address barriers to: a) adequate research literacy and b)equitable clinical trial participation. By increasing minority participation in clinical trials we can effectivelytranslate discoveries and treatments and ultimately improve equity of survival in diverse populations which isa top priority for NCI. We propose to implement COMPRENDO to improve parental research literacy in pediatricleukemia clinical trials using mixed-methods and implementation science (Aim 1). We will compare theeffectiveness of COMPRENDO vs. usual care in improving research literacy outcomes among parents ofchildren with leukemia (Aim 2) using a Hybrid Trial Type 1 effectiveness and implementation design. Wehypothesize that compared to usual care parents randomized to the PNI will show higher comprehensionvoluntariness and accrual and lower mistrust post informed consent discussion and 4 weeks post intervention.This K08 award builds on the formative work of the PI in bioethics and pediatric cancer disparities and maps onto the PIs training goals in implementation science intervention adaptation qualitative methods andbehavioral clinical trial design. This K08 has an important impact: knowledge gained can be generalized toHispanics across the lifespan and will help to: a) inform clinical care and b) design a multi-site randomizedclinical trial in which COMPRENDO will be tested in a larger sample of Hispanics with a broader range ofcancers in a future R01 enabling the PIs transition to independence as a successful physician-scientist. 148614 +No NIH Category available Comprehensive atlas of advanced adenomas and their surrounding primed colon: A multi-omics evaluation and clinical impact assessment n/a NCI 10920978 9/11/23 0:00 PA-20-272 3U54CA274374-02S1 3 U54 CA 274374 2 S1 "PATRIOTIS, CHRISTOS F" 9/20/22 0:00 8/31/27 0:00 ZCA1(M1) 9355 1865649 "GRADY, WILLIAM MALLORY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 174911 152057 22854 No abstract available +No NIH Category available Validation of a lab-free low-cost screening test for prevention of cervical cancer: automated visual evaluation PROJECT NARRATIVEThe proposal involves developing and testing a cervical cancer screening test: automated visual evaluation(AVE) based on an image classification algorithm that runs on smartphone-based colposcope. Included areboth technical development to integrate AVE to a mobile phone application (Phase I) and a prospectivevalidation on a screening population of 10000 women in El Salvador (Phase II). AVE will be compared tostandard tests (conventional cytology and visual inspection with acetic acid: VIA) for primary screening andagainst VIA triage in an HPV+ population. NCI 10920866 9/20/23 0:00 PAR-18-801 4R44CA247137-03 4 R44 CA 247137 3 "ZHAO, MING" 7/1/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-SBIB-T(10)B] 14981979 "LEVITZ, DAVID " Not Applicable 29 Unavailable 117700929 US2TMMJ7N4M6 117700929 US2TMMJ7N4M6 US 10065675 "DL ANALYTICS, LLC" NORTH HOLLYWOOD CA Domestic For-Profits 916023208 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1286675 NCI 1143191 59309 PROJECT SUMMARY/ABSTRACTArtificial intelligence (AI) has the potential to revolutionize medicine by improving productivity reducing humanerror and assisting with diagnosis and treatment. Image classification algorithms can be used to developautomated visual evaluation (AVE): a potential game-changer for cervical cancer prevention in low- andmiddle-income countries (LMICs). AVE technology reads digital photographs of a cervix to provide diagnosisand treatment recommendations in seconds. AVE is a true point of care test low cost and does not require alaboratory. AVE could be used either for stand-alone primary screening or to triage HPV-positive women. Wewill compare AVE to common screening methods in LMICs: visual inspection with acetic acid (VIA) andconventional cytology. Enhanced Visual Assessment (EVA) System by MobileODT is a cloud-connectedmobile colposcope on a smartphone platform. It is FDA cleared and used in 42 countries. MobileODT isuniquely poised to integrate AVE into the EVA System.Our aim is to validate and commercialize AVE on the EVA platform. Phase I aims will adapt AVE to run on theEVA system using an optimal neural network architecture running either directly on the phone or as a cloud-based service. Phase II is a prospective clinical trial of 10000 patients recruited at ministry of health sites in ElSalvador. All screen-positive patients and 10% of negative patients will undergo colposcopy with biopsy.Sensitivity of AVE as a primary screening test will be compared to cytology and to VIA. In HPV-positivewomen AVE will be compared to VIA as a triage test. 1286675 +No NIH Category available Antibodies;Basic Cancer Research;Basic Science;Biological Markers;Breast;Breast Cancer Model;Breast Melanoma;Budgets;CD8B1 gene;Cancer Center Support Grant;Cancer Patient;Cancer Vaccines;Cell Separation;Cell Therapy;Cell surface;Cells;Charge;Chromatin Loop;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Cooperative Group;Clustered Regularly Interspaced Short Palindromic Repeats;Color;Communication;Complex;Comprehensive Cancer Center;Consultations;Copy Number Polymorphism;Correlative Study;Cytometry;Data;Diagnostic;Diet;Direct Costs;Disease Outcome;Doctor of Philosophy;ENG gene;Education;Equipment;Faculty;Fasting;Feedback;Flow Cytometry;Fluorescence;Foundations;Funding;Genome;Genomics;Genomics Shared Resource;Grant;Gynecologic Oncology Group;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Immune;Immune checkpoint inhibitor;Immunologic Monitoring;Immunologics;Immunotherapy;Institution;Laboratories;Last Name;Local Therapy;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mediating;Methods;Mission;Molecular;Names;Natural Killer Cells;Neoplasm Circulating Cells;Neuroblastoma;Oncology;Outcome;Pathogenesis;Pathology;Patients;Peer Review;Phenotype;Population;Proteins;Publications;Regulation;Reporting;Research;Research Design;Research Personnel;Research Support;Resolution;Resource Sharing;Role;Services;Sorting;Surveys;System;T cell clonality;Technology;Therapeutic;Time;Training and Education;Translational Research;Tropism;Tumor-Infiltrating Lymphocytes;University of Southern California Norris Cancer Center;anticancer research;cancer cell;cancer clinical trial;cancer immunotherapy;cancer prevention;chemoradiation;chemotherapy;cost;cost effective;cytotoxic;epigenomics;high throughput analysis;immune function;immunological status;immunoregulation;immunotherapy clinical trials;improved;instrument;ipilimumab;member;mesenchymal stromal cell;mutant;pre-clinical;programs;prostate cancer risk;response;satisfaction;transcriptome sequencing;translational cancer research;tumor heterogeneity;tumor microenvironment;tumor-immune system interactions;vector Flow Cytometry Core n/a NCI 10920816 9/18/23 0:00 PA-20-272 3P30CA014089-47S2 3 P30 CA 14089 47 S2 "HE, MIN" 12/1/96 0:00 11/30/26 0:00 7524 1972649 "KAST, WIJBE MARTIN" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 Research Centers 2023 199418 120494 78924 PROJECT SUMMARY Flow Cytometry and Immune Monitoring Shared ResourceThe mission of the USC Norris Comprehensive Cancer Center (NCCC) Flow Cytometry and Immune MonitoringShared Resource (FCIM) is to provide advanced multi-parameter flow cytometry cell sorting capabilities andimmune monitoring services for advancing basic translational and clinical research with options for full-servicetechnical support for cancer clinical trial immune-monitoring correlative studies. NCCC Administration overseesFCIM with Martin Kast PhD (continuing in the role) and Rong Lu PhD (new in the role in 2015) as the faculty Co-Directors. Kast and Lu have extensive and complementary scientific expertise; they meet monthly to provideexecutive oversight for core services and to promote user access and satisfaction. In response to annual NCCCsurveys of Shared Resources (SR) and feedback from the NCCC External Advisory Board FCIM significantlyenhanced services and new equipment during the current grant cycle including: 1) expanded sorting and highthroughput analysis capabilities with 3 new instruments offering more available colors 2) increased post-sortviability 3) added services for mass cytometry (CyTOF)-assisted projects; and 4) lowered costs due to improvedefficiencies. In the next grant cycle based on user feedback FCIM will expand its services to include T cellreceptor (TCR) clonality determination and other single cell omics using a newly acquired Illumina MiSeq Systemin the Molecular Genomics SR and spatial immune profiling with the recently acquired Vector Polaris system inthe Translational Pathology SR. During the current grant period (2015-2020) 70 NCCC members representingall five programs utilized FCIM resulting in 53 publications and $15.9M in direct cost grant funding as a directresult of usage. The anticipated annual budget of FCIM in the first year of the next grant cycle is $632453 yetthe CCSG request is $143215. Accordingly FCIM leverages extensive institutional and recharge support andseeks only 23% from CCSG funds. +No NIH Category available Applied Research;Area;Authorization documentation;Behavior Therapy;Behavioral;Ethical Review;Ethics;Genetic study;Health Services Research;Information Systems;Institutional Review Boards;Iris;Molecular;National Cancer Institute;Persons;Policies;Prevention;Protocols documentation;Research;Research Project Grants;Risk Assessment;Scientist;Social Aspects of Cancer;Support Contracts;System;United States National Institutes of Health;Work;authority;cancer epidemiology;clinical center;human subject;psychosocial;response IRB and NCI Ethical Review Panel (ERP) Support n/a NCI 10919060 1ZIJCP010208-14 1 ZIJ CP 10208 14 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 251232 NCI The Special Studies Institutional Review Board (SSIRB) was established by the National Cancer Institute (NCI) National Institutes of Health (NIH) in 1992 under the authority of NIH Multiple Project Assurance (MPA) in response to increasing concerns regarding the protection of persons participating in research projects directed by the NCI.The increase in the number of NCI protocols requiring IRB review particularly in non-clinical (non-therapeutic) research areas led to the formation of the NCI SSIRB as a second NCI IRB with the mandate to review research protocols involving human subjects conducted by NCI scientists and staff through facilities other than those of the NIH Clinical Center. Traditionally most of these projects have focused on special areas of applied science such as cancer epidemiology surveillance prevention and control behavioral work and social aspects of cancer and health services research. In recent years the scope of reviewed research has expanded to include molecular and genetic studies relating to cancer epidemiology risk assessment prevention and control psychosocial and behavioral interventions and ethical policy issues.Currently there are on average about 170 studies under review. 251232 +No NIH Category available Address;Adult;Age;Biological;Biological Markers;Cancer Etiology;Cohort Studies;Computerized Medical Record;Data;Development;Division of Cancer Epidemiology and Genetics;Drug Prescriptions;Electronics;Future;Health Maintenance Organizations;Length;Medical;Medical Records;Military Personnel;Outcome;Participant;Procedures;Productivity;Questionnaires;Recording of previous events;Records;Research;Resources;Risk Factors;Running;Sampling;Stable Populations;System;Time;Tumor Tissue;Vertebral column;Work;biobank;cancer risk;clinical infrastructure;cohort;cost effective;follow-up;next generation;novel;prospective;sample collection;tissue archive;working group Cohort and Biobank Development n/a NCI 10919047 1ZICCP010226-10 1 ZIC CP 10226 10 79341436 "KRAFT, PETER " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 25360261 NCI DCEG has a long history of developing and running major cohort studies and these form the backbone of the research portfolio in the division. Existing cohorts including but not limited to AARP PLCO and USRT have been extremely productive and have generated a wealth of information about potential cancer risk factors and biological markers. In the next decade these cohorts will reach the end of their natural lifetime due to the length of time since the baseline questionnaire the average age of the participants and the depletion of biological samples. There is the need therefore to start planning now for the next generation of cohorts that will be able to continue to address current and future hypotheses about the etiology of cancer. A working group within DCEG was formed to discuss potential settings and Health Maintenance Organizations (HMOs) like Kaiser Permanente (KP) and the US Military were selected as some of the most promising for further exploratory work. Major advantages of HMOs and the Military are the availability of electronic medical records a passive follow-up system that is both cost effective and highly complete existing clinical infrastructure for specimen collection and the long-term stability of the population. Furthermore many of the HMOs have archived tissue available and the electronic records provide extensive and reliable information on drug prescriptions medical conditions and procedures. 25360261 +No NIH Category available Androgens;Biological Assay;Biomedical Research;Dedications;Development;Division of Cancer Epidemiology and Genetics;Estrogens;Hormones;Human;Infrastructure;Laboratories;Measurement;Measures;Population Study;Production;Proteomics;Techniques;Technology;liquid chromatography mass spectrometry;method development Endogenous Hormone Measurement Production Assay Infrastructure at the FNLCR n/a NCI 10919046 1ZICCP010223-12 1 ZIC CP 10223 12 15666502 "HENDERSON, MARIANNE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 162408 NCI Dedicated support for production level assays for estrogen and androgen metabolites measured in human biofluids at the Leidos Biomedical Research Inc. Laboratory of Proteomics and Analytical Technologies. This project provides the dedicated production assay support (labor and materials and supplies) and some new assay methods development for the collaborative activities with the Laboratory of Proteomics and Analytical Technologies (LPAT) associated with the development of liquid chromatography-mass spectrometry techniques/assays for the measurement of endogenous hormone metabolites(estrogens and androgens) for population studies in DCEG. 162408 +No NIH Category available Biological Assay;Biological Specimen Banks;Collection;DNA;Division of Cancer Epidemiology and Genetics;Genotype;Laboratories;Methods;Molecular Epidemiology;Population;Research;Sampling;Services;biobank;epidemiology study;repository Biorepository Processing Storage and Research n/a NCI 10919045 1ZICCP010192-16 1 ZIC CP 10192 16 15188145 "BLACK, AMANDA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1017827 NCI The main objective of this project is to investigate current and alternative methods for efficient collecting processing storing and retrieving biospecimens in order to and to establish baseline standards that can be used in molecular epidemiology studies. Other primary objectives are to perform DNA extraction genotyping assays and other laboratory services for biospecimen samples and to provide infrastructural support and management of the Division of Cancer Epidemiology and Genetics biospecimen repository. Efficiencies in collection processing and storage at the DCEG repository and within the population collections are an important focus of this project this year. 1017827 +No NIH Category available Address;Advanced Technology Center;Area;Basic Science;Biological;Biological Assay;Cancer Etiology;Candidate Disease Gene;Clinical;Custom;DNA;DNA sequencing;Data;Data Storage and Retrieval;Division of Cancer Epidemiology and Genetics;Electronics;Employment;Epidemiologist;Equipment and supply inventories;Family;Gene Chips;Genetic;Genetic Fingerprintings;Genetic Markers;Genetic Variation;Genotype;Heritability;Human;Informatics;Information Management;Intramural Research Program;Laboratories;Laboratory Research;Malignant Neoplasms;Management Information Systems;Mission;NCI Center for Cancer Research;Outcome;Predisposition;Preparation;Principal Investigator;Process;Quality Control;Residual state;Sampling;Scientist;Series;Signal Transduction;Statistical Methods;System;Technology;Work;analytical tool;cancer genetics;cancer genomics;design;genetic analysis;genetic linkage analysis;genome wide association study;high risk;instrument;new technology;next generation sequencing;operation;population based;quality assurance;translational genomics;whole genome Cancer Genomics Research Laboratory n/a NCI 10919044 1ZICCP010178-22 1 ZIC CP 10178 22 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 309303 NCI NCI's Advanced Technology Center (ATC) established for the implementation of novel technologies to address biological clinical and genetic questions pertinent to human cancers includes the Cancer Genomics Research Laboratory which is overseen by DCEG. The LTG is adjacent to the CGR and consists of three principal investigators and their respective laboratories which work closely with the expertise in the CGR and DCEG. The aim of the CGR is to meet the genotyping and selected DNA sequencing needs of the DCEG and NCI's Center for Cancer Research. The facility performs high-throughput genotyping and sequencing to support genetic analysis for a broad range of projects for the intramural research program of the NCI. Working in concert with epidemiologists biostatisticians and basic research scientists in the intramural research program the CGR has developed the capacity to conduct genome-wide association studies and candidate gene approaches to identify the heritable determinants of various forms of cancer. The Cancer Genomics Research Laboratory(CGR) offers a wide variety of sample preparation and genotyping operations. All samples received must meet minimum requirements and are taken through the Sample Handling pipeline prior to completing any genotyping. The Sample Handling pipeline includes DNA quantification and genetic fingerprinting. Also offered is current Whole Genome Amplification (WGA) technology designed to increase available DNA from samples with minimal residual DNA. The genotyping platforms cover a wide-range of size and scope. The CGR operates the Illumina BeadLab system which supports Illumina assay technologies including the whole genome genotyping Infinium assays custom GoldenGate OPA assays and Custom Infinium (iSelect) assays. The CGF operates next generation sequencing with two 454/Roche instruments with high throughput analytical capacity for targeted regions identified in GWAS and linkage studies. In addition the CGR offers Affymetrix GeneChip arrays and uniplex TaqMan genotyping. Informatics at the CGR is focused on two main areas: Information Management the electronic storage and retrieval of data and Analytics the employment of the most appropriate statistical methods to effectively and accurately draw conclusions from the data generated by the laboratory. 309303 +No NIH Category available Adult;Africa South of the Sahara;Anogenital cancer;Antibodies;Anus;Biological Assay;Blood;Cancer Control;Cancer Intervention;Country;Development;Dose;Effectiveness;Enrollment;Etiology;Evaluation;Focus Groups;Future;Gardasil;Genotype;Goals;HIV;HIV Seronegativity;HIV Seropositivity;Health;High Risk Woman;Human;Human Papilloma Virus Vaccination;Immune;Immunity;Immunization Programs;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mass in breast;Natural History;Observational Study;Oral;Palpable;Participant;Population;Prevalence;Prevention;Questionnaires;Recording of previous events;Research;Research Project Grants;Risk Factors;Rwanda;Sexual Health;Specimen;Testing;Underserved Population;Vaccinated;Vaccination;Vaccines;Validation;Virus;Woman;Women's Group;cervicovaginal;cohort;low and middle-income countries;malignant mouth neoplasm;new technology;novel strategies;prevent;programs;prophylactic;risk prediction;screening;symptom science;unvaccinated;vaginal microbiome Global Cancer Health n/a NCI 10919026 1ZIACP101237-02 1 ZIA CP 101237 2 10687280 "CASTLE, PHILIP " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2045592 OD My research program and group are focused on discovery development and evaluation/validation of new technologies for the prevention and control of cancer in underserved populations globally. Our current objectives are 1) to optimize screening and prophylactic HPV vaccination to prevent anogenital cancers especially in those living with HIV 2) developing novel strategies to oral cavity cancer; 3) risk prediction of and intervention for cancers of the upper aerodigestive track; 4) management of palpable breast masses in low- and middle-income countries; and 5) symptom science and etiology.This ZIA currently includes research for the research project below:HPV Natural History in HIV-positive and HIV-negative Women: The Long-Term Human Papillomavirus Vaccination (HPV) Effectiveness and Immunity in Rwandan Women Living with and without Human Immunodeficieny Virus (HIV) study is an observational study of women living with HIV (WLWH) and HIV-negative women who did and did not receive the HPV vaccine in Rwanda. Rwanda is a high-burden cervical cancer country where the prevalence of HIV is 3.7% among adult women. In 2011 Rwanda implemented a national HPV vaccination program with Gardasil. To answer questions about HPV effectiveness in WLWH 757 vaccinated WLWH 757 unvaccinated WLWH and 757 vaccinated HIV-negative women will be enrolled in the study. Participants will provide blood anal oral and cervicovaginal specimens and complete a questionnaire on sexual health and history. Cervicovaginal anal and oral specimens will be HPV genotyped using type-specific genotyping assays. Blood will be antibody tested to compare the immune resonse in WLWH and HIV-negative women and the impact of switching from 3 doses to 2 doses of Gardasil in 2015. Participants who test HPV positive at baseline will return in six months to assess type-specific HPV persistence. Risk factors for HPV persistence including vaginal microbiome will also be studied. A long-term goal of the study is to establish a cohort of WLWH in whom we can examine the long-term effectiveness of HPV vaccination in WLWH now and in the future. This research is significant as it will establish the population effectiveness of HPV vaccination in WLWH in sub-Saharan Africa the group of women at the highest risk of cervical cancer for which there is a dearth of evidence. 903220 +No NIH Category available Adult;Africa South of the Sahara;Anogenital cancer;Antibodies;Anus;Biological Assay;Blood;Cancer Control;Cancer Intervention;Country;Development;Dose;Effectiveness;Enrollment;Etiology;Evaluation;Focus Groups;Future;Gardasil;Genotype;Goals;HIV;HIV Seronegativity;HIV Seropositivity;Health;High Risk Woman;Human;Human Papilloma Virus Vaccination;Immune;Immunity;Immunization Programs;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mass in breast;Natural History;Observational Study;Oral;Palpable;Participant;Population;Prevalence;Prevention;Questionnaires;Recording of previous events;Research;Research Project Grants;Risk Factors;Rwanda;Sexual Health;Specimen;Testing;Underserved Population;Vaccinated;Vaccination;Vaccines;Validation;Virus;Woman;Women's Group;cervicovaginal;cohort;low and middle-income countries;malignant mouth neoplasm;new technology;novel strategies;prevent;programs;prophylactic;risk prediction;screening;symptom science;unvaccinated;vaginal microbiome Global Cancer Health n/a NCI 10919026 1ZIACP101237-02 1 ZIA CP 101237 2 10687280 "CASTLE, PHILIP " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2045592 NCI My research program and group are focused on discovery development and evaluation/validation of new technologies for the prevention and control of cancer in underserved populations globally. Our current objectives are 1) to optimize screening and prophylactic HPV vaccination to prevent anogenital cancers especially in those living with HIV 2) developing novel strategies to oral cavity cancer; 3) risk prediction of and intervention for cancers of the upper aerodigestive track; 4) management of palpable breast masses in low- and middle-income countries; and 5) symptom science and etiology.This ZIA currently includes research for the research project below:HPV Natural History in HIV-positive and HIV-negative Women: The Long-Term Human Papillomavirus Vaccination (HPV) Effectiveness and Immunity in Rwandan Women Living with and without Human Immunodeficieny Virus (HIV) study is an observational study of women living with HIV (WLWH) and HIV-negative women who did and did not receive the HPV vaccine in Rwanda. Rwanda is a high-burden cervical cancer country where the prevalence of HIV is 3.7% among adult women. In 2011 Rwanda implemented a national HPV vaccination program with Gardasil. To answer questions about HPV effectiveness in WLWH 757 vaccinated WLWH 757 unvaccinated WLWH and 757 vaccinated HIV-negative women will be enrolled in the study. Participants will provide blood anal oral and cervicovaginal specimens and complete a questionnaire on sexual health and history. Cervicovaginal anal and oral specimens will be HPV genotyped using type-specific genotyping assays. Blood will be antibody tested to compare the immune resonse in WLWH and HIV-negative women and the impact of switching from 3 doses to 2 doses of Gardasil in 2015. Participants who test HPV positive at baseline will return in six months to assess type-specific HPV persistence. Risk factors for HPV persistence including vaginal microbiome will also be studied. A long-term goal of the study is to establish a cohort of WLWH in whom we can examine the long-term effectiveness of HPV vaccination in WLWH now and in the future. This research is significant as it will establish the population effectiveness of HPV vaccination in WLWH in sub-Saharan Africa the group of women at the highest risk of cervical cancer for which there is a dearth of evidence. 1142372 +No NIH Category available Alleles;Data;Disease susceptibility;Genetic Structures;Haplotypes;Libraries;Link;Linkage Disequilibrium;Maps;Measures;Multiomic Data;Pattern;Population;Population Group;Regional Disease;Research Personnel;Susceptibility Gene;Variant;Visualization;design;flexibility;interest;open source;tool;web app;web-based tool LDlink webtool for examining patterns of linkage disequilibrium in diverse popul n/a NCI 10919025 1ZIACP101236-03 1 ZIA CP 101236 3 78381935 "MACHIELA, MITCHELL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 112766 NCI Exploring linkage disequilibrium (LD) across ancestral populations is a powerful approach for investigating population-specific genetic structure as well as functionally mapping regions of disease susceptibility. LDlink is a suite of web-based applications designed to easily and efficiently interrogate linkage disequilibrium in population groups. LDlink consists of several modules for interactively exploring linkage disequilibrium including LDassoc LDexpress LDhap LDmatrix LDpair LDpop LDproxy LDtrait SNPchip and SNPclip. Modules are designed with an emphasis on ease of use query flexibility and interactive visualization of results. Haplotype tables and interactive plots generated by LDlink are tailored for investigators interested in mapping common and uncommon disease susceptibility loci with a focus on linking correlated alleles and highlighting potentially functional variants. 112766 +No NIH Category available Acquired Immunodeficiency Syndrome;Aging;Behavior;Chronic;Chronic Disease;Disease;Disparity;Etiology;General Population;HIV;HIV Infections;Health Services Accessibility;Hepatitis B Virus;Herpesviridae;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immunosuppression;Incidence;Individual;Infection;Inflammation;Intervention;Malignant Neoplasms;Natural History;Oncogenic Viruses;Outcome;Persons;Role;Socioeconomic Status;Tobacco smoking behavior;Virus;antiretroviral therapy;biomarker identification;cancer biomarkers;cancer diagnosis;cancer prevention;cancer therapy;immunosuppressed;improved;prevent;risk stratification;screening Studies of HIV infection and its contribution to the natural history and outcome n/a NCI 10919024 1ZIACP101235-03 1 ZIA CP 101235 3 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3475546 NCI People living with HIV have an elevated incidence of cancer due to a complicated range of issues related to AIDS-related immunosuppression chronic inflammation infection with oncogenic viruses behavior factors including tobacco smoking and poor socioeconomic status. Examples of important cancer-causing viruses include human papillomavirus (HPV) Epstein-Barr virus Kaposi sarcoma-associated herpesvirus and hepatitis viruses B and C. Studies of these factors in people living with HIV can contribute to understanding their role in other immunosuppressed individuals and in the general population. Many of these factors also contribute to poor access to treatment and disparities in outcomes following a cancer diagnosis. As people with HIV infection live longer with better antiretroviral therapies they are aging which is contributing to an increase in the burden of chronic diseases including cancer. There is a major need to develop improved cancer prevention screening and treatment for people living with HIV. This project includes multiple studies of cancer in people living with HIV. 2891478 +No NIH Category available Acquired Immunodeficiency Syndrome;Aging;Behavior;Chronic;Chronic Disease;Disease;Disparity;Etiology;General Population;HIV;HIV Infections;Health Services Accessibility;Hepatitis B Virus;Herpesviridae;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immunosuppression;Incidence;Individual;Infection;Inflammation;Intervention;Malignant Neoplasms;Natural History;Oncogenic Viruses;Outcome;Persons;Role;Socioeconomic Status;Tobacco smoking behavior;Virus;antiretroviral therapy;biomarker identification;cancer biomarkers;cancer diagnosis;cancer prevention;cancer therapy;immunosuppressed;improved;prevent;risk stratification;screening Studies of HIV infection and its contribution to the natural history and outcome n/a NCI 10919024 1ZIACP101235-03 1 ZIA CP 101235 3 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3475546 OD People living with HIV have an elevated incidence of cancer due to a complicated range of issues related to AIDS-related immunosuppression chronic inflammation infection with oncogenic viruses behavior factors including tobacco smoking and poor socioeconomic status. Examples of important cancer-causing viruses include human papillomavirus (HPV) Epstein-Barr virus Kaposi sarcoma-associated herpesvirus and hepatitis viruses B and C. Studies of these factors in people living with HIV can contribute to understanding their role in other immunosuppressed individuals and in the general population. Many of these factors also contribute to poor access to treatment and disparities in outcomes following a cancer diagnosis. As people with HIV infection live longer with better antiretroviral therapies they are aging which is contributing to an increase in the burden of chronic diseases including cancer. There is a major need to develop improved cancer prevention screening and treatment for people living with HIV. This project includes multiple studies of cancer in people living with HIV. 584068 +No NIH Category available Cancer Etiology;Data;Environmental Epidemiology;Epidemiology;Genomics;Histologic;Malignant Neoplasms;Methods;Mission;Molecular Profiling;Research;Risk Factors;genetic epidemiology;molecular pathology;tumor;tumor progression Studies of Genetic and Environmental Epidemiology n/a NCI 10919021 1ZIACP101231-06 1 ZIA CP 101231 6 15666293 "LANDI, MARIA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 5166533 NCI The Integrative Tumor Epidemiology Branch (ITEB) employs molecular pathology somatic and germline genomics and epidemiology to identify environmental and germline risk factors for cancer.Research MissionThe mission of ITEB is to advance understanding of cancer etiology and progression through integrative analyses of environmental and germline risk factors with comprehensive data on histological and molecular profiling of tumors and their precursors including somatic genomic analyses. The branch also develops methods to support this cutting-edge research. 5166533 +No NIH Category available Affect;Age;Bioinformatics;Biological;Biology;Cell Line;Chromosome Fragility;Clinical Research;Collaborations;Consult;Data;Data Pooling;Data Set;Disease;Disease susceptibility;Division of Cancer Epidemiology and Genetics;Elements;Epidemiologist;Epidemiology;Epigenetic Process;Etiology;Event;Family;Gene Mutation;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genetic study;Genome;Genomics;Genotype-Tissue Expression Project;Haplotypes;Health;Human;Human Genome;Individual;Inherited;Interdisciplinary Study;International;Investigation;Laboratories;Laboratory Research;Maintenance;Malignant Neoplasms;Methodological Studies;MicroRNAs;Modeling;Molecular;Molecular Epidemiology;Molecular Evolution;Mosaicism;Mutation;Normal tissue morphology;Outcome;Pathway interactions;Phenotype;Population Genetics;Population Study;Populations at Risk;Predictive Value;Predisposition;Regulatory Element;Research;Research Personnel;Resources;Risk;Risk Factors;Scientist;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Somatic Mutation;Susceptibility Gene;The Cancer Genome Atlas;Therapeutic Intervention;Time;Transcript;Tumor Tissue;Uniparental Disomy;Variant;cancer genomics;cancer heterogeneity;cancer risk;cancer subtypes;cohort;deep sequencing;design;epidemiology study;follow-up;gene environment interaction;genetic analysis;genetic architecture;genetic epidemiology;genetic variant;genome wide association study;genome-wide;high risk;insight;interdisciplinary approach;large scale data;methylation pattern;mosaic;novel;public database;tumor;validation studies Laboratory of Genetic Susceptibility n/a NCI 10919017 1ZIACP010227-09 1 ZIA CP 10227 9 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 711141 NCI The Laboratory of Genomic Susceptibility (LGS) in the Division of Cancer Epidemiology and Genetics (DCEG) is committed to understanding the biological basis for genetic susceptibility to cancer including identification and characterization of cancer susceptibility alleles characterization of the scope of genetic mosaicism and its contribution to cancer risk investigation of the genetic architecture of cancer susceptibility and determination of how germline variation informs our understanding of somatic alterations in cancer. LGS scientists participate in genetic epidemiologic clinical and methodological studies of populations families and persons at risk for cancer. In addition they collaborate and consult with experts in statistical genetics bioinformatics genetic epidemiology and molecular epidemiology in interdisciplinary studies. Using large-scale genome-wide association studies familial linkage studies in high-risk families and publically available databases such as TCGA TARGET ENCODE and GTEx investigators continue to identify loci within the human genome that are associated with cancer risk. The laboratory is at the forefront of applications in bioinformatics and advanced genetic analyses with new platforms designed to evaluate the biological effects of dense sets of single nucleotide polymorphisms (SNPs) which are the most common genetic variants in the human genome. Specifically the laboratory has integrated approaches to identify and validate common SNPs and ancestral haplotypes which could be used to dissect the genetic basis of disease susceptibility. Together with NCIs Cancer Genomics Research Laboratory LGS carries out genome-wide association studies (GWAS). Using data from large-scale GWAS that evaluate millions of SNPs investigators at the LGS are able to identify in great detail new regions in the human genome that are associated with cancer risk and to estimate the magnitude of effect of these risks. GWAS have been instrumental in the discovery of new regions of the genome which influence the basic etiological risk factors. In addition these novel findings may at a later time also bear important predictive value for disease particularly in developing a polygenic model as well as highlight potential molecular pathways related to both disease etiology and perhaps therapeutic intervention. To understand the biology underlying these associations investigators are following up with focused validation studies deep-sequencing and functional analyses such as analyses of expression levels and methylation patterns. This research relies on multidisciplinary approaches from population genetics epidemiology and molecular evolution. Investigation of GWAS signals requires extensive bioinformatic follow-up to examine unannotated transcripts regulatory elements as well as functional elements for novel transcripts. Regulatory effects are queried with respect to the alteration of gene levels epigenetics and long-ranging effects on other genes at a distance using cell lines normal tissue and tumor tissue as well as resources from the TCGA and ICGC. The LGS is also investigating several possible biologic mechanisms including whether variations in these identified regions may affect regulatory elements of neighboring genes the impact of miRNA polymorphisms acting upon fragile chromosomal sites and epigenetic effects across multi-susceptibility regions. We have developed a series of collaborations with leading epidemiologists and biostatisticians in the Division of Cancer Epidemiology and Genetics (DCEG) the NCI Cohort Consortium and multiple other international molecular epidemiologic consortia. Data pooling is being used to achieve the statistical power necessary to detect associations between genomic variants and a variety of health outcomes as well as gene-environment interactions. An interesting outcome from GWAS studies at LGS has been the identification of a sizeable fraction of apparently healthy individuals that harbor large scale (2MB) mosaic events detected as copy number changes or copy-neutral uniparental disomies. Investigating human clonal mosaicism has the potential to offer new insights into genomic maintenance as individuals age as well as explain a portion of the phenotypic heterogeneity of cancer subtypes. With the accumulation of cancer susceptibility regions from GWAS and large new datasets of tumor sequencing data it is now possible to investigate the interplay between inherited germline genetics and acquired somatic mutations. The expertise of LGS staff and collaborations with DCEG experts enables for novel investigation of how germline genetics combined with somatically acquired mutations may affect susceptibility to cancer. 711141 +No NIH Category available Barrett Esophagus;Biological Markers;Biopsy;Biopsy Specimen;Blood;Blood specimen;Clinic;DNA Sequence Alteration;Data;Data Analyses;Disease;Dysplasia;Early Diagnosis;Endoscopes;Endoscopy;Esophagus;Gastroesophageal reflux disease;Genetic Polymorphism;Genetic Transcription;Germ Lines;Goals;Hormones;Laboratories;Medical center;Patient Selection;Patients;Pattern;Periodicals;Pharmaceutical Preparations;Pilot Projects;Proteomics;Questionnaires;Registries;Risk Factors;Sampling;Serum;Study of serum;Testing;Time;Tissue Sample;Tissues;blood-based biomarker;comparison group;follow-up;genotyped patients;patient registry;screening;stomach cardia;tissue biomarkers Barrett's esophagus early detection project n/a NCI 10919016 1ZIACP010225-12 1 ZIA CP 10225 12 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 69043 NCI The goal of this project is to identify a practical blood-based biomarker(s) that can be used as a screening test to determine who has Barrett's esophagus (BE) and who does not. Secondary goals of the project are to characterize germ line and tissue biomarkers associated with BE and compare biomarkers in non-BE patients with and without GERD. Tertiary goals are to explore associations between biomarkers in blood or tissue and progression from BE to dysplasia or EAC and to assess the stability of proteomic patterns over time. This study will be conducted among patients in the Barrett's Esophagus Registry (currently with 206 registrants) established at the National Naval Medical Center (NNMC) in Bethesda beginning in 1992 as well as a comparison group of approximately 600 matched non-BE patients endoscoped in the GI clinic at NNMC for other conditions. Blood and tissue samples will be collected as well as questionnaire data on risk factors and medications as well as GERD. Data analyses will be based primarily on laboratory testing of newly collected esophageal biopsies brush samples and blood samples but secondarily will also include use of archival tissue biopsy samples. Follow-up of BE Registry patients will include standard periodic surveillance endoscopies additional blood samples and ascertainment of disease status (i.e. progression). To distinguish BE versus non-BE patients we will: (i) assess predictability of BE status from serum proteomic patterns; (ii) characterize esophageal biopsies and brush samples for selected DNA alterations RNA expression and proteomic profiles; (iii) genotype patients for selected polymorphisms potentially associated with BE; (iv) compare blood and tissue biomarkers in non-BE patients with and without GERD; (v) explore the association of biomarkers with progression from BE to dysplasia or EAC; and (vi) assess proteomic pattern stability over time in BE patients. Recent studies in this project have (i) profiled and compared tissue RNA expression differences among BE cardia and normal squamous tissues in BE cases; (ii) compared serum hormones in BE cases versus noncases; and (ii) conducted a pilot study of serum proteomics in BE cases and noncases. 69043 +No NIH Category available Area;Biological Specimen Banks;Blood;Blood specimen;Cancer-Predisposing Gene;Case/Control Studies;Cells;County;DNA;Disease;Etiology;Family;Family Study;Fingers;Genetic;Genetic Markers;Genetic Polymorphism;Genome Scan;Goals;Hot Spot;Lesion by Morphology;Malignant Neoplasms;Malignant neoplasm of esophagus;Microsatellite Repeats;Molecular;Morphology;Normal Range;Population;Risk;Role;Sampling;Specimen;Testing;Venous;biomarker identification;cancer biomarkers;cancer genetics;candidate marker;density;esophageal cancer prevention;exome sequencing;gene environment interaction;genome wide association study;genomic biomarker;high risk population;malignant stomach neoplasm;microbiome research;premalignant;stomach cardia;tumor Esophageal cancer genetic project n/a NCI 10919015 1ZIACP010224-12 1 ZIA CP 10224 12 2062427 "GOLDSTEIN, ALISA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 431254 NCI The overall goal of this project is to understand the role of genetics in the etiology and prevention of esophageal cancer and gastric cancer. Five different but complementary approaches have been used to identify esophageal cancer susceptibility genes. First a tumor/nontumor study has been conducted in which a biological specimen bank consisting of samples (tumor nontumor venous blood finger stick blood and buccal cells) from several hundred cases of esophageal cancer and gastric cancer (both cardia and body) was developed in Taiyuan for the identification of esophageal cancer and gastric cancer susceptibility genes and potential early genetic markers of these cancers. High-density genome-wide scans with microsatellite markers have been conducted to identify potential hot spots and further testing of these hot spots and other candidate markers in additional tumor/nontumor samples is in progress. Premalignant morphologic lesions will also be examined. Second blood samples for DNA have been collected from several hundred healthy individuals from high-risk (Yangcheng County) and low-risk (Beijing) areas to examine potential population differences in polymorphisms for selected genomic markers. Third a large case-control study with cases of esophageal cancer and gastric cancer (both cardia and body) has been conducted and is being used to evaluate polymorphisms in the candidate markers identified in other components of this project and to evaluate gene-environment interactions. Fourth a family study is in progress which will permit linkage of candidate markers with cancer in families having 2 or more cases with esophageal cancer or gastric cancer. Finally an endoscopic study is being conducted to obtain specimens from a morphologic spectrum of disease ranging from normal to early invasive esophageal cancer in order to characterize molecular progression. Recent studies have emphasized UGI cancer GWAS and post-GWAS analyses exome sequencing of subjects in the family study profiling of UGI cancer tumors and studies of the microbiome of UGI cancers. 431254 +No NIH Category available Adult;Age;BRAF gene;Benefits and Risks;Benign;Brain;Brain Neoplasms;Child;Childhood;Childhood Leukemia;Cohort Studies;Data;Databases;Dose;Epidemiology;Etiology;Exposure to;Gender;Histopathology;Hospitals;Incidence;International;Intervention;Investigation;Ionizing radiation;KRAS2 gene;Life;Lymphoma;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of thyroid;Methods;Molecular;NRAS gene;Organ;Papillary Carcinoma;Patients;Physicians;Population Study;Predisposition;Procedures;Publications;Publishing;RAS genes;Radiation;Radiation Dose Unit;Radiation exposure;Radiation-Induced Cancer;Research Personnel;Risk;Roentgen Rays;Scientist;Statistical Models;Techniques;Technology;Time;Tissues;Tumor Tissue;United States;X-Ray Computed Tomography;cancer risk;case control;clinical diagnostics;cohort;computed tomography screening;improved;in utero;infancy;leukemia;molecular marker;radiation effect;radiation risk;response;thyroid neoplasm;tool Studies of Populations Exposed to Diagnostic Medical Radiation n/a NCI 10919014 1ZIACP010222-13 1 ZIA CP 10222 13 14721304 "KITAHARA, CARI " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 480266 NCI Computed Tomography Organ Dose Calculations - New tools and methods are being developed by using Monte Carlo transport technique to calculate organ dose for pediatric and adult patients undergoing computed tomography examinations. The organ dose estimates are being used for retrospective epidemiologic cohort and case-control studiesCancer Risks from CT Scan Use in the United States - We are estimating the potential radiation-related cancer risks that may be related to current levels of CT use in adults and also conducting radiation risk-benefit analyses for CT screening examinations.Early Life Radiation and the Risk of Child Cancer - Studying radiation exposure during early life is of particular importance given that many tissues are more susceptible to radiation effects in utero and at younger age of exposure. Results of our analysis published in February 2011 showed some indication of a slight non-significant increase in risk for all childhood cancer and leukemia with exposure to ionizing radiation in utero and potential increased risk of lymphoma following exposure to x-rays in early infancy based on small numbersPediatric CT Scans - REB initiated an international cohort study of 180000 children to evaluate the potential risk of cancer associated with radiation exposure from pediatric CT scans. A comprehensive organ CT dose database was developed in support of a study of pediatric cancer risk and CT exposure. The results from this study published in 2012 suggested for the first time that there are increased risks of leukemia and brain tumors after CT scans in childhood.Pooled Analysis of Radiation-Related Brain Tumors - Preliminary arrangements have been made to conduct a pooled analysis of the risk of radiation-related malignant and benign brain tumors including data from studies worldwide that have information on radiation dose to the brain for individualsMolecular and Histopathologic Clues to the Understanding of Thyroid Cancer Incidence - Thyroid cancer incidence has increased significantly over the last few decades. We are evaluating whether alterations in molecular markers and histopathology of papillary carcinoma have changed over the last three decades using thyroid tumor tissue collected from one US hospital. Molecular markers under investigation are BRAF N-RAS K-Ras H-Ras and RET/PTC.Pooled analysis of Radiation-Related Thyroid Cancer- To improve our understanding of the etiology of thyroid cancer REB scientists have set up an international consortium to study radiogenic thyroid cancer in children and adults. Statistical models of the radiation dose-response will be assessed as well as potential interaction with gender age at exposure attained age and time since exposure. Results for children were submitted for publication in 2012. 480266 +No NIH Category available Adenocarcinoma;Algorithms;Androgens;Barrett Epithelium;Barrett Esophagus;Case/Control Studies;Cells;Chemicals;Clinical;Cohort Studies;Costs and Benefits;Data;Databases;Diagnosis;Disease;Endoscopy;Epithelial Cells;Epithelium;Equation;Esophageal Adenocarcinoma;Esophagitis;Esophagus;Estrogens;Etiology;Exposure to;Gastroenterology;Gastroesophageal reflux disease;General Population;General Practices;Goals;Hepatology;Hormones;Incidence;Individual;Journals;Laboratories;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of esophagus;Manuscripts;Medical History;Medicare;Metabolic syndrome;Metaplasia;Modality;Natural History;Patients;Population;Prognostic Marker;Publications;Publishing;Reflux;Research;Research Personnel;Resources;Risk;Risk Factors;Squamous Cell;Staging;Survival Rate;Testing;Tissues;Triage;United States;bile salts;billing data;cancer epidemiology;cancer risk;clinical practice;cohort;comparative;data harmonization;diagnostic biomarker;diagnostic value;disease natural history;disorder control;follow-up;genotoxicity;high risk;indexing;inflammatory marker;mortality risk;prognostic Barrett's Esophagus n/a NCI 10919013 1ZIACP010220-13 1 ZIA CP 10220 13 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 24645 NCI This project covers a broad range of studies which focus on elucidating risk factors for and the natural history of esophageal adenocarcinoma (esophageal cancer) and the precursor lesion Barretts esophagus (aka Barrett esophagus). Barretts esophagus is a metaplastic change in the lower esophagus which is characterized by the replacement of the native squamous cell epithelium with a glandular-type of epithelium. This metaplastic change is thought to be primarily the result of genotoxic damage induced by gastroesophageal refluxacid and bile salts reflux up into the esophagus exposing cells not equipped to deal with these reactive chemicals. Re-epithelization with the metaplastic Barretts epithelium provides for a tissue which is better able to withstand the exposure to such compounds. However it also increases the risk of esophageal adenocarcinoma approximately 10-50 fold that of the general population. The incidence of esophageal adenocarcinoma has increased over 650% in the United States over the last 35 years and most individuals present with late stage malignancies resulting in a 5-year survival rate of less than 20%. This indicates that researchers need to be able to better identify those at high risk and Barretts esophagus is a good starting point. However although this metaplasia greatly increases the risk of esophageal adenocarcinoma relative to the general population the absolute risk remains low at around 0.5% or 1 in 200 patient years of follow-up. This is because approximately 90% of individuals who develop esophageal adenocarcinoma are diagnosed at their first (index) endoscopy. Thus not only do we need to be able to better identify those with high risk (Barretts esophagus) in the general population we also need to be able to triage these individuals into high and low risk groups so that surveillance resources can be focused on those who most need them which would make the cost-benefit equation of surveillance endoscopy more attractive. Therefore the ultimate goals of all the studies within this project seek to better understand the natural history of this disease risk factors for progression diagnostic markers and modalities with high sensitivity and prognostic biomarkers for efficient triaging of risk.The Barrett's Esophagus Consortium project (CAS ID:10593) is a pooling project that brings together and harmonizes data from eight case-control studies of Barrett's esophagus and fourteen case-control studies of esophageal adenocarcinoma. The consortium has published many articles details of which can be seen at http://beacon.tlvnet.net/ The Esophageal Cancer in SEER-Medicare project (CAS ID:10633) is assessing metabolic syndrome in relation to Barrett's esophagus (published in Journal of Clinical Gastroenterology) and esophageal adenocarcinoma (manuscript submitted) as well as the comparative utility of staging modalities in relation to survival following diagnosis of esophageal adenocarcinoma (published in Cancer). We are also assessing whether there is are demographic medical history and survival differences in esophageal adenocarcinoma by whether there was a prior diagnosis of the precursor condition Barrett's esophagus (submitted for publication). A new project will assess whether we can develop an algorithm to accurately identify diagnoses of esophageal adenocarcinoma using Medicare billing data alone.The CPRD EAC Progression Study has assessed whether metabolic syndrome is a risk factor for progression from Barretts esophagus to esophageal adenocarcinoma. This analysis is based in the Clinical Practice Research Datalink (CPRD) which was formerly called the General Practice Research Database (GPRD). The manuscript has been published in Cancer Epidemiology. In the Hormones in Barrett's Esophagus project (CAS ID:10638) we have assessed circulating androgens and estrogens in Barrett's esophagus patients compared with gastroeosphageal reflux disease controls in the BEEDS study based at the Walter Reed (published in Clinical Gastroenterology and Hepatology). We are currently assessing similar exposures in a second Barrett's esophagus population for external replication (manuscript being drafted) as well as expansion to esophageal cancer (adenocarcinoma) using three cohort studies.The Kaiser BE Cohort project has enabled us to assess cancer and mortality risks amongst a large Barretts esophagus cohort. These analyses will provide evidence that is directly applicable for a Barretts esophagus population undergoing surveillance. The manuscript has been submitted for publication.The inflammation markers and esophageal adenocarcinoma (CAS 10731) is beinging together esophageal adenocarcinoma cases and controls from seven cohorts. We are assessing a suite of circulating inflammation markers and testing whether these are associated with risk of developing esophageal adenocarcinoma. Laboratory analyses are currently being conducted. All of these projects are closely aligned to the aims of elucidating the etiology of Barrett's esophagus and esophageal adenocarcinoma as well as providing potential utility for diagnostics and prognostics. 24645 +No NIH Category available Asthma;Back;Body mass index;Cancer Patient;Child;Childhood Leukemia;Chinese;Chronic;Conceptions;Country;County;Data;Data Set;Disease;Enrollment;Environmental Exposure;Etiology;European;Evaluation;Family;Folic Acid;Gallbladder;Genetic;Hospitals;Incidence;Individual;Interview;Life Style;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of thyroid;Mission;Mothers;Neural Tube Defects;Obesity;Persons;Pilot Projects;Play;Population Programs;Prospective Studies;Province;Publications;Publishing;Radiation Tolerance;Research;Risk;Risk Factors;Risk Reduction;Role;Sampling;Site;Thyroid Gland;Work;cancer subtypes;case control;cohort;community intervention;effectiveness evaluation;epidemiology study;feasibility testing;folic acid supplementation;intervention program;mortality;offspring;rare cancer;tumor;waist circumference Studies of other risk factors for radiosensitive tumors n/a NCI 10919012 1ZIACP010219-13 1 ZIA CP 10219 13 14721304 "KITAHARA, CARI " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 417685 NCI Thyroid cancer incidence rates have been increasing for the last 3 decades in the US and the reasons for this are largely unknown. We have been studying potential risk factors for the disease in a pooled analysis of 5 NCI prospective studies. This pooling project provided some of the strongest evidence to date that obesity may be a risk factor for thyroid cancer and the rising obesity rates could therefore be part of the explanation for the rise in thyroid cancer incidence rates. We are now expanding this pooling project to include data from 15 European and US cohorts to examine the relationship in more detail including the risk associated with central adiposity and the relationship between obesity and rarer thyroid cancer subtypes.NCI Cohort Consortium BMI Pooling Project - We built a rich dataset of lifestyle risk factor and mortality data from 20 prospective studies and over 1.5 million people to study the relationship between BMI and all cause mortality. The results from this detailed analysis published in 2010 suggested that optimal BMI was in the range 20-25. We are currently exploring the association between waist circumference and all cause mortality and expanding the pooling project to look at cancer incidence for rare cancers including thyroid and gallbladder. These cancers are typically difficult to study in individual cohorts because the numbers of cases is limited.Childhood Cancer In Chinese Children and Family Cohorts -We are conducting two pilot studies to test the feasibility of (1) follow and participation in interviews of a sample of 500 families from two county sites where the Community Intervention Program (CIP) was carried out in the mid-1990s and (2) identification of incident pediatric cancers arising among thoseborn during 1994-96 in hospitals serving the CIP population and ability to link these pediatric cancer patients back to the CIP population. The CIP community intervention program trial which was carried out during 1994-96 in three large counties northeast and south of Beijing evaluated the effectiveness of periconceptional folic acid supplements in reducing neural tube defects. There were dramaticreductions in neural tube defects among offspring of mothers who took folic acid supplements during thepericonceptional period. Publications from case-control epidemiologic studies in the past 10 years from Western countries have shown that periconceptional folic acid supplements may reduce risks of pediatric leukemia and potentially other pediatric cancers in offspring of mothers who take these supplements. Otherstudies have shown statistical associations with periconception folic acid and other serious chronic diseasesof offspring including asthma. The pilot studies will attempt to trace enroll and interview 500 families fromTaicang Jiangsu Province and Laoting Hebei Province and will seek to identify all pediatric cancers diagnosedduring 1994 to the present among children born during 1994-96 and link these children back to the CIP cohort. 417685 +No NIH Category available Aflatoxins;Bile fluid;Biliary;Biliary Tract Cancer;Biochemical;Biological;Cancer Patient;Chile;Cholelithiasis;Collection;Complement;DNA;Diet;Epidemiology;Etiology;Evaluation;Evaluation of Cancer Risk Factors;Gallbladder;Gender;Goals;Individual;Investigation;Lesion;Longitudinal Studies;Malignant Neoplasms;Malignant neoplasm of gallbladder;Medical History;Molecular;Participant;Patients;Pilot Projects;Population;Prospective Studies;Questionnaires;Random Allocation;Reproductive History;Risk Factors;Sampling;Serum;Smoking;Structure;Tissue Sample;Validation;Woman;biliary tract;case control;cohort;drinking;insight;multidisciplinary;population based;prospective Etiology of Biliary Tract Cancer n/a NCI 10919011 1ZIACP010218-13 1 ZIA CP 10218 13 11613123 "KOSHIOL, JILL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2769100 NCI This project includes: 1) the Shanghai Biliary Tract Cancer Study 2) the Biliary Tract Cancer Pooling Project (BiTCaPP) 3) the Chile Gallbladder Cancer Study. These studies complement each other and will provide unique insight into the etiology of biliary tract cancer. The Shanghai Study includes more than 3000 subjects including over 600 biliary tract cancer patients 900 gallstone patients and 1000 healthy controls randomly selected from the population. A structured questionnaire was used to elicit information on epidemiologic risk factors including smoking drinking diet medical history and reproductive factors. The study had a strong biochemical and molecular component with an extensive collection of biological samples including serum DNA gallstones bile and tissue samples. BiTCaPP is a pooling project involving 30 prospective studies approximately 3 million participants and over 5000 biliary tract cancer cases. This study allows the first well-powered prospective evaluation of risk factors for cancer across the entire biliary tract. The Chile Gallbladder Cancer Study includes pilot studies (120 case-control subjects 140 individuals with gallstones and complete sampling of the gallbladder and 150 population-based individuals) and the Chile Biliary Longitudinal Study (Chile BiLS) a cohort of 4700 women with gallstones. We have also added a case-control component to Chile BiLS. Chile BiLS complements the Shanghai Study and BiTCaPP by allowing replication and validation of previous findings as well as evaluation of unique exposures such as aflatoxin. It also allows investigation of the contribution of risk factors to gallbladder cancer independent of gallstones since all have gallstones and enables detailed exploration of pre-cursor lesions. 2769100 +No NIH Category available Acquired Immunodeficiency Syndrome;Age;Antibodies;Antibody Avidity;Anus;Blinded;Cervical;Cervix Neoplasms;Cervix Uteri;Clinical;Collaborations;Communities;Costa Rica;Cytology;DNA;Dose;Effectiveness;Enrollment;Evaluation;Frequencies;Funding;HIV Infections;HIV Seropositivity;HPV-16/18 Vaccine;Head and Neck Cancer;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Human papillomavirus 18;Immune response;Immunologics;Infection;Lesion;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Measures;Medical;Methodology;Molecular Conformation;Natural History;Oncogenic;Participant;Phase;Phylogenetic Analysis;Population;Population Group;Preventative vaccination;Public Health;Randomized;Randomized Controlled Trials;Research;Resource-limited setting;Safety;Series;Site;Structural Protein;System;United States National Institutes of Health;Vaccinated;Vaccination;Vaccinee;Vaccines;Viral;Virus-like particle;Woman;Women's Health;Work;dosage;efficacy evaluation;follow-up;high risk;immunogenic;immunogenicity;infection rate;men who have sex with men;oral HPV-positive head and neck cancers;premalignant;prevent;screening program;self assembly;unvaccinated;vaccine formulation;vaccine trial;virtual HPV Vaccine Trial n/a NCI 10919010 1ZIACP010217-13 1 ZIA CP 10217 13 10687321 "KREIMER, AIMEE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3700411 NCI Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide and subsets of various other anogenital and head and neck cancers. Prophylactic vaccination against HPV-16 and HPV-18 two of the most important HPV types could protect against a large majority of the cases of cervical cancer globally and a considerable proportion of other HPV-associated cancers. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct VLPs have been shown to be generally safe immunogenic and effective at preventing precancerous lesions of the cervix associated with HPV-16/18. A community-based phase 3 randomized controlled trial of an HPV16/18 VLP vaccine was conducted in Costa Rica. Costa Rica was chosen for the trial because of our extensive successful scientific collaborations there the high risk of cervical cancer the universal medical system providing national linkage and the likelihood of very high participation over the many needed years of close clinical follow-up. Randomization and 3-dose vaccination of 7466 women enrolled into the HPV-16/18 Vaccine Trial in Costa Rica has been successfully completed. Women have been followed actively on an annual or semi-annual basis in the first four years of follow-up and every two years thereafter. Women have completed their first four years of follow-up in the blinded phase of the trial and have been enrolled in the extended (up to 10 years) follow-up phase of the study. Cross-over vaccination was offered to trial participants at the end of the four-year blinded phase of the trial. Results from this study have shown that 1) the vaccine is highly effective at preventing new infections with HPV types 16 or 18 2) the vaccine confers partial protection against HPV types phylogenetically related to HPV 16 or 18 3) the vaccine does not help treat existing infections 4) fewer than 3 doses of the vaccine protects as well as the full 3-dose series for at least 4 years 5) the vaccine protects against HPV infection at the anus 6) Vaccine impact declines with increasing age at vaccination 7) vaccination induces cross-neutralizing potential in sera of vaccinated individuals 8) modest levels of antibodies generated by natural HPV infection provide partial protection against re-infection and 9) antibody levels generated in vaccines from regions with high HIV infection rates are comparable to those observed among participants in our trial in Costa Rica. In support of the vaccine trials a variety of methodologic and ancillary projects are underway or planned that will maximize the yield of the main effort. This includes evaluation of immunological correlates of protection including viral neutralization total type-specific antibodies and measures of antibody avidity. Immunological correlates of protection among naturally infected women are being examined and studies are underway to better understand why vaccinated women might be protected against HPV types not included in the vaccine formulation and why a single vaccine dose (prime-only) appears to protect for several years. Several analyses are underway or planned to evaluate the natural history of HPV infection at cervical and other sites and of cervical neoplasia in vaccinated and unvaccinated women. This effort is sponsored by Intramural NCI funds and by the NIH Office of Research on Women's Health (ORWH). It was formerly associated with Project Z01 CP010177. 3700411 +No NIH Category available Cross-Sectional Studies;Etiology;Goals;Head and Neck Cancer;Human Papillomavirus;Human papilloma virus infection;Incidence;India;International;Lesion;National Health and Nutrition Examination Survey;Natural History;Population;Prevalence Study;Research Project Grants;cancer site;malignant oropharynx neoplasm;molecular marker;oral HPV infection;screening;trend Studies of Head and Neck Cancers n/a NCI 10919007 1ZIACP010213-14 1 ZIA CP 10213 14 10687326 "CHATURVEDI, ANIL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1465207 NCI Research projects in the past year have focused on evaluating incidence trends for HPV-related and HPV-unrelated head and neck cancer sites internationally; investigating historical trends in the proportion of oropharynx cancers attributable to HPV infection in the US; characterizing the proportion of oropharynx cancers attributable to HPV infection in India a region with very high incidence of head and neck cancers; and studying the prevalence and predictors of oral HPV infection within the U.S. NHANES a representative cross-sectional survey of the U.S. civilian population. 1465207 +No NIH Category available Affect;Antibodies;Antibody Specificity;Behavioral;CYP2E1 gene;Case/Control Studies;Caucasians;Childhood;China;Chinese;Chromosome 14;Clinical;Clinical Markers;DNA Repair;DNA Repair Gene;Development;Dust;Environmental Risk Factor;Enzymes;Ethnic Origin;Etiology;Evaluation;Exposure to;Family;Family Study;Formaldehyde;GEM gene;Gene Expression;General Population;Genes;Genetic;Geography;Human Herpesvirus 4;Immune;Immune Evasion;Individual;Infection;Intake;Integration Host Factors;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Nasopharyngeal Neoplasms;Nitrites;Nitrosamine Metabolism;Nitrosamines;Normal Cell;Occupational;Occupational Exposure;Pathogenesis;Pattern;Population;Risk;Risk Factors;Serology;Taiwan;Testing;Tissues;Variant;Viral;Weaning;Wood material;cancer risk;cigarette smoking;dietary;follow-up;high risk population;improved;neoplastic cell Viral and Host Factors Associated with NPC n/a NCI 10919005 1ZIACP010211-14 1 ZIA CP 10211 14 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 244811 NCI Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer other factors both genetic and exogenous are also thought to be important. To investigate genetic dietary occupational and behavioral factors related to the etiology of NPC several studies were conducted in including a case-control study of approximately 1000 individuals and a multiplex family study of approximately 3000 individuals (350 families) in Taiwan. To date our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes specific patterns of HLA and KIR genes and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk; in contrast formaldehyde exposure was not a significant risk factor. Exogenous risk factors identified within our family study were similar to those observed from our case-control study. Evaluation of gene expression profiles from nasopharynx tumor and normal cells suggest that genes involved in DNA repair and in the metabolism of nitrosamines are involved in NPC pathogenesis. Results from our tissue-based expression studies also suggest the possibility of loss-of-heterozygosity on the telomeric end of chromosome 14 in NPC and that EBV gene expression within NPC tumor cells affect the expression of host genes involved in immune presentation. This suggests a possible mechanism by which EBV manages to evade immune surrveillance in NPC. Uaffected individuals from NPC multiplex families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To follow-up on this finding we have evaluated the value of EBV serology to predict subsequent NPC risk among unaffected individuals from NPC multiplex families. We observed that individual with elevated antibody levels against several EBV markers are at a 4 to 6-fold increased risk of developing NPC within 10 years but the low specificity of the antibodies evaluated suggest that improvements are required before such serology-based tests can be used clinically. 244811 +No NIH Category available Adenocarcinoma Cell;Affect;Antibodies;Case/Control Studies;Cervical;Cervical Adenocarcinoma;Cervix Neoplasms;Cohort Studies;Contraceptive Usage;DNA;Development;Etiology;Evaluation;Funding;GEM gene;Genes;Genetic;Genetic Polymorphism;Goals;HIV;Head and Neck Cancer;Histologic;Histology;Hormonal;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immune;Immunity;Immunologic Factors;Individual;Infection;Knowledge;Lesion;Longitudinal Studies;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Menstrual cycle;Molecular Epidemiology;Mucosal Immunity;Natural History;Oral Contraceptives;Predisposition;Prevention;Prevention strategy;Risk Factors;Role;Sex Behavior;Squamous cell carcinoma;Taiwan;Testing;Vaccination;Variant;Viral;Virus Diseases;Woman;Work;cervical cancer prevention;cofactor;epidemiology study;novel;premalignant;response;screening HPV cervical neoplasia and vaccination n/a NCI 10919004 1ZIACP010210-14 1 ZIA CP 10210 14 10687321 "KREIMER, AIMEE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 461995 NCI HPV is known to be a necessary cause of cervical cancer and a subset of other anogenital and head and neck cancers including many cancers (e.g. cervical and anal cancers) that are elevated in the context of HIV. However while HPV infection is common development of cancer is rare. This suggests that in additional to HPV infection co-factors are important for the development of cervical cancer. This project aims to elucidate the role of HPV and co-factors in the etiology of cervical cancer and its precursors to define whether risk factors are similar or different for different histological forms of cervical cancer and to apply knowledge gained to novel prevention strategies. Several studies have been conducted to date to achieve our goals including a multicenter case-control study of cervical adenocarcinomas and squamous cell carcinomas in the US a longitudinal study of women with low-grade HPV-induced cervical lesions and a cohort study of HPV and cervical cancer in Taiwan. Results from these studies to date have shown that 1) while HPV infection is required for the development of all histological types of cervical cancer the distribution of HPV types/variants observed in cancers vary by histology 2) co-factors associated with distinct histological types of cervical cancer differ and while all histological forms of cervical cancer are associated with sexual behavior variables that predispose to HPV infection cervical adenocarcinomas appear to be preferentially associated with risk factors that indicate hormonal involvement 3) polymorphisms in immune-related genes (including HLA and KIR genes) are associated with the development of cervical cancer and 4) HPV DNA testing is a useful screening test for the prevention of cervical cancer. In addition we have conducted molecular epidemiology studies that have shown that 1) antibodies generated in response to natural infections protect against re-infection with HPV and 2) markers of mucosal immunity vary across the menstrual cycle and are affected by oral contraceptive use suggesting that studies of local immunity and its role in predisposition to HPV persistence and progression need to account for these changes. This effort is sponsored by Intramural NCI funds. 461995 +No NIH Category available Address;Agreement;Anus;Biological;Cancer Etiology;Cervical;Cervix Uteri;Cutaneous;Cytology;Data;Diagnosis;Epidemiology;Evaluation;Genotype;Goals;HIV;HPV-16/18 Vaccine;Head and Neck Cancer;Head and Neck Neoplasms;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Individual;Infection;Infection prevention;Infectious Agent;Larynx;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Multiple Anatomic Sites;Natural History;Oral;Oropharyngeal;Population;Prevalence;Preventive vaccine;Recurrent Malignant Neoplasm;Research;Risk;Role;Site;Skin;Specimen;Testing;Vagina;Vulva;Work;cancer recurrence;carcinogenicity;cohort;conjunctiva;efficacy evaluation;immunosuppressed;malignant mouth neoplasm;men;oral HPV infection;penis;prospective;sample collection;tumor;vaccine efficacy;vaccine trial HPV and cancer at multiple anatomic sites n/a NCI 10919003 1ZIACP010209-14 1 ZIA CP 10209 14 10687321 "KREIMER, AIMEE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 512360 NCI Human papillomaviruses are one of the principal infectious agents known to cause cancers in humans; it is estimated that approximately 5% of cancers worldwide are attributable to HPV infection. HPV-associated cancers occur at particularly high rates among immunosuppressed individuals especially HIV-infected individuals. While it is well established that HPV is a necessary cause of cervical cancer world experts agree that for HPV16 the most carcinogenic of the HPV genotypes data show a causal role in cancers outside the cervix including the vulva vagina penis and anus and some head and neck tumors in the oropharynx. Other cancers hypothesized to be related to HPV infection but for which a causal association has yet to be shown include cancers of the oral cavity larynx conjunctiva and for cutaneous HPV types skin. To that end considerable research within the IIB focuses on the role of HPV infection in cancer at extra-cervical sites. We have many on-going studies whose aims are to: 1) evaluate the natural history of HPV infections at non-cervical sites 2) determine the prevalence and biologic activity of HPV infection in tumors from these sites 3) assess the prospective association between HPV infection and risk of extra-cervical prevalent incident and recurrent cancers 4) evaluate the efficacy of the HPV16/18 prophylactic vaccine against extra-cervical infection 512360 +No NIH Category available Binding Proteins;Biological;Biological Markers;Body Weight decreased;Cancer and Nutrition;Colorectal Cancer;Energy Intake;Estrogens;Etiology;Goals;Growth Factor;Incidence;Inflammatory;Insulin-Like Growth Factor Binding Protein 3;Insulin-Like Growth Factor I;Interleukin-6;Malignant Neoplasms;Malignant neoplasm of pancreas;Obesity;Output;Phenotype;Physical activity;SHBG gene;TNF gene;Testosterone;Weight Gain;cancer prevention;cancer risk;cytokine;energy balance;improved;malignant breast neoplasm;metabolomics;multidisciplinary;novel;sedentary lifestyle;steroid hormone Physical Activity Energy Balance and Cancer n/a NCI 10918996 1ZIACP010197-17 1 ZIA CP 10197 17 9414784 "ALBANES, DEMETRIUS " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1825565 NCI The goals will be achieved by a) evaluating obesity energy balance and physcial activity in relation to cancer incidence and survival; b) Improving assessment of energy intake output and body phenotype; c) Evaluating biomarkers to determine mechanisms including inflammatory cytokines (CRP IL-6 TNF-alpha) growth factors and their major binding proteins (IGF-1 and IGFBP-3) steroid hormones (testosterone estrogen SHBG) in relation to cancer and intermediate outs comes such as weight loss and weight gain d) evaluate novel such as metabolomics in assessing obesity energy balance and physical activity and body phenotype and in relation to cancer risk. Although this project is for all cancer its particular cancer includes breast colorectal and pancreatic cancer. 1825565 +No NIH Category available Age;All-Trans-Retinol;Antioxidants;Area;Beta Carotene;Biochemical;Biological;Biological Markers;Bladder;Bronchi;Cancer Etiology;Cancer Intervention;Carbon;Carotenoids;Categories;Caucasians;Cessation of life;Chest;Cigarette;Cohort Analysis;Collaborations;Colon;Colorectal;Colorectal Cancer;Data;Diagnosis;Diet;Dietary Questionnaires;Dimensions;Disease;Erythrocytes;Evaluation;Extramural Activities;Film;Finland;Folic Acid;Follow-Up Studies;Food;Freezing;Genetic;Genetic Polymorphism;Genome Scan;Genotype;Glioma;Goals;Gonadal Steroid Hormones;Growth Factor;Habits;Head and neck structure;Health;High Density Lipoprotein Cholesterol;Human;Human Resources;Insulin;International;Intervention;Investigation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measurement;Medical;Medical Records;Metabolic;Metabolism;Molecular;National Cancer Institute;Nested Case-Control Study;Nutrient;Nutritional;Occupational;Pancreas;Participant;Pathology;Phase;Phenotype;Placebos;Pleura;Population Registers;Procedures;Productivity;Prospective Studies;Prostate;Public Health;Randomized;Randomized Controlled Trials;Rectum;Renal carcinoma;Research;Research Personnel;Research Project Grants;Resources;Risk;Sampling;Selenium;Serum;Slide;Smoker;Smoking;Specialized Center;Specimen;Structure of nail of toe;Supplementation;Surveys;Testing;Thoracic Radiography;Trachea;Visit;Vitamin D;Vitamin E;Vitamin E Acetate;Vitamins;Whole Blood;alpha Tocopherol;cancer epidemiology;cancer prevention;capsule;case control;cohort;design;diet and cancer;dietary;effectiveness testing;energy balance;epidemiology study;follow-up;genetic analysis;genetic variant;genome wide association study;group intervention;interest;intervention effect;male;malignant breast neoplasm;malignant stomach neoplasm;men;metabolomics;neoplasm registry;nutrition;population based;post intervention;prevent;prostate cancer risk;recruit;rectal;side effect;web site Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study n/a NCI 10918994 1ZIACP010195-17 1 ZIA CP 10195 17 9414784 "ALBANES, DEMETRIUS " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 699632 NCI The ATBC Cohort Follow-up Study has been in place since 1994. Male smokers between the ages of 50 and 69 were recruited from southwestern Finland between April 1985 and June 1988. A total of 29133 men were randomly assigned to one of four intervention groups: 50 mg/day alpha-tocopherol (as dl-alpha-tocopheryl acetate); 20 mg/day beta-carotene; both alpha-tocopherol and beta-carotene; or placebo. They were followed for five to eight years during the trial until death or 30 April 1993 when intervention was stopped (median follow-up 6.1 years). Follow-up for endpoints was continued postintervention. Following invitation for participation and recruitment through a population-based postal survey the trial randomly assigned 29133 Caucasian 50-69 year old male smokers of 5 cigarettes daily to one of four intervention groups based on a 2x2 factorial design: beta-carotene (20 mg/day) vitamin E (50 mg/day as dl-alpha-tocopheryl acetate) both agents or placebo. At entry medical dietary smoking and occupational data were obtained along with physical measurements a chest x-ray and serum and toenail samples. Diet was captured through a 276 food item dietary questionnaire that was developed and validated for the trial. Baseline serum was collected frozen and stored for all participants and vitamin E beta-carotene retinol and total and HDL cholesterol were determined. Follow-up serum and whole blood were collected for all active participants later in the study as were additional serum and red blood cell samples from selected subsets. Active intervention continued for 5-8 years with three study visits annually during which participants were asked about their health and possible subjective side effects capsule compliance and smoking habits since the last visit. Chest films were taken at 2-3 year intervals and at the end of the trial. All incident cancers were identified through the nationwide Finnish Cancer Registry medical records/pathology slides were reviewed / abstracted and deaths/underlying causes were identified through the National Population Register. The ATBC Cohort Follow-up Study has had the overall aim of conducting cancer etiologic research and post-intervention cancer surveillance based on the original trial cohort of 29133 men. Cohort analyses nested case-control investigations analyses of genetic polymorphisms and other molecular parameters and studies of the biological effects of the intervention agents on relevant biomarkers have been conducted and are the focus of ongoing research. Current cumulative totals of diagnosed cases through 2012 include approximately 3900 lung 2700 prostate 900 colorectal 800 bladder 400-500 each for stomach pancreas and kidney cancers and 450 head and neck. Cancer etiologic research in the ATBC Study has evolved naturally from the focus on supplementation into several areas of concentration that reflect both our research interests and the availability of study resources to a continually growing number of highly productive investigators both at NCI and elsewhere. A public website (http://atbcstudy.cancer.gov/) provides information regarding the project's research data personnel and resources including procedures for initiating collaborations. The high-quality study data biological specimens and ongoing endpoint ascertainment have been applied to testing biochemical and genetic hypotheses related to nutritional and other factors having potentially high attributable risks in prostate (based on 2500 cases) lung (3500 cases) colorectal (700 cases) pancreatic (400 cases) and other cancers. GWAS studies of risk for prostate lung renal and bladder cancers as well as NHL and glioma are completed. We have completed investigations of vitamins D E A and selenium status; carotenoids and other antioxidants; one-carbon metabolism; energy balance insulin and growth factors; sex steroids; and genetic variants impacting these exposures. GWAS studies of nutrition phenotypes such as serum vitamin D status are being conducted. Evaluation of these factors within the context of the controlled vitamin supplementation design has afforded us unique opportunities to investigate biological and biochemical interactions.Another important dimension of the ATBC Study has been collaborations with extramural researchers in cancer epidemiological consortia. These include: the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) PanScan the Pooling Project of Prospective Studies of Diet and Cancer and the Harvard Specialized Center on Folate One-Carbon Nutrients Gene Variants and Colorectal Cancer. We contribute scientific expertise data and cohort resources and intramural support to these powerful high-impact studies. 699632 +No NIH Category available Breast Cancer Risk Assessment Tool;Breast Cancer Risk Factor;Calibration;California;Cause of Death;Cessation of life;Clinical Research;Cox Models;Data;Development;Disease;Electronic Health Record;Evaluation;Family Study;Genotype;Goals;Human Papillomavirus;Incidence;Latina;Left;Literature;Logistics;Lung CAT Scan;Malignant neoplasm of lung;Methods;Modeling;National Cancer Institute;New Mexico;Pap smear;Publishing;Registries;Relative Risks;Risk;Risk Estimate;Risk Factors;Single Nucleotide Polymorphism;Smoker;Statistical Methods;Statistical Models;Testing;Validation;Woman;cancer prevention;case control;cohort;data registry;disorder risk;improved;interest;lung cancer screening;malignant breast neoplasm;method development;personalized predictions;population based;risk prediction;risk stratification;screening Risk prediction methods n/a NCI 10918991 1ZIACP010188-19 1 ZIA CP 10188 19 8770483 "GAIL, MITCHELL H" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 375639 NCI "We continued to develop refine and evaluate the National Cancer Institutes Breast Cancer Risk Assessment Tool (BCRAT). Dr. Mateo Banegas a NCI Cancer Prevention Fellow developed a new model for absolute invasive breast cancer risk for Latina women. There is interest in determining whether adding information from single nucleotide polymorphisms (SNPs) can increase the discriminatory accuracy and usefulness for screening of risk models. We demonstrated improved risk stratification of breast cancer by adding SNPs to a variety of more standard risk factors. Using data from 1.4 million women undergoing HPV testing and Pap smears in Kaiser Permanente Northern California (KPNC) we published on: (1) estimating absolute risks based on HPV genotyping tests; (2) calculating and comparing risk versus those in the New Mexico HPV/Pap Registry and (3) calculating risks among those with equivocal Pap smears. We developed and validated models for risk of lung cancer incidence and death and used them to project the impact of risk-based selection of smokers for CT lung-cancer screening in the US. We developed absolute risk models appropriate under left/interval/right-censoring data occurring for screen-detected disease which occurs for electronic health record data called the ""logistic-Weibull"" and the ""logistic-Cox"" models. We explained why a method sometimes used to assess absolute risk models in case-control data does not assess calibration but only fits of relative risk." 375639 +No NIH Category available Acceleration;Brain Neoplasms;Carcinogenesis Mechanism;Cessation of life;Colorectal Cancer;Early Diagnosis;Endometrial Carcinoma;Genes;Genetic Markers;Genetic Research;Genome Scan;Genomics;Goals;Human Genetics;Inherited;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Non-Hodgkin's Lymphoma;Predisposition;Prevention;Renal carcinoma;Research Personnel;Single Nucleotide Polymorphism;Susceptibility Gene;Technology;Variant;Work;breast cancer progression;cancer genetics;cancer risk;cancer therapy;gene environment interaction;human genome sequencing;insight;malignant breast neoplasm;meetings;new technology;novel strategies;tool Cancer Genetic Markers of Susceptibility n/a NCI 10918990 1ZIACP010187-19 1 ZIA CP 10187 19 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 558955 NCI To help meet the Challenge Goal of eliminating suffering and death from cancer by 2015 the NCI must capitalize on the extraordinary momentum generated by advances in human genetic research. The sequencing of the human genome and the annotation of common variations together with new technologies for analyzing single nucleotide polymorphisms (SNPs) have provided the tools for investigators to actively search for inherited variants in genes that can increase or modify cancer risk. The C-GEMS proposal will use the latest genomic technologies to perform dense whole genome scans to identify and validate susceptibility genes in the induction and progression of breast and prostate cancer and clarify gene-gene and gene-environment interactions. This work will provide new insights into mechanisms of carcinogenesis and point the way to novel strategies for meeting the 2015 Challenge Goal by accelerating the prevention early detection and treatment of cancer.Prostate cancer lung cancer bladder cancer breast cancer colorectal cancer kidney cancer non-Hodgkin's lymphoma (NHL) ovarian cancer brain tumors and endometrial cancer are the main focus of current and planned replication studies. 558955 +No NIH Category available Affect;Amoxicillin;Antibiotic Therapy;Biometry;Breast;Breast Cancer Detection;Cancer Control;Case/Control Studies;China;Cohort Studies;Collaborations;Collection;Consult;Control Groups;Data;Data Collection;Development;Division of Cancer Epidemiology and Genetics;Egypt;Endometrial Carcinoma;Enrollment;Epidemiology;Exclusion;Female;First Degree Relative;Follow-Up Studies;Garlic;Helicobacter pylori;Histopathology;Hospitals;Incidence;Inpatients;Intervention Trial;Lead;Lesion;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Malignant neoplasm of ovary;Measurement;Morocco;National Cancer Institute;Nebraska;Northern Africa;Omeprazole;Paper;Paraffin Embedding;Participant;Population;Procedures;Province;Publishing;Questionnaires;Random Allocation;Randomized;Rural;Saliva;Selenium;Stomach;Subgroup;Supplementation;Time;Translations;Tumor Tissue;Tunisia;Universities;Vitamins;Woman;Work;cohort;digital;field study;follow-up;gastric cancer prevention;gastric carcinogenesis;inflammatory breast cancer;malignant breast neoplasm;malignant stomach neoplasm;member;mortality;premalignant;prevent Epidemiologic Field Studies n/a NCI 10918988 1ZIACP010182-21 1 ZIA CP 10182 21 8770483 "GAIL, MITCHELL H" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 637770 NCI BCDDP: Breast Cancer Detection Demonstration Project follow-up study (01030). This study follows about 60000 former participants in the Breast Cancer Demonstration Project (BCDDP). Current analyses include a variety of cohort consortium pooling projects. Gastric cancer: Randomized multi-intervention trial to inhibit precancerous gastric lesions in Linqu Shandong Province (00446). We gathered fifteen year follow-up data from an 8-year trial in rural China to determine whether any of three treatments would affect gastric cancer incidence or specific causes of mortality. The treatments were long-term vitamin (C E and selenium) supplementation and garlic supplementation given from 1995 to 2003 and one time administration of amoxicillin/omeprazole given in 1995. A paper published in 2012 showed that amoxicillin/omeprazole treatment reduced gastric cancer incidence by 39% over a fifteen year period. We examined subgroups and determined that antibiotic treatment was effective for older members of the population and for members with advanced precancerous gastric lesions at the beginning of the study despite the fact that Helicobacter pylori is thought to act on early stages of gastric carcinogenesis. Thus antibiotic treatment can be applied broadly to prevent gastric cancer and need not be restricted to the young or to those with mild histopathology. This work was published in 2014. Inflammatory breast cancer (IBC) case-control study (00314) This case-control study includes approximately 250 IBC cases accrued at 5 centers in North Africa (1 center in Tunisia 2 in Egypt and 2 in Morocco). Two control groups are being included: 1) 250 non-IBC breast cancer cases and; 2) 250 visitor controls (excluding first-degree relatives) to randomly selected female inpatients (excluding those with breast ovarian endometrial and nasopharyngeal cancer) in the study hospitals. The study involves the administration of a questionnaire anthropometric measurements saliva collection digital photographs of the breasts of IBC cases and the collection of paraffin-embedded tumor tissue for IBC cases and non-IBC breast cancer controls. The study has been conducted as a collaboration with the University of Nebraska with forms development and translation coordinated at the National Cancer Institute-USA. The NCI-DCEG is responsible for developing study procedures at the study centers in Egypt Tunisia and Morocco. Data collection began in March 2009 in Egypt August 2009 in Tunisia and January 2011 in Morocco. Data collection in Egypt and Tunisia stopped on 09/30/2013. Data collection for the project will end in Morocco by August 2016. 637770 +No NIH Category available Address;Area;Biological Markers;Biometry;Blood;Breast;Breast Cancer Detection;Breast Cancer Education;Bronchi;Calibration;Cancer Detection;Categories;Cervical Cancer Screening;Colon;Colorectal Cancer;Complex;Computer software;Data;Data Analyses;Differential Equation;Dimensions;Disease;Division of Cancer Epidemiology and Genetics;Dose;Electronic Health Record;Environmental Risk Factor;Epidemiologic Methods;Equilibrium;Family;Genes;Genetic;Genetic Markers;Genomics;Genotype;Household;Individual;International;Left;Lung;Malignant neoplasm of lung;Measurement;Methods;Mission;Modeling;National Health and Nutrition Examination Survey;Observational epidemiology;Outcome;Pathway Analysis;Pleura;Procedures;Rectum;Research;Risk;Risk Estimate;Sampling;Seasons;Surveys;Testing;The Cancer Genome Atlas;Trachea;Vitamin D;beta diversity;design;detection limit;disorder risk;electronic health data;epidemiology study;genetic variant;improved;malignant breast neoplasm;member;method development;microbiome;novel;novel strategies;population based;protective effect;rectal;response;screening guidelines;semiparametric;statistics;trait Methods for Epidemiology Studies n/a NCI 10918987 1ZIACP010181-21 1 ZIA CP 10181 21 15187126 "ALBERT, PAUL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 813306 NCI Extensions of likelihood-based sufficient dimension reduction methods were proposed and studied for analyzing biomarkers that are left and/or right censored due to lower or upper limits of detection. These methods apply generally to any type of outcome including continuous and categorical outcomes. Bias of estimates of exposure effects conditional on covariates was assessed when summary scores of confounders instead of the confounders themselves were used to analyze observational data. Two scores the propensity score (PS) and the disease risk score (DRS) were studied in detail. New procedures were developed for seasonal adjustment and calibration of blood measurements of vitamin D to support the multicenter international Vitamin D Pooling Project for Breast and Colorectal Cancer. These methods were used to guide the analysis on the associations of blood levels of Vitamin D with the risk of breast and of colorectal cancer with findings that indicate protective effects for colorectal cancer. Parametric and semi-parametric mixture models have been proposed for analyzing left or interval-censored data from electronic health records. The new approach was used for risk estimates that underlie current U.S. risk-based cervical cancer screening guidelines. A multiple imputation approach based on Additive Regression Bootstrapping and Predictive mean matching (ARBP) methods was introduced to accurately impute the missing values for steps collected in the 2003-2004 National Health and Nutrition Examination Survey NHANES. A novel class of functional data analysis models based hierarchical stochastic differential equations was developed to address some limitations by existing methods. An efficient Hardy Weinberg Equilibrium test was developed to analyze genetic data collected from population-based household surveys utilizing pairwise composite likelihood methods that incorporate the sample weighting effect and genetic correlation induced by the complex sample designs. A general procedure was developed for conducting gene and pathway analysis that uses only SNP-level summary statistics in combination with genotype correlations estimated from a reference panel of individual-level genetic data. A family of multi-locus testing procedures were developed for detecting the composite association between a set of genetic markers and two traits based on a random effect model with two variance components with each presenting the genetic effect on one trait. A likelihood-based test was developed for mutual exclusivity analysis in detection of cancer driver gene and applied to TCGA data as well as a DCEG lung cancer study. A statistical framework and a computationally efficient software package were developed for identifying host genetic variants associated with microbiome beta diversity with or without interacting with an environmental factor. 813306 +No NIH Category available 8q24;Africa;African;Age;Androgen Metabolism;Androgens;Biochemical;Biological;Biological Assay;Biological Markers;Blood;Burkitt Lymphoma;Case Series;Central obesity;China;Cities;Classification;Clinical;Collection;Colorectal;Consent;Data;Databases;Diagnosis;Dietary Factors;Dietary Practices;Epidemiology;Ethnic Population;Fasting;Freezing;Fresh Tissue;Gene Expression;Genes;Genetic;Genetic Markers;Genotype;Ghana;Health;Hormonal;Hormonal Carcinogenesis;Hormones;Human;Human Genetics;Insulin;Insulin-Like Growth Factor I;Interview;Isoflavones;Life Style;Link;Low-Density Lipoproteins;Lung;Malaria;Malignant neoplasm of prostate;Manuscripts;Maps;Medicare;Meta-Analysis;Methodological Studies;Molecular;Molecular Genetics;Nature;Nested Case-Control Study;Non-Steroidal Anti-Inflammatory Agents;Nutritional;Obesity;Outcome;Ovarian;Pathway interactions;Pharmaceutical Preparations;Population;Predisposition;Prevalence;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Prostatic Diseases;Publishing;Questionnaires;Recurrence;Research;Resources;Risk;Risk Assessment;Risk Factors;Risk Marker;Role;Sampling;Series;Serum;Stage at Diagnosis;Stains;Study Subject;Surveys;TMPRSS2 gene;Techniques;Testosterone;Time;Tissue Banks;Tissue Microarray;Tissue Sample;Tissues;Tumor Markers;Variant;androgenic;cancer risk;cancer type;candidate identification;clinical practice;clinically relevant;cohort;design;dietary;follow-up;genetic risk factor;genetic variant;genome wide association study;indexing;insight;men;metabolic profile;mortality;multi-racial;multidisciplinary;novel;population based;population survey;prostate cancer risk;prostate carcinogenesis;racial difference;racial population;recruit;resistance gene;soy;tumor;western diet Prostate Cancer Studies n/a NCI 10918986 1ZIACP010180-22 1 ZIA CP 10180 22 9414784 "ALBANES, DEMETRIUS " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 370871 NCI In Ghana Africa we have conducted a population-based survey of men to assess the population prevalence of prostatic disease (CAS ID:01130). We have also collected consented into the study a clinical series of men diagnosed with prostate cancer. This dynamic epidemiologic design of a population survey combined with a larger case series is enabling us to assess the burden of prostate cancer in African men as well as assess risk factors associated with prostate cancer in an important and understudied population. Biological samples collected from the 1038 healthy men in the population survey component will allow us to establish the nutritional hormonal and genetic profiles of African men. In addition linking interview data from these 1038 healthy subjects with biomarkers will produce insights into whether westernization in African men is associated with an adverse metabolic profile (obesity; abdominal obesity; higher levels of insulin low-density lipoprotein and insulin-like growth factor I) which has been associated with excess prostate cancer risk. The additional 677 prostate cancer cases that we recruited through the clinical component has enabled us to conduct a genome wide association study (GWAS) of prostate cancer in this unique population (published in Human Genetics). In addition we have sequenced the 8q24 region and identified several novel variants (published in Prostate) as well contributed to a pooled fine-mapping study of this region in African Men (published in JNCI) and an imputation and subset based meta-analysis of chr5p15.33 across multiple cancer types (published in Human Molecular Genetics). We have also contributed data to multi-racial GWAS and have identified 23 novel genetic (SNP) associations with prostate cancer (published in Nature Genetics). We have recently contributed to an integrative analysis to identify candidate functional SNPs at prostate cancer susceptibility regions of the geonome (published in Human Molecular Genetics). We are now extending this GWAS effort to include additional cases and controls that were recruited for this study. We are also using the population component of the Ghana Prostate Study to assess the prevalence of malaria-resistance genes with a view to uncovering the genetic risk factors of Burkitt lymphoma in Africa. We are assessing whether IFNL4 is also prominent in African men by genotyping the IFNL4 variant in 350 population-based controls in the Ghana Prostate Study. We are also assessing whether this variant can be imputed using the existing GWAS data. We are assessing whether IFNL4 is associated with age and/or stage at diagnosis of prostate cancer in the Ghana Prostate Study. We are also currently assessing the prevalence of TMPRSS2-ERG fusions in prostate cancer tissues of these African prostate cancer cases (manuscript being drafted). We have also begun analyses of questionnaire components of this study to further elucidate associations of prostate cancer in this novel population. We have conducted a multidisciplinary study in China to assess risk factors for prostate cancer in a low-risk population in order to understand more clearly the reasons for the large racial differences in prostate cancer risk (CAS ID:01140). That study involved the collection of multiple biologic samples with a primary aim of assessing risk factors and how westernization influences the risk of prostate cancer. The study also involved the collection of tissue samples from prostate cancer tumors to permit precise tumor classification as well as assays of tumor biomarkers in some cases using newly developed tissue microarray techniques. In addition to specific dietary factors dietary patterns will be identified and compared with those of controls to evaluate whether a western-style diet in China is related to excess prostate cancer risk. The study is also assessing biological correlates of westernization to look for potential biological links between westernization and excess prostate cancer risk. Data on genotypes and circulating levels of hormones provide a unique opportunity to investigate the interrelationships between serum hormones and genetic variants to gain insights into the functional significance of these genetic markers. In another study of prostate cancer in 15 cities in China we are assessing the role of soy in prostate cancer by developing a dietary isoflavone index. In addition several nested case-control studies in large cohorts including Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial the SEER-Medicare database total Medicare and Clinical Practice Research Datalink (CPRD) we are assessing the relationships of hormone-related factors with subsequent risks of prostate cancer and prostate cancer-specific mortality. A methodologic study is currently underway to evaluate whether circulating levels of androgens reflect intraprostatic androgenicity a key issue in hormonal carcinogenesis of the prostate (CAS ID:01072). This methodologic study has collected samples of fasting blood and snap-frozen fresh tissue (over 3000 pieces) from 600 study subjects in three racial/ethnic groups. Data from this study will provide a unique opportunity to investigate the interrelationships among serum and tissue hormones and variants in genes involved in the androgen metabolism pathways to provide critical data for determining the functional significance of these genetic markers. The collection of tissue samples also will provide a unique opportunity for gene expression studies. This manuscript is currently being drafted.In continuing the theme of hormonal perturbations in relation to prostate cancer we are also using a large health database to assess whether testosterone replacement medications are associated with prostate cancer risk (CAS ID: 10667). For more accurate and detailed follow up in PLCO to enable prostate recurrence analyses and analyses of outcomes post-diagnosis in this resource we are currently extending the follow-up time beyond the first year post-diagnosis to capture all clinically relevant data (CAS ID: 10515). Biochemical recurrence is being assessed in relation to tissue IHC stains.Lastly we are using data from AARP to investigate the association of NSAID use and subsequent risk of cancer including prostate cancer (CAS ID: 10547) the manuscript of which is currently under review. 370871 +No NIH Category available 20 year old;Acquired Immunodeficiency Syndrome;Affect;African Burkitt's lymphoma;Age;Anogenital cancer;Antibodies;Antigens;Bar Codes;Biological;Biological Markers;Black Populations;Breast;Burkitt Lymphoma;Cancer Etiology;Case/Control Studies;Categories;Cell Cycle Progression;Child;Clinical;Code;Collaborations;Comparative Study;Confidence Intervals;Data;Data Analyses;Development;Diagnosis;Disease;Enrollment;Epidemiology;Etiology;Extramural Activities;Falciparum Malaria;Fostering;General Population;Genetic Predisposition to Disease;Genetic Variation;Ghana;Goals;HIV;HIV Seronegativity;HIV Seropositivity;HIV diagnosis;HIV/AIDS;Head and Neck Cancer;Helicobacter pylori;Hepatitis B Virus;Hepatitis C virus;Hispanic Populations;Hodgkin Disease;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immune response;Immunity;Immunologics;Incidence;Individual;Infection;Infectious Agent;Injecting drug user;Kaposi Sarcoma;Laboratories;Link;Liver;Lymphoma;Malaria;Malawi;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of penis;Malignant neoplasm of testis;Measures;Modeling;Molecular;Mutation;Natural History;Neck Cancer;Non-Burkitt's Lymphoma;Non-Hodgkin's Lymphoma;Oncornaviruses;Organ Transplant Research;Pathogenesis;Pathway interactions;Patients;Persons;Plasmodium falciparum;Population;Population Attributable Risks;Privatization;Proteins;Residual state;Risk;Role;SEER Program;Saliva;Specimen;Stomach;T cell factor 3;TCF3 gene;Testing;Time;Tissue Banks;Tissue Microarray;Tissues;Transplant Recipients;Tumor Tissue;United States;Virus;age group;cancer risk;cancer therapy;cancer transplantation;cohort;comparative;data registry;detection method;disorder risk;experience;high risk;malaria infection;malignant breast neoplasm;malignant stomach neoplasm;men who have sex with men;metropolitan;mortality;multidisciplinary;neoplasm registry;novel;pathogen;peripheral blood;population based;prospective;rational design;seropositive;tumor;viral transmission;virus related cancer Epidemiology and Natural History of Cancer-Associated Viruses n/a NCI 10918985 1ZIACP010176-23 1 ZIA CP 10176 23 10693148 "MBULAITEYE, SAM M" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1617068 NCI This project consists of several overlapping comprehensive multidisciplinary population-based cohort and/or case-control studies to quantify the association between cancer-causing viruses (oncoviruses) with linked cancers. The projects include the HIV-AIDS Cancer Match (HACM) Study that links some 780000 people with HIV-AIDS in 14 U.S. states and metropolitan regions with cancer registry data to examine cancer risk among HIV-infected individuals and the Transplant Cancer Match (TCM) Study that links some 175000-transplant recipients to cancer registry data in 13 cancer for comparative studies. In addition focused projects on BL include the Ghana BL Study and the EMBLEM Study with broad goals to study the role of infections including HIV immune responses to EBV and Plasmodium falciparum malaria and genetic susceptibility in the etiology to BL. The studies focus on the role of the role of immunological alteration infection and risk for cancer including BL NHL Hodgkin lymphoma Kaposi sarcoma lung cancer cervical cancer head and neck cancer testicular cancer breast cancer penile cancer and gastric cancer. Biological specimens (peripheral blood saliva tumor tissues) when available are used to measure load of infectious agents including HIV EBV and KSHV also called HHV8 Pf malaria and genetic variation in the pathogens a or the host to characterize association of biomarkers with cancer. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses. Study of the US HACM provides continuing evidence of strong and durable impact of HIV on cancer risk in HIV infected persons. Using cancer incidence rates for the United States HIV-infected and general populations and applying Poisson models to linked HIV and cancer registry data and from Surveillance Epidemiology and End Results program data an estimated 7760 (95% confidence interval [CI] = 7330 to 8320) cancers occurred in 2010 among HIV-infected people. Of these 3920 cancers (95% CI = 3480 to 4470) or 50% (95% CI = 48 to 54%) were in excess of expected. The most common excess cancers were non-Hodgkin's lymphoma (NHL; n = 1440 excess cancers occurring in 88% excess) Kaposi's sarcoma (KS n = 910 100% excess) anal cancer (n = 740 97% excess) and lung cancer (n = 440 52% excess). The proportion of excess cancers that were AIDS defining (ie KS NHL cervical cancer) declined with age and time since AIDS diagnosis (both P .001). For anal cancer 83% of excess cases occurred among men who have sex with men and 71% among those living five or more years since AIDS onset. Among injection drug users 22% of excess cancers were lung cancer and 16% were liver cancer. An analysis of risk of cancers associated with infection persons diagnosed HIV in the United States in 2008 showed that 40% (95% CI 39-42) of the cancers are attributable to an infection particularly Kaposi sarcoma herpes virus Epstein-Barr virus and human papillomavirus which together were responsible for 90% of the new cancers (mainly Kaposi sarcoma lymphomas and ano-genital cancers). The infection attributable fraction was highest in the age group 20-29 years (69% 95% CI 65-72) and in men who have sex with men (48% 95% CI 46-50). Further analysis of data from HACM also showed that HIV-infected patients with cancer experienced higher cancer-specific mortality than in HIV-uninfected patients regardless of the cancer stage or receipt of cancer treatment. A study to investigate the role of protective immunity to Plasmodium falciparum (Pf) malaria in Burkitt lymphoma (BL) using data from Ghana was completed. Cases were children with Burkitt lymphoma enrolled in Ghana during 1965-1994 and controls were healthy children from the same village as the cases. Malaria immunity was measured using novel antibodies to HRP-II (an antigen believed to mark recent malaria) and Pf SE36 (thought to be protective) in 354 cases and 384 matched controls. BL was positively associated with HRP-II seropositivity (OR = 1.60; 95% CI 1.08-2.36) and inversely associated with SE36 seropositivity (OR = 0.37; 95% CI = 0.21-0.64) after control for confounding factors. Furthermore BL risk was 21 times higher (95% CI = 5.8-74) in HRP-II-seropositive and SE36-seronegative responders compared with HRP-II-seronegative and SE36-seropositive responders suggesting that individuals with evidence of recent malaria who lack protective antibodies are at highest risk for this disease. Using a sensitive and specific 24 SNP Pf molecular-barcode array developed by the Broad Institute BL cases from Malawi were shown to have greater genetic diversity than non-BL cancers from Malawi (mean genetic diversity score: 153.9 [se=5.8] versus 133.1 [se=7.7] t-test p=0.036). This suggested that there is a positive correlation between genetic diversity score of Pf malaria infection in BL in Malawi shedding new light on how infections might drive risk for an AIDS defining cancer such as BL. In studies focusing on BL tumor tissues study novel mutations were discovered in the transcription factor TCF3 (E2A) its negative regulator ID3. The mutations in TCF3/ID3 were present in about 70% of HIV-associated and sporadic BL and 40% of endemic BL while mutations in CCND3 which codes for proteins that drive cell cycle progression were present in 38% of sporadic BL but in only 1.8% of endemic BL. These results point to novel pathways for BL pathogenesis which can be targeted rational design of simpler and less toxic treatment for BL. To understand the role of EBV in BL in the US 91 confirmed BL tissues from the SEER Residual Tissue Repository (SRTR)were studied by tissue microarray (TMA). About one-third of the BL cases were EBV tumor positive. EBV positivity was lowest in cases aged 20 years and 60 years higher in Blacks/Hispanics compared to Whites and higher HIV positive cases compared to those who were HIV negative. These results suggest that EBV positive and EBV negative BL are distinct types whose distribution is different in different demographic groups. 1617068 +No NIH Category available Adolescent;Adult;Androgens;Asia;Asian;Asian Americans;Asian population;Biochemical Pathway;Biological;Biological Assay;Biological Markers;Blood;Body of uterus;Breast Cancer Cell;Breast Cancer Risk Factor;Breast Carcinogenesis;Cancer Etiology;Carbon;Carotenoids;Case/Control Studies;Categories;Childhood;Cohort Studies;Collaborations;Colorectal Adenoma;Colorectal Cancer;Communities;DNA biosynthesis;Darkness;Data;Diagnosis;Diagnostic;Diet;Dietary Practices;Disease;Environmental Exposure;Enzymes;Epidemiology;Erythrocytes;Estrogen Metabolism;Estrogens;Etiology;Family;Folic Acid;Follow-Up Studies;Food;Fruit;Genes;Genetic;Genetic Markers;Genetic Polymorphism;Genotype;Goals;Hawaiian;Health;Height;Homocysteine;Hormonal;Hormones;Human;Hydroxyestrones;Incidence;Individual;Indolent;Insulin-Like Growth Factor Binding Protein 3;Insulin-Like Growth Factor I;Intake;International;Interview;Japanese;Life Style;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Manuscripts;Measurement;Measures;Metabolic;Metabolism;Methionine;Methylation;Methylenetetrahydrofolate reductase (NADPH);Micronutrients;Migrant;Mothers;Mutation;NCI Center for Cancer Research;Nested Case-Control Study;Nutritional;Obesity;Papillomavirus;Participant;Pathway interactions;Pattern;Physiological;Phytoestrogens;Plasma;Play;Population;Postmenopause;Premenopause;Principal Component Analysis;Procedures;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Proteomics;Publishing;Recording of previous events;Relative Risks;Reproducibility;Riboflavin;Risk;Risk Factors;Role;Sampling;Series;Serum;Sexually Transmitted Diseases;Smoking;Societies;Somatomedins;Specificity;Testing;Tissues;Urine;Variant;Vegetables;Vitamin B6;Weight Gain;Woman;alpha-carotene;beta-cryptoxanthin;cancer risk;case control;cohort;design;diet and cancer;dietary;epidemiology study;folic acid metabolism;follow-up;fruits and vegetables;genetic variant;liquid chromatography mass spectroscopy;lung cancer prevention;lycopene;malignant breast neoplasm;men;methyl group;migration;multidisciplinary;nutrition;population based;pre-clinical;prospective;prostate cancer cell;prostate cancer risk;protective effect;repaired;screening;soy Nutrition Metabolism and Cancer n/a NCI 10918983 1ZIACP010169-22 1 ZIA CP 10169 22 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 258316 NCI FOLATE AND ONE-CARBON METABOLISM Folate is essential for one-carbon (methyl group) metabolism a biochemical pathway involved in DNA synthesis repair and methylation. Efficient one-carbon metabolism also requires vitamins B-6 and B-12 riboflavin and optimal activity of 10-20 enzymes. In a community-based case-control study of invasive cervical cancer we showed that high serum homocysteine was associated with a statistically significant 100-200% increase in risk and low serum or red blood cell folate with only a 20-60% increase. This pattern suggests that circulating homocysteine may be an integratory measure of insufficient folate in tissues or a biomarker of disruption of one-carbon metabolism. Variant forms of two common polymorphisms in the methylene tetrahydrofolate reductase gene and a common polymorphism in the methionine synthase gene were each associated with elevated cervical cancer risk. Risk generally increased as copies of the variant gene increased. These results suggest that both genetic variability in the one-carbon metabolism pathway and micronutrient inadequacy can contribute to increased risk of cervical cancer. Additional polymorphisms in pathway genes are now being assayed. We are also exploring the role of one-carbon metabolism in the etiology of both colorectal and breast cancer in the Prostate Lung Colorectal and Ovarian Cancer (PLCO) cohort. The large number of advanced colorectal adenomas (1200) identified will allow us to systematically search for main effects of polymorphic variation in key one-carbon metabolism genes using spaced polymorphisms as biomarkers of genetic change. The relationships among circulating levels of homocysteine and various folate forms and genotype will also be explored.VEGETABLES FRUITS AND CAROTENOIDS The protective effect of vegetables and fruits is frequently touted as the most persuasive finding to emerge from epidemiologic studies of diet and cancer with evidence strongest for lung and colorectal cancer. Individual carotenoids measured in diet or blood are reliable measures of intake of a variety of vegetables and fruits. In a nested case-control study of lung cancer in a cohort of Hawaiian Japanese men individual carotenoids were measured in prediagnostic sera. Low serum levels of beta-cryptoxanthin lycopene and alpha-carotene but not beta-carotene were each modestly associated with elevated lung cancer risk (smoking-adjusted RRs = 1.3-1.5). There was no evidence of combined or synergistic effects for individual carotenoids. Thus carotenoids at physiologic levels may not contribute substantially to lung cancer prevention. In the PLCO screening trial we are investigating the relationship of vegetable and fruit intake with quantity and variety assessed in several ways to risk of colorectal adenoma. Greater intake of fruits and some vegetables particularly deep yellow and dark green vegetables is modestly but significantly associated with decreased risk for colorectal adenoma. Pyramid servings a more comprehensive and quantitative approach to estimating food group intake did not produce substantially different results than the more traditional number of servings/day.BREAST CANCER AND PROSTATE CANCER IN ASIAN-AMERICAN POPULATIONS International variation in breast cancer incidence and migrant studies indicate that modifiable factors play a major role in breast cancer etiology although the specific lifestyles and environmental exposures remain elusive. We designed a large population-based case-control study of breast cancer in Asian-American women to take advantage of their diversity in lifestyle and breast cancer risk. Childhood adolescent and adult exposures were assessed by interviewing both study participants and their mothers. We observed a six-fold gradient in breast cancer incidence by migration patterns comparable to the international differences in breast cancer incidence rates. Using the blood and urine samples that were collected we initially focused on relationships in the controls between endogenous hormones and migration patterns. Estrogens did not differ significantly between Asian-American women born in Asia and the West. However androgen levels were higher among Asian-Americans born in Asia. Thus further efforts to understand the hormonal mechanisms underlying breast carcinogenesis should consider androgens as well as estrogens. The ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone an indicator of estrogen metabolism pathways was consistently lower (by 20%) in Asian-American women born in the West. The 2:16alpha ratio may reflect Asian lifestyles that influence estrogen metabolism and reduce breast cancer risk. We are now analyzing insulin-like growth factors (IGFs). Adiposity and weight gain in the decade preceding diagnosis as well as height were critical determinants of breast cancer risk in these Asian-American women. We are seeking biologic explanations with emphasis initially on the IGFs.Childhood adolescent and adult soy intake were each independently associated with reduced risk of breast cancer. The strongest effect was seen for childhood soy intake with a statistically significant 60% reduction in risk between extreme tertiles. Further analysis of the dietary and cultural pattern information collected will clarify whether soy seems uniquely protective or may only be serving as an indicator of other Asian lifestyles. Preliminary results suggest that the relative risk of breast cancer for a positive family history is similar in Asian-American women at different levels of Westernization. This constancy implies that the lifestyles responsible for lower risk among Asians may also modify genetically determined breast cancer risk.Foci of prostate cancer cells like foci of breast cancer cells seem to advance more rapidly in Western societies than in Asian societies. Elevated IGF-I has been postulated as a biomarker of more rapid progression and possibly a cause. With prospectively stored serum samples from a cohort of Hawaiian Japanese men we are exploring the relationship of IGF-I IGFBP-3 free IGF-I PSA and proteomic patterns to risk of prostate cancer. Two important questions are whether IGF-I is equally predictive of indolent and aggressive prostate cancer and whether it is a true risk factor preceding diagnosis by many years or simply an early marker of preclinical disease.ENDOGENOUS HORMONE MEASUREMENT We have published a series of manuscripts on the reproducibility and utility of the commercial kits currently used to measure estrogens estrogen metabolites and androgens in blood and urine from premenopausal women postmenopausal women and men. While some of the assays are sufficiently reliable to discriminate among individuals others are more problematic. In collaboration with Drs. Xia Xu and Timothy Veenstra at NCI-Frederick and Dr. Larry Keefer in the NCI Center for Cancer Research we have developed a robust relatively rapid liquid chromatography/mass spectroscopy procedure that can measure simultaneously 16 estrogens and estrogen metabolites in 0.5 ml of urine. A formal test of reproducibility sensitivity and specificity in a range of samples is being implemented. We anticipate that our approach can be extended to estrogen metabolite measurement in serum/plasma and tissue and that it can be modified to also measure androgens and phytoestrogens.NATIONAL HEALTH EPIDEMIOLOGIC FOLLOW-UP STUDY With prospective dietary data from the nationally representative U.S. Health Examination Epidemiological Follow-up Study we used principal component analysis to explore the role of dietary patterns in the etiology of prostate cancer. 258316 +No NIH Category available AFP gene;Adult;Adult Children;Androstenedione;Animal Model;Behavioral;Biological Assay;Birth;Birth Weight;Blood specimen;Body of uterus;Boston;Breast Cancer Risk Factor;Categories;China;Cohort Studies;Collaborations;Collection;Contractor;Data;Daughter;Dehydroepiandrosterone Sulfate;Diethylstilbestrol;Disease;Electronics;Estradiol;Estriol;Estrogens;Estrone;Europe;Exposure to;Female;Functional disorder;Gestational Age;Health Sciences;Hormones;Immune system;Insulin-Like Growth Factor Binding Protein 3;Label;Laboratories;Link;Louisiana;Malignant Neoplasms;Maternal Age;Medical Records;Medical center;Mothers;National Institute of Child Health and Human Development;Pathology Report;Perinatal;Pharmaceutical Preparations;Phase;Placenta;Pre-Eclampsia;Pregnancy;Pregnant Women;Premature Birth;Preneoplastic Conditions;Prevention;Progesterone;Prolactin;Questionnaires;Reporting;Son;Spontaneous abortion;Standardization;Testosterone;Twin Multiple Birth;Umbilical Cord Blood;Umbilical cord structure;Universities;Uterine Diseases;Work;cancer risk;cohort;dehydroepiandrosterone;early life exposure;follow-up;high risk;in utero;male;medical schools;member;neoplasm registry;offspring;prenatal exposure;prostate cancer risk;reproductive;vaginal clear cell adenocarcinoma Early Life Exposures and Subsequent Cancer Risk n/a NCI 10918982 1ZIACP010168-23 1 ZIA CP 10168 23 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1028736 NCI 00020 - Diethylstilbestrol (DES) a drug first synthesized in 1938 was administered to several million pregnant women in the U.S. and Europe for the prevention of spontaneous abortion and premature delivery. In 1971 Herbst reported a strong association between DES use in pregnancy and the occurrence of vaginal clear cell adenocarcinoma (CCA) in exposed female offspring. Animal models have demonstrated a range of DES effects on offspring exposed in utero including reproductive dysfunction immune system changes behavioral and sexual abnormalities and increases in various reproductive cancer in males and females. NCI in collaboration with five field centers reassembled previously studied cohorts of DES-exposed and unexposed mothers daughters and sons and identified subjects with documented exposure status who had not been studied previously through familial links within the cohorts. Standardized baseline questionnaires were mailed to cohort members to ascertain the risk of cancer and other disorders. Pathology reports were collected for reported cancers and preneoplastic conditions. Theree separate phases of follow-up have been conducted. The purpose of this study is to continue the follow-up by means of mailed questionnaires and medical record collection which was begun during the the first phase of the study. Concern has arisen that DES-exposed daughters may be at higher risk of breast cancer. Exposure to high levels of endogenous estrogen in utero has been hypothesized to increase the risk of breast cancer and DESis a potent estrogen. Cacner risk in the sons will also continure to be assessed especailly for increased risks of prostate cancer. since the offspring who were exposed to DES in utero are currently reaching their late forties when cancer rates begin to rise it is important to continue the follow-up of these cohorts to determine if there are long-term increases in cancer risk. 10039 - The proposed study involves collecting maternal and cord blood samples from monochorionic twin dichorionic twin and singleton pregnancies of similar gestational age to quantify differences in concentrations of several hormones and other pregnancy products including estriol estradiol estrone testosterone androstenedione dehydroepiandrosterone (DHEA) DHEA-sulfate progesterone AFP prolactin IGF and IGF-binding protein 3. Data from medical records and pathology reports will be abstracted to provide information on the mother baby pregnancy and placenta. The work will be done at Dartmouth Hitchcock Medical Center Dartmouth Medical School. Blood samples labeled with a unique ID number only will be sent to Bioreliance NCI's contractor for preperation and shipment to the laboratory that will perform the hormone assays. NCI will receive the abstracted data in electronic form. no personal identifying information will be received by NCI or its contractor. The study has been approved by Dartmouth Medical School. 10041 - The Norwegian birth and cancer registries will be used to investigate the association of several pregnancy and perinatal factors and risk of cancer in adult offspring. 10032 - Collaboration with NICHD on a study of preeclampsia conducted at Louisiana State University Health Sciences Center. Blood samples are being collected from mothers and from umbilical cords with and without preeclampsia. The relationship of pregnancy hormone levels and preeclampsia will be analyzed. 01132 - In this study using data from a cohort study of preeclamptic and uncomplicated pregnancies at the University of Pittsburgh we are analyzing maternal and cord blood samples from preeclamptic and normal pregnancies of similar gestational age to quantify differences in levels of various hormones. We will evaluate associations of several maternal perinatal and pregnancy factors such as maternal age and birth weight with hormone levels in normal pregnancies. In addition we will determine how well maternal levels represent levels in cord blood. 00043 - Umbilical cord blood samples were collected from 75 pregnancies in Boston MA and 175 in Shanghai China. Pregnancy hormone concentrations will be determined and correlated with putative breast cancer risk factors. 1028736 +No NIH Category available Area;Breast;Case/Control Studies;Categories;Characteristics;Clinical;Collaborations;Colon;Development;Environmental Risk Factor;Exposure to;Follow-Up Studies;Genetic;Health;Hormonal;Hospitals;Immune System Diseases;Immune system;Immunization;Immunize;Immunologic Stimulation;Individual;Infectious Agent;Laboratories;Life Style;Long-Term Effects;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Maryland;Medical Staff;National Cancer Institute;Occupations;Persons;Positioning Attribute;Recording of previous events;Rectal Diseases;Risk Assessment;case control;cohort;disorder risk;epidemiology study;experience;genetic risk factor;genome wide association study;hyperimmunization;malignant breast neoplasm;mortality;osteosarcoma;pathogen;reproductive General Studies of Epidemiology n/a NCI 10918981 1ZIACP010167-23 1 ZIA CP 10167 23 79341436 "KRAFT, PETER " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1222963 NCI 00015 - Breast cancer and prostate cancer cases occuring within the PLCO cohort will be evaluated in a nested case-control manner to assess risks associated with early reproductive characteristics including likely early hormonal profiles (via genetic inference) 00022 - The National Cancer Institute is studying the health effects among persons receiving large numbers of immunizations while employed as civilians at Fort Detrick Maryland. These individuals were employed in a variety of positions which required them to enter areas where they were potentially exposed to a variety of infectious agents. To protect individuals against these exposures immunizations were administered to them by the medical staff at the Fort whenever their job required entry to particular areas. Some individuals received as many as 50 or more immunizations to a particular agent and some persons were immunized to as many as 30 different infectious agents. While these immunizations protected the individuals against specific pathogens the long term effects of such challenges to the immune system are unknown. A study of 100 persons receiving multiple immunizations at this facility found no immediate clinical illness as a result of their immunizations. However the study did show several laboratory aberrations following intensive immunizations that suggest the possibility of long term deleterious effects. We are conducting a follow-up study of this hyper-immunized cohort to examine their mortality experience relative to their immunization history. The results of this study may add to our understanding of the effects of high levels of immune stimulation and disease development including cancer. 00400 - a multi-center case-control study of bladder cancer 1978. There are 10 SEER centers. 00028 - A hospital based case-control study of osteosarcoma was conducted in the 1990s and is still under analysis relating lifestyle environmental and genetic risk factors to risk of this disease. This study will be participating in the first Genome-Wide Association Studies (GWAS) of osteosarcoma in collaboration with several other groups. 1222963 +No NIH Category available Address;Autoimmunity;Development;Division of Cancer Epidemiology and Genetics;Elderly;HIV;HIV/AIDS;Hodgkin Disease;Human Papillomavirus;Immune;Immunity;Immunologic Epidemiology;Immunosuppression;Infection;Inflammation;Kaposi Sarcoma;Link;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Medicare;Multiple Myeloma;National Cancer Institute;Non-Hodgkin's Lymphoma;Organ Transplantation;Persons;Population;Population-Based Registry;Renal carcinoma;Risk;Risk Factors;Role;Skin Carcinoma;Tissues;Transplant Recipients;cancer risk;cancer transplantation;chronic infection;data registry;immunosuppressed;interest;melanoma;neoplasm registry Infections immunity and inflammation in cancer n/a NCI 10918978 1ZIACP010150-24 1 ZIA CP 10150 24 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2020405 NCI Infection immune disturbances and inflammation overlap in the ways that they damage tissues and promote development of cancer. Major studies under this project include the HIV/AIDS Cancer Match Study and Transplant Cancer Match Study which link population-based registries of HIV infected people and transplant recipients to cancer registries in the U.S. Additional studies characterize risk factors for specific cancers in HIV-infected people and transplant recipients. Risk of non-Hodgkin lymphoma and lung cancer is elevated in immunosuppressed populations and these two malignancies are an important focus of study. Other cancers of interest because they are associated with HIV or organ transplant include Kaposi sarcoma liver cancer cancers related to human papillomavirus (such as cervical cancer and anal cancer) Hodgkin lymphoma melanoma non-melanoma skin cancers kidney cancer and multiple myeloma. Some studies under this project address the role of HIV other chronic infections immune disturbance and inflammation in these and other cancers. Other studies which focus on cancer risk in the elderly related to immune and other conditions involve analyses of linked SEER-Medicare registry data. 2020405 +No NIH Category available Acoustic Neuroma;Adult;Agreement;Apoptosis;Behavioral;Benign;Biological;Biological Assay;Brain Neoplasms;Cancer Etiology;Cancer Patient;Carbon Tetrachloride;Case/Control Studies;Cell Cycle Regulation;Cellular Phone;Colon;DNA Damage;DNA Repair;DNA Repair Gene;Data;Diagnostic;Division of Cancer Epidemiology and Genetics;Electromagnetic Energy;Electromagnetic Fields;Environment;Epidemiology;Etiology;Exposure to;Female;Future;Genes;Genetic;Genetic Polymorphism;Glioma;Hour;Incidence;International Agency for Research on Cancer;Ionizing radiation;Lead;Lung;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Measures;Mutation;Neomycin;Nonionizing Radiation;Occupational;Occupational Exposure;Ovary;Oxidative Stress;Pathway interactions;Pesticides;Phenotype;Pilot Projects;Population;Predictive Value;Prostate;Questionnaires;Radiation;Radiation exposure;Radiation-Induced Cancer;Radiology Specialty;Reporting;Reproducibility;Research Personnel;Risk;Sampling;Skin;Skin Cancer;Solvents;Source;Specimen;Testing;Time;Time Study;Time trend;UV Radiation Exposure;Ultraviolet Rays;Woman;cancer diagnosis;cancer risk;carcinogenicity;cytokine;diaries;dosimetry;epidemiology study;farmer;follow-up;genetic analysis;genome wide association study;improved;magnetic field;meningioma;radio frequency;response;screening;solar ultraviolet radiation;trend;volunteer Studies of Non-Ionizing Radiation-Related Cancer n/a NCI 10918973 1ZIACP010135-28 1 ZIA CP 10135 28 15666236 "CAHOON, ELIZABETH " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 428758 NCI Case referent study of brain tumors - 04030 The etiology of brain tumors and brain cancer is poorly understood and recorded incidence rates have increased dramatically over the past several decades. In response to these findings and to advance understanding of environmental behavioral and genetic causes of brain tumors we conducted a case-control study of malignant and benign brain tumors (glioma meningioma and acoustic neuroma). Excess risks of glioma were found among electricians and farmers and an elevated risk of meningioma was seen among auto-body painters. Detailed occupational exposure assessments were conducted for electromagnetic radiation lead and pesticides. No associations were seen for electromagnetic radiation but an association was suggested for meningioma and lead. No consistent evidence was found of an association between any of six chlorinated solvents and risk of glioma or meningioma although there was limited evidence of an association between carbon tetrachloride and risk of glioma. Recent genetic analyses have indicated associations between brain tumor risk and polymorphisms in cytokine apoptosis/cell cycle control DNA repair and oxidative stress genes. Findings for these pathways are being followed up in larger and more comprehensive studies. Cellular Telephone Use and Cancer Risks Ionizing radiation is known to increase cancer risks but there is no consistent evidence that non-ionizing radiofrequency radiation (cell phones) or magnetic field (power lines and electrical appliances) exposures increase cancer risk. As a result of public and Congressional concern the Radiation Epidemiology Branch (REB) launched an early case-control study and found no relationship between cell phone use and risk of glioma meningioma or acoustic neuroma. A study of time trends in glioma incidence in the U.S. led by REB showed no rise despite dramatic increases in cell phone use. A subsequent REB assessment demonstrated that the elevated glioma risks associated with cell phone use in a Swedish study that influenced IARCs conclusion of possible carcinogenicity was not consistent with U.S. incidence trends though incidence trends could be consistent with the small excess of glioma in the highest level users in the Interphone study. UV Dosimetry - 10262 A pilot study of 125 volunteer radiologic technologists was performed by REB investigators in which daily diaries and polysulfone UV dosimeters were used to develop better questionnaire approaches to ascertain environmental UV exposure for future studies of skin and other cancers in this largely female occupational population. The volunteers were queried 6 months later to test the reproducibility of responses to time outdoors. Agreement between reported time on weekdays was significantly higher than for weekends and the reproducibility of hour-based compared to activity-based questionnaires was poorer in adult women. Improved exposure assessment may enable us to characterize more quantitatively the effects of UV and ionizing radiation on skin and other cancers. PLCO Lung DNA Damage Study - 10334 It is unclear whether the reported associations between functional assays and increased lung cancer risk represent a true association because the tests were performed on biologic specimens collected after cancer diagnosis. It may be that they are measuring the consequence rather than the underlying cause of cancer (termed reverse causation bias). Several DCEG investigators are participating in the effort to determine the predictive value of multiple phenotypic or functional assays in pre-diagnostic samples from lung cancer patients included in the Prostate Lung Colon and Ovary (PLCO) screening trial. Primary study findings were that neomycin mutation sensitivity was associated with increased lung cancer risk. Further study of DNA repair genes will be done using existing GWAS data. 428758 +No NIH Category available Accidents;Age;Aircraft;Alcohols;Basal cell carcinoma;Binding Sites;Biological Markers;Body of uterus;Brain;Breast;Breast Cancer Risk Factor;Bronchi;Case/Control Studies;Categories;Central Nervous System;Certification;Cessation of life;Chernobyl Nuclear Accident;Chromosome abnormality;Chronic;Chronic Lymphocytic Leukemia;Circadian Rhythms;Cohort Studies;Colon;Contracts;Cosmic Radiation;Data;Development;Diagnostic Procedure;Diet;Discipline of Nuclear Medicine;Disease;Disease Outcome;Dose;Dose Rate;Employment;Endocrinology;Excess Mortality;Exposure to;External Beam Radiation Therapy;Faculty;Feedback;Female;Fluorescent in Situ Hybridization;Flying body movement;Focus Groups;Frequencies;General Population;Hematological Disease;Incidence;Individual;Interview;Ionizing radiation;Joints;Length;Literature;Lung;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pharynx;Malignant neoplasm of thyroid;Maternal Exposure;Medical;Medicine;Methods;National Cancer Institute;Nervous System;New York;Nuclear;Occupational;Occupational Exposure;Occupational Groups;Occupations;Organ;Paper;Patients;Pattern;Pleura;Plutonium;Population;Population Study;Procedures;Publishing;Radiation;Radiation Dose Unit;Radiation exposure;Radiation-Induced Cancer;Radiology Specialty;Recording of previous events;Rectum;Reporting;Research;Risk;Role;Scientist;Seasons;Site;Skin;Skin Carcinoma;Solid;Source;Suicide;Survivors;Testing;Time;Trachea;Travel;Ukraine;United States;Universities;Update;Vitamin D;Vitamins;Woman;Work;atomic bomb;biodosimetry;cancer risk;case control;cohort;comparison group;design;dosimetry;experience;follow-up;improved;in utero;leukemia;malignant breast neoplasm;malignant mouth neoplasm;melanoma;mortality;mortality risk;pilot test;radiation carcinogenesis;radiation effect;reconstruction;rectal;response;telomere;trend;work-study Studies of Populations Exposed to Occupational Sources of Radiation n/a NCI 10918972 1ZIACP010133-28 1 ZIA CP 10133 28 14721304 "KITAHARA, CARI " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2475812 NCI Markers of Cosmic Radiation Exposure Among Flight Crew A biodosimetry study study was conducted to determine if there were differences in the frequency of chromosome aberrations by assess cosmic radiation exposure and frequency of chromosome aberrations by fluorescence in situ hybridization among 83 pilots (given their increased levels of cosmic radiation exposure) and 51 university faculty with minimal flying experience. The mean frequency of translocations did not differ between the airline pilots and a comparison group of university faculty however there was a significant increasing trend among the pilots for number of years flying commercial aircraft and translocation frequency. In addition radiation exposure from personal diagnostic procedures among the pilots was positively associated with translocation frequencies after adjustment for age and number of years flying. Some diet and vitamin supplements were also associated with translocation frequency. Cancer and Other Mortality Risks in a Cohort of U.S. Radiologic Technologists In 1982 the REB initiated a nationwide cohort study of all cancer incidence and mortality among 146022 U. S. radiologic technologists who were certified during 1926-1980. The cohort with 73% females. From work history data (collected 1983-89 1994-98 2003-2005 and beginning in 2012) along with tracing and matching with death information we found significantly elevated incidence risks for breast cancer leukemias other than chronic lymphocytic leukemia basal cell carcinoma of the skin melanoma and circulatory diseases among technologists first working before 1950 and a suggested increase in thyroid cancer in those first working before 1960. The and very high response rates and development of the first comprehensive historical occupational dose reconstruction offers a rare opportunity to study effects of occupational protracted low- to moderate-dose radiation exposure on breast and thyroid cancer the two most sensitive organ sites for radiation carcinogenesis in women. All other cancer and non-cancer serious disease outcomes are also being evaluated in relation to protracted low-to-moderate dose exposures. Cancer Mortality in Russian Nuclear Workers A cohort of 26000 Mayak nuclear facility workers is being studied because they comprise a unique occupational group for protracted exposure to external radiation at high doses and for exposure to plutonium. Improved dosimetry and updated mortality data confirm earlier findings of external dose-response relationships for leukemia and for all solid cancers. Mortality analyses have clearly demonstrated that risks for lung cancer liver cancer and bone cancer increase with increasing dose from plutonium. Dose-response analyses of cancer mortality in relation to in utero radiation exposure from maternal employment at the Mayak facility provide no evidence of an effect. Chernobyl Leukemia Study This is a joint US-Ukrainian case-control study of leukemia and other hematological diseases in a cohort of clean-up workers in Ukraine following the Chornobyl accident carried out from 1986 to 2006 - one of the largest analytical studies performed in Chornobyl liquidators taking into account the whole period of observation since the accident cohort size (approximately 110000) and collective dose. A total of137 cases of leukemia have been ascertained in the cohort. With a case-control ratio of 1:5 this number of cases provides adequate power to test the hypothesis of an association between radiation and leukemia risk. The study should also have adequate power to test the hypothesis that the risk is different from that seen in the atomic bomb survivors study if the previously pattern of CLL increases observed in the Chornobyl liquidators from Ukraine is confirmed. The study is conducted by scientists of the Ukrainian Research Center for Radiation Medicine (RCRM) scientists from the U.S. National Cancer Institute (NCI) and scientists and consultants from Columbia University New York (through a contract with NCI). The field work for the study has been completed. A paper has been published reporting a significant increase risk of both chronic lymphocytic leukemia and other types of leukemia. Dosimetry for Nuclear Medicine Patients Despite the growing use of nuclear medicine procedures in the United States very little is known regarding patterns of exposure in medical radiation workers. 20% of radiologic technologists in the U.S. radiologic technologist (USRT) study have reported working as nuclear medicine technologists at some time in their job history. In November 2010 REB held a focus-group discussion in which 8 to 10 experts provided input on historical practices. Based on these findings as well as the literature we have developed a detailed interview work module for radiologic technologists working with nuclear medicine procedures. We plan to refine this module based on feedback from additional feedback from focus group attendees and other experts and to perform extensive pilot testing of the new nuclear medicine module. Studies of UV and cancer at various sites in the USRT cohort This project is designed to facilitate study of the role of UV/ vitamin D in relation to several cancers. We recently completed an analysis in a USRT subpopulation of the UV and other determinants of circulating 25(OH)D which is in press in AJE. An additional analysis of how well 25(OH)D tracks in individuals across seasons will soon be submitted to J Clin Endocrinology. Other analysis planned involve the relationship between 25(OH)D and telomere length. We also plan to examine the relationship between specific UV wavelengths and various skin and other cancers. Leukemia and Other Cancer Incidence in Baltic Clean-up Workers Workers received an average radiation dose of approximately 10 cGy. No clear evidence of increased risk was seen for leukemia thyroid cancer or radiation-related cancer sites combined relative to incidence in the general population. An elevated risk was found for cancers of the pharynx esophagus central nervous system and a broad category of alcohol-related sites. Excess mortality was observed for cancer of the mouth and pharynx alcohol-related sites taken togetherand suicide. Twenty-five years of follow-up suggest that non-radiation determinants of cancer incidence and mortality predominate over direct effects of radiation in this cohort. Incidence of Cancers in Female Flight Attendants Flight attendants may be at increased risk of breast and other cancers due to work-place exposures including cosmic radiation and circadian rhythm disruption from traveling across multiple time zones. We are investigating the risk of breast and other cancers in 9631 female flight attendants and whether the risk is cosmic radiation dose-related. 2475812 +No NIH Category available Accidents;Affect;Animals;Area;Belarus;Benign;Case/Control Studies;Cessation of life;Chernobyl Nuclear Accident;Child;Childhood;Clinical;Cohort Studies;Collection;Consumption;Country;Coupled;Dairying;Data;Data Set;Databases;Development;Dose;Environment;Environmental Exposure;Ethnic Population;Etiology;Event;Exposure to;External Beam Radiation Therapy;Fertility;Focus Groups;General Population;Genes;Genetic Predisposition to Disease;Glioma;Group Interviews;Gynecologist;Head circumference;Health;Hormones;Human;I131 isotope;Individual;Interview;Investigation;Ionizing radiation;Kazakhstan;Length;Life;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of thyroid;Manuscripts;Measurement;Measures;Medical;Methodology;Milk;Mothers;National Health and Nutrition Examination Survey;National Institute of Child Health and Human Development;Nature;Neonatal;Newborn Infant;Nuclear;Nuclear Accidents;Occupational Exposure;Organ;Persons;Play;Population;Population Study;Pregnancy;Pregnant Women;Preparation;Prevention;Province;Publishing;Questionnaires;Radiation;Radiation Accidents;Radiation Dose Unit;Radiation Protection;Radiation exposure;Radiation-Induced Cancer;Radioactive;Radioactive Fallout;Radioactive Iodine;Radioactive Waste;Radioisotopes;Radiology Specialty;Records;Resources;Risk;Risk Assessment;Risk Estimate;Risk Factors;Role;Russia;Seasons;Site;Skin Cancer;Skin Carcinoma;Solid;Source;Statistical Data Interpretation;Structure;Sunlight;System;Techniques;Testing;Testosterone;Thyroid Diseases;Thyroid Gland;Time;UV Radiation Exposure;Ukraine;Uncertainty;Vitamin D;Vitamins;Work;cancer risk;cohort;computer program;design;dosimetry;drinking water;environmental radiation;epidemiology study;feeding;fetal;field study;follow-up;genome wide association study;improved;in utero;internal radiation;leukemia;medical countermeasure;melanoma;member;mortality;neoplasm registry;offspring;population based;prenatal;prenatal exposure;prospective;racial population;radiation effect;reconstruction;reproductive function;reproductive outcome;response;screening;solar ultraviolet radiation;study population;ultraviolet;weapons Studies of Populations Exposed to Environmental Sources of Radiation n/a NCI 10918971 1ZIACP010132-28 1 ZIA CP 10132 28 15666236 "CAHOON, ELIZABETH " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 3276704 NCI Cancer Mortality Among Populations Exposed to Radioactive Waste in the Techa River by Mayak Nuclear Facility Cancer mortality is being evaluated in a cohort of approximately 30000 people who lived by the banks of the Techa River in the Southern Urals of Russia and had protracted environmental radiation exposure from radioactive waste released into the river by the Mayak nuclear facility. Current efforts focus on statistical analyses using the recent follow-up data and dosimetry system and manuscript preparation. Significant dose-response relationships have been observed for both solid cancer and leukemia mortality. Chernobyl Thyroid Study in Belarus/Ukraine The Chernobyl accident in Ukraine contaminated large parts of Belarus northwestern Ukraine and bordering Russian provinces. Two case-control studies with individual dose estimates demonstrated a statistically significant link between thyroid cancer and environmental radiation dose from fallout related to the accident. REB and collaborators organized follow-up screening studies of benign and malignant thyroid disease among those exposed as children to fallout from the accident in Belarus and in Ukraine. The thyroid glands of approximately 12000 subjects in each country have been screened biennially for four cycles in Ukraine and three cycles in Belarus. The projects have transitioned from active screening to other forms of follow-up using existing national cancer registries. Cohort-based GWAS of Glioma We have completed a cohort-based genome wide association study of glioma including 18 studies from the Cohort Consortium with the aim of confirming gene regions associated with glioma risk identifying new regions of genetic susceptibility that may be more apparent in a cohort setting and conducting targeted gene-environment analyses based on the covariate data available from cohorts. Development of Computer Program for Organ Dose Calculations The computer program is based on Monte Carlo transport technique coupled with computational human phantoms to provide organ dose estimates for individuals exposed to radiological accidents or terrorist events. Dose reconstruction and Health Effects of In-utero and Early Life Radiation Exposure Appropriate medical countermeasures for prevention of adverse health effects following radiological or nuclear incidents are critical to radiation protection of exposed populations and are of particular scientific medical and public concern when pregnant women and their offspring are involved. Several thousands of children born in Belarus during the period from April 26 1986 through February 28 1987 were exposed in utero and in early life as a result of the Chernobyl accident. This study will establish a cohort of about 2500 Belarusian individuals exposed in utero and in early life to radioactive iodine and other radioactive isotopes from Chernobyl fallout reconstruct doses to the thyroid gland from internal and external radiation exposure ascertain thyroid cancer and other thyroid diseases and assess radiation dose-responses. NHANES III: Prospective Vitamin Study The NHANES III data set with measured vitamin D levels on about 20000 people is a resource that allows investigation of the relationship between vitamin D and specific causes of mortality. This cohort includes actual vitamin D measurements and about 2253 deaths of which nearly 900 are cancer deaths. In a published study of this data we found no relationship between circulating 25(OH)D and cancer mortality across racial/ethnic groups. The dataset also allows examination of relationships between 25(OH)D and other circulatinf hormones (e.g. testosterone) which we are reviewing. Skin Cancer in Radiologic Technologists Exposure to ultraviolet (UV) radiation from sunlight plays a predominant role in the etiology of melanoma and non-melanoma skin cancer but the nature of the relationship is not fully understood. We recently completed questionnaire-based collection of lifetime UV sun-related radiation exposure from more than 70000 U.S. radiologic technologists and have undertaken analyses to assess risks of specific forms of cancer in relation to exposure. We also plan to evaluate whether skin cancer risks associated with occupational exposures to ionizing radiation might be modified by questionnaire-derived estimates of UV radiation exposures. Study to Improve Thyroid Doses from Fallout Exposure in Kazakhstan This builds on an existing study of radiation exposure and thyroid disease among individuals in Kazakhstan exposed during childhood to radioactive fallout from nuclear tests conducted at the Semipalatinsk Nuclear Test Site between 1949 and 1962. High thyroid doses to this population from both internal and external radiation sources present a unique opportunity to quantify and compare the two types as risk factors for thyroid disease in a single population. A field study using focus group interviews has been conducted to investigate aspects of typical village life in areas affected by fallout that might influence individual radiation doses to the thyroid gland. We collected retrospective information about factors influencing radiation dose to the thyroid gland in children of two distinct ethnic groups including milk and milk product consumption seasonal practices of pasturing and supplemental feeding of dairy animals at the time of the nuclear tests time spent outdoors and radiation shielding provided by buildings. These data will fill key gaps in the current dose-reconstruction methodology and should result in improved dose estimates providing the basis for evaluating and quantifying dosimetric uncertainty and related biases in risk estimates. NICHD_NCI_Health Effects of in Utero Exposure to I-131 in Chernobyl Fallout The population-based epidemiologic study was designed to evaluate potential adverse reproductive outcomes associated with prenatal exposure to Iodine-131 as a result of radioactive releases from the April 1986 Chernobyl nuclear accident. The study population is a well-defined cohort of 2582 mother-child pairs from contaminated areas of northern Ukraine originally assembled to investigate the risk of benign and malignant thyroid disease through in-depth clinical screening examinations of the offspring and structured interviews with the mothers carried out in 2003-2006. Data for the current study of reproductive outcomes were ascertained by retrieving and reviewing cohort members' prenatal delivery and newborn records. Data were recorded on an Abstract Form designed with the help of study gynecologists and registered in analytic data base. Individual estimates of fetal thyroid Iodine-131 dose are available for all subjects. Statistical analyses to examine the relationship of fetal I-131 dose with neonatal anthropometrics and length of gestation have been carried out on a subset of cohort members with complete data (N=1167). Preliminary results show dose-dependent relationships with head circumference and gestational length. We are currently carrying out more extensive analyses to pursue these initial findings. We are also extending the work to explore radiation effects on reproductive function/fertility among the in-utero exposed offspring. 3276704 +No NIH Category available Acceleration;Age;Anti-Inflammatory Agents;Antidiabetic Drugs;Aspirin;Benign;Breast Cancer Risk Factor;Cardiovascular system;Central Nervous System Neoplasms;Chemopreventive Agent;Chemoprophylaxis;Cholesterol;Chronic;Clinic;Clomiphene;Collaborations;Consumption;Data;Data Set;Development;Diabetes Mellitus;Diagnostic Factor;Dose;Drug usage;Endometrial Carcinoma;Estrogens;Etiology;Evaluation;Event;Exposure to;Fertility;Fertility Agents;Fertilization in Vitro;Fibroid Tumor;Fracture;Gender;Gynecologic;Health;Hepatotoxicity;Hormonal;Hormones;Hypertension;Incidence;Individual;Infertility;Inflammation;International Agency for Research on Cancer;Intervention;Investigation;Link;Literature;Liver diseases;Long-Term Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of ovary;Medical;Medicare;Menopause;Metabolic syndrome;Metformin;Methodology;Michigan;Modeling;Non-Steroidal Anti-Inflammatory Agents;Norway;Obesity;Overweight;Pattern;Persons;Pharmaceutical Preparations;Population;Preparation;Primary carcinoma of the liver cells;Progestins;Publications;Publishing;Regimen;Research;Research Personnel;Risk;Risk Factors;Risk Reduction;Severities;Therapeutic;Therapeutic Intervention;Thinness;Thyroid Diseases;Time;United States National Institutes of Health;Weight;Woman;bone loss;cancer risk;clinical practice;cohort;demethylation;endometriosis;follow-up;high risk;high risk population;hormone related cancer;hypertension treatment;insight;interest;liver development;malignant breast neoplasm;neoplasm registry;pharmacologic;prospective;protective effect;rare cancer;reproductive;therapeutic evaluation Therapeutic and Diagnostic Factors as Related to Cancer Risk n/a NCI 10918969 1ZIACP010128-28 1 ZIA CP 10128 28 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 240155 NCI A large part of our portfolio within this Project has focused on the effects on cancer risk of exogenous hormones. Descriptive analyses using data from SEER documented increases in endometrial cancer incidence after 2002 when results from the Womens Health Initiative (WHI) Trial were published. We hypothesized that this reflected widespread decreases in continuous estrogen plus progestin (E+P) MHT use (the therapy linked with increased breast cancer risk within WHI) given that this is an exposure that we as well as others have documented as leading to reductions in endometrial cancer risk in overweight and obese women. In contrast in another analysis we found long-term sequential E+P use (which involves substantial exposure to unopposed estrogens) is associated with increased risk; this association was restricted to thin-to-normal weight women presumably reflecting their lower endogenous estrogen levels. In an additional investigation focused on ovarian cancer we found that both sequential and continuous E+P usage was associated with ovarian cancer risk increases. In fact in a descriptive study we noted an accelerated decline in ovarian cancer incidence among women 50 years and older in age-period-cohort models following the marked reduction in MHT use that occurred after publication of the WHI results. The notable gender discrepancy in rates of liver cancer has suggested that hormones influence risk leading to an interest in the effects of MHT use. However in the Liver Cancer Pooling Project (LCPP) we found no evidence that liver cancer risk was related to MHT use although we had limited information of the specific types of preparations used.In addition to MHT we have also been concerned regarding the long-term use of fertility drugs. In an extended followup of our large U.S. infertility cohort we saw no relationship of clomiphene use to either ovarian or endometrial cancers. However women exposed to 12 or more clomiphene cycles were at an increased risk of invasive breast cancers. In an evaluation of the long-term effects of in vitro fertilization (IVF) undertaken in collaboration with investigators at one of Israelis largest HMOs we saw no significant associations with breast endometrial or ovarian cancer risk but a significant reduction in cervical cancer presumably reflecting increased surveillance and treatment of precursor conditions among women availing themselves of reproductive assistance. We also collaborated on a study in Norway that evaluated cancer risk following IVF exposures. There were no increases in risk for most cancer although some elevated risk of breast cancer for the subjects followed for the longest periods of time. In addition some increases in risk were also observed for central nervous system tumors and for ovarian cancers among women who remained childless. To continue the evaluation of long-term cancer risks following IVF exposure we are conducting a retrospective linkage of nationwide IVF fertility clinic data with the national cancer registry. Once completed we will be able to evaluate both maternal and childhood cancer risk following IVF treatment.In 1999 the International Agency for Research on Cancer (IARC) reviewed the existing literature on OC use and hepatocellular carcinomas (HCC) and concluded that there was sufficient evidence of a causal relationship. However the number of studies included in the review was small and the number of cases per study modest. In the LCPP which involved large numbers we found no evidence that OC use was related to an increased risk of HCC. The increasing recognition of the importance of chronic inflammation in the etiology of ovarian cancer has prompted an interest in risk associated with usage of non-steroidal anti-inflammatory drug (NSAID) usage. In the NIH-AARP study we evaluated aspirin use and ovarian cancer risk but did not find an association possibly due to limited information on use patterns. In a large pooled analysis of individual data within the ovarian cancer association consortium (OCAC) a significant reduction in ovarian cancer risk was associated with regular aspirin use with evidence that the reduced risk was strongest for daily low-dose (100 mg) usage. This suggested that the same aspirin regimen proven to protect against cardiovascular events and associated with risk reduction of several cancers might have chemopreventive implications for ovarian cancer. We are following up on our aspirin finding for ovarian cancer using pooled prospective data in the ovarian cancer cohort consortium (OC3). [Ovarian cancer studies are described in Z01 CP010126 Hormone-related Cancers]The majority of risk factors for HCC cause chronic inflammation; thus we hypothesized that use of NSAIDs might be related to reduced risk. In analyses within the NIH-AARP study we found that aspirin but not non-aspirin NSAID use was significantly inversely associated with HCC risk. As most aspirin use in the population was on a daily basis the result suggested that consuming an 80 mg dose for cardiovascular chemoprophylaxis might also lead to a reduction in HCC risk.In an analysis that we conducted in the SEER-Medicare dataset we demonstrated that metabolic syndrome is a risk factor for HCC. As high cholesterol levels are one of the defining conditions of metabolic syndrome we sought to determine whether use of cholesterol-lowering drugsstatins--would decrease risk. In an analysis within the Henry Ford HMO in Detroit Michigan we did indeed find that persons who took statins were at significantly decreased risk of developing HCC. A subsequent analysis within the U.K.s Clinical Practice Research Datalink (CPRD) confirmed the inverse association between statin use and liver cancer risk. Analyses restricted to higher-risk individuals (i.e. those with pre-existing liver disease and those with diabetes) found similarly strong inverse associations suggesting that the observed risk reduction associated with statins was unlikely to reflect confounding by contraindication (concerns about hepatotoxicity with the use of statins that may result in biased prescribing patterns) and that statins may be beneficial even among persons at high-risk for liver cancer.A number of prior studies had suggested that use of metformin an anti-diabetic drug is inversely associated with development of liver cancer. Most of these studies however have compared metformin use to that of all other anti-diabetes medications. However anti-diabetic medications are strongly linked to diabetes duration and severity. To assess whether the apparent protective effect of metformin was due to it being a first line therapy we conducted an analysis in the CPRD that compared HCC cases with diabetes to controls with diabetes. Our analysis found that metformin was not strongly inversely associated with the development of HCC and has offered important methodologic insights related to the use of appropriate comparison populations while studying cancer risk associated with pharmacologic exposures. [Liver cancer studies are described in Z01 CP010158 Studies of Rare-Cancers] 240155 +No NIH Category available Alcohols;Anatomy;Asian;Asian population;Awareness;Breast;Cancer Etiology;Coffee;Colon;Colorectal;Databases;Diabetes Mellitus;Diet;Dietary Component;Etiology;Fatty acid glycerol esters;Fruit;Glioma;Glucose;Goals;Hepatitis B;Hepatitis C;Incidence;Insulin;Iron;Juice;Life Style;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Measures;Meat;Medicare;Metabolic Diseases;Nested Case-Control Study;Non-Steroidal Anti-Inflammatory Agents;Nutrition Disorders;Obesity;Pernicious Anemia;Physical activity;Process;Prospective cohort study;Reflux;Resources;Risk Factors;Role;Serum;Smoking;Stomach;Ulcer;United States National Institutes of Health;Vitamin D;Work;cancer risk;cohort;diet and cancer;dietary;drinking;energy balance;fruits and vegetables;lifestyle factors;melanoma;mortality Etiologic Studies of Diet and Cancer n/a NCI 10918968 1ZIACP010127-28 1 ZIA CP 10127 28 11613071 "FREEDMAN, NEAL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 154782 NCI Studies of diet and obesity with liver cancer: Liver cancer is the third leading cause of cancer-related mortality worldwide. Numerous hypotheses link different aspects of the diet e.g. alcohol meat fat fruits and vegetables coffee fruit juice with liver cancer. However of that list only alcohol is an established risk factor. In addition to dietary components there is a growing awareness of the importance of energy balance including obesity diabetes and physical activity with liver cancer. We are investigating these dietary and energy balance hypotheses taking advantage of large prospective cohort studies. In the past couple of years we have measured Hepatitis B (HBV) and Hepatitis C (HCV) positivity in several of our studies. HBV and HCV are strong risk factors for liver cancer and so now we can take account of these possible risk factors in our analyses. We have also measured several other analytes including insulin glucose vitamin D and serum iron and aim to determine the association of these analytes with cancer. We are also in the process of examining associations with specific dietary components such as meat fat coffee and fruits and vegetables. Finally we are examining lifestyle factors such as smoking and NSAID use.SEER-Medicare. We have worked to create a nested-case control study in the SEER-Medicare database in which to examine the association of diet and obesity related exposures with cancer risk. The very large size of the SEER-Medicare database allows us to examine hypotheses which are difficult to conduct other places-- for example the association of diabetes with particular anatomic sub-sites of the colon. We have developed the database and examined an initial set of exposures including obesity diabetes smoking ulcers gastric reflux and pernicious anemia.Coffee. Finally our work has potentially implicated coffee drinking in the etiology of liver and other cancers. Therefore we are comprehensively examining the association between coffee drinking and a wide range of different cancers including liver colorectal melanoma glioma breast and lung in the NIH-AARP and other studies. 154782 +No NIH Category available Address;African;African American population;Androgens;Area;Atypical hyperplasia;Biological;Biological Assay;Breast Cancer Risk Factor;Case/Control Studies;Catechols;Caucasians;Characteristics;Clinical;Collaborations;Cryptorchidism;Data;Development;Diagnosis;Disease;Endometrial Carcinoma;Endometrial Hyperplasia;Epidemiology;Estradiol;Estrogen receptor negative;Estrogens;Etiology;Excretory function;Exhibits;Female Genital Neoplasms;Finland;Genetic;Gestational Diabetes;Ghana;Glucuronides;Gynecologic Oncology Group;Health;Health Maintenance Organizations;Heterogeneity;High Prevalence;Histologic;Hormonal;Hormones;Hydroxylation;Hypospadias;Impairment;Incidence;Individual;Inguinal Hernia;Investigation;Israel;Knowledge;Laboratories;Learning;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of esophagus;Malignant neoplasm of male breast;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of testis;Mammographic Density;Mammography;Measures;Medical Records;Menopause;Metabolic;Metabolic Pathway;Methods;Methylation;Mothers;Natural History;Nested Case-Control Study;Parents;Participant;Physical activity;Polishes;Postmenopause;Prepaid Health Plans;Prognosis;Prognostic Factor;Questionnaires;Reporting;Research;Research Personnel;Rest;Risk;Risk Factors;Risk Marker;Role;Sampling;Site;Spermatogenesis;Standardization;Sweden;Syndrome;Terminal Ductal Lobular Unit;Testicular Dysgenesis Syndrome;Testicular Germ Cell Tumor;Urine;Woman;anxious;base;bisphenol A;boys;cancer risk;clinical prognostic;cohort;congenital anomaly;design;examination questions;genotoxicity;hormone related cancer;interest;liquid chromatography mass spectrometry;male;malignant breast neoplasm;multidisciplinary;novel;programs;reproductive system disorder;risk prediction;screening;tumor;urinary Hormone-Related Cancers n/a NCI 10918967 1ZIACP010126-28 1 ZIA CP 10126 28 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 8450375 NCI This project covers a broad base of studies aimed at assessing the epidemiology of the majority of hormonally-related cancers. Major efforts are underway for breast cancer endometrial cancer ovarian cancer and testicular cancer. We also have an active research program on prostate cancer covered in a separate report (Z01 CP010180-02). Our efforts for all of these cancers relate to a variety of environmental genetic and hormonal predictors of risk. It is well recognized that breast cancers that occur among Africans and African-Americans tend to exhibit different clinical characteristics as compared with Caucasians including a higher prevalence of estrogen receptor negative and triple negative tumors cancers associated with a generally poor prognosis. To better understand the reasons for the occurrence of these cancers we are conducting a case-control study in Ghana where incidence rates of breast cancer have been increasing. The study has been designed to evaluate some novel etiologic hypotheses as well as to relate risk factors to carefully defined subtypes of breast cancers. We have also had a major interest in studying a number of intermediate markers of breast cancer risk including mammographic breast density and terminal duct lobular unit involution. We have developed and used some novel methods for measuring both of these presumed breast cancer precursors and have related breast cancer risk factors to varied measures. We are also examining how these measures relate to subsequent breast cancers. In collaboration with the Gynecologic Oncology Group we have administered a standardized questionnaire to women in a large endometrial cancer trial. This has enabled analyses which have demonstrated that there is great etiologic heterogeneity of endometrial cancer across histologic subtypes. We have also assessed how these factors relate to survival after adjusting for other clinical prognostic factors. We have learned much about the natural history of cervical cancer (as described in another project report) and are now anxious to expand our knowledge in this area to address the natural history of another gynecologic tumor namely endometrial cancer. Endometrial hyperplasias are recognized to increase the subsequent risk of endometrial cancer but data with which to accurately predict risk are lacking and it is unknown how other factors might influence those risks. We have conducted a nested case-control study within a prepaid health plan to better understand the risk of endometrial cancer in women diagnosed with endometrial hyperplasia. Data from this study have supported the notion that atypical hyperplasia is strongly related to subsequent endometrial cancer risk. We are also conducting a study to assess early markers which may be important to the development of ovarian cancer and endometrial cancer. To further our understanding of testicular cancer we have conducted a number of studies regarding Testicular Dysgenesis Syndrome (TDS) a group of etiologically related male reproductive disorders which included cryptorchidism hypospadias impaired spermatogenesis and testicular germ cell tumors (TGCTs). While the associations among cryptorchism impaired spermatogenesis and TGCT have been widely acknowledged the linkage of hypospadias to the rest of the syndrome has been unclear. To examine this question we analyzed linked medical records data from Sweden and found that hypospadias was significantly associated with both cryptorchidism and TGCT. We also found that another congenital anomaly inguinal hernia was significantly associated thereby suggesting that both hypospadias and inguinal hernia should be included in TDS. Given that a previous study in Finland found that boys born to mothers with gestational diabetes were at an increased risk of cryptorchidism we examined the association in a health maintenance organization (HMO) in Israel However we found no association between gestational diabetes and either congenital cryptorchidism or hypospadias. This project has also included a focus on the etiologic role of endogenous hormones for a variety of tumor sites. We have established a close collaboration with a laboratory in Frederick which has developed a liquid chromatography/mass spectrometry assay that measures 15 estrogen metabolities. We have assessed the relationship of these metabolites to breast cancer risk in three large cohorts. Although there were some differences across these studies in terms of the effects of individual metabolites all three showed significant associations of risk with high estradiol levels. Several of the studies suggested that increased 2- or 4-hydroxylation of parent estrogens might lower postmenopausal breast cancer risk of interest given that this metabolic pathway involves less extensive methylation of potentially genotoxic catechols. We have also contributed our data to several consortial efforts that have further clarified the effects of endogenous hormones on breast cancer risk.To address mounting concerns regarding a possible link between bisphenol A (BPA) and breast cancer risk we used an assay that we recently helped develop and validate to measure its primary excreted metabolic conjugateBPA-glucuronide (BPA-G). Using urine samples collected in our Polish Breast Cancer Study (PBCS) we found that BPA-G concentrations were higher among women reporting extended use of menopausal hormones and a prior screening mammogram but there was no relationship with breast cancer risk. We are currently collaborating with investigators of the Womens Health Initiative to measure estrogens in relation to ovarian and endometrial cancers that developed among participants in the observational component of that investigation. We also have measured estrogens and androgens in relation to male breast testicular and esophageal cancers. Finally in the Polish study we have measured urinary estrogens among the control subjects in order to more fully understand relationships with identified risk factors including physical activity levels that have been objectively determined. . 8450375 +No NIH Category available African American population;Agricultural Health Study;Agriculture;Animal Feed;Asian;Benzene;Blood;Breast;California;Carcinogens;Case/Control Studies;Cells;Child;Childhood Leukemia;China;Collaborations;Colon Carcinoma;Data;Diesel Exhaust;Employment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Equipment;Ethnic Population;European;Evaluation;Exposure to;Farm;Female;Goals;Hispanic;Incidence;Industrialization;Industry;Iowa;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Melatonin;Minority;Monitor;Municipal Government;New England;Occupational;Occupational Exposure;Occupations;Ovarian;Participant;Passive Smoking;Pesticides;Population;Prospective cohort study;Renal Cell Carcinoma;Renal carcinoma;Reporting;Research;Risk;Risk Factors;Role;Sampling;Spouses;Thyroid Gland;Universities;Urine;Wife;Woman;Women's Health;Work;cancer risk;cancer type;cigarette smoking;drinking water;epidemiology study;farmer;leukemia;leukemia/lymphoma;men;mortality;non-smoking;operation;pesticide exposure;population based;racial disparity;racial population;respiratory;shift work Occupational and Environmental Determinants of Cancer among Women and Minorities n/a NCI 10918964 1ZIACP010123-28 1 ZIA CP 10123 28 15666226 "HOFMANN, JONATHAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 592815 NCI Traditionally occupational research has focused primarily on white men even though women comprise nearly half of the U.S. civilian workforce and minorities are often employed in jobs with hazardous exposures. The OEEB has undertaken a number of population-based epidemiologic studies which include women and minorities during the past year with a substantial focus in occupation . In the Agricultural Health Study a prospective cohort study of more than 90000 subjects including approximately 32000 women and 2000 minorities both direct occupational exposure and indirect environmental exposure to pesticides and other exposures are being evaluated for association with breast ovarian thyroid and other cancers. Diesel exhaust from farm equipment has also been evaluated for associations with lung cancer among the spouses of farmers. In addition living near concentrated animal feeding operations (CAFOs) are being evaluated for associations with several cancer types including lung and other respiratory cancers. The Shanghai Women's Study is a prospective cohort study of 75000 women conducted by Vanderbilt University in collaboration with NCI and the Shanghai Cancer Institute. Blood/buccal cell and urine samples have been collected from nearly 90% of participants. Exposure assessment to benzene has been based on industrial monitoring data maintained by the Shanghai municipal government and is being evaluated for associations with leukemia and lymphoma. Cancer risk in relation to occupation and industry of employment is being evaluated including a recent report of lung cancer risk associated with employment in certain occupations that may have exposure to potential industrial carcinogens. Two studies have also been conducted within this study focused on the effect of night shift work on melatonin levels and on overall cancer risk. The New England Bladder Cancer study a large multicenter case-control study of bladder cancer is on-going to examine environmental and occupational risk factors and the reasons for the consistently elevated incidence and mortality of this cancer in New England and includes the largest number of women of any previous case-control study. The U.S. kidney cancer study is the first study of this cancer that included a sufficient number of African Americans for separate evaluation of their risks and the contribution of environmental and occupational risk factors to the racial disparity in incidence of this cancer. NCI is leading the environmental sampling component of the California childhood leukemia case-control study. The approximately 40% Hispanic and 10% Asian participants in this study provide an opportunity to evaluate agricultural and other risk factors among these minorities. In the Iowa Women's Health Study environmental contaminants in drinking water are being evaluated for associations with cancers of the bladder ovary pancreas and colon. 592815 +No NIH Category available 24-Dichlorophenoxyacetic Acid;Air;Algorithms;Aromatic Amines;Aromatic Polycyclic Hydrocarbons;Arsenic;Asbestos;Asian;Atrazine;Benzene;Benzene Exposure;Biological Markers;Cadmium;Carbon Black;Carcinogens;Case/Control Studies;Chemicals;Childhood Malignant Brain Tumor;Chlorinated Hydrocarbons;Chromium;Classification;Code;Cohort Studies;Computer software;Cross-Sectional Studies;Data;Databases;Development;Diesel Exhaust;Dose;Dust;Electromagnetic Fields;Ewings sarcoma;Exposure to;Formaldehyde;Gasoline;Germ cell tumor;Goals;Hormonal;Human;Immune;Individual;Lead;Link;Lymphatic;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of larynx;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Measurement;Metals;Methodological Studies;Methods;Modeling;Neoplasms;New England;Occupational;Occupational Epidemiology;Occupational Exposure;Occupations;Participant;Particulate;Pattern;Performance;Pesticides;Physical activity;Polychlorinated Biphenyls;Population Study;Procedures;Publishing;Questionnaires;Renal carcinoma;Reporting;Solvents;Spain;Specificity;System;Techniques;Text;Training;Trichloroethylene;Urine;Validation;Woman;Wood material;Work;air monitoring;case control;cohort;data mining;design;exhaust;farmer;gender difference;genotoxicity;improved;lead exposure;leukemia;malignant breast neoplasm;mathematical model;men;novel;population based;programs;response;urinary Occupational Exposure Assessment n/a NCI 10918963 1ZIACP010122-28 1 ZIA CP 10122 28 10271059 "FRIESEN, MELISSA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 787363 NCI Assessment of occupational exposures is a crucial factor in evaluating dose-response relationships and most human population-based studies conducted by the Branch have an extensive exposure assessment component. Major assessment efforts in cohort studies have involved exposures to pesticides benzene polycyclic aromatic hydrocarbons and diesel exhaust fumes and to a broad range of exposures in a cohort study of women in Shanghai and shipyard workers. Cross-sectional studies are being conducted to study the effect of benzene diesel exhaust trichloroethylene and atrazine on genotoxic immune and hormonal parameters. In the case-control design jobs have been evaluated for a wide variety of exposures including solvents (including chlorinated hydrocarbons aromatic and other solvents) metals (arsenic chromium cadmium lead) electromagnetic fields polychlorinated biphenyls dusts (wood dust and other types) asbestos formaldehyde physical activity nitrosoamines polycyclic aromatic hydrocarbons gasoline and diesel exhausts aromatic amines and pesticides. These exposures have been evaluated in studies of cancer of the bladder brain breast kidney lung larynx and the lymphatic and hemtopoietic system and of childhood brain cancer germ cell tumor cancer and leukemia Ewings sarcoma and possible associations with parental occupations. Methodologic studies are also conducted to improve exposure assessment techniques and to understand exposure patterns such as peak exposures. A study has been conducted in Shanghai to evaluate assessments made from detailed occupational questionnaires with air measurements. A report describing the exposure assessment procedures for evaluating EMF exposures in a brain cancer case-control study has been published. Reports describing the occurrences of pesticides polychlorinated biphenyls chlorinated and aromatic solvents wood dust lead cadmium and nitrosoamines are being prepared. Detailed questionnaires have been developed for several case-control studies: a kidney cancer study in the US a bladder cancer study in New England a NHL study in the US and a bladder cancer study in Spain and neoplasmic lyphomas in four Asian centers (AsiaLymph Study). A comparison of assessments to pesticides has been compared to pesticide metabolites in the urine. Important determinants of exposure to 24-D has been evaluated using urinary levels. Historical benzene and lead exposure estimates have been developed using a novel framework that combines job-exposure matrices with databases of inspection measurements to predict exposure for a population-based cohort of women in Shanghai. Air monitoring of particulate black carbon and bioaerosol exposures is being conducted on farmers. Data mining models have been used to extract decision rules from questionnaire responses and previously assessed exposure metrics for occupational diesel exhaust exposure so that the decision rules can be used in subsequent studies. The same data mining approaches is being used for other agents including lead and chlorinated solvents. An algorithm-based approach that efficiently links expert-based exposure decisions to participants responses to exposure-oriented modules was developed to estimate occupational diesel exhaust exposure and was compared to estimates from an expert review of each individual job. Exposure estimates for lead and cadmium exposure are being developed for the kidney cancer study. Occupational questionnaire data was used to evaluate gender differences in work tasks and exposure within men and women reporting the same job title. A software program to automatically assign occupation codes based on free-text entries of job title has been developed to improve the efficiency of conducting occupational epidemiology; a revised algorithm is being developed by expanding the training database. 787363 +No NIH Category available Aircraft;Benzene;Biochemical;Body of uterus;Brain;Cancer Etiology;Carcinogenesis Mechanism;Case/Control Studies;Categories;Cessation of life;Chemicals;Chronic;Coast Guard;Cohort Studies;Colon;Diesel Exhaust;Electromagnetic Fields;Employment;Etiology;Europe;Exposure to;Formaldehyde;Hour;Individual;Industrial Health;Industrialization;Industry;Investigation;Iowa;Kidney Diseases;Link;Liver Cirrhosis;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Malignant neoplasm of nasopharynx;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Measures;Medical;Meleagris gallopavo;Mesothelioma;Methodological Studies;Methods;Myeloid Leukemia;Nervous System;Occupational;Occupational Exposure;Occupational Malignant Neoplasm;Occupations;Organic solvent product;Pattern;Pesticides;Poland;Population;Predisposition;Pulmonary Emphysema;Rectum;Renal carcinoma;Reporting;Rheumatic Heart Disease;Risk;Rubber;Russia;Silicon Dioxide;Spain;Techniques;Telecommunications;Textile Industry;Time;Trichloroethylene;Uterine Diseases;Woman;cancer risk;carcinogenicity;cohort;combustion product;design;follow-up;improved;leukemia;malignant breast neoplasm;marine;mortality;rectal;repaired;response;trend;urinary Studies of Occupational Cancer n/a NCI 10918961 1ZIACP010120-28 1 ZIA CP 10120 28 10271053 "LAN, QING " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 1206641 NCI Major etiologic investigations focus on working populations exposed to benzene trichloroethylene other organic solvents formaldehyde diesel exhausts combustion products electromagnetic fields pesticides and silica. Findings linking cancer with occupational exposures included an excess of nasopharyngeal cancer and leukemia among workers exposed to formaldehyde. Results from two studies suggest an association with myeloid leukemia. The first an industrial cohort study of workers in formaldehyde industries indicate an association with myeloid leukemia with risks that were persistently elevated over 40 years of follow-up time. In the second study a case-control study of workers in the funeral industry an elevated OR was found for those whose estimated cumulative formaldehyde exposure exceeded 9253 parts per million hours (OR = 3.1; 95% CI = 1.0 to 9.6 P = .047). Nasopharyngeal cancer was also associated with formaldehyde as measured by average intensity peak exposure cumulative and duration of exposure (p-trend = 0.066 0.025 0.001 and 0.147 respectively). Breast cancer among women in Shanghai was associated with employment in the textile industry medical profession and the telecommunications industry. A cohort of U.S. Coast Guard shipyard workers was found to have elevated mortality from emphysema lung cancer and mesothelioma while a cohort of Coast Guard marine inspectors who carry out ship inspections involving exposure to a variety of chemicals showed excess deaths from cirrhosis of the liver and chronic rheumatic heart disease. Among other industrial studies a cohort of workers engaged in the repair and maintenance of aircraft and missiles showed no clear exposure-response gradient for TCE with any cancer but did show an approximately two-fold excess of renal disease. In a case-control study in Europe evaluated the risk of renal cancer increased risk was observed among subjects ever TCE-exposed (OR=1.63;(1.04-2.54) compared to those never exposed. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR=1.38;(0.81-2.35); OR=2.34;(1.05-5.21) p-trend=0.02). We have also reported findings from a variety of case-control studies that have examined occupation and cancer risks including bladder cancer in Spain kidney cancer in Europe lung cancer in Russia and Turkey pancreas cancer in Iowa and breast cancer in Poland. Other studies are evaluating brain cancer risk from electromagnetic fields (EMF) relying on quantitative exposure estimates from job-specific modules. Methodologic studies dealt with confounding and exposure misclassification quantitative exposure assessment and exposures and urinary mutagenicity in rubber workers. 1206641 +No NIH Category available 24-Dichlorophenoxyacetic Acid;Agricultural Health Study;Agriculture;Agrochemicals;Aromatic Amines;Biological;Birth;Blood;Carbaryl;Case/Control Studies;Cells;Chemicals;Child;Chronic Disease;Computer Assisted;Data;Defect;Diet;Disease;Dust;Enrollment;Epigenetic Process;Etiology;Evaluation;Exposure to;Family history of;Farm;Future;Genomic DNA;Home;Insecta;Insecticides;Iowa;Length;Life;Limb structure;Link;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of thyroid;Malignant neoplasm of urinary bladder;Medical;Methodology;Molecular;Multiple Myeloma;National Institute of Environmental Health Sciences;North Carolina;Occupational Exposure;Occupational Malignant Neoplasm;Organophosphates;Outcome;Paper;Participant;Pesticides;Plants;Population;Productivity;Prospective cohort study;Public Health;Publishing;Questionnaires;Research Personnel;Risk;Rodent;Self Administration;Source;Specimen;Spouses;Telephone Interviews;Update;Woman;cancer risk;cohort;commercial application;design;early life exposure;epidemiology study;farmer;interest;lifestyle factors;malignant breast neoplasm;men;offspring;pesticide exposure;programs;recruit;statistics;telomere;vector control Studies of Occupational Cancer (Pesticides) n/a NCI 10918960 1ZIACP010119-28 1 ZIA CP 10119 28 11613066 "BEANE FREEMAN, LAURA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2409818 NCI There are several studies within this project. However the largest of these is the Agricultural Health Study (AHS). This prospective cohort study was designed to evaluate the relationship between pesticides and other agricultural factors and the risk of cancer and other diseases. Enrollment in this study includes about 90000 men and women from Iowa and North Carolina. From 1993-1997 detailed information was obtained by self-administered questionnaire and from 1998 through September 2003 and again from 2004 through 2010 computer assisted telephone interviews updated the information collected at enrollment. Telephone interviews include questions on pesticides used and other agricultural exposures lifestyle factors medical and family history of disease and diet. A questionnaire focused on chronic disease other than cancer was administered in 2010-2015 and focused on chronic disease other than cancer was led by investigators from NIEHS. The AHS has provided information on a number of pesticide-cancer associations over the years. In this FY several papers were published including one on bladder cancer showing a link between aromatic amine pesticides and bladder cancer risk in the pesticide applicators. Another evaluation showed an increased association between metolachlor use and liver cancer which had been previously linked to liver cancer in rodents. The AHS spouses represent an important population in which to evaluate lower exposure levels as well as cancer among women. A study among this group showed an increased risk of thyroid and ovarian cancers with exposure to specific organophosphate insecticides. Buccal cells are available from approximately 50% of the cohort and provides a source of genomic DNA for GXE studies and studies of epigenetic mechanisms. Smaller sub-studies have biological specimens for the evaluation of intermediate effects of exposure and outcome. This year a study was published evaluating the association between telomere length and a number of pesticides and showed an association between 24-D use and shorter telomeres. There is currently an effort underway to recruit 1600 farmers within the AHS to update exposure information and collect blood and other biological specimens and dust for the purpose of evaluating several hypotheses related to pesticide exposure. A paper describing the methodology and preliminary statistics was published this year. The AHS has been a productive study with which to evaluate many hypotheses related to pesticides. However early life exposures and future cancer risk are of great interest. At enrollment AHS participants provided information on their offspring. A new effort was launched to enumerate these offspring and follow them with the purpose of evaluating their early life pesticide and other farm exposures and future cancer risk. The AHS also contributes data to AGRICOH the consortium of agricultural cohorts. An initial paper describing the harmonization of exposure across studies was published this year with etiologic results focused on lymphohematopoietic malignancies to follow. Pooled studies of breast and prostate cancer have also been initiated within the consortium. Other studies within the Branch are also evaluating risks associated with pesticide exposure. A pooled study of case-control studies of multiple myeloma demonstrated an increased risk associated with the use of DDT carbaryl and captan. maternal occupational exposure to agricultural chemicals may increase the risk of giving birth to a child with limb defects. 2409818 +No NIH Category available Age;Area;Asian;Attention;Autoimmune Diseases;Autoimmunity;BRAF gene;Blood;Brain;Breast Cancer Genetics;Breast Cancer Patient;Breast Cancer Risk Factor;Canada;Cancer Hospital;Candidate Disease Gene;Case/Control Studies;Categories;Cells;Characteristics;Childhood Medulloblastomas;China;Chinese;Chordoma;Chronic;Clinic;Clinical;Cohort Effect;Collaborations;Complement;Complex;Country;Cutaneous Melanoma;DNA;Data;Dentistry;Development;Disparity;Dysplastic Nevus;Eating;Embryo;Epidemiologist;Estrogen Receptor Status;Estrogen receptor negative;Estrogen receptor positive;Estrogens;Etiology;Exposure to;Expression Profiling;Family;Family Study;Family history of;General Population;Genes;Genetic;Genetic Diseases;Genetic Research;Germ-Line Mutation;Goals;Hematologic Neoplasms;High-Risk Cancer;Hong Kong;Human Microbiome;Immune;Incidence;Individual;Investigation;Italy;Korea;Lesion;Link;Malaysia;Malaysian;Malignant Bone Neoplasm;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical;Medical History;Melanocortin 1 Receptor;Melanocytic nevus;Menopausal Status;Metabolism;Molecular;Molecular Profiling;Monoclonal gammopathy of uncertain significance;Morphology;Multiple Myeloma;Mutation;Neoplasm Metastasis;Neoplasms;Nervous System;Nevus;Normal tissue morphology;Not Hispanic or Latino;Oncogenes;Outcome;Pathogenesis;Pathway interactions;Patients;Pattern;Philadelphia;Pilot Projects;Polishes;Population;Predisposition;Process;Prognostic Factor;Protocols documentation;Questionnaires;Receptor Gene;Recording of previous events;Registries;Regulation;Reporting;Research Personnel;Rest;Risk;Risk Assessment;Risk Factors;Role;Rural;Sampling;San Francisco;Sarawak;Scandinavia;Singapore;Site;Skeleton;Skin;Smoker;Somatic Mutation;Spain;Specimen;Structure;Sun Exposure;Sunscreening Agents;Susceptibility Gene;Taiwan;Tea;Terminal Ductal Lobular Unit;Testing;Time;Tissue Sample;Tissues;Tumor Subtype;Tumor Tissue;Ulcerative Colitis;United States;United States National Institutes of Health;Universities;Variant;Woman;age effect;cancer subtypes;cancer type;carcinogenesis;case control;cdc Genes;cohort;comorbidity;data registry;disorder risk;drinking;early onset;environment related cancer;exome sequencing;follow-up;genetic epidemiology;genome wide association study;high risk;human disease;individualized medicine;malignant breast neoplasm;medical schools;melanoma;microbiome;molecular subtypes;neoplasm registry;non-smoker;older women;oral microbiome;parity;polygenic risk score;population based;preservation;rare variant;receptor;risk variant;stem cells;tanning booths;telomere;tumor;young woman Genetic Epidemiology n/a NCI 10918958 1ZIACP005803-29 1 ZIA CP 5803 29 2062427 "GOLDSTEIN, ALISA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2224011 NCI Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies.Analyses of a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco showed modest non-significant decreased risk of melanoma among susceptible individuals who used sunscreens most of the time. Young women were the individuals most likely to use tanning beds and use was related to melanoma risk. Those who used tanning beds were more likely to have melanomas in sites not usually exposed to sun. These observations may help explain the increasing rates and changing distribution of melanoma among young women in the general population. Questionnaire data tumor and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy showed a strong association between germline variants in the melanocortin-1 receptor (MC1R) gene and melanoma with somatic mutations in the BRAF oncogene in subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage. We confirmed this association in an independent population. Data from other Mediterranean populations have been collected and harmonized to extend the analyses of association between melanoma risk and several risk factors also including immune-related genes. In this combined sample we identified suggestive evidence for a role of telomere-related genes in the etiology of melanoma. Moreover a genome-wide association study (GWAS) of melanoma cases from Mediterranean countries and appropriate controls is ongoing. A polygenic risk score analysis using the GWAS data and additional data from melanoma consortia is also ongoing. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure body site nevi count susceptibility genes and molecular alterations is planned. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway we are currently collecting multiple tissue samples of normal skin common melanocytic nevi dysplastic nevi melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. A project was developed to collect personal and family medical history buccal cells and tumor tissue from sporadic chordoma patients from the United States and Canada. Using DNA from 100 sporadic chordoma patients in this study we identified several common and rare variants in the T gene that are related to disease risk providing more evidence for the importance of the T gene in the pathogenesis of both familial and sporadic chordoma. Currently we are using whole-exome sequencing (WES) to identify additional susceptibility genes in chordoma families without T duplication and sporadic chordoma cases. The WES analysis identified several genes that are potentially related to chordoma predisposition and functional follow-up is in process. We are also collaborating with cancer hospitals in Beijing China to collect germline DNA and chordoma tumor tissues from Chinese chordoma patients to follow up on variants we identify from the WES project. Alterations in the normal microbiome are increasingly recognized to play a role in human disease. Using protocols adapted from the NIH Human Microbiome Project we conducted pilot studies with investigators from the School of Medicine and Dentistry University of Rochester to evaluate differences in the oral microbiome between smokers and nonsmokers. Analysis of the resultant microbiome data is in progress. Using data we collected from the Polish Breast Cancer Study and breast cancer association consortium we demonstrated that risk factors for breast cancer and morphology and molecular characteristics of terminal duct lobular units (TDLUs) the structures from which breast cancers arise varied by molecular subtypes. In addition we found that parity-related molecular changes were preserved in breast cancer patients with ER-positive tumors but disrupted in patients with ER-negative tumors a finding that may partially account for the observed differential effect of parity in these two tumor subtypes. We are currently analyzing the expression profiling data to identify molecular signatures for TDLU involution and parity. Recently we initiated several breast cancer projects with clinicians and epidemiologists in Asian countries to study breast cancer among Asian women. Using data collected from Sarawak Malaysia we showed that the overrepresentation of early-onset and ER-negative tumors among Malaysian women was largely due to the disproportionally lower incidence of late-onset ER-positive tumors rather than an absolute increase in ER-negative cancers. We extended this finding using cancer registry data from several Asian countries (Singapore Taiwan Hong Kong China Korea) and reported that after the adjustment of period and cohort effects the age effects of breast cancer may be more similar between Asian and Western women than previously recognized. Our results also showed that rapidly rising cohort specific rates have narrowed the historic disparity between Chinese and US NHW breast cancer populations particularly in regions with the lowest baseline rates (such as rural China) and among older women. We developed a new tissue-based breast cancer study in Hong Kong and plan to collect breast tumor and adjacent normal tissues from up to 1000 breast cancer cases with the goal of identifying molecular changes that are related to risk and clinical factors for breast cancer subtypes among Chinese women in Hong Kong. Using the Hong Kong data we collected we found a complex relationship between tea drinking and breast cancer risk that is modified by menopausal status age at tea drinking and possibly ER status. We also identified an interesting association between nighttime eating and increased breast cancer risk among Hong Kong women.We are continuing to conduct studies of hematologic malignancies using the Swedish linked registry data to complement the family studies in GEB. However the current level of activity of these studies is low. We have recently completed a study with some additional data added which describes the effect of prior autoimmune diseases on survival of patients with MGUS and multiple myeloma (MM). As expected in control individuals autoimmune diseases lower overall survival. We also found that survival of MGUS and MM patients was decreased in patients with pre-existing autoimmune diseases. When analyzing different types of autoimmune diseases a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors or that patients with a personal history of autoimmunity develop more severe cases of MM and MGUS or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM and underlines the need for studies aimed at tailoring therapy according to comorbidity. 2224011 +No NIH Category available Ablation;Acetaldehyde;Adult;Age;Animals;Antibodies;Area;Aromatic Polycyclic Hydrocarbons;Beta Carotene;Beverages;Biopsy;Black Tea;Brazil;Cancer Etiology;Cardiovascular system;Carotenoids;Case/Control Studies;Cessation of life;Characteristics;China;Clinic;Clinical;Cohort Studies;Consumption;County;DNA;Death Rate;Dental Hygiene;Development;Diagnosis;Dietary Intervention;Disease;Dose;Dryness;Dysplasia;Early Diagnosis;Early treatment;Enrollment;Environmental Risk Factor;Esophageal Squamous Cell Carcinoma;Esophageal Tissue;Esophagus;Ethnic Origin;Etiology;Evaluation;Evaluation Studies;Excision;Feasibility Studies;Freezing;Fumonisins;Gastric Cardia Adenocarcinoma;General Population;Genetic Polymorphism;Genetic Risk;Geography;Glucuronides;Goiter;Helicobacter pylori;High grade dysplasia;Human Papillomavirus;Human papillomavirus 16;Human papillomavirus 18;In complete remission;Individual;Intervention Trial;Iodine;Iran;Kenya;Laboratories;Lesion;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Measures;Methods;Minerals;Neighborhoods;Participant;Partner in relationship;Patient Self-Report;Patients;Persons;Population;Prevention;Prevention strategy;Probability;Prognosis;Province;Radiofrequency Interstitial Ablation;Randomized;Residual state;Resolution;Risk;Risk Factors;Role;Ruminants;Sampling;Selenium;Serology;Serum;Specimen;Stains;Stomach;Stroke;Supplementation;Symptoms;Tea;Techniques;Temperature;Testing;Tissues;Tobacco use;Tooth Loss;Upper digestive tract structure;Vital Status;Vitamin E;Vitamins;Zinc;alpha Tocopherol;cancer risk;cancer therapy;carcinogenesis;cohort;design;drinking;field study;follow-up;genetic risk factor;high risk population;human papilloma virus oncogene;insight;low socioeconomic status;malignant stomach neoplasm;microendoscopy;modifiable risk;molecular marker;mortality;opium use;response;screening;stomach cardia;tumor;upper gastrointestinal cancer;urinary Upper Gastrointestinal Cancer Studies n/a NCI 10918955 1ZIACP000185-19 1 ZIA CP 185 19 8770361 "DAWSEY, SANFORD M" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 2002437 NCI BACKGROUND: Gastric cancer and esophageal cancer are the second and sixth most common causes of cancer death worldwide. Both of these upper gastrointestinal tract (UGI) cancers have a very poor prognosis largely because symptoms usually do not occur until late in the disease. Significant reduction in UGI cancer mortality will probably require development of new prevention strategies based on identification of new modifiable risk factors and development of new methods to diagnose and treat more cases at earlier more curable stages of disease. PURPOSE: The aims of this project are (1) to examine hypotheses relating to the etiology and prevention of upper gastrointestinal cancers and (2) to develop successful clinical strategies for the early detection and treatment of these cancers. METHODS: Both etiologic and early detection studies are most efficiently done in high-risk populations so many of the studies in this project are performed in such populations. (1) Etiologic studies: (a) China: Between 1985 and 1991 we conducted two randomized nutrition intervention trials (NIT) in Linxian China a county where cumulative death rates due to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) exceed 20%. These trials with a combined enrollment of nearly 33000 people evaluated the effect of supplementation with several vitamin/mineral combinations on UGI cancers and found significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium beta-carotene and vitamin E. Since 1991 we have followed the NIT participants as a cohort and have performed nested studies evaluating the association between baseline characteristics and later development of UGI cancers. In addition we have performed other etiologic studies specifically designed to evaluate individual exposures such as polycyclic aromatic hydrocarbons (PAHs) acetaldehyde human papillomavirus (HPV) and Helicobacter pylori (H. pylori). (b) Iran: We have recently performed two etiologic studies in Golestan Province Iran another population with very high rates of ESCC. Between 2003 and 2007 the Golestan Case-Control Study enrolled 300 ESCC cases 571 neighborhood controls and 300 clinic controls and between 2004 and 2008 the Golestan Cohort Study enrolled 50000 participants. Comparing results from high-risk populations in Iran and China which are quite distinct geographically ethnically and culturally should give us insight into which environmental and genetic risk factors are most important for the development of this disease. (c) Brazil: We have performed several studies evaluating PAH exposure in a high ESCC risk population in southern Brazil; (d) Kenya: We have completed a feasibility study for a case-control study of ESCC in western Kenya which has high rates of this disease and the unusual occurrence of 8% of the cases in individuals younger than 30 years old. (2) Early Detection of Esophageal Cancer: This part of the project includes three studies: (a) the Primary Screening Studies to develop practical and accurate primary screening tests for esophageal squamous dysplasia and early ESCC; (b) Endoscopic Evaluation Studies to develop methods for endoscopic localization and evaluation of esophageal squamous dysplasia; and (c) Endoscopic Therapy Studies to evaluate new techniques for endoscopic treatment of high-grade squamous dysplasia and early ESCC. PROGRESS: (1) Etiologic studies: (a) China: Recent follow-up through 10 years after the end of the Linxian General Population Nutrition Intervention Trial has shown continued significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium beta-carotene and vitamin E especially among those who were less than the median age (55 years) at the beginning of the trial. Results from nested studies in the NIT cohort have shown: (i) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (ii) no relation between serum carotenoids and risk of UGI cancers; (iii) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (iv) a strong association between low tissue zinc levels and increased ESCC risk; (v) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (vi) no association between positive serology for HPV 16 HPV 18 or HPV 73 and ESCC gastric cardia cancer or non-cardia gastric cancer; (vii) no relation between fumonisin exposure and ESCC risk; (viii) an association between tooth loss and risk of UGI cancers; (ix) an association between self-reported goiter and non-cardia gastric cancer; and (x) associations between several genetic polymorphisms and risk of ESCC and/or gastric cardia cancer. We also found no evidence of HPV DNA or HPV oncogene activity in fresh-frozen tumor samples from 272 consecutive ESCC resection specimens in Linxian. (b) Iran: Results from the Golestan Case-Control Study have shown an significant associations between case status and tobacco use opium use or both; poor oral hygiene; drinking hot-temperature black tea; ruminant animal contact; and various measures of low socioeconomic status. Comparison of normal esophageal tissue biopsies from cases and controls has shown a striking dose-response relationship between PAH exposure in the esophageal tissue (measured by intensity of immunohistochemical staining with anti-PAH antibodies) and case status consistent with a causal role for PAH exposure in ESCC carcinogenesis. The participants in the Golestan Cohort Study are being followed annually for vital status and cancer endpoints; through June 2013 there have been 3537 deaths (34% cardiovascular 22% cancer 17%stroke) and 1127 incident cancers (19% esophagus 15% stomach) and fewer than 1% of the cohort has been lost to follow-up. (c) Brazil: Recent results from southern Brazil have show an association between urinary 1-hydroxypyrene glucuronide (a PAH metabolite) and consumption of mate a local tea which has consistently been associated with ESCC risk. Laboratory analysis of dry mate leaves and mate beverages have shown high levels of PAHs in both. (d) Kenya: We have recently finished a feasibility study for the case-control study of ESCC in western Kenya and will soon begin the full study of 300 cases and 300 controls. (2) Early Detection of Esophageal Cancer: (a) Primary Screening Studies: We recently completed the first endoscopic screening study of asymptomatic adults in Western Kenya; preliminary results from the 300 participants show that 3% had high-grade and 11% had low-grade esophageal squamous dysplasia. We are currently planning evaluation of several new primary screening tests in China using molecular biomarkers. (b) Endoscopic Evaluation Studies: We recently completed the first field study of high resolution microendoscopy (HRME) for endoscopically distinguishing dysplastic from non-dysplastic Lugol's iodine unstained lesions in the squamous esophagus; analysis of this study which was performed in China is ongoing. (c) Endoscopic Therapy Studies: We recently completed the first study of radiofrequency ablation (RFA) for treatment of flat high-grade squamous dysplasia and early invasive ESCC in China; preliminary results from the first 100 patients show complete response (defined as no residual high-grade dysplasia or ESCC in the treated area) at 3 months (after one ablation session) in 72% and complete response at 12 months (after 1-3 ablation sessions) in 90% of patients. 2002437 +No NIH Category available Antioxidants;Arsenic;Biochemical;Biological;Biological Specimen Banks;Cancer Etiology;Carotenoids;Cessation of life;Cohort Studies;DNA Sequence Alteration;Detection;Diagnostic;Disease;Early Diagnosis;Environmental and Occupational Exposure;Etiology;Evaluation;Exposure to;Future;Goals;Heterogeneous-Nuclear Ribonucleoproteins;Human papilloma virus infection;Incidence;Localized Disease;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Methods;Modality;Molecular;Monoclonal Antibodies;Occupational Exposure;Patients;Pilot Projects;Radon;Research;Sampling;Selenium;Serum;Smelts;Smoking;Sputum;Sputum Cytology Screening;Survival Rate;Thoracic Radiography;Tin;Tobacco;Tocopherols;Update;Validation;cancer biomarkers;case control;cohort;data repository;dietary;experience;follow-up;genetic risk factor;high risk;lung cancer screening;microbiome;microbiome research;mortality;screening;screening program;serological marker;tumor Biologic Specimen Bank for Early Lung Cancer Markers n/a NCI 10918954 1ZIACP000176-19 1 ZIA CP 176 19 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 410495 NCI OBJECTIVE: The overall goal of this project is to identify strategies to reduce lung cancer incidence and mortality. Specific objectives are to 1) establish a biologic specimen bank and data bank that can be used for the validation and refinement of potential early markers of lung cancer and 2) establish a cohort for the study of environmental (including dietary) and genetic risk factors for lung cancer. BACKGROUND: Lung cancer is the leading cause of cancer death in the U.S. While relative survival rates for localized disease are dramatically better than for nonlocalized disease most patients are not diagnosed early enough for present therapies to be effective and early detection by screening with conventional modalities (i.e. chest x-ray and/or sputum cytology) has not been shown to be beneficial. Potential strategies to reduce the incidence and mortality of lung cancer include new methods of early detection and identification and alteration of etiologic factors. METHODS: Miners in the Yunnan Tin Corporation have an extraordinary rate of lung cancer due to exposure to radon arsenic and tobacco. Over 7000 high-risk miners (40+ years old with 10+ years of underground and/or smelting experience)have been the target of an annual lung cancer screening program (CXR and sputum cytology)for the past 20+ years. Between 1992 and 1999 sputum samples were collected and stored annually for future early marker research and new cases of lung cancer ascertained. Prediagnostic sputum and other biologic samples are stored for analysis for potential early markers (e.g. biochemical molecular or monoclonal antibody markers) utilizing a nested case-control approach. PROGRESS: Over 450 lung cancer were identified through 1999 in this cohort. Analyses to date have evaluated occupational exposures (arsenic and radon) smoking and medical conditions; a number of serum antioxidants (carotenoids selenium tocopherols); and one potential marker in sputum (Mab 703D4 in the detection of hnRNP). New follow-up has been initiated to update vital and cancer status through 2005. New studies initiated in the YTC cohort include: (i) an analysis of serologic markers of HPV infection in relation to lung cancer; (ii) studies of the microbiome in sputum samples collected as part of the YTC lung cancer screening to include evaluation of the relation of the microbiome to lung cancer etiology early detection and environmental and occupational exposures (tobacco radon arsenic); and (iii) a pilot study to compare DNA alterations in sputum and tumors in lung cancer cases. 410495 +No NIH Category available Age;Beta Carotene;Biological;Blood;Bronchi;Cancer Death Rates;Carotenoids;Categories;China;Cohort Studies;Consumption;Cytology;Data Analyses;Death Rate;Dietary Intervention;Disease;Double-Blind Method;Dysplasia;Esophagus;Etiology;Food;Fumonisins;General Population;Genetic Polymorphism;Genetic Risk;Goiter;Helicobacter pylori;Human Herpesvirus 4;Human Papillomavirus;Human papillomavirus 16;Incidence;Ingestion;Intervention;Intervention Studies;Intervention Trial;Lung;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Micronutrients;Millet;Minerals;Nitrosamines;Nutrient;Participant;Patient Self-Report;Persons;Placebo Control;Pleura;Prevention;Probability;Proliferating;Randomized;Risk;Selenium;Serology;Serum;Silicon Dioxide;Specimen;Stomach;Structure of nail of toe;Supplementation;Testing;Tissues;Tooth Loss;Trachea;Trauma;Vegetables;Vitamin E;Vitamins;Zinc;alpha Tocopherol;cancer risk;carcinogenesis;esophageal cancer prevention;follow-up;histological specimens;malignant stomach neoplasm;mortality;post intervention;stomach cardia Nutrition Intervention Trials n/a NCI 10918953 1ZIACP000112-19 1 ZIA CP 112 19 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 284019 NCI OBJECTIVE: The primary objective of this project is to determine if supplementation with multiple vitamin-minerals reduces the incidence and mortality of esophageal cancer gastric cancer and total mortality. Secondary objectives are to assess supplement effects on intermediate endpoints in carcinogenesis and to examine new hypotheses relating to the etiology and prevention of esophageal cancer and gastric cancer. BACKGROUND: Probably the highest worldwide rates of esophageal cancer occur in Linxian China where cumulative death rates to age 75 for this cancer exceed 20%. Widespread deficiencies of multiple nutrients are considered the most likely cause but consumption of pickled vegetables moldy foods and nitrosamines and physical trauma from silica fragments in ingested millet may play a role. METHODS: Two double-blind placebo-controlled randomized intervention studies were conducted to evaluate multiple vitamins/minerals in the prevention of esophageal and other cancers. The Dysplasia Trial evaluated 3318 persons with cytologic evidence of dysplasia supplemented for 6 years while the General Population Trial evaluated 29584 persons supplemented for 5 1/4 years. Biologic specimens (blood toenails cytology and histology specimens) were collected periodically throughout the trials. PROGRESS: TRIALS - Both trials concluded in 1991 and results showed that the combination of beta-carotene/vitamin E/selenium significantly reduced total mortality total cancer mortality and stomach cancer incidence and mortality. Results from endoscopic and cytologic examinations suggested that multiple vitamins/minerals may decrease proliferation and enhance cytologic reversion to nondysplasia. POST-TRIAL FOLLOW-UP - Analysis of data from 10 years of post-intervention followup (through May 2001) indicate that for the General Population Trial the beneficial effects of the beta-carotene/vitamin E/selenium supplementation continued after termination of the intervention and that the benefits were greater in the younger participants. None of the four factors tested influenced lung cancer death rates. ETIOLOGY STUDIES - A number of nested case-cohort studies relating baseline serum values of micronutrients fumonisins Helicobacter pylori HPV and EBV to cancer have recently been completed. Results of recent analyses have shown: (1) an especially strong association with increased risk for esophageal cancer and gastric cardia cancer among subjects with low serum selenium levels; (2) no relation of serum carotenoids with esophageal cancer or gastric cancer; (3) a strong association for low serum alpha-tocopherol levels and esophageal cancer risk; (4) a strong association between low tissue zinc levels and increased esophageal cancer risk; (5) increased risk for H pylori exposure for gastric cancer both cardia as well as body; (5) no relation of fumonisin exposure with esophageal cancer risk; (6) an association between tooth loss and risk of esophageal cancer and gastric cancer; (7) associations between several genetic polymorphisms and risk of esophageal cancer and gastric cardia cancer; (8) increased risk of gastric noncardia cancer in persons with self-reported goiter; and (9) no relation for HPV 16 18 or 73 serology and esophageal cancer or gastric cancer. 284019 +No NIH Category available Age;Alcohol consumption;Alcohols;Androstenedione;Antioxidants;Ascorbic Acid;Autoantibodies;Beta Carotene;Binding;Biological Availability;Breast Cancer Risk Factor;Calories;Cardiovascular Diseases;Carotenoids;Chemopreventive Agent;Clinical Nutrition;Clinical Trials;Colorectal Cancer;DNA Damage;Dehydroepiandrosterone Sulfate;Diet;Diet Records;Diet and Nutrition;Dietary Alcohol;Dietary Fats;Dose;Drug Kinetics;Energy Intake;Energy Metabolism;Estradiol;Estrogens;Estrone-Sulfate;Evaluation;Food;Frequencies;Hormones;Human;Insulin-Like Growth Factor I;Intake;Intervention;Leptin;Lipids;Lipoproteins;Malignant Neoplasms;Malignant neoplasm of esophagus;Menstrual cycle;Menstruation;Metabolic;Methodological Studies;Micronutrients;Nulliparity;Nutritional Study;Observational Study;Oxidative Stress;Physical activity;Plasma;Postmenopause;Pregnancy;Premenopause;Questionnaires;Research;Role;SHBG gene;Safety;Selenium;Serum;Statistical Models;Testosterone;United States Department of Agriculture;Woman;age related;alpha-carotene;cancer chemoprevention;cardiovascular risk factor;dietary;doubly-labeled water;feeding;high-fat/low-fiber diet;improved;insulin sensitivity;malignant breast neoplasm;men;parous;safety assessment;urinary;zeaxanthin Human Studies of Diet and Nutrition n/a NCI 10918952 1ZIACP000101-19 1 ZIA CP 101 19 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2023 109822 NCI OBJECTIVE: The objectives of this research are to evaluate the metabolic effects of dietary changes relevant to cancer and to assess the safety pharmacokinetics bioavailability and mechanisms of action of macro- and micronutrients with cancer chemoprevention potential. BACKGROUND: Clinical nutrition studies provide information that helps bridge the gap between observational research and clinical trials by assessing potential mechanisms of action and other parameters important in developing intervention strategies. METHODS: Since 1983 collaborative efforts with the Beltsville Human Nutrition Research Center of the USDA in clinical nutrition research has resulted in conduct of over 10 studies focused primarily on antioxidant and hormone research. Studies have evaluated the dose bioavailability and safety of selenium carotenoids and vitamin C and the potential modulating role of dietary fat and alcohol on hormones. PROGRESS: PAST STUDIES - (1) Evaluation of carotenoids in premenopausal women on and off alcohol on the same controlled diet showed that plasma levels of both beta- and alpha-carotene were higher on alcohol while lutean/zeaxanthin levels were lower. (2) In another controlled diet study all plasma carotenoid levels were found to vary over the menstrual cycle: concentrations were lowest at menses and each peaked following the peak of its lipoprotein carrier. (3) Hormone evaluations in premenopausal women have shown that taller women have higher estradiol (E2) that pregnancy may modify the age-related changes in E2 levels (E2 decreases with age in parous women but increases in nulliparous) that energy intake is inversely related to serum levels of androstenedione and DHEAS and P:S ratio is inversely related to E2 and E1 levels. (4) In men a controlled high-fat/low-fiber diet resulted in higher plasma levels of total and SHBG-bound testosterone higher urinary testosterone and lower urinary estrogens compared to a low-fat/high-fiber diet. RECENT STUDIES - (1) A recently completed controlled alcohol feeding study in postmenopausal women determined that alcohol ingestion led to increased levels of both estrone sulfate and DHEA sulfate providing support for one possible mechanism of action for the observed relation of alcohol to breast cancer risk. In other analyses from this study alcohol consumption reduced lipid-related risk factors for cardiovascular diseases bioavailable IGF-1 and serum B12 levels; improved insulin sensitivity; increased serum leptin and some markers of oxidative stress; and did not affect autoantibodies to DNA damage. Dietary methodology studies conducted as part of this study compared energy expenditure from four physical activity questionnaires with doubly labeled water estimates and documented calorie intake misreporting by diet record and food frequency questionnaires (also in relation to doubly labeled water). (2) A study of the pharmacokinetics of selenium a particularly promising chemopreventive agent has been completed and statistical modeling is ongoing. 109822 +No NIH Category available 1 year old;Acceleration;Acute;Acute Myelocytic Leukemia;Adolescent;Australia;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Complication;Country;Development;Diagnosis;Disease;Dose;Eligibility Determination;Enrollment;Ensure;Family;Foundations;Functional disorder;Generations;Goals;Hormonal;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Positioning Attribute;Productivity;Prognosis;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Survivors;Tissues;Translational Research;United States;Universities;Work;anticancer research;cancer diagnosis;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;multidisciplinary;novel therapeutic intervention;operation;organizational structure;reproductive;small molecule;success;survivorship;translational study COG NCTN Network Group Operations Center - Year 10 STAR Act COG) Outcomes & Survivorship (LTE) Committee PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcomes for all children with cancer. NCI 10918928 9/18/23 0:00 PA-20-272 3U10CA180886-10S4 3 U10 CA 180886 10 S4 "MOONEY, MARGARET M" 9/18/23 0:00 2/29/24 0:00 10871228 "HAWKINS, DOUGLAS S." Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 9/18/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 3243049 NCI 3103396 139653 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of the500000 survivors of childhood cancer (estimated as of 2020) experiencing a significant health related quality oflife complication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildrens Oncology Group (COG) the worlds largest organization devoted exclusively to childhood andadolescent cancer research was founded 20 years ago. The COGs multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading childrens hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institutes (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life for children with cancer and childhood cancer survivors. As more than90% of children diagnosed with cancer in the US are treated at COG member institutions COG has the abilityto offer a diverse population of children with cancer and their families the opportunity to participate in innovativeresearch. This research effort includes allowing for collection and annotation of biospecimens from all childrenwith cancer providing the foundation for discovery and accelerating the most promising research effortsconducted in laboratories around the world. The proposal is for support of the COG Network Operations Centerclinician-scientists who develop and conduct research and for member sites to participate through enrollment ofeligible subjects. 3243049 +No NIH Category available Research Education Core n/a NCI 10918640 9/6/23 0:00 PA-21-071 3U54CA156732-13S1 3 U54 CA 156732 13 S1 "WALI, ANIL" 9/27/10 0:00 8/31/26 0:00 ZCA1(A1)-S 6586 10463030 "BURNS WHITE, KAREN ANN" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 6/1/23 0:00 8/31/23 0:00 Research Centers 2023 103666 84166 19500 No abstract available +No NIH Category available Amiloride;Apoptosis;Apoptotic;Autophagocytosis;Biochemical;Biological;Breast Cancer Cell;Caspase;Cathepsins;Cell Cycle;Cell Death;Cell Death Induction;Cell Death Process;Cell Differentiation process;Cell Membrane Permeability;Cell Survival;Cell membrane;Cell model;Cells;Ceramides;Cessation of life;Clinical;Communication;Complement;Cytosol;DNA Sequence Alteration;Development;Disease;Disease Management;Diuretics;Drug Modelings;Drug resistance;ERBB2 gene;Enzymes;Event;Failure;Future;Genes;Genetic;Goals;Induction of Apoptosis;Lactosylceramides;Lead;Lipids;Lysophosphatidylcholines;Lysosomal Storage Diseases;Lysosomes;Malignant - descriptor;Mammalian Cell;Mammary Neoplasms;Mediating;Membrane;Membrane Lipids;Metabolism;Mitochondria;Modeling;Molecular;Molecular Target;Morphology;Necrosis;Normal Cell;Organelles;Pathway interactions;Patient-Focused Outcomes;Peptide Hydrolases;Permeability;Pharmaceutical Preparations;Phenotype;Potassium;Production;Publishing;Reactive Oxygen Species;Recurrent Malignant Neoplasm;Recurrent tumor;Reporting;Resistance;Rupture;Second Messenger Systems;Secondary to;Signal Transduction;Sphingolipidoses;Sphingomyelins;Supplementation;Testing;Therapeutic;Therapeutic Agents;Tissues;Tumor Subtype;amphiphilicity;bis(monoacylglyceryl)phosphate;blood pressure control;cancer cell;cancer recurrence;cancer stem cell;cell transformation;cell type;cytotoxic;cytotoxicity;improved;insight;knock-down;lipid metabolism;lipidomics;metabolomics;metaplastic cell transformation;molecular modeling;neoplastic cell;novel;novel anticancer drug;novel strategies;novel therapeutics;overexpression;oxidation;peroxidation;response;stem cell population;stem cells;targeted treatment;therapy resistant;tool;tumor Lysosomal-mitochondrial signaling in non-apoptotic cancer cell death PROJECT NARRATIVEThe proposed studies are aimed at understanding inter-organelle communication between lysosomes andmitochondria in mammalian cells and how this communication contributes to cell viability and disease state.The successful completion of the studies could shed light on the cellular and molecular mechanisms underlyingsome of the genetic lysosomal storage diseases and could provide an avenue for the development of novelanti-cancer drugs. NCI 10918534 9/13/23 0:00 PAR-17-203 3R01CA250211-04S2 3 R01 CA 250211 4 S2 "SALNIKOW, KONSTANTIN" 7/1/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-CB-H(55)R] 1880465 "CARRAWAY, KERMIT L" Not Applicable 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 79134 NCI 55530 23604 PROJECT SUMMARYThe overwhelming majority of conventional and targeted chemotherapeutics in clinical use or underdevelopment rely on engaging apoptotic pathways to elicit tumor cell death. However resistance to apoptosis-inducing agents is a particularly thorny clinical problem. A novel approach to targeting therapy-resistant cells isto engage cell death mechanisms other than apoptosis to eradicate these malignant subpopulations. Theoverall goal of the proposed studies is to define the lysosomal-mitochondrial inter-organelle signalingmechanisms underlying tumor cell-specific and programmed necrotic lysosomal cell death (LCD) processinduced by a number of drugs. Our lead compound hexamethylene amiloride (HMA) a derivative of a drug thathas been employed clinically in the management of blood pressure for over forty-five years kills differentiatedand stem cancer cells independent of tumor type subtype or species but does not efficiently kill normaldifferentiated cells or stem cells. Moreover HMA kills cancer cells independent of cell cycle autophagyengagement and caspase-dependent apoptosis; indeed cell death appears to result from drug-inducedpermeabilization of the lysosomal limiting membrane and subsequent cathepsin-mediated plasma membranerupture. Our observations indicate that efficient HMA-induced cell death requires the production and action ofmitochondrially-produced reactive oxygen species (ROS). Our observations also indicate that HMA induceshallmarks of some of the sphingolipidosis lysosomal storage diseases including the accumulation of a varietyof lipid species that are normally broken down by the lysosome. Notably lipids such as lactosylceramide andlysophosphatidylcholine that have been demonstrated to act as signaling second messengers in the productionof mitochondrial ROS accumulate specifically in tumor cells but not normal cells upon HMA treatment. Ourobservations point to a model where drug-induced aberrant lipid accumulation and ROS-mediated lysosomalmembrane lipid oxidation disrupt lysosomal membrane integrity allowing cathepsin release and induction ofnecrotic cell death. To test this model we will use biochemical cell biological and metabolomics approaches.In Aim 1 we will assess the contribution of bis(monoacylglycerol)phosphate (BMP) a lysosome resident lipidthat is suppressed in tumor relative normal cells and is further suppressed with HMA treatment in regulatinglysosomal membrane stability and cell viability via its ability to activate lysosomal enzymes of thesphingomyelin breakdown pathway. Complementing these studies will be an in-depth analysis of lipidomic andmetabolomic changes associated with cellular transformation and LCD-inducing agents. In Aim 2 we willexamine lysosomal-mitochondrial signaling events that couple mitochondrial ROS production to dysregulatedlysosomal lipid metabolism. These studies will uncover lysosomal targets that will allow future development ofnovel therapeutic agents that more effectively elicit cancer cell-specific programmed necrotic cell death. 79134 +No NIH Category available Antineoplastic Agents;Canada;Clinical Trials;Communities;Conduct Clinical Trials;Korea;Latin America;Malignant Neoplasms;Mission;National Clinical Trials Network;Prevention;Principal Investigator;Quality of life;Recording of previous events;Research;Research Personnel;Role;Saudi Arabia;Site;Southwest Oncology Group;United States Food and Drug Administration;United States National Institutes of Health;cancer therapy;design;novel anticancer drug;operation;process improvement;survivorship SWOG Network Group Operations Center of the NCTN n/a NCI 10916745 8/30/23 14:47 PA-20-272 3U10CA180888-10S1 3 U10 CA 180888 10 S1 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 ZCA1(O1) 7180 6765159 "BLANKE, CHARLES D." Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 Other Research-Related 2023 1336498 1090765 245733 SWOG Network Group Operations Center of the NCI National Clinical Trials Network (NCTN)NIH/NCI U10 CA180888 (PI: Blanke) 04/17/2014 - 02/28/2025Role: Principal Investigator SWOG Group ChairSWOG is a research organization with over 6000 cancer investigators distributed across over 1000academic and community sites throughout the U.S. Canada Latin America Korea and Saudi Arabia. TheGroup has a long history of conducting clinical trials that have changed standard of oncologic practice andthat have led to Food and Drug Administration approval of new anti-neoplastic agents. SWOG's mission isto design direct and participate in clinical trials that will result in effective prevention and treatment ofcancer in the process improving quality of life and quality of survivorship for those with malignancies. +No NIH Category available Administrative Core n/a NCI 10916640 8/30/23 10:47 PA-21-071 3U54CA274513-02S2 3 U54 CA 274513 2 S2 "VIKRAM, BHADRASAIN" 9/14/22 0:00 4/30/27 0:00 ZCA1(M1) 5141 9306964 "CHAN, TIMOTHY AN-THY" Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 66643 44225 22418 No abstract available +No NIH Category available Accounting;Animal Experimentation;Animals;Cancer Center;Clinic;Clinical;Clinical Management;Clinical Trials;Collaborations;Combined Modality Therapy;Communication;Comprehensive Cancer Center;Core Facility;Data;Development Plans;Documentation;Education;Enrollment;Ensure;Feedback;Florida;Funding;Genomics;Goals;Grant;Human;Human Resources;Human Subject Research;Institution;Investigation;Laboratories;Leadership;Manuscripts;Monitor;Multi-Institutional Clinical Trial;Multicenter Trials;National Cancer Institute;Office of Administrative Management;Oral;Performance;Preparation;Progress Reports;Radiation;Research;Resources;Schedule;Services;Site;Study Subject;System;Time;Training;Treatment Efficacy;Universities;Work;Writing;experience;human subject;innovation;meetings;operation;programs Administrative Core n/a NCI 10916639 8/30/23 10:45 RFA-CA-21-040 3U54CA274513-02S1 3 U54 CA 274513 2 S1 "VIKRAM, BHADRASAIN" 9/14/22 0:00 7/31/27 0:00 ZCA1-SRB-X(M1) 5141 9306964 "CHAN, TIMOTHY AN-THY" Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 70904 44040 26864 PROJECT SUMMARYAdministrative CoreThe Administrative Core is responsible for the overall leadership management and execution of the ROBIN center and it will provide overall organizational administrative scientific and clinical management. The Administrative Core will oversee and coordinate all ROBIN program components and centrally monitor and evaluate their performance. In addition the Administrative Core will facilitate all interactions with the External Advisory Board (EAB) the Steering Committee and the other sites of the national ROBIN program. This ROBIN center involves 3 institutions (Cleveland Clinic Emory University and Case Western Reserve University) with multiple enrollment sites (Cleveland Clinic system Cleveland Clinic Florida system Emory University system) across 2 NCI-designated Comprehensive Cancer Centers (Case Comprehensive Cancer Center Emory Cancer Center) with representation across these institutions as project and core leaders. The Administrative Core personnel will be led by Drs. Chan Yu and Scott with collaboration from the trial and project leads. Both Drs. Chan and Yu (ROBIN PIs) have extensive experience in managing multi-institution clinical trial and laboratory-based research programs. The specific aims for the Administrative Core are as follows. In Aim 1 the Core will provide all organizational administrative educational and scientific coordination for the ROBIN center projects and cores by cultivating and promoting the ROBIN team through innovation and excellence collaboration leveraging resources and providing constructive feedback. In Aim 2 the Core will provide centralized administrative management for all fiscal aspects of the ROBIN center including but not limited to clinical trial execution accounting of grant funds progress reports communication meeting scheduling and minutes and manuscript and grant preparation. In Aim 3 the Core will evaluate research progress through oral and written documentation with regular input from the EAB Steering Committee and National Cancer Institute (NCI) leadership to ensure that each project meets its objectives within the proposed time frame and to facilitate interactions with other ROBIN sites for trans-ROBIN center projects. In Aim 4 the Core will ensure integration across ROBIN components including projects and cores across all sites and provide interaction through scientific exchanges coordination of an annual scientific retreat and through training and development plans that will ensure state-of-the-art practices. In Aim 5 the Core will ensure and monitor best practices for human subjects and animal research for all ROBIN center projects and cores as well as clinical and data operations and to ensure adequate human and animal biospecimens for all projects (with the Translational and Clinical Correlates Core). +No NIH Category available Accounting;Adjuvant;Aging;Amino Acids;Base Excision Repairs;Biochemical;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer cell line;Breast Epithelial Cells;CDK4 gene;CRISPR screen;Cell Line;Cell Survival;Cells;Chemicals;Clinical;Collaborations;Compensation;Complex;Computer Models;Cytosine;DNA;DNA Damage;DNA Repair;DNA Repair Pathway;DNA glycosylase;Data Set;Deaminase;Deamination;Dependence;Development;Diagnosis;Diagnostic;Dinucleoside Phosphates;Disease;Drug resistance;Enzymes;Estrogen receptor positive;Event;Fluorescence;Future;Generations;Genetic;Genetic Transcription;Genomic Segment;Genomics;Goals;Knowledge;Lesion;Malignant Neoplasms;Mediating;Membrane Proteins;Methylation;Mismatch Repair;Molecular;Mutagenesis;Mutation;Neoplasm Metastasis;Nucleotides;Outcome;PIK3CA gene;Pathologic;Pathway Analysis;Pathway interactions;Physiological;Primary Neoplasm;Process;Proteins;Proteomics;RNA Splicing;Real-Time Systems;Recurrence;Regulation;Reporter;Reporting;Resistance;Role;Single-Stranded DNA;Source;Surface;System;Technology;Testing;Therapeutic;Therapeutic Intervention;Time;Uracil;antiviral immunity;base;base editing;breast cancer diagnosis;cancer cell;experimental study;homologous recombination;inhibitor;innovation;insight;malignant breast neoplasm;new technology;overexpression;preference;prevent;programs;protein protein interaction;rapid testing;small molecule;structural biology;technology development;therapeutic development;tumor PROJECT 1 PROJECT 1 - BIOLOGY OF DNA DEAMINASES IN BREAST CANCERNARRATIVEA major endogenous source of mutation has emerged with the discovery of APOBEC mutagenesis inbreast and other cancers. Project 1 studies will yield innovative systems for quantification of APOBEC activityin living breast cancer cells and key insights into protein-level regulatory processes and downstream DNArepair pathways. This technology and mechanistic information will expedite Program efforts to diagnose andtreat tumors that are evolving at higher rates due to APOBEC mutagenesis. NCI 10916617 8/30/23 9:34 PAR-18-290 3P01CA234228-05S1 3 P01 CA 234228 5 S1 "READ-CONNOLE, ELIZABETH LEE" 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L(M1) 6192 8004071 "HARRIS, REUBEN S" Not Applicable 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 80536 80536 PROJECT 1 - BIOLOGY OF DNA DEAMINASES IN BREAST CANCERABSTRACTEstrogen receptor (ER)-positive breast cancer is the most common form of breast cancer accounting forover 75% of invasive breast cancers diagnosed each year. The overall mutation landscape in ER-positivebreast cancer is multifactorial but the DNA deaminase APOBEC3B (A3B) accounts for nearly 20% of base-substitutionmutations in primary disease and over 50% in metastases. A3B is not expressed in normalmammary epithelial cells and becomes overexpressed in the majority of breast cancers. A3B overexpressioncorrelates with poor clinical outcomes for ER-positive breast cancer including recurrence metastasis anddrug resistance. Our Program is testing the overarching hypothesis that A3B inhibition as an adjuvant toprimary treatment options will help to prevent detrimental mutation-driven outcomes such as drug resistanceand metastasis. Project 1 will contribute directly to collaborative Program efforts to test this hypothesis through3 specific aims. In Aim 1 we propose to develop reporter systems for quantifying A3B-mediated editing inliving cells including an innovative transportable reporter. In one potential application this system will enablerapid testing of candidate small molecule A3B inhibitors in a panel of breast cancer cell lines as candidatecompounds are developed through the concerted activities of all Program components. In Aim 2 we willdelineate mechanisms of protein-level A3B regulation in normal and breast cancer cells. These studies willfocus on protein-protein interactions prioritized by proteomics data sets. Comprehensive characterization ofdirect interactions is also anticipated to reveal potentially druggable surfaces for collaborative studies onchemical probes (Project 2) computational modeling (Core C) and structural biology (Project 3). In Aim 3 wewill address how A3B-catalyzed genomic uracil lesions are processed into error-free and mutagenic outcomesby different DNA repair pathways. These studies have the potential to reveal molecular dependencies in DNArepair that are specific to breast tumor cells undergoing elevated levels of DNA damage catalyzed by A3B.Thus Project 1 is an integral component of this overall Program because it will provide innovative assays forquantifying A3B activity in living breast cancer cells yield molecular insights into regulatory and potentiallydruggable protein surfaces and uncover genetic dependencies that may constitute new opportunities fordiagnostic and therapeutic development. +No NIH Category available Address;Affect;Archives;Bioinformatics;Biological Assay;Biological Markers;Cancer Etiology;Cells;Chemical Agents;Chemoprevention;Chemopreventive Agent;Chronic;Cirrhosis;Clinical;Clinical Chemoprevention;Clinical Trials;Clinical assessments;Collection;Detection;Development;Diet;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Etiology;FDA approved;Future;Genes;Goals;Hepatic Stellate Cell;Hepatocyte;Human;Kupffer Cells;Libraries;Liver;Liver Fibrosis;Macrophage;Malignant Neoplasms;Malignant neoplasm of liver;Modeling;Molecular;Monitor;Organ;Pathway interactions;Patients;Pharmaceutical Preparations;Population;Prevention strategy;Prevention therapy;Process;Proteins;Rattus;Reverse engineering;Risk;Sampling;Screening for Hepatocellular Cancer;Serum;Serum Proteins;Specimen;System;Testing;Tissues;Toxic effect;cancer chemoprevention;cancer initiation;cancer risk;cancer type;candidate identification;candidate validation;carcinogenicity;cell type;clinical application;clinical biomarkers;clinical translation;clinically relevant;cohort;cost effective;detection assay;diagnostic platform;follow-up;genetic signature;immune cell infiltrate;improved;in vivo;inhibitor;injured;innovation;liver cancer prevention;loss of function;lysophosphatidic acid;member;multidisciplinary;nano-string;nonalcoholic steatohepatitis;novel;patient prognosis;precision cancer prevention;prevent;prevention clinical trial;research clinical testing;risk prediction;screening;transcriptome;transcriptomic profiling;transcriptomics Reverse-engineering precision liver cancer chemoprevention Liver cancer chemoprevention will substantially improve the dismal patient prognosis althoughstill impossible. We have developed Precision Liver Cancer Prevention Consortium and willemploy an innovative multidisciplinary reverse-engineering approach to simultaneously identifyliver cancer chemoprevention biomarkers targets and drugs ready for subsequent clinicalassessment and deployment with special focus on non-alcoholic steatohepatitis the fastestrising etiology of liver cancer globally. NCI 10916614 9/15/23 0:00 PA-18-484 3R01CA233794-05S1 3 R01 CA 233794 5 S1 "PERLOFF, MARJORIE" 9/23/19 0:00 8/31/24 0:00 Chemo/Dietary Prevention Study Section[CDP] 9925976 "HOSHIDA, YUJIN " Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 199439 NCI 121609 77830 Identification of clinically relevant cancer chemoprevention targets has been challenging. Our multidisciplinaryteam (Precision Liver Cancer Prevention Consortium) will employ an innovative reverse-engineering approachstarting from transcriptome analysis of archived clinical specimens with long-term clinical follow-up thenmoving to multifold experimental verification of only clinically well-validated targets to elucidatechemoprevention targets with the highest likelihood of successful clinical application. With this approach wecould successfully identify liver cancer risk signatures and chemoprevention dugs leading to a clinical trial(NCT02273362). To achieve our long-term goal of establishing clinically applicable chemoprevention strategieshere we aim to elucidate molecular dysregulation underlying carcinogenic milieu in livers affected with non-alcoholic steatohepatitis (NASH) the fastest rising liver cancer etiology as clues to refined chemopreventiontargets drugs and biomarker assays which are expected to enable personalized patient management andmore cost-effective liver cancer chemoprevention clinical trials and lead to revolutionary improvement ofpatient prognosis and establishment of a new paradigm reverse-engineering precision cancer prevention.Aim 1. Computationally-targeted screening of liver cancer chemoprevention agents. Candidate livercancer chemopreventive compounds will be computationally prioritized and screened together with LPApathway inhibitor library in liver cancer risk signature-inducible cell system for the gene signature reversal. Forselected compounds in the screen mechanisms of action will be interrogated by gain- or loss-of-functionassessment in the cell system.Aim 2. Functional validation of candidate liver cancer chemoprevention agents. In vivo liver cancerchemopreventive effect of the candidate agents will be validated in a diet-induced fibrotic/carcinogenic ratmodel mimicking global human cirrhosis transcriptome. Human relevance of the agents will be evaluated inorganotypic ex vivo culture of clinical fibrotic liver tissues (n=30). To determine target cell type(s) andmechanisms of action for the agents major hepatic cell types will be isolated from the rats and transcriptomeprofiling will be performed to assess liver cancer risk signature member genes the inferred target genes for thecompounds and related molecular pathways. Human fibrotic/cirrhotic NASH livers will be similarly profiled forcell type-specific transcriptomic dysregulation to verify that the modulated genes are relevant in human.Aim 3. Development of tissue- and serum-based liver cancer risk biomarker assays. Liver tissue-basedcancer risk signatures will be implemented in clinically applicable tissue- (NanoString) and serum- (Luminex)based assays and evaluated for technical validity and capability to predict future cancer risk in a cohort of 200NASH patients with paired serum and liver tissue specimens as well as completed long-term clinicalobservation for cancer development. 199439 +No NIH Category available Address;Aging;Amputees;Architecture;Behavior;COVID-19 pandemic;Clinical;Clinical Trials;Computer Vision Systems;Computer software;Data;Data Collection;Data Set;Environment;Feedback;Future;Goals;Health;Home;Hour;Infrastructure;Machine Learning;Marketing;Measures;Modeling;Movement Disorders;Outcome;Patients;Performance;Phase;Physical Function;Physical Performance;Physical activity;Physical assessment;Population;Posture;Research;Research Personnel;Software Tools;System;Taxonomy;Testing;Time;Training;Visit;Walking;acceptability and feasibility;cancer rehabilitation;clinical outcome assessment;clinically relevant;cohort;cost;health application;improved;innovation;insight;machine learning model;novel;prototype;telehealth;tool;trend;usability TOPIC 425: POSTURE ANALYSIS THROUGH MACHINE LEARNING (PATHML) PHASE II n/a NCI 10915803 75N91023C00031-0-9999-1 N44 9/1/23 0:00 8/31/25 0:00 79332419 "KAGAN, VADIM " Not Applicable 8 Unavailable 793779237 QC8LYF3ND8A4 793779237 QC8LYF3ND8A4 US 39.02196 -77.120217 10031634 "SENTIMETRIX, INC." BETHESDA MD Domestic For-Profits 208141847 UNITED STATES N R and D Contracts 2023 2049554 NCI The availability of low-cost video has tremendous potential to provide new insight into how physical behavior is associated with health define clinical trial outcomes and assess physical function within the homeresearch and clinical environments. The COVID-19 pandemic required a rapid shift to incorporate video-based data collection and clinical visits establishing the feasibility of using video for clinical outcome assessments (COA). However there is a lack of software tools to automate and incorporate video into health-related applications. Our Phase I project resulted in a proof-of-concept PathML software prototypethat included several sufficiently accurate machine learning models to annotate posture physical activity intensity and features of the environment. The Phase II project has two goals. The first goal is to enhance the functionality of the Phase I PathML prototype through innovative machine learning approaches to annotate relevant to physical behavior research taxonomies and UX enhancements that will result in amarket-ready tool addressing the needs of physical behavior researchers. Additionally this project seeks to extend the software to include automatic identification and scoring of clinically relevant COAs (e.g. 30second sit-stand test two-minute walk test) partnering with clinical researchers with expertise in aging movement disorders amputees and cancer rehabilitation. 2049554 +No NIH Category available Project 1: Systematic Physical and Spatial Mapping of Cancer Driver Networks n/a NCI 10915768 8/29/23 0:00 PA-20-272 3U54CA274502-02S1 3 U54 CA 274502 2 S1 "DUECK, HANNAH RUTH" 9/14/22 0:00 8/31/27 0:00 ZCA1(M2) 9989 15401017 "LUNDBERG, EMMA " Not Applicable 11 OTHER BASIC SCIENCES 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 152275 100000 52275 No abstract available +No NIH Category available Collaborations and NCORP Collective Management n/a NCI 10915754 9/5/23 0:00 PA-20-272 3UG1CA189823-10S1 3 UG1 CA 189823 10 S1 "MCCASKILL-STEVENS, WORTA J" 8/1/14 0:00 7/31/25 0:00 ZCA1(M1) 7931 1991760 "BUCKNER, JAN C" Not Applicable 7 Unavailable 117404554 F4BMNBQK9BM1 117404554 F4BMNBQK9BM1 US 41.879725 -87.636406 10060073 ALLIANCE NCTN FOUNDATION CHICAGO IL Other Domestic Non-Profits 606064404 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 406615 344589 62026 No abstract available +No NIH Category available Address;Affect;Atrophic;Blood Vessels;Blood capillaries;Body Weight;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Patient;Carcinoma;Cells;Cessation of life;Chronic;Clinical;Compensation;Complex;Data;Development;Dietary Intervention;Distant;Early Diagnosis;Endothelial Cells;Endothelium;Etiology;Evaluation;Failure to Thrive;Fibrosis;Food;Functional disorder;Genetically Engineered Mouse;Goals;Greater sac of peritoneum;Growth;Impairment;Implant;Individual;Inflammation;Inflammatory;Intercellular Junctions;Intervention;Intervention Trial;Intestines;KDR gene;Knowledge;Lipids;Liquid substance;Location;Lymphatic;Lymphatic Endothelium;Lymphatic function;MAP3K7 gene;Malabsorption Syndromes;Malignant Neoplasms;Measurable;Metabolic;Metabolic Diseases;Molecular;Mus;Muscle;Neoplasm Metastasis;Nodule;Normal tissue morphology;Organ;Patients;Phenotype;Phosphorylation;Proteolysis;Quality of life;Recovery;Regulation;Research Personnel;Risk;Signal Pathway;Signal Transduction;Site;Skeletal Muscle;Skin;Survival Rate;Testing;Therapeutic;Time;Treatment Efficacy;Tumor Burden;Tumor stage;Tumor-Derived;Vascular Endothelium;Vascular Permeabilities;Villus;Weight;absorption;cancer cachexia;cancer therapy;carcinogenesis;cytokine;design;dietary;effective therapy;efficacy evaluation;experimental study;extracellular vesicles;food consumption;improved;innovation;intestinal villi;lacteal;lymphatic dysfunction;lymphatic vessel;metabolic abnormality assessment;mouse model;muscle form;preclinical trial;prevent;reduced food intake;repaired;response;sarcopenia;subcutaneous;therapeutic evaluation;trafficking;treatment response;tumor;tumor progression REWIRING CANCER-INDUCED ABNORMALITIES IN THE VASCULAR BARRIER NarrativeProgressive weight loss has been frequently associated with cancer progression with approximately 50-80% ofpatients developing this condition. This application seeks to identify the mechanisms that trigger cachexia andexplore therapeutic opportunities to reverse this chronic condition in the context of cancer. NCI 10915752 9/19/23 0:00 PA-20-185 1R56CA279689-01 1 R56 CA 279689 1 "WATSON, JOANNA M" 9/19/23 0:00 8/31/24 0:00 Integrative Vascular Physiology and Pathology Study Section[IVPP] 6168294 "IRUELA-ARISPE, M. LUISA " Not Applicable 5 ANATOMY/CELL BIOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 120000 NCI 75000 45000 SummaryTumors are known to induce the formation of unique microenvironments in distant organs that facilitate seedingsurvival and growth of metastatic nodules. These sites known as pre-metastatic niches emerge as a responseto the combined systemic effects of tumor-derived factors and shed extracellular vesicles. Aside from pre-metastatic niches distant alterations in otherwise normal tissues of cancer-bearing subjects have not beenidentified. While evaluating the systemic vasculature of tumor-bearing mice we serendipitously found thatpresence of certain types of carcinomas implanted subcutaneously have a deleterious effect on intestinallymphatics and blood vessels. This surprising finding was directly correlated with severe weight loss andprogressive reduction of skeletal muscle mass a condition known as cachexia. Importantly in cancer patientscachexia has a meaningful negative impact in their ability to respond and recover from therapy and thusidentification of individuals at risk and effective treatments to reverse this condition are imperative. Blockingcachexia offers not only a significant improvement in the quality of life for these patients but it also improvestolerance and response to cancer treatment with measurable increase in survival rates. Although the clinicalconsequences of cachexia and its positive response to therapy are well known read-outs for early diagnosisand effective treatment remain challenging.Our preliminary findings uncovered that tumors with high circulating levels of specific inflammatory cytokinesinduced vascular and lymphatic barrier dysfunction in the intestine. In particular the capillaries and centrallymphatic lacteal of intestinal villi showed prolonged and exacerbated levels of VEGFR2/3 signaling TAK1phosphorylation and other alterations that yield compromised junctional complexes. In turn we documentedchanges in food absorption despite unaltered levels of food consumption and associated weight loss.Collectively the findings indicate that cancer-induced alterations in the vasculo-lymphatic compartment ofintestinal villi contribute to and perhaps trigger the development of cachexia by affecting their ability to absorblipids. The goal of this project is to determine whether deficiencies in lymphatic and vascular endothelium are asignificant underlying cause of cancer-induced cachexia that can be targeted to reverse the condition. Our two-progued approach will delve into further understanding of the underlying molecular mechanisms while pursuingpre-clinical trials in mouse models to test therapeutic avenues aimed at correcting the vascular deficiencies.The contribution of the vasculature as an important culprit in cachexia has not been recognized and it could betransformative as it may offer an unprecedented opportunity for intervention at early stages by focusing onrewiring endothelial barrier and blocking this devastating condition. 120000 +No NIH Category available Behavior;Benign;Biological Markers;Biopsy;Biopsy Specimen;Board Certification;Breast;Businesses;Cancer Etiology;Cancer Patient;Cancer Survivor;Caspase;Cell Culture Techniques;Cell Survival;Cells;Certification;Clinical;Clinical Trials;Cultural Sensitivity;Cytotoxic agent;Data;Dental;Dysplasia;Excision;Glioma;Growth;Human;Immunohistochemistry;Inflammation;Institutional Review Boards;Intervention Trial;Lectin;Legal patent;Lesion;Lesion by Morphology;Leukoplakia;Lung;Maackia amurensis;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Membrane;Methods;Microscopy;Migration Assay;Morphology;Mus;Necrosis;Oncology;Operative Surgical Procedures;Oral;Oral Administration;Oral Surgeon;Oral cavity;Pathologist;Patients;Persons;Phase;Phase I Clinical Trials;Placebos;Positioning Attribute;Quality of life;Radiation;Reagent;Resistance;Sampling;Skin Cancer;Survivors;T cell infiltration;Technology;Tissues;Vascularization;Weight;Western Blotting;Work;angiogenesis;cancer infiltrating T cells;cell motility;chemotherapeutic agent;chemotherapy;clinical effect;combat;commercialization;drug market;effector T cell;improved;malignant mouth neoplasm;mortality;mouth squamous cell carcinoma;mucin receptor;nanomolar;oral lesion;podoplanin;premalignant;prevent;receptor;therapeutic target;treatment response;tumor;tumor growth;tumor progression;wound healing Targeting OSCC cells with a lozenge to treat oral cancer NarrativeConventional cytotoxic drugs are very toxic and more targeted chemotherapies are limited to only a handful ofreagents. Malignant oral cancers do not respond well to current chemotherapies. Developing a strategy targetto target PDPN on OSCC cells could open new ways to prevent and treat cancer. NCI 10915138 11/29/23 0:00 PA-21-261 6R41CA268160-03 6 R41 CA 268160 3 "ZHAO, MING" 11/1/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-T(10)B] 11344391 "GOLDBERG, GARY " Not Applicable 1 Unavailable 80819971 CLFYGDBZ96B3 010268211; 080819971 CLFYGDBZ96B3 US 39.855182 -74.961054 10031240 "SENTRIMED, INC." MULLICA HILL NJ Domestic For-Profits 80624446 UNITED STATES N 11/1/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 247657 NCI 203107 39300 Abstract/Summary Oral cancer kills over 8000 people in the USA and 120000 people worldwide every year. Over 90% oforal cancers are caused by oral squamous cell carcinoma (OSCC) and these cells are notoriously resistant tochemotherapeutic agents. Radiation and surgery are used to treat oral cancer patients but causedisfigurations and sequelae that drastically decrease the quality of life for survivors. The vast majority of OSCC cells express PDPN which is a transmembrane mucin receptor thatpromotes oral cancer progression. Precancerous oral lesions (e.g. leukoplakia) that express high levels ofPDPN are several times more likely to become oral cancers than lesions that do not express PDPN. ThusPDPN presents a functionally relevant target that can be used to detect and treat oral cancer. We found thatMaackia amurensis seed lectin (MASL) targets PDPN to kill OSCC cells. Moreover MASL is nontoxic and canbe administered orally to inhibit tumor growth and vascularization in mice. We propose 3 Specific Aims to evaluate the effects of MASL on OSCC cells ex vivo and in a Phase 1human clinical trial. In Aim 1 we will evaluate OSCC morphology PDPN expression vascularization and T-cell infiltration in oral cancer patients by IHC. Patients with lesions containing OSCC cells that express robustlevels of PDPN will be considered for treatment. In Aim 2 we will evaluate effects of MASL on OSCCmorphology PDPN expression angiogenesis and T-cell infiltration in oral cancer lesions taken from patientsby biopsy or resections. In Aim 3 we will evaluate the effects of MASL on PDPN expression motility andgrowth of OSCC cells cultured from oral cancer patients examined in Aims 1 and 2. We will produce oral lozenges containing MASL that will dissolve in the mouths of oral cancer patientsfor direct and systemic administration to treat oral lesions that express PDPN as defined in Aim 1. We willanalyze OSCC morphology PDPN expression angiogenesis and T-cell infiltration in samples taken fromthese excisions. We hypothesize that MASL will decrease OSCC dysplasia PDPN expression andvascularization in these patients. We also suspect that MASL will increase T-cell tumor infiltration since PDPNhas been identified as an inhibitory receptor on effector T-cells. These data will also determine how PDPNexpression and MASL sensitivity in actual patients compares to their ex vivo cell culture studies from Aim 2. Positive results from this project will change the clinical paradigm currently used to treat oral cancer.Benign oral lesions are currently watched and waited while OSCC is treated by surgery and radiation. Ournew paradigm will use MASL to target PDPN which enables benign cells to develop into OSCC. Thereforethis work should improve our ability to treat oral cancer and other malignancies that express PDPN includingbreast glioma lung and skin cancer. 247657 +No NIH Category available African American population;Aliquot;Anthropometry;Bayesian Modeling;Biological Markers;Blood;Blood specimen;Calibration;California;Cancer health equity;Cessation of life;Chemicals;Chronic Disease;Clinical;Cohort Studies;Computerized Medical Record;Consultations;Cost efficiency;Cryopreservation;Cultural Diversity;Data;Data Analyses;Data Management Resources;Data Security;Data Set;Databases;Diagnosis;Diagnostic;Dietary intake;Disease Outcome;Energy Intake;Energy Metabolism;Ensure;Environment;Environmental Epidemiology;Environmental Exposure;Environmental Risk Factor;Epigenetic Process;Ethnic Origin;Ethnic Population;Etiology;Funding;Genetic;Genomics;Genotype;Geographic Locations;Grant;Hawaii;Health;Health behavior;Hospitals;Incidence;Indirect Calorimetry;Infrastructure;Intake;Japanese American;Latino Population;Leadership;Life Style;Lymphocyte;Maintenance;Malignant Neoplasms;Measurement;Measures;Medical;Medicare/Medicaid;Methodology;Native Hawaiian;Neighborhoods;Normal tissue morphology;Oral;Outcome;Paper;Participant;Phenotype;Physical activity;Physiological;Pilot Projects;Planning Techniques;Postdoctoral Fellow;Prospective cohort study;Publishing;Questionnaires;Race;Registries;Research;Research Methodology;Research Personnel;Research Project Grants;Residual state;Resources;Rest;Risk Factors;Saliva;Sampling;Science;Slide;Social Environment;Specimen;Structural Racism;Students;Testing;Tissue Banks;Tissue Sample;Training;Tumor Tissue;United States National Institutes of Health;Urine;Vertebral column;Vital Statistics;Woman;actigraphy;biobank;blood product;climate change;cohort;complex data;computerized;data harmonization;data sharing;database of Genotypes and Phenotypes;design;dietary;digital repositories;disorder prevention;epigenomics;ethnic difference;ethnic disparity;ethnic diversity;ethnic health disparity;ethnic minority;follow-up;genetic risk factor;genome wide association study;improved;indexing;innovation;member;men;metabolomics;microbiome research;multi-ethnic;neoplasm registry;novel strategies;nutrition;programs;prospective;racial disparity;racial diversity;racial health disparity;racial minority;racial population;social health determinants;stool sample;tumor;tumor registry;web platform;willingness Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study This renewal application seeks support for the infrastructure maintenance of the Multiethnic Cohort (MEC)Study established in 1993-1996 to continue a well-integrated program of research testing innovativehypotheses aimed at ensuring that racial/ethnic disparities are investigated and progress in disease preventionapplies to major US racial/ethnic minorities. By including 215251 men and women mostly of 5 racial/ethnicpopulations (African Americans Japanese Americans Latinos Native Hawaiians and Whites) the MEC is themost racially and ethnically diverse cancer cohort and its value for etiologic research on chronic diseases iswidely recognized. Leadership of the MEC entails a highly interactive team-science approach; investigatorshave amply demonstrated willingness to share data and samples. NCI 10915071 8/31/23 0:00 PAR-20-294 3U01CA164973-12S1 3 U01 CA 164973 12 S1 "MAHABIR, SOMDAT" 9/1/12 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 1898900 "LE MARCHAND, LOIC " "HAIMAN, CHRISTOPHER ALAN; WILKENS, LYNNE R" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 124621 NCI 124621 0 This renewal application seeks support for the infrastructure of the Multiethnic Cohort (MEC) Study which wasestablished in Hawaii and southern California in 1993-1996 to study risk factors for cancer and other chronicdiseases. The study was designed to take advantage of the ethnic and cultural diversity of the two geographicareas as well as the expertise of the investigators in nutrition ethnic/racial disparities studies and genetics. Itis the most ethnically diverse cancer cohort in existence. It achieves high cost-efficiency by significantlysupplementing active follow-up information with computerized linkages to SEER cancer registries vitalstatistics hospital-discharge diagnoses medical claim data electronic medical records and geospatialinformation. At baseline the cohort included information on 215000 men and women comprised almostentirely of five ethnic/racial populations: Japanese Americans Latinos Whites African Americans and NativeHawaiians. The resource was later expanded to include a prospective biorepository of blood specimens from~70000 of the participants and urine specimens on a large subset. Leadership of the MEC entails a highlyinteractive team-science approach and the investigators have amply demonstrated their willingness to sharedata/samples and to participate actively in consortia. Research accomplishments include significantcontributions to understanding both genetic and environmental risk factors for cancer. Over 291 papersdescribing our findings have been published during the current grant cycle. In addition over the last 28 years129 NIH grants/supplements have been built around the MEC (77 were active in the current cycle) and morethan 136 students and postdoctoral fellows have been trained on the study. This application describes ouraims over the next 5 years for maintaining and enhancing the infrastructure of the MEC as well as plans formethodological research. We project adding 7253 incident cancer cases in the new 5 years to the current48064 cases; 2670 of these cases will have pre-diagnostic blood samples to be added to the current 10957cases. We will add 6K FFPE tumor samples to the current ~13K. In addition this grant renewal will makepossible the continuation of a well-integrated program of research aimed at evaluating lifestyle environmentaland genetic risk factors and social determinants of health for cancer and other common chronic diseasestaking advantage of new approaches such as dietary quality indices exposomics genomics epigenomicsmicrobiomics metabolomics and multilevel exposures including spatial environment structural racism andclimate change. The MEC will allow the testing of innovative research hypotheses aimed at ensuring thatracial/ethnic health disparities are investigated and that progress in disease prevention applies to all major USracial/ethnic minorities. 124621 +No NIH Category available Infrastructure IGF::OT::IGF BLDG. 433- NORTH REFURBISHMENT & BLDG. 433- INFRASTRUCTURE n/a NCI 10914626 261201500003I-P00009-26100022-1 N01 8/15/16 0:00 9/6/19 0:00 15721138 "IRELAND, RYAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 71361 NCI IGF::OT::IGF BLDG. 433- NORTH REFURBISHMENT & BLDG. 433- INFRASTRUCTURE 71361 +No NIH Category available Antisense Oligonucleotides;Attenuated;Biological;Biological Markers;Biological Models;Biomedical Research;Breast Cancer Cell;Breast Cancer cell line;Cancer Patient;Cell Proliferation;Clinical;Communities;Computing Methodologies;Data;Development;Diagnostic;Drug resistance;Exhibits;FDA approved;Fatty acid glycerol esters;Foundations;Future;Genetic;Genetic Transcription;Goals;Growth;In Vitro;Individual;Invaded;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Molecular;Multiomic Data;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Play;Process;Prognosis;Proliferating;Quantitative Trait Loci;RNA;RNA-targeting therapy;Research;Research Personnel;Role;Sampling;Signal Pathway;Signal Transduction;Small Nucleolar RNA;Solid Neoplasm;System;The Cancer Genome Atlas;Therapeutic;Transcription Alteration;Work;Xenograft procedure;cancer drug resistance;cancer initiation;cancer subtypes;cancer type;clinically relevant;clinically significant;data portal;data resource;deep learning;diagnostic value;differential expression;disease diagnostic;drug response prediction;effective therapy;genetic variant;improved;in vivo;individual response;insight;large scale data;malignant breast neoplasm;mammary;mouse model;novel;prognostic;prognostic value;refractory cancer;response;success;survival outcome;targeted cancer therapy;targeted treatment;therapeutic RNA;therapeutic target;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumorigenesis;user-friendly Systematic Characterization of Small Nucleolar RNAs in Cancer Project NarrativeDespite improvements in clinical considerations for cancer a considerable number of cancer subtypescontinue to lack effective targeted therapies resulting in the urgent need for the development of previouslyunconsidered treatment approaches and therapeutic strategies. Following the emergence of preliminary dataimplicating snoRNAs as key players in a significant number of cancer-related processes and signalingpathways this project seeks to determine the functional effects of snoRNAs in vitro and in vivo elucidate thedrug response effects of snoRNAs and provide a comprehensive data resource for exploring the biomedicalsignificance of snoRNAs. The proposed study will shed light on future clinical considerations for thedevelopment of targeted therapies for cancer types currently lacking effective treatment options and it is alsoexpected that the computational methods and experimental systems established in the proposed research willbe applicable to other cancer types thereby greatly leveraging the impact of this project. NCI 10914508 9/4/23 0:00 PA-21-268 7R01CA262623-03 7 R01 CA 262623 3 "WEINREICH, MICHAEL DALE" 9/1/23 0:00 8/31/26 0:00 Cancer Genetics Study Section[CG] 10652634 "HAN, LENG " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 414725 NCI 284511 130214 AbstractDespite recent advancements in treatment options for cancer a majority of cancer types continue to lack fullycharacterized and effective targeted therapies. This insufficiency has resulted in the demand for alternativepreviously unconsidered treatment approaches to improve disease diagnostics prognoses and patientsurvival outcomes. Recently we performed integrative analysis for small nucleolar RNA (snoRNAs) in a largenumber of patient samples and identified 46 snoRNAs that exhibit broad-spectrum clinical significance with 12or more types of cancer. We developed a data portal snoRNA in cancers (SNORic) which allows researchersto explore the significance of individual snoRNAs in cancer. SNORic has been accessed >100000 times sinceits release in 2017 suggesting its broad impact in the biomedical research community. We provided initialgenetic evidence indicating that elevated expression of snoRNAs facilitated the tumorigenesis of mammarygland malignancies. Mechanistically we demonstrated that SNORD46 plays important roles in promoting theinitiation growth invasion and progression of TNBC. Therefore elucidation of the roles of snoRNAs inpromoting tumorigenesis serves as the first step in the development of a novel class of snoRNA-basedbiomarkers and therapeutic targets. Our central hypothesis is that snoRNAs serve as essential RNA targets in promoting cancer initiationprogression and drug resistance which could be attenuated in vivo by an antisense oligonucleotide-basedtargeted therapy. In specific aim 1 we will delineate the diagnostic and prognostic values of these snoRNAs intriple-negative breast cancer (Aim 1.1). We will demonstrate the molecular mechanism that these snoRNAspromote TNBC cell proliferation mobility and invasion (Aim 1.2). We will demonstrate that antisenseoligonucleotide-based snoRNA targeted therapy effectively inhibits TNBC growth in vivo (Aim 1.3). We willevaluate and interpret causal effects through molQTL analysis (Aim 1.4). In specific aim 2 we will determinethe role of three snoRNAs in breast cancer drug resistance (Aim 2.1). We will understand the molecularmechanisms for drug resistance through multi-omics data (Aim 2.2). To expand our perspective on drugresistance we will predict the drug response from individual snoRNA expression with the augmentation ofdeep learning (Aim 2.3). We will study the drug responses effects among snoRNA-based subtypes (Aim 2.4).We will build a user-friendly data portal for releasing the date generated through integrative analysis (Aim 2.5).This study will significantly advance the prognostic diagnostic and therapeutic potential of snoRNAs; theabsence of this research work will greatly hinder the realization of snoRNA-based therapeutic considerationsfor cancer patients. 414725 +No NIH Category available Adjuvant Chemotherapy;Alleles;Animals;Antigen Presentation;Antigen Presentation Pathway;Antigen Targeting;Antigens;Basic Science;Biological Response Modifiers;Biopsy;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Breast Cancer therapy;Breast Melanoma;CD8-Positive T-Lymphocytes;Cell Line;Clinic;Clinical;Clinical Data;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Data;Down-Regulation;Elements;Estrogen receptor positive;HLA-A gene;Human;Immune;Immune response;Immunocompetent;Immunosuppression;Immunotherapy;Individual;Inflammatory;Institution;Laboratories;Laboratory Research;MAP Kinase Gene;MEK inhibition;MEKs;Major Histocompatibility Complex;Malignant Neoplasms;Mediating;Mediator;Metastatic breast cancer;Molecular;Molecular Target;Mus;Neoadjuvant Therapy;Outcome;PD-1/PD-L1;Pathologic;Pathway interactions;Patients;Resistance;Rodent Model;Role;Schedule;Signal Transduction;Solid Neoplasm;Testing;Therapeutic;Translating;Tumor Antigens;Tumor Escape;Tumor Immunity;Up-Regulation;Validation;Work;anti-PD-1;anti-PD-1/PD-L1;anti-PD-L1;anti-PD-L1 antibodies;cancer immunotherapy;clinical biomarkers;clinical efficacy;colon cancer patients;cytokine;drug sensitivity;efficacy testing;improved;in vivo;inhibitor;laboratory experiment;malignant breast neoplasm;melanoma;metastatic colorectal;mouse model;neoplastic cell;novel;novel marker;patient stratification;preclinical study;predicting response;programmed cell death protein 1;response;response biomarker;synergism;targeted agent;targeted treatment;tissue resource;translational approach;translational study;treatment optimization;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Targeting antigen presentation to improve immunotherapy responses in breast cancer PROJECT NARRATIVE: TARGETING ANTIGEN PRESENTATION TO IMPROVEIMMUNOTHERAPY RESPONSES IN BREAST CANCERThis is a translational proposal that seeks to extend our preclinical studies which identified synergy betweenMEK inhibitors and anti-PD-L1 immunotherapy to two (2) human metastatic breast cancer trials testing the samecombination. Tumor correlates associated with MEK inhibition in animals and subsequent response toimmunotherapy will be evaluated in paired patient tumor biopsies; furthermore we will perform laboratoryexperiments to optimize therapy sequence and schedule and confirm the functionality of MHC-II expression(induced by MEK inhibition) in tumor cells as a mediator of immunologic response. Successful completion of thiswork will elucidate possible clinical biomarkers for response or resistance to immunotherapy in breast canceras well as novel mechanisms of tumor immune-evasion. NCI 10912877 9/18/23 0:00 PA-20-272 3P50CA098131-21S1 3 P50 CA 98131 21 S1 "BASA JANAKIRAM, NAVEENA" 8/7/03 0:00 7/31/24 0:00 ZCA1 8644 10166490 "BALKO, JUSTIN M" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 125000 91338 33662 PROJECT SUMMARY/ABSTRACT: TARGETING ANTIGEN PRESENTATION TO IMPROVEIMMUNOTHERAPY RESPONSES IN BREAST CANCERCancer immunotherapies particularly those targeting the PD-1/L1 axis are revolutionizing treatment paradigms.Although these therapies have proven effective in a wide variety of solid tumors response rates to single agentanti-PD-1/L1 in breast cancer have been underwhelming centering around 5%-15% of treated patients.However given the durable responses observed in other tumor types finding ways to increase breast cancersensitivity to immunotherapy is a valuable endeavor. Our recent work in breast cancer and melanoma hasidentified an important role for major histocompatibility complex-II (MHC-II) expression on tumor cells as amediator of enhanced anti-tumor immunity and subsequent response to immunotherapies targeting the PD-1/PD-L1 axis. Furthermore our preliminary studies suggest that both MHC-I and MHC-II expression (antigen-presenting molecules) on breast tumor cells directly influences the tumor microenvironment through expandedanti-tumor immunity. We found that activation of the Ras/MAPK pathway suppresses the expression of bothMHC-I and MHC-II and therefore may be an actionable target for enhancing antigen presentation to promoteanti-tumor immunity and potentiate immunotherapy responses. Based on these data we have initiated trials inboth metastatic triple-negative breast cancer (TNBC) and ER+ breast cancer testing the efficacy of thiscombination. In this proposal we will perform clinical validation of the molecular effects of MEK inhibition withanti-PD-L1 in ongoing clinical trials at our institution as well as perform direct translational studies exploring theimmune mechanism behind MEK inhibition that promotes anti-tumor immunity. Our central hypothesis is thattherapeutic modulation of antigen presentation via MEK inhibition will promote immunotherapy response inbreast cancer through enhanced MHC-I and MHC-II responses. The proposed studies will elucidate mechanismvalidate clinical utility and identify new targets for combinations of therapies that promote anti-tumor immunitythrough enhancing antigen presentation. Thus this proposal will use a translational approach to bring rationalcombinations of immunotherapy and molecularly targeted agents to breast cancer patients. +No NIH Category available Academic Medical Centers;Advocate;Basic Science;Biological Sciences;Biology;Cancer Center;Clinical Research;Clinical and Translational Science Awards;Collaborations;Colorectal Cancer;Communication;Communities;Development;Digestive System Disorders;Education;Ensure;Epithelium;Evaluation;Fostering;Institution;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Molecular;Monitor;Mucositis;National Cancer Institute;Occupational activity of managing finances;Patient advocacy;Patients;Pharmacologic Substance;Regulation;Report (document);Reporting;Reproduction spores;Research;Research Personnel;Research Project Grants;Resources;Schedule;Series;Tanzania;Tennessee;Translational Research;Universities;career;gastrointestinal;improved;malignant breast neoplasm;medical schools;meetings;outreach;programs Administrative Core PROJECT NARRATIVE: Administrative Core The Administrative Core will be responsible for the organizational administrative and scientific management (both basic and clinical research) of the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer program which focuses on translational research that will substantially improve the management of colorectal cancer. This management and support will be accomplished through a series of oversight committees and organized administrative and scientific meetings of GI SPORE investigators institutional representatives and external advisors. NCI 10912861 9/19/23 15:12 PA-20-272 3P50CA236733-05S1 3 P50 CA 236733 5 S1 "NOTHWEHR, STEVEN F" 7/9/19 0:00 5/31/24 0:00 ZCA1 8241 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 125000 93535 31465 PROJECT SUMMARY/ABSTRACT: Administrative Core The Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer Administrative Core will support all GI SPORE cancer-related research projects and investigators by managing SPORE resources communication and outreach and by fostering interactions among investigators collaborators other VICC SPOREs other GI SPOREs the patient and advocate community and the National Cancer Institute. This management and support will be accomplished by administrative and scientific meetings of GI SPORE investigators with oversight provided by the Internal and External Advisory Boards. +No NIH Category available PROMINENT: Discovering the molecular signatures of cancer PROMotion to INform prevENTion n/a NCI 10912837 9/19/23 0:00 RFA-OT-A2-013 1OT2CA290880-01 1 OT2 CA 290880 1 "GHOSH-JANJIGIAN, SHARMISTHA" 8/23/23 0:00 5/31/24 0:00 ZCA1-SRC(99) 8867800 "GUNTER, MARC JAMES" Not Applicable n/a Unavailable 227092590 T9F5NHX87N25 227092590 T9F5NHX87N25 UK 51.50853 -0.12574 3527407 "IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE" LONDON Unavailable SW7 2AZ UNITED KINGDOM N 8/23/23 0:00 5/31/24 0:00 393 Other 2023 107654 NCI 99680 7974 No abstract available 107654 +No NIH Category available Cancer Therapy Evaluation Program;Contractor;Contracts;Databases;Government;Maintenance;Pamphlets;Persons;Pharmaceutical Services;Pharmacologic Substance;Policies;Recovery;Regulation;Research Personnel;Services;programs SUPPORT SERVICES FOR THE CTEP PHARMACEUTICAL MANAGEMENT BRANCH (PMB) n/a NCI 10912416 75N91022C00012-P00001-9999-1 N02 9/1/22 0:00 8/31/24 0:00 78754535 "GRAY, ARIE " Not Applicable 11 Unavailable 43690788 CAM5K35PN6D7 43690788 CAM5K35PN6D7 US 38.934471 -77.428684 10022495 "EDJ ASSOCIATES, INC." RESTON VA Domestic For-Profits 201911244 UNITED STATES N R and D Contracts 2023 1850000 NCI The objective of the Support Services for the Pharmaceutical Management Branch (PMB) contract is to provide logistical and administrative support to Government staff within PMB and across multiple Programs within DCTD. The Contractor supports PMB functions by primarily providing support of IND agent management and distribution (e.g. order processing transfers local destruction investigator brochure distribution stock recovery notice distribution etc.) person registration processing and maintenance curation of a database [Enterprise Core Module (ECM)] containing an NCI list of organizations associated with NCI trials as well as helpdesks for managing the investigator sub-investigator associate and organizations databases in compliance with IND regulations and DCTD policies. 1850000 +No NIH Category available Behavioral Research;Contractor;Division of Cancer Control and Population Sciences;Grant;Logistics;Persons;Preparation;Services;Tobacco Control Research;Writing;editorial;meetings;programs;symposium;tobacco regulatory science;virtual Tobacco Control Research Branch Scientific and Logistic Support Core Services n/a NCI 10912409 75N91022D00010-P00004-759102200001-1 N02 8/1/22 0:00 7/31/27 0:00 78832466 "KLEIN, AMANDA " Not Applicable Unavailable JP6YLTEYJLT5 JP6YLTEYJLT5 US -519575 WASHINGTON DC Other Domestic Non-Profits 200371542 UNITED STATES N R and D Contracts 2023 759000 NCI The Contractor shall provide scientific and logistical support services to the Tobacco Control Research Branch (TCRB) and the Division of Cancer Control and Population Sciences (DCCPS) in the conduct of:1) scientific writing editorial and graphic services 2) project management to support completion of scientific projects 3) coordination of scientific conferences and meetings4) programmatic support for Tobacco Regulatory Science Program (TRSP) tasks and 5) programmatic support for behavioral research tasks. 759000 +No NIH Category available Acupuncture Therapy;Affect;American Society of Clinical Oncology;Analgesics;Brief Pain Inventory;Cancer Center;Cancer Patient;Cancer Survivor;Chemotherapy-induced peripheral neuropathy;Chinese Traditional Medicine;Clinical;Clinical Trials Design;Complication;Data;Double-Blind Method;Effectiveness;Electroacupuncture;Fatigue;Fiber;Goals;Headache;Hour;Impairment;Intervention;Longterm Follow-up;Measurement;Measures;Methods;Nausea;Neurobiology;Numbness;Numeric Rating Scale;Pain;Pain Measurement;Pain Threshold;Participant;Patient Care;Patient Preferences;Patients;Peripheral Nervous System Diseases;Pharmaceutical Preparations;Phase;Pilot Projects;Placebos;Prediction of Response to Therapy;Quality of life;Randomized;Randomized Controlled Trials;Recommendation;Recovery;Research;Role;Sample Size;Scientist;Sensory;Severities;Solid Neoplasm;Symptoms;Tactile;Techniques;Testing;Treatment-related toxicity;United States;afferent nerve;arm;blind;care providers;chemotherapy;chronic musculoskeletal pain;conditioned pain modulation;duloxetine;effective therapy;efficacy evaluation;experience;follow-up;functional improvement;improved;minimally invasive;multidisciplinary;neurotoxic;novel strategies;outcome prediction;pain reduction;painful neuropathy;personalized chemotherapy;pharmacologic;placebo controlled study;predicting response;pressure;primary outcome;randomized placebo-controlled clinical trial;side effect;standard of care;three-arm trial;treatment as usual;treatment effect;treatment response;vibration Acupuncture for Chemothrapy-induced Peripheral Neuropathy Treatment (ACT) Trial PROJECT NARRATIVEThe findings from this study will help determine the efficacy of acupuncture on reducingchemotherapy-induced peripheral neuropathy pain when compared to placebo. It will also helpevaluate acupuncture's effect on improving sensory nerve recovery and identify neurobiologicalmarkers to predict acupuncture's treatment effect. The study findings may contribute toidentification of a non-pharmacological method to improve patients' quality of life and helppersonalize acupuncture treatment. NCI 10912231 1/2/24 0:00 PA-21-268 7R37CA248563-04 7 R37 CA 248563 4 "UMAR, ASAD" 12/1/23 0:00 11/30/25 0:00 Clinical Management of Patients in Community-based Settings Study Section[CMPC] 10281142 "BAO, TING " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 602673 NCI 461162 141511 Project SummaryOne of the most harmful side effects of chemotherapy is chemotherapy-induced peripheralneuropathy (CIPN) a common painful and disabling side effect of many chemotherapy agentsfor which there is no effective treatment. Our pilot phase IIB three-arm trial showed thatacupuncture treatment is associated with reduced CIPN pain and improved tactile thresholdcompared to placebo and usual care control. We aim to increase cancer patients' function andquality of life by identifying effective treatments to alleviate chemotherapy-related toxicities. Thegoal of the proposed project is to determine the efficacy of acupuncture in treating CIPN painand improving function as well as to improve sensory nerve recovery in cancer survivorssuffering from moderate to severe CIPN pain. We will conduct a phase III 250-patientrandomized placebo (sham acupuncture)-controlled trial to: 1) determine the efficacy of aneight-week EA treatment on CIPN symptoms among cancer survivors with moderate to severeCIPN pain; 2) evaluate the effect of EA vs. SA on small sensory fiber function; and 3) evaluatewhether baseline QST outcomes predict response to EA. 602673 +No NIH Category available AML/MDS;Accreditation;Acute;Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Acute T Cell Leukemia;Acute leukemia;Address;Adoptive Immunotherapy;Adverse event;Advocacy;Agonist;Allogenic;Alternative Splicing;Animals;Antibody Therapy;Applications Grants;Award;Basic Science;Bioinformatics;Biological Assay;Biological Availability;Biological Specimen Banks;Biology;Biometry;Biostatistics Core;Bispecific Antibodies;Blood;Bone Marrow;Bone Marrow Aspiration;Bone Marrow Cells;CRISPR screen;Cancer Center;Cancer Control Research;Cancer Research Project;Catalogs;Cell Count;Cell Death;Cell Line;Cell Therapy;Cell model;Cells;Cellular biology;Characteristics;Chronic Myelomonocytic Leukemia;Citrus;Clinic;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Combined Modality Therapy;Communication;Communities;Consent;Consult;Contracts;Cyclophosphamide;Cytometry;Cytoprotection;DNA;DNA Damage;DNA Sequence Alteration;DNA damage checkpoint;Data;Data Analyses;Databases;Decitabine;Development;Development Plans;Diagnosis;Disabled Persons;Disease;Disease Progression;Disease remission;Disease-Free Survival;Disparity;Documentation;Dose;Drug Combinations;Dysmyelopoietic Syndromes;Early Diagnosis;Education;Educational Status;Educational workshop;Effectiveness;Electronics;Engraftment;Enrollment;Ensure;Environment;Equipment and supply inventories;Equity;Erythropoietin;Ethics;Etiology;Evaluable Disease;Exclusion;Exhibits;Faculty;Family;Feedback;Female;Financial Support;Fostering;Funding;Future;Genes;Genetic;Genetically Engineered Mouse;Genome;Genomic Instability;Genomics;Goals;Grant;Grant Review;Group Meetings;Guidelines;Haptens;Health Insurance Portability and Accountability Act;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Human;Hybrids;Immune;Immune system;Immunology;Immunotherapy;In Vitro;Incidence;Individual;Infrastructure;Institution;Institutional Review Boards;Interleukin-15;Investigation;Joints;Journals;Laboratories;Leadership;Leukemic Cell;Licensing;Ligands;Link;Longevity;Malignant Neoplasms;Manuscripts;Measures;Mediating;Memory;Mentors;Methods;Minority;Minority Participation;Minority Recruitment;Mission;Modeling;Molecular;Monitor;Multi-Institutional Clinical Trial;Multiple Myeloma;Mutate;Mutation;Myeloproliferative disease;NK cell therapy;Natural Killer Cell Immunotherapy;Natural Killer Cells;Natural Selections;Newly Diagnosed;Newsletter;Nucleic Acids;Operative Surgical Procedures;Oral;Outcome;Output;Participant;Pathogenesis;Patient Care;Patients;Peer Review;Phase;Phase I/II Trial;Phenotype;Physicians;Pilot Projects;Population;Population Sciences;Postbaccalaureate;Pre-Clinical Model;Preparation;Prevention;Process;Professional Competence;Prognosis;Prognostic Factor;Program Evaluation;Program Reviews;Progress Reports;Progression-Free Survivals;Property;Protocols documentation;PubMed;Publications;Publishing;Qualifying;Quality Control;RNA;RNA Splicing;Receptor Cell;Recommendation;Recurrence;Recurrent disease;Refractory;Regimen;Regulatory T-Lymphocyte;Relapse;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Research Training;Residual state;Resistance;Resolution;Resource Sharing;Resources;Risk;Running;SRSF2 gene;Safety;Salvage Therapy;Sampling;Science;Serum;Services;Signal Pathway;Signal Transduction;Single-Stranded DNA;Skin;Specialized Program of Research Excellence;Specificity;Specimen;Spliceosomes;Statistical Methods;Structure;Students;T-Lymphocyte;Talents;Testing;Therapeutic;Therapeutic Trials;Time;Tissue Procurements;Tissues;Toxic effect;Training;Training Programs;Transfusion;Translating;Translational Research;Travel;United States National Institutes of Health;Universities;Virus Diseases;Visit;Wages;Washington;Woman;Work;Writing;anticancer research;biobank;biomarker identification;cancer genomics;cancer health disparity;cancer prevention;career;career development;cell type;chronic graft versus host disease;chronic leukemia;clinical database;clinical development;conditioning;cost;cytokine;data sharing;design;efficacy testing;epidemiologic data;epidemiology study;exome sequencing;experience;experimental study;first-in-human;functional status;fundamental research;genome-wide;graft vs host disease;graft vs leukemia effect;hematopoietic cell transplantation;high risk;human study;improved;in vivo;informatics tool;inhibitor;innovation;laboratory experiment;leukemia;leukemia relapse;leukemia treatment;meetings;member;mid-career faculty;minority investigator;mortality;mouse model;multidimensional data;mutant;novel;novel marker;novel therapeutic intervention;novel therapeutics;older patient;operation;outreach;patient oriented;peer;pharmacologic;phase 2 study;phase II trial;pre-clinical;preclinical study;preservation;primary endpoint;programs;prospective;recruit;research and development;research study;response;response biomarker;secondary endpoint;skill acquisition;small molecule;standard care;standard of care;success;targeted treatment;tool;transcriptome sequencing;translational approach;translational cancer research;translational clinical trial;tumor;web-based tool Specialized Program Of Research Excellence (SPORE) in Leukemia. PROJECT NARRATIVEThe goal of this SPORE is to develop and test new therapies for acute myeloid leukemia acute lymphoidleukemia and myelodysplastic syndrome. This SPORE also will recruit and train new investigators in leukemiaresearch. NCI 10912197 9/20/23 0:00 PA-20-272 3P50CA171963-10S1 3 P50 CA 171963 10 S1 "KUZMIN, IGOR A" 9/3/13 0:00 6/30/24 0:00 1917511 "LINK, DANIEL C" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 918606 NCI 636514 282092 ABSTRACTThe Washington University SPORE in Leukemia is a highly dynamic translational cancer research program thatfocuses specifically on leukemias and myelodysplastic syndromes (MDS). We have assembled an outstandinggroup of investigators with complementary expertise in basic and clinical leukemia research. In this SPORE weleverage expertise in cancer genomics immunology and hematopoiesis to develop innovative translationalresearch in leukemia. Our long-term goal is to develop novel biomarkers and treatments for leukemias andmyelodysplastic syndromes and to develop and promote innovative translational leukemia research. To achievethese goals the following specific aims are proposed. Aim 1. We will exploit institutional expertise in cancer genomics immunology and hematopoiesis todevelop novel biomarkers and treatments for leukemias and myelodysplastic syndromes. Basic researchat WUSM has led to the development of the following five translational research projects all featuring innovativeinvestigator-initiated therapeutic trials for leukemias or MDS. Project 1. Molecular determinants of decitabine responsiveness Project 2. Targeted therapies for T cell acute lymphoblastic leukemia (T-ALL) Project 3. Novel therapies for splicesome-mutant MDS Project 4. Bi-specific antibody-based therapies for AML Project 5. Memory-like NK cell augmented hematopoietic cell transplantation for AML Aim 2. We will enhance the infrastructure that supports translational leukemia research. This SPOREwill support the following Shared Research Resources: 1) Core A. Biospecimen Processing; 2) Core B.Biostatistics; and 3) Core C. Administration. Aim 3. We will recruit and train new investigators in translational research. This SPORE will supporta Career Enhancement Program (CEP) to recruit and mentor new investigators in translational leukemiaresearch. The SPORE has established a successful minority post-baccalaureate training program. The SPOREalso will support a Developmental Research Program (DRP) to support innovative translational concepts. Aim 4. We will facilitate inter-SPORE collaboration. Four of the SPORE projects include multi-institutionalclinical trials including three at other Leukemia SPORE institutions. We have established CEP educationalexchange and grant review programs with peer Leukemia SPORE institutions. We will continue to organize andparticipate in joint meetings of Leukemia SPOREs at MD Anderson and Harvard. 918606 +No NIH Category available African American;African American population;Algorithms;American;Apoptosis;Area;Biological Availability;Biological Models;Black Populations;Bone Matrix;Bone Regeneration;Bone necrosis;Cancer Patient;Caucasians;Cell Cycle Arrest;Cells;Chloroplasts;Coupled;Data;Dentistry;Deposition;Diabetic mouse;Diagnosis;Disadvantaged;Disease;Fracture;Goals;Histologic;Human;Immunologics;Induction of Apoptosis;Injectable;Insulin-Like Growth Factor I;Jaw;Lettuce - dietary;Malignant Neoplasms;Mandible;Mesenchymal Stem Cells;Modeling;Molecular;Oral;Osteoblasts;Osteocytes;Osteogenesis;Osteoradionecrosis;Outcome;Patients;Peptides;Pharmaceutical Preparations;Plants;Population;Positron-Emission Tomography;Predisposition;Quality of life;Race;Radiation;Radiation therapy;Radio;Rattus;Reporting;SEER Program;Severities;Site;Survival Rate;System;Testing;Therapeutic;Therapeutic Index;Transplantation;United States;X-Ray Computed Tomography;bone;bone cell;bone healing;cancer radiation therapy;cancer therapy;comorbidity;compliance behavior;density;efficacy evaluation;functional disability;healing;health disparity;high risk;improved;improved outcome;innovation;insight;irradiation;low socioeconomic status;malignant oropharynx neoplasm;microCT;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;orofacial;osteogenic;osteoprogenitor cell;preclinical efficacy;prevent;protein expression;racial disparity;racial population;remediation;skeletal;socioeconomics;stem cells;survival outcome;survivorship;translational applications Novel therapeutic approaches to remediate radiotherapy-induced bone necrosis PROJECT NARRATIVEOropharyngeal cancers (OPCs) are among the `Top 10' cancers in the United States and 26% of patients donot survive the first year after diagnosis due to treatment complications. Racial disparity associated with poorOPC survival outcomes are due to low socio-economic status comorbidities and treatment complications suchas osteoradionecrosis. Novel therapeutic model systems will be used to improve healing of radiation-inducedbone necrosis with the goal of improving overall survivorship of oropharyngeal cancer patients. NCI 10912194 9/15/23 0:00 PAR-21-323 1R56CA283140-01 1 R56 CA 283140 1 "WALLACE, TIFFANY A" 9/15/23 0:00 8/31/24 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 7618421 "AKINTOYE, SUNDAY O" Not Applicable 3 DENTISTRY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF DENTISTRY/ORAL HYGN 191046205 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 200000 NCI 123077 76923 PROJECT SUMMARYOropharyngeal cancer (OPC) is the 9th most common cancer in the United States and 26% of patients do notsurvive the first year after diagnosis due to cancer severity and treatment complications. African-Americans (AA)who develop OPC consistently demonstrate poorer survival than Caucasians. Assessments of the SurveillanceEpidemiology and End Results (SEER) data have shown that 5-year relative survival of Caucasians with OPCis close to 57% while AA had a survival rate close to 33%. Post-cancer therapy complications account for majorityof the racially disparate poor OPC survival outcomes. While radiotherapy for OPC improves survivalosteoradionecrosis (ORN) of the jaw and altered quality of life are unfortunate outcomes. Radiation promotesosteoblast and osteocyte apoptosis and induces G0G1 cell cycle arrest of jaw (orofacial) mesenchymal stem cells(OFMSCs) to deplete jaw osteoprogenitor cells. Lower levels of circulating progenitor cells in AA is an establishedcontributor to health disparities. Coupled with high jaw susceptibility to ORN compared to other skeletal sitesthe AA OPC patient has higher disadvantage of developing ORN complications and poor OPC survivaloutcomes. Understanding efficacy of OFMSC therapy for ORN in AA with lower circulating progenitor cells isvital for improving OPC outcomes. Injectable osteoanabolic drugs are attractive therapies for promoting bonehealing in radio-damaged bone but they are often unaffordable by AA from low socioeconomic group resultingin poor patient compliance. Penn Center for Innovation and Precision Dentistry has pioneered expression ofprotein drugs (PDs) in plant chloroplasts (lettuce leaves) for oral delivery that demonstrated bioavailability andefficacy to treat several diseases. Oral delivery of a novel aglycosylated IGF-1 with E-peptide bioencapsulatedin plant cells restored bone healing with increased bone volume density and area in diabetic mouse model ofbone fracture. Collectively these suggest that enhancing osteogenesis with grafted OFMSCs and orallydelivered IGF-1 are promising novel approaches to remediate jaw ORN maximize therapeutic index of OPCradiotherapy and reduce racially disparate OPC outcomes. In Aim 1 will remediate jaw ORN in a rat model usinggrafted OFMSCs from two racial groups (AA vs. Caucasian) as rescue therapy. Aim 2 will evaluate efficacy oforally bioavailable IGF-1 and combined IGF-1/OFMSCs (AA vs. Caucasians) to mitigate jaw ORN. We predictthat therapeutic applications of racially distinct OFMSCs and orally bioavailable IGF-1 will promote healing byprotecting jaw bone cells from radiation-induced apoptosis. The outcome of this novel therapeutic models isexpected to increase affordability and patient compliance especially in the underprivileged and low socio-economic populations associated with majority of the poor OPC survival outcomes. 200000 +No NIH Category available Acceleration;Address;Affect;Age;Aging;Androgen Receptor;Androgens;BRCA1 Mutation;BRCA1 gene;Basic Science;Benefits and Risks;Body Image;Breast;Breast Cancer Risk Factor;Breast Cancer Treatment;Breast Oncology;Cancer Control;Caring;Chest;Clinical;Clinical Treatment;Communities;Development;Diagnosis;Disease;Endocrinology;Estradiol;Estrogen Therapy;Estrogen receptor positive;FDA approved;Female;Fulvestrant;Future;Genetic Transcription;Goals;Gonadal Steroid Hormones;Guidelines;Health;Hormones;Human;Implant;Incidence;Individual;Investigation;Knowledge;Lesbian Gay Bisexual Transgender Queer;Letrozole;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mammary Neoplasms;Mastectomy;Mediating;Messenger RNA;MicroRNAs;Modeling;Molecular;Mouse Mammary Tumor Virus;Mus;Mutation;Operative Surgical Procedures;Organ;Outcome;PIK3CA gene;Patients;Persons;Pharmaceutical Preparations;Population;Postmenopause;Premenopause;Recommendation;Research;Risk;Risk Assessment;Role;Study models;Testosterone;Treatment outcome;Treatment-Related Cancer;United States National Institutes of Health;Well in self;Woman;Work;alpelisib;arm;breast cancer diagnosis;breast tumorigenesis;cancer care;cancer health disparity;cancer risk;cancer therapy;carcinogenesis;cis-female;cis-male;cisgender;emotional distress;epidemiology study;estrogen-related receptor;gender affirmation;gender affirming hormone therapy;gender dysphoria;health care disparity;hormone regulation;improved;insight;male;malignant breast neoplasm;mammary gland development;medically underserved;mortality;mouse model;novel;novel strategies;preclinical study;programs;prophylactic mastectomy;prospective;response;therapeutic miRNA;transfeminine;transgender;transmasculine;treatment guidelines;tumor Gender-Affirming Testosterone Therapy on Breast Cancer Risk and Treatment Outcomes Project NarrativeThere is a lack of knowledge about the effect of gender-affirming hormone therapy on cancerrisk and cancer treatment. We will utilize mouse models to understand the extent to whichtestosterone therapy affects breast cancer development (Aim 1) and breast cancer treatmentoutcome (Aim 2). Our proposal will gain new insights about breast cancer risk as well as developnew approaches to improve cancer outcome in both the underserved transmasculine communityand the cisgender population. NCI 10912193 9/18/23 0:00 PAR-21-322 1R56CA284564-01 1 R56 CA 284564 1 "BERA, TAPAN K" 9/18/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-BTC-C(02)M] 12553513 "HENG, YU JING JAN " "WULF, GERBURG M" 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 299940 NCI 173476 126464 This proposal will undertake preclinical studies to address breast cancer (BC) risk and treatment concerns oftransmasculine people (female-to-male transition). This proposal will also elucidate the interplay of miRNAsand testosterone in mammary gland development carcinogenesis and response to BC treatment. Mosttransmasculine individuals pursue testosterone therapy (TT) to treat their gender dysphoria. The breast is asex hormone-sensitive organ. Transmasculine individuals who receive TT are now a subject of concern verylittle is known about how such high levels of testosterone affect the breast and subsequently risk of developingBC. Prospective human studies will take decades. Mouse aging is accelerated by a factor of 70 compared tohumans and the hormone regulation of breast development is similar in mice and humans. Aim 1 will use twomouse models to clarify the extent to which TT affects the risk of developing estrogen receptor positive (ER+)and negative (ER-) BC. We will compare the incidences and tumor specific survival in female mice (intact) andoophorectomized female mice receiving TT with their respective counterparts that do not receive TT (Aim 1.1).On the other end of the spectrum for transmasculine patients diagnosed with BC there are neither clinicalguidelines nor risk-benefit studies on whether they can continue TT while being treated for BC. There is a gap inknowledge about whether testosterone affects the efficacy of BC treatment. The discontinuation of TT isundesirable as it affects these patients emotional wellbeing and body image and compounds their cancer-induced emotional distress. Aim 2 will address the clinical treatment issue of whether continuing testosteroneaffects BC treatment outcomes. Aim 2 will use the same two mouse models to investigate whether continuingtestosterone affects alpelisib (FDA approved therapy for ER+ tumors harboring a PIK3CA mutation) or olaparib(FDA approved therapy for ER- tumors harboring a BRCA1 mutation) treatment outcomes (Aim 2.1). We willleverage Aims 1.1 and 2.1 to conduct molecular investigations about the effect of TT on androgen receptor andER mediated transcriptional programsmRNA and miRNA expressionon regulating mammary glanddevelopment and carcinogenesis (Aim 1.2) and response to BC treatment (Aim 2.2). Transgender people arethe fastest growing group in the LGBTQ community. We need to start understanding their cancer risk and thelong-term health outcomes of TT. Our proposal will be the first to lead to fundamentally new insights tounderstand BC risk and develop clincial treatment guidelines to improve BC outcome in the medicallyunderserved transmasculine population. The increased understanding of the role of sex hormones in BC riskand treatment as well as the miRNA landscape in regulating androgen expression in BC are not onlyimportant to improve transmasculine health and reduce their healthcare disparities. These knowledge will havedirect implications for understanding BC risk and open up new avenues of treatment for cisgender men andwomen as well. 299940 +No NIH Category available Address;Affect;African American population;Age;American;Biochemical;Biology;Blood Circulation;Bone Marrow;Bone Marrow Aspiration;Bone Marrow Neoplasms;Breast;Cancer Detection;Cancerous;Cell Fraction;Cells;Chromosome abnormality;Colon;Complex;Cytosine;DNA;DNA Modification Process;Data Set;Development;Diagnosis;Disease;Disparity;Dissection;Endothelial Cells;Enhancers;Epigenetic Process;Ethnic Population;Etiology;European;Evaluation;Extramedullary;Genes;Genetic;Genetic Predisposition to Disease;Genomics;Genotype;Goals;Hematologic Neoplasms;Human;Incidence;Individual;Investigation;Knowledge;Lymphoma;Malignant Neoplasms;Malignant lymphoid neoplasm;Mendelian randomization;Modification;Molecular;Multiple Myeloma;Mutation;Obesity;Pathway interactions;Patients;Peripheral Blood Lymphocyte;Plasma;Plasma Cells;Play;Population;Primary Neoplasm;Proliferating;Prostate;Research;Resources;Risk;Risk Factors;Role;Sampling;Socioeconomic Factors;Solid Neoplasm;Source;Specimen;Standardization;Techniques;Technology;Tissues;Tumor-Derived;United States;Work;bone cell;cell free DNA;cell type;epidemiology study;epigenetic marker;epigenomics;ethnic difference;ethnic disparity;genome wide association study;genome-wide;genome-wide analysis;high risk;high risk population;improved;individualized prevention;innovation;neoplastic cell;non-genetic;novel;novel strategies;preventive intervention;prognostication;promoter;racial difference;racial disparity;racial population;recruit;seal;sex;trait;tumor initiation;tumor microenvironment;tumorigenesis Elucidating novel epigenetic modifications implicated in multiple myeloma risk disparities PROJECT NARRATIVECompared with European Americans (EA) African Americans (AA) have two-to-three times higher risk ofdeveloping multiple myeloma (MM) for reasons that remain unclear. This work seeks to elucidate the influenceof novel epigenetic modifications (i.e. 5-hydroxymethylation) in circulating cell-free DNA (cfDNA) as well astumor cells and cells from bone marrow microenvironment on the excess risk of MM in AA compared to EA.Successful completion of this study will not only significantly enhance our understanding of epigeneticmechanisms that underlie the racial/ethnic differences in MM risk but also provide novel approaches forindividualized prevention of this incurable disease. NCI 10912191 9/21/23 0:00 PA-20-185 1R56CA282891-01 1 R56 CA 282891 1 "CAGA-ANAN, EMILIE CHARLISSE F" 9/22/23 0:00 8/31/24 0:00 Cancer and Hematologic Disorders Study Section[CHD] 6131243 "CHIU, BRIAN C-H" "ZHANG, WEI " 1 PUBLIC HEALTH & PREV MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 299993 NCI 201317 98676 PROJECT SUMMARYMultiple myeloma (MM) the second most common hematologic malignancy in the United States is anincurable plasma cell malignancy with standardized incidence rates that are typically 2- to 3-times higheramong African Americans (AA) compared to European Americans (EA). Reasons for this apparent racial/ethnicdisparity remain largely unclear. Genetic susceptibility socioeconomic factors and obesity are important riskfactors for MM but they do not fully explain the excess risk of MM in AA. Epigenetic modifications particularlycytosine modifications play a critical role in the development and progression of MM. However unlike solidtumors (e.g. breast prostate colon etc.) where distinct epigenetic changes in racial/ethnic groups have beenshown to account for the differences in tumor initiation progression and aggressiveness the epigeneticcontributions to the excess risk of MM in AA are not well characterized. Differences in epigenetic modificationsare an intrinsic feature between human populations and associated with complex traits and diseases. Themajority of previous epigenetic studies have used technologies that cannot distinguish 5-hydroxymethylcytosines (5hmC) a biochemically stable epigenetic mark showed distinct genome-widedistributions and regulatory roles from the well-studied modified cytosines 5-methylcytosines (5mC). Inaddition epigenetic epidemiology studies have predominantly used DNA from peripheral blood lymphocytes assurrogate specimens because obtaining CD138+ tumor cells from the bone marrow aspirates in healthyindividuals is not feasible. Therefore we propose to elucidate the influence of novel DNA modificationsspecifically the 5hmC in circulating cell-free DNA (cfDNA) on racial/ethnic disparities in MM. Circulating cfDNAfragments are released into the bloodstream by circulating dead or proliferating cancerous cells. Thus cfDNAproduced by tumor cells hiding in the bone marrow bone marrow microenvironment or extramedullary diseasecan be detected in plasma. We have demonstrated the relevance of cfDNA-derived 5hmC in MM and otherhematological malignancies including that specific 5hmC modifications in cfDNA were associated with overallsurvival of MM; distinct 5hmC signatures reflected molecular differences between subtypes of lymphoma; andpopulation-specific pathways involving 5hmC were identified between MM and its precursors. Our centralhypotheses are that specific 5hmC signatures associated with MM in cfDNA reflect primary tumor cells andspecific 5hmC modifications contribute to the excess risk in AA. We will identify genome-wide 5hmC signaturesfor MM in cfDNA (Aim 1) and investigate MM-associated 5hmC in cfDNA-paired bone marrow tumor cells andmicroenvironment (Aim 2). We will elucidate population-specific 5hmC signatures and pathways between EAand AA patients with MM (Aim 3). This project is significant because it offers a timely and comprehensivestrategy to identify novel epigenetic contributors to MM and its disparities that will provide new targets forindividualized preventive interventions in high-risk populations for this incurable disease. 299993 +No NIH Category available Project1: The role of intravascular pressure and shear stress on tumor cell arrest survival and proliferation in the microvascular niche n/a NCI 10912091 8/30/23 10:17 PA-20-272 3U54CA261694-03S1 3 U54 CA 261694 3 S1 "NADEAU, CHRISTINE FRANCES" 9/17/21 0:00 8/31/26 0:00 ZCA1(M1) 6517 1961918 "KAMM, ROGER D" Not Applicable 7 Unavailable 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA Domestic Higher Education 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 177313 147813 29500 No abstract available +No NIH Category available Address;Advanced Glycosylation End Products;Basic Science;Biological Sciences;Biomedical Research;Cancer Center;Cancer health equity;Clinical Sciences;Clinical Trials;Community Outreach;Ensure;Faculty;Generations;Goals;Instruction;Leadership;Medical;Mentors;NCI Center for Cancer Research;Oncology;Population Sciences;Program Development;Research;Research Personnel;Research Project Grants;Resource Sharing;Science;Series;South Carolina;Stress;Training;Universities;Work;anticancer research;biobank;biomedical scientist;cancer health disparity;career;career development;community engagement;community planning;education research;faculty mentor;interest;meetings;next generation;outcome disparities;physical science;programs;research and development;skills;symposium;training opportunity;undergraduate student Research Education Core n/a NCI 10911647 9/13/23 0:00 PA-20-272 3U54CA210962-05S2 3 U54 CA 210962 5 S2 "AGUILA, HECTOR NELSON" 9/1/23 0:00 8/31/24 0:00 5888 78335812 "FINDLAY, VICTORIA " Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 49555 32818 16737 RESEARCH EDUCATION CORE SUMMARY The goal of the Research Education Core is to attract and catalyze a new generation of diverse research professionals and biomedical scientists who are committed to elucidating and addressing the cancer disparities outcomes faced by so many in South Carolina and the US. During the five-year U54 project period undergraduates at South Carolina State University (SCSU) and junior faculty at SCSU and the Medical University of South Carolina (MUSC-HCC) will be designated as South Carolina Cancer Disparities Research Center (SC CADRE) Scholars. Building from multiple ongoing efforts the leaders of the SC CADRE are proposing a dual-level integrated Research Education Core with an explicit focus on cancer health disparities. Expanded research education and training opportunities will be directed to both levels of Scholars. To realize the goal of the SC CADRE Research Education Core the SCSU and MUSC-HCC Core Co-Leads plan to establish a new undergraduate SC CADRE Honors Program in Applied Oncology Sciences Research within the Department of Biological and Physical Sciences at SCSU to increase the pipeline of highly skilled diverse undergraduates who pursue careers in biomedical research and cancer disparities. A new cancer research career development program at SCSU and MUSC-HCC will also be implemented for junior faculty who are interested in establishing independent careers in cancer disparities research. Within the Research Education Core the SC CADRE undergraduate and junior faculty Scholars will interact as they participate in coursework and/or career development programming weekly SC CADRE Research Club meetings monthly seminar series and an annual SC CADRE Cancer Health Equity Research Symposium. Through the Research Education Core SCSU will hire two new junior faculty Scholars and MUSC-HCC will hire one new junior faculty Scholar all of whom will be early-stage investigators (ESIs). Both levels of Scholars will actively engage in numerous SC CADRE enrichment activities and activities planned by the Community Outreach Core which will work directly with Research Education Core leadership to stress the importance of community engagement in developing conducting and disseminating cancer disparities research. +No NIH Category available Address;Cancer Intervention;Charge;Collaborations;Communication;Communities;Community Outreach;Development;Early Diagnosis;Early treatment;Faculty;Goals;Health;Health Personnel;Health system;Individual;Infrastructure;Institution;Leadership;Malignant Neoplasms;National Cancer Institute;Outcome;Patients;Qualifying;Recommendation;Research;Research Personnel;Scholars Program;Screening for cancer;South Carolina;Students;anticancer research;cancer health disparity;cancer prevention;community engagement;community partnership;ethnic diversity;evidence base;improved;innovation;member;outreach;racial diversity;recruit;tool Community Outreach Core n/a NCI 10911644 9/13/23 0:00 PA-20-272 3U54CA210962-05S2 3 U54 CA 210962 5 S2 "AGUILA, HECTOR NELSON" 9/1/23 0:00 8/31/24 0:00 5883 8815029 "MAGWOOD, GAYENELL SMITH" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 24666 16335 8331 COMMUNITY OUTREACH CORESUMMARYOne of the most important values within SC CADRE is to ensure that principles of community engagement areincorporated at every level within the Center. To realize this value the SC CADRE leadership has charged theCommunity Outreach Core a highly qualified team of community engagement experts to facilitate ongoing bi-directional communication between community members SC CADRE investigators and Scholars to addresscancer disparities in South Carolina (SC). This Core will build upon existing community partnerships andcollaborations to further develop and sustain a community outreach infrastructure to support and expand theoutreach activities associated with SC CADRE-generated research. Core leaders will also engage communityand academic (SCSU students staff and faculty) stakeholders in the development and deployment ofevidence-based approaches to communicate disseminate and promote implementation of National CancerInstitute (NCI) recommendations for cancer prevention early detection and treatment. The CommunityOutreach Core also aims to employ lay navigators to assist underserved patients in receiving timelyinterventions for cancer early detection and treatment as well as recruit and retain racially and ethnicallydiverse patients in cancer research. Additionally the Community Outreach Core will establish an innovativecancer-focused Community-Engaged Scholars Program to enable the capacity of community-academicpartnerships to conduct cancer disparities research. Community outreach as practiced in the SC CADRE willbe a collaborative effort among partner institutions communities and health systems to effectively reachindividuals and health care providers with information and tools to improve cancer health outcomes with thegoal of reducing cancer disparities in South Carolina and beyond. +No NIH Category available Academic Medical Centers;Address;African ancestry;Biological;Black Populations;Blood;Breast Cancer Patient;Cancer Center;Caring;Clinical;Clinical Research;Clinical Trials;Communities;Data;Development;Enrollment;Ethnic Origin;Faculty;Funding;Future;Goals;Health Services Research;Infrastructure;Leadership;Malignant Neoplasms;Malignant neoplasm of prostate;Medical center;Minority;Morbidity - disease rate;Outcome;Patients;Population Heterogeneity;Provider;Quality of life;Research;Research Personnel;Research Project Grants;Resource Sharing;South Carolina;Specimen;Survivors;Tissues;Universities;anticancer research;biobank;cancer care;cancer health disparity;care delivery;clinical center;clinical trial implementation;community setting;ethnic diversity;implementation facilitation;improved;mortality;outcome disparities;patient oriented;patient population;racial diversity;racial minority;research study;rural area Core: Biorepository and Clinical Trial Office Shared Resource n/a NCI 10911643 9/13/23 0:00 PA-20-272 3U54CA210962-05S2 3 U54 CA 210962 5 S2 "AGUILA, HECTOR NELSON" 9/1/23 0:00 8/31/24 0:00 5882 1865937 "CARROLL, STEVEN L." Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 22239 14728 7511 BIOREPOSITORY AND CLINICAL TRIALS OFFICE SHARED RESOURCESUMMARYThe establishment and implementation of the South Carolina Cancer Disparities Research Center (SCCADRE) Biorepository/Clinical Trials Office (CTO) Shared Resource is expected to significantly expand theresearch capacity of the SC CADRE investigators at South Carolina State University (SCSU) thus enhancingtheir ability to compete for independent R01-level funding. This new dual-component Shared Resource willalso augment SCSU's ability to attract additional junior faculty researchers who will have access tobiospecimens from racially and ethnically diverse patient populations as well as to clinical trials infrastructure atthe Regional Medical Center of Orangeburg Mabry Cancer Center (RMC-MCC). The overarching goal of theBiorepository/CTO Shared Resource is to support the development of cancer research at SCSU through botha Biorepository component and a CTO component. The Biorepository component will give SC CADREinvestigators access to the RMC-MCC's patient blood and tissue specimens that were previously unavailablefor research due to the lack of a biorepository infrastructure. Likewise the CTO component will facilitate theimplementation of clinical trials providing an infrastructure for SCSU investigators to conduct research in theirOrangeburg SC community as well as providing the Orangeburg community immediate access to other NCI-approved clinical trials which have not been available to date. This Shared Resource will support theimplementation of two initial SC CADRE clinical trials in Years 1-3 which will provide the biological andoutcomes data needed to evaluate the hypothesized relationships that are being assessed in each of the threeinitial SC CADRE Full and Pilot Research Projects. Additionally this Biorepository/CTO Shared Resource willsupport future SC CADRE Full and Pilot Research Projects as well as other NCI-approved clinical researchstudies at the RMC-MCC with the goal of enhancing participation of diverse populations in cancer clinicalresearch. +No NIH Category available Bioinformatics;Biometry;Biostatistics Shared Resource;Cancer Center;Educational Models;Faculty;Goals;Health Sciences;Infrastructure;Leadership;Medical;Methods;Mission;Public Health;Research;Research Personnel;Research Project Grants;Resource Sharing;South Carolina;Training and Education;Universities;anticancer research;cancer health disparity;computer science;cost effective;mathematical sciences;mid-career faculty;professor;undergraduate student Biostatistics and Quantitative Methods Shared Resource n/a NCI 10911641 9/13/23 0:00 PA-20-272 3U54CA210962-05S2 3 U54 CA 210962 5 S2 "AGUILA, HECTOR NELSON" 9/1/23 0:00 8/31/24 0:00 5880 78335806 "ALEKSEYENKO, ALEXANDER " Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 47822 31670 16152 BIOSTATISTICS AND QUANTITATIVE METHODS SHARED RESOURCE SUMMARY The primary goal of the South Carolina Cancer Disparities Research Center (SC CADRE) Biostatistics and Quantitative Methods Shared Resource is to expand the biostatistical and quantitative methods infrastructure at South Carolina State University (SCSU) to sustain a long-term commitment to cancer research. This new Shared Resource aims to provide outstanding biostatistics leadership and support in a cost-effective manner for the SC CADRE and has been developed jointly by SCSU and the Medical University of South Carolina Hollings Cancer Center (MUSC-HCC). The Biostatistics and Quantitative Methods Shared Resource will provide biostatistical and bioinformatics support for the initial SC CADRE research projects as well as for subsequent research initiatives led by SC CADRE investigators. This Shared Resource will also provide ongoing quantitative methods education and training for SC CADRE investigators undergraduates at SCSU and junior faculty at SCSU and MUSC-HCC. Additionally the Biostatistics and Quantitative Methods Shared Resource will expand the biostatistical research capacity at SCSU by hiring a full-time masters-level biostatistician. In summary this Shared Resource will act as a hub to facilitate the interaction among the SC CADRE investigators other shared resources and SC CADRE undergraduates and junior faculty Scholars. +No NIH Category available Advisory Committees;Budgets;Cancer Center;Cancer health equity;Charge;Communication;Communities;Community Outreach;Complement;Dedications;Education;Electronics;Ensure;Evaluation;Facebook;Faculty;Financial Support;Generations;Geography;Goals;Human Resources;Institution;Leadership;Logistics;Malignant Neoplasms;Medical;NCI-Designated Cancer Center;National Cancer Institute;Newsletter;Participant;Persons;Public Relations;Qualifying;Research;Research Personnel;Research Project Grants;Resources;Services;South Carolina;Structure;Teacher Professional Development;Teleconferences;Underrepresented Students;Universities;anticancer research;cancer health disparity;cancer initiation;career development;education research;health disparity populations;institutional capacity;inter-institutional;meetings;programs;recruit;sound;success;web page Administration Core n/a NCI 10911640 9/13/23 0:00 PA-20-272 3U54CA210962-05S2 3 U54 CA 210962 5 S2 "AGUILA, HECTOR NELSON" 9/1/23 0:00 8/31/24 0:00 5879 7354246 "FORD, MARVELLA ELIZABETH" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2023 159752 107477 52275 ADMINISTRATIVE COREThe South Carolina Cancer Disparities Research Center (SC CADRE) is a partnership between the SouthCarolina State University (SCSU an institution serving underserved health disparity populations andunderrepresented students (ISUPS)) and the Medical University of South Carolina Hollings Cancer Center(MUSC-HCC a National Cancer Institute-designated cancer center). The overarching goals of the SCCADRE are to increase SCSU's capacity to conduct transdisciplinary cancer research and to furtherstrengthen and extend a longitudinal research education pipeline that will catalyze a new diverse generation ofbiomedical researchers focused on cancer disparities. To ensure the success of the SC CADRE's goals andstrategies outlined throughout this application the Administrative Core is charged with the following aims:Aim 1. Provide inter-institutional as well as external scientific and community-based leadership in the guidanceand oversight of the activities of SC CADRE.Aim 2. Support the SC CADRE's efforts in cancer research research education community outreach and theCenter's planning and evaluation efforts by providing the essential day-to-day administrative and financialsupport coordination and logistical services needed to make this inter-institutional partnership functioneffectively.Aim 3. Facilitate the inter-institutional as well as external communications required to ensure the promotion ofSC CADRE activities +No NIH Category available Breast Cancer Cell;Breast Cancer cell line;CRISPR interference;CRISPR screen;Cancer Model;Cell Communication;Development;Drug Targeting;Drug resistance;Effectiveness;Estrogen receptor positive;Growth;Immune system;In Vitro;Macrophage;Magnetism;Malignant Neoplasms;Metastatic breast cancer;Neoplasm Metastasis;Phagocytosis;Phenotype;Property;Resistance;Resistance development;System;breast cancer progression;cancer cell;cancer therapy;genome-wide;hormone therapy;in vivo;neoplastic cell;parent grant;relapse risk;targeted treatment;three dimensional cell culture;tumor;tumor microenvironment Project 3: Systematic characterization of factors controlling breast cancer progression and resistance n/a NCI 10911510 8/22/23 0:00 PA-21-071 3U54CA261719-03S1 3 U54 CA 261719 3 S1 "NADEAU, CHRISTINE FRANCES" 9/14/21 0:00 8/31/26 0:00 ZCA1(M1) 6746 2186789 "BASSIK, MICHAEL C" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 66233 42897 23336 Summary of the Parent Grant Project 3: Systematic characterization of factors controlling breastcancer progression and resistanceTwo central challenges limit effectiveness of cancer therapies and enable metastasis: development of intrinsicresistance to targeted drugs and development of resistance to recognition and destruction of cancer cells bythe immune system. Traditional in vitro cancer models have been limited in scale and often lack key propertiesof the tumor microenvironment. We recently developed a scalable cancer spheroid system that enabled thefirst genome-wide CRISPR screens in 3D culture; phenotypes in this system much better reflect in vivo tumors(Han et al. 2020). In addition we developed a magnetic separation strategy to rapidly identify regulators ofphagocytosis by macrophages (Haney et al. 2018) and have successfully extended this strategy to studymacrophage-tumor cell interactions. Here we propose to use these systems to identify regulators ofresistance to targeted and endocrine therapies and macrophage killing in metastatic breast cancer.Aim 1: Identify critical drivers of growth and drug resistance in high relapse risk ER+ breast cancer celllines and PDOs using CRISPRi/a screenAim 2: Systematic identification and characterization of factors limiting macrophage phagocytosis of breastcancer cells +No NIH Category available Accounting;Address;Affect;Area;CD147 antigen;CRISPR/Cas technology;Cancer Patient;Carrier Proteins;Cell Communication;Cells;Cellular Metabolic Process;Clinical;Clinical Data;Clinical Research;Clinical Trials;Data;Data Set;Dependence;Disease Progression;Dissection;Genetic;Glucose;Goals;Growth;Heterogeneity;Histologic;Histopathology;Human;Image;Immune;Immune checkpoint inhibitor;Immunotherapy;Impairment;Infusion procedures;Intrinsic factor;Label;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methods;Modeling;Molecular;Molecular Profiling;Mus;Needle biopsy procedure;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nutrient;Oncogenic;Outcome;Patients;Pattern;Phenotype;Population;Positioning Attribute;Pre-Clinical Model;Predisposition;Progression-Free Survivals;Proteins;Recording of previous events;Reporting;Source;Squamous Cell Lung Carcinoma;Structure of parenchyma of lung;System;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Tissues;Translating;Work;anti-tumor immune response;biological heterogeneity;cancer cell;cell type;clinically relevant;cohort;design;exome sequencing;follow-up;human subject;immune checkpoint blockade;in vivo;inhibitor;innovation;interest;metabolic phenotype;metabolomics;mouse model;multidisciplinary;multiparametric imaging;new therapeutic target;novel;patient derived xenograft model;pharmacologic;pre-clinical;predict clinical outcome;predictive marker;somatic cell gene editing;therapeutic target;transcriptome sequencing;treatment response;tumor;tumor growth;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumor progression;tumor xenograft;tumor-immune system interactions;uptake Project 1: Targeting Metabolic Vulnerabilities in Lung Cancer Project 1 Project NarrativeThe goal of SPORE Project #1 Targeting Metabolic Vulnerabilities in Lung Cancer is to identify previouslyunknown acquired vulnerabilities related to tumor cell metabolism in lung cancer and in preclinical models testthe effect of targeting these vulnerabilities alone and with clinically available therapies. This proposal will identifyspecific metabolic activities that predict disease progression in humans and will thoroughly study the effect oftherapeutically inhibiting one such activity lactate transport on tumor growth and metastasis in preclinicalmodels in mice. In addition this project will provide some of the first data on how lung cancer metabolism affectsits tumor microenvironment (and vice versa) particularly related to anti-tumor immune responses which will beof value to all of the other SPORE Projects. NCI 10911395 8/29/23 14:59 PAR-18-313 3P50CA070907-24S1 3 P50 CA 70907 24 S1 "UJHAZY, PETER" 9/5/97 0:00 8/31/25 0:00 ZCA1-RPRB-J 5952 1900629 "DEBERARDINIS, RALPH J" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 118034 71972 46062 Project 1 Project Summary/AbstractHuman lung tumors are metabolically distinct from adjacent lung tissue. It is unknown whether thesereprogrammed activities predict clinical outcomes or represent meaningful therapeutic liabilities. The majorbottleneck in understanding the clinical relevance of cancer metabolism has been a lack of data about humantumor metabolism in vivo. For the first time we have overcome this limitation and used intra-operative infusionswith 13C-glucose to define metabolic phenotypes in human non-small cell lung cancer (NSCLC). We reportedthat one NSCLC subset displays prominent import of lactate while another subset produces lactate fromglucose. Our observation that lactate uptake via monocarboxylate transport protein-1 (MCT1) correlates withrapid disease progression in lung adenocarcinoma is the first and to date only metabolic flux phenotypedemonstrated to predict clinical outcomes in any human cancer. In this Project we will expand the scope ofmetabolic analysis in human NSCLC performing 13C infusions in more than 100 patients assessing hundredsof metabolites in each tumor and following clinical histories to identify new activities correlating with outcomes.In Specific Aim 1 tumors infused with 13C will be analyzed by imaging quantitative histopathology RNAsequencing and whole exome sequencing to understand relationships between these features and cancermetabolism. We will focus on identifying metabolic features that correlate with reduced progression-free survivalunder the rationale that such activities are attractive therapeutic targets to test in preclinical models. We willestablish patient-derived xenografts (PDXs) from these tumors to test the importance of predictive metabolicactivities for tumor growth and metastasis. While our open-ended metabolomics approach is designed to uncovernovel therapeutic targets based on our earlier work we will specifically test whether inhibiting MCT1 reducestumor growth and metastasis in mice. In Specific Aim 2 we will follow up on our observation that lung squamouscell carcinomas require lactate export for maximal growth. We will test whether genetic or pharmacologicalinhibition of novel molecular components of MCT4-mediated lactate export suppresses tumor growth in mousemodels and PDXs. Specific Aim 3 will examine metabolic crosstalk among cancer cells and several importantimmune cell populations in the tumor microenvironment in mice and humans. We will test the hypothesis thatlactate metabolism impacts these metabolic exchanges and that blocking lactate transport enhances the efficacyof immune checkpoint blockade therapy. Overall these efforts will produce the most detailed and clinically-relevant view of NSCLC metabolism to date. The ability to combine our ongoing study assessing metabolic fluxin human NSCLC with large legacy clinical datasets ideally positions us to understand the relationship betweentumor metabolism and cancer progression and to advance high-priority therapeutic targets into clinical trials.The immediate Human Endpoint of this project is the direct detailed examination of tumor metabolism andtumor microenvironment patients with lung cancer following 13C-glucose infusions while later Human Endpointswill involve therapeutic interventions targeting MCT1 and MCT4. +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Advanced Malignant Neoplasm;Apoptosis;Award;Binding;Biological;Biological Assay;Biology;Breast;CRISPR screen;Cancer Model;Cause of Death;Cell Cycle;Cell Cycle Regulation;Cell Death Induction;Cell surface;Cells;Cessation of life;Cities;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Collaborations;Colon;Colon Carcinoma;Combined Modality Therapy;Complex;Computer Models;Cutaneous T-cell lymphoma;Data;Docking;Drug Targeting;Energy Transfer;Essential Genes;FDA approved;Fellowship;Genes;Goals;Impairment;In Vitro;Integrin alphaV;Integrin beta Chains;Integrins;Invaded;Knock-out;Laboratories;Liquid substance;MAPK10 gene;Machine Learning;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Measurable;Methods;Mitogen-Activated Protein Kinases;Modeling;Monitor;Mutate;Mutation;Oncogenic;Pancreas;Patients;Pharmaceutical Preparations;Phase;Phosphotransferases;Play;Postdoctoral Fellow;Proteomics;Research;Research Project Grants;Role;Scanning;Scientist;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Structure;System;Techniques;Technology;Therapeutic;Time;Training;Translational Research;United States;Validation;Western Blotting;Work;beta catenin;biomarker discovery;cancer cell;cancer survival;cell killing;comparison control;density;design;effective therapy;high throughput screening;improved;in silico;inhibitor;lead candidate;malignant breast neoplasm;mathematical model;migration;nemo-like kinase;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;pre-doctoral;predictive modeling;prevent;skills;small molecule;statistics;triple-negative invasive breast carcinoma;tumor Targeting a Novel Pocket on ITGAV Project NarrativeThe proposed research aims to fill an unmet clinical need in treating aggressive cancers such as colonpancreatic and breast. We found that Integrin Alpha V (ITGAV) is necessary for the survival of these cancersand that a novel pocket on its structure can be targeted with a drug. Additionally we will investigate the complexsignaling controlled by ITGAV to propose combinational therapies and create new therapeutic strategies to treatthese cancers. NCI 10911393 9/18/23 0:00 RFA-CA-21-059 4K00CA274649-03 4 K00 CA 274649 3 "ELJANNE, MARIAM" 9/29/23 0:00 8/31/27 0:00 ZCA1-PCRB-H(M1) 16553342 "MATTSON, NICOLE " Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/29/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 83462 NCI 77280 6182 Project Summary. Cancer deaths remain at an all-time high in the United States leaving an urgent clinical needto develop novel therapeutic strategies to help patients. The lack of effective treatments is in part due tounderlying complexities in cancer that current scientific approaches are just beginning to uncover. Technologicaladvances are rapidly changing the landscape of scientific discovery; for example the combination ofmathematical modeling in tandem with laboratory based validation leading to better combinational therapies totreat cancer. For this reason I propose training in both with the F99/K00 Predoctoral to Postdoctoral FellowTransition Award. For the F99 phase the dissertation research I will focus on laboratory based research skillsto identify and propose a novel therapeutic to treat cancers. In a high level CRISPR screen targeting about 580genes on the cell surface we found that Integrin Alpha V (ITGAV) is essential for the survival of solid tumors(colon pancreatic and breast cancer). To validate ITGAV as the most essential integrin we designed a secondlayer screen targeting all 26 integrins and found that ITGAV and Integrin Beta 5 (ITGB5) are the only essentialintegrins in solid tumors. Interestingly integrins must for an obligate heterodimer between an alpha and a betasubunit of which ITGAV and ITGB5 are one of the known 24. As the more essential pair ITGAV was probed witha high-density CRISPR tiling scan and we found a small pocket to be essential for ITGAV function and it wasamendable to small molecule binding. A structure based analysis found a loop structure of the beta pair of ITGAVinteracts with the discovered pocket leading to our hypothesis that the pocket is essential for the heterodimerstability between ITGAV and its beta pair. Indeed from a high-throughput screen of 500 small molecules wefound one compound that appears to bind in our pocket and disrupt the heterodimer between ITGAV and ITGB5.Further validation of this potential will be the remaining work to be done for the dissertation research and uponcompletion will fill an unmet clinical need since no there no FDA approved drugs targeting integrins approvedfor cancer indications. To further advance the potential to treat cancer I plan to use mathematical modelingapproaches to identify novel therapeutic strategies by understanding the complexities of cancer signaling duringthe K00 phase the proposed postdoctoral work. To study complex cancer signaling in collaboration with Dr.Pirrotte we generated kinase activity scores in cells where ITGAV was knocked out. With this data we can modelthe effects of signaling as it relates to measurable changes in the cancer cells. Specifically we will study cellcycle control which is inhibited with ITGAV loss. Additionally we can model known inhibitors to commonsignaling cascades as novel combinational therapeutic strategies. To confirm our model I will use laboratorybased skill developed during the F99 phase. Overall with the training with the F99/K00 award I will gain skills tobe able to build mathematical models to study cancer and validate those models with laboratory based skills.This will allow me to become and independent research and leading scientist in translational research. 83462 +No NIH Category available Acceleration;Aging;Biological Markers;Blood;Blood Pressure;Cancer Survivor;Cardiotoxicity;Cardiovascular Diseases;Collection;Control Groups;Data;Data Collection;Development;Diet;Funding;Future;Genomics;Goals;Inflammation;Inflammatory;Insulin Resistance;Intervention;Life Style;Lipids;Long-Term Survivors;Measurement;Methods;Nature;Parents;Participant;Phenotype;Physical Function;Physical activity;Physical assessment;Randomized Controlled Trials;Recording of previous events;Risk;Sampling;Testing;Time;Weight;actigraphy;active lifestyle;adipokines;arm;cancer therapy;cardiovascular risk factor;childhood cancer survivor;design;frailty;functional outcomes;improved;insight;mHealth;premature;primary outcome;randomized trial;response;secondary outcome;sedentary;trial design SALSA - Study of Active Lifestyle Activation PROJECT NARRATIVEThe proposed supplement to R01 CA263144 seeks to enhance data collection on the parent SALSArandomized trial by enabling the collection of detailed physical function assessments and genomic samplesand the processing of additional inflammatory biomarkers. These data can provide insight into the phenomenaof accelerated aging and early frailty that has been increasingly recognized in long-term cancer survivors. Thiswill then facilitate the development of future interventions that seek to improve physical function directly as astrategy to forestall frailty and potentially alter the aging trajectory in cancer survivors. NCI 10910785 9/12/23 0:00 PA-20-272 3R01CA263144-04S1 3 R01 CA 263144 4 S1 "AGURS-COLLINS, TANYA" 9/21/21 0:00 8/31/26 0:00 ZCA1(M1) 8441297 "CHOW, ERIC JESSEN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 199496 NCI 113350 86146 PROJECT SUMMARYThe proposed supplemental funding request is in response to PA 20-272 and to support R01 CA263144(SALSA: Study of Active LifeStyle Activation; NCT05075759; funding period 2021-2026). SALSA is a remotelyconducted 12-month randomized controlled trial testing a multi-faceted approach at improving physical activityand diet quality in long-term survivors of childhood cancer at an increased risk of early cardiovascular (CV)disease. The primary outcomes of the trial are reductions in sedentary time and improvements in diet qualityafter 12 months. Secondary outcomes include other CV risk factors such as changes in blood pressure andweight and the measurement of various blood biomarkers known to be associated with CV disease (e.g. lipidprofile insulin resistance general inflammation and adipokines). Collectively many of these CV risk factorsmay contribute to the phenotype of accelerated aging and premature frailty which is now increasinglyrecognized among cancer survivors including survivors of childhood cancer. The proposed supplement seeksto enhance our understanding of the accelerated aging phenotype in survivors of childhood cancer.Specifically we propose to approach SALSA participants who have completed the 12-month intervention with:1) more in-depth phenotyping of physical function (via remote methods) beyond the actigraphy data collectedby the parent trial and 2) collect additional biomarkers known to be associated with accelerated aging incancer survivors. Leveraging SALSAs randomized trial design we will also explore differences by study arms(i.e. control group; clinician-led goal-setting; mHealth-based goal setting) and among those participants(irrespective of study arm) who have better lifestyle profiles while adjusting for history of cardiotoxic cancertreatment exposures. While the limited nature of this supplement may preclude our ability to identify statisticallysignificant differences between groups it will provide important preliminary data demonstrating feasibility ofassessing physical function using remote methods and data on potentially detectable differences that mayinform the design of future interventions that seek to target specific functional outcomes and other biomarkersof frailty and accelerated aging. 199496 +No NIH Category available Acceleration;Address;Adherence;Administrative Supplement;Affect;Aftercare;Age;Aging;Air;Area;Biological Markers;Black race;Blood;CDKN2A gene;Cancer Center;Cancer Survivor;Cancer Survivorship;Caring;Cell Aging;Cell Cycle;Cells;Chemotherapy-Oncologic Procedure;Childhood;Childhood Cancer Survivor Study;Childhood Leukemia;Chronic;Clinic;Clinic Visits;Clinical;Clinical Trials;Cognitive;Cohort Studies;Collaborations;Communities;Data;Disparity;Drug Targeting;Early Diagnosis;Early identification;Elderly;Energy Metabolism;Ensure;Ethnic Origin;Evaluation;Exercise;Exposure to;Financial Hardship;Food;Fracture;Funding;Future;Goals;Grant;Health;Healthcare;Household;Housing;Impaired cognition;Income;Individual;Information Systems;Insurance Coverage;Intervention;Latinx;Lead;Long-Term Survivors;Malignant Childhood Neoplasm;Measurement;Measures;Morbidity - disease rate;Neighborhoods;Not Hispanic or Latino;Patient Outcomes Assessments;Patient Participation;Patients;Pediatric Oncology Group;Peripheral Nervous System Diseases;Persons;Phenotype;Physical Function;Physical activity;Physicians;Prevalence;Publications;Quality of life;Race;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research;Research Personnel;Risk;Rural;Saint Jude Children's Research Hospital;Sampling;Second Primary Neoplasms;Seminal;Service delivery model;Siblings;Site;Skeletal Muscle;Structure;Survivors;T-Lymphocyte;Work;childhood cancer survivor;clinical examination;cognitive function;cohort;deprivation;ethnic diversity;exhaustion;experience;frailty;health care availability;health care delivery;improved;indexing;innovation;instrument;kinase inhibitor;muscle form;neighborhood safety;older patient;premature;racial diversity;research clinical testing;social health determinants;social vulnerability;socioeconomic disadvantage;survivorship;tobacco exposure;treatment duration;walkability BRidging Information Divides and Gaps to Ensure Survivorship: the BRIDGES Randomized Controlled Trial of a Multilevel Intervention to Improve Adherence to Childhood Cancer Survivorship Many young childhood cancer survivors experience accelerated aging manifesting as health problemsdeclines in physical and cognitive function and damage to their cells typical of people many decades older.Among half of the patients participating in our ongoing BRIDGES clinical trial that is investigating how to bestdeliver health care to a diverse sample childhood cancer survivors who are just 2-4 years post-therapy wepropose to do clinical and blood measures indicative of accelerated aging to see if it is 1) detected early in thesurvivorship and 2) whether it is associated with individual and neighborhood social vulnerabilities. Data fromour study will inform future interventions to try to slow aging in childhood cancer survivors. NCI 10910674 9/12/23 0:00 PA-20-272 3R01CA261881-03S1 3 R01 CA 261881 3 S1 "MOLLICA, MICHELLE A" 9/21/21 0:00 8/31/26 0:00 ZCA1(M1) 7753669 "KADAN-LOTTICK, NINA S" Not Applicable 98 NONE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC ORGANIZED RESEARCH UNITS 200570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 200000 NCI 128205 71795 Approximately 30-40% of long-term childhood cancer survivors (CCS) experience accelerated aging: thepremature onset of cellular senescence and aging-related morbidities manifesting with physical and cognitivefrailty and pre-frailty. Accelerated aging is associated with more frequent and severe chronic health complicationsthat impact health care delivery needs. Critical research gaps in accelerating aging remain as past studies weredone predominantly in non-Hispanic white survivors a median of 2-3 decades post-therapy with assessmentof frailty in the research setting. The BRIDGES Study (R01CA261881) is our ongoing multi-site NCI-fundedrandomized control trial that investigates a shared health care delivery model with community primary physicianscompared to cancer center survivorship clinic care to provide recommended surveillance for chronic conditionsamong CCS. Our R01s overarching goal is to better meet the health care delivery needs of CCS with anintervention that can potentially overcome disparities. Unique strengths of this trial include high proportions oftypically understudied survivors (Latinx Black rural socioeconomically disadvantaged) targeting of earlysurvivors who are only 2-4 years off-therapy and baseline assessment of individual and area-level socialdeterminants of health. With administrative supplemental funding (PA-20-272) and within the scope of our R01we seek to address many of the gaps in accelerated aging research. Within the structure of the ongoingBRIDGES study and building on previous work within the investigator team we propose to measure physicalfrailty with the modified Fried Phenotype cognitive impairment with the PROMIS Pediatric Cognitive FunctionShort Form instrument and cellular senescence with p16INK4a expression among the 66 CCS who will berandomized to cancer center survivorship clinic over the next 12 months. Feasibility is supported by theintegration of measures into the overall survivorship clinic visit and previous research on accelerated aging byour research team. Race ethnicity and individual- and area-level social determinants of health are alreadyavailable from the baseline pre-randomization evaluation. Our Specific Aims are in a racially and ethnicallydiverse sample of CCS to 1) Determine the prevalence of accelerated aging early in the post-treatment periodas measured by physical frailty cognitive frailty and cellular senescence 2-4 years post-therapy and 2) Measureassociations between disparities in individual (e.g. insurance status household income food and housinginsecurity) and area-level (e.g. neighborhood safety access to health care days access to exercise) disparitiesand accelerated aging. Transformative Impact: If a diverse sample of childhood cancer survivors affected byaccelerating aging can be identified early in the post-therapy period and with routine assessments done byclinical staff our data would support future interventions that could improve survivors aging trajectory. 200000 +No NIH Category available Admin-Core-002 n/a NCI 10910616 9/21/23 0:00 RFA-CA-21-054 7U54CA274375-02 7 U54 CA 274375 2 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 5282 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 4/20/23 0:00 8/31/23 0:00 Research Centers 2023 310117 192023 118094 No abstract available +No NIH Category available Clinical specimen tumor-TME acquired resistance n/a NCI 10910588 9/21/23 0:00 PA-20-272 3U54CA224081-06S1 3 U54 CA 224081 6 S1 "KONDAPAKA, SUDHIR B" 9/30/17 0:00 8/31/27 0:00 ZCA1(M1) 8917 9547125 "BIVONA, TREVER G" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 80750 50000 30750 No abstract available +No NIH Category available Affect;Attenuated;B-Lymphocytes;BCL2L11 gene;Bioinformatics;Burkitt Lymphoma;CDK4 gene;Cell Proliferation;Collaborations;Complex;Development;EZH2 gene;Epigenetic Process;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Generations;Genes;Genome;Growth;Helper-Inducer T-Lymphocyte;Hodgkin Disease;Human;Human Genetics;Human Herpesvirus 4;Immune response;Immunohistochemistry;Impairment;In Vitro;LMP1;Latent virus infection phase;Lymphocyte;Lymphoma;Lymphomagenesis;Lytic;Mediating;Methylation;MicroRNAs;Modeling;Molecular Biology;Molecular Genetics;Mutation;Oncogenes;Oncogenic Viruses;Pathway interactions;Pharmaceutical Preparations;Phenotype;Play;Proteins;RNA;Role;Supporting Cell;T-Lymphocyte;TNFSF5 gene;Therapeutic;Tumor Suppressor Proteins;Umbilical Cord Blood;Viral;Viral Antigens;Viral Pathogenesis;Virus;Virus Latency;Xenograft Model;humanized mouse;immunogenicity;in vivo;inhibitor;insight;large cell Diffuse non-Hodgkin's lymphoma;lymphoblastoid cell line;mouse model;mutant;novel therapeutic intervention;novel therapeutics;promoter;transcription factor;transforming virus;tumor;tumorigenesis Project 5 - EBV Drivers of Oncogenesis and Novel Therapies PROJECT 5 PROJECT NARRATIVEEpstein-Barr virus (EBV) transforms B cells in vitro but many EBV-infected human tumors including Burkittlymphomas (BLs) contain stringent viral latency types that are not transforming in vitro. In this project wewill use two different humanized mouse models to examine the roles of two different EBV genes/RNAsexpressed in human BLs (the virally encoded BARTs microRNAs and the viral EBNA3A gene) in vivo. Inaddition using these models we will ask if drugs that block EBNA3A function inhibit the growth of EBV-inducedlymphomas. NCI 10910339 9/13/23 0:00 PA-20-272 3P01CA022443-45S1 3 P01 CA 22443 45 S1 "DASCHNER, PHILLIP J" 9/1/23 0:00 1/31/24 0:00 8187 1860327 "KENNEY, SHANNON CELESTE" Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 Non-SBIR/STTR 2023 72407 46564 25843 PROJECT 5 PROJECT SUMMARY/ABSTRACTEpstein-Barr virus (EBV) latent infection of B lymphocytes in vitro results in their growth transformation;however in vivo the growth of EBV-infected lymphocytes is normally constrained by robust immuneresponses against viral antigens. As a result EBV genes essential for growth in vitro (such as LMP1 andEBNA2) are often not expressed in EBV-positive lymphomas such as Burkitt lymphoma (BL) HodgkinDisease and diffuse large B cell lymphomas. Thus in vitro transformation studies cannot adequately modelhow EBV infection promotes common types of EBV-positive human lymphomas that have more stringentforms of viral latency. The EBV BARTs microRNAs and EBNA3A are amongst the very few EBV-encodedgenes/microRNAs expressed in human BLs and are likely to play important driver roles in this type oflymphoma. We have shown that BARTs play an important role in maintaining the viability of EBV-positiveBLs in vitro and in decreasing the immunogenicity of EBV-transformed lymphoblastoid cell lines. The latentEBNA3A protein encodes a transcription factor that is essential for in vitro growth of EBV-transformed B cellsand is thought to collaborate with the closely related EBNA3C protein to inhibit expression of important tumorsuppressors (including p16 p15 and BIM) by inducing EZH2-mediated H3K27 trimethylation of theirpromoters. However the roles of BARTs and EBNA3A in promoting EBV-induced lymphomas in vivo havenot been well studied particularly in the context of lymphomas with more stringent latency. EBV-infectedhumanized mice provide sophisticated models for understanding the complex interactions between EBV Tcells cellular pathway alterations and the microenvironment. We have recently developed a new cord blood-humanized mouse model that allows EBV mutants that are non-transforming in vitro (including EBNA2-deleted EBV) to form lymphomas with stringent viral latency in vivo. We propose to use two differenthumanized mouse models to examine the roles of BARTs and EBNA3A for EBV-induced lymphomas in vivoand to determine if drugs which block essential EBNA3A functions inhibit lymphoma development. In Aim 1we will examine how loss of BARTs affects viral pathogenesis in the context of type III versus Wp-restrictedviral latency and examine potential mechanisms by which BARTs expression is upregulated in vivo. In Aim2 we will use the cord blood-humanized mouse model to explore the role of the EBNA3A protein in vivo. InAim 3 we will explore the therapeutic potential of drugs (CK4/6 and EZH2 inhibitors) that block essentialEBNA3A/3C-regulated pathways. This project interacts extensively with Projects 3 and 4 and uses the coresfor immunohistochemistry bioinformatics and generation of EBV mutant genomes. The results of thesestudies should provide key insights into the mechanism(s) by which stringent EBV infection causeslymphomas in vivo and may identify new therapeutic approaches for treating EBV-induced lymphomas. +No NIH Category available Anogenital cancer;Biology;Cells;Cervical;Chemicals;Collaborations;Cutaneous;Data;Development;Disease;Disease model;Environment;Epithelium;Estrogens;Etiology;Event;Fanconi's Anemia;Funding;Genes;Genetic Diseases;Head and Neck Cancer;Herpesviridae;Human;Human Genetics;Human Papillomavirus;Human papilloma virus infection;Immune;Immune system;Immunosuppression;Infection;Integration Host Factors;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Molecular;Molecular Biology;Molecular Genetics;Mucous Membrane;Mus;Mutation;Oncogenic Viruses;Oral;Organ Transplantation;Papilloma;Papillomavirus;Pathologic;Patients;Role;Skin;Skin Cancer;Stromal Neoplasm;Study models;Testing;The Cancer Genome Atlas;Transplant Recipients;Viral;cervical carcinogenesis;epithelial stem cell;high risk;human papilloma virus oncogene;insight;keratinocyte;mouse model;neoplastic;novel strategies;prevent;skin disorder;tumor microenvironment;tumorigenesis Project 1 - Molecular Genetics of Human Papillomavirus Infection and Oncogenesis PROJECT 1 NARRATIVEPapillomaviruses cause 5% of human cancers. In this project we will investigate the interplay between viraland host factors in the development of these cancers in order to develop new approaches to prevent and treatpapillomavirus-induced disease. NCI 10910335 9/13/23 0:00 PA-20-272 3P01CA022443-45S1 3 P01 CA 22443 45 S1 "DASCHNER, PHILLIP J" 9/1/23 0:00 1/31/24 0:00 8183 1942923 "LAMBERT, PAUL F." Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 Non-SBIR/STTR 2023 154456 99329 55127 PROJECT 1 SUMMARY/ABSTRACTA subset of human papillomaviruses (HPVs) cause 5% of human cancers including the majority of cervicalcancers. Over the current funding period we discovered that interactions between the cervical epithelium andits stromal tumor environment are key to cervical carcinogenesis. We will test specific hypotheses for how thetumor microenvironment contributes to cervical carcinogenesis. We will also evaluate the role of mutations incellular genes in cervical carcinogenesis based upon insights gained from The Cancer Genome Atlas initiativeand identify mutations in cancer related genes that cause cervical cancers arising in FA patients to becomeHPV-independent. In the second aim we will continue utilizing the recently discovered mouse papillomavirusMmuPV1 to investigate the role of high risk cutaneous HPVs in neoplastic skin disease as seen in patientswith epidermodysplasia verrucoformis using powerful new mouse models for that disease developed in ourlabs. We will also study the importance of immunosuppression and epithelial progenitor cells in papillomavirusinduced skin disease. +No NIH Category available Acute;Affinity;Antigen Targeting;Automobile Driving;Beds;Binding;Biological;Biological Assay;Biological Markers;Bombesin Receptor;Cancer Detection;Cancer Etiology;Cancer Patient;Cancerous;Cell Line;Cessation of life;Chemicals;Chemistry;Clinical;Clinical Trials;Clinical Trials Design;Cues;Data;Detection;Development;Diameter;Disease;Distant Metastasis;Dose;Drug Kinetics;Dyes;Encapsulated;Ethics;Evaluation;Excision;FOLH1 gene;Failure;Feedback;Fluorescence;GRP gene;Generations;Goals;Histology;Human;Hybrids;Image-Guided Surgery;Imaging Techniques;Imaging technology;In Vitro;Individual;Integrins;Kinetics;LAPC4;LNCaP;Lead;Ligands;Localized Disease;Lymph Node Mapping;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Metastatic Melanoma;Metastatic Neoplasm to Lymph Nodes;Microscopic;Modality;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Neoplasm Metastasis;Nodal;Oncogenic;Operative Surgical Procedures;Optics;Organoids;Outcome;Patient-Focused Outcomes;Patients;Peptides;Phase;Phenotype;Positron-Emission Tomography;Pre-Clinical Model;Process;Property;Prostate;Radiolabeled;Radiometry;Recurrent tumor;Resected;Residual Neoplasm;Resolution;Rodent Model;Safety;Screening for Prostate Cancer;Silicon Dioxide;Specificity;Staging;Surface;Surgeon;Surgical Management;Surgical margins;Systemic Therapy;Tactile;Techniques;Therapeutic;Time;Tissues;Toxicology;Tracer;Translational trial;Translations;Tumor Burden;VCaP;Variant;Visual;Visualization;Visualization software;Work;Xenograft Model;cancer biomarkers;cancer heterogeneity;clinical candidate;clinical translation;cyanine dye 5;cytotoxicity;design;detection limit;detection sensitivity;disease heterogeneity;dosimetry;draining lymph node;early phase clinical trial;first-in-human;fluorescence imaging;high risk;human subject;image guided;imaging capabilities;imaging probe;imaging study;improved;in vivo;inhibitor;lead candidate;lymph nodes;melanoma;men;molecular imaging;molecular phenotype;nanoparticle;near infrared dye;next generation;optical imaging;overexpression;particle;patient stratification;pre-clinical;prostate cancer cell line;prostate cancer model;prostate cancer risk;prototype;safety study;safety testing;screening;targeted treatment;tool;tumor;uptake Molecular Phenotyping and Image-Guidance for Surgical Treatment of High-Risk Prostate Cancer Using Ultrasmall Silica Nanoparticles Project Narrative:Although surgery remains the cornerstone of treatment for patients with localized high-riskprostate cancer current intraoperative management is limited by a lack of specific image-guidedvisualization tools to accurately define tumor margins map lymph node metastases andinvestigate cancer heterogeneity which in turn can adversely impact patient outcomes. Wepropose to develop clinically-translatable ultrasmall particle imaging technologies that not onlyvisualize the extent of local disease but molecularly characterize tumor in vivo by targetingmultiple molecular signatures each driving a different oncogenic process. Such a precision-basedapproach may better identify patients that are potentially curable by surgical resection improvesurgical curability and better tailor targeted treatment management. NCI 10908927 11/30/23 0:00 PA-21-268 7R01CA243085-05 7 R01 CA 243085 5 "DARDZINSKI, BERNARD JOSEPH" 12/1/23 0:00 11/30/25 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 9369123 "BRADBURY, MICHELLE S" Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 431104 NCI 327588 103516 Project Summary: High-risk prostate cancer (PC) is the second most common cause of cancer-related deathin men. Improvements in overall survival and long-term morbidity will depend on the ability of the operatingsurgeon to completely resect regional metastatic lymph nodes (LNs) and obtain negative surgical margins; failureto do so increases the likelihood of local tumor recurrence and added tumor burden. Unfortunately surgicalresection techniques have principally relied upon visual cues and tactile information. While significant advanceshave been made in real-time intraoperative fluorescence imaging techniques there are no targetedintraoperative imaging probes that can specifically detect local disease or identify one or more molecularsignatures defining the cancer itself. This highlights the importance of developing new and clinically translatablehigh-resolution intraoperative visualization tools that can specifically localize nodal metastases and residualdisease along margins while permitting accurate molecular characterization or phenotyping of tumor. One suchnext-generation imaging technology is an ultrabright sub-8-nm diameter fluorescent core-shell silicananoparticle Cornell prime dots (C dots) that can be surface-modified with PC-targeting peptides for accuratelyidentifying one or more metastatic markers including PSMA. Since not all high-risk PCs express PSMA it isimportant to assay other targets such as GRPr as part of a complementary multiplexing strategy. Therefore along-term goal of this proposal is to create PC-targeting fluorescence-based multiplexing tools (Cornell primedots C dots) for improving the intraoperative detection of cancer targets in high-risk PC patients. Such aprecision-based approach can be used to stratify high-risk PC patients potentially curable by surgical resectionfrom those requiring systemic therapy. This strategy also builds upon our prior successful translational andclinical trial efforts. As an extension of our previous R01 application we completed a Phase 1 first-in-humanPET imaging trial in metastatic melanoma patients using a first-generation FDA IND-approved integrin-targetingparticle tracer with favorable target-or-clear capabilities. Our active intraoperative clinical trials have exploitedthis highly-fluorescent particle technology for image-guided treatment of nodal metastases in melanoma patients.In this application we will target two well-characterized PC markers PSMA and GRPr using Cy5.5-containingPSMA- and cw800-containing GRPr-targeting C dots according to the following aims: (1) determine tunablesurface chemistries for near-infrared dye (NIR)-encapsulated PSMA- and GRPr-targeted C' dots to optimize invitro biological properties; (2) assess tumor-selective uptake and pharmacokinetic profiles of optimized hybrid Cdots in PSMA- and GRPr-expressing models; (3) develop spectrally-distinct NIR dye-containing C dots fromlead candidates to permit accurate and sensitive concurrent detection of multiple markers expressed on nodaland distant metastases; and (4) identify a lead PSMA-targeting C dot candidate for IND-enabling studies andan early-phase clinical trial to assess feasibility particle safety dosimetry and cancer-detection capabilities. 431104 +No NIH Category available Abstinence;Adherence;Adoption;Adult;Behavior Therapy;Behavioral;Biochemical;Caring;Cellular Phone;Cigarette;Clinical;Clinical Treatment;Collaborations;Communicable Diseases;Cost Effectiveness Analysis;Cost Measures;Data;Effectiveness;Epidemic;HIV;Health Services;Home;Income;India;Individual;International;Intervention;Measures;Medical center;Modeling;Outcome;Patients;Penetration;Persons;Pharmaceutical Preparations;Pharmacotherapy;Population;Positioning Attribute;Proctor framework;Provider;Randomized;Reporting;Research;Research Personnel;Resources;Safety;Self Efficacy;Site;Smoke;Smokeless;Smokeless Tobacco;Smoker;Smoking;Testing;Tobacco;Tobacco Dependence;Tobacco Use Cessation;Tobacco smoke;Tobacco use;Viral;Work;antiretroviral therapy;bidis;brief advice;care systems;clinical research site;comparison intervention;cost;cost effective;cost effectiveness;design;effective therapy;effectiveness evaluation;effectiveness study;effectiveness testing;health communication;hookah;implementation evaluation;implementation process;implementation strategy;interest;low and middle-income countries;mHealth;medication compliance;models and simulation;novel;open label;programs;quitline;randomized trial;randomized clinical trials;scale up;smokeless tobacco cessation;smokeless tobacco use;smoking prevalence;social cognitive theory;stakeholder perspectives;standard care;success;theories;timeline;tobacco abstinence;tobacco cessation intervention;tobacco control;tobacco smokers;tobacco user;treatment program;two-arm trial;varenicline;years of life lost Varenicline and mobile behavioral assistance for tobacco cessation in HIV care in India NarrativeThere is an urgent need to adapt and implement effective tobacco cessation interventions in HIV careprograms in low- and middle-income settings. This study will evaluate the effectiveness and cost-effectivenessof an integrated varenicline and mobile behavioral intervention among smokers and dual tobacco users in HIVcare in Chennai India. Combining a scalable mobile health intervention with cost-effective pharmacotherapycould reduce the harmful impacts of tobacco among people living with HIV. NCI 10908792 9/13/23 0:00 RFA-CA-20-037 3U01CA261614-04S1 3 U01 CA 261614 4 S1 "RICCIARDONE, MARIE D" 9/23/21 0:00 8/31/26 0:00 ZCA1-SRB-2(M1) 11990793 "KRUSE, GINA RAE" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 150247 NCI 122661 27586 AbstractThere is an urgent need to implement effective tobacco cessation interventions in HIV care programs in low-and middle-income countries (LMICs) where most tobacco users and people with HIV live. India is animportant setting in which to test tobacco cessation interventions with an estimated 275 million tobacco usersand 2 million people living with HIV (PWH). Effective medications and behavioral interventions have not beenwell tested in HIV care settings in LMICs. In high income settings Positively Smoke Free (PSF) a theory-based behavioral intervention has demonstrated efficacy among PWH and been adapted for mobile phonedelivery (PSF-M). Mobile health interventions offer scalability and may be more effective among PWH thanface-to-face. Varenicline is the cessation medication with the strongest evidence of efficacy in PWH butachieving sufficient adherence to sustain long-term success is a challenge. We propose to combine the twomost promising cessation interventions among PWH varenicline and PSF-M enhanced with vareniclineadherence support. They will be tested at the Voluntary Health Services (VHS) Infectious Disease MedicalCenter Chennai Antiviral Research and Treatment Clinical Research Site where 24% of patients new to HIVcare are current smokers or dual users of smoked and smokeless tobacco and 83% own mobile phones. Inthis setting we propose the following specific aims: (1) To demonstrate the effectiveness of an integratedintervention combining varenicline plus mobile behavioral treatment among tobacco users in HIV care onbiochemically verified tobacco abstinence at 24 weeks compared to a standard care control; (2): To evaluatethe implementation processes of the integrated intervention in an LMIC HIV practice; and (3): To measure thecosts and cost-effectiveness of an integrated intervention with varenicline and PSF-M. To accomplish theseaims PSF-M will be adapted to the VHS context and novel content about smokeless tobacco and medicationadherence self-efficacy will be added. A randomized two-arm trial will compare the combination of vareniclineand PSF-M to a standard care control. We will evaluate implementation processes within HIV care workflowsincluding acceptability appropriateness feasibility and costs and conduct cost-effectiveness analysis to assessthe clinical impact and value of the integrated intervention if scaled-up. The work proposed is responsive to thespecific interests in RFA-CA-20-037 by testing the effectiveness of tobacco cessation interventions withdemonstrated efficacy in other settings and adapted for an LMIC context evaluating the implementationprocess from multiple stakeholder perspectives in an HIV care practice and assessing the clinical impact andvalue of the integrated intervention if implemented at scale. The successful completion of this work will movethe field forward by advancing our understanding of the effectiveness of an integrated tobacco cessationintervention in HIV care settings and projecting the population level impacts of implementing the integratedintervention for PWH in India or other LMICs. 150247 +No NIH Category available ACCISIS-Chicago PROJECT NARRATIVEAccelerating Colorectal Cancer Screening and Follow-up through Implementation Science in Chicago(ACCSIS-Chicago) is a two-phase study to examine the effectiveness and impact of a multilevelmulticomponent intervention on increasing rates of CRC screening follow-up and referral-to-care. This studywill provide the evidence base for multilevel interventions and best practices for how to scale up thisintervention to reduce the unnecessary burden of colorectal cancer. NCI 10908140 1/5/24 0:00 PA-21-268 7UH3CA233229-06 7 UH3 CA 233229 6 "GRIMES, GENEVIEVE M" 9/1/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-AARR-N(52)R] 9420304 "KIM, KAREN E" "POLITE, BLASE N." 10 INTERNAL MEDICINE/MEDICINE 129348186 TNKGNDAWB445 129348186 TNKGNDAWB445 US 40.264414 -76.674014 1524204 PENNSYLVANIA STATE UNIV HERSHEY MED CTR HERSHEY PA SCHOOLS OF MEDICINE 170332360 UNITED STATES N 1/5/24 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2022 254727 NCI 163000 91727 PROJECT SUMMARYScreening for colorectal cancer (CRC) not only detects disease early but also prevents cancer by finding andremoving precancerous polyps. The overall goal of our project Accelerating Colorectal Cancer Screeningand Follow-up through Implementation Science in Chicago (ACCSIS-Chicago) is to test a multilevelmulticomponent intervention to increase rates of CRC screening follow-up and referral-to-care amongracial/ethnic minority and low income populations in Chicago Illinois. In this project we will include twodifferent types of implementation strategies: 1) evidence-based multilevel multicomponent intervention toincrease rates of CRC screening follow-up and referral-to-care; and 2) implementation support strategies tosupport the implementation process that contribute to the adoption implementation and sustainment of ourproposed multilevel multicomponent intervention. We will partner with 4 federally qualified health centers(FQHCs) which have 35 clinics in the Chicago area and provided primary care service to nearly 188000racial/ethnic minority and low income populations in 2016. During the UG3 Planning-Exploratory Phase we willwork with one of the 4 FQHC partners to pilot test measure and refine our proposed multilevelmulticomponent intervention in preparation for the experimental trial in the UH3 Implementation Phase as wellas assess the effectiveness of our implementation support strategies. In the UH3 Implementation Phase wewill use a stepped wedge cluster randomized trial design to examine the effectiveness and impact of ourmultilevel multicomponent intervention on increasing rates of CRC screening follow-up and referral-to-careacross our 4 partner FQHCs. The selection of our intervention components will be based on intensive literaturereview and findings and lessons learned from our previous studies and projects. Our multilevel interventioncomponents will include EMR provider reminders provider assessment and feedback patient navigationprovider education and community outreach. We will also test one local innovation IL ColonCARES during theUGH Phase to increase the rate of follow-up after a positive stool test among uninsured patients by linkinguninsured patients with specialty services. We expect the finding from this study to have broad impact onunderstanding the implementation process to increase colorectal cancer screening follow up and referral tocare across diverse health systems. 254727 +No NIH Category available Acetates;Adrenal Glands;Adrenergic Antagonists;Affect;Agonist;Alleles;Androgen Metabolism;Androgen Receptor;Androgens;Androstenedione;Anions;Automobile Driving;Biological Factors;Biological Markers;Biology;Castration;Cessation of life;Clinical;Clinical Trials;Data;Development;Disease;Disease Progression;Dutasteride;Enzyme Inhibition;Enzymes;Evaluation;Failure;Fostering;Future;Genes;Genetic;Genetic Polymorphism;Genetic Variation;Genomics;Genotype;Hydroxysteroid Dehydrogenases;Individual;Ketoconazole;Malignant neoplasm of prostate;Mediating;Metabolism;Modeling;Neoadjuvant Therapy;Nomograms;Outcome;Oxidoreductase;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase III Clinical Trials;Play;Population;Prevalence;Process;Production;Progression-Free Survivals;Race;Randomized;Residual Neoplasm;Resistance;Resistance profile;Risk;Role;SRD5A2 gene;Science;Selection Criteria;Selection for Treatments;Series;Serology;Serum;Symptoms;TP53 gene;Testing;Testosterone;Testosterone 5-alpha-Reductase;Variant;Work;abiraterone;acquired treatment resistance;arm;biomarker driven;castration resistant prostate cancer;chemotherapy;dehydroepiandrosterone;design;efficacy testing;enzalutamide;experience;gain of function;genetic variant;genomic biomarker;high risk;inhibitor;inhibitor therapy;member;men;novel;patient population;pharmacologic;phase 2 study;phase III trial;predicting response;prognostic model;prognostic of survival;prospective;radiological imaging;response;solute;study population;success;targeted treatment;therapy resistant;treatment strategy;tumor;tumor progression;uptake Interactions of Androgen Production Uptake and Metabolism on outcome in Castration Resistant Prostate Cancer Project NarrativeThis proposal seeks to identify genetic variances in the metabolism abiraterone an androgen synthesisinhibitor that can be used to identify abiraterone metabolites that may hasten disease progression. A clinicaltrial tests the efficacy of inhibiting metabolism of an active metabolite that may worsen outcomes. If positivethis trial of pharmacologic 5 alpha reductase inhibition may prolong the sensitivity to abiraterone in certainpatients delaying progression of the disease symptoms and death and would validate the targeting of activeabiraterone metabolites in this disease. NCI 10908110 8/23/23 0:00 PA-21-268 7R01CA249279-03 7 R01 CA 249279 3 "SONG, MIN-KYUNG H" 9/1/21 0:00 8/31/26 0:00 Clinical Oncology Study Section[CONC] 2794302 "HALABI, SUSAN " "SHARIFI, NIMA " 4 BIOSTATISTICS & OTHER MATH SCI 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 466468 NCI 404892 61576 Project Summary:We have identified a collective series of factors that affect variability in the production uptake and conversion ofandrogens capable of activating the androgen receptor and driving tumor progression in prostate cancer.Paradoxically however these same factors may predict response to specific therapies that target thesemechanisms. We hypothesize that genetic variation in HSD3B1 SLCO2B1 and SRD5A2 each critical driversof androgen production uptake and conversion (APUC) in prostate cancer confer cumulative effects onoutcome in populations determining both high and low likelihoods of response to AR directed agents and canform effective biomarker-based therapy selection approaches in the context of treatment resistance.Following successful development of both enzalutamide and abiraterone (led by the PI of this proposal) inchemotherapy nave CRPC members of our team designed and completed A031201 a randomized phase IIINCI Cooperative Group trial of Enzalutamide (E) vs Enzalutamide+Abiraterone Acetate (E/AA). This trial isnow complete and the data were recently presented. Clinical and genetic data from nearly all patients affordsthe opportunity to evaluate outcomes based on HSD3B1 SLCO2B1 and SRD5A genotype their relationshipto disease biology (factors such as wild type versus altered TP53) and clinical outcomes to guide futurebiomarker-driven treatment science.In this proposal we perform analyses of patient genetic factors and match it to clinical outcome and androgenmetabolites based on the APUC model. In the first aim we define the prevalence and magnitude of effect ofvariants in genetic related to androgen production uptake and conversion (APUC). Next we seek to constructa multivariable model to identify APUC sensitive and APUC resistant profiles integrating disease biologicalfactors known to confer primary and acquired treatment resistance to abiraterone and potentiallyenzalutamide. Finally we will test the pharmacodynamic reduction of an abiraterone metabolite 3-keto5abiraterone with agonist capabilities with the drug Dutasteride in patients who harbor the 1245c variation inthe HSD3B1 gene. This variant of HSD3B1 leads to a gain of function and we hypothesize that theaccumulation of this agonist drives resistance to abiraterone. Dutasteride inhibits 5 reductase and thereforethe production of the 5 abiraterone metabolite that functions as an AR agonist. Based on the rPFS data wemay propose a phase III clinical trial through the cooperative group mechanisms. We will screenapproximately 300 individuals on abiraterone to randomize 100 patients to dutasteride or observation. Thestudy has adequate power to demonstrate a meaningful radiographic progression free survival (rPFS) benefit.We will integrate our APUC model into an understanding of the outcomes of this phase II study. 466468 +No NIH Category available Address;Anxiety;Birth;Cancer Patient;Cancer Survivorship;Caring;Cause of Death;Cessation of life;Characteristics;Clinical;Country;Data;Diagnosis;Disease;Distress;Drug Use Disorder;Early Intervention;Education;Educational workshop;Ethnic Origin;Health;Hospitals;Incidence;Income;Individual;Inpatients;Intervention;Knowledge;Long-Term Care;Longitudinal Studies;Major Depressive Disorder;Malignant Neoplasms;Malignant neoplasm of prostate;Marital Status;Mental Depression;Mental Health;Mental disorders;Military Personnel;Modeling;Operative Surgical Procedures;Outcome;Outpatients;Patients;Persons;Population;Predisposition;Primary Care;Prostate Cancer therapy;Public Health;Quality of life;Race;Radiation;Registries;Relative Risks;Research;Risk;Risk Assessment;Sample Size;Self Care;Sexual Dysfunction;Spouses;Stress;Subgroup;Suicide;Suicide attempt;Sweden;Testing;Time;United States National Institutes of Health;Urinary Incontinence;Vulnerable Populations;alcohol use disorder;cancer diagnosis;cancer survival;cancer therapy;caregiving;cohort;cost;cost efficient;follow-up;high risk;improved;innovation;medical specialties;men;mortality;population based;premature;prevent;prostate cancer survivors;psychosocial;side effect;stress resilience;tumor Long-Term Mental Health Outcomes in Prostate Cancer Survivors and Their Partners NARRATIVEProstate cancer survivorship is common and increasing and may have substantial mental health impacts inpatients and their intimate partners that are understudied and preventable. This project will provide the firstlong-term assessment of mental health outcomes in prostate cancer survivors and their partners by integratinghighly complete data from primary care specialty outpatient and inpatient settings for a large population-based cohort. The results will identify the long-term mental health sequelae in prostate cancer survivors theirpartners and high-risk subgroups and guide early interventions to improve their long-term health. NCI 10908089 8/24/23 0:00 PA-21-268 7R01CA269553-03 7 R01 CA 269553 3 "NELSON, WENDY" 6/21/22 0:00 3/31/26 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 11176688 "CRUMP, CASEY " "SIEH, WEIVA ; SUNDQUIST, KRISTINA " 18 FAMILY MEDICINE 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF MEDICINE 770305400 UNITED STATES N 8/16/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 418130 NCI 308843 109287 "Prostate cancer (PC) is the most commonly diagnosed cancer among men in the US and in most countriesworldwide. Over 3.6 million US men are currently living with PC and this number is expected to increase to >5million by 2030. Approximately 90% of PC cases are diagnosed at a local or regional stage when the 5-yearsurvival is >99%. Consequently most men with PC survive >15-20 years after diagnosis. However PCdiagnosis and treatment can be devastating for men and their partners and may increase risks of mentalillness. Importantly mental disorders are treatable and early intervention could reduce suffering improvequality of life and prevent premature death. Despite the high public health burden of mental disorders theyare severely understudied compared with somatic outcomes of PC. A comprehensive understanding of long-term mental health sequelae is critically needed to improve care and outcomes for PC survivors and theirpartners. The few prior studies have had important limitations including limited follow-up times and samplesizes and ascertainment of mental disorders using only hospital data which captures only the most severecases. No large-scale studies have included partners. We will address these limitations by conducting the firstcomprehensive long-term study of mental health outcomes in PC survivors and partners in a national cohort (N>4 M) using highly complete data from primary care specialty outpatient and inpatient settings. Wehypothesize that PC survivors and their partners have increased risks of major mental disorders and suicide.To test this hypothesis we will examine these outcomes in 210432 men diagnosed with PC in Sweden in1987-2018 and their 163085 partners compared with 2.1 M men without PC and their 1.6 M partners followedfor up to 34 years through 2020. Sweden is an ideal setting because individual-level data an PC diagnosestreatment and mental health outcomes are available for the entire population with over 3 decades of follow-upand the incidence and treatment of PC and common mental disorders are comparable to the US. Thisproposal addresses key priorities identified by the 2019 NCI workshop on ""Evidence Gaps in CancerSurvivorship Care"". Our specific aims are to identify: (1) long-term risks of 4 mental disorders (majordepression anxiety alcohol and drug use disorders) and suicide in PC survivors; (2) high-risk subgroups whomay benefit most from interventions; (3) whether mental disorders are associated with higher PC-specificmortality; and (4) long-term risks of mental disorders and suicide in partners of PC survivors. The proposedresearch is significant because millions of men are surviving with PC and their mental health sequelae mayhave substantial impacts that are understudied and preventable. It is innovative because it will provide the firstlong-term assessment in a national cohort of PC survivors and partners by integrating unparalleled individual-level data for >4 M people. The results will identify the long-term mental health outcomes in PC survivors theirpartners and high-risk subgroups and guide early interventions to improve their long-term health." 418130 +No NIH Category available Animals;Apoptosis;BRAF gene;Benchmarking;Biological Assay;Biology;Cancer Etiology;Cancer Model;Cells;Cessation of life;Chemical Modifier;Chemicals;Chemistry;Clinical;Colorectal Cancer;Complex;Computer Models;Data;Development;Diagnosis;Disease;Drosophila genus;Drug Design;Drug Kinetics;Epidermal Growth Factor Receptor;Excretory function;FDA approved;Genes;Genetic;Genetic Screening;Goals;Half-Life;Human;Immunotherapy;In Vitro;KRAS2 gene;Lead;Libraries;Malignant Neoplasms;Maps;Mediating;Metabolism;Modeling;Modification;Monomeric GTP-Binding Proteins;Mus;Nature;Neoplasm Metastasis;Oncogenic;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phosphotransferases;Primary carcinoma of the liver cells;Property;Protein Isoforms;RAF1 gene;Refractory;Series;Signal Transduction;Structure;Structure-Activity Relationship;Survival Rate;TP53 gene;Testing;Therapeutic;Therapeutic Index;Time;Toxic effect;Treatment Efficacy;United States;Variant;Xenograft Model;Xenograft procedure;absorption;analog;aurora kinase A;chemical genetics;colon cancer cell line;colon cancer patients;comparative;cost;design;drug development;fly;gastrointestinal;genetic analysis;genetic approach;improved;in vivo;inhibitor;innovation;insight;interdisciplinary approach;kinase inhibitor;metastatic colorectal;mortality;mutant;neoplastic cell;network attack;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;side effect;small molecule;structural biology;tumor;tumor growth;tumor initiation A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer Project NarrativeSynthetic tailoring of polypharmacological drugs is often difficult as the most appropriate targets may not bereadily apparent and therefore few roadmaps exist to guide chemistry. In this application we propose amultidisciplinary approach for accessing novel target and chemical space so as to derive highly precisepolypharmacological compounds. By combining chemical and genetic modifier screens with computationalmodelling we will identify distinct kinases that can strongly enhance (pro-targets) or limit (anti-targets) theactivity of kinase inhibitors within models of KRAS variant metastatic colorectal cancer and then harness thisinformation to predict and synthesize novel compounds optimized towards whole animal networks. NCI 10908073 8/23/23 0:00 PA-21-268 7R01CA258736-04 7 R01 CA 258736 4 "AGYIN, JOSEPH KOFI" 6/1/23 0:00 2/28/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 9752313 "DAR, ARVIN " "CAGAN, ROSS LEIGH" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 6/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 504213 NCI 327499 176714 Project SummaryMetastatic colorectal cancer (mCRC) is the second leading cause of cancer-related mortality in the UnitedStates and annually accounts for nearly 500000 deaths worldwide. Currently the small molecule kinaseinhibitor (KI) regorafenib is the primary second line therapy for metastatic CRC that is not treatable withimmunotherapy or anti-EGFR therapies. However regorafenib generally provides only modest improvements insurvival typically monthsand often at the cost of significant side effects. Proposed targets for regorafenibinclude kinases that act within tumor cells as well as non-autonomously; however with over 500 possible targetsin the human kinome the exact mechanism by which this compound operates remains controversial and notfully known. This presents a daunting challenge; without a verifiable target or mechanism no clear path existsto guide the development of improved therapies for mCRC. Here we propose an alternative approach to drug development that focuses on kinase networks in thecontext of the whole animal. Specifically we will take a multidisciplinary approach to define kinases that arebeneficial to inhibit (pro-targets) or avoid (anti-targets) in the context of KRAS-variant CRC. Using Drosophilaand mammalian models we will identify kinases thatwhen reducedalter the efficacy of regorafenib andsimilar compounds. We will also conduct extensive structure-activity relationship analyses evaluating howmodifications in already identified lead compounds impact changes in efficacy and therapeutic index. Finally wewill use computational structural biology to convert our chemical genetic insights into highly optimized andprecise polypharmacological leads. In this final step we generate new analogs to selectively eliminate putativeanti-target activity while maintaining or increasing inhibitory activity against other beneficial targets. We have used our chemical genetic platform to identify a promising lead compound APS5-86-2 thatdemonstrates significant activity relative to regorafenib in several mCRC models including human patientderived xenografts (PDX). Comparative analysis suggests that the improved activity of APS5-86-2 relative toregorafenib derives from distinct polypharmacology on several RTKs and critical cancer drivers including CDK9AURKA EGFR BRAF and RAF1. In this proposal we examine the mechanism and importance of these andother putative pro- and anti-target kinases using genetic analysis and in vivo target engagement. The objectiveis to identify the kinase networks that mediate KRAS-variant mCRC by combining chemical biology with geneticsand to then derive inhibitors that best attack these networks through structure-based drug design. We have beensuccessful previously with a similar approach but in less complex tumor models (Dar et al. Nature 2012;Sonoshita et al. Nature Chem. Bio. 2018); here we seek to extend our platform to a more prevalent diseasewith the goal of directly impacting mCRC by creating new highly differentiated and improved drugs. 504213 +No NIH Category available Acceleration;Acute T Cell Leukemia;Adolescent;Age;Automobile Driving;B lymphoid malignancy;B-Lymphocytes;Benchmarking;Benign;Biological Assay;Biological Markers;Blood Platelets;Bone marrow failure;Cell Differentiation process;Cell Line;Cells;Characteristics;Chicago;Classification;Clinic;Clinical Trials;Clinical assessments;Clonal Expansion;Collection;Country;Data;Defect;Dendritic Cells;Development;Differentiation and Growth;Disease;Drug usage;Dysmyelopoietic Syndromes;Extramural Activities;Family;Gene Mutation;General Population;Growth;Health;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Immune;Immunologic Deficiency Syndromes;In Vitro;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Inherited;Laboratories;Ligands;Malignant Neoplasms;Monosomy 7;Mus;Mutation;Mycoses;Myeloproliferative disease;Natural Killer Cells;Oregon;Pathogenicity;Pathway interactions;Patients;Pennsylvania;Pre-Clinical Model;Predisposition;RUNX1 gene;Research Personnel;Risk;Role;Sampling;Science;Signal Transduction;Somatic Mutation;Source;Syndrome;TLR4 gene;Testing;Translational Research;United States National Institutes of Health;Universities;Variant;Viral;Wisconsin;Work;Xenograft procedure;acute infection;cell growth;chemokine;chronic infection;clinical center;cytokine;derepression;design;driver mutation;hematopoietic stem cell expansion;high risk;improved;inflammatory milieu;innovation;interest;leukemia;leukemogenesis;mesenchymal stromal cell;monocyte;mouse model;mutant;mutation carrier;non-tuberculosis mycobacteria;novel strategies;prevent;programs;research clinical testing;response;stem cell growth;systemic inflammatory response;transcription factor;variant of unknown significance The role of inflammation in driving leukemogenesis in germline predisposition syndromes PROJECT NARRATIVEThe proposed U01 consortium will expand long-standing work centered at the NIH Clinical Center focused onindividuals with germline GATA2- or RUNX1-mutations who are at high-risk for developing bone marrow failure(BMF) and hematopoietic malignancies (HMs). Intramural and four extramural investigators will test thehypothesis that inflammation derived from intrinsic and extrinsic sources drives BMF in GATA2-mutant patientsplus clonal hematopoiesis that frequently evolves into HMs in both syndromes. The results of the planned workwill identify new biomarkers and pathways associated with BMF and HMs and lead to novel strategies to lowersystemic inflammation and slow or prevent clonal expansion that could be tested in a clinical trial. NCI 10908063 9/14/23 0:00 PA-21-268 7U01CA257666-02 7 U01 CA 257666 2 "HENDERSON, LORI A" 5/1/22 0:00 4/30/26 0:00 ZCA1-SRB-K(O2) 1881079 "GODLEY, LUCY ANN" "AGARWAL, ANUPRIYA ; BRESNICK, EMERY H; SPECK, NANCY " 5 INTERNAL MEDICINE/MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 687587 NCI 581582 106005 PROJECT SUMMARYGermline predisposition to hematopoietic malignancies (HMs) is more common than previously appreciated butindividuals are spread throughout the country with few local experts. The NIH provides focused clinics forpatients with germline GATA2 mutations under Drs. Holland and Hickstein and for those with germline RUNX1mutations under Dr. Liu. The proposed U01 consortium will engage four extramural investigators Drs. LucyGodley (The University of Chicago) Anupriya Agarwal (Oregon Health & Science University) Emery Bresnick(University of Wisconsin-Madison) and Nancy Speck (University of Pennsylvania) to perform complementarystudies using primary samples from patients seen at the NIH Clinical Center. Increased inflammation ischaracteristic of the infections suffered by immunodeficient individuals with germline GATA2 mutations andpreliminary data from the extramural investigators suggest that germline RUNX1-mutant cells produce increasedlevels of inflammatory molecules. The U01 investigators hypothesize that inflammation derived from intrinsic andextrinsic sources drives bone marrow failure (BMF) in GATA2-mutant patients plus clonal hematopoiesis (CH)that frequently evolves into HMs in both syndromes. The U01 consortium will test this hypothesis using threeAims: Aim 1- Identify which germline GATA2 and RUNX1 VUSs are deleterious by analyzing their influences onBM hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). VUSs identifiedin patients presenting to the NIH Clinical Center will be characterized functionally using growth and differentiationassays of patient-derived HSPCs non-hematopoietic MSCs and an MSC cell line benchmarking them againstwild-type and known deleterious or benign variants. Aim 2- Establish how inflammatory mechanisms interfacewith germline GATA2 and RUNX1 mutations to alter HSPC and MSC growth and differentiation. We will identifythe inflammatory cytokines/chemokines overproduced by RUNX1- and GATA2-mutant BM cells in response toTLR4 ligands and determine their impact as well as that of LPS on colony formation serial-replating anddifferentiation of RUNX1- and GATA2-mutant HSPCs and MSCs. We will establish a pre-clinical model ofinflammation-induced BMF in Gata2-deficient mice and determine the contribution of elevated TLR signaling totheir hematopoietic defects. Aim 3- Determine how acquired mutations and inflammation promote the expansionof germline-mutant HSCs. CH occurs more frequently and at an earlier age in patients with germline GATA2-and RUNX1-mutations compared to the general population. We will use xenograft and syngeneic mouse modelsto determine how inflammation drives bone marrow failure in Gata2-deficient mice and facilitates thegrowth/survival of germline GATA2- or RUNX1-mutant HSPCs with acquired somatic mutations providing aclonal advantage that ultimately evolves into leukemia. The results of these studies will be used to design aclinical trial to decrease systemic inflammation and delay or prevent clonal expansion and risk of developingBMF and HMs thus improving the lives of our patients. 687587 +No NIH Category available Academic Medical Centers;Address;Advocate;Aging;Area;Attention;Behavior;Blood;Cancer Burden;Cancer Patient;Cancer Research Project;Caregivers;Clinical;Clinical Oncology;Clinical Research;Clinical Trials;Collaborations;Collection;Committee Membership;Communities;Community Clinical Oncology Program;Companions;Data;Data Reporting;Databases;Development;Diagnosis;Disease;Disparity;Early Diagnosis;Education;Elderly;Functional disorder;Funding;Funding Opportunities;Grant;Health;Human;Incidence;Intervention;Maintenance;Malignant Neoplasms;Manuscripts;Mentors;Mentorship;Metastatic Neoplasm to the Bone;Metastatic malignant neoplasm to brain;Minority;Minority Groups;Mission;Monitor;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Natural History;Nausea and Vomiting;Oncologist;Oncology;Outcome;Outcome Assessment;Outcomes Research;Parents;Patient Outcomes Assessments;Patients;Pharmacologic Substance;Population;Prevalence;Prevention;Publishing;Quality of life;Research;Research Methodology;Research Personnel;Research Priority;Risk;Site;Source;Symptoms;Technology;Tissue Sample;Toxic effect;Training;Translational Research;Tumor Tissue;Underserved Population;United States;Work;base;cancer care;cancer clinical trial;cancer health disparity;cancer prevention;cancer risk;cancer therapy;care delivery;chemotherapy;clinically relevant;clinically significant;community engagement;curative treatments;data sharing;disparity elimination;disparity reduction;experience;financial toxicity;forging;health disparity;high risk;improved;innovation;mortality;multidisciplinary;next generation;novel;older patient;premalignant;prevent;programs;reduce symptoms;repository;skeletal-related events;survivorship;translational oncology;treatment trial;underserved community Alliance NCORP Research Base Alliance NCORP Research BaseProject NarrativeThe Alliance NCI Community Oncology Research Program (NCORP) Research Base conductsresearch in cancer prevention cancer symptom control and cancer care delivery with a specialemphasis on minority underserved and older patients and with a strong commitment to buildingcollegial relationships with NCORP Community sites and Minority/Underserved Communitysites. The Alliance NCORP seeks to continue its mission into the next grant cycle of generatingpractice-changing research that directly and favorably impacts the lives of cancer patients andthose at risk for cancer. NCI 10908061 8/18/23 0:00 RFA-CA-18-015 3UG1CA189823-09S2 3 UG1 CA 189823 9 S2 "MCCASKILL-STEVENS, WORTA J" 8/1/14 0:00 7/31/25 0:00 ZCA1-GRB-S(M1) 6356949 "GEORGE, SUZANNE " "HAHN, OLWEN ; PASKETT, ELECTRA D." 7 Unavailable 117404554 F4BMNBQK9BM1 117404554 F4BMNBQK9BM1 US 41.879725 -87.636406 10060073 ALLIANCE NCTN FOUNDATION CHICAGO IL Other Domestic Non-Profits 606064404 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 399 Other Research-Related 2023 597362 NCI 475607 121755 Alliance NCORP Research BaseProject Summary/AbstractThe Alliance for Clinical Trials in Oncology (Alliance) one of five National Clinical Trials Network groupsserves as the parent organization for the Alliance NCI Community Oncology Research Program (NCORP)Research Base (Alliance NCORP). The Alliance NCORP conducts interventional and observational clinicaland translational research as well as database studies all of which address important questions relevant tocancer prevention symptom control and cancer care delivery. In addition the Alliance NCORP conductsclinically important quality of life studies that are embedded within cancer treatment trials. It places specialemphasis on minority underserved and older patients at risk for or diagnosed with cancer and on buildingstrong collegial relationships with NCORP Community sites and Minority/Underserved Community sites. TheAlliance NCORP committee membership includes rich representation from both community-based andacademic medical centers as well as patient advocates thus generating research results relevant to cancerpatients across the United States. The Alliance NCORP also emphasizes mentorship and training of juniorinvestigators. Over this past grant cycle i.e. since August 2014 the Alliance NCORP has published 148manuscripts and abstracts. This work has included practice-changing research in such areas as theprevention of chemotherapy-induced nausea and vomiting the prevention of skeletal-related events fromosseous metastases the management of brain metastases and the integration of patient-reported outcomesinto cancer clinical trials. The Alliance NCORP conducts translational research that requires the collection oftumor tissue premalignant tissue samples blood and other human biospecimens; and shares data andbiospecimens for pooled analyses and other scientific collaborations. These biospecimens create aninvaluable repository for understanding clinical observations from a mechanistic standpoint. The AllianceNCORP also collaborates broadly with other NCI-funded investigators and consortia as well as withinvestigators supported through non-NCI sources. This practice-changing research and the scientificquestions answered by the Alliance NCORP provide meaningful and innovative contributions to clinical andtranslational oncology which can be conducted only within a publicly-funded research network. 597362 +No NIH Category available Androgens;BCL2 gene;Back;Binding;Biological Assay;Biological Availability;Cancer Patient;Cell Cycle;Cell Cycle Progression;Cells;Complex;Data;Development;Dose;Drug Kinetics;Drug Targeting;Excretory function;Failure;Funding;Genetic;Growth Factor;Human;Immunity;In Vitro;Intravenous;Link;Liver Microsomes;MDM2 gene;Malignant Neoplasms;Malignant neoplasm of prostate;Marketing;Mediating;Membrane;Metabolism;Metastatic Prostate Cancer;Modeling;Mus;Normal Cell;Oral;Organoids;Paper;Pharmaceutical Preparations;Phase I Clinical Trials;Phenotype;Plasma;Process;Property;Protac;Proteins;Resistance;Safety;Signal Transduction;Skp2 Proteins;Specimen;Testing;Therapeutic;Ubiquitination;Xenograft Model;Xenograft procedure;absorption;analog;androgen deprivation therapy;cancer cell;cancer therapy;castration resistant prostate cancer;cell killing;chemical synthesis;chimera drug;clinical candidate;cytotoxicity;design;drug candidate;drug development;improved;in vitro Assay;in vivo;in vivo Model;inhibitor;meter;mouse model;novel;patient derived xenograft model;pharmacologic;phase 1 study;prostate cancer model;prostate cancer progression;protein protein interaction;recruit;scale up;small molecule inhibitor;tumor;ubiquitin-protein ligase Drug Development of Skp2 PROTACs in Cancer NarrativeSkp2 SCF complex E3 ligase is a highly validated drug target for cancer. Due to the lack of effective inhibitorsSkp2 SCF complex E3 ligase is considered as non-drugable. Drug development of the Skp2 proteolysis targetingchimera (PROTAC) drugs with superior potency and safety window would transfer Skp2 to be durgable for thetreatment of cancer. NCI 10908041 8/31/23 0:00 PA-21-268 7R01CA277682-02 7 R01 CA 277682 2 "AGYIN, JOSEPH KOFI" 5/31/23 0:00 4/30/28 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 10738456 "LI, HONG-YU " "LIN, HUI-KUAN " 20 PHARMACOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 658049 NCI 524554 133495 AbstractSkp2 an F-box protein that constitutes one of the four subunits of the SCF ubiquitin E3 ligase complex regulatescell-cycle progression by targeting ubiquitination and degradation of its substrates such as the cell-cycle inhibitorp27. Skp2 E3 ligase has a broad implication in cancer especially for androgen-independent human metastaticprostate cancer. We showed that Skp2 expression was upregulated in metastatic prostate cancer specimensand castration-resistant prostate cancer (CRPC) and correlated with Myc expression. We further demonstratedthat Skp2 is a novel E3 ligase for Akt that triggers nonproteolytic K63-linked ubiquitination of Akt facilitatinggrowth factor-mediated Akt membrane recruitment and activation. All together suggest that Skp2 simultaneouslyregulates Akt signaling and p27 degradation and TWIST-mediated EMT to promote CRPC progression andresistance to androgen deprivation therapy (ABT). Although Skp2 SCF complex E3 ligase is a highly validateddrug target for cancer due to the lack of an effective protein-protein interaction inhibitors Skp2 SCF complexE3 ligase is still considered as non-drugable. The proteolysis targeting chimera (PROTAC) approach couldincrease potency of non-drugable inhibitors due to its catalytic degradation. In this proposal we have discovereda potent Skp2 PRO-1 by improving therapeutic window more than 100 fold in vitro over small molecule inhibitors.Skp2-PRO-1 can completely degrade Skp2 with 100 nM concentration in cancer cells and demonstrate thecomplete in vivo Skp2 degradation and robust antitumor efficacy in challenging and advanced CRPC tumormodels including the genetic CRPC mouse model with intact immunity. To obtain two clinical candidates wewill evaluate the PK properties of Skp2-PRO-1 a Cereblon based PROTAC and improve its PK and drugproperties as the first clincial candidate. We will further develop a VHL/or MDM2 based Skp2 PROTAC as theback-up candidate. Finally we will validate the clinical candidates in advanced CRPC in vivo models usingdiverse xenograft modes cancer organoids patient-derived xenografts (PDXs) and genetic mouse models. Theresulted clinical candidates will be advanced into the IND enabling studies for the phase I clinical trials for thetreatment of cancer. 658049 +No NIH Category available A Federated Galaxy for user-friendly large-scale cancer genomics research Project NarrativeThis project will develop a user-friendly scientific analysis workbench for analyzing cancer genomics data on the NCI Cancer Research Data Commons cloud platform. The workbench will democratize access to cloud-based cancer genomic analyses. It will also aid in precision cancer medicine by benchmarking and identifying the most accurate analytic methods for classifying tumors and predicting drug response. NCI 10908030 9/7/23 0:00 PA-21-268 7U24CA231877-06 7 U24 CA 231877 6 "LI, JERRY" 9/11/18 0:00 8/31/24 0:00 ZCA1-SRB-X(M2) 10490342 "GOECKS, JEREMY " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2022 171200 NCI 155000 16200 Project SummaryCancer research is now a data-driven discipline but only a minority of cancer researchers are data scientists. This severely restricts our ability to effectively study and cure the disease. The far reaching significance of our project is in federating disparate data and computational resources in order to provide a unifying analysis platform for computational cancer research.We will extend the popular scientific workbench Galaxy (https://galaxyproject.org) so that it can integrate with distributed data and compute resources used and needed by cancer researchers including those resources in the NCI Cancer Research Data Commons (NCR DC). Our Federated Galaxy system will allow users to seamlessly access NCR DC data across multiple resources. It will support multiple analysis scenarios tuned to skills and computational requirements of individual researchers.The aims of this project are:Aim 1. Extend Galaxy for working with distributed cancer genomics and phenotypic data. This will enable Galaxy users to access both public and private cancer data regardless of their actual physical location. Best-practice approaches will be used for accessing restricted datasets.Aim 2. Enhance Galaxy for context-aware distributed cancer genomics analyses using shared workflow representations. This will enable Galaxy users to run genomics analyses on different clouds ultimately reducing the time cost and data transfer associated with analyses.Aim 3. Apply Federated Galaxy to precision oncology research. Workflows developed in this aim will leverage the technologies in Aims 1 and 2 to benchmark machine learning algorithms for predicting tumor phenotype and drug response. Interactive reports will summarize benchmarking results and utilize ITCR visualizations for deep dives into results.Our system will provide a singular access point to distributed cancer datasets and will enable these data to be analyzed within a single portal in a way that satisfies multiple analysis scenarios and utilizes diverse computational resources. Finally a cloud-centric Galaxy built for the NCR DC will substantially grow the community of users working with the GDC and the NCR DC. This is because Galaxy brings with itself a vibrant world-wide community of users and developers which numbers tens of thousands of scientists. These individuals will help to tune the GDC and other resources within the NCR DC to the needs of real-life analysis scenarios and will enrich the set of tools accessible to cancer researchers. 171200 +No NIH Category available Accounting;Acute Myelocytic Leukemia;Address;Alleles;Allogenic;American Society of Hematology;Biology;Blood Platelets;CEBPA gene;Cancer Detection;Caring;Categories;Childbirth;Classification Scheme;ClinVar;Clinical;Clinical Management;Consensus;Copy Number Polymorphism;Country;Databases;Defect;Deposition;Development;Diagnostic;Dysmyelopoietic Syndromes;ETV6 gene;Enhancers;Familial Platelet Disorder;Family;Funding;Genes;Germ-Line Mutation;Guidelines;Hematologic Neoplasms;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic Stem Cell Transplantation;Immune;Individual;Inherited;Institution;Laboratories;Lymphedema;Mediating;Methods;Monosomy 7;Mutation;Myeloid Leukemia;Myeloproliferative disease;Natural Immunity;Operative Surgical Procedures;Organ;Paper;Pathway interactions;Patient Care;Patients;Persons;Phenotype;Population;Predisposition;Process;Productivity;Prognosis;Publications;Publishing;RNA;RUNX1 gene;Recommendation;Review Literature;Risk;Site;Solid Neoplasm;Susceptibility Gene;Syndrome;Teenagers;Testing;Thrombocytopenia;Time;Untranslated RNA;Update;Variant;Work;World Health Organization;cancer cell;clinical care;curative treatments;forging;genetic testing;genetic variant;genome resource;innovation;leukemia;member;next generation sequencing;platelet function;precision medicine;transcription factor;working group;young adult Myeloid Malignancy Variant Curation Recognizing the emerging importance of germline predisposition to myeloid malignancies and knowing that theconsistent functional annotation of gene variants will be increasingly important for optimal clinical managementthe American Society of Hematology (ASH) and ClinGen partnered to pilot a Myeloid Malignancy VariantCuration Expert Panel (MM-VCEP) co-chaired by Drs. Lucy A. Godley and David Wu. The MM-VCEP has beeninnovative and productive to date having published two papers on its RUNX1 variant curation rules and workingcurrently on developing similar rules for GATA2 variants. The MM-VCEP seeks three years of support beyondthe ASH funding commitment so that they can continue to curate RUNX1 and GATA2 variants according to ourestablished rules and to develop curation rules for variants in four additional genes that confer risk for myeloidmalignancies: ANKRD26 ETV6 CEBPA and DDX41. NCI 10907993 9/8/23 0:00 PA-21-268 7U24CA258118-04 7 U24 CA 258118 4 "ROTUNNO, MELISSA" 4/20/21 0:00 3/31/24 0:00 Special Emphasis Panel[ZRG1-GGG-K(50)R] 1881079 "GODLEY, LUCY ANN" "WU, DAVID " 5 INTERNAL MEDICINE/MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 3/31/24 0:00 393 Other Research-Related 2023 266334 NCI 166459 99875 Germline predisposition to hematopoietic malignancies is more common than previously appreciated and is bestunderstood currently for the myeloid malignancies. Variants in genes such as RUNX1 GATA2 ANKRD26ETV6 CEBPA and DDX41 are among those commonly identified in patients. Recognizing the emergingimportance of germline predisposition to myeloid malignancies the World Health Organization included thisentity as a provisional diagnostic category in its newest leukemia classification scheme. The American Societyof Hematology (ASH) and ClinGen partnered in 2017 to pilot a Myeloid Malignancy Variant Curation Expert Panel(MM-VCEP) knowing that the consistent functional annotation of gene variants is crucial to clinical managementespecially considering that allogeneic hematopoietic stem cell transplantation (HSCT) using related donors is amainstay of treatment for myeloid leukemias. Drs. Lucy A. Godley and David Wu have co-chaired the MM-VCEPwhich first developed RUNX1 variant curation rules resulting in two publications: one that outlines the rules indetail and the other that provides a more clinical perspective on how the rules change variant interpretation. TheMM-VCEP is now engaged in developing similar rules for GATA2 variants and to facilitate this process they areemploying the Delphi method to come to consensus on a formal description of GATA2 deficiency syndrome. TheMM-VCEP has also been innovative as the first VCEP to develop rules for germline copy number variants andfor variants in a non-coding GATA2 enhancer. As a highly motivated and productive group the MM-VCEP seeksthree years of support beyond the ASH funding commitment so that they can continue to curate RUNX1 andGATA2 variants according to our established rules and to develop curation rules for variants in four additionalgenes that confer risk for myeloid malignancies: (1-2) ANKRD26 and ETV6: Individuals with deleterious variantsin ANKRD26 and ETV6 have life-long thrombocytopenia decreased platelet function and risk of developingmyeloid malignancies like germline carriers of deleterious RUNX1 mutations allowing the MM-VCEP to developthese curation rules in one year; (3) CEBPA: Myeloid leukemias with bi-allelic CEBPA mutations have a favorableprognosis and in about 10% of these cases one of the CEBPA mutations is a germline mutation usually the 5end mutation. For this reason germline genetic testing for CEBPA variants is recommended for those whosemalignant cells have bi-allelic mutations. (4) DDX41: Germline DDX41 mutations are the most common mutationcausing myeloid malignancies accounting for about 1% of all cases of acute myeloid leukemias. To date alltruncating DDX41 mutations are found as germline alleles and several alleles are common in particularpopulations. Thus the MM-VCEP seeks to continue its important work in providing worldwide standards forconsistent variant curation so that patients at risk of developing myeloid malignancies can receive optimal careespecially at the time of consideration of related donors for HSCT; elective surgeries and childbirth for those withplatelet defects; as well as appropriate surveillance for cancer detection and organ function. 266334 +No NIH Category available Adolescent and Young Adult;Clinical Trials;Collaborations;Collection;Communication;Contracts;Data;Data Coordinating Center;Dedications;Development;Ensure;Funding;Individual;Infrastructure;Institution;Legal;Link;Mission;Monitor;Occupational activity of managing finances;Organizational Policy;Policies;Population;Procedures;Process;Protocols documentation;Publications;Records;Reporting;Research;Safety;Serious Adverse Event;Site;Southwest Oncology Group;Specimen;Speed;Structure;Tissue Banks;Training Programs;Translational trial;Work;adjudication;financial conflict of interest;improved;meetings;member;operation;organizational structure;patient safety;process improvement;quality assurance SWOG Network Group Operations Center of the NCTN n/a NCI 10907926 9/21/23 13:28 PA-20-272 3U10CA180888-10S2 3 U10 CA 180888 10 S2 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 7180 6765159 "BLANKE, CHARLES D." Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 Other Research-Related 2023 663307 526434 136873 The Administrative Core provides essential infrastructure linking our member core and clinical trialsdevelopment teams. It provides expert guidance and oversight to SWOG develops and maintains ourOperations Center organizational structure and policies and supports an up-to-date set of StandardOperating Procedures that cover all aspects of the Network Group's activities.Administrative Core duties include: Establishing conditions for maintaining records of and monitoring SWOG institutional and individual membership; Operationalizing clinical and translational trial proposals and protocols continuously searching for development process improvements Serious Adverse Event collection and monitoring as well as patient safety reporting Quality assurance and onsite auditing Developing conducting and assessing training programs Tracking and adjudicating financial conflicts of interest Establishing maintaining and monitoring institutional and individual regulatory requirements Meetings management Group financial management Communications Publications and presentations management Contracting Legal support Administering tissue banking including release of specimens Interacting with key members of the NCTN and other organizationsThe Administrative Core works seamlessly with other SWOG components which have different funding (e.g.our Statistical and Data Management Center) and it oversees SWOG interactions with a variety of NCTN andexternal components. +No NIH Category available EGFR signaling network adaptations to overcome RAS-induced membrane stress in glioblastoma n/a NCI 10907884 8/30/23 10:42 PA-20-272 3U54CA274499-02S2 3 U54 CA 274499 2 S2 "DUECK, HANNAH RUTH" 9/12/22 0:00 8/31/27 0:00 ZCA1(M2) 9942 8200505 "LAZZARA, MATTHEW J" Not Applicable 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 166977 127202 39775 No abstract available +No NIH Category available Address;Administrator;Advisory Committees;Area;Basic Science;Boston;Budgets;Cancer Center;Cell Nucleus;Clinical Sciences;Collaborations;Colon;Color;Communication;Communities;Complex;Dedications;Development;Education;Educational Activities;Electronic Mail;Ensure;Faculty;Foundations;Funding;Goals;Grant;Growth;Infrastructure;Institution;Institutional Review Boards;Joints;Lead;Leadership;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Newsletter;Participant;Population Sciences;Postdoctoral Fellow;Research;Research Personnel;Research Project Grants;Resources;Role;Running;Structure;Training;Universities;Update;cancer health disparity;education research;equity diversity and inclusion;experience;innovation;meetings;member;multidisciplinary;outreach;programs;recruit;social media;success;symposium;synergism;web site Administrative Core n/a NCI 10907855 9/19/23 0:00 PA-20-272 3U54CA156734-13S2 3 U54 CA 156734 13 S2 "WALI, ANIL" 9/28/10 0:00 8/31/26 0:00 ZCA1 8815 8606765 "COLON-CARMONA, ADAN " Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 255274 201819 53455 Summary: The Administrative Core of the University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC) Partnership takes an integrated approach to operational structure tosupport the growth of broad-based transdisciplinary cancer and cancer disparities research at both institutions.Partnership PIs Drs. K Vish Viswanath and Gregory Goyo Abel from DF/HCC and Drs. Adn Coln-Carmona and Jill Macoska from UMass Boston lead the Administrative Core and provide complementaryexpertise and abiding dedication to the sustained success of this research program. As the nucleus of theleadership and administrative teams the PIs with the support of effective internal (Internal AdvisoryCommittee (IAC)) external (Program Steering Committee (PSC)) and institutional leaders provide rigorousoversight for the research projects programs and cores to maximize the impact of the Partnership at theinstitutional level. In addition a single Partnership Program Manager shared by both institutions createsoperational synergies in the management of this multi-institutional research collaboration.The aims of the Administrative Core are to: 1) Provide administrative and fiscal oversight for Partnership coresand research projects and ensure responsible stewardship of funds; 2) Coordinate joint Partnership activitiesat UMass Boston and DF/HCC and facilitate networking opportunities; 3) Ensure proper infrastructural supportfor funded projects and cores; 4) Manage Partnership communications with all critical stakeholders in greaterBoston; 5) Support a new institutionally-funded DEI Manager who will leverage the expertise of the PartnershipCores to begin to investigate reasons for faculty of color attrition train a dedicated group of mentors for beforeand after hire and develop a new network for diverse post-docs in the Boston metro area; and 6) Trackinstitutional commitment in support of Partnership initiatives particularly toward recruitment efforts for EarlyStage Investigators (ESIs) and leverage institutional resources for this effort. +No NIH Category available Accounting;Attenuated;CD47 gene;CRISPR/Cas technology;Cancer Patient;Cancer cell line;Cell membrane;Cells;Clinical;Data;Drug resistance;Endowment;Epidermal Growth Factor Receptor;Genetic;Goals;Immune;Immune Evasion;Immune signaling;Immunity;Immunotherapy;Impairment;Integral Membrane Protein;Knock-in Mouse;Knowledge;LATS1 gene;Ligands;Light;Lung Adenocarcinoma;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Organoids;PD-1/PD-L1;Patients;Phagocytosis;Phagocytosis Induction;Phosphotransferases;Platinum;Population;Process;Prognosis;Property;Protein Family;Protein Phosphatase 2A Regulatory Subunit PR53;Regulation;Reporting;Resistance;Role;Sampling;Signal Transduction;Survival Rate;Technology;Testing;Thrombospondin 1;Tumor Escape;Tumor Stem Cells;Xenograft procedure;anti-PD-1;cancer cell;cancer initiation;cancer stem cell;cancer therapy;chemotherapy;cytokine;empowerment;humanized mouse;immune checkpoint blockers;immunoregulation;innovation;insight;lung cancer cell;mouse genetics;mouse model;neoplastic cell;novel;overexpression;patient derived xenograft model;pharmacologic;recruit;resistance mechanism;response;standard of care;stem cell function;stem cell population;survival outcome;targeted treatment;therapeutically effective;therapy resistant;transcriptomics;transmission process;tumor;tumor progression;tumorigenesis Identification of a novel targetable cancer stem cell regulator promoting cancer progression and metastasis in non-small cell lung cancer Advanced non-small cell lung cancer (NSCLC) accounting for 85% of lung cancer is a highly aggressive cancerwith poor prognosis and short survival rate. The goal of this study is to characterize a novel and unique cancerstem cell (CSC) population in NSCLC progression and metastasis and dissect its regulatory mechanisms thatcan be harnessed for developing a novel effective strategy for targeting progression and metastasis of NSCLCand overcoming the resistance to current standard of care treatments. Our proposal represents a paradigm-shifting concept in that the successful implementation of our proposal will not only reveal new insight into CSCregulation leading to cancer progression and metastasis but also offer a new strategy for targeting advancedNSCLC with metastasis. NCI 10907315 9/4/23 0:00 PA-21-268 7R01CA270617-02 7 R01 CA 270617 2 "KAI, MIHOKO" 2/9/23 0:00 1/31/28 0:00 Tumor Progression and Metastasis Study Section[TPM] 9090324 "LIN, HUI-KUAN " Not Applicable 4 PATHOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 400890 NCI 249000 151890 Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer. The5-year survival rate is about14% for stage IIIA NSCLC while it is about5% for stage IIIB. However onceNSCLC has reached to the stage IVand metastasized to different places it is very difficult to treat. The5-year survival rate for stage IVNSCLC isjust about 1%. Targeted therapy such as anti-EGFR or anti-ALK is the frontline treatment for advanced NSCLCwith EGFR or ALK mutations while platinum-based chemotherapy is the first line treatment for advancedNSCLC without targetable mutations. Interestingly recent studies suggest that anti-PD1/PDL1 immunotherapyis a new and effective strategy for advanced NSCLC. While NSCLC patients initially show great benefit from thesetreatments the response is only transient with relatively short duration likely due to acquiring resistantmechanisms. Identification of novel and effective therapeutic strategies is therefore an urgent need for advancedNSCLC with metastasis. A small cell population with CSC properties contributes to cancer initiation progressionand metastasis as well as drug resistance in various cancers such as NSCLC but an effective strategy to eliminateCSCs is currently lacking representing an unmet clinical need for CSC and NSCLC targeting. While CSCs possessimmune escape properties it is unclear how non-CSC cancer cells accounting for the majority of total cancer cellpopulations could also resist from immune cell attack. The goal of this study is to characterize a novel and uniqueCSC population in NSCLC and its regulatory mechanisms that can be harnessed for developing a novel effectivestrategy for advanced NSCLC and/or for overcoming the resistance to current standard of care. Our studyidentifies a novel druggable regulator localized in cell membrane for maintaining CSCs cancer progression andmetastasis of NSCLCs and its overexpression predicts poor survival outcome NSCLC patients. Genetically orpharmacologically targeting this newly identified regulator attenuates oncogenic signal for maintain CSCproperties and immune escape leading to cancer progression and metastasis of NSCLC. We hypothesized that aunique cell population with CSC properties existed in cancer can transmit an oncogenic and immune escapesignal to non-CSC cancer cells thereby endowing bulk cancer cells with immune escape properties. We proposedthree specific aims which are highly supported by our innovative preliminary results to further characterize theroles and underlying mechanisms of this novel regulator and its ligand as well as their targeting in regulatingCSCs progression and metastasis of NSCLC. Our proposal is highly original and significant as we have proposeda breakthrough concept identified a novel checkpoint blocker with CSC and immune escape properties andutilized cutting technologies including unbiased transcriptomics Cas9/CRISPR editing patient-derivedorganoids patient derived xenograft (PDX) models and humanized mice and genetic knockin mouse modelswith intact immunity to validate our provocative hypothesis and concept. Our study has revolutionized andsignificantly advanced our understanding of CSC and cancer-immune regulation but also offers a new paradigmand strategy for targeting advanced NSCLC. 400890 +No NIH Category available PROJECT 1: TIME-Based Spatiotemporal Cancer Immunograms Predictive for Immunotherapy-Targeted Therapy Sequential Combinations n/a NCI 10907268 8/31/23 0:00 PA-20-272 3U54CA274509-02S1 3 U54 CA 274509 2 S1 "ZAMISCH, MONICA" 9/22/22 0:00 8/31/27 0:00 ZCA1(M2) 5098 8126809 "HEATH, JAMES R." Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 147236 99940 47296 No abstract available +No NIH Category available Research;South Carolina;cancer health disparity South Carolina Cancer Disparities Research Center (SC CADRE) PROJECT NARRATIVE .N/A. Description is included in the original proposal. NCI 10907250 9/13/23 0:00 PA-20-272 3U54CA210962-05S2 3 U54 CA 210962 5 S2 "FUQUA, CHANTEL FAYSAN" 9/1/23 0:00 8/31/24 0:00 7354246 "FORD, MARVELLA ELIZABETH" "SALLEY, JUDITH " 6 PUBLIC HEALTH & PREV MEDICINE 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 350000 NCI 233469 116531 SUMMARY .ABSTRACTN/A. Description is included in the original proposal. 350000 +No NIH Category available AKT Signaling Pathway;Ablation;Androgens;Automobile Driving;Back;Biochemical;Biological Assay;Cancer Etiology;Cancer Patient;Cell Maintenance;Cell Proliferation;Cell Survival;Cells;Cessation of life;Defect;Development;Drug resistance;Genetic;Goals;Human;Impairment;Inositol;Light;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Mitochondria;Neoplasm Metastasis;Oncogenic;Outcome;Pathologic;Patients;Phosphotransferases;Physiological;Play;Population;Prostate;Prostate Ablation;Prostate Cancer therapy;Proteins;RNA Splicing;Regulation;Reporting;Resistance;Role;Signal Pathway;Signal Transduction;Solid;Specimen;Stem Cell Factor;Testing;United States;Validation;Variant;Xenograft Model;advanced prostate cancer;aldehyde dehydrogenases;androgen deprivation therapy;assay development;cancer drug resistance;cancer initiation;cancer stem cell;castration resistant prostate cancer;clinically relevant;clinically significant;druggable target;experimental study;genetic approach;in vivo;innovation;insight;knock-down;men;metabolomics;mouse model;new therapeutic target;novel;overexpression;patient derived xenograft model;pharmacologic;prostate cancer cell;prostate cancer progression;resistance mechanism;stem cell biomarkers;stem cell population;stemness;survival outcome;therapeutic target;therapeutically effective;therapy resistant;transcriptomics;tumor;tumor metabolism Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance Prostate cancer stem cells (PCSCs) constitute prostate initiation progression metastasis as well as drug resistance leading to castration-resistant prostate cancer (CRPC) which represents a highly aggressive cancer with poor outcome due to the lack of an effectively targeting strategy. Our study aims to identify novel druggable targets critical for maintaining PCSCs and CRPC progression in order to develop an effectively therapeutic strategy to target PCSC-mediated CRPC progression and drug resistance. Our study will not only reveal a paradigm-shift concept and novel mechanistic insight for PCSC regulation but also offer a highly effective strategy for targeting CRPC. NCI 10907171 9/6/23 0:00 PA-21-268 7R01CA256158-03 7 R01 CA 256158 3 "MERCER, NATALIA" 1/3/22 0:00 8/31/27 0:00 Molecular Oncogenesis Study Section[MONC] 9090324 "LIN, HUI-KUAN " Not Applicable 4 PATHOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/6/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 506358 NCI 314508 191850 SummaryProstate cancer is the second leading cause of cancer deaths in the United States. While androgen ablationtherapy (ABT) is the mainstay of therapy for men with prostate cancer most patients with prostate cancer willinevitably develop castration-resistant prostate cancer (CRPC) which no longer responds to ABT treatment.Thus understanding of the mechanisms leading to CRPC and ABT resistance is urgently needed. Severalmechanisms account for the occurrence of CRPC such as activation of 3-kinase/Akt signaling pathway whichplays a critical role in cell proliferation and cell survival and higher expression of AR and AR splicing variantswhich facilitate prostate cancer cell survival under very low androgen concentrations. Of note is that prostatecancer stem cells (PCSCs) also known as cancer initiating cells (CICs) which account for a small cell populationprostate cancer cells are critically involved in the development of CRPC. But how PCSCs are regulated andhow they can be pharmacologically targeted are currently not well understood. While several stem cell factorssuch as SOX2 playing an important role in maintaining PCSC pool and functions are identified there is noeffective strategy to block the action of these proteins in order to eradicate PCSCs within the cancer. Thusidentifying key druggable targets maintaining PCSCs could provide novel paradigms and effective strategies forprostate cancer therapy and overcoming ABT resistance. Our goal in this study is to identify a novel mechanismunderlying PCSC maintenance which could be harnessed to develop an effective strategy for CRPC targeting.Using systematic metabolomics and transcriptomics in conjunction with biochemical validation and in vivo tumordevelopment assays we unraveled a novel oncogenic and metabolic signaling pathway which was elevatedduring ABT treatment and in advanced human prostate cancer is critical for maintaining the stemness and poolof PCSCs and CRPC development. Of note we observed aberrant AMPK activation and AMPK-dependentmitochondria fission upon loss of this metabolic signaling correlated with the defect in stemness and pool ofPCSCs and prostate cancer progression. In light of these findings we hypothesized that this newly discoveredmetabolic signaling is crucial for restricting aberrant AMPK-dependent mitochondrial fission to maintain the pooland stemness of PCSCs thereby leading to CRPC and ABT resistance. Our hypothesis has been formulatedbased on our solid and innovative preliminary results. In this proposal we proposed three specific aims to testthis paradigm-shift hypothesis. Our study has not only revolutionized and significantly advanced ourunderstanding of cancer metabolism in PCSC regulation but also offered a promising strategy to treat advancedprostate cancer and overcoming ABT resistance. 506358 +No NIH Category available Address;Automobile Driving;Biochemical;Biological;Biological Process;Cancer Intervention;Cell Proliferation;Complex;Development;Dose;Event;Genetic;Goals;Growth Factor;Human;Insulin-Like Growth Factor I;Knock-in Mouse;Knowledge;Ligase;Link;Malignant Neoplasms;Mediating;Membrane;Metabolism;Methylation;Methyltransferase;Modeling;Modification;Mus;Oncogenic;Organoids;PIK3CG gene;PRKDC gene;Patients;Phosphorylation;Phosphotransferases;Play;Post-Translational Protein Processing;Process;Proteomics;Regulation;Research;Role;SETDB1 gene;Signal Pathway;Signal Transduction;TRAF6 gene;Technology;Treatment Factor;Ubiquitination;Xenograft procedure;cancer initiation;cancer therapy;druggable target;frontier;innovation;insight;mouse model;novel;pharmacologic;recruit;side effect;small molecule inhibitor;therapeutic target;tumor;tumor progression;tumor xenograft;tumorigenesis;ubiquitin-protein ligase Regulation of oncogenic Akt ubiquitination and activation by diverse mechanisms in cancer NarrativeThe PI3K/Akt signaling is one of most important oncogenic events in human cancers which regulates manyaspects of biological functions including cell proliferation survival and metabolism important for cancerinitiation and progression. The objectives of this study are to dissect the upstream regulatory mechanisms bywhich growth factors activate and recruit SETDB1 and E3 ligases TRAF6 to elicit Akt methylation andsubsequent K63-linked ubiquitination to understand how Akt ubiquitination triggers Akt membranerecruitment and activation and to explore these regulatory mechanisms and its targeting in oncogenicprocesses. Our study represents a highly innovative and paradigm-shift proposal that will not only open up anew avenue for PI3K/Akt signaling regulation but also offer new concepts and strategies for cancer targeting. NCI 10907082 9/6/23 0:00 PA-21-268 7R01CA248037-03 7 R01 CA 248037 3 "LUO, RUIBAI" 7/1/23 0:00 6/30/26 0:00 Molecular Oncogenesis Study Section[MONC] 9090324 "LIN, HUI-KUAN " Not Applicable 4 PATHOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 485743 NCI 306434 179309 SummaryThe PI3K/Akt signaling is one of most important oncogenic events in human cancers. It regulates many aspectsof biological functions including cell proliferation survival and metabolism important for cancer initiation andprogression. While extensive efforts have been made in the last three decades to understand the downstreameffectors responsible for the biological and oncogenic processes regulated by PI3K/Akt signaling the upstreamsignals mediating PI3K/Akt signaling activation upon diverse growth factor stimulation is not well understood.Understanding and defining the upstream mechanisms responsible for PI3K/Akt signaling activation will notonly provide new insight into how PI3K/Akt signaling activation is orchestrated but also offer novel paradigmsand therapeutic targets for cancer intervention. Although it has been well established that PIP3 is critical forthe membrane recruitment and subsequent activation of Akt our recent studies provide the evidence that Aktundergoes methylation and subsequent non-proteolytic K63-linked ubiquitination which are crucial for Aktmembrane recruitment and subsequent phosphorylation and activation upon stimulation with diverse growthfactors opening up a new frontier for Akt signaling regulation. Of note we identified SETDB1 as amethyltransferase for Akt K64 methylation and TRAF6 ligase as an upstream E3 ligase triggering K63-linkedubiquitination and activation of Akt and these events are required for cancer progression. However theoutstanding questions remained to be addressed are how SETDB1 and TRAF6 are activated or recruited to theAkt complex upon growth factor treatment to trigger Akt methylation and subsequent Akt ubiquitination andactivation thus promoting oncogenic processes. The goal of this study is to dissect the upstream regulatorymechanisms by which growth factors activate and recruit SETDB1 and TRAF6 ligase to Akt complex to elicitAkt methylation and subsequent Akt ubiquitination define the mechanism by which Akt ubiquitinationfacilitates Akt membrane localization and activation and finally explore the role of these regulatory modes incancer development and develop small molecule inhibitors targeting these regulatory mechanisms. Ourpreliminary results revealed that SETDB1 and TRAF6 undergo novel posttranslational modifications which arecrucial for methylation ubiquitination and activation of Akt by growth factors and oncogenic activity. Wehypothesized that SETDB1 and TRAF6 undergo the novel posttranslational modification upon growth factortreatment which recruits SETDB1 to the Akt complex and activates TRAF6 E3 ligase to facilitate Aktmethylation and subsequent Akt ubiquitination and activation thus leading to tumorigenesis. Our innovativehypothesis has been formulated based on our preliminary results and prior research. We proposed threespecific aims to validate this provocative and paradigm-shifting concept using cutting-edge technologiesincluding xenograft organoids from genetic mouse tumor models and patient derived tumors patient-derivedmodels (PDX) knockin mouse models genetic mouse tumor models and pharmacological approaches. Thisapplication is significant therefore because it is expected to provide the knowledge needed to developpharmacologic strategies that will allow concurring cancers with aberrant PI3K/Akt activation. Our study willopen up a new avenue for PI3K/Akt signaling regulation but also offer new concepts and strategies for cancertargeting. 485743 +No NIH Category available ATAC-seq;Affect;Androgen Antagonists;Androgen Receptor;Androgens;BRD2 gene;Binding;Binding Sites;Bromodomain;Cancer Patient;Cell Line;Cell model;Cells;ChIP-seq;Chromatin;Clinic;Clinical;Complex;DNA Binding;Data;Data Set;Development;Disease;Disease Progression;Enzymes;Gene Activation;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic Transcription;Genetically Engineered Mouse;Genomics;Glycolysis;Glycolysis Pathway;Goals;Growth;Hormones;In Vitro;LNCaP;Left;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Manuscripts;Maps;Mass Spectrum Analysis;Mediating;Metabolic;Metabolic Diseases;Metabolism;Modeling;Molecular;Mus;Oncogenic;Outcome;Pathway interactions;Patients;Phenotype;Primary Neoplasm;Prognosis;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;RNA Splicing;Receptor Signaling;Regulator Genes;Research;Resistance;Role;Sampling;Side;Signal Transduction;Site;TP53 gene;Terminal Disease;Testing;Therapeutic;Translating;Treatment Failure;Tumor Promotion;Tumorigenicity;VCaP;Validation;Variant;Warburg Effect;YY1 Transcription Factor;Zinc Fingers;advanced prostate cancer;castration resistant prostate cancer;cell growth;clinically relevant;cofactor;cohort;enzyme pathway;experimental study;improved;in vivo Model;inhibitor;innovation;insight;knock-down;loss of function;metabolomics;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;pharmacologic;programs;prostate cancer cell;prostate cancer cell line;prostate cancer model;prostate cancer progression;prostate carcinogenesis;recruit;standard care;targeted agent;therapy development;therapy resistant;transcription factor;transcriptome sequencing;tumor;tumor metabolism The Role of YY1 in Castration-Resistant Prostate Cancer PROJECT NARRATIVECastration-resistant prostate cancer (CRPC) is a lethal disease demanding new treatment strategies.Aggressive phenotypes and/or therapy failure seen in CRPC patients have been linked to the increased tumorcell metabolism and an androgen receptor (AR) splicing variant termed AR-V7 both of which are correlatedwith poorer prognosis in the clinic. However the mechanisms underlying altered tumor metabolism and AR-V7-releated oncogenic programs in CRPC are far from clear. Our recent preliminary studies point to YY1 a zincfinger transcription factor showing significant overexpression during disease progression of CRPC. YY1maintains high expression of both metabolic genes and the AR-V7-related gene targets. YY1 thus constitutes acompletely new mechanism that might account for major malignant alterations in metabolism and androgensignaling seen in CRPC. The current proposal will explore this novel mechanism that underscores CRPCprogression and therapeutic resistance. The successful completion of the proposed research shall allow adeeper understanding of how the terminal CRPC disease progresses and will help to rationally develop novelstrategies to treat the affected patients. Thus this proposal is significant innovative and may potentiallytranslate into the clinic to improve CRPC treatment. NCI 10907068 8/28/23 0:00 PA-21-268 7R01CA262903-03 7 R01 CA 262903 3 "KONDAPAKA, SUDHIR B" 7/15/21 0:00 8/31/26 0:00 Tumor Cell Biology Study Section[TCB] 15714486 "CAI, LING " Not Applicable 4 PATHOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 435136 NCI 281184 153952 PROJECT SUMMARY/ABSTRACTStandard treatment of prostate cancer with current agents fails due to development of therapy resistance andcastration-resistant prostate cancer (CRPC) a terminal disease. CRPC differs from early-staged prostatecancer in its increased reliance on glycolysis (the Warburg effect) as well as emergence of therapy resistancedue to the androgen receptor (AR) splice variant 7 (AR-V7) a truncated constitutively active AR that mediatesoncogenic programs in a hormone-independent manner. However mechanisms underlying altered metabolismand AR-V7-incuded signaling in CRPC remain largely unclear. Our analyses of tumor versus paired normalsamples uncovered overexpression of YY1 a zinc-finger transcription factor during progression of CRPC. Bygenomic profiling (ChIP-seq and RNA-seq) in CRPC cells we demonstrate that YY1 binds to and induces hightranscription of metabolic genes such as PFKP a rate-limiting enzyme for glycolysis. Loss-of-function andrescue studies show a YY1-PFKP axis essential for sustaining glycolysis and malignant growth of CRPC in cellmodels. Additionally YY1 interacts with AR-V7 co-occupying a majority of AR-V7 targets where combinedactions of AR-V7 and YY1 maintain oncogenic signaling. Mass spectrometry-based identification of YY1interactome uncovered YY1s partners including bromodomain proteins. Knockdown of YY1 or blockade ofbromodomain proteins suppressed CRPC growth. We hypothesize that YY1 and AR-V7 act in concert tosustain both tumor metabolism (glycolysis)-related and AR-V7-related gene-expression programs therebyproducing more aggressive tumor phenotypes and therapy resistance in terminal CRPCs; we also hypothesizethat targeting YY1s co-activators reverses oncogenic signaling providing an attractive anti-CPRC therapeutic.Dissecting the molecular mechanisms underlying the YY1-mediated CRPC progression should provide criticalinsights into new treatment strategies. Towards this goal we will use additional models to further define theYY1:AR-V7 co-targeted gene pathways in CRPC; validation of this finding with primary tumor samples will beparadigm-shifting and change current views regarding how oncogenic signaling is wired in CRPC (Aim 1). Wewill define YY1 as a new oncogenic factor in promoting CRPC formation and tumor cell metabolism with celland murine models (Aim 2). Lastly we will determine blockade of YY1-associated co-activator machinery asnew means for treatment of CRPC (Aim 3). Because certain glycolysis pathway enzymes and YY1 cofactorsare potentially druggable with inhibitors completion of the proposed research should not only promote a newmechanistic understanding of CRPC but will yield innovative therapeutics for treatment of affected patients. 435136 +No NIH Category available Age;Aging;Architecture;Area;Atlases;Bar Codes;Cell Aging;Cell Nucleus;Cell Separation;Cells;Colon;Complement;Cytoplasm;Data;Detection;Dissociation;Eye;Fibrosis;Freezing;Genes;Genome;Genomics;Hepatic;Hepatocyte;Heterogeneity;Histologic;Human;In Situ Hybridization;Inferior;Inflammation;Libraries;Lipids;Literature;Liver;Liver diseases;Location;Methodology;Methods;Microscope;Microscopic;Mitochondria;Molecular Target;Monitor;Mus;Names;Oligonucleotide Microarrays;Optics;Output;Performance;Phase;Population;Printing;Procedures;Process;Proteins;RNA;RNA Sequences;Research Personnel;Resolution;Resources;Sampling;Slide;Solid;Surface;System;Techniques;Technology;Time;Tissues;Transcript;Visualization;Vulnerable Populations;Work;cell type;droplet sequencing;histological slides;human tissue;improved;in situ sequencing;liver injury;protein biomarkers;response;senescence;single-cell RNA sequencing;technology development;tissue mapping;transcriptome;transcriptomics Seq-Scope: Microscopic Examination of Spatial Single Cell Transcriptome in Cell and Tissue Senescence PROJECT NARRATIVEWe recently developed Seq-Scope a spatial transcriptomics solution which can provideunprecedented resolution and outstanding data output. In the enclosed proposal we propose toadapt Seq-Scope for detection and characterization of senescent cells from normal humantissue. NCI 10907056 8/28/23 0:00 RFA-RM-21-009 4UH3CA268091-03 4 UH3 CA 268091 3 "JHAPPAN, CHAMELLI" 9/20/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CB-T(70)R] 10376815 "LEE, JUN HEE " Not Applicable 6 PHYSIOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 768615 OD 496676 271939 SUMMARYStandard immunostaining or RNA in situ hybridization can examine only one or a handful of target molecularspecies at a time; therefore the amount of information obtained from a single experimental session is limited.To overcome this emerging Spatial Transcriptomics (ST) techniques aim to examine all genes expressed fromthe genome from a single histological slide. There are three major methodologies of experimentallyimplementing ST: the sequential in situ hybridization method in situ sequencing method and spatial barcodingmethod. Among these the spatial barcoding method is the most straightforward comprehensive and so far theonly method scalable for large amount of samples. The spatial barcoding method reveals both the RNAsequence and their spatial locations by capturing tissue RNA using a spatially-barcoded oligonucleotide array.The current spatial barcoding method however are intrinsically limited by their low resolution and low RNAcapture efficiencies; correspondingly all currently available technologies failed to reveal the microscopicdetails of the spatial transcriptome. We recently developed a technology named Seq-Scope which overcomesall these limitations. Seq-Scope has an effective resolution of 0.5-1 m and reveals over 20 transcripts perm2 area (~50 transcripts/m2 estimated at library saturation). Both resolution and transcriptome captureoutput of Seq-Scope are the best among all available technologies described in the literature so far. With thisunprecedented performance Seq-Scope visualized spatial transcriptome heterogeneity at multiple histologicalscales including tissue zonation according to the portal-central (liver) crypt-surface (colon) and inflammation-fibrosis (injured liver) axes cellular components including single cell types and subtypes and subcellulararchitectures of nucleus cytoplasm and mitochondria. Seq-Scope also has a potential to improve andcomplement current scRNA-seq approaches. In response to the SenNet announcement we propose to adaptand utilize Seq-Scope to provide atlases of cellular senescence in multiple tissues during normal human agingfocusing on the following three aims: (1) Identify and Characterize Hepatic Senescent Cell Population duringLiver Disease. (2) Characterize Age-Associated Changes of Hepatic Spatial Transcriptome. (3) Combine Seq-Scope with Detection of Senescence Protein and Cell-type Marker Proteins.For all aims we will begin with analyzing mouse tissue to establish the feasibility of monitoring cell and tissuesenescence (UG3) and then expand the work in human tissues using the tissue obtained from diverseresources including the SenNet tissue mapping center (TMC) (UH3). Seq-Scope is a versatile technologywhich is quick straightforward scalable and adaptable. Once optimized a single researcher can process 5-10frozen tissue blocks every week to generate a high-quality spatial single cell transcriptome data. Therefore ourteam is confident that we will be able to adapt our technology to any of the tissue systems that are provided bythe SenNet TMC in the UH3 phase. 768615 +No NIH Category available ATAC-seq;Acrylamides;Adult;Affinity;Aging;Antibodies;Bar Codes;Biological Assay;Cell Aging;Cell Communication;Cell model;Cells;Chromatin;Chromosome Mapping;Collaborations;Complex;DNA;Data;Detection;Disease;Dissociation;Equipment;Excision;Fishes;Gel;Gene Expression;Gene Expression Regulation;Generations;Goals;Heart;Heterogeneity;Human;Human Cell Line;In Situ;In Vitro;Individual;Laboratories;Libraries;Life;Liver;Longevity;Lung;Maps;Methodology;Methods;Microfluidics;Mission;Modification;Molecular;Morphology;Mus;Organ;Phase;Phenotype;Post-Translational Protein Processing;Process;Production;Protein Isoforms;Proteins;Proteome;Public Health;RNA;Reagent;Research;Research Personnel;Resolution;Running;Site;Slide;Spatial Distribution;Specificity;Structure of parenchyma of lung;Surface;Surgeon;Techniques;Technology;Time;Tissue Donors;Tissue Procurements;Tissues;United States National Institutes of Health;Validation;Work;cell type;cellular imaging;combinatorial;cost;fabrication;healthspan;human tissue;image guided;improved;in vivo;indexing;innovation;luminescence resonance energy transfer;meter;model organism;multimodal data;multimodality;multiple omics;multiplexed imaging;nanobodies;new technology;novel;olfactory bulb;paracrine;programs;scale up;senescence;success;tissue mapping;transcriptome;transcriptome sequencing;transcriptomic profiling PIXEL-seq-based spatial multi-omic profiling for senescent cell mapping with single-cell resolution NARRATIVEThe proposed research is relevant to public health because it focuses on developing a novel technology formapping senescent cells in human tissues. This technology will be used to spatially map gene expressionprotein and open chromatin in cells with high spatial resolution. Thus the proposed research is relevant to theNIHs mission that pertains to understanding of the aging process and treatment of aging-related diseases. NCI 10907054 8/29/23 0:00 RFA-RM-21-009 4UH3CA268096-03 4 UH3 CA 268096 3 "JHAPPAN, CHAMELLI" 9/24/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CB-T(70)R] 10418917 "GU, LIANGCAI " Not Applicable 7 BIOCHEMISTRY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 851525 OD 550000 301525 ABSTRACTComprehensive identification and characterization of senescent cells in morphologically intact human tissues isimportant for understanding senescence in vivo and the targeted removal of these cells to improve healthspanand lifespan. This task has been challenging due to the lack of universal and unequivocal markers characterizingthe senescence state which reflects the complexity of the senescence phenotype and the existence of highlyheterogeneous senescence programs. A preferred avenue for discovering senescence markers is to spatiallymap omics states of cell types in different tissues and life stages at single cell resolution. The overall goal ofthis project is to (i) develop a spatial single-cell-resolution multimodal method that simultaneously analyzetranscriptome open chromatin and proteome (or secretome) and (ii) optimize and scale it for mappingsenescent cells in human tissues. The PIs laboratory has recently developed a novel technique PIXEL-seq(polony-indexed library-sequencing) and applied it to spatially profile transcriptome with 1-m resolution and highRNA capture efficiency. To realize its potential for studying in vivo senescence mechanism and production-scaledata generation three specific aims will be pursued: 1) In UG3 Year 1 demonstrate PIXEL-seq-based spatialtranscriptome proteome and ATAC-seq assays with single-cell resolution; 2) In UH3 Year 2 optimize andcombine these assays for human tissue mapping; and 3) In UH3 Years 3-4 scale up application to human heartliver and lung tissue mapping. Under the first aim PIXEL-seq will be developed to achieve single-cell resolutionby image-guided cell segmentation (Aim 1A) and expanded to spatial proteome (Aim 1B) and open chromatinaccessibility assays (Aim 1C) by rendering DNA-tagged antibodies and Tn5-treated chromosomal DNAsrespectively to capture by polony gels. For the second aim the proteome assay will be optimized and scaled to200-plex using polyclonal mini-binders allowing the cross-validation of senescence markers and associatedisoforms and post-translational modifications (Aim 2A). These assays will be integrated for multimodal datacapture and validated using human tissues (Aim 2B). In the third aim the application will be scaled up byincreasing throughput of polony gel fabrication (Aim 3A) and to deliver to the CODCC for public release of high-quality data on several sites of multiple organs from several individual tissue donors (Aim 3B and 3C). Theinvestigators will also participate in the Consortium common project and other collaborations yet to be formed.The proposed project is innovative in that this method will for the first time generate the spatial multimodal humantissue data at unprecedented depth and resolution. It is significant because the assays do not require specializedequipment and can be widely implemented in the SenNet and other single cell consortia. 851525 +No NIH Category available 3-Dimensional;Address;Aging;Autophagocytosis;Behavior;Biological Models;Biology;CDKN2A gene;Cell Aging;Cell Cycle Arrest;Cells;Chromatin;Cytolysis;Cytoplasm;Data Analyses;Detection;Disease;Disease Progression;Embryonic Development;Flow Cytometry;Gamma-H2AX;General Hospitals;Goals;Harvest;Heterogeneity;Human;Impairment;Inflammation;Inflammatory;Inflammatory Response;Institutional Review Boards;Intervention;Lamin B1;Lung;Lung diseases;Macrophage;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Massachusetts;Mission;Mus;New England;Nuclear;Pathologic;Pathway interactions;Phase;Population;Procedures;Proteins;Proteome;Proteomics;Protocols documentation;Research Personnel;Resolution;SIRT1 gene;Services;Specimen;Stimulator of Interferon Genes;Structure of parenchyma of lung;Technology;Testing;Tissues;aged;beta-Galactosidase;biomarker identification;biomarker panel;cell type;cohort;data acquisition;detection sensitivity;embryonic stem cell;human disease;human tissue;improved;innovation;invention;new technology;novel;novel marker;protein complex;senescence;single-cell RNA sequencing;stem cell differentiation;telomere;tissue mapping;tissue preparation;tissue regeneration;tool;tumorigenesis;wound healing Single-cell proteomic identification of novel markers of senescence PROJECT NARRATIVESenescence is a terminal cellular state that contributes to many human diseases. Identification and mapping ofsenescent cells in tissues will help understand the mechanisms of diseases with the potential to discover noveldisease therapies. We propose to employ a newly invented single-cell proteomic approach to investigate theproteomes of senescent cells in the lungs to reveal novel markers of senescent cells. The identified novelmarkers will facilitate our understanding of lung biology and disease and further promote the identification andcharacterization of senescent cells in other human tissues. NCI 10907052 9/13/23 0:00 RFA-RM-21-009 4UH3CA268117-03 4 UH3 CA 268117 3 "JHAPPAN, CHAMELLI" 9/22/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CB-T(70)R] 11729543 "DOU, ZHIXUN " "RAJAGOPAL, JAYARAJ ; SLAVOV, NIKOLAI " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/13/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 901848 OD 683771 218077 PROJECT SUMMARYCellular senescence is a stable form of cell cycle arrest associated with pro-inflammatory responses. On the onehand senescent cells are a barrier for tumorigenesis and promote wound healing and embryogenesis. On the otherhand senescent cells accumulate in aged and diseased tissues where they impair tissue renewal and contribute toinflammation and disease progression. Identification and characterization of senescent cells in human tissues willcontribute to our understanding of human diseases. Thus mapping senescent cells at the 3-dimensional level andsingle-cell resolution in human tissues is an important biomedical objective.Accurate mapping of senescent cells requires reliable markers to specifically identify senescent cells.Currently the senescence field has limited markers to unambiguously distinguish between senescent cells andcells in other pathological states. In addition the available markers do not address the heterogeneity of senescentcells in tissues. To overcome these limitations we propose to employ a novel single-cell proteomic technologyto investigate the proteomes of senescent cells at the single-cell level with the goal to reveal novel markers ofsenescence which can be used to identify and map senescent cells in human tissues.Our group has recently developed a novel technology termed Single-Cell ProtEomics by MassSpectrometry (SCoPE2). This platform combines automated cell lysis improved detection sensitivity andoptimized data acquisition and analyses allowing detection and quantification of thousands of proteins within asingle cell. We have applied this technology to study embryonic stem cell differentiation and macrophagepolarization revealing their heterogeneity and alterations of proteomes at the single-cell level.In this application we will use the lung as a model system which accumulate senescent cells thatcontribute to aging and lung diseases. In the UG3 phase we will isolate senescent cells from the lungs of naturallyaged mice. The isolated senescent cells together with control cells will be subjected to SCoPE2 procedure toquantify their proteomes at the single-cell level allowing us to create unique signatures for potentially diversesenescent cell populations. This will help discover novel markers of senescent cells that are not possible withtraditional technologies. In the UH3 phase we will apply this technology to human lungs to validate and toidentify new markers of senescence. In aggregate we will establish new ways of identifying senescent cellsthat should offer new tools to probe senescent cells in human tissues facilitating tissue mapping of senescentcells of the SenNet initiative. In addition this study has the potential to reveal new biology of senescenceaddressing the heterogeneity and proteome alterations at the single-cell level. 901848 +No NIH Category available 3-Dimensional;Affect;Age;Animal Model;Arthritis;Atlases;Attenuated;Autoradiography;Biological;Biological Markers;Bone Marrow;Cartilage;Cartilage Matrix;Cartilage injury;Cell Aging;Cell Cycle;Cell Cycle Arrest;Cell division;Cells;Characteristics;Chondrocytes;Chronic;Collaborations;Communities;Data;Defect;Degenerative Disorder;Degenerative polyarthritis;Detection;Diagnosis;Diagnostic tests;Direct Costs;Disease Progression;Enzymes;Event;Facilities and Administrative Costs;Femur;Flow Cytometry;Fluorine;Goals;Health;Hip Osteoarthritis;Hospitalization;Human;Human Volunteers;Hyaline Cartilage;Image;Imaging Device;Imaging technology;Immunohistochemistry;In Situ;Individual;Infection;Inflammation;Inflammatory;Intravenous;Investigation;Joints;Label;Link;Macrophage;Magnetic Resonance Imaging;Malignant Neoplasms;Maps;Measures;Medical Care Costs;Medical Imaging;Monitor;Morbidity - disease rate;Mus;Musculoskeletal;Musculoskeletal Diseases;Natural regeneration;Outpatients;Oxidative Stress;Pain;Pathogenesis;Patients;Phase;Phase I Clinical Trials;Phenotype;Play;Positron-Emission Tomography;Process;Production;Proteins;Reactive Oxygen Species;Reference Standards;Reporter Genes;Research;Resolution;Rheumatoid Arthritis;Rodent;Role;Sensitivity and Specificity;Signal Transduction;Source;Specimen;Standardization;Stress;Synovial Cell;Synovial Membrane;System;Techniques;Telomere Shortening;Testing;Therapeutic;Thick;Time;Tissues;Trauma;Traumatic Arthropathy;United States;Visit;Visualization;age related;arthropathies;articular cartilage;beta-Galactosidase;bone;cartilage repair;clinical translation;cytokine;disability;early childhood;first-in-human;fluorescence imaging;glycation;healing;human tissue;hydrophilicity;imaging approach;imaging biomarker;improved;in situ imaging;in vivo;intravenous administration;intravenous injection;joint injury;lost earning;mouse model;musculoskeletal disorder diagnosis;novel;novel strategies;prevent;radiotracer;response;senescence;tissue mapping;tissue repair;treatment response;uptake Cellular Senescence Network: New Imaging Tools for Arthritis Imaging PROJECT NARRATIVECellular senescence the cessation of cell divisions with increasing age has been recently identified as a majorcause for the inability of the body to self-repair tissue damage due to trauma infection/inflammation anddegenerative disorders. The goal of our project is to test the first medical imaging biomarker for the detection ofsenescent cells first in animal models and then in human volunteers. Results will be used to map age-dependent distributions of senescent cells in the body and monitor the efficacy of novel senolytic therapies. NCI 10907051 9/1/23 0:00 RFA-RM-21-009 4UH3CA268112-03 4 UH3 CA 268112 3 "JHAPPAN, CHAMELLI" 9/23/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CB-T(70)R] 8527084 "DALDRUP-LINK, HEIKE ELIZABETH" Not Applicable 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 642815 OD 443454 199361 Cellular Senescence Network: New Imaging Tools for Arthritis ImagingSenescent cells play a key role in the pathogenesis of major musculoskeletal diseases such as chonicinflammatory joint disorders rheumatoid arthritis (RA) and osteoarthritis (OA). Cellular senescence in articularjoints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhancedproduction of inflammatory cytokines which in turn perpetuates joint damage and leads to significantmorbidities of afflicted patients. It has been recently discovered that clearance of senescent cells by novelsenolytic therapies can attenuate the chronic inflammatory microenvironment of RA and OA and therebyprevent further disease progression and support healing processes. In order to identify patients who mightbenefit from these new senolytic therapies and to monitor therapy response there is a significant unmet needin identifying and mapping of senescent cells in articular joints and related musculoskeletal tissues. To fill thisgap we propose to develop a new imaging biomarker that will significantly improve our capabilities to identifyand characterize senescent cells in human musculoskeletal tissues. We have generated exciting preliminarydata that show that 3-D-galacto-2-nitropyridine (PyGal) a known hydrophilic b-gal substrate can be labeledwith 18F-fluorine. Upon intravenous injection 18F-PyGal enters senescent cells and is selectively cleaved by b-galactosidase a senescence-specific enzyme in these cells. The trapped radiotracer can be detected withpositron emission tomography (PET) and autoradiography thereby serving as an imaging biomarker forsenescent cells. We propose to introduce 18F-PyGal as the first clinically translatable radiotracer whichcan detect senescent cells in vivo in bones and joints of animal models and human volunteers. In theinitial UG3 phase of our project we will demonstrate proof-of-principle of this new imaging technology in amouse model of RA and a large animal model of OA. In the subsequent UH3 phase we will scale optimizeand validate 18F-PyGal PET for mapping human tissues first in human joint specimen and second in a first-in-human phase I clinical trial. At the end of the UH3 phase we will have delivered a novel imaging tool that canvisualize and quantify the presence and distribution of senescent cells in multiple musculoskeletal tissuesdirectly non-invasively and longitudinally in vivo. Results will be catalogized in a planned senescence cell atlasand shared with the cellular senescence network. Our 18F-PyGal-PET imaging tool will significantly improveupon state-of-the-art imaging technologies for the diagnosis of musculoskeletal disorders can be integratedwith other imaging technologies such as MRI and is ultimately capable of being scaled to map senescent cellsin multiple human tissues in a high-throughput fashion. Since 18F-PyGal targets senescent cells in multipledifferent tissues and can be easily imaged with widely available medical imaging technologies ourproposed new senescence imaging biomarker can be expected to be used widely by tissue mappingcenters and relevant research communities. 642815 +No NIH Category available Adnexal Mass;Affect;Age;Antigens;Artificial Intelligence;Benign;Biological Markers;Biometry;Blood;CA-125 Antigen;Cancer Detection;Cancer Etiology;Cancer Patient;Cancerous;Cessation of life;Clinical;Clinical Research;Data;Data Set;Detection;Development;Diagnosis;Diagnostic;Diagnostic Procedure;Diagnostic Specificity;Disease;Early Diagnosis;Evaluation;Excision;Female;Future;Goals;Gynecologic Oncology;Histologic;Human;Image;Immune response;Immune system;Immunogenomics;Immunology;Irrigation;Lesion;Life;Logistic Regressions;Low Prevalence;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Methods;Modeling;Neoplasm Metastasis;Operative Surgical Procedures;Ovarian;Ovarian Mass;Ovarian Serous Adenocarcinoma;Ovary;Patients;Pelvis;Performance;Peripheral;Pilot Projects;Planned Pregnancy;Process;Proliferating;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Public Domains;Reporter;Representational Oligonucleotide Microarray Analysis;Research Personnel;Risk;Role;Route;Sampling;Screening for Ovarian Cancer;Sensitivity and Specificity;Serum;Signal Transduction;Skates;Specificity;Specimen;Stage at Diagnosis;Symptoms;T cell receptor repertoire sequencing;T-Cell Receptor;T-Lymphocyte;T-cell receptor repertoire;Testing;Tissues;Training;Tumor Antigens;Tumor Markers;Ultrasonography;Unnecessary Surgery;Uterus;Vagina;Validation;Woman;accurate diagnosis;antigen-specific T cells;biobank;biomarker development;cancer biomarkers;cancer diagnosis;cohort;collaborative trial;detection method;detection sensitivity;diagnosis standard;diagnostic accuracy;diagnostic biomarker;diagnostic criteria;disease diagnosis;immunogenicity;improved;indexing;innovation;machine learning method;machine learning model;machine learning prediction;mortality;multimodality;multiplex assay;noninvasive diagnosis;novel;preservation;prospective;recruit;reproductive;screening;sequencing platform;software development;specific biomarkers;tool;transcriptome sequencing;tumor;tumor progression;young woman Tracking Peripheral T-Cell Repertoire Changes for Preoperative and Early Ovarian Cancer Diagnosis Project NarrativeOvarian cancer is the deadliest female cancer in the world and currently there is no effective preoperativediagnostic biomarker. We have demonstrated that the circulating T cells can be used as indicators of cancerstatus and plan to prospectively collect an ovarian cancer patient cohort with matched immunogenomics dataand to train a machine learning model to obtain a novel TCR-based biomarker. Successful delivery of our Aimswill provide a validated independent ovarian cancer biomarker with improved diagnostic accuracy. NCI 10906611 9/21/23 0:00 PA-21-268 7R01CA258524-03 7 R01 CA 258524 3 "PATRIOTIS, CHRISTOS F" 1/1/22 0:00 12/31/26 0:00 Clinical Oncology Study Section[CONC] 15395861 "LI, BO " "LEA, JAYANTHI S; SKATES, STEVEN J" 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 9/1/23 0:00 12/31/23 0:00 394 Non-SBIR/STTR 2023 647582 NCI 423676 223906 Project SummaryOvarian cancer is the most lethal female cancer. When the disease can be diagnosed at early stage there isstriking survival improvement (five year survival 90%) compared to late stages ( 40%). However currentlyno early detection method for ovarian cancer has enough accuracy and most tumors already progressed toadvanced stages at diagnosis. Furthermore over 70% of the adnexal masses detected on preoperativeimaging are found to be benign after pelvic surgery. Current clinical tests rely on serum CA-125 andsonograms to diagnose the ovarian adnexal masses. However CA-125 is elevated by many common benignconditions; and ultrasound imaging of ovary frequently misses small but malignant lesions. As a result surgicalremoval of the lesion and histologic evaluation remains the only gold standard for diagnosis. These limitationsdictate an urgent clinical need of a better preoperative diagnostic method with high detection accuracy tolower the mortality rate reduce unnecessary surgeries and preserve the life choices for many patientsespecially young women at reproductive age planning for pregnancies. Here we propose a completelydifferent route to detect ovarian cancer signals from the blood T cell repertoire. This is feasible because the Tlymphocytes recognize tumor antigens at initial stages proliferate and alter the peripheral T cell repertoire.Therefore detection of cancer-associated T cells (CAT) in the blood provides an exciting novel opportunity fornon-invasive cancer diagnosis. However no prior studies have achieved this goal because it is difficult toidentify CAT in high-throughput as most of the cancer antigens remain unknown. To prepare for this task wedeveloped the software TRUST and iSMART to obtain antigen-specific TCRs from cancer datasets. Thesetools have enabled us to produce a large training set of CATs which allowed us to identify diagnostic TCRs forthe ovarian cancer patients. Following this result we further developed DeepCAT for pan-cancer predictionusing blood TCR sequencing data and demonstrated over 99% specificity and 86% sensitivity in a pilot studyto predict ovarian cancer patients (n=14) from healthy donors (n=176). To develop this approach into a novelovarian cancer specific biomarker we have established a biorepository to prospectively collect specimens frompatients with benign or malignant ovarian lesions and from healthy donors of similar age span with relatedclinical information. In Aim 1 we will generate TCR sequencing data of the new patient samples to develop anovel TCR-based ovarian cancer predictor using machine learning method. In Aim 2 we will combine thisapproach with existing clinical tests to obtain a multi-modality biomarker and independently test it using thesamples from the Uterine Lavage cohort led by Dr. Steven Skates. These Aims will be delivered by the PIs andco-investigators with complementary expertise covering gynecological oncology clinical cohort recruitmentbiostatistics artificial intelligence immunology and ovarian cancer biomarker development. 647582 +No NIH Category available Acceleration;Adoption;Blood;Cancer Detection;Cancer Patient;Cloud Computing;Contracts;Data;Data Analyses;Data Commons;Data Set;Diagnostic;Ensure;Genomics;Goals;Image;Imaging Device;Methylation;Multiomic Data;Patient Care;Phase;Population;Small Business Innovation Research Grant;Testing;Tube;anticancer research;cancer therapy;clinical application;cloud based;computational platform;data repository;deep learning;diagnostic tool;epigenomics;informatics tool;liquid biopsy;multiple omics;petabyte;prototype;radiomics;recruit;tool;tumor;usability NCI SBIR Contract Topic 428 Phase II (Solicitation Number: BAA 75N91022R00027): Cloud-based Liquid-biopsy and Radiomics Platform for the Cancer Research Data Commons n/a NCI 10906504 75N91023C00022-0-9999-1 N44 8/15/23 0:00 8/14/25 0:00 79309991 "LIU, CHUN-CHI (JIM) " Not Applicable 36 Unavailable 81137109 SGJ1NZDE89G4 81137109 SGJ1NZDE89G4 US 34.070199 -118.45102 10053541 "EARLYDIAGNOSTICS, INC." LOS ANGELES CA Domestic For-Profits 90095 UNITED STATES N R and D Contracts 2023 1994911 NCI Integrative analysis of multi-omics datasets is revolutionizing cancer research and patient care. To take advantage of the full breadth of CRDCs petabyte-scale data EarlyDx will seamlessly integrate its liquid biopsy cloud-computing platform with CRDC data repositories. Liquid biopsies provide a non-invasive approach for interrogating the genomic and epigenomic profiles of tumors. Co-analysis of CRDC datasets with userprovided data from a tube of blood will ensure broad user adoption of the CRDC. To that end in Phase I EarlyDx has developed a prototype that successfully integrates its informatics tools with the CRDC multi-omics datasets through the DCF. The goal of this Phase II project is to finalize the Phase I prototype and expand the prototype to integrate imaging data in the CRDC and implement deep learning tools for integrative multi-omics and radiomics analysis. Specifically we will conduct the following aims: 1) finalize the Phase I prototype for multi-omics analysis; 2) expand the platform for CRDC imaging data analysis; 3) implement integrative analysis tools; 4) implement diagnostic tools; 5) recruit at least 100 users for usability testing. Our platform with CRDC integration will accelerate cancer research and promote clinical applications such as cancer detection and treatment in broad populations. 1994911 +No NIH Category available Address;African American;American Indians;Biomedical Research;Black race;Cancer Center;Cancer Center Support Grant;Cancer health equity;Catchment Area;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Communities;Community Outreach;Disparity;Education;Ensure;Faculty;Fostering;Funding;Goals;Grant;Growth;Health;Health Professional;Health Technology;Incidence;Individual;Infrastructure;Intervention;Investments;Leadership;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of pancreas;Mentorship;Minority Groups;Mission;NCI-Designated Cancer Center;Oklahoma;Oncology;Persons;Population;Positioning Attribute;Publications;Reporting;Research;Research Activity;Research Peer Review;Resources;Rural Population;Science;Site;Strategic Planning;Students;Therapeutic;Training;Training Activity;Translating;Translations;Tribes;United States National Institutes of Health;Universities;Vision;Vulnerable Populations;Woman;cancer care;cancer health disparity;cancer prevention;cancer risk;community setting;design;health equity;health equity promotion;improved outcome;innovation;mHealth;member;morphogens;mortality;multidisciplinary;next generation;novel;outreach;patient oriented;programs;recruit;social health determinants;tobacco control;underserved minority Stephenson Cancer Center - Cancer Center Support Grant OVERALL: PROJECT NARRATIVEThe OU Stephenson Cancer Center fulfills a unique need in Oklahoma and the region by conducting innovativeand impactful research that seeks to translate novel discoveries into the clinical or community setting through atransdisciplinary team-based approach. The goal of these efforts is to decrease cancer incidence and improveoutcomes for Oklahomans and all individuals with a special emphasis on promoting cancer health equityamong the states underserved minority populations. NCI 10906448 9/4/23 0:00 PAR-21-321 3P30CA225520-06S4 3 P30 CA 225520 6 S4 "SHAFIK, HASNAA" 5/1/18 0:00 4/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 2488117 "MANNEL, ROBERT S." Not Applicable 5 OBSTETRICS & GYNECOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 5/8/23 0:00 4/30/24 0:00 353 Research Centers 2023 523281 NCI 409949 113332 OVERALL: ABSTRACTSince achieving NCI designation in 2018 the Stephenson Cancer Center (SCC) at the University of Oklahomahas continued to grow and mature as an organization. The SCCs vision to eliminate cancer in Oklahoma andbeyond is advanced through its mission to provide patient-centered research-driven multidisciplinary cancercare to all Oklahomans. As Oklahomas only NCI-designated cancer center the SCC serves a statewidecatchment area that presents unique challenges with social determinants of health and high disparities incancer incidence and mortality especially for the states American Indian (AI) Black/African American andrural populations. The SCC has the ability to be impactful in its catchment area and nationally due tostrategically targeted recruitments and investments that have leveraged key differentiating factors: 1) the SCCcontinues to invest in creating and sustaining health and research partnerships with AI tribal partnersthroughout Oklahoma and currently has 22 NIH funded projects addressing AI cancer disparities; 2) the SCCcontinues to be a national leader in the NCI/NCTN and has established a statewide network of affiliate sites toensure access to NCI-sponsored clinical trials throughout its catchment area; 3) the SCC has developed strongteam-based research across all of its programs with national leadership in gynecologic colon and pancreaticcancers cancer prevention cancer therapeutics gero-oncology and tobacco control; and 4) the SCC isbuilding upon its national leadership in mobile health technologies to address the burden on cancer in rural andvulnerable populations.Multiple NCI CCSG metrics emphasize the growth and maturation of the SCC during the reporting period(2017-21). SCC membership increased from 83 to 120 (45%) with 31 of these new members being externallyrecruited to add expertise to programs. Annual peer-reviewed research funding (DC) grew 61% ($14.28M $22.97M) and total annual research funding grew 42% ($30.13M $43.09M). The overall five-year number ofscientific publications has increased by 54% since the last reporting period (945 1454) with 16% having animpact factor 10 (up from 7%). Team science has been emphasized resulting in 139 collaborative grants(36% increase) and a 17% inter-programmatic publication rate (up from 4%) over the prior reporting period.The number of annual active interventional IITs has doubled from 20 to 40 over the past five years with annualaccruals to interventional IITs increasing from 661 (2017) to 927 (2021) a 40% increase. This degree ofimpactful growth has been possible due to the infrastructure made available through the CCSG and haspositioned the SCC for a successful renewal as a NCI-designated cancer center. 523281 +No NIH Category available AIDS Malignancy Consortium;AIDS clinical trial group;AIDS related cancer;African;Area;Clinical Research;Clinical Trials;Collaborations;Communication;Country;Data;Dedications;Electronic Mail;Evaluation;Flowers;Funding;Goals;Grant;HIV;Hospitals;Human Subject Research;Individual;Infrastructure;Institution;Kaposi Sarcoma;Leadership;Lymphoma;Malawi;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Names;Patients;Personal Satisfaction;Progress Reports;Records;Reporting;Research;Research Activity;Research Personnel;Research Support;Resource Sharing;Resources;Schedule;Site;South Africa;Training;Trust;Universities;Work;cancer care;low and middle-income countries;meetings;member;operation;programs;social stigma;success;web site Administrative Core PROJECT NARRATIVE: ADMINISTRATIVE COREThis application responds to RFA-CA-20-001 and will establish a HIV-Associated Malignancy Research Centerin the U.S. and Low- and Middle-Income Countries (LMIC) named the UNC-Malawi-South Africa CancerConsortium (UMSACC). This is a collaborative research center between sites in the USA Malawi and SouthAfrica. The Administrative Core will oversee operation coordination management evaluation of projects andcores and collaborations of the consortium. NCI 10906424 9/7/23 0:00 PA-20-272 3U54CA254564-04S1 3 U54 CA 254564 4 S1 "DOMINGUEZ, GERALDINA" 8/13/20 0:00 7/31/25 0:00 ZCA1 7674 6931559 "DAMANIA, BLOSSOM A" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 172245 143864 28381 ABSTRACT: ADMINISTRATIVE COREThis application responds to RFA-CA-20-001 and will establish a HIV-Associated Malignancy Research Centerin the U.S. and Low- and Middle-Income Countries (LMIC) named the UNC-Malawi-South Africa CancerConsortium (UMSACC). This is a collaborative research center between sites in the USA Malawi and SouthAfrica and builds upon strong prior collaborations. The Administrative Core is led by a team of leaders whoalso serve as multiple PIs for the overall U54 application. These include Dr. Blossom Damania (USA) Dr. SamPhiri (Malawi) Dr. Paul Ruff (South Africa) Dr. Carla Chibwesha (USA and South Africa) Dr. Yuri Fedoriw(USA) and Dr. Dirk Dittmer (USA). The Administrative Core is supported by strong administrative units at allUMSACC participating institutions in the USA Malawi and South Africa.The Administrative Core will coordinate and manage the individual components including projects and coresof the consortium. The Administrative Core will assist with operational and budgetary aspects includingsubmission of progress reports communication among consortium partners local stakeholders and the NCI.The Administrative Core will initiate and conduct activities that enhance collaborations among partners in theUSA Malawi and South Africa as well as partners and consortia in other sub-Saharan African countries.These activities will focus on research and training related to HIV-associated malignancies at UNC Chapel HillUSA; Lighthouse Trust Malawi; UNC Project-Malawi; Kamuzu Central Hospital Malawi; University ofWitwatersrand South Africa; and Stellenbosch University South Africa. The Administrative Core will alsoassemble an External Advisory Board and a Scientific Advisory Board and coordinate UMSACC participationin annual NCI consortia Meetings. Thus in summary the Administrative Core will oversee operationcoordination management evaluation of projects and cores and collaborations of the consortium. +No NIH Category available Improving the Generalizability of Deep Neural Networks by Teaching Single Nucleotide Polymorphisms Associated with LDCT Features PROJECT NARRATIVEStandard diagnostic practice for non-small cell lung cancer (NSCLC) focuses on nodular characteristics such asdiameter and growth rate over sequential scans thus ignoring important diagnostic features in the surroundingparenchyma such as emphysema and chronic inflammation that are associated with an increased risk of a nodulebeing malignant. Understanding the key parenchymal and tumor-specific features together with other biologictraits that determine whether a nodule is malignant or benign will improve early diagnosis of NSCLC. We willdevelop convolutional neural networks (CNNs) that utilize these features and traits to provide improveddiagnostic accuracy of indeterminate pulmonary nodules seen in low-dose computed tomography images. NCI 10905205 9/8/23 0:00 RFA-CA-21-059 4K00CA274713-02 4 K00 CA 274713 2 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/27 0:00 ZCA1-PCRB-H(M1) 16005858 "MASQUELIN, AXEL HERVE" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 97200 NCI 90000 7200 PROJECT SUMMARYDiagnostic and treatment approaches for non-small cell lung cancer (NSCLC) have evolved over the last decadefrom primarily empirical methodologies to objective strategies that rely on clinical characteristics of the patientand morphological features of the nodule. Following recommendations by the United States Preventive ServiceTask Force (USPSTF) high-risk individuals are screened yearly with low-dose computed tomography (LDCT)as this provides high sensitivity with acceptable specificity for lung cancer. However the introduction of LDCTas the primary screening modality for lung cancer has increased detection rates of indeterminate pulmonarynodules that then require invasive investigation. This decreases the quality of life for at-risk individuals throughrepeated follow-ups and procedures and greatly increases anxiety over what usually turns out to a benignnodule. In this proposal we aim to improve upon these outcomes by determining the features that convolutionalneural networks (CNNs) utilize when classifying lung nodules as either or benign. We will also determine ifproviding CNNs with pre-specified histologic image features known to be associated with lung cancer improvestheir ability to generalize to novel images outside the image set used to train them. The central hypothesis ofthis proposal is that increasing the attention of a CNN on LDCT image features that are accepted asbeing pathophysiologically relevant will improve its generalizability to novel images and thus its abilityto accurately distinguish between malignant versus benign nodules. In the F99 Aim of this proposal wewill address this hypothesis by utilizing LDCT images from the National Lung Screening Trial (NLST) togetherwith concept activation vectors to determine which parenchymal and tumor-specific features are used by CNNsto classify lung nodules. In the K00 aim we will determine if endophenotypes extracted from the COPDgeneLDCT image set can be used to improve CNN generalizability. Completion of these aims will lead to an increasedunderstanding of the morphologic biomarkers of lung cancer inherent in LDCT images of the lung that are mostimportant for accurate diagnosis. This will have potential application to the improvement of CNN classificationperformance in other medical domains. In addition by adhering to the training program outlined in this proposalI will gain high levels of expertise in image biomarkers early cancer pathogenesis and detection geneticnetworks and genomics. These will collectively serve as a solid foundation for my future career as anindependent biomedical investigator. 97200 +No NIH Category available 17 year old;Address;Area;Cancer Survivor;Caring;Clinic;Clinical;Cluster randomized trial;Evidence based intervention;General Population;Health Personnel;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Intervention;Knowledge;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;National Cancer Institute;Outcome;Parents;Pediatric Oncology;Persons;Prevention;Provider;Recommendation;Research;Research Priority;Testing;Vaccines;childhood cancer survivor;chronic infection;effectiveness evaluation;follow-up;health care delivery;high risk;improved;prevent;skills;uptake;vaccine acceptance;young cancer survivor Implementation of a Provider-Focused Intervention for Maximizing HPV Vaccine Uptake in Young Cancer Survivors receiving Follow-Up Care in Pediatric Oncology Practices: A Cluster-Randomized Trial The proposed research is relevant to public health because it focuses on increasing the uptake of the humanpapillomavirus (HPV) vaccine in young cancer survivors a vulnerable population at high risk for developing newcancers (such as cervical and anal cancer) caused by persistent HPV infection. An effective vaccine exists thatcan prevent these cancers but HPV vaccine uptake is low among young cancer survivors (fewer than 1 in 4have received the vaccine). This proposed research will provide important information that can be used toimplement new strategies to increase the uptake of the HPV vaccine among young cancer survivors and thusis relevant to the NIHs mission to reduce illness and disability. NCI 10905151 9/14/23 0:00 RFA-CA-19-033 4U01CA246567-02 4 U01 CA 246567 2 "GRIMES, GENEVIEVE M" 9/18/20 0:00 8/31/25 0:00 ZCA1-RPRB-L(M2) 8874439 "LANDIER, WENDY " "KLOSKY, JAMES " 7 PEDIATRICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 581623 NCI 514254 67369 Modified Project Summary/Abstract SectionPROJECT SUMMARY/ABSTRACTChildhood cancer survivors are at high risk for developing new cancers (such as cervical and anal cancer)caused by persistent infection with the human papillomavirus (HPV). An effective vaccine exists that can preventthese cancers but uptake of the HPV vaccine is low among young cancer survivors (fewer than 1 in 4 havereceived the vaccine). Lack of a healthcare provider recommendation for the HPV vaccine is the most commonreason that cancer survivors fail to get the HPV vaccine. Strategies that are most successful in increasing HPVvaccine uptake in the general population focus on improving healthcare provider knowledge about the HPVvaccine enhancing the skills that healthcare providers need to effectively recommend the vaccine to youngpeople and their parents and reducing barriers to receiving the vaccine. This proposed research will evaluatethe effectiveness and implementation of an evidence-based intervention adapted for use by healthcare providersin pediatric oncology clinics to increase the uptake of HPV vaccine among young cancer survivors (9 to 17 yearsof age and at least one year off-therapy). If the intervention is effective in improving and sustaining increaseduptake of the HPV vaccine in young cancer survivors this study will contribute important information needed tomove forward with testing the widespread use of the intervention in pediatric oncology practices. This proposedresearch addresses improving healthcare delivery and clinical outcomes for cancer survivors through preventionof HPV-associated cancers which are high-priority research areas for the National Cancer Institute. 581623 +No NIH Category available Acceleration;Area;Award;Biological Markers;Cancer Burden;Cancer Center;Cancer Control;Cancer Model;Catchment Area;Clinical;Clinical Research;Communication;Communities;Comprehensive Cancer Center;Developmental Therapeutics Program;Diagnosis;Education;Ensure;Epigenetic Process;Equity;Faculty;Family;Funding;Goals;Grant;Growth;Human;Image;Immunologics;Incidence;Individual;Infrastructure;Innovative Therapy;Institution;Intervention;Journals;Knowledge;Leadership;Malignant Neoplasms;Manuscripts;Minority Groups;Minority Participation;Mission;Names;Nature;Patients;Peer Review;Persons;Population;Prevention;Provider;Public Health;Publications;Publishing;Radiation;Research;Research Infrastructure;Research Personnel;Research Priority;Resource Sharing;Resources;Schools;Science;Services;Societies;Technology;Training;Underrepresented Minority;Underserved Population;Universities;Wisconsin;Work;anticancer research;cancer care;cancer genetics;cancer imaging;cancer prevention;cancer therapy;equity diversity and inclusion;evidence base;health care delivery;improved;innovation;inter-institutional;medical schools;member;mortality;next generation;population based;programs;recruit;tumor microenvironment;virology UW Comprehensive Cancer Center Support PROJECT NARRATIVEThe University of Wisconsin Carbone Cancer Center (UWCCC) which is a matrix center within the University ofWisconsin School of Medicine and Public Health (SMPH) seeks to dramatically reduce the burden of cancerwithin and beyond our catchment. Specifically the UWCCC will do this by decreasing cancer incidence andmortality among populations within our catchment area and beyond including our minority and underservedpopulations. We will facilitate pursuit of this goal through partnerships with other health delivery systems andstate and community agencies for dissemination of evidence-based findings. The UWCCC will accomplish ourgoals through nurturing a diverse and supportive cancer community reliable infrastructure and efficientresources. During the current funding period UWCCC continued to decrease the burden of cancer in ourcatchment and beyond through prioritized research areas (e.g. innovative therapies and biomarkers cancerimaging and expanded population-based cancer research) enhanced research platforms (e.g. improved clinicalresearch infrastructure and shared resources) increased efforts to build mission-related philanthropy andexpanded local-to-global partnerships. NCI 10905065 9/4/23 0:00 PAR-21-321 3P30CA014520-49S3 3 P30 CA 14520 49 S3 "SHAFIK, HASNAA" 4/25/97 0:00 3/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 1877637 "BAILEY, HOWARD H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 6/21/23 0:00 3/31/24 0:00 397 Research Centers 2023 194375 NCI 125000 69375 PROJECT SUMMARY/ABSTRACTThe University of Wisconsin Carbone Cancer Center (UWCCC) seeks continued funding for years 49-53 tofurther accelerate its mission to dramatically reduce the burden of cancer within and beyond its catchment theState of Wisconsin. The UWCCC which is a matrix center within the University of Wisconsin School of Medicineand Public Health (SMPH) is composed of 218 faculty members from 38 departments and 9 schools of theUniversity of Wisconsin-Madison (UW). Our members pursue cancer care research and education through 6scientific programs (Human Cancer Virology Cancer Genetic and Epigenetic Mechanisms TumorMicroenvironment Imaging and Radiation Sciences Developmental Therapeutics and Cancer Prevention andControl) supported by 12 Shared Resources. During the current grant period (2017-2021) leadership hassuccessfully recruited >40 new and more diverse members and strengthened existing or new infrastructurefacilitating our membership publishing 3351 cancer-relevant manuscripts (31% inter- or intra-programmatic53% inter-institutional) with a significant increased proportion in high (10) impact factor journals (prior grant11% compared to current 23%) increasing our NCI research (Direct 2017 $18.6M 2021 $24.9M) and totalresearch funding (Direct 2017 $70.4M 2021 $76.3M) obtaining more multi-project awards (P U) supportingmore trainees and supporting communities throughout our expanded catchment.The UWCCC will accomplish this mission through nurturing a diverse and supportive cancer community reliableinfrastructure and efficient resources. The UWCCC worked to decrease the burden of cancer in our catchmentand beyond through prioritized research areas (e.g. innovative therapies and biomarkers cancer imaging andexpanded population-based cancer research) enhanced research platforms (e.g. improved clinical researchinfrastructure and shared resources) increased efforts to build mission-related philanthropy and expanded local-to-global partnerships. 194375 +No NIH Category available Address;Adult;Adverse effects;Affect;African American population;Age;Air;Alcohol consumption;Animals;Arsenic;Biological Specimen Banks;Body Burden;Cadmium;Cancer Etiology;Carcinogens;Case/Control Studies;Cessation of life;Chemicals;Chronic;Cirrhosis;Classification;Communities;DNA Methylation;Data;Data Collection;Disparity;Dose;Environment;Environmental Exposure;Environmental Pollutants;Epigenetic Process;Ethnic Origin;Excretory function;Exposure to;Fatty Liver;Federally Qualified Health Center;Female;Fibrosis;Food Packaging;General Population;Geography;Health;Health system;Hepatology;Hispanic Americans;House Dust;Human;Incidence;Industrialization;International Agency for Research on Cancer;Knowledge;Link;Liquid substance;Liver;Liver Cirrhosis;Liver Fibrosis;Liver diseases;Longitudinal cohort study;Malignant Neoplasms;Malignant neoplasm of liver;Mass Spectrum Analysis;Measures;Mediating;Metals;Molecular;Mycotoxins;National Health and Nutrition Examination Survey;Nested Case-Control Study;North Carolina;Not Hispanic or Latino;Obesity;Outcome;Participant;Phase;Poison;Poly-fluoroalkyl substances;Population Heterogeneity;Prevalence;Primary Care;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Probability;Protocols documentation;Reporting;Research;Resources;Risk;Risk Factors;Role;Rural;Rural Minority;Sampling;Source;Susceptibility Gene;Testing;Textiles;Time;United States;Universities;Variant;Viral hepatitis;Water;aged;alcohol exposure;bioaccumulation;cancer diagnosis;cancer risk;case control;cohort;community clinic;data modeling;data repository;design;disease registry;environmental chemical;ethnic diversity;ethnic minority;exposed human population;fatty liver disease;follow-up;human data;insight;male;mouse model;non-alcoholic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;participant enrollment;pollutant;programs;progression risk;recruit;response;rural dwellers;sex;toxic metal Southern Liver Health Cohort NarrativeHepatocellular carcinoma is one of few cancers with a rising incidence a rise that disproportionally affects ethnicminorities and rural residents however known risk factors including viral hepatitis fatty liver disease andcirrhosis cannot fully explain these disparities. Environmental contaminants such as cadmium are commonpollutants ranked in the top ten chemicals of concern and can cause cancer in animals. We will create a cohortof 16000 participants to determine whether exposure to multiple common environmental contaminants increasesliver cancer risk whether risk differentially impacts rural and ethnic minorities and whether epigeneticmechanisms mediate these associations. NCI 10905062 9/12/23 0:00 RFA-CA-20-049 4UH3CA265842-03 4 UH3 CA 265842 3 "MOMIN, BEHNOOSH RAMJI" 9/21/21 0:00 8/31/27 0:00 ZCA1-SRB-T(O2)R 7621397 "HOYO, CATHRINE " "MOYLAN, CYNTHIA A; SCHILDKRAUT, JOELLEN M." 2 BIOLOGY 42092122 U3NVH931QJJ3 42092122 U3NVH931QJJ3; XRPPWZ3TK937 US 35.784675 -78.677233 578204 NORTH CAROLINA STATE UNIVERSITY RALEIGH RALEIGH NC SCHOOLS OF ARTS AND SCIENCES 276957514 UNITED STATES N 9/8/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2489960 NIEHS 2227688 262272 PROJECT SUMMARY/ABSTRACTPrimary liver cancer the vast majority of which is hepatocellular carcinoma (HCC) is one of the few cancers withincreasing incidence in the US. Incidence of HCC has tripled since 1980 which is particularly worrisome giventhat HCC confers a median survival of less than two years. The steepest increases in incidence are in Southernrural states and among ethnic minorities. While the prevalence of HCC had paralleled high rates of viral hepatitisin the last several decades recent increases in the prevalence of nonalcoholic fatty liver disease (NAFLD) andits progression to nonalcoholic steatohepatitis (NASH) with fibrosis and cirrhosis has fueled HCC in recent years.Yet these factors alone do not explain the substantial regional and ethnic variation in HCC progression. Oneunderstudied but potentially potent HCC risk factor with increasing prevalence that disproportionately affectsethnic minorities is exposure to environmental contaminants. These contaminants degrade slowly and thereforepersist in the environment providing a stable exogenous source for human exposure. Toxic metal(oid)s such ascadmium and arsenic are classified as probable carcinogens and emerging data from murine models suggestthat exposure is associated with hepatic steatosis cirrhosis and liver cancer. Per- and poly-fluoroalkylsubstances (PFAS) exposure in humans is associated with obesity and NASH. Further emerging evidenceindicates that these environmental exposures can induce epigenetic alterations that may promote adverseeffects on the liver but we lack longitudinal human data. These data underscore the need for longitudinal humandata to assess whether and how these contaminants impact HCC risk. To address these knowledge gaps andin response to RFA-CA-20-049 we propose the Southern Liver Health Study a longitudinal cohort study of twosub-cohorts comprising 16000 males and females aged 40 years and older in two Southeastern states NorthCarolina and Georgia. We will test the overarching hypothesis that cadmium alone or in a mixture with othertoxic metals and PFAS increases the risk of progression from NAFLD to liver fibrosis and HCC. The cohort willbe recruited from community clinics including Federally Qualified Health Centers and University Health SystemsPrimary Care Centers and Hepatology programs at Duke UNC Chapel Hill and Emory. Sub-cohort I will comprise10000 otherwise healthy adults who will be followed for 15 years anticipating that ~800 fibrosis casesincluding cirrhosis will develop and sub-cohort II will comprise 6000 advanced fibrosis cases anticipating ~750HCC cases will develop. We will nest case-control studies within the cohorts evaluate associations betweenenvironmental exposures and HCC incidence and identify epigenetic marks responsive to contaminants thatpredict progression to HCC. Impact: This will be the first large-scale effort to longitudinally determine the linkbetween environmental contaminants liver disease and cancer in a residentially and ethnically diversepopulation. Additionally we will create a data and specimen repository that will provide the research communitywith an invaluable resource to study HCC and other cancers. 2489960 +No NIH Category available Acoustics;Animal Model;Animals;Antineoplastic Agents;Apoptosis;Apoptotic;Biological Process;Breast Cancer Model;Breast Cancer Treatment;Bypass;Cell Aggregation;Cell Death;Cell Nucleus;Cell Size;Cell Survival;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Color;Custom;Data;Dependence;Diffusion Magnetic Resonance Imaging;Discrimination;Disease Management;Dose;Drug resistance;Early Diagnosis;Early treatment;Environment;Exhibits;Frequencies;Goals;Health;Histologic;Hormones;Image;Imaging Techniques;Imaging technology;In complete remission;Induction of Apoptosis;Knowledge;Localized Malignant Neoplasm;Magnetic Resonance Imaging;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Measurement;Measures;Methods;Modality;Monitor;Neoadjuvant Therapy;Nuclear;Operative Surgical Procedures;Output;Pathologic;Pathology;Patients;Pattern;Pharmaceutical Preparations;Physiologic pulse;Play;Pre-Clinical Model;Property;Recurrence;Research;Research Project Grants;Resolution;Role;Scanning;Series;Signal Transduction;Structure;System;Techniques;Technology;Testing;Therapeutic;Time;Tissue Sample;Tissues;Transducers;Transgenic Animals;Treatment Failure;Treatment Protocols;Ultrasonic Transducer;Ultrasonic wave;Ultrasonography;attenuation;breast imaging;cancer cell;cancer therapy;chemotherapy;clinical imaging;deep learning algorithm;design;human disease;human study;imaging approach;imaging system;improved;in vivo;innovation;irradiation;malignant breast neoplasm;neoplastic cell;next generation;non-invasive imaging;pre-clinical;prevent;quantitative ultrasound;real-time images;response;routine imaging;soft tissue;standard of care;success;targeted imaging;theories;transmission process;treatment response;tumor;ultrasound Multifrequency ultrasound imaging for improved breast tissue characterization PROJECT NARRATIVEThe goal of this research project is to develop and test a next-generation system and method for soft tissuecharacterization using ultrasound images of breast cancer. NCI 10904411 9/6/23 0:00 PA-21-268 7R01CA269973-02 7 R01 CA 269973 2 "PEREZ, J MANUEL" 8/15/22 0:00 7/31/27 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 9776193 "HOYT, KENNETH " Not Applicable 10 Unavailable 847205572 QD1MX6N5YTN4 847205572 QD1MX6N5YTN4 US 30.561542 -96.253207 8266919 TEXAS ENGINEERING EXPERIMENT STATION COLLEGE STATION TX Domestic Higher Education 778433577 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 555370 NCI 390014 165356 PROJECT SUMMARYThe use of noninvasive ultrasound for quantitative tissue characterization has been an exciting research prospectfor several decades now. Herein the challenge is to find hidden patterns in the ultrasound data to reveal moreinformation about tissue function and pathology that cannot be seen in the more conventional ultrasound images.Bypassing some of the limitations associated with traditional tissue characterization approaches a new modalityhas emerged for the ultrasound classification of acoustic scatterers like cancer cells. Termed H-scan ultrasound(where the H stands for Hermite or hue) this innovative real-time imaging technique reveals the local frequencydependence of different-sized scatterer aggregates found in soft tissue. Our preliminary preclinical findings usingin vivo H-scan ultrasound have indicated that this new imaging technique is useful for detecting apoptotic activityand an early response to chemotherapy. Here changes in H-scan ultrasound image intensity were shown tohave a strong correlation to local cancer cell nuclear size. Guided by knowledge gained from these previousstudies the purpose of the current research project is to develop a next-generation in vivo H-scan ultrasoundimaging system and tumor characterization method. Our first goal is to implement a multifrequency H-scanultrasound imaging functionality on programmable scanner equipped with a wideband capacitive micromachinedultrasonic transducer (CMUT). This new ultrasound imaging technology will be tested and optimized using aseries of phantom materials embedded with scatterers of known size. Next we will quantify success of H-scanultrasound imaging for monitoring an early response to chemotherapy using a preclinical model of breast cancerthat recapitulates human disease. We will then compare H-scan ultrasound findings to physical measurementsof cancer cell size and results obtained by competing imaging technologies. Lastly we will conduct the firsthuman study of multifrequency H-scan ultrasound imaging of breast cancer and evaluate the potential for helpingwith disease management. 555370 +No NIH Category available 3-Dimensional;Atlases;Bioinformatics;Cataloging;Cells;Censuses;Classification;Clinical;Clonality;Communities;Copy Number Polymorphism;Data;Data Analyses;Database Management Systems;Databases;Digital Imaging and Communications in Medicine;Dimensions;FAIR principles;Foundations;Genes;Genomics;Goals;Human;Image;Immune;Individual;Infrastructure;Length;Link;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Meta-Analysis;Methodology;Modeling;Monitor;Mutate;Mutation;Pathology;Pathway interactions;Patients;Phenotype;Picture Archiving and Communication System;Ploidies;Positron-Emission Tomography;Post-Translational Protein Processing;Process;Proteomics;Reporting;Research;Resolution;Sampling;Secure;Shapes;Site;Solid Neoplasm;Standardization;System;Text;Time;Universities;Washington;automated segmentation;bioinformatics tool;cancer type;cell type;cohesion;computerized data processing;data dissemination;data integration;data sharing;data streams;density;diverse data;driver mutation;ex vivo imaging;image processing;indexing;information organization;metabolome;metabolomics;multidimensional data;neoplastic cell;relational database;scaffold;single cell sequencing;single-cell RNA sequencing;statistics;tool;triple-negative invasive breast carcinoma;tumor;web portal Data Processing Analysis and Modeling Unit n/a NCI 10904041 8/21/23 0:00 PA-20-272 3U2CCA233303-05S1 3 U2C CA 233303 5 S1 "LI, JERRY" 4/4/23 0:00 8/31/24 0:00 8293 9766169 "DING, LI " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2023 172389 110861 61528 Project Summary/Abstract: Data Analysis UnitThe over-arching goal of the Data Analysis Unit for the Washington University Human Tumor Atlas ResearchCenter (WU-HTARC) is to provide bioinformatics tools and processing/analysis infrastructure for in-depthanalyses of the data generated in the Characterization Unit. Most importantly we will integrate data acrossboth the methodological (omics/imaging/phenotypic analyses) and the dimensional (1D/2D/3D/time) spectrumsinto coherent and accessible tumor atlases for each of the three cancer types: GBM PDAC and BRCA/TNBC.At the basic level each atlas will consist of first cataloging a variety of numerically-computed metrics for celltypes including fractions (1D) density dispersion and location measures for individual cell types andEuclidean measures of spatial interspersedness of different cell types e.g. immune and tumor cells (2D and3D) and how these metrics change with time. We will then correlate this information with both genomicanalyses such as mutation signatures clonality and significantly mutated genes/regions/pathways proteomicand metabolomics analyses and image-derived data. The core of the atlas will be a MySQL relationaldatabase that not only stores all collected data but links them along these different dimensions. Users willinterface with the atlas through a sophisticated viewer/query browser-based web portal that will support bothtraditional text-based queries as well as spatial-based queries (shape feature locations etc.). The cohesionamong the three atlases in terms of the spectrum of data used and the approaches of their construction willallow users to generate new types of hypotheses not now possible and to perform pan-cancer analyses toreveal commonalities and differences in the three representative solid tumors and to potentially extrapolatethese findings to other tumors. +No NIH Category available Adjuvant Therapy;Antibodies;Apoptosis;Atlases;Biopsy;Cell Proliferation;Cells;Clinical Data;Collection;Complement;Coupled;Cytometry;DNA;Data;Data Analyses;Data Set;Diagnosis;Diffusion;Disease;Disseminated Malignant Neoplasm;Elements;Eligibility Determination;Evaluation;Excision;Future;Glioblastoma;Goals;Histology;Human;Image;Imaging technology;Immune;Immune Targeting;Immunofluorescence Immunologic;Immunotherapy;Individual;Institution;Link;Location;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Metadata;Mission;Molecular;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Non-Malignant;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Patient Recruitments;Patients;Phenotype;Primary Neoplasm;Procedures;Prognosis;Proteins;RNA;Recurrence;Recurrent disease;Research;Research Personnel;Resistance;Resistance development;Sampling;Signal Transduction;Site;Slide;Specimen;Stromal Cells;Structure;Technology;Time;Tissues;Training;Universities;Visualization;Washington;Work;aggressive breast cancer;cancer stem cell;cancer type;cellular imaging;design;immune cell infiltrate;in vivo;insight;multidimensional data;neoplastic cell;new technology;novel;optical imaging;patient response;protein activation;radiomics;response;single cell analysis;single-cell RNA sequencing;therapeutic development;therapy resistant;traditional therapy;transcriptome sequencing;treatment response;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Molecular Cellular and Tissue Characterization Unit n/a NCI 10904040 8/21/23 0:00 PA-20-272 3U2CCA233303-05S1 3 U2C CA 233303 5 S1 "LI, JERRY" 4/4/23 0:00 8/31/24 0:00 8292 1938279 "GILLANDERS, WILLIAM E." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2023 349813 224960 124853 Project Summary/Abstract: Biospecimen UnitThe over-arching goal of the Biospecimen Unit for the Washington University Human Tumor Atlas ResearchCenter (WU-HTARC) is to collect human tumor biospecimens for use by the Characterization and DataAnalysis Units to construct the proposed tumor atlases. Our Biospecimen Unit will procure and banklongitudinal biopsies and excised tumors from 300-375 patients (selected from ~750 recruited patients) with agoal toward studying the transition from primary malignancy to recurrence and metastasis in conjunction withthe development of therapeutic resistance in triple negative breast cancer (TNBC) glioblastoma (GBM) andpancreatic ductal adenocarcinoma (PDAC). Each of the three tumors chosen for this study poses uniquechallenges for both clinicians and researchers. From their often late onset of diagnosis highly metastaticnature challenges in achieving complete surgical resection and primary and acquired resistance to treatmenteach of these tumors represents an opportunity identified by the NCI Cancer Moonshot Initiative (CMI) tosignificantly advance our understanding of cancer and how to intervene on its initiation and progression. Tosupport the overall mission of WU-HTARC the Biospecimen Unit will perform the following: (1) identification ofeligible patients at WU with TNBC GBM and PDAC; (2) rigorous and systemic collection of tumors includinglongitudinal collection of all patients throughout their treatment course; (3) complete collection of associatedclinical data and metadata; and (4) storage and processing of all samples with current and future experimentaland analytical pipelines. The Biospecimen Unit will work closely with other Units within WU-HTARC to developstandard operating procedures and to make adjustments in line with the changing technologies. +No NIH Category available Address;Animal Model;Atlases;Bioinformatics;Biological Models;Biopsy;Cancer Center;Classification;Clinical;Clinical Data;Collaborations;Collection;Comprehensive Cancer Center;DNA;Data;Data Analyses;Databases;Dedications;Diagnosis;Eligibility Determination;Emerging Technologies;Ensure;Excision;Future;Genomics;Glioblastoma;Goals;Hospitals;Human;Immunologics;In Vitro;Infrastructure;Institution;Institutional Review Boards;Malignant Neoplasms;Metadata;Methodology;Mission;Molecular;Nature;Neoplasm Metastasis;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Patient Recruitments;Patients;Procedures;Program Development;Protocols documentation;Quality Control;RNA;Recurrence;Research;Research Personnel;Resistance;Resources;Sampling;Solid;Specimen;Technology;Testing;Tissue Preservation;Tissue Procurements;Tissues;Universities;Washington;Work;companion diagnostics;design;follow-up;follower of religion Jewish;in vivo;medical schools;neoplastic cell;novel;precision medicine;preservation;programs;prospective;quality assurance;targeted treatment;therapeutic development;therapy resistant;translational oncology;treatment effect;triple-negative invasive breast carcinoma;tumor Biospecimen Acquisition Processing and Classification Unit n/a NCI 10904039 8/21/23 0:00 PA-20-272 3U2CCA233303-05S1 3 U2C CA 233303 5 S1 "LI, JERRY" 4/4/23 0:00 8/31/24 0:00 8291 8182718 "FIELDS, RYAN C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2023 169727 109149 60578 Project Summary/Abstract: Biospecimen UnitThe over-arching goal of the Biospecimen Unit for the Washington University Human Tumor Atlas ResearchCenter (WU-HTARC) is to collect human tumor biospecimens for use by the Characterization and DataAnalysis Units to construct the proposed tumor atlases. Our Biospecimen Unit will procure and banklongitudinal biopsies and excised tumors from 300-375 patients (selected from ~750 recruited patients) with agoal toward studying the transition from primary malignancy to recurrence and metastasis in conjunction withthe development of therapeutic resistance in triple negative breast cancer (TNBC) glioblastoma (GBM) andpancreatic ductal adenocarcinoma (PDAC). Each of the three tumors chosen for this study poses uniquechallenges for both clinicians and researchers. From their often late onset of diagnosis highly metastaticnature challenges in achieving complete surgical resection and primary and acquired resistance to treatmenteach of these tumors represents an opportunity identified by the NCI Cancer Moonshot Initiative (CMI) tosignificantly advance our understanding of cancer and how to intervene on its initiation and progression. Tosupport the overall mission of WU-HTARC the Biospecimen Unit will perform the following: (1) identification ofeligible patients at WU with TNBC GBM and PDAC; (2) rigorous and systemic collection of tumors includinglongitudinal collection of all patients throughout their treatment course; (3) complete collection of associatedclinical data and metadata; and (4) storage and processing of all samples with current and future experimentaland analytical pipelines. The Biospecimen Unit will work closely with other Units within WU-HTARC to developstandard operating procedures and to make adjustments in line with the changing technologies. +No NIH Category available Administrator;Atlases;Budgets;Collaborations;Communication;Companions;Development;Disease;Documentation;Electronics;Focus Groups;Funding;Glioblastoma;Goals;Human;Infrastructure;Leadership;Maintenance;Malignant neoplasm of pancreas;Newsletter;Pancreas;Pilot Projects;Preparation;Progress Reports;Publications;Reporting;Research;Research Personnel;Universities;Washington;Work;meetings;symposium;triple-negative invasive breast carcinoma;tumor;web site Administrative Core n/a NCI 10904038 8/21/23 0:00 PA-20-272 3U2CCA233303-05S1 3 U2C CA 233303 5 S1 "LI, JERRY" 4/4/23 0:00 8/31/24 0:00 8290 9766169 "DING, LI " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2023 182748 117523 65225 Project Summary/Abstract: Administrative Core The Administrative Core will provide executive oversight and administrative support for the construction of the tumor atlases for TNBC Pancreas and Glioblastoma by the Washington University Human Tumor Atlas Research Center (WU-HTARC). The Administrative Core will also provide the infrastructure for communications across the three disease groups that are the focus for the atlases and also for scientific collaborations within the Human Tumor Atlas Network and other companion NCI initiatives. To achieve these goals the admin core will: 1. Facilitate executive oversight of the HTARC and each of the Units. Facilitate executive oversight by providing timely reporting to the HTARC Leadership Committee and by coordinating Leadership Committee meetings and Internal Advisory Board meetings. 2. Provide administrative and fiscal oversight for all HTARC components. This will include but is not limited to the management of budgets and subcontracts as appropriate and preparation of annual progress reports with input from the Unit Leaders. 3. Coordinate all HTARC meetings. Coordination of all internal HTARC and external HTAN meetings will be executed by the Center Administrator. 4. Facilitate HTARC-HTANet communications and collaborations. Facilitate HTARC-HTANet communications through development and maintenance of a HTARC website monthly Unit meetings and Leadership Committee meetings annual symposium and monthly electronic newsletter. 5. Coordinate and manage the HTARC. Support developing collaborations to include pilot projects to be funded through the HTARC Pilot funds specifically for Trans-HTAN projects. 6. Provide general administrative support for HTARC investigators. Assist investigators with the preparation of scholarly presentations publications regulatory documentation and all other paperwork generated by the HTARC and necessary to conduct HTAN collaborative work. +No NIH Category available Adenoviruses;Algorithms;Anus;Biological Assay;Biopsy;California;Cellular Immunology;Cervical;Clinic;Clinical;Clinical Research;Clinical Trials;Comprehensive Cancer Center;DNA;Data;Diagnostic;Disease;Disease regression;Ensure;Equipment;Grant;HIV;HIV Seropositivity;HPV-High Risk;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immune response;Laboratories;Leadership;Lesion;Malignant Neoplasms;Measures;Mentorship;Mexico;Participant;Pathology;Population;Prevention;Probiotics;Procedures;Protocols documentation;Puerto Rico;Quality Control;Reporting;Research;Research Personnel;Risk Reduction;Role;Safety;Sampling;Science;Scientist;Site;Specimen;Squamous intraepithelial lesion;Techniques;Technology Transfer;Testing;Training;Training Programs;Training Support;Universities;Woman;Work;career;career development;cell mediated immune response;cervical cancer prevention;data management;disorder prevention;high risk;laboratory facility;men;microbiome analysis;microbiome research;microbiota profiles;primary outcome;programs;quality assurance;research study;screening;statistics;therapeutic HPV vaccinations;therapeutic HPV vaccine;therapeutic vaccine;vaccine trial;virtual;working group CAMPO Central Laboratory Core NARRATIVE FOR THE CENTRAL LABORATORY COREThe CAMPO Central Laboratory Core will perform laboratory assays in support of the three clinical research studies to be performed as part of the CAMPO Clinical Trials Program. It will also perform correlative science studies using clinical samples obtained from research participants in order to answer important questions about how different treatment approaches may work to treat cancer precursors or reduce the risk of persistent HPV infection. NCI 10903229 8/9/23 0:00 RFA-CA-18-018 3U54CA242646-05S1 3 U54 CA 242646 5 S1 "FRECH, MARIA SILVINA" 9/12/19 0:00 7/31/25 0:00 ZCA1-RTRB-R(M2) 7972 8893994 "DARRAGH, TERESA MARIE" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 32114 25103 7011 ABSTRACT FOR THE CENTRAL LABORATORY COREThe California-Mexico-Puerto Rico (CAMPO) Consortium will perform three clinical research studies focused on the prevention of cervical cancer among HIV-positive women in Mexico and Puerto Rico. Study 1will examine new screening algorithms for cervical high-grade squamous intraepithelial lesions (HSIL) in 4000 HIV-positive women in Mexico and Puerto Rico. Study 2 will evaluate the impact of anogenital probiotic use on anal and cervical microbiota profiles and the relationship to anal and cervical HSIL regression in 600 HIVpositive women and men as well as reduction of high-risk HPV DNA persistence among those with no lesions. Study 3 will evaluate the safety and efficacy of a multivalent replication-defective adenovirus-based therapeutic HPV vaccine to treat cervical and anal HSIL in 300 HIV-positive women and men and identify immune response correlates of HSIL regression. Working with the Data Management and Statistics Core the Administrative and Coordinating Core and the Clinical Trials Program the Central Laboratory Core (CLC) will perform laboratory assays for each of the three studies. The aims of the CLC are: (1) To perform laboratory assays required to achieve the primary aims of the clinical research studies conducted within the CAMPO Consortiums Clinical Trials Program; (2) To perform laboratory assays for correlative science studies for the CAMPO Consortium; (3) To expand research capacity of consortium partners in Mexico and Puerto Rico through technology transfer; (4) To participate in rigorous quality control programs to ensure the validity of laboratory data; and (5) To support training and career development of early career investigators in laboratorybased research. The CLC will be led by Dr. Alejandro Garcia-Carranca of INCan and co-led by Drs. Filipa Godoy-Vitorino of UPR and Joel Palefsky of UCSF. Similar to the other CAMPO Cores the CLC will be comprised of a network of investigators and facilities across the three Consortium sites working closely together but with each site tasked with a role based on their specific expertise. The CLC will have both virtual and physical components with CLC laboratory facilities at INCan INSP and the Condesa Clinic in Mexico the University of Puerto Rico Comprehensive Cancer Center the University of Puerto Rico Clinical Trials Center and UCSF. The network will use GlobalTraceTM to track and ship laboratory specimens between the sites. The CLC will form working groups centered on CAMPOs scientific agenda- HPV diagnostics microbiome research and cellular immunology- with representation from scientists at each site and will participate on CAMPO Clinical Trials Program study protocol teams. The CLC will perform a rigorous quality assurance program and report results on a regular basis to CAMPO leadership. +No NIH Category available Targeting antioxidant vulnerabilities in KEAP1/NRF2 mutant NSCLC KEAP1/NRF2 pathway are commonly mutated in NSCLC but targeted therapies for patients with thesemutations are lacking. I have identified novel antioxidant vulnerabilities for NSCLC cells harboring KEAP1 andNRF2 mutations. The proposed studies will define the mechanisms of these vulnerabilities and how thesevulnerabilities can be exploited in order to develop potent therapeutic strategies for patients with KEAP1/NRF2mutations. NCI 10902960 9/13/23 0:00 PA-20-188 4R00CA270423-02 4 R00 CA 270423 2 "SALNIKOW, KONSTANTIN" 9/1/22 0:00 8/31/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15236460 "JIANG, CHANG " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/4/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 248866 NCI 147695 101171 The transcription factor NRF2 is a central regulator of cellular redox balance. Mutations in NRF2 and its negativeregulator KEAP1 are found in 15-34% of non-small cell lung cancer (NSCLC). The result of these mutations isconstitutive NRF2 activation and chronic induction of a battery of NRF2 target genes which confers resistanceto chemo/radiation therapy. While targeting NRF2 holds great therapeutic potential there is no effective strategyto inhibit the consequences of pathogenic KEAP1/NRF2 signaling. It is therefore critical to identify andunderstand vulnerabilities of KEAP1/NRF2 mutant NSCLC to develop effective therapies for patients harboringthese mutations. NRF2 controls the transcription of many antioxidant enzymes thereby regulating thedetoxification of reactive oxygen species. However it remains largely unknown which specific antioxidantenzymes can be therapeutically targeted to reverse the profound resistance of NRF2/KEAP1 mutations tooxidative stress the key mediator of chemo/radiation therapy. Glutathione (GSH)/GSH reductase (GSR) andthioredoxin (TXN)/thioredoxin reductase (TXNRD) are two parallel compensating thiol-dependent antioxidantpathways that critically regulate and maintain cellular thiol redox homeostasis and protein dithiol/disulfidebalance. My preliminary results indicate that both GSR and TXNRD1 are strongly induced by NRF2 activationand contribute to the intrinsic resistance to the pro-oxidant therapies. However they play unique roles in differentcellular compartments. Specifically NRF2 induced GSR acts to protect mitochondria from oxidation whileTXNRD1 protects the cytosol. Further TXNRD1 upregulation is associated with the suppression of otherselenoproteins suggesting that NRF2 activation causes an imbalance in selenium distribution. Given the keyrole of selenoprotein in redox biology the switch in the production of the different selenoproteins induced byNRF2 activation may create novel vulnerabilities of NRF2 active NSCLC with therapeutic potential. This proposalis designed to further strengthen these observations by defining the mechanistic basis of how GSR contributesto NRF2-mediated resistance to oxidative stress and to leverage the imbalanced selenoprotein translation todevelop potent therapeutic strategies for KEAP1/NRF2 mutant NSCLC. The following specific aims are pursuedin this application: Aim 1. Investigate the role of GSR in NRF2-mediated resistance to oxidative stress. Aim 2.Define the role of NRF2 as a modulator of the selenoproteome in NSCLC. The knowledge and scientific expertisethat I acquire from these proposed studies will facilitate my transition to an independent position. My long-termgoal is to study the antioxidant enzymes in cancer with a major focus on selenoproteins. In addition to thescientific goal I have outlined a detailed career development plan to obtain skillsets that are key for leading aresearch laboratory and establishing a strong research program. I will conduct the proposed research and carryout the training plan under the guidance of my mentoring committee. I will embark on the excellent academicenvironment provided by Moffitt Cancer Center to achieve these goals and transition to an independent position. 248866 +No NIH Category available 3-Dimensional;ATAC-seq;Aftercare;Atlases;Biological;Biological Assay;Biological Process;Biopsy;CDK4 gene;Cancer Patient;Cells;Characteristics;Communities;Computer software;Data;Data Analyses;Data Management Resources;Data Storage and Retrieval;Dimensions;Disseminated Malignant Neoplasm;Electron Microscopy;Generations;Genes;Goals;Image;Image Analysis;Immune checkpoint inhibitor;Immunofluorescence Immunologic;Immunohistochemistry;Immunomodulators;Individual;Malignant Neoplasms;Malignant neoplasm of prostate;Maps;Measurement;Metastatic breast cancer;Methods;Modeling;Mutation;Neoplasm Metastasis;Pathway interactions;Patients;Periodicity;Poly(ADP-ribose) Polymerase Inhibitor;Population;Primary Neoplasm;Reproducibility;Research;Resistance;Resistance development;Running;Sampling;Services;Standardization;Statistical Data Interpretation;Structure;System;Techniques;Time;Tissues;Visualization;Visualization software;animation;blood vessel development;castration resistant prostate cancer;cohort;computerized data processing;dashboard;data management;enzalutamide;epigenomics;hormone receptor-positive;hormone therapy;immune cell infiltrate;immune checkpoint;immune modulating agents;indexing;individual patient;inhibitor;malignant breast neoplasm;molecular imaging;molecular targeted therapies;multimodal data;multimodality;novel;prospective;refractory cancer;resistance mechanism;single cell sequencing;statistical and machine learning;targeted treatment;temporal measurement;therapy resistant;triple-negative invasive breast carcinoma;tumor Data Processing Analysis and Modeling Unit n/a NCI 10902925 8/18/23 0:00 PA-20-272 3U2CCA233280-05S1 3 U2C CA 233280 5 S1 "HUGHES, SHANNON K" 4/4/23 0:00 8/31/24 0:00 8200 10490342 "GOECKS, JEREMY " Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2023 923254 679450 243804 ABSTRACT Data Analysis UnitWe propose to create a Data Analysis Unit in service of the Omics and Multidimensional Spatial (OMS) Atlas.The OMS Atlas will enable discovery of mechanisms of resistance that arise in individual patients withmetastatic breast and prostate cancer during treatment with current generation of targeted therapeuticcombinations and immune checkpoint inhibitors. Treatment will these therapies in metastatic cancer is rarelyeffective for an extended period of time and understanding the mechanisms by which these cancers becomeresistant to therapy is the primary goal of the OMS Atlas. The Data Analysis Unit will support this goal bydeveloping and deploying data management processing analysis and visualization methods and software tocreate the Atlas. The OMS Atlas will collect two biopsies one before treatment and one during treatment for 3different cohorts of cancer patients. The final product of the Data Analysis Unit will be a complete tumor atlasaccessible via an interactive portal that enables use-case biologists in the OMS Atlas the HTAN and the largerresearch community to develop hypotheses about tumor resistance mechanisms through quantifiedlongitudinal and spatially-resolved comparisons of pre- and on/post-treatment biopsies from individualpatients. Using primary data generated from omics and imaging assays (Tier 1 data) the Data Analysis Unitwill generate three additional tiers of data: (Tier 2) single gene/cell measurements obtained by processing datafrom a single data platform; (Tier 3) tumor maps generated by combining single-cell and spatially-resolvedomics and imaging data as well as quantification of systems-level functions such as biological pathway activityand the cells comprising the tumor and its surrounding tissue using integrative analyses of multiple dataplatforms; (Tier 4) a tumor atlas that can be used to compare pre- and on/post-treatment biopsies and identifyfeatures potentially correlated with resistance to treatment. Data tiers will be generated using a robust softwarepipeline consisting of a data management system image management software a workflow execution systemand visualization tools. Standardized and reproducible workflows that run on this platform will be implementedto generate all tiers of data. Statistical and machine learning approaches will be used to create tumor maps byconnecting mirror image sections and cell populations across different assays. The OMS Atlas portal willprovide a single interface with access to 10 different visualizations of tumor maps. Tumor maps can bevisualized and compared longitudinally within a single patient or laterally across patients. Many visualizationscan be displayed simultaneously using a dashboard approach where visualizations can be progressively addedas desired making it possible to view many different types of data about tumor maps simultaneously.Specialized animation approaches and 3D techniques will be used in visualizations to effectively displaymultidimensional spatially resolved tumor map data. +No NIH Category available Achievement;Alveolar Rhabdomyosarcoma;Amino Acids;Animal Model;Base Sequence;Binding;Binding Proteins;Biotin;CHD4 gene;CRISPR/Cas technology;Catalogs;Cell model;Characteristics;Chemicals;Chimeric Proteins;Chromatin;Co-Immunoprecipitations;Credentialing;DNA Binding;Dependence;Drug Targeting;Emerging Technologies;FOXO1A gene;Face;Fusion Oncogene Proteins;Future;Genes;Goals;Immunodeficient Mouse;In Vitro;Label;Libraries;Malignant Childhood Neoplasm;Maps;Mediating;Modeling;Molecular;Mutagenesis;Neighborhoods;Oncogenes;Oncogenic;Oncoproteins;PAX3 gene;Patients;Pharmaceutical Preparations;Portraits;Post-Translational Protein Processing;Proteins;Resolution;Signal Transduction;Techniques;Technology;Therapeutic;Validation;Work;combinatorial;design;drug development;genetic approach;genetic manipulation;in vivo;insight;knockout gene;lead candidate;loss of function;member;mutant;mutation screening;neoplastic cell;patient derived xenograft model;pharmacologic;protein function;protein protein interaction;screening;therapeutic development;therapeutic target;tool;transmission process;tumorigenesis Defining and targeting the PAX3-FOXO1 interactome n/a NCI 10902753 8/21/23 0:00 PA-20-272 3U54CA231630-01A1S4 3 U54 CA 231630 1 A1S4 "WITKIN, KEREN L" 7/1/23 0:00 8/31/24 0:00 5068 1930899 "LINARDIC, CORINNE MARY" Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/17/19 0:00 8/31/24 0:00 Research Centers 2023 157719 99950 57769 ABSTRACT Project 2: Defining and targeting the PAX3-FOXO1 interactomeAlveolar rhabdomyosarcoma (ARMS) is a deadly childhood malignancy driven by the PAX3-FOXO1 fusiononcoprotein. While genetic approaches have rigorously validated this oncoprotein as a therapeutic target thelack of compounds inhibiting PAX3-FOXO1 function has earned it the moniker of being undruggable. Althoughundruggable proteins can be pharmacologically targeted doing so requires a thorough understanding of howthe protein functions. It is well established that PAX3-FOXO1 exerts its transforming activities both throughfunctional domains and physical interactions with other cellular proteins that either serve as modulators or co-regulators. Indeed members of this team previously found that CHD4 co-regulates PAX3-FOXO1 function byindirectly associating with the oncoprotein via co-localization in chromatin neighborhoods. The overarching goalof this FusOnc2 Center is to advance the therapeutic tractability of the PAX3-FOXO1 fusion protein in ARMS bycomprehensively identifying the druggable co-regulators modulators and intrinsic activities of PAX3-FOXO1.This Projects objective is to systematically identify therapeutically exploitable components of the oncogenicPAX3-FOXO1 interactome the catalog of proteins that interact with PAX3-FOXO1 that are also essential forits oncogenic activity. To identify the PAX3-FOXO1 domains and interacting proteins that mediate oncogenesisthis Project proposes a stepwise comprehensive approach through the following Specific Aims: 1) Define thedifferential interactome of functional PAX3-FOXO1 using BirA proximity labeling; 2) Map PAX3-FOXO1functional domains at amino acid resolution using saturation mutagenesis; 3) Define functional and combinatorialdependencies within the PAX3-FOXO1 interactome; 4) Credential interactome dependencies in cellular andanimal models of PAX3-FOXO1 ARMS. The protein interactome defined in Aim 1 will be used to generate single-and dual-targeting CRISPR/Cas9 loss-of-function libraries in Aim 3. Work in Aim 2 will reveal the key functionaldomains and amino acid residues necessary for the oncogenic activity of the fusion oncoprotein an achievementexploited throughout the Center to inform regions involved in PAX3-FOXO1 stability in Project 1 and prioritizationof chemical probes in Project 3 and to refine the interacting proteins mediating PAX3-FOXO1 transformation inAim 3 of this Project. Top candidates emerging from Aim 3 will then be nominated for in-depth analysis in Aim 4using established cellular and animal models to define validated targets for near- and long-term development ofdrugs targeting either key interacting proteins themselves or their interactions with PAX3-FOXO1. +No NIH Category available Address;Anatomy;Archives;Atlases;Biological Assay;Biopsy;Boston;Breast biopsy;CDK4 gene;Cells;Clinic;Clinical;Clinical Data;Collaborations;Communication;Dana-Farber Cancer Institute;Data;Data Analyses;Data Set;Development;Dissociation;Ecosystem;Excision;Freezing;Generations;Genomics;Geography;Goals;Histopathology;Human;Human Resources;Immunotherapy;Infrastructure;Laboratories;Large Intestine Carcinoma;Lead;Link;Location;Malignant - descriptor;Malignant Neoplasms;Maps;Measurement;Measures;Metastatic Melanoma;Microsatellite Instability;Microsatellite Repeats;Modality;Molecular;Non-Malignant;Operative Surgical Procedures;Pathologic;Pathology Report;Patient Outcomes Assessments;Patients;Process;Proteins;Quality Control;RNA;Research;Research Design;Research Personnel;Resistance;Sampling;Schedule;Secure;Services;Solid Neoplasm;Space Perception;Stains;System;Tissues;Training;Treatment outcome;Vertebral column;adaptive learning;experience;genomic data;immune checkpoint blockade;malignant breast neoplasm;melanoma;operation;refractory cancer;single nucleus RNA-sequencing;single-cell RNA sequencing;spatial integration;success;therapy resistant;treatment response;tumor;tumor progression Biospecimen Unit n/a NCI 10902520 8/28/23 0:00 PA-20-272 3U2CCA233195-05S1 3 U2C CA 233195 5 S1 "ZHANG, YANTIAN" 4/4/23 0:00 8/31/24 0:00 7887 2092519 "JOHNSON, BRUCE E." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2023 1241085 1055989 185096 Most patients who die from cancer do so because their cancer is resistant to available therapies. Tumors are comprised of diverse multicellular ecosystem that include malignant and non-malignant cells. Changes in the cellular state spatial organization and interaction between subsets of cells in that ecosystem are likely to be central to cancer progression and therapeutic resistance but invisible by bulk analyses. Thus there is urgent need to chart an atlas of the cells that compose a tumor their spatial organization and functional relationships and how those features differ in tumors that are resistant to therapy. The Boston Human Tumor Atlas Network Research Center (HTA-RC) will create three comprehensive atlases of the cellular geography of human cancer to understand how changes in the tumor ecosystem lead to therapeutic resistance. The atlases will chart the dynamic changes associated with resistance to targeted and immune-based therapies in: (1) Primary and acquired resistance to CDK4/6 inhibition in breast cancer; (2) Primary and acquired resistance to immune checkpoint blockade in metastatic melanoma; and (3) Primary resistance to immunotherapy in microsatellite stable (MSS) colorectal carcinoma (CRC) compared with microsatellite instable (MSI) CRC. To enable these goals the Biospecimens Unit (BSU) will provide a comprehensive rigorous and nimble sample acquisition platform that provides the bridge between the clinic and a set of state-of-the-art cellular and spatial analytic assays that will form data backbone for the atlases. It will provide at least 100 clinically and pathologically annotated samples/year to the Molecular Characterization Unit (MCU) in a manner adequate for three downstream measurement modalities: (1) histopathology based on H&E stains and pathology reports; (2) spatial multiplex RNA and protein data (by MERFISH IHC CODEX and MIBI); and (3) single-cell genomics data especially single cell and single nucleus RNA-Seq (scRNA-seq snRNA-Seq). The proposed studies build on an established tight local collaboration network that has already proven as a highly effective pioneer in generation of pilot-scale tumor atlas datasets. expand this infrastructure and the extensive experience within our clinical units to assure its success in the following aims: Aim 1: Collect biospecimens from resections and biopsies of breast cancer melanoma and colorectal carcinoma. The BSU will identify procure and traffic samples from surgical suite to the laboratory. Aim 2: Conduct pre-analytic processing of biospecimens: The BSU will perform pre-analysic processing steps of biospecimens including tissue dissociation snap freezing sectioning for spatial analysis and archiving. Rigorous SOPs and quality control measures for each step already well-developed and employed routinely. Aim 3: Acquire and maintain clinical data associated with each sample: Accurate and comprehensive clinical pathological annotation will be linked to each sample including careful assessment of the patients' outcomes. +No NIH Category available Administrative Core n/a NCI 10902230 8/15/23 0:00 PA-20-272 3U54CA263001-02S1 3 U54 CA 263001 2 S1 "NADEAU, CHRISTINE FRANCES" 9/15/22 0:00 7/31/27 0:00 ZCA1(J1) 6637 9107364 "HERNANDO, EVA " Not Applicable 12 Unavailable 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY Domestic Higher Education 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 50850 30000 20850 No abstract available +No NIH Category available Authorization documentation;Behavioral Sciences;Biometry;Cancer Center;Clinical Oncology;Clinical Research;Clinical Trials;Collaborations;Committee Membership;Communication;Comprehensive Cancer Center;Data Science Core;Discipline;Disease;Doctor of Philosophy;Ensure;Goals;Grant;Health Sciences;Malignant Neoplasms;Monitor;NCI Center for Cancer Research;Patients;Pharmacy facility;Protocols documentation;Research;Review Committee;Role;System;Translational Research;authority;clinically relevant;falls;improved;member;multidisciplinary;programs Protocol Review and Monitoring System n/a NCI 10902202 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5380 1894210 "BENSON, AL B" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 171974 108844 63130 ABSTRACT PROTOCOL REVIEW AND MONITORING SYSTEMThe Protocol Review and Monitoring System (PRMS) of the Robert H. Lurie Comprehensive Cancer Center(LCC) falls under the purview of the Scientific Review Committee (SRC) one of several committees thatcomprise LCC's research oversight program. The LCC's PRMS has received continuous NCI approval since1998. The SRC is a multidisciplinary committee that consists of a core group of members providing the necessaryexpertise in the principal disciplines of clinical oncology research with expertise of representatives from LCC'sQuantitative Data Sciences Core (which includes biostatistics) Translational Research Behavioral and HealthSciences and Pharmacy groups. The SRC is chaired by A. B. Benson III MD and co-chaired by A. RademakerPhD and J. Sosman MD (new in this grant period). The focus of the SRC is the review of cancer relevant clinicaltrials for scientific merit prioritization and monitoring scientific progress. The SRC has the authority to approveprotocols that meet the scientific merit and scientific priorities of the center and to terminate protocols that do notdemonstrate sufficient scientific progress. Improvements made over this grant cycle include an enhanced rolefor Disease Teams in protocol prioritization and monitoring improved communication among the researchoversight committees and with the Clinical Trials Office as well as broadened representation of SRCmembership. +No NIH Category available Address;African American population;Area;Cancer Center;Catchment Area;Child;Childhood;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Research Protocols;Clinical Trials;Communities;Comprehensive Cancer Center;Conduct Clinical Trials;Consent Forms;County;Data;Development;Disease;Disparity;Education;Ensure;Ethnic Origin;Grant;Incidence;Institutional Policy;Intervention;Intervention Trial;Logistics;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Minority;Minority Groups;Monitor;Office Management;Patients;Population;Procedures;Process;Protocols documentation;Regulation;Reporting;Research;Research Personnel;Resources;Review Committee;Safety;Scientific Evaluation;Series;Services;Site;Site Visit;Standardization;System;Training;Training and Education;Underserved Population;Woman;Work;clinically relevant;data management;design;improved;member;online repository;participant enrollment;patient population;patient safety;programs;protocol development;sound;tool;web-based tool Clinical Protocol and Data Management n/a NCI 10902201 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5379 10298722 "MAHALINGAM, DEVALINGAM " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 557881 360594 197287 ABSTRACT CLINICAL PROTOCOL AND DATA MANAGEMENT Clinical Protocol and Data Management (CPDM) is overseen by the Lurie Cancer Center (LCC) Clinical Trials Office (CTO). The CTO provides a centralized resource to facilitate the development conduct and oversight of cancer-relevant clinical trials at the LCC. The office manages a large volume of trials with about 30% increase in accrual over the project period (389 interventional trials with 2367 participants enrolled in 2013 vs. 357 trials with 3059 participants enrolled in 2016). Support services offered to investigators include protocol development regulatory services (including IND submission) study coordination data management maintenance of centralized record keeping and multisite coordination. CTO accomplishments over the grant period include increased and reorganized staffing to better serve PIs; creation of a Logistics Team; and increased staffing/integration of the finance team to reduce study activation times creation of a web-based tool (LaunchTrack) to track key study activation milestones and improved clinical research education and training for CTO staff and PIs. Data Safety and Monitoring activities are an integral part of the LCC's robust clinical research oversight system which is comprised of multiple teams and committees that work collaboratively including: Disease Teams Scientific Review Committee (SRC) Data Safety Monitoring Committee (DSMC) and Clinical Trial Audit Committee (CTAC). Disease Teams manage clinical trials portfolios and endorse scientifically sound protocols that are submitted to the SRC for scientific evaluation and approval. The SRC is responsible for reviewing scientific merit priorities and progress of the clinical protocol research at the LCC (described in the PRMS section of this application). The activities of both the DSMC and the CTAC ensure that the NCI-approved LCC Data and Safety Monitoring Plan (DSMP) is effectively executed. LCC serves a 9-county catchment area (CA) that represents a diverse community. Minority accrual by ethnicity is robust (~20% accrued to interventional trials) over this grant period. Although accrual of African Americans to interventional trials has more than doubled since last grant period (from 4.7% in 2012 to 12.3% in 2016) and it closely resembles the percentage of patients seen at the LCC it is below the catchment area proportion. The LCC has developed a series of initiatives (detailed in Part 3: Inclusion of Women and Minorities below) to address disparities in accruals among African Americans relative to the catchment area. Since the last site visit the number of analytic pediatric cancer cases has increased by 20% now at 284 cases and accrual of children remains strong with 129 interventional accruals in 2016. In the most recent 12 months accrual of women to interventional trials stands above catchment area rates at 58.9% (51.0% LCC CA population; 51.3% LCC CA incidence; 54.2% LCC patient population). +No NIH Category available Acceleration;Achievement;Address;Adherence;Area;Atypia;Automobile Driving;Basic Science;Behavior;Behavior Therapy;Behavioral;Biological Markers;Breast Cancer Detection;Breast Cancer Prevention;Cancer Burden;Cancer Center;Cancer Prevention Intervention;Catchment Area;Cellular Phone;Cervical Cancer Screening;Chicago;Clinical;Collaborations;Colon Carcinoma;Colonic Neoplasms;Communities;Comprehensive Cancer Center;DNA Methylation;Development;Devices;Direct Costs;Discipline;Disease;Doctor of Philosophy;Early Diagnosis;Enrollment;Environment;Environmental Risk Factor;Epithelium;Faculty;Fostering;Funding;Genetic Markers;Genetic Predisposition to Disease;Goals;Health;Incidence;Individual;Indolent;Interruption;Intervention;Intervention Trial;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Methods;MicroRNAs;Oncogenic Viruses;Participant;Pathway interactions;Peer Review;Pharmaceutical Preparations;Phase;Population;Predisposition;Prevention;Prevention Research;Prevention approach;Prevention program;Preventive;Primary Cancer Prevention;Psychologist;Publications;Research;Research Personnel;Risk;Risk Assessment;Risk Factors;Risk Reduction;Risk Reduction Behavior;Safety;Schools;Screening for cancer;Secondary Cancer Prevention;Smoking Cessation Intervention;Source;Surgeon;Technology;Testing;Therapeutic;Translating;Translational Research;Underserved Population;United States National Institutes of Health;Vertebral column;Virus Diseases;Weight maintenance regimen;Work;behavioral study;cancer prevention;cancer risk;carcinogenicity;community setting;design;epigenetic marker;improved;individualized prevention;innovation;inter-institutional;interest;malignant breast neoplasm;member;metropolitan;mortality;multidisciplinary;new technology;novel;novel marker;novel strategies;pharmacologic;prevent;programs;psychosocial;risk stratification;screening;skin lesion;smoking cessation;social media;specific biomarkers;success;sun protection;tool;translational scientist;transmission process;wearable sensor technology Cancer Prevention (CP) Research Program n/a NCI 10902196 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5374 1942839 "KHAN, SEEMA AHSAN" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 52781 33406 19375 ABSTRACT CANCER PREVENTIONThe broad goal of the Cancer Prevention (CP) program is to reduce the burden of malignant disease throughearly detection and prevention. This goal is supported by three specific aims: (1) identify novel strategies forcancer risk stratification and early detection; (2) discover and develop new devices and therapeutics to reducecancer risk; and (3) develop and implement innovative interventions to promote risk-reducing behaviors andadherence to screening early detection and cancer prevention approaches.The multi-disciplinary program is co-led by Seema Khan MD a surgeon and translational investigator whoseresearch focuses on cancer risk biomarkers and novel pharmacologic approaches to cancer prevention andBonnie Spring PhD a clinical health psychologist whose research focuses on behavioral risk factors and noveltechnology-supported behavioral interventions to prevent cancer. The Cancer Prevention Program's 26 facultymembers from 11 departments and 2 schools conduct research on primary and secondary cancer prevention.From 2013 to 2017 there were 405 cancer-relevant publications from CP members of which 71 (18%) representintra-programmatic collaborations 85 (21%) represent inter-programmatic collaborations and 333 (82%)represent inter-institutional collaborations. Total cancer relevant peer reviewed funding for the PreventionProgram is $10679123 (direct costs) with $4345075 (41%) from the NCI $5610841 from other NIH institutesand $723207 from other peer reviewed sources. A total of 8230 individuals were enrolled into CancerPrevention Program studies with 4037 enrolled into interventional trials. Among them 3971 individuals accruedto studies of risk biomarkers 147 subjects accrued to Phase I-II trials of preventive medications and 1349participants to studies of behavioral interventions to reduce cancer risk. The importance of this work is evidencedby: 1) the demonstrated success of cancer prevention agents in reducing cancer risk; 2) the large portion of thecancer burden that can be attributed to mutable behavioral and environmental factors; and 3) the contribution ofscreening and early detection to recent declines in cancer mortality. Better adherence to preventive agentspromotion of risk-reducing behavior and improved implementation of cancer screening and risk assessment allpromise to yield rich dividends in reducing the burden of cancer. The CP program actively expands thecapabilities and efficacy of cancer prevention by developing and employing cutting edge technology andinnovative measurement tools and methods for drug- and behavioral cancer prevention interventions. Theprogram's integrated interdisciplinary focus on prevention provides an environment that fosters intra- and inter-program collaboration and has spawned cutting-edge advances in the field. +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Acute leukemia;Area;Cancer Center;Caring;Cells;Chronic Lymphocytic Leukemia;Chronic Myeloid Leukemia;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Combination Drug Therapy;Comprehensive Cancer Center;Cytotoxic agent;Data;Disease;Elderly;Epigenetic Process;Faculty;Fostering;Funding;Gene Expression;Goals;Hematologic Neoplasms;Hematological Disease;Hematopoiesis;High Density Lipoproteins;Hodgkin Disease;Institution;Intervention;Investigation;Laboratories;Laboratory Scientists;Laboratory Study;Lymphoid;Lymphoma;Lymphopoiesis;Malignant - descriptor;Malignant Neoplasms;Malignant lymphoid neoplasm;Megakaryocytes;Modification;Molecular;Molecular Target;Multiple Myeloma;Myelogenous;Myeloid Leukemia;Myelopoiesis;Myeloproliferative disease;Non-Hodgkin's Lymphoma;Outcome;Paper;Pathway interactions;Patients;Peer Review;Pharmaceutical Preparations;Prognosis;Publications;Publishing;Research;Research Personnel;Schools;Scientist;Signal Transduction;Source;Subgroup;Supportive care;Survival Rate;Talents;Therapeutic Clinical Trial;Translational Research;Translations;United States National Institutes of Health;Universities;Work;adverse outcome;chronic leukemia;efficacy evaluation;evidence base;improved;inter-institutional;interest;investigator-initiated trial;kinase inhibitor;large cell Diffuse non-Hodgkin's lymphoma;leukemia;member;molecular targeted therapies;multidisciplinary;nanoparticle;novel;programs;symposium;therapeutic target;therapeutically effective;translational scientist;translational study Hematologic Malignancies (HM) Research Program n/a NCI 10902195 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5373 1898025 "EKLUND, ELIZABETH ANN" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 60775 38465 22310 ABSTRACT HEMATOLOGIC MALIGNANCIESThe Hematologic Malignancies (HM) Program of the Lurie Cancer Center (LCC) combines the talents andexpertise of outstanding basic scientists nationally recognized clinical researchers and translationalinvestigators. The goal of the program is to leverage discoveries from member laboratories into clinicalinterventions for the treatment of malignant hematologic diseases. This goal is pursued through two programaims: a) Identify key pathways that regulate hematopoiesis and lymphopoiesis and determine the functionalsignificance of their alteration in hematologic malignancies and b) Define molecular therapeutic targets andevaluate the efficacy of novel agents in clinical trials for hematologic malignancies. Disease specific areas offocus for program members include acute and chronic myeloid leukemia myeloproliferative neoplasms (MPNs)acute and chronic lymphoid leukemia lymphomas and multiple myeloma. HM members have made significantcontributions to our understanding of molecular and cellular drivers of hematologic malignancies; specifically inthe areas of epigenetic modification cellular signaling and gene expression. Translation of these results toclinical trials is facilitated by an extensive network of collaborative interactions between laboratory-based facultyand clinical investigators in the program. During the current funding period such intra-programmatic interactionsresulted in a number of therapeutic clinical trials that were developed from work in investigator laboratories.This multidisciplinary inter-departmental program has 32 members from 10 departments in 3 schools. During thecurrent funding period program members published 520 papers that were relevant to malignant hematologicdiseases. 131 (25%) of these publications represented intra-programmatic collaborations 91 (18%) inter-programmatic collaborations and 68% involved inter-institutional collaborations. 143 (28%) were high impact(impact factor >9). Peer reviewed funding for program members totaled $5190595 (direct) with $2117851(direct) from the NCI and $3072744 (direct) from other NIH institutes and other sources. Program LeaderElizabeth Eklund MD and co-leader Leo Gordon MD have complementary expertise in the areas of laboratoryinvestigation translational research and clinical trials for hematologic malignancies. They work together to fostercollaborative interactions between program members through regularly occurring clinical and research orientedconferences retreats and other program activities.! +No NIH Category available Acceleration;Area;Award;Basic Science;Binding;Biological;Biological Assay;Biological Markers;Biomedical Engineering;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Diagnostics;Cancer Science;Chemistry;Clinic;Clinical;Clinical Trials;Clone Cells;Collaborations;Communities;Comprehensive Cancer Center;Coupled;Detection;Development;Diagnosis;Diagnostic;Doctor of Philosophy;Drug Delivery Systems;Early Diagnosis;Educational workshop;Emerging Technologies;Engineering;Evolution;Exhibits;Faculty;Faculty Recruitment;Fostering;Funding;Future;Genomics;Image;Imaging technology;Industry;Infrastructure;International;Investigation;Journals;Leadership;Link;Malignant Neoplasms;Methods;Modality;Molecular;Nanotechnology;Oncology;Pathway interactions;Peer Review;Physics;Process;Publications;Research;Research Personnel;Resolution;Schools;Science;Scientist;Screening for cancer;Social Network;Technology;Therapeutic;Therapeutic Agents;Translational Research;Translations;Universities;Visualization;Work;anti-cancer therapeutic;anticancer research;cancer cell;cancer therapy;carcinogenesis;clinical care;clinical translation;design;imaging agent;imaging modality;in vivo;innovation;materials science;member;nanoscale;new technology;novel;novel therapeutics;physical science;practical application;prognostication;programs;recruit;symposium;synergism;systemic toxicity;targeted agent;targeted treatment;technology development;tool;translational pipeline;tumor;tumor heterogeneity;tumorigenesis;webinar Cancer and Physical Sciences (CAPS) Research Program n/a NCI 10902193 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5371 7125025 "BACKMAN, VADIM " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 63337 40087 23250 ABSTRACT CANCER AND PHYSICAL SCIENCESThe Cancer and Physical Sciences (CAPS) program capitalizes on the unique strengths and internationalleadership of Northwestern University in nanotechnology and physical sciences. The program brings togetherfundamental chemistry nano-technology imaging and bioengineering groups to develop cancer-relevanttherapeutic and diagnostic agents using nanoscale materials and physical sciences approaches. The resultingsynergies have been leveraged by the Lurie Cancer Center (LCC) into the NCI-funded Center for CancerNanotechnology Excellence (CCNE) and the NCI-funded Physical Sciences in Oncology Center (PSOC).The CAPS Program received Exceptional to Outstanding merit at the last CCSG renewal application. Sincethen the program has been further strengthened by enhancing the integration of engineering and physicalsciences investigators within the arena of cancer research developing new strategies and technologies thatfacilitate efficient interactions among program members and by accelerating translational efforts. VadimBackman PhD a bioengineer is the Program Leader and Gayle Woloschak PhD a biochemist and molecularbiologist is the Program Co-Leader. This uniquely interdisciplinary program comprises 28 faculty members from11 departments and 3 schools. Between 2013 and 2017 there have been 417 cancer-relevant publications fromthe program members. Sixty-eight (16%) of these publications represent intra-programmatic collaborations 87(21%) represent inter-programmatic collaborations and 207 (50%) represent external collaborative publications.154 (37%) of the publications were in high impact (>9) journals. Current cancer-relevant funding is $12212040(direct) in total peer-reviewed funding out of which $4253788 (direct) is from NCI. CAPS investigators focuson (1) the elucidation of fundamental mechanisms and molecular pathways that control oncogenesis by physicalscience methods (2) the development of novel technologies for early cancer detection and (3) the discovery anddevelopment of nanotechnology- and physical sciences based tumor targeting agents and therapeuticmodalities. Towards reaching these objectives CAPS serves as a forum to link basic biological investigationwith practical applications from the fields of chemistry physics engineering and nanotechnology. It provideswebinars symposia and financial awards to stimulate intra- and inter-programmatic collaborations on a broadspectrum of translational projects. CAPS has facilitated the creation of innovative tools for the diagnosisdetection and treatment of cancer including new imaging agents a new technology for early cancer detectionand novel therapeutic modalities. A number of these developments have advanced from basic engineeringresearch to clinical trials and clinical care. CAPS future plans are designed to further accelerate discovery andtranslation within the LCC through faculty recruitment and bridge building increasing opportunities for scientificexchange and fostering partnerships with industry. +No NIH Category available Acceleration;Address;Articulation;Basic Science;Binding;Biochemical Reaction;Biogenesis;Biological Markers;Biological Sciences;Biology;Cancer Center;Cell Proliferation;Cell membrane;Cells;Cellular Membrane;Cellular biology;Clinical;Collaborations;Communication;Comprehensive Cancer Center;Core Facility;Cytokine Signaling;Development;Diagnosis;Division of Basic Sciences;Doctor of Philosophy;Educational workshop;Faculty;Fostering;Funding;Future;Gene Expression;Gene Expression Regulation;Laboratories;Lead;Leadership;Life;Link;Malignant - descriptor;Malignant Neoplasms;Medicine;Membrane;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Molecular;Molecular Biology;Neoplasm Metastasis;Normal Cell;Organelles;Oxidative Stress;Pathway interactions;Peer Review;Prognosis;Publications;Research;Research Personnel;Research Support;Resources;Risk Assessment;Schools;Series;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Source;System;Translations;Work;cancer cell;cell growth;cell transformation;cohort;data sharing;design;meetings;member;metabolomics;neoplastic cell;novel therapeutics;pathogen;professor;programs;recruit;response;scientific organization;symposium;synergism;therapeutic target;tool;tumor;tumor growth;tumor metabolism;tumor progression;tumorigenesis Membranes Organelles and Metabolism (MOM) Research Program n/a NCI 10902191 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5369 1949914 "CHANDEL, NAVDEEP S" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 50668 32068 18600 ABSTRACT MEMBRANES ORGANELLES AND METABOLISMMembranes Organelles and Metabolism (MOM) is a new program that was created during the reorganizationof the Basic Science Division in the Lurie Cancer Center (LCC). The program is founded on the emerging conceptthat signaling and metabolic pathways rely on association with a physically interconnected network of cellmembranes and membrane-bound organelles which are exploited by developing tumors to promote malignanttransformation and progression. Integration of the classic view of cellular signaling as a series of biochemicalreactions with this current perspective provides a clearly articulated focus for an outstanding group of basicscience investigators studying mitochondrial biogenesis and function metabolism signal transduction and host-pathogen interactions. The broad objectives of MOM are to elucidate how cellular membranes and organellesdrive cell response and effector cascades to determine how tumors and tumor-causing pathogens exploit thesepathways and to identify pathway components as therapeutics targets. These objectives are pursued in threespecific aims: (1) Understand how cells utilize metabolic pathways to dictate cell proliferation metabolicadaptation and gene expression thereby modulating tumor growth; (2) Define the molecular mechanisms bywhich pathogens disrupt and/or utilize host pathways to stimulate tumorigenesis; (3) Determine how signaltransduction pathways initiated from plasma membrane and/or organelles are integrated in cancer cells topromote tumorigenesis.The MOM program leader is Navdeep S. Chandel Ph.D. Professor in the Department of Medicine and theDepartment Cell and Molecular Biology. He is an expert in cancer metabolism mitochondrial biology andoxidative stress. The co-leader is Curt Horvath Ph.D. a Professor in the Department of Molecular Bioscienceswhose expertise is in mechanisms of cytokine signal transduction and gene regulation in normal and malignantcells. Drs. Chandel and Horvath lead an interdepartmental cohort of investigators comprising 36 faculty from 10departments and 3 schools. Between 2013 and 2017 there were 405 cancer-relevant publications from theprogram 71 (18%) of which represent intra-programmatic collaborations and 157 (39%) represent inter-programmatic collaborations. Work in the MOM program is supported by cancer-relevant peer-reviewed fundingof $12161291 (direct) with $2187789 (direct) from NCI and $9973502 (direct) from other peer-reviewedsources. The MOM program provides its members with the research support tools and scientific networkingopportunities to achieve an understanding of how interference with membrane networks and metabolismcontributes to cell transformation and tumor progression. Through MOM-sponsored monthly membershipmeetings workshops symposia and seminar series the program fosters collaboration between programmembers and their clinical/translational partners and links investigators with new opportunities to advance theirresearch within the LCC. +No NIH Category available 3-Dimensional;Acceleration;Address;Advocate;Affect;Architecture;Arts;Basic Science;Biological Models;Biological Sciences;Caenorhabditis elegans;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Nucleus;Cells;Cellular biology;Chromatin;Clinic;Clinical;Clinical Investigator;Collaborations;Comprehension;Comprehensive Cancer Center;DNA;Data Science Core;Development;Doctor of Philosophy;Drosophila genus;Ensure;Epigenetic Process;Faculty;Frequencies;Funding;Future;Gene Expression;Gene Expression Regulation;Genetic Transcription;Genome;Goals;Human;Human Genome;Immunologic Surveillance;Leadership;Malignant - descriptor;Malignant Neoplasms;Mediator;MicroRNAs;Microscopy;Modification;Molecular;Mutation;Neoplasm Metastasis;Nuclear;Oncogenes;Organelles;Organizational Change;Organizational Objectives;Peer Review;Pharmacology;Positioning Attribute;Process;Property;Proteins;Proteomics;Publications;RNA;RNA Polymerase II;Research;Research Personnel;Research Support;Resource Sharing;Schools;Science;Series;Signal Transduction;Source;Structure;Technology;Therapeutic;Translating;Translational Research;Translations;Tumor Suppressor Proteins;United States National Institutes of Health;Untranslated RNA;Work;Yeasts;cancer cell;cancer type;cell behavior;chemotherapy;clinical translation;college;epigenetic regulation;genome-wide;insight;medical schools;meetings;member;mouse model;neoplastic cell;novel anticancer drug;novel diagnostics;novel therapeutics;professor;programs;symposium;transcription factor;translational scientist;tumor;tumor progression;tumorigenesis Cancer Epigenetics and Nuclear Dynamics (CEND) Research Program n/a NCI 10902190 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5368 1965800 "CARTHEW, RICHARD W." Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 55347 35030 20317 ABSTRACT CANCER EPIGENETICS AND NUCLEAR DYNAMICSCancer Epigenetics and Nuclear Dynamics (CEND) is a new basic science research program in the Robert H.Lurie Comprehensive Cancer Center (LCC) that emerged after the re-organization of the basic science programsin 2015. The goals of the CEND program are to understand how the nucleus is structurally organized andfunctionally regulated in cancer cells as compared to non-transformed cells and to accelerate translation of basicdiscoveries in cancer epigenetics and gene regulation to develop new therapeutic and diagnostic applications.With this focus CEND brings together faculty from the former Cancer Cell Biology and Signal TransductionPrograms plus six new LCC members. These faculty have a broad range of expertise and they use diversemodel systems ranging from yeast Drosophila and C. elegans to mouse models and primary human malignantcells. The aims of CEND are to: 1. Understand how genome organization changes during tumorigenesis andwhether organizational changes contribute to tumor progression. 2. Understand how epigenetic regulationchanges during tumorigenesis. 3. Understand how non-coding RNAs affect tumorigenesis. 4. Understand therelationship between transcription factors and cancer.The Program is led by Richard Carthew PhD Professor of Molecular Biosciences at the College of Arts andSciences and Debabrata Chakravarti PhD Professor of Pharmacology at the Feinberg School of Medicine.Both leaders have held program leadership positions in LCC prior to this latest funding cycle. CEND membershipcomprises 29 faculty from 9 departments and 2 schools. Current cancer-relevant peer-reviewed direct fundingis $8175046 with $2670481 from NCI and $5504565 in funding from other NIH institutes and peer reviewsources. There have been 375 cancer-relevant publications since last competing CCSG review. Of these 17%of publications arose from intra-programmatic collaborations 39% arose from inter-programmatic collaborationsand 64% arose from collaborations with other cancer centers. 114 (30%) were high impact (>9) publications.Thus CEND members effectively collaborate within and outside of the program. Another priority for CEND is topromote interactions between program members and clinical/translational researchers in order to harness basicdiscoveries to develop new therapeutic and diagnostic applications. CEND thus adds significant value to thecancer center by providing a conceptually renewed and focused framework for promoting clinical translation ofbasic discoveries. +No NIH Category available Animal Husbandry;Archives;Biological Assay;Breeding;CRISPR/Cas technology;Cancer Center;Cell Culture Techniques;Chimera organism;Cloning;Clustered Regularly Interspaced Short Palindromic Repeats;Comprehensive Cancer Center;Consultations;Cryopreservation;DNA Sequence Alteration;DNA purification;Dedications;Derivation procedure;Development;Diagnostic;Doctor of Philosophy;ES Cell Line;Effectiveness;Embryo;Emerging Technologies;Engineering;Epididymis;Equipment;Faculty;Fertilization in Vitro;Foundations;Freezing;Future;Gene Targeting;Generations;Genes;Genetic;Genetic study;Genetically Engineered Mouse;Genome engineering;Genomics;Genotype;Germ;Germ Lines;Individual;Infrastructure;Laboratories;Maintenance;Malignant Neoplasms;Mediating;Methodology;Methods;Microinjections;Microsurgery;Mission;Modification;Molecular;Mouse Strains;Mus;Mutagenesis;Mutant Strains Mice;Mutation;Positioning Attribute;Production;Reagent;Recovery;Recurrence;Research;Research Personnel;Resource Sharing;Resources;Role;Services;Solid;System;Technical Expertise;Techniques;Technology;Therapeutic;Time;Transgenic Mice;Transgenic Organisms;Translating;Universities;Validation;Work;base;blastocyst;cost;cryobiology;design;embryonic stem cell;flexibility;genome editing;insight;laboratory facility;member;mouse model;mutant;novel;pathogen;programs;screening;skills;sperm cell;sperm cryopreservation;tumor progression;vector Transgenic and Targeted Mutagenesis Laboratory Shared Resource n/a NCI 10902189 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5367 8899699 "AWATRAMANI, RAJESHWAR B" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 176584 111762 64822 ABSTRACT TRANSGENIC AND TARGETED MUTAGENESIS LABORATORYThe Transgenic and Targeted Mutagenesis Laboratory (TTML) is a Northwestern University-wide resourcededicated to the generation import recovery/rederivation and cryopreservation of genetically engineered mice.TTML provides Lurie Cancer Center (LCC) members a broad range of services including generation oftransgenic gene edited and targeted transgenic mouse models via microinjection; gene targeting/editing ofembryonic stem (ES) cells; ES cell microinjection into blastocysts to create germline competent chimera;importation and recovery/rederivation of mouse lines from germplasm; and cryopreservation of mouse spermand embryos. Since the last review the core has introduced full-scale start-to-finish mutagenesis capabilities.These changes were necessary to facilitate the development of newly emerging genome engineeringtechnologies such as CRISPR. The TTML team works with LCC members to design customized geneticmodification strategies and genotyping assays and provides confirmed founders to investigators. These newcapabilities in addition to our traditional methods for creating transgenic and ESC derived mutant lines enableinvestigators the opportunity to employ overarching approaches to genetic modification mutagenesis through thefacility.The TTML facility is essential for the research programs of investigators of the Lurie Cancer Center who usemouse models to study mechanisms underlying malignancy and validate targets for translational projects. Itprovides the necessary infrastructure that allows the Centers investigators access to transgenic technology thatnormally requires expensive microinjection equipment and skilled staff with expertise in microinjectionmicrosurgeries embryo manipulation animal husbandry ES cell culture and genome engineering. In additionTTML staff provide in-house consultation and recurrent guidance on all transgenic-related technologies includingCRISPR-mediated genome editing systems transgenic and targeting vector design appropriate screeningstrategies DNA purification methods breeding and analysis of founder mice appropriate methods for importingmouse lines and cryopreservation options. Since the inclusion of the TTML as a resource within the Lurie CancerCenter in 1995 Center investigators have consistently been the primary group of NU faculty utilizing the TTMLemphasizing its pivotal role in the overall research mission of the LCC. +No NIH Category available ATAC-seq;Advanced Malignant Neoplasm;Applications Grants;Area;Basic Science;Bioinformatics;Biometry;Biostatistics Core;Biotechnology;Cancer Center;Cancer Center Support Grant;Cancer health equity;ChIP-seq;Chicago;Clinical;Clinical Cancer Center;Clinical Informatics;Clinical Sciences;Clinical Trials;Complex;Comprehensive Cancer Center;Computerized Medical Record;Core Facility;Custom;Data;Data Analyses;Data Science;Data Science Core;Databases;Development;Dimensions;Discipline;Disease;Doctor of Philosophy;Faculty;Gene Expression;Genes;Genetic;Goals;Image;Informatics;Information Retrieval;Information Systems;Journals;Laboratories;Machine Learning;Maintenance;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Medicine;Methylation;Microarray Analysis;Monitor;Natural Language Processing;Outcome;Paper;Pathology;Pathway interactions;Phase;Physiological;Population Sciences;Publications;Reporting;Research;Research Design;Research Personnel;Resource Sharing;Secure;Services;Statistical Data Interpretation;Statistical Methods;Surveys;System;Variant;Work;cancer clinical trial;data management;data repository;data submission;data visualization;data warehouse;design;electronic data;informatics infrastructure;informatics tool;member;next generation sequencing;oncology trial;personalized medicine;preclinical study;programs;protocol development;public database;randomized clinical trials;statistics;success;tool;transcriptome;variant detection;web platform Quantitative Data Sciences Core Facility Shared Resource n/a NCI 10902187 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5365 8559840 "KOCHERGINSKY, MASHA " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 507381 321127 186254 ABSTRACT QUANTITATIVE DATA SCIENCES CORE The Quantitative Data Sciences Core (QDSC) provides a state-of-the-art integrated approach for Data Science support to Lurie Cancer Center (LCC) members in the basic clinical and population sciences. Data Sciences includes the three disciplines of Biostatistics Bioinformatics and Clinical Informatics. Since the last CCSG review the former Biostatistics Core and Cancer Informatics Core have been integrated into a new QDSC to provide a unified approach to data definition acquisition management analysis and reporting. The QDSC Director is Alfred Rademaker PhD; Associate Directors are Denise Scholtens PhD (Biostatistics) Matthew Schipma PhD (Bioinformatics) and Firas Wehbe MDPhD (Clinical Informatics). As part of this consolidation the core has been expanded through the addition of faculty and staff effort bridging the fields of informatics and statistics areas of expertise often sought together by members of the LCC. The QDSC also works collaboratively with the Pathology Core Facility the Outcomes Measurement and Survey Core and the LCC Clinical Trials Office. The Biostatistics component provides power calculations and statistical analyses to investigators who are planning and conducting basic and preclinical studies and assists in the development of early phase and randomized clinical trials. The Bioinformatics component provides support for the analysis of next generation sequencing data pathway identification variant detection methylation analysis and data visualization. The Clinical Informatics component provides clinical trial management disease-based database and informatics tools project specific Research Electronic Data Capture (REDCap) development pathology data management and support for accessing and analyzing Northwestern Medicine Electronic Data Warehouse (NMEDW) data. QDSC Clinical Informatics has integrated and augmented the Northwestern Oncology Trial Information System (NOTIS) LCCs clinical trial management system and the electronic medical record (Epic) used by our clinical partners. QDSC has been heavily used by cancer researchers with 109 LCC members using the Core in the last year and it has been instrumental in the publication of 151 papers many in high impact journals. Moreover it has contributed to the success of many grant applications notable among them a renewal of a SPORE in Prostate Cancer and a new U54 Chicago Collaborative to Promote and Advance Cancer Health Equity. +No NIH Category available Acetylation;Affect;Amino Acid Sequence;Amino Acids;Biological;Biological Assay;Biological Markers;Blood;Blood specimen;Body Fluids;Cancer Center;Cancer Center Support Grant;Cell Culture Techniques;Cells;Clinical;Clinical Trials;Comprehensive Cancer Center;Computer software;Core Facility;Data;Data Analyses;Detection;Diagnosis;Disease;Doctor of Philosophy;Early Diagnosis;Emerging Technologies;Epigenetic Process;Flow Cytometry;Fluorescence-Activated Cell Sorting;Funding;Gel;Generations;Genes;Health Services Accessibility;Histones;Label;Laboratory Personnel;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Methodology;Methods;Methylation;Mission;Mitochondria;Monitor;Peptides;Pharmaceutical Preparations;Phosphorylation;Post Translational Modification Analysis;Post-Translational Protein Processing;Preparation;Prognosis;Proteins;Proteomics;Proteomics Shared Resource;Publications;Reaction;Research;Research Design;Research Personnel;Research Support;Resolution;Resource Sharing;Resources;Saliva;Sampling;Services;Signal Pathway;Site;Site-Directed Mutagenesis;Stable Isotope Labeling;System;Technology;Time;Tissues;Training and Education;Ubiquitination;Universities;Urine;Work;anticancer research;biomarker identification;biomarker validation;cell type;cost;cost effective;data analysis pipeline;drug discovery;exosome;glycosylation;histone modification;instrumentation;liquid chromatography mass spectrometry;member;neoplastic cell;new therapeutic target;next generation;operation;palmitoylation;patient screening;pre-clinical;protein complex;research facility;response;technology development;treatment response;validation studies Proteomics Core Facility Shared Resource n/a NCI 10902186 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5364 1886884 "KELLEHER, NEIL L" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 184032 116476 67556 ABSTRACT PROTEOMICS SHARED RESOURCE FACILITYThe mission of the Proteomics Shared Resource Facility is to provide cost-effective state-of the-artinstrumentation and analytical proteomics expertise to investigators in the Lurie Cancer Center (LCC). TheProteomics Core provides a full array of services including study design sample preparation data generationand analysis and interpretation of results. The Core supports work involving the following types ofmethodologies: 1) protein identification from gels and BioID samples. 2) Quantitative proteomics labeled andlabel-free. 3) Top-down proteomics - qualitative and quantitative 4) Site-specific PTM analyses includingphosphorylation acetylation methylation glycosylation palmitoylation and ubiquitination; 5) Targetedproteomics using selective reaction monitoring (SRM) and related methods; 6) Histone Modification Panelanalysis covering all major histone marks and 7) Advanced proteomics sample preparation from body fluids(blood urine saliva CSF) tissue secretome exosome and mitochondria. In addition the Proteomics Corestaff provides education and training in sample preparation instrumental analysis and data analysis to LCCinvestigators and their laboratory personnel. The Core operates eight liquid chromatography-mass spectrometrysystems and since its inception as a former developing core at the time of the last CCSG review has servedover 90 LCC investigators resulting in over 60 research publications.The Proteomics Core is located on both campuses of Northwestern University (NU). Neil Kelleher PhD directsthe Facility and works closely with Young Ah Goo PhD the Operations Director of the Facility. As a cross-university cross-campus resource access to service is available to all Northwestern University investigatorswith priority given to LCC researchers. During the next funding period the Proteomics Core will continue to workclosely with LCC researchers to ensure that efficient access and technological expertise in proteomics isavailable to all research teams engaged in basic clinical and translational cancer studies. +No NIH Category available Address;Adult;Area;Attention;Attitude;Cancer Center;Characteristics;Child;Clinic;Clinical Cancer Center;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communities;Comparative Effectiveness Research;Comprehensive Cancer Center;Computers;Consult;Consultations;Core Facility;Data Collection;Data Reporting;Data Science Core;Development;Ensure;Evaluation;Funding;Goals;Health Services Research;Health behavior;Human Resources;Intervention Studies;Knowledge;Language;Longevity;Malignant Neoplasms;Measurement;Methods;Minority Groups;Minority Recruitment;Mission;NCI Center for Cancer Research;Observational Study;Oncology;Outcome;Outcomes Research;Participant;Patient Outcomes Assessments;Patient Recruitments;Patient Self-Report;Patients;Play;Population Heterogeneity;Population Sciences;Protocols documentation;Psychometrics;Qualitative Research;Questionnaires;Recommendation;Reporting;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Sampling;Science;Services;Survey Methodology;Surveys;Symptoms;Vulnerable Populations;Work;cancer clinical trial;community based participatory research;community based research;community setting;efficacy evaluation;experience;improved;information gathering;instrument;interest;literacy;member;novel therapeutics;preference;programs;recruit;research study;skills;sociodemographics;tool Outcomes Measurement and Survey Core Facility Shared Resource n/a NCI 10902184 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5362 9525368 "BUTT, ZEESHAN AHMAD" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 153239 96987 56252 ABSTRACT OUTCOMES MEASUREMENT AND SURVEY CORE The goal of the Outcomes Measurement and Survey Core (OMSC) is to provide consultation and support for projects that involve collecting analyzing and interpreting self-report data and to promote the understanding of measurement fundamentals and the improvement of survey research practice. By offering our expertise gained from years of experience with research on self-report data and community-based participatory research this shared resource provides vital support services for clinical trials observational studies and health services research projects. OMSC personnel have expertise in survey research methodology Patient-Reported Outcomes (PRO) measurement qualitative research methods psychometrics as well as study recruitment and retention for adults and children with diverse language literacy cognitive functional and computer skills. The aims of the core are: 1) to provide consultative and practical expertise on self-report measurement analysis and interpretation in culturally diverse populations across the lifespan; 2) to serve as a central resource for state- of-the-science PRO instruments and survey methods; and 3) to provide assistance with recruitment of community participants for research studies. To accomplish these aims OMSC members work closely with Lurie Cancer Center (LCC) investigators and interact with several other complementary Shared Resource Facilities particularly the Quantitative Data Science Core. During the current usage reporting period the OMSC worked with 43 different LCC members on 52 projects across six different LCC research programs. Over the next funding period the OMSC will continue to provide the Lurie Cancer Center with psychometric and survey research support in the areas of study design data collection analysis and interpretation and will add support for recruitment and retention of community participants in cancer-relevant research. +No NIH Category available Animal Model;Antineoplastic Agents;Biological Sciences;Cancer Center;Cancer Center Support Grant;Cells;Chicago;Clinical;Clinical Research;Collaborations;Comprehensive Cancer Center;Computer software;Core Facility;Development;Developmental Therapeutics Program;Engraftment;Equipment;Flow Cytometry;Funding;Goals;Grant;Histologic;Histology;Image;Image Analysis;Imaging technology;Individual;Isotope Labeling;Label;Magnetic Resonance Imaging;Malignant Neoplasms;Medical Imaging;Methods;Modality;Molecular;Multimodal Imaging;Mus;Near-infrared optical imaging;Neoplasm Metastasis;Outcome Study;PET/CT scan;Patient Care;Peer Review;Phenotype;Production;Radiochemistry;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Schedule;Services;Site;Sorting;Technology;Testing;Therapeutic Agents;Universities;Validation;Work;anticancer research;cell behavior;clinical imaging;data analysis pipeline;efficacy evaluation;image processing;image translation;imaging approach;imaging capabilities;imaging modality;imaging study;improved;in vivo;instrumentation;member;non-invasive monitor;novel diagnostics;novel strategies;novel therapeutics;nuclear imaging;pre-clinical;preclinical imaging;preclinical study;single photon emission computed tomography;tool;tumor growth Molecular and Translational Imaging Core Facility Shared Resource n/a NCI 10902182 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5360 11280383 "KIM, DONG-HYUN " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 179014 113300 65714 ABSTRACT MOLECULAR AND TRANSLATIONAL IMAGING CORE The Molecular and Translational Imaging Core (MTIC) provides Lurie Cancer Center (LCC) members with multi- modal imaging capabilities that support their cancer research by enabling users to apply advanced imaging technologies to their preclinical and clinical studies. The ability to track injected or engrafted cells administered agents and tumor growth and metastasis in a non-invasive fashion is an invaluable tool in the development and testing of new diagnostic and therapeutic agents that can improve patient care. The MTIC has sites on both the Evanston and Chicago campuses. Instrumentation that is available to users at one or both sites includes MRI PET/CT SPECT/CT and IVIS (fluorescent bioluminescent and near infrared optical imaging). The MTIC provides expert staff in each of these modalities and allows investigators to apply the most appropriate imaging methods to their cancer studies. The MTIC collaborates closely with other LCC core facilities including the Developmental Therapeutics Core the Flow Cytometry Core and the Mouse Histology and Phenotyping Core. During the most recent reporting period MTIC scientific and technical staff provided support to 45 LCC users 43 of whom had peer-reviewed funding. The scheduled installation of a radiochemistry production facility on the Chicago campus and plans by the MTIC to offer additional state-of- the-art imaging modalities during the next CCSG cycle will further increase the value of this facility to Lurie Cancer Center members. +No NIH Category available Biochemical;Biochemistry;Biological Assay;CRISPR library;Cancer Biology;Cancer Center Support Grant;Cell physiology;Cells;Cellular biology;Certification;Collaborations;Collection;Communities;Complex;Comprehensive Cancer Center;Computer software;Confocal Microscopy;Consultations;Crystallization;Data;Data Analyses;Data Collection;Development;Developmental Therapeutics Program;Ensure;Environment;Equipment;Experimental Designs;Future;Genes;Hand;Human;Industry;Laboratories;Libraries;Liquid substance;Malignant Neoplasms;Miniaturization;Mission;Molecular Biology;Mus;Organoids;Pharmaceutical Chemistry;Productivity;Reader;Reporting;Research;Research Personnel;Resource Sharing;Resources;Robotics;Running;Sampling;Science;Services;Speed;Structural Biologist;Structure-Activity Relationship;Support Groups;System;Technical Expertise;Technology;Therapeutic Agents;Training;Translational Research;Validation;Work;assay development;cell behavior;cost;data management;design;experimental study;gene function;genome-wide;high throughput analysis;high throughput screening;instrument;instrumentation;interest;laboratory experience;lead optimization;member;nanolitre;new therapeutic target;novel therapeutics;parallelization;screening;tissue culture High Throughput Analysis Laboratory Shared Resource n/a NCI 10902179 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5357 1904007 "HORVATH, CURT M" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 145229 91917 53312 ABSTRACT HIGH THROUGHPUT ANALYSIS LABORATORY The High Throughput Analysis laboratory (HTA) enables LCC researchers to develop perform and analyze large scale experiments that elucidate the fundamental biology of cancer and launch the discovery of novel therapeutic agents. Such projects can involve parallel manipulation of tens of thousands of samples as well as data collection and analysis at a similar scale. To support this work the facility provides advanced technology technical expertise and resources like compound and gene disruptor libraries for diverse high throughput screens (HTS) on biochemical targets and cell processes. HTA staff partner with LCC researchers to adapt bench-scale studies into assays that are tractable for such large-scale experiments and to use these assays to run screens. HTA capabilities also support non-HTS projects requiring the use of robotic liquid handling and plate readers. LCC members use a wide range of experimental systems and technical approaches in their research. HTA is therefore configured to develop and run assays ranging from fundamental biochemistry to cell-based studies involving high throughput confocal microscopy (known as high content screening or HCS). The facility maintains a suite of instruments for large-scale experiments that include advanced liquid handling platforms for nanoliter to microliter volumes a diverse set of high-end photometric systems and two different platforms for high-content screening (one of which is a new confocal instrument). The facilitys staff acquires and analyzes data from all instruments as a service assists with experimental design and trains researchers to use its analytical and acquisition software independently. Importantly HTA is a fully-equipped conventional laboratory for cell and molecular biology with significant bench space and a newly renovated in-house tissue culture facility. Users can run complex experiments entirely in the facility. The number of LCC research groups supported by HTA instruments and services during the most recent one-year reporting period is more than double that reported in the previous CCSG renewal application. The increased usage of the facility corresponds to a significant expansion of its instrumentation services and screening resources. This has included significant compound library acquisitions and newly developed capabilities for multiplexed and parallelized CRISRP/Cas9 screening for large scale functional analysis. HTA actively maintains a productive collaboration with ChemCore speeding the cycle of lead optimization and ensuring that compound library selection maximizes the potential for medicinal chemistry with screening hits. Moreover HTA works with the Developmental Therapeutics Core to develop new assays that use advanced tissue culture approaches. +No NIH Category available 3-Dimensional;Acceleration;Address;Adherent Culture;Animals;Apoptotic;Applications Grants;Area;Biological;Biological Assay;Cancer Center;Cancer Center Support Grant;Cancer Model;Cancer Patient;Cell Line;Cellular Assay;Client;Clinical Trials;Comprehensive Cancer Center;Consumption;Data;Developmental Therapeutics Program;Drug Formulations;Drug Kinetics;Drug Stability;Engraftment;Evaluation;Faculty;Goals;Grant;Human;IACUC;Image;Immune response;Immune system;Immunocompetent;Immunologics;Immunotherapy;In Vitro;Invaded;Legal patent;Libraries;Malignant Neoplasms;Manuscripts;Modeling;Modification;Molecular;Molecular Profiling;Mus;Operative Surgical Procedures;Organoids;Patients;Peer Review;Pharmaceutical Preparations;Preclinical Testing;Preparation;Process;Proliferating;Protocols documentation;Publications;Research;Research Activity;Research Design;Research Personnel;Resource Sharing;Route;Services;Study models;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Toxicology;Training;Translation Initiation;Translational Research;Treatment Efficacy;Tumor Cell Line;Xenograft procedure;analytical tool;cancer subtypes;cancer therapy;cancer type;chemotherapy;clinical translation;cost;discount;exome sequencing;first-in-human;immune system function;immunocytochemistry;improved;in vitro testing;in vivo;in vivo evaluation;interest;member;migration;model development;mouse model;neoplastic cell;novel;novel therapeutics;operation;patient derived xenograft model;repository;response;screening;subcutaneous;targeted treatment;testing services;therapeutic candidate;therapeutic evaluation;three dimensional cell culture;transcriptome;transcriptome sequencing;translational cancer research;translational impact;treatment effect;treatment response;tumor;tumor growth;tumor immunology;uptake Developmental Therapeutics Core Shared Resource n/a NCI 10902177 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5355 6762263 "JAMES, CHARLES DAVID" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 113221 86669 26552 ABSTRACT DEVELOPMENTAL THERAPEUTICS COREThe Developmental Therapeutics Core (DTC) supports LCC investigators in the preclinical testing of noveltherapeutics as well as established agents that are being repurposed with the primary intent of addressing themerit of advancing novel agents and strategies for clinical trial evaluation. The DTC provides a range ofpreclinical testing services that include: in vitro tumor cell assays; in vivo subcutaneous and orthotopic modelsfor studying tumor growth as well as for studying tumor response to therapy; exploratory pharmacokinetics; andexploratory toxicology. The DTC also assists investigators with drug formulations and initial assessments of drugstability. A patient-derived xenograft (PDX) repository provides investigators with more than 60 tumor modelsrepresenting 12 different types of cancer for in vivo testing of therapies against human tumors. The DTC alsomaintains a repository with more than 200 human tumor cell lines many of which can also be used for xenograftestablishment and therapeutic testing. DTC staff are proficient in all routes of treatment administration and insmall animal surgery provide consulting and training and accelerate implementation of studies through simplemodification of blanket IACUC protocols. DTC staff advise faculty on study design and assist with theinterpretation and presentation of results for manuscripts and grant applications. The DTC coordinates studieswith other LCC shared resources in providing LCC members an integrated and expeditious process for achievingstudy objectives.During the most recent CCSG grant year the core has had a significant impact on LCC research in aiding 52Cancer Center members contributing to publications and generating results that have helped in obtaining anIND from the FDA for two novel therapeutics that are undergoing clinical trial evaluation in first in human studies.During the current CCSG term the DTC has assisted LCC members in the preparation of more than 40 grantapplications that have resulted in $17M in new external support for LCC research. Experimental results obtainedin association with DTC assistance have resulted in 5 patents and 7 applications and have contributed to thefounding of six start-up companies. During the next period of CCSG support the DTC will continue its robustlevel of PDX research activity but will also emphasize the use of syngeneic mouse model tumors for studyingimmunologic effects of therapy as well as for testing immunotherapies in animal subjects with an intact fullyfunctioning immune system. +No NIH Category available 3-Dimensional;Applications Grants;Award;Calcium;Cancer Biology;Cancer Center;Cells;Comprehensive Cancer Center;Computer software;Conceptions;Confocal Microscopy;Core Facility;Data;Data Analyses;Data Storage and Retrieval;Decentralization;Dedications;Education;Education and Outreach;Educational workshop;Electron Microscope;Electron Microscopy;Equipment;Fluorescence;Fluorescence Resonance Energy Transfer;Funding;Hour;Image;Image Analysis;Imaging Techniques;Imaging technology;Investigation;Journals;Leadership;Light;Manuscripts;Microscope;Microscopy;Organ;Phase;Platinum;Plug-in;Preparation;Reagent;Research;Research Personnel;Resource Sharing;Resources;Scanning;Secure;Services;Slice;Source;Specialist;System;Techniques;Technology;Testing;Tissue imaging;Tissues;Training;United States;Universities;Whole Organism;base;cell fixing;data exchange;data management;imaging approach;imaging facilities;imaging system;improved;instrument;instrumentation;light microscopy;live cell imaging;luminescence;member;model organism;novel imaging technology;programs;routine imaging;single molecule;success;technology platform;ultra high resolution Center for Advanced Microscopy Shared Resource n/a NCI 10902176 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5354 7379855 "ARVANITIS, CONSTADINA " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 158705 100446 58259 ABSTRACT CENTER FOR ADVANCED MICROSCOPY The Center for Advanced Microscopy (CAM) provides training access support and expertise that enable Lurie Cancer Center (LCC) members to successfully utilize advanced microscopy techniques and instrumentation in their studies. It is heavily used by Northwestern University (NU) investigators with 104 LCC members using the facility last year. Our facility is open 24 hours/7 days a week and provides access to a wide array of state of the art light and electron microscopy (EM) instrumentation auxiliary equipment and reagents permitting imaging to be performed across a range of spatial scales. Our continuously expanding portfolio of instruments and the expertise of CAM staff enable users to image single molecules macromolecular networks live cells tissue sections whole organs and model organisms with brightfield fluorescence and luminescence. We support advanced imaging techniques such as FRET FRAP FLIP TIRF photo-conversion and immuno-gold and platinum replica EM. The facility has aggressively and with a high degree of success pursued funding from a variety of sources to maintain the LCCs leadership in novel imaging technologies. For example CAM is one of only three Nikon Imaging Centers in the United States allowing our users to test the latest technologies from Nikon. CAM also provides workstations a suite of software and expert support including a recently hired Image Analysis Specialist to facilitate imaging data transfer storage management and analysis. The facility also provides a wide array of educational programs including courses seminars journal clubs and hands-on workshops. +No NIH Category available Area;Award;Cancer Biology;Cancer Center;Caregivers;Catchment Area;Chicago;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Comprehensive Cancer Center;Dedications;Education;Educational Activities;Environment;Faculty;Funding;Future;Grant;Health Professional;Healthcare;International;Journals;Laboratories;Malignant Neoplasms;Medical;Mentored Clinical Scientist Development Program;Mentors;Mentorship;Molecular;Oncologist;Oncology;Oncology Nurse;Participant;Population Sciences;Postdoctoral Fellow;Prize;Professional Education;Research;Research Personnel;Scientist;Series;Special Event;Students;Training;Training and Education;Travel;United States National Institutes of Health;anticancer research;career;career development;clinical development;clinically relevant;doctoral student;lectures;malignant breast neoplasm;meetings;member;novel;outreach;posters;precision medicine;programs;symposium;training opportunity;translational oncology;tumor;undergraduate education;undergraduate student Cancer Research Career Enhancement andRelated Activities n/a NCI 10902175 8/30/23 0:00 PAR-17-095 4P30CA060553-29 4 P30 CA 60553 29 8/15/97 0:00 7/31/25 0:00 ZCA1-RTRB-C 5353 9830818 "BONINI, MARCELO G" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 216749 137183 79566 ABSTRACT CANCER RESEARCH CAREER ENHANCEMENT AND RELATED ACTIVITIES The Lurie Cancer Center (LCC) provides a comprehensive training environment to enhance the career development of cancer researchers and caregivers at all levels. Education and training at the LCC is led by Dr. John Crispino Associate Director for Education and Training since 2012 with support of several faculty and LCC staff. The combination of substantial NIH training grant funding and dedicated philanthropic support enables numerous training opportunities for students research fellows clinical fellows oncology nurses and junior faculty. These include numerous seminar series symposia retreats intramural grants and travel awards. The LCC manages five NCI T32 grants and trainees are further supported by four other cancer relevant T32 grants and two K12 grants. New to this cycle are a formal mentorship program for clinical trainees and the Translational Bridge Initiative which provides combined laboratory and clinical mentor oversight for selected post-doctoral fellows. In addition there are LCC-sponsored education opportunities for health care professionals and oncologists in the Chicago area nationally and internationally. Over the next funding period the LCC will continue to expand the ongoing activities optimize training for precision medicine and other emerging fields and intensify efforts to increase the diversity of our trainees. +No NIH Category available Biological;Clinical;Clinical Chemoprevention;Clinical Research;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Institution;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs OTHER FUNCTIONS - CANCER PREVENTION AGENT DEVELOPMENT PROGRAM: EARLY PHASE CLINICAL RESEARCH n/a NCI 10901815 261201200034I-P00004-759101900129-1 N01 9/23/19 0:00 9/22/24 0:00 16187666 "BROWN, POWEL " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N R and D Contracts 2023 183238 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 183238 +No NIH Category available 15 year old;Abstinence;Academic Medical Centers;Address;Adjuvant Chemotherapy;Affect;Alcohol consumption;Biological Assay;Biology;Blood specimen;Cancer Survivor;Caring;Cessation of life;Chemotherapy and/or radiation;Clinical;Clinical Data;Cohort Studies;Connective Tissue;DNA Repair Gene;DNA analysis;Data;Dedications;Diagnosis;Diet;Disease;Electronic Health Record;Exercise;Foundations;Future;Gene Expression;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Goals;Grant;Health;Heart Diseases;Incidence;Individual;Infrastructure;Investigation;Kidney Diseases;Knowledge;Life;Life Style;Liver diseases;Longevity;Lung diseases;Medical Oncologist;Mesenchymal;Micrometastasis;Monitor;Neoadjuvant Therapy;Newly Diagnosed;Normal tissue morphology;Oncogenes;Organ;Orthopedics;Outcome;Participant;Patient Outcomes Assessments;Patients;Pediatric Oncologist;Population;Precision therapeutics;Predictive Factor;Prevalence;Prognostic Factor;Prognostic Marker;Prospective cohort;Quality of life;Radiation Oncologist;Radiation therapy;Recurrence;Relapse;Research;Residual Neoplasm;Risk Factors;Role;Sampling;Severities;Somatic Mutation;Specialist;Surveys;Survivors;Tennessee;Therapeutic Intervention;Time;Toxic effect;Treatment Efficacy;Treatment-Related Cancer;Treatment-related toxicity;Tumor Biology;Tumor Subtype;Tumor Tissue;United States;Variant;cancer diagnosis;cancer therapy;childhood cancer survivor;cigarette smoking;circulating biomarkers;cohort;design;drug metabolism;epidemiologic data;financial toxicity;follow-up;functional status;genetic risk factor;genome sequencing;healthy lifestyle;improved;improved outcome;indexing;lifestyle factors;liquid biopsy;molecular marker;mortality;next generation sequencing;peripheral blood;physical conditioning;polygenic risk score;predictive marker;prognostic value;programs;prospective;psychologic;psychosocial;rare cancer;recruit;response;sarcoma;social;sociodemographics;surveillance strategy;survivorship;tool;transcriptomics;treatment center;treatment response;tumor;tumor DNA;whole genome CAUSAL: Cohort to Augment the Understanding of Sarcoma Survivorship Across the Lifespan NARRATIVESarcomas represent a heterogenous group of tumors that affect individuals across the lifespan. Determiningdisease survivor treatment lifestyle and genomic factors that contribute to oncologic (treatment responserecurrence) and non-oncologic outcomes (treatment toxicity quality of life) and survival in sarcoma patients iscritical for strategic surveillance for current survivors and to inform future therapies. Furthermore strategies tomonitor disease through liquid biopsy approaches has tremendous potential as both a prognostic and predictivebiomarker to guide therapeutic interventions. NCI 10900883 9/22/23 0:00 RFA-CA-20-030 4UH3CA260318-03 4 UH3 CA 260318 3 "FILIPSKI, KELLY" 9/22/21 0:00 8/31/27 0:00 ZCA1-SRB-1(J2)R 1891854 "FRIEDMAN, DEBRA L" "PAL, TUYA ; PARK, BEN H; SHU, XIAO-OU " 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/30/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1936770 NCI 1129817 806953 PROJECT SUMMARYSarcomas represent a rare and highly heterogeneous subtype of tumors that may develop across the lifespan.In the United States (US) there are approximately 14000 new cases annually with approximately 65% survival.Aside from those included in pediatric cancer survivor cohort studies there are no sarcoma survivor cohorts inwhich to systematically study recurrence organ toxicity function quality of life and survival as well as theirpredictors. We propose to address these critical gaps in knowledge by establishing a cohort of approximately2100 sarcoma survivors through the Vanderbilt University Medical Center (VUMC) Sarcoma Treatment Centerwhich is amongst the largest sarcoma programs in the US in existence since 1987. In this cohort we willsystematically collect repeated information on disease treatment response relapse treatment-related toxicitysociodemographics lifestyle functional status quality of life physical health outcomes and survival togetherwith biospecimens (tumor tissue and peripheral blood samples). We hypothesize that: 1) extrinsic factors tumorbiology and germline genomics contribute to oncologic outcomes and long-term organ toxicity; 2) healthylifestyle e.g. high quality of diet exercise abstinence from cigarette smoking and alcohol drinking mitigate theadverse health consequences improve survival and quality of life among sarcoma survivors; and 3) liquid biopsytools developed through identifying genomic drivers of sarcoma will be of predictive and prognostic utility. Ouraims for current grant period are to evaluate1) the impact of disease treatment sociodemographic and lifestylecontributors on adverse oncologic and non-oncologic outcomes and mortality in the cohort; 2) the role of drugmetabolism and DNA repair gene functional polymorphisms genetically predicted gene expression levels andpolygenic risk scores on treatment efficacy and therapy-induced normal tissue toxicity; and 3) genomic driversof sarcoma to develop personalized liquid biopsy assays for monitoring treatment response recurrence andminimal residual disease. Establishment of a prospective cohort of sarcoma survivors across the lifespan withextensive and well characterized clinical and epidemiologic data patient reported outcomes tumor tissue andserial blood samples builds a foundation for a long-term prospective investigation on life after sarcoma. Thiseffort is critically important to improve the understanding of a rare tumor affecting the lifespan but seriouslyunderrepresented in research. Identification of health outcomes and their predictive and prognostic factors canlead to precision treatment and survivorship care which are currently clinically unmet needs. 1936770 +No NIH Category available Agreement;Atlases;Cells;Collaborations;Colorectal;Communication;Data;Data Analyses;Development;Dictionary;Ensure;Environment;Evaluation;Expenditure;Feedback;Fostering;Funding;Infrastructure;Institution;Interdisciplinary Study;Lead;Leadership;Metadata;Neoplastic Cell Transformation;Policies;Procedures;Process;Regulation;Reporting;Research;Resource Sharing;Sampling;Secure;Shapes;System;United States National Institutes of Health;Vision;Work;adenoma;data exchange;data sharing;experience;improved;member;multidisciplinary;operation;organizational structure;premalignant;programs;recruit;success;tool Administrative Core n/a NCI 10900839 8/18/23 0:00 PA-20-272 3U2CCA233291-01S2 3 U2C CA 233291 1 S2 "MAZURCHUK, RICHARD V" 5/1/23 0:00 8/31/24 0:00 8249 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/18 0:00 8/31/23 0:00 Other Research-Related 2023 1040698 706743 333955 Project Summary: Administrative CoreThe leadership of the Vanderbilt Pre-Cancer Atlas (PCA) Center builds on an existing multidisciplinary teamthat has been working together for over 15 years on the Vanderbilt GI Special Programs of ResearchExcellence (SPORE). We have also recruited additional team members from Johns Hopkins to round outexpertise for the atlas construction. Each team member also has extensive experience in collaborativeresearch efforts across multiple studies and multiple institutions. The Administrative Core will provide theprimary scientific oversight for the Vanderbilt PCA activities. It will have primary management and oversightresponsibility for all Pre-Cancer Atlas (PCA) activities which include reviewing and regulating financialexpenditures creating and preparing necessary reports internal and external communications researchcoordination and ensuring compliance with all federal regulations and reporting requirements (including NIHpublic access policy). Thus the core directly supports all members and organizational components of the PCA.The Administrative Core will coordinate collaborations with NCI and the HTAN. Our team has extensiveexperience working within NCI-funded networks. As the funded HTAN centers are developed there will bemultiple opportunities to find shared aims and potential new collaborative projects in which the Vanderbilt PCAwill enthusiastically participate and even lead. The Administrative Core will also ensure full compliance with thedata and resource sharing plans agreed upon with NCI and the HTAN. This will be accomplished by workingclosely with the Data Analysis Unit to ensure that all relevant data and tools are transferred securely and in atimely manner to the DCC. During the initial development of HTAN the Unit Co-Leads will work closely withDCC and HTAN centers in the development of SOPs and CDEs and metadata dictionaries to be collectedwithin the Vanderbilt PCA Adenoma Center and across the network. Based on our past experience andpresent shared vision we are fully committed to the success of the PCA Center and the common success ofthe HTAN. +No NIH Category available 3-Dimensional;Accounting;Atlases;Behavior;Breast;Classification;Collaborations;Communication;Complement;Comprehensive Cancer Center;Data;Data Analyses;Ensure;Ethics;Evaluation;Expenditure;Extramural Activities;FAIR principles;Feedback;Funding;Human;Human Resources;Infrastructure;Institution;Leadership;Life;Longitudinal cohort;Malignant Neoplasms;Manuscripts;Modeling;Molecular;Monitor;Natural History;Noninfiltrating Intraductal Carcinoma;Office of Administrative Management;Parents;Patients;Policies;Preparation;Quality Control;Reporting;Reproducibility;Research;Research Personnel;Resource Development;Resources;Retrospective cohort;Teleconferences;Testing;Tissues;United States National Institutes of Health;Work;computerized data processing;conflict resolution;data integrity;data sharing;expectation;innovation;meetings;member;multimodality;novel;operation;premalignant;programs;skills;success;synergism;tumor Administrative Core n/a NCI 10900830 8/15/23 0:00 PA-20-272 3U2CCA233254-01S3 3 U2C CA 233254 1 S3 "MAZURCHUK, RICHARD V" 4/4/23 0:00 8/31/24 0:00 8118 6985255 "HWANG, E.SHELLEY " Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/18 0:00 8/31/19 0:00 Other Research-Related 2023 133667 115455 18212 ABSTRACT Administrative Core The Administrative Core will support the general objectives of the Breast Pre-Cancer Atlas which are to 1) develop a findable accessible interoperable and reusable platform for organizing and sharing three- dimensional multi-modal breast pre-cancer data derived that facilitates the discovery of both the natural history of the pre-cancer and predictors of progression to life-threatening cancers and 2) populate that platform with data from both retrospective and longitudinal cohorts of patients with DCIS and demonstrate its use to construct an atlas to test novel predictors of progression. To do this the Administrative Core will facilitate administrative management of the Breast Pre-Cancer Atlas cultivate collaboration and communication within the Atlas as well as with other HTAN Pre-Cancer Centers ensure fiscal and regulatory compliance and provide consistent evaluation and monitoring to ensure effective progress of the program. The Specific Aims of this Core will be: 1) To provide organizational administrative and scientific leadership by having mPIs with complementing skill sets to provide credible examples of research success demonstrate respect and concern for all team members build team identity culture and coherence cultivate expectations of innovation and excellence leverage institutional as well as extramural resources provide constructive feedback and conflict resolution and model ethical behavior; 2) To provide administrative management by overseeing distribution of funds to and accounting for all expenditures in the Center including Research Units and provide clerical support. It will also coordinate with other PCA and HTA Research Centers to implement compliance with NIH policies oversee quality control and product release and ensure fiscal and regulatory compliance; 3) To promote integration within the Breast Pre- Cancer Atlas Center and across the Institutional PCA and HTA Research Centers by leveraging institutional support and working closely with the infrastructure of the affiliated NCI-designated Comprehensive Cancer Centers to ensure that resources and infrastructure are optimally utilized economies of scale are realized and overlaps eliminated. The Administrative Core also will help to plan and coordinate HTAN meetings and teleconferences; 4) To develop capabilities and oversee data operations by confirming data sharing and defining and developing best practices for data operations in collaboration with the Data Analysis Unit to ensure that reliable and valid data are generated managed and analyzed in a way that ensures data integrity and reproducibility of research findings; 5) To evaluate and report research progress and to ensure bidirectional exchange of research findings between the Breast Pre-Cancer Atlas Center and other PCA and HTAN Centers. +No NIH Category available Adaptive Immune System;Adopted;Amino Acid Sequence;Animal Model;Antigens;Autoimmune;Autoimmunity;Autologous;BRAF gene;Binding;Biochemical;Biological Assay;Biological Markers;CD28 gene;Cancer Patient;Cancer cell line;Cell Line;Cell Separation;Cellular immunotherapy;Classification;Clinical;Clinical Trials;Computer software;Computing Methodologies;Data;Data Set;Development;Diagnosis;Future;Genes;Goals;HLA-A gene;Hematopoietic stem cells;Human;IL2RA gene;Immune;Immune response;Immunodeficient Mouse;Immunotherapy;Individual;Infiltration;Innate Immune System;Machine Learning;Malignant Neoplasms;Melanoma Cell;Methods;Oncogenes;Open Reading Frames;Outcome;Patients;Post-Translational Protein Processing;Prognosis;Safety;Sampling;Sorting;Source;T cell infiltration;T-Cell Receptor;T-Lymphocyte;Testing;Tissue-Specific Gene Expression;Tissues;Training;Treatment Efficacy;Tumor Antigens;Tumor Expansion;Tumor stage;Umbilical Cord Blood;Validation;Xenograft procedure;anti-cancer;anticancer treatment;antigen binding;antigen-specific T cells;biomarker identification;cancer biomarkers;cancer cell;cancer diagnosis;cancer genomics;cancer immunotherapy;cancer infiltrating T cells;clinical application;complementarity-determining region 3;deep learning;design;gag Gene Products;genetic signature;genomic data;humanized mouse;improved;in vivo;learning strategy;machine learning method;neoantigens;neoplastic cell;novel;peripheral blood;predictive marker;receptor;reconstitution;response;side effect;single cell sequencing;single-cell RNA sequencing;software development;success;therapy development;tool;transcriptome;transcriptome sequencing;tumor;tumor immunology;tumor microenvironment;unsupervised learning Antigen-independent prediction and biomarker identification of cancer-specific T cells Project NarrativeIdentification of tumor-specific T cells is critical to immunotherapy development yet remains a challenging task.In this project we will develop a novel machine learning method to study: 1) which T cells in the tumormicroenvironment are reactive to malignant cells; 2) what signature genes can be used to track the cancer-specific T cells. Outcomes from this project are expected to improve the efficacy and precision of cancerimmunotherapies. NCI 10900208 8/24/23 0:00 PA-21-268 7R01CA245318-04 7 R01 CA 245318 4 "DEY, SUMANA MUKHERJEE" 9/1/20 0:00 5/31/25 0:00 Cancer Biomarkers Study Section[CBSS] 15395861 "LI, BO " Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 399032 NCI 224175 174857 Project Summary/AbstractCancer immunotherapy has achieved remarkable clinical success treating late-stage tumors yet the responserates remain low and the side effects are often severe. Designing effective immunotherapies relies on accurateidentification of tumor-reactive T cells. This is an extremely difficult task because 1) most of the cancerantigens are unknown; 2) the majority of the tumor-infiltrating T cells (TIL) does not recognize cancer cells; and3) without known antigens the only approach to acquire such T cells is to perform ex vivo expansion of TILsstimulated by autologous cancer cells which generates non-specific T cells and is infeasible to many patients.Nonetheless this strategy is widely adopted in current clinical trials for anti-cancer treatment despite itsreduced therapeutic efficacy and unpredictable side effects of autoimmunity. Therefore unbiased antigen-independent identification of tumor-reactive T cells if possible will be a major clinical priority as it willsignificantly increase the efficiency and safety of T cell based immunotherapies. Here we propose to achievethis goal through the development of novel machine learning methods. Such approach has not yet beenexplored because the fundamental difference between cancer and non-cancer T cells lies in their receptorsequences (TCR) and training data of cancer-specific TCRs is currently unavailable. To prepare for this taskwe have developed the software TRUST to extract the T cell antigen-binding CDR3 regions from bulk tumorRNA-seq data and the software iSMART to group these CDR3s into antigen-specific clusters. These toolsallowed us to develop a new rationale for producing large training sets of tumor-reactive TCRs even withoutknowing cancer antigens. In our preliminary analysis we observed that TCRs from the training data can bematched to tumor antigens that bind to HLA-A*02:01 and elicit immune response in vivo. The cancer-specificCDR3 amino acid sequences also show significantly different biochemical features from non-cancer onesbased on which we further developed software DeepCAT to demonstrate the feasibility of de novo prediction ofcancer TCRs. These exciting results highlighted the importance to develop better computational method totrack the tumor-reactive T cells for clinical applications. Accordingly we propose the following Specific Aims: InAim 1 we will deliver a new machine learning method for accurate classification of tumor-reactive T cells usingthe CDR3 sequences. In Aim 2 we will derive a set of biomarkers for the cancer-specific T cells for fast andaccurate flow sorting of these T cells from TILs. In Aim 3 we will perform single cell sequencing and functionalvalidation of cancer-specific T cells using humanized animal model to validate the predicted genes and toproduce a prioritized list of promising targets for cancer diagnosis prognosis and therapy development. TheseAims will be accomplished with the great support from the excellent collaborators specialized in cancerimmunology at UTSW. Successful completion of this proposal will provide an exciting new paradigm to identifytumor-reactive T cells for precision cancer immunotherapies. 399032 +No NIH Category available Ablation;American;Animal Model;Antineoplastic Agents;Automobile Driving;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer therapy;CD8-Positive T-Lymphocytes;Cancer Biology;Cancer Etiology;Cessation of life;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinical;Combination Drug Therapy;Complex;DNA;Data;Development;Drug usage;Epigenetic Process;Foundations;Genetic Transcription;Genetically Engineered Mouse;HDAC5 gene;Histones;Hypermethylation;Immunotherapy;In Vitro;KDM1A gene;Knock-out;Malignant Neoplasms;Mediating;Molecular;Neoplasm Metastasis;Oncogenic;Oncoproteins;Patient-derived xenograft models of breast cancer;Patients;Post-Translational Protein Processing;Prognosis;Protein Overexpression;Proteins;Recurrence;Refractory;Regimen;Relapse;Repression;Repressor Proteins;Resistance;Resistance development;Role;T cell infiltration;Therapeutic Effect;Transcription Repressor;Treatment Efficacy;Tumor Immunity;Tumor Suppression;Tumor Suppressor Genes;Woman;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;anti-tumor immune response;breast cancer progression;cancer clinical trial;cancer stem cell;cancer subtypes;cancer therapy;cancer type;cell killing;chemokine;chemotherapeutic agent;chemotherapy;clinical efficacy;clinically relevant;demethylation;effector T cell;epigenetic silencing;genetic corepressor;histone demethylase;histone modification;immunogenic;improved;in vivo;inhibitor;insight;malignant breast neoplasm;mammary;mouse model;novel;novel therapeutic intervention;overexpression;pre-clinical;programmed cell death ligand 1;response;restraint;stem-like cell;targeted agent;targeted treatment;therapeutic target;therapy resistant;tissue-factor-pathway inhibitor 2;trait;treatment response;triple-negative invasive breast carcinoma;tumor;tumor progression;tumorigenesis Role of LSD1 in Triple Negative Breast Cancer Development and Therapeutic Response PROJECT NARRATIVE This application proposes to identify a novel regulatory mechanism by which overexpression of oncoproteinLSD1 facilitates triple negative breast cancer (TNBC) progression. This project is also aimed at utilizing novelLSD1-targeting agents to enhance tumor suppression augment antitumor immunity and overcome therapeuticresistance in TNBC. The results from the proposed studies are expected to provide novel mechanistic insightand rationale for effective combination of leading LSD1 inhibitors with standard or immune therapies as newtreatment strategies for patients with advanced TNBC. NCI 10898981 10/31/23 0:00 PA-21-268 7R01CA260357-04 7 R01 CA 260357 4 "KONDAPAKA, SUDHIR B" 8/15/23 0:00 2/28/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 8134266 "HUANG, YI " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF MEDICINE 522421320 UNITED STATES N 8/15/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 348592 NCI 224175 124417 PROJECT SUMMARY/ABSTRACTBreast cancer (BC) is the most common cancer and the second leading cause of cancer death in Americanwomen. About 10-20% of breast cancers are triple-negative breast cancer (TNBC) which has a propensity tometastasize recur and develop resistance to chemotherapy. TNBC is the only subtype of BC for which there isno targeted therapy. Chemotherapies remain the mainstay of treatment for TNBC but their clinical efficacy isoften limited by resistance. Immunotherapy is emerging as an exciting new treatment option for TNBC patients.While TNBC is more likely to respond to immunotherapy overall response rate is still low. Developing novel andmore effective TNBC therapies is an unmet biomedical need as most of advanced TNBCs do not respond wellto current therapies. Epigenetic alterations such as DNA hypermethylation and histone dysregulation have beenassociated with all stages of TNBC formation and progression. Lysine-specific demethylase 1 (LSD1) is the firstidentified histone demethylase which specifically demethylates H3K4me1/2. LSD1 is a key component of multipletranscription repressor complexes. Tumors in TNBC patients frequently express higher level of LSD1 comparedto other BC groups. Clinically LSD1 protein overexpression is significantly associated with worse prognosis inTNBC patients making it an attractive therapeutic target. Our recent study has revealed a new mechanismdriving LSD1 protein overexpression in TNBC through HDAC5-mediated posttranslational modification.Treatment with LSD1 inhibitors effectively suppresses tumor progression and sensitizes TNBC cells tochemotherapeutic agents. Furthermore LSD1 ablation stimulates antitumor immunity and potentiates theefficacy of anti-PD-1 antibody in poorly immunogenic TNBC. LSD1 inhibition leads to reexpression of a keyepigenetically silenced tumor suppressor gene Tissue Factor Pathway Inhibitor 2 (TFPI2) which is required fortumor suppression and responsiveness to immunotherapy. Based on these findings we hypothesize that LSD1overexpression facilitates TNBC development and inhibition of LSD1 improves TNBC therapies by inducingTFPI2-mediated cell killing and antitumor immunity. Aim1. Determine the functional roles of LSD1overexpression in TNBC development; Aim2. Evaluate the in vitro and in vivo therapeutic efficacy of LSD1inhibition against TNBC; Aim3. Elucidate the immunogenic effects of LSD1 inhibition in TNBC. The results fromthe proposed studies are expected to provide new mechanistic insights and key preclinical evidence for usingLSD1 inhibitors in TNBC. In the long run these studies may lead to new and improved therapies for patientswith relapsed and refractory TNBC. 348592 +No NIH Category available Administrative Supplement;Bioinformatics;Cancer Etiology;Disease;Engineering;Etiology;Family;Funding;Genes;Genome;Goals;Herpesviridae;Histology;Human;Human Biology;Human Genetics;Human Herpesvirus 4;Human Papilloma Virus-Related Malignant Neoplasm;Institution;Kaposi Sarcoma;Left;Letters;Life Cycle Stages;Lytic;Malignant Neoplasms;Microscopy;Molecular Biology;Molecular Genetics;Oncogenic Viruses;Papillomavirus;Pathway interactions;Prevention;Production;Program Research Project Grants;Translating;Viral;Virus;Virus Diseases;cancer therapy;carcinogenesis;cell type;cost;instrumentation;live cell imaging;novel strategies;prevent;statistics;tumor;virus related cancer Molecular Biology and Genetics of Human Tumor Viruses PROJECT NARRATIVEViruses contribute to at least 21 different human cancers representing approximately 15% of all human cancers.Understanding how the biology of these human tumor viruses and how they cause cancer will provide newapproaches for preventing and treating the associated cancers. NCI 10898452 9/13/23 0:00 PA-20-272 3P01CA022443-45S1 3 P01 CA 22443 45 S1 "DASCHNER, PHILLIP J" 9/1/23 0:00 1/31/24 0:00 1942923 "LAMBERT, PAUL F." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 500000 NCI 322436 177564 PROJECT SUMMARY/ABSTRACTViruses cause approximately 15% of human cancers. A viral etiology to a human cancer can have substantiveconsequences on its treatment and prevention. For example many virally-caused human cancers express virallyencoded products which are potential targets for anti-viral tumor-specific therapies. In addition unique sets ofcellular genes and pathways contribute to virally-associated cancers many of which are currently being pursuedas targets for anti-cancer therapies. This program project grant (PPG) has two major objectives: to use molecularbiology and genetics to elucidate the life cycles of and transformation by human tumor viruses and to translatethis understanding into the identification of targets for specific anti-viral anti-tumor therapies. We are focused onstudying human tumor viruses in three different virus families: papillomaviruses Epstein Barr Virus and KaposiSarcoma Virus. Together these three families of viruses cause many of the virally-associated human cancers.This request for an Administrative Supplement to provide 5 months of bridge funding until the competitiverenewal is funded in early 2024 is to support 4 of the 5 projects in the current PPG (the one project left out hasbeen sunsetted because Dr. Dan Loeb Project Leader for Project 2 has retired). The goals of the four projectsare: Project 1) to identify and characterize cellular genes that drive human papillomavirus-associated cancer andmodulate viral infection; Project 3) to study the replication and inheritance of herpesviral genomes in relevantcell types using novel approaches for live cell imaging; Project 4) to characterize cellular and viral factors thatregulate the switch from the latent to lytic viral state of Epstein Barr virus (EBV); and Project 5) to define driversof EBV- associated carcinogenesis and develop novel approaches for treating these cancers and diseasescaused by herpesviruses. There are three cores to this PPG that provide expertise in A) administration statisticsand bioinformatics B) instrumentation microscopy and histology and C) virus engineering and production.These cores will be funded during this no cost extension period from institutional support as indicated in thecover letter. 500000 +No NIH Category available Adoption;American;Cancer Center;Cancer Patient;Caregivers;Clinic Visits;Clinical;Clinical Trials;Cluster randomized trial;Communities;Disease;Effectiveness;Electronic Health Record;Electronics;Emergency Care;Excision;Goals;Health;Health system;Hospitalization;Impairment;Intervention;Knowledge;Lead;Monitor;Oncology;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Penetration;Phase;Population;Quality of life;Reporting;Research;Research Personnel;Rural;Site;Symptoms;System;acute care;cancer care;cancer diagnosis;cancer surgery;cancer therapy;care delivery;effectiveness evaluation;evidence base;experience;falls;implementation barriers;implementation outcomes;implementation process;implementation strategy;improved;multidisciplinary;palliative chemotherapy;prevent;prototype;reduce symptoms;symptom management;symptomatic improvement SIMPRO Research Center: Integration and Implementation of PROs for Symptom Manage Project NarrativeElectronic tracking of patient-reported outcomes (ePROs) has been shown to reduce symptom burden relatedto cancer treatment however evidence for the effectiveness of these systems is limited to large cancer centersand optimal strategies for implementation are uncertain. The proposed 6-site Research Center will adaptexisting ePRO symptom management systems integrate them into an EHR and conduct a pragmatic clusterrandomized trial with stepped wedge rollout to investigate the effectiveness of ePRO monitoring to alleviatesymptom burden following major cancer surgery or during receipt of palliative chemotherapy. The project willfocus on implementation outcomes so that knowledge about the strategies that facilitate adoption andsustainability can inform deployment of this intervention in other contexts. NCI 10898322 9/19/23 0:00 PA-20-272 3UM1CA233080-01S1 3 UM1 CA 233080 1 S1 "ADAMS, LYNN S" 9/20/18 0:00 8/31/24 0:00 8580673 "HASSETT, MICHAEL JAMES" "OSAROGIAGBON, RAYMOND U; SCHRAG, DEBORAH ; WONG, SANDRA L" 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 42500 NCI 38227 4273 Project SummaryIn 2018 more than 1.7 million Americans will receive a new cancer diagnosis and nearly 600000 will die fromtheir disease. Cancer treatments including major surgical resection and palliative chemotherapy areassociated with frequent adverse symptoms. The primary burden for managing symptoms falls on patients andtheir caregivers and there is ample evidence that untreated symptoms impair quality of life lead to inefficientuse of emergency care avoidable hospitalizations and even shorten survival. Electronic tracking of patient-reported outcomes (ePROs) between face-to-face clinic visits has been shown to both reduce symptom burdenand decrease the need for acute care. Although there is abundant evidence that symptom monitoring canimprove cancer care current experience has been largely limited to single centers or as part of clinical trials.Using ePROs to facilitate symptom control is an attractive strategy but evidence for effectiveness in differenttreatment contexts and across varied populations is needed. Further ePRO tracking systems have not beenfully integrated into health systems' electronic health records (EHR) and this deficit prevents them fromdelivering the maximal benefits of proactive symptom management.To fill gaps in the evidence base about the optimal strategy for deploying ePROs a multidisciplinary team from6 health systems have formed the Symptom Management IMplementation of Patient Reported Outcomes inOncology (SIMPRO) Research Center. SIMPRO's overarching goal is to develop implement and evaluate amulti-component ePRO reporting and management system to improve symptom control for patients recoveringfrom cancer surgery or patients receiving palliative chemotherapy in small rural and community cancercenters. The Specific Aims of the project are to: (1) Adapt existing ePRO symptom management systems andintegrate them into the EHR and routine clinical workflow at six health systems; (2) Determine the effectivenessof an EHR-integrated ePRO symptom management system on health outcomes; and (3) Evaluate thefacilitators and barriers to implementation of an EHR-integrated ePRO symptom management system from thepatient clinical and organizational perspectives. Following the adaptation of operational ePRO prototypes andfull integration into an EHR the SIMPRO investigators will conduct a pragmatic cluster randomized trial withstepped wedge rollout to investigate the effectiveness of a symptom monitoring system from a patient clinicianand health system perspective. Across all study phases the implementation process itself including ePROadoption appropriateness acceptability penetration/scalability and adaptation will be critically evaluated.This approach will create knowledge that can be used to guide dissemination of ePROs and other interventionsto improve cancer care delivery. 42500 +No NIH Category available Acetylation;Aging;Animals;Attention;Beds;CTAG1 gene;Cancer Patient;Cell physiology;Cells;Cellular Metabolic Process;Citric Acid Cycle;Complement;Data;Deacetylase;Deacetylation;Development;Endowment;Enzymes;Genes;Genetic Engineering;Genetic study;Glucose;Glutamine;Glycolysis;Histone Deacetylase;Human;Human Engineering;Immune;Immune Targeting;Immune response;Immunologics;Immunotherapeutic agent;Immunotherapy;Impairment;In Vitro;Infiltration;Laboratories;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Memory;Metabolic;Metabolism;Modeling;Molecular;Molecular Biology;Molecular Genetics;Mus;Nivolumab;Non-Small-Cell Lung Carcinoma;Oxidative Phosphorylation;Patients;Phenotype;Phosphorylation;Physiological;Post-Translational Protein Processing;Proliferating;Protein Acetylation;Proteins;Proteomics;Reproducibility;Resistance;Resveratrol;Role;Sampling;Signal Transduction;T cell regulation;T-Cell Activation;T-Cell Development;T-Lymphocyte;Testing;Treatment Efficacy;Tumor Escape;Tumor Immunity;Up-Regulation;aerobic glycolysis;cancer cell;cancer immunotherapy;cancer therapy;clinical translation;combinatorial;effector T cell;exhaustion;fatty acid metabolism;fatty acid oxidation;frontier;immune checkpoint;immune function;immunoregulation;immunotherapy clinical trials;improved;in vivo;inhibitor;melanoma;metabolic fitness;metabolomics;neoplastic cell;novel;novel strategies;overexpression;pharmacologic;potential biomarker;predicting response;pressure;programs;response;tumor;tumor microenvironment;ubiquitin-protein ligase Role of Sirt2 in T Cell Metabolism PROJECT NARRATIVEThis project will investigate the role of Sirt2 a protein involved in regulating metabolism of T lymphocytes thatmediate immune responses against cancer. We will explore this problem by analyzing mice deficient in Sirt2 orits partner molecules as well as genetically engineered human T lymphocytes isolated from lung cancer andmelanoma patient tumor samples. Our studies may guide development of novel strategies to improvemetabolic fitness of T lymphocytes and thus enhance the capacity of these cells to elicit effective immunedefense against cancer. NCI 10898140 9/11/23 0:00 PA-21-268 7R37CA248298-04 7 R37 CA 248298 4 "ZAMISCH, MONICA" 3/1/21 0:00 2/28/26 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 12142773 "KIM, SUNGJUNE " Not Applicable 5 Unavailable 153223151 GKPBCFV1QMM3 153223151 GKPBCFV1QMM3 US 30.264703 -81.444793 4976105 MAYO CLINIC JACKSONVILLE JACKSONVILLE FL Other Domestic Non-Profits 322241865 UNITED STATES N 7/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 177605 NCI 106096 71509 PROJECT SUMMARYMetabolism is a key driver of T cell functions and the switch from oxidative-phosphorylation to aerobicglycolysis is a hallmark of T cell activation. Unfortunately tumor reactive T cells often display a compromisedmetabolic status due to metabolic competition with cancer cells within the tumor microenvironment (TME).Therefore strategies to enhance metabolic fitness of T cells within the metabolically challenging tumor bedmay rescue resistance to existing cancer immunotherapies. In this context we have focused on the regulationof T cell metabolism by Sirt2 an NAD-dependent histone deacetylase. Our preliminary data demonstrate thatSirt2 functions as a metabolic checkpoint that harnesses T cell effector functions and impairs anti-tumorimmunity. Specifically upregulation of Sirt2 expression in human tumor-infiltrating T lymphocytes (TILs)negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer.Mechanistically Sirt2 suppresses glycolysis and oxidative-phosphorylation by deacetylating key metabolicenzymes. Accordingly Sirt2-deficient T cells manifest increased glycolysis and oxidative-phosphorylationdisplay enhanced proliferation and effector functions and have superior anti-tumor activity. Importantlypharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and enhancedeffector functions. These findings indicate targeting Sirt2 may allow reprogramming of T cell metabolism toaugment a broad spectrum of cancer immunotherapies. Guided by this scientific premise we propose theoverall hypothesis that Sirt2 activity governs the metabolic fitness of T cells at tumor beds andtherefore controls the magnitude of immune pressure against malignant progression. We will test thishypothesis in the following specific aims: Aim 1 will investigate the precise molecular mechanisms via whichSirt2 regulate glycolysis TCA cycle glutaminolysis and fatty acid oxidation and the post-translationalmechanisms that govern Sirt2 expression and function in tumor-reactive T cells. Aim 2 will explore themetabolic functions of Sirt2 in physiologic contexts of T cells during activation differentiation maturation andas they are subjected to metabolic constraints within the tumor beds. Aim 3 will determine the metabolic andimmunologic consequences of Sirt2 inhibition in human TILs for clinical translation and correlate Sirt2expression in TILs with response to immunotherapy. These aims will be achieved by employing a variety ofexperimental strategies involving in vitro and in vivo metabolic and immunologic analyses of various geneticallyengineered animals complemented by molecular biology and genetic studies using primary human T cells andpatient-derived TILs from lung cancer and melanoma. Collectively our proposed studies will provide acomprehensive view of the role of Sirt2-regulated metabolic processes in tumor-reactive T cells. The resultsfrom our proposed studies will validate Sirt2 as an actionable metabolic and immunologic target and Sirt2inhibition will be a tractable means to improve cancer immunotherapy. 177605 +No NIH Category available Acetic Acids;Africa;Asia;Biological Assay;Cancer Etiology;Clinical;Colposcopy;Communication;Complex;Consumption;Cytology;Detection;Developed Countries;Developing Countries;Devices;Disease;Genotype;HPV-High Risk;Health Personnel;Health Policy;Human Papillomavirus;Human papilloma virus infection;Latin America;Location;Low income;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medical;Pap smear;Performance;Physicians;Poverty;Procedures;Provider;Resource-limited setting;Resources;Site;Specimen;Testing;Time;Transportation;Visual;Woman;cervicovaginal;clinical research site;cost;health training;low and middle-income countries;point of care testing;rural setting;screening;screening program Rapid Point of Care Test to Screen Human Papillomavirus in Low-Resource Settings n/a NCI 10897682 75N91023C00034-0-9999-1 N43 8/7/23 0:00 8/6/24 0:00 79288756 "LI, QIAN " Not Applicable 4 Unavailable 80123728 GAMMMRQ6QMN1 80123728 GAMMMRQ6QMN1 US 35.9138 -78.848911 10042923 ZYMERON CORPORATION DURHAM NC Domestic For-Profits 277092072 UNITED STATES N R and D Contracts 2023 13720 NCI Cervical cancer caused by human papillomavirus (HPV) is the fourth most common cancer among women worldwide but it is preventable by screening asymptomatic women before HPV infection progresses to an invasive disease. The screening programs in developed countries use the cytology-based approach (Pap testing) followed by colposcopy which require a high degree of organization and management. They are not available in low-resource settings i.e. LMICs due to poverty a lack of medical providers inconsistent health policies inconvenient transportation and communication facilities. Visual inspection with acetic acid (VIA) as an alternative to Pap screening has been being applied in Africa Asia and Latin America but the procedure must be performed by well-trained health care providers and it is not accessible for the rural places which have limited professional staffs. FDA has approved several PCR devices for high-risk HPV screening in developing countries. However PCR assay is complex time consuming expensive and is not suitable for the low-income sites. Zymeron develops a rapid (less than 20 min) highly sensitive and low-cost POC assay to detect and genotype high-risk HPV from multiple self-collected cervicovaginal specimens to rapidly inform physicians on timely treatment in resource-limited sites. 13720 +No NIH Category available Biology;Chemical Structure;Chemicals;Collection;Databases;Diversity Library;Dryness;Environment;Equipment and supply inventories;Film;Individual;Informatics;Knowledge;Libraries;Monitor;Mothers;Sampling;Solid;Structure;Test Result;Tube;Update;Vendor;Vial device;Work;design;indexing;interest;screening;small molecule;stereochemistry CBC LIBRARY SCREENING n/a NCI 10897680 261201500010I-P00005-759102000001-1 N01 9/29/20 0:00 9/28/24 0:00 77858333 "JOBLING, MICHAEL " Not Applicable Unavailable 930243360 LA7FUVX1EZQ7 930243360 LA7FUVX1EZQ7 US 37.66323 -122.385783 -410278 SOUTH SAN FRANCISCO CA Other Domestic Non-Profits 940801934 UNITED STATES N R and D Contracts 2023 282378 NCI Chemical Biology Consortium Screening Library Center (CBCSLC) 282378 +No NIH Category available ATR gene;Address;Administrative Supplement;Antigen Presentation;Antigen-Presenting Cells;Biological;CD80 gene;CD86 gene;Cancer Center Support Grant;Cell Cycle Checkpoint;Cell Death;Cell surface;Cells;Center Core Grants;Chemosensitization;Clinical;DNA Damage;DNA biosynthesis;Data;Ensure;Exposure to;Failure;Immune;Immune Evasion;Immune checkpoint inhibitor;Immunotherapy;Interferon Type I;Leadership;Low Dose Radiation;Malignant Neoplasms;Merkel cell carcinoma;Mitosis;PD-1 pathway;Patients;Phosphotransferases;Production;Protein Inhibition;Quality Control;Radiation;Randomized;Refractory;Resistance;Signal Transduction;Solid Neoplasm;T-Cell Activation;TP53 gene;Testing;Text;Therapeutic;Tumor Immunity;Up-Regulation;advanced disease;anti-PD-L1;anti-tumor immune response;calreticulin;disorder control;experimental study;immune activation;immune checkpoint blockade;immunogenic;immunogenic cell death;immunogenicity;in situ vaccine;inhibitor;neoplastic cell;novel;pembrolizumab;phase 2 study;phase II trial;pre-clinical;programmed cell death protein 1;replication stress;response;success;tumor CCSG Supplement: ATR Inhibition in Advanced PD(L)1-Refractory Merkel Cell Carcinoma EDDOP Leadership Award-P30 Administrative Supplement: The MATRiX StudyTitle: A Phase 2 Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell CarcinomaNarrative (no more than 3 sentences)With limited therapeutic indications for the nearly half of patients with PD-1 refractory Merkel cellcarcinoma (MCC) ATR inhibition will be explored for its immunogenic potential in this advanceddisease setting. Given its high replication stress inherent immunogenicity and sensitivity to DNAdamage MCC is a nearly ideal cancer in which to test whether an ATR inhibitor could helpstimulate an anti-tumor immune response. Characterization of immune correlates of clinicalbenefit will be performed through our NCI-approved multicenter Phase II study. NCI 10897578 9/12/23 0:00 PA-20-272 3P30CA015704-48S2 3 P30 CA 15704 48 S2 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 397 Research Centers 2023 125000 NCI 106000 19000 EDDOP Leadership Award-P30 Administrative Supplement: The MATRiX StudyTitle: A Phase 2 Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell CarcinomaAbstract (30 lines of text)The success of checkpoint blockade immunotherapy for patients with advanced Merkel cellcarcinoma (MCC) has transformed the management of this cancer. Specifically trials of anti-PD-(L)1 agents led by our Seattle-based translational team resulted in three FDA approvals(avelumab pembrolizumab and retifanlimab). Nearly 50% of MCC patients achieve durabledisease control with immune checkpoint inhibitors however novel salvage treatment options arerequired to address the unmet clinical need for patients with primary and acquired resistance.Aggressive solid tumors that rapidly multiply such as MCC are under increased replication stress(as evidenced by high Ki-67 positivity). This happens in part through loss of early cell cyclecheckpoints biologically characterized by dysregulation of Rb and p53 signaling paired with Mycupregulation. Dividing cells rely on ATR (ataxia telangiectasia and Rad3-related protein) kinasethat acts as a quality control mechanism to ensure completion of DNA replication prior to thebeginning of mitosis failure of which results in cell death. After more than a decade of effortmultiple potent and specific ATR inhibitors (ATRi) are now available and being explored inrelevant preclinical and clinical settings.Excitingly early preclinical experiments performed by several labs in addition to our preliminarydata suggest that ATRi alone or in combination with low-dose radiation induces canonical markersof immunogenic cell death. MCC tumor cells treated with an ATRi (with or without radiation)demonstrate increased innate immune activation as evidenced by expression of calreticulin andMHC-I on the cell surface as well as type I interferon production. In addition antigen presentingcells (APCs) become activated following exposure to ATRi-treated tumor cells. APCs upregulateMHC-I CD80 (B7-1) and CD86 (B7-2) expression in this setting augmenting both signals 1 and2 required for T-cell activation. This suggests that tumors could thus become an in situ vaccine.Importantly the ability of ATRi to promote MHC-I expression and induce antigen presentationmachinery may help overcome immune evasion associated with PD-1 resistance in MCC patients.Excitingly these studies have led to the recent approval of LOI #10592 an NCI-sponsoredmulticenter Phase II trial that will explore an ATR inhibitor in patients with MCC resistant to PD-1pathway blockade. The trial will be randomized to investigate the capacity of ATRi +/- anti-PD-L1agents for potentiation of anti-tumor immunity in refractory tumors. Detailed characterization ofbiological correlates of response will help evaluate the immunostimulatory mechanismsunderlying ATR inhibition in MCC and other biologically analogous cancers. 125000 +No NIH Category available Aggressive behavior;Antitumor Response;Binding;Biological Assay;CSF3 gene;Cell Death;Cell Death Induction;Cells;Clinical;Clinical Data;Clinical Research;Communication;Cytokine Activation;Cytoprotection;Cytotoxic T-Lymphocytes;Cytotoxic agent;Data;Development;Disease;Disease Progression;Effectiveness;Epithelium;Generations;Goals;Heat-Shock Proteins 70;IL6 gene;Immune;Immune checkpoint inhibitor;Immune system;Immunosuppression;Immunotherapy;In Vitro;Inflammatory;Knockout Mice;Literature;Longevity;Macrophage;Mediating;Mesenchymal;Metastatic breast cancer;Molecular;Molecular Target;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Natural Killer Cells;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Phenotype;Play;Process;Production;Prognosis;Progressive Disease;Property;Publishing;Research;Role;Sampling;Signal Transduction;Site;Stress;Stromal Cells;Testing;Therapeutic;Toll-like receptors;Transactivation;Tumor Promotion;Tumor-Derived;Tumor-Infiltrating Lymphocytes;Woman;Work;anti-tumor immune response;cancer cell;cancer stem cell;cancer subtypes;chemotherapy;clinically relevant;cytokine;epithelial to mesenchymal transition;granulocyte;immune checkpoint blockade;improved;inhibitor;malignant breast neoplasm;metastatic process;mouse model;neoplastic cell;neutrophil;permissiveness;pre-clinical;resistance mechanism;response;standard of care;therapeutic evaluation;therapy resistant;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Dual function of HSP70 in cytoprotection of tumor cells and generation of permissive microenvironment PROJECT NARRATIVEOur goal is to improving treatment options and lifespan of women with metastatic breast cancer by improvingthe understanding of the molecular co-evolution of the tumors and the immune system during tumor developmentand progression. Our expected outcomes include; 1) advancing our current understanding of resistancemechanisms; 2) determining how stress-induced HSP70 may regulate immunosuppression; and 3) testing thetherapeutic utility of HSP70 inhibitor to improve effectiveness of current therapies in metastatic breast cancer.Our impact includes the identification of molecular targets that regulate critical steps in metastatic process andwill lead to improved therapeutic approaches for the treatment of women with metastatic disease. NCI 10897559 9/19/23 0:00 PA-21-268 7R01CA251676-04 7 R01 CA 251676 4 "BERA, TAPAN K" 5/1/21 0:00 4/30/26 0:00 Tumor Microenvironment Study Section[TME] 9763714 "KORKAYA, HASAN " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 7/1/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 230387 NCI 149602 80785 It has been widely accepted that distinct epithelial to mesenchymal transition (EMT) phenotype and cancer stemcell (CSC) properties as well as the immunosuppressive tumor microenvironment (TME) in triple negative breastcancer (TNBC) subtype account for the aggressive behavior of this disease. Although increased levels of tumor-infiltrating lymphocytes (TILs) in TNBC predicted better clinical outcome the majority of these patients displayprogressive disease due to the immunosuppressive TME. Although the clinical relevance of TME/pre-metastaticniche in disease progression has been well recognized the molecular mechanisms that regulate theseprocesses remain elusive. Preclinical and clinical data provide compelling evidence that immune cells of myeloidorigin (macrophages neutrophils MDSCs) are major components of the TME and predictive of poor prognosisas well as therapeutic resistance. Therefore further research is required to understand the underlying molecularmechanism of formation of immunosuppressive TME/pre-metastatic niche and its role in disease progressionand therapeutic resistance. Our primary objectives in this application are; to determine how stress-inducedHSP70 regulates two fundamental processes; i) protecting tumor cells from cytotoxic cell death by inducing anepithelial mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype and ii) generating a permissivemicroenvironment via the modulation of immunosuppressive myeloid cells. Our central hypothesis is that A20induced HSP70 in TNBCs protects tumor cells from cytotoxic cell death while inducing an EMT phenotype andinflammatory cytokines which in turn promote the accumulation of immunosuppressive MDSCs. Thereforetargeting HSP70 will have a dual activity on tumors and MDSCs. Our rationale is that the identification ofmolecular mechanism(s) that sensitize tumor cells to cytotoxic agents while reversing immunosuppression willimprove the effectiveness of currently available therapeutics. We previously demonstrated that growth of tumorsat metastatic sites is dependent of granulocytic MDSCs and suppression of anti-tumor responses and thusblocking HSP70 in combination with standard of care and/or checkpoint inhibitors could have significant clinicalbenefit. Based on these concepts we propose to test our hypothesis by investigating the following specific aims:Aim 1 will test the hypothesis that a reciprocal A20/HSP70 signaling axis provides cytoprotection to tumor cellsby inducing EMT/CSC phenotype in TNBC subtype. Aim 2 will test the hypothesis that HSP70 regulatesimmunosuppressive MDSC induction and acitivity. Aim 3 will determine the molecular mechanism and functionalimportance of HSP70 in generation of TME and pre-metastatic niche. At the completion of our proposal weexpect to elucidate the molecular mechanism by which HSP70 cytoprotects tumor cells from cytotoxic agents byinducing EMT/CSC phenotype while regulating the immunosuppressive MDSCs in response tumor secretedcytokines facilitating the tumor progression. It will also determine whether blocking HSP70 potentiates theefficacy of the chemotherapies and/or immunotherapy in syngeneic mouse models representing TNBC subtype. 230387 +No NIH Category available Adverse event;Biological Markers;Cancer Center;Clinical;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Services;Collaborations;Communication;Complex;Consent;Correlative Study;Data;Databases;Disease;Effectiveness;Ensure;Evaluation;Funding;Glioma;Goals;Grant;Human Resources;Image;Individual;Informed Consent;Infrastructure;Institutional Review Boards;Laboratories;Leadership;Manuscripts;Metabolic;Molecular;Monitor;Neurosurgeon;Nursing Research;Patient Rights;Patient imaging;Patients;Pharmaceutical Preparations;Preparation;Procedures;Progress Reports;Protocols documentation;Reporting;Research;Research Assistant;Research Personnel;Research Project Grants;Research Subjects;Research Support;Safety;Scientist;Specific qualifier value;Subgroup;Therapeutic Research;Tissues;Toxic effect;United States National Institutes of Health;design;experience;follow-up;improved;individual patient;meetings;member;molecular subtypes;multiparametric imaging;neuro-oncology;operation;participant enrollment;programs;radiologist;research study;success Admin-Core-001 The proposed P01 consists of four highly integrated projects focused on identifying metabolic signatures associated with molecular subgroups of glioma and combining them with multi-parametric imaging strategies to evaluate spatial and temporal changes in individual patients during the course of their disease. This Core will provide administrative and fiscal oversight for all four projects and clinical services for the two projects that will be performing patient studies. NCI 10897356 8/29/23 14:52 PAR-18-290 3P01CA118816-15S1 3 P01 CA 118816 15 S1 "WANG, YISONG" 7/1/07 0:00 7/31/24 0:00 ZCA1-RPRB-6 8241 7690446 "CHANG, SUSAN M" "VIGNERON, DANIEL B" 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 12280 8086 4194 The Director of the Administrative and Clinical Services (ACS) Core will be Dr. Susan Chang and the Associate Director will be Dr. Jennifer Clarke. The Administrative component will be led by Dr. Chang and the Clinical component will be led by Dr. Clarke. Dr. Sarah Nelson and Dr. Daniel Vigneron will serve as co-investigators in order to provide oversight of the technical aspects of the Projects planned. Dr. Chang is the Director of the Division of Neuro-Oncology and is the overall PI of the PI and was as well as the director of the Administrative Core of the prior PPG. She is experienced in the coordination of multiple projects and cores and has effectively provided the leadership for the successful activities of the previous cycle. She has demonstrated clear commitment to providing oversight of the PPG. The specific aims of the ACS Core are to provide Administrative and Clinical services to all our Projects to accomplish their Specific Aims and Research Plans. Administrative support will include fiscal grants management and clerical support for annual progress reports and manuscript preparation and organization for meetings between the key personnel from the projects and cores as well as for meetings with the External Advisory Board. Two of the Projects will involve patient research studies and the clinical component will provide the infrastructure and personnel to allow the conduct of non-therapeutic and therapeutic research studies. This will include clinical scientists neurosurgeons research nurses and clinical research assistants as well as clinical space to obtain informed consent treat and follow patients enrolled in clinical studies within all the Projects. The overall goal of the ACS Core will be to facilitate the interactions of the members of this P01 provide clinical research support for the Projects and administratively coordinate activities of the P01investigators. The following table depicts the distribution of effort provided to the four Projects by the two components of the ACS Core. Component Project 1 Project 2 Project 3 Project 4 Total Administrative 25% 25% 25% 25% 100% Clinical 60% 0% 0% 40% 100% +No NIH Category available Adverse event;Biological Markers;Cancer Center;Clinical;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Services;Collaborations;Communication;Complex;Consent;Correlative Study;Data;Databases;Disease;Effectiveness;Ensure;Evaluation;Funding;Glioma;Goals;Grant;Human Resources;Image;Individual;Informed Consent;Infrastructure;Institutional Review Boards;Laboratories;Leadership;Manuscripts;Metabolic;Molecular;Monitor;Neurosurgeon;Nursing Research;Patient Rights;Patient imaging;Patients;Pharmaceutical Preparations;Preparation;Procedures;Progress Reports;Protocols documentation;Reporting;Research;Research Assistant;Research Personnel;Research Project Grants;Research Subjects;Research Support;Safety;Scientist;Specific qualifier value;Subgroup;Therapeutic Research;Tissues;Toxic effect;United States National Institutes of Health;design;experience;follow-up;improved;individual patient;meetings;member;molecular subtypes;multiparametric imaging;neuro-oncology;operation;participant enrollment;programs;radiologist;research study;success Administrative and Clinical Services Core The proposed P01 consists of four highly integrated projects focused on identifying metabolic signaturesassociated with molecular subgroups of glioma and combining them with multi-parametric imaging strategies toevaluate spatial and temporal changes in individual patients during the course of their disease. This Core willprovide administrative and fiscal oversight for all four projects and clinical services for the two projects that willbe performing patient studies. NCI 10897354 8/29/23 14:52 PAR-18-290 3P01CA118816-15S1 3 P01 CA 118816 15 S1 "WANG, YISONG" 7/1/07 0:00 7/31/24 0:00 ZCA1-RPRB-6 8239 7690446 "CHANG, SUSAN M" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 12280 8086 4194 The Director of the Administrative and Clinical Services (ACS) Core will be Dr. Susan Chang and the AssociateDirector will be Dr. Jennifer Clarke. The Administrative component will be led by Dr. Chang and the Clinicalcomponent will be led by Dr. Clarke. Dr. Sarah Nelson and Dr. Daniel Vigneron will serve as co-investigators inorder to provide oversight of the technical aspects of the Projects planned. Dr. Chang is the Director of theDivision of Neuro-Oncology and is the overall PI of the PI and was as well as the director of the AdministrativeCore of the prior PPG. She is experienced in the coordination of multiple projects and cores and has effectivelyprovided the leadership for the successful activities of the previous cycle. She has demonstrated clearcommitment to providing oversight of the PPG. The specific aims of the ACS Core are to provide Administrativeand Clinical services to all our Projects to accomplish their Specific Aims and Research Plans. Administrativesupport will include fiscal grants management and clerical support for annual progress reports and manuscriptpreparation and organization for meetings between the key personnel from the projects and cores as well asfor meetings with the External Advisory Board. Two of the Projects will involve patient research studies and theclinical component will provide the infrastructure and personnel to allow the conduct of non-therapeutic andtherapeutic research studies. This will include clinical scientists neurosurgeons research nurses and clinicalresearch assistants as well as clinical space to obtain informed consent treat and follow patients enrolled inclinical studies within all the Projects. The overall goal of the ACS Core will be to facilitate the interactions of themembers of this P01 provide clinical research support for the Projects and administratively coordinate activitiesof the P01investigators. The following table depicts the distribution of effort provided to the four Projects by thetwo components of the ACS Core.Component Project 1 Project 2 Project 3 Project 4 TotalAdministrative 25% 25% 25% 25% 100%Clinical 60% 0% 0% 40% 100% +No NIH Category available Acceleration;Address;Affect;Alleles;Binding;Binding Proteins;Binding Sites;Brain Neoplasms;CRISPR interference;Candidate Disease Gene;Cell Aging;Cell Survival;Cells;ChIP-seq;Clinical;Clinical Trials;Data;Family;Funding;Genes;Genetic;Genetic Transcription;Glioblastoma;Glioma;Goals;Growth;Human;In Vitro;Individual;Length;Libraries;Link;Malignant Neoplasms;Mediating;Metabolic;Modeling;Molecular;Mus;Mutate;Mutation;Patient-Focused Outcomes;Process;Proliferating;Promoter Regions;Proteins;Publications;Recurrence;Regulation;Repression;Role;Scheme;TERT gene;Telomerase;Testing;Toxic effect;Transcriptional Activation;Tumor Suppressor Proteins;Xenograft procedure;cancer cell;cancer type;cell immortalization;experimental study;improved;in vivo;knock-down;loss of function;loss of function mutation;molecular subtypes;mutant;neoplastic cell;new therapeutic target;novel;novel therapeutics;oligodendroglioma;promoter;protein expression;recruit;resistance mechanism;stem cells;telomere;transcription factor;tumor;tumor growth;tumorigenesis;ubiquitin ligase Project 2: The GABP-TERT axis in immortality of Oligodendroglioma and Glioblastoma Brain tumors and many other tumor types achieve immortality the ability to proliferate indefinitely through amutation in the promoter of the TERT gene which is the third most common mutation in human cancer. Webelieve that understanding how the proteins uniquely attracted by the promoter mutation and those proteinsthat are native to the promoter may be the key to tumor cell immortality. One or more of these proteins mayprove to be valuable as a new therapeutic target to reverse tumor immortality specifically in TERT promotermutant cancer cells sparing TERT-expressing normal stem cells. This would be a fundmentally differentapproach than targeting TERT directly an approach that has failed in clinical trials due to stem cell toxicity.Findings from this project will provide the mechanistic basis for the MRS-detectable metabolic changesassociated with TERT expression which will be studied in Project 3. NCI 10897351 8/29/23 14:52 PAR-18-290 3P01CA118816-15S1 3 P01 CA 118816 15 S1 "WANG, YISONG" 7/1/07 0:00 7/31/24 0:00 ZCA1-RPRB-6 8236 6867892 "COSTELLO, JOSEPH F" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 12281 8087 4194 PROJECT SUMMARY/ABSTRACTThe goal of Project 2 is to understand how factors uniquely recruited to the mutant TERT promoter (TERTp)together with factors that are native to the wildtype (WT) promoter activate TERT to achieve tumor cellimmortality. TERTp mutation occurs in nearly all glioblastoma (GBM) and oligodendroglioma (OD) enablingtumor cells to become immortal. We showed that the mutations allow the GA-binding protein (GABP) toaberrantly activate the mutant TERTp across many cancer types. In our preliminary data and new publicationreduction of GABP in GBM causes decreased TERT and a gradual and nearly complete loss of viability in aTERTp mutation-dependent manner. GABP is not normally present at the TERTp however little else is knownabout this newly discovered central node in tumor cell immortality. We have discovered two novel candidatemolecules - RNF2 an ubiquitin ligase that appears to drive activation of the mutant TERTp; and the tumorsuppressor CIC that represses WT and mutant TERTp but is recurrently mutated in OD and downregulated inGBM. Here we will test the hypothesis that activation of the mutant TERTp and tumor immortality by GABPinvolve critical contributions from mutant allele-specific factors and native factors. In Aim 1 we will define therole of mutant-specific recruitment of RNF2 in promoting TERT expression and immortality. We will examineRNF2 recruitment to and regulation of mutant TERTp across GBM and OD cultures determine if knockdownof RNF2 alters telomerase activity telomere length and tumor cell viability in vitro and tumorigenesis in vivoand if combined inhibition of GABP and RNF2 accelerates these processes. Potential resistance mechanismsin tumors that grow despite reduced GABP will be addressed. In Aim 2 we will determine how WT and mutantCIC regulates TERT expression and immortality. WT CIC suppresses transcription several ETS factors whichwe previously demonstrated normally activate the WT and mutant TERT promoter. We will test CICsuppression of TERT expression across GBM and OD cultures then test whether the recurrent loss of functionmutations found in OD upregulate TERT and which ETS factors mediate the effect. We will knockdown theCIC-regulated ETS factors and determine if they alter telomerase activity telomere length and tumor cellimmortality. In Aim 3 we propose to more broadly discover novel regulators of immortality using an in vivoCRISPRi screen. The gene inhibition will be modeled in TERTp mutant GBM cells with and without GABP-editing in order to identify factors that regulate cellular immortality in vivo either independently of orsynergistically with GABP. Our results in glioma will build upon the central node of TERT-GABP interactionwhich we discovered and may be relevant to the wider spectrum of TERTp mutant tumor types. Bycontrasting mechanisms of TERT regulation in two clinically distinct glioma subtypes -OD and GBM- we willidentify TERTp regulatory mechanisms that are shared or subtype-specific and potentially linked to thedifferent patient outcomes. The tumor cell specific regulators may present new therapeutic opportunities. +No NIH Category available Area;Artificial Intelligence;Biological;Biological Assay;Biological Monitoring;Brain Neoplasms;Categories;Cellularity;Characteristics;Classification;Clinical;Data;Data Analyses;Data Set;Decision Making;Diffusion Magnetic Resonance Imaging;Disease;Excision;Functional Imaging;Glioma;Gliosis;Goals;Heterogeneity;Histologic;Histopathology;Hypoxia;Image;Infiltration;Institution;Intelligence;Knowledge;Learning;Lesion;Link;Location;Machine Learning;Magnetic Resonance Imaging;Malignant - descriptor;Maps;Metabolic;Modality;Modeling;Molecular;Multiparametric Analysis;Mutation;Newly Diagnosed;Operative Surgical Procedures;Patient Care;Patients;Perfusion Weighted MRI;Proliferating;Property;Protocols documentation;Radiation therapy;Recurrence;Recurrent tumor;Residual Neoplasm;Risk;Sampling;Scanning;Source;Standardization;Statistical Models;Subgroup;Surrogate Markers;Testing;Time;Tissue Sample;Tumor Biology;Work;accurate diagnosis;anatomic imaging;clinical diagnosis;cohort;deep learning model;direct patient care;genomic biomarker;image guided;imaging biomarker;imaging modality;improved;in vivo imaging;innovation;metabolic imaging;molecular marker;molecular subtypes;multimodality;multiparametric imaging;non-invasive imaging;novel;novel strategies;outcome prediction;patient stratification;prediction algorithm;promoter;prospective;response;spectroscopic imaging;treatment response;tumor;tumor heterogeneity;tumor progression Project 1: Predicting tumor biology from multiparametric MRI and image-guided tissue samples NARRATIVEThe goal of Project 1 is to assess the clinical value of combining multi-parametric imaging with novel advancesin statistical modeling machine learning and artificial intelligence to evaluate tumor heterogeneity and identifyregions at risk for tumor progression in patients with glioma. Predictive spatial maps of tumor biology will begenerated using image-guided tissue samples to link anatomic physiological and metabolic imaging parameterswith histological characteristics. This approach will contribute to patient care by directing tissue sampling to makemore accurate diagnoses improving the characterization of residual disease assisting in the planning of focaltherapy and detecting malignant progression. NCI 10897350 8/29/23 14:52 PAR-18-290 3P01CA118816-15S1 3 P01 CA 118816 15 S1 "WANG, YISONG" 7/1/07 0:00 7/31/24 0:00 ZCA1-RPRB-6 8235 10389857 "LUPO, JANINE MARIE" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 12281 8087 4194 PROJECT SUMMARYThe goal of this work is to assess the clinical value of voxel-wise predictive spatial maps of tumor heterogeneitythat directly reflect histopathologically defined tumor biology. It is well known that tissue samples used for clinicaldiagnosis come from a relatively small portion of a vastly heterogenous lesion and are obtained infrequentlyduring the course of the disease. Non-invasive imaging markers that are able to assess intratumoralheterogeneity and serially monitor biological properties of the tumor are critical for assessing response to therapyand directing patient care.The modalities that have shown the most promise in quantifying surrogate markers of malignant characteristicsin patients with gliomas include diffusion-weighted MRI perfusion-weighted MRI and 1H MR spectroscopicimaging (MRSI). During previous cycles of our P01 and SPORE projects we have accumulated multi-parametricphysiologic and metabolic imaging data from pre-surgical scans in order to target over 2000 tissue samples frommore than 750 patients with glioma. These samples are unique in that they have each been specifically selectedto target heterogeneous regions of tumor biology including: hypoxia proliferation cellularity gliosis andmalignant transformation using a combination of anatomic physiologic and metabolic imaging. Using this well-characterized cohort our novel approach will leverage multi-parametric imaging features from tissue samplesobtained from known image coordinates as well as advanced statistical- machine- and deep-learning modelsto construct spatial maps that predict tumor biology. In a new cohort of 400 patients with glioma (200 newly-diagnosed and 200 at the time of suspected recurrence) we will prospectively acquire multi-modal MRI and 1200tissue samples with known image coordinates that are targeted based on our predictive spatial maps to bothvalidate the best performing models in this independent test set and generate enhanced spatial maps to assessclinical value at time points that are critical for making decisions about patient care.In Aim 1 we will predict intra-tumoral heterogeneity and the extent of infiltrating tumor and in newly-diagnosedglioma using multi-parametric imaging from tissue samples with known imaging coordinates in order to identifyareas of malignant characteristics that will direct tissue sampling for a more accurate diagnosis and predict thespatial location and characteristics of residual disease. Aim 2 will define characteristics of treatment relatedchanges vs recurrent tumor and malignant transformation within lower grade molecular sub-groups of gliomawithin patients undergoing surgery for suspected tumor progression.This innovative study will enhance and expand current strategies for evaluating patients with glioma and providea framework for incorporating newly identified imaging molecular and genomic markers. This is imperative forintelligently combining novel imaging data and generating comprehensive predictive spatial maps that can beintegrated with current response assessment criteria for evaluating standard and experimental treatments. +No NIH Category available Acceleration;Behavior;Biological;Biological Assay;Biological Markers;Brain;Categories;Cells;Characteristics;Clinic;Clinical;Clinical Services;Data;Data Analyses;Data Set;Development;Diagnosis;Diffusion;Disease;Evaluation;Foundations;Functional Imaging;Genes;Genomics;Geography;Glioblastoma;Glioma;Goals;Grant;Heterogeneity;Image;Imaging Techniques;Infrastructure;Lesion;Magnetic Resonance Imaging;Malignant - descriptor;Maps;Metabolic;Metabolic Marker;Metabolism;Molecular;Monitor;Multimodal Imaging;Mutation;Outcome;Patients;Perfusion;Physiological;Positioning Attribute;Pre-Clinical Model;Predictive Value;Prognosis;Program Research Project Grants;Property;Protocols documentation;Recurrent tumor;Regulation;Research;Residual Neoplasm;Resources;Role;Sampling;Scanning;Signal Transduction;Spectrum Analysis;Subgroup;Techniques;Technology;Telomerase;Therapeutic;Tissue Sample;Translating;Tumor Biology;Tumor Burden;Tumor Markers;World Health Organization;biomarker identification;cell immortalization;clinical translation;clinically relevant;data acquisition;image guided;imaging biomarker;imaging modality;imaging scientist;improved;in vivo;individual patient;innovation;insight;large datasets;metabolic imaging;molecular subtypes;multimodality;multiparametric imaging;mutant;mutational status;neoplastic cell;neuro-oncology;neuroimaging;novel;novel imaging technology;novel therapeutic intervention;novel therapeutics;oligodendroglioma;pre-clinical;prediction algorithm;prognostic value;programs;promoter;recruit;tool;treatment response;tumor;tumor behavior Noninvasive Metabolic Signatures to Improve Management of Molecular Subtypes of Glioma The objective of the proposed program project grant is to improve the management of patients with differentmolecular subgroups of glioma defined by their 1p19q co-deletion IDH mutation and TERT promotor mutationstatus. This will be achieved by identifying multi-parametric imaging markers that are specific to each sub-typeelucidating mechanisms that influence the regulation of mutant TERT promotor in subgroups with divergentmolecular and clinical features defining metabolic signatures of TERT expression and implementing novel 1Hand 13C metabolic imaging strategies for monitoring individual patients during the course of their disease. NCI 10897349 8/9/23 0:00 PAR-18-290 3P01CA118816-15S1 3 P01 CA 118816 15 S1 "WANG, YISONG" 7/1/07 0:00 7/31/24 0:00 ZCA1-RPRB-6(M1) 7690446 "CHANG, SUSAN M" "VIGNERON, DANIEL B" 11 NEUROSURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 85963 NCI 56605 29358 The overall goal of this P01 proposal is to improve the management of patients with different molecularsubgroups of glioma focusing on novel neuroimaging surrogates associated with metabolic and physiologicchanges in each group. The delineation of histopathological and molecular subgroups of glioma hasrevolutionized the field of neuro-oncology by improving diagnosis and prognosis. Interrogating metabolic andphysiologic signatures of these subgroups will be one of the next critical advances in the field of neuroimaging.In the previous cycle of our P01 we acquired a large dataset of image-guide tissue samples matched with MRdiffusion perfusion and spectroscopy scans. We now seek to combine these techniques using sophisticateddata analysis tools to more efficiently predict tumor burden and malignant behavior by subgroup. Our preliminarydata also indicate that there are differences in metabolism associated with changes in IDH status and TERTexpression that have the potential for being used in developing in vivo signatures for specific molecular subtypes.In this new proposal we will identify multi-parametric imaging markers that are specific to each subtype; usenovel gene editing tools to elucidate mechanisms that influence the regulation of mutant TERT promotor insubgroups with divergent molecular and clinical features; define metabolic signatures of TERT expression; andimplement novel 1H and 13C metabolic imaging strategies for monitoring individual patients during the course oftheir disease. This would set the stage for developing clinical 1H and hyperpolarized 13C metabolic imagingassays that could provide early assessment of tumor recurrence and treatment response. These integratedstudies will be supported by specialized resources from the Administrative and Clinical Services Core and theBiospecimen and Biomarker Core. To translate our mechanistic findings and novel imaging technologies intoclinically relevant actions we will use the unique infrastructure that our group has established over the priorcycles of this P01 to perform studies in cells pre-clinical models and patients. The innovative research describedin this proposal will take advantage of the exceptional resources assembled by the well-established collaborativegroup of clinical biological and imaging scientists at UCSF. 85963 +No NIH Category available 3-Dimensional;Affect;Anabolism;Animal Model;Apoptosis;Architecture;Automobile Driving;Biochemistry;Biological Models;Biology;CDKN2A gene;CUL3 gene;Cancer Etiology;Cell Line;Cell model;Cells;Cellular biology;Cessation of life;Clinic;Data;Data Set;Development;Diagnosis;Drug Metabolic Detoxication;Drug Screening;Epithelial Cells;Epithelium;Esophageal Squamous Cell Carcinoma;Esophagus;Event;Experimental Models;Expression Profiling;Future;Genes;Genetic;Genetic Transcription;Growth;Human;Hyperactivity;Hyperplasia;In Vitro;Lesion;Longevity;LoxP-flanked allele;Lung;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Modeling;Molecular;Multiomic Data;Mus;Mutate;Mutation;Neoplasm Metastasis;Normal Cell;Oncogenic;Organoids;PI3K/AKT;PIK3CA gene;PIK3CG gene;Pathway interactions;Patients;Pharmacology;Pharmacology Study;Phase;Phenotype;Phosphotransferases;Preventive;Proliferating;Proteomics;Pyrimethamine;Pyruvate Kinase;Recurrence;Regulation;Reporting;Research;Signal Pathway;Signal Transduction;Stains;Stress;Surveys;Survival Rate;TP53 gene;Tamoxifen;Testing;Therapeutic;Therapeutic Agents;Tissue Microarray;Tissues;Translating;Tumor Promoters;United States;Validation;Work;Xenograft procedure;advanced disease;cancer type;design;differential expression;empowerment;experimental study;genomic locus;glycosylation;in vivo;inhibitor;insight;member;metabolomics;new therapeutic target;novel;novel therapeutics;pharmacologic;programs;response;small molecule;small molecule inhibitor;synergism;targeted treatment;therapeutic evaluation;transcription factor;transcriptome sequencing;tumor progression Mechanisms and Targeted Therapy of NRF2-high Esophageal Squamous Cell Carcinoma Esophageal squamous cell carcinoma (ESCC) is prevalent in the world with a 5-year survival rate around18%. Using human cells and animal models we will characterize the molecular consequences of NRF2hyperactivation in ESCC determine the mechanisms of action and efficacy of NRF2 inhibitors and find NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. If successful this work will help developtargeted therapy of NRF2high ESCC in human patients. NCI 10897094 1/3/24 0:00 PA-19-056 5R01CA244236-05 5 R01 CA 244236 5 "YASSIN, RIHAB R" 6/1/20 0:00 12/31/25 0:00 Developmental Therapeutics Study Section[DT] 6907189 "CHEN, XIAOXIN LUKE" "MAJOR, MICHAEL BENJAMIN" 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 575675 NCI 382619 193056 This multiple-PI R01 proposal is designed to incorporate genetic and pharmacological approaches tounderstand the mechanisms of NRF2 hyperactivation in ESCC and to develop targeted therapy for Nrf2highESCC. We believe Nrf2 and kinases are functionally interrelated and thus cooperatively contribute to ESCC.In this proposal we aim to characterize the molecular and phenotypic consequences of NRF2 hyperactivationin ESCC determine the mechanisms of action and efficacy of NRF2 small molecule inhibitors in ESCC andidentify NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. Through threeindependent yet tightly related Specific Aims we will provide novel insights into pathway regulation and noveltherapeutic targets/agents for NRF2high ESCC. If proven effective some compounds may be further translatedinto the clinic for targeted therapy of NRF2high ESCC in the future. 575675 +No NIH Category available Acids;Adjuvant Therapy;Affect;Anabolism;Analytical Chemistry;Apoptotic;Biological Availability;Biological Markers;Bladder;Breast;Cancer Model;Cancer cell line;Canis familiaris;Cell Death;Cell Line;Cell Survival;Cell physiology;Chemoresistance;Clinical Trials;Clinical Trials Design;Colon;Combined Modality Therapy;Data;Disease;Dose;Drug Formulations;Drug Kinetics;Drug resistance;ERBB2 gene;Enzymes;Essential Fatty Acids;Fatty Acids;Food and Drug Administration Drug Approval;Formulation;Generations;Grant;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunocompetent;Immunology;Immunosuppression;Immunotherapy;Inflammatory;Inhibition of Cell Proliferation;Investigation;Kidney;Lead;Life;Link;Liver;Malignant Neoplasms;Malignant neoplasm of pancreas;Maximum Tolerated Dose;Measures;Mediating;Mediator;Melanoma Cell;Membrane;Metabolic;Monounsaturated Fatty Acids;Mus;New Drug Approvals;No-Observed-Adverse-Effect Level;Nutrient;Nutrient availability;Oncogenic;Oral;Ovarian;PD-1 inhibitors;Pathway interactions;Patients;Pharmacology and Toxicology;Phase;Phase I Clinical Trials;Phase III Clinical Trials;Phenotype;Play;Principal Investigator;Property;Proteins;Reporting;Role;Saturated Fatty Acids;Signaling Molecule;Site;Small Business Innovation Research Grant;Small Interfering RNA;Solid Neoplasm;Stearoyl-CoA Desaturase;Synthesis Chemistry;T-Cell Activation;T-Lymphocyte;Therapeutic;Thyroid Gland;Toxic effect;Toxicology;Translations;WNT Signaling Pathway;adaptive immune response;adaptive immunity;antagonist;anti-PD1 antibodies;anti-PD1 therapy;anti-cancer;antitumor effect;arm;attenuation;calreticulin;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cancer survival;cancer type;capsule;carcinogenesis;cell killing;clinical practice;combat;computational chemistry;deprivation;design;early phase clinical trial;endoplasmic reticulum stress;fatty acid biosynthesis;fatty acid metabolism;first-in-human;immune activation;immune cell infiltrate;immune checkpoint blockade;immunogenic;immunogenicity;in vivo;inhibitor;insight;lipid biosynthesis;lipid metabolism;malignant breast neoplasm;mouse model;neoplastic cell;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;patient response;patient stratification;phase I trial;predictive marker;refractory cancer;response;response biomarker;small molecule;synergism;targeted treatment;therapeutic target;therapeutically effective;therapy resistant;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumorigenic Modulation of cancer induced immune suppression via inhibition of SCD1 PROJECT NARRATIVEA novel fatty acid synthesis inhibitor MTI-301 (aka SSI-4) sensitizes cancers to immune checkpoint inhibitors. This new therapeutic strategy should increase the number of patients responding to treatment and may lead to cures through prolonged activation of immune T cells in drug resistant cancers. NCI 10896572 8/23/23 0:00 PA-21-260 4R44CA272064-02 4 R44 CA 272064 2 "WEBER, PATRICIA A" 9/15/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-S(12)B] 16056231 "HAYES, KAREN E" "COPLAND, JOHN A.; TAN, WINSTON " 2 Unavailable 968675244 FPRRYGJGEHB1 968675244 FPRRYGJGEHB1 US 39.75467 -75.627199 10029690 "MODULATION THERAPEUTICS, INC." MORGANTOWN WV Domestic For-Profits 265069115 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1301808 NCI 1014158 265093 PROJECT SUMMARYMetabolic reprogramming plays a critical role in carcinogenesis in part due its ability to promote immune suppressive properties within tumors. It remains unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. We show that inhibition of stearoyl CoA desaturase 1 (SCD1) the rate limiting enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids (MUFAs) increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell-based cancer immunotherapy. In so doing our novel lead SCD1 inhibitor (MTI-301; aka SSI-4) singly and in combination with immune checkpoint inhibitors (ICIs) using immune competent mouse models demonstrates anti-tumor synergy sensitizing tumors to ICIs as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be useful for the design and stratification of patients in the critical Phase III clinical trial. SCD1 is universally upregulated in aggressive cancers and validated by MTI-301 antitumor activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically MUFA deprivation in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We discovered using immune competent mouse cancer models that MTI-301 activates the adaptive immune response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor MTI-301 sensitizes tumors to immune checkpoint inhibitors in mouse triple negative breast cancer (TNBC) and HER2 breast cancer mouse models. Based upon these data our central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicity. Three aims are proposed in this fast-track Phase 1/2 SBIR proposal. In Aim 1 (Milestone 1 Phase I SBIR) GLP dog toxicology study will be completed to identify the No-observedadverse-effect level (NOAEL) enabling calculation of the first in human dose for the phase I clinical trial. In Aim 2 (Milestone 2 Phase II SBIR) GMP MTI-301 will be synthesized and capsulated along with submission of the investigation of new drug (IND) application for FDA Phase I trial approval. In Aim 3 (Milestone 3 Phase II SBIR) a Phase I clinical trial will be performed and exploratory biomarkers including identification of immune infiltrates into the tumor site will be assessed. In summary we envision SCD1 as a broad-spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful MTI-301 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade leading to dramatic adaptive immune mediated tumor cell killing. This combination therapy should enhance patient response rates and be well tolerated in patients. 1301808 +No NIH Category available Point of Care HPV 16/18/45 DNA Test for Cervical Cancer Point of Care HPV 16/18/45 DNA Test for Cervical Cancer.CrossLife Technologies Inc.RESEARCH & RELATED Other Project InformationNarrativeHuman cervical cancer is the third most common cancer among women worldwide [1]. Cervicalcancer is closely associated with HPV infection and 99% of cervical cancer is due to persistentHPV infection. HPV is a DNA virus which has many types of HPV (<150) and many do notcause problems. HPV infections usually clear up without any intervention within a few monthsafter acquisition and about 90% clear within 2 years. A small proportion of infections withcertain types of HPV can persist and progress to cervical cancer. NCI 10896570 9/18/23 0:00 PA-19-272 4R44CA250663-02 4 R44 CA 250663 2 "LOU, XING-JIAN" 9/22/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-IMST-J(10)B] 12008130 "CHO, HYUNDAE " Not Applicable 49 Unavailable 41375710 LFE6DJ6KL4E5 41375710 LFE6DJ6KL4E5 US 33.102266 -117.196363 10034968 "CROSSLIFE TECHNOLOGIES, INC." CARLSBAD CA Domestic For-Profits 92008 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 994004 NCI 663554 265422 Point of Care HPV 16/18/45 DNA Test for Cervical Cancer.CrossLife Technologies Inc.Project Summary/AbstractHuman cervical cancer is the fourth most common cancer among women worldwide [1].Despite cervical cancer has been thoroughly studied and the mortality has beensignificantly reduced through efficient screening these preventive programs are found tobe less effective in developing countries [2-3]. There are unmet needs for nucleic acidsnew diagnostics that can be applied at the point-of-care to detect HPV 16/18/45 DNA forcervical cancer.A simple sensitive multiplex and robust testing kits for detecting cervical cancerbiomarker HPV 16/18/45 DNA at the point-of-care will be developed. The competitiveadvantage of TARA is the utilization of a novel chemical reaction with similar detectionsensitivity and specificity compared to the Hologic Aptima HPV 16 18/45 Genotype assayand simple readout on paper-strip more suitable for field devices without an instrument.TARA also offers the potential for direct detection in complex sample matrices such ascervical sample or blood without sample preparation. Building on the chemistry anddevice innovations (TARAplex and 1D paper network) we have made significantprogress and begun to explore integration through our established collaborations.We aim to develop a rapid point-of-test that detects HPV at the point-of-need in < 30minutes and is appropriate for non-laboratory settings and non-technical personnel. Ourproprietary test exploits a novel probe reaction chemistry that allows multiplexed detectionof DNA or RNA without sample purification making it operable as a simple hand-heldtest. Patient samples to be input directly into the device without pre-processing and adisposable cartridge carry out amplification of all targets and reports visible results thatcan be read by eye. We expect a sensitivity (>90%) and specificity (>90%) to the U.S.commercially-available the Aptima HPV 16 18/45 Genotype assay (HOLOGIC) data onthe same samples.We will conduct a large-scale validation and obtain World Health Organization (WHO)expedited review approval and recommendation for procurement on our product andmarket it first to non-governmental organizations (NGO) such as the Doctors WithoutBorders or the Gates Foundation. We will obtain USFDA 510 K clearance in Phase 3 inorder to market our product in the U.S. 994004 +No NIH Category available Determinants of Liver Metastasis n/a NCI 10895782 7/28/23 14:58 PAR-18-290 3P01CA233452-04S1 3 P01 CA 233452 4 S1 "WATSON, JOANNA M" 1/21/20 0:00 12/31/24 0:00 ZCA1-RPRB-F(O1) 8338 1895258 "LU, SHELLY CHI-LOO" "BHOWMICK, NEIL A." 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 Non-SBIR/STTR 2023 19749 11826 7923 No abstract available +No NIH Category available Address;Advisory Committees;Antineoplastic Agents;Authorship;Biological;Biological Assay;Biometry;Biostatistics Core;Budgets;Chemicals;Chicago;Collaborations;Cyanobacterium;Data;Data Display;Databases;Dependence;Development;Disputes;Drug Kinetics;Effectiveness;Electronics;Ensure;Evaluation;Experimental Designs;Fostering;Goals;Grant;Housing;Illinois;Industrialization;Information Dissemination;Institution;Investigation;Laboratories;Leadership;Lichen - organism;Malignant Neoplasms;Methods;Modeling;Molds;North Carolina;Occupational activity of managing finances;Ohio;Persons;Pharmaceutical Chemistry;Pharmacologic Substance;Plants;Program Effectiveness;Program Efficiency;Program Research Project Grants;Provider;Research;Research Personnel;Research Project Grants;Resource Allocation;Scientist;Services;Statistical Methods;Structure;Teleconferences;Telephone;Training;Universities;Validation;Visual;Work;chemotherapeutic agent;computerized data processing;design;experimental analysis;fungus;meetings;member;multidimensional data;novel;operation;preservation;programs;symposium;tumor;videoconference Core A: Administrative and Biostatistics Core n/a NCI 10895774 7/28/23 14:51 PAR-18-290 3P01CA125066-14S1 3 P01 CA 125066 14 S1 "FU, YALI" 7/1/07 0:00 4/30/25 0:00 ZCA1-TCRB-Q(O1) 6314 1877686 "KINGHORN, ALAN DOUGLAS" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Non-SBIR/STTR 2023 50567 32415 18152 PROJECT SUMMARY ADMINISTRATIVE AND BIOSTATISTICS CORE (CORE A)The overall goals of the Administrative and Biostatistics Core (Core A) are to 1) continue to provide a structureto facilitate effective interactions toward the accomplishment of the aims of this Program Project and specifically to foster and promote the goals of the Program and each component (cores and projects) by providing scientific direction administrative and budgetary support oversight integration of program activities and the industrial partner and ensuring operational efficiency; and 2) to continue to provide biostatistics and other statistical support for the P01. The following are the objectives of Core A: 1) provide research direction by setting the research agenda focused on the discovery of novel chemicals from selected tropical rainforest plants as well as lichens cyanobacteria and filamentous fungi for development as cancer chemotherapeutic agents particularly for tumors not cured by present treatment methods. 2) Ensure operational efficiency for Program componentsby providing centralized grant administration information dissemination budget data processing and exchangeof information and services. 3) Promote integration of the Research Projects and Cores to promote interactionamong the three primary universities represented by the investigators and relevant external entities and 4) provide biostatistics support for the three Projects and the two Cores of the P01 Program. Core A will continue to ensure that all components of the Program work seamlessly together to accomplish the overall and specific project goals of the P01 Program. +No NIH Category available Address;Algorithms;Anesthesia procedures;Animals;Clinic;Clinical;Clinical Treatment;Collimator;Communities;Computational Technique;Computer software;Cost Analysis;Dedications;Development;Development Plans;Disparity;Dose;Engineering;Ensure;Freedom;Functional Imaging;Generations;Hour;Human;Hypoglycemia;Image;Immune response;Impairment;Intensity-Modulated Radiotherapy;Interruption;Intuition;Investigation;Joints;Learning;Lung;Malignant Neoplasms;Manuals;Mechanics;Medical;Medical center;Modality;Modernization;Normal tissue morphology;Organ;Physiological;Positron-Emission Tomography;Price;Process;Radiation;Radiation Dose Unit;Radiation therapy;Radiobiology;Radiotherapy Research;Rattus;Reliability of Results;Research;Resources;Risk;Sales;Sample Size;Shapes;Side;Software Design;Speed;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Translating;Translations;Validation;anatomic imaging;cone-beam computed tomography;cost;design;design and construction;evidence base;experience;frontier;image guided;imaging modality;imaging platform;improved;industry partner;innovation;natural hypothermia;new technology;next generation;novel;pre-clinical;pre-clinical research;preclinical study;product development;prototype;reconstruction;research study;response;systems research;treatment planning;treatment response;tumor Next generation small animal radiation research platform NARRATIVETechnology in current small animal radiation research (SARR) has significantly lagged behind that in human radiotherapy (RT) impairing SARR study relevance to human RT impeding explorations in RT research and hindering rapid conduction of SARR studies. This project will develop a next-generation SARR platform with novel imaging planning delivery and computation techniques to fill this critical void between SARR and human RT. The developed system will become an essential component in preclinical research for the exploration of novel radiotherapeutic strategies with high relevance to human RT. NCI 10895120 8/31/23 0:00 PA-21-268 4R37CA214639-07 4 R37 CA 214639 7 "OBCEMEA, CEFERINO H" 2/9/18 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)] 10291013 "JIA, XUN " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 471111 NCI 315946 155165 PROJECT SUMMARYSmall Animal Radiation Research (SARR) is of paramount importance for the advancement of human radiotherapy (RT) by serving as a critical counterpart to perform comprehensive preclinical studies on a large number of subjects under controlled experimental conditions at low costs. SARR relies on dedicated platforms to administer radiation dose to animals in a similar way as in the clinic. Current-generation SARR irradiators developed in the past decade have failed to keep pace with technology advancements in human RT. In stark contrast to modern RT treatments where novel anatomical and functional imaging inverse treatment planning and intensity modulated delivery techniques are routinely employed to precisely form an extremely conformal dose distribution to the tumor the therapeutic form in current SARR systems resembles an obsolete form of human RT. This technology disparity has substantially impaired SARR study relevance to human RT impeded explorations in RT research and hindered rapid conduction of SARR studies. Towards addressing this problem in response to PAR-15-075 this project will develop and translate a next-generation SARR platform through an academic-industrial partnership joining medical physicists and radiobiologists at UT Southwestern Medical Center (UTSW) with engineering experts at Faxitron Bioptics LLC (Faxitron). The developed system will be substantially superior to the current state-of-the-art SARR platform due to its novel imaging methods (dual energy cone beam CT and PET) intensity modulated radiotherapy and high computation and treatment delivery efficiency. These novel features are expected to improve SARR research relevance to human RT by delivering treatments of clinical quality to support exploration in modern RT by offering technical freedom to realize novel imaging and therapy approaches and to increase research efficiency by enhancing computational speed and workflow. We will perform studies with the following specific aims (SAs): SA1: Refine hardware design and construct the hardware system including mechanical imaging and therapy subsystems. SA2: Refine software design and develop an imaging and treatment planning system accompanied with the hardware platform. SA3: Perform comprehensive system tests develop a translation plan and demonstrate achieved advantages of the system via an animal study on image-guided intensity-modulated lung stereotactic body radiotherapy using rats. The innovation of this project includes novel technological capabilities enabled by the next-generation SARR platform as well as coherent translation activities to deliver new capabilities to endusers. Project feasibility is ensured by extensive preliminary studies and the research team integrating medical physicists and radiobiologists (UTSW) with strong clinical and research expertise and engineers (Faxitron) with extensive commercial product development experience. By filling the critical void between SARR and human RT the developed system will become an essential component in preclinical research for the exploration of novel radiotherapeutic strategies with high relevance to human RT. 471111 +No NIH Category available Clinical;Clinical Research;Clinical Trials;Contractor;Contracts;Extramural Activities;Funding;Integrative Medicine;Monitor;National Center for Complementary and Integrative Health;Services;clinical research site;quality assurance THE CONTRACTOR SHALL PROVIDE COMPREHENSIVE CLINICAL SITE AND STUDY MONITORING SERVICES FOR THE NCCIH-FUNDED (PRIMARY OR SECONDARY) EXTRAMURAL CLINICAL n/a NCI 10894583 75N91021C00033-P00003-9999-1 N01 8/1/21 0:00 7/31/24 0:00 78296579 "HENNESSEY, ROSLYN " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2023 746782 NCCIH CLINICAL STUDIES MONITORING SERVICE (CSMS) NATIONAL CENTER FOR COMPLEMENTARY AND INTEGRATIVE HEALTH. This is a monitoring contract that performs quality assurance on NCCIH-funded extramural clinical trials in integrative health. 746782 +No NIH Category available Biological;Clinical;Clinical Chemoprevention;Clinical Research;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Institution;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs CANCER PREVENTION AGENT DEVELOPMENT PROGRAM: EARLY PHASE CLINICAL RESEARCH n/a NCI 10894578 261201200035I-P00005-759101900130-1 N01 9/23/19 0:00 3/24/24 0:00 16187672 "KHAN, SEEMA " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N R and D Contracts 2023 73029 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 73029 +No NIH Category available Affinity;Alpha Particles;Animal Model;Antineoplastic Agents;Beta Particle;Binding;Biodistribution;Biological;Blood;Blood flow;Cell Line;Cell model;Cells;Chemicals;Childhood;Collaborations;Complex;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;Data;Deposition;Disease;Dose;Dose Limiting;Electrons;Energy Transfer;Ensure;Event;Foundations;Gamma Rays;Grant;Human;Hypoxia;Impairment;In Vitro;Investigation;Knowledge;Laboratories;Leadership;Learning Skill;Length;Ligands;Liquid substance;Location;Lymphocyte;Malignant Neoplasms;Mentors;Metastatic Neoplasm to the Bone;Methods;Microscopic;Modality;Modeling;Monte Carlo Method;Neoplasm Metastasis;Neuroblastoma;Normal tissue morphology;Organ;Organism;Pattern;Pennsylvania;Phase;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Positioning Attribute;Prediction of Response to Therapy;Principal Investigator;Prognosis;Proteins;Publishing;Radiation;Radiation Dose Unit;Radiation Interaction;Radiation Tolerance;Radiation therapy;Radiobiology;Radioisotopes;Radiometry;Radiopharmaceuticals;Relative Biological Effectiveness;Research;Roentgen Rays;Running;Site;Solid Neoplasm;Structure;Subcellular structure;Techniques;Tissues;Toxic effect;Treatment outcome;Universities;Variant;Water;Writing;Xenograft Model;absorption;analytical method;cancer cell;cancer type;clinical application;clinical effect;dosimetry;enhancing factor;experience;high risk;in vivo;interest;irradiation;method development;neoplastic cell;neuroblastoma cell;overexpression;particle;radiation absorbed dose;radiation effect;repaired;response;side effect;simulation;skills;symposium;theories;tool;tumor;uptake Radiation dosimetry for alpha-particle radiopharmaceutical therapy and application to pediatric neuroblastoma Project NarrativeThe use of -emitting radionuclides is rapidly growing as a promising approach to treat several types of cancerand metastases. In these radiation-based treatments maximizing efficacy while minimizing non-desired toxicitiesis only achievable through an accurate knowledge and prediction of the radiation interaction with the organism.This project will contribute decisively to a rigorous and complete determination of the radiation dosimetry andbiological effects of -particles in the context of radiopharmaceutical treatments. NCI 10894477 9/12/23 0:00 RFA-CA-20-056 4R00CA267560-03 4 R00 CA 267560 3 "CAPALA, JACEK" 12/10/21 0:00 8/31/26 0:00 ZCA1-RTRB-U(O1) 78001348 "BERTOLET REINA, ALEJANDRO " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 346438 NCI 247244 99194 Project Summary/AbstractRadiopharmaceutical treatments with -particles represent a promising approach to treat some tumors andmetastases. This modality leverages the short range of -particles up to tens of microns to deliver radiationonly to cancer cells while sparing the surrounding healthy tissue. To do so an -emitting radionuclide is boundedto an affinitive ligand which is used to target biomolecules expressed in tumoral cells. Currently here are severalclinical applications either approved such as 223Ra for the treatment of bony metastases or under investigation.Particularly -RPT could be used for the treatment of high-risk pediatric neuroblastoma whose prognosis keepspoor. As the rationale behind radiopharmaceutical treatments is to exploit the differential amount of radiationimparted to tumors and healthy tissue a rigorous determination of radiation dosimetry and effects is requestedto develop this technique to their full extent. Starting with the study of -particles in general this research will beoriented to the treatment of pediatric neuroblastoma using the radiopharmaceutical [211At]MM4 which targetsthe overexpression of PARP-1 proteins in these tumors. In general the absorbed dose generally predicts thebiological or clinical effect of X-rays or radiation. However heavy-particle-based radiations such as -particles deposit their energy in a much denser fashion and are capable to produce more concentrated damageto biological structures as the DNA which tends to impair the repair mechanisms of a cell. Microdosimetry is thestudy of these patterns of interaction at the microscopic level and allows for a better determination of the effectof -particles than absorbed dose. The principal investigator has previously investigated methods to calculatemicrodosimetric quantities for -particles. Therefore this project is structured as follows. First thosemicrodosimetric calculations will be connected with actual damage to the DNA using the Monte Carlo toolkitTOPAS and its extension for subcellular structures TOPAS-nBio. Second initial damage to neuroblastoma celllines will be studied using the affinity of [211At]MM4 for PARP-1 in these cell lines to create realistic sub-cellularmodels of -particle irradiation. Permanent damage after the occurrence of repair mechanisms will be alsomodelled assessed through experimental data published by Dr. Makvandis group from the University ofPennsylvania. Finally biodistribution of radiopharmaceutical across organs and blood in animal models andphantoms will be assessed and used to predict treatment outcomes. The principal investigator will use theexperience and expertise of his mentoring team (Dr. Harald Paganetti and Dr. Jan Schuemann) to learn the skillsand abilities necessary to accomplish the proposed research. He will also attend seminars coursework andconferences on radiobiology Monte Carlo simulations and grant writing and leadership skills which will ensurea strong foundation for running an independent laboratory after this project. 346438 +No NIH Category available Academic Medical Centers;Address;Advisory Committees;Age;Area;Cancer Center Support Grant;Cancer Etiology;Cessation of life;Colonoscopy;Colorectal;Colorectal Cancer;Communities;Complement;Data;Detection;Diagnostic;Early Diagnosis;Effectiveness;Endoscopy;Ensure;Family Practice;Frequencies;Geography;Goals;Guidelines;Health Services Accessibility;Incidence;Individual;Information Systems;Intervention;Intestines;Intubation;Knowledge;Link;Literature;Modeling;North Dakota;Operative Surgical Procedures;Oregon;Outcome;Patients;Performance;Physicians;Population;Probability;Provider;Recommendation;Reporting;Research;Residencies;Resources;Response Elements;Rural;Rural Community;Services;Societies;Standardization;Testing;Texas;Time;Training;Training Programs;United States;Universities;Withdrawal;Work;adenoma;cancer diagnosis;clinical practice;colorectal cancer screening;cost effectiveness;follow-up;improved;instrument;medical specialties;mortality;outreach;programs;quality assurance;screening;screening guidelines;screening program;screening services;suburb;urban area Addressing Colonoscopy Quality to Increase Capacity for Colorectal Cancer Screening (CCSG YR13) Project NarrativeEffectiveness of Colorectal cancer screening and diagnostic follow up are influenced by colonoscopy quality. In 2007 astandardized colonoscopy reporting and data system (CO-RADS) was developed using the key indicators for continuousquality improvement identified by the Multi-Society Task Force on Colorectal Cancer (MSTF-CRC) to serve as a qualityimprovement instrument and to provide referring physicians with a colonoscopy report demonstrating the quality of theexamination. Access to high quality colonoscopies have been linked to reduced incidence and CRC-related mortalityhowever most studies are from urban and suburban academic medical centers this analysis aims to provide morerecent data describing colonoscopy quality in large rural colorectal screening programs. NCI 10893842 8/14/23 0:00 PA-20-272 3P30CA142543-13S1 3 P30 CA 142543 13 S1 "BELIN, PRECILLA L" 9/1/10 0:00 7/31/26 0:00 1894038 "ARTEAGA, CARLOS L" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 49331 NCI 30080 19251 Colorectal cancer (CRC) is the third most diagnosed cancer in the United States. Routine CRC screening is recommendedfor individuals ages 45 and older but is only effective when completed appropriately like completing diagnosticcolonoscopy after a fecal immunochemical test (FIT). Effectiveness is further impacted by colonoscopy quality. In 2007 astandardized colonoscopy reporting and data system (CO-RADS) was developed using the key indicators for continuousquality improvement identified by the Multi-Society Task Force on Colorectal Cancer (MSTF-CRC). Based on theliterature some variability in the quality of colonoscopy provided in clinical practice is expected but there is an urgentneed to standardize colorectal early detection screening services particularly as we consider how best to addresscolonoscopy capacity issues in underserved settings.Our long-term goal is to ensure the quality of colonoscopies in communities where capacity may be limited. Our overallobjective is to determine what resources for colorectal cancer screening are available and the quality of service by arange of provider specialties and types. Our rationale for the proposed research is e to improve the effectiveness ofcolonoscopies in CRC screenings by impacting cecal intubation rates adenoma detection rates mean withdrawal timeand adequate bowel preps.We plan to accomplish our overall objective for this project through the following three specific aims: 1. Identify the challenges for colonoscopy completion in rural geography. The emphasis in this aim is gaining the knowledge about service availability and patient need from a population perspective. 2. Examine providers alignment with guideline recommendations for screening and frequency. The study focus of this aim is the variability in screening performance based on provider type. 3. Developing a new endoscopy training program for physicians completing a general surgery residency. The training program will address the major areas of improvement needed based on the findings from the previous aims.With respect to outcomes we expect to identify the full complement of response elements which determine the overallquality of colorectal cancer screening services. Such results are expected to vertically advance the outcomes of screeninginterventions and maximize cost-effectiveness. Equally important the results are expected to have a positive impactbecause it is probable this highly specific and sensitive training model will save resources that are currently strained. 49331 +No NIH Category available Biological Markers;Funding;Image;Quality of life;Southwest Oncology Group;anticancer research;programs;research study FY23 Supplement for NRT BIQSFP This is a supplement application for Biomarker Imaging and Quality of Life Studies Funding Program(BIQSFP) funding for the following SWOG Cancer Research studies: S1602 NCI 10893173 9/18/23 0:00 PA-20-272 3U10CA180888-10S2 3 U10 CA 180888 10 S2 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 6765159 "BLANKE, CHARLES D." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 8/1/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 663307 NCI 526434 136873 This is a supplement application for Biomarker Imaging and Quality of Life Studies Funding Program(BIQSFP) funding for the following SWOG Cancer Research studies: S1602 663307 +No NIH Category available Address;Affect;African American;Area;Award;Biomedical Engineering;Bone neoplasms;Breast Cancer Early Detection;Cancer Research Project;Cell Line;Cellular biology;Cities;Clinical;Collaborations;Communities;Community Health Aides;Community Networks;Community Outreach;Computers;Data;Deuterium Oxide;Development;Drug Delivery Systems;Education;Education and Outreach;Educational process of instructing;Elderly;Engineering;Environment;Ethnic Origin;Funding;Future;Genome Stability;Goals;Grant;Health Disparities Research;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Resources;Image;Immersion;Immunoglobulin Genes;Immunology;Institution;Institutional Policy;Intervention;Label;Latino;Limited English Proficiency;Linguistics;Low income;Malignant Neoplasms;Measures;Mechanics;Medical;Medical Imaging;Memorial Sloan-Kettering Cancer Center;Mentorship;Minority;Modeling;Multilingualism;New York;Obesity;Pilot Projects;Policies;Populations at Risk;Positioning Attribute;Raman Spectrum Analysis;Recording of previous events;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Risk Reduction;Role;Schools;Scientist;Series;Students;Testing;Training;Translational Research;Translations;Underrepresented Minority;United States Health Resources and Services Administration;Universities;Woman;anticancer research;cancer care;cancer cell;cancer clinical trial;cancer education;cancer health disparity;cancer risk;cancer subtypes;career;clinical care;college;colorectal cancer screening;community engaged research;computer science;disparity reduction;economic determinant;education research;experience;health disparity;high risk;improved;innovation;interest;low socioeconomic status;medical schools;medically underserved;molecular imaging;multiphoton microscopy;outreach;pedagogy;post-doctoral training;programs;screening;socioeconomics;student retention;success;translational cancer research;translational medicine;triple negative cancer;tumor;underrepresented minority student;underserved community;working group 1/2 CCNY-MSKCC Partnership for Cancer Research Education and Community Outreach NarrativeThis proposal describes our plans to continue and enhance the City College of New York - Memorial SloanKettering Cancer Center Partnership for Cancer Research Education and Community Outreach. The CCNY-MSKCC Partnership is a mutually beneficial cross-institutional collaboration that has promoted translationalresearch created an education pipeline for minority and low-income students to advance in cancer researchcareers and has established community networks and resources for conducting culturally-responsivecommunity engaged research among diverse at-risk populations in the New York area. NCI 10893172 9/12/23 0:00 PAR-18-767 3U54CA132378-15S1 3 U54 CA 132378 15 S1 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 1922320 "HUBBARD, KAREN " "AHLES, TIM ALAN; GANY, FRANCESCA M; VUONG, BAO Q" 12 BIOLOGY 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY SCHOOLS OF ARTS AND SCIENCES 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 396416 OD 265075 131341 The CCNY-MSKCC Partnership has successfully created a mutually beneficial cross-institutional collaborationthat has emphasized research across the translational continuum the creation of an education pipeline forattracting minority and low-income students to careers in cancer research and the establishment of communitynetworks and resources for conducting linguistically and culturally-responsive community engaged researchamong diverse at-risk populations. Over the last five years areas of particular strength have been developedincluding: 1) rich collaborations between engineers and computer scientists at CCNY and clinicians and imagingexperts at MSKCC to develop innovative solutions to improve cancer care and 2) sustainable translationalhealth disparities research and activities that directly benefit underserved communities in New York and serveas national models in terms of: a) screening / identification of cancer risk factors that disproportionately affectminorities; b) socioeconomic determinants of access to and successful completion of treatment; and c) policychange. Consistent with these areas of emphases we propose two full projects that focus on: 1) Tumorensemble models to predict tumor dormancy and reactivation and testing how these models perform acrossvarious ethnic cell lines e.g. triple negative tumors that disproportionately affect African American women and2) Characterizing the Role of ATM in Immunoglobulin Gene Diversification and Genome Stability. Two proposedpilot projects include: 1) Raman spectroscopy with heavy water labeling and multiphoton microscopy to allowearly detection of breast cancer subtypes including triple negative cancers and 2) Development of MechanicalInterventions to Enhance Drug Delivery to Bone Tumors. New innovative Partnership components include: 1)development of the Linguistic and Cultural Responsiveness Shared Resource Core; 2) formation of theEngineering Health Disparities working group; and 3) new educational programs including the Scholars for theFuture program and the Certificate for Medical Translation and Interpretation. The Partnership specific aims areto: 1) Continue to develop outstanding cancer research programs in health disparities biomedicalengineering computer science / medical imaging cancer cell biology and immunology along theTranslational Research Continuum; 2) collaborate with diverse communities to conduct and facilitate trailblazingcancer disparities research and outreach education risk reduction and navigation activities to define andaddress cancer disparities with the goal of improving cancer care in the large medically underserved local andnational communities; 3) continue to develop and expand educational opportunities in a robust translationalcancer research environment to attract and retain students interested in cancer research (particularly minorityand low income students); these opportunities will be enhanced by educational opportunities and increasedmentorship and support; and 4) expand and integrate the personnel resources and environment needed forscientific collaboration across institutions and influence institutional policies in support of this objective. 396416 +No NIH Category available 1 year old;Acceleration;Acute Myelocytic Leukemia;Adolescent;Brain Stem Glioma;Canada;Cancer Center;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Trials;Clinical Trials Design;Collection;Complication;Country;Development;Diagnosis;Disease;Eligibility Determination;Enrollment;Family;Foundations;Functional disorder;Hormonal;Immunotherapy;Institution;Interdisciplinary Study;Laboratories;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Mission;Molecular;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;Organ;Outcome;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Prognosis;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Tissues;Universities;Work;anticancer research;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;novel therapeutic intervention;operation;reproductive;small molecule;translational study NCTN BIQSFP ANBL1531 (NRT) PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcomes for all children with cancer. NCI 10892605 8/31/23 0:00 PA-20-272 3U10CA180886-10S3 3 U10 CA 180886 10 S3 "MOONEY, MARGARET M" 3/1/23 0:00 2/29/24 0:00 10871228 "HAWKINS, DOUGLAS S." Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 1619532 NCI 1579500 40032 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhoodcancers many of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a numberof childhood cancers however has been limited with approximately 50% of children with acute myelogenousleukemia 50% of children with high-risk neuroblastoma and more than 90% of children with brainstem gliomastill succumbing to their disease. In the US cancer remains the leading cause of death from disease in childrengreater than one year of age. Moreover the late effects of cancer treatment including permanent organ andtissue damage hormonal and reproductive dysfunction and second cancers are of special concern with morethan 40% of the 500000 survivors of childhood cancer (estimated as of 2020) experiencing a significant healthrelated quality of life complication from childhood cancer and its treatment. Thus despite our advancesdevelopment of new therapeutic approaches must be a priority for childhood cancer basic translational andclinical researchers. The Childrens Oncology Group (COG) the worlds largest organization devotedexclusively to childhood and adolescent cancer research was founded 20 years ago. The COGsmultidisciplinary research team comprised of more than 9000 members conducts research at more than 220leading childrens hospitals universities and cancer centers. This proposal is for COG as part of the NationalCancer Institutes (NCI) National Clinical Trials Network (NCTN) to continue its collaborative research workthat supports the mission of improving the outcome for all children with cancer. The COG will design andconduct clinical-translational studies for children with cancer that builds on an increasing understanding of themolecular basis for pediatric malignancies and has the highest potential to improve the outcome. Usinginnovative clinical trial designs suitable for the study of rare diseases we will study novel therapeuticapproaches including but not limited to targeted small molecule drugs immunotherapies and cellular therapies.The COG research portfolio importantly also includes clinical trials focused on improving the quality of life forchildren with cancer and childhood cancer survivors. As more than 90% of children diagnosed with cancer inthe US are treated at COG member institutions COG has the ability to offer a diverse population of childrenwith cancer and their families the opportunity to participate in innovative research. This research effort includesallowing for collection and annotation of biospecimens from all children with cancer providing the foundationfor discovery and accelerating the most promising research efforts conducted in laboratories around the world.The proposal is for support of the COG Network Operations Center clinician-scientists who develop andconduct research and for member sites to participate through enrollment of eligible subjects. 1619532 +No NIH Category available Acceleration;Address;Administrative Supplement;Adolescent;Adolescent and Young Adult;Adult Children;Advisory Committees;Africa;African;African American;African American population;African ancestry;Age;Amerindian;Anus;Artificial Intelligence;Artificial Intelligence platform;Asian;Attitude;Award;Behavior;Belief;Black church;Cancer Center;Catchment Area;Cervical;Cervical Cancer Screening;Cervix Uteri;Child;Chinese;Chinese American;Clinic;Collaborations;Communication;Communities;Community Health;Community Health Aides;Consent;County;Data;Development;Education;Educational Materials;Effectiveness;Elements;Ethiopian;Evaluation;Family;Female;Female Adolescents;Feminization;Focus Groups;Goals;Health;Health Educators;Hispanic;Hispanic Populations;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Imagery;Immigrant;Immigrant community;Indigenous;Individual;Infection;Knowledge;Language;Latin America;Latina Population;Latino;Latino Population;Life;Los Angeles;Male Adolescents;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Media Campaign;Medical;Medical Records;Misinformation;Monitor;Multicultural Education;Multimedia;Nigerian;Oropharyngeal;Outcome;Parents;Participant;Population;Reporting;Research;Resistance;Resources;Safety;Services;Sex Bias;Site;Surveys;Technology;Testing;Time;Training;Translation Process;Trees;United States;University of Southern California Norris Cancer Center;Vaccination;Vaccines;Vagina;Vision;Vulva;Work;Youth;artist;boys;cancer education;cancer health disparity;disparity reduction;evidence base;health inequalities;health literacy;improved;low health literacy;male;men;penis;recruit;side effect;social media;tribal community;vaccine acceptance;vaccine hesitancy;vulnerable adolescent;vulnerable community;young adult Es Tiempo/Its Time: A Multi-Channel Multi-Cultural Communication Campaign for Improvements in Education and Outcomes on Human Papilloma Virus Vaccinations and HPV Related Cancers in Vulnerable popula Project NarrativeDespite tremendous progress in reductions in cancer with the Human Papilloma Virus (HPV) vaccine HPV-related infections in vulnerable communities and vaccine initiation still lag contributing to pervasive cancerdisparities. The ET-MICEO HPV campaign will reduce disparities by enhancing knowledge on HPV-relatedcancers and promoting initiation of the HPV vaccine among adolescents and young adult males and females inthe Hispanic/Latino Chinese and African Americans/African immigrant communities. NCI 10892597 9/18/23 0:00 PA-20-272 3P30CA014089-47S2 3 P30 CA 14089 47 S2 "HE, MIN" 12/1/96 0:00 11/30/26 0:00 1875698 "LERMAN, CARYN " Not Applicable 37 INTERNAL MEDICINE/MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 397 Research Centers 2023 199418 NCI 120494 78924 AbstractAlthough much progress has been made with the Human Papilloma Virus (HPV) vaccine still some communitieslag in HPV vaccination rates. Reasons for this vary. HPV vaccination is lowest amongHispanic/Latinos/Latinas(H/L) Asian adolescent boys and H/L adolescent girls of non-US-born parents and foradolescents of African immigrant parents living in the U.S. These include indigenous groups from Latin America(Amerindians) and Africa (Ethiopians Nigerians Senegalese) In Los Angeles. LA data show one-fifth of parentsfrom H/L African ancestry and Chinese American families (n = 357) high HPV vaccine resistance and over 50%worried about safety or side effects. Research showslow health literacy on HPV related factors vaccinemisconceptions are important factors contributing to low vaccine uptake in these groups.Further though HPV isnot gender-specific the feminization of HPV with a focus on cervical cancer has been impacted by its sexualtransmissibility; and this in turn has influenced the acceptance of HPV related information and its applicationamong boys and men especially lacking has been information on other HPV related cancers and culturallytailored age appropriate and in language materials for immigrant origin groups. The USC Norris ComprehensiveCancer Center (USC NCCC) proposes to work on Track 1 (youth and adolescents) to develop and test acommunication campaign with culturally and age-tailored educational materials on HPV related cancers andpromote initiation of the HPV Vaccine among both male and female adolescent/young adults (10-30ys) in theHL Chinese and African American/African-origin immigrant communities. We will collaborate with communitypartners Barrio Action Youth Center Celebrate Life Black Churches Ministry Vision y Compromiso and 7 localFQHC clinics part of Clinicas Monsenor Oscar Romero and the Chinatown Service Center (CSC) and Vision yCompromiso (promotores de salud). Leveraging USC NCCC Cancer Center COE resources and informed byfindings from our previous administrative supplement (Tsui/Baezconde-Garbanati) we will extend our reach toboth male and female vulnerable adolescents/young adults (AYA) in diverse audiences. Both quantitative (preand post campaign) and qualitative data from listening sessions and focus groups will support development ofcampaign elements and its evaluation. Cultural experts and age-appropriate experts (including adolescents) ourCommunity Advisory Committee and partners will support campaign development. We will use ArtificialIntelligence (AI) technology/platforms to produce age and culturally appropriate educational materials inlanguage. Proof of vaccinations will be via medical records review and reports by our FQHC clinics regardingconsented participants. Community partners will help identify train and establish a community workforcecomposed of community health educators and promotores de salud for dissemination. 199418 +No NIH Category available Award;California;Cancer Center;Cancer Center Support Grant;Child;Computational Biology;Development;Development Plans;Din Nation;Educational workshop;Elements;Faculty;Fostering;Funding;Geography;Goals;Grant;Grant Review;Guam;Health Disparities Research;Hispanic-serving Institution;Historically Black Colleges and Universities;Institution;Leadership;Malignant Neoplasms;Mentors;Minority-Serving Institution;Monitor;New Mexico;Pacific Islander;Pathway interactions;Positioning Attribute;Postdoctoral Fellow;Productivity;Recording of previous events;Research;Research Personnel;Scholarship;Stimulus;Training;Training Programs;Travel;United States National Institutes of Health;Universities;Washington;Work;Writing;anticancer research;cancer health disparity;career;career development;career preparation;college;ethnic minority;experience;geographic disparity;interest;job market;member;outreach;parent grant;programs;racial minority;symposium;tribal college;undergraduate student;virtual group CCSG Supplement: To Strengthen the Research Training and Outreach Capacity NarrativeThis supplement supports enhanced partnerships between the Fred Hutchinson/University ofWashington/Seattle Childrens Cancer Consortium and Minority-Serving Institutions in order todiversify the cancer research workforce and expand capacity to conduct cancer disparitiesresearch. NCI 10892587 9/14/23 0:00 PA-20-272 3P30CA015704-48S3 3 P30 CA 15704 48 S3 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 397 Research Centers 2023 199691 NCI 113461 86230 AbstractThe Fred Hutchinson/University of Washington/Seattle Childrens Cancer Consortium is deeplycommitted to increasing the diversity of the cancer research workforce. Central to our efforts isenhancing our existing partnerships with Minority-Serving Institutions (MSIs) as well asdeveloping new partnerships. Summer undergraduate training programs currently exist betweenour cancer center and Morehouse College (a HBCU) Spelman College (a HBCU) and NewMexico State University (a Hispanic-Serving Institution). Additionally we have experienceidentifying and supporting the career development of scholars and early-stage investigatorsthroughout the west coast through our 10+ year history leading our regions NCI-funded Centerto Reduce Cancer Disparities (CRCHD) Geographic Management of Cancer Health DisparitiesProgram (GMaP). In particular our current 2-year GMaP cycle directly engaged with 83potential CURE scholars and supported them by providing annual career developmentworkshops expert grant reviews research stimulus awards and conference travel awards.Thus we are ideally positioned to execute this supplement and achieve each of the followingspecific aims:Aim 1: Identify URM trainees and ESIs through our cancer centers Minority Serving Institution (MSI) partners and engage them in the NCI/NIH-supported scholar pathway programs with an emphasis on those interested in cancer health disparities research.Aim 2: Provide robust and comprehensive support for the career development of URM trainees and ESIs by providing career development workshops tailored to their specific needs 1:1 support for grant writing through leveraging our team of Training Navigators (TNs) and awarding travel scholarships.Aim 3: Track and monitor the progress and productivity of newly identified URM scholars and develop tailored strategies to support each of their longer-term career developmentplans.A critical element of our program is our cadre of 8 Training Navigators who are faculty at ourcancer center and all of whom themselves are underrepresented racial and ethnic minoritiesbased on the NIH definition. Our aims will be completed through partnering with a total of 8MSIs including five that we have existing collaborative programs/relationships with (MorehouseCollege New Mexico State University Spelman College the University of California Irvine andthe University of Guam) and three that are new partnerships (Clark Atlanta University DinCollege and Stillman College). Of note these institutions include a mix of four HBCUs twoHispanic-Serving Institutions one Tribal College and two Pacific Islander-Serving Institutions. 199691 +No NIH Category available Address;African American;American Indians;Applications Grants;Area;Black race;Cancer Center;Cancer Center Support Grant;Cancer health equity;Career Mobility;Catchment Area;Clinical;Clinical Trials;Colon Carcinoma;Dedications;Ecosystem;Ensure;Face;Faculty;Funding;Goals;Grant;Growth;Health;Health Disparities Research;Health Technology;Incidence;Individual;Infrastructure;Institution;Intervention;Investments;Knowledge;Leadership;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of pancreas;Mentors;Mentorship;Methods;Minority;Minority Groups;Mission;Monitor;NCI-Designated Cancer Center;Occupations;Oklahoma;Oncology;Pathway interactions;Play;Positioning Attribute;Preparation;Productivity;Professional Organizations;Publications;Reporting;Research;Research Peer Review;Research Personnel;Role;Rural Population;Science;Site;Talents;Therapeutic;Training;Translating;Tribes;United States National Institutes of Health;Universities;Vision;Vulnerable Populations;Writing;anticancer research;cancer care;cancer health disparity;cancer prevention;career;career development;community organizations;community setting;diversity and equity;empowerment;experience;improved;improved outcome;innovation;insight;interest;mHealth;member;morphogens;mortality;multidisciplinary;novel;organizational climate;patient oriented;programs;prospective;recruit;research and development;retention rate;satisfaction;skills;social health determinants;tobacco control;underserved minority D.R.I.V.E: Developing Research Initiatives through Versatile Oncology Exploration OVERALL: PROJECT NARRATIVEThe OU Stephenson Cancer Center fulfills a unique need in Oklahoma and the region by conducting innovativeand impactful research that seeks to translate novel discoveries into the clinical or community setting through atransdisciplinary team-based approach. The goal of these efforts is to decrease cancer incidence and improveoutcomes for Oklahomans and all individuals with a special emphasis on promoting cancer health equityamong the states underserved minority populations. NCI 10892498 9/1/23 0:00 PA-20-272 3P30CA225520-06S3 3 P30 CA 225520 6 S3 "SHAFIK, HASNAA" 5/8/23 0:00 4/30/28 0:00 2488117 "MANNEL, ROBERT S." Not Applicable 5 OBSTETRICS & GYNECOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 5/8/23 0:00 4/30/24 0:00 397 Research Centers 2023 193978 NCI 133778 60200 OVERALL: ABSTRACTSince achieving NCI designation in 2018 the Stephenson Cancer Center (SCC) at the University of Oklahomahas continued to grow and mature as an organization. The SCCs vision to eliminate cancer in Oklahoma andbeyond is advanced through its mission to provide patient-centered research-driven multidisciplinary cancercare to all Oklahomans. As Oklahomas only NCI-designated cancer center the SCC serves a statewidecatchment area that presents unique challenges with social determinants of health and high disparities incancer incidence and mortality especially for the states American Indian (AI) Black/African American andrural populations. The SCC has the ability to be impactful in its catchment area and nationally due tostrategically targeted recruitments and investments that have leveraged key differentiating factors: 1) the SCCcontinues to invest in creating and sustaining health and research partnerships with AI tribal partnersthroughout Oklahoma and currently has 22 NIH funded projects addressing AI cancer disparities; 2) the SCCcontinues to be a national leader in the NCI/NCTN and has established a statewide network of affiliate sites toensure access to NCI-sponsored clinical trials throughout its catchment area; 3) the SCC has developed strongteam-based research across all of its programs with national leadership in gynecologic colon and pancreaticcancers cancer prevention cancer therapeutics gero-oncology and tobacco control; and 4) the SCC isbuilding upon its national leadership in mobile health technologies to address the burden on cancer in rural andvulnerable populations.Multiple NCI CCSG metrics emphasize the growth and maturation of the SCC during the reporting period(2017-21). SCC membership increased from 83 to 120 (45%) with 31 of these new members being externallyrecruited to add expertise to programs. Annual peer-reviewed research funding (DC) grew 61% ($14.28M $22.97M) and total annual research funding grew 42% ($30.13M $43.09M). The overall five-year number ofscientific publications has increased by 54% since the last reporting period (945 1454) with 16% having animpact factor 10 (up from 7%). Team science has been emphasized resulting in 139 collaborative grants(36% increase) and a 17% inter-programmatic publication rate (up from 4%) over the prior reporting period.The number of annual active interventional IITs has doubled from 20 to 40 over the past five years with annualaccruals to interventional IITs increasing from 661 (2017) to 927 (2021) a 40% increase. This degree ofimpactful growth has been possible due to the infrastructure made available through the CCSG and haspositioned the SCC for a successful renewal as a NCI-designated cancer center. 193978 +No NIH Category available Acceleration;Address;Adult;American Indians;Arapaho;Area;Cancer Etiology;Catchment Area;Cessation of life;Cheyenne;Clinic;Colorectal Cancer;Communication;Communities;Cues;Decision Making;Early Diagnosis;Education;Eligibility Determination;Face;Feces;Feeling;Florida;Focus Groups;Future;Health;Health Educators;Health care facility;Health education;Healthcare Systems;Home;Incidence;Inequity;Intervention;Knowledge;Life;Link;Morbidity - disease rate;Nature;Oklahoma;Outcome;Participant;Patients;Persons;Phase;Population;Public Health;Race;Randomized;Randomized Controlled Trials;Recommendation;Rural Community;Rural Minority;Screening for cancer;Self Determination;Services;Source;Surveys;Symptoms;Technology;Testing;Text;Tribes;Trust;United States;United States Indian Health Service;United States Preventative Services Task Force;Woman;aged;clinical trial enrollment;colorectal cancer screening;comparison intervention;efficacy evaluation;empowerment;follow-up;health literacy;implementation science;improved;innovation;insight;interest;member;men;minority patient;mortality;novel;post intervention;preference;primary outcome;programs;racial minority;screening;screening disparities;screening guidelines;screening services;social media;success;three-dimensional modeling;tribal Nation;tribal community;tribal healthcare;virtual;virtual human Feasibility of a Multi-Channel Intervention to Promote Colorectal Cancer Screening among American Indians in Oklahoma PROJECT NARRATIVEAmerican Indians in Oklahoma endure a disproportionate burden of colorectal cancer incidence and colorectalcancer-specific mortality which is partly explained by poor rates of colorectal cancer screening. The proposedstudy aims to co-develop and disseminate a multi-channel communication intervention that uses virtual humantechnology to create and deliver a virtual Tribal community health educator. This study offers a substantialpublic health impact to reduce avoidable CRC morbidity and mortality among American Indians and willprovide valuable insight on how to scale culturally sensitive multi-channel communication interventions acrossour Tribal partners in Oklahoma. NCI 10892482 9/18/23 0:00 PA-20-272 3P30CA225520-06S5 3 P30 CA 225520 6 S5 "SHAFIK, HASNAA" 5/1/18 0:00 4/30/28 0:00 2488117 "MANNEL, ROBERT S." Not Applicable 5 OBSTETRICS & GYNECOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 9/16/23 0:00 4/30/24 0:00 397 Research Centers 2023 199944 NCI 142547 57397 PROJECT SUMMARYColorectal cancer (CRC) is the second-leading cause of cancer death in both men and women in the UnitedStates. Compared to national averages American Indians (AI) endure a disproportionate burden of CRCincidence and CRC-specific mortality. Screening is an effective early detection strategy to decrease preventableCRC-related deaths but AI have some of the lowest CRC screening rates. In Oklahoma only 51% of AI are upto date with screening compared to nearly two-thirds of eligible US adults. Efforts to improve screening rateshave focused on increasing access to home stool screening (i.e.. fecal immunochemical test; FIT) as many AIlive in rural communities and must drive long distances to access screening services. Tribal community healtheducators (TCHE) are an effective strategy to promote FIT screening within AI communities as they canovercome historical mistrust health literacy gaps and provide culturally concordant educational messaging.However success of TCHE is limited by their reach as they cannot logistically engage with all necessary AIcommunities. Virtual human technology which can create photorealistic interactive virtual TCHE (v-TCHE) offera scalable strategy to overcome the logistical barriers inherent with in-person delivered health education.Therefore the overall objective of this proposal is to leverage existing relationships with Indian Health ServiceClinton Service Unit and the Cheyenne and Arapaho Tribes to examine the feasibility of co-developing anddisseminating a v-TCHE as part of a multi-channel communication intervention. The intervention will bedisseminated across two channels: (1) Social Media (i.e. accessed via online study adverts) and (2) Clinic (i.e.direct messaging to patients via a study link in a SMS text). Across both channels we will examine reach (primaryoutcome) of the intervention and its potential efficacy (on improving CRC knowledge and completing a FIT kit)via a randomized controlled trial. Once participants click on the study link they will be randomized 1:1 to one oftwo intervention conditions: (1) watch a Narrative Testimonial Video of a real-life Tribal community healtheducator (control) or (2) an interaction with a v-TCHE. Participants will then complete a post-intervention surveyin which they can click to order a FIT kit afterwards. The first study aim will co-develop a multi-channelcommunication intervention with AI in Oklahoma. The second study aim will determine its reach and potentialefficacy. This proposal is highly responsive to Track 2 in the PA-20-272 as it attempts to address inequities inCRC outcomes among AI populations. We examine the feasibility of co-developing and disseminating a multi-channel communication intervention to promote a United States Preventive Services Taskforce recommendedcancer screening test. If successful findings will support a first-of-its-kind highly scalable approach to overcomethe reach limitations that Tribal community health educators face. A future R01 will determine the efficacy ofdifferent v-TCHE to promote FIT screening across other Tribal healthcare systems. 199944 +No NIH Category available Address;Attitude;Awareness;Behavior;Cancer Center;Communication;Communities;Community Health;Community Health Education;Community Outreach;Comprehensive Cancer Center;Film;Goals;Health;Health education;Imagery;Indigenous;Knowledge;Malignant Neoplasms;Modeling;NCI-Designated Cancer Center;Native-Born;Prevention;Resources;Screening for cancer;Series;Surveys;System;Transportation;cancer health disparity;cancer prevention;community based practice;community engagement;digital media;digital repositories;health communication;indigenous community;intertribal;outreach;population health;screening;service delivery;social media;tribal community Films for Indigenous Cancer Health: Roswell Park Comprehensive Cancer Center Indigenous Nations and Health Communications Project NarrativeCancer health education rely on digital media to inform. To address cancer disparities among Indigenouspopulations health films were co-created between a cancer center health communications team and Indigenousinfluencers to increase cancer-based awareness. NCI 10892472 9/15/23 0:00 PA-20-272 3P30CA016056-46S2 3 P30 CA 16056 46 S2 "HE, MIN" 6/16/97 0:00 4/30/24 0:00 1894074 "JOHNSON, CANDACE S." Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 397 Research Centers 2023 200000 NCI 116482 83518 Project Summary/AbstractCancer and health-related community outreach and education efforts progressively rely on digital media to reachand inform important target audiences. To address cancer disparities among Indigenous populations the aim ofthis project creates a series of health communication films with social media influencers and Indigenous iconsfor use in community-based health centers and is guided by the Transportation-Imagery Model of NarrativeCommunication. The project will integrate community-based practice prevention messaging cancer screeninginformation to increase cancer-based knowledge intent and behaviors among Indigenous communities. Thiswill be accomplished by collaborative efforts from an NCI-designated cancer centers Department of IndigenousCancer Health Community Outreach and Engagement and Health Communications Resources alongsideIndigenous media networks and community-based film companies. Objectives include film creation hostingscreenings panel discussions and the embedment of films into the cancer centers Indigenous outreachengagement and prevention digital repository. Evaluative efforts include co-produced films guided by an inter-tribal community advisory board pre-post surveys on knowledge attitude cancer prevention and screeningbehaviors. The long-term goal is the continuance of community outreach for Indigenous communities Indigenousurban centers with sustainable integration into Indigenous services delivery systems Overall results areexpected to increase community-based collaborative efforts through health messaging. 200000 +No NIH Category available Address;Award;Basic Science;Biological Markers;Cancer Biology;Cancer Burden;Cancer Center;Cancer Control;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Development;Direct Costs;Early Diagnosis;Education;Environment;Fostering;Funding;Health care facility;Healthcare;Intervention;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medical center;Medicine;Mission;Modeling;NCI-Designated Cancer Center;Names;Nebraska;Organoids;Patients;Pharmaceutical Chemistry;Physicians;Population Sciences;Positioning Attribute;Prevention;Prognosis;Reporting;Research;Research Infrastructure;Research Peer Review;Research Support;Resource Sharing;Resources;Risk;Role;Scientific Advances and Accomplishments;Synthesis Chemistry;Teacher Professional Development;Tissue Microarray;Training;Training and Education;Translational Research;Universities;anticancer research;cancer care;cancer education;cancer health disparity;cancer initiation;clinical care;community engagement;computational chemistry;health disparity;innovation;interdisciplinary collaboration;member;metabolomics;multidisciplinary;novel therapeutic intervention;outreach;patient oriented;preclinical imaging;programs;recruit;research facility;translational cancer research;tumor progression;underserved community Buffett Cancer Center Supplement to Strengthen Research Training and Outreach PROJECT NARRATIVEThe Fred & Pamela Buffett Cancer Center (BCC) the only NCI-designated cancer center in Nebraska is a matrixcancer center at the University of Nebraska Medical Center and our affiliated healthcare network NebraskaMedicine. The Mission of the BCC is to promote innovative translational cancer research excellence in cancereducation and training and outstanding patient-centered cancer care and to reduce the burden of cancer andcancer health disparities across Nebraska and beyond. NCI 10892347 9/20/23 0:00 PA-20-272 3P30CA036727-37S4 3 P30 CA 36727 37 S4 "BELIN, PRECILLA L" 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 2401856 "COWAN, KENNETH H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 200000 NCI 130293 69707 PROJECT SUMMARYThe Fred & Pamela Buffett Cancer Center (Buffett Cancer Center or BCC) an NCI-designated Cancer Centersince 1984 is committed to basic translational clinical and population science research comprehensiveeducational programs and outreach to underserved communities in our catchment area (Nebraska). The newBCC integrated cancer research and care facility increased Cancer Center-controlled research space 1.7-fold(total 400000 sq ft) creating an environment which fosters scientific innovation and transdisciplinarycollaborations. The Cancer Center is fully integrated into the university and its affiliated healthcare networkNebraska Medicine (NM) with the Director reporting directly to the UNMC Chancellor and CEO NM andappointed BCC Physician-in-Chief. Two Cancer Center leadership positions were established since the lastreview Deputy Director and Associate Director for Community Outreach and Engagement (COE) with the latterleading efforts to reduce cancer burden and disparities in diverse communities across Nebraska. The BCC alsoappointed four new senior leaders and eliminated dual leadership roles to promote clinical and translationalresearch. The centralization expansion and reorganization of the BCC Clinical Trials Office was completed anda new CTMS (OnCore) installed culminating in a 1.8-fold increase in accrual to interventional clinical trials.Research infrastructure was enhanced by the addition of a new Preclinical Imaging Shared Resource as well asseveral new resources (e.g. Metabolomics Organoids Patient-Derived Models Tissue Microarrays Syntheticand Medicinal Chemistry and Computational Chemistry). The BCC has three Research Programs: CancerBiology Program (CBP); Targets Modulators and Delivery Program (TMDP); and GI Cancer Program (GICP).Two programs CBP and TMDP changed names reflecting the strategic realignment of their missions themesand memberships. With 28 Members recruited during the current funding period the BCC has a robust trackrecord of clinical and translational research supported by 14 multidisciplinary awards (P01 P50 P20s U awards;6 from NCI) and 16 new MPI awards (11 from NCI). Cancer-relevant peer-reviewed research funding in the BCCincreased 1.4-fold to $25.3M (Annual Direct Costs) and NCI funding increased 1.3-fold to $12.5 M (Annual DirectCosts) since our last review. 200000 +No NIH Category available Address;Administrative Supplement;Award;Awareness;Behavioral Sciences;California;Cancer Center;Cancer Center Support Grant;Caring;Catchment Area;Development;Diverse Workforce;Education;Educational workshop;Evaluation;Exhibits;Florida;Funding;Goals;Grant;Health;Hybrids;Individual;Learning;Malignant Neoplasms;Measures;Mentorship;Mission;Monitor;Online Systems;Outcome;Pathway interactions;Postdoctoral Fellow;Preparation;Productivity;Public Health;Publications;Research Personnel;Research Training;Series;System;Training;Underrepresented Minority;United States National Institutes of Health;Universities;Work;Writing;anticancer research;cancer health disparity;career development;education research;health equity;improved;innovation;minority disparity;minority trainee;minority undergraduate;next generation;pre-doctoral;programs;recruit;success;symposium UF Health Cancer Center Support Grant - Training Navigator Supplement The proposed Administrative Supplement application is relevant to public health because it focuses onimproving the inclusive recruitment engagement education training and development of the next generationof cancer researchers who are Underrepresented Minorities (URM). Implementing a Training Navigation Teamat the University of Florida Health Cancer Center will facilitate the entry of URM into the cancer researchtraining pipeline and prepare trainees and ESIs to pursue career development opportunities. Thus theproposed application is relevant to the part of NCI's mission that pertains to supporting targeted cancerresearch training for individuals from backgrounds underrepresented in the biomedical and behavioral sciencesto achieve and sustain a diverse workforce. NCI 10892335 9/15/23 0:00 PA-20-272 3P30CA247796-01A1S1 3 P30 CA 247796 1 A1S1 "ROBERSON, SONYA" 6/1/23 0:00 5/31/24 0:00 1900296 "LICHT, JONATHAN D." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 195882 NCI 128447 67435 The University of Florida Health Cancer Center (UFHCC) recognizes that achieving health equity requiresinclusive education training recruitment retention and promotion of the next generation of cancer researchers.Therefore this Administrative Supplement application aims to recruit and develop a cadre of independentresearchers prepared to address cancer disparities in our catchment area. This supplement will enhance thesynergistic impact of CaRTEC DEI and the Florida-California Cancer Research Education and Engagement(CaRE2) Health Equity Center by focusing on developing underrepresented minority (URM) pre-doc post-docand early-stage investigators (ESIs). To expand upon the success of CaRTEC and CaRE2 and achieve theirlong-term goal of improving training outcomes of URM trainees and ESIs a Training Navigator Team (TNT) willbe implemented to 1) bridge activities between CaRTEC DEI and CaRE2 programs at the UFHCC; 2) facilitatethe entry of URM into the cancer research training pipeline; and 3) prepare trainees and ESIs to pursue careerdevelopment opportunities provided by the Center to Reduce Cancer Health Disparities CURE program andbeyond. This collaborative effort seeks to build upon the successes of each program through the followingobjectives: 1) implement a TNT to attract recruit and support competitive underrepresented trainees and ESIsand facilitate their entry into NIH-supported pathway programs at the UFHCC and the attainment of NCI funding;2) provide professional preparation and networking opportunities for scholars through grant writing and technicalassistance workshops (TAWs); and 3) monitor track and evaluate the progress and productivity of trainees andESIs. In particular the TNT will help recruit URM trainees regionally from partnering MSIs as well as nationalconferences to exhibit the work of minoritized undergraduate researchers. In addition a series of 5 trainingassistance workshops (TAWs) will be developed to prepare trainees and ESIs to pursue CURE funding. AllTAWs will be recorded and content will be used to develop an innovative hybrid and asynchronous course thatwill be offered through the University's web-based learning management system. Metrics will be tracked on newcancer-relevant awards and publications proposals and supplements submitted and the corresponding fundingrate and mentorship activities for trainees. Evaluations using the CPACHE U54 Research Education SharedMeasures Toolkit will also determine the impact of proposed activities on funding and career development. Thisapplication is significant because it will increase the number of URM trainees at the UFHCC increase theawareness around URM- and cancer disparities-relevant funding and improve the capacity for URM UFHCCtrainees to pursue external funding. This program will be impactful because it will help recruit >15 post-bacspre-docs post-docs and fellows and will engage >40 pre-docs post-docs fellows and ESIs in TAWs who willsubmit a total of 10 CURE-supported applications in 2023-2024. 195882 +No NIH Category available Amendment;Cancer Therapy Evaluation Program;Cancer Trials Support Unit;Clinical Trials;Communication;Contractor;Contracts;Goals;Letters;Process;Protocols documentation;Research Personnel;Standardization;Time;Writing;clinical development;programs TASK ORDER 5A: CENTRALIZED PROTOCOL WRITING SUPPORT; CONTRACT TITLE: CANCER TRIALS SUPPORT UNIT CTSU. n/a NCI 10892009 75N91022D00014-P00004-759102200001-2 N01 8/1/22 0:00 7/31/24 0:00 78802111 "CARAVOULIAS, CHRISTINA " Not Applicable 8 Unavailable 57052391 FAA2LVENETH4 57052391 FAA2LVENETH4 US 39.02704 -77.126432 1603501 "TECHNICAL RESOURCES INTERNATIONAL, INC." BETHESDA MD Domestic For-Profits 208171197 UNITED STATES N R and D Contracts 2023 700005 NCI The Contractor shall reduce the administrative burden of protocol writing for investigators by establishing implementing and maintaining a CTEP Centralized Protocol Writing Support (CPWS) program which shall include but is not limited to processes for standardized communication document writing and tracking to streamline the development of clinical trials. The contractor shall provide standardized centralized Protocol ICD writing support to select studies as directed by CTEP from Letter of Intent (LOI) approval through initial Protocol approval. This task order would also cover potential amendments after approval of the COR. The goals are to reduce the time from LOI approval to protocol approval and to minimize the number of protocol revisions to less than two. 700005 +No NIH Category available Administrative Supplement;Advanced Development;Affinity;Awareness;Cancer Center;Cancer Center Support Grant;Career Mobility;Climate;Clinical Sciences;Collaborations;Data;Development;Education;Educational workshop;Ensure;Exposure to;Fostering;Geography;Goals;Grant;Health Disparities Research;Individual;Inequity;Infrastructure;Institution;Intention;Interview;Malignant Neoplasms;Medicine;Mentors;Mentorship;Minority-Serving Institution;Monitor;Outcome;Patient-Focused Outcomes;Population;Postdoctoral Fellow;Preparation;Process;Research;Research Personnel;Research Support;Resources;Services;Surveys;Training;Training and Education;Translational Research;Travel;Woman;Work;Writing;anticancer research;cancer health disparity;career;career development;community engaged research;community engagement;equity diversity and inclusion;graduate school;health disparity;improved;innovation;interest;member;outreach;primary outcome;programs;recruit;response;success;tool Cancer Center Support Grant Project NarrativeSiteman Cancer Center (SCC) is committed to overcoming structural barriers that have limited diversity inacademic medicine and the cancer research workforce. The overarching goal of the SCC initiative toStrengthen Research Training and Outreach Capacity is to provide personalized trainee navigation to cancerresearch supports. SCC staff will collaborate to implement infrastructure and processes that increase: traineeawareness and use of shared cores and resources appropriate to their interests; identification of mentorshealth disparities and community engaged research opportunities; and grant writing scientific editing andtravel supports to advance the career development and trajectory of SCC trainees. NCI 10891963 9/14/23 0:00 PA-20-272 3P30CA091842-22S4 3 P30 CA 91842 22 S4 "ROBERSON, SONYA" 8/2/01 0:00 6/30/25 0:00 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 198993 NCI 127970 71023 Project SummaryInstitutional efforts are required to achieve the level of diversity equity and inclusion that will ensurerecruitment and advancement of individuals now underrepresented in academic medicine. Siteman CancerCenter (SCC) is committed to overcoming structural barriers that have limited diversity in the cancer researchworkforce. In alignment with the NCI National Cancer Plan Goals 4 and 8 to eliminate inequities and tooptimize the workforce SCC will implement a strategy to support a sustainable Trainee Navigation program.The overarching goal of the SCC proposal is to provide personalized navigation to resources and services thatenhance the career development and trajectory of underrepresented in medicine (URiM) and women trainees.This SCC effort is a collaboration between Cancer Research Training and Education Coordination (CRTEC)and Plan to Enhance Diversity (PED). Importantly CRTEC and PED staff will collaborate to ensure that newand current trainees benefit from navigation support and programming and that all SCC trainees receiveexceptional support during graduate school postdoctoral work and as they transition to the next stage of theircareers. To support trainees particularly URiM and women our primary focus is the development oforganizational infrastructure and processes to implement cancer trainee navigation that promotes resourceaccess and assists in building a climate conducive to persistence. A PED staff member will be trained as anavigator to provide hands-on support to assist scholars with their educational advancement and careerdevelopment activities. Our objectives are to: (1) Identify competitive and promising underrepresented scholarsand investigators through the CRTEC and PED led collaborations with minority serving institutions and(2) Provide professional preparation and networking opportunities for scholars through travel support grantwriting and informational workshops seminars and trainings on cancer and cancer health disparities researchmentorship and affinity groups. The primary outcomes of the SCC Effort to Strengthen the Research Trainingand Outreach Capacity of Trainees initiative are to (1) increase the proportion of URiM and women traineesparticipating in cancer and cancer health disparities research; (2) conduct activities that improve the trainingclimate; (3) increase URiM and women trainee participation in career enhancing activities; increase intention toparticipate in grant writing related to cancer research; and increase in grant submissions from URiM andwomen trainees. 198993 +No NIH Category available Administrative Supplement;Cancer Center Support Grant;Cancer Institute of New Jersey;Healthcare;Malignant Neoplasms;New Jersey;Public Health;Research;Research Personnel;Training;Underrepresented Populations;anticancer research;cancer health disparity;career;outreach Scholars and Early-Stage Investigator Advancement Initiative (SEA) Project NarrativeThe Scholars and Early-Stage Investigator Advancement Initiative (SEA) is relevant to public healthbecause it will develop a more diverse biomedical cancer research and healthcare workforce to reduce cancerhealth disparities in New Jersey and nationally. This project at the Rutgers Cancer Institute of New Jersey willsupport and motivate scholars and Early-Stage Investigators from underrepresented groups to pursue careersin cancer and cancer health disparities. NCI 10891822 9/14/23 0:00 PA-20-272 3P30CA072720-24S2 3 P30 CA 72720 24 S2 "HE, MIN" 3/1/97 0:00 2/29/24 0:00 9845089 "LIBUTTI, STEVEN K." Not Applicable 10 SURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 9/1/23 0:00 2/29/24 0:00 397 Research Centers 2023 200000 NCI 127389 72611 Project Summary/AbstractNot required for submission to Administrative Supplement to Cancer Center Support Grants (P30 CCSGs) toStrengthen the Research Training and Outreach Capacity 200000 +No NIH Category available Address;Administrative Supplement;Adult;Age;Awareness;Behavioral;Breast;COVID-19 impact;COVID-19 pandemic effects;Cancer Center;Cancer Center Support Grant;Catchment Area;Cervical;Characteristics;Collaborations;Colorectal;Communication;Communities;Community Health;Country;Economically Deprived Population;Education and Outreach;Effectiveness;Evaluation;Federally Qualified Health Center;Geography;Goals;Health;Health Educators;Health Service Area;Individual;Intervention;Lung;Malignant Neoplasms;Medical;Michigan;Outcome;Patients;Performance;Population;Positioning Attribute;Prevention;Primary Care;Reporting;Risk Factors;Screening for cancer;Social Marketing;Tobacco use;Underserved Population;Universities;Voice;Work;cancer education;cancer prevention;crowdsourcing;digital;evidence base;implementation tool;improved;innovation;medically underserved;mortality;outreach;pandemic impact;patient engagement;peer;perceived discrimination;population health;programs;recruit;satisfaction;screening;social health determinants;social media;socioeconomic disadvantage;success;tool Administrative Supplements for the NCI P30 Cancer Center Support Grants for Multi-Channel Communication Campaigns for Improvements in Cancer Education and Outcomes (MICEO) in Underserved Populations Project NarrativeThe University of Michigan Rogel Cancer Center and Packard Health (local Federally Qualified Health Centeror FQHC) will partner to develop a community-engaged personally tailored cancer screening and preventiondigital planning tool (CanPlan) to address common misconceptions about cancer prevention and increase ratesof cancer screening (e.g. breast cervical colorectal lung) and tobacco use intervention among adults age 30+who are patients at Packard Health or live in Packard Healths service area. We will promote and evaluateCanPlan engagement and outcomes through multi-channel outreach (Direct-to-patient messaging proactiveCHE outreach health center focused social marketing local community focused social media peer-to-peersnowball recruitment by CanPlan users). The innovative CanPlan program will engage individuals in thecreation of a personalized cancer screening and prevention action plan while 1) Speaking in the voice of CHEs(tailored video) 2) Sharing community and crowdsourced screening and prevention messages andrecognizing and responding to 3) Everyday experience of discrimination 4) Medical mistrust and 5) UnmetSDOH needs. NCI 10891776 9/12/23 0:00 PA-20-272 3P30CA046592-34S1 3 P30 CA 46592 34 S1 "BELIN, PRECILLA L" 6/1/97 0:00 5/31/28 0:00 1870217 "FEARON, ERIC R." Not Applicable 6 INTERNAL MEDICINE/MEDICINE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/12/23 0:00 5/31/24 0:00 397 Research Centers 2023 199992 NCI 128200 71792 Project SummaryThe goal of our project is to address common misperceptions about cancer prevention increase rates ofcancer screenings (e.g. breast cervical colorectal lung) and tobacco use intervention among otherwisemedically underserved adults age 30+ (Track 2). This project builds on our ongoing collaboration with theMichigan Primary Care Association (our state FQHC network) and Packard Health (our local FQHC). Over thepast three years we have worked together on the UM Rogel Cancer Center supported Catch Up on CancerScreening initiative to address the impact of COVID-19 pandemic on cancer screening. While we have hadinitial success in these efforts we have also identified critical needs to increase the effectiveness of populationhealth outreach leverage and magnify the contributions of community health educators (CHEs) and identifyoptimal strategies for patient engagement.We propose to address these critical needs by 1) Developing a community-engaged personally tailored cancerscreening and prevention digital planning tool (CanPlan) 2) Promote CanPlan engagement through multi-channel outreach (Direct-to-patient messaging Proactive CHE outreach Health center focused socialmarketing Local community focused social media Peer-to-peer snowball recruitment). The tailored CanPlanprogram will engage users to create a personally tailored cancer prevention action plan. Innovative features ofthe CanPlan program include 1) Speaking in the voice of CHEs (through tailored video) 2) Incorporation oflocal community and crowdsourced cancer screening and prevention messages and 3) Recognizing andresponding to user reported everyday experience of discrimination medical mistrust and unmet socialdeterminants of health (SDOH) needs.We will evaluate CanPlan implementation (e.g. engagement engagement efficiency user characteristics) andpatient-reported (understanding of cancer prevention key facts behavioral activation program satisfaction)and utilization (e.g. cancer screening) outcomes. Evaluation will address CanPlan performance overall andseparately for each outreach channel. Upon completion of the proposed work we will be in a strong position todisseminate the CanPlan program and guide CanPlan promotion with stakeholders throughout the state andpotentially across the country. 199992 +No NIH Category available Acceleration;Affinity;Aftercare;Antibodies;Benchmarking;Biological;Biological Assay;Biomedical Research;Biopsy Specimen;Clinical;Clinical Trials Network;Communities;Competence;Complex Mixtures;Core Biopsy;Custom;Investigational Therapies;Laboratories;Liquid substance;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Methods;Modeling;Molecular;National Cancer Institute;Patients;Peptides;Pharmacodynamics;Phosphorylation;Post-Translational Protein Processing;Proteins;Proteome;Proteomics;Reagent;Research Institute;Specimen;Standardization;Tissues;Translating;anticancer research;assay development;early phase clinical trial;genome analysis;improved;mass spectrometer;method development;patient derived xenograft model;programs;proteogenomics;repository;translational cancer research;treatment effect;tumor THIS TASK ORDER IS FOR THE PROTEOMIC CHARACTERIZATION LABORATORY. n/a NCI 10890565 75N91019D00024-P00002-759102100010-1 N01 9/25/21 0:00 9/24/26 0:00 78379976 "BOCIK, WILLIAM " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 2120234 NCI The National Cancer Institute (NCI)s Clinical Proteomic Tumor Analysis Consortium (CPTAC) is a national effort to accelerate the understanding of the molecular basis of cancer through the application of large-scale proteome and genome analysis or proteogenomics. NCI supports an Antibody Program operated by Leidos Biomedical Research Inc (Leidos Biomed) that comprehensively characterizes affinity reagents for cancer research via the Leidos Biomed Antibody Characterization Laboratory (ACL) located at the Frederick National Laboratory for Cancer Research (FNLCR) in Frederick MD. Within the Leidos Biomed ACL a Proteome Characterization Laboratory (PCL) was established for comprehensive Mass Spectrometry (MS)-based proteomic characterization (global- and phospho-proteomes) and targeted (fit-for-purpose) assays. This Task Order (TO) aims not only to expand both the number of assays analyzed by the Leidos Biomed PCL but also broadens the capabilities with method development of additional Post Translational Modifications (PTMs) fit for purpose antibodies for application such as iMRM and custom assay development. The Leidos Biomed PCL will develop and implement standardized proteomic measurements (comprehensive and targeted) for projects within CPTAC/DCTD. The Leidos Biomed PCL is equipped with two state-of-art mass spectrometers to provide the best sensitivity and accuracy for protein and peptide analysis and benchmarked for proteomic competency in coordination with CPTAC Proteome Characterization Centers (PCCs). The Leidos Biomed PCL will be available for the NCI research community to enhance translational cancer research with priority given to CPTAC and other DCTD programs. 2120234 +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;Architecture;Attention;Breast;Cancer Center;Certification;Characteristics;Classification;Clinical;Clinical Data;Clinical Trials;Code;Complex;Computer software;Data;Data Element;Data Set;Development;Diagnostic;Ensure;Family;Fostering;Foundations;Goals;Handedness;Histology;Institution;Instruction;International Statistical Classification of Diseases and Related Health Problems Tenth Revision (ICD-10);Knowledge;Label;Language;Language Pathology;Length;Lesion;Link;Location;Malignant Neoplasms;Manuals;Methodology;Methods;Microscopic;Modeling;Natural Language Processing;Nomenclature;Oncology;Pathologist;Pathology;Pathology Report;Performance;Physicians;Play;Population;Process;Prognosis;PubMed;Rare Diseases;Reporting;Research;Resources;Role;SNOMED Clinical Terms;Selection for Treatments;Site;Solid Neoplasm;Source;Stains;Standardization;Stomach;Structure;Supervision;Techniques;Terminology;Testing;Tissue Sample;Training;Variant;Work;anticancer research;cancer prevention;cancer therapy;cancer type;convolutional neural network;cost effective;deep learning;ethnic minority;experience;gender minority;impression;improved;innovation;malignant breast neoplasm;malignant stomach neoplasm;multitask;neoplasm registry;open source;operation;phrases;prognostic;racial minority;rare cancer;research and development;response;risk stratification;screening;statistical and machine learning;success;text searching;transfer learning;tumor;tumor diagnosis;unstructured data;vector Applying Large Language Models to Accelerate Abstraction of Cancer Pathology Reports for Cancer Registry (LLMs for Unstructured Data Extraction) This research aims to train Large Language Models (LLMs) to extract five key oncological data elements frompathology reports focusing on common (breast) cancer and rare (gastric) cancer. Different training methodswill be used for each cancer type utilizing supervised fine-tuning for the common cancer and parameter-efficient inference/tuning for the rare type. The ultimate goal is to develop high-throughput software to improvethe efficiency of cancer registry operations. NCI 10890243 9/7/23 0:00 PA-20-272 3P30CA076292-25S4 3 P30 CA 76292 25 S4 "PTAK, KRZYSZTOF" 2/18/98 0:00 1/31/27 0:00 1877243 "CLEVELAND, JOHN L." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 397 Research Centers 2023 299999 NCI 178041 121958 Pathology reports containing critical information on tissue samples and lesions play a significant role indetermining cancer treatment selection prognosis risk stratification and clinical trial screening. Yet manuallyextracting tumor characteristics from these unstructured or semi-structured reports is a complex laboriousprocess. Recent advances in Natural Language Processing (NLP) via deep learning methodologies showpromising potential. Though Bidirectional Encoder Representations from Transformers (BERT) has achievednotable results in various NLP tasks its application in pathology is constrained due to the limited allowableinput length. Our recent study addressed this by transfer learning a BERT-based model on increasinglycomplex knowledge sources including Wikipedia PubMed MIMIC-III and Moffitt institutional pathologyreports. This language model was further fine-tuned to identify site histology and associated ICD-O-3 codesfrom pathology reports. Despite the promising preliminary results our pilot work focuses on extractivequestion-anwsering of single primary solid tumor diagnosis overlooking rich terminology and variation of thepathology language.Our long-term goal is to employ Large Language Models (LLMs) to extract information from all types of clinicalnotes assisting institutional certified tumor registrars in data abstraction for the Cancer Registry. In this workwe specifically focus on pathology reports and proposes to train LLMs on 349544 institutional pathologyreports to identify five key cancer data elements: primary site histology stage grade and laterality. The studywill focus on common (breast) and rare (gastric) cancers.We will leverage existing LLMs pretrained on large public corpora retrain them on institutional pathologyreports and finally fine-tune them to predict specific cancer data elements.We pursue two specific aims. Aim 1: predict breast cancer data elements by abstractive question-asweringusing the existing cabernet architecture (Aim 1a) and by a prompt-based finetuning technique (Aim 1b). Aim 2:utilize zero-shot inference (Aim 2a) and soft-prompt tuning (Aim 2b) on these fine-tuned models to predictgastric cancer data elements. This proposal is innovatite by using LLMs to identify key cancer data elements inreal-world settings and has broad impacts by accelerating research streamlining cancer registry operationsand fostering the development of effective cancer prevention and treatment therapies. 299999 +No NIH Category available 1 year old;Acceleration;Acute;Acute Myelocytic Leukemia;Adolescent;Australia;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Complication;Country;Development;Diagnosis;Disease;Dose;Eligibility Determination;Enrollment;Ensure;Family;Foundations;Functional disorder;Generations;Goals;Hormonal;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Positioning Attribute;Productivity;Prognosis;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Survivors;Tissues;Translational Research;United States;Universities;Work;anticancer research;cancer diagnosis;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;multidisciplinary;novel therapeutic intervention;operation;organizational structure;reproductive;small molecule;success;survivorship;translational study Children's Oncology Group PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively tochildhood and adolescent cancer research. Over 220 leading childrens hospitals universitiesand cancer centers across US Canada and other countries participate in COG research whichis focused on developing better treatments that can improve the cure rate and outcomes for allchildren with cancer. NCI 10889845 9/19/23 0:00 PA-20-272 3U10CA180899-10S1 3 U10 CA 180899 10 S1 "MOONEY, MARGARET M" 9/19/23 0:00 2/28/25 0:00 1857551 "ALONZO, TODD A" Not Applicable 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/19/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 1576321 NCI 1559988 16333 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of the500000 survivors of childhood cancer (estimated as of 2020) experiencing a significant health related quality oflife complication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildrens Oncology Group (COG) the worlds largest organization devoted exclusively to childhood andadolescent cancer research was founded 20 years ago. The COGs multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading childrens hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institutes (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life for children with cancer and childhood cancer survivors. As more than90% of children diagnosed with cancer in the US are treated at COG member institutions COG has the ability tooffer a diverse population of children with cancer and their families the opportunity to participate in innovativeresearch. This research effort includes allowing for collection and annotation of biospecimens from all childrenwith cancer providing the foundation for discovery and accelerating the most promising research effortsconducted in laboratories around the world. The proposal is for support of the COG Network Operations Centerscientists who develop and conduct research and for member sites to participate through enrollment ofeligible subjects. 1576321 +No NIH Category available Affinity;Antitumor Response;Automobile Driving;Binding;Biology;CD8-Positive T-Lymphocytes;Cancerous;Cell Death;Cell Death Induction;Cells;Characteristics;Chemicals;Cytotoxic agent;Data;Dimensions;Disease;Dose;Encapsulated;Exhibits;Fluorescent Dyes;Gel Chromatography;Genetic Engineering;Goals;High Pressure Liquid Chromatography;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunotherapy;In Vitro;Inflammatory;Inflammatory Response;Intravenous;Invaded;Iron;Lead;Lesion;Link;Lipid Peroxides;Macrophage;Malignant Neoplasms;Melanocortin 1 Receptor;Melanoma Cell;Modeling;Molecular;Mus;Mutation;Necrosis;Outcome;Pathway interactions;Pharmaceutical Preparations;Phenotype;Population;Process;Property;Research;Research Design;Series;Signal Transduction Pathway;Silicon Dioxide;T-Lymphocyte;Therapeutic;Therapeutic Effect;Time;Toxic effect;Translations;Transplantation;Treatment Efficacy;anti-CTLA4;anti-PD-1;anti-cancer;anti-cancer therapeutic;anti-tumor immune response;anticancer activity;antitumor effect;aqueous;cancer cell;cancer immunotherapy;cancer regression;cancer therapy;carcinogenesis;combat;cytokine;design;experimental study;immune checkpoint blockade;immune-related adverse events;immunoregulation;improved;in vivo;inhibitor;insight;intravenous administration;melanoma;mouse model;nanomaterials;nanoparticle;nanotherapeutic;novel;overexpression;particle;pharmacologic;programs;recruit;response;small molecule;synergism;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Ultrasmall particle-based solutions for inducing ferroptosis and improving anti-tumor immune responses in cancer Project NarrativeNanoparticles have emerged as highly specialized multifunctional probes for disease targeting and delivery ofsmall molecule drugs to treat cancerous lesions. Non-toxic ultrasmall fluorescent core-shell silica nanoparticlesthat induce a potent form of cell death in cancer cells has emerged as an alternative anti-cancer strategy offeringwide-ranging potential that harnesses the unique intrinsic therapeutic potential of these particles to combatdisease without the need for a cytotoxic agent in addition to activating immune cells within the tumormicroenvironment. The proposed studies will identify particle structural and chemical features that can maximizethese intrinsic therapeutic responses in melanoma models in addition to elucidating their underlying molecularmechanisms and relative contributions to anti-cancer therapies solutions that may better inform our in vivostudy designs and offer a more effective path for product translation. NCI 10888788 7/19/23 0:00 PA-21-268 7R01CA253658-05 7 R01 CA 253658 5 "GRODZINSKI, PIOTR" 6/1/20 0:00 5/31/25 0:00 Special Emphasis Panel[ZRG1-IMST-H(55)R] 9369123 "BRADBURY, MICHELLE S" "OVERHOLTZER, MICHAEL H.; WIESNER, ULRICH " 12 RADIATION-DIAGNOSTIC/ONCOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 7/18/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 550839 NCI 405025 145814 Project Summary: Enormous strides continue to be made in the design of nanoparticles as highly specializedtherapeutics for achieving superior outcomes over standard pharmacological agents the latter often associatedwith significant toxicity that limits treatment efficacy. While cancer immunotherapies have revolutionized thetreatment of disease and shown therapeutic benefits in hard-to-treat cancers these agents are limited forexample by immune-related adverse events and off-target effects in immunosuppressive microenvironments.Novel emerging anti-cancer strategies are therefore critically needed to overcome these limitations and improvedurable response rates in combination with immune therapies. One promising strategy exploits the unique self-therapeutic capabilities of the nanomaterials themselves the treatment of tumors without the need for cytotoxicdrugs. These capabilities are governed by the intrinsic physico-chemical properties of these materials which canlead to disruption of signal transduction pathways cell cross-talk or invasion and/or induced cell death programswithin the tumor microenvironment (TME) providing unprecedented opportunities for combating disease. Wehave developed specialized ultrasmall fluorescent core-shell silica nanoparticles Cornell prime dots (C' dots)with intrinsic therapeutic capabilities enabling a distinct combination of activities that (1) selectively and directlyinduce cancer cell death through the iron-dependent mechanism of ferroptosis and (2) modulate immune cellsdirectly by priming T cells and polarizing macrophages toward a pro-inflammatory phenotype. As CD8+ T cellsare known to also regulate ferroptosis during immunotherapy such effects are expected to synergize with thoseinduced by C' dots. A long-term goal of this proposal is to determine critical C' dot physico-chemical parametersresponsible for maximizing responses to these intrinsic therapeutic activities. In Aim I we will examine the extentto which changes in the structural properties of PEG-coated C' dots plain or modified to specifically bind tomelanocortin-1 receptor (MC1-R; a well-established target overexpressed by our syngeneic murine models andhuman melanomas) influence therapeutic efficacy in syngeneic melanoma models by modulating ferroptosisand the tumor microenvironment in the presence and absence of checkpoint blockade. In Aim II we will probeunderlying mechanisms driving regulation of immune cell phenotype and/or induction of ferroptosis in vitro. Thesuccessful completion of the project will provide critical insights into (i) key structural parameters modulating thecombined self-therapeutic activities of these particles related to their induction of ferroptosis and priming thetumor immune microenvironment; (ii) whether critical differences exist in particle characteristics needed tooptimize these distinct activities; (iii) mechanisms underpinning these activities; and (iv) therapeutic strategiesthat maximize potent anti-tumor effects in syngeneic melanoma models by administering therapeutic doses ofparticles in tandem with checkpoint inhibitors (anti-PD-1 and anti-CTLA-4). 550839 +No NIH Category available Targeting Glioblastoma Cells and Tumor Microenvironment with CAR-T Cell Therapy n/a NCI 10888586 8/14/23 0:00 PAR-20-305 5P50CA211015-07 5 P50 CA 211015 7 "HUBBARD, LEAH" 8/1/23 0:00 7/31/27 0:00 ZCA1-RPRB-N(M1)S 9664 11244664 "CHEN, YVONNE YU-HSUAN" Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 342606 219594 123021 No abstract available +No NIH Category available Academic Medical Centers;Cancer Center;Cancer Model;Clinical;Collaborations;Computational Biology;Country;Data;Data Analyses;Development;Discrimination;Ethics;Evaluation;Future;Guidelines;Machine Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Medical center;Modeling;Mutation;Patients;Privacy;Records;Research;Risk;Security;Site;Testing;Work;data de-identification;data quality;data sharing;deep learning model;federated learning;high dimensionality;learning network;multimodality;precision oncology;prototype;social stigma;tumor OHSU Knight Federated Learning Network Prototype to Support Multimodal Cancer Models PROJECT NARRATIVEThere are numerous challenges which hamper data sharing across cancer centers. Federated learning is apromising approach which may mitigate many of these challenges (privacy compliance security). This workwill implement and evaluate a federated learning network with an initial use case focused on prostate cancerwhich can inform future use of this approach by cancer centers and medical centers across the country. NCI 10888579 9/18/23 0:00 PA-20-272 3P30CA069533-25S2 3 P30 CA 69533 25 S2 "ROBERSON, SONYA" 8/1/97 0:00 6/30/27 0:00 Cancer Centers Study Section (A)[NCI-A] 1894087 "DRUKER, BRIAN J" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 299750 NCI 194643 105107 PROJECT SUMMARY/ABSTRACTTraditional data-sharing models typically centralize de-identified data for analysis. Patientrecords have become more multifaceted and high-dimensional such that de-identification aloneis inadequate to safeguard privacy. Privacy violations can result in harms to patients that can beboth deontological (ethically problematic) or consequentialist (harm such as discriminationfinancial consequences and stigma). Current regulatory guidelines are not designed for thecomplexity of AI/ML. Moreover each academic medical center will have their own ethics boardsgovernance models privacy standards and security requirements. Risk of a privacy breachlimits access and sharing of patient data a barrier to research across cancer centers andacademic medical centers. Given its outstanding strengths in precision oncology computationalbiology machine learning clinical curation data governance and data quality and regional datasharing OHSU Knight Cancer Institute is uniquely situated to assist NCI in the development of afederated learning network. The long-term objective is to develop the best practices andguidance to support large-scale federated learning across cancer centers to achieve optimalbenefit through broad data sharing. In the near term the focus of this project is to support thedevelopment and testing of a federated learning network prototype. To do this the OHSUKnight Cancer Institute proposes the following aims. Aim 1 is to develop a multi-modal deeplearning model to predict tumor mutational burden in prostate cancer. Aim 2 is to implement andevaluate our federated learning prototype focusing on privacy compliance and bias reduction.This will also include assessment of the impact of adversarial attacks and how well differentdefense strategies mitigate this. Finally Aim 3 is the evaluation of the federated model on thefederated learning network in collaboration with partner sites (other cancer centers NCI). 299750 +No NIH Category available 1 year old;Acceleration;Acute;Acute Myelocytic Leukemia;Administrative Supplement;Adolescent;Australia;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Complication;Country;Development;Diagnosis;Disease;Dose;Eligibility Determination;Enrollment;Ensure;Family;Foundations;Functional disorder;Generations;Goals;Hormonal;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Positioning Attribute;Productivity;Prognosis;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Survivors;Tissues;Translational Research;United States;Universities;Work;anticancer research;cancer diagnosis;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;multidisciplinary;novel therapeutic intervention;operation;organizational structure;reproductive;small molecule;success;survivorship;translational study COG NCTN Network Group Operations Center - Year 10 Administrative Supplements PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcomes for all children with cancer. NCI 10888036 9/21/23 0:00 PA-20-272 3U10CA180886-10S5 3 U10 CA 180886 10 S5 "MOONEY, MARGARET M" 9/21/23 0:00 2/29/24 0:00 10871228 "HAWKINS, DOUGLAS S." Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 9/21/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 3541929 NCI 3541929 0 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of the500000 survivors of childhood cancer (estimated as of 2020) experiencing a significant health related quality oflife complication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildrens Oncology Group (COG) the worlds largest organization devoted exclusively to childhood andadolescent cancer research was founded 20 years ago. The COGs multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading childrens hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institutes (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life for children with cancer and childhood cancer survivors. As more than90% of children diagnosed with cancer in the US are treated at COG member institutions COG has the abilityto offer a diverse population of children with cancer and their families the opportunity to participate in innovativeresearch. This research effort includes allowing for collection and annotation of biospecimens from all childrenwith cancer providing the foundation for discovery and accelerating the most promising research effortsconducted in laboratories around the world. The proposal is for support of the COG Network Operations Centerclinician-scientists who develop and conduct research and for member sites to participate through enrollment ofeligible subjects. 3541929 +No NIH Category available Administrator;Advocate;Award;Back;Beds;Biomedical Engineering;Biomedical Research;Cancer Biology;Cancer Center;Cancer Patient;Chromatin;Collaborations;Communication;Communities;Comprehensive Cancer Center;Decision Making;Development;Educational workshop;Engineering;Ensure;Equity;Evaluation;Event;Fostering;Funding;Goals;Human Resources;Image;Imaging Techniques;Infrastructure;Knowledge;Leadership;Malignant Neoplasms;Mission;Modeling;Monitor;Patients;Process;Program Evaluation;Publications;Quality Control;Recommendation;Records;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resource Allocation;Resource Sharing;Resources;Schedule;Schools;Site Visit;Specialist;Techniques;Testing;Training;Underrepresented Minority;Universities;Validation;Veterans;Work;anticancer research;cancer imaging;cancer stem cell;cancer therapy;data quality;data sharing;design;diversity and equity;diversity and inclusion;equity diversity and inclusion;experience;graduate school;improved;innovation;medical schools;meetings;member;minority health;molecular modeling;nanoimaging;programs;recruit;research data dissemination;synergism;technology development;technology research and development;tumor progression;web site Administration and Coordination Core n/a NCI 10887664 9/19/23 16:21 PA-20-272 3U54CA268084-02S1 3 U54 CA 268084 2 S1 "BECKER, STEVEN" 12/10/21 0:00 11/30/26 0:00 7225 7125025 "BACKMAN, VADIM " Not Applicable 5 Unavailable 160079455 EXZVPWZBLUE8 160079455 EXZVPWZBLUE8 US 42.050479 -87.680046 6144601 NORTHWESTERN UNIVERSITY Chicago IL Domestic Higher Education 606114579 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 Research Centers 2023 169298 130299 38999 Administrative and Coordination Core: PROJECT SUMMARY The proposed Northwestern University Center for Chromatin NanoImaging in Cancer (NU-CCNIC) will bring together leading cancer research biologists from the Robert H. Lurie Comprehensive Cancer Center in the Feinberg School of Medicine and world-renowned imaging and molecular modeling specialists from the McCormick School of Engineering with the goal of facilitating innovation and application of cutting-edge imaging techniques to help solve some of the most pressing problems in cancer biology research. The Administrative and Coordination Core (ACC) will be led by PI Vadim Backman. The day-to-day administration of the NU-CCNIC will be managed by the Center Administrator who will be responsible for maintaining all records relative to this award and ensuring communication synergy and resource sharing across the NU-CCNIC. Additionally Center administration will be supported by a Program Manager who in collaboration with the Center Administrator will be responsible for the development of the NU-CCNIC website scheduling meetings and events facilitating the sharing of resources determine whether there will be pre-publication data sharing across the NU-CCNIC and aid in conversations about data quality control cross validation and reproducibility. An External Advisory Panel (EAP) will be formed bringing together investigators with expertise in fields related to cancer stem cell plasticity and chromatin nanoimaging. The EAP is envisioned as a group of highly active members engaged to advise the NU-CCNIC leadership on scientific direction and review progress evaluation research strategies and implementation leadership and dissemination all in the effort to maximize the impact of the NU-CCNIC. The NU-CCNIC will enhance the translational value and potential impact of its research by engaging a Cancer Research Advocate who will be a member of the EAP and will be invited to attend NU-CCNIC workshops and site visits. The ACC will support weekly bi-weekly monthly and quarterly research meetings to foster communication collaboration and integration of the NU-CCNIC and will further support communication and wide- reaching knowledge dissemination through bi-annual workshops with outside speakers. In Aim 1 the Administrative Core will promote and ensure clear and effective communication across the Technology Development (TECH) and Research Test-Bed (RTB) Units. In Aim 2 we will plan and establish regular Center meetings and research workshops to foster communications within the NU-CCNIC and to the broader community that are critical to our research mission and dissemination. In Aim 3 we will work to increase representation and training of underrepresented minorities in the biomedical research workforce of the NU-CCNIC. In Aim 4 we will partner with the cancer research advocate to ensure the critical importance of the patient perspective in the NU- CCNIC. In Aim 5 we will work with the EAP and Cancer Research Advocate on NU-CCNIC evaluation programs to ensure Center progress is accomplished on a timely basis and that resources are allocated judiciously. +No NIH Category available Abstinence;Address;Adoption;Adult;Applications Grants;Behavior Therapy;Biochemical;Cambodia;Cambodian;Cellular Phone;Cigarette;Clinics and Hospitals;Collaborations;Communication;Confidence Intervals;Control Groups;Country;Data;Developed Countries;Development;Ecological momentary assessment;Educational workshop;Enrollment;Evaluation;Future;Goals;Health;Health Promotion;Health Technology;Hospitals;Image;Income;Influentials;Inservice Training;Institution;Intervention;Language;Laos;Manuscripts;Mobile Health Application;Morbidity - disease rate;Outcome;Participant;Patient Self-Report;Patients;Persons;Phase;Pilot Projects;Preparation;Prevalence;Proliferating;Province;Public Health;Publishing;Randomized;Randomized Controlled Trials;Relative Risks;Reporting;Research;Research Methodology;Research Personnel;Smoker;Smoking Cessation Intervention;Surveys;Technology;Tobacco;Tobacco Use Cessation;Tobacco smoke;Tobacco use;Training;Wireless Technology;Woman;World Health Organization;Writing;brief advice;cost effective;efficacy evaluation;follow-up;global health;health care service;insight;knowledge base;low and middle-income countries;mHealth;men;mobile computing;mortality;nicotine replacement;novel;personalized intervention;personalized medicine;pilot test;programs;randomized trial;recruit;secondary outcome;self help;sex;smoking cessation;smoking prevalence;social culture;standard care;support network;text messaging intervention;tobacco cessation intervention;tobacco control;tool;treatment group;treatment program Mobile Health Technology for Personalized Tobacco Cessation Support in Laos PROJECT NARRATIVEThis project is a collaborative initiative between US researchers and Lao public health officials to determine theefficacy of a novel mHealth intervention for smoking cessation among Lao patients. The proposed research isrelevant to public health because it is expected to advance mHealth applications in tobacco-cessationtreatment in low- and middle-income settings and subsequently reduce tobacco-related morbidities andmortality. The mHealth intervention is also affordable and scalable and thus is appropriate for widespreadadoption in low- and middle-income countries. NCI 10886151 9/15/23 0:00 PAR-19-376 4R33CA253600-03 4 R33 CA 253600 3 "PEARLMAN, PAUL C" 9/1/20 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-IMST-K(55)R] 12544394 "BUI, THANH C." Not Applicable 5 FAMILY MEDICINE 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 233072 NCI 194988 33084 PROJECT SUMMARY: Tobacco use remains the leading cause of preventable morbidity and mortalityworldwide. Although tobacco use has declined in developed nations in recent decades smoking prevalenceremains strikingly high in many low- and middle-income countries (LMICs). In Lao People's DemocraticRepublic (Lao PDR) 51% of adult men and 7% of adult women smoke tobacco. The development andevaluation of sustainable tobacco cessation interventions suitable for widespread adoption in nations such asLao PDR are pressing public health needs. To address this need we propose a project that adapts ourtheoretically and empirically based mobile health (mHealth) technology to help people quit smoking cigarettesin Lao PDR. This mHealth approach includes a fully automated interactive personalized smartphone-delivered intervention for behavioral treatment delivered through our Insight platform. mHealth interventionsare proliferating in developed countries but efforts to utilize similar approaches in Lao PDR are extremelylimited. The World Health Organization acknowledges that using mHealth for health promotion is cost-effectivescalable and sustainable including for the least-developed countries. Additionally text-messaginginterventions for smoking cessation have been shown to be effective cost-effective and affordable for tobaccocontrol globally. We have already developed the mHealth platform and intervention approach proposed for thisstudy and pilot tested this technology with a group of Cambodian smokers. Preliminary results demonstratedthat our mHealth technology is efficacious highly feasible appropriate and potentially scalable for LMICsettings. This proposed project for Lao PDR includes 2 main phases. In the R21 Phase we will use formativeresearch methods to adapt our intervention content to the sociocultural context language and communicationstyles of Laotians. In the subsequent R33 Phase we will conduct a randomized controlled trial (RCT) toevaluate the efficacy of our mHealth intervention and technology. Adult smokers of both sexes will be recruitedthrough 2 large hospitals: Setthathirath Hospital in Vientiane and Champasak Hospital in ChampasakProvince. Participants (n=500) will be randomized to 1 of 2 treatment groups: Standard Care (SC; n=250) orAutomated Treatment (AT; n=250). SC consists of brief advice to quit smoking delivered by research staff self-help written materials and a 2-week supply of NRT (transdermal patches). AT consists of all SC componentsplus a fully automated smartphone-based treatment program that involves interactive and personalizedproactive messages images or videos. The primary health outcome of the trial is biochemically confirmed self-reported 7-day point prevalence abstinence 12 months post study enrollment. The project also aims toadvance mHealth research capacity in Lao PDR and sustain the US-Lao PDR research network. The projecthas the potential to transform healthcare services for tobacco cessation treatment throughout the country andultimately to significantly reduce tobacco-induced morbidity and mortality. 228072 +No NIH Category available Abstinence;Address;Adoption;Adult;Applications Grants;Behavior Therapy;Biochemical;Cambodia;Cambodian;Cellular Phone;Cigarette;Clinics and Hospitals;Collaborations;Communication;Confidence Intervals;Control Groups;Country;Data;Developed Countries;Development;Ecological momentary assessment;Educational workshop;Enrollment;Evaluation;Future;Goals;Health;Health Promotion;Health Technology;Hospitals;Image;Income;Influentials;Inservice Training;Institution;Intervention;Language;Laos;Manuscripts;Mobile Health Application;Morbidity - disease rate;Outcome;Participant;Patient Self-Report;Patients;Persons;Phase;Pilot Projects;Preparation;Prevalence;Proliferating;Province;Public Health;Publishing;Randomized;Randomized Controlled Trials;Relative Risks;Reporting;Research;Research Methodology;Research Personnel;Smoker;Smoking Cessation Intervention;Surveys;Technology;Tobacco;Tobacco Use Cessation;Tobacco smoke;Tobacco use;Training;Wireless Technology;Woman;World Health Organization;Writing;brief advice;cost effective;efficacy evaluation;follow-up;global health;health care service;insight;knowledge base;low and middle-income countries;mHealth;men;mobile computing;mortality;nicotine replacement;novel;personalized intervention;personalized medicine;pilot test;programs;randomized trial;recruit;secondary outcome;self help;sex;smoking cessation;smoking prevalence;social culture;standard care;support network;text messaging intervention;tobacco cessation intervention;tobacco control;tool;treatment group;treatment program Mobile Health Technology for Personalized Tobacco Cessation Support in Laos PROJECT NARRATIVEThis project is a collaborative initiative between US researchers and Lao public health officials to determine theefficacy of a novel mHealth intervention for smoking cessation among Lao patients. The proposed research isrelevant to public health because it is expected to advance mHealth applications in tobacco-cessationtreatment in low- and middle-income settings and subsequently reduce tobacco-related morbidities andmortality. The mHealth intervention is also affordable and scalable and thus is appropriate for widespreadadoption in low- and middle-income countries. NCI 10886151 9/15/23 0:00 PAR-19-376 4R33CA253600-03 4 R33 CA 253600 3 "PEARLMAN, PAUL C" 9/1/20 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-IMST-K(55)R] 12544394 "BUI, THANH C." Not Applicable 5 FAMILY MEDICINE 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 233072 FIC 4275 725 PROJECT SUMMARY: Tobacco use remains the leading cause of preventable morbidity and mortalityworldwide. Although tobacco use has declined in developed nations in recent decades smoking prevalenceremains strikingly high in many low- and middle-income countries (LMICs). In Lao People's DemocraticRepublic (Lao PDR) 51% of adult men and 7% of adult women smoke tobacco. The development andevaluation of sustainable tobacco cessation interventions suitable for widespread adoption in nations such asLao PDR are pressing public health needs. To address this need we propose a project that adapts ourtheoretically and empirically based mobile health (mHealth) technology to help people quit smoking cigarettesin Lao PDR. This mHealth approach includes a fully automated interactive personalized smartphone-delivered intervention for behavioral treatment delivered through our Insight platform. mHealth interventionsare proliferating in developed countries but efforts to utilize similar approaches in Lao PDR are extremelylimited. The World Health Organization acknowledges that using mHealth for health promotion is cost-effectivescalable and sustainable including for the least-developed countries. Additionally text-messaginginterventions for smoking cessation have been shown to be effective cost-effective and affordable for tobaccocontrol globally. We have already developed the mHealth platform and intervention approach proposed for thisstudy and pilot tested this technology with a group of Cambodian smokers. Preliminary results demonstratedthat our mHealth technology is efficacious highly feasible appropriate and potentially scalable for LMICsettings. This proposed project for Lao PDR includes 2 main phases. In the R21 Phase we will use formativeresearch methods to adapt our intervention content to the sociocultural context language and communicationstyles of Laotians. In the subsequent R33 Phase we will conduct a randomized controlled trial (RCT) toevaluate the efficacy of our mHealth intervention and technology. Adult smokers of both sexes will be recruitedthrough 2 large hospitals: Setthathirath Hospital in Vientiane and Champasak Hospital in ChampasakProvince. Participants (n=500) will be randomized to 1 of 2 treatment groups: Standard Care (SC; n=250) orAutomated Treatment (AT; n=250). SC consists of brief advice to quit smoking delivered by research staff self-help written materials and a 2-week supply of NRT (transdermal patches). AT consists of all SC componentsplus a fully automated smartphone-based treatment program that involves interactive and personalizedproactive messages images or videos. The primary health outcome of the trial is biochemically confirmed self-reported 7-day point prevalence abstinence 12 months post study enrollment. The project also aims toadvance mHealth research capacity in Lao PDR and sustain the US-Lao PDR research network. The projecthas the potential to transform healthcare services for tobacco cessation treatment throughout the country andultimately to significantly reduce tobacco-induced morbidity and mortality. 5000 +No NIH Category available Address;Advocate;California;Cancer Burden;Cancer Center;Cancer Control;Center Core Grants;Cities;Clinic;Clinical;Clinical Treatment;Clinical Trials;Communication;Communities;Community Outreach;Dissemination and Implementation;Eligibility Determination;Ensure;Equity;Family;Focus Groups;Goals;Guidelines;Health Personnel;Health Policy;Health system;Intervention;Interview;Learning;Linguistics;Medical;Medical Research;Minority;Minority Access;Minority Enrollment;Minority Groups;Modality;Notification;Outcome;Parents;Patients;Policies;Provider;Research;Research Personnel;Science;Statutes and Laws;Strategic Planning;Structure;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Vulnerable Populations;cancer care;cancer health disparity;community engagement;implementation evaluation;implementation facilitators;implementation science;innovation;interest;medical specialties;medical vulnerability;medically underserved population;member;parent grant;response;stakeholder perspectives;treatment trial A multi-stakeholder health policy study using implementation science to advance access to cancer care and clinical trials for medically vulnerable populations: A focus on our Catchment Community PROJECT NARRATIVEThis application is responsive to NOT-CA-23-044; and is being re-submitted in response to our P30-CA033572-40 strategic priority and aim 3 of our COE strategy to reduce cancer burden and disparities by increasingmedically underserved populations access to cancer care and clinical trials; thus we propose a health policystudy built on multi-stakeholder engagement to increase access to cancer care and clinical trials for medicallyvulnerable populations especially targeting our Catchment Communities. We will evaluate the implementationof The California Cancer Care Equity Act (CCEA-SB987) that took effect in January 2023 which expands accessto specialized cancer care and clinical trials. We will use the findings from this research to co-create (advocateclinician and researcher) communication strategies for optimal provider and patient activation to increase accessto the highest quality cancer care and clinical interventional treatment studies at NCI Cancer Centers. NCI 10885732 8/23/23 0:00 PA-20-272 3P30CA033572-40S3 3 P30 CA 33572 40 S3 "ROBERSON, SONYA" 8/1/97 0:00 11/30/27 0:00 6367572 "CARPTEN, JOHN D." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 125000 NCI 71023 53977 PROJECT SUMMARYThis application is being re-submitted as a PA-20-272 investigator-initiated request responsive to the Notice ofSpecial Interest (NOSI) identified as NOT-CA-23-044 and in response to our P30-CA033572-40 strategicpriority to reduce cancer burden and disparities by increasing underrepresented and minority populationaccess to cancer care and clinical trials. Increasing minority access to specialized cancer care and clinicalinterventional treatment trials are top priorities for medical research organizations including NIH NCI and ourCity of Hope Cancer Center. The strategic plan of the parent P30 grant and in particular aim 3 of ourCommunity Outreach and Engagement (COE) prioritizes increasing minority enrollment and addressingcancer disparities. To advance our P30 strategic priorities and our COE aim we propose a health policy studybuilt on multi-stakeholder engagement to increase access to specialty cancer care and clinical trials formedically vulnerable populations especially targeting our Catchment Communities. The unacceptably lowrepresentation of minorities in cancer control policy studies and clinical trials continue to hamper public benefitof medical advancement and legislation. To address this gap we propose evaluating the implementation ofThe California Cancer Care Equity Act (CCEA-SB987) that took effect in January 2023 which expands accessto specialized cancer care and clinical trials. By ensuring community responsiveness in CCEA-SB987implementation our long-term goal is to rapidly increase minority access to cancer care and clinical trials atNCI Cancer Centers. Our innovative approach will enable patients and families health care providers healthsystems payors and community members to better understand guidelines and eligibility and act upon theinformation. Guided by dissemination and implementation conceptual frameworks we aim to: (1) Evaluatepatient perspectives of notification strategies payors use to inform patients about CCEA-SB987 guidelines andeligibility using focus groups with patient advisors. We will explore patient perspectives on payor notificationstrategies (type and delivery modality) payor notification quality (content clarity and cultural and linguisticresponsiveness) and eligibility guidelines; and (2) Evaluate organization stakeholder perspectives on CCEA-SB987 implementation using semi-structured interviews with organization/clinic leaders and providers. We willconduct in-depth qualitative interviews to learn about perspectives on engagement in policy implementationbarriers and facilitators to implementation and eligibility guidelines. We will use the findings from this policydiscovery science research to co-create (advocate clinician and researcher) communication strategies foroptimal provider and patient activation to increase access to the highest quality cancer care and clinicaltreatment studies afforded by CCEA-SB987. This outcome has direct relevance to our parent grant that targetsunderrepresented ethnic minorities for increased access to specialty cancer care including clinical treatmentstudies at NCI Cancer Centers. 125000 +No NIH Category available Address;Algorithmic Analysis;Blood Vessels;Breast biopsy;Clinical;Code;Collaborations;Collagen;Color;Consumption;Cues;Data Analyses;Descriptor;Development;Diagnostic;Diagnostic Imaging;Dimensions;Environment;Evaluation;Evolution;Fluorescence;Future;Generations;Geometry;Glass;Goals;Grant;Hematoxylin and Eosin Staining Method;Histology;Histopathology;Image;Image Analysis;Image Enhancement;Imaging Techniques;Immunofluorescence Immunologic;Interruption;Light;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mathematics;Measures;Methodology;Methods;Modality;Morphology;Needles;Organism;Pathologist;Pattern;Phenotype;Pilot Projects;Pre-Clinical Model;Procedures;Process;Property;Reporting;Research;Role;Sampling;Scanning;Slide;Specimen;Speed;Stains;Structure;Surface;Taxonomy;Techniques;Thick;Thinness;Time;Tissue Sample;Tissue imaging;Tissues;Tumor Biology;Universities;Validation;Visual;Visualization;X-Ray Computed Tomography;algebraic topology;anticancer research;biomedical imaging;cancer subtypes;clinical diagnostics;clinical practice;cost effectiveness;deep learning;design;diagnostic tool;diagnostic value;imaging modality;improved;innovation;insight;interest;learning strategy;malignant breast neoplasm;novel;point of care;predictive modeling;prognostic tool;response;three dimensional structure;tissue fixing;tool;tumor;tumor microenvironment IMAT-ITCR Collaboration: Combining FIBI and topological data analysis: Synergistic approaches for tumor structural microenvironment exploration NARRATIVE: This IMAT-ITCR collaborative pilot study between Stony Brook University and UC Davis aims to developtopological measures for assessing image content and structure in FIBI (Fluorescence Imitating Brightfield Imaging) images.FIBI provides immediate high-quality images of tissues without the time- and labor-intensive processing methods of conven-tional histopathology. Topological Data Analysis will be used to (1) quantify differences between FIBI and traditional H&Eimages focusing on fine-scale structures such as collagen bundles and blood vessels and (2) develop new mathematics-basedinsights based on FIBI-enhanced tissue features; the goal is to enhance understanding of FIBI as an imaging modality refineanalysis methods and ultimately advance FIBI as a diagnostic and prognostic tool. NCI 10885376 9/18/23 0:00 PA-20-272 3R33CA278544-01S1 3 R33 CA 278544 1 S1 "OSSANDON, MIGUEL" 6/1/23 0:00 5/31/26 0:00 2064867 "LEVENSON, RICHARD M." Not Applicable 4 PATHOLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 79979 NCI 50000 29979 SUMMARY: In response to PA-20-272 we propose a collaborative pilot study between teams at Stony Brook University(ITCR - MPIs Prasanna and Chen) and UC Davis (IMAT - PI Levenson). By leveraging novel mathematical topology toolsdeveloped by the ITCR team we aim to understand and quantify the similarities and differences in the structural microenvi-ronment across Fluorescence Imitating Brightfield Imaging (FIBI) and conventional hematoxylin and eosin (H&E) images.FIBI an inexpensive slide-free tissue imaging technique developed by the IMAT team provides immediate high-quality im-ages from fresh or fixed tissues that resemble those generated after time-consuming methods used to prepare traditional H&Eslides. A key advantage of FIBI is that it can detect continuous linear structures that are interrupted or poorly visualized onstandard slides a feature with significance to the evaluation of tumor micro-structural environment and clinical diagnostics.However to advance FIBI as a diagnostic imaging modality it will be important to gain a deeper understanding of suchintricate structural features. While a pilot validation report has shown that FIBI images retain diagnostic power comparedto H&E images a comprehensive quantification of the differences between these two imaging modalities is lacking; further-more there are no FIBI-specific quantitative histomorphometry tools that can help characterize and quantitatively evaluatedifferent structures that are more salient on thickly vs. thinly cut tissue sections. The ITCR team will adapt topological data analysis (TDA) tools proposed in their R21 project to study the 3D structuresin FIBI images generated by the IMAT team in their R33 project. This analysis will focus on fine-scale structures withconnectivity and surface-profile features easily appreciable in FIBI images such as collagen bundles and blood vessels.The extracted features will be color coded and mapped onto the FIBI images for interpretable visualization to establishcomprehensive taxonomies for the discovered topology profiles. Analysis will include at least 100 FIBI samples eachcontaining FIBI and H&E images with comparisons between the topological features extracted from images to quantifythe differences in describing the structural microenvironment. Expert segmentations of specific structures of interest withinFIBI images will be obtained followed by the extraction of descriptors to characterize topology. The relationships betweenstructures and regions of interest such as cancer and normal regions and different subtypes of cancer will be investigatedusing statistical techniques and predictive models. The study will enhance the understanding of FIBI (IMAT team) as adiagnostic imaging modality and refine topological analysis methodology (ITCR team). Deliverables will include a set oftools and techniques for holistic characterization of the structural environment as observed on the FIBI scans. The effortwill leverage the teams expertise in mathematical tools and image analysis building upon previous collaborations on breastcancer image analysis. Successful identification of meaningful phenotype-feature associations will demonstrate the clinicalutility of the FIBI technique particularly as a diagnostic tool for guiding treatment decisions. 79979 +No NIH Category available Development and Commercialization of a New Molecularly Targeted Imaging Agent for Multiple Myeloma PROJECT NARRATIVEIn this study Sarya LLC (Sarya) will develop and commercialize a new specific positron emission tomography(PET) imaging agent 64Cu-LLP2A for diagnosis staging and treatment of the hematological cancer multiplemyeloma (MM). The development of this technology will fulfill an unmet need for molecularly targeted sensitiveand specific MM imaging agents that can accurately stage and restage MM identify high-risk MM patientsguide personalized MM treatment and evaluate clinical response to treatment. NCI 10885315 9/21/23 0:00 PA-19-271 4R42CA257797-02 4 R42 CA 257797 2 "ZHAO, MING" 5/1/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-SBIB-T(10)B] 14873026 "BLACKLEDGE, JAMES " Not Applicable 1 Unavailable 117341583 X7KLFUPEEJN8 117341583 X7KLFUPEEJN8 US 38.678663 -90.421335 10058821 "SARYA, LLC" SAINT LOUIS MO Domestic For-Profits 631465558 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1025350 NCI 684543 273817 PROJECT SUMMARYSarya LLC (Sarya) is a nuclear medicine technology company formed to commercialize radiopharmaceuticals.The goal of this Fast-Track STTR is to develop a new specific imaging agent for diagnosis staging andtreatment of the hematological cancer multiple myeloma (MM). MM is the 2nd most common blood cancer withan estimated 32000 new cases and 13000 deaths per year. Accurate detection is critical for enhancingsurvival in MM patients. Traditional skeletal survey and bone scans have sensitivity limitations for osteolyticlesions manifested in MM. Positron Emission Tomography (PET) performed with a PET radiopharmaceutical(imaging agent) is a sensitive quantitative and non-invasive clinical imaging technology to accurately detectlocalize and phenotype MM cells throughout the body. 18F-fluorodeoxyglucose (FDG) is the only FDA-approvedPET imaging agent for MM. Unfortunately MM cells express low levels of GLUT-1 transporter and hexokinasewhich are required for FDG uptake and retention. Additionally MM bone marrow harbors FDG-avidinflammatory cells. There is an unmet need for molecularly targeted sensitive and specific MM imaging agentsthat can accurately stage and restage MM identify high-risk MM patients guide personalized MM treatmentand evaluate clinical response to treatment. The product of this STTR will be a specific and sensitive PETimaging agent (64Cu-LLP2A) for MM. Published data and ongoing first-in-human trial results have significantlyinformed the Phase I and II aims of this proposal. The Phase I Segment consists of two specific aims: (1)Perform dose escalation and single dose toxicity testing in mice. (2) Compile data for new dose and submitamendment of eIND to FDA. Three milestones will be met in Phase I: (1) A new mass will be selected basedon no-observed-adverse-effect level (NOAEL) i.e. clinical signs of organ toxicity (vehicle vs experimental). (2)Based on the new determined mass and in vivo preclinical image quality data a new specific activity (Ci/mol)will be established. (3) Obtain FDA approval of Sarya sponsored amended eIND application. The Phase IIsegment involves a clinical trial and has one specific aim: Quantify the efficacy of 64Cu-LLP2A-PET imaging fordetecting active MM in humans in a prospective imaging trial. Phase II milestones are: (1) Demonstrate highdetection rates (% of scans that are positive for a focal lesion p<0.05) for 64Cu-LLP2A versus FDG in MMpatients. (2) Accuracy of 64Cu-LLP2A for active MM will be assessed using standard-of-care bone marrow(BM) biopsies and serum biomarker M-protein levels as the standards of reference. A correlation coefficient of0.7 will be considered reasonably strong. In summary Phase I will prove feasibility that 64Cu-LLP2A is tolerablewith NOAEL resulting in a new eIND. Phase II will provide 64Cu-LLP2A-PET preliminary performance data tosupport a New Drug Application for 64Cu-LLP2A as a New Molecular Entity (NME) for FDA approval of Phase 2clinical trials. 1025350 +No NIH Category available Adoptive Transfer;CXCL10 gene;Cancer Etiology;Cancer Vaccines;Cell Therapy;Cells;Cellular immunotherapy;Chemotactic Factors;Childhood;Clinical;Combined Modality Therapy;Data;Development;Ewings sarcoma;FDA approved;Flow Cytometry;Gene Delivery;Gene Expression;Genomics;Glioma;Human;Immune;Immunocompetent;Immunologic Monitoring;Immunosuppression;Immunotherapy;Impairment;Inflammatory;Liposomes;Macrophage;Malignant Childhood Neoplasm;Measures;Mediating;Modeling;Monoclonal Antibody Therapy;Myeloid-derived suppressor cells;NK cell therapy;Natural Killer Cells;Neuroblastoma;Oncolytic;Oncolytic viruses;Phagocytes;Phagocytosis;Phenotype;Population;Relapse;Research Personnel;Resource Sharing;Rhabdomyosarcoma;Role;Shapes;Signal Transduction;Solid Neoplasm;Stress;Suppressor-Effector T-Lymphocytes;T cell clonality;T cell receptor repertoire sequencing;T-Lymphocyte;Testing;Treatment Efficacy;Tumor-associated macrophages;Tumor-infiltrating immune cells;Vaccines;Virotherapy;Virus;Virus Diseases;Work;Xenograft Model;Xenograft procedure;bisphosphonate;cancer cell;cancer immunotherapy;cancer regression;cancer therapy;cancer type;chemokine;chemotherapy;chimeric antigen receptor T cells;cytotoxic;exhaustion;gain of function;herpes virotherapy;innate immune mechanisms;loss of function;member;nanodiamond;neoplastic cell;neutrophil;new technology;osteosarcoma;pediatric patients;permissiveness;recruit;synergism;therapeutic target;time of flight mass spectrometry;trafficking;transcriptomics;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions;vaccine strategy Project 4:Targeting M2-like Macrophages and MDSC with Myelolytic-Virotherapy n/a NCI 10885263 9/13/23 0:00 PA-20-272 3U54CA232561-01A1S8 3 U54 CA 232561 1 A1S8 "BOURCIER, KATARZYNA" 9/1/23 0:00 8/31/24 0:00 5452 1884239 "CRIPE, TIMOTHY P" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 8/1/19 0:00 7/31/20 0:00 Research Centers 2023 366900 296900 70000 Abstract - Project 4:Cure rates for pediatric patients with relapsed or metastatic solid tumors remain unacceptably low. Cancerimmunotherapies hold great promise but scores of disappointing studies highlight our relative ignorance inunderstanding the immunosuppressive microenvironment within solid tumors. Because of their central role inmediating immunosuppression tumor associated macrophages (TAMs) typically polarized to a so-called M2-like immunosuppressive phenotype and myeloid-derived suppressor cells (MDSC) are thought to be importanttherapeutic targets. We have found a clinically viable strategy that simultaneously reduces TAMs/MDSC (we dubmyelolytic) and polarizes the microenvironment (via oncolytic virus infection) resulting in significant antitumorefficacy. We hypothesize that targeting TAM and MDSC by combining myelolytic therapies with pro-inflammatory therapies activates innate antitumor mechanisms that cause cancer regressions andreshapes the solid tumor microenvironment to be more permissive to cellular immunotherapies. In aim1 we will determine the mechanism(s) by which combined myelolytic-virotherapy drives tumorregressions. We will use novel technologies such as fluorescent nanodiamonds to determine effects on innateimmune cell phagocytosis of tumor cells. We will utilize the Genomics & Immune Monitoring Shared ResourceCore B directed by Dr. Elaine Mardis to conduct flow cytometry with time-of-flight mass spectrometry and singlecell transcriptomics to determine the effects on immune cell composition and polarization. We will also utilizegain- and loss-of-function approaches to determine if loss of MDSC are critical for enabling tumor regressionswith myelolytic-virotherapy. We will also test combination therapies in xenograft and immunocompetent modelsof other cancer types to confirm its generalizability (osteosarcoma Ewing sarcoma rhabdomyosarcomaneuroblastoma). In aim 2 we will determine the effects of myelolytic-virotherapy on T cell-mediatedimmunotherapies. We will examine the effect of myelolysis alone and combined with virotherapy on the efficacyof antitumor T cells in a T cell exhaustion setting and with CAR-T cells (with Project 1 Leader Dean Lee and co-investigator Ruoning Wang PI-DDN U01 member). We will work with Core B to examine the effects on T cellclonality using TCR sequencing. In aim 3 we will determine whether combined myelolytic-virotherapyenhances the efficacy of NK-based cellular therapies. We will work with Project 1 Leader Dean Lee andProject 2 Leader Mitch Cairo to study the effects on adoptive NK and CAR-NK cell therapy. Overall with thisproject we will further elucidate test and develop strategies to modulate the tumor microenvironment to facilitateinnate immune cells as cancer therapy. Our findings may be applicable across a broad panel of pediatric cancertypes and thus fits well into the aims of the Pediatric Immunotherapy Discovery and Development Network. +No NIH Category available Adoptive Transfer;CXCL10 gene;Cancer Etiology;Cancer Vaccines;Cell Therapy;Cells;Cellular immunotherapy;Chemotactic Factors;Childhood;Clinical;Combined Modality Therapy;Data;Development;Ewings sarcoma;FDA approved;Flow Cytometry;Gene Expression;Genomics;Human;Immune;Immunocompetent;Immunologic Monitoring;Immunosuppression;Immunotherapy;Impairment;Inflammatory;Liposomes;Macrophage;Malignant Childhood Neoplasm;Measures;Mediating;Modeling;Monoclonal Antibody Therapy;Myeloid-derived suppressor cells;NK cell therapy;Natural Killer Cells;Neuroblastoma;Oncolytic;Oncolytic viruses;Phagocytes;Phagocytosis;Phenotype;Population;Relapse;Research Personnel;Resource Sharing;Rhabdomyosarcoma;Role;Shapes;Signal Transduction;Solid Neoplasm;Stress;Suppressor-Effector T-Lymphocytes;T cell clonality;T cell receptor repertoire sequencing;T-Lymphocyte;Testing;Treatment Efficacy;Tumor-associated macrophages;Tumor-infiltrating immune cells;Vaccines;Virotherapy;Virus;Virus Diseases;Work;Xenograft Model;Xenograft procedure;bisphosphonate;cancer cell;cancer immunotherapy;cancer regression;cancer therapy;cancer type;chemokine;chemotherapy;chimeric antigen receptor T cells;cytotoxic;exhaustion;gain of function;herpes virotherapy;immunoregulation;innate immune mechanisms;loss of function;member;nanodiamond;neoplastic cell;neutrophil;new technology;novel;osteosarcoma;pediatric patients;permissiveness;recruit;synergism;therapeutic target;time of flight mass spectrometry;trafficking;transcriptomics;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions;vaccine strategy Project 4:Targeting M2-like Macrophages and MDSC with Myelolytic-Virotherapy n/a NCI 10885260 9/7/23 0:00 PA-20-272 3U54CA232561-01A1S7 3 U54 CA 232561 1 A1S7 "BOURCIER, KATARZYNA" 9/1/23 0:00 8/31/24 0:00 5452 1884239 "CRIPE, TIMOTHY P" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 8/1/19 0:00 7/31/20 0:00 Research Centers 2023 253700 214500 39200 Abstract - Project 4:Cure rates for pediatric patients with relapsed or metastatic solid tumors remain unacceptably low. Cancerimmunotherapies hold great promise but scores of disappointing studies highlight our relative ignorance inunderstanding the immunosuppressive microenvironment within solid tumors. Because of their central role inmediating immunosuppression tumor associated macrophages (TAMs) typically polarized to a so-called M2-like immunosuppressive phenotype and myeloid-derived suppressor cells (MDSC) are thought to be importanttherapeutic targets. We have found a clinically viable strategy that simultaneously reduces TAMs/MDSC (we dubmyelolytic) and polarizes the microenvironment (via oncolytic virus infection) resulting in significant antitumorefficacy. We hypothesize that targeting TAM and MDSC by combining myelolytic therapies with pro-inflammatory therapies activates innate antitumor mechanisms that cause cancer regressions andreshapes the solid tumor microenvironment to be more permissive to cellular immunotherapies. In aim1 we will determine the mechanism(s) by which combined myelolytic-virotherapy drives tumorregressions. We will use novel technologies such as fluorescent nanodiamonds to determine effects on innateimmune cell phagocytosis of tumor cells. We will utilize the Genomics & Immune Monitoring Shared ResourceCore B directed by Dr. Elaine Mardis to conduct flow cytometry with time-of-flight mass spectrometry and singlecell transcriptomics to determine the effects on immune cell composition and polarization. We will also utilizegain- and loss-of-function approaches to determine if loss of MDSC are critical for enabling tumor regressionswith myelolytic-virotherapy. We will also test combination therapies in xenograft and immunocompetent modelsof other cancer types to confirm its generalizability (osteosarcoma Ewing sarcoma rhabdomyosarcomaneuroblastoma). In aim 2 we will determine the effects of myelolytic-virotherapy on T cell-mediatedimmunotherapies. We will examine the effect of myelolysis alone and combined with virotherapy on the efficacyof antitumor T cells in a T cell exhaustion setting and with CAR-T cells (with Project 1 Leader Dean Lee and co-investigator Ruoning Wang PI-DDN U01 member). We will work with Core B to examine the effects on T cellclonality using TCR sequencing. In aim 3 we will determine whether combined myelolytic-virotherapyenhances the efficacy of NK-based cellular therapies. We will work with Project 1 Leader Dean Lee andProject 2 Leader Mitch Cairo to study the effects on adoptive NK and CAR-NK cell therapy. Overall with thisproject we will further elucidate test and develop strategies to modulate the tumor microenvironment to facilitateinnate immune cells as cancer therapy. Our findings may be applicable across a broad panel of pediatric cancertypes and thus fits well into the aims of the Pediatric Immunotherapy Discovery and Development Network. +No NIH Category available APC gene;Adult;Affect;American Cancer Society;Biological Models;C57BL/6 Mouse;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Model;Cessation of life;Chemoprevention;Chemoprotective Agent;Clinical Research;Colectomy;Colon Carcinoma;Colonic Diseases;Colonoscopy;Colorectal Cancer;Colorectal Polyp;Death Rate;Detection;Development;Diagnosis;Disease;Dose;Duodenum;Eicosapentaenoic Acid;Ellagic Acid;Enterocytes;FDA approved;FRAP1 gene;Familial Adenomatous Polyposis Syndrome;Familial colorectal cancer;Gastric Polyp;Gastrointestinal tract structure;Genetic Engineering;Incidence;Inflammation;Inflammatory;Intestinal Neoplasms;Intestinal Polyps;Left;Lesion;Life Style;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of thyroid;Morbidity - disease rate;Muscle function;Non-Steroidal Anti-Inflammatory Agents;Oral;Oral Administration;Pathogenicity;Pathway interactions;Patients;Pharmaceutical Preparations;Phytochemical;Polyps;Proliferating;Rectal Cancer;Reporting;Risk;Risk Factors;Rodent;Rodent Model;SDZ RAD;Signal Transduction;Sirolimus;Skeletal Muscle;Sulindac;Supplementation;Syndrome;Tumor Suppressor Genes;United States;Variant;WNT Signaling Pathway;Woman;cancer diagnosis;cancer prevention;cancer therapy;celecoxib;clinical effect;colorectal cancer prevention;colorectal cancer treatment;dextran sulfate sodium induced colitis;early screening;fruits and vegetables;improved;interest;lifetime risk;mTOR Inhibitor;mTOR inhibition;men;microbiota metabolites;mortality;mouse model;muscle aging;polyphenol;polyposis;preclinical study;predicting response;predictive marker;premalignant;prevent;prophylactic;sex;standard of care;tumor growth;tumor initiation;young adult Colorectal Cancer (CRC) Prevention by Urolithin A in Rodent CRC models n/a NCI 10885222 75N91019D00022-0-759102300001-1 N01 7/10/23 0:00 7/9/26 0:00 1885626 "CLAPPER, MARGIE L." Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N R and D Contracts 2023 1038958 NCI Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States as per the current estimates of The American Cancer Society. The number of CRC cases in the United States for 2022 are 106180 new cases of colon cancer and 44850 new cases of rectal cancer. The lifetime risk of developing CRC is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women. CRC is also the third leading cause of cancer-related deaths in men and in women and the second most common cause of cancer deaths when numbers from both sexes are combined. Although changes in lifestyle-related risk factors improved CRC treatments and early screening has helped reduce the diagnosis and overall death rates considerably over the years there has been a steady increase in CRC incidence and death rate among younger adults (<55 years).Familial adenomatous polyposis (FAP) is a hereditary CRC syndrome caused by germline pathogenic variants of the APC tumor suppressor gene . FAP affects the gastrointestinal tract and is characterized by the development of hundreds to thousands of precancerous colorectal polyps. FAP patients when left untreated carry a 100% risk of developing CRC. The current standard of care for FAP patients includes frequent colonoscopies and prophylactic colectomy upon detection of advanced lesions. However colectomy is associated with significant morbidity and does not prevent extra- colonic disease manifestations including gastric polyposis duodenal polyposis and cancer and thyroid cancer . While some clinical studies have demonstrated chemoprotective benefit of the NSAIDs including sulindac celecoxib and eicosapentaenoic acid (EPA) for FAP there are no FDA-approved drugs for this indication.In line with the growing interest in phytochemicals for cancer treatment and prevention recent studies have demonstrated that Ellagic acid (EA) a polyphenol found in fruits and vegetables and its microbiota metabolites the urolithins suppress cancer associated pathways and inflammation in various model systems . Out of all urolithins Urolithin A (UA) has been shown to display high bioactivity against cancer signaling and related inflammatory diseases in preclinical studies. A recent report demonstrated that oral administration of UA suppresses intestinal tumor growth in a sporadic CRC mouse model through induction of mitophagy and Wnt-signaling in CD8+ T cells. Oral administration of UA has also been shown to prevent TNBS- and DSS- induced colitis in C57BL/6 mice by enhancing the gut barrier integrity through activation of Nrf2 pathway. There has been a growing interest in the field on exploiting mTOR inhibition in chemoprevention of FAP. The mTORC1 pathway is activated in intestinal polyps of FAP mouse models activation of which has been shown to be required for the proliferation of APC-deficient enterocytes . Blocking mTORC1 pathway with mTOR inhibitors rapamycin and everolimus limited intestinal tumor initiation polyp formation and reduced mortality in FAP mouse models. Oral administration of UA decreased activation of mTOR signaling and inhibited tumor growth while improving survival in a genetically engineered pancreatic cancer interception mouse model. UA has been studied clinically for effects on various diseases including aging and skeletal muscle function . These clinical studies have shown that direct supplementation with UA is well tolerated and can yield high systemic concentrations in healthy adults. 1038958 +No NIH Category available 3-Dimensional;4T1;Ablation;Aftercare;Artificial Intelligence;Biology;Biosensor;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Bypass;Cancer Etiology;Categories;Cell model;Cell surface;Cells;Cessation of life;Characteristics;Classification;Collaborations;Computational Biology;Data;Development;Discriminant Analysis;Disease;Distant;Distant Metastasis;Endoplasmic Reticulum;Enhancers;Excision;Funding;Gene Expression Profile;Generations;Genetic;Genetic Engineering;Genomics;Goals;Grant;Heterogeneity;Imaging Device;Immunofluorescence Immunologic;Joints;Label;Location;Lysosomes;Machine Learning;Malignant Neoplasms;Metastatic breast cancer;Methods;Mitochondria;Modeling;Molecular;Morphology;Neoplasm Metastasis;Normal Cell;Organ;Organelles;Patients;Pattern;Phenotype;Population;Primary Neoplasm;Proliferating;Property;Recurrent Malignant Neoplasm;Regulator Genes;Research Design;Resistance;Sampling;Signal Pathway;Source;Spatial Distribution;Specificity;System;Technology;Testing;Time;Tissues;analysis pipeline;analytical tool;cancer cell;cancer recurrence;classification algorithm;design;genetic manipulation;improved;in vivo;insight;machine learning classifier;machine learning method;malignant breast neoplasm;monolayer;mortality;mouse model;neoplastic cell;new technology;novel;novel strategies;prevent;programs;random forest;rare cancer;sensor;side effect;synthetic biology;targeted treatment;therapy development;tool;tumor;two photon microscopy IMAT-ITCR Collaboration: Artificial intelligence enhanced breast cancer dormancy cell classification-based organelle-morphology and topology Project NarrativeThis project proposes to apply OTCCP in the contest of disseminated tumor cell (DTC) dormancy and applyorganelle topology as a novel way to classify DTCs in vivo and ex vivo. NCI 10884760 9/13/23 0:00 PA-20-272 3R61CA278402-01S1 3 R61 CA 278402 1 S1 "LI, JERRY" 7/1/23 0:00 6/30/24 0:00 9803149 "BRAVO CORDERO, JOSE JAVIER " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 84500 NCI 50000 34500 PROJECT SUMMARY/ABSTRACTBackground: Metastasis in distant organs years after treatment is the primary cause of cancer death. Lateprogression occurs through the reactivation of dormant tumor cells that disseminated early in the disease. Todate no therapy has been designed to target those cells and the lack of understanding on their biology preventsthe development of selective strategies to kill them. We aim to gain molecular insight into the gene regulatorysignature of the cancer dormancy state and use this information to devise a dormant cancer cell biosensor thatwill allow us to identify profile and genetically manipulate them in vivo.Hypothesis: We hypothesize that the application of intersectional genetics tools to define the uniquetranscriptional profile of dormant cells will reveal vulnerabilities that could be exploited to eliminate those cells.Specific Aims: Aim 1. To obtain and validate the enhancer activity profiles of dormant cancer cells in an in vivocontext Aim 2. To develop a dormant cancer cell biosensor and test its in vivo potential to selectively identifydormant cancer cells.Study design/Methods: To increase the specificity of dormant cancer cell identification in vivo reduce side-effects on non-target normal cells and allow the systematization of the generation of dormant cell-specificbiosensors and its downstream applications such as targeted cell ablation therapies we propose to develop anew dormant cell biosensor that bypasses cell-surface marker requirements distinguishing them instead viaintracellular properties that can be harnessed to allow the precise and exclusive genetic manipulation of thesecells within the body. We will validate our biosensor in vivo by using cellular dormancy models and intravital two-photon microscopy.Relevance: The mechanisms of cancer cell dormancy are poorly understood hence the options available fortheir targeted treatment to prevent metastasis are limited. Here we propose to use state-of-the-art genomicactivity profiling technology to gain molecular insight into the genetic program that defines the cancer dormancystate in vivo. We will then couple our unique computational and synthetic biology know-how to define uniquesignatures of the dormancy program to engineer genetic sensors that can be systemically-delivered into the bodyto find dormant cancer cells. With this strategy we hope to develop strategies to eliminate metastatic dormantcells the source of metastasis. 84500 +No NIH Category available 3-Dimensional;4T1;Acceleration;Algorithms;Artificial Intelligence;Biology;Biosensor;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Categories;Cell model;Cells;Cellular biology;Characteristics;Classification;Collaborations;Cytometry;Data;Development;Discriminant Analysis;Disease;Disseminated Malignant Neoplasm;Distant Metastasis;Endoplasmic Reticulum;Excision;Funding;Genetic;Genomics;Goals;Grant;Heterogeneity;Imaging Device;Immunofluorescence Immunologic;Individual;Informatics;Joints;Label;Location;Lysosomes;Machine Learning;Malignant Neoplasms;Metastatic breast cancer;Methodology;Methods;Mitochondria;Modeling;Morphology;Neoplasm Metastasis;Organelles;Patients;Pattern;Phenotype;Population;Primary Neoplasm;Proliferating;Proteomics;Recurrent Malignant Neoplasm;Regulator Genes;Resistance;Sampling;Signal Pathway;Spatial Distribution;Technology;Time;Tissues;analysis pipeline;analytical tool;anticancer research;cancer cell;cancer recurrence;cancer site;cancer type;classification algorithm;deep learning;diagnostic value;genetic manipulation;improved;in vivo;innovation;machine learning classifier;machine learning method;malignant breast neoplasm;monolayer;mortality;mouse model;multiplexed imaging;neoplastic cell;new technology;novel;novel strategies;prevent;prognostic value;protein biomarkers;random forest;rare cancer;success;synthetic biology;therapy development;tool;transcriptomics;tumor IMAT-ITCR Collaboration: Artificial intelligence enhanced breast cancer dormancy cell classification-based organelle-morphology and topology Project NarrativeThis project proposes to apply OTCCP in the contest of disseminated tumor cell (DTC) dormancy and applyorganelle topology as a novel way to classify DTCs in vivo and ex vivo. NCI 10884759 9/13/23 0:00 PA-20-272 3R21CA274622-02S1 3 R21 CA 274622 2 S1 "MILLER, DAVID J" 9/1/22 0:00 8/31/24 0:00 ZCA1(M1) 1973884 "BARROSO, MARGARIDA " "KRUGER, UWE " 20 PHYSIOLOGY 190592162 G6VVMPNK4Y48 190592162 G6VVMPNK4Y48 US 42.652632 -73.77526 8455007 ALBANY MEDICAL COLLEGE ALBANY NY SCHOOLS OF MEDICINE 122083479 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 81500 NCI 50000 31500 ABSTRACTBreast cancer is a highly heterogenous disease both phenotypically and genetically. The quantity andsubcellular location of cancer protein biomarkers are used to classify breast cancer types. Transcriptomicsmultiplexed imaging or mass cytometry have been used to classify breast tumor cell heterogeneity with varyingsuccess. Although genomics and proteomics have been successful in the identification of tumor cell populationsinvolved in metastatic progression the ability to determine whether patient tumors contain metastaticsubpopulations is still lacking. Recently organelle morphology and function has been used as a direct readoutof the functional phenotypic state of an individual cancer cell. We propose to use the spatial context of organellesspecifically their subcellular location and inter-organelle relationships (topology) to classify novel and distinctmetastatic cancer cell subpopulations. We developed an Organelle Topology-based Cell Classification Pipeline(OTCCP) to quantify for the first time the topological features of subcellular organelles defined as the distancebetween each organelle object and all its neighbors within a cell. Under RFA-CA-21-013 (Development ofInnovative Informatics Methods and Algorithms for Cancer Research and Management) we will adapt or developMachine learning and Deep Learning methodologies to accelerate and automate OTCCP-based organelle-based topology cancer cell classification to identify subpopulations of metastatic cells within heterogeneousprimary tumors with potential diagnostic and prognostic value. This approach will also have major impact as adiscovery tool to advance our understanding of cancer cell biology on a subcellular level. 81500 +No NIH Category available Adverse event;American College of Radiology Imaging Network;Aromatase Inhibitors;Common Terminology Criteria for Adverse Events;Data;Demographic Factors;Development;Disparity;Dose;Early treatment;Eastern Cooperative Oncology Group;Immunotherapy;Individual;Insurance Coverage;Measurement;Methods;Modeling;Monitor;Patient Outcomes Assessments;Patients;Phenotype;Prediction of Response to Therapy;Predictive Value;Provider;Reporting;Risk;Severities;Standardization;Symptoms;Time;Treatment Protocols;Treatment outcome;Woman;anticancer research;cancer therapy;experience;improved;indexing;innovation;longitudinal analysis;malignant breast neoplasm;novel;public health relevance;targeted agent;treatment adherence;treatment risk Analysis of ECOG-ACRIN adverse event data to optimize strategies for the longitudinal assessment of tolerability in the context of evolving cancer treatment paradigms (EVOLV) Project Narrative / Public Health RelevanceImproved methods for analyzing and interpreting adverse event data would lead to a more accurate andprecise understanding of patients' experiences with cancer treatment including newly emerging treatmentregimens. The development of an effective approach to identifying patients who are experiencing (or who areat risk of experiencing) treatment tolerability issues could trigger improved AE management and maximizetreatment outcomes. NCI 10884567 8/16/23 0:00 PA-20-272 3U01CA233169-05S1 3 U01 CA 233169 5 S1 "ALTSHULER, RACHEL DINA" 7/10/23 0:00 8/31/24 0:00 1883998 "GRAY, ROBERT J" "WAGNER, LYNNE I." 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 7/10/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 350000 NCI 271510 78490 Project SummaryEVOLV proposes to deliver sophisticated and standardized methods for assessing monitoring analyzing andreporting adverse events (AEs) experienced by individuals undergoing cancer treatment. These methods willharness the potential of the patient-reported outcomes version of the NCI Common Terminology Criteria forAdverse Events (PRO-CTCAETM) to provide previously unavailable patient perspectives on the tolerability oftreatments (including targeted agents immunotherapies and other evolving treatments for which the typeseverity timing and trajectory of adverse events is less known). Such information will help providers betteridentify and support patients at risk for treatment discontinuation dose reductions and treatment delays.Specifically this study aims to: 1) perform longitudinal analyses of CTCAE and PRO-CTCAE data from trialsconducted within the ECOG-ACRIN Cancer Research Group using traditional and innovative strategies toexamine AE trajectories and to produce a new reporting standard that reflects severity and fluctuations overtime; 2) examine PRO-CTCAE and CTCAE predictors of treatment adherence and discontinuation; and 3)validate the broader predictive value of GP5 a single item from the Functional Assessment of Cancer Therapy-General (FACT-G) shown to predict early treatment discontinuation among women with breast cancer takingaromatase inhibitors. The study will also explore two novel measurement models for PRO-CTCAE scores andCTCAE grades: a phenotypic model including co-occurrence of symptoms and a cumulative burden index(CBI) for characterizing the quantity of burden accumulated by patients over time. Analyses will includedemographic factors and insurance status to identify potential disparities. 350000 +No NIH Category available Acceleration;Area;Award;Biological Markers;Cancer Burden;Cancer Center;Cancer Control;Cancer Model;Catchment Area;Clinical;Clinical Research;Communication;Communities;Comprehensive Cancer Center;Developmental Therapeutics Program;Diagnosis;Education;Ensure;Epigenetic Process;Equity;Faculty;Family;Funding;Goals;Grant;Growth;Human;Image;Immunologics;Incidence;Individual;Infrastructure;Innovative Therapy;Institution;Intervention;Journals;Knowledge;Leadership;Malignant Neoplasms;Manuscripts;Minority Groups;Minority Participation;Mission;Names;Nature;Patients;Peer Review;Persons;Population;Prevention;Provider;Public Health;Publications;Publishing;Radiation;Research;Research Infrastructure;Research Personnel;Research Priority;Resource Sharing;Resources;Schools;Science;Services;Societies;Technology;Training;Underrepresented Minority;Underserved Population;Universities;Wisconsin;Work;anticancer research;cancer care;cancer genetics;cancer imaging;cancer prevention;cancer therapy;equity diversity and inclusion;evidence base;health care delivery;improved;innovation;inter-institutional;medical schools;member;mortality;next generation;population based;programs;recruit;tumor microenvironment;virology UW Comprehensive Cancer Center Support PROJECT NARRATIVEThe University of Wisconsin Carbone Cancer Center (UWCCC) which is a matrix center within the University ofWisconsin School of Medicine and Public Health (SMPH) seeks to dramatically reduce the burden of cancerwithin and beyond our catchment. Specifically the UWCCC will do this by decreasing cancer incidence andmortality among populations within our catchment area and beyond including our minority and underservedpopulations. We will facilitate pursuit of this goal through partnerships with other health delivery systems andstate and community agencies for dissemination of evidence-based findings. The UWCCC will accomplish ourgoals through nurturing a diverse and supportive cancer community reliable infrastructure and efficientresources. During the current funding period UWCCC continued to decrease the burden of cancer in ourcatchment and beyond through prioritized research areas (e.g. innovative therapies and biomarkers cancerimaging and expanded population-based cancer research) enhanced research platforms (e.g. improved clinicalresearch infrastructure and shared resources) increased efforts to build mission-related philanthropy andexpanded local-to-global partnerships. NCI 10884535 8/29/23 0:00 PAR-21-321 3P30CA014520-49S2 3 P30 CA 14520 49 S2 "SHAFIK, HASNAA" 4/25/97 0:00 3/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 1877637 "BAILEY, HOWARD H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 6/21/23 0:00 3/31/24 0:00 397 Research Centers 2023 229000 NCI 148552 80448 PROJECT SUMMARY/ABSTRACTThe University of Wisconsin Carbone Cancer Center (UWCCC) seeks continued funding for years 49-53 tofurther accelerate its mission to dramatically reduce the burden of cancer within and beyond its catchment theState of Wisconsin. The UWCCC which is a matrix center within the University of Wisconsin School of Medicineand Public Health (SMPH) is composed of 218 faculty members from 38 departments and 9 schools of theUniversity of Wisconsin-Madison (UW). Our members pursue cancer care research and education through 6scientific programs (Human Cancer Virology Cancer Genetic and Epigenetic Mechanisms TumorMicroenvironment Imaging and Radiation Sciences Developmental Therapeutics and Cancer Prevention andControl) supported by 12 Shared Resources. During the current grant period (2017-2021) leadership hassuccessfully recruited >40 new and more diverse members and strengthened existing or new infrastructurefacilitating our membership publishing 3351 cancer-relevant manuscripts (31% inter- or intra-programmatic53% inter-institutional) with a significant increased proportion in high (10) impact factor journals (prior grant11% compared to current 23%) increasing our NCI research (Direct 2017 $18.6M 2021 $24.9M) and totalresearch funding (Direct 2017 $70.4M 2021 $76.3M) obtaining more multi-project awards (P U) supportingmore trainees and supporting communities throughout our expanded catchment.The UWCCC will accomplish this mission through nurturing a diverse and supportive cancer community reliableinfrastructure and efficient resources. The UWCCC worked to decrease the burden of cancer in our catchmentand beyond through prioritized research areas (e.g. innovative therapies and biomarkers cancer imaging andexpanded population-based cancer research) enhanced research platforms (e.g. improved clinical researchinfrastructure and shared resources) increased efforts to build mission-related philanthropy and expanded local-to-global partnerships. 229000 +No NIH Category available Adverse event;Benefits and Risks;Clinical Data;Clinical Trials;Code;Collaborations;Common Terminology Criteria for Adverse Events;Communication;Contracts;Data;Data Adjustments;Data Set;Development;Diarrhea;Dose;Drug Evaluation;Equilibrium;Evaluation;Grant;Hospitalization;Industry;Libraries;Measures;Methods;National Cancer Institute;National Clinical Trials Network;Nausea;Participant;Patient Outcomes Assessments;Patient Self-Report;Patients;Performance Status;Pharmaceutical Preparations;Process;Reporting;Research Personnel;Role;Standardization;Statistical Methods;Symptoms;Techniques;Testing;Time;Toxic effect;Work;cancer clinical trial;data sharing;data visualization;experience;flexibility;member;multidisciplinary;pandemic disease;patient oriented;side effect;symptomatology;tool Analyzing and Interpreting PRO-CTCAE with CTCAE and Other Clinical Data to Characterize Drug Tolerability PROJECT NARRATIVEThe National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria forAdverse Events (PRO-CTCAE) was previously developed to elicit symptomatic toxicity information directlyfrom participants in cancer clinical trials. This supplement will conclude development of a host ofadvanced statistical and data visualization methods using newly available clinical trial data setspreviously delayed by the pandemic to analyze relationships of PRO-CTCAE with other clinical trial datain evaluations of drug tolerability. In collaboration with other U01 consortium members this work willproduce standardized techniques for longitudinal PRO-CTCAE data that adjust for missingness and baselinesymptomatology and can inform analytical best practices for this tool. NCI 10884103 8/15/23 0:00 PA-20-272 3U01CA233046-05S1 3 U01 CA 233046 5 S1 "ALTSHULER, RACHEL DINA" 7/8/23 0:00 8/31/24 0:00 8704946 "BASCH, ETHAN M." "DUECK, AMYLOU CONSTANCE" 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/8/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 269200 NCI 296461 53537 PROJECT ABSTRACTIn cancer clinical trials it is essential to understand and communicate the negative impact of drugs on patientparticipants in order to balance risks and benefits. Symptom side effects such as nausea and diarrhea areparticularly common and impactful on the patient experience. However historically this information has beenreported by clinicians on behalf of their patients rather than by patients themselves a process that has beenshown to miss up to half of patients' symptoms. Therefore the National Cancer Institute (NCI) supporteddevelopment of the Patient-Reported Outcomes version of the Common Terminology Criteria for AdverseEvents (PRO-CTCAE) a library of questions to enable systematic patient self-reporting of side effectinformation. To date the PRO-CTCAE questions have been developed and tested for validity and feasibility ofuse in clinical trials work that was led by the investigators on this proposal under contracts to the NCI.However it is not yet established how best to combine PRO-CTCAE information with traditional measures oftreatment impact such as clinician-reported adverse events time on treatment drug dose levels performancestatus and hospitalizations. The purpose of this supplement is to complete work towards understanding therole of the PRO-CTCAE in combination with these traditional measures of treatment impact in assessments ofdrug tolerability. In this supplement advanced statistical methods will be used to analyze data fromnewly available clinical trials delayed by the pandemic accessible to the team through the NationalClinical Trial Network (cooperative groups) and industry. The specific aims are to: 1) characterizerelationships between the PRO-CTCAE and traditional measures of treatment impact and tolerability; 2)test and standardize analytic techniques for the PRO-CTCAE; 3) refine approaches to analyzing missingPRO-CTCAE data; and 4) develop and refine tabular and graphical data visualizations for longitudinalPRO-CTCAE data. To accomplish these aims our multi-disciplinary team will work collaboratively andflexibly with other investigators and stakeholders through the U01 consortium chaired by Dr. Amylou Dueckand will continue to share data statistical programming code and ideas freely. This work is intended toinform best practices for tabulating and reporting PRO-CTCAE data and will enable more systematicand patient-centered evaluations of tolerability in cancer clinical trials. This supplement will extend the grantby 12 months. 269200 +No NIH Category available Alleles;BRCA deficient;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Breast;Cells;Cessation of life;Chemoprevention;Clinical Trials;Complement;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Disorder;DNA Repair Enzymes;DNA Repair Gene;DNA Repair Inhibition;DNA-Directed DNA Polymerase;Dependence;Development;Digestion;Double Strand Break Repair;Drug Targeting;Early Intervention;Excision;Fatigue;Funding;Future;Gene Mutation;Genes;Genotype;Germ-Line Mutation;Goals;Grant;Heritability;High-Risk Cancer;Image;Longevity;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Molecular Target;Monitor;Mus;Myelosuppression;Nausea;Normal Cell;Organ;Ovarian;PALB2 gene;Parents;Patients;Pharmaceutical Preparations;Phase;Pilot Projects;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Predisposition;Prevention strategy;Proteins;Publishing;Research Personnel;Role;Serous;Specialized Center;Testing;Therapeutic;Transgenic Mice;United States;Validation;Wild Type Mouse;Work;cancer cell;cancer initiation;cancer prevention;cancer therapy;cell type;design;efficacy evaluation;helicase;high risk population;inhibitor;inhibitor therapy;interest;lifetime risk;luminescence;malignant breast neoplasm;mouse model;mutant;neoplastic;novel;nuclease;premalignant;prevent;repaired;response;small molecule;small molecule inhibitor;therapeutic target;tumor initiation;tumorigenesis Assessing DNA Polymerase Theta as a Therapeutic Target in BRCA1 Mutant Cancer PROJECTIVE NARRATIVEThere are approximately 55000 deaths from breast and ovarian cancer annually in the United States withBRCA1 and BRCA2 mutations found in 5-7% of breast and 6-15% of ovarian cancers cases. Suitablepreneoplastic interception strategies are lacking for patients with BRCA1 and BRCA2 mutations. The goal of thisproject is to determine whether Pol is a suitable target for preventing BRCA1 mutant cancer development. NCI 10884036 9/18/23 0:00 PA-20-272 3R01CA262466-02S1 3 R01 CA 262466 2 S1 "WITKIN, KEREN L" 3/1/22 0:00 2/28/27 0:00 10620424 "JOHNSON, NEIL " Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 9/18/23 0:00 2/29/24 0:00 393 Non-SBIR/STTR 2023 200000 NCI 106383 93617 PROJECT SUMMARY/ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-064. BRCA1 PALB2 and BRCA2 (BRCA) germline mutations increase lifetime risk of developing breast andovarian cancer. BRCA-deficient cells whether cancer or pre-cancer are homology directed repair (HDR)-defective and thus highly sensitive to drugs that cause DNA damage or inhibit DNA repair. Loss of HDR activityprovides therapeutic opportunities for example PARP inhibitors (PARPi) selectively kill HDR-deficient cells andare approved to treat BRCA-mutant cancers. PARPi therapy although generally well-tolerated in the setting ofcancer treatment is not an ideal preventative agent given therapy causes nausea fatigue andmyelosuppression. Therefore there is an unmet need for new preventative targets and agents that block or delaythe development of BRCA-associated cancer. In this supplement we will carry out proof-of-principle studies anddetermine whether DNA Polymerase Theta (Pol) is an effective target for BRCA1 cancer prevention. We willuse an ovarian cancer mouse model to examine the impact of Polq gene status on Brca1 cancer development.These ideas will be tested in the following Aim: Evaluate Brca1 cancer initiation and Polq gene mutations. Wewill use a syngeneic mouse model derived from transgenic mice with high-grade serous ovarian cancer (HGSOC)to examine tumor initiation These preliminary studies will determine whether Pol is an effective target for theinterception and lay the ground work for future studies using small molecule Pol inhibitors. 200000 +No NIH Category available Acceleration;Achievement;Address;Affect;Aging;B lymphoid malignancy;Basic Science;Biological;California;Cancer Burden;Cancer Center Support Grant;Cancer Patient;Caring;Catchment Area;Cell Therapy;City of Hope Comprehensive Cancer Center;Clinical;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;County;Development;Diagnosis;Early Diagnosis;Education;Enrollment;Fostering;Funding;Grant;Growth;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Trial;Investigation;Leadership;Licensing;Longevity;Los Angeles;Malignant Neoplasms;Mission;Oranges;Pathway interactions;Patient Care;Patients;Peer Review;Persons;Policies;Population;Population Heterogeneity;Population Research;Population Study;Populations at Risk;Prevention;Prevention approach;Productivity;Publications;Publishing;Research;Research Personnel;Research Support;Resolution;Resource Sharing;Resources;Risk;Rural;Science;Scientist;Speed;Strategic Planning;Teacher Professional Development;Training;Training and Education;Translational Research;Translations;Urban Population;Vision;anticancer research;base;cancer prevention;cell growth;chimeric antibody;clinical practice;community engagement;equity diversity and inclusion;experience;first-in-human;frontier;gene function;health equity promotion;improved;manufacturing facility;member;next generation;novel;novel therapeutic intervention;outreach;participant enrollment;population based;precision medicine;programs;research clinical testing;skills;success;survivorship;treatment trial Cancer Center Support Grant Narrative OverallThe City of Hope Comprehensive Cancer Center leverages the scientific expertise of 175 cancer-focusedinvestigators who form five productive Research Programs spanning basic translational clinical and population-based research that are supported by unique institutional resources and a robust cancer-focused researchfunding base. An active clinical trials portfolio builds on institutional research discoveries to facilitate advancesacross the translational research continuum that benefit the population of a diverse Catchment Area and thelarger community of people at risk for or affected by cancer. NCI 10883812 7/26/23 0:00 PAR-21-321 3P30CA033572-40S2 3 P30 CA 33572 40 S2 "ROBERSON, SONYA" 8/1/97 0:00 11/30/27 0:00 Cancer Centers Study Section (A)[NCI-A] 6367572 "CARPTEN, JOHN D." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 249999 NCI 142045 107954 Abstract OverallThe City of Hope Comprehensive Cancer Center (COHCCC) received NCI-designation in 1981 andComprehensive status in 1998. Led by Steven T. Rosen MD the COHCCC is composed of 175 full Membersfive productive Research Programs eleven established Shared Resources and one developing SharedResource a robust cancer-focused research funding base (76% growth in NCI funding in the current fundingcycle) and an active clinical trials portfolio that builds on institutional research discoveries. The COHCCCfacilitates advances across the translational research continuum by providing infrastructure strategic planningadministrative support and mechanisms for transdisciplinary interactions that catalyze cancer-focused activitiestraversing basic discovery clinical and population-based investigations. These activities are aligned to reducecancer burden of a highly populated and diverse Catchment Area of nearly 18 million people that encompasses33109 square miles and ranges from urban population centers concentrated in Los Angeles and OrangeCounties to rural and frontier regions in eastern San Bernardino and Riverside Counties. To foster high-impacttransdisciplinary cancer-focused research the COHCCC leverages a spectrum of state-of-the-art SharedResources including in-house GMP manufacturing facilities; informatics and precision medicine resources;notable breadth and depth of in-house experience in conducting clinical trials; and a centralized administrativeinfrastructure. The COHCCC is also committed to developing and enhancing the diversity of the next generationof leaders in basic clinical and population-based cancer-related research through robust training initiatives thatbegin at K-12 outreach and continue through junior faculty development. To enhance cancer prevention improveearly detection and accelerate translation of novel therapeutic approaches that impact patients across thelifespan and from diverse populations the COHCCC will pursue the following Specific Aims: 1) Identify developproduce and advance first-in-field and first-in-human new treatments; 2) Implement four strategic initiatives:advancing precision medicine expanding cellular therapeutics promoting health equity and enhancing clinicalresearch in the clinical network; 3) Assess and address the cancer burden in the COHCCC Catchment Areapromoting early detection prevention novel treatments aging and survivorship; 4) Advance training andeducational initiatives to support the next generation of cancer-focused scientists and clinicians; 5) Enactconcrete policies to enhance diversity equity and inclusion in the COHCCC Membership and Leadership.During the next cycle the COHCCC will expand on historic strengths and advance critical initiatives that willbenefit the diverse population of the Catchment Area and the larger community of individuals at risk for oraffected by cancer. 249999 +No NIH Category available Acceleration;Achievement;Address;Affect;Aging;B lymphoid malignancy;Basic Science;Biological;California;Cancer Burden;Cancer Center Support Grant;Cancer Patient;Caring;Catchment Area;Cell Therapy;City of Hope Comprehensive Cancer Center;Clinical;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;County;Development;Diagnosis;Early Diagnosis;Education;Enrollment;Fostering;Funding;Grant;Growth;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Trial;Investigation;Leadership;Licensing;Longevity;Los Angeles;Malignant Neoplasms;Mission;Oranges;Pathway interactions;Patient Care;Patients;Peer Review;Persons;Policies;Population;Population Heterogeneity;Population Research;Population Study;Populations at Risk;Prevention;Prevention approach;Productivity;Publications;Publishing;Research;Research Personnel;Research Support;Resolution;Resource Sharing;Resources;Risk;Rural;Science;Scientist;Speed;Strategic Planning;Teacher Professional Development;Training;Training and Education;Translational Research;Translations;Urban Population;Vision;anticancer research;base;cancer prevention;cell growth;chimeric antibody;clinical practice;community engagement;equity diversity and inclusion;experience;first-in-human;frontier;gene function;health equity promotion;improved;manufacturing facility;member;next generation;novel;novel therapeutic intervention;outreach;participant enrollment;population based;precision medicine;programs;research clinical testing;skills;success;survivorship;treatment trial Cancer Center Support Grant Narrative OverallThe City of Hope Comprehensive Cancer Center leverages the scientific expertise of 175 cancer-focusedinvestigators who form five productive Research Programs spanning basic translational clinical and population-based research that are supported by unique institutional resources and a robust cancer-focused researchfunding base. An active clinical trials portfolio builds on institutional research discoveries to facilitate advancesacross the translational research continuum that benefit the population of a diverse Catchment Area and thelarger community of people at risk for or affected by cancer. NCI 10883810 7/20/23 0:00 PAR-21-321 3P30CA033572-40S1 3 P30 CA 33572 40 S1 "ROBERSON, SONYA" 8/1/97 0:00 11/30/27 0:00 Cancer Centers Study Section (A)[NCI-A] 6367572 "CARPTEN, JOHN D." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 250000 NCI 142046 107954 Abstract OverallThe City of Hope Comprehensive Cancer Center (COHCCC) received NCI-designation in 1981 andComprehensive status in 1998. Led by Steven T. Rosen MD the COHCCC is composed of 175 full Membersfive productive Research Programs eleven established Shared Resources and one developing SharedResource a robust cancer-focused research funding base (76% growth in NCI funding in the current fundingcycle) and an active clinical trials portfolio that builds on institutional research discoveries. The COHCCCfacilitates advances across the translational research continuum by providing infrastructure strategic planningadministrative support and mechanisms for transdisciplinary interactions that catalyze cancer-focused activitiestraversing basic discovery clinical and population-based investigations. These activities are aligned to reducecancer burden of a highly populated and diverse Catchment Area of nearly 18 million people that encompasses33109 square miles and ranges from urban population centers concentrated in Los Angeles and OrangeCounties to rural and frontier regions in eastern San Bernardino and Riverside Counties. To foster high-impacttransdisciplinary cancer-focused research the COHCCC leverages a spectrum of state-of-the-art SharedResources including in-house GMP manufacturing facilities; informatics and precision medicine resources;notable breadth and depth of in-house experience in conducting clinical trials; and a centralized administrativeinfrastructure. The COHCCC is also committed to developing and enhancing the diversity of the next generationof leaders in basic clinical and population-based cancer-related research through robust training initiatives thatbegin at K-12 outreach and continue through junior faculty development. To enhance cancer prevention improveearly detection and accelerate translation of novel therapeutic approaches that impact patients across thelifespan and from diverse populations the COHCCC will pursue the following Specific Aims: 1) Identify developproduce and advance first-in-field and first-in-human new treatments; 2) Implement four strategic initiatives:advancing precision medicine expanding cellular therapeutics promoting health equity and enhancing clinicalresearch in the clinical network; 3) Assess and address the cancer burden in the COHCCC Catchment Areapromoting early detection prevention novel treatments aging and survivorship; 4) Advance training andeducational initiatives to support the next generation of cancer-focused scientists and clinicians; 5) Enactconcrete policies to enhance diversity equity and inclusion in the COHCCC Membership and Leadership.During the next cycle the COHCCC will expand on historic strengths and advance critical initiatives that willbenefit the diverse population of the Catchment Area and the larger community of individuals at risk for oraffected by cancer. 250000 +No NIH Category available Acceleration;Area;Award;Biological Markers;Cancer Burden;Cancer Center;Cancer Control;Cancer Model;Catchment Area;Clinical;Clinical Research;Communication;Communities;Comprehensive Cancer Center;Developmental Therapeutics Program;Diagnosis;Education;Ensure;Epigenetic Process;Equity;Faculty;Family;Funding;Goals;Grant;Growth;Human;Image;Immunologics;Incidence;Individual;Infrastructure;Innovative Therapy;Institution;Intervention;Journals;Knowledge;Leadership;Malignant Neoplasms;Manuscripts;Minority Groups;Minority Participation;Mission;Names;Nature;Patients;Peer Review;Persons;Population;Prevention;Provider;Public Health;Publications;Publishing;Radiation;Research;Research Infrastructure;Research Personnel;Research Priority;Resource Sharing;Resources;Schools;Science;Services;Societies;Technology;Training;Underrepresented Minority;Underserved Population;Universities;Wisconsin;Work;anticancer research;cancer care;cancer genetics;cancer imaging;cancer prevention;cancer therapy;equity diversity and inclusion;evidence base;health care delivery;improved;innovation;inter-institutional;medical schools;member;mortality;next generation;population based;programs;recruit;tumor microenvironment;virology UW Comprehensive Cancer Center Support PROJECT NARRATIVEThe University of Wisconsin Carbone Cancer Center (UWCCC) which is a matrix center within the University ofWisconsin School of Medicine and Public Health (SMPH) seeks to dramatically reduce the burden of cancerwithin and beyond our catchment. Specifically the UWCCC will do this by decreasing cancer incidence andmortality among populations within our catchment area and beyond including our minority and underservedpopulations. We will facilitate pursuit of this goal through partnerships with other health delivery systems andstate and community agencies for dissemination of evidence-based findings. The UWCCC will accomplish ourgoals through nurturing a diverse and supportive cancer community reliable infrastructure and efficientresources. During the current funding period UWCCC continued to decrease the burden of cancer in ourcatchment and beyond through prioritized research areas (e.g. innovative therapies and biomarkers cancerimaging and expanded population-based cancer research) enhanced research platforms (e.g. improved clinicalresearch infrastructure and shared resources) increased efforts to build mission-related philanthropy andexpanded local-to-global partnerships. NCI 10882940 8/28/23 0:00 PAR-21-321 3P30CA014520-49S1 3 P30 CA 14520 49 S1 "SHAFIK, HASNAA" 4/25/97 0:00 3/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 1877637 "BAILEY, HOWARD H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 6/21/23 0:00 3/31/24 0:00 397 Research Centers 2023 254830 NCI 165163 89667 PROJECT SUMMARY/ABSTRACTThe University of Wisconsin Carbone Cancer Center (UWCCC) seeks continued funding for years 49-53 tofurther accelerate its mission to dramatically reduce the burden of cancer within and beyond its catchment theState of Wisconsin. The UWCCC which is a matrix center within the University of Wisconsin School of Medicineand Public Health (SMPH) is composed of 218 faculty members from 38 departments and 9 schools of theUniversity of Wisconsin-Madison (UW). Our members pursue cancer care research and education through 6scientific programs (Human Cancer Virology Cancer Genetic and Epigenetic Mechanisms TumorMicroenvironment Imaging and Radiation Sciences Developmental Therapeutics and Cancer Prevention andControl) supported by 12 Shared Resources. During the current grant period (2017-2021) leadership hassuccessfully recruited >40 new and more diverse members and strengthened existing or new infrastructurefacilitating our membership publishing 3351 cancer-relevant manuscripts (31% inter- or intra-programmatic53% inter-institutional) with a significant increased proportion in high (10) impact factor journals (prior grant11% compared to current 23%) increasing our NCI research (Direct 2017 $18.6M 2021 $24.9M) and totalresearch funding (Direct 2017 $70.4M 2021 $76.3M) obtaining more multi-project awards (P U) supportingmore trainees and supporting communities throughout our expanded catchment.The UWCCC will accomplish this mission through nurturing a diverse and supportive cancer community reliableinfrastructure and efficient resources. The UWCCC worked to decrease the burden of cancer in our catchmentand beyond through prioritized research areas (e.g. innovative therapies and biomarkers cancer imaging andexpanded population-based cancer research) enhanced research platforms (e.g. improved clinical researchinfrastructure and shared resources) increased efforts to build mission-related philanthropy and expanded local-to-global partnerships. 254830 +No NIH Category available American;Dedications;Funding;Location;Malignant Neoplasms;Methodology;National Cancer Institute;Process;Registries;Research Personnel;System;minimal risk;neoplasm registry;surveillance data;virtual VIRTUAL POOLED REGISTRY (VPR) PROJECT n/a NCI 10880204 75N91021D00018-P00004-759102100002-1 N02 9/19/21 0:00 6/30/24 0:00 78362694 "KPHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2023 346667 NCI Coordinated by the North American Association of Cancer Registries (NAACCR) with funding from the National Cancer Institute the Virtual Pooled Registry Cancer Linkage System provides a single location to facilitate timely access to and use of high quality cancer surveillance data for minimal risk linkage studies. Use of an automated standard linkage methodology and streamlined application process will significantly reduce the level of effort researchers and registries must dedicate to the linkage and approval process. 346667 +No NIH Category available Active Sites;Aging;BRAF gene;Benchmarking;Binding;Binding Sites;Biological Assay;Biology;Cancer Model;Cell Line;Cells;Chemicals;Clinical;Colorectal Cancer;Complex;Data;Development;Diagnosis;Drug Kinetics;Drug Receptors;Drug Targeting;Drug resistance;Excretory function;Extracellular Signal Regulated Kinases;Feedback;Genetic study;Glues;Homologous Gene;Human;Immunotherapy;In Vitro;Individual;KRAS2 gene;KSR gene;Laboratories;Ligands;MAP Kinase Gene;MEKKs;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolism;Microsomes;Mitogen-Activated Protein Kinase Inhibitor;Modality;Molecular;Mus;Mutate;Nature;Oncogenes;Oncogenic;Oncology;Organoids;Parents;Pathway interactions;Patients;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Phosphotransferases;Physiological;Predisposition;Property;Protein Family;Protein Kinase;Proteins;Publishing;Ras/Raf;Rationalization;Resistance;Roentgen Rays;Role;Safety;Series;Signal Transduction;Structure;Testing;Therapeutic;Therapeutic Index;Time;Toxic effect;Work;X-Ray Crystallography;Xenograft procedure;absorption;analog;antagonist;combinatorial;design;effective therapy;efficacy evaluation;improved;in silico;in vivo;inhibitor;insight;interfacial;next generation;novel;novel drug class;novel therapeutics;paralogous gene;pharmacologic;pharmacophore;pre-clinical;receptor binding;residence;resistance mechanism;response;scaffold;small molecule;targeted treatment;therapeutic development;tool;treatment duration;triple-negative invasive breast carcinoma;tumor Molecular Glues to Target RAS-MAPK Driven Cancers NARRATIVEMolecular glues display several important pharmacodynamic advantages over drugs that operate throughsingle targets including enhanced on-target residence time and an ability to fundamentally rewire signaltransduction networks. In this proposal we will seek to build new compounds and next-generation drugs fortargeting RAS-MAPK driven cancers that possess molecular glue-like features thereby offering a newtherapeutic path for selectively antagonizing RAS-MAPK driven malignancies in patients. Compounds will bebuilt to overcome key efficacy and safety limitations of currently available drugs thereby offering a new mode-of-action for targeting the RAS-MAPK pathway. NCI 10880005 8/24/23 0:00 PA-21-268 7R01CA227636-07 7 R01 CA 227636 7 "AGYIN, JOSEPH KOFI" 7/1/23 0:00 2/29/28 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 9752313 "DAR, ARVIN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 356264 NCI 201279 154985 SUMMARYWe seek to develop a new class of drugs for RAS-MAPK driven cancers by targeting the interfacial bindingsites of key regulatory complexes within the cascade. By moving away from conventional active site-baseddrugs we have the potential for a unique class of compounds with advantages in terms of selectivity targetengagement therapeutic index and combinatorial activity to mitigate the emergence of drug resistance.The MAPK/ERK Kinase (MEK) MEK is a shared effector of KRAS and BRAF which are among the mostfrequently mutated oncogenes and protein kinases across all human cancers. As such MEK has long beenpursued as a drug target in oncology and more recently in immunotherapy and aging. However many drugsthat target MEK are limited due to on-target associated toxicities and drug resistance. Accordingly amolecular understanding of the structure and function of MEK within physiological complexes could provide atemplate for the design of safer and more effective therapies. My laboratory has made initial steps in thisdirection through the determination of X-ray crystal structures of MEK bound to the RAF paralog KinaseSuppressor of Ras (KSR) and in complex with various MEKi including the first ever co-crystal structuresbound to the clinical drug trametinib (Khan et al. Nature 2020). Unlike most targeted therapies trametinib wasserendipitously identified through phenotypic screens and X-ray crystal structures had been lacking. Our novelstructural and functional insights have revealed an unexpected mode of binding in which the inhibitor pocket fortrametinib is formed through the interface between MEK and KSR revealing KSR as a direct co-receptor of thedrug and trametinib as an interfacial binder. Moreover our studies suggest that the unique therapeuticproperties of trametinib derive from the ability of the drug to bind at the interface of the complex. Building fromthese insights we have developed a tool compound trametiglue with enhanced interfacial binding propertiesand several novel pharmacological features including unprecedented potency and an ability to overcome acommon resistance mechanism to trametinib and other clinical MEKi. This proposal focuses on developing anadvanced set of analogs through structure-based design and synthesis. Our targets include advancedtrametiglue analogs including paralog-selective molecular glues to target individual MAPK signalingcomplexes that have been implicated in RAS-MAPK driven cancers and sensitivity to currently available drugs(Aim 1). In vivo target engagement and optimization of drug-like properties with this expanded set of analogs(Aim 2). Testing in preclinical cancer models including patient derived organoids and xenografts (Aim 3).There are over 5 million individuals diagnosed globally with RAS-MAPK driven cancers on a yearly basis.Despite recent therapeutic breakthroughs with for example KRAS-G12C and BRAF-V600E inhibitors over90% of RAS-MAPK tumors are unactionable. Advances in this proposal will lead to next generation drugs anda new therapeutic modality for selectively antagonizing RAS-MAPK driven malignancies in patients. 356264 +No NIH Category available Acute Myelocytic Leukemia;Address;Administrative Supplement;Adolescent and Young Adult;Award;Bioinformatics;Biological Markers;Bone marrow failure;Cancer Center Support Grant;Cells;Childhood;Childhood Acute Myeloid Leukemia;Classification;Clinical;Clonal Expansion;Computational Biology;Consumption;Cytogenetic Analysis;Data;Detection;Diagnosis;Ecosystem;Epigenetic Process;Foundations;Gene Transfer;Genes;Genomics;Goals;Healthcare;Hematopathology;Hematopoiesis;Hematopoietic Neoplasms;Immunophenotyping;Impairment;Intelligence;International;Knowledge;Learning;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical Imaging;Methods;Modeling;Molecular;Molecular Profiling;Morphology;Multiomic Data;Mutation;Myelogenous;Neurosciences;Outcome;Parents;Patients;Performance;Positioning Attribute;Process;Prognosis;Research;Sampling;Selection for Treatments;Time;anticancer research;biomarker discovery;cancer subtypes;cancer type;cell type;cost;cost effective;deep learning;diverse data;epigenomics;experience;flexibility;genetic signature;image processing;improved;individualized medicine;kernel methods;leukemia;leukemia/lymphoma;machine learning framework;machine learning method;machine learning model;multidisciplinary;multimodality;multiple omics;next generation sequencing;novel;rare cancer;risk stratification;single cell analysis;single-cell RNA sequencing;specific biomarkers;therapy design;transcriptome sequencing;transcriptomics;treatment optimization An Accurate Machine Learning Framework for Childhood Acute Myeloid Leukemia Subtype Identification by Integrating Bulk and Single-Cell Multi-Omics Data Within and Beyond the CCDI Ecosystem Project NarrativeIn this NCI Childhood Cancer Data Initiative (CCDI) supplement project we propose to develop an accurate andcost-effective machine learning (ML) framework for childhood acute myeloid leukemia subtype identification byintegrating various types of multi-omics data. If successful our study will directly improve downstream childhoodAML diagnosis prognosis and treatment. Our proposed framework in this study can also be extensible toidentifying subtypes of other pediatric adolescent and young adult (AYA) cancers especially ultra-rare tumors. NCI 10879909 9/26/23 0:00 PA-20-272 3P30CA036727-37S5 3 P30 CA 36727 37 S5 "BELIN, PRECILLA L" 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 2401856 "COWAN, KENNETH H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/26/23 0:00 8/31/24 0:00 397 Research Centers 2023 500000 NCI 336189 163811 AbstractAs a fatal childhood hematopoietic malignancy characterized by clonal expansion of immature myeloidprecursors acute myeloid leukemia (AML) usually leads to bone marrow failure and impaired hematopoiesis.AML has multiple distinct subtypes characterized by morphological molecular and genetic alterations.Identifying AML subtypes can facilitate downstream risk stratification and tailored treatment design. While variousconventional methods like morphological analysis cytogenetic analysis immunophenotyping or molecularprofiling have been used for AML subtype identification they are usually costly time-consuming labor-intensiveand sometimes inaccurate. Recent progress has witnessed the application of next generation sequencing (NGS)for identifying AML subtypes but they are limited to bulk NGS data or single omics data only. With tons of omicsdata being generated within and beyond the Childhood Cancer Data Initiative (CCDI) ecosystem wehypothesize that integration of single-cell and bulk multi-omics data including genomics transcriptomics andepigenetics data will significantly facilitate subtype-specific biomarker discovery and boost the accuracy of AMLsubtype identification. Under our parent award (CA036727) in this supplemental project we propose todevelop an integrated machine learning (ML) framework for accurate and cost-effective AML subtypeidentification by combining bulk and single-cell multi-omics data within and beyond CCDI ecosystem.To achieve this we plan to undertake two specific aims. In Aim 1 we will establish a knowledge-transfer MLmodel that leverages large-scale bulk and single-cell transcriptomics data for AML subtype identification. Besidesidentifying well-annotated AML subtypes we will also explore novel AML subtypes by detecting rare cell typesfrom large-scale single cell data from which cluster-specific and rare-cell-type specific gene signatures can betransferred to the bulk transcriptomics data for improving performance of AML subtype identification. In Aim 2we will develop a multi-kernel learning and a multi-modal deep learning framework to systematically andautomatically integrate deep information related with AML subtypes from single-cell and bulk multi-omics data(including genomics transcriptomics epigenomics) to further boost AML subtype identification. Our model isflexible to tackle cases when only partial or incomplete multi-omics data are available for new patients. Webelieve successful completion of this study will have direct impacts on improving downstream childhood AMLrisk stratification facilitating diagnosis and prognosis and optimizing treatment selection. We also expect thatour proposed framework in this study can be customized and extensible to identifying subtypes of other pediatricadolescent and young adult (AYA) cancers especially ultra-rare tumors. 500000 +No NIH Category available 18 year old;Administrative Supplement;African American;Artificial Intelligence;Asian;Award;Biological;Cancer Center Support Grant;Cancer Patient;Catchment Area;Categories;Cause of Death;Central Nervous System Neoplasms;Child;Childhood;Childhood Cancer Treatment;Cities;Clinical Data;Collaborations;Comprehensive Cancer Center;DNA Methylation;Data;Data Set;Development;Diagnosis;Diagnostic;Disease;Ecosystem;Expert Systems;Genetic;Genomics;Health;Health Personnel;Health Services Accessibility;Hematopoietic Neoplasms;Hispanic;Human;Image;Information Systems;Institution;Language;Licensing;Los Angeles;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Methylation;Minority Groups;Mission;Modality;Modeling;Molecular;National Cancer Institute;Native Americans;Not Hispanic or Latino;Patients;Pediatric Hospitals;Pediatric Oncology;Population;Process;Research;Resources;Services;Solid Neoplasm;Standardization;Therapeutic Studies;Tumor Markers;Underrepresented Minority;University of Southern California Norris Cancer Center;Work;accurate diagnosis;anticancer research;artificial intelligence algorithm;cancer genome;cancer type;cloud based;cohort;data integration;database of Genotypes and Phenotypes;diagnostic accuracy;effective therapy;federal poverty level;genomic data;global health;improved;innovation;insight;methylome;multi-ethnic;multimodality;novel therapeutics;patient population;pediatric patients;racial population;rapid diagnosis;sarcoma;therapeutic development;tool;tumor;tumor DNA;web services;web-accessible;whole genome;whole slide imaging Administrative Supplements for P30 Cancer Centers Support Grants (CCSG) to Enhance the Utility of Data Available through the Childhood Cancer Data Initiative (CCDI) Ecosystem NarrativeAggregation and sharing of diverse types of data resulting from scientific studies of childhood cancer is essentialfor generating new insight and supporting the development of new therapies. Previously the partnershipbetween Childrens Hospital Los Angeles and the USC Norris Comprehensive Cancer Center resulted in theaddition of data from more than 1000 pediatric cancer patients to the Childhood Cancer Data Initiative. In thecurrent proposal we outline plans to enrich the CCDI with new types of data including tumor DNA methylationand histopathologic images and introduce innovative tools for more rapid and accurate diagnosis of pediatriccancers. NCI 10878559 9/15/23 0:00 PA-20-272 3P30CA014089-47S1 3 P30 CA 14089 47 S1 "HE, MIN" 12/1/96 0:00 11/30/24 0:00 1875698 "LERMAN, CARYN " Not Applicable 37 INTERNAL MEDICINE/MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 500000 NCI 500000 0 SummaryCancer remains the leading cause of death from disease in children. Development of therapeutic options for theremaining lethal cancers has seen little progress hampered by the rarity of childhood cancers and institutionallyisolated data systems holding tumor biomarker genetic genomic treatment and clinical data which impedesmaximally powered therapeutic studies. The National Cancer Institutes Childhood Cancer Data Initiative (CCDI)seeks innovation in pediatric cancer research approaches by markedly increasing data-sharing. Under theauspices of a previous P30 Supplement award the USC Norris Comprehensive Cancer Center (NCCC) inpartnership with Childrens Hospital Los Angeles (CHLA) successfully curated and contributed to CCDI genomicand clinical data of 1039 patient of three major categories (hematopoietic malignancies solid tumors and CNStumors) and 186 subtypes. We now propose to enrich the data sets that we submitted and to develop an onlinediagnostic resource for pediatric cancers driven by augmented Artificial Intelligence (A2I) which aims to improvepediatric cancer care access and affordability by providing a scalable and standardized diagnostic process. Theproposed A2I system will develop an AI-powered classifier for pediatric CNS and sarcomas and ultimately allpediatric cancer using whole-slide images and molecular findings in combination. Aim 1 will collect whole-slideimage (WSI) from 599 solid tumors and whole-genome methylome data of 200 CNS tumors. Collected WSI andmethylation data of these 599 tumors will be contributed to CCDI and become an integral part of our existingCHLA CCDI data set. Aim 2 will develop a multi-modal classifier of sarcomas and CNS tumors using anAugmented AI (A2I) framework. The proposed classifier is entitled Multi-Modal AI-based Diagnosis for PediatricOncology (MAD4PO) which will be cloud-based and web-accessible. To build this classifier we will leveragethe Amazon Web Services (AWS) A2I framework and associated services and tools to facilitate human-AIcollaboration for optimal diagnostics and to scale out access to the developed ML/AI models for globalhealthcare providers. Work carried out under this supplement will facilitate efforts to understand the biologicbasis of childhood cancers and to develop improved treatment for these diseases while providing new tools formore rapid and accurate diagnosis of pediatric cancers. 500000 +No NIH Category available Acceleration;Address;Adult;Affect;Black Populations;Black race;Characteristics;Clinical;Data;Development;Diagnosis;Dimensions;Disparity;Ethnic Origin;Family Cancer History;Goals;Health;Hispanic;Hispanic Populations;Malignant neoplasm of lung;Measures;Modeling;Not Hispanic or Latino;Pattern;Population;Prevention approach;Race;Research;Respondent;Sampling;Sex Differences;Survival Rate;Tobacco use;United States National Institutes of Health;Woman;Work;cancer health disparity;cancer risk;effective intervention;epidemiology study;ethnic difference;experience;improved;innovation;lung cancer prevention;men;minority health;minority health disparity;protective effect;public health intervention;public health research;racial difference;sex;social determinants;social health determinants;sociodemographic factors;sociodemographics;therapeutic target;therapy development Relative and intersectional analysis of social determinants of lung cancer risk among Black and Hispanic All of Us respondents PROJECT NARRATIVE This project promises to inform public health research by identifying concomitant social determinants ofhealth that uniquely influence sex differences in lung cancer risk among NH Black and Hispanic adults. Thiswork will advance our understanding of diminished gains for Black and Hispanic individuals from lung cancerprevention approaches. The results will identify new potential therapeutic targets for clinical and public healthintervention development. NCI 10878511 9/18/23 0:00 PA-20-272 3U54CA132378-15S2 3 U54 CA 132378 15 S2 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1(A1)-R 1922320 "HUBBARD, KAREN " "ESPINOSA, ADRIANA ; RUGLASS, LESIA MONIQUE" 12 BIOLOGY 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY SCHOOLS OF ARTS AND SCIENCES 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 853 Research Centers 2023 199999 OD 127388 72611 PROJECT SUMMARYNon-Hispanic (NH) Black adults and Hispanic adults particularly men experience significant lung cancerdisparities. Those who are diagnosed with lung cancer tend to be diagnosed at more advanced stages andhave lower survival rates than NH White counterparts. Identifying the factors that explain sex and racial/ethnicdifferences in lung cancer risk among NH Black and Hispanic individuals is critical for the development oftailored interventions that effectively address lung cancer and related disparities in these populations. Whilesocial determinants of health (SDOH) are important factors necessary for understanding minority health andhealth disparities little is known about their relative and combined influence on lung cancer risk. This newinformation is key for the development of effective approaches to mitigate lung cancer disparities affecting NHBlack and Hispanic individuals. We propose a theoretically grounded and innovative conceptual model thatexamines the relative and combined influence of traditional dimensions of SDOH on lung cancer risk at theintersection of sex and race/ethnicity among NH Black and Hispanic adults in the US. We will use datacollected as part of the All of Us epidemiological study a national effort supported by the National Institutes ofHealth with the goal of accelerating research and improving health. We will measure lung cancer risk as acomposite score of tobacco use and lung cancer family history. Our aims include cross-sectional examinationsfrom a large sample of NH Black and Hispanic men and women. First we will identify the SDOH that relativeto sociodemographic characteristics have the strongest associations with lung cancer risk. These analyses willindicate how specific SDOH may overpower the effect of protective sociodemographic factors therebyinforming diminished gains from current lung cancer prevention approaches among NH Black and Hispanicindividuals. Second we will examine how patterns of SDOH inform lung cancer risk among NH Black andHispanic adults. These analyses will highlight how unique combinations of SDOH inform sex by race/ethnicitydifferences in lung cancer risk among NH Black and Hispanic adults. This studys findings will advance ourunderstanding of diminished gains for NH Black and Hispanic individuals from lung cancer preventionapproaches. Further this study will identify new potential therapeutic targets for clinical and public healthintervention development. Thus findings from this project will have a sustained and powerful impact on thefield of lung cancer disparities research. 199999 +No NIH Category available Adolescent;Adolescent and Young Adult;Adolescent and young adult cancer patients;Adult;Brain Neoplasms;Caring;Cephalic;Child;Childhood;Childhood Brain Neoplasm;Clinical;Clinical Data;Clinical Oncology;Clinical Trials;Combined Modality Therapy;Communities;Community Clinical Oncology Program;Computerized Medical Record;DNA Sequence Alteration;Dana-Farber Cancer Institute;Data;Data Collection;Data Element;Data Set;Databases;Dose;Drug usage;Ecosystem;Enrollment;Exclusion;Formulation;Future;Genes;Genomics;Goals;Health Services Accessibility;Individual;Institution;Investigational Drugs;Label;Malignant Childhood Neoplasm;Malignant Neoplasms;Modification;Mutation;Oncologist;Oncology;Outcome;Patient-Focused Outcomes;Patients;Pediatric Oncology;Pharmaceutical Preparations;Pilot Projects;Principal Investigator;Protocols documentation;Publications;Refractory;Registries;Relapse;Reporting;Research;Resources;Role;Solid Neoplasm;Testing;Time;Toxic effect;United States Food and Drug Administration;Work;Writing;cBioPortal;cancer genomics;clinical care;clinically relevant;cohort;data submission;data visualization;experience;feasibility testing;first-in-human;genomic data;genomic profiles;high risk;leukemia;molecular targeted therapies;novel therapeutics;off-label use;oncology trial;pediatric patients;response;search engine;targeted treatment;tool;treatment and outcome;treatment duration;tumor;young adult Real-World Molecularly Targeted Treatment Registry (MaTTeR): a Pilot Study to Enrich CCDI Data Utilizing Directed Electronic Medical Record (EMR) Extraction Project NarrativeThe incorporation of genomic profiling into the clinical care of pediatric and AYA cancer patientshas resulted in identification of targetable alterations and use of molecularly targeted therapies(MTT). There is a critical need to collect and report the outcomes (efficacy dosing and toxicity)of real-world use of MTT outside of clinical trials to inform the ongoing and future role of thesedrugs in pediatric and AYA patients with cancer. This project will utilize existing genomic datacontributed to the CCDI pilot targeted clinical data extraction from the Electronic MedicalRecord (EMR) and establish an expandable and accessible resource for MTT treatment datafor the pediatric and AYA cancer community. NCI 10878384 9/18/23 0:00 PA-20-272 3P30CA006516-58S4 3 P30 CA 6516 58 S4 "PTAK, KRZYSZTOF" 9/1/23 0:00 11/30/26 0:00 1871771 "GLIMCHER, LAURIE HOLLIS" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 495880 NCI 278584 217296 Project Summary AbstractIntegration of genomic profiling into the care of pediatric adolescent and young adult (AYA)patients with cancer has resulted in the identification of potentially targetable alterations and theuse of molecularly targeted therapies (MTT). Pediatric and AYA cancer patients are increasinglytreated with MTT outside of clinical trials. Systematic data collection and publication of MTT useoutside of clinical trials are lacking such that these real-world experiences are not optimallycontributing to the current understanding of MTT use in pediatric and AYA cancers. This projectwill utilize genomic data previously contributed to the Childrens Cancer Data Initiative (CCDI)as well as additional Dana-Farber Cancer Institute (DFCI) institutional cohorts to identifypatients with targetable genomic alterations. We will then identify patients who received targetedtherapies off of a clinical trial and extract key treatment data including drug information dosedosing formulation combination treatment duration of treatment best response time to bestresponse duration of response dose modifications due to toxicity toxicities manner oftreatment access (off-label single patient investigational new drug (IND) protocol). Thesystematic clinical data collection of MTT use of the CCDI cohort of patients proposed in thisproject will serve as the proof of concept of accessing and enriching CCDI data with highlyvaluable data that is otherwise imprisoned within the electronic medical record. This project willestablish the feasibility of creating a scalable registry of real-world targeted therapy experiencethat can be expanded to additional CCDI datasets and serve as an important future resource forthe pediatric and AYA cancer community. 495880 +No NIH Category available Apoptosis;Attenuated;Binding;Biological Assay;Brain Neoplasms;Cell Death;Cell Maintenance;Cell Proliferation;Cells;Chemotherapy and/or radiation;Co-Immunoprecipitations;Communication;Cysteine Proteinase Inhibitors;Data;Development;Fellowship;Foundations;Future;Glioblastoma;Growth;Heterogeneity;Immunoprecipitation;In Vitro;Inhibition of Apoptosis;Invaded;LIF gene;Laboratories;Lysine;Lysosomes;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Mass Spectrum Analysis;Membrane;Mentorship;Molecular;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Phenotype;Phosphorylation Site;Physicians;Population;Proliferating;Protein Secretion;Proteins;Proto-Oncogene Proteins c-akt;Radiation therapy;Recombinants;Recurrence;Regulation;Reporting;Research;Resistance;Role;Scientist;Serine;Serpins;Signal Transduction;Site;Testing;Therapeutic;Therapeutic Intervention;Training;Transforming Growth Factor beta;Up-Regulation;cancer stem cell;career;chemotherapy;crosslink;disease prognostic;disuccinimidyl suberate;experience;inhibitor;insight;junctional adhesion molecule;knock-down;liquid chromatography mass spectrometry;meetings;mortality;nerve stem cell;neutralizing antibody;new therapeutic target;next generation;novel;overexpression;pluripotency;protein expression;protein function;self-renewal;standard of care;stem cell function;stem cell model;stem cell self renewal;stem cells;therapeutic development;therapy resistant;transcription factor;treatment response;tumor;tumor growth;tumor initiation;tumorigenic Role of SerpinB3 in glioblastoma cancer stem cells Project Narrative ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLSGlioblastoma (GBM) is the most common primary malignant brain tumor and a population of cancer stem cells(CSCs) allows the tumor the tumor to quickly regrow after aggressive standard-of-care treatment. The objectiveof my project is to determine the mechanism through which GBM CSCs signal through junctional adhesionmolecule-A (JAM-A) via Serpin B3 a serine/cysteine protease inhibitor that interacts with JAM-A and has beenshown to signal through TGF- in other cancers. The successful completion of this proposal will further ourunderstanding of the signaling networks used by GBM CSCs for their self-renewal identify new therapeutictargets and provide essential training toward my development as a physician scientist. NCI 10877960 12/20/23 0:00 PA-19-191 5F30CA250254-05 5 F30 CA 250254 5 "DAMICO, MARK W" 7/1/22 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16036969 "LAUKO, ADAM " Not Applicable 11 PATHOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 Project Summary ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLSGlioblastoma (GBM) is the most aggressive primary malignant brain tumor with a median survival of 18-20months. Despite therapeutic interventions including surgery radiation and chemotherapy multiple clones ofchemo- and radiotherapy-resistant cells repopulate the tumor resulting in recurrence and a high rate of patientmortality. These cells are referred to as cancer stem cells (CSCs) due to their ability to self-renew and generatethe cellular heterogeneity present in the tumor. Our lab identified junctional adhesion molecule-A (JAM-A) onCSCs and through functional studies demonstrated that JAM-A is both necessary and sufficient for self-renewaland tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcriptionfactor activity; however the intermediate signaling network is yet to be fully elucidated. To further delineate thispathway we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry to determine theproteins to which JAM-A directly binds. This analysis led to the identification of the serine/cysteine proteaseinhibitor SerpinB3 as a binding partner. Interestingly SerpinB3 does not contain the conserved PDZ domain thatis present on nearly every other known JAM-A binding partner. Although multiple pro-tumorigenic mechanismsincluding regulation of TGF-1 and inhibition of apoptosis have been proposed for SerpinB3 in the context ofother cancers very little is known about the function of the protein in GBM CSCs and its relationship to JAM-Ais yet to be elucidated. Using in vitro CSC functional assays I have accumulated evidence that SerpinB3 isnecessary for the maintenance of CSCs and that reduction of SerpinB3 attenuates TGF-1 expression. Basedon these observations I hypothesize that SerpinB3 interaction with JAM-A is essential for the maintenance ofGBM CSCs through regulation of TGF-1 and inhibition of apoptosis. Aim 1 will test the hypothesis that SerpinB3maintains the CSC state through inhibition of apoptosis and upregulation of TGF-1. I will disrupt the lysosomalmembrane with siramesine to elucidate the role of SerpinB3 in the inhibition of apoptosis. Additionally I willinvestigate the role of SerpinB3 in the regulation of TGF-1 signaling in CSCs. Aim 2 will test the hypothesis thattargeting the JAM-A/SerpinB3 interaction will compromise self-renewal and GBM growth. I will utilize DSSOcrosslinking to determine the region of interaction between the two proteins. Finally I will determine theconsequence of disrupting the JAM-A/SerpinB3 interaction on the CSC state with small interfering peptides.Successful completion of this project will advance our understanding of how the CSCs state is maintained inGBM via specific JAM-A intracellular binding domains bridging cellular communication and cell signaling. Thestudies outlined in this fellowship will provide me an opportunity to gain experience in brain tumor research andallow me to continue my training though scientific meetings and mentorship opportunities preparing for a careeras a physician scientist. 52694 +No NIH Category available Address;Adolescent;Child;Childhood;Childhood Cancer Survivor Study;Cohort Studies;Collection;DNA sequencing;Data;Data Collection;Diagnosis;Digital Imaging and Communications in Medicine;Disease susceptibility;Eligibility Determination;Future;Genetic Predisposition to Disease;Genotype;Health;Infrastructure;Institution;Intervention;Investigation;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Methodology;Methods;Modernization;Morbidity - disease rate;Outcome;Paper;Participant;Pilot Projects;Process;Publications;Quality of life;Radiation therapy;Radiometry;Records;Research;Research Personnel;Resources;Risk;SNP array;Source;Survival Rate;Survivors;Testing;biobank;childhood cancer survivor;cohort;computerized data processing;data standards;follow-up;health related quality of life;high risk population;improved;mortality;multidisciplinary;recruit;screening guidelines;survivorship CCSS Expansion Study Supplement Survival rates for many childhood and adolescent cancers have improved at a remarkable pace over the pastfive decades. The CCSS cohort has been the source of some of the most significant publications to dateaddressing the long-term mortality morbidity and quality of life of survivors of childhood cancer. Understandingthe risk for late effects of childhood cancer and its therapy provides the basis for health screeningrecommendations and interventions that can mitigate long-term health problems in this high-risk population. NCI 10876211 9/18/23 0:00 PA-20-272 3U24CA055727-29S1 3 U24 CA 55727 29 S1 "HENDERSON, LORI A" 7/1/23 0:00 11/30/26 0:00 8819228 "ARMSTRONG, GREGORY " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 7/1/23 0:00 11/30/23 0:00 395 Other Research-Related 2023 962957 NCI 870695 92262 ABSTRACTThe Childhood Cancer Survivor Study (CCSS) is a multi-institutional multi-disciplinary collaborative researchresource established to systematically evaluate long-term outcomes among children diagnosed with cancer whosurvived five or more years from diagnosis. With the successful recruitment and longitudinal follow-up of thecohort that includes survivors diagnosed and treated over three decades (1970-1999) the CCSS is the worldslargest established open resource for survivorship research with 38036 eligible survivors available forinvestigation of late mortality and 25665 participants who have contributed health-related and quality of lifeoutcomes. The resource includes comprehensive annotation of treatment exposures ongoing longitudinalfollow-up and an established biorepository from which genotype (SNP array) and DNA sequencing of 8380survivors are available to investigators for identification of genetic susceptibility for disease- and treatment-related late effects. Radiation therapy (RT) has substantially evolved over the past two decades since theestablishment of the CCSS cohort. As opposed to previous CCSS methods which required paper copies of RTplanning documents for review by the CCSS Radiation Dosimetry Center at MD Anderson data from modernRT planning collection and processing multi-institutional RT DICOM data spanning two decades will require anew and robust infrastructure. In this pilot study we propose to collect and process 100 radiotherapy recordsfrom each of five representative CCSS institutions with the aim of a developing and testing a standardized datacollection and processing methodology for use in a future CCSS expansion. 962957 +No NIH Category available Antibody-drug conjugates;Automobile Driving;Biography;Biological Markers;Biological Products;Bladder;Breast Cancer Patient;Cancer Patient;Chemotherapy and/or radiation;Cisplatin;Clinic;Clinical;Combined Modality Therapy;DNA Damage;Data;Disease;Event;Foundations;Gene Expression;Genetic;Genetic Transcription;Genomics;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Immune;Immune checkpoint inhibitor;Immune system;Immunologic Factors;Immunologics;Immunotherapy;International;Malignant neoplasm of urinary bladder;Modality;Molecular;Mutation;Oncology;Outcome;Pathogenesis;Patients;Radiation;Radiation Tolerance;Radiation therapy;Radiobiology;Research;Research Personnel;Resistance;Robin bird;Roentgen Rays;Testing;Therapeutic;Treatment Efficacy;Work;antitumor effect;cancer therapy;cancer type;checkpoint therapy;chemotherapy;immune checkpoint blockade;improved;improved outcome;innovation;insight;multidisciplinary;multimodality;next generation;preservation;programs;radiation effect;radiation resistance;radiation response;radiomics;response;standard of care;treatment strategy;tumor Genomic and Microenvironmental Determinants Temporal Dynamics and Treatment Efficacy of Radiation-Based Combination Therapies PROJECT NARRATIVEOverall Section This proposal focuses on elucidating the genomic and microenvironmental determinants and temporaldynamics underlying efficacy of radiation-based combination therapies. We will use an innovative molecularcharacterization trial testing radiation plus antibody-drug conjugate in bladder cancer and radiation plusimmunotherapy in head and neck cancer to characterize the mechanistic drivers underlying these nextgeneration RT-based therapies. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. NCI 10875876 8/1/23 0:00 RFA-CA-21-040 3U54CA274513-02S1 3 U54 CA 274513 2 S1 "VIKRAM, BHADRASAIN" 9/14/22 0:00 7/31/27 0:00 ZCA1-SRB-X(M1) 9306964 "CHAN, TIMOTHY AN-THY" "YU, DAVID SUNG-WEN" 11 INTERNAL MEDICINE/MEDICINE 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 70904 NCI 44040 26864 PROJECT SUMMARYOverall Section Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants andtemporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT) alone orin combination with other treatments is used to treat about two-thirds of all cancer patients. Despite thewidespread use of radiation therapy in oncology our understanding of the mechanisms driving response andresistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy andresistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus onusing combination therapies in which radiation is used with systemic agents highlighting the urgent need tounderstand the drivers of efficacy. Among the most promising new biologics being studied for use withradiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use aninnovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI inhead and neck cancer to characterize the mechanistic drivers underlying these next generation RT-basedcombinations. The central hypothesis of this U54 application is that specific genetic and immunologicmechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will addressthese questions through 3 specific aims. In Aim 1 we will work to understand the molecular mechanisms thatunderlie efficacy of treatment with radiation plus ADC. Here our working hypothesis is that specific genetic andimmunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage ourmolecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservationtherapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT +SG. In Aim 2 we will improve identification of patients who are sensitive or resistant to RT-based therapiesbased on new insights into transcriptional dynamics and temporal reprogramming during treatment withradiation-based therapies. Here we will leverage our molecular characterization trial treating head and necksquamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG orICI. We will build on recent experimental and clinical breakthroughs led by our research groups which haveidentified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim3 we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT +immune checkpoint blockade. Here using our head and neck trial (Part B) we will uncover the unique geneticand immunologic factors that govern response to RT when combined with these two classes of agents. Wewill elucidate the differential molecular effects of the two approaches immune reprogramming andmechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. 70904 +No NIH Category available Acute Myelocytic Leukemia;Address;Animals;Apoptotic;Biology;Cell Line;Cells;Chemoresistance;Clinical;Clinical Skills;Clonal Expansion;Communication;Comprehensive Cancer Center;Critical Thinking;Cytotoxic Chemotherapy;Data;Data Set;Development;Disease;Disease Progression;Disease-Free Survival;Doctor of Philosophy;Engraftment;Experimental Designs;FDA approved;FLT3 gene;Foundations;Frequencies;Future;Genes;Genetic;Goals;Hematologic Neoplasms;Hematology;Human;Immune;Immunodeficient Mouse;Immunophenotyping;Immunosuppression;Impairment;Inferior;Interleukin-10;Knowledge;Laboratories;MAP Kinase Gene;MCL1 gene;Malignant - descriptor;Measures;Modeling;Mus;Mutate;Mutation;Myeloid Cells;Myeloid Progenitor Cells;NF-kappa B;New Agents;Ohio;Outcome;PIK3CG gene;PTPN11 gene;PTPN22 gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenocopy;Phenotype;Play;Pre-Clinical Model;Proliferating;Proteins;Proto-Oncogene Proteins c-akt;Relapse;Reporting;Research;Research Personnel;Research Proposals;Research Training;Resistance;Rest;Role;Signal Pathway;Signal Transduction;Supervision;T-Lymphocyte;Technical Expertise;Testing;Therapeutic;Time;Training;Transgenic Organisms;acute myeloid leukemia cell;adverse outcome;anticancer research;chemotherapy;cytokine;doctoral student;effective therapy;human disease;improved;leukemogenesis;mouse model;mutant;novel;novel therapeutics;nucleophosmin;overexpression;patient population;patient subsets;preclinical study;programs;resistance mechanism;response;skills;targeted treatment;therapy development;transcription factor;translational scientist;treatment response;treatment strategy The role of PTPN11 and NPM1 mutations in acute myeloid leukemia development and therapy resistance PROJECT NARRATIVEThe goal of this proposal is to study the immunophenotype of PTPN11 and NPM1 mutant acute myeloidleukemia (AML) and the mechanism of resistance to cytotoxic and targeted therapies. Because PTPN11mutations can activate similar signaling pathways as FLT3-ITD we hypothesize that the addition of PTPN11mutations to NPM1+ AML can clinically phenocopy NPM1+/FLT3-ITD AML with adverse outcomes and therapyresistance. Successful completion of these aims will provide an understanding of the biology of PTPN11 andNPM1 mutant AML and how these cells resist treatment so that more effective therapies can be developed forthis patient population. NCI 10874122 1/5/24 0:00 PA-21-049 7F30CA265281-03 7 F30 CA 265281 3 "PURI, ANU" 1/1/22 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 15551000 "FOBARE, SYDNEY " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 5/1/23 0:00 12/31/23 0:00 398 "Training, Individual" 2023 35447 NCI 35447 0 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) is a disease characterized by clonal expansion of myeloid cells with blockeddifferentiation. Despite newly approved targeted therapies for AML there is still a large subset of patientswhose disease progresses or does not respond to treatment. One group of patients that have demonstratedresistance to targeted therapy (entospletinib enasidenib ivosidenib and venetoclax) have protein tyrosine-phosphatase non-receptor type 11 (PTPN11) mutations. The PTPN11 gene encodes for the phosphataseShp2 which regulates multiple signaling pathways including the RAS-MAPK pathway. PTPN11 mutations(PTPN11+) commonly co-occur with mutations in the nucleophosmin (NPM1) gene. Our preliminary datademonstrates that the co-association of PTPN11 and NPM1 mutations results in inferior outcomes for patientstreated with intensive chemotherapy. Intriguingly we have seen that PTPN11+/NPM1+ patients rarely haveFLT3-ITD an alteration that is well-known to worsen outcomes in NPM1+ AML. Because PTPN11 mutationsactivate many downstream signaling pathways similar to FLT3-ITD we hypothesize that the addition ofPTPN11 mutations to NPM1+ AML can clinically phenocopy NPM1+/FLT3-ITD AML in terms of adverseoutcomes and therapy resistance. Therefore we have generated a novel transgenic Ptpn11E76K/Npm1cA mousemodel to study the development of AML and the resulting immunosuppressive phenotype. Using this modelwe will interrogate whether expanded myeloid cells from Ptpn11E76K/Npm1cA animals can initiate AML inimmunodeficient mice and confer resistance to chemotherapy. In addition we will use modified AML cell linesto study the mechanism of resistance particularly the roles signaling pathways antiapoptotic proteins andimmunosuppression play. The knowledge gained will clarify the biology of PTPN11 mutations in AML andprovide the foundation to develop therapies that will be effective in patients with PTPN11+ AML.This research will be completed by an MD/PhD student under the supervision of two leading translationalresearchers in the field of AML. The MD/PhD program is well established at Ohio State and cancer researchat the Comprehensive Cancer Center is robust and exceptionally strong. The training plan containsopportunities for the development of critical thinking scientific knowledge technical expertise clinical skillscommunication capabilities and rigorous experimental design. Successful completion of the research proposaland training plan will provide the skills necessary to become an independent researcher in the field ofhematology. 35447 +No NIH Category available Advanced Malignant Neoplasm;Area;Biological Models;Biology;CRISPR/Cas technology;Cancer Biology;Cancer Patient;Cell Line;Chimeric Proteins;Chromatin Remodeling Factor;Clinical Trials;DNA Damage;Development;Funding;Future;Genetically Engineered Mouse;Goals;Human;Immune;Immunotherapy;Knowledge;Late Effects;Maintenance;Malignant Neoplasms;Mediating;Modeling;Mus;Mutation;Myxoid Liposarcoma;Neoplasm Metastasis;Normal tissue morphology;Patient-Focused Outcomes;Patients;Phosphorylation;Quality of life;Radiation;Radiation Injuries;Radiation Oncologist;Radiation Tolerance;Radiation therapy;Radiobiology;Research;Resistance;Sampling;Testing;Therapeutic;Work;acute toxicity;cancer therapy;checkpoint inhibition;design;improved;improved outcome;in vitro Model;innovation;novel;palliating symptoms;prion-like;programs;radiation carcinogenesis;radiation effect;radiation response;randomized clinical trials;response;sarcoma;success;tumor;tumor progression Advancing Cancer Therapy through Groundbreaking Research in Radiation Biology PROJECT NARRATIVERadiation therapy is one of the pillars of cancer treatment as approximately half of all cancer patients receiveradiation therapy. The overarching goal of this R35 research program is to widen the therapeutic window ofradiation therapy by using sophisticated genetically engineered mice human sarcoma cell lines and sarcomapatient samples. By dissecting mechanisms of sarcoma development normal tissue injury from radiation andtumor response to radiation therapy alone and in combination with immunotherapy I anticipate that our studieswill not only reveal fundamental mechanisms of radiation and cancer biology but will also lead to improvedtreatment for sarcomas and other cancers. NCI 10873384 9/8/23 0:00 PA-21-268 7R35CA197616-09 7 R35 CA 197616 9 "BUCHSBAUM, JEFFREY" 1/16/16 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 8042298 "KIRSCH, DAVID GUY" Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 902223 NCI 670415 231808 PROJECT SUMMARY/ABSTRACTRadiation therapy is utilized to treat approximately half of all cancer patients. For some patientsradiation therapy can achieve local tumor control and cure. For other patients radiation therapypalliates symptoms and alleviates suffering. However radiation therapy can also cause acute toxicityand late effects that diminish quality of life. The goal of our research program is to widen thetherapeutic window of radiation therapy by dissecting mechanisms of normal tissue radiation injury andtumor response to radiotherapy. As I am a sarcoma radiation oncologist my research group not onlystudies sarcoma response to radiation therapy but also sarcoma development and metastasis. Duringthe prior funding period we adapted CRISPR/Cas9 technology to develop novel genetically engineeredmouse models of sarcoma that facilitated lineage tracing of sarcoma clones during tumor progression.This approach identified novel regulators of metastasis which are potential targets for new cancertherapies. We also used new mouse and in vitro models to discover a novel mechanism for theexquisite radiosensitivity of myxoid liposarcoma: DNA-damage induced phosphorylation of a prion-likedomain in the FUS-CHOP fusion protein disrupts interactions with chromatin remodeling complexesthat are required for tumor maintenance. We initiated new projects with a novel sarcoma model withhigh tumor mutation burden that revealed tumor-intrinsic and immune-mediated mechanisms ofresponse and resistance to radiotherapy and immunotherapy. Our findings provided the rationale for arandomized clinical trial in sarcoma patients testing radiation therapy with immune checkpoint inhibition.We also used our genetically engineered mice to uncover mechanisms regulating acute toxicity andlate effects of radiation such as radiation carcinogenesis. Our proposed research will build on thesuccess of our recent work. We will use innovative model systems and sophisticated approaches tomake discoveries in three broad areas:1. Response of sarcomas to radiotherapy2. Response and resistance of sarcomas to radiation and immunotherapy3. Normal tissue injury from radiationThe knowledge gained from the proposed studies will not only deepen our understanding of radiationand sarcoma biology but will also inform the design of future clinical trials that aim to widen thetherapeutic ratio of radiation therapy to improve the outcome for patients with sarcomas and othercancers. 902223 +No NIH Category available Address;Adult;Bioconductor;Bioinformatics;Biometry;Cancer Center Support Grant;Clinical;Collaborations;Combined Modality Therapy;Communities;Creativeness;Data Collection;Data Coordinating Center;Fostering;Funding;Immune;Immune Targeting;Immunooncology;Immunotherapy;Infrastructure;Institution;Malignant Neoplasms;Methods;Oncology;Preventive;Productivity;Research;Research Personnel;Resource Sharing;Resources;Site;biobank;biomedical data science;community engagement;cost effective;data centers;data integration;data management;data repository;data sharing networks;design;experience;flexibility;high standard;improved;innovation;multidisciplinary;novel;predictive marker;prevent;programs;resistance mechanism;translational oncology;translational study Immuno-Oncology Translation Network: Data Management and Resource-Sharing Center at RPCI Project NarrativeWhile several innovative and creative immuno-oncology (IO) strategies have shown promising results asignificant expansion of their clinical use will require collaborative efforts to elucidate the resistance mechanismdiscover new immune targets identify predictive biomarkers evaluate combination therapies and developpreventive approaches. Utilizing a multi-disciplinary team approach we will support Immuno-OncologyTranslation Network (IOTN)-funded components to discover new immune targets and evaluate novel immune-based therapies and combination approaches that eliminate established cancers in adults or to preventcancers before they occur. NCI 10872397 7/14/23 0:00 PA-20-272 3U24CA232979-01S9 3 U24 CA 232979 1 S9 "KUO, LILLIAN S" 7/1/23 0:00 8/31/24 0:00 6773960 "HUTSON, ALAN DAVID" "LIU, SONG ; MORGAN, MARTIN T" 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 7/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 433750 NCI 250000 183750 Project SummaryWhile several innovative and creative immuno-oncology (IO) strategies have shown promising results asignificant expansion of their clinical use will require collaborative efforts to elucidate the resistance mechanismdiscover new immune targets identify predictive biomarkers evaluate combination therapies and developpreventive approaches. Utilizing a multi-disciplinary team approach we will support Immuno-OncologyTranslation Network (IOTN)-funded components to discover new immune targets and evaluate novel immune-based therapies and combination approaches that eliminate established cancers in adults or to preventcancers before they occur. Our DMRC strategy is to serve as an administrative and analytic hub at every stepof the IOTNs translational studies focusing to reduce the barrier for access to analytic expertise improve theproductivity of IOTN investigators maintain a high standard for data collection and management design andperform rigorous analytical strategies and foster a collaborative and supportive research community.An experienced multidisciplinary team has been assembled to pursue four specific aims: First we will providea centralized administration infrastructure to coordinate IOTN activities building upon the NRG OncologyStatistical and Data Coordinating Centers experience of coordinating over 450 translational cancer studiesacross hundreds of participating sites. Second we will provide multidisciplinary analytic expertise to supportIOTN collaborative research leveraging five of RPCI CCSGs shared resources: Biostatistics BioinformaticsBiomedical Data Science Data Bank and BioRepository and Immune Analysis. Our analytic support will bearmed with professional IT staff and informed by an experienced IO researcher team. Third we will developinnovative data integration methods to enhance IOTN research capacity capitalizing on the well-respectedBioconductor project and the independent research programs of the RPCI department of Biostatistics andBioinformatics. Fourth we will actively promote the IOTN and engage in trans-consortium interactions wherewe will leverage Bioconductors decade-long experience in community engagement and the NRG data centersrich expertise in project coordination. Leveraging our active NCI-funded RPCI-committed resource to supportthe proposed multi-institutional trans-disciplinary IO research is not only cost-effective but also flexible in itsstudy-dependent scalability. Taken together we envision that our DMRC in close collaboration with the IOTNwill allow us to conduct highly effective and innovative translational studies to address the significantly unmetclinical needs related to IO. 433750 +No NIH Category available Funding;Laboratories;Malignant Neoplasms;National Institute of Allergy and Infectious Disease;anticancer research;research and development FFRDC TASK ORDER - LEASES n/a NCI 10871669 75N91019D00024-P00019-759101900133-1 N02 8/31/19 0:00 8/30/24 0:00 16146764 "HAYES, BEVERLY " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 19389623 NCI Lease requirements at the Federally Funded Research and Development Center (FFRDC) at the Frederick National Laboratory for Cancer Research (FNLCR) for the National Cancer lnstitute's (NCI) Divisions Offices and Centers (DOCs) and National Institute of Allergy and Infectious Diseases (NIAID). 19389623 +No NIH Category available ATAC-seq;Address;Affect;Alleles;Alveolar;Atlases;Basal Cell;Benign;Cancer Biology;Cancer Etiology;Carcinoma;Cells;Cessation of life;Chromatin;Classification;Clinical;DNA sequencing;Data;Development;Disease model;Disseminated Malignant Neoplasm;Distal;Epigenetic Process;Epithelium;Event;Gene Expression;Gene Proteins;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genome;Genomics;Genotype;Goblet Cells;Hematologic Neoplasms;Hematopoietic Neoplasms;Histologic;Histology;Human;Individual;Knowledge;Link;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Modeling;Morphology;Mutation;Neuroendocrine Cell;Normal Cell;Outcome;Patients;Pattern;Pharmaceutical Preparations;Prognosis;Research;STK11 gene;Sampling;Signal Transduction;Single Nucleotide Polymorphism;Somatic Mutation;Sorting;Stress;Study models;Tattooing;Testing;Therapeutic;Tissues;Tumor Biology;Untranslated RNA;Woman;Work;alveolar type II cell;benign state;blood treatment;cancer cell;cancer subtypes;cancer type;cell type;clinically significant;cohort;driver mutation;genome sequencing;genome-wide;insertion/deletion mutation;insight;mouse model;mutant;mutational status;never smoker;novel;novel strategies;response;single cell sequencing;single-cell RNA sequencing;standard of care;surfactant;targeted sequencing;tumor;tumor progression;whole genome Cell-of-Origin Footprints of Passenger Mutations in Human Lung Cancer Project narrativeThe normal cell of origin (COO) from which a tumor arises is central to the treatment of blood cancers but doesnot factor into the standard of care for lung adenocarcinoma a leading cause of world cancer death. We willexplore a novel approach to map COOs in lung cancer where COOs are not precisely known by using thepatterns of passenger mutations in their genome. This work may provide a new way to identify COOs forindividual tumor samples and build a much needed bridge between human lung cancer biology and mousemodels of this disease. NCI 10871512 8/30/23 0:00 PA-21-268 7R37CA229861-03 7 R37 CA 229861 3 "JOHNSON, RONALD L" 7/1/23 0:00 8/31/26 0:00 Cancer Genetics Study Section[CG] 6983374 "IMIELINSKI, MARCIN " Not Applicable 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 522542 NCI 331314 191228 Project summary / abstractThe normal cell of origin (COO) from which a cancer arises is fundamental to our basic notions of cancerdevelopment. COOs are central to the standard of care for hematopoietic cancers where they informprognosis and guide therapy. However COOs are not incorporated into the clinical paradigms for treating lungadenocarcinomas an epithelial cancer that is among the leading causes of cancer death worldwide. The majorreason for this is that we still dont know the COO for most lung adenocarcinomas or whether the COO variesfrom patient to patient. One major scientific obstacle to addressing this question is the limited understanding oflung cell types and epithelial types in general. A second obstacle is lineage infidelity that occurs during lungcancer progression which can obscure the COO when one analyzes tumors morphologically ortranscriptionally. As a result the field has been required to rely on genetically engineered mouse modelswhich are still limited in their ability to fully recapitulate genotypes and clinical features of human lungadenocarcinomas. Recent work by us and others in the field has shown that genome-wide patterns ofpassenger mutations can provide a patient-specific COO signal. However this hypothesis has not been testedrigorously for lung cancer or for other malignancies. In this study we investigate how passenger mutationpatterns inform COOs in lung cancer. In particular we focus on noncoding surfactant protein gene (SPG)insertions and deletions which our recent study (Cell 2017) and preliminary data establishes as one of themost common mutational events in lung adenocarcinoma (30-40% of patients). In this study we hypothesizethat this mysterious but highly prevalent mutational pattern is a somatic genetic tattoo of alveolar type II (AT2)cell origin in SPG mutant lung adenocarcinomas. We will investigate this through deep profiling of tumoradjacent tissue using targeted and single cell sequencing. In addition we will investigate whether SPG mutantlung adenocarcinomas are associated with distinct evolutionary trajectories with respect to their mutationaltranscriptional and histological state. Finally we will build on our preliminary studies that establish compellinglinks between genome distributions of somatic single nucleotide variants (SNVs) in lung cancer and cell-typespecific gene expression profiles obtained from single-cell RNA sequencing of benign lung. These preliminarydata indicate that some lung adenocarcinomas may have proximal (club or basal cell) rather than distal (AT2cell) origins. We will build on our initial findings to generate and analyze higher depth atlases of healthy lungand correlate the patterns of cell type specific transcriptional and open chromatin profiles with genomicdistributions of somatic SNVs. This work will provide some of the first direct evidence to map human lungadenocarcinoma to specific COOs. Furthermore our establishment of rigorous links between passengermutational patterns and COO in lung cancer may have broader applicability to the study of COOs in otherprevalent and deadly human epithelial cancers. 522542 +No NIH Category available Address;Advanced Malignant Neoplasm;Astronomy;Biological;Biological Sciences;Biology;Boston;Cancer Center;Communication;Communities;Community Developments;Couples;Coupling;Data;Data Science;Discipline;Education;Educational workshop;Genomics;Goals;Human;Immersion;Interdisciplinary Education;Investments;Knowledge;Malignant Neoplasms;Massachusetts;Mentors;Multilingualism;Parents;Program Development;Program Sustainability;Research;Resource Development;Science;Scientist;Students;Training;Training and Education;Translating;Translations;Underrepresented Minority;Universities;cancer health disparity;community building;design;education research;experience;genome sciences;genomic data;innovation;insight;institutional capacity;outreach;skills;training opportunity;undergraduate student 1/2 The University of Massachusetts Boston - Dana-Farber/Harvard Cancer Center U54 Comprehensive Partnership for Cancer Disparities Research Translating data into biological insights remains a critical challenge and there is a growing need totrain multilingual scientists with a broad range of skills and knowledge in both data and biologicalsciences and the ability to effectively communicate and exchange ideas across disciplines. Thegoal of this project is to invest in both human and institutional capacity for computational genomicsdata sciences (CGDS) at University of Massachusetts Boston through a three-part educational andcommunity development program. This approach couples the need to embrace new paradigms forcomputational research to equally urgent requirements to diversify and grow the CGDS researchworkforce. NCI 10870936 9/19/23 0:00 PA-20-272 3U54CA156734-13S2 3 U54 CA 156734 13 S2 "WALI, ANIL" 9/28/10 0:00 8/31/26 0:00 ZCA1(A1)-S 8606765 "COLON-CARMONA, ADAN " "MACOSKA, JILL A." 8 BIOLOGY 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA SCHOOLS OF ARTS AND SCIENCES 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 255274 OD 201819 53455 The goal of the parent University of Massachusetts Boston (UMass Boston) and Dana-Farber/HarvardCancer Center (DF/HCC) U54 CA156734 Partnership is to pursue Partnership activities and research thatwill bridge the divides in cancer disparities science research education and outreach through innovativeresearch training and practice. This NOSI will extend these activities into the data science space bycoupling the need to embrace new paradigms for computational research to equally urgent requirementsto diversify and grow the computational genomics data sciences (CGDS) research workforce. This will bepursued through the accomplishment of 3 Specific Aims designed as a three-part educational andcommunity development program: 1) Build a CGDS immersion workshop for undergraduate students ofdiverse backgrounds; 2) Develop complementary courses in CGDS and 3) Aim 3: Build a data sciencecommunity through mentored research and an inclusive data club. The scientific goal of this project is toresource the development and implementation of interdisciplinary education and training in biological datasciences that will enable the translation of data into biological insights to address cancer and cancerdisparities. The community goal of this project is to offer many opportunities for training education andcommunity building including experiences specifically aimed at expanding participation ofunderrepresented minorities in genomics-focused biology and data science. The accomplishment of thesegoals will build a sustainable program to train diverse students as multilingual scientists with a broadrange of skills and knowledge in both data and biological sciences that can effectively communicate andexchange ideas across disciplines to advance cancer- and cancer disparities-focused genomic sciencesresearch. 255274 +No NIH Category available Affect;Anatomy;Animal Model;Animals;Architecture;Award;Biopsy;Biopsy Specimen;Blood Vessels;Brain Neoplasms;Canis familiaris;Carcinogens;Carcinoma;Cell Communication;Clinic;Clinical;Clinical Trials;Collaborations;Colorado;Combination immunotherapy;Complex;Drug Combinations;Endothelial Cells;Evaluation;Exposure to;Flow Cytometry;Genetic Transcription;Head and Neck Cancer;Human;Immune response;Immunity;Immunohistochemistry;Immunologic Monitoring;Immunologics;Immunotherapy;Irrigation;Laboratories;Link;Losartan;Manuscripts;Mentors;Modeling;Mus;Myelogenous;Myeloid Cells;Nose;Occupational;Operative Surgical Procedures;Parents;Patients;Perfusion;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Prognosis;Propranolol;Protocols documentation;Publishing;Quality of life;Radiation therapy;Sampling;Slice;T cell infiltration;T cell response;Testing;Therapy trial;Time;Toxic effect;Translational Research;Tumor Angiogenesis;Tumor Antigens;Tumor Immunity;Tumor Promotion;Universities;X-Ray Computed Tomography;anti-PD-L1;antigen-specific T cells;cancer imaging;career;contrast enhanced computed tomography;drug repurposing;head and neck cancer patient;immune cell infiltrate;improved;interest;lymph node biopsy;member;novel;novel therapeutic intervention;programs;response;sarcoma;single-cell RNA sequencing;tool;transcriptome sequencing;treatment group;treatment response;tumor;tumor microenvironment Colorado Head and Neck Cancer SPORE NarrativeSinonasal carcinoma (SC) is an important head and neck cancer (HNC) with a poor prognosis unfortunatelyunderstudied due to lack of predictive translational animal models. We propose that SC in pet dogs representsa spontaneous animal model of this HNC that can be used to investigate novel therapeutic approaches such aspromising radiotherapy and immunotherapy combinations. In this supplemental project to the Colorado Headand Neck Cancer SPORE we will investigate the local and systemic immune responses and changes in tumorperfusion of canine SC when myeloid cell targeted immunotherapy with repurposed drugs (losartan andpropranolol) administered to deplete or reprogram myeloid cells and promote tumor vascular normalization iscombined with stereotactic body radiotherapy. NCI 10868331 9/18/23 0:00 PA-20-272 3P50CA261605-02S1 3 P50 CA 261605 2 S1 "HUBBARD, LEAH" 9/1/23 0:00 8/30/24 0:00 8665415 "JIMENO, ANTONIO " "WANG, XIAO-JING " 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/30/24 0:00 397 Research Centers 2023 475000 NCI 415218 59782 AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-059. Sinonasal carcinoma (SC) is an important head and neck cancer (HNC) globally but prognosis remainspoor. SC is understudied in the laboratory and in the clinic. We propose that SC in pet dogs represents aspontaneous animal model of this HNC. Our team has validated approaches to investigate immunotherapy andstereotactic body radiation therapy (SBRT) in canine SC clinical trials. Our current efforts incorporate myeloidcell targeted immunotherapy (MTI) with two repurposed drugs (losartan and propranolol) to deplete or reprogrammyeloid cells when combined with SBRT. Our early results in dogs with SC treated with the MTI + SBRT protocolprovide evidence of enhanced local T cell responses and improved overall survival compared to SBRT alone.The proposed study represents a logical addition to the parent program (Colorado Head and Neck CancerSPORE) which seeks to advance translational research to improve survival and quality of life for HNC patients.Our project will therefore be consistent with the overall immunotherapy/radiotherapy SPORE theme. In this studywe propose to expand the canine MTI/SBRT trial with more animals and add new immune monitoring to assesslocal and systemic tumor immunity as well as functional tumor imaging to understand the impact of MTI/SBRTon tumor perfusion. We will test the overall hypothesis that combining MTI with SBRT will significantly increaseSC tumor immunity perfusion and improve SBRT clinical responses. Results from this MTI/SBRT study canexert an immediate and substantial impact on the management of human SC as the 2-drug combination ofalready approved and safe drugs for MTI can be readily implemented clinically.Specific Aim 1: Determine whether addition of myeloid-targeted immunotherapy (MTI) to SBRT augmentslocal and systemic tumor immunity in dogs with SC. Subaim 1.1 will investigate local tumor immuneresponses to SBRT and MTI/SBRT using tumor biopsy and nasal lavage samples to include analysis of immunecell infiltrates (immunohistochemistry flow cytometry) and transcriptional status (scRNA-seq bulk RNAseq). InSubaim 1.2 regional and systemic tumor immune responses will be examined using lymph node biopsies (flowcytometry RNAseq) and PBMC samples (T cell responses to SC tumor antigens). The clinical impact ofcombined MTI/SBRT on tumor responses will be assessed in Subaim 1.3 by serial CT evaluation (pre-treatment3 mos 6 mos) and determination of progression-free interval (PFI) and overall survival time (OST) will becompared between treatment groups.Specific Aim 2: Elucidate the impact of combined MTI/SBRT on tumor perfusion in dogs with SC.Dynamic contrast enhanced-CT will be used in Subaim 2.1 to determine how adding MTI to SBRT affects tumorperfusion parameters at 3- and 6-mos following treatment. In Subaim 2.2 the impact of adding MTI to SBRT ontumor angiogenesis and vessel architecture will be determined using serial tumor biopsies and IHC analyses. 475000 +No NIH Category available Address;Allogenic;Autologous;B lymphoid malignancy;B-Lymphocytes;Biological Models;Blood Component Removal;CAR T cell therapy;Canis familiaris;Cell Therapy;Cells;Clinical;Clinical Trials;Collaborations;Companions;Development;Diameter;Disease;Disease model;Disease remission;Engineering;Enrollment;FDA approved;Fine needle aspiration biopsy;Functional disorder;Generations;Goals;Hematologic Neoplasms;Human;Human Engineering;Image;Infusion procedures;Lymphoma;MS4A1 gene;Measurement;Measures;Modeling;Monitor;Mus;Myelogenous;Non-Hodgkin's Lymphoma;Oncologist;Outcome;Patients;Pilot Projects;Positron-Emission Tomography;Publishing;Regimen;Reporter;Resistance;SLC5A5 gene;Sampling;Serum;Signal Transduction;Site;Solid Neoplasm;Sum;Symptoms;System;T-Lymphocyte;Techniques;Testing;Time;Toxic effect;Transgenes;Translations;Visualization;Work;alpha-beta T-Cell Receptor;analog;beta-2 Microglobulin;cancer therapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical predictors;cytokine;cytokine release syndrome;design;first-in-human;graft vs host disease;immunogenicity;in vivo;in vivo imaging;interest;large cell Diffuse non-Hodgkin's lymphoma;lymph nodes;manufacture;mouse model;neurotoxicity;novel;novel strategies;peripheral blood;pre-clinical;preclinical study;prevent;response;safety testing;success;therapy development;trafficking;tumor;tumor microenvironment Towards Safer and More Effective CART Cell Therapy Through the Modulation of Myeloid Cytokines PROJECT NARRATIVEOur goal is to develop novel strategies to prevent toxicities enhance efficacy and increase access to chimericantigen receptor T (CART) cell therapy for the treatment of cancer. We have developed and optimized the useof sodium iodide symporter (NIS) as a platform to track CART cells by PET imaging in vivo in mouse models andhave previously launched CART cell therapy pilot studies in companion dogs. We are planning to study the abilityof PET imaging of xenogeneic NIS+ CART cells to detect their expansion trafficking activity and toxicity incanine patients with spontaneous diffuse large B cell lymphoma. NCI 10867998 9/18/23 0:00 PA-20-272 3R37CA266344-02S1 3 R37 CA 266344 2 S1 "HU, ZHANG-ZHI" 12/9/21 0:00 11/30/26 0:00 15738149 "KENDERIAN, SAAD J." "WIERSON, WESLEY " 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 8/1/23 0:00 11/30/23 0:00 395 Non-SBIR/STTR 2023 475000 NCI 345467 129533 PROJECT SUMMARYDespite the impressive activity of chimeric antigen receptor T (CART) cell therapy in the treatment of B-cellmalignancies the therapy is limited by the development of toxicities including cytokine release syndrome (CRS)and neurotoxicity as well as by lower rates of durable responses. The in vivo expansion of CART cells is acritical determinant of their antitumor activity as well as of the development of toxicities. Over the last 5 yearswe have focused our work on addressing limitations related to CART complexity toxicity and resistance. Weutilized companion dogs as a proof-of-concept model to test engineered allogeneic human CART cells as atherapy for spontaneous disease including diffuse large B-cell lymphoma (DLBCL). We engineered canineCD20-targeting xenogeneic human CART cells (T-cell receptor alpha (TRAC)- and beta-2 microglobulin (B2M)-disrupted) developed and optimized a canine-specific lymphodepleting regimen and tested the safety ofxenogeneic CART cells in healthy beagles. Then to track CART cell fates and functions in real time in vivo wedeveloped and recently published the utility of sodium iodide symporter (NIS) as a platform to detect CART cellexpansion trafficking and toxicity in mouse models. In this application we propose to utilize our NIS reportersystem novel canine lymphodepletion regimen and established canine clinical trial expertise to test NIS+ humanCART cells in companion dogs. We hypothesize that 18F-tetrafluoroborate (TFB) PET imaging of NIS+ canineCD20-targeting xenogeneic human CART cells is a sensitive strategy to detect CART cell rejection expansionand trafficking to tumor sites in canine patients with DLBCL. To test this hypothesis we have designed twospecific aims. In Aim 1 we will study the utility of TFB-PET imaging of NIS+ CART cells to measure CARTexpansion rejection and trafficking in canine patients with DLBCL. We will determine how quantitative PETsignal (qPET) correlates with quantitative PCR (qPCR) measurement of the CAR transgene in peripheral bloodand lymph node samples. In Aim 2 we will determine how TFB-PET imaging of CART cell expansion andtrafficking correlates with their activity and toxicity. Completion of these aims will validate qPET imaging as anon-invasive platform to study CART dynamics in canine lymphoma and provide additional rationale to proposea first-in-human clinical trial of NIS+ CART cells in patients with lymphoma. 475000 +No NIH Category available Behavior;Cells;Clinical;Collaborations;Complex;Computational Biology;Data;Databases;Dermal;Development;Disease;Distant;Environment;Evolution;Financial Support;Frequencies;Genes;Genetic;Genetic Diseases;Genetic Transcription;Genetically Engineered Mouse;Genomics;Heterogeneity;Human;Immune Evasion;Immune response;Immunologic Surveillance;Infrastructure;Institution;Intercept;Knowledge;Link;Malignant - descriptor;Malignant Neoplasms;Maps;Mediating;Methods;Modeling;Molecular;Molecular Evolution;Neoplasm Metastasis;Non-Malignant;Organ;Output;Patient Care;Patient-Focused Outcomes;Patients;Population;Productivity;Recurrence;Research;Research Personnel;Resources;Risk;Sampling;Signal Transduction;Site;Skin;System;Testing;Therapeutic;Therapeutic Intervention;Thick;Tissues;Tumor stage;biomarker identification;cancer type;cell behavior;cell type;clinically relevant;computer framework;draining lymph node;epigenetic regulation;improved;innovation;lymph nodes;melanoma;melanoma biomarkers;millimeter;mouse genetics;mouse model;multidisciplinary;neoplastic cell;new therapeutic target;novel;novel therapeutics;participant enrollment;permissiveness;prevent;programs;prospective;stem cell biology;survival outcome;synergism;temporal measurement;transcriptomics;tumor;tumor immunology;tumor microenvironment;tumor progression;tumorigenic NYULH Metastasis Research Network Center - Admin Supplement OVERALL NARRATIVEThe NYULH MetNet Center will leverage the complementary expertise of the NYU Melanoma programinvestigators to build an in-depth transcriptional and cellular characterization of tumor-microenvironmentinteractions that dictate early dissemination using novel clinically relevant mouse models and well-annotatedpatient biospecimens. NCI 10867093 8/15/23 0:00 PA-20-272 3U54CA263001-02S1 3 U54 CA 263001 2 S1 "NADEAU, CHRISTINE FRANCES" 9/15/22 0:00 7/31/27 0:00 ZCA1(J1) 9107364 "HERNANDO, EVA " "OSMAN, IMAN " 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 50850 NCI 30000 20850 OVERALL SUMMARYConventional views of cancer as a predominantly genetic disease that proceeds in a step-wise linear mannerhave ceded to an understanding that tumor progression involves a multifaceted set of tumor cell-intrinsic andmicro-environmental adaptations that co-evolve dynamically and non-linearly. However much remains to bediscovered about how different cell populations in the local environment drive metastatic behavior at differentstages of tumor progression. Primary melanomas that are only millimeters thick can disseminate to lymph nodesand distant organs. This clinical feature suggests that egress of tumor cells from a primary site occurs early inmelanoma development making melanoma an exceptional model to study these dynamic adaptations during theearliest stages of tumor progression. Our central hypothesis is that melanoma metastasis is driven by acombination of tumor cellintrinsic features and interactions with micro-environmental compartmentsthat govern early dissemination and immune evasion in the regional draining lymph nodes. To test thishypothesis we propose three inter-related projects supported by three cores that will collectively build an in-depth transcriptional and cellular map of critical compartments in the tumor microenvironment during earlymelanoma dissemination in both mouse models and patient biospecimens. Successful completion of theseprojects will identify genes and transcriptional programs within those compartments that drive and maintaintumorigenic adaptations and ultimately metastatic dissemination. Our aims are to: 1. Map the cellular andmolecular evolution of primary melanomas and their local and regional microenvironments to identify criticalswitches that drive non-linear tumor progression; 2. Mechanistically dissect the emergence and functionalrelevance of transcriptionally defined cell state heterogeneity of malignant and non-malignant cell populations;3. Identify novel therapeutic vulnerabilities to intercept early dissemination mobilize systemic immunesurveillance and improve patient outcomes; and 4. Leverage the information gained to define new biomarkersof melanoma metastasis. We expect that knowledge generated through our approach may define newbiomarkers of melanoma metastasis and therapeutic strategies to manage early disease. Our approach canserve as a roadmap to study early tumor progression at an unprecedented level of cellular spatial and temporalresolution. It will provide a comprehensive picture of interactions both within the tumor microenvironment andtumor draining lymph nodes that influence tumor cell behavior and condition the host to be receptive to metastaticspread. We will leverage the complementary and synergistic expertise of our research team with an establishedrecord of productive collaboration our novel genetically engineered mouse model that recapitulates earlyprogression of human melanoma and our access to high quality clinically annotated patient samples from over4700 patients enrolled in a prospective clinicopathological database. The scope and scalability of the knowledgegained will serve other sites of the Metastasis Research Network. 50850 +No NIH Category available Activin Receptor;Biological Process;Cancer Biology;Cancer Etiology;Cell Surface Receptors;Cell surface;Cessation of life;Chemoresistance;Data;Disease;GOLPH3 gene;Galectin 3;Genes;Golgi Apparatus;Human;Immunotherapy;Incidence;Invaded;Knowledge;Ligands;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Molecular;Mutate;Mutation;Myosin ATPase;Neoplasm Metastasis;Pathogenesis;Phenotype;Prognosis;Protein Secretion;Public Health;Resistance;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Solid Neoplasm;Specimen;Structure;Survival Rate;TGF-beta type I receptor;Therapeutic;Transforming Growth Factor beta;Transforming Growth Factor beta Receptors;cancer initiation;gemcitabine;glycosylation;glycosyltransferase;in vivo;in vivo Model;insight;loss of function;novel;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;pancreatic tumorigenesis;predictive marker;receptor;receptor expression;receptor-mediated signaling;targeted treatment;trafficking;tumor progression Role of ALK4 in Regulating Receptor Trafficking and Pancreatic Cancer Biology Activin receptor-like kinase 4 (ALK4) is a type I transforming growth factor- (TGF-) superfamily receptor thatis mutated in a broad spectrum of human cancers with frequent loss of ALK4 expression associated with apoorer prognosis. While ALK4 has been identified in an unbiased screen as a gene whose disruption enhancesRas mediated pancreatic tumorigenesis in vivo the role and mechanism of action of ALK4 loss of function incancer progression is largely unknown. We have uncovered a novel mechanism by which ALK4 regulatesGolgi ribbon formation/extension to regulate receptor trafficking and signaling. Here we will investigatemechanisms by which loss of function of ALK4 regulates Golgi body structure/function to regulate receptortrafficking signaling and cancer biology in pancreatic cancer cells. These studies are important to perform andrelevant to public health as these mechanistic insights will define the biological functions of ALK4 in the contextof pancreatic cancer increase understanding of the role of loss of ALK4 function in regulating pancreaticcancer progression and aid in targeting ALK4 and ALK4-regulated signaling pathways for the treatment ofpatients with pancreatic cancers and other solid tumors with loss of ALK4 function. NCI 10866981 9/19/23 0:00 PA-20-272 3R01CA226925-05S1 3 R01 CA 226925 5 S1 "XU, WANPING" 9/19/19 0:00 8/31/24 0:00 Molecular Oncogenesis Study Section[MONC] 1931205 "BLOBE, GERARD C" Not Applicable 4 INTERNAL MEDICINE/MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 189169 NCI 117496 71673 Pancreatic cancer is an aggressive and difficult to treat disease with an overall 5-year survival rate of 3-5%. Theincidence of pancreatic cancer is increasing and it is projected to be the 2nd leading cause of cancer death within5 years. Despite detailed knowledge of its molecular pathogenesis targeted therapies have had minimal impactand immunotherapy has been ineffective. Activin receptor-like kinase 4 (ALK4) is a type I transforming growthfactor- (TGF-) superfamily receptor that mediates signaling for several TGF- superfamily ligands. Mutationor copy number loss of ALK4 occurs in 35% of pancreatic cancer patients with loss of ALK4 expressionassociated with a poorer prognosis. In addition ALK4 has been identified in an unbiased screen as a genewhose disruption enhances Ras mediated pancreatic tumorigenesis in vivo. We demonstrate that loss of ALK4expression increases type I (TRI/ALK5) and type II (TRII) TGF- receptor (TR) levels leading to increasedactivation of canonical TGF- signaling enhanced acquisition of EMT markers and phenotypes and increasedcancer invasion and metastasis in vivo. We also find that ALK4 selectively regulates the cell surface expressionof receptors by promoting their glycosylation and processing/trafficking to the cell surface through effects onGolgi ribbon formation/extension which may be regulated by the interaction of the Golgi regulator GOLPH3with myosin 18A. Based on these preliminary results we hypothesize that loss of ALK4 function promotespancreatic cancer progression and chemotherapy resistance by promoting Golgi ribbon formation/extension toincrease TR receptor glycosylation and trafficking to the cell surface increasing TR cell surface levelsdownstream signaling and cancer biology. We further hypothesize that blocking these effects in pancreaticcancer patients with loss of ALK4 function may provide therapeutic benefit. We propose three Specific Aims.Aim 1: The mechanism by which loss of ALK4 promotes TGF- signaling will be explored including definingeffects on Golgi ribbon formation/extension. Aim 2: We will define whether loss of ALK4 expression in pancreaticcancer cells facilitates cancer initiation and/or progression or resistance to gemcitabine in pancreatic cancermodels in vivo. Aim 3: We will define whether pancreatic cancer specimens with ALK4 loss have increased TGF- signaling and Golgi ribbon formation/extension and whether loss of ALK4 creates unique vulnerabilities inthese pancreatic cancer patients which can be exploited for therapeutic benefit. These studies will define novelmechanisms by which ALK4 loss regulates TGF- signaling and downstream pancreatic cancer biology andcould identify ALK4 loss as a predictive biomarker for anti-TGF- approaches in pancreatic cancer and otherhuman cancers with mutation or loss of ALK4 expression. 189169 +No NIH Category available Adult Precursor T Lymphoblastic Leukemia;Adult T-Cell Leukemia/Lymphoma;Animal Model;Animals;Attenuated;Binding;Binding Proteins;Biological Assay;Bone Diseases;Cancer Model;Cell Proliferation;Cell Survival;Cells;Cellular biology;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;DNA Double Strand Break;Data;Disease;Disease Progression;Foundations;Funding;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Human T-lymphotropic virus 1;Human T-lymphotropic virus 2;IRF1 gene;In Vitro;Individual;Infection;Knock-out;Knowledge;Malignant - descriptor;Malignant Neoplasms;Mediating;Messenger RNA;Modeling;Nitric Oxide Synthase;Oncoproteins;Oryctolagus cuniculus;Osteolytic;Outcome;Pathogenesis;Pathogenicity;Pathway interactions;Persons;Play;Process;Protein Interaction Mapping;Proteins;Proteomics;RNA;Repression;Retroviridae;Role;Signal Pathway;Signal Transduction;Structure;TOP1 gene;Taxes;Transactivation;Transforming Growth Factor beta;Transgenic Mice;Translating;Viral;Viral Genes;Viral Vector;Virus Diseases;Work;chronic infection;design;effective therapy;experimental study;in vivo;insight;leukemia/lymphoma;leukemogenesis;metaplastic cell transformation;nervous system disorder;novel;p65;prevent;protein expression;senescence;tax Genes;therapeutic target;tumor;ubiquitin-protein ligase;vector;virus host interaction Project 1: Role of HTLV-1 Hbz in Transformation and Disease PROJECT NARRATIVE PROJECT 1Approximately 15-25 million people worldwide are infected with HTLV-1 with a small percentage developing adultT-cell leukemia. The cancer is aggressive and there is currently no effective treatment. This project focuses ona novel viral gene encoded by the antisense strand of the HTLV-1 genome termed hbz and the proposedstudies will provide a significant advance in our basic knowledge of the role of hbz in transformation and diseaseand will have significant implications for therapeutic targeting. NCI 10866638 7/28/23 14:49 PA-21-071 3P01CA100730-19S1 3 P01 CA 100730 19 S1 "READ-CONNOLE, ELIZABETH LEE" 4/21/03 0:00 5/31/25 0:00 ZCA1 5681 1866427 "GREEN, PATRICK LEE" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 76801 54467 22334 PROJECT SUMMARY PROJECT 1The study of retroviruses has resulted in important discoveries and led to insights into basic cell biology includingmechanisms of cell signaling regulation of gene expression and ultimately cellular transformation and cancer.Our collaborative work within this PPG focuses on HTLV-1 which is associated primarily with adult T-cellleukemia (ATL) and neurological disease (HAM/TSP) in a small percentage of infected individuals. Diseaseprogression by HTLV-1 has been attributed to Tax although we and others have hypothesized and provide datathat another viral gene termed Hbz plays a critical role in the malignant process. Our presented data as wellas the work of others indicate that hbz is multi-functional playing important roles in both the RNA and proteinform throughout infection and establishment of latency. We have extended our proposed work through PPGcollaborations to better understand the manner in which hbz promotes proliferative and survival activity in cells.Proteomic analyses identified a panel of cellular proteins that distinctly interact with hbz RNA and HBZ protein.Functional characterization of these interactions are the next critical steps and the basis for this highly integrativecontinuation project designed to further define the role of hbz in transformation and disease. Our overallhypothesis is that uncovering the mechanism of actions of hbz RNA and HBZ protein will provide importantinsight into HTLV-1 cellular transformation and disease and ultimately will provide means for therapeutictargeting to eradicate HTLV-1 persistence in the host. This highly integrated proposal as referenced by Projectand Core collaborations below has two Specific Aims. Aim 1 will dissect the mechanism(s) of action of hbz RNAand determine its contributions to the pathogenic process. We hypothesize that cellular protein interaction withhbz mRNA 2o structure translates to cell signaling pathways important for viral persistence and cellularproliferation. Our new proteomics data has identified and we further validated distinct cellular proteins that bindhbz mRNA. This aim will utilize in vitro approaches (Projects 2 and 3 Cores Admin/Biostats and Viral Vector)to identify the hbz RNA interactive region and determine the functional role of cellular binding proteins in cellproliferation. We will use in vivo approaches (Animal Core) to understand the contribution of the RNA andinteractive proteins in the establishment of persistence and tumor formation. Aim 2 will dissect the mechanism(s)of action of HBZ protein and determine its contributions to HTLV-1 pathobiology. Our new proteomics data hasidentified and we further validated distinct cellular proteins that bind HBZ. In vitro approaches (Project 3 CoresAdmin/Biostats and Viral Vector) including protein interaction mapping cellular proliferation assays andcellular transformation assays will be utilized to identify the HBZ interactive region and the functional role of keycellular binding proteins in HTLV-1 pathobiology. In vivo approaches (Animal Core Project 2) will be used todetermine the contribution of these HBZ interactive proteins in the establishment of persistence infected cellsurvival and tumor formation. +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mission;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting The CANcer Cachexia Action Network (CANCAN):a Multidisciplinary Virtual Institutewith the Mission to Cure Cancer CachexiaCANCAN - BEATSON n/a NCI 10866151 8/3/23 0:00 RFA-OT-A2-013 3OT2CA278662-01S1 3 OT2 CA 278662 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78666267 "LEWIS, DAVID Y" Not Applicable n/a Unavailable 236454286 KSMLKX69QXS5 236454286 KSMLKX69QXS5 UK 55.86515 -4.25763 1092001 BEATSON INSTITUTE FOR CANCER RESEARCH GLASGOW Unavailable G61 1BD UNITED KINGDOM N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 121428 NCI 143079 11446 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 121428 +No NIH Category available Advisory Committees;Affect;Agar;Angiogenic Factor;Animal Experiments;Animal Model;Animals;Automobile Driving;Behavior;Biological Assay;Biological Markers;Biological Models;Biology;Blood Vessels;Cancer Center;Cell Communication;Cell Density;Cell Line;Cell model;Cells;Chicago;Clinical;Clinical Data;Coculture Techniques;Collaborations;Communities;Computational Biology;Computer Analysis;Consensus;DNA Sequence Alteration;Data Set;Dedications;Development;Development Plans;Dissociation;Drug Targeting;Educational process of instructing;Endothelial Cells;Endothelium;Environment;Genes;Genomics;Goals;Hep3B;Hepatic;Heterogeneity;Human;In Vitro;International;Invaded;Investigation;Knock-out;Link;Maintenance;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mentorship;Metastatic Carcinoma;Modeling;Molecular;Molecular Biology;Morbidity - disease rate;Neoplasm Circulating Cells;Neoplasm Metastasis;Oncologist;Outcome;PECAM1 gene;Pathway interactions;Patient Care;Patients;Phenotype;Physicians;Primary Neoplasm;Primary carcinoma of the liver cells;Prognosis;Proliferating;RNA Binding;RNA immunoprecipitation sequencing;RNA-Binding Proteins;Recurrence;Regulatory Pathway;Research;Research Personnel;Role;Scientist;Series;Solid Neoplasm;Specimen;Stains;Tail;Technology;Time;Tissue Stains;Tissues;Training;Translational Research;Tube;Tumor Tissue;Universities;Veins;Work;biomarker development;cancer cell;cancer genomics;career;career development;clinical practice;drug development;experience;experimental study;fitness;gain of function;implantation;improved;in vitro Assay;in vivo Model;migration;mortality;mortality risk;nano-string;new therapeutic target;novel;oncofetal antigen;overexpression;paracrine;pharmacologic;pluripotency;preimplantation;recruit;single-cell RNA sequencing;spatial relationship;tool;transcriptome sequencing;transcriptomics;tumor;tumor microenvironment Defining pro-metastatic and endothelial-regulatory roles for LIN28B in hepatocellular carcinoma PROJECT NARRATIVELIN28B is a pleiotropic RNA-binding oncofetal protein that correlates with poor prognosis in hepatocellular carcinoma (HCC). This proposal seeks to understand how LIN28B contributes directly to the metastatic phenotype of HCC cells and how it contributes to the angiogenic and endothelial modulatory phenotype of HCC cells using a combination of cell animal and human specimen studies. I anticipate that these results will provide rationale and targets for novel drug and biomarker development for HCC. NCI 10865508 8/22/23 0:00 PA-21-268 7K08CA263551-02 7 K08 CA 263551 2 "LIM, SUSAN E" 8/1/23 0:00 7/31/27 0:00 Career Development Study Section (J)[NCI-J] 11022632 "FRANSES, JOSEPH WANG" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 265315 NCI 245662 19653 PROJECT SUMMARYHepatocellular carcinoma (HCC) is a lethal solid tumor that is highly dependent on recruitment of new blood vessels and has no common genomic targets. As for most solid tumors metastasis causes a disproportionate degree of morbidity and mortality. LIN28B an RNA-binding protein expressed in tumors and in developing tissues is essential for HCC development and elevated LIN28B expression in HCC correlates with an increased risk of death. We recently identified LIN28B as a novel driver of pancreatic cancer metastasis and propose in Aim 1 to use an integrated series of molecular cellular and animal experiments to determine if HCC metastasis is driven by LIN28B. In Aim 2 I propose to couple robust co-culture (HCC cell and endothelial cell) in vitro and in vivo models to define how LIN28B expression in HCC cells modulates its effect on endothelial cells which in turn stimulate the HCC metastatic phenotype. In Aim 3 I will utilize our expertise in novel circulating tumor cell purification/analysis technologies and computational analysis of conventional and novel tissue staining technologies to characterize the metastasis-driving and endothelial regulatory roles of LIN28B using primary human circulating tumor cell and tumor tissue specimens. Collectively this work will provide functional rationalefor the development of new therapies targeting the LIN28B pathway and linked vascular-regulatory pathways in HCC and for the development of novel matched biomarkers. The applicant Dr. Joseph Franses is an oncologist at the University of Chicago Cancer Center. He will spend 75% of his time performing translational research and 25% in clinical practice caring for patients with cancer. He has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational research. Dr. Franses has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He has established collaborations with experts in cancer genomics molecular biology tumor animal modeling and computational biology to provide experimental advice and specific training in the field. Dr. Franses will conduct this research and leverage the exceptional research and teaching environment at the University of Chicago Cancer Center. The University of Chicago harbors an outstanding research community and has a long track record for successful mentorship of independent physician-scientists. This will be an ideal environment for successful completion of these experiments and the realization of Dr. Franses career goal of becoming an independent physician-scientist dedicated to improving the care of patients with gastrointestinal cancers. 265315 +No NIH Category available Adult;Alcohol consumption;Alcohols;American;Attention;Awareness;Behavioral;Body Weight;Body part;Cancer Patient;Communication;Consumption;Data;Development;Disease;Effectiveness;Emotions;Focus Groups;Foundations;Goals;Harm Reduction;Health;Image;Individual;Intention;Intestinal Cancer;Knowledge;Label;Link;Malignant Neoplasms;Measurement;Measures;Medical;Methods;Patient Self-Report;Persons;Persuasive Communication;Phase;Principal Investigator;Public Health;Publishing;Reaction;Research;Resistance;Risk;Risk Factors;Role;Shock;Smoking;Testing;Text;Tobacco;Tobacco Control Research;Tobacco use;United States;Visual;Visual attention;Work;alcohol risk;behavior change;cancer risk;design;drinking;drinking behavior;effectiveness evaluation;experience;health communication;health warning;high risk;improved;innovation;modifiable risk;motivated behavior;response;risk perception;sustained attention;tool;visual tracking;warning label Communicating Cancer Risk of Alcohol: Impact of Narrative Pictorial Warning Labels Project NarrativeAlcohol use is a major preventable risk factor for cancer in the United States but few Americans are awareof the risk. A promising approach to raising awareness of risk is to include pictorial warning labels onalcohol-containing products but there is a limited understanding of the design and impact of such warnings.The proposed project is relevant to public health because determining the effectiveness of pictorial warninglabels that feature narrative content to communicate cancer risk can raise awareness and potentiallyreduce harm. NCI 10864591 8/3/23 0:00 PA-21-268 7R03CA273391-02 7 R03 CA 273391 2 "BLAKE, KELLY D" 9/1/22 0:00 8/31/24 0:00 ZCA1-RTRB-B(M1)S 78403314 "MA, ZEXIN " Not Applicable 2 PSYCHOLOGY 614209054 WNTPS995QBM7 614209054 WNTPS995QBM7 US 41.811419 -72.247553 1506602 UNIVERSITY OF CONNECTICUT STORRS STORRS-MANSFIELD CT SCHOOLS OF ARTS AND SCIENCES 62691133 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 84969 NCI 52776 32193 Project SummaryAlcohol consumption is a major modifiable risk factor for cancer along with tobacco use and excess bodyweight. However knowledge about the link between alcohol and cancer risk is poor in the United States.Research on tobacco labels has shown that placing pictorial warning labels (PWLs) improves consumerawareness of risks and decreases consumption. These results suggest that a similar approach to usingPWLs on alcohol-containing products would raise awareness of risks and decrease alcohol consumption.Yet one standing issue is that the typical graphic or shocking images used in such warnings can causeavoidance and reactance which can lower message effectiveness and public support for pictorial warnings.A potential solution is to design PWLs that feature narrative content focused on people such as cancerpatients in medical settings to capture attention and counteract reactance. The proposed project aims todevelop and evaluate the impact of narrative PWLs on visual attention message reactance riskperceptions and intentions to reduce and stop drinking. To accomplish these aims the proposed projectwill include two phases: (1) Developing alcohol PWLs in narrative and conventional non-narrative formatsusing existing research and focus group methods; and (2) Experimentally testing the effect of narrativeversus non-narrative PWLs among adult alcohol users using objective measures of attention (eye tracking)and self-report measures of reactance risk perceptions and intentions. The approach is innovativebecause we will explicitly test the impact of visual narrative warnings on attention and message reactanceand provide an objective and direct measurement of attention by using eye tracking. With theseapproaches this study will lay the groundwork for understanding the mechanisms by which visual narrativewarnings communicate health risks and promote behavioral change. Findings of this early-stage projectwill also provide the foundation for a controlled trial of effective warning labels designed to increase publicawareness of risks and decrease the overall alcohol consumption in the United States. 84969 +No NIH Category available Address;Adolescent Development;Adolescent and Young Adult;Adolescent and young adult cancer patients;Adult;Age;Area;Assessment tool;Behavior;Behavior Therapy;Behavioral;Behavioral Model;Buffers;Cancer Control;Clinical Trials Design;Collaborations;Communication;Complement;Data;Development;Distress;Elements;Emotional;Enrollment;Evidence based intervention;Feedback;Friends;Funding;Goals;Individual;Intervention;Intervention Trial;Learning;Length;Malignant Neoplasms;Manuals;Measures;Modeling;Monitor;Newly Diagnosed;Obesity;Oncology;Outcome;Pathway interactions;Patients;Phase;Phase Ib Trial;Population;Postdoctoral Fellow;Problem Solving;Procedures;Protocols documentation;Qualitative Research;Quality of life;Randomized;Randomized Controlled Trials;Recording of previous events;Reporting;Research;Research Methodology;Research Training;Resources;Risk;Science;Scientist;Self Efficacy;Site;Social outcome;Social support;Support Groups;Supportive care;Training;Treatment Efficacy;Work;acceptability and feasibility;base;cancer diagnosis;cancer therapy;career;coping;design;efficacy testing;efficacy trial;evidence base;experience;family support;follow-up;high risk;improved;innovation;interest;novel;novel strategies;outcome disparities;phase II trial;phase III trial;pilot test;pre-doctoral;prevent;programs;promote resilience;psychological distress;psychosocial;psychosocial wellbeing;recruit;resilience;secondary outcome;skills;social;social deficits;social relationships;social skills;stress management;success;survivorship;theories;therapy development;treatment arm;treatment as usual;uptake Addressing Social Needs of Adolescents and Young Adults (AYAs) with Cancer PROJECT NARRATIVEEvidence-based interventions addressing unmet social needs of adolescents and young adults (AYAs) withcancer are critical to reducing psychosocial outcome disparities. Applying a novel conceptual framework the goalof the proposed study is to adapt an established multi-component resilience program to target AYA social supportneeds and establish proof-of-concept for this adaptation. If successful this program has the potential to improveAYA outcomes and create a promising paradigm for comprehensively addressing psychosocial needs of AYAswith cancer and other serious illnesses. NCI 10864103 9/6/23 0:00 RFA-CA-20-057 4R00CA267481-03 4 R00 CA 267481 3 "GUIDA, JENNIFER LYN" 3/1/22 0:00 7/31/26 0:00 ZCA1-RTRB-U(O1) 15268258 "FLADEBOE, KAITLYN MARIE" Not Applicable 7 Unavailable 48682157 SZ32VTCXM799 48682157 SZ32VTCXM799 US 47.66243 -122.282291 1531401 SEATTLE CHILDREN'S HOSPITAL SEATTLE WA Independent Hospitals 981053901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 142063 106937 PROJECT SUMMARYAdolescents and young adults (AYAs) with cancer are at high risk for poor psychosocial and quality of life outcomes.One way cancer may confer risk is through compromising social support a robust predictor of psychosocial wellbeing.AYAs highly value support from family friends and other AYA patients. However many AYAs with cancer feelisolated and report that their relationships are strained during their treatment resulting in long term social supportdeficiencies. Despite established demand few programs targeting AYA social support needs exist. Those that dolack theoretical bases or developmental tailoring. The current study uses a novel approach to address theseneeds by adapting an evidence-based multicomponent supportive care program to target social relationshipcoping efficacy (SRCE). Defined as ones perceived ability to maintain or enhance close relationships in thecontext of illness SRCE is a new construct with a strong theoretical basis that is well aligned with AYAsdevelopmental needs. Bolstering SRCE will enable AYAs to manage cancer-related relational challenges andseek and maintain supportive relationships thereby buffering the negative impact of cancer on perceivedsupport. Moreover targeting SRCE within the Promoting Resilience in Stress Management (PRISM) program askill based AYA resilience intervention with a history of successful adaptation will enable the success of thiswork and potential for later dissemination. Building on preliminary data and following the Obesity-RelatedBehavioral Intervention Trials (ORBIT) model for behavioral intervention development the first phase of this study(K99 2 years) aims to refine the PRISM+SRCE adaptation. Specifically the goals of this phase are to (1)iteratively refine SRCE component content using AYA (n12) stakeholder feedback; (2) refine practical aspectsof the combined PRISM+SRCE program including delivery training and fidelity monitoring using AYA (n=15)and PRISM interventionist (n=3) stakeholder feedback; and (3) develop a final intervention manual and deliveryprotocol. Additionally K99 activities will provide applied opportunities to complement the learning goals of apromising early career behavioral scientist including developing expertise in qualitative research methods andtraining in conceptual and practical aspects of clinical trial design and conduct. The second independent phaseof this study (R00 3 years) aims to establish proof-of-concept of this adaptation. Through a two-site randomized-controlled trial of N=100 AYAs newly diagnosed with cancer the goals of this phase are to (1) establish feasibilityand acceptability of the PRISM+SRCE program; and (2) explore whether PRISM+SRCE improves psychosocialoutcomes compared to usual care. Findings from this study will critically inform a subsequent (R01-funded)Phase III efficacy trial of this adaptation. This project fulfills the objectives of RFA-CA-20-057 in the CancerControl Science area by aiming to enhance an applied behavioral intervention to improve AYA quality of life. Ifsuccessful this adaptation will both improve AYA social outcomes and bolster the overall impact of the PRISMprogram thus creating a promising paradigm for comprehensively addressing AYA psychosocial needs. 249000 +No NIH Category available Address;Adolescent;Adolescent and Young Adult;Advertising;Award;Behavior;Characteristics;Communication;Data;Development;Electronic cigarette;Environment;Focus Groups;Goals;Grant;Health;Incentives;Influentials;Knowledge;Location;Marketing;Mentorship;Phase;Policies;Predisposition;Prevention program;Price;Randomized;Randomized Controlled Trials;Regulation;Research;Research Personnel;Risk;Statistical Methods;Surveys;Tobacco use;Training;Youth;combat;design;effectiveness evaluation;electronic cigarette use;experimental study;multi-component intervention;multidisciplinary;prevent;skills;tobacco control;tobacco prevention;tobacco regulatory science;uptake Countering E-cigarette Marketing in the Retail Environment among Adolescents and Young Adults PROJECT NARRATIVEMillions of youth use e-cigarettes spurred in part by pervasive marketing in brick-and-mortarretail stores. To prevent youth uptake of e-cigarettes and health risks the proposed project willask adolescents and young adults to identify appealing and influential characteristics of e-cigarette marketing in the retail environment and address these influences in a counter-marketing lesson. Study findings will also inform e-cigarette-retail-marketing related regulations. NCI 10862375 7/25/23 0:00 PA-20-272 3K99CA267477-02S1 3 K99 CA 267477 2 S1 "RADAEV, SERGEY" 8/1/23 0:00 12/31/23 0:00 16119482 "GAIHA, SHIVANI MATHUR" Not Applicable 16 PEDIATRICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 12/31/23 0:00 77 Other Research-Related 2023 61222 OD 56687 4535 PROJECT SUMMARY/ ABSTRACTDespite significant efforts to limit youth from accessing and using electronic cigarettes (e-cigarettes) manyadolescents and young adults are directly purchasing e-cigarettes from brick-and mortar retail stores. Studiesshow that pervasive e-cigarette marketing in the retail environment such as e-cigarette product displayslocation/size of advertising and price incentives and coupons increase adolescent e-cigarette susceptibilityand actual use. However studies have not directly asked adolescents and young adults to identify appealingand influential characteristics of e-cigarette marketing in the retail environment that impact their e-cigarettepurchase and use intentions. Such data will support the FDAs aim of understanding marketing influences onyouth tobacco use and will inform the development of communications to prevent e-cigarette use through acounter-marketing lesson addressing appealing e-cigarette marketing characteristics in the retail environment.The proposed project will address three Specific Aims towards the development of a counter-marketing lessonand regulatory solutions: (1) Examine adolescents and young adults descriptions of e-cigarette marketing inthe retail environment and its influence on their e-cigarette purchase and use behavior. (2) Identify the mostimportant appealing characteristics intrinsic to e-cigarette marketing in the retail environment influencingadolescents and young adults intentions to purchase and use e-cigarettes. (3) AIM 3. Develop and evaluatethe effectiveness of an e-cigarette counter-marketing lesson combating marketing in the retail environment toreduce intent to use and actual use of e-cigarettes among adolescents. In the K99 phase focus groupdiscussions (Aim 1) and surveys including an embedded discrete-choice experiment (Aim 2) will identify howand which e-cigarette marketing characteristics influence adolescent and young adult e-cigarette purchase anduse. Aims 1 and 2 will identify which characteristics require counter-marketing and would benefit fromstrengthened regulation. In the R00 phase a randomized controlled trial will randomly assign adolescents-onlyto one of two conditions: 1) an online counter-marketing lesson about e-cigarette marketing in the retailenvironment (developed in this phase) or 2) an existing online e-cigarette overview lesson to assess influenceon adolescents' intent to use and actual use of e-cigarettes (Aim 3). This Award and proposed research willenable the PI to grow expertise in impactful e-cigarette prevention programs and policy solutions to reduceadolescent tobacco use a long-term goal. A training plan involving mentorship from multidisciplinary tobaccocontrol experts in tobacco prevention marketing policy survey design statistical methods and counter-marketing design and complementary didactic training will fill gaps in knowledge of tobacco regulatory scienceand vital research skills allowing the PI to transition to an independent investigator. By utilizing preliminarydata and leveraging new skills the PI will submit a R01 grant that will examine a multi-component interventionto combat marketing which will substantially reduce adolescents and young adults e-cigarette use. 61222 +No NIH Category available Adherence;Adoption;Adverse drug effect;Adverse event;Authorization documentation;Behavior;Cancer Etiology;Cessation of life;Classification;Coping Behavior;Data;Development;Disease;Drug Costs;Drug Targeting;Eligibility Determination;Familiarity;Financial Hardship;Financial Support;Fostering;Heterogeneity;Home;Improve Access;Incentives;Malignant neoplasm of prostate;Measures;Medical;Medical Oncologist;Medical Oncology;Medicare;Modeling;Oral;Outcome;Patients;Pharmaceutical Preparations;Pharmacy facility;Phase;Physicians;Population;Prednisone;Price;Recommendation;Risk;Safety;Secure;System;Time;Toxic effect;Underrepresented Populations;Urologist;Urology;Work;abiraterone;advanced prostate cancer;authority;black men;cancer care;chemotherapy;cost;enzalutamide;financial incentive;improved;interest;medical specialties;medication compliance;men;mortality;patient safety;point of care;targeted treatment;therapy duration;trend Physician dispensing of oral specialty drugs for advanced prostate cancer and its implications for patients PROJECT NARRATIVEThis study will assess the effects of physician dispensing of oral specialty drugs (i.e. dispensingof medications directly to patients by the physician) for advanced prostate cancer on utilizationfinancial consequences and safety. Results from this study will have real-world implications formen with advanced prostate cancer who are intent on getting the highest quality cancer carewhile avoiding financial consequences and toxicity associated with these medications. NCI 10862259 8/15/23 0:00 PA-21-268 7R01CA275993-02 7 R01 CA 275993 2 "HALPERN, MICHAEL TOUBER" 2/1/23 0:00 1/31/28 0:00 Organization and Delivery of Health Services Study Section[ODHS] 2053176 "HOLLENBECK, BRENT K." "SHAHINIAN, VAHAKN B" 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 6/1/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 530886 NCI 345114 185772 PROJECT SUMMARYNearly 35000 succumb to advanced prostate cancer each year making it the second leading cause of cancerdeath among men. The development of oral specialty drugs targeting specific molecules has led to a paradigmshift in which men can receive treatment for their prostate cancer at home. Oral specialty drugs such asabiraterone and enzalutamide have similar efficacy as physician administered chemotherapy with less toxicityand are the most common first-line treatment for advanced prostate cancer as of 2015. This new treatmentparadigm has been accompanied by concurrent changes in in the delivery system. Increasingly prescriptionsfor oral specialty drugs are dispensed directly by the urologist or medical oncologist in their office (referred toas physician dispensing). Patients may benefit from this delivery model as it places the onus for authorizationand identification of financial assistance on the prescribing physician. Combined with the integration andcoordination implied by dispensing at the point of care this delivery model may improve access timeliness andadherence to these specialty drugs. However financial incentives associated with physician dispensingthrough a margin generated by each prescription fill may foster prescribing behaviors promoting utilization thatundermine the value of this delivery system change such as use of these therapies in patients with preexistingconditions that predispose them to adverse drug effects. To understand the implications of this delivery modelfor patients we propose the following: (1) To measure the effects of physician dispensing on use of specialtydrugs for prostate cancer; (2) To determine the impact of physician dispensing of specialty drugs for prostatecancer on financial outcomes and coping behaviors; and (3) To measure the relationship between physiciandispensing of specialty drugs for prostate cancer and patient safety. Results from this study will have real-worldimplications for men with advanced prostate cancer who are naturally interested in getting the highest qualitycancer care while avoiding the financial consequences commonly associated with oral specialty drugs. 530886 +No NIH Category available Ablation;Address;Adverse effects;Aftercare;Algorithms;Anatomy;Animals;Binding;Biological;Biological Markers;Biological Process;Biosensor;Blood flow;Breast Cancer Model;CAR T cell therapy;Cell Survival;Cell physiology;Cell surface;Cells;Clinical;Collaborations;Contrast Media;DNA;Detection;Development;Disease;Doctor of Medicine;Doctor of Philosophy;Dose;Engineering;Exhibits;Foundations;Goals;Granzyme;Histologic;Hydroquinones;Image;Imaging Techniques;Imaging technology;Immune;Immunotherapeutic agent;In Vitro;Infiltration;Infusion procedures;Interferon Type II;Interleukin-2;Interleukin-6;Knowledge;Label;Lasers;Life;Location;Maleimides;Malignant Neoplasms;Medical Imaging;Medicine;Mentors;Mentorship;Methods;Modification;Monitor;Nanosphere;Nanotechnology;Oncology;Optics;Oxygen;Phase;Physiologic pulse;Precision therapeutics;Prediction of Response to Therapy;Program Development;Reaction Time;Research;Research Personnel;Resolution;Scientist;Signal Transduction;Site;Solid Neoplasm;Sulfhydryl Compounds;Surface;System;T-Lymphocyte;Therapeutic;Time;Tissues;Training;Translating;Translations;Treatment outcome;Ultrasonography;Universities;Urology;absorption;aptamer;cancer immunotherapy;cancer type;career;career development;cell behavior;cellular engineering;cellular imaging;chimeric antigen receptor;chimeric antigen receptor T cells;contrast imaging;cytokine;cytokine release syndrome;design;engineered T cells;experimental study;image guided;image guided therapy;imaging agent;imaging system;improved;in vivo;innovation;instrumentation;leukemia;malignant breast neoplasm;manufacture;mid-career faculty;miniaturize;mouse model;multidisciplinary;nanoGold;nanobiomaterial;nanomaterials;nanoparticle;nanorod;nanosensors;neurotoxicity;photoacoustic imaging;plasmonics;preservation;prevent;professor;programs;remote control;remote sensing;response;sensor;side effect;therapy outcome;tumor;tumor immunology;tumor microenvironment;ultrasound Nanoparticle-augmented image-guided CAR T therapy and post-treatment assessment NARRATIVEThe limited ability to monitor the infused CAR T cells location and activity in real-time contributes to less efficient therapy and more systemic side effects. This proposal seeks to develop an image-guided therapy and activity monitoring/controlling system based on the combination of nanotechnology combined ultrasound and photoacoustic imaging and cell engineering to increase treatment precision and decrease side effects. NCI 10861106 8/22/23 0:00 PA-20-188 4R00CA263016-02 4 R00 CA 263016 2 "AVULA, LEELA RANI" 7/1/22 0:00 8/31/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15696438 "KIM, JINHWAN " Not Applicable 4 SURGERY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 177334 71666 SUMMARYThis proposal describes a five-year career development program to prepare the candidate Dr. Jinhwan Kim for a career as an independent investigator. This program will build on Dr. Kims background as a material scientist and nanobiomaterial engineer by providing additional expertise in medical imaging cell engineering and nanomaterials. The primary mentor Stanislav Emelianov Ph.D. (Professor of BME at Georgia Tech) has expertise in instrumentation imaging systems and algorithms image-guided therapy and imaging contrast agents. Co-mentors are Younan Xia Ph.D. (Professor of BME at Georgia Tech) who has expertise in nanoparticles and Gabriel Kwong Ph.D. (Associate Professor of BME at Georgia Tech) whose expertise in T cell engineering. Dr. Kim will collaborate with Kevin Kalinsky M.D. (Associate Professor of Medicine at Emory University) on breast cancer oncology Haydn Kissick Ph.D. (Assistant Professor of Urology at Emory University) on cancer immunology and Krishnendu Roy Ph.D. (Professor of BME at Georgia Tech) on T cell manufacturing.In this application Dr. Kim will demonstrate the use of plasmonic nanoparticles with tunable peak optical absorption as contrast agents for the combined ultrasound and photoacoustic (US/PA) imaging. The developed imaging agents and US/PA system will be used for image-guided chimeric antigen receptor (CAR) T cell therapy in breast cancer and sensing the activity of delivered CAR T cells in the tumor microenvironment (TME). Current approaches in CAR T cell therapy lack the ability to monitor the location and activity of the infused CAR T cells in real-time which is critical to understand the biological effect of CAR T cells and to predict the treatment outcome. By labeling CAR T cells with gold nanorods (AuNRs) absorbing in near-infrared (NIR) spectral range this project aims to enable tracking of the CAR T cells after infusion for image-guided therapy (Aim 1). Implementing the US/PA imaging technique will allow the real-time high-resolution detection of the CAR T cells with great anatomical information in reliable imaging depth (Aim 2). Furthermore the design of the gold nanoparticle-based US/PA imaging sensors that selectively and sensitively detect cytokines released from injected CAR T cells will enable monitoring CAR T cell activity thereby assessing and controlling the microenvironment with additional external stimulation (Aim 3). Aims 1 and 2 (K99 phase) will be guided under the strong mentorship from mentor/co-mentors with extensive training on nanotechnology (Younan Xia Ph.D.) CAR T cell engineering (Gabriel Kwong Ph.D.) and US/PA imaging (Stanislav Emelianov Ph.D.). Dr. Kim will independently conduct the proposed aim 3 with the extended expertise gathered during the K99 phase. The multidisciplinary knowledge gained during the overall research and career training this project will provide a foundation for Dr. Kim an independent investigator in the R00 phase to develop advanced applications of nanotechnology in innovative therapeutic approaches to treat cancer and other diseases. 249000 +No NIH Category available ABCB1 gene;ATP-Binding Cassette Transporters;Actinobacteria class;Adjuvant;Affect;Affinity;Antineoplastic Agents;Binding;Biochemical;Biological Availability;Body Weight decreased;CRISPR/Cas technology;California;Cancer Model;Candidate Disease Gene;Cell Death;Cell Line;Cells;Cellular Assay;Chemoresistance;Chemotherapy-Oncologic Procedure;Colorectal Cancer;Cytotoxic agent;Data;Dose Limiting;Doxorubicin;Drug Efflux;Drug Kinetics;Drug toxicity;Effectiveness;Environment;Enzymes;Escherichia coli;Etiology;Fluorescence;Fluorescent Probes;Foundations;Fractionation;Genes;Genetic Polymorphism;Genetic Transcription;Germ-Free;Gnotobiotic;Goals;Guide RNA;Health;Healthcare;Heterogeneity;Histology;Human;In Vitro;Incubated;Kinetics;Knock-out;Measures;Mediating;Medical;Metabolism;Methods;Microbe;Morbidity - disease rate;Mus;Nature;Oral;Patients;Pharmaceutical Preparations;Physicians;Play;Prognostic Marker;Proliferating;Reader;Rectal Cancer;Rectal Neoplasms;Research;Research Project Grants;Resistance;Resources;Risk;Role;San Francisco;Scientist;Serum;Shapes;Specificity;Staging;Testing;Therapeutic;Toxic effect;Toxicity due to chemotherapy;Training;Training Programs;Transcriptional Activation;Transplantation;Treatment outcome;Universities;Variant;Vesicle;Weights and Measures;Xenograft Model;cancer cell;cancer therapy;career;chemotherapeutic agent;chemotherapy;colon cancer cell line;comorbidity;comparative;comparative genomics;cytotoxic;demographics;diagnostic biomarker;drug disposition;drug efficacy;drug response prediction;experimental study;gut microbes;gut microbiome;host microbiome;imaging system;improved;in vitro Assay;in vitro Model;in vivo;in vivo fluorescence imaging;inhibitor;insight;inter-individual variation;medical schools;member;metabolomics;microbial;microbial community;microbiome;microbiome research;microbiota;mortality;predictive marker;small molecule;therapy outcome;treatment response;tumor Impact of the microbiome on chemotherapeutic outcomes PROJECT NARRATIVEInterindividual variation in the effectiveness of cancer chemotherapy cannot be fully explained or predictedresulting in health risks to patients and inefficient utilization of limited healthcare resources. While variations inthe gut microbiome of patients have been shown to influence treatment outcomes the mechanisms by whichthese microbes change chemotherapeutic drug disposition remain poorly understood. Based on our strong invivo and in vitro data showing that a prevalent gut microbe inhibits a key drug efflux transporter this proposalwill expand our mechanistic understanding of host-microbiome interactions in drug disposition and provide thefirst step towards using microbial genes and/or metabolites as predictive markers for cancer chemotherapy. NCI 10860926 12/20/23 0:00 PA-19-191 5F30CA257378-04 5 F30 CA 257378 4 "PURI, ANU" 1/1/21 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 15120601 "KYAW, THAN SOE" Not Applicable 11 MICROBIOLOGY/IMMUN/VIROLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACT Cytotoxic chemotherapeutic agents are a key component of cancer therapy but they have unpredictabletreatment responses and considerable treatment-related morbidity and mortality. Factors such as patientdemographics comorbidities tumor types genetic polymorphisms and the gut microbiome may contribute tointerindividual variations in chemotherapy treatment response. Of these factors the gut microbiome is mostamenable to manipulation to improve the efficacy and limit the toxicity of chemotherapy. However themechanisms and extent to which the microbiota affects drug disposition and thus efficacy remain elusive. P-glycoprotein (P-gp) a key mammalian drug efflux transporter plays a critical role in chemotherapeutictreatment outcomes since it affects the pharmacokinetics of many cytotoxic agents and renders cancer cellsresistant to anticancer drugs. Preliminary results demonstrate that the prevalent human gut ActinobacteriumEggerthella lenta inhibits P-gp function in mice resulting in increased drug concentrations in the serum. In vitromodels with human colorectal cancer (CRC) cells replicated this in vivo finding and suggested that the P-gpinhibition is mediated by a secreted bacterial metabolite. Furthermore the P-gp inhibitor sensitized human CRCcells against a P-gp substrate anticancer drug doxorubicin. Together these findings provide a strong scientificevidence to support the hypothesis that E. lenta secretes small molecule(s) that inhibit P-gp leading to increaseddrug accumulation in the tumor and improved efficacy of doxorubicin anticancer therapy. This hypothesis will betested through 2 aims. P-gp inhibitor will be identified using comparative genomics comparative metabolomics and activity-guided biochemical fractionations (Aim 1a). The mechanism and the transporter specificity will be investigatedwith various in vitro methods (Aim 1b 1c). The effect of E. lenta colonization on the efficacy and toxicity ofdoxorubicin treatment will be evaluated in a mouse rectal tumor xenograft model (Aim 2). Results from theseaims will elucidate the mechanism of microbiome-transporter interactions that impacts cancer treatmentoutcomes. These experiments will lay a strong foundation to use the candidate genes and metabolites asprognostic biomarkers for treatment response and potential adjuvants to therapy. These research projects will be conducted at the University of California San Francisco (UCSF) whichoffers a unique combination of an exceptional microbiome research environment with a top-tier medical school.These research goals in combination with a comprehensive training plan from the UCSF Medical ScientistTraining Program will be crucial to shaping the applicant's career as a physician-scientist. 52694 +No NIH Category available Biological Markers;Blood;Cancer Etiology;Cellular Metabolic Process;Cholestasis;Cholesterol;Cirrhosis;Clinical;Clinical Research;Clinical Trials;Cohort Studies;Collaborations;Compensation;Cryptogenic cirrhosis;Cytometry;Diagnostic;Etiology;Fatty Acids;Fibrosis;Gastroenterology;Glucose;Glutamine;Hepatic;Hepatology;Homeostasis;Human;Hydroxymethylglutaryl-CoA Reductase Inhibitors;Immune;Immune system;Immunologic Markers;Immunologic Surveillance;Inflammation;Knowledge;Laboratories;Lead;Letters;Libraries;Lipids;Liver Cirrhosis;Liver diseases;MYC gene;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Medical Oncology;Meta-Analysis;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;National Institute of Diabetes and Digestive and Kidney Diseases;Nature;Oncology;Oxidative Stress;Oxidoreductase;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Prevention;Preventive;Preventive therapy;Primary carcinoma of the liver cells;Proliferating;Property;Publishing;Reporting;Research;Research Personnel;Risk;Risk Reduction;Sampling;Series;Signal Transduction;System;Tetanus Helper Peptide;Therapeutic Effect;Transgenic Mice;Transgenic Model;Transgenic Organisms;Travel;Tumor Suppressor Genes;United States National Institutes of Health;Work;anti-cancer;anticancer research;atorvastatin;biomarker identification;cancer therapy;carcinogenesis;cytokine;epidemiology study;fighting;imaging agent;improved;inhibitor;insight;ionization;lipid biosynthesis;liver cancer model;mass spectrometric imaging;member;metabolomics;mortality;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;patient derived xenograft model;pre-clinical;prevent;programs;prospective;rosuvastatin;single-cell RNA sequencing;tumor;tumor immunology;tumor initiation;tumor progression;tumorigenesis Molecular Mechanisms by which Statins Prevent and Reverse Hepatocellular Carcinoma Project Narrative Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. HMG-CoAreductase (HMGCR) inhibitors statins show high potential in the prevention and treatment of cancer includingHCC. We hypothesize that the MYC pathway is suppressed by statins and this is a mechanism by which statinscan prevent and treat HCC both through direct anti-oncogene effects as well as by restoring immune surveillance.We will determine the mechanisms by which statins protect against HCC as well as identify biomarkers that canpredict when these agents are most likely to be useful in preventing HC. NCI 10856787 9/19/23 0:00 RFA-CA-23-023 1U01CA288433-01 1 U01 CA 288433 1 "READ-CONNOLE, ELIZABETH LEE" 9/19/23 0:00 8/31/27 0:00 ZCA1-TCRB-Q(O2) 1889454 "FELSHER, DEAN W" "VERNA, ELIZABETH CLARICE" 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 341920 NCI 229715 112205 Project Summary/Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. HMG-CoAreductase (HMGCR) inhibitors statins show high potential in the prevention and treatment of cancer includingHCC. We will investigate the mechanism by which statins fight against HCC and discovering the biomarkers topredict the therapeutic effects. Through our previously published work we have used our conditional transgenicmouse models of HCC to identify a novel pathway that statins suppress MYC signaling to execute the anti-cancerproperties. Also we identified that MYC rewires metabolic pathways to promote fatty acid synthesis in additionto glucose and glutamine pathways. Inhibition of fatty acid synthesis by TOFA elicits dramatic regression of MYCdriven tumors and the efficacy correlates to MYC level. Statin (e.g. Atorvastatin) blocks MYC phosphorylation inour MYC-driven HCC model and inhibit tumor initiation and progression (see our Preliminary Results). Wehypothesize that the MYC pathway is suppressed by statins and this is a mechanism by which statins can preventand treat HCC both through direct anti-oncogene effects as well as by restoring immune surveillance. We willdetermine the mechanisms by which statins protect against HCC we propose to 1) evaluate the anti-cancerefficacy of statins at different progression stages of MYC driven HCC (before MYC induction early stage oftumorigenesis late stage of HCC) and the condition of association with NASH; 2) identify specific metabolismpathways regulated by statin in MYC-HCC; 3) define the changes of immune system and specificeffectors/cytokines influenced by statin; 4) discover the biomarkers that can predict the therapeutic effect of statinin prevention of HCC. Our team includes expertise in Medical Oncology the MYC oncogene and TumorImmunology (Felsher) Gastroenterology and HCC (Dhanasekaran) and Hepatology and liver disease (Vernaand Brown). Dr. Verna and Dr. Brown are members of the Liver Cirrhosis Network (LCN) clinical program (RAF-CA-23-023) and are currently investigating the effect of lipid lowing medications (Statins) in patients withcompensated NASH ALD cholestatic and cryptogenic cirrhosis. The LCN study provides us with a uniqueopportunity to identify mechanisms through use of our preclinical transgenic mouse model of HCC that can beevaluated using human clinical samples to available to us through the LCN. Our work will help identify lead tothe identification of the mechanisms by which statins can block HCC as well as identify biomarkers that canpredict when these agents are most likely to be useful in preventing HCC. 341920 +No NIH Category available Address;Architecture;Area;Aristolochic Acids;Automobile Driving;Awareness;Black American;Black Populations;Black race;Cancer Etiology;Chronic Hepatitis C;Cirrhosis;Coal;Collaborations;Complex;DNA Damage;Data;Diagnosis;Disease Outcome;Disparity;Enrollment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Exposure to;Frequencies;Genes;Genetic;Genetic Risk;Genomics;Heavy Metals;Hepatotoxicity;High Prevalence;Histologic;Human;Immunogenomics;Immunophenotyping;Interferons;Intervention;Knowledge;Liver;Liver Cirrhosis;Liver diseases;Low Prevalence;Malignant Neoplasms;Malignant neoplasm of liver;Maps;Minority Groups;Molecular;Mutagens;Mutate;Mutation;Nature;Not Hispanic or Latino;Oncogenic;Oncology;Participant;Pathway interactions;Patients;Phenotype;Population Heterogeneity;Prevalence;Prevention;Prevention strategy;Primary carcinoma of the liver cells;Production;Prostatic Neoplasms;Provider;Research Personnel;Resistance;Risk;Risk Factors;Science;Single Nucleotide Polymorphism;Slide;Smoke;Special Population;Specimen;Study Subject;Susceptibility Gene;The Cancer Genome Atlas;Time;Toxin;Variant;biobank;black patient;cancer initiation;cancer predisposition;cancer risk;cohort;digital;exome sequencing;experience;innovation;insight;liver injury;mortality;multidisciplinary;neoplastic cell;nonalcoholic steatohepatitis;novel;people of color;polygenic risk score;risk variant;socioeconomics;synergism;tool;transcriptomics;treatment strategy;tumor;tumor progression;tumorigenesis;underserved minority Genomic and environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture NarrativeThe project is expected to yield actionable mechanistic insights into environmental exposurestumor immunophenotype and genetic factors driving the atypical presentation of HCC in Blacksand may identify new targets for intervention and prevention. The study will also yield apolygenic risk score for cirrhosis for use among ancestrally diverse populations. The results willalert patients and providers to the fact that HCC risk is disproportionate to cirrhosis stage inBlacks raising awareness and encouraging early enrollment in surveillance. NCI 10856546 9/21/23 0:00 RFA-CA-23-023 1U01CA288425-01 1 U01 CA 288425 1 "READ-CONNOLE, ELIZABETH LEE" 9/21/23 0:00 8/31/27 0:00 ZCA1-TCRB-Q(O2) 1973146 "BRANCH, ANDREA D." "STERLING, RICHARD K." 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 360350 NCI 237941 122409 Genomicand environmental drivers of HCC in Non-Hispanic Blacks: Nature and nurture:Non-Hispanic Black Americans (Blacks) develop hepatocellular carcinoma (HCC) at about twice the rate ofWhites and have far higher mortality. HCC has an atypical presentation in Blacks with lower cirrhosis stage atthe time of HCC diagnosis and more advanced and aggressive HCC. Blacks have higher exposure toenvironmental pollutants than Whites and these exposures are associated with liver damage. Although heavymetals and toxins are known to cause liver injury and cancer they are often overlooked. This project addressesthe need to understand the genomic and environmental factors causing the atypical presentation of HCC inBlacks so that effective prevention and treatment strategies can be implemented. It is responsive to RFA-CA-23-023 in the topic area: Liver cancer in underserved minority populations. This innovative collaboration betweenexperts in the Liver Cirrhosis Network and liver cancer researchers is expected to yield actionable mechanisticinsights into environmental exposures tumor immunophenotype and genetic factors driving the atypicalpresentation of HCC in Blacks and may identify new targets for intervention and prevention. The study will alsoyield a polygenic risk score for cirrhosis for use among ancestrally diverse populations. The results will alertpatients and providers to the fact that HCC risk is disproportionate to cirrhosis stage in Blacks raising awarenessof the threat and encouraging early enrollment in surveillance. This project will expand HCC tumor sequencingand transcriptomic data from Black patients over 4-fold. The Cancer Genome Atlas (TCGA) has only 17 HCCsfrom Blacks.Aim I: Hypothesis: Mutational signatures of toxic damage are more prevalent in HCCs of Blacks than in HCCsof Whites. We will perform whole exome sequencing on paired HCC/non-HCC specimens from Blacks and useour in-house pipeline to identify somatic single nucleotide variants (SNVs) to find known and novel mutationalsignatures to define the tumor mutational burden and to identify mutated genes.Aim II: Hypothesis: The HCC tumor cells and surrounding microenvironment in Blacks are primed for pro-tumoractivity. We will perform global transcriptomic analysis on paired HCC/non-HCC specimens of Blacks to identifyoncogenic drivers and computationally immunophenotype the microenvironment. Multiplexed IHC will be usedto map the molecular findings onto the histological architecture of the patient's human liver specimens.Aim III: Hypothesis: Blacks with HCC have a lower prevalence of cirrhosis risk variants than Whites with HCCbut they have a high prevalence of cancer risk variants including rare penetrant variants. We will compare theprevalence of cancer predisposition variants in Blacks with HCC vs. healthy controls developscorecirrhosisa polygenic riskfor cirrhosis compare cirrhosis risk between Blacks and Whites with HCC and explore genetic risks forin study subjects in the Liver Cirrhosis Network who develop HCC. 360350 +No NIH Category available 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol;4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;Acrolein;Base Sequence;Biological Markers;Cancer Etiology;Carcinogens;Cardiovascular Diseases;Cells;Chemicals;Cigarette;Cigarette Smoker;Classification;DNA;DNA Adduction;DNA Adducts;DNA Damage;DNA Repair;Data;Deoxyguanosine;Deoxyribonucleosides;Derivation procedure;Disease;Dose;Electronic cigarette;Excision;Excision Repair;Exposure to;Fostering;Genomic Instability;Goals;Habits;Health;Homeostasis;Human;Hydrolysis;Hydroxylamine;In Vitro;International Agency for Research on Cancer;Investigation;Leukocytes;Link;Liquid Chromatography;Liver;Location;Lung;Lung diseases;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Membrane;Metabolic Activation;Methods;Morphologic artifacts;Mucous Membrane;Mutation;N'-nitrosonornicotine;Nitrosamines;Oral;Oral cavity;Oral mucous membrane structure;Oropharyngeal;Predisposition;Prevention;Probability;Process;Purines;Pyrimidine;Rattus;Reaction;Site;Smokeless Tobacco;Smoker;Structure of mucous membrane of nose;Survival Rate;Tissues;Tobacco;Tobacco use;Tobacco-Associated Carcinogen;Tobacco-Related Carcinoma;United States;adduct;age effect;analytical method;base;cancer prevention;cancer risk;carcinogenicity;cigarette smoke;cigarette smoke-induced;cigarette smoking;cytotoxic;design;electronic cigarette user;epidemiologic data;epidemiology study;exposed human population;genotoxicity;human DNA;in vivo;malignant mouth neoplasm;non-smoker;oral cancer prevention;prevent;response;silochrome;smokeless tobacco user;smoking cessation;tandem mass spectrometry;tobacco exposure;tobacco products;tobacco user;urinary Carcinogenic tobacco-specific nitrosamines induction of apurinic/apyrimidinic sites in DNA of human oral cells Project NarrativeCigarette smoke smokeless tobacco and electronic cigarettes may induce DNA damage and cause lung andoral cavity cancer. We will quantify DNA damage in oral cells of humans exposed to different types of tobaccoproducts in order to provide an effective biomarker of human exposure to carcinogens. Our goal is to advanceour understanding of tobacco-induced cancer and ultimately develop effective strategies for cancer prevention. NCI 10856299 9/11/23 0:00 PA-21-268 7R03CA259652-03 7 R03 CA 259652 3 "JOHNSON, RONALD L" 6/5/23 0:00 12/31/24 0:00 ZCA1-RTRB-U(O2)S 15254409 "GUO, JIEHONG " Not Applicable 1 ENGINEERING (ALL TYPES) 65453268 GKMSN3DA6P91 65453268 GKMSN3DA6P91 US 47.116169 -88.53931 5230701 MICHIGAN TECHNOLOGICAL UNIVERSITY HOUGHTON MI BIOMED ENGR/COL ENGR/ENGR STA 499311295 UNITED STATES N 6/5/23 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2023 71741 NCI 50000 21741 Project SummaryCigarette smoking is the leading cause of lung and oral cancer in the United States. Smokeless tobacco causescancer of the mouth esophagus and pancreas. The health effects of e-cigarettes are still under investigation butmay disturb oral cavity homeostasis and cause lung and cardiovascular diseases. The tobacco-specificnitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) areclassified as human carcinogens by the International Agency for Research on Cancer and are recognizedcauses of these diseases. Metabolic activation of NNK and NNN results in formation of reactive electrophilesthat modify DNA to produce a variety of products such as N7-[4-(3-pyridyl)-4-oxobut-1-yl]-deoxyguanosine(N7POBdG) that can result in apurinic/apyrimidinic (AP) sites in DNA by facile hydrolysis of the base-deoxyribonucleoside bond; other tobacco constituents may also induce AP sites. AP site accumulation mayinitiate the carcinogenic process. Oral cells provide the direct link between tobacco use and oral cancer inhumans and elevated DNA damage has been found in oral cells of tobacco users. We propose to analyze APsites in oral cell DNA with two specific aims: to develop a highly sensitive mass spectrometric method to quantifyAP sites in human oral cell DNA and to quantify AP sites in oral cell DNA induced by cigarette smoke smokelesstobacco and e-cigarettes. The goals are to establish oral cell DNA AP sites as biomarkers of tobacco inducedDNA damage in cigarette smokers smokeless tobacco users and e-cigarette users and to ultimately identifysusceptible tobacco users and design effective strategies to prevent cancer. This study may also providepreliminary data for a large epidemiologic study. We have strong preliminary data to support this proposal. 71741 +No NIH Category available Affect;Aflatoxins;Alanine Transaminase;All of Us Research Program;Behavioral;Biological Markers;Black race;California;Candidate Disease Gene;Case/Control Studies;Characteristics;Chronic Hepatitis B;Cicatrix;Cirrhosis;Clinical;Collaborations;Community Health;Comprehensive Cancer Center;Country;Data;Detection;Diabetes Mellitus;Diet;Disparate;Disparity;Enrollment;Ensure;Environmental Risk Factor;Epidemiology;Ethnic Population;Fatty Liver;Genetic;Genetic Polymorphism;Genetic Risk;Genetic study;Goals;HIV;Hepatic;Hepatitis C;Incidence;Indigenous American;Individual;Institution;Insulin Resistance;Latino;Latino Population;Lead;Liver;Liver Cirrhosis;Liver Fibrosis;Los Angeles;Malignant Neoplasms;Malignant neoplasm of liver;Medical;Metabolic syndrome;Mexico;Neighborhoods;Nucleotides;Obesity Epidemic;Participant;Patient Recruitments;Patients;Persons;Poverty;Prevalence;Primary carcinoma of the liver cells;Principal Investigator;Progressive Disease;Prospective cohort;Puerto Rico;Race;Research;Research Personnel;Resources;Risk;Risk Factors;Risk Reduction;STAT4 gene;Sampling;Severities;Single Nucleotide Polymorphism;Site;Steatohepatitis;United States;United States National Institutes of Health;Universities;Vulnerable Populations;Work;burden of illness;clinical risk;cohort;disease phenotype;disease prognosis;disorder risk;epidemiology study;gene environment interaction;genetic association;genome wide association study;high risk;improved;liver transplantation;member;modifiable risk;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;participant enrollment;personalized approach;personalized medicine;personalized screening;phenome;polygenic risk score;population based;precision medicine;prospective;racial diversity;racial population;recruit;risk prediction model;risk stratification;screening program;simple steatosis;social;social culture;treatment strategy Genetic and Environmental risk of NAFLD-related HCC In All Latinos: the GENIAL Study Non-alcoholic fatty liver disease (NAFLD) commonly known as fatty liver is a leading cause of liver cancerand disproportionately affects Latinos in the United States and worldwide. The proposed study will determinehow genetic differences lead to increased risk of NAFLD and NAFLD-related complications such as cirrhosis(scarring of the liver) and hepatocellular carcinoma the most common form of liver cancer. Understanding howthese genetic differences interact with environmental risk factors will allow us to (1) identify which individualshave the highest risk of developing liver cancer (2) implement personalized treatment strategies aimed atreducing the risk of NAFLD-related complications and (3) create personalized screening programs that targetthose individuals before cancer develops. NCI 10856113 9/21/23 0:00 RFA-CA-23-023 1U01CA288421-01 1 U01 CA 288421 1 "MOMIN, BEHNOOSH RAMJI" 9/21/23 0:00 8/31/27 0:00 ZCA1-TCRB-Q(O2) 11113614 "JONES, PATRICIA DENISE" "FLORES, YVONNE NICOLE" 27 INTERNAL MEDICINE/MEDICINE 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 341018 NCI 262261 78757 The burden of hepatocellular carcinoma (HCC) due to non-alcoholic fatty liver disease (NAFLD) has increasedsubstantially over the past two decades. Although both NAFLD and HCC disproportionately affect Latinoindividuals few Latinos were included in genetic and epidemiologic studies evaluating HCC risk. Prior geneticstudies examining NAFLD risk that did include Latinos were limited in that they used candidate-gene approacheswhich cannot detect novel genetic associations. Other studies limited inclusion to individuals from one countryand thus could not consider how the incredible diversity among Latinos might drive genetic risk or differences inNAFLD phenotype risk of cirrhosis or HCC risk. In the proposed study Drs. Jones and Flores will workcollaboratively as multiple principal investigators. Along with co-investigators they will collaborate with othermembers of the Liver Cirrhosis Network (LCN) to develop precise personalized approaches to NAFLDprognostication and HCC risk stratification targeted specifically to Latinos a vulnerable population with excessdisease burden. In Aim 1 Drs. Flores and Jones will leverage existing data from two studies (UCLA ATLASCommunity Health Initiative and NIH All of Us Research Program) to conduct a genome wide association study(GWAS) phenome-wide association study and create polygenic risk scores in persons with NAFLD. All of Usand ATLAS aim to enroll diverse participants to ensure inclusivity and generalizability in Precision Medicineresearch. As such the proposed study represents the largest most racially diverse GWAS in NAFLD with 21199individuals with NAFLD already identified. We will define the relationship between known and novel singlenucleotide polypmorphisms (SNPs) and risk of NAFLD NASH NAFLD-cirrhosis and NAFLD-HCC stratified byrace region of origin and genetic ancestry. In collaboration with LCN investigators Drs. Flores and Jones willenroll Latino participants with NAFLD into a prospective case-control study that aims to characterize gene-environment interactions between known and novel genetic NAFLD-associated SNPs and environmental riskfactors including HIV diabetes and metabolic syndrome. They will engage new and existing LCN Cohortparticipants as well as participants enrolled in existing cohorts at the University of Miami (UM) the University ofLos Angeles California (UCLA) and the University of Puerto Rico Comprehensive Cancer Center (UPRCCC). Allsites will identify and recruit new cases with NAFLD and healthy controls. We will develop polygenic risk scoresthat incorporate genetic clinical sociocultural behavioral and environmental characteristics to predict (1) riskof cirrhosis in persons with NAFLD (2) hepatic decompensation in NAFLD patients with cirrhosis and (3) HCCrisk in NAFLD patients with or without cirrhosis. NAFLD is the fastest growing cause of cirrhosis in the US anddisproportionately impacts Latinos who also have the highest HCC burden. By identifying the strongest riskfactors that drive differences in NAFLD phenotype cirrhosis decompensation and HCC risk in a large diverseLatino sample we can identify those at greatest risk and intervene on modifiable risk factors. 341018 +No NIH Category available 2019-nCoV;Address;Antibodies;Antibody Repertoire;Antibody Response;Antigens;Applied Research;Automobile Driving;B-Cell Antigen Receptor;B-Lymphocytes;Basic Science;Biology;COVID-19;COVID-19 treatment;Cessation of life;Clinical;Data;Development;Disease;Funding;Future;Goals;Health system;Hospitalization;Human;Humoral Immunities;Immune;Immune response;Immunity;Immunoglobulin A;Immunoglobulin G;Immunologics;Individual;Infection;Infrastructure;International;Intervention;Kinetics;Maps;Mediating;Medical;Medical center;Memory;Memory B-Lymphocyte;Molecular;Mucous Membrane;North Carolina;Pathogenesis;Pathogenicity;Patient Recruitments;Persons;Productivity;Protein Chemistry;Proteins;Reagent;Recombinants;Reporting;Research;Research Project Grants;Resource Sharing;Resources;Role;SARS coronavirus;SARS-CoV-2 antibody;SARS-CoV-2 antigen;SARS-CoV-2 infection;Sampling;Science;Serology;Serology test;Serum;Services;Techniques;Testing;Texas;Therapeutic Intervention;Time;US State;Vaccines;Virus Diseases;Writing;cohort;convalescent plasma;design;human monoclonal antibodies;improved;innate immune function;neutralizing antibody;new technology;novel;novel coronavirus;pathogen;post SARS-CoV-2 infection;programs;response;sample collection North Carolina Seronet Center for Excellence Project NarrativeOur highly integrated Center uses novel technologies and reagents to build a portfolio of critical reagentsdesigned to map track and potentially treat SARS-CoV2 and related infections in the future while addressingfundamental questions into the molecular and immunologic mechanisms that regulate serologic responses inthe mucosal and systemic compartments after natural infection or medical interventions. NCI 10855051 6/2/23 0:00 RFA-CA-20-038 3U54CA260543-02S1 3 U54 CA 260543 2 S1 "READ-CONNOLE, ELIZABETH LEE" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 1885536 "BARIC, RALPH S" "WOLFGANG, MATTHEW C" 4 PUBLIC HEALTH & PREV MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PUBLIC HEALTH 275995023 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Research Centers 2023 2950055 OD 2223777 726278 C4 Abstract.The UNC Center for Excellence in SARS-CoV2 Serologic Research uses basic and applied researchstrategies to improve our understanding of the molecular and cellular mechanisms driving serological andhumoral immune responses after SARS-CoV2 infection. Our overall goals are to 1) characterize the immuneresponses elicited to SARS-CoV2 infection 2) understand the mechanisms driving the serological humoral andcellular immune responses 3) determine modifiers of the serologic memory and 4) determine the serologicalcorrelates of disease pathogenesis and protection against future infection. The program includes threeResearch Projects led by internationally renowned exerts in coronavirus emergence pathogenesis and immunity(Project 1: Baric) clinical and translational mucosal and systemic immune correlates of disease (Project 2:Bartelt & Margolis) and host-pathogen interactions driving innate and serological immunity (Project 3: Wallet& Maile). Program-wide support is provided by an Administrative Core A and two Shared Resource Cores B andC. Core A includes a robust infrastructure for programmatic oversight as well as participant recruitment samplecollection tracking and sharing (Core A: Baric & Wallet). Core B is led by world renowned experts incharacterization of human antibodies in protection and pathogenesis of disease (Core B: de Silva &Lakshmanane) and will provide recombinant spike protein antigens from SARS-CoV-2 as well as antigen-specific serological assays required for accomplishing the aims of all three Research Projects. Core C is led byserological experts (Core C: Ippolitto Georgiou & Lavinder) who have revolutionized techniques tocomprehensively analyze the molecular composition of the serological antibody repertoire (IgG and IgA) and thecellular antibody repertoire (i.e. B cell receptor) and thus will delineate these repertoires in and isolate humanmonoclonal antibodies from SARS-CoV-2+ individuals in cohorts defined in each Research Project. All threeResearch Projects are integrated and each require the support of all three Cores. To this end Project 1 willcharacterize the breadth and potency of polyclonal neutralizing antibody responses as well as determine thekinetics magnitude and durability of the type-specific and cross neutralizing responses in both the systemic andmucosal compartments. Project 2 will determine the durability and the breadth of anti-SARS-CoV-2 serumantibodies and memory B-cells generated among convalescent plasma donors as well as determine the effectof convalescent plasma on the innate adaptive and antibody repertoire in recipients. Project 3 will reveal innateimmune signatures as a function of serology across the span of natural disease as well as identify signatureswhich promote development of protective vs. pathogenic antibody repertoires while delineating mechanisms ofantibody mediated activation and suppression of innate immune function which drives severe vs. mild diseaserespectively. The integrated expertise of our Team is necessary and sufficient to address the novel cross-cuttinghypotheses put forth which will improve our understanding of SARS-CoV2 serological and humoral immunity. 2950055 +No NIH Category available 2019-nCoV;ACE2;Address;Affect;Affinity;Age;Animal Model;Antibodies;Antibody Response;B cell repertoire;B-Lymphocytes;Biological Assay;Biology;Blocking Antibodies;Blood;Blood Cells;COVID-19;COVID-19 diagnosis;COVID-19 outbreak;Cells;Circulation;Clinical;Clinical Trials;Communicable Diseases;Coronavirus Infections;Development;Disease;Evaluation;Event;Female;Frequencies;Future;Generations;Hour;Household;Human;Humoral Immunities;Immune;Immune response;Immunity;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunologic Memory;Immunologics;Immunology;Impairment;In Vitro;Individual;Infection;Inflammatory Response;Innate Immune Response;Invaded;Knowledge;Learning;Long-Term Effects;Lymphopenia;Measures;Mediating;Memory;Modeling;Molecular;Molecular Biology;Mucosal Immunity;Mucous Membrane;Nature;Onset of illness;Oral;Oral cavity;Oropharyngeal;Patients;Peripheral;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Post-Translational Protein Processing;Production;Proteins;Proteomics;Public Health;RNA;Role;SARS coronavirus;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 positive;Saliva;Sampling;Secretory Immunoglobulin A;Serology test;Severity of illness;Shapes;Site;Symptoms;T-Lymphocyte;Testing;Time;Vaccines;Validation;Variant;Viral;Viral Load result;Viral Proteins;Viremia;Virus;adaptive immune response;age stratification;antigen-specific T cells;cell killing;chemokine;comparative;cross reactivity;cytokine;experience;high risk population;indexing;long term memory;male;multidisciplinary;nasopharyngeal swab;neutralizing antibody;novel;peripheral blood;prevent;prospective;receptor;response;serological marker;transcriptome sequencing;vaccine immunogenicity;virology Early Drivers of Humoral Immunity to SARS-CoV-2 Infections The study examines events associated with initial exposure to COVID-19 by following close householdcontacts of individuals with documented COVID-19 over a period of 28 days. From this study we will begin tolearn why most individuals are asymptomatic or develop mild symptoms following infection and whether somepre-existing immunity is important. We will also learn whether they develop partial immunity to the SARS-CoV2virus what are markers of this immunity and how long this persists. We will develop novel tests using the mostinformative markers to screen the mouth upper airways and blood in high risk populations which will predictwho will get seriously sick and who will be minimally impacted by the virus. NCI 10855050 6/2/23 0:00 RFA-CA-20-039 3U01CA260539-02S1 3 U01 CA 260539 2 S1 "KUO, LILLIAN S" 9/18/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 1877985 "KING, CHRISTOPHER L" Not Applicable 11 PATHOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 1004770 OD 624080 380690 C4 The duration and nature of humoral immunity to SARS-CoV-2 (CoV2) infection is poorly understood. Moststudies have focused on the immune response in patients with clinical illness but little is known about antibodyresponse to CoV2 regarding the earliest immunological events immediately after exposure and prior to onset ofillness or in asymptomatic individuals and how this impacts long-term immunological memory. This proposaladdresses these gaps in our knowledge by prospectively following household contacts with clinical cases ofCoV2 to determine innate and adaptive immune events associated with this early viral exposure over a 28 dayperiod. Detailed evaluation of samples from these patients including RNAseq of peripheral blood cells andproteomic analysis of oral secretions the site of initial CoV2 replication. We will determine whether potentiallycross-reactive T cells and secretory IgA may contribute to this early protective immune response and if presentdo they enhance the subsequent humoral immune responses by providing greater T cell help to B cells. Thesestudies will also provide a detailed knowledge of innate immune responses to CoV2 and how this shapes thenature and duration humoral immunity. Our central hypothesis is that peripheral blood lymphocytes andoropharyngeal secretions collected from individuals at the time of viral exposure and prior to onset ofsymptoms will show innate and adaptive immune responses that correlate with viral clearance andpredict whether or not effective humoral immunity and long-term immunological memory develops.This hypothesis will be addressed by exploring the following aims; i) evaluating the early immune humoral andcellular immune responses to CoV2 in close contacts of individuals diagnosed with COVID-19; ii) to assessearly innate immune responses in close contacts of individuals diagnosed with COVID-19 and assess theirrelationship with humoral immune responses and viremia; and iii) to examine early drivers of humoral immunityon the durability of immunological memory and responses to vaccines. This comprehensive evaluation of therelationships between early infection with innate and adaptive immune on long-term memory and immunity willprovide a rigorous basis for the development of highly informative and scalable serological tests. Our approachis therefore highly responsive to RFA-CA-20-039 through the development and validation of novel assays thatsimultaneously measure innate and adaptive immune responses to CoV2 from early infection; this approachwill help define immune parameters and serological markers associated with asymptomatic vs. symptomaticinfection and disease severity. 1004770 +No NIH Category available 2019-nCoV;ACE2;Adult;Advocate;Age;Aggressive course;Antibodies;Antibody Response;Bioinformatics;Biology;Biometry;Budgets;COVID-19;COVID-19 mortality;COVID-19 patient;COVID-19 susceptibility;COVID-19 vaccination;COVID-19 vaccine;Cancer Control;Cancer Patient;Cardiopulmonary;Cells;Characteristics;Clinical;Clinical Sciences;Clinical Trials;Complement;Contracts;Control Groups;Cytoprotection;Data Science;Data Science Core;Demographic Factors;Development;Disease;Doctor of Philosophy;Epithelial Cells;Ethnic Origin;Fatality rate;Gender;Histology;Immune;Immune response;Incidence;Individual;Infection;Informatics;Institution;Kinetics;Knowledge;Longevity;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Morbidity - disease rate;Normal tissue morphology;Patient Recruitments;Patients;Persons;Population Control;Predisposition;Race;Recording of previous events;Research;Risk Factors;SARS-CoV-2 antibody;SARS-CoV-2 infection;Science;Serology;Seroprevalences;Smoking;Smoking History;Tobacco;Vaccination;Vaccines;Viral;Viral Load result;Virus;Virus Diseases;Virus Replication;cancer therapy;cigarette smoking;comorbidity;data dissemination;human old age (65+);human subject;inter-individual variation;lung cancer cell;member;multidisciplinary;neoplastic cell;neutralizing antibody;patient population;programs;protective efficacy;public database;response;sample collection;tumor;vaccine trial Vulnerability of SARS- CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses OVERALL: Vulnerability of SARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody AnalysesProgram Director: Fred R. Hirsch MD PhD; Co-PI: Adolfo Garcia-Sastre PhD. PROJECT NARRATIVEThe overarching research theme for the Serological Center of Excellence at Mount Sinai NY is to understandfactors contributing to the vulnerability of SARS-CoV-2 infection in patients with lung cancer through serologicalanalysis of antibody response and to characterize and compare the antibody response to SARS-CoV-2 infectionor SARS-CoV-2 vaccines in patients with lung cancer compared to a matched healthy control group. NCI 10855044 6/2/23 0:00 RFA-CA-20-038 3U54CA260560-02S2 3 U54 CA 260560 2 S2 "MARQUEZ, GUILLERMO" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 7822511 "HIRSCH, FRED R" "GARCIA-SASTRE, ADOLFO " 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Research Centers 2023 3271928 OD 2441880 830048 C4 OVERALL ABSTRACTThe overarching research theme for the Mount Sinai U54 Serological Center of Excellence Vulnerability ofSARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses is to fill the vital knowledgegap in factors contributing to the great vulnerability of lung cancer patients to morbidity and mortality from SARS-CoV-2 infection through serological analysis of antibody responses and studies of inter-individual variation inpatient-derived lung tumor and epithelial cells to SARS-CoV-2 infection. We will characterize and compare lungcancer patients antibody responses to SARS-CoV-2 infection or SARS-CoV-2 vaccines with a matched non-lung cancer control group; quantitate differences in SARS-CoV-2 viral replication in lung cancer and normal lungepithelial cells from different lung cancer patients; and quantitate differences in neutralizing antibody responsesin lung cancer patients. This information is urgently needed to enact vaccine and other strategies for protectinglung cancer patients against development of COVID-19. While antibodies induced by infection or vaccines areprotective against many viruses it has not yet been established if antibodies to SARS-CoV-2 are protective howmuch and what types of antibody are needed for protection and how long protection will last are unknown.Likewise we do not know if lung cancer patients can mount an effective immune response and if different aspectsof lung cancer or its treatment influences this immune response. Our overall hypothesis is that lung cancerpatients have a different (e. g. weaker) antibody response to SARS-CoV-2 infection compared to persons withoutlung cancer and that their lung cancer or lung epithelial cells play a role in viral replication of host responseswhich together could explain the aggressive course and high fatality rate demonstrated in lung cancer patientswith COVID-19. Our U54 will determine whether natural infection or SARS-CoV-2 vaccines (forecast fordeployment) will give comparable serological antibody responses longitudinally in 1000 lung cancer patientsand a matched non-lung cancer control group (1000 individuals); and determine if there are differences inantibody responses related to age gender tobacco history and race/ethnicity. The U54 proposal has twoProjects and three Cores (Administrative Clinical and Data Sciences). Project 1: Characterization of theAntibody Response to SARS-CoV-2 in Lung Cancer Patients quantitatively characterizes anti-SARs-CoV-2antibody responses and their functionality longitudinally in lung cancer patients compared to a control populationafter natural infection and vaccination and relates the serological response characteristics to key clinicaldemographic information. Project 2: Susceptibility of Lung Cancer Cells to SARS-CoV-2 Infection and Antibody-Mediated Neutralization determines the inter-individual variation in lung cancers and lung epithelial cells tosupport SARS-CoV-2 viral replication the inter-individual variation of antibodies to neutralize viral infection andhow these host viral responses relate to host cell characteristics and important clinical demographic information. 3271928 +No NIH Category available 2019-nCoV;Acceleration;Address;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Biological Assay;Blood;COVID-19;COVID-19 pandemic;COVID-19 screening;COVID-19 surveillance;COVID-19 vaccine;Clinical;Communities;Dryness;Employee;Essential worker;Food Services;General Population;Goals;HIV/HCV;Health;Health Personnel;Human;Immunity;Immunoassay;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Individual;Infection;Laboratories;Liquid substance;Measures;Methodology;Methods;Microspheres;Mission;Modeling;Nasopharynx;National Cancer Institute;National Institute of Allergy and Infectious Disease;New York;Population;Principal Investigator;Proteins;SARS-CoV-2 antibody;SARS-CoV-2 antigen;SARS-CoV-2 exposure;SARS-CoV-2 immunity;Saliva;Sampling;Schools;Science;Sensitivity and Specificity;Serology;Serology test;Seroprevalences;Serum;Specificity;Spottings;Technology;Testing;Time;United States;Virus;Work;co-infection;cohort;convalescent plasma;first responder;immunological status;improved;member;minimally invasive;neutralizing antibody;neutralizing monoclonal antibodies;nonhuman primate;outbreak prediction;pre-clinical;saliva sample;sample collection;serosurveillance;serosurvey;technology platform;vaccine candidate;vaccine trial;vaccinology High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology Project NarrativeThis project will improve validate and advance the use of dried blood spot technologies toenable population-wide serological testing for SARS COV-2 exposure and immunity inaccordance with the mission of the Serological Sciences Network (SeroNet) established by theNational Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute(NCI). NCI 10855042 6/2/23 0:00 RFA-CA-20-039 3U01CA260508-02S1 3 U01 CA 260508 2 S1 "KOHAAR, INDU" 9/30/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 1876035 "MANTIS, NICHOLAS J." Not Applicable 20 Unavailable 153695478 LQK1DD1EYZK9 153695478 LQK1DD1EYZK9 US 42.645888 -73.797658 5966012 WADSWORTH CENTER MENANDS NY Research Institutes 122042893 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 824595 OD 633244 191351 C4 Project SummaryAs the COVID-19 pandemic continues to spread across the United States it is imperative that we implementtechnologies to screen large swaths of the population for the presence of antibodies to SARS-CoV-2.Serological surveillance not only affords a measure of virus exposure within a community at large but alsoprovides information necessary to predict outbreak dynamics. Furthermore as our understanding of howhumoral factors contribute to controlling (and possibly exacerbating) COVID-19 it will be essential to havemethods in place to measure the quantity and quality of antibodies associated with both natural SARS-CoV-2 exposure and candidate SARS-CoV-2 vaccines. This U01 proposal seeks to advance the use of dried bloodspots (DBS) in conjunction with a Luminex-based microsphere immunoassay (MIA) to enable high-throughput(HT) population-wide serological surveillance for SARS-CoV-2. Specifically the proposal will expand the HT-DBS assay to capture the breadth and complexity of SARS-CoV-2 antibody responses following naturalinfection and develop a high-throughput competitive immunoassay (CIA) as a surrogate measure of SARS-CoV-2 neutralizing antibody titers in DBS. The proposed platform technologies to be developed at theWadsworth Center will contribute directly to NCIs mission to develop validate improve and implementserological testing and associated technologies to address the COVID-19 pandemic. 824595 +No NIH Category available 2019-nCoV;Antibodies;Automobile Driving;Bar Codes;Biological Assay;Biology;COVID-19;COVID-19 monitoring;COVID-19 pandemic;COVID-19 patient;COVID-19 risk;COVID-19 severity;COVID-19 vaccine;Cancer Patient;Cardiovascular system;Cells;Cessation of life;Clinical;Collaborations;Complex;Data;Disease;Enzyme-Linked Immunosorbent Assay;Flow Cytometry;General Population;Hematologic Neoplasms;Hematological Disease;Hematology;Hematopathology;Hematopoietic Neoplasms;Immune;Immune response;Immunoassay;Immunoglobulin G;Immunoglobulin M;Immunosuppression;Institutional Review Boards;Laboratories;Lymphopenia;Malignant Neoplasms;Measurement;Measures;Mediating;Medicine;Memorial Sloan-Kettering Cancer Center;Microfluidics;Molecular;Monitor;Motivation;Multiple Myeloma;Multiple Organ Failure;Myelosuppression;Pathology;Patient Monitoring;Patient Selection;Patients;Peripheral Blood Mononuclear Cell;Plasma;Plasma Proteins;Population;Production;Prospective cohort;Proteins;Public Health;Research Personnel;Retrospective cohort;Risk;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Sampling;Serology;Severities;Specimen;Stains;Technology;Testing;Time;Tissue Banks;Vaccination;Vaccines;Validation;Vulnerable Populations;angiogenesis;blood treatment;cell type;chemokine;clinical translation;cohort;combat;coronavirus disease;cytokine;density;design;effective therapy;high risk;high throughput screening;immune activation;immune function;improved;individualized medicine;lung injury;microchip;novel;peripheral blood;personalized strategies;protein biomarkers;response;success;synergism;transcriptome sequencing;vaccine efficacy;vaccine evaluation;vaccine response Immuno-Serological Assays for Monitoring COVID19 in Patients with Hematologic Malignancies PROJECT NARRATIVEThis project aims to develop two novel immuno-serological assays for highly informative measurement of plasmaprotein markers and single-cell cytokine signatures in order to identify molecular correlates with COVID-19 riskseverity vaccine response in patients with hematologic malignancies. They can be applied to monitoring ofCOVID-19 patients without a malignancy or other cancers and potentially guide the design of effective treatments.This project is of vital importance and urgency to public health during the COVID-19 pandemic. NCI 10855033 6/2/23 0:00 RFA-CA-20-039 3U01CA260507-02S2 3 U01 CA 260507 2 S2 "KOHAAR, INDU" 9/30/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 9372328 "FAN, RONG " "HALENE, STEPHANIE " 3 ENGINEERING (ALL TYPES) 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT BIOMED ENGR/COL ENGR/ENGR STA 65208327 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 1137992 OD 778003 359989 C4 SUMMARYPatients with hematologic malignancies appear to have a higher risk of SARS-CoV-2 infection. Diseasecourses are variable in severity influenced by immunosuppression due to the malignancy and its treatmentdetermining the degree of immune-mediated hyperinflammation implicated in lung damage multi-organ failureand death. This highlights the need for comprehensive clinical tests to monitor COVID19 patients specificallywith hematologic malignancies. We propose to develop and validate two novel immuno-serological assays thatwill be deployed to conduct longitudinal measurement of plasma markers and peripheral blood immune cellsfrom COVID patients with different hematologic malignancies. First we will develop an automated 32-plexedplasma protein assay to quantify SARS-COV-2 IgG/IgM antibodies cytokines/chemokines angiogenesismarkers endotheliopathy markers and pro-thrombotic markers all combined in a high-density antibodybarcode array microchip. Second we will develop a microchip assay for single-cell immune functionmeasurement to quantify cell types and 30+ immune effector proteins in peripheral blood immune frompatients. Single-cell transcriptome sequencing will be performed on select samples to cross-validate the resultsand reveal the mechanisms of action in COVID-induced immune activation. Third these new assays will bedeployed to measure a cohort of COVID19 patients with or without hematological malignancies and healthydonors in order to identify potential molecular correlates with immune-mediated pathology and COVID diseaseseverity uniquely in hematological cancer patients. As the COVID19 vaccines become available we will applythese assays to monitoring vaccine-induced humoral cellular and immunological response in hematologicalcancer patients and compare to non-cancer populations to understand differences and ways to improve thesuccess of vaccination in patients with hematologic malignancies a vulnerable group of patients who may notfollow the same mechanisms as general populations in COVID19. 1137992 +No NIH Category available 2019-nCoV;Address;Affect;Age;Antibodies;Antibody Response;Antibody-mediated protection;Antigens;Basic Science;Biometry;COVID-19;COVID-19 patient;COVID-19 severity;Cell surface;Cells;Cessation of life;Clinical;Clinical Sciences;Collaborations;Communicable Diseases;Complement;Complex;Coupled;Data;Development;Diabetes Mellitus;Disease;Ensure;Enzyme-Linked Immunosorbent Assay;Epidemiology;Ethnic Origin;Evaluation;Flow Cytometry;Foundations;Gender;Goals;HIV;Health;Healthcare Systems;Heart Diseases;Human;Immune;Immune response;Immunity;Immunoglobulin Class Switching;Immunology;Immunomodulators;Infant;Infection;Inflammasome;Inflammatory;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Leadership;Mediating;Metabolic;Methods;Mission;Modeling;Monoclonal Antibody Therapy;Myeloid-derived suppressor cells;Outcome;Pathogenesis;Pathologic;Pathology;Patients;Peripheral Blood Mononuclear Cell;Persons;Population;Populations at Risk;Prospective cohort;Proteins;Protocols documentation;Public Health;Race;Reagent;Regimen;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Respiratory Tract Infections;Risk;SARS-CoV-2 antibody;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sampling;Science;Serology;Serology test;Severity of illness;Sex Differences;Solid;Stains;Statistical Data Interpretation;Statistical Models;Surrogate Markers;Symptoms;T-Lymphocyte;Testing;Therapeutic;Training;Translational Research;Vaccine Design;Viral;Viral Pathogenesis;Virus;age difference;antibody-dependent cell cytotoxicity;biosafety level 3 facility;comorbidity;current pandemic;experimental study;gender difference;human old age (65+);innate immune sensing;insight;intersectionality;male;neutralizing antibody;new therapeutic target;novel;novel marker;organ transplant recipient;racial difference;rational design;response;sample fixation;severe COVID-19;sex;single cell analysis;therapeutic evaluation;therapy development;vaccine candidate;vaccine development;vaccine evaluation;virology Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS) Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)Overall NarrativeThe goal of the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)is to define the immune responses that can either protect or harm during infection. The JH-EPICS team willevaluate the immune responses required to detect the presence of SARS-CoV-2 initiate inflammatoryresponses eliminate infected cells and engage the antibody responses against the virus in COVID-19patients. Using statistical analyses and modeling JH-EPICS will identify the variables such as demographic(e.g. age sex gender race and ethnicity) and clinical (e.g. severity of COVID-19 and comorbidities) factorsthat predict COVID-19 immune responses and outcomes. NCI 10855020 6/2/23 0:00 RFA-CA-20-038 3U54CA260492-02S2 3 U54 CA 260492 2 S2 "KUO, LILLIAN S" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 3088131 "KLEIN, SABRA L." "COX, ANDREA L" 7 MICROBIOLOGY/IMMUN/VIROLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF PUBLIC HEALTH 212182680 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Research Centers 2023 3398577 OD 2293788 1104789 C4 Johns Hopkins has broad expertise in the science of human health with viral immunity pathogenesisepidemiology biostatistics and surveillance emerging as integral components of the multidisciplinary researchmounted at Johns Hopkins during the current pandemic. We propose development of a Serological SciencesCenter of Excellence: the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2(JH-EPICS). The overarching goal of JH-EPICS is to distinguish immune responses that protect from thosethat cause pathology during infection. Under the Multiple PI leadership of Drs. Klein and Cox the JH-EPICSAdministrative Core will ensure resources and samples are available to systematically evaluate innate T celland antibody responses to SARS-CoV-2 in peripheral blood mononuclear cells and serological samples fromCOVID-19 patients sampled longitudinally. JH-EPICS contains three interconnecting Research Projects (RPs).RP1 focuses on innate immune sensing and activation of the human inflammasome by SARS-CoV-2 withevaluation of how anti-SARS-CoV-2 antibodies modulate innate sensing. RP2 uses a novel flow-cytometrybased platform that enables single cell analysis of traditional cell surface markers combined with intracellularstaining for proteins involved in metabolic programming. Using this platform we have identified distinct myeloidderived suppressor cells (MDSCs) and T cells abundant in COVID-19. RP1 will characterize these MDSCswhile RP2 will explore novel populations of T cells identified in COVID-19 patients. RP2 will also define novelbiomarkers in order to predict severity of disease track the course of disease and define novel surrogatemarkers for testing therapeutic regimens. Together RP1 and RP2 will identify novel therapeutic targets. InRP3 the magnitude duration and class switching of SARS-CoV-2-specific antibody isotypes as well as virus-specific neutralizing antibody responses will be analyzed and compared with non-neutralizing antibodyfunctions e.g. complement fixation and antibody-dependent cellular cytotoxicity using a novel core set ofserological assays. A centralized Virology Reagent Core will provide antigen for ELISAs reagents to identifyvirus-specific immune cell populations inactivated SARS-CoV-2 viruses methods for quantifying SARS-CoV-2 and access to biosafety level 3 facilities and training needed to perform any experiments involving liveSARS-CoV-2. The Analysis Resource Core will provide statistical modeling and analysis to frame and testhypotheses about the mechanisms mediating the severity of COVID-19 as well as the intersectionality of sexgender age and racial differences in immune mechanisms of COVID-19. In concert with the trans-networkcollaborations this research will provide significant insights into pathologic immune responses to SARS-CoV-2identification of novel therapeutic targets and definition of immunity against SARS-CoV-2 infection. Byuncovering the correlates of protective immunity JH-EPICS research will further enhance vaccine design andevaluation of vaccine candidates. 3398577 +No NIH Category available 2019-nCoV;Antibodies;Antibody Response;Antibody titer measurement;Automobile Driving;COVID-19 pandemic;COVID-19 therapeutics;COVID-19 vaccination;COVID-19 vaccine;Cessation of life;Clinical;Collaborations;Coronavirus;Data;Development;Disease;Disease Outcome;Dose;Europe;Human;Humoral Immunities;Immune;Immunity;Immunologics;Individual;Infection;Infection Control;Institution;Intervention;Israel;Kinetics;Knowledge;Macaca mulatta;Mediating;Medical center;Phase;Population;Resolution;SARS-CoV-2 antibody;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 spike protein;Schedule;Science;Serology;United States;Vaccinated;Vaccination;Vaccine Clinical Trial;Vaccinee;Vaccines;antigen binding;efficacy testing;follow-up;insight;manufacture;neutralizing antibody;nonhuman primate;post SARS-CoV-2 infection;prevent;success;transmission process;vaccine development;vector-based vaccine Immunologic Signatures of SARS-CoV-2 Vaccination and Disease SUMMARYThis project seeks to define the humoral correlates of immunity following infection as well as the durability ofthis protective humoral immunity both following natural infection or vaccination to inform vaccine development. NCI 10855012 6/2/23 0:00 RFA-CA-20-039 3U01CA260476-02S1 3 U01 CA 260476 2 S1 "KUO, LILLIAN S" 9/30/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 6849698 "BAROUCH, DAN H." Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 897731 OD 726658 171073 C4 ABSTRACTThe development of a SARS-CoV-2 vaccine may be critical to ending the COVID-19 pandemic. However acritical gap in knowledge is the lack of understanding of correlates of SARS-CoV-2 immunity in humans.Our preliminary data suggest that antibodies correlate with protection following vaccination in nonhumanprimates and that unique antibody functional profiles appear to predict disease outcome in natural infection inhumans. Our data also point to a converging antibody profile including both the antigen-binding domain drivingneutralization and Fc-mediated effector functions driving protective immunity. Another gap in knowledge is theunknown durability of protective immunity following SARS-CoV-2 infection and vaccination in humans.Our preliminary data suggest that antibody titers may wane quickly following SARS-CoV-2 infection in humansbut larger studies and longer follow-up are needed to define the kinetics of antibody responses in convalescentindividuals. Moreover the durability of vaccine-elicited antibody responses remains to be determined.We hypothesize that both convalescent and vaccinated humans will develop the functional antibodysignature that correlates with vaccine protection against SARS-CoV-2 challenge in rhesus macaques.We further hypothesize that vaccination will induce antibodies with greater durability than those inducedby natural infection and that an immunologic correlate of durability can be defined.Specific Aim 1. Define the antibody profiles following SARS-CoV-2 infection or vaccination that correlatewith protection. We will dissect the functional antibody responses elicited in SARS-CoV-2 infected individualsand in SARS-CoV-2 vaccinated individuals to provide insight into correlates of protection.Specific Aim 2. Define the immunologic correlates of durability of SARS-CoV-2 antibody responsesfollowing infection or vaccination. We will compare the durability of antibody responses induced in SARS-CoV-2 infected and vaccinated individuals and we will define an immunologic correlate of durability. 897731 +No NIH Category available 2019-nCoV;African American;African American population;Anti-Inflammatory Agents;Antibodies;Attenuated;Attitude;Behavior;Biological Assay;Biological Markers;Biological Process;Biological Sciences;COVID-19;COVID-19 disparity;COVID-19 pandemic effects;COVID-19 testing;Cities;Clinical;Cognition;Collaborations;Collection;Communication;Communities;Disparity;Early Diagnosis;Evaluation;Funding;Goals;Health;Health Resources;Healthcare;Herd Immunity;Home;Incidence;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Knowledge;Link;Malignant Neoplasms;Measures;Medical;Methods;Michigan;Mission;Pathway interactions;Population;Prevalence;Process;Public Health;Race;Recovery;Registries;Research;Research Personnel;Risk;Role;Route;SARS-CoV-2 antibody;SARS-CoV-2 infection;SARS-CoV-2 positive;Saliva;Salivary;Serology;Services;Severities;Skin;Testing;United States;Water;biobehavior;experience;grasp;health communication;improved;innovation;insight;interest;mortality;novel;programs;racial difference;racial disparity;racial minority population;racial population;racism;response;salivary assay;screening;social health determinants;stem;transmission process;uptake Culturally-targeted communication to promote SARS-CoV-2 antibody testing in saliva: Enabling evaluation of inflammatory pathways in COVID-19 racial disparities Project NarrativeThe proposed project is relevant to public health because communicating effectively to African Americansabout SARS-CoV-2 antibody testing as well as providing an option of at-home non-invasive antibodyscreening in saliva could enhance uptake of antibody testing among African Americans a racial minoritypopulation that has been especially impacted by the COVID-19 pandemic. Greater uptake of antibody testingamong African Americans is also critical to better grasping how inflammatory process contribute to racialdisparities in SARS-CoV-2 infection and recovery. The proposed research is relevant to the NCI mission toconduct and fund research that improves early detection and diagnosis and reduces cancer-related disparities. NCI 10855010 6/2/23 0:00 RFA-CA-20-039 3U01CA260469-02S1 3 U01 CA 260469 2 S1 "BLAKE, KELLY D" 9/22/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 9341233 "LUCAS, TODD WILLIAM" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 193247145 R28EKN92ZTZ9 193247145 R28EKN92ZTZ9 US 42.653979 -84.492032 5245901 MICHIGAN STATE UNIVERSITY EAST LANSING MI SCHOOLS OF MEDICINE 488242600 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 964759 OD 690915 273844 C4 Project SummaryAfrican Americans develop and die from SARS-CoV-2 infection more than any other racial group in the UnitedStates including in majority African American cities such as Flint Michigan. SARS-CoV-2 disparities stem frommany interconnected causes. Yet connections to inflammatory biological processes in COVID-19 disparitiesremain largely unknown. Evaluating inflammatory responses can be facilitated by SARS-CoV-2 antibodytesting which can be used to identify and compare inflammation among those with and without confirmedSARS-CoV-2 infection and to conduct cross-race comparisons of inflammatory factors. However AfricanAmericans will be reluctant to partake in conventional antibody testing programs due to medical mistrust andexperiences with racism that are salient in the COVID-19 era. There is thus an urgent need to develop anddeploy culturally-relevant communication and antibody testing programs. Our long-term goal is to identify andreduce unjust COVID-19 racial disparities. The immediate objective is to better encourage understanding anduptake of SARS-CoV-2 antibody testing. The central hypothesis is that African-Americans will be receptive toantibody testing when benefits and limitations are communicated in a culturally effective manner and whennon-invasive salivary collection methods and assays are used. Our rationale is that combining culturallyeffective health communication with salivary testing will reduce mistrust and promote uptake that can lead tobetter grasping the role of inflammation in COVID-19 disparities. Our aims are to 1) develop and compareeffects of a general versus culturally-targeted video about antibody testing on African American and White Flintresidents antibody testing attitudes and uptake; 2) identify and compare effects of a general versus culturally-targeted video on activation of medical mistrust and racism-related cognition among African Americans whenconsidering antibody testing; 3) measure and identify multi-analyte inflammatory biomarker profiles among FlintRegistry enrollees who complete salivary antibody testing and compare inflammatory biomarker profiles byrace and antibody status. In collaboration with clinical and community partners we will prepare and evaluategeneral and culturally-targeted video tutorials about SARS-CoV-2 antibody testing. These brief videos will bedistributed to the Flint community through the Flint Registry a highly visible local health resource exchange.In collaboration with leading salivary bioscience experts we will furnish an opportunity to engage in at-homesalivary antibody screening a non-invasive route to antibody testing that is highly suited to disparities-oriented COVID-19 research. The proposed research is innovative and significant in highlighting that culturally-targeted communication and non-invasive antibody testing are vital to propelling disparities-orientedinflammatory COVID-19 research. Knowledge to be gained includes video tutorials and insights aboutcommunity-facing salivary collection that can be immediately disseminated across SeroNet to better promoteincluding racial monitories in ongoing studies of inflammation and antibody testing. 964759 +No NIH Category available 2019-nCoV;Address;Affect;Area;Autoimmune Diseases;Basic Science;COVID-19;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;California;Caring;Characteristics;Chronic Disease;Clinical;Clinical Sciences;Cohort Studies;Collaborations;Communities;Coronavirus;Data;Data Analyses;Data Collection;Disease;Enrollment;Ensure;Epidemiologist;Ethnic Origin;Evaluation;Evaluation Studies;Exposure to;Foundations;Funding;Goals;Health;Health Personnel;Health system;Healthcare Systems;Immune;Immunity;Immunologist;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Knowledge;Los Angeles;Malignant Neoplasms;Metabolic Diseases;Minority;Molecular Profiling;Natural History;Nature;Outcome;Patients;Pattern;Persons;Population Heterogeneity;Population Sciences;Populations at Risk;Predisposition;Public Health;Publishing;Recovery;Recovery of Function;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;Scientific Advances and Accomplishments;Scientist;Seroprevalences;Signal Transduction;Structure;Subgroup;Techniques;Therapeutic;Translational Research;Viral;Virus;Vulnerable Populations;World Health Organization;base;biobank;clinical phenotype;disorder risk;experience;immune function;immune reconstitution;innate immune function;insight;novel;operation;pandemic disease;programs;racial diversity;racial population;recruit;response;severe COVID-19;stay-at-home order;trait;translational scientist Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2 NARRATIVE: OverviewOur study will be centered on the ethnically/racially diverse population served by our health system in LosAngeles given then critical need for more knowledge regarding the determinants of COVID-19 related risks inthese minority subgroups. Leveraging our collective experience resources and infrastructure at major academicinstitutions from across Southern California (Cedars Sinai UCSD UCLA and USC) we will advance thescientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidatethe natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure infectionrecovery and clinical immunity patterns across the spectrum of persons at risk; Project 2 will investigate thedeterminants of SARS-CoV-2 response in persons with altered innate immune function with a focus onindividuals with pre-infection susceptibility traits (e.g. metabolic disease states); and Project 3 will investigatethe determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus onindividuals with immune-altered status arising from select malignancies autoimmune disease and/or theirdirected therapies. NCI 10855003 6/2/23 0:00 RFA-CA-20-038 3U54CA260591-02S3 3 U54 CA 260591 2 S3 "PATRIOTIS, CHRISTOS F" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 9537080 "FIGUEIREDO, JANE C." "KARIN, MICHAEL ; MERCHANT, AKIL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Research Centers 2023 2350878 OD 1782762 568116 C4 ASBTRACT OverviewEvery day Californians continue to experience high levels of exposure to the novel severe acute respiratorycoronavirus 2 (SARS-CoV-2) virus. There is an ever-growing urgent need to better understand the nature ofexposures course of illness and recovery and potential for immunity among persons at particularly heightenedrisk for the worst COVID-19 outcomes. As part of a rapid scientific response to the present public health crisiswe convened on March 18 2020 a collaborative of frontline clinicians and scientists to form the Coronavirus RiskAssociations and Longitudinal Evaluation (CORALE) studies (corale-study.org). We established two base studycohorts with enrollment centered on (i) patients with suspected or confirmed COVID-19 treated in our healthsystem (currently N>8300) and on (ii) healthcare workers directly or indirectly involved in delivering their care(currently N=6679). In response to NIH RFA-CA-20-038 we are now highly motivated and prepared to leverageour existing infrastructure to directly address the critical need for comprehensive longitudinal data collection andanalyses to advanced our understanding of SARS-CoV-2 risks the course of disease the nature of recoveryand the potential for immunity across populations at risk. By establishing the CORALE-SeroNet U54 programour goal will be to form a robust and sustainable structure of academic activities centered on investigating theresponses elicited by SARS-CoV-2 exposure and the extent to which carefully phenotyped clinical and molecularprofiles can signal robust immune reconstitution and complete functional recovery. Our study will be centeredon the ethnically/racially diverse population served by our health system in Los Angeles given then critical needfor more knowledge regarding the determinants of COVID-19 related risks in these minority subgroups. Ourscientific objectives will be achieved by an outstanding collaborative team of clinician-scientists epidemiologistsimmunologists basic and translational scientists analytical chemists and biostatisticians. Leveraging ourcollective experience resources and infrastructure at major academic institutions from across SouthernCalifornia (Cedars Sinai UCSD UCLA and USC) we will advance the scientific enterprise through the threedistinct yet closely integrated research Projects: Project 1 will elucidate the natural history and longitudinaltrajectories that represent the diversity of SARS-CoV-2 exposure infection recovery and clinical immunitypatterns across the spectrum of persons at risk. Project 2 will investigate the determinants of SARS-CoV-2response in persons with altered innate immune function with a focus on individuals with pre-infectionsusceptibility traits (e.g. metabolic disease states); and Project 3 will investigate the determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus on individuals with immune-altered status arising from select malignancies autoimmune disease and/or their directed therapies. As a wholethis research program will integrate population clinical translational and basic science resources with a world-class investigator team to meet the urgent need for new mechanistic insights and therapeutic approaches toaddress key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity. 2350878 +No NIH Category available 2019-nCoV;Acute;Address;African American population;Agonist;Antibodies;Antigen Targeting;Attention;Award;B-Lymphocytes;Biopsy;Blood;COVID-19;COVID-19 diagnosis;COVID-19 pandemic;COVID-19 patient;COVID-19 test;Cancer Patient;Caucasians;Cells;Clinical;Collaborations;Communities;Convalescence;Data;Data Set;Dedications;Disease;Elderly;Evaluation;Female;Hispanic Americans;Human;Immune;Immune response;Immune system;Immunity;Immunologic Memory;Immunologics;Individual;Infection;Institution;Knowledge;Laboratories;Longitudinal Studies;Mucosal Immune Responses;Mucous Membrane;Nose;Patient Recruitments;Patients;Peripheral Blood Mononuclear Cell;Phenotype;Physicians;Plasma;Plasma Cells;Populations at Risk;Prognosis;Protocols documentation;Research;Risk;Route;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Science;Serology;Severity of illness;Site;T cell response;T-Lymphocyte;Testing;Tissue Sample;Toll-like receptors;Translational Research;Translations;Vaccination;Validation;Viral Antigens;adaptive immune response;adaptive immunity;clinical development;cohort;data sharing;immune checkpoint blockade;interest;male;medically underserved;medically underserved population;member;mucosal site;novel therapeutic intervention;pandemic disease;patient population;research clinical testing;response;tool;vaccine candidate;young adult Mechanisms and Duration of Immunity to SARS-CoV-2 OVERALL: NARRATIVEWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world. We willemphasize deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanningserological B cell and T cell responses; analysis of immune responses in the blood as well as mucosal tissuesites; comparing immune responses induced by infection to those induced by candidate vaccines; and payingparticular attention to the understanding the clinical needs and immune responses of underservedunderrepresented and at-risk patient populations. Within these parameters we will attempt to determine thefactors that result in effective and durable immunity to SARS-CoV-2 infection and provide useful knowledge andtools for physicians and patients. NCI 10854997 6/2/23 0:00 RFA-CA-20-038 3U54CA260517-02S2 3 U54 CA 260517 2 S2 "LIU, YIN" 9/23/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 10429455 "BOYD, SCOTT DEXTER" Not Applicable 16 PATHOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Research Centers 2023 2997978 OD 1941695 1056283 C4 OVERALL: SUMMARYWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world.Our Center will be based on four scientific pillars: Deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanning serological B cell and T cell responses Analysis of immune responses in the blood as well as mucosal sites Comparing immune responses induced by infection to those induced by candidate vaccines and Studying medically underserved underrepresented and at-risk patient populationsWithin these parameters we will attempt to determine the factors that result in effective and durable immunityto SARS-CoV-2 infection.We are dedicated to broad collaboration rapid sharing of data and technical knowledge nimbleness inresponding to the rapidly changing pandemic and rapid translation of research findings to CLIA Lab clinicaltesting and development of new therapeutic approaches. We feel these are the best routes forward foraddressing gaps in our understanding of the determinants of protective immunity to SARS-CoV-2 andproviding useful tools for physicians and patients. 2997978 +No NIH Category available 2019-nCoV;Animal Model;Antibody Response;CD8-Positive T-Lymphocytes;COVID-19 patient;COVID-19 severity;Cessation of life;Chemotherapy-Oncologic Procedure;Child;China;Chronic;Clinical;Consensus;Coronavirus;Coupled;Data;Development;Disease;Generations;Genetic Variation;Goals;Hematological Disease;Herd Immunity;Immune;Immune response;Immunity;Immunocompetence;Individual;Infection;Maintenance;Malignant Neoplasms;Middle East Respiratory Syndrome;Natural History;Nature;Outcome;Patient-Focused Outcomes;Patients;Pattern;Play;Population;Predisposition;Preventive vaccine;Recovery;Research Personnel;Resistance;Resolution;Role;SARS coronavirus;SARS-CoV-2 antibody;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 infection history;SARS-CoV-2 variant;Secondary to;Serology test;Severe Acute Respiratory Syndrome;Severity of illness;Sickle Cell Anemia;Stratification;Suggestion;Symptoms;System;T cell response;Testing;Therapeutic Monoclonal Antibodies;Time;Translating;Upper respiratory tract;Vaccines;Variant;Viral;Viral Antibodies;Virus;Virus Replication;Virus Shedding;acute infection;adaptive immune response;adaptive immunity;chemotherapy;clinical phenotype;cohort;convalescent plasma;defined contribution;human monoclonal antibodies;improved;in vivo;insight;microbial;novel;novel coronavirus;optimism;pandemic disease;passive immunoprophylaxis;patient population;patient subsets;prevent;response;study population;unvaccinated;vaccine candidate;vaccine development Adaptive Immunity and Persistent SARS-CoV-2 Replication Project Narrative:Children undergoing cancer chemotherapy and those with hematologic disorders such as sicklecell disease have been observed to shed the novel coronavirus SARS-CoV-2 for prolongedperiods often without significant clinical disease. As these children have varying levels ofimmune competence we propose that deficits in immune responsiveness leads to inadequatecontrol of virus replication and shedding. The proposed studies will define the relationshipbetween adaptive immunity and virus replication/shedding including the contribution of viralvariants that could arise during poorly controlled virus replication in children with ineffectiveimmune responses. NCI 10854996 6/2/23 0:00 RFA-CA-20-039 3U01CA260462-02S2 3 U01 CA 260462 2 S2 "SINGH, ANJU" 9/22/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 1866460 "BOPPANA, SURESH B" "BRITT, WILLIAM JARVIS; PINNINTI, SWETHA GEETHA " 7 PEDIATRICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 1512103 OD 1072370 439733 C4 Project Summary/AbstractThe pandemic caused by the novel coronavirus SARS-CoV-2 (SARS2) has so far infected greater than3.5 million individuals and resulted in >138000 deaths in the US. Although it has been suggested thatadaptive immunity plays an important role in improving clinical outcomes of patients infected withSARS2 protective immune responses have not been specifically defined. Also the variability in clinicaldisease and outcome in patients with SARS2 infection has not been explained based on qualitative andquantitative antiviral immune responses. Interestingly a significant proportion of children with presumeddeficits in immune competence secondary to cancer chemotherapy and hematologic disorders havebeen observed to shed virus from the upper respiratory tract for prolonged periods of time (>4 weeks)even after complete resolution of clinical symptoms. This finding raises the possibility that specificqualitative or quantitative deficits in adaptive immune responses in some individuals can result inincomplete control of virus replication and prolonged virus shedding. Therefore an understanding of theimmune responses that lead to control of virus shedding could help define correlates of protectiveimmunity and perhaps more importantly determine the potential value of vaccines to limit spread ofSARS2 to unvaccinated populations. The major goal of our studies is to quantify adaptive immuneresponses to SARS2 in a cohort of children with varying levels immune responsiveness and to relatethese responses to the control of virus shedding in the upper respiratory tract thus allowing stratificationimmune reactivity and control of virus replication. Defining relationships between variations in immunecompetence and virus shedding could provide novel insight into the level and nature of adaptiveimmunity more specifically antiviral antibodies that can restrict or eliminate viral shedding in SARS2infected patients. Our studies will also identify SARS2 variants that arise during poorly controlled virusreplication in these patients as prolonged virus replication coupled with ineffective immunity offers anideal opportunity for the generation of viral variants. Analysis of these variants in terms of the quality andquantity of SARS2 antibody responses will help elucidate the role of SARS2 sequence variation andpersistent virus replication as a mechanism for prolonged virus replication. Together these studies willtest our hypothesis that variations in immune responsiveness contribute to prolonged viral replicationand shedding. 1512103 +No NIH Category available Agreement;Aliquot;Brain;Brain Neoplasms;Cancer Model;Childhood;Clinical;Clinical Data;Communities;Contracts;DNA;DNA sequencing;Data;Data Element;Diffuse intrinsic pontine glioma;Enrollment;Funding;Generations;Genomic Data Commons;Infrastructure;Institutional Review Boards;Laboratories;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Normal tissue morphology;Operative Surgical Procedures;Parents;Patients;Policies;Process;Protocols documentation;Reporting;Resources;Sampling;Solid;Time;Tissues;Treatment outcome;Tumor Tissue;chemoradiation;data sharing;follow-up;human subject;programs;sample collection;transcriptome sequencing;tumor CANCER MODELS FROM PEDIATRIC BRAIN AND SOLID CANCERS (CMDC) n/a NCI 10854681 75N91019D00024-P00006-759102000035-1 N01 9/28/20 0:00 6/30/24 0:00 77878846 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 701651 NCI Under this contract the plan is to support the generation of ~90 pediatric NGCMs of which ~20 are from brain tumors including diffuse intrinsic pontine gliomas. It is expected that existing CMDCs are best poised to respond to this need as they have infrastructure in place for some of the process. Since the HCMI models materials and data generated under this project are considered Community Resources each laboratory has to ensure that all models delivered allow downstream use and distribution is unencumbered. The regulatory and technical requirements for this contract are listed below:1.The models will require a sufficient aliquot of the parent tumor tissue for DNA and RNA sequencing (~2ug each) and DNA from normal case-matched sample clinical data at the time of sample collection and at a minimum of 3 months follow-up once treatment (surgery chemo- radiation- or other- therapies) has been initiated. This latter depends on the proposed pipeline and will be finalized when the CMDC is funded.2.The list of the general clinical data is attached. In addition a number of pediatric cancer specifics clinical report forms are already available (see https://ocg.cancer.gov/programs/hcmi/resources) and additional cancer-specific data elements would be agreed upon for new types of tumors once a contract is initiated. It is essential that all required clinical data elements as annotated in the CRFs (https://ocg.cancer.gov/programs/hcmi/resources) are collected.3.The cancer models will be developed from tissue obtained under an IRB-approved human subjects protocol which informs the patient and their guardian about the project including the fact that these models: a.may be a perpetual resource b.the tumor as well as normal tissue will be sequenced c.clinical data will be collected including outcome of treatment 3 months or longer after enrollment d.the data sharing policy with data made available through controlled access at the NCIs Genomic Data Commonse.the models are distributed through a 3rd party f.the patients will not benefit from participating and g.results will not be shared with patients or their doctor. 701651 +No NIH Category available Biological Markers;Case/Control Studies;Characteristics;Chemoprevention;Cirrhosis;Clinical;Clinical Trials;Complication;Epigallocatechin Gallate;Erinaceidae;Erlotinib;Fright;Funding;Future;Goals;Guide prevention;Health;Incidence;Liver;Liver Cirrhosis;Longitudinal cohort study;Medical;Nature;Operative Surgical Procedures;Patients;Placebos;Prevention;Prevention therapy;Prevention trial;Primary carcinoma of the liver cells;Prognosis;Prospective cohort;Proteomics;Randomized Controlled Trials;Recording of previous events;Recurrence;Refractory;Research Personnel;Retrospective Studies;Risk;Risk Marker;Sampling;Series;Serum;Signal Pathway;Signal Transduction;Surrogate Endpoint;Testing;Therapeutic;Validation;arm;atorvastatin;cancer chemoprevention;case control;clinical translation;cohort;hydrophilicity;improved;lipophilicity;mortality;novel strategies;preclinical study;prognostic;prospective;randomized clinical trials;risk prediction;rosuvastatin Therapeutic modulation of a proteomic HCC risk signature with statins in patients with liver cirrhosis Hepatocellular carcinoma (HCC) is a feared complication of liver cirrhosis and has unacceptably high mortality.Prevention of HCC is a major need but a great challenge because it needs large long trials. We will use apromising HCC risk marker as a surrogate to define the efficacy of statins for HCC chemoprevention. NCI 10853142 9/25/23 0:00 RFA-CA-23-023 1U01CA288375-01 1 U01 CA 288375 1 "YOUNG, MATTHEW R" 9/25/23 0:00 8/31/27 0:00 ZCA1-TCRB-Q(O2) 9925976 "HOSHIDA, YUJIN " "CHUNG, RAYMOND T; DIEHL, ANNA MAE ELIZABETH; MOYLAN, CYNTHIA A" 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/25/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 366710 NCI 273908 92802 Hepatocellular carcinoma (HCC) is a major cirrhosis complication producing an alarming rise in mortality. Theprognosis for HCC is poor due to extremely high recurrence rate even after curative-intent surgical therapies andlimited efficacy of available medical therapies. Given its refractory nature prevention of HCC in cirrhosis patientswill be the most impactful strategy to improve its poor prognosis; however effective HCC prevention remains amajor unmet need. Retrospective and pre-clinical studies have suggested that statins are a viable form of HCCchemoprevention with a differential effect between lipophilic and hydrophilic statins. Further evidence suggeststhat statins may modulate HCC risk through Hedgehog and Hippo signaling pathways. However the clinicalvalidation of statins has been hampered by the requirement for large and lengthy clinical trials to define theirclinical utility. To overcome these challenges we have developed a serum-based HCC risk biomarker thePrognostic Liver Secretome signature (PLSec). Of note PLSec is therapeutically modifiable and the magnitudeof PLSec modulation is associated with future HCC incidence as demonstrated by our previous and preliminarystudies. In a retrospective case-control series PLSec-based HCC risk level was lower in cirrhosis patients onstatins compared to non-users. Based on these observations PLSec is now being tested as a surrogate endpointin HCC chemoprevention trials of atorvastatin (TORCH trial). To achieve the goal of establishing statins as viableHCC chemoprevention with PLSec as a surrogate endpoint we have assembled a team of cirrhosis and HCCexperts to analyze serum samples from three nation-wide multi-center prospective cohorts (Liver CirrhosisNetwork Southern Liver Health Study and Mass General Brigham cohorts) and two randomized controlled trials(TORCH and LCN RESCU trials). Aim 1. Validate lower biomarker-based HCC risk level in cirrhosis patients onstatins compared to non-users. We will validate our preliminary finding in prospective case-control series ofcirrhosis patients form the three cohorts. We will explore patient characteristics and types of statins associatedwith the PLSec-based HCC risk level along with mechanistic markers of Hedgehog/Hippo signaling. Aim 2.Determine magnitude of biomarker-based HCC risk modulation after starting or stopping statins. We will conducttarget trial emulation mimicking single-arm clinical trials with statins to determine the magnitude of PLSecmodulation in patients who start or stop statins from three cohorts. We will explore patient characteristics andtypes of statins associated with PLSec-based HCC risk modulation along with mechanistic markers. Aim 3.Compare biomarker-based HCC risk modulation between lipophilic and hydrophilic statins. We will compare themagnitude of placebo-adjusted PLSec modulation between lipophilic (atorvastatin) and hydrophilic (rosuvastatin)statins by analyzing serum samples from two parallel randomized clinical trials. We will explore patientcharacteristics associated with differential PLSec modulation along with mechanistic markers. Our strategyshowcases a novel approach to substantially advance clinical translation of HCC chemoprevention therapies. 366710 +No NIH Category available 2019-nCoV;Accounting;Address;Age;Antibodies;Attention;Binding;Biological Assay;COVID-19;Caregivers;Cessation of life;Characteristics;Communicable Diseases;Compensation;Contact Tracing;Coronavirus;Data;Data Set;Detection;Disease;Disease Outbreaks;Disparity;Dose;Ethnic Origin;Future;Goals;Herd Immunity;Heterogeneity;Human;Immune response;Immunity;Immunoglobulin G;Individual;Infection;Infection prevention;Influenza;Intervention;Longevity;Malignant Neoplasms;Mathematics;Methods;Modeling;Nature;Nursing Homes;Outcome;Persons;Population;Population Heterogeneity;Population Study;Predisposition;Prevention;Prisons;Public Health;Race;Recurrence;Reporting;Risk;Risk Factors;Role;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 transmission;Sample Size;Sampling;Sampling Biases;Scientific Advances and Accomplishments;Seasons;Sensitivity and Specificity;Serology;Serology test;Seroprevalences;Severities;Signal Transduction;Statistical Models;Structure;Symptoms;System;Testing;Time;Vaccination;Vaccines;Variant;Visit;Writing;age group;cohort;comorbidity;design;improved;infection risk;innovation;mathematical model;novel;novel strategies;pandemic disease;response;serosurvey;transmission process;trend Casual Statistical and Mathematical Modeling with Serologic Data n/a NCI 10852367 6/2/23 0:00 RFA-CA-20-038 4U01CA261277-02 4 U01 CA 261277 2 "MARIOTTO, ANGELA B" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 1878571 "LIPSITCH, MARC " "HANAGE, WILLIAM " 7 PUBLIC HEALTH & PREV MEDICINE 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 6/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2023 1151877 OD 1267103 641029 C4 We will develop methods to enhance the design and analysis of serologic studies of populations with respect to COVID-19 including methods that may be generalized in the future to address challenges raised by other seasonal diseases (such as influenza) and newly emerging diseases. In addition we will use serologic data in innovative ways to underpin mathematical models that can project population-level trends. Early serosurveys using convenience samples of the population and serologic assays with variable and often uncertain sensitivity and specificity were heavily criticized for unrepresentativeness and inadequate accounting for test characteristics resulting in bias and overconfidence (unduly narrow confidence bounds). Aim 1 will develop methods for valid inference of seroprevalence specifically by (a) accounting for biased sampling (b) accounting for imperfect tests and (c) developing and testing a novel approach to snowball sampling employing serologic tests to enhance outbreak detection and contact tracing. Valid comparisons that assess seroprotectionwhether how much and how long an individual is protected by an immune response to a COVID-19 infection (specifically by antibodies) against reinfectionrely on adequate control for confounding an issue that arises in multiple ways specific to seroprotection studies. Likewise waning of seroprotection may be inferred in error if studies are not carefully designed and analyzed. The unprecedented efforts to develop detailed serologic and systems serologic data sets provide new forms of data that can be leveraged to better inform these inferences. Aim 2 will develop a suite of methods to enhance causal inference in seroprotection studies including (a) sample size and power calculations; and (b) improved exploitation of serological data to reduce biases due to confounding and risk compensation. Aim 3 will develop new mathematical modeling approaches and apply them to quantify the likely reduction in the herd immunity threshold for COVID-19 due to various forms of risk heterogeneity and assortativeness in mixing. Aim 4 will develop models of COVID-19 transmission that accommodate emerging evidence about the duration and nature of immunity to infection shedding and symptoms to obtain estimates of how illness attack rates will differ under varying assumptions about the progress of immunity. Aim 5 will develop transmission models to assess optimal cohorting arrangements in congregate facilities (eg prisons and nursing homes) with special attention to the nature of immunity required for these arrangements to be beneficial. Finally vaccine supplies may be initially limited necessitating efficient use of them. Aim 6 will investigate the use of serologic data in combination with other types of data to optimize allocation of scarce vaccines. 1151877 +No NIH Category available Address;Adolescent;Child;Childhood;Childhood Cancer Survivor Study;Cohort Studies;DNA sequencing;Data;Diagnosis;Disease susceptibility;Ecosystem;Eligibility Determination;Future;Genetic Predisposition to Disease;Genotype;Health;Institution;Intervention;Investigation;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Morbidity - disease rate;Outcome;Participant;Publications;Quality of life;Research;Research Personnel;Resources;Risk;SNP array;Source;Survival Rate;Survivors;biobank;cancer therapy;childhood cancer survivor;cohort;follow-up;health related quality of life;high risk population;improved;mortality;multidisciplinary;recruit;screening guidelines;survivorship;tool ExtractEHR Pilot Childhood Cancer Data Initiative (CCDI) Survival rates for many childhood and adolescent cancers have improved at a remarkable pace over the pastfive decades. The CCSS cohort has been the source of some of the most significant publications to dateaddressing the long-term mortality morbidity and quality of life of survivors of childhood cancer. Understandingthe risk for late effects of childhood cancer and its therapy provides the basis for health screeningrecommendations and interventions that can mitigate long-term health problems in this high-risk population. NCI 10852234 9/20/23 0:00 PA-20-272 3U24CA055727-29S3 3 U24 CA 55727 29 S3 "HENDERSON, LORI A" 6/1/23 0:00 11/30/26 0:00 8819228 "ARMSTRONG, GREGORY " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 395 Other Research-Related 2023 917581 NCI 707964 209617 ABSTRACTThe Childhood Cancer Survivor Study (CCSS) is a multi-institutional multi-disciplinary collaborative researchresource established to systematically evaluate long-term outcomes among children diagnosed with cancer whosurvived five or more years from diagnosis. With the successful recruitment and longitudinal follow-up of thecohort that includes survivors diagnosed and treated over three decades (1970-1999) the CCSS is the worldslargest established open resource for survivorship research with 38036 eligible survivors available forinvestigation of late mortality and 25665 participants who have contributed health-related and quality of lifeoutcomes. The resource includes comprehensive annotation of treatment exposures ongoing longitudinalfollow-up and an established biorepository from which genotype (SNP array) and DNA sequencing of 8380survivors are available to investigators for identification of genetic susceptibility for disease- and treatment-related late effects. The objective of the current supplement application is to pilot an extraction tool to capturecancer treatment information for survivors of childhood cancer. Results will inform a future expansion of theChildhood Cancer Survivor Study. All data from this supplement will be submitted to the Childhood Cancer DataInitiative (CCDI) Ecosystem. 917581 +No NIH Category available Acetaminophen;Address;Administrative Supplement;Age;Amblyopia;Asthma;Autoimmune Diseases;Birth;Caring;Case/Control Studies;Cerebral Palsy;Child;Childhood Leukemia;Chronic Obstructive Pulmonary Disease;Code;Cohort Studies;Colitis;Collaborations;Communities;Complex Analysis;Confounding Factors (Epidemiology);Congenital Heart Defects;Control Groups;Data;Databases;Denmark;Diagnosis;Diagnostic;Down Syndrome;Eczema;Epilepsy;Foundations;Funding;Goals;Grant;Guidelines;Health;Hospitals;Hypertension;ICD-9;Individual;Infantile spasms;Intake;International Statistical Classification of Diseases and Related Health Problems Tenth Revision (ICD-10);Investigation;Link;Longevity;Malignant Childhood Neoplasm;Malignant Neoplasms;Managed Care;Maternal Age;Maternal and Child Health;Medical;Medical Records;Mental Health;Musculoskeletal;National Health Insurance;Obstructive Sleep Apnea;Occupational;Parents;Participant;Patient Care Management;Patients;Persons;Pharmacologic Substance;Phenotype;Pneumonia;Population;Population Registers;Pregnancy;Prevalence;Prevalence Study;Registries;Reporting;Research;Research Design;Resources;Risk;Risk Estimate;Sample Size;Sampling;Selection Bias;Taiwan;Thyroid Gland;abortion;autism spectrum disorder;cancer diagnosis;cohort;community setting;comorbidity;early childhood;health care service utilization;hypercholesterolemia;improved;leukemia;neoplasm registry;population based;prenatal;prospective;respiratory;screening;screening guidelines;young adult Maternal acetaminophen use and childhood cancer Project NarrativeIn the US the population prevalence of Down syndrome is 250000 persons and 6000 children with Downsyndrome are born in the US each year; these numbers are expected to rise with greater abortion restrictions.With increasing prevalence and longer lifespans of individuals with DS it is vital to understand commoncomorbidities across the lifespan for more appropriate screening practices improved utilization of health careresources tailored medical care guidelines and improved management of care. Herein we propose to utilizelarge national databases to examine the prevalence and risk of comorbid conditions in Down syndrome withadjustment for potential confounding variables such as maternal age. NCI 10852089 9/18/23 0:00 PA-20-272 3R03CA273608-02S1 3 R03 CA 273608 2 S1 "MAHABIR, SOMDAT" 8/1/22 0:00 7/31/24 0:00 ZCA1(M1)-S 9958106 "HECK, JULIA " Not Applicable 13 NONE 614168995 G47WN1XZNWX9 614168995 G47WN1XZNWX9 US 33.21077 -97.147769 6108501 UNIVERSITY OF NORTH TEXAS DENTON TX SCHOOLS OF ARTS AND SCIENCES 762035017 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 31045 OD 26192 4853 Project Summary/AbstractThis proposal is responsive to NOT-OD-22-137: Availability of Administrative Supplements for the INCLUDE(INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project. We aimto address Component 2: Assembly of a large cohort of individuals with Down syndrome across the lifespan toperform deep phenotyping and study co-existing conditions. We will build upon our large study of 2.3 millionTaiwanese births in which we are investigating maternal pharmaceutical intake in pregnancy and associationswith childhood cancer; Aims of the parent study will not change. In the US the population prevalence of Downsyndrome (DS) is 250000 persons and 6000 children with DS are born in the US each year. Children with Downsyndrome have a substantially increased risk for leukemia and elevated risk for a number of other conditions.The proposed study will utilize data from a large cohort of Taiwanese children to examine comorbid conditionsin children with Down syndrome. Participants in our study include all children born in Taiwan 2004-2015. Downsyndrome and other diagnoses will be ascertained from the National Health Insurance Database in Taiwan.Results will be confirmed in a large cohort of Danish children. The goals of this project are to better understandcomorbidities in Down syndrome to improve screening guidelines and management of patient care. 31045 +No NIH Category available Mechanisms and Targeted Therapy of NRF2-high Esophageal Squamous Cell Carcinoma NARRATIVE Esophageal squamous cell carcinoma (ESCC) is prevalent in the world. The 5-year survival rate of ESCCis ~18%. Thus it is important to better understand the molecular mechanisms of ESCC and develop targetedtherapy. NextGen sequencing of human ESCC samples has identified multiple driver mutations among whichmutations of NRF2 KEAP1 (a NRF2 inhibitor) or CUL3 (a scaffold protein for NRF2 ubiquitination anddegradation) cause hyperactive NRF2 signaling in a subset of patients (NRF2high ESCC). As a transcriptionfactor NRF2 regulates expression of many Phase I and Phase II metabolism genes. Although it is primarilycancer-preventive for normal cells in response to oxidative and electrophilic stress hyperactive NRF2 hascarcinogenic functions. However the molecular mechanisms of NRF2-associated carcinogenesis have notbeen clearly understood. Based on our preliminary data we hypothesize that hyperactive NRF2reprograms the kinome to drive ESCC and that this reprogramming reveals new therapeuticvulnerabilities. Using cell and mouse models we plan to test our hypothesis with the following specific aims:(1) To characterize the molecular and phenotypic consequences of NRF2 hyperactivation in ESCC; (2) Todetermine the mechanisms of action and efficacy of NRF2 small molecule inhibitors in ESCC; (3) To identifyNRF2-responsive kinases and their functions in NRF2-driven ESCC biology. These studies are aimed toelucidate the consequences of NRF2 hyperactivation in the esophagus push NRF2 small molecule inhibitorsfurther toward the clinic and solidify connections between NRF2 and kinome. If successful this work willstrengthen a foundation for targeted therapy of NRF2high ESCC in human patients. NCI 10851493 8/21/23 0:00 PA-21-268 3R01CA244236-04S1 3 R01 CA 244236 4 S1 "YASSIN, RIHAB R" 6/1/20 0:00 12/31/25 0:00 Developmental Therapeutics Study Section[DT] 6907189 "CHEN, XIAOXIN LUKE" "MAJOR, MICHAEL BENJAMIN" 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2022 81195 NCI 81195 0 PROJECT SUMMARYThis multiple-PI R01 proposal is designed to incorporate genetic and pharmacological approaches tounderstand the mechanisms of NRF2 hyperactivation in ESCC and to develop targeted therapy for Nrf2highESCC. We believe Nrf2 and kinases are functionally interrelated and thus cooperatively contribute to ESCC.In this proposal we aim to characterize the molecular and phenotypic consequences of NRF2 hyperactivationin ESCC determine the mechanisms of action and efficacy of NRF2 small molecule inhibitors in ESCC andidentify NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. Through threeindependent yet tightly related Specific Aims we will provide novel insights into pathway regulation and noveltherapeutic targets/agents for NRF2high ESCC. If proven effective some compounds may be further translatedinto the clinic for targeted therapy of NRF2high ESCC in the future. 81195 +No NIH Category available Abandoned Child;Address;Administrative Supplement;Administrator;Affect;Africa;Africa South of the Sahara;Area;Automobile Driving;Awareness;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Diagnostics;Cancer Family;Cancer Patient;Caregivers;Child;Cities;Country;Diagnosis;Disparity;Distant;Economics;Educational workshop;Ensure;Environment;Equity;Family;Financial Hardship;Fostering;Goals;Government;Health;Health system;Healthcare Systems;Hospital Records;Hospital Referrals;Hospitalization;Hospitals;Improve Access;Income;Inequity;Intervention;Interview;Leadership;Length of Stay;Letters;Link;Locales;Location;Malignant Childhood Neoplasm;Malignant Neoplasms;Organizational Objectives;Outcome;Pathway interactions;Patients;Pediatric Hospitals;Perception;Policies;Poverty;Recommendation;Research;Research Personnel;Resource-limited setting;Risk;Running;Rural;Services;Social Identification;Survival Rate;Teaching Hospitals;Testing;Time;Treatment Cost;Treatment outcome;Work;World Health Organization;Zambia;acceptability and feasibility;cancer care;cancer diagnosis;cancer health disparity;cancer therapy;career;cost;design;experience;hybrid type 2 trial;implementation outcomes;improved;interest;low and middle-income countries;meetings;member;programs;response;rural families;rural patients;rural setting;social;social group;social stigma;sociodemographic group;synergism;time interval Cancer Center Support Grant PROJECT NARRATIVECure rates for childhood cancer in Zambia are low and significant unmet costs hinder access to childhoodcancer diagnoses and treatments particularly for rural patients and those far from treatment. Our study willidentify the formal and informal costs that affect childhood cancer diagnosis and treatment for children living farfrom cancer treatment. By including government input into designing the form and function of a cash transferintervention for childhood cancer we will ensure that our next step upon completing the study a cash transferprogram for childhood cancer is both acceptable and feasible within the current policy environment. NCI 10851292 9/4/23 0:00 PA-20-272 3P30CA091842-22S3 3 P30 CA 91842 22 S3 "ROBERSON, SONYA" 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 149994 NCI 104733 45261 "PROJECT SUMMARY/ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as ""NOT-CA-23-052: Economicsof Cancer Control in LMICs. Childhood cancer survival rates are less than 20% in low-and-middle-income countries (LMICs) compared to 80% in high income countries. ALMICsmoveoutcomesstaysdistancedrivingdiagnosislivingdriveidentifyZambiaoutwhocashensureoutcomesZambiantreatmentdeliverycarryadministratorsanddevelopedwillemphasizingresearchinsubstantial challenge in like Zambia is that l imited treatment locations in urban centers necessitate that hildren and caregiversfrom more distant or rural places. Because of this childhood cancer i s frequently diagnosed late whenare poor. Adding t o this rural and distant patients and families in LMICs can have longer hospitalincur more expenses nd are at greater risk of abandoning treatment. In effect cost-driving factors (e.g.time and treatment costs) further intersect with multiple social identities (e.g. poverty rural i dentity)further inequities in outcomes. Thus elucidating and intervening in costs that delay and disruptand treatmen will be critical to improving access to diagnosis and t reatment for children with cancerin distant remote and/or rural locales. Cash transfer interventions may address the multiple costs thatchildhood cancer diagnostic and treatment delays and treatment abandonment. Thus our objective is tomodes of delivering cash transfers t o rural and remote childhood cancer patients and families in LMICs.is an ideal setting to carry out cash transfer interventions t o improve childhood cancer outcomes. Nine of every 10 children in Zambia with cancer do not reach either diagnosis or treatment and 90% of thosedo abandon treatment or die before treatment ompletion Zambia also has one of the longest runningtransfer programs in the region but has no yet been used for treatable health conditions like cancer. Tothe appropriateness and sustainability of cash transfers o reduce costs and improve treatment for rura l and remote children with cancer we propose two aims with strong support from theMinistry of Health. Aim 1: To identify the multiple costs associated with cancer diagnostic anddelay and abandonment for children from distant locales. Aim 2: Determine mechanisms for the and sustainability of cash transfers for childhood cancer care at the healthcare system level. We willout document review participatory workshops and meetings with legislative members and health systemto adapt cash transfers to the health system. Upon completion we will have identified t he formalinformal costs that drive childhood cancer diagnostic and treatment delay and abandonment anda pathway for introducing a treatment f ocused cash transfer intervention for childhood cancer. Weuse these findings to propose an R01 to carry out a hybrid type 2 trial of this cash transfer interventioncost and sustainability as implementation outcomes. Successful completion wil l also foster thecareers of promising j unior members of our LMIC research team a necessary step to build capacityZambia and in global cancer equity researcher and leadership.catc .tt" 149994 +No NIH Category available Abdomen;Address;Africa;Africa South of the Sahara;Biopsy;Businesses;Cancer Control;Cancer Patient;Caring;Chest;Complement;Computers;Conscious;Cost Measures;Costs and Benefits;Country;Data;Decision Trees;Devices;Economics;Electricity;Engineering;Ensure;Environment;Equipment;Excision;Expenditure;Face;Financial Hardship;Food;Foundations;Goals;Health Care Costs;Health Expenditures;Health system;Home;Hospitals;Household;Human Resources;Image;Incisional Biopsy;Income;Individual;Infection;Interdisciplinary Study;Intra-abdominal;Laparoscopic Surgical Procedures;Laparoscopy;Length of Stay;Maintenance;Malignant Neoplasms;Marketing;Maryland;Measures;Medical;Medical Device;Modeling;Nongovernmental Organizations;Oncologist;Operating Rooms;Operative Surgical Procedures;Pain;Patient-Focused Outcomes;Patients;Policies;Population;Postoperative Period;Poverty;Price;Questionnaires;Recovery;Recycling;Risk;Surgeon;Surgical Oncology;Surgical complication;Surgical incisions;System;Technology;Time;Transportation;Travel;Uganda;Universities;Work;World Bank;cancer care;cancer therapy;cohort;cost;cost effective;economic impact;economic outcome;empowerment;first-in-human;global health;health organization;high risk;human study;improved;instrument;interest;laptop;low and middle-income countries;manufacture;payment;primary outcome;response;rural area;scale up;societal costs;standard of care Unlocking the Economics of Cancer Control in Uganda Using KeyScope PROJECT NARRATIVECancer patients requiring intra-abdominal or intra-thoracic surgery in low- and middle-incomecountries (LMICs) have high risks of catastrophic health expenditures due to out-of-pocketcosts. Our study aims to measure that risk in Uganda and the economic impact of a low-costlaparoscopic system compared to open surgery. NCI 10851065 9/20/23 0:00 PA-20-272 3U01CA269190-02S1 3 U01 CA 269190 2 S1 "WANG, YISONG" 9/20/23 0:00 5/31/27 0:00 8509755 "FITZGERALD, TAMARA N" Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/20/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 150000 NCI 93168 56832 PROJECT SUMMARY / ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI)identified as NOT-CA-23-052. Surgery is the foundation of cancer treatment but patients inlow- and middle-income countries (LMICs) have limited surgical access due in part toinaccessibility of equipment and substantial out-of-pocket (OOP) healthcare costs. An estimated33 million individuals in LMICs face catastrophic health expenditures (CHE) related to directOOP surgical costs. In this context household protection against CHE has emerged as aleading policy goal with the World Bank and WHO setting targets of 100% protection fromfinancial hardships arising from OOP payments. Laparoscopic (keyhole) surgery has thepotential to provide protection against CHE and is the standard of care in high-income countriesfor many cancer excisions in the chest and abdomen. It avoids large incisions by using acamera and instruments manipulated through tiny incisions and therefore advantages include:smaller incisions decreased pain improved recovery time minimized post-surgical infectionsand shorter hospital stays reducing CHE. Our team in Uganda has developed a low-costdurable laparoscopic system (KeyScope) for use in LMICs through a unique multi-disciplinarycollaboration. The proposed project aims to measure the risk of CHE due to OOP costs amongindividuals seeking surgical care for cancers in the chest and abdomen at the Uganda CancerInstitute and measure the cost-benefit of using KeyScope versus the standard of care (opensurgery) among a simulated cohort of patients with cancer needing surgery. In our current U01study we are performing a First-In-Human study of KeyScope at the Uganda Cancer Institute.The proposed study is a direct extension of this project and will complement the U01 bymeasuring the economic impact of KeyScope within the same population of cancer patients atthe Uganda Cancer Institute. 150000 +No NIH Category available Mechanisms and Targeted Therapy of NRF2-high Esophageal Squamous Cell Carcinoma Esophageal squamous cell carcinoma (ESCC) is prevalent in the world with a 5-year survival rate around18%. Using human cells and animal models we will characterize the molecular consequences of NRF2hyperactivation in ESCC determine the mechanisms of action and efficacy of NRF2 inhibitors and find NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. If successful this work will help developtargeted therapy of NRF2high ESCC in human patients. NCI 10850620 8/1/23 0:00 PA-21-268 7R01CA244236-04 7 R01 CA 244236 4 "YASSIN, RIHAB R" 6/1/20 0:00 12/31/25 0:00 Developmental Therapeutics Study Section[DT] 6907189 "CHEN, XIAOXIN LUKE" "MAJOR, MICHAEL BENJAMIN" 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2022 364093 NCI 224322 139771 This multiple-PI R01 proposal is designed to incorporate genetic and pharmacological approaches tounderstand the mechanisms of NRF2 hyperactivation in ESCC and to develop targeted therapy for Nrf2highESCC. We believe Nrf2 and kinases are functionally interrelated and thus cooperatively contribute to ESCC.In this proposal we aim to characterize the molecular and phenotypic consequences of NRF2 hyperactivationin ESCC determine the mechanisms of action and efficacy of NRF2 small molecule inhibitors in ESCC andidentify NRF2-responsive kinases and their functions in NRF2-driven ESCC biology. Through threeindependent yet tightly related Specific Aims we will provide novel insights into pathway regulation and noveltherapeutic targets/agents for NRF2high ESCC. If proven effective some compounds may be further translatedinto the clinic for targeted therapy of NRF2high ESCC in the future. 364093 +No NIH Category available Address;Administrative Supplement;Alcohols;Biochemical;Budgets;Bupropion;Cancer Control;Cardiovascular Diseases;Caring;Cause of Death;Cessation of life;Clinic;Communicable Diseases;Cost-Benefit Analysis;Counseling;County;Data;Economics;Education;Expenditure;Financial Hardship;Food;General Population;HIV;HIV Infections;Household;Incidence;Intervention;Kenya;Malignant Neoplasms;Modeling;Parents;Patients;Pattern;Persons;Policy Developments;Prevalence;Randomized;Resource Allocation;Respondent;Sampling;Specific qualifier value;Surveys;Tobacco;Tobacco Dependence;Tobacco Use Cessation;Tobacco use;Treatment outcome;brief intervention;cancer risk;cancer therapy;experience;interest;mortality;nicotine replacement;parent grant;programs;public policy on tobacco;quitline;response;scale up;sociodemographic disparity;syndemic;tobacco cessation intervention;tobacco control;tobacco user;treatment and outcome Effect of integration of tobacco control into HIV care in Kenya on distribution of household expenses PROJECT NARRATIVEThis study will compare household spending patterns among people living with HIV (PLHIV) who use tobaccoto household spending patterns among people in the general population who use tobacco in Kenya. It will alsoassess the impact of cessation interventions on these expenditures and model the national impact of scalingup cessation programs on household expenditures for PLHIV. NCI 10850616 9/15/23 0:00 PA-20-272 3U01CA261620-03S1 3 U01 CA 261620 3 S1 "RICCIARDONE, MARIE D" 9/16/21 0:00 8/31/26 0:00 ZCA1(M1) 8879004 "BIALOUS, STELLA AGUINAGA" Not Applicable 11 OTHER HEALTH PROFESSIONS 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF NURSING 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 150000 NCI 99475 50525 PROJECT SUMMARYThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-052. Kenya is experiencing a syndemic of HIV and cancer that is aggravated by consumption of tobacco.Use of tobacco negatively impacts HIV treatment outcomes increase the risks of cancer and negativelyimpacts cancer treatment outcomes and people living with HIV (PLHIV) have higher tobacco use rates thanthe general population. In Kenya cancer is the third leading cause of death after infectious and cardiovasculardiseases. From 2012 to 2018 the annual incidence of cancer increased from 37000 to 47887 newcases/year. During the same period annual cancer mortality rose almost 16% to 32987 cancer-relateddeaths. There are significant socio-demographic disparities in tobacco with people in the lower educationaland economic strata having higher rates of tobacco use. Therefore it is important to understand howhousehold expenditures on tobacco impacts a household ability to access essential goods such as food andeducation. In this proposed administrative supplement we will ask a sample of PLHIV who use tobacco abouttheir expenditures on tobacco and other goods. The primary study (U01 CA261620-03) is a cluster randomizedsuperiority trial assessing the impact of integrating tobacco use cessation into HIV care in 20 clinics in KisumuCounty Kenya. The primary study will compare 12-months biochemically verified point prevalence amongtobacco users who received a brief intervention with tobacco users who received an intensive intervention.One of the primary study aims was to conduct in a cost-benefit analysis of the interventions but did not includethe impact of the interventions on expenditures. Therefore the Aims of this study are to: 1) Comparehousehold spending patterns among PLHIV who use tobacco to household spending patterns among people inthe general population who use tobacco in Kenya; 2) Compare the potential effect of a brief and an intensivetobacco cessation interventions on household expenditures among a sample of PLHIV who use tobacco and3) Model the potential effect of brief and intensive tobacco cessation interventions on household expendituresamong PLHIV in Kenya. We will use items from the 2015- 2016 National Household Expenditure Survey to askour sample (N=580) of PLHIV who use tobacco about their expenditures. We will then compare the resultsfrom this sample with the results of the national survey which does not provide HIV-status of respondents. Thiswill allow us to assess any financial burden related to tobacco expenditures among PLHIV. Further we will beable to assess the impact of brief and intensive cessation interventions on household expenditures. This willprovide data to model what the impact of scaling up a cessation intervention on national householdexpenditures on tobacco. The results of this project will inform allocation of resources for tobacco dependencetreatment within tobacco and cancer control plans. 150000 +No NIH Category available Data;Methodology;National Cancer Institute;SEER Program;cohort;design SPECIALIZED ANALYTIC DATA SUPPORT for SEER-MHOS DATA EXPANSIONS n/a NCI 10850505 75N91021F00279-P00005-0-1 N02 9/24/21 0:00 9/23/24 0:00 78388091 "BOGGS, ABBEY " Not Applicable 4 Unavailable 4868105 JJHCMK4NT5N3 4868105 JJHCMK4NT5N3 US 35.9138 -78.848911 6939101 RESEARCH TRIANGLE INSTITUTE RESEARCH TRIANGLE PARK NC Research Institutes 277092194 UNITED STATES N R and D Contracts 2023 185436 NCI The purpose of this solicitation is to obtain specialized analytic data support to demonstrate the utility of recentSEER-MHOS data expansions and to investigate new methodological approaches taking advantage of the MHOSrepeated multi-cohort design. 185436 +No NIH Category available Animal Cancer Model;Antibodies;Automobile Driving;Binding;Biological Availability;Biological Products;Cancer Patient;Cancer cell line;Cell model;Chemicals;Clinical;Cyclic Peptides;Development;Dimerization;Drug Kinetics;Drug Targeting;ERBB3 gene;Epidermal Growth Factor Receptor;Exhibits;Extracellular Domain;Family;Gene Amplification;Generations;Genetic;Goals;Growth;Heterodimerization;Homo;Human;In Vitro;Intestines;Knowledge;Lead;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Molecular;Mus;Mutate;Mutation;Non-Small-Cell Lung Carcinoma;Oral;Outcomes Research;Pathologist;Pathway interactions;Patients;Peptides;Periodicity;Pertuzumab;Pharmacologic Substance;Phosphotransferases;Plants;Play;Process;Property;Protein Inhibition;Protein Overexpression;Proteins;Reporting;Research;Research Project Grants;Resistance;Resistance development;Role;Scientist;Signal Pathway;Signal Transduction;Specificity;Structure;Sunflowers;Survival Rate;Therapeutic;Therapeutic Agents;Therapeutic Effect;Trypsin Inhibitors;Tyrosine Kinase Inhibitor;Variant;Xenograft Model;cancer cell;cancer therapy;cancer type;design;dimer;disulfide bond;functional group;humanized antibody;humanized monoclonal antibodies;improved;in vitro Model;in vivo;inhibitor;lung cancer cell;malignant breast neoplasm;mutant;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;patient subsets;peptide drug;peptidomimetics;prevent;protein protein interaction;receptor;small molecule;stability testing;targeted treatment;therapeutic target;therapy resistant;tumor;tumor growth;tumor progression Molecular mechanism of EGFRs protein-protein interaction inhibition by a grafted peptide in NSCLC Narrative: The project involves designing a grafted peptide molecule from a plant-based peptide which can beused to modulate protein-protein interactions of EGFR proteins that are overexpressed or mutated in lungcancer. The research outcomes from this project will help in developing therapeutic grafted peptides that couldhave an impact on lung cancer that becomes resistant to treatment. These grafted peptides will form the basisof a new therapeutic approach to NSCLC that could improve the survival rate of lung cancer patients. NCI 10850407 6/30/23 0:00 PA-21-268 7R01CA255176-04 7 R01 CA 255176 4 "FU, YALI" 4/1/21 0:00 3/31/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 8656613 "JOIS, SEETHARAMA D" "BILLADEAU, DANIEL D" 6 PATHOLOGY 75050765 ECQEYCHRNKJ4 75050765 ECQEYCHRNKJ4 US 30.408018 -91.188669 577907 LOUISIANA STATE UNIV A&M COL BATON ROUGE BATON ROUGE LA SCHOOLS OF VETERINARY MEDICINE 708030001 UNITED STATES N 5/27/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 333654 NCI 237593 96061 Project Summary: The long-term objective of this research project is to understand the role of dimerization inextracellular domains (ECD) of epidermal growth factor receptors (EGFRs) in cancer. The short-term goal is todesign sunflower trypsin inhibitor (SFTI)-grafted peptides for treatment of lung cancer. Nearly 85% of lung cancerpatients have a type of cancer called non-small-cell lung cancer (NSCLC). The five-year survival rate of NSCLCpatients has not improved in more than a decade because most tyrosine kinase inhibitors (TKIs) developresistance to therapy within five years. Dimerization of EGFRs (EGFR HER2 HER3) is known to play a key rolein NSCLC. Apart from EGFR human epidermal growth factor receptor-2 (HER2) gene amplification and HER2protein overexpression or mutation seem to play major roles in the development of resistance in NSCLC therapy.Although HER2 overexpression or mutation is observed in 2-4% of NSCLC HER2 may be a driver of bothNSCLC progression and resistance to EGFR. Understanding the details of dimers of EGFRs and inhibitingdimerization has a significant impact on not only HER2 overexpressed but EGFR-mutated NSCLC and thiswould fill a gap in our knowledge. Inhibition of EGFRs extracellular domain dimerization has a significant impacton its therapeutic effect on NSCLC. This will be done by targeting the clinically validated target domain IV ofhuman epidermal growth factor receptor-2 (HER2) with peptides. However peptides have limitations in terms oforal bioavailability. Multicyclic peptides with a disulfide bond such as sunflower trypsin inhibitors are known tohave a stable structure that is resistant to thermal chemical and enzymatic degradation. These peptides canbe grafted with functional groups that can inhibit protein-protein interactions. Grafted peptides overcome thelimitations of peptides as therapeutic agents and are orally available. A grafted peptidomimetic molecule hasbeen designed that specifically binds to the HER2 protein and inhibits the dimerization process of EGFR proteins.This approach is novel because the molecule designed disrupts EGFR homo- as well as heterodimers. Themolecular mechanism of how the grafted peptide inhibits EGFR dimerization and alters the signaling for canceris not well understood. We propose to characterize details of the mechanism of inhibition of EGFR dimerizationand the biopharmaceutical properties of the grafted peptide. As a proof-of-concept the grafted peptide will beevaluated in different models of lung cancer including patient-derived cancer cell model in mice. Aims in thisproject are: 1) to evaluate the molecular mechanism of protein-protein interactions of EGFRs via inhibition bythe grafted peptide and its effect on downstream signaling in HER2-activated and EGFR-resistant lung cancercells; 2) to evaluate the therapeutic effect of grafted peptides on reducing the growth of lung tumors in mice; 3)to evaluate the oral availability and biopharmaceutical properties of grafted peptides. Such grafted peptides thatare orally available will have an impact on lung cancer treatments that develop resistance and on the survivalrate of lung cancer patients. 333654 +No NIH Category available Varenicline and mobile behavioral assistance for tobacco cessation in HIV care in India NarrativeThere is an urgent need to adapt and implement effective tobacco cessation interventions in HIV careprograms in low- and middle-income settings. This study will evaluate the effectiveness and cost-effectivenessof an integrated varenicline and mobile behavioral intervention among smokers and dual tobacco users in HIVcare in Chennai India. Combining a scalable mobile health intervention with cost-effective pharmacotherapycould reduce the harmful impacts of tobacco among people living with HIV. NCI 10850221 7/28/23 0:00 PA-21-268 7U01CA261614-03 7 U01 CA 261614 3 "RICCIARDONE, MARIE D" 9/23/21 0:00 8/31/26 0:00 ZCA1-SRB-2(M1) 11990793 "KRUSE, GINA RAE" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 6/1/23 0:00 8/31/23 0:00 393 Non-SBIR/STTR 2022 364586 NCI 281121 83465 AbstractThere is an urgent need to implement effective tobacco cessation interventions in HIV care programs in low-and middle-income countries (LMICs) where most tobacco users and people with HIV live. India is animportant setting in which to test tobacco cessation interventions with an estimated 275 million tobacco usersand 2 million people living with HIV (PWH). Effective medications and behavioral interventions have not beenwell tested in HIV care settings in LMICs. In high income settings Positively Smoke Free (PSF) a theory-based behavioral intervention has demonstrated efficacy among PWH and been adapted for mobile phonedelivery (PSF-M). Mobile health interventions offer scalability and may be more effective among PWH thanface-to-face. Varenicline is the cessation medication with the strongest evidence of efficacy in PWH butachieving sufficient adherence to sustain long-term success is a challenge. We propose to combine the twomost promising cessation interventions among PWH varenicline and PSF-M enhanced with vareniclineadherence support. They will be tested at the Voluntary Health Services (VHS) Infectious Disease MedicalCenter Chennai Antiviral Research and Treatment Clinical Research Site where 24% of patients new to HIVcare are current smokers or dual users of smoked and smokeless tobacco and 83% own mobile phones. Inthis setting we propose the following specific aims: (1) To demonstrate the effectiveness of an integratedintervention combining varenicline plus mobile behavioral treatment among tobacco users in HIV care onbiochemically verified tobacco abstinence at 24 weeks compared to a standard care control; (2): To evaluatethe implementation processes of the integrated intervention in an LMIC HIV practice; and (3): To measure thecosts and cost-effectiveness of an integrated intervention with varenicline and PSF-M. To accomplish theseaims PSF-M will be adapted to the VHS context and novel content about smokeless tobacco and medicationadherence self-efficacy will be added. A randomized two-arm trial will compare the combination of vareniclineand PSF-M to a standard care control. We will evaluate implementation processes within HIV care workflowsincluding acceptability appropriateness feasibility and costs and conduct cost-effectiveness analysis to assessthe clinical impact and value of the integrated intervention if scaled-up. The work proposed is responsive to thespecific interests in RFA-CA-20-037 by testing the effectiveness of tobacco cessation interventions withdemonstrated efficacy in other settings and adapted for an LMIC context evaluating the implementationprocess from multiple stakeholder perspectives in an HIV care practice and assessing the clinical impact andvalue of the integrated intervention if implemented at scale. The successful completion of this work will movethe field forward by advancing our understanding of the effectiveness of an integrated tobacco cessationintervention in HIV care settings and projecting the population level impacts of implementing the integratedintervention for PWH in India or other LMICs. 364586 +No NIH Category available Administrator;Affect;Alaska Native;American Indians;Biopsy;Cancer Center;Cancer Center Support Grant;Caring;Cervical Cancer Screening;Clinic;Clinical;Colonoscopy;Colorectal Cancer;Colposcopy;Communication;Communities;Data Reporting;Diagnostic;Diagnostic tests;Disparity;Distress;Early Diagnosis;Economics;Ensure;Feces;General Population;Geography;HPV-High Risk;Health Insurance;Health care facility;Healthcare;Healthcare Systems;Immunofluorescence Immunologic;Incidence;Indigenous;Individual;Institution;Intervention;Interview;Knowledge;Lesion;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Native Americans;Oklahoma;Outcome;Patients;Persons;Population;Process;Provider;Qualitative Evaluations;Questionnaires;Race;Readiness;Reporting;Screening Result;Screening for cancer;Screening procedure;Site;Specialist;Structure;System;Testing;Transportation;Travel;Tribes;United States;United States Indian Health Service;Visualization;Woman;cancer health disparity;cancer therapy;clinical care;colorectal cancer screening;deprivation;distrust;evidence base;experience;follow-up;implementation study;improved;men;mortality;organizational climate;process improvement;screening;screening disparities;screening program;social;social health determinants;urban Native American Stephenson Cancer Center - Cancer Center Support Grant -Understanding Key Factors and Processes Affecting Follow-up of Abnormal Cancer Screening Tests in American Indian Patients Project NarrativeThe reduction of cancer health disparities for screen-detectable cancers such as cervical cancer andcolorectal cancer is a significant priority for American Indian communities. This project features a multilevelapproach to systematically identify barriers and facilitators to receipt of diagnostic colposcopy among AmericanIndian women with positive initial cervical cancer screening results and receipt of diagnostic colonoscopy inAmerican Indian men and women with positive initial stool-based colorectal cancer screening results. Findingswill provide essential information for extending navigator-based screening programs to include diagnosticfollow-up testing. NCI 10850136 8/30/23 0:00 PA-20-272 3P30CA225520-06S1 3 P30 CA 225520 6 S1 "SHAFIK, HASNAA" 5/8/23 0:00 4/30/24 0:00 2488117 "MANNEL, ROBERT S." Not Applicable 5 OBSTETRICS & GYNECOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 5/8/23 0:00 4/30/24 0:00 353 Research Centers 2023 261430 NCI 216512 44918 Project Summary/AbstractAmerican Indian populations in the United States (US) experience major disparities compared to the generalpopulation in incidence and mortality for cervical cancer (CC) and colorectal cancer (CRC). Highly effectiveevidence-based screening tests exist for CC and CRC but in order to be effective diagnostic testing must becompleted when the initial screening result is positive. In Indian Health Service Tribal and Urban Indian (ITU)healthcare facilities in Oklahoma initial screening for CC includes Papanicolaou (Pap) smear testing eitheralone or with high-risk human papilloma virus (hrHPV) co-testing. Initial screening for CRC typically relies onstool-based tests (e.g. fecal immunofluorescence testing testing). Unfortunately many persons with positiveinitial screens do not receive timely diagnostic colposcopy after a positive CC screen or colonoscopy after apositive stool-based CRC screen likely contributing to worse outcomes. A clear understanding of the factorsand processes of care that impede or facilitate follow-up to diagnostic testing after CC or CRC screening inAmerican Indian persons has never been reported. Completion of diagnostic follow-up is influenced byindividual- structural- and system-level factors including social determinants of health (SDOH). Economicdeprivation lack of health insurance geographic travel barriers distrust of the healthcare system lack ofknowledge and communication about screening procedures and others may impede diagnostic testing. Thisstudy uses a multilevel approach to identify barriers and facilitators to diagnostic colposcopy and colonoscopyamong American Indian patients in Oklahoma who receive care in ITU clinical settings. The study has thefollowing specific aims: 1) To conduct semi-structured interviews of patients providers staff and administratorsat ITU clinic facilities and when applicable providers and staff at non-ITU specialist facilities; and 2) Tounderstand clinic flow processes and the organizational climate for process improvement from initial screeningthrough completion of colposcopy or colonoscopy in ITU clinic facilities. This study will identify critical points inthe process of healthcare in which navigated intervention would help ensure smooth progression fromscreening to diagnostic testing. Detailed flow maps will be created for each cancer for each participating ITUsite and specialist practices performing diagnostic testing. To assess organizational climate and practicereadiness for improving diagnostic testing the Change Process Capability Questionnaire will be administered toeach ITU practice. Taken together Aims 1 and 2 set the stage for navigation-based implementation studies toimprove completion of diagnostic testing. 261430 +No NIH Category available Adverse event;Cancer Therapy Evaluation Program;Contracts;Databases;Division of Cancer Treatment and Diagnosis;Electronic Mail;Lead;Letters;National Cancer Institute;Outcome;Process;Protocols documentation;Reporting;meetings;operation;symposium;timeline;working group OPERATION & SUPPORT OF THE CTEP PROTOCOL AND INFORMATION OFFICE (PIO) n/a NCI 10849596 75N91021C00007-P00004-9999-1 N02 6/1/21 0:00 5/31/24 0:00 78070504 "BALACHANDRAN, DESMA " Not Applicable Unavailable 80245497 MCLKHED4JJX5 80245497 MCLKHED4JJX5 US -504214 GAITHERSBURG MD Other Domestic Non-Profits 208772630 UNITED STATES N R and D Contracts 2023 1375000 NCI The Protocol Information Office (PIO) Cancer Therapy Evaluation Program (CTEP) Division of Cancer Treatment and Diagnosis (DCTD) National Cancer Institute (NCI) is responsible for the receipt and facilitating review of documents used in the majority of NCI sponsored treatment and non-treatment trials. The purpose of this contract is to provide support of CTEP functions mainly in support of protocol related reviews (e.g. all processes surrounding tracking reviews and distributing review outcomes database abstraction recording decisions supporting review meetings and conference calls consolidating reviews distributing outcome letters) distributing adverse event reports to lead protocol organizations tracking Operational Efficiancy Working Group (OEWG) timelines as well as maintaining an email box for protocol related inquiries. 1375000 +No NIH Category available 2019-nCoV;Address;Adopted;Biological;Biological Assay;Biological Markers;Biometry;Blood;COVID-19;Cancer Control;Cancer Patient;Characteristics;Clinical;Clinical Data;Clinical Management;Clinical Trials;Clinical Trials Network;Collaborations;Communication;Computers;Consult;Consultations;Contractor;Custom;Data;Data Analyses;Data Collection;Data Commons;Data Element;Data Files;Data Security;Data Set;Databases;Detection;Development;Diagnosis;Disease;Division of Cancer Treatment and Diagnosis;Documentation;Effectiveness;Electronic Mail;Electronics;Enrollment;Ensure;Event;Excision;Extramural Activities;Failure;Frequencies;Generations;Genomics;Grant;Group Meetings;Human Resources;Image;Immune response;Individual;Institution;Laboratories;Laboratory Study;Length;Link;Logic;Logistics;Manuals;Master of Science;Medidata;Methods;Mission;Modification;Molecular Analysis;Monitor;Names;National Cancer Institute;National Cancer Program;Natural History;Online Systems;Outcome;Patients;Performance;Positive Test Result;Preparation;Prevention;Process;Production;Quality Control;Radiation Oncology;Recurrence;Reporting;Research;Research Personnel;Resources;Secure;Serology;Services;Shipping;Specific qualifier value;Specimen;Statistical Data Interpretation;Structure;Support Contracts;System;Techniques;Telephone;Text;Time;United States Dept. of Health and Human Services;United States National Institutes of Health;United States Public Health Service;Update;Virus;anticancer research;application programming interface;biobank;cancer diagnosis;cancer palliative treatment;cancer rehabilitation;clinical database;clinical research site;data acquisition;data de-identification;data exchange;data management;data repository;design;experience;falls;follow-up;individual responsibility;meetings;member;programs;sample collection;statistics;success;symposium;timeline;working group DATA MANAGEMENT FOR CANCER DIAGNOSIS PROGRAM ACTIVITIES n/a NCI 10849595 75N91021D00017-P00001-759102200003-1 N02 8/1/23 0:00 7/31/24 0:00 78792328 "ANNETTE, DAVE " Not Applicable 4 Unavailable 83656892 LGGFBF8YVA71 83656892 LGGFBF8YVA71 US 39.047465 -77.125049 1069201 "INFORMATION MANAGEMENT SERVICES, INC." CALVERTON MD Domestic For-Profits 207053407 UNITED STATES N R and D Contracts 2023 842461 NCI C6 The National Cancer Institute (NCI) is an institute within the National Institutes of Health (NIH) one of eight agencies that compose the Public Health Service (PHS) Department of Health and Human Services (DHHS). The mission of the NCI is to plan conduct and coordinate the National Cancer program and involves (a) research on the causes detection diagnosis prevention treatment and palliative care of cancers and on rehabilitation of the cancer patient and (b) demonstration of the effectiveness of cancer control methods and techniques.II. BackgroundThe Division of Cancer Treatment and Diagnosis (DCTD) of the NCI has initiated a natural history study NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study to investigate the course of disease in cancer patients with positive test results for SARS-CoV-2 the virus that causes thedisease COVID-19. Across the NCIs clinical trials networks patients who enroll will have clinical data imaging data and longitudinal blood or other biospecimens collected over a two-year period for laboratory analysis. NCI will use its existing Medidata Rave system to acquire and manage the clinical data and the Imaging and Radiation Oncology Core (IROC) to manage the imaging data. Several different kinds of laboratory analyses are planned to investigate biological aspects of the disease including but not limited to genomics serology and immune response and to examine associations of biological features with clinical variables and outcomes. Laboratory studies will take place at multiple institutionsboth at NCI-Frederick and at several non-government academic and commercial laboratories. The data analysis effort will be led by the Biometric Research Program (BRP) in DCTD in collaboration with the participating laboratories and other members of the study team. 842461 +No NIH Category available Address;Administrative Supplement;Adult;Architecture;Autoantigens;Autoimmune;Autoimmune Diseases;Autoimmune Responses;Autoimmunity;Award;Basic Science;Bioinformatics;Biological Assay;Blood;CD8-Positive T-Lymphocytes;Cancer Patient;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Characteristics;Clinical;Clinical Data;Clone Cells;Cytometry;Data Set;Development;Down Syndrome;Experimental Designs;Frequencies;Funding;Goals;Hashimoto Disease;Immune;Immune checkpoint inhibitor;Immunology;Individual;Infrastructure;Knowledge;Longevity;Longitudinal cohort;Malignant Neoplasms;National Cancer Institute;Oncology;Outcome;Parents;Patients;Peptides;Persons;Phenotype;Property;Public Health;Registries;Research;Research Institute;Resources;Risk;Sampling;Solid Neoplasm;System;T cell regulation;T cell response;T-Lymphocyte;Therapeutic;Thyroid Gland;Treatment Efficacy;Tumor Antigens;Work;antigen-specific T cells;antitumor effect;autoimmune thyroid disease;autoreactive T cell;biobank;cancer immunotherapy;checkpoint inhibition;checkpoint therapy;cohort;high reward;high risk;immune-related adverse events;improved;insight;parent grant;predicting response;predictive marker;recruit;repository;transcriptome sequencing;treatment response;tumor Anti-tumor and autoimmunity signatures in Down syndrome NarrativeThe proposed research is relevant to public health because it investigates why individuals with Downsyndrome are at increased risk for autoimmune disease yet are protected from development of solid tumors. Itwill advance our understanding of anti-tumor mechanisms and thus provide insight into how to improve cancerimmunotherapy. This knowledge will also be important for developing therapeutic approaches to treatautoimmune disease in Down syndrome. NCI 10848979 9/18/23 0:00 PA-20-272 3R01CA231226-05S1 3 R01 CA 231226 5 S1 "SONG, MIN-KYUNG H" 9/1/19 0:00 8/31/25 0:00 ZCA1(M2)-R 7703043 "BUCKNER, JANE HOYT" "LINSLEY, PETER S" 7 Unavailable 76647908 PK9FMGRDRVD5 76647908 PK9FMGRDRVD5 US 47.609997 -122.329217 8961401 BENAROYA RESEARCH INST AT VIRGINIA MASON SEATTLE WA Research Institutes 981012795 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 648776 OD 374366 274410 Summary/AbstractThis is a request for an Administrative Supplement for the INCLUDE Project for R01 CA231226 Defining thefeatures of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy. Theproposed studies for the Administrative Supplement are within the scope of the active parent grant focused onDown syndrome (DS) and address two of the three components prioritized by the INCLUDE Project(Component 1: Targeted high risk high reward basic science studies highly relevant to DS and Component 2Assembly of a large cohort of individuals with DS across the lifespan to perform deep phenotyping and studyco-existing conditions. Our objectives are: 1) To define an optimal anti-tumor signature by characterizing theimmune landscape in individuals with DS with co-occurring autoimmune disease and then comparing to theimmune landscape in patients with solid tumors who develop irAE after immune checkpoint inhibitor (ICI)therapy in order to identify an optimal anti-tumor signature (Component 1); and 2) Expand our existing DSbiorepository to include more adults and more individuals with co-occurring autoimmune disease (Component2). The central hypothesis for the proposed studies is that the immune features in DS that promoteautoimmunity are the same immune features that protect from solid tumors and promote therapeutic responseto ICI therapy. It is based on 1) observations that people with DS are protected from developing solid tumorsand also predisposed to autoimmunity; and 2) Growing evidence of an association between therapeuticresponse to ICI therapy and development of autoimmune irAEs. The goal of Aim 1 is to increase both thenumber of adults and the number of individuals with co-occurring autoimmune disease in our existingbiorepository. The goal of Aim 2 is to define an optimal anti-tumor signature by identifying sharedcharacteristics of the immune architecture between people with DS and those treated with ICI who develop anirAE. These studies will determine the global immune landscape and antigen-specific T cell responses inindividuals with DS and co-occurring autoimmune thyroid disease and then compare to cancer patients whodevelop ICI induced-autoimmune thyroiditis. The global immune landscape will be characterized using masscytometry and RNA-sequencing. Antigen-specific T cell frequency and phenotype will be determined usingactivation-induced assays and single cell Cellular Indexing of Transcriptomes and Epitopes by Sequencing(scCITE-seq). The proposed work will extend understanding of anti-tumor mechanisms and thus improve ICIoutcomes and elucidate potential ways to mitigate autoimmunity in people with DS without diminishing anti-tumor effect. Importantly it is within the scope of the parent award as it focuses on understanding T cellresponses in individuals that develop irAEs after ICI therapy. It also leverages the expertise and resourcesalready in place in the parent grant and utilizes the same approach and experimental design as the parentgrant to assess the global immune landscape and antigen-specific T cells. 648776 +No NIH Category available Address;Binding;Bioinformatics;Biological Process;Bladder Neoplasm;C-terminal;Categories;Cell Nucleus;Cell secretion;Cells;Cessation of life;ChIP-seq;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Collagen Receptors;Communication;Conceptions;DNA Binding;Data;Disease;Disease Management;Distal;Ectopic Expression;Extracellular Matrix;Family;Fibroblasts;Funding;Genes;Goals;Image;Invaded;Investigation;Kininogenase;Knock-out;Knowledge;Ligands;Luciferases;Lung;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Metastatic Neoplasm to the Lung;Modality;Mutate;N-terminal;Nature;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Pattern;Peptide Hydrolases;Phenotype;Phosphorylation;Phosphorylation Site;Pilot Projects;Play;Primary Neoplasm;Process;Progression-Free Survivals;Property;Protein Fragment;Proteins;Receptor Activation;Receptor Signaling;Regulation;Role;Signal Transduction;Site;Smooth Muscle Myocytes;Specific qualifier value;Survival Rate;Testing;Therapeutic Intervention;Tumor Volume;Tyrosine Phosphorylation;Tyrosine Phosphorylation Site;bladder Carcinoma;bladder transitional cell carcinoma;cancer cell;cancer type;clinical translation;design;gamma secretase;in vivo;innovation;lead candidate;metastatic process;migration;neoplastic cell;notch protein;novel;novel strategies;overexpression;pharmacologic;precision medicine;receptor;respiratory smooth muscle;scaffold;src Homology Region 2 Domain;success;therapeutic target;tumor;tumor microenvironment Distinct Tumor and Metastatic Collagen Microenvironments: Divergent Targeting Approaches PROJECT NARRATIVEMetastatic bladder cancer is a devastating disease with a 5-year survival rate of only 5.4%. While the initialsteps of the metastatic cascade are rather well defined identification of targets to block this processcontinues to be a major clinical challenge. Discovering the regulatory mechanisms by which the metastaticmicroenvironment support tumor cell colonization and survival will enable design of new strategies not onlytargeting the primary tumors but also eradicating metastatic foci a potential new breakthrough. NCI 10847208 9/7/23 0:00 PA-21-268 7R01CA175397-09 7 R01 CA 175397 9 "SNYDERWINE, ELIZABETH G" 9/30/13 0:00 4/30/26 0:00 Tumor Microenvironment Study Section[TME] 8781273 "CHAN, KEITH SYSON " Not Applicable 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 400962 NCI 254815 146147 PROJECT SUMMARYMetastatic progression of the primary tumor accounts for the majority of cancer deaths. While the initial steps ofthe metastatic cascade are rather well defined identification of targets to block this process remains a majorclinical challenge. Previous studies have elegantly investigated the mechanistic contribution of tumor cell intrinsicproperties that promote metastasis in bladder urothelial carcinomas. However the functional significance of thetumor microenvironment and its contribution to this complicated process is not well characterized and thereforewarrants investigation. The long-term goal of this renewal application is to continue explore how collagensamajor extracellular matrix component of the microenvironmentact as a ligand to mediate crosstalk with theirreceptor on tumor cells to facilitate the metastatic cascade. We will investigate the downstream regulatorymechanisms of collagen receptor signaling in both the primary tumor and metastatic sites and to exploit theseregulatory processes as a revolutionizing approach to target metastases. Such innovative approaches to perturbcollagen-cancer crosstalknot only at the primary tumor but also at the metastatic nichewill move the fieldforward by providing a new conception in metastatic disease management and likely extend beyond bladdercarcinomas to other cancer types. 400962 +No NIH Category available Astrocytes;Biologic Characteristic;Biological;Cell Maintenance;Cell Proliferation;Cell Survival;Cells;Characteristics;Childhood;Childhood Brain Neoplasm;Childhood Central Nervous System Neoplasm;Childhood Glioma;Clinical Trials;Complementary DNA;Control Groups;Copy Number Polymorphism;DNA sequencing;Data;Development;Disease;Drug Screening;Effectiveness;Foundations;Genes;Genomic DNA;Goals;Growth;Heterogeneity;Histology;Histones;Individual;Institution;Investigation;Knowledge;Lysine;Malignant Neoplasms;Mediating;Methionine;Methods;Molecular;Mus;Mutation;Normal Cell;Nucleotides;Oncogenic;Operative Surgical Procedures;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Play;Population;Population Decreases;Postdoctoral Fellow;Predisposition;Proliferating;Radiation therapy;Radiation-Sensitizing Agents;Recurrence;Research;Resistance;Role;Sampling;Somatic Mutation;Survival Rate;Testing;Therapeutic;Therapeutic Effect;Tumor Bank;Tumor Biology;Tumor Stem Cells;Variant;Work;Xenograft Model;Xenograft procedure;cell growth;cell type;chemotherapy;childhood cancer mortality;diffuse midline glioma;drug candidate;effective therapy;in vivo;knock-down;lentivirally transduced;mouse model;neoplastic cell;neural;oligodendrocyte progenitor;patient derived xenograft model;pharmacologic;pre-doctoral;progenitor;radiation effect;resistance mechanism;self-renewal;single cell analysis;single-cell RNA sequencing;small hairpin RNA;stem;stem cell differentiation;stem cell population;stem cells;therapy design;therapy resistant;tool;tumor;tumor growth;tumor heterogeneity;tumor initiation;tumor xenograft;tumorigenesis Investigation of tumor stem cell maintenance and cellular hierarchy in pediatric high-grade glioma Project NarrativePediatric high-grade glioma (PHGG) a deadly childhood brain tumor likely originates from tumor stem cells that differentiate into proliferating tumor cells. PHGG tumors are heterogeneous and include several different types of proliferating cells leading to the question of how tumor stem cells and proliferating tumor cells relate to one another. I will investigate whether a single multipotent tumor stem cell population produces the multiple proliferating cell types of PHGG to provide a biological foundation for the development of critically needed advances in therapeutic alternatives for this deadly childhood disease. NCI 10846885 7/18/23 0:00 RFA-CA-21-059 4K00CA274654-02 4 K00 CA 274654 2 "ELJANNE, MARIAM" 8/1/22 0:00 6/30/27 0:00 ZCA1-PCRB-H(M1) 16431693 "DESISTO, JOHN A" Not Applicable 6 PEDIATRICS 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 86502 NCI 80094 6408 Project SummaryThe projects overall goal is to determine important biological characteristics and investigate therapeutic options for pediatric high-grade gliomas (PHGG) the most aggressive of childhood central nervous system tumors and most common cause of childhood cancer mortality. PHGG survival rates are less than 5% for the subtype diffuse midline glioma and 20% for hemispheric histone 3-wild type (H3-wt) PHGG. PHGG are highly invasive and often grow diffusely among normal cells limiting surgery as a therapeutic option. Radiation therapy (RT) is transiently effective but the tumors nearly always recur. Despite hundreds of clinical trials no chemotherapy has shown a definitive survival benefit in PHGG. Effective PHGG therapies are critically needed.PHGG likely originates from stemlike tumor initiating cells (PICs). PHGG tumors comprise several distinct cell types of glial origin in varying proportions. This tumor heterogeneity complicates understanding PHGG tumor biology and designing therapies. Aim 1 will investigate how each distinct cell type in PHGG contributes to overall tumorigenesis in a mouse model. Single-cell RNA-Seq (scRNA-Seq) analysis of orthotopic patient derived PHGG xenografts (PDX) will be used to define the cell types present and identify differentially regulated oncogenic pathways that drive their growth. Pathway expression will be knocked down by targeting key effector genes with shRNA using stable lentiviral transduction. The effect on tumor growth will be evaluated using survival histology and single-cell RNA-Seq. Aim 2 will perform lineage tracing to determine whether a single PIC cell type produces all of the proliferating cell types that comprise PHGG. Lineage tracing will be performed in a mouse PDX model. Singlecell genomic DNA sequencing will be performed on PDX tumors. Mutational signatures consisting of single and multiple nucleotide variations as well as copy number variation will be used to define each cell type. Conserved patterns of mutation among cell types will be used to determine the hierarchical relationships among cell types. Once the lineage relationships are worked out resistance to RT will be studied in the PDX model. RT is the most consistently effective therapy against PHGG but works only temporarily before cells regrow. RT resistance by cell type will be determined based upon differential survival of cell types versus control following RT. Drug screening of resistant cell types to identify radiation sensitizers will be performed. The candidate drugs will be combined with RT to investigate their effectiveness at increasing the duration of the RT effect. 86502 +No NIH Category available Address;Adopted;Affect;Africa;Africa South of the Sahara;African;Area;Award;Cancer Control;Cervical;Cervical Cancer Screening;Cognitive;Collection;Communities;Community Health Aides;Community Surveys;Data Analyses;Disease;Disparity;Doctor of Philosophy;Eligibility Determination;Evaluation;Female Adolescents;Future;Geography;Goals;Health;Health Fairs;Human Papilloma Virus Vaccination;Human Papillomavirus;Immunization Programs;Incidence;Kenya;Learning Skill;Liberia;Liberian;Life Cycle Stages;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Manuscripts;Mentors;Methods;Parents;Persons;Physicians;Preventive;Preventive service;Principal Investigator;Public Health;Research;Research Design;Research Personnel;Resources;Scientist;Senior Scientist;Services;Site;Statistical Data Interpretation;Training;Uganda;United States National Institutes of Health;Universities;Vaccination;Woman;Work;World Health Organization;anticancer research;career development;cervical cancer prevention;data dissemination;disparity reduction;early experience;experience;follow-up;implementation intervention;interest;low and middle-income countries;member;mortality;novel;novel strategies;parent grant;peer;population based;premalignant;preventive intervention;programs;response;satisfaction;screening;screening program;skills;uptake A Mentored Research Experience in Investigating the Socio-geographic Expansion to Liberia of a Novel Campaign-based Public Health Approach to Cervical Cancer Prevention Women in sub-Saharan Africa bear the greatest burden of cervical cancer in the world and the reasons areclear: lack of HPV vaccination screening for pre-cancer and treatment. In East Africa we have developedwhat we call a campaign-based public health approach in which we bring vaccination screening andtreatment directly to where residents live in their communities. In this supplement application we willevaluate our approach in another resource-limited socio-geographic context Liberia in West Africa while concurrently providing a mentored career development experience for an early-stage Liberianinvestigator. NCI 10846445 9/18/23 0:00 PA-20-272 3U54CA254571-04S2 3 U54 CA 254571 4 S2 "DOMINGUEZ, GERALDINA" 7/13/20 0:00 6/30/26 0:00 ZCA1(M1) 1895356 "MARTIN, JEFFREY N" "KAMBUGU, ANDREW DDUNGU" 11 PUBLIC HEALTH & PREV MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 124481 NCI 99123 25358 This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-038. Women in sub-Saharan Africa bear the greatest burden of cervical cancer in the world and thereasons are clear: lack of HPV vaccination screening for pre-cancer and treatment. In recognition of theglobal disparities surrounding cervical cancer and that preventive solutions exist the WHO has adopted aglobal strategy for cervical cancer elimination. It calls for 90% vaccination coverage 70% screeningcoverage and treatment of 90% of those with cervical disease. Lacking in this strategy however is a clearpath to implementation. Furthermore a shortage in the research workforce in areas most affected such assub-Saharan Africa hinders the ability for context-specific evidence to be generated to reduce the disparities. Through parent award U54 CA254571 we have developed in East Africa what we call a campaign-basedpublic health approach to address gaps in the implementation of preventive interventions for cervical cancercontrol. Our approach features Community Health Worker-led mobilization of eligible community members toattend local Health Fairs at which HPV vaccination and HPV-based cervical cancer screening (via self-collection) are offered followed by ablative therapy for those found to be HPV-infected by a Mobile TreatmentTeam at a convenient central site in the community. In Kenya and Uganda these community-basedcampaigns have been well-attended and well-accepted. NOT-CA-23-038 is a well-timed opportunity for us toexpand our work in East Africa to another resource-limited socio-geographic context Liberia in West Africa while concurrently providing a research practicum for an early-stage low- and middle-income country(LMIC) investigator (ESLI) from Liberia. Accordingly our specific aims are to: Aim 1: Evaluate the uptake and acceptability of HPV vaccination and cervical cancer screening offered through a campaign-based public health approach to cervical cancer control in Liberia. Aim 2: Determine the factors explaining non-participation in either community-based HPV vaccination among adolescent girls or in cervical cancer screening among women in Liberia. Aim 3: Provide a mentored career development experience for Dr. Cozie Gwaikolo a Liberian ESLI.To address our aims we will evaluate a community-based integrated cervical cancer vaccination andscreening program (developed in parent grant U54 CA254571) which will be implemented by our Ministry ofHealth (MOH) partners in Liberia. Evaluation will include assessment of acceptability and follow-up amongHealth Fair attendees as well as a population-based door-to-door community survey after completion of thecampaign which will determine uptake of the program and reasons for non-participation. Findings from thiswork may form a blueprint for the ultimate elimination of cervical cancer in the region. Finally the project isan incomparable opportunity for Dr. Gwaikolo in his quest to become an independent principal investigator. 124481 +No NIH Category available Acceleration;Administrative Supplement;Area;Award;California;Cancer Control;Center for Translational Science Activities;Clinical Research;Elements;Geographic Locations;Guidelines;HIV;Integrated Health Care Systems;Knowledge;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medical Sociology;Mentors;Methods;Modeling;National Comprehensive Cancer Network;Nigeria;Nigerian;Palliative Care;Personal Satisfaction;Pilot Projects;Recommendation;Research;Research Project Grants;Services;Teaching Hospitals;Time;Training;Universities;Woman;Women's Health;Work;acceptability and feasibility;care systems;career development;clinical care;community based participatory research;implementation framework;implementation research;implementation science;innovation;interest;low and middle-income countries;peer coaching;practice-based research network;professor;programs;response;skill acquisition;skills;sociology/anthropology ACCESS: Accelerating Cervical Cancer Elimination through the integration of Screen-and-treat Services PROJECT NARRATIVEWhile Palliative Care (PC) is a key component of the comprehensive cancer control program major challengesremain in making PC services accessible in low- and middle-income countries (LMICs). PC services remainsunderdeveloped and limited in scope and practice within Nigeria. In this study we aim to develop and explore thefeasibility and acceptability of a culturally adapted and integrated PC package to promote wellbeing of women livingwith HIV and cervical cancers. NCI 10846404 9/18/23 0:00 PA-20-272 3U01CA275118-02S1 3 U01 CA 275118 2 S1 "VEDHAM, VIDYA" 9/7/22 0:00 8/31/24 0:00 ZCA1(M2) 2792918 "AARONS, GREGORY " "EZEANOLUE, ECHEZONA EDOZIE" 50 PSYCHIATRY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 125000 NCI 124548 452 PROJECT SUMMARYMy proposal is a submission in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-038.I am an Assistant Professor of Medical Sociology and Anthropology and a Research Fellow at the Center forTranslation and Implementation Science (CTAIR) at the University of Nigeria Nsukka. My research focuses onpalliative care (PC) cancer and womens health in low- and middle-income countries (LMICs). Thisadministrative supplement mentor award will provide me with the support needed to achieve the following 3 keycareer development objectives for research in LMIC settings: (1) Sharpen my skills in community basedparticipatory research stakeholders engagement and program integration especially in PC clinical settings; (2)Acquire in-depth knowledge of implementation frameworks and methods to help close the gap betweenimplementation science and implementation practice; (3) Acquire skills and content expertise in PC research. Iwill conduct research and work with my mentors for a minimum of 40% of my time within the NigerianImplementation Science Alliance-Model Innovation and Research Centers (NISA-MIRCs) a practice-basedresearch network across the six geographical regions in Nigeria. To accomplish these objectives I have puttogether a mentoring team including: (1) a US Primary Mentor Prof. Gregory Aarons from University of CaliforniaSan Diego who is an expert in Implementation Science; (2) a LMIC Primary Mentor Prof. Echezona Ezeanoluefrom the University of Nigeria who is an expert in community-based participatory research and clinical research;(3) a LMIC Co-Mentor Dr Tonia Onyeka from University of Nigeria Teaching Hospital [UNTH] who is an expertin PC research and practice; (4) a LMIC Peer-Mentor Dr John Olawepo from Center of Translation andImplementation Research [CTAIR] who is an expert in health systems integration. My team of mentors willsupport my capacity building and research project which includes a pilot study to explore the feasibility andacceptability of a culturally adapted and integrated PC package to promote wellbeing of women living with HIV(WLHIV) and cervical cancers. My specific aims are to: (1) Co-create and develop feasible culturally adaptedand sustainable PC service package with WLHIV and cervical cancer from the NISA-MIRCs. We will adapt coreelements of PC services recommended in the National Comprehensive Cancer Network (NCCN) guideline usingwell-established mixed method approaches; and (2) Pilot the adapted multicomponent PC package to determinefeasibility and acceptability at two NISA-MIRCs facilities. During the year of this administrative award my Nigeria-and US-based mentors co-mentor and peer-mentor will provide additional training and guidance in their areasof expertise including implementation science community based participatory research PC and health systemsintegration. 125000 +No NIH Category available 8q24;Academic/Teacher Award;African American;American;Archives;Basic Science;Biological;Biological Markers;Blood;Chromosomes;Clinical;Comprehensive Cancer Center;DNA Methylation;DNA analysis;Data;Data Analyses;Data Discovery;Diagnostic;Disease;Disparity;Erectile dysfunction;European;Genetic Transcription;Genitourinary system;Genomic Segment;Gleason Grade for Prostate Cancer;Goals;Incidence;Individual;Lead;Literature;MYC gene;Malignant Neoplasms;Malignant neoplasm of prostate;Maryland;Mentors;Methylation;Microarray Analysis;Modeling;Molecular;Molecular Epidemiology;Molecular Epidemiology of Cancer;Oncologist;Oncology;Outcome;Pathology;Patient-Focused Outcomes;Pilot Projects;Prognosis;Prognostic Marker;Prospective Studies;Prostate;Prostatic Neoplasms;Public Health;Race;Radical Prostatectomy;Reporting;Research;Research Personnel;Risk;Sampling;Technology;Tissues;Training;Tumor Markers;Tumor Tissue;United States;Universities;Urinary Incontinence;aggressive therapy;biomarker identification;biomarker signature;blood-based biomarker;cancer health disparity;career;clinically significant;disparity reduction;epidemiology study;epigenome;epigenomics;experience;follow-up;health disparity;high dimensionality;improved;improved outcome;individual patient;insight;man;men;methylation biomarker;mortality;mortality disparity;multidimensional data;novel marker;outcome disparities;patient population;personalized management;personalized medicine;prognostic;prognostication;prospective;risk stratification;tissue biomarkers;transcriptome;transcriptomics;treatment strategy Epigenomic and transcriptomic markers of aggressive prostate cancer among African American men Project narrative:The overall public health objective of this proposed study is to identify biomarkers that will improve risk-stratification for African American men with prostate cancer who bear a disproportionate burden of aggressivedisease and prostate cancer mortality but have been underrepresented in previous studies. This research inturn will allow for more personalized treatment/management strategies that have potential to improve patientoutcomes and reduce disparities in prostate cancer mortality. NCI 10846346 8/9/23 0:00 PA-20-272 3K07CA230182-05S1 3 K07 CA 230182 5 S1 "BIAN, YANSONG" 7/15/18 0:00 6/30/24 0:00 10876548 "BARRY, KATHRYN HUGHES" Not Applicable 7 PUBLIC HEALTH & PREV MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 135511 NCI 125473 10038 PROJECT SUMMARY African American men experience a disproportionate burden of aggressive prostate cancer andprostate cancer mortality when compared with European American men. The underlying reason for thedisparity is unclear and the ability to predict an individual patients disease trajectory remains limited. Thismakes treatment decisions difficult particularly as available treatments range widely from active surveillance toradical prostatectomy which can have severe consequences such as urinary incontinence and erectiledysfunction. There is growing evidence to support the potential of DNA methylation (DNAm) and RNAexpression markers in prostate tumors to enhance prostate cancer prognostication beyond clinical factors butfew studies to date have focused on African American men. The present pilot study will leverage a unique patient population (>40% African American) and archivalradical prostatectomy prostate tissue from the University of Maryland Greenebaum Comprehensive CancerCenter. Aims 1 and 2 propose to leverage array-based technology to investigate whether DNAm and RNAexpression markers can discriminate between aggressive (total Gleason score>=7) and non-aggressiveprostate cancer (total Gleason score<7) in African American men. We will use Gleason score as our endpointbecause it is available for all samples and because recent studies have supported its utility as an intermediateendpoint in the discovery of prognostic markers. Aim 3 proposes integrated analyses of DNAm and RNAexpression data to investigate the hypothesis that some DNAm markers are associated with aggressivedisease independently of expression thereby providing unique prognostic information. The K07 mechanism will allow me to receive essential training in the integration/application of tumortissue biomarkers in epidemiological studies and analysis of high-dimensional data under the guidance of astrong team of mentors with synergistic expertise in molecular epidemiology prostate tumor biomarkers highdimensional data analysis and predictive oncology modeling. This project will also include an additional advisorwho is a genitourinary oncologist and basic science researcher in prostate cancer and will contribute to theinterpretation and assessment of clinical significance of findings. My previous research has focused on blood-based biomarkers in targeted genomic regions and I will greatly benefit from specialized training in tumortissue markers and expanding to high-dimensional data as I move towards independence in molecular cancerepidemiology. Moreover this study will provide preliminary data that will build toward a larger (R01) applicationin which I will integrate epigenomic and transcriptomic data for the discovery of novel biomarkers of aggressiveprostate cancer among African American men. My long-term goal is to lead studies that will promote improvedpublic health and reduce disparities in cancer outcomes through personalized medicine. 135511 +No NIH Category available Acetic Acids;Adopted;Adoption;Artificial Intelligence;Attitude;Awareness;Behavior Therapy;Behavioral;Cancer Control;Caring;Cervical Cancer Screening;Cervix Uteri;Client;Clinic;Cold Therapy;Collaborations;Communication;Communities;Country;Databases;Decision Aid;Decision Making;Diagnosis;Education;Effectiveness;Evaluation;Focus Groups;Future;Goals;Grant;Gynecologic Oncologist;HIV;HIV Seropositivity;Health;Health Personnel;Health Professional;Health Status;Health care facility;Home;Image;Infrastructure;Intention;Interdisciplinary Study;Iodine;Journals;Lesion;Malignant neoplasm of cervix uteri;Manuscripts;Mentors;Modality;Modeling;Mothers;Nigeria;Nigerian;Nongovernmental Organizations;Nurses;Patient Monitoring;Patients;Perception;Phase;Physicians;Prevention;Public Health;Public Health Practice;Publications;Reach Effectiveness Adoption Implementation and Maintenance;Receiver Operating Characteristics;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resource-limited setting;Risk;Sampling;Science;Scientist;Secure;Series;Services;Site;Stains;Technology;Telephone;Testing;Time;Training;Training Activity;Translating;Visual;Woman;Women's Group;Work;World Health Organization;Writing;care recipients;chatbot;clinical epidemiology;compliance behavior;design;diagnostic accuracy;epidemiological model;epidemiology study;experience;follow-up;global health;health care settings;implementation framework;implementation process;improved;innovation;interest;peer;premalignant;programs;psychosocial;response;satisfaction;scale up;screening;screening services;skill acquisition;skills;social media;statistics;treatment services;treatment strategy;virtual The CHESS (Community Home-based Education Screening Services) Strategy to increase cervical cancer control access for HIV positive women in Nigeria Project NarrativeDespite the increased risk of cervical cancer for women living with HIV access to cervical cancer screening inNigeria is limited. We will leverage existing HIV treatment infrastructure in Nigeria to integrate cervical cancercontrol activities into the successful MoMent (MOther MENTor) peer-based HIV support program. Usingimplementation science frameworks we will implement and evaluate the sustainability of the adapted MoMentHIV + Homebased Cervical Cancer program to advance cervical cancer control in Nigerian women living withHIV. NCI 10846292 9/13/23 0:00 PA-20-272 3U01CA275113-02S1 3 U01 CA 275113 2 S1 "VEDHAM, VIDYA" 9/1/22 0:00 8/31/27 0:00 ZCA1(M2) 1872503 "FLOWERS, LISA C." "GAYDOS, LAURA M" 5 OBSTETRICS & GYNECOLOGY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 125000 NCI 119054 5946 "Project SummaryThis application is being submitted in response to the Notice of Special Interest (NOSI) NOT-CA-23-038. The candidate Oluseye Ajayi is a Senior Science Officer and Prevention Advisor in a non -governmental organization APIN Public Health Initiatives in Nigeria. The goals of his application areto use the protected time provided through the program to (1) Build and strengthen mentoringrelationships and skills transfer through regular interactions with mentors and co-mentors; (2) Acquireexperiential skills in clinical epidemiologic research and be able to translate this to public healthpractice (3) Conduct the rigorous research proposed in the application; (4) Acquire skills inepidemiological modeling and artificial intelligence; (5) Establish research collaboration network andeffectively coordinate multidisciplinary research projects and (6) Be able to write secure and managegrants to conduct studies as well as write manuscripts for publication in high-impact journals.The proposed research titled AVIVA-AI Mentored Approach to Building Artificial Intelligence is aimedat utilizing artificial intelligence (AI) matching strategy to design and integrate a client-oriented chatbotto an existing app ""AVIVA"" used in improving cervical cancer screening among women living with HIV(WLWH) in Nigeria. In AIM 1 we will design deploy and integrate the chatbot into the AVIVA app usinga multi-stage implementation model. In stage 1 we will gather WLWH questions and concerns aboutcervical screening and treatment over 3 months through a deployed real-time social media platform-WhatsApp manned by virtual support health care professionals (HCP). The questions and responsesgathered from the social media platform will be used to build pre-defined information on an offlinechatbot. In stage 2 the built chatbot will be deployed for real-time online utilization by the recipient ofcare (ROCs) and AI-matching of questions and concerns on a small scale and the chatbot responseappropriateness to ROCs questions will be assessed over 3 months by expert gynecologic-oncologist.In stage 3 the chatbot will be scaled up for utilization across HIV clinics in the two selected states. InAIM 2 we will conduct a brief assessment of WLWH Chatbot technology experience behavioralintention to continue using the technology and their perception of technology scalability among WLWHin HIV settings in Nigeria while the full evaluation of the innovation (AIM 3) is proposed forimplementation in future grant opportunities.This application builds on the candidates background experience and the expertise of his team ofmentors and co-mentors in Nigeria and the US to achieve the training and research goals of thisprogram. In the long term the proposed research and training activities will provide the candidate witha unique set of experiential skills that will enable him to transition to independence as a scientist." 125000 +No NIH Category available Acute Megakaryocytic Leukemias;Affect;Animal Model;Binding;Biological;Biological Assay;Cell Death;Cell Line;Cells;Chimeric Proteins;Chromatin;Complex;Coupled;DNA;Data;Data Set;Dependence;Development;Disease;Dominant-Negative Mutation;Doxycycline;Event;Fetal Liver;Fusion Protein Expression;Gene Expression;Genes;Genetic Engineering;Genetic Transcription;Genomic approach;Growth;Hematopoietic;Human;Immunoprecipitation;Individual;Knock-in Mouse;Light;Link;Malignant Neoplasms;Maps;Mediating;Megakaryocytes;Messenger RNA;Methylation;Methyltransferase;Mission;Modeling;Modification;Molecular;Mus;Mutation;Oncogenes;Oncogenic;Pathway interactions;Patients;Play;Publishing;RNA;RNA Stability;RNA metabolism;RNA methylation;Recurrence;Regulation;Role;Sampling;Serum Response Factor;Site;Testing;Therapeutic;Transcript;Translations;United States National Institutes of Health;Xenograft procedure;acute megakaryoblastic leukemia cell;cancer type;clinically relevant;cofactor;crosslink;epitranscriptome;genome-wide analysis;improved;inducible gene expression;innovation;insight;leukemia;leukemogenesis;novel;overexpression;posttranscriptional;prevent;programs;promoter;recruit;response;tRNA Methyltransferases;transcription factor;transcriptome sequencing;translatome;treatment optimization;tumorigenesis Mechanisms of Leukemogenesis in AMKL PROJECT NARRATIVEThis project is focused on the fundamental molecular mechanisms underlying leukemia.Highly relevant to the mission of the NIH the data obtained will provide new insightsinto how modifications to RNA by oncogenes can lead to cancer. The highly innovative studies will reveal novel targets that can be applied to the development of improved therapeutic approaches for other cancer types as well. NCI 10845929 6/22/23 0:00 PA-19-056 4R01CA222518-02 4 R01 CA 222518 2 "KLAUZINSKA, MALGORZATA" 5/1/20 0:00 4/30/25 0:00 Molecular Oncogenesis Study Section[MONC] 1859405 "KRAUSE, DIANE S" "HALENE, STEPHANIE " 3 PATHOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 662414 NCI 395471 266943 Project Summary/Abstract Fundamental analysis of the mechanisms of leukemogenesis is required in order to develop optimizedtreatment approaches. N6-methyladenosine (m6A) the most abundant RNA modification plays key roles in RNA metabolism transcript stability and translation efficiency. Aberrant regulation of m6A writers and erasers contributes to leukemogenesis though the exact mechanisms how the methyltransferase machinery is altered in leukemia remains to be shown. Mutations in methyltransferase writers have not been identified to date with one exception: in the recurrent t(1;22) translocation in acute megakaryoblastic leukemia (AMKL) a component of the m6A writer machinery RBM15 is fused with MKL1 a transcriptional cofactor of serum response factor (SRF). Understanding the mechanism by which the RBM15-MKL1 (RM) fusion protein causes leukemia will shed light on the role of disordered m6A RNA methylation in leukemogenesis specifically AMKL but also AML and to cancer in general. We hypothesize that for RM-associated AMKL to develop the MKL1 domain aberrantly targets RBM15 activity to sites of SRF binding and that RBM15 recruits the m6A writer complex to associated RNAsaltering m6A mRNA methylation and expression of genes that are required for transformation and/or are important for megakaryocyte fate commitment and maturation. We propose focused unbiased genome-wide studies to determine how the m6A epitranscriptome and the SRF transcriptional networks are coopted in RBM15-MKL1 AMKL. The functional effects of candidate target genes common to the genomic approaches (m6A RNA immunoprecipitation chromatin mapping RNA stability assays and mapping of the translatome) as well as the relevance of critical domains in RM-mediated leukemogenesis will be tested with assays of growth differentiation and oncogene dependence in RM-induced murine AMKL as well as primary human AMKL patient derived xenotransplants (PDX). The studies are highly clinically relevant as they address a unique mechanism causative of AMKL via comprehensive analysis of fundamental biologic mechanisms and will reveal previously unidentified regulation of the epitranscriptome that may be a novel shared oncogenic mechanism in AML and other cancers. The proposed approaches are multifaceted using cell lines as well as genetically engineered animal models and primary human and murine leukemia samples. The studies will contribute to our understanding of leukemogenesis by elucidating the direct role of a component of the m6A RNA methylase complex in leukemia shedding light on the broader role of m6A mRNA modifications in AML. 662414 +No NIH Category available Address;Binding;Binding Proteins;Biochemical;Biological Assay;Calibration;Cell Nucleus;Cells;Cellular Assay;Child;Chimeric Proteins;Chromatin;Clinical Trials;Collaborations;Complex;Coupled;Couples;DNA;DNA Binding;Data;Development;Digestion;Disease;Drug Targeting;Environment;Experimental Drug Development;Functional disorder;Fusion Oncogene Proteins;Gene Expression;Gene Fusion;Genetic;Genetic Transcription;Genome;Goals;Human Genome;Inflammation;Instruction;Label;Length;Leukemic Cell;Maintenance;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Methods;Mixed-Lineage Leukemia;Modeling;Multiprotein Complexes;National Cancer Institute;Neurologic;Nuclear;Oncogenes;Oncogenic;Organelles;Patients;Peptides;Performance;Pharmaceutical Preparations;Pharmacological Treatment;Phase;Proteins;Proteome;Proteomics;Recurrence;Regulator Genes;Reporting;Research;Science;Small Business Innovation Research Grant;Sodium Chloride;Specificity;Stimulus;Structural Protein;System;Talus;Technology;Testing;Therapeutic;Tissues;Universities;Validation;Variant;Washington;cancer cell;cancer type;cofactor;commercialization;data quality;drug candidate;drug development;drug discovery;genetic regulatory protein;in vitro activity;inhibitor;invention;leukemia;member;pharmacologic;prevent;quality assurance;response;sarcoma;screening;small molecule;small molecule inhibitor;technology development;tool;transcription factor;tumor Simultaneous pharmacological profiling of oncogenic gene fusion proteins in cancer PROJECT NARRATIVEThis research aims to develop a technology to enable drug development for gene regulators incancer. Traditional tools to study these proteins have proven ineffective so we are developingan in-cell system that specifically tests a drugs ability to block cancer-causing gene regulators. NCI 10845876 6/16/23 0:00 RFA-CA-21-001 4R44CA268146-02 4 R44 CA 268146 2 "BOZZA, WILLIAM PATRICK" 7/1/23 0:00 6/30/25 0:00 ZCA1-TCRB-V(A1) 14641875 "FEDERATION, ALEXANDER " Not Applicable 9 Unavailable 117669625 NKSRDDRQK175 117669625 NKSRDDRQK175 US 47.511928 -122.162788 10063986 "TALUS BIOSCIENCE, INC." RENTON WA Domestic For-Profits 980593610 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 SBIR/STTR 2023 1000000 NCI 667557 267023 RESEARCH SUMMARYThe human genome encodes more than 1600 transcription factors (TFs) along with additionalcofactors chromatin regulators and structural proteins that collectively execute the regulatoryinstructions encoded within the nuclear DNA. Dysfunctions of these proteins collectively knownas Gene Regulatory Proteins (GRPs) are known to drive multiple diseases such as cancerinflammation-related and neurological conditions. In cancer these proteins are frequentlyrearranged and fused to create new proteins which cause the initiation and progression ofvarious types of leukemia sarcoma and other tumors. Despite the importance of these proteinsGRPs have been considered undruggable due to challenges in modeling their activity in vitro.We have solved these shortcomings by implementing an in-cell functional proteomics drugdiscovery platform that quantifies the effects of small-molecules on the abundance of GRPsbound to the genome in a diversity of cell and tissue types. The platform is based on ChromatinExtraction by Salt Separation coupled to Data Independent Analysis mass spectrometry(ChESS-DIA) which was recently reported. In this proposal we will apply this technology fordrug development of oncogenic fusion proteins. First we will use Mixed Lineage Leukemia(MLL) rearranged leukemia to perform technology development of the oncogenic fusion proteinproteomics strategy. MLL rearrangements are found in a subset of AML and ALL patientscommonly in children and remain challenging to treat with existing therapeutic options. Severaldrug candidates for MLL-rearranged leukemia are currently in clinical trials and these will beused to validate the accuracy of the ChESS-DIA assay for reporting the ability of MLL-targetingcompounds to disrupt the MLL complex in live cells. With a validated MLL ChESS-DIA assaywe will then conduct a pilot screen to prove the assays utility in a screening setting using theNational Cancer Institutes Mechanistic Diversity compound set supplemented with knowninhibitors of the MLL complex. These compounds contain a diverse array of bioactivities manyof which act through unknown mechanisms. This provides an opportunity to find newcompounds capable of disrupting the MLL complex. Lastly we will use the roadmap developedfor MLL to develop ChESS-DIA assays for many of the common oncogenic fusions thendevelop a method to unify these assays together in a single unified in-cell assay for oncogenicfusion proteins. 1000000 +No NIH Category available Address;Adult;Agreement;Antigens;Area;Autologous;B-Cell Acute Lymphoblastic Leukemia;B-Lymphocytes;Back;Biological;Brain Neoplasms;CAR T cell therapy;Cancer Patient;Cancer Relapse;Cell Therapy;Cell physiology;Characteristics;Child;Childhood;Childhood Cancer Treatment;Childhood Leukemia;Childhood Solid Neoplasm;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Complex;Coupled;Coupling;Custom;Cytometry;Data;Data Collection;Databases;Development;Disease;Engineering;Generations;Genetic Engineering;Heart;Hematologic Neoplasms;Immune;Immune Evasion;Immunosuppression;Immunotherapy;Knowledge;Learning;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant lymphoid neoplasm;Mass Spectrum Analysis;Methods;Modeling;Mutation;Neuroblastoma;Operative Surgical Procedures;Patients;Pediatric Neoplasm;Pediatric Oncology;Plasma Cells;Pre-Clinical Model;Primary Neoplasm;Program Development;Protein Engineering;Radiation;Refractory;Relapse;Research Design;Research Personnel;Resistance;Route;Solid;Solid Neoplasm;Structure;Surface Antigens;Survival Rate;Survivors;System;T cell therapy;T-Lymphocyte;Technology;Testing;Text;Therapeutic;Toxic effect;Translating;Vision;Work;Xenograft procedure;bench to bedside;cancer cell;cancer type;cellular engineering;chemotherapy;childhood sarcoma;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;clinical translation;comorbidity;data complexity;data integration;data sharing;design;diffuse midline glioma;engineered T cells;high risk;immune checkpoint blockade;improved;in vivo;in vivo Model;manufacture;neoplastic cell;next generation;novel;phase I trial;pre-clinical;preclinical development;programs;receptor;response;sharing platform;small molecule;standard of care;tumor;tumor heterogeneity;tumor microenvironment NGTC - INSERM No Text NCI 10845786 8/1/23 0:00 RFA-OT-A2-013 3OT2CA279634-01S1 3 OT2 CA 279634 1 S1 "SINGH, ANJU" 7/8/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78605485 "DONNADIEU, EMMANUEL " Not Applicable n/a Unavailable 735277618 FKH8SLAU3ZY5 735277618 FKH8SLAU3ZY5 FR 48.85341 2.3488 10023550 INSERM PARIS 5 PARIS Unavailable 75013 FRANCE N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 55041 NCI 73964 0 Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies solid cancers are challenging due to a lack of targets tumor heterogeneity and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function WP4 will mostly use intact tumor models such as immune PDXs. In WP5 clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies improving cure rates and mitigation of long-term toxicity to realize our Vision. 55041 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN - SALK n/a NCI 10845781 7/31/23 0:00 RFA-OT-A2-013 3OT2CA278714-01S1 3 OT2 CA 278714 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 10222630 "AYRES, JANELLE S" Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 357827 NCI 188330 169497 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 357827 +No NIH Category available Address;Aging;Alcohol consumption;Architecture;Bioinformatics;Biological;Biological Models;Body Weight decreased;Breast;CRISPR screen;Cancer Etiology;Cancer Model;Cells;Clonal Evolution;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Colorectal;Communities;Country;DNA;Data;Data Set;Development;Endogenous Factors;Endometrial;Environment;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Event;Excision;Exposure to;Gene Expression;Generations;Genetic;Genomics;Goals;High-Risk Cancer;Human;Individual;Inflammation;Intervention;Intervention Studies;Investigation;Life Style;Limited Stage;Link;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Maps;Measures;Methods;Modeling;Molecular;Molecular Target;Mus;Mutate;Mutation;Neoplasms;Normal Cell;Normal tissue morphology;Obesity;Organoids;Pathway Analysis;Pathway interactions;Pattern;Phenotype;Population;Prevalence;Process;Proteome;Proteomics;Research Personnel;Risk;Risk Factors;Role;Route;Sampling;Structure of parenchyma of lung;Testing;Time;Tissue Donors;Tissue Sample;Tissue imaging;Tissues;Tumor Promoters;Tumor Promotion;Tumor Tissue;Tumor stage;Unhealthy Diet;anticancer research;cancer prevention;cancer risk;carcinogenesis;cellular targeting;chemical property;chemotherapy;data integration;detection method;driver mutation;environmental agent;epidemiology study;epigenomics;experience;genome-wide;hematopoietic tissue;human tissue;immune cell infiltrate;in vivo Model;inhibitor;innovation;lifestyle factors;mouse model;multidisciplinary;neoplastic;novel;promoter;response;small molecule;smoking cessation;stem;stem cells;tool;transcriptomics;tumor;tumorigenesis;whole genome PROMINENT - Stanford n/a NCI 10845780 9/22/23 0:00 RFA-OT-A2-013 3OT2CA278713-01S1 3 OT2 CA 278713 1 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 15401017 "LUNDBERG, EMMA " Not Applicable 16 BIOMEDICAL ENGINEERING 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 744867 NCI 533489 211378 The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA either spontaneous or environmentally induced are essential for cancer development recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated but most of the emphasis has been on the origins of the driver mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity alcohol consumption inflammation and poor diet in cancer risk it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast recent sequencing studies have uncovered abundant mutations in normal human tissues suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models some carried out more than 50 years ago showing that promotion is the rate-limiting step in tumour development.To identify the mechanisms that control mutated normal cells and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology genetics computational network analysis and machine learning tissue imaging of gene expression single cell transcriptomics and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples together with detailed intervention studies in human populations mouse models and human organoids will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents. 744867 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC - UCL n/a NCI 10845779 8/21/23 0:00 RFA-OT-A2-013 3OT2CA278702-01S1 3 OT2 CA 278702 1 S1 "FINGERMAN, IAN M" 9/6/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78683333 "JAMAL-HANJANI, MARIAM " Not Applicable n/a Unavailable 225410919 KSBTBM8584V1 225410919 KSBTBM8584V1 UK 51.50853 -0.12574 3527409 UNIVERSITY COLLEGE LONDON LONDON Unavailable WC1E 6BT UNITED KINGDOM N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 273299 NCI 253517 19782 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 273299 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANcer Cachexia Action Network/CANCAN n/a NCI 10845778 8/22/23 0:00 RFA-OT-A2-013 3OT2CA278701-01S1 3 OT2 CA 278701 1 S1 "WATSON, JOANNA M" 9/8/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78683333 "JAMAL-HANJANI, MARIAM " Not Applicable n/a Unavailable 225410919 KSBTBM8584V1 225410919 KSBTBM8584V1 UK 51.50853 -0.12574 3527409 UNIVERSITY COLLEGE LONDON LONDON Unavailable WC1E 6BT UNITED KINGDOM N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 180544 NCI 174622 13970 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 180544 +No NIH Category available Address;Adult;Agreement;Antigens;Area;Autologous;B-Cell Acute Lymphoblastic Leukemia;B-Lymphocytes;Back;Biological;Brain Neoplasms;CAR T cell therapy;Cancer Patient;Cancer Relapse;Cell Therapy;Cell physiology;Characteristics;Child;Childhood;Childhood Cancer Treatment;Childhood Leukemia;Childhood Solid Neoplasm;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Complex;Coupled;Coupling;Custom;Cytometry;Data;Data Collection;Databases;Development;Disease;Engineering;Generations;Genetic Engineering;Heart;Hematologic Neoplasms;Immune;Immune Evasion;Immunosuppression;Immunotherapy;Knowledge;Learning;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant lymphoid neoplasm;Mass Spectrum Analysis;Methods;Modeling;Mutation;Neuroblastoma;Operative Surgical Procedures;Patients;Pediatric Neoplasm;Pediatric Oncology;Plasma Cells;Pre-Clinical Model;Primary Neoplasm;Program Development;Protein Engineering;Radiation;Refractory;Relapse;Research Design;Research Personnel;Resistance;Route;Solid;Solid Neoplasm;Structure;Surface Antigens;Survival Rate;Survivors;System;T cell therapy;T-Lymphocyte;Technology;Testing;Text;Therapeutic;Toxic effect;Translating;Vision;Work;Xenograft procedure;bench to bedside;cancer cell;cancer type;cellular engineering;chemotherapy;childhood sarcoma;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;clinical translation;comorbidity;data complexity;data integration;data sharing;design;diffuse midline glioma;engineered T cells;high risk;immune checkpoint blockade;improved;in vivo;in vivo Model;manufacture;neoplastic cell;next generation;novel;phase I trial;pre-clinical;preclinical development;programs;receptor;response;sharing platform;small molecule;standard of care;tumor;tumor heterogeneity;tumor microenvironment NextGen - CRI No Text NCI 10845777 9/1/23 0:00 RFA-OT-A2-013 3OT2CA278700-01S1 3 OT2 CA 278700 1 S1 "SINGH, ANJU" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 8160777 "BOLLARD, CATHERINE M." Not Applicable 98 Unavailable 143983562 M3KHEEYRM1S6 143983562 M3KHEEYRM1S6 US 38.927274 -77.014396 1518602 CHILDREN'S RESEARCH INSTITUTE WASHINGTON DC Research Institutes 200102916 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 738441 NCI 477999 391959 Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies solid cancers are challenging due to a lack of targets tumor heterogeneity and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function WP4 will mostly use intact tumor models such as immune PDXs. In WP5 clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies improving cure rates and mitigation of long-term toxicity to realize our Vision. 738441 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC - FREDHUTCH n/a NCI 10845776 7/31/23 0:00 RFA-OT-A2-013 3OT2CA278693-01S1 3 OT2 CA 278693 1 S1 "FINGERMAN, IAN M" 6/24/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 8039624 "MALIK, HARMIT S" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 93187 NCI 90816 69020 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 93187 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC - SCRIPPS n/a NCI 10845774 7/28/23 0:00 RFA-OT-A2-013 3OT2CA278692-01S1 3 OT2 CA 278692 1 S1 "FINGERMAN, IAN M" 6/24/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 2132494 "CRAVATT, BENJAMIN F" Not Applicable 50 Unavailable 781613492 PHZJFZ32NKH4 781613492 PHZJFZ32NKH4 US 32.903062 -117.243592 7375802 "SCRIPPS RESEARCH INSTITUTE, THE" LA JOLLA CA Other Domestic Non-Profits 920371000 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 334504 NCI 188453 146051 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 334504 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN - Kaiser n/a NCI 10845773 8/4/23 0:00 RFA-OT-A2-013 3OT2CA278691-01S1 3 OT2 CA 278691 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 1968571 "CAAN, BETTE J" Not Applicable 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 459366 NCI 408174 157724 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 459366 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN - COLDSPRING n/a NCI 10845772 7/31/23 0:00 RFA-OT-A2-013 3OT2CA278690-01S1 3 OT2 CA 278690 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 15723236 "JANOWITZ, TOBIAS " Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 386428 NCI 222825 204999 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 386428 +No NIH Category available Address;Adult;Agreement;Antigens;Area;Autologous;B-Cell Acute Lymphoblastic Leukemia;B-Lymphocytes;Back;Biological;Brain Neoplasms;CAR T cell therapy;Cancer Patient;Cancer Relapse;Cell Therapy;Cell physiology;Characteristics;Child;Childhood;Childhood Cancer Treatment;Childhood Leukemia;Childhood Solid Neoplasm;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Complex;Coupled;Coupling;Custom;Cytometry;Data;Data Collection;Databases;Development;Disease;Engineering;Generations;Genetic Engineering;Heart;Hematologic Neoplasms;Immune;Immune Evasion;Immunosuppression;Immunotherapy;Knowledge;Learning;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant lymphoid neoplasm;Mass Spectrum Analysis;Methods;Modeling;Mutation;Neuroblastoma;Operative Surgical Procedures;Patients;Pediatric Neoplasm;Pediatric Oncology;Plasma Cells;Pre-Clinical Model;Primary Neoplasm;Program Development;Protein Engineering;Radiation;Refractory;Relapse;Research Design;Research Personnel;Resistance;Route;Solid;Solid Neoplasm;Structure;Surface Antigens;Survival Rate;Survivors;System;T cell therapy;T-Lymphocyte;Technology;Testing;Text;Therapeutic;Toxic effect;Translating;Vision;Work;Xenograft procedure;bench to bedside;cancer cell;cancer type;cellular engineering;chemotherapy;childhood sarcoma;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;clinical translation;comorbidity;data complexity;data integration;data sharing;design;diffuse midline glioma;engineered T cells;high risk;immune checkpoint blockade;improved;in vivo;in vivo Model;manufacture;neoplastic cell;next generation;novel;phase I trial;pre-clinical;preclinical development;programs;receptor;response;sharing platform;small molecule;standard of care;tumor;tumor heterogeneity;tumor microenvironment NextGen - CHOP No Text NCI 10845769 8/4/23 0:00 RFA-OT-A2-013 3OT2CA278687-01S1 3 OT2 CA 278687 1 S1 "SINGH, ANJU" 6/24/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 1938303 "MARIS, JOHN M" Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 537702 NCI 361794 274963 Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies solid cancers are challenging due to a lack of targets tumor heterogeneity and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function WP4 will mostly use intact tumor models such as immune PDXs. In WP5 clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies improving cure rates and mitigation of long-term toxicity to realize our Vision. 537702 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN ? CORNELL n/a NCI 10845767 8/4/23 0:00 RFA-OT-A2-013 3OT2CA278685-01S1 3 OT2 CA 278685 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 8791247 "GONCALVES, MARCUS DASILVA" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 318225 NCI 244509 162999 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 318225 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN - PENNINGTON n/a NCI 10845766 9/18/23 0:00 RFA-OT-A2-013 3OT2CA278684-01S1 3 OT2 CA 278684 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 11981520 "BROWN, JUSTIN C" Not Applicable 6 Unavailable 611012324 MWYVQTQ32ME5 611012324 MWYVQTQ32ME5 US 30.403353 -91.122687 577909 LSU PENNINGTON BIOMEDICAL RESEARCH CTR BATON ROUGE LA Domestic Higher Education 708084124 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 230310 NCI 203089 101545 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 230310 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC-TEXASSW n/a NCI 10845765 7/28/23 0:00 RFA-OT-A2-013 3OT2CA278683-01S1 3 OT2 CA 278683 1 S1 "FINGERMAN, IAN M" 6/24/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 7998706 "CHEN, ZHIJIAN J" Not Applicable 30 BIOCHEMISTRY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 380633 NCI 259584 166134 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 380633 +No NIH Category available Address;Aging;Alcohol consumption;Architecture;Bioinformatics;Biological;Biological Models;Body Weight decreased;Breast;CRISPR screen;Cancer Etiology;Cancer Model;Cells;Clonal Evolution;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Colorectal;Communities;Country;DNA;Data;Data Set;Development;Endogenous Factors;Endometrial;Environment;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Event;Excision;Exposure to;Gene Expression;Generations;Genetic;Genomics;Goals;High-Risk Cancer;Human;Individual;Inflammation;International Agency for Research on Cancer;Intervention;Intervention Studies;Investigation;Life Style;Limited Stage;Link;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Maps;Measures;Methods;Modeling;Molecular;Molecular Target;Mus;Mutate;Mutation;Neoplasms;Normal Cell;Normal tissue morphology;Obesity;Organoids;Pathway Analysis;Pathway interactions;Pattern;Phenotype;Population;Prevalence;Process;Proteome;Proteomics;Research Personnel;Risk;Risk Factors;Role;Route;Sampling;Structure of parenchyma of lung;Testing;Time;Tissue Donors;Tissue Sample;Tissue imaging;Tissues;Tumor Promoters;Tumor Promotion;Tumor Tissue;Tumor stage;Unhealthy Diet;anticancer research;cancer prevention;cancer risk;carcinogenesis;cellular targeting;chemical property;chemotherapy;data integration;detection method;driver mutation;environmental agent;epidemiology study;epigenomics;experience;genome-wide;hematopoietic tissue;human tissue;immune cell infiltrate;in vivo Model;inhibitor;innovation;lifestyle factors;mouse model;multidisciplinary;neoplastic;novel;promoter;response;small molecule;smoking cessation;stem;stem cells;tool;transcriptomics;tumor;tumorigenesis;whole genome PROMINENT - IARC n/a NCI 10845761 8/4/23 0:00 RFA-OT-A2-013 3OT2CA278681-01S1 3 OT2 CA 278681 1 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 6717605 "BRENNAN, PAUL JOSEPH" Not Applicable n/a Unavailable 279551881 HSMZYXZ7M358 279551881 HSMZYXZ7M358 FR 45.74846 4.84671 337706 INTERNATIONAL AGENCY FOR RES ON CANCER LYON Unavailable 69007 FRANCE N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 450879 NCI 479861 19946 The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA either spontaneous or environmentally induced are essential for cancer development recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated but most of the emphasis has been on the origins of the driver mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity alcohol consumption inflammation and poor diet in cancer risk it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast recent sequencing studies have uncovered abundant mutations in normal human tissues suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models some carried out more than 50 years ago showing that promotion is the rate-limiting step in tumour development.To identify the mechanisms that control mutated normal cells and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology genetics computational network analysis and machine learning tissue imaging of gene expression single cell transcriptomics and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples together with detailed intervention studies in human populations mouse models and human organoids will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents. 450879 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC-QMUL n/a NCI 10845760 7/28/23 0:00 RFA-OT-A2-013 3OT2CA278670-01S1 3 OT2 CA 278670 1 S1 "FINGERMAN, IAN M" 6/24/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78669589 "HUANG, WEINI " Not Applicable n/a Unavailable 231822839 THE2VARBDFC5 231822839 THE2VARBDFC5 UK 51.50853 -0.12574 3527424 UNIV/LONDON-QUEEN MARY& WESTFIELD COLL LONDON Unavailable E1 4NS UNITED KINGDOM N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 29372 NCI 181826 14546 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 29372 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN - Cambridge n/a NCI 10845759 7/31/23 0:00 RFA-OT-A2-013 3OT2CA278669-01S1 3 OT2 CA 278669 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 16008535 "BIFFI, GIULIA " "O'RAHILLY, STEPHEN " n/a Unavailable 226552610 LY2ZWNG2HKF8 226552610 LY2ZWNG2HKF8 UK 52.2 0.11667 1113401 UNIVERSITY OF CAMBRIDGE CAMBRIDGE Unavailable CB2 1TN UNITED KINGDOM N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 179137 NCI 324687 25975 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 179137 +No NIH Category available Address;Aging;Alcohol consumption;Architecture;Bioinformatics;Biological;Biological Models;Body Weight decreased;Breast;CRISPR screen;Cancer Etiology;Cancer Model;Cells;Clonal Evolution;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Colorectal;Communities;Country;DNA;Data;Data Set;Development;Endogenous Factors;Endometrial;Environment;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Event;Excision;Exposure to;Gene Expression;Generations;Genetic;Genomics;Goals;High-Risk Cancer;Human;Individual;Inflammation;Institutional Review Boards;Intervention;Intervention Studies;Investigation;Life Style;Limited Stage;Link;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Maps;Measures;Methods;Modeling;Molecular;Molecular Target;Mus;Mutate;Mutation;Neoplasms;Normal Cell;Normal tissue morphology;Obesity;Organoids;Pathway Analysis;Pathway interactions;Pattern;Phenotype;Population;Prevalence;Process;Proteome;Proteomics;Research Personnel;Risk;Risk Factors;Role;Route;Sampling;Structure of parenchyma of lung;Testing;Time;Tissue Donors;Tissue Sample;Tissue imaging;Tissues;Tumor Promoters;Tumor Promotion;Tumor Tissue;Tumor stage;Unhealthy Diet;anticancer research;cancer prevention;cancer risk;carcinogenesis;cellular targeting;chemical property;chemotherapy;data integration;detection method;driver mutation;environmental agent;epidemiology study;epigenomics;experience;genome-wide;hematopoietic tissue;human tissue;immune cell infiltrate;in vivo Model;inhibitor;innovation;lifestyle factors;mouse model;multidisciplinary;neoplastic;novel;promoter;response;small molecule;smoking cessation;stem;stem cells;tool;transcriptomics;tumor;tumorigenesis;whole genome PROMINENT - IRB n/a NCI 10845758 8/2/23 0:00 RFA-OT-A2-013 3OT2CA278668-01S1 3 OT2 CA 278668 1 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 12211428 "LOPEZ-BIGAS, NURIA " Not Applicable n/a Unavailable 477003821 Q1QYYSBN8M88 477003821 Q1QYYSBN8M88 SP 41.38879 2.15899 10037616 FUNDACIO INSTITUT DE RECERCA BIOMEDICA BARCELONA Unavailable 8028 SPAIN N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 307531 NCI 747121 0 The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA either spontaneous or environmentally induced are essential for cancer development recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated but most of the emphasis has been on the origins of the driver mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity alcohol consumption inflammation and poor diet in cancer risk it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast recent sequencing studies have uncovered abundant mutations in normal human tissues suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models some carried out more than 50 years ago showing that promotion is the rate-limiting step in tumour development.To identify the mechanisms that control mutated normal cells and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology genetics computational network analysis and machine learning tissue imaging of gene expression single cell transcriptomics and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples together with detailed intervention studies in human populations mouse models and human organoids will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents. 307531 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC - NYU n/a NCI 10845757 7/28/23 0:00 RFA-OT-A2-013 3OT2CA278666-01S1 3 OT2 CA 278666 1 S1 "FINGERMAN, IAN M" 6/24/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 1862124 "BOEKE, JEF D" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 318207 NCI 187733 130474 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 318207 +No NIH Category available Address;Aging;Alcohol consumption;Architecture;Bioinformatics;Biological;Biological Models;Body Weight decreased;Breast;CRISPR screen;Cancer Etiology;Cancer Model;Cells;Clonal Evolution;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Colorectal;Communities;Country;DNA;Data;Data Set;Development;Endogenous Factors;Endometrial;Environment;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Event;Excision;Exposure to;Gene Expression;Generations;Genetic;Genomics;Goals;High-Risk Cancer;Human;Individual;Inflammation;Intervention;Intervention Studies;Investigation;Life Style;Limited Stage;Link;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Maps;Measures;Methods;Modeling;Molecular;Molecular Target;Mus;Mutate;Mutation;Neoplasms;Normal Cell;Normal tissue morphology;Obesity;Organoids;Pathway Analysis;Pathway interactions;Pattern;Phenotype;Population;Prevalence;Process;Proteome;Proteomics;Research Personnel;Risk;Risk Factors;Role;Route;Sampling;Structure of parenchyma of lung;Testing;Time;Tissue Donors;Tissue Sample;Tissue imaging;Tissues;Tumor Promoters;Tumor Promotion;Tumor Tissue;Tumor stage;Unhealthy Diet;anticancer research;cancer prevention;cancer risk;carcinogenesis;cellular targeting;chemical property;chemotherapy;data integration;detection method;driver mutation;environmental agent;epidemiology study;epigenomics;experience;genome-wide;hematopoietic tissue;human tissue;immune cell infiltrate;in vivo Model;inhibitor;innovation;lifestyle factors;mouse model;multidisciplinary;neoplastic;novel;promoter;response;small molecule;smoking cessation;stem;stem cells;tool;transcriptomics;tumor;tumorigenesis;whole genome PROMINENT - UCSF n/a NCI 10845756 8/1/23 0:00 RFA-OT-A2-013 3OT2CA278665-01S1 3 OT2 CA 278665 1 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 6107724 "BALMAIN, ALLAN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 1207862 NCI 906873 520827 The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA either spontaneous or environmentally induced are essential for cancer development recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated but most of the emphasis has been on the origins of the driver mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity alcohol consumption inflammation and poor diet in cancer risk it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast recent sequencing studies have uncovered abundant mutations in normal human tissues suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models some carried out more than 50 years ago showing that promotion is the rate-limiting step in tumour development.To identify the mechanisms that control mutated normal cells and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology genetics computational network analysis and machine learning tissue imaging of gene expression single cell transcriptomics and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples together with detailed intervention studies in human populations mouse models and human organoids will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents. 1207862 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN-Glasgow n/a NCI 10845754 7/31/23 0:00 RFA-OT-A2-013 3OT2CA278663-01S1 3 OT2 CA 278663 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78676187 "MADDOCKS, OLIVER " Not Applicable n/a Unavailable 229076096 ZFXKN51UZW96 229076096 ZFXKN51UZW96 UK 55.86515 -4.25763 2910801 UNIVERSITY OF GLASGOW Glasgow Unavailable G12 8QQ UNITED KINGDOM N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 87759 NCI 109109 8729 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 87759 +No NIH Category available Address;Aging;Alcohol consumption;Architecture;Bioinformatics;Biological;Biological Models;Body Weight decreased;Breast;CRISPR screen;Cancer Etiology;Cancer Model;Cells;Clonal Evolution;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Colorectal;Communities;Country;DNA;Data;Data Set;Development;Endogenous Factors;Endometrial;Environment;Environmental Risk Factor;Epidemiology;Epigenetic Process;Epithelial Cells;Event;Excision;Exposure to;Gene Expression;Generations;Genetic;Genomics;Goals;High-Risk Cancer;Human;Individual;Inflammation;Intervention;Intervention Studies;Investigation;Life Style;Limited Stage;Link;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Maps;Measures;Methods;Modeling;Molecular;Molecular Target;Mus;Mutate;Mutation;Neoplasms;Normal Cell;Normal tissue morphology;Obesity;Organoids;Pathway Analysis;Pathway interactions;Pattern;Phenotype;Population;Prevalence;Process;Proteome;Proteomics;Research Personnel;Risk;Risk Factors;Role;Route;Sampling;Structure of parenchyma of lung;Testing;Time;Tissue Donors;Tissue Sample;Tissue imaging;Tissues;Tumor Promoters;Tumor Promotion;Tumor Tissue;Tumor stage;Unhealthy Diet;anticancer research;cancer prevention;cancer risk;carcinogenesis;cellular targeting;chemical property;chemotherapy;data integration;detection method;driver mutation;environmental agent;epidemiology study;epigenomics;experience;genome-wide;hematopoietic tissue;human tissue;immune cell infiltrate;in vivo Model;inhibitor;innovation;lifestyle factors;mouse model;multidisciplinary;neoplastic;novel;promoter;response;small molecule;smoking cessation;stem;stem cells;tool;transcriptomics;tumor;tumorigenesis;whole genome PROMINENT-DUKE n/a NCI 10845753 8/1/23 0:00 RFA-OT-A2-013 3OT2CA278661-01S1 3 OT2 CA 278661 1 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 6388871 "COUNTER, CHRISTOPHER M" Not Applicable 4 PHARMACOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 238338 NCI 148036 90302 The cancer research community is on the verge of a major leap in our understanding of the factors that contribute to human cancer risk. While it is clear that mutations in DNA either spontaneous or environmentally induced are essential for cancer development recent advances have highlighted the importance of non-mutagenic factors as rate-limiting determinants of cancer risk in human populations and in mouse cancer models. The root causes of human cancer have been widely debated but most of the emphasis has been on the origins of the driver mutations that are ubiquitous in human tumours. Although epidemiology studies have highlighted the possible roles of lifestyle factors such as obesity alcohol consumption inflammation and poor diet in cancer risk it has generally been assumed that these factors act directly or indirectly to cause mutations in DNA thus contributing to tumour mutational burden and resulting in increased cancer risk. In contrast recent sequencing studies have uncovered abundant mutations in normal human tissues suggesting that even strong cancer driver mutations are not sufficient for cancer formation. These results were presaged by studies of mouse tumour models some carried out more than 50 years ago showing that promotion is the rate-limiting step in tumour development.To identify the mechanisms that control mutated normal cells and to elucidate the precise mechanisms by which promoting factors stimulate the conversion of these cells to neoplastic growth we have assembled a multidisciplinary team of investigators with wide-ranging experience in epidemiology genetics computational network analysis and machine learning tissue imaging of gene expression single cell transcriptomics and genome-wide CRISPR functional screens. We will focus human analysis on a unique collection of several thousand human normal and matched tumour samples from >20 countries including regions of both high and low cancer risk. Detailed risk factor information and whole genome sequence data is available from all these samples as part of the Grand Challenge Mutographs study. Analysis of these samples together with detailed intervention studies in human populations mouse models and human organoids will allow us to develop a roadmap of tumour promotion from single normal cells carrying driver mutations through to malignant progression. Our findings will facilitate identification of the causative environmental factors that promote cancer and provide routes to new methods and approaches to cancer prevention based on a deeper understanding of the process of initiated cell selection by tumour promoting agents. 238338 +No NIH Category available Address;Adipose tissue;Affect;Algorithmic Analysis;Animals;Anorexia;Atlases;Atrophic;Autophagocytosis;Basic Science;Behavior;Biological Markers;Blood;Body Composition;Body Weight decreased;Cachexia;Cancer Etiology;Cancer Model;Cancer Patient;Catabolic Process;Cells;Characteristics;Classification;Clinic;Clinical;Clinical Research;Clinical Trials;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytometry;Data;Desire for food;Diagnosis;Eating;Endocrine;Energy Metabolism;Epidemiology;Etiology;Fatty acid glycerol esters;Feeding behaviors;Foundations;Future;GDF15 gene;Gene Expression Profiling;Generations;Genes;Genetic;Geography;Goals;High-Risk Cancer;Histologic;Hormonal;Hormones;Human;Image;Immune;Immunology;Inflammatory;Inflammatory Response;Interleukin-6;International;Intervention;Intrinsic factor;Investigation;Isotopes;Lead;Life Expectancy;Link;Lipolysis;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediator;Medical;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Methods;Mus;Muscle;Neuroendocrinology;Neurologic;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Nutrient;Observational Study;Organ;Organoids;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Performance Status;Peripheral;Phenotype;Physical Function;Physiological;Pre-Clinical Model;Prospective cohort study;Quality of life;Recovery;Risk;Science;Scientist;Skeletal Muscle;Specialist;System;Therapeutic;Time;Tissues;Toxin;Translations;Ubiquitin;Validation;Vision;Wasting Syndrome;Whole Organism;Work;Xenograft procedure;anorexic;anticancer treatment;behavioral study;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;clinical biomarkers;clinical care;clinical phenotype;clinical subtypes;clinically relevant;cohort;cytokine;dietary;effective therapy;gut microbiome;host neoplasm interaction;imaging Segmentation;improved;improved outcome;in vivo;innovation;insulin signaling;lung microbiome;metabolic phenotype;microbial;microbiome;microbiota;molecular subtypes;mortality;mouse model;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;novel;nuclear imaging;optogenetics;patient population;pharmacologic;recruit;response;tool;treatment response;treatment strategy;treatment trial;tumor;tumor metabolism;tumor microenvironment;tumor progression;uptake;virtual;wasting CANCAN-HARVARDTHCHAN n/a NCI 10845749 7/31/23 0:00 RFA-OT-A2-013 3OT2CA278654-01S1 3 OT2 CA 278654 1 S1 "WATSON, JOANNA M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 14364712 "HUI, SHENG " Not Applicable 7 Unavailable 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA Domestic Higher Education 21156028 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 182233 NCI 119499 71102 BackgroundCancer cachexia (CC) is a systemic metabolic wasting syndrome featuring body weight loss due to skeletal muscle and adipose tissue wasting. CC is suffered by ~80% of cancer patients that causes reduced performance status intolerance to chemotherapy and increased mortality. This debilitating condition is poorly understood and has no effective treatment. If CC therapy existed it would improve treatment responses increase quality of life and prolong survival. With 50 years of study the field has focused on defining pathways that promote atrophy in the end-organs most affected by cachexia. While this work has been fruitful it has not led to identification of the upstream mediators of CC nor has it generated effective therapies. There is an urgent need for high-quality discovery science and more detailed clinical phenotyping. We have created a virtual institute comprised of diverse international multidisciplinary scientists and clinicians with expertise in cancer metabolism neuroendocrine function immunology human metabolic diseases preclinical models and clinical phenotyping. We hypothesize that CC is driven by tumor-intrinsic factors that activate neurohormonal sickness pathways which then induce anorexia metabolic dysfunction and tissue atrophy.MethodsOur approach involves sophisticated measures of host-tumor interactions including innovative investigation of (1) systemic metabolic flux in mice using isotope tracing imaging mass spectroscopy dynamic nuclear imaging and dietary and pharmacologic interventions; (2) cellular components and secreted factors from the tumor microenvironment using imaging mass cytometry patient-derived organoid xenografts microbial toxins and CRISPR-based manipulations; (3) central pathways regulating appetite behavior and peripheral organ metabolism using human metabolic phenotyping optogenetic and pharmacological methods. We will perform the largest most comprehensive observational study in CC subjects to thoroughly define CC subtypes and their clinical biomarkers using epidemiologic tools novel image segmentation algorithms and cluster analyses.Project GoalsOur vision is to develop mechanistically informed treatments for cancer cachexia (CC) to improve quality of life and life expectancy for patients. Working as a multidisciplinary team with expertise in basic science clinical research and epidemiology we will establish a therapeutically relevant classification of molecular and clinical subtypes of CC. We will build therapies to normalize metabolism and neuroendocrine dysregulation in CC to enable successful anti-cancer treatment and systemic recovery for patients. In 5 years we will have laid the foundation for a new generation of CC treatment trials and strategies that will for the first time deliver practice-changing evidence for improved outcomes for patients with cancer who are at risk of or suffer from CC. 182233 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC - CHARITE n/a NCI 10845744 8/7/23 0:00 RFA-OT-A2-013 3OT2CA278644-01S1 3 OT2 CA 278644 1 S1 "FINGERMAN, IAN M" 6/10/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 78668012 "HENSSEN, ANTON GEORGE" Not Applicable n/a Unavailable 320463029 MKXQG14WLDE8 320463029 MKXQG14WLDE8 GM 52.52437 13.41053 10002599 "CHARITE, UNIVERSITAETSMEDIZIN BERLIN" BERLIN Unavailable 10117 GERMANY N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 27692 NCI 124107 0 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 27692 +No NIH Category available Acceleration;Advocate;Affect;Architecture;Blood;Cancer Patient;Cells;Chemicals;Chemistry;Chromosome Pairing;Chromosomes;Collaborations;Communities;Computers;DNA;Data;Diagnostic;Drug Targeting;Drug resistance;Early Diagnosis;Education;Evolution;Family;Fingerprint;Fostering;Funding Mechanisms;Gene Expression Regulation;Gene Order;Generations;Genes;Genetic;Genetic Transcription;Genome;Human;Immune Evasion;Immune system;Immunobiology;Immunologics;Immunology;Immunotherapy;Infrastructure;International;Licensing;Ligands;Maintenance;Malignant Neoplasms;Medicine;Modeling;Monitor;Mutation;Nucleic Acids;Oncogenes;Patients;Pharmaceutical Preparations;Process;Productivity;Research Personnel;Resources;Role;Scientist;Therapeutic;Tissues;Tumor Promotion;Work;Yeast Model System;cancer genomics;cancer heterogeneity;cancer type;combinatorial;epigenomics;experience;extrachromosomal DNA;genome sequencing;innovation;insight;live cell imaging;machine learning algorithm;mathematical model;multiple omics;novel;prevent;programs;time use;tool;tumor;tumor growth;whole genome;yeast genetics eDyNAmiC - UCSD n/a NCI 10845739 7/28/23 0:00 RFA-OT-A2-013 3OT2CA278635-01S1 3 OT2 CA 278635 1 S1 "FINGERMAN, IAN M" 6/22/22 0:00 5/31/24 0:00 ZCA1-SRC(99) 7612243 "BAFNA, VINEET " Not Applicable 50 BIOSTATISTICS & OTHER MATH SCI 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF ARTS AND SCIENCES 920930621 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other 2023 329400 NCI 263254 131944 eDyNAmiC (extrachromosomal DNA in Cancer)Human genes are arranged on 23 pairs of chromosomes but in cancer tumour-promoting genes can free themselves from chromosomes and relocate to circular extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal rules of chromosomal inheritance enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago the critical importance of ecDNA has only recently come to light and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form how they function how they move around the cell how they evolve to resist treatment how they impact the immune system and how they can be effectively targeted are lacking. We bring together an internationally recognized pioneering interdisciplinary team of cancer biologists geneticists computer scientists evolutionary biologists mathematicians clinicians and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancers Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics yeast genetics epigenomics artificial genome synthesis longitudinal patient tracking combinatorial and machine learning algorithms mathematical modelling immunobiology and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer and we will find new ways to drug the undruggable. This bold programme which consists of 7 work packages and a committed international infrastructure generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients. 329400 +No NIH Category available African;Age Years;Awareness;Breast Cancer Patient;Clinical;Cohort Studies;Data Set;Development;Disease;Doctor of Philosophy;Early Diagnosis;Early treatment;Epidemiologist;Epidemiology;Fellowship;Female;Funding;Goals;Grant;HIV;HIV Seronegativity;HIV Seropositivity;Health Services Research;Hospitals;International;Interview;Investments;Knowledge;Lead;Leadership;Link;Malignant Neoplasms;Manuscripts;Medical Oncologist;Mental Health;Mentors;Outcome;Patient-Focused Outcomes;Postdoctoral Fellow;Program Development;Public Health;Research;Research Personnel;Research Project Grants;Research Proposals;South Africa;South African;Specialist;Stage at Diagnosis;Students;Supervision;Treatment Factor;Universities;Wit;Woman;anticancer research;career;career development;comorbidity;disparity reduction;experience;graduate student;interest;malignant breast neoplasm;mortality;novel;oncology service;parent grant;professor;programs;response;skills;sociodemographics;socioeconomics;survival prediction;young woman Novel predictors of survival among breast cancer patients with/without HIV in South Africa Project NarrativeSABCHO Mentored Research on Breast Cancer in South AfricaDr Witness Mapanga is a young epidemiologist researcher at the Strengthening Oncology Services ResearchUnit (SOSRU) University of Witwatersrand Johannesburg South Africa. Support to Dr Mapanga would bean excellent investment for his personal career development and through this for South African and SouthernAfrican cancer research for decades to come. He is at the optimal career stage having a strong academicbackground (Ph.D. in Epidemiology and postdoctoral Fellowships) to supervise students and develop hisown research program. His proposed study for this NOSI will be on breast cancer among HIV-positive and -negative women less than 40 years old within our parent grant the South African Breast Cancer and HIVOutcomes (SABCHO) cohort study aligning with SABCHO goals. NCI 10845712 9/18/23 0:00 PA-20-272 3R01CA250012-04S1 3 R01 CA 250012 4 S1 "DOMINGUEZ, GERALDINA" 6/1/20 0:00 5/31/25 0:00 Special Emphasis Panel[ZRG1(53)-R] 11022542 "JOFFE, MAUREEN " "CUBASCH, HERBERT ; EL-SADR, WAFAA M.; JACOBSON, JUDITH S; NEUGUT, ALFRED I.; RUFF, PAUL " n/a Unavailable 639391218 KNNNGEN9MQB8 639391218 KNNNGEN9MQB8 SF -26.20227 28.04363 10006783 "WITS HEALTH CONSORTIUM (PTY), LTD" PARKTOWN Unavailable 2193 SOUTH AFRICA N 9/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 124999 NCI 117340 7659 Project AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-038. In this research and mentoring application linked to our existing R01-funded South AfricanBreast Cancer and HIV Outcomes (SABCHO) cohort study Dr Witness Mapanga proposes to conduct a studyto characterize and compare the sociodemographic clinical determinants of stage at diagnosis and overallsurvival among young women (less than 40 years old) with breast cancer (BC) with and without comorbid HIV.Dr Mapanga will also assess through in-depth interviews among 30 young women with BC with and withoutcoexisting HIV their knowledge and awareness of BC experiences of their disease and its treatmentssocioeconomical and mental health impacts and support needs at the Chris Hani Baragwanath AcademicHospital (CHBAH) in Soweto Johannesburg South Africa (SA). Dr Mapanga is a young epidemiologist andpublic health researcher with experience in cancer and other noncommunicable diseases (NCD) based at theStrengthening Oncology Services Research Unit (SOSRU) of the University of Witwatersrand (Wits)Johannesburg South Africa. His leadership mentoring and grants acumen development supported by SouthAfrican and international mentoring group would be an excellent investment for his independent careerdevelopment in Southern African cancer research for decades to come. Having completed a PhD inEpidemiology and postdoctoral Fellowships he is now ready to establish lead and sustain his own researchprogram and supervise embedded postgraduate students.Dr Mapanga together with his parent grant mentors Dr Maureen Joffe (SA contact PI and primary mentor)Professor Dan ONeil (Medical Oncologist co-I from Yale U USA) and Professor Shane Norris (SA mentoringco-I) has developed the research proposal which aims to (i) characterize 480 young women (<40 years of age)with breast cancer from the SABCHO dataset comparing the 59% HIV-positive and 41% HIV-negative cases onsociodemographic clinical and treatment factors and overall survival; (ii) compare determinants of the stage atdiagnosis among them and iii) from in-depth interviews with 30 young women (<40 years) with BC (50% HIV-positive) assess their experiences and impact of BC and its treatments and support needs. To hone Witnessssupervision skills he will include in the research 3 young female cancer specialists at CHBAH who treat ourSABCHO patients to develop manuscripts from research findings and upskill their research acumen. Findingswill support strategies to reduce mortality from breast cancer among young women and reduce disparities totheir early diagnosis and treatment in SA. Dr Mapanga will gain invaluable experience in independently leadingthe research project supervising his mentees and will receive skilled leadership supervision grantsmanshipmentoring and research program development guidance to equip him to establish and lead his own independentresearch program within SOSRU. 124999 +No NIH Category available Apoptosis;Attenuated;Binding;Biological Assay;Brain Neoplasms;Cell Death;Cell Maintenance;Cell Proliferation;Cells;Chemotherapy and/or radiation;Co-Immunoprecipitations;Communication;Cysteine Proteinase Inhibitors;Data;Development;Fellowship;Foundations;Future;Glioblastoma;Growth;Heterogeneity;Immunoprecipitation;In Vitro;Inhibition of Apoptosis;Invaded;LIF gene;Laboratories;Lysine;Lysosomes;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Mass Spectrum Analysis;Membrane;Mentorship;Molecular;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Phenotype;Phosphorylation Site;Physicians;Population;Proliferating;Protein Secretion;Proteins;Proto-Oncogene Proteins c-akt;Radiation therapy;Recombinants;Recurrence;Regulation;Reporting;Research;Resistance;Role;Scientist;Serine;Serpins;Signal Transduction;Site;Testing;Therapeutic;Therapeutic Intervention;Training;Transforming Growth Factor beta;Up-Regulation;cancer stem cell;career;chemotherapy;crosslink;disease prognostic;disuccinimidyl suberate;experience;inhibitor;insight;junctional adhesion molecule;knock-down;liquid chromatography mass spectrometry;meetings;mortality;nerve stem cell;neutralizing antibody;new therapeutic target;next generation;novel;overexpression;pluripotency;protein expression;protein function;self-renewal;standard of care;stem cell function;stem cell model;stem cell self renewal;stem cells;therapeutic development;therapy resistant;transcription factor;treatment response;tumor;tumor growth;tumor initiation;tumorigenic Role of SerpinB3 in glioblastoma cancer stem cells Project Narrative ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLSGlioblastoma (GBM) is the most common primary malignant brain tumor and a population of cancer stem cells(CSCs) allows the tumor the tumor to quickly regrow after aggressive standard-of-care treatment. The objectiveof my project is to determine the mechanism through which GBM CSCs signal through junctional adhesionmolecule-A (JAM-A) via Serpin B3 a serine/cysteine protease inhibitor that interacts with JAM-A and has beenshown to signal through TGF- in other cancers. The successful completion of this proposal will further ourunderstanding of the signaling networks used by GBM CSCs for their self-renewal identify new therapeutictargets and provide essential training toward my development as a physician scientist. NCI 10845572 6/29/23 0:00 PA-19-191 5F30CA250254-04 5 F30 CA 250254 4 "DAMICO, MARK W" 7/1/22 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16036969 "LAUKO, ADAM " Not Applicable 11 PATHOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 Project Summary ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLSGlioblastoma (GBM) is the most aggressive primary malignant brain tumor with a median survival of 18-20months. Despite therapeutic interventions including surgery radiation and chemotherapy multiple clones ofchemo- and radiotherapy-resistant cells repopulate the tumor resulting in recurrence and a high rate of patientmortality. These cells are referred to as cancer stem cells (CSCs) due to their ability to self-renew and generatethe cellular heterogeneity present in the tumor. Our lab identified junctional adhesion molecule-A (JAM-A) onCSCs and through functional studies demonstrated that JAM-A is both necessary and sufficient for self-renewaland tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcriptionfactor activity; however the intermediate signaling network is yet to be fully elucidated. To further delineate thispathway we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry to determine theproteins to which JAM-A directly binds. This analysis led to the identification of the serine/cysteine proteaseinhibitor SerpinB3 as a binding partner. Interestingly SerpinB3 does not contain the conserved PDZ domain thatis present on nearly every other known JAM-A binding partner. Although multiple pro-tumorigenic mechanismsincluding regulation of TGF-1 and inhibition of apoptosis have been proposed for SerpinB3 in the context ofother cancers very little is known about the function of the protein in GBM CSCs and its relationship to JAM-Ais yet to be elucidated. Using in vitro CSC functional assays I have accumulated evidence that SerpinB3 isnecessary for the maintenance of CSCs and that reduction of SerpinB3 attenuates TGF-1 expression. Basedon these observations I hypothesize that SerpinB3 interaction with JAM-A is essential for the maintenance ofGBM CSCs through regulation of TGF-1 and inhibition of apoptosis. Aim 1 will test the hypothesis that SerpinB3maintains the CSC state through inhibition of apoptosis and upregulation of TGF-1. I will disrupt the lysosomalmembrane with siramesine to elucidate the role of SerpinB3 in the inhibition of apoptosis. Additionally I willinvestigate the role of SerpinB3 in the regulation of TGF-1 signaling in CSCs. Aim 2 will test the hypothesis thattargeting the JAM-A/SerpinB3 interaction will compromise self-renewal and GBM growth. I will utilize DSSOcrosslinking to determine the region of interaction between the two proteins. Finally I will determine theconsequence of disrupting the JAM-A/SerpinB3 interaction on the CSC state with small interfering peptides.Successful completion of this project will advance our understanding of how the CSCs state is maintained inGBM via specific JAM-A intracellular binding domains bridging cellular communication and cell signaling. Thestudies outlined in this fellowship will provide me an opportunity to gain experience in brain tumor research andallow me to continue my training though scientific meetings and mentorship opportunities preparing for a careeras a physician scientist. 52694 +No NIH Category available BLDG. 433 REFURBISHMENT PROJECT n/a NCI 10845253 261201500003I-P00012-26100018-1 N02 9/26/15 0:00 9/6/19 0:00 14274965 "IRELAND, RYAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 10833 NCI BLDG. 433 REFURBISHMENT PROJECT 10833 +No NIH Category available Address;Adoption;Advocate;African American population;African Caribbean;Belief;Black race;Cancer Control Research;Cancer Intervention;Cancer Prevention Intervention;Caribbean region;Catchment Area;Cervical Cancer Screening;Clinical;Communication;Communities;Community Health Aides;Consolidated Framework for Implementation Research;County;Data;Disparity;Dissemination and Implementation;Early Diagnosis;Educational Curriculum;Ensure;Evidence based intervention;Evidence based practice;Face;Family;Focus Groups;Funding;Future;Grenada;Guidelines;Health;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Immigrant;Immigration;Incidence;Individual;Intervention;Interview;Low income;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Modification;Morbidity - disease rate;Patients;Population;Population Study;Preventive;Preventive care;Process;Provider;Punishment;Readiness;Research;Research Personnel;Role;Stigmatization;Surveys;Tobago;Trinidad;Woman;cancer health disparity;cancer prevention;care seeking;cervical cancer prevention;community engagement;curriculum enhancement;dissemination strategy;ethnic minority;evidence base;implementation barriers;implementation science;implementation strategy;improved;infancy;innovation;interest;low and middle-income countries;mortality;multidisciplinary;novel;parent grant;population based;programs;psychologic;response;screening;social;social stigma;stakeholder perspectives;uptake;vaccination strategy;vaccine acceptance Implementation Strategies Addressing Caribbean Stigma to Improve the Woman-to- Woman Cervical Cancer Prevention Intervention PROJECT NARRATIVEAddressing cancer stigma for the Caribbean contexts is urgent but in its infancy; still findings from ourpopulation-based study (N=2233) show Caribbean readiness to participate and benefit from our program ofstigma research. Hence leveraging community and clinical partners' input and informed by our stigma surveydata we will employ implementation science to improve the Woman to Woman intervention curriculum andstrategies to reduce stigma and increase cervical screening and HPV vaccination. NCI 10845236 9/4/23 0:00 PA-20-272 3P30CA033572-40S4 3 P30 CA 33572 40 S4 "ROBERSON, SONYA" 8/1/97 0:00 11/30/27 0:00 6367572 "CARPTEN, JOHN D." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 235100 NCI 147700 87400 PROJECT SUMMARYThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-036. The overall objective of the proposed study is to build upon our program of Caribbean stigma researchrelevant to cancer prevention. Our preliminary study shows that in the Caribbean stigma bars preventive careincluding cervical cancer screening and HPV vaccination. In response to address cancer stigma for theCaribbean contexts we will employ implementation science approaches to improve the evidenced Woman toWoman intervention (W2W) to reduce stigma and increase cancer prevention. Rooted in implementationscience we will be guided by diverse stakeholder perspectives and the preliminary results of our recentpopulation-based Caribbean stigma survey (CCSS N=2233) to enhance the W2W intervention by including astigma reduction component to the curriculum. We will leverage our vast African Caribbean Cancer Consortium(AC3) of community partners including Lay Health Advisors and clinicians to inform and guide the improvementsto W2W using implementation science approaches to enhance the curriculum and strategies of W2W to reducecancer stigma and increase cervical cancer screening and HPV vaccination. To accomplish this objective wepropose the following specific aims: Aim 1: Informed by our Caribbean Cancer and Stigma Study survey (N=2233) and qualitative results using the Evidenced Based Process (EBP) modification strategies to improve thecurrent W2W intervention with a stigma reduction curriculum. Aim 2: Engage multi-stakeholder perspectivesusing community health workers focus groups and clinician interviews to further refine the improved Aim 1 W2Wintervention. We will incorporate cultural stigma consideration and reduction domain and content derivedfrom the clinician and community health workers; address HPV vaccination improvements and enhanceimplementation strategy to create the enhanced W2W_End Stigma-End Cervical Cancer intervention.Multi-sectoral stakeholders will ensure W2W_End Stigma-End Cervical Cancer interventions culturalcongruence to reduce cancer stigma as a barrier to cervical cancer screening and HPV vaccination. Thisimplementation science research will be the first to provide novel and requisite stakeholder results to inform co-created (community advocate clinician and researcher) stigma reduction curriculum and communicationstrategies for optimal provider and patient activation for increased uptake of cervical cancer screening and HPVvaccination. Therefore our study findings will improve the evidenced W2W intervention creating theW2W_End Stigma-End Cervical Cancer to eliminate stigma as a barrier to cervical cancer screening andHPV vaccination for near future Caribbean intervention dissemination. 235100 +No NIH Category available Academic Medical Centers;Administrative Supplement;Cancer Center;Caring;Characteristics;Clinical;Colon Carcinoma;Colorectal;Colorectal Cancer;Epidemiologist;Funding;Knowledge;Laboratories;Malignant neoplasm of gastrointestinal tract;Medical center;Mentors;Molecular;Oncology;Pathology;Patients;Pattern;Records;Rectal Cancer;Registries;Research;Research Assistant;Research Personnel;Research Project Grants;Role;Sampling;Surgeon;Tanzania;Testing;Training;Travel;Wages;career;career development;colon cancer patients;early onset;interest;laptop;low and middle-income countries;prospective;response;social;tumor Distribution of Molecular Features for Colorectal Cancers in Northern Tanzania n/a NCI 10845027 9/18/23 0:00 PA-20-272 3P50CA236733-05S1 3 P50 CA 236733 5 S1 "NOTHWEHR, STEVEN F" 7/9/19 0:00 5/31/24 0:00 ZCA1(J1) 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 125000 NCI 93535 31465 PROJECT SUMMARY/ABSTRACT: Vanderbilt-Ingram Cancer Center SPORE in GastrointestinalCancer (P50CA236733)This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-038.The Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer focuses on colorectal cancer. Thisproject for the Administrative Supplement for NCI Global Oncology Mentored Research will assess thepattern of molecular characteristics for colorectal cancer and assess feasibility for molecular testing for CRCthrough a formal mentored research relationship between researchers at Vanderbilt University MedicalCenter and a mentee (a colorectal surgeon) at Kilimanjaro Christian Medical Center (KCMC) Tanzania. Dr.Ayesiga Herman is an early-career low-middle income country researchers (ESLIs) who is actively involvedin the care of colorectal cancer patients in Northern Tanzania. He has observed an increasing proportion ofpatients with early onset CRC in Tanzania and the molecular features of these tumors are not known. Wethink the knowledge to these features in will play a role on management and surveillance for CRC. Wetherefore propose a study to look at the distribution of molecular features for CRC patients and assess theirassociation with social demographic and clinical factors. Also we will assess the feasibility for a prospectiveregistry for these molecular features at KCMC. We will retrospectively review records and analyze themolecular features for colon and rectal cancer samples banked in KCMC pathology laboratory for the past 5years. Also a prospective registry will be established for the new CRC patients and assess the feasibility formolecular testing at KCMC. Funds from this subcontract will be used for molecular features analysis supportthe salaries for ESLIs a research assistant and a laptop for the research assistant. Dr. Alexander Hawkins(colorectal surgeon) Martha J. Shrubsole (colorectal cancer epidemiologist) and Robert J. Coffey MD(Researcher) comprise the research mentoring team at Vanderbilt. Prof Blandina Mmbaga will be the localmentor for Dr. Herman and she will meet monthly to assess the progress of the project. As primary mentorDr. Hawkins will be responsible for career development and research project mentoring for Dr. Herman. Inthat role he will meet weekly via zoom to discuss the progress of the project will travel once to KCMCTanzania for training during the year and will the ESLIs for training at Vanderbilt once during the year. 125000 +No NIH Category available AIDS Malignancy Consortium;AIDS clinical trial group;AIDS related cancer;AIDS-Related Lymphoma;Achievement;Acquired Immunodeficiency Syndrome;Address;Adult;Africa;Africa South of the Sahara;African;Award;Biological Markers;Biopsy;Cancer Hospital;Cancer Patient;Caring;Characteristics;Clinical;Clinical Research;Clinical Trials;Collaborations;Communicable Diseases;Comprehensive Cancer Center;Continuity of Patient Care;Crystallization;Data;Eligibility Determination;Enrollment;Epidemic;Flowers;Future;Goals;Grant;HIV;Health;Hospitals;Individual;Institution;International;Intervention;Kaposi Sarcoma;Knowledge;Lead;Leadership;Lymphoma;Malawi;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Medicine;Mental Health;Molecular;Morbidity - disease rate;Newly Diagnosed;North Carolina;Outcome;Parents;Patient-Focused Outcomes;Patients;Personal Satisfaction;Persons;Policies;Positioning Attribute;Prevalence;Prognosis;Qualifying;Qualitative Research;Quality of life;Recurrence;Research;Research Infrastructure;Research Personnel;Research Project Grants;Science;Site;South Africa;Surveys;Survival Rate;Training;Training and Infrastructure;Translational Research;Trust;UNC Lineberger Comprehensive Cancer Center;United States National Institutes of Health;Universities;anticancer research;cancer care;career;clinical research site;cohort;college;combat;data sharing;detection method;experience;global health;high risk;improved;innovation;insight;interest;internalized stigma;intersectionality;low and middle-income countries;mortality;next generation;oncology program;programs;progression risk;prospective;resilience;response;screening;social stigma;translational impact;treatment and outcome;tumor Supplement: The Association Between Stigma and Wellbeing among Kaposi sarcoma and Lymphoma Patients in Malawi PROJECT NARRATIVEStigma hampers the cancer care continuum leading to delayed presentation to care elevated morbidity andmortality and reduced quality of life particularly for patients with HIV-associated cancers. The proposedsupplement will use new locally-developed cancer stigma measures to: 1) document the prevalence of cancerstigma among patients with Kaposi sarcoma and lymphoma in Malawi; and 2) identify cancer (characteristicstreatment and outcomes) and patient (quality of life mental health and resilience) factors associated withcancer stigma while investigating the intersectionality of HIV and cancer stigma. The results of our proposedsupplement will yield detailed insights into stigma and its association with the health and well-being of cancerpatients that will inform future global cancer research efforts to reduce stigma and improve patients clinicaloutcomes and quality of life. NCI 10844951 9/7/23 0:00 PA-20-272 3U54CA254564-04S1 3 U54 CA 254564 4 S1 "DOMINGUEZ, GERALDINA" 8/13/20 0:00 7/31/25 0:00 ZCA1(M1) 6931559 "DAMANIA, BLOSSOM A" "FEDORIW, YURI " 4 MICROBIOLOGY/IMMUN/VIROLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 172245 NCI 143864 28381 ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-036. Stigma hampers the cancer care continuum leading to delayed presentation to care elevatedmorbidity and mortality and reduced quality of life particularly for patients with HIV-associated cancers.Qualitative research has elucidated the lived experience of stigma among cancer patients and the adverseimpact of this stigma on mental health self-isolation and engagement in care. However there remains a gap inquantifying the prevalence and distribution of cancer-related stigma and its impact on health-related outcomesfor patients with HIV-associated cancers. In response we are currently developing and validating measures ofenacted anticipated internalized stigma in Malawi (P30CA042014-33S5 Lead Kimani). With this supplementthe overall goal is to embed these new cancer stigma measures in existing cohorts of cancer patients in Malawiin order to better understand the prevalence and impact of cancer stigma in an African public cancer hospital.Our long-term goal is to use the results from this study to develop R01-level grants for targeted multi-levelinterventions to address cancer stigma in Africa and ultimately improve cancer outcomes. In this proposedsupplement we will build on the parent award (U54CA254564 PI Damania) by leveraging the U54 prospectiveKaposi sarcoma (KS) and lymphoma cohorts to explore the experience of cancer-related stigma its impact onclinical outcomes and its intersection with HIV stigma. Specifically we will survey newly diagnosed adultpatients with biopsy-proven KS or lymphoma who are receiving or eligible for active cancer care and enrolledin the parent study to measure cancer and HIV stigma and abstract cancer and patient data from the U54routine study assessments. We will then quantify the prevalence of cancer stigma among KS and lymphomapatients in Malawi (Aim 1). We will additionally identify key cancer (characteristics treatment and outcomes)and patient (quality of life mental health resilience) factors correlated with cancer stigma and assess theintersectionality of HIV and cancer stigma (Aim 2). Ultimately this innovative research will generate findingsthat will stimulate and strengthen global cancer stigma build local capacity to conduct cancer stigma researchand lay the ground-work for future R01 proposals to implement and evaluated multi-level interventions thataddress cancer stigma in Africa and ultimately improve cancer care and outcomes. 172245 +No NIH Category available Abbreviations;Adherence;Administrative Supplement;Adoption;Age Years;Attitude;Cancer Etiology;Cervical Cancer Screening;Cessation of life;Clinic;Clinical;Communities;Comprehension;Consult;Country;Cross-Sectional Studies;Data;Development;Disclosure;Distress;Dose;Education;El Salvador;Eligibility Determination;Ensure;Factor Analysis;Focus Groups;Fright;Funding;Future;HIV;Health;Health Personnel;Health Services Accessibility;Human Papillomavirus;Human papilloma virus infection;In complete remission;Incidence;Income;Intervention;Interview;Literature;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Measurement;Measures;Methods;Modeling;Municipalities;Perception;Population;Prevention program;Preventive service;Protocols documentation;Provider;Psychometrics;Sampling;Self Perception;Shame;Structure;Surveys;Testing;Time;Translating;Treatment Efficacy;Vaccinated;Vaccination;Woman;aged;brief intervention;cervical cancer prevention;cognitive interview;design;experience;formative assessment;health seeking behavior;improved;instrument;interest;low and middle-income countries;member;mortality;parent grant;pilot test;programs;recruit;response;screening;screening program;social stigma;socioeconomic disparity;therapy design;tool;treatment adherence;uptake Development of an HPV stigma assessment scale and a stigma-reducing intervention to improve cervical cancer prevention in El Salvador Project NarrativeThere is widespread evidence that women experience distress fear and shame associated with cervicalcancer screening but there is a lack of validated psychometric assessments that measure cervical cancer orHPV-related stigma. There is also very limited data on the impact of stigma on screening and treatmentadherence low- and middle-income countries (LMICs). This project will adapt and abridge a scale to measureHPV-related stigma and collect mixed-methods data to design a stigma-reducing intervention that can besubsequently tested in a LMIC setting. NCI 10844859 9/14/23 0:00 PA-20-272 3R01CA266059-02S1 3 R01 CA 266059 2 S1 "SAHASRABUDDHE, VIKRANT V" 4/1/23 0:00 3/31/27 0:00 9832286 "CREMER, MIRIAM " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 180289 NCI 125000 55289 Project AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-036. Cervical cancer is a leading cause of cancer death for women in low and middle income countries(LMICs). Women often experience distress fear and shame associated with cervical cancer screening butthere is a lack of validated psychometric assessments that measure cervical cancer or HPV-related stigma.Internalized and anticipated stigma from partners community members or healthcare providers have beenshown to reduce health-seeking behaviors in other health conditions and it is likely that cervical cancer andHPV-related stigma impact screening rates in LMICs even when screening is offered. In El Salvador up to 30%of women invited to screening do not attend. Thus there is an urgent need to better understand and measurehow HPV stigma is understood and manifested and to design interventions that can reduce HPV-relatedstigma and increase uptake of cervical cancer preventive services. The purpose of this AdministrativeSupplement is to adapt an existing psychometric tool to assess HPV stigma and to design a pilot-ready stigma-reducing brief intervention. This proposal is aligned with the parent grant which will clinically validate a newHPV test for use in LMICs. This Supplement will focus on the following Specific Aims: 1) Adapt the BergerStigma Scale (BSS) to HPV and abridge it for use in El Salvador and other LMIC settings 2) Conduct a mixed-methods formative assessment of cervical cancer and HPV-related stigma in the context of El Salvador'scervical cancer prevention program and 3) Design a pilot-ready brief intervention (BI) to reduce HPV-relatedstigma and increase adherence in El Salvador cervical cancer prevention program. Milestones for this projectwill be a validated short-form scale to assess HPV-related stigma in LMICs and a completed briefintervention protocol that is ready for testing. We plan to seek subsequent funding to test intervention efficacy.We have the tools to eliminate cervical cancer in our lifetime but there is a critical need for improved strategiesto implement vaccination screening and treatment efforts. Identifying and measuring HPV-related stigma is anecessary step to reduce barriers and increase adoption of cervical cancer prevention and to close theunacceptable gap in global cervical cancer incidence and mortality. 180289 +No NIH Category available Address;Administrative Supplement;Affect;Award;Biopsy;Blood;Cancer Patient;Canis familiaris;Cells;Circulation;Clinical;Collecting Cell;Collection;Custom;DNA;DNA Methylation;DNA analysis;DNA copy number;DNA methylation profiling;Data;Data Correlations;Data Set;Detection;Diagnosis;Diagnostic;Disease;Elements;Evaluation;Goals;Hemangiosarcoma;Hematopoiesis;Histologic;Human;Incidence;Length;Licorice;Location;Lymphoma;Machine Learning;Malignant Neoplasms;Methodology;Methylation;Monitor;Mutation;Patient-Focused Outcomes;Patients;Peripheral;Plasma;Point Mutation;Procedures;Proteins;RNA;Recurrence;Relapse;Residual state;Sampling;Sensitivity and Specificity;Standardization;Techniques;Technology;Tissues;Tumor Burden;Tumor-Derived;Veins;Work;cancer therapy;design;diagnostic platform;exosome;genome sequencing;improved;interest;large cell Diffuse non-Hodgkin's lymphoma;liquid biopsy;methylome;multimodality;neoplastic cell;osteosarcoma;outcome prediction;prevent;prospective;tool;tumor;tumor DNA;whole genome Leveraging canine spontaneous cancer to optimize the power of blood biopsy n/a NCI 10844821 9/18/23 0:00 PA-20-272 3R01CA255319-03S1 3 R01 CA 255319 3 S1 "NADEAU, CHRISTINE FRANCES" 6/7/21 0:00 5/31/26 0:00 Special Emphasis Panel[ZRG1(55)-R] 10971324 "KARLSSON, ELINOR " "LONDON, CHERYL A" 2 BIOSTATISTICS & OTHER MATH SCI 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 44963 NCI 44963 0 ABSTRACTBlood biopsy is a rapidly advancing technology in which circulating elements (DNA RNA proteins exosomes)released from tumor cells are collected and assessed. In most cases the circulating free DNA (cfDNA) iscollected and the circulating tumor DNA (ctDNA) within the cfDNA is quantified and analyzed. Blood biopsy hasthe potential to transform cancer treatment but several challenges remain that prevent widespread applicationincluding the need to standardize collection and processing procedures optimize sequencing/analysis platformsand correlate data generated with long-term patient outcomes. Our current NCI R01 award (CA255319)leverages pet dogs with spontaneous cancer as a tool for improving blood biopsy technologies and as a tool foradvancing effective implementation in human patients. The aims of this work award are to 1) assessctDNA/tumor mutation concordance and optimize the parameters for diagnostic sampling; 2) utilize cancer in petdogs to improve ctDNA deep duplex sequencing diagnostics; and 3) determine the accuracy of blood biopsy formonitoring disease status and predicting outcome in affected dogs. Over the past 2 years we have madesignificant progress on these goals including sequencing more than 260 samples from over 110 dogs. Our datademonstrate that location of blood draw (central versus peripheral vein) influences ctDNA yield and that ctDNAbecomes detectable an average of 90 days prior to clinical relapse in dogs with lymphoma. We further identifiedclonal hematopoiesis of indeterminate potential (CHIP) mutations in 10.8% of samples supporting the routineincorporation of CHIP detection in blood biopsy diagnostics. However up to 20% of canine samples had nodetectable copy number changes and a low tumor fraction despite a very high clinical tumor burden. These dataare concordant with recent findings in human cancer patients creating a diagnostic challenge particularly intumors with high structural complexity and low incidence of recurrent point mutations. To address these issuesthere is broad interest in evaluating other factors affecting cfDNA such as methylation. Indeed unique tissue-specific methylation signatures can determine the cell of origin of DNA in circulation and in combination withtumor fraction and copy number analysis have the potential to increase sensitivity and accuracy of liquid biopsydetection. As such the purpose of this administrative supplement is to analyze the methylome of cfDNA fromdogs with histologically confirmed cancers and incorporate these results into our existing ctDNA copy numberpipeline. To accomplish this we propose to first validate the methylation signatures of cfDNA in canine cancersthen characterize the accuracy of multi-modal cfDNA analysis for detection and monitoring of these cancers. Allnecessary samples have already been collected along with associated patient outcome data permittingcompletion of planned studies within 12 months. Data generated from this administrative supplement will supportprospective incorporation of tumor methylome analytics into a multi-parameter blood biopsy diagnostic platformdesigned to enhance clinical impact in human cancer patients. 44963 +No NIH Category available AIDS related cancer;Accounting;Address;Adherence;Administrative Supplement;Affect;Africa;Africa South of the Sahara;Area;Attitude to Health;Award;Behavior;Behavioral;Caring;Cessation of life;Characteristics;Cognitive;Complex;Comprehension;Data;Development;Dimensions;Discrimination;Early Diagnosis;Enrollment;Ensure;Epidemiology;Ethnic Origin;Exposure to;Factor Analysis;Funding;Gender Identity;General Population;Goals;HIV;HIV diagnosis;Health;Health behavior;Healthcare;Incidence;Individual;Infection;Intervention;Interview;Investigation;Kenya;Label;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Measures;Mental Depression;Mental Health;Methods;Morbidity - disease rate;Outcome;Outcome Measure;Parents;Participant;Patients;Persons;Population;Prevention;Process;Quality of life;Race;Reporting;Research;Resource-limited setting;Risk;Sampling;Screening for cancer;Self Efficacy;Social support;Stigmatization;Structure;Target Populations;Techniques;United States;Validation;Work;adherence rate;cancer diagnosis;career development;community involvement;design;experience;follow-up;improved;interest;intersectionality;member;mortality;multidisciplinary;parent grant;patient population;patient subsets;response;screening services;social exclusion;social stigma;sociodemographics;tool;treatment adherence;treatment services;virus related cancer Developing measurements to evaluate intersectional stigma related to cancer and HIV PROJECT NARRATIVEIntersectional stigma exists when an individual experiences multiple co-occurring and potentially synergisticstigmatizing conditions which can affect patient quality of life and health-related behaviors. As the rates ofcancer rise particularly in subSaharan Africa the dual burden of HIV-related stigma and cancer-relatedstigma becomes a crucial point of investigation yet no scale exists to measure intersectional stigma of thoseliving with concurrent cancer and HIV diagnoses. This study aims to develop an intersectional stigma scale forpatients with concurrent HIV and cancer diagnoses. NCI 10844755 8/30/23 0:00 PA-20-272 3U54CA254571-04S1 3 U54 CA 254571 4 S1 "DOMINGUEZ, GERALDINA" 7/13/20 0:00 6/30/26 0:00 ZCA1(M1) 1895356 "MARTIN, JEFFREY N" "KAMBUGU, ANDREW DDUNGU" 11 PUBLIC HEALTH & PREV MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 202350 NCI 150786 51564 PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-036. Sub-Saharan Africa (SSA) bears a disproportional burden of HIV globally. Additionally therisk for malignancy in this population far exceeds the general population with higher associated morbidity andmortality. As the dual burden of HIV and cancer in the global population increases investigation of the impactof stigma on this population is crucial for improving health outcomes. Stigma is a well-studied construct that occurs when individuals are recognized and labeled as otherdue to various sociodemographic behavioral or health-related characteristics and has been linked to poorquality of life and health-related outcomes. Stigma associated with HIV and cancer diagnoses in particularhave been associated to poor mental health low treatment adherence rates and decreased healthcareengagement. When an individual has multiple co-occurring stigmatizing characteristics they have the potentialfor a more complex stigma experience termed intersectional stigma. Individuals living with HIV and cancermay experience stigma more prominently due to one dominant stigmatizing condition or may experience asynergistic or multiplicative effect. Intersectional stigma has been measured via validated scales for constructssuch as race ethnicity gender identity and behavior but no scale exists to measure the intersectionality ofHIV and cancer stigma. The ability to measure the stigma experience in people living with HIV and cancer iscrucial for assessing its influence on health-related behaviors and for designing more targeted interventions. As an administrative supplement to U54 CA254571 our overall goal is to initiate the development of ascale that effectively measures intersectional stigma in patients with concurrent HIV and cancer diagnoses.Our specific aims are: 1) To develop a preliminary pool of scale questions that capture key dimension of HIVand cancer intersectional stigma. We will use both pre-existing and de-novo qualitative interviews andquantitative data to develop this initial pool. 2) To involve community stakeholders and participants with HIVand cancer in further refinement of the pool of scale questions. We will use techniques including memberchecking and cognitive debriefing. 3) To complete preliminary item validation on a population subset of patientsliving with both HIV and cancer. To achieve these aims we leverage a multidisciplinary team of leaders in stigma scale developmentHIV-associated cancers and epidemiology. We will develop an intersectional stigma scale for HIV and cancersupported by our already existing laboratory for HIV and malignancies in the AMPATH network in westernKenya funded by parent grant U54 CA254571. Findings from this work are expected to lead to thedevelopment of an intersectional stigma scale that will help to better characterize co-occuring potentiallysynergistic HIV and cancer stigma and ultimately allow us to develop more informed health interventions. 202350 +No NIH Category available Address;Botswana;Cancer Etiology;Cancer Family;Cancer Survivor;Caring;Cervical Cancer Screening;Cessation of life;Church;Cognitive;Communities;Development;Diagnosis;Educational workshop;Evaluation;Family member;Feedback;Foundations;Fright;Gender;Grant;HIV;Health;Health Personnel;High Prevalence;Impairment;Individual;Infertility;Influentials;Intervention;Interview;Knowledge;Length;Life;Link;Logic;Maintenance;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mediator;Modeling;Morbidity - disease rate;Newly Diagnosed;Nurses;Outcome;Physicians;Pregnant Women;Process;Recovery;Reproductive Health;Research;Research Design;Risk;Risk Factors;Shapes;Survivors;Testing;Vulnerable Populations;Woman;Work;acceptability and feasibility;barrier to care;cancer care;cancer diagnosis;cancer therapy;care providers;combat;comorbidity;coping;depressive symptoms;experience;follow-up;improved;innovation;interest;low and middle-income countries;member;mortality;motherhood;parent project;promote resilience;psychoeducation;psychoeducational;resilience;response;social stigma;survivorship;uptake Thibang Diphatlha: Testing adaptive strategies to close the gap from cervical cancer diagnosis to treatment in Botswana Stigma and fear surrounding cervical cancer present significant barriers to care in Botswana ascancer and its treatment are often paired with negative associations concerns over impairedreproductive health and self-blame. We propose qualitative assessments to understand howcervical cancer stigma impacts survivors at multiple levels throughout the care cascade and howother intersectional factors such as HIV status manifest in the stigma process. Withstakeholders we will also co-produce an intervention logic model and pre-test individualintervention components to inform development of an anti-stigma intervention for cervical cancersurvivors in Botswana. NCI 10844698 9/19/23 0:00 PA-20-272 3U01CA275032-02S1 3 U01 CA 275032 2 S1 "VEDHAM, VIDYA" 9/6/22 0:00 8/31/27 0:00 ZCA1(M2) 12105432 "GROVER, SURBHI " "RENDLE, KATHARINE " 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 219374 NCI 145459 73915 This application is being submitted in response to the Notice of Special Interest (NOSI) identifiedas NOT-CA-23-025.Cervical cancer is the leading cause of cancer-related death in Botswana. About half of thewomen with cervical cancer in Botswana do not receive timely treatment increasing their risk ofgreater morbidity and mortality. Stigma and fear surrounding cervical cancer present significantbarriers to care in this cultural context as cancer and its treatment are often paired with negativeassociations concerns over impaired reproductive health and self-blame. While prior studieshave explored the impact of stigma on cervical cancer screening in low- and middle-incomecountries (LMIC) there is limited knowledge regarding how cancer stigma manifests during thesubsequent stages of post-diagnosis care and survivorship. This proposed study builds upon itsparent project Thibang Diphatlha (U01CA275032) which tests adaptive strategies to close thegap from cervical cancer diagnosis to treatment initiation in Botswana. In this supplemental studywe propose to conduct additional qualitative assessments to understand how cervical cancerstigma impacts survivors at multiple levels throughout the care cascade and how otherintersectional factors such as HIV status manifest in the stigma process. Through engagementwith different stakeholder groups we will also co-produce an intervention logic model and pre-test individual intervention components to inform development of an efficient parsimonious anti-stigma intervention for cervical cancer survivors in Botswana. The proposed research will advanceour understanding of culture salient experiences of stigma among invasive cervical cancersurvivors to inform the development optimization and pre-testing of a targeted intervention toreduce stigma and facilitate resilience and recovery among this highly vulnerable population inBotswana and other LMIC contexts. 219374 +No NIH Category available Address;Adolescent;Child;Childhood;Childhood Cancer Survivor Study;Cohort Studies;DNA sequencing;Data;Diagnosis;Disease susceptibility;Eligibility Determination;Genetic Predisposition to Disease;Genotype;Health;Institution;Intervention;Investigation;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Methylation;Morbidity - disease rate;Outcome;Participant;Publications;Quality of life;Research;Research Personnel;Resources;Risk;SNP array;Source;Survival Rate;Survivors;biobank;childhood cancer survivor;cohort;follow-up;health related quality of life;high risk population;improved;mortality;multidisciplinary;recruit;screening guidelines;survivorship CHILDHOOD CANCER SURVIVOR STUDY NARRATIVESurvival rates for many childhood and adolescent cancers have improved at a remarkable pace over the pastfive decades. The CCSS cohort has been the source of some of the most significant publications to dateaddressing the long-term mortality morbidity and quality of life of survivors of childhood cancer. Understandingthe risk for late effects of childhood cancer and its therapy provides the basis for health screeningrecommendations and interventions that can mitigate long-term health problems in this high-risk population NCI 10844314 9/19/23 0:00 PA-20-272 3U24CA055727-29S2 3 U24 CA 55727 29 S2 "HENDERSON, LORI A" 6/1/23 0:00 11/30/26 0:00 8819228 "ARMSTRONG, GREGORY " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 395 Other Research-Related 2023 1370657 NCI 753108 617549 ABSTRACTThe Childhood Cancer Survivor Study (CCSS) is a multi-institutional multi-disciplinary collaborative researchresource established to systematically evaluate long-term outcomes among children diagnosed with cancerwho survived five or more years from diagnosis. With the successful recruitment and longitudinal follow-up ofthe cohort that includes survivors diagnosed and treated over three decades (1970-1999) the CCSS is theworlds largest established open resource for survivorship research with 38036 eligible survivors available forinvestigation of late mortality and 25665 participants who have contributed health-related and quality of lifeoutcomes. The resource includes comprehensive annotation of treatment exposures ongoing longitudinalfollow-up and an established biorepository from which genotype (SNP array) and DNA sequencing of 8380survivors are available to investigators for identification of genetic susceptibility for disease- and treatment-related late effects. The current supplement application will expand the resource to provide methylationprofiling data for more than 2800 participants. 1370657 +No NIH Category available Acceleration;Achievement;Address;Affect;Aging;B lymphoid malignancy;Basic Science;Biological;California;Cancer Burden;Cancer Center Support Grant;Cancer Patient;Caring;Catchment Area;Cell Therapy;City of Hope Comprehensive Cancer Center;Clinical;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;County;Development;Diagnosis;Early Diagnosis;Education;Enrollment;Fostering;Funding;Grant;Growth;Individual;Informatics;Infrastructure;Institution;Intervention;Intervention Trial;Investigation;Leadership;Licensing;Longevity;Los Angeles;Malignant Neoplasms;Mission;Oranges;Pathway interactions;Patient Care;Patients;Peer Review;Persons;Policies;Population;Population Heterogeneity;Population Research;Population Study;Populations at Risk;Prevention;Prevention approach;Productivity;Publications;Publishing;Research;Research Personnel;Research Support;Resolution;Resource Sharing;Resources;Risk;Rural;Science;Scientist;Speed;Strategic Planning;Teacher Professional Development;Training;Training and Education;Translational Research;Translations;Urban Population;Vision;anticancer research;base;cancer prevention;cell growth;chimeric antibody;clinical practice;community engagement;equity diversity and inclusion;experience;first-in-human;frontier;gene function;health equity promotion;improved;manufacturing facility;member;next generation;novel;novel therapeutic intervention;outreach;participant enrollment;population based;precision medicine;programs;research clinical testing;skills;success;survivorship;treatment trial Cancer Center Support Grant Narrative OverallThe City of Hope Comprehensive Cancer Center leverages the scientific expertise of 175 cancer-focusedinvestigators who form five productive Research Programs spanning basic translational clinical and population-based research that are supported by unique institutional resources and a robust cancer-focused researchfunding base. An active clinical trials portfolio builds on institutional research discoveries to facilitate advancesacross the translational research continuum that benefit the population of a diverse Catchment Area and thelarger community of people at risk for or affected by cancer. NCI 10843114 1/4/24 0:00 PAR-21-321 5P30CA033572-41 5 P30 CA 33572 41 "ROBERSON, SONYA" 8/1/97 0:00 11/30/27 0:00 Cancer Centers Study Section (A)[NCI-A] 6367572 "CARPTEN, JOHN D." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 397 Research Centers 2024 3536183 NCI 2009195 1526988 Abstract OverallThe City of Hope Comprehensive Cancer Center (COHCCC) received NCI-designation in 1981 andComprehensive status in 1998. Led by Steven T. Rosen MD the COHCCC is composed of 175 full Membersfive productive Research Programs eleven established Shared Resources and one developing SharedResource a robust cancer-focused research funding base (76% growth in NCI funding in the current fundingcycle) and an active clinical trials portfolio that builds on institutional research discoveries. The COHCCCfacilitates advances across the translational research continuum by providing infrastructure strategic planningadministrative support and mechanisms for transdisciplinary interactions that catalyze cancer-focused activitiestraversing basic discovery clinical and population-based investigations. These activities are aligned to reducecancer burden of a highly populated and diverse Catchment Area of nearly 18 million people that encompasses33109 square miles and ranges from urban population centers concentrated in Los Angeles and OrangeCounties to rural and frontier regions in eastern San Bernardino and Riverside Counties. To foster high-impacttransdisciplinary cancer-focused research the COHCCC leverages a spectrum of state-of-the-art SharedResources including in-house GMP manufacturing facilities; informatics and precision medicine resources;notable breadth and depth of in-house experience in conducting clinical trials; and a centralized administrativeinfrastructure. The COHCCC is also committed to developing and enhancing the diversity of the next generationof leaders in basic clinical and population-based cancer-related research through robust training initiatives thatbegin at K-12 outreach and continue through junior faculty development. To enhance cancer prevention improveearly detection and accelerate translation of novel therapeutic approaches that impact patients across thelifespan and from diverse populations the COHCCC will pursue the following Specific Aims: 1) Identify developproduce and advance first-in-field and first-in-human new treatments; 2) Implement four strategic initiatives:advancing precision medicine expanding cellular therapeutics promoting health equity and enhancing clinicalresearch in the clinical network; 3) Assess and address the cancer burden in the COHCCC Catchment Areapromoting early detection prevention novel treatments aging and survivorship; 4) Advance training andeducational initiatives to support the next generation of cancer-focused scientists and clinicians; 5) Enactconcrete policies to enhance diversity equity and inclusion in the COHCCC Membership and Leadership.During the next cycle the COHCCC will expand on historic strengths and advance critical initiatives that willbenefit the diverse population of the Catchment Area and the larger community of individuals at risk for oraffected by cancer. 3536183 +No NIH Category available Behavior Therapy;Body mass index;Businesses;Carotenoids;Chronic;Cluster randomized trial;Communities;Community Outreach;Computer software;Consumption;Control Groups;Country;Data;Dermal;Diet;Dose;Eating;Education;Effectiveness;Evaluation;Face;Fatty acid glycerol esters;Feedback;Fingers;Food;Food Access;Food Preferences;Funding;Future;Health;Health Food;Healthy Eating;Heart Diseases;Height;Hour;Housing;Improve Access;Income;Individual;Intake;Intervention;Interview;Knowledge;Low Income Population;Low income;Malignant Neoplasms;Marketing;Measurement;Measures;Minority;Minority Groups;Modeling;Neighborhood Health Center;Neighborhoods;Nonprofit Organizations;North Carolina;Obesity;Outcome;Participant;Patient Self-Report;Periodicals;Persons;Population;Preparation;Price;Process;Process Measure;Program Effectiveness;Qualifying;Randomized;Randomized Controlled Trials;Reporting;Request for Proposals;Research;Running;Sales;Scanning;Selection Criteria;Self Efficacy;Site;Socioeconomic Status;Sodium;Surveys;Techniques;Telephone;Testing;Time;Unhealthy Diet;Update;Vulnerable Populations;Weight;cluster randomized design;community college;community engagement;community organizations;cooking;cost;design;dietary;effectiveness measure;effectiveness testing;effectiveness/implementation hybrid;environmental intervention;farmers markets;flexibility;follow-up;food environment;fruits and vegetables;health disparity;hybrid type 1 design;implementation framework;implementation process;improved;informant;intervention participants;member;nutrition education;process evaluation;programs;recruit;research study;saturated fat;skills;social cognitive theory;success;sugar;theories;underserved community Effectiveness and Implementation of a Research Tested Mobile Produce Market Designed to Improve Diet in Underserved Communities NarrativeOur research demonstrated that a mobile produce market can have a significant positive impact on diets ofresidents in lower-income communities. We want to test this program more widely to determine if the effectcan be replicated and develop a best-practices toolkit to help others sustainably implement the program. NCI 10842494 7/31/23 0:00 PAR-21-138 3R37CA215232-06S1 3 R37 CA 215232 6 S1 "AGURS-COLLINS, TANYA" 7/1/23 0:00 11/30/24 0:00 10598093 "LEONE, LUCIA A" Not Applicable 26 PUBLIC HEALTH & PREV MEDICINE 38633251 LMCJKRFW5R81 38633251 LMCJKRFW5R81 US 43.003074 -78.785924 5992614 STATE UNIVERSITY OF NEW YORK AT BUFFALO AMHERST NY SCH ALLIED HEALTH PROFESSIONS 142282567 UNITED STATES N 7/1/23 0:00 11/30/23 0:00 394 Non-SBIR/STTR 2023 82247 NCI 51284 30963 AbstractLower-income and minority groups face significant health disparities with respect to obesity cancer heartdisease and other diet-related chronic conditions. Poor diets low in fruits and vegetables (F&V) and high insaturated fat sodium and sugar contribute to many of the health problems faced by vulnerable groups. Whilesocioeconomic status and other individual level factors (i.e. food preferences time and skills to preparehealthy food etc.) can lead to reduced F&V consumption these must be viewed in an environmental context.Compared with higher-income neighborhoods lower-income and minority neighborhoods are less likely tohave stores that sell a variety of F&V and other healthy foods. And when stores are available produce maynot be affordable high quality or culturally appropriate. Farmers' markets and mobile produce markets (MM)have become increasingly popular strategies to alleviate food access concerns in underserved communities.However it is unclear if these programs have the necessary components to have an appreciable impact ondiet. Our research team recently completed one of the first randomized controlled trials of a MM program calledthe Veggie Van. Veggie Van was run in partnership with our team and a small non-profit organization in NorthCarolina; it delivered boxes of fresh locally grown produce and food-focused education to communities withsignificant barriers to F&V consumption including availability affordability quality and knowledge. In this smallcluster-randomized trial in 12 communities (N=201) we saw impressive changes in F&V intake withintervention participants eating almost 1 more cups per day of F&Vs than the control group. Interventionparticipants also reported increases in perceived access to healthy foods and Veggie Van customers attributedmany dietary changes to the MM program. While these results are very promising we believe it is important totest the effectiveness of the Veggie Van program when implemented by different organizations in multiplecommunities. If shown to be effective we can create a research-tested intervention toolkit which can bedisseminated to communities across the country. For this research we will use a request for proposalsprocess to identify 8 organizations nationwide that are well-qualified to implement the Veggie Van model.Organizations will identify appropriate sites for MM deliveries (32 total) and we will randomize them to either animplementation or planning condition. With the help of our team's technical assistance and provided fundingpartner organizations will engage community members in the process and initiate a MM program. We will usea Type 1 Hybrid Effectiveness-Implementation to measure effectiveness (diet BMI dermal carotenoids) andimplementation (customer reach and sales process measures qualitative interviews with MM staff). We willalso examine sustainability of MM financial models and determine implementation standards (i.e. dose neededto maintain impact) for inclusion in our MM toolkit for future dissemination. 82247 +No NIH Category available Academic Medical Centers;Applications Grants;Appointment;Basic Science;Benchmarking;Budgets;Cancer Center;Cancer Center Support Grant;Capital;Clinical;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Communication;Community Outreach;Comprehensive Cancer Center;Contracts;Data;Direct Costs;Education and Outreach;Enrollment;Ensure;Environment;Equipment;Evaluation;Faculty;Fostering;Funding;Future;Grant;Guidelines;Health;Human Resources;Individual;Information Systems;Institution;Intervention Trial;Investments;Joints;Knowledge;Leadership;Link;Measurement;Meridians;Methods;Mission;Monitor;National Cancer Institute;New Jersey;Office Management;Peer Review;Policies;Population Research;Process;Productivity;Protocols documentation;Publications;Reporting;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Safety;Strategic Planning;System;Talents;Training and Education;Translational Research;Universities;Vision;Washington;anticancer research;cancer education;equipment acquisition;experience;meetings;member;operation;peer;programs;recruit;tool Cancer Center Administration n/a NCI 10842468 6/21/23 0:00 PA-20-272 3P30CA051008-29S2 3 P30 CA 51008 29 S2 "HE, MIN" 1/31/23 0:00 4/30/24 0:00 8082 15130451 "LEVY, SHARON GAIL" Not Applicable 98 Unavailable 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC Domestic Higher Education 200570001 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 Research Centers 2023 2340000 1500000 840000 ABSTRACT The mission of the Lombardi Comprehensive Cancer Center (LCCC) Consortiums Administration is to facilitate and implement LCCCs vision and create support and sustain an environment that fosters research interactivity and optimal productivity of Cancer Center investigators and adds value to the Center. The LCCC Consortium is comprised of Georgetown Lombardi Comprehensive Cancer Center based in Washington DC (LCCC-DC) and the John Theurer Cancer Center (JTCC) of Hackensack Meridian Health (HMH) based in Hackensack NJ (LCCC-NJ). Supporting four Research Programs nine Shared Resources and 114 members focused on basic translational clinical and population-based research the Administration oversees $13.57M ($11.98M LCCC-DC $1.58M LCCC-NJ) ADC in peer-reviewed funding and $23.1M ($21.4M LCCC-DC $1.7M LCCC-NJ) in other grants and contracts (direct costs). Michael Vander Hoek MHSA Associate Director (AD) for Administration heads the administrative team supporting LCCC leadership planning strategic investments benchmarking evaluation and communication with constituencies. In addition to building an experienced management team to support Cancer Center members Vander Hoek managed the recruitment of numerous investigators and supported their faculty appointments and promotions. He and his team have successfully managed institutional commitments to support these strategic initiatives. The Administration tracks and manages LCCCs $216.9M in institutional investments from Georgetown University Medical Center (GUMC) MedStar Health (MH) and HMH ensuring that investments are linked to LCCCs strategic plan. The Administration documents and executes LCCCs policies on membership pilot funding equipment purchases Shared Resources and space. The Administration also coordinates cancer research education and training. Significant expansion of administrative activities has supported an increasingly productive relationship with MH as a clinical partner and JTCC which is LCCCs clinical campus in New Jersey aimed at increasing accrual to interventional trials and increasing the diversity of individuals enrolling in trials. For example the Administration led the implementation of the OnCore enterprise-wide Clinical Trial Management System (CTMS). Other activities are highlighted in the narrative. +No NIH Category available Address;Cancer Center;Cancer Control;Competence;Disabled Persons;Disparity population;Educational Curriculum;Employment;Ensure;Equity;Evidence based intervention;Food;Goals;Growth;Guidelines;Housing;Inequity;Lesbian Gay Bisexual Transgender Queer;Malignant Neoplasms;Mentors;Mentorship;Methods;Minority Groups;Modeling;Persons;Phase;Population;Process;Public Health;Research;Research Personnel;Resources;Scanning;Shapes;Testing;Training;Training Programs;Transportation;Underrepresented Minority;Universities;Washington;cancer prevention;design;health disparity;health equity;implementation framework;implementation science;innovation;learning materials;pilot test;preference;recruit;social health determinants;tool Washington University Implementation Science Center for Cancer Control (WU-ISCCC) PROJECT NARRATIVEThe proposed study is relevant to public health because it will provide a model for a trainingprogram to address cancer equity and implementation science. The application of ourconceptual training framework will enhance diversity in the workforce leading to more rapid andequitable implementation of evidence-based interventions practices and guidelines. NCI 10841763 8/22/23 0:00 PA-20-272 3P50CA244431-05S1 3 P50 CA 244431 5 S1 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 ZCA1(A1) 1885266 "BROWNSON, ROSS C" "COLDITZ, GRAHAM A." 1 PUBLIC HEALTH & PREV MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF SOCIAL WELFARE/WORK 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 155498 NCI 99999 55499 PROJECT SUMMARYBackground: A more explicit focus on health equity in implementation science is needed.Incorporating a strong equity focus in implementation science requires not only the scientifictools and processes but also the workforce to carry out the research. We need more workforcecapacity with particular growth needed among underrepresented minority individuals and otherhistorically disadvantaged groups (e.g. people with disabilities LGBTQ populations).Goal: The goal of this project is to create a robust and actionable mentoring and training planfor under-represented scholars (URS) in implementation science for cancer prevention andcontrol that is both tailored to the unique needs and preferences of these scholars andaddresses cancer inequities.Methods: This project builds on previous efforts to conduct an environmental scan of healthequity and implementation science training programs and will develop the curriculum andmentorship plan (Phase 1). In Phase 2 we have two aims:Aim 1: We will pilot test an equity in implementation science training course with a diverse groupof scholars and trainers. Activities will include: recruiting of scholars; planning and conducting acourse; and evaluating the course.Aim 2: We will actively disseminate our findings to a set of core audiences (e.g. trainersresearchers funders). Activities will include: identifying key audiences and conducing activedissemination of findings.Innovations and impact: The proposed training program in implementation science and healthequity will fill a significant gap in capacity building. Scholar training will be designed based on aset of evidence-informed competencies and a model curriculum specific to cancer equity andimplementation science will be produced. It will be developed with user-input to ensure it meetsthe needs of URS to promote scalability and sustainability. The training program will beapplicable to numerous other health equity content areas. 155498 +No NIH Category available Adjuvant;Adverse effects;Antibodies;Antigen-Presenting Cells;Area;Bacteria;Body Temperature;Body Weight;CD47 gene;CTLA4 gene;Cancer Model;Clinical;Clinical Trials;Clone Cells;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Combination immunotherapy;Cytolysis;Distant;Dose;Dose Limiting;Engineered Probiotics;Engineering;Escherichia coli;Evaluation;Excision;Exhibits;Genetic Engineering;Goals;Growth;Health;Heart Rate;Hepatic;Immune;Immune Targeting;Immune checkpoint inhibitor;Immune response;Immunity;Immunologic Adjuvants;Immunophenotyping;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Intravenous;Kinetics;Lead;Lesion;Liver;Liver neoplasms;Local Therapy;Lung;Malignant Neoplasms;Measurement;Metastatic Neoplasm to the Liver;Methods;Modality;Monitor;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mus;Mutate;Mutation;Necrosis;Neoplasm Metastasis;Oral;Oral Administration;Patients;Penetration;Primary Neoplasm;Probiotics;Production;Recombinants;Regimen;Renaissance;Research;Safety;Solid Neoplasm;Specificity;Survival Rate;System;T cell response;T-Lymphocyte;Therapeutic;Toxic effect;Treatment Efficacy;Treatment Protocols;Tumor Antigens;Tumor Immunity;Tumor Promotion;Vascularization;Work;antagonist;anti-cancer;anti-tumor immune response;autoimmune toxicity;cancer immunotherapy;cancer therapy;clinical practice;colon cancer patients;colorectal cancer metastasis;comparative efficacy;cytokine;delivery vehicle;exhaustion;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;immune-related adverse events;immunoregulation;in vivo imaging system;innovation;metastatic colorectal;mouse model;nanobodies;neoantigens;novel;patient subsets;prevent;probiotic therapy;programmed cell death ligand 1;response;side effect;success;synthetic biology;systemic toxicity;tumor;tumor growth;tumor microenvironment Engineering immunotherapeutic probiotics to mitigate irAE PROJECT NARRATIVECancer immunotherapies have demonstrated significant clinical success for subgroups of patients with varyingmalignancies. However due in part to their systemic administration therapeutic limitations include immune-related adverse effects and diminished efficacy due to poor tumor penetration. This proposal seeks to engineerimmunotherapeutic probiotic bacteria that target primary cancers and associated metastases and locally deliverimmunotherapy and adjuvants to stimulate systemic antitumor immunity with minimal side effects. NCI 10841389 12/20/23 0:00 RFA-CA-19-044 5U01CA247573-05 5 U01 CA 247573 5 "KUO, LILLIAN S" 1/21/20 0:00 12/31/24 0:00 ZCA1-RTRB-Y(O1) 10884699 "DANINO, TAL " "ARPAIA, NICHOLAS " 13 BIOMEDICAL ENGINEERING 49179401 F4N1QNPB95M4 49179401 F4N1QNPB95M4 US 40.81207 -73.954377 1833202 COLUMBIA UNIV NEW YORK MORNINGSIDE NEW YORK NY BIOMED ENGR/COL ENGR/ENGR STA 100276900 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 353 Non-SBIR/STTR 2024 541580 NCI 337500 204097 PROJECT SUMMARY/ABSTRACTIn recent years the field of cancer immunotherapy has seen a renaissance with the use of monoclonalantibodies that target immune checkpoints to activate anticancer immune responses demonstrating unparalleledclinical success. Several of these therapies have now gained FDA approval and are part of routine treatmentregimens for several malignancies. Despite the overall success of immunotherapeutic regimens existingmodalities present complications that current research efforts seek to overcome: (1) systemic delivery ofcheckpoint blockade monoclonal antibodies lead to diverse and unpredictable immune-related adverse events(irAE) (2) boosting responses from the endogenous antitumor repertoire often relies on the existence of pre-primed antitumor T cells which in the case of highly immunosuppressive tumors or those with low mutationalburden may be extremely rare and (3) attempts to combine immunotherapies to additively boost T cell responsesdemonstrate increased on-target off-tumor toxicity. Thus to circumvent toxicity and immunosuppressioncontemporary strategies focus on developing methods to deliver potent immunostimulants directly into a tumorlocally priming antitumor T cells to attack disseminated metastases exhibiting a similar antigenic profile. Bridgingthese observations the goals of this proposal are to engineer probiotic strains of bacteria that selectively colonizecolorectal cancer (CRC) and locally release immune checkpoint blockade. We hypothesize that this approachwill result in more robust and diversified antitumor T cell immunity and promote the clearance of colonizedprimary and metastatic colorectal cancer lesions and systemically growing CRC-derived foci. The primaryinnovations of this proposal are in engineering probiotics as an immunotherapeutic delivery vector to locallyrelease high-dose immune checkpoint blockade. Specifically the proposed system has several advantages overcurrent therapeutic strategies including: (1) tumor-specific production of immunotherapies and LPS adjuvant(2) bacteria lysis leading to effective release of novel immunotherapeutics and LPS (3) local delivery of novelimmunotherapeutics that are toxic to deliver systemically and (4) oral delivery of probiotics that selectivelycolonize CRC metastases. This work seeks to shift current research and clinical practice paradigms to overcomecurrent limitations of immunotherapies by providing a unique vehicle to locally deliver immunotherapies thatstimulate antitumor immunity while preventing systemic toxicity and mitigating irAE. 541580 +No NIH Category available Abstinence;Address;Adult;Aftercare;Alkaloids;Anabasine;Area;Behavior Therapy;Behavioral;Behavioral Sciences;Boston;Carbon Monoxide;Cessation of life;Clinic;Clinical Trials;Cognitive;Collaborations;Communities;Control Groups;Counseling;Data Collection;Dimensions;Distant;Economically Deprived Population;Enrollment;Exhalation;Future;Goals;Guidelines;Healthcare;High Prevalence;Homeless persons;Homelessness;Incentives;Incidence;Income;Intervention;Interview;Investigation;Malignant neoplasm of lung;Medical center;Methods;Modification;Operant Conditioning;Participant;Patients;Persons;Pharmacological Treatment;Population;Productivity;Public Health;Publishing;Randomized;Randomized Controlled Trials;Resistance;Resources;Rewards;Sampling;Schedule;Shelter facility;Site;Smoke;Smoker;Smoking;Testing;Time;Tobacco;Tobacco use;Urine;Vulnerable Populations;Work;arm;attributable mortality;behavioral economics;cigarette smoke;cigarette smoking;comorbidity;comparison control;contextual factors;design;disparities in morbidity;experience;experimental study;financial incentive;improved;innovation;malignant oropharynx neoplasm;mortality;multidisciplinary;nicotine patch;nicotine replacement;payment;programs;recruit;reduce tobacco use;response;retention rate;smoking abstinence;smoking cessation;socioeconomic disadvantage;standard care;theories;treatment effect;treatment response Financial incentives for homeless smokers: A community-based RCT PROJECT NARRATIVEHomeless people have a 3.5-fold higher prevalence of cigarette smoking in comparison to non-homelesspeople contributing to 2-fold higher rates of lung cancer and 3- to 5-fold higher rates of tobacco-attributabledeath. To advance the public health objective of improving smoking cessation in socioeconomicallydisadvantaged populations we will conduct a community-based randomized controlled trial to assess the effectof financial incentives on smoking abstinence among adult smokers at Boston Health Care for the HomelessProgram. The findings of this study could inform tobacco treatment efforts for the 934000 people servedannually in US Health Care for the Homeless programs. NCI 10841386 11/20/23 0:00 PAR-18-559 5R01CA235617-05 5 R01 CA 235617 5 "PRUTZMAN, YVONNE M" 4/1/19 0:00 11/30/24 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 9785944 "BAGGETT, TRAVIS P." Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 379218 NCI 225725 153493 PROJECT SUMMARY / ABSTRACTHomeless people have a 3.5-fold higher prevalence of cigarette smoking in comparison to non-homelesspeople contributing to 2-fold higher rates of lung cancer and 3- to 5-fold higher rates of tobacco-attributabledeath. Homeless smokers want to quit but studies have not yet uncovered the optimal approach to help themdo so. In a recently published 8-week pilot randomized controlled trial (RCT) at Boston Health Care for theHomeless Program (BHCHP) we found that financial incentives for smoking abstinence were associated with7-fold higher odds of brief smoking abstinence in comparison to a non-incentivized control condition. Theseresults suggest that financial incentives are a promising approach for reducing smoking in this vulnerablepopulation although further investigation in a larger sample is needed to improve the duration of on-treatmentabstinence assess post-treatment effects and better understand mechanisms of action and contextual factorsthat may influence treatment response. To address these gaps we will conduct a community-based RCT offinancial incentives for smoking abstinence among adult smokers at BHCHP. We will recruit 400 participantsfrom 3 BHCHP sites and randomize them to receive guideline-concordant standard care with (N=200) orwithout (N=200) financial incentives for smoking abstinence. Standard care will consist of 8 weeks ofcombination nicotine replacement therapy (NRT) and 5 sessions with a tobacco coach who will providebehavioral counseling distribute NRT and coordinate referrals to existing tobacco treatment resources.Incentive arm participants will additionally receive a 24-week schedule of 20 debit card payments contingent onshort-term abstinence based on exhaled carbon monoxide levels augmented with 16 interspersed paymentscontingent on longer-term abstinence based on urine anabasine levels. We will use an embedded-experimentmixed methods design where qualitative (qual) data collection is embedded within a larger quantitative(QUAN) RCT with the following aims: Aim 1. (QUAN) To determine the effect of the financial incentivesintervention on anabasine-verified 7-day smoking abstinence at A) the end of treatment (24 weeks) and B) 24weeks after treatment (48 weeks). We hypothesize that incentive arm participants will have greater abstinenceat both timepoints. Aim 2. (qual) To assess why how and under what circumstances homeless smokers A)achieve abstinence in response to financial incentives and B) maintain abstinence after incentives are stopped.To accomplish this aim we will interview selected participants at 24 and 48 weeks probing cognitiveprocedural and contextual dimensions of their response to financial incentives to generate hypotheses aboutmechanisms for on-treatment and post-treatment effects and to inform future work in this area. Our findingscould have important tobacco treatment implications for the 934000 people served annually in US Health Carefor the Homeless programs advancing NCIs objective of reducing smoking in vulnerable populations. 379218 +No NIH Category available Adoption;Area;Artificial Intelligence;Basic Science;Biomedical Research;Biopsy;Classification;Clinical;Clinical Research;Collaborations;Data;Data Commons;Data Set;Deposition;Development;Diagnosis;Division of Cancer Biology;Drops;Ensure;Evaluation;Exclusion;FAIR principles;Failure;Funding;Future;Genotype;Genotype-Tissue Expression Project;Grant;Health Resources;Histology;Image;Inferior;Infrastructure;Learning;Link;Machine Learning;Manuals;Masks;Modeling;Morphologic artifacts;Morphology;Multiomic Data;National Cancer Institute;Nephrotic Syndrome;Output;Performance;Play;Process;Prognosis;Quality Control;Reader;Readiness;Reporting;Reproducibility;Research;Research Personnel;Role;Sampling;Science;Slide;Synapses;Techniques;The Cancer Genome Atlas;Time;Tissues;Training;Translational Research;Trust;United States National Institutes of Health;Universities;Validation;Work;anticancer research;biomarker discovery;cohort;comparative;cost;data management;data mining;data quality;data sharing;deep learning;digital pathology;generalist repository;histological image;imaging biomarker;imaging detection;improved;interest;machine learning method;machine learning model;multiple omics;open data;open source;parent grant;programs;prospective;prototype;public repository;repository;success;tool;treatment response;whole slide imaging Assuring AI/ML-readiness of digital pathology in diverse existing and emerging multi-omic datasets through quality control workflows Project NarrativeThe project will improve the AI/ML readiness of existing and emerging NIH-supported digital pathology publicdatasets and research programs supported by the MC2 Center by automatically evaluating and reportingartifacts and batch effects using open-source NIH-funded tools.These enriched datasets will enable researchers to exclude artifacts from their training and validation sets in areproducible manner providing greater trust in cross-investigator dataset reuse while enhancing AI/ML modelperformance and robustness.To quantitatively demonstrate the provided value-add of cleaned AI/ML-ready data in downstream tasks aprototypical deep learning use case is planned. NCI 10841333 9/12/23 0:00 PA-20-272 3U24CA274494-02S2 3 U24 CA 274494 2 S2 "TURNER, MICHELLE C" 9/14/22 0:00 8/31/24 0:00 ZCA1(M2) 1891838 "BLETZ, JULIE A" "EDDY, JAMES A" 7 Unavailable 830977117 TPALZA9N4M11 830977117 TPALZA9N4M11 US 47.62803 -122.330082 10023027 SAGE BIONETWORKS SEATTLE WA Other Domestic Non-Profits 981211031 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 270000 OD 200000 70000 AbstractIn an era of multi-omics histology remains an essential approach for basic translational and clinical researchproviding valuable low-cost and non-destructive information about tissue morphology. The adoption of wholeslide imaging (WSI) and digital pathology (DP) has led to large clinical and research repositories beinginstantiated for computational data mining of image-based biomarkers associated with genotype diagnosisprognosis and therapy response. Importantly data quality plays a critical role in the usage of these WSIespecially when employing artificial intelligence (AI) and machine learning (ML) methods. Artifacts and batcheffects may arise at many points in the process from biopsy to digitization and while several tools to detect themhave been developed consistent application and reporting are lacking with none being routinely applied in publicrepositories. This leaves a unique opportunity to immediately provide added value to existing and future NIH-supported datasets. This proposal sees a collaboration between Sage Bionetworks experts in FAIR data sharingand Team Science and Dr. Andrew Janowczyk a leader in automated quality control (QC) of WSI who hasspearheaded the development of an open-source DP QC tool HistoQC. We propose to enhance the AI/MLreadiness of existing and future DP data by providing transparent reproducible reporting of detected imagingartifacts and batch effects within NIH-sponsored datasets in an automated fashion via the extension of ourexisting QC workflows. Implementing transparent reporting of DP data quality will enable researchers to excludeartifacts from their training sets in a consistent cross-investigator manner. Our work will provide greater trust indataset reuse and experimental reproducibility while also easing AI/ML model creation and enhancing theirperformance. We will build on strong preliminary data and prototypes demonstrating both significantly improvedcross-reader QC reproducibility and technical feasibility with three specific aims. Aim 1 sees this enrichmentprocess will be applied to WSI from NIH-supported public datasets including TCGA and GTEx and for NIH/NCIDivision of Cancer Biology research programs supported by the Multi-Consortia Coordinating (MC2) Centerparent grant. Aim 2 employs the lessons learned from the enhancement of raw DP data to be AI/ML ready inAim 1 to deploy a scalable workflow for QC of all incoming DP data from MC2-supported programs providingcontinual prospective data enrichment to assure AI/ML readiness. Lastly Aim 3 demonstrates enhanced AI/MLreadiness of DP data subjected to our automated QC processes using a prototypical self-supervised tissueclassification task. Our deliverables include (a) 5000 WSI annotated by our QC workflow and enhanced intoAI/ML ready datasets; (b) workflows to enable processing of incoming datasets for AI-readiness (c) a failure rateof identifying poor quality slides is <1%; and (d) our QC comparative AI/ML demonstration yields an improvementof >10% performance in terms of tissue classification performance as a result of our data enhancements. 270000 +No NIH Category available Africa South of the Sahara;Anatomy;Biological;Biological Markers;Carcinogens;Cervical;Cervical Cancer Screening;Cervix Uteri;Collection;Country;Cytology;DNA;DNA Methylation;Data;Data Analyses;Detection;Development;Disease;Enrollment;Epigenetic Process;Ethics;Exposure to;Fingers;Future;Genes;Genotype;Goals;Grant;HIV;HIV/AIDS;HPV-High Risk;Hand;High Prevalence;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Human papillomavirus 18;Income;Infection;Laboratories;Lead;Learning;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Manuals;Manuscripts;Masturbation;Mentors;Methylation;Molecular Epidemiology;Nigeria;Oral;Oral Examination;Oral Stage;Oropharyngeal;Parents;Participant;Peer Review;Persons;Population;Progress Reports;Protocols documentation;Recording of previous events;Research;Research Design;Research Technics;Risk;Sampling;Sex Behavior;Sexually Transmitted Diseases;Site;Squamous Cell;Supervision;Swab;Technology;Testing;Time;Training;United States National Institutes of Health;Universities;Vagina;Validation;Woman;Women's Group;Work;Writing;assay development;cancer biomarkers;cancer invasiveness;computerized data processing;epigenetic marker;epigenetic profiling;epigenomics;ethical legal and social implication;high risk;interest;malignant mouth neoplasm;malignant oropharynx neoplasm;men;oral HPV;oral HPV infection;premalignant;progression risk;recruit;research study;response;screening;screening program;sexually active;skills;sound;tool Epigenetic biomarkers of Cervical HPV in women with oral and oropharyngeal HPV precancer and cancer NARRATIVEHuman Papillomavirus (HPV) is a prevalent sexually-transmitted infection worldwide and is linked to cervicaloral and oropharyngeal cancer. This project aims to identify epigenetic biomarkers for women with high-risk oralHPV infection and concurrent high-risk HPV infections in the cervix. The mentored research will train SundayOyerinde MBBS in various skills including epigenetic testing assay development and grant and manuscriptwriting. NCI 10841283 9/15/23 0:00 PA-20-272 3R01CA274952-02S1 3 R01 CA 274952 2 S1 "LIDDELL HUPPI, REBECCA" 9/16/22 0:00 8/31/26 0:00 ZDE1(15) 9243845 "HOU, LIFANG " "MORHASON - BELLO, IMRAN " 5 PUBLIC HEALTH & PREV MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 125000 NCI 105085 19915 SummaryThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-038. Human Papillomavirus (HPV) is the most common sexually-transmitted infection worldwide with nearlyall sexually active women and men infected during their lifetime. HPV infection is highly prevalent in Sub-SaharanAfrica (SSA) due to the lack of widespread HPV vaccination. Infection of hr-HPV strains mainly HPV 16 and 18strains accounts for most cervical cancer (~99%) and oral and oropharyngeal cancer (85-96% of squamous cellvariety). HPV associated cancers are rapidly increasing in SSA due to lack of HPV vaccination and cervicalcancer screening programs like high income countries (HICs) such as U.S. as well as high prevalence ofHIV/AIDS. Infection with high-risk HPV (hr-HPV) mainly HPV 16 and 18 leads to oral potentially malignantdisorders (OPMD) the precancerous stage of oral and oropharyngeal cancers (OOPCs). Unlike cervical cancer(CC) there are no well-developed population-level screening programs for OOPC even in high income countries(HICs) such as the U.S. Epigenetic changes are a hallmark of cancer and epigenetic biomarkers represent afield with untapped potential for identifying women at risk of progression from exposure to carcinogens such ashrHPV infection to pre-malignancy and ultimately to invasive cancers. Now there is no universal screeningstrategy for women with oral or oropharyngeal cancer compared to cervical cancer. It is important to takeadvantage of the ongoing R01 grant Epigenetics of oral HPV and associated oral/oropharyngeal cancer inpeople living with HIV in Nigeria (EpOOCH) study to identify women that might also be at risk of having high-risk HPV in the cervix at the same time (synchronous concordance) or in the nearest future (asynchronousconcordance). The aims of this project are: 1) To conduct cervical swab epigenetic profiling (at Northwestern) intwo groups of women: oral hrHPV and cervical HPV (n=30 Group 1) vs. oral hrHPV only (n=30 Group 2) toidentify cervical hrHPV-associated DNAm biomarkers also seen in oral and oropharyngeal sites. We will compareepigenetic profile in both cervical swab (will be profiled by this supplement) and oral swab (have been obtainedin the parent R01 project R01CA27495201); and 2) To validate the hrHPV-associated biomarkers in cervix usinggene-specific DNAm PCR technology identified in Aim 1. This validation will be performed at University of IbadanNigeria. Our long-term goal for this mentored research is to develop biomarkers or tools that can screen oridentify women with hrHPV infections that could persist and develop into cervical cancer in future. This mentoredresearch Supplement will train the applicant Sunday Oyerinde MBBS to gain new skills and expertise in studydesign of molecular epidemiology projects epigenomic processing and analysis new assay developmentethical and economically sound research techniques and writing for peer review and grants. 125000 +No NIH Category available Administrative Supplement;Artificial Intelligence;Awareness;Bioinformatics;Biology;Biomedical Engineering;Biomedical Research;Clinical;Collaborations;Communities;Complex;Comprehension;Data;Data Set;Development;Discipline;Drug Modelings;Ensure;Event;Fostering;Gene Expression;Gene Mutation;Genes;Genomics;Goals;Image;Malignant Childhood Neoplasm;Malignant Neoplasms;Methodology;Methods;Modeling;Multiomic Data;Parents;Pediatric Neoplasm;Pharmaceutical Preparations;Pharmacogenomics;Prediction of Response to Therapy;Readiness;Research Personnel;Resources;Scientist;Structure;United States National Institutes of Health;artificial intelligence method;cancer cell;community engagement;data format;deep learning;deep learning model;drug sensitivity;genomic data;image guided;improved;multidimensional data;multiple omics;novel;novel therapeutics;parent project;predictive modeling;response;symposium;tool;web server Enhancing AI-readiness of multi-omics data for cancer pharmacogenomics NarrativeUnderstanding the mechanisms by which drugs operate against pediatric cancers is challenging. We proposeto use artificial intelligence (AI) to comprehensively integrate available data sets and create a predictive modelfor drug responses in cancer cells. In this supplement we aim to improve the organization of complex genomicdata to enhance the comprehension by AI make tools and data more accessible to other scientists andfacilitate collaboration by bringing together researchers from diverse fields. NCI 10840074 9/8/23 0:00 PA-20-272 3R00CA248944-04S1 3 R00 CA 248944 4 S1 "DUECK, HANNAH RUTH" 3/1/20 0:00 6/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 15588534 "CHIU, YU-CHIAO " Not Applicable 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Non-SBIR/STTR 2023 318000 OD 200000 118000 Summary/AbstractThe scarcity of comprehensive pharmacogenomics resources poses a significant obstacle to the developmentof new therapies for pediatric cancers. Our parent R00 project seeks to overcome this challenge by creating andvalidating a novel deep learning model for predicting drug sensitivity of pediatric tumors using integrative multi-omics profiles. However the utilization of cutting-edge deep learning models to analyze multi-omics is oftenchallenging since the data are high-dimensional and unstructured. Under the parent project we have evaluatedseveral embedding methods to transform multi-omics data into a structured format that enables artificialintelligence (AI) applications. In response to NOT-OD-23-082 Administrative Supplements to SupportCollaborations to Improve the AI/ML-Readiness of NIH-Supported Data we propose to supplement the parentproject by further enhancing the AI-readiness of multi-omics data for studying cancer pharmacogenomics. Ourhypothesis is that biology-guided image embedding of unstructured multi-omics data enhances the informationcaptured by deep learning enabling accurate modeling and prediction of treatment responses. We aim toachieve three relevant but independent goals: 1) methodology: to develop better data conversion methods forAI-readiness of cancer multi-omics 2) accessibility: to make AI-ready tools and data more accessible to thebiomedical research community and 3) engagement: to promote collaboration on AI-readiness among thecommunities of bioinformatics biomedical engineering and biomedicine. Specifically Aim 1 will evaluate acomprehensive array of biologically meaningful ways to transform unstructured multi-omics data including genemutation and gene expression profiles to an image-like data format that can be analyzed by convolutionalmodels. Our approach will embed functional similarities of genes to ensure interpretability. In Aim 2 we willdevelop an interactive web server that provides easy access to data conversion tools and AI-ready cancer data.Finally in Aim 3 we will organize a community engagement event at a flagship conference of bioinformatics toenhance awareness of current gaps in AI-readiness and foster collaboration and diversity among clinical basicand computational scientists and trainees. The proposed supplement has brought together a collaborative teamof experts from diverse disciplines covering cancer bioinformatics genomics and pharmacogenomics AImethodology and community engagement events. Successful completion of this supplement will have asignificant impact on advancing the AI-readiness of large cancer data aligning with the objectives of the parentR00 project. 318000 +No NIH Category available Endovascular ChemoFilter to Reduce Doxorubicin Toxicity during Intra-Arterial Chemotherapy PROJECT NARRATIVEWe propose a paradigm shift in cancer therapy: ChemoFilter an endovascular catheter-based medical device that will beinserted under image guidance into the veins of the body to directly filter specific chemotherapy drugs out of the blood streamafter these drugs have had their effect on a tumor but before they have caused systemic toxic effects. ChemoFilter wouldhelp patients fight cancer by minimizing drug toxicity allowing for high-dose therapy to better treat their disease and improvesurvival. Patients suffering from primary and oligometastatic liver cancers are the first targets for this device. NCI 10840035 9/18/23 0:00 PA-20-261 4R42CA265316-02 4 R42 CA 265316 2 "EVANS, GREGORY" 9/23/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-SBIB-Y(12)B] 10213717 "HETTS, STEVEN WILLIAM" Not Applicable 19 Unavailable 117630144 CNTFFZCVNEA3 117630144 CNTFFZCVNEA3 US 37.391757 -122.044139 10062854 FILTRO MEDICAL INC. San Jose CA Domestic For-Profits 951204212 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1000000 NCI 853374 103258 PROJECT SUMMARY Dosing of chemotherapeutics is limited by systemic toxic side effects. We are developing a new class of image-guided temporarily deployable endovascular catheter-based medical devices that selectively remove specific drugs from theblood stream to reduce systemic toxicities. The proposed ChemoFilters incorporate specialized materials that bind targetdrugs in situ through a variety of mechanisms. During intraarterial chemotherapy (IAC) infusion to a target organ (e.g. a solidorgan containing a tumor) excess drug not trapped in the target organ passes through to the veins draining the organ andthen is circulated to the rest of the body causing toxicities in distant locations. By temporarily deploying a ChemoFilter in thevein(s) draining the organ undergoing IAC we seek to bind excess drug before it can escape to cause systemic toxicity. TheChemoFilter would then be removed in the interventional radiology suite shortly after the IAC procedure thus removingexcess drug from the patient. Although paired intraaterial infusion and venous filtration can theoretically be used for any drugthat has its site of therapeutic action in one location and its site of dose-limiting toxicity in another location the most compellingapplication for this technology is increasing efficacy and safety of locoregional cancer chemotherapy. Primary and metastatic liver tumors are among the top three causes of cancer death worldwide. Image-guidedtransarterial chemoembolization (TACE) a form of IAC cost-effectively increases survival in this population. Doxorubicin(Dox) is a low-cost highly effective chemotherapeutic agent frequently used in IAC. Dox use is limited by systemic toxicitiesmost importantly irreversible cardiac failure. Dox follows a therapeutic linear dose-response model in which increasing doselinearly increases tumor cell kill providing motivation for higher-dose Dox therapy. Our initial project has yielded ChemoFiltersthat can reduce Dox deposition in the heart by 46% in animal models. We seek to build upon that success by designingbuilding and testing new devices that can be more easily navigated to the hepatic veins in human patients. Prototype ChemoFilters will be modeled built validated in vitro for efficacy and tested in vivo in a large animal modelfor navigability in Phase I by experienced teams from Filtro Inc and UCSF. In phase II the optimized devices from phase Iwill then be tested for efficacy and safety in a large animal model and a first-in-man safety and efficacy study in patients withunresectable liver cancer will be planned and initiated. Achievement of these aims will create new minimally invasive medicaldevices that should markedly increase the efficacy of image-guided locoregional intraarterial chemotherapy by loweringsystemic drug concentrations and reducing systemic toxicities for the usual dose of Dox as part of TACE. Completion of thisstudy will poise the ChemoFilter technology for a pivotal clinical trial that would assess Dox dose escalation in any givenIAC/TACE procedure to achieve better local tumor control in fewer IAC/TACE sessions. 1000000 +No NIH Category available Address;Administrative Supplement;Adolescent and young adult cancer patients;American College of Surgeons Oncology Group;Cancer and Leukemia Group B;Clinical;Clinical Research;Clinical Trials;Community Clinical Oncology Program;Education;Effectiveness;Enrollment;Ensure;Fostering;Goals;Healthcare Systems;Infrastructure;Institution;Lead;Leadership;Malignant Neoplasms;North Central Cancer Treatment Group;Oncology;Patients;Policies;Principal Investigator;Research;Research Personnel;Research Priority;Services;Site;Surgeon;Translational Research;U-Series Cooperative Agreements;Work;design;member;older patient;operation;patient population;programs;rare cancer;recruit;translational cancer research;translational scientist Member Site Core The Project Narrative has been addressed in the Overall Component per the RFA NCI 10840031 8/2/23 11:27 PA-20-272 3U10CA180821-10S2 3 U10 CA 180821 10 S2 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 ZCA1 8218 1879065 "BERTAGNOLLI, MONICA M" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 Other Research-Related 2023 1529099 1269838 259261 The Project Summary/Abstract has been addressed in the Overall Component per the RFA +No NIH Category available AR gene;Acceleration;Acetates;Address;Adenocarcinoma;Aftercare;Androgen Receptor;Appearance;Area;Biological;Biological Assay;Biological Markers;Biomedical Engineering;Biopsy;Blood;Blood Cells;CLIA certified;Cancer Center;Cancer Patient;Categories;Cells;Cellular Assay;Centrifugation;Circulation;Clinical;Clinical Research;Clinical Trials;Clonal Expansion;Collaborations;DNA;Data Analyses;Detection;Development;Diagnostic;Disease;Disease Resistance;Early Diagnosis;Early identification;Enhancers;Ensure;Evaluation;Evolution;Exclusion;Exposure to;Failure;Foundations;Frequencies;Future;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Genetic Transcription;Goals;Histologic;Hygiene;Institution;Laboratories;Left;Ligand Binding Domain;Liquid substance;Liver;Magnetism;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Memorial Sloan-Kettering Cancer Center;Messenger RNA;Metastatic Prostate Cancer;Methods;Molecular;Mutation;Neoplasm Circulating Cells;Neuroendocrine Prostate Cancer;Neuroendocrine Tumors;Output;Patient Care;Patients;Performance;Population;Preparation;Probability;Process;Prognosis;Progression-Free Survivals;Prospective Studies;Protein Analysis;Provenge;RNA;RNA Splicing;Radium;Reagent;Receptor Signaling;Recommendation;Research Personnel;Resistance;Resistance development;Risk;Sampling;Site;Specificity;Surface Properties;Surface Tension;System;Systematic Bias;Technology;Testing;Therapeutic;Time;Tissues;Tube;Universities;Validation;Variant;Wisconsin;abiraterone;advanced prostate cancer;bone;cancer biomarkers;cancer cell;castration resistant prostate cancer;chemotherapy;clinically relevant;cohort;detection method;diagnostic accuracy;diagnostic tool;drug development;enzalutamide;hormone therapy;improved;inhibitor;liquid biopsy;lymph nodes;men;novel diagnostics;novel therapeutics;optimal treatments;particle;patient biomarkers;patient subsets;precision medicine;predictive marker;prognostic;prognostic of survival;prognostic value;prospective;radiological imaging;randomized clinical trials;research clinical testing;resistance mechanism;response;success;targeted treatment;taxane;therapy resistant;tool;treatment strategy;treatment stratification;tumor;virtual Validation of predictive liquid biomarkers for patients with metastatic prostate cancer Project NarrativeRecent studies have found that expression of the androgen receptor splice variant 7 in circulating tumor cellscan identify resistance to hormone therapies in approximately 10% men with prostate cancer. We havedeveloped a new test that builds upon this assay to identify other patients at risk for resistance to thesetherapies. This proposal validates this new assay to move us closer to the goal of achieving better precision intreating patients. NCI 10840022 9/15/23 0:00 PAR-18-317 4UH3CA260389-03 4 UH3 CA 260389 3 "MCKEE, TAWNYA C" 6/1/21 0:00 5/31/26 0:00 ZCA1-SRB-2(J2) 10134900 "LANG, JOSHUA MICHAEL" "ARMSTRONG, ANDREW J; HALABI, SUSAN ; RATHKOPF, DANA " 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 363463 NCI 299949 63514 Project Summary/AbstractThe University of Wisconsin Carbone Cancer Center (UWCCC) Duke University and Memorial Sloan KetteringCancer Center (MSKCC) seek support for establishing the analytical and clinical validity of a Circulating TumorCell (CTC) biomarker assay via the UH2/UH3 mechanism. This biomarker assay will evaluate a gene expressionsignature of treatment resistant castration-resistant prostate cancer (CRPC).While many patients with prostate cancer benefit from Androgen Receptor Signaling Inhibitors (ARSIs) a subsetof patients do not respond to this class of treatments while nearly all others develop resistance within 1-2 years.Identified mechanisms of resistance include development of Neuroendocrine Prostate Cancer (NEPC) andexpression of Androgen Receptor Splicing Variants (AR-Vs). Early detection of NEPC or AR-Vs as drivers oftreatment resistant prostate cancer would eliminate the need to wait for clinical manifestations of resistanceaccelerating the time to administration of more suitable therapy and increasing survival.While precision medicine approaches are increasing in popularity and reliability their ultimate capacity toimprove patient care hinges on their diagnostic accuracy. Realization of a clinically relevant assay requiresthorough analytical and clinical evaluation and while many biomarker assays have successfully demonstratedanalytical performance failure to address clinical utility has left many unable to improve on existing diagnostics.By focusing our efforts on evaluation of both analytical and clinical validity we aim to provide diagnostic accuracyin assessing an expression of NEPC and AR-Vs building a necessary foundation for future clinical trials.To that end we have optimized a multi-plexed gene expression assay on CTCs that identifies these two majorcategories of resistance to ARSIs. This assay has shown promising initial results in a preliminary cohort ofpatients with aggressive CRPC. Optimization of this assay has taken into consideration the rarity of CTCs andthe diversity of other blood cells in circulation; ensuring efficient RNA extraction probe specificity andappropriate data interpretation. The manipulation and retention of rare cells is enabled by our Exclusion-basedSample Preparation (ESP) technology wherein centrifugation and wash steps are eliminated. This automatedand commercially available platform also called the Gilson ExtractMax offers minimal user variability thusmaximizing precision. Our collaboration with Dr. Kaitlin Sundling at the Wisconsin State Lab of Hygiene a CAP-approved clinical testing laboratory provides expert oversight for planning and execution of analytical validation.In collaboration with Dr. Andrew Armstrong Dr. Susan Halabi and Dr. Dana Rathkopf we have assembled ateam of clinical researchers and biostatisticians to rapidly validate this multi-plexed biomarker in a prospectivestudy. This RNA-based CTC assay shows potential for identifying treatment resistant prostate cancer inpreliminary studies of patients and is thus poised for success in both analytical and clinical validation. 363463 +No NIH Category available Cancer Control;Cancer Surveillance Research Program;Code;Contracts;Data;Data Collection;Data Linkages;Development;Division of Cancer Control and Population Sciences;Generations;Information Systems;Knowledge;Maintenance;Malignant Neoplasms;Methodology;Methods;Population Research;Quality Control;Recommendation;Science;Statistical Models;Technology;Testing;United States National Institutes of Health;Visualization;annotation system;cancer statistics;case finding;data mining;data quality;novel;population based;programs;simulation;statistics;tool;usability PROFESSIONAL SUPPORT FOR CANCER CONTROL AND POPULATION BASED RESEARCH NIH/NCI/DCCPS SURVEILLANCE RESEARCH PROGRAM n/a NCI 10839745 26116004B91021F00210-P00003-0-1 N02 8/16/21 0:00 8/15/24 0:00 78316759 "DUNN, MARSHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2023 1662302 NCI This contract provides support for the activities related to: cancer data collection quality control analysis dissemination of reliable population-based cancer statistics geospatial data systems statistical modeling and other novel methodological and technological solutions relevant to cancer surveillance. 1662302 +No NIH Category available Address;Alaska Native;American Indians;Cancer Center;Cancer Control;Classification;Data;Epidemiologic Monitoring;Ethics;Ethnic Origin;Goals;Hawaiian population;Incidence;Indigenous;Journals;Knowledge;Malignant Neoplasms;Native Hawaiian;Native-Born;Pattern;Population;Prevalence;Process;Race;Reporting;Structure;Tribes;United States Indian Health Service;Update;Writing;cancer statistics;data dissemination;digital;dissemination strategy;improved;indigenous community;innovation;mortality Cancer Data Talks in AI/AN/Native Hawaiian and Indigenous Landscapes PROJECT NARRATIVEThe objective of this supplement is to advance knowledge in cancer data discussions in American Indian AlaskaNative Native Hawaiian and Indigenous Landscapes. Discussions will include current surveillance prevalenceincidence and mortality patterns across populations with overall goals of understanding and utilizing datatowards cancer control. Partners will engage in conversations on data as it relates to race ethnicity andIndigenous related classifications. NCI 10839576 6/15/23 0:00 PA-20-272 3P30CA016056-46S1 3 P30 CA 16056 46 S1 "HE, MIN" 5/15/23 0:00 4/30/24 0:00 1894074 "JOHNSON, CANDACE S." Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 5/15/23 0:00 4/30/24 0:00 397 Research Centers 2023 50000 NCI 29121 20879 PROJECT SUMMARY/ABSTRACTCancer Data Talks in American Indian Alaska Native Native Hawaiian and Indigenous Landscapes is a projectthat engages conversations with Indigenous community leaders data experts and thought leaders in cancerdata through presentations networking and discussions focused on cancer control. 50000 +No NIH Category available Acceleration;Address;Adult;Affect;Asthma;California;Carcinogens;Censuses;Clinical;Cohort Studies;Complex;Computer software;Data;Data Commons;Data Linkages;Databases;Disease;Education;Emergency department visit;Energy-Generating Resources;Environment;Ethnic Origin;Event;Exposure to;Flare;Future;Gases;Green space;Health;Home;Hospitalization;Human;Immune System Diseases;Income;Individual;Industry;Liver diseases;Location;Malignant Neoplasms;Measures;Neighborhoods;Oils;Participant;Patient Self-Report;Pattern;Persons;Play;Population;Population Density;Population Sciences;Positioning Attribute;Production;Race;Recording of previous events;Research;Research Personnel;Research Priority;Resources;Risk;Schools;Secure;Services;Site;Socioeconomic Status;Subgroup;Surveys;System;Time;Toxin;Vulnerable Populations;Woman;Work;Workplace;World Health;anticancer research;climate change;climate impact;climate-related health;cloud based;cohort;data access;data integration;data resource;data visualization;exposed human population;follow-up;greenhouse gases;human disease;improved;interest;large scale data;mortality;nervous system disorder;novel;pollutant;prospective;respiratory;study population;teacher;tool;user-friendly;walkability Oil and Gas as Drivers of Climate Change and Health: Developing unique resources to investigate multi-level and diverse effects of exposure to oil and gas wells PROJECT NARRATIVEThe significant increase in domestic oil production in the US over the last decade has also significantlyincreased the number of people who live close to and oil and gas wells especially in California. Oil and gasproduction generates carcinogens toxins pollutants and other harmful exposures but the health effects onpopulations that live near oil and gas sites are not well understood. This project will generate detailed data onexposure to oil and gas wells in the California Teachers Study cohort so that those data can be used to bettercharacterize the real-world health effects of these exposures and better understand how potential futuremitigation might impact human exposures and disease. NCI 10839157 8/30/23 0:00 PA-20-272 3U01CA199277-09S1 3 U01 CA 199277 9 S1 "MAHABIR, SOMDAT" 9/1/15 0:00 8/31/25 0:00 ZCA1(M2) 10290448 "LACEY, JAMES V" "MARTINEZ, MARIA ELENA" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 113 Non-SBIR/STTR 2023 650629 NIEHS 551935 98694 PROJECT SUMMARY / ABSTRACTThe oil and gas industry generates half of all global greenhouse gasses. On the ground local oil and gasproduction creates myriad exposures that can increase risks of developing asthma and cancer as well as liverimmune and neurologic diseases. Millions of California residents live work and play near active oil and gaswells because the State does not require any minimum distance between those wells & schools homes parksor workplaces. Exposure to oil & gas wells is complex and dynamic but few studies include the breadth anddepth of data necessary to fully assess contemporary health effects or understand future changes. TheCalifornia Teachers Study (CTS) is a prospective observational cohort that has followed N=133477 adultwomen almost all of whom live in California continuously since 1995-1996. We propose to create detailedindividual-level data on CTS participants' exposure to oil and gas wells during CTS follow-up. First we will usedetailed data on all oil and gas wells in California from the California Department of Conservation GeologicEnergy Management Division (CalGEM) well statewide tracking system (WellSTAR) and from Enverus acommercial service that maintains a national database of all oil and gas well drilling system to identify whowas exposed to oil and gas well sites. We will create time-dependent exposure metrics that capture individuals'exposures to active idle and capped wells by time distance and production volume as well as flaringevents. Second we will integrate those exposures with other neighborhood-level measures of socioeconomicstatus (from the US Census Bureau) and environment burden (from CalEnviroScreen). Third we willcharacterize the real-world exposure distribution of oil and gas wells and production over time and across CTSparticipant subgroups of interest. These summary data and data visualizations will provide the specific anddetailed data researchers need to accelerate their planning and future research. We will also conduct a proof-of-concept project by comparing respiratory-related emergency department visit patterns among participantswho were exposed vs. unexposed to oil and gas wells. The CTS is an ideal setting in which to generate thesenovel data that can accelerate research on climate change. All of these data and resources will be openlyavailable to researchers everywhere via the secure user-friendly and cloud-based CTS Researcher Platform.These data will enable a broad range of research that can quantify the effects of oil and gas productionexposure on numerous disease endpoints; evaluate the potential interactions between these exposures andother aspects of the built and natural environment; and assess the potential impacts of past and futurechanges in exposure such as when well production is paused or permanently ended. These data will positionthe CTS to support a broad range of hypothesis-driven population-sciences research on how oil and gasproduction affects human health and influences the impact of climate change on human health. 650629 +No NIH Category available Alternative Splicing;Antigens;Automobile Driving;BRCA mutations;Benign;Binding;Breast;Cell surface;Computer software;Data;Development;Disease;Goals;Immunooncology;MHC antigen;Malignant Neoplasms;Medically Underserved Area;Messenger RNA;Methods;Mutation;Organoids;Pancreas;Patients;Pediatric Neoplasm;Phase;Preventive;Prostate;Protein Isoforms;Proteome;RNA Splicing;Readiness;Regulation;Research;Small Business Innovation Research Grant;Source;Therapeutic;Tissues;Tumor Burden;Tumor stage;Validation;brca gene;cancer immunotherapeutics;clinical care;commercialization;deep sequencing;exome sequencing;mammary;mutation carrier;neoantigens;novel strategies;prospective;tandem mass spectrometry;tool;transcriptome sequencing;tumor Comprehensive validation and commercial readiness of SpliceIO a software platform for neoantigen discovery using RNA-seq data PROJECT NARRATIVEImmuno-oncology (IO) therapies offer great promise in effectively treating cancers however current tools for IOtarget identification are not amenable to tumors with low tumor mutational burden (TMB) and/or are skewedtowards the identification of tumor neoantigens that are MHC bound. Envisagenics has developed SpliceIO asoftware platform for neoantigen discovery that detects splicing errors using only RNAseq data which caneffectively identify both MHC-presented and MHC-independent tumor neoantigens and do so in low TMBtumors. This project will validate the SpliceIO platform in BRCA1/2+ mammary tissue derived organoids andupon completion Envisagenics will achieve commercial readiness for SpliceIO thus providing a valuable toolfor IO target identification in numerous cancers. NCI 10838973 7/12/23 0:00 PA-21-345 3R44CA265446-02S1 3 R44 CA 265446 2 S1 "ZHAO, MING" 7/1/22 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1(15)-B] 10512346 "AKERMAN, MARTIN " "ARUN, GAYATRI " 7 Unavailable 79493898 DDJBJ4APF8S3 79493898 DDJBJ4APF8S3 US 40.871019 -73.428647 10037243 "ENVISAGENICS, INC." Long Island City NY Domestic For-Profits 11101 UNITED STATES N 7/1/23 0:00 3/31/24 0:00 394 SBIR/STTR 2023 77000 NCI 55000 22000 PROJECT SUMMARYAccurate splicing is critical for the assembly of viable mRNA isoforms. Splicing errors resulting in disease-causing mRNAs occur frequently. In fact ~50% of all cancer-driving synonymous mutations are predicted tocause splicing errors. Since the introduction of analytic software to quantify alternative splicing (AS) from RNAsequencing (RNAseq) data evidence pointing to the importance of splicing regulation in cancer has mounted.Splicing errors are a major source of tumor-specific neoantigens thus splicing research opens tremendousopportunities for the development of cancer immunotherapeutics and preventives. Envisagenics has developedSpliceIO a software platform for neoantigen discovery using only RNAseq data. Most other methods forneoantigen prediction rely on whole-exome sequencing for the discovery of mutation-based neoantigens amethod that is not amenable to cancers with low tumor mutational burden (TMB) such as breast prostatepancreatic pediatric tumors and other benign conditions. These cancers however are rich in splicing errorswhich can be detected with SpliceIO making neoantigen discovery possible in this currently underserved areaof medical need. Moreover current methods predict neoantigens based on their ability to bind and be presentedby MHC molecules which are downregulated in >60% of late-stage tumors. Since SpliceIO focuses on splicingerrors it has the ability to predict both MHC-presented and MHC-independent antigens that are directly bound tothe cell surface. The goal of this Direct-to-Phase II proposal is to build upon strong preliminary data and attain commercialreadiness for SpliceIO. Envisagenics has been at the forefront of RNAseq-based target discovery since thedevelopment and commercialization of SpliceCore a software platform for the identification of druggablesplicing isoforms. Envisagenics will utilize a proven commercialization strategy which consists of comprehensiveexperimental validation to solidify a strong value proposition and commercial offering to prospective biopharmapartners. In this proposal we will develop a novel strategy for large-scale neoantigen validation using tandemmass spectrometry (MS/MS). In addition we will scale identification of neoantigens using mammary organoidsfrom BRCA1/2 mutation carriers. We present preliminary data equivalent to results from a Phase I SBIR anddemonstrate the utility of splicing-derived target discovery for cancer therapeutics. To accomplish these goals and obtain commercial readiness for SpliceIO we will complete the followingspecific aims in this proposal: Aim 1: Develop a high-depth/high-sensitivity reference proteome for SpliceIOvalidation using MS/MS data. Aim 2: Neoantigen identification in BRCA1/2 mutation carriers using ultra-deepsequencing. Aim 3: Experimental validation of splicing-derived neoantigens. Completion of these aims will bringSpliceIO to a level of development proven to support successful commercialization and make a significantdifference patient treatment and clinical care. 77000 +No NIH Category available Acceleration;Affinity;Animal Model;Antibodies;Antibody Therapy;Antigens;Binding;Biological;Bispecific Antibodies;Breast Cancer cell line;Cancer cell line;Cell Line;Cell surface;Clinical Trials;Complement;Correlative Study;Cytoplasm;DNA Sequence Alteration;Data;Diagnostic Procedure;Drug Delivery Systems;Drug Exposure;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelium;Erlotinib;Future;Gene Amplification;Goals;Growth Factor Receptors;Half-Life;Heterogeneity;Image;Imaging Techniques;Immunohistochemistry;In Vitro;Individual;Label;Ligands;MET gene;Measures;Mesenchymal;Methods;Monitor;Mutation;Non-Small-Cell Lung Carcinoma;Patient Selection;Patients;Positron-Emission Tomography;Pre-Clinical Model;Predictive Value;Radioactive;Receptor Inhibition;Resistance;Resistance development;Role;Specificity;Techniques;Testing;Therapeutic;Tissue Sample;Tracer;Translating;Xenograft Model;Xenograft procedure;cancer cell;companion diagnostics;design;imaging approach;imaging biomarker;in vivo;in vivo Model;innovation;mortality;mutant;mutational status;non-invasive imaging;novel;novel therapeutics;overexpression;preclinical study;predicting response;radioligand;radiotracer;receptor;receptor expression;resistance mechanism;response;response biomarker;standard of care;targeted treatment;tool;translational study;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;uptake Imaging the multifaceted response to a bispecific antibody therapy Project NarrativeWe need better ways to select patient most likely to respond to new antibody treatments with multiple ways tokill cancer cells. We propose to produce a highly useful imaging toolkit to understand the different ways thatthe antibody kills cancer cells in animal models of triple negative breast cancer and non-small cell lung cancer. NCI 10838763 8/30/23 0:00 PA-21-268 7R01CA255226-03 7 R01 CA 255226 3 "LIN, CHARLES" 7/15/21 0:00 6/30/26 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 9297201 "MARQUEZ-NOSTRA, BERNADETTE " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 490678 NCI 382390 108288 Project SummaryResistance to the standard of care treatments contributes to mortality in patients with metastatic triple negativebreast cancer (TNBC) or non-small cell lung cancer (NSCLC). In metastatic TNBC the epidermal growth factorreceptor (EGFR) and cytoplasmic mesenchymal-epithelial transition (cMET) receptor are both overexpressedin the basal-like subtype of TNBC. Metastatic NSCLC often harbors mutations in the epidermal growth factorreceptor (EGFR) in which patients can develop resistance to EGFR tyrosine kinase inhibitors (TKI). MET geneamplification is also a resistance mechanism for EGFR TKIs. To overcome resistance to EGFR TKI abispecific antibody called JNJ-61186372 (BsAb) was developed that targets both EGFR and cMET receptorssimultaneously inhibiting receptor-ligand activation and degrading these receptors upon internalization of thebsAb. Currently there are no effective methods to predict and monitor response to bsAb making it difficult toselect patients most likely to respond to this new therapy in a clinical trial setting and save those unlikely torespond from undue drug exposure. We aim to develop PET imaging biomarkers to look at the multifacetedresponse to bsAb therapy: bsAb delivery to the tumor (Aim 1) and changes in individual receptor status in vivo(Aim 2). Through correlative studies among PET imaging response to bsAb therapy and known geneticmutation status in EGFR we will produce the right PET imaging toolkit to understand the mechanisms of actionof bsAb in vivo. Our techniques can complement standard of care analysis of EGFR mutation status to selectpatients most likely to respond to bsAb therapy and monitor response to treatment. This future goal will requirean IND for which our studies will provide proof-of-feasibility in preclinical models. Ultimately establishing ourimaging techniques as companion diagnostic agents could have high impact in accelerating FDA-approval ofbsAb for the treatment of patients with NSCLC or TNBC who have developed resistance to standard of care oftreatments. 490678 +No NIH Category available Clinical;Maintenance;Malignant Neoplasms;Proteomics;Research;Services;base;web site BASE IDIQ TITLE: TECHNICAL PROGRAMMATIC AND OTHER SUPPORT SERVICES TO THE NCI CSSI.TASK ORDER TITLE: NCI OCCPR WEBSITE MAINTENANCE n/a NCI 10838725 75N91020D00004-P00002-759102100001-2 N02 11/18/20 0:00 11/17/23 0:00 79045941 "GHALEB, GHALEB " Not Applicable Unavailable 964955558 T52YD1L9GCA8 964955558 T52YD1L9GCA8 US -502839 MCLEAN VA Other Domestic Non-Profits 22102 UNITED STATES N R and D Contracts 2023 37645 NCI This task order is for the website maintenance service to NCI Office of Cancer Clinical Proteomics Research (OCCPR). 37645 +No NIH Category available Clinical Translation of Near Infrared Nerve-Specific Fluorophores for Nerve-sparing Prostatectomy PROJECT NARRATIVE Iatrogenic nerve injury is one of the most feared complications of surgery with up to 600000 patientsaffected annually in the United States alone. At present there is no technology to improve visual recognition ofnerve tissue during surgery leaving surgeons to rely largely on anatomical knowledge to locate small or buriednerves invisible to the naked eye. We have developed first-in-kind targeted near-infrared (NIR) fluorophores thatlabel nerve tissue with high affinity for direct nerve visualization during fluorescence-guided surgery andcompletion of the proposed aims will establish pre-clinical testing of our lead compound towards first-in-humantrials to significantly reduce iatrogenic nerve injury rates and revolutionize surgery as we know it. NCI 10838010 9/7/23 0:00 PA-19-272 6R44CA247639-03 6 R44 CA 247639 3 "POND, MONIQUE ADRIANNE" 7/1/22 0:00 7/1/25 0:00 Special Emphasis Panel[ZRG1-SBIB-T(10)B] 12435426 "BARTH, CONNOR WILLIAM" Not Applicable 1 Unavailable YGDTEJXJC9G8 YGDTEJXJC9G8 US 10074417 TRACE BIOSCIENCES INC PORTLAND OR Domestic For-Profits 972394232 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 SBIR/STTR 2022 937594 NCI 721226 216368 PROJECT SUMMARY Iatrogenic nerve injury is one of the most feared complications of surgery. Nerves are critically importantto the function of most tissues and nerve injury can lead to permanent disability. Surgery is performed commonlyin the U.S. with approximately 40 million operations annually incurring up to 600000 iatrogenic nerve injuries.One procedure particularly plagued by nerve damage is radical prostatectomy (RP) where nerve damage occursin up to 60% of patients despite the practice of nerve sparing surgical methods for >30 years. At present thereis no clinically approved technology to improve visual recognition of nerve tissue during surgery leavingsurgeons to rely largely on anatomical knowledge to locate small or buried nerves invisible to the naked eye.Fluorescence-guided surgery (FGS) is a nascent field with demonstrated efficacy in improving surgical outcomesfor cancer resection and normal anatomy preservation using molecularly-targeted fluorophores and commercialFGS imaging systems. We have developed several first-in-kind targeted near-infrared (NIR) fluorophores thatlabel nerve tissue with high affinityto date the most promising is IT01-08. IT01-08 specifically labels rodentswine and canine nerves following systemic administration and demonstrates cross reactivity in ex vivo humanspecimen staining. Notably we have developed a library of IT01-08 derivatives several of which have displayedvastly improved water solubilities and toxicity profiles in preliminary testing increasing the no observed adverseeffect level (NOAEL) doses 2-10X. Final solubility toxicology and pharmacology testing is required to select alead compound from IT01-08 and its derivatives. Following lead compound selection clinical translation of theoptimal NIR nerve-specific fluorophore will enhance nerve identification during nerve-sparing RP resulting inreduced nerve injury and improved patient outcomes. This studys immediate milestones include Phase I: (1)selection of a clinically viable NIR nerve-specific fluorophore for translation (2) relevant pharmacokinetics doseranging pharmacodynamics and biodistribution quantification and (3) preliminary toxicology analysis to guideinvestigational new drug (IND)-enabling studies. Phase II: (4) good laboratory practice (GLP) synthesizedfluorophore and formulation product for (5) a GLP two-species pharmacology and toxicology (pharm/tox) studyfacilitating (6) a successful IND application to the FDA. Our long-term strategic plan is to develop our NIR nerve-specific fluorophores for human use to enhance the identification and preservation of nerves with broad clinicalimpact for all surgical subspecialties. Completion of the proposed aims will establish pre-clinical testing of thesepromising nerve highlighting agents towards first-in-human trials and provide a strong foundation for industrypartnerships and investment for clinical translation. 937594 +No NIH Category available ATAC-seq;Address;Animal Model;Automobile Driving;Behavior;Biological;Cells;Circulation;Clinical Trials;Complement;Development;Disease Outcome;Epigenetic Process;Female;Foundations;Glioblastoma;Histones;Immunosuppression;Immunotherapy;Incidence;Individual;Infiltration;Interleukin-1 beta;Intervention;Intrinsic factor;Lead;Lysine;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Myeloid-derived suppressor cells;OX40;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Play;Pre-Clinical Model;Predisposition;Primary Brain Neoplasms;Prognosis;Regulation;Role;Specimen;T-Cell Activation;Testing;Tumor Immunity;Variant;anti-CTLA4;anti-PD-1;anti-tumor immune response;biological sex;complement pathway;complement system;drug repurposing;efficacy evaluation;epigenetic regulation;epigenetic variation;fludarabine;genetic signature;granulocyte;improved;in vitro activity;in vivo;inhibitor;insight;male;monocyte;novel;pharmacologic;response;sex;success;therapy resistant;treatment response;tumor;tumor progression;tumor-immune system interactions;tumorigenesis Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma PROJECT NARRATIVESuppression of anti-tumor immune response is a major mechanism facilitating the progression and therapeuticresistance of glioblastoma (GBM) the most malignant primary brain tumor. The objective of this project is to gainmechanistic insight into the cell-intrinsic factors that drive sex-specific accumulation and function of myeloid-derived suppressor cell (MDSC) subtypes in GBM and elucidate epigenetic regulation of the complement systemin MDSCs. The successful completion of this proposal will elucidate novel interventions targeting MDSC subsetvariation by epigenetic reprogramming and account for sex as a biological variable for improved immunotherapyresponse. NCI 10837997 9/20/23 0:00 PA-21-071 3R00CA248611-03S1 3 R00 CA 248611 3 S1 "FORRY, SUZANNE L" 3/7/23 0:00 2/28/26 0:00 15337100 "BAYIK WATSON, DEFNE " Not Applicable 27 PHARMACOLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 7/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 80426 NCI 52395 28031 PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary malignant brain tumor with a mediansurvival of up to 20 months. Males have a 1.6-fold higher incidence of GBM compared to females and worsedisease outcomes. Immunotherapies which are currently in clinical trials have had limited success in improvingpatient outcomes. An immunosuppressive microenvironment facilitating tumor progression and restricting anti-tumor immune response likely underlies therapeutic resistance. Although the accumulation of myeloid-derivedsuppressor cells (MDSCs) plays a critical role in the establishment of this immunosuppressive milieu themechanisms by which individual MDSC subsets promote tumorigenesis and are regulated remain poorly defined.We previously demonstrated that monocytic MDSCs (mMDSCs) infiltrated male tumors at higher rates inpreclinical models and patient specimens. In contrast granulocytic MDSCs (gMDSCs) expand in the peripheralcirculation of female animal models and the gMDSC gene signature is associated with poor prognosis in femalepatients. This variation in MDSC subsets also informed sex-specific therapeutic responses to fludarabine andanti-IL-1 in preclinical models. More recently we observed that mMDSCs and gMDSCs have a distinctepigenetic landscape which is also informed by biological sex. While this highlights the potential role ofepigenetic regulation of MDSC subset activity there is limited insight into the mechanisms driving distinct MDSCsubset functions. Our preliminary results suggested that the complement pathway could be one such mechanismas complement component 1q (C1q) was highly expressed by gMDSCs and elevated in females. Based on theseobservations we hypothesize that epigenetic regulation of C1q informs sex-specific behavior of MDSC subsetsand epigenetic reprogramming of MDSCs will improve the efficacy of T cell-activating strategies. Specific Aim1 will test the hypothesis that the unique epigenetic signatures of MDSC subsets make them susceptible todifferent histone modifiers that can be combined with checkpoint modulators. Sub-Aim 1A will examine theefficacy of histone lysine demethylase inhibitors on MDSC activity in vitro and in vivo while Sub-Aim 1B willattempt to achieve durable anti-tumor immune response by combining lead inhibitors with anti-PD-1 anti-CTLA-4 and anti-OX40. Specific Aim 2 will test the hypothesis that the C1q locus is differentially accessible betweenmale versus female MDSC subsets. Sub-Aim 2A will use ATAC-seq and CUT & RUN to evaluate the epigeneticlandscape of complement proteins and specific histone mark occupancy based on the differential histone lysinedemethylase expression profile. Sub Aim 2B will use pharmacological inhibitors to test the sex-specific effect ofhistone lysine demethylases on complement regulation. These studies lay the foundation for the development ofepigenetic modifiers for GBM immunotherapies by addressing variations in anti-tumor immunity repurposingdrugs and defining targetable pathways. These results are broadly applicable to other cancers and can lead toadvanced treatment opportunities and improved patient outcomes. 80426 +No NIH Category available SUPPORT FOR THE SEER-CAHPS INITIATIVE n/a NCI 10836965 75N91020F00215-P00003-0-1 N02 8/31/22 0:00 8/30/24 0:00 77839069 "BOGGS, ABBEY " Not Applicable 4 Unavailable 4868105 JJHCMK4NT5N3 4868105 JJHCMK4NT5N3 US 35.9138 -78.848911 6939101 RESEARCH TRIANGLE INSTITUTE RESEARCH TRIANGLE PARK NC Research Institutes 277092194 UNITED STATES N R and D Contracts 2023 197671 NCI SCIENTIFIC EXPERTISE TECHNICAL ASSISTANCE PROGRAMMING AND ANALYTICAL ASSISTANCE TO SUPPORT THE SEER-CAHPS INITIATIVE 197671 +No NIH Category available Acceleration;Adherence;Administrative Efficiency;Area;Awareness;Basic Science;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Community Outreach;Computer software;Data;Data Management Resources;Development;Documentation;Education;Educational Activities;Ensure;Faculty Recruitment;Funding;Goals;Guidelines;Infrastructure;Institution;Investments;Leadership;Malignant Neoplasms;Marketing;Mission;NCI Center for Cancer Research;NCI-Designated Cancer Center;Operations Research;Policies;Population Sciences;Process;Productivity;Reporting;Research;Research Personnel;Resource Sharing;Resources;Role;Services;Strategic Planning;Structure;System;Training;Training Support;Translational Research;Universities;Update;Work;administrative database;anticancer research;career;data management;digital;implementation strategy;member;operation;outreach;programs;social media Cancer Center Administration n/a NCI 10836633 6/16/23 0:00 PA-20-272 3P30CA056036-23S3 3 P30 CA 56036 23 S3 "PTAK, KRZYSZTOF" 6/22/95 0:00 5/31/24 0:00 5788 12630208 "HUESSER, MATTHEW HOWARD" Not Applicable 2 Unavailable 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA Domestic Higher Education 191074418 UNITED STATES N 6/1/22 0:00 5/31/23 0:00 Research Centers 2023 2871106 1861386 1009720 PROJECT SUMMARYThe Administration unit of the Sidney Kimmel Cancer Center (SKCC) provides comprehensive programmaticdirection and administrative support to all aspects of the Center. Under the direction of Dr. Knudsen and there-aligned leadership structure an entirely new Administration mission and focus was implemented alignedwith the strategic plan (IMPACT). Administration strives to complete this mission by providing comprehensiveoversight in the follow seven areas: 1) Facilitating the strategic planning processes and continuedimplementation of IMPACT; 2) Prioritizing catchment-related issues pertaining to programmatic developmentand community outreach; 3) Documentation organization and communication related to SKCC-organizedactivities; 4) Oversight of the CCSG application fiscal management of funds adherence to NCI guidelines andCCSG reporting; 5) Operational oversight of space and Shared Resources; 6) Administration of SKCC facultyrecruitment and retention efforts; 7) Oversight of pilot fund processes and clinical research operations; 8)Governance of membership processes and consortium relations and/or partner institutions; 9) Facilitatescancer research career enhancement related-initiatives. Through these mechanisms Administration providesa strong foundational platform to support the Center Director Senior Leaders Programs Shared ResourcesTIPS mechanism and key leadership committees. Furthermore Administration is integrated into the SKCCExecutive Committee which is now the governing body of the Center. This committee meets weekly andincludes major responsibilities outlining: strategy resource deployment policy strategic alliances high-levelmanagement of SKCC clinical operations research education assessment of catchment area needs andoutreach activities.SKCC Administration is comprised of a well-trained comprehensive staff that are aligned to support the 159members of SKCC as well as Senior Leaders the Clinical Research Organization and Shared Resourceoperations. Although SKCC Administration is comprised of more than 15 members in various diverse rolessupport for only 2 FTE equivalents is requested during this CCSG project period. In the next funding cycleAdministration endeavors to: 1) Refine mechanisms to support the expanding SKCC research missionincluding basic clinical and population science related to catchment area needs; 2) Enhance communicationefforts that promote the goals of the strategic plan awareness and outreach through the facilitation oftransdisciplinary research; 3) Tighten administrative efficiencies to reduce the burden on investigators anddevelop new capabilities for administrative oversight. +No NIH Category available Address;Adoption;Automation;Biological Assay;Biology;Biopsy;Breast Cancer Detection;Breast Cancer Patient;Breast Cancer therapy;Cancer Diagnostics;Cancer Patient;Caring;Cells;Clinic;Clinical;Clinical Data;Clinical Laboratory Improvement Amendments;Clinical Protocols;Clinical Research;Complex;Development;Devices;Drug Screening;ERBB2 gene;Emulsions;Face;Fine needle aspiration biopsy;Funding;Future;Gel;Generations;Genomics;Goals;Institutional Review Boards;Lead;Malignant Neoplasms;Medicine;Methods;Microfluidics;Minority;Modeling;Needle biopsy procedure;Neoadjuvant Therapy;Oncologist;Oncology;Organoids;Outcome;Patients;Performance;Pharmaceutical Preparations;Phase;Predisposition;Process;Refractory;Regimen;Risk;Robotics;Running;Sample Size;Sampling;Technology;Temperature;Testing;Therapeutic;Time;Tissues;Validation;Work;arm;cancer therapy;cancer type;clinical diagnostics;clinical predictors;commercialization;cost;data integration;data integrity;design;diagnostic assay;drug testing;experience;feasibility testing;flexibility;improved;individual patient;malignant breast neoplasm;microfluidic technology;miniaturize;neoplastic cell;novel;novel strategies;participant enrollment;patient response;patient screening;precision oncology;predicting response;predictive modeling;prototype;research clinical testing;response;scale up;screening;standard of care;success;technology platform;treatment response;tumor;validation studies Micro-Organospheres Drug Screen to Lead Care (MODEL): a Precision Oncology Platform to Guide Breast Cancer Therapy PROJECT NARRATIVEThe practice of oncology continually faces the immense challenge of matching the right therapeutic regimen with the right patient while balancing relative benefit with risk to achieve the most favorable outcome. As the number of new and increasingly sophisticated cancer medicines grows conventional approaches to finding the best match are based on assumptions that only end up benefiting a minority of patients. We propose to completely re-define the precision oncology paradigm by developing the Micro-Organoids Drug Screen to Lead Care (MODEL) platform which uses a viable functional model of a patients individual tumor to identify which drug(s) actually work in less than 10 days. NCI 10836600 9/1/23 0:00 PA-20-260 4R44CA261579-02 4 R44 CA 261579 2 "WEBER, PATRICIA A" 5/9/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-BST-R(10)B] 16468954 "DELUBAC, DANIEL " Not Applicable 4 Unavailable 117345890 HUBZGFA8NE97 117345890 HUBZGFA8NE97 US 35.936618 -79.031728 10058805 "XILIS, INC." Durham NC Domestic For-Profits 27709 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 SBIR/STTR 2023 998506 NCI 775853 157330 PROJECT SUMMARY/ABSTRACTThe goal of precision oncology is to match cancer patients with medicines based on the specific biology of theirtumor. Crucially the current precision oncology paradigm which is largely based on tumor genomic profiling doesnt work for the majority of patients. Since every patients tumor is uniquely complex a potential solution tothis precision problem involves creating a viable functional model of a patients individual tumor in order todirectly test its susceptibility to different drugs. The broad adoption of such patient-derived functional models intothe clinic thus far has been hindered by several limitations centered on scalability time and success rate.Specifically any assay for guiding therapy must be: i) amenable to the amount of material derived from needlebiopsies ii) established with a high success rate and iii) completed within 10-14 days to minimize unacceptabletreatment delays. To address these clinical limitations we have developed the novel Micro-Organosphere DrugScreen to Lead Care (MODEL) platform. MODEL is based on novel microfluidics technology that generatesPatient-Derived Micro-Organospheres (PDMO) from clinical samples (e.g. biopsies) and performs drugscreening within 10 days to guide therapy. The objective of our proposal is to further develop and validate ourMODEL technology in breast cancer with a view to advancing it further towards becoming a standard of carediagnostic assay. Phase I of our proposal will focus on preparing our MODEL device for rigorous clinicalevaluation. In Aim 1 we will make key upgrades to our device prototype to improve sample efficiency deviceperformance and operability. Specifically the goal of these improvements will be to reduce sample sizerequirements (extending our capabilities down to fine-needle aspirates) enhance device performance reinforceconsistency of key parameters during and between runs and increase process automation. In Aim 2 we willrigorously test the ability of our second-generation device to i) successfully generate PDMO from breast cancerbiopsies and ii) perform drug screens in less than 10 days total. In Phase II we will make key device upgrades to prepare the MODEL platform for commercialization focusing on improving features related to data integrity and ease-of-use (Aim 1). In Aim 2 we will perform the first validation of our MODEL platform in a HER2+ breastcancer clinical protocol consisting of 50 patients with the goal of testing MODELs ability to predict response to standard of care neoadjuvant therapy. If successful the development of our platform will revolutionizeprecision oncology by arming oncologists with the information needed to optimally match cancer patients withmedicines. 998506 +No NIH Category available Active Sites;Acute;Address;Antineoplastic Agents;Apoptotic;Applications Grants;Binding;Biological Assay;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer cell line;Canis familiaris;Cell Proliferation;Cells;Clinic;Clinical;Clinical Trials;Combined Modality Therapy;Data;Databases;Development;Diagnosis;Disease;Documentation;Dose;Doxorubicin;Drug Combinations;Drug Targeting;Drug resistance;Genes;Goals;Growth;Human;Impairment;In Vitro;Induction of Apoptosis;Invaded;Investments;Lead;Malignant Neoplasms;Methods;Mission;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncogenic;Outcome;Outcome Study;Paclitaxel;Patient Care;Patient-derived xenograft models of breast cancer;Patients;Pharmaceutical Preparations;Phase;Phosphoric Monoester Hydrolases;Positioning Attribute;Publishing;Rattus;Research;Risk-Benefit Assessment;Route;Safety;Scientist;Serum;Small Business Innovation Research Grant;Specificity;Survival Rate;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Translating;United States National Institutes of Health;Validation;Xenograft procedure;black women;cell killing;cell motility;chemotherapeutic agent;chemotherapy;clinical development;clinically significant;combinatorial;commercialization;design;detection method;disorder subtype;drug development;empowerment;experience;functional genomics;genome-wide;high risk;improved;improved outcome;in silico;in vitro activity;in vivo;insight;knock-down;malignant breast neoplasm;mouse model;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;pharmacokinetics and pharmacodynamics;phase 1 study;phase 2 study;pre-Investigational New Drug meeting;pre-clinical;predictive marker;prevent;relapse risk;research clinical testing;resistance mechanism;response biomarker;side effect;small hairpin RNA;standard of care;synergism;targeted treatment;therapy resistant;timeline;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor xenograft;young woman VDX-111: A novel targeted therapeutic for triple-negative breast cancer PROJECT NARRATIVETriple-negative breast cancer is the most aggressive of the major sub-types of breast cancer and is overrepresented in young women and black women. The present proposal seeks to bring a novel therapeutic agent VDX-111 to a stage sufficiently mature to seek IND approval and to attract the investment required to initiate human trials. Whether VDX-111 proves efficacious as a stand-alone therapy for triple-negative breast cancer or improves outcome in combination with standard of care chemotherapy the proposed project directly impacts the mission of NIH to develop new therapies that will improve the capability to treat and/or prevent disease. NCI 10836599 7/10/23 0:00 PA-19-272 4R44CA250674-02 4 R44 CA 250674 2 "POND, MONIQUE ADRIANNE" 7/1/21 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OTC-T(10)B] 12243330 "GARI, HAMID H" Not Applicable 6 Unavailable 116929581 F4JDLH763ZK5 116929581 F4JDLH763ZK5 US 39.889269 -105.038267 10056055 "VONA ONCOLOGY, LLC" Aurora CO Domestic For-Profits 80045 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 SBIR/STTR 2023 995137 NCI 767210 162825 PROJECT SUMMARYTriple-negative breast cancers (TNBC) represent a significant challenge to basic scientists studying the molecular underpinnings of the disease and to patients and clinicians who deal directly with this most deadly and therapy-resistant of breast cancers. Presently targeted approaches toward the treatment of TNBC are lacking. This project directly addresses this critical unmet need. We have developed VDX-111 a novel drug that exerts potent pro-apoptotic action in TNBC cell lines but interestingly has little or no effect on the majority of nonTNBC and non-tumorigenic breast cells. In vivo VDX-111 reduces tumor xenograft growth from TNBC cell lines and a TNBC patient-derived xenograft (PDX) model. To elucidate the mechanism of VDX-111action we carried out a genome-wide shRNA functional genomics screen designed to identify genes required for VDX-111 actionin TNBC and provide insight into potential resistance mechanisms. The highest-ranking hit from this screen was the gene PTP4A3 encoding the oncogenic phosphatase PRL-3. To evaluate the clinical significance of PRL-3 in TNBC we probed the TCGA database. PRL-3 is amplified in approximately 50% of invasive TNBCs. Wevalidated PRL-3 as a target of VDX-111. Knockdown of PRL-3 significantly impaired the ability of VDX-111 to induce apoptosis. VDX-111 directly blocked the catalytic activity of purified PRL-3 and promotes the degradation of PRL-3. VDX-111 inhibited PRL-3-dependent TNBC cell migration and invasion. These findings indicate thatPRL-3 is a major target for VDX-111 in TNBC and is potentially a predictive biomarker for response to VDX-111.In TNBC cells VDX-111 synergizes with standard of care drugs frequently administered to TNBC patientshighlighting its potential as a combinatorial therapeutic agent that could bolster efficacy while reducing the doses of the chemotherapeutics. In Phase I we will extend our in vitro proof of concept studies of VDX-111 in combination with doxorubicin and paclitaxel in murine TNBC PDX tumor models. To develop the commercialization potential of VDX-111 with the ultimate goal of moving it into clinical trials IND-enabling studies are proposed. In Phase II we will (i) complete development and validation of bioanalytical methods for clinical testing and (ii) complete IND-enabling safety toxicity and PK/PD testing in two species. Phase II studieswill position us for subsequent IND approval and the initiation of human trials. Moreover accomplishing the proposed Phase II goals will empower the commercialization and investment required to bring VDX-111 to the clinic for use in TNBC. The expected outcomes of these studies will enable optimization of VDX-111 for improved therapeutic options for TNBC patients and determine the safety and PK/PD parameters required for a pre-IND meeting with the FDA. These outcomes will establish an attractive investment opportunity to acquire the support needed to make VDX-111 an integral part of standard of care for patients with TNBC. 995137 +No NIH Category available 3-Dimensional;Adaptor Signaling Protein;Adhesions;Biochemical;Biological Assay;Biophysical Process;Biophysics;Blood;Blood Circulation;Blood specimen;Brain;Breast;Cancer Diagnostics;Cell Adhesion;Cell Adhesion Molecules;Cell surface;Cells;Clinical;Coagulation Process;Cytoskeleton;DNA;Detection;Development;Diagnostic;Doctor of Philosophy;Early Diagnosis;Elements;Fibrinogen;Fluorescence Microscopy;Fluorescence Polarization;Glioblastoma;Glycocalyx;Glycoproteins;Human;Image;Image Analysis;Immobilization;Individual;Integrins;Invaded;Letters;Literature;Lung;Maps;Measures;Mechanics;Mediating;Methods;Modeling;Molecular;Molecular Conformation;Motor;Nature;Neoplasm Circulating Cells;Neoplasm Metastasis;Observation in research;Outcomes Research;Phase;Platelet Activation;Postdoctoral Fellow;Process;Property;Recurrence;Research;Role;Sampling;Screening for cancer;Series;Specificity;Structure;Techniques;Technology;Testing;Thick;Tissues;Vinculin;Work;anticancer research;cancer cell;cancer type;career;design;detection method;experience;experimental study;fluorophore;improved;mechanical device;mechanical properties;nano;nanosensors;overexpression;recruit;screening;simulation;skills;soft tissue;targeted cancer therapy;therapeutic target;tool The mechanical role of the glycocalyx in cancer cell adhesion Project NarrativeMany types of cancer cell utilize a special outer layer called a glycocalyx to help stick to andinvade soft tissues such as the brain lung and breast. This proposal seeks to 1) use DNA-basednanosensors to elucidate how the glycocalyx helps cancer cells become invasive and 2) developscreening methods for early detection of glycocalyx-coated cancer cells in the bloodstream. Theoutcome of this research may offer new design principles for targeted cancer therapy as well astechnologies for early detection of cancer. NCI 10836336 11/24/23 0:00 RFA-CA-19-002 5K00CA245789-05 5 K00 CA 245789 5 "DAMICO, MARK W" 9/16/20 0:00 11/30/24 0:00 ZCA1-RTRB-R(A1) 15610000 "BLANCHARD, AARON " Not Applicable 4 BIOMEDICAL ENGINEERING 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC BIOMED ENGR/COL ENGR/ENGR STA 277054673 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Other Research-Related 2024 96143 NCI 89021 7122 Project Summary Many types of cancer such as recurrent glioblastoma multiform which is invariably lethal overexpressbulky glycoproteins to form a thick glycocalyx layer. The glycocalyx physically separates the cell from itssurroundings but recent work has shown that the glycocalyx can paradoxically increase adhesion to soft tissuesand therefore promote the metastasis of cancer cells. This surprising phenomenon occurs because theglycocalyx forces adhesion molecules (called integrins) on the cell's surface into clusters. These integrin clustershave cooperative effects that allow them to form stronger adhesions to surrounding tissues than would bepossible with equivalent numbers of un-clustered integrins. These cooperative mechanisms have been intenselyscrutinized in recent years; a more nuanced understanding of the biophysical underpinnings of glycocalyx-mediated adhesion could uncover therapeutic targets deepen our general understanding of cancer metastasisand elucidate general biophysical processes that extend far beyond the realm of cancer research. Here I present the hypothesis that the glycocalyx has the additional effect of increasing mechanical tensionexperienced by clustered integrins. Integrins function as mechanosensors that undergo structure-switching intoactive conformations when subjected to mechanical tension. As such my hypothesis would if true suggest amore immediate regulatory role of the glycocalyx in adhesion than previously realized. This hypothesis (which Icall the local organization hypothesis) is well-supported through indirect observation in the research literaturebut has not been directly tested due to challenges associated with measuring mechanical tension on individualbiomolecules in live cells. However I have devoted much of my career to developing DNA-basedmechanosensor tools that can be used to directly measure piconewton-scale integrin tension in live cells. HereI propose to utilize these tools to test the local organization hypothesis and bring clarity to this rapidly-growingresearch field. I plan to image integrin forces during the early stages of cellular adhesion and test for a set ofspecific observations that would support or refute the local organization hypothesis. In parallel I plan to leveragemy computational skills to test this hypothesis using a sophisticated chemomechanical simulation method. For my postdoctoral (K00) work I will transition into translational work and develop tools that leverage theprinciples of glycocalyx-mediated adhesion for cancer diagnostic purposes. Because glycocalyx-presentingcancer cells adhere more readily to soft substrates I will develop a flow-based method for detecting circulatingtumor cells (CTCs) using soft substrates and substrates of varying stiffness that facilitate mechanoselection ofglycocalyx-presenting cancer cells. This mechanoselection-based method will enable mechanical profiling ofCTCs to determine what types of tissues are most vulnerable to metastasis and will also allow for conventionalbiochemical profiling in parallel. This work will deliver a substantially enhanced understanding of the mechanismsof metastasis as well as tools that can put this improved understanding to diagnostic use in clinical settings. 96143 +No NIH Category available Affect;Age;Aging;American;Area;Biology;Cancer Detection;Cell physiology;Clinical;Clinical Data;Collaborations;Communities;DNA Sequence Alteration;DNA Sequence Rearrangement;Data;Development;Diagnosis;Disease;Environmental Exposure;Environmental Risk Factor;Etiology;Event;Evolution;Exposure to;Genes;Genetic;Genetic Polymorphism;Genetic Risk;Genetic Transcription;Genome;Genomic approach;Genomics;Germ-Line Mutation;Head and neck structure;Health Priorities;Healthcare Systems;Homeostasis;Human Papillomavirus;Immunosuppression;Incidence;Joints;Knowledge;Link;Malignant Neoplasms;Modeling;Mutation;Mutation Analysis;Mutation Detection;Neoplasm Metastasis;Oncogenes;Oncogenic;Organ;Outcome;Pathogenesis;Persons;Pigmentation physiologic function;Predisposition;Prevalence;Prevention strategy;Process;Publishing;Reproducibility;Research;Research Personnel;Resources;Risk;Risk Assessment;Risk Factors;Site;Skin Carcinogenesis;Smoking;Smoking History;Somatic Mutation;Specimen;Squamous cell carcinoma;Stratification;Sun Exposure;Technology;The Cancer Genome Atlas;Therapeutic Intervention;Tissues;Treatment Cost;UV Radiation Exposure;Ultraviolet Rays;United States;Validation;Variant;Work;cancer cell;cancer genomics;cancer risk;clinical predictors;clinical risk;cohort;cost;data integration;data portal;diagnostic biomarker;driver mutation;epidemiology study;epigenomics;exome;exome sequencing;genetic epidemiology;genetic risk factor;genome sequencing;genome wide association study;genomic data;improved;innovation;member;molecular targeted therapies;mortality;new therapeutic target;novel;novel diagnostics;predictive tools;prevent;prognostic;public health relevance;repository;risk prediction;risk variant;sex;skin cancer prevention;skin squamous cell carcinoma;sun damage;therapeutic biomarker;transcriptome;transcriptome sequencing;treatment strategy;tumor;tumor heterogeneity;tumor progression;whole genome PQ3 Cutaneous squamous cell carcinoma: Integrating germline and somatic alterations that underlie tumor progression PUBLICHEATHRELEVANCECutaneoussquamouscellcarcinoma(cSCC)isthesecondmostcommoncancerinAmericaandwhenitmetastasizesithashighdisease-associatedmortality.ToimproveunderstandingofcSCCetiologyandbiologyitiscriticaltounderstandtheconnectionbetweengermline(person)andacquiredsomatic(tumor)genomesparticularlythosealterationsassociatedwithaggressivetumorsthatmetastasize.WeproposetoidentifytumormutationaldataandtointegratethisdatawithourpreviouslyidentifiedgermlinedatatounderstandthegeneticinteractionsofthepersonandtumorincSCCevolution.ThecomprehensiveintegratedcharacterizationofkeygenomicchangesinoneofthemostprevalentandcostlycancerswillsupportadvancesindevelopingmoreeffectivewaystodiagnosetreatandpreventcSCCs. NCI 10836131 9/20/23 0:00 PA-21-268 7R01CA231264-05 7 R01 CA 231264 5 "CARRICK, DANIELLE M" 4/16/19 0:00 3/31/24 0:00 ZCA1-SRB-K(J1)R 2101782 "ASGARI, MARYAM MANDANA" Not Applicable 6 DERMATOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 5/3/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 374307 NCI 298816 75491 ABSTRACTCutaneoussquamouscellcarcinoma(cSCC)isthesecondmostcommoncancerintheUnitedStatesaffectingoveramillionpeopleannuallyandwithsignificantmortalityduetometastasis.DespiteitprevalenceandhightreatmentcostscSCCsarenotincludedinlarge-scalecancergenomicseffortsaimedatunderstandingthegeneticchangesarisingincancercellssuchasTheCancerGenomeAtlas(TCGA)project.ThusgenomicalterationsincSCChavenotbeencomprehensivelycharacterizedandnovelmolecularly-targetedtreatmentshavenotbeendeveloped.ThisproposalmodeledafterTCGAwhichisco-ledbyDr.GadGetz(Co-Iofthisapplication)representsthelargesteffortofitskindtoanalyzegenomicchangesthatdrivecSCCprogression.ThiscriticaldataisneededtoidentifytargetsfornoveltreatmentandpreventionstrategiesofcSCC.Ourteamwasthefirsttopublishagenome-wideassociationstudythatidentifiedtennovelgermlinelociassociatedwithincreasedcSCCriskusingthelargeGeneticEpidemiologyResearchonAging(GERA)cohort.TheoverallscientificobjectiveofthisproposalistoidentifyandintegratenoveltumormutationaldatawithpreviouslycharacterizedinformationonhostgeneticriskfactorsandclinicalriskfactorstobetterunderstandhowcancerriskallelescontributetothedevelopmentofcSCCscapableofmetastasis.Wewillanalyze290cSCCs(145primarycSCCsthatprogressedtometastasisand145non-metastaticprimarycSCCs)arisinginthewell-characterizedGERAcohorttoprovideacomprehensivelandscapeofgenomicalterationsincSCCs.Weproposethefollowingspecificaims:1)characterizethegenomeandtransciptomeof290cSCCswithexistinggermlinedatausingatieredapproachincludingwhole-exomewhole-genomeandRNAsequencingtoidentifydrivermutationsaswellasepigenomicchanges;2)integratethesomaticmutationalanalysiswithenvironmentalexposuredatatounderstandhowenvironmentalexposuresimpactcSCCswithdistinctsomaticmutationalprofiles;and3)developaclinicallymeaningfulriskpredictiontoolforidentifyingsubjectsatriskformetastaticcSCCsthatcombinesgermlinesomaticandclinicaldata.TheapproachisinnovativebecauseitwillincreaseunderstandingofthejointcontributionofthegermlineandsomaticgenomesforcSCCriskanditwillcreateapubliclyaccessiblecSCCgenomicdataportalprovidinganovelresourceforthescientificcommunity.TheproposedresearchissignificantbecauseitwillintegrategermlineandsomaticgeneticdatatogainacomprehensivepictureofhowthegeneticsofboththepersonandthetumorinteracttoaffectcSCCevolutionandprogression.ThecomprehensiveintegratedcharacterizationofkeygenomicchangesinoneofthemostprevalentandcostlycancerswillsupportadvancesindevelopingmoreeffectivewaystodiagnosetreatandpreventcSCCsandpotentiallysquamouscellcarcinomaarisinginotherorgans. 374307 +No NIH Category available 3-Dimensional;Affect;Africa;African;African American;African American population;African Caribbean;African ancestry;Age;Alleles;Anthropology;Area;Automobile Driving;Biodiversity;Biology;Breast Cancer Patient;Breast Cancer Treatment;Cells;Characteristics;Clinical;Country;Coupled;Cytometry;DNA;Data;Data Set;Diabetes Mellitus;Diagnosis;Disease;Disparity;Epithelium;Equitable healthcare;Ethiopia;Etiology;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Risk;Genetic Variation;Genomics;Ghana;Heterogeneity;High Prevalence;Immune;Immune response;Immunologics;Immunotherapy;In Situ;Incidence;Individual;Infiltration;Inflammation;Inflammatory;Investigation;Kenya;Latinx;Leucocytic infiltrate;Leukocytes;Link;Malignant Neoplasms;Mammary Neoplasms;Modeling;Multiomic Data;Myelogenous;Nigeria;North African;Obesity;Organoids;Outcome;Pathologic;Pathologist;Pathology;Pathway interactions;Patient Self-Report;Patients;Pattern;Phenotype;Population;Population Genetics;Population Heterogeneity;Primary Neoplasm;Privatization;Proteins;Proteomics;Race;Regulation;Reporting;Risk;Side;Stage at Diagnosis;Surgical Oncologist;Survival Rate;Tissue-Specific Gene Expression;Tumor Biology;Tumor Subtype;Tumor-infiltrating immune cells;Variant;Woman;Work;cancer genome;cancer health disparity;cancer subtypes;caucasian American;cell behavior;cell type;cohort;comorbidity;gene network;genetic variant;genome sequencing;health outcome disparity;immune cell infiltrate;improved;inflammatory marker;innovation;insight;malignant breast neoplasm;mortality;mortality disparity;multi-ethnic;multidisciplinary;multiple omics;multiplexed imaging;neoplastic cell;novel;patient stratification;personalized care;population based;prognostic;prospective;racial population;recruit;response;targeted treatment;transcriptome;transcriptome sequencing;translational study;treatment response;triple-negative invasive breast carcinoma;tumor;tumor heterogeneity;tumor microenvironment;tumor-immune system interactions;whole genome The DARC side of Breast Cancer Disparities - African Ancestry and Cancer- Related Immune Response PROJECT NARRATIVE (lay abs)The mortality gap between African Americans and Whites with breast cancer in the US reflected the unmasking ofdifferences in the biology of breast cancer between AA and WA women related to targeted therapies. Our previousfindings implicated African alleles of the DARC gene in etiology of breast cancer phenotypes and its tumor expressionwith survival suggesting ancestry-related differences in tumor immunological responses that may stratify patients forimproved use of immunotherapy treatments to decrease tumor-subtype-related disparities in mortality. Our proposed workwill define the clinical associations of DARC in African breast cancer patients and DARC tumor characteristics thatwill give insight to shared genetic risk among women of the African diaspora who share unique burdens of aggressivebreast tumor phenotypes. NCI 10835674 8/25/23 0:00 PA-21-268 7R01CA259396-03 7 R01 CA 259396 3 "DUGLAS TABOR, YVONNE" 9/23/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-B(55)R] 1951049 "DAVIS, MELISSA B" "NEWMAN, LISA A." 5 MICROBIOLOGY/IMMUN/VIROLOGY 102005451 X5S7PNXMJMC7 102005451 X5S7PNXMJMC7 US 33.746607 -84.414781 1726701 MOREHOUSE SCHOOL OF MEDICINE ATLANTA GA SCHOOLS OF MEDICINE 303101458 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 468366 NCI 360547 107819 PROJECT SUMMARY (tech abs)Even with the typical delays in diagnosis more advanced stage distribution at diagnosis and inadequate multidisciplinarybreast cancer treatment these combined factors do not completely explain disparities in breast cancer mortality outcomeswhich persist after controlling for stage at diagnosis and have been so for the past 50 years. The approximately two-foldincreased risk of TNBC in AA women has been confirmed by population-based incidence rates regionally as well asnationally and across all age intervals. Compared to non-TNBC triple negative disease has been confirmed to be an adverseprognostic feature in AA patients driving some of the mortality disparities. We hypothesize that altered mechanisms oftumor immune responses which underlies TNBC tumor biology differences between SRR are caused by population-privategenetic variants among individuals with shared west African ancestry. These evolutionarily selected variants alter immunecell behavior and inflammatory mechanisms leading to novel tumor-immune cell types and significant differences inleukocyte infiltration patterns which may be associated with poor outcomes. We will perform an innovative multiomicsinvestigation of African-specific gene expression in TNBC linked to immunological tumor phenotypes. We will harnessthe novelty of rarely-investigated breast cancer patient populations from diverse African regions with TNBC cases from gadmixed populations (i.e. African-American and Afro-Caribbean). The most impactful innovation of this study is thecharacterization of differential gene expression coupled with integrated proteomics data to identify novel tumor phenotypesthat are shared among women of the African diaspora. This work will be transformative to our understanding of tumorheterogeneity and biological diversity across patient groups. We propose the follow aims: 1- Determine the ancestry-associated differential gene expression profiles of immune and inflammatory-related genes in primary tumors across anAfrican-enriched cohort of 400 clinically annotated TNBC cases to immune profiles linked to shared west African geneticancestry. 2- Characterize ancestry-associated differences in pathological tumor immune response characteristics includingdifferences in tumor inflammation and/or tumor infiltration of specific immune cell types. 3-Create an African-enrichedpanel of ex vivo models to validate/investigate the ancestry-associated drivers of altered genetic pathways and immuneresponses. By completing these aims we expect to yield an African-enriched set of population-private validated eQTLsassociated with TNBC immune response mechanisms that can be further interrogated by our authenticated ex vivo models. 468366 +No NIH Category available APC gene;Amino Acids;Animals;Aryl Hydrocarbon Receptor;Automobile Driving;Binding;Biogenesis;Biomass;Cancer Cell Growth;Cell Nucleus;Cell Proliferation;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Colon;Colon Carcinoma;Development;Enzymes;Epithelial Cells;Gene Expression;Genes;Genetic;Genetic Transcription;Growth;Human;In Vitro;Knock-out;Kynurenine;Label;Ligands;MYC gene;Maintenance;Malignant Neoplasms;Manuscripts;Mediating;Metabolic;Metabolic Pathway;Modeling;Molecular;Monitor;Mus;Oncogenes;Oncogenic;Organoids;Pathway interactions;Physiological;Play;Preparation;Production;Proliferating;Protein Biosynthesis;Proteins;Proto-Oncogene Proteins c-myc;Regulation;Research;Ribosomes;Role;Seminal;T-Lymphocyte;Testing;Therapeutic Intervention;Translations;Tryptophan;cancer cell;cancer therapy;cell growth;colon growth;in vivo;inhibitor;knock-down;macromolecule;novel;novel strategies;nutrient absorption;prevent;transcription factor;tumor;tumor growth;tumor metabolism;uptake The kynurenine-AHR pathway in biomass production PROJECT NARRATIVE The continuous proliferation of cancer cells demands profound translational and metabolicreprograming. Nevertheless we still lack a clear picture of the unique adaptations that facilitateaberrant biomass accumulation specifically in cancer cells. This proposal seeks to understand the role ofthe transcription factor aryl hydrocarbon receptor (AHR) and its ligand kynurenine in protein synthesis andproliferation of colon cancer cells. NCI 10835135 5/3/23 0:00 PA-19-056 3R01CA245548-04S2 3 R01 CA 245548 4 S2 "WILLIS, KRISTINE AMALEE" 3/1/20 0:00 2/28/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10247449 "CONACCI-SORRELL, MARALICE " Not Applicable 30 ANATOMY/CELL BIOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 82932 NCI 50568 32364 PROJECT SUMMARY Increased uptake and synthesis of macromolecules is essential to sustain the demands of hyperproliferativecancer cells. Therefore developing approaches to limit biomass production specifically in tumors could haveprofound implications for cancer treatment. While seminal studies have shown that the universal oncogeneMYC promotes protein synthesis in cancer cells there is still a gap in our understanding of how MYC molecularlycontrols translation during oncogenic transformation. We found that the transcription factor aryl hydrocarbonreceptor (AHR) and its ligand kynurenine a byproduct of the amino acid tryptophan are induced by MYC incolon cancer cells. Our preliminary results indicate that AHR is necessary for the expression of genes involvedin ribosomal biogenesis and protein synthesis in proliferating cells. Our hypothesis is that AHR senses andresponds to tryptophan-derived kynurenine by translocating into the nucleus and inducing the transcription ofgenes that mediate ribosome biogenesis and translation in colon cancer cells. Aim 1 will directly test the role ofAHR in protein synthesis in colon cancer cells using genetic silencing in isogenic lines of human colonicepithelial cells and of mouse organoids progressed to colon cancer. Aim 2 will establish the contribution ofkynurenine to AHR-regulated protein synthesis and cell proliferation by examining the requirement forkynurenine for the expression of AHR target genes protein synthesis and growth. We will utilize AHR knockoutcells and animals and a competitive inhibitor that prevents the binding of kynurenine to AHR to define AHR-specific functions regulated by kynurenine. Aim 3 will directly test the importance of tryptophan-metabolizingenzymes in generating kynurenine and in regulating proliferation of colonic cells. We will determine the effectsof knocking down or knocking out enzymes in the kynurenine pathway to define their requirement for AHRactivity protein synthesis and proliferation of colon cancer cells and organoids. This study has the potential todefine a direct physiological role for the kynurenine-AHR pathway in driving increased biomass production andcell proliferation in colon cancer. Moreover this study will broaden the understanding of the role of kynurenineas an oncometabolite. Our findings could become the basis for the development of novel approaches to limitkynurenine production and AHR activity as a means to treat MYC-dependent tumors. 82932 +No NIH Category available 90Y;Adverse event;Aftercare;Apoptosis;Back;Blood Vessels;Bolus Infusion;Cancer Etiology;Catheters;Chemoembolization;Clinical;Clinical Trials;Consent;Contrast Media;Data;Disease Progression;Dose;Early identification;Evaluation;Fetal Proteins;Glass;Hour;Image;Incidence;Injections;Liver;Liver neoplasms;Magnetic Resonance Imaging;Malignant - descriptor;Measures;Metastatic Neoplasm to the Liver;Microbubbles;Monitor;Nude Rats;Output;Patient Schedules;Patient-Focused Outcomes;Patients;Perfusion;Physiologic pulse;Prediction of Response to Therapy;Primary carcinoma of the liver cells;Progression-Free Survivals;Property;Radiation;Radiation therapy;Radioactive;Radioembolization;Radioisotopes;Radiosensitization;Randomized;Recovery;Reperfusion Therapy;Reporting;Retreatment;Safety;Schedule;Solid Neoplasm;Source;Techniques;Testing;Therapeutic;Therapeutic Effect;Therapeutic Embolization;Time;Tissues;Vascular Endothelial Cell;Vascular Permeabilities;Yttrium;blood fractionation;blood perfusion;contrast enhanced;contrast imaging;dosage;effective therapy;experimental group;first-in-human;follow-up;improved;liver cancer model;liver function;local drug delivery;mortality;nuclear imaging;randomized clinical trials;response;safety and feasibility;tool;treatment response;treatment strategy;tumor;tumor vascular supply;ultrasound Microbubble Cavitation for Improving Hepatocellular Carcinoma Radioembolization The use of radioembolization has been shown to be successful for the treatment and downstaging ofhepatocellular carcinoma as well as liver metastases with response rates of 25-60%. Localized microbubblecavitation triggered by noninvasive ultrasound has been shown to sensitize malignant tissue to radiotherapy byinducing vascular endothelial-cell apoptosis. We propose a first-in-humans randomized clinical trial todetermine the benefits of using localized microbubble cavitation to improve patient outcomes and predicttreatment response. NCI 10834872 11/14/23 0:00 PAR-18-560 5R01CA238241-05 5 R01 CA 238241 5 "VIKRAM, BHADRASAIN" 12/11/19 0:00 11/30/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11944169 "EISENBREY, JOHN " "ANTON, KEVIN " 2 RADIATION-DIAGNOSTIC/ONCOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 302610 NCI 193981 108629 The use of radioembolization has been shown to be successful for the treatment and downstaging ofhepatocellular carcinoma (HCC) as well as liver metastases and advantages over traditional chemoembolizaionhave been reported. The local beta emissions from this technique have been shown to provide therapeutic effectwithin the tumor. Dosages range from 110-150 Gy but radiation delivered to malignant tissue is dependent ondistance from the yttrium source. Radiotherapy is only effective in treating HCC in doses above 50 Gy.Consequently treatment response after radioembolization is between 25-60% when based on response criteriain solid tumors (mRECIST). We propose to use ultrasound-triggered microbubble destruction (UTMD) to improveradioembolization of HCC. This technique uses commercial ultrasound contrast agents whose ultrasoundtriggered cavitation results in a variety of well documented bioeffects. Localized microbubble cavitation has beenshown to sensitize malignant tissue to radiotherapy by inducing vascular endothelial-cell apoptosis. Thuslocalized UTMD after radioembolization of HCC may potentially improve tumor response by selectivelysensitizing malignant tissue to radiotherapy. In addition the rate of contrast reperfusion after a destructive pulsecan be quantified and used to estimate blood perfusion and fractional vascularity. Changes in fractionalvascularity and perfusion may be a potential earlier indicator of treatment response thereby enabling earlierretreatment in non-responding patients. We propose a clinical trial using localized microbubble cavitation followed by imaging of contrast washingback into the tumor (termed reperfusion) to improve patient outcomes and predict treatment response earlierthan the current clinical standards. Patients scheduled for radioembolization of HCC will be randomized toreceive radioembolization alone or radioembolization in combination with a contrast ultrasound exam 2-4 hoursand 7 and 14 days post radioembolization. A flash destruction-replenishment technique will be used to inducemicrobubble cavitation at multiple planes within the tumor vasculature. Tumoral response safety radioactivebead distribution liver function and alpha fetal protein will then be evaluated and compared between groups.As a secondary aim tumor perfusion will be quantified in the experimental group based on the rate of contrastagent reperfusion following each destructive ultrasound pulse. Patients will then be stratified according tomRECIST criteria 3-4 months post treatment based on their clinically scheduled follow-up MRI/CT study.Microbubble-derived tumor reperfusion rate will be compared between groups to determine if treatment responsecan be predicted 7-14 days post therapy. Once validated this technique is expected to improve patient outcomesby selectively sensitizing malignant tissue to radiotherapy and by enabling alternative forms of treatment throughearlier identification of patients not responding to therapy. 302610 +No NIH Category available Malignant Childhood Neoplasm;neoplasm registry NATIONAL CHILDHOOD CANCER REGISTRY (NCCR) n/a NCI 10834816 75N91021D00018-P00002-759102200001-1 N02 7/1/22 0:00 6/30/23 0:00 78754532 "KOHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2023 1294998 NCI NATIONAL CHILDHOOD CANCER REGISTRY (NCCR): The National Childhood Cancer Registry (NCCR) is envisioned as a connected data infrastructure to enable sharing of childhood cancer data from multiple and heterogeneous data sources. Incorporating available data on genomic and tumor characterization residential history social determinants of health and measures of financial toxicity longitudinal treatments including oral agents and longitudinal outcomes data including recurrence and subsequent cancers can enhance the core infrastructure of registry data on pediatric patients. 1294998 +No NIH Category available Address;Adoptive Immunotherapy;Adoptive Transfer;Adult;Antigens;Binding;Biological Products;Cancer Burden;Cancer Model;Case Study;Cell surface;Cells;Childhood;Childhood Solid Neoplasm;Clinical;Clinical Trials;Combination immunotherapy;Complement;Cytometry;Data;Data Set;Development;Drug Modulation;Effectiveness;Ewings sarcoma;Funding;Future;Genomic approach;Genomics;Goals;Homing;Hybrids;Immune;Immune response;Immunologic Adjuvants;Immunologic Monitoring;Immunotherapy;Inflammatory;Innate Immune Response;Interruption;Knowledge;Macrophage;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Minnesota;Modality;Mutation;Myeloid-derived suppressor cells;Natural Immunity;Natural Killer Cells;New York;Normal Cell;Ohio;Oncolytic viruses;Patients;Pediatric Hospitals;Physicians;Pre-Clinical Model;Proteins;Regimen;Research Personnel;Resistance;Resource Sharing;STAT3 gene;Scientist;Signal Transduction;Site;Solid Neoplasm;Source;T cell response;Technology;Testing;Therapeutic;Traction;Transforming Growth Factor beta;Tumor Immunity;Universities;Virotherapy;Virus;Virus Diseases;adaptive immunity;anti-tumor immune response;cancer cell;cancer immunotherapeutics;cancer immunotherapy;chemokine;chemoradiation;chimeric antigen receptor;chimeric antigen receptor T cells;combinatorial;conventional therapy;cytokine;data integration;effective therapy;embryo/fetus antigen;experience;immune cell checkpoints;immunogenicity;immunoregulation;immunotherapy clinical trials;improved;innate immune mechanisms;medical schools;neoantigens;novel;oncolytic virotherapy;pharmacologic;pre-clinical;rational design;resistance mechanism;response;small molecule;success;synergism;trafficking;transcriptomics;translational study;tumor;tumor microenvironment;tumor-immune system interactions Novel Immunomodulation and Facilitation of Suppression Proof CAR NK cell against Ewing sarcoma Overall Center Project NarrativeWe seek to discover and validate strategies to leverage both innate and adaptive immunity to devise and testnovel immunotherapies for cancer. We also explore ways to enhance the effectiveness of cellular and virusderived immunotherapies by combining them with other biologics or small molecule drugs that modulate thetumor immune microenvironment. Our collective projects supported by two shared resource cores will reducethe burden of cancer by providing the nonclinical data needed to launch combination immunotherapyclinical trials and ultimately this project will lead to new and more effective treatment options for patientswith childhood cancers. NCI 10834579 9/7/23 0:00 PA-20-272 3U54CA232561-01A1S7 3 U54 CA 232561 1 A1S7 "BOURCIER, KATARZYNA" 9/1/23 0:00 8/31/24 0:00 1884239 "CRIPE, TIMOTHY P" "CAIRO, MITCHELL S." 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 253700 NCI 214500 39200 Overall Center AbstractThis application describes the Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center created inresponse to the RFA as a second nidus for the Pediatric Immunotherapy Discovery and DevelopmentConsortium (PI-DDN). To complement the funded U54 (Maris and Mackall MPI) of the PI-DDN that largelyseeks to harness adaptive immunity to further develop CAR-T cells against newly identified antigens we proposeto harness innate immunity to target pediatric cancers to circumvent resistance to conventional therapy and tofurther enable adaptive/hybrid immune approaches.Our aims are to (1) Identify and overcome barriers to utilizing NK and CAR-NK cells as cancer therapeutics (2)break tolerance to self cancer-associated proteins and (3) enhance immunotherapies by targeting suppressivemyeloid cells. We will accomplish our aims through four projects based at two major sites based in Ohio(Nationwide Childrens Hospital) and New York (New York Medical College) with subsites in Columbus (TheOhio State University) and Minneapolis (Univeristy of Minnesota). In addition to an Administrative SharedResource (Core A directed by Dr. Timothy Cripe and Associate Director Dr. Mitchell Cairo) the projects arescientifically supported by a comprehensive Genomics & Immune Monitoring Shared Resource (Core B directedby Dr. Elaine Mardis with several subspecialy assistant directors). Core B provides integrated datasets via state-of-the-art technologies including mass cytometry single cell transcriptomics and an array of other genomicsapproaches that enable detailed characterizations and tracking of cancer cell immunogenicity the tumor immunemicroenvironment and immunologic responses. We have also assembled strong external and internal scientificadvisory boards of renowned leaders whose expertise spans the projects and shared resources. The projectsare highly integrated and cross-informative. We propose that therapeutic regimens that combine modalities willproduce synergy that drives anti-tumor immune responses in preclinical pediatric cancer models overcomingthe limitations of low mutational burdens. Our goal is to generate a sufficient body of knowledge with compellingdata to inform the rational design of future clinical trials and thereby improve the lives of children with cancer.1 253700 +No NIH Category available Architecture;Atomic Force Microscopy;Behavior;Binding;Biochemical;Biochemistry;Biological Assay;Biological Models;Biology;Biophysical Process;Biophysics;Breast Cancer Patient;Breast Cancer cell line;Breast cancer metastasis;CRISPR interference;Cancer cell line;Cell Line;Cell Nucleus;Cell physiology;Cells;Characteristics;Chromatin;Chromatin Fiber;Chromatin Structure;Chromosome Segregation;Complex;Confocal Microscopy;Coupled;DNA;DNA-Protein Interaction;Development;Disease;Distal;Down-Regulation;Electron Microscopy;Estrogen receptor positive;Exhibits;Fluorescence Microscopy;Gene Expression Regulation;Gene Silencing;Gene Structure;Genes;Genetic Transcription;Genome;Goals;Heterochromatin;Histologic;Histone H3;In Vitro;Individual;Injections;Integral Membrane Protein;Intermediate Filament Proteins;Invaded;Label;Lamin Type B;Lamins;Length;Liquid substance;Lysine;MCF7 cell;Malignant Neoplasms;Mechanics;Mediating;Mediator;Membrane;Metastatic/Recurrent;Methylation;Modification;Molecular;Monitor;Morphology;Mus;Neoplasm Metastasis;Nuclear;Nuclear Envelope;Nuclear Inner Membrane;Nuclear Pleomorphism;Nucleosomes;Organism;Output;Patient-Focused Outcomes;Phase;Physiological;Play;Pleomorphism;Postdoctoral Fellow;Proliferating;Protein Region;Proteins;Research;Research Project Grants;Role;Severities;Shapes;Sum;System;T47D;Techniques;Tertiary Protein Structure;Testing;Time;Trophoblast Cancer;Tumor Markers;Up-Regulation;Variant;Visualization;Work;biophysical properties;cancer cell;diagnostic biomarker;disease phenotype;experimental study;gene repression;heterochromatin-specific nonhistone chromosomal protein HP-1;histone methylation;histone modification;in vivo;lamin B receptor;malignant breast neoplasm;micronucleus;migration;mouse model;neoplastic cell;novel;overexpression;physical model;programs;protein expression;public health relevance;receptor binding;reconstitution;recruit;restoration;single molecule;targeted cancer therapy;therapy development;tumor progression;ultra high resolution Dissecting the mechanistic role of multinucleation in breast and trophoblast cancers Project Narrative and Public Health Relevance StatementSilencing large regions of the genome is essential for proper cell function and these heterochromatic regionsare organized at the nuclear periphery. A diagnostic marker of tumor severity and patient outcome aredistortions to the size and shape of the nucleus termed pleomorphism. The research program proposed aimsto develop a fundamental understanding of heterochromatin formation at the nuclear envelope which willprovide tangible targets for cancer therapies that aim to restore proper regulation of gene expression andnuclear morphology. NCI 10834418 7/20/23 0:00 RFA-CA-19-002 7K00CA245719-06 7 K00 CA 245719 6 "DAMICO, MARK W" 1/1/21 0:00 12/31/24 0:00 ZCA1-RTRB-R(A1) 14207598 "KEENEN, MADELINE " Not Applicable 4 ANATOMY/CELL BIOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/15/23 0:00 12/31/23 0:00 393 Other Research-Related 2023 69883 NCI 65000 4883 Project Summary/Abstract A key driver of cancer is the global deregulation of transcription networks in the cell. Transcriptional outputis dependent on chromatin structure and topology; repressed genes are sequestered from active genes intoregions of compacted DNA near the nuclear membrane. Dense chromosomal domains termed heterochromatinare associated with Heterochromatin Protein-1 (HP1) and are tethered to the periphery via an interaction withthe nuclear transmembrane protein Lamin Binding Receptor (LBR) and the intermediate filament protein LaminB. Consequently cancer cells that undergo global rewiring of transcription also often exhibit aberrant proteinexpression of Lamin B LBR and HP1. The physical manifestation of the misregulation of these proteins isdistortion in the size and shape of the nuclear envelope. Indeed this nuclear pleomorphism is used as ahistological marker of tumor progression. In estrogen receptor positive (ER+) breast cancer patientsdownregulation of HP1 and upregulation of Lamin B and LBR is strongly correlated with earlier occurrence ofdistal metastasis. Understanding the biophysical properties that govern the assembly of heterochromatin at thenuclear periphery will facilitate the development of therapies aimed at restoring proper gene regulation. HP1 wasrecently found to concentrate DNA and chromatin into liquid-liquid phase separated (LLPS) droplets in vitro. Thissuggests a potential mechanism of DNA organization in vivo. To investigate the molecular details of HP1-mediated compaction and phase separation I utilized DNA curtains and confocal microscopy. I identified keyregions of HP1 required for multivalentLLPS interactions and DNA compaction. This preliminary researchfocused on DNA and the graduate work in Aim 1 will build on these studies by evaluating HP1 interactions withcomplex nucleosomal substrates. Heterochromatin in vivo is distinguished by evenly spaced nucleosomes andthe trimethylation of histone H3 lysine 9 (H3K9me3). I will make chromatin substrates that range from mono-nucleosomes to 50kb chromatin fibers with variations in spacing and methylation modification. I will monitor thebinding oligomerization and phase separation of HP1 on these substrates by a combination of bulk biochemicalassays and a novel single molecule chromatin assay. The proposed postdoctoral research in Aim 2 will focuson determining a physical model of the nuclear periphery. I will reconstitute the interactions between chromatinand the lamina with single molecule studies in vitro and super resolution studies in cells. I will use cell lines andmouse models of breast cancer metastasis to determine the molecular mechanism guiding metastatic recurrenceof ER+ breast cancer patients with high expression of Lamin B and LBR. This research program will propel metoward my ultimate goal of leading my own lab studying how nuclear topology is coupled to cell fate determinationin development and the misregulation that leads to disease. 69883 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER - Core Infrastructure n/a NCI 10833984 261201800008I-P00006-26100001-1 N01 5/1/18 0:00 4/30/24 0:00 16187737 "GERSHMAN, SUSAN " Not Applicable 8 Unavailable 878298900 DLKMR1QVDX34 878298900 DLKMR1QVDX34 US 42.358074 -71.057586 652402 MASSACHUSETTS STATE DEPT OF PUB HEALTH BOSTON MA Other Domestic Non-Profits 21084603 UNITED STATES N R and D Contracts 2023 795623 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 795623 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10833979 75N91021D00006-P00004-759102100001-1 N01 3/3/21 0:00 4/30/24 0:00 78082185 "KOCH, LORI " Not Applicable 13 Unavailable 806660296 NN66PR7QMLR8 806660296 NN66PR7QMLR8 US 39.803167 -89.662345 3549201 ILLINOIS STATE DEPT OF PUBLIC HEALTH SPRINGFIELD IL Other Domestic Non-Profits 627610002 UNITED STATES N R and D Contracts 2023 1393638 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 1393638 +No NIH Category available Academia;Active Sites;Adult;Alcohols;Automobile Driving;BAY 54-9085;Binding;Binding Sites;Bromodomain;CD47 gene;Cancer Biology;Catalytic Domain;Chemicals;Childhood;Childhood Solid Neoplasm;Clinical Trials;Collaborations;Combined Modality Therapy;Consensus;Data;Development;Diagnostic;Digit structure;Epigenetic Process;Evaluation;Formulation;Funding;Generations;Genetic Transcription;Goals;Grant;Growth;Head and Neck Squamous Cell Carcinoma;Human;Immunooncology;Industry;Laboratories;Lead;Legal patent;Lysine;MAP Kinase Gene;MYCN gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Mission;Modeling;Molecular;Morbidity - disease rate;Mus;Mutation;Neuroblastoma;Oncogenes;Oncoproteins;Oral;PIK3CA gene;PIK3CG gene;Pathway interactions;Patients;Phase;Phase I Clinical Trials;Phosphotransferases;Play;Preparation;Primary carcinoma of the liver cells;Proliferating;Property;Proteins;Proto-Oncogene Proteins c-myc;Public Health;Receptor Cell;Regulation;Reporting;Research;Resistance;Role;Safety;Signal Pathway;Signal Transduction;Specificity;Structure;Structure-Activity Relationship;Study models;Subgroup;Therapeutic;Therapeutic Studies;Toxic effect;Tumor Immunity;United States National Institutes of Health;Validation;Viral;adaptive immune response;analog;c-myc Genes;cancer cell;cancer therapy;cell transformation;clinical application;clinical candidate;clinical development;design;design verification;disability;drug candidate;immunoregulation;improved;in silico;in vitro testing;in vivo;inhibitor;innovation;insight;kinase inhibitor;medulloblastoma;molecular modeling;mortality;neoplastic cell;novel;novel therapeutics;overexpression;pharmacokinetics and pharmacodynamics;preclinical development;preclinical study;predictive marker;prognostic significance;programmed cell death ligand 1;scaffold;single molecule;small molecule;small molecule inhibitor;success;technology development;technology platform;therapeutic evaluation;transcription factor;transcriptome;tumor;tumor growth;tumorigenesis;tumorigenic Dual PI3K/BRD4 Inhibitory Chemotype for Maximum Inhibition of MYC and Cancer The planned research is relevant to public health because data we and others have acquiredshows that our proposed grant to develop the first potent PI3 kinase-BRD4 dual inhibitor totarget MYC oncogenesis in cancer cells. Moreover the proposal is designed to produce aplatform technology for the development of dual small molecule inhibitors of PI3K combined withinhibitors of other targets thereby having a broad impact on public health. Thus the proposedresearch which will involve a close collaboration between academia and industry is relevant tothe part of the NIHs mission that pertains to the development of new therapeutics able toreduce the burden of human disability via improved treatment of adult and childhood cancer. NCI 10833761 7/27/23 0:00 PA-16-160 6R01CA215651-06 6 R01 CA 215651 6 "FORRY, SUZANNE L" 12/27/17 0:00 7/31/24 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1882337 "DURDEN, DONALD " Not Applicable 5 PEDIATRICS 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 390037 NCI 296555 93482 There is an unmet need to inhibit the key cancer promoting transcription factor MYC (both c-MYC and MYCN)that act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cellresistance tumor growth and the control of antitumor immunity. To date small molecule inhibitors of MYChave remained elusive. In our preliminary data we developed a lead compound SF2523 which displays potentorthogonal inhibitory activity against MYC by blocking PI-3 kinase (PI-3K) and the highly dominant regulator ofepigenetic machinery BRD4. Herein we set out to develop SF2523 and other chemotypes through additionalin silico crystal structure and NMR analysis and optimization in preparation for advanced preclinical studies fortherapeutic application in Myc dependent cancers. The transcription factor MYC (c-MYC and MYCN) plays a key role in cancer growth proliferation survivaland more recently in the control of antitumor immunity. It is overexpressed in a subgroup of most humancancers resulting in resistance to PI-3K and other signaling pathway inhibitors. Both MYC and PI-3K are well-established onco-proteins that are confirmed drivers in a large number of tumor types. Moreover BRD4 israpidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance tokinase inhibition. Therefore there is general consensus in the cancer biology arena that inhibition of BRD4and/or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor celltransformation and resistance. Our innovative approach centers on our central hypothesis that a dual PI-3K/BRD4 inhibitor SF2523 will potently inhibit MYC activity by enhancing its degradation via PI-3K inhibitionAND block MYC transcriptional activity via BRD4 inhibition. Our preliminary data supports our success in thatwe solved the crystal structure of SF2523 in the active site of BRD4 and determined the structure activityrelationships (SAR) around dual PI-3K/BRD4 inhibitors designed by validated molecular modeling studies anddemonstrated the safety of our dual-targeting single inhibitor versus the accumulated toxicity of using twoseparate inhibitors. Our preliminary studies support our specific aims which include: 1) SAR to optimize thedual inhibitory chemotype (Aim 1) built around our crystal structure and NMR analyses (Aim 2) in parallel with2) the evaluation of safety PK/PD modeling and antitumor efficacy of each oral optimized chemotype (Aim 3).The objective of our proposal is to advance the preclinical development and validation of this novel dual PI-3K/BRD4 inhibitor SF2523 or its derivative as a final drug candidate against PI-3K/MYC-driven malignancieswith high mortality rates e.g. hepatocellular carcinoma (HCC) and squamous cell carcinoma of the head/neck(SCCHN) and obtain an optimized oral candidate for final development. Moreover our aims seek to identifyPI-3K and MYC tumor signatures which will define sensitivity to SF2523 as we move toward a Phase I clinicaltrial of this first in class dual PI-3K/BRD4 inhibitory chemotype for individualized cancer therapeutics. 390037 +No NIH Category available Acceleration;Address;Administrative Supplement;Adoption;Archives;Award;Cancer Patient;Cancer Survivorship;Collaborations;Communication;Communication Tools;Communities;Continuity of Patient Care;Custom;Data;Data Aggregation;Data Set;Development;Documentation;Education;Electronic Health Record;Ensure;Fostering;Frequencies;Goals;International;Intervention;Lead;Leadership;Malignant Neoplasms;Manuscripts;Maps;Methods;Minority;Monitor;Patients;Process;Productivity;Publications;Quality of life;Recommendation;Reporting;Research;Research Personnel;Running;Schedule;Site;Symptoms;System;Work;anticancer research;cancer care;cancer therapy;common treatment;data harmonization;data modeling;data sharing;data standards;effectiveness outcome;evidence base;implementation evaluation;implementation outcomes;improved;medically underserved population;meetings;palliative;preservation;side effect;success;symposium;symptom management;symptomatic improvement;treatment research;web site;web-based tool Coordinating Center for Research Centers for Improving Management of Symptoms During and Following Cancer Treatment Project NarrativeMillions of cancer patients across the cancer care continuum suffer from complications associated with theirillness including high symptom burden and poor quality of life. RTI Internationals Coordinating Centerproposes to continue support of the Improving Management of Symptoms Across Cancer Treatments(IMPACT) Consortium by providing expert leadership logistical support and data coordination to the projectsimplementing methods to improve symptom management across the cancer treatment continuum and addressthe unique challenges of minority and medically underserved populations. NCI 10833736 9/18/23 0:00 PA-20-272 3U24CA232980-01S1 3 U24 CA 232980 1 S1 "ADAMS, LYNN S" 5/1/23 0:00 8/31/24 0:00 10803187 "ARDINI, MARY-ANNE " Not Applicable 4 Unavailable 4868105 JJHCMK4NT5N3 4868105 JJHCMK4NT5N3 US 35.9138 -78.848911 6939101 RESEARCH TRIANGLE INSTITUTE RESEARCH TRIANGLE PARK NC Research Institutes 277092194 UNITED STATES N 5/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 451000 NCI 324571 126429 Project SummaryTo advance the Beau Biden Cancer MoonshotSM Initiative to accelerate cancer research and the Blue RibbonPanels recommendation to minimize cancer treatments debilitating side effects RTI International will continueto serve as the Coordinating Center (CC) for the Research Centers (RCs) for Improving Management ofSymptoms Across Cancer Treatments (IMPACT) Consortium. As the CC RTI will provide leadership scientificexpertise and logistical support to the consortium projects that seek to improve symptom management acrossthe cancer treatment continuum (i.e. treatment with curative intent treatment with noncurative/palliative intentcancer survivorship) and address the unique challenges of minority and medically underserved populations.Specifically we will enhance research efficiency productivity and impact by facilitating collaboration andproviding the logistical communications and operational support necessary to run a multicenter researchConsortium; facilitate the development of evidence-based symptom management recommendations based onresults across studies and research sites; and accelerate adoption of integrated systems for monitoring andmanaging patient-reported symptoms by collaborating with RCs to broadly disseminate findings. Thisapplication has specific strengths that will enhance the scientific productivity of the Consortium. The CC willfoster collaboration within the IMPACT Consortium by uniting diverse researchers around shared goals andharmonized studies. RTI will promote effective communication by developing and maintaining custom web-based tools for communications and document sharing. RTI will leverage data standards and harmonizationacross the Consortium to catalyze data sharing and aggregation. 451000 +No NIH Category available Academy;Accounting;Administrative Supplement;American;American Society of Clinical Oncology;Antineoplastic Agents;Blue Cross;Blue Shield;Cancer Patient;Caring;Direct Costs;Disadvantaged;Drug Utilization;Ensure;Face;Fee-for-Service Plans;Health;Health Policy;Health Services Accessibility;Health system;Healthcare;Hospitals;Improve Access;Incentives;Insurance Carriers;Integrated Health Care Systems;Malignant Neoplasms;Marketing;Medicare;Medicine;Mentors;Modality;Names;Oncology;Oncolytic;Oral;Outcome;Ownership;Parents;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacy facility;Policies;Policy Maker;Price;Principal Investigator;Provider;Quality of Care;Reporting;Research;Societies;System;Time;Trust;United States Federal Trade Commission;Vulnerable Populations;Work;cancer care;care delivery;chemotherapy;clinical practice;cost;evidence base;health care delivery;health economics;health plan;interest;longitudinal dataset;malignant mouth neoplasm;medical specialties;medication compliance;meetings;member;novel;parent grant;participant enrollment;pharmacy benefit;response;symposium;trend The Impact of a Changing Health Care Delivery System on the Quality of Oncology Care - Administrative Supplement Project Narrative/RelevanceThis study will examine changes in health plan ownership of specialty pharmacies over time and the impact ofthese changes on access and quality of care for cancer patients using oral cancer drugs. These findings willprovide oncology practitioners payers and policymakers valuable information to improve access quality andoutcomes of cancer care. Our results also will be especially informative to policymakers in crafting anappropriate policy response to growing integration between plans and pharmacies. NCI 10832790 8/15/23 0:00 PA-20-272 3R01CA255035-03S2 3 R01 CA 255035 3 S2 "WEAVER, SALLIE JAYNE" 12/15/20 0:00 11/30/25 0:00 2087176 "KEATING, NANCY L" "LANDRUM, MARY BETH" 7 ADMINISTRATION 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 393 Non-SBIR/STTR 2023 122677 NCI 72376 50301 Project Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-044. The cancer care delivery system that frequently provides care that is not patient-centeredevidence-based or accessible to vulnerable populations. In recent years there has also been increasingconsolidation among providers which could have important implications for the quality of cancer care. Under the parent R01 we are studying the implications of growing integration across providers forpatients with cancer. One key outcome we have considered is the impact of integration on the delivery of oraloncolytics. Oral oncolytics are an increasingly important treatment modality accounting for nearly half ofchemotherapy spending among patients enrolled in Medicare Fee-for-Service and Part D in 2019.Nonetheless patients face significant challenges in accessing these medicines including high rates ofprescription abandonment non-adherence and early discontinuation. Integration between health plans and specialty pharmacies may also impact patients using oraloncolytics. Indeed many health plans have acquired a specialty pharmacy. This includes Centene andAcariaHealth (2013) CVS and Aetna (2018) Cigna and Accredo Pharmacy (2018) and Anthem and Bioplus(2022). Similarly UnitedHealthcare has long been integrated with Optum Specialty Pharmacy but has alsorecently acquired Avella (2018) and Diplomat (2019). Humana has long been integrated with HumanaSpecialty Pharmacy. Yet the implications for patients are unclear. On the one hand plan-pharmacy integrationmay allow plans to better assure patients receive and are adhering to medications especially when it mayreduce other forms of avoidable costs. On the other hand plan-pharmacy integration may harm patients if itreduces the pharmacys incentive to assure access as utilization poses a direct cost to the parent company. We propose describing and studying the effects of health plan and specialty pharmacy integration incancer care. We will first build a unique longitudinal dataset identifying the pharmacies owned by each healthinsurer carrier in each year between 2010 and 2021. We will then seek to accomplish the following aims:1. Describe trends in the degree to which oral oncolytics are filled through health plan-integrated pharmacies2. Evaluate the association between health plan-pharmacy integration and patient outcomes including time- to-fill and medication adherence for oral oncolytics This proposal is closely related to the parent R01 and policy in two ways. First this project studies anovel form of integration that has gone understudied: integration between health plans and pharmacies. Thisform of integration is also highly relevant for anti-trust policy as the Federal Trade Commission is interested incrafting policy related to integration between plans pharmacy benefit managers and pharmacies. Second theproject focuses on a key policy lever namely health plan policy that influences quality and access to care. 122677 +No NIH Category available Antigens;Biological Products;Cancer Burden;Cancer Model;Cells;Childhood;Clinical Trials;Combination immunotherapy;Complement;Cytometry;Data;Data Set;Development;Drug Modulation;Effectiveness;Funding;Future;Gene Delivery;Genomic approach;Genomics;Glioma;Goals;Hybrids;Immune;Immune response;Immunologic Monitoring;Immunotherapy;Knowledge;Malignant Childhood Neoplasm;Malignant Neoplasms;Minnesota;Modality;Mutation;Myeloid-derived suppressor cells;Natural Immunity;Natural Killer Cells;New York;Ohio;Oncolytic viruses;Patients;Pediatric Hospitals;Proteins;Regimen;Resistance;Resource Sharing;Site;Technology;Testing;Therapeutic;Universities;Virus;adaptive immunity;anti-tumor immune response;cancer cell;cancer immunotherapy;chimeric antigen receptor T cells;conventional therapy;data integration;effective therapy;immunogenicity;immunotherapy clinical trials;improved;medical schools;novel;pre-clinical;rational design;response;small molecule;synergism;transcriptomics;tumor-immune system interactions Oncolytic virus bispecific gene delivery for high grade gliomas Overall Center Project NarrativeWe seek to discover and validate strategies to leverage both innate and adaptive immunity to devise and testnovel immunotherapies for cancer. We also explore ways to enhance the effectiveness of cellular and virusderived immunotherapies by combining them with other biologics or small molecule drugs that modulate thetumor immune microenvironment. Our collective projects supported by two shared resource cores will reducethe burden of cancer by providing the nonclinical data needed to launch combination immunotherapyclinical trials and ultimately this project will lead to new and more effective treatment options for patientswith childhood cancers. NCI 10832350 9/13/23 0:00 PA-20-272 3U54CA232561-01A1S8 3 U54 CA 232561 1 A1S8 "BOURCIER, KATARZYNA" 9/1/23 0:00 8/31/24 0:00 1884239 "CRIPE, TIMOTHY P" "CASSADY, KEVIN A" 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 366900 NCI 296900 70000 Overall Center AbstractThis application describes the Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center created inresponse to the RFA as a second nidus for the Pediatric Immunotherapy Discovery and DevelopmentConsortium (PI-DDN). To complement the funded U54 (Maris and Mackall MPI) of the PI-DDN that largelyseeks to harness adaptive immunity to further develop CAR-T cells against newly identified antigens we proposeto harness innate immunity to target pediatric cancers to circumvent resistance to conventional therapy and tofurther enable adaptive/hybrid immune approaches.Our aims are to (1) Identify and overcome barriers to utilizing NK and CAR-NK cells as cancer therapeutics (2)break tolerance to self cancer-associated proteins and (3) enhance immunotherapies by targeting suppressivemyeloid cells. We will accomplish our aims through four projects based at two major sites based in Ohio(Nationwide Childrens Hospital) and New York (New York Medical College) with subsites in Columbus (TheOhio State University) and Minneapolis (Univeristy of Minnesota). In addition to an Administrative SharedResource (Core A directed by Dr. Timothy Cripe and Associate Director Dr. Mitchell Cairo) the projects arescientifically supported by a comprehensive Genomics & Immune Monitoring Shared Resource (Core B directedby Dr. Elaine Mardis with several subspecialy assistant directors). Core B provides integrated datasets via state-of-the-art technologies including mass cytometry single cell transcriptomics and an array of other genomicsapproaches that enable detailed characterizations and tracking of cancer cell immunogenicity the tumor immunemicroenvironment and immunologic responses. We have also assembled strong external and internal scientificadvisory boards of renowned leaders whose expertise spans the projects and shared resources. The projectsare highly integrated and cross-informative. We propose that therapeutic regimens that combine modalities willproduce synergy that drives anti-tumor immune responses in preclinical pediatric cancer models overcomingthe limitations of low mutational burdens. Our goal is to generate a sufficient body of knowledge with compellingdata to inform the rational design of future clinical trials and thereby improve the lives of children with cancer.1 366900 +No NIH Category available Address;Administrative Supplement;Adolescent;Adolescent and Young Adult;Adverse effects;Age;Age Months;Anxiety Disorders;Attention deficit hyperactivity disorder;Behavioral;California;Cannabinoids;Cannabis;Characteristics;Chronic;Chronology;Cigarette;Data;Data Analyses;Data Sources;Dependence;Development;Devices;Disease;Disparity;Drug abuse;Drug usage;Emotional;Ethnic Origin;Expectancy;Flavoring;Frequencies;Friends;Funding;Future;Gender;Gender Identity;Goals;Health;High School Student;Impulsivity;Individual;Inequity;Intervention;JUUL;Left;Link;Longitudinal cohort study;Low Prevalence;Malignant Neoplasms;Manuscripts;Marijuana Smoking;Measurement;Measures;Modeling;Mood Disorders;Nicotine;Oils;Outcome;Parents;Participant;Persons;Pharmaceutical Preparations;Plants;Play;Policies;Policy Maker;Population;Preparation;Prevention;Prevention strategy;Problem behavior;Proliferating;Public Health;Race;Research;Research Personnel;Rewards;Risk;Risk Factors;Role;Sampling;Schools;Science;Scientist;Self Administration;Sex Orientation;Sexuality;Students;Surveys;THC concentration;Technology;Testing;Time;Tobacco;Tobacco use;Variant;Vulnerable Populations;Wages;Waxes;Youth;aged;asexual;biopsychosocial;cancer health disparity;catalyst;cohort;combustible tobacco;design;deviant;digital;distress tolerance;electronic cigarette use;experience;experimental study;flexibility;follow-up;habituation;health equity promotion;heated tobacco products;high risk;high school;interest;marijuana use;marijuana vaping;multiple drug use;nicotine exposure;nicotine use;ninth grade;nonbinary;novel;pansexual;parent project;prevent;programs;public health priorities;recruit;response;risk prediction;secondary analysis;sexual identity;sexual minority;social;stem;tobacco products;trait;uptake;vaping;vaping nicotine;young adult Enhancing Precision of Estimates of Sexual Orientation and Gender Identity Disparities in Tobacco and Cannabis use in Young People PROJECT NARRATIVE FOR ADMINISTRATIVE SUPPLEMENT PROJECTThis administrative supplement project will provide detailed information on whether adolescents or young adultswith minority sexual orientation and gender identities are at increased risk of using tobacco or cannabis products.This information will inform which sexual and gender identity populations should be prioritized in public healthprograms and policies to promote health equity in young people. NCI 10831803 9/12/23 0:00 PA-20-272 3R01CA229617-05S1 3 R01 CA 229617 5 S1 "RODITIS, MARIA LEIA" 9/20/19 0:00 8/31/25 0:00 Addiction Risks and Mechanisms Study Section[ARM] 9227137 "LEVENTHAL, ADAM MATTHEW" "BARRINGTON-TRIMIS, JESSICA LOUISE" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 95959 NCI 57952 38007 PROJECT SUMMARY FOR ADMINISTRATIVE SUPPLEMENT PROJECTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-032. Obtaining estimates of disparities in tobacco product and cannabis use associated with sexualorientation and gender identity (SOGI) among adolescents and young adults (AYAs) is vital for informingstrategies to reverse cancer inequities. Existing estimates of SOGI disparities use measures that areinsufficiently inclusive leaving unclear whether disparities extend to specific SOGIs that are often overlooked(e.g. asexual pansexual gender non-binary). To address this gap this administrative supplement will conducta new secondary analysis of the association of 8 different sexual orientation identities and 5 different genderidentities with the use and poly-use of 8 different tobacco and cannabis products. We leverage a NCI-fundedR01 parent project (R01-CA0229617) including longitudinal cohort studies of 3915 adolescents and 2526 youngadults that examines risk factors and consequences of nicotine and cannabis vaping. At each of 5 (semi)annualsurvey waves conducted 2019-2023 detailed data on tobacco and cannabis product use are being collected forthe parent R01s primary aims and detailed SOGI data are being collected for descriptive information about thecohorts. This supplement requests funding to cover salary effort for investigators and statisticians to conductdata analysis and manuscript preparation for this new secondary analysis. The primary goal of the supplementproject is to determine the concurrent association of various SOGIs with past-30-day tobacco and cannabisproduct use frequency and poly-use statuses in an adolescent cohort and in a young adult cohort. The secondarygoals are to examine whether these associations vary across individuals with changing vs. static SOGIschronological time and race/ethnicity. Because we have repeated measures of SOGI and tobacco/cannabisuse we will have up to 14843 and 9103 data points for adolescent and young adult cohorts respectively whichwill provide unprecedented power to examine lower prevalence SOGIs (e.g. asexual pansexual questioningsexuality gender non-binary). At the end of this Administrative Supplement project we will have some of themost contemporary inclusive and detailed estimates of SOGI disparities in tobacco and cannabis product usein the vulnerable population of AYAs. This will inform: (a) precise public health measures to reduce SOGI cancerdisparities; and (b) if more inclusive measurement of SOGI is needed in national tobacco/cannabis use surveysof AYAs in order to avoid overlooking disparities and in turn groups in need of intervention. 95959 +No NIH Category available Acceleration;Affect;Aging;Animals;Area;Biological Assay;Biological Models;Biopsy;Blood;Blood specimen;Canis familiaris;Carcinogens;Chemical Exposure;Chemicals;Chronic Disease;Collaborations;Collection;Communities;Companions;Data;Data Collection;Deposition;Dioxins;Disasters;Disease Progression;Enrollment;Environment;Environmental Exposure;Exposure to;Funding;Future;Goals;Grant;Hazardous Chemicals;Health;Hematopoiesis;Human;Incidence;Individual;Laboratories;Longevity;Longitudinal Studies;Malignant Neoplasms;Measurement;Modeling;Molecular Toxicology;Monitor;National Institute of Environmental Health Sciences;Ohio;Oregon;Outcome;Parents;Phase;Polycyclic Hydrocarbons;Positioning Attribute;Public Health;Reporting;Research;Risk;Role;Sampling;Secure;Sentinel;Site;Soil;Surveys;Technology;Testing;Time;Training;United States;Universities;Vinyl Chloride;Volatilization;Work;anticancer research;cancer care;cancer epidemiology;chemical spill;combustion product;community science;detection method;environmental toxicology;epidemiology study;improved;novel strategies;professor;recruit Connecting individual-level environmental exposures to cancer-related outcomes in a shorter-lived natural model system We propose to use dogs as environmental sentinels to investigate chemical exposures andhealth outcomes near a train derailment in East Palestine Ohio that releases more than100000 gallons of hazardous chemicals. With their shorter lifespans and accelerated onset andprogression of disease dogs could provide faster outcomes for longitudinal studies andpotentially demonstrate the utility of individual environmental exposure measurements. We willpair blood biopsy technology with passive environmental samplers and investigate the feasibilityand efficacy of using dogs to monitor for health consequences. NCI 10831774 9/19/23 0:00 PA-20-272 3R01CA255319-03S2 3 R01 CA 255319 3 S2 "NADEAU, CHRISTINE FRANCES" 6/7/21 0:00 5/31/26 0:00 Special Emphasis Panel[ZRG1(55)-R] 10971324 "KARLSSON, ELINOR " "LONDON, CHERYL A" 2 BIOSTATISTICS & OTHER MATH SCI 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 100001 NCI 59702 40299 Following a train derailment in East Palestine Ohio on February 3 2023 more than 100000gallons of hazardous chemicals consisting of vinyl chloride and other carcinogens werereleased into the environment directly and through controlled burn. This disaster offers anunfortunate opportunity to explore the role of external environmental exposure assessments incancer epidemiology.We propose to use companion dogs as a model system to investigate chemical exposures nearthe disaster site and correlations with cancer incidence. Dogs share both indoor and outdoorenvironments with their human caretakers and spontaneously acquire many of the same chronicdiseases that occur in humans including cancer. With their shorter lifespans and acceleratedonset and progression of disease large numbers of dogs can be recruited in a shorter timespan and provide faster outcomes for longitudinal studies informing human health.In our parent R01 we are using dogs as a model system for enhancing blood biopsy technologyto improve its accuracy and utility for helping to guide cancer care. We have developed andvalidated methods for detecting clonal hematopoiesis (a possible precursor to cancer) andcancer in dogs through blood biopsies. We also developed a community science platform fordog cancer research that includes a study of environmental passive samplers in dogs.Here we propose to pair blood biopsy technology with passive environmental samplers toinvestigate the feasibility and efficacy of using dogs as environmental sentinels to monitor forhealth consequences resulting from the train derailment and chemical spill. We will:Aim 1: Evaluate the relationship between proximity to the train derailment increases in chemicalexposures to combustion products and health outcomes.Aim 2: Evaluate the relationship between TD-CP exposures and the occurrence of clonalhematopoiesis and cancer using blood biopsies.This collaborative research effort will evaluate the utility of capturing individual-levelenvironmental exposure information in cancer epidemiology. 100001 +No NIH Category available Address;Affect;Antitumor Response;B-Lymphocytes;Basic Science;Benchmarking;Bioinformatics;Biological;Biological Markers;Biology;Bladder;Cancer Biology;Cancer Patient;Carcinogens;Cell Communication;Cells;Clinical;Coin;Communication;Communities;Data;Development;Diagnosis;Disease;Ensure;Fibroblasts;Fingerprint;Funding;Future;Genes;Genomics;Goals;Human;Immune;Immunoassay;Individual;Knowledge;Lesion;Lymphoid Tissue;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Maps;Mediating;Medical center;Modeling;Multi-Institutional Clinical Trial;Muscle;Organ;Outcome;Paracrine Communication;Pathologic;Pattern;Persons;Pilot Projects;Population;Primary Lesion;Prognosis;Property;Protein Secretion;Proteins;Proteomics;Recurrence;Recurrent Malignant Neoplasm;Reporting;Research;Research Personnel;Resource Sharing;Role;Sampling;Side;T-Lymphocyte;Tumor Promotion;Urine;Urothelial Cell;Validation;War;Yin;anticancer research;biomarker development;biomarker validation;cancer recurrence;cancer type;candidate marker;carcinogenesis;cell type;clinical practice;cohort;driving force;fibroblast-activating factor;functional genomics;induced pluripotent stem cell;innovation;insight;knowledge integration;lymphotoxin beta receptor;mouse model;multidisciplinary;neoplastic cell;non-muscle invasive bladder cancer;novel;personalized intervention;progenitor;programs;prospective;recombinase;recruit;restraint;risk stratification;single cell technology;success;tertiary lymphoid organ;transcriptomics;translational oncology;tumor;tumor growth;tumor progression;understudied cancer;urinary;urologic The stromal microenvironment as a co-organizer of bladder carcinogenesis and progression OVERALL PROJECT NARRATIVEBladder cancer is the second most common urologic malignancy; yet remained a significantly underfunded andunderstudied cancer type. Major clinical gaps in early bladder lesions [defined as non-muscle invasive bladdercancer (NMIBC)] include 1) lack of mechanistic insights defining NMIBC progression and 2) lack of platform forrisk stratifying NMIBC that recur but never progress from those that progresses into MIBC and consequentlydemonstrate poor prognosis. The knowledge gained by our Center will inform future NIMBC managementthrough 1) the development of novel urinary profiling strategies that could risk stratify aggressive NMIBC (Project1-3); 2) the identification of targets for future precision intervention either by enhancing/sustaining the tumor-restraining mechanisms (Project 1) and/or inhibiting the tumor-promoting mechanisms (Project 2). NCI 10831757 9/21/23 0:00 RFA-CA-21-054 7U54CA274375-02 7 U54 CA 274375 2 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1657891 NCI 1366860 291031 OVERALL PROJECT SUMMARYBladder cancer (BC) is the second most common urologic malignancy affecting 573278 people worldwide in2020. Pathologically BC is diagnosed as non-muscle-invasive (NMI) and muscle-invasive (MI) disease. Herewe define early bladder lesions as NMIBC. Major clinical gaps in NMIBC include i) lack of mechanistic insightsdefining NMIBC progression and ii) lack of platform for risk stratification of NMIBC that recur but never progress(non-progressors) from those that progresses into MIBC (progressors) and consequently demonstrate poorprognosis. The goal of our Center is to tackle this clinical issue by deciphering the underlying mechanismsrestraining or promoting the progression of early lesions (Project 1 & 2) and to leverage this novel biology ascandidate biomarkers to risk-stratify aggressive NMIBC (Project 3). This proposal seeks to shift the currentresearch paradigm in the field of NMIBC by proposing a conceptually innovative tug-of-war between a tumor-restraining (Project 1) and a tumor-promoting mechanism (Project 2) in determining the outcome of early bladderlesions/NMIBC in becoming progressors or non-progressors (Project 3). Clinically why non-progressorsoften recur but seldom progress and what are the driving forces advancing progressors into MIBC with poorsurvival remain fundamental questions in field. Our tug-of-war hypothesis with two opposing forces isconceptually different to most other studies which primarily focus on one side of the coin. Further the integrationof knowledge from Project 1 and 2 as a unified spatial proteomics and transcriptomics map by the SharedResource Core will reveal spatial and temporal relationships between distinct fibroblast populations withopposing functions their physical interactions with tumor and immune cell clusters as well as their relationshipto the biomarkers from Project 3. Benchmark of success: The knowledge gained here will shift clinical practiceparadigm by informing future NIMBC management through 1) the development of novel urinary profilingstrategies that could risk stratify aggressive NMIBC (Project 1-3); 2) the identification of targets for futureprecision intervention either by enhancing/sustaining the tumor-restraining mechanisms (Project 1) and/orinhibiting the tumor-promoting mechanisms (Project 2). The overall success of our program is further ensuredby an extraordinary multi-investigator team that integrates three organ-specific bladder cancer investigatorswithin Cedars-Sinai Medical Center. All have active R01s and individual NCI-funding track record in performingbasic science research translational bladder cancer research or leading multi-center clinical trials on thediscovery and validation of biomarkers. Finally they propose to collect valuable retrospective and prospectiveNMIBC cohorts which are essential to address the clinical questions posed within this proposal and will becomeavailable to the research community as a shared resource to advance the field. 1657891 +No NIH Category available Address;Basic Science;Biomedical Engineering;Biometry;Cancer Burden;Cancer Etiology;Cancer Patient;Catchment Area;Clinical Research;Communities;Complex;County;Development;Diagnosis;Effectiveness;Equity;Financial Support;Fostering;Foundations;Health Services Accessibility;Health system;Hospitals;Incentives;Incidence;Malignant Neoplasms;Medical;Mission;Outcome;Patients;Policies;Population Heterogeneity;Population Sciences;Research;Resources;System;Translations;Universities;access disparities;anticancer research;cancer care;cancer health disparity;cancer prevention;cancer survival;care burden;care delivery;care systems;charity care;clinical care;community building;community engagement;design;disparity reduction;evidence base;improved;innovation;interest;outcome disparities;research study;response;simulation;technology development;tool Stanford Cancer Institute NarrativeHospital based community benefit policies (e.g. charity care) are a critical lifeline to many cancer patients.However recent studies suggest that patients and communities with the greatest needs may be least likely tobenefit from these policies. In direct response to a request from the Stanford Cancer Institute CommunityAdvisory Board this study is designed to enhance our understanding of the factors that influence the allocationof community benefit dollars and foster bidirectional partnerships to redesign equity-focused policy solutions. NCI 10831721 8/29/23 0:00 PA-20-272 3P30CA124435-15S1 3 P30 CA 124435 15 S1 "BELIN, PRECILLA L" 6/4/07 0:00 5/31/27 0:00 Cancer Centers Study Section (A)[NCI-A] 7810696 "ARTANDI, STEVEN E" Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 124999 NCI 80958 44041 Project Summary/AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-044.The Stanford Cancer Institutes (SCI) [2P30CA124435-14] mission is to leverage the broad and uniquestrengths of Stanford University in basic science bioengineering population science biostatistics technologydevelopment clinical research clinical care and translation to (1) improve the diagnosis treatment andoutcomes of cancer patients; (2) understand cancer etiologies among diverse populations; and (3) decreasecancer incidence in the SCI catchment area and beyond. SCI is committed to understanding and addressingthe cancer burden and reducing cancer disparities in our community. This proposal is in direct response to arequest from the SCI Community Advisory Board to foster research on strategies to reduce disparities inaccess to evidence-based cancer care services in the catchment area at the patient and community level.Cancer research discoveries over the last 30 years have stimulation critical innovations in cancer preventionand care delivery greatly improving cancer survival. However communities with the greatest cancer burdenare often last to benefit from these innovations. Community benefit policies including medical financialassistance and community-building initiatives aim to incentivize hospital systems to address the needs ofunderserved patients and communities. Yet the effectiveness of these policies in addressing persistentdisparities in cancer care access and burden are largely unknown.Building on our prior research on community benefits this proposal aims to engage community and healthsystem partners in the development of more equity-focused community benefit policies to improve canceroutcomes and reduce disparities. Specifically we seek to understand the complex and interacting factors thatdrive community benefit spending in order to inform equity-focused allocation decisions in the 10-county SCIcatchment area. Activities proposed in this research supplement will establish a foundation for future researchstudies to develop and validate a simulation-based tool to inform the allocation of community benefits in waysthat better address critical financial assistance needs for cancer patients and foster a more equitable allocationof community benefit resources. 124999 +No NIH Category available Cancer Center Support Grant;Cancer Model;Clinical;Clinical Trials;Clinical effectiveness;Complex;Development;Effectiveness;Evaluation;Future;Goals;Investigation;Malignant neoplasm of lung;Malignant neoplasm of ovary;Meta-Analysis;Methods;Patient-Focused Outcomes;Preventive care;Process;Recommendation;Research;Research Design;Risk;Risk Assessment;Risk Management;Science;United States;cancer risk;cancer site;clinical implementation;clinical practice;clinical translation;experience;genetic information;improved;interest;mathematical model;mortality;polygenic risk score;research clinical testing;response;risk prediction;systematic review Cancer Center Support Grant Project NarrativePolygenic risk scores mathematical models that use germline genetic information to estimate cancer risk havethe potential to improve preventive care and risk management. However additional research is needed tounderstand the clinical utility of these scores. This project will conduct a systematic evidence review todescribe the state of the science of polygenic risk scores for lung and ovarian cancer risk assess the currentevidence for efficacy and/or effectiveness of clinical utility and potential benefits and harms of their clinical useand make recommendations for future research on polygenic risk scores. NCI 10831719 9/1/23 0:00 PA-20-272 3P30CA091842-22S2 3 P30 CA 91842 22 S2 "ROBERSON, SONYA" 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 149963 NCI 96439 53524 Project SummaryThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-046.Polygenic risk scores (PRS) for cancer risk have the potential to clarify risk assessment and improve preventivecare and risk management. However the development evaluation and implementation of PRS alone orcombined with other risk models for cancer risk assessment are complex and require thorough investigation toensure that they can be effectively used in clinical practice in diverse settings to improve patient outcomes.Specifically research is needed to establish the validity of PRS in predicting the risk of lung and ovarian canceras well as to assess the clinical benefits and harms associated with their use. Furthermore the evaluation ofclinical utility (CU) is also necessary before the widespread implementation of PRS for lung and ovarian cancerrisk assessment.The goal of this project is to conduct a systematic evidence review on the clinical utility of lung and ovariancancer risk. These cancer sites were chosen for their high burden and mortality in the United States as well astheir available PRS. To evaluate the state of the science on lung and ovarian cancer risk PRS the research teamwill systematically search select and review existing studies evaluate them for potential bias and synthesizetheir results. Specifically the research team will perform the following aims: (1) perform a systematic evidencereview following best practices to describe the state of the science in terms of lung and ovarian cancer specificPRS development and evaluation (2) systematically review the current evidence for the efficacy andeffectiveness of lung and ovarian cancer PRS in the context of clinical utility and (3) propose criteria and optimalstudy designs and methods for which PRS are candidates for evaluation of CU through clinical trials.We will achieve these aims by following a strict systematic evidence review process based on best practices andthe research team's extensive experience performing systematic reviews and meta-analyses. The proposedsystematic review will inform future trials and research direction for clinical translation and implementation. 149963 +No NIH Category available Functional Consequences of Racially Associated Ephrin Alterations on the Prostate Tumor Microenvironment NarrativeThe molecular mechanisms responsible for the higher incidence of developing early and more aggressiveprostate cancer (PCa) in African American (AA) men are still unknown. We aim to investigate the functionalconsequences of common genetic alterations affecting the tumor microenvironment (TME) associated withincreased risk. In addition we will evaluate the clinical utility with emphasis on developing potential newtherapies. NCI 10831717 8/23/23 0:00 PA-21-268 7R01CA242920-05 7 R01 CA 242920 5 "HILDESHEIM, JEFFREY" 7/3/19 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OBT-B(55)R] 10406322 "FRANCO CORONEL, OMAR " Not Applicable 4 BIOCHEMISTRY 95439774 FA4VKPTJRLY8 95439774 FA4VKPTJRLY8 US 32.481648 -93.760821 577905 LOUISIANA STATE UNIV HSC SHREVEPORT SHREVEPORT LA SCHOOLS OF MEDICINE 711034228 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2022 212472 NCI 153403 59069 Project SummaryProstate cancer (PCa) incidence and mortality remain significantly higher in African American (AA) mencompared to Caucasians (CA). Although socioeconomic factors may contribute to such differences recentstudies suggest that biological factors could potentially explain racial disparities (RD) in PCa. A few high-penetrance genes (HPG) have been found to predispose to high risk of PCa in AA men. These include EphB2mutations. EphB2 is a tyrosine kinase (RTK) receptor that binds to the Ephrin ligand and initiates bidirectionalsignals that affect both receptor (forward signaling) and Ephrin-expressing cells (reverse signaling). Ourpreliminary observations suggest a potential supportive role of Ephrin signaling activation within stromal cells inthe tumor microenvironment (TME) due to the pathogenicity of these EphB2 genetic alterations. However thefunctional consequences of EphB2 alterations on prostate cancer cell biology have not been experimentallyvalidated. To better understand the intrinsic mechanism(s) responsible for these pathogenic effects wehypothesize that EphB2 alterations commonly seen in AA men may induce aberrant forward signalingreducing its tumor suppressor function in cancer cells and abnormal reverse signaling increasing theactivation of stromal in the TME overall resulting in support for PCa progression. This proposal seeks tounderstand the downstream molecular effectors of disrupted Eph-Ephrin signaling in AA men in both tissuecompartments (epithelium and stroma) on PCa progression.The long-term goal is to identify novel targetable molecules within the cancer and/or stromal compartmentthat can be used to improve diagnosis and treatment of patients at high-risk of developing aggressive PCadisease in AA men.Three complementary areas will be investigated:1. Determine the functional effects of racial EphB2 alterations on PCa progression. We will study thefunctional consequence of common EphB2 alterations seen in AA men with PCa on proliferation and motilityof PCa cells in vitro and in vivo. The role of EphB2 in PCa cell biology is unknown.2. Determine the role of Ephrin reverse signaling on CAF activation in the TME of AA men. Weobserved increased expression of EphB2 ligands in the TME of AA compared to CA men suggesting adysfunctional regulation of Ephrin-reverse signaling. In addition we observed that prostate stromal cell from AApatients with PCa induce increased proliferation and motility of PCa cell lines in vitro and in vivo.3. Evaluate the utility of targeting the Eph-Ephrin signaling to inhibit PCa progression. It has beenshown in experimental models that normalizing Eph-Ephrin signaling can reduce colon cancer progression.The utility in PCa has not been previously studied. Using an in vivo PCa model we will assess the feasibility oftargeting Eph-Ephrin signaling frequently altered in AA men to inhibit PCa tumorigenesis. 212472 +No NIH Category available Address;Award;Basic Science;Biological Markers;Cancer Biology;Cancer Burden;Cancer Center;Cancer Control;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Development;Direct Costs;Early Diagnosis;Education;Environment;Fostering;Funding;Health care facility;Healthcare;Intervention;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medical center;Medicine;Metastatic breast cancer;Mission;Modeling;NCI-Designated Cancer Center;Names;Nebraska;Organoids;Patients;Pharmaceutical Chemistry;Physicians;Population Sciences;Positioning Attribute;Prevention;Prognosis;Reporting;Research;Research Infrastructure;Research Peer Review;Research Support;Resource Sharing;Resources;Risk;Role;Scientific Advances and Accomplishments;Synthesis Chemistry;Teacher Professional Development;Tissue Microarray;Training and Education;Translational Research;Universities;anticancer research;cancer care;cancer education;cancer health disparity;cancer initiation;clinical care;community engagement;computational chemistry;digital tool;health disparity;innovation;interdisciplinary collaboration;member;metabolomics;multidisciplinary;novel therapeutic intervention;outreach;patient oriented;patient-clinician communication;preclinical imaging;programs;recruit;research facility;translational cancer research;tumor progression;underserved community Metastatic Breast Cancer Digital Tool to Promote Patient-Provider Communication PROJECT NARRATIVEThe Fred & Pamela Buffett Cancer Center (BCC) the only NCI-designated cancer center in Nebraska is a matrixcancer center at the University of Nebraska Medical Center and our affiliated healthcare network NebraskaMedicine. The Mission of the BCC is to promote innovative translational cancer research excellence in cancereducation and training and outstanding patient-centered cancer care and to reduce the burden of cancer andcancer health disparities across Nebraska and beyond. NCI 10831716 9/19/23 0:00 PA-20-272 3P30CA036727-37S3 3 P30 CA 36727 37 S3 "BELIN, PRECILLA L" 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 2401856 "COWAN, KENNETH H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 100000 NCI 65147 34853 PROJECT SUMMARYThe Fred & Pamela Buffett Cancer Center (Buffett Cancer Center or BCC) an NCI-designated Cancer Centersince 1984 is committed to basic translational clinical and population science research comprehensiveeducational programs and outreach to underserved communities in our catchment area (Nebraska). The newBCC integrated cancer research and care facility increased Cancer Center-controlled research space 1.7-fold(total 400000 sq ft) creating an environment which fosters scientific innovation and transdisciplinarycollaborations. The Cancer Center is fully integrated into the university and its affiliated healthcare networkNebraska Medicine (NM) with the Director reporting directly to the UNMC Chancellor and CEO NM andappointed BCC Physician-in-Chief. Two Cancer Center leadership positions were established since the lastreview Deputy Director and Associate Director for Community Outreach and Engagement (COE) with the latterleading efforts to reduce cancer burden and disparities in diverse communities across Nebraska. The BCC alsoappointed four new senior leaders and eliminated dual leadership roles to promote clinical and translationalresearch. The centralization expansion and reorganization of the BCC Clinical Trials Office was completed anda new CTMS (OnCore) installed culminating in a 1.8-fold increase in accrual to interventional clinical trials.Research infrastructure was enhanced by the addition of a new Preclinical Imaging Shared Resource as well asseveral new resources (e.g. Metabolomics Organoids Patient-Derived Models Tissue Microarrays Syntheticand Medicinal Chemistry and Computational Chemistry). The BCC has three Research Programs: CancerBiology Program (CBP); Targets Modulators and Delivery Program (TMDP); and GI Cancer Program (GICP).Two programs CBP and TMDP changed names reflecting the strategic realignment of their missions themesand memberships. With 28 Members recruited during the current funding period the BCC has a robust trackrecord of clinical and translational research supported by 14 multidisciplinary awards (P01 P50 P20s U awards;6 from NCI) and 16 new MPI awards (11 from NCI). Cancer-relevant peer-reviewed research funding in the BCCincreased 1.4-fold to $25.3M (Annual Direct Costs) and NCI funding increased 1.3-fold to $12.5 M (Annual DirectCosts) since our last review. 100000 +No NIH Category available Black Populations;Calibration;Cancer Intervention and Surveillance Modeling Network;Development;Diagnosis;Disparity;Economic Policy;Economics;Ensure;Financial Hardship;Funding;Health Care Costs;Health Services Accessibility;Hematologic Neoplasms;Incubators;Inequity;Infrastructure;Laws;Medicare;Modeling;Multiple Myeloma;Natural History;Not Hispanic or Latino;Patients;Pattern;Prevention;Public Health;Reporting;Research;Shock;Treatment Cost;Universities;Washington;cancer site;comparative;cost;cost-effectiveness evaluation;design;disparity reduction;evidence base;health disparity;improved;innovation;interest;model design;models and simulation;novel;parent grant;patient population;programs;racial disparity;response;treatment disparity Comparative modeling of multiple myeloma across myeloma control continuum: prevention treatment and disparity reduction PROJECT NARRATIVERELEVANCE: Multiple myeloma (MM) is a common incurable hematologic malignancy whose management isextremely costly with long-established disparities disproportionally inflicting non-Hispanic Black populations.Recent inflation surge has drastically increased patient out-of-pocket (OOP) cost leading to the passing of theInflation Reduction Act (IRA) including a cap of OOP spending to reduce the financial burden of MedicarePart D enrollees. The proposed supplement will build on the existing infrastructure of the CISNET MMIncubator Program to evaluate the impacts of the recent inflation surge and the IRA OOP cap on noveltreatment utilization patient survival and MM health disparities in Medicare Part D enrollees with MM. NCI 10831693 8/9/23 0:00 PA-20-272 3U01CA265735-03S1 3 U01 CA 265735 3 S1 "ZHU, LI" 9/20/21 0:00 8/31/26 0:00 ZCA1(A1)-R 10675721 "CHANG, SU-HSIN " "COLDITZ, GRAHAM A.; WANG, SHIYI " 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 138880 NCI 102693 36187 PROJECT SUMMARY/ABSTRACTThis application is being submitted in response to the Notice of Special Interest identified as NOT-CA-23-044.Multiple myeloma (MM) is a common and lethal hematologic malignancy. With the recent development of novelMM treatments median survival has significantly improved; however the long-established racial disparities inMM continue to exist. This may be attributable to the high cost of these treatments and inequitable access tocare which was further exacerbated by the recent inflation surge since 2021. The inflation has negativelyimpacted patients with MM as the management of MM is the most costly among all cancer sites. To curb thisinflation and reduce the financial burden of Medicare enrollees the Inflation Reduction Act (IRA) was signedinto law in 2022. Among several provisions the cap placed on patient out-of-pocket (OOP) spending of $2000starting in 2025 for Medicare Part D enrollees is expected to significantly reduce the skyrocketing high OOPcost potentially increase accessibility of novel treatments and mitigate disparities for patients diagnosed withMM. However to what extent these impacts remains unknown. To assess these impacts we propose toinvestigate the relationship between OOP costs and treatment utilization pattern among Medicare Part Denrollees with MM (Aim 1). Furthermore we will predict the impact of the IRA OOP cap on Part D enrolleeswith MM including the impacted size of patient population novel treatment utilization patient survival lifetimehealthcare cost and racial disparities in MM survival (Aim 2).The proposed supplement will utilize the established infrastructure of NCI-funded CISNET Multiple MyelomaIncubator Program (U01CA265735) including 1) CISNET-standard evidence-based calibrated models ofnatural history of MM from Washington University and Yale University modeling groups; and 2) thecoordination of the Coordinating Center for comparative modeling to ensure robust and credible conclusionswith transparent model assumptions design and parameterization as well as high-quality reporting of thefindings. This supplement will expand the two models designed to evaluate the cost-effectiveness of noveltreatments to ones with the capability to evaluate external economic shocks and the corresponding economicpolicies. The expanded models will significantly strengthen the public health impact of the parent grant.This supplement is significant in its capability to 1) predict and quantify the impacts of the recent inflationsurge and the IRA OOP cap in patients diagnosed with MM to better our understanding about the potentialimpacts on novel treatment utilization MM survival and MM health disparities; and 2) expand the models fornatural history of MM to allow for the assessment of external shocks. It is also innovative in its approach usedto answer the research question including state-of-the-art evidence-based simulation models for MM andcomparative modeling to ensure robust conclusions. Successful completion of this study will provide evidencein tangible metrics to assess the impacts of the recent inflation surge and the IRA OOP cap in MM patients. 138880 +No NIH Category available Acceleration;Address;Administrative Coordination;Adolescent;Adoption;Area;Behavioral;Cancer Control;Clinic;Clinical;Communication;Communities;Data;Data Collection;Decision Aid;Educational Intervention;Effectiveness;Evolution;Face;Goals;Healthcare Systems;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Intervention;Malignant Neoplasms;Medical;National Cancer Institute;Nurse's Role;Online Systems;Parents;Perception;Prevention;Primary Care;Program Research Project Grants;Provider;Recommendation;Research;Research Activity;Research Project Grants;Resources;Rural;Surveys;System;Testing;Training;Training Activity;Training Programs;Work;budget impact;cancer prevention;contextual factors;cost;cost effectiveness;data management;effective intervention;financial incentive;improved;insight;intervention program;models and simulation;novel;population health;prevent;primary care team;programs;randomized clinical trials;rural area;support tools;synergism;uptake;vaccine acceptance Program Project Improving Provider Announcement Communication Training (IMPACT) NARRATIVE Overall The Program Project's goal is to improve HPV vaccine communication and coverage in healthcaresystems a critically important opportunity for cancer prevention. We will create a package of interventionmodules to accelerate improvements in HPV vaccine communication and uptake in healthcare systems. NCI 10831654 9/12/23 0:00 PA-20-272 3P01CA250989-03S1 3 P01 CA 250989 3 S1 "KOBRIN, SARAH" 9/23/21 0:00 8/31/26 0:00 ZCA1(M1)-P 8226109 "BREWER, NOEL TODD" Not Applicable 4 NONE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 125000 NCI 80386 44614 ABSTRACT Overall Widespread HPV vaccination in the US could prevent 32100 cancers every year. Despite this tremendouspotential HPV vaccination coverage is far short of the nation's goal of 80%. Provider recommendations areuniquely powerful in increasing HPV vaccine uptake. However primary care teams and healthcare systemsface barriers to effective HPV vaccine communication and many questions remain unanswered about how toincrease the potency of provider recommendations. We propose the P01 Program Project Improving ProviderAnnouncement Communication Training (IMPACT). The goal of IMPACT is to improve HPV vaccinecommunication and uptake among adolescents. IMPACT's specific aims are to 1) Identify opportunities toimprove HPV vaccine communication; 2) Evaluate the impact and cost of HPV vaccine communicationinterventions in cluster randomized clinical trials; and 3) Support implementation of HPV vaccinecommunication interventions in healthcare systems. The IMPACT Program Project's shared theme isamplifying the impact of a Research-Tested Intervention Program to improve HPV vaccinecommunication in healthcare systems. The projects will work together to enhance the impact of theAnnouncement Approach Training (AAT) an HPV vaccine communication training for primary careprofessionals which received designation as a Research-Tested Intervention Program (RTIP) from theNational Cancer Institute. Project 1 will establish how to involve the whole primary care team in HPV vaccinerecommendations. The project will examine whether optimizing the use of standing orders support increasesHPV vaccine uptake in clinics receiving the AAT. Project 2 will examine what motivates providers torecommend HPV vaccination. The project will establish whether clinic-level financial incentives increasevaccine uptake in clinics receiving the AAT. Project 3 will examine who should facilitate the trainings. Theproject will establish whether engaging clinical champions in healthcare systems to implement the AAT withintheir own systems increases vaccine uptake. Project 4 will examine which interventions fit systems' resources.The project will examine the budget impact cost-effectiveness and population health impact of HPV vaccineinterventions in rural and nonrural communities and aid decision makers with a decision support tool tofacilitate the adoption of promising interventions. The research projects will receive support from 3 cores:Administrative Data and Intervention. IMPACT's activities will culminate with the creation of the AATIntervention Package to support improving HPV vaccine uptake in healthcare systems. Throughout theproposed Program Project the shared theme and AAT focus will create synergies among the projects andcores that generates significant and novel scientific insights into how to improve HPV vaccine communicationand uptake. Our approach will also accelerate the evolution of communication trainings for primary careprofessionals accomplishing in 5 years what might otherwise take two decades. 125000 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10831368 261201800016I-P00007-26100002-2 N01 8/15/18 0:00 4/30/24 0:00 78147086 "DOHERTY, JENNIFER " Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N R and D Contracts 2023 2212420 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 2212420 +No NIH Category available Address;Automobile Driving;Award;Biological Process;Cancer Cell Growth;Cell Communication;Cell Compartmentation;Cells;Collaborations;Data;Development;Disease;Epithelial-Stromal Communication;Epithelium;Fibroblasts;Foundations;Future;Gene Expression;Genetic;Genetically Engineered Mouse;Genitourinary system;Genomics;Grant;Growth;Human;Immune;Immunohistochemistry;In Situ;In Situ Hybridization;Institution;Intercept;Invaded;Investigation;Knowledge;Lesion;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Mediating;Membrane Glycoproteins;Methods;Modeling;Molecular;Mutation;Nature;Neoplasm Metastasis;Paracrine Communication;Parents;Patient-Focused Outcomes;Phenotype;Pilot Projects;Population;Process;Public Health;Research;Role;Stromal Cells;Testing;Therapeutic;Tissues;Tumor Promotion;Urogenital Cancer;Validation;Work;angiogenesis;cancer cell;cancer invasiveness;cancer type;carcinogenicity;clinically relevant;fibroblast-activating factor;human tissue;improved;insight;inter-institutional;interest;molecular phenotype;muscle invasive bladder cancer;nano-string;novel;novel strategies;novel therapeutic intervention;overexpression;programs;response;risk stratification;spatial integration;spatial relationship;theranostics;therapeutic target;transcriptomics;tumor;tumor growth;tumor microenvironment;tumor progression Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer NARRATIVEThis project aims to unravel the role of fibroblast activation protein (FAP)-expressing fibroblasts in aggressiveprostate and bladder cancers which are the most common genitourinary malignancies. By investigating themolecular mechanisms and functional role of FAP+ fibroblasts our research may lead to the identification ofnovel strategies to detect risk stratify intercept and treat these cancers more effectively. This pilot study willestablish a foundation for inter-institutional collaborative research that can ultimately lead to improved patientoutcomes and reduced public health burden associated with prostate and bladder cancers. NCI 10831342 9/22/23 0:00 PA-20-272 3U54CA274375-02S1 3 U54 CA 274375 2 S1 "KAI, MIHOKO" 9/22/22 0:00 8/31/27 0:00 ZCA1(M1) 8781273 "CHAN, KEITH SYSON " "THEODORESCU, DAN " 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 83500 NCI 50000 33500 ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Prostate and bladder cancers are the two most frequent genitourinary cancers and their progressionfrom low to high aggressiveness remains poorly understood. Stromal-epithelial-immune interactions particularlyinvolving fibroblast activation protein (FAP)-expressing fibroblasts may contribute to tumor aggressiveness.However the precise role of these cells in the tumor microenvironment (TME) and the molecular mechanismsdriving cancer progression remain unclear. We hypothesize that FAP+ fibroblasts engage in cell-cell interactionsand paracrine signaling supporting cancer cell growth and invasion leading to aggressive cancer formation. Totest this hypothesis we propose two specific aims: (1) Integrate spatial transcriptomics and multipleximmunohistochemistry/in situ hybridization (IHC/ISH) analyses of human prostate and bladder cancer tissues todefine the molecular phenotype and spatial relationships between FAP+ fibroblasts cancer cells and otherstromal cell compartments in the TME; and (2) Investigate the functional role of FAP+ fibroblasts in aggressiveprostate and bladder cancer using genetically engineered mouse models (GEMMs) and spatial transcriptomicalterations with and without FAP genetic disruption. We will perform cutting-edge spatially resolvedtranscriptomic and multiplex IHC/ISH analysis of human prostate and bladder cancer tissues using advancedplatforms. These data will be integrated using the AstroPath platform which will be extended to handle the spatialtranscriptomics data alongside the multiplex in situ methods. To investigate the functional role of FAP+ fibroblastsin aggressive cancer development we will employ GEMMs and evaluate spatial transcriptomic alterations withand without FAP genetic disruption. These data will augment phenotypic studies and allow investigation of FAP'srole in cell-cell spatial relationships and paracrine signaling mechanisms. Findings will be validated usingmultiplex IHC/ISH panels. Expected Results and Impact: Our study will provide insights into FAP's role in prostateand bladder cancer and its potential as a therapeutic and theranostic target. The use of spatial transcriptomicsand multiplex in situ immunohistochemistry will enable identification of FAP-expressing cells and their spatialrelationship with other TME components. The use of GEMMs will facilitate investigating FAP's functional role intumor growth angiogenesis and metastasis. Validating findings in human tissues will provide clinical relevance.Overall this study will contribute to understanding the molecular mechanisms underlying prostate and bladdercancer potentially leading to novel therapeutic strategies targeting FAP. This pilot study will establish thefeasibility of these methods and models in our groups allowing comparison of FAP+ fibroblasts' role in bothcancer types and laying the foundation for longitudinal collaboration beyond the Supplement award to facilitateinter-institutional collaboration through our U54 TBEL consortium. 83500 +No NIH Category available Address;Adenocarcinoma;Automobile Driving;Cancer Etiology;Cancerous;Cell Lineage;Cells;Cessation of life;Chief Cell;Chronic;Clonal Evolution;Derivation procedure;Dysplasia;Epigenetic Process;Evolution;Gene Activation;Gene Mutation;Genetic Transcription;Goals;Heterogeneity;Human;In Vitro;Inflammation;Injury;Intestinal Intraepithelial Neoplasia;Intestinal Metaplasia;Metaplasia;Modeling;Molecular;Mucous Membrane;Mutation;Neoplastic Processes;Oncogenic;Organoids;Patients;Population;Process;Property;Recovery;Sampling;Stomach;Therapeutic Intervention;Transgenic Mice;carcinogenicity;cell type;gastric cancer prevention;gastric carcinogenesis;high risk;in vivo;interest;malignant stomach neoplasm;mouse model;neoplastic;novel;precursor cell;premalignant;response;response to injury;spasmolytic polypeptide;stem cells;transdifferentiation;tumor progression Hierarchy of oncogenic gene mutations in gastric carcinogenesis n/a NCI 10831328 9/14/23 0:00 PA-20-272 3R01CA272687-02S1 3 R01 CA 272687 2 S1 "YASSIN, RIHAB R" 9/1/22 0:00 8/31/27 0:00 ZCA1(M)-2 11760284 "CHOI, EUNYOUNG " "GOLDENRING, JAMES RICHARD" 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 184000 NCI 127750 56250 ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-045. Gastric cancer is the 4th leading cause of cancer-related death worldwide and it mostcommonly develops within a carcinogenic cascade from pre-cancerous metaplasia to dysplasia andadenocarcinoma. Metaplasias first arise as a response to injury through the chief cell transdifferentiation intospasmolytic polypeptide- expressing metaplasia (SPEM) cells. While this initial process is possibly reversibleoncogenic gene activation or chronic inflammation can activate SPEM cell plasticity which promotes SPEMcell progression to intestinal metaplasia (IM) and dysplasia. This neoplastic process may also lead totranscriptional and epigenetic changes and incite cell lineage conversion where multiple intermediate celltypes are produced that can evolve into cancerous cells including dysplastic stem cells which may ariseduring the neoplastic transition. Furthermore the oncogenic gene mutation burden may be associated with thecell lineage conversion and diversification of the dysplastic stem cells to cancerous cells. However it is notclear whether the SPEM cell plasticity is responsible for the cell heterogeneity and evolution of pre-cancerousmetaplasia to incomplete IM which carries a higher risk of patient progression to dysplasia and whatmechanisms are involved in the carcinogenic process. We therefore hypothesize that SPEM cells are keygastric cancer precursor cells which display functional properties and cell lineage conversion capacity to drivemetaplasia progression to dysplasia. Our overarching goal is to define mechanisms that control the celllineage conversion of reparative SPEM cells towards incomplete IM and more cancerous cell lineages whichdisplay a higher mutational burden. To address these questions directly we have established novel in vivotransgenic mouse models and in vitro metaplastic or dysplastic organoid models derived from transgenicmouse stomachs following induction of active Kras or from human patient samples with metaplasia ordysplasia. Using these novel models we will assess critical SPEM cell lineage derivation and define cellpopulations that account for the key transcriptional and epigenetic changes arising during metaplasiaprogression. We will pursue three specific aims: First we will assess functional properties of SPEM cellsduring mucosal recovery or neoplastic progression following mucosal injury. Second we will examineregulatory mechanisms of cell lineage diversification and conversion during metaplasia progression. Third wewill investigate molecular mechanisms driving cell linage diversification and clonal evolution of dysplastic stemcells to adenocarcinoma. Our studies will define critical transition points which lead to neoplastic transitions forSPEM cells as the origin of gastric carcinogenesis. An understanding of regulatory mechanisms in cellplasticity and the ability to reverse such transitions could lead to therapeutic interventions to prevent gastriccancer. 184000 +No NIH Category available Acceleration;Address;Adoptive Cell Transfers;Algorithms;Automobile Driving;Biological;Biopsy;Calibration;Cell physiology;Cells;Clinical;Clinical Data;Clinical Trials;Clinical Trials Design;Combination immunotherapy;Combined Modality Therapy;Communities;Coupled;Data;Databases;Development;Dimensions;Disadvantaged;Disease model;Distal;Dose;Education and Outreach;Educational Models;Environment;Environment Design;Epigenetic Process;Evaluation;Genetic Transcription;Immune;Immune system;Immunologic Factors;Immunooncology;Immunotherapy;Individual;Internships;K-12 Education;Kinetics;Knowledge;Lead;Leadership;Malignant Neoplasms;Measurement;Metastatic Melanoma;Metastatic malignant neoplasm to brain;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Nature;Neoplasm Metastasis;Outcome;Patients;Pharmaceutical Preparations;Pilot Projects;Play;Primary Neoplasm;Proteomics;Research;Research Personnel;Research Project Grants;Resistance;Resources;Role;Science;Science Technology Engineering and Mathematics Education;Scientist;Self-Examination;Series;Structure;System;Systems Biology;Therapeutic;Time;Tissues;Visual;Work;biobank;cancer immunotherapy;combinatorial;computing resources;demographics;design;immune checkpoint blockade;in silico;in vivo;inhibitor;inhibitor therapy;medical schools;melanoma;model design;mouse model;multiple omics;outreach;outreach program;predicting response;prevent;programs;recruit;spatiotemporal;tool;transcriptomics;tumor;tumor-immune system interactions Data-driven Patient-Specific Agent Based Models of Metastatic Melanoma for Immunotherapy Response Prediction Overall NarrativeThe proposed U54 program Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor --Immunotherapy Combinations (ST-Analytics) is designed to develop the recent conceptual advance thattargeted inhibitor + cancer immunotherapy (IT) combination treatments may yield significantly greater patientbenefit if those treatments are administered in sequence rather than as monotherapies or as simultaneouslyadministered combinations. NCI 10831325 8/31/23 0:00 PA-20-272 3U54CA274509-02S1 3 U54 CA 274509 2 S1 "ZAMISCH, MONICA" 9/22/22 0:00 8/31/27 0:00 ZCA1(M2) 8126809 "HEATH, JAMES R." "SHMULEVICH, ILYA " 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 147236 NCI 99940 47296 Overall Project SummaryThe proposed U54 program Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor --Immunotherapy Combinations (ST-Analytics) is designed to develop the recent conceptual advance thattargeted inhibitor + cancer immunotherapy (IT) combination treatments may yield significantly greater patientbenefit if those treatments are administered in sequence rather than simultaneously. Analysis of retrospectiveclinical data coupled with in vivo therapeutic modeling using syngeneic models of murine melanoma stronglysupport this concept. In fact the picture that has emerged in melanoma is that immune factors can play a strongrole in driving resistance to MAPK inhibitor (MAPKi) therapy and that lead-in immune checkpoint blockade (ICB)can prime both the primary tumor and distal metastases (including brain metastases) for eradication when theIT is subsequently combined with MAPKi. This observation opens the doors for immune based strategies suchas ICB or adoptive cell therapy (ACT) as sequential combinatorial agents to prevent MAPKi resistance.However this concept introduces a number of new variables including dosing sequence and timing. This canmake the design and execution of clinical trials that can yield statistically significant outcomes impractical. Thisis the scientific and translational problem we address in the proposed ST-Analytics U54.The ST-Analytics U54 center is populated by leading scientists at the ISB the UCLA Geffen School of Medicineand Yale and is comprised of two research projects and two research cores with each project integrating bothstate-of-the-art experimentation and computational work. This structure is further designed to bring together thescientific experimental and computational and administrative resources to develop a data base that capturesthe kinetics of lead-in monotherapy tumor priming and apply that data base to the development of predictive insilico models that can inform the design of such targeted inhibitor immunotherapy sequence combinations forclinical trials. This requires close integration and cycles of iteration between of state-of-the-art experimentationleading edge computation and realistic disease models continuously calibrated through the analysis of highlyrelevant biopsied patient tumors. The resulting science also provides exciting opportunities for high impactSTEM outreach. We propose to act on those opportunities by leveraging a long-standing systems educationoutreach program at ISB that already has impacted K-12 STEM education in all 50 states and places anemphasis on those communities that have been historically under-represented in STEM. 147236 +No NIH Category available Actomyosin;Apical;Apoptosis;Area;Basal Cell;Basic Science;Biological Assay;Biomechanics;Breast Epithelial Cells;Cadherins;Cell division;Cell membrane;Cells;Cellular Assay;Clinical;Collagen Type IV;Development;Diffuse;Disease;Elasticity;Environment;Epithelial Cells;Epithelium;Extracellular Matrix;Fibronectins;Frequencies;Grant;Homeostasis;Human;In Situ;Intercellular Junctions;Invaded;Laminin;Lateral;Length;Liquid substance;Mammary Neoplasms;Measurement;Measures;Mechanics;Membrane;Modeling;Myoepithelial cell;Neoplasm Metastasis;Noise;Oncogenes;Organoids;Output;P-Cadherin;Patients;Phase Transition;Physiological Processes;Play;Process;Production;Property;Role;Solid;Source;Surface;System;Tissues;Traction;Traction Force Microscopy;assay development;cancer cell;cancer invasiveness;cell behavior;cell transformation;exosome;interest;mammary epithelium;neoplastic cell;polyacrylamide gels;professor;programs;response;tumor microenvironment;tumor progression;wound healing A single cell assay for tissue activity NarrativeIn situ breast tumors must transition to a solid-like to fluid-like form in order to undergo the structuralrearrangements necessary to become invasive. Tumor cells must also release exosome to reprogram themetastatic niche prior to invasion. This proposal aims to identify the specific subcellular programs responsiblefor these activities. NCI 10831316 8/21/23 0:00 PA-20-272 3U01CA244109-04S1 3 U01 CA 244109 4 S1 "MILLER, DAVID J" 5/1/20 0:00 4/30/25 0:00 ZCA1(J1) 9583811 "GARTNER, ZEV JORDAN" "GOGA, ANDREI ; LABARGE, MARK A; THOMSON, MATTHEW W." 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 161345 NCI 99904 61441 AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045.Fluctuations in the active biomechanical properties of cells are understudied but evidence suggest they play acritical role in both core physiological processes and in disease. For example tissue phase transitions fromelastic- to fluid-like (or jammed to unjammed) are thought to arise in part from increased noise in cell junctionalmechanics. These forces can also result in shedding of cellular material like exosomes. Both of theseprocesses play a central role in cancer progression most notably in invasion and metastasis. However amajor challenge is identifying the specific subcellular origin of these forces and the machinery responsible forthem. For example studies of tissue fluidization using vertex modeling approaches have defined the necessaryand sufficient geometric changes for tissue fluidization in epithelia. Specifically active fluctuations in celljunction length are required for the T1 transitions that change junctional topology and allow cells to diffuse likea fluid. Actomyosin dynamics can drive these transition in the absence of cell division and apoptosis but thesemodels focus on actomyosin activity at apical/lateral interfaces (between cells) but largely ignore more indirectsources of activity for example deriving from tractions generated at the basal surface which acts to sheerlateral and apical cell junctions. By tracking the dynamics of single cells in both normal and transformedprimary human mammary epithelial organoids we see evidence that the activity necessary to fluidize a tissuederives from interactions between cells and their basal interface at the ECM. At the single cell level we reasonthat this activity manifests as fluctuations in cell tractions specifically at basal cell-ECM interfaces and at thetens of minutes timescale. In this supplemental proposal we will first develop a platform allowing themeasurement of dynamic cell tractions at the cell-ECM interface which we will apply to single normal andtransformed mammary epithelial cells. Second we will develop a parallel assay for measuring cell tractions atthe cell-cell interface. We hypothesize that the magnitude of fluctuations at the cell-ECM interface will beseveral fold higher than at lateral interfaces and that the largest fluctuations will occur at the tens of minutestimescale consistent with that of junctional fluctuations in intact tissues. Successful development of this assaywill allow us to investigate the impact of mechanical fluctuations in processes spanning tissue fluidizationcancer cell invasions and exosome shedding. 161345 +No NIH Category available Analysis of Variance;Biological Models;Carcinoma;Cell Line;Cells;Collaborations;Dimensions;Disease Progression;Ductal Epithelial Cell;Epithelial Cells;Epithelium;Excision;Exhibits;Feedback;Freezing;Growth Factor;Human;Hypoxia;Immune;Institution;Investigation;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mesenchymal;Metabolic;Metabolic Pathway;Mitogen-Activated Protein Kinases;Modeling;Oxygen;Pancreatic Ductal Adenocarcinoma;Phase;Phenotype;Population;Principal Investigator;Sampling;Sorting;Systems Biology;Techniques;Testing;Time;Vascularization;Work;driving force;histone demethylase;histone methylation;interest;liquid chromatography mass spectrometry;member;metabolomics;mouse model;novel;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;patient derived xenograft model;programs;response;tumor Metabolic changes accompanying durable hypoxia-driven EMT in pancreas cancer PROJECT NARRATIVEThe Lazzara lab recently showed that hypoxia drives an especially durable epithelial-mesenchymal transition(EMT) in pancreas cancer that can last for weeks compared to a relatively short-lived EMT driven by growthfactors. Because cellular metabolic adaptations accompany EMT and because hypoxia drives broad metabolicrewiring in pancreas cancer cells we hypothesize that hypoxia-driven EMT in pancreas cancer could beaccompanied by durable metabolic rewiring effects that promote disease progression. In this project we willtest this hypothesis through a collaboration between two labs associated with the Cancer Systems BiologyConsortium that have expertise in pancreas cancer EMT (Lazzara) and metabolomic profiling (Graham). NCI 10831307 9/8/23 0:00 PA-20-272 3U01CA243007-05S1 3 U01 CA 243007 5 S1 "DUECK, HANNAH RUTH" 8/1/19 0:00 7/31/24 0:00 ZCA1(M1) 8200505 "LAZZARA, MATTHEW J" Not Applicable 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 167870 NCI 128095 39775 PROJECT SUMMARYThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045.Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit regions of low oxygen tension (hypoxia) due tocharacteristically poor vascularization. The Lazzara lab recently showed that hypoxia drives an especiallydurable epithelial-mesenchymal transition (EMT) in transformed PDAC ductal cells that can last for weekscompared to a persistence timescale of just days when EMT is driven by growth factors. The mechanismleading to durable EMT involves a positive feedback between histone methylation and MAP kinase activationthat is initiated by loss of histone demethylase activity in low-oxygen settings. Because metabolic rewiringaccompanies EMT in some cancer contexts we propose the novel hypothesis that hypoxia promotesespecially durable metabolic changes in PDAC cells that persist long after the hypoxic driving force is relieved.These durable changes to the metabolic state may promote disease progression by reconfiguring cellularenergetic needs and by increasing the abundance of immune-suppressive metabolites. We will explore thisnovel hypothesis using multiple models of hypoxia-mediated PDAC cell EMT and metabolomic profiling. Thework will be undertaken collaboratively by two principal investigator members of the NCI Cancer SystemsBiology Consortium who are located at different academic institutions. In Phase I of the proposed work we willuse three different model systems to create samples of PDAC cell lines driven to undergo EMT in response tohypoxia or growth factors. The model systems include established human PDAC lines cell lines derived frompatient-derived xenografts and cell lines derived from spontaneous PDAC tumors generated in a lineage-traced autochthonous mouse model. At several time points after removal of the EMT driving force (hypoxia orgrowth factors) cells will be flow-sorted into mesenchymal and epithelial populations and frozen cell sampleswill be generated. In Phase 2 samples will be analyzed by liquid chromatography-mass spectrometrymetabolomics to probe for changes in metabolomic programs and accumulation of hypoxia-associatedimmunosuppressive metabolites. Dimensionality reduction techniques will be applied to identify metabolite andmetabolic pathway changes that maximally explain variance among the samples. In Phase 3 metabolicpathways nominated by the analysis of variance among samples will be tested for their ability to control EMTpersistence. These investigations will uncover the degree to which durable hypoxia-driven EMT isaccompanied by durable metabolic changes and how such changes may alter the phenotypes of mesenchymalPDAC ductal cells. Understanding these issues will ultimately reveal new druggable vulnerabilities that can beexploited for treating PDAC. 167870 +No NIH Category available Aberrant DNA Methylation;Affect;Atlases;Basic Cancer Research;Behavior;Biological Markers;Biology;Cancer Etiology;Cancer Research Project;Cells;Cessation of life;Clinic;Clinical;Collaborations;Colon;Colonic Adenoma;Colorectal Adenoma;Colorectal Cancer;DNA Sequence Alteration;Data Set;Epigenetic Process;Epithelial Cells;Fibroblasts;Gene Mutation;Goals;Human;Immune;Individual;Indolent;Lesion;Light;Malignant Neoplasms;Mission;Molecular;Multiomic Data;Mutation;Natural History;Pathogenesis;Patients;Persons;Positioning Attribute;Recording of previous events;Research Personnel;Resolution;Science;Sessile Lesion;Technology;Testing;Tissues;Translational Research;Translations;Tumor Promotion;adenoma;cancer genetics;cancer type;clinical application;cohort;colon cancer patients;colorectal cancer prevention;colorectal cancer progression;deep sequencing;dysbiosis;early onset colorectal cancer;experience;gut microbiome;human disease;innovation;methylation pattern;methylome;microbiome;mouse model;mutant;novel;premalignant;risk prediction;senescence;translational cancer research High-resolution mutational landscape of the primed colon in early onset colorectal cancer NARRATIVEAdenomas are early lesions of colorectal cancer but only a subset of adenomas progress and become cancer.In light of the well characterized clinical natural history of adenomas we plan to study them as early lesions andto determine the mechanisms involved in the formation and progression of early precancerous lesions. Wehypothesize that adenoma progression requires a suite of hallmark behaviors and that these behaviors areinduced by adenoma autonomous factors (e.g. cancer driver gene mutations) and adenoma nonautonomousfactors from the primed colon or adenoma microenvironment. Our proposed studies will integrate basic andtranslational cancer research projects to iteratively examine the direct causal relationships and interactions ofadenomas the colon primed microenvironment and host-systemic factors as co-organizers of adenomainitiation and/or progression. NCI 10831306 9/11/23 0:00 PA-20-272 3U54CA274374-02S1 3 U54 CA 274374 2 S1 "PATRIOTIS, CHRISTOS F" 9/20/22 0:00 8/31/27 0:00 ZCA1(M1) 1865649 "GRADY, WILLIAM MALLORY" "DEY, NEELENDU ; HALBERG, RICHARD BROTT" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 174911 NCI 152057 22854 SUMMARYColorectal cancer (CRC) affects ~145000 people/year in the US and is the 3rd most common cause of cancerrelated deaths. CRC arises from early lesions that are pre-cancerous; these early lesions are colon adenomasand serrated sessile lesions (SSL). Colon adenomas account for 80-85% of the CRC precancerous lesions andprogress to CRC via an early adenomaadvanced adenomaCRC sequence. In light of the well characterizedclinical natural history of adenomas we plan to study them as early lesions and to determine the mechanismsinvolved in the formation and progression of early precancerous lesions. Notably only a few early adenomas willprogress to advanced adenomas (AA) and even fewer will progress to CRC. Our group and others have shownthat mutations alone are not sufficient to cause adenoma initiation and/or progression in the majority of cases.There are likely multiple adenoma nonautonomous mechanisms that cooperate with the DNA alterations in theadenomas to cause progression and these mechanisms are likely operative in discrete subsets of affectedindividuals. We and others have observed alterations such as tissue senescence high cancer driver genemutation loads aberrant DNA methylation patterns and dysbiotic gut microbiomes in the normal colon of peoplewith advanced adenomas and CRC patients. We have termed normal colons with these features primed colonsand propose that these features are plausible mechanisms that affect adenoma initiation and progression.Based on these observations and our prior studies we hypothesize that early lesion progression requires a suiteof hallmark behaviors and that these behaviors are induced by adenoma autonomous factors (e.g. cancer drivergene mutations) and adenoma nonautonomous factors from the primed colon or adenoma microenvironment. Our proposed studies will integrate basic and translational cancer research Projects to iteratively examine thedirect causal relationships and interactions of adenomas the colon primed microenvironment and host-systemic factors as co-organizers of adenoma initiation and/or progression. The Specific Aims are:Aim 1) To determine the adenoma cell autonomous molecular factors that distinguish nonadvanced adenomasfrom advanced adenomas and that regulate nonadvanced adenoma progression. (Projects 1 and 2)Aim 2) To determine the adenoma nonautonomous factors from the primed colon and from the adenomamicroenvironment that associate with advanced human colon adenomas and regulate adenoma progression.These factors will include the following primed colon states: 1. senescence state; 2. cancer driver gene mutationburden; 3. gut microbiome state; 4. colon methylome and 5. colon immune activity state. (Projects 1-3)Aim 3)To determine how adenoma autonomous and nonautonomous factors from the adenomamicroenvironment and the primed colon cooperate to drive adenoma formation and progression.(Projcts 1-3) 174911 +No NIH Category available Address;Award;Basic Science;Biological Markers;Cancer Biology;Cancer Burden;Cancer Center;Cancer Control;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Development;Direct Costs;Early Diagnosis;Education;Environment;Fostering;Funding;Health care facility;Healthcare;Intervention;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medical center;Medicare;Medicine;Mission;Modality;Modeling;NCI-Designated Cancer Center;Names;Nebraska;Organoids;Patients;Pharmaceutical Chemistry;Physicians;Population Sciences;Positioning Attribute;Prevention;Prognosis;Reporting;Research;Research Infrastructure;Research Peer Review;Research Support;Resource Sharing;Resources;Risk;Role;Scientific Advances and Accomplishments;Synthesis Chemistry;Teacher Professional Development;Telemedicine;Tissue Microarray;Training and Education;Translational Research;Universities;anticancer research;cancer care;cancer education;cancer health disparity;cancer initiation;clinical care;community engagement;computational chemistry;health disparity;innovation;interdisciplinary collaboration;member;metabolomics;multidisciplinary;novel therapeutic intervention;outreach;patient oriented;preclinical imaging;programs;recruit;research facility;translational cancer research;tumor progression;underserved community Impact of Expanded Medicare Reimbursement for Telemedicine on Use of Telemedicine Modalities to Access Cancer Care PROJECT NARRATIVEThe Fred & Pamela Buffett Cancer Center (BCC) the only NCI-designated cancer center in Nebraska is a matrixcancer center at the University of Nebraska Medical Center and our affiliated healthcare network NebraskaMedicine. The Mission of the BCC is to promote innovative translational cancer research excellence in cancereducation and training and outstanding patient-centered cancer care and to reduce the burden of cancer andcancer health disparities across Nebraska and beyond. NCI 10831304 9/13/23 0:00 PA-20-272 3P30CA036727-37S2 3 P30 CA 36727 37 S2 "BELIN, PRECILLA L" 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 2401856 "COWAN, KENNETH H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 125000 NCI 81433 43567 PROJECT SUMMARYThe Fred & Pamela Buffett Cancer Center (Buffett Cancer Center or BCC) an NCI-designated Cancer Centersince 1984 is committed to basic translational clinical and population science research comprehensiveeducational programs and outreach to underserved communities in our catchment area (Nebraska). The newBCC integrated cancer research and care facility increased Cancer Center-controlled research space 1.7-fold(total 400000 sq ft) creating an environment which fosters scientific innovation and transdisciplinarycollaborations. The Cancer Center is fully integrated into the university and its affiliated healthcare networkNebraska Medicine (NM) with the Director reporting directly to the UNMC Chancellor and CEO NM andappointed BCC Physician-in-Chief. Two Cancer Center leadership positions were established since the lastreview Deputy Director and Associate Director for Community Outreach and Engagement (COE) with the latterleading efforts to reduce cancer burden and disparities in diverse communities across Nebraska. The BCC alsoappointed four new senior leaders and eliminated dual leadership roles to promote clinical and translationalresearch. The centralization expansion and reorganization of the BCC Clinical Trials Office was completed anda new CTMS (OnCore) installed culminating in a 1.8-fold increase in accrual to interventional clinical trials.Research infrastructure was enhanced by the addition of a new Preclinical Imaging Shared Resource as well asseveral new resources (e.g. Metabolomics Organoids Patient-Derived Models Tissue Microarrays Syntheticand Medicinal Chemistry and Computational Chemistry). The BCC has three Research Programs: CancerBiology Program (CBP); Targets Modulators and Delivery Program (TMDP); and GI Cancer Program (GICP).Two programs CBP and TMDP changed names reflecting the strategic realignment of their missions themesand memberships. With 28 Members recruited during the current funding period the BCC has a robust trackrecord of clinical and translational research supported by 14 multidisciplinary awards (P01 P50 P20s U awards;6 from NCI) and 16 new MPI awards (11 from NCI). Cancer-relevant peer-reviewed research funding in the BCCincreased 1.4-fold to $25.3M (Annual Direct Costs) and NCI funding increased 1.3-fold to $12.5 M (Annual DirectCosts) since our last review. 125000 +No NIH Category available Adopted;Aneuploidy;Automobile Driving;Cancer Biology;Cancer Model;Cell Culture Techniques;Cell membrane;Cells;Cellular biology;Charge;Chromosomes;Chronic;Clinical and Translational Science Awards;Collaborations;Colorectal Cancer;Complex;Couples;Cultured Cells;Data;Decision Making;Dedications;Defect;Disease;Ecosystem;Education;Elements;Epidermal Growth Factor Receptor;Eukaryota;Faculty;Fostering;Genetically Engineered Mouse;Genomics;Glioblastoma;Goals;Growth;Image;Immunofluorescence Immunologic;Indirect Immunofluorescence;Institution;Joints;KRAS2 gene;Lead;Leadership;Length;Lesion;Life;Malignant Neoplasms;Malignant neoplasm of brain;Mentorship;Metabolic;Metaphase;Metastatic Neoplasm to the Liver;Mitochondria;Mitotic;Modeling;Mutation;NCI Center for Cancer Research;Neoplasm Metastasis;Oncogene Activation;Oncogenes;Oncogenic;Organelles;PTPN11 gene;Pathway interactions;Phase;Phenotype;Pilot Projects;Play;Positioning Attribute;Primary Neoplasm;Process;Proliferating;Records;Recurrence;Research;Research Personnel;Research Project Grants;Resistance;Resolution;Resource Sharing;Resources;Rest;Role;Secondary to;Signal Transduction;Site Visit;Standardization;Stress;Structure;System;Systems Analysis;Systems Biology;Testing;Training;Universities;Virginia;Vision;cancer cell;cancer type;career;cell type;clinical practice;cost;experimental study;feature detection;feature extraction;image registration;innovation;interoperability;learning strategy;malignant breast neoplasm;mitochondrial membrane;multidisciplinary;mutant;outreach;programs;repaired;residence;response;success;summer research;transcription factor;tumor;tumorigenesis;undergraduate research experience A synthetic systems biology approach to predict context-specific mechanisms for SHP2 functional activity and resistance to SHP2 inhibition PROJECT NARRATIVECancers cannot initiate or progress if their subcellular components are unable to overcome the stresses thataccompany uncontrolled proliferation and growth. This Center seeks a predictive understanding of subcellularadaptations that must take place to accommodate and subvert the stresses that naturally occur in response tocancer-causing genetic alterations. Successful models of such adaptations will lead to secondary inferencesabout where cancer cells become vulnerable as a result of their internal adaptations. NCI 10831287 8/17/23 0:00 PA-20-272 3U54CA274499-02S2 3 U54 CA 274499 2 S2 "DUECK, HANNAH RUTH" 9/12/22 0:00 8/31/27 0:00 ZCA1(M2) 9677317 "JANES, KEVIN A" "LAZZARA, MATTHEW J" 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 166977 NCI 127202 39775 PROJECT SUMMARY/ABSTRACTOncogene activation is modulated by normal subcellular compartments that execute specialized functionsrelated to hallmark cancer phenotypes. These organelles must adapt to oncogenic stress in order for tumorsto initiate and progress but there is little to no systems-level understanding of how such adaptations occur andwhat vulnerabilities might be created. The Systems Analysis of Stress-adapted Cancer Organelles (SASCO)Center at the University of Virginia will address this challenge by mechanistic modeling of organellar processesthat iterates with quantitative experiments in disease-relevant cell cultures and primary tumors. The workingSASCO Center hypothesis is that organelle-specific adaptation to oncogenic stress occurs through a fewcritical bottlenecks which become identifiable once the relevant signaling metabolic and transport pathwayshave been properly integrated. The Center brings together 14 investigators with primary and collaborativetrack records in cancer biology systems biology genetically engineered mouse models of cancer and clinicalpractice. Three Research Projects and one Shared Research Core will pursue a common research strategywhich leverages mechanistic models to test competing alternative hypotheses about how organelles adapt tostresses from proximal oncogenes that drive specific types of cancer. The Projects are organizedhierarchically as organelle stresses downstream of proliferation-inducing oncogenes. Project 1 will examinethe chromosome passenger complex and its regulated phase separation during metaphase as an organellethat senses and repairs spindle defects to suppress breast cancer aneuploidy driven by mitotic transcriptionfactors. Project 2 will evaluate the metabolic consequences of chronic mitochondrial fragmentation caused bymutant KRAS in primary colorectal cancers and secondary liver metastases. Project 3 will investigate localizedsignal-transduction rebalancing as a mechanism for alleviating plasma-membrane stress caused by EGFRamplification in glioblastoma. All Research Projects will rely on the High-Content Imaging & Analysis Core toobtain iterative multichannel immunofluorescence data with organelle-level resolution and quantification. TheSASCO Outreach Core amplifies ongoing programs at the University of Virginia to provide summer researchexperiences for undergraduates and faculty scholars from historically underrepresented backgrounds as wellas introductory systems biology modeling materials for clinicians across the Commonwealth of Virginia. TheSASCO Center will thus create a national headquarters for subcellular cancer systems biology within thebroader Cancer Systems Biology Consortium. 166977 +No NIH Category available Address;Administrative Supplement;Aging;Cancer Center;Cluster randomized trial;Collection;Communication;Electronics;Funding;Goals;Hematologic Neoplasms;Malignant Female Reproductive System Neoplasm;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of thorax;Patient-Focused Outcomes;Patients;Population;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Research;Rural Population;Site;care coordination;care delivery;digital;digital platform;digital tool;effectiveness/implementation hybrid;electronic patient reported outcomes;improved;interest;patient oriented;patient-clinician communication;response;rural underserved;sustainability framework;symptom management Implementation of electronic patient reported outcomes and impact on communication with patients Project NarrativeThis proposal Implementation of Electronic Patient Reported Outcomes and Impact on Communication withPatients leverages a unique opportunity (1) to evaluate sustainability of the use of an existing electronicsymptom management platform (eSym) and (2) to evaluate the impact of eSyM reporting on patient-cliniciancommunications. There is a critical need to rapidly assess the sustainability of eSyM beyond a federally-fundedtype II hybrid effectiveness-implementation cluster randomized trial which recently completed accrual across asix-site consortium. Further we will also be able to assess tradeoffs between increasing utilization of digitaltools and impact on direct patient-clinician communications as well as widening of the so-called digital divide inrural populations served by the Dartmouth Cancer Center. NCI 10831266 9/18/23 0:00 PA-20-272 3P30CA023108-44S1 3 P30 CA 23108 44 S1 "BELIN, PRECILLA L" 8/4/97 0:00 11/30/24 0:00 1899930 "LEACH, STEVEN D" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 397 Research Centers 2023 100000 NCI 70815 29185 Project AbstractThis application is submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-041.Implementation of Electronic Patient Reported Outcomes and Impact on Communication with Patientsleverages a unique opportunity (1) to evaluate sustainability of the use of an existing electronic symptommanagement platform (eSym) and (2) to evaluate the impact of eSyM reporting on patient-cliniciancommunications. Since eSyM was recently developed and implemented at the Dartmouth Cancer Center(DCC) for patients with gastrointestinal thoracic and gynecologic cancers there is a critical need to rapidlyassess the sustainability of this digital platform beyond a six-site federally-funded type II hybrid effectiveness-implementation cluster randomized trial (UM1 CA23080-01; NCT03850912) guided by RE-AIM and theDynamic Sustainability Framework. Further we will also be able to assess tradeoffs between increasingutilization of digital tools and potential for unintended consequences of a decrease in the quality of directpatient-clinician communications as well as widening of the so-called digital divide in rural and agingpopulations. Alternatively collection of electronic patient reported outcomes as part of the eSyM platform mayenhance communication and patient-clinician partnerships in care delivery and coordination for patients with ahematologic malignancy. This administrative supplement aligns with the NOSI by examining the effects ofdigital tools on patient-clinician communications and supports the goals of DCC in addressing improved patientoutcomes through research in advancing patient-clinician communication especially in underserved ruralpopulations. 100000 +No NIH Category available Address;Advocate;Biology;Brain;Brain Neoplasms;Breast;CRISPR library;Cancer Patient;Characteristics;Clinical;Clinical Trials;Communication;Communities;Data;Dedications;Deterioration;Development;Diagnostic;Disease model;Ensure;Exclusion;Experimental Models;Foundations;Goals;Human;Immune system;Immunotherapy;In Vitro;Incidence;Malignant Neoplasms;Mediator;Metastatic malignant neoplasm to brain;Methods;Microglia;Modeling;Molecular;Mus;Neoplasm Metastasis;Neuroimmune;Neurologic;Office of Administrative Management;Organoids;Patient risk;Patients;Physicians;Primary Neoplasm;Production;Productivity;Quality of life;Research;Sampling;Scientist;Site;Specimen;Technology;Testing;Therapeutic;Translating;Translations;Tropism;Tumor Tissue;Work;brain cell;data management;design;experience;glycoproteomics;high throughput screening;human disease;human tissue;improved;in vivo Model;innovation;insight;interest;melanoma;multidisciplinary;neoplastic cell;neuropathology;new therapeutic target;novel;organizational structure;programs;synergism;therapy resistant;tool;tumor;tumor microenvironment Identifying and Targeting Shared Molecular Characteristics of Breast- and Melanoma-Derived Brain Metastases NARRATIVE OVERALL COMPONENTThe Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improvingour understanding and treatment of brain metastases a currently increasing yet underserved subset of cancerpatients. To accomplish the above goal we have developed highly innovative and complementary Projects tounderstand and disrupt the cancer-neuro-immune axis supporting brain metastases and created ResearchCores to make human specimens and cutting-edge technologies readily accessible to participating scientists.We expect to identify and target key mediators of brain metastasis with therapeutic benefit for patients. NCI 10831246 9/15/23 0:00 PA-20-272 3U54CA261717-03S1 3 U54 CA 261717 3 S1 "GRIL, BRUNILDE M" 9/21/21 0:00 8/31/24 0:00 ZCA1(M1) 10312066 "HAYDEN GEPHART, MELANIE " "HERNANDO, EVA " 16 NEUROSURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 175610 NCI 134750 40860 1 ABSTRACT OVERALL COMPONENT 2 3 The development of brain metastases experienced by up to 40% of cancer patients marks a clear inflection 4 point in survival and quality of life. The inaccessibility of brain tumor tissue has stymied progress in our 5 understanding and treatment of brain metastases and patients are regularly excluded from clinical trials. The 6 Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improving our 7 understanding and treatment of brain metastases a currently increasing yet underserved subset of cancer 8 patients. To accomplish the above goal we have: (1) designed an organizational structure that supports 9 scientists in our integrated work; (2) developed highly innovative and complementary Projects to understand10 and disrupt the cancer-neuro-immune axis supporting brain metastases; and (3) created NeuroPathology11 and ToolKit Cores to make human specimens and cutting-edge technologies readily accessible to participating12 scientists. We expect to identify and target key mediators of brain metastasis with therapeutic benefit for13 patients.14 Little is known about the distinct mechanisms that drive tumor cells to the brain and allow them to grow in this15 unique microenvironment supported in part by normal brain cells. Streamlined access to human brain16 specimens combined with innovations in modeling and manipulation of the tumor microenvironment create this17 collaborative opportunity for fundamental advancement. Our expert integrated team of productive collaborators18 aims to understand how the intrinsic features of tumor cells (Project 1) resident microglia (Project 2) and the19 systemic immune system (Project 3) contribute to the onset and progression of brain metastases. These projects20 are facilitated by centralized access to human patient brain metastases samples (NeuroPathology Core) and21 novel multiplexed analyses and disease modeling (ToolKit Core). Our multidisciplinary physician Consultant22 Network provides clinical insight and helps in the rapid translation of our findings into clinical trials for patients23 with brain metastases. The Administrative and Data Management Core will provide the operational support24 necessary to successfully achieve the goals of the program. Our Patient Advocates help to integrate and25 communicate our work to the greater scientific and patient communities.26 We have formed one of the few groups with the expertise interest and capacity to address the underlying27 mechanisms of and therapeutic opportunities for brain metastases. Only through this combined synergy would28 this project be possible. These innovative methods will ensure our findings are reflective of and translatable to29 the human disease enabling our multidisciplinary team to lay the foundation for diagnostic and therapeutic30 advancements. 175610 +No NIH Category available Address;Adherence;Adoption;Adverse event;Agreement;Anxiety;Attitude;Cancer Patient;Caring;Center Core Grants;Cessation of life;Clinical;Collaborations;Communication;Complex;Comprehensive Cancer Center;Computers;Control Groups;Data;Devices;Early identification;Effectiveness;Effectiveness of Interventions;Eligibility Determination;Ensure;Exercise;Fostering;Foundations;Frequencies;Funding;Goals;Grant;Hand;Health;Health Personnel;Health Services Accessibility;Hospitalization;Hospitals;Improve Access;Individual;Industry;Infection;Instruction;Intervention;Interview;Judgment;Malignant Neoplasms;Managed Care;Mental Depression;Modeling;Monitor;Oncologist;Oncology;Operative Surgical Procedures;Outcome;Participant;Patient Care;Patients;Pharmaceutical Preparations;Pilot Projects;Population Sciences;Provider;Quality of Care;Questionnaires;Randomized;Randomized Controlled Trials;Recurrent Malignant Neoplasm;Resources;Risk;Sampling;Science;Stress;Stretching;Symptoms;System;Tablets;Technology;Telephone;Time;Universities;Update;Voice;acceptability and feasibility;adverse event risk;cancer prevention;cancer recurrence;care coordination;care fragmentation;care providers;clinical efficacy;comparison control;design;diaries;digital;effectiveness validation;empowerment;follow-up;group intervention;hospital care;hospital readmission;improved;intelligent personal assistant;interest;member;mortality;multidisciplinary;new technology;patient oriented;patient-clinician communication;personalized care;physical symptom;prevent;programs;provider adherence;psychological symptom;response;shared decision making;stress reduction;success;symptom management;treatment planning;user-friendly;validation studies;web portal Empowering Cancer Patient-Provider Communication: A Personal Virtual Assistant for Automated Post-Discharge Engagement Project NarrativePost-hospital discharge for oncology patients involves challenges such as insufficient communicationinadequate symptom management limited healthcare provider access and fragmented care. To tackle theseissues our team has developed an AI-based Personal Virtual Assistant (PVA) that offers a hands-freeautomated digital engagement suite leveraging data for patients and care teams. In response to NOSI NOT-CA-23-041 this supplement application aims to assess the PVA's feasibility scalability and effectiveness inreducing stress and anxiety among oncology patients undergoing surgical procedures utilizing resources fromthe Dan L Duncan Comprehensive Cancer Center (DLDCCC) currently supported by a P30 grant. NCI 10831223 8/25/23 0:00 PA-20-272 3P30CA125123-17S1 3 P30 CA 125123 17 S1 "SHAFIK, HASNAA" 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 2413379 "HESLOP, HELEN E" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 93600 NCI 58500 35100 Project Summary/AbstractThis application is submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-041.Inadequate communication between patients and providers following hospital discharge poses a significantchallenge for oncology patients. The complex multidisciplinary care these patients require often results ininsufficient follow-up and misunderstandings of treatment plans leading to increased anxiety stress andreduced compliance. This in turn elevates the risk of hospital readmission cancer recurrence heightenedsuffering and even mortality.To address these issues our team has collaborated with the Dan L Duncan Comprehensive Cancer Center(DLDCCC) supported by a P30 grant to develop an AI-based Personal Virtual Assistant (PVA) designed toenhance the frequency quality and timeliness of patient-provider communication. The PVA is a hands-freevoice-activated AI-driven system that utilizes care plan data for both patients and healthcare providersfostering continuous communication. The PVA comprises: 1) a voice-enabled user-friendly AI kiosk-basedinteractive tablet that presents patients with essential plan details such as reviewing discharge instructionsreceiving post-discharge reminders (e.g. medication care tasks) providing guidance for exercise andstretching therapy and facilitating bi-directional messaging with clinical staff; and 2) a comprehensive webportal that enables care providers to monitor compliance modify patient-centered multidisciplinary care plansengage in shared decision-making and remotely update the PVA tablet to prevent care overlap. The webportal can be accessed through any computer tablet or phone app.Our pilot study has demonstrated the feasibility and acceptability of the PVA among oncology patients andclinical experts. Building on this preliminary data we propose a supplemental grant to further assess the PVA'sfeasibility scalability and proof-of-concept effectiveness in enhancing patient-provider communication andadherence to care plans.We will conduct a pilot randomized controlled trial (RCT) with 20 oncology patients undergoing surgicalprocedures to evaluate the improvement of communication acceptability and scalability of the PVA as well asits effectiveness in reducing post-discharge adverse events. This supplemental grant will help establish thenecessary power for clinically validating the PVA's acceptance and effectiveness in mitigating adverse eventsassociated with inadequate patient-provider communication. 93600 +No NIH Category available Acceleration;Administrative Supplement;Alkylating Agents;Astrocytes;Automobile Driving;Benchmarking;Biocompatible Materials;Blood Vessels;Boston;Brain;Brain Neoplasms;Cell Line;Cell Proliferation;Cells;Clinical;Coculture Techniques;Complex;DNA Repair;Data;Development;Diffuse;Drug resistance;Ecosystem;Engineering;Evaluation;Excision;Gelatin;Genetic Transcription;Genome;Glioblastoma;Goals;Growth;Human;Hydrogels;Immunofluorescence Immunologic;Invaded;Laboratories;Libraries;Link;MGMT gene;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Metabolic;Microfluidics;Modeling;Nature;Operative Surgical Procedures;Outcome;Paracrine Communication;Parents;Patient-Focused Outcomes;Patients;Pattern;Perfusion;Pericytes;Pharmaceutical Preparations;Phenotype;Play;Process;Proteins;Radiation therapy;Recurrence;Research;Resistance;Role;Signal Transduction;Surgical margins;Synthetic Genes;Technology;Tissue Engineering;Tissue constructs;Universities;Variant;Vascular Endothelial Cell;Vascular remodeling;Work;Zinc Fingers;anti-cancer;brain based;improved;improved outcome;interest;mortality;neurovascular;new therapeutic target;novel;parent project;pressure;response;standard of care;stem;synthetic biology;temozolomide;tool;transcriptomics;tumor;tumor microenvironment Synthetic manipulation of engineered perivascular niches NARRATIVEGlioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems fromits diffuse invasion throughout the brain and drug resistance. This project will develop a platform for syntheticmanipulation of engineered perivascular niches to investigate glioblastoma cell proliferation invasion and drugresponse. NCI 10831221 8/15/23 0:00 PA-20-272 3R01CA256481-03S3 3 R01 CA 256481 3 S3 "BECKER, STEVEN" 12/1/23 0:00 11/30/24 0:00 9109865 "HARLEY, BRENDAN A." Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2023 164197 NCI 119500 44697 ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Glioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgicalresection followed by treatment with the alkylating agent temozolomide (TMZ) and radiotherapy. Resectionremoves the tumor bulk and TMZ provides some benefit to many patients. The parent Cancer TissueEngineering Collaborative project (R01 CA256481) is developing a tissue engineering approach to acceleratethe evaluation of new anticancer compounds that overcome TMZ resistance. We are developing tissueengineered models of the perivascular niches (PVNs) that extend from the tumor into the surroundingparenchyma and which are believed to play a dominant role in invasion recurrence TMZ resistance and poorsurvival. Our efforts focus on developing an engineered PVN biomaterial investigating pathophysiologicalprocesses driving GBM invasion and TMZ resistance and accelerating evaluation of novel TMZ derivativesthat target GBM regardless of MGMT status. The objective of this NOT-CA-23-045 NOSI AdministrativeSupplement is to support a new collaborative initiative to incorporate synthetic gene circuits into ourengineered PVN models. Current tissue engineering brain vascular models lack orthogonal regulatable controlover the growth and maturation of the perivascular niche. The ability to enact independent quantitative controlover PVN growth and maturation would represent a significant advance and would enable us to deeplyexamine reciprocal interactions within the PVN that may yield novel therapeutic targets to improve outcomes.To realize this objective we propose a new collaborative effort to with Dr. Ahmad Khalil (Boston University) toapply his laboratorys genome-orthogonal synthetic zinc finger transcriptional regulator (synZiFTR) technologyto enable drug-regulated orthogonal control over PVN growth vs. maturation in the perivascular niche modelsunder development by this project. To do this we will regulate growth and maturation of a synthetic engineeredperivascular niche (Aim S1). We will subsequently benchmark patterns of TMZ resistance and invasion inresponse to synthetic vasculature (Aim S2). This proposed supplement will support a collaborative team todevelop a new yet complementary capability to integrate advanced tissue engineering and synthetic biologytoolsets to provide regulatable control over brain perivascular niche models. Collaboratively we will establishhuman synthetic tissue constructs as an important new tool to investigate reciprocal GBM-PVN signaling withinthe brain tumor microenvironment. Such capabilities are essential for investigating patterns of GBM cell drugresistance invasion and vascular remodeling necessary for improving patient outcomes. 164197 +No NIH Category available Address;Affect;Alleles;Binding;Biogenesis;Biological;Biology;Blood Vessels;COL1A2 gene;Cancer Cell Growth;Cancer Etiology;Cells;Collaborations;Collagen;Collagen Receptors;Collagen Type I;Complex;DOK1 gene;Deposition;Desmoplastic;Elements;Epigenetic Process;Extracellular Matrix;Extracellular Matrix Proteins;Fiber;Fibrillar Collagen;Fibroblasts;Fibrosis;Future;Goals;Growth;Immune;Infiltration;Integrins;Laboratories;Laboratory Finding;Lesion;Malignant Neoplasms;Malignant neoplasm of pancreas;Matrix Metalloproteinases;Mediating;Metabolism;Metalloproteases;Mitochondria;NF-kappa B;Nutrient;Oncogenic;Pancreatic Ductal Adenocarcinoma;Pancreatic Endocrine Carcinoma;Patients;Play;Protein Tyrosine Kinase;Reagent;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Resistance;Role;Signal Pathway;Signal Transduction;Technology;Time;Tumor Promotion;United States;Variant;autocrine;cancer cell;cellular engineering;design;discoidin receptor;experimental study;improved;insoluble fiber;interest;islet;mortality;mutant;pancreatic ductal adenocarcinoma cell;patient prognosis;prevent;receptor;response;restraint;survival prediction;therapeutic development;therapeutic target;treatment response;tumor;tumor growth;tumor metabolism;tumor microbiome;tumor progression The effect of cancer cell produced collagen 1 homotrimers on DDR1 signaling activation by microenvironmental collagen 1 fragments. NarrativePancreatic cancer (PDAC) islets are surrounded by vast amounts of stroma and extracellular matrix (ECM)containing heterotrimeric collagen type 1 (Col I) that is either intact or cleaved by matrix metalloproteases(MMP). The cancer cells also produce small amounts of homotrimeric Col I that is resistant to MMP cleavage.This project will decipher how PDAC-produced Col I homotrimers affect the metabolism of PDAC cells embeddedwithin an ECM containing heterotrimeric Col I fibers and/or soluble Col I fragments that are either inhibit orstimulate tumor growth and metabolism. NCI 10831212 9/5/23 0:00 PA-20-272 3U01CA274295-02S1 3 U01 CA 274295 2 S1 "MERCER, NATALIA" 9/21/22 0:00 8/31/27 0:00 ZCA1(M1) 1861927 "KARIN, MICHAEL " "LOWY, ANDREW M; SCHWABE, ROBERT F." 50 PHARMACOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 174500 NCI 131000 43500 AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Pancreatic Ductal Adenocarcinoma (PDAC) accounts for over 90% of pancreatic malignancies and isthe third leading cause of cancer mortality in the United States. Elucidating the biology of this pernicious cancerremains the key to improving prognosis for patients. PDAC is characterized by a complex desmoplastic stromacomposed largely of fibroblasts and extracellular matrix (ECM) that can function to either restrain or promotetumor progression. Type 1 Collagen (Col I) typically a heterotrimer consisting of two a1 and one a2 chains isthe major ECM protein found in the PDAC-associated stroma and in recent years has been proven to play animportant role in regulating tumor growth progression and response to therapy through the discoidin domainreceptor tyrosine kinase 1 (DDR1) and a3b1 integrin receptor signaling pathways. The Karin lab discovered thatinsoluble and intact Col I fibrils in the ECM are cleaved by matrix metalloproteinases (MMPs) to form soluble and Col I fragments. Unlike intact Col I fibrils which induce DDR1 degradation and inhibit DDR1s downstreameffectors the Col I fragment binds to DDR1 activates its tyrosine kinase activity and stimulates PDACmetabolism mitochondrial biogenesis and tumor growth. The Kalluri lab however discovered that PDAC cancercells epigenetically silence the COL1A2 gene to produce small amounts of MMP-resistant Col1a1 homotrimersconsisting solely of three a1 chains unlike the heterotrimer normally produced by cancer associated fibroblasts(CAF) in the PDAC stroma. The homotrimer changes the immune landscape by altering the tumor microbiomeand stimulates tumor growth in an autocrine manner through a3b1 integrin receptor mediated oncogenicsignaling. The effect of cleaved and intact Col I heterotrimers that constitute a majority of the PDAC ECMand act via DDR1 on Col I homotrimer modulation of cancer cell growth via a3b1 integrin and vice versais a critical biological and translational question that is yet to be answered. This proposal addresses thegap in our understanding of Col I function in PDAC using two aims. The first aim focuses on whether Col Ia13homotrimers produced by PDAC cells can activate or inhibit DDR1 signaling in the presence of intact and/orcleaved Col I heterotrimers. The second aim determines how Col Ia13 expressing and Col Ia1-null PDAC cellsrespond to ECM containing cleavable and non-cleavable Col I heterotrimers. Deciphering the mechanisticinterplay between the Col I subtypes identified in the PDAC ECM is a critical step in designing successful stroma-targeting treatments for pancreatic cancer. 174500 +No NIH Category available Address;CD47 gene;Cancer Etiology;Cancer Patient;Cell Survival;Cells;Chronic;Clinical;Communities;Cues;Data Science Core;Data Set;Development;Disease;Drug resistance;Ecosystem;Ensure;Epidermal Growth Factor Receptor;Event;Extracellular Matrix;Fibroblasts;Foundations;Funding;Future;Geography;Goals;Human;Immune;KRAS2 gene;Link;Lung;Lung Adenocarcinoma;Macrophage;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of lung;Medicine;Methods;Modeling;Molecular;NF-kappa B;Nature;Non-Small-Cell Lung Carcinoma;Oncogenic;Organoids;PD-1/PD-L1;PDPK1 gene;Paracrine Communication;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Process;Progress Reports;Proteomics;Public Health;Refractory;Research;Research Project Grants;Resistance;Signal Transduction;Specimen;System;Testing;Therapeutic;acquired drug resistance;cancer cell;cancer therapy;cancer type;clinical translation;cytokine;data sharing;humanized mouse;immunosuppressive checkpoint;improved;improved outcome;innovation;molecular targeted therapies;mortality;mouse model;mutant;neoplastic cell;patient derived xenograft model;precision oncology;prevent;programs;resistance mechanism;response;success;targeted treatment;therapeutic evaluation;therapy resistant;treatment strategy;tumor;tumor microenvironment;tumor progression;tumor xenograft ARTNet NOSI Supplement Project Narrative: Cancer is a substantial public health burden. Despite recent progress through the use ofprecision cancer medicines that have improved outcomes for cancer patients the development of acquiredresistance to these medicines has impeded transforming most cancers into chronic or curable conditions. ThisNCI ARTNet Research Program aims to understand the basis of acquired drug resistance to improve cancertreatments and patient survival. NCI 10831209 9/21/23 0:00 PA-20-272 3U54CA224081-06S1 3 U54 CA 224081 6 S1 "KONDAPAKA, SUDHIR B" 9/30/17 0:00 8/31/27 0:00 ZCA1(M1) 9547125 "BIVONA, TREVER G" "ROTH, JACK " 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 80750 NCI 50000 30750 Project Summary/Abstract: The goal of this BAATAAR-UP renewal program application within the NCI ARTNetis to characterize the mechanisms of and therapeutically counteract acquired resistance to molecular therapiesin non-small cell lung cancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem andits plasticity during treatment. Acquired resistance is defined as tumor progression that occurs during therapyand after an initial tumor response. The overarching hypothesis is that acquired resistance to molecular therapiescan be thwarted by defining and exploiting vulnerabilities in the cellular signaling and geographic tumorecosystem networks that allow tumors to survive and grow during therapy. In lung cancer and other cancer typesthe use of targeted therapies that inhibit important and common oncogenic driver alterations such as mutantEGFR and KRAS (G12C) and block immunosuppressive checkpoints such as PD1/PDL1 is improving patientoutcomes. A major challenge to transforming cancers into chronic or curable diseases is acquired resistancewhich enables lethal cancer progression in patients. Understanding the mechanisms underlying acquiredresistance is essential to develop counteracting strategies that improve patient survival. During the prior NCIU54 DRSC funding period our team uncovered several mechanisms of acquired resistance to targeted therapyin human NSCLC by studying clinical specimens and innovative patient-derived models including humanizedmurine models bearing patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) with an intactTME. Our expert team proposes to investigate these mechanisms and identify others synergistically anditeratively via 3 Research Projects and optimal interactions with 2 Cores. A Data Science Core will analyzeharmonize centralize and share data obtained across the basic and translational continuum using innovativemethods. An Administrative Core will ensure optimal project integration and internal and external interactionswith the ARTNet Consortium and scientific and lay communities. Project 1 (Clinical tumor-TME acquiredresistance) is translational and uses clinical specimens and patient-derived models to test the hypothesis thattumor macrophages and tumor fibroblasts promote acquired resistance via paracrine signaling interactionsincluding cytokine CD47 and extracellular matrix (ECM) cues sensed by cancer cells and converging on survivalpathways such as YAP and NF-kB. Project 2 (PDX tumor-TME acquired resistance) is translational and useshumanized mouse models to test the hypothesis that an immune-suppressive TME and activation of macrophageand fibroblast signaling circuits that support tumor cell survival via PDK1 YAP and NF-kB signaling promoteacquired resistance. Project 3 (PDO tumor-TME acquired resistance) is basic and uses synthetic lethal andproteomic profiling in PDOs with a TME to test the hypothesis that signaling interactions involving the ECMTROP2 and CD47 promote acquired resistance. Synergistic iterative interactions to study these mechanismsacross projects and systems will yield robust translatable treatment strategies to counteract acquired resistance. 80750 +No NIH Category available Address;Biometry;Black race;Communication;Communications Media;Communities;Development;Equity;Health Personnel;Hispanic;Instagram;Malignant Neoplasms;Malignant neoplasm of prostate;Misinformation;Outcome Study;Patients;Physicians;Qualitative Research;Research;Social Network;TikTok;Work;cancer care;clinical decision-making;digital communication;digital health;field study;health literacy;improved;interest;multidisciplinary;response;social media Addressing Misinformation to Promote Equity in Prostate Cancer Care - Revision - 1 Project NarrativeSocial networks are widely used by patients and healthcare providers related to prostate cancer; however littleis known about the use and impact of social media for patient-physician communication. We will study thequality and understandability of social media postings made by healthcare providers their use of social mediafor direct communication with patients and their perspectives on the impact of social media for patient-physician communications. Our proposed work seeks to advance the field through a better understanding ofthe effects of social media as a form of digital health on patient-physician communications to inform thedevelopment of more effective digital communications about cancer from healthcare providers. NCI 10831190 8/22/23 0:00 PA-20-272 3R01CA278997-01S1 3 R01 CA 278997 1 S1 "CHOU, WEN-YING" 2/7/23 0:00 1/31/28 0:00 11549896 "LOEB, STACY " Not Applicable 12 UROLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/1/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 96610 NCI 56997 39613 PROJECT SUMMARY/ABSTRACTThis application is in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-041. Prostatecancer information shared through popular social networks such as YouTube Instagram and TikTok is widelyviewed but misinformation is common. The impact of social networks on patient-physician communications aboutprostate cancer is unknown. We will address this research gap using three main approaches: (1) compare thequality of information understandability and actionability between social media posts about prostate cancer inEnglish and Spanish by healthcare providers versus other publisher types; (2) explore the use of social mediaplatforms for direct patient-physician communications about prostate cancer; and (3) explore the perspectives ofhealthcare providers serving diverse communities on the positive and/or negative impacts of social media forpatient-physician communications. Results of this study will be used to create a tip sheet for health care providerson best practices for patient-facing social media communication and will be moved forward in later years of theproject to discuss with Black and Hispanic patients the impact of social media for their communications withhealthcare providers and clinical decision-making. Our multi-disciplinary team is well-suited to conduct this studywith expertise in prostate cancer biostatistics qualitative research health literacy and social media. Theexpected outcomes of this study will advance the field by studying ways that social media can be leveraged toimprove patient-physician communications. 96610 +No NIH Category available Address;Affect;Algorithms;Appointment;Area;Assessment tool;Cancer Biology;Cancer Center;Cancer Detection;Cancer Science;Cancer-Predisposing Gene;Caring;Clinical;Clinical Trials;Collaborations;Collection;Communication;Dana-Farber Cancer Institute;Demographic Factors;Development;Early Diagnosis;Early identification;Electronic Health Record;Eligibility Determination;Endometrial Carcinoma;Epidemiology;Equity;Evaluation;Family;Family history of;Feeling;Funding;Future;Genetic;Genetic Counseling;Genetic testing for cancer risk;Geography;Goals;Guidelines;Health;Healthcare;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Hereditary Nonpolyposis Colorectal Neoplasms;Human;Individual;Inherited;Intervention;Interview;Malignant Neoplasms;Medical Records;Methods;Modeling;Morbidity - disease rate;Mutation;Oncogenes;Oncology;Patient-Focused Outcomes;Patients;Persons;Prevention;Primary Care;Principal Investigator;Provider;Publishing;Recommendation;Recording of previous events;Reporting;Research;Resources;Risk;Risk Assessment;Risk Reduction;Risk-Benefit Assessment;Role;Screening for cancer;Structure;Surveys;Syndrome;Technology;Testing;Time;Visit;Vulnerable Populations;Work;Writing;assessment application;barrier to care;cancer care;cancer genetics;cancer risk;cancer therapy;care delivery;clinical care;clinical decision support;clinical practice;colon cancer risk;data management;design;eHealth;effective intervention;electronic health data;electronic health record system;future implementation;gene panel;genetic testing;health application;improved;innovation;insight;interest;lifetime risk;literacy;mortality;multidisciplinary;new technology;non-genetic;novel strategies;patient-clinician communication;patient-level barriers;personalized approach;premalignant;programs;response;support tools;technological innovation;testing uptake;tool;underserved community;uptake Understanding the impact of an EHR-integrated hereditary cancer risk assessment application on patient-provider communication We built a patient-facing app (PREMM5) to assess Lynch syndrome risk and implemented it in the EHR butobserved persistent low rates of uptake of genetic counseling and testing. We will use medical record reviewand interviews to improve patient-provider communication regarding hereditary cancer risk assessment. NCI 10831167 9/15/23 0:00 PA-20-272 3P30CA006516-58S3 3 P30 CA 6516 58 S3 "PTAK, KRZYSZTOF" 9/1/23 0:00 11/30/23 0:00 1871771 "GLIMCHER, LAURIE HOLLIS" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 100000 NCI 56180 43820 This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-041. Our current approach to cancer care remains reactive with late presentation of many patients. Thoughinnovation is rapidly advancing effective interventions are often not perpetuated into practice. The Program inCancer Risk Prevention and Early Detection (CaRPED) of the Dana-Farber/Harvard Cancer Center(DF/HCC) arose out of growing recognition of the importance of bridging technology with DF/HCC expertise incancer science to detect cancer at earlier stages when interventions are most effective. The Cancer CareDelivery Research (CCDR) program was designed to investigate strategies to improve care delivery to ensurethat interventions that theoretically can work based on clinical trials do work in the context of oncologypractice and that vulnerable populations are not left behind. The Principal Investigator is co-leader of theCaRPED program and has led the development of the PREMM models (funded by RO1CA132829 2008-present). The PREMM5 algorithm assesses for one of the most common hereditary cancer syndromes Lynchsyndrome (LS) which affects 1 in 279 people and causes high lifetime cancer risk. PREMM5 is now theguideline-recommended standard for assessing LS risk. We have recently developed a literacy-adaptedpatient-facing hereditary cancer risk assessment app based on PREMM5. When embedded in the electronichealth record (EHR) PREMM5 was able to identify a large number of at-risk patients however three quartersof at-risk patients eligible did not receive genetics referral or testing. To optimize the benefit of riskassessment it is critical to understand the role of the PREMM5 app as a clinical decision support tool andpatient-provider communication support tool in clinical practice. This proposed supplemental project representsa collaboration between the DF/HCC CaRPED and CCDR programs and the Survey and Data ManagementCore and will investigate the role of PREMM5 in patient-provider communication through evaluation of patientoutcomes in order to identify key areas for improvement. We will used a mixed-methods approach in Aim 1we will quantitatively assess whether there are associations between demographic factors and patientoutcomes including discussion of PREMM5 during the clinical visit referral receipt referral uptake andgenetic testing uptake in individuals who chose to proceed with genetics referral versus those who didnt. InAim 2 we will use in-depth semi-structured interviews with at-risk patients per their PREMM5 scores and theirproviders to elucidate key barriers and facilitators to use of PREMM5 as a communication support tool tofacilitate downstream care. The result will be a more equitable and clinically useful version of PREMM5that can be implemented DF/HCC-wide to improve patient-provider communication about risk for LS.Further we plan to use insights gained in this study to guide development of a multi-gene panel patient-facingrisk assessment tool (PREMMplus) to assess risk for 19 hereditary cancer genes. 100000 +No NIH Category available 3-Dimensional;Address;Adhesions;Adhesives;Affect;Basement membrane;Biological Assay;Blood Platelets;Breast Melanoma;Cell Communication;Cell Death;Cell Survival;Cells;Cessation of life;Chromatin;Chromatin Structure;Circulation;Complex;Computer Analysis;Cytoskeleton;Dermis;Disease;Disseminated Malignant Neoplasm;E-Cadherin;Endothelium;Environment;Extracellular Matrix;Extravasation;Fibrin;Gene Expression;Genomics;Goals;Image;In Vitro;Individual;Intervention;Liver;Malignant Neoplasms;Measurement;Mechanics;Methods;Microcirculation;Modeling;Molecular;Neoplasm Circulating Cells;Neoplasm Metastasis;Nuclear;Organ;Organ Specificity;Pathway interactions;Phenotype;Primary Neoplasm;Probability;Process;Proliferating;Property;Resolution;Role;Site;Stress;Techniques;Technology;Therapeutic;Thrombus;Time;Tissues;Tumor Cell Invasion;Vision;Work;cell behavior;cell type;computer studies;coping;experience;experimental study;hemodynamics;in vitro Model;in vivo;insight;intravital imaging;metastatic process;migration;monolayer;mortality;neoplastic cell;novel therapeutics;prevent;programs;response;shear stress;stressor;transcriptome;transcriptomics;triple-negative invasive breast carcinoma Studying E-cadherin dynamics during extravasation and metastatic colonization U54 CENTER: NARRATIVEMetastatic organ colonization by circulating tumor cells depends on a response program in tumor cellstermed mechano-adaptation to cope with mechanical and molecular stresses. In this U54 MetNet Centerwe will integrate mechanical genomic and ultrastructural information during metatastatic organ colonizationand identify mechanical mechanisms of tumor cell fate decisions and identify pathways and potentialtherapeutic strategies to eliminate tumor cells prior to metastasis. NCI 10831158 8/23/23 0:00 PA-20-272 3U54CA261694-03S1 3 U54 CA 261694 3 S1 "NADEAU, CHRISTINE FRANCES" 9/17/21 0:00 8/31/26 0:00 ZCA1(M1) 1961918 "KAMM, ROGER D" "SHENOY, VIVEK " 7 ENGINEERING (ALL TYPES) 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA BIOMED ENGR/COL ENGR/ENGR STA 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 177313 NCI 147813 29500 Overall: PROJECT SUMMARYMetastatic disease is responsible for the vast majority of cancer mortality. Understanding of the fundamentalmechanisms leading to metastatic cancer has been hampered by the need for models that replicate the step-wise metastatic process in vivo yet are amenable to tight control and facilitate high-resolution time-lapseimaging and quantitative analysis of cell behavior. Over the past decade our team has developed in vivo andin vitro methods capable of simulating many steps of the metastatic cascade including tumor cell invasionintravasation trapping in the microcirculation or adhesion to the vessel walls and extravasation into thesurrounding extracellular matrix. In parallel we have developed computational studies that provided detailedinsights often not possible through experiments. This collective prior work has shed new light on central aspectsof single-cell and collective cell behavior during metastasis and identified mechanical adaptations andvulnerabilities of the tumor cell with promise for targeted interventions. The goal of our proposed U54 Center isto employ these developed assays and methods in combination with new measurement techniques to interrogatethe full spectrum of stressors experienced by tumor cells in the metastatic niche during arrest and extravasationand couple these with parallel studies of changes in chromatin structure and the transcriptome of tumor cells(Core B). These changes are critical to mechano-adaptation of the tumor cells towards an organ-preferentialinitiation of a metastatic colony or transition to dormancy. A hallmark of our proposed center is the use of state-of-the-art in vitro (Project 1) and in vivo (Project 2) experiments and computation (Core A) to uncover and probethe factors that ultimately determine tumor cell fate. We anticipate that such integrated studies will provide newinsights into metastatic cancer not possible by the use of any method alone and enhance our ability to identifyand screen for new therapies to inhibit the tendency for metastatic spread of disease. 177313 +No NIH Category available Acute;Address;Aging;Animal Model;Atrophic;Automobile Driving;Basic Science;Cancer Etiology;Cancer Model;Carcinoma;Cell Death;Cell Proliferation;Cells;Characteristics;Chronic;Clinical;DNA Sequence Alteration;Development;Disease;Disease Outcome;Disease Progression;Environmental Risk Factor;Epidemiology;Epigenetic Process;FDA approved;FOLH1 gene;Fibroblasts;Genes;Genetic;Genome;Genomics;Gleason Grade for Prostate Cancer;Growth;Heterogeneity;Image;Imaging technology;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Surveillance;Immunotherapy;Inflammation;Inflammatory;Innate Immune Response;Intercept;Lesion;Life Style;Link;Localized Disease;Longitudinal Studies;Macrophage;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Metastatic Neoplasm to Lymph Nodes;Metastatic Prostate Cancer;Molecular;Mus;Mutation;Myeloid-derived suppressor cells;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Outcome;PET/CT scan;PTEN gene;Pathologic;Phase;Population;Positron-Emission Tomography;Process;Prostate;Prostate carcinoma;Prostatectomy;Prostatic;Research;Research Project Grants;Resource Sharing;Risk;Role;Signal Transduction;TP53 gene;Testing;Therapeutic;Tissue Sample;Tissues;United States;Up-Regulation;Visualization;X-Ray Computed Tomography;adaptive immune response;adaptive immunity;anti-cancer;cancer cell;cancer diagnosis;cancer initiation;carcinogenesis;carcinogenicity;cell injury;disorder control;epigenetic silencing;epigenomics;fibroblast-activating factor;high risk men;human tissue;imaging agent;immune cell infiltrate;immunoreaction;improved;innovation;men;microbial;molecular imaging;mortality;mouse model;neoplastic;neoplastic cell;preneoplastic cell;prevent;programmed cell death ligand 1;prospective;prostate cancer cell;prostate cancer progression;prostate carcinogenesis;recruit;response;stem;synergism;translational study;tumor;tumor microenvironment Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer NARRATIVEProstate cancer is the most common serious cancer diagnosed in men in the United States and a leadingcause of cancer mortality. This proposal is focused on understanding whether prostate cancer emerges frominflamed regions of the prostate and in the process gains the ability to evade the immune system. Throughthis research we will identify new ways to prevent and intercept the development of aggressive prostatecancer. NCI 10831131 9/18/23 0:00 PA-20-272 3U54CA274370-02S1 3 U54 CA 274370 2 S1 "GHOSH-JANJIGIAN, SHARMISTHA" 9/15/22 0:00 8/31/27 0:00 ZCA1(M1) 2146873 "DE MARZO, ANGELO MICHAEL" "YEGNASUBRAMANIAN, SRINIVASAN " 7 PATHOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 82234 NCI 50219 32015 Project Summary: Epidemiological and pathological studies have implicated lifestyle microbial andenvironmental factors in prostate cancer etiology/risk. A potential link between these factors and prostatecarcinogenesis is the presence of chronic inflammation associated with atrophy (PIA) in prostates of agingmen. Yet there is a paradox surrounding the role of the immune response in prostate cancer: theinflammation paradox. On one hand inflammation may be a driver of carcinogenesis. On the other theimmune system is known to seek and destroy cancer cells. The majority prostate cancer lesions are immunedeserts and ICIs are ineffective in most cases. Why is there an evidently strong immune reaction in non-neoplastic regions in PIA but a lack of a robust immune response in most prostate cancers? We hypothesizethat chronic inflammation in PIA represents evidence of an innate immune response that drivescarcinogenesis. However in this inflammatory proving ground only cells that can epigeneticallyswitch off this response can emerge to become aggressive neoplastic precursors. We hypothesize thatthe paucity of immune infiltrates and lack of PD-L1 is evidence that prostate cancer cells develop a number ofdifferent mechanisms that evade anti-tumor adaptive immunity. We postulate that additional cell non-autonomous immune suppressive mechanisms enable disease progression. We propose 3 synergisticResearch Projects (2 basic1 translational) to mechanistically test key questions stemming from our provingground hypothesis. In Proj 1 (Basic Science) we hypothesize that the STING induction in PIA drives acuteand chronic inflammation leading to cell injury/cell death and proliferation. Second in a subset of PIA cellsepigenetic silencing of STING dampens of the immune response allowing them to emerge as overt pre-neoplastic cells. We will test this in animal models and in translational studies employing annotated andmolecularly characterized prostatectomies. The combination of PTEN loss and MYC copy number gain is anindependent predictor of poor outcome in prostate cancer. We hypothesize that the combination of MYC andPTEN stimulates a cell non-autonomous immune evasion mechanism induced by the recruitment of immuno-suppressive myeloid cells and fibroblast activation protein (FAP)-positive fibroblasts. Proj 2 (Basic Science)will test these hypotheses in animal models and in human tissues. Recently introduced imaging technologieshave raised the hypothesis that PET/CT imaging results may be able to predict molecular and tumoral micro-environmental characteristics of aggressive prostate cancer. PET imaging for PSMA using PyL PET/CT hasbeen FDA approved for imaging high risk men prior to prostatectomy. In Proj 3 (Translational) we employPET/CT scanning for PSMA and combine this with mpMRI to address these hypotheses. Also in Proj 3 we willapply newly developed/developing PET imaging agents to non-invasively and longitudinally study the extent ofM2 macrophages and cancer associated fibroblasts in our mouse prostate progression cancer models. 82234 +No NIH Category available Affect;Behavior;Biochemical;CD44 gene;Cell Therapy;Cell physiology;Cell surface;Cells;Chemistry;Coculture Techniques;Data;Doxorubicin;Drug Screening;Effectiveness;Fingerprint;Fluorescence-Activated Cell Sorting;Heterogeneity;Label;Lipids;Malignant Neoplasms;Measurement;Measures;Mechanics;Methods;Microscopy;Molecular;Molecular Profiling;Morphology;Nucleic Acids;Phenotype;Population;Predisposition;Proteins;Speed;Structure;Surface;Testing;Therapeutic;Training;cancer cell;cancer therapy;convolutional neural network;experimental study;imaging approach;interest;malignant breast neoplasm;molecular imaging;molecular phenotype;response;stem;therapeutic effectiveness;therapy resistant;tool;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor initiation Using label-free Raman microscopy to predict therapeutic resistance of TNBC cells PROJECT NARRATIVEHeterogenous cell populations are a hallmark of all cancers and have severely limited the effectiveness of cell-based therapies. Existing tools to quantify single cell phenotypes probe biochemical or mechanicalheterogeneity; however they are imperfect due to limited ability to provide a holistic characterization of themolecular cellular fingerprints that ultimately determine cell function. Developing a method based on molecularphenotyping offers a new method to relate phenotypic heterogeneity with functional heterogeneity and helpresolve the underpinnings of therapeutic resistance in cancer treatment. NCI 10831127 9/5/23 0:00 PA-20-272 3U01CA253540-04S2 3 U01 CA 253540 4 S2 "ZAMISCH, MONICA" 9/8/20 0:00 8/31/25 0:00 ZCA1(M1) 10352775 "BROCK, AMY " "PAREKH, SAPUN H" 37 BIOMEDICAL ENGINEERING 170230239 V6AFQPN18437 170230239 V6AFQPN18437 US 30.291188 -97.737568 578403 UNIVERSITY OF TEXAS AT AUSTIN AUSTIN TX BIOMED ENGR/COL ENGR/ENGR STA 787121139 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 143802 NCI 100000 43802 This application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-045.Cellular heterogeneity has become critically important limiting the effectiveness of therapeutics incancer treatment. The manifestations of cellular heterogeneity can be observed at the biochemical(molecular composition and structure) morphological and mechanical level ultimately affecting cellfunction. When considering non-invasive single-cell methods the primary methods to assesspopulation biochemical heterogeneity are based on fluorescence activated cell sorting (FACS) of cellsurface markers. While extremely rapid this method quantifies only specific molecules chosen by theuser; but what if the marker is unreliable? For example studies have shown that enriching cells basedon FACS of CD44 surface markers only provides a population of cells in which 5% show stem-likebehavior. What about all the other potential molecular changes in lipids or nucleic acid chemistry thatwere invisible in the FACS experiment which might be informative as differentiating features in cells?In this supplement request we propose to develop a label-free molecular imaging approach tocharacterize cellular Raman fingerprints and train a convolutional neural network (CNN) to predicttherapeutic resistance in heterogenous populations. We will use high-speed label-free nonlinearRaman scattering which captures a holistic molecular fingerprint of a cell by quantifying abundance ofmetabolites lipids proteins and nucleic acids and couple this data with CNN training and functionaldrug screening. Building off our preliminary findings a CNN will be developed and trained by culturingdifferent breast cancer subpopulations with increasing concentrations of doxorubicin and measuringboth live and dead cell Raman fingerprints (Aim 1). The CNN developed in Aim 1 will be tested for itsability to predict subpopulation therapeutic susceptibility in co-cultures of the two subpopulations (Aim2). This project offers not only a new take on phenotyping heterogeneous cancer cells but it will alsobe fully compatible with downstream functional or molecular testing such as tumor initiation or RNAseqmeasurements. 143802 +No NIH Category available Achievement;Administrative Supplement;Advisory Committees;Basic Science;Cancer Center;Cancer Patient;Cancer cell line;Cell Death;Cell Death Induction;Cells;Clinical;Clinical Trials;Cloning;Collaborations;Communication;Cystine;Data;Development;Drug resistance;Esophageal Adenocarcinoma;Failure;Family;Feedback;Fostering;Foundations;Future;Genes;Genomics;Goals;Grant;Guidelines;Human;Hypoxia;Hypoxia Inducible Factor;Image;Imaging Device;Immune;Immunologics;Immunotherapy;Infrastructure;Iron;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of thorax;Mediating;Medical;Metabolic;Modality;Modeling;Monitor;Mus;National Cancer Institute;Nature;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Patient-Focused Outcomes;Patients;Play;Policies;Positron-Emission Tomography;Pre-Clinical Model;Production;Prognostic Marker;Radiation;Radiation Oncology;Radiation therapy;Radiation-Sensitizing Agents;Reagent;Recurrence;Recurrent disease;Reporter Genes;Research;Research Project Grants;Resistance;Resource Sharing;Resources;Risk;Role;Sampling;Techniques;Testing;Therapeutic;Therapeutic Agents;Tracer;Transfection;Transgenic Organisms;Translating;Translational Research;Tumor Suppression;University of Texas M D Anderson Cancer Center;Xenograft Model;activating transcription factor 4;bioluminescence imaging;cancer cell;cancer imaging;cancer therapy;cancer type;chemoradiation;clinically significant;cohort;determinants of treatment resistance;drug sensitivity;effective therapy;hormone therapy;imaging program;improved;individual patient;member;molecular imaging;multidisciplinary;novel;novel therapeutic intervention;novel therapeutics;pre-clinical;programs;radiation resistance;radioresistant;single cell sequencing;solute;stable cell line;synergism;targeted treatment;therapy resistant;treatment strategy;tumor;tumor growth;tumor hypoxia;tumor microenvironment Administrative Supplement: Metabolic Alterations Associated with Acquired Resistance to Ferroptosis in Esophageal Cancer Project NarrativeThe Acquired Resistance to Therapy and Iron (ARTI) Center at The University of Texas MD Anderson CancerCenter will establish a foundation for understanding the role of iron in cancer resistance to therapies and willfocus on deciphering the mechanisms of acquired resistance to radiation therapy which can be extrapolated toother types of cancer therapy. The overarching goals of the ARTI Center are: 1) to bridge the basic sciencemechanism of a novel type of iron-dependent cell death called ferroptosis in acquired resistance to radiationtherapy with translational research in preclinical models and human patient samples; 2) to identify cohorts ofpatients who are at greatest risk to develop acquired radiation therapy resistance; and 3) to investigate the abilityof novel therapeutic agents to re-sensitize cancer cells to radiation by inducing ferroptosis. The long-termoutcomes from the ARTI Center will foster collaborations with other centers in the Acquired Resistance toTherapy Network (ARTNet) build upon and iteratively feedback into research projects focused on drugresistance and sensitivities and ultimately lead to cancer treatment strategies tailored to the individual patient. NCI 10830901 9/18/23 0:00 PA-20-272 3U54CA274220-02S1 3 U54 CA 274220 2 S1 "KAI, MIHOKO" 9/20/22 0:00 8/31/27 0:00 ZCA1(M1) 9939858 "GAN, BOYI " "LIN, STEVEN HSESHENG; ROSARIO, SPENCER RAE" 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 182349 NCI 135849 46500 Overall SummaryApproximately 50% of cancer patients are treated with radiation therapy (RT) but local recurrence can still occureven with the use of advanced RT techniques. This local recurrence which commonly develops in 30-50% ofcancer cases is exacerbated by the acquisition of RT resistance. This RT resistance is especially true forpatients with locally advanced thoracic cancers such as lung and esophageal cancers. RT can lead to an iron-dependent cell death modality called ferroptosis but whether ferroptosis resistance occurs within tumors givingrise to acquired RT resistance is not known and is the central theme of the proposed Acquired Resistance toTherapy and Iron (ARTI) Center. The overarching goals of the ARTI Center are: 1) to bridge the basic sciencemechanisms of ferroptosis in acquired resistance with translational research in preclinical models and humanpatient samples; 2) to identify cohorts of patients who are at greatest risk to develop acquired RT resistance;and 3) to investigate the ability of novel therapeutic agents to re-sensitize lung and esophageal cancer cells toradiation by inducing ferroptosis. The ARTI Center comprises two basic/mechanistic projects (Project 1 andProject 2) one preclinical/translational project (Project 3) and one shared resource core (Molecular ImagingCore [MIC]). Project 1 will focus on elucidating whether ferroptosis evasion is a key driver in acquired RTresistance using radioresistant lung cancer and esophageal cancer cell lines and xenograft models that will beused in Project 2. Project 2 will test the hypothesis that hypoxia a long-recognized driver of tumorradioresistance suppresses ferroptosis induction during RT and contributes to RT-induced acquired resistanceto ferroptosis. Furthermore expression of hypoxia-related genes and other targets of acquired RT resistance willbe analyzed by single-cell sequencing in Project 3. Project 3 investigates changes in immune cells in the tumormicroenvironment of humanized tumor models derived from chemoradiation therapy-responsive or -non-responsive esophageal adenocarcinoma patients. These ferroptosis-mediated immunologic changes in thetumor microenvironment may serve as prognostic biomarkers for identifying tumors that may acquire RTresistance and predicting cancer patient outcomes which could in the future be modulated by the ferroptosis-inducing agents tested in Projects 1 and 2. Projects 1 2 and 3 will be supported by the MIC that utilizesbioluminescence imaging to monitor tumor growth positron emission tomography (PET) tracers to monitorcystine transporter activity and to identify hypoxic regions within tumors as well as novel redox-tuned PETtracers for identifying activated innate immune cells. The ARTI Center will develop an Administrative Core foreffective communication and collaboration between the ARTI Center Project and Core Leaders and Co-Leaderswith National Cancer Institute (NCI) of Acquired Resistance to Therapy Network (ARTNet) program staff as wellas other ARTNet centers to synergize ARTI Center-related activities. 182349 +No NIH Category available ATAC-seq;Age;Aging;Alveolar;Alveolar Cell;Atlases;CD8-Positive T-Lymphocytes;Cancer Etiology;Cell physiology;Cells;Cessation of life;Clinical;Complex;Data;Defect;Distal;Epithelium;Exhibits;Flow Cytometry;Future;Gene Expression Profile;Gene Expression Regulation;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Granzyme;Homeostasis;Immune;Immune system;Immunologic Surveillance;Impairment;Inflammatory;Interferon Type II;Interferons;Joints;Laboratories;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Mus;Organoids;Parents;Population;Predisposition;Prevalence;Process;Proteins;Regenerative capacity;Risk Factors;Role;Shapes;Signal Transduction;TNF gene;Tumor Immunity;Tumor-infiltrating immune cells;Up-Regulation;Variant;age related;aged;anti-tumor immune response;cancer cell;cell injury;cell killing;cell type;cytokine;cytotoxic;draining lymph node;immune function;immunogenicity;improved;in vivo;interest;lung tumorigenesis;mouse model;neoplastic cell;progenitor;programs;repaired;response;self-renewal;single cell sequencing;single-cell RNA sequencing;stem cells;tumor;tumor growth;tumor immunology;tumor initiation;tumor microenvironment;tumorigenesis;tumorigenic Profiling immune cells in aged lung tumor initiation Project NarrativeAging is a primary risk factor for lung cancer which accounts for the largest cause of cancer deaths. Theimmune system provides critical anti-tumor defenses that decline with age. This supplement will use newmodels generated in the parent U01 to investigate how immune cell profiles change with age in the lungat homeostasis and during lung tumorigenesis. NCI 10830688 8/10/23 0:00 PA-20-272 3U01CA267827-03S1 3 U01 CA 267827 3 S1 "KLAUZINSKA, MALGORZATA" 9/24/21 0:00 8/31/26 0:00 ZCA1(O1) 9078088 "HAIGIS, MARCIA " "KIM, CARLA F." 7 ANATOMY/CELL BIOLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 171750 NCI 123100 48650 Project SummaryThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. The immune system can control tumor growth and shape tumor immunogenicity through theprocess of cancer immunoediting which results in the selection of tumor cell variants that can resistavoid or suppress the anti-tumor immune response and leads to outgrowth of clinically apparent tumors.Studying the impact of age on immunoediting in the cell type that gives rise to the most common type oflung cancer is critical to understanding the early stages of tumorigenesis. The predominant cell-of-originin lung adenocarcinoma is the alveolar type 2 cells (AT2 cells) a progenitor cell population in the distallung. In the first year of the parental U01 studies we demonstrated that aged AT2 cells exhibit defects inself-renewal exhibited by decreased organoid formation in culture and impaired ability to repair alveolarcell injury in vivo. We also established a genetically engineered mouse model (GEMM) of lungadenocarcinoma in young and aged mice and identified altered immune cell proportions and cytokinesin aged vs. young tumors. In this supplement we seek to uncover changes in immune cells in the agedmilieu that may influence AT2 cell functions and define alterations in immune cells that may contribute toincreased tumorigenesis during aging. We investigate these questions in two specific aims: Aim 1: Toassess age-related gene regulation changes in lung lymphocytes and interacting lung epithelialprogenitors. We will 1a) use multiparameter flow cytometry to determine age-related compositionalchanges of lung epithelium and immune cells and 1b) single cell sequencing to identify age-relateddifferences in interactions between immune cells and lung epithelial progenitors at homeostasis. Aim 2:To define the changes in young vs. aged immune cell populations in the GEMM model of lungadenocarcinoma. We will 1a) define the immune cell populations altered by age in the TME vs. peripheryusing flow cytometry and 1b) dissect single cell transcriptional programs in immune cells from tumorsfrom young vs. aged mice. This supplement will bring together the expertise of the Haigis and Kim labsin the parental U01 with the expertise of the Sharpe lab in cancer immunology to identify immune cellsthat are perturbed with age and begin to understand how aging impacts cell populations critical toimmune surveillance and tumorigenesis in vivo. The proposed studies will create a single-cell atlas ofyoung vs. aged lung at homeostasis and immune cell populations in young vs. aged lung tumors layingthe groundwork for future studies aimed at elucidating mechanisms of diminished anti-tumor control withage. 171750 +No NIH Category available Acceleration;Address;Architecture;Area;Clinical;Collaborations;Communities;Complex;Data;Data Set;Development;Disease;Division of Cancer Biology;Ensure;Fostering;Foundations;Future;Gene Expression;Gene Expression Profile;Generations;Genes;Genomics;Image;Investigation;Knowledge;Malignant Neoplasms;Metadata;Methodology;Multimodal Imaging;Normal tissue morphology;Play;Research;Research Personnel;Resources;Sampling;Services;Side;Standardization;Techniques;Technology;Testing;Tissues;Visualization;Visualization software;access restrictions;cancer genomics;cohort;complex data;computerized data processing;computing resources;cost;data access;data modeling;data sharing;data visualization;design;experience;genomics cloud;image visualization;insight;interest;large datasets;multidimensional data;nano-string;open source;prototype;repository;response;spatial integration;tool;transcriptomics;user-friendly;web app Spatial Transcriptomics Explorer (STE): An open-source resource for visualizing spatial gene expression data Project NarrativeSpatial transcriptomics (ST) is revolutionizing our understanding of gene expression patterns in thecontext of the tissue microenvironment through generation of large complex and expensive multimodalimaging and transcriptomics data. To optimize resource usage and foster collaborations we proposethe development of a modular user-friendly web-based application the Spatial TranscriptomicsExplorer (STE). This application will be deployable for a single research group or for a consortium orresearchers to address the 1) challenges of analyzing ST data from different platforms side-by-side and2) reduce the computational and administrative burden of downloading large datasets under accessrestrictions. In partnership with clinician-researchers we aim to create a platform-agnostic open-sourcevisualization resource compatible with multiple ST platforms. Our respective expertise in ST datageneration analysis and visualization platform development will ensure a scientifically insightful buteasily generalizable product. We hope that the STE will facilitate collaborations within the Division ofCancer Biology consortia stimulate hypothesis generation and testing and make these complex dataeasily accessible to researchers and clinicians without extensive computational resources. NCI 10830668 8/21/23 0:00 PA-20-272 3U24CA274494-02S1 3 U24 CA 274494 2 S1 "TURNER, MICHELLE C" 9/14/22 0:00 8/31/27 0:00 ZCA1(M2) 1891838 "BLETZ, JULIE A" "EDDY, JAMES A" 7 Unavailable 830977117 TPALZA9N4M11 830977117 TPALZA9N4M11 US 47.62803 -122.330082 10023027 SAGE BIONETWORKS SEATTLE WA Other Domestic Non-Profits 981211031 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 152500 NCI 100000 52500 AbstractThis application is being submitted in response to the Notice of Special Interest (NOSI)identified as NOT-CA-23-045.Spatial transcriptomics (ST) is transforming our understanding of gene expression patterns inrelation to tissue architecture. Various ST techniques such as 10x Genomics Visium andNanostring GeoMx DSP have advanced our knowledge but the resulting data is large complexand costly to generate. Collaborations and data sharing among researchers with respect tothese data can greatly benefit the scientific community. However challenges like difficulties inanalyzing data from different platforms and the computational and administrative burden ofdownloading large datasets currently hinder effective collaborations. To address these issueswe propose the development of a prototype Spatial Transcriptomics Explorer (STE) a modularuser-friendly application for visualizing ST data within various Division of Cancer Biology (DCB)consortia. STE will offer a platform-agnostic open-source visualization resource compatiblewith data from multiple platforms. Through the cohort builder gene-based query and spatialquery modules the STE will help researchers quickly examine genes or regions in diseased andnormal tissues. Deployment of this resource widely in the DCB consortia will provide a valuabletool for researchers and clinicians with varying computational expertise promoting inclusivedata sharing and accelerating discoveries in spatial transcriptomics. 152500 +No NIH Category available Advanced Malignant Neoplasm;Area;Atlas of Cancer Mortality in the United States;Attention;Binding;Bioinformatics;Biological Assay;Biology;Breast;California;Cancer Center;Cataloging;Catalogs;Cell Line;Cell Proliferation;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Complex;Copy Number Polymorphism;Cryoelectron Microscopy;Data;Dependence;Development;Disease;Expert Systems;FDA approved;Faculty;Funding;Gene Mutation;Genes;Genetic Diseases;Genetic Screening;Head and Neck Neoplasms;Heterogeneity;Image;Immunofluorescence Microscopy;Information Networks;Institution;Laboratories;Logic;Lung;Malignant Neoplasms;Maps;Mind;Mission;Modeling;Molecular;Mutation;NCI Center for Cancer Research;Neoplasm Metastasis;Other Genetics;PIK3CA gene;Pathogenesis;Pathway interactions;Patients;Pattern;Phenotype;Physiological;Point Mutation;Principal Investigator;Proliferating;Proteins;Research Personnel;Resources;Science;Scientist;Sister;Squamous Cell;Structural Models;Structure;System;Systems Biology;TP53 gene;Techniques;The Cancer Genome Atlas;Time;Training;Translating;Universities;anticancer research;cancer cell;cancer genome;cell motility;combinatorial;computerized tools;deep learning;driver mutation;drug response prediction;experimental study;genome-wide;interest;knockout gene;molecular modeling;mouse model;neoplastic cell;next generation;patient response;personalized medicine;precision medicine;precision oncology;pressure;protein complex;rare cancer;scale up;simulation;spatiotemporal;training opportunity;transfer learning;treatment response;tumor;tumor initiation Development of ex-vivo tumor culture for systems network biology and personalized medicine THE CANCER CELL MAP INITIATIVE v2.0OVERALL NARRATIVEAlthough much attention has been devoted to mapping the tumor genome understanding cancer requires thatwe move beyond simply cataloguing the genes associated with it. It is critical to understand the many interactionsamong these genes and the corresponding proteins and how these complex networks give rise to tumorinitiation progression and metastasis. The Cancer Cell Map Initiative (CCMI) is applying systematic approachesto comprehensively map the molecular networks that underlie cancer and to use these maps as key resourcesfor precision medicine. NCI 10830630 8/29/23 0:00 PA-20-272 3U54CA274502-02S1 3 U54 CA 274502 2 S1 "DUECK, HANNAH RUTH" 9/14/22 0:00 8/31/27 0:00 ZCA1(M2) 8727857 "KROGAN, NEVAN J" "IDEKER, TREY " 11 OTHER BASIC SCIENCES 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 152275 NCI 100000 52275 THE CANCER CELL MAP INITIATIVE v2.0OVERALL SUMMARYThe Cancer Genome Atlas and sister projects have now sequenced over 20000 tumor genomes providing acatalog of gene mutations copy number variants and other genetic alterations associated with cancer. Thesedata have made it clear that every cancer is a distinct genetic disease with tumors that look physiologicallysimilar often driven by patterns of gene mutations that are strikingly different. Due to this molecular heterogeneityit is typically unclear what are the key driver mutations or dependencies in a given cancer and how theseinfluence pathogenesis and response to therapy. One key observation for interpreting tumor genomes is that themany rare tumor mutations can be shown to converge on common molecular networks. Based on this premisewe created the Cancer Cell Map Initiative (CCMI) whose mission is to create comprehensive maps of cancermolecular networks and to use these maps in intelligent systems for personalized therapy. In 2017 the CCMIwas funded as an NCI U54 Research Center for Cancer Systems Biology integrating expertise in networkmapping bioinformatic analysis and cancer research from leading academic laboratories at two University ofCalifornia campuses (UCSF and UCSD). We have since generated comprehensive networks of proteininteractions in breast and head-and-neck tumor cells and from these data identified several hundred proteincomplexes under selective mutational pressure in cancer (NeST v1.0). We have piloted deep learning systems(DCell DrugCell and TCRP) that can use this protein network information to translate a patients tumor mutationprofile to a predicted drug response including FDA-approved and exploratory agents. We have implemented arich portfolio of training opportunities and leveraging UC institutional support expanded the CCMI consortiumto include more than a dozen faculty at UC and most recently Stanford. In the next five years the CCMI willseek to: (1) Generate comprehensive protein interaction networks centered on key cancer driver genes in lungsquamous cells (in healthy and diseased states) as well as the PIK3CA and TP53 pathways which are centralto many tumor types; (2) Systematically extend the CCMI collection of cancer protein interaction data with proteinimmunofluorescent imaging and cryo-electron microscopy to formulate multi-scale cancer cell maps; (3) Dissectthe functional logic of these networks and maps by systematic genetic screening experiments in the same tumortypes and pathways using a panel of scalable cell proliferation phenotype and pathway readouts; (4)Significantly advance and harden our DrugCell interpretable deep learning system for cancer precision medicine;(5) Train the current and next generation of scientists in network biology and its applications to cancer research;and (6) Continue to build a cadre of leading investigators to expand CCMI into a global coordinated partnership. 152275 +No NIH Category available Accounting;Address;Advanced Malignant Neoplasm;Age;Antineoplastic Agents;Black Populations;Cancer health equity;Clinical;Data;Disparity;Disseminated Malignant Neoplasm;Enrollment;Equity;Ethnic Population;Future;Genomics;Guide prevention;Health Insurance;Health Policy;Healthcare;Improve Access;Insurance;Insurance Benefits;Low income;Malignant Neoplasms;Medicare;Medicine;Oral;Oral Administration;Parents;Pathogenicity;Patients;Pharmaceutical Preparations;Policies;Risk;Role;Services;Testing;Variant;access disparities;beneficiary;cancer genomics;cancer therapy;design;effective therapy;ethnic disparity;experience;genetic testing;improved;interest;mortality;next generation;next generation sequencing;payment;primary outcome;racial disparity;racial population;response;socioeconomic disparity;targeted cancer therapy;targeted treatment;tumor Multilevel factors associated with disparities in the use of targeted cancer therapies in Medicare Medicare implemented a national coverage policy for next-generation sequence testing to improve access togenetic testing and use of targeted therapies. Despite the coverage expansion and clinical benefits ofgenetically targeted anticancer drugs little is known about whether there are disparities in somatic testing andthe related use of these therapies. This study examines whether the new coverage policy for genetic testingequitably addresses the use of both testing and orally prescribed genomically targeted anticancer drugs andinvestigates insurance factors associated with racial and socio-economic disparities. NCI 10830588 9/20/23 0:00 PA-20-272 3R01CA277599-02S1 3 R01 CA 277599 2 S1 "WEAVER, SALLIE JAYNE" 3/9/23 0:00 1/31/28 0:00 Special Emphasis Panel[ZRG1(90)-S] 3056913 "KINNEY, ANITA Y." "SCHWARTZ, MARC D" 10 BIOSTATISTICS & OTHER MATH SCI 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 9/15/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 125000 NCI 110750 14250 ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-044. Identification of patients with pathogenic variants is crucial to enable the use of treatment and guideprevention. Yet there are important racial disparities in genomic cancer medicine: for example Black personsexperience significant disparities in access to germline cancer genomic services and bear the largest cancermortality burden of any racial/ethnic group. Preliminary evidence suggests that there may also be disparities inthe use of genomically-targeted therapies. While the parent R01 focuses on well-known disparities in germlinecancer genomic risk testing considerably less is known about whether there are disparities in the use ofgenomically-targeted cancer therapies. We will assess these disparities and the potentially important role ofhealth policy factors as they relate to disparities among cancer cases ages in Medicare. In March 2018 toimprove Medicare beneficiaries access to targeted genomic cancer therapies CMS issued a nationalcoverage determination (NCD) paying for Next Generation Sequencing (NGS) based tumor genomic tests forpatients with advanced or metastatic cancer and no previous NGS testing. Implementing the new paymentpolicy by Medicare is intended to increase the use of genomically-targeted cancer treatments. However little isknown about how the implementation of the national policy for NGS testing has influenced disparities in theuse of genomically-targeted therapies. To inform future healthcare coverage policies around genomic cancermedicine it is important to assess whether the coverage policy equitably addresses access to effectivetreatment given the disparities observed in both genetic testing and targeted treatments. This study willaddress this gap. Using the most recent five years of SEER-Medicare Part D data we will first documentwhether the implementation of NCD for NGS testing has increased the use of genomically-targeted therapies.Then we will examine whether there are racial and socio-economic disparities in the use of these therapiesaccounting for the 2018 NCD for NGS testing. The use of selected genomically-targeted oral anticancer drugsbefore vs. after the NCD will be the primary outcome of interest. Policy-level variables will include healthinsurance factors such as patients Medicare Advantage enrollment low-income subsidy status and patientswith coordination of benefits from third parties. The specific aims of the proposed study are to 1) compare theuse of orally administered genomically-targeted cancer agents among Medicare beneficiaries before and afterthe implementation of the 2018 NCD policy for NGS testing; 2) examine racial-ethnic and socioeconomicdisparities in the use of oral genomically-targeted cancer drugs associated with insurance benefit designs.Findings from this study can be used to inform policy decisions for advancing cancer health equity andimproving access to genomically-targeted cancer therapies. This approach could be applied to other drugs andgenomic medications as well as value-based healthcare initiatives. 125000 +No NIH Category available Award;Breast Cancer Model;CDH1 gene;Cancer Etiology;Carcinogens;Cell Culture Techniques;Cell Membrane Proteins;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Credentialing;DNA Sequence Alteration;Duct (organ) structure;E-Cadherin;Endocrine;Engineering;Estrogen receptor negative;Estrogen receptor positive;Gene Expression;Genes;Genetic;Goals;Histopathology;Human;Injections;Laboratories;Lead;Lobular;Mammary Neoplasms;Mammary gland;Methods;Modeling;Mus;Mutate;Mutation;NF1 gene;Oncology;Organoids;PIK3CA gene;Parents;Proteins;Proto-Oncogenes;Publishing;Rattus;Reporting;Specimen;Testing;Virus;breast tumorigenesis;cancer initiation;clinically relevant;dimethylbenzanthracene;genetic manipulation;genome editing;in vivo;interest;malignant breast neoplasm;mammary;mammary gland development;mouse model;response;treatment strategy;tumor Mutating E-cadherin in rats to model lobular breast cancer The parent award R01CA271498 is focused on studying rat models of ductal breast cancer but it does notstudy invasive lobular breast cancer which accounts for up to 40000 cases yearly in the US. Invasive lobularbreast cancer is predominantly estrogen receptor-positive and is caused by loss of the cell membrane proteinE-cadherin. The goal of this supplement award is to engineer mutations into the gene encoding E-cadherin inrats to develop a clinically relevant rat model of estrogen receptor-positive invasive lobular breast cancer. NCI 10830164 7/24/23 0:00 PA-20-272 3R01CA271498-02S1 3 R01 CA 271498 2 S1 "NADEAU, CHRISTINE FRANCES" 3/14/22 0:00 2/28/27 0:00 8036125 "LI, YI " "ZHANG, XIANG " 9 ANATOMY/CELL BIOLOGY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 3/1/23 0:00 2/28/24 0:00 396 Non-SBIR/STTR 2023 174600 NCI 123600 51000 This application is being submitted in response to the Notice of Special Interest (NOSI) identified asNOT-CA-23-045.The parent award R01CA271498 is focused on studying rat models of ductal breast cancerbut it does not study invasive lobular breast cancer (ILC) which accounts for up to 40000 cases yearly in theUS. ILC is predominantly estrogen receptor-positive (ER+). Loss of E-cadherin (encoded by the CDH1 gene)is the pathognomonic feature of ILC being lost at the protein level in over 95% of cases while mutations ofCDH1 occur in 65% of cases. Genetic loss of CDH1 has not been engineered into rat mammary gland cells forstudying ILC but we now have the technical capabilities to engineer CDH1 mutations into rat mammaryglands. We predict that CDH1 loss will predispose rat mammary glands for ER+ ILC. In this supplement awardwe will team up with the Oesterreich-Lee laboratory which has extensive expertise in studying ILC usinghuman specimens cell culture and organoids of carcinogen-induced rat tumors. The goal is to develop aclinically relevant rat model of ER+ ILC. Two specific aims are pursued: Aim 1: Examine the effect of somaticCDH1 deletion on rat mammary gland development and function. This somatic CDH1 KO will be achievedusing our recently published method using intraductal injection of virus for high efficiency in vivo CRISPR-genome editing. Aim 2: Test whether the combination of somatic CDH1 deletion and PIK3CA activation orDMBA treatment results in rat ER+ mammary tumors with a histopathology and gene expression similar tohuman ILC. We select the combination of CDH1 KO and PIK3CA activation because CDH1 KO alone isunlikely to sufficient to cause cancer and because PIK3CA is the protooncogene most commonly mutated inhuman breast cancer including ILC. 174600 +No NIH Category available Address;Administrative Supplement;Cellular Phone;Clinical;Data;Enrollment;Feedback;Future;Goals;Interview;Literature;Monitor;Parents;Patients;Provider;Sampling;Structure;Symptoms;System;Time;Visualization;Work;acceptability and feasibility;cancer care;chemotherapy;clinical care;design;digital tool;future implementation;interest;machine learning model;machine learning prediction;mobile sensing;mobile sensor;parent grant;patient engagement;patient-clinician communication;preference;prototype;response;sensor;symptom self management;tool;wearable device;wearable sensor technology;web app Mobile sensors in cancer care: Patient and provider perspectives and impact on patient-provider communication The proposed administrative supplement builds on an ongoing study developingmachine learning models to predict real-time symptoms during chemotherapy usingmobile sensor data as input. This supplemental work aims to identify patient- andprovider-perceived barriers benefits and preferences related to how mobile sensortools and data could be used to support patient-provider communication duringchemotherapy and how to best support patient and provider use of these digital tools.Findings will address a gap in the literature about how wearable devices and otherpassive sensors might impact patient-provider communication and will inform futurework integrating mobile sensing into clinical cancer care. NCI 10830155 8/10/23 0:00 PA-20-272 3R37CA242545-05S1 3 R37 CA 242545 5 S1 "DIVI, RAO L" 7/1/19 0:00 6/30/24 0:00 Nursing and Related Clinical Sciences Study Section[NRCS] 10408330 "LOW, CARISSA A" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 96401 NCI 60630 35771 Mobile sensors in cancer care: Patient and provider perspectives and impact on patient-provider communicationThis application is being submitted in response to the Notice of Special Interest (NOSI)identified as NOT-CA-23-041. The goal of the parent grant R37CA242545 is to developa system that uses smartphone and wearable sensors to passively monitor symptomburden during chemotherapy. The parent study aims to develop machine learningmodels predicting next-day symptoms using mobile sensor features as input tointegrate these predictions into a patient-facing web application and to evaluate thefeasibility and acceptability of using these predictions to trigger symptom self-management advice or patient-provider communication. The proposed administrativesupplement will focus on understanding patient and provider preferences forintegrating mobile sensor-based metrics and predictions into clinical care in ways thatsupport patient-provider communication. We will conduct semi-structured and designinterviews with patients (n = 20) and providers (n = 20) that are participating in theparent study using purposive sampling to enroll both highly and less engagedparticipants. We will develop several mid-fidelity prototypes that (1) visualize patientsown sensor data from the parent grant and (2) visualize and explain sensor-basedpredictions about next-day symptoms. Specific aims of this supplement are (1) toidentify barriers benefits and preferences related to how mobile sensor tools and datacould be used to support patient-provider communication during chemotherapy andhow to best support patient and provider use of these digital tools and (2) to obtainpatient and provider feedback on prototypes and visualizations. Findings from thissupplemental study will be used to support patient and provider engagement with ourmobile sensing system to add new features supporting patient-providercommunication and to address potential barriers to future implementation. Results willalso address a gap in the literature about how wearable and other passive sensors mightimpact patient-provider communication and will inform future work integrating mobilesensing into clinical cancer care. 96401 +No NIH Category available Acute Myelocytic Leukemia;Adult;Age;Aging;Automobile Driving;Bar Codes;Blood;Bone Marrow;Cardiovascular Diseases;Cell Aging;Cell secretion;Cells;Contracts;Data;Development;Disease;Elderly;Environment;Epigenetic Process;Evolution;Foundations;Gene Mutation;Health;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Heterogeneity;Immune;Inflammatory;Knowledge;Longevity;Malignant Neoplasms;Mus;Outcomes Research;Pathway interactions;Phenotype;Prevention;Prevention strategy;Production;Proliferating;Rejuvenation;Risk;Somatic Mutation;Testing;Transplantation;Wild Type Mouse;Work;age related;aged;anticancer research;bone aging;cytokine;fitness;forging;human old age (65+);interest;leukemia;novel therapeutics;post-transplant;preventive intervention;response;senescence;single-cell RNA sequencing;stem cell function;stem cells;transcriptomics The impact of reduction of cellular senescence on age-related epigenetic heterogeneity PROJECT NARRATIVEAcute myeloid leukemia (AML) is a deadly blood cancer that occurs mostly in adults over 65 and is associatedwith the abnormal overproliferation of blood stem cells a common age-related condition called 'clonalhematopoiesis' (CH). Although we know that aging and specific gene mutations in the blood stem cells contributeto the development of CH and its progression to AML we do not understand how old age and CH interact topromote the evolution of AML. Here we will elucidate how aging and CH influence the propensity of blood stemcells to adapt to altered environments (evolvability) which could not only forge a new paradigm for ourunderstanding of leukemia onset but also provide candidate pathways for the development of preventativeinterventions. NCI 10830053 8/14/23 0:00 PA-20-272 3U01CA271830-03S1 3 U01 CA 271830 3 S1 "KLAUZINSKA, MALGORZATA" 9/23/21 0:00 8/31/26 0:00 ZCA1(O1)-R 12243946 "LI, SHENG " "DEGREGORI, JAMES V" 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 201295 NCI 108223 93072 PROJECT SUMMARYThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. The decline in hematopoietic stem and progenitor cell (HSPC) function with aging can lead to improperblood and immune cell production contributing to reduced health and life span. Aged HSPCs accumulatesomatic mutations that confer a selective fitness advantage leading to clonal hematopoiesis (CH) a bloodphenotype that increases the risk of leukemia and various diseases of aging including cardiovascular diseases.Cellular senescence a hallmark of aging is another potent extrinsic candidate driver for age-related CH in thebone marrow microenvironment. Senescent cells secrete inflammatory factors that can influence the functionand differentiation of surrounding cells including cytokines that are crucial for driving CH. Determining the impactof reducing cellular senescence on the epigenetic heterogeneity of HSPC in aged bone marrow of mice issignificant for aging and cancer research given that greater epigenetic heterogeneity of HSPC with age shouldalter both stem cell functionality in hematopoiesis and increase the odds of leukemic progression. We will testthe hypothesis that rejuvenating the bone marrow microenvironment by reducing senescence will reduceepigenetic heterogeneity of HSPC. This knowledge can contribute to the development of novel therapeutic andpreventative strategies for mitigating age-related blood disorders ultimately benefiting prevention of bothhematopoietic decline and increased blood malignancy risk in the elderly. To follow the fate of specific subclonesof HSCs we will uniquely barcode thousands of HSC from old wildtype mice which will be transplanted intothree groups of host mice with vehicle or senolytic treatment to determine how aged vs. rejuvenated BMmicroenvironment influences HSPC heterogeneity. We will use scRNA-seq and snATAC-seq analysis to identifycell cluster-associated epigenetic and transcriptomic signatures and associated heterogeneity for expanded vs.contracted HSC clones. We will also identify senescence-dependent epigenetic signatures and associatedheterogeneity from post-transplantation snATAC-seq data. The expected outcomes of this research will be todetermine the impact of cellular senescence reduction on the epigenetic heterogeneity of HSPC in aged bonemarrow of mice and identify the specific pathways that are modulated given the rejuvenated less inflammatorymicroenvironment. This work can provide a mechanistic foundation for understanding the initiation of age-relatedblood disorders. 201295 +No NIH Category available Acceleration;Adenocarcinoma Cell;Affect;Alveolar;Binding;Bypass;Caring;Cell Line;Cell Proliferation;Cell Survival;Cells;Clinical;Collaborations;DNA Sequence Alteration;Data;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epigenetic Process;Experimental Models;Exposure to;Frequencies;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic;Genetic Determinism;Genetic Epistasis;Genetic Transcription;Genetically Engineered Mouse;Goals;Human;In Vitro;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Mesenchymal;Modeling;Molecular;Mouse Strains;Mutation;Nature;Neurosecretory Systems;Non-Malignant;Oncogenic;Organoids;Patient Care;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Play;RB1 gene;Recurrence;Research;Research Personnel;Residual Neoplasm;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;Study models;TP53 gene;Testing;Therapeutic;Variant;acquired drug resistance;cancer cell;clinically relevant;experimental study;genetically modified cells;improved;in vivo;inhibitor therapy;interest;loss of function mutation;mutant;non-genetic;novel;off-target mutation;programs;response;standard of care;synergism;targeted treatment;therapeutic development;therapeutic gene;therapy outcome;therapy resistant;transdifferentiation;treatment response;tumor microenvironment;tumor-immune system interactions;virtual YAP1 and RB1 cooperate to regulate lung cancer lineage plasticity and therapeutic resistance Project NarrativeEGFR tyrosine kinase inhibitors (EGFR TKI) are standard of care for patients with advanced EGFR mutantlung cancer but they are not curative because of acquired therapeutic resistance. This application will identifymolecular determinants of lung cancer lineage plasticity that contribute to acquired EGFR TKI resistance. NCI 10829724 9/18/23 0:00 PA-20-272 3U24CA274159-02S2 3 U24 CA 274159 2 S2 "SAID, RABIH" 9/1/22 0:00 8/31/27 0:00 ZCA1(M1) 1898849 "GOODRICH, DAVID W." "GOODRICH, DAVID W.; LIU, SONG ; MORGAN, MARTIN T" 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Other Research-Related 2023 85850 NCI 50000 35850 PROJECT SUMMARYThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Patients with EGFR mutant lung adenocarcinoma (LUAD) are treated with EGFR tyrosine kinaseinhibitors (TKI) because they yield better patient outcomes than previous standards of care. EGFR TKI are notcurative however as virtually all patients progress on therapy due to acquired drug resistance. While geneticmechanisms of acquired EGFR TKI resistance are well understood non-genetic mechanisms also play animportant role. Dynamic and reversible transcriptional adaptations involving lineage state changes support thesurvival and progression of LUAD cells during treatment. The mechanisms and genetic determinants controllingthis LUAD lineage plasticity are not well understood. Advancing fundamental understanding of LUAD lineageplasticity is a prerequisite for the development of therapeutic approaches to predict it suppress it and improvetherapeutic outcomes. Through analysis of both clinical specimens and experimental models the collaboratinginvestigators have discovered that minimal residual disease surviving EGFR TKI shows induction of a quiescentalveolar lineage state. This state is lost in cells proliferating and progressing through EGFR TKI and is replacedby alternative lineage states less dependent on oncogenic EGFR signaling. In currently parallel lines of researchwithin the collaborating investigators labs YAP1 activity has been demonstrated to drive the alveolar lineagestate while RB1 loss accelerates the further transition to alternative EGFR independent lineage states. Thesefindings suggest YAP1 and RB1 interact to control lineage state transitions during EGFR TKI therapy thatultimately facilitate acquired therapeutic resistance. This ARTNET supplement application is proposed tosupport collaborative research in two specific aims that will test this hypothesis and validate new geneticallyengineered mouse models for studying LUAD lineage plasticity in vivo additionally enabling the study of hownon-malignant cells within the tumor microenvironment influence LUAD lineage plasticity and vice versa. 85850 +No NIH Category available Research;Scholars Program;health care delivery;visiting scholar HEALTHCARE DELIVERY RESEARCH VISITING SCHOLARS PROGRAM n/a NCI 10829323 75N91022P00839-P00001-0-1 N02 9/1/22 0:00 8/31/24 0:00 78844050 "KING, TAMIKA " Not Applicable 98 Unavailable 804535342 ERAEDE6KENE6 804535342 ERAEDE6KENE6 US 38.905341 -77.038765 1638101 ACADEMYHEALTH WASHINGTON DC Other Domestic Non-Profits 200364647 UNITED STATES N R and D Contracts 2023 54877 NCI NCI support for HEALTHCARE DELIVERY RESEARCH VISITING SCHOLARS PROGRAM 54877 +No NIH Category available Affect;Asian population;Award;Baltimore;Basic Science;Behavior;Biology;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Catchment Area;Cigarette;Cities;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Comprehensive Cancer Center;County;Dentistry;Detection;Discipline of Nursing;Doctor of Medicine;Education;Ethnic Origin;Faculty;First Independent Research Support and Transition Awards;Flow Cytometry;Funding;Future;Genomics;Head Cancer;Human;Image;Investigational Therapies;Investments;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maryland;Medical;Medical center;Middle School Student;Minority;Minority Groups;Mission;Molecular;Molecular Biology;Names;National Cancer Institute;Neck;Participant;Pathology;Patient Care;Patient Participation;Patients;Pharmacy Schools;Pharmacy facility;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention Research;Prevention strategy;Public Health Schools;Reporting;Research;Research Activity;Research Design;Research Personnel;School Dentistry;School Nursing;Schools;Screening for cancer;Services;Structure;Students;System;Talents;Therapeutic;Therapeutic Trials;Training;Translational Research;Translations;Underrepresented Minority;Universities;Work;acronyms;anticancer research;biobank;cancer care;cancer health disparity;cancer therapy;clinical care;clinical phenotype;clinical training;clinically relevant;college;community based research;design;fundamental research;health disparity;healthy lifestyle;hormone related cancer;innovation;medical schools;member;minority communities;mortality;multidisciplinary;neoplasm immunotherapy;news;patient-clinician communication;prevent;programs;racial diversity;science education;smartphone application;standard of care;structural biology;tumor immunology;tumor registry;virology Patient-provider communication about healthy lifestyle behaviors facilitated by a smartphone app 1.1 Project Narrative: OverallThe mission of the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center(UMGCCC) is to undertake innovative basic and clinical and population research that will impact theunderstanding and treatment of cancer around the world and to provide state-of-the-art clinical care to cancerpatients in Maryland and beyond. NCI 10829156 9/1/23 0:00 PA-20-272 3P30CA134274-16S2 3 P30 CA 134274 16 S2 "BELIN, PRECILLA L" 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 1967833 "CULLEN, KEVIN J." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 97752 NCI 62723 35029 1.0 Abstract: OverallOur strategy at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center(UMGCCC) is to take advantage of discoveries in basic cancer biology in conjunction with clinical populationand prevention research to (a) develop and apply innovative therapeutic and preventive strategies to cancerpatients (b) describe the molecular mechanisms involving specific clinical phenotypes and behaviors (c) applydiscoveries and strategies to the Maryland community with a specific focus on cancer disparities and (d) providetraining in cancer biology and cancer care for students fellows clinicians and staff. These strategies collectivelywill serve the clinical and research missions of the Cancer Center for the Maryland community well into thefuture. In this application UMGCCC seeks the second competitive renewal of the Cancer Center Support Grant(CCSG) which was first awarded to UMGCCC in August 2008; Comprehensive designation was awarded in2016. For this application UMGCCC is represented by 137 full and 88 associate members working in 5 researchprograms unchanged since our 2015 application. The application describes seven shared services. UMGCCCprovides an effective structure to support the multidisciplinary cancer research activities of this talented group ofinvestigators. Total direct cancer funding is $79.1 million with $14.2 million from the National Cancer Institute.Direct cancer funding has increased 70 percent in the last cycle. In 2019 UMGCCC served 3095 new cancerpatients. In the last funding cycle a total of 9702 patients participated in clinical trials. Fifty-six percent of allparticipants in clinical trials were minorities reflecting UMGCCC's unique position and mission to involve theminority community in state-of-the-art clinical and translational research. This includes 48.2 percentunderrepresented minorities as well as 7.8 percent Asians the latter reflecting clinical trials examining healthdisparities in that group. Underrepresented minority accrual to therapeutic trials is 34.7 percent. UMGCCCcontinues to make outstanding contributions to understanding cancer biology and important recent work fromUMGCCC labs and clinics is now the standard of care or in advanced clinical trials. The U.S. News & WorldReport ranking of U.S. cancer programs has named UMGCCC in the top 50 for 13 consecutive years. Reflectingremarkable and continued progress UMGCCC seeks to renew its CCSG to enhance and expand its efforts andsupport high-quality and clinically relevant cancer research. 97752 +No NIH Category available Adopted;Aneuploidy;Automobile Driving;Cancer Biology;Cancer Model;Cell Culture Techniques;Cell membrane;Cells;Cellular biology;Charge;Chromosomes;Chronic;Clinical and Translational Science Awards;Collaborations;Colorectal Cancer;Complex;Couples;Cultured Cells;Data;Decision Making;Dedications;Defect;Disease;Ecosystem;Education;Elements;Epidermal Growth Factor Receptor;Eukaryota;Faculty;Fostering;Genetically Engineered Mouse;Genomics;Glioblastoma;Goals;Growth;Image;Immunofluorescence Immunologic;Indirect Immunofluorescence;Institution;Joints;KRAS2 gene;Lead;Leadership;Length;Lesion;Life;Malignant Neoplasms;Malignant neoplasm of brain;Mentorship;Metabolic;Metaphase;Metastatic Neoplasm to the Liver;Mitochondria;Mitotic;Modeling;Mutation;NCI Center for Cancer Research;Neoplasm Metastasis;Oncogene Activation;Oncogenes;Oncogenic;Organelles;Pathway interactions;Phase;Phenotype;Pilot Projects;Play;Positioning Attribute;Primary Neoplasm;Process;Proliferating;Records;Recurrence;Research;Research Personnel;Research Project Grants;Resolution;Resource Sharing;Resources;Rest;Role;Secondary to;Signal Transduction;Site Visit;Standardization;Stress;Structure;System;Systems Analysis;Systems Biology;Testing;Training;Universities;Virginia;Vision;cancer cell;cancer type;career;cell type;clinical practice;cost;experimental study;feature detection;feature extraction;image registration;innovation;interoperability;learning strategy;malignant breast neoplasm;mitochondrial membrane;multidisciplinary;mutant;outreach;programs;repaired;residence;response;success;summer research;transcription factor;tumor;tumorigenesis;undergraduate research experience Open phase-separation models for cancer systems biology PROJECT NARRATIVECancers cannot initiate or progress if their subcellular components are unable to overcome the stresses thataccompany uncontrolled proliferation and growth. This Center seeks a predictive understanding of subcellularadaptations that must take place to accommodate and subvert the stresses that naturally occur in response tocancer-causing genetic alterations. Successful models of such adaptations will lead to secondary inferencesabout where cancer cells become vulnerable as a result of their internal adaptations. NCI 10829012 8/16/23 0:00 PA-20-272 3U54CA274499-02S1 3 U54 CA 274499 2 S1 "DUECK, HANNAH RUTH" 9/12/22 0:00 8/31/27 0:00 ZCA1(M2) 9677317 "JANES, KEVIN A" "LAZZARA, MATTHEW J" 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 166402 NCI 116489 49913 PROJECT SUMMARY/ABSTRACTOncogene activation is modulated by normal subcellular compartments that execute specialized functionsrelated to hallmark cancer phenotypes. These organelles must adapt to oncogenic stress in order for tumorsto initiate and progress but there is little to no systems-level understanding of how such adaptations occur andwhat vulnerabilities might be created. The Systems Analysis of Stress-adapted Cancer Organelles (SASCO)Center at the University of Virginia will address this challenge by mechanistic modeling of organellar processesthat iterates with quantitative experiments in disease-relevant cell cultures and primary tumors. The workingSASCO Center hypothesis is that organelle-specific adaptation to oncogenic stress occurs through a fewcritical bottlenecks which become identifiable once the relevant signaling metabolic and transport pathwayshave been properly integrated. The Center brings together 14 investigators with primary and collaborativetrack records in cancer biology systems biology genetically engineered mouse models of cancer and clinicalpractice. Three Research Projects and one Shared Research Core will pursue a common research strategywhich leverages mechanistic models to test competing alternative hypotheses about how organelles adapt tostresses from proximal oncogenes that drive specific types of cancer. The Projects are organizedhierarchically as organelle stresses downstream of proliferation-inducing oncogenes. Project 1 will examinethe chromosome passenger complex and its regulated phase separation during metaphase as an organellethat senses and repairs spindle defects to suppress breast cancer aneuploidy driven by mitotic transcriptionfactors. Project 2 will evaluate the metabolic consequences of chronic mitochondrial fragmentation caused bymutant KRAS in primary colorectal cancers and secondary liver metastases. Project 3 will investigate localizedsignal-transduction rebalancing as a mechanism for alleviating plasma-membrane stress caused by EGFRamplification in glioblastoma. All Research Projects will rely on the High-Content Imaging & Analysis Core toobtain iterative multichannel immunofluorescence data with organelle-level resolution and quantification. TheSASCO Outreach Core amplifies ongoing programs at the University of Virginia to provide summer researchexperiences for undergraduates and faculty scholars from historically underrepresented backgrounds as wellas introductory systems biology modeling materials for clinicians across the Commonwealth of Virginia. TheSASCO Center will thus create a national headquarters for subcellular cancer systems biology within thebroader Cancer Systems Biology Consortium. 166402 +No NIH Category available Abstinence;Adult;Affect;Affective;Behavior;Cancer Control;Cigarette;Cigarette Smoker;Data;Decision Making;Disease;Down-Regulation;Event;Fire - disasters;Functional Magnetic Resonance Imaging;Future;Goals;Health Professional;Health Promotion;Health behavior;Individual;Individual Differences;Informal Social Control;Intervention;Knowledge;Lateral;Light;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Medial;Motivation;Multivariate Analysis;Neurophysiology - biologic function;Participant;Pathway interactions;Pattern;Personality Traits;Persons;Poverty;Process;Provider;Psychology;Public Health;Regulation;Reporting;Research;Risk;Sample Size;Sampling;Scanning;Science;Smoke;Smoker;Smoking;Stimulus;System;Techniques;Testing;Theoretical model;Time;Training;Triage;United States;Up-Regulation;Work;arm;cigarette craving;cigarette smoking;cognitive process;cognitive reappraisal;cost;craving;efficacy trial;experience;experimental study;fighting;insight;lens;neural;neuroimaging;neuromechanism;novel;personalized medicine;personalized strategies;preventable death;response;smoking cessation;theories;tobacco control;tool;treatment as usual;treatment response Construal level as a novel pathway for affect regulation and cancer control 8. Project NarrativeCigarette smoking is among the leading causes of preventable death in the United States because smokingincreases risk for lung cancer and various diseases. Though U.S. smoking rates have declined a substantialpercentage of adults particularly those living in poverty who have repeatedly tried and failed to quit still smokeand therefore could benefit from novel interventions for cessation that operate through different mechanismsthan those of traditional treatments. This study will use neuroimaging to uncover the mechanisms of action of apromising strategy for affect regulation and smoking cessation and also build profiles of individuals for whomthis strategy does and does not work thereby providing tangible and practical information that public healthprofessionals and clinicians can use to inform personalized treatments for cigarette smoking cessation. NCI 10828952 5/31/23 0:00 PAR-18-681 3R01CA240452-04S2 3 R01 CA 240452 4 S2 "FERRER, REBECCA" 3/1/20 0:00 3/31/25 0:00 Addiction Risks and Mechanisms Study Section[ARM] 9164882 "BERKMAN, ELLIOT TODD" Not Applicable 4 PSYCHOLOGY 79289626 Z3FGN9MF92U2 079289626; 948117312 J2KGU972RXG3; Z3FGN9MF92U2 US 44.045509 -123.069741 6297005 UNIVERSITY OF OREGON EUGENE OR SCHOOLS OF ARTS AND SCIENCES 974035219 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 143062 NCI 96991 46071 7. Project Summary/AbstractLung cancer is the leading major cause of preventable death in the United States and cigarette smoking is acontributor to lung cancer in 80%90% of cases. Though adult cigarette smoking rates have declinedsubstantially during the past 50 years they remain as high as 30% in certain groups such as individuals livingin poverty. Quitting is difficult: a given quit attempt results in cessation in fewer than 10% of cases and mostadult cigarette smokers have attempted and failed to quit and often many times. What is urgently needed arenovel interventions for cigarette smoking cessation that operate through different mechanisms from thosetargeted by existing interventions which are likely to have been unsuccessful for persistent smokers. A barrierto progress is that the mechanisms of action of most treatments are not known which makes it difficult to knowwhich treatment will work best for whom. We turn to affective science to identify a candidate technique thatcould serve as the basis for a novel intervention. Research on affect regulation typically focuses on down-regulation of affective states such as craving for cigarettes using effortful strategies such as cognitivereappraisal. However a new insight in affect regulation is that people can construe or subjectively understandevents with varying levels of abstraction and that construing health-related behaviors in high- versus low-levelterms promotes health behavior in several domains. For example smokers who want to quit are more likely toresist a cigarette when they construe the same event (e.g. abstinence) in more abstract high-level terms(e.g. becoming a better me) versus more concrete low-level terms (e.g. not smoking this cigarette). Thereis some evidence that high-level construal might rely on distinct mechanisms from traditional affect regulationand smoking reduction interventions but its mechanisms of action are unknown. Directly comparing itsmechanisms to those of alternative affect regulation strategies and developing tools to induce high-levelconstrual are the next steps on the path toward developing a novel intervention. Also establishing individualdifferences in the effects of high-level construal will allow future interventions to be targeted to the individualsfor whom they will be maximally effective. We identified two candidate mechanisms through which high-levelconstrual might operate: down-regulation of craving and up-regulation of goal energization (i.e. motivation toquit). Functional magnetic resonance imaging (fMRI) revealed the neural systems engaged by those processesto be distinct. So we will use multivariate analyses of fMRI data to quantify the similarity of high-level construalto each candidate (Aim 1). This will be done in a longitudinal translational experiment with 4 conditionshigh-level construal down-regulation of craving up-regulation of goal energization and treatment-as-usualin asample of persistent smokers in poverty who are the most likely to benefit from a novel theory-basedtreatment. The sample size (N = 240) affords an examination of individual differences in the effect of high-levelconstrual on neural activity and craving and the degree to which they predict smoking reduction (Aim 2). 143062 +No NIH Category available Address;Androgen Receptor;Androgens;Automobile Driving;Autophagocytosis;Bioenergetics;Biological Availability;Cancer Biology;Cancer Cell Growth;Cancer Etiology;Catabolism;Cell Line;Cell physiology;Cessation of life;Cholesterol;Clinical;Combined Modality Therapy;Disease;FRAP1 gene;Fatty Acids;Feedback;Genotype;Growth;Heterogeneity;Homeostasis;In Vitro;Lipids;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator;Metabolic;Metabolism;Metastatic Prostate Cancer;Mitochondria;Modeling;Nature;Normal Cell;Oncogenic;Oral;Organoids;PI3K/AKT;PIK3CG gene;Pathway interactions;Phase;Phenotype;Play;Proliferating;Prostate Cancer therapy;Protein Biosynthesis;Proteins;Public Health;Receptor Cross-Talk;Receptor Signaling;Refractory;Regulation;Resistance;Resistance development;Role;Scaffolding Protein;Series;Signal Pathway;Signal Transduction;Technology;Therapeutic Agents;Toxic effect;Up-Regulation;abiraterone;androgen deprivation therapy;antitumor effect;cancer cell;castration resistant prostate cancer;cell growth regulation;cohort;deprivation;design;enzalutamide;fatty acid oxidation;improved;in vitro Model;in vivo;inhibitor;lipid biosynthesis;lipid metabolism;lipidomics;men;novel;novel strategies;novel therapeutic intervention;patient derived xenograft model;prostate cancer cell;prostate cancer model;prostate cancer progression;protein metabolism;proteostasis;receptor;resistance mechanism;small molecule inhibitor;small molecule therapeutics;standard of care;targeted agent;targeted treatment;treatment strategy;tumor;tumor growth;tumor metabolism;uptake Multifunctional Regulation of Prostate Cancer Metabolism by Sigma1 Modulators NARRATIVE STATEMENTThese studies are relevant to public health because despite considerable progress in our understanding ofprostate cancer biology prostate cancer remains a significant cause of suffering and the second leading causeof cancer death among men and there is a pressing need for new and better approaches to treatment. Theremarkably adaptive nature and complexity of prostate cancer progression and the uniform development ofresistance underscores the importance of developing a broader range of therapeutic agents and approachesthat would increase chances of overcoming the resistance to current therapies. This proposal focuses onelucidating how a novel small molecule therapeutic agent may be used to treat prostate cancer by regulating anovel target and an under-exploited cellular process in cancer cells. NCI 10828305 12/8/23 0:00 PA-19-056 5R01CA244749-05 5 R01 CA 244749 5 "MERCER, NATALIA" 1/13/20 0:00 12/31/24 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 10788380 "KIM, FELIX JINHYUN" Not Applicable 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 566281 NCI 419611 146670 Abstract: Prostate cancer (PCa) is a remarkably adaptive disease. First line therapy for PCa is androgendeprivation. However resistance invariably emerges resulting in a lethal phase termed castration-resistant PCa(CRPC). Even with the profound AR-targeting achieved by current standard of care agents abiraterone andenzalutamide CRPC remains incurable. CRPC is characterized by multiple compensatory signalingmechanisms including reciprocal activation of PI3K/Akt/mTOR signaling and AR-ErbB receptor cross-talk.Notably these pathways converge on the signaling networks feedback loops and cellular mechanisms thatmediate oncogenic lipid metabolism which is now recognized as a central driver of CRPC growth andprogression. Meaningful improvement in anti-tumor efficacy is likely to require novel strategies thatsimultaneously target the AR axis and the network of compensatory signaling pathways on which CRPC depends.We have identified Sigma1 as a multi-functional scaffolding protein that is aberrantly expressed in PCa and thatit is required for PCa cell growth proliferation. Sigma1 allosterically modulates cancer-specific associatedproteins involved in driving oncogenic lipid metabolism including AR and ErbB receptors. Sigma1 also regulatescellular lipid and protein homeostasis pathways and plays a critical role in supporting the increased demand forlipid and protein synthesis associated with tumor growth. We have developed a series of novel small moleculeinhibitors of Sigma1 that disrupt lipid homeostasis and induce targeted degradation of AR and ErbB receptors inPCa cells resulting in inhibition of PCa growth in vitro and in vivo with minimal toxicity to normal cells. Theoverarching problem addressed in this proposal is how to target the critical mechanisms by which lethal CRPCbecomes resistant to AR-targeted therapy. We hypothesize that Sigma1 serves as a multifunctional nexusbetween oncogenic driver proteins and lipid metabolism in PCa such that Sigma1 inhibition disrupts not onlykey drivers of tumor growth and lipid metabolism (AR ErbB) but also inhibit their downstream and convergentpathways. In Aim 1 we will define a novel Sigma1-AR-ErbB/PI3K/mTOR-lipid metabolism pathway and feedbackloop that engages ErbB/PI3K signaling in CRPC. We will show that the anti-tumor efficacy of Sigma1 inhibitorsin PCa is due to suppression of this pathway as well as disruption of key convergent and complementary cellularprocesses critical for PCa growth fueled by lipid metabolism. In Aim 2 we will demonstrate the efficacy of Sigma1inhibition in a cohort of patient derived xenograft (PDX) models that encompass the genotypic and phenotypicheterogeneity of CRPC using in vitro organoid and in vivo tumor models. Inhibition of Sigma1 in PCa representsa novel therapeutic approach that targets multiple interdependent mechanisms involved in CRPC progression anddevelopment of resistance and it provides a rational basis for designing vertical and horizontal combinationtreatment strategies to block the enhanced lipid metabolism that fuels lethal treatment-refractory CRPC. 566281 +No NIH Category available Address;Area;Atmosphere;Awareness;California;Cells;Chemicals;Clinic;Collaborations;Communities;DNA;DNA Damage;DNA Repair;DNA Repair Pathway;Disabled Persons;Drug Targeting;Ethnic Population;Exposure to;Faculty;Feedback;Fostering;Future;Gender;Genome Stability;Genomic Instability;Goals;Individual;Institution;Laboratories;Los Angeles;Malignant Neoplasms;Mentors;Mutagenesis;Oral;Positioning Attribute;Postdoctoral Fellow;Principal Investigator;Recurrent Malignant Neoplasm;Research;Science;Science Technology Engineering and Mathematics;Scientist;Senior Scientist;Sex Orientation;Signal Transduction;Students;Time;Underrepresented Populations;Universities;Woman;cancer recurrence;cancer therapy;cancer type;career;career development;disadvantaged background;driving force;environmental mutagens;experience;frontier;graduate student;improved;marginalized population;meetings;member;novel;novel therapeutics;peer;posters;racial population;response;socioeconomic disadvantage;symposium 2023 SoCal Genome Stability Symposium PROJECT NARRATIVEMany novel cancer therapies have been developed to target genomic instability which is a hallmark and adriving force of cancer. These new therapies are currently moving from the lab to the clinic and we are poisedfor a rapid expansion of new DNA repair pathway-targeting drugs that will be used to eliminate different typesof cancer. The 2023 SoCal Genome Stability Symposium will focus on research related to genomic instabilityand its implications in cancers and therapies. NCI 10828290 12/7/23 0:00 PA-21-151 1R13CA287953-01 1 R13 CA 287953 1 "SHARMAN, ANU" 12/7/23 0:00 11/30/24 0:00 ZCA1-PCRB-9(O1) 10556025 "CHIOLO, IRENE E" Not Applicable 37 BIOCHEMISTRY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA GRADUATE SCHOOLS 900894304 UNITED STATES N 12/7/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 5000 NCI 5000 0 ABSTRACTThe 2023 SoCal Genome Stability Symposium is a one-day conference that will be held at the University ofSouthern California Los Angeles. The conference will focus on genomic instability DNA mutagenesisenvironmental mutagens DNA damage signaling mechanisms of DNA repair and their implications in cancersand therapies. In recent years many novel cancer therapies have been developed to target DNA repairpathways. These new therapies are currently moving from the lab to the clinic and we are poised for a rapidexpansion of DNA repair pathway-targeting drugs that will be used to treat different types of cancer. At thesame time treatments can induce DNA damage accumulation and cancer recurrences. Thus understandingthe mechanisms of DNA repair and cell responses to DNA repair-targeting chemicals is necessary to improvetreatments. At the conference graduate students and postdoctoral fellows from laboratories located inSouthern California will present their ongoing unpublished research. The goals and objectives of theconference are: 1) to expose students and postdocs to the new frontiers of rapidly progressing research areascritically important to addressing cancer; 2) to provide a formal platform for presentations to trainees and anopportunity to receive feedback on their research progress; 3) to stimulate new collaborations betweenlaboratories across different research institutions; 4) to catalyze opportunities for young scientists to networkwith a diverse group of scientists including by receiving formal and informal mentoring and by opening futurepostdoctoral or faculty position opportunities; 5) to provide an atmosphere of inclusion and rigor for the traineesparticipating in the symposium. The symposium will enhance interactions among students and postdoctoralfellows from all genders backgrounds and origins including historically marginalized groups such as thosefrom underrepresented racial and ethnic groups individuals with disabilities individuals with different sexualorientations and individuals from socioeconomically disadvantaged backgrounds. Broader awareness of thefield gained through local meetings such as this is particularly important to prepare trainees for their nextcareer stages as postdoctoral fellows principal investigators or other careers in science. 5000 +No NIH Category available Address;Adoption;Characteristics;Chemotherapy-Oncologic Procedure;Clinical;Cloud Computing;Cloud Service;Communities;Computers;Cost Analysis;Costs and Benefits;Cyclophosphamide;Data;Data Analyses;Data Set;Dependence;Discipline of Nursing;Education;Educational workshop;Engineering;Environment;Evaluation;Extramural Activities;Fatigue;Genomics;Knowledge;Machine Learning;Malignant Neoplasms;Maps;Memory;Methylation;Modeling;Molecular;Nurses;Nursing Research;Parents;Pathway interactions;Patients;Performance;Phenotype;Predictive Cancer Model;Quality of life;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Running;Scientist;Severities;Time;Validation;analysis pipeline;analytical tool;associated symptom;common symptom;computing resources;design;experience;machine learning pipeline;parent grant;predictive modeling;prevent;risk prediction model;symptom science;tool;trait;transcriptome sequencing;transcriptomics An Evaluation of Cloud Computing for Symptom Science Research: Moving Genomics and Machine Learning Analyses of Cancer Chemotherapy-Related Fatigue to the Cloud Using on premises computing resources the parent grant evaluated for associations betweenphenotypic and molecular characteristics associated with changes in cancer-related fatigue(CRF) and developed prediction models to assist clinicians to determine which patients aremost likely to experience high levels of CRF. Given the high computational resources neededfor these analyses and the need for increased adoption of genomics and machine learningapproaches in symptom science our first objective is to deploy and assess the resourcedemanding analyses to the cloud. Our second objective is to provide a description of theexperience and provide recommendations for nursing and symptom science researchers in thedeployment of analyses to the cloud. NCI 10827722 9/6/23 0:00 PA-20-272 3R37CA233774-05S1 3 R37 CA 233774 5 S1 "HECKMAN-STODDARD, BRANDY" 7/3/19 0:00 6/30/24 0:00 Nursing and Related Clinical Sciences Study Section[NRCS] 11975518 "KOBER, KORD MICHAEL" Not Applicable 11 OTHER HEALTH PROFESSIONS 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF NURSING 941432510 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 242197 OD 149967 92230 Cancer-related fatigue (CRF) is the most common symptom associated with cancer and its treatments.Moderate to severe CRF has a negative impact on patients ability to tolerate treatments as well as on theirquality of life. The parent grant addressed two of the major knowledge gaps for CRF: the lack of a riskprediction model and a lack of knowledge of its underlying mechanisms. Given these analyses are data andresource intensive they are unavailable to many symptom science researchers. In terms of implementationtwo of the major gaps for symptom science researchers are the lack of access to the necessary computationalresources and a lack of understanding of benefits and costs of a cloud deployment. Symptom science is aprominent research focus for many extramural and intramural nurse scientists. An evaluation of the analyticpipelines of the parent grant would identify resource intensive analyses that could be efficiently deployed to thecloud. Given the potential benefits of cloud services increased knowledge of the opportunities for using thecloud for symptom science research and an evaluation of the costs and benefits could guide future researchplanning and an increased adoption of cloud computing in the nursing research community. To address theselimitations we propose to deploy and evaluate the performance of the RNA-seq and machine learningpipelines to the cloud; develop and release a cloud-supported container for performing expression quantitativemethylation (eQTM) mapping in the cloud; and provide educational opportunities for the nursing researchcommunity describing our experience deploying these analytic pipelines to the cloud and providing guidance toaid in planning omics and machine learning symptom science research projects. 242197 +No NIH Category available Ablation;Acceleration;Antibodies;Binding;Bispecific Antibodies;Bispecific Monoclonal Antibodies;Body Weight decreased;CDKN2A gene;Cachexia;Cancer Patient;Cells;Cessation of life;Complication;Disease;Dose;Drug toxicity;Embryo;Epithelium;Event;Fibroblasts;Functional disorder;Gene Expression;Genes;Genetic;Heterozygote;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;KRASG12D;Lead;Life;Malignant neoplasm of pancreas;Mediating;Membrane;Modeling;Mus;Muscle;Muscle function;Muscular Atrophy;Nuclear;Organ;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Phenotype;Quality of life;Recombinants;Reporting;Resistance development;Role;Signal Transduction;Skeletal Muscle;Syndrome;Testing;Therapeutic;Transforming Growth Factor alpha;Transgenes;Treatment Efficacy;Tumor Necrosis Factor Receptor;Wasting Syndrome;cancer cachexia;cancer cell;combat;design;experimental study;human model;improved;innovation;insight;mouse model;muscle form;muscle strength;mutant;neoplastic cell;novel therapeutics;overexpression;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pharmacologic;receptor;reduced muscle mass;therapeutic evaluation;transcriptome sequencing;translational potential;virtual Targeting cancer cachexia drivers using antibody-based approaches PROJECT NARRATIVEPancreatic cancer-mediated muscle cachexia is a severe wasting syndrome that occurs invirtually every patient and strongly predicts poor outcome. How pancreatic cancer drives musclecachexia is still unfolding. Upon completion this study will shed new insights into mechanisticparadigms of muscle cachexia and hopefully thereby pave the way for therapeutic breakthroughsto curb this life-threatening condition. NCI 10826907 12/11/23 0:00 PA-20-185 1R01CA281207-01A1 1 R01 CA 281207 1 A1 "XU, WANPING" 12/11/23 0:00 11/30/28 0:00 Mechanisms of Cancer Therapeutics A Study Section[MCTA] 9977356 "ATFI, AZEDDINE " Not Applicable 4 BIOCHEMISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 12/11/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 411209 NCI 264869 146340 PROJECT SUMMARYCancer-associated cachexia is a debilitated syndrome that has a dramatic impact on the quality of life andoutcome of patients. Cancer cachexia occurs with a remarkably high incidence in pancreatic ductaladenocarcinoma (PDAC) patients. Cancer cachexia is characterized by the progressive depletion of muscleskeletal mass which often culminates in general organ dysfunction and patient death. Therefore a deeperunderstanding of the underlying mechanisms of cancer cachexia would ultimately lead to the identification ofinnovative therapeutics to improve the management of muscle wasting in cancer patients. Our recent studies have shown that pancreas-specific ablation of the Tgif1 gene in a KrasG12D backgroundled to a dramatic acceleration of PDAC in mice. Quite intriguingly despite having this severe PDAC phenotypethese mice do not display any prominent sign of cancer cachexia such as progressive weight loss and decreasedmuscle mass and function. This contrasts with our previous study using two different mouse models of humanPDAC KPC (KrasG12D and heterozygous deletion of Trp53) and KICLuc (KrasG12D and homozygous deletion ofp16Ink4a) which consistently manifest severe cancer cachexia during PDAC progression. These findings hintat the possibility that TGIF1 might function in PDAC cells to initiate events that culminate in muscle cachexia. Inefforts to probe this possibility we generated a new mouse model that allows for conditional overexpression ofTgif1 and found that enforcing TGIF1 expression in the pancreatic epithelium was sufficient to induce musclecachexia. Subsequent mechanistic experiments revealed an ability of TGIF1 to induce expression of FN14which functions as a transmembrane receptor in cancer cells to drive inflammation leading to muscle cachexia.Enforced TGIF1 expression also induced the expression of the membrane-bound form of transforming growthfactor alpha (TGFa) whose overexpression in the pancreas also drives an inflammatory phenotype similar towhat we observed in mice with conditional overexpression of TGIF1. Inspired by these intriguing findings wecreated a new bispecific antibody (Bis-14a) to simultaneously neutralize the pro-cachectic activities of FN14 andTGFa. This tremendous progress prompted us to design a variety of innovative genetic and antibody-basedpharmacological approaches to provide irrefutable proof-of-principle that targeting FN14 and TGFa downstreamof TGIF1 could offer innovative therapeutic strategies to curb cancer cachexia. Overarching specific aims are: Specific Aim 1: Expand role and translational potential of TGIF1 in PDAC-driven muscle cachexia Specific Aim 2) Explore the mechanisms by which TGIF1 facilitates PDAC-driven muscle cachexia Specific Aim 3) Test the therapeutic efficacy of monoclonal and bispecific antibodies targeting FN14 and TGFa signaling in PDAC-mediated muscle cachexia As such completion of this highly innovative proposal will likely culminate in a paradigm shift in ourunderstanding and treatment of this lethal wasting syndrome. 411209 +No NIH Category available Adherence;Award;Behavior;Behavioral;Clinical Trials;Computer Models;Data;Engineering;Ensure;Equation;Fostering;Health;Intervention;Knowledge;Learning;Maintenance;Measures;Methods;Modeling;Parents;Participant;Process;Psychological reinforcement;Reinforcement Schedule;Research;Self Efficacy;Structure;System;Techniques;Testing;behavior change;digital health;improved;insight;mHealth;mathematical model;novel;novel strategies;physical model;secondary analysis;social cognitive theory;theories Optimizing Individualized and Adaptive mHealth Interventions via Control Systems Engineering Methods Project Narrative:Reinforcement schedules are understood to be valuable for behavioral change maintenance and adherencehowever more research is needed to understand reinforcement schedules to allow them to be incorporated indigital health interventions at scale. The purpose of this supplement is to conduct rigorous analyses to betterunderstand reinforcement schedules to improve fundamental knowledge about this important mechanism ofaction. Our novel approach will generate rigorous scientific evidence that could advance fundamental knowledgethat could result directly in improving health via digital health interventions. NCI 10826070 9/13/23 0:00 PA-20-272 3R01CA244777-04S2 3 R01 CA 244777 4 S2 "BLAKE, KELLY D" 7/14/20 0:00 6/30/25 0:00 Psychosocial Risk and Disease Prevention Study Section[PRDP] 8576782 "HEKLER, ERIC " "RIVERA, DANIEL E" 50 FAMILY MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 256353 OD 185151 71202 Background: While reinforcement schedules are in general understood to be valuable for behavioral change17-19 maintenance20-22 and adherence2324 there is still much more research needed to better understand themechanisms of action (MoA) for these processes such that more robust digital health interventions canincorporate them systemically and at scale. The Parent R01 approach for continuously adapting supportincludes two states: the initiation state in which it relies on a continuous reinforcement schedule and amaintenance state in which it shifts to the use of a variable reinforcement schedule. Primary purpose: Tosystematically study the dynamic MoA of reinforcement schedules on behavior change via computationalmodeling and rigorous secondary analyses. Hypotheses: We hypothesize that 1) idiographic black-boxdynamical models can identify key measured social cognitive theory (SCT) constructs like self-efficacy that areimportant to understanding behavioral maintenance; 2) the use of grey-box/semi-physical models incorporatingreinforcement schedules into models will explain a larger portion of variance and 3) Model-on-Demand withSimultaneous Perturbation Stochastic Approximation (MoD-SPSA) approaches will identify optimal modelstructure and adjustable parameters in the estimation method that better fit non-linear assumptions. Methods:We will build on our previously validated SCT dynamical model which is foundational to the Parent R01 but withadded incorporation of key insights about reinforcement schedules incorporated into the model structures. Thenusing the data generated from first 100 participants of the Parent R01 clinical trial (see research strategy for ourapproach to ensure trial integrity) we will conduct black-box auto-regressive dynamical models which doesnot incorporate prior domain knowledge save SCT variable selection. Next we will conduct grey-box modelingwhich is much like a dynamical structural equation model in that it incorporates prior domain knowledge into themathematical model. Increased percent variance explained of steps/day of the grey-box modeling is indicativeof the added value of prior domain knowledge about the MoA of reinforcement learning thus a robust test of thisdynamic MoA. Finally we will use MoD-SPSA25 as an aid for identifying optimal features model structure andadjustable parameters in the estimation method to examine potential nonlinear interactions and relationships.Implications: This research has a number of synergistic benefits including: 1) it will generate rigorous scientificevidence for better understanding the MoA reinforcement schedules for behavioral maintenance; 2) it willproduce key novel ways to operationalize dynamically different reinforcement schedules for fostering behavioralmaintenance via digital health interventions; and 3) for the Parent R01 this research will allow the approachesand techniques to be refined with a specific emphasis on improving behavior maintenance. Thus thissupplement remains within the original scope of the parent award and will maximize the impact of the knowledgegained from it especially for advancing the behavior maintenance with the behavioral theory testing. 256353 +No NIH Category available 26S proteasome;Acceleration;Affinity;Algorithm Design;Algorithms;Alveolar Rhabdomyosarcoma;Amino Acid Sequence;Amino Acids;Architecture;Awareness;Base Sequence;Benchmarking;Binding;Binding Proteins;Binding Sites;Cause of Death;Cell Line;Cell model;Cells;Child;Childhood;Chimeric Proteins;Chromatin;Code;Data;Databases;Development;Disease;FOXO1A gene;Funding;Fusion Oncogene Proteins;Gene Expression;Generations;Glues;Glycine;Goals;High-Risk Cancer;Language;Learning;Ligands;Malignant Childhood Neoplasm;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Modeling;Molecular;Oncogenic;Oncoproteins;Outcome;PAX3 gene;Pathogenicity;Pathway interactions;Peptides;Phage Display;Pharmaceutical Preparations;Protac;Protein Engineering;Proteins;Reporter;Rhabdomyosarcoma;Risk;Serine;Skeletal Muscle;Sodium Chloride;Soft tissue sarcoma;Structure;System;Technology;Testing;Therapeutic;Toxic effect;Training;Translations;Ubiquitin;United States;Validation;Western Blotting;Work;Yeasts;clinically relevant;deep learning model;design;effective therapy;high risk population;histogenesis;improved;in vitro Model;in vitro testing;in vivo;in vivo Model;model design;multicatalytic endopeptidase complex;new technology;novel;protein aminoacid sequence;protein degradation;protein protein interaction;public health relevance;recruit;screening;small molecule;transcription factor;tumorigenic;ubiquitin-protein ligase;vector Proteasomal recruiters of PAX3-FOXO1 Designed via Sequence-Based Generative Models Public Health RelevanceCancer is the leading cause of death by disease in children in the United States. While outcomes for some lowand intermediate risk-groups have improved significantly over the last several decades survival for high-riskgroups has remained stagnantly poor. The goal of this project is to develop a novel protein degrader systemtargeting the main oncogenic driver of one such high-risk cancer called fusion-positive rhabdomyosarcoma inorder to develop more effective and less toxic therapies. NCI 10826068 8/21/23 0:00 PA-20-272 3U54CA231630-01A1S4 3 U54 CA 231630 1 A1S4 "WITKIN, KEREN L" 7/1/23 0:00 8/31/24 0:00 1930899 "LINARDIC, CORINNE MARY" "COUNTER, CHRISTOPHER M" 4 PEDIATRICS 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 157719 NCI 99950 57769 AbstractFusion-positive alveolar rhabdomyosarcoma (FP-ARMS) one of the most fatal childhood cancers is primarilydependent on the PAX3-FOXO1 fusion oncoprotein a chimeric transcription factor that hijacks normal geneexpression and chromatin state. The five-year survival for children with PAX3-FOXO1-positive ARMS is ~30%and <10% when metastatic. PAX3-FOXO1 is largely considered an undruggable protein with no small moleculedeveloped to bind and inhibit its activity. Recently we have developed novel algorithms to design specificpeptides that selectively bind and degrade pathogenic proteins including classically undruggable transcriptionfactors and fusion oncoproteins. In this proposal we will ensemble our state-of-the-art generative models to denovo design high-affinity peptide-guided degraders selective to PAX3-FOXO1 (and not PAX3 or FOXO1) anddemonstrate degradation within in vitro models of FP-ARMS. The outcomes of this work will motivatedownstream in vivo studies and accelerate protein-targeting medicines for FP-ARMS. 157719 +No NIH Category available 2 arm randomized control trial;Abstinence;Address;Adult;Advertisements;Alaska Native;American Indians;Behavioral;Biochemical;Cellular Phone;Cessation of life;Cigarette;Communities;Complex;Data;Enrollment;Ethnic Origin;Ethnic Population;Family;Female;Future;Geography;Goals;Group Therapy;Health Insurance;Healthcare Systems;Heart Diseases;Hospitals;Income;Indian reservation;Individual;Industry;Inequity;Institutional Racism;Intervention;Interview;Knowledge;Malignant neoplasm of lung;Mediating;Morphologic artifacts;National Cancer Institute;Northern Plains Tribe;Outcome;Participant;Patient Self-Report;Persons;Pharmaceutical Preparations;Planet Earth;Play;Policies;Population;Prevalence;Process;Provider;Race;Randomized;Randomized Controlled Trials;Research;Respiratory Disease;Ritual compulsion;Scientific Advances and Accomplishments;Smoke;Smoking;Smoking Cessation Intervention;Spirituality;Subgroup;System;Testing;Time;Tobacco;Training;Trauma;United States;cigarette smoke;cigarette smoking;comparative efficacy;cost;digital;digital intervention;efficacious intervention;efficacy evaluation;efficacy testing;experience;follow-up;health equity;health inequalities;improved;intervention program;long-standing disparities;male;maltreatment;member;public health relevance;racial population;recruit;rural area;secondary analysis;sex;smartphone application;smoking cessation;smoking cue;smoking prevalence;smoking-related cancer;social health determinants;theories;treatment effect;trial comparing Digital smoking cessation intervention for nationally-recruited American Indians and Alaska Natives: A full-scale randomized controlled trial PUBLIC HEALTH RELEVANCE STATEMENTThe overall aim of this project is to determine the efficacy of a smartphone application aimed at helpingAmerican Indians and Alaska Natives (AIANs) quit smoking. Positive results would improve health equity byproviding a highly accessible and efficacious intervention for AIANs nationwide. NCI 10826067 9/20/23 0:00 PAR-21-035 1R01CA284687-01A1 1 R01 CA 284687 1 A1 "CICCOLO, JOSEPH THOMAS" 9/20/23 0:00 8/31/28 0:00 Health Promotion in Communities Study Section[HPC] 7905616 "BRICKER, JONATHAN B" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 744186 NCI 432512 311674 PROJECT SUMMARY/ABSTRACT (DESCRIPTION)Since the early 1980s American Indians and Alaska Natives (AIANs) have maintained the highest rates ofcommercial cigarette smoking of any racial/ethnic group in the US. Currently 27% of AIANs smoke cigarettes.Compared to other racial/ethnic groups they have 6 times higher rates of developing smoking-related cancers.AIANs are only half as likely to quit smoking compared to other races/ethnicities. The result is that commercialcigarette smoking accounts for half of all deaths among AIANs nationwide. A major cause of theselongstanding inequities is the lack of access to efficacious smoking cessation interventions among AIANs.Compounding the barrier of lack of access to smoking cessation interventions is the barrier of lack of researchon the efficacy of smoking cessation interventions for AIANs. Despite having the highest smoking prevalenceof any racial/ethnic group in the US for over 40 years a mere 0.3% of all full-scale smoking cessationrandomized controlled trials (RCTs) have focused on AIANs. Regarding accessibility a smartphone application(app) has the potential to deliver a low-cost smoking cessation intervention with wide geographic reach toAIANs and in regions of the US with smoking rates as high as 57% in this group (i.e. Northern Plains).Regarding efficacy our preliminary data provides promising evidence for our Acceptance and CommitmentTherapy (ACT)-based smartphone app called iCanQuit to help AIANs quit smoking. We compared theiCanQuit app with the NCIs QuitGuide app among the AIAN subsample (N = 165 recruited from 32 US states)enrolled in our full-scale RCT. This secondary analysis of AIANs showed descriptively higher rates of smokingcessation at the 12-month follow-up (30% for iCanQuit vs. 18% for QuitGuide; OR = 1.96; 95% CI = 0.90 4.26p = .089). While encouraging analyses were exploratory non-significant and not a substitute for a full-scaleefficacy test. To address weaknesses of prior research a fully-powered comparative efficacy RCT of iCanQuitvs. QuitGuide focusing nationwide on AIANs who smoke is now needed. Thus the goal of this project is toconduct a nationally recruited and fully-powered two-arm RCT comparing iCanQuit (n = 388) to QuitGuide (n =388) in order to determine: (1) the efficacy of iCanQuit relative to the QuitGuide app for biochemically verified30-day point prevalence abstinence (PPA) at 12 months post-randomization and (2) whether iCanQuits (butnot QuitGuides) 12-month smoking cessation outcomes are significantly mediated by improvements in coreACT-based processes. This study will be the first full-scale RCT of a digital intervention for helping AIANsnationwide stop smoking. Qualitative interviews with (1) a subsample of iCanQuit participants to thematizetestimonials of their experience with iCanQuit and (2) AIAN members from our study Community AdvisoryBoard (CAB) will guide our plan for broadly disseminating iCanQuit to AIAN adults nationwide. Positive resultswould improve health equity by providing a highly accessible and efficacious intervention with potential forsustainability and broad dissemination for AIANs nationwide. 744186 +No NIH Category available AIDS-Related Lymphoma;Address;Algorithms;Autopsy;Biological Assay;Biopsy;Cause of Death;Cessation of life;Characteristics;Chemotherapy-Oncologic Procedure;Chromosomes;Classification;Clinical;Clinical Trials;Consent;Control Groups;Country;Coupled;DNA;Deterioration;Diagnosis;Diagnostic;Diagnostic Procedure;Disease;Disparity;Enlargement of lymph nodes;Enrollment;Ensure;Epstein Barr Virus associated tumor;Epstein-Barr Virus-Related Lymphoma;Evaluation;Excision biopsy;Fine needle aspiration biopsy;General Population;HIV;HIV Infections;Histologic;Hodgkin Disease;Hospitals;Human Herpesvirus 4;Immunoglobulins;Inferior;Infrastructure;Knowledge;Laboratories;Lymphoma;Malignant Neoplasms;Measures;Methylation;Modernization;Molecular;Mutation;Newly Diagnosed;Observational Study;Odds Ratio;Operative Surgical Procedures;Organ;Outcome;Participant;Pathologic;Patient Triage;Patients;Pattern;Performance;Performance Status;Persons;Plasma;Population Study;Predictive Value;Prognosis;Progression-Free Survivals;Reporting;Resources;Risk Factors;Role;Somatic Mutation;South Africa;South African;Specificity;Specimen;Symptoms;Techniques;Testing;Time;Tuberculosis;Tumor Markers;Validation;antiretroviral therapy;cancer care;chemotherapy;co-infection;cohort;cost;diagnostic algorithm;diagnostic strategy;experience;follow-up;high risk;improved;infection rate;information gathering;minimally invasive;molecular diagnostics;molecular marker;mortality;novel diagnostics;outcome disparities;programs;prospective;response;standard of care;treatment response;tuberculosis diagnostics;tuberculosis treatment;tumor;tumor progression Hodgkin Lymphoma in PLWH in South Africa: TB EBV and Tumor Molecular Markers PROJECT NARRATIVEWe propose to investigate factors that may contribute to poor outcomes in Hodgkin lymphomain people living with HIV in South Africa where the difference in outcomes is striking. Presentevidence suggests that at least part of the difference in outcomes reflects long delays inHodgkin lymphoma diagnosis in PLWH. As such we will develop and test a new diagnosticalgorithm based on plasma tumor molecular markers that may expedite the diagnosis ofHodgkin lymphoma in PLWH. NCI 10824451 4/24/23 0:00 RFA-CA-19-032 3R01CA250069-04S1 3 R01 CA 250069 4 S1 "LIDDELL HUPPI, REBECCA" 4/1/20 0:00 3/31/25 0:00 ZCA1-SRB-1(J2) 1942371 "AMBINDER, RICHARD FREDERICK" "XIAN, RENA " 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 310 Non-SBIR/STTR 2023 104391 OD 63750 40641 PROJECT SUMMARY Hodgkin lymphoma (HL) outcomes in PLWH in South Africa (S.A.) are inferior to those in HIV(-) patientsalthough outcomes compare favorably in clinical trials. Advanced stage disease and consistent EBV-associationare well recognized in PLWH. In S.A. at the time of diagnosis some PLWH are in such poor clinical conditionthat they are not treated. Diagnostic delays contribute to late presentations as HL diagnoses require surgicalbiopsies for a definitive pathologic evaluation. Resources and infrastructure in S.A. are limited in this regard. To better understand disparate outcomes in PLWH in standard-of-care settings we propose a prospectiveobservational study of HIV(+) and HIV(-) HL in S.A. (Aim 1). Performance status (PS) organ function clinicalstage tumor histological subtype EBV association and mutational landscape will all be assessed as willchemotherapy regimen response to treatment and cause of death as determined by a minimally invasiveautopsy in consenting participants. Since tuberculosis (TB) is the leading cause of death in PLWH in S.A. thesymptoms of which mimic HL HL patients are often empirically treated and repeatedly tested for TB beforeexcisional biopsies are pursued. A high co-infection rate coupled with immunosuppressive chemotherapy maylead to TB progression in PLWH during therapy and may contribute to ultimate mortality. Therefore Aim 1 willalso have a major focus on the contributions of TB. The results of this study will lead to a better understandingof the roles that PS organ function and TB have in HL prognosis in PLWH as well as aspects of the EBVassociation and the mutational features. The near uniform association of EBV in HIV(+) HL may aid in the recognition of HL in PLWH via a non-invasiveplasma EBV test that can identify patients needing urgent excisional biopsy. To explore this possibility wepropose to develop a diagnostic algorithm (Aim 2A) in a discovery cohort of PLWH with HL and withoutmalignancy. EBV DNA will be assessed along with additional plasma markers to increase specificity. The optimalcombination of markers will be used to develop an algorithm that will be tested in a validation cohort of high riskPLWH (Aim 2B). Baseline PS and organ function will be obtained and a rigorous yearlong follow-up will ensureaccurate classification of persons with lymphoma. In those who are diagnosed with HL or other lymphoma PSand organ function will be re-assessed. Participants who experience a marked decline in these measures to thepoint that they do not receive standard chemotherapy will be considered potential lives saved if the diagnosticalgorithm could be applied clinically. We note that much of the infrastructure needed to implement the moleculartechniques is available in S.A. and that our South African collaborators have a track record of introducingsophisticated molecular diagnostics for TB to the entire country.1 104391 +No NIH Category available Acceleration;Childhood;Communication;Development;Funding Opportunities;Fusion Oncogene Proteins;Immunotherapy;Malignant Childhood Neoplasm;Malignant Neoplasms;Research;Research Activity;Resources;Translational Research;clinical candidate;flexibility;research clinical testing NCI Moonshot: Pediatric Core n/a NCI 10823193 75N91019D00024-P00017-759101900134-2 N01 8/31/19 0:00 9/30/24 0:00 16146767 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 66552 NCI The Pediatric Immunotherapy Translational Science Network and the Fusion Oncoproteins inChildhood Cancers Implementation Teams propose an NCI Moonshot Pediatric Core tosupport and accelerate the activities of the research teams that have been establishedthrough funding opportunity announcements (FOAs) in FY 2018 and FY 2019. The CancerMoonshot Pediatric Core will serve as a research resource coordination center to the researchteams and will have the flexibility to provide capabilities that are complementary to theresearch teams and that will focus on accelerating the pace at which potential clinicalcandidates can be identified by the research teams and then progressed to clinicalevaluations. 66552 +No NIH Category available Accounting;Acute;Adjuvant Chemotherapy;Adolescent;Biological Assay;C-Type Natriuretic Peptide;Cancer Model;Canis familiaris;Chest;Child;Cisplatin;Clinical;Clinical Research;Clinical Trials;Cyclic GMP;Data;Data Set;Development;Diagnosis;Disease;Dose;Doxorubicin;Engineering;Excision;Feedback;Femur;Formulation;Freeze Drying;Freezing;Funding;Human;In Vitro;Lead;Life;Liquid substance;Localized Disease;Lung;Malignant Neoplasms;Measures;Metastatic Neoplasm to the Lung;Metastatic Osteosarcoma;Methods;Methotrexate;Micrometastasis;Modeling;Neoadjuvant Therapy;Neoplasm Metastasis;Newly Diagnosed;Operative Surgical Procedures;Patients;Pediatric Neoplasm;Peptides;Perioperative;Pharmaceutical Preparations;Phase;Population Control;Primary Lesion;Process;Progressive Disease;Property;Rattus;Reporting;Sampling;Small Business Innovation Research Grant;Specific qualifier value;Survival Rate;Time;Translations;Work;analytical method;antifibrotic treatment;bone;cancer type;chemotherapy;humerus;immunoregulation;improved;limb bone;long bone;manufacture;meetings;novel therapeutics;osteosarcoma;product development;standard of care;success;tibia;tool;tumor Development of an immunomodulating peptide as a therapy for osteosarcoma in canine and human Narrative: The 5-year survival rate for children with metastatic osteosarcoma (OSA) is extremelylow hovering around 20%-30% a rate that has not improved in over 30 years. Novel therapiesare in critically needed specifically molecules capable of inhibiting the process of OSAmetastasis. This SBIR Phase 2 application will support IND enablement of animmunomodulating peptide with unique anti-tumor and anti-fibrotic properties that PharmaIN isdeveloping for the treatment of osteosarcoma and other cancer types. NCI 10822577 9/19/23 0:00 PA-22-176 1R44CA278570-01A1 1 R44 CA 278570 1 A1 "FRANCA-KOH, JONATHAN C" 9/19/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 14360820 "ALFARO, JOSHUA " Not Applicable 1 Unavailable 167580682 G1NAHNEAVKK9 167580682 G1NAHNEAVKK9 US 47.771876 -122.188929 10003781 PHARMAIN CORPORATION BOTHELL WA Domestic For-Profits 980118202 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 995100 NCI 744000 186000 Osteosarcoma (OSA) is the most common primary malignancy of bone in children andadolescents accounting for approximately 5% of all childhood tumors (www.cancer.gov).Osteosarcoma occurs primarily in the long bones of the limbs including most commonly thefemur tibia and humerus1. The current standard of care therapy for human patients diagnosedwith OSA includes multi-agent neoadjuvant chemotherapy (doxorubicin + cisplatin +/-methotrexate) followed by surgical resection of the primary lesion and adjuvant chemotherapycuring approximately 60 to 70% of patients 13. However up to 40% of newly diagnosed patientspresenting with localized disease eventually develop metastases to the lung indicating thatmany patients already have micrometastases present in the lung at the time of diagnosis ordevelop them during the perioperative period 4. The 5-year survival rate for children withmetastatic OSA is extremely low hovering around 20%-30% a rate that has not improved inover 30 years 2. Clearly novel therapies are in critical need specifically molecules capable ofinhibiting the process of OSA metastasis. PharmaIN is developing immunomodulating peptidewith unique anti-tumor and anti-fibrotic properties for the treatment of osteosarcoma and othercancer types. The peptides anti-tumor activity has been demonstrated as a monotherapy andcombination with other immuno/chemotherapies in multiple cancer models including OSAmetastatic model. Pilot tox data has been obtained and PharmaIN proposes to conduct a clinicaltrial in canine OSA patients as a translation tool for human and concurrent product developmentfor veterinary applications. The additional proposed work is IND enabling for a Phase 1 humanclinical trial and consists of manufacturing drug substance and drug product needed for GLP-toxand clinical studies completion of GLP-tox studies and submission of the IND for the OSAindication. 995100 +No NIH Category available Address;Administrative Supplement;Adopted;Adoption;Appointment;Cancer Center;Caring;Clinic;Clinical;Collaborations;Colonoscopy;Communication;Communities;Community Health;Community Health Networks;Databases;Documentation;Electronic Health Record;Ensure;Evaluation;Face;Federally Qualified Health Center;Funding;Healthcare;Informatics;Intervention Studies;Laboratories;Learning;Medicaid;Methods;Neighborhood Health Center;Patients;Persons;Phase;Population;Positioning Attribute;Preparation;Prevention;Primary Care;Principal Investigator;Process;Recommendation;Reporting;Resources;Risk;Role;Rural;Screening for cancer;Series;Services;Site;Social Work;Social Workers;Testing;Transportation;Universities;Variant;Washington;Work;Writing;design;evidence base;guidebooks;health equity;implementation barriers;implementation science;implementation strategy;improved;member;patient navigation;patient screening;pilot test;preventive intervention;primary care clinic;primary care practice;rapid test;referral services;response;rural area;social;social interventions;waiver Developing a pragmatic guide to implementing social risk referrals: A partnership between Caring Health Center (CHC) and the Implementation Science Center for Cancer PROJECT NARRATIVEThis supplement is a collaborative effort across four ISC3 Centers: BRIDGE-C2 Harvard ISCCCE Universityof Washington OPTICC and Washington University-ISC3. We propose to: (1) develop a pragmatic appliedguidebook (the Guide) for clinics seeking to implement or expand efforts to address patient-reported socialrisks using Assistance strategies; (2) use rapid-cycle testing to identify best practices for implementing theGuide; (3) iterate and disseminate the refined Guide; and (4) and create a toolkit to package learning from theprior Phase 1 Health Equity Supplement along with that from the ISC3 Phase 2 projects and make the toolkitavailable through the NCI. NCI 10822141 7/24/23 0:00 PA-20-272 3P30CA006516-58S2 3 P30 CA 6516 58 S2 "PTAK, KRZYSZTOF" 6/1/23 0:00 4/14/24 0:00 1871771 "GLIMCHER, LAURIE HOLLIS" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 6/1/23 0:00 11/30/23 0:00 353 Research Centers 2023 224723 NCI 224723 0 PROJECT SUMMARYThis supplement is a collaborative effort across four ISC3 Centers: BRIDGE-C2 Harvard ISCCCE Universityof Washington OPTICC and Washington University-ISC3. ISCCCE collaborates with a network of communityhealth centers (CHCs) which serve as its implementation laboratory. CHCs face some of the most difficultimplementation challenges as they primarily serve patients with high social needs. Addressing patients socialneeds is a critical part of enabling patients to access evidence-based cancer screening and preventioninterventions. Well-documented challenges in addressing social needs include determining how best tomaintain up-to-date information about available service agencies to which persons with social needs may bereferred and developing and adopting optimal workflows for doing so. Social service resource locators(SSRLs) that identify currently available resources take varying forms ranging from a social worker maintaininga hard-copy binder of resources to an informatics platform integrated into the electronic health record (EHR)and designed to enable bidirectional communication with local organizations about referred patients receipt ofservices (also called community resource referral platforms). Building on the findings from the Phase Isupplement we propose to: (1) develop a pragmatic applied guidebook (the Guide) for clinics seeking toimplement or expand efforts to address patient-reported social risks using Assistance strategies; (2) use rapid-cycle testing to identify best practices for implementing the Guide; (3) iterate and disseminate the refinedGuide; and (4) create a toolkit to package learning from the prior Phase 1 Health Equity Supplement along withthat from the ISC3 Phase 2 projects and make the toolkit available through the NCI. 224723 +No NIH Category available ASCL1 gene;Antigen Presentation;Automobile Driving;BETA2 protein;Biological;Biology;CD8-Positive T-Lymphocytes;CRISPR-mediated transcriptional activation;Cancer Biology;Cancer Model;Cancer Patient;Cell Line;Chemoresistance;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Data Set;Epithelial Cells;Etoposide;Exhibits;Gene Expression;Gene Mutation;Genes;Genetic Transcription;Genetically Engineered Mouse;Heterogeneity;Human;Immune;Immunohistochemistry;Kinetics;Libraries;Link;Lung;Mining;Modeling;Molecular Analysis;Molecular Target;Mus;Neurons;Neurosecretory Systems;Outcome;Pathway interactions;Patients;Phenotype;Platinum;Publishing;Reagent;Repression;Resistance;Role;Running;Switch Genes;T cell infiltration;TP53 gene;Testing;Therapeutic;Transcriptional Silencer Elements;cancer subtypes;cancer therapy;chemotherapy;gain of function;immune checkpoint blockade;immunogenicity;improved;in vivo;lentivirally transduced;loss of function;lung cancer cell;mouse model;neoantigens;neural;novel;overexpression;patient derived xenograft model;programmed cell death ligand 1;programmed cell death protein 1;programs;response;small cell lung carcinoma;transcriptome sequencing;treatment response;tumor;tumor-immune system interactions Interrogating roles for REST in small cell lung cancer therapy response and resistance Project NarrativeSmall cell lung cancer (SCLC) exhibits distinct biological subsets including strongly neuroendocrine and lowneuroendocrine (low-NE) subsets with recent data linking low-NE SCLC to improved responses to immunecheckpoint blockade in patients. Lack of mouse models of low NE-SCLC has been a barrier to progress in thefield which we will overcome using mouse models that overexpress the REST repressor ofneural/neuroendocrine state. Our preliminary data also link REST to chemotherapy resistance; we will modellow-NE SCLC and test the impact of REST activity on responses to chemotherapy and immune checkpointblockade. NCI 10822088 12/22/23 0:00 PA-20-185 1R01CA287573-01 1 R01 CA 287573 1 "FORRY, SUZANNE L" 12/22/23 0:00 11/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 9856130 "MACPHERSON, DAVID " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 12/22/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 582076 NCI 330725 251351 SUMMARYSmall cell lung cancer (SCLC) is a lethal tumor type characterized by exquisite response to chemotherapyfollowed by rapid emergence of chemoresistance. Addition of PDL-1 inhibition to platinum/etoposidechemotherapy leads to improved clinical responses but only a small subset of SCLC patients benefit. Distinctsubsets of SCLC have been identified including high-neuroendocrine and low-neuroendocrine (NE) subtypes.High-NE SCLC expressing high levels of ASCL1 (SCLC-A) or NEUROD1 (SCLC-N) is best understood withgenetically engineered mouse models available. However our understanding of low-NE subtypes is poor owingin part to a lack of mouse models. A low-NE immune inflamed subset of SCLC (SCLC-I) exhibited increasedresponse to immune checkpoint blockade and high expression of RE-1 Silencing Element (REST) a suppressorof neuronal and neuroendocrine gene expression. Aim 1 tests hypotheses that REST overexpression in amouse model of SCLC will result in low-NE SCLC and that REST increases immunogenicity. We will use gainand loss of function studies to dissect the contribution of REST to SCLC and to model low-NE SCLC. RNA-seqanalyses will use data from mouse GEM models and isogenic cell lines with REST perturbation to identify genesconsistently regulated by REST while CUT&RUN will identify direct targets of REST. We will perform gain andloss of function studies to assess pathways through which REST alters the biology of SCLC with an initial focuson how REST controls the expression of MHC-I. Aim 2 builds from our preliminary data that implicate RESTexpression in driving chemotherapy resistance. We performed an in vivo functional CRISPR activation(CRISPRa) screen to identify genes that switch chemosensitive patient derived xenograft (PDX) models tobecome chemoresistant when overexpressed and among the top screen hits was REST. We will study theimpact of REST perturbation on chemotherapy response and will test our hypothesis that REST expression willcause a switch to chemoresistance. We will perform immunohistochemistry and molecular analyses tocharacterize the response of REST-perturbed PDX models to chemotherapy in vivo. With the increasedappreciation of low-NE SCLC but poor understanding of the underlying biology it is critical that this importantsubset of SCLC be modelled and understood. This proposal provides new in vivo GEM and PDX models of low-NE SCLC which are essential reagents to link biologically distinct SCLC subsets to the most promisingtherapeutic approaches. 582076 +No NIH Category available Ablation;Acute;Address;Adverse event;Affect;Alcohol consumption;Biological Assay;Businesses;Cellulose;Cervical;Cervix Uteri;Cessation of life;Clinic;Clinical;Clinical Research;Cold Therapy;Communities;Complex;Country;Data;Deposition;Diagnosis;Diameter;Disease;Electrocoagulation;Ensure;Ethanol;Excision;Family suidae;Formulation;Foundations;Funding;Gel;Goals;Grant;Health;Hour;Human;Income;Injectable;Injections;Institution;Interview;Investigational New Drug Application;Length;Lesion;Link;Liquid substance;Liver neoplasms;Low income;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Modeling;Monitor;Necrosis;Needles;Nitrogen;Outcome;Pelvis;Phase;Polymers;Power Sources;Protocols documentation;Provider;Public Health;Quality Control;Radiofrequency Interstitial Ablation;Recurrence;Research;Research Design;Small Business Innovation Research Grant;Stains;Sterility;Surveys;Technology;Testing;Therapeutic;Time;Tissues;Toxic effect;Translations;Vial device;Vision;Woman;Work;X-Ray Computed Tomography;cervical cancer prevention;combinatorial;conventional therapy;cost;design;disability-adjusted life years;experimental study;improved;interest;intervention cost;loop electrosurgical excision procedure;low and middle-income countries;manufacture;medically underserved;mortality;point of care;population health;potency testing;premalignant;pressure;prevent;prototype;safety assessment;screening;stability testing;tool;treatment arm;underserved area;usability Optimizing ablation of cervical precancer with ethyl cellulose ethanol to enable translation to women in low and middle-income countries Project NarrativeThe goal of this SBIR is for PIs from academic and small business institutions to work in partnership to developa technological strategy that will transform treatment of cervical pre-cancer in low-income communities. Theproposed research is significantly relevant to public health as the developed technologies will contribute to theimprovement of cervical cancer prevention and thus a reduction in the mortality rate of this imminentlypreventable disease. NCI 10821975 9/20/23 0:00 PA-22-176 2R44CA257303-02A1 2 R44 CA 257303 2 A1 "LOU, XING-JIAN" 9/14/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 78493392 "CROUCH, BRIAN " Not Applicable 4 Unavailable 116993626 U93NDFLVGKL3 116993626 U93NDFLVGKL3 US 36.001691 -78.89891 10054178 CALLA HEALTH FOUNDATION DURHAM NC Domestic For-Profits 27701 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 909585 NCI 728727 121352 AbstractCervical cancer affects the lives of half a million women worldwide each year and over half of these women die.Preventative solutions that are widely used in wealthy countries are not practical for use in medically underservedregions due to sophisticated technologies and expertise needed to sustain these solutions. Thus alternativeprotocols that employ low-cost simple-to-use technologies are needed to prevent cervical cancer. Our vision isto develop high quality low-cost interventions that will be effective in low and middle-income countries (LMICs)to address shortcomings of current solutions for cervical cancer prevention. The Calla Health Foundation isdeveloping the tools needed to help meet the WHO metrics for cervical cancer elimination in the next 100 years.Under fast track SBIR funding (R44CA240019) we are developing tools for point-of-care screening anddiagnosis. However screening and diagnosis alone will not lead to decreases in cervical cancer mortality ifaccess to point-of-care treatment remains limited. While Loop Electrosurgical Excision procedure (LEEP) is themost widely used treatment in high-income settings cryotherapy is more commonly used in LMICs. Recentlythermocoagulation has gained acceptance for ablation of cervical pre-cancer as it does not require consumables(continuous supply of pressurized liquid nitrogen for cryotherapy) or a stable power supply (for LEEP). Howeverthermocoagulation is limited by bioheat transfer and therefore the depth of necrosis it can achieve. To developa complementary therapeutic approach to thermocoagulation the goal of our Phase I SBIR grant was to establishan injectable low-cost ablative therapy based on controlled delivery of a ubiquitous agent ethanol to treat cervicalpre-cancer. Specifically we developed a new formulation of ethanol using a polymer called ethyl cellulose (EC)to act as a slow-release gel limiting off target toxicity and an automated injector to reliably deliver ethanol intothe region of interest. Moving forward the goal of our Phase II SBIR grant is to develop beta versions of theautomated injector develop packaging and quality control metrics for EC-ethanol and assess if a combinatorialtherapy in which sequential EC-ethanol ablation and thermocoagulation are applied to the cervix is synergisticand enhances efficacy. This work will include the following specific aims: 1) evaluate usability and repeatabilityof hand-held injectors for EC-ethanol delivery; 2) establish EC-ethanol stability and potency testing plan andrelease criteria; 3) assess safety and efficacy of sequential EC-ethanol ablation and thermocoagulationcompared to monotherapies; and 4) assess clinical workflow and population health impact of monotherapies andcombinatorial therapy. 909585 +No NIH Category available Adenosine;Aftercare;Antibodies;Antitumor Response;Architecture;Biological;Biology;CRISPR/Cas technology;Cancer Patient;Cell Line;Cells;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Development;Diagnosis;Disease;Dose;Double-Stranded RNA;Drug Kinetics;Engineering;FDA approved;Feedback;Formulation;Genes;Genomics;Goals;Guide RNA;Human;Human Papillomavirus;Immune;Immunologic Memory;Immunotherapy;In Vitro;Injections;Inosine;Interferon Type I;Knock-out;Leukocytes;Macrophage;Malignant neoplasm of anus;Mediating;Methods;Modality;Modeling;Monoclonal Antibodies;Mus;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Persons;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase;Process;Quality of life;Regimen;Resistance;Ribonucleoproteins;Safety;Solid Neoplasm;Streptococcus pyogenes;Survival Rate;T cell response;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Tumor Burden;anti-tumor immune response;cancer immunotherapy;cancer therapy;chemical conjugate;chemical synthesis;chemotherapy;design;dsRNA adenosine deaminase;effective therapy;humanized mouse;immune checkpoint blockade;immunogenic;improved;in vivo;knockout gene;lead candidate;lead optimization;manufacturability;meetings;microbial;neoplastic cell;novel;nuclease;patient population;permissiveness;pre-clinical;programs;prototype;response;standard of care;targeted delivery;trafficking;tumor;tumor microenvironment;tumor-immune system interactions In vivo delivery of Ab-directed CRISPR ribonucleoproteins for anal cancer immunotherapy PROJECT NARRATIVE:Metastatic anal cancer is a devastating disease in urgent need of new treatment options to improve patientoutcomes and quality of life. The 5-year survival rate with standard of care chemotherapy is only ~30% thereare no FDA-approved regimens after chemotherapy has failed and only limited benefit has been shown withsingle agent immune checkpoint blockade (ICB). Spotlight Therapeutics is developing a novel antibody-directedin vivo CRISPR gene editor to knockout ADAR in immune cells thereby reprogramming the tumormicroenvironment to an immune permissive state for use in combination with ICB to treat patients with metastaticanal cancer who have failed chemotherapy. NCI 10821884 9/21/23 0:00 PA-22-176 1R44CA287699-01 1 R44 CA 287699 1 "TRIPURANI, SWAMY KRISHNA" 9/21/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 79394674 "HAAK-FRENDSCHO, MARY " Not Applicable 14 Unavailable F4WPQQ5TC552 F4WPQQ5TC552 US 10070548 SPOTLIGHT THERAPEUTICS HAYWARD CA Domestic For-Profits 945453720 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1043843 NCI 886867 88687 PROJECT SUMMARY:This year in the US 9760 people are expected to be diagnosed with anal cancer. The 5-year survival rate formetastatic anal cancer is only ~30% with standard of care chemotherapy. No regimens have been FDA-approved after chemotherapy has failed and only limited benefit has been shown with single agent immunecheckpoint blockade (ICB). New treatment options are urgently needed to improve patient outcomes. The goalof this Direct to Phase II project is to develop TAGE-201 an intratumorally administered Antibody (Ab)-directed CRISPR gene editor to knockout ADAR in TME immune cells for use in combination with ICB.This new biologic is based on Spotlight Therapeutics proprietary Targeted Active Gene Editor (TAGE)platform. TAGE is a non-viral non-nanoparticle delivery modality comprised of an engineered CRISPR-Cas9ribonucleoprotien (RNP) fused to an Ab enabling cell-targeted delivery and gene knockout in vivo. ADAR(adenosine deaminase acting on RNA) disruption stimulates dsRNA sensing pathways and a type I interferonresponse which can drive a shift the state of the tumor microenvironments (TMEs) to be immune permissiveovercoming a major barrier to generating an optimal anti-tumor immune response with ICB. TAGE enablesgene knockout of ADAR which has been difficult to drug despite compelling preclinical evidence. Preliminarydata with a murine surrogate prototype of TAGE-201 with optimized Ab and CRISPR-Cas suggests Adarknockout in conjunction with ICB treatment mediates systemic anti-tumor responses in syngeneic murine tumormodels that do not respond to ICB alone. This Direct to Phase II project aims to 1) identify a TAGE-201 leadcandidate by optimizing RNP architecture and guide RNA components 2) generate a preclinical data packagedemonstrating Adar knockout in TME immune cells of a murine tumor after direct local injection with murinesurrogate of TAGE-201 (msTAGE-201) anti-tumor efficacy in multiple murine and PDX tumor modelspharmacodynamics effects that align with ADAR biology and pharmacokinetics and toxicity studies thatdemonstrates an acceptable safety profile and 3) conduct an INTERACT meeting with the FDA to present thepreclinical manufacturability assessment and preliminary formulation data packages and an IND-enablingstudy plan. Upon successful completion of the Direct to Phase II project the TAGE-201 developmentcandidate will be poised to initiate IND-enabling studies followed by clinical trials with the goal to provide aneffective treatment option for a population of patients that currently do not have FDA-approved therapeuticstrategies to improve overall outcomes and quality of life. 1043843 +No NIH Category available Accelerometer;Affect;Boston;Child;Competence;Development;Effectiveness;Equity;Family;Female;Focus Groups;Home;Intervention;Learning;Life;Literacy Programs;Measurement;Mediating;Methods;Motivation;New York;New York City;Obesity;Outcome Assessment;Overweight;Parents;Phase;Random Allocation;Recommendation;Research;Research Design;Schools;Testing;Universities;Weight;design;efficacy testing;experience;falls;feasibility trial;implementation evaluation;implementation outcomes;implementation process;literacy;moderate-to-vigorous physical activity;pilot test;policy recommendation;programs;randomized trial;randomized controlled study;sex;tool Supporting Physical Literacy at School and Home (SPLASH) Study n/a NCI 10821567 6/13/23 0:00 PAR-18-307 4R33CA226829-03 4 R33 CA 226829 3 "PERNA, FRANK" 3/1/19 0:00 2/28/26 0:00 Special Emphasis Panel[ZRG1-RPHB-W(55)R] 9168231 "HENNESSY, ERIN " "SACHECK, JENNIFER " 7 NONE 39318308 C1F5LNUF7W86 39318308 C1F5LNUF7W86 US 42.3498 -71.06149 8422704 TUFTS UNIVERSITY BOSTON BOSTON MA SCHOOLS OF NUTRITION 21111901 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 394 Non-SBIR/STTR 2023 251027 NCI 174881 76146 Modified Project Summary/Abstract SectionPROJECT SUMMARYMost U.S. children fall short of the recommended 60 minutes of daily moderate-to-vigorous physical activity(MVPA). Our research and that of others show that this gap disproportionately affects children who are femaleand overweight/obese. Programs designed to increase children's physical literacy (PL) defined as thecompetence confidence and motivation to be physically active for life hold particular promise for closing thisgap and achieving equity. Furthermore policy recommendations promote school- and home-based PAinterventions and evidence suggests that interventions incorporating both settings may have synergisticeffects. However no prior studies have tested the efficacy of a multilevel PL-focused intervention. Our overallobjective is fill this gap by designing and testing a program that will reach children both at school and at hometo increase their PL and in turn total daily PA and MVPA. We will meet this objective through a partnershipbetween Tufts University and the New York Road Runners. This partnership is a unique and significantstrength given our organizations' collective dissemination experience and networks to scale PA programsnationwide. Our preliminary studies include a feasibility trial of the school component of the physical literacyprogram. This informs our proposed study in which we aim to further develop a family engagement componentand subsequently pilot test the multilevel program: Supporting Physical Literacy at School and Home(SPLASH). The SPLASH home component will be informed by focus groups with n=80 parents in NYC (n=40)and Greater Boston MA (n=40). We will then pilot the multilevel SPLASH program to evaluate implementationprocesses and outcomes. This will be accomplished in n=8 New York City (NYC) schools using a mixed-methods approach. The learnings from the R21 phase will further inform the final development andimplementation of the SPLASH program during the R33. In the R33 phase we will conduct a grouprandomized trial in MA to determine the impact of the full multilevel SPLASH program on children's PL andtotal daily PA and MVPA. We propose to assess these outcomes in n=8 randomly selected schools (n=4intervention n=4 control delayed intervention) using a pre-post study design with objective measurement(accelerometry) of PA and valid reliable tools for PL assessment. We will further examine whether effects ofthe multilevel program differ by child sex or weight status and test whether changes in PL mediate changes indaily total PA volume or MVPA. This randomized and controlled study will provide empirical evidence about theefficacy of a multilevel PL-focused program on children's PL and PA. If the results demonstrate effectivenessTufts and New York Road Runners collectively have the dissemination experience and networks to scale theprogram nationally. 251027 +No NIH Category available Acceleration;Adaptive Immune System;Address;Antibodies;Antigen Receptors;Antigen Targeting;Antigens;Autologous;B-Cell Antigen Receptor;B-Lymphocytes;Binding;Binding Sites;Bispecific Antibodies;Cell Line;Cell Maturation;Cell Surface Proteins;Cells;Cessation of life;Clinical;Clinical Trials;Development;Disease Progression;Down-Regulation;Engineering;Engraftment;Goals;Growth;Hagfish;Hematologic Neoplasms;Human;Human Volunteers;Immune;Immune Targeting;Immunoglobulins;Immunologic Receptors;Immunotherapy;In Vitro;Individual;Lampreys;Lentivirus;Leucine-Rich Repeat;Lymphocyte;Malignant Neoplasms;Modeling;Monoclonal Antibodies;Monoclonal Antibody Therapy;Monoclonal gammopathy of uncertain significance;Multiple Myeloma;Mus;Natural Killer Cells;Normal Cell;Patients;Pharmacology and Toxicology;Phase;Plasma Cells;Plasmablast;Prior Therapy;Production;Refractory;Refractory Disease;Relapse;Resistance;Small Business Innovation Research Grant;Source;Specificity;Surface Antigens;T cell therapy;T-Lymphocyte;Therapeutic;Toxic effect;Tumor Cell Line;Tumor-Derived;Vertebrates;antigen binding;antitumor effect;beta pleated sheet;cell preparation;cell type;chimeric antigen receptor T cells;cytotoxicity;experience;first-in-human;humanized mouse;immune modulating agents;improved;in vitro Assay;in vivo;in vivo evaluation;monomer;mouse model;multicatalytic endopeptidase complex;neoplastic;neoplastic cell;novel;novel strategies;novel therapeutics;phase 1 study;receptor;recoverin protein;relapse patients;resistance mechanism;response;targeted treatment;therapeutic target;tumor Novel targeted CAR-T multiple myeloma therapy PROJECT NARRATIVEIn spite of major therapeutic advances including recent CAR-T and bispecific antibody T cell-directedtherapies multiple myeloma remains an incurable cancer for most patients. The goal of this phase 1 SBIRapplication is to accelerate development of a new CAR-T multiple myeloma therapy for patients that havefailed all other therapies including the recent T cell-directed therapies. NCI 10821186 9/19/23 0:00 PA-22-176 1R43CA287584-01 1 R43 CA 287584 1 "TRIPURANI, SWAMY KRISHNA" 9/19/23 0:00 2/29/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 12073550 "CANNON, LOVICK EDWARD" Not Applicable 5 Unavailable 79083146 WKYDVLA9B616 79083146 WKYDVLA9B616 US 33.837181 -84.256909 10035415 "NOVAB, INC." ATLANTA GA Domestic For-Profits 303361627 UNITED STATES N 9/19/23 0:00 2/29/24 0:00 395 SBIR/STTR 2023 301956 NCI 230312 51890 PROJECT SUMMARYMultiple myeloma (MM) a malignancy of plasma cells (PCs) is responsible for over 12500 deaths in the US and over117000 deaths worldwide annually. Over 91000 individuals in the US and over 300000 worldwide currently live withMM. In spite of major therapeutic advances in the past two decades MM remains incurable and most MM patientssuccumb to the underlying malignancy. Recent therapies redirecting T cells via chimeric antigen receptor-T cells (CAR-Ts)or bispecific antibodies that target B Cell Maturation Antigen (BCMA) have significantly improved survival of patients withdisease refractory to prior therapies. However nearly all MM patients experience disease progression and becomerefractory to these BCMA-targeted T cell therapies. There is therefore an urgent unmet need to develop new targets forthese potent T cell-directed MM therapies. This phase 1 SBIR application addresses that need with a novel monoclonalantibody (mAb) designated MM3. MM3 belongs to a new class of antibodies Variable Lymphocyte Receptor B (VLRB)antibodies produced by the B cells of jawless vertebrates lamprey and hagfish and specifically binds to a distinctive formof a well-validated MM therapeutic target multimeric forms of the CD38 cell surface protein with no detectable bindingto CD38 monomers. CD38 multimers are uniquely expressed by PCs and MM tumors whereas CD38 monomers areexpressed by numerous other normal cell types including NK and T cell immune effectors. CAR-T cells that utilize MM3 astarget recognition domain therefore avoid potential on-target/off-tumor toxicity associated with binding to monomericCD38 fratricide among CAR-T cells that express both monomeric CD38 and CAR antigen binding domains that bindmonomeric CD38 and depletion of NK and T cell immune effectors. Multimeric CD38 is highly expressed by the tumorcells of relapsed-refractory MM (RRMM) patients refractory to proteasome and/or immunomodulator drugs. Althoughdownregulation of CD38 expression is one of several mechanisms of resistance to anti-CD38 mAb therapy e.g.daratumumab high levels of CD38 and multimeric CD38 expression return within 3 to 6 months of anti-CD38 mAb therapydiscontinuation and MM tumor cells of over 87% of RRMM patients express high levels of CD38 multimers detected withMM3. MM3 human CAR-T cells have been produced and shown with in vitro assays to direct CAR-T killing only to cellsthat express multimeric CD38. This application will extend those results by: (1) producing MM3 CAR-T cells with T cellpreparations derived from healthy human volunteers and from patients relapsed following anti-BCMA CAR-T therapy andevaluating in vitro target-specific activation and cytotoxicity against a MM cell line and autologous MM tumor cells fromanti-BCMA CAR-T relapsed MM patients and (2) evaluating the in vivo anti-tumor efficacy of MM3 CAR-T cells withMISTRG6 humanized mice engrafted with a human MM tumor cell line. These phase 1 studies will be followed by phase2 in vivo evaluations of MM3 CAR-Ts produced with RRMM patient T cells against tumors from those same patients in theMISTRG6 model and by GMP production of MM3 CAR lentivirus and MM3 CAR-T cells and IND-enablingpharmacology/toxicology studies to support first in human clinical trials of this new CAR-T therapy for MM patients thathave failed all other therapies. 301956 +No NIH Category available Acute;Antineoplastic Agents;Biochemical;Bioinformatics;Biological Assay;Biology;Categories;Cells;Chemical Structure;Chemicals;Collaborations;Collection;Complex;Consumption;Data;Data Set;Development;Evaluation;FDA approved;Genes;Image;Libraries;Link;Methods;Natural Products;Natural Source;Nature;Pathway interactions;Pharmaceutical Preparations;Phenotype;Pilot Projects;Process;Proteomics;Research;Research Personnel;Services;Signal Pathway;Structure;System;Systems Biology;Techniques;Technology;Time;Work;Yeasts;anti-cancer;anticancer activity;bioprocess;chemical genetics;cost;drug development;drug discovery;economic value;follow-up;fungus;in silico;interest;novel;novel anticancer drug;novel strategies;pharmacologic;preclinical development;response;scaffold;screening;transcription factor;transcriptomics;wasting Assigning mode of action to phenotypically discovered anticancer leads. Title: Assigning mode of action to phenotypically discovered anticancer leads.Narrative.Developing drugs from natural sources is difficult because we don't know how they work. Herewe use advanced Attagene's technology to create a new method to understand the mechanismof action of anticancer compounds from fungi. If it works it could make it much easier todevelop new anticancer drugs. NCI 10821103 9/21/23 0:00 PA-22-176 1R44CA285062-01A1 1 R44 CA 285062 1 A1 "BOZZA, WILLIAM PATRICK" 9/21/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-MBBC-G(10)B] 8906160 "MAKAROV, SERGEI S" "OBERLIES, NICHOLAS H." 4 Unavailable 147164193 Z8AYGD59N8U4 147164193 Z8AYGD59N8U4 US 35.857153 -78.870868 4440101 "ATTAGENE, INC." RESEARCH TRIANGLE PARK NC Domestic For-Profits 277092054 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 396 SBIR/STTR 2023 1000000 NCI 734062 213605 ABSTRACT.Assigning the mode of action to bioactive compounds is an essential step in drug discovery and a major challengein chemical biology. This problem is particularly acute for drug discovery from nature. Natural products (NP)provide unique scaffolds not found in synthetic libraries and the abundant NP collections are a vast diversityreservoir for drug development. However the lack of mechanistic understanding is a major hindrance to preclinicaldevelopment. Existing HTS techniques permit efficacious screening of NP libraries but the follow-up purificationchemical structure identification and MOA assessment of purified metabolites are lengthy costly and tedious.Worse as the MOA is determined only at the end much effort is wasted on isolating redundant and irrelevant hits.Since the purification of active constituents requires significant work it should be performed only for high-valuemolecules with pharmacological novelty. Currently used MOA assessment approaches employ various platforms including panels of cell-based andbiochemical assays and systems biology techniques but none provide a satisfactory solution for the MOAproblem. Here we describe an alternative MOA evaluation technique based on a systems biology approachdeveloped at Attagene. Under this approach cell response is characterized by the activity of transcription factors(TF) that link cellular signaling pathways to genes. The enabling technology is the FACTORIAL a proprietaryAttagene platform for quantitative TF activity profiling (TFAP). We demonstrated that TFAP signatures enable astraightforward MOA assessment of chemicals by pinpointing perturbed bioprocesses and cell systems. Mostimportantly this approach does not involve complex bioinformatic inferences. Here we will extend the TFAPapproach to ascribe the MOA to anticancer drug leads from nature. In pilot studies we examined TFAPsignatures of approved anticancer drugs and anticancer fungal metabolites. We found that (i) major classes ofapproved anticancer drugs have specific TFAP signatures; (ii) anticancer fungal metabolites too have distinctTFAP signatures. Moreover these signatures allowed correct identification of metabolites' MOA; (iii) mostunexpectedly crude fungal extracts and purified active metabolites showed identical TFAP signatures. These datasuggest a new approach to the mechanistic evaluation of nature-derived anticancer leads. We will develop thisapproach with a UNC-Greensboro team with over 700 purified anticancer fungal metabolites with establishedstructures. First we will obtain TFAP signatures for all FDA-approved drugs and a large fraction of the UNCGlibrary (SA1). Then we will analyze these TFAP datasets and compare the 'MOA spaces' for the anticancer fungalmetabolites and approved drugs to identify metabolites with novel MOA (SA2). Finally we will validate theapproach to identify the MOA in crude fungal extracts allowing prioritizing high-value strains for purification(SA3). Implementing this proposal will establish a new approach that uses a single instrumental platformdoes not involve bioinformatic analyses and allows ascribing the MOA to unpurified NP extracts. 1000000 +No NIH Category available Adverse effects;Age;Algorithms;Archives;Biochemical;Biological Assay;Biological Markers;Biopsy;Blood Tests;Businesses;Clinical;Collection;Custom;DNA;DNA copy number;Data;Diagnosis;Diagnostic Neoplasm Staging;Discrimination;Disease;Event;Eye;Formalin;Foundations;Genetic;Genomics;Gleason Grade for Prostate Cancer;Goals;Guidelines;Hospitals;Indolent;Laboratories;Legal patent;Licensing;Malignant neoplasm of prostate;Metastatic Prostate Cancer;Methods;Microscope;Minor;Modeling;Morbidity - disease rate;Neoplasm Metastasis;Newly Diagnosed;Operative Surgical Procedures;Outcome;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patients;Performance;Phase;Predictive Value;Principal Investigator;Prostate;Prostate-Specific Antigen;Prostatic Neoplasms;Publishing;RNA;Radiation therapy;Rectum;Recurrence;Reporting;Retrospective Studies;Risk;Risk Marker;Sampling;Sensitivity and Specificity;Serinus;Services;Small Business Innovation Research Grant;Specificity;Stage at Diagnosis;Sushi Domain;Testing;Time;Tissue Embedding;Tissues;Tube;United States National Institutes of Health;Validation;Work;cancer diagnosis;cohort;commercialization;digital;genomic biomarker;improved;individualized medicine;innovation;men;overtreatment;prostate cancer risk;public health relevance;rectal;risk prediction;side effect;surveillance study;targeted sequencing;tool;treatment choice;tumor Genomic marker to distinguish aggressive and indolent prostate cancer Public Health RelevanceSome prostate tumors appear similar under a microscope to a pathologists eye but follow drastically differentdisease courses. Although primary treatment (e.g. surgery) can be curative it can have serious side effects. Wehave developed a tool to assist the clinician at diagnosis to identify which patients have tumors that are moreaggressive and are in need of immediate therapy and those that are more indolent and candidates for ActiveSurveillance. NCI 10820859 9/22/23 0:00 PA-22-176 1R43CA287601-01 1 R43 CA 287601 1 "FRANCA-KOH, JONATHAN C" 9/22/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CDPT-V(13)B] 79365246 "DAVIS, RANDALL " "PARIS, PAMELA L" 15 Unavailable 118137529 CDKBYQB7U4Q6 118137529 CDKBYQB7U4Q6 US 10066193 BIOMARKER CORPORATION SOUTH SAN FRANCISCO CA Domestic For-Profits 940801998 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 404201 NCI 316829 63099 ABSTRACTProstate cancer is the most commonly diagnosed cancer in men with an estimated 268490 new cases in theU.S. in 2022. At the time of a prostate cancer biopsy pathologists use the tumor material to determine the gradeand stage. Primary treatment decisions are based on the biopsy tissue information and the PSA (prostate specificantigen blood test). About 80% of newly diagnosed cases are considered low-risk. Since in the majority of newlydiagnosed low-risk prostate cancer cases the disease is indolent (~70%) and surgery comes with significantadverse effects a unique treatment option for many men with prostate cancer is Active Surveillance. There isan urgent need for biomarkers that could supplement standard clinical variables (i.e. Gleason score PSA tumorstaging number of positive biopsies patient age) to predict tumors that will become aggressive cases thatrequire treatment and those that can safely elect Active Surveillance. The DNA copy number signature of thetumor called GEMCaP (Genomic Evaluators of Metastatic Cancer of the Prostate) was discovered by thePrincipal Investigator. GEMCaP was validated in the post-surgery setting to identify those cases poised forbiochemical recurrence and metastasis. GEMCaP was recently evaluated in the Active Surveillance setting usingarchived surgical tissue adjacent to where the biopsy was sampled in men with low-risk prostate cancer asdefined by clinical variables. GEMCaP independently predicted adverse pathology alongside a commerciallyavailable RNA risk predictor. When combined with clinical variables GEMCaP resulted in improved predictivepower of biochemical recurrence post-surgery compared to a commercial RNA assay. GEMCaP was also shownto identify cases that can safely be managed with Active Surveillance which has not previously been achievedby commercially-available RNA competitor products. The goal of Biomarker Corporations NIH SBIR Phase Iproject is to work toward commercializing GEMCaP using biopsy tissue and a custom sequencing panel. Biopsybiospecimens for this study will be provided by the Canary Foundations well-annotated Active Surveillancebiospecimen collection of biopsy tissue with associated clinical variables and outcome data. The study will usea commercial RNA biomarker assay as a comparator. The aims of this project are to 1) Determine if GEMCaPcan identify aggressive CaP in a cohort of patients considered clinically low-risk based on biopsies and compareBiomarker Corp.s proprietary algorithm in the Active Surveillance setting with the binary cut-off method 2) TestGEMCaP in identifying low-risk cases who can safely stay on Active Surveillance 3) Compare GEMCaPsperformance to a commercially available RNA predictor. In Phase II we will validate our findings in a larger cohortusing the calling method identified in Aim 1. Successful clinical validation as a Phase II and implementation ofGEMCaP will improve prediction accuracy and thereby reduce overtreatment of men with indolent prostatecancer. 404201 +No NIH Category available Academy;Actinic keratosis;Address;Aftercare;American;Area;Biological Sciences;CD4 Positive T Lymphocytes;Calcipotriene;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cold Therapy;Cream;Curettage procedure;Data;Dermatologist;Dermatology;Development;Diagnosis;Diffuse;Dose;Double-Blind Method;Drug Prescriptions;Effectiveness;Effector Cell;Exhibits;Face;Fluorouracil;Formulation;Goals;Health Insurance;Healthcare Systems;Immune response;Immune system;Immunity;Immunocompetent;Incentives;Individual;Insurance;Insurance Carriers;Keratosis;Knowledge;Legal patent;Lesion;Malignant Neoplasms;Market Research;Marketing;Metabolic Clearance Rate;Mission;Morbidity - disease rate;Multicenter Studies;National Cancer Institute;National Comprehensive Cancer Network;Neck;Outcome;Patients;Pharmaceutical Preparations;Pharmacy facility;Phase;Phase II Clinical Trials;Physicians;Placebo Control;Placebos;Price;Probability;Public Health;Publishing;Randomized;Reaction;Recommendation;Regimen;Regulation;Reporting;Research;Research Design;Risk;Risk Reduction;Safety;Sales;Scalp structure;Skin;Skin Carcinoma;Small Business Innovation Research Grant;Technology;Treatment Cost;UV induced;United States;United States Food and Drug Administration;adaptive immune response;arm;beneficiary;cancer type;commercial application;cost;design;dosage;efficacy evaluation;improved;interest;melanoma;mortality;open label;phase 3 study;premalignant;prevent;price lists;primary endpoint;randomized trial;recruit;secondary endpoint;side effect;skin lesion;skin squamous cell carcinoma;technological innovation;treatment duration;willingness A Phase 2 randomized double-blind 4-arm multicenter study to demonstrate the efficacy and safety of topical dosage formulations of a prescription drug product for actinic keratosis PROJECT NARRATIVENon-melanoma skin cancers are a growing public health challenge that cost the United States (U.S.) healthcaresystem more than $1 billion in treatment costs annually. Actinic Keratoses (AK) are ultraviolet light inducedpremalignant skin lesions that are precursors to cutaneous squamous cell carcinoma (CSCC). CSCC is thesecond most common type of cancer is associated with significant morbidity and results in more deaths thanfrom melanoma in the U.S. each year. This Direct Phase II SBIR proposal builds upon two successfullycompleted clinical trials and aims to complete a Phase 2 randomized double-blind 4-arm multicenter study todemonstrate the efficacy and safety of topical dosage formulations of Calcipotriol (CPO) plus 5-Fluorouracil (5-FU) for the treatment of AK. NCI 10820810 9/14/23 0:00 PA-22-177 1R44CA288166-01 1 R44 CA 288166 1 "POND, MONIQUE ADRIANNE" 9/14/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-MSOS-D(10)B] 10122259 "ISAACMAN, STEVEN " Not Applicable 50 Unavailable 831297770 PM3SN3WEQW86 831297770 PM3SN3WEQW86 US 40.730918 -73.993819 10023522 "NANOMETICS, LLC" La Jolla CA Domestic For-Profits 920374614 UNITED STATES N 9/14/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1000000 NCI 667557 267023 PROJECT SUMMARY / ABSTRACTAcinic Keratoses (AK) are premalignant skin lesions with the potential to develop into Cutaneous Squamous cellCarcinoma (CSCC) which is the second most common type of cancer and when metastatic has a mortality ratethat is higher than melanoma. There is a high unmet need for topical AK medications with shorter treatmentdurations and enhanced efficacy that can eradicate AK and treat the surrounding cancerized field.The Product of this SBIR will be a Food and Drug Administration approved fixed dose combination creamcontaining calcipotriol (CPO) and 5-fluorouracil (5-FU) as a treatment for AK in immunocompetent patients.Technological Innovation: Topical co-administration of CPO / 5-FU eradicates AKs by activating CD4+ T celldominated immunity an upstream activator of the adaptive immune response which then recruits an array ofdownstream effector cells to block CSCC development.The Long-Term Goal is the registration of the SBIR product which directly addresses the mission of the NationalCancer Institute by harnessing the power of the immune system to treat AKs and prevent CSCC.Phase I SBIR Equivalent Studies demonstrated the clinical and commercial feasibility of the PHD technologyfor AK treatment. Successfully completed randomized (n=130) and open label clinical studies (n=18)demonstrated the feasibility of the CPO / 5-FU combination as the best-in-class treatment for AK and the onlyproduct ever reported to reduce the risk of CSCC development at 3-years post treatment. The high impact of thepublished data has resulted in the National Comprehensive Cancer Network and the American Academy ofDermatology recommending CPO / 5-FU as a treatment for AK. Market research demonstrated prescriber andpatient enthusiasm for the PHD product and confirmed that health insurance companies will provide broadcoverage to beneficiaries at a price that will generate meaningful revenues for the company.Specific Aim 1. Complete a Phase 2 Randomized Double-blind 4-Arm Multicenter Study to Demonstrate theEfficacy and Safety of Topical Dosage Formulations of CPO plus 5-FU for the treatment of AK.Phase II Objectives: Conduct a Phase 2 clinical trial to assess the efficacy and safety of topical dosageformulations containing two different concentrations of CPO plus 5-FU in 160 AK patients.Expected Outcomes: 5-FU / CPO is expected to be well-tolerated and significantly more efficacious than 5-FUmonotherapy and placebo. The data will enable dose selection and design of the Phase 3 registrational studies.Commercial Opportunity: The target customer will be dermatologists and peak revenues of $285 mil areprojected at the lowest probable list price with 93% of patients paying $25 out-of-pocket. 1000000 +No NIH Category available Adoption;Architecture;Automobile Driving;Award;Benchmarking;California;Caring;Categories;Certification;Clinical;Clinical Data;Clinical/Radiologic;Collaborations;Communication;Computer Vision Systems;Computer software;Data;Development;Diagnosis;Digital Imaging and Communications in Medicine;Dose;Electronic Health Record;Electronics;Equity;Fast Healthcare Interoperability Resources;Feedback;Funding;Graph;Health;Health Insurance Portability and Accountability Act;Health Status;Healthcare Systems;Hospitals;Image;Informatics;Information Systems;Information Technology;Ingestion;Inpatients;Intellectual Property;Interview;Link;Machine Learning;Malignant Neoplasms;Measures;Medical Imaging;Minority;Modernization;Outpatients;Patient imaging;Patients;Performance;Persons;Physicians;Picture Archiving and Communication System;Radiation;Radiation Dose Unit;Radiology Information Systems;Radiology Specialty;Randomized Controlled Trials;Recommendation;Report (document);Reporting;Resources;Risk;San Francisco;Secure;Services;Site;Source;Specific qualifier value;Standardization;Surveys;System;Techniques;Technology;Testing;Time;U-Series Cooperative Agreements;United States Centers for Medicare and Medicaid Services;Universities;Visualization;Work;X-Ray Computed Tomography;cancer diagnosis;cancer risk;comparative;data access;data management;data visualization;electronic health data;financial incentive;firewall;health disparity;imaging facilities;imaging software;novel;patient safety;payment;peer;prevent;programs;radiological imaging;radiologist;service organization;software development;structured data;success The Alara Imaging Gateway: Linking Electronic Health Records and Radiology Imaging Exams to Report on National Quality Measures to Reduce Cancer Risk from Computed Tomography (Alara Imaging Gateway) Project NarrativeA quality gap exists in the performance of computed tomography (CT) as radiation doses are higher thanneeded for diagnosis and vary depending on where a patient goes for care. Alara Imaging has developedpatient safety measures that are focused on the radiation dose and image quality for CT and are beingconsidered for use in the Centers for Medicare and Medicaid Services (CMS) quality payment programs; theuse of these measures has the potential to reduce the doses used for CT to make CT safer. Alara Imaging isseeking funding to support the development of commercially built software that hospitals and physicians canuse to report on these measures as well as seeking funding to build software to help guide physicians to lowerthe doses they use for CT. NCI 10820279 9/19/23 0:00 PA-22-176 1R44CA287536-01 1 R44 CA 287536 1 "TRIPURANI, SWAMY KRISHNA" 9/19/23 0:00 2/28/25 0:00 Special Emphasis Panel[ZRG1-HSS-J(10)B] 79107643 "MAZONSON, NATHAN " Not Applicable 4 Unavailable 117696627 JLBVYU6MLDL8 117696627 JLBVYU6MLDL8 US 10070785 ALARA IMAGING INC. WESTPORT CT Domestic For-Profits 6880 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1316275 NCI 1203162 113113 AbstractAlara Imaging Inc. (Alara) is seeking funding to support the development of robust IP-protected HIPAA-compliant commercial quality software to calculate and report on quality measures that will be reported forevery radiologist and hospital group in the nation. Further Alara is seeking funding to develop enhancedfeedback that leverages machine learning data visualization and benchmarking to guide physicians andhospitals on safe approaches for lowering their CT radiation doses. Once implemented at scale through thesupport of this award Alaras software has the potential to reduce the cancers that result from CT by up to30% preventing as many as 10000 cancers annually.The use of CT has grown substantially over the last 2 decades with 90 million CT exams performed annually inthe U.S. A major quality gap exists in the performance of CT as the radiation doses used for these exams arehigher than needed for diagnosis and in the range where they increase a person's risk of developing cancer; itis estimated that CT use causes 36000 cancers annually in the U.S.1 The inconsistency in how CT exams areperformed represents a modifiable health risk as radiation doses can be reduced through audit and feedbackas shown in a UCSF led NCI funded trial.2In 2019 UCSF was awarded a cooperative agreement from CMS to develop CT radiation dose and imagequality measures for use in the agencys pay-for-performance programs. The intent of this award was tomotivate radiologists and hospitals and to reduce unnecessarily high radiation doses through financialincentives. UCSF created the approach to judge each CT by combining clinical and radiology data located indisparate health data systems including the Electronic Health Record Radiology Information System andPicture Archiving and Communication System. These data systems communicate poorly and properlyingesting and normalizing these data in real time was a technological challenge. Additionally as a stipulation ofthe funding CMS required UCSF to develop these measures as electronic clinical quality measures (eCQM);however the resources required to develop and implement an eCQM at the national level were beyond whatwas available to Dr. Smith-Bindman from CMS. As a result Dr. Smith-Bindman in collaboration with UCSF asa minority equity stakeholder worked with radiology informatics experts to create a commercial entity Alara todevelop the eCQMs and software for national implementation. The measures are now being considered foruse in CMS quality payment programs and Alara is now seeking funding to implement the measures at scale.In addition to the CMS measure functionality the softwares architecture will represent a meaningfultechnological advancement and creates value beyond measure reporting by linking and providing access tocombined clinical and radiology data connected to the cloud. Information technology companies that aredriving care forward in radiology using novel machine learning and computer vision techniques need access tothe same linked data so that they can leverage modern technology applications. Alaras software TheGateway solves this integration and data access challenge and Alara will sell access to the Gateway totechnology companies opening possibilities for technology companies to develop additional solutions that takeadvantage of the linked and structured data. 1316275 +No NIH Category available Academic Medical Centers;Address;American College of Surgeons;American College of Surgeons Oncology Group;Cancer and Leukemia Group B;Clinical Research;Clinical Trials;Collaborations;Community Clinical Oncology Program;Decision Making;Development;Effectiveness;Ensure;Environment;Funding;Goals;Infrastructure;Institution;Leadership;Malignant Neoplasms;North Central Cancer Treatment Group;Oncology;Operative Surgical Procedures;Policies;Positioning Attribute;Principal Investigator;Procedures;Process;Productivity;Research;Research Personnel;Research Priority;Structure;System;Time;Translational Research;conflict resolution;design;health care delivery;innovation;meetings;member;operation;organizational structure;programs;response;rural setting;success;symptom management;treatment group;urban setting Administrative Core The Project Narrative has been addressed in the Overall Component per the RFA NCI 10820176 5/1/23 0:00 PA-20-272 3U10CA180821-10S1 3 U10 CA 180821 10 S1 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 ZCA1 8322 1879065 "BERTAGNOLLI, MONICA M" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 Other Research-Related 2023 2824605 2347717 476888 The Project Summary/Abstract has been addressed in the Overall Component per the RFA +No NIH Category available Address;Baltimore;Benign;Biological Markers;Blinded;Blood Plasma Volume;Cancer Detection;Caring;Certification;Cessation of life;Clinic;Clinical;Clinical Laboratory Improvement Amendments;Clinical Research;Collaborations;Complement;Complex;Data;Development;Diagnosis;Diagnostic Procedure;Diagnostic tests;Environment;Evaluation;Future;Growth;Healthcare Systems;Institutional Review Boards;Laboratories;Laboratory Research;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maryland;Medical;Medicare;MicroRNAs;Morbidity - disease rate;Non-Small-Cell Lung Carcinoma;Performance;Phase;Plasma;Population;Preparation;Procedures;Process;Protocols documentation;Quality Control;Recommendation;Reflex action;Reproducibility;Resources;Reverse Transcription;Sampling;Scanning;Scientist;Secure;Smoker;Specificity;Specimen;System;Target Populations;Technology;Testing;Therapeutic procedure;Translating;United States Centers for Medicare and Medicaid Services;Universities;Variant;biomarker panel;biomarker validation;cancer diagnosis;cohort;computed tomography screening;cost;design;effective therapy;follow-up;geographically distant;laboratory equipment;low dose computed tomography;lung cancer screening;microRNA biomarkers;mortality;multidisciplinary;new technology;next generation sequencing;performance tests;predictive modeling;prospective;research clinical testing;sample collection;screening program;smoking-related disease;success Plasma biomarkers for lung cancer diagnosis Project narrative This proposed project will develop a plasma test that can supplement CT screening forprecisely detecting lung cancer. NCI 10820171 9/6/23 0:00 PAR-18-317 4UH3CA251139-03 4 UH3 CA 251139 3 "MARQUEZ, GUILLERMO" 9/17/20 0:00 3/31/26 0:00 ZCA1-SRB-K(M2)S 7820514 "JIANG, FENG " "STASS, SANFORD A" 7 PATHOLOGY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 394 Non-SBIR/STTR 2023 324669 NCI 213149 111520 Project Summary-Abstract Because the early detection of lung cancer by low-dose CT (LDCT) can reduce the mortalityannual LDCT screening is now being reimbursed by Centers for Medicare & Medicaid Services(CMS) for smokers insured through Medicare. However more than one-quarter of screensdiscover indeterminate pulmonary nodules (PNs). 4% of PNs are early-stage lung cancers whilethe remaining 96% are benign. Therefore LDCT has over-diagnosis. There is an unmet need fora reflex test for LDCT follow-up to focus care on the 4% smokers need it. The objective of thisproject is to develop and validate a plasma test for differentiating malignant from benign PNs atbaseline LDCT. Future use of this test for discriminating between malignant and benign PNs willcomplement LDCT for lung cancer detection by reducing the over-diagnosis and eventuallydecrease the deaths and cost. 324669 +No NIH Category available Address;Atlases;Bacteria;Biological Assay;Biology;Blood;Carcinoma;Cells;Chemistry;Classification;Clinical Data;Collection;Colon;Colonic Adenoma;Colonoscopy;Colorectal;Colorectal Cancer;Colorectal Polyp;Communities;Data;Data Analyses;Data Analytics;Data Collection;Data Set;Detection;Ecosystem;Epidemiology;Epithelial Cells;Excision;Fluorescent in Situ Hybridization;Future;Gene Expression Profile;Goals;Grant;Guidelines;Human;Immunofluorescence Immunologic;Incidence;Injury;Laboratories;Lead;Lesion;Location;Malaysia;Malignant Neoplasms;Medical;Microbial Biofilms;Modeling;Molecular;Neoplastic Cell Transformation;Operative Surgical Procedures;Participant;Patients;Polyps;Precancerous Polyp;Prevention strategy;Process;Proteomics;Publishing;Research;Sampling;Specimen;Standardization;T-Cell Proliferation;Tissues;Training;Tumor Tissue;Tumor-Infiltrating Lymphocytes;Validation;Work;adenoma;analytical tool;base;clinically relevant;colon carcinogenesis;colorectal cancer prevention;data integration;design;epidemiologic data;exome sequencing;exposed human population;genome sequencing;human tissue;improved;member;microbiome;mortality;premalignant;prevent;prospective;risk stratification;sample collection;screening;single-cell RNA sequencing;stem cells;transcriptomics;tumor Integrative Single-Cell Atlas of Host and Microenvironment in Colorectal Neoplastic Transformation n/a NCI 10820067 8/18/23 0:00 PA-20-272 3U2CCA233291-01S2 3 U2C CA 233291 1 S2 "MAZURCHUK, RICHARD V" 5/1/23 0:00 8/31/24 0:00 1901947 "COFFEY, ROBERT J." "SHRUBSOLE, MARTHA J." 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 5/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 1040698 NCI 706743 333955 Statement of WorkDr. Sears will be co-leader of the Tissue Characterization Core of this Atlas grant working withDr. Ken Lau (Vanderbilt). Dr. Sears and her laboratory will provide technical and analyticalexpertise on biofilm detection on human colon tissues. The Sears laboratory will train membersof the Tissue Characterization Core in colon biofilm detection and will serve to independentlyread and validate a subset of colon tissue specimens once training is complete. This validationand cross-checking process will continue throughout the grant period. Furthery Dr. Sears andher laboratory will participate in studies to address the relationship and contribution of colonbiofilm formation to early colon carcinogenesis. This goal will be addressed through 2 core aims:1) identifying the epidemiology of biofilm formation in colon adenomas; and 2) defining changes insingle epithelial cell expression and proteomics in biofilm-positive vs biofilm-negative adenomas.Clinically relevant parameters for detecting and quantifying colon biofilms will be developed.Dr. Anders is an expert in defining the type number and location of cells in tumor samples. Hehas published on the MANAFEST assay which is put forth as a proof of concept in year 5 of thisapplication. He will assist Dr. Lau on the collection and processing of blood and patient tissuefor MANAFEST assays as described in year 5 of this Atlas grant. Once processed the materialwill be shipped from Vanderbilt to Ors. Anders' laboratory who will help with the exomesequencing of the tumor tissue the quantification and characterization of tumor infiltratinglymphocytes and the wet chemistry involved in the T-cell proliferation assay.1. The Lau Lab will perform scRNA-seq on human tissues and deliver the data.2. The Lau Lab will perform spatial transcriptomics on human tissues and deliver the data.3. The Lau Lab will perform exome and genome sequencing on human tissues and deliver the data.4. The Lau Lab will coordinate with other centers and conduct trans-atlas analyses on the colon. 1040698 +No NIH Category available 3-Dimensional;Acceleration;Affect;Ally;Anatomy;Archives;Area;Atlases;Biological Markers;Biopsy;Biopsy Specimen;Cancer Biology;Cancer Center;Cancer Model;Cancer Patient;Cataloging;Cells;Clinical;Clinical Oncology;Clinical Research;Clinical Treatment;Clinical Trials;Clonal Evolution;Clonality;Collaborations;Communities;Comprehensive Cancer Center;Cytometry;DNA;Data;Data Analyses;Data Set;Dimensions;Discipline;Disease;Ecosystem;Ensure;Evolution;FAIR principles;Fostering;Foundations;Future;Generations;Genes;Genome;Genomics;Glioblastoma;Goals;Histopathology;Human;Image;Immune;Immunofluorescence Immunologic;Individual;Informatics;Infrastructure;Institution;Knowledge;Link;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Medicine;Methodology;Minority Groups;Modeling;Molecular;Mutate;Mutation;Neoplasm Metastasis;Organ;Pancreatic Ductal Adenocarcinoma;Pathology;Pathway Analysis;Pathway interactions;Patient Recruitments;Patients;Phase;Phenotype;Physicians;Pilot Projects;Positron-Emission Tomography;Process;Prognosis;Proteins;Proteome;Proteomics;Recurrence;Reporting;Research;Research Personnel;Resistance;Sampling;Series;Site;Slice;Solid Neoplasm;Spatial Distribution;Specimen;Structure;Time;Tissues;Translational Research;United States National Institutes of Health;Universities;Validation;Washington;analysis pipeline;anticancer research;cancer cell;cancer therapy;cancer type;cell type;chemotherapy;clinical application;clinical care;clinical imaging;cohesion;data integration;density;dimensional analysis;diverse data;drug resistance development;exome sequencing;experience;genome sequencing;improved;in vivo;innovation;liquid chromatography mass spectrometry;malignant breast neoplasm;medical schools;metabolome;metabolomics;multidisciplinary;neoplastic cell;new technology;new therapeutic target;patient population;premalignant;relational database;response;single-cell RNA sequencing;synergism;therapeutic development;therapy resistant;three dimensional structure;three-dimensional modeling;tool;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor progression;whole genome WASHINGTON UNIVERSITY HUMAN TUMOR ATLAS RESEARCH CENTER Project NarrativeThe recent Cancer Moonshot Blue Ribbon Panel Report (2016) laid out a roadmap for accelerating cancerresearch and clinical application of findings one of the necessary components being the generation of tumoratlases. We propose to combine our expertise in clinical oncology cancer biology Omics imaging andinformatics to establish a WU-HTARC with the goal of constructing detailed 4D atlases for three important cancertypes BRCA GBM and PDAC. These Atlases will leverage the recent advances in multiple related fields andwill provide highly comprehensive data sets at the molecular cellular and tissue levels over multiple time pointsof clinical treatment. Such longitudinally collected diverse data sets connected by spatial coordinates will helpreveal the evolution of the cancer cells the tumor ecosystem the development of drug resistance andmetastasis. These interconnected atlases the precious specimens collected and the knowledge gained fromthis pilot project will set the foundation for future large scale atlas building across cancer types and will help solvethe most intractable challenges in cancer therapy. NCI 10819927 8/21/23 0:00 PA-20-272 3U2CCA233303-05S1 3 U2C CA 233303 5 S1 "LI, JERRY" 4/4/23 0:00 8/31/24 0:00 9766169 "DING, LI " "FIELDS, RYAN C; GILLANDERS, WILLIAM E." 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 874677 NCI 562493 312184 Project Summary/AbstractDiverse areas of cancer research have progressed to the point that it is now feasible to meaningfully integrateresearch data and clinical information across the molecular cellular and tissue realms into a larger moredetailed picture of the onco-dynamics of cancer including spatial-temporal details during cancer treatment andprogression. Physicians and researchers at Washington University School of Medicine (WUSM) and the SitemanCancer Center (WUSM-SCC) are longtime leaders in the allied sub-disciplines of cancer including genomicsproteomics imaging functional characterization pathology clinical trials and clinical care. WUSM-SCC is anNCI-designated Comprehensive Cancer Center which sees ~9000 new cancer patients annually. Building onour expertise established infrastructure large patient population and extraordinary institutional commitment wepropose to develop the Washington University Human Tumor Atlas Research Center (WU-HTARC) within theNIH Human Tumor Analysis Network (HTAN).We will focus on generating organ-specific human tumor atlases for three high priority cancer types associatedwith exceptionally poor prognosis: the triple negative breast cancer (TNBC) glioblastoma (GBM) and pancreaticductal adenocarcinoma (PDAC). Collectively we will analyze ~1600-2000 samples collected from spatiallyseparated locations and at different time points along the clinical treatment course from 300-375 patients(selected from ~750 recruited patients) for the duration of the project. In addition to standard histopathologicalanalyses bulk DNA/RNA sequencing proteomics and clinical imaging etc. we will conduct cutting-edgecomprehensive analyses including single cell RNA-Seq (scRNA-Seq) multiplexed immunofluorescent proteinlocalization (MxIF) mass cytometry/Cytometry by Time of Flight (CyTOF) cellular characterization metabolomicsanalysis innovative imaging and 3-D modeling.We have established infrastructure covering the aforementioned areas from specimen procurement(Biospecimen Unit) to multidisciplinary analyses modules (Characterization Unit) and to analysis pipelines (DataAnalysis Unit). Data generated from this study will be valuable for revealing the clonal evolution of the tumorcells from longitudinally collected specimens and to reconstruct the tumor ecosystem involving non-cancer cellsand acellular structures. Our atlases will have comprehensive data integration at the 3D level over time providingunprecedented 4D models for the 3 selected cancer types. Our established infrastructure and continuous effortsin incorporating new technologies in omics imaging and informatics will help ensure our atlases will be thestate-of-the-art taking full advantage of the latest progress in these fields and will continue to evolve beyond thepilot phase to facilitate cancer research and improve clinical care.The proposed atlases target a set of critically important clinical questions including tumor resistance that haslong been a challenge for GBM treatment and also an important clinical problem in BRCA/TNBC and PDAC inwhich minority populations are disproportionately affected. Other emphases are BRCA response/resistance tochemotherapy PDAC metastasis and GBM local recurrence in conjunction with resistance to therapy. Theseatlases can cross reference each other for pan-cancer analyses. We will also seek to cooperate with any Pre-Cancer Atlas (PCA) centers studying these disease types to maximize the temporal continuity of research onthese cancers. The similarities and differences among the three selected cancer types will provide synergyamong the three atlases and will also allow us to accumulate valuable knowledge in atlas building for othercancer types. The data specimens and experience gained by our center will be shared with HTAN and thebroader research community to foster the next important discoveries in personalized cancer medicine. 874677 +No NIH Category available Affect;African ancestry;Autoantibodies;Biological;Biological Markers;Boron;Cell surface;Characteristics;Chemoresistance;Clinical;Development;Disparity;Enzymes;European ancestry;Genes;Genetic;Immune;Immune Targeting;Immune response;Incidence;Inflammatory;Life Style;Malignant neoplasm of prostate;Molecular;Pathway interactions;Patients;Pre-Clinical Model;Property;Protein Isoforms;Proteins;Race;Resistance;Role;Therapeutic;Tumor Antigens;advanced prostate cancer;anti-tumor immune response;antitumor effect;cancer health disparity;cancer immunobiology;design;differential expression;enolase;immunoreactivity;innovation;insight;men;migration;mortality;mortality disparity;neoplastic cell;new therapeutic target;novel;prostate cancer cell;racial disparity;response;small molecule;socioeconomics;taxane;theranostics;therapy resistant;tumor "Administrative Diversity Supplement to: ""Role and Theranostics Potential of Enolase in Prostate Cancer Health Disparities""" NARRATIVEMen of African ancestry have a higher incidence and mortality from prostate cancer (PCa) than men ofEuropean ancestry. There is currently an urgency to understand the molecular mechanisms underlyingthese race-related differences and to harness them for identifying novel therapeutic targets. The highmortality of advanced PCa is attributed to therapy resistance thus there is also an urgent clinical needto develop innovative approaches to circumvent this resistance. The proposed study will uncover themolecular basis for specific race-related differences in PCa immunobiology which could provide keyinsights into immune determinants contributing to PCa mortality disparities. The study will also establishthe glycolytic enzyme Enolase as a potential therapeutic and theranostic target for advanced PCa whichcould lead to innovative clinical strategies to reduce overall PCa mortality disparities. NCI 10819907 9/14/23 0:00 PA-21-071 3R21CA280647-01S1 3 R21 CA 280647 1 S1 "WALLACE, TIFFANY A" 4/5/23 0:00 3/31/25 0:00 1876034 "CASIANO, CARLOS A." "ALMAGUEL, FRANKIE G; DAS, BHASKAR CHANDRA" 23 INTERNAL MEDICINE/MEDICINE 9656273 SZAKFNU35ZX5 9656273 SZAKFNU35ZX5 US 34.051744 -117.261784 4562901 LOMA LINDA UNIVERSITY Loma Linda CA SCHOOLS OF MEDICINE 923540001 UNITED STATES N 6/1/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 63587 NCI 48750 14837 Men of African ancestry (AA) have a higher incidence and mortality from prostate cancer (PCa) than men ofEuropean ancestry (EA). These disparities are driven by the interplay between socioeconomic lifestyleenvironmental and biological/genetic factors. Growing evidence indicates that AA and EA men have differencesin their PCa immunobiology resulting in the differential expression of inflammatory gene pathways. Thesedifferences may impact the anti-tumor immune response including the immune targeting of cell surface tumorassociated antigens (TAAs). There is an urgency to understand the molecular mechanisms underlying theserace-related differences and to harness them for identifying novel therapeutic targets. In this multi-PI exploratoryapplication we propose to investigate differences in anti-tumor autoantibody responses to the glycolytic enzymeenolase (ENO) in AA and EA men with PCa and exploit these differences for guiding the development of smallmolecules targeting this protein as novel theranostics agents for advanced PCa. The rationale for the proposedstudies is supported by several key observations: 1) ENO particularly the ENO1 isoform is emerging as a cellsurface TAA with characteristics of an ideal theranostics target whereas the ENO2 isoform could be atheranostic biomarker for NEPC tumors; 2) AA and EA men with PCa produce a differential autoantibodyresponse to ENO; 3) this response has a distinctive impact on the migration of chemoresistant PCa cells; 4) theexpression of ENO2 a cell surface NEPC marker but not that of ENO1 is lost in PCa cells with NEPC markersas they transition to taxane resistance; and 5) we have initiated the design and characterization of novel boron-based ENO1-targeting small molecules that will be evaluated for their antitumor activity and theranosticspotential in pre-clinical models of chemoresistant AA and EA PCa. These observations support the hypothesisthat EA and AA patients with PCa have distinctive immune responses to ENO that differentially affect tumor cellproperties and that these responses may reveal tumor vulnerabilities that could be exploited for the developmentof novel PCa theranostics agents. Aim 1 will determine the mechanisms underlying the differential reactivity andantitumor effects of anti-ENO autoantibodies in AA and EA men with PCa. Aim 2 will synthesize and functionallycharacterize novel boron-based small molecule ENO1 compounds as potential therapeutics for PCa. Theproposed study has high relevance as it will uncover the biological basis for the race-related differential anti-ENO immunoreactivity. This will provide key insights into immune determinants contributing to PCa mortalitydisparities. The study will also establish ENO as a potential theranostic target for advanced PCa which couldlead to innovative clinical strategies to reduce overall PCa mortality and its racial disparities. 63587 +No NIH Category available Award;Geography;Malignant Neoplasms;Parents;Research;therapy resistant The Cellular Geography of Therapeutic Resistance in Cancer Project NarrativeNo changes to Project Narrative from the parent award. NCI 10819853 8/28/23 0:00 PA-20-272 3U2CCA233195-05S1 3 U2C CA 233195 5 S1 "ZHANG, YANTIAN" 4/4/23 0:00 8/31/24 0:00 2092519 "JOHNSON, BRUCE E." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 4/4/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 1241085 NCI 1055989 185096 AbstractNo changes to abstract from parent award. Please see Research Strategy. 1241085 +No NIH Category available 3-Dimensional;Address;Anxiety;Atlases;Bilateral;Breast;Breast Epithelial Cells;Cell Compartmentation;Cells;Chemotherapy and/or radiation;Clinical;Clinical Trials;Communities;Confusion;Data;Data Analyses;Data Set;Data Storage and Retrieval;Detection;Development;Diagnosis;Dimensions;Disease;Disease Management;Distress;Duct (organ) structure;Ecology;Elements;Enrollment;Epithelium;Evolution;FAIR principles;Future;Gene Expression;Histologic;Image;Immune;Inflammatory;Informatics;Intervention;Intraductal Hyperplasia;Investigation;Life;Longitudinal Studies;Malignant Neoplasms;Mammography;Manuscripts;Mastectomy;Methodology;Methylation;Modeling;Molecular;Morbidity - disease rate;Mutation;Natural History;Noninfiltrating Intraductal Carcinoma;Operative Surgical Procedures;Outcome;Parents;Pathologic;Pathway interactions;Patient Care;Patient observation;Patients;Phase;Proteomics;Provider;Publishing;Quality of life;RNA;Radiology Specialty;Research Personnel;Resources;Risk;Sampling;Sum;Testing;Tissues;Toxic effect;United States;Woman;Work;breast lumpectomy;calcification;cancer invasiveness;cell type;clinical diagnosis;cohort;data integration;data visualization;design;disease natural history;evidence base;experience;flexibility;genomic signature;improved;knowledge of results;malignant breast neoplasm;multimodal data;multimodality;multiscale data;nano-string;next generation;novel;pandemic impact;premalignant;prevent;progression marker;progression risk;prospective;risk stratification;sample collection;screening;single-cell RNA sequencing;tool;tumor Breast Pre-Cancer Atlas Center PROJECT NARRATIVE OverallOver 60000 women in the United States will be presented with a diagnosis of breast ductal carcinoma in situ(DCIS) each year with relatively weak evidence-based guidance for disease management which ranges fromactive surveillance to bilateral mastectomy. We propose to compile multi-dimensional and multi-scaleinformation on DCIS to construct a Pre-Cancer Atlas that can be used to better understand the disease butalso to better stratify risk of progression a useful translational endpoint. NCI 10819754 8/15/23 0:00 PA-20-272 3U2CCA233254-01S3 3 U2C CA 233254 1 S3 "MAZURCHUK, RICHARD V" 4/4/23 0:00 8/31/24 0:00 6985255 "HWANG, E.SHELLEY " "MALEY, CARLO ; WEST, ROBERT B" 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 4/4/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 133667 NCI 115455 18212 ABSTRACTDevelopment of invasive breast cancer may frequently progress through a preinvasive precursor calledductal carcinoma in situ (DCIS). DCIS is a common clinical diagnosis that is essentially a disease ofscreening triggered by the detection of abnormal breast calcifications on mammography. Before theadvent of mammography DCIS was an incidental and relatively uncommon finding. Over 60000 womenin the United States will be presented with this diagnosis each year with relatively weak evidence-basedguidance for disease management which ranges from active surveillance to bilateral mastectomy. Wepropose to compile multi-dimensional and multi-scale data on DCIS to construct a Pre-Cancer Atlas thatcan be used to better understand the disease but also to better stratify risk of progression. To do this wehave assembled a team of investigators with deep and complementary clinical experimental andquantitative expertise and experience with DCIS and breast cancer. Further we conduct these studieswith full consideration of tumor evolution and ecology as it pertains to precancer development andprogression. Specific aspects of the proposed Atlas construction include: 1) Several types of DCIScohorts that will capture spatial and longitudinal information including a prospective clinical trial cohortundergoing active surveillance 2) Analyses designed to maintain relevant spatial organization of thedisease for evolutionary and Atlas building considerations based on 3) Radiologic-histologic-cellular-molecular registration approaches 4) Characterization at multiple scales including whole tumor singleduct and single cell levels 5) Characterization of relevant parameters including mutations copy numberchanges methylation gene expression and microenvironmental elements including inflammatory cellprofiles. 6) Incorporation of the breast cancer intrinsic subtype paradigm into the analytic phase and 7)Layered spatial and longitudinal data visualization. Overall this work will provide a comprehensiveplatform to guide the next generation of studies on DCIS and other precancers. 133667 +No NIH Category available Blood;Cancer Prevention Trial;DNA;Development;Family member;Frameshift Mutation;Hereditary Nonpolyposis Colorectal Neoplasms;Immunoprevention;Individual;Inuits;Malignant Neoplasms;Mucous Membrane;Mutation;PMS2 gene;Preventive;RNA;Reagent;Recurrence;Sampling;Syndrome;Testing;Tumor Tissue;Vaccines;cancer prevention;cohort;high risk;high risk population;mouse model;neoantigen vaccine;neoantigens;next generation sequencing;tumor;vaccine strategy DCP -Development of Cancer Immunoprevention in a High-Risk Population of Canadian Inuits: Characterization of Frame-Shift Neoantigen Expression in Homozygous Individuals and Carriers of PMS2 Mutations n/a NCI 10819464 75N91019D00024-P00025-759102000003-56 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 210001 NCI Project hypothesizes that the recurrent frame-shift mutations observed in Lynch Syndrome will also occur in CMMRD Syndrome and that the neoantigen vaccine strategy and reagents will be directly relevant to cancer prevention in CMMRD Syndrome. 210001 +No NIH Category available Academia;Cancer Center;Cancer Model;Catalogs;Clinical;Communities;Data;Data Sources;Foundations;Genomic Data Commons;Genomics;Goals;Human;In Vitro;Institution;Intellectual Property;International;Libraries;Malignant Neoplasms;Methods;Modeling;Molecular;National Cancer Institute;Office of Cancer Genomics;Online Systems;Organoids;Research Personnel;Resources;Source;System;Technology;Tissue Donors;Trust;anticancer research;biopharmaceutical industry;cancer genomics;clinical diagnostics;data modeling;interest;member;model development;next generation;novel;query tools;response HCMI Searchable Catalog n/a NCI 10819463 75N91019D00024-P00025-759102000003-55 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 201651 NCI Systematic application of novel culture methods now presents an opportunity to develop a large library of cancer models that can be made available as a community resource to investigators in academia and the biopharmaceutical industry. In response to the opportunity the National Cancer Institutes (NCI) Office of Cancer Genomics (OCG) in the Center for Cancer Genomics (CCG) together with international institutions has established a consortium the Human Cancer Models Initiative (HCMI). HCMIs goal is to make available to the scientific community large numbers of next generation in vitro cancer models that are not encumbered with excessive intellectual property (IP) constraints. To support the US contribution to HCMI OCG established four Cancer Model Development Centers (CMDCs). The other founding HCMI collaborators are Cancer Research UK (CRUK) Wellcome Trust Sanger Institute (WTSI) and the Hubrecht Organoid Technology foundation (HUB). 201651 +No NIH Category available Address;Advocate;American;Cancer Control;Cessation of life;Congresses;Consultations;Contractor;Country;Data;Data Analyses;Data Reporting;Documentation;Extramural Activities;Goals;Grant;Individual;Knowledge;Leadership;Malignant Neoplasms;Mission;Oncology;Play;Publications;Reporting;Research;Research Personnel;Resources;Scientist;Site;Training;Training Activity;Travel;Work;Writing;anticancer research;data visualization;experience;global health;international partnership;low and middle-income countries;meetings;technical writing;web site CGH - Center for Global Health Data Analysis Technical Support and Dialogues n/a NCI 10819459 75N91019D00024-P00025-759102000003-51 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1264730 NCI The Center for Global Health (CGH) supports the NCI mission by advancing global cancer research and coordinating NCI engagement in global cancer control. CGH also represents NCI in international research partnerships playing a key role in coordinating multinational research efforts for global benefit. The contractor provides data support to compile analyze and prepare written reports on global health grant portfolios. CGH produces a variety of documents and publications each year targeted at various audiences (most frequently Congress advocates scientists NCI leadership and the American and global publics). The Contractor provides additional scientific and technical writing support for NCI-prepared documents NCI publications and CGH Web site content.The contractor provides technical knowledge through expert consultancies for the work of the CGH as relevant to CGHs mission. The contractor supports global oncology discussions through arrangements for meetings and scientific exchange (travel of non-USG mostly LMIC scientists) for the meetings. They provide logistical support for the documentation that is shared during the dialogues. The contractor also provides logistical support for individual training activities that involve bringing an individual trainee who may be from the U.S. or any other country to the site of his/her training experience either inside the U.S. or in another country. 1264730 +No NIH Category available Area;Caribbean region;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Contractor;Contracts;Development;Development Plans;HIV;Human Papilloma Virus-Related Malignant Neoplasm;Knowledge;Laboratories;Latin American;Marketing;Monitor;Nursing Research;Performance;Phase;Procedures;Process;Protocols documentation;Quality Control;Regulatory Affairs;Site;Specialist;Specimen;Therapeutic;Vaccines;clinical development;experience;human biological material;manufacturing capabilities;operation;pre-clinical;prevention clinical trial;product development;programs;public-private partnership;quality assurance;research clinical testing;skills DCP - Clinical Trials Regulatory & Monitoring Support for US-Latin American-Caribbean HIV/HPV-Cancer Prevention Clinical Trials Network n/a NCI 10819457 75N91019D00024-P00025-759102000003-48 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 547118 NCI The Contractor shall conduct program analysis activities upon request and provide on-site staff to assist in creation of product development plans for vaccines and therapeutics. The Contractor shall provide information and knowledge in areas including but not limited to: product (vaccine or therapeutic) development analysis; creation of target product profiles; preclinical strategy; manufacturing capacity analysis; regulatory strategy; clinical development strategy with transition plan to advanced phase clinical testing; candidate down-selection strategy; and market analysis of public-private partnerships. The Contractor shall identify deficiencies in these areas and independently close those deficiencies using their skills and abilities and those of subcontractors. 547118 +No NIH Category available Area;Biological Products;Cell Culture Techniques;Cell Therapy;Clinical;Clinical Trials;Contractor;Development;Good Manufacturing Process;Guidelines;Immunoconjugates;Industry;Investigational Drugs;Mission;Monoclonal Antibodies;Peptides;Pharmacologic Substance;Phase;Phase I Clinical Trials;Phase III Clinical Trials;Program Development;Recombinant Proteins;Regulation;Research Personnel;Sterility;Testing;United States Food and Drug Administration;Vial device;Virus;Work;manufacture;plasmid DNA;vector vaccine DCP - Biopharmaceutical Development Program (BDP) Support n/a NCI 10819456 75N91019D00024-P00025-759102000003-47 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 434033 NCI The Contractor shall operate a Biopharmaceutical Development Program (BDP) currently a contractor-operated facility in contractor-leased space established by the NCI to develop and produce clinical-grade biopharmaceuticals including but not limited to: monoclonal antibodies recombinant proteins immunoconjugates peptide and DNA plasmid vaccines viruses cell therapies and other biologicals. The BDP also provides biopharmaceutical development expertise in the areas of cell culture purification characterization analysis vialing and Food and Drug Administration (FDA) regulatory compliance. Although the mission of the BDP in support of the NCI and other entities as requested through NCI is to manufacture small to medium scale quantities of clinical-grade biopharmaceuticals under current Good Manufacturing Practices (cGMPs) for use in Phase I and II clinical trials in exceptional circumstances NCI may also require the use of this facility to conduct similar work for synthetic pharmaceuticals (e.g. sterile filling for i.v. solutions). The BDP shall comply with U.S. FDA regulations and guidelines as is appropriate to meet compliance level requirements for each product manufactured. Products intended for use in Exploratory IND clinical trials shall be manufactured and tested in accordance with the FDAs guideline Guidance for Industry Investigators and Reviewers Exploratory IND Studies. Products intended for Phase I clinical trials are manufactured in accordance with the guideline Guidance for Industry cGMP for Phase I Investigational Drugs. Products intended for Phase II and non-pivotal Phase III clinical trials shall be manufactured following those aspects of 21 CFR 211 that apply to investigational use products. 434033 +No NIH Category available 2019-nCoV;Antibody Response;Automobile Driving;COVID-19;COVID-19 pandemic;COVID-19 test;Diagnosis;Disease;Goals;Immune response;Laboratories;Light;Methods;Molecular;Procedures;Public Health;Reagent;Research;Science;Serology;Serology test;Standardization;Testing;novel coronavirus;pathogen;response Serological Science for COVID-19 SeroNet n/a NCI 10819452 75N91019D00024-P00025-759102000003-43 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 678192 NCI In light of the emergence of the novel coronavirus SARS-CoV-2 and the urgent need to mitigate the pathogens spread. There is a crucial need for accurate laboratory-based methods for initial diagnosis asymptomatic carriage and overall public health understanding of the extent of this disease. The current lack of validated and widely available standardized tests procedures and reagents for assessment of SARS-CoV-2-specific antibody responses is a critical gap in the rapid response to the SARS-CoV-2 pandemic. a major goal and focus of SeroNet is determining the molecular and cellular components of the immune response to SARS-CoV-2 to understand the innate humoral and adaptive response as well as to understand barriers to access 678192 +No NIH Category available Clinical;Computers;Contract Services;Contractor;Contracts;Development;Funding;Information Services;International;Libraries;Maryland;National Cancer Institute;Office of Administrative Management;Research Personnel;Science;Services;Support Contracts;United States National Institutes of Health;base;clinical center;data management;improved;operation;programs;repaired;statistical service NCI-Frederick Operational Support n/a NCI 10819450 75N91019D00024-P00025-759102000003-41 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 128435052 NCI This funding supports operations services provided by the Office of Scientific Operations of the National Cancer Institute at Frederick. The National Cancer Institute at Frederick (NCI-Frederick) part of the National Institutes of Health (NIH) is one of two NCI campuses. The NCI's clinical researchers and the NIH Clinical Center are located on the NIH campus in Bethesda Maryland. The NCI's Frederick campus is located within Fort Detrick a U.S. Army base in Frederick MD. 128408142 +No NIH Category available Clinical;Computers;Contract Services;Contractor;Contracts;Development;Funding;Information Services;International;Libraries;Maryland;National Cancer Institute;Office of Administrative Management;Research Personnel;Science;Services;Support Contracts;United States National Institutes of Health;base;clinical center;data management;improved;operation;programs;repaired;statistical service NCI-Frederick Operational Support n/a NCI 10819450 75N91019D00024-P00025-759102000003-41 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 128435052 NCATS This funding supports operations services provided by the Office of Scientific Operations of the National Cancer Institute at Frederick. The National Cancer Institute at Frederick (NCI-Frederick) part of the National Institutes of Health (NIH) is one of two NCI campuses. The NCI's clinical researchers and the NIH Clinical Center are located on the NIH campus in Bethesda Maryland. The NCI's Frederick campus is located within Fort Detrick a U.S. Army base in Frederick MD. 26910 +No NIH Category available Acquired Immunodeficiency Syndrome;Area;Budgets;Computers;Contract Services;Contractor;Contracts;Development;Diagnosis;Funding;HIV Infections;HIV/AIDS;Head;Health;Human Herpesvirus 8;In Vitro;International;Laboratory Animal Science;Libraries;Maintenance;Malignant Neoplasms;Modeling;Molecular Virology;Office of Administrative Management;Prevention;Principal Investigator;Research;Safety;Satellite Viruses;Services;Technology;Viral Epidemiology;Virus;Work;data management;improved;in vivo;multidisciplinary;nonhuman primate;operation;programs;repaired;repository;research and development;statistical service;tumor AIDS and Cancer Virus Program (ACVP) n/a NCI 10819448 75N91019D00024-P00025-759102000003-39 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 15778446 OD These funds are used to provide support for the NCI AIDS & Cancer Virus Program (ACVP) and overhead/management support for all the AIDS research within the $425M FY2013 NCI budget at the NCI-Frederick. This overhead/management support includes appropriate allocations of the following areas: facility maintenance; building support; utilities; scientific library; computer and statistical services; environmental health and safety programs; subcontract staff; repository services; advanced technology and laboratory animal science program support; and general Federally Funded Research and Development Center (FFRDC) Contract administration. The ACVP headed by Dr. Jeff Lifson is an integrated multidisciplinary program that pursues basic and applied studies aimed at improving our understanding of AIDS-associated viruses including studies intended to facilitate the improved diagnosis prevention and treatment of HIV infection and AIDS and AIDS related tumors particularly those associated with other viruses such as KSHV. The Program consists of six independent but highly interactive research Sections headed by Principal Investigators whose work spans from fundamental molecular virology through in vitro studies to in vivo studies in non-human primate (NHP) models to international viral epidemiology. 1416683 +No NIH Category available Acquired Immunodeficiency Syndrome;Area;Budgets;Computers;Contract Services;Contractor;Contracts;Development;Diagnosis;Funding;HIV Infections;HIV/AIDS;Head;Health;Human Herpesvirus 8;In Vitro;International;Laboratory Animal Science;Libraries;Maintenance;Malignant Neoplasms;Modeling;Molecular Virology;Office of Administrative Management;Prevention;Principal Investigator;Research;Safety;Satellite Viruses;Services;Technology;Viral Epidemiology;Virus;Work;data management;improved;in vivo;multidisciplinary;nonhuman primate;operation;programs;repaired;repository;research and development;statistical service;tumor AIDS and Cancer Virus Program (ACVP) n/a NCI 10819448 75N91019D00024-P00025-759102000003-39 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 15778446 NCI These funds are used to provide support for the NCI AIDS & Cancer Virus Program (ACVP) and overhead/management support for all the AIDS research within the $425M FY2013 NCI budget at the NCI-Frederick. This overhead/management support includes appropriate allocations of the following areas: facility maintenance; building support; utilities; scientific library; computer and statistical services; environmental health and safety programs; subcontract staff; repository services; advanced technology and laboratory animal science program support; and general Federally Funded Research and Development Center (FFRDC) Contract administration. The ACVP headed by Dr. Jeff Lifson is an integrated multidisciplinary program that pursues basic and applied studies aimed at improving our understanding of AIDS-associated viruses including studies intended to facilitate the improved diagnosis prevention and treatment of HIV infection and AIDS and AIDS related tumors particularly those associated with other viruses such as KSHV. The Program consists of six independent but highly interactive research Sections headed by Principal Investigators whose work spans from fundamental molecular virology through in vitro studies to in vivo studies in non-human primate (NHP) models to international viral epidemiology. 14361763 +No NIH Category available Clinical Trials;Maintenance;System;knowledge base;operation DCP - Clin Trl Info Mgt -DCP Enterprise System Knowledge Base (DESK) n/a NCI 10819447 75N91019D00024-P00025-759102000003-38 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 663829 NCI To support clinical trials operations. Provide Operations and Maintenance (O & M) support for DESK . Integration with existing or New DCP and /or NCI Systems may be required. 663829 +No NIH Category available Biological Specimen Banks;Contracts;Phase;biobank;cancer prevention;clinical research site;prevention clinical trial;programs DCP - Cancer Prevention Phase 0/I/II Cancer Prevention Clinical Trials Program (Consortia) BioRepository n/a NCI 10819446 75N91019D00024-P00025-759102000003-37 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 15374 NCI Establish a bio specimen repository from DCP Contracted clinical sites 15374 +No NIH Category available Contractor;Dedications;Immunoprevention;Laboratories;Malignant Neoplasms;Methods;Standardization;Work;preclinical development DCP- Cancer Immunoprevention Laboratory Support n/a NCI 10819445 75N91019D00024-P00025-759102000003-36 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 3450913 NCI Establish a new Cancer Immunoprevention Laboratory Dedicated to DCP and serve as a reference lab confirming key results from Task order contractors using standardize methods and performing work to advance successful immunoprevention concepts in preclinical development. 3450913 +No NIH Category available Area;Contractor;Development;Development Plans;Knowledge;Laboratories;Marketing;Monitor;Performance;Phase;Procedures;Process;Protocols documentation;Quality Control;Site;Specimen;Therapeutic;Vaccines;clinical development;human biological material;manufacturing capabilities;operation;pre-clinical;product development;programs;public-private partnership;quality assurance;research clinical testing;skills DCP - COPTRG - SELECT/PCPT n/a NCI 10819444 75N91019D00024-P00025-759102000003-32 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 907044 NCI The Contractor shall conduct program analysis activities upon request and provide on-site staff to assist in creation of product development plans for vaccines and therapeutics. The Contractor shall provide information and knowledge in areas including but not limited to: product (vaccine or therapeutic) development analysis; creation of target product profiles; preclinical strategy; manufacturing capacity analysis; regulatory strategy; clinical development strategy with transition plan to advanced phase clinical testing; candidate down-selection strategy; and market analysis of public-private partnerships. The Contractor shall identify deficiencies in these areas and independently close those deficiencies using their skills and abilities and those of subcontractors.The Contractor shall maintain a Quality Control/Quality Assurance (QC/QA) program to monitor performance including the development of standard operating procedures (SOPs) for each protocol or process optimized for maintaining the integrity of human biological material; for monitoring the quality of products; for the operation of the laboratories; and for tracking specimen influx processing and efflux. 907044 +No NIH Category available Clinical;Clinical Research;Early Detection Research Network;Funding;Histologic;Prevention;Screening for cancer;Specimen;Tissues;Vial device;biomarker validation;interest;repository DCP - Early Detection Research Network (EDRN) Repository n/a NCI 10819443 75N91019D00024-P00025-759102000003-31 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 384341 NCI In addition DCP funds the Early Detection Research Network to develop and validate biomarkers for the early detection of cancer. Many of these studies have collected specimens with specific histological endpoints of clinical interest for cancer screening and prevention. Currently almost 300000 vials of various tissue types are stored in conjunction with 15 clinical studies. 384341 +No NIH Category available Blood;Breast Cancer Prevention Trial;Clinical Trials;Leukocytes;Maintenance;National Surgical Adjuvant Breast and Bowel Project;Plasma;Specimen;Study of Tamoxifen and Raloxifene;Woman;cost;repository DCP - COPTRG Support [National Surgical Adjuvant Breast and Bowel Project (NSABP) n/a NCI 10819442 75N91019D00024-P00025-759102000003-30 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 230604 NCI Abstract: This cost center is for the storage of specimens collected on the Study of Tamoxifen and Raloxifene (STAR) study (>19.000 women) and the WBC specimens collected on the Breast Cancer Prevention Trial (BCPT). The National Surgical Adjuvant Breast and Bowel Project (NSABP) Repository for STAR includes ongoing storage of specimens and the maintenance of the freezers that store blood white cells and plasma on over 19000 women on the STAR clinical trial. The tasks involve regular checks of specimens and freezers accession of specimens record storage and interaction with the NSABP. 230604 +No NIH Category available AIDS related cancer;Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Automobile Driving;Bioinformatics;Biology;Burkitt Lymphoma;Child;Chromosomes;Clinical;Collaborations;Communities;DNA Resequencing;DNA Sequence;DNA Sequence Alteration;Data;Data Coordinating Center;Data Display;Data Set;Detection;Development;Ethics;Event;Family;Future;Gene Expression Profile;Genes;Genetic;Genome;Genomic approach;Genomics;Goals;HIV;HIV Seropositivity;HIV/AIDS;Human;Incidence;Informatics;Infrastructure;Kidney Neoplasms;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Methodology;Methods;Methylation;Molecular;Molecular Abnormality;Molecular Target;Mutation;Nephroblastoma;Neuroblastoma;Non-Hodgkin's Lymphoma;Pathway interactions;Patients;Prevalence;Prevention;Prognostic Marker;RNA Interference;Refractory;Research;Research Personnel;Resolution;Resources;Role;Sampling;System;Techniques;Therapeutic;Time;Tissue Banks;Translating;Translations;Tumor Biology;Validation;burden of illness;cancer diagnosis;cancer genome;cancer genomics;cancer therapy;cohort;data access;data portal;data sharing;diagnostic biomarker;effective therapy;exome;functional genomics;genome sequencing;high risk;high throughput screening;human tissue;innovation;insight;medulloblastoma;miRNA expression profiling;new technology;next generation sequencing;novel;novel strategies;novel therapeutic intervention;novel therapeutics;operation;osteosarcoma;precision medicine;programs;rare cancer;small molecule;therapeutic target;transcriptome sequencing;tumor;whole genome OCG Data Coordinating Center n/a NCI 10819440 75N91019D00024-P00025-759102000003-28 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 7846961 NCI "This proposal proposes to continue operations and maintenance of the OCG (ocg.cancer.gov) Data Coordinating Center (DCC) to accept QC and display data and data types generated by the TARGET CGCI CTD2 and other cancer genomics and translation projects. The primary focus of the TARGET and CGCI Initiatives remain identifying genomic alterations that offer pathways to novel therapeutic interventions that may lead to more effective treatments for cancers. NCI-CBIIT provides informatics support for the OCG programs. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative focuses to rapidly identify potential therapeutic targets in childhood cancers so that new more effective treatments can be developed in shorter time and ultimately bring new hope to children and their families who face the devastating burden of these diseases. The TARGET Initiative (is focused on identifying therapeutic targets as well as prognostic and diagnostic markers in multiple childhood cancers. The initiative includes the study of high-risk Acute Lymphoblastic Leukemia (ALL) neuroblastoma (NBL) high-risk and treatment refractory Acute Myeloid Leukemia (AML) osteosarcoma (OS) and kidney tumors (including high risk Wilms tumor). These cancers were the chosen for study because of their prevalence among children the inadequacy of current treatment options the ongoing NCI-supported efforts to molecularly characterize these cancers and the availability of clinically annotated high-quality human tissue collections that met TARGET's strict scientific technical and ethical requirements. In the coming year TARGET will include validation cohorts and other studies. The Cancer Genome Characterization Initiative (CGCI) supports cutting-edge genomics research on rare cancers. Researchers develop and apply advanced sequencing and other genome-based methods to identify novel genetic abnormalities in tumors. The extensive genetic profiles generated by CGCI may inform better cancer diagnosis and treatment. CGCI is another OCG program. CGCI focuses Burkitt Lymphoma and HIV+ Tumor Molecular Characterization Project (HTMCP). Previous projects included early stage Lung Cancers Medulloblastoma and Non-Hodgkin Lymphoma. The goal of the Burkitt Lymphoma Genome Sequencing Project (BLGSP) is to explore potential genetic changes in patients with Burkitt lymphoma that could lead to better prevention detection and treatment of this rare and aggressive cancer. The OCG along with the Office of HIV and AIDS Malignancies (OHAM) initiated the HTMCP to gain insight into the genetic events driving HIV-associated cancers and to determine why certain cancers but not others have higher incidences in HIV-positive patients. The data generated by these projects are stored at the DCC. Cancer Target Discovery and Development (CTD) initiative bridges the gap between the enormous volumes of data generated by genomic characterization studies and the ability to use these data for the development of human cancer therapeutics. It specializes in computational and functional genomics approaches critical for translating next-generation sequencing data. The Cancer Target Discovery and Development (CTD2) initiative is a collaborative network of OCG-supported Centers. The program strives to functionally validate discoveries from large-scale genomic initiatives and advance them toward precision medicine through the efforts of the Centers and open access data sharing. Through cross-Network collaborations CTD2 uses innovative bioinformatics and functional biology to: (1) mine data to find alterations that potentially influence tumor biology (2) characterize the functional roles of candidate alterations in cancers and (3) identify novel approaches that target causative alterations either directly or indirectly. Because CTD2 is a community resource project all information in the Data Portal is openly available to the scientific community and can be accessed without restrictions. Project descriptions datasets and methodologies generated by the Centers are shared through the CTD2 Data Portal (i.e. the OCG Data Coordinating Center). OCG oversees other genomics and translation projects which may generate molecular data that will be stored in the DCC. The formats file types etc. is ever changing and the DCC evolves as needed. It is expected that the infrastructure already developed and being developed will be useable for the OCG data generated. The research conducted by OCG programs is divided into three distinct yet tightly integrated components that together form a system for selecting new molecular targets for the development of novel therapies for these childhood cancers: Genomic Characterization: Using high-resolution array-based methods a)determine differences in the patterns of gene expression in cancer samples and non-cancerous samples and b) genome changes to characterize genome structural changes that correlate with each cancer such as chromosome region gains and losses methylation changes etc. are integrated to provide a complete genomic ""overview"" of each cancer. Sequencing: Up-to-date genetic sequencing techniques are used to ""read"" genes that have been identified to have altered expression and/or structural alterations to identify the specific cancer-related mutations in the DNA sequence. Additionally new technologies to sequence the whole-genome whole-exome RNA-seq and miRNA-seq have and will be employed. Identification of Therapeutic TargetsFor example RNA interference (RNAi) small molecule high-throughput screens are used to identify and initially validate potential targets identified from the genomic characterization and re-sequencing efforts. In the future other approaches may be added." 7846961 +No NIH Category available Clinical Data;Collection;Communities;Data Set;Genomic Data Commons;Genomic approach;Malignant Childhood Neoplasm;Molecular;Research;Therapeutic;Update;anticancer research;cancer genomics;data repository;data sharing;effective therapy;follow-up;precision medicine;treatment program GDC Clinical Data Update n/a NCI 10819439 75N91019D00024-P00025-759102000003-27 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 14186692 NCI This project provides for the collection and updating of follow-up clinical data for 14000 cases in the Genomic Data Commons including the TARGET dataset and other datasets as determined feasible. The NCI's Genomic Data Commons (GDC) provides the cancer research community with a unified data repository that enables data sharing across cancer genomic studies in support of precision medicine. 14186692 +No NIH Category available Affect;Cell Line;Charge;Chronic;Cryopreserved Cell;Databases;Diabetes Mellitus;Diabetic Nephropathy;Disease;Eligibility Determination;End stage renal failure;Family;Genes;Genetic Predisposition to Disease;Goals;Hyperglycemia;Hypertension;Individual;Institution;Intervention;Investigation;Kidney Diseases;Link;National Institute of Diabetes and Digestive and Kidney Diseases;Non-Insulin-Dependent Diabetes Mellitus;Patients;Phenotype;Plasma;Predisposition;Prognostic Factor;Research Personnel;Sampling;Secure;Serum;Urine;genetic technology;preservation;repository;sample collection Repository for the Family Investigation of Nephropathy & Diabetes n/a NCI 10819437 75N91019D00024-P00025-759102000003-25 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 185774 NIDDK Diabetic nephropathy (DN) is a multifactoral disease and a large proportion of patients affected with either type 1 or type 2 diabetes develop diabetic nephropathy and progress to end stage renal disease (ESRD). When poor prognostic factors such as hypertension and chronic hyperglycemia are aggressively treated the rate of progression of diabetic nephropathy can be slowed. However no interventions have been shown to reliably halt the progression of diabetic nephropathy. Numerous studies have suggested that genetic predisposition to diabetic nephropathy exists but genes for nephropathy have not yet been isolated. It is anticipated that a comprehensive analysis of a large number of uniformly phenotyped ESRD families will be necessary to isolated genes for ESRD. Such a database of families may not be available at any single institution. The charge of the FIND consortium was to acquire sets of families and individuals with well-characterized diabetic nephropathy establish a secure master FIND database and use genetic technologies to identify chromosomal regions linked with diabetic nephropathy in order to identify diabetic nephropathy susceptibility or protection genes. A Repository of samples collected during the FIND is essential for the FIND study to achieve its goals and for subsequent studies of this valuable sample collection. 185774 +No NIH Category available Back;Bioinformatics;Clinical;Databases;Funding;Informatics;Infrastructure;Research;Resources;Software Tools;Speed;Translational Research;open source;tool Informatics Support at FNLCR n/a NCI 10819436 75N91019D00024-P00025-759102000003-24 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 41393702 NCI This funding is in support of informatics activities conducted by the NCI Center for Bioinformatics. 28393702 +No NIH Category available Clinical;Computers;Contractor;Contracts;Development;Funding;Libraries;Maryland;National Cancer Institute;Office of Administrative Management;Research Personnel;Services;United States National Institutes of Health;base;clinical center;improved;operation;programs;repaired;research and development;statistical service NCI-F Operations and Technical Support II n/a NCI 10819435 75N91019D00024-P00025-759102000003-23 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 12205518 NCI This funding supports operations services provided by the Office of Scientific Operations of the National Cancer Institute at Frederick. The National Cancer Institute at Frederick (NCI-Frederick) part of the National Institutes of Health (NIH) is one of two NCI campuses. The NCI's clinical researchers and the NIH Clinical Center are located on the NIH campus in Bethesda Maryland. The NCI's Frederick campus is located within Fort Detrick a U.S. Army base in Frederick MD. 12205518 +No NIH Category available Capital;Core Facility;Development;Equipment;Expenditure;Funding;Gene Mutation;Institution;Intramural Research Program;Laboratories;Laboratory Research;Malignant Neoplasms;Modeling;RAS genes;Research;Research Personnel;Signal Transduction;Technology;Therapeutic;United States Dept. of Health and Human Services;anticancer research;programs;research and development RAS Program at FNL n/a NCI 10819434 75N91019D00024-P00025-759102000003-22 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 15244132 NCI The RAS Program is a targeted plan to develop therapeutic strategies against cancers driven by abnormal RAS signaling especially as a consequence of RAS gene mutations under the auspices of the Frederick National Laboratory for Cancer Research (FNLCR) the only Federally Funded Research and Development Center (FFRDC) in the Department of Health and Human Services. It is envisioned that the program will be a hub and spoke model with scientific leaders core facilities and important technologies at the FNLCR hub and research led by investigators at companies academic institutions and the NCI intramural research program at the spokes. There are five projects currently under development in FY14 to target these cancers. This expenditure is for the purpose of capital equipment to carry out laboratory research at FNLCR. 15244132 +No NIH Category available Address;Cryoelectron Microscopy;Data Collection;Goals;Image;Laboratories;Macromolecular Complexes;Malignant Neoplasms;Microscope;National Cancer Institute;Resolution;Structural Biologist;United States National Institutes of Health;anticancer research;interest Cryo-EM n/a NCI 10819432 75N91019D00024-P00025-759102000003-20 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 3219387 NCI The National Cancer Institute NIH is launching a nationally accessible cryo-EM user facility under the umbrella of the Frederick National Laboratory for Cancer Research. The primary goal of the facility will be to allow users to collect high quality cryo-EM images with the smallest possible delay between expression of user interest and data collection. The creation of this pilot facility will begin to address the pressing national and regional need for structural biologists in the US to have access to advanced microscopes capable of supporting high resolution cryo-EM studies especially of macromolecular complexes of fundamental interest to cancer. 3219387 +No NIH Category available Address;Area;Communities;Contractor;Employee;Goals;Government;Incubators;Information Systems;Needs Assessment;Pilot Projects;Recommendation;Research;Resources;Services;design;flexibility;programs Strategic Scientific Pilot Support n/a NCI 10819429 75N91019D00024-P00025-759102000003-17 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1764373 NCI The goal of the Strategic Pilots Incubator (SPI) is to coordinate CSSI-related FNLCR resources and projects to facilitate advancement of CSSI and trans-NCI initiatives. The SPI team will research evaluate recommend develop implement and assist with pilot projects information systems and services in support of CSSI and trans-NCI research initiatives projects and programs. 1764373 +No NIH Category available Acute Myelocytic Leukemia;Acute Promyelocytic Leukemia;Agonist;Anaphase;Aneuploidy;Antineoplastic Agents;Biological Assay;Chimeric Proteins;Differentiation Therapy;Etiology;FDA approved;Genetic;Immunotherapy;Laboratories;Malignant Neoplasms;Molecular;Normal Cell;Pathway interactions;Pharmacology;Play;RXR;Retinoic Acid Receptor;Retinoids;Signal Transduction;antagonist;combat;companion diagnostics;retinoic acid receptor alpha;targeted cancer therapy;tool;ubiquitin isopeptidase Molecular Pharmacology Lab n/a NCI 10819428 75N91019D00024-P00025-759102000003-16 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1043878 NCI This laboratory uses retinoic acid receptor (RAR retinoid) and retinoid X receptor (RXR rexinoid) agonists or antagonists and other agents as discovery tools to uncover critical antineoplastic pathways. The laboratory played a key role in identifying retinoid-based differentiation therapy as a successful (and FDA-approved) way to combat acute promyelocytic leukemia (APL) an early example of targeted cancer therapy. This team cloned the etiologic fusion protein PML/RAR and developed the companion diagnostic genetic assay for Acute Promyelocytic Leukemia (APL). Currently they are exploring the retinoid-regulated deubiquitinase USP18 and how retinoids cooperate in immune-based therapy. Recently they discovered a pathway called anaphase catastrophe that can target aneuploid cancers (a hallmark of cancer) while sparing normal cells. Signals that trigger anaphase catastrophe are now under intensive study. 1043878 +No NIH Category available Antibodies;Benign;Calibration;Capsid Proteins;Cells;Cervarix;Communities;Development;Dose;Evaluation;Gardasil;Genotype;Goals;Human;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Human papillomavirus 18;Human papillomavirus HPV L1 protein;Insecta;Laboratories;Licensing;Malignant neoplasm of cervix uteri;Oncogenic;Qualifying;Reagent;Recombinants;Regimen;Resources;Serology;Serology test;Serum;Standardization;Testing;Vaccines;Virus-like particle;Work;Yeasts;high risk;vaccine development;vaccine-induced immunity;virtual HPV Serology n/a NCI 10819427 75N91019D00024-P00025-759102000003-15 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1628942 NCI Human Papillomavirus infection is mostly benign and self-limiting however certain genotypes are considered high risk and oncogenic. HPV has been found in virtually all cervical cancers with HPV 16 causing 50% and HPV 18 another 20%. Currently there are three licensed human papillomavirus (HPV) vaccines with excellent efficacy but poorly characterized correlates of vaccine induced immunity. One of the vaccines is bivalent (Cervarix GSK) the second is quadrivalent (Gardasil Merck) while the third is nonavalent (Gardasil9). All three vaccines utilize virus like particles (VLPs) based on the L1 major capsid protein from HPV. VLPs are noninfectious protein capsids which can be produced by expressing the capsid protein in yeast or insect cells. The recombinant L1 capsid protein assembles in into the 60-nm HPV VLP. The efficacy of each vaccine has been evaluated with different standards making comparison of the vaccines difficult. There has also been indication suggesting that one dose of these vaccines may be as efficacious as the three-dose regimen currently in use however there is no set of serological standards that could be used for evaluation. Currently pooled human serum serves as the best standard and is used to create a curve from which results are extrapolated in arbitrary Units/ml. However the pooled serum is a finite resource and subsequent studies require the development of a new pool that is calibrated against the previous pool and therefore has its limitations as a standard. The goal is to establish a laboratory that would standardize and harmonize serological assays for Human Papillomavirus (HPV) antibody testing through development of validated reagents and standards that will be available to the scientific community. The laboratory will provide well qualified and standardized high-throughput testing that adheres to regulatory requirements defined for vaccine development and implementation. The laboratory will work with the scientific community and regulatory entities to identify unmet needs in HPV serology. 1628942 +No NIH Category available Antineoplastic Agents;Biological;Biological Assay;Biological Markers;Biological Products;Clinic;Clinical;Clinical Trials;Collaborations;Contracts;Correlative Study;Cyclic GMP;Data Science;Development;Diagnostic;Diagnostic tests;Discipline of Nursing;Division of Cancer Treatment and Diagnosis;Drug Kinetics;Evaluation;Funding;Genomics;Image;In Vitro;Informatics;Information Systems;Laboratories;Libraries;Malignant Neoplasms;Medical;Molecular;Nanotechnology;Natural Products;New Agents;Patients;Performance;Pharmaceutical Preparations;Pharmacology;Pre-Clinical Model;Precision medicine trial;Production;Radiochemistry;Radiopharmaceuticals;Research;Services;Technology;Testing;Therapeutic Intervention;Toxicology;Translational Research;United States National Institutes of Health;Work;assay development;biobank;biopharmaceutical industry;clinical center;drug development;drug discovery;drug production;high throughput screening;in vivo;manufacture;novel diagnostics;novel therapeutic intervention;patient derived xenograft model;pharmacodynamic biomarker;programs;repository;tumor Division of Cancer Treatment and Diagnosis- Operational Task Order n/a NCI 10819419 75N91019D00024-P00025-759102000003-7 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 51636719 NCI The Division of Cancer Treatment and Diagnosis (DCTD) supports the development of novel diagnostic and therapeutic approaches for cancer by expediting the initial and subsequent large-scale testing of new agents biomarkers imaging tests and other diagnostic and therapeutic interventions in patients. Within DCTD eight major programs and a patient clinic work together to bring unique molecules diagnostic tests and therapeutic interventions from the laboratory bench to the patient bedside. Activities supported under this contract include: isolation and evaluation of natural products; molecular pharmacology; high-throughput screening of compound libraries; pharmacodynamic marker and pharmacokinetic assay development and utilization in clinical trials; drug toxicology research; information systems technologies and data science; drug discovery; radiochemistry and radioactive drug production; archival of clinical trial images in vitro and in vivo translational research; repository support for natural products patient-derived xenografts tumors and biologic anti-cancer agents; a biopharmaceutical production facility; medical writers; nursing support services for clinical trials performed in the NIH Clinical Center correlative studies in collaboration with biopharmaceutical companies; support for precision medicine trials; advanced genomics capabilities supporting tumor evaluation in pre-clinical models and clinical trials; patient biorepositories for NCI-funded clinical trials; nanotechnology characterization and evaluation. 51636719 +No NIH Category available Biological;Biological Assay;Biological Process;Blood specimen;CLIA certified;Cell Line;Cells;Cervical;Clinical;Contracts;Cryopreservation;Cryopreserved Cell;Cytology;DNA;Detection;Diagnostics Research;Division of Cancer Epidemiology and Genetics;Electronics;Epidemiology;Erythrocytes;Feces;Fibroblasts;Flow Cytometry;Fluorescence-Activated Cell Sorting;Freeze Drying;Freezing;Hormones;Human;Human Herpesvirus 4;Immunologic Monitoring;Immunologic Tests;Immunologics;In Vitro;Infrastructure;Laboratories;Liquid substance;Malignant neoplasm of cervix uteri;Mass Spectrum Analysis;Measurement;Molecular;Molecular Epidemiology;Mutation Detection;Nitrogen;Nucleic Acids;Paraffin Embedding;Pathogen detection;Pathogenesis;Peripheral Blood Mononuclear Cell;Phenotype;Plasma;Polymorphism Analysis;Preparation;Prevention;Process;Proteins;Quality Control;RNA;Reporting;Research Personnel;Scientist;Serum;Services;Single Nucleotide Polymorphism;Specimen;Specimen Handling;Spectrophotometry;Structure;Techniques;Technology;Tissue Embedding;Tissues;Urine;Virus;Whole Blood;anticancer research;biobank;bioprocess;blood fractionation;cancer epidemiology;cell immortalization;cold temperature;epidemiology study;established cell line;instrumentation;molecular diagnostics;programs;quality assurance;repository;small molecule;transforming virus;tumor DCEG- Molecular Assays for epidemiology studies n/a NCI 10819417 75N91019D00024-P00025-759102000003-5 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 320564 NCI Activities performed within this project provide DNA extraction alliquoting bioprocessing of human epidemiology specimens for cancer research. Several facilities are utilized to process human specimens and to provide the necessary infrastructure to support human specimen processing and storage in support of epidemiology cancer research. The Mass Spectrometry Center is equipped with the latest in mass spectrometry (MS) instrumentation for analyzing both small and large protein biomolecules including endogenous hormones. The Center offers corresponding expertise in detection quantitation structure confirmation and mass measurements. The Center also educates scientists on the use interpretation and applications of MS technologies. The CLIA-certified Molecular Diagnostics Laboratory provides state-of-the-art clinical and research diagnostics including mutation detection single nucleotide polymorphism analysis and pathogen detection. The Human Immunological Monitoring Laboratory supports cervical cancer research by examining human host immunological parameters potentially important in the pathogenesis or prevention of virus-related tumors. The laboratory's capabilities include: receipt and processing of human specimens including whole blood and cervical specimens; cryopreservation DNA extraction and Epstein-Barr virus transformation of peripheral blood mononuclear cells (PBMC); immunological testing including a variety of in vitro PBMC functional assays; HLA and PBMC phenotyping by flow cytometry (fluorescence activated cell sorting FACS); temporary low temperature storage of biological specimens and transfer to the DCEG biorepository; electronic tracking of biospecimens and reporting of assay results to DCEG investigators; maintain quality control/quality assurance programs; apply state-of-the-art techniques as they become available. The Bioprocessing Laboratory processes biological specimens prior to their storage in the DCEG repository or dispersal to collaborators. The processing laboratory provides: processing and freezing of biological specimens including whole blood serum plasma urine and feces; lyophilization of specimens; flash-freezing of tissue in liquid nitrogen; separation and viable cryopreservation of cell lines including the routine assessment of viability; cryopreservation of red blood cells to maintain enzymatic activity; establishment of cell lines; large scale propagation of cell lines; nucleic acid extraction; distribution of specimens. The DNA Extraction Laboratory a part of the CGR extracts DNA from whole blood specimens blood fractions transformed lymphoblastic lines cultured fibroblasts tumor specimens buccal cells paraffin-embedded tissue Guthrie cards cytology preparations or other biological specimens. Activities performed within this project provide DNA extraction alliquoting bioprocessing of human epidemiology specimens for cancer research. 320564 +No NIH Category available Biological;Collection;Contracts;Development;Division of Cancer Epidemiology and Genetics;Epidemiology;Equipment;Equipment and supply inventories;Human;Maintenance;Molecular Epidemiology;Procedures;Sampling;Services;Specimen;Transportation;cold temperature;computerized;epidemiology study;preservation;programs;repository DCEG- Repository Services for epidemiology studies n/a NCI 10819416 75N91019D00024-P00025-759102000003-4 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 439657 NCI Under this project a state-of-the-art repository for the storage of biospecimens for human epidemiology is operated. The repository activities include: sample receipt and distribution; ambient and low temperature storage of environmental and biological specimens; computerized sample inventory maintenance; maintain QC and QA programs; development or identification of biospecimen collection and storage conditions to preserve specimen and target analyte integrity; support to field centers in collection procedures equipment materials and sample transportation as requested. This contract supplies support for Human molecular epidemiology research. 439657 +No NIH Category available Affect;American Cancer Society;Area;Basic Science;Beta Carotene;Biological Assay;Cancer Burden;Cervical Cancer Screening;Colon;Custom;DNA;Data;Data Analyses;Data Storage and Retrieval;Development;Disease;Disease Outcome;Division of Cancer Epidemiology and Genetics;Electronics;Employment;Environmental Risk Factor;Epidemiologist;Experimental Designs;Family;Generations;Genes;Genetic;Genetic Markers;Genetic Variation;Genome Scan;Genomics;Genotype;Heritability;Human Genome;Human Papillomavirus;Image;Immunohistochemistry;Individual;Informatics;Information Management;Intramural Research Program;Laboratories;Laboratory Research;Lung;Malignant Neoplasms;Meta-Analysis;Molecular Epidemiology;Mutation;Normal tissue morphology;Nucleic Acids;Outcome;Ovarian;Phenotype;Population;Population Group;Predisposition;Prostate;Publishing;Research;Research Support;Resources;Sampling;Scanning;Scientist;Specimen;Statistical Methods;Support Groups;Surveys;Techniques;Technology;Tissues;Work;alpha Tocopherol;anticancer research;bioinformatics pipeline;cancer genomics;cancer prevention;clinically relevant;cohort;cost;data access;database of Genotypes and Phenotypes;design;digital;digital pathology;epidemiology study;exome;exome sequencing;follow-up;genetic epidemiology;genetic variant;genome sequencing;genome wide association study;genome-wide;human genomics;interest;molecular pathology;novel;rare variant;response;screening;tissue processing;tumor DCEG- Genotyping for epidemiology studies n/a NCI 10819415 75N91019D00024-P00025-759102000003-3 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 5200555 NCI The Cancer Genomics Research (CGR) Laboratory was established to investigate the contribution of genetic variation to cancer susceptibility and outcomes. Working in concert with epidemiologists biostatisticians and basic research scientists in DCEGs intramural research program the CGR provides the capacity to conduct genome-wide discovery studies and targeted regional approaches to identify the heritable determinants of various forms of cancer. New work has begun in somatic research with the use of tumor/normal tissue nucleic acids for cross-platform comparisons in subjects of interest. A support group for molecular and digital pathology research within CGR has been added to support these efforts. CGR supports DCEG in all stages of cancer research from planning to publishing including experimental design and project management sample handling genotyping and sequencing assay design and execution tissue research support development and implementation of bioinformatic pipelines and downstream research and analytical support. These factors make CGR a unique collaborative center for NCI-driven scientific endeavors. 5200555 +No NIH Category available Affect;Biological;Cancer Intervention;Case/Control Studies;Collaborations;Complex;DNA;Data;Data Set;Diagnostic;Disease;Division of Cancer Epidemiology and Genetics;Ensure;Extramural Activities;Genes;Genetic Markers;Genetic Predisposition to Disease;Genome Scan;Genomics;Individual;Inherited;Malignant Neoplasms;Malignant neoplasm of prostate;Maps;Persons;Phenotype;Pilot Projects;Population Study;Predisposition;Preventive;Private Sector;Research;Research Personnel;Resources;Risk;Scanning;Scientist;Series;Techniques;Therapeutic Intervention;United States National Institutes of Health;Variant;cancer genetics;cancer risk;case control;cohort;data access;deep sequencing;disorder risk;epidemiology study;gene environment interaction;genetic variant;genome wide association study;large datasets;malignant breast neoplasm;programs;trait DCEG- GWAS Studies n/a NCI 10819414 75N91019D00024-P00025-759102000003-2 N01 8/31/20 0:00 8/30/23 0:00 79112606 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1104589 NCI The Cancer Genetic Markers of Susceptibility (CGEMS) project began in 2005 as a 3-year pilot study to identify inherited genetic susceptibility to prostate and breast cancer (cgems.cancer.gov). CGEMS has developed into a robust research program involving genome-wide association studies (GWASs) for dozens of different cancer phenotypes to identify common genetic variants that affect an individuals risk of developing cancer. In collaboration with extramural scientists NCI's Division of Cancer Epidemiology and Genetics (DCEG) has carried out genome-wide scans for common and/or highly lethal cancers extensively studied by the Division. CGEMS relies upon data from the NCI Consortium as well as collaborative case-control epidemiologic studies with biospecimens. By scanning the DNA collected from individuals participating in these cohort or case-control studies scientists have identified common inherited genetic variants associated with cancer risk that may lead to new preventive diagnostic and therapeutic interventions. The pooling of large data sets provides the statistical power to quantify the risks associated with specific gene variants and exposures and enables subset analyses that uncover gene-gene and gene-environment interactions. Researchers are applying fine-mapping and deep sequencing techniques to regions or loci identified by these scans to pinpoint the specific functional variants responsible for disease risk and the biologic mechanisms involved. Ultimately findings from these studies may yield new preventive diagnostic and therapeutic interventions for cancer. 1104589 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10819410 261201800006I-P00006-26100001-2 N01 5/1/18 0:00 4/30/23 0:00 78152476 "JOHNSON, CHRISTOPHER " Not Applicable 2 Unavailable 126141076 XBMCHUMKK6L3 126141076 XBMCHUMKK6L3 US 43.619429 -116.198351 653401 IDAHO HOSPITAL ASSOCIATION BOISE ID Other Domestic Non-Profits 837025195 UNITED STATES N R and D Contracts 2023 588337 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 588337 +No NIH Category available Adjuvant Chemotherapy;Adriamycin PFS;Antineoplastic Agents;Bladder Neoplasm;Cancer Biology;Cessation of life;Cisplatin;Clinical;Clonality;Data;Development Plans;Disease;Dose;Educational process of instructing;Equipoise;FGFR3 gene;Fellowship;Fibroblasts;Gene Expression Profile;Generations;Genetically Engineered Mouse;Immune;Immunotherapy;Institution;Laboratories;Learning;Level of Evidence;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Methotrexate;Modality;Modeling;Muscle;Neoadjuvant Therapy;Operative Surgical Procedures;Oral;Patients;Postdoctoral Fellow;Pre-Clinical Model;Process;Professional Competence;Regimen;Research;Research Project Grants;Resistance;Resolution;Schedule;Survival Rate;T-Cell Receptor;TGFB1 gene;Therapeutic;Training Programs;United States;Urothelium;Validation;Vincristine;Work;Writing;anti-PD1 therapy;anticancer research;bladder transitional cell carcinoma;cancer therapy;career;career development;checkpoint inhibition;chemotherapy;cost;drug development;gemcitabine;genetic signature;genomic platform;immune cell infiltrate;improved;in vivo;men;molecular subtypes;muscle invasive bladder cancer;novel;peripheral blood;permissiveness;research and development;response;responsible research conduct;single cell analysis;single-cell RNA sequencing;skills;tumor;tumor microenvironment;tumor-immune system interactions In vivo Assessment of Chemotherapy Remodeling of the Bladder Cancer Immune Microenvironment NARRATIVEThis project will focus on understanding how chemotherapy used for bladder cancer alters the immunemicroenvironment of bladder tumors using faithful preclinical models of bladder cancer.1 NCI 10819107 7/25/23 0:00 PA-21-071 3R01CA241810-04S1 3 R01 CA 241810 4 S1 "VENKATACHALAM, SUNDARESAN" 8/1/20 0:00 4/30/25 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 6772358 "KIM, WILLIAM Y." "VINCENT, BENJAMIN G" 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 74967 NCI 52076 22891 ABSTRACTIn the United States urothelial carcinoma (UC) of the bladder is the 4th most frequent malignancy in men andthere will be an estimated 80500 new cases and 17500 deaths in 2019. Despite being the most costly cancerto treat over a patients lifetime bladder cancer remains underfunded. High-grade (HG) muscle invasivebladder tumors account for the majority of these deaths as patients with metastatic disease have a 5-yearsurvival rate of only 15%. In patients with clinically localized muscle-invasive bladder cancer (MIBC) there isa high level of evidence to support the use of cisplatin-based neoadjuvant chemotherapy. Two widelyaccepted regimens with therapeutic equipoise are MVAC (methotrexate vincristine adriamycin and cisplatin)and GC (gemcitabine cisplatin). While trials in advanced bladder cancer therapy are evaluating thecombination of chemo and immunotherapy to rationally combine these two therapeutic modalities it isimperative to precisely understand how MVAC and GC impact the immune microenvironment and how to bestsequence chemo and immunotherapy. Preliminary studies from the Kim and Vincent laboratories show that MVAC and GC have differingeffects on the immune microenvironment in bladder cancers of the luminal molecular subtype. Tumors of theluminal subtype which have low baseline immune infiltration have a significant increase in immune genesignature expression and clonality of tumor-specific T cell receptor (TCR) clonotypes in the peripheral bloodafter MVAC but not GC treatment. In contrast GC significantly increases gene signatures known to promoteresistance to IC therapy in bladder cancer (Fibroblast TGFB Response Signature [FTBRS] and EMT-Stroma).These results suggest that in luminal bladder cancers MVAC promotes an inflamed tumor immunemicroenvironment permissive to IC inhibition while GC increases stromal activation known to correlate with ICresistance. The diversity supplement candidate will leverage a novel faithful genetically engineered murine (GEM)model of bladder cancer of the luminal molecular subtype as well as single cell RNA sequencing (scRNAseq)to examine the effect of MVAC and GC at high resolution on the tumor microenvironment. Moreover he willdetermine the best sequence of administration of chemo and immunotherapy in these faithful models. Thecomprehensive career development plan will teach presentation writing and networking skills to leverage forthe next steps in his career. Successful completion of this scientific work and training program will poise thecandidate for a selective academic post-doctoral fellowship and an effective academic career.1 74967 +No NIH Category available 3-Dimensional;Address;Biological Models;Breast;Breast Cancer Model;Breast Cancer Patient;Breast cancer metastasis;CRISPR screen;CRISPR/Cas technology;Cancer Relapse;Cell Communication;Cells;Classification;Clinical;Collection;Computer Models;Data;Dependence;Development;Diagnosis;Disease;ERBB2 gene;Estrogen receptor positive;Experimental Models;Genomic approach;Genomics;Goals;Image;Immune;Immune system;In Situ;Lead;Longitudinal cohort;Machine Learning;Macrophage;Malignant Neoplasms;Metastatic breast cancer;Modeling;Molecular;Molecular Profiling;Multiplexed Ion Beam Imaging;Nature;Neoplasm Metastasis;Non-linear Models;Oncogenic;Organoids;Outcome;Pathologist;Pathology;Patients;Phagocytosis;Population;Primary Neoplasm;Process;Property;Relapse;Research Project Grants;Research Support;Resistance;Resolution;Resource Sharing;Sampling;Site;Spatial Distribution;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stromal Cells;Subgroup;System;Systems Biology;Technology;Therapeutic;Time;Tissue Model;Tissue Sample;Tissues;Tumor Tissue;Vision;Visualization;bean;biobank;breast cancer progression;cancer cell;cohort;computer framework;computerized tools;data integration;disease heterogeneity;functional genomics;genome-wide;high risk;hormone therapy;innovation;invention;malignant breast neoplasm;multidisciplinary;neoplastic cell;prospective;relapse risk;response;single cell technology;targeted treatment;therapeutic target;therapy resistant;tissue resource;triple-negative invasive breast carcinoma;tumor Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer Project NarrativeMetastatic breast cancer and relapse following therapy are dependent on (1) development of intrinsic resistanceto targeted and endocrine therapies and (2) resistance to recognition and destruction of cancer cells by theimmune system. The Stanford Breast Metastasis Center (SBMC) is focused on (1) quantifying the timing ofmetastatic dissemination in breast cancer (2) functionally delineating the contribution of cellular andmicroenvironmental crosstalk on metastatic proclivity and (3) characterizing the mechanisms of responses bymetastatic cells to therapies. To achieve these goals we harness an integrated systems biology functionalgenomic and evolutionary dynamic approach applied to longitudinal breast cancer tissue cohorts and patient-derived organoid models. NCI 10819066 8/22/23 0:00 PA-21-071 3U54CA261719-03S1 3 U54 CA 261719 3 S1 "NADEAU, CHRISTINE FRANCES" 9/14/21 0:00 8/31/25 0:00 ZCA1(M1) 10842134 "CURTIS, CHRISTINA N" Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 66233 NCI 42897 23336 Abstract/Project SummaryMetastatic breast cancer and relapse following therapy are dependent on (1) development of intrinsic resistanceto targeted and endocrine therapies and (2) resistance to recognition and destruction of cancer cells by theimmune system. The Stanford Breast Metastasis Center (SBMC) is focused on (1) quantifying the timing ofmetastatic dissemination in breast cancer (2) functionally delineating the contribution of cellular andmicroenvironmental crosstalk on metastatic proclivity and (3) characterizing the mechanisms of responses bymetastatic cells to therapies. In order to achieve these goals mechanistic computational models that capture dynamic andemergent tumor cell intrinsic and extrinsic properties are needed as are clinically annotated longitudinaltissue cohorts and experimental models that capture disease heterogeneity. The SBMC addresses each of theseoutstanding challenges. First we have established an unparalleled collection of clinically annotated breastcancer cohorts sampled through treatment and metastasis including both prospective and retrospectivelongitudinal cohorts with multiple metastatic sites. We leverage a living biobank of breast cancer patient-derived organoids (PDOs) from primary tumors and metastases that recapitulate the heterogeneity ofdisease high-risk of relapse subgroups and tumor-immune interactions and greatly facilitating the proposedfunctional studies. We characterize these vast tissue resources and model systems using state-of-the-artmolecular profiling technologies to probe tumor tissue in situ at single cell and subcellular resolution. Specificallywith Multiplexed Ion Beam Imaging by Time of Flight (MIBI-TOF) and matrix-assisted laser desorption ionizationimaging (MALDI) we simultaneously visualize the composition lineage function and spatial distribution of tumorand stromal cell populations and perform co-registered analysis of the glycome. We integrate these data withinthe genomic landscape of metastatic disease and analyze these data within robust machine learning andcomputational frameworks to uncover disease dynamics and features associated with clinical outcomes.Lastly we conduct genome-scale CRISPR screens in 3D breast cancer models to systematically defineoncogenic dependencies therapeutic vulnerabilities and macrophage-tumor cell interactions. This integrated systems biology and functional genomics approach will contribute to a quantitative andmechanistic understanding of metastatic breast cancer and the dynamic relationship between tumor cells andthe host with implications for therapeutic targeting. 66233 +No NIH Category available Acetylation;Age;Aging;Automobile Driving;Biology;Cancer Biology;Cell Aging;Cell physiology;Cells;Chemicals;Chromatin;Chromatin Structure;Coupled;DNA;DNA Damage;DNA Methylation;Deacetylase;Defect;Disease;Enzymes;Epigenetic Process;Family;Gene Activation;Genetic Transcription;Genomic Instability;Genomics;Goals;Histone Acetylation;Histone Deacetylation;Histone H3;Histones;Human Genome;Link;Longevity;Lysine;Malignant Neoplasms;Mammals;Metabolic Diseases;Methylation;Modeling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Nuclear;Oncogenic;Oncoproteins;Pathology;Pathway interactions;Phenotype;Process;Regulation;Research;Role;Saccharomycetales;Signal Transduction;System;Testing;Therapeutic Intervention;Transact;Yeasts;cancer cell;cell type;chromatin modification;chromatin remodeling;histone modification;human cancer mouse model;in vivo;insight;lung Carcinoma;new therapeutic target;novel;pre-clinical;prevent;programs;response Histone Deacetylation Signaling in Aging and Cancer Pathways PROJECT NARRATIVEWe propose to investigate novel mechanisms of action of the SIRT7 enzyme in regulating chromatin thestructure in which the human genome is packaged and how these mechanisms are linked to mammalianaging and cancer biology. Defects in chromatin regulation can contribute to numerous aging-associatedpathologies including cancer metabolic and neurodegenerative disease. This proposal will provide newinsights into how chromatin mechanisms regulate important cellular functions and has the potential to identifynew targets for therapeutic intervention. NCI 10819057 9/18/23 0:00 PA-21-071 3R01CA268925-03S1 3 R01 CA 268925 3 S1 "OKANO, PAUL" 7/9/21 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1(02)-M] 1907889 "CHUA, KATRIN F" Not Applicable 16 Unavailable 624218814 H58TR2D7DNE3 624218814 H58TR2D7DNE3 US 37.400877 -122.138324 2357101 PALO ALTO VETERANS INSTIT FOR RESEARCH PALO ALTO CA Research Institutes 943041207 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 65899 NCI 46408 19491 Our broad research goal is to understand chromatin regulatory mechanisms in nuclear and epigeneticprograms and how these mechanisms are deregulated in aging and disease. A fundamental mechanism forregulating chromatin involves the reversible modification of histones by chemical moieties such as acetyl-methyl- and phospho-groups. These different histone marks are linked to discrete chromatin states andregulate the accessibility of DNA to transacting factors. In budding yeast histone deacetylation by thechromatin silencing factor Sir2 prevents genomic instability and aging and in mammals de-regulation ofhistone acetylation is linked to cellular senescence and aging-related pathologies from neurodegeneration tocancer. Here we focus on SIRT7 a chromatin regulatory lysine deacetylase enzyme in the Sir2 family ofaging-regulatory factors. This project will study new roles of SIRT7-dependent histone deacetylation inchromatin regulatory mechanisms that are deregulated in aging and age-associated cancer biology.Inactivation of SIRT7 in mice leads to genomic instability shortened lifespan and aging-related phenotypesand preliminary studies suggest that increased SIRT7 protects against aging pathologies in mice. HoweverSIRT7 can also sustain oncogenic transcriptional programming in cancer cells. Thus uncovering distinctpathways of SIRT7 chromatin regulation may be important to dissect pleiotropic functions of SIRT7 in agingand cancer pathways. Recently we identified a novel substrate of SIRT7 acetylated lysine K36 of histone H3(H3K36ac) which is dramatically hyper-acetylated upon SIRT7-inactivation. H3K36ac is implicated inchromatin remodeling and DNA damage responses in yeast but its regulation and functions in mammalianbiology are largely obscure. In preliminary studies we found that the increased H3K36 acetylation in SIRT7-deficient cells is coupled to decreased di-methylation at this residue (H3K36me2) a chromatin modificationthat has important roles in gene activation DNA methylation and oncogenic transformation. Moreover SIRT7interacts physically with the oncoprotein NSD2 the enzyme that generates the bulk of H3K36me2 in many celltypes. Here we will investigate a new model that SIRT7 clears acetylation at H3K36 from large swaths ofchromatin to help prime NSD2-catalyzed methylation at H3K36. In Aim 1 we explore the connection of SIRT7and NSD2 in aging-related processes using genomic cellular and mouse systems and in Aim 2 we test therole of SIRT7-H3K36-NSD2 methylation axis in driving lung carcinoma in vivo using pre-clinical mouse andhuman cancer models. By uncovering distinct pathways of SIRT7 chromatin regulation this project may suggststrategies to selectively enhance functions of SIRT7 that are protective in aging without promoting oncogenicSIRT7 activities. Together these studies should provide insights into fundamental chromatin mechanisms inaging and cancer biology. 65899 +No NIH Category available African;Allografting;Artificial Intelligence;Autophagocytosis;Biological;Breast Cancer Cell;Carcinoma;Cell Nucleus;Computers;Cytoplasm;Data Scientist;Disparity;European;Gene Expression;Genetic Transcription;Immunohistochemistry;Link;Machine Learning;Malignant Neoplasms;Modeling;Mus;Outcome;Pathologist;Pathway interactions;Population;Prognostic Marker;Race;Regulator Genes;Role;Scientist;Specimen;Technology;Variant;Woman;breast cancer survival;cancer health disparity;cohort;deep learning;malignant breast neoplasm;mortality;multidisciplinary;novel;pharmacologic;predictive marker;racial difference;racial disparity;racial diversity;survival outcome;transcription factor;tumor behavior;tumor microenvironment;tumor progression;tumor-immune system interactions The linkage between Race Kaiso and the tumor microenvironment in breast cancer health disparities Elevated expression of the multifunctional transcriptional regulator Kaiso (ZBTB33) isassociated with worse breast cancer survival based on race. In this study we leveragemachine learning and artificial intelligence to study a novel breast cancer healthdisparities cohort to define new functional linkages between Kaiso autophagy and thetumor microenvironment that contribute to racially disparate breast cancer outcome. NCI 10819011 8/4/23 0:00 PA-21-071 3R01CA253368-04S1 3 R01 CA 253368 4 S1 "MERCER, NATALIA" 9/24/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1(55)-R] 1926891 "GARDNER, KEVIN L." Not Applicable 13 PATHOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 70872 NCI 43083 27789 Women of African heritage suffer a higher breast cancer mortality compared to their European counterparts.Though the biologic basis for these disparities remains poorly defined recent studies suggest definitive rolesfor biological variation in the gene expression pathways governing tumor behavior and alterations in the tumormicroenvironment. The transcription factor Kaiso (ZBTB33) is a gene regulatory factor found in both thenucleus and cytoplasm of breast cancer cells that has been functionally linked to racial differences in survivaloutcome in several epithelial cancers. In this study we leverage machine learning and artificial intelligence todefine functional linkages between Kaiso autophagy and the immmune tumor microenvironment thatcontribute to racial differences in breast cancer survival. We accomplish this through application of machinelearning and artificial intelligence to characterize the Kaiso dependent differences in spatial and topologicalfeatures of the tumor microenvironment using multiplex immunofluorescent technologies to profile a uniquebreast cancer health disparities cohort (Specific Aim One). We then apply this technology to examine theimpact of Kaiso disruption on autophagy and the immune tumor microenvironment using a murine orthotopicallograft model for Kaiso depletion in the presence and absence of pharmacologic blockade of autophagy(Specific Aim Two). We then perform a large-scale application of artificial intelligence and deep learning toprofile the spatial and topological features of the tumor microenvironment in 901 racially diverse breast cancerspecimens by multiplex immunohistochemistry to define the detailed role of Kaiso autophagy and the tumormicroenvironment in population-specific differences in breast cancer outcome (Specific Aim Three). Togetherwith a closely integrated multi-disciplinary team of breast cancer pathologists cancer biologists computerscientists biostatisticians bioinformaticians and data scientists we will define new prognostic and predictivebiomarkers that link Kaiso to tumor progression the immune tumor microenvironment breast cancer outcomeand how their association differs by race. 70872 +No NIH Category available Acupressure;Anti-Inflammatory Agents;Attitude;Brain Injuries;Brief Pain Inventory;Cancer Patient;Cellular Phone;Clinical;Clinical Trials Design;Data;Data Analyses;Development;Dose;Ear;Educational process of instructing;Faculty;Foundations;Functional Magnetic Resonance Imaging;Goals;Individual;Manuscripts;Mentors;Modality;Nonpharmacologic Therapy;Pain;Participant;Patient Outcomes Assessments;Quality of life;Questionnaires;Research;Research Personnel;Resources;Scientist;Secure;Self Management;Sensory;Signal Transduction;Symptoms;Testing;Training;career;chemotherapy induced neuropathy;cytokine;data management;experience;follow-up;imaging biomarker;imaging study;improved;innovation;mobile application;opioid use;pain relief;parent grant;participant retention;recruit;side effect;treatment duration The relationship between fMRI and patient-reported outcomes in chemotherapy-induced neuropathy: A diversity supplement Project NarrativeThis diversity supplement secures clinical scientist mentors who will support the development ofDr. Nguyen towards becoming an independent clinician-researcher. Dr. Nguyen will gainexperience to clinical trial design recruitment participant retention data management andanalysis manuscript and proposal development. As a junior faculty this supplement will provideneeded resources and scientific training to establish a foundation for Dr. Nguyen to start aresearch career focused on nonpharmacological therapies patient-reported outcomes andquality of life among individuals with brain injuries. NCI 10819004 9/13/23 0:00 PA-21-071 3R01CA245054-04S1 3 R01 CA 245054 4 S1 "ALTSHULER, RACHEL DINA" 9/1/20 0:00 5/31/25 0:00 Clinical Management of Patients in Community-based Settings Study Section[CMPC] 8223918 "JOHNSON, CONSTANCE MARGARET" "LUKKAHATAI, NADA " 18 MISCELLANEOUS 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF NURSING 770305400 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 197872 NCI 126841 71031 Summary of Parent Grant (R01CA245054)Chemotherapy induced neuropathy (CIN) is a severe side effect that impacts greater than 60%of cancer patients. CIN impacts treatment duration and dosing functional mobility and quality oflife. This proposal examines the effect of auricular point acupressure (APA) as an innovatedsolution for CIN. APA utilizes a non-invasive active modality of treatment stimulating points onear to improve CIN symptoms. Utilizing a mobile application on smartphones this projectteaches participants how to stimulate their ears for three minutes 3 times a day to alleviatepain. Given limited understanding of the mechanism of pain relief participants will completemultiple questionnaires: Quantitative Sensory Test Revised Brief Pain Inventory-CIN PROMIS-29 Opioid Use Experience and Attitude and Demographic data. Additionally imaging studiesand biomarkers will be obtained. Functional MRI (fMRIs) will obtain pre- post- and follow-upAPA evoked signal changes and pro- and anti- inflammatory cytokines will be collected. Thegoal of this study is to ascertain the efficacy of APA as a self-managed adjunctive therapy toenhance CIN management through understanding the underlying mechanisms of APA on CIN. 197872 +No NIH Category available BRCA2 gene;Malignant Neoplasms;Mutate;Poly(ADP-ribose) Polymerase Inhibitor;Resistance Mechanisms of PARPi Resistance in BRCA2 Mutated Cancer Project NarrativeNot needed for this submission. NCI 10819001 8/7/23 0:00 PA-21-071 3R01CA270788-02S1 3 R01 CA 270788 2 S1 "WITKIN, KEREN L" 6/7/22 0:00 4/30/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 10196806 "JENSEN, RYAN BROWN" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 66593 NCI 39757 26836 Project SummaryNot needed for this submission. 66593 +No NIH Category available Automobile Driving;Binding;Cell Survival;Chemicals;DNA Binding;Data;Development;Disease;Drug Design;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Malignant Neoplasm;Foundations;Generations;Genome;Goals;Growth;Human Herpesvirus 4;Investigation;Malignant Neoplasms;Medical;Modification;Molecular;Nuclear Protein;Patient-Focused Outcomes;Pharmaceutical Preparations;Recording of previous events;Resolvase;Structure;Testing;Therapeutic Agents;Treatment Efficacy;Viral;cancer therapy;combinatorial;endonuclease;improved;inhibitor;insight;latent infection;multicatalytic endopeptidase complex;neoplastic cell;next generation;novel therapeutic intervention;response;small molecule;small molecule inhibitor;tumor;tumor growth Drugging EBNA1 to Treat EBV-Associated Cancers - Diversity Supplement Project NarrativeEBV-associated cancers represent an important unmet medical need. New therapeutic strategies arerequired to improve patient outcomes. We have developed small molecules inhibitors to EBNA1 totreat EBV latent infection driving EBV-associated cancers. We now propose to better understandhow tumor cells respond to these inhibitors and enhance their efficacy by rational combinatorialtherapies and structure-based chemical modifications. NCI 10818976 9/20/23 0:00 PA-21-071 3R01CA259171-03S1 3 R01 CA 259171 3 S1 "AGYIN, JOSEPH KOFI" 6/15/21 0:00 5/31/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1869983 "LIEBERMAN, PAUL M" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 135781 NCI 74564 61217 Project SummaryEBV latent infection is responsible for ~200000 new cancers per year. To date there are no EBV-specific therapeutic agents that selectively and efficaciously treat EBV-positive tumors. All knownEBV tumors consistently express one viral nuclear protein EBNA1 that is required for maintainingthe EBV genome and promoting infected cell survival. We have developed highly selective drug-likesmall molecules that bind EBNA1 and block its ability to bind DNA maintain EBV genomes andpromote host-cell survival. Here we propose to better understand the mechanism through whichdisruption of EBNA1 DNA binding leads to tumor growth inhibition and use this information to identifyrational combinatorial agents to enhance chemotherapeutic efficacy. We propose to enhance thepotency of the first generation EBNA1 inhibitors by attaching proteasome targeting molecules(PROTACS) to selectively target EBNA1 for degradation. Finally we will take advantage of newmechanistic data revealing that EBNA1 functions as an OriP-specific endonuclease and resolvase.We propose to develop new structure and mechanism-based inhibitors of EBNA1 that can increasepotency necessary for highly efficacious cancer therapy. By integrating these strategies tounderstand the growth arrest response of EBNA1 inhibition (aim 1) to better develop rationalapproaches for combinatorial therapies (aim 2) and develop next generation molecule withstructure/mechanism based drug design principles (aim 3) we will advance EBNA1 inhibitors for thetreatment of EBV-associated malignancies and related-diseases. We will test the overarchinghypothesis that EBNA1 is an effective target for small molecule inhibitors to treat EBVcancers. The major goal of this proposal is to understand the tumor cell response to EBNA1inhibition and to enhance efficacy of EBNA1 inhibitors to treat EBV-associated cancers moreefficaciously. The team associated with this proposal has the unique expertise and strongcollaborative history to execute the aims of this proposal. Collectively these investigations willprovide fundamental insights into how EBNA1 functions at the molecular level and will lay thefoundation for the development of new strategies to treat EBV cancers. 135781 +No NIH Category available Antibody-drug conjugates;Automobile Driving;Biography;Biological Markers;Biological Products;Bladder;Breast Cancer Patient;Cancer Patient;Chemotherapy and/or radiation;Cisplatin;Clinic;Clinical;Combined Modality Therapy;DNA Damage;Data;Disease;Event;Foundations;Gene Expression;Genetic;Genetic Transcription;Genomics;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Immune;Immune checkpoint inhibitor;Immune system;Immunologic Factors;Immunologics;Immunotherapy;International;Malignant neoplasm of urinary bladder;Modality;Molecular;Mutation;Oncology;Outcome;Pathogenesis;Patients;Radiation;Radiation Tolerance;Radiation therapy;Radiobiology;Research;Research Personnel;Resistance;Robin bird;Roentgen Rays;Testing;Therapeutic;Treatment Efficacy;Work;antitumor effect;cancer therapy;cancer type;checkpoint therapy;chemotherapy;immune checkpoint blockade;improved;improved outcome;innovation;insight;multidisciplinary;multimodality;next generation;preservation;programs;radiation effect;radiation resistance;radiation response;radiomics;response;standard of care;treatment response;treatment strategy;tumor Project 3 Molecular Mechanisms Underlying Therapy Response to Radiation and Immune Checkpoint Blockade PROJECT NARRATIVEOverall Section This proposal focuses on elucidating the genomic and microenvironmental determinants and temporaldynamics underlying efficacy of radiation-based combination therapies. We will use an innovative molecularcharacterization trial testing radiation plus antibody-drug conjugate in bladder cancer and radiation plusimmunotherapy in head and neck cancer to characterize the mechanistic drivers underlying these nextgeneration RT-based therapies. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. NCI 10818969 8/2/23 0:00 PA-21-071 3U54CA274513-02S2 3 U54 CA 274513 2 S2 "VIKRAM, BHADRASAIN" 9/14/22 0:00 4/30/27 0:00 ZCA1(M1) 9306964 "CHAN, TIMOTHY AN-THY" "YU, DAVID SUNG-WEN" 11 INTERNAL MEDICINE/MEDICINE 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 66643 NCI 44225 22418 PROJECT SUMMARYOverall Section Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants andtemporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT) alone orin combination with other treatments is used to treat about two-thirds of all cancer patients. Despite thewidespread use of radiation therapy in oncology our understanding of the mechanisms driving response andresistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy andresistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus onusing combination therapies in which radiation is used with systemic agents highlighting the urgent need tounderstand the drivers of efficacy. Among the most promising new biologics being studied for use withradiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use aninnovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI inhead and neck cancer to characterize the mechanistic drivers underlying these next generation RT-basedcombinations. The central hypothesis of this U54 application is that specific genetic and immunologicmechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will addressthese questions through 3 specific aims. In Aim 1 we will work to understand the molecular mechanisms thatunderlie efficacy of treatment with radiation plus ADC. Here our working hypothesis is that specific genetic andimmunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage ourmolecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservationtherapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT +SG. In Aim 2 we will improve identification of patients who are sensitive or resistant to RT-based therapiesbased on new insights into transcriptional dynamics and temporal reprogramming during treatment withradiation-based therapies. Here we will leverage our molecular characterization trial treating head and necksquamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG orICI. We will build on recent experimental and clinical breakthroughs led by our research groups which haveidentified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim3 we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT +immune checkpoint blockade. Here using our head and neck trial (Part B) we will uncover the unique geneticand immunologic factors that govern response to RT when combined with these two classes of agents. Wewill elucidate the differential molecular effects of the two approaches immune reprogramming andmechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. 66643 +No NIH Category available Address;Adult;African American;African American population;Age;Attention;Award;Awareness;Behavior;Biology;Biomedical Research;Black race;Cancer Center;Cancer Center Planning Grant;Cancer Etiology;Career Choice;Caring;Cellular Phone;Cessation of life;Clinical;Code;Collaborations;Colon Carcinoma;Colorectal Cancer;Communities;Data;Development Plans;Diagnosis;Disease;Disparity;Ethics;Faculty;Foundations;Funding;Future;Goals;Grant;Growth;Health;Healthcare;Historically Black Colleges and Universities;Incidence;Individual;Institution;Intervention;Intuition;Knowledge;Lead;Link;Malignant Neoplasms;Medical;Mentorship;Modeling;National Research Service Awards;Obesity;Older Population;Outcome;Parents;Patient Self-Report;Pattern;Pilot Projects;Population;Race;Regional Cancer;Research;Research Personnel;Research Project Grants;Research Training;Resources;Risk Factors;Students;Surveys;Survival Rate;Testing;Text;Time;Tobacco use;Training;Training Activity;Training Programs;Underserved Population;Unhealthy Diet;Uninsured;United States National Institutes of Health;Universities;Virginia;Vulnerable Populations;Work;World Health Organization;associated symptom;cancer diagnosis;cancer education;cancer health disparity;career;colorectal cancer screening;design;early onset colorectal cancer;experience;health care availability;health disparity;health knowledge;knowledge base;low socioeconomic status;mHealth;male;member;men;mortality;parent grant;physical inactivity;programs;psychosocial;racial discrimination;racial disparity;racial population;screening;social media;social norm;therapy design;tool;trend;young adult Diversity Supplment to P20 SUCCEED (5P20CA264068-02) for Chelsey Cooper PROJECT NARRATIVEThe proposed diversity supplement will allow doctoral candidate Chelsey Cooper to receive training in biomedicalresearch intervention design and cancer disparities through coursework and her pilot project which willdetermine the barriers to colorectal cancer health knowledge in young adult African American men. Results fromthis pilot project will further inform colorectal cancer knowledge interventions in the Petersburg Virginiacommunity; a community with extremely high rates of colorectal cancer and poor screening rates. The trainingMs. Chelsey Cooper (Candidate) will receive over the course of two years will be critical for her career path incancer disparities within the African American community.1 NCI 10818947 9/20/23 0:00 PA-21-071 3P20CA264068-02S1 3 P20 CA 264068 2 S1 "RODRIGUEZ, LARITZA MARIA" 9/20/21 0:00 8/31/25 0:00 1923259 "FAISON, MILTON O" "ROBERTS, DANIEL M." 4 BIOLOGY 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA SCHOOLS OF ARTS AND SCIENCES 238032520 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 397 Research Centers 2023 9192 NCI 6383 2809 PROJECT SUMMARYAbstract of Parent Grant and Pilot Project 2.The overarching goal of the Virginia State University (VSU)-Virginia Commonwealth University (VCU) MasseyCancer Center (MCC) PartnErship for Cancer Disparities Research and Training (SUCCEED) program is to leadin the transformation of cancer-related outcomes for Virginians and to serve as a model of transdisciplinarydisparities research. The institutions will jointly conduct pilot research projects addressing local cancer-relatedhealth disparities and will develop a training program for VSU faculty and students designed to attract andprepare investigators for careers in cancer disparities. Researchers from VSU a Historically Black College orUniversity and (VCU) MCC understand the importance of collaboration and resources of both intuitions toeducate young adults who will help with the decline of colon cancer disparities in Virginia. A part of the parentgrant Pilot Project 2 fills a gap in translational cancer disparities research by leveraging a promising screeningintervention Screen to Save (S2S) to develop and test an enhanced mobile health (mHealth) S2S interventionculturally tailored for AA men. Clinically this is significant because AA men remain a dramatically underservedgroup that has not equally benefited from existing CRC education or screening interventions.Pilot Project 2 Specific Aim 1: Determine factors associated with self-reported CRC screening behaviorsamong (n=175) AA men in Petersburg VA.Pilot Project 2 Specific Aim 2: Develop tailored S2S content for AA men to be delivered using a combinationof short video and text-based information optimized for delivery via QR codes for smartphones.If this Research Supplement to Promote Diversity in Health-Related Research is awarded Ms. Chelsey Cooperwill leverage the numerous resources at VSU VCU and MCC in her tailored training development plan and pilotproject. Given the cancer disparities training tenets within MCC Ms. Cooper will have access to both courseworkand hands-on experience to continue to develop into an independent investigator with the tools and abilities tocompete for NCI NRSA or CURE funding. Her project will be focused on identifying psychosocial andenvironmental barriers for CRC knowledge in African American young adults which fits very well with the ParentP20 Pilot Project 2 and the goals of the overall P20 SUCCEED initiative (5P20CA264068-02). Moreover Ms.Chelsey Coopers work is naturally and logically aligned with her mentorship team Drs. Larry Keen (co-PI) MariaThomson (PI) and Michael Preston (co-I).1 9192 +No NIH Category available Brain Neoplasms;Caring;Cells;Clinical;Data;Development;Diagnosis;Disease;Etiology;Excision;Funding;Glioblastoma;Immune;Immunity;Malignant - descriptor;Malignant Neoplasms;Mediating;MicroRNAs;Modeling;Operative Surgical Procedures;Patients;Primary Brain Neoplasms;Proliferating;Radiation therapy;Regimen;Research;Role;Therapeutic;Therapeutic Effect;Validation;chemotherapy;clinical care;combinatorial;immune checkpoint blockade;in vivo;innovation;mouse model;novel;restoration;tumor;tumor heterogeneity;tumor progression microRNA therapies for advanced brain tumors NARRATIVEThis proposal emphasizes on evaluating the therapeutic potential of a combinatorial approach of microRNAmodulation and immune checkpoint blockade for advanced brain tumors. This therapeutic strategy oncevalidated can be incorporated into the clinical care regimen for brain tumor therapy. NCI 10818943 9/13/23 0:00 PA-21-071 3R00CA245030-03S1 3 R00 CA 245030 3 S1 "MAAS, STEFAN" 4/1/20 0:00 12/31/24 0:00 11728143 "BHERE, DEEPAK " Not Applicable 6 PATHOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF MEDICINE 292080001 UNITED STATES N 7/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2023 40663 NCI 30579 10084 ABSTRACTEach year upwards of 14000 patients are diagnosed with Glioblastoma (GBM) the most malignant form ofprimary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options for GBMbut patients generally succumb to the disease. Tumor heterogeneity presents a major challenge to developmentof successful therapies making it increasingly apparent that the use of combination or cocktail therapies wouldpresent innovative strategies to tackle GBM. MicroRNAs (miR) are emerging as key regulators of cellulardifferentiation and proliferation; have been implicated in the etiology of a variety of cancers including GBM.Numerous groups including us have demonstrated the role of microRNA modulation and their therapeutic effectson GBM tumor progression. Our data from the R00 funded research have revealed the critical role of microRNA-124 restoration and its effect on host immunity in GBM. This in this study we will evaluate the combinatorialeffects of miR-124 modulation with immune checkpoint blockade. The effects of the proposed strategy will bemechanistically evaluated and efficacy will be evaluated using in vivo GBM models. The use of mouse modelsof GBM tumor resection will mimic clinical scenario of GBM care and further trigger the surgery mediated immuneeffects on GBM cells. Successful validation of our proposed therapeutic strategy will open avenues for noveltreatment options for GBM. 40663 +No NIH Category available ABCG2 gene;Address;Aminolevulinic Acid;Clinical;Detection;Doctor of Philosophy;Excision;FDA approved;Family;Female;First Generation College Students;Fluorescence;Fluorescent Probes;Funding;Future;Generations;Goals;Heterogeneity;Inter-tumoral heterogeneity;Knowledge;Malignant Neoplasms;Mediating;Metabolic;Minority;Molecular Probes;Normal tissue morphology;PUVA Photochemotherapy;Pathway interactions;Research;Research Personnel;Research Project Grants;Research Support;Training;Variant;Woman;Work;anticancer research;cancer imaging;cancer therapy;career;college;fluorescence imaging;heme biosynthesis;neoplastic cell;parent grant;protoporphyrin IX;skills;tumor;tumor heterogeneity Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment This supplement research focuses on addressing the intra- and inter-tumor heterogeneity of 5-aminolevulinic acid (ALA)-mediated protoporphyrin IX (PpIX) fluorescence so that ALA can be betterused for tumor detection and photodynamic therapy. This application is also important for supportinga first-generation female college graduate to start her future career as a cancer researcher. NCI 10818914 9/15/23 0:00 PA-21-071 3R15CA268200-03S1 3 R15 CA 268200 3 S1 "WANG, CHIAYENG" 6/1/22 0:00 12/31/25 0:00 8136828 "CHEN, BIN " Not Applicable 3 PHARMACOLOGY 75495937 YGSGAA2XKP71 75495937 YGSGAA2XKP71 US 39.993744 -75.239641 7862501 SAINT JOSEPH'S UNIVERSITY PHILADELPHIA PA SCHOOLS OF PHARMACY 191311308 UNITED STATES N 6/1/23 0:00 12/31/25 0:00 394 Non-SBIR/STTR 2023 118970 NCI 82048 36922 NCI Diversity Supplement ApplicationParent grant: Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment (R15CA268200-02 PI: Bin Chen)This diversity supplement application is to support Ms. Jordyn Olsen a first-generation college graduate in herfamily to pursue PhD training in cancer research with the goal of promoting women and minorities in cancerresearch workforce. Aminolevulinic acid (ALA) is one of a few FDA-approved intraoperative fluorescent probesand the only molecular probe based on the metabolic alterations in tumor cells. ALA has no fluorescence on itsown and needs to be metabolized in the heme biosynthesis pathway in tumor cells to produce a fluorescent andphotosensitizing metabolite protoporphyrin IX (PpIX) which enables tumor fluorescence imaging for tumordetection and photodynamic therapy (PDT) for cancer treatment. Although ALA-PpIX has been clinically usedfor fluorescence-guided tumor resection and cancer treatment its applications are limited by low tumor PpIXfluorescence high tumor fluorescence heterogeneity and low tumor-to-normal tissue fluorescence contrast.Research supported by the parent grant has led to the identification of ABCG2 transporter activity as a criticalfactor in reducing tumor PpIX fluorescence. More importantly we have identified clinically used agents tosuppress ABCG2 activity to enhance tumor PpIX fluorescence. In this supplement research Jordyn willdetermine whether variation in ABCG2 expression results in intra-tumor and inter-tumor heterogeneity in ALA-PpIX fluorescence. In addition she will investigate whether PpIX fluorescence heterogeneity in tumor cells canbe suppressed by ABCG2 inhibition. This proposed research is related to the on-going work supported by theparent grant funding and will further expand scope of parent grant research. Support from this supplementfunding will enable Jordyn to complete the necessary training in cancer research so that she will have theknowledge and skills to start her career as a cancer researcher. 118970 +No NIH Category available AMP-activated protein kinase kinase;Affect;Affinity;Allografting;Angiogenesis Inhibitors;Angiogenic Factor;Angiostatic Proteins;Autophagocytosis;Binding;Biological;Biology;Breast Cancer cell line;Breast Carcinoma;C-terminal;Cancer Biology;Cells;Cellular Stress;Chemicals;Communication;Complex;Core Protein;Cues;Development;Disease;Eating;Endothelial Cells;Endothelium;Enzymes;Exons;Female;Fibroblast Growth Factor Receptors;Funding;GADD45A gene;Gene Targeting;Genetic;Genetic Transcription;Grant;Growth;HAS2 gene;Heparan Sulfate Proteoglycan;Hyaluronan;Immunologics;In Vitro;Integrins;KDR gene;Knowledge;Laboratories;Ligation;Link;Malignant Neoplasms;Mediating;Methodology;Modality;Modeling;Molecular;Mus;Mutate;Names;Neoplasm Metastasis;Nutrient;Oxygen;PTPN6 gene;Parents;Parkin;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Phosphotransferases;Protein Tyrosine Phosphatase;Proteins;Proteoglycan;Recombinants;Regulation;Research;Role;Second Primary Cancers;Sensitivity and Specificity;Signal Transduction;Specificity;Stromal Cells;Tamoxifen;Technology;Testing;Time;Transgenic Mice;Translating;Tumor Angiogenesis;VEGFA gene;Vascular Endothelium;Vascularization;Work;Zebrafish;adhesion receptor;aggressive breast cancer;angiogenesis;antagonist;attenuation;cancer cell;cell behavior;cellular engineering;clinically relevant;combat;confocal imaging;experimental study;genetic signature;in vivo;inducible Cre;inhibitor;innovation;interdisciplinary approach;mTOR Inhibitor;mTOR inhibition;malignant breast neoplasm;mortality;mouse model;mutant;nano-string;neoplastic cell;neovascularization;novel;novel therapeutics;nutrient deprivation;overexpression;paracrine;perlecan;predict clinical outcome;programs;promoter;receptor;sensor;transcriptome;transcriptomics;tumor;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic;ultra high resolution Proteoglycan regulation of tumor angiogenesis and endothelial cell autophagy We discovered that endorepellin a soluble fragment of the heparan sulfate proteoglycan perlecan evokesexcessive autophagy or self-eating in the endothelial cells lining breast cancer vessels with no direct effects onthe cancer cells. This novel bioactivity of endorepellin via selective and specific targeting of the endothelia willbe investigated utilizing state-of-the-art molecular methodologies combined with highly-innovative mouse modelsof mammary carcinomas. Our research by focusing on the tumor microenvironment and tumor secretome willunravel unique avenues of study using endorepellin as a valuable treatment modality to combat this devastatingdisease in both primary and secondary malignancies. NCI 10818834 9/18/23 0:00 PA-21-071 3R01CA245311-04S1 3 R01 CA 245311 4 S1 "MERCER, NATALIA" 7/1/20 0:00 6/30/25 0:00 Intercellular Interactions Study Section[ICI] 1898950 "IOZZO, RENATO V." Not Applicable 2 PATHOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 61776 OD 39600 22176 Chief among female mortality is the development progression and metastasis of aggressive breast cancer. Thebidirectional communication between the neoplastic cells and the tumor microenvironment which suppliesoxygen and nutrients is essential for promoting unchecked tumorigenic development aberrantneovascularization and widespread metastasis. Thus a better understanding of embedded cues and solublemessages exchanged between these two compartments will prove invaluable for furthering our knowledge ofthe pathobiology of cancer and for reliably predicting clinical outcomes. Our central hypothesis is that endorepellin a proteolytic fragment of perlecan a multi-domain heparan sulfateproteoglycan exploits a dual-receptor antagonism to preclude endothelial cells from participating in tumorangiogenesis. This working hypothesis is based on an impactful and promising body of work all generated underthe auspices of this grant. We discovered that: [a] Endorepellin simultaneously ligates with high affinityVEGFR2 and the 2Engagement of both receptors underscores the exquisite sensitivity and specificity of endorepellin in targetingthe endothelia. [b] Endorepellin triggers co-internalization of VEGFR2 and 2 1 integrin with concurrentactivation of the SHP-1 tyrosine phosphatase and attenuation of VEGFA signaling. [c] Endorepellin inducesendothelial cell autophagy in a Peg3-dependent manner by modulating Beclin 1 LC3 and p62 expressionprocessing and cellular localization. [d] Endorepellin evokes protracted activation of the energy-sensor kinaseAMPK irrespective of energy levels. Indeed this regulation is considered non-canonical as AMPKphosphorylation occurred under nutrient-enriched conditions. [e] Downstream of AMPK endorepellin evokesautophagic flux in endothelial cells that mechanistically parallels the mTOR inhibitor Torin 1. These strikingfindings demonstrate that protracted and sustained autophagy is a novel mechanism by which endorepellinpromotes angiostasis independent of nutrient deprivation. Based on these discoveries we plan to: [1] Elucidate the mechanism of endorepellin-evoked endothelial cell stress autophagy and mitophagy. [2] Unravel the mechanism by which endorepellin induces autophagic suppression of HAS2. [3] Generate novel mouse models of tumorigenesis to explain the pro-autophagic and anti-angiogenic programsactivated by endorepellin. These concerted research aims will enable us to translate our findings procured with highly innovative mousemodels of stromal autophagy into clinically relevant paradigms. The discovery of endorepellin-inducedendothelial cell autophagy downstream of dual receptor antagonism will lead to new therapeutic advances thatactively induce autophagy within the tumor microenvironment to combat this devastating disease. 61776 +No NIH Category available Acoustics;Angiography;Biomedical Engineering;Biopsy;Blood Vessels;Cancer Detection;Cancerous;Clinical;Collaborations;Contrast Media;Data;Development;Diagnostic;Early Diagnosis;Frequencies;Generations;Health Care Costs;Human;Image;Imaging technology;Lesion;Magnetic Resonance Imaging;Malignant Neoplasms;Modality;Modernization;Morphology;Noise;Performance;Population;Public Health;Research;Rural Population;Safety;Screening for cancer;Sensitivity and Specificity;Solid;Solid Neoplasm;System;Techniques;Technology;Testing;Tissues;Training;Translations;Ultrasonic Transducer;Ultrasonography;Underserved Population;career development;cooking;cost;imaging approach;imaging modality;improved;industry partner;innovation;parent grant;portability;pre-clinical;signal processing;tool;ultrasound Academic-Industrial Partnership for Translation of Acoustic Angiography RELEVANCE TO PUBLIC HEALTHThis project is a continuation of a collaboration which aims to develop new tools and approaches for imaging themicrovasculature with ultrasound. Data suggests that imaging the microvasculature will provide us with animproved ability to detect and differentiate cancer in humans and if successful our approach may lead to a newlow-cost safe portable imaging modality that is better at early detection of cancers than currently availablemodalities. To pursue this we will develop new ultrasound hardware and imaging approaches and test theirperformance in preclinical and clinical populations. NCI 10818833 9/8/23 0:00 PA-21-071 3R01CA189479-07S1 3 R01 CA 189479 7 S1 "PEREZ, J MANUEL" 9/4/14 0:00 8/31/26 0:00 Imaging Technology Development Study Section[ITD] 9239482 "DAYTON, PAUL A" Not Applicable 4 BIOMEDICAL ENGINEERING 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 85125 NCI 59087 26038 PROJECT SUMMARYTraditional grayscale ultrasound imaging is widely used in diagnostics because of its accessibility low-costportability and safety. Ultrasound is the only modality which is getting smaller and less expensive and therebymore accessible to rural and underserved populations. Modern ultrasound systems can now be handheld andcost ~ 1/1000th of an MRI system. However the major challenge remains that ultrasound is poorly specific tosolid cancers. Techniques to improve the specificity and sensitivity of ultrasound to solid tumors would have asignificant impact in early detection and reduction of unnecessary biopsies saving lives and reducing healthcarecosts. Our team is developing an innovative microvascular imaging technology based on hardware advances inmulti-frequency ultrasound transducers as well as signal processing techniques to specifically detect contrastagents while reducing background noise. Preliminary data using the first generation of this technology has shownsubstantial potential to improve our ability to differentiate cancerous lesions from healthy tissue based on theability to resolve differences in angiogenic vasculature morphology from healthy tissue. This diversity supplementwill support Ms. Jadyn Cooks career development and scientific training in biomedical engineering of ultrasoundtools to improve our detection of cancer. Her research focus relevant to the parent grant will focus on thedevelopment and testing of dual-frequency ultrasound techniques. 85125 +No NIH Category available 3-Dimensional;Address;Aging;Biological Models;Biology;Cell Aging;Cell Cycle Arrest;Cells;Cytolysis;Data Analyses;Detection;Disease;Disease Progression;Embryonic Development;Goals;Heterogeneity;Human;Impairment;Inflammation;Inflammatory Response;Lung;Lung diseases;Macrophage;Maps;Mass Spectrum Analysis;Mus;Pathologic;Phase;Population;Procedures;Proteins;Proteome;Proteomics;Resolution;Technology;Tissues;aged;data acquisition;detection sensitivity;embryonic stem cell;human disease;human tissue;improved;invention;new technology;novel;novel marker;senescence;stem cell differentiation;tissue mapping;tissue regeneration;tool;tumorigenesis;wound healing Single-cell proteomic identification of novel markers of senescence Senescence is a terminal cellular state that contributes to many human diseases and hence identification andmapping of senescent cells in tissues will help understand the mechanisms of diseases with the potential todiscover novel disease therapies. We propose to employ a newly invented single-cell proteomic approach toinvestigate the proteomes of senescent cells in the lungs to reveal novel markers of senescent cells. Theidentified novel markers will facilitate our understanding of lung biology and disease and further promote theidentification and characterization of senescent cells in other human tissues. NCI 10818822 9/19/23 0:00 PA-20-272 3UH3CA268117-03S1 3 UH3 CA 268117 3 S1 "JHAPPAN, CHAMELLI" 9/22/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1(70)-R] 11729543 "DOU, ZHIXUN " "RAJAGOPAL, JAYARAJ ; SLAVOV, NIKOLAI " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 108590 OD 91840 16750 Cellular senescence is a stable form of cell cycle arrest associated with pro-inflammatory responses. On the onehand senescent cells are a barrier for tumorigenesis and promote wound healing and embryogenesis. On the otherhand senescent cells accumulate in aged and diseased tissues where they impair tissue renewal and contribute toinflammation and disease progression. Identification and characterization of senescent cells in human tissues willcontribute to our understanding of human diseases. Thus mapping senescent cells at the 3-dimensional level andsingle-cell resolution in human tissues is an important biomedical objective. Accurate mapping of senescent cells requires reliable markers to specifically identify senescent cells.Currently the senescence field has limited markers to unambiguously distinguish between senescent cells andcells in other pathological states. In addition the available markers do not address the heterogeneity of senescentcells in tissues. To overcome these limitations we propose to employ a novel single-cell proteomic technologyto investigate the proteomes of senescent cells at the single-cell level with the goal to reveal novel markers ofsenescence which can be used to identify and map senescent cells in human tissues. Our group has recently developed a novel technology termed Single-Cell ProtEomics by MassSpectrometry (SCoPE2). This platform combines automated cell lysis improved detection sensitivity andoptimized data acquisition and analyses allowing detection and quantification of thousands of proteins within asingle cell. We have applied this technology to study embryonic stem cell differentiation and macrophagepolarization revealing their heterogeneity and alterations of proteomes at the single-cell level. In this application we will use the lung as a model system which accumulate senescent cells thatcontribute to aging and lung diseases. In the UG3 phase we will isolate senescent cells from the lungs of naturallyaged mice. The isolated senescent cells together with control cells will be subjected to SCoPE2 procedure toquantify their proteomes at the single-cell level allowing us to create unique signatures for potentially diversesenescent cell populations. This will help discover novel markers of senescent cells that are not possible withtraditional technologies. In the UH3 phase we will apply this technology to human lungs to validate and toidentify new markers of senescence. In aggregate we will establish new ways of identifying senescent cellsthat should offer new tools to probe senescent cells in human tissues facilitating tissue mapping of senescentcells of the SenNet initiative. In addition this study has the potential to reveal new biology of senescenceaddressing the heterogeneity and proteome alterations at the single-cell level. 108590 +No NIH Category available Malignant Neoplasms;Translational Research Translational Research in Cancer N/A NCI 10818814 6/16/23 0:00 PA-20-272 3P30CA056036-23S3 3 P30 CA 56036 23 S3 "PTAK, KRZYSZTOF" 6/22/95 0:00 5/31/24 0:00 15023178 "CHAPMAN, ANDREW " Not Applicable 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 2871106 NCI 1861386 1009720 N/A 2871106 +No NIH Category available Acceleration;Administrative Supplement;Alkylating Agents;Animal Model;Animals;Automobile Driving;Benchmarking;Biocompatible Materials;Biomechanics;Biomedical Engineering;Blood Vessels;Brain;Cancer Center;Career Mobility;Cell Communication;Cell Line;Cell model;Cells;Chemical Engineering;Chemotherapy and/or radiation;Clinical;Coculture Techniques;Collaborations;Complex;Cues;DNA Repair;Diffuse;Dimensions;Disease Progression;Drug resistance;Engineering;Evaluation;Evolution;Excision;Female;Glioblastoma;Glioma;Goals;Hydrogels;Hypoxia;Illinois;Infiltration;Invaded;Libraries;Link;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Mentors;Mentorship;Meta-Analysis;Methyltransferase;Modeling;Monitor;Neurites;Neurons;Operative Surgical Procedures;Outcome;Paracrine Communication;Parents;Patients;Pattern;Peripheral;Play;Process;Proliferating;Proteins;Radiation;Radiation therapy;Recurrence;Research;Research Assistant;Research Personnel;Research Project Grants;Resistance;Role;Surgical margins;Survival Rate;Therapeutic Intervention;Tissue Engineering;Tissue Model;Tissues;Training;Training Programs;Training Support;Tumor Cell Invasion;Universities;Variant;anti-cancer;antitumor effect;bioelectricity;brain tissue;career;chemotherapy;cytotoxic;extracellular;in vivo;innovation;miniaturize;mortality;neoplastic cell;neurovascular;novel;novel therapeutics;parent grant;professor;programs;radiation response;response;standard of care;stem;temozolomide;tool;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma NARRATIVEGlioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems fromits diffuse invasion throughout the brain and drug resistance. This project will develop hydrogel models ofneuron-glioma connectivity at the periphery of glioblastoma tumors investigate patterns of glioblastomaresponse to neuronal co-culture and evaluate dynamic changes in neuron-glioma crosstalk in response totherapeutic intervention (chemotherapy radiation). NCI 10818804 8/11/23 0:00 PA-21-071 3R01CA256481-03S1 3 R01 CA 256481 3 S1 "BECKER, STEVEN" 5/1/23 0:00 11/30/25 0:00 9109865 "HARLEY, BRENDAN A." Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 5/1/23 0:00 11/30/23 0:00 396 Non-SBIR/STTR 2023 88697 NCI 55925 32772 ABSTRACTThis application is being submitted in response to PA-21-071. Glioblastoma (GBM) is the most common andlethal form of brain cancer. Standard of care is surgical resection followed by treatment with the alkylating agenttemozolomide (TMZ). Resection removes the tumor bulk and TMZ provides some benefit to many patients. Theparent Cancer Tissue Engineering Collaborative project (R01 CA256481) is developing tissue engineeringapproach to accelerate the evaluation of new anticancer compounds that overcome TMZ resistance. This projectis developing processes to create engineered models of the perivascular niches (PVNs) that extend from thetumor into the surrounding parenchyma and which are believed to play a dominant role in invasion recurrenceTMZ resistance and poor survival. Conventional bulk hydrogels even miniaturized variants do not provide anavenue to tailor or trace the evolution of the local microenvironment surrounding unique cell subpopulations.The objective of this NCI Diversity Administrative supplement is to support a female Research AssistantProfessor within a chemical engineering department to develop a fully independent research program developinghierarchical models of neuronglioma connectivity within the glioblastoma tumor microenvironment and aftertherapeutic intervention. The unique microenvironment established in the tumor edge is responsible for neuronalhyperexcitability tumor invasion and recurrence after therapeutic intervention. This project will evaluate thehypothesis that neuronal input is a key factor for tumor progression. To do this this project will first \inspectneuronglioma connectivity as the main driver of tumor growth using engineered hydrogel models of the brainmicroenvironment (Aim S1). We will subsequently determine the repercussions of therapeutic intervention onthe neuron-glioma unit (Aim S2). This proposed supplement will enable a junior female investigator to develop afully independent research program as a Research Assistant Professor at the University of Illinois at Urbana-Champaign. Through this independent research as well as interactions within the host department the campusCancer Center at Illinois and external senior mentors we have identified a complementary but independentresearch trajectory as well as mentoring programs to support the full independence of an exemplary juniorinvestigator. 88697 +No NIH Category available Affect;Aftercare;Behavioral;Behavioral Sciences;Cancer Control;Cancer Control Research;Cancer Patient;Cancer Survivor;Cancer Survivorship;Caregiver Burden;Caregiver support;Caregivers;Caring;Chronic;Chronic Disease;Communication Barriers;Communities;Companions;Complex;Data;Distress;Eligibility Determination;Enrollment;Face;Family;Financial Hardship;Future;Geography;Goals;Health;Health Promotion;Health system;Healthcare;Healthcare Systems;Home Health Aides;Intervention;Interview;Knowledge;Malignant Neoplasms;Medical;Medicine;Mentorship;Methodology;Methods;Mexican Americans;Modeling;Oncologist;Oncology;Outcome;Parents;Pathway interactions;Patient Care;Patient Participation;Patients;Population;Postdoctoral Fellow;Primary Care;Quality of life;Randomized;Randomized Controlled Trials;Research;Research Methodology;Research Personnel;Residual state;Resources;Risk;Scientist;Self Management;Statistical Data Interpretation;Support Groups;Support System;Surveys;Survivors;System;Time;Training;Uncertainty;Visit;Work;cancer care;cancer diagnosis;cancer risk;cancer therapy;care coordination;care delivery;care outcomes;career;career development;caregiver interventions;caregiving;caregiving research;college;comorbidity;enhanced care;experience;follow-up;health care availability;health care service;health disparity;health equity;health literacy;improved;improved outcome;informal caregiver;medically underserved;multiple chronic conditions;novel;post-doctoral training;preference;primary care provider;recruit;respite care;safety net;skill acquisition;skills;survivorship;training opportunity Supplement: Effects of Comorbidity Management and Complex Care Coordination on Cancer Caregivers PROJECT NARRATIVEMedically underserved patients have the highest burden of multiple chronic conditions and are at increased riskfor poor cancer outcomes. Despite the increased need for caregiving and care coordination little is known abouthow patient comorbidities and comorbidity management affects caregivers. This supplemental research willelucidate caregiver experiences during and after cancer-directed treatment and in so doing yield crucialpreliminary data to launch Dr. Rangels career as an independent investigator. NCI 10818788 8/3/23 0:00 PA-21-071 3R01CA258040-03S1 3 R01 CA 258040 3 S1 "WEAVER, SALLIE JAYNE" 6/1/21 0:00 5/31/27 0:00 ZCA1(J1) 7852459 "BADR, HODA J" "MIMS, MARTHA P." 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 127435 NCI 79647 47788 PROJECT SUMMARY. The overarching goal of this Diversity Supplement is to prepare and launch Dr. MariaLizette Rangel into an academic career as an independent scientist. Dr. Rangel is a behavioral scientist andpost-doctoral research associate with a strong commitment to working with medically underserved cancerpatients families and communities. Through this Diversity Supplement she will gain crucial training in cancercontrol research focusing on cancer caregiving challenges of comorbidity management during/after cancer-directed treatment and advanced statistical analysis. With an eye toward developing interventions to supportcaregivers in managing patient comorbidities across the cancer control continuum specific aims of thissupplemental research are to: 1) Examine whether patient participation in the parent OPTIMISE (Oncology-Primary Care Partnership to Improve Comprehensive Survivorship Care) enhanced care pathway for comorbiditymanagement results in improved outcomes for caregivers in terms of lower levels of caregiver burden distressand financial hardship relative to usual medical care (UMC); 2) Describe the challenges that caregivers face inmanaging patient comorbidities during cancer-directed treatment; and 3) Describe the challenges thatcaregivers experience as the patient transitions from cancer-directed treatment to post-treatment survivorship.Dr. Rangel will achieve these aims by recruiting the caregivers of patients who are eligible and enrolled in theparent OPTIMISE trial and conducting a mixed-methods companion study using caregiver interview and surveydata. To supplement the research plan career development goals include 1) gaining a foundationalunderstanding of cancer control health equity research 2) develop theoretical and conceptual knowledge incancer caregiving research 3) continue developing the methodological and analytical qualitative quantitativeand mixed methods skills required to conduct rigorous mixed methods research and 4) acquire professionaldevelopment skills to support a career as an independent investigator. Along with the valuable training andcareer development opportunities afforded through this supplement the findings supported by Dr. Rangelsresearch will provide crucial data on the unmet needs of cancer caregivers and enable her to develop acompetitive K99/R00 proposal to develop an intervention for caregivers of cancer patients with comorbidities andlaunch her career as an independent investigator. 127435 +No NIH Category available Androgen Antagonists;Androgen Receptor;Applications Grants;Biological Process;Chromatin;Complex;Disease;Genes;Genetic Transcription;Goals;Malignant neoplasm of prostate;Mediating;Mediator;Nuclear Receptors;Phosphorylation;Phosphotransferases;Play;RNA Polymerase II;Receptor Signaling;Refractory;Role;Signal Transduction;Transcription Coactivator;Transcriptional Regulation;addiction;advanced prostate cancer;castration resistant prostate cancer;clinically relevant;enzalutamide;in vivo Model;inhibitor;mortality;novel;novel therapeutics;prostate cancer model;transcription factor Role of MED1 in the AR-dependent transcription in advanced prostate cancer Project Narrative:In this grant application we propose to study the biological functions of transcription coactivator in advancedand treatment-refractory prostate cancer. As such the studies proposed here will lead to the identification ofnovel signaling components that facilitate transcription addiction and will offer novel therapies in treatingprostate cancer. NCI 10818781 9/8/23 0:00 PA-21-071 3R01CA249210-04S1 3 R01 CA 249210 4 S1 "JOHNSON, RONALD L" 3/6/20 0:00 2/28/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 12001657 "ASANGANI, IRFAN AHMED" Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 393 Non-SBIR/STTR 2023 49000 NCI 34000 15000 Project Summary:Advanced metastatic castration-resistant prostate cancer (CRPC) is an aggressive disease with high mortalityrate primarily resulting from the transcriptional addiction driven by Androgen Receptor (AR) signaling. Theevolutionarily conserved multi-subunit Mediator complex plays a central role in the regulation of transcription byvirtue of its ability to functionally bridge gene-specific transcription factors with the RNA polymerase II-associated basal transcription machinery. MED1 is a key component of the Mediator complex and isresponsible for targeting and anchoring the complex to a broad range of nuclear receptors including AR. Wehave identified phosphorylation of MED1 catalyzed by CDK7 transcriptional kinase is required for its interactionwith AR and as a rate-limiting step in AR-mediated transcription. The underlying hypothesis of this proposal isthat the CDK7 mediated phosphorylation of MED1 is necessary for the formation and stability of MED1-ARcomplex at the chromatin in both nave and anti-androgen refractory CRPC which could be targeted by CDK7specific inhibitors. The goals of this grant application are to investigate the mechanistic basis of MED1-ARinteraction further and evaluate the CDK7 specific inhibitors in reversing the AR-dependent transcriptionaladdiction in advanced prostate cancer. The three specific aims of the projects are:Specific Aim 1: Investigate the role of p-MED1 in hyper-activation of AR-signalingSpecific Aim 2: Investigate the mechanism of increased p-MED1 in enzalutamide refractory PCa.Specific Aim 3: Establish the efficacy of CDK7 inhibitor in clinically relevant nave and refractory CRPCmodels in vivo. 49000 +No NIH Category available Acceleration;Administrative Supplement;Alkylating Agents;Biomedical Research;Blood Vessels;Brain;Cell Proliferation;Cells;Clinical;Data;Diffuse;Drug resistance;Encapsulated;Engineering;Evaluation;Evolution;Excision;Foundations;Glioblastoma;Hydrogels;Invaded;MGMT gene;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Mediating;Modeling;Operative Surgical Procedures;Outcome;Parents;Patients;Pharmaceutical Preparations;Play;Population;Process;Recurrence;Resistance;Role;Structure;System;Tissue Engineering;Tissue Model;Treatment Efficacy;Underrepresented Populations;Variant;anti-cancer;graduate student;high throughput screening;mimetics;miniaturize;nanolitre;novel;particle;response;standard of care;stem;stem cells;temozolomide;treatment response;tumor;tumor microenvironment;two-dimensional Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma NARRATIVEGlioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems fromits diffuse invasion throughout the brain and drug resistance. This project will develop a microdroplet-basedtissue engineering approach to create granular hydrogel models of the brain microenvironment to studyglioblastoma cell proliferation and drug response. NCI 10818769 8/14/23 0:00 PA-21-071 3R01CA256481-03S2 3 R01 CA 256481 3 S2 "BECKER, STEVEN" 5/1/23 0:00 11/30/25 0:00 9109865 "HARLEY, BRENDAN A." Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 5/1/23 0:00 11/30/23 0:00 396 Non-SBIR/STTR 2023 44356 NCI 31741 12615 ABSTRACTThis application is being submitted in response to PA-21-071. Glioblastoma (GBM) is the most common andlethal form of brain cancer. Standard of care is surgical resection followed by treatment with the alkylatingagent temozolomide (TMZ). Resection removes the tumor bulk and TMZ provides some benefit to manypatients. The parent Cancer Tissue Engineering Collaborative project (R01 CA256481) is developing tissueengineering approach to accelerate the evaluation of new anticancer compounds that overcome TMZresistance. This project is developing processes to create engineered models of the perivascular niches(PVNs) that extend from the tumor into the surrounding parenchyma and which are believed to play a dominantrole in invasion recurrence TMZ resistance and poor survival. Conventional bulk hydrogels evenminiaturized variants do not provide an avenue to tailor or trace the evolution of the local microenvironmentsurrounding unique cell subpopulations. The objective of this NCI Diversity Administrative supplement is tosupport a novel initiative to create granular hydrogel assemblies that can mimic the multicellular tumormicroenvironment yet are amenable to high-throughput screening approaches conventionally used to examinedrug responses using two-dimensional culture. We have generated the technical foundation to create granularhydrogel to study GBM therapeutic response. Granular hydrogels are macroscale structures generated asjammed assemblies of microscale hydrogel particles. To date they have been predominantly used as acellularhydrogel particles with cells cultured in the voids between particles. As part of a recent administrativesupplement we developed capacity to encapsulate GBM cells in distinct nanoliter-volume hydrogelmicrodroplets that can be rapidly formed have their matrix composition tailored for discrete cell populationsand be non-toxically degraded. Now we seek to expand efforts with granular hydrogel systems to examinehigh-throughput response data for glioblastoma cells. To do this this project will first measure therapeuticresponses of GBM cells to brain-mimetic HA and the perivascular secretome in granular hydrogels (Aim S1).We will subsequently examine the role of multicellular aggregations on GBM cell invasion and therapeuticefficacy using both macroscale and granular hydrogel models (Aim S2). This proposed supplement will supporta graduate student from a historically underrepresented group in biomedical research to develop hierarchicalmodels of the glioblastoma tumor microenvironment. This granular hydrogel approach provides the basis tointerrogate the role of glioblastoma aggregation size and relative spacing on glioblastoma stem cell activityGBM invasion and resistance to frontline therapies. We will show granular hydrogels can be integrated intohigh-throughput screening approaches to accelerate the evaluation of novel TMZ derivatives created to targetdiffuse GBM cells regardless of MGMT status. 44356 +No NIH Category available Address;Adrenal Glands;Attenuated;Autonomic nervous system;Award;Biological;Biological Models;Biology;Cells;Chronic;Citric Acid Cycle;Clinical Management;Congenital Heart Defects;Detection;Diagnosis;Drug Screening;Effectiveness;Enzymes;Event;Experimental Models;Future;Genes;Genetic;Geometry;Grant;Growth;Histologic;Hydroxylation;Hypoxia;Hypoxia Pathway;Investigation;Knowledge;Lead;Light;Malignant - descriptor;Metastatic Pheochromocytoma;Metastatic/Recurrent;Methods;Modeling;Molecular;Molecular Profiling;Mutate;Mutation;Neoplasm Metastasis;Neuroendocrine Tumors;Organoids;Oxygen;Paraganglia structure;Paraganglioma;Parents;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Pheochromocytoma;Population;Primary Neoplasm;Property;Recurrence;Regimen;Regulation;Reporting;Resistance;Resistance profile;Resolution;Risk;Survival Rate;Susceptibility Gene;Testing;Therapeutic;Therapeutic Uses;Tumor-Derived;Ubiquitination;Work;anticancer research;bHLH-PAS factor HLF;clinical application;design;driver mutation;drug sensitivity;drug-sensitive;effective therapy;experimental study;fitness;human disease;improved;inhibitor;innovation;insight;neuroendocrine cancer;normoxia;novel;novel therapeutics;parent grant;potential biomarker;predictive marker;preference;response;screening;single-cell RNA sequencing;therapeutic evaluation;transcription factor;tumor Addressing biological and therapeutic gaps in rare neuroendocrine cancer with a novel organoid-based model NarrativeTo address PQ9: What methods can be developed to effectively study small or rare populations relevant tocancer research we will develop organoids of rare neuroendocrine tumors pheochromocytomas andparagangliomas (PPGL). Here we will include a critical control for these cultures- we will test whether culturingthe organoids under different levels of hypoxia impact the fitness of the culture and the response to drugs. Theseresults will offer new insights to identify potential biomarkers and new therapies. NCI 10818715 9/18/23 0:00 PA-21-071 3R01CA264248-03S1 3 R01 CA 264248 3 S1 "LI, JERRY" 9/8/21 0:00 8/31/26 0:00 ZCA1(M2)-R 8773354 "DAHIA, PATRICIA LEAL" "SORAGNI, ALICE " 20 INTERNAL MEDICINE/MEDICINE 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 74115 NCI 50740 23375 AbstractThe work proposed on the parental grant is focused on developing new organoid models of rare andunderstudied neuroendocrine tumors pheochromocytomas and paragangliomas to improve our understandingof their biology and serve as a drug screen platform. Mutations in genes of the hypoxia pathway are a feature ofapproximately 40% of pheochromocytomas and paragangliomas and involve most metastatic forms of thesetumors. In this diversity supplement we propose to extend the parent grant by testing the effects of hypoxia inthe fitness and molecular features of the organoid cultures. We will also investigate whether hypoxia alters theorganoids drug response profile. These findings will improve our knowledge of factors that influence organoidproperties and may offer insights into drug sensitive/resistance patterns that might impact on future therapeutictesting. 74115 +No NIH Category available Acceleration;Archives;Atlases;Cells;Clinical;Cloud Computing;Collaborations;Communities;Coupled;Dana-Farber Cancer Institute;Data;Data Analyses;Data Commons;Data Coordinating Center;Data Scientist;Development;Documentation;Education and Outreach;Educational Materials;Ensure;Evolution;Fostering;Funding;Genomics;Human;Image;Immunogenomics;Individual;Institution;Intuition;Location;Malignant Neoplasms;Memorial Sloan-Kettering Cancer Center;Molecular;Patients;Performance;Prevention strategy;Procedures;Research;Research Personnel;Research Support;Resistance development;Resources;Services;Slide;Synapses;Systems Biology;Technology;Translational Research;Visualization;Work;anticancer research;application programming interface;cBioPortal;cancer genomics;cancer therapy;centralized portal;cloud based;cloud platform;community building;community involvement;data acquisition;data dissemination;data hub;data management;data portal;data resource;data standards;data submission;data visualization;digital;human genome sequencing;improved;large scale data;novel;open source;operation;outreach program;pathology imaging;radiological imaging;shared database;software development;success;tool;treatment strategy;tumor;tumor progression;tumorigenesis;web portal;working group Human Tumor Atlas Network: Data Coordinating Center Extension Project NarrativeThis is a request for a funded extension for the performance period (09/01/2023 08/31/2024).The Human Tumor Atlas Network (HTAN) aims to leverage the power of human genomesequencing and other state-of-the-art profiling technologies to analyze spatial and temporalmolecular changes in individual tumors. The Data Coordination Center (DCC) will ensure that alldata will use the same data standards that all data is hosted in one centralized location that alldata will be shared within HTAN and eventually with the wider scientific community and that tomaximize the research impact of the data generated powerful analysis and visualizationfeatures will enable researchers to make novel discoveries about the initiation and progressionof cancer as well as the development of resistance to cancer therapy. NCI 10818705 9/18/23 0:00 PA-20-272 3U24CA233243-01S2 3 U24 CA 233243 1 S2 "HANLON, SEAN E" 4/4/23 0:00 8/31/24 0:00 9809745 "CERAMI, ETHAN " "EDDY, JAMES A; SCHULTZ, NIKOLAUS ; THORSSON, VESTEINN " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 4/4/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 2007216 NCI 1800000 207216 Project Summary/AbstractWe propose to continue managing the operations of the data coordinating center (DCC) for theHuman Tumor Atlas Network (HTAN) with responsibilities for managing curating anddisseminating the data and resources generated through this network. We have provided andwill continue to provide key services to organize and support the Research Centers thatcomprise the network and foster a community based on collaboration transparency andsharing. Our primary scientific objective is to accelerate the discovery of mechanisms governingtumorigenesis progression and evolution which will lead to improved prevention and treatmentstrategies for patients. We aim to achieve this by providing technology services coupled withbest practices to expedite data acquisition and dissemination to HTAN researchers as well asthe broader scientific community. HTAN data is now available via the HTAN Data Portal theSynapse platform Minerva CellXGene cBioPortal Google BigQuery the NCI Cancer ResearchData Service (CDS) and the NCI Image Data Commons (IDC). We will continue to releaseHTAN data to the wider scientific community and further develop visualization annotation andanalysis tools in order to meet the needs of HTAN and the diverse cancer research community including data scientists and statisticians to biologists and clinicians as new types of data aregenerated. 2007216 +No NIH Category available Affect;CXCL9 gene;Cancer Etiology;Cancer Patient;Cells;Cessation of life;ChIP-seq;Clinical;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Flow Cytometry;Gene Expression;Genes;Genetic Transcription;Genotype;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Major Histocompatibility Complex;Malignant neoplasm of lung;Mesenchymal;Methyltransferase;Molecular;Mus;Myeloid Cells;NGFR gene;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;System;T-Lymphocyte;Testing;Therapeutic;Tumor stage;Update;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;cancer immunotherapy;cell type;clinically relevant;combinatorial;conditional knockout;cytokine;effector T cell;immunogenic;improved;in vivo;inhibitor;migration;mouse model;neoplastic cell;neutrophil;parent grant;programmed cell death ligand 1;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Targeting Epigenetic Heterogeneity to Improve Lung Cancer Immunotherapy Response PI: Brainson Christine FillmorePROJECT NARRATIVELung cancer is the leading cause of cancer-related deaths worldwide and is a very complex disease withdifferent cell types that comprise each tumor. Immunotherapy is ground-breaking because it is able to cure somepatients with late stage tumors but the number of patients that have this great response is still low. In thisproposal we will test the combination of a second drug with immunotherapy to increase the likelihood thatsquamous lung tumors will respond to treatment. NCI 10818680 8/16/23 0:00 PA-21-071 3R01CA237643-05S2 3 R01 CA 237643 5 S2 "SOMMERS, CONNIE L" 7/1/19 0:00 6/30/24 0:00 Developmental Therapeutics Study Section[DT] 10317047 "BRAINSON, CHRISTINE FILLMORE" Not Applicable 6 PHARMACOLOGY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 77275 NCI 55356 21919 PROJECT SUMMARY Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. Our central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing immunogenic PD-L1 expressing cellsand by depleting immunosuppressive tumor associated neutrophils. The overarching goal of the proposedstudy is to validate combining EZH2 inhibition with PD1/PD-L1 targeted immunotherapy and learn the molecularmechanisms when the treatment is successful as well as when it is not successful. In Aim 1 we will use both mouse models and human patient derived organoid cultures to examine NGFRCXCL9/10/11 PD-L1 and MHC expression in lung SCC cells after EZH2 inhibitor treatment. The epigenetic andtranscriptional consequences of EZH2 inhibition on squamous and bronchiolar lung tumor cells will be assessedby ChIP-seq and RNA-seq. In Aim 2 we will focus on the tumor associated neutrophils (TANs). We will compareTANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migration capacityand ability to suppress T cells. We will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 we will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. We will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. We will also develop tumoroid multi-cultures containing tumor cellsmesenchymal cells T cells and myeloid cells to be able to test responses of systems to EZH2 inhibition and anti-PD1 inhibition ex vivo. Completion of these aims will solidify the efficacy of a promising therapeutic combinationand uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2 inhibitorsin squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibition with anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue. 77275 +No NIH Category available Acceleration;Acute;Address;Affect;Award;Binding;Cancer Biology;Cancer Model;Carcinoma;Cell physiology;Cells;Chromatin;Chronic Disease;Classification;Colitis;Colitis associated colorectal cancer;Colon;Colorectal Cancer;Complex;Coupled;Development;Disease Progression;Disease model;Disseminated Malignant Neoplasm;Enhancers;Epigenetic Process;Epithelium;Event;Exposure to;Family;Genes;Genetic Diseases;Genetic Screening;Genomics;Goals;Head;Homeostasis;Human;Immunology;Inflammation;Inflammatory;Inflammatory Response;Institution;Lead;Life;Long-Term Effects;MAP Kinase Gene;Maintenance;Malignant Neoplasms;Memory;Modeling;Molecular;Molecular Biology;Mus;Mutation;Natural regeneration;Oncogenic;Organoids;Papilloma;Pathogenesis;Pathway interactions;Patients;Phase;Physiological;Play;Postdoctoral Fellow;Predisposition;Recurrence;Regenerative capacity;Research;Resolution;Risk;Risk Factors;Role;STAT3 gene;Shapes;Signal Pathway;Skin;Skin Carcinogenesis;Specialized Epithelial Cell;Squamous cell carcinoma;Stimulus;Stress;Students;System;Technical Expertise;Techniques;Tissues;Training;Transcription Factor AP-1;Transforming Growth Factor beta;Tumor Burden;Work;activating transcription factor 3;anticancer research;biological adaptation to stress;chromatin remodeling;cytokine;effective therapy;epigenetic memory;epigenome;epigenomics;epithelial stem cell;experience;histone modification;human disease;in vivo;inflammatory milieu;insight;jun Oncogene;member;mouse genetics;novel;novel strategies;premature;prevent;professor;progenitor;recruit;regeneration potential;restoration;stem;stem cell biology;stem cell population;stem cells;stressor;tissue stem cells;transcription factor;transcriptomics;tumor;tumorigenesis;wound healing Dissecting mechanisms of inflammation driven cancer susceptibility in epithelial barrier tissues Project Narrative: The bodys epithelial barriers are routinely subjected to inflammatory stressors necessitating robustregenerative potential to sustain barrier integrity. Following recurrent exposures to inflammatory stressorstissues and their stem cells become increasingly susceptible to cancer formation. The proposed research willevaluate the long term effects that inflammation has on barrier tissues and how these effects lead to epigeneticrewiring in stem cell populations that results in cancer susceptibility and tumor formation. NCI 10818671 6/29/23 0:00 RFA-CA-20-048 4K00CA264439-03 4 K00 CA 264439 3 "ELJANNE, MARIAM" 9/1/21 0:00 6/30/27 0:00 ZCA1-SRB-H(M1) 15883250 "COWLEY, CHRISTOPHER " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 89230 NCI 82620 6610 Project Summary/Abstract: Inflammation has long been known to increase risk of tumorigenesis. Epithelial barrier tissues areperpetually exposed to a myriad of environmental and inflammatory insults that necessitates robust regenerativecapacity of their tissue-specific epithelial stem cells (EpSCs) to restore barrier integrity. The long termconsequences of these inflammatory encounters on the tissue and EpSCs is poorly understood. Here I seek tounderstand how exposure to inflammation results in epigenetic and cellular rewiring of EpSCs and their lineagesin different barrier tissues and how this rewiring can be maladaptive leading to increased cancer susceptibility. The F99 phase of this proposal is focused on the mechanisms by which inflammatory experience isencoded within the chromatin of skin epithelial stem cells (EpSCs) and how inflammation-experienced skinaccelerates tumor formation. I have begun to uncover the molecular mechanisms of how EpSCs acquire andmaintain chromatin accessibility at key domains associated with stress response genes that contribute to aninflammatory response. My studies suggest that this phenomenon occurs through the complex and dynamicinterplay between transcription factors (TFs) that are naturally present in steady state EpSCs but cannot gainaccess to stress response enhancers without inflammation-induced TFs. As I unearth the molecular mechanismsinvolved I will interrogate how this inflammatory rewiring of skin EpSCs epigenome accelerates tumor formationas EpSCs acquire oncogenic mutations that lead to squamous cell carcinomas (SCCs) a life-threateningmetastatic cancer for which there are few effective therapies. At the completion of the F99 phase l will havegained strong experience in in vivo high-throughput epigenetics mouse genetics and epithelial stem cell biologyand transition to a postdoc to gain advanced expertise and training in human cancer and immunology. For the K00 phase I will shift my focus to how inflammatory experience can reshape colonic epitheliumcomposition in the gut and how this reshaping along with EpSC epigenetic rewiring results in colorectal cancer(CRC). Interestingly colitis can result in colitis-induced CRC that follows a different molecular drivenpathogenesis than traditional CRC. Thus to further understand the mechanisms that drive colitis-induced CRCI plan to expand my technical expertise to include colitis-induced CRC modeling single-cell epigenomic andtranscriptomic techniques genetic screening and human organoid modeling. These new approaches coupledwith my already strong background in molecular biology and high-throughput genomic analyses will allow me toaddress the most pressing and challenging issues in inflammation experience and cancer biology today. Withthe aid of this award I intend to continue my research contribution and gain the necessary experience to becomean Assistant Professor at a major academic institution. There I will head my own lab and guide my students inepithelial cancer research with the ultimate goal of finding new targets to treat these aggressive cancers. 89230 +No NIH Category available 2019-nCoV;Adopted;Affinity;Antiviral Agents;Apoptosis;Architecture;Award;Behavior;Binding;Binding Sites;Biochemical;Biological Assay;Biological Process;Biophysics;COVID-19;COVID-19 pandemic;Cancer Biology;Cancerous;Cell physiology;Cells;Cessation of life;Charge;Chimeric Proteins;Chromosomal translocation;Collection;Computational Technique;Coronavirus;Coronavirus nucleocapsid protein;DNA Binding Domain;DNA Repair;Development;Dimerization;Disease;Disease Outbreaks;Disease Progression;Elements;Enhancers;Etiology;Event;Family;Fluorescence;Fluorescence Spectroscopy;Functional disorder;Fusion Oncogene Proteins;Gene Expression;Genes;Genetic Transcription;Genome;Grain;Human;In Vitro;Intrinsic drive;Knowledge;Lead;Length;Malignant Neoplasms;Mediating;Microscopy;Middle East Respiratory Syndrome;Modeling;Molecular;Molecular Conformation;Nucleic Acids;Nucleocapsid;Nucleocapsid Proteins;Oncogenes;Oncogenic;Output;Phase;Physical condensation;Play;Postdoctoral Fellow;Process;Proliferating;Proteins;RNA;RNA Binding;RNA Recognition Motif;RNA-Binding Proteins;Regulation;Research;Role;Severe Acute Respiratory Syndrome;Signal Transduction;Site;Specificity;Spectrum Analysis;Structure;Surface;Techniques;Testing;Therapeutic;Therapeutic Intervention;Training;Transcriptional Regulation;Viral Genome;Virion;Virus;Virus Diseases;Work;betacoronavirus;biophysical properties;biophysical techniques;cancer type;career;cell growth;combat;dimer;fluorescence imaging;genomic RNA;improved;in vitro Assay;in vivo;insight;member;molecular imaging;molecular modeling;novel;programs;protein function;rational design;simulation;single molecule;success;superresolution microscopy;targeted treatment;transcription factor Single Molecule Biophysics of Intrinsically Disordered Proteins in Disease Project Narrative: Despite their lack of a fixed structure disordered proteins have emerged as central drivers of biologicalfunction with key roles in cell signaling transcription and genome organization all of which contribute to diseases rangingfrom viral infections to cancer. Although clear examples in which disordered proteins are essential for disease progressionexist our understanding of the role of intrinsically disordered regions in disease etiology is limited. This proposal will studydisordered protein-nucleic acid interactions in SARS-CoV-2 and in the context of cancer using a collection of single-molecule techniques. NCI 10818667 8/1/23 0:00 RFA-CA-20-048 4K00CA264413-03 4 K00 CA 264413 3 "ELJANNE, MARIAM" 8/1/21 0:00 7/31/27 0:00 ZCA1-SRB-H(M1) 11471920 "ALSTON, JHULLIAN JAMILLE" Not Applicable 7 Unavailable 76593722 Z1L9F1MM1RY3 76593722 Z1L9F1MM1RY3 US 42.337481 -71.104964 1504801 BOSTON CHILDREN'S HOSPITAL BOSTON MA Independent Hospitals 21155724 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 93924 NCI 87300 6624 Abstract: Intrinsically disordered proteins (IDPs) are found in over 50% of human proteins where they play essential rolesin a wide range of cellular functions including transcriptional regulation DNA repair cell signaling and apoptosis. As aresult of their importance in key processes associated with cellular growth proliferation and death proteins containingIDPs are often associated with cancer. The ability of IDPs to adopt a wide range of conformations raises a number of keychallenges to standard biochemical biophysical and computational techniques. Despite these challenges our ability to treatmany cancers depends on an understanding of the molecular basis for diseases. This in turn presents a pressing need tounderstand the mechanistic basis of IDP function and dysfunction. This proposal will study protein-nucleic acid interactionsdriven by intrinsically disordered proteins in two pressing diseases: COVID-19 and cancer. For the F99 phase (Aim 1) ofthe award I will build upon my computational and experimental biophysics training to continue investigating the SARS-CoV-2 nucleocapsid protein and its ability to package its viral genome. The COVID-19 pandemic preceded by previouscoronavirus outbreaks caused by SARS and MERS necessitates study of these viruses in order to better combat them.Coronaviruses contain large RNA genomes that are packaged into a relatively small virion mediated by the nucleocapsidprotein a highly disordered multidomain RNA binding protein. A current outstanding question is how SARS-CoV-2package their 30 kb genomes into a relatively small (<100 nm) virion. The conserved structural motifs in coronavirusgenomes known as packaging signals has been shown to confer genome specificity yet the relationship between packagingsignals and genome compaction are opaque. My thesis work combines single-molecule fluorescence spectroscopy with all-atom and coarse-grained simulations to construct a mechanistic understanding of how N protein drives RNA packaging.Success of this project will reveal the role of IDP-encoded multivalency in selective genome packaging. Since thearchitecture of the nucleocapsid protein is conserved throughout coronaviruses it will also present new insight intomechanisms that can be broadly targeted for therapeutic intervention. The K00 phase (Aim 2) of this proposal will studythe contribution of IDPs in transcriptional regulation genome organization and cancer development. Fusion-oncogenes area common genetic translocation event which often involve a DNA binding domain becoming fused to an IDP. During thepost-doctoral phase I will obtain training in super-resolution microscopy to investigate the effects of transcriptionally activefusion-oncogenes. Several studies have shown that IDPs from transcription factors drive the formation of transcriptionalassemblies (transcriptional condensates) at sites of gene expression. I will test the hypothesis that fusion-oncoproteins leadto the formation of long-lived aberrant transcriptional condensates that drive the expression of proliferative genes. This willprovide direct mechanistic insight into the molecular basis of fusion-oncogene driven cancers. These combined trainingplans will prepare me for a successful research career using quantitative biophysical and single-molecule techniques in thefield of mechanistic cancer biology. 93924 +No NIH Category available Address;Adherence;Affect;Algorithms;Benefits and Risks;Breast Cancer Detection;Cancer Etiology;Cervical Cancer Screening;Cessation of life;Characteristics;Clinical;Clinical Trials;Cognitive;Computerized Medical Record;Consumption;Counseling;Data;Dedications;Development;Diagnosis;Effectiveness;Effectiveness of Interventions;Eligibility Determination;Exposure to;Goals;Guideline Adherence;Guidelines;Health;Health Benefit;Health behavior;Human Resources;Hybrids;Image;Individual;Intervention;Intervention Studies;Interview;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medical;Mentors;Methods;Outcome;Outcome Measure;Parents;Participant;Patients;Phase;Postdoctoral Fellow;Process;Provider;Recommendation;Reminder Systems;Reporting;Research;Research Design;Research Methodology;Research Personnel;Research Training;Scanning;Scientist;Screening for cancer;Smoker;Smoking;Specialist;Surveys;System;Testing;Time;Training;Training Programs;Visit;acceptability and feasibility;cancer diagnosis;career;clinically significant;colorectal cancer screening;computed tomography screening;cost;design;dissemination science;effective intervention;effectiveness evaluation;effectiveness outcome;effectiveness/implementation study;effectiveness/implementation trial;evidence base;experience;former smoker;health application;high risk;high risk population;implementation outcomes;implementation research;implementation science;improved;informant;information processing;innovation;intervention program;low dose computed tomography;lung cancer screening;mortality;patient engagement;person centered;population based;population health;pragmatic study;primary care provider;programs;protective behavior;risk perception;routine screening;screening;screening guidelines;screening program;shared decision making;skills;social;social health determinants;social stigma;theories;therapy development;tool;user centered design Optimizing adherence to lung cancer screening: Applying theory and implementation science to participant engagement PROJECT NARRATIVELung cancer screening efficacy is highly dependent on adherence to recommended guidelines with annualscreening indicated for approximately 90% of all individuals who receive baseline scans. Initial reports of real-world screening implementation show adherence to annual screening guidelines are less than 50%demonstrating a critical need for improvement to optimize the individual and population health benefits of lungcancer screening. I aim to address the urgent need for low-cost feasible and effective interventions focused onfacilitating lung cancer screening adherence by developing and implementing a set of clear and engagingreminder messages that target and tailor information specific to lung cancer screening participants. NCI 10818665 8/22/23 0:00 RFA-CA-20-048 4K00CA264409-03 4 K00 CA 264409 3 "ELJANNE, MARIAM" 9/1/21 0:00 8/31/27 0:00 ZCA1-SRB-H(M1) 14114314 "HIRSCH, ERIN " Not Applicable 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 92952 NCI 86400 6552 PROJECT SUMMARYLung cancer is the leading cause of cancer death in the US with most lung cancer diagnosed at advancedstages. Low-dose CT screening of high-risk individuals is the only evidence-based tool available to diagnoselung cancer at an early stage when curable treatment options exist. The promising mortality reduction benefit oflung cancer screening (LCS) is presently overwhelmingly unfulfilled due to suboptimal population-basedadherence to annual screening guidelines. Outside of research settings adherence to annual LCS is less thanhalf of the rates observed in the practice-changing landmark clinical trials. There is an urgent need for effectiveand feasible interventions to improve LCS adherence and achieve optimal individual and population healthbenefits. Research during the F99 phase will leverage an innovative multi-phase mixed methods design todescribe how LCS patients process health information regarding health protective behavior and utilize thisinformation to develop and evaluate reminder messages with individuals eligible for LCS. Using a four-stepprocess data collected in a survey of LCS program participants (step 1) will inform the development of a pool ofcandidate reminder messages (step 2). In the final two steps the reminder messages will be evaluated by LCSexperts (step 3) and further evaluated and refined with LCS program participants (step 4) using mixed methodsincluding surveys and interviews. Differences between health information processing constructs by demographicor clinical characteristics found to be significant from step 1 will be the focus for message targeting (group level)and/or tailoring (individual level). At the conclusion of the F99 phase I will have a formalized set of clearengaging and efficient messages to support LCS annual adherence ready to be evaluated in a clinical setting.Research proposed in the K00 phase will focus on gaining real-world experience with hybrid effectivenessimplementation study designs and pragmatic outcome measures to simultaneously assess effectiveness andimplementation outcomes. Specifically I propose a mentored pre-post type 1 hybrid effectiveness-implementation trial within a parent trial that will allow concurrent assessment of effectiveness andimplementation outcomes of the F99 reminder strategy in real-world LCS programs. Effectiveness will be testedusing a pre-post design comparing percent screening participants adherent to annual screening guidelinesbefore and after implementation of the reminder strategy. Secondary implementation outcomes (i.e.acceptability and feasibility) will be assessed with surveys and key informant interviews of personnel involved inthe reminder system implementation (e.g. LCS program directors navigators coordinators). This body ofresearch will prepare me for a career as an independent cancer-focused intervention scientist with expertise inthe development and implementation of effective low-burden interventions aimed at improving LCS adherencemaximizing screening benefit and reducing lung cancer mortality. 92952 +No NIH Category available Acceleration;Agonist;Architecture;Autoimmunity;Biodistribution;Blood;Cancer Patient;Cells;Chemistry;Clinic;Clinical;Clinical Trials;Combination immunotherapy;Cream;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Development;Disease;Disease model;Disseminated Malignant Neoplasm;Dose;Drug Delivery Systems;Drug Kinetics;Endosomes;Equilibrium;Evaluation;Failure;Formulation;Functional disorder;Gel;Genetically Engineered Mouse;Goals;Grant;Human;Imiquimod;Immune;Immune Tolerance;Immune response;Immune system;Immunity;Immunologic Stimulation;Immunomodulators;Immunotherapeutic agent;Immunotherapy;Investigation;Kinetics;Lesion;Ligands;Malignant Neoplasms;Metastatic Melanoma;Molecular;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Polymers;Population;Postdoctoral Fellow;Primary Neoplasm;Prodrugs;Progression-Free Survivals;Property;Ramp;Receptor Activation;Refractory;Reporter;Research;Research Project Grants;Safety;Schedule;Scheme;Site;T-Lymphocyte;TLR7 gene;Technical Expertise;Therapeutic;Therapeutic Index;Toll-like receptors;Topical application;Toxic effect;Translating;Tumor Antigens;Tumor Immunity;Work;anti-CTLA4;anti-PD1 antibodies;anti-tumor immune response;appropriate dose;cancer cell;cancer immunotherapy;cancer therapy;clinical practice;design;effective therapy;efficacy evaluation;experimental study;immune checkpoint blockade;immune modulating agents;immune-related adverse events;immunoregulation;improved;in vitro Assay;in vivo;insight;melanoma;mouse model;patient subsets;pharmacologic;pre-clinical;rational design;resiquimod;response;small molecule;therapy development;time interval;tumor;tumor microenvironment;uptake Toward safe systemic immunotherapies for treatment of metastatic disease: Developing dendritic cell-biased immunomodulators with precise control over magnitude and timing of immune stimulation Project NarrativeThis proposal describes a comprehensive approach to systemically deliver small molecule immunomodulatorsfor improving the therapeutic index of combination cancer immunotherapy. The key objective is to developthese therapies using safe prodrug linkers precise sizes and dosing schedules tuned to circumvent tolerancewhich will improve the ability of these drugs to induce a potent and selective immune response. This work willfocus formulation design efforts and dosing schemes to advance anti-cancer immunotherapy platforms into theclinic sooner. NCI 10818663 8/31/23 0:00 RFA-CA-20-048 4K00CA264404-03 4 K00 CA 264404 3 "ELJANNE, MARIAM" 8/11/21 0:00 8/31/27 0:00 ZCA1-SRB-H(M1) 15607889 "BHAGCHANDANI, SACHIN " Not Applicable 3 MICROBIOLOGY/IMMUN/VIROLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 93794 NCI 87180 6614 Project SummaryOn October 1st 2015 the FDA granted accelerated approval for the combination of anti-CTLA-4 and anti-PD-1monoclonal antibodies showing 1-year survival of 94% and 2-year survival of 88% in patients with metastaticmelanoma. These treatments collectively referred to as immune checkpoint blockade therapies (ICBs)comprise a successful class of systemic immunotherapies. Nevertheless a major subset of patients still do notrespond in the long-term to current ICBs and this failure is likely due to the inability of ICBs to generate potentcytotoxic T lymphocyte (CTL) responses against cancer antigens as well as the tolerizing effects of so-calledcold tumors. Thus in order to turn non-responsive cold tumors into treatable hot tumors there are countlesspreclinical investigations exploring other immune pathways that can be pharmacologically modulated ascombination immunotherapy strategies. This has resulted in more than 1800 ongoing clinical trials in the USalone looking to combine ICBs with synthetic immunomodulators (IMs) in order to improve long-term survival incancer patients. A major unmet need with these IMs is the ability to administer multiple therapeutic dosessystemically in a safe manner to effectively treat the disease in a metastatic setting.Drug delivery systems and rational dosing schedules have the potential to reduce the toxicity of suchcompounds that activate the immune system and they could enable treatment of tumors that do not respond toICBs via kinetically controlled targeted and precisely timed delivery of immunomodulating drugs.In the F99-phase of the proposed research Sachin Bhagchandani will leverage the control of bottlebrushpolymers (BBPs) to improve cancer immunotherapy through increasing the therapeutic index of IMs byenabling precise control over the release of these compounds and targeting them to the necessary immunecell subsets in the tumor microenvironment.In the K00-phase of the proposed research Sachin will focus on understanding immune tolerance post initialdosing of IMs in order to design appropriate dosing schemes to circumvent tolerance since theseimmunotherapy treatments will require repeat dosing in order to drive an antitumor immune response.The preliminary data generated with BBPs provides a strong basis to systemically deliver these IMs by tuningdrug-linker chemistry and aspect ratio (F99 phase) and defining tolerance mechanisms and dosing schedulesto obtain parameters that are effective in genetically engineered mouse models which are currently refractiveto ICBs (K00 phase). 93794 +No NIH Category available Address;Animals;Apoptosis;Axilla;Base Pairing;Bioinformatics;Biological;Biological Markers;Biological Models;Biology;CRISPR/Cas technology;Cancer Center;Cancer Detection;Cancer Patient;Cell Culture Techniques;Cerebrospinal Fluid;Circulation;Clinical;Complex;Comprehensive Cancer Center;DNA;DNA analysis;DNA purification;DNA sequencing;Data;Detection;Development;Disease Progression;Disseminated Malignant Neoplasm;Doctor of Philosophy;Early Diagnosis;Elements;Epidermal Growth Factor Receptor;Excision;Exclusion;Genetic;Genomics;Genotype;Goals;Head and neck structure;Incisional Biopsy;Inflammatory Response;Jordan;Length;Leukocytes;Libraries;Machine Learning;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Measurement;Mentorship;Methodology;Methods;Methylation;Modeling;Modernization;Monitor;Mutate;Mutation;Nature;Non-Small-Cell Lung Carcinoma;Oncogenic;Oncology;Oral;Organoids;Outcome;Patients;Pharmacotherapy;Phase;Plasma;Population;Positioning Attribute;Postdoctoral Fellow;Preparation;Process;Protocols documentation;Regulatory Pathway;Research;Research Project Grants;Sampling;School Dentistry;Screening for cancer;Selection Bias;Single-Stranded DNA;Testing;Therapeutic;Tissues;Training;Urine;Validation;Work;anticancer research;cancer cell;cancer genetics;cancer type;career;cell free DNA;cohort;deep sequencing;design;ds-DNA;electric field;experimental study;extracellular;improved;insight;interest;liquid biopsy;methylation pattern;mutant;next generation sequencing;novel;professor;saliva sample;skills;theories;tumor;tumor DNA;tumor progression Cell-free DNA Analysis for Liquid Biopsy of Cancer PROJECT NARRATIVEThe proposed research in the first phase of this proposal is to investigate a new methodology to capture anddefine a novel ultrashort circulating tumor DNA species in the plasma of lung cancer patients. In the secondphase the usage of various other molecules additional to the ultrashort DNA species in biofluids will be exploredin hopes to detect multiple cancer types with liquid biopsy. These findings will contribute to improved clinicaloutcomes for cancer patients by leading to the development of new liquid biopsy approaches for improveddetection and treatment monitoring. NCI 10818662 9/6/23 0:00 RFA-CA-20-048 4K00CA264398-03 4 K00 CA 264398 3 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/27 0:00 ZCA1-SRB-H(M1) 77899737 "CHENG, JORDAN C" Not Applicable 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 85925 NCI 79560 6365 PROJECT SUMMARY/ABSTRACTCirculating tumor DNA (ctDNA) which mirrors the parental tumor is present in the plasma of non-small cell lungcarcinoma (NSCLC) patients. Liquid biopsy analysis of ctDNA allows early detection and genetic monitoring.However current PCR-based liquid biopsy methods often have difficulty detecting ctDNA due to low copies incirculation. In contrast the electric field-induced release and measurement liquid biopsy (eLB) platform detectsmutant EGFR (L858R exon19del T790M) ctDNA with a >90% tissue-genotype concordance in <50ul ofunprocessed plasma of NSCLC patients. Preliminary data demonstrate that the ctDNA detected by eLB may beultrashort single-stranded ctDNA (usssctDNA) which contrasts the typically described 160-basepairinternucleosomal double-stranded ctDNA. This new subpopulation is undetectable through PCR-based liquidbiopsy methods due to size-selection bias. The goal of the F99 Phase is to use usssctDNA-seq a novel NGSpipeline to explore if NSCLC plasma contains high quantities of ctDNA that are ultrashort and single-stranded.This pipeline consists of a usssctDNA-specific extraction library preparation deep sequencing and bioinformaticanalysis. To verify 80 late-stage NSCLC EGFR-mutated plasma samples will undergo usssctDNA-seq. Thediscovery of usssctDNA will open up a wealth of previously unnoticed information leading to improved treatmentand survival of NSCLC patients. Afterward during the K00 Phase the trainee hopes to explore the biologicalorigins of biofluid ctDNA and the incorporation of usssctDNA into modern multi-analyte approaches for pan-cancer detection. This will involve training in new skills such as organoid modeling methylation and leukocytesequencing and bioinformatic machine learning at a world-leading cancer-oriented institute. Ultimately the goalof this proposed F99/K00 project will to prepare the trainee for a career in cancer research with an expertise inliquid biopsy and cell-free DNA biology. 85925 +No NIH Category available APC gene;Address;Automobile Driving;Award;Binding;Biological Assay;Cancer Etiology;Cancer Patient;Cell Proliferation;Cells;Chromatin;Clinic;Colorectal Cancer;Complex;Cryoelectron Microscopy;Data;Fusion Oncogene Proteins;Gene Activation;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genetic Transformation;Genomics;Goals;Histone H2A;Human;Invaded;Knowledge;Lead;Malignant Neoplasms;Modeling;Molecular;Mutate;Mutation;Nucleosomes;Oncogenic;Oncoproteins;Patients;Phase;Phenotype;Postdoctoral Fellow;Proliferating;Proteins;Publications;Publishing;Reader;Regulator Genes;Repression;Research;Research Project Grants;Role;Running;Site;Structure;Surface;Testing;Therapeutic;Training;Transcriptional Activation;Tumor Promotion;Tumor Suppressor Proteins;Ubiquitin;Up-Regulation;WNT Signaling Pathway;Work;arm;beta catenin;biophysical properties;cancer cell;cancer initiation;colon cancer patients;genomic locus;inhibitor;lead candidate;loss of function;loss of function mutation;member;mortality;novel;novel strategies;novel therapeutics;programs;promoter;recruit;response;scaffold;small molecule inhibitor;soft tissue;synovial sarcoma;therapeutic target;transcription factor;tumor;tumor initiation;tumor progression;tumorigenesis Exploiting Oncogenic Chromatin Regulators in Cancer Initiation and Progression PROJECT NARRATIVE Chromatin-bound regulators are aberrantly activated in cancer cells to promote transcriptional programsimportant for driving tumor initiation and progression. However despite identification of oncogenic regulators inmultiple tumor types a gap in this rapidly evolving field is the definition of how those regulators mechanisticallyoperate which is required to identify interaction surfaces that can be used to target them in cancer. In both theF99 and K00 phases of this award I will elucidate the underlying molecular mechanisms by which chromatin-bound regulators sustain oncogenic transcriptional programs and define critical surfaces required for hallmarksof cancer thereby allowing me to devise novel therapeutic vulnerabilities in cancer. NCI 10818659 12/21/23 0:00 RFA-CA-20-048 4K00CA264296-03 4 K00 CA 264296 3 "ELJANNE, MARIAM" 9/1/21 0:00 11/30/27 0:00 ZCA1-SRB-H(M1) 15264540 "HYDER, USMAN " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 92304 NCI 85800 6504 PROJECT SUMMARY Genetic alterations in cancer cells can cause activation of regulatory factors that bind chromatin at targetgene loci to turn on transcription programs that drive tumor initiation and progression. However despiteidentification of these oncogenic regulatory factors in multiple tumor types a gap in this rapidly evolving field isthe delineation of molecular mechanisms that open opportunities to target those regulators. Thus my long-termgoal is to define interaction surfaces within chromatin-bound regulators critical for their oncogenic functions. In the F99 phase of this proposal I will focus on the transcription regulator KAP1 and its previouslyunprecedented role in activating oncogenic WNT signaling in colorectal cancer (CRC). Despite the well-established knowledge that WNT signaling drives CRC transformation and promotes tumor progression atherapeutic arm that successfully inactivates WNT in CRC has yet to be employed. Potentially addressing thisgap in knowledge my studies have discovered that KAP1 is required for expression of WNT target genes inresponse to oncogenic WNT stimulation. Importantly compelling preliminary data support two non-mutuallyexclusive mechanisms explaining how KAP1 may regulate WNT signaling. First KAP1 could directly activateWNT by scaffolding key transcriptional machinery to WNT target gene promoters using its chromatin readermodule. Second KAP1 could interact with and regulate -Catenin stability (the WNT transcription effector). I willtest these two models and then evaluate whether perturbing the KAP1chromatin and/or KAP1-Catenininteractions will block WNT-induced CRC phenotypes. In the K00 phase I will shift focus to another biomedically relevant chromatin regulatory complex (SWI/SNF).SWI/SNF normally remodels nucleosomes on chromatin to activate target gene expression but its dysregulationin cancer can cause aberrant activation of oncogenic programs. Likewise in the soft-tissue malignancy SynovialSarcoma (SS) the transforming genetic alteration is translocation of SS18 a member of SWI/SNF to the SSXtranscription factor. Because SSX but not SSX18 normally binds modified nucleosomes SSX abnormallyredirects SS18 to a cancer-specific set of genomic sites causing upregulation of genes that promotetumorigenesis. Despite this mechanistic understanding the molecular and structural basis of the SS18-SSXnucleosome interaction remains unclear and a strategy to target SS18-SSX is currently undefined. To achievethese unmet needs I will biophysically characterize the SS18-SSX-nucleosome interaction and then identifysmall-molecule inhibitors that disrupt the SS18-SSX-nucleosome interaction. Finally I will test lead inhibitorcandidates in hallmarks of cancer assays (proliferation and invasion). The training obtained under both phases will fulfill my long-term goal of running my own lab with an emphasison molecular mechanisms of gene regulation allowing me to have a positive impact on cancer patients. 92304 +No NIH Category available Development Plans;Grant;Guidelines;Malignant neoplasm of cervix uteri;Mentors;Radiation-Sensitizing Agents;Research;career development;novel;parent grant Identifying Novel Radiation Sensitizers in Cervical Cancer PROJECT NARRATIVEProject Narrative is not requested.This is an NCI Diversity Supplement to Dr. Lauren Colberts grant (R21CA277332) titled Identifying NovelRadiation Sensitizers in Cervical Cancer. NCI 10818291 7/20/23 0:00 PA-21-071 3R21CA277332-01S1 3 R21 CA 277332 1 S1 "PRASANNA, PAT G" 12/7/22 0:00 11/30/24 0:00 11517691 "COLBERT, LAUREN ELIZABETH" Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 7/1/23 0:00 11/30/23 0:00 395 Non-SBIR/STTR 2023 31645 NCI 19534 12111 PROJECT SUMMARY/ABSTRACTPer the additional NCI guidelines for PA-21-01 the parent grant abstract is uploaded as part of the six-page requirementfor Research Mentoring and Career Development Plan. 31645 +No NIH Category available Award;Parents;Research;Translating;cell free DNA;precision oncology;tumor Translating the tumor regulome from cell-free DNA for precision oncology PROJECT NARRATIVEPer the FOA this section is not required. The research supplement proposal does not change the activities ofthe parent award. NCI 10818290 7/26/23 0:00 PA-21-071 3DP2CA280624-01S1 3 DP2 CA 280624 1 S1 "OSSANDON, MIGUEL" 9/13/22 0:00 8/31/25 0:00 15167932 "HA, GAVIN " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/1/23 0:00 8/31/25 0:00 394 Non-SBIR/STTR 2023 214790 NCI 136318 78472 PROJECT SUMMARY/ABSTRACTPer the FOA this section is not required. The research supplement proposal does not change the activities ofthe parent award. 214790 +No NIH Category available Affect;CXCL9 gene;Cancer Etiology;Cancer Patient;Cells;Cessation of life;ChIP-seq;Clinical;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Flow Cytometry;Gene Expression;Genes;Genetic Transcription;Genotype;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Major Histocompatibility Complex;Malignant neoplasm of lung;Mesenchymal;Methyltransferase;Molecular;Mus;Myeloid Cells;NGFR gene;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;System;T-Lymphocyte;Testing;Therapeutic;Tumor stage;Update;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;cancer immunotherapy;cell type;clinically relevant;combinatorial;conditional knockout;cytokine;effector T cell;immunogenic;improved;in vivo;inhibitor;migration;mouse model;neoplastic cell;neutrophil;parent grant;programmed cell death ligand 1;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Targeting Epigenetic Heterogeneity to Improve Lung Cancer Immunotherapy Response PI: Brainson Christine FillmorePROJECT NARRATIVELung cancer is the leading cause of cancer-related deaths worldwide and is a very complex disease withdifferent cell types that comprise each tumor. Immunotherapy is ground-breaking because it is able to cure somepatients with late stage tumors but the number of patients that have this great response is still low. In thisproposal we will test the combination of a second drug with immunotherapy to increase the likelihood thatsquamous lung tumors will respond to treatment. NCI 10818203 8/15/23 0:00 PA-21-071 3R01CA237643-05S1 3 R01 CA 237643 5 S1 "SOMMERS, CONNIE L" 7/1/19 0:00 6/30/24 0:00 Developmental Therapeutics Study Section[DT] 10317047 "BRAINSON, CHRISTINE FILLMORE" Not Applicable 6 PHARMACOLOGY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 77275 NCI 55356 21919 PROJECT SUMMARY Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. Our central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing immunogenic PD-L1 expressing cellsand by depleting immunosuppressive tumor associated neutrophils. The overarching goal of the proposedstudy is to validate combining EZH2 inhibition with PD1/PD-L1 targeted immunotherapy and learn the molecularmechanisms when the treatment is successful as well as when it is not successful. In Aim 1 we will use both mouse models and human patient derived organoid cultures to examine NGFRCXCL9/10/11 PD-L1 and MHC expression in lung SCC cells after EZH2 inhibitor treatment. The epigenetic andtranscriptional consequences of EZH2 inhibition on squamous and bronchiolar lung tumor cells will be assessedby ChIP-seq and RNA-seq. In Aim 2 we will focus on the tumor associated neutrophils (TANs). We will compareTANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migration capacityand ability to suppress T cells. We will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 we will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. We will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. We will also develop tumoroid multi-cultures containing tumor cellsmesenchymal cells T cells and myeloid cells to be able to test responses of systems to EZH2 inhibition and anti-PD1 inhibition ex vivo. Completion of these aims will solidify the efficacy of a promising therapeutic combinationand uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2 inhibitorsin squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibition with anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.1 77275 +No NIH Category available DNA Damage;Pathway interactions;mutant;response Targeting Defective DNA Damage Response Pathways in IDH1/2-mutant AML Project NarrativeNot needed for this submission. NCI 10818177 7/12/23 0:00 PA-21-071 3R01CA266604-02S1 3 R01 CA 266604 2 S1 "WITKIN, KEREN L" 2/3/22 0:00 1/31/27 0:00 11263286 "BINDRA, RANJIT " "HALENE, STEPHANIE " 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 162244 NCI 96862 65382 Project SummaryNot needed for this submission. 162244 +No NIH Category available Address;Antibodies;Area;B-Lymphocytes;Binding;Biochemical;Biogenesis;Biology;Blood Platelets;Cancer Biology;Cancer Control;Cell surface;Client;Clinical;Clinical Trials;Collaborations;Complex;Degradation Pathway;Development;Docking;Endoplasmic Reticulum;Eragrostis;Foundations;GRP94;Goals;Growth Factor Receptors;Heat-Shock Proteins 90;Human;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immunity;Immunologics;Immunotherapeutic agent;Immunotherapy;Insulin-Like Growth Factor I;Insulin-Like Growth Factor II;Integrins;LRRC32 gene;Laboratories;Malignant Neoplasms;Manuscripts;Mediating;Membrane Glycoproteins;Molecular;Molecular Chaperones;Myelogenous;Nature;Oncogenic;PD-1/PD-L1;Pathway interactions;Pharmaceutical Preparations;Phase;Play;Pre-Clinical Model;Proteins;Publishing;Quality Control;Regulation;Regulatory T-Lymphocyte;Renaissance;Resistance;Role;Signal Pathway;Signal Transduction;Structural Biologist;Suppressor-Effector T-Lymphocytes;Surface;T cell therapy;T-Lymphocyte;Therapeutic;Thrombin;Transforming Growth Factor beta;Translational Research;Tumor Escape;VWF gene;anti-cancer;cancer cell;cancer immunotherapeutics;cancer immunotherapy;cancer therapy;cell growth;cell type;chimeric antigen receptor;convict;design;effector T cell;engineered T cells;genetic approach;immune checkpoint;immune resistance;inhibitor;insight;leucine-rich repeat protein;migration;new therapeutic target;next generation;novel;novel therapeutics;overexpression;paralogous gene;pre-clinical;preclinical study;protein degradation;receptor;response;side effect;targeted treatment;tumor microenvironment;tumorigenesis Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy Supplement PROJECT NARRATIVEThis study addresses how a chaperone molecule called GRP94 controls cancer and determines the best strategyto target GRP94 for cancer immunotherapy. Significant discoveries have been made regarding the roles ofGRP94 in controlling the pathway of transforming growth factor beta (TGFb). Several therapeutic leads haveemerged in blocking the GRP94-TGFb pathway; further in-depth study of GRP94 will advance novel therapiesfor cancer. NCI 10818173 9/19/23 0:00 PA-21-071 3R01CA262069-03S1 3 R01 CA 262069 3 S1 "HU, ZHANG-ZHI" 9/1/21 0:00 8/31/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6609948 "LI, ZIHAI " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 72104 NCI 45780 26324 PROJECT SUMMARYAs a ubiquitous HSP90 paralog in the endoplasmic reticulum (ER) GRP94 plays important roles in protein qualitycontrol in the secretory pathway by participating in both the unfolded protein response and the ER-associatedprotein degradation pathway. My laboratory has demonstrated that GRP94 is a strategically important target forcancer because it controls multiple key molecular pathways in cell growth migration immune tolerance anddifferentiation including integrins TLRs IGF-II Wnt co-receptor LRP6 and GARP (or LRRC32). GARP(Glycoprotein A Repetitions Predominant) is responsible for surface docking and activation of latent TGFb anda focus of this proposal We have made significant contributions to this area through immunological andbiochemical studies including: 1) that GARP is an important molecule for cancer immune evasion via regulatingmultiple cell types (e.g. cancer cells platelets regulatory T cells B cells). 2) We discovered a novel mechanismof TGFb activation from cell surface GARP-TGFb complex via proteolytic cleavage of GARP. 3) GARP has beenfound to be aberrantly expressed in multiple human cancers to promote oncogenesis via both cancer cell-intrinsicand -extrinsic mechanisms. 4) Preclinical studies suggest that GARP is a novel therapeutic target for cancerimmunotherapy. These accomplishments have deepened our conviction that the study of GRP94 and its clientnetwork will lead to better understanding of this chaperone biology in cancer and to development of novel cancertherapeutics alone or in combination with approved immunotherapeutic agents. In the next phase of the studywe will address the hypothesis that GRP94/GARP-targeted therapy applied to multiple vulnerable cancers willovercome immune resistance to checkpoint inhibitors.First we will determine the roles and molecular mechanism involved in GRP94 regulation of TGFb biogenesisactivation and signaling. This aim will focus on structural analysis of the GRP94-GARP complex and on resolvingmechanisms of GRP94 in folding two other molecules important in regulating TGFb signaling: LRRC33 andLRG1. Second we will develop novel cancer immunotherapeutic strategies targeting GRP94 and GARP. Thegoal is to advance the top first-in-class agent(s) among several pre-clinical leads through a milestone-drivenstrategy. This includes agents to inhibit GARP cleavage GARP-specific antibodies drug-like GRP94-selectiveinhibitors antibodies against the cell surface GRP94 (ectoGRP94) preferentially expressed on cancer cells andT cells engineered to express chimeric antigen receptor (CAR) composed of a single-chain antibody againstectoGRP94 fused with T cell signaling motifs (GRP94-CAR-T). Overall the impact of this study lies infundamental understanding of GRP94 in regulating the TGFb pathway and in developing promising nextgeneration immunotherapeutic agents. 72104 +No NIH Category available 3-Dimensional;Architecture;Basement membrane;Blood Vessels;Breast Cancer Cell;Breast Cancer Model;Cell Communication;Cell-Cell Adhesion;Cells;Cessation of life;Circulation;Collagen;Collagen Fiber;Complex;Computer Models;Development;Disease;Environment;Equilibrium;Extracellular Matrix;Feedback;Fiber;Fibroblasts;Heterogeneity;Human;Hypoxia;In Vitro;Intercellular Junctions;Invaded;Lead;Lymphatic;Malignant Neoplasms;Mammary Neoplasms;Measures;Mechanics;Microfluidic Microchips;Modeling;Movement;Neoplasm Circulating Cells;Neoplasm Metastasis;Organoids;P-Cadherin;Population;Process;Property;Role;Signal Transduction;Stromal Cells;Subgroup;Tumor Cell Invasion;Validation;alpha catenin;breast cancer progression;cell motility;cell type;chemokine;crosslink;density;experimental study;in vivo;malignant breast neoplasm;migration;mouse model;novel;parent grant;predictive modeling;preservation;response;simulation;three dimensional structure;tumor;tumor microenvironment Leader cell development and function in Breast Tumor Collective Migration Project Narrative for Parent GrantThe majority of breast cancer deaths result from metastatic disease. Accumulated evidence indicates thatbreast tumor cells invade as complex heterogeneous clusters rather than single cells and to do so they are ledby cells called leader cells. How these leader cells develop to lead directed collective migration and whetherthis phenomenon is necessary and sufficient to effect directed collective migration is largely unknown. This is afocus of the current proposal.Project Narrative for SupplementBreast tumor microenvironment involves heterogeneities due to varying properties of leader cells cancer-associated fibroblasts follower cells collagen fibers chemokine gradients and hypoxia. Both in vivo and invitro experimentation has revealed different roles for these variables. However due to inherent complexity andnumerous possibilities computational modeling and validations against experiments are needed to makepredictions about breast cancer progression. This supplement will be devoted towards computational modelingand comparisons against experimental results obtained in the parent grant. NCI 10818106 8/29/23 0:00 PA-21-071 3R01CA254060-02S1 3 R01 CA 254060 2 S1 "AULT, GRACE S" 5/5/22 0:00 3/31/27 0:00 1900293 "LONGMORE, GREGORY D." "PATHAK, AMIT " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 55621 NCI 35731 19890 Project Summary for Parent Grant Accumulated evidence in human breast cancer and mouse models of breast cancer have shown that tumorcells invade collectively through the basement membrane (BM) and continue as collective groups to traversethe collagen-rich ECM to access lymphatic and vascular vessels. Rather than single cells in the circulationclusters of heterogeneous circulating tumor cells (CTCs) that also contain tumor-associated stromal cells suchas cancer associated fibroblasts (CAFs) account for >90% of metastases. To move collectively requires coordinated cellcell and cellmatrix interactions. Hallmarks of collective cellmigration include: 1) Cells remain physically and functionally connected such that the integrity of cellcelljunctions are preserved during movement. 2) A subgroup of cells typically defines the leading edge and thusthe direction of collective migration. These are known as leader cells and differ in function from followercells. 3) Collective movement also involves intimate interaction with accessory stromal cells that releasepolarity-inducing and pro-migratory factors as well as contribute to path finding by physically remodeling thesurrounding ECM. Several hypotheses have been proposed to explain cancer leader cell development during collectivemigration. Yet how these leader cells develop arrive and define the front edge then lead directed collectivemigration and whether this phenomenon is necessary and sufficient to effect directed collective migration arelargely unknown. We have developed novel microfluidic devices in which to study the collective migration ofprimary breast tumor organoids in response to multiple environmental signals In the present proposal we propose to use primary breast tumor organoids with their inherent cellularheterogeneity to determine how leader cells develop and function in response to multiple environmentalsignals so as to direct collective migration. To do so we propose two specific aims. Specific Aim 1. Todetermine how K14 leader cells within primary breast tumor organoids polarize to the leading edge and thenfunction to direct collective migration. Specific Aim 2: To understand chemo-mechanical feedback betweenCAF-based ECM remodeling and leader-based invasion.Project Summary for SupplementIn breast tumor invasion clustered cells invade through surrounding stromal collagen to enter circulation. Thisprocess is regulated by leader cells that come to the front of a breast tumor collective and lead the entireorganoid to invade collagen. The supplement project asks whether there is an optimal balance of cellularforces and collagen density and crosslinking. This is a multivariate problem that requires modeling predictions;it would otherwise be much more difficult to straightaway perform numerous experiments to try all possiblecombinations of cell types and collagen compositions. This supplement project studies how dysfunctional cell-cell communication can alter cell invasion modes in 3D environments of varying stiffness and fiber architecture.Cell populations are captured in a cellular Potts lattice-based modeling framework and collagen as a 3D fieldthat can evolve by cellular forces. Modeling parameters corresponding to cell protrusions (regulated by P-cadherin and Rac) cell-cell adhesions (-catenin) and cellular contractility (RhoA) are varied in a given cellpopulation. In parallel collagen concentration degradation rate crosslinking rate and long-distance forcepropagation are also varied. Simulations are performed to measure how invasion modes of these differentpopulations vary according to fiber microstructure of 3D collagen matrices. The modeling predictions from thissupplement project particularly relating to the roles of P-cadherin Rac -catenin and RhoA in collective cell3D invasion inform other projects in the parent grant. 55621 +No NIH Category available Aftercare;Algorithms;Animal Model;Animals;Automation;Breast Cancer Model;Cancer Patient;Clinic;Clinical;Clinical Research;Computer software;Data;Detection;Development;Devices;Diagnosis;Disease;Electron Spin Resonance Spectroscopy;Engineering;Environment;Evaluation;Funding;Goals;Health;Human;Hypoxia;Image;Implant;In Vitro;Knowledge;Laboratory Research;Location;Malignant Neoplasms;Measurement;Measures;Medical center;Methods;Modeling;Modification;Monitor;Myocardial Infarction;Noise;Oryctolagus cuniculus;Outcome;Oxygen;Oxygen saturation measurement;Parents;Partial Pressure;Pathology;Patients;Performance;Physiologic pulse;Pre-Clinical Model;Procedures;Prognosis;Radiation therapy;Research;Roentgen Rays;Safety;Signal Transduction;Site;Technology;Testing;Time;Tissues;Translations;Visual;Visualization;anatomic imaging;cancer therapy;clinical application;clinical imaging;clinical practice;clinically relevant;clinically significant;cohort;contrast imaging;design;detection sensitivity;first-in-human;human subject;image processing;imaging biomarker;imaging modality;in vivo;innovation;multimodality;nanoGold;new technology;novel;operation;parent project;phantom model;pre-clinical;response;sensor;solid state;therapy outcome;tissue phantom;tool;treatment planning;tumor;ultrasound;usability;user-friendly;wound healing Multimodal Marker for imaging oximetry in radiotherapy PROJECT NARRATIVEMeasurement of tissue oxygen levels is important in terms of diagnosis long-term tracking and treatment ofseveral diseases and health situations including cancer wound healing and heart attack. In this project we willdevelop a novel technology to monitor tissue oxygen levels in the clinic. NCI 10818101 8/24/23 0:00 PA-21-071 3R01CA269234-01A1S1 3 R01 CA 269234 1 A1S1 "SORG, BRIAN S" 1/1/23 0:00 12/31/25 0:00 1986495 "KUPPUSAMY, PERIANNAN " Not Applicable 2 ENGINEERING (ALL TYPES) 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH BIOMED ENGR/COL ENGR/ENGR STA 37551421 UNITED STATES N 9/1/23 0:00 12/31/23 0:00 394 Non-SBIR/STTR 2023 99226 NCI 78271 20955 PROJECT SUMMARYDespite the clinical significance and importance of tissue oxygen levels in the diagnosis prognosis andtreatment of several pathologies currently there is clearly an unmet need for methods to quantify tissueoxygen levels with a reasonable degree of accuracy reliability and robustness required for use in the clinicalsettings. The overall objective of this proposal is to bring the unique capability of electron paramagneticresonance (EPR) oximetry to the clinical realm particularly for enhancement of cancer treatment. We havediscovered unique solid-state sensors called OxyChips and procedures that enable unsurpassed reliability andrepeated interrogation of tissue oxygen levels at specific tissue sites over a periodpossibly indefinitely.However these sensors are limited primarily to laboratory research involving small animals. We haveobservedin a small cohort of cancer patientsthat translation of this novel technology to clinical applicationswould require innovative sensors to provide enhanced detection capability safety stability and robustness asa routine clinical tool. We propose to develop a novel class of the OxyChip sensor with enhanced detectionsensitivity easy identification during clinical imaging and long-term safety and stabilityall specificallydesigned and optimized for measurement in deeper tumors. The proposed developments combined with theunique capabilities of the EPR oximetry technology will be a valuable clinical tool capable of providing real-time knowledge of tumor oxygen levels for enhanced cancer treatments and clinical outcomes. The followingspecific aims are proposed: (1) Characterization of OxyChips to establish their suitability for temporal andspatial localization in routine clinical imaging. The OxyChips embedded with GNP will be subjected to carefulevaluation under clinically relevant imaging conditions to determine its suitability for temporal and spatiallocalization during routine clinical imaging. Evaluation will include regional conspicuity (i.e. visibility of OxyChipwith respect to its local tumor environment) quantitative measure of detectability (i.e. signal-to-noise ratio andcontrast-to-noise ratio) and image processing methods for visual and quantitative enhancement of theOxyChips. (2) Evaluation of the new OxyChips embedded with GNP in a pre-clinical rabbit tumor model toestablish their safety robustness and utility for imaging and oxygen measurements in the clinical settings. Wewill determine the capability of the new sensors for clinical applicability using rabbit breast tumor model. Theevaluation criteria will include visualization of the sensors in the tumor using clinical imaging modalities suchas CT CB-CT planar X-ray and ultrasound. The proposed research will further advance the capability of EPRoximetry with OxyChip for cancer treatment. 99226 +No NIH Category available Accounting;Acetylation;Aconitate Hydratase;Anabolism;Automobile Driving;Cancer Patient;Citrates;Clinical;Communication;Competence;Disease;Enzymes;Fatty acid glycerol esters;GRIP1 gene;Genetic;Genetic Transcription;Goals;Growth;Hormones;Human;Link;Malignant neoplasm of prostate;Metabolic;Metabolic stress;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Mitochondria;Molecular;Morbidity - disease rate;NCOA2 gene;Neoplasm Metastasis;Nuclear;Nuclear Receptors;Organ;Pathogenesis;Patients;Play;Prostatic Neoplasms;Refractory;Repression;Resistance development;Role;Sirtuins;Steroid Receptors;Transcriptional Activation;Transcriptional Regulation;Tumor Suppressor Proteins;Visceral;androgen deprivation therapy;bone;castration resistant prostate cancer;fatty acid biosynthesis;hormone refractory prostate cancer;lipid biosynthesis;men;mitochondrial metabolism;mortality;prostate cancer cell;prostate cancer progression;therapy resistant;tumor Mechanisms of metabolic stress-induced transcriptional regulation in prostate cancer Majority of the patients with aggressive prostate cancer develop resistance to therapy and the tumormetastasizes to bones and other visceral organs accounting for high morbidity and mortality. The goal of thisproject is to define the underlying mechanisms that promote the survival and colonization of prostate tumorcells in the bone microenvironment. Our study will uncover molecular links between mitochondrial metabolismand transcriptional regulation that enables PCa adaptation survival and ultimately metastatic competency. NCI 10818087 8/9/23 0:00 PA-21-071 3R01CA252092-03S1 3 R01 CA 252092 3 S1 "MERCER, NATALIA" 4/1/23 0:00 3/31/26 0:00 12313122 "DASGUPTA, SUBHAMOY " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 6/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 52626 NCI 30332 22294 Metastatic prostate cancer (PCa) remains a major clinical challenge. Although androgen deprivation therapy(ADT) is effective in treating PCa majority of the patients quickly develop resistance to therapy and the tumorrelapses as hormone refractory castration-resistant prostate cancer (CRPC). Men with CRPC frequentlyprogress to an aggressive lethal disease that metastasizes to bones and other visceral organs accounting forhigh morbidity and mortality. Transcriptional activation of steroid receptor coactivator-2 (SRC-2; also known asNCOA2/TIF2/GRIP1) plays a critical role in the pathogenesis of PCa by driving a metabolic switch towards denovo fatty acid biosynthesis. Although increased lipogenesis is a known hallmark of hormone refractory PCaprogression it is less clear how mitochondrial enzymes communicate with nuclear receptor coregulators torapidly fuel and support fat biosynthesis. Our preliminary findings indicate that sustained activity of mitochondrialaconitase (ACO2) enzyme is critical for regulating citrate synthesis. We found that acetylation of ACO2 isessential for enzyme functions which is negatively regulated by sirtuin-3 (SIRT3). In human prostate cancerpatients SIRT3 expression is repressed and increased expression of SRC-2 with concomitant reduction ofSIRT3 was found to be a genetic hallmark in metastatic PCa. Based on these findings we hypothesize that thetranscriptional coregulator SRC-2 drives the nuclear-mitochondrial regulatory axis by repressing tumorsuppressor SIRT3 thus promoting prostate tumor survival and metastasis competence. So our objectives in thisproposal are (1) to investigate the mechanisms regulating sustained activation of mitochondrial ACO2 to promotelipogenesis (2) define the role of nuclear receptor coregulator SRC-2 regulating SIRT3 expression and (3)evaluate the impact of this nuclear-mitochondrial regulatory axis on prostate tumor survival and adaptationleading to bone colonization and growth. Our study will uncover molecular links between mitochondrialmetabolism and transcriptional regulation that enables hormone refractory PCa adaptation survival andultimately metastatic competency. 52626 +No NIH Category available ATAC-seq;Acceleration;Aftercare;Atlases;Biological;Biological Assay;Biological Markers;Biological Process;Biopsy;Blood;Breast Cancer Treatment;CDK4 gene;Cells;Chromatin;Clinical;Collection;Communities;Core Biopsy;Coupled;DNA sequencing;Data;Data Analyses;Data Coordinating Center;Data Set;Development;Diagnostic Procedure;Dimensions;Electron Microscope;Evaluation;Formalin;Foundations;Freezing;Generations;Genomics;Goals;Heterogeneity;Image;Immune checkpoint inhibitor;Immunofluorescence Immunologic;Immunohistochemistry;Ions;Malignant Neoplasms;Manuscripts;Maps;Metadata;Metastatic breast cancer;Molecular;Noninfiltrating Intraductal Carcinoma;Paraffin Embedding;Pathway interactions;Patients;Periodicity;Plant Resins;Poly(ADP-ribose) Polymerase Inhibitor;Publications;Resistance;Resource Sharing;Resources;Sampling;Scanning;Scientist;Specimen;Structure;Therapeutic;Three-Dimensional Image;Time;Tissues;Tumor-Derived;Visualization;Work;anticancer research;biological systems;cancer subtypes;cohort;data integration;data sharing;hormone receptor-positive;hormone therapy;immune checkpoint;immune modulating agents;individual patient;inhibitor;innovation;malignant breast neoplasm;multimodal data;multimodality;neoplastic cell;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;operation;paraform;programs;prospective;resistance mechanism;sample collection;success;targeted treatment;therapy resistant;tool;treatment response;triple-negative invasive breast carcinoma;tumor;tumor-immune system interactions Omic and Multidimensional Spatial Atlas of Metastatic Breast Cancer PROJECT NARRATIVETreatments of metastatic breast cancer typically are not durable. The OMS Atlas project will apply state-of-the-art analysis tools to tumor samples taken at multiple times during treatment in order to identify changes in thecomponents and structures of these cancers that enable them to escape therapeutic control. This informationwill help guide the development of new therapeutic approaches that can be used to reestablish control anddevelop new diagnostic procedures that will guide the use of these treatments. NCI 10818062 8/18/23 0:00 PA-20-272 3U2CCA233280-05S1 3 U2C CA 233280 5 S1 "HUGHES, SHANNON K" 4/4/23 0:00 8/31/24 0:00 10490342 "GOECKS, JEREMY " "MILLS, GORDON B.; THOMAS, GEORGE VICTOR" 1 NONE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR OVERALL MEDICAL 972393098 UNITED STATES N 4/4/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 923254 NCI 679450 243804 PROJECT ABSTRACTWe will continue development of our Omic and Multidimensional Spatial (OMS) Atlas that enables discovery ofmechanisms of resistance that arise in individual patients with metastatic breast cancer during treatment withcurrent generation targeted therapeutic combinations and immune checkpoint inhibitors. The OMS Atlas ismotivated by the fact that these treatments typically are only transiently effective in the metastatic setting.Possible resistance mechanisms may be intrinsic to the tumor cells or derive from the diverse microenvironmentsin which the tumor cells live. The OMS Atlas focuses on elucidating these resistance mechanisms in two currentgeneration clinical scenarios: (a) hormone-receptor positive breast cancer (HRBC) undergoing treatment with aCDK4/6 inhibitor in combination with endocrine therapy and (b) triple negative breast cancer (TNBC) undergoingtreatment with a PARP inhibitor and an immunomodulatory agent. We are accomplishing this through work viafour coordinated units. A Biospecimen Unit is prospectively collecting and distributing longitudinal clinicalinformation blood and biopsies from 30 cases across the two metastatic breast cancer cohorts. ACharacterization Unit is analyzing (a) OCT frozen specimens using single-cell DNA-seq and single-cell ATAC-seq to elucidate spatially defined genomic changes and chromatin accessibility in single cells (b) formalin fixedparaffin embedded (FFPE) specimens using multiplex immunohistochemistry (mIHC) to assess the immunemicroenvironment and cyclic Immunofluorescence (cycIF) to assess the composition and molecular states oftumor cells and their microenvironments and (c) paraformaldehyde fixed resin embedded (PFRE) specimensusing a Focused Ion Beam Scanning Electron Microscope (FIB-SEM) to identify ultrastructural changes in 2Dimages and targeted 3D images. Omic characterization of the same tumor samples is provided by the SMMARTProgram. A Data Analysis Unit is developing and deploying tools to (a) manage analyze and visualize omicsand imaging datasets (b) integrate omics and imaging datasets through crosswise mapping to create singletimepoint tumor maps and quantify systems biological functions of tumor cellular subpopulations and (c) exploredifferences between pre- and on/post-treatment tumor maps to reveal mechanisms of resistance. TheAdministrative Unit facilitates the coordination operation interaction and evaluation of activities within the OMSAtlas and between OMS Atlas scientists and the HTAN. In this project we will complete our planned OMS Atlasproject through the following Aims: (1) perform characterization of five additional patient cases using our omicsand multiscale imaging assays; (2) upload our remaining datasets and metadata to the HTAN data coordinatingcenter; and (3) perform integrated data analysis across our atlas case datasets as well as HTAN trans-networkproject datasets to identify tumor changes on therapy and the implications of those changes on breast cancertreatment. By accomplishing these aims we will complete and fully share our multimodal spatial atlas of 30metastatic breast cancer cases undergoing treatment. 923254 +No NIH Category available Ablation;Amino Acids;Antioxidants;Cancer Intervention;Catabolism;Cysteine;Cystine;Data;Dipeptides;Gamma-glutamyl transferase;Glutathione;Glycine;Goals;Growth;Malignant Neoplasms;Mammary Neoplasms;Mediating;Plasma Cells;Research;Source;Supplementation;Testing;Therapeutic;Tissues;Tumor Promotion;Work;cancer cell;cancer subtypes;cancer therapy;cell growth;cysteinylglycine;experimental study;extracellular;in vivo;interest;novel;therapeutic target;triple-negative invasive breast carcinoma;tumor;tumor growth;tumorigenesis Impact of extracellular glutathione catabolism on triple-negative breast cancer Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. We havemade the surprising discovery that the antioxidant glutathione (GSH) functions extracellularly not intracellularlyto support TNBC growth. Our research will challenge the paradigm of antioxidant function in cancer by describinga novel mechanism of GSH function as a circulating source of amino acids and has the potential to reveal acompletely new set of therapeutic targets for TNBC intervention. NCI 10818004 7/17/23 0:00 PA-21-071 3R01CA269813-02S2 3 R01 CA 269813 2 S2 "WILLIS, KRISTINE AMALEE" 5/1/23 0:00 4/30/26 0:00 12481152 "HARRIS, ISAAC SPENCER" Not Applicable 25 GENETICS 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 5/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 49639 NCI 32233 17406 Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. There isan emerging interest in blocking antioxidants for cancer therapy but how antioxidants promote cancer growth isunclear. Glutathione (GSH) is the most abundant antioxidant in the body and our previous work has shown thatGSH promotes tumorigenesis of triple-negative breast cancers (TNBC). It is generally assumed that GSH actsintracellularly as an antioxidant in cancer cells. However our preliminary studies show that blocking intracellularGSH synthesis does not impede TNBC growth. These surprising results suggest an alternative mechanismwhere extracellular GSH supports breast tumor growth. The overarching goal of this proposal is to determinehow extracellular GSH promotes tumor growth. It is known that extracellular GSH is present in plasma but cellscannot import GSH. Instead GSH is metabolized by gamma-glutamyl transferase (GGT1) to produce a glutamyl-dipeptide and cysteinylglycine which yields cystine and glycine. Indeed we find that ablation of GSH synthesisin vivo not only lowers circulating GSH but also reduces the levels of cysteinylglycine cysteine and glycine intissues. Further we show that supplementation with GSH and cysteinylglycine can rescue TNBC growth uponcystine depletion in GGT1-dependent and -independent manners respectively. Together these preliminary datasuggest an alternative mechanism where GSH functions as a circulating source of metabolites rather than as adirect antioxidant. In this proposal we describe experiments that will test the hypothesis that the catabolism ofextracellular GSH by tumor GGT1 supports TNBC growth. In Aim 1 we will elucidate the impact of extracellularGSH on TNBC growth. In Aim 2 we identify the reliance of TNBC on GGT1-mediated GSH catabolism. In Aim3 we will determine the mechanisms by which cysteinylglycine supplies cysteine for TNBC growth. Our researchwill challenge the paradigm of antioxidant function in cancer by describing a novel mechanism of GSH functionas a circulating source of amino acids. Further these studies have the potential to reveal a completely new setof unrealized targets and therapeutic strategies for TNBC. 49639 +No NIH Category available Academic Medical Centers;Advanced Malignant Neoplasm;Aftercare;Applications Grants;Back;Biological;Biopsy;Cells;Clear cell renal cell carcinoma;Clinical;Clinical Trials;Clonality;Combined Modality Therapy;Data Set;Disease;Dose;Drug resistance;Endothelial Growth Factors Receptor;Evaluation;Extrahepatic;Freezing;Fresh Tissue;Funding;Genomic approach;Genomics;Goals;Grant;Image;Immune checkpoint inhibitor;Immunofluorescence Immunologic;Immunotherapy;Infiltration;Institution;Interleukin-2;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Melanoma Cell;Metastatic Melanoma;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Methods;Modeling;Molecular;Myeloid-derived suppressor cells;Nivolumab;Outcome;Patient Care;Patient Selection;Patients;Pharmaceutical Preparations;Preclinical Testing;RNA;Resistance;Resolution;Role;Site;Specimen;Structure;T cell clonality;T cell receptor repertoire sequencing;T-Cell Receptor;TNFSF15 gene;Technology;Testing;Therapeutic;Tissues;Toxic effect;Vascular Endothelial Growth Factors;Work;cancer cell;cancer immunotherapy;checkpoint therapy;clinically relevant;cohort;combinatorial;complex data;computer framework;cytotoxic CD8 T cells;experience;genome sequencing;immune cell infiltrate;improved;inhibitor;inhibitor therapy;multimodal data;multimodality;novel;patient stratification;predicting response;programs;resistance mechanism;response;spatiotemporal;transcriptome sequencing;tumor;tumor microenvironment;whole genome Mechanisms of liver metastasis and associated resistance to immunotherapy PROJECT NARRATIVECancer immunotherapies have revolutionized the care of patients with a variety of advancedcancers including patients with melanoma and clear cell renal cell carcinoma (ccRCC). Whilesome patients experience durable responses most do not. The mechanisms of resistance tocancer immunotherapies are poorly understood and may involve clinical features (e.g. thepresence of liver metastasis) or molecular features within the tumor or tumor-microenvironment.Combination therapies may provide a strategy to overcome drug resistance. Here we will usecutting-edge technologies to study malignant cell states and the tumor-microenvironment inpatients undergoing combination therapies. NCI 10818003 9/20/23 0:00 PA-21-071 3R37CA258829-03S1 3 R37 CA 258829 3 S1 "WATSON, JOANNA M" 3/9/21 0:00 2/28/25 0:00 14551452 "IZAR, BENJAMIN " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 5/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 144895 NCI 88082 56813 PROJECT SUMMARYCancer immunotherapies have revolutionized the therapy of many cancers including metastaticmelanoma and clear cell renal cell carcinoma (ccRCC). Dating back 30 years the first cancerimmunotherapy high-dose interleukin-2 was successfully tested in melanoma and ccRCC andprovided a first proof-of-concept of a transformative therapeutic potential.1-3 In the last decademelanoma and ccRCC have represented archetypical diseases in which a portion of patientsexperience durable responses to novel immunotherapies such as immune checkpoint inhibitors(ICI) and these observations frequently extrapolated to other cancers as well (e.g. lung cancer).4-8 However most patients do not response to ICI and the underlying mechanisms are unclear.In our initially funded grant (R37CA258829) we explore the role of liver metastasis and their rolein conferring resistance to ICI both locally and in concurrent metastatic sites (e.g. lungmetastases). We leverage cutting-edge models and technologies including single-cell genomicsto dissect this clinically relevant predictor for ICI resistance and explore opportunities for pre-clinical testing of combination therapies that may help overcoming resistance to ICI. In the currentproposal we will expand on these initial studies and study molecular predictors of response andresistance in patients with metastatic ccRCC who are treated with a combination of ICI andinhibitors of vascular endothelial growth factor receptors (VEGFR). For this purpose we havecollected paired snap-frozen tissue specimens from patients before therapy and after a course ofICI and VEGFR inhibitor therapy. In preliminary studies we applied cutting-edge technologiesdeveloped in our laboratory to enable multi-modal single-cell genomics from frozen tissuesachieving excellent technical quality. Furthermore we established panels for multiplexedimmunofluorescence (mIF) on matching tissues. In Aim 1 we will perform mIF on determiningspatio-temporal effects of ICI + VEGFR inhibitor therapy and correlate changes in immuneinfiltrates with clinical outcomes. In Aim 2 we will perform multi-modal single-cell genomicsincluding RNA-sequencing and T cell receptor sequencing (TCR) to determine both cancer cellintrinsic and extrinsic molecular and clonal correlates of response and resistance at single-cellresolution. Together with the proposed work in the initial grant application this supplement willfurther enhance our understanding of molecular and cellular correlates of response andresistance to immunotherapies. 144895 +No NIH Category available Affinity;Apoptosis;BRCA1 gene;BRCA2 gene;Base Sequence;Binding;Binding Proteins;Biochemical;Biophysics;Breast;Cell Cycle;Cell Cycle Arrest;Cell Cycle Regulation;Cell Death Induction;Cell Nucleus;Cell Signaling Process;Cells;Cervix Neoplasms;Chromosome Breakage;Clinical;Colorectal;Complex;Cryoelectron Microscopy;Cytoplasm;DNA;DNA Binding;DNA Damage;DNA Repair;DNA Repair Gene;DNA biosynthesis;DNA metabolism;DNA-Binding Proteins;Defect;Dissociation;Doctor of Philosophy;Eukaryota;Filament;Genes;Genetic;Genetic Recombination;Genomic Instability;Goals;Hela Cells;Homologous Gene;Human;Importins;Investigation;Knowledge;Laboratories;Lesion;Malignant Neoplasms;Metabolism;Modeling;Molecular Chaperones;Molecular Conformation;Mutation;Nuclear;Nuclear Import;Nuclear Pore Complex;Nucleoproteins;Organism;Orthologous Gene;PALB2 gene;Pancreas;Phase;Phenotype;Phosphotransferases;Post-Translational Protein Processing;Postdoctoral Fellow;Process;Prostate;Protein Binding Domain;Protein Isoforms;Proteins;RAD52 gene;Regulation;Research;Research Project Grants;Role;Saccharomyces cerevisiae;Signal Transduction;Single-Stranded DNA;Site;Stomach;Structure;Therapeutic;Training;Work;biological adaptation to stress;cancer cell;carcinogenesis;career;genome integrity;inhibitor;inhibitor therapy;insight;knock-down;medulloblastoma;novel;preservation;prevent;protein function;recruit;repaired;replication factor A;replication stress;response;restraint;skills;small molecule;therapeutic target;tool;tumor Role of nuclear chaperones in genomic instability and carcinogenesis Project Narrative Replication Protein A coordinates all DNA metabolic processes including DNA replication repair and recombination. Here the role of chaperone-like proteins in regulating RPA are dissected. These proteins are important in controlling genomic integrity and cancer-avoidance. NCI 10817984 7/11/23 0:00 RFA-CA-21-059 4K00CA274696-02 4 K00 CA 274696 2 "ELJANNE, MARIAM" 8/1/22 0:00 5/31/27 0:00 ZCA1-PCRB-H(M1) 16604148 "KUPPA, SAHITI " Not Applicable 13 BIOCHEMISTRY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 Other Research-Related 2023 88646 NCI 82080 6566 SUMMARYLesions breaks and errors in DNA are drivers of genomic instability resulting in a variety of cancers. The DNA damage response (DDR) is a signaling cascade that responds to breaks in the DNA and utilizes an array of DNA repair factors to correct the error and preserve genomic integrity. Cellular responses to DDR involve regulation of the cell cycle and signaling processes that either trigger DNA repair or programmed cell death. Proteins that function in DDR are shuttled into the nucleus in response to DNA damage. My PhD thesis work and the proposed goals center around understanding the mechanisms that regulate nuclear-cytoplasmic localization of DDR proteins. The F99 part of the proposal focuses on the regulation of Replication Protein A (RPA) by chaperone-like proteins. RPA is an essential single-stranded DNA (ssDNA) binding DDR factor that regulates all aspects of DNA metabolism including DNA replication repair and recombination. RPA is transported into the nucleus recognizes and binds ssDNA and activates DDR by interacting with over three dozen RPA-interacting proteins (RIPs). How spurious RPA-RIP interactions are prevented in the cell in the absence of ssDNA has been a long-standing mystery. I have uncovered that Rtt105 (Regulator of Ty1 transposition 105) a chaperone-like protein functions as a regulator by interacting with multiple domains of RPA and conformationally restraining the complex. This serves as an inhibitor of RPA-RIP interactions. Using sophisticated biophysical biochemical and structural tools I show that ssDNA binds to the RPA-Rtt105 complex and removes the restraints to promote recruitment of DDR factors. In higher eukaryotes a protein called RPAIN (RPA-interacting protein) serves as the functional ortholog of Rtt105 and I will focus on deciphering its mechanism of action. In addition using cryoEM I will determine the structures of RPA bound to these chaperonelike proteins. In the K00 part of the proposal I will focus on identifying chaperone-like proteins specific to other cancer-related DDR proteins such as BRCA1 BRCA2 RAD52 and PALB2. In addition I will investigate the regulatory and signaling mechanisms that control nuclear-cytoplasmic distribution of DDR factors during DNA damage. Finally using knowledge obtained from the biochemical and cellular studies I will develop targetedsmall molecule cancer therapeutic inhibitors to regulate DDR. The combined F99 and K00 training phases will provide me with the necessary skills towards an independent research career focused on generating targeted cancer therapeutics. 88646 +No NIH Category available Address;B-Lymphocytes;Biologic Characteristic;Biological;Biological Assay;Biological Markers;Blinded;Blood;Blood specimen;Bone Marrow;Bone Marrow Involvement;Categories;Characteristics;Clinical;Clonality;DNA Sequence Alteration;Detection;Development;Diagnosis;Disease;Early Diagnosis;Future;Gene Mutation;Genes;Genomics;Goals;High-Throughput Nucleotide Sequencing;Immunoglobulin Gene Rearrangement;Immunoglobulin Genes;Lymphoma;Malignant Neoplasms;Modeling;Monitor;Mutate;Mutation;Mutation Analysis;Mutation Detection;Operative Surgical Procedures;Patients;Performance;Peripheral Blood Involvement;Peripheral Blood Mononuclear Cell;Population;Prospective cohort;Recurrence;Reproducibility;Research;Residual Neoplasm;Retrospective cohort;Risk;Sampling;Spleen;Splenectomy;Splenic Tissue;Techniques;Testing;Tissues;Training;Tumor Tissue;accurate diagnosis;clinical diagnosis;cohort;diagnostic accuracy;disease diagnosis;early detection biomarkers;exome sequencing;genome sequencing;genomic aberrations;genomic biomarker;immunohistochemical markers;improved;novel;peripheral blood;prospective;virtual;whole genome Genomic biomarkers of splenic lymphoma Project Narrative: Splenic marginal zone lymphoma is the most common form of cancer arising in thespleen. Current diagnosis is based on histopathologic criteria and requires splenectomy despite the fact thatvirtually all cases involve peripheral blood. We and others have recently determined the genomic aberrationsthat characterize this disease and propose to employ stateof-the-art and sensitive genomic sequencingapproaches to achieve early and accurate disease diagnosis. The studies in this proposal will lead todevelopment of simple blood-based assays that will improve early detection and promote implementation ofearly and appropriate treatment. NCI 10817670 12/1/23 0:00 PA-19-056 5R01CA255655-05 5 R01 CA 255655 5 "HODGES, NICHOLAS AARON" 10/1/22 0:00 11/30/25 0:00 Cancer Biomarkers Study Section[CBSS] 6097193 "ELENITOBA-JOHNSON, KOJO S. J." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 449231 NCI 292728 156503 PROJECT SUMMARYGENOMIC BIOMARKERS OF SPLENIC LYMPHOMASplenic marginal zone lymphoma (SMZL) is the most common form of primary cancer in the spleen. SMZLtypically involves the bone marrow and peripheral blood (PB) at presentation. The diagnosis is invariablyestablished in late stages of disease via a splenectomy which is a surgical procedure carrying major risk.Additionally the diagnosis of SMZL is subjective because there are no specific histopathologic orimmunohistochemical biomarkers of the disease. Consequently early diagnosis of SMZL is challenging andnot achieved in most clinical scenarios. Further SMZLs are among the least reproducibly diagnosed categoryof lymphomas. The suboptimal diagnostic accuracy necessitates the development of qualitative and objectivebiomarkers of SMZL. Importantly while all cases of SMZL are characterized by PB involvement at diagnosishowever this biologic feature has not been leveraged for the reliable early detection of the disease. Usingwhole genome and exome sequencing we and others defined the genomic landscape of SMZL and identifiedrecurrently mutated genes in SMZL. An unmet clinical need is the development of reliable biomarkers for theearly and accurate diagnosis of the disease based on the characteristic genomic alterations of SMZL. Wepropose in this application to develop a genomic-based approach that utilizes and validates peripheral blood asfor early and accurate diagnosis of the disease. The overall impact of the application is the establishment of aparadigm for early sensitive and accurate disease diagnosis by analysis of peripheral blood therebypermitting early and appropriate treatment for the disease. 449231 +No NIH Category available Binding Proteins;Biological;CRISPR/Cas technology;Cell Nucleus;Cell model;Cells;Clinical;Combined Modality Therapy;Computational Biology;Correlative Study;Coupled;Critical Pathways;Data;Desmoplastic;Disease;Drug Targeting;Expression Profiling;FBXW7 gene;Fibroblasts;Genes;Global Change;Grant;Growth;Investigation;KPC model;KRAS2 gene;KRASG12D;Karyopherins;Knowledge;Link;MEKs;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mediator;Methodology;Modeling;Mutation;Non-Small-Cell Lung Carcinoma;Normal Cell;Nuclear;Nuclear Export;Nuclear Protein;Oncogenic;Oral Administration;Organoids;Outcome;Paclitaxel;Pancreatic Ductal Adenocarcinoma;Pathway Analysis;Pathway interactions;Patient Recruitments;Patients;Penetrance;Peptide Signal Sequences;Pharmaceutical Preparations;Phase;Phase Ib/II Clinical Trial;Phase Ib/II Trial;Phosphorylation;Process;Proliferating;Protein Export Pathway;Protein Family;Proteins;RAS driven tumor;RNA Interference;Ras/Raf;Recruitment Activity;Regimen;Reporting;Residual Neoplasm;Resistance;Role;Running;Safety;Signal Transduction;Specificity;Specimen;Transgenic Organisms;Tumor Suppressor Proteins;Vascularization;Work;analog;biomarker development;biomarker identification;clinical translation;epithelial to mesenchymal transition;experimental study;exportin 1 protein;gemcitabine;genome editing;improved;in vivo;inhibitor;innovation;mouse model;mutant;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;nucleocytoplasmic transport;objective response rate;overexpression;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;patient derived xenograft model;patient subsets;personalized medicine;pharmacodynamic biomarker;pre-clinical;preclinical study;protein transport;resistance mechanism;response;response biomarker;stemness;subcutaneous;success;synergism;targeted treatment;therapy design;therapy outcome;therapy resistant;transcriptome sequencing;treatment response;tumor Clinical Translation of Nuclear Export Inhibitor in Metastatic Pancreatic Cancer Narrative: Mutant KRAS protein drives several cancer related pathways and remains a highly sought after target.We have discovered that targeting nuclear transporter XPO1 by specific inhibitors of nuclear export drugs cansynergize with KRAS targeted drugs. We will perform critical pre-clinical analysis of this synergy to bring forwarda novel and effective combination therapy targeting the KRAS and nuclear protein transport axis in oncogenicRAS driven tumors. NCI 10817663 12/20/23 0:00 PA-16-160 5R37CA215427-07 5 R37 CA 215427 7 "HENDERSON, LORI A" 1/1/23 0:00 12/31/24 0:00 9609623 "AZMI, ASFAR S" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 316660 NCI 205624 111036 Abstract/Summary: Mutations in KRAS are among the most common aberrations in cancer. Mutant KRASdrives proliferation and survival through canonical RAS-RAF-MEK-ERK-RSK (RAS-RSK) signaling. WhileKRASG12D a major mutation found in cancers remains undruggable a smaller subset of patients carry KRASG12Cmutation for which new targeted drugs have emerged. Several KRASG12C inhibitors have been studied in pre-clinical and Phase I/II/III studies and one such inhibitor sotorasib has received FDA approval for KRASG12C mutantNSCLC patients. Despite this success the objective response rates from sotorasib or other related inhibitors hasbeen modest and durability of response needs to be improved. A number of resistance mechanism have beenproposed and strategies to overcome therapy resistance to KRASG12C inhibitors is a topic of intenseinvestigations. We have discovered that proteins in the RAS can influence the nuclear protein transport. In normalcells the export of nuclear cargoes is mediated by the Karyopherin family protein exportin-1/XPO1 throughnuclear export signal sequence recognition and is facilitated by a RAS downstream effector RanGTP. Thismakes RAN a mediator between growth signaling and nucleocytoplasmic transport that can be activated throughclassical RAS-RSK pathway. Ran binding protein 3 (RanBP3) is recognized to be phosphorylated through RSKresulting in the promotion of RanGDP to RanGTP conversion through RCC1 thereby enhancing Ran-dependentnucleocytoplasmic transport (schema). Such over-active nuclear export has been shown to promote therapyresistance through mislocalization dependent inactivation of tumor suppressor proteins. More significantly ournew findings show that specific inhibitors of nuclear export (SINE) compounds can enhance the efficacy ofKRASG12C inhibitors. We hypothesize that SINE-KRASG12C inhibitors could become a unique combination forKRASG12C mutant tumors. Additionally studying this unique combination will also help uncover the tangible linkbetween KRAS and nuclear protein export signaling. Our specific aims are Aim 1. Characterize the synergybetween SINE compounds and KRASG12Ci using high throughput strategies. Aim 2. Demonstrate synergybetween SINE KRASG12Ci using patient derived xenograft. Impact: Mutant KRAS remains an impenetrablefortress and an unmet clinical need. This work will lead to the advancement of a novel combination that targettwo highly sought after cancer targets i.e. KRASG12C and XPO1. Additionally the proposed experiments will alsoenhance the fundamental understanding of the interaction between mutant KRAS and nuclear protein exportpathways and its consequence of therapy resistance. The proposed pre-clinical studies will bring forward a newand personalized therapy for KRASG12C mutant driven resistant tumors. 316660 +No NIH Category available Acetylation;Address;Alleles;Allografting;Antineoplastic Agents;Bioenergetics;Breast;Breast Cancer Cell;Breast Carcinogenesis;CDK4 gene;Cell Survival;Cells;Cellular Metabolic Process;Chemicals;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Complex;Dependence;Development;Drug Metabolic Detoxication;Endocrine;Enzyme Induction;Enzymes;Epigenetic Process;Equilibrium;Estrogen Receptors;Estrogen Therapy;Estrogen receptor positive;Exhibits;Fasting;Fatty acid glycerol esters;Fulvestrant;Genes;Genetic;Human;Impairment;Implant;In Vitro;Infection;Knock-in Mouse;Laboratories;Lysine;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Medicine;Metabolic;Metabolic stress;Metabolism;Mitochondria;Modeling;Molecular;Mouse Mammary Tumor Virus;Mus;Nature;Nutrient;Oncogenic;Oxygen;Pathway interactions;Peroxidases;Phenotype;Physiological;Physiology;Play;Process;Progression-Free Survivals;Property;Proteins;Reactive Oxygen Species;Receptor Signaling;Recurrence;Research;Research Proposals;Resistance;Resistance development;Risk;Role;SOD2 gene;Sampling;Signal Transduction;Stains;Subgroup;Superoxides;T47D;Tamoxifen;Testing;Therapeutic;Tumor Suppressor Proteins;Tumor stage;Tumor-Derived;Woman;Xenograft procedure;breast malignancies;cancer cell;carcinogenesis;carcinogenicity;cell growth;experimental study;feeding;genomic data;high risk;hormone therapy;human model;in vivo;in vivo Model;inhibitor;knock-down;malignant breast neoplasm;mammary;mimetics;mitochondrial metabolism;molecular marker;monomer;mouse model;mutant;neoplastic cell;novel therapeutic intervention;oncogene addiction;patient derived xenograft model;patient subsets;programs;stemness;targeted agent;therapy resistant;tissue culture;tissue/cell culture;tumor;tumor initiation;tumorigenesis;tumorigenic MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies. NarrativeThis research proposal addresses the question that it is becoming increasing clear that there is adichotomous functional role for MnSOD in tumorigenesis as well as tumor cell resistance.Specifically MnSOD appears to function as a tumor suppressor (TS) during the early proliferativestage of tumor initiation yet once tumorigenesis progresses MnSOD levels appear to positivelycorrelate or contribute to a more aggressive tumor phenotype. In this regard it is hypothesized thatthe acetylation status of K68 directs whether MnSOD functions as a protective homotetramericdetoxification complex versus a monomeric peroxidase enzyme that induces a breast tumorigenicand Tam resistance phenotype. NCI 10817556 8/11/23 0:00 PA-21-071 3R01CA253678-03S1 3 R01 CA 253678 3 S1 "WILLIS, KRISTINE AMALEE" 1/9/21 0:00 12/31/25 0:00 7573491 "GIUS, DAVID " Not Applicable 20 RADIATION-DIAGNOSTIC/ONCOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2023 50736 NCI 32733 18003 Summary - A fundamental theme in personalized cancer medicine is to identify specific subgroupsof patients based on molecular biomarkers and/or tumor signatures which will subsequently benefitfrom new therapeutic strategies including targeted agents. An important and longstanding exampleof this concept is the dependency of a subgroup of breast malignancies on the estrogen receptor(ER) as well as the ER signaling axis. In this regard there is a subgroup of women with ER+ luminalB human breast malignancies that exhibit a significant risk of recurrence due to the development ofresistance to endocrine therapy including Tamoxifen. To address this there is an ongoing searchto define the pathways or molecular mechanism(s) leading to the resistance to endocrine therapy. Asecond significant theme in cancer medicine is based on the idea of oncogene addiction aphenomenon that implies while tumors contain multiple genetic epigenetic signaling and metabolicabnormalities and despite this tumor complexity cell growth and survival can often be impaired bythe targeting of a single driver gene/protein.As such the phenomenon of oncogene addictioninspecific cancers including luminal B breast carcinogenesis provides a scientific rational to identifycarcinogenic drivers in the process luminal B resistance to endocrine therapies. Metabolic stressdue to aberrant reactive oxygen ROS levels is a hallmark of cancer that disrupts mitochondrialphysiology and metabolism leading to an oncogenic addition-like phenotype and resistance toendocrine therapy. Based on these observations it is proposed that K68 acetylation (K68-Ac)promotes a newly discovered monomeric form of MnSOD distinct from the established ROSdetoxification role of tetrameric MnSOD reprograms cellular and mitochondrial metabolism leadingto oncogenic and tumor resistance phenotype. Finally will targeting the MnSOD-K68-Ac axis usinga chemical MnSOD mimic (GC4419) convert endocrine resistance tumors to a sensitive phenotype? 50736 +No NIH Category available Animal Model;Antibiotics;Azithromycin;Biochemical;Biogenesis;Cell Death;Cell Survival;Cells;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Computer software;Coupled;Cytoplasm;Data;Dose;Electron Transport;Enzymes;Event;Exhibits;External Beam Radiation Therapy;FDA approved;Failure;Fluorescence Microscopy;Growth;Homeostasis;Hydrogen Peroxide;Image;Impairment;In Vitro;Macrolides;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mitochondrial DNA;Mitochondrial Proteins;Molecular;Mus;Normal Cell;Oxidation-Reduction;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Property;Prostate;Protein Array;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Radiosensitization;Reactive Oxygen Species;Recurrence;Recurrent Malignant Neoplasm;Regulation;Research Design;Resistance;Resistance development;Resolution;Site;Testing;Therapeutic;Time;Translating;Translational Repression;Translations;Treatment Efficacy;Visualization;Xenograft Model;bioluminescence imaging;cancer cell;cancer heterogeneity;cancer recurrence;cancer subtypes;cancer survival;catalase;fractionated radiation;high risk;improved;in vivo;inhibitor;insight;knock-down;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;mortality;mtTF1 transcription factor;novel;novel therapeutics;overexpression;patient derived xenograft model;prevent;prostate cancer cell;prostate cancer model;prototype;radiation delivery;radiation resistance;radioresistant;response;stable isotope;success;tempol;tumor;tumor growth;tumor heterogeneity Targeting Mitochondrial Redox Capacity to Overcome Cancer Subtype that Regrowth After Radiation PROJECT NARRATIVERadiation-resistant prostate cancer (RR-PCa) is highly unpredictable which frequently results in cancerrecurrence in many patients. This project aims to 1) establish the underlying mechanism(s) of mitochondrialbiogenesis that contribute to RR-PCa cell survival and metabolism and 2) determine if targeting inherentmitochondria and radiation-acquired mitochondria can overcome RR-PCa. The successful completion of thisproject will establish a new and significant therapeutic platform for making radiation therapy more effective. NCI 10817512 9/11/23 0:00 PA-21-071 3R01CA251663-03S1 3 R01 CA 251663 3 S1 "PRASANNA, PAT G" 8/1/23 0:00 3/31/26 0:00 11588541 "CHAISWING, LUKSANA " Not Applicable 6 PHARMACOLOGY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 8/1/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 61648 NCI 45124 16524 ABSTRACT (R01CA251663)Radiation therapy (RT) is widely used to treat localized prostate cancer (PCa). However cancer cells oftendevelop resistance to RT through unknown mechanisms resulting in cancer recurrence. To improve RT thereis a dire need to uncover cellular events that cause cells to become resistant. We previously demonstrated thatPCa heterogeneity particularly in prostate cancers with an abundant mitochondria subpopulation often surviveand regrow after RT (termed radiation resistant prostate cancer or RR-PCa). Elevation of mitochondrial massnumber reactive oxygen species (ROS) and biogenesis markers is acquired in RR-PCa cells. We furtherdemonstrated that knockdown of the mitochondrial biogenesis regulator TFAM (transcription factor Amitochondrial) significantly restored the sensitivity of RR-PCa cells to RT. Hence our overarching hypothesis isthat RT-activated mitochondrial biogenesis via ROS is an acquisition mechanism that drives PCa survival post-RT a premise that will undergo stringent examination in the proposed studies. ROS are known to directly andindirectly regulate mitochondrial homeostasis through fusion fission mitophagy and biogenesis. We screenedFDA-approved drugs in search of compounds that are nontoxic to normal cells and have the ability to raise thelevel of mitochondrial hydrogen peroxide (mtH2O2) in PCa cells while blocking mitochondrial protein translation.We found azithromycin (AZM) a macrolide antibiotic to be an effective prototype compound that possessesboth properties. We further demonstrated that AZM combined with RT enhances the death of PCa cells with anabundant mitochondrial subpopulation compared to AZM or RT alone. Thus we propose to advance our findingsand identify the mechanism(s) that effectively inhibit the survival of post-irradiated cancer cells to improve RTefficacy. The specific aims are: 1) to define the molecular mechanism(s) by which RT-activated mitochondrialbiogenesis promotes cell survival and metabolic adaptations of PCa cells with abundant mitochondria both invitro and in vivo; 2) to determine if overloading mtH2O2 to target inherent mitochondria and RT-acquiredmitochondria while blocking mitochondrial protein translation in RT-acquired mitochondria enhancesradiosensitivity of RR-PCa cells and 3) to improve RT using a mtH2O2 generator and a mitochondrial proteintranslation inhibitor AZM as prototype in an orthotopic mouse xenograft model and a patient-derived xenograftmodel of PCa with activated mitochondrial biogenesis. This study uses state-of-the-art platforms includingreverse phase protein array stable isotope-resolved metabolomics total internal reflection fluorescencemicroscopy with Imaris software TEMPOL-enhanced MRI imaging and a high resolution O2k-FluoRespirometer.The proposed studies are expected to uncover novel molecular insights by which concurrently targetingmitochondrial redox capacity and mitochondrial biogenesis improve RT efficacy in the treatment of RR-PCa. 61648 +No NIH Category available Alanine;Aspartic Acid;Cancer Patient;Cell Death;Cell Line;Cell Survival;Cells;Chromatin;DNA;DNA Damage;DNA Repair;DNA Repair Pathway;Enzymes;Epigenetic Process;Foundations;Genetic Transcription;Genomics;Glutamic Acid;Goals;Growth;Histones;In Vitro;Ionizing radiation;KDM5B gene;Knock-out;Local Therapy;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Measures;Mediating;Modernization;Molecular;Mutate;Non-Small-Cell Lung Carcinoma;Nonhomologous DNA End Joining;Normal tissue morphology;Oncogenic;Pathway interactions;Phosphorylation;Phosphorylation Site;Phosphotransferases;Post-Translational Protein Processing;Predisposition;Radiation;Radiation therapy;Resistance;Role;Signal Transduction;Site;Stress;Therapeutic;Treatment Protocols;Tumor Tissue;ataxia telangiectasia mutated protein;cancer cell;demethylation;enzyme activity;enzyme substrate;gain of function;histone demethylase;homologous recombination;inhibitor;loss of function;mutant;novel;novel strategies;overexpression;palliative;pharmacologic;radiation resistance;recruit;repaired;response;small molecule inhibitor;tumor Post-translational modifications control JARID enzyme activity during DNA damage Project NarrativeThe Jumonji histone demethylases are enzymes that drive cancers uncontrolled growthand allow cancer cells to adapt to therapeutic toxic stress surviving it. Here we proposeto define how a key Jumonji enzyme in lung cancer gets activated when DNA is damagedwith radiation therapy and to find ways to block the activity of this enzyme in order tosensitize non-small cell lung cancers to radiation overcoming radiation resistance. Ourgoal is to make lung tumors exquisitely responsive to radiation therapy locally withoutany damage to normal tissue. NCI 10817495 6/23/23 0:00 PA-21-071 3R03CA273480-01A1S1 3 R03 CA 273480 1 A1S1 "SHARMAN, ANU" 6/1/23 0:00 3/31/25 0:00 8255124 "MARTINEZ, ELISABETH D" Not Applicable 30 PHARMACOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 6/1/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 70955 NCI 47675 23280 Close to 75% of all non-small cell lung cancer (NSCLC) patients receive radiation therapy at some point in theirtreatment regimen whether with curative or palliative intent. Radiation which is currently given in a highlylocalized fashion causes massive DNA damage leading to DSBs and cancer cell death yet on its own is not yetcurative. Indeed while some cancers are intrinsically resistant to IR others acquire resistance by upregulatingDNA repair pathways. Given modern advances in the targeted administration of radiotherapy a paradigm shiftleading to curing NSCLC or other tumors could occur if tumor tissue could be globally sensitized to radiationtherapy. The epigenetic susceptibilities we propose to investigate here may be the key.The oncogenic JARID/KDM5 histone demethylase subfamily of Jumonji enzymes which are overexpressed inmultiple malignancies have recently defined roles in the DNA damage pathway: they mediate DNA repair byerasing trimethyl marks on active chromatin harboring H3K4me3 marks thus stopping transcription andfacilitating the recruitment of both homologous recombination and non-homologous end joining repair factors.The novel concept we propose here is that JARID enzymes must be modified post-translationally upon DNAdamage likely by radiation-activated ATM or ATR kinases to enhance their histone demethylating activity onactive chromatin thus providing a mechanism to stop transcription and recruit repair factors to these sites forcancer-cell survival. If true this novel oncogenic activity of JARID enzymes would have significant implicationsfor developing new approaches to sensitize lung tumors to ionizing radiation (IR) by selectively inhibiting theenhanced demethylase activity of JARID enzymes on chromatin. Our specific aims are to:1.Determine if JARID enzymes are substrates of ATM kinases during the DNA damage response to IR: we will determine by mass spectrometry if JARID1B is phosphorylated by ATM/ATR kinases during the DNA damage response. We will map the site of phosphorylation and will mutate it to alanine (loss of function) or glutamic or aspartic acid (gain of function) to determine the impact on DNA repair dynamics using isogenic cells lines expressing endogenous wt JARID1B (as controls) or null for JARID1B (knock out cells available).2.Define how oncogenic JARID enzyme activity is modulated by post-translational modifications: we will measure the histone demethylase activity of unphosphorylated vs phosphorylated JARID1B enzyme in vitro and in cells. We will also determine the genomic sites JARID1B associates with in control vs. in cells undergoing DNA damage and define if JARID1B recruitment to DSBs is dependent on phosphorylation.In this supplement we will expand the above goals to include a pharmacological approach. We will evaluate ifsmall molecule inhibitors have greater or lesser potency on the loss of function and gain of function JARID1Bmutants compared to the wt enzyme in vitro and in cells alone and in combination with DNA damage.Our study will thus have wide impact to lung cancer patients by providing the molecular and mechanisticfoundation for hypersensitizing tumors to radiation by using Jumonji inhibitors to curtail DNA repair throughblocking the histone signals that trigger this repair. 70955 +No NIH Category available Cancer Therapy Evaluation Program;Clinical;Clinical Distribution;Conduct Clinical Trials;Contract Services;Contracts;Pharmaceutical Preparations;Pharmacologic Substance;Program Development;drug development;repository STORAGE AND DISTRIBUTION OF CLINICAL AGENTS n/a NCI 10817424 75N91023C00002-0-9999-1 N02 2/1/23 0:00 1/31/24 0:00 79045956 "MAHZAD, MEHRINFAR " Not Applicable 8 Unavailable 161157953 LB4PCGLSJ9E6 161157953 LB4PCGLSJ9E6 US 39.099206 -77.133131 3601801 "FISHER BIOSERVICES, INC." ROCKVILLE MD Domestic For-Profits 208505312 UNITED STATES N R and D Contracts 2023 5916500 NCI To support the conduct of clinical trials a non-research repository service contract to provide for receipt storage distribution and final disposition of all clinical agent supplies in support of the CTEP drug development program is required. The objective of the Storage & Distribution of Clinical Drugs contract is to provide support to the Pharmaceutical Management Branch (PMB) within CTEP/ DCTD in maintaining and operating a clinical agent repository facility and project team to receive store distribute and dispose of clinical agent supplies for the conduct of clinical trials world-wide. 5916500 +No NIH Category available 3-Dimensional;Address;BRCA mutations;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Breast;Breast Cancer Prevention;Breast Epithelial Cells;Cells;Complement;DNA sequencing;Data Set;Defect;Development;Ensure;Evolution;Foundations;Funding;Goals;High Risk Woman;High-Risk Cancer;Individual;Inherited;Loss of Heterozygosity;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mammary Gland Parenchyma;Modeling;Monitor;Mutation;Noninfiltrating Intraductal Carcinoma;Normal Cell;Organoids;Pathogenicity;Peptide Sequence Determination;Population;Predisposition;Premalignant Cell;Prevention Measures;Prevention approach;Prevention strategy;Quality of life;Research;Research Project Grants;Role;Single Nucleotide Polymorphism;Technology;Testing;Therapeutic;Tissues;Training;Woman;brca gene;career development;career networking;experience;fitness;high risk;homologous recombination;malignant breast neoplasm;multiple omics;mutant;mutation carrier;parent grant;premalignant;programs;prophylactic mastectomy;protein expression;single cell analysis;single cell technology;skills;symposium;tumor;tumor initiation;tumor progression;tumorigenesis Tracking the evolution of breast cancer through single cell analyses of premalignant breast tissues from women at high risk for cancer development Project NarrativeThe only effective means of breast cancer prevention in women with inherited BRCA1 orBRCA2 mutations is prophylactic mastectomy but issues related to quality of life and otherconsequences highlight the need for better prevention strategies. This research project aims todevelop more effective non-invasive tumor prevention approaches for high-risk mutationcarriers by using single-cell technologies to profile genetic alterations in individual cells fromnormal breast tissues of women with wild-type or mutant BRCA1/2. We have identifiedexpanded populations of ostensibly normal cells carrying copy number alterations (CNAs) andpathogenic single nucleotide variants (SNVs) in breast tissues of high-risk mutation carriers andwill further investigate whether these genetic alterations predispose cells to survive loss ofheterozygosity of BRCA1/2 and/or to progress to malignant cancer. NCI 10817308 8/14/23 0:00 PA-21-071 3R35CA242428-05S1 3 R35 CA 242428 5 S1 "HILDESHEIM, JEFFREY" 9/1/19 0:00 8/31/26 0:00 ZCA1(M1) 2211633 "BRUGGE, JOAN SIEFERT" Not Applicable 7 ANATOMY/CELL BIOLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 114535 NCI 67572 46963 Prophylactic mastectomy is currently the only breast cancer prevention strategy for women with inherited BRCA1or BRCA2 mutations. While often effective this strategy significantly impacts quality of life and does not preventthe development of cancers arising in other tissues (e.g. pancreatic and prostate cancers). Thus betterinterception strategies are urgently needed. The overall goal of the parent grant is to characterize the earliestalterations in breast tissues in individuals at high risk of developing breast cancer and to lay the groundwork forthe discovery of new prevention measures. Our collaborative studies with Dr. Sam Aparicio using single-cell copynumber analyses have identified expanded population of ostensibly normal breast epithelial cells from BRCA1/2mutation carriers that carry copy number alterations (CNAs). Interestingly these CNAs are among those that aremost commonly associated with early (DCIS) and established (IBC) forms of breast cancer and are present priorto BRCA1/2 loss of heterozygosity (LOH) suggesting that these changes may predispose mammary epithelialcells to tumor-initiating genetic alterations. This supplement proposal aims to test the overarching hypothesisthat the genetic alterations that occur prior to LOH of BRCA1 or BRCA2 allow cells to survive eventual loss ofboth copies of BRCA1 or BRCA2 thereby increasing their cellular fitness and predisposition to malignant cancerfollowing accumulation of additional genetic alterations caused by defects in homologous recombination. Weplan to address this hypothesis by 1) complementing our CNA analysis by determining the single nucleotidevariant and mutational landscape of precancerous breast tissues using the Tapestri Platform (MissionBio) astate-of-the-art targeted single cell DNA and protein sequencing technology and 2) utilizing 3D breast organoidmodels to determine the functional role of CNAs/SNVs in survival after loss of BRCA1/2 and whether additionalalterations downstream result in sensitization to tumor development. A better understanding of how earlyCNAs/SNVs influence tumorigenesis can lead to the identification of vulnerabilities of these cells in order toeliminate them before cancer progresses as well as to develop strategies to detect expansion of aberrant cellsas a means of monitoring pre-malignant cell expansion. Importantly accomplishing the goals of this proposal willenable Dr. Oliphant to further strengthen the computational skills needed to analyze single-cell multiomic DNA-seq and protein expression datasets independently as well as leverage 3D organoid models to identify anddevelop actionable therapeutic strategies more effectively. It will also provide Dr. Oliphant with opportunities forengagement in various career development experiences including participating at conferences and expandinghis professional network. Overall the funding of the proposed project will ensure that Dr. Oliphant expands hisscientific and professional training while establishing the foundation for a viable independent academic researchprogram. 114535 +No NIH Category available Acetylation;Actins;Adjuvant Chemotherapy;Affect;Animal Model;Antineoplastic Agents;Apoptotic;Behavior;Biomedical Engineering;Blood Circulation;Blood capillaries;Breast Cancer Cell;Breast Cancer Treatment;Breast Epithelial Cells;CRISPR/Cas technology;Calcium;Calcium Signaling;Cancer Etiology;Cancer Patient;Cell membrane;Cells;Cessation of life;Chemicals;Clinical Treatment;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Desmosomes;Digitoxin;Disease;Distant;Epithelium;Equilibrium;Extracellular Matrix;FDA approved;Foundations;Genes;Genetic;Growth;Hour;Image;In Vitro;Invaded;Lung;Lymphatic;MCAM gene;Mediating;Metastatic breast cancer;Metastatic/Recurrent;Methods;Microfluidics;Microscopy;Microtubule Stabilization;Microtubules;Modeling;Molecular;Mus;Neoadjuvant Therapy;Neoplasm Circulating Cells;Neoplasm Metastasis;Operative Surgical Procedures;Organ;Ouabain;Outcome;Paclitaxel;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphotransferases;Post-Translational Protein Processing;Prognosis;Proteins;Regulation;Resistance;Risk;Role;Surface;System;Techniques;Testing;Therapeutic;Tissues;Translating;Tubulin;Tumor Promotion;Xenograft procedure;Zebrafish;cancer therapy;cell determination;cell growth;cell motility;drug development;drug discovery;improved;in vivo;inhibitor;innovation;malignant breast neoplasm;mechanical properties;mechanotransduction;neoplastic cell;novel therapeutics;patient derived xenograft model;precision medicine;pressure;response;side effect;standard of care;targeted cancer therapy;therapeutic target;treatment strategy;triple-negative invasive breast carcinoma;tumor;whole animal imaging Single cell determination of ROS and calcium roles in breast cancer apoptotic resistance This project will test the role of actin cortical contraction in microtentacle formation and theclustering of circulating breast tumor cells. The PIs lab has established the counterbalancebetween MT extension and actin cortical contraction and identified specific molecularmechanisms to alter this balance. Innovative bioengineering approaches animal models PDXand live patient CTCs will be used to test these mechanisms of targeting the actin cortex to reducemicrotentacles. NCI 10817296 9/6/23 0:00 PA-21-071 3R01CA124704-13S1 3 R01 CA 124704 13 S1 "AULT, GRACE S" 6/1/07 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 6948120 "MARTIN, STUART S" Not Applicable 7 PHARMACOLOGY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 84842 NCI 54914 29928 Tubulin microtentacles in detached mammary epithelial cells. Breast tumor cells metastasize to distant organs through non-adherent microenvironments such as thebloodstream or lymphatics. However very little is known about the dynamic behavior and drug responses ofnon-adherent tumor cells due to the challenges of imaging non-adherent cells without blurring from cell drift. The PIs lab discovered unique microtentacles (McTNs) on the surface of non-adherent tumor cells thatpromote the aggregation and retention of circulating tumor cells (CTCs) in the lung capillaries of living mice. This project will test the hypothesis that actin cortical contraction regulates molecular mechanisms underlyingMcTNs and can be targeted through independent pathways to reduce the clustering and reattachment of CTCsduring metastasis. Predictions of this hypothesis will be tested in the following specific aims.Specific Aim 1: Inhibit kinases regulating actin cortical contraction to impact McTNs.A) Define impact of pathway inhibitors on microtentacles and supporting molecular mechanisms.B) Analyze inhibitor impacts on tumor cell mechanical properties (Brillouin microscopy AFM).C) Test prioritized drugs in zebrafish (CTC reattachment) mice (orthotopic PDX) and live patient tumor cells.Specific Aim 2: Test role of X-ROS mechanotransduction on McTN mechanisms and function.A) Chemically inhibit TRPM8 and calcium signaling to influence McTN mechanisms.B) Gauge effects of pathway inhibitors on MCAM and genetically regulating MCAM or TRPM8 (CRISPR).C) Test prioritized mechanotransduction genes and drugs in zebrafish mice and patient tumor cells.Specific Aim 3: Target mechanisms of McTN-mediated tumor clustering.A) Define McTN mechanisms that inhibit homotypic/heterotypic clustering with Digitoxin or Ouabain.B) Downregulate desmosomal protein DSG3 to reduce McTN-mediated tumor cell clustering.C) Test prioritized anti-clustering mechanisms in zebrafish mice and live patient tumor cells.This project will use innovative bioengineering techniques (TetherChip Brillouin microscopy) and examinehighly-conserved mechanotransduction principles (X-ROS) recently identified by the PIs lab in epithelial tumorcells. Inclusion of FDA-approved therapies and drugs in current clinical trials will increase the potential to rapidlytranslate the outcomes of this project to impact the clinical treatment of metastatic breast cancer. 84842 +No NIH Category available Acceleration;Accreditation;Aerobic;American College of Surgeons;Area;Cancer Burden;Cancer Center;Cancer Death Rates;Cancer Patient;Cancer Survivor;Cancer Survivorship;Caring;Colorectal Cancer;Community Hospitals;Data;Diffusion;Disease;Dissemination and Implementation;Educational workshop;Effectiveness;Equity;Evidence based intervention;Exercise;Extramural Activities;Funding;Future;Goals;Guidelines;Health;Health system;Healthcare;Hospitals;Incidence;Infrastructure;Institution;Intervention;Intervention Trial;Interview;Iowa;Kentucky;Life Style;Malignant Neoplasms;Measures;Mental Health;Methods;Modeling;Monitor;Muscle Weakness;Muscular Atrophy;National Cancer Institute;Osteopenia;Osteoporosis;Outcome;Parents;Pathway interactions;Patients;Performance;Persons;Physical Function;Physical activity;Population;Prevalence;Process;Provider;Quality of Care;Quality of life;Readiness;Recreation;Research;Resource-limited setting;Resources;Rural;Rural Community;Rural Hospitals;Rural Population;Services;Specialist;Structure;Supportive care;Survivors;Testing;Time;Translational Research;United States;Universities;Well in self;Work;acceptability and feasibility;age related;aging in place;behavior change;cancer care;cancer diagnosis;cancer health disparity;cancer therapy;career development;clinical development;community engaged research;community setting;data registry;design;dissemination science;empowerment;evidence base;exercise intervention;exercise program;experience;health difference;health disparity populations;implementation barriers;implementation outcomes;implementation process;implementation science;implementation strategy;improved;insight;malignant breast neoplasm;mortality;neoplasm registry;network models;novel;personalized approach;physical conditioning;physical inactivity;post intervention;preference;programs;psychosocial;randomized trial;rural area;rural disparities;rural dwellers;rural patients;rural setting;sarcopenia;strength training;survivorship;theories An exploration of pathways for exercise referrals in rural cancer community settings PROJECT NARRATIVEThe 60 million rural residents of the United States have a lower rate of new cases of cancer per year comparedto urban residents but have a higher rate of cancer deaths per year partly due to the greater difficulty inaccessing high-quality cancer treatment in rural areas. As rural patients are less likely to receive care in urbancancer centers with cancer specialists who treat very large numbers of cancer patients an effective strategyused by the University of Kentucky Markey Cancer Center has been to share their expertise and resourceswith smaller community hospitals across Kentucky to help improve their quality of care. We propose to studythe Kentucky model in order to identify and characterize its core functions (i.e. what made it effective inimproving quality of care in community hospitals) adapt it to a new rural setting and determine its value to thehospitals and impact on cancer care. NCI 10815891 9/21/23 0:00 PA-21-071 3R01CA254628-03S1 3 R01 CA 254628 3 S1 "WEAVER, SALLIE JAYNE" 4/1/21 0:00 3/31/26 0:00 ZCA1(O1) 9839628 "CHARLTON, MARY E." Not Applicable 1 PUBLIC HEALTH & PREV MEDICINE 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF PUBLIC HEALTH 522421320 UNITED STATES N 7/1/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 114630 NCI 73717 40913 PROJECT SUMMARY/ABSTRACTThere is growing evidence that limited access to high-quality cancer treatment is one of the main drivers ofhigher cancer mortality rates among rural cancer patients. Our analyses of Iowa Cancer Registry data indicatethat 40% of rural patients with breast and colorectal cancers receive most or all definitive treatment in ruralhospitals that do not collect or monitor data on their quality of cancer care and are not accredited by theAmerican College of Surgeons Commission on Cancer (CoC). Our data also shows these patients are lesslikely to receive guideline-concordant care. Given patients needs and preferences to receive cancer carelocally a promising strategy to improve quality of cancer care and outcomes in rural populations is to intervenedirectly with the community hospitals in these areas. New evidence has demonstrated effectiveness of thisapproach: the Markey Cancer Center Affiliate Network (MCCAN) was formed by the University of Kentucky(UK) Markey Cancer Center to improve quality of cancer care in their own rural low-resourced state one thatleads the nation in cancer incidence and mortality. Over the last decade MCCAN has facilitated the sharingand diffusion of resources and best practices throughout their network. As a result affiliates markedlyimproved performance on established cancer care quality measures and expanded their services (e.g.psychosocial and survivorship support). They were also almost 3 times more likely to obtain CoC accreditationthan their matched controls. However the MCCAN model has not been rigorously defined evaluated or testedin any other setting. We propose to adapt this successful health system-level intervention for Iowa establishingthe Iowa Cancer Affiliate Network (I-CAN). Although there are similarities between Iowa and Kentuckyspopulations that suggest the MCCAN model may be a good fit there are also significant differences inhealthcare infrastructure and resources that require careful adaptation of the intervention prior to itsimplementation in order to retain its effectiveness. We will use novel rigorously developed theory-basedimplementation science methods to identify MCCANs core functions (i.e. what makes it effective) study theimplementation process and evaluate how I-CAN performs in a new context. We have identified 4 rural Iowahospitals to participate in this intervention trial and developed expert support teams to assist key stakeholdergroups within each hospital. Through interviews and qualitative analyses we will assess determinants andoutcomes of the implementation process and perceived value of the CoC accreditation standards and theintervention itself as a way to improve the quality of cancer care for their patients. We will compare compliancewith treatment-related quality measures and the proportion of CoC standards of cancer care implemented intarget and control hospitals pre- and post-intervention using a difference-in-difference estimator. This workcould lead to dissemination of similar models across rural settings thereby improving quality of care reducingrural disparities in cancer outcomes and giving rural hospitals an avenue to demonstrate their quality of care. 114630 +No NIH Category available Accreditation;Agreement;Certification;Contractor;Elements;Engineering;Ensure;Exhibits;Government;Guidelines;Hour;Maintenance;Regulation;Specific qualifier value;Work FY22 CONSOLIDATED FACILITIES TASK ORDER C n/a NCI 10815680 75N91019D00024-P00016-759102100006-1 N01 5/19/21 0:00 9/25/24 0:00 78180827 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 4884124 NCI In accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick. The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs. The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines. 4884124 +No NIH Category available Acceleration;Accreditation;Agreement;American;Area;Authorization documentation;Award;Budgets;Businesses;Certification;Code;Computer software;Contingency Fund;Contractor;Contracts;Cost Control;Critical Pathways;Data;Development;Documentation;Effectiveness;Elements;Engineering;Ensure;Event;Exhibits;Expenditure;Feedback;Funding;Government;Growth;Guidelines;Hour;In complete remission;Infrastructure;Maintenance;Manuals;Marketing;Methodology;Monitor;Notification;Parents;Performance;Policies;Procedures;Process;Professional Organizations;Quality Control;Reaction Time;Recovery;Regulation;Reporting;Schedule;Services;Site;Specific qualifier value;Strategic Planning;System;Techniques;Time;United States National Institutes of Health;Work;authority;cost;cost estimate;design;improved;indexing;meetings;operation;professional atmosphere;programs;quality assurance;risk mitigation FY22 Facilities Task Order B Refurbishment and Infrastructure Projects focused on Facility Improvements within the NCI at Frederick Campus n/a NCI 10815678 75N91019D00024-P00004-759102200008-1 N02 4/26/22 0:00 10/24/25 0:00 78650929 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1201616 NCI Statement of Work Appendix: General Requirements FY22 Facilities Task Order B Refurbishment and Infrastructure Projects focused on Facility Improvements within the NCI at Frederick Campus1. General RequirementsIn accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick. The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs. The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines. 2. Facility Operations & Management of Planned WorkThe Contractor shall work closely with the Government to determine needs and priorities associated with customer requirements. The Contractor shall coordinate with EHS during project concept design and closeout to ensure project milestones submitted in project schedules are reflective of both FME and EHS requirements. a) Planned Work ManagementThe Contractor shall have the authority to manage all aspects of work orders to include but not limited to the use of approved project budget schedule and project quality. The Contractor shall estimate the project contingency needs using qualitative and quantitative metrics approval must be obtained in accordance with the task order terms and conditions prior to any release of contingency funds. The Contractor shall keep the customer and FME COR informed of project progress. All project changes must follow Facility Change Management process. During task order performance when an impact to scope cost schedule or performance is identified the Contractor shall notify the Government by inclusion in the monthly progress notification. If the critical path is changed the notification shall include an explanation of the cumulative events that resulted in the change Fragnet and risk mitigation strategy including schedule recovery and/or acceleration. Contractor shall coordinate across all directorates to ensure each project has an integrated Master Schedule. b) Planned Work CloseoutThe Contractor shall work collaboratively with the FME COR to establish standard practices for project closeout. The Contractor shall consistently apply closeout practices. Contractor shall ensure project09/26/20192close-out consideration in scope/cost/schedule account for processes across all Contractor business directorates.3.Facility Strategic PlanningAs a component of the development and ongoing growth and refinement of the Facilities Operations Manual required per the parent IDIQ the Contractor shall continually assess and analyze all aspects of Facility Maintenance and Engineering activities. The Contractor shall seek to consider procedures to improve efficiency in facilities maintenance engineering and renovation/ alteration/ maintenance/ refurbishment/ improvement projects. The Contractor shall to seek to identify improvements in all aspects of performance that will increase the effectiveness or efficiency of contract performance. Identified improvements shall align with Government requirements customer feedback and stakeholder input.4.Quality Assurance/Quality Control (QA/QC)Contractor shall develop and maintain a baseline program of quality assurance (QA) and quality control (QC) that will document performance and quality standards and management controls and assessment techniques to ensure components services and products meet HHS/NIH/NCIs design criteria and other governing and applicable specifications. The Contractor shall identify policies and procedures to improve performance and efficiencies in all project areas. The Contractor shall establish and maintain an effective quality control (QC) system. QC consist of plans procedures and organization necessary to produce a product which complies with the Contract requirements.Contractor shall provide Construction Quality Management (CQM) plan to ensure that work is performed according to plans and specifications on time within a defined budget and a safe work environment. Contractor shall provide a detailed Quality Control Plan (QCP) for all projects > $50000.00 contractor shall identify certified Quality Control Manager for all projects >$1m. The contractor has primary responsibility for compliance with plans and specifications.5.Cost control (EstimatingThe Contractor shall use historical data market analysis and RS Means software to develop cost estimates of any change requests and/ or impact analysis reports. The Contractor must adhere to the requirements established in the DRM (Section 1.6.3). The Contractor shall also follow American Society of Professional Estimators (ASPE) methodology.6.MeetingsThe following meetings between the Contractor and NCI designated representatives are held non-severable projects awarded on task orders shall be included in content and discussions as applicable:1)FME Operations Meeting (Weekly)This meeting to include FME MOSB and FME COR shall be held weekly to review and discussprogram operational priorities and performance.2)Plan of the Week (POW) Meeting (Weekly)09/26/20193This meeting to include FME EHS Program Representatives MOSB OSO and FME and EHS CORs shall be held weekly to review status of all new work orders work orders in development and approved work orders.7.Tracking and Monitoring of MetricsUnder the requirements of the NCI FFRDC Operational Task Order the Contractor and the FME COR shall identify Key Performance Indicators that have designated targets. Once identified the Contractor shall track and monitor metrics to the identified KPIs. For planned work awarded under non-severable task orders the Contractor shall track and monitor at a minimum the following metrics:Percentage of Work orders (WO) rescheduled from the initial approved schedule.Work order expenditure by type:oGeneral Work OrderoInspectionoEmergencyoCorrective MaintenancePercentage of Planned WOs verses all other WOsBacklog (Funding threshold)oSpecial AssistsWork order backlog including 30+ days total and per shopWork order completion response time per shopShop support to FME Planned Work Orders hours and percent of total8.ContingencyContingency notifications shall include:1-Narrative explanation of need for contingency use2-Contingency log tracking each instance of contingency use amount subtotal and remainingbalance3-Contingency Index CalculationContingency Index = Physical % Complete / % Contingency Expended.4-Supporting documentation as applicable including but not limited to:PCORFIsBulletinsSubmittalsChange order code:oAE error omissionsoUnforeseen site conditionsoUser directed change requestsInspectionsSchedule change -Fragnet09/26/20194Additional contingency requirements:1.If LBRs Best & Final subcontractor award is lower than LBR subcontractor estimateper NCI award amt then all excess funds must be returned to NCI controlled reservewithin 15 business days.2.LBR Direct labor cannot use project contingency unless approved by NCI FME CORand CO.3.NCI Reserves the right to request additional information 1201616 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10815677 261201800013I-P00009-26100001-2 N01 5/1/18 0:00 4/30/23 0:00 78147083 "DURBIN, ERIC " Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N R and D Contracts 2023 2834405 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 2834405 +No NIH Category available Cancer Model;Retroviridae Retrovirus models of cancer P01CA100730 Diversity Supplement Project NarrativeNo changes from originally proposed project. NCI 10815100 7/7/23 0:00 PA-21-071 3P01CA100730-19S1 3 P01 CA 100730 19 S1 "READ-CONNOLE, ELIZABETH LEE" 4/21/03 0:00 5/31/25 0:00 ZCA1(M1) 1866427 "GREEN, PATRICK LEE" Not Applicable 3 VETERINARY SCIENCES 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF VETERINARY MEDICINE 432101016 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 76801 NCI 54467 22334 Project Summary/AbstractNo changes from originally proposed project. 76801 +No NIH Category available Acceleration;Adult;American;Biological;Biological Markers;Calories;Cancer Control;Cancer Etiology;Cancer Survivor;Cancer Survivorship;Carcinogens;Caring;Cessation of life;Cohort Studies;Colorectal Cancer;Consumption;Counseling;DNA Damage;Data;Diagnostic;Diet;Dietary Component;Dietary Intervention;Dietary intake;Disease;Eating;Etiology;Follow-Up Studies;Food;Food Processing;Gene Mutation;Genomics;Goals;Health Professional;Inflammatory Response;Intake;Intervention;Link;Long Term Survivorship;Malignant Neoplasms;Measures;Mentorship;Modeling;Molecular;Mutation;Nurses' Health Study;Nutrition Policy;Nutritional Science;Obesity;Oncology;Participant;Pathway interactions;Patients;Phase;Plasma;Postdoctoral Fellow;Process;Processed Meats;Prognosis;Prospective cohort study;Public Health Schools;Recommendation;Relative Risks;Research;Research Project Grants;Research Training;Risk Assessment;Risk Estimate;Risk Factors;Role;Sampling;Schools;Somatic Mutation;Testing;Translating;Tumor Markers;Tumor Tissue;Woman;attributable mortality;biomarker identification;cancer diagnosis;cancer statistics;cancer survival;cancer therapy;career;career development;circulating biomarkers;clinical practice;cohort;colon cancer patients;colorectal cancer progression;colorectal cancer risk;comparative;design;dietary;epidemiologic data;epidemiology study;exome sequencing;food consumption;improved;innovation;insight;men;metabolomics;mortality;negative affect;novel;novel marker;nutrition;precision nutrition;precision oncology;risk stratification;skill acquisition;survival outcome;trend;tumor;tumor microenvironment;tumor progression Integrated Epidemiologic Study of Ultra-processed Foods and Colorectal Cancer Survival PROJECT NARRATIVE Ultra-processed foods (UPFs) are emerging as an important risk factor for colorectal cancer (CRC) and may negatively affect survival outcomes. The proposed research will study how UPFs and the molecular correlates can impact CRC survival leveraging large cohorts and integrating metabolomic profiling and whole-exome sequencing data. This timely innovative research will inform dietary recommendations for CRC patients contribute to the discovery of novel actionable targets with the potential use in precision nutrition and oncology care and provide new insights into the design of nutrition interventions to improve long-term CRC survivorship. NCI 10815098 7/3/23 0:00 RFA-CA-21-059 4K00CA274714-02 4 K00 CA 274714 2 "ELJANNE, MARIAM" 8/1/22 0:00 7/31/27 0:00 ZCA1-PCRB-H(M1) 15030536 "DU, MENGXI " Not Applicable 7 NUTRITION 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 91332 NCI 84900 6432 PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) remains a leading cause of cancer deaths in the US and is one of the cancers most strongly associated with a suboptimal diet. Within various dietary components ultra-processed foods (UPFs) are emerging as an increasingly important risk factor for CRC. UPFs make up nearly 60% of Americans daily calories. A high UPF intake may increase CRC risk or worsen its prognosis through altered metabolites that may impact glycemic or inflammatory responses or tumor microenvironment resulting in cancer progression. Food processing may also introduce carcinogens and certain UPF components can contribute to somatic mutations. Besides a high UPF intake is associated with excess intake of calories leading to adiposity an established risk factor for CRC. Thus UPFs could be an important dietary risk factor for CRC progression and yet the UPF-CRC survival has not been adequately studied. While evidence suggests that CRC progression is associated with metabolites modulated by diet the metabolomic profiles associated with UPFs remain to be characterized. Constituents of UPFs such as red or processed meats have been related to alkylating DNA damage and increased CRC mortality yet the role of UPFs remains unclear. These unknowns highlight the critical need to comprehend the association between UPFs and CRC survival and the molecular determinants of this relationship for improving long-term CRC survivorship. Well-established large prospective cohort studies are crucial to offering rigorous data to elucidate the diet-disease association and infer causality. Advances in high-throughput metabolomic profiling and whole-exome sequencing (WES) show great promise to identify sensitive biomarkers that could better predict the diet-disease relationships. The overarching research goal of this F99/K00 proposal is to investigate the role of UPFs in CRC survival by integrating high throughput -omics and detailed dietary data collected among men and women from large cohorts. The F99 phase will focus on investigating the association between UPF intake and deaths due to CRC and all causes among CRC survivors (Aim 1); the K00 phase will shift the focus to investigating the molecular correlates of UPF-CRC survival relationship by integrating metabolomics profiling and tumor WES data and exploring the feasibility of a pilot intervention to reduce UPF intake among CRC patients (Aim 2). The research findings will inform dietary recommendations for CRC survivors accelerate the discovery of novel biomarkers to pave the way for precision nutrition in oncology care and provide new insights into nutrition interventions for improving the long-term survivorship of CRC. Under the mentorship of sponsors at Tufts Friedman School of Nutrition Science and Policy and Harvard T.H. Chan School of Public Health the candidate will acquire rigorous research training and professional and career development skills for transition to an independent research career focus on studying the role of nutrition in cancer control and translate evidence into effective nutrition interventions and clinical practices to improve cancer survivorship. 91332 +No NIH Category available Address;Administrative Supplement;Adoption;Advanced Malignant Neoplasm;Award;Awareness;Breast Cancer Detection;Cancer Center;Cancer Control;Cancer health equity;Caring;Certification;Characteristics;Clinical;Collaborations;Colorado;Communication;Communities;Competence;Continuity of Patient Care;Cost Analysis;Data;Development;Diagnosis;Documentation;Electronic Health Record;Equity;Evidence based program;Face;Financial Hardship;Goals;Guidelines;Health;Hospitals;Housing;Incidence;Individual;Inequity;Infrastructure;Intervention;Malignant Neoplasms;Measurement;Measures;Mentors;Methods;Modeling;Monitor;Morbidity - disease rate;Oncology;Outcome;Parents;Pathway interactions;Patient-Focused Outcomes;Patients;Phase;Pilot Projects;Population;Practical Robust Implementation and Sustainability Model;Primary Care;Process;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Reporting;Research;Research Personnel;Resources;Risk;Risk Factors;Rural;Science;Screening for cancer;Screening procedure;Shapes;Site;Standardization;Surveys;Testing;Time;Training;Translating;Transportation;Work;cancer care;cancer prevention;cancer therapy;care providers;career;certificate program;colon cancer screening;contextual factors;cost;design;evidence base;experience;food insecurity;forest;health assessment;health care disparity;health equity;health inequalities;implementation science;implementation strategy;implementation study;improved;innovation;interest;lung cancer screening;mortality;outreach;patient health information;pilot test;practice setting;pragmatic implementation;preference;primary care practice;primary care setting;programs;screening;shared decision making;smoking cessation;social;social health determinants Phase 2 ISC3 Administrative Supplement for Advancing Health Equity through Implementation Science Project Narrative (from parent award P50 CA244688)We propose an Implementation Science Center for Cancer Control with a focus of developing validating andsharing innovative pragmatic models and methods related to the costs benefits and value of translatingevidence-based cancer control programs and guidelines into rural primary care practice settings. Our theme isPragmatic implementation science approaches to assess and enhance the value of cancer prevention andcontrol in rural primary care. These approaches will inform strategies to implement lung cancer screening andother cancer prevention and control interventions and advance implementation science by providing measuresreporting guides resources training and certification of competence. NCI 10814693 8/29/23 0:00 PA-20-272 3P50CA244688-05S1 3 P50 CA 244688 5 S1 "VANDERPOOL, ROBIN CLINE" 9/20/19 0:00 8/31/24 0:00 ZCA1(A1) 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 FAMILY MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 125000 NCI 80386 44614 Project Summary/Abstract (from parent award P50 CA244688)The theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. 125000 +No NIH Category available Advanced Development;Antibody-drug conjugates;Atlases;CAR T cell therapy;Cancerous;Cell Line;Cell secretion;Cell surface;Cells;Child;Communities;Data;Data Set;Databases;Development;Disease;Excision;Feedback;Funding;Future;Gene Expression;Genes;Genotype-Tissue Expression Project;Goals;Grant;Human BioMolecular Atlas Program;Human Gene Mapping;Human body;Immunotherapy;Individual;Mining;Molecular Target;Normal tissue morphology;Ontology;Organ;Patients;Physiology;Process;Protein Secretion;Proteins;Research;Research Personnel;Resources;Surface;The Cancer Genome Atlas;Time;Tissues;Visualization;Work;bioinformatics tool;cell type;computerized data processing;document outlines;experience;improved;individual patient;information organization;knowledge integration;neoplastic cell;novel;online resource;protein expression;repository;single-cell RNA sequencing;statistics;transcriptome sequencing;tumor;web server ARCHS4: Massive Mining of Publicly Available RNA Sequencing Data NarrativeThe project will combine data from HuBMAP and ARCHS4 for the purpose of identifying personalized targets forthe development of novel immunotherapies. The identification of cell-surface targets in tumors from individualpatients is a critical initial step in the development of novel antibody-drug conjugates and CAR T-cell therapies. NCI 10814654 8/21/23 0:00 PA-20-272 3U24CA264250-02S1 3 U24 CA 264250 2 S1 "LI, JERRY" 9/1/22 0:00 8/31/27 0:00 ZCA1(M1) 7869507 "MA'AYAN, AVI " Not Applicable 13 PHARMACOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 150000 OD 88758 61242 SummaryThis supplement project will contribute to the enhancement of the TragetRanger and GeneRanger web-basedresources. The work will include: 1) Adding HuBMAP as an additional background atlas for GeneRanger andTargetRanger; 2) Providing the HuBMAP team with feedback about our experience with processing and utilizingthe HuBMAP data for incorporation it in GeneRanger and TargetRanger; and 3) Upgrading GeneRanger andTargetRanger box plot visualizations to organize the information in ontological hierarchies that group togethercells into tissues and tissues into organs. The project will be a supplement to the NCI ITCR U24CA264250 grantthat was funded to support the advanced development of the widely accessed resource ARCHS4. Dataprocessed from ARCHS4 is already incorporated into GeneRanger and TargetRanger but it is currently notorganized into hierarchies. In addition TargetRanger is mainly useful for discovering novel targets for identifyingand removing cancerous cells in tumors. Hence the incorporation of HuBMAP data as normal tissue backgroundwill further strengthen our ability to distill useful targets for the removal of specific cells from tumors while causingminimal damages to normal healthy cells and tissues throughout the human body. Our goal is to make HuBMAPand ARCHS4 data more accessible to researchers while enabling comparisons with other atlasing projects. Byprocessing and incorporating HuBMAP datasets into GeneRanger and TargetRanger resources we can identifyways to improve the accessibility of HuBMAP data for others seeking to utilize it for analysis and for addingvalue to bioinformatics tools and databases. We believe that this knowledge integration effort will enhance theutility of HuBMAP ARCHS4 as well as GeneRanger and TargetRanger for the research community. 150000 +No NIH Category available Address;Administrative Supplement;Adopted;Adoption;Appointment;Cancer Control;Caring;Clinic;Clinical;Collaborations;Colonoscopy;Communication;Communities;Community Health;Data Set;Databases;Decision Making;Documentation;Electronic Health Record;Ensure;Evaluation;Federally Qualified Health Center;Financial Hardship;Funding;Healthcare;Healthcare Systems;Informatics;Intervention Studies;Laboratories;Lead;Learning;Malignant Neoplasms;Medicaid;Methods;Modeling;Patients;Persons;Phase;Population;Positioning Attribute;Preparation;Prevention;Primary Care;Process;Recommendation;Reporting;Resources;Risk;Role;Rural;Screening for cancer;Series;Services;Site;Social Work;Social Workers;Testing;Transportation;Universities;Variant;Washington;Work;design;food insecurity;guidebooks;health equity;health inequalities;housing instability;implementation science;implementation strategy;improved;member;patient navigation;patient screening;pilot test;primary care clinic;primary care practice;rapid test;referral services;response;rural area;social;social health determinants;social interventions;tool;user centered design;waiver Advancing Health Equity through Implementation Science: Phase II Administrative Supplement NARRATIVESocial determinants of health and its downstream social risks such as housing instability food insecurity andfinancial strain are key drivers of cancer health inequities; healthcare systems engagement in identifying andaddressing social needs is a new and evolving field. As limited resources exist to guide healthcare clinics inselecting implementing and optimizing social service resource locators (SSRLs) for their specific context thepurpose of this supplement is to draw on learnings from our teams previous pilot efforts in supporting clinicsadoption of different SSRL approaches to develop a pragmatic guide for implementation of social risk referral-making and documentation. This activities proposed herein will lead to a public guide that can immediately bedisseminated across ISC3 members community partners and nationwide. NCI 10814629 7/10/23 0:00 PA-20-272 3R01CA237322-04S2 3 R01 CA 237322 4 S2 "SARMA, ELIZABETH ANNE" 9/1/19 0:00 8/31/24 0:00 12262879 "HENRIKSON, NORA B" "BANEGAS, MATTHEW P" 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 353 Non-SBIR/STTR 2023 113376 NCI 69132 44244 SUMMARYSocial determinants of health and its downstream social risks such as housing instability food insecurity andfinancial strain are key drivers of cancer health inequities. Healthcare systems engagement in identifying andaddressing social needs is a new and evolving field. In particular limited resources exist to guide healthcareclinics in selecting implementing and optimizing social service resource locators (SSRLs) for their specificcontext. The purpose of this supplement is to draw on learnings from our teams previous pilot efforts insupporting clinics adoption of different SSRL approaches to develop a pragmatic guide for implementation ofsocial risk referral-making and documentation. This supplement is a collaborative effort across four ISC3Centers: BRIDGE-C2 Harvard ISCCCE OPTICC (Optimizing Implementation in Cancer Control) Center andWashington University-ISC3. We propose to: (1) develop a pragmatic applied guidebook (the Guide) for clinicsseeking to implement expand or optimize efforts to address patient-reported social risks using Assistancestrategies; (2) use rapid-cycle testing to identify best practices for implementing the Guide; and (3) iterate anddisseminate the refined Guide. In Aim 1 we will develop a pragmatic Guide to help primary care practices: 1)select an Assistance strategy and a related SSRL approach and associated workflows for conducting thesestrategies in practice including documenting social risk referrals; and 2) adopt optimize and sustain theseworkflows. Subsequently in Aim 2 we will 1) provide the Guide to diverse clinics (urban and rural FederallyQualified Health Centers; primary care clinics) at different stages of SSRL implementation in three ISC3laboratories; 2) identify facilitators and barriers to implementing the Guide; and 3) identify the support neededto use the Guide. ISCCCE OPTICC and WU-ISC3 will use a series of rapid cycle turns with their clinicalpartner sites. We will use the Phase I supplement outer context dataset to identify key social resource needsthat should be addressed in each clinic setting and rapid cycle testing using user-centered designed methodswill be used to refine the Guide based on pilot learnings. Rapid tests using OPTICC state II methods of smallchanges for improvement will be tracked systematically. We will also track the implementation strategies usedto support the Guides use whether provided by ISC3 center staff or participating clinic sites. Clinics wereselected to ensure variation in the community vital signs associated with the populations they serve asdetermined using our outer contextual database that was developed in Phase 1 and in the stages ofimplementing Assistance strategies increasing generalizability. Finally in Aim 3 we will finalize refining theGuide based on the findings of Aim 2 and disseminate it as a public good. Ultimately this proposal will lead apublic guide that can immediately be disseminated across ISC3 members community partners andnationwide. 113376 +No NIH Category available Address;Area;Behavioral Risk Factor Surveillance System;Black Populations;Black race;Budgets;Cancer Patient;Caring;Censuses;Characteristics;Clinical Trials;Code;Commuting;Complex;County;Data;Data Set;Databases;Diagnosis;Disparity;Emergency department visit;Evaluation;Excess Mortality;Future;Geographic Factor;Geographic Locations;Geography;Health;Health Information National Trends Survey;Health Insurance;Health Services Accessibility;Health behavior;Healthcare;Hospitalization;Individual;Inferior;Insurance;Intervention;Link;Malignant Neoplasms;Mediating;Mediation;Methodology;Modeling;Nature;Office Management;Outcome;Participant;Play;Policies;Policy Developments;Policy Maker;Population;Poverty;Poverty Areas;Quality of Care;Race;Reasons for Geographic And Racial Differences in Stroke;Reporting;Research Personnel;Role;Rural;Rural Population;SEER Program;Sampling;Social support;Socioeconomic Status;Specialist;Stroke Belt;System;Transportation;Work;cancer health disparity;cohort;comorbidity;contextual factors;data registry;deprivation;evidence base;experience;health literacy;indexing;malignant breast neoplasm;mortality;mortality disparity;multilevel analysis;neoplasm registry;primary outcome;rural area;rural disparities;rural patients;rural poverty;rural residence;rurality;screening;social vulnerability;sociodemographics;statistics;therapy development;urban area;urban disparity;urban residence;virtual Understanding rural mortality disparities in cancer: a multi-level approach Relevance narrativeApproximately 19% of the US population resides in rural areas; for over three decades this population hasexperienced increasingly inferior health outcomes when compared with their urban counterparts. The underlyingcause(s) of the widening rural/urban gap in cancer outcomes is hypothesized to be multifactorial and this studywill provide a comprehensive multi-level evaluation of rural/urban mortality disparities. Findings will provide thecritical evidence needed to inform policy as well as to inform intervention development to address the systemicdisparities in mortality experienced by rural patients with cancer. NCI 10814517 6/7/23 0:00 PA-21-071 3R37CA266193-02S1 3 R37 CA 266193 2 S1 "DELLAVALLE, CURT TAVIS" 7/1/23 0:00 12/31/24 0:00 11262899 "KENZIK, KELLY " Not Applicable 7 SURGERY 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 7/1/23 0:00 12/31/23 0:00 393 Non-SBIR/STTR 2023 119790 NCI 72600 47190 AbstractCancer mortality rates in the US declined by 26% between 1991 and 2015 but the decline has not been equalacross all populations. Approximately 19% of the US population resides in rural areas; for over three decadesthis population has experienced increasingly inferior outcomes when compared with their urban counterparts.The underlying cause(s) of the widening rural/urban gap in cancer outcomes is hypothesized to be multifactorialwith socioeconomic status (SES) both at the individual-level and geographic area-level likely playing a significantrole. Gaps in evidence include the use of multiple rural definitions a lack of evidence on associated geographicfactors and limited evidence based on multi-level approaches to understand the complex nature of ruraldisparities. Therefore the overall objective of this study is to conduct a comprehensive examination of theunderlying causes of rural/urban disparities in mortality among individuals diagnosed with cancer. In the first aimthe Surveillance Epidemiology and End Results (SEER) population-level data will be used to examine mortalityamong individuals diagnosed with cancer across three definitions of rurality providing researchers and policymakers with the magnitude of differences by each definition. In the second aim SEER will be linked via county-indicators to 16 databases (US Census Bureau Area Deprivation Index Bureau of Labor Statistics CountyHealth Rankings and Roadmaps AMA Healthcare Workforce Mapper BRFSS Social Vulnerability Index HealthInformation National Trends Survey etc.). These linkages will allow us to estimate the contribution of specific area-level factors (e.g. area-level SES access to high-quality care) on rural/urban mortality differences using effectdecomposition methodology. In the third aim the Reasons for Geographic and Racial Differences in Stroke(REGARDS) cohort (U01 NS041588) will be linked to state level cancer registry data using the Virtual PooledRegistry Cancer Linkage System (VPR-CLS). REGARDS includes longitudinally collected data for 30239participants (44% blacks) oversampled from stroke belt/buckle states (56% of participants from NC SC GATN AL MS AK LA) with large rural populations experiencing the highest mortality. REGARDS collectsinformation at the individual level on sociodemographics health literacy and distance to healthcaretransportation and risky health behaviors. Multi-level modeling and mediation modeling approaches will allow forthe examination of the contribution of individual-level characteristics and the area-level characteristics simultaneously.Results will provide estimates of how much of the mortality disparity is explained by differences in urban andrural geographic characteristics overall as well estimates that describe the potential impact of hypotheticalinterventions on specific mediating factors. Findings will provide the critical evidence needed to inform policy andintervention development aimed at addressing the systemic disparities in mortality experienced by rural patientswith cancer. 119790 +No NIH Category available Acetylation;African American;Antineoplastic Agents;Apoptosis;Area;Award;Basic Science;Binding;Biology;COVID-19;Cancer Biology;Cancer Center;Career Mobility;Cell Cycle Progression;Child;Cities;Clinical Research;Clinical Trials;Collaborations;Communities;Complex;DNA Repair;Doctor of Philosophy;Drug Industry;Drug Targeting;Educational workshop;Ensure;Europe;Event;Florida;Funding;Gene Deletion;Gene Mutation;Genes;Genetic Transcription;Goals;Grant;Hispanic;Homologous Gene;Human;Immunity;In Vitro;Individual;International;Japan;Location;MDM2 Gene Amplification;MDM2 gene;Malignant Neoplasms;Mediating;Medicine;Mentors;Minority;Mutate;NCI Center for Cancer Research;New York;Oncogenic;Participant;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Play;Postdoctoral Fellow;Proteins;Public Health;Reagent;Regulation;Research;Research Institute;Research Personnel;Role;Scientist;Senior Scientist;Signal Transduction;Singapore;Students;TP53 gene;Tokyo;Translational Research;Travel;Tumor Suppressor Proteins;Ubiquitination;Underrepresented Minority;Underrepresented Populations;United Kingdom;United States;Universities;Up-Regulation;Woman;Writing;anti-PD-L1;anticancer research;cancer immunotherapy;career;clinically relevant;college;design;drug discovery;graduate student;in vivo;inhibitor;interdisciplinary approach;man;medical schools;meetings;mouse model;overexpression;patient subsets;public health relevance;response;social;tumor;ubiquitin-protein ligase The 10th International MDM2 Workshop Public Health RelevanceOrganization of the timely 10th International MDM2 Workshop at the National Cancer Center Research InstituteTokyo Japan by three organizers including myself will significantly energize cancer research and promotescientific interactions and idea exchanges in the field. Since several drugs that inhibit MDM2 oncoprotein are inclinical trials basic and translational research focusing on this area has substantial scientific and clinicalrelevance. The meeting has traditionally attracted the participation of clinician scientists and pharmaceuticalindustry investigators contributing to anticancer drug discovery and benefiting public health. NCI 10814471 9/15/23 0:00 PA-21-151 1R13CA281369-01A1 1 R13 CA 281369 1 A1 "LUO, RUIBAI" 9/15/23 0:00 8/31/24 0:00 ZCA1-PCRB-9(O1) 8848977 "IWAKUMA, TOMOO " Not Applicable 5 Unavailable 73067480 N52NHWMBZNG5 73067480 N52NHWMBZNG5 US 39.081983 -94.578204 1529501 "CHILDREN'S MERCY HOSP (KANSAS CITY, MO)" KANSAS CITY MO Independent Hospitals 641084619 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 15000 NCI 15000 0 Project Summary/AbstractThe p53 protein is the most frequently mutated gene in human cancers and functions as a tumor suppressor bytranscriptionally regulating numerous downstream target genes involved in cell cycle progression and apoptosis.MDM2 and its homolog MDM4 (also known as MDMX) are two of the most important negative regulators of p53by acting as an E3 ubiquitin ligase complex to promote p53 degradation and by physical binding to inhibit thep53s transcriptional function. These proteins are also overexpressed in approximately 30% of human cancers.Overexpression of MDM2/MDM4 not only inhibits p53 function but also shows p53-independent oncogenicactivities. Intriguingly gene amplification of MDM2 and MDM4 is associated with adverse hyperprogressiveresponse to anti-PDL1 cancer immunotherapy in a subset of patients. Thus inhibitors for MDM2 and MDM4have been developed to inhibit their oncogenic activities and to reactivate wild-type p53 in tumors. Importantlysome MDM2/MDM4 inhibitors are in clinical trials. The first International MDM2 Workshop held in 2001 in theUnited Kingdom was primarily in response to a significant increase in the research related to p53 and its negativeregulators MDM2/MDM4 as well as strong demand for drug discovery targeting MDM2/MDM4/p53. Theexpansion of the scientific community studying MDM2/MDM4 and the need to pursue this area of research witha collaborative multidisciplinary approach have further made the MDM2 Workshop necessary. The MDM2Workshop is held every two or three years at locations alternating between the United States and Europe tobring together the p53/MDM2 field present the latest research and facilitate collaboration and exchange ofreagents. Indeed both the p53 and MDM2 Workshops have become important platforms for long-term scientificexchange and new investigators of the MDM2-p53 pathway. The 10th International MDM2 Workshop will be heldat an auditorium of the newly built National Cancer Center Research Institute (NCCRI) in Tokyo Japan onOctober 15-18 2023. This will be the first International p53/MDM2 Workshop organized and held in Japan. Themeeting will be co-organized by Dr. Rieko Ohki (NCCRI Tokyo Japan) Dr. Koji Itahana (Duke-NUS MedicalSchool Singapore) and Dr. Tomoo Iwakuma (Childrens Mercy Research Institute MO USA). Notably due toCOVID-19 we have not had the MDM2 Workshop for over 4 years since the 9th MDM2 Workshop on November4-7 2018 in Florida. We expect more participants with higher enthusiasm for this 10th MDM2 Workshop ascompared with the previous MDM2 Workshops. Significant numbers of US researchers including theinternational organizing committee (11 out of 16 38% women) are expected to participate in and benefit fromthe meeting. Hence we are applying for R13 funding to support this important and exciting international meetingthat will energize research in US and promote scientific progress and interactions in the p53/MDM2 field. Fundsare requested to support three important specific aims designed to promote participation of the US investigatorsand trainees. 15000 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10814123 261201800009I-P00011-26100001-2 N01 5/1/18 0:00 4/30/23 0:00 78115391 "CRESS, ROSEMARY " Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N R and D Contracts 2023 4431264 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 4431264 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10814122 261201800032I-P00008-26100001-2 N01 5/1/18 0:00 4/30/23 0:00 78112018 "LIN-GOMEZ, SCARLETT " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N R and D Contracts 2023 4923655 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 4923655 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10814120 261201800015I-P00009-26100001-2 N01 5/1/18 0:00 4/30/23 0:00 78115394 "LIU, LIHUA " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N R and D Contracts 2023 4181434 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 4181434 +No NIH Category available Affect;Age;Biological Markers;Biopsy;Caring;Clinical Trials;Cutaneous Lymphoma;Cutaneous T-cell lymphoma;DNA;Diagnosis;Fixatives;Formalin;Freezing;Funding;Future;Goals;Grant;High-Throughput Nucleotide Sequencing;Histology;Link;Measurement;Methods;Morphology;Nucleic Acids;Paraffin Embedding;Parents;Patients;Proteins;RNA;Reproducibility;Sampling;Skin;Skin Tissue;Specimen;T cell receptor repertoire sequencing;T-Cell Receptor Genes;Techniques;Testing;Tissue Embedding;Tissues;cancer type;clinical practice;preservation;response;sample fixation;tissue processing;treatment response Optimizing pre-analytic sample handling for high throughput TCR sequencing in cutaneous T cell lymphoma Project NarrativeIn summary the overall goals of the funded parent U01 grant are to establish new best tissue handling practices to make skin tissues more accessible to study either by using non-cross-linking fixatives or by developing new methods that allow FFPE tissues to be studied in new ways which have the potential to be useful in many cancer types. NCI 10814026 7/31/23 0:00 PA-21-071 3U01CA253190-04S1 3 U01 CA 253190 4 S1 "RAO, ABHI" 9/1/20 0:00 5/31/25 0:00 ZCA1(M2) 1879756 "CLARK, RACHAEL ANN" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 43816 NCI 24478 19338 ABSTRACT AND SPECIFIC AIMS Formalin fixation is a common method used to preserve skin biopsies in both clinical practice and clinical trials. Formalin-fixed paraffin-embedded (FFPE) tissues have excellent tissue morphology but DNA and RNA are degraded by formalin fixation 1 . High throughput sequencing of the rearranged T cell receptor genes (HTS) has transformed the diagnosis care and assessment of therapeutic responses in patients with cutaneous T cell lymphoma (CTCL)2-5. HTS results are highly reproducible in frozen CTCL skin biopsies but the formalin used to preserve skin biopsies in many clinical trials degrades DNA and affects HTS measurements potentially causing errors in patient diagnosis assessment of responses and choices of therapy. The overarching goal of the funded parent U01 grant is to identify a single uniform optimal tissue processing approach for small skin biopsies to study CTCL that will give accurate and reproducible DNA RNA and protein measurements maintain excellent histology and preserve remaining tissue for future measurement of emerging biomarkers. Hypothesis: Non-cross-linking tissue fixatives will maintain nucleic acid and protein integrity without sacrificing histopathologic quality and quantitative corrections for DNA degradation in banked formalin-fixed specimens will allow accurate HTS measurements in existing skin biopsies from patients with CTCL. 43816 +No NIH Category available Address;Algorithms;Antimalarials;Antioxidants;Apoptosis;BRCA1 gene;BRCA2 gene;Benign;Binding Sites;Biological Markers;Breast Cancer Risk Factor;Cancer cell line;Cancerous;Carcinoma;Chemoprevention;Chemopreventive Agent;Chemoresistance;Clinical Trials;Collecting Cell;Contraceptive Usage;Control Animal;Credentialing;Cytochromes b;Cytology;Data;Deterioration;Development;Disease;Dose;Early Diagnosis;Electron Transport;Electron Transport Complex III;Eligibility Determination;Enterobacteria phage P1 Cre recombinase;Epithelium;Evaluation;Excision;Exposure to;FDA approved;Future;Genes;Genetically Engineered Mouse;Germ-Line Mutation;Goals;Growth;Gynecologic;Gynecologic Surgical Procedures;Health;High Risk Woman;Human;Hysteroscopy;In Vitro;Laboratories;Lesion;Malaria;Malignant Neoplasms;Malignant neoplasm of ovary;Mammalian Oviducts;Measures;Mediating;Methods;Mitochondria;Mus;Neurologic;Operative Surgical Procedures;Oral;Oral Contraceptives;Outcome;Ovarian;Ovary;Oxidative Phosphorylation;Oxidative Stress;Participant;Patient Triage;Patients;Penetrance;Pharmaceutical Preparations;Phosphorylation;Placebo Control;Premature Menopause;Prevention;Prevention approach;Prevention strategy;Proteins;Resistance;Resources;Risk;Risk Reduction;Role;Sampling;Schedule;Screening for Ovarian Cancer;Serous;Signal Transduction;Specimen;Structure;Superoxide Dismutase;Surrogate Endpoint;Survival Rate;System;TP53 gene;Tamoxifen;Testing;Time;Tissues;Tube;Tumor Suppressor Genes;Ubiquinone;Variant;Woman;Work;Xenograft procedure;aerobic glycolysis;atovaquone;biomarker evaluation;bone health;cancer cell;cancer risk;cardiovascular health;catalase;cohort;comparative;cytotoxicity;early phase clinical trial;efficacy evaluation;efficacy study;exposed human population;high risk;high risk population;human disease;in vivo;inducible Cre;inhibitor;innovation;interest;lead candidate;lifetime risk;mouse model;multidisciplinary;novel;pharmacologic;pre-clinical;preclinical development;premature;prevent;prospective;randomized clinical trials;reproductive;resistance mechanism;response;screening;success;surgical menopause;transcriptome;tumor Repurposing Atovaquone for Preventing Ovarian Cancer: An Example of Successful Inhibition of Oxidative Phosphorylation Patients who are at high-risk for developing ovarian cancer have limited options to lower theirrisk without enduring surgical menopause and multiple unfavorable health-related outcomes.Atovaquone an orally available anti-malarial medication blocks oxidative phosphorylation byinterfering with mitochondrial electron transport and slows ovarian cancer growth in vitro and invivo. It has the potential to prevent cancerous transformation in the ovaries and fallopian tubesof high-risk women eliminating the need for premature removal of their gynecologic structures. NCI 10813900 4/10/23 0:00 PAR-18-559 3R01CA238423-04S1 3 R01 CA 238423 4 S1 "SAMIMI, GOLI" 5/11/20 0:00 4/30/25 0:00 Cancer Prevention Study Section[CPSS] 11706852 "BARROILHET, LISA M" Not Applicable 2 OBSTETRICS & GYNECOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 70979 NCI 49843 21136 Early detection of ovarian cancer using screening algorithms is ineffective even in high-risk populations.Patients who carry germline mutations such as BRCA have limited options to lower their ovarian cancer riskshort of removing their ovaries and fallopian tubes. There is a critical need for novel methods to preventovarian cancer without the negative consequences of surgical menopause.Drugs that inhibit OXPHOS such as atovaquone have potential as effective chemoprevention agents.Atovaquone is a mitochondrial complex III inhibitor. Preliminary data from our laboratory support atovaquone'sability to effectively block OXPHOS by interfering with mitochondrial electron transport. Atovaquone is currentlyFDA approved for the treatment of malaria and is a well-tolerated orally available medication. It slows ovariancancer growth in vitro and in vivo and increases p53-related apoptosis.Hypothesis: We hypothesize that atovaquone will block oxidative phosphorylation increase oxidative stressand potentially activate p53-mediated apoptosis preventing precursor lesions from progressing to ovariancancer in a genetically engineered mouse model.Aim 1. Examine the role of atovaquone in delaying the onset of ovarian cancer in an OVGP1 mousemodel. The OVGP1 BPRN genetically engineered mouse model is based on fallopian tube transformation andmimics human high-grade serous carcinoma development. This mouse model will be used to determine ifatovaquone delays the onset of ovarian cancer in mice predisposed to develop this disease. Additional studieswill investigate short-term transcriptome changes seen in the ovary and fallopian tube that could serve asadditional exploratory biomarkers in our proposed window-of-opportunity clinical trial.Aim 2. Complete a window of opportunity clinical trial examining the effects of atovaquone on normalfallopian tube and ovarian epithelium in patients undergoing planned gynecologic surgery. Eligiblepatients will be women scheduled to undergo removal of at least one fallopian tube for benign indications.Baseline cytology sampling of the fallopian tube will be performed using office hysteroscopy. Cells collectedcan be used for transcriptome analysis. The subjects will be exposed to atovaquone for 25-35 days pre-operatively. MDA expression a marker of inhibition to OXPHOS will be measured after atovaquone exposureto confirm its proposed mechanism of action. IHC expression for p53 and p53 phosphorylation will beperformed. Additional biomarkers from our mouse work may be added.Aim 3. Investigate potential barriers to atovaquone therapy. The Nrf-2 chemoresistance mechanismspertinent to oxidative phosphorylation will be explored. It is critical to develop strategies to overcome theantioxidant mechanisms induced by Nrf-2 regulated genes including superoxide dismutase (MnSOD)catalase and hemoxygenase-1 (HO-1). 70979 +No NIH Category available 2 arm randomized control trial;Address;Advanced Malignant Neoplasm;Advocate;Arousal;Awareness;Black Populations;Black race;Cancer Patient;Cancer Survivor;Cancer health equity;Caring;Chronic;Clinical;Clinical Oncology;Communication;Communities;Complex;Conflict (Psychology);Counseling;Data;Decision Making;Development;Diagnosis;Disease;Disparity;Distress;Education;Effectiveness;Enrollment;Equity;Ethnic Population;Family;Family member;Fright;Genetic;Genetic Counseling;Genome;Genomics;Goals;Guidelines;Happiness;Health Insurance Portability and Accountability Act;Health Services;Health behavior;Healthcare Systems;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;High-Risk Cancer;Improve Access;Individual;Inequity;Knowledge;Laboratories;Letters;Life;Malignant Neoplasms;Mediating;Mediator;Medical;Methodology;Modeling;Motivation;Not Hispanic or Latino;Oncology;Outcome;Participant;Pathogenicity;Patients;Perception;Physicians;Policies;Population;Prevention;Primary Prevention;Provider;Public Health;Randomized;Regrets;Resources;Risk;Second Primary Cancers;Secondary Cancer Prevention;Secondary Prevention;Service delivery model;Services;Survivors;System;Testing;Time;Underserved Population;Variant;Work;access disparities;arm;black patient;cancer genomics;cancer health disparity;cancer therapy;care delivery;chatbot;clinical practice;community engagement;comparative efficacy;cost;digital intervention;disparity reduction;empowerment;experience;genetic counselor;genetic testing;health care delivery;high risk;implicit bias;individualized prevention;innovation;low socioeconomic status;meetings;mortality;optimism;personalized cancer therapy;personalized care;psychosocial;racial disparity;racial minority;racial population;response;satisfaction;screening;social culture;testing uptake;therapy resistant;treatment as usual;underserved minority;usual care arm Addressing Genomic Disparities in Cancer Survivors PUBLIC HEALTH STATEMENTThis study will use a community-engaged approach to identify an effective culturally relevant and sustainablestrategy for identifying high-risk Black families from an underserved population facilitating genetic testing andexpanding opportunities for personalized cancer treatment prevention and screening. This approach may beof particular benefit to hundreds of thousands Black patients and their relatives because they are often unawareof their risks less likely to have a provider discuss their risk and refer them for GT at the time of diagnosis andare not equably garnering the potentially lifesaving benefits of personalized care. NCI 10813426 6/5/23 0:00 PAR-21-035 7R01CA277599-02 7 R01 CA 277599 2 "WEAVER, SALLIE JAYNE" 3/9/23 0:00 1/31/28 0:00 Special Emphasis Panel[ZRG1-HSS-G(90)S] 3056913 "KINNEY, ANITA Y." "SCHWARTZ, MARC D" 10 BIOSTATISTICS & OTHER MATH SCI 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 3/9/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 679463 NCI 485249 194214 Genetic testing (GT) for hereditary cancer and related health services do not reach all segments of thepopulation equitably. Racial disparities in genomic care are profound persistent and growing. Less than 30%of high-risk cancer patients are referred for germline GT with appreciably lower referral and testing ratesamong racial minorities especially among Blacks. GT of cancer survivors can directly inform treatmentfollowing progression or treatment resistance and can facilitate primary and secondary prevention of cancers intheir unaffected relatives. Demand for GC (genetic counseling) and GT continues to increase with expandingGT indications and decreasing sequencing costs yet supply of genetic counselors remains limited. Theconventional approach of referral to pretest genetic counseling is a common barrier to receiving GT. Furtherevidence suggests that traditional comprehensive pre-test GC does not meet the needs of many survivorsespecially underserved minorities. Thus new models ofgenome-based care are needed that are responsive tocommunity needs improve access do not overburden scarce genetic counseling resources and do not widenexisting disparities. Some health care systems and commercial GT laboratories use digital interventionsincluding videos and relational agents (RAs) instead of traditional pre-test GC sessions without providingspecifics about community engagement development acceptability or efficacy in oncology settings through arigorous methodologic strategy as we propose. Given the life-saving benefits of GT understanding how toeffectively educate empower and test high-risk patients in a culturally acceptable way can move the fieldforward and reduce persistent racial disparities. This study will address this translational gap. In response tocommunity identified needs and enthusiastic support from cancer patients relatives and community advocateswhile also building on our pilot work we will enroll 428 Black cancer patients meeting national guidelines forGT into a 2-arm randomized controlled trial. This approach may be of particular benefit to hundreds ofthousands Black patients and their relatives because they are often unaware of their risks less likely to have aprovider discuss their risk and refer them for GT at the time of diagnosis and are not equably garnering thepotentially lifesaving benefits of personalized prevention screening and treatment. The specific aims are to: 1)Compare the efficacy of a culturally tailored RA vs. Enhanced Usual Care (EUC) on engagement in geneticeducation and GT uptake; 2) Evaluate the impact of the RA vs. EUC on informed decision-making andpsychosocial outcomes; and 3) Explore potential mechanisms by assessing mediators and moderations ofeffectiveness. Data from this trial can be used to guide clinical practice and policy decisions for advancingcancer health equity and improving access to genetic education and GT. If successful this approach could beapplied to other cancers and chronic conditions. 679463 +No NIH Category available 3-Dimensional;Address;Advanced Malignant Neoplasm;Anti-CD47;Biological;Biological Models;Brain;Brain Neoplasms;Cells;Cellular Tropism;Characteristics;Clinical;Complement;Computer Models;Data;Data Set;Disease Progression;Early Diagnosis;Foundations;Genes;Genomic Instability;Genomics;Goals;Growth;Immune;Immunologic Surveillance;Incidence;Interruption;Link;Macrophage;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Metastatic Neoplasm to the Central Nervous System;Metastatic malignant neoplasm to brain;Microglia;Modeling;Molecular;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Neuroimmune;Neurologic;Operative Surgical Procedures;Organoids;Outcome;Pathway interactions;Patients;Peripheral;Play;Prediction of Response to Therapy;Primary Neoplasm;Prognostic Marker;Radiation;Radiation Tolerance;Radiation therapy;Recording of previous events;Resected;Resources;Risk;Role;Sampling;Selection for Treatments;Statistical Models;Testing;Treatment Efficacy;Treatment outcome;Tropism;biobank;brain cell;cancer genome;cancer type;cell type;differential expression;functional status;genomic biomarker;genomic data;genomic predictors;genomic signature;high risk;imaging modality;in vitro testing;insight;mortality;multiple omics;neuropathology;predictive marker;predictive modeling;pressure;programs;radioresistant;response;screening;standard of care;translational study;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Determine the mechanisms of acquired brain-tropism n/a NCI 10813237 9/11/23 0:00 PA-21-071 3U54CA261717-02S1 3 U54 CA 261717 2 S1 "GRIL, BRUNILDE M" 3/1/23 0:00 8/31/25 0:00 7014 8471415 "JI, HANLEE P" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 3/1/23 0:00 8/31/23 0:00 Research Centers 2023 76446 49225 27221 ABSTRACT PROJECT 1For patients with advanced cancer 30% will be afflicted with brain metastases the cause of devastatingneurologic morbidity and mortality. As a result the incidence of brain metastasis is 170000 new cases per ayear. For screening MRI is the preferred imaging modality for brain metastasis but is prohibitively expensiveand lacks relevant molecular information. We lack predictive models to identify patients at high risk for brainmetastases for screening as treatment efficacy and morbidity are linked to early detection. Treatment involvessurgery and radiotherapy but with a noticeable lack of prognostic or predictive biomarkers for diseaseprogression or treatment. Our central hypothesis is that there are common intrinsic features to the tumor andextrinsic features to the brain microenvironment relevant for cancer brain tropism and response to therapies.We will determine these features association to microglia (Project 2) and peripheral immune surveillance(Project 3) leveraging biological models to test these discoveries. We will identify intrinsic cellular genomicfeatures relevant for brain metastasis that can be generalized across many primary tumor types. Likewise wehypothesize there are extrinsic features of the tumor cellular milieu in the brain that facilitate the seeding andmaintenance of these metastases. (1) For determining extrinsic cellular tropism we will characterize the immunecell types states and function in the brain metastasis tumor microenvironment. Using single cell genomics wewill determine the distribution and functional status of the TME microglia and macrophages across different tumortypes that have CNS metastasis. In parallel using three dimensional organoids we will determine the TME-based macrophage response to anti-CD47 a potent modulator of macrophage function. Our results willdetermine the cellular genomic characteristics and functional status of TME macrophages/microglial cells andtheir regulatory states. (2) For intrinsic tropism factors we will analyze genomic features of the primary tumorand extrinsic features of the brain that indicate increased propensity for brain metastasis. We will conductgenomic sequencing analysis on matched primary and metachronous brain metastasis with complete treatmentexposure patient history. With this data we will determine critical cancer genome features such as the extent ofgenomic instability intratumoral clonal diversity treatment selection pressure and TME immune cell compositionthat are associated with brain metastatic risk. Our results will identify genomic biomarkers indicative of increasedrisk of brain metastasis across different tumor types. (3) Finally we will use the overlapping data set for intrinsicgenomic factors to determine if there are predictive genomic signatures of radioresistant brain metastases. Wehypothesize there are specific genomic features of primary tumors that are radiotherapy predictors. Theseresults may yield potential candidates for increasing sensitivity to this mode of treatment that can be tested invitro. +No NIH Category available Address;Aging;Antibodies;BRAF gene;Behavior;Bioinformatics;CD8-Positive T-Lymphocytes;Cell Communication;Cell secretion;Cells;Cessation of life;Clinical;Communication;Cues;Data;Disease;Distal;Doxycycline;Event;Excision;Extracellular Matrix;Family member;Fiber;Fibroblasts;Flow Cytometry;Genetic Induction;Global Change;Goals;Growth;IL2RA gene;Image;Immune;Immune Targeting;Immune system;Immunology;Immunosuppression;Immunotherapy;Knowledge;Left;Ligands;Liquid Chromatography;Lung;MEKs;Malignant Neoplasms;Manuscripts;Melanoma Cell;Metastatic Melanoma;Micrometastasis;Migration Assay;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Nature;Neoplasm Metastasis;Organ;Pathology;Pathway interactions;Patients;Phenotype;Population;Primary Neoplasm;Process;Production;Program Development;Proliferating;Protein Tyrosine Kinase;Proteins;Receptor Protein-Tyrosine Kinases;Recombinants;Regulatory T-Lymphocyte;Research Personnel;Residual Neoplasm;Resistance;Resource Development;Role;Signal Transduction;Site;Sorting;Source;Stromal Cells;Structure of parenchyma of lung;T-Lymphocyte;TNFRSF10B gene;Techniques;Thick;Tissues;Training;Tumor Tissue;Up-Regulation;Visceral;age related;aged;cancer cell;career development;clinical translation;comparative;crosslink;diagnostic tool;immune clearance;in vivo;insight;melanoma;mortality;mouse model;neoplastic cell;novel;patient subsets;permissiveness;programmed cell death protein 1;protein expression;receptor;response;senescence;single-cell RNA sequencing;skills;tandem mass spectrometry;therapy resistant;translational therapeutics;tumor;tumor growth;tumor immunology;tumor-immune system interactions The role of MER/PROS1 in promoting stromal induced emergence from metastatic melanoma dormancy Project NarrativeThe major source of melanoma deaths is metastatic disease largely due to the fact that while tumor removal and therapies look promising for patients in the beginning a large subset of patients will have tumor cells that have left the primary tumor site and are in a state of dormancy in other organs which remain resistant to these therapies and are unable to be detected by clinicians. We have uncovered a receptor called the MER tyrosine kinase receptor that when expressed in dormant melanoma cells results in their reactivation and drives aggressive tumor growth in the lung. We propose to study how these reactivated melanoma cells secrete soluble proteins into the lung to stop our immune system and other healthy cells such as fibroblasts from targeting melanoma cells for destruction and how this process can also lead to resistance against targeted and immunotherapies with the hope of finding pathways that can be targeted clinically for translational therapies against dormant and reactivated metastatic melanoma. NCI 10813230 5/9/23 0:00 PA-20-188 4R00CA263017-02 4 R00 CA 263017 2 "SNYDERWINE, ELIZABETH G" 9/1/22 0:00 4/30/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15215830 "FANE, MITCHELL EDWARD" Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 132447 116553 Project SummaryThe goals of this Pathway to Independence Career Development proposal are to request support for Dr. Faneto develop training in tumor dormancy and underlying cancer immunology and bioinformatics techniques toinvestigate how dormant melanoma cells located within metastatic tissues can regulate stromal cells to facilitate metastatic outgrowth and resistance to therapy. The training plan outlined in this proposal will take advantage of the extensive resources and career development programs available at Johns Hopkins. Dr. Fane has assembled a team of leaders in the field of melanoma dormancy immunology and bioinformatics who will guide his training.Metastasis is the largest cause of melanoma deaths with treatments failing to provide a durable response. While a subset of patients show-remarkable responses initially to therapy most of them will have tumor cells lying dormant in distal organs that persist during therapy but are clinically undetectable. Eventually these cells willreactivate from dormancy to form metastatic colonies now resistant to therapy. There are few labs that focus on melanoma dormancy and as such there are no current treatments or diagnostic tools to identify and target dormant cells. The proposed studies are based on Dr. Fanes novel findings that upregulation of the tyrosine kinase receptor MER promotes cancer growth which allows reactivation of dormant melanoma cells within the lung. It isnt known how reactivated cells overcome targeting by the immune system growth restrictive cues from lung fibroblasts or how they become resistant to therapy. Dr. Fanes preliminary data first shows thatMERhigh melanoma cells regulate lung fibroblasts to alter secretion of the extracellular matrix changing it from being dormancy promoting to allowing melanoma outgrowth. Dr Fane has also shown that following reactivationof melanoma within the lung there is an increase in Myeloid Derived Suppressor Cells (MDSCs) and T-regulatory (Tregs) cells which inhibit the immune system from targeting cancer cells for destruction and are often a commonfeature in patients resistant to immunotherapy. Finally Dr. Fane has shown that reactivated melanoma cells secrete high levels of the soluble protein PROS1 which is known to be involved in regulating the activity ofMDSCs Tregs and lung fibroblasts within other disease states but has not been investigated in metastatic dormancy. Dr. Fane will explore the following scientific aims: 1) Determine whether MER induced secretion of PROS1 regulates lung fibroblast to promote outgrowth and therapy resistance and 2) Investigate the mechanism by which MER induced secretion of PROS1 by melanoma cells in the lung regulates immune cells and response to -PD1. The completion of the scientific aims in this proposal will develop Dr. Fanes scientific and professional skills that are required to be an independent investigator into the field of dormancy and importantly will provide novel insight into how cancer cells overcome targeted and immunotherapies in dormant metastatic disease. 249000 +No NIH Category available The Impact of Cigar Pack Quantity on Tobacco Use Behavior PROJECT NARRATIVECigar use is a significant public health concern particularly among vulnerable populations. The proposedlongitudinal and policy impact analyses will examine the impact of cigar pack quantity on tobacco usebehaviors. This research will directly address the FDA Center for Tobacco Products Scientific Domains ofbehavior and impact analysis and findings may inform future FDA rulemaking on cigar pack quantity. NCI 10812851 5/25/23 0:00 PA-21-268 7K01CA253235-04 7 K01 CA 253235 4 "RADAEV, SERGEY" 4/1/23 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-RPHB-R(57)R] 15101892 "JENSEN, JESSICA KING" Not Applicable 10 PUBLIC HEALTH & PREV MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 4/1/23 0:00 6/30/23 0:00 77 Other Research-Related 2022 135880 OD 125815 10065 PROJECT SUMMARYThis K01 application is designed to provide Jessica King PhD with the mentored training necessary totransition into an independent tobacco regulatory science researcher. Dr. King will be mentored by a team ofrenowned tobacco control and tobacco regulatory scientists and will complete mentored training courseworkand professional development in the areas of advanced statistical analyses policy impact analyses and healthdisparities. This additional career development and mentorship will directly contribute to completing theproposed research strategy which examines the impact of cigar pack quantity on tobacco use behaviors. Cigaruse is the third most commonly used tobacco product among adults and second most commonly used productamong youth with use increasing among low income minority and young adult populations. Given thesignificant health effects attributable to cigar use this represents a critical health disparity. Low cost is oftencited as a reason for increased use among these populations in part due to low taxes and varying packquantities. Research on cigarettes has shown minimum pack quantity laws increase price and decrease use.As of 2016 the FDA has regulatory authority over cigars allowing it to regulate the marketing manufacturingand distribution of cigar products including mandating minimum pack quantities. However cigar-specific dataare needed to inform FDA's regulation. Thus the goal of the proposed analyses are to advance understandingof the relationship between cigar pack quantity and tobacco use behaviors to inform regulation on minimumcigar pack quantity. Specifically we aim to (1) assess whether cigar pack quantity is associated with between-and within-person changes in cigar use and whether there are differences by sociodemographic factors (2-3)identify the impact of local minimum cigar pack quantity laws on cigar and other tobacco use and cigar salesand whether impacts differ across communities of varying demographics and (4) characterize differences inthe implementation and enforcement of minimum cigar pack quantity laws through qualitative interviews withkey implementation personnel. In this mixed-methods approach we will utilize national datasets including thePopulation Assessment of Tobacco and Health Study the Tobacco Use Supplement to the Current PopulationSurvey the Youth Risk Behavior Surveillance System and Nielsen retail scanner data. Each aim will explicitlyexamine the impact among racial and ethnic minorities low income populations youth and young adults eachvulnerable populations. This research will directly address the FDA Center for Tobacco Products ScientificDomains of behavior and impact analysis. The findings from this study may inform future FDA rulemaking oncigar pack quantity. 135880 +No NIH Category available A kinase anchoring protein;Adrenal Gland Neoplasms;Apoptosis;Atrial myxoma with lentigines;BAG2 gene;Binding;Biogenesis;Biology;CCL4 gene;Caring;Catalytic Domain;Cell Line;Cells;Chemicals;Clinical;Clinical Research;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Dependence;Development;Diabetes Mellitus;Disease Progression;Drug Targeting;Elements;Endocrine Gland Neoplasms;Fibrolamellar Hepatocellular Carcinoma;Foundations;Gastrointestinal Neoplasms;Gene Targeting;Generations;Genetic;Genetic Transcription;Growth;Heart failure;Heat-Shock Proteins 70;Holoenzymes;Incidence;Induction of Apoptosis;Island;Lesion;Link;Liver neoplasms;Lung;Lung Neoplasms;Malignant Neoplasms;Modeling;Molecular;Mutation;Oncogenic;Oncology;Outcome;Output;Pathway interactions;Patient Care;Patients;Peptide Initiation Factors;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physiological;Physiological Processes;Production;Proliferating;Property;Protein Inhibition;Protein Kinase;Protein-Serine-Threonine Kinases;Proteins;Proteomics;RNA Helicase;Radial;Rare Diseases;Regimen;Regulation;Research;Research Personnel;Resistance;Ribosomes;Role;Second Messenger Systems;Serine;Signal Transduction;Solid;Specificity;Testing;Therapeutic;Therapeutic Index;Tissue Sample;Toxic effect;Translational Repression;Translations;United States Food and Drug Administration;United States National Institutes of Health;Variant;adenoma;c-myc Genes;c-myc Proto-Oncogenes;chaperonin;clinically relevant;derepression;effective therapy;forging;heat-shock proteins 40;helicase;in vivo;inhibitor;kidney dysfunction;live cell imaging;mRNA Translation;mutant;nano;nanoscale;novel;ovarian neoplasm;patient derived xenograft model;pharmacologic;rare cancer;recruit;response;targeted treatment;therapeutic target;tool;transcriptomic profiling;translational impact;tumor;tumor growth Targeting Oncogenic PKA signaling mechanisms PROJECT NARRATIVEAberrant Protein Kinase A (PKA) signaling drives the growth and progression of a subset of lung ovarian liveradrenal and gastrointestinal tumors. Pharmacologically targeting these aggressive cancers is challenging asdirectly inhibiting PKA has dire consequences such as heart failure kidney dysfunction and diabetes. This multi-investigator project tests if PKAc-driven cancers can be treated by targeting its downstream effects on mRNAtranslation by inhibiting the helicase eIF4A rather than globally blocking the activity of the kinase. NCI 10812795 12/15/23 0:00 PA-20-185 1R01CA279997-01A1 1 R01 CA 279997 1 A1 "FORRY, SUZANNE L" 12/15/23 0:00 11/30/28 0:00 Mechanisms of Cancer Therapeutics A Study Section[MCTA] 11457512 "GORDAN, JOHN D" "SCOTT, JOHN D" 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 12/15/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 616676 NCI 485463 131213 ABSTRACTOf the 6500 known rare diseases only about 5% have U.S. Food and Drug Administration-approved treatments.In cancer rare tumors account for approximately 20% of cancer incidence but often lack established therapeuticregimens. Hence gaining a molecular understanding of rare tumors is key for development of effective therapies.This multi-investigator proposal investigates oncogenic mutations that activate protein kinase A (PKA) to promotedefective cell signaling in rare endocrine and hepatic tumors.Targeted therapeutics have transformed care for patients with rare cancers by targeting oncogenic mutations inprotein kinases. PKAc-driven cancers are challenging to target in this way because this broad specificity kinasecontrols myriad physiological processes. Consequently selective PKAc inhibitors have been relegated to therole of tool compounds rather than clinically viable drugs. Thus alternative strategies must be developed to treatPKAc-driven cancers. Our preliminary profiling of oncogenic PKAc mutants provide compelling evidence thatPKAc engages downstream protein kinase cascades that impact translation in adrenal and hepatic tumors. Wealso observed increased mRNA translation as an emerging hallmark of these PKAc driven malignancies. Thesefindings have forged a working hypothesis that PKAc-driven cancers can be treated by targeting downstreameffectors such the RNA helicase eIF4A rather than globally blocking the catalytic activity of the kinase.Three specific aims will test this transformative premise. 1) Proteomic and transcriptomic profiling of cellsexpressing oncogenic PKAc variants that underlie Carney complex Cushings adenoma and fibrolamellarcarcinoma will elucidate downstream signaling elements that impinge on mRNA translation. 2) Molecularapproaches will investigate new properties imparted by the DNAJ-PKAc-chimeric kinase in fibrolamellarcarcinoma that may confer resistance to chemically induced apoptosis. 3) Clinically relevant compounds andnovel bivalent inhibitors will dissect the mechanism of eIF4A dependence in PKAc-driven malignancies andpatient derived (PDX) models of fibrolamellar carcinoma. This proposal not only builds on a solid foundation ofPKAc research but also affords an unparalleled opportunity to discover develop and validate drug targets for agroup of patients in dire need. 616676 +No NIH Category available 1 year old;Acceleration;Acute;Acute Myelocytic Leukemia;Adolescent;Australia;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Complication;Country;Development;Diagnosis;Disease;Dose;Eligibility Determination;Enrollment;Ensure;Family;Foundations;Functional disorder;Generations;Goals;Hormonal;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Positioning Attribute;Productivity;Prognosis;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Survivors;Tissues;Translational Research;United States;Universities;Work;anticancer research;cancer diagnosis;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;multidisciplinary;novel therapeutic intervention;operation;organizational structure;reproductive;small molecule;success;survivorship;translational study COG NCTN Network Group Operations Center PROJECT NARRATIVEThe Children's Oncology Group (COG) is the world's largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading children's hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcome for all children with cancer. NCI 10812650 4/13/23 0:00 RFA-CA-17-056 3U10CA180886-10S2 3 U10 CA 180886 10 S2 "MOONEY, MARGARET M" 4/11/14 0:00 2/28/25 0:00 ZCA1-GRB-S(O1) 10871228 "HAWKINS, DOUGLAS S." Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 38908 NCI 75824 3412 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of theestimated 360000 survivors of childhood cancer experiencing a significant health related quality of lifecomplication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildren's Oncology Group (COG) the world's largest organization devoted exclusively to childhood andadolescent cancer research was founded 17 years ago. The COG's multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading children's hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institute's (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life children with cancer and survivors. As more than 90% of childrendiagnosed with cancer in the US are treated at COG member institutions the COG has the ability to offer adiverse population of children with cancer and their families the opportunity to participate in innovative research.This research effort includes allowing for collection and annotation of biospecimens from all children with cancerproviding the foundation for discovery and accelerating the most promising research efforts conducted inlaboratories around the world. The proposal is for support of the COG Network Operations Center clinician-scientists who develop and conduct research and for member sites to participate through enrollment of eligiblesubjects. 38908 +No NIH Category available Address;Cause of Death;Clinical Trials;Cohort Studies;Communities;Contracts;Cost Savings;Costs and Benefits;Data;Development;Division of Cancer Control and Population Sciences;Division of Cancer Epidemiology and Genetics;Eligibility Determination;Ensure;Ethical Review;Expenditure;Funding;Human Subject Research;Individual;Institution;Institutional Review Boards;Intake;Leadership;Link;Malignant Neoplasms;Methods;Minimal Risk Study;Modification;Office for Human Research Protections;Participant;Patients;Policies;Procedures;Process;Protocols documentation;Registries;Regulation;Research;Research Personnel;Resources;Risk;Site;Source;Specific qualifier value;Speed;System;Systems Integration;Time;United States;United States Dept. of Health and Human Services;United States National Institutes of Health;Work;adjudication;cohort;cost efficient;data registry;epidemiology study;expectation;expedited review;follow-up;high standard;improved;meetings;minimal risk;neoplasm registry;success;virtual "CENTRALIZED INSTITUTIONAL REVIEW BOARD TO REVIEW MINIMAL RISK REGISTRY LINKAGE STUDIES ""CIRB""" n/a NCI 10812214 75N91021P00419-P00004-0-1 N02 5/7/21 0:00 5/6/23 0:00 78166642 "HART, RAFFAELLA " Not Applicable Unavailable 112007062 L1K7UFDEG5N5 112007062 L1K7UFDEG5N5 US -506654 LAKE SUCCESS NY Other Domestic Non-Profits 110421055 UNITED STATES N R and D Contracts 2023 15224 NCI Over the past 15 years unprecedented capacity and opportunity for large scale epidemiologic research has emerged but a significant barrier still exists. Researchers who seek to efficiently perform a linkage with multiple state cancer registries must submit applications to each individual registry resulting in significant expenditure of time and fiscal resources. This is compounded by the fact that there is no consistency among states in the application approval and linkage procedures. To address this barrier and continue to improve the opportunities for linkages NCI and NAACCR are working together to develop and implement a Virtual Pooled Registry Cancer Linkage System (VPR-CLS).VPR-CLS will provide a streamlined and efficient process for multi-state cancer linkages and IRB approval. Implementation of such an integrated system to link and provide cancer registry data would benefit the NCI with potential cost savings and enhanced efficiency of current linkage processes for cohort studies and follow-up on NCI sponsored clinical trials. Currently NCI DCCPS funds cohorts that annually follow more than 1.2 million individuals. For most of those follow up information on the development of cancer as well as survival and cause of death are essential components. In addition to DCCPS DCP and DCEG also have large cohort studies that would benefit from cost-efficient methods to acquire follow up information.Establishing use of a CIRB is a key component of the VPR-CLS approach. It is bolstered by the NIH policy effective May 25 2017 (Notice Number NOT-OD-16-094) which set the expectation that a single IRB (sIRB) of record will be used in the ethical review of non-exempt human subjects research protocols funded by the NIH that are carried on at more than one site in the United States. While the minimal risk studies that will be submitted will initially be through the VPR-CLS workflow it is expected that the CIRB will also be used for other DCCPS funded studies utilizing or linking or requesting SEER data where there may be some risk of re-identifiability. These studies will also meet the definition of minimal risk and multi-site research so the NIH policy is applicable regardless of sponsor.The CIRB will not only streamline and speed up the review process but will also eliminate duplicative local IRB review minimize locally driven modifications to the study protocol and ensure a standard high-quality patient protection review. 15224 +No NIH Category available Affect;Animal Model;Animals;Antineoplastic Agents;Biological Process;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer therapy;Breast cancer metastasis;Cancer Patient;Cells;Cessation of life;Chemotherapy and/or radiation;Circulation;Code;Combined Modality Therapy;Cytoplasm;Development;Diagnosis;Disease;Down-Regulation;Drug Targeting;Drug resistance;Endosomes;Engineering;Epidermal Growth Factor Receptor;Epigenetic Process;Estrogen Receptors;Exhibits;Gene Expression Regulation;Gene Silencing;Genes;Genetic;Genetic Transcription;Goals;Growth;Hormones;Human;Immune;Immunocompetent;Immunocompromised Host;Immunosuppression;Immunotherapy;Invaded;Life;Lipids;Malignant Neoplasms;Mediating;Metastatic/Recurrent;Modeling;Multi-Drug Resistance;Mus;Neoplasm Metastasis;Normal tissue morphology;Nucleotides;Oncogenic;Outcome;Patients;Phenotype;Physiological;Play;Progesterone Receptors;Proliferating;RNA;Radiation therapy;Refractory;Regimen;Relapse;Resistance development;Role;Signal Pathway;Small Interfering RNA;Survival Rate;Therapeutic;Time;Transcript;Treatment Efficacy;Tumor Immunity;Tumor Specific Peptide;Untranslated RNA;Woman;aggressive breast cancer;amphiphilicity;cancer drug resistance;cancer subtypes;cancer survival;cancer therapy;chemotherapy;curative treatments;effective therapy;efficacious treatment;efficacy evaluation;endosome membrane;improved;ineffective therapies;innovation;ionization;malignant breast neoplasm;mortality;nanoparticle;novel;novel therapeutics;overexpression;peptide drug;pre-clinical;pre-clinical assessment;prevent;prototype;side effect;standard of care;targeted delivery;targeted treatment;therapeutic siRNA;therapeutic target;therapy outcome;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumorigenesis Smart nanoparticles regulating oncogenic IncRNA for breast cancer therapy This project is aimed at developing safe and effective smart lipid siRNAnanoparticles to regulate long noncoding RNAs (lncRNAs) associated with cancermetastasis and drug-resistance in triple-negative breast cancer patients. Tumor-specific silencing of cancer-promoting lncRNAs with the nanoparticles offers a noveltherapy to treat invasive breast cancer with minimal side-effects to enhance theefficacy of chemotherapy and/or immunotherapy and to eventually eradicate thedisease and improve the survival of cancer patients. NCI 10812121 11/24/23 0:00 PA-20-185 2R01CA235152-06 2 R01 CA 235152 6 "FU, YALI" 12/12/18 0:00 11/30/28 0:00 Innovations in Nanosystems and Nanotechnology Study Section [INN] 6899678 "LU, ZHENG-RONG " "SCHIEMANN, WILLIAM " 11 BIOMEDICAL ENGINEERING 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH BIOMED ENGR/COL ENGR/ENGR STA 441061712 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 405116 NCI 251625 153491 The goal of this project is to develop smart targeted lipid ECO/siRNA nanoparticles (ELNP) to targetoncogenic long non-coding RNAs (lncRNAs) as a novel therapy to treat triple-negative breast cancer(TNBC). Metastasis and drug resistance are the main causes for the high mortality rates of womendiagnosed with TNBC worldwide. Although targeted therapies have been developed to treat somesubtypes of breast cancer the TNBC subtype is particularly refractory to these therapies. OncogeniclncRNAs play a critical role in tumorigenesis metastasis drug resistance and immune suppression ofcancer by simultaneously manipulating multiple cancer-associated signaling pathways. We havedemonstrated in this project that onco-lncRNAs are promising therapeutic targets to treat TNBC andthat downregulation of an onco-lncRNA with systemic delivery of targeted ECO/siRNA nanoparticlesresults in significant suppression of TNBC proliferation. We have identified a novel lncRNA BORGwhich is associated with TNBC development metastasis drug resistance and immune invasion as acompelling therapeutic target to treat TNBC. It is overexpressed in invasive BC including TNBC butnot in normal tissues. Downregulation of BORG with targeted ECO/siRNA nanoparticles has potentialto inhibit metastasis sensitize TNBC to chemotherapy and enhance antitumor immunity for curativetreatment of TNBC. In this project we will optimize and develop the smart ECO/siBORG nanoparticlesto efficiently deliver siBORG in TNBC to silence the cancer-promoting lncRNA. We will also explorethe combination therapy of silencing BORG with a tumor-specific peptide drug conjugate and/orimmunotherapy to treat TNBC and to eventually eradicate this deadly disease. The specific aims ofthis project are 1) to optimize and develop smart siBORG-ELNP for efficient and specific genesilencing in breast cancer cells; 2) to determine the efficacy of targeted siBORG-ELNP as singletherapy and in combination with targeted chemotherapy in animal TNBC models; and 3) to determinethe efficacy of targeted siBORG-ELNP in modulating TIME for improved immunotherapy in animalTNBC models. Our long-term goal is to develop a novel and feasible therapy based on the smartnanoparticles to treat life-threatening breast cancer. 405116 +No NIH Category available Aftercare;Breast Cancer survivor;Breast Cancer survivorship;Cancer Survivor;Cancer Survivorship;Caring;Complex;Effectiveness;Guidelines;Hybrids;Interview;Knowledge;Long-Term Care;Methods;Modeling;Oncology;Patient Care;Patients;Policies;Population;Primary Care;Process;Provider;Recording of previous events;Research Design;Risk Management;Risk Reduction;Site;Structure;Symptoms;Testing;Translating;Waiting Lists;clinically actionable;concept mapping;design;evidence base;follow-up;implementation strategy;implementation/effectiveness;malignant breast neoplasm;primary care practice;receptor;research study;survivorship;symptom management;translational potential Diversity Supplement to Adapting and implementing evidence-based breast cancer follow-up in primary care Project NarrativeThe numbers of breast cancer survivors are increasing and their symptom burden after treatment is significant.Despite a growing evidence base of symptom management and risk reduction strategies use of theseactivities in primary care practice remains suboptimal. This study engages critical stakeholders in identifyingand prioritizing evidence based activities to enhance breast cancer survivorship care and has potential toimpact implementation strategies used throughout the U.S. for long-term care for patients with a history ofbreast cancer. NCI 10811996 9/18/23 0:00 PA-21-071 3R01CA257197-03S1 3 R01 CA 257197 3 S1 "SARMA, ELIZABETH ANNE" 7/1/21 0:00 6/30/26 0:00 Science of Implementation in Health and Healthcare Study Section[SIHH] 8775481 "HUDSON, SHAWNA V." "CRABTREE, BENJAMIN F" 10 FAMILY MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 241091 NCI 153561 87530 Project Summary/AbstractBreast cancer survivors are a growing population and their symptom burden is significant. Despite growingevidence on specific symptoms and risk management strategies efforts to translate knowledge into practicehave produced suboptimal results. Primary care is an ideal receptor site for breast cancer survivors withstudies demonstrating the effectiveness of primary care based survivorship care. Nevertheless over the pastdecade the emphasis on survivorship care plans and survivorship models has not had an evident impact onprimary care breast cancer survivorship care processes. Over the past two decades primary care practiceshave redesigned structures and care processes to deliver care to different complex populations; howeverbreast cancer survivors are not among them. Many currently proposed and tested strategies are consideredoncology-centric and do not fit well within the real world contexts of primary care practices. Results from ourrecent research studies indicate that breast cancer survivorship is not considered clinically actionable evenamong primary care practices with advanced staffing models. Therefore capacity building and stakeholderinformed strategies are needed to enhance the translational potential of survivorship evidence into primarycare practices. This project uses a designing for dissemination perspective blending the implementationExploration Planning Implementation and Sustainment (EPIS) framework and the primary care PracticeChange Model (PCM) as a theoretical basis for understanding multilevel factors impacting the implementationof cancer survivorship guidelines in primary care. These perspectives help frame and identify mismatchesamong existing policy practice provider and patient motivators to translate the evidence into clinicallyactionable primary care practice change strategies. Using a blended implementation/primary care practicechange conceptual framework this project aims to: (1) engage diverse primary care stakeholders in identifyingactionable practice-based activities for provision of long-term breast cancer survivorship care in primary careusing depth interviews; (2) prioritize synthesize and identify actionable activities for providing care to longterm cancer survivors in primary care by engaging key stakeholders using modified online Delphi methods andconcept mapping; and (3) implement and evaluate actionable breast cancer survivorship symptom and riskmanagement activities using a hybrid type 1 effectiveness-implementation cluster study design with waitlistcontrol in 26 primary care practices. Study results are poised to have profound impact on implementationstrategies used throughout the U.S. to provide long-term care for patients with a history of breast cancer. 241091 +No NIH Category available Acids;Address;Adherence;Adult;Affect;African;African American population;Amino Acids;Animals;Antineoplastic Agents;Bacteria;Bile Acids;Bilophila wadsworthia;Biometry;Body Weight decreased;Butyrates;Caloric Restriction;Calories;Cell Proliferation;Cells;Cellular biology;Clinical Research;Clostridium;Colon;Colorectal Cancer;Computational Biology;Controlled Study;Coupled;DNA Repair;Data;Deoxycholic Acid;Development;Diet;Dietary Factors;Dietary Fiber;Dietary Practices;Disparity;Epithelial Cells;Exhibits;Fiber;Fostering;Gene Expression;Genes;Genomic Instability;Glycine;Growth;High Prevalence;Human;Hydrogen Sulfide;Incidence;Inflammation;Intake;Intervention;Intestines;Link;Mediating;Medical;Medicine;Mediterranean Diet;Metabolic;Metabolism;Microbiology;Molecular;Mucositis;Not Hispanic or Latino;Obesity;Observational Study;Pathway interactions;Pattern;Persons;Physiology;Plants;Primates;Production;Proliferating;Proteins;Psychology;Public Health;Race;Randomized;Risk Factors;Risk Reduction;Sampling;Structure;Subgroup;Taurine;Testing;Translating;Tumor Promoters;Tumor Promotion;Weight;Weight maintenance regimen;anti-cancer;arm;bile acid metabolism;cancer health disparity;carcinogenesis;colon bacteria;colorectal cancer prevention;colorectal cancer risk;dietary restriction;evidence base;genotoxicity;gut bacteria;gut microbes;gut microbiome;gut microbiota;high risk population;innovation;intervention effect;intestinal epithelium;lifestyle intervention;microbial;microbial composition;modifiable risk;mortality;multidisciplinary;nutrition;personalized approach;post intervention;response;saturated fat Mediterranean Diet and Weight Loss: Targeting the Bile Acid/Gut Microbiome Axis to Reduce Colorectal Cancer Risk PROJECT NARRATIVEAfrican Americans (AAs) have the highest colorectal cancer (CRC) incidence and mortality that we hypothesizecan be attributed to their higher prevalence of obesity intake of low fiber high animal protein and saturated fatdiets and a higher abundance of gut bacteria known to metabolize bile acids to metabolites that are genotoxicand tumor promoting. Obesity and diet determine the extent to which bile acid metabolism is a risk factor forCRC. This proposal will determine if the largely plant-based Mediterranean Diet alone weight loss alone or thetwo interventions combined can affect the bile acid-gut microbiome axis ultimately revealing critical informationon how weight loss and diet can address CRC risk in AAs but also in other high-risk populations. NCI 10811575 12/21/23 0:00 PAR-18-559 5R01CA250390-04 5 R01 CA 250390 4 "ROSS, SHARON A" 1/15/21 0:00 12/31/25 0:00 Cancer Prevention Study Section[CPSS] 1899365 "FITZGIBBON, MARIAN L." "TUSSING-HUMPHREYS, LISA " 7 PEDIATRICS 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL SCHOOLS OF MEDICINE 606124305 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 563557 NCI 391619 171938 ABSTRACT. Colorectal cancer (CRC) is associated with multiple risk factors including obesity low fiber dietsand diets high in animal protein and saturated fat (SFat). African Americans (AAs) have a higher prevalence ofthese risk factors and they have the highest incidence of CRC and related mortality. These multiple risk factorsare also linked to higher circulating and fecal bile acids (BA) and a shift in BA amino acid conjugation from glycineto taurine. These BA-related changes can alter the composition structure and metabolic activity of the gutmicrobiota fostering conditions for gut bacteria to expand and metabolize taurine-conjugated BAs to genotoxichydrogen sulfide (H2S) and the tumor promoter deoxycholic acid (DCA); a colonic milieu conducive to theformation of CRC. We have shown that the abundance of H2S-producing bacteria is significantly higher in thecolon of AAs compared to non-Hispanic whites and is a defining feature among AA CRC cases implicating thesebacteria as contributors to CRC development in a race-dependent manner. Moreover the microbial differenceis associated with higher intake of SFat and animal protein in AAs providing a pivotal intervention target. Wehypothesize that targeting the BA-gut microbiome axis to suppress abundance growth and metabolic activity ofH2S and DCA producing bacteria through diet and weight loss (WL) may reduce CRC risk especially amongAAs. A Mediterranean Diet (MedDiet) a largely plant-based dietary pattern is relevant to CRC prevention andmicrobial production of anti-cancer metabolites in observational studies. A MedDiet can shift BA metabolism asshown in primates and when combined with calorie restriction shows superior adherence and weight control inhumans given its palatability. To date no studies have tested in an RCT the effects of a MedDiet alone (Med-A) WL through lifestyle intervention (WL-A) or a calorie-restricted MedDiet for WL (WL-Med) on the BA-gutmicrobiome axis and its relevance to CRC prevention among AAs. Our multidisciplinary team combiningexpertise in psychology nutrition microbiology molecular cell biology computational biology medicine andbiostatistics propose to conduct a four-arm RCT in which 200 obese AAs 45-75 years old complete one of thefollowing 8-month interventions: Med-A weight stable; WL-A calorie restriction with no diet pattern change; WL-Med; or Control. We will use samples and data collected at baseline mid-study (month-4) and post-interventionto compare the effects of the interventions on 1) Concentration and composition of circulating and fecal BAs; 2)Gut microbiota and metabolic function; and 3) Gene expression profiles of exfoliated intestinal epithelial cells.Our approach is strong given our multidisciplinary team use of evidence-based lifestyle interventions andsophisticated omics analyses to examine crosstalk between diet/WL gut microbiome and host intestinalphysiology. If successful this study could have profound public health impact on CRC risk among AAs and otherhigh-risk populations that would translate into timely dissemination opportunities. 563557 +No NIH Category available Automobile Driving;Autophagocytosis;Basic Cancer Research;Cancer Etiology;Cancer Patient;Cell Death Induction;Cell Migration Inhibition function;Cell Proliferation;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemoresistance;Collaborations;Colon Carcinoma;Colorectal Cancer;Development;Disease;Down-Regulation;EIF-2alpha;Effectiveness;Ensure;Epithelial Cells;Equilibrium;Event;Funding;Grant;HK2 gene;Inflammation;Integrins;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Mutation;Oncogenic;Organism;PH Domain;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Protein Dephosphorylation;Protein Family;Protein Kinase;Protein phosphatase;Proto-Oncogene Proteins c-akt;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Stress;Supporting Cell;Testing;Training;Tumor Suppressor Proteins;United States;biological adaptation to stress;cancer cell;cancer initiation;cancer survival;cancer type;cell growth regulation;chemotherapy;coping mechanism;endoplasmic reticulum stress;improved;in vivo;insight;leucine-rich repeat protein;mitochondrial autophagy;mortality;mouse model;multicatalytic endopeptidase complex;novel;protein expression;response;sensor;success;translational cancer research;tumor initiation;tumor metabolism;tumor progression;tumorigenesis Diversity Supplement Carolina Galeano-Naranjo PROJECT NARRATIVE Colorectal cancer mortality is predominantly due to the development of disseminated disease and resistantto conventional chemotherapy. Our study focuses on developing a mechanistic understanding of PHLPP-mediated regulation of cellular stress signaling to circumvent chemoresistance. Results from our studies will helpidentify new treatment options and better predict the effectiveness of chemotherapy agents. NCI 10811185 7/19/23 0:00 PA-21-071 3R01CA133429-16S1 3 R01 CA 133429 16 S1 "SALNIKOW, KONSTANTIN" 4/1/09 0:00 4/30/25 0:00 Molecular Oncogenesis Study Section[MONC] 7353657 "GAO, TIANYAN " Not Applicable 6 BIOCHEMISTRY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 67241 NCI 49021 18220 Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately145000 new cases and 51000 deaths are predicted for the year 2019; and this mortality is predominantly dueto poor responses to available treatment options. A better understanding of the molecular events leading tocancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients.My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases PHLPP(PH domain Leucine-rich-repeats Protein Phosphatase) in inhibiting colon cancer initiation and progression. Wehave made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor aswell as the molecular mechanism underlying PHLPP regulation. The overall objective of this study is to furtherdevelop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supportingcell survival and tumorigenesis. In exciting recent findings we demonstrated that chemotherapy-induced ERstress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulatingeIF2/ATF4-mediated signaling. In addition we found that downregulation of PHLPP promotes mitochondrialfission by regulating Drp1 phosphorylation. Collectively the central hypothesis driving this proposed study is thatPHLPP serves an essential stress sensor in CRC in which cellular stress signals trigger PHLPP degradation topromote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate the molecularmechanism underlying PHLPP-mediated regulation of eIF2/ATF4 signaling. We will determine ifdownregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagyactivation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics;and 3) to define the role of mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis invivo. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes to tumorinitiation and progression in colon cancer. This supplement will allow Ms. Carolina Galeano-Naranjo to receivefurther training in conducting basic and translational cancer research. Her results will assist in determining therole of PHLPP in CRC by regulating mitochondrial activity. She will determine if PHLPP mutations found in CRCpatients interfer with their ability to control Drp1 phosphorylation and mitochondrial fission. Ultimately byproviding mechanistic insights into PHLPP-dependent regulation of stress response our findings will help identifynew treatment options and better predict the effectiveness of chemotherapy agents based on PHLPP status incancer patients. 67241 +No NIH Category available Bioinformatics;Data;Data Analytics;Division of Cancer Epidemiology and Genetics;Goals;Manuals;Personally Identifiable Information;Process;Secure;Services;Standardization;data management;data modeling;research study;software development;tool development Services for Data Modeling Acquisition and Management n/a NCI 10810623 75N91020D00007-P00003-759102000001-1 N02 9/16/20 0:00 3/15/24 0:00 77865900 "GIFFEN, CAROL " Not Applicable 4 Unavailable 83656892 LGGFBF8YVA71 83656892 LGGFBF8YVA71 US 39.047465 -77.125049 1069201 "INFORMATION MANAGEMENT SERVICES, INC." CALVERTON MD Domestic For-Profits 207053407 UNITED STATES N R and D Contracts 2023 200000 OD The goal of this Task Order is to transition all activities and services of the incumbent and to provide biomedical data management support including manual and automated secure and standardized processes to enter store retrieve and analyze data and documents for DCEG research studies. Data management tasks may include data containing Personally Identifiable Information (PII).1)Data Modeling Acquisition and Management - 2)Data Analytics including Statistical and Bioinformatic Analysis 3)Tool and Software Development 4)Transition-Out Plan 200000 +No NIH Category available Acceleration;Address;Amino Acid Sequence;Artificial Intelligence;Automated Abstracting;Blindness;Calcium;Cardiovascular Diseases;Cell physiology;Classification;Communities;Cryoelectron Microscopy;Darkness;Data;Disease;Disparate;Electrophysiology (science);Epilepsy;Family;Family member;Genome;Goals;Graph;Homeostasis;Informatics;Ion Channel;Kidney Failure;Language;Link;Machine Learning;Malignant Neoplasms;Maps;Methods;Mining;Mission;Molecular;Mutation;Names;Organism;Orthologous Gene;Pathway interactions;Physiological;Proteins;Proteome;Readability;Resources;Semantics;Source;Structural Models;Structure;Structure-Activity Relationship;Testing;Training;Visualization;cell type;deep learning model;drug discovery;experimental study;genome resource;human disease;knowledge graph;knowledge integration;model organism;nervous system disorder;tool Annotating dark ion-channel functions using evolutionary features machine learning and knowledge graph mining (Kennady Boyd) Project Narrative (unchanged)Ion channels are a large family of druggable proteins causatively associated with amultitude of human diseases including neurological disorders cardiovascular diseasesepilepsy kidney failure blindness and cancer to name but a few. However an incompleteunderstanding of their molecular and cellular functions presents a bottleneck in ongoingdrug discovery efforts. By developing cutting edge tools and resources that cater to theunique needs of the ion channel community the proposed studies will accelerate thefunctional annotation of understudied members of this family and address the overallmission of the IDG (Illuminating the Druggable Genome) project in illuminating thedruggable proteome. NCI 10809950 8/24/23 0:00 PA-21-071 3U01CA271376-02S2 3 U01 CA 271376 2 S2 "LI, JERRY" 7/7/22 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1(80)] 9758077 "KANNAN, NATARAJAN " "LU, WEI " 10 BIOCHEMISTRY 4315578 NMJHD63STRC5 4315578 NMJHD63STRC5 US 33.931173 -83.378873 676602 UNIVERSITY OF GEORGIA ATHENS GA SCHOOLS OF ARTS AND SCIENCES 306021589 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 310 Non-SBIR/STTR 2023 9060 OD 6000 3060 Project Summary (unchanged)The overall goal of this proposal is to annotate understudied dark ion channels using acombination of computational and experimental approaches. Our working hypothesis isthat the wealth of evolutionary data encoded in ion-channel sequences from diverseorganisms and integrative mining of evolutionary data with structure function pathwayand expression data will provide important context for predicting and annotating darkchannel functions at the molecular and cellular level. As a preliminary test of ourhypothesis we have generated a functional classification of ion channel sequences usinga protein language based deep learning model trained on 250 million protein sequencesand have delineated the distinguishing sequence and structural features of understudiedCalcium Homeostasis Modulator (CALHM) family. We have also built an integratedKnowledge Graph (KG) linking diverse forms of ion channel information in machinereadable format and deployed the KG for predicting physiological functions using a graphembedding approach that efficiently captures contextual information encoded in largegraphs. We propose to build on these successful studies to accomplish the following twoaims. Aim1 will develop new tools and resources for visualizing mining and annotatingdark channels using evolutionary features and structural models made available throughcryo-EM studies and artificial intelligence based structure prediction methods. The uniquemodes of CALHM family gating and oligomerization mechanisms predicted throughevolutionary studies will be experimentally validated through mutational studies andelectrophysiology experiments. Aim2 will further develop the ion channel KG bysemantically linking multiple disparate sources of data including cell-type specificexpression orthologs from model organisms and electrophysiology parameters.Knowledge graph embedding approaches will be employed to predict links betweenunderstudied channels disease associations and physiological functions and thepredictions will be made available as text summaries in the IDG resource Pharos. Theproposed studies are expected to address the unique informatics needs of the ion channelcommunity by providing new tools and resources for mapping sequence-structure-function relationships. The proposed studies will also provide new testable hypotheseson understudied channels and significantly enhance the value of Pharos in illuminatingthe functions of the understudied druggable proteome. 9060 +No NIH Category available Acceleration;Address;Amino Acid Sequence;Artificial Intelligence;Automated Abstracting;Blindness;Calcium;Cardiovascular Diseases;Cell physiology;Classification;Communities;Cryoelectron Microscopy;Darkness;Data;Disease;Disparate;Electrophysiology (science);Epilepsy;Family;Family member;Genome;Goals;Graph;Homeostasis;Informatics;Ion Channel;Kidney Failure;Language;Link;Machine Learning;Malignant Neoplasms;Maps;Methods;Mining;Mission;Molecular;Mutation;Names;Organism;Orthologous Gene;Pathway interactions;Physiological;Proteins;Proteome;Readability;Resources;Semantics;Source;Structural Models;Structure;Structure-Activity Relationship;Testing;Training;Visualization;cell type;deep learning model;drug discovery;experimental study;genome resource;human disease;knowledge graph;knowledge integration;model organism;nervous system disorder;tool Annotating dark ion-channel functions using evolutionary features machine learning and knowledge graph mining (Rayna Carter) Project Narrative (unchanged)Ion channels are a large family of druggable proteins causatively associated with amultitude of human diseases including neurological disorders cardiovascular diseasesepilepsy kidney failure blindness and cancer to name but a few. However an incompleteunderstanding of their molecular and cellular functions presents a bottleneck in ongoingdrug discovery efforts. By developing cutting edge tools and resources that cater to theunique needs of the ion channel community the proposed studies will accelerate thefunctional annotation of understudied members of this family and address the overallmission of the IDG (Illuminating the Druggable Genome) project in illuminating thedruggable proteome. NCI 10809931 7/21/23 0:00 PA-21-071 3U01CA271376-02S1 3 U01 CA 271376 2 S1 "LI, JERRY" 7/7/22 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1(80)] 9758077 "KANNAN, NATARAJAN " "LU, WEI " 10 BIOCHEMISTRY 4315578 NMJHD63STRC5 4315578 NMJHD63STRC5 US 33.931173 -83.378873 676602 UNIVERSITY OF GEORGIA ATHENS GA SCHOOLS OF ARTS AND SCIENCES 306021589 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 310 Non-SBIR/STTR 2023 9060 OD 6000 3060 Project Summary (unchanged)The overall goal of this proposal is to annotate understudied dark ion channels using acombination of computational and experimental approaches. Our working hypothesis isthat the wealth of evolutionary data encoded in ion-channel sequences from diverseorganisms and integrative mining of evolutionary data with structure function pathwayand expression data will provide important context for predicting and annotating darkchannel functions at the molecular and cellular level. As a preliminary test of ourhypothesis we have generated a functional classification of ion channel sequences usinga protein language based deep learning model trained on 250 million protein sequencesand have delineated the distinguishing sequence and structural features of understudiedCalcium Homeostasis Modulator (CALHM) family. We have also built an integratedKnowledge Graph (KG) linking diverse forms of ion channel information in machinereadable format and deployed the KG for predicting physiological functions using a graphembedding approach that efficiently captures contextual information encoded in largegraphs. We propose to build on these successful studies to accomplish the following twoaims. Aim1 will develop new tools and resources for visualizing mining and annotatingdark channels using evolutionary features and structural models made available throughcryo-EM studies and artificial intelligence based structure prediction methods. The uniquemodes of CALHM family gating and oligomerization mechanisms predicted throughevolutionary studies will be experimentally validated through mutational studies andelectrophysiology experiments. Aim2 will further develop the ion channel KG bysemantically linking multiple disparate sources of data including cell-type specificexpression orthologs from model organisms and electrophysiology parameters.Knowledge graph embedding approaches will be employed to predict links betweenunderstudied channels disease associations and physiological functions and thepredictions will be made available as text summaries in the IDG resource Pharos. Theproposed studies are expected to address the unique informatics needs of the ion channelcommunity by providing new tools and resources for mapping sequence-structure-function relationships. The proposed studies will also provide new testable hypotheseson understudied channels and significantly enhance the value of Pharos in illuminatingthe functions of the understudied druggable proteome. 9060 +No NIH Category available Address;Affect;African American;African American population;American;Area;Automobile Driving;Basic Science;Biology;Body mass index;Characteristics;Clinical;Clinical Data;Clinical Treatment;Clinical Trials;Colon;Colorectal;Colorectal Cancer;Data;Development;Diagnosis;Diet;Disparity;Environmental Exposure;Environmental Risk Factor;Ethnic Origin;Ethnic Population;Exposure to;Feces;Freezing;Frequencies;Future;Gene Expression Regulation;Generations;Goals;Growth;Health Services Accessibility;Health system;Immune response;Individual;Investigation;Knowledge;Link;Location;Malignant Neoplasms;Metabolic;Metabolic Pathway;Metabolism;Microbiology;Modeling;Molecular;Molecular Target;Mutation;Not Hispanic or Latino;Nutrient Depletion;Operative Surgical Procedures;Outcome;Pathway Analysis;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Physical activity;Predisposition;Primary Neoplasm;Production;Quality of Care;Questionnaires;Race;Research;Resected;Sampling;Social Adjustment;Socioeconomic Factors;Socioeconomic Status;Source;Stratification;Testing;Therapeutic;Therapeutic Intervention;Time;Tissue Sample;Tissues;Treatment Efficacy;Treatment Protocols;Tumor Tissue;United States;biological sex;cancer care;cancer diagnosis;cell growth;chemotherapy;cohort;colon cancer patients;colon microbiome;colorectal cancer progression;colorectal cancer treatment;comorbidity;environmental chemical;ethnic difference;fecal microbiome;genotoxicity;improved;indexing;lifestyle factors;metabolic phenotype;metabolome;metabolomics;metagenome;microbial;microbiome;microbiome research;microbiota;mortality;neoplastic cell;novel;prospective;racial difference;racial population;sex;social health determinants;social influence;social vulnerability;stool sample;stressor;survival disparity;therapeutically effective;treatment response;tumor;tumor metabolism;tumor microbiome;tumor progression;uptake Identification of metabolic niches in African Americans with colorectal cancer NARRATIVEColorectal cancer (CRC) mortality is markedly higher in African-American patients than any other racial or ethnicgroup. This proposal aims to understand how tumor metabolites and microbiome differ between racial/ethnicpopulations how socioeconomic status effects this association and potentially impacts patient outcomes. Thelong-term goals of this research are to determine microbiome and metabolic differences between patients withCRC that can be exploited to improve treatment and reduce mortality. NCI 10809162 12/15/23 0:00 PAR-21-323 1R21CA280372-01A1 1 R21 CA 280372 1 A1 "WALLACE, TIFFANY A" 12/15/23 0:00 11/30/25 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 11685486 "JOHNSON, CAROLINE HELEN" "KHAN, SAJID A" 3 PUBLIC HEALTH & PREV MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF PUBLIC HEALTH 65208327 UNITED STATES N 12/15/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 195766 NCI 116875 78891 PROJECT SUMMARYIn the United States colorectal cancer (CRC) mortality is markedly higher in African-American (AA) patients thanany other racial or ethnic group. Treatment options socioeconomic status (SES) comorbidities and tumorcharacteristics contribute to survival disparities. Tumor characteristics focused on metabolism and microbiologyhave been rarely studied in relation to CRC mortality and racial/ethnic group and thus requires furtherinvestigation. Metabolites are substrates and products of metabolism required by tumor cells for gene regulationgrowth and immune responses. They can modulate the metabolism and efficacy of chemotherapeutic drugstherefore are linked to CRC treatment response and mortality rates. Differences in lifestyle factors (i.e. dietphysical activity) social determinants of health and environmental exposures exist between racial/ethnic groupsand affect metabolite production in CRC. In addition the colon microbiome is a major modulator of metabolitesand has been implicated in CRC. Given that metabolites are susceptible to modulation by lifestyle factors thatdiffer between racial/ethnic groups and tumor characteristics contribute to disparities in CRC mortality wehypothesize that differences in CRC metabolites and microbiome between racial/ethnic groups accountfor disparities in clinical outcomes. Our objective is to address the lack of knowledge in this area byperforming a discovery metabolomics approach to identify salient features of CRC metabolism inherent to race.We will also examine how the microbiome and metabolome change during the continuum of CRC care associatewith treatment responses and are affected by SES. In specific aim 1 we will use untargeted metabolomicsmetabolic pathway analysis and molecular networking approaches to identify CRC tumor tissue metabolitesspecific to AAs with stratification by sex stage and SES. This will generate the first ever metabolic signaturesof CRC in AAs and will include exogenous metabolites derived from environmental exposures and themicrobiome. For specific aim 2 we will identify the impact of surgery and chemotherapeutic treatments on theCRC stool microbiome. We will identify microbiota unique to AA patients and determine if factors related to SESincluding diet physical activity and body mass index may confound this association. We will ultimately determinehow the response to treatment differs between AA and non-Hispanic white patients to better understandmechanisms of increased mortality in AAs with CRC. The immediate outcomes of this proposal are: 1) generationof the first metabolic signature of CRC by race 2) identification of novel microbial and environmental metabolitesof CRC by race 3) the first characterization of microbiome and metabolite changes at crucial time points alongthe continuum of CRC care (e.g. diagnosis surgery chemotherapy) and associations to SES. This data willgenerate new hypotheses regarding tumor characteristics and cancer outcomes. Our long-term goal is toimprove patient outcomes by identifying key metabolic pathways and microbiota that differ betweenrace/ethnicity SES and may be exploited for the development of more effective therapeutic interventions. 195766 +No NIH Category available Inactivation of MSH3 in Colorectal Cancer and Race Project Narrative African Americans have the highest incidence and mortality rates from colorectal cancer over any othermajor racial or ethnic group in the United States but it is not fully clear what drives the aggressiveness ofdisease in these patients. We discovered that pro-inflammatory cytokines like IL6 are persistently releasedduring inflammation and directly impede specific repair processes centered around the DNA mismatch repairprotein MSH3 such that subsequent mutations within DNA accumulate and associates with poor patientoutcome. We aim to understand the contribution of MSH3 dysfunction to the poor survival outcome of AfricanAmerican colorectal cancer patients. NCI 10808670 4/12/23 0:00 PA-21-268 7R01CA258519-03 7 R01 CA 258519 3 "SHARMAN, ANU" 8/1/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-B(55)R] 1877321 "CARETHERS, JOHN M" "ASHKTORAB, HASSAN " 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 3/14/23 0:00 7/31/23 0:00 393 Non-SBIR/STTR 2022 438121 NCI 376899 61222 Abstract The occurrence of CRC in the United States shows a large disparity among recognized races andethnicities with African Americans demonstrating the highest incidence and mortality from this disease. Wehave observed a novel loss of function phenotype for the DNA mismatch repair protein MSH3 that is inducedby pro-inflammatory interleukin-6 (IL6) to shuttle MSH3 from the nucleus (where it normally repairs DNAmicrosatellites and double strand breaks) to the cytosol where it no longer can repair DNA with coincidentaccumulation of tetranucleotide microsatellite frameshifts (termed EMAST elevated microsatellite alterations atselected tetranucleotide repeats). These inflammation-associated microsatellite alterations are observed in50% of all sporadic CRCs and is associated with advance-staged disease and poor patient survival. Thisinflammation-induced somatic MSH3 defect is observed in twice as many African American than Caucasianrectal cancers and is associated with poor patient outcome. In this proposal we hypothesize that MSH3disruption contributes to the consequence of advanced stage and poor survival in African American CRCpatients. Our preliminary data demonstrates clear evidence that MSH3 participates in HomologousRecombination repair of DNA double strand breaks as well as prevents aneuploidy. We have identified 6unique somatic deleterious MSH3 mutations among African American CRCs that have not been reported inpublic databases. And we have characterized that chromosome 9p24.2 loss of heterozygosity (LOH) isassociated with EMAST and dramatically modifies survival of patients whose primary CRC demonstratesEMAST and 9p24.2 LOH. In this proposal we will examine the central role of MSH3 dysfunction in itscontribution to the survival outcome of African American CRC patients. Our aim is to assess the role of MSH3-disrupted double strand break mis-repair among African American CRCs determine the functionality of 6unique MSH3 mutations observed in African American CRCs and ascertain the contribution of MSH3-deficiency with chromosome 9p24.2 LOH in the aggressiveness of African American CRCs. Overall thisproposal examines the role and contribution of defective MSH3 protein that likely contributes to the poorphenotype associated with African American CRC patients. 438121 +No NIH Category available Acute Lymphocytic Leukemia;Address;Adverse event;Behavior Therapy;Behavioral;Behavioral Model;Cancer Control;Cancer Survivor;Child;Child Health;Childhood Acute Lymphocytic Leukemia;Childhood Cancer Treatment;Chronic;Clinical;Clinical Trials;Cognitive;Cognitive Therapy;Conduct Clinical Trials;Coping Skills;Data;Development Plans;Diagnosis;Dietary intake;Disease-Free Survival;Disparity;Dose;Eating;Education;Eligibility Determination;Enrollment;Environment;Family;Feedback;Future;Glucocorticoids;Goals;Health;Health Promotion;Health behavior;Intervention;Interview;Knowledge;Malignant Childhood Neoplasm;Malignant Neoplasms;Mentorship;Modeling;Newly Diagnosed;Obesity;Outcome;Participant;Patients;Pharmaceutical Preparations;Phase;Physical activity;Play;Preparation;Process;Prognosis;Protocols documentation;Research;Research Personnel;Role;Scientist;Sepsis;Shapes;Stress;Stress and Coping;Structure;Survival Rate;System;Targeted Research;Testing;Time;Toxic effect;Training;Treatment Protocols;Treatment outcome;Unhealthy Diet;Weight;Weight Gain;Work;Youth;acceptability and feasibility;arm;behavior change;cancer diagnosis;career;career development;clinical practice;coping;design;efficacy testing;efficacy trial;evidence base;excessive weight gain;experience;family structure;family support;follow-up;healthy weight;high risk;improved;intervention refinement;leukemia treatment;multidisciplinary;patient engagement;patient oriented;physical inactivity;pilot test;prevent;preventive intervention;recruit;relapse risk;research and development;retention rate;sedentary;skill acquisition;skills;stress management;stressor;survivorship;therapy development;treatment disparity;weight gain prevention A Healthy Weight Intervention for Family Stress during the Early Phases of ALL Treatment: NOURISH-ALL PROJECT NARRATIVEExcessive weight gain leading to obesity is common during the early phases of pediatric acute lymphoblasticleukemia (ALL) treatment and results in higher risk of relapse lower event-free survival rates and more adverseevents during treatment. To address multiple calls from the NCI and other federal agencies for research targetingdisparities in treatment outcomes among patients who experience obesity this K08 research will adapt refineand pilot test family-based health promotion intervention that aims to curb excessive weight gain among youthwith newly diagnosed ALL. The proposed research and career development plan will yield important patient-centered data regarding components of intervention adaptation feasibility acceptability and participantengagement enhancing the potential for the investigator to advance behavioral cancer control science andimprove clinical outcomes for youth with ALL. NCI 10808650 9/14/23 0:00 PA-20-202 1K08CA279877-01A1 1 K08 CA 279877 1 A1 "RADAEV, SERGEY" 9/15/23 0:00 8/31/28 0:00 Career Development Study Section (J)[NCI-J] 78360570 "BATES, CAROLYN R" Not Applicable 3 PEDIATRICS 16060860 YXJGGNC5J269 16060860 YXJGGNC5J269 US 39.026584 -94.636347 1484303 UNIVERSITY OF KANSAS MEDICAL CENTER KANSAS CITY KS SCHOOLS OF MEDICINE 661608500 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 209314 NCI 194947 14367 PROJECT SUMMARY/ABSTRACTExcessive weight gain leading to obesity is common during the early phases of pediatric acute lymphoblasticleukemia (ALL) treatment and results in higher risk of relapse lower event-free survival rates and more adverseevents during treatment. Yet effective preventive interventions for excessive weight gain during the early phasesof ALL treatment are lacking. Aligned with NCI priorities the long-term objective of this work is to mitigate weight-related disparities in pediatric cancer treatment outcomes. Guided by the ORBIT Model of BehavioralIntervention Development the goal of this proposal is to adapt refine and pilot test a family-based healthpromotion intervention that aims to curb excessive weight gain among youth with ALL by integrating support forfamily coping with stress during the early phases of ALL treatment. Given that ALL is most prevalent in youngchildren families play an essential role in shaping youths health behaviors during treatment. In Aim 1a the PIand her mentorship team will adapt an existing family-based health promotion intervention (NOURISH-T) to meetthe specific needs of families of youth in the early phases of ALL treatment (NOURISH-ALL). Adaptations willincorporate family systems and cognitive behavioral intervention components to support healthy family copingwith diagnosis and treatment stress. Additional patient-centered adaptations regarding intervention content anddelivery will be informed by semi-structured input from families and youth with ALL (n=10 at minimum) andmultidisciplinary clinical experts (n=6 at minimum) until thematic saturation is reached. In Aim 1b theinvestigative team will iteratively refine the NOURISH-ALL intervention through sequential testing with familiesand youth with ALL (n=5 at minimum) and structured participant feedback. Intervention refinement will beongoing until >80% feasibility and acceptability ratings are achieved or until n=10 families complete theintervention and provide structured feedback. In Aim 2 the adapted and refined NOURISH-ALL intervention willbe pilot tested in a single arm trial with 20 newly recruited families of youth in the early phases of ALL treatment.The research team will assess key components of participant engagement to inform the future fully poweredclinical trial including recruitment rate retention at treatment completion and intended intervention dosereceived. By incorporating tailored strategies for health promotion during the early phases of ALL treatment theproposed study seeks to shift clinical practice paradigms to prevent weight-related disparities in treatmentoutcomes. This K08 will provide opportunities for the PI to acquire skills and knowledge in: (1) the early phasesof ALL treatment (2) scientific adaptation and refinement of family-based behavior change interventions and (3)the conduct of clinical trials focused on behavior change interventions. The research and career developmentplan supported by a multidisciplinary team of experts in a rich academic environment will support the PIstransition to independence as a cancer control scientist who possesses the skills and expertise needed to adaptevidence-based behavior change interventions to the pediatric cancer treatment context. 209314 +No NIH Category available Androgen Antagonists;Androgen Receptor;Androgens;Androstenedione;Antiandrogen Therapy;Automobile Driving;Cell Count;Computer Models;Development;Dose;Drug Kinetics;Family;Future;Genes;Goals;Libraries;Metabolism;Oxidoreductase;Pathway interactions;Patients;Play;Receptor Signaling;Resistance;Role;Safety;Signal Transduction;Structure;Testosterone;Toxic effect;Translating;VCaP;Variant;Xenograft procedure;abiraterone;advanced prostate cancer;clinical development;design;efficacy evaluation;enzalutamide;enzyme activity;improved;in vivo;inhibitor;member;neoplastic cell;novel;novel strategies;novel therapeutics;prostate cancer progression;small molecule;targeted treatment;therapy resistant;transcriptome sequencing;treatment response;tumor growth;tumor progression Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer PROJECT NARRATIVEIncreasing evidence showing that AKR1C3 and AR/ARv7 play important roles in promoting prostate cancerprogression and resistance. We have developed a number of novel small molecules that function as dualinhibitors of AR/ARv7 and AKR1C3. This application is aimed to determine the efficacy mechanisms of actionand safety of these small molecules and to develop as novel agents to treat advanced prostate cancer. NCI 10808574 8/2/23 0:00 PA-21-071 3R01CA271327-02S1 3 R01 CA 271327 2 S1 "KONDAPAKA, SUDHIR B" 4/1/22 0:00 3/31/27 0:00 6615638 "GAO, ALLEN C" "LI, PUI-KAI " 4 UROLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 73643 NCI 50278 23365 ABSTRACTContinued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR targeted therapycontributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights theneed for new strategies to block continued AR signaling. Aldo-keto reductase family 1 member C3 (AKR1C3)is one of the most important genes involved in androgen synthesis and metabolism. Activity of this enzymecannot be inhibited by abiraterone. Both AR/AR-V7 and AKR1C3 play key roles in cancer progression anddriving resistance to current therapies. Therefore inhibition of both AR/AR-V7 and AKR1C3 would be an idealstrategy for treating advanced prostate cancer (PCa). We have designed a novel strategy to simultaneouslytarget the AR/AR-V7 and AKR1C3 pathways. We designed and synthesized a library of novel dualAKR1C3/AR/AR-variant inhibitors called LX according to structure-based computer modeling. Of the LXcompounds LX-1 had the greatest effect at reducing cell number AR/AR variant expression and AKR1C3activity. RNA-seq analysis demonstrated a robust reduction in expression of AR and AR-V7 signaling genesby the selected LX. LX-1 inhibited conversion of the testosterone precursor androstenedione into testosteronein tumor cells which express high levels of AKR1C3 in a dose-dependent manner ex vivo. Furthermoretreatment with LX-1 reduced tumor growth in VCaP and LuCaP35CR PDX xenografts in vivo and decreasedintratumoral testosterone. Based on these findings the overall hypothesis is that concurrent inhibition ofAR/AR variants and AKR1C3 using novel LX dual inhibitor suppresses CRPC tumor growth overcomesresistance and improves treatment response to enzalutamide/abiraterone. This project is to furthercharacterize LX by understanding its mechanism of action (MOA) determining its efficacy pharmacokineticsand toxicity and to determine their effects on the sensitivity to anti-androgen therapy with the goal to translateto future clinical development to treat advanced PCa. We hope that completion of the proposed studies willlead to the development of a new class of therapeutic agents that target both intracrine androgen synthesisand the AR signaling. 73643 +No NIH Category available American;Androgen Receptor;Androgen Suppression;BRCA deficient;BRCA mutations;Binding;C-terminal;CHEK2 gene;Cancer Etiology;Cell Line;Cell Survival;Cells;Cessation of life;Complex;DNA;DNA Damage;DNA Repair;DNA Repair Gene;DNA Sequence Alteration;DNA Synthesis Inhibition;DNA Synthesis Inhibitors;DNA biosynthesis;Data;Defense Mechanisms;Development;Diagnosis;Drug Kinetics;Drug resistance;Effectiveness;Evaluation;Excretory function;FANCD2 protein;Family;Fanconi Anemia Complementation Group A Protein;Generations;Genes;Genetic;Germ-Line Mutation;Goals;In Vitro;Lead;Lesion;Ligands;Malignant Neoplasms;Malignant neoplasm of prostate;Mammalian Cell;Mediating;Medical;Metabolism;Modality;Modeling;Mus;Mutagenesis;National Cancer Institute;Pathway interactions;Patient-Focused Outcomes;Patients;Play;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Property;Prostate Cancer therapy;Proteins;Public Health;Receptor Signaling;Regulator Genes;Resistance;Route;Safety;Scaffolding Protein;Shapes;Site;Somatic Mutation;Structure;Structure-Activity Relationship;Therapeutic;Toxic effect;United States;Xenograft procedure;absorption;acquired drug resistance;analog;brca gene;cancer cell;cancer therapy;castration resistant prostate cancer;cost;design;effective therapy;enzalutamide;gene repair;homologous recombination;hormone therapy;improved;improved outcome;in vivo;inhibitor;insight;men;mortality;novel therapeutics;pharmacologic;preclinical development;prostate cancer cell;prostate cancer model;public health relevance;recombinational repair;repaired;replication stress;scaffold;small molecule;small molecule inhibitor;synergism;targeted agent;targeted treatment;tumor;tumor growth;tumor xenograft Inhibiting Rev1-mediated translesion DNA synthesis for cancer therapy Project Narrative (Public Health Relevance Statement) Metastatic castration-resistant prostate cancer (mCRPC)the most lethal form of prostate cancer withlimited treatment optionsis characterized by dysfunctional DNA repair with 20%30% of mCRPC bearinggermline or somatic mutations in DNA repair genes such as BRCA1/2 and others with deficiency in homologousrecombination repair (HRR). Genetic or treatment-induced HRR deficiency renders cancer cells particularlyvulnerable to inhibition of DNA-damage tolerance pathways such as the Rev1-dependent translesion DNAsynthesis (TLS). Hence results from our proposed studies of TLS inhibition in mCRPC are highly relevant topublic health as they will provide valuable insights into the development of new treatment modalities for patientswith lethal mCRPC. NCI 10807991 1/1/24 0:00 PA-20-185 1R01CA279034-01A1 1 R01 CA 279034 1 A1 "AGYIN, JOSEPH KOFI" 1/1/24 0:00 11/30/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 9404899 "HONG, JIYONG " "ZHOU, PEI " 4 CHEMISTRY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF ARTS AND SCIENCES 277054673 UNITED STATES N 1/1/24 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 521760 NCI 336055 185705 Project Summary/Abstract Prostate cancer is a leading cause of cancer death in American men. The National Cancer Institute estimatedthat there would be ~268490 new cases of prostate cancer and ~34500 deaths from prostate cancer within theUnited States for 2022. Despite the development of second-generation hormonal therapies (e.g. enzalutamide)and targeted poly(ADP-ribose) polymerase (PARP) inhibitors (e.g. olaparib) the mortality of prostate cancerremains high as intrinsic and acquired drug resistance is common to all these agents and many patients developincurable metastatic castration-resistant prostate cancer (mCRPC) within 23 years. Accumulating evidence and our preliminary data show that mCRPC cells deficient in homologousrecombination repair (HRR) activities due to genetic mutations of DNA repair genes such as BRCA1/2 or dueto the enzalutamide treatment-induced BRCAness state are particularly vulnerable to disruption of DNA-damagetolerance pathways such as the mutagenic translesion DNA synthesis (TLS). TLS is a fundamental cellulardefense mechanism that enables DNA replication across lesion sites under replication stress in order to promotecell survival at the cost of replication fidelity. The eukaryotic Y-family polymerase Rev1 is an essential scaffolding protein in TLS and the interactionbetween its C-terminal domain (CTD) with translesion polymerase z is absolutely required for function. Aided byour structural elucidation of the Rev1-bridged translesionsome complex in TLS we have identified the first-in-class in vivo active small molecule inhibitor JH-RE-06 that disrupts TLS by directly binding to the Rev1 CTD toblock the Rev1 interaction with the Rev7 component of polymerase z. JH-RE-06 suppresses spontaneous andtreatment-induced mutagenesis in cells and sensitizes cancer cells to a variety of DNA-damaging agents bothin vitro and in a murine xenograft tumor model. Recently we have shown that mCRPC cells in the BRCAnessstate are particularly vulnerable to JH-RE-06 inhibition. The goal of this proposal is to further characterize JH-RE-06 and derivatives in prostate cancer cells optimize their potency safety and other pharmacologicalproperties and demonstrate their effectiveness in treating mCRPC and suppressing acquired drug resistance inmurine tumor models. The successful execution of the proposal will profoundly alter the existing paradigm oflethal prostate cancer treatment by providing effective means to overcome intrinsic and acquired drug resistancethus improving the outcomes for patients with lethal prostate cancer. 521760 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10807951 261201800012I-P00009-26100001-2 N01 3/16/23 0:00 4/30/23 0:00 78113745 "CHARLTON, MARY " Not Applicable 1 Unavailable 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA Domestic Higher Education 522421320 UNITED STATES N R and D Contracts 2023 4271214 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 4271214 +No NIH Category available Anatomy;Area;Automobile Driving;BRAF gene;Benign;Biological Assay;Biological Models;Biology;Biopsy;Chemoprevention;Classification;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Data Set;Dermatologist;Development;Disease;Drug Delivery Systems;Early Diagnosis;Engineering;Event;Genes;Genetic;Growth;Human;Human Engineering;In Vitro;Knowledge;Lesion;Mediator;Melanocytic nevus;MicroRNAs;Mole the mammal;Molecular Profiling;Neoplasms;Nevi and Melanomas;Nevus;Physicians;Pilot Projects;Positioning Attribute;Prevention;Prevention strategy;Reporting;Reproducibility;Skin Cancer;Skin Pigmentation;System;Techniques;Training;Transcript;Validation;aurora B kinase;detection method;diagnostic accuracy;differential expression;driver mutation;high risk population;in vivo;in vivo Model;melanocyte;melanoma;melanoma biomarkers;miRNA expression profiling;novel;pre-clinical;prevent;screening;skin lesion;tumor Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression Project NarrativeMelanomas are pigmented skin cancers that can be difficult to distinguish from benign moles even for trainedprimary physicians and dermatologists and can be deadly if overlooked. Based upon the genes and regulatorymolecules that distinguish moles from melanomas the proposed project explores new methods for detectingand preventing the transformation of moles into melanomas. NCI 10807912 9/18/23 0:00 PA-21-071 3R01CA229896-03S1 3 R01 CA 229896 3 S1 "WEINREICH, MICHAEL DALE" 8/24/21 0:00 7/31/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 11759281 "JUDSON-TORRES, ROBERT LAIRD" Not Applicable 1 DERMATOLOGY 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 59875 NCI 38880 20995 SummaryA single driver mutation BRAFV600E drives half of all melanomas. However in the majority of casesacquisition of BRAFV600E instead drives benign tumors such as melanocytic nevi (the common mole). We seekto decipher the intracellular mechanisms that prevent full transformation and harness this knowledge todevelop candidate early diagnosis and chemoprevention strategies. We have discovered a signature ofmicroRNAs (miRNA) as the most differentially expressed transcripts distinguishing nevi from either normalmelanocytes or melanomas. We have reported that expression of these miRNAs classifies biopsied pigmentedneoplasms with high diagnostic accuracy. To determine whether knowledge of these miRNAs could aid in theprevention of melanoma: First we conducted a comprehensive identification and functional screen of thetargets of the most predictive miRNA MIR211-5p. Using freshly isolated and CRISPR engineered humannormal nevus and melanoma melanocytes we identified inhibition of AURKB expression as a criticalmechanism driving both BRAFV600E and MIR211-5p associated growth arrest in vitro. Therefore in Aim 1 ourobjective is to assess the roll of the MIR211-5p/AURKB axis in nevus formation and transformation in vivo andthe efficacy of disrupting this axis in melanoma chemoprevention. Second we generated a non-invasive assayfor miRNA screening of pigmented lesions prior to biopsy. In a small pilot study we found the high accuracy ofclassification of melanocytic neoplasia was retained. In Aim 2 our objective is to validate the utility of usingnon-invasive profiling of the miRNA signature to screen pigmented skin lesions.Three advances distinguish our proposal. The first is the reproducibility of our miRNA classifier currentlyvalidated on six independent datasets. Second our model systems for this diseaseengineered primaryhuman melanocytes nevi and melanomas combined with an in vivo system that recapitulates both thegenetics and progression of melanomaputs us in a unique position to control for context-specific effectswhen studying these critical events. Third is our development of a non-invasive miRNA profiling assay amolecular profiling technique that is both non-invasive and lesion-specific. Our team consisting of experts inboth the basic biology of miRNA and melanoma in vivo models of melanoma topical drug delivery and thedaily practice of melanoma surveillance allows us to comprehensively tackle this project.This project has both basic and clinical potential significance. Our studies explore novel explanations for nevusinitiation driven by observations made from clinical lesions. We expect these studies to directly result in anincrease in the early detection of melanomas and preclinical validation of a strategy for topicalchemoprevention for particularly high-risk individuals and/oror anatomic areas. 59875 +No NIH Category available Abstinence;Adult;Affect;Affective;Behavior;Cancer Control;Cigarette;Cigarette Smoker;Data;Decision Making;Disease;Down-Regulation;Event;Fire - disasters;Functional Magnetic Resonance Imaging;Future;Goals;Health Professional;Health Promotion;Health behavior;Individual;Individual Differences;Informal Social Control;Intervention;Knowledge;Lateral;Light;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Medial;Motivation;Multivariate Analysis;Neurophysiology - biologic function;Participant;Pathway interactions;Pattern;Personality Traits;Persons;Poverty;Process;Provider;Psychology;Public Health;Regulation;Reporting;Research;Risk;Sample Size;Sampling;Scanning;Science;Smoke;Smoker;Smoking;Stimulus;System;Techniques;Testing;Theoretical model;Time;Training;Triage;United States;Up-Regulation;Work;arm;cigarette craving;cigarette smoking;cognitive process;cognitive reappraisal;cost;craving;efficacy trial;experience;experimental study;fighting;insight;lens;neural;neuroimaging;neuromechanism;novel;personalized medicine;personalized strategies;preventable death;response;smoking cessation;theories;tobacco control;tool;treatment as usual;treatment response Construal level as a novel pathway for affect regulation and cancer control 8. Project NarrativeCigarette smoking is among the leading causes of preventable death in the United States because smokingincreases risk for lung cancer and various diseases. Though U.S. smoking rates have declined a substantialpercentage of adults particularly those living in poverty who have repeatedly tried and failed to quit still smokeand therefore could benefit from novel interventions for cessation that operate through different mechanismsthan those of traditional treatments. This study will use neuroimaging to uncover the mechanisms of action of apromising strategy for affect regulation and smoking cessation and also build profiles of individuals for whomthis strategy does and does not work thereby providing tangible and practical information that public healthprofessionals and clinicians can use to inform personalized treatments for cigarette smoking cessation. NCI 10807262 5/16/23 0:00 PAR-18-681 3R01CA240452-04S1 3 R01 CA 240452 4 S1 "FERRER, REBECCA" 4/1/20 0:00 3/31/25 0:00 Addiction Risks and Mechanisms Study Section[ARM] 9164882 "BERKMAN, ELLIOT TODD" Not Applicable 4 PSYCHOLOGY 79289626 Z3FGN9MF92U2 079289626; 948117312 J2KGU972RXG3; Z3FGN9MF92U2 US 44.045509 -123.069741 6297005 UNIVERSITY OF OREGON EUGENE OR SCHOOLS OF ARTS AND SCIENCES 974035219 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 143396 OD 100682 42714 7. Project Summary/AbstractLung cancer is the leading major cause of preventable death in the United States and cigarette smoking is acontributor to lung cancer in 80%90% of cases. Though adult cigarette smoking rates have declinedsubstantially during the past 50 years they remain as high as 30% in certain groups such as individuals livingin poverty. Quitting is difficult: a given quit attempt results in cessation in fewer than 10% of cases and mostadult cigarette smokers have attempted and failed to quit and often many times. What is urgently needed arenovel interventions for cigarette smoking cessation that operate through different mechanisms from thosetargeted by existing interventions which are likely to have been unsuccessful for persistent smokers. A barrierto progress is that the mechanisms of action of most treatments are not known which makes it difficult to knowwhich treatment will work best for whom. We turn to affective science to identify a candidate technique thatcould serve as the basis for a novel intervention. Research on affect regulation typically focuses on down-regulation of affective states such as craving for cigarettes using effortful strategies such as cognitivereappraisal. However a new insight in affect regulation is that people can construe or subjectively understandevents with varying levels of abstraction and that construing health-related behaviors in high- versus low-levelterms promotes health behavior in several domains. For example smokers who want to quit are more likely toresist a cigarette when they construe the same event (e.g. abstinence) in more abstract high-level terms(e.g. becoming a better me) versus more concrete low-level terms (e.g. not smoking this cigarette). Thereis some evidence that high-level construal might rely on distinct mechanisms from traditional affect regulationand smoking reduction interventions but its mechanisms of action are unknown. Directly comparing itsmechanisms to those of alternative affect regulation strategies and developing tools to induce high-levelconstrual are the next steps on the path toward developing a novel intervention. Also establishing individualdifferences in the effects of high-level construal will allow future interventions to be targeted to the individualsfor whom they will be maximally effective. We identified two candidate mechanisms through which high-levelconstrual might operate: down-regulation of craving and up-regulation of goal energization (i.e. motivation toquit). Functional magnetic resonance imaging (fMRI) revealed the neural systems engaged by those processesto be distinct. So we will use multivariate analyses of fMRI data to quantify the similarity of high-level construalto each candidate (Aim 1). This will be done in a longitudinal translational experiment with 4 conditionshigh-level construal down-regulation of craving up-regulation of goal energization and treatment-as-usualin asample of persistent smokers in poverty who are the most likely to benefit from a novel theory-basedtreatment. The sample size (N = 240) affords an examination of individual differences in the effect of high-levelconstrual on neural activity and craving and the degree to which they predict smoking reduction (Aim 2). 143396 +No NIH Category available Ablation;Affect;Amino Acids;Animals;Architecture;Aspartate;Biochemical Pathway;Bioenergetics;CRISPR library;Cancer Biology;Cell physiology;Cells;Chemicals;Clinical Trials;Coculture Techniques;Communication;Complex;Coupled;Data;Deoxycytidine;Desmoplastic;Disease;Doctor of Philosophy;Effector Cell;Equilibrium;Fellowship;Fibroblasts;GOT2 gene;Genes;Genetic;Genetic Screening;Genome;Glutamates;Goals;Growth;Immune;Immune system;Immunocompetent;Immunotherapy;Impairment;Infiltration;Investigation;Isotopes;Knock-out;Knowledge;Libraries;Macrophage;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mentorship;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Molecular;Mus;Myelogenous;Nature;Nerve;Nervous System;Neurons;Neurotransmitters;Nutrient;Oxaloacetates;Oxidation-Reduction;Oxygen;Pancreatic Ductal Adenocarcinoma;Peripheral Nerves;Phase;Physiological;Population;Postdoctoral Fellow;Production;Proliferating;Pyrimidine;Pyrimidines;Pyruvate;Regulatory T-Lymphocyte;Repression;Research Personnel;Resistance;Role;Signal Transduction;Support System;Supporting Cell;T-Lymphocyte;Technical Expertise;Techniques;Testing;Therapeutic;Tissues;Training;Transaminases;Treatment Efficacy;Tumor-Infiltrating Lymphocytes;Tumor-associated macrophages;Vertebral column;Work;amino acid metabolism;anti-tumor immune response;blood vessel development;cancer cell;cancer infiltrating T cells;career;career development;chemotherapy;conditional knockout;cytotoxic;cytotoxicity;gemcitabine;graduate school;in vivo;in vivo Model;inhibitor;metabolic abnormality assessment;metabolomics;mitochondrial metabolism;mouse model;neural;neural network;neurotransmission;novel therapeutics;nucleobase;pancreatic cancer cells;pancreatic cancer model;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;recruit;response;targeted treatment;therapy resistant;tumor;tumor ablation;tumor growth;tumor metabolism;tumor microenvironment;tumorigenesis;tumorigenic Reprogramming Metabolic Networks in the Tumor Microenvironment PROJECT NARRATIVEInteractions between pancreatic cancer cells and non-transformed cells in a tumor are essential for cancergrowth and progression. Reprogramming these metabolic networks is a promising strategy for enhancingtherapeutic efficacy in pancreatic cancer. I will use new mouse models and cutting-edge metabolomictechniques to determine how immune and nerve cells support pancreatic cancer growth through metabolicinteractions. NCI 10807199 7/14/23 0:00 RFA-CA-20-048 4K00CA264414-03 4 K00 CA 264414 3 "ELJANNE, MARIAM" 9/1/21 0:00 5/31/27 0:00 ZCA1-SRB-H(M1) 15621173 "KERK, SAMUEL ANDREW" Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 Other Research-Related 2023 82620 NCI 76500 6120 PROJECT SUMMARYPancreatic ductal adenocarcinoma (PDA) is a deadly disease and better therapies are urgently needed. Thepancreatic tumor microenvironment is complex and stromal and immune cells induce an inflameddesmoplastic response that hinders proper blood vessel formation resulting in poor nutrient and oxygendelivery. Therefore PDA cells must rewire cellular metabolism to maintain their biosynthetic and energeticrequirements. The stromal and immune cells do not simply change tumor architecture they also supportcancer metabolism suppress anti-tumor immune responses and blunt treatment efficacy. Having previouslyidentified a new pathway of metabolic crosstalk between cancer cells and cancer-associatedfibroblasts (CAFs) I now propose to extend this paradigm to discover how the immune and nervoussystems support tumor metabolism to identify new therapeutic opportunities.Tumor-associated macrophages (TAMs) comprise the bulk of the immune compartment in a pancreatic tumorand support malignant progression and therapeutic resistance. In accordance with this our group previouslydemonstrated that TAMs release the pyrimidine deoxycytidine (dC) which based on its molecular similarity isable to inhibit the cytotoxic activity of the frontline chemotherapeutic gemcitabine. Since the amino acidaspartate (Asp) is required for pyrimidine production and Asp is produced by the glutamate oxaloacetatetransaminases (GOTs) I generated macrophage-specific Got1 or Got2 knockout models to study the role ofthe GOTs in TAM metabolism. In Aim 1a I will evaluate how Asp synthesis and dC release in TAMs impactsPDA sensitivity to gemcitabine using syngeneic tumor models. My preliminary data also suggests that GOTactivity and dC modulate T cell function. Therefore in Aim 1b I will determine how loss of Got1 or Got2 inTAMs affects tumor infiltrating T cells and tumor response to immune-based therapy.During the K00 phase I will apply knowledge gained during graduate school in cancer biology and metabolismto an independent postdoctoral project. Pancreatic tumors are highly innervated and neural ablation impairstumor regression. The metabolic underpinnings by which neurons support cancer cells require furtherinvestigation. Therefore my goal as a postdoctoral fellow is to understand how dysregulated PDA metabolismimpacts neuronal recruitment and function as well as metabolic pathways in neurons that are critical for pro-tumor signaling. I plan to use genetic mouse models of PDA in vivo isotope tracing genome CRISPR librariesand ex vivo neuron-PDA co-culture models to answer these questions. Lastly in addition to the proposedstudies this training plan includes activities important for career development mentorship networking andscientific communication to prepare me for successful transition to a postdoctoral fellowship and my career asan independent investigator studying cancer metabolism. 82620 +No NIH Category available Address;American;Animals;Appearance;Area;Awareness;Beds;Biological Assay;Biometry;Blood;Budgets;Cancer Patient;Cancerous;Case Report Form;Cells;Cervical;Cisplatin;Clinical;Clinical Research;Clinical Trials;Communities;Contracts;Country;Coupled;Data;Data Analyses;Developed Countries;Disease;Disease remission;Documentation;Dose;Dose Limiting;Drug Kinetics;Electronics;Eligibility Determination;Engineering;Enrollment;Ensure;Excision;Exercise;Foundations;Funding;Head;Head and Neck Cancer;Hour;Humidity;Hydrogels;Immune checkpoint inhibitor;Immunotherapy;Incidence;Income;Infrastructure;Institutional Review Boards;Intravenous;Life;Life Style;Malignant Neoplasms;Mediation;Medical;Metastatic Neoplasm to Lymph Nodes;Methods;Micrometastasis;Modality;Monitor;Nanotechnology;Nodal;Operative Surgical Procedures;Outsourcing;Patient Participation;Patient Recruitments;Patients;Pharmaceutical Preparations;Phase;Plasma;Platinum;Prevalence;Prevention;Privatization;Procedures;Production;Prognostic Factor;Progression-Free Survivals;Protocols documentation;Quality Control;RTN4 gene;Radiation;Records;Recurrence;Recurrent tumor;Regimen;Research Personnel;Resource-limited setting;Resources;Risk Factors;Safety;Sampling;Site;Solid Neoplasm;Source;Squamous cell carcinoma;Statistical Data Interpretation;Sterilization;Stress;Stress Tests;Survival Rate;Temperature;Toxic effect;Treatment Failure;Treatment Protocols;Treatment-related toxicity;Tumor Debulking;Tyrosine Kinase Inhibitor;United States;Viscosity;Visit;Whole Blood;aggressive therapy;cancer cell;cancer risk;chemotherapeutic agent;chemotherapy;clinical trial analysis;conventional therapy;cost;data management;design;disorder control;draining lymph node;electronic data;electronic data capture system;experience;follow-up;immunoregulation;improved;lymph nodes;malignant mouth neoplasm;manufacture;mass spectrometer;microbial;mouth squamous cell carcinoma;nanoengineering;nanoparticle;novel;operation;oral HPV;oral care;outreach;oxidation;patient population;phase 2 study;photolysis;prevent;response;side effect;socioeconomics;stability testing;targeted agent;therapeutic nanoparticles;timeline;tool;tumor Clinical Studies for Improving Survival Rates for Oral Cancer Patients in Low Resource Settings Project Narrative Privos Nanotechnology-Engineered Hydrogel PRV211 is applied as an intraoperative therapy for oral cancer patients. Following tumor resection PRV211 is applied directly within the tumor bed to kill remaining cancerous cells and prevent micrometastasis or recurrence. PRV211s safety and efficacy has been proven through multiple sets of animal studies. The team is strongly motivated to pursue effective prevention of tumor recurrence with negligible side effects and planning for a clinical study to evaluate the impact of PRV211 on the recurrence rate and overall survival in OSCC patients. This treatment has the potential for improving the progression free survival rates with a great impact on patients lives. NCI 10807196 3/27/23 0:00 PA-21-260 4R44CA272095-02 4 R44 CA 272095 2 "POND, MONIQUE ADRIANNE" 3/1/22 0:00 3/31/25 0:00 Special Emphasis Panel[ZRG1-OTC1-T(10)B] 10614921 "GOLDBERG, MANIJEH N" "KEITH, DONNA " 6 Unavailable 963247924 E6ACGUBJMQC5 963247924 E6ACGUBJMQC5 US 42.368029 -71.091377 10027190 "PRIVO TECHNOLOGIES, LLC" PEABODY MA Domestic For-Profits 19603840 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 395 SBIR/STTR 2023 987292 NCI 659135 263654 Project SummaryOral cancer (OC) is an underserved disease which is often overlooked by the medical community. Yet it is the 6th most common and deadliest cancer in the world. According to the Oral Cancer Foundation over 90% of all oral cancers are oral squamous cell carcinoma (OSCC) - a common subset of head and neck cancers. OC claims the life of one American every hour of each day. Additionally it is on the rise due to the increasing prevalence of oral human papilloma virus (HPV). Overall OC has a 60% survival rate after 5-year remission target with recurrence being an important prognostic factor. Data shows a high correlation between OC risks and low socioeconomic as well as risk factors related to lifestyle. Even in the clinical settings of industrialized nations such as the United States (US) many patients receive suboptimal care for OSCC due to limited resources. Although targeted agents (i.e. tyrosine kinase inhibitors) and immunotherapy (i.e. checkpoint inhibitors) have shown promise in multiple solid tumor types their applicability in the setting of advanced OSCC remains questionable. Unpredictable side effects complications and (especially) high cost limit their US use in low resource settings and in low/mid-income countries (LMICs). Survival in patients with advanced OSCC is driven primarily by locoregional treatment failure/recurrence (i.e. primary site or cervical nodal basins). Escalation of conventional treatment regimens such as surgery radiation and systemic chemotherapy is not feasible due to dose-limiting toxicities. As a result of these converging factors there is a need for novel treatments that can augment existing modalities while improving locoregional control without toxicities. To address this need Privo has developed the PRV211 intraoperative product(PRV211) a nano-engineered hydrogel that immediately after tumor resection or debulking can be applied directly onto the tumor bed. PRV211 retains high concentration of immuno/chemotherapy nanoparticles locally in tumor bed and regional lymph nodes to treat the locoregional disease and reduce tumor recurrence. 987292 +No NIH Category available Affect;Binding;Bioinformatics;Biometry;Bone Morphogenetic Proteins;Butyrates;CD36 gene;Carcinoma;Cell Surface Receptors;Cell Survival;Cells;Cessation of life;Collaborations;Colon Carcinoma;ENG gene;Ecosystem;Endoglin;Energy-Generating Resources;Engraftment;Epithelial Cells;Epithelium;Exposure to;FOXM1 gene;FRAP1 gene;Fat-Restricted Diet;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Glutamate-Ammonia Ligase;Glutamine;Growth;Hepatic Stellate Cell;Hepatocyte;High Fat Diet;Incidence;Intake;Ligands;Liver;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mediating;Metastatic Neoplasm to the Liver;Mus;Nature;Neoplasm Circulating Cells;Neoplasm Metastasis;Neutralization Tests;Palmitates;Pathway interactions;Play;Primary Neoplasm;Property;Regulation;Resistance;Resources;Role;Saturated Fatty Acids;Signal Pathway;Signal Transduction;Signaling Protein;Site;Solid Neoplasm;Testing;Time;Transforming Growth Factor beta;Tumor Expansion;bone;cancer cell;cancer type;circulating cancer cell;colon cancer metastasis;curative treatments;fatty acid oxidation;feeding;lymph nodes;mortality;neoplastic cell;notch protein;novel;paracrine;patient population;permissiveness;prostate cancer metastasis;receptor;response;saturated fat;stem;synergism;therapeutic target;tumor;tumorigenesis;tumorigenic;uptake Project 1- Role of fat in metastatic engraftment and expansion in the liver PROJECT NARRATIVEThe liver is the most common site of metastasis of solid tumors after the lymph node with no curativeintervention. We found that intake of a high-fat diet even for a relatively short period of time is sufficient toincrease the incidence of liver metastasis in mice. Our project examines whether inhibiting a central pathwayelevated by high-fat diet in both cancer cells and liver hepatocytes will limit liver metastasis of colon pancreasand prostate cancer. The findings could suggest therapeutic targets for the greater solid tumor patient population. NCI 10807146 7/28/23 15:04 PA-21-071 3P01CA233452-04S2 3 P01 CA 233452 4 S2 "WATSON, JOANNA M" 1/21/20 0:00 12/31/24 0:00 ZCA1 6299 2565214 "BHOWMICK, NEIL A." Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 3/1/23 0:00 12/31/23 0:00 Non-SBIR/STTR 2023 140891 84366 56525 PROJECT 1: Role of fat in metastatic engraftment and expansion in the liverABSTRACTThe metastasis of solid tumors to the liver may be a result of acquisition of features that enable survival within asupportive metastatic niche. We found that the liver niche is generally not conducive to the expansion of prostatecancer. However feeding host mice with a high-fat diet for two weeks was sufficient to enable prostate cancergrowth in the liver. Similarly pancreatic and colon cancer cells demonstrated greater expansion if the mice werefed a high-fat diet versus if they were given a low-fat diet. The exposure of hepatocytes and cancer epithelialcells to a saturated fatty acid palmitate was found to promote the expression of transforming growth factor-/bone morphogenic protein co-receptor endoglin as well as their ligands. We found that prostate cancerepithelial expression of CD36 a pro-metastatic fatty acid receptor is dependent on endoglin signaling in thecontext of circulating fat. Based on these novel findings we tested if neutralizing endoglin signaling affected livermetastasis and found that differential endoglin signaling in hepatocytes and cancer epithelial cells couldcooperatively contribute to liver metastasis. We hypothesize that circulating fat can convert the otherwisemetastasis-inhibitory liver microenvironment to be tumor-permissive and that it can promote epithelial cellsurvival in the liver in an endoglin-dependent manner. In Aim 1 we will define endoglin-associated changes inthe liver that enable metastatic engraftment. We will systematically determine how fat affects endoglin-mediatedexpression of glutamine synthetase by hepatocytes and its effects on hepatic stellate cell activation in supportof prostate pancreatic and colon cancer liver engraftment. In Aim 2 we will identify the role of circulating fat ontumor epithelial cells with regard to liver engraftment. We will explore the nature of endoglin-CD36 crosstalk incancer epithelial cells and how it promotes the Yes-associated protein (YAP) signaling axis associated withmetastasis-enabling properties downstream of FOXM1. In Aim 3 we will identify the role that fatty acids haveon the expansion of tumor epithelial cells within the liver niche. We will study the liver ecosystem with signalinginteractions perpetuated by fat in hepatocytes and cancer epithelial cells. We identified that fat induces glutaminesynthesis by hepatocytes in an endoglin-dependent manner. The mechanism by which hepatocyte-derivedglutamine induces hepatic stellate cell activation and cancer epithelial differentiation will be elucidated. We willtest a reciprocal relationship between the liver and tumor epithelial cells as fat impacts circulating cancer cellsand those disseminated to the liver. +No NIH Category available Adenocarcinoma Cell;Affect;Affinity;Affinity Chromatography;Alternative Splicing;Alveolar;Binding;Biological;Biological Assay;Biological Models;CRISPR screen;Cancer Etiology;Cell Cycle Arrest;Cell Differentiation process;Cell Line;Cell Proliferation;Cells;Cessation of life;Disease;Early Diagnosis;Early treatment;Elements;Embryo;Evolution;Fibroblasts;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;Human;Individual;KRASG12D;Knock-in Mouse;Lung Adenocarcinoma;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Modeling;Molecular;Mouse Strains;Mus;Mutate;Mutation;Oncogenes;Parents;Pathway interactions;Play;Proliferating;Property;Proteins;Proteome;Proteomics;Puma;RNA Splicing;RNA-Binding Proteins;Research;Role;Signal Transduction;System;TP53 gene;Testing;Therapeutic;Transactivation;Transcription Coactivator;Transcriptional Activation;Transcriptional Activation Domain;Transplantation;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;Variant;Zinc Fingers;cancer cell;cancer therapy;carcinogenesis;experience;experimental study;improved;in vitro Model;in vivo;insight;knock-down;lung injury;lung regeneration;mouse model;mutant;novel;parent grant;posttranscriptional;programs;protein protein interaction;single-cell RNA sequencing;small hairpin RNA;standard of care;targeted treatment;therapeutic target;tool;tumor;tumor barcoding and sequencing;tumor microenvironment Integrative approaches to elucidate p53 transcriptional networks during carcinogenesis PROJECT NARRATIVEIn the US approximately 1 in every 2-3 individuals will develop cancer a disease of uncontrolledcellular proliferation that can be fatal. The TP53 gene is the most commonly mutated gene in humancancer reflecting the fact that p53 plays an essential role as a tumor suppressor. This research aims toelucidate the mechanisms by which p53 acts to suppress cancer with the ultimate goal of improvingearly detection and treatment of cancer. NCI 10806805 7/24/23 0:00 PA-21-071 3R35CA197591-09S1 3 R35 CA 197591 9 S1 "JOHNSON, RONALD L" 8/14/15 0:00 7/31/29 0:00 ZCA1(M1) 1885021 "ATTARDI, LAURA D" Not Applicable 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 125479 NCI 80475 45004 PROJECT SUMMARY/ABSTRACTThe TP53 tumor suppressor gene is mutated in over half of all human cancers but the mechanisms throughwhich p53 suppresses cancer in vivo remain incompletely understood. Notably there are no standard-of-carecancer therapies based on the p53 pathway. In this proposal we strive to deconstruct the pathways throughwhich p53 suppresses cancer to illuminate pathways dysregulated upon p53 loss that could ultimately betargeted therapeutically. We previously performed unbiased in vivo shRNA and CRISPR/Cas9 screens for p53target genes important for tumor suppression and identified Zmat3 as the top hit in both screens. Zmat3encodes a zinc finger RNA-binding protein that we found acts by modulating alternative splicing revealing anew branch of p53-mediated tumor suppression. Given the critical role for alternative splicing in cancer wehypothesize that studying p53 pathways at the post-transcriptional level such as through splicing andproteomics analyses will yield novel insights into p53-mediated tumor suppression. In Theme 1 we propose toidentify p53-dependent splicing and proteome changes including both Zmat3-dependent and Zmat3-independent ones that could explain tumor suppression in mouse LUAD and HCC. We will test the importanceof genes found in these analyses for LUAD and HCC suppression using a quantitative in vivo tumor assayknown as Tuba-seq. In Theme 2 we will pursue our observation that p53 repurposes a role in lungregeneration in which it drives alveolar type 1 cell differentiation upon lung injury to suppress LUAD. Throughsingle cell (sc)RNA-seq and scATAC-seq analyses we will ask how p53 status dictates the evolutionary pathof KrasG12D-expressing alveolar type 2 cells and how p53 transcriptional programs change with cell stateacross LUAD evolution in mouse models. We will also ask how cells in the tumor microenvironment (TME)affect cancer cell trajectories in wild-type and p53-deficient tumors. To define genes functionally important forcancer cell state transitions and crosstalk between cancer cells and TME components we will employscPerturb-seq. In this diversity supplement Dr. Tambo will perform a new project related to Theme 2 of theR35 to expand our understanding of p53 action in LUAD suppression by using proteomics to identify p53interacting partners. We will perform tandem affinity tag purification of wild-type p53 and p53 transactivationdomain mutants with altered tumor suppression properties to identify those p53-interactors most relevant fortumor suppression. We will then test the roles of these p53-interacting proteins in tumor suppression in amouse transplant system and we will define the roles of these p53-interactors in p53 target gene regulationand proliferation suppression. Ultimately we will identify those p53-interacting proteins most relevant for LUADsuppression in the scPerturb-seq experiments in vivo. Collectively these studies will deconstruct p53-mediatedtumor suppression in vivo at an unprecedented molecular depth which will provide crucial new insight into howto modulate p53 pathways in therapeutic strategies for cancer. 125479 +No NIH Category available Affinity;Antibodies;Antigen Presentation;Antigens;Atomic Force Microscopy;B-Lymphocytes;Binding;Biological Assay;Biology;Biotinylation;Calorimetry;Cancer Patient;Carbohydrates;Carcinoma;Cell Separation;Cell surface;Cells;Chemistry;Collaborations;Compensation;Complex;Development;Entropy;Enzyme-Linked Immunosorbent Assay;Epitopes;Funding;Galactose;Germany;Glycobiology;Glycopeptides;Glycoproteins;Glycosides;Goals;Grant;Heterogeneity;Human;Hydration status;Immune;Immune response;Immune system;Immunology;Journals;Kinetics;Knowledge;Lectin;Lectin Receptors;Letters;Libraries;Ligands;Macrophage;Measurement;Modeling;Molecular;Monoclonal Antibodies;Mucin 1 protein;Mucins;Neoplasm Metastasis;Patients;Pattern;Peptides;Polysaccharides;Positioning Attribute;Primary Neoplasm;Progress Reports;Proteins;Publications;Research;Role;S phase;Scaffolding Protein;Scanning;Scheme;Scientist;Signal Transduction;Solid;Specificity;Tandem Repeat Sequences;Testing;Thermodynamics;Thompson-Friedenreich Antigen;Time;Titrations;Translating;Tumor Antigens;Tumor Escape;Tumor-Associated Carbohydrate Antigens;Universities;Vertebral column;Water;anti-cancer;anti-tumor immune response;antigen binding;atomic interactions;cancer immunotherapeutics;cancer immunotherapy;cancer site;cancer stem cell;carbohydrate binding protein;carbohydrate receptor;combinatorial;density;design;enthalpy;glycosylation;graduate student;immune checkpoint;immunoregulation;improved;insight;interest;neoantigens;next generation;novel;receptor;recruit;screening;sialic acid binding Ig-like lectin;sialylation;tool;trend;tumor;tumor microenvironment;tumor progression;tumorigenic;undergraduate research experience;undergraduate student Mechanistic insight into tumor-associated MUC1 glycopeptides binding to macrophage galactose-type lectin PROJECT NARRATIVEThe main goal of our research is to prepare novel synthetic tools to explore interactions between variousMUC1 glycopeptide models including glycopeptide libraries with lectins involved in cancer immune evasion.These studies will elucidate further the mechanism by which tumor-associated glycans contribute to theobserved immunomodulatory actions by tumors and enable the development of novel and more effective anti-cancer immunotherapeutic strategies. NCI 10806443 12/26/23 0:00 PAR-21-155 2R15CA242351-02 2 R15 CA 242351 2 "AMIN, ANOWARUL" 7/8/19 0:00 12/30/26 0:00 Chemical Synthesis and Biosynthesis Study Section[CSB] 7245299 "CUDIC, MARE " Not Applicable 23 CHEMISTRY 4147534 Q266L2NDAVP1 4147534 Q266L2NDAVP1 US 26.376257 -80.114172 513803 FLORIDA ATLANTIC UNIVERSITY BOCA RATON FL SCHOOLS OF ARTS AND SCIENCES 334316424 UNITED STATES N 1/1/24 0:00 12/30/26 0:00 396 Non-SBIR/STTR 2024 443151 NCI 300000 143151 "PROJECT SUMMARY MUC1 the heavily glycosylated cell-surface mucin is altered in both expression and glycosylation patterns inhuman carcinomas of the epithelium. Tumor-specific glycopeptide epitopes of MUC1 are recognized by a varietyof lectin receptors on immune cells. These interactions have not been extensively studied despite the fact thataberrant tumor glycosylation alters how the immune system perceives the tumor and can also induceimmunosuppressive signaling leading to the creation of a pro-tumor microenvironment favoring tumorprogression and metastasis. In addition it has recently been proposed that the tumor glycocode may beconsidered a novel immune checkpoint. In this renewal application we will continue to examine epitopeheterogeneity the glycoside cluster effect and the steric hindrance effect of neighboring glycans on binding tolectins (Aim 1). Specifically we will focus on the design of novel synthetic tools such as a) structurally well-defined MUC1 glycopeptides with varying multivalency and b) MUC1-derived positional scanning syntheticglycopeptide combinatorial library (PS-SGCL) displaying native-like heterogeneous and aberrant O-glycanepitopes sialylated Tn and ThomsenFriedenreich (TF) antigens. The thermodynamic profile of the interactionof MUC1-derived glycopeptides with macrophage galactose-specific lectin (hMGL) and Siglecs (-7 -9 and/or -15) will be assessed by ITC. The binding kinetics will be determined by direct measurement of the strength ofunbinding of receptor-ligand interactions by AFM (Aim 2). We are particularly interested in how protein scaffoldcontributes to the interactions with lectins and also the role of water in protein hydration and the binding complexformation with the ligand. All these are known variables that may impact the receptor targeting efficacy andimmune response induced by immune cells. Furthermore this renewal application proposes to use MUC1glycopeptides and PS-SGCLs in the discovery and assessment of binding specificities of anti-MUC1 antibodiesfound in sera from cancer patients with MUC1+ tumors (Aim 3). We are focusing on the identification of a newclass of antibodies targeting ""dynamic glycopeptide neoepitopes"". In addition to the research aims we willcontinue to recruit the next generation of scientists into the glycoscience field by offering exciting researchopportunities for undergraduate and graduate students at the interface of chemistry and immunology. Insummary the proposed study will facilitate a deeper understanding of the principles of glycan-protein interactionsand general rules that govern the ability of lectins to regulate immune response by engaging glycoproteins onthe cell surface. This may constitute an important roadmap for translating fundamental MUC1 glycobiologyknowledge toward next-generation cancer immunotherapies." 443151 +No NIH Category available 3-Dimensional;ANXA5 gene;Acceleration;Amino Acids;Apoptosis;Architecture;Artificial Intelligence;Binding;Biological Assay;Cell Death;Cell Line;Cell Survival;Cell model;Cells;Charge;Chimeric Proteins;Clinical;Code;Collaborations;Collection;DNA;Development;Docking;Encapsulated;Engineering;Ensure;Event;FGFR2 gene;Fee-for-Service Plans;Fibroblast Growth Factor Receptors;Flow Cytometry;Formulation;Future;Genetic;Human;Human Cell Line;In Vitro;Intrahepatic Cholangiocarcinoma;Lead;Lentivirus Vector;Licensing;Link;Lipids;Liver;Liver neoplasms;Luciferases;Mediating;Medicine;Messenger RNA;Modeling;Mus;Mutation;Oncogenic;Organoids;Particle Size;Pathway interactions;Patients;Peptides;Plasmids;Proteins;Protocols documentation;Provider;Reporter;Resistance;Stains;Structure;Surface;Technology;Testing;Therapeutic;Tyrosine Kinase Domain;Ubiquitin;Universities;Western Blotting;Work;clinically relevant;design;drug discovery;in silico;in vivo;inhibitor;interest;multicatalytic endopeptidase complex;novel;overexpression;protein degradation;response;small molecule;transcriptome sequencing;tumor;ubiquitin-protein ligase;vector UBIQUIBODY PLATFORM FOR TARGETED DEGRADATION OF ONCOGENIC FUSION PROTEINS n/a NCI 10806354 75N91023C00010-0-9999-1 N43 2/27/23 0:00 2/26/24 0:00 79061891 "BARNETT, MATHEW " Not Applicable 12 Unavailable 117885302 LRA7LGJCZP15 117885302 LRA7LGJCZP15 US 40.787881 -73.973648 10064456 "UBIQUITX, INC." NEW YORK NY Domestic For-Profits 100242934 UNITED STATES N R and D Contracts 2023 354908 NCI UbiquiTx is pioneering a novel class of mRNA therapeutics that potently and selectively degrade targets not historically addressable by small-molecule degraders. Ubiquibodies (uAbs) are protein fusions that can bind to a target of interest and tag it for targeted intracellular degradation via the endogenous ubiquitin-proteasome pathway (UPP). These novel molecules promise to fundamentally transform drug discovery and human medicine by co-opting the UPP to achieve targeted protein degradation. UbiquiTx artificial intelligence-driven discovery platform enables in silico design of thousands of protein targets accelerating the development of protein degraders across a broad range of clinical indications. In thisproject UbiquiTx will design specific uAbs to selectively target and degrade FGFR2 fusions a common genetic event in patients with intrahepatic cholangiocarcinoma (iCCA). Candidates will be encapsulated within LNP formulations to test delivery to iCCA cells and functional degradation capability. The feasibility of our approach is supported by our previous computation-mediated engineering of effective peptide-based uAbs as well as our recent work demonstrating the potential therapeutic benefit of FGFR2 degradation for the treatment of iCCA. Notably the uAbs designed should beeffective even in patients with acquired resistance to small molecule FGFR inhibitors because of secondary mutations in the FGFR tyrosine kinase domain. 354908 +No NIH Category available Amendment;Authorization documentation;Awareness;Budgets;Cancer Therapy Evaluation Program;Cancer Trials Support Unit;Clinical Data;Clinical Research;Collaborations;Computerized Medical Record;Contractor;Contracts;Custom;Data;Data Management Resources;Data Security;Development;Disasters;Education;Federal Government;Good Clinical Practice;Government;Government regulations;Guidelines;Health;Human;Informatics;Information Services;Institution;International;Life Cycle Stages;Malignant Neoplasms;Modeling;Modernization;Monitor;Monitoring Clinical Trials;Oncology;Patients;Performance;Persons;Pharmaceutical Preparations;Phase;Procedures;Process;Protocols documentation;Quality Control;Records;Recovery;Reporting;Secure;Services;Site;Support System;System;Training;United States Dept. of Health and Human Services;Update;Work;authority;data quality;electronic medical record system;improved;operation;programs;tool;web site;working group CANCER TRIALS SUPPORT UNIT (CTSU) CORE SUPPORT SERVICES & THE CTSU ENTERPRISE OF SYSTEMS n/a NCI 10806115 75N91022D00009-P00002-759102200001-1 N01 8/1/22 0:00 7/31/23 0:00 78788334 "HERING, MARTHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2023 17385562 NCI The Contractor shall provide operational regulatory and informaticssupport to conduct clinical studies across multiple institutions for Phase 0 through Phase3 cancer-related studies to include:1.Operational Supporta.Manage user accounts adhere to configuration management guidelines and operate and maintain CTSU websites.b.Operate a customer service support help desk to support queries regarding all facets of CTSU operations.c.Organize working groups; including Government Multicenter Organization (MCO) other contract staff or other appropriate parties; as needed to develop collaborative solutions to eliminate parallel/duplicative MCO and/or contract systems and processes and improvements for activities such as those that are redundant inefficient or duplicative.d.Identify potential gaps and or opportunities to supplement CTSU support servicese.Collaborate with NCI and MCOs to identify and establish standards systems procedures and best practices for trial coordination. f.Collaborate with other multi-center organization(s) and/or institutions that do not traditionally work together.g.Provide MCO budget tracking supporth.Performing site auditing/central monitoring by fulfilling the auditing rules set by the Clinical Trials Monitoring Branch (CTMB) of CTEPi.Provide tools and processes that comply with NCI Data Quality Reporting and Good Clinical Practice (GCP) procedures.j.Develop International Collaboration Administrative Best Practicesk.Coordinate OMB Clearancesl.Provide regulatory document tracking management and supportm.Provide protocol documentation/development supportn.Provide person and site Roster Supporto.Provide Clinical Data Management System Support (CDMS)2.Information (IT) Supporta.Provide CTSU-Enterprise System (ESYS) IT Support:b.Use best practices consistent with Capability Maturity Model Integration (CMMI) Maturity Level 3.c.Follow all Department of Health and Human Services (HHS) Enterprise Performance Life Cycle (EPLC) practices to enhance IT governance.d.Maintain compliance with all regulatory requirements concerning patient records.e.Secure an Authorization to Operate (ATO) in accordance with Federal Information Security Modernization Act (FISMA) and HHS IT Security requirements.f.Provide system/data back-up and disaster recovery in accordance with federal government regulations.g.Maintain update enhance and provide training (in coordination with the Awareness Education and Training contractor) for NCI-developed custom applications commercial-off-the-shelf applications modified to meet NCI needs and integrations from other applications to the included applications under this taskh.Follow best practices for configuration management locatedi.Follow best practices for project management.j.For potential new applications or integrations work with the COR and subject matter experts (SMEs) to develop a list of major technical and operational requirements.k.For potential new applications or integrations perform an analysis of available Commercial Off-the-Shelf (COTS) solutions for new IT initiatives that could potentially meet the project needs to include customization of a COTS solution.The contractor shall:1.Maintain all existing National Coverage Analysis (NCA) and Electronic Medical Record (EMR) materials.2.Create new NCA and EMR materials for specific studies as directed by the COR.3.Modify NCA and EMR materials due to protocol amendments.4.Maintain a Quality Control Program for the NCA and EMR documents.5.Create study specific sharable EMR templates including those for medication orders for the common EMR systems used by major oncology centers and NCORP sites 17385562 +No NIH Category available Acceleration;Administrative Supplement;American;Automation;Cancer Control;Caring;Clinic;Clinical;Collaborations;Communication;Computers;Development;Dissemination and Implementation;Doctor of Philosophy;Electronics;Evaluation;Extramural Activities;Faculty;Feedback;Funding;Grant;Informatics;Institution;Intelligence;Knowledge;Laboratories;Lead;Leadership;Malignant Neoplasms;Manuals;Measurement;Medical Informatics;Mentors;Methods;Monitor;Natural Language Processing;Oncology;Patients;Pattern;Pilot Projects;Postdoctoral Fellow;Process;Public Health Informatics;Publishing;Reference Standards;Research;Research Personnel;Research Project Summaries;Research Proposals;Role;Running;Science;Scientist;Secure;Series;Smoking Cessation Intervention;Students;System;Technology;Testing;Time;Training;Underrepresented Populations;United States National Institutes of Health;Visit;Work;design;eHealth;experience;feasibility testing;health equity;implementation evaluation;implementation facilitation;implementation process;implementation research;implementation science;implementation study;improved;innovation;medical schools;member;population health;professor;programs;prototype;response;shared decision making;skills;sound;survivorship iDAPT: Implementation and Informatics - Developing Adaptable Processes and Technologies for Cancer Control n/a NCI 10805551 5/2/23 0:00 PA-20-272 3P50CA244693-04S1 3 P50 CA 244693 4 S1 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 6134 8842460 "DRESSLER, EMILY VAN METER" Not Applicable 5 Unavailable 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC Domestic Higher Education 271570001 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2023 124953 80615 44338 PROJECT SUMMARYThe Research Program will use three strategies to inform iDAPTs emerging theme to use technologies thatsupport rapid cycle and real time deployment and testing of implementation processes and adaptations withincancer control. First the Research Program will advance the science of technology-supported implementationscience in cancer control through a series of proposed pilot projects conducted in the Implementation Lab.Second it will advance the methods and measurement for implementation science using technology via methodspilot projects and support of the Implementation Studies Unit. Third the Research Program will identify andnurture nascent ideas for new cancer-focused Implementation Science proposals with high potential forextramural funding with an emphasis on assisting students junior faculty and underrepresented populations.The Research Program will lead with two pilot studies aligned with our emerging theme of technology-facilitatedimplementation science. The first is a highly innovative implementation pilot study that will address a gap insurvivorship care. Using a stepped-wedge design in 10 oncology clinics we will test an electronic referralmechanism and computer-tailored communication and intelligent automation to facilitate shared decision makingand survivorship care planning in-between clinical visits. The methods study will advance the field ofimplementation science in cancer control by testing the feasibility of using an automated communication patternmonitoring and feedback system to facilitate implementation programs designed to improve communicationbetween clinical teams and between clinical teams and patient. This study will create manually annotatedreference standard for natural language processing (NLP) train and validate the NLP system test the systemamong patients undergoing smoking cessation treatment and then build and test a prototype system to monitorcommunication extracted from secure messages over time. Both of these iDAPT vanguard pilot studies are ledby junior faculty. The Research Program will seek additional pilot research through a defined process forsoliciting reviewing and selecting promising studies using a validated approach for evaluating implementationresearch proposals for a total of 8-10 pilot studies. The Research Program depends upon a high degree ofcollaboration across the cores to ensure that the selection of pilot studies reflects laboratory member needs(Administrative Core Evaluation Unit) that laboratory members are engaged and have knowledge and skills toserve as equal partners in the research process (Implementation laboratory) and that the knowledge gainedfrom the pilot studies builds the field of implementation science in cancer control aligned with iDAPTs emergingtheme of technology-facilitated implementation science (Administrative Core Network Unit). The ResearchProgram is led by Dr. Thomas Houston (MPI) who is Professor and Chief Health Informatics and ImplementationScience Division at UMMS and is an elected fellow in the American College of Medical Informatics. +No NIH Category available Acute;Brain Neoplasms;Child;Childhood Brain Neoplasm;Clinical;Cranial Irradiation;Data;Deposition;Dose;Education;Family;Impaired cognition;Life;Malignant Neoplasms;Maps;Measures;Medical;Modality;Neurocognitive;Neurocognitive Deficit;Outcome;Parents;Patients;Photons;Physicians;Population;Protons;Publishing;Radiation;Radiation therapy;Research;Risk;Risk Factors;Social Problems;Survivors;Symptoms;Time;Tissues;Toxic effect;Treatment Protocols;Treatment-related toxicity;acute symptom;brain tissue;clinically significant;cognitive function;cost;daily functioning;disability;disorder control;experience;functional independence;functional outcomes;novel;preservation;prospective;proton beam;radiation delivery;reduce symptoms;survivorship;x-ray irradiation Comparison of Symptom Burden/Toxicity Neurocognitive Change and Functional Outcomes in Pediatric Brain Tumor Patients Treated with Proton vs. Photon Radiotherapy. PROJECT NARRATIVEMany consider proton beam radiotherapy (PBRT) to be a promising treatment for children with brain tumors asit may preserve functioning without sacrificing disease control. This Diversity Supplement extends the ParentR01 which is the first large-scale study to prospectively compare symptom burden treatment toxicity andneurocognitive change between patients treated with PBRT vs. conventional photon radiotherapy on comparabletreatment protocols and to assess important measures of daily functioning that will quantify the clinicalsignificance of any differences identified between groups in survivorship. Ultimately this line of research isintended to: (1) help physicians and families better understand the relative effect of PBRT on symptoms andneurocognitive functioning to inform treatment decisions and (2) provide functional outcome data to be usedtoward justifying or reconciling the high cost and access limitations currently associated with PBRT. NCI 10805094 7/14/23 0:00 PA-21-071 3R01CA249988-02S1 3 R01 CA 249988 2 S1 "SCHWEPPE, CATHERINE ANN" 3/1/21 0:00 8/31/26 0:00 8195518 "KAHALLEY, LISA SCHUM" "HINDS, PAMELA S; MABBOTT, DONALD " 9 PEDIATRICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2023 37978 NCI 23662 14316 PROJECT SUMMARY Most children treated for cancer in the US will achieve long-term survival and survivorship presents uniquechallenges for this growing population. Pediatric brain tumor survivors in particular are at risk for neurocognitiveimpairments educational difficulties social problems and medical disabilities. Cranial radiation therapy is anessential lifesaving treatment but is associated with cognitive decline. Proton beam radiation therapy (PBRT) isone of the most promising recent advances in pediatric brain tumor treatment. The proposed medical advantageof PBRT lies in the precision of radiation delivery with proton beams depositing maximum dose to clinical targetswhile minimizing radiation to surrounding tissues. By reducing dose to healthy brain tissue PBRT may sparecognitive functioning and reduce symptom burden better than conventional photon or x-ray irradiation (XRT)leading to greater functional independence in survivorship. The proposed Diversity Supplement Study leverages data collected on the Parent R01 at on-radiotherapy(RT) time points to examine acute experiences of symptom burden and toxicity in this multi-national study.Comparisons of prospectively assessed acute outcomes between PBRT and XRT pediatric brain tumor groupshave not been published to date making this a novel study that will inform our understanding of RT modalitydifferences. The following aims which map onto Aim 1 of the Parent R01 are proposed: (1a) to compare acutesymptom burden/toxicity by RT type (PBRT vs. XRT) in pediatric brain tumor patients and (1b) to examine riskfactors of symptom burden/toxicity during RT. The Diversity Supplement Study is within the scope of the ParentR01 while also providing a clinically meaningful expansion of this line of research. 37978 +No NIH Category available Adolescence;Adolescent;Algorithms;Attention;Attitude;Awareness;Behavior;Belief;Data;Data Analyses;Data Set;Development;Education;Electronic Nicotine Delivery Systems;Electronic cigarette;Feedback;Future;Health;Individual;Learning;Marketing;Measures;Mediating;Mediation;Mediator;Methodology;Methods;Modeling;Nicotine;Pattern;Perception;Persons;Policies;Policy Maker;Population;Population Assessment of Tobacco and Health;Public Health;Research;Research Support;Risk;Source;Surveys;Techniques;Time;Tobacco;Tobacco use;United States;Update;Youth;addiction;cigarette smoking;development policy;examination questions;health care delivery;health data;improved;innovation;nicotine use;response;risk perception;secondary analysis;semiparametric;social influence;social media;substance use;tobacco advertising;tobacco control;tobacco products Does Tobacco Social Media Marketing Alter Adolescent Risk Perceptions and Use? Longitudinal Data-Adaptive Estimators and Causal Inference to Enhance Understanding Project NarrativeYouth are increasingly living their lives filtered through social media account participationa setting wheremarketers are constantly innovating to gain youth attention and influence. Effective e-cigarette controlstrategies for adolescents require a more comprehensive understanding of the potential impact of social mediamarketing on their attitudes and use. The current project will use state-of-the-art techniques to examine thesequestions and thereby increase the ability of public health officials and policymakers to develop appropriatecountermeasures. NCI 10804979 9/25/23 0:00 RFA-OD-21-003 1R21CA287457-01 1 R21 CA 287457 1 "MAYNE, RACHEL G" 9/25/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CDPT-Z(55)R] 10565290 "HARRELL, PAUL TRUMAN" Not Applicable 3 PEDIATRICS 58625146 CTLVX9M7AMR4 58625146 CTLVX9M7AMR4 US 36.855732 -76.295467 471501 EASTERN VIRGINIA MEDICAL SCHOOL NORFOLK VA SCHOOLS OF MEDICINE 235011980 UNITED STATES N 9/25/23 0:00 8/31/24 0:00 77 Non-SBIR/STTR 2023 210480 OD 171614 38866 Project Summary Youth trajectories of tobacco use are of critical importance in the future of public health. Most tobaccouse begins in adolescence and adolescents are particularly vulnerable to long-term tobacco use. Whilecigarette smoking significantly declined among adolescents over the past decade overall tobacco/nicotine useactually increased by some measures primarily due to increased rates of use of electronic nicotine deliverysystems (ENDS). These changes in population levels of adolescent tobacco use are of critical importance inpredicting tobacco control challenges and opportunities in the next decade. As the scientific debate unfoldsregarding ENDS health effects adolescents nationwide are learning about tobacco products and attempting torectify conflicting information to create and refine their own beliefs regarding these products. At the same time youth are increasingly living their lives filtered through social media accountparticipation. Marketers are well aware of this fact and act to influence youth to purchase their products.Tobacco marketers are certainly no exception. Social media marketing is particularly important to examine as itis a prevalent source of adolescent exposure that is amenable to policy change. Social media marketing differsfrom other forms of marketing in that it exploits participatory facilitation algorithmic coordination context-specific promotions real-world enmeshment and seamless integration with purchasing opportunities. Althoughsome research has examined this issue there are important methodological concerns that may lead to flawedor incomplete understanding of the relationships involved and hinder the development of policies or otherapproaches to reduce the influence of social media marketing on youth ENDS use. We will address limitationsin prior research by using both longitudinal data-adaptive semiparametric estimators and a causal inferenceapproach. We will focus on two risk perceptions: harmfulness and addictiveness. The degree to which riskbeliefs act as mediators of the effects of social media marketing on use is unclear. Effective ENDS controlstrategies for adolescents require a more comprehensive understanding of how attitudes change over time andthe potential impact of social media marketing on these changes The Population Assessment of Tobacco and Health (PATH) dataset provides a unique opportunity toexamine youth beliefs about tobacco products marketing exposure and patterns of tobacco use amongadolescents in the United States longitudinally. The current study will examine underutilized recent Waves toexamine the impact of online ENDS marketing on use with longitudinal data-adaptive semiparametricestimators and to examine risk perceptions as potential mediators explaining the effects of adolescentmarketing exposure on ENDS use with a causal inference approach. 210480 +No NIH Category available Address;Affect;Animal Cancer Model;Animal Model;Antibodies;Bypass;CTLA4 gene;Cancer Burden;Cancer Model;Cancer Patient;Clinic;Clinical;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;DNA Polymerase III;DNA-Directed DNA Polymerase;Defect;Development;Generations;Genetically Engineered Mouse;Genome;Goals;Growth;Hand;Human;Immune;Immune response;Immune system;Immunocompetent;Immunotherapy;Induced Mutation;KRASG12D;Knowledge;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thyroid;Minority;Mismatch Repair;Mitochondria;Modeling;Mus;Mutagenesis;Mutation;Nature;Nuclear;Oncogene Activation;Oncogenes;Oncogenic;Patient-Focused Outcomes;Patients;Peptides;Phenotype;Physiological;Polymerase;Predisposition;Resistance;Signal Transduction;Skin;Solid Neoplasm;Somatic Mutation;Specimen;T-Lymphocyte;Testing;Translating;Tumor Immunity;Wild Type Mouse;anti-tumor immune response;cancer therapy;cancer type;checkpoint therapy;immune activation;immune checkpoint;immune checkpoint blockade;immunogenic;melanoma;mitochondrial genome;mouse model;neoantigens;nonsynonymous mutation;novel;patient population;programmed cell death protein 1;rational design;response;success;targeted treatment;treatment response;treatment strategy;tumor;tumor growth Impact of mutation burden on cancer growth and the immune landscape PROJECTNARRATIVEAlthoughimmunotherapyhashadremarkablesuccessesinthetreatmentofcanceritonlybenefitsaminorityofcancerpatientsandwedonotknowhowtorationallycombineimmunotherapywithothertreatments.Advanceshavebeendifficultinpartbecausewedonothaveanimalmodelsthatrespondwelltoimmunotherapy.Thegoalof this project is to develop better mouse cancer models that harbor both the driver and passenger mutationsseeninhumancancersandusethistounderstandmechanismsofresponseandresistancetoimmunotherapyandrationallydesignmoreeffectivecombinationimmunotherapystrategies. NCI 10804590 11/22/23 0:00 PA-19-056 5R01CA243547-05 5 R01 CA 243547 5 "ZAMISCH, MONICA" 12/1/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 1930337 "GANESAN, SHRIDAR " "LATTIME, EDMUND C.; WHITE, EILEEN P." 10 INTERNAL MEDICINE/MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 583485 NCI 371971 211514 PROJECTSUMMARY/ABSTRACTImmune checkpoint blockade (ICB) using antibodies that disrupt PD1 or CTLA4 signaling can lead to durableresponsesinawidevarietyofhumancancers.Unfortunatelyonlyaminorityofpatientsobtainclinicalbenefitfrom ICB. A high non-synonymous nuclear mutation burden has been correlated with increased likelihood ofresponse to ICB suggesting that mutation induced neoantigens may underlie the tumor associated activationofimmunecheckpoints.Althoughthishypothesislinkingmutationburdentopeptideneoantigensiscompellingithasnotbeencompletelyvalidated.MoreoverelevatedmutationburdendoesnotalwaysdictateresponsetoICBwithsomelowmutationtumorssuchasthyroidcancersshowingresponses.Thustherearehugegapsinour knowledge of the underlying mechanisms dictating response to ICB. We hypothesize that a highbackground somatic mutation burden through introduction of mutations in DNA polymerases will alter theimmune landscape of cancers through the presence of truncal tumor specific neoantigens that conferresponsetoICB.WewilltestthishypothesisanddecipherunderlyingmechanismsusingnovelmousemodelsThis will be approached through the following specific aims: Aim 1: Determine the nature of the immuneresponse to cancers with endogenous high nuclear mutation burden arising spontaneously in mice harboringgermline proofreading mutations in Pold1 and Pole and patient tumors harboring POLE and POLD1mutations.; Aim 2: Determine how a high nuclear mutation burden affects the growth of oncogene-drivenautochthonouscancermodelsandsensitivitytoimmunecheckpointtherapy;Aim3:DetermineifproofreadingmutationsinPolgandelevationofmitochondrialgenomemutationburdencontributestoananti-tumorimmuneresponse.. Aim 4: Determine how combining targeted therapy and immune checkpoint therapy are modulatedby presence of high background mutation burden. To address these aims we will utilize mouse models inwhichahighbackgroundmutationrateisinducedthroughgermlineproofreadingmutationsinPoleandPold1(for nuclear mutations) and Polg (for mitochondrial mutations. We will compare how specific oncogenes (BrafinskinandlungandKrasinlung)inducetumorsineitherwildtypemiceorinmicewithgermlineproofreadingpolymerasemutationstodeterminehowhighbackgroundmutationratealterstumorgrowthlocalandsystemicimmune response and response to targeted therapy and ICB. Our overall goal is to develop a betterunderstanding of how mutation burden affects the immune response to solid tumors. Robust models of highmutation burden cancers can be used to guide rational development of combination treatment strategies thatcanbetranslatedintotheclinic. 583485 +No NIH Category available Area;Cancer Patient;Cancer Prevention Trial;Cancer Science;Chemopreventive Agent;Clinical;Clinical Practice Guideline;Clinical Trials;Collection;Conduct Clinical Trials;Contractor;Contracts;Country;Data;Division of Cancer Prevention;Documentation;Early Diagnosis;Ensure;Evaluation;Extramural Activities;Good Clinical Practice;Informatics;Information Systems;International;Intervention;Monitor;National Cancer Institute;New Agents;Pharmacy facility;Phase;Policies;Prevention;Procedures;Process;Protocols documentation;Reporting;Research Personnel;Research Support;Role;Services;Site;Support Contracts;Testing;Toxic effect;Training and Education;Work;cancer prevention;cancer type;clinical research site;data archive;data management;early screening;preclinical study;prevention clinical trial;programs;repository;safety study;symptom management CANCER PREVENTION CLINICAL TRIALS AUDITING AND INFORMATICS SUPPORT n/a NCI 10804570 261201400002I-P00010-759101900129-1 N01 5/16/19 0:00 5/15/23 0:00 15991090 "MALLOY, DAVID " Not Applicable 8 Unavailable 57052391 FAA2LVENETH4 57052391 FAA2LVENETH4 US 39.02704 -77.126432 1603501 "TECHNICAL RESOURCES INTERNATIONAL, INC." BETHESDA MD Domestic For-Profits 208171197 UNITED STATES N R and D Contracts 2023 450000 NCI The National Cancer Institute Division of Cancer Prevention (NCI DCP) conducts and supports research in cancer prevention early detection and screening and on the prevention and management of symptoms and toxicities in cancer patients. As an extramural division DCP supports and promotes investigators around the country and internationally in these critical areas of cancer science. NCI DCP manages a portfolio of scientific and clinical activities that includes identifying and developing chemopreventive agents and interventions with potential cancer prevention activity performing pre-clinical studies conducting Phase 0/I/II trials for testing agents and interventions and moving promising agents and interventions into larger Phase III cancer prevention clinical trials. These cancer prevention trials are conducted by extramural investigators at national and international clinical sites. As a sponsor of a trial NCI DCP is responsible for ensuring that clinical trials are conducted safely and according to protocol from the initial safety studies through the definitive evaluation of the role of the new agent or intervention in the prevention of specific types of cancer. Fulfillment of this responsibility requires careful and thorough auditing and monitoring of a clinical trial throughout its entire process including the verification of clinical trials data as well as investigator and study site compliance with the protocol Good Clinical Practice Guidelines applicable regulatory requirements and clinical trials policies. The Cancer Prevention Clinical Trials Auditing and Informatics Support contract provides comprehensive clinical trial oversight capability for the Phase 0/I/II and selected Phase III cancer prevention clinical trials sponsored by NCI DCP. 450000 +No NIH Category available Ablation;Agonist;Animal Model;Anti-CD47;Antigen Presentation;Antigen-Presenting Cells;Antitumor Response;Architecture;B-Lymphocytes;CD4 Positive T Lymphocytes;CD47 gene;CD8B1 gene;Carcinogens;Cells;Clinical;Clinical Data;Clinical Trials;Data;Dendritic Cells;Eating;Ethanol;Excision;HPV-negative head and neck cancer;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Human Papillomavirus;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Surveillance;Immunologics;Immunotherapy;In complete remission;Investigation;Localized Disease;Lymphatic;Malignant Neoplasms;Metastatic/Recurrent;Modeling;Morbidity - disease rate;Neoadjuvant Therapy;Nivolumab;Nodal;Oncogenic;Operative Surgical Procedures;Outcome;Pathologic;Patients;Phagocytosis;Phase;Phenotype;Primary Neoplasm;Radiation;Radiation therapy;Radioimmunotherapy;Regional Disease;Research;Role;Sentinel Lymph Node;Signal Transduction;Solid Neoplasm;T cell clonality;T-Cell Activation;T-Lymphocyte;Therapeutic;Tobacco;Toll-like receptors;Treatment-related toxicity;Tumor Antigens;Tumor Immunity;anti-cancer;anti-tumor immune response;cancer immunotherapy;cell type;chemoradiation;chemotherapy;combinatorial;conventional therapy;curative treatments;cytokine;cytotoxic;design;draining lymph node;effector T cell;head and neck cancer patient;improved;improved outcome;inhibitor;insight;irradiation;lymph nodes;lymphatic vessel;mortality;mouse model;neoplastic cell;novel;phase I trial;phase III trial;preservation;programmed cell death protein 1;response;trafficking;treatment optimization;tumor;tumor-immune system interactions Optimizing immunoradiotherapy for HNSCC Project NarrativeCancer immunotherapies have led to major treatment breakthroughs for a number of different cancers but themajority of head and neck cancer patients do not respond to immunotherapies and clinical responses are oftennot durable. We have demonstrated that targeting tumors with stereotactic radiation in combination withimmunotherapy while sparing draining lymphatics enhances anticancer immunity resulting in significantlyimproved response profiles. The research outlined in this proposal will leverage targeted tumor radiation incombination with optimized immunotherapy in a particularly lethal form of head and neck cancer to improveclinical outcomes for both tumor control and treatment toxicity using both animal models of head and neckcancer as well as data from clinical trials of combination targeted radiation and immunotherapy. NCI 10804468 9/21/23 0:00 PA-20-185 1R01CA281285-01A1 1 R01 CA 281285 1 A1 "SOMMERS, CONNIE L" 9/25/23 0:00 8/31/28 0:00 Clinical Oncology Study Section[CONC] 1900169 "CALIFANO, JOSEPH A" "SHARABI, ANDREW B." 50 SURGERY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/25/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 692235 NCI 469652 222583 Project SummaryHead and neck squamous cell carcinoma (HNSCC) is driven by tobacco ethanol and other carcinogens as wellas oncogenic human papilloma virus (HPV). In particular HPV negative HNSCC has a high rate of mortality andthe main curative treatment options for local and regional disease including surgery radiation andchemotherapy incur significant morbidity. PD-1 inhibitors are approved for recurrent/metastatic HNSCC yet havelow response rates of 14-20%. Furthermore a recent Phase III trial demonstrated no benefit when a PD-1inhibitor was combined with chemoradiation using large radiation fields targeting tumor and lymph nodes. Whilethe tumor immune microenvironment is key to the activity of immunotherapy the role of draining lymph nodes inthe efficacy of immunotherapy is poorly understood and the impact of conventional therapies anti-tumor immunitydeserves further investigation. Our preliminary data demonstrate nodal irradiation or surgical removal of draininglymph nodes completely blocks the anti-tumor activity of PD-1 inhibitors and surgical disruption of lymphaticchannels alone while maintaining intact draining lymph nodes also blocks immunotherapy responses.Mechanistically we have identified cDC1 and B-cell antigen presenting cells in draining nodes as key immuneeffectors coordinating anti-tumor immune responses. Further a Phase I trial of immunoradiotherapy using PD-1inhibitors combined with lymphatic sparing stereotactic radiation (SBRT) demonstrates a remarkable 67%complete pathologic response rate in HNSCC patients. Our central hypothesis is that intact functionaldraining lymphatics and lymph nodes are critical for anti-tumor immunity and that lymphatic preservingIRT in HNSCC will maximize anti-tumor responses. To explore this hypothesis we will use animal models ofHPV negative HNSCC to 1) determine the role of the draining sentinel lymph nodes in generating andcoordinating immune responses during immunotherapy and SBRT based immunoradiotherapy in HPV negativeHNSCC and 2) maximize immunotherapy responses in HNSCC by optimizing treatment sequencing radiationtargeting and enhancing antigen presentation in draining lymph nodes. To validate this hypothesis in patientswe will define immune phenotypes that correlate with major pathologic responses from a clinical trial ofneoadjuvant immunoradiotherapy in HPV negative HNSCC patients. Completion of this project will elucidate therole of draining sentinel lymph nodes in coordinating anti-tumor immune responses identify optimizedsequencing and novel combinatorial immune therapies in HNSCC and define immune signatures in patientswith complete responses to immunoradiotherapy in HSNCC. These insights will guide and improve the designof therapeutic strategies that leverage draining lymph nodes in coordinating anti-tumor immune response andimprove outcomes in HNSCC and other solid tumor patients. 692235 +No NIH Category available Address;Adenocarcinoma;Adoption;Androgen Receptor;Autopsy;BRCA2 gene;Biological Markers;Biopsy;Blood;Blood specimen;Breast Carcinoma;Cancer Etiology;Cancer Patient;Categories;Cell Cycle;Cessation of life;Characteristics;Classification;Clinical;DNA Sequence Alteration;DNA analysis;DNA sequencing;Detection;Engineering;Evolution;Exhibits;FDA approved;FOLH1 gene;Frequencies;Gene Expression;Gene Expression Regulation;Generations;Genes;Genetic Transcription;Genomics;Genotype;Heterogeneity;Histology;Individual;Inter-tumoral heterogeneity;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Molecular;Monitor;Morbidity - disease rate;Mus;Neoplasm Metastasis;Neuroendocrine Cell;Neuroendocrine Prostate Cancer;Nucleosomes;Oncogenes;Outcome;Patient-Focused Outcomes;Patients;Pattern;Performance;Phenotype;Plasma;Positron-Emission Tomography;Prediction of Response to Therapy;Procedures;Prognosis;Prognostic Marker;Proliferating;Prospective cohort;Prostate Adenocarcinoma;Prostate Cancer therapy;RB1 gene;Receptor Signaling;Research;Research Personnel;Resistance;Resistance development;Sampling;Selection for Treatments;Signal Transduction;Site;Small Cell Carcinoma;TP53 gene;Testing;Therapeutic;Time;Tissues;Transcriptional Regulation;Treatment outcome;Tumor Subtype;Tumor Suppressor Proteins;Variant;androgen deprivation therapy;blood treatment;cancer classification;cancer heterogeneity;cancer subtypes;castration resistant prostate cancer;cell free DNA;clinically relevant;cost effective;curative treatments;fluorodeoxyglucose positron emission tomography;improved;improved outcome;in vivo;inhibitor;inhibitor therapy;innovation;liquid biopsy;lung Carcinoma;medicine man;men;molecular diagnostics;molecular subtypes;mortality;neoplastic cell;neuroendocrine differentiation;patient derived xenograft model;patient screening;patient subsets;potential biomarker;pre-clinical;precision medicine;predicting response;predictive marker;pressure;radiation resistance;radioligand;response;standard of care;targeted treatment;therapy outcome;therapy resistant;tool;transdifferentiation;treatment response;treatment strategy;tumor;tumor DNA;tumor diagnosis;tumor heterogeneity Evaluating prostate cancer phenotype and genotype classification from circulating tumor DNA as biomarkers for predicting treatment outcomes PROJECT NARRATIVEThe proposed research will establish new biomarkers to classify prostate cancer subtypes from the blood andto predict responses to a new generation of treatments. The strategy will provide a cost-effective and non-invasive view of how prostate cancer heterogeneity/variation influences therapy resistance. This research willlead to new molecular diagnostics that will improve the lives and outcomes for patients with prostate cancer. NCI 10804464 9/19/23 0:00 PA-20-185 1R01CA280056-01A1 1 R01 CA 280056 1 A1 "MCKEE, TAWNYA C" 9/19/23 0:00 8/31/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 15167932 "HA, GAVIN " "NELSON, PETER S" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 596466 NCI 338901 257565 PROJECT SUMMARY/ABSTRACTProstate cancer is the second most common cause of cancer mortality among men. The majority of these deathsare due to resistance to androgen deprivation therapy and progression to lethal castration-resistant prostatecancer (CRPC). New generation androgen receptor signaling inhibitors (ARSI) that target the AR signaling axishave been used in the CRPC setting; however the majority of patients still develop resistance. Recentlyprostate-specific membrane antigen (PSMA) has become a promising target for positron-emission tomographyimaging (PSMA-PET) and targeted therapies such as the recently FDA-approved radioligand (PSMA-RL) forCRPC patients who progressed on ARSI treatment. Despite a survival benefit for PSMA-RL therapy theimproved outcome is modest and only half the patients show favorable responses. The emergence of resistanceto ARSI and PSMA-RL may arise through changes in tumor phenotype such as trans-differentiation fromprostate adenocarcinoma (ARPC) into treatment-related small-cell neuroendocrine prostate cancer (NEPC) andother phenotypes with loss of AR activity. Current methods require a biopsy to diagnose tumor histology whichcan be challenging due to invasive procedures accompanied by morbidity and some tumors are not accessibleor have poor sample quality. Furthermore tumor heterogeneity is a major contributor to therapy resistance andis particularly challenging to identify using a biopsy of a single metastatic site. These challenges exemplify majorlimitations of current treatment strategies and precision medicine for men with CRPC. Circulating tumor DNA (ctDNA) released from tumor cells into the blood as cell-free DNA (cfDNA) is a non-invasive liquid biopsy solution for addressing challenges in tissue accessibility. Current research and clinicalefforts have focused on the detection of genetic mutations from ctDNA sequencing as potential biomarkers;however these do not fully explain why treatments fail. The objective of this proposal is to develop and evaluateinnovative methods for classifying aggressive CRPC genotypes and phenotypes from ctDNA overcomingchallenges of tumor heterogeneity. The investigators hypothesize that ctDNA can be used to classify tumorsubtypes in CRPC and that this can be used to predict treatment outcomes. In Aim 1 they will study tumorheterogeneity in men who have undergone rapid autopsy to evaluate the ctDNA classifiers for predictingheterogeneous phenotypes from post-mortem plasma. In Aim 2 they will determine the utility of ctDNA forpredicting prostate cancer treatment outcomes in a prospective cohort of patients treated with ARSI and a subsetof patients screened by PSMA-PET and treated with PSMA-RL therapy. They will evaluate the ctDNA classifiersas biomarker tools to aid in the initial allocation of PSMA-RL therapy and inform early indications of treatmentresistance. In Aim 3 they will develop extensions to ctDNA methods that infer gene expression and tumoraggressiveness in prostate cancer phenotypes using preclinical mouse PDX models including in vivoengineering of phenotype mixtures. 596466 +No NIH Category available Abdomen;Address;Alanine;Anatomy;Assessment tool;CA-19-9 Antigen;Cancer Etiology;Cessation of life;Clinical;Clinical Research;Compensation;DNA Sequence Alteration;Data;Development;Disease;Early treatment;Evaluation;Excision;Future;Genes;Glycolysis;Goals;Image;Investigation;KRAS2 gene;Life;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metabolic;Metabolism;Methods;Minority;Modeling;Monitor;Motion;Neoadjuvant Therapy;Operative Surgical Procedures;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathologic;Pathway interactions;Patient Selection;Patients;Phosphorylation;Play;Prediction of Response to Therapy;Pyruvate;Pyruvate Metabolism Pathway;Research;Resectable;Resected;Resistance;Resolution;Role;Running;Scanning;Serum;Systemic Therapy;Systemic disease;Techniques;Time;Translating;Tumor Markers;United States National Institutes of Health;Variant;X-Ray Computed Tomography;alternative treatment;clinical care;clinical decision-making;clinically relevant;cohort;cost effective;design;fluorodeoxyglucose positron emission tomography;glucose uptake;imaging approach;imaging biomarker;imaging modality;improved;ineffective therapies;lactate dehydrogenase A;metabolic imaging;molecular imaging;novel;novel strategies;outcome prediction;overexpression;predicting response;response;simulation;stable isotope;tool;treatment response;tumor Translating Hyperpolarized 13C MRI as a Novel Tool to Predict Treatment Response in Pancreatic Cancer Project NarrativeThe proposed project will develop a new approach to monitor and predict treatment response in patients withpancreatic ductal adenocarcinoma using hyperpolarized 13C pyruvate MR molecular imaging. The data from thisfirst study will inform future investigations incorporating metabolic imaging biomarkers for defining clinicallyrelevant thresholds enable timely therapy switch in non-responders and guide high-stake decisions about thebenefit of a highly morbid surgery with the overarching goal of better guiding treatment decisions to improvesurvival of patients with this deadly disease. NCI 10804260 12/20/23 0:00 PA-20-185 1R01CA280071-01A1 1 R01 CA 280071 1 A1 "TANDON, PUSHPA" 1/1/24 0:00 12/31/28 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 12293649 "GORDON, JEREMY WILLIAM" "WANG, ZHEN JANE" 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 670223 NCI 414999 255224 Project Summary/AbstractThis project is designed to develop a new approach to monitor and predict treatment response in patients withpancreatic ductal adenocarcinoma (PDA) using hyperpolarized (HP) 13C pyruvate MR molecular imaging. PDAis among the deadliest cancers and is anticipated to become the 2nd leading cause of cancer-related death in theUS by 2030. Most PDA patients present with nonresectable disease where systemic therapy is the only life-prolonging treatment. In the minority of patients (~30%) who present with localized potentially resectable diseaseneoadjuvant therapy (NAT) followed by surgery is an emerging approach to improve patient survival but is onlybeneficial if the selected NAT is effective. For all PDA patients effective systemic therapy is the single mostimportant factor influencing their survival. However current response assessment tools including MRI CT andthe serum tumor marker CA19-9 provide poor early assessment of response in patients with rapidly lethaladvanced PDA and are suboptimal for selecting patients most likely to benefit from a highly morbid surgery afterNAT. Therefore there is a critical unmet need for more timely and accurate indicators of therapy response inPDA to 1) promptly discontinue ineffective treatments and switch to alternative treatments with potentially betterefficacy and 2) better guide clinical decisions regarding surgery following NAT. Metabolic reprogrammingtowards increased glycolysis is a hallmark of PDA. In particular the over-expression of lactate dehydrogenaseA and monocarboxylate transporter 1 and 4 results in high levels of pyruvate conversion to lactate which playsa central role in PDA progression and therapy resistance. Such reprogrammed glycolytic metabolism can benoninvasively interrogated using HP 13C pyruvate MRI an emerging molecular imaging method that providesdynamic and pathway-specific metabolic information not available with current imaging methods including[18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Our preliminary patient studies demonstratereprogrammed glycolytic metabolism in PDA using HP 13C pyruvate MRI with increased conversion to lactateand reduced conversion to alanine in tumors compared to normal pancreas. Our preliminary results also suggestthat early metabolic changes measured by HP 13C pyruvate MRI can predict tumor response to therapy. Buildingon these exciting results we propose to investigate for the first time the value of HP 13C pyruvate MRI for therapyresponse monitoring in PDA patients. In Aim 1 we will develop and refine HP 13C pyruvate MRI acquisition post-processing and analysis strategies optimized for PDA metabolic evaluation. In Aim 2 we will monitor earlytherapy response using this imaging approach in patients with advanced/nonresectable PDA. In Aim 3 we willdetermine whether HP 13C pyruvate MRI can predict response to NAT through correlation with pathologicresponse in patients with resected PDA. Successful completion of this project will provide the first data on HP13C pyruvate metabolism of PDA in response to therapy with the overarching goal of better guiding clinicaldecision making to improve survival for patients with this deadly disease. 670223 +No NIH Category available Amines;Antineoplastic Agents;Binding;CRISPR/Cas technology;Cell Survival;Cells;Chemicals;Chromatin;Chromatin Structure;Chromosome Deletion;Clinic;Clinical;Complex;Data;Deacetylation;Dependence;Dissociation;Drug Targeting;Enzymes;Excision;Genes;Genetic;Genetic Transcription;HDAC1 gene;HDAC2 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;In Vitro;Ligands;Lysine;Malignant Neoplasms;Mediating;Modernization;Multiple Myeloma;Nature;Neuroblastoma;Nucleosomes;Oncology;Output;Pharmaceutical Preparations;Proteins;Proteomics;RNA Interference;Recurrence;Side;Somatic Cell;Structure;Therapeutic;Work;Zinc;anti-cancer therapeutic;cancer cell;cancer subtypes;cancer survival;cancer type;cell type;chromatin remodeling;clinical development;design;experimental study;fitness;in vivo;inhibitor;member;neuroblastoma cell;new therapeutic target;novel;novel therapeutics;paralogous gene;pharmacologic;small molecule;therapeutic development;tool;translational potential;tumor Cancer-specific dependencies within the NuRD chromatin remodeler complex: new targets and chemical tools PROJECT NARRATIVEWhile clinical development of HDAC inhibitors for oncology has been largely unsuccessful we recentlydiscovered a synthetic lethal relationship between HDAC1 and HDAC2 that should offer a greater window fortherapeutic development. Based on our preliminary data that members of the HDAC1/2-containing NuRDchromatin remodeler complex are required for the survival of cancers impacted by HDAC1/2 synthetic lethalitywe propose to (i) determine the mechanistic basis underlying NuRD vulnerabilities in these cancers and (ii)develop small-molecule modulators of NuRD function that target cancer-specific NuRD vulnerabilities. NCI 10804084 12/28/23 0:00 PA-20-185 1R01CA280720-01A1 1 R01 CA 280720 1 A1 "VENKATACHALAM, SUNDARESAN" 1/1/24 0:00 12/31/28 0:00 Special Emphasis Panel[ZRG1-DMPC-J(90)S] 12477056 "ERB, MICHAEL A" Not Applicable 50 Unavailable 781613492 PHZJFZ32NKH4 781613492 PHZJFZ32NKH4 US 32.903062 -117.243592 7375802 "SCRIPPS RESEARCH INSTITUTE, THE" LA JOLLA CA Other Domestic Non-Profits 920371000 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 570856 NCI 315390 255466 PROJECT SUMMARY/ABSTRACTHistone deacetylases (HAT) are zinc-dependent enzymes that catalyze the removal of acetyl groups from theepsilon amine of lysine side chains. These proteins have been widely pursued as anti-cancer drug targets buttherapeutic development has been largely unsuccessful given the essential nature of many HDAC proteins.Recently we discovered a synthetic lethal relationship between HDAC1 and HDAC2 which is caused byrecurrent chromosomal deletions that result in hemizygous deletion of HDAC1 in neuroblastoma and HDAC2 inmultiple myeloma. As a result of HDAC1 deletion neuroblastoma cells are hypersensitive to disruption ofHDAC2 and vice versa in multiple myeloma. Using dTAG-mediated degradation or CRISPR/Cas9-based genedisruption we discovered that targeting HDAC1/2 synthetic lethality (e.g. degrading HDAC2 in neuroblastomacells with a hemizygous HDAC1 deletion) results in dissociation of the NuRD chromatin remodeler complex ofwhich HDAC1/2 are members. Dissociation of the complex results in degradation of NuRD subunits that areselectively required for neuroblastoma and multiple myeloma survival suggesting that HDAC1/2 syntheticlethality can be leveraged to target subunit-specific NuRD vulnerabilities in cancer. We hypothesize that HDAC1deletions cause the NuRD subunits HDAC2 / MBD3 / MTA3 to be essential for neuroblastoma whereas HDAC2deletions cause vulnerabilities to loss of their paralogs HDAC1 / MBD2 / MTA2 in multiple myeloma. Here wewill address this hypothesis and explore the translational potential of these vulnerabilities by developing small-molecule modulators that target NuRD structure and/or function. In Aim 1 we will (i) Determine whether MBDand MTA vulnerabilities are caused by HDAC1/2 deletions using CRISPR/Cas9 inducible RNAi and dTAG-based approaches in vitro and in vivo (ii) Reveal whether the loss of NuRD subunits required for cancer cellsurvival leads to dissociation and/or degradation of the NuRD complex using unbiased proteomics approachesand (iii) Establish if HDAC1/MBD2/MTA2 and HDAC2/MBD3/MTA3 form distinct NuRD sub-complexes as aresult of HDAC2 and HDAC1 deletions respectively. These experiments will determine if subunit-specific NuRDvulnerabilities are caused by HDAC1/2 deletions or simply exploited by HDAC1/2 synthetic lethality. In Aim 2we will develop small molecules targeting the NuRD complex to exploit NuRD vulnerabilities in geneticallydefined cancer sub-types. Specifically we will: (i) develop paralog-selective PROTACs that distinguish betweenHDAC1 and HDAC2 (ii) determine the potential for covalent ligands of MTA3-Cys532 to disrupt NuRD structureand/or function in MTA3-dependent cancers and (iii) develop MTA3-targeted PROTACs based on ligands thatcovalently engage MTA3-C532. Altogether successful completion of these aims will determine the mechanismsunderlying NuRD vulnerabilities in cancer and advance novel chemical tools to drug and study them. 570856 +No NIH Category available 3-Dimensional;Adjuvant Therapy;Affect;Archives;Biological Markers;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Cancer Prognosis;Cell Culture Techniques;Cell Respiration;Cell model;Cessation of life;Clinic;Clinical;Cohort Studies;Cultured Cells;Data;Data Set;Dimensions;Disease;Disease Progression;Exhibits;Flavoproteins;Fluorescence;Freezing;Future;Genetic;Glycolysis;Goals;Human;Hypoxia;Image;Imaging Techniques;Individual;Label;Laboratories;Mammary Neoplasms;Maps;Measures;Metabolic;Metabolism;Mission;Molecular;Mus;Neoadjuvant Therapy;Neoplasm Metastasis;Nicotinamide adenine dinucleotide;Nodal;Operative Surgical Procedures;Optics;Outcome;Oxidation-Reduction;Patient-Focused Outcomes;Patients;Performance;Phenotype;Pilot Projects;Pre-Clinical Model;Prognosis;Prognostic Marker;Prospective Studies;Public Health;Receiver Operating Characteristics;Recurrence;Research;Resolution;Role;Signal Transduction;Specimen;Stains;Techniques;Testing;Time;Training;Tumor Volume;United States National Institutes of Health;Validation;Variant;Vascular blood supply;Warburg Effect;Xenograft Model;Xenograft procedure;cancer diagnosis;cancer type;clinical decision-making;clinical imaging;clinical translation;cohort;disorder risk;fluorescence imaging;high risk;imaging biomarker;imaging modality;imaging study;improved;indexing;individual patient;innovation;lung metastatic;malignant breast neoplasm;metabolic imaging;metabolic phenotype;metabolic profile;metabolomics;meter;millimeter;mouse model;novel;novel marker;nutrition;personalized medicine;predict clinical outcome;prognostic indicator;prognostic model;prognostic significance;prognostic value;prognostication;programs;progression risk;risk prediction;risk stratification;tool;treatment optimization;treatment planning;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor metabolism;tumor microenvironment;tumor progression Label-Free Optical Redox Imaging for Pretreatment Prognosis of Early-Stage Triple Negative Breast Cancer Label-Free Optical Redox Imaging for Pretreatment Prognosis of Early-Stage Triple Negative BreastCancerNarrativeAbnormal metabolism and redox status have been demonstrated in high-risk breast cancer. Using clinicalspecimens mouse xenografts and cell models we will validate an optical redox imaging method to predict therisk of progression in triple negative breast cancer (TNBC). The proposed research is relevant to public healthbecause it will identify clinically translatable novel biomarkers to stratify the progression risk in untreated TNBCpatients supporting the NIHs mission to improve cancer diagnosis and personalized treatment planning. NCI 10803898 9/19/23 0:00 PA-20-185 1R01CA277037-01A1 1 R01 CA 277037 1 A1 "PEREZ, J MANUEL" 9/19/23 0:00 8/31/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 6621382 "LI, LIN Z" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 675960 NCI 425199 250761 Label-Free Optical Redox Imaging for Pretreatment Prognosis of Early-Stage Triple Negative BreastCancerAbstractTriple negative breast cancer (TNBC) has significant intratumor variations in microenvironments and metabo-lism which can substantially affect disease progression and clinical outcomes. A TNBC tumor can contain hy-poxic and normoxic regions and exhibit glycolytic oxidative or mixed metabolic subtypes. These metabolicsubtypes are typically on a submillimeter scale in clinically presented breast tumors below the resolution ofcurrent clinical metabolic imaging methods highlighting the need of new high-resolution metabolic imagingmethods in the clinic. Optical Redox Imaging (ORI) a label-free fluorescence imaging technique developed atthe Britton Chance Laboratory of Redox Imaging can detect intratumor metabolic subtypes three-dimensionally (3D) with a resolution down to 25 m. ORI measures the intrinsic fluorescence signals of re-duced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) and determines the oxidizedand reduced status of redox metabolism. Our preliminary results found redox hotspots the highly oxidized re-dox subtype in treatment-nave specimens from a pilot cohort of early-stage TNBC patients. Notably in thestudied cohort ORI redox hotspots predicted the risk of disease progression better than conventional clinicalindicators (e.g. tumor size stage grade and nodal status). Our data studying untreated TNBC xenografts andcell cultures also suggested that the redox hotspots are underpinned by the Warburg effect (glycolytic switch)corroborating the prediction of risk of progression by ORI. Based on these results the long-term goal of thisprogram is to establish the prognostic value of pretreatment ORI by expanding observations in TNBC clinicalspecimens and preclinical models. Aim 1 will be a full-scale retrospective ORI study of frozen untreated surgi-cal specimens from early-stage TNBC patients. We will test the hypothesis that the intratumor redox hotspotspredict an increased progression risk and add value to conventional prognostic indicators. Aim 2 will assessthe prognostic value of ORI in human TNBC mouse xenografts and cultured cell models using progressionendpoints and confirm that the activated glycolytic switch is the basis for the higher redox hotspot and risk ofprogression. The successful accomplishment of this project will establish ex vivo ORI as a novel pretreatmenttool that is indicative of the intratumor glycolytic switch at submillimeter resolution and inform the risks of pro-gression for individual patients with early-stage TNBC. Our project will help resolve the unmet clinical need foraccurate prognostic biomarkers to improve risk stratification and personalized treatment in TNBC. 675960 +No NIH Category available Accounting;Address;Aggressive behavior;American;Benign;Biochemical;Biological Markers;Biopsy;Biopsy Specimen;Cancer Detection;Cancer Etiology;Cancer Patient;Cessation of life;Clinical;Clinical Data;Clinical Treatment;Computational Technique;Core Biopsy;DNA;Data;Data Set;Decision Making;Diagnosis;Diagnostic;Disease;Evaluation;Functional Imaging;Genetic;Genetic Risk;Genomics;Goals;Graph;Health;Hematoxylin and Eosin Staining Method;Histology;Image;Image Analysis;Individual;Indolent;Institution;Intervention;Learning;Link;Local Therapy;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Medical Imaging;Methods;Modeling;Monitor;Morbidity - disease rate;National Cancer Institute;Nomograms;Operative Surgical Procedures;Outcome;Patients;Performance;Phenotype;Physicians;Probability;Process;Prostate;Prostate specific antigen measurement;Prostate-Specific Antigen;Prostatectomy;Radiation therapy;Radical Prostatectomy;Rectum;Recurrence;Research;Resolution;Resources;Risk;Risk Factors;Sampling;Screening for Prostate Cancer;Serum;Signal Transduction;Source;Specificity;Specimen;Stains;Testing;Tissues;Training;Universities;Washington;Work;algorithm development;cancer diagnosis;cancer genetics;cancer risk;clinical biomarkers;clinical decision-making;cohort;convolutional neural network;cost;digital;functional outcomes;graph neural network;large datasets;men;multi-scale modeling;multimodal data;multimodality;network models;novel;novel marker;overtreatment;patient subsets;predict clinical outcome;prevent;prostate cancer model;rectal;research and development;risk stratification;screening;serum PSA;tool;tumor;unnecessary treatment Computational Feature Profiling and Modeling for Prostate Cancer Detection and Risk Stratification PROJECT NARRATIVEProstate cancer is a leading cause of cancer death in American men but up to 60% of patients who receivetreatment may not require it as they would eventually succumb to a different health problem. The focus of thisresearch is to investigate new methods for more accurately detecting cancer and assessing its aggression us-ing medical imaging data histology data genetic data and other risk factors towards reducing overdiagnosisand overtreatment thus preventing patients from receiving unnecessary treatment and incurring associatednegative functional outcomes. NCI 10803606 12/5/23 0:00 PA-20-185 1R01CA279666-01A1 1 R01 CA 279666 1 A1 "ABRAMS, NATALIE" 12/5/23 0:00 11/30/28 0:00 Clinical Data Management and Analysis Study Section[CDMA] 10643210 "ARNOLD, COREY WELLS" Not Applicable 36 RADIATION-DIAGNOSTIC/ONCOLOGY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 12/5/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 641385 NCI 427665 213720 PROJECT SUMMARY/ABSTRACTProstate cancer is the most common and second deadliest non-skin cancer in American men accounting for26% of new cancer diagnoses and 9% of cancer deaths in men. Active surveillance radical prostatectomy andradiotherapy are commonly used treatments for clinically localized prostate cancer. However current riskstratification methods cannot be used effectively to avoid subjecting patients with clinically indolent cancers tounnecessary interventions causing significant morbidity and cost. The primary components currently involvedin screening are the digital rectal exam (DRE) and serum biomarkers such as PSA PCA3 PHI and 4Kscore.Unfortunately despite advances in these tests overdiagnosis remains a major problem due to limitedspecificity. As a result 90% of patients diagnosed with prostate cancer receive treatment even though up to60% of those patients could be candidates for active surveillance. Such treatment often results in long-termreductions in functional outcomes.The research objective of this R01 is to develop novel markers and models to both more accurately detectaggressive cancer and to forecast its arrival. Using a large cohort of patients we first plan to identify novelpathomic and germline features that indicate the presence of aggressive cancer or its precursors. We thenplan to implement an integrative graph convolutional network (GCN) combined with a convolutional neuralnetwork (CNN) to generate new multi-modal representations of underlying cancer state within the entireprostate. The framework will combine multiparametric magnetic resonance imaging (mpMRI) digital histologyimages germline features biomarkers and other predictors. We will also implement a baseline nomogram riskmodel for comparison as well as several new nomogram models that incorporate our newly identified features. 641385 +No NIH Category available 4T1;American;Binding;Blood;Blood Vessels;Breast;Breast Cancer Cell;Breast cancer metastasis;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Patient;Cell Death;Cell division;Cells;Cessation of life;Clinic;Clinical;Conventional Surgery;Cosmetics;Cryosurgery;Cytosol;Cytotoxic T-Lymphocytes;Dendritic Cells;Disseminated Malignant Neoplasm;Distant;Drug Delivery Systems;Drug usage;Encapsulated;Excision;Freezing;Frostbite;Gene Delivery;Heating;Hematologic Neoplasms;High temperature of physical object;Hour;Ice;Immune;Immune response;Immune system;Immunization;Immunologics;Immunotherapeutic agent;Immunotherapy;In Vitro;Literature;Macrophage;Malignant Neoplasms;Medical;Memory;Microtubule Stabilization;Modeling;Molecular;Monitor;Morbidity - disease rate;Myeloid-derived suppressor cells;Nanotechnology;Nature;Neoplasm Metastasis;Operative Surgical Procedures;Outcome;Paclitaxel;Pattern;Peripheral;Pharmaceutical Preparations;Primary Neoplasm;Proliferating;Public Health;Recurrent Malignant Neoplasm;Regulatory T-Lymphocyte;Reperfusion Therapy;Reporting;Safety;Shapes;Small Interfering RNA;Solid Neoplasm;T-Cell Activation;Temperature;Testing;Therapeutic;Time;Tumor Immunity;Ultrasonography;Woman;Work;cancer cell;cancer immunotherapy;cancer recurrence;cancer therapy;cancer type;chemotherapy;cold temperature;cytotoxic CD8 T cells;hyperthermia treatment;immune cell infiltrate;immunogenic cell death;improved;in vivo;lymphoid organ;malignant breast neoplasm;minimally invasive;mortality;nanomaterials;nanoparticle;neoplastic cell;novel;prevent;programmed cell death ligand 1;programmed cell death protein 1;receptor;response;success;time use;tumor;tumor microenvironment;tumor-immune system interactions Cold-responsive gene and drug delivery-potentiated cryoimmunotherapy Project Narrative-Relevance to Public HealthWe propose to develop a tumor cell and vasculature-targeted cold-responsive nanotechnology-potentiatedcryoimmunotherapy for treating both primary and metastatic cancer. This novel cancer therapy strategy maybe invaluable for combating cancer metastasis and recurrence which are the main causes of mortality inbreast and many other types of cancer to minimize the mortality and morbidity of cancer patients. NCI 10803036 12/19/23 0:00 PA-20-185 1R01CA279810-01A1 1 R01 CA 279810 1 A1 "SOMMERS, CONNIE L" 12/19/23 0:00 11/30/28 0:00 Drug and Biologic Therapeutic Delivery Study Section[DBTD] 9253575 "HE, XIAOMING " Not Applicable 4 BIOMEDICAL ENGINEERING 790934285 NPU8ULVAAS23 790934285 NPU8ULVAAS23 US 38.992333 -76.952986 820102 "UNIV OF MARYLAND, COLLEGE PARK" COLLEGE PARK MD BIOMED ENGR/COL ENGR/ENGR STA 207420001 UNITED STATES N 12/19/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 429350 NCI 276444 152906 Project Summary/AbstractBreast cancer (BC) is the 2nd leading cause of cancer-related death in American women and metastasis is themajor reason of BC-related mortality. Harnessing the immune system to battle cancer via immunotherapy hasemerged as a powerful and potentially revolutionizing strategy for treating cancer metastasis. Although cancerimmunotherapy strategies have shown success in treating hematological malignancies their use for destroyingsolid tumors needs further improvement. The immunosuppressive tumor microenvironment (TME) is a keyfactor that contributes to the poor clinical outcomes of immunotherapy of solid tumors. Cryosurgery has been proposed as a promising strategy to modulate the TME. It is done by freezing tocause ice formation (i.e. frostbite) in tumor which may lead to immunogenic cell death shape an immune-active TME and provoke antitumor immunity. Unlike hyperthermic therapy for which irreversible vascular stasisoccurs during heating there is a temporary (a few hours) reperfusion of the tumor after thawing a frozen tumoriceball. This enhances immune cell infiltration into the tumor after cryosurgery compared to heating. Howevercryosurgery alone is insufficient to activate a potent immune response against cancer via modulating the TME. Moreover cryosurgery has been used in the clinic for treating cancer especially BC. This is because it isminimally invasive with minimal cosmetic damage compared to surgical resection and the hyperechoic frozenBC tumor iceball can be conveniently monitored in real time with medical ultrasonography. Unfortunately atemperature of -20 C or lower is needed for complete cell death while the temperature in the periphery of afrozen tumor iceball is > -20 C. This may result in incomplete tumor killing and cancer recurrence. Thuscombining cryosurgery with other therapies including immunotherapy has been studied to improve cancerkilling in the peripheral region of a frozen tumor iceball. Although this is promising to kill localized tumor aneffective abscopal/immunization effect of cryoimmunotherapy against distant/metastatic tumors has not beenreported and no nanomaterial has been used to enhance cryoimmunotherapy until a recent study of us. In this study we developed a cold-responsive nanoparticle (CRNP) that targets cancer cells actively andreleases its payload (chemotherapy and immunotherapy agents) specifically into the cytosol in responsive tothe cold temperature in the periphery of a frozen tumor iceball for combining with cryosurgery. This induces apotent cryoimmune response against not only primary tumors with freezing but also distant and rechallengedmetastatic tumors without cryosurgery (i.e. the abscopal and immunization effects). We hypothesize theefficacy and safety of the novel cryoimmunotherapy strategy can be further improved by 1) developing theCRNP to actively target both cancer cells and tumor vasculature and 2) delivering chemotherapy andimmunotherapy agents that both perform their therapeutic function in the cytosol. The novel dual-targetingCRNP-potentiated cryoimmunotherapy may be invaluable for combating metastasis of BC and other cancers. 429350 +No NIH Category available 3-Dimensional;Adjuvant Therapy;Binding;CD47 gene;Cancer Biology;Cells;Cessation of life;Circulation;DNA;Data;Development;Diagnostic;Disease;Drug Carriers;Drug Delivery Systems;Eating;Engineering;Epidermal Growth Factor Receptor;Exhibits;Future;Gene Delivery;Genetic Engineering;Genetically Engineered Mouse;Goals;Heterogeneity;Homing;Human;In Vitro;Integrins;Knowledge;Lead;Lipids;Liposomes;Liver;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Medicine;Metabolic Clearance Rate;Modeling;Mononuclear;Nanodelivery;Operative Surgical Procedures;Outcome;Pancreatic Ductal Adenocarcinoma;Patients;Penetration;Peptides;Phagocytes;Phagocytosis;Pharmaceutical Preparations;Property;Proteins;RNA;Regimen;Research;SHPS-1 protein;Signal Transduction;Site;Solid;Spleen;Surface;System;Techniques;Technology;Testing;Therapeutic;Therapeutic Effect;Tumor Escape;United States;Work;biomaterial compatibility;cancer cell;cancer therapy;chemotherapy;clinically relevant;cytotoxic;delivery vehicle;efficacy evaluation;efficacy validation;engineered exosomes;exosome;extracellular;extracellular vesicles;immunogenicity;improved;in vitro Model;in vivo;in vivo Model;innovation;macromolecule;mouse model;nanocarrier;nanoparticle;nanoscale;neoplastic cell;novel;novel therapeutic intervention;overexpression;pancreas xenograft;pancreatic PDX models;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;prevent;receptor binding;small molecule;success;targeted cancer therapy;targeted treatment;translational potential;tumor;uptake Engineering Exosome for Pancreatic Cancer Targeting Therapies This project proposes novel genetically engineered smart exosomes that will overcomeobstacles currently preventing the effective use of nanodelivery technologies in cancertreatment. Our proposed studies aim to advance a safe efficient and stable nanodeliverysystem that actively targets pancreatic cancer (PDAC). The knowledge generated by this workwill contribute to the development of an innovative smart exosome nanocarrier-based platformfor applications ranging from diagnostic medicine to novel therapeutic strategies for treatingcancers such as PDAC. NCI 10803020 9/21/23 0:00 PA-20-185 1R01CA276732-01A1 1 R01 CA 276732 1 A1 "AVULA, LEELA RANI" 9/21/23 0:00 8/31/28 0:00 Biomaterials and Biointerfaces Study Section[BMBI] 15083210 "LIU, SHI-HE " Not Applicable 9 BIOLOGY 807418939 M9ACC5DQCNL6 807418939 M9ACC5DQCNL6 US 41.619554 -83.620727 229501 UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS TOLEDO OH SCHOOLS OF MEDICINE 436142595 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 498038 NCI 322355 175683 Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers and ranks fourth in cancer-related deaths in the United States. Therapies for pancreatic cancer are largely hindered by the lack of aneffective delivery system. Exosomes are emerging as a promising type of nanocarrier for drug/gene delivery dueto the unique properties of these naturally derived nanoscale extracellular vesicles and their innate ability toshuttle proteins lipids and DNA/RNA between cells. However major challenges exist including their inability totarget tumor cells and their high proportion of clearance by the mononuclear phagocyte system (MPS) of theliver and spleen. Our long-term goal is to develop innovative nanocarriers with low immunogenicity highbiocompatibility increased stability longer circulation times and highly active tumor cell targeting. Using novelexosomal engineering techniques we recently found that (a) incorporation of a tumor-homing peptide (RGD)onto exosomal surface marker CD9 (ExoCD9-RGD) results in specific binding to and uptake by integrin v3-expressing cancer cells and (b) exosomes overexpressing CD47 a dont eat me signal via its minimal self-peptide (CD47p110-130) interact with signal regulatory proteins (SIRP CD172A) on macrophages to significantlyreduce liver and spleen clearance of exosomes. These findings lead to our central hypothesis that displayingRGD and CD47p110-130 on exosomes through CD9 engineering will permit exosomes to target PDAC in vivo whileallowing exosomes to evade MPS clearance. Toward this hypothesis we have developed smart exosomes byco-displaying RGD and CD47p110-130 on the exosome surface (ExoSmart). This results in enhanced receptor bindingthereby increasing accumulation and cytotoxic therapeutic effects in 3D stroma-rich PDAC spheroid tumormodels. With these strong preliminary data we propose to pursue three Specific Aims to characterize ExoSmartand validate the application of ExoSmart in drug delivery. (1) To evaluate smart exosomes co-expressing CD9-RGD and CD9-CD47p110-130 (ExoSmart) for exclusive active PDAC targeting therapy using human PDAC stroma-rich 3D spheroid models both in vitro and in vivo. (2) To validate the efficacy of ExoSmart PDAC targetingchemotherapies in a genetically engineered mouse PDAC tumor model (KPC) and clinically relevant patient-derived xenografted (PDX) pancreatic cancer mice models. (3) To extend ExoSmart to personalized PDACtargeting by optimizing multiple insertion sites of CD9 and tumor-targeting peptides for optimal PDAC targeting.Collectively our proposed research will broadly impact the field by developing innovative nanocarriers withoptimized cargos and surfaces for precision PDAC targeting. This project holds great translational potential forcancer therapy while providing a solid basis for future work utilizing novel peptide-engineered exosomestrategies. 498038 +No NIH Category available Aftercare;Animal Model;Animals;Apoptosis;Atherosclerosis;Biological;Biological Markers;Biopsy;Blood;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Control;Cancer Patient;Cancer cell line;Cardiac health;Cell physiology;Cells;Cessation of life;Chemoprevention;Cholesterol;Clinical Research;Clinical Trials;Colon Carcinoma;Combined Modality Therapy;Data;Dendritic Cells;Diagnosis;Disease Progression;Drug Costs;Enrollment;Erectile dysfunction;Experimental Models;Exposure to;FRAP1 gene;Future;Genetic;Genetic study;Goals;Heat shock proteins;Hepatic;High-Risk Cancer;Human;Immune;Immune response;Immune system;Immunologic Memory;Immunologic Stimulation;Immunologics;In Vitro;Incontinence;Infiltration;Intervention;Knockout Mice;Low-Density Lipoproteins;Lymphocyte;Lymphocytic Infiltrate;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measures;Memory;Meta-Analysis;Modeling;Monitor;Multi-Institutional Clinical Trial;Mus;Neoplasm Metastasis;Newly Diagnosed;Operative Surgical Procedures;Outcome;Participant;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Phase;Phase III Clinical Trials;Population;Population Study;Pre-Clinical Model;Prevention strategy;Primary Cancer Prevention;Proliferating;Prostate;Prostatectomy;Radiation;Regulatory T-Lymphocyte;Reporting;Resources;Risk;Secondary Cancer Prevention;Secondary Prevention;Serum;Signal Transduction;Simvastatin;Solid;T memory cell;Testing;Tissues;Tumor Immunity;Tumor Tissue;adaptive immune response;anti-tumor immune response;antitumor effect;cancer type;design;epidemiology study;ezetimibe;high risk men;immunogenic cell death;immunogenicity;immunoregulation;improved outcome;in vivo;individual patient;mTOR Signaling Pathway;mTOR inhibition;malignant breast neoplasm;men;mortality risk;mouse model;neutrophil;patient response;patient subsets;pharmacologic;phase change;preclinical study;prevent;primary endpoint;prospective;prostate biopsy;prostate cancer model;prostate cancer progression;prostate cancer risk;rational design;response;trafficking;trial design;tumor;tumor growth;tumor progression Intensive cholesterol-lowering intervention and anti-tumor immunity modeled in prostate cancer PROJECT NARRATIVEThe proposed study will test the hypothesis that intensive lowering of circulating cholesterol decreases prostatecancer progression by stimulating a long-term antitumor immune response. Key observations made in mousemodels will be examined in a clinical trial in patients diagnosed with prostate cancer on active surveillance.Demonstration that cholesterol-lowering therapy shows activity to activate long-term anti-tumor immunity willhave impact on future trial design for primary and secondary cancer prevention and for examining for cholesterollowering strategies for other cancers where immune stimulation can improve outcomes. NCI 10802975 9/21/23 0:00 PAR-21-033 1R01CA280060-01A1 1 R01 CA 280060 1 A1 "SUEN, CHEN S" 9/21/23 0:00 8/31/28 0:00 Cancer Prevention Study Section[CPSS] 2049173 "KIM, HYUNG L" "THOMPSON, PATRICIA ANN" 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 692001 NCI 414372 277629 PROJECT SUMMARYIn epidemiologic studies a strong association has been noted between cholesterol-lowering therapy with statinsand lower risk of death from prostate cancer. Animal studies suggest that cholesterol-lowering can decreasethe progression of prostate cancer. The biologic effects of lowering-cholesterol in prostate cancer patients arenot fully understood. It is very likely that lowering cholesterol can directly inhibit the growth of the tumor and itspotential to metastasize. However our preliminary data suggest another important mechanism: cholesterol-lowering enhances an antitumor immune response. In our animal models cholesterol-lowering reducedsignaling through the mTOR pathway in immune cells. We show that this same signaling change is seen inprostate cancer patients when their blood cholesterol is lowered. Our preliminary data also suggest thatcholesterol-lowering enhances immune memory cells that are critical for long-term cancer control. Our workinghypothesis is that lowering serum cholesterol (1) decreases TORC2 signaling in lymphocytes and enhancesformation of central memory CD8+ T cell (2) can be optimized by controlling Tregs and (3) directly increasestumor immunogenicity. To test this hypothesis and to relate findings from our mouse models we propose parallelmouse and human clinical studies. Therefore Aim 1 evaluates the effects of cholesterol-lowering on CD8+memory cells as well as other critical components of the adaptive immune response such as regulatory T cells.Our preliminary data show that cholesterol-lowering makes the tumor more visible to the immune system byincreasing the expression of heat shock proteins. We evaluate the effects of cholesterol-lowering on the tumoritself which may then alter the immune response. We also assess the effects of tumor exposed to cholesterol-lowering on dendritic cells macrophages and neutrophils. Aim 2 evaluates cholesterol-lowering in a prospectiveclinical trial in men with low and intermediate-risk prostate cancer being managed with active surveillance. Thesemen are at high risk for cancer progression and needing radical surgery or radiation which often leaves menwith permanent incontinence and erectile dysfunction. In the proposed trial men with newly diagnosed prostatecancer will undergo maximal cholesterol-lowering or standard management. The prostate biopsy tissue beforeand after starting treatment will be compared to determine if cholesterol lowering increases CD8+ T cells in thetumor which are required for an antitumor immune response. We will also examine immune cells in the bloodto identify and enrich for patient subgroups most likely to respond. A positive study will provide a strong rationalefor a phase 3 multicenter clinical trial to determine if cholesterol-lowering can prevent the formation orprogression of prostate cancer. It will also provide an immune mechanism that can potentially improve outcomesin other cancers beyond prostate cancer. 692001 +No NIH Category available Address;Alanine;Automobile Driving;Binding;Biology;Brain;Brain Neoplasms;Cell physiology;Cells;Complex;Cyclic AMP-Dependent Protein Kinases;Cyclin-Dependent Kinases;Data;Development;Enzymes;Event;Family;Genetic study;Glioblastoma;Glioma;Gliomagenesis;Glycogen Synthase Kinase 3;Glycogen Synthase Kinases;Hydroxyl Radical;Hydroxylation;ID2 gene;Impairment;Indolent;Inhibitor of Differentiation Proteins;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Metabolic;Metabolism;Mitochondria;Mitogen-Activated Protein Kinases;Molecular;Molecular Conformation;Mus;Mutation;Neurons;Normal Cell;Oncoproteins;Oxygen;Pathologic;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Play;Primary Neoplasm;Procollagen-Proline Dioxygenase;Proline;Proline-Directed Protein Kinases;Protein Isoforms;Protein Kinase;Proteins;Proteome;Proteomics;Proto-Oncogene Proteins c-akt;Reaction;Regulation;Regulatory Pathway;Reporting;Role;Signal Pathway;Signal Transduction;Site;Specificity;Tissues;Translations;Tumor Promotion;Tumor Suppressor Proteins;Tyrosine Phosphorylation;Work;beta catenin;cancer stem cell;cancer type;comparative;computerized tools;experimental study;inhibitor;inorganic phosphate;interest;member;mind control;mouse model;mutant;notch protein;novel;phosphoproteomics;polypeptide;prognostication;promoter;protein activation;recruit;self-renewal;therapeutic target;tumor;tumorigenesis;ubiquitin ligase Activation of protein kinases by proline hydroxylation Project narrativeEukaryotic protein kinases regulate important cellular processes through their ability to phosphorylatethemselves and substrate proteins and alteration of the mechanisms that control kinase activation leads topathological conditions including cancer. Here we will investigate a novel mechanism of kinase activationthrough hydroxylation of proline residues by proline hydroxylase enzymes. We will determine the functionalimpact of the signaling pathways converging on proline hydroxylases the cancer phenotypes elicited in themouse brain by dysregulation of this novel pathway of kinase activation and the consequences on the globalproteome and phosphoproteome. NCI 10802907 1/5/24 0:00 PA-20-185 1R01CA280560-01A1 1 R01 CA 280560 1 A1 "LUO, RUIBAI" 1/5/24 0:00 12/31/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 7147873 "LASORELLA, ANNA " Not Applicable 27 BIOCHEMISTRY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 1/5/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 446036 NCI 290577 155459 Project summaryEukaryotic protein kinases regulate important cellular processes through their ability to phosphorylatethemselves and substrate proteins. One of the phosphorylation events common to most protein kinases is thephosphorylation that occurs at the activation loop. This phosphorylation event often occur via auto-phosphorylation although how an inactive kinase achieves the phospho-transfer reaction on its own activationloop site is still unclear [2]. We recently reported that activation of dual specificity tyrosine-phosphorylation-regulated kinases 1A and 1B (DYRK1A and DYRK1B) requires prolyl-hydroxylation by the oxygen sensingprolyl hydroxylase PHD1. DYRK1 activation by prolyl-hydroxylation instigates a sequence of events wherebyphosphorylation of ID2 by DYRK1 releases ID2 mediated constraints on VHL ubiquitin ligase tumorsuppressor complex thus regulating the degradation of HIF proteins in brain tumors and cancer stem cells.Our most recent work identified prolyl hydroxylation by PHD1 as the general mechanism required in trans toprime protein kinases of the CMGC family for autophosphorylation and activation. Beside DYRK1 CMGCkinases includes Cyclin dependent kinases (C) Mitogen activated protein kinases (M) Glycogen synthasekinases (G) and CDC-like kinases (C). In this proposal we will follow the long-standing interest of the lab onthe molecular pathways that favor neural cell self-renewal during brain development and are aberrantlyrecruited during gliomagenesis and investigate the mode of regulation of glycogen synthase kinase 3 (GSK3)a central hub in the control of brain functions and oncogenesis. GSK3 shares with other members of theCMGC kinase family the highly conserved CMGC insert domain. We found that this domain harbors a L/xGxPmotif and the highly conserved proline residue Pro-276 which is targeted by hydroxylation by the prolinehydroxylase enzyme PHD1 and is necessary for kinase activation.These observations led us to propose a combination of mechanistic and genetic studies to define thedynamics of GSK3a/b kinase maturation induced by PHD1 and the interaction with other signalingmechanisms that regulate GSK3 kinase activity. The significance of proline hydroxylation for gliomagenesiswill be investigated in knock-in mouse models of Pro to Ala mutation of GSK3a/b (Pro-339 and Pro-276respectively). Mouse tumors will be analyzed using proteomics and phosphoproteomics to reconstruct theactivity of wild type and mutant GSK3 kinases. Given the uncertain role of GSK3 kinases in cancer andglioblastoma (promoter or suppressor) findings will lead to a better understanding of the potentialbenefit/harm of GSK3 inhibitors that are currently proposed for the treatment of glioblastoma. 446036 +No NIH Category available American;Animal Model;Biopsy;Biopsy Specimen;Blood Vessels;Cancerous;Cessation of life;Chemicals;Classification;Clinic;Clinical;Clinical Research;Collaborations;Contrast Media;Detection;Development;Devices;Diagnostic Procedure;Ensure;Functional Imaging;Funding;Gleason Grade for Prostate Cancer;Heterogeneity;Human;Hypoxia;Image;Image Enhancement;Image Guided Biopsy;Imaging Techniques;Indolent;Institution;Intravenous;Light;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Maps;Methods;Modality;Molecular;Needle biopsy procedure;Neoplasm Metastasis;Pathologic;Patient-Focused Outcomes;Patients;Performance;Perfusion;Permeability;Phase I/II Clinical Trial;Procedures;Prognosis;Property;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Provider;Rectum;Regional Cancer;Research;Resolution;Screening for Prostate Cancer;Statistical Data Interpretation;System;Systems Development;Technology;Time;Tissues;Translating;Translations;Transrectal Ultrasound;Ultrasonic Transducer;Ultrasonography;Validation;accurate diagnosis;anatomic imaging;cancer diagnosis;canine model;clinical diagnosis;clinical translation;clinically significant;cost;experience;fabrication;high resolution imaging;human subject;image guided;imaging biomarker;imaging detection;imaging modality;imaging platform;imaging system;improved;in vivo;in vivo imaging system;men;molecular imaging;novel;personalized medicine;photoacoustic imaging;prototype;rectal;safety assessment;structural imaging;tool;tumor;ultrasound;uptake;user-friendly Clinical Translation of dual-modality transrectal ultrasound and photoacoustic imaging for detection of aggressive human prostate cancer PROJECT NARRATIVEProposed novel dual-modality transrectal ultrasound and photoacoustic imaging platform with uniquecapabilities to map functional chemical and molecular information reflecting pathological conditions over theentire human prostate in vivo will likely help differentiate aggressive from non-aggressive prostate cancer. NCI 10802712 9/19/23 0:00 PA-20-185 1R01CA278833-01A1 1 R01 CA 278833 1 A1 "TATA, DARAYASH B" 9/19/23 0:00 8/31/28 0:00 Clinical Translational Imaging Science Study Section[CTIS] 11377077 "KOTHAPALLI, SRI RAJASEKHAR" "WANG, XUEDING " 15 BIOMEDICAL ENGINEERING 3403953 NPM2J7MSCF61 3403953 NPM2J7MSCF61 US 40.870717 -77.83415 1524202 "PENNSYLVANIA STATE UNIVERSITY, THE" UNIVERSITY PARK PA BIOMED ENGR/COL ENGR/ENGR STA 168027000 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 572318 NCI 475122 97196 ABSTRACTProstate cancer (PCa) with an annually increasing incident rate has become the most commonly diagnosedcancer in American men. The accurate diagnosis of aggressive PCa is critical for the survival of patients.Transrectal ultrasound (TRUS) guided biopsy the current standard procedure for evaluating the presence andaggressiveness of PCa suffers from low core yield leading to under-sampling and under-grading of clinicallysignificant tumors. To fill this long-standing and serious technical gap in PCa diagnosis we propose to developa novel dual-modality imaging platform which integrates the emerging photoacoustic (PA) molecular imagingtechnique with the established TRUS for improved detection and differentiation of clinically significant PCatumors. With the unique capability to map functional chemical and molecular information reflecting pathologicalconditions over the entire human prostate in vivo non-invasively the proposed TRUS and PA (namely TRUSPA)imaging can sensitively detect spatially distributed tumors and more importantly differentiate aggressive vs.non-aggressive PCa tumors.This proposed multi-institutional research will leverage the extensive experience of Dr. Kothapallis lab indeveloping and translating TRUSPA imaging systems for in vivo human prostate imaging and the expertise ofDr. Wangs lab in developing novel functional imaging biomarkers of PCa. The central hypothesis is that theTRUSPA is capable of mapping a list of functional and structural imaging biomarkers in human prostate in a real-time non-invasive manner for detecting and differentiating clinically significant PCa. To validate this hypothesiswe will develop a clinical grade TRUSPA platform through the collaborations with Verasonics Inc. a world leadingprovider of research ultrasound systems and Blatek Inc. a company providing customized ultrasoundtransducer array fabrication. Based on this platform a set of new imaging biomarkers for detecting prostatetumors and characterizing PCa aggressiveness will be rigorously examined via the parallel clinical studies at thetwo participating institutions. To pave the road toward successful translation this research will focus on thefollowing specific aims: Aim 1. Develop and fully characterize a clinical grade TRUSPA dual imaging system forPCa detection; and Aim 2. Via the studies on human subjects examine the clinical performance of TRUSPA byassessing a list of structural and functional imaging biomarkers in distinguishing aggressive from indolent PCa.Once the performance of the proposed TRUSPA imaging of PCa is validated this low-cost and user-friendlytechnology will be ready for appropriate phase I/II clinical trials in the next funding cycle. TRUSPA imaging withthe unique capability of detecting and differentiating clinically significant PCa in vivo non-invasively in real timecan seamlessly fit into the current clinical procedure of TRUS image-guided biopsy and holds great potential toshift the paradigm of PCa management. 572318 +No NIH Category available Address;Advisory Committees;Animal Disease Models;Animal Model;Animals;Area;California;Cellular biology;Chicago;Colorado;Development;Disease;Educational workshop;Endogenous Retroviruses;Ethics;Fostering;Goals;Illinois;Immune response;Immunodeficiency and Cancer;Immunologics;International;Italy;Location;Manuscripts;Mechanics;Medical;Modeling;Molecular;Nobel Prize;Ohio;Participant;Pathogenesis;Postdoctoral Fellow;Principal Investigator;Process;Publications;Research;Research Personnel;Retroviridae;Students;Underrepresented Minority;Universities;Woman;Work;Writing;editorial;emerging pathogen;graduate student;human disease;human model;human pathogen;innovation;symposium;tumorigenesis;virology;virus host interaction 33rd International Workshop on Retroviral Pathogenesis Project NarrativeRetroviruses have long been recognized as important pathogens of humans and animals andresearch on these agents has uncovered important discoveries in cell biology and mechanismsin human disease. The 33rd International Workshop on Retroviral Pathogenesis will continue along tradition of intimate engaged scientific interaction on all aspects of retroviral pathogenesiswith strong emphasis on animal retroviruses as models of human disease. The conference willconvene national and international scientific leaders in the field together with junior investigatorspostdoctoral and student trainees for scientific presentation and engaged discussion. NCI 10802677 11/28/23 0:00 PA-21-151 1R13CA287389-01 1 R13 CA 287389 1 "SAYYED, ZULEKHA I" 12/1/23 0:00 11/30/24 0:00 ZCA1-PCRB-9(O1) 1866427 "GREEN, PATRICK LEE" Not Applicable 3 NONE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH ORGANIZED RESEARCH UNITS 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 10000 NIAID 5000 0 Project Summary/AbstractThe International Workshop on Retroviral Pathogenesis now in its 33rd year has long served asa forum for the exchange of new research findings and concepts on all aspects of retroviralpathogenesis from molecular mechanisms to the immunological parameters of host-virusinteraction. The conference will continue a tradition of intimate engaged scientific interaction onall aspects of retroviral pathogenesis with strong emphasis on animal retroviruses as models forhuman disease. Retroviral pathogens of humans and animals in all retroviral genera are thesubject of scientific presentation and vibrant discussion. Topics at the workshop will includeretrovirus entry and integration replication and restriction assembly immune responsesoncogenesis pathogenesis new and emerging pathogens endogenous retroviruses and animalmodels of disease. Approximately 100 participants are anticipated including principalinvestigators postdoctoral trainees and graduate students. Planned for December 4-7 2023 inTrento Italy the small size and format of the conference supports concentrated interaction anddeep scientific engagement. The conference fosters the professional development of juniorinvestigators by affording them the opportunity to present their current work to a panel of engagedcolleagues and to serve as Session Chairs. The overarching goal of the conference is to providea forum that fosters continued scientific engagement leading to innovative conceptual advancesand research in the area of retroviral pathogenesis broadly defined. The conference will addressthis goal through three specific aims: (1) Bring together national and international scientific leadersin the field together with junior investigators postdoctoral and student trainees; (2) Provideopportunities for four invited keynote scientific presentations and discussions as a groupinterspersed with more intimate opportunity for discussion and interaction; (3) Provide platformopportunities for junior investigators women and underrepresented minority scholars throughscientific presentation and/or designation as Session Chairs; and (4) Provide Writing Workshopcovering topics such as how to frame research findings for publication the steps a manuscriptgoes through in the editorial process the mechanics of writing and research and publicationethics. 5000 +No NIH Category available Address;Advisory Committees;Animal Disease Models;Animal Model;Animals;Area;California;Cellular biology;Chicago;Colorado;Development;Disease;Educational workshop;Endogenous Retroviruses;Ethics;Fostering;Goals;Illinois;Immune response;Immunodeficiency and Cancer;Immunologics;International;Italy;Location;Manuscripts;Mechanics;Medical;Modeling;Molecular;Nobel Prize;Ohio;Participant;Pathogenesis;Postdoctoral Fellow;Principal Investigator;Process;Publications;Research;Research Personnel;Retroviridae;Students;Underrepresented Minority;Universities;Woman;Work;Writing;editorial;emerging pathogen;graduate student;human disease;human model;human pathogen;innovation;symposium;tumorigenesis;virology;virus host interaction 33rd International Workshop on Retroviral Pathogenesis Project NarrativeRetroviruses have long been recognized as important pathogens of humans and animals andresearch on these agents has uncovered important discoveries in cell biology and mechanismsin human disease. The 33rd International Workshop on Retroviral Pathogenesis will continue along tradition of intimate engaged scientific interaction on all aspects of retroviral pathogenesiswith strong emphasis on animal retroviruses as models of human disease. The conference willconvene national and international scientific leaders in the field together with junior investigatorspostdoctoral and student trainees for scientific presentation and engaged discussion. NCI 10802677 11/28/23 0:00 PA-21-151 1R13CA287389-01 1 R13 CA 287389 1 "SAYYED, ZULEKHA I" 12/1/23 0:00 11/30/24 0:00 ZCA1-PCRB-9(O1) 1866427 "GREEN, PATRICK LEE" Not Applicable 3 NONE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH ORGANIZED RESEARCH UNITS 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 10000 NCI 5000 0 Project Summary/AbstractThe International Workshop on Retroviral Pathogenesis now in its 33rd year has long served asa forum for the exchange of new research findings and concepts on all aspects of retroviralpathogenesis from molecular mechanisms to the immunological parameters of host-virusinteraction. The conference will continue a tradition of intimate engaged scientific interaction onall aspects of retroviral pathogenesis with strong emphasis on animal retroviruses as models forhuman disease. Retroviral pathogens of humans and animals in all retroviral genera are thesubject of scientific presentation and vibrant discussion. Topics at the workshop will includeretrovirus entry and integration replication and restriction assembly immune responsesoncogenesis pathogenesis new and emerging pathogens endogenous retroviruses and animalmodels of disease. Approximately 100 participants are anticipated including principalinvestigators postdoctoral trainees and graduate students. Planned for December 4-7 2023 inTrento Italy the small size and format of the conference supports concentrated interaction anddeep scientific engagement. The conference fosters the professional development of juniorinvestigators by affording them the opportunity to present their current work to a panel of engagedcolleagues and to serve as Session Chairs. The overarching goal of the conference is to providea forum that fosters continued scientific engagement leading to innovative conceptual advancesand research in the area of retroviral pathogenesis broadly defined. The conference will addressthis goal through three specific aims: (1) Bring together national and international scientific leadersin the field together with junior investigators postdoctoral and student trainees; (2) Provideopportunities for four invited keynote scientific presentations and discussions as a groupinterspersed with more intimate opportunity for discussion and interaction; (3) Provide platformopportunities for junior investigators women and underrepresented minority scholars throughscientific presentation and/or designation as Session Chairs; and (4) Provide Writing Workshopcovering topics such as how to frame research findings for publication the steps a manuscriptgoes through in the editorial process the mechanics of writing and research and publicationethics. 5000 +No NIH Category available Address;Animal Model;Astrocytes;Attenuated;Brain;CCL2 gene;CD8-Positive T-Lymphocytes;Cell Communication;Cells;Cessation of life;Chronic;Clinic;Clinical;Coculture Techniques;Combined Modality Therapy;Complex;Data;Development;Disease Progression;Disseminated Malignant Neoplasm;Distal;Growth;IFNAR1 gene;Imaging Techniques;Immune;Immune checkpoint inhibitor;Immunologics;In Vitro;Incidence;Infiltration;Interferon Activation;Interferon Type I;Interferon-beta;Interferons;Invaded;Knockout Mice;Lesion;Location;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical;Metastatic malignant neoplasm to brain;Modeling;Molecular;Mus;Myelogenous;Myeloid Cells;Neoplasm Metastasis;Organ;Pathway interactions;Patients;Pre-Clinical Model;Process;Production;Recurrent Malignant Neoplasm;Reporter;Research;Research Proposals;Sampling;Shapes;Signal Induction;Signal Transduction;Stromal Cells;Study models;Survival Rate;Systemic Therapy;Testing;Therapeutic;Therapeutic Effect;Time;Visualization;Work;angiogenesis;brain cell;cancer cell;cancer recurrence;chemokine;chemokine receptor;chemotherapy;druggable target;effective therapy;efficacy testing;experimental study;immune cell infiltrate;improved;in vivo;inhibitor;insight;malignant breast neoplasm;metastatic process;monocyte;mouse model;new therapeutic target;notch protein;novel;optimal treatments;pre-clinical;receptor;reconstruction;recruit;response;side effect;therapeutic target;therapeutically effective;transcriptome sequencing;tumor;tumorigenic;type I interferon receptor Interrogating Type I Interferon signaling in breast cancer brain metastasis PROJECT NARRATIVEThe brain is one of the common organs for breast cancer recurrence. With rising incidence breast cancerbrain metastasis has become a major problem in clinic. Metastasis is a multi-step process that requires thecomplex interplay between cancer cells and the stromal cells. In this proposal we focus on how type Iinterferon response in astrocytes the unique stromal cells in the brain microenvironment facilitates breastcancer brain metastasis. If we define microenvironmental changes during brain metastasis we can yield realand actionable targets on the brain instead of on cancer cells to provide more effective therapies for brainmetastasis patients. NCI 10802082 12/1/23 0:00 PA-20-185 1R01CA279117-01A1 1 R01 CA 279117 1 A1 "GRIL, BRUNILDE M" 12/1/23 0:00 11/30/28 0:00 Tumor Host Interactions Study Section[THI] 10943112 "CHEN, QING " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 529002 NCI 290501 238501 PROJECT SUMMARYThe brain is one of the common organs for breast cancer recurrence. Breast cancer brain metastasis isincreasingly becoming a significant clinical problem due to its rising incidence and limited efficacy of existingsystemic therapies. Metastasis is the consequence of favorable interactions between the invaded cancer cellsand the microenvironment in the distal organ. To cancer cells the brain has the most uniquemicroenvironment since the stromal cells in the brain do not exist in any other organs. This explains whytherapeutic strategies which efficiently diminish primary and non-brain metastatic breast tumors areineffective in controlling the established brain lesions. Our current work aims to understand the unique brainmetastasis microenvironment and delineate how it facilitates metastatic outgrowth. Type I interferon (IFN)signaling is a well-recognized anti-tumor pathway. However experiments from our animal models show thattype I response in astrocytes the unique brain stromal cells has a pro-metastatic effect in the brain. Basedon these findings we will further address the following questions: 1) Define the underlying mechanisms inhow the type I IFN response in astrocytes mediates brain metastasis. We will test the hypothesis that theactivated IFN response in astrocytes helps the recruitment of specific immune cells into the brain lesions. 2)Validate the type I IFN activation at different stages of brain metastasis. We will apply the top-notch imagingtechnique in our mouse models to directly visualize cellular and molecular changes as they occur in real-timeand validate these observations in clinical samples. 3) Investigate the therapeutic effect of inhibition ofimmune cell recruitment on brain metastasis. We will not only identify the druggable targets but also optimizethe therapeutic windows in our pre-clinical mouse models. Overall our idea is that once we know how thebrain microenvironment helps cancer growth in the brain we can focus our efforts on stopping it. Our researchproposal will yield real and actionable targets on brain microenvironment instead of on cancer cells to treatbrain metastasis. More importantly our studies on tracking the dynamic changes during brain metastaticprocess will help identify the optimal therapeutic strategies to effectively treat brain metastasis and minimizepotential side effect. 529002 +No NIH Category available Affect;Alkylating Agents;Antibodies;Antibody Therapy;Antigens;Biological Models;Bispecific Antibodies;Bite;Bone Marrow;Bortezomib;CAR T cell therapy;CD3 Antigens;Cancer Therapy Evaluation Program;Cell physiology;Cells;Clinical;Clinical Trials;Combined Modality Therapy;Complex;Credentialing;Cyclophosphamide;Cytotoxic T-Lymphocytes;DNA;Data;Development;Dexamethasone;Disease;Disease remission;Extramedullary;Genomics;Glucocorticoids;Harvest;Hematopoietic Neoplasms;Human;Immune;Immune checkpoint inhibitor;Immune system;Immunocompetent;Immunologic Deficiency Syndromes;Immunologics;Immunooncology;Immunotherapy;In complete remission;Long-Term Effects;Longitudinal Studies;Malignant - descriptor;Mediating;Melphalan;Modeling;Multiple Myeloma;Mus;Patient-Focused Outcomes;Patients;Phase;Phase II Clinical Trials;Plasma Cells;Prednisone;Proteasome Inhibitor;Randomized;Refractory;Relapse;Reporting;Research Personnel;Resistance;Shapes;Surface Antigens;T cell therapy;T-Cell Activation;T-Lymphocyte;TNFRSF17 gene;Thalidomide;Toxic effect;Transgenes;Tumor Burden;Tumor Debulking;Validation;Vertebral column;Xenograft Model;chimeric antigen receptor T cells;clinical development;clinical practice;clinical predictors;clinically relevant;co-clinical trial;conventional therapy;cost;cytokine release syndrome;cytotoxic;design;exhaust;exhaustion;immune modulating agents;improved;lenalidomide;leukemia/lymphoma;mouse model;neoplastic cell;novel drug combination;patient response;pomalidomide;pre-clinical;preclinical study;receptor;reconstitution;relapse patients;response;retransplantation;single-cell RNA sequencing;standard of care;targeted treatment;tool;treatment response;tumor;tumor microenvironment;tumor-immune system interactions preclinical optimization of BCMA directed T cell therapy PROJECT NARRATIVET-cell directed therapies are the most exciting recent advances in treatment of patients but after the initialresponse patients inevitably relapse to this disease and myeloma remains incurable. We will credential amouse model for developing novel combinations of drugs with T-cell directed treatments which will allow fortheir rapid clinical development. These studies will likely inform clinical practice on how combine standard ofcare agents with immunotherapy. NCI 10802050 9/19/23 0:00 PAR-20-131 1R01CA272426-01A1 1 R01 CA 272426 1 A1 "HENDERSON, LORI A" 9/20/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-CTH-E(55)R] 9046430 "CHESI, MARTA " "BERGSAGEL, PETER LEIF" 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 621878 NCI 373500 248378 PROJECT SUMMARYThe pillars of multiple myeloma (MM) therapy are DNA alkylators (cyclophosphamide melphalan) proteasomeinhibitors (bortezomib carfilzomib ixazomib) glucocorticoids (dexamethasone prednisone) and IMiDs(thalidomide lenalidomide pomalidomide). Despite achieving an initial response patients inevitably relapseand MM remains incurable. More recently remarkable responses have been obtained with immunotherapy:antibodies against CD38 (daratumumab) bi-specific antibodies or BiTEs to BCMA CAR-T cells against BCMA.However similarly to what observed with conventional therapy none of these immune-oncology agents arecurative. We believe that in order to improve patient outcome we need to better define the changes induced bythe tumor on the surrounding immune cells and the effects that conventional and immunotherapy exert on thetumor and its microenvironment. Unfortunately most preclinical studies are conducted on xenograft modelslacking an immune system or transiently reconstituted with human immune subsets and fail to capture thecomplex interaction between tumor and immune cells.Using the clinically predictive fully immunocompetent Vk*MYChCRBN mouse model of MM we have generatedwe discovered that sensitivity to anti-BCMA bispecific antibody is affected by high tumor burden which drivesexcessive antigenic stimulation and T cell exhaustion. Combination therapies aimed to boost T cell functionincrease the short-term activity of the bispecific antibody but mice eventually relapse with modest improve inoverall survival. Surprisingly the addition of cyclophosphamide proved very effective by inducing a temperedbut durative T cell activation which was curative in a fraction of mice.Based on our results in VkMYChCRBN MM we have designed a phase 1 randomized phase 2 clinical trial of aBCMA/CD3 bispecific antibody teclistamab with the addition either iberdomide or cyclophosphamide. In thisproposal we aim to use the results of treating MM patients with either single agent teclistamab or combinationswith iberdomide or cyclophosphamide to credential the Vk*MYChCRBN MM model for T-cell directedimmunotherapy. Finally we will investigate factors that regulate the development of immunologic protectionand cure after bispecific antibody therapy. Overall these data will further credential the Vk*MYChCRBN mousemodel of MM and inform the clinical development of bispecific antibodies in MM. 621878 +No NIH Category available Active Sites;Adopted;Amino Acids;Benchmarking;Binding;Biological;Biopsy;Blood Circulation;CXCR4 gene;Cancer Patient;Cell membrane;Characteristics;Clinical;Clinical Trials;Complex;Copper;Coupling;Data;Detection;Discipline of Nuclear Medicine;Dissociation;Dose;Drug Kinetics;FOLH1 gene;Female;Fibroblasts;Goals;Growth;Histologic;Hour;Human;Image;Injections;Ionizing radiation;Isotopes;Lead;Ligands;Malignant Neoplasms;Membrane;Membrane Lipids;Modality;Modeling;Molecular Conformation;Molecular Target;Molecular Weight;Mus;PET/CT scan;Patient imaging;Patients;Peptides;Pharmaceutical Preparations;Phase;Phospholipids;Population;Positron-Emission Tomography;Property;Proteins;Proteolysis;Radioisotopes;Radiolabeled;Radiopharmaceuticals;SSTR2 gene;Safety;Serum;Site;Solid Neoplasm;Substrate Specificity;Swelling;Targeted Radiotherapy;Testing;Therapeutic;Time;Toxic effect;Translating;Urothelium;analog;anatomic imaging;antitumor effect;cancer cell;cancer imaging;cancer radiation therapy;cancer type;clinical imaging;cohort;dosimetry;drug candidate;experience;extracellular;first-in-human;human study;imaging study;innovation;interest;male;novel;overexpression;radioligand;receptor;residence;response;safety assessment;safety testing;serial imaging;small molecule;targeted delivery;therapeutically effective;tumor;uptake;virtual Maximizing tumor responses to targeted radiotherapy with a conditionally activated membrane binding probe Project Narrative:The overall goal of this project is to develop a new platform for the precision delivery of targeted radiotherapies totumors. Over three specific aims we will evaluate if proteolytically activated membrane binding peptides can beleveraged to deliver a more substantial dose of ionizing radiation to tumors than conventional radioligandtherapies. In parallel a lead drug candidate conjugated to copper-64 will be translated into cancer patients toassess safety dosimetry and pharmacokinetics as well as the feasibility of tumor targeting using PET. NCI 10802000 12/22/23 0:00 PA-20-185 1R01CA279328-01A1 1 R01 CA 279328 1 A1 "CAPALA, JACEK" 12/22/23 0:00 9/30/28 0:00 Clinical Translational Imaging Science Study Section[CTIS] 10718110 "EVANS, MICHAEL JOHN" "AGGARWAL, RAHUL ; CRAIK, CHARLES SCOTT" 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 12/22/23 0:00 9/30/24 0:00 395 Non-SBIR/STTR 2024 616174 NCI 381532 234642 Project Abstract:The recent FDA approvals (Lutathera Azedra Pluvicto) and the swell of promising experimental agents in clinicaltrials underscore the surging enthusiasm to investigate molecularly targeted radiotherapy (TRT) as a treatmentmodality for cancers. However tumor responses to TRTs are often transient and/or variable among patients.Thus there is an urgent unmet need to develop new strategies to maximize the therapeutic benefit of TRT forcancer patients. For the past several years the nuclear medicine field has prioritized developing low MW smallmolecule or peptide radioligands (RLTs) that rapidly exit the bloodstream to minimize host toxicity. Howevertumoral responses to RLTs are limited by several factors including heterogeneous target expression amongtumors dissociation or degradation of ligand/receptor complexes and incomplete target saturation due to lowmass doses and infrequent repeat dosing. Thus exploring new strategies beyond RLTs for the tumoral deliveryof radioisotopes is a worthwhile goal. We have approached this challenge by developing a new class of radiopharmaceuticals termedrestricted interaction peptides (RIPs) which are linear and unstructured low MW peptides that are internallycleaved by a tumor endoprotease of interest to unmask a radiolabeled helical membrane binding peptide. Onceliberated the radiolabeled helical peptide immediately and irreversibly attaches to a nearby phospholipidmembrane in the tumor. Using PET we have found that RIPs may have several properties advantageous forTRT including catalytic amplification of tumor uptake and long persistence of the radioisotope in tumors due tothe stability of the peptide/lipid membrane interaction. Thus RIPs offer an unusual combination of the desirablesafety profile characteristic of a low MW RLT with a high tumoral uptake more typical of a large MW TRT.Collectively these findings provide a strong scientific rationale to test for the first time if radiolabeled RIPs canbe effectively leveraged to treat tumors. Over three specific aims we will evaluate the antitumor effects of anovel RIP termed FRIP2 by coupling it to a representative - (Lu-177) or alpha (Ac-225) emitter. Furthermorewe will translate 64Cu-FRIP2 into patients to test the safety dosimetry and pharmacokinetics of the platformwhile also evaluating the feasibility of tumor targeting. In summary this project represents the first use of aconditionally activated membrane binding probe for TRT which may overcome the well documentedshortcomings of conventional RLT. 616174 +No NIH Category available Acceleration;Address;Anxiety;Behavior Therapy;Characteristics;Clinic;Clinical Trials;Clinical Trials Design;Combined Modality Therapy;Complex;Computer software;Data;Decision Making;Disease;Evaluation;Event;Futility;Future;Generations;Goals;Health;Intervention;Joints;Knowledge;Malignant Neoplasms;Methodology;Methods;Modality;Monitor;Outcome;Pain;Participant;Patient-Focused Outcomes;Patients;Phase;Play;Population;Prevention;Probability;Process;Quality of life;Randomized;Research;Research Design;Research Priority;Role;Selection for Treatments;Sequential Multiple Assignment Randomized Trial;Sequential Treatment;Series;Software Engineering;Symptoms;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Update;Work;adverse outcome;anticancer research;cancer clinical trial;cancer prevention;cancer therapy;design;evidence base;handheld mobile device;improved outcome;individual patient;ineffective therapies;innovation;interest;mHealth;malignant breast neoplasm;multimodality;next generation;novel;optimal treatments;participant enrollment;patient population;preservation;psychologic;randomized trial;response;screening;secondary analysis;side effect;standard of care;success;therapy adverse effect;therapy design;treatment optimization;treatment strategy;trial design;uptake Next-generation SMARTs for Discovery and Evaluation of Sequential Cancer Therapeutic Strategies Treatment management and prevention of cancer involves a series of decisions over time based on accruingpatient information. This research will develop methods for the design and analysis of specialized clinical trialsthat are ideally suited to discovery and evaluation of overall strategies for cancer treatment management andprevention over an entire sequence of decisions with the goal of identifying strategies that lead to the greatestexpected patient benet. NCI 10801628 12/11/23 0:00 PA-20-185 1R01CA280970-01A1 1 R01 CA 280970 1 A1 "UNDALE, ANITA H" 12/11/23 0:00 11/30/28 0:00 Analytics and Statistics for Population Research Panel A Study Section[ASPA] 11132411 "LABER, ERIC BENJAMIN" Not Applicable 4 BIOSTATISTICS & OTHER MATH SCI 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF ARTS AND SCIENCES 277054673 UNITED STATES N 12/11/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 369941 NCI 282347 87594 Treatment of cancer is an ongoing process during which clinicians make a series of decisions at critical pointsin a patient's disease by synthesizing baseline and evolving patient information with the goal of optimizingexpected long-term patient benet. We use the term treatment to refer broadly to therapeutic agents andsupportive behavioral interventions to mitigate adverse effects of therapies or symptoms as well as to inter-ventions focused on prevention and screening. An evidence-based approach to optimizing decision makingis to study entire sequential treatment strategies which can be formalized as treatment regimes. A treatmentregime is a sequence of decision rules each of which is associated with a key decision and uses accruedinformation on a patient to select a treatment option from among the feasible options for the patient. Anoptimal regime is one that maximizes expected patient benet in the population. Sequential multiple assign-ment randomized trials (SMARTs) in which subjects are randomized at each of several key decision points tofeasible treatment options based on their accrued information are ideally suited to discovery and evaluationof treatment regimes and a number of SMARTs in cancer have been conducted. At the same time greatinnovations have been made in cancer clinical trials; platform and response-adaptive trials that seek to op-timize treatment for both participants and future patients and that allow for incorporation of new options andelimination of ineffective options are increasingly being conducted. The potential for SMARTs to advance op-timal sequential decision making in cancer treatment thus requires a next generation of design and analysismethods for SMARTs that incorporate similar innovations in the more complex setting of multiple decisionsand repeated randomization of subjects and that address current cancer research priorities. The goal of thisproject is to develop a comprehensive statistical framework for next-generation SMARTs in cancer researchthe rst steps toward which we will undertake through four specic aims. Our rst aim is to develop methods fordesign and analysis of platform SMARTs that use response-adaptive randomization to favor optimal treatmentassignments and allow introduction of new treatments and discontinuation of ineffective treatments at any de-cision point. Aim 2 is to develop methods for design and analysis of SMARTs involving multi-component andmulti-modal treatments at each decision point. Our third aim proposes a novel trial framework that merges aSMART with a micro-randomized trial to allow joint optimization of sequential therapeutic decisions and selec-tion of supportive mHealth interventions that address the adverse consequences of cancer therapy where thesupportive interventions are chosen to maximize the success of therapy. In Aim 4 we develop a framework forinterim analysis of SMARTs for which little methodology is available. The methods handle binary continuousand censored time-to-event outcomes of interest in cancer research. A software package will be developed toassist users in the design and analysis of next-generation SMARTs. 369941 +No NIH Category available Acetylation;Acetyltransferase;Apoptosis;Biological Models;Carcinoma;Cell Cycle Arrest;Cell Cycle Regulation;Cell Line;Cell Proliferation;Cells;Cervix Uteri;Cessation of life;ChIP-seq;Chemoresistance;Chemotherapy and/or radiation;Cisplatin;Combination Drug Therapy;Combined Modality Therapy;Cytoplasm;DNA Damage;DNA metabolism;Data;Death Rate;Diagnosis;Etiology;FBXW7 gene;Failure;Genes;Genetic Transcription;HTATIP gene;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Health;Immunotherapy;In Vitro;Individual;Induction of Apoptosis;Ionizing radiation;Knowledge;Lung;M cell;MDM2 gene;Malignant Neoplasms;Mediating;Mediator;Mission;Modality;Modeling;Molecular Chaperones;Morbidity - disease rate;Nasopharynx Carcinoma;Oncogenic;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Prognosis;Proliferating;Proteins;Proto-Oncogenes;Public Health;Publishing;Radiation therapy;Recurrence;Recurrent disease;Recurrent tumor;Regulation;Reporting;Research;Research Support;Resistance;Resistance development;Role;Signal Transduction;Site;Squamous cell carcinoma;Testing;Therapeutic;Therapeutic Agents;Transcriptional Regulation;Ubiquitination;United States National Institutes of Health;Validation;Xenograft Model;chemoradiation;chemotherapy;cisplatin-DNA adduct;clinically relevant;clinically significant;defined contribution;disability;effectiveness evaluation;efficacy evaluation;efficacy study;gain of function;histone acetyltransferase;improved;in vivo;in vivo Model;inhibitor;insight;knock-down;loss of function;lung Carcinoma;melanoma;new therapeutic target;novel;novel therapeutics;overexpression;patient derived xenograft model;pharmacologic;response;skin squamous cell carcinoma;standard care;standard of care;therapeutic target;therapy resistant;transcriptome sequencing;treatment response;treatment strategy;tumor;tumor growth;tumor progression;tumor xenograft;ubiquitin-protein ligase Role of DeltaNp63 alpha and TIP60 in SCC progression and chemoresistance PROJECT NARRATIVEThis study aims to delineate the specific mechanism(s) by which TIP60-mediated acetylationstabilizes Np63 levels and modulates the DNA damage response apoptosis therapeuticresistance and squamous cell carcinoma (SCC) tumor progression using a combination of in vitroand in vivo models. This study is relevant to public health because it will provide (1) a mechanisticinsight into the development of resistance to standard treatment modalities for SCC (2) identifynovel therapeutic targets in SCC with elevated TIP60 and Np63 and (3) assess the efficacy ofTIP60 inhibition in sensitizing patient-derived (PDX) cisplatin-resistant head and neck SCCtumors to cisplatin and IR therapy. Thus the proposed research is relevant to the NIHs missionpertaining to the pursuit of fundamental knowledge to enhance health and reduce disability andspecifically to support of research into the mechanism of action of cancer therapeutic agents inboth in vitro and in vivo model systems and the identification and validation of new druggabletargets. NCI 10801585 12/7/23 0:00 PA-20-185 1R01CA280075-01A1 1 R01 CA 280075 1 A1 "O'HAYRE, MORGAN" 12/7/23 0:00 11/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 7929742 "KADAKIA, MADHAVI P" Not Applicable 10 BIOCHEMISTRY 47814256 NPT2UNTNHJZ1 47814256 NPT2UNTNHJZ1 US 39.766782 -84.085913 253101 WRIGHT STATE UNIVERSITY DAYTON OH SCHOOLS OF MEDICINE 454350001 UNITED STATES N 12/7/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 651120 NCI 485744 165376 PROJECT SUMMARY / ABSTRACTCisplatin is frequently used to treat squamous cell carcinoma (SCC) frequently in combination with other drugsor ionizing radiation (IR). Tumor recurrence due to therapeutic failure occurs in approximately 8% of patientswithin 5 years of treatment and the 5-year survival for individuals with recurrent disease remains around 55%despite the recent introduction of targeted immunotherapies. The mechanisms regulating cisplatin resistanceremain poorly understood representing a significant gap in knowledge with high clinical relevance. This proposalwill elucidate novel mechanisms of cisplatin resistance in SCC thus opening new avenues for much neededtreatment strategies for chemoresistant HNSCC and enabling rapid advancements in the field.Np63 is a proto-oncogene implicated in cisplatin resistance and overexpressed in SCC of the skin head andneck cervix and lung. We previously published that the TIP60 acetyltransferase directly acetylates andstabilizes Np63 to promote SCC cell proliferation. Our preliminary data indicate that (a) chemoresistance tocisplatin correlates with high Np63 and TIP60 levels in HNSCC tumors and skin SCC cell lines (b) TIP60inhibits the ubiquitination and degradation of Np63 while increasing its acetylation (c) silencing TIP60 orinhibiting its HAT activity using TH1834 downregulates Np63 reduces its acetylation increases cell apoptosisand sensitizes cells to cisplatin and (d) we demonstrated an increased efficacy of cisplatin-IR treatment and theIR-TH1834 combination demonstrating that TIP60 inhibition increases sensitivity to IR. We hypothesize thatTIP60 promotes cSCC and HNSCC proliferation and cisplatin resistance via enhanced stability of Np63 andfunction. To test this hypothesis we will (Aim 1) determine how acetylation of Np63 by TIP60 impacts theubiquitination and proteasomal degradation of Np63 (Aim 2) investigate how TIP60 mediated acetylation ofNp63 alters transcriptional activity to impact apoptosis the DDR and ultimately cisplatin resistance and (Aim3) elucidate the role of the TIP60/Np63 axis in SCC progression and therapeutic response utilizing cell derivedxenograft models and efficacy studies in HNSCC PDX models to determine the effectiveness of a TIP60 inhibitoras a potential therapeutic adjunct to standard of care chemoradiation (cisplatin and IR) treatment.Together the combined use of gain- and loss-of-function in vitro analyses in vivo xenograft and PDX models ofcisplatin-resistant SCC will provide a statistically rigorous characterization of TIP60/Np63 signaling in cisplatinresistance apoptosis and the DNA damage response in SCC; and will assess a potential novel therapy. Thiswill aid in the identification of additional potential therapeutic targets for the treatment of SCC and other epithelialcancers including nasopharyngeal and lung carcinomas and provide critical insights into the therapeuticpotential of acetyltransferase inhibitors. 651120 +No NIH Category available Ablation;Adipose tissue;Area;Back;Body Weight decreased;Cachexia;Catabolism;Clinical Trials;Collaborations;Data;Development;Dietary Intervention;Disease;Eating;Energy-Generating Resources;Fasting;Fatigue;Fatty Acids;Fatty acid glycerol esters;Genetic;Glucose;Goals;Hepatic;Heterogeneity;Homeostasis;Human;Impairment;In Vitro;Infection;Inflammation;Inflammatory;Interleukin-6;Intervention;Isotope Labeling;Ketones;Life;Link;Lipid Mobilization;Lipids;Lipolysis;Liver;Longevity;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolism;Molecular Target;Monitor;Morbidity - disease rate;Mus;Muscle;Muscular Atrophy;Nutrient;Nutritional;Organ;Organism;Outcome;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Physical Function;Physiological;Physiology;Plasma;Pre-Clinical Model;Prevention;Process;Quality of life;Research;Role;Sampling;Signal Transduction;Site;Skeletal Muscle;Starvation;Supplementation;Testing;Therapeutic;Tissue Banks;Tumor-Derived;Wasting Syndrome;cancer cachexia;cancer complication;cytokine;effective therapy;energy balance;fatty acid oxidation;frailty;genetic approach;in vivo;insight;lipid metabolism;metabolomics;mortality;mouse model;muscle form;novel;nutrition;oxidation;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pharmacologic;pre-clinical;preservation;prevent;profiles in patients;prospective;resilience;skeletal muscle wasting;stable isotope;therapeutic target;therapeutically effective;tissue resource;tool;tumor Metabolic vulnerability due to dysregulated lipid metabolism in PDAC cachexia PROJECT NARRATIVEThe majority of patients with pancreatic cancer suffer from involuntary weight loss fatigue and frailty knownas cachexia. These effects of cancer limit patients' quality of life their ability to tolerate treatment and cancontribute to mortality. Our studies investigate how pancreatic cancer changes metabolism of fat stores tocause cachexia in the hopes of developing new effective treatments. NCI 10801439 9/22/23 0:00 PA-20-185 1R37CA280692-01A1 1 R37 CA 280692 1 A1 "XU, WANPING" 9/22/23 0:00 8/30/28 0:00 Tumor Host Interactions Study Section[THI] 9605952 "GROSSBERG, AARON " Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/22/23 0:00 8/30/24 0:00 396 Non-SBIR/STTR 2023 389052 NCI 254248 134804 PROJECT SUMMARYCachexia is a devastating complication of cancers and other inflammatory conditions that is defined by rapidand persistent loss of fat and muscle that is not reversed by caloric supplementation. Cachexia is a majordeterminant of both lifespan and quality of life that compromises the ability of patients to recover from life-saving or extending interventions. Although descriptions of cachexia go back as far as Hippocrates themechanisms underlying this catabolic state are poorly understood and there remain no effective treatments.Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia at some pointduring their cancer journey adding significant morbidity and mortality to an already dire disease. We haverecently found that PDAC alters the ability of the body to utilize fat stores as fuels. The ability of an organism tosurvive metabolic challenges including low nutrition or infection is dependent upon accessing energy stored infat and oxidizing it in the liver. In this proposal we will investigate the role of this altered lipid metabolism inPDAC-associated cachexia and examine the relationship between adipose tissue the liver and skeletalmuscle preservation. The significance of this proposal resides in its use of genetic and metabolomic tools anda unique patient tissue resource to investigate an unexplored area of the cancer macroenvironment with newcollaborations and efforts directed at isolating and defining the interorgan processes that enable resilience tophysiologic threats. The long-term goal of our research is to gain a mechanistic understanding of how lipidmetabolism impacts skeletal muscle homeostasis in normal physiology and how this is modified in cancercachexia in order to develop more effective therapeutic approaches. 389052 +No NIH Category available Antineoplastic Agents;Apoptosis;Area;Autophagocytosis;Biological Models;CRISPR screen;Cancer Model;Cancer Patient;Cancer cell line;Cell Death;Cell Death Induction;Cell membrane;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Complex;Cyclophilins;Cyclosporine;Cytoplasm;D Cells;Data;Development;Drug Targeting;Endoplasmic Reticulum;Epithelial Cells;Family member;Functional disorder;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Human;In Vitro;Laboratories;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Modeling;Molecular;Mus;Outcome;Output;Pathway interactions;Peptidylprolyl Isomerase;Phenotype;Physiological;Play;Population;Predisposition;Proline;Protein Family;Proteins;RNA Splicing;Regulation;Rest;Role;Rupture;Scientist;Signal Transduction;Specificity;Stimulus;Swelling;TP53 gene;Testing;Therapeutic;Transcriptional Activation;Transcriptional Regulation;Tumor Suppression;Vacuole;Variant;cancer initiation;cancer therapy;cell type;cis trans isomerization;clinically relevant;comparative genomics;design;driver mutation;endoplasmic reticulum stress;experimental study;genomic data;in vivo Model;innovation;insight;lung cancer cell;member;molecular subtypes;mouse model;novel;programs;restoration;senescence;small cell lung carcinoma;small molecule inhibitor;tool;tumor;ubiquitin-protein ligase Context dependent tumor suppression Project NarrativeAutonomous programs of cell death are targetable vulnerabilities for cancer treatment. However mostprograms of cell death are poorly understood and only active in specific contexts suggesting additional fruitfulareas for cancer drug target discovery exist. In our project we have identified a novel cell death mechanismcontrolled by the p53 tumor suppressor in small cell lung cancer that we aim to functionally characterize anddevelop strategies to exploit for therapeutic gain. NCI 10801396 12/29/23 0:00 PA-20-185 1R01CA279698-01A1 1 R01 CA 279698 1 A1 "SALNIKOW, KONSTANTIN" 1/1/24 0:00 12/31/28 0:00 Cancer Cell Biology Study Section[CCB] 10328995 "FELDSER, DAVID " Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 454922 NCI 279952 174970 Project Summary We have identified a novel mode of autonomous programmed cell death that is controlled by p53 insmall cell lung cancer (SCLC) the most deadly form of lung cancer. We capitalized on a geneticallyengineered mouse model that we created to regulate endogenous p53 inactivation and its temporallycontrolled reactivation in established mouse models of SCLC. We found that p53 controls a canonicalsenescence program in approximately half of the tumors and a non-apoptotic cell death program in the rest.The mechanism of cell death is distinct from known forms of programmed cell death but is dependent onmultiple members of the cyclophilin protein family of peptydyl-prolyl isomerases. We demonstrate that p53regulates a distinct transcriptional program in dying SCLC tumors not active in senescing SCLC. Moreover theactivation of this transcriptional program is abolished by small molecule inhibitors of cyclophilins. In aim 1 ofour project we will interrogate the molecular underpinnings of this p53-cyclophilin interaction. At the cellphysiological level p53-mediated SCLC cell death is associated with features of paraptosis; a poorly definedmode of cell death not previously associated with p53 but characterized by excessive accumulation ofcytoplasmic vacuoles cell swelling and plasma membrane dysfunction. Additionally we observed massiveinduction of an endoplasmic reticulum-directed autophagy program (ER-phagy) during p53-mediated SCLCdeath. In aim 2 of our project we will interrogate the molecular features and dissect the molecular determinantsof paraptosis and ER-phagy in this context. Finally we present comparative genomics that implicates that the`classical' molecular subtype of SCLC is represented by SCLC tumors that die after p53 restoration and thatthe `variant' molecular subtype of SCLC is represented by SCLC tumors that senesce after p53 restoration. Inaim 3 of our project we will determine if the effects of p53 restoration are distinct based on either the cell oforigin or the collection of driver mutations as each of these impacts the molecular subtype that develops inSCLC. Together our project will elucidate an important molecular mechanism for controlling SCLC shed lighton targetable vulnerabilities and identify specific subsets of SCLC patients that may be susceptible to suchapproaches. 454922 +No NIH Category available Address;Advocate;Association of Community Cancer Centers;Baltimore;Baptist Church;Benchmarking;Black race;Boston;Breast Cancer Patient;Cancer Biology;Cancer Center;Cancer Patient;Caring;Collection;Communities;Continuity of Patient Care;Data;Data Collection;Diagnosis;Disparity;Equity;Evaluation;Failure;Feedback;Fostering;Future;Geography;Goals;Health;Health Disparities Research;Healthcare;Healthcare Systems;Hospitals;Institutional Racism;Intervention;Knowledge;Learning;Malignant Neoplasms;Maryland;Medical center;Methodist Church;Methods;Modeling;National Institute on Minority Health and Health Disparities;Neighborhood Health Center;Oncology;Outcome;Outcome Measure;Patient Outcomes Assessments;Patients;Phase;Positioning Attribute;Privacy;Public Health;Quality of life;Reach Effectiveness Adoption Implementation and Maintenance;Reduce health disparities;Reporting;Research;Resources;Science;Structural Racism;Time;Training;United States;Universities;Woman;Work;black patient;black women;cancer care;care delivery;clinical care;clinical practice;community organizations;community setting;disparity reduction;ethnic minority;experience;flexibility;health care disparity;health equity;health information technology;health outcome disparity;implementation outcomes;implementation science;improved;improved outcome;inattention;innovation;malignant breast neoplasm;member;mortality;multidisciplinary;patient engagement;patient population;patient-clinician communication;preference;programs;racial minority;response;success;symptom management;technology platform;tool Increasing Engagement in Patient Reported Outcome Measurement to Address Breast Cancer Care Disparities using Health Information Technology in Community Cancer Settings Project NarrativeDisparities in breast cancer-related outcomes are pervasive and have been widely documented among racialand ethnic minorities especially Black women. Substantial evidence demonstrates that routine patient-reportedoutcome (PRO) data collection using health information technology (HIT) results in improved cancer caredelivery; however PRO reporting remains low among Black patients and within the community cancer care(CCC) settings where they often receive care and this increases disparities. The objectives of this project inpartnership with the Association of Community Cancer Centers are to use implementation science and healthequity frameworks to develop and implement routine HIT-assisted collection of PRO data at CCCs serving ahigh proportion of Black patients with breast cancer to produce and disseminate generalizable knowledge thatcan be used to unlock the benefits of PRO reporting to historically underserved patients and advance equitablecancer care and hence is directly relevant to public health. NCI 10801375 9/21/23 0:00 PAR-22-145 1R01CA280619-01A1 1 R01 CA 280619 1 A1 "JENSEN, ROXANNE ELAINE" 9/21/23 0:00 8/31/27 0:00 Organization and Delivery of Health Services Study Section[ODHS] 7032224 "EDELEN, MARIA ORLANDO" "PUSIC, ANDREA LOUISE" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 817746 NCI 471720 346026 Project Summary/AbstractMajor disparities in breast cancer-related outcomes have been widely documented across the cancer carecontinuum with Black patients experiencing higher mortality and decreased quality of life (QOL) compared toWhite patients. Despite compelling evidence that routine patient-reported outcome (PRO) measurement canimprove outcomes and patient experiences in oncology PRO reporting remains low among Black patients andwithin the community cancer care (CCC) setting where they often receive care. The overall goal of thisproposed study is to increase Black breast cancer patient engagement in PRO reporting by establishingflexible and contextually aligned HIT-assisted PRO implementation models in CCCs serving a high proportionof Black patients. Completing this work will set the stage to increase routine use of PROs in clinical care toimprove health outcomes and reduce disparities among Black patients. In partnership with the Association ofCommunity Cancer Centers (ACCC) we will develop models for successful implementation of PRO reportingin five CCCs in the ACCC network that serve a high proportion of Black cancer patients (Boston MedicalCenter Boston MA; Baptist Hospital Memphis TN; Brooklyn Methodist Brooklyn NY; University of MarylandBaltimore MD; Luminis Health Lanham MD). The HIT platform for this study will be imPROVE an Epic-integrated PRO platform with automated feedback and resources (AFR) centered around the preferencesneeds and values of Black patients. In line with the priorities of the NCI and NIMHD we will (Aim 1) identifychallenges barriers and enablers to HIT-assisted PRO data collection among Black breast cancer patientsreceiving care in CCCs and develop PRO implementation models that address these factors; (Aim 2) conducta phased implementation of the PRO data collection models in five CCCs using PDSA cycles to refine modelsand the RE-AIM framework to evaluate success; and (Aim 3) explore the potential of detecting disparities inoutcomes based on PRO data used in clinical care to inform future quality improvement efforts. Our expectedoutcomes are generalizable knowledge of the factors that trigger or deter Black breast cancer patientengagement and models with training materials and tools for feasible pragmatic and sustainable PROprogram implementation across the ACCC network. More than 80% of cancer patients nationwide receive theircare at CCCs and approximately 65% of the nations cancer patients are treated by a member of the ACCCnetwork. The completion of this foundational work with broad dissemination of lessons learned through theACCC and beyond will unlock the benefits of PRO reporting to historically underserved patients and advanceequitable cancer care. This work will also support a continued program of research to expand implementationand evaluation of PRO programs among other diverse patient populations in oncology determine the addedbenefit of AFR and further the use of PRO data for quality improvement. 817746 +No NIH Category available Acute Myelocytic Leukemia;Apical;Basic Science;Binding;Biological;Biological Assay;Biological Process;Biology;Bone Marrow;Bone Marrow Transplantation;CXCR4 gene;Cells;Chemicals;Chemoresistance;Clonal Expansion;Coupled;Cytosine;DNA;DNA binding protein B;DNMT3a;Data;Development;Dioxygenases;Drug resistance;Enzymes;FLT3 gene;Genetic Transcription;Hematopoietic Neoplasms;Homing;In Vitro;Investigation;Knock-in Mouse;Knockout Mice;Knowledge;Ligands;MLL-AF9;MLL-rearranged leukemia;Maintenance;Mass Spectrum Analysis;Mediating;Medical;Messenger RNA;Methylation;Modeling;Modification;Molecular;Mus;Mutate;Mutation;NPM1 gene;Nucleotides;Pathway interactions;Patient-Focused Outcomes;Patients;Play;Prognosis;RNA;RNA Stability;RNA-Binding Proteins;RUNX1 gene;Regimen;Regulation;Relapse;Reporting;Resolution;Role;Signal Transduction;Stromal Cell-Derived Factor 1;Survival Rate;Testing;Therapeutic;Transcript;Transfer RNA;Transgenic Organisms;Treatment Efficacy;Validation;adverse outcome;bisulfite sequencing;chemokine receptor;clinical prognosis;conventional therapy;crosslinking and immunoprecipitation sequencing;demethylation;epitranscriptomics;gain of function;hematopoietic stem cell self-renewal;high risk;improved;in vivo;infancy;inhibitor;leukemia;leukemogenesis;loss of function;migration;mouse model;mutant;new therapeutic target;novel;overexpression;oxidation;patient derived xenograft model;pharmacologic;programs;self-renewal;stem;transcriptome;transcriptome sequencing;translational medicine;tumor microenvironment TET2-mediated epitranscriptomic regulation in leukemia microenvironment Project Narrative:Despite considerable improvement in treatment-adapted strategies the five-year survival rate of acute myeloidleukemia (AML) patients especially those with TET2 deficiency or suppression is still lower than 30% and thusthere is an unmet medical need to identify new therapeutic target(s) and develop improved therapies. This proposalaims to determine the role of TET2 in leukemia stem/initiating cell homing self-renewal and bone marrowmicroenvironment and delineate the molecular mechanism(s) by which TET2 loss in AML confers a moreaggressive clinical prognosis. We will also develop novel effective approaches by combining CXCR4 inhibitors withhypomethylating agents and assess its therapeutic potential to cure high-risk AML patients with TET2 deficiencyor suppression. NCI 10801348 9/21/23 0:00 PA-20-185 1R01CA280389-01A1 1 R01 CA 280389 1 A1 "KLAUZINSKA, MALGORZATA" 9/21/23 0:00 8/31/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 8470188 "CHEN, JIANJUN " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 684230 NCI 388767 295463 PROJECT SUMMARY: Background: Acute myeloid leukemia (AML) is one of the most aggressive types ofhematopoietic malignancies with various genetic alterations. Ten-Eleven Translocation 2 (TET2) an enzymeinvolved in DNA demethylation is deleted or mutated in 15-20% of AML patients. Those patients with TET2deficiency are poorly responsive to currently available therapeutic regimens leading to more adverse outcomesthan patients with other AML subtypes. Thus it is urgent to identify new therapeutic target(s) and develop noveleffective approaches to treat TET2-deficient AMLs. Tet2 loss in mice facilitates the self-renewal of hematopoieticstem cells (HSCs) and leukemic stem/initiating cells (LSCs/LICs). The LSCs/LICs reside in a specializedmicroenvironment called niche in the bone marrow (BM) to support their survival and self-renewal. There areseveral critical gaps in our current knowledge of the molecular mechanism underlying LSC/LIC homingand of the role of TET2 deficiency in the BM microenvironment. Meanwhile evidence is emerging to supporta novel function for TET2-mediated oxidation of methyl-5-cytosine (m5C) in RNAs including messenger RNA(mRNA). However it is unknown whether and (if so) how TET2-mediated RNA m5C demethylation contributesto leukemogenesis. Our preliminary study showed that Tet2 deficiency stimulates the Tetraspanin 13(Tspan13)/C-X-C motif chemokine receptor 4 (Cxcr4) axis to facilitate AML homing/migration into the BMmicroenvironment giving rise to increased LSC/LIC self-renewal and fast leukemogenesis in vivo. Tet2deficiency-mediated increase of mRNA m5C modification in Tspan13 is recognized by Y-box binding protein 1(YBX1) which in turn stabilizes Tspan13 transcript and increases its expression thereby activating the Cxcr4signaling. Pharmacological inhibition of CXCR4 suppresses LSC/LIC homing into the BM microenvironment andshows a synergistic effect with hypomethylating agents in killing TET2-deficient AMLs. These results lead to ourcentral hypothesis that TET2-mediated mRNA m5C demethylation is involved in reprogramming BMmicroenvironment. Guided by strong preliminary data we propose three Specific Aims to test our hypothesis: (1)Determine the definitive role of TET2 in the homing of LSCs/LICs into BM microenvironment; (2) Characterizethe mRNA m5C-dependent and functionally essential targets of TET2 and decipher the molecular mechanismsunderlying the role of TET2 in LSC/LIC homing and self-renewal; and (3) Assess the therapeutic potential oftargeting the TET2/CXCR4 axis in high-risk TET2-deficient AMLs. Overall our proposed studies will substantiallyadvance our understanding of the fundamental biology of TET2-mediated epitranscriptomic changes in BMmicroenvironment and may result in the development of novel effective approaches to treat AMLs with TET2deficiency. Thus our project is of high novelty and significance in both basic research and translational medicine. 684230 +No NIH Category available Acute Myelocytic Leukemia;Address;Adopted;BCL2 gene;Biogenesis;Blood Cells;Cell surface;Cells;Clinic;Clinical;Complement;Dependence;Development;Disease;Evaluation;Exhibits;Gene Expression;Gene Mutation;Generations;Genetic;Genetically Engineered Mouse;Goals;Green Fluorescent Proteins;Hematopoietic stem cells;Human;Impairment;Knowledge;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Modeling;Molecular;Monoclonal Antibodies;Outcome;Patient-Focused Outcomes;Patients;Process;Protein Biosynthesis;Protein Synthesis Inhibition;Proteins;Recurrent disease;Regulation;Reporter;Research;Resistance;Ribosomal Proteins;Ribosomes;Role;Stress;System;Testing;Therapeutic;Toxic effect;Transcript;Translating;Translations;Tumor Suppressor Proteins;Work;Xenograft procedure;biological adaptation to stress;cancer stem cell;cytotoxicity;design;effective therapy;genetic manipulation;high risk;improved;in vivo;inhibitor;innovation;insight;leukemia;leukemic stem cell;mouse model;novel;novel therapeutic intervention;novel therapeutics;overexpression;patient derived xenograft model;prevent;progenitor;programs;proteotoxicity;response;ribosome profiling;self-renewal;stem cell function;stem cell model;stem cell self renewal;stem cells;stem-like cell;targeted treatment;therapy development;therapy resistant;transcriptome sequencing Regulation of Protein Synthesis in Leukemia Stem Cells NarrativeLeukemia stem cells are responsible for poor clinical outcomes in patients with acute myeloid leukemia and theproposed research addresses a need to better understand the mechanisms that underlie their function. Werecently discovered that the cell surface marker CD99 promotes leukemia stem cell self-renewal by constrainingprotein synthesis establishing a new link between regulated protein synthesis and leukemia stem cell function.By elucidating the mechanisms underlying why leukemia stem cells depend on regulation of protein synthesisacross different subtypes of acute myeloid leukemia this project has the potential to establish a new paradigmfor how cancer stem cells sustain themselves as well as to guide the design of more effective therapies targetingleukemia stem cells to improve clinical outcomes for patients with acute myeloid leukemia. NCI 10801320 9/21/23 0:00 PA-20-185 1R37CA273232-01A1 1 R37 CA 273232 1 A1 "KLAUZINSKA, MALGORZATA" 9/21/23 0:00 8/31/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 10605544 "CHUNG, STEPHEN SHIU-WAH" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 475420 NCI 289890 185530 Summary/AbstractLeukemia stem cells (LSCs) promote therapeutic resistance and poor clinical outcomes in acute myeloidleukemia (AML). Central to the function of LSCs is a capacity for aberrant self-renewal but the mechanismsunderlying this activity are not well understood. The long-term goal is to identify these mechanisms to developnew therapies that can eradicate LSCs to improve clinical outcomes. The overall objectives in this applicationare to (i) determine if LSCs from specific genetic subtypes of AML are dependent on regulation of proteinsynthesis (ii) determine whether LSCs in high-risk hematopoietic stem cell (HSC)-like AMLs are more dependenton regulated protein synthesis and (iii) test a novel therapeutic strategy inhibiting protein synthesis in LSCs. Thecentral hypothesis is that LSCs aberrantly self-renew by adopting from normal HSCs a dependence on tightlyregulated protein synthesis. The rationale for this project is based on the finding that the cell surface markerCD99 is selectively overexpressed on LSCs and serves to regulate protein synthesis to promote LSC function.This offers a strong scientific framework by which new strategies to deplete LSCs can be developed. The centralhypothesis will be tested by pursuing three specific aims: 1) Determining the role of regulated protein synthesisin promoting LSC function; 2) Determining if the cell-of-origin of AML influences the dependence of LSCs onregulated protein synthesis; and 3) Determining if inhibition of protein synthesis can deplete LSCs in high-riskAML. In the first aim genetically engineered mice will be used to generate models of AML lacking CD99 to testif this leads to dysregulated protein synthesis that impairs LSC self-renewal. LSCs from these models will beevaluated to determine if they require low protein synthesis rates to prevent induction of tumor suppressors theunfolded protein response and the integrated stress response. Ribosome profiling will be performed to identifykey LSC regulators selectively translated in the context of regulated protein synthesis. In the second aim we willgenerate a mouse model of HSC-like AML which mimics high-risk human AML. We will assess if LSCs in HSC-like AML exhibit heightened sensitivity to dysregulated protein synthesis. These studies will be complementedwith an evaluation of protein synthesis in HSC-like human LSCs to determine if they also require maintenanceof low levels of protein synthesis. The third aim will test if the combination of a ribosome biogenesis-inhibitor witha BCL2-inhibitor currently used to treat AML can eradicate LSCs in high-risk HSC-like AML. The proposal isinnovative in the applicants opinion because it aims to leverage a novel LSC-specific cell surface marker toestablish a new paradigm for understanding mechanisms underlying LSC self-renewal. The proposed researchis significant because it is expected to provide a strong scientific justification for the development of therapiesinhibiting protein synthesis to overcome therapeutic resistance in patients with high-risk AML. Ultimately theknowledge gained from these studies may offer insights into the mechanisms that promote the function of cancerstem cells in general opening up opportunities for the development of new strategies to treat cancer. 475420 +No NIH Category available Adaptor Signaling Protein;Alleles;Binding;Binding Proteins;Biochemical;Biological Assay;Biological Markers;Biological Process;Cancer Biology;Cancer Model;Cancer cell line;Cell Proliferation;Cells;Chemicals;Clinic;Clinical;Complex;Cues;Development;Dimerization;Disease;Family;Future;Gene Expression Profile;Genes;Glioblastoma;Growth;Guanosine Diphosphate;Guanosine Triphosphate Phosphohydrolases;Hydrolase;Hydrolysis;Impairment;In Vitro;Knowledge;Lung Adenocarcinoma;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mediating;Medicine;Modeling;Molecular;Molecular Conformation;Molecular Profiling;Mouse Strains;Multiprotein Complexes;Mutation;Nature;Nucleotides;Oncogenic;Oncoproteins;Pathway interactions;Pharmacological Treatment;Physiological;Play;Pre-Clinical Model;Process;Proliferating;Protac;Proteins;Proteolysis;Protomer;Regulation;Reproducibility;Resistance;Role;Series;Signal Pathway;Signal Transduction;Somatic Mutation;Specificity;Structure;Structure-Activity Relationship;Substrate Specificity;Technology;Tertiary Protein Structure;Therapeutic;Tumor Subtype;Ubiquitination;Work;cancer initiation;cancer subtypes;cancer type;cell growth;cofactor;cullin-3;experimental study;genetic approach;in vivo;inhibitor;innovation;insight;leukemia;loss of function mutation;melanoma;member;mouse genetics;mouse model;novel;novel therapeutic intervention;novel therapeutics;pharmacologic;protein degradation;ras Proteins;response;small molecule;targeted treatment;therapeutically effective;therapy development;therapy resistant;tumor;tumor growth;tumorigenesis;ubiquitin ligase;ubiquitin-protein ligase Regulation and tumorigenesis of non-classical RAS oncoproteins - Resubmission PROJECT NARRATIVEThe family of RAS oncoproteins drive tumor growth and have been widely characterized in cancer; howevernon-classical RAS proteins remain poorly studied despite their relevance in this disease. We have discovered anovel cellular mechanism that results in the degradation of the non-classical RAS oncoproteins RIT1 and MRASand it is mediated by a complex that includes the protein LZTR1. Our work into this mechanism will lead to novelinsights into the regulation of non-classical RAS oncoproteins the relevance during tumor formation andpotential innovative therapeutic approaches. NCI 10801289 12/22/23 0:00 PA-20-185 1R01CA279171-01A1 1 R01 CA 279171 1 A1 "LUO, RUIBAI" 1/1/24 0:00 12/31/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 14585964 "CASTEL, PAU " Not Applicable 12 BIOPHYSICS 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 543820 NCI 320838 222982 PROJECT SUMMARYOncoproteins drive tumor development and aggressive growth by dysregulating the signaling pathways involvedin cell growth survival and proliferation. Targeting oncoproteins directly or their downstream pathways hasresulted in novel therapies currently being used for the treatment of different cancer subtypes.The RAS family of guanosine triphosphatase (GTP) hydrolases (GTPases) are a group of oncoproteins thathave roles in cancer initiation progression and resistance to therapies. Furthermore mutations in genesencoding classical RAS proteins are very frequent in cancer. RAS proteins cycle between a guanosinediphosphate (GDP) inactive form and a GTP active form. In its GTP-bound conformation RAS proteins promoteactivation of downstream signaling pathways that contribute to the growth and proliferation of cells. Thisnucleotide cycle is assisted by accessory proteins that catalyze the loading or hydrolysis of GTP anddysregulation of this mechanism is also frequent in cancer.Emerging evidence has shown that non-classical RAS proteins also play critical roles in cancer biology; howevertheir mechanisms of regulation and tumorigenesis are not well-understood and differ from classical RAS proteins.We have recently discovered a novel mechanism of regulation of the non-classical RAS proteins RIT1 and MRASthat is mediated by ubiquitination and proteasomal degradation of the inactive GDP-bound form. Our workidentified LZTR1 a novel protein that binds RIT1 and MRAS and forms a complex with the E3 Ubiquitin ligaseCullin-3 (CRL3LZTR1). Cancer-associated mutations in RIT1 or LZTR1 disrupt their interaction and lead to theaccumulation of non-classical RAS GTPases and activation of downstream signaling.In this application we propose to study critical aspects regarding the regulation of this novel complex itscontribution to tumorigenesis and potential pharmacological strategies to restore protein degradation.In Aim 1 we will use biochemical and structural approaches to understand the determinants of LZTR1 selectivitytowards the non-classical RAS GTPases RIT1 and MRAS and the function of its protein domains.In Aim 2 we plan to elucidate the signaling mechanisms that regulate CRL3LZTR1 activity in cells and how thesepathways can contribute to the resistance to specific targeted therapies.In Aim 3 we will develop novel mouse models that are driven by an oncogenic RIT1 mutation that is resistant toLZTR1-mediated proteasomal degradation and analyze the molecular signatures of these tumors. In additionwe will develop proof-of-concept pharmacological treatments for RIT1-driven cancers.Overall our project will address a major knowledge gap in the mechanisms of regulation of non-classical RASoncoproteins and will provide novel preclinical models and therapeutic strategies for these cancers. The workdescribed in this application is the first step to develop mechanism-based and precise medicines for targetingthese oncogenic pathways in cancer. 543820 +No NIH Category available ATAC-seq;Acute Myelocytic Leukemia;Adult;Binding;Biogenesis;Biological Models;C57BL/6 Mouse;CD34 gene;CRISPR/Cas technology;Categories;Cell model;Cells;Child;Childhood Acute Myeloid Leukemia;Childhood Leukemia;Chromatin;Clinical;Collaborations;Cytogenetics;Data;Development;Diagnosis;Engraftment;Epigenetic Process;Event;Exons;FLT3 gene;Fusion Oncogene Proteins;Future;Gene Expression Profile;Gene Expression Profiling;Gene Frequency;Genes;Genetic;Genetic Transcription;Genome;Genomics;Goals;Growth;Hematopoiesis;Hematopoietic;Heterozygote;Human;Immunodeficient Mouse;Inferior;Karyotype;Lead;Lesion;MLL gene;Maintenance;Mediating;Modeling;Molecular;Mus;Mutation;Nucleolar Proteins;Outcome;Patients;Penetrance;Phenotype;Proliferating;Proteins;Recurrence;Recurrent disease;Relapse;Reporting;Residual Neoplasm;Resistance;Ribosomes;Role;Sampling;Series;Testing;Therapeutic;Transplantation;Trisomy 8;Umbilical Cord Blood;WT1 gene;chemotherapy;conventional therapy;genetic variant;high risk;human model;improved;in silico;in vivo Model;insight;knowledge of results;leukemia;leukemic transformation;leukemogenesis;loss of function mutation;molecular subtypes;mouse model;multiple omics;novel;patient derived xenograft model;programs;self-renewal;small molecular inhibitor;therapeutic target;tool;transcription factor UBTF Tandem Duplications in Pediatric Acute Myeloid Leukemia PROJECT NARRATIVE:UBTF tandem duplications (UBTF-TD) in exon 13 were recently described by our group as a new recurrentand likely class-defining somatic alteration in pediatric AML that is associated with poor outcome. In thisproposal we will use newly developed human and mouse models and a large series of primary patientsamples to dissect the molecular impact of UBTF-TD expression through a combination of functional andmulti-omic approaches. The successful completion of these studies will provide the first mechanistic insightsinto how this recently identified mutation in a gene that encodes for a nucleolar protein disrupts hematopoieticdevelopment to drive leukemia formation and will ultimately aid in the identification of therapeutic options forthis new high-risk subtype of pediatric AML. NCI 10801150 9/22/23 0:00 PA-20-185 1R01CA276079-01A1 1 R01 CA 276079 1 A1 "KLAUZINSKA, MALGORZATA" 9/22/23 0:00 8/31/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 7005832 "KLCO, JEFFERY M" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 416325 NCI 228750 187575 PROJECT SUMMARY:Children diagnosed with acute myeloid leukemia (AML) continue to have an overall poor outcome with ratesof relapse that approach 40%. Relapsed disease is particularly resistant to conventional therapy.Unfortunately the molecular alterations that are common in relapsed pediatric AML have been poorly defined.Recently our group reported on the spectrum of genetic changes in 136 children with relapsed AML andidentified tandem duplications of exon 13 of UBTF (upstream binding transcription factor) in nearly 10% ofchildren with relapsed AML. We further demonstrated that UBTF-tandem duplication (UBTF-TD) AMLs arealso present in 4% of children at diagnosis yet are rare in adults and commonly occur with FLT3-ITD andWT1 mutations along with either normal karyotype cytogenetics or trisomy 8. Importantly we demonstratedthat children with UBTF-TD AML have an inferior overall survival and high rates of minimal residual diseaseafter induction chemotherapy. Our preliminary functional studies have confirmed that UBTF-TD expressionis sufficient to drive proliferation and self-renewal of primary human hematopoietic cells and that UBTF-TDproteins maintain canonical interactions of wild-type UBTF but also interact with new proteins/networksimportant in leukemia development such as KMT2A and XPO1. Collectively these genomic functional andclinical findings suggest that UBTF-TD AMLs represents a new molecular category of pediatric AML andestablishes a strong scientific premise to investigate the molecular impact of UBTF tandem duplications inprimary hematopoietic cells. We hypothesize that UBTF-TD represents in new initiating lesion that drives theexpression of specific transcriptional networks in particular the HOXB program through new interactions withthe genome and from collaboration with unique cooperating mutations and interacting proteins. We will testour hypothesis with the following specific aims using a combination of genetic tools in human and mousehematopoietic cells. Specific Aim 1: Decipher the molecular mechanisms of UBTF-TD in leukemogenesis;Specific Aim 2: Dissect the contribution of UBTF-TD and co-occurring mutations to leukemogenesis using invivo models; Specific Aim 3. Establish the contribution of UBTF domains and interacting proteins to UBTF-TD mediated transformation. Not only will the proposed studies elucidate the transcriptional and epigeneticimpact of UBTF-TD expression in primary hematopoietic cells including patient samples but they will alsoestablish multiple mouse and human model systems for this new subtype of high-risk pediatric AML andevaluate potential vulnerabilities. The successful completion of these proposed studies and the resultingmodel systems will ultimately be used to develop therapeutic approaches to target UBTF-TD AMLs and mostimportantly to improve the long-term outcome of children with these leukemias. 416325 +No NIH Category available B cell-dependent anti-tumor immunity in ovarian cancer PROJECT NARRATIVE Despite its devastating prognosis ovarian cancer is an immunogenic disease wherethe presence of organized lymphoid structures containing complex immune cellpopulations is associated with better outcome. The proposed studies will exert a profound effect in the field by elucidating themechanisms leading to the spontaneous formation of these structures in ovarian cancer.This mechanistic understanding could lead to optimized interventions aimed to promotetheir assembly as a novel immunotherapy thus providing a significant advance towardsthe goal of personalized Medicine and the cure of this devastating disease.Equally important our studies could lead to the identification of antibodiesspontaneously produced at tumor beds with significant anti-tumor (or conversely tumor-promoting) activity which could be used as novel therapeutic tools or targets. NCI 10801106 4/11/23 0:00 PA-21-268 7U01CA232758-06 7 U01 CA 232758 6 "KUO, LILLIAN S" 9/20/18 0:00 1/31/24 0:00 ZCA1-SRB-C(A1) 8439405 "CONEJO-GARCIA, JOSE R" Not Applicable 4 MICROBIOLOGY/IMMUN/VIROLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 3/7/23 0:00 1/31/24 0:00 353 Non-SBIR/STTR 2022 384851 NCI 239038 145813 ABSTRACT Within tumor beds T and B cells often interact to form highly organized structures similar tolymph nodes termed tertiary lymphoid structures (TLS) which are associated with betteroutcomes in many tumors. TFH cells are crucial for the formation of germinal centers andhumoral responses and our new data show that TFH cells become the main producers ofCXCL13 and TNFS14/LIGHT upon vaccination. The assembly and maintenance of TLS shouldbe therefore dependent on TFH responses. Our new data demonstrate that Special AT-richsequence-binding protein-1 (Satb1) ablation specifically in T cells leads to enhanced TFHdifferentiation and augmented Ag-specific humoral responses which is associated withconcurrent ICOS and PD-1 de-repression. Accordingly our central hypothesis is thatLIGHT+CXCL13+ TFH cell formation and subsequently the orchestration of TLS in cancer isgoverned by Satb1 silencing in CD4 T cells by both de-repressing ICOS in TFH cells andsuppressing Foxp3+PD-1highCXCR5+ T follicular regulatory (TFR) cell formation through PD-1up-regulation. Therefore TGF- paradoxically enhances the generation of TFH cells and theformation of TLS through Satb1 repression. In Aim 1 we will define the role of SATB1-dependent ICOS expression during TFHdifferentiation. Through ChIP-PCR and functional analysis of Satb1-competent vs. Satb1-deficient T cells in vivo we will substantiate a novel epigenetic mechanism whereby the mastergenomic organizer Satb1 governs ICOS expression leading to enhanced TFH differentiation inthe absence of Satb1. In Aim 2 we will determine the role of SATB1 in TGF--driven Treg-dependent TFHdifferentiation. Here we will combine geentic manipulation and existing transgenic models toestablish to what extent the mechanism of TGF--driven TFH differentiation is Satb1- and PD-1-dependent in a manner that requires decreased TFR formation. In Aim 3 we will recapitulate the mechanisms leading to the formation and protective activityof TLS in vivo in ovarian cancer. By leveraging unique transgenic models our ovarian cancer-specific CAR T cells and our viable single-cell suspensions from freshly dissociated ovariancarcinomas we will define a novel TGF- Satb1 silencing TFH cell formation axis drivingrelevant anti-tumor humoral responses. Our work will exert a profound effect in the field by elucidating how epigenetic programscontrolled by SATB1 govern the generation of TFH cells at tumor beds in a TGF--dependentmanner. Recapitulating these mechanisms in vivo will pave the way for more effectiveimmunotherapies aimed to promote combined humoral and T cell responses through theorchestration of TLS in irresectable/metastatic tumors and could lead to the identification ofantibodies with anti-tumor activity spontaneously produced at tumor beds. 384851 +No NIH Category available Address;Animals;Antibodies;Blocking Antibodies;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Cells;Chronic;Clinical Trials;Combined Modality Therapy;Data;Dendritic Cells;Development;Disease;Dose;Eye;Future;Gene Expression;Gene Expression Profile;Goals;Heterozygote;Human;IL1R1 gene;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Stimulation;Immunosuppression;Immunotherapeutic agent;Incidence;Infiltration;Inflammatory;Interleukin-1;Interleukin-1 alpha;Interleukin-1 beta;Knowledge;Ligands;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Memory;Mus;Myelogenous;Myeloid Cell Activation;Myeloid Cells;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Process;Production;Publishing;Receptor Signaling;Role;Signal Transduction;System;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Therapeutic Uses;Time;Tissues;Toxic effect;Tumor Immunity;Tumor Promotion;Visualization;Work;anakinra;anti-PD1 antibodies;anti-cancer;antibody inhibitor;autocrine;cancer immunotherapy;cancer therapy;cell type;cytokine;design;immune cell infiltrate;improved;in vivo;interest;mouse model;neutrophil;novel;novel therapeutics;paracrine;programmed cell death protein 1;programs;promoter;success;synergism;systemic toxicity;therapeutic candidate;trafficking;tumor;tumor growth;tumor microenvironment Using the IL-1R1 and its ligands to optimize the T cell immune response to cancer We have been studying the mechanism by which Canakinumab (an IL-1 blocking antibody) stimulates theimmune response to cancer in treated patients. We have discovered that this occurs by blocking theproduction of immunosuppressive factors by myeloid cells that skew the tumor microenvironment in favor oftumor growth but also unexpectedly by permitting the immunostimulatory effect of IL-1 on CD8 T cells. Inthis proposal we explore the detailed mechanism of this pathway further and utilize novel therapeuticcompounds to selectively stimulate or block cytokine activity on specific cells towards the end of designing adefinitive immunotherapeutic treatment for cancer. NCI 10801033 9/19/23 0:00 PA-20-185 1R01CA279457-01A1 1 R01 CA 279457 1 A1 "HU, ZHANG-ZHI" 9/19/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 1879892 "KUPPER, THOMAS S." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 618713 NCI 398179 220534 IL-1 and were discovered more than 50 years ago and knowledge about these pleiotropic cytokines hasgrown exponentially since that time. Therapeutic use of these molecules has been limited by toxicity and theirblockade has had limited success in inflammatory disorders. In 2017 the CANTOS trial using canukinumaband antibody to IL-1 showed an unexpected association of blocking IL-1 and a dose dependant reduction inthe incidence of cancers rekindling interest in the role of IL-1s molecules in tumor immunity. However ourdata thus far suggests unappreciated complexity. We and others have shown that the of blocking IL-1 inmouse models of cancer and our published and preliminary data suggest that the mechanism by which anti-tumor immunity evolves is not straightforward. For example blocking IL-1 permits immunostimulatory T cellactivation by IL-1 to proceed unopposed favoring tumor immunity. In parallel blocking IL-1s effects onmyeloid cells modifies the tumor microenvironment independently to favor CD8 T cell mediated anti-cancerimmunity. The immunotherapeutic effects of IL-1 appear to be operating through the CD8 T cell IL-1R1 andwe propose that by understanding this pathway more completely we can greatly enhance its activity.Moreover IL-1R1-driven effects on myeloid cells appear to inhibit anti-cancer immunity in the TME and wehypothesize that understanding these effects will allow us to target this pathway with precision. To visualizethese changes histopathologically we have employed the powerful CyCIF platform. To test hypotheses invivo we will use novel molecules known as AcTakines. These compounds target cytokine activity or blockadeprecisely to specific cell types in vivo without systemic toxicity and will help us to dissect these immunepathways in tumor-bearing animals. Because these drugs are being developed for future use in humans ourwork will serve as a basis for a better mechanistic understanding of their future use in cancer immunotherapy.We believe this is a new and unexplored pathway through which we can greatly enhance anti-tumor immunitycontributing fundamentally to immunotherapy of cancer. 618713 +No NIH Category available Address;Alleles;Biological Markers;Biological Process;Blood;Breast Melanoma;Cancer Patient;Circulation;Clinical;Clinical Research;Collection;DNA;Data;Detection;Detection of Minimal Residual Disease;Disease;Drug resistance;Early Diagnosis;Effectiveness;Esophagus;Fingerprint;Genome;Glioma;Grant;Human;Image;Malignant Neoplasms;Malignant neoplasm of esophagus;Medicine;Methods;Minor;Monitor;Mutation;Mutation Detection;Neoplasm Metastasis;Noise;Oligonucleotides;Patients;Preparation;Primary Neoplasm;Recurrence;Renal carcinoma;Residual Neoplasm;Sampling;Screening for cancer;Somatic Mutation;Specificity;Technology;Testing;Time;Translations;Tumor Markers;Tumor stage;Work;cancer genome;cancer type;circulating DNA;clinical practice;detection method;detection sensitivity;empowerment;esophageal cancer patient;experience;experimental study;field study;genome sequencing;genome-wide;improved;innovation;internal control;liquid biopsy;malignant breast neoplasm;malignant stomach neoplasm;neoplastic cell;new technology;novel;precision medicine;prevent;repaired;technology development;tumor;tumor DNA;tumor heterogeneity;volunteer;whole genome Comprehensive minimal residual disease tracking in cancer PROJECT NARRATIVE Liquid biopsies have made significant strides in cancer medicine but substantial questions remain suchas whether cancers which shed little tumor DNA into blood could be detected with higher sensitivity methods.This proposal builds on work performed during the first cycle of this grant aiming to develop and optimize a newtechnology DS-DR-MAESTRO (minor allele enriched sequencing through recognition oligonucleotides) thataffords extremely high sensitivity to detect circulating tumor DNA. The optimized DS-DR-MAESTRO technologywill be applied in detecting MRD in samples collected from esophageal cancer patients a type of cancer that isnotorious for shedding low amounts of DNA in circulation. NCI 10800951 12/4/23 0:00 PA-20-185 2R01CA221874-04 2 R01 CA 221874 4 "OSSANDON, MIGUEL" 6/1/18 0:00 11/30/26 0:00 "Genomics, Computational Biology and Technology Study Section[GCAT]" 1883913 "MAKRIGIORGOS, G. MIKE" "ADALSTEINSSON, VIKTOR " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/4/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 463940 NCI 366115 97825 PROJECT ABSTRACT Liquid biopsies have made significant strides in cancer medicine with applications spanning early cancerdetection assessment of therapy effectiveness and drug-resistance monitoring tumor-dynamics and earlydetection of minimal residual disease MRD. Yet substantial questions remain prohibiting translation to clinicalpractice on many occasions. For instance the inability to detect tumor-circulating DNA (ctDNA) in a fraction ofgliomas gastric and renal cancers even for advanced stages has led to the notion that some tumors are non-shedders thus postulating there are biological processes preventing some cancers from shedding DNA in theblood. If true this would prohibit the use of ctDNA as a tumor biomarker that precedes imaging and clinicalmanifestation of disease. Similar questions apply to early-stage tumors that test negative for ctDNA but patientsdo experience clinical recurrence: was ctDNA never there or was it simply too low to be detected? Yet improveddetection techniques applied to non-shedder cancers have recently led to major increases in the ctDNAdetection rate converting previously ctDNA-negative samples to positive. This indicates that possibly all cancersshed DNA in the circulation but some can only be detected with methods providing extremely high sensitivity. This R01 competing continuation builds on two technologies developed during the first grant cycle andcan address the questions. (a) MAESTRO -minor allele enriched sequencing through recognitionoligonucleotides- that enables extremely high sensitivity MRD detection. And (b) Duplex Repair (DR) thatreduces noise during subsequent duplex sequencing. We aim to show that the combined technology DS-DR-MAESTRO enables detection of ctDNA as sensitive as a single tumor-cell genome-equivalent circulating in the~5l human blood pool at the time of blood collection while retaining specificity. This sensitivity can be achievedfollowing sequencing of the primary tumor and collecting total circulating-DNA (cfDNA) typically recovered froma standard 10-40ml blood collection. We will optimize the technology to the level required for subsequentapplication in clinical studies. Aims 1-2 will optimize the technical aspects of the technology using serial dilutionsof cfDNA from tumor patients and normal volunteers. Aim 3 will apply the technology for detection of minimalresidual disease in circulating DNA from esophageal cancer patients whose tumors tend to shed very little ctDNA.Successful technology development is anticipated to extend the use of cfDNA for detecting MRD in low-sheddercancers and significantly shrink the size of cancers detectable. It will also increase the predictive power formultiple endpoints and assist pre/post-surgery ctDNA management decisions thereby providing a window ofopportunity for many additional patients and improving precision medicine. 463940 +No NIH Category available AT Rich Sequence;Ablation;American Cancer Society;Automobile Driving;Binding Proteins;Biological;Blood;CD4 Positive T Lymphocytes;Cancer Center;Chromatin;Clinic;Clinical;Clinical Investigator;Collection;Cutaneous T-cell lymphoma;Deacetylation;Deletion Mutation;Dermatology;Diagnosis;Disease;Down-Regulation;Drug Combinations;Epigenetic Process;Etiology;Functional disorder;GPR2 gene;Genetic Transcription;Genomics;Goals;Growth and Development function;Hematologist;Hematology;Histone Deacetylase;Histone Deacetylation;Homing;Human;Immunologist;Intervention;Lymphocyte;Lymphoma cell;Lysine;Malignant - descriptor;Mature T-Lymphocyte;Methyltransferase;Molecular;Oncogenic;Organ;Outcome;Pathogenesis;Pathogenicity;Patients;Peripheral;Phosphorylation;Point Mutation;Rare Diseases;Repression;Role;Sampling;Scheme;Sezary Syndrome;Sezary cell;Signal Transduction;Skin;Small-Cell Lymphoma;Specimen;Stat5 protein;Survival Rate;T-Cell Development;T-Cell Lymphoma;T-Lymphocyte;Testing;Therapeutic;Thymus Gland;Tumor Suppressor Proteins;Work;chemokine receptor;clinical translation;cytokine;derepression;design;effective intervention;effective therapy;epigenetic drug;epigenetic silencing;histone methylation;inhibitor;insight;leukemia;lymph nodes;malignant phenotype;mouse model;notch protein;novel;overexpression;palliative;prevent;programs;promoter;transcription factor Targetable epigenetic mechanism driving Cutaneous T cell Lymphoma PROJECT NARRATIVE Nearly 3000 Cutaneous T-cell lymphomas (CTCLs) patients are diagnosed everyyear in the US. The lack of a clear understanding of CTCL etiology has impededtherapeutic advances and currently there is no cure with 5-year survival rates at ~50%. Our proposed Aims represent a concerted effort by a team of clinical investigatorsand translational immunologists at Moffitt to design new treatments for CTCL patientsthrough urgently needed new biological understanding. Our work will exert a profoundeffect in the field by elucidating how epigenetic repression of the master genomicorganizer SATB1 governs the malignant transformation of mature CD4 T cells incoordination with NOTCH signaling leading to fatal skin accumulation of lymphocytes inCTCL in a HELIOS-dependent manner. This mechanistic insight will inform the mosteffective combination of epigenetic drugs needed to de-repress the SATB1 locus whichis expected to reverse the malignant phenotype of Sezary cells. This understanding willprovide our team with a mechanistic rationale for immediate clinical interventions inCTCL patients at Moffitt. NCI 10800864 7/3/23 0:00 PA-21-268 7R01CA240434-05 7 R01 CA 240434 5 "JHAPPAN, CHAMELLI" 7/2/19 0:00 6/30/24 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8439405 "CONEJO-GARCIA, JOSE R" "PINILLA, JAVIER ; SOKOL, LUBOMIR " 4 MICROBIOLOGY/IMMUN/VIROLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 387981 NCI 312533 75448 ABSTRACTThe lack of a clear understanding of the pathophysiology of Cutaneous T cell Lymphoma(CTCL) and in particular its aggressive leukemic form Szary Syndrome has impededtherapeutic advances and current treatments are only palliative. Although CTCL is a relativelyrare disease Moffitt Cancer Center Malignant Hematology and USF Dermatology Departmentsmanages about 100 new patients with CTCL annually. This study represents a concerted effortby a team of clinical investigators and translational immunologists at Moffitt to identify neweffective treatments for CTCL patients with aggressive disease based on the discovery of keymolecular regulators of Szary Syndrome development and growth. Specifically our newmouse models indicate that Special AT-rich region binding protein 1 (SATB1) a mastergenomic organizer and a key regulator of T-cell development and maturation prevents mature Tcell malignization by repressing crucial pathogenic drivers of Szary cells. Our centralhypothesis is that SATB1 acts as a tumor suppressor in CTCL by repressing STAT5 activationchemokine receptors that govern T cell homing to the skin and transcription factors commonlyde-regulated in malignant T cells. Accordingly restoring SATB1 expression by targeting histonemethylation and de-acetylation will avert the malignant phenotype of Szary cells. We willleverage a growing collection of aphaeresis specimens and unique mouse models to dissect theepigenetic mechanisms governing the pathogenesis of Szary Syndrome with the overarchinggoal of subsequently targeting them through more effective interventions in our clinic. In Aim 1 we will elucidate how SATB1 silencing drives the pathogenesis of CTCL. Based onour preliminary results our hypothesis is that Satb1 silencing cooperates with Notch signaling toelicit a STAT5- CCR10- IKZF2/HELIOS-dependent transcriptional program leading to theprogressive expansion skin homing and malignant transformation of post-thymic CD4 T cells. In Aim 2 we will define the complementary mechanisms leading to epigenetic silencing ofthe SATB1 locus in Szary Syndrome. We will test the hypothesis that SATB1 is silenced inSzary cells through a combination of histone methylation at K27 and K9 that along with andlysine de-acetylation resulting in significant changes in chromatin accessibility. In Aim 3 we will leverage our new biological understanding to identify the combination ofepigenetic drugs that more effectively restore SATB1 expression and thwart oncogenic signalsin Szary cells. Our work will exert a profound effect in the field by elucidating how epigenetic repression ofthe master genomic organizer SATB1 governs the malignant transformation of mature CD4 Tcells in coordination with NOTCH signaling leading to fatal skin accumulation of lymphocytes inSzary patients. This mechanistic insight will inform the most effective combination of drugsneeded to de-repress the SATB1 locus and antagonize oncogenic signals which will overturnmalignant Szary cells. This biological understanding will be followed by clinical interventions atMoffitt for patients with aggressive CTCL including Szary Syndrome. 387981 +No NIH Category available Behavior Therapy;Body mass index;Businesses;Carotenoids;Chronic;Cluster randomized trial;Communities;Community Outreach;Computer software;Consumption;Control Groups;Country;Data;Dermal;Diet;Dose;Eating;Education;Effectiveness;Evaluation;Face;Fatty acid glycerol esters;Feedback;Fingers;Food;Food Access;Food Preferences;Funding;Future;Health;Health Food;Healthy Eating;Heart Diseases;Height;Hour;Housing;Improve Access;Income;Individual;Intake;Intervention;Interview;Knowledge;Low Income Population;Low income;Malignant Neoplasms;Marketing;Measurement;Measures;Minority;Minority Groups;Modeling;Neighborhood Health Center;Neighborhoods;Nonprofit Organizations;North Carolina;Obesity;Outcome;Participant;Patient Self-Report;Periodicals;Persons;Population;Preparation;Price;Process;Process Measure;Program Effectiveness;Qualifying;Randomized;Randomized Controlled Trials;Reporting;Request for Proposals;Research;Running;Sales;Scanning;Selection Criteria;Self Efficacy;Site;Socioeconomic Status;Sodium;Surveys;Techniques;Telephone;Testing;Time;Unhealthy Diet;Update;Vulnerable Populations;Weight;cluster randomized design;community college;community engagement;community organizations;cooking;cost;design;dietary;effectiveness measure;effectiveness testing;effectiveness/implementation hybrid;environmental intervention;farmers markets;flexibility;follow-up;food environment;fruits and vegetables;health disparity;hybrid type 1 design;implementation framework;implementation process;improved;informant;intervention participants;member;nutrition education;process evaluation;programs;recruit;research study;saturated fat;skills;social cognitive theory;success;sugar;theories;underserved community Effectiveness and Implementation of a Research Tested Mobile Produce Market Designed to Improve Diet in Underserved Communities NarrativeOur research demonstrated that a mobile produce market can have a significant positive impact on diets ofresidents in lower-income communities. We want to test this program more widely to determine if the effectcan be replicated and develop a best-practices toolkit to help others sustainably implement the program. NCI 10800642 11/27/23 0:00 PA-16-160 5R37CA215232-07 5 R37 CA 215232 7 "AGURS-COLLINS, TANYA" 12/1/22 0:00 11/30/24 0:00 10598093 "LEONE, LUCIA A" Not Applicable 26 PUBLIC HEALTH & PREV MEDICINE 38633251 LMCJKRFW5R81 38633251 LMCJKRFW5R81 US 43.003074 -78.785924 5992614 STATE UNIVERSITY OF NEW YORK AT BUFFALO AMHERST NY SCH ALLIED HEALTH PROFESSIONS 142282567 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 588854 NCI 366887 221967 AbstractLower-income and minority groups face significant health disparities with respect to obesity cancer heartdisease and other diet-related chronic conditions. Poor diets low in fruits and vegetables (F&V) and high insaturated fat sodium and sugar contribute to many of the health problems faced by vulnerable groups. Whilesocioeconomic status and other individual level factors (i.e. food preferences time and skills to preparehealthy food etc.) can lead to reduced F&V consumption these must be viewed in an environmental context.Compared with higher-income neighborhoods lower-income and minority neighborhoods are less likely tohave stores that sell a variety of F&V and other healthy foods. And when stores are available produce maynot be affordable high quality or culturally appropriate. Farmers' markets and mobile produce markets (MM)have become increasingly popular strategies to alleviate food access concerns in underserved communities.However it is unclear if these programs have the necessary components to have an appreciable impact ondiet. Our research team recently completed one of the first randomized controlled trials of a MM program calledthe Veggie Van. Veggie Van was run in partnership with our team and a small non-profit organization in NorthCarolina; it delivered boxes of fresh locally grown produce and food-focused education to communities withsignificant barriers to F&V consumption including availability affordability quality and knowledge. In this smallcluster-randomized trial in 12 communities (N=201) we saw impressive changes in F&V intake withintervention participants eating almost 1 more cups per day of F&Vs than the control group. Interventionparticipants also reported increases in perceived access to healthy foods and Veggie Van customers attributedmany dietary changes to the MM program. While these results are very promising we believe it is important totest the effectiveness of the Veggie Van program when implemented by different organizations in multiplecommunities. If shown to be effective we can create a research-tested intervention toolkit which can bedisseminated to communities across the country. For this research we will use a request for proposalsprocess to identify 8 organizations nationwide that are well-qualified to implement the Veggie Van model.Organizations will identify appropriate sites for MM deliveries (32 total) and we will randomize them to either animplementation or planning condition. With the help of our team's technical assistance and provided fundingpartner organizations will engage community members in the process and initiate a MM program. We will usea Type 1 Hybrid Effectiveness-Implementation to measure effectiveness (diet BMI dermal carotenoids) andimplementation (customer reach and sales process measures qualitative interviews with MM staff). We willalso examine sustainability of MM financial models and determine implementation standards (i.e. dose neededto maintain impact) for inclusion in our MM toolkit for future dissemination. 588854 +No NIH Category available Aftercare;Alginates;Antibodies;Antigens;B lymphoid malignancy;Biocompatible Materials;Blood;Blood - brain barrier anatomy;Brain;Brain Neoplasms;CAR T cell therapy;CD276 gene;CD28 gene;Cells;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Data;Development;Disease;Disease Progression;Dose;Encapsulated;Engraftment;Excision;Generations;Glioblastoma;Goals;Immunologics;Immunosuppression;Immunotherapy;Implant;Infusion procedures;Interleukin-2;Interleukins;Intraventricular;Kinetics;Liquid substance;Malignant neoplasm of brain;Mediating;Medical;Methods;Modality;Modeling;Nature;Non-Hodgkin's Lymphoma;Operative Surgical Procedures;Organ;Patient Isolation;Patients;Peripheral Blood Mononuclear Cell;Phenotype;Preparation;Primary Brain Neoplasms;Proliferating;Property;Public Health;Publishing;Radiation therapy;Recurrence;Recurrent tumor;Resected;Retroviral Vector;Retroviridae;Rheology;Route;Solid;Solid Neoplasm;Speed;Structure;Surgically-Created Resection Cavity;Swelling;Symptoms;T cell infiltration;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Toxic effect;Translating;Translations;Treatment Efficacy;Viral;Virus;biomaterial compatibility;bioscaffold;cellular transduction;chimeric antigen receptor;chimeric antigen receptor T cells;clinical application;clinical translation;cost;density;efficacy evaluation;engineered T cells;implantation;improved;in vivo;innovation;manufacture;manufacturing process;multidisciplinary;neurosurgery;overexpression;patient population;pre-clinical;preclinical trial;prevent;response;scaffold;success;technology platform;temozolomide;therapeutic target;tool;tumor;tumor progression;ventricular system Bioinstructive Scaffolds for Potent and Affordable CAR-T Cell Therapy Against Brain Tumors RELEVANCE TO PUBLIC HEALTHCAR T cell therapy is a revolutionary established therapeutic modality with incredible potential to treat both solidand liquid tumors but suffers from very expensive (~$500000) and labor intensive (>2 weeks) manufacturing.We will develop a technology to manufacture CAR T cells within a patients own body and target these CAR Tcells toward a tumor specific B7H3 antigen. B7H3-targeted in vivo produced CAR T cells could be transformativein the treatment of glioblastoma a deadly brain cancer and this technology holds the potential to reduce manu-facturing time enhance therapeutic efficacy and provide local delivery of CAR T cells. NCI 10800468 9/19/23 0:00 PA-20-185 1R01CA278961-01A1 1 R01 CA 278961 1 A1 "SALOMON, RACHELLE" 9/19/23 0:00 8/31/28 0:00 Biomaterials and Biointerfaces Study Section[BMBI] 11876861 "BRUDNO, YEVGENY " "AGARWALLA, PRITHA " 2 ENGINEERING (ALL TYPES) 42092122 U3NVH931QJJ3 42092122 U3NVH931QJJ3; XRPPWZ3TK937 US 35.784675 -78.677233 578204 NORTH CAROLINA STATE UNIVERSITY RALEIGH RALEIGH NC BIOMED ENGR/COL ENGR/ENGR STA 276957514 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 587968 NCI 414999 172969 PROJECT SUMMARYGlioblastoma multiforme (GBM) is a fatal and difficult to treat brain tumor with a dismal median survival of lessthan 2 years. Standard therapy consists of surgical tumor resection radiotherapy and temozolomide which onlydelay tumor recurrence. Recent success of CAR T cell therapy against Non-Hodgkins Lymphomas have gener-ated significant excitement for the application of CAR T cells in GBM and several clinical trials have demonstratedefficacy of CAR T cells in patients with GBM. However both immunosuppression and the blood brain barrier actas major impediments limiting CAR T cell efficacy in glioblastoma. Preclinical trials with localized administrationfor CAR T cells via intratumoral or intraventricular routes enhance CAR T cell infiltration to brain tumor andoutperforms i.v. infusions. With locoregional control CAR T cells are infused into the resected tumor cavityfollowed by repeated infusions into the ventricular system. Multiple administrations are necessary to maintain alarger dose of CAR T cells without causing toxicity and to enhance persistence of functional CAR T cells over alonger time. However this repetitive dosing is a major obstacle to clinical translation of CAR T cells against GBM.CAR T cell manufacturing takes weeks and carries high costs - ~$500000 per dose. The long manufacturingtime creates delays of weeks to months to infuse CAR T cells to patients with rapidly progressing disease.Additionally lengthy ex vivo manipulations create CAR T cells with heterogeneous composition and terminaldifferentiation limiting their engraftment and persistence. Taken together the many shortfalls of current CAR Tcell manufacturing urgently demand development of innovative tools to reduce manufacturing time and provideoptimal CAR T cell phenotype and distribution. In this proposal we describe the application of MultifunctionalAlginate Scaffold for T cell Engineering and Release (MASTER) for use in GBM. MASTER will be implanted inthe surgical cavity of GBM to generate and release CAR T cells in vivo with improved efficacy and persistence.Based on significant published and preliminary data we show that MASTER provides bio-instructive ques toactivate transduce expand and release fully functional CAR T cells in vivo. The scaffold includes anchoredactivating antibodies and interleukins to guarantee T cell activation and proliferation. Scaffold macroporosityfacilitates homogeneous distribution of T cells creates an interface for interaction between viruses and T cellsand enables in vivo release of fully functional CAR T cells. MASTER reduces CAR T manufacturing times fromweeks to a single day substantially reducing costs. We demonstrate in preliminary data and propose further thatMASTER seeded with nave PBMCs and anti-B7H3 CAR-encoding retrovirus will be implanted in the resectioncavity of a brain tumor. B7H3 is overexpressed in brain tumors and serves as a promising therapeutic target forCAR T cell therapy. This approach could have enormous clinical impact by significantly reducing therapy costsand dramatically expanding the patient population benefiting from CAR T cell therapy. These studies will providea foundational technology platform for CAR T cell manufacturing and promote widespread patient access. 587968 +No NIH Category available Address;Affect;Allografting;Antigens;Automobile Driving;Bile duct carcinoma;Biological;Biology;CD8-Positive T-Lymphocytes;CRISPR screen;CTLA4 blockade;Cell Differentiation process;Cells;Cholangiocarcinoma;Cytotoxic T-Lymphocytes;DNA;DNA Repair;Data;Double-Stranded RNA;Endogenous Retroviruses;Enzymes;Epigenetic Process;Epithelium;FDA approved;Frequencies;Gene Expression;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Glioma;Growth;HNF4A gene;Hepatocyte;Human;IFNGR1 gene;IRF3 gene;Immune;Immune Evasion;Immune signaling;Immune system;Immunologic Surveillance;Immunologics;Immunosuppression;Interferon Type II;Interferons;Intrahepatic Cholangiocarcinoma;Isocitrate Dehydrogenase;MAP3K7 gene;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Mediator;Metabolic;Metabolism;Modeling;Molecular;Mutate;Mutation;Natural Immunity;Oncogenes;Pathway interactions;Patients;Phenotype;Process;Production;Proteins;Recurrence;Recurrent tumor;Regulatory T-Lymphocyte;Resistance;Reverse Transcription;Role;Sampling;Signal Transduction;Solid Neoplasm;Stimulator of Interferon Genes;T cell infiltration;T-Cell Depletion;T-Lymphocyte;T-cell receptor repertoire;Testing;Treatment Failure;Tumor Immunity;Tumor Promotion;Up-Regulation;Work;alpha ketoglutarate;bile duct;cancer type;demethylation;derepression;ds-DNA;fascinate;immune checkpoint;immune checkpoint blockade;immunoregulation;improved;in vivo;inhibitor;innate immune pathways;insight;mutant;neoplastic cell;novel;pharmacologic;prevent;programs;recruit;response;restoration;sensor;synergism;therapeutic development;transcription factor;transcriptomics;treatment response;tumor;tumor growth;tumor progression Functions of mutant IDH in cholangiocarcinoma PROJECT NARRATIVEIsocitrate dehydrogenase is the most commonly mutated metabolic gene across all cancers with a particularhigh frequency of mutation in cholangiocarcinoma a deadly cancer of the liver bile ducts. Our prior studiesusing novel genetically engineered mouse models patient-derived models and patient samples showed thatmutant IDH has central roles in driving immune-evasion and subverting cell differentiation. This proposalexplores the underlying mechanisms and interplay of these process and determines how their reversal uponpharmacological inhibition of the mutant IDH1 contributes to biological and therapeutic response therebyinforming the improved treatment of cholangiocarcinoma and potentially the range of other cancer typesharboring IDH mutations. NCI 10800231 9/20/23 0:00 PA-20-185 1R01CA280085-01A1 1 R01 CA 280085 1 A1 "KUO, LILLIAN S" 9/20/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 7337359 "EL-BARDEESY, NABEEL " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 653532 NCI 405727 247805 PROJECT SUMMARYIsocitrate dehydrogenase 1 is the most frequently mutated metabolic gene across all cancers. Among epithelialmalignancies IDH1 mutations are particularly common in cholangiocarcinoma a deadly cancer of the liver bileducts. These hot-spot mutations generate the oncometabolite (R)-2-hydroxyglutarate which inhibits -ketoglutarate-dependent enzymes altering epigenetics and metabolism. While pharmacological inhibition ofmutant IDH1 shows efficacy in cholangiocarcinoma the effects are not durable and there has been limitedinsight into the basis for response and resistance. Recently by developing mIDH1-driven geneticallyengineered mouse models and utilizing patient samples and models we demonstrated that mIDH1 causestumor cells to evade attack by the immune system. We find that inhibitors of mutant IDH1 slow tumor growth byreverting this immune evasion phenotype leading to sensitization to immune checkpoint blockade. A majormechanism of this evasion involves the (R)-2HG-mediated inactivation of the TET2 demethylase whichprevents the tumor cells from responding to interferon gamma produced by immune cells. The secondmechanism involves limiting the recruitment and activity of cytotoxic T cells although we have yet to fullyelucidate the associated molecular basis. Based on our extensive new preliminary data we hypothesize thatIDH1-mediated control of cellular differentiation and of innate immune signaling are potential mediators of thisT cell cross-talk. The present proposal will test this hypothesis and investigate the interplay between T cellrecruitment and the IFN-g-TET2 program in IDH1 inhibitor response and eventual resistance. These studieswill inform the improved treatment of cholangiocarcinoma and potentially the range of other cancer typesharboring IDH mutations. 653532 +No NIH Category available Address;Adoption;Advanced Malignant Neoplasm;Age;Blue Cross;Blue Shield;Clinical;Clinical effectiveness;Continuity of Patient Care;Data Set;Decision Making;Decision Modeling;Diagnosis;Effectiveness;Epidermal Growth Factor Receptor;FDA approved;Fee-for-Service Plans;Frequencies;Genomics;Geography;Health;Histology;Insurance;Insurance Coverage;KRAS2 gene;Label;Malignant Neoplasms;Malignant neoplasm of lung;Medicare;Modeling;Mutation;Neighborhoods;Non-Small-Cell Lung Carcinoma;Oncology;Outcome;Patient-Focused Outcomes;Patients;Policies;Policy Maker;Population Study;Prevalence;Professional Organizations;Recommendation;Research;Research Personnel;Smoking Status;Socioeconomic Status;Solid Neoplasm;Testing;Time;Treatment Cost;Treatment outcome;Uncertainty;actionable mutation;cancer care;cancer therapy;cancer type;care costs;clinical decision-making;clinical practice;clinically relevant;comorbidity;cost;cost effective;cost effectiveness;cost outcomes;frailty;genetic testing;improved;innovation;large datasets;patient population;personalized cancer therapy;research study;targeted agent;targeted treatment;timeline;treatment pattern Broad Genomic Profiling in patients with advanced lung cancer: empirically assessing adoption clinical utility and the value of additional evidence in an evolving landscape of cancer care Personalized cancer treatment is becoming a reality with the real-world adoption of broad genomic profiling(BGP) which has enabled the simultaneous testing of hundreds of potentially targetable genetic alterations inpatients with lethal cancer. The implications of BGP for cancer treatment outcomes and costs represent asubstantial yet moving target in oncology that requires clinicians and policy makers to make decisions in theface of uncertainty. In this proposal we address the critical need to understand real-world 1) BGP use and itsimpact on 2) clinical decision-making 3) treatment outcomes and costs and 4) the value of additional researchstudies in uncertainty regarding BGP by leveraging the strengths of multiple complementary real-worlddatasets. NCI 10800129 9/20/23 0:00 PA-20-185 1R01CA280359-01A1 1 R01 CA 280359 1 A1 "FILIPSKI, KELLY" 9/20/23 0:00 8/31/28 0:00 Organization and Delivery of Health Services Study Section[ODHS] 6618672 "GROSS, CARY P." "DINAN, MICHAELA ANN" 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 706720 NCI 423131 283589 Personalized cancer treatment is becoming a reality. The real-world adoption of broad genomic profiling (BGP)has enabled the simultaneous testing of hundreds of potentially targetable genetic alterations in patients withcancer. Professional societies have endorsed BGP in clinical practice for several cancer types includingadvanced stage non-small cell lung cancer (aNSCLC). Yet evidence regarding the impact of BGP on patientoutcomes is constantly evolving with changes in the availability utilization and efficacy of targeted agents. Assuch BGP use raises a fundamental question in cancer care: how can stakeholders make the most informeddecisions in the presence of uncertainty? We posit that Value of Information (VOI) analysis which explicitlyquantifies the trade-off between the benefits of collecting further evidence compared to a decision based oncurrent evidence can be used to guide decisions regarding BGP. In this proposal we address the critical needto understand real-world 1) BGP use and its impact on 2) clinical decision-making 3) treatment outcomes andcosts and 4) the value of additional research to empirically inform decisions about the adoption of BGP intocancer care by leveraging the strengths of multiple complementary real-world datasets.Aim 1: Utilization of BGP across contemporary U.S. cancer care. We will examine BGP use in advancedcancer and drivers of testing within patients with (Aim 1A) Medicare 100% Fee-for-Service and MedicareAdvantage and (Aim 1B) Blue Cross Blue Shield insurance coverage.Aim 2: BGP results and their impact on treatment patterns in NSCLC. We will quantify the frequency ofactionable mutations among patients with aNSCLC (Aim 2A) and assess the relationship between BGP andcancer management strategy given that less than half of patients with a targetable mutation may receive thecorresponding FDA-approved targeted therapy (Aim 2B).Aim 3: BGP cost and survival. We will determine the relationship between BGP use and cancer care costs(Aim 3A) and overall and cancer-specific survival (Aim 3B).Aim 4: Cost Effectiveness & Value of Information. We will use VOI analysis to determine whether additionalevidence/research is needed to support the use of BGP. Specifically we will compare the long-term health andcost outcomes associated with 1st line BGP in patients with aNSCLC (currently recommended butcontroversial) with two alternate strategies that focus on a smaller number of genetic tests. We will quantifycritical gaps in the evidence that drive uncertainty regarding effectiveness of BGP and quantify the value ofconducting additional research on BGP in order to improve decisions about optimal implementation of BGP.The proposed research is significant given uncertainty regarding the use and effectiveness of BGP innovativegiven the triangulation across multiple large datasets and incorporation of VOI to guide practice and informpolicy and clinically relevant given the high burden of advanced cancer and the burgeoning use of BGP. 706720 +No NIH Category available Address;Adult;Bioconductor;Bioinformatics;Biometry;Cancer Center Support Grant;Clinical;Collaborations;Combined Modality Therapy;Communities;Creativeness;Data Collection;Data Coordinating Center;Fostering;Funding;Immune;Immune Targeting;Immunooncology;Immunotherapy;Infrastructure;Institution;Malignant Neoplasms;Methods;Oncology;Preventive;Productivity;Research;Research Personnel;Resource Sharing;Resources;Site;biobank;biomedical data science;community engagement;cost effective;data centers;data integration;data management;data repository;data sharing networks;design;experience;flexibility;high standard;improved;innovation;multidisciplinary;novel;predictive marker;prevent;programs;resistance mechanism;translational oncology;translational study Immuno-Oncology Translation Network: Data Management and Resource-Sharing Center at RPCI Project NarrativeWhile several innovative and creative immuno-oncology (IO) strategies have shown promising results asignificant expansion of their clinical use will require collaborative efforts to elucidate the resistance mechanismdiscover new immune targets identify predictive biomarkers evaluate combination therapies and developpreventive approaches. Utilizing a multi-disciplinary team approach we will support Immuno-OncologyTranslation Network (IOTN)-funded components to discover new immune targets and evaluate novel immune-based therapies and combination approaches that eliminate established cancers in adults or to preventcancers before they occur. NCI 10800071 4/14/23 0:00 PA-20-272 3U24CA232979-01S8 3 U24 CA 232979 1 S8 "KUO, LILLIAN S" 9/30/18 0:00 6/30/23 0:00 6773960 "HUTSON, ALAN DAVID" "LIU, SONG ; MORGAN, MARTIN T" 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 4/14/23 0:00 6/30/23 0:00 396 Other Research-Related 2023 26025 NCI 15000 11025 Project SummaryWhile several innovative and creative immuno-oncology (IO) strategies have shown promising results asignificant expansion of their clinical use will require collaborative efforts to elucidate the resistance mechanismdiscover new immune targets identify predictive biomarkers evaluate combination therapies and developpreventive approaches. Utilizing a multi-disciplinary team approach we will support Immuno-OncologyTranslation Network (IOTN)-funded components to discover new immune targets and evaluate novel immune-based therapies and combination approaches that eliminate established cancers in adults or to preventcancers before they occur. Our DMRC strategy is to serve as an administrative and analytic hub at every stepof the IOTNs translational studies focusing to reduce the barrier for access to analytic expertise improve theproductivity of IOTN investigators maintain a high standard for data collection and management design andperform rigorous analytical strategies and foster a collaborative and supportive research community.An experienced multidisciplinary team has been assembled to pursue four specific aims: First we will providea centralized administration infrastructure to coordinate IOTN activities building upon the NRG OncologyStatistical and Data Coordinating Centers experience of coordinating over 450 translational cancer studiesacross hundreds of participating sites. Second we will provide multidisciplinary analytic expertise to supportIOTN collaborative research leveraging five of RPCI CCSGs shared resources: Biostatistics BioinformaticsBiomedical Data Science Data Bank and BioRepository and Immune Analysis. Our analytic support will bearmed with professional IT staff and informed by an experienced IO researcher team. Third we will developinnovative data integration methods to enhance IOTN research capacity capitalizing on the well-respectedBioconductor project and the independent research programs of the RPCI department of Biostatistics andBioinformatics. Fourth we will actively promote the IOTN and engage in trans-consortium interactions wherewe will leverage Bioconductors decade-long experience in community engagement and the NRG data centersrich expertise in project coordination. Leveraging our active NCI-funded RPCI-committed resource to supportthe proposed multi-institutional trans-disciplinary IO research is not only cost-effective but also flexible in itsstudy-dependent scalability. Taken together we envision that our DMRC in close collaboration with the IOTNwill allow us to conduct highly effective and innovative translational studies to address the significantly unmetclinical needs related to IO. 26025 +No NIH Category available Aggressive behavior;Antineoplastic Agents;B-DNA;Binding;Cells;Characteristics;Chemicals;Chemotherapy-Oncologic Procedure;Chromatin;Clinic;Clinical;DNA;DNA Damage;DNA Methyltransferase Inhibitor;Data;Disease;Dose;Drug Targeting;Environment;Future;Genes;Genetic Materials;Goals;Histone Deacetylase Inhibitor;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunotherapy;Interferon Activation;Interferon Type I;Interferons;Knowledge;Lead;Left;Mainstreaming;Malignant Neoplasms;Mediating;Modeling;Monitor;Mus;Mutation;Nuclear;Nucleosomes;Patients;Pattern recognition receptor;Pharmaceutical Preparations;Proliferating;Property;Regimen;Research;Resistance;Rest;Role;Sampling;Signal Pathway;Signal Transduction;Technology;Testing;Time;Toxic effect;Transcript;Treatment Protocols;Z-DNA Binding Protein;Z-Form DNA;anti-cancer;anti-tumor immune response;anticancer activity;biomarker identification;cancer therapy;cancer type;cell stroma;cell type;chemotherapy;experimental study;immunogenicity;improved;in vivo;mouse model;neoplastic cell;next generation;novel;phase I trial;predictive marker;response;sensor;single-cell RNA sequencing;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Induction of interferon response by chromatin damaging anti-cancer therapy Project NarrativeWe have developed a group of novel anticancer chemicals curaxins which are currently tested in clinic; theyact via disrupting of packaging of genetic material DNA in tumor cells. Contrary to exiting drugs targeting DNAthey do not cause mutations. We recently identified a new feature of these compounds that they can activateimmune response against tumors; in this proposal we will figure out how they do this and how we can utilize thisproperty in the clinic to get maximal benefit for patients. NCI 10799847 11/24/23 0:00 PA-20-185 1R01CA266216-01A1 1 R01 CA 266216 1 A1 "VENKATACHALAM, SUNDARESAN" 12/1/23 0:00 11/30/28 0:00 "Advancing Therapeutics A Study Section +[ATA]" 7888559 "GUROVA, KATERINA V" Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 396881 NCI 228750 168131 "Abstract. DNA-targeting drugs are a mainstream therapy for cancer but it is becoming clearer that some of theiranti-cancer activity is due not only to DNA damage but also chromatin decondensation which we call chromatindamage (CD). Moreover it has been shown that some drugs cause only CD without DNA damage and these""CD-only"" drugs are as potent anti-cancer drugs as compounds causing both CD and DNA damage but lack thetoxicity associated with DNA damage. The focus of our study is to understand how CD activates IFN and howthis property can be used in the clinic to gauge the potency of CD drugs. Our ultimate goal of our research is toshow that CD is a superior mechanism to DNA damage for the next generation of anti-cancer chemotherapywhich is more effective less toxic and more powerful in activating an anti-tumor immune response. To achieve this goal we have developed a new group of ""CD-only"" chemicals curaxins. The anti-canceractivity of curaxin clinical lead CBL0137 has been demonstrated in multiple mouse models. Phase I trial hasshown manageable toxicities and evidence of antitumor activity. These studies confirmed induction of IFNsignaling by CBL0137 in mice and humans. Notably curaxins cause stronger and faster IFN induction than DNAdamaging agents DNA methyltransferase inhibitors and HDAC inhibitors. It is well established now that IFNinduction significantly improves their anti-cancer efficacy of DNA damaging therapy. CD causes IFN inductionvia different mechanisms but our data showed that IFN activation enhances anti-cancer efficacy of CD. Therefore we propose that anti-cancer activity of CD agents is mediated in vivo via two complementarymechanisms: direct killing of tumor cells and engagement of anti-tumor immune attack. This proposal focuseson the hypothesis that IFN signaling in tumor and/or non-tumor cells is induced by CD via a mechanism differentfrom DNA damage and potentiates the anti-cancer activity of CD drugs. We will focus on triple negative breast cancer (TNBC) a challenging disease to treat due to its aggressivebehavior and lack of actionable targets. Our specific aims are: 1. Determine the impact of the IFN activationin tumor and non-tumor cells on the anti-tumor activity of CD therapy. 2. Define the mechanisms of IFNactivation by CD agents. 3. Develop strategies for reversing the immune suppressive environment intriple-negative breast cancer using CD agents." 396881 +No NIH Category available Achievement;Automobile Driving;Biological Markers;Cancer Patient;Cancer Prognosis;Clinical;Clinical Treatment;Code;Computer Models;Data;Decision Making;Dimensions;Disease;Disease Progression;Family;Future;Genes;Genetic;Goals;HPV oropharyngeal cancer;Habitats;Head and Neck Cancer;Heterogeneity;Human Papillomavirus;Image;Imaging Techniques;Incidence;International;Machine Learning;Medical Imaging;Methodology;MicroRNAs;Modeling;Nature;Oncogenic;Oropharyngeal Neoplasms;Oropharyngeal Squamous Cell Carcinoma;Outcome;Patients;Phenotype;Play;Prognosis;Prognostic Marker;Proteins;Research;Retrospective Studies;Risk;Role;Site;Survival Rate;Techniques;Testing;Therapeutic;Treatment Failure;Treatment outcome;Uncertainty;United States;Untranslated RNA;Validation;Variant;biomarker identification;cancer biomarkers;cancer epidemiology;cancer therapy;cancer type;clinical application;clinical biomarkers;clinical decision-making;clinically relevant;cohort;effective therapy;high dimensionality;high risk;imaging biomarker;improved;individualized medicine;malignant oropharynx neoplasm;microRNA biomarkers;mortality risk;multimodality;non-invasive imaging;novel;outcome prediction;patient biomarkers;patient prognosis;patient stratification;patient subsets;precision oncology;predictive modeling;prognostic;prognostic model;prognostic value;response;tool;treatment strategy;tumor Multimodal Biomarkers For Oropharyngeal Cancer NarrativeThe achievement of this project forms a basis of combining non-invasive imaging biomarkers with miRNAsHPV clinical and histopathologic biomarkers for accurate cancer prognosis and discovering the correlationwith genetic mechanisms leading to specific tumor phenotypes. This clinical decision-making tool can provideuseful information to support patient stratification and individualized treatment. We anticipate that many of themethodological improvements established in this proposal will improve oropharyngeal squamous cellcarcinoma treatment and tumor response assessment and treatment in other disease sites as well. NCI 10799539 11/28/23 0:00 PA-18-484 5R01CA233873-06 5 R01 CA 233873 6 "TANDON, PUSHPA" 2/1/22 0:00 11/30/24 0:00 Biomedical Computing and Health Informatics Study Section[BCHI] 9017498 "LI, HUA " Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 350017 NCI 279370 70647 AbstractHead and neck cancers are the fifth most common cancer type in the United States with an overall survivalrate lower than 50%. Although the incidence of other sub-sites of head and neck cancer has decreasedsteadily in past decades the number of oropharyngeal squamous cell carcinoma (OPSCC) cases hasincreased significantly. Most OPSCC patients receive standard cancer therapy.4 However the clinicaloutcomes vary significantly and are difficult to predict. Predicting early in treatment whether a tumor is likely torespond to treatment is one of the most difficult yet important tasks in providing individualized cancer care. Human papillomavirus (HPV) is a known driving oncogenic factor in oropharyngeal cancer as well as asignificant prognostic biomarker for patient survival. Retrospective studies conducted by the International Headand Neck Cancer Epidemiology Consortium (INHANCE) have demonstrated that clinical biomarkers haveprognostic value in helping stratify OPSCC patients into groups with differing risks of death or diseaseprogression. However HPV-positive oropharyngeal cancer patients have similar rates of metastatic spread toHPV-negative patients. The same is true for patient groups stratified with other clinical biomarkers. More robustprognostic biomarkers are needed to accurately stratify patients for optimally effective treatment. MicroRNAs (miRNAs) are a family of small non-coding RNA molecules that collectively control theexpression of thousands of protein-coding genes. Multiple studies indicate that miRNAs are promising cancerbiomarkers and play critical regulatory roles in oropharyngeal cancer. Imaging features extracted from medicalimages are an exciting new class of cancer biomarkers for characterizing tumor habitats. For several tumorsites imaging biomarkers have shown promise in accurately separating favorable and unfavorable prognosispatients. However current efforts to utilize high-dimensional multimodal biomarkers for treatment outcomeprediction have been compromised by small patient numbers relative to the feature space dimensionality;feature redundancy heterogeneity and uncertainty; and patient cohorts with unbalanced outcomes. Thecorrelation independence and complementary nature of multimodal biomarkers (imaging miRNA HPVclinical and histopathologic biomarkers) remains unexplored as well. The major goal of this research is to develop a multimodal biomarker-based model that can reliably predictsubsets of OPSCC patients with low and high risks for treatment failure. The model will serve as a clinicaldecision-making tool. Specifically we propose a novel principle and systematic machine learning-basedstrategy to effectively identify and seamlessly combine prognostic information carried by multimodalbiomarkers. Aim 1: Identify prognostic multimodal biomarkers given OPSCC patient data. Aim 2: Develop andtest a comprehensive multimodal biomarker-based model for predicting OPSCC treatment outcomes. Aim 3:Assess the clinical benefit of the model for OPSCC patient stratification and individualized treatment. 350017 +No NIH Category available Ablation;Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Address;Aftercare;Allogenic;Animal Model;Antigen Targeting;Antigen-Presenting Cells;Bone Marrow;Bone Marrow Cells;Cell Compartmentation;Cell Proliferation;Cells;Chromosome abnormality;Clinical;Cytogenetics;DNA Damage;Development;Drug Targeting;Engraftment;FLT3 gene;Funding;Hematologic Neoplasms;Hematopoietic;Hematopoietic Stem Cell Transplantation;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immunity;Immunologic Stimulation;Immunologic Surveillance;Immunotherapy;Implant;Interferon Type I;Knock-out;Laboratories;Leukemic Cell;Lymphoma;MLL-AF9;Machine Learning;Malignant Neoplasms;Modeling;Molecular;Mononuclear;Mus;Non-Hodgkin's Lymphoma;Oncogenic;Outcome;PD-1 inhibitors;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Production;Protein-Arginine N-Methyltransferase;Proteins;Reporting;Repression;STING agonists;Signal Transduction;Specimen;Stimulator of Interferon Genes;T-Lymphocyte;Testing;Therapeutic;Therapeutic Uses;Translations;Transplantation;Treatment outcome;Work;acute myeloid leukemia cell;anti-PD-1;cancer cell;cell type;cellular engineering;checkpoint therapy;chimeric antigen receptor T cells;effective therapy;extracellular;high risk;humanized mouse;immune activation;immune checkpoint;immunotoxicity;in vivo;inhibitor;lead optimization;leukemia;leukemia treatment;molecular dynamics;mouse model;novel;overexpression;pharmacologic;programmed cell death protein 1;protein function;relapse risk;response;risk stratification;single-cell RNA sequencing;targeted treatment;transcriptome;transcriptomics;transplant model;tumor Targeting Protein Arginine Methyltransferases to Eradicate Acute Myeloid Leukemia Project NarrativeOverall outcome for patients with acute myeloid leukemia (AML) remains unfavorable. The limited applicabilityof allogeneic hematopoietic stem cell transplantation (allo-HSCT) as well as the rise of the immunotherapy erahighlights a pressing need to develop novel immune-stimulating drugs for AML eradication. To address thischallenge herein we will determine whether targeting PRMT9 promotes a sustained leukemia-eliminatingimmunity and assess whether a PRMT9 inhibitor combined with an immune checkpoint inhibitor eliminates AMLcells in-vivo. NCI 10799434 12/8/23 0:00 PA-20-185 1R01CA279595-01A1 1 R01 CA 279595 1 A1 "KLAUZINSKA, MALGORZATA" 12/8/23 0:00 11/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 11807514 "LI, LING " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 12/8/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 727057 NCI 433072 293985 Project SummaryTreatment outcomes for patients with acute myeloid leukemia (AML) have continued to lag behind outcomesreported for other hematological malignancies like acute lymphoblastic leukemia (ALL) in part because of therelatively slow development of immunotherapy (including immune checkpoint inhibitors [ICI]) compared with ALL.However translation of currently available immunotherapies to AML treatment has been challenging and novelAML-targeting drugs with immune-stimulating activity are greatly needed. The cGAS-STING signaling is a majorpathway that promotes an extrinsic type I Interferon (IFN-I) response which potently primes T cells in immune-cold cancers including AML. My laboratory has been active in defining the function of protein argininemethyltransferases (PRMTs) in leukemia. Herein our preliminary studies on the basis of primary AML cells aswell as murine AML models reveal an anti-AML immune activation seen after inhibition of PRMT9 a mostrecently defined PRMT. Specifically PRMT9 inhibition stimulated leukemia-intrinsic cGAS as evidenced bycGAMP (an immunotransmitter) production and induced a leukemia-eliminating IFN-I response in murine AML-microenvironment (ME). When combined with an ICI (PD1 inhibitor) the in-house PRMT9 inhibitor LD2eradicated AML in animal models. Thus we hypothesize that PRMT9 activity allows AML cells to evade immunesurveillance by repressing cGAS-STING activity in the ME and that LD2 alone or combined with an ICI (PD1inhibitor) elicits T cell activity to eliminate AML cells. Extracellular cGAMP which is hydrolyzed by ENPP1 andSTING activation in host immune cells are reportedly essential for immunity. Thus in Aim 1 using two AMLtransplant models we will determine whether downregulating cGAMP (via either ENPP1-overexpression orcGAS-knockout (KO) in AML cells) or STING-KO in the immune cell compartment of recipient mice would reversePRMT9 inhibition-induced AML regression. In Aim 2 we will determine the mechanisms underlying cancer-intrinsic cGAS activation seen after PRMT9 inhibition. Specifically we will define PRMT9 targets that whenunmethylated underlie cGAS activation. In Aim 3 we will assess anti-AML activity of LD2 alone or combined witha PD1 inhibitor using AML mouse models. Moreover to define potential shifts in immune cell types/states afterPRMT9 inhibition we will perform single-cell transcriptome analysis on AML PDX cells from humanized mousetreated with LD2 or the combination. We are the first to identify PRMT9 as a druggable immune activation targetagainst cancer. If successful this work would support combining a PRMT9 inhibitor with ICIs as a therapy forAML in which single ICI therapy has very limited effects. 727057 +No NIH Category available 1 year old;Acceleration;Acute;Acute Myelocytic Leukemia;Adolescent;Australia;Biology;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Cancer Treatment;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Clinical Trials Design;Collaborations;Collection;Communities;Companions;Complication;Country;Data;Data Coordinating Center;Development;Diagnosis;Disease;Ensure;Family;Foundations;Functional disorder;Generations;Genomics;Goals;Hormonal;Immunotherapy;Industry;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Prognosis;Quality of life;Rare Diseases;Reporting;Research;Research Personnel;Science;Second Primary Cancers;Survival Rate;Survivors;Tissues;Translational Research;United States;Universities;Work;anticancer research;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;data centers;data management;data sharing;density;design;experience;functional outcomes;health related quality of life;high risk;improved;improved outcome;innovation;member;mortality;multidisciplinary;novel;novel therapeutic intervention;organizational structure;programs;reproductive;small molecule;statistics;survivorship;translational clinical trial;translational scientist;translational study;trial design Children's Oncology Group Statistics and Data Center PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcome for all children with cancer. NCI 10799432 3/30/23 0:00 PA-21-268 7U10CA180899-10 7 U10 CA 180899 10 "MOONEY, MARGARET M" 3/1/23 0:00 2/28/25 0:00 ZCA1-GRB-S(O1) 1857551 "ALONZO, TODD A" Not Applicable 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 8448105 NCI 8368398 1025019 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of theestimated 360000 survivors of childhood cancer experiencing a significant health related quality of lifecomplication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildrens Oncology Group (COG) the worlds largest organization devoted exclusively to childhood andadolescent cancer research was founded 17 years ago. The COGs multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading childrens hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institutes (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life children with cancer and survivors. As more than 90% of childrendiagnosed with cancer in the US are treated at COG member institutions the COG has the ability to offer adiverse population of children with cancer and their families the opportunity to participate in innovative research.This research effort includes allowing for collection and annotation of biospecimens from all children with cancerproviding the foundation for discovery and accelerating the most promising research efforts conducted inlaboratories around the world. The proposal is for support of the COG Network Statistics and Data ManagementCenter which collaborates with COG scientific leaders to design conduct analyze and report the results ofclinical-translational trials for the treatment of childhood cancers. 8448105 +No NIH Category available African;African American;African ancestry;All of Us Research Program;Asian population;BRCA2 gene;CHEK2 gene;Cancer Etiology;Candidate Disease Gene;Categories;Cessation of life;Complex;Data;Disease;Disparity;East Asian;Economics;Education;European;European ancestry;Genes;Genetic;Genetic Risk;Genetic Variation;Genetic study;Genotype;Goals;Healthcare;Heritability;Hispanic Populations;Incidence;Indolent;Inherited;Investigation;Knowledge;Life Style;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Modeling;Obesity;Outcome;PALB2 gene;Pathogenicity;Population;Population Heterogeneity;Preventive measure;Relative Risks;Reporting;Research;Resources;Risk;Risk Factors;Sample Size;Screening for Prostate Cancer;Smoking Status;Socioeconomic Factors;Variant;carrier status;cost;exome;genetic risk factor;genetic variant;genome sequencing;genome-wide;health care availability;health disparity;healthy lifestyle;high risk men;improved;lifestyle factors;man;men;modifiable risk;mortality;non-genetic;novel;polygenic risk score;prostate cancer prevention;prostate cancer risk;rare variant;risk variant;screening;social;unhealthy lifestyle;whole genome Germline Genetics and Risk of Prostate Cancer in Diverse Populations from the All of Us Program PROJECT NARRATIVEWhile prostate cancer is strongly influenced by inherited genetic factors most genetic studies of prostate cancerhave been limited to men of European ancestry limiting our knowledge of genetic risk of prostate cancer in otherpopulations. In this study we will investigate genetic risk of prostate cancer in the All of Us Research Programacross diverse populations combining findings with previous large-scale prostate cancer genetic studies tostrengthen our ability to identify novel genetic risk factors and we will investigate whether genetic risk of prostatecancer can be modified by lifestyle and socioeconomic factors. We anticipate that findings from this investigationwill improve our ability to identify men with increased risk of prostate cancer and aggressive disease which couldhave important implications for screening and early detection of prostate cancer. NCI 10798864 9/19/23 0:00 RFA-PM-23-002 1R03CA287235-01 1 R03 CA 287235 1 "DAEE, DANIELLE L" 9/19/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-IVBH-A(51)R] 14153859 "DARST, BURCU FRANCES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 192600 OD 109432 83168 PROJECT SUMMARYProstate cancer is the second most common cancer and the second leading cause of cancer death in US menwith African American men having the highest incidence and mortality rates. Prostate cancer is stronglyinfluenced by genetic factors and polygenic risk scores (PRS) of common genetic variants are highly predictiveof prostate cancer risk in men from European African East Asian and Hispanic populations. Rare pathogenicvariants also contribute to overall and aggressive prostate cancer risk with 15% of metastatic cases carryingsuch variation. However due to high sequencing costs our knowledge of the contribution of rare genetic variationto prostate cancer risk is largely based on candidate gene studies with of the few whole-exome or whole-genomestudies conducted to date having sample sizes that are large enough for the discovery of novel rarevariants/genes. Further the majority of men included in common and rare genetic variant investigations ofprostate cancer risk have been from European ancestry populations limiting our knowledge on genetic risk ofprostate cancer in other populations. The objective of this research is to elucidate genetic factors that contributeto risk of overall and aggressive prostate cancer across diverse populations and how such factors can becombined with lifestyle environmental and socioeconomic factors to more accurately characterize risk ofprostate cancer. In Aim 1 we will investigate the contribution of rare and common genetic variants to prostatecancer risk across diverse populations with the goal of validating known genetic risk factors and discoveringnovel genetic risk regions. In Aim 2 we will investigate whether genetic risk of prostate cancer as measured bya PRS of known common genetic risk variants can be modified by rare pathogenic variant carrier status lifestylefactors and socioeconomic factors across diverse populations. This research will be conducted in the All of UsResearch Program combining results from Aim 1 with other large-scale investigations to improve our ability toidentify novel genetic risk regions. Findings from this investigation are expected to identify novel mechanismsnovel mechanisms to target for preventative measures and improve our understanding of the complex interplayof genetic risk and modifiable risk factors of prostate cancer. Further this investigation is anticipated to improveour ability to identify men at increased risk of overall and aggressive prostate cancer which could have importantscreening and healthcare implications for prostate cancer prevention. 192600 +No NIH Category available Bar Codes;Cell Line;Cells;Cessation of life;Characteristics;Clinical Trials;Cytidine;Cytidine Deaminase;DNA Double Strand Break;Data;Deamination;Decision Making;Development;Diagnosis;Drug resistance;Evolution;FGFR3 gene;Family;Future;Genes;Genetic;Genetic Heterogeneity;Genetic Induction;Genomics;Goals;Human;In Vitro;Induced Mutation;Knowledge;Laboratories;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Mediator;Methods;Modeling;Mutagenesis;Mutation;Organoids;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Phosphotransferases;Phylogenetic Analysis;Polymerase;Proto-Oncogene Proteins c-akt;Public Health;Publishing;Relapse;Reporting;Research;Resistance;Resistance development;Role;Sampling;Signal Transduction;Specific qualifier value;System;Systemic Therapy;Testing;Therapeutic;Transitional Cell Carcinoma;Tumor Bank;United States;Urothelium;Work;Xenograft procedure;biomarker identification;cancer cell;clinical biomarkers;clinical risk;co-clinical trial;de novo mutation;improved;improved outcome;in vivo;inhibitor;innovation;insertion/deletion mutation;novel;novel strategies;novel therapeutic intervention;pharmacologic;precision medicine;pressure;prevent;refractory cancer;repaired;response biomarker;standard of care;success;targeted treatment;therapeutically effective;therapy resistant;tumor;tumor heterogeneity Targeting APOBEC3A-induced genetic heterogeneity and drug resistance in bladder cancer PROJECT NARRATIVEThe proposed research is relevant to public health because it will transform our understanding ofAPOBEC3A-induced genetic intra-tumoral heterogeneity as a driver of targeted therapy resistance inbladder cancer. Successful completion of this project will 1- Identify targetable kinase hubs downstreamof APOBEC3A-induced intra-tumoral heterogeneity to treat advanced bladder cancers that developedFGFR3 inhibitor resistance 2- Define novel synthetic lethal strategies to eliminate cancer cells withAPOBEC3A activity. These advances will increase cure rates for patients with advanced bladdercancer. NCI 10798615 9/20/23 0:00 PA-20-185 1R37CA279737-01A1 1 R37 CA 279737 1 A1 "FORRY, SUZANNE L" 9/20/23 0:00 8/31/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 10658242 "FALTAS, BISHOY MORRIS" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 515976 NCI 323963 192013 PROJECT SUMMARY/ ABSTRACTEvery five minutes a new patient is diagnosed with urothelial carcinoma (UC) in the United States resulting inthe death of 18000 patients annually. Nearly all patients with advanced UC will develop resistance to systemictreatment. Intratumoral heterogeneity (ITH) is a major contributor to treatment resistance by increasing thechance for resistant subclones to emerge. However genetic ITH is currently not druggable and not consideredin therapeutic decision-making thus worsening drug-resistant patient phenotypes. The fundamental knowledgegap regarding genetic drivers of ITH impedes the development of effective therapeutic strategies to prevent andeliminate drug resistance. Our long-term goal is to define targetable mechanisms of ITH and treatment resistanceto develop an effective precision strategy to achieve cures in patients with advanced UC. The overall objectiveis to define targetable mechanisms by which APOBEC3A-mediated ITH drives drug resistance and identifystrategies to eliminate UC cells with APOBEC3A activity. Our central hypothesis is that APOBEC3A-inducedcytidine deamination drives genetic ITH leading to the emergence of therapy-resistant UC clones and inso doing simultaneously creating unique targetable vulnerabilities. This hypothesis was formulated basedon our published work and strong preliminary data showing that APOBEC3A expression in isogenic UC cell linesand patient-derived organoids drives genetic ITH. We found that APOBEC3A-induced de novo mutations in thePIKC3A-AKT-MTOR signaling hub drive the resistance to erdafitinib an FGFR3-inhibitor (FGFR3i) approved forUC treatment. Our preliminary data also revealed that APOBEC3A-induced double-stranded DNA breaks arepreferentially repaired by the microhomology-mediated end-joining (MMEJ) pathway and that targeting thecritical MMEJ mediator polymerase theta (Pol) is synthetically lethal in APOBEC3A-expressing clones. Therationale is that identifying targetable mechanisms by which APOBEC3A-induced ITH drives drug resistance anddeveloping strategies to eliminate APOBEC3A-expressing UC cells will improve cure rates for patients. We willtest our hypothesis by pursuing two specific Aims. Aim 1: Identify targetable mechanisms by which APOBEC3A-induced mutational ITH drives treatment resistance in UC. Aim 2: Identify synthetic lethal strategies to target UCtumors with APOBEC3A-induced DNA double-strand breaks. Aim 1 will use longitudinal clonal barcoding and invitro and in vivo laboratory evolution to identify targetable APOBEC3A-driven kinase hubs that mediate FGFR3iresistance and validate them in patient samples from FGFR3i clinical trials. Aim 2 will use genetic andpharmacologic inhibition of Pol in APOBEC3A-expressing UC models and a co-clinical trial of patient-derivedUC organoids and xenografts to identify clinical biomarkers of response to APOBEC3A-MMEJ synthetic lethality.The approach is conceptually and technically innovative creating a new paradigm for eliminating treatment-resistant cancers. Impact: Completion of the proposed research will establish APOBEC3A as a genetic driver oftreatment resistance and enable synthetic lethal approaches to increase cure rates. 515976 +No NIH Category available Address;Advisory Committees;Age;Anatomy;Artificial Intelligence;Benign;Biological;Cancer Patient;Cancer Prognosis;Cancerous;Cause of Death;Characteristics;Classification;Clinical;Clinical Data;Collaborations;Committee Members;Computer Vision Systems;Data;Data Set;Databases;Decision Trees;Detection;Devices;Diagnosis;Dimensions;Discipline of Nuclear Medicine;Disease;Early Diagnosis;Engineering;Environment;Glean;Grant;Health;Heterogeneity;High Performance Computing;Image;Knowledge;Lead;Learning;Lesion;Logistic Regressions;Machine Learning;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Manuals;Medical;Medical Device;Medical Imaging;Mentors;Methods;Modality;Modeling;Morphology;Outcome;Pathology;Patient imaging;Patient-Focused Outcomes;Patients;Phase;Physicians;Physics;Population;Positron-Emission Tomography;Process;Prognosis;Progression-Free Survivals;Protocols documentation;Publications;Radiology Specialty;Reproducibility;Research;Resolution;Resources;Roentgen Rays;Sampling;Source;Standardization;Techniques;Technology;The Cancer Imaging Archive;Tracer;Training;United States;United States Food and Drug Administration;Universities;Variant;Visual;X-Ray Computed Tomography;biomarker discovery;cancer imaging;cancer therapy;cancer type;clinical database;clinical imaging;clinical prognosis;deep learning;digital;image reconstruction;imaging biomarker;imaging modality;improved;insight;interest;large datasets;learning strategy;machine learning model;mortality;multilayer perceptron;patient population;predict clinical outcome;prognostic;prognostication;radiological imaging;radiomics;radiotracer;random forest;reconstruction;sex;simulation;standardize guidelines;success;support vector machine;task analysis;tool;transfer learning;treatment response;tumor;ultrasound;uptake Large-scale artificial intelligence using radiomics deep learning and physics-based generative modeling to improve clinical outcomes in nuclear medicine Project NarrativeCancer is a major worldwide health concern where delays in the diagnosis and treatment of cancer lead toincreased mortality. The proposed project will enable large-scale artificial intelligence studies using radiomicsdeep learning and physics-based generative modeling in nuclear medicine imaging for the automaticcharacterization of malignant diseases. The developed approach will be generalizable across a range ofcancer types and will help improve patient outcomes by facilitating the early detection diagnosis prognosisand treatment of cancer. NCI 10797660 1/4/24 0:00 RFA-CA-22-035 1K99CA287045-01 1 K99 CA 287045 1 "RADAEV, SERGEY" 1/4/24 0:00 12/31/26 0:00 ZCA1-RTRB-U(O1) 14741115 "LEUNG, KEVIN HO-YIN" Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 1/4/24 0:00 12/31/25 0:00 398 Other Research-Related 2024 177600 NCI 165800 11800 Project Summary/AbstractCancer is the second leading cause of death in the United States where delays in diagnosis and treatment leadto increased mortality and advanced-stage disease. Developing artificial intelligence (AI) and deep learning (DL)approaches for the automatic characterization of malignant disease can facilitate the early detection diagnosisprognosis and treatment of cancer. Radiomics and DL approaches extract quantitative information and visualfeatures from radiological data to glean insights into a patients disease. Traditional radiomics approaches sufferfrom reproducibility issues due to small dataset sizes and differences in imaging scanners reconstructionmethods and operator variability in regions of interest segmentation. DL methods require training on largedatasets with annotated ground truth which is difficult to obtain due to the limited availability of physician-definedannotations and histopathological ground truth. Radiomics and DL methods are often trained on datasets thatencompass a specific malignancy which additionally limits their generalizability and overall utility. Nuclearmedicine imaging modalities provide important functional information regarding radiotracer uptake in benign andmalignant pathologies that can help inform diagnosis and treatment. There is a significant unmet need to developresearch and clinical tools that address the challenges of enabling large-scale AI-based pipelines in nuclearmedicine. Aim 1 will build a large database of clinical positron emission tomography (PET)/computed tomography(CT) images with physician-annotated ground truth. Aim 2 will develop a physics-guided deep generativemodeling approach to generate realistic simulated PET/CT data with known ground truth. Aim 3 will quantify therobustness of radiomic features using both simulated and clinical PET/CT data. Aim 4 will develop and validatea simulation-based transfer learning approach on automated lesion detection segmentation and classificationtasks. Aim 5 will develop and validate a multipronged approach that combines robust radiomics DL andensemble meta-learning to predict clinical outcomes from PET/CT images of patients with cancer. In the K99training phase of this grant Dr. Kevin H. Leung will conduct the proposed research under the guidance of Dr.Martin G. Pomper with the support of outstanding advisory committee members with extensive expertise inradiology oncology PET CT and medical imaging physics. The major objective of the mentored research phaseis to create a large clinical PET/CT database encompassing a wide range of cancers and to develop a physics-guided approach to generate realistic simulated PET/CT data that reflect clinical population-level characteristics.The technology developed from the K99 phase will be expanded in the independent R00 phase into a generalizedplatform that will enable large-scale AI in nuclear medicine for a wide range of medical image analysis tasks.The rich resources and strong collaborations available at Johns Hopkins provide an ideal training environmentthat is completely supportive of the proposed research and the academic advancement of Dr. Leung. 177600 +No NIH Category available Abstinence;Address;Adult;Age;Anhedonia;Biochemical;Bupropion;Carbon Monoxide;Cessation of life;Characteristics;Chronic Disease;Clinical Trials;Communities;Complex;Counseling;Dependence;Disparity population;Dose;Education;Effectiveness;Ensure;Environment;Evaluation;Evidence based intervention;FDA approved;Failure;Future;General Population;Heterogeneity;Household;Income;Medicaid eligibility;Medical;Mental Health;Methods;Moods;Nicotine Dependence;Nicotine Withdrawal;Outcome;Participant;Patient Selection;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Phase;Population Heterogeneity;Process;Provider;Psychosocial Factor;Public Health;Race;Randomized;Relapse;Rural;Sampling Studies;Sequential Multiple Assignment Randomized Trial;Sexual and Gender Minorities;Smoker;Smoking;Smoking Cessation Intervention;Source;Texas;Time;Treatment Protocols;Treatment outcome;Uninsured;Withdrawal;comorbidity;comparative effectiveness;comparative effectiveness trial;craving;depressive symptoms;disability;dosage;evidence base;experience;gender minority group;innovation;negative affect;nicotine patch;nicotine replacement;optimal treatments;premature;primary outcome;rural area;secondary outcome;side effect;smoking abstinence;smoking cessation;timeline;treatment strategy;trial comparing;trial design;uptake;varenicline;virtual delivery;virtual platform;volunteer Comparative Effectiveness of Sequential Pharmacotherapeutic Strategies and Virtually Delivered Treatment to Optimize Smoking Cessation "PROJECT NARRATIVE Smoking is a significant public health problem that results in over 480000 premature deaths in the USeach year. While many smokers attempt to quit annually most relapse to smoking within a year meaning thatthere is a critical need for better treatments. The objective of this proposal is to estimate the effects of differentmedication treatment strategies used for both initial smoking cessation and for ""rescue therapy"" among thosewho fail to quit or relapse to smoking which may lead to more personalized smoking cessation treatments." NCI 10797577 12/20/23 0:00 PAR-21-035 1R01CA278938-01A1 1 R01 CA 278938 1 A1 "CICCOLO, JOSEPH THOMAS" 1/1/24 0:00 12/31/28 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 1864476 "CINCIRIPINI, PAUL MICHAEL" "ROBINSON, JASON D" 9 PSYCHOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 923199 NCI 578780 344419 PROJECT SUMMARY There is a critical need for treatment approaches that conveniently deliver evidence-based interventions ofcounseling and pharmacotherapy to a wide range of smokers and address the complex timeline of cessationattempt failure and re-attempt. The objective of this proposal is to identify the best individualizedpharmacological treatment strategies used for both initial smoking cessation and for rescue therapy amongthose who fail to quit or relapse. The trial will use a SMART design (Sequential Multiple AssignmentRandomized Trial) to estimate the comparative effectiveness of (1) an initial 6-week course of either standarddose varenicline or dual nicotine replacement (our two best performing pharmacotherapies) and (2) amongthose smokers who initially fail to quit after the first 6 weeks to estimate the effects of either continuing onsame medication for another 6 weeks switching to the medication they did not receive initially or augmentingcurrent pharmacotherapy by increasing the dose or adding additional FDA-approved cessation medications. Alltreatments will occur via a virtual delivery method ensuring the widest possible application with the fewestbarriers and will include both dynamic pharmacotherapy and counseling delivered in a unified environment toenhance uptake effectiveness and patient experience. The proposed trial will include 2000 adult participantsfrom throughout Texas who are seeking to quit smoking. Participants will be initially randomly assigned to oneof our two best-performing smoking cessation treatments either dual nicotine replacement therapy (NRT;nicotine patch plus lozenge) or varenicline (2 mg/twice daily). After 6 weeks smoking abstainers will remain ontheir current treatment and non-abstainers will be re-randomized to either (a) switch therapies (i.e. receive thetreatment not given in the first 6 weeks) (b) augment their current therapy (change dosage and/or add othermedications e.g. bupropion) or (c) continue the same medication for 6 more weeks. The treatments willfunction as comparators with each other at the selected timepoints specific to each treatment phase. Ourprimary outcomes will be biochemically verified (carbon monoxide <6 ppm) continuous smoking abstinence atWeek 6 and at end-of-treatment (EOT) + 30 days. Our secondary outcomes include 6-month abstinence andwithdrawal craving positive and negative affect and depressive symptoms (anhedonia) Week 6 and at end-of-treatment (EOT) + 30 days. Our results will inform the patient-provider discussion on the optimal treatmentapproach of the future dissemination of our findings. This addresses a critical gap in treating nicotinedependence because while the majority of smokers relapse within two weeks of an initial cessation attemptthere is little empirical evidence to guide clinicians or patients on the best subsequent treatment to enhance thelikelihood of cessation. Our study sample will be representative of the general population of smokers drawingvolunteers from diverse community sources as well from disadvantaged populations (Medicaid eligible ruraland uninsured). 923199 +No NIH Category available 3-Dimensional;ATP phosphohydrolase;Administrative Supplement;Antibodies;Architecture;Area;Award;BMI1 gene;Binding;Binding Proteins;Biological;Biological Assay;Biological Models;Biology;Budgets;CRISPR/Cas technology;Cell Line;Cell model;ChIP-seq;Chemicals;Childhood;Chromatin;Chromatin Remodeling Factor;Clinical;Collaborations;Complex;Computer Analysis;Cryoelectron Microscopy;DNA;Data;Data Collection;Development;Disease;EWS-FLI1 fusion protein;Equilibrium;Funding;Fusion Oncogene Proteins;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic study;Genomics;Goals;Histones;Human;Institution;Knowledge;Laboratories;Lesion;Link;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Methods;Mission;Molecular;Mutate;Mutation;Nature;Nucleosomes;Oncogenic;PRC1 Protein;Parents;Pathway interactions;Preparation;Process;Productivity;Protein Biochemistry;Proteins;Regulation;Research;Research Project Grants;Role;Running;Series;Site;Structure;Testing;Therapeutic;Time;Work;cancer type;combat;cost;experimental study;falls;fitness;genome-wide;genomic profiles;histone modification;inhibitor;interdisciplinary approach;lethal factor;meetings;member;multidisciplinary;novel;novel therapeutic intervention;novel therapeutics;permissiveness;programs;protein complex;screening;soft tissue;spatiotemporal;structural biology;synovial sarcoma;targeted treatment;therapeutic development;therapeutic target;three dimensional structure The Center for Synovial Sarcoma Biology and Therapeutics Project NarrativeThis section is unchanged from the U54 CA231638 parent award.Synovial sarcoma is a highly aggressive soft-tissue cancer for which there exist no effective targetedtherapeutic approaches despite the pathognomonic genomically well-defined molecular lesion hallmark toevery case: the SS18-SSX fusion. Understanding the function of the SS18-SSX fusion in the context of themacromolecular machine to which it binds and hijacks as well as the features of the chromatin landscapewhich are uniquely permissive of these activities represent the most critical next steps and are atpresent major barriers to therapeutic progress. Our Center on Synovial Sarcoma Biology and Therapeuticsseeks to challenge existing paradigms efficiently define the underlying biology and to present the field withnovel highly-specific targeted therapeutics to combat this aggressive and devastating disease.Project Narrative Page 70 NCI 10797558 4/12/23 0:00 PA-20-272 3U54CA231638-01S3 3 U54 CA 231638 1 S3 "WITKIN, KEREN L" 4/1/23 0:00 6/30/24 0:00 11672745 "KADOCH, CIGALL " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 4/1/23 0:00 6/30/24 0:00 353 Research Centers 2023 200000 NCI 112360 87640 Project Summary/AbstractThis section is unchanged from the U54 CA231638 parent award.The overarching goal of this FusOnC2 Center for Synovial Sarcoma Biology and Therapeutics is to developand execute a comprehensive multidisciplinary set of approaches rooted in protein biochemistry andstructural biology to define the mechanistic underpinnings of synovial sarcoma and unmask opportunities fortherapeutic development. This Centers mission is tightly aligned with that of the larger Consortium on FusionOncoproteins in Childhood Cancers as well as the goals of the Beau Biden Cancer Moonshot Initiative. Indeedowing in part to our groups recent findings surrounding the discovery of SS18-SSX as a stable and integratedmember of the mammalian SWI/SNF (BAF) chromatin remodeling complex a major impetus for thedevelopment of this Consortium has been the growing knowledge that pediatric fusion oncoproteins thatare pathognomonic for specific cancer types often function via disruption of the structure and/or activity ofprotein complexes that govern chromatin architecture and hence gene control. We have shown that at leasttwo of the fusion oncoproteins highlighted as major areas of emphasis within the Consortium SS18-SSXand EWS-FLI1 act specifically through BAF complexes to drive their cancer-specific oncogenic geneexpression patterns. Study of multimeric BAF complexes and their functions structure and interactions arefurther suggested by genetic studies across human cancer types which have indicated that among allchromatin remodeling complexes genes encoding mSWI/SNF complex subunits are among the mostfrequently mutated at over 20% of all human cancers.Here we present a multi-institutional highly collaborative and multidisciplinary approach to comprehensivelyinterrogate biologic mechanisms underpinning the function of the SS18-SSX oncogenic fusion in synovialsarcoma and to use each of these approaches and the results generated to launch targeted therapeuticdiscovery campaigns that are directly linked to the mechanisms identified. Specifically our approachencompasses three major areas: (1) BAF complex targeting gene regulation and chromatin state; (2)Understanding the role of the wild-type SS18 protein in the context of the SS18-SSX fusion its protein-levelregulation and mechanisms by which its stabilization can be exploited for therapeutic benefit; (3) Usinggenome-scale genetic perturbation strategies to discover and mechanistically characterize SS-specificvulnerabilities especially those in chromatin-bound protein complexes and related pathways. As a Centerthe unique expertise of each PI and the highly integrative nature of the research projects cores andcollaborators provide the strongest possible likelihood that the aims will be successfully achieved and thatnovel therapeutic strategies will emerge from this Center.Project Summary/Abstract Page 69 200000 +No NIH Category available Alleles;Biological Models;Cancer Biology;Cell Cycle;Cell Cycle Checkpoint;Cell Death;Cells;Chromosomes;DNA Damage;DNA biosynthesis;DNA metabolism;Dependence;Dihydroorotate Dehydrogenase Inhibitor;Embryo;Endometrial Carcinoma;Exhibits;FDA approved;Fiber;Fibroblasts;Glioblastoma;Glutamine;Goals;Growth;Knowledge;Label;Leflunomide;Length;Lipids;LoxP-flanked allele;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Molecular;Mus;Mutate;Normal tissue morphology;Nucleotide Metabolism Pathway;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphatidylinositols;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiologic pulse;Proliferating;Proteins;Proto-Oncogene Proteins c-akt;Pyrimidine;Regulation;Research;Role;S phase;Second Messenger Systems;Signal Pathway;Signal Transduction;Solid Neoplasm;Specificity;Therapeutic;Thymidine;Tumor Suppressor Proteins;Visualization;Work;analog;cancer cell;design;inorganic phosphate;live cell imaging;malignant breast neoplasm;nucleotide metabolism;pharmacologic;replication stress;response;targeted treatment;tumor The role of PTEN in DNA metabolism and replication Research NarrativePTEN is one of the most frequently lost or mutated tumor suppressors in cancer commonly lost in endometrialcancer glioblastoma breast cancer and prostate cancer; and work in our lab has implicated PTEN in cellsignaling and DNA metabolism and replication. In this project we will investigate how the loss of PTENexpression sensitizes cells to inhibition of DNA metabolism and we will characterize the impact of PTEN losson DNA replication dynamics. This project would further the understanding of the mechanism of action in cancerof FDA-approved medications and further the understanding of the basic mechanisms of how tumor suppressorsavoid growth suppression in cancer. NCI 10797177 4/11/23 0:00 PA-20-272 3F31CA243201-03S1 3 F31 CA 243201 3 S1 "ODEH, HANA M" 3/1/23 0:00 8/11/23 0:00 11895030 "LUBIN, ABIGAIL ROSE" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 3/1/23 0:00 8/11/23 0:00 398 "Training, Individual" 2023 23047 NCI 23047 0 RESEARCH SUMMARYThe goal of this project is to understand the role of PTEN in DNA metabolism and replication. Phosphatase andtensin homolog deleted on chromosome ten (PTEN) is one of the most frequently lost or mutated tumorsuppressors in cancer commonly lost in endometrial cancer glioblastoma breast cancer and prostate cancer.PTEN is a dual-specificity phosphatase whose main substrate is the lipid second messengerphosphatidylinositol-345-trisphosphate (PIP3) and PTEN activity negatively regulates the phosphoinositide 3-kinase (PI3K)/AKT growth signaling pathway. Work in our lab and others has shown that the deletion of bothalleles of PTEN causes increased growth rate and proliferation in a variety of normal tissues including in primarymouse embryonic fibroblasts (MEFs). Additionally we have demonstrated a glutamine dependency anincreased glutamine flux into de novo pyrimidine synthesis and an increased sensitivity to pharmacologicinhibition of de novo pyrimidine synthesis in primary Pten/ MEFs. We propose that these results implicate thenucleotide metabolism the cell cycle and DNA replication as potential avenues through which the loss of PTENcould contribute to deregulated growth. We posit to explore these pathways using primary Ptenflox/flox MEFs as amodel system.In Aim 1 we will investigate how the loss of PTEN expression sensitizes cells to inhibition of de novo pyrimidinesynthesis through altered cell cycle dynamics. To investigate the molecular basis of this sensitivity we willexamine DNA damage and replication stress cell death and cell cycle checkpoint activation after pharmacologicinhibition of de novo pyrimidine synthesis in primary Pten/ MEFs. Given the potential use of leflunomide forpatients with PTEN-deficient tumors a comprehensive understanding of the cellular consequences ofleflunomide treatment in the context of PTEN loss will enable more effective use.In Aim 2 we will characterize the impact of PTEN loss on the duration of S phase and DNA replication efficiency.To determine the length of S phase in primary Pten/ MEFs we will use two experimental methods that allowfor the determination of S phase length: dual-pulse DNA replication labeling with thymidine analogs and live cellimaging in combination with fluorescent-labeled cell cycle-specific proteins. To investigate DNA replicationefficiency we will perform fiber combing to directly visualize replicating DNA. Knowledge of the mechanismbehind altered replication dynamics in the context of PTEN loss would contribute to the basic understanding ofthe mechanisms of evading growth regulation in cancer cells. 23047 +No NIH Category available OVERCOMING STROMAL BARRIERS TO THERAPEUTICS IN PANCREAS CANCER PROJECT NARRATIVEPancreas cancer kills essentially every patient it afflicts and with a rising incidence and unabatedmortality it is now the third leading cause of cancer-related deaths in this country. We have developedgenetically engineered animal models of pancreas cancer that have exposed unique points ofvulnerability for the development of new treatments. We propose a systematic program of investigationto target distinct components of the stromal reaction in pancreas cancer as the basis for new treatmentstrategies against this highly resistant disease. NCI 10796681 6/22/23 0:00 PA-21-268 7R01CA161112-13 7 R01 CA 161112 13 "FORRY, SUZANNE L" 8/11/22 0:00 5/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 1926329 "HINGORANI, SUNIL R" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 3/1/23 0:00 5/31/23 0:00 395 Non-SBIR/STTR 2022 322912 NCI 233218 89694 PROJECT SUMMARYPancreatic ductal adenocarcinomas (PDA) are unrivaled in their lethality. PDAs have the highest 1-year 5-year and 10-year mortalities of any cancer and are expected to become the second-leadingcause of cancer-related death by 2030. An invasive PDA represents the coordinated evolution of cell-intrinsic and extrinsic processes and capabilities that subvert and repurpose the dictums of normaltissue composition architecture and physiology to foster unbridled growth and colonization. This neworganizational entity is constructed largely at the behest of the mutated epithelial cell. The resultingPDA neo-organ contains a minority of tumor epithelial cells amidst a heterogeneous sea of non-epithelial cells; a complex interstitial stew of proteins proteoglycans and glycosaminoglycans togetherwith both freely mobile and complexed water; and a paucity of vessels that otherwise resemble anormal vasculature in lacking fenestrae or interendothelial junctions but that are collapsed underintense interstitial pressures. We have undertaken a systematic exploration of the cell autonomous andnon-cell autonomous processes that drive PDA pathogenesis and resistance. We have developedgenetically engineered animal models that faithfully recapitulate the clinical syndrome metastaticbehavior histopathology and molecular features of the human disease as primary platforms to bothuncover critical principles of disease biology and to rigorously test strategies to overcome them.Through such investigations we have identified unusually high concentrations of intratumoralhyaluronan (HA) as the primary culprit in the extraordinarily elevated interstitial pressures in PDA thatin turn cause the vascular collapse and hypoperfusion characteristic of this disease. The stromalbarrier to perfusion also serves as a primary mechanism of drug resistance in limiting the penetration ofsystemically delivered agents. We have additionally identified multiple mechanisms of immunesuppression that prevent the development of an endogenous effector T cell response. Collectivelythese unique aspects of stromal biology in PDA conspire to create a drug- and immune-privilegedsanctuary for unimpeded growth of the pancreas cancer cell. Very recently we have elaboratedstrategies to overcome critical aspects of these physical and immunological barriers to therapyrevealing a perhaps unexpected degree of vulnerability once the barriers are breached. We describe aseries of continuing investigations into this overarching strategy of stromal re-engineering to build uponthe significant inroads made and the important lessons learned in the hopes of radicallytransforming the approach and prognosis for this formidable disease. 322912 +No NIH Category available Affect;Aging;Animal Model;Area;Biological Models;Biology;Cell Proliferation;Cell model;Cells;Cellular biology;Computer Analysis;Computer Models;Defect;Dependence;Development;Diploid Cells;Diploidy;Disease;Event;Evolution;Frequencies;Gene Amplification;Genetic;Goals;Growth;Human;Image;In Vitro;Kinesin;Lethal Genes;Malignant Neoplasms;Methodology;Mitotic;Normal Cell;Pathologic;Phenotype;Play;Ploidies;Polyploid Cells;Proliferating;Role;Solid Neoplasm;Testing;Therapeutic;Tissues;cancer cell;design;human disease;human tissue;in vivo;innovation;insight;small molecule inhibitor;tumor;tumorigenesis;whole genome Mechanisms of cell proliferation in whole-genome doubled cells Unscheduled whole-genome doubling events give rise to genetically unstable polyploid cells that can promotedisease. The aims of this proposal are designed to identify unique the genetic adaptations acquired by polyploidcells that enable their sustained proliferation and survival. Successful completion of these aims will providesignificant insight into the genesis and evolution of whole genome-doubled cells in vivo as well as revealinnovative therapeutic avenues to selectively kill pathological polyploid cells while sparing the normal cells thatcomprise human tissue. NCI 10796612 9/15/23 0:00 PA-21-071 3R01CA274743-02S1 3 R01 CA 274743 2 S1 "WITKIN, KEREN L" 5/1/22 0:00 4/30/26 0:00 Special Emphasis Panel[ZRG1(02)-M] 8831758 "GANEM, NEIL J." Not Applicable 7 PHARMACOLOGY 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 9/1/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 66328 NCI 40199 26129 Unscheduled whole-genome doubling events (WGD) give rise to polyploid cells that are associated with humandisease. Most significantly WGD generates genetically unstable tetraploid cells that can fuel tumorigenesis.Recent computational analyses have revealed that nearly 40% of all solid tumors have undergone at least oneWGD often early in their development demonstrating that such events play significant roles in both the initiationand/or progression of human malignancies. Gaining a comprehensive understanding of the mechanisms throughwhich whole-genome doubled cells arise and promote tumorigenesis is therefore a critical albeit largelyunexplored area of cell biology. The goal of this proposal is to combine computational cell biological and animalmodel methodologies to test the overarching hypothesis that whole genome-doubled cells must acquire specificgenetic adaptations that enable them to tolerate the numerous defects imparted by doubled DNA content andthat these cells are therefore imparted with specific genetic dependencies that are not present in normal diploidcells (i.e. ploidy-specific lethality). These hypotheses will be tested in three specific aims. Aim 1: Use aninnovative approach to rapidly quantitate the frequency and underlying cause of WGD in different tissues in vivoand determine if this frequency is affected by aging. Aim 2: Validate KIF18A which encodes for a mitotic kinesinas a ploidy-specific lethal gene in vivo and use isogenic diploid/tetraploid cell models to perform an imaging-based phenotypic screen to identify small molecule inhibitors of KIF18A. Aim 3: Identify genetic aberrations (e.g.gene amplifications/deletions) that are significantly and specifically enriched in whole genome-doubled tumorsand mechanistically define how such alterations provide ploidy-specific growth advantages in vitro and in vivo.Successful completion of these aims will provide significant insight into the genesis biology and evolution ofwhole-genome doubled cells as well as potentially reveal new and innovative therapeutic avenues to selectivelykill whole-genome doubled cancer cells while sparing the normal healthy diploids from which they arose. 66328 +No NIH Category available Address;African American population;American Association of Cancer Research;American Cancer Society;Applications Grants;Area;Awareness;Biology;Cancer Control;Cancer Survivor;Cessation of life;Classification;Collaborations;Continuance of life;Country;Coupled;Data;Development;Diagnosis;Disease;Disparity;Distress;Early Diagnosis;Endometrial Carcinoma;Epidemiology;Etiology;Future;Genetic;Goals;Gynecologic Oncology;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Heterogeneity;High Risk Woman;Histologic;Incidence;Intake;Intervention;Knowledge;Lead;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Manuscripts;Methods;Michigan;Modeling;Molecular;Molecular Analysis;Molecular Biology;Molecular Epidemiology;Monitor;Morbidity - disease rate;Not Hispanic or Latino;Omega-3 Fatty Acids;Oncology;Outcome;Pap smear;Paper;Pathology;Population Heterogeneity;Prevention;Prognosis;Publishing;Quality of life;Research;Research Personnel;Risk Reduction;Seminal;Stage at Diagnosis;Survival Rate;The Cancer Genome Atlas;Time;Uterine Cancer;Uterine hemorrhage;Uterus;Woman;Work;anticancer research;black women;cancer risk;clinical practice;cohort;dietary;early detection biomarkers;genetic association;improved;insight;meetings;metabolomics;microbiome;mortality;multidisciplinary;novel;novel marker;patient population;racial disparity;risk prediction;survivorship;symposium;tumor;tumor DNA Approaches to Curtail Endometrial Cancer Incidence and Mortality PROJECT NARRATIVEEndometrial cancer is the most common gynecologic cancer among U.S. women and one of the few cancersthat continues to rise in incidence. As concerning are the stagnant survival rates and the large racialdisparities in survival after a diagnosis. This symposium will bring together experts in epidemiology molecularbiology pathology and gynecologic oncology along with endometrial cancer survivors to review the currentstate of knowledge and develop a list of priorities for future collaborative research. NCI 10796487 4/5/23 0:00 PA-21-268 7R13CA250188-02 7 R13 CA 250188 2 "MECHANIC, LEAH E" 7/1/20 0:00 4/30/23 0:00 ZCA1-PCRB-C(J1) 10977616 "DU, MENGMENG " "COTE, MICHELE L" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 3/1/23 0:00 4/30/23 0:00 393 Other Research-Related 2023 27000 NCI 27000 0 ABSTRACTEndometrial cancer incidence rates continue to rise and it is the most common gynecologic cancer amongwomen in the US. Distressingly unlike most other cancers the survival rates have been stagnant over the lastseveral decades. There is a significant racial disparity in survival with non-Hispanic black women having thepoorest outcomes regardless of stage at diagnosis or histologic subtype. The reasons for this disparity as wellas other gaps in knowledge such as approaches to monitor high risk women or understanding survivorshipissues stand in the way of reducing the burden of endometrial cancer. This symposium will bring togetherexperts from the fields of epidemiology biology pathology oncology genetics and clinical practice toexchange knowledge and ideas. The discussions generated at and from this symposium will guide research toreduce incidence morbidity and mortality from this disease.We plan a two-day symposium to be held in Detroit Michigan in June 2020. There will be seven sessions onspecific topics each with three to four speakers and a discussion leader. At the end of the second day therewill be group discussion sessions to develop priorities for future research that will identify the researchinitiatives that will have the greatest impact on reducing risk and improving survival from this common disease. 27000 +No NIH Category available Acceleration;Address;Advisory Committees;Algorithms;Automobile Driving;Award;Behavior;Bioinformatics;Biological;Biology;CRISPR screen;Cancer Biology;Catalogs;Cells;Chromatin;Chromosomal Duplication;Chromosomes;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Computer software;Computing Methodologies;DNA amplification;DNA-Protein Interaction;Data;Data Set;Development;Drug Targeting;Drug resistance;Engineering;Environment;Epigenetic Process;Evolution;Exhibits;Foundations;Future;Gene Expression;Genetic;Genetic study;Goals;Heterogeneity;Immune Evasion;Individual;Learning;Malignant Neoplasms;Mediating;Mentorship;Methylation;Mitosis;Modeling;Molecular;Molecular Profiling;Mutation;Neoplasm Metastasis;Oncogenes;Phase;Population;Process;Proliferating;Property;Recording of previous events;Research;Resolution;Science;Solid;Techniques;Technology;Time;Training;Universities;Work;acquired drug resistance;cancer cell;computerized tools;effective therapy;epigenomics;extrachromosomal DNA;fitness;improved;innovation;insight;intermolecular interaction;multiple omics;novel therapeutic intervention;patient stratification;response;segregation;single molecule;spatiotemporal;stem;targeted treatment;tool;training opportunity;training project;treatment strategy;tumor;tumor progression Quantitative modeling of extrachromosomal DNA (ecDNA) evolution in tumors Tumor evolution is often the cause of outstanding clinical challenges such as acquired drug resistance andmetastasis. Recent work has demonstrated that oncogene amplification on extrachromosomal DNA (ecDNA) isa major driver of tumor evolution but remains difficult to study due to its elusive evolutionary dynamics andsubstantial variability. This project proposes the development of innovative new computational tools that willilluminate ecDNA heterogeneity and evolution at unparalleled resolution which will in turn be used to nominatenew therapeutic strategies that target ecDNA-mediated tumor evolution. NCI 10796251 12/26/23 0:00 RFA-CA-22-035 1K99CA286968-01 1 K99 CA 286968 1 "RADAEV, SERGEY" 1/1/24 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 15204085 "JONES, MATTHEW GREGORY" Not Applicable 16 DERMATOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 Other Research-Related 2024 167508 NCI 155100 12408 Project Summary. Cancer is governed by evolutionary principles whereby sequential changes at the geneticand epigenetic level enable proliferation immune evasion drug resistance and metastasis. An outstanding goalin cancer biology is to understand the spatiotemporal processes underpinning this evolution. To do so wouldgreatly improve our ability to create more effective treatment strategies and forecast tumor development far intothe future. However this goal remains elusive due to our incomplete catalog of molecular processes drivingevolution and lack of molecular and computational tools for holistically profiling tumors. One emerging driver is extrachromosomal DNA (ecDNA). Found in approximately half of cancers andstrongly associated with poor survival ecDNAs are a unique form of oncogene amplification: they reside outsideof chromosomes and exhibit elevated copy-number gene expression and chromatin accessibility as comparedto chromosomal amplifications. New evidence has underscored the importance of ecDNA dynamics andheterogeneity in driving tumor progression: first ecDNAs asymmetrically segregate during mitosis leading toaccelerated copy-number gains and rapid adaptation to stressful conditions. Second several varieties ofecDNAs can exist in single cells where they form cooperative intermolecular hubs. Despite this appreciationthese features of ecDNA have remained elusive to study due to a scarcity of tools for profiling their vastheterogeneity and stochastic evolutionary dynamics. In this project I will develop the requisite computationaltools for profiling ecDNA variability and evolution in cancer and use these tools to more thoroughly investigatehow ecDNA heterogeneity is created maintained and leveraged in response to targeted therapies. First I willbuild on breakthroughs in long-read sequencing to develop tools that enable unbiased multi-omic profiling ofecDNA variability across biological conditions (Aim 1). Second I will leverage new molecular techniques to inferthe phylodynamic properties of ecDNA lineages and learn the molecular fitness landscape of ecDNA (Aim 2).Third I will explore the co-evolutionary principles of ecDNA by combining evolutionary modeling and CRISPR-based screens (Aim 3). Together these studies will illuminate properties of ecDNA evolution nominate newtherapeutic strategies and provide innovative computational tools for the greater scientific community. This work will be performed in the excellent training environment of Stanford University under thementorship of Dr. Howard Chang an expert in epigenomics and ecDNA. An advisory committee of leaders inthe fields of ecDNA cancer biology bioinformatics and tumor evolution will provide additional expertise andmentorship. The first half of each aim will be completed predominantly during the K99 phase of the awardproviding a solid foundation for the aims in the R00 phase and eventually an independent R01 application. 167508 +No NIH Category available Acids;Antibody Therapy;Antigen Presentation;Antigen-Presenting Cells;Attenuated;Binding;Biological Markers;Breast Cancer Patient;Breast Cancer Prevention;Breast Cancer Treatment;Breast cancer metastasis;Cancer Patient;Collaborations;Combination immunotherapy;Communities;Complex;Cyclic AMP-Dependent Protein Kinases;Data;Dependence;Development;Diagnosis;Disease;Down-Regulation;Duct (organ) structure;Effectiveness;Environment;Event;Exhibits;FDA approved;Formulation;Future;Genetic;Genetic Transcription;Goals;HIF1A gene;Human;Immune checkpoint inhibitor;Immunologic Surveillance;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;Infiltration;Kinetics;Knock-in;Link;Major Histocompatibility Complex;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Mediating;Metabolic;Metastatic Neoplasm to the Lung;Molecular;Morbidity - disease rate;Morphology;Mouse Mammary Tumor Virus;Mus;Neoplasm Metastasis;Oncogenes;Oncogenic;Outcome;PD-1/PD-L1;PD-L1 blockade;Pathway interactions;Patient-Focused Outcomes;Patient-derived xenograft models of breast cancer;Patients;Peptides;Play;Process;Prognosis;Prognostic Marker;Proto-Oncogene Proteins c-akt;RNA;Research;Resistance;Role;Signal Pathway;Signal Transduction;Site;T cell infiltration;Therapeutic;Tissues;Toxic effect;Transgenic Mice;Treatment Efficacy;Tumor Suppressor Proteins;Ubiquitination;Untranslated RNA;Work;anti-PD-1;anti-PD1 antibodies;anticancer research;cancer clinical trial;cancer initiation;cancer risk;clinical effect;combinatorial;cytotoxic CD8 T cells;diagnostic biomarker;immune checkpoint blockers;immune resistance;improved;in vivo;inhibitor;innovation;malignant breast neoplasm;mortality;mouse genome;novel;patient stratification;predictive marker;prevent;programmed cell death ligand 1;protein degradation;response;restoration;targeted treatment;therapeutic RNA;therapeutic target;tool;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor initiation;tumor progression;tumorigenesis;ubiquitin-protein ligase Development of Long non-coding RNA-directed Target Therapy for Triple-Negative Breast Cancer Project NarrativeTriple-negative breast cancer (TNBC) remains as the only subtype of breast cancer without a targeted therapywith less than 20% response rate upon anti-PD1/PD-L1 blockage demanding characterization of biomarkersand molecular mechanisms of immunoresistance by which long non-coding RNAs (lncRNA) show promise. Ourpreliminary data indicated the correlation of lncRNAs and the resistance of TNBC patients upon anti-PD-1antibody treatment and demonstrated the lncRNA-dependent antigenicity loss during mammary gland tumorinitiation and progression with genetic evidence. The proposed study will dissect the underlying molecularmechanism of lncRNA-dependence antigenicity loss and determine that targeting lncRNAs restores antigenicityto prevent the tumor initiation and further sensitizing TNBC tumors upon immunotherapy. NCI 10796215 6/1/23 0:00 PA-18-484 3R01CA231011-05S1 3 R01 CA 231011 5 S1 "FINGERMAN, IAN M" 3/1/19 0:00 2/29/24 0:00 Tumor Cell Biology Study Section[TCB] 10941578 "LIN, CHUNRU " Not Applicable 9 MICROBIOLOGY/IMMUN/VIROLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 353 Non-SBIR/STTR 2023 361866 NCI 249580 112286 Project Summary As a deadly disease lacking an FDA-approved targeted therapy triple-negative breast cancer (TNBC)involves a complicated and entangled network of oncogenic processes in which long non-coding RNAs(lncRNAs) a novel class of regulatory RNA molecules may play important roles. The proposed study willgenetically exploit lncRNA-regulated cellular networks in TNBC to identify an improved therapeutic strategy. Ourresearch has illuminated lncRNA involvement in TNBC metastasis and metabolic reprogramming. OnelncRNA LINK-A is upregulated in TNBC and is negatively correlated with breast cancer patient outcomes.Tissue-specific expression of LINK-A in mouse mammary glands drives tumor development and lung metastasiswhich shares morphological and transcriptional similarity to human TNBC. Furthermore the expression of LINK-A facilities an immunosuppressive environment and profoundly impacts CD9+ T-cell infiltration via lncRNA-mediated antigenicity loss. Mechanistically LINK-A concurrently activates multiple oncogenic signalingpathways and promotes TRIM71-dependent degradation of the peptide-loading complex leading to impairedantigen presentation. Therefore LINK-A transgenic mice should serve as a powerful tool for dissecting themolecular complexity of TNBC and assessing precise therapeutic formulations against TNBC. Since mostpathway inhibitors in TNBC clinical trials have been unsuccessful a lncRNA-directed therapeutic approach withthe appropriate combination of immunotherapy may optimize the efficacy of therapies for TNBC.The long-term goal of the proposal is to demonstrate the molecular mechanisms of lncRNA-mediated antigenicityloss and immunosuppression so that improved strategies can be developed to reduce TNBC morbidity andmortality. Our central hypothesis is that LINK-A promotes the initiation and immunoresistance of breast cancerwhich can be attenuated in vivo by a combinatorial treatment approach. We will address our hypothesis fromfollowing aspects: we will first define the underlying molecular mechanism of lncRNA-dependent antigenicityloss. We will then restore antigenicity by targeting lncRNA and lncRNA-related signaling events. Finally we willascertain the functional importance of lncRNAs in breast cancer tumorigenesis.Emerging evidence of the oncogenic involvement of lncRNAs as well as their implicated roles in mediatingimmunosurveillance and immunosuppression warrants further characterization of TNBC-specific lncRNAs andfuture applications that hinge on their activity. Our goal is to demonstrate that LINK-A as a hallmark of TNBCmay serve as a diagnostic marker that predicts a cancers sensitivity to immunotherapy. Thus a strategy thatcombines immune checkpoint blockers and lncRNA-based therapeutic strategies has the potential to significantlyadvance TNBC treatment. In the long run these research findings will benefit the cancer community byintroducing the robust clinical effects of targeting lncRNAs and a well-defined means of stratifying patients basedon these oncogenic lncRNAs. 361866 +No NIH Category available Acceleration;Address;Adopted;Bioconductor;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Catalogs;Characteristics;Collaborations;Communities;Comprehension;Computer software;Data;Data Analyses;Data Coordinating Center;Data Science;Databases;Development;Ecosystem;Ensure;Fostering;Funding;Goals;Hand;Immune Targeting;Immunooncology;Immunotherapy;Informatics;Information Technology;Infrastructure;Intercept;Malignant Neoplasms;Methods;Molecular Target;Multiomic Data;National Human Genome Research Institute;Oncogenic;Police;Policies;Principal Investigator;Process;Productivity;PubMed;Records;Reproducibility;Research;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Resources;Risk;Services;Text;United States National Institutes of Health;Visualization;biomedical informatics;cancer prevention;central database;cloud based;community engagement;data acquisition;data ecosystem;data harmonization;data integration;data management;data sharing;data sharing networks;data standards;design;experience;genomic data;high risk population;improved;innovation;interest;interoperability;multidisciplinary;open source;operation;outreach;pre-clinical;precision cancer prevention;prevent;programs;quality assurance;response;support network;targeted agent;therapy resistant;tool;translational oncology;translational study;tumor progression;virtual Data and Resource Coordination Center for Cancer Prevention-Interception Targeted Agent Discovery Program Project NarrativeTo close the gap in discovering and bringing risk-tailored targeted agents to the higher-risk populations for cancerprevention and interception will require collaborative efforts to identify potentially exploitable oncotargetsvalidate their oncogenic characteristics discover innovative targeted agents and advance promising efficaciousagents for further development. The goal of our proposed Data and Resource Coordinating Center (DRCC)application is to coordinate the activities across the Cancer Prevention-Interception Targeted Agent DiscoveryProgram (CAP-IT) and to manage integrate and disseminate the data and resources generated through thenetwork. Leveraging cutting-edge multi-disciplinary team approaches we will support the CAP-IT to discovermolecularly or immunologically targeted agents designed to prevent or intercept the oncogenic process forprecision cancer prevention and interception. NCI 10796105 9/14/23 0:00 PA-20-272 3U24CA274159-02S1 3 U24 CA 274159 2 S1 "SAID, RABIH" 9/1/22 0:00 8/31/27 0:00 ZCA1(M1) 6773960 "HUTSON, ALAN DAVID" "LIU, SONG " 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Other Research-Related 2023 771165 NCI 451871 319294 Project Summary/Abstract: This application is being submitted in response to the Notice of SpecialInterest (NOSI) identified as NOT-CA-23-012. The goal of our proposed Data and Resource Coordinating Center(DRCC) application is to coordinate the activities across the Cancer Prevention-Interception Targeted AgentDiscovery Program (CAP-IT) and to manage integrate and disseminate the data and resources generatedthrough the network. Leveraging cutting-edge multi-disciplinary team approaches we will support the CAP-IT todiscover molecularly or immunologically targeted agents designed to prevent or intercept the oncogenic processfor precision cancer prevention and interception. Our strategy is to enhance the productivity of CAP-ITinvestigators by fostering a collaborative and synergistic research community accelerate the progress of CAP-IT research by reducing barriers to accessing analytics expertise ensure the reproducibility of CAP-IT data bydeploying best practices for data acquisition and harmonization and unleash the full potential of CAP-IT activitiesby developing enhanced tools to enable resource sharing to the broader scientific community. First we will provide a centralized administrative infrastructure to coordinate CAP-IT activities buildingupon our well-functioning infrastructure that currently coordinates network studies under the umbrella of the NCICancer Moonshot initiatives. Second we will actively promote the CAP-IT and engage in trans-consortiuminteractions where we will leverage our demonstrable experience in Cross-Moonshot outreach andBioconductors decades-long record in community engagement. Third we will in coordination with each CAP-IT centers informatics group provide multidisciplinary analytics expertise to support CAP-ITs collaborativeresearch leveraging three of Roswell Park CCSGs shared resources: Biostatistics Bioinformatics BiomedicalInformatics. Fourth we will develop improved data integration and analysis software database and workflows toenhance CAP-ITs research capacity capitalizing on our extensive track-record in developing NIH-supportedCancer Moonshot Bioconductor and AnVIL ecosystems. Taken together we envision that our DRCC in closecollaboration with the CAP-IT U54 Centers and NCI staffs will allow us to support highly effective and innovativetranslational studies to address the significantly unmet needs related to precision cancer prevention-interception. The main deliverables from the proposed aims will be administrative and outreach support to coordinatenetwork activities facilitate network collaboration and engage in interaction with the broader community (Aim1); workflows to ensure that all data generated by the CAP-IT will be harmonized using standards interoperablewith the broader cancer data ecosystem analysis tools and database to integrate CAP-IT data and facilitatecross-study analysis and multidisciplinary analytics supports to accelerate CAP-IT research progress (Aim 2);polices and infrastructures to ensure that all resources generated by the CAP-IT will be findable in a centralizedvirtual information hub and that all resources will be shared with the broader scientific community (Aim 3). 771165 +No NIH Category available Address;Affect;Antibody-drug conjugates;Attention;Biosensor;Cancer Histology;Cancer Patient;Categories;Cells;Chemotherapy and/or radiation;Clinical;Cytotoxic Chemotherapy;DNA Damage;DNA Repair;Data;Diagnosis;Drug Delivery Systems;Drug Sensitization;Drug usage;Family;Foundations;Frustration;Goals;Heterogeneity;Human;Ionizing radiation;Label;Link;MEKs;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mus;Nonmetastatic;Normal tissue morphology;Oncogenes;Organ;Pathway interactions;Patient-Focused Outcomes;Patients;Penetration;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Process;Prodrugs;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Resistance;Role;Schedule;Serine;Signal Pathway;Signal Transduction;Techniques;Technology;Testing;Therapeutic;Therapeutic Index;Toxic effect;Translating;Treatment Efficacy;Tumor Cell Line;Tumor Tissue;Unresectable;Work;biomarker driven;cancer cell;cancer survival;cancer therapy;cell killing;chemotherapy;clinical translation;clinically relevant;curative treatments;cytotoxic;delivery vehicle;extracellular;flexibility;genetic approach;homologous recombination;improved;improved outcome;inhibitor;innovation;insight;kinase inhibitor;molecular targeted therapies;neoplastic cell;novel;novel therapeutics;p21 activated kinase;p21-activated kinase 1;patient derived xenograft model;peptide drug;pharmacologic;radiation resistance;radioresistant;response;side effect;small molecule;subcutaneous;tool;tumor;tumor microenvironment;tumor xenograft;tumorigenesis;tumorigenic Elucidation and therapeutic exploitation of PAK mediated radioresistance PROJECT NARRATIVEUnderstanding how tumors respond to radiotherapy is critical to producing new molecularly targeted treatmentsthat overcome radiation resistance and improve survival for cancer patients. Based on our preliminary data wepredict that p21 activated kinases cause resistance to radiotherapy and that by targeting these kinases we cansensitize tumors to radiotherapy. In this proposal we will investigate the mechanisms though which p21activated kinases produce resistance to radiotherapy which will allow us to develop biomarker driven treatmentapproaches to increase radiotherapy's ability to destroy tumors while decreasing side effects. NCI 10795910 11/13/23 0:00 PA-16-160 5R37CA215081-07 5 R37 CA 215081 7 "PRASANNA, PAT G" 12/18/17 0:00 11/30/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11182831 "ADVANI, SUNIL J" Not Applicable 50 RADIATION-DIAGNOSTIC/ONCOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 325283 NCI 205875 119408 PROJECT SUMMARY/ABSTRACTTumor resistance to radiotherapy remains a critical barrier to improving outcomes for patients diagnosed withlocally advanced unresectable cancers. Cellular sensitivity to ionizing radiation (IR) is governed by intracellularand extracellular factors. To overcome tumor radioresistance drugs that sensitize tumor cells to ionizingradiation (IR) are used. Non-targeted cytotoxic chemotherapies given concurrently with radiotherapy havedemonstrated improved tumor control and overall survival in cancer patients. However since this paradigmshifting approach occurred in the 1980's there has been a shocking lack of progress in developing molecularlytargeted radiosensitization approaches. Improving the therapeutic ratio of IR in combination with systemicallydelivered drugs can be achieved by two general approaches 1) using drugs that block DNA damage repairresponses 2) delivering radiosensitizing drugs selectively to tumors. These two methods are orthogonaltechniques to achieve the same end goal of increasing IR induced tumor kill while reducing normal tissuetoxicities. To address both of these fundamental cancer therapy problems we have focused on targetdiscovery and tumor selective drug delivery vehicles. With regards to target discovery our recent studies onnon-canonical CRAF functions led to our discovery of an unexpected role for PAK in DNA damage repair andsensitivity to IR. PAK is comprised of a family of six kinases subdivided in Group I and II. Importantly PAK areinvolved in process central to oncogenesis tumor aggressiveness and patient survival. To tackle tumorselective drug delivery we are developing drug conjugated activatable cell penetrating peptides (ACPP) toselectively deliver potent radiosensitizers to tumors based on extracellular tumor protease activity. ACPPconsist of a drug conjugated polycationic cell penetrating peptide and an autoinhibitory polyanionic peptideseparated from each other by a flexible peptide linker. This peptide linker is specifically cleaved by proteasesenriched in the extracellular tumor microenvironment. While ACPP is intact the drug conjugated cellpenetrating peptide is neutralized (i.e. held in a pro-drug state) by the polyanionic peptide so that the drugcannot gain access to its intracellular target. Tumor microenvironment proteases cleave ACPP and release thedrug conjugated cell penetrating peptide which is then taken up by tumor cells. The goals of our proposal areto gain insight into how PAK governs radioresistance and then therapeutically exploit this with targeted PAKinhibitors. In Aim 1 we will genetically determine the mechanisms through which Group I and II PAKs governIR resistance. In Aim 2 we will pharmacologically test the ability to radiosensitize tumors with small moleculePAK inhibitors. In Aim 3 we will test if tumor targeted ACPP increase the therapeutic ratio of conjugated PAKinhibitors. Our approach has complementary innovations in both DNA damage target discovery and tumorselective drug delivery. Combining these approaches will lay a foundation for moving away from non-targetedcytotoxic radiosensitization to biomarker driven molecularly guided radiosensitization. 325283 +No NIH Category available Age;Cancer Center;Community Clinical Oncology Program;Data;Division of Cancer Prevention;Ethnic Population;Genomics;Histologic;Malignant Neoplasms;Minority Groups;Molecular;Research;Risk;Services;biobank;cancer genomics;cancer type;early onset;operation;programs;racial population BIOSPECIMEN PROCESSING CENTER (BPC) - EARLY ONSET MALIGNANCIES INITIATIVE n/a NCI 10795613 261201700015I-P00004-759102100001-1 N01 3/1/21 0:00 2/29/24 0:00 78076695 "BOWEN, JAY " Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N R and D Contracts 2023 155597 NCI This Task Order provides support to the Early Onset Malignancies Initiative (EOMI). The EOMI is a collaborative initiative between CCG and the Division of Cancer Preventions NCI Community Oncology Research Program (NCORP) investigating why certain racial and ethnic populations are at increased risk of developing cancer at an early age The EOMI will focus on six cancer types that in certain minority populations develop at an earlier age occur in higher rates and are typically more aggressive. The Center for Cancer Genomics (CCG) Biospecimen Processing Center (BPC) supports the EOMI genomics projects by providing the following services: Biospecimen and associated Data Procurement Biospecimen Management and Biorepository Operations Biospecimen Histological Review Biospecimen Processing into Molecular Analytes and Biospecimen and Analyte Distribution. 155597 +No NIH Category available Vimentin Phospho-Malleability is Critical for Maintaining Stemness and Metastatic Properties Project NarrativeThe epithelial-mesenchymal transition (EMT) program endows breast cancer cells with stemness therapyresistance and metastatic competence. The intermediate filament protein vimentin serves an important biologicalrole in sustaining cells that have undergone EMT and regulated changes in its phosphorylation status (termedphospho-malleability) are critical for its function. The proposed studies aim to link vimentin phospho-malleabilityuniquely to cancer stem cells and develop strategies to treat metastasis including increasing sensitivity tocommonly used chemotherapeutic drugs. NCI 10795597 8/7/23 0:00 PA-21-268 7R01CA262106-02 7 R01 CA 262106 2 "AULT, GRACE S" 7/1/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 9340088 "MANI, SENDURAI AYYAVOO" Not Applicable 1 PATHOLOGY 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF MEDICINE 29034202 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2022 397152 NCI 248998 148154 Project SummaryMetastasis remains a major obstacle in the treatment of breast cancer. A key contributor to metastasis is theepithelial-to-mesenchymal transition (EMT) program. During EMT cancer cells gain mesenchymal migratoryinvasive and stem cell properties. Cancer stem cells (CSCs) play crucial roles in metastatic progression cancerrecurrence and chemoresistance. There is an urgent need for CSC-targeting therapies to combat recurrenceand prevent metastasis. The premiere strategy to exploit the vulnerabilities of CSCs is to identify essential factorsthat support the stemness phenotype. Recent research has shown that the EMT process does not move cellsbetween the binary epithelial and mesenchymal states. Instead it is a continuum and the cells can maintainboth epithelial and mesenchymal characteristics (hybrid E/M) and possess high cellular plasticity and stemness.During EMT changes in intermediate filaments particularly upregulation of the mesenchymal-associatedfilament protein vimentin have been documented. However the role of vimentin in EMT and stemness and theconsequence of co-expression of vimentin and cytokeratin (CK) in hybrid E/M cells with high stemness are notknown. Besides the function of vimentin is regulated through dynamic phosphorylation and dephosphorylationon critical sites also known as vimentin phospho-malleability. Preliminary data show that inhibiting phospho-malleability of vimentin serine-56 (S56) inhibits stemness and induces multinucleation in triple-negative breastcancer (TNBC) cells. It does not affect cancer cells with epithelial phenotypes which do not express vimentinor fibroblasts which only express vimentin. Among the various phosphorylation sites the phospho-malleabilityof S56 alone can induce multinucleation and inhibit stemness. Therefore we hypothesize that vimentin S56phospho-malleability is critical for maintaining the stemness of carcinoma cells expressing vimentinand it is a driver of metastasis. Interfering with vimentin S56 phosphorylation will result in selectiveelimination of CSCs inhibition of metastasis and increased chemo-sensitivity. We propose the followingaims to test this hypothesis: (1) Characterize how vimentin S56 phospho-malleability influences EMT and stemcell properties. (2) Define how the interaction between phospho-malleable vimentin and CK affects stemness inhybrid E/M cells with plasticity. (3) Determine the importance of vimentin S56 phospho-malleability onmetastasis. Through innovative experiments using hybrid E/M cell lines we will identify signaling pathways andvimentin-interacting proteins in the context of vimentin S56 phospho-malleability. Using patient TNBC samplessyngeneic tumor xenografts and human patient-derived xenografts we will demonstrate the biologicalimportance of vimentin S56 phospho-malleability for stemness in vitro and metastasis in vivo. Understanding theimportance of vimentin S56 phospho-malleability and the impact of impairing this will aid in developing novelEMT and CSC-targeting therapies to treat metastasis-prone TNBCs. 397152 +No NIH Category available APRIN gene;Acute Myelocytic Leukemia;Affect;Animals;Binding;Biogenesis;Biology;Cell Line;Cell Nucleus;Cell Proliferation;Cells;Chromosome abnormality;Classification;Clinical;Code;Complex;Cytogenetics;Cytoplasm;Data;Disease;Dose;Drug Kinetics;Ensure;Epigenetic Process;Future;Gene Expression;Gene Expression Regulation;Gene Mutation;Genes;Genetic Transcription;Genome Stability;Goals;Heterozygote;In Vitro;Leukemic Cell;Maintenance;Modeling;Molecular Abnormality;Mus;Mutate;Mutation;Myelogenous;Names;Neoplasm Metastasis;Nucleolar Proteins;Nucleotides;Outcome;Patients;Pattern;Pharmacodynamics;Plasma;Play;Pre-Clinical Model;Prognosis;Proliferating;Protein Biosynthesis;Proteins;Proteomics;RNA;RNA-Binding Proteins;Recurrence;Regulator Genes;Reporting;Ribosomes;Role;Schedule;Solid Neoplasm;Stress;Therapeutic;Toxic effect;Transcript;Transferrin;Untranslated RNA;Up-Regulation;Work;acute myeloid leukemia cell;antileukemic activity;carcinogenesis;cohort;comparative;effective therapy;experimental study;improved;in vivo;knock-down;leukemia;leukemogenesis;locked nucleic acid;loss of function;nanoparticle;novel;novel therapeutics;nucleophosmin;overexpression;patient derived xenograft model;patient subsets;pharmacodynamic model;preclinical study;prognostic significance;simulation;targeted treatment;therapeutic target;therapeutically effective;treatment strategy Biology and Targeting of noncoding RNAs in AML The ultimate goal is to elucidate the role of HOXB-AS3 in the biology of NPM1 mutated acute myeloid leukemia(AML) and developed therapeutic strategies to target this gene. At completion of this project we will have anincreased understanding of the role of long noncoding RNAs in NPM1 mutated AML and incorporated thesefindings into future treatment strategies that may improve overall outcomes. NCI 10794593 9/20/23 0:00 PA-21-268 7R01CA240612-04 7 R01 CA 240612 4 "FU, YALI" 2/24/23 0:00 3/31/26 0:00 Developmental Therapeutics Study Section[DT] 8895982 "GARZON, RAMIRO " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 4/1/23 0:00 3/31/25 0:00 395 Non-SBIR/STTR 2023 342534 NCI 224175 118359 The prognosis of acute myeloid leukemia (AML) is still very poor. Thus understanding the mechanismsregulating the biology of AML is important for developing effective therapies for this disease. Non-randomchromosomal abnormalities are identified in 50-55% of all AML patients. In contrast about 45-50% of all AMLcases are cytogenetically normal (CN-AML). Recent work has identified novel recurrent gene mutations in CN-AML. Among them mutations of the nucleophosmin (NPM1) gene represent the most common geneticalteration in CN-AML. Recently a novel class of noncoding RNAs (transcripts longer than 200 nucleotides)named long noncoding RNAs (lncRNAs) was discovered. While lncRNAs contribute to carcinogenesis in solidtumors their role in AML has not been characterized. Our group recently identified the lncRNA HOXB-AS3among the top up-regulated lncRNAs in NPM1 mutated (NPM1mut) CN-AML cases. We further showed thatHOXB-AS3 knockdown leads to a decrease blast proliferation and colony formation in AML cell lines andprimary AML patients in vitro. Silencing HOXB-AS3 in vivo using locked nucleic acid (LNA) gapmers resulted inan increased survival of treated patient derived xenograft (PDX) mice with respect to controls. Comparativeproteomics identified several RNA binding protein partners of HOXB-AS3 such as EBP1 which are associatedwith ribosomal biogenesis. Further experiments indicated that HOXB-AS3 binds to EBP1 and regulatesribosomal biogenesis in AML by affecting the interactions between EBP1 and NPM1 complex. Altogether ourpreliminary data supports our hypothesis that HOXB-AS3 plays an important role in NPM1mut AML andblocking HOXB-AS3 may be a viable therapeutic target in NPM1mut AML. The overall goal of this is proposalis to dissect the mechanisms through which HOXB-AS3 contributes to myeloid leukemogenesis and to explorehow to target therapeutically this lncRNA. We will accomplish this goal through the following Specific Aims(SA): 1) Specific Aim 1: To elucidate the mechanisms by which HOXB-AS3 promotes leukemogenesisin AML. We will perform in vitro and in vivo studies to elucidate how HOXB-AS3 modulates cell proliferationand ribosome biogenesis; 2) Specific Aim 2: To investigate in vivo the pharmacokinetic(PK) pharmacodynamics (PD) and anti-leukemic activity of a synthetic nanoparticle tagged LNAgapmer against HOXB-AS3 using PDX models of AML. In this aim we will conduct preclinical studies ofsynthetic Tf-NP LNA gapmer against HOXB-AS3 in PDX models of AML overexpressing HOXB-AS3 toevaluate: a) toxicity; b) plasma PK and intracellular concentrations; c) PD endpoints; d) PK/PD modeling; ande) efficacy At completion of this project we will have an increased understanding of the role of lncRNAs inNPM1mut AML and incorporated these findings into future treatment strategies that may improve overalloutcomes. 342534 +No NIH Category available Address;Adverse drug effect;Anemia;Antigens;Apoptosis;Apoptotic;Autoimmune Diseases;Blood;CD8B1 gene;Cell Death;Cell Death Induction;Cells;Cessation of life;Chronic;Clinical;Clinical Trials;Clonal Expansion;Data;Dependence;Development;Diagnosis;Disease;Dose;FDA approved;Flow Cytometry;Future;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genomics;Growth Factor;Hour;Immune;Immunosuppressive Agents;In Vitro;Individual;Infection;Inflammatory;Infusion procedures;Interleukin-15;Intervention Trial;Investigation;Laboratories;Laboratory Study;Lead;Leukemic Cell;Mediating;Multicenter Trials;NF-kappa B;Neutropenia;PIK3CG gene;Pathogenesis;Pathogenicity;Pathway Analysis;Pathway interactions;Patient Selection;Patients;Peptides;Pharmaceutical Preparations;Phase I/II Clinical Trial;Population;Proliferating;Reporting;Resistance;Risk;STAT3 gene;Sampling;Secondary to;Signal Pathway;Specimen;T cell receptor repertoire sequencing;T memory cell;T-Cell Large Granular Lymphocyte;T-Lymphocyte;Techniques;Technology;Testing;Time;Tissue-Specific Gene Expression;Transfusion;Tumor Necrosis Factor Ligand Superfamily Member 6;Up-Regulation;Validation;chronic T-cell leukemia;clinical remission;cohort;combinatorial;cytokine;cytopenia;cytotoxic CD8 T cells;deprivation;effective therapy;follow-up;in vivo;in vivo Model;insight;leukemia;leukemic transformation;novel;novel therapeutics;recurrent infection;resistance mechanism;responders and non-responders;response;single cell sequencing;single-cell RNA sequencing;targeted treatment;therapeutic evaluation;therapeutic target;transcriptomics;translational impact Mechanisms of Resistance and Therapeutic Targets in T-LGL Leukemia NARRATIVET-cell large granular lymphocytic leukemia (T-LGLL) is an incurable leukemia that results in frequent infectionstransfusions and death with no FDA-approved therapies and few marginally effective treatment options. T-LGLLis caused by an inflammatory growth factor interleukin-15 (IL-15) that was recently targeted in a clinical trialwith an IL-15 blocking drug (BNZ-1) with some efficacy though laboratory studies demonstrated that leukemiacell populations became resistant to BNZ-1 by gene changes that disable anti-self-destruct (apoptotic) genes.This proposal seeks to use cutting-edge genomic techniques that enable the identification of gene changes inevery single leukemia cell to test the hypothesis that decrease in apoptotic gene pathways in populations of T-LGLL lead to resistance to treatment with BNZ-1; thereby providing targets for future novel drug trials for T-LGLL. NCI 10794011 12/28/23 0:00 PAR-23-058 1R03CA286694-01 1 R03 CA 286694 1 "DUGLAS TABOR, YVONNE" 1/1/24 0:00 12/31/25 0:00 ZCA1-SRB-K(O1)S 14788941 "BRAMMER, JONATHAN EDWARD" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 78750 NCI 50000 28750 ABSTRACTT-cell large granular lymphocytic leukemia (T-LGLL) is an incurable underdiagnosed proliferation of clonal CD8+cytotoxic T-lymphocytes that results in severe neutropenia and anemia with resultant recurring infectionstransfusion dependence and death. There are no FDA-approved therapies for T-LGLL and current immune-suppressive based therapies have marginal efficacy. Even if a response is attained with current therapiespatients shift between immune-suppressive agents are subject to the adverse effects of these drugs and forthose with any effect indefinite therapy is required. Urgent investigation into the pathogenesis of T-LGLL anddevelopment of rational targeted therapies are needed. T-LGLL is a cytokine-dependent disease driven byinterleukin-15 (IL-15) which has been identified as the master switch crucial to induce and potentiate T-LGLL.IL-15 induces pathogenesis in T-LGLL through up-regulation of STAT3 with resultant decrease in Fas/Fas-Ligand mediated apoptosis with resultant T-LGLL proliferation and cytopenias. We evaluated BNZ-1 ac-inhibiting peptide that blocks IL-15 in patients with T-LGLL in only the second major multicenter trialcompleted in T-LGLL. Clinical responses were observed in 20% of patients but in vivo data revealed that nearlyall patients had dramatic apoptosis of T-LGLL cells 24 hours post-BNZ-1 though apoptosis persisted only inresponding patients at day 29. These results (in revision Blood) provide in vivo proof that BNZ-1 induces T-LGLL cell apoptosis and that T-LGLL cells are dependent on IL-15 in vivo in patients. To evaluate themechanisms of resistance to IL-15 deprivation induced cell death we performed single-cell RNA sequencing(scRNAseq) on samples from a non-responder. We identified the emergence of unique T-LGLL sub-populationson day 29 with corresponding up-regulation of anti-apoptotic pathways PI3K and NF-kB; implicating up-regulation of these alternate pathways in T-LGLL as key mechanisms of resistance of T-LGLL to IL-15deprivation. Yet validation in a larger sample set is needed to confirm these findings and identify therapeutictargets. To address these translational and clinical gaps we will perform scRNAseq and single-cell T-cellreceptor sequencing (scTCRseq) on remaining clinically annotated samples from 3 responders and 3 non-responders from the BNZ-1 trial to test our hypothesis that resistance to IL-15 deprivation with BNZ-1 is causedby expansion of resistant T-LGLL populations with upregulation of anti-apoptotic pathways (e.g. NF-kB PI3K).In Aim 1 we will perform scRNAseq at serial timepoints (baseline 24 hours post-BNZ-1 29 days post BNZ-1)to identify key anti-apoptotic pathways genes and therapeutic targets in resistant populations. In Aim 2 we willapply scTCRseq to evaluate T-LGLL clonal populations (clonotypes) and determine the impact of IL-15deprivation on gene expression and anti-apoptotic pathways in these groups. Upon completion we will gaincrucial mechanistic insights on the critical genes and anti-apoptotic pathways in T-LGLL that lead to resistanceto IL-15 deprivation and identify therapeutic targets for a future NCI R01 proposal and BNZ-1 combinatorial trial. 78750 +No NIH Category available Age;Asia;Authorization documentation;Bone neoplasms;Cancer Center;Cell Line;Cells;Clinical;Data;Development;Disease;Disease-Free Survival;Europe;GAG Gene;Growth;Human;Immune;Immune response;In Vitro;Malignant - descriptor;Metastatic Neoplasm to the Lung;Metastatic Osteosarcoma;Multiple Myeloma;Mus;Neoplasm Metastasis;Nonmetastatic;Operative Surgical Procedures;Oral;Oral Administration;Orphan Drugs;Outcome;Patients;Phase I Clinical Trials;Phase I/II Clinical Trial;Phosphotransferases;Production;Proliferating;Proto-Oncogenes;Regulation;Research;Role;Signal Transduction;Site;Solid Neoplasm;Survival Rate;TGF-beta type I receptor;Therapeutic;Therapeutic Effect;Transforming Growth Factor beta;Transforming Growth Factors;Tumor Cell Invasion;authority;c-myc Genes;chemotherapy;clinical prognosis;cytokine;humanized mouse;in vitro Model;in vivo;inhibitor;lung metastatic;mouse model;novel;novel therapeutic intervention;novel therapeutics;osteosarcoma;overexpression;patient derived xenograft model;pediatric patients;pre-clinical;primary bone cancer;receptor;response;side effect;small molecule inhibitor;therapeutic target;therapeutically effective;tumor;tumor microenvironment;tumor progression c-Myc regulation by TGF-beta signaling as a therapeutic target in Osteosarcoma PROJECT NARRATIVEOsteosarcoma (OS) is the most common bone tumor in pediatric patients and the survival rates for patients withlung metastatic OS (pOS) have remained poor for more than 3 decades despite encouraging progress in themanagement of non-metastatic primary OS. For this reason novel and directed therapy approaches that targetpOS are desperately needed. It has been shown that TGF- production is increased in the sera of OS patientsand this increase in TGF- production is correlated with high grade OS and associated with the presence of lungmetastases suggesting that targeting TGF- signaling may be a novel therapeutic approach for pOS. Thisproposal seeks to establish an orally available small molecule inhibitor of TGF- Type 1 Receptor as a noveltherapy for pOS. NCI 10793802 11/22/23 0:00 PAR-23-058 1R03CA273468-01A1 1 R03 CA 273468 1 A1 "COVELL, DAVID G" 12/1/23 0:00 11/30/25 0:00 ZCA1-SRB-P(O2)S 12108372 "CHOI, SUNG HEE " Not Applicable 11 PEDIATRICS 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 80500 NCI 50000 30500 PROJECT SUMMARYOsteosarcoma (OS) is an aggressive malignant primary bone cancer with a high propensity for lung metastasis.Since the development of aggressive chemotherapy and surgery the 5-year event-free survival rate for non-metastatic patients has attained 70%. In contrast the outcome for pulmonary metastatic osteosarcoma (pOS)remains poor and the 5-year event-free survival has not improved significantly over the past 3 decades (20%).Therefore treating pOS effectively remains a challenge. Transforming growth factor- (TGF-) is one of the mostpotent immune suppressive cytokines in tumor microenvironment (TME) and can promote metastasis in solidtumors. TGF- production is increased in the sera of OS patients. This increase in TGF- production is correlatedwith high grade OS and associated with the presence of lung metastases. Therefore target TGF- is the newtherapeutic approach for the treatment of OS. In this proposal we will demonstrate the therapeutic effects of anovel inhibitor of TGF- signaling TEW-7197 on OS growth in vitro and in vivo and associated immuneresponses in the OS TME. TEW-7197 (Vactosertib) is the first-in-class small molecule inhibitor of the TGF-type I Receptor (TRI) kinase and currently in Phase I clinical trial at UH Seidman Cancer Center for MultipleMyeloma another disease with high TGF- (#NCT03143985). TEW-7197 is orally available (taken qD or BID)and well tolerated with minimal side effects. Our preliminary data show that blocking TGF- signaling with TEW-7197 inhibited OS proliferation in vitro and oral administration of TEW-7197 to OS-bearing mice significantlyreduced established pOS in vivo. Our preliminary observation has resulted in an Orphan Drug Designationauthorization by the FDA in August 2021 as well as Fast-track IND issuance in January 2023 for the use of TEW-7197 in OS. More recently a multi-center phase I/II clinical trial using Vactosertib as monotherapy for thetreatment of advanced osteosarcoma in patients age 14 and up been organized and planned for accrual in spring2023 (#NCT05588648) at 21 sites across US Europe and Asia. Recently we have made the additionalobservation that TGF- induced c-Myc expression in OS cells and those inductions were completely inhibited byTEW-7197 in OS cells. c-Myc is a major proto-oncogene which is highly amplified in OS. c-Myc overexpressionin human OS correlates with aggressive tumor cell invasion and metastasis and worsens overall patient clinicalprognosis. Therefore these new results suggest that c-Myc regulation by TGF- may be an important therapeutictarget in OS. We hypothesize that TGF- signaling inhibition may be an effective therapeutic strategy againstmetastatic pOS by modifying tumor-intrinsic signaling (c-Myc regulation) and extrinsic immune-related TME toachieve optimal immune-effector function and maximal clinical response in pOS. To confirm this hypothesis wewill utilize various mouse and human OS cell lines and PDX models in vitro and in vivo. Two specific aims willbe pursued to accomplish the overall objective. Specific aim 1 will Determine effects of TGF- inhibition on c-Myc regulation in OS cells in vitro. Specific aim 2 will Determine whether daily oral administration of TEW-7197suppresses pOS tumor progression in the syngeneic and humanized mouse models. A fully humanized mousemodel will be employed to interrogate TEW-7197 effects on cellular immune responses with preclinical humanOS TME in vivo. This research will establish a critical role of TGF- signaling in pOS progression and providescientific rationale that targeting TGF- signaling with orally available small molecule inhibitor should bedeveloped as a viable therapeutic arsenal for pOS patients. 80500 +No NIH Category available Address;Adult;Affect;Amines;Apoptosis;Atherosclerosis;Barrett Esophagus;Bile Acids and Salts;Bile fluid;Binding;Biological;Biological Models;Biology;Cell physiology;Cells;Clinical;DNA Damage;DNA Repair;Data;Defense Mechanisms;Development;Diagnosis;Disease;Disease Progression;Duodenum;Epithelial Cells;Epithelium;Esophageal Adenocarcinoma;Esophageal Tissue;Esophagus;Exhibits;Exposure to;Free Radicals;Gastric Acid;Gastroesophageal reflux disease;Gene Expression Profile;Genes;Genetic Transcription;Health;Histologic;Human;Hypertension;In Vitro;Inflammation;Injury;Link;Lipid Peroxidation;Lipids;Lysine;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of esophagus;Mediating;Modification;Molecular;Outcome;Oxidative Stress;Pathogenicity;Pathologic;Patients;Play;Population;Post-Translational Protein Processing;Precancerous Conditions;Preneoplastic Conditions;Process;Proliferating;Prostaglandin-Endoperoxide Synthase;Proteins;Reactive Oxygen Species;Reflux;Regulation;Risk Factors;Role;Signal Pathway;Signal Transduction;Stomach;Stratified Epithelium;Survival Rate;System;Testing;Therapeutic;Time;Tissues;United States;adduct;clinically significant;gastrointestinal;improved;in vitro Model;in vivo;inhibitor;innovation;mouse model;neoplastic;novel;novel therapeutic intervention;novel therapeutics;pharmacologic;prevent;senescence;stemness;tissue injury;transcription factor;translational approach;tumor;tumorigenesis;tumorigenic Regulation of esophageal tumorigenesis by protein adduction PROJECT NARRATIVEEsophageal adenocarcinoma is a serious health problem in the United States with a low survival rate and fewtreatment options. This proposal will examine how protein adduction by isoLGs affects the cellular and molecularmechanisms to promote cancer which may lead to the development of novel therapeutic interventions. NCI 10793751 1/1/24 0:00 PAR-23-058 1R03CA286671-01 1 R03 CA 286671 1 "LUO, RUIBAI" 1/1/24 0:00 12/31/25 0:00 ZCA1-TCRB-9(O2)S 78726815 "CASPA GOKULAN, RAVINDRAN " Not Applicable 27 SURGERY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 76750 NCI 50000 26750 SUMMARYEsophageal adenocarcinoma (EAC) is the most prevalent histological type of esophageal malignancy in the USand many Western nations. This tumor remains deadly as approximately 80% of patients are diagnosed atadvanced stages and have a low five-year survival rate. Gastroesophageal reflux disease (GERD) is one of thestrongest risk factors for EAC. In GERD patients the epithelial lining of the esophagus is exposed to thegastroesophageal reflux (GER) that contains gastric acid frequently mixed with duodenal bile. The esophagealepithelial cells undergoes severe damage from exposure to acid and bile salts. This exposure also promotesinflammation which can exacerbate tissue damage and lead to the development of Barrett's esophagus (BE).BE is a preneoplastic condition that is disposed to malignant transformation. The molecular mechanisms ofesophageal tumorigenesis in conditions of esophageal reflux injury remain poorly understood. We havedeveloped an innovative hypothesis to investigate how isolevuglandin (isoLG) lipid derivatives that adductmultiple proteins in conditions of esophageal reflux facilitate tumorigenic processes by protein adduction. IsoLGsare formed from the free radicals induced peroxidation of lipids and cyclooxygenase (COX) and are highlyreactive for lysine as well as other cellular amines. IsoLGs bind covalently with the protein molecules to inflictdamage before being recognized by cellular defense mechanisms. In our experimental conditions of esophagealreflux p63 is found to be one of the most adducted proteins by isoLGs. P63 is a master regulator of esophagealepithelial development which also regulate a broad spectrum of genes involved in different cellular processessuch as DNA repair stemness proliferation and differentiation. Our preliminary data strongly support thehypothesis by providing evidence of the alteration of p63 protein by adduction. In aim 1 using in vitro cellsystems this proposal will examine the unique mechanisms regulating p63 signaling pathway by proteinadduction and its biological impact in conditions of esophageal reflux injury. In aim 2 we will study the p63protein adduction in in vivo mice model and test various pharmacological options to reverse this process. Ifsuccessful this study will provide a new therapeutic approach to prevent the pro-tumorigenic alterations ofesophageal cancer. 76750 +No NIH Category available Address;Automobile Driving;Binding;Biological;Blood;Cell Line;Clinic;Clustered Regularly Interspaced Short Palindromic Repeats;Dependence;Development;Dose Limiting;Drug Targeting;Embryo;Engineering;Epithelial Cells;Exhibits;Fibroblasts;Future;Genes;Genetic Crosses;Genetic Engineering;Genetic Models;Genetic study;Human;Intervention;KPC model;KRAS oncogenesis;KRAS2 gene;Knock-in;Knowledge;MAPK1 gene;MAPK3 gene;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mitogens;Modeling;Molecular;Mus;Mutation;Myeloproliferative disease;Oncogenes;Oncogenic;Pancreas;Pancreatic Adenocarcinoma;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Play;Proliferating;Proteomics;RAS driven cancer;RNA Interference;Role;Signal Pathway;Signal Transduction;Solid;Substrate Interaction;Testing;Therapeutic;Therapeutic Intervention;Toxic effect;Work;attenuation;cancer therapy;carcinogenesis;cell growth;cell transformation;conditional knockout;cost;in vitro Model;inhibitor;innovation;insight;kinase inhibitor;malignant phenotype;mouse genetics;mouse model;mutant;mutant mouse model;novel therapeutic intervention;pancreatic cancer cells;pancreatic tumorigenesis;paralogous gene;pharmacologic;senescence;targeted treatment;tool;transcriptome;tumor progression;tumorigenesis Divergent Functions of ERK2 Substrate Binding Domains in Pathogenesis of KRAS-Driven Pancreatic Cancer PROJECT NARRATIVEGaining insight into the molecular basis for the opposing roles that the ERK2-DBP and D domains play in PDACpathogenesis will enable us to exploit this information to develop new strategies for therapeutic intervention.Moreover because the RAS/ERK cascade is a critical driver in human PDAC these findings will have profoundimplications for the treatment including conceptually innovative ERK2 drug targeting strategies. NCI 10793732 12/13/23 0:00 PAR-23-058 1R03CA286669-01 1 R03 CA 286669 1 "LUO, RUIBAI" 12/13/23 0:00 11/30/25 0:00 ZCA1-SRB-F(O1)S 10639342 "ASTSATUROV, IGOR " "WIEST, DAVID L." 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 12/13/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 94000 NCI 50000 44000 PROJECT SUMMARY/ABSTRACTThe central KRAS-ERK signaling axis is activated in most human pancreatic adenocarcinomas (PDAC).Attempts to target ERK1 and ERK2 signaling with non-selective kinase inhibitors have produced only limitedefficacy in the clinic at the cost of dose-limiting toxicity. Our breakthrough discovery for this proposal is thatERK2 and not ERK1 is an essential driver of pancreatic carcinogenesis but is dispensable in non-transformedpancreatic epithelial cells. Based on this ERK2 represents a new potent target for therapeutic intervention inPDAC. This proposal is built on the results of our recent studies of genetic models of myeloid neoplasms in whichwe have established ERK2 as a central oncogenic effector via its unique substrate interaction domains. In ourERK2 knock-in mouse genetic models the D domain of ERK2 promotes cancer progression while the ERK2DBP domain opposes progression and induces senescence in oncogene-transformed cells. However the roleof the ERK2-D and DBP domains in driving KRAS-initiated PDAC tumorigenesis has not been investigated.Hence our central hypothesis is that pancreatic carcinogenesis driven by mutant KRAS is dependent on domain-specific functions of ERK2. We propose the following aims:Aim 1. To assess the opposing functions of the ERK2-D and DBP domains in pancreatic carcinogenesis. Ourpreliminary results indicate that conditional deletion of ERK2 (Mapk1 gene) in the KPC model dramaticallyimpedes PDAC development. We will intercross KPC mice in which the wild type Mapk1 gene is replaced withthe D- and DBP-domain mutants (knock-in models already available in our lab) to pinpoint which of substratebinding pockets is critical for pancreatic cancer development and progression.Aim 2. Determine the mechanistic basis by which the ERK2-D and DBP domains exert their distinct functions.We will generate in vitro models of ERK2 deletion and replacement with D- and DBP-domains mutations by RNAiand CRISPR-targeting of ERK2 in PDAC cell lines and assess the effects on cell growth and MAPK pathwaysignaling. These models will be essential discovery tools for future proteomic and transcriptome analyses topinpoint the ERK2 domains interactors that are essential for exerting the KRAS malignant phenotype and willallow us to decipher the molecular basis for the opposing functions of ERK2 D and DBP domains.Through these efforts we expect to bring new insights into the role of ERK2 substrate binding modules inregulating pancreatic cancer progression and how to exploit this information therapeutically. 94000 +No NIH Category available Actins;Address;Affect;Biogenesis;C57BL/6 Mouse;CCL2 gene;CCR5 gene;CD8-Positive T-Lymphocytes;CD81 gene;CD86 gene;CRISPR/Cas technology;Calpain;Cell Culture Techniques;Cell Line;Cell membrane;Cell surface;Cells;Cellular Structures;Cellular biology;Communication;Coupled;Diagnosis;Diameter;Endosomes;Endothelial Growth Factors;Epidermal Growth Factor;Excision;Flow Cytometry;Gene Expression Regulation;Glioblastoma;Glioma;Goals;Golgi Apparatus;Growth Factor;Guanosine Triphosphate;Human;Immunofluorescence Immunologic;Immunologic Markers;Infiltration;Inflammatory;Integrins;Knock-out;Label;Laboratories;Life Extension;MAPK8 gene;MMP14 gene;Malignant neoplasm of brain;Mediating;Messenger RNA;Microglia;Modeling;Molecular Sieve Chromatography;Molecular Target;Monocyte Chemoattractant Proteins;Mus;Myeloid Cell Activation;Myeloid Cells;PTK2 gene;PTK2B gene;Population;Prognostic Marker;RANTES;Regulation;Reverse Transcriptase Polymerase Chain Reaction;Role;STAT3 gene;Signal Transduction;Specimen;TNF gene;Testing;Therapeutic;Treatment Protocols;Tumor-Derived;Up-Regulation;Vascular Endothelial Growth Factors;Western Blotting;brain tissue;chemokine;cytokine;extracellular vesicles;gene repression;implantation;improved;in vitro Model;inhibitor;mouse model;myosin light chain 2;neoplastic cell;pharmacologic;polarized cell;rho;temozolomide;therapy resistant;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;uptake;vesicular release Pyk2 regulates extracellular vesicles release in GBM cells and modulates activation of tumor infiltrating myeloid cells This project is aimed at improvement of glioblastoma (GBM) therapeutic strategies taking intoconsideration the supporting role of tumor infiltrating myeloid cells on tumor progression andtreatment resistance. The studies will elucidate the Pyk2-dependent machinery of cytokinesrelease through the extracellular vesicles (EVs) mechanism in GBM cells Pyk2 dependentpopulations of tumor-derived EVs and their effect on tumor infiltrating myeloid cells activation. Theresults of the study will help to identify molecular targets for managing tumor immunemicroenvironment and to enhance current GBM treatment protocols. NCI 10793667 11/28/23 0:00 PAR-22-060 1R15CA287203-01 1 R15 CA 287203 1 "DUGLAS TABOR, YVONNE" 12/1/23 0:00 11/30/26 0:00 Special Emphasis Panel[ZRG1-CDPT-J(80)A] 9507829 "KUCHERYAVYKH, LILIA " Not Applicable 98 BIOCHEMISTRY 90534694 XVQJLM5S8L85 90534694 XVQJLM5S8L85 US 18.180281 -66.116276 1204101 UNIVERSIDAD CENTRAL DEL CARIBE BAYAMON PR SCHOOLS OF MEDICINE 9606032 UNITED STATES N 12/1/23 0:00 11/30/26 0:00 396 Non-SBIR/STTR 2024 381843 NCI 300000 81843 Glioblastoma (GBM) is the most aggressive brain cancer and usually fatal within a year after diagnosis. Currenttreatment approaches provide only a modest few months life extension. Tumor infiltrating myeloid cells (TIM)provide strong impact on tumor growth dispersal and treatment resistance. The current unmet need in GBMtreatment is to address the TIM contribution on tumor growth and treatment resistance in treatment protocols.The goal of the study is to identify molecular targets for the GBM treatment approaches aimed at modulation oftumor immune microenvironment.Our recent studies identified significant up-regulation of Proline-Rich Tyrosine Kinase 2 (Pyk2) in GBM tumorscompared with healthy brain tissue as well as a positive correlation between Pyk2 activation in tumor cells andcytokines expression profile of TIM. Additionally both tumor resection and temozolomide treatment up-regulatePyk2 in GBM tumors and affect activation state of TIM. This identified Pyk2 as a candidate prognostic markerfor the immune state in GBM tumor microenvironment. Preliminary studies in GL261 glioma cells identified thatcells knocked out for Pyk2 do not release the population of EVs with diameter bigger them 600nm and reduceexpression of monocyte chemoattractant protein (CCL2) CCL12 and vascular endothelium growth factor (VEGF)in EV fraction compared with Pyk2WT cells. Correspondingly increase of CD86+/CD206+ inflammatory myeloidcell and CD8+ lymphocytes populations were found in TIMs purified from Pyk2KO tumors compared with Pyk2WTtumors in GL261/C57Bl/6 mouse glioma implantation model. Based on these findings we hypothesize thatPyk2 is involved in signaling regulation of release of inflammatory cytokines CCL2 CCL12 and CCL5 throughthe EVs mechanism leading to modulation of TIM cells polarization. In this study we will utilize mouse gliomaimplantation model and primary human GBM cell cultures with high and low levels of Pyk2 expression coupledwith cell biology approaches to dissect the role of Pyk2 in regulation of biogenesis and cytokines content ofglioma cell derived EVs. We will also examine in mouse and human in vitro models the modulation of activationstate of microglial cells through the glioma-derived EV mechanism. The purpose of the project is to identifymechanisms of interaction between glioma and TIM cells and the role of Pyk2 signaling in this communication.To test our hypothesis we propose the following specific aims:Specific Aim 1. To investigate the role of Pyk2 in release of cytokines through the EV mechanism in GBM cells.Specific Aim2. To investigate the role of Pyk2 in regulation of actin-related release of EVs populations.Specific Aim3. To assess the role of vesicular Pyk2 in EV internalization by microglial cells. 381843 +No NIH Category available Address;Advanced Malignant Neoplasm;Animals;Antigen Targeting;Antigens;Biology;CAR T cell therapy;CXCL10 gene;CXCR3 gene;Cells;Cerebrospinal Fluid;Characteristics;Cities;Clinical;Clinical Trials;Combined Modality Therapy;Disease;Effectiveness;Environment;Generations;Glioblastoma;Glioma;Goals;Hematologic Neoplasms;IL13RA1 gene;Immune;Immunocompetent;Immunologics;Immunophenotyping;Immunosuppression;Immunotherapy;In complete remission;Intraventricular;Lead;Letters;Malignant Glioma;Mediating;Modeling;Molecular;Mus;Neoplasm Metastasis;Nivolumab;PD-1 blockade;PD-1/PD-L1;PDL1 pathway;Pathway interactions;Patient-Focused Outcomes;Patients;Phase;Phase I Clinical Trials;Phenotype;Population;Positioning Attribute;Recurrence;Resistance;Role;Safety;Sampling;Solid Neoplasm;T cell response;T cell therapy;T-Lymphocyte;T-Lymphocyte Subsets;T-cell inflamed;Therapeutic;Translating;Treatment Efficacy;Vertebral column;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;anti-cancer;anti-tumor immune response;cancer therapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical candidate;cohort;design;experience;experimental study;immune checkpoint blockade;immune resistance;improved;improved outcome;innovation;insight;interleukin-13 receptor;manufacture;mouse model;phase I trial;pre-clinical;preclinical study;programmed cell death ligand 1;programmed cell death protein 1;programs;recruit;research clinical testing;response;safety and feasibility;standard of care;success;synergism;therapeutic development;therapy resistant;timeline;tumor;tumor microenvironment Clinical evaluation of IL13Ra2-targeted CAR T cell therapy in combination with nivolumab in patients with recurrent malignant glioma NARRATIVEWe propose to evaluate a combination therapy to enhance the effectiveness of chimeric antigen receptor (CAR)T cells for malignant glioma (MG) by relieving tumor-induced immune suppression using the anti-PD-1 antibodynivolumab. We anticipate that CAR T cells will directly target antigen-positive glioma cells and that anti-PD1 willaugment endogenous and CAR T cell responses. The proposed studies aim to improve our understanding ofthe glioma microenvironment and identify key drivers of response or resistance to combining CAR T and anti-PD-1 immunotherapies. NCI 10793527 1/5/24 0:00 PAR-18-560 5R01CA236500-06 5 R01 CA 236500 6 "UNDALE, ANITA H" 1/1/19 0:00 12/31/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 8798416 "BROWN, CHRISTINE " "BADIE, BEHNAM " 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 767288 NCI 473326 293962 PROJECT SUMMARYChimeric antigen receptor (CAR) T cell therapy is emerging as a powerful anti-cancer strategy that may offernew opportunities to improve outcomes for patients with malignant gliomas (MG). Although CAR T cells havedemonstrated remarkable clinical responses against hematologic malignancies success against solid tumorsremains an important therapeutic goal. The immunosuppressive solid tumor microenvironment (TME) presentsobstacles to therapy that must be overcome in order to achieve therapeutic efficacy. City of Hope was the firstto clinically translate CAR T cells for the treatment of MG and the lead CAR program targets the glioma-associated antigen IL13 receptor alpha 2 (IL13R2). Initial findings have demonstrated that the treatment is welltolerated and shows evidence of antitumor activity. One patient with recurrent multifocal glioblastoma (includingmetastatic lesions in the spine) with characteristics of an inflamed TME achieved a complete response (CR)that was durable for more than 7 months. Importantly this case provides evidence that CAR T cells can mediateprofound antitumor activity against one of the most lethal and difficult-to-treat solid tumors and also providescritical information on how the tumor landscape can modulate response to CAR T cell immunotherapy.Our goal is to implement strategies to overcome the underlying causes of immunosuppression within the tumormicroenvironment that limit CAR T cell responses to MG. The PD-1/PD-L1 pathway has emerged as a criticaldriver of immune suppression in solid tumors including MG. We hypothesize that checkpoint blockade willsynergize with CAR T cells to create a tumor landscape more favorable to immunotherapy.We propose to clinically evaluate IL13R2-CAR T cell therapy in combination with anti-PD1 (nivolumab) inpatients with IL13R2+ recurrent MG (Specific Aim 1). Interrogating correlative samples from this clinical trialwe will assess tumor and TME changes that occur post T cell therapy with and without nivolumab as well asmolecular pathways that dominantly correlate with response and/or resistance to therapy (Specific Aim 2). Inaddition we will preclinically evaluate in immunocompetent mice the impact of an inflamed versus non-inflamedTME on the efficacy of the combination therapy. These preclinical studies will aid in elucidating mechanisms ofresponse and resistance in the two immunological landscapes (Specific Aim 3).This project builds upon our prior preclinical and clinical experience with IL13R2-CAR T cell therapy as well asour understanding of PD-1/PDL-1 biology and its impact on immunotherapy. We anticipate these experimentswill provide insights for improved MG therapies which also may apply to other advanced cancers. 767288 +No NIH Category available Attenuated;Biological Models;Biological Sciences;Cancer Biology;Cancer cell line;Cell Line;Cells;Clinic;Clinical;Clinical Trials;Collaborations;Colorado;Environment;Genes;Goals;IRF1 gene;Immune;Immune Evasion;In Vitro;Investigation;Literature;Macrophage;Malignant neoplasm of ovary;Mediating;Modeling;Pathway interactions;Poly(ADP-ribose) Polymerase Inhibitor;Publishing;Regulation;Research Personnel;Resistance;Role;Serous;Signal Transduction;T cell differentiation;T-Cell Activation;Therapeutic;Tumor Immunity;Tumor Promotion;Tumor Suppressor Proteins;Universities;WNT Signaling Pathway;Work;anti-PD-1;anti-tumor immune response;antitumor effect;beta catenin;cancer cell;cancer type;effector T cell;humanized mouse;immune activation;immune checkpoint;immune checkpoint blockade;immune checkpoint blockers;improved;in vivo Model;inhibitor;mouse model;novel;patient derived xenograft model;programmed cell death ligand 1;response;therapy resistant;tumor Diversity Supplement - Targeting Wnt signaling in therapy-resistant ovarian cancer PROJECT NARRATIVE PARP inhibitor resistance is a growing clinical problem and alternative therapeutic strategies areneeded. Hyperactivation of Wnt/beta-catenin signaling drives PARP inhibitor resistance and immune evasion.Thus we hypothesize that combining a Wnt inhibitor with a checkpoint blockade (e.g. anti-PD-1) couldovercome PARPi resistance and activate an anti-tumor immune response. In our unique PARP inhibitor-resistant models we propose to examine the anti-tumor effect of a first-in-class Wnt/ beta-catenin inhibitor in asyngeneic and humanized mouse models. NCI 10793115 9/7/23 0:00 PA-21-071 3R37CA261987-03S1 3 R37 CA 261987 3 S1 "O'HAYRE, MORGAN" 7/9/21 0:00 6/30/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 8762673 "BITLER, BENJAMIN G" Not Applicable 6 OBSTETRICS & GYNECOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 81678 NCI 81678 0 PROJECT SUMMARY PARP inhibitor (PARPi) use in the clinic is expanding into multiple cancer types and consequentlyPARPi resistance is a growing clinical problem. High grade serous ovarian cancer (HGSOC) tumors and cellsremain an optimal model system to assess PARPi response and resistance. We have developed a panel ofunique isogenic PARPi sensitive and resistance HGSOC cell lines and patient-derived xenograft (PDX)models. We published that hyperactivation of the Wnt/-catenin pathway promotes PARPi resistance. Throughthe current literature and our preliminary investigation we have discovered that Wnt-mediated PARPi resistantHGSOC cells have increased expression of the immune checkpoint PD-L1 and reduced expression of thetumor suppressor interferon regulatory factor 1 (IRF1). Further Wnt/-catenin signaling directly inhibitseffector T cell differentiation and promotes a tumor-promoting M2-like macrophage. We will continue tocollaborate with MD2 Biosciences to investigate a first-in-class allosteric -catenin inhibitor 1525. Wehypothesize that Wnt-dependent PARPi resistance inhibits anti-tumor immunity and combining ICB with Wntinhibition will promote immune activation to eradicate PARPi resistant HGSOC. We are proposing to useboth in vitro and in vivo models to determine the role of PARPi resistance and Wnt signaling in promoting animmune-suppressive environment. In Aim 1 we will use our unique PARPi resistant cell line models toestablish -catenin regulation of PD-L1 (gene CD274) and IRF1. In Aim 2 we will determine whethersecreted factors from PARPi resistant cells attenuates T cell activation and promotes macrophage M2differentiation. In Aim 3 we will use our novel syngeneic and humanized mouse models to assess the 1525 -catenin inhibitor combined with anti-PD-1. The proposed work has the potential for a high impact onunderstanding ovarian cancer biology and improving therapeutic options. We anticipate combining -catenininhibition with an immune checkpoint blocker will overcome PARPi resistance and provide a therapeutic optionfor those who are no longer responding to PARP inhibitors. Thus the proposed work's long-term goal is todevelop an investigator-initiated clinical trial at the University of Colorado. 81678 +No NIH Category available Age;Area;Arousal;Attitude;Behavior;Behavioral;Cigarette Smoker;Cognition Disorders;Communication;Credentialing;Data;Data Set;Development;Education;Electronic cigarette;Galvanic Skin Response;Goals;Health;Heart Rate;Measures;Methods;Misinformation;Mood Disorders;Nicotine Dependence;Participant;Patient Self-Report;Perception;Persons;Persuasive Communication;Phase;Population;Predisposition;Prevention;Psychology;Psychophysiology;Public Health;Randomized;Reporting;Research;Research Activity;Research Personnel;Role;Scientist;Side;Source;Testing;Text Messaging;Tobacco;Tobacco use;Training;Trust;United States Food and Drug Administration;Visual attention;arm;biobehavior;cigarette smoking;crowdsourcing;design;electronic cigarette use;follow-up;health communication;improved;individual response;peer;prevent;public education;public health priorities;randomized trial;reduce tobacco use;response;tailored text messaging;text messaging intervention;theories;tobacco products;tobacco regulatory science;tobacco user;vaper;vaping;visual tracking;young adult Identifying and examining the effects of source and presentation on responses to electronic cigarette public education messages in young adult vapers and non-vapers PROJECT NARRATIVEDespite the increased effort to curtail e-cigarette use in young adults the current public healthcommunication campaign messages may fail to influence young adults e-cigarette harmperceptions and behavior. Vapers and non-vapers may trust different health information sourcesand respond differently to messages based on how they are presented but little research hasexamined the effects of these communication principles. The proposed study uses online andin-lab studies (Phase 1) and a randomized trial (Phase 2) to understand the role of using anoptimal source (expert and peer) and message presentation type (one sided and two sided) ine-cigarette education messages to increase young adult vapers and non-vapers messageacceptance and change their vaping behavior. NCI 10793062 12/28/23 0:00 RFA-OD-22-026 1K99CA281094-01A1 1 K99 CA 281094 1 A1 "RADAEV, SERGEY" 1/1/24 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-RCCS-Q(50)R] 78294233 "LEE, DONGHEE NICOLE" Not Applicable 2 BIOSTATISTICS & OTHER MATH SCI 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 Other Research-Related 2024 151913 OD 140750 11163 PROJECT SUMMARYE-cigarette use (vaping) in 18-24-year-olds is a public health crisis. It is an urgent public healthpriority to communicate to young adults about the health harm of vaping to stop and preventthem from vaping. However effective communication has become challenging in the new age ofhealth misinformation and low trust in health experts. My goal is to investigate the role of atrusted source and strategic message presentation to increase young adults acceptance of e-cigarette education messages to impact their behavior. In this two-phased study I will determinean optimal source and message presentation type for young adult vapers and non-vapersrespectively (K99) and examine the effects of messages optimized for source and presentationon young adults vaping cessation and vaping prevention (R00). In phase 1 (K99) I will use amulti-method approach to examine two source (expert and peer) and two message presentationtypes (one-sided and two-sided) to identify the optimal message type for each vaping statuspopulation. First I will use crowdsourcing testing to collect self-report measures on messageacceptance source trust message reactance and harm perceptions. Second I will usepsychophysiological testing to measure participants eye-tracking heart rate and skinconductance to assess their visual attention orienting responses and arousal during messageexposure. I will produce a single dataset integrating the crowdsourced and psychophysiologicaldata to determine the optimal source and presentation type for vapers and non-vapers. In phase2 (R00) I will use a text messaging intervention in a randomized trial to examine the behavioraleffects of messages optimized for source and presentation to ones vaping status (vapers andnon-vapers). Participants in each vaping status will be randomized to either the treatment(receiving e-cigarette education messages with a source and presentation type optimized toones vaping status) or control arm (receiving non-tobacco health messages) via text messagingover the course of 6 months. I will examine vaping cessation rates among vapers and vapinginitiation rates among non-vapers. Results will inform the public health communicationcampaign development and may apply to other public education campaigns to reduce tobaccouse in young people. 151913 +No NIH Category available Agreement;American;Area;Attention;Authorization documentation;Behavior;Cigarette;Data;Descriptor;Electronic cigarette;Evolution;Family Smoking Prevention and Tobacco Control Act;Focus Groups;Future;Generations;Goals;Grant;Image;Imagery;Industry;Joints;Light;Literature;Manufacturer;Marketing;Methodology;Methods;Modified Risk Tobacco Product;Monitor;Participant;Perception;Persons;Predisposition;Product Packaging;Randomized;Reaction;Regulation;Research;Research Activity;Research Personnel;Review Literature;Risk;Safety;Series;Stimulus;Tobacco;Tobacco Industry;Training;Variant;Water;Work;Youth;authority;career;cigarillos;combustible tobacco;experimental study;health communication;low nicotine content cigarette;natural product inspired;preference;public policy on tobacco;research study;risk perception;skills;tobacco advertising;tobacco control;tobacco products;tobacco user;trend;visual tracking;young adult A new generation of misleading tobacco marketing: Assessing the evolution of misleading combustible tobacco marketing features and detrimental implications for vulnerable youth and young adults Project NarrativeThis research will apply a mixed-methods approach to assess the use and impact of a new generation ofmisleading descriptors and imagery in combustible tobacco marketing. Research activities (including focusgroups a discrete choice experiment and eye tracking) will focus on identifying the effects of such marketingfor cigarettes and cigarillos on attention product appeal and risk perceptions of current and susceptible youthand young adult tobacco users and will inform future research and appropriate regulatory remedies. NCI 10793051 1/3/24 0:00 RFA-OD-22-023 1K01CA281062-01A1 1 K01 CA 281062 1 A1 "RADAEV, SERGEY" 1/3/24 0:00 12/31/28 0:00 Special Emphasis Panel[ZRG1-RCCS-Q(50)R] 78029673 "GRATALE, STEFANIE " Not Applicable 10 MISCELLANEOUS 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ ORGANIZED RESEARCH UNITS 71073001 UNITED STATES N 1/3/24 0:00 12/31/24 0:00 398 Other Research-Related 2024 221851 OD 205418 16433 Project Summary/AbstractThe purpose of this research is to assess the use and effects of a new generation of misleading descriptorsand imagery in combustible tobacco marketing. While regulatory efforts to date have made strides in restrictingthe use of especially misleading terms in tobacco marketing (e.g. mild natural) industry marketing hasevolved to utilize newer descriptors and imagery that are known to be associated with these restricted terms;yet research studying this evolution is quite limited. As the tobacco industry continues to mislead consumerswith attempts to skirt regulatory actions via implied reduced risk claims (e.g. organic tobacco and water) itis crucial to track their misleading marketing tactics and monitor effects on vulnerable youth and young adults(YYAs) especially as this suggestive marketing for traditional tobacco products now exists alongside otherproducts actually authorized for designation as modified risk (i.e. Modified Risk Tobacco Products or MRTPs).Through a preliminary literature and marketing content review under Aim 1 this research will characterizenewer descriptors and imagery utilized in misleading marketing for combustible tobacco products (becausethese products pose the greatest harms) focusing specifically on cigarettes and cigarillos. Aim 1 focus groupswith YYAs will assess attention product appeal and risk perceptions for products advertised/packaged withthese descriptors and imagery as well as other products by the same brands and MRTPs. Results will inform adiscrete choice experiment (DCE) (Aim 2) that manipulates a series of target descriptors and images as well asmodified risk claims on cigarette and cigarillo packs in order to isolate independent and joint effects of thetarget features on product appeal and preferences. Under Aim 3 an eye-tracking study will examine youngpeoples attention to ads and packs using salient descriptors and images (per focus group and DCE results)and in combination with the prior activities will provide preliminary data to inform research avenues for futureregulatory efforts. This K01 will support the pursuit of my long-term career goal of becoming an independenttobacco control researcher at the intersection of tobacco policy health communication and tobacco misbeliefs;it will develop my content expertise (i.e. trends in/effects of cigarette and cigarillo marketing) and cultivate newmethodological skillsets (i.e. focus groups DCE eye-tracking). The proposed research will allow me to worktowards research independence and an R01 grant to further study misleading tobacco marketing with a newfocus on additional products and an emphasis on regulatory remedy. 221851 +No NIH Category available Adjuvant Therapy;Anabolism;Automobile Driving;Biochemical;Biological Markers;Biological Models;COX7A2L gene;Carbon;Cardiolipins;Cell Death;Cell Death Induction;Cell Line;Cell Proliferation;Cell Survival;Cells;Chronic;Citric Acid Cycle;Clear cell renal cell carcinoma;Clinical;Coenzymes;Complex;Copper;Coupled;Data;Development;Electron Transport;Enzymes;Event;Excision;Exposure to;Genetic;Glucose;Glycolysis;Growth;Human;Hydrogen Sulfide;Inner mitochondrial membrane;Investigation;Knowledge;Lipids;Malignant - descriptor;Metabolic;Metabolic Diseases;Metabolism;Metals;Mitochondria;Modeling;Molecular;Oncogenic;Operative Surgical Procedures;Pathogenicity;Pathway interactions;Patients;Pharmacotherapy;Phenotype;Phospholipids;Play;Process;Protein Family;Proteins;Regulation;Relapse;Renal Cell Carcinoma;Renal carcinoma;Research;Respiration;Respiratory physiology;Role;Source;System;Testing;Therapeutic;Therapeutic Intervention;Tumor Suppressor Proteins;Work;Xenograft Model;auxotrophy;cancer cell;cancer therapy;clinical application;cytochrome c oxidase;dietary;experimental study;inhibitor;insight;mitochondrial metabolism;novel;oxidation;preclinical trial;pyruvate dehydrogenase;relapse patients;respiratory;small molecule;standard of care;targeted treatment;transcription factor;tumor;tumor growth;tumor progression;uptake Metabolic effects of cooper in renal cancer The project investigates mechanisms contributing to tumor progression in clear cell renal cellcarcinoma. The proposal is focused on the role of copper that accumulates in tumors in regulationof mitochondrial activities and tumor growth. The work will identify novel vulnerabilities with clinicalapplication for treatment of ccRCC in the context of adjuvant therapies. NCI 10792732 9/20/23 0:00 PA-20-185 1R01CA287260-01 1 R01 CA 287260 1 "SALNIKOW, KONSTANTIN" 9/20/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-BTC-D(02)M] 1901028 "CZYZYK-KRZESKA, MARIA F" Not Applicable 1 ANATOMY/CELL BIOLOGY 41064767 DZ4YCZ3QSPR5 41064767 DZ4YCZ3QSPR5 US 39.129719 -84.520554 1523902 UNIVERSITY OF CINCINNATI CINCINNATI OH SCHOOLS OF MEDICINE 452210001 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 578465 NCI 408105 170360 Clear cell renal cell carcinoma (ccRCC) is a frequent and malignant renal cancer with a glycolytic phenotype dueto the loss of VHL tumor suppressor and activation of HIF transcription factors. Up to 50% of patients relapsewithin five years after surgical resection. Thus there is an urgent clinical need to understand the molecularmechanisms leading to ccRCC relapse and advancement. Pathogenic mechanisms underlying ccRCCprogression represent a key knowledge gap. Our recent discoveries demonstrate a copper accumulation inadvanced ccRCC. In this proposal we interrogate impact for copper-dependent metabolic reprogramming indriving ccRCC progression. Copper (Cu) is a metal cofactor of enzymes including cytochrome c oxidasecomplex (CuCOX) essential for mitochondrial respiration and a metalloallosteric regulator of cell proliferationand survival. Using patients primary ccRCCs we found accumulation of Cu and increased CuCOX stronglycorrelated with advanced ccRCC and relapse. In cell line xenograft models functional evidence shows thatdietary Cu drives growth of tumors and stimulates formation of CuCOX in cancer cells. We discovered that Cuenhances electron transfer chain (ETC) activity with important functional consequences. High Cu induces (i)assembly of the respiratory supercomplex (RSC) associated with regulatory subunit COX7A2L and (ii)accumulation and remodeling of cardiolipins (CLs) phospholipids of the inner mitochondrial membranenecessary for ETC activity. Surprisingly despite glycolytic phenotype Cu-reprogrammed cells recovermitochondrial respiration become hyperdependent on glucose and on the activity of CuCOX and therefore arehighly sensitive to CuCOX inhibitors including hydrogen sulfide (H2S). Importantly we discovered that theendocytic process of macropinocytosis is responsible for major proportion of Cu uptake by renal cancer cells.Small molecules that function as donors of H2S are in preclinical trials while inhibitors of MP are developed forpharmacotherapies prompting investigation of these pathways as targets for therapeutic interventions. Wepropose that chronic accumulation of Cu in RCC cells promotes glucose oxidation via TCA cycle and ETC activitycausing glucose auxotrophy and stimulating bioenergy and biosynthesis required for tumor growth. To determinethe source of Cu we will investigate macropinocytosis as little understood but major mechanism of Cu uptakeand its role in allocation of Cu to CuCOX (Aim 1). To understand Cu-dependent regulation of ETC activity wewill investigate mechanisms of RSC formation cardiolipin synthesis and the flux of glucose carbon (Aim 2).Finally because Cu-reprogramming creates new functional vulnerability to CuCOX inhibitors we will investigateeffects of H2S in cell death and tumor formation (Aim 3). We will use several model systems including RCCcells ex-vivo tumor fragments and patient derived tumor grafts. The study will identify basic mechanisms bywhich high level of Cu in cancer cells regulate their metabolism supporting tumor growth. The research will leadto the development of new biomarkers and therapies for cancer 578465 +No NIH Category available Affinity;Antigens;Antitumor Response;Bacteria;Binding;Biological Assay;C57BL/6 Mouse;CAR T cell therapy;CD8-Positive T-Lymphocytes;CD8B1 gene;CTLA4 gene;Cells;Cellular Immunity;Clinical Research;Colon Carcinoma;Core Facility;Discrimination;Epitopes;Exclusion;Future;Genetic;Hematologic Neoplasms;Hybridomas;Immune;Immune response;Immune system;In Vitro;Individual;Infection;Infiltration;Infusion procedures;Knowledge;Ligands;Lymphocytic choriomeningitis virus;MC38;Malignant Neoplasms;Mediating;Methylcholanthrene;Modality;Modeling;Monoclonal Antibodies;Mus;Mutate;Neoplasm Transplantation;Ovum;Patients;Peptides;Physiologic pulse;Play;Population;Proliferating;Reporting;Research Personnel;Ribosomal Proteins;Role;Sensitivity and Specificity;T cell response;T-Cell Activation;T-Cell Development;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Epitopes;Testing;Therapeutic;Transgenes;Transgenic Mice;Transgenic Organisms;Transplantation;Tumor Antigens;Tumor-Infiltrating Lymphocytes;Vaccination;Virus;Virus Diseases;antigen-specific T cells;chimeric antigen receptor T cells;cytotoxic CD8 T cells;cytotoxicity;fighting;fungus;immune checkpoint blockade;mouse model;neoantigens;neoplastic cell;novel;preclinical study;programmed cell death protein 1;recruit;response;success;targeted treatment;tumor;tumor microenvironment;weapons Novel TCR transgenic mice to study tumor neoantigen-specific T cell responses Project NarrativeThe immune system is important for fighting off infection with bacteria viruses and fungi and can also eliminatetumors in some individuals with cancer. One type of immune cell that plays a particularly important role ineliminating viruses some bacteria and tumor cells is the so-called CD8 T cell. The studies described in thisproposal will lead to a better understanding of how CD8 T cells respond (or not) to cancer and as such maylead to better therapies for treating cancer by identifying novels ways to enhance immune responses to cancer. NCI 10792669 11/24/23 0:00 PAR-23-058 1R03CA286594-01 1 R03 CA 286594 1 "DUGLAS TABOR, YVONNE" 12/1/23 0:00 11/30/25 0:00 ZCA1-SRB-K(O1)S 1868435 "KANE, LAWRENCE P." Not Applicable 12 MICROBIOLOGY/IMMUN/VIROLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 66992 NCI 50000 16992 PROJECT SUMMARYActivated CD8+ T cells are capable of responding to tumor neoantigens and can aid in the clearance of tumors.Indeed CD8+ T cells are critical for the beneficial effects of immune checkpoint blockade therapies in thosepatients that respond to such therapies (mAbs to CTLA-4 PD-1/L1 LAG3). In addition CD8+ T cells themselvescan be deployed as therapies in the form of CAR-T cells for some hematological malignancies. Other therapeuticor preventative modalities still under active study include expansion and infusion of tumor-infiltrating lymphocytes(TIL) and vaccination. All of these approaches require either the presence of tumor specific CD8+ T cells whosefunction can be augmented or knowledge about a tumor neoantigen that can be directly targeted therapeutically.Despite advances there are still significant gaps in knowledge regarding how tumor-specific CD8+ T cells areprimed how they are recruited to (or excluded from) the tumor and how they become dysfunctional in the tumormicroenvironment. Our understanding of the rules of T cell development function and antigen discrimination have been greatlyenhanced using T cell receptor transgenic (TCR Tg) mice. These models provide a traceable pool of antigen-specific T cells that can be studied over the course of an infection. Many investigators have also taken advantageof TCR Tg T cells to model responses to tumor antigens by expressing the cognate antigen (e.g. LCMV GPOVA) in transplantable tumor lines or genetic tumor models. One of the limitations of such studies is that theyhave mostly employed non-tumor antigens and their respective TCRs which often represent high affinity outlierTCR-ligand pairings. There is thus a need for additional models that employ naturally arising tumor neo-antigensand matching TCRs. One of the most commonly used transplantable murine syngeneic tumor lines in the C57BL/6 background isMC38 a colon carcinoma model originally derived from C57BL/6 mice treated with methylcholanthrene. A recentstudy reported the identification of a tumor neo-antigen in the MC38 model a mutated form of the ribosomalprotein Rpl18 referred to hereafter as Rpl18* presented by H-2Kb. We have now validated that this representsa major T cell epitope in C57BL/6 mice bearing MC38 tumors. We have also identified TCRs that recognize thisepitope and confirmed that these TCRs can mediate T cell activation and effector function. We now propose touse two of the TCRs that we have identified to generate TCR Tg mouse lines that can be used for future studyof T cell anti-tumor responses in mouse models. 66992 +No NIH Category available Address;Cessation of life;Contractor;Data Collection;Data Linkages;Databases;Institutional Review Boards;National Cancer Institute;Participant;Process;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Screening for cancer;Telephone;United States Centers for Medicare and Medicaid Services;Update;data exchange;data management;data repository;data submission;indexing;neoplasm registry;participant retention Support for the Central Data Collection Center (CDCC) n/a NCI 10792457 261201600007I-P00004-759102100001-1 N02 2/27/21 0:00 2/26/24 0:00 78070483 "MATHEW, SUNITHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2023 1203503 NCI The Contractor Westat conducts participant retention activities as well as passive data collection for approximately 155000 participants in the National Cancer Institutes Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial. Westat coordinates data linkages and is responsible for attaining and maintaining approvals with institutional review boards cancer registries the National Death Index (NDI) and the Centers for Medicare and Medicaid Services (CMS). Westat manages data transfers with various entities and processes the data for submission to a data repository. Westat continues participant retention activities primarily by sending out mailings updating changes in address and answering questions by phone with any changes in status documented and managed in a study database. Additionally Westat oversees similar activities with subcontracted cancer screening centers in the study. 1203503 +No NIH Category available Adenocarcinoma Cell;Animals;Cancerous;Catheters;Cause of Death;Chronic;Device Designs;Drug Delivery Systems;Drug Exposure;Drug toxicity;Drug usage;Elements;Eligibility Determination;Esophageal Tissue;Esophagus;Family suidae;Goals;Heating;Human;Intravenous;Irrigation;Malignant Neoplasms;Malignant neoplasm of esophagus;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase;Plasma;Squamous cell carcinoma;Survival Rate;System;Testing;Tube;United States;biomaterial compatibility;comparative;cost;design;design verification;first-in-human;gastrointestinal;human study;metastatic esophageal;systemic toxicity;tumor PHASE I -TOPIC 431 - DRUG DELIVERY BY ENDOESOPHAGEAL LAVAGE (EEL) TO TREAT ESOPHAGEAL CANCER n/a NCI 10792456 75N91022C00018-P00001-9999-1 N43 9/15/22 0:00 9/14/23 0:00 78834669 "BRIAN, CRAIG " Not Applicable 5 Unavailable 116996412 M3QDM72NME75 116996412 M3QDM72NME75 US 44.922937 -93.318008 10054313 ISOLA THERAPUETICS MINNEAPOLIS MN Domestic For-Profits 55410 UNITED STATES N R and D Contracts 2023 55000 NCI Cancer is the second leading cause of death in the United States and esophageal cancer has the 6th lowest survival rate for all cancers. Systemic drug therapy is first-line therapy for widely metastatic esophageal cancer but is limited by systemic toxicity patient eligibility or cost. The proprietary Isola system consists of a drug delivery catheter tubing heating element and a drug lavage solution. A proof-of concept animal study demonstrated that Isola can deliver drug directly to esophageal tissue while minimizing drug in plasma by using balloons to isolate the esophagus from the gastrointestinal track when a drug solution is delivered in the lumen of the esophagus. The goal of is to treat cancerous tumors (adenocarcinoma and squamous cell carcinoma) in the esophagus while minimizing systemic drug exposure and toxicity. The objective of this proposal is to advance activities to eventually complete a first in human (FIH) study using the Isola drug delivery system by a) finalizing the drug delivery system design and selecting the ideal drug for delivery b) completing device design verification and biocompatibility testing to use drug delivery system in humans and c) conducting comparative chronic animal studies to compare Isola drug delivery to standard intravenous drug delivery. 55000 +No NIH Category available Address;Adjuvant;African American;American;Anxiety;Attention;Autologous Stem Cell Transplantation;Belief;Black race;Bortezomib;Cancer Patient;Cannabis;Clinics and Hospitals;Cohort Studies;Common Terminology Criteria for Adverse Events;Communication;Communities;Complex Variables;Computer software;Counseling;Data;Data Collection;Dexamethasone;Disease-Free Survival;Dose;Education;Ensure;Ethnic Origin;Gatekeeping;Goals;Health Personnel;Hematologic Neoplasms;Herb;Immune checkpoint inhibitor;Immunotherapy;Impaired cognition;Knowledge;Latino;Legal;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical Marijuana;Multiple Myeloma;National Health and Nutrition Examination Survey;Neoadjuvant Therapy;Newly Diagnosed;Nivolumab;Non-Small-Cell Lung Carcinoma;Oncologist;Oncology;Operative Surgical Procedures;PD-1 inhibitors;Participant;Patients;Pattern;Perception;Pharmaceutical Preparations;Phytotherapy;Platinum;Population;Positioning Attribute;Prevalence;Prospective Studies;Prospective cohort study;Psychoses;Quality of life;Race;Recommendation;Reporting;Sampling;Schedule;Socioeconomic Factors;Solid Neoplasm;Standardization;Surveys;Symptoms;Therapeutic;Treatment Protocols;Washington;abuse liability;active method;cancer therapy;cancer type;cannabis use behavior;chemotherapy;cohort;compliance behavior;demographics;inflammatory marker;instrument;lenalidomide;marijuana use;marijuana user;patient population;side effect A Prospective Cohort Study of Patients with Non-Small Cell Lung Cancer and Multiple Myeloma to Assess the Benefits and Harms Related to Cannabis Use During Treatment Project NarrativeA significant proportion of patients with cancer are using medical cannabis and limited data exists regardingthe potential benefits and harms of this use during active treatment. This prospective study will provideinformation regarding cannabis use by patients with lung cancer and multiple myeloma including assessing thebenefits and harms between cannabis users and non-users. NCI 10792363 9/20/23 0:00 RFA-CA-22-052 1U01CA286808-01 1 U01 CA 286808 1 "FILIPSKI, KELLY" 9/20/23 0:00 8/31/28 0:00 ZCA1-TCRB-V(A1) 10568482 "LEE, RICHARD T" "CULLEN, JENNIFER " 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 622059 NCI 404525 217534 With the majority of Americans supporting legalization of medical cannabis the number of patients asking theirclinicians about medical cannabis has also significantly increased. Many clinicians however feel that theyhave inadequate knowledge about the efficacy side effects and abuse potential of medical cannabis. Onenational survey of oncologists reported that only 30% felt sufficiently informed to make recommendationsregarding medical cannabis use even though 80% regularly conducted conversations about medical cannabiswith patients. A study from Washington State found 21% of patients with cancer surveyed had used cannabisin the past month. Despite the common belief among many patients that herbal therapies such as cannabis areinherently safe the evidence is growing that greater caution is needed with cannabis as it may have potentialdirect side effects and may lead to interactions between herbs such as cannabis and medications. Thus animportant knowledge gap exists regarding the use of cannabis by patients with cancer during active cancertreatment and this prospective cohort study is proposed to address these questions. This study aims to assessthe prevalence and patterns of cannabis use among patients with cancers of the lung and multiple myelomaduring active treatment as well as inquire about the communication patterns regarding cannabis use with theirtreating medical team. In order to reduce the complex variables that exist between the types of cancers andtreatments we will study two unique cancer populations non-small cell lung cancer (NSCLC) and multiplemyeloma (MM) with each cohort studied separately. These patients provide a homogenous population ofpatients with cancer that have generally standardized treatment regimens. Cancer patients currently receiveplatinum-based chemotherapy either before (neoadjuvant) or after (adjuvant) receiving surgery together with aPD-1 inhibitor (a type of immune checkpoint inhibitor (ICI) ex. nivolumab). Newly diagnosed MM patients arerecommended to receive induction therapy with lenalidomide bortezomib and dexamethasone (RVd) for threeto six months followed by an autologous stem cell transplant (ASCT). These two cohorts provide uniqueopportunities to study the impact of cannabis use in both a solid tumor and hematologic cancer duringchemotherapy. For the NSCLC cohort we will also assess the effect of cannabis on immunotherapy efficacy.For the MM cohort we will assess the effects of cannabis during ASCT. Concurrently we will survey oncologyhealthcare providers about their perceptions education and practice patterns regarding cannabis use bypatients. Data collection will include information about all the medications including prescription over-the-counter herbs and supplements in order to assess for the prevalence of potential medication interactions withcannabis. We hypothesize that a substantial proportion of patients receiving cancer treatment are usingcannabis (~20%) and that there are different patterns of cannabis related benefits and harms based on cancertype and treatment as well as patient demographics including socioeconomic factors. 622059 +No NIH Category available Address;Adverse effects;Adverse reactions;Aftercare;Anxiety;Biological;Biological Markers;Blood specimen;Breast Cancer Patient;Breast Cancer therapy;Cancer Center;Cancer Patient;Cannabinoids;Catchment Area;Cellular Phone;Characteristics;Clinic;Clinical;Cohort Studies;Common Terminology Criteria for Adverse Events;Country;County;Data;Decision Making;Dose;Drops;Ecological momentary assessment;Enrollment;Ensure;Environment;Florida;Frequencies;Funding;Health;Health Benefit;Immunotherapy;In complete remission;Individual;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Interdisciplinary Study;Knowledge;Longitudinal cohort;Measurement;Measures;Mediating;Medical Marijuana;Medical Technology;Minority;Monitor;Nausea;Oncologist;Outcome;Outcomes Research;Pain;Pathway interactions;Patient Outcomes Assessments;Patients;Pattern;Persons;Pharmaceutical Preparations;Physical Function;Physical activity;Physicians;Positioning Attribute;Prospective cohort study;Quality of life;Reporting;Research;Route;Sleep;Sleep disturbances;Smoking;Source;Stable Disease;Surveys;Symptoms;Technology;Testing;Therapeutic;United States National Institutes of Health;Visit;Work;anticancer research;appetite loss;cancer therapy;cannabinoid treatment;chemotherapy;chronic pain;cognitive function;design;disorder control;dosage;emotional functioning;fitbit;high throughput technology;immunoregulation;improved;innovation;malignant breast neoplasm;multidisciplinary;new technology;novel;objective response rate;partial response;patient population;patient subsets;prevent;prospective;response;sensor;side effect;success;symptom management;symptomatic improvement;treatment planning;treatment response;tumor progression;underserved minority;vaping;wearable sensor technology Assessing Benefits and Harms of Medical Cannabis and Cannabinoid Use in Breast Cancer Patients During and After Treatments PROJECT NARRATIVE Breast cancer patients represent fast-growing medical cannabis and cannabinoid (MCC) users in thiscountry mainly for symptom management. However research on its benefits and harms in cancer patients duringand after treatments remains limited. Therefore we propose a prospective breast cancer cohort study (50%minorities) to address knowledge gaps and build evidence of the benefits and harms of MCC use during andafter cancer treatments. We anticipate that the outcomes will provide crucial evidence for physicians and breastcancer patients to make informed decisions about the use of MCC for managing treatment-related symptoms. NCI 10792287 9/20/23 0:00 RFA-CA-22-052 1U01CA286810-01 1 U01 CA 286810 1 "FILIPSKI, KELLY" 9/20/23 0:00 8/31/28 0:00 ZCA1-TCRB-V(A1) 1967824 "HU, JENNIFER J" "WANG, YAN " 27 PUBLIC HEALTH & PREV MEDICINE 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 663626 NCI 334429 79197 PROJECT SUMMARY/ABSTRACT Breast cancer patients represent fast-growing medical cannabis and cannabinoid (MCC) users in thiscountry; a recent survey indicates that about 42% of breast cancer patients use MCC to alleviate treatment-related symptoms and many of these patients do not discuss their use with their oncologists. Despite beingconsidered safe and well-tolerated MCC may result in potential interactions with cancer treatments adversereactions and tumor progression. Unfortunately despite the increase in MCC use research on its health effectsincluding the potential benefits and harms remains limited. Therefore we propose a prospective cohort studyof breast cancer patients (50% underserved minorities) to address gaps in knowledge and build evidence ofthe types of products in use frequency dosage of use and the benefits and harms of MCC use during and aftercancer treatment. Our central hypothesis is that MCC may improve treatment-related symptoms and clinicaloutcomes in some patients by targeting the inflammasome/inflammatory pathway. Therapeutic strategiestargeting inflammasome may prevent treatment-related symptoms and improve clinical outcomes. We will test anew paradigm that the inhibition of inflammasome-mediated inflammatory responses by MCC plays a role in itsbiological effects. We plan to enroll 600 breast cancer patients (300 MCC users and 300 non-MCC users) andcollect data on patient characteristics treatment plans clinician-reported outcomes adverse reactions andpatient-reported outcomes. We will monitor MCC use through in-person visits and technology-basedassessments such as smartphone and sensor-based measurement bursts. We will also collect blood samplesfor MCC quantitation/characterization and inflammasome/inflammatory biomarkers. Aim 1 will evaluate thebenefits and harms of MCC in breast cancer patients during and after treatment. Aim 2 will elucidate whetherinflammasome/inflammatory biomarkers mediate the benefits and harms of MCC in breast cancer therapies andother medications used. Aim 3 will investigate how MCC product characteristics impact benefits and harms (Aim1) and inflammasome and inflammatory biomarkers (Aim 2). Leveraging our promising preliminary data adiverse patient population state-of-the-art high-throughput technologies and a multidisciplinary research teamwith complementary expertise we are well-positioned to conduct this study and address the scientificknowledge gaps surrounding the benefits and harms of MCC in breast cancer patients. We will provide scientificevidence on the impact of MCC on breast cancer patients during and after treatments the biological effects ofMCC during treatments potential interactions between MCC and cancer therapies and other medications andthe types and patterns of MCC use that present the best benefits/harms ratio. Our results will be of great valueto physicians and cancer patients as they will inform decision-making regarding MCC to enhance therapiesimprove quality of life and minimize adverse effects. If funded we will work closely with the coordinating centerand NCI in sharing assessment measures and disseminating study findings. 413626 +No NIH Category available Address;Adverse effects;Adverse reactions;Aftercare;Anxiety;Biological;Biological Markers;Blood specimen;Breast Cancer Patient;Breast Cancer therapy;Cancer Center;Cancer Patient;Cannabinoids;Catchment Area;Cellular Phone;Characteristics;Clinic;Clinical;Cohort Studies;Common Terminology Criteria for Adverse Events;Country;County;Data;Decision Making;Dose;Drops;Ecological momentary assessment;Enrollment;Ensure;Environment;Florida;Frequencies;Funding;Health;Health Benefit;Immunotherapy;In complete remission;Individual;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Interdisciplinary Study;Knowledge;Longitudinal cohort;Measurement;Measures;Mediating;Medical Marijuana;Medical Technology;Minority;Monitor;Nausea;Oncologist;Outcome;Outcomes Research;Pain;Pathway interactions;Patient Outcomes Assessments;Patients;Pattern;Persons;Pharmaceutical Preparations;Physical Function;Physical activity;Physicians;Positioning Attribute;Prospective cohort study;Quality of life;Reporting;Research;Route;Sleep;Sleep disturbances;Smoking;Source;Stable Disease;Surveys;Symptoms;Technology;Testing;Therapeutic;United States National Institutes of Health;Visit;Work;anticancer research;appetite loss;cancer therapy;cannabinoid treatment;chemotherapy;chronic pain;cognitive function;design;disorder control;dosage;emotional functioning;fitbit;high throughput technology;immunoregulation;improved;innovation;malignant breast neoplasm;multidisciplinary;new technology;novel;objective response rate;partial response;patient population;patient subsets;prevent;prospective;response;sensor;side effect;success;symptom management;symptomatic improvement;treatment planning;treatment response;tumor progression;underserved minority;vaping;wearable sensor technology Assessing Benefits and Harms of Medical Cannabis and Cannabinoid Use in Breast Cancer Patients During and After Treatments PROJECT NARRATIVE Breast cancer patients represent fast-growing medical cannabis and cannabinoid (MCC) users in thiscountry mainly for symptom management. However research on its benefits and harms in cancer patients duringand after treatments remains limited. Therefore we propose a prospective breast cancer cohort study (50%minorities) to address knowledge gaps and build evidence of the benefits and harms of MCC use during andafter cancer treatments. We anticipate that the outcomes will provide crucial evidence for physicians and breastcancer patients to make informed decisions about the use of MCC for managing treatment-related symptoms. NCI 10792287 9/20/23 0:00 RFA-CA-22-052 1U01CA286810-01 1 U01 CA 286810 1 "FILIPSKI, KELLY" 9/20/23 0:00 8/31/28 0:00 ZCA1-TCRB-V(A1) 1967824 "HU, JENNIFER J" "WANG, YAN " 27 PUBLIC HEALTH & PREV MEDICINE 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 663626 NCCIH 202134 47866 PROJECT SUMMARY/ABSTRACT Breast cancer patients represent fast-growing medical cannabis and cannabinoid (MCC) users in thiscountry; a recent survey indicates that about 42% of breast cancer patients use MCC to alleviate treatment-related symptoms and many of these patients do not discuss their use with their oncologists. Despite beingconsidered safe and well-tolerated MCC may result in potential interactions with cancer treatments adversereactions and tumor progression. Unfortunately despite the increase in MCC use research on its health effectsincluding the potential benefits and harms remains limited. Therefore we propose a prospective cohort studyof breast cancer patients (50% underserved minorities) to address gaps in knowledge and build evidence ofthe types of products in use frequency dosage of use and the benefits and harms of MCC use during and aftercancer treatment. Our central hypothesis is that MCC may improve treatment-related symptoms and clinicaloutcomes in some patients by targeting the inflammasome/inflammatory pathway. Therapeutic strategiestargeting inflammasome may prevent treatment-related symptoms and improve clinical outcomes. We will test anew paradigm that the inhibition of inflammasome-mediated inflammatory responses by MCC plays a role in itsbiological effects. We plan to enroll 600 breast cancer patients (300 MCC users and 300 non-MCC users) andcollect data on patient characteristics treatment plans clinician-reported outcomes adverse reactions andpatient-reported outcomes. We will monitor MCC use through in-person visits and technology-basedassessments such as smartphone and sensor-based measurement bursts. We will also collect blood samplesfor MCC quantitation/characterization and inflammasome/inflammatory biomarkers. Aim 1 will evaluate thebenefits and harms of MCC in breast cancer patients during and after treatment. Aim 2 will elucidate whetherinflammasome/inflammatory biomarkers mediate the benefits and harms of MCC in breast cancer therapies andother medications used. Aim 3 will investigate how MCC product characteristics impact benefits and harms (Aim1) and inflammasome and inflammatory biomarkers (Aim 2). Leveraging our promising preliminary data adiverse patient population state-of-the-art high-throughput technologies and a multidisciplinary research teamwith complementary expertise we are well-positioned to conduct this study and address the scientificknowledge gaps surrounding the benefits and harms of MCC in breast cancer patients. We will provide scientificevidence on the impact of MCC on breast cancer patients during and after treatments the biological effects ofMCC during treatments potential interactions between MCC and cancer therapies and other medications andthe types and patterns of MCC use that present the best benefits/harms ratio. Our results will be of great valueto physicians and cancer patients as they will inform decision-making regarding MCC to enhance therapiesimprove quality of life and minimize adverse effects. If funded we will work closely with the coordinating centerand NCI in sharing assessment measures and disseminating study findings. 250000 +No NIH Category available Address;Affect;African American population;African ancestry;Alleles;Biological;Cancer Etiology;Candidate Disease Gene;Characteristics;Complex;Data;Development;Disease;Environment;Environmental Exposure;Etiology;European;European ancestry;Event;Family;Family Cancer History;Family history of;First Degree Relative;Frequencies;Genes;Genetic;Genetic Determinism;Genetic Structures;Genotype;Habits;Health;Health Benefit;Heritability;Individual;Inflammation;Inherited;Investigation;Joints;Knowledge;Link;Lung;Machine Learning;Malignant neoplasm of lung;Maps;Methods;Modeling;Molecular;Nicotine Dependence;Pathway Analysis;Phenotype;Population;Predisposition;Prevention;Public Health;Recording of previous events;Research;Resources;Risk;Risk Factors;Role;Signal Transduction;Smoking;Smoking Behavior;Source;Subgroup;Susceptibility Gene;Trees;Variant;cancer risk;case control;cigarette smoking;epidemiology study;family influence;gene interaction;genetic analysis;genetic architecture;genetic epidemiology;genetic risk factor;genetic signature;genetic variant;genome wide association study;genomic data;genomic locus;high risk;improved;insight;large datasets;machine learning algorithm;novel strategies;phenotypic data;rare variant;repository;screening Heterogeneous Genetic Architecture in Lung Cancer Risk Title: Heterogeneous genetic architecture in lung cancer riskProject NarrativeLarge-scale genetic analyses of lung cancer have identified numerous genetic variants influencing both the riskof lung cancer and nicotine dependence the major risk factor for lung cancer. The proposed research capitalizeson existing well-curated phenotype and genotyped repositories of lung cancer with both sporadic and familialcases in Europeans and African Americans and aims to characterize shared and distinct genetic profiles in lungcancer risk in the different subgroups defined according to family history status of lung cancer using machine-learning. The findings could unravel complex genetic structures of lung cancer etiology with potentialimplications for improved prevention screening and management of lung cancer. NCI 10792257 12/22/23 0:00 PAR-23-058 1R03CA277197-01A1 1 R03 CA 277197 1 A1 "CARRICK, DANIELLE M" 12/22/23 0:00 11/30/25 0:00 ZCA1-TCRB-9(O2)S 11867163 "BYUN, JINYOUNG " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 12/22/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 80000 NCI 50000 30000 Title: Heterogeneous genetic architecture in lung cancer riskProject Summary/Abstract Lung cancer is a multifactorial disease driven by environmental exposures inherited germline geneticvariants and an accumulation of somatic genetic events. Most lung cancer cases are attributed to cigarettesmoking. Approximately 10% of lung cancer cases have a family history of at least one first-degree relative.Genome-wide association studies (GWAS) have identified about 45 susceptibility loci directly influencing lungcancer risk. The genetic architecture in individuals with a family history of lung cancer differs from those withsporadic lung cancer although there are common genetic loci influencing both cases. The magnitude of theassociation between smoking and lung cancer risk varies by family history status. There is also a familialcomponent to smoking behaviors which may confound the association of lung cancer risk with smoking inhereditary cases. Each locus however exerts only a modest effect and most of the heritability remains unexplained. Newapproaches are therefore needed to address the problem of missing heritability. Since relatively weak signals ofa genetic risk factor are difficult to detect an improvement would be to jointly model multiple genetic factors todetermine the impact of the risk. Using machine-learning high-order interaction models among numerousgenetic features in subsets of cases defined according to the family history status also considering smokingbehaviors can help illustrate how these genetic variants in each stratified subset jointly influence lung cancerrisk. The overarching aims of this proposal are to characterize the shared and distinct genetic contributions tolung cancer development and provide better insight into homogeneous and heterogeneous genetic architecturesof lung cancer etiology across family history status in different populations. The specific aims of the proposedresearch are to identify the hierarchical combination of multiple genetic variants for lung cancer susceptibilityusing machine-learning and to explore in depth the impact of genetic factors in lung cancer GWAS of European-and African-ancestry populations. This proposal capitalizes on existing well genotype-phenotype repositories ofsporadic and familial lung cancers using subset-based and machine-learning association methods in differentpopulations. This proposal addresses a comprehensive approach to improve our understanding of howhomogeneous and heterogeneous genetic architectures and biological mechanisms contribute to lung cancerdevelopment and how specific genetic effects additive dominant or recessive explain lung cancer risk. Finallywe can identify subgroups of individuals at high-risk based on the individuals genetic characteristics withpotential implications for the prevention screening and management of lung cancer. 80000 +No NIH Category available Adverse effects;Anxiety;Area;Biological;Blood Cell Count;CSF3 gene;Cancer Patient;Cancer Science;Cannabis;Clinical;Clinical Data;Cognitive;Collaborations;Computerized Medical Record;Consumption;Cross-Sectional Studies;Data;Disease;Disease Progression;Disparity;District of Columbia;Dizziness;Ecological momentary assessment;Exhibits;Fatigue;Funding;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Immune checkpoint inhibitor;Immune system;Immunologic Markers;Immunology;Immunooncology;Immunotherapy;Individual;Interdisciplinary Study;Interleukin-2;Interleukin-6;Knowledge;Legal;Link;Longitudinal Studies;Malignant Neoplasms;Measures;Medical Marijuana;Memory impairment;Mental Health;Methods;Moods;NCI-Designated Cancer Center;Oncologist;Oncology;Outcome;Pain;Patient Care;Patient Outcomes Assessments;Patients;Performance;Persons;Prevalence;Prospective cohort study;Qualifying;Quality of life;Renal function;Reporting;Research;Role;Sampling;Schedule;Science;Severities;Site;Sleep;Sleep disturbances;Solid;Surveys;Symptoms;TNF gene;Telephone;Testing;Therapeutic;Therapeutic Uses;Time;cancer immunotherapy;cancer therapy;checkpoint therapy;cognitive task;deprivation;disparity reduction;electronic data;evidence base;health equity;immune function;immunoregulation;improved;improvement on sleep;indexing;liver function;marijuana use;marijuana use disorder;marijuana user;multidisciplinary;neighborhood disadvantage;patient safety;patient subsets;programs;progression marker;prospective;response;secondary outcome;side effect;social health determinants;substance misuse;symptom management;tumor;tumor progression;virtual Assessing benefits and harms of cannabis use in patients treated with immunotherapy for cancer: a prospective cohort study Project NarrativeAs both immunotherapy and cannabis use are becoming more widespread therapeutic options in oncology thedemand for prospective data on the effects of cannabis among those being treated with immunotherapy forcancer will continue to grow. Our proposed project fills a gap by providing crucial long-term data on the role ofcannabis use on benefits and harms among those receiving immunotherapy. Overall this study will have asustained impact on the science of cancer symptom management and ultimately improve patient care and safety. NCI 10792109 9/15/23 0:00 RFA-CA-22-052 1U01CA286811-01 1 U01 CA 286811 1 "FILIPSKI, KELLY" 9/15/23 0:00 8/31/28 0:00 ZCA1-TCRB-V(A1) 8950071 "ASHARE, REBECCA " "MEGHANI, SALIMAH H.; NUGENT, SHANNON MADORE" 26 PSYCHOLOGY 38633251 LMCJKRFW5R81 38633251 LMCJKRFW5R81 US 43.003074 -78.785924 5992614 STATE UNIVERSITY OF NEW YORK AT BUFFALO AMHERST NY SCHOOLS OF ARTS AND SCIENCES 142282567 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 676418 NCI 545580 130838 Project AbstractUp to 40% of patients report using cannabis for symptom management during and after cancer treatmentsdespite gaps in our understanding of its longitudinal therapeutic uses and harms. Simultaneously immuno-oncology is a rapidly advancing field of cancer treatment. Nearly 44% of cancer patients across 20 tumor typesreceive treatments with immunotherapy notably Immune Checkpoint Inhibitors (ICIs) which can lead topersistent changes in the immune system for months or even years. Given cannabis also has immunomodulatoryeffects there is a critical need to generate long-term data on the impact of cannabis use on longitudinal benefitsand harms immune function and disease progression in cancer patients treated with ICIs. This proposal buildsupon our existing program of research. Our team has conducted 4 NCI-funded projects regarding cannabis usein cancer patients including 3 large cross-sectional surveys of cannabis use among patients treated at 3 NCIdesignated cancer centers. Across sites 26% (n=831 of 3169) of cancer patients reported using cannabis duringtreatment. However the rate was considerably higher among patients treated with immunotherapy (32%). Theoverarching goal of this study is to advance the science regarding the longitudinal benefits and harms ofcannabis use among those treated with ICIs for cancer. We propose a multi-site 12-month prospective cohortstudy (N=450; 150 per site) with cancer patients treated with ICI (within 3 months): 225 cannabis users (regularweekly use in the prior month) and 225 cannabis non-users (no use in the past 6 months). Cannabis usebenefits and harms will be assessed via ecological momentary assessment (collected 7 days/time point; 49days total) patient reported outcomes will be assessed via online/phone surveys and routine clinical data willbe extracted from electronic medical records. Among a subset of 60 patients who have not yet started ICItreatment (30 cannabis users; 30 non-users) we will examine immunological markers (e.g. TNF- IL-6 CRP)at baseline (prior to starting ICI) 2 6 & 12 months. The Specific Aims are to: 1) assess benefits (pain severity& interference sleep disturbance anxiety quality of life) and harms (difficulty concentrating impaired memorydizziness fatigue) of cannabis use over time; 2) test whether cannabis use over time moderates the associationsbetween neighborhood disadvantage (Area Deprivation Index) and benefits and harms in Aim 1; & 3) among asubset of 60 patients with non-skin solid malignancies who have not yet started ICI explore the association ofcannabis use with disease progression and immunological markers. This timely and comprehensive study inresponse to RFA-CA-22-052 will fill critical gaps in knowledge about longitudinal benefits and harms of cannabisuse in persons treated with ICIs. The strong multidisciplinary team brings the requisite expertise in cancersymptom management medical cannabis health equity oncology immunology and substance misuse. Incollaboration with other funded U01s and U24 this research will have a sustained impact on the science ofcancer symptom management and ultimately improve patient care and safety. 676418 +No NIH Category available Acceleration;Acute T Cell Leukemia;Adenosine;Adult;Biology;Cell Maintenance;Cells;Child;Childhood Precursor T Lymphoblastic Leukemia;Classification;Clinical;Collection;Communities;DNA Sequence Alteration;Data Set;Development;Disease Outcome;Double-Stranded RNA;Evaluation;Event;Exhibits;Future;Gene Expression;Genes;Genetic;Goals;Hematopoietic stem cells;Human;Impairment;Individual;Innate Immune Response;Inosine;Knowledge;Lesion;Life Expectancy;Link;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Medical;Mission;Modification;Mutation;Oncogenes;Oncogenic;Outcome;Pathogenesis;Patients;Pediatric Research;Play;Prevention strategy;Prognostic Marker;RNA;RNA Editing;Recurrence;Recurrent disease;Refractory;Regulation;Relapse;Reporting;Research;Role;Sample Size;Site;Survival Rate;T-Cell Leukemia;Tumor Suppressor Proteins;United States National Institutes of Health;Work;adenosine deaminase;cancer type;clinically relevant;cohort;conventional therapy;dsRNA adenosine deaminase;epitranscriptomics;insight;interest;leukemia;leukemia initiating cell;leukemia relapse;molecular subtypes;mouse model;novel;novel therapeutics;prevent;progenitor;programs;self-renewal;success;therapeutic target;therapy resistant;transcriptome;transcriptomics;tumorigenesis Profiling Epitranscriptomic RNA editing in Pediatric Cancer NARRATIVEThe proposed work is relevant to NIH's mission statement because it seeks to dissect the precise RNA editinglandscape mediated by the oncogenic RNA deaminase ADAR1 in T-cell leukemia initiating cell propagation.Thus it will accelerate future epi-transcriptomic research in pediatric cancer and will open new avenues toprevent disease relapse in T-ALL. NCI 10791452 11/30/23 0:00 PAR-23-075 1R03CA287274-01 1 R03 CA 287274 1 "DAEE, DANIELLE L" 1/1/24 0:00 12/31/25 0:00 Cancer Genetics Study Section[CG] 10958250 "JIANG, QINGFEI " Not Applicable 50 MISCELLANEOUS 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF ARTS AND SCIENCES 920930621 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 158000 NCI 100000 58000 SUMMARY/ABSTRACTRelapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL) is often refractory to conventional therapy andis associated with a dismal survival rate of less than 25%. Thus the development of novel therapies for relapsedT-ALL represents an urgent unmet medical need in children. Adenosine deaminase acting on RNA 1 (ADAR1)mediates the conversion of adenosine (A) to inosine (I) in the mammalian transcriptome. Malignant ADAR1activation and over-editing was reported in extensively reported in adult cancer type. As a result there is anintense interest to understand the mechanisms by which ADAR1-directed A-to-I RNA editing regulates geneexpression and how these editing events influence tumorigenesis. However the global landscape of A-to-I RNAediting in pediatric cancer has not been systematically characterized. Fulfilling this knowledge gap will allowmechanistic and functional studies of these RNA editing modifications that can ultimately aid in formulating newtherapeutic and preventive strategies. We discovered that 70% of T-ALL patients exhibit high expression ofADAR1 and this is associated with a significantly worse clinical outcome. Our RNA editing analysis of over 260T-ALL patients revealed wide-spread A-to-I RNA mutations in the relapsed T-ALL cohort. Strikingly we foundthat inhibiting ADAR1 impairs malignant T-ALL progenitor propogation. These discoveries need to be validatedin a large cohort of T-ALL patients to further delineate the critical RNA editing mutations associated withrelapse. The overall objective of this study is to leverage on the large sample size in Kids First Program to fullyunderstand the heterogenous RNA editing landscape in T-ALL pathogenesis. Our central hypothesis that ADAR1promotes unique A-to-I RNA editing changes in T-ALL which drives disease relapse and therapeutic resistance.In this proposal we will 1) define the ADAR1-controlled A-to-I RNA editing landscape in 1304 T-ALL patients bycombining the Kids First and NCI TARGET datasets 2) identify novel RNA editing events that predict diseaseoutcome and 3) compare the RNA editing landscapes in various molecular subtypes to reveal any critical linkbetween RNA editing and genetic background. Our preliminary studies and the proposed work together willprovide the first complete A-to-I RNA editing landscape in T-ALL that will be shared within the pediatricresearch community. In addition we will provide new insights into the mechanisms and functions of ADAR1 inT-ALL pathogenesis and will substantially advance our understanding of the epitranscriptomic regulation inpediatric malignancies. The success of this work will reveal a comprehensive evaluation of the RNA editingnetwork that provides advantages for leukemia expansion and RNA hyper-editing events which may serve asan attractive therapeutic target. 158000 +No NIH Category available 19 year old;Address;American;Atlases;Automobile Driving;BRAF gene;Biological;Biological Markers;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cancer Etiology;Cancer Histology;Central Nervous System Neoplasms;Cessation of life;Child;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Clinical;Copy Number Polymorphism;Correlative Study;DNA;DNA Repair Gene;DNA Sequence;DNA Sequence Alteration;DNA sequencing;Data;Diagnosis;Disease;Epidemiology;Evaluation;Event;Future;Gene Fusion;Gene set enrichment analysis;Genes;Genetic;Genetic Counseling;Genetic study;Genomics;Germ-Line Mutation;Glioma;Goals;Health;Heritability;Histology;Inherited;Intervention;MEKs;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Medical Genetics;Mismatch Repair;Mission;Modeling;Mutation;Oncogenic;Outcome;Parents;Pathogenicity;Pathway interactions;Patients;Pediatric Neoplasm;Predisposition;Process;Protein Isoforms;Public Health;RNA;RNA Sequences;Recurrence;Reporting;Research;Research Project Grants;Sampling;Single Nucleotide Polymorphism;Solid Neoplasm;Spinal Cord Neoplasms;Structural Congenital Anomalies;Survival Analysis;Susceptibility Gene;Testing;Therapeutic;Therapeutic Intervention;Time;Transcript;United States;United States National Institutes of Health;Variant;cancer initiation;cancer predisposition;chemotherapy;clinically actionable;cohort;comparison control;computational pipelines;data integration;data resource;design;evidence base;gene repair;genetic risk factor;genetic variant;improved;improved outcome;in silico;inhibitor;insertion/deletion mutation;insight;kinase inhibitor;medical schools;molecular targeted therapies;novel;proband;rare variant;risk prediction;risk stratification;success;tool;transcriptome sequencing;tumor;tumor DNA;tumor heterogeneity;tumor initiation;tumor progression;tumorigenesis;virulence gene Identification and characterization of genetic risk factors in pediatric brain tumors Project NarrativeThe proposed research project is relevant to public health because we address a major gap in our understandingof the genetic basis of cancer initiation and progression in pediatric brain tumor patients. The proposed researchis highly relevant to the NIH mission of improving health outcomes as the heritability of pathogenic germlinevariants will inform genetic counseling and discoveries of basic genetic mechanisms of tumor initiation andprogression will lead to rational clinical interventions. NCI 10790813 11/23/23 0:00 PAR-23-075 1R03CA287169-01 1 R03 CA 287169 1 "DAEE, DANIELLE L" 12/1/23 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-BTC-H(02)M] 10208179 "DISKIN, SHARON " "ROKITA, JO LYNNE " 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 178000 NCI 100000 78000 PROJECT SUMMARYBrain tumors are the most common form of cancer in children between 0-19 years of age in the United Statesand are the largest cause of cancer-related deaths. Our long term goal is to improve the outcomes of childrendiagnosed with brain tumors by characterizing the germline and somatic events driving tumorigenesis so thatrational evidence-based therapies can be developed. Our objective here is to perform an integrative germline-tumor analysis of the Gabriela Miller Kids First (GMKF) X01 CA267587 pediatric brain tumor cohort to identifyboth inherited and de novo pathogenic or likely pathogenic (P-LP) genetic variants that may be exploitable forsubtyping risk prediction and/or therapeutic intervention. Data from the GMKF cohort will be combined withextant sequencing data from the Pediatric Brain Tumor Atlas (PBTA) to yield 3849 germline DNA and 4438tumor DNA/RNA sequences. The combined cohort spans seventeen broad histologies and includes robustly-annotated patient-parent triads/dyads (n=771). Our central hypothesis is that both inherited and de novo P-LPgermline variants influence the initiation and progression of pediatric brain tumors. Here we will test ourhypothesis and accomplish our objective in two specific aims: Aim 1) Identify and assess heritability of rareP-LP variants in pediatric brain tumor triads and dyads. Rare single nucleotide variants (SNVs) and insertion-deletions (INDELS) will be investigated through a well-developed computational pipeline. Pathogenicity will beassessed using our American College of Medical Genetics (ACMG)-guided approach. Triad/dyads will be studiedto assess whether variants are inherited or acquired de novo. Rare variant burden testing will be performedthrough comparison to multiple cancer-free cohorts. Clinical and tumor-biological correlative studies and survivalanalyses will be undertaken. Aim 2) Perform integrative tumor-normal analyses to elucidate functionalrelevance of germline P-LP variants. Somatic second hits at the gene and pathway level will be assessed forthe entire cohort (N=2558). Next using pediatric high-grade glioma (pHGG) as a model an expanded integrativein silico evaluation of recurrent or aggregate germline events using matched tumor DNA and RNA sequencingwill be performed (N=367 pHGGs). Germline copy number variants (CNVs) will be identified and heritabilityassessed. Tumor sequencing data will be processed through OpenPBTA somatic workflows designed toevaluate SNV INDELS structural variants (SVs) and mutational signatures in DNA and account for expressionprofiles isoforms fusions and other novel transcripts in RNA. Through integration of the X01 CA267587 pediatricbrain tumor cohort with extant childhood cancer and structural birth defect data we expect to advance ourunderstanding of the genetic basis of a diverse array of pediatric brain tumors with insights here being applicableto the genetic basis of other childhood conditions. Moreover we will address for the first time whether pediatricbrain tumor genetic risk factors are inherited or acquired de novo. Completion of this project will have a sustainedand positive impact on the field by identifying clinically actionable genetic alterations in these important cancers. 178000 +No NIH Category available Environment;Mentorship;Training Enhancing Culturally Responsive Mentorship in the T32 Training Environment PROJECT NARRATIVEThis supplement will provide education and training in culturally responsive mentorship to two cohorts ofmentors: our own T32 mentors and the alumnae of our T32 Program serving as Sponsors to our currenttrainees. In conjunction and consultation with the Center for the Improvement of the Mentored Experience inResearch (CIMER) the Harvard Core Team will offer an workshops on the science of mentorship how tofacilitate mentor education and training and an advanced course in culturally aware mentorship. This capacity-building work which will be formally evaluated at the end of the 1-year supplement will substantially improvethe ecosystem of mentorship by elevating the awareness of conversations about and ability to mentor andwork in a diverse equitable and inclusive environment. NCI 10790206 8/21/23 0:00 PA-20-272 3T32CA057711-30S1 3 T32 CA 57711 30 S1 "LIM, SUSAN E" 9/2/19 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1863832 "EMMONS, KAREN M." "FRAZIER, ANNE LINDSAY" 7 SOCIAL SCIENCES 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 72360 OD 67000 5360 PROJECT SUMMARYBackground: Culturally responsive mentorship acknowledges the prior experiences socio-cultural contextsand frames of reference that may inhibit the development of a science identity sense of belonging and outcomeexpectations that are critical for the success and persistence of under-represented trainees in STEMM fields.The Harvard Education Program in Cancer Prevention and Control (5 T32 CA057711) identified enhancementof mentorship as one of its three specific aims at the time of the last competitive renewal. The Programpartnered with the Center for the Improvement of the Mentored Experience in Research (CIMER) to enhancementorship training with the appointment of Dr. Frazier a Principal Facilitator with CIMER as a multiple PI ofthe T32. In addition Dr. Chris Pfund CIMER Director joined the External Advisory Board. Over the last 2years the Programs primary mentors have all undergone mentorship training using the CIMER EnteringMentoring curriculum composed of 6 core competencies.Objectives: 1) Enhance the professional development of our current trainees by creating a SponsorshipProgram with our diverse and accomplished alumnae assigning an alumnae sponsor to each of our currentfellows. 2) Build the capacity for offering evidence-based mentor training by offering facilitator (leader) training ofthe Entering Mentoring curriculum developed by the Center for the Improvement in Mentored Experience inResearch (CIMER) to our alumnae Sponsors and the rest (new mentors secondary mentors affiliated mentors)of our T32 mentors cohort 3)Deepen the training of our mentors and alumni sponsors by focusing on culturally-aware mentorship by offering CIMERs new Culturally Aware Mentoring curriculum.Methods: We plan to kick-off this work with a workshop on the State of the Science of Mentorship and anassessment of the current mentorship landscape within our T32. We plan to establish a Sponsorship Programfor our current T32 fellows by recruiting Sponsors from our T32 Alumnae network. We will also offer EnteringMentoring to our Alumnae Network as part of establishing the Sponsorship program. We plan to increase thepool of CIMER-certified facilitators to meet the demand for mentorship training by offering training on how tofacilitate (lead) the basic mentorship training course called Entering Mentoring. These trained facilitators can inturn train the rest of their research teams (dissemination). Finally we plan to offer advanced training inCulturally Aware Mentoring with those from the above cohorts who have completed basic mentorship training.We will then evaluate this training program and make plans to further disseminate it and imbed it within theinstitutions that comprise the DF/HCC. With this multi-tiered approach we anticipate enhancing mentorshipexcellence across the entire training ecosystem of our T32. 72360 +No NIH Category available ARNTL gene;Acceleration;Address;Affect;Area;Biological Markers;Biological Models;Biological Process;Biological Rhythm;Biology;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Cell Line;Cells;Circadian Dysregulation;Circadian Rhythms;Coupled;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Diurnal Rhythm;Dominant-Negative Mutation;Doxycycline;Drosophila genus;Ectopic Expression;Engineering;Exclusion;Fasting;Gene Expression;Genes;Growth;Heterogeneity;Hour;Human;Human Engineering;Immune;Immune signaling;Immunity;Immunocompetent;Immunologics;Immunotherapy;Infiltration;Inflammation;Inflammatory;Interferons;Intermittent fasting;Knock-out;Link;Malignant Neoplasms;Melanoma Cell;Metabolic;Metabolism;Modeling;Molecular;Mus;Mutation;Null Lymphocytes;Oncogenic;Patients;Phenocopy;Polycomb;Prognosis;Proteins;Proteome;Reagent;Research;Resistance;Role;Series;Signal Transduction;Sleep;System;T cell infiltration;Testing;The Cancer Genome Atlas;Therapeutic;Tumor Biology;Tumor Immunity;anti-PD-1;anti-PD1 therapy;cancer cell;cancer risk;chemokine;circadian;circadian pacemaker;comparison control;cytokine;cytotoxic CD8 T cells;exhaustion;feeding;humanized mouse;immune reconstitution;immune resistance;immunoregulation;in vivo;melanoma;metabolome;monocyte;mouse model;novel;programmed cell death ligand 1;reconstitution;response;shift work;targeted treatment;therapy resistant;transcription factor;transcriptome;transcriptome sequencing;treatment response;tumor;tumor heterogeneity;tumor progression;tumorigenesis;vector;virtual Defining the Role of the Cancer Circadian Clock in Tumor Immunity and Tumorigenesis Project NarrativeDisruption of circadian rhythm which are biological processes that oscillate with a period of 24 hours has beenlinked to increased cancer risk in night-shift workers. Cancer cells can have disrupted cellular circadian clocksthat could make them more or less aggressive or resistant to therapy. This unexplored research area whichis likely to contribute to a better understanding of resistance to standard and immunotherapy will be the focusof this application which is expected to provide concepts for better therapeutic strategies. NCI 10789994 11/29/23 0:00 PA-19-056 5R01CA051497-32 5 R01 CA 51497 32 "ZAMISCH, MONICA" 1/1/90 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 1870828 "DANG, CHI V." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 298434 NCI 182250 116184 Project SummaryCircadian rhythms are biological processes a period of 24 hours driven by the circadian CLOCK-BMAL1transcription factor that regulates diurnal variations of cellular metabolism and inflammation signaling.Disruption of the circadian clock has been linked to cancer but mechanisms of how the clock affects cancerprogression are not well understood. We previously shown that oncogenic MYC could disrupt the circadianclock in cancer cells and in vivo in Drosophila and note that analysis of TCGA data indicates widespreadmutations in the circadian clock circuitry genes. To address the role of the clock heterogeneity in tumor biologywe chose to study melanomas which respond to immunotherapy and targeted therapy with varying degrees oftherapeutic resistance. In preliminary studies of a panel of 14 patient-derived melanoma cell lines we foundheterogeneity in clock function and increased interferon response genes when the clock is molecularlydisrupted in engineered cells. Further we found in a mouse model of melanoma that clock disruption wasassociated with accelerated tumorigenesis in immunocompetent but not immunocompromised mice. Increasedor decreased BMAL1 the central clock component induced dedifferentiation rendering mouse melanomacells immune privileged with altered chemokine expression and resistance to immunotherapy in vivo. Basedon our preliminary studies we hypothesize that functional clock heterogeneity alters cancer cell immunity andcontribute variable therapeutic responses. We propose to alter clock function through loss and gain of BMAL1function in engineered human and mouse melanoma cell lines and determine the molecular mechanismsunderlying resistance of melanoma to anti-PD1 treatment. We will use a humanize mouse (Hu-mice) system tostudy the clock-engineered human melanoma cells in vivo. These findings are expected to contribute novelconcepts of therapeutic resistance biomarkers based on clock biology and eventual better therapeuticstrategies. 298434 +No NIH Category available Actins;Actomyosin;Award;Basement membrane;Benign;Biocompatible Materials;Biophysical Process;Breast Cancer Cell;Bulla;Carcinoma;Cell Cycle Progression;Cells;Characteristics;Clinical Trials;Collagen;Collagen Type I;Disease;Ductal Carcinoma;Elasticity;Endothelium;Epithelium;Exhibits;Extracellular Matrix;Extravasation;Failure;Filopodia;Goals;Human;Individual;Integrin Binding;Integrins;Intervention;Invaded;Knowledge;Lesion;Ligands;Malignant - descriptor;Malignant Epithelial Cell;Matrix Metalloproteinase Inhibitor;Measures;Mechanics;Mediating;Mesenchymal;Mission;Mitotic;Modeling;Molecular;Molecular Target;Morphology;Nanoporous;Nature;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Peptide Hydrolases;Phase;Physiological;Polymers;Process;Proliferating;Public Health;Research;Resistance;Role;Testing;Tissues;United States National Institutes of Health;Viscosity;Work;breast cancer progression;breast lesion;cancer cell;cancer type;cell motility;cell type;crosslink;density;disability;epigenome;infiltrating duct carcinoma;innovation;malignant breast neoplasm;malignant phenotype;mammary epithelium;mechanical properties;migration;mortality;novel;novel diagnostics;novel therapeutic intervention;pharmacologic;polymerization;prevent;three dimensional cell culture;tumor progression;viscoelasticity Role of extracellular matrix malleability in mediating breast cancer cell invasion and migration PROJECT NARRATIVEThe proposed research is relevant to public health because invasion and metastasis during breast cancerprogression are associated with increased mortality yet the biophysical mechanisms underlying these twoprocesses are not well understood. Therefore the proposed research on understanding how extracellularmatrix malleability regulates the collective invasion and migration of breast cancer cells is relevant to the partof NIH's mission that seeks to develop fundamental knowledge that will help reduce the burdens of humandisability and disease. Ultimately it is anticipated that this study will uncover previously un-described modes ofinvasion and migration thereby leading to new diagnostic measures of pre-invasive breast cancer and newtherapeutic strategies to block invasion and metastasis. NCI 10789843 12/21/23 0:00 PA-16-160 5R37CA214136-07 5 R37 CA 214136 7 "BECKER, STEVEN" 1/1/18 0:00 12/31/24 0:00 10283976 "CHAUDHURI, OVIJIT " Not Applicable 16 ENGINEERING (ALL TYPES) 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA BIOMED ENGR/COL ENGR/ENGR STA 943052004 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 311840 NCI 201969 109871 Ductal carcinoma is the most common form of breast cancer and progresses to invasive ductal carcinoma (IDC)when the carcinoma invades through the basement membrane (BM) into the stromal tissue. Invasion is a keystep in ductal carcinoma progression that is associated with an increased likelihood for metastasis the mostdeadly aspect of breast cancer. During metastasis cancer cells must also invade BM during intravasation andextravasation. The overall goal of our work is to determine how matrix mechanical plasticity (malleability)regulates breast cancer invasion and migration. In the initial 5-year phase of this R37 award we found that breastcancer tissue is mechanically plastic and that individual breast cancer cells can migrate through nanoporousmatrices independent of proteases using invadopodia if the matrix exhibits sufficient matrix mechanical plasticity.We also found that increased covalent crosslinking of the matrix or increased stiffness inhibits invadopodiaformation and that cancer cells can utilize filopodia to migrate along soft basement-membrane-like substrates ifthe substrate is sufficiently viscoelastic or malleable. We have also pursued related lines on inquiry finding thatextracellular matrix viscoelasticity regulates cell-cycle progression that cancer cells generate force in order toundergo mitotic elongation and divide in confining type-1 collagen rich matrices that increased stiffnessregulates breast cancer progression through a YAP-independent mechanism and that increased stiffnessinduces broad changes in the epigenome that functionally mediate a stiffness-induced malignant phenotype inmammary epithelium. While our initial studies on the role of malleability in invasion focused on single cell invasioninitial invasion of the BM during cancer progression is thought to be collective in nature involving the coordinatedactivity of multiple cells. The specific hypothesis to be tested in this R37 extension application is that matrixmechanical plasticity (malleability) is a key physical parameter mediates collective invasion of the BM andsubsequent migration through the type-1 collagen rich stromal matrix during cancer progression. This hypothesiswill be tested by pursuing the following two specific aims: (1) Determine how basement membrane mechanicalplasticity (malleability) mediates collective cell invasion; (2) Determine how mechanical plasticity (malleability) oftype-1 collagen rich matrices mediates collective migration of breast cancer cells. This approach is innovativebecause of its focus on understanding the role of malleability in mediating protease-independent and -dependentinvasion and migration as malleability is a physical characteristic of ECM related to matrix viscosity but distinctfrom elasticity or density which has been largely ignored in studies to date. This work is also innovative in itsfocus on collective invasion of the basement membrane instead of single cell invasion. The proposed researchis significant because it will reveal the role of ECM malleability in mediating both protease-dependent andprotease-independent collective invasion and migration by breast cancer cells potentially uncovering previouslyun-described modes of invasion or migration. 311840 +No NIH Category available Address;Adopted;Adoption;Adult;Affect;Air;Area;Authorization documentation;Biological Markers;Biological Monitoring;Cessation of life;Cigarette;Cities;Communities;Cotinine;Data;Development;Disparity;Disparity population;Economics;Effectiveness;Environment;Experimental Designs;Focus Groups;Health Benefit;Home;Home environment;Household;Housing;Interdisciplinary Study;Intervention;Interview;Knowledge;Learning;Location;Low Income Population;Low income;Measures;Methods;Movement;Neighborhoods;New York City;Outcome;Participant;Passive Smoking;Patient Education;Patient Self-Report;Persons;Policies;Policy Compliance;Population;Predisposition;Process;Property;Provider;Public Housing;Random Allocation;Randomized Controlled Trials;Reporting;Research;Resources;Sales;Salivary;Sampling;Sensory;Services;Smoke;Smoke-free home;Smoker;Smoking;Smoking Behavior;Smoking Status;Source;Surveys;System;Testing;Time;Tobacco;Tobacco use;United States;Vulnerable Populations;arm;authority;community engagement;density;design;disparity reduction;environmental tobacco smoke exposure;ethnic minority;experience;frontier;hazard;high risk;high risk population;implementation intervention;informant;non-smoker;non-smoking;novel;patient navigator;post intervention;premature;preventable death;racial minority;recruit;residence;smoke-free policy;smoking cessation;social;social media;tobacco products;trial design;ventilation A randomized controlled trial to support smoke-free policy compliance in public housing Project NarrativeSmoke-free housing policies in multiunit housing are promising and increasingly widespread interventions toreduce smoking and secondhand smoke exposure. Little research has identified factors that impedecompliance with smoke-free housing policies in low-income multiunit housing and test corresponding solutions.The proposed RCT addresses key gaps in knowledge and capitalizes on key scientific opportunities by: 1)leveraging the federal mandate to ban smoking in a public housing system of more than sufficient size toconduct an adequately powered RCT; 2) expanding our understanding of smoke-free policy compliancebeyond policy implementation by testing two novel treatments: a) in-residence smoking cessation and b)resident endorsement while 3) addressing population and location-specific tobacco-related disparities. NCI 10789842 12/15/23 0:00 PAR-18-675 5R01CA240555-04 5 R01 CA 240555 4 "LAND, STEPHANIE R" 8/1/20 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-RPHB-N(56)R] 10807240 "HERNANDEZ, DIANA " Not Applicable 13 PUBLIC HEALTH & PREV MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF PUBLIC HEALTH 100323725 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 493940 NCI 304901 189039 Project SummaryTobacco use remains a leading cause of preventable premature death in the United States especially forracial/ethnic minorities and low-income populations. Public and multiunit housing are closely tied to tobacco-related disparities as vulnerable populations are most likely to live in multiunit housing with the highest rates ofsmoking and secondhand smoke exposure while also the least likely to have access to smoke-free homeenvironments. For example New York City Housing Authority (NYCHA) residents smoke at higher rates reporthigher secondhand smoke exposure from an outside source and are surrounded by high density tobacco retailenvironments compared to other New Yorkers. Public housing is at the forefront of the smoke-free policymovement. In 2016 HUD mandated that all housing authorities adopt smoke-free policies which affects all3300 housing authorities and 1.2 million households nationwide. NYCHA is the largest public housing providerin the nation; it houses more than 400000 people in 326 public housing developments spanning over 2400buildings citywide. As of July 2018 all NYCHA housing units adopted a smoke-free policy affecting allproperties. The implementation of this policy the largest of its kind represents a critical opportunity to examineand reduce public housing-related tobacco hazards. To date no randomized controlled trials (RCT) have beenconducted to test the effects of compliance strategies on resident smoking behavior and secondhand smokeexposure. The proposed design will be a borough-stratified four-arm factorial-design cluster RCT that willtarget 128 randomly selected buildings (32 buildings per arm) in separate NYCHA developments. We willrecruit and follow 8 randomly selected residents stratified by smoking status- 4 smokers and 4 non-smokers-per building (n=1024) into four arms: (1) relocation/cessation (2) resident endorsement (3) relocation/cessation plus resident endorsement and (4)the standard approach (256 participants per arm). Outcomeswill be assessed longitudinally using salivary cotinine and resident surveys to measure smoking behaviors andsecondhand smoke exposures at 4 time points: baseline 2 6 and 12 months post-intervention. Qualitativedata will also be collected via key informant interviews focus groups and sensory observations of buildings.This mixed methods pre-post with comparison RCT design overseen by a highly experienced interdisciplinaryteam in partnership with NYCHA and a stakeholder advisory board. Aims include to experimentally test if policycompliance interventions reduce personal smoking behavior (Aim 1); reduce secondhand smoke exposure(Aim 2) and determine if the tobacco retail environment surrounding each building moderates the relationshipbetween compliance interventions and smoking-related outcomes (Aim 3). This comprehensive communityengaged and social-ecologically informed RCT supports the design and implementation of interventions tooptimize smoke-free housing compliance for populations with high burdens of tobacco-related disparities. 493940 +No NIH Category available Adherence;Biological Assay;Biological Products;Cancer Center;Clinical Trials;Clinical Trials Network;Collaborations;Community Clinical Oncology Program;Conduct Clinical Trials;Contract Services;Data;Division of Cancer Treatment and Diagnosis;Ensure;Funding;Funding Agency;Good Clinical Practice;Good Manufacturing Process;Guidelines;Institution;International;Investigational Therapies;Laboratories;Medidata;Monitor;Monitoring Clinical Trials;Patients;Phase;Phase II Clinical Trials;Policies;Procedures;Process;Protocols documentation;Quality Control;Randomized;Regulation;Research;Resources;Services;Site;Site Visit;Support Contracts;System;United States Dept. of Health and Human Services;United States Food and Drug Administration;Visit;data integrity;data management;early phase clinical trial;good laboratory practice;manufacturing facility;patient registry;quality assurance;research and development;symposium CLINICAL TRIALS MONITORING SERVICE_ Moonshot support n/a NCI 10789829 75N91022C00013-P00002-9999-2 N01 5/1/22 0:00 4/30/23 0:00 78653629 "ANDERSON, BARRY " Not Applicable 12 Unavailable 61814323 HFYTJGWFPMR7 61814323 HFYTJGWFPMR7 US 40.362811 -74.600076 1721601 "THERADEX SYSTEMS, INC." PRINCETON NJ Domestic For-Profits 85405748 UNITED STATES N R and D Contracts 2023 360000 NCI This is a Research and Development Support contract. The purpose of this acquisition is to assist the NCI in fulfilling its responsibilities to the Food and Drug Administration (FDA) and Department of Health and Human Services (DHHS) regulations as IND sponsor and funding agency. The scope of the Clinical Trials Monitoring Service (CTMS) contract is to provide data management quality assurance clinical trial monitoring and auditing capability for NCI sponsored clinical trials conducted by the NCI's Experimental Therapeutics Clinical Trials Network (ETCTN) at participating sites both domestically and internationally. Additionally the CTMS contract provides a mechanism for the auditing of biopharmaceutical manufacturing facilities to ensure compliance with current Good Manufacturing Practices (GMP) and compliance with Good Laboratory Practices (GLP) for laboratories performing integral assays. 360000 +No NIH Category available Adherence;Biological Assay;Biological Products;Cancer Center;Clinical Trials;Clinical Trials Network;Collaborations;Community Clinical Oncology Program;Conduct Clinical Trials;Contract Services;Data;Division of Cancer Treatment and Diagnosis;Ensure;Funding;Funding Agency;Good Clinical Practice;Good Manufacturing Process;Guidelines;Institution;International;Investigational Therapies;Laboratories;Medidata;Monitor;Monitoring Clinical Trials;Patients;Phase;Phase II Clinical Trials;Policies;Procedures;Process;Protocols documentation;Quality Control;Randomized;Regulation;Research;Resources;Services;Site;Site Visit;Support Contracts;System;United States Dept. of Health and Human Services;United States Food and Drug Administration;Visit;data integrity;data management;early phase clinical trial;good laboratory practice;manufacturing facility;patient registry;quality assurance;research and development;symposium CLINICAL TRIALS MONITORING SERVICE n/a NCI 10789828 75N91022C00013-P00002-9999-1 N01 5/1/22 0:00 4/30/23 0:00 78653629 "ANDERSON, BARRY " Not Applicable 12 Unavailable 61814323 HFYTJGWFPMR7 61814323 HFYTJGWFPMR7 US 40.362811 -74.600076 1721601 "THERADEX SYSTEMS, INC." PRINCETON NJ Domestic For-Profits 85405748 UNITED STATES N R and D Contracts 2023 8607355 NCI C6 This is a Research and Development Support contract. The purpose of this acquisition is to assist the NCI in fulfilling its responsibilities to the Food and Drug Administration (FDA) and Department of Health and Human Services (DHHS) regulations as IND sponsor and funding agency. The scope of the Clinical Trials Monitoring Service (CTMS) contract is to provide data management quality assurance clinical trial monitoring and auditing capability for NCI sponsored clinical trials conducted by the NCI's Experimental Therapeutics Clinical Trials Network (ETCTN) at participating sites both domestically and internationally. Additionally the CTMS contract provides a mechanism for the auditing of biopharmaceutical manufacturing facilities to ensure compliance with current Good Manufacturing Practices (GMP) and compliance with Good Laboratory Practices (GLP) for laboratories performing integral assays. 8607355 +No NIH Category available Ablation;Acoustics;Address;Adjuvant Chemotherapy;Animals;Biodistribution;Biological;Biomedical Engineering;Blood - brain barrier anatomy;Brain;Brain Glioblastoma;Brain Neoplasms;CAR T cell therapy;CD276 gene;Cell Therapy;Cells;Clinical;Clinical Research;Clinical Trials;Deposition;Diagnosis;Disease;Essential Tremor;Excision;FDA approved;Focused Ultrasound;Focused Ultrasound Therapy;Glioblastoma;Human;Immunotherapy;In Vitro;Inflammatory;Injections;Intravenous;Intraventricular;Malignant Neoplasms;Mechanics;Mediating;Microbubbles;Microglia;Modeling;Mus;Normal tissue morphology;Operative Surgical Procedures;PTPRC gene;Patients;Phase I Clinical Trials;Physiologic pulse;Physiological;Pilot Projects;Positioning Attribute;Pre-Clinical Model;Primary Brain Neoplasms;Proliferating;Proteins;Public Health;Qualifying;Radiation therapy;Rodent;Rodent Model;Role;Route;Safety;Specimen;Survival Rate;System;T-Lymphocyte;Tail;Technology;Therapeutic;Time;Time Study;Tissues;Tumor Cell Line;Tumor-associated macrophages;Ultrasonic Therapy;Ultrasonography;Veins;Xenograft Model;Xenograft procedure;antitumor effect;blood-brain barrier disruption;blood-brain barrier permeabilization;brain tissue;chemokine;chemotherapeutic agent;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical translation;efficacy evaluation;exhaustion;experience;experimental study;high reward;high risk;image guided;immunoregulation;improved;improved outcome;in vivo;indexing;intercellular cell adhesion molecule;leukemia;mouse model;nanoparticle;neoplastic cell;novel;novel strategies;overexpression;patient population;response;small molecule;success;synergism;technology development;trafficking;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;ultrasound Novel approaches to enrich CAR-T cell Therapy in brain tumors using focused ultrasound RELEVANCE TO PUBLIC HEALTHIn this high-risk high-reward project we have assembled a uniquely qualified team to explore novel applicationsof FUS to improve Chimeric antigen receptor T cell (CAR-T) therapy for glioblastoma (GBM) treatment. CAR-Tsare a promising new treatment platform that allows directed targeting and killing of tumor cells. We hypothesizethat FUS-mediated BBB disruption will result in increased trafficking of systemically administered B7-H3.CAR-Ts to GBM tumors; and FUS therapy will improve overall anti-tumor efficacy of B7-H3.CAR-Ts by modulating theimmunosuppressive tumor microenvironment. NCI 10789255 12/8/23 0:00 PAR-22-216 1R21CA286897-01 1 R21 CA 286897 1 "HU, ZHANG-ZHI" 1/1/24 0:00 12/31/25 0:00 ZCA1-SRB-P(O2) 9239482 "DAYTON, PAUL A" "RAUF, YASMEEN " 4 BIOMEDICAL ENGINEERING 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 175425 NCI 116875 58550 PROJECT SUMMARYFocused Ultrasound (FUS) is a powerful technology now FDA approved for several ablative brain therapies andhas demonstrated an impressive safety and efficacy profile for treating diseases such as essential tremor.Beyond ablation early human studies demonstrate efficacy and safety of noninvasive microbubble-mediatedblood-brain barrier (BBB) disruption with FUS for advanced therapeutic applications. In this high-risk high-reward biomedical engineering project we have assembled a uniquely qualified team to explore novelapplications of FUS to improve Chimeric Antigen Receptor T cell (CAR-T) therapy for glioblastoma (GBM)treatment. CAR-Ts are a promising new treatment platform that allows directed targeting and killing of tumorcells. Locally administered CAR-Ts have demonstrated promising efficacy against GBM. However likechemotherapeutic agents systemically administered CAR-Ts suffer from limited access to the brain. We andothers have demonstrated applications of focused ultrasound (FUS) with FDA approved microbubbles to amplifythe deposition of ultrasound energy into tissue inducing a variety of biological effects. Under certain ultrasoundconditions FUS can temporarily and reversibly alter the permeability of the BBB to deliver exogenouscompounds into the brain which has been demonstrated in preclinical models and early-stage clinical trials inhumans. We have developed an ultrasound image-guided FUS therapeutic platform specific for rodents capableof consistent and accurate targeting of BBB disruption and delivery of therapeutics to the brain a necessaryrequirement for the proposed studies. Furthermore we have identified the immunoregulatory protein B7-H3 asan attractive CAR-T target which is highly expressed in clinical GBM isolates but not in normal tissue. We havedeveloped both murine B7-H3.CAR-Ts which demonstrate efficacy in xenograft models and human B7-H3.CAR-Ts which are currently being evaluated in phase 1 clinical trials for safety and antitumor activity at ourfacility. Our team is therefore in a unique position to study the potential application of FUS to improve CAR-Ttherapy for GBM. Specifically we hypothesize that FUS-mediated BBB disruption will result in increasedtrafficking of systemically administered B7-H3.CAR-Ts to GBM tumors; and FUS therapy will improve overallanti-tumor efficacy of B7-H3.CAR-Ts by modulating the immunosuppressive tumor microenvironment. Thesehypotheses will be addressed by 1) first establishing the effects of FUS with varying parameters to increasetrafficking of B7-H3.CAR-Ts to GBM tumors 2) determining B7-H3.CAR-T biodistribution proliferation andpersistence over time following systemic administration with FUS therapy and finally 3) a pilot study to determinethe impact of FUS therapy on the tumor immune microenvironment and how those changes augment B7-H3.CAR-T efficacy. Success of this biomedical engineering project would pave the way for further technologydevelopment as well as exploration and clinical translation of the synergy of these two relatively new and powerfultechnologies to make a substantial impact in the lives of GBM patients. 175425 +No NIH Category available Automation;Binding;Binding Sites;Biological;Biological Availability;Brain;Brain imaging;Cell Nucleus;Central Nervous System;Chemistry;Communities;Cyclooctenes;Development;Evaluation;Feedback;Future;Hydrophobicity;Image;Imaging Device;In Vitro;Kinetics;Label;Ligands;Ligation;Malignant Neoplasms;Maps;Medical Imaging;Methodology;Methods;Peptides;Permeability;Pharmaceutical Preparations;Positron-Emission Tomography;Preparation;Procedures;Property;Proteins;Protocols documentation;Radiochemistry;Radiolabeled;Rattus;Reaction;Reporter;Research;Site;Technology;Toxic effect;Translations;Variant;cancer imaging;commercialization;commercialization readiness;design;drug development;drug discovery;drug distribution;hydrophilicity;improved;in vivo;lipophilicity;nanobodies;prevent;radiochemical;rapid technique;reaction rate;scaffold;small molecule;success;technological innovation;technology validation;tool Development of an Efficient 18F labeling technology based on tetrazine trans-cyclooctene ligation Project NarrativeIn this collaborative project we will develop efficient methods for the construction of 18F labeled agents using thetetrazine-trans-cyclooctene ligation. We will develop new 18F labeled trans-cyclooctenes and tetrazines asreporters for large molecule distribution in the CNS. The success of this approach will lead to a comprehensiveplatform for Positron Emission Tomography (PET) agent preparation and drug distribution mapping. NCI 10788977 12/5/23 0:00 PAR-22-127 1R01CA287184-01 1 R01 CA 287184 1 "LIN, CHARLES" 12/5/23 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-ISB-C(03)M] 10236919 "LI, ZIBO " "FOX, JOSEPH M" 4 RADIATION-DIAGNOSTIC/ONCOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 12/5/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 643360 NCI 484659 158701 Abstract:Proposed is the development of readily available tools for radiochemistry based on tetrazine ligation abioorthogonal reaction with rapid kinetics that has been studied for over a decade as a uniquely powerful tool forradiochemical labeling of biomolecules. Limitations in accessing tetrazine and trans-cyclooctene (TCO) labelingprecursors with appropriate kinetic and physicochemical properties have prevented the broader application ofthis technology. This proposal builds on several technological innovations in reaction chemistry that have beendeveloped in the groups of PIs including a methodology for introducing 18F into aromatic molecules viaphotocatalysis via C-H activation or aromatic substitution a new methodology for the practical and scalablesynthesis of trans-cyclooctenes with favorable kinetic and physiochemical properties and new methodologiesfor the preparation of functionalized tetrazines. Through this collaborative technology proposal our groups willleverage these methodologies for the development of new tools for the efficient radiolabeling of proteins in site-selective fashion and the application of these tools in vitro. In Aim 1 we will develop improved methods for thesynthesis of 18F-labeled trans-cyclooctenes with balanced reactivity hydrophilicity and stability. Late-stagephotoisomerization will also be used to obtain highly reactive 18F-TCOs and we will develop methodology forthe site-selective attachment to the C-terminus of cancer-targeting proteins. In Aim 2 a rapid and mild methodfor the preparation of 18F-labeled tetrazine reporters will be developed using photoredox radiofluorinationreactions for PET probe construction. In Aim 3 we will validate the newly developed 18F-TCOs and 18F-tetrazinesusing the hydrophilic FAPI ligand the hydrophobic SR142948A and proteins. The brain permeability of the 18F-TCO/tetrazine reporters will also be evaluated in normal rats. Because this application focuses solely on thedevelopment of 18F-labeling technologies the studies in Aim 3 are primarily intended to provide importantfeedback to Aims 1-2 which will result in the design of 18F-TCOs and 18F-tetrazines of high utility to the broaderradiolabeling community (in other words comprehensive evaluation/characterization of specific probes will notbe performed in this application). In summary we are developing a general labeling toolbox to generate 18Flabeled PET agents. We aim to develop labeling precursors that can be readily commercialized so that thedeveloped technologies will be widely used as efficient and simple labeling methods to modify biologically activesmall molecules/peptides/proteins/drugs which could have a significant impact on medical imaging drugdiscovery and development. 643360 +No NIH Category available Acylation;Address;Adenocarcinoma;Affect;Antibiotics;Antitumor Response;B-Lymphocytes;Bacteria;Bacteroides;Breast Carcinoma;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Model;Cancer Patient;Cell Compartmentation;Cell surface;Cells;Clinical;Collaborations;Colon;Colon Adenocarcinoma;Data;Dedications;Dendritic Cells;Development;Dose;Eligibility Determination;Enhancers;Escherichia coli;Exhibits;Experimental Models;FDA approved;Flow Cytometry;Frequencies;Gammaproteobacteria;Genetic Transcription;Germ-Free;Glycolipids;Gnotobiotic;Goals;Gram-Negative Anaerobic Bacteria;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunological Models;Immunologics;Implant;In Vitro;Industrialization;Intestines;Isomerism;Laboratories;Lamina Propria;Lipid A;Literature;Location;MC38;Macrophage;Malignant Neoplasms;Membrane;Microbe;Modeling;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Natural Killer Cells;Oral;Organism;PD-1 pathway;Pathway interactions;Patients;Pentas;Peripheral;Phenotype;Population;Publishing;Regulatory T-Lymphocyte;Signal Pathway;Signal Transduction;Structure;Surface;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Therapeutic;Tissues;Tumor Immunity;analog;anti-PD-L1 therapy;anti-tumor immune response;cancer immunotherapy;cancer type;cell type;checkpoint therapy;clinical application;commensal bacteria;comparison control;draining lymph node;fighting;germ free condition;granulocyte;gut microbiome;gut microbiota;immunogenicity;improved;lipooligosaccharide;medical schools;melanoma;mesenteric lymph node;microbiome;monocyte;novel therapeutics;patient response;programmed cell death ligand 1;response;restraint;subcutaneous;success;therapeutic target;therapy outcome;tumor;tumor growth;tumor microenvironment Tetraacylated lipid A enhancement of checkpoint blocking cancer immunotherapy NarrativeWe have discovered a molecule from the microbiome that enhances checkpoint blocking therapy in 2experimental models of cancer. This molecule is a glycolipid that is found on anaerobic gram-negative bacteriathat live in the intestine and is a tetraacylated monophosphorylated analog of lipid A (4A1P-MPLA). Using asynthetic form of 4A1P-MPLA that enhances regulatory T cells in the gut we will determine mechanisms ofaction and breath of therapeutic targets. NCI 10788868 12/4/23 0:00 PAR-22-062 1R21CA287104-01 1 R21 CA 287104 1 "XI, DAN" 12/4/23 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 1870456 "KASPER, DENNIS L." Not Applicable 7 MICROBIOLOGY/IMMUN/VIROLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 12/4/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 237724 NCI 140250 97474 PROJECT SUMMARYImmune checkpoint inhibitor (ICI) therapy is a therapeutic approach that blocks pathways that inhibit anti-tumorimmunity and activates the immune system to fight cancer. Although ICI therapy has seen significant successin some patients unfortunately most eligible patients still fail to respond to treatment. Several studies havehighlighted the modulatory capacity of the microbial composition of the gut microbiome as well as certainorganisms to direct a patients response to ICI. Our preliminary data show that the human gut commensalBacteroides ovatus 8483 has the capacity to enhance -PD-L1 (Programmed Death-Ligand 1) therapy ingerm-free (GF) and antibiotic-treated mice. The lipooligosaccharide (LOS) of B. ovatus is a major cell surfacemolecule comprising about 50% of the surface of this microbes outer membrane. The LOS exists naturally inseveral different structural analogs. We have found that among the many analogs of lipid A produced by B.ovatus an orally delivered tetra-acylated monophosphorylated lipid A (4A-MPLA) can potently enhance theefficacy of -PD-L1 in mice that would otherwise fail to clear tumors. We propose to determine whether 4A-MPLA could serve as a novel therapeutic for enhancing the current cancer immunotherapy arsenal. Our long-term goal is to use 4A-MPLA in combination with PD-1 pathway blockade to treat cancer patients particularlynon-responders to -PD-L1 alone.Over the course of the next two years we aim to understand: 1) the cell types and signaling pathways bywhich 4A-MPLA influences local and systemic improvement of the -PD-L1 response and 2) understand thetypes of cancers that may respond to this treatment. Given our preliminary studies demonstrating the effect ofB. ovatus on colonic regulatory T cells (Tregs) we hypothesize that B. ovatus is affecting peripheral Tregs inthe colon and disrupting their ability to restrain antitumor immunity. To test this hypothesis we will compare theimmune profiles of cells in several tissues including the gut lamina propria mesenteric lymph nodes tumordraining lymph nodes and the tumor itself in gnotobiotic antibiotic-treated and specific-pathogen-free (SPF)mice treated with 4A-MPLA compared to controls. Tregs as well as other relevant compartments of the tumormicroenvironment (TME) such as CD8+ and CD4+ T cells NK cells NKT cells B cells dendritic cells M1 andM2 macrophages and monocytic and granulocytic myeloid-derived suppressor cells will be analyzed in mousetumor models for immunologic responses to -PD-L1 therapy with or without 4A-MPLA. Finally we willdetermine which murine tumor models respond to this therapy to better predict its clinical applicability. 237724 +No NIH Category available Address;Age;American College of Surgeons;Area;Binding;Breast Cancer survivor;Cancer Control;Cancer Patient;Cancer Survivor;Characteristics;Clinical Trials;Cohort Studies;Computer software;Data;Data Sources;Databases;Effectiveness;Effectiveness of Interventions;Electronic Health Record;Enrollment;Ethnic Origin;Failure;Goals;Health Sciences;Health system;Individual;Internet;Intervention;Malignant Neoplasms;Measures;Methodology;Methods;Modeling;Modification;Outcome;Participant;Patients;Pattern;Population;Proxy;Race;Randomized;Randomized Controlled Trials;Research Personnel;SEER Program;Sampling;Sampling Studies;Selection Bias;Source;Surveys;Survivors;Target Populations;Testing;Treatment Effectiveness;Treatment outcome;United States National Institutes of Health;Work;cancer prevention;data sharing;design;indexing;neoplasm registry;non-compliance;novel;prevent;public health relevance;randomized trial;randomized clinical trials;simulation;study characteristics;treatment effect;tumor A sensitivity analysis framework for generalizing randomized clinical trial results in the presence of unmeasured treatment effect modifiers PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCERandomized trials are the gold standard for assessing interventions for preventing and treating cancer buteven a well-designed and well-executed trial can fail to replicate outside of the study if characteristics of thetrial sample and the target population differ in ways related to the effectiveness of the intervention. This projectwill develop a novel method of assessing the generalizability of trial results to external populations whenfactors that are associated with treatment effects are unmeasured in the trial. This work will have broadapplicability beyond cancer trials as generalizability is a universal concern of randomized trials acrossapplication areas. NCI 10788836 12/29/23 0:00 PAR-23-058 1R03CA280007-01A1 1 R03 CA 280007 1 A1 "UNDALE, ANITA H" 1/1/24 0:00 11/30/25 0:00 ZCA1-SRB-2(O2)S 10222045 "ANDRIDGE, REBECCA ROBERTS" Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF PUBLIC HEALTH 432101016 UNITED STATES N 1/1/24 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 90722 NCI 57601 33121 ABSTRACTRandomized controlled trials (RCTs) are the gold standard for assessing interventions for preventing andtreating cancer but their external validity is only guaranteed if the trial participants are a random sample fromthe target population. Unfortunately most cancer-related RCTs use convenience samples not probabilitysamples and differences between the trial sample and the target population are likely to exist. If thesedifferences are related to the effectiveness of the treatment being studied (effect modifiers) trial results willfail to generalize. While observable differences may be assessed and potentially adjusted for (e.g.underrepresentation of certain demographic groups) these differences have been shown to not completelyexplain the so-called efficacy-effectiveness gap. We posit that unmeasured differences between who choosesto participate in an RCT and who does not may be an important contributor to the failure of some trial results togeneralize. In this project we propose to develop a statistical framework for quantifying the potential impact ofunmeasured differences between the trial sample and the target population on trial results. The resultingsensitivity analysis will bound the potential bias in the treatment effect estimate when generalizing from the trialsample to a target population. The methodology will be based on our prior work developing sensitivity analysesin the areas of survey nonresponse and selection bias which similarly consider the issue of differencesbetween who is in a study sample and who is not. This work will have broad applicability beyond cancer trialsas generalizability is a universal concern of randomized trials across application areas. 90722 +No NIH Category available Affect;Biological;CRISPR/Cas technology;Cancer Etiology;Cancer Family;Cell Line;Cellular biology;Collection;DNA Library;Data;Development;Environmental Exposure;Epidermal Growth Factor Receptor;Etiology;Family;Family Cancer History;Family Study;Family history of;Family member;Frequencies;Generations;Genes;Genetic;Genotype;Goals;Grant;Individual;Inherited;Joints;Malignant Neoplasms;Malignant neoplasm of lung;Modality;Mutation;PARK2 gene;Participant;Pathway interactions;Penetrance;Phenotype;Population;Predisposition;Prevention;Prevention Measures;RB1 gene;Recording of previous events;Research;Resources;Risk;Risk Factors;Role;Sampling;Sampling Studies;Second Degree Relative;Smoking;Smoking Behavior;Smoking History;Specimen;TCF3 gene;TP53 gene;Testing;Tobacco smoking behavior;Toxic Environmental Substances;Update;Variant;cancer risk;data resource;exome sequencing;genetic analysis;genetic epidemiology;genetic linkage analysis;genetic selection;genetic variant;genome wide association study;high risk;high risk population;indexing;insight;member;mortality;next generation;novel;proband;risk variant;screening;smoking exposure;targeted sequencing;tobacco smoke exposure;tumorigenesis Sequencing Familial Lung Cancer NARRATIVEAlthough tobacco smoke exposure is the most important risk factor for lung cancer inheritedgenetic factors also play a role as shown by many family and genome wide association studies.The proposed studies will detect novel rare genetic factors examine interactions between smoking history andthe rare genetic factors and evaluate the impact on the cellular phenotypes of these mutations. NCI 10788313 1/3/24 0:00 PA-19-056 5R01CA243483-05 5 R01 CA 243483 5 "CARRICK, DANIELLE M" 1/22/20 0:00 12/31/24 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 1881790 "AMOS, CHRISTOPHER I." "PINNEY, SUSAN MENGEL" 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 590394 NCI 492976 97418 Lung cancer (LC) is the leading cause of cancer mortality in the U.S. Although tobacco smoking and someenvironmental exposures contribute substantially to lung cancer risk family studies show an additional strongcontribution from genetic factors. The Genetic Epidemiology of Lung Cancer Consortium (GELCC) has beencollecting samples and data from individuals with a strong family history of LC for the last 20 years and hasassembled a unique resource of specimens and data. We have cancer phenotypes smoking exposure dataand biological specimens available on multiple relatives in over 150 highly aggregated LC families (high-riskfamilial lung cancer families HRFLC cases/families) as well as phenotype genotype and smoking data onover 800 additional lung cancer cases who have a family history of at least one first or second degree relativewith lung cancer but for whom biospecimens were not available from additional relatives (familial cases frombiospecimen limited families FLC cases). The goal of this research application is to identify geneticfactors that confer a high risk for lung cancer and to perform research to characterize further themechanisms by which these factors influence lung cancer risk. Identifying genetic factors for lung cancerprovides insight into the specific causes and pathways underlying its development. In addition if high-riskindividuals can be identified they will reap the greatest benefit from screening modalities. We propose three aims. In aim 1 we will identify genetic factors conferring a high-risk of lungcancer development.. In this aim we will complete analyses of WES data from 33 HRFLC familiescomprising 291 individuals along with 114 FLC cases and case/control analyses of 1084 lung cancer casescompared with 919 controls. We will use these data along with linkage analysis to prioritize uncommon variantsthat have a strong effect on lung cancer risk. In Aim 2 we will extend and validate findings to a broaderpopulation. We will also collect additional samples from LC cases in HRLFC. We will sequence the moststrongly associated variants and genes from Aim 1 in additional affected and unaffected individuals in thesequenced families and an additional set of FLC cases and frequency matched controls. This aim will allow usto a) validate findings from aim 1 using a larger collection of cases with a family history of lung cancer andcontrols and b) assess the impact on risk in families according to smoking behavior and genetic contributions.In Aim 3 we will study the impact that variants found in aims 1 and 2 have on cellular biology. We willstudy the effect that specific mutations have on cellular phenotypes identified in aims 1 and 2 using CRISPRtechnology. We will begin by studying mutations in PARK2 that we recently identified in 5 HRLFC families andin E2A we previously studied. The proposed research will bring new insights into the etiology of lung cancer. 590394 +No NIH Category available Accreditation;Agreement;Certification;Contractor;Elements;Engineering;Ensure;Exhibits;Government;Guidelines;Hour;Infrastructure;Maintenance;Regulation;Specific qualifier value;Work;improved THIS CPFF TO IS FOR REFURBISHMENT AND INFRASTRUCTURE PROJECTS FOCUSED ON FACILITY IMPROVEMENTS WITHIN THE NCI AT FREDERICK CAMPUSMOD001 n/a NCI 10788206 75N91019D00024-P00002-759102200026-1 N01 9/23/22 0:00 8/1/25 0:00 78877449 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 88573 NCI In accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick.The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs.The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines 88573 +No NIH Category available Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend SEER CORE INFRASTRUCTURE SUPPORT n/a NCI 10788115 261201800011I-P00006-26100001-2 N01 5/1/18 0:00 4/30/23 0:00 78146713 "HERNANDEZ, BRENDA " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N R and D Contracts 2023 1824955 NCI The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data. 1824955 +No NIH Category available Air;Contracts;Funding;Infrastructure;Phase;Physical condensation;Steam;System;base;design;improved;research and development NCI FEDERALLY FUNDED RESEARCH AND DEVELOPMENT CENTER (FFRDC) CONTRACT - FY19 FACILITIES TO A n/a NCI 10788111 75N91019D00024-P00017-759101900141-1 N02 9/28/19 0:00 2/21/24 0:00 16188713 "LEAMAN, KEITH " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 41354 NCI Refurbishment and Infrastructure Projects focused on Facility Improvements within the NCI at Frederick Campus. 41354 +No NIH Category available Air;Area;Computer Security;Floor;Monitor;Paint;Repository Operations;Retrieval;Secure;System;Vacuum;Work;design;exhaust;repository;symposium WEDGEWOOD EXPANSION DESIGN SUITES M & N n/a NCI 10788097 75N91019D00024-P00003-759102100019-1 N01 9/20/21 0:00 11/14/23 0:00 78385914 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 5769691 NCI Suite H and K at 4600 Wedgwood Boulevard houses the NCI-F Central Repository. LBR has finalized leases with the landlord to secure the adjacent suites M and N and expand the Central Repository to these areas. The suites are currently office and warehouse space so it is likely that the suites will be gutted and rebuilt. This project will expand the Wedgewood Central Repository operations currently in Suites H and K into the adjacent Suites M and Suite N. The scope of work will include the complete demo of all existing walls/ceilings/utilities patch/paint epoxy paint existing floors. New construction encompasses roof structural upgrade installation of LN2 vacuum-jacketed piping Automated Storage Retrieval System (ASRS) freezers new electrical room and electrical distribution system sprinkler system stand-by generators LN2 bulk tanks receiving area bathrooms gown-in area conference room LAN room custodial room AHUs exhaust and supply fans air-cooled chillers O2 monitoring system security system Rees scientific monitoring system and access hallways to Suite K. 5769691 +No NIH Category available Cell Therapy FY19 FACILITIES TO B n/a NCI 10788061 75N91019D00024-P00007-759101900142-1 N02 9/27/19 0:00 3/15/23 0:00 16188656 "LEAMAN, ADAM " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 447257 NCI FY19 Facilities Task Order B 125543 ATRF B3210-3220 Cell Therapy Suites 447257 +No NIH Category available American;Area;Cancer Surveillance Research Program;Collaborations;Contracts;Malignant Neoplasms;Methods;National Cancer Institute;Registries;Research;Services;data registry;improved;neoplasm registry;operation;surveillance data TASK ORDER 75N91021F00001 FOR SUPPORT SERVICES FOR DEVELOPING AND PROMOTING METHODS AND STANDARDS FOR CANCER REGISTRY OPERATIONS AND SURVEILLANCE DATA n/a NCI 10788057 75N91021D00018-P00004-759102100001-1 N02 7/1/21 0:00 6/30/23 0:00 78314328 "KOHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2023 1786302 NCI The objective of this contract is to provide support to the North American Association of Central Cancer Registries (NAACCR) in order to make the National Cancer Institutes (NCI) cancer Surveillance Research Program (SRP) more responsive to the needs of the division institute and nation and more integrated with other partners within the national cancer surveillance enterprise.This contract focuses on three specific areas:1.Strengthening the national capacity for collecting analyzing and using comparable cancer registry data for cancer surveillance and research.2.Developing and improving methods for assessing the quality and comparability of cancer registry data. This includes but is not limited to timeliness completeness and accuracy.3.Improving the efficiency and quality of registry operations through promoting established standards disseminating technical information and facilitating collaboration among Federal state provincial and local registry professionals. 1786302 +No NIH Category available FY20 CONSOLIDATED FACILITIES TASK ORDER D n/a NCI 10788056 75N91019D00024-P00016-759102000013-1 N02 8/25/20 0:00 9/18/24 0:00 77829853 "BRISCOE, LYNN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 1066230 NCI FY20 CONSOLIDATED FACILITIES TASK ORDER D 1066230 +No NIH Category available Biological;Clinical;Clinical Chemoprevention;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Institution;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs CORE INFRASTRUCTURE SUPPORT FOR THE CANCER PREVENTION AGENT DEVELOPMENT PROGRAM n/a NCI 10788046 261201200042I-P00005-759101900129-1 N01 9/23/19 0:00 9/22/23 0:00 16187684 "LIMBURG, PAUL " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N R and D Contracts 2023 158652 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 158652 +No NIH Category available Apoptosis;Cause of Death;Cessation of life;Clinical Treatment;Collaborations;Computing Methodologies;Development;Drug Targeting;Drug resistance;Genes;Genetic Variation;Growth;Health;Heart Diseases;Interview;Machine Learning;Malignant Neoplasms;Modeling;Molecular;Oncologist;Pathway interactions;Patients;Proteins;Research;Severities;Software Design;Systems Biology;Variant;Work;acquired drug resistance;cancer drug resistance;clinical decision-making;experience;genetic variant;hands-on learning;molecular dynamics;network models;prototype;shift work;simulation;software development;tumor TOPIC 438 - PREDICTION OF CANCER DRUG RESISTANCE TO AID IN CLINICAL DECISION MAKING n/a NCI 10788020 75N91022C00025-P00001-9999-1 N43 9/15/22 0:00 9/14/23 0:00 78846872 "ANDRABI, SUMAIRA " Not Applicable 8 Unavailable 6989629 MHRXDJYJAPU9 6989629 MHRXDJYJAPU9 US 10067020 PATHODYNAMICS LLC POTOMAC MD Domestic For-Profits 208541024 UNITED STATES N R and D Contracts 2023 55000 NCI Cancer is the second leading cause of death behind heart disease with ~600000 deaths annually according to the CDC. Approximately 90% of cancer deaths are attributed to drug resistance making it a major health problem. Both intrinsic and acquired drug resistance in cancers have been attributed to the presence of genetic variant in the genes involved in growth or apoptosis. However many of the variants found in patients tumor are of unknown significance. The proposed research develops a computational method that leverages machine learning applied to molecular dynamics simulations of wild-type and variant proteins that are drug targets to predict drug resistance and its severity. This quantitative information will be incorporated into protein network models describing cancer growth and apoptosis to predict how off-target variants can cause drug resistance through pathway interactions. This proposal brings together a collaborating team of experts in molecular simulation machine learning pathway modeling software design and development and systems biology accomplishing this paradigm shifting work. At the conclusion of the proposed work a prototype will be developed that can help oncologists and their team to understand and deliver information to patients about possible drug resistance in the patients tumor and to make clinical treatment decisions. 55000 +No NIH Category available Africa;American Cancer Society;Antioxidants;Arachidonic Acids;Asia;Asian population;Atrophic Gastritis;Bioflavonoid;Biological;CXCL10 gene;CXCR3 gene;Cancer Burden;Cancer Etiology;Central America;Cessation of life;Chemopreventive Agent;Country;Curcumin;DNA Damage;Developing Countries;Diagnosis;Disease;Eastern Europe;Encapsulated;Europe;Far East;Flow Cytometry;Formulation;Gamma-H2AX;Gastric mucosa;Genotype;Histology;Human;IL8 gene;Incidence;Individual;Inflammatory;Interleukin-1 beta;Intestinal Metaplasia;Intestinal Mucosa;Investigation;Japan;Lecithin;Legal patent;Liposomes;Lipoxygenase;Malignant Neoplasms;Metabolism;Methods;Molecular;Multifocal Lesion;North America;Outcome;Participant;Pathway interactions;Persons;Placebos;Plants;Populations at Risk;Prevention strategy;Prostaglandin-Endoperoxide Synthase;Randomized;Reporting;Research Personnel;Resources;Rhizome;Risk;Safety;South America;Southern Europe;Stomach;Survival Rate;TNF gene;Technology;Tumeric;Woman;absorption;cancer type;chemokine;cytokine;dietary;disability-adjusted life years;double-blind placebo controlled trial;gastric carcinogenesis;immunoregulation;inflammatory marker;inhibitor;magnetic beads;malignant stomach neoplasm;men;mortality;premalignant;primary endpoint;routine screening;secondary endpoint;soy;years of life lost RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL OF MERIVA (R) AS A CANDIDATE CHEMOPREVENTION AGENT FOR GASTRIC CARCINOGENESIS n/a NCI 10787981 261201200042I-P00010-26100010-1 N01 8/1/16 0:00 3/31/23 0:00 14652670 "LIMBURG, PAUL " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N R and D Contracts 2023 11000 NCI Gastric cancer (GC) is the 4th most common incident cancer and the 2nd leading cause of cancer death worldwide.1 Approximately 990000 people are diagnosed with GC worldwide of whom close to 75% die from this disease.2 GC also is responsible for one of the highest cancer burdens as determined by disability-adjusted life years lost.3 Despite the overall decrease in the incidence of GC since the 1930s the annual global burden of cancer is projected to double by 2030 to 22.2 million incident cases and 13.1 million deaths with over two-thirds of the burden in resource-limited nations.4 5 In the US the American Cancer Society estimates that in 2015 24590 new cases of GC will be diagnosed and approximately 10720 individuals will die from this type of cancer.6 The average risk that a person will develop GC in his/her lifetime is about 1 in 111 with the risk being 2 to 3-fold higher in men than women. However GC incidence rates vary dramatically across different countries and are higher in less developed countries.2 GC is more common in East Asia Southern and Eastern Europe and South and Central America whereas the lowest incidence rates are observed in Africa and North America.7 Although nearly 60% of the new GC cases are diagnosed in Asia8 significantly better outcomes have been reported among Asian individuals compared to those diagnosed in Western countries.9 Five-year GC survival rates are 40% lower in the US and Europe compared to Japan.10 With the high GC mortality-to-incidence ratio and the lack of routine screening methods available for asymptomatic individuals the management of GC remains a challenge and warrants further investigations to more fully understand the biologic basis of progression and to develop chemopreventive strategies for individuals at increased risk.Curcumin is a phenolic antioxidant compound derived from the rhizome of the plant Curcuma longa. This bioflavonoid is a potent inhibitor of arachidonic acid metabolism and blocks both lipoxygenase and cyclooxygenase activity in the intestinal mucosa. Curcumin exerts a variety of additional immunomodulatory and antioxidant effects and is thought to have broad chemopreventive potential through a variety of molecular mechanisms and cellular pathways as recently reviewed.11The investigators (Drs. Cruz-Correa & Morgan) from the Mayo Consortium are proposing a chemopreventive trial on a population at risk for gastric cancer (GC) using Meriva (a liposome-encapsulated formulation of curcumin) and placebo. The hypothesis is that curcumin given to individuals with gastric precancerous lesions multifocal atrophic gastritis (MAG) & intestinal metaplasia (IM) will have a decrease in markers of inflammation including DNA damage as compared to placebo after six months of taking the study agent. Meriva (Curcumin) is a patented formula of curcumin that includes a dietary phenolic with soy lecithin (non-GMO). The curcumin content and the curcuminoid absorption is 27 fold higher when compared to curcumin alone. 11000 +No NIH Category available Childhood;Clinical Trials;Conduct Clinical Trials;Data;Funding;Goals;Malignant Childhood Neoplasm;Molecular;Pediatric Oncology Group;Science;Specimen;participant enrollment;programs CHILDHOOD CANCER DATA INITIATIVE: CLINICAL TRIAL SPECIMEN MOLECULAR CHARACTERIZATION (CTSMC) PROGRAM n/a NCI 10787973 75N91019D00024-P00005-759102000021-1 N01 9/25/20 0:00 9/24/25 0:00 77878831 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2023 18042059 NCI The National Cancer Institute (NCI) Childhood Cancer Data Initiative (CCDI) focuses on the critical need to collect analyze and share data to address the burden of cancer in children adolescents and young adults (AYAs). The initiative supports childhood cancer research and aims to make it easier for researchers to learn from each of the approximately 16000 children and adolescents diagnosed with cancer in the United States each year.Through the CCDI NCI seeks to enhance data collection for childhood cancers ensure that data is accessible and thereby incentivize the cancer research community to develop new treatments for children with cancer. More specifically to increase data use and sharing in pursuit of progress against childhood cancers the CCDI aims to: Maximize every opportunity to improve treatments and outcomes for children with cancer Build a connected data infrastructure to enable sharing of childhood cancer data from multiple sources Identify opportunities to make data work better for patients clinicians and researchers Develop and enhance tools and methods to extract knowledge from dataCancer clinical trials are available for children and AYAs through the NCI-funded Pediatric Early Phase Clinical Trials Network (PEP-CTN) and Childrens Oncology Group (COG). Through these clinical trials pediatric and AYA cancer patients across the U.S. and around the world can access state-of-the-art therapies and specimens are routinely collected from patients enrolled across these clinical trials. Other NCI-supported studies collect patient data and specimens from pediatric and AYA cancer patients to better understand these diseases and find potential treatments.Tissue samples from children and AYAs with cancer are critically limited and a valuable resource. Data generated from these specimens are often fragmented and not broadly available to researchers and oncology teams. Next-generation sequencing technologies are increasingly available to quickly sequence DNA and RNA and identify gene mutations genetic alterations and changes in global gene expression that are associated with different tumor types and stages of disease. Other complementary technologies for molecular characterization such as assays for metabolomics epigenomics and proteomics as well as more established IHC or FISH assays are also now accessible. Att. 1 75N91019D00024 Task Order 75N91020F00021 through modification 6. 04/13/2023Pg 3Maximizing the use of childhood and AYA cancer specimens collected on NCI-supported clinical trials and studies and making the resulting data broadly available for research will have a profound impact on our ability to prevent diagnose and treat this patient population and can serve as a model for improving the use of data across cancer types and other disease continuums. 18042059 +No NIH Category available Absenteeism;Address;Administrative Supplement;Advanced Malignant Neoplasm;Area;Biology;Boston;Cancer Center;Cancer Control;Cancer Science;Cancer health equity;Charge;Color;Communities;Community Networks;Community Outreach;Creativeness;Data;Data Set;Dedications;Discipline;Disparity;Education;Ethnic Origin;Experimental Designs;Faculty;Foundations;Funding;Genomics;Goals;Government;Grant;Health Disparities Research;Incidence;Infrastructure;Institution;Joints;Lasers;Leadership;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Methods;Modeling;Morbidity - disease rate;Phase;Population;Population Group;Population Heterogeneity;Population Sciences;Postdoctoral Fellow;Race;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Solid;Source;Students;Training;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;anticancer research;cancer health disparity;career;career development;community engagement;community organizations;dissemination science;education research;equity diversity and inclusion;experience;experimental study;implementation science;innovation;member;mortality;outreach;outreach program;programs;research and development;research study;socioeconomic disparity;translational model;translational potential Administrative Supplement to Recognize Excellence in Diversity Equity Inclusion and Accessibility Mentorship at UMass Boston PROJECT NARRATIVEThe University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC)Partnership is committed to further developing a shared rigorous and collaborative transdisciplinary cancer anddisparities-related research program that is primed for Bridging the Divides: Innovations to Address Gaps inCancer Disparities Research Education Outreach and Infrastructure. Sophisticated research projects areproposed across several areas of basic biomedical and population sciences that will employ evidence andmethods to converge upon and impact cancer and cancer health disparities at multiple levels of analysis.These projects together with state-of-the-art Outreach and Research Education Cores and creative ResearchDesign and Analysis Core and Genomics Cores will serve to build research capacity and infrastructure atUMass Boston expand the cancer disparities platform and community outreach programs at DF/HCC; andmake at an elevated level significant advances to the science of cancer control. NCI 10786771 8/11/23 0:00 PA-20-272 3U54CA156734-13S1 3 U54 CA 156734 13 S1 "WALI, ANIL" 9/28/10 0:00 8/31/26 0:00 ZCA1(A1)-S 8606765 "COLON-CARMONA, ADAN " "MACOSKA, JILL A.; VISWANATH, KASISOMAYAJULA " 8 BIOLOGY 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA SCHOOLS OF ARTS AND SCIENCES 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 368125 OD 250000 118125 SUMMARYThe University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC)Partnership is primed for Bridging the Divides: Innovations to Address Gaps in Cancer DisparitiesResearch Education Outreach and Infrastructure. Our goal is to pursue Partnership activities andresearch that will bridge the divides in cancer disparities science research education and outreach throughinnovative research training and practice serving as models for translation at the state and national level. ThePartnerships to Advance Cancer Health Equity (PACHE) program itself is a prime example of bridged divides:partnerships formed between institutions have enhanced the education of underrepresented population groupsand provided well-established cancer centers with the necessary resources and research infrastructure toaddress cancer disparities.The specific aims of the UMass BostonDF/HCC Partnership are to: 1) Advance Partnership transdisciplinarycancer and cancer health disparities research programs reflecting the theme Bridging the Divides; 2) Developeducational experiences for students and trainees from a diverse population typically underrepresented inbiomedical careers; 3) Promote hiring and retention of diverse scholars particularly those fromunderrepresented populations by leveraging institutional resources; 4) Bridge research-community dividesthrough innovative platforms: forming and engaging networks of community-based organizations to advanceoutreach drawing on state of the science from dissemination and implementation sciences (D&I); 5) Developcutting-edge approaches to address data-absenteeism the lack of representation of underserved groups inpopulation- community- and genomics-based cancer and cancer disparities datasets and projects; and 6)Promote sustainability of partnership activities by reinforcing institutional support and grant matching with NIH-mechanisms and other sources of government foundation and philanthropic support. 368125 +No NIH Category available Ablation;Address;Anti-CD40;Antibodies;Antigen Presentation;Biological;C57BL/6 Mouse;Cancer Etiology;Cancer Patient;Carbon;Carbon ion;Cell surface;Cells;Cessation of life;Characteristics;Clinical;Coculture Techniques;Combination immunotherapy;Combined Modality Therapy;Complex;DNA;DNA Damage;DNA Double Strand Break;DNA Viruses;Disease;Disseminated Malignant Neoplasm;Distant Metastasis;Dose;Effectiveness;Engineering;Epigenetic Process;Event;Experimental Designs;Exposure to;Fire - disasters;Genetically Engineered Mouse;Goals;Heavy Ions;High-LET Radiation;Histocompatibility Antigens Class I;Histone Deacetylase;Histone Deacetylase Inhibitor;Immune;Immune Evasion;Immune response;Immunity;Immunocompetent;Immunologics;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Vitro;Infiltration;Interferon Type I;Irradiated tumor;Linear Energy Transfer;Local Therapy;MHC Class I Genes;Malignant Neoplasms;Malignant neoplasm of pancreas;Measurement;Measures;Methods;Modality;Modeling;Molecular;Mus;Myeloid Cells;Natural Immunity;Nature;Neoplasm Metastasis;Normal tissue morphology;Organ;Outcome;Patients;Pattern;Photons;Phototherapy;Prediction of Response to Therapy;Proteins;Protons;Quality of life;Radiation;Radiation therapy;Radio;Relative Biological Effectiveness;Reporting;Roentgen Rays;Role;Signal Transduction;Solid Neoplasm;Splenocyte;Survival Rate;System;T-Cell Activation;T-Lymphocyte;TNFRSF5 gene;Techniques;Testing;Therapeutic;Travel;Treatment Protocols;Treatment outcome;Tumor Antigens;Tumor Cell Line;Tumor Immunity;Tumor Tissue;Unresectable;Vaccinated;Viral;X-Ray Therapy;absorption;adaptive immunity;anti-PD-1;anti-PD1 antibodies;antigen processing;chemoradiation;clinical efficacy;clinically relevant;compare effectiveness;design;dosimetry;epigenetic silencing;exhaust;fighting;immunodeficient mouse model;immunogenic;immunoregulation;improved;in vivo;indexing;inhibitor;interest;ionization;irradiation;kinetic model;member;mouse model;neoplastic cell;pancreas radiation therapy;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;pancreatic neoplasm;particle;particle beam;prognostic of survival;programmed cell death protein 1;programs;proton therapy;randomized trial;repaired;response;standard of care;success;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions Relative Immunological Effectiveness (RIE) of Carbon Ion Radiation Therapy for Pancreatic Cancer NARRATIVECarbon ion radiotherapy (CIRT) is currently the worlds most advanced radiotherapeutic technique;compared with traditional photon radiotherapy it has unique physical characteristics andbiological advantages. It is better at protecting the normal tissue and organs surrounding thetumor and is more effective at killing tumor tissue and particularly tumor cells that can normallyresist photon radiotherapy. While X-ray therapy using photons travel through our body carbonion is like a dart. It stops at a depth inside our body and releases all its energy in the form of apeak dose in the tumor. Since the track stops at a depth the particle beam does not go throughthe body thereby causing less harm to surrounding normal tissues. Since the particles causeDNA damage and the irradiated cells behave as if they are infected by a DNA virus and increasethe bodys anti-viral defense system. We are looking into possible immune activating role of CIRTthat possibly helps us fight cancer. We are going to look into the immunological consequences ofCIRT for the treatment of pancreatic cancer a devastating disease where we are losing our battle.Our goal is to determine the immunological effectiveness of CIRT compared to XRT (X rays) inmouse pancreatic cancer models for the treatment of both primary and metastatic cancer. Ifsuccessful this will allow us to bring a very sophisticated therapy for our cancer patients. NCI 10786030 1/3/24 0:00 RFA-CA-20-032 5R01CA257509-04 5 R01 CA 257509 4 "BUCHSBAUM, JEFFREY" 1/14/21 0:00 12/31/25 0:00 ZCA1-SRB-2(O2) 7274991 "GUHA, CHANDAN " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 434451 NCI 322235 112216 AbstractPancreatic cancer is the leading cause of cancer-related death with less than 5% (5-year) survival rate withcurrent treatment regimen involving chemo-radiation therapy. Almost all patients with pancreatic cancereventually develop metastatic disease with poor prognosis for survival. There remains a significant opportunityfor breakthrough strategies to improve the quality of life and outcomes for pancreatic cancer patients. Recentstudies have shown some success with proton therapy and the interest in proton RT has grown progressivelywith increasing evidence indicating substantial benefit over photons (XRT). The success of proton therapy relieson precise delivery of high dose in tumor tissue sparing normal tissue due to the nature of its Braggs peakwhile maintaining similar therapeutic advantages as XRT. Carbon ion radiation therapy (CIRT) offers steepBraggs peak and less scatter but also higher LET (Linear Energy Transfer) resulting in greater ionizing eventsand greater biological damage. We hypothesize that greater complex DNA damage also defined as relativebiological effect (RBE) of CIRT can induce stronger immune response. In the current proposal we are testingthe hypothesis that high-LET CIRT has unique ability of enhancing tumor immune response when applied aloneor combine with other immunotherapeutic agents. Our goal is to determine the immunomodulation effectivenessof CIRT compared to XRT in pancreatic cancer mouse model. We will test the effect of high LET-CIRT on tumorcells as well as the immune cells at local and systemic level. We will correlate biological end points such as DNAdouble strand breaks (DSB) complex DNA damage and clonogenic survival in XRT/CIRT-irradiated cells withtheir ability to induce immune response under aim 1. We will also determine whether HDAC inhibition enhancesantigen presentation by pancreatic tumor cells in aim 2. Under aim 3 we will enhance the efficacy of CIRT byreprogramming tumor microenvironment (TME) using concurrent treatment with check point inhibitors andantigen presentation activators.Relevance. Successful completion of these studies could establish the significance and help us design uniquecombination therapy of immunotherapy with CIRT for solid tumors. 434451 +No NIH Category available Accounting;Animals;Antigens;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Clinical;Clinical Trials;Culture Media;Cytomegalovirus;Data;Development;Enzyme-Linked Immunosorbent Assay;Epitopes;Extravasation;Flow Cytometry;Grant;Growth;Herpesviridae;Histology;Human;Immune response;Immune system;Immunity;Immunofluorescence Immunologic;Immunotherapy;Implant;Incubated;Individual;Injections;Integrin alphaV;Intra-abdominal;Long-Term Survivors;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Measures;Mediating;Medicine;Memory;Methods;Modeling;Murid herpesvirus 1;Mus;Mutation;Mutation Analysis;Necrosis;Neuropilin-1;Pancreas;Patients;Penetration;Peptides;Persons;Pharmaceutical Preparations;Phase II Clinical Trials;Phenotype;Population;Production;Resected;Resistance;Site;Slice;Solid;Solid Neoplasm;T cell infiltration;T cell response;T memory cell;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Epitopes;Testing;Therapeutic;Tumor Promotion;Tumor Tissue;Viral;Viral Antigens;anti-cancer;anti-tumor immune response;antiviral immunity;cancer cell;cancer immunotherapy;checkpoint therapy;chemotherapy;clinical efficacy;clinically relevant;cytokine;experimental study;gemcitabine;immune checkpoint blockade;improved;microorganism antigen;mouse model;neoantigens;neoplastic cell;novel strategies;optimal treatments;pancreatic cancer cells;pancreatic cancer model;pancreatic neoplasm;personalized medicine;subcutaneous;translational potential;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;ultrasound Harnessing Cytomegalovirus (CMV)-specific T-cells for pancreatic cancer immunotherapy Project Narrative Pancreatic tumors have low mutational burdens rendering them largely resistant to currentimmunotherapies. We propose a novel approach using a tumor penetrating peptide (iRGD) and cytomegalovirus(CMV)-specific antigens to re-direct pre-existing CMV immunity against these tumors. NCI 10785992 12/22/23 0:00 PAR-22-216 1R21CA286198-01 1 R21 CA 286198 1 "SOMMERS, CONNIE L" 12/22/23 0:00 11/30/25 0:00 ZCA1-SRB-F(O1)S 11726910 "HURTADO DE MENDOZA, TATIANA " "BENEDICT, CHRISTOPHER A" 50 SURGERY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 12/22/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 242178 NCI 163574 78604 Abstract Immunotherapy is a promising therapeutic strategy for many cancers. Anti-tumor immune responses areelicited against neoantigens that arise from genetic alterations within tumor cells that give rise to a repertoire ofpeptides that the immune system recognizes as non-self and attack killing the tumor cells harboring them.Cancers with a high mutational load generally benefit from immune checkpoint therapy but some solidmalignancies like pancreatic cancer have a low mutational burden that hampers immunotherapy. One strategyto overcome this limitation is to deliver exogenous neoantigens to cancer cells. Here we propose an approachthat uses the tumor penetrating peptide iRGD to deliver neoantigens to pancreatic tumors. Unlike conventionalRGD peptides iRGD is not only able to target and the tumor vasculature through v integrin but also toextravasate and penetrate tumor tissue via neuropilin-1 delivering conjugated or co-administered drugs orpeptides. Pancreatic cancer long term survivors often have neoantigens that mimic common viral epitopessuggesting the possibility that these individuals benefited from an immune response against neoantigens thatmimic viral components. We posit that iRGD-mediated delivery of these antigens to pancreatic tumors willredirect pre-existing antiviral immunity against them. For this purpose we will use peptides activatingcytomegalovirus (CMV)-specific T cells. CMV is a -herpesvirus infects >60% of the population and elicits astrong immune response accounting for >10% of all circulating CD4 and CD8 T cells. Our preliminary data show that mice latently infected with CMV containing orthotopic pancreatic tumorsrespond to treatment with iRGD plus CMV peptides with tumor regression associated to increased necrosis andmarked T cell infiltration. Here we propose experiments to determine in an orthotopic pancreatic tumor mousemodel what are the best neoantigens and the optimal treatment conditions for achieving long lasting tumorregression (Aim 1). We will also assess the presence of CMV specific T cells in human pancreatic tumors anecessary step toward the eventual translatability of this approach (Aim 2). 242178 +No NIH Category available 3-Dimensional;Auranofin;Biological Markers;Cancer Relapse;Cancer cell line;Cell Culture System;Cell Differentiation process;Cell Line;Cell Nucleus;Cell Proliferation;Cells;Chemoresistance;Chromosomal translocation;Cisplatin;Clinic;Clinical Data;Collection;Complex;D Cells;DNA;Data;Development;Dose Limiting;Drug Kinetics;Drug Synergism;Dyes;Environment;Exclusion;FBXW7 gene;FDA approved;Gene Targeting;Genes;Genetic Transcription;Goals;Ligands;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Methods;Mutation;NOTCH3 gene;Notch Signaling Pathway;Organoids;Pathway interactions;Patients;Peritoneal;Pharmaceutical Preparations;Pharmacotherapy;Platinum;Platinum Compounds;Play;Pre-Clinical Model;Progression-Free Survivals;Proliferating;Property;Public Health;Receptor Activation;Recurrence;Recurrent Malignant Neoplasm;Relapse;Retreatment;Role;Serous;Signal Transduction;Testing;The Cancer Genome Atlas;Time;Toxic effect;Tumor Burden;acute T-cell lymphoblastic leukemia cell;cancer cell;cancer drug resistance;cancer recurrence;cancer stem cell;cancer therapy;cancer type;cell type;chemotherapeutic agent;chemotherapy;drug testing;gamma secretase;inhibitor;interest;mouse model;neoplastic cell;notch protein;novel;ovarian neoplasm;overexpression;patient derived xenograft model;personalized medicine;pharmacologic;precision medicine;receptor;receptor expression;response;secretase;stem cell expansion;synergism;targeted treatment;taxane;therapeutic target;transcriptome;tumor Repurposing Auranofin As a Novel Notch Pathway Inhibitor for Combinational Ovarian Cancer Therapy Project NarrativeNotch signaling pathway is a therapeutic target of great interest for cancer treatment. The values of current Notchinhibitors in cancer therapy remain to be proven. Therefore our proposal to repurpose auranofin as a novelNotch pathway inhibitor for combinational ovarian cancer therapy is of great relevance to public health. NCI 10785855 1/1/24 0:00 PAR-22-216 1R21CA286210-01 1 R21 CA 286210 1 "O'HAYRE, MORGAN" 1/1/24 0:00 11/30/25 0:00 ZCA1-RTRB-S(O1) 6064248 "FAN, HUA-YING " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM SCHOOLS OF MEDICINE 871310001 UNITED STATES N 1/1/24 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 213881 NCI 140250 73631 Ovarian cancer is the deadliest gynecologic cancer with ~20000 new cases predicted for 2023.Although first-line treatment with a platinum compound and taxane yields a response rate of more than 80% inadvanced ovarian cancer the median time of progression-free survival is only 18 months. Retreatment can beperformed after relapse but chemoresistance becomes a major issue. Therefore new options for the treatmentof both primary and relapsed ovarian cancer are urgently needed. The Notch signaling pathway regulates cellproliferation and differentiation. Aberrant Notch activation plays roles in the initiation progression andchemoresistance of a variety of cancer types. Data from The Cancer Genome Atlas reveal that Notch-pathwayaberrations associate with 22% of high-grade serous ovarian cancer and Notch pathway disruption can sensitizeovarian tumor cells to platinum-based therapy. Accordingly drugs that inhibit Notch signaling will be of greatvalue for treatment of Notch-associated ovarian cancers. To date the utility of Notch-pathway inhibitors is limitedby dose-dependent and off-target toxicities. Most Notch inhibition strategies have focused on the level Notchreceptor activation. We hypothesized that modulating the interaction of RBPJ the sole Notch transcriptionaleffector with its gene targets would provide a means to intervene in all Notch-associated cancers regardless ofthe mechanisms of aberrant pathway activation. We discovered that the FDA-approved drug auranofin is a potentNotch pathway inhibitor. Moreover we found that auranofin interacts synergistically with cisplatin preferentiallyreducing the viability of high Notch-expressing ovarian cancer cells. In this proposed study we will use differentpreclinical models to test the utility ofauranofin and cisplatin cotreatment for targeted ovarian cancer therapy.We will use a collection of ovarian cancer cell lines to examine how levels of the different Notch receptors andligands impact the auranofin response. We will also use patient-derived tumor organoids (PDO) and patient-derived xenograft (PDX) mouse models to examine auranofin and cisplatin synergy in 3-D culture and theperitoneal environment.We will also study how auranofin impacts cancer stem-cell expansion and cancerrelapse. The impact of these studies if successful will be significant as our proposal has the potential torepurpose an FDA-approved agent for immediate deployment in targeted therapy of both primary and relapsedovarian cancers that are Notch-dependent. 213881 +No NIH Category available 4T1;ATAC-seq;Address;Adult;Animals;Antigen Presentation Pathway;Antitumor Response;Bioinformatics;Biological Assay;Biological Models;Biophysics;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Bromodomain;Cells;Cellular Assay;Chromatin;Chromatin Remodeling Factor;Clinical;Combined Modality Therapy;Complex;DNA;DNA Methyltransferase Inhibitor;Disease remission;Down-Regulation;Drug Targeting;Effectiveness;Effector Cell;Enzymes;Epigenetic Process;Flow Cytometry;Generations;Human;Immune;Immune system;Immunocompetent;Immunologic Stimulation;Immunotherapy;In Vitro;Knockout Mice;Lead;Liver Microsomes;Malignant Neoplasms;Mammals;Mediating;Metabolic;Mind;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;NURF;Natural Killer Cells;Nucleosomes;Outcome;Pathway interactions;Patient-derived xenograft models of breast cancer;Permeability;Pharmaceutical Preparations;Property;Sampling;Series;Sorting;Structure;Structure-Activity Relationship;T-Lymphocyte;Testing;Therapeutic;Transferase;Translating;Tumor Antigens;Tumor Immunity;Up-Regulation;Validation;analog;anti-tumor immune response;antitumor effect;cancer cell;chemokine;chemotherapy;chromatin remodeling;cytokine;design;drug efficacy;epigenetic therapy;genome-wide;genome-wide analysis;humanized mouse;immunogenic;immunogenicity;immunoregulation;improved;in vivo;in vivo Model;inhibitor;innovation;mouse model;neoplastic cell;new therapeutic target;novel;novel strategies;overexpression;pharmacologic;small molecule;success;synergism;targeted treatment;therapy outcome;transcriptome sequencing;translational potential;translational study;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth Enhancing Tumor Cell Immunogenicity using Improved Molecules Targeting Chromatin Remodeling NARRATIVE STATEMENTThis project is designed to address the problem of low cancer immunogenicity by evaluating the capacity of acombination of epigenetic inhibitory agents to eliminate breast tumor cells by enhancing the antitumorimmune response. Studies will include the optimization of novel inhibitors to epigenetic remodeling complexesto achieve improved effectiveness in animals. NCI 10785798 12/13/23 0:00 PAR-22-216 1R21CA277437-01A1 1 R21 CA 277437 1 A1 "VENKATACHALAM, SUNDARESAN" 12/13/23 0:00 11/30/25 0:00 ZCA1-SRB-A(O1) 8903361 "LANDRY, JOSEPH WILLIAM" "POMERANTZ, WILLIAM CHARLES KRAUSE" 4 GENETICS 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 12/13/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 230523 NCI 168947 61576 PROJECT SUMMARY Few therapies have yet to achieve durable remission of advanced stage triple negative breast cancer(TNBC). One promising approach to improve clinical outcomes is to combine multiple chemotherapies tostimulate an antitumor response. An underlying premise for this approach is that select chemotherapies enhanceTNBC immunogenicity thereby stimulating the anti-tumor immune response improving tumor growth control. With this strategy in mind we have discovered that inhibiting the epigenetic regulator BPTF of thenucleosome remodeler NURF either genetically or pharmacologically is a novel approach for improving TNBCimmunogenicity. In this proposal we now show using two different TNBC tumor models that when BPTF depletionis combined with the DNA methyl transferase inhibitor (DNMTi) Guadecitabine (Guad) we further stimulate tumorcell immunogenicity and dramatically improve tumor growth control in immune competent but not immunecompromised mice. Genome wide analysis shows that the combination therapy enhances immune stimulatorypathways with an enrichment for immune stimulatory cytokines. Thus using a novel combination approach wehypothesize that BPTF depletion/inhibition will synergize with immune stimulating therapies targeting epigeneticfactors (Guadecitabine) for TNBC treatment improving therapeutic outcomes.In Aim1 will identify the immune reactive effector cells required for the antitumor effects of Guad + BPTFdepletion using the mouse E0771 TNBC tumor model. Additional flow cytometry and ex vivo immune cell assayswill characterize and further define the immune cells required for these antitumor activities. The BPTF inhibitorBZ1 + Guad will be used in parallel tumor studies using the E0771 model to determine if it has in vivo activityand in molecular studies (RNA-Seq and ATAC-Seq) from FACS sorted E0771 tumor cells to determine if it hassimilar effects to that of BPTF KO. Humanized mouse models and TNBC PDX samples will validate thetranslatability of these findings. In Aim2 we will optimize the drug-like properties of our second generation leadBPTF inhibitor. Validating the therapeutic potential for BPTF inhibition has been significantly limited due to a lackof potent inhibitors for BPTF. Our first generation BPTF bromodomain inhibitor AU1 while effective for initialvalidation of BPTF inhibition in cells and in vivo its poor physiochemical properties and modest activity in vivohave limited further validation of BPTF as a drug target. Using structure-based design we have now developeda second and highly potent inhibitor series. Here we focus on optimizing its drug-like properties using bothestablished biophysical and cell-based assays to translate our findings to our in vivo model system in Aim 1. The completion of these Aims will deepen our understanding of cancer cell epigenetics and cancer cellimmunogenicity by characterizing the effects of inhibiting the chromatin factor NURF in combination with DNMTi.Our approach is further designed to enhance antitumor immunity to TNBC by improving therapy induced tumorimmunogenicity through a combination epigenetic therapy. 230523 +No NIH Category available Abate;Acute Graft Versus Host Disease;Alloantigen;Allogeneic Bone Marrow Transplantation;Allogenic;Antibodies;Antigen Presentation;Antigen-Presenting Cells;Antigens;Attenuated;Bone Marrow;Bone Marrow Transplantation;CXCR4 gene;Cell Lineage;Cell physiology;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Cessation of life;Clinical;Clinical Research;Colon;Data;Disease;Endothelial Cells;Excision;Exposure to;Extramedullary;Failure;Flow Cytometry;Fluorochrome;Gastrointestinal tract structure;Glucocorticoids;Hematopoietic;Hematopoietic Neoplasms;IL18 gene;ITGAX gene;Immune;Immunofluorescence Microscopy;Immunologics;Immunotherapy;Lead;Light;MHC Class I Genes;MHC Class II Genes;Maintenance;Malignant Neoplasms;Mediating;Monoclonal Antibodies;Monozygotic twins;Mus;Natural Killer Cells;Nature;New Agents;Normal tissue morphology;Opportunistic Infections;Organ;Outcome;Phase;Prevention;Procedures;Process;Proto-Oncogene Protein c-kit;Recurrent disease;Relapse;Resistance;Risk Reduction;Role;SELL gene;Site;Stromal Cells;Syngeneic Bone Marrow Transplantation;T cell response;T-Cell Activation;T-Cell Depletion;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Transgenic Organisms;Transplant Recipients;Transplantation;Viola;cancer cell;cell motility;curative treatments;graft failure;graft vs host disease;graft vs leukemia effect;immunological intervention;improved;in vivo;interleukin-18 binding protein;intravenous injection;leukemia;leukemia relapse;lymph nodes;lymphoid organ;male;migration;mortality;mouse model;nanobodies;novel;novel therapeutic intervention;pre-clinical;prevent;relapse prevention;response;stem cells;therapeutic development;therapy development;transcriptome sequencing;villin Targeting alloantigen presentation in bone marrow to enhance graft-versus-leukemia effects PROJECT NARRATIVEBlood cancers account for approximately 10% of all malignancies and allogeneic bone marrow transplantation(BMT) is a preferred curative therapy due to the graft-versus-leukemia (GVL) effects in which donor T and NKcells eradicate host malignancy. Although recently the types of APC that induce and enhance GVHD have beenelucidated the presence and nature of GVL-specific APC remain unknown. In this proposal we will focus onidentifying GVL-dependent APC in order to generate new therapeutic approaches to enhance GVL within bonemarrow that do not exacerbate GVHD. NCI 10785793 12/8/23 0:00 PAR-22-216 1R21CA286216-01 1 R21 CA 286216 1 "SINGH, ANJU" 1/1/24 0:00 12/31/25 0:00 ZCA1-SRB-K(O1)S 16173317 "KOYAMA, MOTOKO " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 246840 NCI 140250 106590 ABSTRACTBlood cancers account for approximately 10% of all malignancies and allogeneic bone marrow transplantation(BMT) is a preferred curative therapy for these serious conditions. While the therapeutic potential of thisprocedure lies in graft-versus-leukemia (GVL) effects in which donor T and NK cells eradicate host malignancyBMT outcomes are limited by transplant-related complications mainly graft-versus-host disease (GVHD) inwhich donor T cells attack host normal tissues and opportunistic infections. Indeed 15-20% of BMT patientsdevelop severe GVHD that is fatal particularly when involving the gastrointestinal tract however relapse of theprimary malignancy is still high and eventually responsible for the majority (40-60%) of transplant failures anddeath. Current prevention and treatment of GVHD which rely on the broad suppression of T cells abate GVLeffects. Thus the immunological intervention to minimize GVHD with promoting GVL is unmet need in BMT. Theinitiation and maintenance of donor T cell responses are dependent on alloantigen presentation by antigen-presenting cells (APC). Although recently the types of APC that induce and enhance GVHD and theimmunological mechanisms therein have been elucidated their role in GVL and the presence of GVL-specificAPC remain unknown. In this proposal we focus on GVL-requiring APC to enhance GVL and precent leukemiarelapse. In particular we will build on our preliminary data to test the hypothesis that donor T cells primed atextramedullary sites migrate into the BM where their anti-leukemic capacity is maintained via alloantigenpresentation by recipient stromal APC. We will utilize cutting-edge mechanistic preclinical murine studies usingadvanced flow cytometry multiplexed immunofluorescence microscopy RNASeq and REAP/CITE-seq tounderstand antigen presentation required for effective GVL and relapse prevention. Finally we will test a novelattenuated synthetic IL-18 resistant to the IL-18 binding protein (decoy resistant (DR-18)) that has been fused toCXCR4 nanobody or CD117 antibody to selectively enhance IFNg and antigen presentation locally in the bonemarrow. The proposal will lead to a new clinically tractable approach to selectively promote GVL and preventrelapse after allogeneic BMT. 246840 +No NIH Category available Amino Acids;Amino Acyl Transfer RNA;Area;Back;Biological Assay;Blood - brain barrier anatomy;Brain;Cancer Patient;Cancer cell line;Carnosine;Cell Proliferation;Cells;Cephalic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Codon Nucleotides;Complementary DNA;Complication;Culture Media;Data;Defect;Diabetic Nephropathy;Dipeptidases;Disease;Doxycycline;Ectopic Expression;Electron Microscopy;Environment;Enzymes;Excision;FRAP1 gene;Flow Cytometry;Gene Silencing;Genes;Genetic;Genetic Polymorphism;Genus Hippocampus;Global Change;Growth;Histidine;Immunotherapy;Impairment;In Vitro;Injections;Investigation;Ligase;Liver;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Measures;Mediating;Melanoma Cell;Metabolic;Metastatic malignant neoplasm to brain;Mitochondria;Mitochondrial Proteins;Modeling;Molecular;Morphology;Muscle;Neoplasm Metastasis;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Phosphorylation;Oxidative Stress;Patient-Focused Outcomes;Patients;Play;Pre-Clinical Model;Proliferating;Proteins;Proteomics;RNA;Radio;Role;Specificity;Supplementation;Surface;Systemic Therapy;Testing;Therapeutic Effect;Translations;Up-Regulation;Xenograft procedure;beta-Alanine;biological adaptation to stress;brain parenchyma;brain size;cancer type;cohort;diabetic patient;dietary supplements;improved;in vivo;inhibitor;knock-down;loss of function;mRNA Decay;malignant breast neoplasm;melanoma;metabolomics;mouse model;mutant;neuroprotection;novel;novel therapeutic intervention;pharmacologic;pre-clinical;preference;prevent;research clinical testing;ribosome profiling;small hairpin RNA;small molecule inhibitor;therapeutic evaluation;transcriptome sequencing;transcriptomics;tumor;tumor progression;tumorigenic Metabolic adaptations in melanoma brain metastasis NARRATIVEBrain metastasis remains a serious complication for melanoma patients. We aim to study the contribution ofCNDP1 to melanoma cells adaptation to the brain microenvironment and assess the value of targeting thisenzyme as a novel therapeutic approach against these tumors. NCI 10785565 12/20/23 0:00 PAR-22-216 1R21CA286244-01 1 R21 CA 286244 1 "O'HAYRE, MORGAN" 1/1/24 0:00 12/31/25 0:00 ZCA1-SRB-P(O2)S 9107364 "HERNANDO, EVA " Not Applicable 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 198103 NCI 116875 81228 ABSTRACT Melanoma brain metastasis (MBM) is a deadly poorly understood consequence of melanoma for whichpatients need improved treatment options. In integrating proteomics and transcriptomics data from independentpatient cohorts CNDP1 was identified as a commonly upregulated gene in MBM. CNDP1 or carnosinedipeptidase-1 cleaves carnosine into its component amino acids L-histidine and -alanine. Carnosine isabundant in muscle liver and in the brain where it exerts neuroprotective effects5. While carnosine itself isthought to exert anti-tumorigenic effects the role of CNDP1 in cancer remains vastly unknown. To probe the functional role of CNDP1 in MBM we assessed the effects of CNDP1 depletion in MBM invitro and in vivo. Constitutive CNDP1 silencing reduced melanoma cells ability to colonize the brain parenchymaand inducible suppression impaired growth of established MBMs in preclinical mouse models. Mechanisticallyour preliminary studies suggest that in addition to carnosine cleavage CNDP1 may regulate cellular amino acidpools aminoacyl-tRNA availability and protein translation particularly of mitochondrial proteins. Our findingssuggest the possibility that higher CNDP1 levels allow melanoma cells to withstand high carnosine levels andoxidative stress during brain metastasis. This proposal aims to: 1) solidify the value and specificity of CNDP1 as a novel MBM target usingpreclinical models and genetic and pharmacological approaches and 2) dissect its mechanism(s) of action. 198103 +No NIH Category available Address;Affect;Attenuated;Biological Assay;Biological Availability;Brain;CCL2 gene;Cell Line;Cells;Child;Childhood Glioma;Chronic;Clone Cells;Data;Development;Diet;Diffuse intrinsic pontine glioma;Dose;Genetically Engineered Mouse;Glioma;Growth;Histone H3.3;Hour;Human;Immunocompetent;Immunotherapy;In Vitro;Inflammation;Interdisciplinary Study;Intraperitoneal Injections;Lead;Ligands;Macrophage;Malignant Childhood Neoplasm;Malignant neoplasm of brain;Mediating;Medical;Methionine;Microglia;Modeling;Mole the mammal;Molecular Analysis;Molecular Target;Mus;Mutation;Myeloid Cell Activation;NF-kappa B;New Agents;Oral;Oral Administration;Outcome;Patients;Pharmacodynamics;Positioning Attribute;Pre-Clinical Model;Production;Publishing;Radiation;Recovery;Recurrence;Refractory;Reporter;Research;Rodent;STAT3 gene;Signal Transduction;Terpenes;Therapeutic;Time;Toxic effect;Tumor-associated macrophages;United States;Up-Regulation;Xenograft procedure;cancer therapy;chemokine;design;glial activation;glioma cell line;high risk;in vivo;inhibitor;insight;monocyte;mouse model;nano;neurogenesis;novel;novel therapeutics;oleanane;patient derived xenograft model;pediatric patients;pre-clinical;radiation resistance;radiation response;rare cancer;recruit;response;stem cells;success;tumor;tumor microenvironment Development of a novel CNS-penetrant synthetic triterpenoid for pediatric high-grade glioma. PROJECT NARRATIVEThe product of this research effort will be new scientific insight into mechanisms of activity of a novel syntheticoleanane triterpenoid (SOT) known as CDDO-2P-Im or 2P-Im and a clear demonstration of the capacity of2P-Im to enhance the response radiation. The success of this effort will define an approach to increasingsurvival of pediatric patients with a rare cancer Diffuse Intrinsic Pontine Glioma (DIPG) and other pediatrichigh-grade gliomas (HGG). The multidisciplinary research team utilizes established preclinical models of DIPGwhich remains a significant unmet medical need as less than 1% of patients survive 5 years (the mediansurvival is only 9 months). NCI 10785249 11/30/23 0:00 PAR-22-216 1R21CA280426-01A1 1 R21 CA 280426 1 A1 "SINGH, ANJU" 12/1/23 0:00 11/30/25 0:00 ZCA1-SRB-P(O2)S 8615010 "LETTERIO, JOHN JAMES" Not Applicable 11 PEDIATRICS 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 225803 NCI 140250 85553 PROJECT ABSTRACTThis application is focused development of a new therapeutic for pediatric high-grade glioma (HGG) including arare subset known as Diffuse Intrinsic Pontine Glioma (DIPG). DIPG is a rare brain cancer primarily affectingchildren with approximately 200-300 new annual cases in the United States less than 2 percent survival at 2years and with a limited response to therapeutic radiation (RT). Recently published studies in preclinical gliomamodels have revealed that RT results in a progressive accumulation of monocyte derived macrophages (MDMs)and activated microglia and that inhibition of the recruitment of MDMs delays glioma recurrence. There issubstantial evidence demonstrating a key role for chemokine (C-C motif) ligand 2 or CCL2 also known asmonocyte chemoattractant protein-1 (MCP-1) in RT-induced inflammation including the recruitment of MDMsinto the brain and tumor microenvironment (TME). These studies not only show that RT induces a transient andselective upregulation of CCL2 within hours of exposure but also demonstrate disruption of CCL2 signalingduring this time frame alone is sufficient to attenuate chronic microglial activation and to allow the recovery ofneurogenesis in the weeks following radiation. However there is a desperate need for new agents that are notonly potent inhibitors of CCL2 production and signaling but that are also safe for administration in combinationwith RT. The synthetic oleanane triterpenoids (SOTs) evaluated in this application meet these criteria. Theresearch team pursues ground-breaking high-risk high-gain studies that address our central hypothesis thatchronic systemic oral administration of a newly developed SOT (CDDO-2P-Im or 2P-Im) will enhance theradiation response of DIPG through mechanisms that include suppression of RT-induced recruitment andactivation myeloid cells in the brain with potential to also limit RT-related toxicity. Preliminary data show 900nanomoles of 2P-Im/kg of brain at 6 hours after a 1 mole dose given either by intraperitoneal injection or byoral gavage in mice and that 2P-Im inhibits CCL2 production by activated human macrophages at picomolarconcentrations in vitro. The project is organized around three specific aims that: (1) define the effect of 2P-Im(both alone and in combination with RT) on in vitro clonogenic survival of DIPG cell lines including thoseharboring the histone H3.3 Lys 27-to-methionine (K27M) mutation and the relationship to direct moleculartargets of 2P-Im (AIM 1); (2) determine the dose- and time-dependent effects of 2P-Im on RT-induced recruitmentof MDMs and on microglial activation (AIM 2); and (3)demonstrate the in vivo efficacy and activity of2P-Im(administered in rodent diet) in established orthotopic PDX models of DIPG including the capacity of 2P-Im toenhance the radiation response of DIPG xenografts in vivo (AIM 3). Data generated in this proposal will position2P-Im for advancement to critical IND-enabling studies and as a novel orally bioavailable therapy for a highlyaggressive refractory rare childhood cancer. 225803 +No NIH Category available Apoptosis;Autophagocytosis;BCL2 gene;BCL2L1 gene;Binding Sites;Biological Assay;Biological Process;CASP2 gene;CRISPR/Cas technology;Caspase;Cell Death;Cells;Chimera organism;Chimeric Proteins;Clustered Regularly Interspaced Short Palindromic Repeats;Computer Models;Consumption;Cysteine;Data;Development;Family;Foundations;Future;Genes;Human;In Vitro;Knock-out;Libraries;Ligands;Lysosomes;MCL1 gene;MDM2 gene;Mediating;Modality;Names;Natural Products;Oncoproteins;Process;Property;Protac;Proteins;Proteolysis;Series;Site;Site-Directed Mutagenesis;Solid;Structure;System;Tacrolimus Binding Proteins;Technology;Testing;Therapeutic;Time;Ubiquitin;activity-based protein profiling;analog;anti-cancer;cancer therapy;design;dietary;experimental study;flexibility;inhibitor;interest;multicatalytic endopeptidase complex;novel strategies;protein degradation;protein function;recruit;screening;small molecule;success;tool;ubiquitin-protein ligase;weapons Development of Caspase Cleavage Targeting Chimeras (CACTACs) for Targeted Protein Cleavage PROJECT NARRATIVEWe propose a novel approach called caspase cleavage targeting chimera (CACTAC) for targeted proteincleavage by recruiting caspases. Protein function can be abruptly stopped by the one-step CACTAC-inducedprotein cleavage. CACTACs that target oncoproteins could be developed as potential cancer therapies. NCI 10785026 11/29/23 0:00 PAR-22-216 1R21CA286307-01 1 R21 CA 286307 1 "AGYIN, JOSEPH KOFI" 12/1/23 0:00 11/30/25 0:00 ZCA1-TCRB-V(O1)S 14108036 "LYU, DONGWEN " Not Applicable 20 BIOCHEMISTRY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 192844 NCI 141419 51425 PROJECT SUMMARYCaspases are a family of cysteine proteases which can cleave proteins containing cleavage sites on the flexibleregion to trigger cell death through apoptosis or pyroptosis. Recently bifunctional small molecules such asproteolysis targeting chimeras (PROTACs) lysosome targeting chimeras (LYTACs) or autophagy targetingchimeras (AUTACs) have emerged as potential therapeutic modalities by hijacking the ubiquitin-proteasomesystem (UPS) lysosome or autophagy to degrade proteins of interest (POIs). Caspase cleavage is a one-stepprocess that instantly terminate protein function. Here we discovered that piperlongumine (PL) a dietary naturalproduct can recruit caspase(s) to cleave Bcl-xL when conjugated with a Bcl-xL/2 inhibitor ABT263. This findingmotivated us to further develop bifunctional small molecules for targeted protein cleavage by recruiting caspaseswhich could be superior to or complementary to the known degraders. We termed this kind of compoundscaspase cleavage targeting chimeras (CACTACs). In this proposal we will apply a series of state-of-the-arttechnologies to find the caspase(s) recruited by the current PL-based Bcl-xL CACTAC and confirm themechanism of action. In addition we will build a Halo-FKBP system to further genetically explore the potential ofCACTAC-mediated targeted protein cleavage by various caspases. The caspase-cleavage site pairs will besystematically identified to inform the future CACTAC design. We will also further develop new caspase-2recruiters through PL analog library screening and structure/computer modeling-based optimization. MoreCACTACs targeting other POIs will be synthesized and tested to expand the application of CACTACs. TheCACTAC platform proposed here will offer a revolutionary weapon against oncoproteins for cancer therapy. 192844 +No NIH Category available Address;Adherence;Adolescent and Young Adult;American;Antineoplastic Agents;Award;Biological Markers;Cancer Center;Cancer Therapy Evaluation Program;Catchment Area;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Contracts;Development;Disease;Drug Kinetics;Early Therapeutic-Clinical Trials Network;Education;Elderly;Enrollment;Goals;Good Clinical Practice;Grant;Guidelines;Image;Institution;Intervention;Laboratories;Lead;Malignant Neoplasms;Mentors;Mentorship;Minority;Minority Groups;Molecular Analysis;Monitor;Outcome;Pathologist;Patients;Pharmacodynamics;Phase;Physicians;Productivity;Publications;Regulation;Reporting;Request for Applications;Research Personnel;Rural Population;Science;Site;Texas;Time;Tissue Banks;Toxic effect;Training;Translational Research;Tumor Tissue;Underserved Population;Universities;Virginia;biomarker development;career;career development;demographics;drug development;early phase clinical trial;early phase trial;human subject protection;improved;inner city;investigator-initiated trial;member;minority patient;next generation;novel;participant enrollment;phase II trial;precision oncology;programs;radiologist;response;success;tissue biomarkers;translational scientist North American Star Consortium The North American Star Consortium for UM1 ETCTN trials consists of leading investigators from the Moffitt Cancer Center Princess Margaret Cancer Centre VCU-Massey Cancer Center University of Texas Southwestern Simmons Cancer Center and Northwestern University Lurie Cancer Center. This consortium is focused on producing and enrolling patients on high-quality clinical trials to significantly impact cancer outcomes the incorporation of state-of-the-art precision science in the trials the accrual of minority underserved elderly and adolescent and young adult patients and training the next generation of physician researchers in cancer drug development. NCI 10784850 5/9/23 0:00 RFA-CA-19-007 4UM1CA186644-07 4 UM1 CA 186644 7 "IVY, S PERCY" 4/7/14 0:00 2/28/26 0:00 ZCA1-RPRB-N(J1) 10842735 "BEDARD, PHILIPPE " "COURTNEY, KEVIN D; GRANT, STEVEN ; LANCET, JEFFREY ; MAHALINGAM, DEVALINGAM ; SIU, LILLIAN L" n/a Unavailable 208469486 ENZFJ8Q5KX39 208469486 ENZFJ8Q5KX39 CA 43.70011 -79.4163 3836301 UNIVERSITY HEALTH NETWORK TORONTO ON Unavailable M5G 2C4 CANADA N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 2106066 NCI 2052461 53605 This UM1 renewal application is designated the North American Star Consortium (NASC) which includes Moffitt Cancer Center (MCC) as the Lead Academic Organization (LAO) with Daniel Sullivan MD as the contact PI. MCC is joined by four highly productive Academic Organizations (AO) including Princess Margaret Cancer Center (PMCC; Philippe Bedard MD multi-PI) Virginia Commonwealth University-Massey Cancer Center (VCU-Massey; Steven Grant MD multi-PI) University of Texas Southwestern Simmons Cancer Center (UTSW; Muhammad Beg MD multi-PI) and Northwestern Lurie Cancer Center (NWU; Jeffrey Sosman MD multi-PI). The NASC evolved from the Princess Margaret Phase 1 Consortium (PMP1C) where PMCC was the LAO and MCC and VCU-Massey AOs. The two new sites (UTSW and NWU) bring additional depth in basic/translational science and biomarker (BM) development have active early phase clinical trial programs prioritize the accrual of minority patients have active mentorship programs for Early Career Clinical Investigators (ECIs) and expand the NASC expertise in investigational imaging. The PMP1C has existed from April 2014 to the present and during this time 14 ETCTN trials have been activated and 4 are pending activation. The average yearly accrual during this time was 52 patients/year (yearly goal was 50 patients/year) with 97 patients enrolled March 2018 February 2019. The 5 NASC institutions have enrolled a total of 1703 patients on their top 50 trials (ETCTN + non-ETCTN) with appropriate minority patient accrual exceptionally strong mentoring of ECIs and significant correlative molecular analyses for integrated and exploratory BM. This productivity of the PMP1C and UTSW/NWU will now go forward with MCC as the LAO to address the following specific aims. 1. To plan develop and activate novel phase 1 and phase 2 ETCTN trials through participation in the Project Team Member Application mechanism or as investigator-initiated trials (IITs) that emerge from NASC investigators. The NASC goal is to activate a minimum of six trials/year. 2. To enroll patients on ETCTN trials from the NASC or other sites that require the acquisition of high-quality tumor tissue for biomarker and pharmacodynamic analyses include pharmacokinetic (PK) endpoints and closely follow Good Clinical Practice and Human Subject Protection guidelines. The NASC annual accrual goal on ETCTN trials is a minimum of 100 patients/year (30 at MCC 20 each at PMCC and VCU-Massey and 15 each at UTSW and NWU). 3. To focus on the career development of ECIs within the NASC by providing educational opportunities regarding clinical research and its regulation at the 5 institutions by having the ECI serve as the PI of ETCTN studies and pairing them with senior investigator mentors and by focusing on ECI exposure and education regarding biomarkers correlative molecular analyses PK studies and precision cancer medicine. 4.To ensure that ETCTN trials performed at NASC sites have appropriate accrual of minority patients other underserved populations adolescent and young adults the elderly and rural populations. 2106066 +No NIH Category available Acceleration;Amendment;American Indians;Antineoplastic Agents;Area;Award;Back;Biological Assay;Biological Markers;Biology;California;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Catchment Area;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Trials Network;Collaborations;Data;Development;Discipline;Disease;Drug Delivery Systems;Drug Kinetics;Early Therapeutic-Clinical Trials Network;Education;Eligibility Determination;Evolution;Faculty;Funding;Generations;Genomics;Geography;Goals;Health Service Area;Histologic;Immunology;Immunotherapy;Infrastructure;Institution;Investigation;Investigational Therapies;Knowledge;Laboratories;Leadership;Letters;Malignant Neoplasms;Mentors;Mentorship;Methods;Minority Groups;Mission;Molecular;Monitor;National Cancer Institute;Oklahoma;Oncology;Patient Recruitments;Patient Selection;Patient-Focused Outcomes;Patients;Pharmacodynamics;Pharmacopoeias;Phase;Philosophy;Population;Protocols documentation;Reporting;Research;Research Design;Research Personnel;Resistance;Rural Population;Science;Serum;Services;Site;Special Population;Stratification;Testing;Therapeutic;Toxic effect;Training;Translating;Translational Research;Translations;Universities;Variant;Work;Yale Cancer Center;bench to bedside;biomarker driven;cancer clinical trial;career;clinical investigation;clinical trial recruitment;design;drug development;early phase clinical trial;early phase trial;experience;imaging biomarker;improved outcome;member;multidisciplinary;next generation;novel;novel anticancer drug;novel marker;novel therapeutic intervention;novel therapeutics;patient biomarkers;patient population;patient subsets;phase II trial;rare cancer;recruit;resistance mechanism;response;rural Americans;skills;student mentoring;tissue biomarkers;tool;translational medicine;treatment optimization;trial design;tumor VICKtOrY Early Clinical Trials Consortium This re-competition application describes the previous experience of our multidisciplinary group in conducting early Phase clinical trials of experimental cancer therapeutics and related correlative translational science studies through the National Cancer Institute Experimental Therapeutics-Clinical Trials Network (ETCTN). It details the continued plans of our consortium to perform comprehensive conduct of early clinical trials more selective and sophisticated clinical and translational investigational strategies and seamless advancement of experimental agents through early stages of development. Finally it highlights our prioritization for mentoring the next generation of cancer clinical trialists and describes opportunities for them to develop their leadership and educational skillsets. NCI 10784848 5/30/23 0:00 RFA-CA-19-007 4UM1CA186689-07 4 UM1 CA 186689 7 "IVY, S PERCY" 7/10/14 0:00 2/28/26 0:00 ZCA1-RPRB-N(J1) 2790620 "LORUSSO, PATRICIA M." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 2044455 NCI 1630792 743745 The new era in cancer drug development represents a paradigm shift in how early phase studies are conductedrelative to the conventional approach of treating without consideration to underlying tumor genomics biology and immunology. Translational endpoints including levels of target expression engagement and modulation of downstream effectors are being assessed as early as possible and increasing emphasis is being placed on early patient selection utilizing novel biomarker assays and molecular characterization to identify patients most likely to respond. The ultimate purpose of the NCI Experimental Therapeutics-Clinical Trials Network (ETCTN) is to develop new therapeutic options while also defining better approaches for the development of novel anticancer agents that capitalize on the ability to characterize tumors molecularly and by also finding appropriate biomarkers to select patients most likely to respond. As biomarker-driven trials become the cornerstone of early phase investigation allowing for the study of potential mechanisms of response and resistance incorporation of these biomarkers is lending itself to novel trial designs which incorporate fewer and often rarer patient subsets defining greater patient outcomes with smaller recruited populations. As a result a unique network such as the ETCTN consisting of multiple scientifically-driven sites and investigators with a vast array of expertise is needed. The ETCTN allows investigators to test relevant bench-to-bedside findings and through integrated analysis and the development of interdisciplinary teams incorporates reverse translation to bring the bedside back to the bench. This application is a re-competition of our previous ETCTN UM1 award (1UM1CA186689) demonstrating both our progress over the past funding period as well as our capabilities to conduct early phase clinical trials. We have slightly amended our original partnerships which now include Vanderbilt-Ingram University of California San Diego Karmanos Cancer Institute University of Oklahoma Stephenson Cancer Center (new) and the Yale Cancer Center (VICKtOrY). Our team aims to 1) leverage novel scientific discoveries for translation into early phase trials using the CTEP pharmacopeia in rare cancers common cancers and uncommon variants of common cancers; 2) incorporate serum tissue and imaging biomarkers to better understand the effects of novel agents either alone or in combination; 3) train early career investigators to be knowledgeable and proficient in conducting early phase clinical trials by providing clinical research leadership opportunities and mentoring; and 4) include as a component of our early phase clinical trial recruitment no less than 10% underserved/special populations. The members of our team have a unique set of complementary expertise and a similar philosophy regarding collaborative research and mentorship of the next generation of cancer investigators. VICKtOrY is committed to utilizing our areas of expertise integrating the science at our institutions and maximizing our collaborative relationships to conduct cutting-edge early phase trials within the ETCTN with the ultimate mission of improving outcomes for cancer patients. 2044455 +No NIH Category available Acceleration;Adult;Albert Einstein Cancer Center;Antineoplastic Agents;Biological Markers;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Catchment Area;Characteristics;Clinical;Clinical Drug Development;Clinical Trials;Clinical Trials Network;Comprehensive Cancer Center;Conduct Clinical Trials;Development;Drug Kinetics;Early Therapeutic-Clinical Trials Network;Enrollment;Florida;Goals;Health;Infrastructure;Institution;Investigation;Investigational Therapies;Lead;Leadership;Malignant Neoplasms;Mission;Molecular;National Cancer Institute;Patients;Pennsylvania;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Process;Productivity;Program Development;Regimen;Series;Therapeutic Agents;Toxic effect;Universities;University of Pittsburgh Cancer Institute;Work;anticancer research;appropriate dose;cancer care;cancer therapy;clinical development;drug development;early phase clinical trial;experience;interest;member;novel;novel therapeutics;phase I trial;phase II trial;programs;response;tumor NCI ETCTN Pittsburgh Cancer Consortium (PCC) NarrativeThe overarching goal of the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) is to enhance and facilitate the efficient and comprehensive conduct of early-phase clinical trials of NCI Investigation New Drug (IND) agents. The UPMC Hillman Cancer Center (HCC) proposes to be a member of the NCI ETCTN as the Pittsburgh Cancer Consortium (PCC) Lead Academic Organization in a consortium with the University of Florida Health Cancer Center (UFHCC) and the Albert Einstein Cancer Center (AECC). The mission of the PCC is to create a unified integrated clinical trials network that will allow for more seamless advancement and progress of novel experimental agents and/or combinations through early stages of drug development. The long-term goal is to guide the development and conduct of early-phase clinical trials that may have the potential to change the standard of cancer care in the U.S. and worldwide. NCI 10784844 5/26/23 0:00 RFA-CA-19-007 4UM1CA186690-07 4 UM1 CA 186690 7 "IVY, S PERCY" 3/25/14 0:00 2/28/26 0:00 ZCA1-RPRB-N(J1) 8952707 "BEUMER, JAN HENDRIK" "LUKE, JASON JOHN; VILLARUZ, LIZA COSCA" 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 611743 NCI 854637 259136 AbstractFor more than 40 years the National Cancer Institute (NCI) has supported an infrastructure program to conduct clinical trials across the US. To enhance facilitate and expedite the process of early-phase drug development the NCI implemented a comprehensive plan transforming the NCI-sponsored early-phase clinical trials program from a series of separate institutions and effortsto a new consolidated integrated program referred to as the NCI Experimental Therapeutics Clinical Trials Network (ETCTN). The UPMC Hillman Cancer Center (formerly the University of Pittsburgh Cancer Institute hereafter referred to as HCC) has been an NCI-designated comprehensive cancer center since 1990 and has been involved in the NCI Early Drug Development Program since 1999. Our group was one of 12 academic centers to be selected as an ETCTN Lead Academic Organization (LAO) for the phase 1 component and subsequently selected as one of 10 academic centers to integrate phase 2 clinical trial efforts with responsibility for developing leading and accruing to ETCTN clinical trials for adult cancer patients. We now propose to be a member of the NCI ETCTN as the Pittsburgh Cancer Consortium (PCC) Lead Academic Organization in a consortium with the University of Florida Health Cancer Center and the Albert Einstein Cancer Center. The goal of the PCC is to create a unified integrated clinical trials network that will allow for more seamless advancement and progress of novel experimental agents and/or combinations through early stages of drug development. The eventual goal of our program is to greatly facilitate and accelerate the delivery of new cancer therapies to the citizens of Pennsylvania North-Central Florida Bronx NY and their respective catchment areas. 611743 +No NIH Category available Acceleration;Biological;Biological Assay;Biological Markers;Biopsy Specimen;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Characteristics;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Collection;Comprehensive Cancer Center;Development;Discipline;Disease;Drug resistance;Educational Activities;Eligibility Determination;Environment;Evaluation;Evolution;Fostering;Goals;Good Clinical Practice;Grant;Image;Immunologic Monitoring;Infrastructure;Institution;Intervention;Investigational Therapies;Kimmel Cancer Center at the Thomas Jefferson University;Laboratories;Laboratory Study;Lead;Leadership;Letters;Location;Malignant Neoplasms;Medical;Memorial Sloan-Kettering Cancer Center;Mentors;Methodology;Molecular;NCI-Designated Cancer Center;National Clinical Trials Network;New Agents;Organizational Affiliation;Participant;Pathologist;Pathway interactions;Patient Selection;Patients;Pharmacodynamics;Phase;Phase I Clinical Trials;Protocols documentation;Quality of Care;Research;Research Personnel;Resource Sharing;Resources;Rural;Science;Site;Statistical Data Interpretation;Team Process;Toxic effect;Training;Translating;Translational Research;Universities;University of Virginia Cancer Center;Wisconsin;assay development;biomarker development;biomarker validation;cancer clinical trial;career;clinical care;clinical development;clinical investigation;clinical translation;data sharing;design;drug development;drug sensitivity;early phase clinical trial;early phase trial;experience;innovation;interest;meetings;member;molecular subtypes;next generation;novel;novel anticancer drug;novel therapeutics;participant enrollment;patient population;radiologist;rare cancer;response;stem;success;trial design The Johns Hopkins Translational Science Team and Consortium for ETCTN Studies Our Consortium will continue its long- standing contribution to the drug development efforts of the NCI by leveraging its collective experience commitment to collaboration and legacy of training young investigators to impact the clinical care of cancer patients. We promote inclusiveness of the many medical disciplines that are required to conduct innovative informative and insightful early phase clinical trials. We anticipate enhanced interactions with the National Clinical Trials Network to bring forward successes from the efforts of the ETCTN. NCI 10784843 6/14/23 0:00 RFA-CA-19-007 4UM1CA186691-07 4 UM1 CA 186691 7 "IVY, S PERCY" 3/13/14 0:00 2/28/26 0:00 ZCA1-RPRB-N(J1) 1877600 "CARDUCCI, MICHAEL A" "GENTZLER, RYAN ; LIU, GLENN ; MESSERSMITH, WELLS A; RUDEK, MICHELLE A" 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 1836359 NCI 2274006 232060 With the evolution of the Experimental Therapeutics Clinical Trials Network (ETCTN) the Johns Hopkins Translational Science Team (JHTST) expanded in 2016 by bringing 5 (now 6) Affiliate Organizations (AO) under our Lead Academic Organization (LAO) with the goal to enhance and accelerate our collective contribution to the drug development efforts of the NCI. We have organized a comprehensive and cohesive infrastructure that can conduct high-quality clinical trials evaluating novel anticancer agents in combinations in molecularly selected patient populations or rare tumor sites. Our infrastructure stems from the need to be clinically efficient regulatory compliant and scientifically rigorous in our approach as we collaborate as network members within the ETCTN. Our infrastructure consists of seven experienced NCI-designated Cancer Centers: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Emory Winship Cancer Institute Georgetown Lombardi Comprehensive Cancer Center Sidney Kimmel Cancer Center at Thomas Jefferson University Memorial Sloan Kettering Cancer Center University of Virginia Cancer Center and University of Wisconsin Carbone Cancer Center. This collection of Centers brings together many unique discovery strengths diverse patient volumes and locations both urban and rural. We will focus on 4 Specific Aims: Aim 1- To lead and maintain a clinical trial consortium that will support cancer clinical trials from Phase 1 initiation through proof-ofactivity and foster seamless Phase 2 clinical development of NCI CTEP IND agents; Aim 2- To actively participate and engage disease-focused clinical investigators in the ETCTN by promoting accrual to a range of ETCTN studies led by other LAO/AO members; Aim 3- To incorporate and implement innovative correlative and biological laboratory studies in the context of or as eligibility for participation in early phase clinical studies that enhance our understanding of determinants of toxicity and response that will be used for further definitive practice-changing clinical trial evaluation; and Aim 4- To train the next generation of investigators in drug development. With 7 Centers within our Consortium we anticipate no problem in meeting the grant metrics of 100 accruals per year submitting enough LOI concepts to have 6 new studies approved each year functioning as a network by having Disease-Focused Clinical Investigators champion ETCTN studies at each Site across disease sites and to provide opportunities to engage and train early career investigators in drug development. We anticipate that our contributions within the ETCTN will impact the clinical care of cancer patients. 1836359 +No NIH Category available Advanced Malignant Neoplasm;American;Appalachian Region;Basic Science;Biomedical Research;Biopsy;Blood;Blood Circulation;Cancer Burden;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Catchment Area;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Comprehensive Cancer Center;Dedications;Development;Discipline;Dose;Drug Combinations;Drug Kinetics;Drug resistance;Early Therapeutic-Clinical Trials Network;Enrollment;Ensure;Evaluation;Faculty;Funding;Future;Genomics;Goals;Grant;Hematologic Neoplasms;Hematology;Immunotherapy;Investigational Drugs;Investigational Therapies;Kentucky;Laboratories;Laboratory Study;Lead;Leadership;Letters;Malignant Neoplasms;Methods;Modality;Modernization;Molecular;Molecular Target;New Agents;Nurses;Ohio;Oncologist;Oncology;Outcome;Pathway interactions;Patient Monitoring;Patient Selection;Patients;Pattern;Pharmaceutical Preparations;Pharmacodynamics;Pharmacogenomics;Pharmacology;Phase;Physicians;Population;Positioning Attribute;Preparation;Reporting;Research;Research Personnel;Resistance;Resources;Sampling;Schedule;Science;Scientist;Site;Solid Neoplasm;Surgeon;Testing;Therapeutic;Therapeutic Agents;Therapeutic Studies;Tissues;Training;Training and Education;Underserved Population;Universities;Utah;Vocational Guidance;cancer cell;cancer clinical trial;cancer therapy;cancer type;career;career development;design;early phase clinical trial;effective therapy;exhaust;experience;innovation;member;multidisciplinary;novel;novel therapeutics;prevent;programs;resistance mechanism;response;rural area;skills;success;targeted treatment;translational scientist;translational study;tumor The Ohio State University as a Lead Academic Organization (LAO) for the Experimental Therapeutics Clinical Trials Network PROJECT NARRATIVEThe Early Therapeutics Clinical Network (ETCTN) at The Ohio State University (OSU) will identify new agents with promising laboratory studies and develop them into new drugs for the treatment of patients with advanced cancer who have exhausted their treatment options. Physicians nurses and research coordinators will carefully monitor patients receiving these drugs to make sure that they are safe. Patients will also undergo sampling of their blood and have their tumors biopsied. These tissues will be analyzed by modern methods to determine the levels of the new drug in the bloodstream and test whether they are having the predicted effect on the cancer cells. The aim of the clinical study may be to simply determine if the drug can be given safely (phase I) and in other instances the goal of the study will be to see whether the new drug or drug combination can shrink the tumor and enable the patient to live longer. The consortium will consist of OSU the University of Kentucky andthe University of Utah in order to bring the evaluation of novel agents to three states with a high burden of cancer. NCI 10784839 7/17/23 0:00 RFA-CA-19-007 4UM1CA186712-07 4 UM1 CA 186712 7 "IVY, S PERCY" 3/28/14 0:00 2/28/26 0:00 ZCA1-RPRB-N(J1) 1871184 "CARSON, WILLIAM E." "ARNOLD, SUSANNE M; GARRIDO-LAGUNA, IGNACIO " 3 SURGERY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 1722607 NCI 1427862 332593 PROJECT SUMMARYThis project encompasses a multi-disciplinary team of basic scientists and clinical investigators dedicated to finding effective new therapies for patients with cancer. The Ohio State University Comprehensive Cancer Center (OSUCCC) is a comprehensive biomedical research campus with strong collaborations between experienced investigators from multiple oncologic disciplines and a vibrant pattern of discovery in the basic sciences. For the purposes of this proposal the OSUCCC will partner with investigators at the University ofKentucky Markey Cancer Center (MCC) and the University of Utah Huntsman Cancer Institute (HCI) with whom they have had a strong relationships in the past. These sites provide access to a large population of cancerpatients that requires access to cancer clinical trials many of whom reside in rural areas such as Appalachia or the American West. Under the leadership of Dr. William Carson a surgeon with experience in immune therapy and Translational Scientist Dr. Jennifer Woyach a hematologic oncologist with skill in developing targeted therapies this highly integrated team will explore novel therapeutic agents and treatment modalities test new immune-based therapies evaluate drug resistance mechanisms and explore the promise of genomic profiling of the cancer cell in order to develop more effective treatments for cancer. Notably investigators in this experimental therapeutics program have been engaged in the conduct of phase I/II cancer studies for decades and are experienced in the design and conduct of correlative laboratory studies that can confirm the ability of a new drug to hit a specific molecular target and define a precise mechanism of action. Ohio State has collaborated extensively with other cancers centers dedicated to experimental therapeutics and will continue to do so within the context of the UM1 mechanism. The existence of strong laboratory bench research and pharmacology at each site will ensure that this group of translational investigators will continue to generate new concepts for submission within the NCIs Experimental Therapeutics Clinical Trials Network (ETCTN) mechanism. A major goal of this consortium is to accrue over 100 patients per year to ETCTN studies and in the last grant year 102enrollments were recorded in a variety of cancer types. Of prime importance to this consortium is the education and training of early career investigators so that they are prepared to lead new translational studies. Indeed each of the last six studies from this clinical research group has had an early career investigator as its leader. The experience diversity and cohesiveness of this research team combined with an unwavering commitment to ETCTN goals and principles will position it for continued success and innovation within this exciting clinical research mechanism. 1722607 +No NIH Category available Address;Age;Biopsy;Budgets;Cancer Center Support Grant;Cancer Patient;Cancer Survivor;Child;Clinical Data;Clinical Investigator;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;Clinical Trials Support Unit;Comprehensive Cancer Center;Conduct Clinical Trials;Contracts;Data;Databases;Development;Diagnosis;Education;Enrollment;Ensure;Ethnic Origin;Gender;Goals;Healthcare Systems;Infrastructure;Institution;Intervention;Intervention Studies;Intervention Trial;Laboratories;Malignant Childhood Neoplasm;Malignant Neoplasms;Monitor;National Clinical Trials Network;Nursing Research;Outcome;Patients;Peer Review;Policies;Procedures;Protocols documentation;Provider;Race;Reporting;Research;Research Personnel;Resources;Safety;Services;Socioeconomic Status;Tissues;Training and Education;Translations;Writing;clinical care;data integrity;data management;improved;insight;investigator-initiated trial;patient safety;prevent;quality assurance;research study;sex;therapy design Clinical Protocol and Data Management n/a NCI 10784831 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9184 11221769 "GERDS, AARON THOMAS" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 753139 467788 285351 CLINICAL PROTOCOL AND DATA MANAGEMENT PROJECT SUMMARY/ABSTRACT The Case Comprehensive Cancer Center (Case CCC) is committed to the translation of laboratory insights into routine clinical care. This requires a deep infrastructure to support the conduct of clinical trials of new interventions designed to prevent diagnose and treat cancer and improve the long-term outcomes for cancer survivors. The Clinical Protocol and Data Management services of the Case CCC provide a centralized resource for the oversight and management of clinical trials from concept development through reporting of study results. Services include assistance with concept development and protocol writing; feasibility assessment; budgeting and contracting; research nursing and data management; database development and oversight; regulatory management including IND applications; interactions with sponsors; study registration; quality assurance; staff education; and reporting of results. Data and safety monitoring to ensure the integrity of data and patient safety is a critical centralized function. As our goal is to ensure access to clinical trials for all of our patients special efforts are undertaken to provide the opportunity to participate in clinical trials regardless of sex/gender race ethnicity socioeconomic status or age. The Specific Aims are to: 1) Provide a highly efficient and coordinated infrastructure to assist clinical investigators in the development conduct and reporting of clinical trials. 2) Oversee data integrity and ensure the safety of patients who participate in clinical trials. 3) Provide access to clinical trials for all cancer patients regardless of sex/gender race ethnicity age and socioeconomic status and proactively identify and address barriers to clinical trial participation among patients providers research staff and healthcare systems. 4) Support a robust portfolio of research studies relevant to children and address special considerations for children with cancer to facilitate their participation in clinical trials. In 2016 2474 patients were enrolled onto Case CCC interventional trials (73 percent increase since 2012) including 866 patients on treatment studies. In 2016 thirty one percent of accruals to treatment studies and seventy percent of all interventional accrual was to investigator-initiated trials (peer-reviewed institutional). There is a substantial commitment to support of National Clinical Trials Network (NCTN) studies with 209 patients accrued to treatment intervention studies in the third year of the NCTN. Furthermore in 2016 the Case CCC enrolled and biopsied 93 patients on the NCI MATCH trial supported by the Clinical Trials Units via rapid activation centralized registration and coordination of tissue acquisition and processing. ! +No NIH Category available 21 year old;Adopted;Advanced Malignant Neoplasm;Affordable Care Act;American Society of Clinical Oncology;Attention;Award;Behavior Therapy;Behavioral Medicine;Biometry;Breast Cancer therapy;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Prognosis;Caring;Catchment Area;Cigar;Cities;Clinical;Clinical Practice Guideline;Clinical Trials;Collaborations;Communities;Comprehensive Cancer Center;Data Sources;Databases;Death Certificates;Direct Costs;Disparity;Early Diagnosis;Economics;Education;Environmental Risk Factor;Funding;Future;Genetic;Genomics;Goals;Goserelin;Grant;HIV;Health;Health Care Reform;Health Policy;Health Services Research;Healthcare Systems;High Prevalence;Incidence;Individual;Intervention;Laws;Leadership;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mammography;Medicare;Methods;Monitor;Multiomic Data;National Comprehensive Cancer Network;Neighborhoods;Nicotine;Ohio;Online Systems;Outcome;Palliative Care;Patient Care;Peer Review;Policies;Population;Population Research;Population Study;Prevention;Prevention strategy;Preventive service;Primary Prevention;Program Research Project Grants;Public Health;Publications;Publishing;Quality of Care;Recommendation;Research;Research Personnel;Resource Sharing;Risk Reduction;Sales;Screening for cancer;Text;Tissues;Tobacco;Tobacco Use Cessation;Underserved Population;Urban Population;Work;Youth;anticancer research;beneficiary;cancer diagnosis;cancer epidemiology;cancer prevention;cancer risk;chemotherapy;clinical practice;colon cancer screening;data resource;epidemiology study;improved;improved outcome;member;neoplasm registry;novel;novel strategies;ovarian failure;population health;prediction algorithm;programs;screening;smoking cessation;smoking intervention;social;success;survivorship;synergism;tobacco control;tobacco products;uptake;urban underserved;working group Cancer Prevention Control and Population Research Program n/a NCI 10784827 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9180 1877561 "COOPER, GREGORY S." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 86951 54007 32944 CANCER PREVENTION CONTROL AND POPULATION RESEARCH (CPC) PROGRAMPROJECT SUMMARY/ABSTRACTThe goal of the Cancer Prevention Control and Population Research (CPC) Program is to develop andevaluate interventions that reduce the incidence and improve the outcomes of cancer in the CaseComprehensive Cancer Center (Case CCC) catchment area and beyond. Program members establish novelapproaches in risk reduction screening and early detection. They also conduct research to implement andmonitor improved delivery of recommended preventive services therapies and survivorship care after cancerdiagnosis. The program is organized around 3 scientific aims: (1) Discover strategies and develop andimplement behavioral interventions to reduce cancer risk and improve outcomes after cancer diagnosis; (2)Evaluate and facilitate effective cancer screening surveillance and treatment policies and their impact onpractice and the healthcare system; and (3) Discover and characterize genetic and environmental factorslinked to cancer. These aims reflect major working groups and initiatives that coalesces program members withother cancer center investigators through inter-programmatic collaborations that have impacted paradigms forpatient care health policy and the larger cancer research community. Extensive use of an array of sharedresources in particular Biostatistics Cancer Outcomes Genomics and Tissue facilitate all aspects of memberdiscoveries.Under the leadership of Gregory Cooper (Co-Leader) and Susan Flocke (Co-Leader) the CPC Program has 38members including 30 full 1 associate and 7 clinical members. Members represent 20 departments givingrise to a total of $10.8M in grant funding (annual direct costs) of which $8.2M is peer-reviewed and $2.3M isNCI-funded. Between 2012 and 2016 CPC program members published 1174 publications. Cancer andprogram related publications included 25% inter-programmatic 16% intra-programmatic 6% inter- and intra-programmatic and 11% that involved collaborations with another Cancer Center. This highly effectiveProgram has successfully created synergy among Case CCC CPC members and collaborations withinvestigators in other research Programs as evidenced by new initiatives in cancer prevention in underservedurban populations tobacco control new approaches to colon cancer screening and prevention palliative careof patients with advanced cancer and cancer risk in HIV infected individuals. +No NIH Category available Animals;Area;Automobile Driving;Biology;Biometry;Brain Neoplasms;Breast Cancer Detection;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Detection;Canis familiaris;Chemistry;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Communication;Comprehensive Cancer Center;Cytometry;Data;Detection;Development;Developmental Therapeutics Program;Diagnostic;Direct Costs;Engineering;Evaluation;Fibronectins;Fingerprint;Fostering;Foundations;Funding;Generations;Goals;Hematopoietic;Image;Immune;Institution;International;Leadership;Machine Learning;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Medicine;Metastatic malignant neoplasm to brain;Methodology;Micrometastasis;Microscopic;Mus;NCI-Designated Cancer Center;Nature;Oncologist;Pathogenesis;Pathologic;Pathologist;Patient Care;Patients;Peer Review;Physicians;Physics;Plants;Population Research;Positron-Emission Tomography;Program Research Project Grants;Publications;Publishing;Research;Research Personnel;Research Project Grants;Resource Sharing;Scientist;Specimen;Technology;Therapeutic;Three-Dimensional Imaging;Toy;Translating;Tumor Pathology;Ultrasonography;Viral;Visualization;Work;attenuation;cancer imaging;cancer prevention;cancer therapy;clinical diagnosis;clinical investigation;clinical prognosis;computerized tools;design;digital pathology;ideation;imaging agent;imaging detection;imaging modality;imaging program;imaging scientist;improved;in vivo imaging;innovation;interdisciplinary collaboration;interest;invention;malignant breast neoplasm;man;meetings;melanoma;member;molecular oncology;multimodality;nano;nanomedicine;nanoparticle;neuroimaging;new technology;new therapeutic target;novel;novel imaging technology;optical imaging;particle;programs;radiologist;radiomics;recruit;targeted agent;targeted treatment;tool;translational research program;treatment response;tumor;ultrasound;working group Cancer Imaging Research Program n/a NCI 10784826 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9179 8479886 "BASILION, JAMES PETER" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 85834 53313 32521 CANCER IMAGING (CI) RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe Cancer Imaging (CI) Program is a transdisciplinary program that integrates imaging engineering researchwith the study of cancer biology. The goals of this program are to build novel imaging technologies fordiscerning mechanisms of cancer biology designing new targeted therapies and developing innovativeimaging modalities for improving patient care. The CI program covers a continuum of imaging researchreaching from molecules to mice to man that forms the basis for the following three Specific Aims: (1) Utilizeimaging agents to study cancer pathogenesis and develop cancer-targeting therapeutics (2) Codifyquantifiable imaging metrics to study cancer biology and improve cancer treatments and (3) Translate novelimaging methodologies to patient care. These aims reflect major working groups and initiatives that activelyengage researchers from basic biology medicine chemistry physics and engineering backgrounds with otherCancer Center investigators through inter-programmatic collaborations that result in highly impactful advancesin imaging and nanomedicine. Extensive use of an array of shared resources in particular Imaging AthymicCytometry and Biostatistics facilitate all aspects of member discoveries.Under the leadership of James Basilion (Co-Leader) and Zhenghong Lee (Co-Leader) the CI Program has 29members including 19 full 2 associate and 8 clinical members. Members represent 9 departments giving riseto a total of $8.1M in research grant funding (annual direct costs) of which $7.3M is peer-reviewed and $4.0Mis NCI-funded. Between 2012 and 2016 CI program members published 639 publications. Cancer andprogram related publications included 27% inter-programmatic 25% intra-programmatic 10% inter- and intra-programmatic and 7% that involved collaborations with another Cancer Center. This highly effective programhas made major advances in imaging and nanomedicine. Examples include: the discovery and internationaldistribution of a novel quantitative MRI imaging analysis tool based on random magnetic wave generation (MRfingerprinting); development of novel nanoparticle diagnostics and therapeutics including plant derived viralparticles to stimulate host immune rejection of tumors that is now in clinical studies in dogs with melanoma;generation of a fibronectin-targeting agent for detection of breast cancer micrometastases; and the invention ofa multimodal in vivo imaging method for following the disposition of nanoparticles on a microscopic scale aswell as visualizing the microvasculature of tumors in live animals. +No NIH Category available AML/MDS;ATP phosphohydrolase;Address;Advanced Malignant Neoplasm;Apoptosis;Azacitidine;BCL2 gene;BH4 Domain;Back;Base Excision Repairs;Biological Markers;Biotechnology;Brain;Breast;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Therapy Evaluation Program;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Colon;Comprehensive Cancer Center;Creativeness;Cytometry;DNA Repair;DNA Repair Inhibition;Decitabine;Development;Developmental Therapeutics Program;Differentiation Therapy;Direct Costs;Disease;Drug Kinetics;Drug resistance;Drug resistance pathway;Drug usage;Effectiveness;Epidermal Growth Factor Receptor;Epigenetic Process;Funding;Gene Mutation;Genetic;Genetic Markers;Genomics;Goals;Grant;Growth;Hematopoietic;Image;Immune;Laboratories;Leadership;Link;Malate Dehydrogenase;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mentors;Mutation;New Agents;Non-Small-Cell Lung Carcinoma;Oral;Outcome;Ovary;Oxidoreductase;Pancreas;Pathway interactions;Peer Review;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Program Research Project Grants;Protein Phosphatase 2A Regulatory Subunit PR53;Proteomics;Protocols documentation;Publications;Publishing;RNA Splicing;Radiation;Relapse;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Role;SMARCA5 gene;Sampling;Scientist;Series;Solid Neoplasm;System;TP53 gene;TP53-mutant acute myeloid leukemia;Tetrahydrouridine;Therapeutic;Therapeutic Research;Training;Transforming Growth Factor beta;Tumor Escape;Uracil;Validation;Work;advanced breast cancer;analog;anticancer activity;cancer cell;cancer drug resistance;cancer genetics;cancer immunotherapy;clinical development;combinatorial;drug development;drug discovery;early phase clinical trial;early phase trial;first-in-human;forging;glycogen synthase kinase 3 beta inhibitor;immune checkpoint;improved;inhibitor;member;methoxyamine;molecular marker;molecular targeted therapies;new therapeutic target;novel;novel strategies;novel therapeutics;nucleoside analog;nucleotide metabolism;patient derived xenograft model;phase II trial;pre-clinical;pre-clinical assessment;pre-clinical research;preclinical development;preclinical study;programs;pyrimidine metabolism;response;small cell lung carcinoma;tumor;working group Developmental Therapeutics Research Program n/a NCI 10784825 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9178 8615010 "LETTERIO, JOHN JAMES" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 93151 57858 35293 DEVELOPMENTAL THERAPEUTICS (DT) RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe Developmental Therapeutics (DT) Research Program develops and evaluates novel therapeutics andcombinations that: 1) overcome drug resistance of cancer cells mediated by a spectrum of genetic andepigenetic mechanisms; 2) inhibit growth and drug-resistant pathways of cancer; and 3) utilize novel immunecheckpoint therapeutics to increase the proportion of cancer patients who benefit. The overall approach of theDT Program is to leverage the creativity and expertise of basic scientists in the Case Comprehensive CancerCenter (Case CCC) Programs by analyzing new agents for specific validated molecular targets and newtherapeutic compounds for preclinical and clinical validation in early-phase clinical trials. DT members guidetheir development and convey clinical samples back to laboratory investigators to drive further discovery. Thisbidirectional interchange enables DT's continued role as a major convener of new therapeutic concepts for theCenters Programs. The program is organized around 3 scientific aims: (1) Interrogate cancer pathways todevelop new efficacious therapeutics; (2) Implement early-phase clinical trials around novel pathway targetsnew agents and combinatorial approaches; and (3) Implement early-phase trials around novel approaches tocancer immunotherapies to widen their activity spectra. These aims reflect major working groups andinitiatives that coalesces program members with other cancer center investigators through inter-programmaticcollaborations that result in preclinical and clinical research efforts grants and trial protocols. Extensive use ofan array of shared resources in particular Translational Cytometry Imaging Proteomics and Drug Discoveryfacilitate all aspects of member discoveries.Under the leadership of Yogen Saunthararajah (Co-Leader) and John Letterio (Co-Leader) the DT Programhas 52 members including 18 full 5 associate and 29 clinical members representing 21 different departmentsacross the consortium. Members are funded by a total of $12.5M in research grant funding (annual directcosts) of which $5.1M is peer-reviewed and $2.9M is NCI-funded. Between 2012 and 2016 DT programmembers published 1012 publications. Cancer and program related publications included 35% inter-programmatic 25% intra-programmatic 14% inter- and intra-programmatic and 10% that involvedcollaborations with another Cancer Center. This highly effective Program has made major practice-changingcontributions benefiting cancer patients. Examples include: discoveries of first-in-class compounds(SMARCA5 inhibitor PP2A activator malate dehydrogenase inhibitor base excision repair target withmethoxyamine); discoveries targeting EGFR resistance inhibition of uracil glycosylase and the inhibition of theBH4 domain of Bcl-2; analysis into the genetic markers of resistance to radiation; and identification of severalsmall cell lung cancer genetic subsets.! +No NIH Category available Adjuvant;Adult;Advisory Committees;Aging;Antigens;Architecture;Area;Biological;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Caring;Cell Therapy;Cellular Immunity;Cellular immunotherapy;Clinical;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Consensus;Cytometry;DNA Sequence Alteration;Dendritic Cell Vaccine;Dendritic Cells;Development;Developmental Therapeutics Program;Diagnosis;Direct Costs;Disease;Elderly;Engineering;Epigenetic Process;Evolution;Failure;Funding;Future;Generations;Genes;Genetic;Genomics;Genotype;Germ Lines;Grant;Health;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Immune;Immune Evasion;Immune response;Immunologic Surveillance;Immunotherapy;Institution;International;Investments;Lead;Leadership;Lymphoma;Malignant Neoplasms;Marrow;Mediating;Molecular;Molecular Target;Multiple Myeloma;Myelogenous;Myeloid-derived suppressor cells;Myeloproliferative disease;Names;Natural Killer Cells;Neoplasms;Pathogenesis;Pathway interactions;Peer Review;Population;Process;Program Research Project Grants;Property;Protocols documentation;Publications;Publishing;Refractory;Regimen;Relapse;Research;Research Personnel;Resource Sharing;Role;Solid Neoplasm;Southwest Oncology Group;Stem cell transplant;Syndrome;T-Lymphocyte;Therapeutic;Tissues;Transgenic Organisms;Translational Research;Tumor Escape;Vaccines;anti-cancer;blood neoplasm;cancer diagnosis;cancer immunotherapeutics;cancer therapy;clinical application;demethylation;design;disease classification;drug discovery;immunoreactivity;improved;improved outcome;innovation;leukemia;lymphoid neoplasm;member;mutation screening;neoplastic cell;new therapeutic target;novel;novel therapeutics;personalized medicine;pharmacologic;pre-clinical research;prognostication;programs;targeted treatment;tumor;working group Hematopoietic and Immune Cancer Biology Research Program n/a NCI 10784824 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9177 1902289 "HUANG, ALEX YEE-CHEN" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 93151 57858 35293 HEMATOPOIETIC AND IMMUNE CANCER BIOLOGY (HICB) REASEARCH PROGRAM PROJECT SUMMARY/ABSTRACT The objectives of the Hematopoietic and Immune Cancer Biology (HICB) Program are to improve cancer diagnosis care and cure rates through better understanding of molecular pathogenesis of blood neoplasms and optimizing the efficacy of cellular immunotherapy and stem cell transplantation (SCT). Program members investigate the roles of hematopoietic processes in health and disease including the evolution of hematologic neoplasms from normal hematopoiesis and the roles of cellular immunity in cancer immune responses especially toward developing new treatments for hematological malignancies. The program is organized around 3 scientific aims: (1) Discover novel molecular features of hematologic neoplasms to improve diagnosis prognostication and develop a new generation of rationally-targeted therapeutic approaches (2) Interrogate mechanisms of tumor immune surveillance and evasion to develop and apply new anti-tumor cell- based immune therapies and (3) Develop and administer an innovative portfolio of clinical trials based on rationally-targeted molecular cellular and immune cancer therapeutics. These aims reflect major working groups and initiatives that coalesces program members with other Cancer Center investigators through inter- programmatic collaborations that result in preclinical and clinical research efforts grants and trial protocols. Extensive use of an array of shared resources in particular Genomics Hematopoietic Cytometry Athymic Biostatistics Transgenic Tissue and Translational Research facilitate all aspects of member discoveries. Under the leadership of Jaroslaw Maciejewski (Co-Leader) Marcos de Lima (Co-Leader) and Alex Huang (Co-Leader) the HICB Program has 59 members including 32 full 7 associate and 20 clinical members representing 18 different departments across all 3 consortium institutions. Members are funded with a total of $13.4M in grant funding (annual direct costs) of which $8.9M is peer-reviewed and $2.2M is NCI-funded. Between 2012 and 2016 HICB program members published 1264 publications. Cancer and program related publications included 17% inter-programmatic 24% intra-programmatic 5% inter- and intra-programmatic and 6% that involved collaborations with another Cancer Center. This highly effective program has made major practice-changing contributions benefiting cancer patients. Examples include: the discovery of novel driver genes in the evolution of MDS leading to improved disease classification and molecular prognostication; new and effective strategies for MDS treatment emerged using demethylating agents; and members have led a SWOG study identifying significant survival advantage for Inotuzumab ozogamicin in relapsed/refractory ALL. +No NIH Category available 26S proteasome;Acceleration;Address;Award;Basic Science;Biometry;Blood Vessels;Brain Neoplasms;Breast;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cell Proliferation;Cell secretion;Cell-Matrix Junction;Cells;Clinical;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Cytometry;DNA Damage;DNA Repair;Defect;Development;Devices;Direct Costs;Disease;Down-Regulation;Drug resistance;Funding;Gene Expression Regulation;Genetic Recombination;Genomic Instability;Glioblastoma;Glioma;Goals;Grant;Head and Neck Cancer;Home;Hyperthermia;Image;Immune Evasion;Incubators;Integrins;Invaded;Investigation;Iron;Journals;Kinesin;Leadership;Maintenance;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Meiosis;Mitotic;Molecular;Mus;Nature;Normal Cell;Obesity;Obesity associated cancer;Pathway interactions;Peer Review;Pericytes;Phenotype;Population;Population Research;Prevalence;Productivity;Program Research Project Grants;Proliferating;Proteins;Proteomics;Protocols documentation;Publications;Publishing;Radiation-Sensitizing Agents;Radiosensitization;Regulation;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Schedule;Science;Scientist;Signal Transduction;Stem Cell Development;TLR4 gene;Translations;Tumor Cell Invasion;Tumor Promotion;Tumor-associated macrophages;Vertebral column;angiogenesis;anticancer research;cancer cell;cancer genetics;cancer imaging;cancer prevention;cancer stem cell;cancer therapy;catalyst;cell motility;cell type;fatty acid metabolism;host neoplasm interaction;interest;macromolecule;malignant breast neoplasm;member;molecular oncology;multicatalytic endopeptidase complex;neoplastic cell;novel;novel strategies;novel therapeutics;oncology program;periostin;pre-clinical research;precision medicine;programs;recruit;response;self-renewal;stem cell biology;stem cells;stem-like cell;symposium;therapy resistant;tissue resource;trafficking;transdifferentiation;translational cancer research;treatment response;tumor;tumor growth;tumor heterogeneity;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic;working group Molecular Oncology Research Program n/a NCI 10784822 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9175 9673622 "LATHIA, JUSTIN D." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 62101 38572 23529 MOLECULAR ONCOLOGY (MO) RESEARCH PROGRAM PROJECT SUMMARY/ABSTRACT The Molecular Oncology (MO) Research Program is the basic science backbone of the Case Comprehensive Cancer Center (Case CCC). The program is home to diverse groups of basic scientists with a wide spectrum of interests that encompass contemporary cancer research. The exceptional expertise in the Program ranges from fundamental cell signaling mechanisms to structural elucidation of macromolecules to cancer stem cell biology and DNA damage response tumor microenvironments and nationally recognized disease-specific groups in brain tumors and breast cancer. The Program's overarching goal is to elucidate fundamental mechanisms of oncogenesis encompassing the general themes of cancer stem cell regulation DNA damage and repair and host-tumor interactions. This is organized around 3 scientific aims: (1) Discover cancer stem cell mechanisms for cancer prevention and treatment; (2) Identify how defective DNA damage repair promotes genomic instability and alters therapeutic response and (3) Reveal key host-tumor interactions that promote tumor progression and therapeutic resistance. These aims support the key function of the MO program to serve as an incubator to develop and nurture new research initiatives expected to mature into new research themes within the Center. The major working groups and initiatives that coalesces program members with other cancer center investigators through interprogrammatic collaborations that result in preclinical and clinical research efforts grants and trial protocols. Extensive use of an array of shared resources in particular Cytometry Imaging Tissue Resources Proteomics and Biostatistics facilitate all aspects of member discoveries. Under the leadership of Alex Almasan (Co-Leader) and Bing-Cheng Wang (Co-Leader) the MO Program has 53 members including 44 full 8 associate and 1 clinical member. Members represent 18 departments and are funded with a total of $14.7M in annual research grant direct costs $14.2M of which is peer-reviewed and $6.7M NCI-funded. Between 2012 and 2016 MO program members published 716 publications. Cancer and program related publications included 37% inter-programmatic 19% intra-programmatic 9% inter- and intra- programmatic and 7% that involved collaborations with another cancer center. This highly effective program has made major advances to contemporary cancer research. Examples include: discovery that glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth; elucidation that the mitotic kinesin KIF11 is a driver of invasion proliferation and self-renewal in glioblastoma; identification of the revealed preferential iron trafficking in glioblastoma stem-like cells; examination of the control of meiotic pairing and recombination by chromosomally tethered 26S proteasome; and the discovery that glioblastoma stem cells secrete periostin to recruit tumor-associated macrophages. +No NIH Category available Aberrant DNA Methylation;Address;Adoption;African American population;Aspirin;Award;Barrett Esophagus;Big Data;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Detection;Cancer Patient;Chromatin;Clinical;Clinical Research;Clinical Trials;Collaborations;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Comprehensive Cancer Center;DNA;DNA Methylation;Detection;Development;Diagnosis;Direct Costs;Disparity;Drug usage;Early Detection Research Network;Early Diagnosis;Epidemiology;Epigenetic Process;Esophageal Adenocarcinoma;Esophageal Neoplasms;Esophagus;Ethnic Origin;Faculty;Feces;Follow-Up Studies;Foundations;Funding;Gene Mutation;Genetic;Genetic Research;Genomics;Germ-Line Mutation;Goals;Grant;Health Professional;Individual;Leadership;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Methods;Modeling;Mutation;National Cancer Advisory Board;Nurses' Health Study;Organoids;PIK3CG gene;Pathway interactions;Peer Review;Phase II Clinical Trials;Predisposition;Prevention;Prognosis;Program Research Project Grants;Proteomics;Protocols documentation;Publications;Publishing;Race;Recommendation;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Role;Science;Systems Biology;Technology;Translating;Tumor Suppressor Proteins;United States Preventative Services Task Force;Validation;Work;anticancer research;bioinformatics tool;biomarker driven;cancer cell;cancer chemoprevention;cancer genetics;cancer therapy;carcinogenesis;causal variant;clinical development;clinical implementation;cohort;colorectal cancer screening;drug response prediction;early detection biomarkers;early phase clinical trial;epigenetic marker;epigenome;gene environment interaction;genome editing;in vivo Model;innovation;interest;invention;malignant phenotype;member;mutant;new therapeutic target;novel;novel strategies;novel therapeutic intervention;novel therapeutics;pre-clinical research;predictive marker;programs;racial disparity;recruit;screening;small molecule inhibitor;stem cells;success;therapeutic development;therapeutic target;tissue resource;working group GI Cancer Genetics Research Program n/a NCI 10784821 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9174 1888502 "MARKOWITZ, SANFORD D." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 62101 38572 23529 GASTROINTESTINAL CANCER GENETICS RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe Gastrointestinal Cancer Genetics (GICG) Research Program is a basic discovery program with a strongtranslational focus. The overarching goals of the GICG program are to discover genetic and epigenetic causesof GI cancers and to translate these discoveries into development of novel therapeutic approaches andbiomarkers for early detection prevention diagnosis prognosis and prediction of drug responses for GIcancers. The program is organized around 3 scientific aims: (1) Discover and clinically translate geneticalterations in GI cancers; (2) Discover and clinically translate epigenetic changes in GI cancers; and (3)Develop novel methods and models to facilitate basic and translational GI cancer research. The aims reflectthe programs work to continue to: i) make groundbreaking discoveries in the genetic and epigenetic causes ofGI cancers and ii) achieve major clinical impact by translating these discoveries into new approaches forcancer detection prevention and treatment resulting in working groups and initiatives that coalesces programmembers with other cancer center investigators through interprogrammatic collaborations that result inpreclinical and clinical research efforts grants and trial protocols. Extensive use of an array of sharedresources in particular Genomics Biostatistics and Tissue Resources facilitate all aspects of memberdiscoveries.Under the leadership of Sanford Markowitz (Co-Leader) and Zhenghe (John) Wang (Co-Leader) the GICGProgram includes 18 full members and 3 associate members. Members represent 11 departments and 83% ofmembers are funded by 64 projects that give rise to a total of $5.5M in research grant funding (annual directcosts) of which $5.1M is peer-reviewed and $3.8M is NCI-funded. Between 2012 and 2016 GICG programmembers published 534 publications. Cancer and program related publications included 28% inter-programmatic 18% intra-programmatic 8% inter- and intra-programmatic and 8% that involved collaborationwith another Cancer Center. This highly effective program has made major practice-changing contributionsbenefiting cancer patients. Examples include: i) an ongoing investigator-initiated (and Stand Up To Cancer[SU2C] supported) clinical trial of a novel targeted therapy for PI3KCA mutant CRCs; ii) an ongoinginvestigator-initiated clinical trial for biomarker driven detection of Barrets esophagus; iii) FDA approval andcommercial adoption of stool DNA screening for CRC based on detecting methylated DNA an approachpioneered by GICG investigators and continued in an ongoing investigator-initiated clinical trial; iv) validation intwo iconic epidemiology cohorts the Nurses Health Study and the Health Professionals Follow-Up Study ofthe discovery of a predictive biomarker of sensitivity or resistance to colon cancer chemoprevention by aspirin;and v) adoption by the NCI NEXT program of clinical development of a small molecule inhibitor of 15-PGDHinvented by GICG investigators. +No NIH Category available Accounting;Adopted;Area;Biology;CRISPR/Cas technology;Cancer Center;Cancer Center Support Grant;Cancer Model;Comprehensive Cancer Center;Consult;Consultations;Cryopreservation;Derivation procedure;Disease;Doctor of Philosophy;Ensure;Evolution;Fertilization in Vitro;Funding;Gene Targeting;Genes;Genetic;Genetic Models;Goals;Human;Institution;Investigation;Knock-in Mouse;Knock-out;Malignant Neoplasms;Methods;Missense Mutation;Mus;Mutation;NCI Center for Cancer Research;Operative Surgical Procedures;Play;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Services;Susceptibility Gene;Technology;Training and Education;Transgenic Organisms;animation;anticancer research;cancer imaging;cancer type;cost effective;follow-up;genetic variant;genome sciences;human model;humanized mouse;improved;in vivo imaging;member;mid-career faculty;mouse genetics;mouse model;new technology;programs;skills;success;web site Transgenic and Targeting Shared Resource n/a NCI 10784819 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9172 1963368 "CONLON, RONALD A." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 66644 41394 25250 TRANSGENIC AND TARGETING SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe Transgenic and Targeting Shared Resource (Transgenic SR) is an essential asset to Case ComprehensiveCancer Center (Case CCC) members' research illustrated by the breadth of scientific program involvement andreflected in the large number of investigators who use this SR. Last year alone 45 investigators 40% of whomwere Case CCC members accounting for 39% of total usage from 5 out of 7 of the Centers programs used theSR. The Transgenic SR makes transgenic chimeric knockout and knock-in mice and provides services inrederivation cryopreservation reanimation in vitro fertilization and surgery. Central to the success ofinvestigators with new mouse genetic models is the role this facility plays in consultation education and trainingas well as support after service. The Specific Aims of the Transgenic SR are to: 1. Provide Case CCC members with consultation education and training. The Director of the Transgenic SR consults with Cancer Center members and their research staff to ensure they utilize the best technology to meet their experimental goals. The rapid evolution of CRISPR/Cas9 technologies makes consultation particularly important. 2. Provide Case CCC members with new mouse genetic models. The Transgenic SR generates the genetic variants of mice in a timely and cost-effective manner. 3. Provide Case CCC members with follow-up support through direct interaction and through the wealth of information available on the facility website.At last review the Transgenic SR was rated Outstanding Merit. Throughout the current funding cycle (2012-2016) the Transgenic SR provided services to 133 registered users 41 (31%) of whom are Case CCCmembers representing 5 of the Centers 7 Programs.The Transgenic SR has had great success in gene targeting using CRISPR/Cas9. Since 2014 the SR hassuccessfully completed over 30 new gene-targeted mutations in mice using this approach the vast majority ofwhich have been disease-causing missense mutations. The Transgenic SR is in the vanguard of transgeniccores in applying CRISPR/Cas9 technology. In the last funding period the Transgenic SR assisted Case CCCmembers in: generating mice that model human mutations leading to cancer; identifying cancer susceptibilityloci; generating mice for in vivo imaging of tumors; and investigating the basic biology of genes implicated incancer. This SR is the only transgenic core in the Cleveland area and it serves investigators throughout theregion. As a consequence it is strongly supported by CWRU. All Case CCC members have access to this jointlymanaged SR. +No NIH Category available Accounting;Animal Experimentation;Area;Basic Science;Bioinformatics;Biology;Breast;CRISPR/Cas technology;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinic;Clinical;Clinical Data;Clinical Investigator;Clinical Trials;Collaborations;Collection;Comprehensive Cancer Center;Computer software;Consult;Consultations;Cryopreservation;Data;Databases;Derivation procedure;Development;Disease;Dissection;Doctor of Philosophy;Ensure;Evolution;Fertilization in Vitro;Funding;Gene Targeting;Genes;Genetic Models;Genitourinary system;Goals;Heterogeneity;Histology;Human;Human Resources;Immunohistochemistry;Immunologic Monitoring;Immunotherapy;In Situ Hybridization;Institution;Knock-in Mouse;Knock-out;Link;Lung;Malignant Neoplasms;Malignant neoplasm of central nervous system;Malignant neoplasm of gastrointestinal tract;Methods;Missense Mutation;Mission;Molecular Medicine;Mus;Mutation;NCI Center for Cancer Research;Operative Surgical Procedures;Ophthalmology;Pathology;Patients;Play;Policies;Population Research;Preparation;Procedures;Protocols documentation;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Secure;Services;Solid Neoplasm;Specimen;Standardization;Susceptibility Gene;Technology;Tissue Banks;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Training and Education;Transgenic Organisms;University Hospitals;animal tissue;animation;anticancer research;biobank;cancer genetics;cancer imaging;cancer prevention;cost effective;design;experimental study;follow-up;genetic variant;human model;human tissue;improved;in vivo imaging;melanoma;member;migration;mouse genetics;mouse model;patient population;professor;programs;sample collection;sarcoma;success;tissue resource;web site Tissue Resources Shared Resource n/a NCI 10784818 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9171 11992088 "COUCE, MARTA " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 184084 114338 69746 TRANSGENIC AND TARGETING SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe Transgenic and Targeting Shared Resource (Transgenic SR) is an essential asset to Case ComprehensiveCancer Center (Case CCC) members' research illustrated by the breadth of scientific program involvement andreflected in the large number of investigators who use this SR. Last year alone 45 investigators 40% of whomwere Case CCC members accounting for 39% of total usage from 5 out of 7 of the Centers programs used theSR. The Transgenic SR makes transgenic chimeric knockout and knock-in mice and provides services inrederivation cryopreservation reanimation in vitro fertilization and surgery. Central to the success ofinvestigators with new mouse genetic models is the role this facility plays in consultation education and trainingas well as support after service. The Specific Aims of the Transgenic SR are to: 1. Provide Case CCC members with consultation education and training. The Director of the Transgenic SR consults with Cancer Center members and their research staff to ensure they utilize the best technology to meet their experimental goals. The rapid evolution of CRISPR/Cas9 technologies makes consultation particularly important. 2. Provide Case CCC members with new mouse genetic models. The Transgenic SR generates the genetic variants of mice in a timely and cost-effective manner. 3. Provide Case CCC members with follow-up support through direct interaction and through the wealth of information available on the facility website.At last review the Transgenic SR was rated Outstanding Merit. Throughout the current funding cycle (2012-2016) the Transgenic SR provided services to 133 registered users 41 (31%) of whom are Case CCCmembers representing 5 of the Centers 7 Programs.The Transgenic SR has had great success in gene targeting using CRISPR/Cas9. Since 2014 the SR hassuccessfully completed over 30 new gene-targeted mutations in mice using this approach the vast majority ofwhich have been disease-causing missense mutations. The Transgenic SR is in the vanguard of transgeniccores in applying CRISPR/Cas9 technology. In the last funding period the Transgenic SR assisted Case CCCmembers in: generating mice that model human mutations leading to cancer; identifying cancer susceptibilityloci; generating mice for in vivo imaging of tumors; and investigating the basic biology of genes implicated incancer. This SR is the only transgenic core in the Cleveland area and it serves investigators throughout theregion. As a consequence it is strongly supported by CWRU. All Case CCC members have access to this jointlymanaged SR. +No NIH Category available Accounting;Address;Applications Grants;Automation;Biological Assay;Biotechnology;Cancer Center Support Grant;Clinic;Collaborations;Comprehensive Cancer Center;Consultations;Data;Doctor of Philosophy;Drug Utilization;Equipment;Extramural Activities;Future;Genetic;In Vitro;Infrastructure;Lead;Libraries;Link;Malignant Neoplasms;Manuscripts;Medicine;Mission;Pathway interactions;Pharmaceutical Chemistry;Pharmacology;Proteomics;Recommendation;Research;Research Personnel;Resource Sharing;Scientist;Therapeutic;Training;Universities;University Hospitals;Work;assay development;cheminformatics;cost;design;drug development;genome sciences;high throughput screening;in vivo;in vivo evaluation;innovation;instrument;interest;member;operation;professor;programs;screening;screening services;small molecule;small molecule libraries Small Molecule Drug Development Shared Resource n/a NCI 10784817 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9170 10411050 "ADAMS, DREW JAMES" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 85195 52916 32279 SMALL MOLECULE DRUG DEVELOPMENT SHARED RESOURCESPROJECT SUMMARY/ABSTRACTThe Small Molecule Drug Development Shared Resource (Drug Development SR) was established inSeptember 2015 to address the lack of critical infrastructure enabling small molecule screening and theidentification of small-molecule probes. The mission of the Drug Development SR is to enable investigators tooptimize robust assays in 384-well format and to screen these assays across large chemical libraries to identifynew small molecules that may be the starting point for innovative cancer therapeutics. In the first year a widerange of investigators from Case Western Reserve University (CWRU) University Hospitals (UH) ClevelandClinic (CC) a collaborator from Duke University and a Cleveland biotech startup utilized the DrugDevelopment SR testifying to the large demand for small-molecule screening.Since its establishment the Drug Development SR has worked with 17 investigators approximately 65% ofwhom are Case CCC members accounting for 79% of total usage and representing 4 of the 7 Case CCCPrograms. The Specific Aims of the Small Molecule Drug Development Shared Resource are to:1. Provide assay development and high-throughput screening services using both high-throughput and high- content approaches to screen libraries of known bioactive compounds (bioactives) and diverse screeninglibraries.2. Share expertise to design and optimize robust high-throughput assays tailored to specific projects by consultation between the PI the Director and the Managing Director to inform project design execution and troubleshooting.3. Train new users including PIs research scientists and trainees in proper and safe operation of the SR's automation equipment at reasonable cost and welcome/include their participation during assay development and execution.4. Offer advice and guidance to advance hits to leads using cheminformatics and medicinal chemistry by providing recommended strategies for prioritizing hits and linking investigators with medicinal chemists.5. Guide users toward SRs and potential collaborating investigators in Case CCC Programs with complementary capabilities relevant to drug development as projects evolve including connections to researchers with expertise in proteomics in vitro and in vivo pharmacology and in vivo testing.Moving forward the Drug Development SR aims to complete 3 or more full high-throughput screens per yearand 6 or more pilot screens to maintain a pipeline of robust assays for future large-scale screens. Additionallythe facility will expand its equipment set to provide redundancy in several key instruments and will expand itsscreening libraries to 100000 small molecules to match typical screen sizes performed in other academicscreening centers. +No NIH Category available Accounting;Applications Grants;Award;Bioinformatics;Biological;Budgets;Cancer Center Support Grant;Case Management;Cells;Clinic;Clinical;Communication;Complement;Comprehensive Cancer Center;Consultations;Data Analyses;Data Set;Dedications;Developmental Therapeutics Program;Doctor of Philosophy;Drug Kinetics;Equipment;Experimental Designs;Funding;Grant;Human Resources;Institution;Journals;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Manuscripts;Medical;Mission;Molecular Medicine;NCI Center for Cancer Research;Nature;Paper;Pathway interactions;Professional Education;Proteomics;Proteomics Shared Resource;Publishing;Research;Research Institute;Research Personnel;Resource Sharing;Resources;Science;Services;Site;System;Systems Biology;Techniques;Technology;Training;Universities;anticancer research;bioinformatics resource;bioinformatics tool;cancer genetics;cancer pharmacology;clinical investigation;computing resources;data integration;experimental study;imaging system;instrument;investigator training;lipidomics;medical schools;member;metabolomics;molecular oncology;new technology;nutrition;phosphoproteomics;professor;programs;small molecule;structural biology;tool Proteomics Shared Resource n/a NCI 10784815 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9168 2424126 "CHANCE, MARK R" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 126409 78515 47894 PROTEOMICS SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe Proteomics Shared Resource (Proteomics SR) is an essential asset to Case Comprehensive Cancer Center(Case CCC) members' research illustrated by the breadth of scientific program involvement and reflected in thelarge number of investigators who use this SR. Last year alone over 120 investigators 35% of whom were CaseCCC members accounting for 44% of total usage from all 7 of the Case CCC Programs used the SR. Themission of the Proteomics SR is to provide advanced proteomic and metabolomic technologies and small-molecule analysis especially for pharmacokinetic (PK) studies via state-of-the-art instruments computationalresources and trained staff to support clinical translational and structural biology research. The Specific Aimsof the Proteomics SR are to: 1) Provide advanced proteomic and metabolomics technologies and instrument resources to solve unmet needs in cancer research. 2) Develop and apply systems biology tools to solve challenges in analysis and integration of large omicsdatasets. 3) Provide professional education consultation and training to Case CCC members.At last review the Proteomics SR was rated Exceptional merit. Throughout the current funding cycle (2012-2016) the Proteomics SR provided services to 268 registered users 83 (31%) of whom are Case CCCmembers representing all 7 of the Case CCC programs.The Proteomics SR continues to attract new users and to provide multiple sophisticated proteomic techniquesand technique-specific training to investigators' cancer-related projects. The SR has also developed newtechnologies and bioinformatics tools that directly facilitate Case CCC members' research including a globalmetabolomic and lipidomic platform that will complement both targeted metabolomics and global proteomicexperiments. The Proteomics SR consists of two sites; the first site was established at the Cleveland Clinic (CC)Lerner Research Institute (LRI) in 1999 and the second site the Center for Proteomics & Bioinformatics (CPB)at Case Western Reserve University (CWRU) in 2005. This multi-site Shared Resource jointly supported andmanaged by the Case CCC the CWRU School of Medicine (SOM) and CC provides access to a full spectrumof proteomic and metabolomic technologies. The services of the Proteomics SR are essential for enhancing thequality of the science in the Case Comprehensive Cancer Center. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;Area;Biological Models;Cancer Burden;Cancer Center Support Grant;Cancer Control;Catchment Area;Cohort Studies;Collaborations;Communities;Complex;Comprehensive Cancer Center;Data;Data Collection;Database Management Systems;Databases;Development;Doctor of Philosophy;Economics;Evaluation;Funding;Healthcare Systems;Individual;Infrastructure;Intervention;Intervention Studies;Investments;Link;Malignant Neoplasms;Measures;Methodology;Methods;NCI Center for Cancer Research;Neighborhoods;Observational Study;Ohio;Outcome;Outcome Measure;Outcomes Research;Participant;Patient Outcomes Assessments;Persons;Phase;Population Research;Public Health;Qualitative Methods;Research;Research Design;Research Personnel;Research Support;Resource Sharing;Risk Factors;Services;Siccoral;Site;Transcend;anticancer research;behavior measurement;cancer health disparity;cancer prevention;cancer risk;community based participatory research;community organizations;community partnership;comorbidity;data infrastructure;health care service organization;implementation intervention;improved;information framework;member;models and simulation;neoplasm registry;novel;population based;population health;practice-based research network;programs;social;social health determinants;therapy design;therapy development Multimethod Cancer Outcomes Research Shared Resource n/a NCI 10784814 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9167 8118864 "KOROUKIAN, SIRAN M." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 182980 113652 69328 MULTIMETHOD CANCER OUTCOMES RESEARCH SHARED RESOURCE PROJECT SUMMARY/ABSTRACT The Multimethod Cancer Outcomes Research Shared Resource (Cancer Outcomes SR) is an essential asset to Case Comprehensive Cancer Center (Case CCC) members' research illustrated by the breadth of scientific program involvement and reflected in the number of investigators who use this SR. Last year alone 25 investigators 88% of whom were Case CCC members from 5 out of the 7 Case CCC programs used the SR. The Cancer Outcomes SR helps researchers address complex multifactorial challenges in cancer prevention or control that require a connected multimethod approach. The Cancer Outcomes SR connects people organizations and data to advance cancer research across the spectrum: discovery to intervention development implementation dissemination and outcome evaluation. The Cancer Outcomes SR invests in developing deep partnerships with community organizations large database infrastructure and methodological expertise that integrates quantitative and qualitative methods to support complex systems modeling and multilevel interventions to improve cancer outcomes. The Specific Aims of the Cancer Outcomes SR are to: 1. Cultivate rich community partnerships data infrastructures and methodological expertise to enable the conduct of relevant cancer-focused research. 2. Ground cancer research in understanding of cancer risk factors co-morbidities social determinants of health behavioral measurement and intervention opportunities. 3. Connect diverse methods and partners to support observational and intervention research on complex cancer control problems. At last review the Cancer Outcomes SR was rated Outstanding to Excellent merit. Throughout the current funding cycle (2012-2016) the Cancer Outcomes SR provided services to 104 registered users 29 (28%) of whom are Case CCC members representing 5 out of the 7 Case CCC programs. The aims of the Cancer Outcomes SR are accomplished by: Developing collaborations with diverse community research partners that transcend individual projects; Providing expertise in behavioral & outcome measurement; Integrating quantitative and qualitative methods; Supporting multilevel intervention design; Linking and analyzing public health and health care system databases; and Supporting simulation modeling. The Cancer Outcomes SR is actively expanding its population health data infrastructure to support novel research and to accelerate the integration of neighborhood- and community-based contextual data for investigators with cohort studies conducting catchment area relevant research. +No NIH Category available Accounting;Adult;Animal Cancer Model;Animal Housing;Applications Grants;Basic Science;Bioluminescence;Biomedical Engineering;Cancer Center Support Grant;Cancer Patient;Cancer Research Project;Caring;Cells;Childhood;Clinic;Clinical;Clinical Research;Communication;Comprehensive Cancer Center;Cyclotrons;Dedications;Doctor of Philosophy;Fingerprint;Fluorescence;Funding;Goals;Human;Image;Image Analysis;Individual;Infrastructure;Institution;Journals;Magnetic Resonance Imaging;Malignant Neoplasms;Medical center;Methodology;Mission;NCI Center for Cancer Research;Nanotechnology;Nature;Pathway interactions;Patients;Pediatrics;Positron-Emission Tomography;Publications;Radiochemistry;Radiology Specialty;Research;Research Institute;Research Personnel;Resource Sharing;Resources;Screening for cancer;Services;Site;Technology;Training;United States National Institutes of Health;Universities;University Hospitals;anticancer research;cancer imaging;cancer initiation;clinical imaging;cost effective;design;experimental study;flasks;imaging capabilities;imaging facilities;imaging system;improved;in situ imaging;in vivo;instrumentation;member;mid-career faculty;novel;novel therapeutic intervention;operation;pre-clinical;pre-clinical research;preclinical imaging;programs;quantitative imaging;radiotracer;tumor progression Imaging Research Shared Resource n/a NCI 10784813 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9166 8569494 "FLASK, CHRISTOPHER A" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 115451 71709 43742 IMAGING RESEARCH SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe Imaging Research Shared Resource (Imaging SR) is an essential asset to Case Comprehensive CancerCenter (Case CCC) members' research illustrated by the breadth of scientific program involvement andreflected in the number of investigators who use this SR. Last year alone over 45 investigators 54% of whomwere Case CCC members accounting for 71% of total usage from 6 out of the Centers 7 Programs used theSR. The mission of the Imaging SR is to provide all cancer investigators with a comprehensive array ofpreclinical and clinical imaging capabilities to deliver in vivo and in situ imaging assessments of cancer. TheImaging SR is an institutional facility integrating state-of-the-art and comprehensive imaging capabilities bothfor animal models of cancer as well as pediatric and adult patients. Enabling these efforts is the Imaging SRsestablished operational and administrative infrastructure including a fully equipped preclinical imaging facilitywith onsite animal housing; a research-dedicated human MRI scanner; as well as research radiochemistryfacilities including a cyclotron and multiple hot cells. The Specific Aims of the Imaging SR are to: 1. Provide preclinical and clinical research imaging services to cancer investigators. 2. Provide imaging expertise to design effective cancer imaging experiments. 3. Provide project-specific quantitative image analysis capabilities. 4. Synthesize both conventional and novel radiotracers for PET cancer studies. 5. Train new users in the proper and safe operation of the imaging systems.At last review the Imaging SR was rated Excellent to Outstanding Merit. Throughout the current funding cycle(2012-2016) the Imaging SR provided services to 83 registered users 48 (58%) of whom are Case CCCmembers representing all 7 of the Case CCC programs.The Imaging SR also has access to the full breadth of imaging resources provided by the Departmentof Radiology at Case Western Reserve University (CWRU) / University Hospitals (UH) ClevelandMedical Center including multiple clinical imaging scanners. Additional preclinical imaging capabilitiesare housed at the Lerner Research Institute (LRI) at Cleveland Clinic (CC) including a new preclinicalMRI scanner and multiple in vivo bioluminescence and fluorescence scanners. Overall the Imaging SRpresents an efficient and cost-effective opportunity for cancer investigators to comprehensively evaluate novelpathways in cancer initiation and progression as well as new therapeutic strategies and methodologies forearly cancer detection with the ultimate goal of improved care and longer lives of cancer patients. +No NIH Category available Accounting;Adopted;Attention;Basic Science;Bioinformatics;Biological Assay;CLIA certified;Cancer Center Support Grant;Cancer Research Project;Case Management;Cells;ChIP-seq;Clinic;Clinical Research;Clustered Regularly Interspaced Short Palindromic Repeats;Comprehensive Cancer Center;Computational Biology;Computer software;Consultations;Custom;DNA;DNA analysis;Data;Data Analyses;Development;Dideoxy Chain Termination DNA Sequencing;Doctor of Philosophy;Ensure;Evaluation;Experimental Designs;Funding;Gene Expression;Gene Expression Profiling;Generations;Genetic;Genetic Transcription;Genomics;Genomics Shared Resource;Genotype;Individual;Informatics;Institution;Malignant Neoplasms;Methylation;Microarray Analysis;Mission;Names;Nucleic Acids;Oncology;Phase;Preparation;Published Comment;Quality Control;RNA;RNA analysis;Research;Research Institute;Research Personnel;Research Project Grants;Resources;Sampling;Services;Site;Technology;Time;Training;Translational Research;Universities;Validation;cost effectiveness;data analysis pipeline;data integration;exome;experience;genome sciences;medical schools;member;microbiome analysis;mid-career faculty;next generation sequencing;programs;resource guides;success;transcriptome sequencing;whole genome Integrated Genomics Shared Resource n/a NCI 10784811 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9164 10573198 "CAMERON, MARK JAMES" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 211127 131135 79992 INTEGRATED GENOMICS SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe Integrated Genomics Shared Resource (Genomics SR) is an essential asset to Case ComprehensiveCancer Center (Case CCC) members' research illustrated by the breadth of scientific program involvement andreflected in the large number of investigators who use this SR. Last year alone over 230 investigators 36% ofwhom were Case CCC members accounting for 65% of total usage from all 7 of the Case CCC Programs usedthe SR. The mission of the Genomics SR is to enable robust use of high-throughput genomics technologies anddata analysis for cancer research projects. This multi-site SR is jointly supported and managed by the CaseCCC the Case Western Reserve University (CWRU) School of Medicine (SOM) and Cleveland Clinic (CC)Lerner Research Institute (LRI). It provides access to a full spectrum of genomics technologies including multi-site Next Generation Sequencing (NGS) for DNA and RNA analyses. The Specific Aims of the Genomics SR areto:1. Provide project-level genomics consultation services to assist investigators in experimental design technology selection assembling of key resources to execute projects collect samples assure overall project quality control and identify best analytical approaches.2. Provide access to a full range of genomic technologies including: a) Sample preparation & sample quality assessment services: Nucleic Acid Isolation from difficult samples; Evaluation of nucleic acid quality for downstream analysis. b) Comprehensive genomics analyses: RNA-based services: RNA-seq custom Illumina RNA panels RNA expression analysis using Affymetrix microarray technology real-time PCR; DNA-based services: Next- Generation Sequencing (whole genome and -exome custom amplicon sequencing microbiome analysis CRISPR validation ChIP-Seq analysis); methylation analysis Sanger sequencing and genotyping (TaqMan Assays Microarrays).3. Provide a range of genomics analysis support including access to and training on genomics analysis software; and execution of high-end analysis including development of genomics pipelines for specific projects and for investigators with limited analysis experience.Throughout the current funding cycle (2012-2016) the Genomics SR provided services to 479 registered users134 (28%) of whom are Case CCC members representing all 7 of the Case CCC programs.Finally the Genomics SR feels that rapid access to a focused well-executed data analysis pipeline is critical tothe success of investigators genomic studies. To this end the Genomics SR developed an AnalyticsComponent which ensures that each project has robust experiment design and data analysis plans beforeinitiation. +No NIH Category available Accounting;Acoustics;Address;Applications Grants;Appointment;Area;Automation;Biological Assay;Cancer Center Support Grant;Case Management;Cell Cycle;Cell Death;Cell Separation;Cells;Clinic;Clinical;Clinical Investigator;Clinical Trials;Communication;Comprehensive Cancer Center;Consult;Consultations;Cost Savings;Cytometry;Development;Distant;Environmental Health;Equipment;Financial Support;Funding;Future;Glioma;Goals;Grant;Guidelines;Hypoxia;Immunologic Monitoring;Immunophenotyping;Lasers;Malignant Neoplasms;Manufacturer;Measurement;Microscope;Microscopy;Mission;Nature;Paper;Pathway Analysis;Pathway interactions;Pharmaceutical Preparations;Play;Ploidies;Proteins;Publishing;Radiation;Research;Research Assistant;Research Institute;Research Personnel;Research Support;Resource Sharing;Role;Safety;Science;Services;Shapes;Site;Specific qualifier value;Supporting Cell;Training;United States National Institutes of Health;Universities;University Hospitals;Validation;aged;anticancer research;assay development;cancer therapy;cellular imaging;data sharing networks;design;drug discovery;imaging facilities;instrument;medical schools;meetings;member;programs;response;success Cytometry and Microscopy Shared Resource n/a NCI 10784810 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9163 8192870 "GRIMBERG, BRIAN T." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 230538 143191 87347 The Cytometry and Microscopy Shared Resource (Cytometry SR) is an essential asset to Case Comprehensive Cancer Center (Case CCC) members' research illustrated by the breadth of scientific program involvement and reflected in the large number of investigators who use this Shared Resource (SR). Last year alone over 300 investigators 37% of whom were Case CCC members accounting for 40% of total usage from all 7 of the Case CCC Programs used the SR. The mission of the Cytometry SR is to support cell-based assays in basic translational and clinical cancer research and clinical trials. This multi-site SR jointly supported and managed by the Case Comprehensive Cancer Center (Case CCC) Case Western Reserve University (CWRU) School of Medicine (SOM) University Hospitals (UH) and Cleveland Clinic (CC) Lerner Research Institute (LRI) provides formal access to expensive instruments and professional expertise and assistance in the areas of cytometry microscopy and cell sorting. The Specific Aims of the Cytometry SR are to: 1. Provide well-maintained flow cytometers cell sorters microscopes and associated equipment. 2. Provide training and consultation by cytometry and microscopy professional staff. 3. Provide full or partial cell-based assay development to support clinical investigators. At last review the Cytometry SR was rated Excellent to Very Good Merit. Throughout the current funding cycle (2012-2016) the Cytometry SR provided services to 484 registered users 132 (27%) of whom are Case CCC members representing all 7 of the Case CCC programs. The Cytometry SR provides current well-maintained instruments that perform within the manufacturers specifications and are compliant with the safety guidelines from Environmental Health and Safety (EHS) Departments (CWRU CC) and NIH. The SR Director Co-Directors Manager and Assistants (collectively Staff) provide professional consultation research management and training at any level to support research programs and grant applications. SR commitment to assay development ranges from consults to full responsibility. Through the Cytometry SR Case CCC members have access to world class comprehensive microscopy services; the Cytometry SR has successfully implemented a Full Service facility that is designed to support clinical trials by providing correlative assays (ie design development optimization and/or validation as required by the user). The Cytometry SR provides high quality and essential cell imaging services to multiple investigators across the Case CCC. Use of distant SRs would be inefficient and uncertain and principle investigators could not complete the aims of NIH grants without access to cytometry and microscopy. +No NIH Category available Adopted;Bioinformatics;Bioinformatics Shared Resource;Biometry;Cancer Center Support Grant;Clinic;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Computational Biology;Computer software;Data;Data Analyses;Data Science;Data Set;Database Management Systems;Databases;Development;Doctor of Philosophy;Education;Ensure;Environment;Epidemiology;Experimental Designs;Formulation;Funding;Future;Grant;Hour;Human Resources;Informatics;Institution;Malignant Neoplasms;Manuscripts;Medicine;Mission;Modeling;Monitor;Peer Review;Pilot Projects;Process;Productivity;Protocols documentation;Quality Control;Reporting;Research;Research Personnel;Research Project Grants;Resources;Safety;Sample Size;Science;Secure;Services;Statistical Computing;Statistical Data Interpretation;Translational Research;United States National Institutes of Health;Universities;Work;Writing;bioinformatics tool;data quality;data warehouse;design;meetings;member;mid-career faculty;novel;operation;professor;programs;protocol development;research study;response;success Biostatistics and Bioinformatics Shared Resource n/a NCI 10784809 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9162 8965146 "CULLEN, JENNIFER " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 352986 219246 133740 BIOSTATISTICS AND BIOINFORMATICS SHARED RESOURCE PROJECT SUMMARY/ABSTRACT The Biostatistics and Bioinformatics Shared Resource (Biostats SR) is an essential asset to Case Comprehensive Cancer Center (Case CCC) members' research illustrated by the breadth of scientific program involvement and reflected in the large number of investigators who use this SR. Last year alone over 140 investigators 53% of whom were Case CCC members from all 7 of the Center's Programs used the SR on over 300 projects for a combined 6500 hours. The primary focus of the Biostats SR is to provide statistical support for proposal/clinical protocol development pilot studies or other NIH-funded peer-reviewed studies. In addition using a standard chargeback model and collaborative grant effort model this SR provides data analysis services including big and dense omic datasets. The Biostats SR also leverages institutional resources from the Institute for Computational Biology (ICB) to provide and strengthen informatics support. The Biostats SR brings together expertise and intellectual resources in biostatistics bioinformatics informatics clinical trials epidemiology and statistical computing. The Biostats SR provides data analysis services using standard chargeback and collaborative grant effort models. Biostats SR biostatisticians serve on the Protocol Review and Monitoring Committee (PRMC) assisting with review of new studies and monitoring of ongoing studies. Specific aims of the Biostatistics & Bioinformatics Shared Resource are to: 1) Provide biostatistical bioinformatics and research informatics support to Case CCC members for design planning conduct analysis and reporting of research studies. 2) Ensure that Case CCC studies are designed conducted and monitored properly by reviewing protocols and proposals and contribute to quality control and data and safety monitoring of ongoing clinical studies. 3) Provide and coordinate informatics support by using the OnCore clinical trials management database and other secure research databases and serve as a concierge for translational informatics in the Case CCC. At last review the Biostats SR was rated Outstanding Merit. Throughout the current funding cycle (2012-2016) the Biostats SR provided services to 298 registered users 134 (45%) of whom are Case CCC members representing all 7 of the Case CCC programs. The value-added services (formulation of research questions and experimental design power and sample size calculations data quality assessment and control statistical analysis results interpretation as well as proposal/manuscript writing and support) provided by the Biostats SR is demonstrated by the successful contribution of Biostats SR personnel to the Centers research productivity. Initial collaborations supported by the Center often lead to successful new funding via collaborative research grants on which Biostats SR personnel serve as co-investigators. Biostats SR services are essential in enhancing the quality of science in the Center. +No NIH Category available Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Science;Career Mobility;Clinical;Clinical Oncology;Clinical Research;Clinical Sciences;Collaborations;Communication;Comprehensive Cancer Center;Education;Enrollment;Exposure to;Faculty;Genomics;Grant;Health Professional;Healthcare;High School Student;Individual;Institution;Institutional Review Boards;Laboratories;Malignant Neoplasms;Manuscripts;Medical Students;Mentors;Minority Groups;Monitor;NCI Center for Cancer Research;Peer Review;Physicians;Productivity;Research;Research Personnel;Research Training;Scientist;Series;Training;Training Activity;Training Programs;Training and Education;Travel;Underrepresented Minority;anticancer research;biomedical scientist;cancer education;career;career development;clinical training;clinical trial protocol;design;education research;experience;faculty mentor;graduate student;high school;human subject protection;improved;member;multidisciplinary;programs;skill acquisition;summer research;tumor;undergraduate student Cancer Research Career Enhancement and Related Activities n/a NCI 10784806 4/20/23 0:00 PAR-17-095 4P30CA043703-33 4 P30 CA 43703 33 8/1/97 0:00 3/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9160 9492815 "JACKSON, MARK W." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2023 98479 61167 37312 CANCER RESEARCH CAREER ENHANCEMENT AND RELATED ACTIVITIESPROJECT SUMMARY/ABSTRACTThe Cancer Research Career Enhancement and Related Activities are centered in the Case ComprehensiveCancer Center (Case CCC) Office of Cancer Trainee Education and Research (OCTER) which coordinatesexisting research education and training activities across the consortiums institutions and develops neweducational initiatives with emphasis on integrating cancer researchers and health care professionals. CaseCCC supported programs have facilitated career enrichment activities for 1622 cancer trainees during the lastcycle spanning career stages from high school students through junior faculty. The impact of these efforts areevidenced by: 1) the portfolio of peer-reviewed training grants in cancer research and clinical training; 2) thehigh-impact basic and clinical science performed by Center trainees; 3) robust trainee involvement in Center-sponsored career enrichment activities; 4) successful career advancement for all Case CCC trainees; 5)coordination of Center-wide research education and training activities by the Cancer Education and ResearchCommittee (CERC); and 6) Center efforts to engage underrepresented minority (URM) groups at all levelsincluding high school and undergraduate students to enter cancer-oriented biomedical scientific research andhealthcare professions.To maintain excellence and expand Center cancer research career enrichment activities the OCTER hasdeveloped the following three specific aims that will carry it forward in the next grant cycle:Aim 1: Provide cancer research career enrichment activities across the continuum of trainees.Aim 2: Coordinate Center-wide cancer education and training activities.Aim 3: Integrate cancer research mentoring and training of biomedical scientists and healthcare professionals.The Case CCC strives to provide rigorous training in cancer research as well as career enhancement activitiesthat prepare all trainees for productive careers as biomedical cancer researchers or healthcare professionals. +No NIH Category available Acute Myelocytic Leukemia;Address;Alleles;Apoptosis;Apoptotic;Area;BCL-2 Protein;BCL2 gene;Biological;Biological Assay;Biological Models;Biology;Blastic plasmacytoid dendritic cell neoplasm;Blood;Bone Marrow;Cancer Biology;Cells;Chemoresistance;Clinical;Clinical Research;Clinical Trials;Complex;Confusion;Cutaneous Involvement;DNA;DNA sequencing;Data;Dendritic Cells;Dependence;Diagnosis;Diphtheria Toxin;Disease;Female;Frequencies;Functional disorder;GNB1 gene;Genes;Genetic;Genetic Engineering;Genetic Models;Genetic Transcription;Genetic study;Goals;Hematologic Neoplasms;Hematopoiesis;Heterotrimeric G Protein Subunit;Human;IL3RA gene;Incidence;Interleukins;Knowledge;Laboratories;Leukemic Cell;Leukemic Natural Killer Cell;Lymphoma;Malignant - descriptor;Malignant Neoplasms;Measures;Medical;Medicine;Mission;Modeling;Mus;Mutate;Mutation;NCAM1 gene;Names;Nature;Neoplasms;Oncogenes;Ontology;Orphan;Outcome;Output;Pathogenesis;Patients;Phenotype;Public Health;RNA Splicing;Recurrence;Refractory;Relapse;Research;Resistance;Role;Sampling;Sex Bias;Signal Transduction;Site;Somatic Mutation;Spliceosomes;System;Targeted Resequencing;Testing;Therapeutic;Therapeutic Studies;Transplantation;Tumor Suppressor Proteins;United States National Institutes of Health;Validation;Woman;X Chromosome;X Inactivation;cancer type;cell transformation;chemotherapy;clinically relevant;clinically significant;cohort;effective therapy;exome;exome sequencing;improved;improved outcome;in vivo;in vivo Model;inhibitor;innovation;insight;loss of function mutation;lymph nodes;mRNA Precursor;male;men;mimetics;mutant;novel;novel therapeutic intervention;optimal treatments;patient derived xenograft model;premature;protective pathway;sex;standard care;stem cells;targeted sequencing;therapeutic target;transcriptome;treatment response;treatment strategy;tumor Targeting blastic plasmacytoid dendritic cell neoplasm (BPDCN) Project NarrativeThe proposed research is relevant to public health because BPDCN is a highly fatal yet understudiedmalignancy in which there is no standard therapy and the mechanisms of dendritic cell transformation are notknown. This project is relevant to the NIH's mission to gain fundamental knowledge to reduce illness because itwill elucidate treatment strategies in BPDCN based on understanding of the genetic basis of the disease. NCI 10784797 6/2/23 0:00 PA-16-160 4R37CA225191-06 4 R37 CA 225191 6 "SALNIKOW, KONSTANTIN" 2/1/18 0:00 1/31/25 0:00 Molecular and Cellular Hematology Study Section[MCH] 10504721 "LANE, ANDREW A" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 392412 NCI 224176 168236 Project SummaryBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan hematologic malignancy that is clinicallyaggressive and fatal in most patients within one year of diagnosis. The disease pathogenesis is largelyunknown there is no standard treatment and patients with BPDCN have a clear unmet medical need. Thelong-term goal is to improve outcomes in BPDCN by deeper understanding of disease biology. DNAsequencing in BPDCN revealed a high frequency of mutations in RNA splicing factors with particularenrichment in loss-of-function mutations in ZRSR2 compared to other cancers. Functional assessment ofpatient tumors found that BPDCN is uniquely dependent on the anti-apoptotic protein BCL2 and is highlysensitive to treatment with the BH3 mimetic venetoclax. New genetically engineered models of dendritic cellleukemia and BPDCN patient-derived xenografts offer a unique opportunity to test the contribution of diseasealleles to splicing abnormalities and therapeutic response. The overall objective of this application is to test thehypothesis that genetic alterations associated with BPDCN contribute to dendritic cell transformation andcreate targetable vulnerabilities. Guided by strong preliminary data from the applicant's laboratory and anestablished network of expert collaborators this central hypothesis will be tested by pursuing two specific aims:1) Determine how ZRSR2 mutation promotes dendritic cell transformation; and 2) Identify factors that generateunique apoptotic dependencies in BPDCN. Under the first Aim the applicant will use genetic models of ZRSR2deficiency in dendritic cells and BPDCNs to determine how splicing mutations alter the transcriptome andcause transformation of the dendritic lineage. They will also test how mutations in ZRSR2 a gene located onthe X chromosome that escapes X-inactivation in female cells contributes to the male bias of BPDCN andsensitizes to splicing modulator therapy. Under the second Aim the mechanisms of BCL2 dependence innormal and malignant dendritic cells will be investigated in human and mouse hematopoiesis. Adaptations tochemotherapy in BPDCN will be measured to determine if BCL2 inhibition can overcome chemoresistancewhich is the major barrier to improved outcomes in patients. The approach is innovative by making use ofnovel model systems and samples from BPDCN patients on active clinical trials. The downstream effects ofZRSR2 mutations on BPDCN and male cancer predominance have not been clarified and the mechanisms ofprotection from apoptosis in normal and malignant dendritic cells are unknown. The proposed research issignificant because it is expected to define the biological role of clinically-relevant mutations in anunderstudied and highly fatal disease. The expected output for the proposed research is that the knowledgegained will be immediately clinically significant for patients with BPDCN because it will inform new treatmentstrategies in a cancer that is currently lacking in significant biological and therapeutic insight. 392412 +No NIH Category available Achievement;Address;Arizona;Classification;Development;Education;Educational Curriculum;Eligibility Determination;Employment Opportunities;Enrollment;Ensure;Fostering;Funding;Geography;Goals;Health;Health Disparities Research;Hispanic;Institution;Link;Malignant Neoplasms;Mentors;Mentorship;Minority Groups;Minority-Serving Institution;National Cancer Institute;New Mexico;Occupations;Osteopathic Medicine;Persons;Population;Population Heterogeneity;Postdoctoral Fellow;Poverty;Productivity;Professional Competence;Research;Research Activity;Research Personnel;Resources;Role;Science;Scientist;Site;Southwestern United States;Students;System;Talents;Technical Expertise;Training;Training and Education;Underrepresented Minority;Underserved Population;United States;Universities;anticancer research;cancer health disparity;career;college;community engagement;demographics;doctoral student;education research;ethnic minority population;experience;falls;health disparity;higher education;improved;minority communities;multimodality;next generation;peer coaching;post-doctoral training;pre-doctoral;programs;racial minority population;role model;skills;skills training;symposium;tool;training opportunity;web platform;web site;webinar Southwest Transformative Educational Advancement and Mentoring (STEAM) Network NARRATIVEThe Southwest Transformative Educational Advancement and Mentoring network brings together four MinorityServing Institutions across the US Southwest: University of New Mexico New Mexico State University NorthernArizona University and Burrell College of Osteopathic Medicine to train the next generation of scientists in cancerand cancer health disparities. This network aims to foster the development of underrepresented and diversescientists and investigators and strengthen the career pipeline for pre- and post-doctoral trainees and EarlyStage Investigators. This proposed network will enhance the capacity of the scientific workforce to addresscancer and cancer health disparities experienced by diverse populations in the Southwest United States. NCI 10784521 9/18/23 0:00 RFA-CA-23-013 1R25CA285817-01 1 R25 CA 285817 1 "BARFIELD-STEWARD, WHITNEY" 9/18/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9803600 "GUEST, DOLORES " "MISHRA, SHIRAZ I.; WANDINGER-NESS, ANGELA " 1 INTERNAL MEDICINE/MEDICINE 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM SCHOOLS OF MEDICINE 871310001 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 412791 NCI 385822 26969 PROJECT SUMMARYThe Southwest Transformative Educational Advancement and Mentoring (STEAM) network leveragespartnerships at the University of New Mexico (UNM) New Mexico State University (NMSU) Northern ArizonaUniversity (NAU) and Burrell College of Osteopathic Medicine (BCOM) to strengthen the career pipeline for pre-and post-doctoral trainees and Early Stage Investigators (ESIs) engaged in cancer and cancer health disparities(CHD) research. As Hispanic and Minority Serving Institutions each of these institutions is poised to make much-needed improvements in diversifying the CHD workforce in the Southwest region in the coming years. TheSTEAM network affords many reciprocal benefits to the partners based on unique resources and trainingopportunities at each of the partner institutions. Training Champions (TCs) representative of the minoritizedcommunities in the Southwest and who have training and expertise in cancer research will serve as role modelsand near-peer mentors at each institution. TCs will have central roles in helping trainees to identify paths toachieve their training and career goals. TCs will contribute to cancer research and skill building forunderrepresented minority pre- and post-doctoral students as well as provide vital navigation support to ESIspursuing careers in cancer and CHD research. TCs will: 1) provide scholars with access to a comprehensivearray of resources and technical and professional career skill building tools to promote professional developmentand attainment of educational and career goals; 2) facilitate scientific community engagement by linking traineesin a diverse multi-site and interdisciplinary network; 3) offer culturally responsive cancer and cancer healthdisparities focused curricula; 4) aid in identifying mentoring opportunities; 5) assure inter-programmaticconnectivity. Southwestern populations across New Mexico and Arizona experience high rates of poverty healthdisparities insufficient attainment of higher education and geographic diversity that limits access to scientificeducation and professional development opportunities. Formal connections of STEAM founding institutions willensure that trainees have greater access to the research education and training expertise of each institution tomeet the following objectives: 1) disseminate National Cancer Institute and Center to Reduce Cancer HealthDisparities priorities and professional development offerings across an established and growing network; 2)facilitate continued development of talent from the region's unique populations and those underrepresented incancer research through the provision of targeted cancer curricula and research skills training; 3) ensurepersistence and successful transitions beyond pre-/post-doctoral training through targeted mentoring andprogrammatic offerings for early stage investigators that prepare them to assume productive cancer research orhealth careers. 412791 +No NIH Category available 3-Dimensional;Address;Age Years;American;Biopsy;Cancer Etiology;Cancer Patient;Classification;Clinical;Clinical Trials;Cold Therapy;Detection;Development;Diagnosis;Diffusion;Diffusion Magnetic Resonance Imaging;Disease Management;Echo-Planar Imaging;Focused Ultrasound Therapy;Goals;Guidelines;High-Risk Cancer;Hip region structure;Histopathology;Image;Implant;Incidence;Individual;Information Systems;Lesion;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Metals;Methods;Monitor;Morphologic artifacts;Noise;Operative Surgical Procedures;Outcome;Patient Care;Patient Monitoring;Patients;Pelvis;Peripheral;Play;Prevalence;Prostate;Prostate-Specific Antigen;Prostatectomy;Quality of life;Recommendation;Reference Standards;Reporting;Role;Signal Transduction;Techniques;United States;Urethra;Visualization;age group;cancer risk;clinical imaging;clinical translation;clinically significant;density;experience;follow-up;healthy volunteer;high risk men;hip replacement arthroplasty;human subject;improved;in vivo;magnetic field;men;mortality;next generation;novel;patient population;prospective;prostate biopsy;prostate cancer risk;prostate lesions;radioligand;reconstruction;research clinical testing;targeted treatment;treatment planning;ultrasound ablation;urologic Novel 3D DWI for Detection and Characterization of Prostate Cancer in Men with Pelvic Metal Implants Project Narrative The incidence of prostate cancer the most common malignancy and the second leading cause of cancer-related mortality in men in the United States increases substantially over 50 years of age and in parallel theprevalence of hip replacement surgery also increases in that age group. Multiparametric magnetic resonanceimaging (mpMRI) plays an important role in the diagnosis and disease management of prostate cancerhowever mpMRI is challenging in men with hip implants due to severe image distortions and signal loss. Inthis study we will establish a robust mpMRI using our novel acquisition and reconstruction strategy that can bewidely implemented across all MR scanners for better management of prostate cancer patients with hipimplants and subsequently improve their quality of life and overall survival. NCI 10784471 12/14/23 0:00 PAR-22-216 1R21CA277138-01A1 1 R21 CA 277138 1 A1 "KIM, BOKLYE" 12/14/23 0:00 11/30/25 0:00 ZCA1-SRB-X(O1)S 11324178 "MADHURANTHAKAM, ANANTH JAYASEELAN" Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/14/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 191675 NCI 116875 74800 Project Summary Prostate cancer is the most common malignancy and the second leading cause of cancer-related mortalityin men in the United States. The American Urological Association recommends the use of multiparametricmagnetic resonance imaging (mpMRI) for diagnosis and disease management in all men at high risk forprostate cancer. mpMRI is also beneficial in men: 1) with an increasing prostate-specific antigen (PSA)following an initial negative prostate biopsy; 2) during longitudinal follow-up in active surveillance for biopsy-proven low-risk prostate cancer; and 3) for guidance of locally targeted therapies including cryotherapy highintensity focused ultrasound (HIFU) MR-guided transurethral ultrasound ablation (TULSA) and emergingradioligand targeted treatments for intermediate to high-risk cancers. These recommendations are onlyrealizable through accurate localization and characterization of individual prostate lesions on MRI which issignificantly challenging in men with pelvic metal implants. This is important since the incidence of prostatecancer increases substantially over 50 years of age and in parallel the prevalence of hip replacement surgeryalso increases in that age group (estimated to reach ~4 million by 2030 in the US). Most of the metal implantsin current clinical use are MR compatible however they distort the local magnetic field (B0) causing significantsignal loss and image distortion. This is particularly problematic with echo-planar based diffusion-weightedimaging (EP-DWI) rendering these images non-diagnostic. This is a major limitation since DWI according tothe prostate imaging reporting and data system (PI-RADS) classification is the pivotal sequence for lesiondetection and characterization in the peripheral zone where 70-75% of prostate cancers arise. To address thisunmet clinical need we propose to establish a 3D turbo spin echo (TSE) based DWI that is robust and can bewidely implemented across all MR scanners. This is built upon our recently introduced novel acquisition andreconstruction strategy utilizing variable density Cartesian acquisition with spiral profile reordering (VD-CASPR). The volumetric acquisition of 3D VD-CASPR-DWI provides higher signal to noise ratio and the TSEreadout improves the robustness to B0 inhomogeneities. This provides superior image quality and enables thevisualization of the entire prostate gland without image distortions facilitating accurate detection andcharacterization of prostate lesions in men with pelvic metal implants. We will optimize the novel 3D VD-CASPR-DWI in phantoms and in-vivo prostate imaging of healthy volunteers. We will then validate thistechnique in 20 patients without and 20 patients with pelvic metal implants evaluated for known or suspectedprostate cancer. The successful outcome of this project will be an optimized mpMRI with our novel 3D VD-CASPR-DWI that provides pertinent clinical information for better management of prostate cancer patients andsubsequently improve their quality of life and overall survival. 191675 +No NIH Category available Adaptor Signaling Protein;Affinity;Amino Acids;Antisense Oligonucleotide Therapy;Basal Cell;Basal cell carcinoma;Breeding;CRISPR/Cas technology;Carcinoma;Cell Line;Cells;Characteristics;Child;Childhood Acute Lymphocytic Leukemia;Childhood Leukemia;Chimera organism;Chromosomal translocation;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Complementary DNA;DNA;DNA cassette;Data;Dependence;Development;Diagnosis;Ectopic Expression;Ensure;Epithelial Cells;Epithelium;Event;Fostering;Gene Components;Gene Structure;Genes;Genetic;Genetically Engineered Mouse;Genomic DNA;Genomics;Human;Human Characteristics;Karyotype;Knowledge;Malignant Epithelial Cell;Malignant Neoplasms;Messenger RNA;Modeling;Molecular;Mus;Mutation;Nuts;Oncogenic;Patients;Pattern;Pre-Clinical Model;Prognosis;Proliferating;Protac;Proteins;Proteolysis;Publishing;Quality Control;RNA Splicing;Reagent;Reporter;Rest;Site;Squamous Differentiation;Squamous cell carcinoma;Study models;Testis;Therapeutic;Therapeutic Index;Time;Tissues;Transcript;cancer initiation;childhood sarcoma;design;effective therapy;fusion gene;gene replacement;gene therapy;homologous recombination;humanized mouse;in vivo;knock-down;mouse model;nanobodies;novel;novel therapeutics;preclinical development;preclinical study;protein aminoacid sequence;side effect;small molecular inhibitor;stem cells;targeted treatment;therapeutic target;therapy development;transcriptome;tumor;tumor growth Developing humanized Nut Carcinoma mouse model for developing NUTM1 targeted therapies. Project Narrative:Nut Carcinoma (NC) is an aggressive cancer with no effective treatment. We have built the first geneticallyengineered mouse model of NC and will genetically humanize the model to allow preclinical studies of humanNUTM1-targeted therapies. The humanized model can potentially transform the landscape of NC therapydevelopment and benefit NC patients. NCI 10784174 12/29/23 0:00 PAR-23-058 1R03CA286646-01 1 R03 CA 286646 1 "SHARMAN, ANU" 1/1/24 0:00 12/31/25 0:00 ZCA1-SRB-P(O2)S 16611662 "GU, BIN " Not Applicable 7 OBSTETRICS & GYNECOLOGY NH77YPDEGG84 NH77YPDEGG84 US 10071230 HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES EAST LANSING MI SCHOOLS OF MEDICINE 488242600 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 78500 NCI 50000 28500 Title: Developing humanized Nut Carcinoma mouse model for developing NUTM1 targeted therapies.Project Summary:NUT carcinoma (NC) is a highly aggressive cancer with no effective treatment (medium survival time ~6 monthsfrom diagnosis). Although considered rare the decimal prognosis of NC call for the development of bettertreatment. Clinically NC is strongly associated with chromosome translocations that lead to the formation offusion genes between a testis-specific gene NUTM1 and various fusion partners including BRD4 (70% of cases)and BRD3 NSD3 ZNF532 etc. (the rest 30% of cases). Functionally knockdown of the BRD4-NUTM1 fusiongene in human NC cell lines suppresses their proliferation suggesting a strong dependency on BRD4-NUTM1by NC. However because the ectopic expression of BRD4-NUTM1 in non-NC cell lines is unequivocally toxicthe oncogenic activity of the fusion gene has not been proved previously. Recently we developed the firstgenetically engineered mouse model (GEMM) of NC by recapitulating the Brd4-Nutm1 forming chromosometranslocation in the basal cells of epithelial tissues. The mouse model developed highly aggressive lowdifferentiation squamous cell carcinoma similar to human NCs. Our GEMM study provided the first functionalproof of BRD4-NUTM1 as the oncogenic driver of NC. The high dependency of NC on the BRD4-NUTM1 fusiongene for both cancer initiation and development presented it as an ideal target for therapy. Moreover the testis-specific expression profile would make therapeutic strategies targeting NUTM1 highly specific and with a hightherapeutic index. Because NUTM1 is an adaptor protein that is primarily consisted of low-complexity sequencesthere are no apparent target sites for small molecular inhibitors. New therapeutic modules that target its DNA(e.g. CRISPR-based gene therapy) and mRNA (antisense therapy) sequences or the ones that target its proteinby synthetic affinity agents (e.g. nanobody-directed Proteolysis Chimera (PROTAC)) would likely be needed.Due to the limited conservation in genomic DNA (~3%) and peptide sequence (66%) our NC model basedon the mouse genes is not ideal for developing NUTM1-targeting therapeutics. We propose to humanizethe NC GEMM by replacing the mouse Nutm1 gene component with a human NUTM1 coding sequence (Aim 1)and characterize the NC tumors generated by this humanized model (Aim 2). We expect this well-characterizedhumanized NC GEMM to serve as a valuable preclinical model for developing NUTM1 targeting therapies forNC.Overall Impact. This project will produce a humanized GEMM for NC. By allowing the preclinical developmentof human NUTM1 targeting therapies our new model can transform the landscape of NC therapy developmentand benefit NC patients. More broadly the knowledge around targeting NUTM1 that the humanized NC modelwill foster can provide critical clues for developing NUTM1 targeting therapies for other NUTM1 rearrangedcancers such as childhood leukemia and sarcoma. 78500 +No NIH Category available Academia;Address;Advanced Malignant Neoplasm;Area;Calendar;California;Cancer Center;Cancer Science;Cancer health equity;Career Choice;Caring;Collaborations;Communities;Coupled;Critical Thinking;Dedications;Development;Educational process of instructing;Educational workshop;Environment;Faculty;Feeling;Fostering;Funding;Geography;Grant;Individual;Infrastructure;Institution;Knowledge acquisition;Lead;Learning;Malignant Neoplasms;Mentors;Mentorship;Methodology;National Cancer Institute;Postdoctoral Fellow;Preparation;Program Development;Research;Resources;Scholarship;Science;Scientist;Services;Strategic Planning;Structure;Students;Training;Training Support;Underrepresented Students;Universities;Writing;anticancer research;cancer health disparity;career;career development;career networking;catalyst;commune;community building;course development;doctoral student;experience;graduate student;improved;innovation;peer;pre-doctoral;programs;skill acquisition;skills;university student San Diego State University Advancing Cancer Careers for ExceLlence (ACCEL) PROJECT NARRATIVESan Diego State Universitys Advancing Cancer Careers for ExceLlence (ACCEL) Program in partnership withUniversity of California San Diego (UCSD) Moores Cancer Center will provide 70 SDSU postdoctoral fellowsand graduate students each year with a coordinated and innovative array of resources to support excellenceinclusion and transformation of the cancer research science force. ACCEL will leverage existing infrastructureand develop new programming to a) expand and strengthen the pipeline of underrepresented (UR) scholarspursuing cancer research; and b) broaden SDSUs capacity to support and advance UR pre- and postdoctoralcancer research scholars. NCI 10784133 9/18/23 0:00 RFA-CA-23-013 1R25CA285813-01 1 R25 CA 285813 1 "BARFIELD-STEWARD, WHITNEY" 9/18/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 14132468 "LEWISON, REBECCA " Not Applicable 51 BIOLOGY 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA SCHOOLS OF ARTS AND SCIENCES 921821901 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 322757 NCI 300000 22757 PROJECT SUMMARY / ABSTRACTSan Diego State Universitys Advancing Cancer Careers for ExceLlence (ACCEL) Program in partnership withUniversity of California San Diego (UCSD) Moores Cancer Center will provide 70 SDSU postdoctoral fellowsand graduate students each year with a coordinated and innovative array of resources to support excellenceinclusion and transformation of the cancer research science force. ACCEL will leverage existing infrastructureand develop new programming to a) expand and strengthen the pipeline of underrepresented (UR) scholarspursuing cancer research; and b) broaden SDSUs capacity to support and advance UR pre- and postdoctoralcancer research scholars.Three distinct and complimentary aims have been developed to meet these larger objectives. Led by aTraining Champion (TC) team with diverse areas of expertise the ACCEL program will a) implement mentoringactivities and community-building engagement that reduce feelings of isolation and increase sense ofbelonging to increase doctoral student and postdoctoral scholar participation and retention in cancer research;b) provide structured support services including skills development courses for doctoral students andpostdoctoral scholars to broaden advancement in cancer research and promote diversity in the scientificworkforce; and c) build tailored and sustainable linkages for SDSU students and scholars to existing supportand resources through the National Cancer Institute and other partners.While ACCEL program development and implementation will benefit greatly from strong integration withexisting partners and programs including the UC San Diego Moores Cancer Center SDSU-UCSD CREATECancer Partnership and the NCI Center to Reduce Cancer Health Disparities (CRCHD) training navigationACCEL will also introduce innovative methodologies to address isolation and build community and belonging intandem with skills building. 322757 +No NIH Category available Address;Biological Assay;Biological Markers;Cancer Model;Cancer Patient;Cells;Clinic;Clinical;Clinical Trials;Coculture Techniques;Complement;Cytometry;Data;Development;Effectiveness;Extracellular Matrix;Fibroblasts;Future;Genes;Goals;Immune checkpoint inhibitor;Immunohistochemistry;Immunotherapy;Infiltration;Intervention;KRAS oncogenesis;KRAS2 gene;KRASG12D;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Mus;Mutation;Myeloid Cells;Non-Small-Cell Lung Carcinoma;Oncogenes;Oncogenic;Organoids;PD-1/PD-L1;PDL1 inhibitors;Patients;Phase;Preclinical Testing;Process;Recurrent tumor;Relapse;Resistance;Resistance development;Resources;Role;Signal Pathway;Smoker;TP53 gene;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;Time;Tumor Suppressor Proteins;Tumor-Associated Process;anti-PD-L1;anti-PD-L1 antibodies;anti-PD-L1 therapy;checkpoint therapy;cytokine;effective therapy;efficacy evaluation;experimental study;immune activation;immune checkpoint;immunological status;inhibitor;molecular targeted therapies;mouse model;mutant;never smoker;outcome prediction;programmed cell death ligand 1;research clinical testing;resistance mechanism;response;single-cell RNA sequencing;targeted treatment;therapeutic target;therapy resistant;treatment strategy;tumor;tumor microenvironment The Role of the Tumor Microenvironment in Resistance to Oncogenic KRAS Inhibition in Lung Cancer PROJECT NARRATIVEKRASG12D inhibitors are currently entering clinical testing for various malignancies includingnon-small cell lung cancer (NSCLC) but the development of resistance to these treatmentsandtherefore tumor relapseis anticipated. To address the need for treatments that will produce long-term responses we will investigate how resistance in KRASG12D-mutant NSCLC tumors is linkedto remodeling of the lung cancer tumor microenvironment (TME). Describing these processes inthe TME will provide actionable biomarkers and therapeutic targets in relapsed tumors that willinform the development of future treatments with long-term effectiveness for NSCLC patients. NCI 10783852 12/21/23 0:00 PAR-22-216 1R21CA286372-01 1 R21 CA 286372 1 "BOURCIER, KATARZYNA" 12/21/23 0:00 11/30/25 0:00 ZCA1-TCRB-9(O2)S 10567549 "GALBAN, STEFANIE " "PASCA DI MAGLIANO, MARINA " 6 RADIATION-DIAGNOSTIC/ONCOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 12/21/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 218790 NCI 140250 78540 PROJECT SUMMARYInhibitors against mutant KRASthe oncogene once deemed undruggableare impressively showing tumorcontrol in preclinical testing entering the clinic for testing in various malignancies and in the case of theKRASG12C inhibitor Sotorasib gaining FDA approval. MRTX1133 a KRASG12D inhibitor now entering phase 1clinical testing represents hope for patients bearing other KRAS mutations including a significant number ofnever smokers with non-small cell lung cancer (NSCLC) 56% of whom have a KRASG12D-mutant cancer.MTRX1133 will likely result in a paradigm shift for these NSCLC patients. Moreover NSCLC responds well toimmunotherapy and thus the efficacy of combining KRAS inhibition with immune checkpoint immunotherapy(ICI) is expected to be even greater. However for many molecularly targeted therapies resistance and thereforerelapse is common. This has been observed in patients treated with Sotorasib and there is concern thatresistance to MRTX1133 and other KRAS inhibitors will also develop. Resistance is often linked to theremodeling of the tumor microenvironment (TME) and thus an imperative need has emerged to understandthis remodeling process during intervention and tumor recurrence to guide development of future therapeutictreatment paradigms with long-term responses.Our analysis of the TME in a unique KrasG12D inducible and reversible mouse model of NSCLC using single cellRNA sequencing data shows KrasG12D-dependent control of the TME. Upon initiating KrasG12D the expression ofPDL1 decreased in a subset of myeloid cells potentially indicating that patients with mutant KrasG12D are unlikelyto respond to immune checkpoint therapy using PD1/PDL1 inhibitors. Interestingly when KrasG12D was turnedOFF the expression of PDL1 increased providing strong rationale for co-treatment of KRAS inhibitors with ICIfor these patients. Thus we hypothesize that a) inactivation of oncogenic KrasG12D in advanced tumorssensitizes lung cancer to anti-PDL1 antibodies and b) therapeutic interventions targeting KrasG12D willresult in remodeling of the tumor microenvironment. To test our hypothesis we will determine tumorregression and survival benefit of KrasG12D inhibition wherein oncogenic KRAS is inhibited either genetically orby MRTX1133 in combination with anti-PDL1. Importantly we will also study tumor recurrence in NSCLC dueto therapeutic resistance in our model (Aim 1). To address the urgent needs to devise effective treatmentswith long-term responses and understand the interaction between oncogenic KRAS expressing cells and thesurrounding TME during treatment and relapse we will thoroughly evaluate fibroblasts and immune status inrelapsed KrasG12D-driven lung cancer in these mice. The intricate mechanisms of a KRASG12D-regulated TMEparticularly fibroblast cells will also be scrutinized in patient derived organoid models using MRTX1133 inco-cultures with matching fibroblasts (Aim 2). Successful completion of this proposal will provide actionablebiomarkers and therapeutic targets in relapsed tumors for developing long-term therapeutic solutions. 218790 +No NIH Category available Address;Adipocytes;Affect;Antibodies;Antibody-Dependent Enhancement;Antigen Targeting;Biochemical;Bioinformatics;Biological Assay;CD47 gene;CRISPR screen;CRISPR/Cas technology;Cancer Etiology;Cancer Patient;Cell Extracts;Cell membrane;Cessation of life;Clinical;Communication;Computer Analysis;Development;Development Plans;ERBB2 gene;Enabling Factors;Environment;Enzymes;Foundations;GPR84 gene;Genetic Screening;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immunocompetent;Immunologics;Immunotherapy;In Vitro;Inflammatory;Knock-out;Knowledge;Laboratories;Lipids;Lymphocyte;Lymphocyte Suppression;Lymphoma;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Medium chain fatty acid;Membrane Glycoproteins;Membrane Proteins;Mentors;Mentorship;Methods;Modeling;Molecular;Monitor;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mus;Natural Killer Cells;Outcome;Pathway interactions;Patient-Focused Outcomes;Phagocytes;Phagocytosis;Phagocytosis Inhibition;Phase;Prognosis;Protein Deficiency;Regulation;Research Personnel;Research Training;Resistance;Role;Series;Signal Transduction;Testing;Therapeutic;Therapeutic Monoclonal Antibodies;Training;Trastuzumab;Tumor Antigens;Tumor Cell Line;Tumor Escape;Universities;Work;adaptive immune response;anti-CD20;anti-cancer;anti-tumor immune response;antibody-dependent cellular phagocytosis;cancer cell;cancer immunotherapy;cancer therapy;cancer type;career;career development;experience;experimental study;fatty acid metabolism;functional genomics;genome wide screen;immune cell infiltrate;immune checkpoint;improved;in vivo;innovation;lipid metabolism;lung cancer cell;mouse model;neoplastic cell;novel;novel therapeutics;pre-clinical;receptor;resistance mechanism;rituximab;skills;small cell lung carcinoma;standard of care;success;synergism;technique development;therapeutic target;tumor;tumor immunology;tumor microenvironment Systematic Discovery and Characterization of Novel Cancer Anti-Phagocytic Mechanisms Project NarrativeMonoclonal antibody (mAb) therapies can drive potent anti-tumor immune responses and havethus become part of the standard of care in the treatment of many cancers but their efficacy isimpeded by diverse cancer resistance mechanisms. This proposal aims to characterize a novelmechanism that enables cancer cells to evade macrophage phagocytosis which is a majorpathway of cancer killing driven by mAbs. Establishment of this novel mechanism using acombination of in vitro and in vivo approaches will advance our understanding of cancer-macrophage interactions and will lay the foundation for therapeutic strategies aimed atcounteracting cancer resistance to mAbs. NCI 10783846 5/5/23 0:00 PA-20-188 4R00CA259218-03 4 R00 CA 259218 3 "KUO, LILLIAN S" 3/15/22 0:00 3/31/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15235393 "KAMBER, ROARKE ALEXANDER" Not Applicable 11 ANATOMY/CELL BIOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 162875 86125 Project Summary/AbstractRecent strategies to stimulate anti-cancer immune responses have transformed treatment options for manycancer patients but are critically hindered by the low abundance and/or suppression of lymphocytes in thetumor microenvironment of many cancers. This work aims to address this significant problem in the contextof small cell lung cancer (SCLC) which has among the worst prognoses among all cancers and for whichadaptive immune checkpoint inhibitors have shown limited success in improving patient outcomes. Strategiesto stimulate macrophage activity are increasingly being investigated as macrophages constitute a highpercentage of total tumor cell mass in SCLC and many other cancers. Therapeutic monoclonal antibodies(mAbs) can induce macrophages to both kill cancer cells via phagocytosis and to prime adaptive immuneresponses. However anti-phagocytic factors expressed by cancer cells only some of which have beenidentified enable resistance to phagocytosis. My long-term goal is to advance our fundamental knowledgeof the mechanisms by which cancer cells evade antibody-dependent phagocytosis which might create newtherapeutic avenues to enhance mAb efficacy. I will build on an innovative CRISPR/Cas9-screeningapproach I have developed to identify factors that modulate cancer sensitivity to phagocytosis. This approachrevealed a suite of known and novel anti-phagocytic pathways. The objective of this proposal is to investigateone of the most potent novel mechanisms I identified and to test the central hypothesis that cancer cellsmetabolize inflammatory lipids to avoid activating macrophages. In Aim 1 I will undertake a series of in vitroexperiments to understand the mechanistic basis of macrophage regulation by cancer-derivedimmunostimulatory lipids. In Aim 2 I will determine how cancer lipid regulation affects innate and adaptiveanti-cancer immune responses using an immunocompetent mouse model for SCLC. Finally in Aim 3 I willsystematically characterize synergies between diverse anti-phagocytic pathways in SCLC to reveal how lipidregulators and other factors cooperate to block macrophage attack which may suggest possible newcombination therapeutic strategies. The expected outcome of these related but independent aims is anunderstanding of the molecular mechanisms of a novel immunosuppressive lipid metabolism pathway usedby diverse cancers including SCLC to evade mAb therapies. These aims will be pursued within the stellarscientific environment of Stanford University with research training and mentorship by an experienced teamof experts in functional genomics cancer immunology lipid signaling and bioinformatics. The careerdevelopment plan involves research training in lipid analysis methods mouse tumor models andcomputational analysis of genetic screens as well as professional training in communication mentoring andlaboratory management and will establish a strong foundation for my career as an independent investigator. 249000 +No NIH Category available Acute Promyelocytic Leukemia;Acute leukemia;Affect;Apoptosis;Arsenic Trioxide;B-Cell Leukemia;B-Lymphocytes;Binding;Biological;Blast Cell;Cancer Biology;Cell Aging;Cell Cycle Inhibition;Cell Death;Cell Differentiation process;Cell Line;Cell Maturation;Cell Reprogramming;Cell Survival;Cells;Chromatin;Chromatin Structure;DNA;DNA Binding;DNA biosynthesis;Data;Differentiation Therapy;EZH2 gene;Epigenetic Process;Exhibits;Failure;Foundations;Gene Targeting;Genes;Genetic Transcription;Genome;Goals;Hematopoietic stem cells;Heterogeneity;Immunodeficient Mouse;Immunophenotyping;Induction of Apoptosis;Knowledge;Laboratories;Leukemic Cell;Ligand Binding;Ligands;Lymphoblastic Leukemia;Lymphoid;Lymphoma cell;Molecular;Mus;Mutate;Mutation;Nature;Nucleic Acid Regulatory Sequences;Nucleosomes;Outcome;Patient-Focused Outcomes;Patients;Physical condensation;Process;Proliferating;Publishing;Repression;Role;Sampling;Solid;Specific qualifier value;Structure;T cell differentiation;T-Cell Leukemia;Testing;Therapeutic Agents;Tretinoin;Work;Xenograft procedure;cancer cell;cancer therapy;clinical application;cytokine;experience;gene repression;genome-wide;histone methyltransferase;in vivo;inhibitor;leukemia;leukemia/lymphoma;mouse model;neoplastic cell;novel;novel strategies;pharmacologic;programs;receptor;self-renewal;small molecule;stem cells;transcription factor;transcriptional reprogramming;treatment strategy A novel strategy for transcriptional reprogramming of lymphoid leukemia cells Project NarrativePrevious work suggested that normal hematopoietic progenitor cells undergo transient de-condensation of nascent chromatin in order to allow lineage-specific transcription factors to bindto their gene targets and to activate new transcriptional programs leading to cell differentiation.Lymphoid B-ALL and TCLL leukemic cells lost this ability to de-condense nascent chromatinwhich may explain their inability to differentiate and their increased proliferative capability. Wepropose to overcome these barriers of reprogramming-based therapies of lymphoid leukemiccells through de-condensing their nascent chromatin and by inducing transcriptionalreprogramming which will lead to reduced proliferation differentiation and cell death. NCI 10783708 12/22/23 0:00 PA-20-185 5R01CA268899-03 5 R01 CA 268899 3 "KLAUZINSKA, MALGORZATA" 1/1/22 0:00 12/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-H(02)M] 1880445 "CALABRETTA, BRUNO " "MAZO, ALEXANDER M" 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 487186 NCI 312299 174887 AbstractLymphoid B-ALL and TCLL leukemia consists of leukemic blast cells (LBCs) arrested at early stages ofdifferentiation which exhibit high proliferative potential and capability for self-renewal. The idea to inducereprogramming of leukemic and other cancer cells leading to cell maturation and senescence gained highpopularity but its clinical applications are rarely successful and are mainly limited to the therapy of the APLleukemia with ATRA and arsenic trioxide. This strategy may have been unsuccessful due to a gap in theknowledge of the mechanisms through which transcriptional reprogramming occurs. Our published datasuggest that normal hematopoietic progenitor cells (HPCs) undergo transient de-condensation of chromatin toallow lineage-specific transcription factors (TFs) to bind to their gene targets and to activate new transcriptionalprograms leading to cell differentiation. This transient de-condensation occurs through very low accumulationof H3K27me3 on DNA just after DNA replication. H3K27me3 is a mark of the most condensed arrays ofnucleosomes in the genome and is found at regulatory regions of all repressed genes. Our results suggest thattested cultured and primary lymphoid B-ALL and TCLL cells have lost this inherent ability to open nascentchromatin thus creating a barrier for their transcriptional reprogramming. In this proposal we will test a newreprogramming strategy which overcomes these barriers of reprogramming-based therapies and may lead toelimination of leukemic cells. The key feature of this new strategy is the first step which includespharmacological inhibition of the H3K27me3 histone methyltransferases (HMTs) EZH1/EZH2 thus creating de-condensed structure of nascent chromatin at regulatory regions of all genes. At the second step we will usesmall molecules to activate endogenous inducible TFs which can then readily bind to their target genes due tothe de-condensed structure of nascent chromatin. Tumor cells including leukemic cells are commonly knownto accumulate mutations in inducible TFs and receptors; thus screens of small molecule inducers for a varietyof TFs/receptors will be performed to determine the best possible inducer for distinct subtypes of B-ALL.Preliminary results suggest that induction by small molecule inducers leads to transcriptional reprogramming ofcell lines and primary B-ALL and TCLL cells changes in their immunophenotype and apoptosis. Moreover thisstrategy strongly suppresses lymphoid leukemia burden in mice. The goal of this project is to develop a widelyapplicable treatment strategy for transcriptional reprogramming and loss of cell viability for many types oflymphoid leukemic cells. To this end we propose to: 1. Extend and generalize the lymphoid leukemic cellsreprogramming approach; 2. Examine the mechanisms and biological outcomes of reprogramming of lymphoidleukemic cells; 3. Examine the effects of our treatment strategy in vivo. 487186 +No NIH Category available 18F-fluorothymidine;3-Dimensional;Acute Myelocytic Leukemia;Acute leukemia;Address;Adipocytes;Affect;Aftercare;Allogenic;Area;Biological;Bioluminescence;Biophysics;Biopsy;Blood;Bone Marrow;Bone marrow biopsy;Cause of Death;Cells;Cellularity;Clinical;Clinical Trials;Complement;Cues;Detection;Disease;Disease remission;Dose;Engraftment;Environment;Evaluation;Exposure to;Extramedullary;Fatty acid glycerol esters;Funding;Generations;Global Change;Goals;Grant;Hematopoietic stem cells;Hybrids;Image;Imaging technology;Immunocompetent;Individual;Kinetics;Knowledge;Lead;Leukemic Cell;Location;Luciferases;MLL-AF9;Magnetic Resonance Imaging;Marrow;Measurement;Measures;Mesenchymal Differentiation;Mesenchymal Stem Cells;Methodology;Methods;Modality;Monitor;Multimodal Imaging;Mus;Organ;Outcome;Paint;Pathologic;Pathology;Patients;Phase;Positron-Emission Tomography;Process;Progression-Free Survivals;Publications;Publishing;Radiation;Radiation Dose Unit;Recurrence;Recurrent disease;Red Marrow;Refractory;Regimen;Relapse;Reporting;Research Personnel;Residual state;Risk;Rodent Model;Role;Safety;Sampling;Site;Skeletal bone;Skeletal system;Spatial Distribution;Survival Rate;Therapeutic;Tissues;Toxic effect;Transplantation;Transplantation Conditioning;Validation;Variant;Water;Whole-Body Irradiation;Work;Yellow Marrow;bone;bone preservation;burden of illness;cell killing;chemoradiation;conditioning;design;disorder control;efficacy evaluation;experience;hematopoietic cell transplantation;hematopoietic stem cell self-renewal;imaging modality;imaging system;improved;insight;irradiation;leukemia;leukemia relapse;lipid biosynthesis;lymphoid irradiation;mouse model;multidisciplinary;neoplastic cell;non-invasive imaging;preconditioning;preservation;prospective;relapse patients;response;self-renewal;simulation;skeletal;spatiotemporal;standard of care;treatment planning;treatment response;tumor Conformal Total Body and Marrow Irradiation for Leukemia Relapse is the major cause of death in patients with acute leukemia. We have developed the total marrow andlymphoid irradiation (TMLI) regimen to precisely direct radiation to areas of disease while sparing healthy organs;however relapses are still common. This project is designed to provide improved tumor control and safeoutcomes by discovering optimal dose escalation strategies and by developing methods to limit damage anddestabilization to surrounding tissues. NCI 10783685 12/12/23 0:00 PAR-18-560 5R01CA154491-11 5 R01 CA 154491 11 "VIKRAM, BHADRASAIN" 9/13/11 0:00 12/31/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 8574291 "HUI, SUSANTA K" "WONG, JEFFREY Y" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 622989 NCI 387921 235068 Relapse is the major cause of death in patients with poor-risk leukemia. Increasing the dose of conventional totalbody irradiation (TBI) as preconditioning for hematopoietic cell transplantation (HCT) potentially reduces relapsebut results in increased toxicity to vital organs and no survival benefit. Therefore in the last several years totalmarrow and lymphoid irradiation (TMLI) preparative HCT regimens have been developed to safely targetincreased doses to sites of disease. This continuation application expands on previous successful doseescalation strategies using TMLI to enhance the therapeutic gain (dose ratio of bone marrow to vital organs) inrefractory and relapsed leukemia patients compared to conventional TBI. Phase I TMLI trials demonstrate thatdose escalation is feasible with acceptable toxicities. Initial results are encouraging in patients with refractory orrelapsed leukemia not eligible for standard of care transplant regimens as exemplified in one study showing atwo-year progression-free survival rate of 27%. However the disease relapse rate is still high (~65%). To addressthis problem the investigators have developed a state-of-the-art non-invasive hybrid imaging technology a multi-modal imaging methodology that detects a heterogeneous spatial association between acute myeloid leukemia(AML) and the bone marrow environment (BME) to identify areas of FLT-avid high disease burden and potentialsites for disease relapse and to uncover skeletal-wide spatial variations in BME damage or destabilization(BMED) that may adversely affect bone marrow (BM) engraftment. Thus based on the knowledge gained in thelast funding period the objective is to maximize the benefit of tumor cell killing without increasing BME damagethat is reflected by reduced cellularity/hematopoietic stem cell (HSC) self-renewal capacity and increaseddifferentiation of mesenchymal stem cells (MSCs) towards adipogenesis. Initial study reveals that escalatedTMLI radiation doses lead to tolerable BMED. This work will be expanded in Aim 1 to assess spatial and temporaleffects of TMLI on BMED in an ongoing clinical trial using patient-derived biological samples and non-invasiveimaging namely whole body dual energy CT (DECT) and water fat MRI (wfMRI) for longitudinal assessment ofBMED. In Aim 2 a hybrid 3-deoxy-3[(18)F] -fluorothymidine positron emission tomography (FLT PET)-DECT-wfMRI imaging system to assess skeletal-wide spatial distribution of disease and its association with treatmentresponse (relapse/remission) will be utilized. The feasibility of this functional TMLI (fTMLI) to allow augmenteddoses (or dose painting) to areas of FLT-avid high disease burden for targeted specific dose escalation will alsobe characterized. In Aim 3 the investigators will use a newly developed mouse model of clinical TMLI to studyhow TMLI doses impact BMED and engraftment. Identifying an optimal dose to minimize BMED and maximizeleukemia cell killing will complement the goals of Aims 1 and 2. This strategy has the potential to significantlyimprove the safety and efficacy of TMLI as HCT conditioning for AML patients by reducing disease relapsewithout significantly increasing toxicity. 622989 +No NIH Category available Address;Affect;Age;Benefits and Risks;Biological Assay;Body Image;Breast;Breast Cancer Model;Breast Cancer Treatment;Cancer Prognosis;Clinical;Communities;Complement;Diagnosis;Estrogen Therapy;Estrogen receptor negative;Estrogen receptor positive;Female;Feminine;Gender;Goals;Gonadal Steroid Hormones;Grant;Guidelines;Histology;Immune;Immunofluorescence Immunologic;Individual;Knowledge;Mass Spectrum Analysis;Measures;Medical;Modeling;Molecular;Mus;Parents;Patient risk;Patients;Population;Stains;Treatment outcome;Well in self;Work;alpelisib;assigned male at birth;cancer risk;cancer therapy;carcinogenesis;cis-female;cis-male;clinical translation;emotional distress;experimental study;gender affirmation;gender affirming hormones;improved;male;malignant breast neoplasm;mouse model;transcriptome sequencing;transfeminine;transgender;treatment strategy;tumor;tumor growth Admin Suppl Gender-affirming estrogen therapy and breast cancer treatment outcome Project NarrativeAs the transgender population increases there will be a substantial number of transgenderindividuals at risk for cancer as they age within the next 20 to 50 years. The medical communityneeds to be ready with knowledge and clinical guidelines to manage their cancer treatment.Towards that goal we utilize established mouse models of estrogen receptor positive andnegative breast cancers to study the effect of gender-affirming estrogen treatment on breastcancer treatment outcome. NCI 10783533 9/14/23 0:00 PA-20-272 3R21CA267088-02S1 3 R21 CA 267088 2 S1 "WALLACE, TIFFANY A" 5/1/23 0:00 11/30/24 0:00 12553513 "HENG, YU JING JAN " "WULF, GERBURG M" 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 5/1/23 0:00 11/30/24 0:00 310 Non-SBIR/STTR 2023 89920 OD 52007 37913 Project SummaryOur parent R21 grant (R21 CA267088) was to understand transfeminine patients risks andbenefits of continuing gender-affirming estrogen therapy (ET) during their breast cancer (BC)treatment. Transfeminine individuals are assigned male at birth and most pursue ET to affirm theirfeminine identity. As the transgender population increases there will be a substantial number oftransgender individuals at risk for cancer as they age within the next 20 to 50 years. Fortransfeminine patients diagnosed with BC there is no clinical guideline whether they can continuereceiving ET during BC treatment and whether ET affects their BC prognosis. Thediscontinuation of gender-affirming hormones for a transgender individual is undesirable as itgreatly affects their emotional well-being and body image and compounds their cancer-inducedemotional distress. In order to address the clinical question of the risks and benefits oftransfeminine patients continuing ET during BC treatment the overall strategy of our parent R21was to use three mouse models of BCPik3camut Brca1mut or Tp53mutto understand theeffect of ET on BC treatment outcomes. We will compare tumor growth rates breast histologyand treatment outcomes between male mice that continue and discontinue ET during BCtreatment with alpelisib (for Pik3camut tumors) olaparib (for Brca mut tumors) or eribulin (forTp53mut tumors). In Year 1 we completed the experiments for Brca1mut tumors and olaparibtreatment. For the first half of Year 2 we will focus on completing experiments for Tp53muttumors to complement our Brca1mut findings. This will allow us to obtain a general overview ofhow ET affects estrogen receptor negative (ER-) BC treatment. This supplement proposes threeadditional molecular assays to explain our findings for Brca1mut and Tp53mut tumor models: 1) tomeasure olaparib/eribulin levels in the tumors using mass spectrometry; 2) to profile ER- tumorsusing RNASeq to identify gender and sex-hormone related molecular mechanisms influencingBC treatment outcomes; and 3) assess the effect of gender and/or sex-hormone on tumorimmune contexture using multiplex immunofluorescence staining. Collectively our work willhave direct and immediate clinical translation to inform ER- BC treatment options and decisionsfor the transfeminine community. Our findings will also inform us why BC occurring in males aremore aggressive than in females thus improving treatment strategies for cisgender men andwomen with BC as well. 89920 +No NIH Category available AML1-ETO fusion protein;Acute;Acute Myelocytic Leukemia;Address;Binding;Binding Sites;Biochemical;Biological;Biological Markers;Cells;Chimeric Proteins;Clinical;DNA Methylation;DNA Sequence Alteration;DNMT3a;Disease;Disease Progression;Disease remission;Environment;Epigenetic Process;Genes;Genetic Transcription;Goals;Growth;HIF1A gene;Hormones;Hyperactivity;Hypoxia;Hypoxia Inducible Factor;In Vitro;Intervention;Investigation;Leukemic Cell;Link;Literature;Malignant Neoplasms;Mediating;Mediator;Medicine;Molecular;Nature;Oncogenic;Outcome;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Positioning Attribute;Prognosis;Prognostic Marker;Proteins;RUNX1 gene;Recurrence;Recurrent disease;Refractory;Relapse;Research;Role;Signal Transduction;Techniques;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Therapeutic Index;Time;Transcription Initiation;Transcriptional Regulation;Transgenic Mice;Transgenic Organisms;Treatment Protocols;Work;acute myeloid leukemia 1 protein;acute myeloid leukemia cell;cell growth;chemotherapy;clinical efficacy;cofactor;cytokine;driver mutation;drug testing;druggable target;improved;in vivo;inhibitor;innovation;insight;leukemia;leukemia treatment;leukemic stem cell;leukemogenesis;molecular pathology;mouse model;new therapeutic target;normoxia;novel;novel therapeutics;patient derived xenograft model;pharmacologic;predictive signature;promoter;relapse patients;response;t(8;21)(q22;q22);targeted treatment;therapeutic biomarker;therapeutic development;therapy outcome;transcription factor The Role of HIF1A-DNMT3A axis in AML1/ETO-Driven Acute MyelogenousLeukemia Leukemia patients harboring AML1/ETO fusion protein achieve complete remission initially but many of them relapse and die. This project aims to understand the ways in which AML/ETO contributes to leukemogenesis. Findings will inform intervention strategies for leukemia therapy. NCI 10783081 11/30/23 0:00 PA-19-056 5R01CA248019-04 5 R01 CA 248019 4 "KLAUZINSKA, MALGORZATA" 12/7/20 0:00 11/30/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 9226287 "LIU, SHUJUN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 572092 NCI 450105 121987 "The fusion protein AML 1/ETO (AE) resulting from the t(8;21) translocation is a leukemia-initiating transcription factor that is frequently associated with acute myeloid leukemia (AML). Despite being defined as a ""favorable"" subtype of AML many AE positive (AE+) patients relapse and die with largely unknown causes. It is also unclear how AE mediates a disease-predictable DNA methylation signature. The long-term goals are to elucidate further the mechanisms of AE+ AML leukemogenesis discover new therapeutic targets and develop effective targeted therapies. The objective of this proposal is to explore the molecular basis of a disease-predictable DNA methylation signature underlying AE+ AML with a focus on the impact of hypoxia-independent HIF1alpha-DNMT3a signaling axis activation. The rationale underlying this proposal is that the hypoxia-independent HIF1alpha signaling activation is a new hallmark of cancer. In relation to this project the hyperactive HIF1alpha signaling may be a disease-promoting factor and an epigenetic mediator in AE+ AML. HIF1alpha forms a feedforward loop with AE and transactivates DNMT3a another prognostic marker in AE+ AML. HIF1alpha inhibition suppresses AML cell growth. However the detailed mechanistic and biochemical links between HIF1alpha signaling and AE AML pathogenesis and disease recurrence are poorly defined. The central hypothesis is that HIF1alpha promotes AE leukemogenicity through enhancing AE transcriptional activities and modulating the AE-governed DNA methylation landscape in AML cells; therefore HIF1alpha may be a vulnerable and druggable target in AE+ AML. This hypothesis will be tested by pursuing three specific aims: 1.) Dissect the mechanistic details of how HIF1alpha is critical for AE-driven leukemogenesis; 2) Determine the role of HIF1alpha in AE-dependent DNA methylation; 3) Test pharmacological targeting of HIF1alpha as a therapeutic option for AE+ AML. To pursue our aims we will use innovative combinations of biological techniques with unique transgenic and patient-derived xenograft (POX) mouse models as well as innovative integration of aberrant HIF1alpha signaling and epigenetics in understanding and treating AE+ AML. The proposed research is significant because it will disclose new genes/mechanistic pathways that are necessary for AE leukemogenicity identify the therapeutic biomarkers and discover new medicinal agents for AE+ AML. Further it will thoroughly investigate the epigenetic and oncogenic role of HIF1alpha in cancer. The proximate expected outcomes are to demonstrate HIF1alpha-epigenetics crosstalk in defining AE-initiated transcriptional regulation and leukemia pathogenesis and to establish the feasibility of using HIF1alpha inhibitors to enhance the therapeutic index of the existing treatment regimens. The results will have an important impact because they will advance our understanding of AE+ AML molecular pathology aberrant epigenetics in leukemia and the oncogenic functions of hypoxia-independent HIF1alpha signaling in cancers. The findings will also lay the groundwork to develop newer strategies to better target AE+ AML." 572092 +No NIH Category available Adjuvant;Affect;Animals;Benchmarking;Blood Vessels;Bone Marrow;Brain;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Prevention;Breast cancer metastasis;Cell Cycle;Cell Survival;Cell Therapy;Cells;Chemoprotective Agent;Cytoprotection;DNA Damage;Data;Distant;Endothelial Cells;Endothelium;Estrogen receptor positive;Evolution;Future;Goals;Individual;Integrin Inhibition;Integrins;Left;Ligands;Liver;Lung;Measures;Mediating;Metastatic Neoplasm to the Bone;Modeling;Mus;Mutagens;NTN1 gene;Neoplasm Metastasis;Output;Patients;Phase;Pre-Clinical Model;Primary Neoplasm;Protein Array;Recurrence;Regimen;Resistance;Risk;Role;Safety;Signal Pathway;Signal Transduction;Site;Source;Stereotyping;Stress;Testing;Therapeutic;Tissues;Toxic effect;Transgenic Organisms;Translating;Up-Regulation;Vascular Cell Adhesion Molecule-1;Vascular Endothelium;Vertebral column;Work;ataxia telangiectasia mutated protein;breast cancer survival;chemotherapy;extracellular;genotoxicity;hormone therapy;improved;in vivo;innovation;knock-down;malignant breast neoplasm;metastasis prevention;neoplastic cell;novel;novel strategies;pre-clinical;prevent;protective factors;response;sensor;stem;synergism;targeted treatment;therapy resistant;vascular factor;von Willebrand Factor Chemotherapy-driven evolution of the vascular secretome and its role in therapeutic resistance Project NarrativeWe have proposed that it is necessary to eradicate disseminated tumor cells (DTCs) in distant tissues likebone marrow in order to prevent breast cancer metastasis. We have shown that DTCs are resistant tochemotherapy because of the niche that they occupy and found that chemotherapy triggers robust changeswithin this niche that paradoxically actually protect DTCs from therapy. We propose to identify and target thisresponse in order to deprive DTCs of pro-survival signals thus preventing their ability to cause lethalcomplications in the future. NCI 10782988 12/26/23 0:00 PA-19-056 5R01CA249528-05 5 R01 CA 249528 5 "KONDAPAKA, SUDHIR B" 1/1/21 0:00 12/31/25 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8087685 "GHAJAR, CYRUS M" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 362340 NCI 205875 156465 PROJECT SUMMARYOur continued inability to develop selective therapies that prevent the emergence of disseminated breast tumorcells into lethal metastases necessitates new approaches. We have shown that disseminated tumor cells(DTCs) occupy the perivascular niche (PVN) that this niche promotes chemotherapeutic resistance and thattargeting interactions between DTCs and the PVN sensitizes DTCs to chemotherapy. Translating thisapproach to pre-clinical models of breast cancer prevented metastases in over 60% of at-risk mice.Questioning the mechanism(s) of resistance in the remainder of mice led us to consider the dynamic responseof the vascular niche to chemotherapy. Our preliminary data indicate that genotoxic agents trigger thesecretion of pro-survival factors into the PVN and that the major trigger of this chemotherapy-associatedvascular secretome is the DNA damage response (DDR). Therefore here our goal is to target the cause (i.e.the DDR) and the consequence (i.e. the chemotherapy-associated vascular secretome) of vascular evolutionwhich we suspect promotes therapeutic resistance of DTCs. We will pursue this goal through 2 specific aims:Specific Aim 1. To determine whether individual extracellular factors elicited from vascular endothelium bychemotherapy protect DTCs. We have defined a global vascular response to DNA damaging agents. Netrin-1is a prominent component of this secretome with documented pro-survival functions. Our data show that endo-thelial-derived Netrin-1 protects DTCs from chemotherapy. Using organotypic transgenic and preclinical mod-els we will determine: i) whether endothelial cells are the relevant source of chemotherapy-elicited Netrin-1 invivo; ii) whether targeting Netrin-1 as an adjuvant sensitizes DTCs to chemotherapy; iii) whether this syner-gizes with targeting pre-existing protective factors in the PVN; and iv) the safety of these approaches.Specific Aim 2. To identify DNA damage driven signaling pathways in vascular endothelium that induce thechemotherapy-associated vascular secretome. Our preliminary data demonstrate that genotoxic therapy elicitsa stereotypic DDR from quiescent endothelium and that targeting a nucleator of this response mutes the ma-jority of the chemotherapy-associated vascular secretome. This approach may be a more robust alternative totargeting a single pro-survival factor such as Netrin-1. Here we will identify and target the signaling pathwaythat connects DDR to the vascular secretome and measure the efficacy and toxicity of this approach.The significance and innovation of this work lie in the discovery of origins and outputs of chemoprotectivefactors in the DTC niche. Targeting both will result in the first approach to specifically target DTCs impactingbreast cancer survival in a positive and lasting fashion. 362340 +No NIH Category available 3-Dimensional;Algorithms;Animal Model;Architecture;Beds;Binding;Biochemical;Cancer Model;Cell model;Cells;Cellular Morphology;Collaborations;Collagen;Collagen Fiber;Communities;Complement;Computer Analysis;Computer software;Computing Methodologies;Data Analyses;Development;Dimensions;Extracellular Matrix;Fiber;Fluorescence;Fluorescence Resonance Energy Transfer;Foundations;Generations;Glioblastoma;Goals;Image;Imaging technology;Immune;In Vitro;Individual;Investigation;Label;Machine Learning;Malignant Neoplasms;Malignant neoplasm of pancreas;Measurement;Metabolic;Metabolism;Methods;Minnesota;Mission;Modeling;Molecular;Optical Coherence Tomography;Photochemistry;Prognosis;Protocols documentation;Research;Research Personnel;Resources;Role;Signal Transduction;Solid Neoplasm;Sorting;Spectrum Analysis;T-Lymphocyte;Techniques;Technology;Testing;Time;Tissue Model;Tissues;Tumor Immunity;Tumor Tissue;Universities;Wisconsin;cancer imaging;candidate marker;cell behavior;cell type;crosslink;design;fabrication;fluorescence lifetime imaging;fluorophore;human data;imaging approach;imaging biomarker;imaging modality;imaging platform;immune cell infiltrate;improved;insight;microscopic imaging;multi-photon;multiparametric imaging;multiphoton microscopy;neoplasm immunotherapy;new technology;open source;optical imaging;physical property;second harmonic;second harmonic generation imaging;technology development;tumor microenvironment;tumor-immune system interactions TECH Core n/a NCI 10782987 11/22/23 0:00 RFA-CA-21-002 5U54CA268069-03 5 U54 CA 268069 3 12/9/21 0:00 11/30/26 0:00 ZCA1-SRB-X 8930 7908263 "ELICEIRI, KEVIN WILLIAM" Not Applicable 5 Unavailable 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN Domestic Higher Education 554552070 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 413582 413582 0 This TECH core of the U54 Center for Multiparametric Imaging of Tumor Immune Microenvironments (C-MITIE)will develop an integrated toolkit of advanced imaging and data analysis to power quantitative mechanisticinvestigations of immune-microenvironment dynamics in poor prognosis solid tumors. There is great need forimproved imaging methods that can advance understanding of the physical and molecular mechanismsgoverning immune infiltration distribution and function in native tumor microenvironments. We propose anumber of multiparametric imaging and computational methods for the two research test beds that seek to definethe physical and molecular barriers to effective anti-tumor immunity and immunotherapies. A major theme ofthe TECH approach is to use label-free imaging approaches that can characterize and quantitate the interactionsbetween immune cells and the tumor microenvironment. These label free methods are largely built on theplatform method of multiphoton microscopy and can be used on intact cell and tissue models with minimalperturbation. T-cell identity and activation will be tracked by metabolic profiling using new fluorescence lifetime(FLIM) and hyperdimensional imaging (HDIM) approaches. These metabolically sensitive methods will becomplemented by Full-Field Optical Coherence Tomography (FFOCT) to reveal new insight into metabolicallyrelevant architecture. FLIM based FRET can be used to yield new insights into signaling molecular interactionsrelevant to immune-microenvironment dynamics The collagen rich extracellular matrix (ECM) will be queriedwith Second Harmonic Generation (SHG) imaging for collagen fiber topology measurement and collagen cross-linking measurements with Enhanced Backscattering Spectroscopy (EBS). Multiphoton Excitation (MPE)photochemistry fabrication can be used to create in vitro cell ready models of collagen fiber organization that aredirectly based on human data blueprints. Advanced computational analysis methods including algorithmic andmachine learning approaches will be used to examine all multiparametric signals and make correlation betweenimmune and microenvironment interactions. All imaging and computational methods will be shared not onlywidely within the UW and UMN research teams but importantly with the general cancer imaging community usingestablished hardware and open source software dissemination protocols. +No NIH Category available Abbreviations;Acceleration;Address;Adverse effects;Affect;Aging;Blood - brain barrier anatomy;Blood Vessels;Blood capillaries;Brain;Cancer Burden;Cancer Patient;Cancer Survivor;Cell Aging;Cells;Cerebrovascular Circulation;Clinical;Cognition;DNA Damage;Data;Detection;Development;Disease;Endothelial Cells;Endothelium;Exposure to;Functional Magnetic Resonance Imaging;Ganciclovir;Hemorrhage;Impaired cognition;Impairment;Intervention;Knowledge;Laser Speckle Imaging;Long-Term Survivors;Maintenance;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of ovary;Memory;Microvascular Dysfunction;Mission;Modality;Mus;Neurons;Outcome;Oxidative Stress;Paclitaxel;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Play;Pre-Clinical Model;Prevention;Process;Proteins;Protocols documentation;Public Health;Publishing;Quality of life;Regulation;Reporter;Research;Resistance;Role;Series;Symptoms;Testing;Therapeutic;Treatment outcome;United States National Institutes of Health;Vascular Cognitive Impairment;Vascular Diseases;Vasodilator Agents;Work;attentional control;blood-brain barrier disruption;cancer therapy;cerebral microvasculature;cerebrovascular;chemobrain;chemotherapeutic agent;chemotherapy;clinically relevant;cognitive capacity;cognitive function;contrast imaging;density;executive function;experience;genetic manipulation;improved;innovation;insight;irradiation;liposomal delivery;loss of function;malignant breast neoplasm;mouse model;negative affect;neuroinflammation;neurovascular;neurovascular coupling;novel;novel therapeutic intervention;pharmacologic;prevent;preventive intervention;programs;red fluorescent protein;response;senescence;spatiotemporal;two-photon;vascular cognitive impairment and dementia Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence PROJECT NARRATIVEThe proposed research is relevant to public health as cancer treatment with chemotherapeuticdrugs induces progressive long-lasting adverse effects on cognitive function in 30 to 50% ofpatients yet its pathogenesis is not well understood. Increasing clinical and experimentalevidence suggest that chemotherapeutic agents cause cerebral vascular damage whichimpairs cerebral blood flow and vascular responses contributing to chemotherapy-inducedcognitive impairment. The discovery of the cellular mechanisms responsible for decreasedcognitive capacity after cancer treatment is ultimately expected to enhance understanding ofthe pathogenesis of the disease and will lead to the development of novel therapeuticinterventions for prevention; thus the proposed research is relevant to the part of NIH's missionthat pertains to developing fundamental knowledge that will help to reduce the burdens ofcancer. NCI 10782975 12/8/23 0:00 PAR-19-325 5R01CA255840-04 5 R01 CA 255840 4 "CHEN, WEIWEI" 1/1/21 0:00 12/31/25 0:00 Brain Injury and Neurovascular Pathologies Study Section[BINP] 8629725 "CSISZAR, ANNA " Not Applicable 5 NEUROSURGERY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 298519 NCI 205875 92644 "Project SummaryMany long-term survivors of cancer experience progressive chemotherapy-induced cognitive impairment (CICIcommonly referred to as ""chemobrain""). Importantly no strategies exist to prevent/reverse CICI.Chemotherapeutics do not cross the blood brain barrier and mature neurons are resistant to chemotherapeuticagents. In contrast endothelial cells are exposed to the highest concentrations of these drugs and are highlysensitive to their effects. We discovered that chemotherapeutic drugs including paclitaxel (PTX) inducecerebromicrovascular endothelial cells to undergo cellular senescence a common DNA damage response.Endothelial cells play critical roles in regulation of basal CBF moment-to-moment adjustment of CBF to neuronalactivity via neurovascular coupling (NVC) and maintenance of the microcirculatory network. Each of theseendothelial functions are critical for healthy brain function. The central hypothesis of this application is thatchemotherapeutic agents induce endothelial senescence which impairs cerebral blood flow promotemicrovascular rarefaction and compromise endothelium-dependent neurovascular coupling responses andbarrier integrity contributing to CICI. This hypothesis will be tested using an innovative mouse model: cancer-free senescence reporter mice treated with the chemotherapeutic drug paclitaxel (PTX) which allows thedetection and selective elimination of senescent cells. Specific Aims: 1) Determine how chemotherapy-inducedendothelial senescence alters neurovascular coupling responses and CBF. We postulate that chemotherapyinduces senescence in endothelial cells which impairs endothelial vasodilator function compromisesendothelium-dependent NVC responses and decreases capillary density dysregulating CBF. Our predictionbased on this hypothesis is that elimination of senescent endothelial cells through genetic manipulation or throughtranslatable senolytic therapies will restore neurovascular function and improve CBF in mice treated with clinicallyrelevant PTX protocol. 2) Determine how chemotherapy-induced endothelial senescence impacts microvasculardensity. We postulate that chemotherapy -induced endothelial senescence compromises the maintenance of themicrocirculatory network and/or impairs endothelial barrier function and that elimination of senescent cells willincrease cerebromicrovascular density and restore barrier function attenuating neuroinflammation. 3) Determine howchemotherapy-induced endothelial senescence impacts cognitive function. We postulate that PTX-inducedmicrovascular dysfunction contribute to the impairment of multiple domains of cognition and that elimination ofsenescent cells will prevent/delay the development of CICI. Our expected outcomes will generate an integratedunderstanding of the mechanisms that underlie microvascular dysfunction after chemotherapy and establishendothelial senescence as a translationally relevant target for prevention of CICI." 298519 +No NIH Category available Acceleration;Acids;Antibiotics;Area;Automobile Driving;Bacteria;Barrett Esophagus;Bile Acids;Case/Control Studies;Cell Differentiation process;Cessation of life;Chronic;Clinical;Collaborations;Colon;Colon Carcinoma;Data;Deoxycholic Acid;Development;Dysplasia;Enrollment;Enterobacteriaceae;Epithelium;Esophageal Adenocarcinoma;Esophageal Neoplasms;Esophageal Tissue;Esophagus;Feedback;Future;Gastroesophageal reflux disease;Goals;Goblet Cells;Helicobacter Infections;Helicobacter pylori;High grade dysplasia;Homeostasis;Incidence;Inflammation;Intervention;Intestines;Knowledge;Lesion;Logistic Regressions;Malignant Neoplasms;Malignant neoplasm of esophagus;Microbial Biofilms;Minority;Modeling;Mucins;Mucous body substance;Mutagens;NF-kappa B;Neoplasms;Obesity;Organoids;Pathway interactions;Patients;Population;Prevalence;Probiotics;Production;Prognosis;Prospective cohort;Public Health;Research;Risk;Risk Factors;Role;Sampling;Series;Signal Transduction;Stomach;Study models;Testing;Thinness;Time;Tissue Sample;Translating;Upper digestive tract structure;Work;aspirate;carcinogenesis;carcinogenicity;cohort;experimental study;gastric microbiome;gastrointestinal epithelium;gut microbiome;high risk;infection rate;microbiome;microbiome alteration;microbiome composition;modifiable risk;mouse model;notch protein;novel;prevent;prospective;trend The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma PROJECT NARRATIVEDeaths from esophageal adenocarcinoma continue to rise yet factors driving this trend remain poorlyunderstood. We hope to demonstrate that the inter-relationship between gastro-esophageal reflux bile acidcomposition Notch signaling activity and esophageal bacterial composition is key to driving esophagealneoplasia. This knowledge can in turn be translated to future efforts to modify these factors to preventesophageal cancer. NCI 10782972 1/5/24 0:00 PA-19-056 5R01CA255298-04 5 R01 CA 255298 4 "DASCHNER, PHILLIP J" 1/1/21 0:00 12/31/25 0:00 Cancer Prevention Study Section[CPSS] 9047196 "ABRAMS, JULIAN " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 443752 NCI 304157 139595 PROJECT SUMMARYThe incidence of esophageal adenocarcinoma (EAC) has risen 10-fold over the past half century andcontinues to have a dismal prognosis. Known modifiable risk factors for EAC do not adequately explain theseincidence trends; the rise in EAC cases began a decade before increases in the prevalence of both gastro-esophageal reflux disease and obesity. Helicobacter pylori infection rates have plummeted since the mid-20thcentury and absence of H. pylori is associated with a ~2-fold increased risk of Barretts esophagus (BE) theEAC precursor lesion and of EAC itself. Loss of H. pylori is associated with profound shifts to gastricmicrobiome composition. Thus dramatic changes in the upper GI microbiome in western populations likelyoccurred at the same time that BE and subsequently EAC began to rise in incidence. While prior work hasshown correlations between the microbiome BE and EAC there is a critical knowledge gap on mechanismsby which bacteria interact with the epithelium and potentially promote cancer. The mucus layer that overlies thegut epithelium is critical to maintaining host-bacteria homeostasis. We hypothesize that increased levels of thebile acid deoxycholic acid in gastro-esophageal refluxate results in increased Notch activity which in turninhibits goblet cell differentiation and decreases mucus production. This may lead to mucus layer thinningfacilitating the development of biofilms and leading to increased bacterial-epithelial interaction and chronicinflammation which promotes the development of esophageal adenocarcinoma (EAC). In Aim 1 we will carryout a case-control study of patients with and without BE dysplasia or EAC. We will focus on deoxycholic acidin gastro-esophageal refluxate and its association with Notch signaling and bacterial composition. In Aim 2 wefocus on the relationship between Notch signaling and Enterobacteriaceae which is increased in patients withhigh grade dysplasia and early EAC. Finally in Aim 3 we will perform a series of organoid-based experimentsto test the inter-relatedness between Notch deoxycholic acid and bacteria in BE. The microbiome representsa novel and potentially modifiable risk factor for the development of BE and EAC. Elucidation of microbiomefeatures and mechanisms that promote neoplasia is a critical step that will lead to subsequent trials ofantibiotics probiotics and other interventions targeted to altering the microbiome with the goal of lowering therisk of this highly lethal malignancy. 443752 +No NIH Category available Accounting;Address;Adenocarcinoma;Architecture;Biological;Biology;Cell Communication;Cell Fraction;Cells;Characteristics;Classification;Clinical;Clinical Management;Common Neoplasm;Complex;Coupling;Cytokine Signaling;Cytometry;Data;Diffuse;Disease Outcome;Disease Progression;Ecosystem;Foundations;Future;Gastrointestinal Carcinoid Tumor;Gastrointestinal tract structure;Genetic;Goals;Grouping;Heterogeneity;Human;Image;Immune;Immunologics;Immunosuppression;Immunotherapy;Incidence;Infiltration;Intestinal Neuroendocrine Neoplasm;Islet Cell Tumor;Knowledge;Link;Lymphoid;Lymphoid Cell;Macrophage;Malignant Neoplasms;Measures;Mediating;Molecular;Mutation;Myelogenous;Myeloid Cells;Natural History;Neoplasms;Neuroendocrine Cell;Neuroendocrine Tumors;Pancreas;Pathologic;Pathway interactions;Patients;Pattern;Population;Prevalence;Process;Prognosis;Prognostic Marker;Proteins;Resolution;Retrospective cohort;Role;Signal Transduction;Small Intestines;Spatial Distribution;Stratification;Structure;System;Systemic Therapy;Technology;Testing;Therapeutic;Tissues;Tumor Biology;Tumor Subtype;Tumor-associated macrophages;United States;Variant;Work;biomarker discovery;biomarker identification;cancer cell;cell type;chemokine;clinical biomarkers;cytokine;gene panel;high dimensionality;holistic approach;immune cell infiltrate;improved;innovation;innovative technologies;insight;new therapeutic target;novel;novel marker;novel strategies;outcome prediction;pancreatic neoplasm;prognostic;prognostic indicator;programmed cell death ligand 1;programmed cell death protein 1;response;single-cell RNA sequencing;specific biomarkers;targeted treatment;therapeutic development;therapeutic target;transcriptomic profiling;transcriptomics;treatment response;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Delineating the myeloid-centric immunosuppressive crosstalk as targets for prognosis and therapy in neuroendocrine tumors Project NarrativeThere is an urgent need to improve the prognostic classification of patients with neuroendocrine tumors (NETs)a tumor type rapidly rising in prevalence and incidence. We propose that NET progression and aggressivenessis linked with multi-factorial alterations in patient-specific factors encoded within the tumor microenvironment(TME) such as the spatial distribution patterns and cellular interactions of the different macrophage populationsthat underlie the creation of an immunosuppressive milieu. If identified understanding these spatial TMEcharacteristics will lead to a more accurate prognosis and may provide a robust foundation for future therapeuticdevelopment of novel and holistic approaches that target NETs. NCI 10782892 12/27/23 0:00 PAR-22-216 1R21CA286402-01 1 R21 CA 286402 1 "BHARTI, SANITA" 1/1/24 0:00 12/31/25 0:00 ZCA1-SRB-K(O1)S 9580294 "HEAPHY, CHRISTOPHER M" "DRIES, RUBEN " 7 Unavailable 5492160 JZ8RQC4EMDZ5 5492160 JZ8RQC4EMDZ5 US 42.336854 -71.070881 3617301 BOSTON MEDICAL CENTER BOSTON MA Independent Hospitals 21182908 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 223377 NCI 125858 97519 Project Summary / AbstractNeuroendocrine tumors (NETs) that are clinically and pathologically similar display significant differences indisease progression therapeutic response and overall survival. The limited accuracy of current prognosticbiomarkers is a major unmet clinical need particularly in a tumor type rapidly rising in prevalence and incidence.While genetic drivers have been identified these genetic alterations are limited to cancer cells and do not providea systematic assessment of information encoded within the intact tumor microenvironment (TME) including therole of the tumor architecture and the spatially organized immunological processes. For example while emergingevidence proposes a key role for tumor-associated macrophages (TAMs) in orchestrating animmunosuppressive TME patient-specific factors that mediate cell-to-cell interactions and localized chemokineand cytokine signaling in NETs are currently unknown. To address this knowledge gap work from our group onsingle-cell transcriptomic profiling of NETs has established that TAMs display an adverse continuum of cell states(i.e. not separated into the historical M1 or M2 groupings) while expressing tumor-specific chemokines andcytokines involved in regulating key immune pathways. Our findings highlight the significant heterogeneity withinthe myeloid compartments of NETs particularly TAMs and may offer potential promising targets for prognosisand therapy. However unlocking this potential requires the systematic understanding of the spatial distributionsand interactions of these different macrophage cell populations with both the cancer cell and lymphoid cellpopulations which together - as a multi-cellular system - dictate immunosuppression or activation. Theseintricate spatial insights are still majorly lacking and obtaining them is only recently possible with the advent ofnew spatial technologies. To understand the underlying processes that drive NET progression as well as revealpotential therapeutic vulnerabilities we will test our hypothesis across two mutually reinforcing aims. In Aim 1we will identify the exact spatial composition architecture and cellular crosstalk of the tumor and TME of archivalNETs and connect the obtained information with macrophage-centric signaling and processes. In Aim 2 we willdetermine if systematic spatial distributions and interactions of the macrophage cell populations and NET-specific chemokine profiles are associated with disease outcomes in NETs. The successful implementation ofthe proposed studies could provide innovative and data-driven insights into complex macrophage biology andconcurrently establish high-dimensional profiling of the TME as clinical biomarkers thereby transformingprognostic stratification and clinical management for patients with NETs and potentially identifying noveldruggable targets within the tumor as a whole. 223377 +No NIH Category available Address;Award;Caring;Clinic;Colonoscopy;Colorectal Cancer;Community Healthcare;Disparity;Educational workshop;Health;Hispanic;Infrastructure;Intervention;Maintenance;Malignant Neoplasms;Measures;Medicaid;Modeling;Oregon;Parents;Patients;Phase;Pilot Projects;Population;Quasi-experiment;Research;Rural;Rural Community;Testing;Trainers Training;Training;Training Programs;Vendor;acceptability and feasibility;cancer health disparity;care outcomes;colorectal cancer screening;community-level factor;design;effectiveness evaluation;effectiveness/implementation study;effectiveness/implementation trial;feasibility testing;follow-up;frontier;frontier counties;health plan;implementation facilitation;implementation study;improved;learning strategy;multi-component intervention;multidisciplinary;outreach;patient navigation;patient outreach;practice-based research network;primary care clinic;programs;recruit;rural counties;rural health clinic;scale up;screening;webinar Smarter CRC Supplement for ACCSIS Patient Navigation PROJECT NARRATIVE (PARENT AWARD)Disparities in colorectal cancer (CRC) screening follow-up and referral to care exist in ruralcommunities and for sub-populations within (e.g. Medicaid enrollees Hispanic patients). In SMARTERCRC our multidisciplinary team will adapt pilot then test the implementation and scale-up of targeteddirect-mail and patient navigation programs two effective multicomponent interventions inpartnership with rural clinics health plans (payers) and commercial vendors. Our approach leveragesan established rural practice-based research network; addresses patient clinic and healthplan/community level factors; and will ultimately reduce CRC disparities in rural Medicaid patients. NCI 10782890 9/18/23 0:00 PA-20-272 3UH3CA244298-05S1 3 UH3 CA 244298 5 S1 "GRIMES, GENEVIEVE M" 9/23/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1(52)-R] 10844684 "DAVIS, MELINDA MARIE" "CORONADO, GLORIA D" 1 NONE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR OVERALL MEDICAL 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 80000 NCI 80000 0 PROJECT SUMMARY/ABSTRACT (PARENT AWARD):This two-phase project is designed to achieve the Cancer Moonshot objectives by reducing the burdenof CRC on the US population. Specifically we aim to improve CRC screening rates follow-upcolonoscopy and referral to care in rural Medicaid patients by implementing a direct mail fecal testingprogram with targeted outreach and patient navigation for follow-up colonoscopy. We leveragepartnerships with the Oregon Rural Practice-based Research Network (ORPRN) Kaiser NorthwestCenter for Health Research and Medicaid Health Plans and deliver training and implementationsupport to participating rural primary care clinics using practice facilitation. In total we anticipateworking with 30 organizations to facilitate implementation with 130 primary care clinics(reaching 17000+ rural Medicaid patients).In Phase I (Year 01) we will conduct a milestone driven pilot to build the necessary infrastructure for alarge-scale implementation-effectiveness trial including adapting the clinic-health plan-vendorsupported direct mail program for rural Medicaid patients that have not established care and/or neverbeen screened; conducting a pilot study testing the feasibility and acceptability of patient navigation tosupport follow-up colonoscopy following an abnormal fecal test; engaging Medicaid Health Plans andrecruiting 30 primary care clinics located in rural and frontier counties in Oregon; and developing thetraining and support materials needed to implement a large-scale trial in these settings.In Phase II (Years 02-05) we will conduct an implementation-effectiveness study using a quasi-experimental stepped wedge design in 30 rural primary care clinics using program training and practicefacilitation to support implementation. As in the pilot the intervention combines: (1) a clinic-health plan-vendor supported direct-mail fecal testing program with targeted outreach for patients who have neverbeen screened or who have yet to establish care and (2) patient navigation for those who are referredfor colonoscopy as either the primary screening or for follow-up from an abnormal fecal test. We willevaluate effectiveness implementation and maintenance of the intervention through quantitative andqualitative measures. Results from the implementation study will inform scale-up of the programthrough partnerships with 20 regional and national organizations that serve rural/frontier primary careclinics using webinars train-the-trainer workshops and collaborative learning activities using the ECHO(Extension for Community Healthcare Outcomes) model. 80000 +No NIH Category available Binding Proteins;Biological;Breast Cancer Cell;Breast Cancer Model;Breast Cancer cell line;Cancer Biology;Cancer Model;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;ChIP-seq;Consumption;DNA;DNA Modification Process;Data;Development;Epigenetic Process;Eukaryota;Excretory function;Exhibits;Exposure to;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Histones;Human;Hypoxia;In Vitro;Individual;Link;MDA MB 231;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Messenger RNA;Methylation;Methyltransferase;Modeling;Modernization;Modification;Mus;Neoplasm Metastasis;Niacinamide;Nicotinamide N-Methyltransferase;Oncogenic;Pathology;Pathway interactions;Patients;Phenotype;Physiology;Play;Polymerase;Postdoctoral Fellow;Process;Proteome;RNA;RNA methylation;Rattus;Regulator Genes;Relapse;Research;Research Project Grants;Role;S-Adenosylhomocysteine;S-Adenosylmethionine;Small Interfering RNA;Sprague-Dawley Rats;Stimulus;Systemic Therapy;Testing;Therapeutic Agents;Transcript;Translational Regulation;Urine;cancer cell;cancer gene expression;cancer stem cell;cancer therapy;differential expression;epitranscriptomics;genetic regulatory protein;histone modification;in vivo;knock-down;malignant breast neoplasm;methylome;mouse model;novel;nutrient deprivation;patient derived xenograft model;pharmacologic;posttranscriptional;prevent;protein expression;response;single-cell RNA sequencing;stem-like cell;stressor;trait;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression Biological and cancer-associated role of epitranscriptomic gene expression regulation PROJECT NARRATIVENicotinamide N-methyltransferase (NNMT) is a likely master regulator of triple-negative breast cancer (TNBC)gene expression through its hypomethylating effect on DNA histones and mRNA; however a link betweenNNMT expression and mRNA hypomethylation has not previously been established as a mechanismcontributing to cancer progression. In my dissertation project I am testing the hypothesis that NNMT activity inTNBC cells results in 1) reduced m6A mRNA modification associated with altered protein expression ofpathways mediating cellular stress response and 2) cancer stem cell-like traits associated with survivalmetastatic potential and increased in vivo tumor-forming capacity. As accumulating research has beenhighlighting the biological relevance of RNA modifications both in terms of normal physiology and pathologyincluding cancer I plan to pursue my post-doctoral research on the biological and cancer-associated role ofepitranscriptomic gene expression regulation with a translational focus as an endpoint to develop novelmodulators of RNA modifications as potential cancer therapeutic agents. NCI 10782553 11/10/23 0:00 RFA-CA-19-002 5K00CA245784-04 5 K00 CA 245784 4 "DAMICO, MARK W" 9/11/19 0:00 11/30/26 0:00 ZCA1-RTRB-R(A1) 15839373 "DOLCEN, DENIZ NESLI" Not Applicable 16 GENETICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Other Research-Related 2024 89563 NCI 82988 6575 PROJECT SUMMARY My lab discovered that NNMT is a direct GR transcriptional target gene in TNBC. I then observed relativelyhigh NNMT expression in several aggressive patient-derived TNBC cell lines. NNMT consumes the universalmethyl donor S-adenosyl methionine (SAM) for methylation of nicotinamide. High NNMT activity depletes SAM;as a result methyltransferase targets are hypomethylated in cells with high NNMT expression. NNMT-inducedDNA and histone hypomethylation have been shown to result in oncogenic gene expression in cancer cells butNNMT mechanism of action in TNBC biology remains unclear. A link between NNMT expression and mRNAhypomethylation has not previously been established as a mechanism contributing to cancer progression. N6-methyladenosine (m6A) is an abundant and reversible RNA modification in eukaryotes. Our collaborator Dr.Chuan He discovered that m6A-binding proteins mediate translational regulation by altering stability andtranslational efficiency of m6A-modifed mRNAs. Importantly altered m6A mRNA methylation is implicated in theprogression of several human cancers via causing changes in post-transcriptional gene expression of cancerpathways. To our knowledge I am the first to characterize the m6A methylome of a patient-derived TNBC cellline model (MDA-MB-231): ~ 7000 m6A-modified transcripts are significantly enriched for pathways involved incellular stress response cell death and cell survival. In addition I have data suggesting that NNMT activity inthe MDA-MB-231 TNBC cell line results in 1) reduced m6A modification of mRNAs regulating key cancerpathways and 2) increased in vivo tumor-growth. In my dissertation research I am testing the hypothesis thatNNMT activity in TNBC cells results in 1) reduced m6A mRNA modification associated with altered proteinexpression of pathways mediating cellular stress response and 2) cancer stem cell-like traits associated withsurvival metastatic potential and increased in vivo tumor-forming capacity. During my postdoctoral research I aim to test whether epitranscriptomic gene expression regulatesdynamic cellular phenotypes including adaptation to the changing microenvironment. I will first characterize theactively transcribed genes with polymerase ChIPseq and perform whole proteome quantification with massspectrometry in cells exposed to distinct microenvironmental stressors (e.g. nutrient deprivation hypoxia). I willthen determine whether differential transcription of genes correlate with protein expression in different cellularstates. If there is not a strong correlation I will perform individual siRNA knockdown of all known m6A-regulatory genes and determine the effect on protein expression. I will then utilize patient-derived xenograftmouse models and the Sprague Dowley rat model of spontaneous breast cancer to determine whether them6A-regulatory proteins are differentially expressed in distinct tumor regions with single-cell RNA sequencing. 89563 +No NIH Category available Biochemical;Cancer Patient;Cell Death Induction;Cells;Chemoresistance;Clinic;Clinical;Clinical Trials;Data;Development;Drug resistance;Family;In Vitro;Knowledge;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mediating;Molecular;Outcome;Paclitaxel;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phospho-Specific Antibodies;Phosphorylation;Phosphorylation Site;Phosphotransferases;Play;Prognostic Marker;Protein Family;Protein Tyrosine Kinase;Recurrence;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Stress;Testing;Therapeutic;Translating;Tubulin;Tyrosine Kinase Inhibitor;Ubiquitin;antitumor agent;cancer cell;cancer recurrence;cancer therapy;cancer type;chemotherapy;clinical development;cytotoxicity;drug sensitivity;fibroblast growth factor receptor 4;improved;in vivo;inhibitor;malignant breast neoplasm;mortality;new therapeutic target;novel;patient response;protein degradation;protein function;response;screening;success;therapeutic target;tumorigenesis Targeting FGFR4 to overcome chemoresistance in ovarian cancer NarrativeThe identification of new regulators and/or signaling pathways triggered by Taxol will shed lighton the mechanisms underlying chemoresistance. Our study identifies the FGFR4 signaling as apotential therapeutic target and suggests that combining inhibitors of FGFR4 with Taxol will haveenhanced efficacy in the treatment of Taxol-resistant and/or recurrent patients. NCI 10782061 12/5/23 0:00 PAR-22-216 1R21CA280020-01A1 1 R21 CA 280020 1 A1 "O'HAYRE, MORGAN" 12/5/23 0:00 11/30/25 0:00 ZCA1-RTRB-S(O1) 10491869 "DONG, JIXIN " Not Applicable 2 NONE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE OVERALL MEDICAL 681987835 UNITED STATES N 12/5/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 215284 NCI 140250 75034 AbstractMany anti-tubulin agents such as paclitaxel (Taxol) have been used extensively for treatment ofseveral types of cancer including ovarian lung and breast cancers. Despite their wide use incancer treatment however patient response is highly variable and drug resistance remains amajor clinical issue. It is therefore essential to identify prognostic markers to predict the patientresponse and to enhance drug sensitivity. Protein tyrosine kinases (PTKs) play significant rolesin cancer development and many PTK inhibitors have been widely used for treatment ofmalignancies and in clinical trials. We conducted Phos-tag-based biochemical screenings todetermine the regulation and function of PTKs during Taxol chemotherapeutics. In response toTaxol treatment one of the most significant changes in the PTK family is the marked proteindegradation of fibroblast growth factor receptor 4 (FGFR4). In addition FGFR4 controls Taxolchemosensitivity in ovarian cancer cells. Importantly FGFR4 expression levels are elevated inrecurrent post-chemotherapy ovarian cancer patients. These preliminary results provide a strongpremise in support of our hypothesis that the FGFR4 signaling functions as a therapeutic targetfor paclitaxel-based chemotherapeutics in treatment of drug-resistant and/or recurrent patients.We will test our central hypothesis by two specific aims. Aim 1: Determine how FGFR4 isregulated during Taxol treatment; Aim 2: Targeting FGFR4 to overcome paclitaxelchemoresistance in ovarian cancer. The identification of new regulators and/or signalingpathways triggered by anti-tubulin drugs will shed light on the mechanisms underlyingchemoresistance. Our study identifies the FGFR4 signaling as a potential therapeutic target inrecurrent ovarian cancer and suggests that combining selective inhibitors of FGFR4 (in clinicaldevelopment) with Taxol will have enhanced efficacy in the treatment of chemo-resistant and/orrecurrent patients. 215284 +No NIH Category available Address;Adjuvant Therapy;Aftercare;Animal Model;Animals;Autopsy;Brain;Brain Neoplasms;Canis familiaris;Cell Death;Chemotherapy and/or radiation;Clinical;Clinical Research;Clinical Trials;Computer Models;DNA Double Strand Break;Data;Deposition;Dose;Effectiveness;European;Excision;Exposure to;External Beam Radiation Therapy;Finite Element Analysis;Formulation;Foundations;Generations;Glioblastoma;Glioma;Heat shock proteins;Heating;Histopathology;Human;Hyperthermia;Image;Infiltration;Injections;Iron;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Methodology;Modeling;Mus;Nanotechnology;Normal Cell;Normal tissue morphology;Oral Administration;Oryctolagus cuniculus;Patients;Penetration;Pilot Projects;Prognosis;Radiation therapy;Recurrence;Rodent;Safety;Solid;Study of magnetics;Technology;Temperature;Tissues;Toxic effect;Treatment Efficacy;Tumor Debulking;Work;antitumor effect;bioluminescence imaging;brain tissue;cancer cell;chemoradiation;chemotherapy;clinical translation;clinically relevant;design;effective therapy;fractionated radiation;hyperthermia treatment;hyperthermia tumor treatment;image guided;imaging modality;improved;innovation;iron oxide nanoparticle;magnetic dipole;magnetic field;nanoparticle delivery;neoplastic cell;radiation effect;safety and feasibility;temozolomide;therapy resistant;tissue injury;tool;translation to humans;translational applications;translational potential;treatment planning;treatment response;tumor;tumor microenvironment Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma Project NarrativeGlioblastoma (GBM) is one of the most devastating human cancers that almost always recurs due to thepresence of invasive therapy-resistant infiltrating cancer cells at the tumor margin. Magnetic hyperthermiatherapy (MHT) is a powerful nanotechnology-based treatment that may enhance the effects of radiation therapy(RT) and chemotherapy against infiltrating GBM tumors. NCI 10782010 12/28/23 0:00 PA-19-056 5R01CA247290-05 5 R01 CA 247290 5 "BUCHSBAUM, JEFFREY" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-OTC-E(02)M] 7078345 "HADJIPANAYIS, CONSTANTINOS GEORGE" "IVKOV, ROBERT " 12 NEUROSURGERY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 591742 NCI 515769 75973 Project Summary/AbstractGlioblastoma (GBM) remains a fatal brain cancer for which there is no cure. Maximal safe tumor resectioncombined with adjuvant therapies such as fractionated external beam radiation therapy (RT) and temozolomide(TMZ) chemotherapy known as chemoradiation (CRT) has provided the greatest benefit to GBM patients.However local recurrence occurs in most patients due to invasive therapy-resistant infiltrating cancer cells atthe tumor margin. Magnetic hyperthermia therapy (MHT) is a powerful nanotechnology-based treatment thatmay enhance the effects of CRT. MHT consists of local heat generation in the tumor region through directdelivery of magnetic iron-oxide nanoparticles (MIONPs) that are activated by exposure to an external alternatingmagnetic field (AMF) that is safe to normal cells. The AMF interacts with the magnetic dipoles of the MIONPs togenerate local heat and hyperthermia. Human clinical trials have demonstrated overall survival benefits of MHTwith fractionated RT in recurrent GBM resulting in European approval. Current MHT strategies howeverrequire high concentrations of nontargeted MIONPs (>100 mg/ml; 50-100mg Fe/g of tumor) delivered byinjection with leakback and without image-guided control of energy deposition. As a result normal tissueinjury limits MHT effectiveness and treatment of the infiltrative tumor margins is poorly defined whichcompromises MHT efficacy. Our proposal is designed to address these challenges and optimize the translationalpotential for enhanced MHT of GBM in combination with CRT using both small and large animal models withclinical proof-of-concept demonstration in spontaneous canine gliomas. We have recently completed a pilot studyin spontaneous canine gliomas demonstrating feasibility and safety of image-guided MIONP delivery alone. Wehypothesize that image-guided MHT will enhance CRT of GBM. Key innovations of our proposal are to: 1)evaluate the enhancement of CRT by MHT in mouse GBM models with an innovative proprietary MIONPformulation that requires 20-fold lower Fe concentration in tumors for more effective treatment than currentapproved MIONPs; 2) optimize image-guided MIONP delivery and MHT treatment planning with computationalmodelling in a rabbit brain tumor model; 3) enhance thermal treatment at the infiltrative tumor margins bycontrolling power deposition with innovative AMF power application that will also limit off target heating; and 4)complete a clinically relevant proof-of-concept study of our MHT approach in a spontaneous canine gliomamodel. We have Preliminary Data that demonstrate intracranial hyperthermia with a 3-fold increase in TMZconcentration within GBM tumors leading to a robust antitumor effect with increased survival after MHT + CRTin a therapy-resistant rodent glioma model. Overall this interdisciplinary work will provide a solid foundation formeaningful clinical translation of MHT with CRT for treatment of GBM. Imaging methods that correlate tumorheat distribution after MHT will be developed for translation to human patients. 591742 +No NIH Category available Targeting tumor repopulation and the immune microenvironment to overcome chemoresistance NARRATIVEPoor response to chemotherapy poses a major obstacle for muscle-invasive bladder cancer patients sincechemotherapy only generates a dismal 5% improvement in overall survival. The success of chemotherapynot only results from its direct cytotoxic effects on tumor cells but also depends on 1) a wound response ofcancer stem cells to repopulate tumors and 2) an effective anti-tumoral immune response. Our proposal willinvestigate the above two understudied phenomena with the long-term goal to exploit these processes fortherapeutic targeting. NCI 10781577 5/10/23 0:00 PA-21-268 7R01CA255609-03 7 R01 CA 255609 3 "MERCER, NATALIA" 8/1/21 0:00 7/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8781273 "CHAN, KEITH SYSON " Not Applicable 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 5/10/23 0:00 7/31/23 0:00 396 Non-SBIR/STTR 2022 226446 NCI 140214 86232 PROJECT SUMMARYThis application is in response to PAR-19-183: Biology of Bladder Cancer. Muscle invasive bladder cancer(MIBC) claims approximately 18000 deaths annually in the United States. Funding and research devoted tothis cancer-type are significantly under-proportioned. An unmet clinical need for MIBC treatment lies in thepoor patient response towards chemotherapy with treatments providing only a dismal 5% improvement inoverall survival. The long-term goal of this application is to address this urgent need for adjuvant therapiesto improve chemotherapeutic response. The success of chemotherapy is historically thought to solely dependon its direct cytotoxic effects on tumor cells. However there is growing evidence as shown by our ownresearch and others that chemotherapeutic efficacy is also dependent on 1) successful prevention of cancerstem cells in repopulating residual tumors and 2) an effective anti-tumoral immune response. These twophenomena are often investigated separately but their possible synergy has been overlooked. Our researchproject is conceptually innovative to examine a common upstream pathway that regulates both tumorrepopulation and immune response. We hypothesize that the inhibition of this common pathway will providean effective therapeutic target for clinical translation. Our specific aims include: Aim 1) Decipher this pathwayby investigating the non-canonical downstream mechanism leading to the extracellular release of pleiotropicfactors. This is significant since these extracellular factors can modulate both tumor repopulation andimmune response. Aim 2) Evaluate how these extracellular factors and their cognate receptors drive therepopulation of quiescent cancer stem cells. Aim 3) Investigate how inhibition of this upstream pathway cancollectively abrogate tumor repopulation and immunosuppression and thus enhance chemotherapeuticresponse. Success of this proposal will pose drug targets capable of augmenting patient response tochemotherapy. Moreover these findings will provide insights to how these drugs can reestablish animmunostimulatory tumor microenvironment in MIBCs. In summary the studies outlined in this proposal aresignificant to address an unmet need i.e. to improve a dismal response of MIBC patients to standardchemotherapy. The conceptual advance from this study will likely extend beyond MIBC to benefit patientsfrom other epithelial malignancies. 226446 +No NIH Category available AR gene;Address;Androgen Receptor;Androgen Therapy;Biological Assay;Biological Markers;Biometry;Cancer Patient;Cancer Personalized Profiling by Deep Sequencing;Cells;Clinic;Clinical;Computational Biology;DNA Sequence Alteration;DNA analysis;DNA methylation profiling;Data;Detection;Development;Diagnosis;Disease;Disease Progression;Disease Resistance;Enhancers;Evolution;Exposure to;Genomics;Goals;Lead;Malignant neoplasm of prostate;Measures;Metastatic Prostate Cancer;Monitor;Neoplasm Circulating Cells;Oncologist;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Plasma;Plasma Cells;Positioning Attribute;Prognosis;Resistance;Resistance development;Resolution;Technology;Time;Tumor Markers;Tumor Tissue;Upstream Enhancer;Variant;Work;abiraterone;cancer genomics;cancer type;castration resistant prostate cancer;cell free DNA;design;detection sensitivity;determinants of treatment resistance;enzalutamide;epigenomics;genome wide methylation;genome-wide;genomic locus;human tissue;improved;liquid biopsy;men;multiple omics;novel;personalized medicine;predictive marker;prospective;response;sequencing platform;standard of care;survival outcome;therapy development;therapy resistant;translational impact;treatment strategy;tumor Novel ctDNA biomarker for androgen therapy in metastatic prostate cancer PROJECT NARRATIVETreatment-resistant metastatic castration-resistant prostate cancer (mCRPC) is the deadliest form ofprostate cancer with a dismal median survival of only ~5.5 months. Unfortunately by the time thisdeadly form of disease is diagnosed patients are already progressing on androgen receptor (AR)-directed drugs and prognosis is very poor. We developed a liquid biopsy biomarker referred to asEnhanceAR-Seq to more sensitively detect resistance early with the longer-term goal of advancingpersonalized treatment strategies to improve patient outcomes and survival. NCI 10780794 12/6/23 0:00 PA-20-185 1R01CA286127-01 1 R01 CA 286127 1 "MCKEE, TAWNYA C" 12/6/23 0:00 11/30/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 9231962 "MAHER, CHRISTOPHER A" "CHAUDHURI, AADEL ; PACHYNSKI, RUSSELL K." 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/6/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 596475 NCI 383585 212890 PROJECT SUMMARYThe deadliest form of advanced-stage prostate cancer is treatment-resistant metastatic castration-resistant prostate cancer (mCRPC) which occurs in ~35% of patients after exposure to androgenreceptor (AR)-directed therapies such as Abiraterone and Enzalutamide resulting in a dismal mediansurvival of only ~5.5 months. Unfortunately detection of treatment-resistant disease typically occurstoo late when patients are already progressing on AR-directed drugs after which they succumb rapidlyto their disease. There is therefore a critical need to detect AR resistance more sensitively and earlierin the disease course. To address this our team designed a novel cell-free DNA assay called Enhancerand Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq) built upon the CancerPersonalized Profiling by deep Sequencing (CAPP-Seq) platform and demonstrated superb sensitivityfor detecting AR gene body and enhancer locus alterations in plasma collected from mCRPC patients.Notably we applied our EnhanceAR-Seq technology to mCRPC patient plasma and showed that theresults correlate strongly with clinically verified resistance to AR-directed therapy and significantlyoutperform circulating tumor cell (CTC) AR-V7 detection. Building upon this the current proposal willevaluate whether our EnhanceAR-Seq technology can be used to predict both (Aim 1) pre-treatmentand (Aim 2) on-treatment resistance to AR-directed therapy in mCRPC patients. Further in Aim 3 wewill investigate whether integrating EnhanceAR-Seq with genome-wide methylation sequencing cangranularly refine our ability to predict treatment resistance and monitor both clonal and phenotypicevolution in mCRPC. We are uniquely positioned to accomplish this through our interdisciplinary teamcomprised of cell-free DNA genomicists bioinformaticians oncologists and statisticians. Overall thisstudy has significant translational impact by establishing cell-free genomic and epigenomic biomarkersof tumor evolution and resistance to AR-directed therapy in men with lethal prostate cancer. 596475 +No NIH Category available Acute Myelocytic Leukemia;Adaptive Immune System;Adoptive Cell Transfers;Adoptive Transfer;Affinity;Alleles;Antigen Presentation;Antigen Presentation Pathway;Antigens;Binding;Biochemical;Biometry;Blocking Antibodies;Blood;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CRISPR screen;Cancer Patient;Cell Therapy;Cell physiology;Cellular immunotherapy;Clinical;Collection;Colorectal Cancer;Complex;Cytolysis;Data;Defect;Epitopes;FDA approved;Frequencies;Genes;Genetic;Genetic Determinism;Genetic Engineering;Genomics;HLA Antigens;HLA-A gene;Histocompatibility Antigens Class I;Immune;Immunotherapy;Knowledge;MHC Class I Genes;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mediating;Medical;Modeling;Molecular;Mutate;Mutation;Oncogenes;Oncology;Patients;Peptides;Population;Pre-Clinical Model;Protein Isoforms;Recurrence;Resistance;Sampling;Skin Cancer;Solid;Structure;Surface;T cell response;T-Cell Antigen Receptor Specificity;T-Cell Development;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;Testing;Therapeutic;Time;Tissues;Treatment Failure;Tumor Immunity;Woman;beta-2 Microglobulin;cancer cell;cancer immunotherapy;cell killing;cross immunity;cross reactivity;disorder control;engineered T cells;experience;gene therapy;genome-wide;immune checkpoint;immune checkpoint blockade;immune function;immunogenic;immunogenicity;improved;in vivo evaluation;innovation;melanoma;men;multidisciplinary;neoantigens;neoplastic cell;novel;novel therapeutic intervention;pharmacologic;preservation;response;screening;selective expression;small molecule inhibitor;structural biology;therapeutic target;therapy resistant;translational approach;tumor;tumor immunology Novel cell therapy approaches for molecularly defined subsets of therapy-resistant melanoma PROJECT NARRATIVEAlthough some patients have durable disease control with current cancer immunotherapies many fail torespond or progress after initially experiencing tumor regression. This proposal seeks to develop newmechanism-based cellular immunotherapies to target melanoma and other common cancers with specificgenetic alterations associated with resistance to current treatments. As part of these studies newgeneralizable knowledge will be generated that improves our molecular understanding of how the adaptiveimmune system can distinguish between normal and transformed tissues. NCI 10780289 9/21/23 0:00 PA-20-185 1R01CA286507-01 1 R01 CA 286507 1 "ZAMISCH, MONICA" 9/21/23 0:00 8/31/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 14179238 "KLEBANOFF, CHRISTOPHER AUSTIN" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 506551 NCI 365353 141198 PROJECT SUMMARY/ABSTRACTMelanoma (MEL) is a model malignancy for studying the mechanisms of cancer immunotherapy. Antibodiesthat block negative regulators of T cell function termed immune checkpoint blockade (ICB) have transformedthe treatment of MEL and other solid cancers. Although some patients have durable disease control many failto respond or progress after initially experiencing tumor regression. Therapeutic resistance is enriched in twomolecularly defined MEL subtypes. Twenty eight percent of MELs possess activating mutations (Mut) in thedriver oncogene NRAS the second most common Mut RAS isoform. Beyond MEL Mut NRAS occurs in otherprevalent malignancies including colorectal cancer (CRC). We and others recently discovered that patientswith Mut NRAS MEL and CRC have a significantly shorter time to treatment failure. Separately ~30% of MELsacquire mutations in beta-2-microglobulin (B2M) an essential component of the human leukocyte antigenclass I (HLA-I) complex following ICB progression. Cancers with Mut B2M are intrinsically resistant to CD8+ Tcell killing. Thus two major gaps in knowledge that limit the potential of immunotherapy in MEL and othercommon cancers include: (1) identification of immunogenic antigens expressed by Mut NRAS tumors and (2)therapeutic strategies to overcome genetic loss of HLA-I presentation. We hypothesize that cancers with MutNRAS or Mut B2M can be therapeutically targeted using T cell receptor (TCR)-based immunotherapies. Insupport of our hypothesis we discovered using a mass spectrometry (MS) screen that the three most commonNRAS hotspot substitutions generate shared (or public) neoantigens (NeoAgs) presented by a prevalent HLAallele. Using a unique collection of biospecimens from patients who express an NRAS public NeoAg wegenerated T cells specific for these epitopes retrieved their TCR gene sequences and transferred publicNeoAg reactivity to polyclonal T cells. These results confirm the immunogenicity of screen-identified NRASpublic NeoAgs and enable the development of TCR-based therapies. We further discovered that a significantproportion of MELs undergo direct killing by T cells that express an HLA class II (HLA-II) restricted TCR. Usinga genome-scale CRISPR screen we found that cancer eradication is preserved when B2M and other HLA-Igenes are disrupted. Building on these preliminary data we propose in Aim 1 to develop a novel therapeuticapproach for cancers expressing an NRAS public NeoAg using TCR genetic engineering and adoptive celltransfer. In Aim 2 we will study the physical mechanisms underlying NRAS public NeoAg TCR specificityincluding the unique capacity of some TCRs to accommodate multiple hotspot substitutions. In Aim 3 we willdefine the molecular basis for direct cancer cell killing by HLA class II-restricted TCRs and test combinations toenhance the antitumor efficacy of adoptively transferred CD4+ T cells. By completing these aims we willdevelop novel mechanism-based cellular immunotherapies for Mut NRAS and HLA-I deficient cancers. 506551 +No NIH Category available Abstinence;Adult;American;Belief;Biochemical;Contracts;Costs and Benefits;Counseling;Data;Economics;Education;Effectiveness;Eligibility Determination;Evidence based practice;Exclusion;Exposure to;Group Homes;Health Care Costs;Home;Hour;Human;Hybrids;Intervention;Low Income Population;Low income;Measures;Medicaid;Participant;Policies;Population;Poverty;Practical trial;Prevalence;Provider;Psychological Stress;Randomized;Readiness;Recommendation;Reporting;Research;Services;Smoke-free home;Smoker;Smoking;Smoking treatment;Societies;Subgroup;Telephone;Testing;Tobacco;Treatment Cost;Uninsured;cigarette smoke;comparison intervention;cost effectiveness;design;economic cost;environmental tobacco smoke;evidence base;follow-up;home smoking ban;hybrid type 2 design;long term abstinence;non-smoker;policy implication;programs;quitline;randomized trial;recruit;service providers;smoking prevalence;smoking-related cancer;treatment services Expanding population-level interventions to help more low-income smokers quit NarrativeLow-income Americans are much more likely to smoke cigarettes than other population sub-groups and sufferserious and costly health consequences because of it. Telephone quitlines that are designed to help low-income smokers only provide services to those who are ready to quit in the next 30 days but 70-80% of low-income smokers are NOT ready to quit in the next 30 days. This study will test a new strategy that helps low-income smokers get ready to quit by combining a proven Smoke Free Homes program with Quitline services. NCI 10778919 2/10/23 0:00 PAR-18-559 3R01CA235773-04S2 3 R01 CA 235773 4 S2 "MAYER, MARGARET ELIZABETH" 7/23/19 0:00 6/30/24 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 1911852 "KREUTER, MATTHEW W." "MCQUEEN, AMY " 1 SOCIAL SCIENCES 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF SOCIAL WELFARE/WORK 631304862 UNITED STATES N 12/1/22 0:00 6/30/23 0:00 310 Non-SBIR/STTR 2023 49893 OD 31678 18215 C6 AbstractThere is an urgent need to engage more low-income smokers in activities that lead to quitting. The currentstandard of practice for population-level tobacco treatment is phone-based cessation counseling delivered bystate tobacco quitlines. But quitline services are restricted to smokers who are ready to quit in the next 30days a criterion met by only 20-30% of low-income smokers. Thus current population level tobacco treatmenthas nothing to offer 70-80% of low-income U.S. smokers. Based on extensive preliminary research by ourstudy team we assert that offering a pre-cessation intervention Smoke Free Homes to low-incomesmokers who are not yet ready to quit will: (1) engage more smokers in using proven interventions; (2)increase their readiness to quit and quit attempts; (3) reduce the number of cigarettes they smoke per day; and(4) increase cessation. These benefits will accrue in addition to reducing exposure to harmful secondhandsmoke for non-smokers in the home. In a Hybrid Type 2 randomized trial 1980 low-income smokers from ninestates with high smoking prevalence will be recruited from 2-1-1 helplines to receive either current standardpractice (Quitline) or expanded services (Quitline + Smoke Free Homes) both delivered by Optum the largestU.S. quitline service provider. In the latter condition smokers will be offered cessation counseling first just likecurrent standard practice but those who decline will then be offered Smoke Free Homes. At 3-month follow-up those in the latter condition who accepted quitline services but did not quit will be offered Smoke FreeHomes and those that accepted Smoke Free Homes but did not quit will be offered quitline services. Theeffectiveness portion of the Hybrid Type 2 design (Aim 1) will use intent-to-treat analyses to compare groupdifferences at 3- and 6-month follow-up in 7- and 30-day point prevalence abstinence with biochemicalverification as well as 24-hour quit attempts and cigarettes smoked per day. The implementation portion of theHybrid Type 2 design (Aims 2-3) will measure smokers acceptance and use of the interventions as well ascost-effectiveness and cost-benefits of adding Smoke Free Homes to quitline services. With rates of smokingand smoking-related cancers much higher in low-income populations and treatment costs exceeding tens ofbillions of dollars annually in Medicaid alone this large-scale practical trial will provide strong evidence withhigh external validity to answer an important policy question : Will changing the standard practice forpopulation-level treatment of smoking result in increased cessation in low-income populations? 49893 +No NIH Category available Acute Myelocytic Leukemia;Allogenic;Apoptosis;Attenuated;BCL2 gene;Biochemical;Biological Availability;Biology;Bone Marrow;CD34 gene;CRISPR/Cas technology;Catabolism;Cell Death;Cell Line;Cell Survival;Cells;Clinical;Data;Dependence;Development;Drug Targeting;Energy Metabolism;Enzymes;Equilibrium;Exhibits;FLT3 gene;FLT3 inhibitor;Fatty Acids;Future;Gene Expression Profile;Genes;Genetic;Genotype;Glutamine;Glycolysis;Growth;Hematologic Neoplasms;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic Stem Cell subsets;Hematopoietic stem cells;Homeostasis;Impairment;In Vitro;In complete remission;Isocitrate Dehydrogenase;Knock-out;Lead;Leukemic Cell;Leukocytes;Lysine;MLL-AF9;Malignant - descriptor;Metabolic;Metabolic Pathway;Metabolic stress;Metabolism;Minor;Mitochondria;Mus;Myelogenous;Myeloid Leukemia;Myeloproliferative disease;Oncogenes;Organ;Oxidation-Reduction;Oxidative Phosphorylation;Patients;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Prognosis;Proliferating;Reagent;Reduced Glutathione;Regulation;Relapse;Resistance development;Role;Sampling;Sirtuins;Solid Neoplasm;Somatic Mutation;Stem cell transplant;Stress;Superoxides;Testing;Therapeutic;Validation;Work;acute myeloid leukemia cell;biomarker identification;branched-chain-amino-acid transaminase;cancer cell;chemotherapy;clinical development;exome sequencing;experience;flexibility;in vivo;inhibitor;knock-down;leukemia;leukemia initiating cell;leukemia treatment;leukemogenesis;meter;mitochondrial metabolism;mouse model;mutant;nanomolar;new therapeutic target;novel;novel therapeutics;oxidation;relapse patients;resistance mutation;response;scaffold;segregation;small hairpin RNA;stable isotope;stem;stem cells;targeted treatment;tool;transcriptome sequencing;tumor heterogeneity Targeting the Metabolic Regulator SIRT5 in Acute Myeloid Leukemia PROJECT NARRATIVEAcute myeloid leukemia is an aggressive blood cancer that is typically incurable and fatal with current treatments.We have discovered that the survival of AML cells unlike healthy white blood cells depends on an enzymecalled Sirtuin 5 for which there are no drug or targeted treatment options. We will thoroughly characterize thebiology of Sirtuin 5 and simultaneously work to develop a drug to treat patients with acute myeloid leukemia. NCI 10778676 8/28/23 0:00 PA-19-056 3R01CA254354-05S1 3 R01 CA 254354 5 S1 "KLAUZINSKA, MALGORZATA" 7/1/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OBT-Q(02)M] 8093590 "DEININGER, MICHAEL W." Not Applicable 4 Unavailable 57163172 JZDRNT166LE4 57163172 JZDRNT166LE4 US 43.037892 -87.935338 5304801 "VERSITI WISCONSIN, INC." MILWAUKEE WI Research Institutes 532332121 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 353 Non-SBIR/STTR 2023 371250 NCI 225000 146250 PROJECT SUMMARYTARGETING THE METABOLIC REGULATOR SIRT5 IN ACUTE MYELOID LEUKEMIA. AML is an aggressivehematologic malignancy with <30% long-term survival. The current therapy standard chemotherapy alone orcombined with allogeneic stem cell transplant has not changed for decades. Despite initial responses mostpatients eventually relapse suggesting persistence of leukemia initiating cells in protective niches. Inhibitors ofFLT3 or mutant isocitrate dehydrogenase 1/2 (IDH1/2) have expanded therapy options and validated theparadigm of genotype-directed therapy. However even with these new drugs relapse is common and frequentlydue to selection of subclones with resistance mutations in the drug target. Unlike FLT3 and IDH1/2 inhibitorsthe BCL2 inhibitor venetoclax is active in multiple AML genotypes indicating that targeting shared vulnerabilitiesin a genotype-agnostic manner can be effective. Unfortunately many venetoclax-induced responses are notdurable as leukemia cells adapt by activating alternative anti-apoptosis mechanisms or by reprogrammingmitochondrial metabolism. Microenvironmental protection intra-tumoral heterogeneity and metabolic flexibilitylimit the utility of current AML therapies. To identify new therapy targets in AML we adapted an shRNA screenfor testing primary AML cells under bone marrow microenvironment-like conditions. We discovered that manyAML patient samples are highly dependent on SIRT5 while normal CD34+ cells are not. SIRT5 is a lysinedeacylase implicated in the regulation of energy metabolic pathways including oxidative phosphorylation(OXPHOS) fatty acid -oxidation and glycolysis. SIRT5 knockdown (KD) reduces growth and increasesapoptosis in most AML cell lines with consistent results upon disruption of SIRT5 using CRISPR/Cas9 orNRD167 a novel cell-permeable SIRT5 inhibitor. Genetic absence of Sirt5 impairs in vitro transformation ofmouse hematopoietic cells by several myeloid oncogenes including MLL-AF9 and attenuates leukemogenesisin vivo. At a biochemical level SIRT5 KD or inhibition with NRD167 is associated with reduced OXPHOSreduced glutathione levels and increased mitochondrial superoxide suggesting that AML cells depend on SIRT5to maintain redox homeostasis. Sirt5-/- mice are viable with minor metabolic abnormalities suggesting that invivo inhibition of SIRT5 would be tolerated. We hypothesize that SIRT5 is a therapy target in AML and will testthis in three Specific Aims: (1) Identify and validate SIRT5-regulated metabolic pathways in normal andAML stem and progenitor cells. (2) Identify biomarkers of sensitivity to SIRT5 inhibition in primary AMLcells. (3) Identify a potent selective and bioavailable SIRT5 inhibitor starting from the NRD167 toolcompound. Our work will rigorously test whether SIRT5 is a therapy target in AML clarify the mechanismsunderlying SIRT5 dependence and identify potent and selective SIRT5 inhibitors for future clinical development. 371250 +No NIH Category available Address;Adolescent;Australia;CD4 Lymphocyte Count;Cancer Burden;Cancer Control;Cancer Intervention and Surveillance Modeling Network;Cervical;Cervical Cancer Screening;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Comparative Carcinogenesis;Cost Effectiveness Analysis;Country;Data;Decision Making;Development;Disease;Disease Outcome;Disparity;Effectiveness;Ensure;Equity;Evaluation;Guidelines;HIV;Health;Health Benefit;Health Policy;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Infection;Information Dissemination;Kenya;Knowledge;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Modeling;Netherlands;New Mexico;North Dakota;Outcome;Policies;Policy Maker;Population;Populations at Risk;Preventative vaccination;Prevention strategy;Process;Productivity;Public Health;Reporting;Research Personnel;Risk;Route;Series;South Africa;Technology;Testing;Time;Uganda;United States;Update;Vaccinated;Vaccination;Vaccines;Woman;base;cancer health disparity;cervical cancer prevention;cervical carcinogenesis;co-infection;cohort;comparative;comparative effectiveness;cost;cost effective;cost effectiveness;disparity reduction;effectiveness evaluation;evidence base;improved;innovation;low and middle-income countries;mathematical model;new technology;programs;scale up;screening;screening guidelines;sexually transmitted virus;tool;vaccination strategy;working group Comparative Modeling to Inform Cervical Cancer Control Policies Project NarrativeNew technologies including screening tests and vaccines against human papillomavirus (HPV) a sexually-transmitted virus known to cause cervical cancer are dramatically changing the landscape of cervical cancercontrol in the US and worldwide. In order to address important evidence gaps our CISNET-Cervical workinggroup consisting of five teams who have been at the forefront of modeling cervical cancer prevention overthe last decade will continue this comparative modeling collaboration to evaluate the harms benefits andcost-effectiveness of screening and vaccination strategies and disseminate findings to inform health policiesand decisions. NCI 10778675 8/30/23 0:00 RFA-CA-19-054 3U01CA253912-04S1 3 U01 CA 253912 4 S1 "TATALOVICH, ZARIA" 9/8/20 0:00 8/31/25 0:00 ZCA1-SRB-T(M3) 8689652 "KIM, JANE JOOYUN" "BARNABAS, RUANNE VANESSA; CANFELL, KAREN ; DE KOK, INGE MCM; KULASINGAM, SHALINI L." 7 PUBLIC HEALTH & PREV MEDICINE 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 375112 NCI 340130 34982 Project SummaryDespite successful cervical cancer screening in the United States (US) over 13000 women develop and 4000women die from cervical cancer each year. The discovery of human papillomavirus (HPV) as the necessarycause of cervical cancer precipitated a surge of new evidence and development of innovative HPV-basedtechnologies both screening and prophylactic vaccination that have allowed for significant changes in ourapproach to cervical cancer control over the past two decades. These new technologies represent tremendousopportunities for effective equitable and efficient cervical cancer programs in the US but also pose significantchallenges for decision-making. Given the limited availability of outcomes data for new screening andvaccination approaches from empirical studies policy-makers have become uniquely reliant on mathematicalmodeling to provide a synthesized evidence base for decision-making for cervical cancer control strategies.These models can be used to integrate the most up-to-date data extrapolate short-term findings into long-termoutcomes and evaluate what-if scenarios that would otherwise be impractical or infeasible to conduct inclinical studies. The proposed CISNET project will represent the continued productive collaboration of fiveindependent modeling groups from the US Australia and the Netherlands that will leverage a series of state-of-the-art mathematical models of HPV and cervical carcinogenesis for comparative modeling. We will pursueanalyses related to the impact of newly-revised screening and HPV vaccination guidelines the comparativeeffectiveness of forthcoming screening and HPV vaccination strategies and approaches the optimal routes forreducing cervical cancer disparities the potential for cervical cancer elimination in the US and optimalscreening and vaccination strategies in women living with HIV. Our efforts will also involve wide disseminationof findings to various stakeholders to increase transparency and confidence in model-based analyses. 375112 +No NIH Category available Address;Binding;Bioinformatics;Biological Process;Bladder Neoplasm;C-terminal;Categories;Cell Nucleus;Cell secretion;Cells;Cessation of life;ChIP-seq;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Collagen Receptors;Communication;Conceptions;DNA Binding;Data;Disease;Disease Management;Distal;Ectopic Expression;Extracellular Matrix;Family;Fibroblasts;Funding;Genes;Goals;Image;Invaded;Investigation;Kininogenase;Knock-out;Knowledge;Ligands;Luciferases;Lung;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Metastatic Neoplasm to the Lung;Modality;Mutate;N-terminal;Nature;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Pattern;Peptide Hydrolases;Phenotype;Phosphorylation;Phosphorylation Site;Pilot Projects;Play;Primary Neoplasm;Process;Progression-Free Survivals;Property;Protein Fragment;Proteins;Receptor Activation;Receptor Signaling;Regulation;Role;Signal Transduction;Site;Smooth Muscle Myocytes;Specific qualifier value;Survival Rate;Testing;Therapeutic Intervention;Tumor Volume;Tyrosine Phosphorylation;Tyrosine Phosphorylation Site;bladder Carcinoma;bladder transitional cell carcinoma;cancer cell;cancer type;clinical translation;design;gamma secretase;in vivo;innovation;lead candidate;metastatic process;migration;neoplastic cell;notch protein;novel;novel strategies;overexpression;pharmacologic;precision medicine;receptor;respiratory smooth muscle;scaffold;src Homology Region 2 Domain;success;therapeutic target;tumor;tumor microenvironment Distinct Tumor and Metastatic Collagen Microenvironments: Divergent Targeting Approaches PROJECT NARRATIVEMetastatic bladder cancer is a devastating disease with a 5-year survival rate of only 5.4%. While the initialsteps of the metastatic cascade are rather well defined identification of targets to block this processcontinues to be a major clinical challenge. Discovering the regulatory mechanisms by which the metastaticmicroenvironment support tumor cell colonization and survival will enable design of new strategies not onlytargeting the primary tumors but also eradicating metastatic foci a potential new breakthrough. NCI 10778669 9/19/23 0:00 PA-19-056 3R01CA175397-09S1 3 R01 CA 175397 9 S1 "SNYDERWINE, ELIZABETH G" 9/30/13 0:00 4/30/26 0:00 Tumor Microenvironment Study Section[TME] 8781273 "CHAN, KEITH SYSON " Not Applicable 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 353 Non-SBIR/STTR 2023 382828 NCI 237045 145783 PROJECT SUMMARYMetastatic progression of the primary tumor accounts for the majority of cancer deaths. While the initial steps ofthe metastatic cascade are rather well defined identification of targets to block this process remains a majorclinical challenge. Previous studies have elegantly investigated the mechanistic contribution of tumor cell intrinsicproperties that promote metastasis in bladder urothelial carcinomas. However the functional significance of thetumor microenvironment and its contribution to this complicated process is not well characterized and thereforewarrants investigation. The long-term goal of this renewal application is to continue explore how collagensamajor extracellular matrix component of the microenvironmentact as a ligand to mediate crosstalk with theirreceptor on tumor cells to facilitate the metastatic cascade. We will investigate the downstream regulatorymechanisms of collagen receptor signaling in both the primary tumor and metastatic sites and to exploit theseregulatory processes as a revolutionizing approach to target metastases. Such innovative approaches to perturbcollagen-cancer crosstalknot only at the primary tumor but also at the metastatic nichewill move the fieldforward by providing a new conception in metastatic disease management and likely extend beyond bladdercarcinomas to other cancer types. 382828 +No NIH Category available Academia;Acute Myelocytic Leukemia;Address;Affinity;Antibodies;Antigens;Binding;Biological Assay;Biology;Blood;Bone Marrow;Bypass;CD34 gene;Cell Line;Cells;Cellular Immunity;Cellular Stress;Clinical;Clinical Trials;Collaborations;Cytotoxic T-Lymphocytes;Dichloromethylene Diphosphonate;Drug Combinations;Effector Cell;Engraftment;Epigenetic Process;Extracellular Domain;Fc Receptor;Fc domain;Goals;Grant;HDAC4 gene;Hematopoietic Neoplasms;Hematopoietic stem cells;Histone Deacetylase Inhibitor;Human;IgG1;Immune;Immunity;Immunocompetent;Immunologic Surveillance;Immunotherapeutic agent;Immunotherapy;Leukemic Cell;Lymphocyte;Macrophage;Malignant - descriptor;Malignant Neoplasms;Mediating;Membrane Proteins;Messenger RNA;Metalloproteases;Modeling;Monoclonal Antibodies;Mus;Mutation;Natural Killer Cells;Outcome;Pathway interactions;Patients;Pattern;Phagocytosis;Phagocytosis Induction;Pharmacologic Substance;Phase;Phase I Clinical Trials;Point Mutation;Post-Translational Protein Processing;Pre-Clinical Model;Protein Disulfide Isomerase;Proteins;Publishing;Regimen;Series;Signal Transduction;Solid Neoplasm;Structure;Surface;T-Lymphocyte;Testing;Time;Translating;Treatment Efficacy;Universities;acute myeloid leukemia cell;analog;antileukemic activity;cancer cell;cancer type;cytotoxic;experimental group;experimental study;human model;humanized mouse;immunogenicity;in vivo;in vivo Model;inhibiting antibody;leukemia;leukemic stem cell;mRNA Expression;monocyte;mouse model;novel;pre-clinical;protein expression;receptor;response;synergism Promoting immunity against acute myeloid leukemia through Fc effector-optimized antibody inhibitory of MICA/B shedding PROJECT NARRATIVEAcute myeloid leukemia (AML) is a blood cancer that often generates poor clinical outcomes whereas antibody-mediated inhibition of MICA/B shedding is a new means of promoting immunity against a variety of cancers andthat now has entered into clinical phase. Here we show that the first-of-its-kind inhibitory antibody of MICA/Bshedding induces Fc receptor-driven immunity against AML in pre-clinical models and now we modified it todisplay higher affinity to Fc activating receptors while maintaining the low affinity to inhibitory receptor. Wepropose to establish the anti-AML activity of this new molecule thus generating important information about howto induce protective immunity against AML and supporting clinical transition with the best version of suchMICA/B-targeted antibody. NCI 10778600 11/28/23 0:00 PA-20-185 5R37CA269982-02 5 R37 CA 269982 2 "SOMMERS, CONNIE L" 2/6/23 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-OTC-S(09)F] 14132186 "FERRARI DE ANDRADE, LUCAS " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 443557 NCI 262460 181097 SUMMARYAcute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized bypoor clinical outcomes. Malignant transformation triggers expression of surface proteins that serve as dangersignals such as MICA and MICB (MICA/B) that are commonly expressed by leukemia cells in response tocellular stress pathways. Natural killer (NK) cells and cytotoxic T lymphocytes recognize MICA/B with the NKG2Dreceptor which in turn induces cytotoxic functions against leukemia cells. However they often escaperecognition by shedding MICA/B via an intriguing post-translational modification called proteolytic cleavage. Inprevious and revolutionary study we developed a series of MICA/B-targeted monoclonal antibodies that inhibitthe shedding of MICA/B by blocking the extracellular domain that undergoes an unfolding by disulfide isomerasewhich enables subsequent cleavage by metalloproteases. One of them was further characterized and itpromotes NK cell-mediated immunity against solid tumors by dual signaling of NKG2D and Fc receptors.Recently we discovered that the antibody also promotes macrophage-driven immunity in AML models byenabling antibody-dependent phagocytosis of leukemia cells in the blood and bone marrow. In this settingMICA/B serve as leukemia antigens for Fc receptor-driven immunity although contributions by NKG2D NKcells and T cells were also detected. Now we developed a new version of this antibody with three pointmutations in the Fc domain to increase the binding affinity to all three Fc activating receptors while maintaininglow affinity to the Fc inhibitory receptor. This new version is humanized and induces potent NK cell effectorfunctions against human AML cells compared to the humanized wild type version. We also established mousemodels of human Fc receptor biology and both murine and human AML models to establish the anti-leukemiaactivity of our now enhanced molecule in vivo. Furthermore we propose a mechanism-driven drug combinationregimen whereby a histone deacetylase inhibitor (romidepsin) induces human leukemia cells to express MICA/BmRNAs that are then translated to MICA/B proteins which are followed by stabilization on cellular surface byour antibody that inhibits the shedding. We propose that immunotherapy for AML can be achieved via this drugcombination which increases the innate immunogenicity of leukemia cells. For these reasons our studies willgenerate important information about how to induce protective immunity against AML. Antibody-mediatedinhibition of MICA/B shedding is a new immunotherapeutic opportunity pioneered by us and now validatedindependently by multiple pharmaceutical companies one of which has recently began phase-I clinical trialtesting an antibody analog to ours but the wild type version in patients with advanced solid tumors. Thereforeour studies will generate compelling rationale to test MICA/B-targeted antibodies in AML trials by pharmaceuticalcompanies ourselves in academia or both by working in collaboration. 443557 +No NIH Category available Actins;Adhesions;Albumins;Antibodies;Apoptosis;Apoptotic;B lymphoid malignancy;Binding;CD20 Antigens;Calcium;Caspase;Cell Separation;Cell surface;Cells;Cessation of life;Chlorambucil;Chronic Lymphocytic Leukemia;Clinical;Combined Modality Therapy;Complex;Cyclophosphamide;Cytoskeleton;Diagnosis;Diffuse Large-Cell Lymphoma;Disease;Disease Resistance;Doxorubicin;Ensure;Evaluation;Exposure to;FDA approved;Female;Follicular Lymphoma;Generations;Genes;Goals;Half-Life;Heavy-Chain Immunoglobulins;Human;In Vitro;Induction of Apoptosis;Length;Lymphoma;Lymphoma cell;Lysosomes;MS4A1 gene;Mantle Cell Lymphoma;Mediating;Membrane Microdomains;Modeling;Modification;Molecular Conformation;Nanoconjugate;Non-Hodgkin's Lymphoma;Oligonucleotides;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Prednisone;Recurrent disease;Relapse;Resistance;Sampling;Serum Albumin;Somatic Mutation;Structure;System;Testing;Therapeutic;Time;Treatment Efficacy;Vertebral column;Vincristine;anti-CD20;chemotherapeutic agent;chemotherapy;crosslink;design;disulfide bond;drug efficacy;flexibility;genetic predictors;improved;in vivo;in vivo evaluation;indexing;large cell Diffuse non-Hodgkin's lymphoma;macromolecule;male;mutational status;neonatal Fc receptor;novel;novel drug class;novel strategies;novel therapeutics;patient subsets;prognostic;receptor;response;rituximab;thioether;tositumomab;translational potential;treatment strategy;tumor Drug-Free Macromolecular Therapeutics NARRATIVEThe proposal presents a new paradigm for apoptosis induction based on morpholino oligonucleotidehybridization at the cell surface. This novel approach will be developed into a new class of drug-freemacromolecular therapeutics suitable for the treatment of various B cell malignancies. NCI 10778533 11/15/23 0:00 PA-19-056 5R01CA246716-13 5 R01 CA 246716 13 "FU, YALI" 7/1/11 0:00 11/30/24 0:00 Nanotechnology Study Section[NANO] 1863659 "KOPECEK, JINDRICH H." Not Applicable 1 BIOMEDICAL ENGINEERING 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT BIOMED ENGR/COL ENGR/ENGR STA 841129049 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 313959 NCI 205875 108084 Rituximab (RTX) and other anti-CD20 antibodies (ofatumumab and obinutuzumab (OBN)) dramaticallyimproved treatment of Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Alone or incombination with chemotherapy (e.g. R-CHOP a combination with cyclophosphamide doxorubicinvincristine and prednisone) they produced better clinical outcomes. However relapses frequently occur withpoor patient outcomes. In 2017 in the USA there were an estimated 72240 new cases of NHL and 20140deaths 20110 new cased of CLL and 4660 deaths in both males and females. This demonstrates the needfor improved treatment strategies. The goal of the proposed studies is to design synthesize and evaluate thesecond generation of drug-free macromolecular therapeutics (DFMT) for the treatment of B-cell malignancies.Anti-CD20 antibodies are divided into Type I such as RTX and Type II such as OBN; they have differentpatterns of binding to CD20 receptor. RTX binds between CD20 tetramers resulting in accumulation in lipidrafts calcium influx and caspase activation. OBN binds within one tetramer with the conformation compatiblewith homotypic adhesion regions leading to actin cytoskeleton remodeling and lysosome disruption. Ourdesign enhances the activity of Type II OBN by triggering the apoptosis activation pathways of both types ofantibodies. This new system is composed of two nanoconjugates: a) bispecific engager OBN-MORF1 (OBNconjugated to one morpholino oligonucleotide MORF1); and b) a crosslinking (effector) component HSA-(MORF2)X (human serum albumin (HSA) grafted with multiple copies of complementary morpholinooligonucleotide 2). Modification of OBN with one MORF1 does not impact the binding of OBN-MORF1 toCD20 and following binding to CD20 Type II effects occur. Further exposure to multivalent effector HSA-(MORF2)X results in clustering the OBN-MORF1-CD20 complexes into lipid rafts and Type I effects occur.This new approach called clustered OBN (cOBN) combines effects of both antibody types resulting in veryhigh apoptotic levels. In the bispecific engager MORF1 will be attached to OBN via thioether bond followingreduction of OBN's disulfide bonds. The structure of the multivalent crosslinking effector HSA-(MORF2)x willbe optimized to ensure the highest efficiency of the cOBN system on disseminated models of NHL. Recentlycombination of OBN with chlorambucil was FDA approved. We have shown that HSA-based DFMT sensitizesNHL cells to different chemotherapeutic agents. Thus we plan to evaluate the impact of combining cOBN withchemotherapeutics on the mechanism and efficiency of apoptosis induction. Finally we demonstratedefficacy of DFMT on resistant lymphomas and cells isolated from patients diagnosed with various subtypes ofB cell malignancies. We shall identify subsets of patients that respond favorably to our new therapeutics. Insummary this proposal is scientifically novel and has great translational potential. Also it provides a newparadigm for the design of macromolecular therapeutics applicable to other diseases beyond lymphomas. 313959 +No NIH Category available 6-Phosphofructokinase;Apoptosis;Apoptosis Regulation Gene;Automobile Driving;BCL2 gene;Binding;Biochemical;Carcinoma;Catabolism;Cell Compartmentation;Cell Death;Cell Proliferation;Cells;Clinical Trials;Coupled;Coupling;Cyclin D1;Data;Disease;Disparate;Down-Regulation;Drug Targeting;Enzymes;Fibroblasts;Fructose;Future;Genes;Genetic Epistasis;Glucose;Glycolysis;Glycolysis Induction;Growth;HIF1A gene;Human;IL6 gene;In Vitro;Inflammation;Inflammatory;Knowledge;Link;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Mus;NF-kappa B;Outcome;Oxidation-Reduction;Oxidative Phosphorylation;Oxidative Stress;Pathway interactions;Pentosephosphate Pathway;Prognostic Marker;Proliferating;Public Health;Resistance;Role;Sampling;Signal Transduction;Stromal Cells;TGFB1 gene;TP53 gene;Testing;Therapeutic;Transforming Growth Factor beta;Tumor Promotion;Variant;cancer cell;carcinogenesis;caveolin 1;ductal breast carcinoma;experimental study;in vivo;infiltrating duct carcinoma;knock-down;metabolic abnormality assessment;mitochondrial fitness;neoplastic cell;novel;novel therapeutics;outcome prediction;overexpression;patient subsets;predictive marker;sound;tumor;tumor growth;tumor metabolism;tumor microenvironment;uptake Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast Project NarrativeInvasive ductal carcinoma of the breast (IDC) is very common and is associated with poor outcomes makingthis disease a major public health issue. We propose to study the metabolic interactions between different cellsin these tumors to determine if this drives aggressive cancer. The discovery of new metabolic mechanisms thatpromote aggressive disease may enable us to better predict outcomes and how to overcome this with targeteddrugs. NCI 10778529 12/1/23 0:00 PA-19-056 5R37CA234239-05 5 R37 CA 234239 5 "MERCER, NATALIA" 12/11/19 0:00 11/30/24 0:00 Tumor Microenvironment Study Section[TME] 10656585 "MARTINEZ OUTSCHOORN, UBALDO " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 321165 NCI 205875 115290 Project Summary/Abstract:Outcomes in breast invasive ductal carcinoma (IDC) are poor. Our project focuses on the role of metabolicabnormalities driving aggressive cancer and how inflammation and oxidative stress regulate IDCaggressiveness via altered metabolism. Tumor cells in IDC frequently use one of two metabolic pathways:glycolysis with glucose catabolism to lactate and mitochondrial oxidative phosphorylation (OXPHOS). Alteredmetabolism with coupling based on release and uptake of metabolites between different cells in the tumormicroenvironment is a feature of IDC. However it is not known if metabolic coupling induces canceraggressiveness. Targeting tumor metabolism may also be an effective way of treating IDC and allow us todevelop new prognostic and predictive biomarkers. Multiple metabolic compartments are linked viainflammation glycolysis and shuttles of lactate. Fibroblasts which are the most common non-cancer cells inIDC tumors have low OXPHOS high glycolysis high expression of lactate exporters and high oxidativestress. Conversely the carcinoma cells have high expression of transporters involved in the uptake of lactatehigh OXPHOS and low glycolysis. We have identified high TP53 Induced Glycolysis and Apoptosis Regulator(TIGAR) in IDC carcinoma cells as a driver of tumor microenvironment metabolic coupling. TIGAR reducesglycolytic flux as a fructose-26 bisphosphatase enzyme. Phospho-fructo-kinase 1 (PFK1) activity which is arate limiting step in glycolysis is positively allosterically regulated by fructose 26 bisphosphate (Fru-26-P2).Hence TIGAR reduces glycolytic flux via reduced PFK1 activity. Our overall hypothesis is that tumormicroenvironment metabolic coupling induced by TIGAR is sufficient to induce carcinoma cellproliferation and resistance to cell death and that tumor microenvironment metabolic uncoupling willovercome tumor aggressiveness. We aim to use this knowledge on tumor microenvironment metaboliccoupling to discover metabolic mechanisms of IDC aggressiveness. In Aim 1 we will test the hypothesis thatmetabolic coupling induced by TIGAR is sufficient to promote aggressive IDC. In Aim 2 we will test thehypothesis that inflammatory signaling is a driver of TIGAR-induced metabolic coupling andaggressiveness. Finally in Aim 3 we will test the hypothesis that oxidative stress is a driver of TIGAR-induced metabolic coupling and aggressiveness. In summary understanding how metabolic interactionsbetween different cells in IDC tumors drive aggressiveness may provide opportunities to develop noveltherapeutics for IDC. 321165 +No NIH Category available ARID1A gene;ATP Hydrolysis;Affect;Antigen Presentation;Antigen Presentation Pathway;Automobile Driving;Back;Biological Process;Biology;CDKN2A gene;CRISPR/Cas technology;Cancer Patient;Cancer cell line;Cells;Chromatin;Chromatin Remodeling Factor;Clinical;Clinical Trials;Cytoplasm;Cytosol;Cytotoxic T-Lymphocytes;DNA;DNA biosynthesis;Defect;Endosomes;Enzymes;Excision;Exhibits;Failure;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Markers;Goals;Homeostasis;Human;Hybrids;IFNAR1 gene;Immune system;Immunologic Markers;Immunoprecipitation;Immunotherapy;Individual;Inflammatory;Inflammatory Response;Interferon Type I;Interferons;Ligands;Lymphocytic Infiltrate;Malignant Neoplasms;Measures;Mediating;Microsatellite Repeats;Modeling;Molecular;Molecular Profiling;Mus;Mutate;Mutation;Nuclear;Nucleic Acids;Nucleosomes;Outcome;Pathway interactions;Patient Selection;Patients;Pattern recognition receptor;Poly(ADP-ribose) Polymerase Inhibitor;RNA;Retrospective Studies;Role;SWI/SNF Family Complex;Signal Transduction;Single-Stranded DNA;Solid Neoplasm;T-Cell Activation;T-Lymphocyte;TLR3 gene;TP53 gene;TREX1 gene;Testing;Tumor Immunity;Tumor Suppressor Proteins;Work;anti-tumor immune response;cancer biomarkers;cancer cell;cancer immunotherapy;cancer therapy;cancer type;cell killing;chemokine;combat;effective therapy;endonuclease;genetic signature;immune cell infiltrate;immune checkpoint blockade;improved;in vivo;inhibitor;knock-down;molecular marker;mouse model;mutant;neoplastic cell;overexpression;patient response;pharmacologic;pre-clinical;prevent;programs;receptor;replication stress;response;small molecule inhibitor;transcriptomics;translational impact;treatment response;tumor;tumor growth;tumor-immune system interactions The Role of the Tumor Suppressor ARID1A in R loop Homeostasis and Tumor Immunity PROJECT NARRATIVEWhile immune checkpoint blockade is an effective cancer treatment many individuals do not respond. Patientswith a mutation in the ARID1A gene respond better to immune checkpoint blockade indicating that ARID1Amay be a biomarker for immune checkpoint blockade therapy. ARID1A mutation results in DNA replicationstress in the form of R loops which may drive heightened anti-tumor immunity and immune checkpointblockade responsiveness through activation of an inflammatory response. NCI 10778116 12/26/23 0:00 PA-20-185 1R01CA285867-01 1 R01 CA 285867 1 "CARDONE, MARCO" 1/1/24 0:00 12/31/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 10320457 "HARGREAVES, DIANA CLARE" Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 596336 NCI 351024 245312 PROJECT SUMMARYCancer immunotherapy is the practice of harnessing the activity of the immune system to combat cancer.Immune checkpoint blockade (ICB) is a type of cancer immunotherapy that unleashes the activity of cytotoxic Tcells by blocking the interaction of inhibitory receptors on T cells with ligands expressed on tumor cells. ICBhas been an effective treatment for many resulting in durable even curative anti-tumor immune responses.However in most cancer types less than 50% of patients respond spurring efforts to understand genetic andmolecular signatures associated with ICB response as well as therapies that can be used in combination toimprove ICB efficacy. Retrospective studies have shown that mutations in the ARID1A gene are enrichedamong patients that respond to ICB in pan-cancer and cancer type specific trials. ARID1A is a subunit of theSWI/SNF chromatin remodeling complex which utilizes energy derived from ATP hydrolysis to movenucleosomes along DNA. Genes encoding subunits of the SWI/SNF complex are frequently mutated in humancancer with ARID1A being the most frequently mutated subunit and the third most commonly mutated tumorsuppressor behind TP53 and CDKN2A. ARID1A mutation could thus serve as an important biomarker forcancer immunotherapy potentially affecting treatment of hundreds of thousands of cancer patients.It is not known whether ARID1A mutation is causal or how ARID1A mutation sensitizes tumors to ICBtreatment. Indeed ARID1A mutation is commonly found in microsatellite unstable (MSI) or tumor mutationburden-high (TMB-high) tumors which are themselves independent predictors of ICB responsiveness.However ARID1A mutation is beneficial independent of MSI and TMB status and additive for patients with MSIor TMB-high tumors. It was found that Arid1a mutant tumors grow more slowly than isogenic wild-type lines inmurine models with increased immune infiltration and T cell activation. Further Arid1a mutant cancer cellsupregulate a subset of genes in the Type I Interferon response including chemokines and antigen presentationand processing genes. Mechanistically genetic or pharmacologic inhibition of ARID1A results in increased Rloops as well as cytoplasmic accumulation of RNA:DNA hybrids and ssDNA. This proposal will utilize geneticdeletion and small molecule inhibitors of ARID1A to determine 1) how ARID1A deficiency causes cytosolicnucleic acid release 2) the pathway by which inflammatory genes are activated in ARID1A deficient cells 3)the role of R loop driven inflammatory responses in ARID1A mutant anti-tumor immunity and ICB response.This will be accomplished using ARID1A mutant human cancer cell lines and mouse models of Arid1a mutantcancer. Finally studies pioneering the in vivo use of small molecule inhibitors of ARID1A in combination withICB will be performed. These studies will reveal the molecular mechanism by which ARID1A mutant cancersrespond to ICB with the potential to improve patient selection for ICB and to augment ICB efficacy with ARID1Ainhibitors. 596336 +No NIH Category available ASCL1 gene;Adrenergic Agents;Age;Antibodies;Applications Grants;Categories;Cell Death;Cessation of life;Child;Childhood;Clinic;Clinical;Clinical Trials;Combined Modality Therapy;Complex;Data;Disease;Down-Regulation;Drug Targeting;Genetic Transcription;Genomics;Goals;Grant;Hypersensitivity;Immunotherapy;In Vitro;MYCN gene;Maintenance Therapy;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Modeling;Mutation;NK Cell Activation;Natural Killer Cells;Neuroblastoma;Oncogenic;Pathway interactions;Patient-Focused Outcomes;Patients;Pediatric Neoplasm;Pharmacologic Substance;Phosphotransferases;Proteomics;Relapse;Research Design;Research Personnel;Retinoids;Safety;Series;Sumoylation Pathway;Surface;Testing;Therapeutic;Time;Toxic effect;Tretinoin;addiction;clinically actionable;combat;disorder risk;effective therapy;efficacy testing;high risk;improved outcome;in vivo;inhibitor;mouse model;neuroblastoma cell;novel;novel therapeutics;participant enrollment;patient derived xenograft model;pre-clinical;preclinical study;programs;research clinical testing;transcription factor;transcriptome;tumor;weapons MYCN drives a druggable SUMOylation program in neuroblastoma Project NarrativeDespite being rare MYCN-amplified neuroblastoma (NB) accounts for ~7% of all pediatric cancer relateddeaths and is driven by the oncogenic transcription factor MYCN and a MYCN-directed adrenergic (ADRN)core regulatory complex (CRC) of self-regulating and inter-regulated transcription factors that drive the MYCN-amplified NB transcriptome. In this proposal we demonstrate MYCN drives a SUMOylation program in NB andMYCN confers synthetic lethality to the in-clinic SUMOylation inhibitor TAK-981. TAK-981 disrupts the ADRNCRC only in the presence of MYCN to induce ADRN CRC collapse and cell death and thus represents anexciting new therapy for this recalcitrant pediatric tumor. NCI 10777626 12/27/23 0:00 PA-20-185 1R01CA285692-01 1 R01 CA 285692 1 "FORRY, SUZANNE L" 1/1/24 0:00 12/31/28 0:00 Mechanisms of Cancer Therapeutics A Study Section[MCTA] 10310162 "FABER, ANTHONY CHARLES" Not Applicable 4 DENTISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF DENTISTRY/ORAL HYGN 232980568 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 434312 NCI 279750 154562 Project Summary: High-risk neuroblastoma (NB) is responsible for ~15% of pediatric cancer-related deathswith nearly half of these characterized by MYCN amplification. The addition of anti-GD2 antibodies andretinoids to maintenance therapy has improved the outcomes of these patients but still more than 50% perish.Omics studies in NB tumors has revealed that most NBs are driven by an adrenergic (ADRN) core regulatorycomplex (CRC) of transcription factors that can be driven by MYCN and includes GATA-3 TBX2 HAND2PHOX2B ISL1 and ASCL1. Genomically targeting the CRCs has been demonstrated to be highly effectivehowever a pharmaceutical way to target the CRCs and in particular one that would be tolerated by the patienthas not been developed. Here we demonstrate a remarkable therapeutic vulnerability of MYCN-amplified NBto SUMOylation inhibition. We provide evidence that toxicity involves disruption of the ADRN CRC whichrequires the presence of MYCN. This pathway has become actionable with the advent of the SUMOylationinhibitor TAK-981 (Subasumstat) now in multiple clinical trials. Thus we propose we have uncovered anADRN CRC inhibition strategy that is effective in MYCN-amplified NB suggesting a real therapeutic window.Specific AimsSpecific Aim 1: Test a diverse set of well-annotated high-risk patient-derived xenograft (PDX) models forefficacy and safety of SUMOylation inhibition in neuroblastoma alone and combined with maintenance therapySpecific Aim 2: Investigate the mechanism of adrenergic (ADRN) core regulatory complex (CRC) disruptionfollowing SUMOylation targetingStudy Design: We will further characterize the high sensitivity of TAK-981 in high-risk MYCN-amplified NBpatient-derived xenograft (PDX) models either alone or in combination with the anti-GD2 therapy dinutuximab.Through a series of genomic and proteomic studies we will further categorize the mechanism of sensitivity toSUMOylation inhibition. As TAK-981 induces NK cell activation it is a rational inducing partner with the anti-GD2 immunotherapy dinutuximab. We will also investigate this combination in NB mouse models. In all wewill attempt to gather the preclinical evidence that TAK-981 should be clinically evaluated in MYCN-amplifiedNB patients. 434312 +No NIH Category available Ablation;Address;Adoptive Transfer;Agonist;Algorithms;Anti-CD40;Antibodies;Antigen-Presenting Cells;Antigens;B-Lymphocytes;Biological Process;Biology;Blood;CD44 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cancer cell line;Cell Differentiation process;Cell Line;Cell Lineage;Cell physiology;Cells;Cellular Immunity;Chimeric Proteins;Chronic;Collaborations;Complement;Data;Development;Fc Receptor;Fibroblasts;Flow Cytometry;Fourier Transform;Frequencies;Generations;Genes;Genetic;Genomics;Graph;Helper-Inducer T-Lymphocyte;High Endothelial Venule;Human;Immune;Immunity;Immunofluorescence Immunologic;Immunologic Memory;Immunologics;Immunotherapy;In Situ;KRAS oncogenesis;Knockout Mice;LoxP-flanked allele;Luciferases;Lymphatic;Maintenance;Malignant Neoplasms;Mediating;Memory;Methods;Modeling;Molecular;Mus;Mutation;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Peripheral;Phenotype;Primary Neoplasm;Publishing;Reaction;Reporter;Reporting;Research;Resected;Residencies;Resistance;Role;SELL gene;SIYRYYGL;Sampling;Signal Transduction;Solid Neoplasm;Spleen;Structure of germinal center of lymph node;T cell differentiation;T cell response;T memory cell;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;TP53 gene;Testing;Time;Tissues;Transgenic Mice;Translating;Tumor Antigens;Tumor Immunity;Tumor Promotion;Work;anti-PD-1;cancer type;chronic infection;computer framework;design;draining lymph node;driver mutation;effector T cell;genetic signature;immune activation;immune checkpoint blockade;immune function;immunoreaction;implantation;improved;innovation;insight;interleukin-21;interleukin-21 receptor;lymph nodes;lymphotoxin beta receptor;mouse model;multidisciplinary;mutant;neoantigens;novel;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;permissiveness;pre-clinical;predicting response;prognostic;prognostic of survival;programmed cell death protein 1;response;stem;tertiary lymphoid organ;tissue biomarkers;transcriptomics;tumor;tumor growth;tumor microenvironment;tumorigenesis ROLES AND MECHANISMS OF TERTIARY LYMPHOID STRUCTURES IN ANTI-TUMOR IMMUNITY PROJECT NARRATIVEThe presence of tertiary lymphoid structures (TLS) in solid tumors is prognostic for survival in cancer patientsincluding pancreatic ductal adenocarcinoma associated with the expression of MHCI-neoantigens and markersof enhanced immune memory. However there is no evidence that TLS directly augment tumor specific T cellimmunity or the mechanisms of how this occurs. We hypothesize that TLS in pancreatic tumors promote thedifferentiation of stem-like T cells through IL-21 programming thereby enhancing effector T cell responsesleading to improved tumor control. NCI 10777149 1/1/24 0:00 PA-20-185 1R01CA286017-01 1 R01 CA 286017 1 "LIU, YIN" 1/1/24 0:00 12/31/28 0:00 Special Emphasis Panel[ZRG1-BTC-Q(80)S] 11640730 "GUNDERSON, ANDREW " Not Applicable 3 SURGERY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 404798 NCI 270649 134149 PROJECT SUMMARYTertiary lymphoid structures (TLS) are T and B lymphocytes in aggregation with antigen presenting cellsfibroblasts and high endothelial venules observed in some chronically inflamed tissues. TLS formation in tumorsof cancer patients is associated with improved adaptive immune function and increased overall survival. Insurgically resected human pancreatic ductal adenocarcinoma (PDAC) a significant proportion of patients formspontaneous TLS in their primary tumors. Other groups have demonstrated similar findings but no evidencecurrently exists showing TLS directly influence T cell immunity. In this application we propose to investigate ifTLS enhance T cell immunity in the context of PDAC tumorigenesis and the mechanism of how this occurs. Ourpreliminary data in TLS+ mouse and human PDAC tumors shows TCF1+ stem-like T cells (T-stem) are enrichedspecifically within TLS relative to the surrounding tumor and stroma. We posit that TLS in PDAC tumors supportthe development of stem-like T cell phenotypes (T-stem) dependent on interleukin-21 signaling. These uniqueT cell subsets have previously been shown to sustain cellular immunity during chronic infection and cancerproviding continual repletion of memory effector and terminally differentiated cells following antigenic recall orimmune checkpoint blockade treatment. We model this biology using a panel of mouse PDAC cell lines derivedfrom transgenic mouse tumors that conditionally express mutant KRas and p53 the most common drivermutations in PDAC and encode for a model MHCI-restricted antigen to track tumor antigen-specific responses.These cancer cell lines despite sharing a similar genetic and mutational background induce tumors with uniquephenotypes and heterogenous tumor microenvironments. We will deploy a novel method to induce TLS in thesemouse tumors through lymphotoxin beta receptor (LTBR) agonism whereby some of our mouse tumor lines arepermissive for TLS formation and others are resistant. We will test if the TLS-mediated generation of T-stem isresponsible for improved tumor control in CD8 conditional TCF1-knockout mice. We will determine if theirenrichment in TLS is due to IL-21 signals derived directly from TLS that promote their formation independent oflymphatic involvement utilizing a combination of cell lineage tracing and genetically modified mouse models.We will complement these studies by investigating tumor samples from PDAC patients for phenotypic pathwaysunique to specific regions of these tumors. We will achieve this by performing spatial transcriptomics on humanPDAC tumor sections analyzed by an innovative algorithm that transforms spatial variable genes into functionaltissue modules to determine region-specific immune phenotypes localized to the TLS compared to non-TLSregions and tumors without TLS. This approach identifies the mechanism of how TLS supports T cell function inauthentic mouse models of TLS+ PDAC and translates these findings to human cancer patients so novelimmunotherapy options designed to elicit and activate TLS can be offered to patients with a treatment resistantmalignancy. 404798 +No NIH Category available Aberrant DNA Methylation;Acute Myelocytic Leukemia;Applications Grants;Azacitidine;Base Pairing;Basic Science;Biochemical;Biological Assay;Breast Epithelial Cells;Cancer Center;Cancer Patient;Cancer cell line;Catalytic Domain;Cell Death Induction;Cell Line;Chemicals;Chromatin Structure;Chronic Myelomonocytic Leukemia;Collaborations;Complex;CpG dinucleotide;Crystallization;Cytidine;Cytosine;DNA;DNA Binding;DNA Damage;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Modification Methylases;DNA biosynthesis;DNMT3B gene;DNMT3a;Dacogen;Data;Decitabine;Deoxycytidine;Development;Disease;Dysmyelopoietic Syndromes;Embryo;Enzymes;Epigenetic Process;Exhibits;FDA approved;Family;Fibroblasts;Follow-Up Studies;Gene Expression;Gene Silencing;Goals;Health;Hematologic Neoplasms;Human;Hypermethylation;Knockout Mice;Knowledge;Laboratories;Lead;Maintenance;Malignant Neoplasms;Mediating;Methylation;Methyltransferase;Mission;Modification;Mus;Mutation;Oncogenic;Pattern;Proliferating;Public Health;Regulation;Reporting;Research;Solid Neoplasm;System;Testing;Therapeutic;Toxic effect;Transfection;Tumor Suppressor Genes;United States National Institutes of Health;Vidaza;Work;analog;anti-cancer;biophysical properties;cancer cell;cancer therapy;cell growth;chemical group;cytotoxicity;demethylation;design;embryonic stem cell;human DNA;improved;in vitro activity;inhibitor;intercalation;mammalian genome;methylation pattern;novel;nucleoside analog;preclinical study;public health relevance;quinoline Preclinical studies of non-nucleoside DNMT3A/3B inhibitors PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because inhibitors ofhuman DNA methyltransferases (DNMT3A/3B) have therapeutic potential for cancer and other diseases.Thus the proposed research is relevant to the part of NIHs mission that pertains to developing fundamentalknowledge for ultimately protecting and improving health. NCI 10776264 12/26/23 0:00 PAR-22-216 1R21CA277152-01A1 1 R21 CA 277152 1 A1 "GREENBERG, WILLIAM A" 12/19/23 0:00 11/30/25 0:00 ZCA1-TCRB-V(O1)S 1896477 "CHENG, XIAODONG " "CHEN, TAIPING " 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 12/19/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 227205 NCI 140250 86955 PROJECT SUMMARY/ABSTRACTDNA cytosine methylation yielding 5-methylcytosine (5mC) is a major epigenetic modification involved in theregulation of chromatin structure and gene expression. Mammalian DNA methylation is catalyzed by three DNAmethyltransferases (DNMTs) belonging to two structurally and functionally distinct families. DNMT3A andDNMT3B establish the initial cytosine methylation pattern whereas DNMT1 maintains that pattern on newlyreplicated DNA. Cancer cells exhibit aberrant DNA methylation patterns including global hypomethylation whichis associated with low maintenance efficiency and regional hypermethylation which is mainly due to abnormalde novo methylation and/or deficient demethylation. Although the demethylating agents 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) have been approved by FDA for treating some hematological malignanciesthese nucleoside analogs incorporate into DNA leading to substantial DNA damage and cellular toxicity andare ineffective in treating solid tumors. Recently GlaxoSmithKline (GSK) reported the discovery of a new classof dicyanopyridine-containing DNMT1-selective inhibitors with therapeutic potential. The long-term goal of thisresearch is to develop a highly potent and selective non-nucleoside DNMT3A/3B inhibitor for cancer treatment.The objective of this 2-year exploratory project is to identify one or more promising leads for further development.The rationale is that remedying hypermethylation by inhibiting DNMT3A/3B would reactivate abnormally silencedgenes including tumor suppressor genes and thus provide therapeutic benefits for cancer patients. Theproposal is based on preliminary data generated in the applicants laboratories showing that somedicyanopyridine-containing derivatives and quinoline-based derivatives can selectively inhibit DNMT3A/3B. Theapplicants propose to perform biochemical and structural studies to improve the potency and selectivity ofDNMT3A/3B inhibitors (Aim 1); and validate the compounds for their potency and selectivity using wild-type andDNMT-deficient mouse embryonic stem cells (mESCs) determine their anti-cancer effects using cancer cell lineswith or without mutations in components of the DNA methylation and demethylation enzymes (DNMT3A TET2and IDH1/2) and assess their cytotoxicity using untransformed cell lines (Aim 2). The potential impact ofidentifying non-nucleoside DNMT3A/3B inhibitors is likely to be very substantial.. 227205 +No NIH Category available Adjuvant;Adjuvant Therapy;Animals;Arginine;Arginine decarboxylase;Breast;Breast Cancer Cell;Breast Cancer Prevention;Clinical Trials;Drug resistance;ERBB2 gene;Enzymes;FDA approved;Future;Glycine;Goals;Growth;Human;Immune;Immunosuppression;Immunotherapy;Incidence;Ligands;Macrophage;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Measures;Mediating;Metabolic Diseases;Metabolic Pathway;Metabolism;Methods;Mus;Nature;Nitric Oxide Synthase;Ornithine Carbamoyltransferase;Ornithine Decarboxylase;Outcome;Pathway interactions;Phenylketonurias;Polyamine Synthesis Inhibition;Polyamines;Prevention;Production;Public Health;Reaction;Refractory;Reporting;Safety;Shunt Device;Testing;Time;Tumor Promotion;Tumor Suppression;Tumor-associated macrophages;Work;antitumor effect;arginase;argininosuccinate lyase;argininosuccinate synthase;cancer cell;cancer immunotherapy;cancer type;cell growth;cofactor;efficacy evaluation;immunogenicity;improved;innovation;malignant breast neoplasm;mouse model;neoplastic cell;novel;prevent;programmed cell death ligand 1;sepiapterin;side effect;systemic toxicity;tetrahydrobiopterin;translational impact;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Normalizing arginine metabolism with sepiaptein for immunostimulatory-shift ofHER2+ breast cancer PROJECT NARRATIVEIn cancer arginine metabolism is often shunted into the pathways that produce polyamines essential for cellgrowth and immuno-suppression; however there is a critical gap in developing a method to correct argininemetabolism to suppress cancer growth. The proposed project aims to test whether sepiapterin the naturally-occurring precursor of nitric oxide synthase (NOS) cofactor BH4 could normalize arginine metabolism toprevent breast cancer formation or enhance the efficacy of immunotherapy for breast cancer. The proposedproject is relevant to public health because it will justify the use of sepiapterin as an adjuvant to immunotherapyor preventative agent for breast cancer. NCI 10776256 3/8/23 0:00 PA-21-268 7R01CA248304-04 7 R01 CA 248304 4 "MALONE, WINFRED F" 3/1/23 0:00 2/28/25 0:00 Special Emphasis Panel[ZRG1-OTC-Y(55)R] 10261695 "FURUTA, SAORI " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 393 Non-SBIR/STTR 2023 360922 NCI 224175 136747 In cancer cells and the tumor microenvironment arginine metabolism is often shunted into the pathways thatproduce polyamines small polycationic metabolites essential for cell growth and immuno-suppression. Suchmechanisms in part account for the refractoriness of certain types of cancers including breast cancer toimmunotherapy. However there is a critical gap in developing a method to correct arginine metabolism toimprove the immunogenicity of breast cancer. The long-term goal of our project is to develop an adjuvanttreatment to improve breast cancer immunotherapy with little side effects. Specifically the objective of thisstudy is to test whether sepiapterin the naturally-occurring precursor of nitric oxide synthase (NOS) cofactorBH4 could normalize arginine metabolism in the breast to prevent cancer formation or enhance the efficacy ofbreast cancer immunotherapy. Our central hypothesis is that sepiapterin shunts arginine metabolism into thepathways for NO synthesis in breast cancer cells and tumor-associated macrophages (TAMs). Such shiftsreduce polyamine production suppress tumor growth and immuno-suppressive mechanisms. This improvesthe efficacy of cancer immunotherapy with little systemic toxicity. Our hypothesis is based on the results of ourand others previous studies. The two major arginine metabolic pathways NO production vs. polyaminesynthesis antagonize each other. Consistently we found that sepiapterin elevates NO synthesis and inhibitsgrowth-stimulatory and immune-suppressive molecules such as polyamines while converting TAMs from M2(immuno-suppressive) to M1 (immuno-stimulatory) types within tumors. Besides sepiapterin has been safelyutilized in humans and animals to treat certain metabolic disorders. The rationale is that this study will helpdevelop a novel method to normalize arginine metabolism and improve the immunogenicity of breast cancer.Our hypothesis will be tested through two SPECIFIC AIMS: 1) Determine whether sepiapterin normalizesarginine metabolism in mammary tumor cells and tumor microenvironment Determine the efficacy andsafety of sepiapterin for the treatment and prevention of HER2-positive mammary tumor. In Aim 1 breastcancer cells TAMs and mammary tumors are treated with sepiapterin in culture and their metabolites and therespective enzymes are measured. In Aim 2 mice bearing or prone to HER2-positive mammary tumors aretreated with sepiapterin and tested for the inhibition or prevention of tumor growth. The proposed study isinnovative because it tests for the first time whether sepiapterin the naturally produced precursor of the NOS; and 2)cofactor could normalize arginine metabolism improve the immunogenicity of breast cancer to inhibit thegrowth or prevent breast cancer formation. The study is significant because it will have a positive translationalimpact by justifying the use of sepiapterin as an adjuvant to breast cancer immunotherapy or a preventativeagent for breast cancer. Given that there is currently no FDA-approved immunotherapy for HER2-positivebreast cancer successful results of this study will warrant future clinical trials. 360922 +No NIH Category available 13q;Adjuvant Chemotherapy;Affect;Aromatase Inhibitors;Biological;Breast Cancer Model;Breast Cancer Patient;Bypass;CDK2 gene;CDK4 gene;Cell Cycle;Cell Cycle Arrest;Cell Cycle Deregulation;Cell Cycle Progression;Cell Cycle Regulation;Cell model;Cessation of life;Clinic;Clinical;Complex;Critical Pathways;Cytostatics;Data;Disease;Disease Progression;Estrogen Antagonists;Estrogen Receptor Status;Estrogen Receptors;Estrogen Therapy;Estrogen receptor positive;Estrogens;Event;Evolution;Fulvestrant;Gene Dosage;Gene Expression Profile;Gene Targeting;Genetic;Goals;Hormonal;Intervention;Malignant Neoplasms;Metastatic breast cancer;Modeling;Molecular Target;Neoplasm Metastasis;Organoids;Pathway interactions;Patients;Pharmacologic Substance;Pre-Clinical Model;Process;Proliferating;Publishing;Recurrent disease;Regimen;Regulatory Pathway;Relapse;Resistance;Retinoblastoma Genes;Risk;Sampling;Seminal;Signal Pathway;Therapeutic;Therapeutic Intervention;Tumor Suppressor Proteins;United States;Woman;Work;antagonist;de novo mutation;drug use screening;genetic evolution;genetic selection;hormone therapy;improved;in vivo;inhibitor;malignant breast neoplasm;next generation;patient derived xenograft model;personalized approach;pressure;prognostic;programs;public health relevance;receptor function;response;targeted agent;targeted treatment;therapeutic target;therapy resistant;treatment response;tumor;tumor heterogeneity;tumor progression RB tumor suppressor as a therapeutic target in ER-positive breast cancer RELEVANCE: Breast cancer is the 2nd leading cause of the womens cancer related death in the UnitedStates. Understanding improved means for the treatment of the disease is of clear public health relevance.The overall goal of this project is to advance the understanding of disease recurrence and means to moreeffectively intercede. NCI 10775865 3/28/23 0:00 PA-19-056 3R01CA247362-04S1 3 R01 CA 247362 4 S1 "AGYIN, JOSEPH KOFI" 3/1/20 0:00 2/28/25 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 1871577 "KNUDSEN, ERIK " "WITKIEWICZ, AGNIESZKA " 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 353 Non-SBIR/STTR 2023 351338 NCI 202500 148838 ABSTRACT: Our work over the last several years indicates that cell cycle regulatory pathways are criticaldeterminants of the response to endocrine therapy as well as targeted therapies that are frequently employedin the treatment of ER+ metastatic breast cancer. Here we will focus on the RB-tumor suppressor pathway asa central node controlling proliferation downstream of multiple pathways of relevance to therapy of ER+ breastcancer (e.g. endocrine therapy and CDK4/6 inhibitors). While RB is required for the effective cytostaticresponse to a range of targeted therapies employed in ER+ breast cancer multiple pathways can contribute tocell cycle plasticity and therefore represent distinct means for generating therapeutic resistance. Here we willdelineate the processes underlying this form of resistance means to elicit durable cell cycle arrest andapproaches to target resistance as observed clinically (Aim 1). Our data and newly published studies indicatethat RB loss occurs in ER+ breast cancer as a means to escape from cytostatic therapies. Analysis of the RBlocus in ER+ breast cancer indicates loss of one copy of 13q occurs in a significant fraction of ER+ breastcancers suggesting that such tumors are primed for RB loss. How to subsequently treat tumors that areheterogeneous for RB or are solely RB deficient represents a significant challenge. Using drug screening andorganoid approaches we have defined several regimens that are particularly effective against RB-negativetumors and could represent a general means to target ER+ tumors that progress on CDK4/6 inhibitors (Aim 2).Together these aims will interrogate means to further leverage the RB tumor suppressor for a precisionapproach to the treatment of ER+ breast cancer. 351338 +No NIH Category available Address;Affinity;Binding;Cell Line;Cells;Chromatin;Complex;Coupled;DNA Sequence Alteration;Development;Epigenetic Process;Epithelium;Gene Expression;Gene Expression Profiling;Gene Silencing;Genes;Genetic Engineering;Goals;Histologic;Histones;Human;Hypoxia;Invaded;Link;Lysine;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mesenchymal;Methylation;Molecular;Morphology;Mus;Mutation;Neoplasm Metastasis;Oxygen;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Phenotype;Play;Polycomb;Positioning Attribute;Property;Regulation;Resistance;Role;Therapeutic;Up-Regulation;cancer cell;chromatin immunoprecipitation;clinically relevant;demethylation;disorder subtype;experimental study;genetic signature;histone demethylase;in vivo;innovation;insight;malignant phenotype;migration;molecular subtypes;mouse model;normoxia;novel;novel strategies;novel therapeutic intervention;pancreatic ductal adenocarcinoma cell;programs;stemness;transcriptome;tumor microenvironment Elucidation of hypoxia-induced metastatic reprogramming through the regulation of KDM8 function in pancreatic cancer NARRATIVEThe basal-like subtype of PDAC associates with resistance to treatment and poor patient outcome. Our studywill provide mechanistic insights into the molecular mechanism by which intratumoral hypoxia promotes thebasal-like state through the suppression of the histone demethylase KDM8. Our findings will likely uncovernovel approaches to reverse hypoxia-induced basal-like state while promoting the treatment-sensitive classicalsubtype. NCI 10775599 1/1/24 0:00 PA-20-185 1R01CA285774-01 1 R01 CA 285774 1 "AULT, GRACE S" 1/1/24 0:00 12/31/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 15935877 "CHIOU, SHIN-HENG " Not Applicable 10 NONE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ ORGANIZED RESEARCH UNITS 71073001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 480423 NCI 314483 165940 ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Full transcriptome definesclinically relevant subtypes of disease and the basal-like subtype of PDAC is associated with advancedstage metastasis resistance to treatment and poor patient survival. The mechanism by which the tumormicroenvironment drives PDAC subtype differentiation remains uncharacterized. Understanding the cancer-extrinsic factors in the tumor microenvironment that promotes the basal-like state could uncover cancervulnerabilities and lead to the development of new therapeutic approaches. We found that inactivation of thehistone demethylase gene Kdm8 reprograms PDAC cells into a highly metastatic state. Morphologically Kdm8inactivation reduces the expression of genes defining the classical PDAC subtype and drives a profound lossof differentiation in a genetically engineered PDAC mouse model. Importantly the enzymatic function of Kdm8requires molecular oxygen and hypoxia diminished the phenotypic changes induced by Kdm8 inactivation. Wenoted a global upregulation of histone 3 lysine 27 (H3K27) trimethylation upon the inactivation of Kdm8supporting the involvement of its demethylase function in regulating the chromatin and cell state. In humanPDAC KDM8-regulated gene signatures are an exceptionally good predictor of the disease subtype. Ourpreliminary results suggest that hypoxia within the tumor microenvironment restricts the demethylase functionof Kdm8 thereby suppressing the classical PDAC subtype while promoting a basal-like state and metastasisthrough epigenetic reprogramming. We hypothesize that a hypoxia-KDM8-chromatin axis plays a critical role inPDAC subtype determination and metastatic ability.In the proposed study we aim to determine the mechanism by which Kdm8 controls PDAC subtypes andmetastatic progression and the mechanism by which hypoxia suppresses Kdm8 function to promote chromatinreprogramming and PDAC metastasis. Overall our study will fill the major gap in our understanding of howhypoxia within the PDAC tumor microenvironment promotes the basal-like molecular subtype and metastasis.Our mechanistic study will uncover fundamental insights into the role of KDM8 in subtype determination andmay discover novel vulnerabilities of the basal-like PDAC state. The long-term objective is to gain a betterunderstanding of the key cell-extrinsic factors in the tumor microenvironment that promote the aggressive orbasal-like PDAC subtypes. 480423 +No NIH Category available Optimizing Age-based Anal Cancer Screening Among People Living with HIV using Decision Analytic Modeling PROJECT NARRATIVEThe objective of this study is to optimize cancer screening algorithms for prevention of anal cancer amongHIV+ men and women. Towards this end we will develop and validate a mathematical model of anal cancernatural history and treatment that will accurately determine the optimal use of screening tailored to thispopulation. Our results will inform age-specific risk targeted anal cancer screening regimen to maximizesurvival and quality of life of HIV+ men and women. NCI 10775089 3/30/23 0:00 PA-21-268 7R01CA232888-05 7 R01 CA 232888 5 "LIDDELL HUPPI, REBECCA" 12/19/22 0:00 2/29/24 0:00 Population and Public Health Approaches to HIV/AIDS Study Section[PPAH] 12232123 "DESHMUKH, ASHISH A." Not Applicable 6 PUBLIC HEALTH & PREV MEDICINE 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 12/19/22 0:00 2/29/24 0:00 399 Non-SBIR/STTR 2022 488913 NCI 406402 82511 PROJECT SUMMARY/ABSTRACTAnal cancer is the second most common non-AIDS defining cancer and a leading cause of morbidity amongHIV-infected (HIV+) persons in the United States (US). The incidence of anal cancer increases with age. Withnearly 50% HIV+ persons are now 50-years or older preventative health care in the form of screening is amajor public health priority to decrease their risk of developing anal cancer. Because anal cancer is biologicallysimilar to cervical cancer current guidelines (inferred from cervical cancer literature) recommend screeningHIV+ men and women using anal cytology for detection of high-grade squamous intraepithelial lesions (theanal cancer precursor); however optimal screening regimen (age to start and stop screening as well asoptimal screening frequency) for the prevention of anal cancer still remains unknown. Due to the lack of clearunderstanding of harms versus benefits of screening only 11% of HIV+ persons had an anal cytology in thepreceding year leading to 50% of diagnoses occurring at stage III or worse when the 5-year survival rate isless than 40%.The goal of the proposed research is to identify appropriate candidates for screening and determine age-specific screening algorithms to reduce anal cancer morbidity and mortality among HIV+ men and women. Wewill integrate evidence from two large clinical trials and several large databases into mathematical modelinga complementary approach to randomized clinical trials. In Aim 1 we will measure the impact of age and HIVdisease status (i.e. HIV viral suppression CD4 count) on the incidence of anal HSIL HSIL recurrence andprogression to anal cancer. In Aim 2 we will develop a clinically-valid mathematical model of anal cancernatural history in HIV+ men and women and use it to determine optimal age-specific anal cancer screeningalgorithm. Finally in Aim 3 we propose to determine the minimum necessary efficacy (by age) of anal HSILtreatment for HIV+ men and women to provide clinically significant benefits for screening and finally determineareas of future research to improve the value of anal cancer screening.The proposed research is innovative because it applies advanced modeling approach with multiple datasets toaddress a problem that has not been solved by empirical methods. The research team is ideally suited with anestablished track record in HIV and HPV epidemiology cancer outcomes research and clinical care havingsubstantial experience in developing mathematical models to inform clinical decision making. The end resultsof the proposed study will be age-specific anal cancer screening recommendations for HIV+ men and womenthat will inform anal cancer prevention policies and practice and ultimately reduce morbidity and mortality. 488913 +No NIH Category available Achievement;Active Immunization;Address;Adjuvant;Age;Animal Model;Antigen Presentation Pathway;Antigen Targeting;Antigen-Presenting Cells;Antigens;Basic Science;Biological Assay;Biological Response Modifiers;Biomedical Engineering;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Vaccines;Canis familiaris;Capsid;Cells;Clone Cells;Companions;Complex;Cross Presentation;Cutaneous Melanoma;Cytomegalovirus;DNA biosynthesis;DNA cassette;Data;Dendritic Cells;Dependovirus;Development;Disease Progression;Dissection;Disseminated Malignant Neoplasm;Dopachrome isomerase;Dose;Dose Limiting;Engineering;Environmental Exposure;Enzyme-Linked Immunosorbent Assay;Equilibrium;Flow Cytometry;Gene Expression;Gene Transduction Agent;Genes;Genetic;Genetic Markers;Heterogeneity;Histocompatibility Antigens Class I;Human;Immune;Immune response;Immune system;Immunologic Stimulation;Immunotherapy;Individual;Inflammatory Response;Injections;Interferon Type II;Intramuscular;Kinetics;Local Therapy;Malignant Neoplasms;Measures;Methods;Modeling;Modification;Molecular;Monophenol Monooxygenase;Mouth Neoplasms;Mucous Membrane;Mutagens;Neoplasm Metastasis;Nuclear Translocation;Oncologist;Operative Surgical Procedures;Oral;Patients;Persons;Population;Pre-Clinical Model;Prevalence;Production;Proliferating;Property;Public Health;Recurrent tumor;Reporting;Research;Resistance;SILV gene;Safety;Serine;Serotyping;Signal Transduction;Site;Surface;T-Cell Proliferation;T-Lymphocyte;TNF gene;Testing;Therapeutic;Threonine;Toxic effect;Treatment Failure;Treatment outcome;Tumor Antigens;Tumor Immunity;Tyrosinase related protein-1;Vaccination;Vaccine Therapy;Vaccines;Valine;Viral;Viral Genome;Virus;adaptive immune response;adeno-associated viral vector;antigen processing;cancer immunotherapy;cancer therapy;chemokine;chemotherapy;clinically relevant;combinatorial;cytokine;design;dosage;experimental study;functional disability;immunogenic;immunogenicity;immunoregulation;improved;in vivo;melanoma;mucosal melanoma;multiplex assay;next generation;novel;novel therapeutic intervention;novel vaccines;pre-clinical;preclinical study;programs;promoter;response;side effect;therapeutic development;trafficking;transduction efficiency;tumor;tumor diagnosis;vaccine development;vaccine platform;vaccine strategy;vector;viral DNA Development of novel AAV vaccine strategy in a pre-clinical model of oral melanoma. Project NarrativeOur study expected to validate novel vaccine in dogs with spontaneous oral melanoma and gain betterunderstanding towards possible use of viral-based immunotherapy in human patients which has direct relevanceto public health. NCI 10775061 12/8/23 0:00 PA-20-185 1R01CA285620-01 1 R01 CA 285620 1 "SALOMON, RACHELLE" 12/8/23 0:00 11/30/28 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 10326548 "ASLANIDI, GEORGE V" "BORGATTI, ANTONELLA M" 5 NONE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN ORGANIZED RESEARCH UNITS 554552070 UNITED STATES N 12/8/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 503863 NCI 316895 186968 Project Summary/AbstractVaccination is a potent regulator of the immune system and much research is being conducted to understandhow antigen-specific stimulation can be used to induce and redirect anti-tumor immunity. Our team develops acancer immunotherapy program using novel AAV vectors to deliver antigens both directly and by cross-presentation to antigen presenting cells. Optimization of naturally occurring AAV serotypes and novel methodsof AAV production are necessary to warrant wide use of these vectors for cancer immunotherapy. The main aimsof this proposal is to determine the safety and efficacy of our novel AAV-based vaccines as part of preclinicalstudies by using companion dogs with oral melanoma.In recent years we have undertaken studies to gain a better understanding of the underlying molecularmechanisms of AAV and host immune system interaction via the high efficiency transduction of DCs. We havemade the following scientific achievements which form the basis of the current proposal: Identified and mutagenized critical surface-exposed serine and threonine residues on the AAV capsid that are involved in intracellular trafficking of virus in the host cells. Demonstrated that rational modifications in the AAV expression cassette results in antigen processing by dendritic cells (DCs) leading to a stronger and prolonged antigen-specific immune response. Developed the next generation of highly efficient AAV-vectors that expressed a tumor-associated antigens (premelanosome protein gp100 (also known as Pmel) tyrosinase (Tyr) tyrosinase-related protein 1(TRP1) and dopachrome tautomerase (TRP2). Tested these novel AAV vectors for their ability to stimulate a specific T-cell clone proliferation and protective immune response in a small animal model.In this proposal we will test ability of our recently developed optimized AAV capsid and expression cassettewhose unique properties enhance a cellular/humoral immune response toward vector encoded tumor antigens.Successful completion of the current proposal will result in: Production of high titers of a therapeutic AAV-based vaccine. Identification of an optimal AAV-based dose for vaccination that can be used to slow/eliminate the progression of melanoma cancer in a large animal model such as companion dog-patients with spontaneouscancer. Mechanism of the novel cancer vaccine function in the most appropriate animal model. The optimized AAV vector can be potentially used as a vaccine platform for the treatment of cancers in canine and humans. 503863 +No NIH Category available Address;Advance Care Planning;Advanced Malignant Neoplasm;Aftercare;American;Anxiety;Bereavement;COVID-19 pandemic;Caregiver Burden;Caregiver support;Caregivers;Caring;Cessation of life;Child Care;Communication;Critical Care;Data;Diagnosis;Disabled Persons;Discipline of Nursing;Disease;Distress;Emotional;Employment;Face;Family;Family Caregiver;Family member;Feeling hopeless;Friends;Goals;Grief reaction;Health;Healthcare;Intervention;Left;Life;Long-Term Care for Elderly;Maintenance;Malignant Neoplasms;Manuals;Meaning and purpose;Mediating;Mediator;Medical;Memorial Sloan-Kettering Cancer Center;Mental Depression;Mental Health;Mission;Outcome;Palliative Care;Participant;Patient Care;Patients;Personal Satisfaction;Persons;Play;Post-Traumatic Stress Disorders;Proxy;Psychopathology;Psychotherapy;Quality of life;Randomized;Randomized Controlled Trials;Readiness;Regrets;Reporting;Research;Risk;Role;Shoulder;Social support;Solid Neoplasm;Spirituality;Supportive care;Time;United States;United States National Institutes of Health;Vulnerable Populations;Well in self;cancer care;caregiving;community based care;depressive symptoms;effective intervention;efficacy evaluation;end of life;experience;follow up assessment;follow-up;healing;high risk;improved;injured;innovation;life-limiting cancer;loved ones;primary endpoint;primary outcome;psychosocial;resilience;screening;secondary outcome;success;telehealth;therapy design;treatment arm;treatment as usual;treatment effect Meaning-Centered Psychotherapy to Meet Palliative Care Needs of Cancer Caregivers PROJECT NARRATIVEThe increasingly crucial role played by family and friend caregivers of patients with advanced cancer iscomplicated by existential distress but to date current psychosocial interventions fail to address such distress.This project is relevant to NIHs mission as it represents a critical step in the refinement of a targetedinterventionMeaning-Centered Psychotherapy for Cancer Caregivers (MCP-C)that has shown encouragingresults in improving caregivers sense of meaning in life and spiritual wellbeing and ameliorating anxiety anddepression. If successful MCP-C holds significant promise to not only improve the quality of life for caregiversacross the caregiving trajectory from diagnosis through bereavement but also to yield downstream benefits tothe patients for whom they provide care. NCI 10775050 1/1/24 0:00 PAR-21-035 1R01CA285621-01 1 R01 CA 285621 1 "FERRER, REBECCA" 1/1/24 0:00 12/31/28 0:00 "Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]" 11077187 "APPLEBAUM, ALLISON " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 444572 NCI 300499 144073 PROJECT SUMMARYIn 2020 53 million people in the U.S. served as family caregivers the partners relatives and friends whoprovide assistance (i.e. physical emotional) to patients with often life-threatening incurable illnesses.Caregivers are increasingly tasked with responsibilities once performed by medical professionals and theavailability and health of supportive caregivers is more critical than ever. A growing number of caregiversprovide care to patients with advanced life-limiting cancers and are tasked with critical patient careresponsibilities and play a significant role in healthcare communication and advanced care planning ashealthcare proxies. The burden of these responsibilities is great and is driven largely by existential distresswhich contributes to anxiety depression poor quality of life and mental health challenges in bereavement.Concurrently caregiving is an opportunity to experience a profound sense of meaning and purpose; caregivingallows for the realization of new strengths and capacities healing of relationships and refinement of life goals.When existential distress is addressed caregivers can experience an enhanced sense of well-being despitetheir challenges. While many interventions have been developed to support cancer caregivers none directlytarget existential distress. Our group adapted Meaning-Centered Psychotherapy (MCP) a highly effectiveintervention in decreasing existential distress and enhancing well-being among patients with advanced cancerfor cancer caregivers. Meaning-Centered Psychotherapy for Cancer Caregivers (MCP-C) is a stakeholder-informed innovative manualized intervention designed to assist caregivers to connect to meaning andpurpose in life despite the challenges of caregiving. Results of our pilot randomized controlled demonstratedMCP-Cs feasibility acceptability and superiority in improving meaning benefit-finding depression andspiritual wellbeing. In the proposed trial we will more rigorously evaluate the efficacy of MCP-C through arandomized controlled trial of 200 caregivers of patients with advanced (Stage III/IV solid tumor) cancer whowill receive 7 sessions of MCP-C or Supportive Psychotherapy for Caregivers (SP-C) the standard ofcommunity-based caregiver care. Participants will undergo assessments of meaning and spiritual wellbeing(primary outcomes) and anxiety depression benefit finding caregiver burden and social support (secondaryoutcomes) at baseline post-treatment and at 6- and 12-months follow-up. Bereavement outcomes includingpre- and post-loss grief preparedness for loss and regret will also be evaluated at each time point. We predictMCP-C will result in greater improvements in primary and secondary outcomes and that sense of meaning inlife will mediate treatment effects. We also predict that MCP-C will result in better preparedness for loss andimproved pre- and post-loss grief and regret. Our results will enhance our capacity to powerfully targetexistential distress in caregivers of patients with advance cancer and by extension improve their capacity toprovide critical care to patients at end-of-life. 444572 +No NIH Category available Achievement;Address;Adherent Culture;Antibiotics;Antineoplastic Agents;Biochemical Reaction;Breast;Cancer Model;Cancer cell line;Capital;Cardiac Glycosides;Cell Culture System;Cell Culture Techniques;Cell Line;Cell Proliferation;Cell model;Cells;Clinic;Coculture Techniques;Combined Modality Therapy;Communicable Diseases;Credentialing;Culture Media;Data;Data Set;Development;Disease;Epithelium;Fibroblasts;Fine needle aspiration biopsy;Genome;Genotype;Goals;Growth;Growth Factor;Histologic;Human;Individual;Infectious Agent;Institution;Investments;Kidney;Life;Liquid substance;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mammalian Cell;Manuscripts;Metabolic;Methods;Modeling;Molecular;Molecular Profiling;Muscarinic Agonists;Mutation;Normal Cell;Nutrient;Organoids;Outcome;Ovarian Adenocarcinoma;Ovary;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Preparation;Proliferating;Prostate;Proteome;Publishing;Reagent;Renal carcinoma;Research;Research Personnel;Residual Neoplasm;Sampling;Serum;Solid Neoplasm;Stromal Cells;System;Techniques;Technology;Testing;Time;Tissues;Tumor Tissue;Valine;Visceral metastasis;Vitamin A;Xenograft procedure;anticancer research;cancer cell;cancer therapy;cancer type;cell growth;chemotherapy;cost;cytokine;drug development;drug discovery;expectation;experimental study;fighting;improved;innovation;leukemia;longitudinal analysis;malignant breast neoplasm;monolayer;neoplastic cell;pathogen;patient derived xenograft model;precision oncology;repository;response;success;targeted treatment;transcriptome;treatment response;tumor Culture of tumor versus normal cells PROJECT NARRATIVEStandard cancer cell lines have had an important impact on cancer research and greatly facilitated developmentof a variety of cancer treatments. However new mammalian cancer culture models are difficult to establish. Wedeveloped a new cell culture system that allows us to establish cancer cell cultures that retain the accuratemolecular features and patient outcome and drug response profile; in this application we propose to implementthis technology and compare monolayer and organoid models and PDX from the same patient to establish bestpractices in the use of these models. NCI 10774867 11/28/23 0:00 PAR-20-131 1R01CA285335-01 1 R01 CA 285335 1 "WATSON, JOANNA M" 1/1/24 0:00 12/31/28 0:00 Special Emphasis Panel[ZRG1-CTH-E(55)R] 8742197 "INCE, TAN A." Not Applicable 12 PATHOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 364140 NCI 214832 149308 PROJECT SUMMARYBackground: Mammalian models of cancer have been instrumental in the development of many targetedtherapies. It is however difficult to establish these models such as patient-derived cell cultures (PDCC) andxenografts (PDX). As a result most cancer types have only a limited number of models available which do notaccurately reflect the diversity of human cancer in real life.Innovation: The majority of the patient-derived models were developed using untreated primary samples withplenty of tumor tissue. The next challenge in tumor modeling will require much more difficult samples such asminute residual tumor foci in a patient with a partial chemotherapy response. Even though cancer is a diseaseof unchecked cell growth in the body normal cells paradoxically proliferate faster than malignant cells in cellculture. As a result in the majority of PDCC models the cancer cells eventually disappear. To address the issueof normal cell overgrowth we are creating a tumor-specific medium (TSM) that suppresses normal cellproliferation.Preliminary data: As a proof-of-concept we published twenty-five new ovarian cancer cell (OvCa) lines thatretained the molecular histologic and outcome features of the patient tumors.Objectives: Our goal is to create innovative and simple culture methods that enable the creation of patient-derived cell cultures and PDX models and develop best practices for validating these models.Specific Aims: We are working on five major solid tumor types (lung breast prostate kidney and ovary) anda liquid tumor (leukemia) to illustrate that our system can be adapted to culture the full spectrum of tumor types.Aim 1: Patient-Derived Culture of Solid Tumors: We will establish patient-derived lung breast prostatekidney and ovary adenocarcinoma cultures and compare their molecular profiles with the original patient tumor.Aim 2) Patient-Derived Culture of Solid Tumors: We will establish patient-derived AML cultures and comparetheir molecular and phenotypic profiles with the original patient tumor.Research Strategy: We will compare the genome transcriptome and proteome of each cell line with the originalpatient tumor existing cell lines and tumor datasets.Innovation: By suppressing the expansion of normal stromal cells and normal epithelium the TSM culturesystem can maintain cancer cell lines long-term without feeder layers drugs or extracts.Impact: Predicting drug activity in the clinic has always been difficult using traditional cultural models. Thereforehaving access to biologically relevant lung breast prostate kidney ovary and AML cell lines could revolutionizecancer drug development. 364140 +No NIH Category available Address;Adult;Age;American Society of Clinical Oncology;Automobile Driving;Back;Body Size;Body Surface Area;Body mass index;Breast;Breast Cancer Patient;California;Cancer Patient;Cardiotoxicity;Cardiovascular Diseases;Characteristics;Clinical Management;Cytotoxic agent;Data;Data Sources;Diabetes Mellitus;Diagnosis;Disease;Dose;Epidemiology;Ethnic Origin;Fright;Gender;Guidelines;Health;Hepatic;Hormone Receptor;Impairment;Integrated Delivery of Health Care;Intervention;Investigation;Kidney;Kidney Diseases;Knowledge;Link;Mediating;Mediator;Medical Oncology;Meta-Analysis;Modification;Morbid Obesity;Neuropathy;Neutropenia;Nodal;Non obese;Obesity;Outcome;Patients;Pharmaceutical Preparations;Pharmacology;Positioning Attribute;Prevalence;Prognosis;Provider;Race;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Reporting;Research;Risk;Role;System;Toxic effect;Treatment-related toxicity;Uncertainty;United States;Weight;Woman;adverse outcome;breast cancer survival;cancer recurrence;cancer survival;chemotherapy;clinically relevant;comorbidity;data integration;epidemiology study;experience;follow-up;improved;malignant breast neoplasm;mortality;novel;obese patients;optimal treatments;provider factors;study population Obesity chemotherapy dosing and breast cancer outcomes PROJECT NARRATIVEEpidemiologic studies have linked obesity to poor breast cancer outcomes and it has been suggested thatobese women may experience poorer outcomes in part due to dose reductions of chemotherapy drugs; thisis because most cytotoxic agents are dosed according to body size and clinicians may scale back the highdoses administered to obese women due to concern about inducing toxicity. Given persisting uncertaintyabout dosing obese women in a study population of nearly 34000 women with breast cancer who werediagnosed and treated in two integrated healthcare delivery systems Kaiser Permanente Northern Californiaand Group Health we propose to: i) examine the relationship between body size and dose intensity and willfurther examine how the factors contributing to dose reductions vary by body size ii) evaluate whetherchemotherapy dose reductions mediate the associations between obesity and adverse breast canceroutcomes and iii) evaluate the association between body size and toxicity among women identified asreceiving the full body-size determined dose of chemotherapy. Addressing these questions will provide theevidence needed to better inform clinicians treating the 102000 obese women diagnosed with breast cancereach year in the United States. NCI 10774335 11/22/23 0:00 PA-16-160 5R37CA222793-07 5 R37 CA 222793 7 "SHELBURNE, NONNIEKAYE F" 1/1/18 0:00 12/31/24 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 11112095 "KANTOR, ELIZABETH DAVID" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 510574 NCI 381351 129223 ABSTRACT Epidemiologic studies have linked obesity to poor breast cancer outcomes and it has been suggested thatobese women may experience poorer outcomes in part due to inadequate dosing of cytotoxic agents amongobese women. Specifically most cytotoxic agents are dosed according to body surface area and therefore thelarger the woman the higher the absolute dose. However evidence shows that clinicians are more likely todepart from recommended dosing among heavier women for fear of inducing chemotherapy-associated toxicity.In 2012 the American Society of Clinical Oncology (ASCO) released guidelines stating that obese womenshould be dosed according to their full body surface area largely based on evidence that suggested that fully-dosed obese women do not appear to experience more toxicity than fully-dosed normal-weight women.However the guidelines acknowledge that data are extremely limited with regard to more severe obesity and inthe real-world context of comorbidities. Furthermore these guidelines cite that this practice of `dose reducing'obese women may be one reason contributing to the poorer outcomes observed in this group. However todate no empirical investigations have sought to determine if and to what extent dose-reduced chemotherapymay explain differences in breast cancer survival. These guidelines were met with some criticism citing theneed for further evidence and data suggest continuing uncertainty about proper dosing of obese cancerpatients. Understanding the drivers of dose reductions may help better inform our understanding of thispractice and efforts to disseminate guidelines; however we know little about factors driving dose intensity andhow these factors may vary by body size. We therefore propose to address these gaps using data on nearly 34000 Stage I-IIIA breast cancerpatients diagnosed and treated at Kaiser Permanente Northern California and at Group Health. Specifically wewill use the rich data from these integrated healthcare delivery systems to examine the relationship betweenbody size and dose intensity and will further examine how the factors contributing to dose reductions vary bybody size (Aim 1). We will also evaluate if and to what extent dose reductions mediate the associationbetween obesity and breast cancer recurrence and survival (Aim 2). Lastly we will evaluate the associationbetween body size and toxicity among women identified as receiving the full BSA-determined dose ofchemotherapy (Aim 3). Our findings will provide critical and timely information to support or to warrantmodification of current recommendations for chemotherapy dosing for obese breast cancer patients. Given thehigh and increasing prevalence of obesity in the United States it is critical that we improve our understanding ofchemotherapy dosing. The knowledge gained from this study can be used to better inform optimal treatment forthe estimated 102000 obese women diagnosed with breast cancer each year in the United States. 510574 +No NIH Category available Active Sites;Adverse effects;Affect;Amino Acids;Autophagocytosis;Binding;Binding Proteins;Biochemical;Biogenesis;Biological Assay;Birt-Hogg-Dube Syndrome;Cell Line;Cellular Metabolic Process;Clinic;Complex;Cryoelectron Microscopy;Dissociation;EIF4EBP1 gene;FRAP1 gene;Genetic Transcription;Glioblastoma;Growth Factor;Guanosine Triphosphate Phosphohydrolases;Hereditary Malignant Neoplasm;In Vitro;Knock-out;Laboratories;Link;Lysosomes;Malignant Neoplasms;Maps;Molecular;Molecular Conformation;Multiprotein Complexes;Mus;Mutate;Mutation;Nucleotides;Nutrient;Pathway interactions;Patients;Phenotype;Phosphorylation;Phosphotransferases;Proteins;Recombinants;Regulation;Regulatory Pathway;Renal Cell Carcinoma;Repression;Ribosomal Protein S6 Kinase;Signal Transduction;Sirolimus;Starvation;Structure;Substrate Interaction;Surface;Tacrolimus Binding Protein 1A;Testing;Tuberous Sclerosis;Tumor Suppressor Proteins;Work;Xenograft Model;cell growth;cofactor;dimer;feeding;follow-up;inhibitor;recruit;response;sensor;therapeutic target;transcription factor;tumorigenesis Molecular and structural mechanisms of mTORC1 regulation in cancer Project NarrativeDespite great efforts to target mTORC1 in cancer adverse effects related to the multiplicity of mTORC1-regulated substrates limit the use of mTORC1 inhibitors in the clinic. Recent cryo-EM work from our labrevealed the structural basis of substrate-specific regulatory pathways that could be targeted with greaterprecision than heretofore. We will determine how regulation of canonical and non-canonical mTORC1substrates differs and reveal the structural basis of mTORC1 regulation by the still largely mysteriousmechanisms of the GATOR and KICSTOR complexes. NCI 10773768 12/29/23 0:00 PA-20-185 1R01CA285366-01 1 R01 CA 285366 1 "AMIN, ANOWARUL" 1/1/24 0:00 12/31/28 0:00 Macromolecular Structure and Function C Study Section[MSFC] 6480673 "HURLEY, JAMES H" Not Applicable 12 MISCELLANEOUS 124726725 GS3YEVSS12N6 124726725 GS3YEVSS12N6 US 37.870017 -122.268624 577502 UNIVERSITY OF CALIFORNIA BERKELEY BERKELEY CA ORGANIZED RESEARCH UNITS 947101749 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 584036 NCI 370408 213628 PROJECT SUMMARYThe mechanistic Target of Rapamycin Complex 1 (mTORC1) is master regulator of cell growth andmetabolism. Dysregulation of mTORC1 is observed in sporadic and familial cancers. mTORC1 inhibitionis an established treatment for renal cell carcinoma (RCC). Despite great efforts to target mTORC1 incancer adverse effects limit the use of mTORC1 inhibitors in the clinic. Recent work from our lab andcollaborators has revealed the existence and structural basis of substrate-specific regulatory pathwaysthat may be targeted with greater precision than heretofore. mTORC1 is activated on the surface of lysosomes in response to nutrient signals by conversionof the nucleotide state of the Rag GTPases from inactive (RagA/BGDP-RagC/DGTP) to active (RagA/BGTP-RagC/DGDP). The Rags are targeted to the lysosome by the Ragulator complex. Rag states areinterconverted by the RagC/D GAP FLCN-FNIP and the RagA/B GAP GATOR1. Subunits of thesecomplexes and the Rags are mutated in cancer. RagA/BGTP and GATOR1 inactivation is required forphosphorylation of all mTORC1 substrates. RagC/DGDP and FLCN-FNIP activity is only required forphosphorylation of non-canonical substrates which include TFEB the key transcriptional regulator oflysosome biogenesis and autophagy. Cryo-EM studies of the Rag Ragulator and FLCN-FNIP pathwayfrom our laboratory provided a start-to-finish structural explanation for the repression and reactivation ofFLCN GAP activity in starvation and refeeding. These studies contributed to the discovery thatRagC/DGDP uniquely regulates TFEB and MiT-TFE transcription factors which in turn explained the tumorsuppressor activity of FLCN in Birt-Hogg-Dub (BHD) syndrome. This pathway has now been linked toRHEB activity and Tuberous Sclerosis Complex (TSC). We then demonstrated the existence anddetermining the structure and function of the mTORC1-TFEB-Rag-Ragulator megacomplex containinga full mTORC1 dimer two copies of TFEB and four copies of the heptameric complex of active Rags andRagulator showing how RagC/DGDP specifically recruits TFEB. In aims 1 and 2 we will explore the new avenues opened up the analysis of the megacomplex.We will determine how the megacomplex is turned over following TFEB phosphorylation and whether theprinciples of substrate specific activation seen for TFEB and RagC also apply to canonical substrates.Findings will be followed up in BHD and TSC cell lines and a BHD mouse xenograft model. While we nowhave a start-to-finish structural mapping of FLCN/RagC/D pathway the still mysterious regulatorymechanisms operating in the GATOR1/RagA/B pathway will be elucidated in aim 3 and the cancerimplications explored in knock-out and Glioblastoma cell lines. 584036 +No NIH Category available 3' Untranslated Regions;5' Untranslated Regions;Adopted;Affinity;Antibodies;Antineoplastic Agents;Apoptosis;Binding;Biological;Biological Assay;Bypass;CTLA4 gene;Cancer Cell Growth;Cancer Control;Cell Proliferation;Cell physiology;Cells;Cellular biology;Chemicals;Clinic;Clinical;Computer Assisted;DNA Repair;Data;Development;Dose;Down-Regulation;Drug Combinations;Drug Design;Effectiveness;Eukaryotic Initiation Factor-4G;Exhibits;FRAP1 gene;Feedback;Generations;Goals;Growth;Heterogeneous-Nuclear Ribonucleoproteins;Homeostasis;Human;Immune;Immune Evasion;Immune Targeting;Immune checkpoint inhibitor;Immune response;Immunologist;In Vitro;Lead;Malignant Neoplasms;Mantle Cell Lymphoma;Medicine;Messenger RNA;Metabolism;Methods;Modeling;Modification;Mus;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Oncologist;PIK3CG gene;Pathway interactions;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Plasma;Proliferating;Property;Protein Biosynthesis;Protein Inhibition;Proteins;RNA;RNA Binding;RNA Polymerase Inhibitor;RNA Recognition Motif;RNA-Binding Proteins;RNA-Protein Interaction;Regulatory Pathway;Renal Cell Carcinoma;Reporter;Resistance;Reverse Transcriptase Inhibitors;Ribonucleoproteins;Role;Schedule;Solid Neoplasm;Solubility;Specificity;Stress;Structural Biologist;Therapeutic;Therapeutic Agents;Therapeutic Index;Toxic effect;Transcript;Translation Initiation;Translational Repression;Translations;Tuberous Sclerosis;Viral;Xenograft Model;Xenograft procedure;analog;angiogenesis;cancer cell;cancer drug resistance;cancer therapy;cancer type;chemotherapy;design;drug resistance development;efficacy testing;flexibility;immune checkpoint;improved;in vivo;inhibitor;innovation;multidisciplinary;novel;overexpression;precision medicine;prevent;rational design;response;scaffold;small molecule;small molecule inhibitor;structural biology;targeted cancer therapy;three dimensional structure;tumor;tumor growth;tumor progression;virtual First in Class Small molecules to simultaneously inhibit protein translation and an immune checkpoint in cancers NARRATIVEAnticancer drug resistance often results from cancer cells bypassing the targeted pathway by adoptingalternative mechanisms to maintain their growth. We have identified hnRNP A18 as a key regulator of severalcellular pathways controlling cancer growth and immune protection. Using structural biology Computer AidedDrug Design medicinal chemistry and cellular biology we are developing small molecules that can selectivelyinhibit hnRNP A18 to prevent cancer cells growth and immune evasion. NCI 10773355 12/11/23 0:00 PA-20-185 1R01CA285468-01 1 R01 CA 285468 1 "AGYIN, JOSEPH KOFI" 12/11/23 0:00 11/30/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 2188008 "CARRIER, FRANCE " "FLETCHER, STEVEN ; WEBER, DAVID JOSEPH" 7 INTERNAL MEDICINE/MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 12/11/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 639330 NCI 413806 225524 PROJECT SUMMARYTherapeutic approaches in cancer therapies have evolved from the use of highly toxic chemotherapy agents toprecision medicine with well-defined targets and minimal toxicities. While precision medicine is highlydesirable its effectiveness depends on the presence of the activating agents and typically target a singlepathway which is conducive to the development of drug resistance when alternative pathways and or feedbackmechanisms are used. These limitations are best exemplified by anti-cancer therapies targeting the proteintranslation regulator mammalian Target Of Rapamycin (mTOR). Although these inhibitors show clear benefit insome cancers such as mantle cell lymphomas Renal Cell Carcinoma and Tuberous Sclerosis Complex-relatedtumors they have limited efficacy as single agents in most other cancers due to compensatory feedbackmechanisms. In addition targeting components of the general protein translational machinery that are alsoessential for normal cell functions would likely contribute to normal tissue toxicity. Agents that could targetsimultaneously a number of limited key pathways essential for cancer cells progression and survival wouldthus be expected to decrease toxicity and resistance. To this Aim we have identified first in class smallmolecule inhibitors of hnRNP A18 a regulator of protein translation in cancer cells. hnRNP A18 targetstranscripts that are involved in cancer progression metastasis angiogenesis anti-apoptosis and tumorimmune checkpoint. Our working hypothesis is that small molecule inhibitors of hnRNP A18 will inhibit thetranslation of specific RNA transcripts devoted to conferring growth advantages and immune protection tocancer cells. To verify this hypothesis three complementary specific Aims have been designed: Aim 1:Design synthesize and improve small molecule inhibitors of hnRNP A18. Aim 2: Prioritize compounds throughin vitro methods including RNA binding cell reporter assay proliferation and toxicity. Aim 3: Determine in vivoanti-tumor and ADMET properties of lead compounds employing xenograft syngeneic and Patients Derived(PDX) tumors models. A multidisciplinary team of experts composed of medicinal chemists structuralbiologist theoretical chemists cancer biologist immunologist and an oncologist has been assembled todevelop and optimize this new class of anticancer agents with the ultimate goal of bringing them into the clinic. 639330 +No NIH Category available Acceleration;Address;Affect;Age;Animal Model;Basic Science;Binding;Biology;Bromodomain;Bromodomains and extra-terminal domain inhibitor;CD4 Positive T Lymphocytes;CD8B1 gene;CDKN2A gene;Carcinoma;Cells;Chromatin;Color;Communities;Complement;Credentialing;Disease;EP300 gene;EZH2 gene;Enhancers;Epigenetic Process;Ewings sarcoma;Excision;Fusion Oncogene Proteins;Gene Activation;Gene Expression;Gene set enrichment analysis;Genetic;Genetically Engineered Mouse;Goals;Growth;Histones;Histopathology;Human;Immune;Immune Evasion;Immune system;Immunocompetent;Immunofluorescence Immunologic;Immunologics;Immunophenotyping;Immunotherapy;Knock-in;Luciferases;Maintenance;Malignant Epithelial Cell;Malignant Neoplasms;Measures;Minority;Modeling;Mus;No Evidence of Disease;Oncogenic;Operative Surgical Procedures;Outcome;Pathogenicity;Pathway interactions;Patients;Population;Pre-Clinical Model;Protein Family;Proteomics;Repression;Role;Solid Neoplasm;Squamous cell carcinoma;T-Cell Depletion;T-Cell Receptor;Tamoxifen;Translational Research;Tumor Antigens;Tumor Suppressor Genes;Vaccination;burden of illness;chromatin remodeling;defined contribution;design;effective therapy;experimental study;histone acetyltransferase;human disease;human imaging;immune checkpoint blockade;immunomodulatory therapies;improved;novel;pre-clinical;protein complex;rapid growth;recruit;relapse prevention;response;small molecule;therapeutic development;therapeutic evaluation;therapeutic target;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Genetically engineered mouse model to improve therapy of NUT carcinoma Successful credentialing and therapeutic development of the NC GEM will provide the global scientificcommunity with a much-needed animal model that recapitulates the human disease in all important aspectsthus greatly accelerating NC translational and basic research ultimately towards a cure. NCI 10773306 9/19/23 0:00 PAR-20-131 1R01CA285308-01 1 R01 CA 285308 1 "WATSON, JOANNA M" 9/19/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-CTH-E(55)R] 8451865 "FRENCH, CHRISTOPHER A" "KESKIN, DERIN B; SHAPIRO, GEOFFREY I" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 672468 NCI 521427 151041 NUT carcinoma (NC) is an aggressive squamous carcinoma driven by the BRD4-NUT fusion oncoprotein. NCaffects all ages and is highly lethal (>90%) a median survival of 6.5 months. There are no effective treatmentoptions for NC; thus this disease represents an extreme unmet need. The overarching goal of this proposal isto improve survival of these patients through mechanism-driven identification and testing of therapeutic targets.In response to the need for an immunocompetent animal model in which both NC cell-autonomous and -non-autonomous pathogenic mechanisms can be investigated rigorously we have developed the first geneticallyengineered mouse (GEM) model of NC. As a squamous carcinoma NC serves as a paradigm for fusiononcoprotein-driven solid tumors. The NC GEM will expand that paradigm to understanding how tumor intrinsicand extrinsic interactions sustain NC growth. Mechanistically BRD4 is a BET family protein whose dual bromodomains bind acetyl-histones that when fusedto NUT recruits the histone acetyltransferase p300 forming enormous super-enhancers called megadomains.BRD4-NUT megadomains maintain expression of pro-growth anti-differentiation transcription factors includingMYC SOX2 and TP63. Our demonstration that treatment with BET bromodomain inhibitors (BETi) smallmolecules that competitively inhibit binding of BET bromodomains to chromatin can inhibit growth of NC inhumans led to a new field investigating the role of BRD4 in cancer. However it has become clear thatmonotherapy with BETi does not fully address NC biology. We have recently found that repression of tumorsuppressor gene expression such as that of CDKN2A/B by the histone methyltransferse EZH2 highlycomplements oncogenic activation by BRD4-NUT in maintaining NC growth. Targeting of this pathway withtazemetostat (taz) is highly synergistic with BETi and will be explored in the proposed GEM model. It is now recognized that NC harbors an immune-evasive tumor microenvironment (TME) and can respond toimmune modulation therapy. Epigenetic modulators such as taz and BETi are known to promote an anti-tumorimmune TME. Thus pre-clinical animal models with intact immune systems such as our NC GEM are needed tofully evaluate effects of epigenetic modifiers and the role of immune therapy in this disease. Our GEM has atamoxifen-inducible conditional knock-in fusion of murine Brd4 with human NUTM1 encoding a BRD4-NUTfusion oncoprotein. Invasive tumors formed in our NC GEM (`mNC') have provided the most definitive evidencethat BRD4-NUT is the sole driver of this cancer. mNC closely mimics human NC demonstrating rapid growthmetastatic spread and an indistinguishable histopathology and immunophenotype. Moreover the immune cellcomposition of the mNC TME also resembles that of human NC. We will make use of our novel GEM to addressthe following aims: 1. establish the applicability of the NC GEM (mNC) to human NC (hNC) biology.; 2. deviseimproved primary therapy for NUT carcinoma.; 3. explore approaches to prevent relapse of NC. 672468 +No NIH Category available Address;Aftercare;Biguanides;Biological Markers;Body mass index;Cancer Biology;Cancer Patient;Cancer cell line;Carboplatin;Cations;Cells;Cessation of life;Characteristics;Chemoresistance;Clinical Research;Clinical Trials;Data;Databases;Diabetes Mellitus;Disease;Down-Regulation;Endometrial Carcinoma;Endometrial Neoplasms;Endometrium;Energy Metabolism;Epidemiology;FRAP1 gene;Fasting;Fatty Acids;Gene Expression;Gene Expression Profile;Genotype;Glucose;Glycolipids;Goals;Growth;Growth Factor;Human;Insulin;Insulin Resistance;Knowledge;Link;Lipid Synthesis Pathway;Lipids;Malignant - descriptor;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Measurement;Metabolic;Metabolic Marker;Metformin;Modeling;Molecular;Mus;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Oncology Group;Outcome;Paclitaxel;Pathway interactions;Patients;Pharmaceutical Preparations;Phase 0 Clinical Trial;Phase 0 Trial;Phase II/III Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Play;Pre-Clinical Model;Production;Proliferating;Randomized;Research;Risk;Role;Serum;Signal Transduction;Testing;The Cancer Genome Atlas;Therapeutic;Thinness;Toxin;Tumor Tissue;Up-Regulation;Waist-Hip Ratio;Weight;Woman;Work;anti-cancer;cancer risk;cancer therapy;chemotherapy;clinically relevant;diabetic patient;diet-induced obesity;genetic signature;insulin regulation;insulin signaling;lipid biosynthesis;lipid metabolism;lipoprotein lipase;mTOR inhibition;metabolomics;molecular marker;mouse model;neoplastic cell;obese patients;obese person;oxidation;patient population;pre-clinical;preclinical study;predicting response;predictive marker;receptor;reproductive organ;response;standard of care;targeted agent;targeted treatment;tumor;tumor growth;tumorigenic;uptake Obesity-driven Metabolic and Molecular Biomarkers of Metformin Response in Endometrial Cancer PROJECT NARRATIVEEpidemiological and pre-clinical data suggest that metformin may be efficacious in endometrial cancer treatment.However two important questions that need to be addressed are: (1) Will metformin be universally effective inendometrial cancer or be more efficacious in the obese/insulin-resistant patient population? and (2) What role dotransporters play in metformin uptake and action in the malignant endometrium? These fundamental questions will beexplored in endometrial cancer a disease driven by obesity and insulin resistance and key molecular and metabolicbiomarkers of metformin responsiveness will be determined using endometrial cancer mouse models and an ongoingphase 2/3 clinical trial in endometrial cancer patients. NCI 10773270 2/16/23 0:00 PA-17-073 4R37CA226969-06 4 R37 CA 226969 6 "SAMIMI, GOLI" 3/14/18 0:00 2/28/25 0:00 Cancer Biomarkers Study Section[CBSS] 9761500 "BAE-JUMP, VICTORIA LIN" Not Applicable 4 OBSTETRICS & GYNECOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 348592 NCI 224175 124417 PROJECT SUMMARY Obesity diabetes and insulin resistance are associated with increased risk and worse outcomes for endometrialcancer (EC). Metformin is a biguanide that is widely used in the treatment of type 2 diabetes. Epidemiological and pre-clinical data suggest that metformin may have anti-tumorigenic activity due to its indirect effects within the metabolicmilieu (insulin glucose) and direct effects on tumor cells through AMPK activation/mTOR inhibition and suppressionof fatty acid/lipid biosynthesis. Metformin is dependent on cation-selective transporters for entry into cells and themulti-drug and toxin extrusion transporters MATE1 and 2 are expressed in human EC cell lines and tumors. Thusmetformin may break the link between obesity and EC emerging as a metabolically targeted agent for this disease. Within The Cancer Genome Atlas database endometrioid ECs arising in obese versus non-obese women havedistinguishing patterns of gene expression including upregulation of lipoprotein lipase and modulators of theinsulin/insulin growth factor-1 (IGF-1) pathway. These findings suggest that ECs arising in obesity may have distinctmetabolic vulnerabilities that could be targeted for treatment. In a phase 0 clinical trial of obese EC patients short-termmetformin treatment reduced proliferation and decreased expression of the IGF-1 receptor and targets of the mTORpathway within the endometrial tumor tissues. Responders to metformin had higher pre-treatment levels of fattyacids/glycolipids in their serum and MATE2 in their ECs suggesting that these biomarkers might predict metforminresponse. Lastly in the LKB1fl/flp53fl/fl EC mouse model diet-induced obesity led to a doubling of tumor sizeaccompanied by increases in energy metabolism and lipid biosynthesis. Importantly metformin had increased efficacyagainst EC in obese versus lean mice and reversed the detrimental metabolic effects of obesity in the ECs via shuntingfatty acids to beta-oxidation as opposed to lipid production. The overall goal of this proposal is to assess the contribution of indirect effects (via downregulation ofinsulin/IGF-1 signaling) and direct effects (via transporter-dependent cell entry activation of AMPK/inhibition of mTORsignaling blunting of fatty acid/lipid biosynthesis) of metformin (+/- chemotherapy) to its overall anti-cancer efficacy in(i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluatingmetformin versus placebo in combination with standard of care paclitaxel/carboplatin for the treatment of EC [throughthe NRG Oncology Group]. Our central hypothesis is that predictors of metformin response (+/- chemotherapy) willinclude both molecular and metabolic biomarkers specifically obesity insulin resistance upregulation of insulin/IGF-1 signaling heightened fatty acid/lipid biosynthesis and higher MATE 1/2 expression. The proposed research willrigorously test this hypothesis in parallel pre-clinical and clinical studies and support it with diverse measurements ofmetabolic and molecular markers associated with obesity and modulated by metformin treatment. This strategy shoulddelineate the interplay of metformins indirect and direct effects on tumor growth identify metabolic and molecularbiomarkers predictive of response to metformin and define the role of this agent in obesity-driven EC treatment. 348592 +No NIH Category available ATAC-seq;Acceleration;Affect;Apoptosis;Apoptotic;Biological;Biology;Bone Tissue;Bone neoplasms;Cardiovascular Diseases;Cell Survival;Cells;Cessation of life;Charge;Child;Chromatin;Chromatin Structure;Clinical;Clinical Trials;Cytotoxic Chemotherapy;Data;Disease;Drug Kinetics;Drug Targeting;EWSR1 gene;Enhancers;Ewings sarcoma;FDA approved;FLI1 gene;Family;Family member;Fusion Oncogene Proteins;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Family;Genes;Genetic Transcription;Goals;Growth;Health;Histones;Impairment;In Vitro;Knockout Mice;Libraries;Link;Localized Disease;Lysine;Malignant Childhood Neoplasm;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Maximum Tolerated Dose;Microsomes;Mission;Modality;Modification;Mus;Normal Cell;Nuclear;Oncogenic;Operative Surgical Procedures;Pathway interactions;Patients;Pediatric Oncology;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phenotype;Post-Translational Protein Processing;Prognosis;Property;Proteins;Proteomics;Public Health;Publishing;Quality of life;Radiation;Reader;Recurrence;Relapse;Research;Research Support;Role;Second Primary Cancers;Sirtuins;Site;Specificity;Structure;Survival Rate;Survivors;Testing;Therapeutic;United States National Institutes of Health;Western Blotting;Work;analog;bone;cell type;druggable target;epigenomics;experimental study;fusion gene;genome-wide;histone modification;human disease;improved;in vivo;inhibitor;innovation;insight;long-term sequelae;loss of function;new therapeutic target;novel;novel therapeutic intervention;programs;side effect;small molecule;soft tissue;therapeutic target;tool;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;tumor;young adult SIRT5 inhibitors and degraders as novel treatments for Ewing sarcoma NarrativeThe proposed studies are relevant to public health because discovery of novel means to treat Ewing sarcomaexerting fewer deleterious sequelae in survivors represents a significant unmet need in pediatric oncology. Thiswork is thus relevant to NIHs mission in the context of supporting research to identify cures for human disease. NCI 10773206 1/2/24 0:00 PA-20-185 5R01CA253986-03 5 R01 CA 253986 3 "AGYIN, JOSEPH KOFI" 1/1/23 0:00 12/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 9675661 "LOMBARD, DAVID BENNER" "NEAMATI, NOURI " 27 PATHOLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 463396 NCI 383412 79984 AbstractEwing sarcoma (EWS) is an aggressive tumor arising in soft tissue and bone of children and youngadults. EWS is treated with a combination of cytotoxic chemotherapy local radiation and/or surgery.Patients with localized disease show a favorable overall survival rate. However there is still a pressingneed for new therapeutic approaches for EWS. Patients with metastatic or recurrent EWS have a verypoor prognosis. Moreover current EWS treatments are associated with many short- and long-termsequelae e.g. accelerated cardiovascular disease and secondary cancers. EWS-FLI1 is the fusiononcoprotein present in most cases of EWS. It functions as a pioneer transcription factor to affectexpression of many target genes. The aberrant EWS transcriptome represents a potential therapeutictarget in EWS. This proposal focuses on the sirtuin SIRT5 as a novel therapeutic target in EWS. SIRT5is found throughout the cell and regulates protein targets in diverse pathways by removing negativelycharged modifications on lysine residues including succinylation. Although normal cell types and wholemice tolerate loss of SIRT5 with minimal phenotypes we have found that specific cancers notablyincluding EWS are exquisitely dependent on SIRT5 and rapidly undergo apoptosis following SIRT5depletion. We have linked this effect to a role for SIRT5 in desuccinylating nuclear histones therebymodulating gene expression in EWS. We and others have shown that SIRT5 is in principle amenable toselective inhibition or degradation with small molecules. Our long-term goal is to evaluate SIRT5 as apotential therapeutic target for EWS. The objective of this proposal is to generate new biological insightsinto SIRT5 function in EWS and characterize SIRT5 inhibitors and SIRT5 PROTAC-based degraders.The central hypotheses of this application are that: 1) SIRT5 is required for EWS cell survival via histonedesuccinylation and regulation of gene expression; and 2) SIRT5 inhibitors and degraders will representuseful tool compounds to interrogate SIRT5 biology and a starting point for potential future EWStherapeutics. The rationale for this application is that EWS cells show exquisite vulnerability to SIRT5loss-of-function while other cell types and whole mice show no major ill effects. Hence SIRT5 inhibitionwould likely be well tolerated clinically. The work will take place in the context of two Specific Aims. Firstwe will elucidate the impact of SIRT5 and Ksucc on histones and gene expression using massspectrometry along with transcriptomic and epigenomic approaches. Second we will optimize andvalidate SIRT5 inhibitors and degraders using medicinal chemistry approaches and based in part onSIRT5-inhibitor co-crystal structures. The application is innovative in that no published data currentlylink SIRT5 to EWS and no potent and selective SIRT5 inhibitors or PROTACs have as yet beendescribed. The work is significant since there is an unmet clinical need for improved therapies for EWS. 463396 +No NIH Category available Acceleration;Address;Adolescent;Age;Aging;Behavior;Biological;Cancer Survivorship;Caring;Cessation of life;Child;Childhood;Childhood Cancer Survivor Study;Cohort Studies;Communities;DNA sequencing;Data;Data Analyses;Data Collection;Data Reporting;Diagnosis;Disease susceptibility;Early Diagnosis;Ecosystem;Eligibility Determination;Ensure;Evaluation;Functional disorder;Funding;Future;Genetic;Genetic Predisposition to Disease;Genotype;Goals;Grant;Guidelines;Health;Health Services Research;Healthcare;Healthcare Systems;Home;Immunotherapy;Infrastructure;Institution;International;Intervention;Intervention Trial;Investigation;Investigator-Initiated Research;K-Series Research Career Programs;Knowledge;Late Effects;Level of Evidence;Life;Life Style;Longevity;Longterm Follow-up;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Modeling;Molecular;Morbidity - disease rate;Neurocognitive;Online Systems;Outcome;Participant;Patient Outcomes Assessments;Patients;Pediatric Oncology Group;Performance;Phenotype;Physiological;Population;Positioning Attribute;Prevention;Productivity;Provider;Publications;Publishing;Quality of life;Radiation;Recommendation;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Risk;Role;SNP array;Sampling;Siblings;Source;Strategic Planning;Surveys;Survival Rate;Survivors;Update;Visualization;Vulnerable Populations;age related;biobank;care costs;career;childhood cancer survivor;clinical care;cloud based;cohort;comorbidity;data access;data sharing;data tools;exome;follow-up;functional outcomes;genetic analysis;genetic information;genome sequencing;health related quality of life;high risk population;improved;innovation;member;mortality;multidisciplinary;novel therapeutics;premature;proton beam;randomized trial;recruit;sample collection;screening;screening guidelines;shared database;sharing platform;survivorship;whole genome;working group Childhood Cancer Survivorship Study RELEVANCESurvival rates for many childhood and adolescent cancers have improved at a remarkable pace over the pastfive decades. The CCSS cohort has been the source of some of the most significant publications to dateaddressing the long-term mortality morbidity and quality of life of survivors of childhood cancer. Understandingthe risk for late effects of childhood cancer and its therapy provides the basis for health screeningrecommendations and interventions that can mitigate long-term health problems in this high-risk population. NCI 10773193 12/11/23 0:00 RFA-CA-20-052 5U24CA055727-30 5 U24 CA 55727 30 "HENDERSON, LORI A" 7/20/93 0:00 11/30/26 0:00 ZCA1-GRB-I(M1) 8819228 "ARMSTRONG, GREGORY " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Other Research-Related 2024 3777365 NCI 2567853 1209512 ABSTRACTThe Childhood Cancer Survivor Study (CCSS) is a multi-institutional multi-disciplinary collaborative researchresource established to systematically evaluate long-term outcomes among children diagnosed with cancer whosurvived five or more years from diagnosis. With the successful recruitment and longitudinal follow-up of thecohort that includes survivors diagnosed and treated over three decades (1970-1999) the CCSS is the world'slargest established open resource for survivorship research with 38036 eligible survivors available forinvestigation of late mortality and 25665 participants who have contributed health-related and quality of lifeoutcomes. The resource includes comprehensive annotation of treatment exposures ongoing longitudinalfollow-up and an established biorepository from which genotype (SNP array) and DNA sequencing of 8380survivors are available to investigators for identification of genetic susceptibility for disease- and treatment-related late effects. Extensive use by the research community has resulted in: 381 published or in pressmanuscripts now cited over 26500 times; 347 presented abstracts; 59 investigator-initiated grants fundedtotaling $67 million in funding; utilization by a diverse group of 1225 investigators including 91 early careertrainees; conduct of 11 randomized trials; increased knowledge to inform exposure-based clinical careguidelines; and a highly successful model for multiple national and international collaborative initiatives ofpediatric cancer survivorship research. During the next five years activities will ensure the functioning of CCSSas a strong and productive resource by maintaining enhancing and promoting its use. We will expand thecollection of data to evaluate physiologic and neurocognitive function with aging characterize accelerated agingand investigate underlying pathophysiology of aging of survivors as they enter into their fourth fifth and sixthdecades of life. To develop a population resource for intervention trials targeting age-related outcomes in-homefunctional performance assessment and specimen collection will be performed in a sub-cohort of 1000 survivors.Further we will enhance the CCSS resource by facilitating the conduct of health services research throughcollection of data to evaluate patient provider and health care system factors and their associations with accessquality and cost of care. To maximize the research community's access and use of the CCSS resource we willleverage a cloud-based data sharing platform and develop a data analysis ecosystem with tools for data accessvisualization and analysis of genetic treatment and phenotypic/outcome data. In the future assessment of lateoutcomes of novel therapies (immunotherapy targeted/biologic proton beam radiation) will be essential.Therefore with NCI oversight CCSS will formulate a comprehensive plan for future expansion. These initiativeswill enhance and promote CCSS to further achieve the overarching goal of the CCSS resource to increase theconduct of innovative and high impact research related to pediatric cancer survivorship. 3777365 +No NIH Category available Abbreviations;Area;Award;Cancer Center;Cancer Center Support Grant;Cancer Control;Cells;Clinical;Clinical Trials;Communities;Community Outreach;Development;Diagnosis;Direct Costs;Discipline;Faculty;Faculty Recruitment;Fostering;Funding;Goals;Grant;Immunobiology;Intervention;Journals;Malignant Neoplasms;Manuscripts;Medicine;Nature;Oncology;Outcome;Paper;Pediatric Hospitals;Pediatric Oncology;Peer Review;Performance;Philadelphia;Pilot Projects;Population Sciences;Process;Publications;Radiobiology;Research;Research Personnel;Research Project Grants;Resource Sharing;Scientist;Services;Strategic Planning;Talents;Translational Research;Update;Work;acronyms;cancer prevention;community engagement;environmental carcinogenesis;imaging program;innovation;lung cancer screening;member;peer;programs;recruit;tobacco carcinogenesis;tumor;tumor metabolism Developmental Funds n/a NCI 10773032 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8320 9558302 "DOMCHEK, SUSAN M" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 1325736 815838 509898 PROJECT SUMMARY Developmental FundsDuring the current project period the Abramson Cancer Center (ACC) used Developmental Funds to supportinnovative new research through a robust Pilot Project Program to support our Staff Investigators to supportour Developing Shared Resources and to support new and talented faculty recruits. These funds stimulatedresearch in areas of strategic importance to the ACC. This support is essential to the ACC's ability to executeits responsibilities in stimulating transdisciplinary and translational research and to encourage research inareas of priority to both the ACC and the NCI. Pilot awards are issued based on a long-standing well-established peer-review process involving senior and junior ACC members from multiple Programsdepartments and disciplines. This process is similar to the peer-review process used by the NCI. During thecurrent project period plus the last two years of the previous project period 34 pilot projects were awarded.Fifteen new externally funded grants were awarded to pilot recipients (totaling $14.3M in direct costs) andanother three external grants are pending review. Additionally this work was disseminated to peers through 31manuscripts in high-impact journals including Nature Nature Medicine JAMA Cancer Discovery and J ClinOnc. Other noteworthy outcomes from our pilots include performance of nine interventional clinical trials andlaunching of a Translational Center of Excellence in Cardio-Oncology and the Population Science Center ofExcellence in lung cancer screening. Developmental Funds during the current cycle supported three StaffInvestigators and two Developing Shared Resources (one in Circulating Tumor Material and one in CancerMetabolism). Both Developing Shared Resources supported multiple high-impact publications (includingpapers in Nature Cell JCI and PNAS) and services are now incorporated into full Shared Resources in thisrenewal application. Finally Developmental Funds were used to aid in the recruitment of three talented facultymembers (Dr. Kathrin Bernt Pediatric Oncology; Dr. Kara Maxwell Cancer Control; and Dr. Robert Maki whoarrived at Penn in 2020). In the coming cycle we are requesting Developmental Funds to continue our PilotProject Program to provide support for two Staff Investigators and to continue our recruitment of faculty-levelscientists in areas of strategic need. +No NIH Category available Abbreviations;Acceleration;Address;Affect;Alcohol consumption;Area;Aromatic Polycyclic Hydrocarbons;Behavioral Risk Factor Surveillance System;Black race;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Clinical Trials;Clinical and Translational Science Awards;Colorectal Cancer;Communication;Communities;Community Outreach;County;Data;Dedications;Delaware;Disparity;Electronic Health Record;Ensure;Environmental Hazards;Evaluation;Evidence based intervention;Evidence based treatment;Family;Foundations;Funding;Funding Mechanisms;Future;General Population;Geography;Goals;Guidelines;HIV/AIDS;Health;Health system;Human Papilloma Virus Vaccination;Human Papillomavirus;Impact evaluation;Incidence;Investments;Leadership;Liver;Logic;Lung;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Minority Participation;Mission;Modeling;New Jersey;Non-Hodgkin's Lymphoma;Obesity;Outcome;Output;Pediatric Hospitals;Pennsylvania;Perception;Personal Satisfaction;Persons;Philadelphia;Policies;Population;Population Sciences;Process;Prostate;Provider;Public Health;Reporting;Research;Research Project Grants;Resources;Risk Factors;Scientist;Screening for cancer;Shapes;Signal Recognition Particle;Smoking;Superfund;Sushi Domain;Tobacco use;Universities;Update;Work;acronyms;cancer health disparity;cancer prevention;cancer risk;carcinogenicity;chimeric antigen receptor T cells;community center;community engaged research;community engagement;design;detection method;disparity reduction;environmental carcinogenesis;evidence base;experience;health management;improved;medically underserved;melanoma;member;mortality;outreach;patient oriented;prevent;programs;residence;severe mental illness;skills;success;tobacco carcinogenesis;tool;treatment services;uptake Community Outreach and Engagement n/a NCI 10773023 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8317 7020943 "GUERRA, CARMEN E." Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 456211 280746 175465 PROJECT SUMMARY - Community Outreach and Engagement (COE)Community Outreach and Engagement (COE) is a longstanding priority of the Abramson Cancer Center (ACC)and leverages decades of commitment to address the cancer burden in our catchment area. COE's mission isto engage with the catchment area community; understand the cancer burden in the catchment area; ensurethat our Research Programs work to reduce cancer burdens; and disseminate evidence-based interventionsand policies in our catchment area and beyond. Leading our COE are two highly skilled and experiencedpopulation scientists: Dr. Karen Glanz Associate Director (AD) for Community-Engaged Research and Dr.Carmen Guerra AD for Diversity and Outreach who together bring the expertise and dedication needed toachieve the COE mission. They led the effort to comprehensively characterize our catchment area ageographically-defined area of 12 contiguous counties in Southeastern Pennsylvania New Jersey andDelaware with over 7 million residents which captures the residences of 81.4% of all ACC patients seenduring the current funding period. The ACC has invested heavily to systematically understand the uniquecancer burdens including cancer incidence and mortality rates disparities and cancer-related risk factorsacross the catchment area. Key aspects of the cancer burden in the catchment area include: a high overallcancer incidence; high incidence of prostate lung pancreas and liver cancers melanoma and non-Hodgkin'slymphoma; variable cancer incidence between Philadelphia County (lung liver) and the other counties in thecatchment area (breast prostate melanoma); differential cancer incidence and mortality between Black (lungliver) vs. White (breast prostate melanoma) catchment area residents; many medically underserved residentsparticularly in Philadelphia; areas with concentrated carcinogenic environmental hazards; and high rates ofobesity smoking and alcohol use. COE leaders manage a bidirectional process of communication workingwith the Community Advisory Board ACC leadership and Program Leaders to understand catchment areaneeds in order to shape research and outreach to reduce the cancer burden. COE uses a logic model as aconceptual framework to guide its activities objectives and evaluation of impact. During the current fundingperiod COE developed new tools (the ACC Catchment Explorer and Catchment Report) and catalyzedresearch to ensure an emphasis on data-driven priorities. Significant impacts of COE to date include achievinghigh rates of minority participation in clinical trials accelerating uptake of early cancer detection methodspromoting high rates of HPV vaccination and increasing tobacco use treatment. The accomplishments of COEto date reflect the ACC's deep commitment to community engagement catchment area-relevant research andthe dissemination of cancer prevention information and policies that directly affect the ACC catchment area. +No NIH Category available Abbreviations;Academy;Address;Adult;Affect;Animals;Area;Basic Science;Behavioral;Behavioral Sciences;Bioethics;Bioinformatics;Biometry;Biostatistics Shared Resource;Breast Cancer gene;Businesses;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cancer Model;Cancer Survivor;Cancer Survivorship;Caring;Catchment Area;Childhood;Clinical;Clinical Management;Clinical Medicine;Clinical Research;Clinical Trials;Cognitive Science;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Comparative Pathology;Data Analytics;Detection;Diet;Disparity;Early Diagnosis;Economics;Education;Electronic Health Record;Electronics;Enrollment;Environmental Risk Factor;Epidemiology;Equity;Faculty;Funding;Genes;Genetic;Genetic Counseling;Genetic Predisposition to Disease;Genomics;Goals;Grant;Health;Health Policy;Health Services;Health behavior;Healthcare;Hematologic Neoplasms;Image;Immunobiology;Incentives;Incidence;Individual;Informatics;Institution;Interdisciplinary Study;Intervention;Intervention Trial;Investments;Late Effects;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Mentors;Methods;Modeling;Morbidity - disease rate;Obesity;Outcome;Patient-Centered Care;Patient-Focused Outcomes;Pediatric Hospitals;Pediatric Oncology;Peer Review;Penetrance;Pennsylvania;Phenotype;Philadelphia;Population;Population Heterogeneity;Population Sciences;Predisposition;Prevention;Productivity;Public Health;Publications;Quality of life;Radiation;Radiobiology;Research;Research Personnel;Resources;Risk;Risk Factors;School Nursing;Schools;Science;Science of genetics;Scientific Inquiry;Screening for cancer;Social Psychology;Social Sciences;Testicular Germ Cell Tumor;Therapeutic;Training;Translating;Universities;Vulnerable Populations;Work;acronyms;biobank;cancer care;cancer genomics;cancer health disparity;cancer risk;cancer therapy;care outcomes;clinical practice;communication behavior;community engaged research;community engagement;comparative efficacy;end of life care;environmental carcinogenesis;evidence base;high school;imaging program;improved;improved outcome;innovation;malignant breast neoplasm;medical schools;member;metabolomics;microbiome;mortality;next generation;novel;nutrition;population health;pragmatic trial;programs;recruit;risk variant;survivorship;telehealth;tobacco carcinogenesis;tobacco control;treatment disparity;treatment trial Cancer Control Program n/a NCI 10773009 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8313 1871396 "GLANZ, KAREN " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 74931 46111 28820 PROJECT SUMMARY Cancer Control ProgramThe Cancer Control Program (CCP) is a highly collaborative and transdisciplinary Program that focuses onidentifying and analyzing the genetic behavioral and health care determinants of cancer susceptibility andoutcomes in diverse and vulnerable populations and on developing evaluating and implementing interventionsto lower risk and improve cancer outcomes. CCP is one of two Population Science Research Programs of theAbramson Cancer Center (ACC). CCP has 39 members who work intra- and inter-Programmatically to applyadvances in science to population health and cutting-edge data analytics address the cancer burdens and riskfactors in our catchment area and train the next generation of cancer control researchers. Members conductresearch within four broad and interconnected Program aims: 1) Cancer Genomics and Risk; 2)Communication and Health Behavior; 3) Cancer Survivorship; and 4) Health Care Outcomes. CCP hasproduced a substantial body of high impact work in the current funding period. In Cancer Genomics and Riskmembers have established the basis for clinical management of individuals with moderate penetrance riskgenes for breast and colorectal cancer identified risk loci associated with susceptibility to testicular germ celltumors and established the comparable efficacy of genetic counseling delivered through telehealth. InCommunication and Health Behavior members have conducted innovative studies on the use of incentives forimproving early detection and novel transdisciplinary research in diet obesity and cancer. In CancerSurvivorship members have established clinical paradigms for cancer survivors through patient-centered careplans and have revealed important complexities in end of life care. In Health Outcomes members haveinnovated methods to use the electronic health record to improve health behaviors and have conductedpragmatic trials to innovate new models of high-quality cancer care. CCP recruited 17 new members during thecurrent funding period in the areas of epidemiology genomics biostatistics informatics nutrition and themicrobiome. CCP works closely with the Tobacco and Environmental Carcinogenesis Program to create arobust population science presence at the ACC. CCP members come from ten departments in the PerelmanSchool of Medicine School of Nursing Wharton School of Business and Annenberg School forCommunication. There have been 640 cancer-related publications over the current funding period (13% intra-Programmatic 35% inter-Programmatic 76% multi-institutional). Members have 30 R01-equivalents $14.5M(direct) in annual cancer-related research funding of which $11.6M is peer-reviewed and $3.8M is from NCI.During the funding period CCP members enrolled 10768 subjects onto interventional trials (with 819 ontotreatment trials) and 2923 subjects onto non-interventional trials. In sum CCP is a vibrant community ofinteractive population science investigators working across four inter-connected aims to further researchimpacting our catchment area and beyond. +No NIH Category available Address;Basic Science;Biological;Cancer Burden;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Community Outreach;Consultations;Department chair;Development;Direct Costs;Discipline of Nuclear Medicine;Disease;Doctor of Philosophy;Education and Outreach;Ensure;Environment;Funding;Goals;Hypoxia;Image;Imaging Device;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunobiology;Immunotherapy;Institution;Intervention;Intervention Trial;Ionizing radiation;Lead;Leadership;Malignant Neoplasms;Metabolic stress;Modality;Nonionizing Radiation;Normal tissue morphology;Patient-Focused Outcomes;Patients;Pediatric Oncology;Peer Review;Play;Protons;Publications;Radiation;Radiation Oncology;Radiation Tolerance;Radiation therapy;Radiobiology;Radiology Specialty;Radiopharmaceuticals;Research;Research Personnel;Research Project Grants;Resolution;Resource Sharing;Resources;Role;Schools;Senior Scientist;Technology;Testing;Therapeutic;Time;Translational Research;Tumor Biology;Tumor Tissue;Vision;Work;anti-cancer;cancer care;cancer therapy;checkpoint therapy;chimeric antigen receptor T cells;community engagement;designbuildtest;environmental carcinogenesis;epidemiology study;imaging agent;imaging biomarker;imaging modality;imaging program;improved;innovation;investigator-initiated trial;malignant breast neoplasm;member;mid-career faculty;novel;nuclear division;optimal treatments;professor;programs;proton beam;proton therapy;recruit;research and development;response;theranostics;tobacco carcinogenesis;translational pipeline;translational study;treatment response;tumor metabolism;tumor microenvironment Radiobiology and Imaging Program n/a NCI 10773003 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8311 11044822 "GADE, TERENCE P" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 74931 46111 28820 PROJECT SUMMARY Radiobiology and Imaging Program (RBI)The Radiobiology and Imaging Program (RBI) seeks to advance the understanding of the interaction ofionizing and non-ionizing radiation with cancer and normal tissues. RBI addresses the cancer burden withinour catchment area through collaboration with our Community Outreach and Engagement (COE). ScientificAims are to: 1) Develop and characterize agents to improve cancer therapy with radiation; 2) Investigateradiobiological or imaging methods of altering or interrogating the immune environment to improve therapeuticresponse; 3) Gain a deeper understanding of the tumor microenvironment (TME) and metabolism with the aimto leverage this understanding to improve therapeutic response; 4) Develop novel imaging to optimally guidecancer care; and 5) Understand the biological effects of protons to optimize their clinical use and determinewhich patients will benefit most from proton beam therapy. The Program is led by Amit Maity MD PhDProfessor and Executive Vice-Chair of the Department of Radiation Oncology and Daniel Pryma MDAssociate Professor of Radiology and Chief of the Division of Nuclear Medicine. Drs. Maity and Pryma areNCI-funded researchers who bring their scientific vision to this Program which is focused on basic andtranslational research and the development of investigator-initiated trials. Since the last renewal the ProgramLeaders recruited new junior and senior scientists enhanced collaborative peer-reviewed funding and morethan doubled accruals to interventional clinical trials especially investigator-initiated trials (which constitute91.6% of interventional accruals). Drs. Maity and Pryma expanded the Program's focus on imaging modalitiesand theranostics and further enhanced the integration and interplay between radiobiology and imaging in RBI.A major development has been the substantial expansion of both translational and clinical studies of protontherapy. RBI has critical interactions with other ACC Programs including Tumor Biology ImmunobiologyCancer Therapeutics Breast Cancer Cancer Control Tobacco and Environmental Carcinogenesis andPediatric Oncology. The 44 Program members represent seven departments from four schools at Penn. RBImembers have $12M in research grant funding (annual direct costs) of which $10.9M is peer-reviewed and$7M is NCI-funded. There were 654 cancer-related publications authored by Program members during theproject period. Of these 27% are intra-Programmatic 35% are inter-Programmatic and 64% are multi-institutional. RBI has 36 R01-equivalents. Program members accrued 1476 subjects to interventional trialsand 3611 subjects to non-interventional trials. +No NIH Category available Achievement;Acute;Acute Lymphocytic Leukemia;Adult Acute Lymphocytic Leukemia;Allogenic;Amaze;Antibody-drug conjugates;Area;B-Cell Acute Lymphoblastic Leukemia;Basic Science;Behavioral;Biology;Brain Neoplasms;CD19 gene;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cell Therapy;Cell Transplantation;Cellular biology;Chief Cell;Child;Childhood;Childhood Acute Lymphocytic Leukemia;Childhood Leukemia;Childhood Solid Neoplasm;Clinical Pharmacology;Clinical Research;Clinical Trials;Collaborations;Communities;Data Set;Development;Disease;Doctor of Philosophy;Educational Activities;Ensure;Epidemiology;Evaluation;FDA approved;Frequencies;Funding;Genomic approach;Genomics;Glioma;Goals;Grant;Hematologic Neoplasms;Immunobiology;Immunogenomics;Immunotherapy;Institution;Interleukin-6;International;Intervention Trial;Ki-1 Large-Cell Lymphoma;Laboratories;Leadership;Lesion;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Medicine;Molecular;Multicenter Trials;Nature;Neuroblastoma;Newly Diagnosed;Oncology;Pathogenesis;Pathway interactions;Patients;Pediatric Oncology;Pediatric Oncology Group;Pediatrics;Peer Review;Pharmaceutical Preparations;Philadelphia;Phosphotransferases;Physician Executives;Play;Precision therapeutics;Predisposition;Protocols documentation;Publications;Relapse;Research;Research Personnel;Risk;Role;Signal Transduction;Solid Neoplasm;Stem cell transplant;Systems Biology;T cell therapy;Testing;Therapeutic;Toxic effect;Translating;Translational Research;Tumor Biology;Work;bench to bedside;cancer genomics;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;clinical investigation;crizotinib;cytokine release syndrome;drug development;engineered T cells;fundamental research;gene therapy;genomic data;high risk;improved;inhibitor;innovation;kinase inhibitor;large scale data;leukemia;medical schools;member;mid-career faculty;neoplasm immunotherapy;novel;novel diagnostics;novel strategies;novel therapeutic intervention;novel therapeutics;oncology program;preclinical development;professor;programs;recruit;sarcoma;standard of care;success;survivorship;targeted treatment;tumor;tumor immunology;young adult Pediatric Oncology Program n/a NCI 10773000 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8309 1888808 "GRUPP, STEPHAN A." Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 74594 74594 0 PROJECT SUMMARY Pediatric Oncology (PO) ProgramThe Pediatric Oncology (PO) Program of the Abramson Cancer Center (ACC) discovers develops andtranslates novel therapeutic approaches to improve cure rates and reduce acute and long-term toxicities inchildren with cancer. Established in 1992 the Program has the overall goal to change the standard of care forchildren with cancer in the US and across the world. Scientific aims are: 1) Characterize molecularmechanisms of childhood cancers and predisposition for risk evaluation and precision therapies; 2) Furtherdevelop innovative cell therapies for hematologic malignancies to improve cure rates and minimize the use ofallogeneic stem cell transplantation; and 3) Identify targets in high risk and relapsed solid tumors and developnew therapies for these challenging tumors. The Program is led by Stephan Grupp MD PhD Professor ofPediatrics Chief of the Cell Therapy and Transplant Section and Medical Director of the Cell and GeneTherapy Laboratory and Kai Tan PhD Associate Professor of Pediatrics. Dr. Grupp is a world leader incellular therapy immunotherapy and translational research. Dr. Tan is a leading researcher in cancergenomics and systems biology. They provide translational and transdisciplinary leadership for 35 Programmembers who form a dynamic community of investigators from three Departments in the Perelman School ofMedicine. The Program has integrated basic translational and clinical research components with a diversegroup of investigators who have expertise in cancer genomics cell biology and signal transduction tumorimmunology and immunotherapy drug development clinical pharmacology epidemiology clinical researchcancer control survivorship and behavioral oncology. Members collaborate within Pediatric Oncology andwith the Cancer Control Cancer Therapeutics Tumor Biology Hematologic Malignancies and ImmunobiologyPrograms. Clinical investigations are robust with 1156 accruals to interventional trials and 2946 to non-interventional trials in the current funding period. Members engage in research that is relevant to majorpediatric cancer issues within our catchment area and are highly engaged in educational activities acrossPenn and beyond. Most notably in the current funding period PO members worked collaboratively withmembers of other Programs to develop CD19-targeted CAR-T cells (tisagenlecleucel) taking the first CAR-Ttherapy to FDA approval for children and young adults with ALL. Other accomplishments include advances fortargeted therapy of pediatric leukemia discovery of novel cancer pathways in neuroblastoma and gliomas andtwo new FDA approved drugs for pediatric solid tumors. Program members also play major leadership roles inthe national pediatric cooperative groups. Program members have $15.1M in annual grant funding (direct) ofwhich $9M is peer-reviewed and $6.3M is NCI-funded. The Program holds 21 R01 equivalents. There were570 cancer-related publications from the Program since 2015. Of these 30% are intra-Programmatic 18%resulted from inter-Programmatic collaboration and 83% are multi-institutional. +No NIH Category available Acceleration;Achievement;Address;Adult;American College of Radiology Imaging Network;Antineoplastic Agents;Autophagocytosis;Basic Science;Biological;Biological Assay;Biological Markers;Biotechnology;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Cellular Metabolic Process;Clinical Research;Clinical Trials;Collaborations;Community Outreach;DNA Damage;DNA Repair;Data;Direct Costs;Disease;Eastern Cooperative Oncology Group;Ensure;Epigenetic Process;Focus Groups;Funding;Goals;Grant;Hematologic Neoplasms;Immune response;Immunology;Immunotherapy;Industry;Institution;Intervention;Intervention Trial;Lead;Leadership;Liquid substance;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Modernization;Molecular Analysis;Monoclonal Antibodies;Oncogenes;Oncology;PD-1/PD-L1;Patient Care;Patient Monitoring;Patients;Pediatric Oncology;Peer Review;Pharmacodynamics;Phase;Phase I Clinical Trials;Phase III Clinical Trials;Play;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Program Research Project Grants;Publications;Research;Research Design;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Role;Safety;Schools;Scientific Advances and Accomplishments;Scientist;Series;Serious Adverse Event;Signal Transduction;Solid Neoplasm;Structure;TNFRSF5 gene;Testing;Therapeutic;Therapeutic Research;Translating;Translational Research;Vision;Work;anti-PD-1;anti-PD-L1 antibodies;anti-PD1 therapy;biobank;cancer cell;cancer therapy;chimeric antigen receptor;chimeric antigen receptor T cells;circulating DNA;clinical practice;community engagement;drug development;experience;improved;inhibitor therapy;innovation;insight;investigator-initiated trial;liquid biopsy;malignant breast neoplasm;melanoma;member;multidisciplinary;novel;novel therapeutics;oncology program;operation;phase I trial;phase II trial;phase III trial;precision medicine;programs;recruit;response biomarker;targeted treatment;translational scientist;trial design;tumor;tumor metabolism Cancer Therapeutics Program n/a NCI 10772989 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8306 1877669 "HAAS, NAOMI B" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 74933 46112 28821 PROJECT SUMMARY Cancer Therapeutics Program (CTP)The overall goal of this 25-year-old Program at the Abramson Cancer Center (ACC) is to use mechanisticinsights emerging from our basic science labs and CCSG Programs to improve cancer therapy for patients withadvanced solid tumors. CTP accomplishes this goal through three Specific Aims: 1) Translate mechanisticbiologic insights into Phase I trials; 2) Use data from Phase I trials to perform Phase II and Phase III trials tochange clinical practice; and 3) Discover and develop innovative biomarkers that enhance safety and efficacyof cancer therapies. This Program is co-led by Program Leaders (PLs) Drs. Ravi Amaravadi and Naomi Haasboth appointed in 2013. Drs. Amaravadi and Haas are NCI-funded researchers who bring highlycomplementary scientific visions and a notable depth of experience as accomplished translational researchers.CTP encompasses a full range of basic translational and clinical research. CTP works closely with leaders ofthe ACC Community Outreach and Engagement (COE) to understand the cancer burden in the ACCcatchment area and ensure that CTP research addresses the major unmet needs in our catchment area. CTPmembers work on improving cancer therapies for patients with advanced lethal and often highly symptomaticsolid tumors including lung prostate and pancreas cancer as well as melanoma and others. During thecurrent funding period the PLs aggressively recruited new junior and senior investigators to CTP reorganizedthe Program into disease-focused groups and promoted intra-Programmatic interactions through carefullyselected and relevant scientific themes including autophagy cancer cell metabolism targeted therapies andimmunotherapy. These efforts resulted in new multi-investigator grants including NCI Program Project grantsand SPORES that include CTP members new leadership positions in National Groups and an increase incollaborative publications. Interventional trial accruals were more than 640 per year on average (in CTP alone)representing an increase compared to the prior funding period; 59% of interventional accruals were oninvestigator-initiated trials. Major accomplishments include validating autophagy as a cancer target translatingbasic findings in DNA damage to new therapies in ovarian and pancreatic cancer determining thepharmacodynamics of PD-1 therapy in patients with earlier stage melanoma testing novel immunotherapiessuch as monalizumab CD40 mAb and CAR T cells in patients with solid tumors and advancing circulatingDNA as a biomarker of response in lung cancer. The 31 CTP full members and 28 CTP associate membersrepresent six departments from two schools at Penn. CTP members have $14.7M in annual cancer-relatedresearch grant funding (direct costs) of which $3.1M is NCI-funded and $4.5M is peer-reviewed. Thisrepresents an increase in total funding of $8M (120% increase) since 2015. Our Program has 16 R01-equivalents. There are 540 cancer-related publications from the Program since 2015. Of these 19% are intra-Programmatic 38% resulted from inter-Programmatic collaborations and 74% are multi-institutional. +No NIH Category available Accreditation;Address;Aftercare;Autophagocytosis;Award;Basic Science;Biological;Biological Markers;Biological Specimen Banks;Biology;Breast;Breast Cancer Cell;Breast Cancer Detection;Breast Cancer Treatment;CDK4 gene;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Cancer Research Project;Cancer Science;Caring;Catchment Area;Cell Cycle Progression;Cell Cycle Regulation;Cell Survival;Cessation of life;Clinical;Clinical Research;Clinical Trials;Collaborations;County;DNA Damage;Detection;Development;Diagnosis;Direct Costs;Disease;Faculty;Fostering;Foundations;Funding;Genes;Genetic;Genetic Predisposition to Disease;Genomics;Goals;Grant;Image;Immune response;Immunology;Immunotherapy;Inherited;Institution;Interferons;International;Intervention Trial;Ionizing radiation;Knowledge;Laboratories;Magnetic Resonance Imaging;Malignant Neoplasms;Modeling;Modernization;Molecular;Monitor;Multicenter Trials;Nature;Needles;Neoadjuvant Therapy;Oncogenic;Outcome;PARP inhibition;Paper;Peer Review;Penetrance;Population;Pre-Clinical Model;Prediction of Response to Therapy;Prevention;Productivity;Publishing;Radiation;Recurrence;Research;Research Personnel;Residual Neoplasm;Risk;Risk Adjustment;Role;Schools;Signal Transduction;Sorbus;Technology;Testing;Translating;Translations;Universities;Woman;anticancer research;brca gene;breast cancer diagnosis;cancer diagnosis;cancer prevention;chimeric antigen receptor T cells;circulating biomarkers;clinical biomarkers;clinical translation;combinatorial;design;genetic testing;genome integrity;imaging approach;imaging modality;imaging probe;immune activation;immunogenicity;improved;individualized medicine;inhibitor;innovation;malignant breast neoplasm;member;mortality;mouse model;multidisciplinary;mutant;new technology;new therapeutic target;novel;novel strategies;novel therapeutics;personalized screening;predictive test;prevent;programs;radiomics;radiotracer;recruit;response;response biomarker;screening;skills;success;surveillance strategy;survivorship;tomosynthesis;treatment and outcome;treatment response;treatment strategy;tumor Breast Cancer Program n/a NCI 10772984 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8305 1857505 "DEMICHELE, ANGELA " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 74933 46112 28821 PROJECT SUMMARY Breast Cancer ProgramThe Breast Cancer Program (BCP) of the Abramson Cancer Center (ACC) is a multidisciplinary team of highlyproductive investigators focused on a common goal: to reduce the burden and mortality of breast cancer byelucidating biological mechanisms underlying the disease and translating this knowledge to improveddetection prevention and treatment. BCP members are highly collaborative working on interconnectedscientific aims that span the continuum from basic science to clinical research. Specific Aims are: 1) Elucidatethe biologic genetic and molecular mechanisms of breast cancer development and progression; 2) Advanceunderstanding of genetic susceptibility to optimize screening and prevention for those at risk; 3) Developinnovative imaging approaches to improve breast cancer screening detection and biomarkers to guidetreatment and assess therapeutic response and 4) Translate laboratory discoveries to clinical trials of noveltherapeutics incorporating biomarkers of response and outcome. Members made fundamental discoveries toidentify breast cancer drivers mechanisms of tumor dormancy and genome integrity interferon response andthe relationship between radiation and immunogenicity. These findings were translated into new targetedtherapeutics novel combinations genomic and predictive assays and cutting-edge imaging methods andprobes. Program members design and implement innovative clinical trials leading clinical/translational teamswithin the ACC nationally and internationally. In the current funding period there were 1386 accruals ontointerventional trials and 14079 accruals onto non-interventional trials. The complementary skills of Programco-Leaders (PLs) Angela DeMichele MD MSCE (clinical trials/biomarkers) and Roger Greenberg MD PhD(basic science/genetics) facilitate intra- and inter- Programmatic collaborations. With clinical translation of basicscience as a major focus the PLs expanded clinical research units for breast cancer and genetics grew andcurated large biospecimen banks and recruited exceptional senior and junior faculty. These developmentshave fostered new ideas and collaborations supported by ACC pilot funds. The PLs also initiated two newbasic science centers the Center for Genome Integrity and the Mark Foundation Center. The 25 members ofBCP come from seven University Departments and two Schools reflecting diverse expertise. BCP membershold $10.4M in cancer-related grant funding (annual direct costs) of which $6.6M is peer-reviewed and $4.3Mis NCI-funded. Members hold 26 R01s or equivalent (of which six are multi-PI awards) an NCI R33 MoonshotGrant and a DOD Breast Cancer Center of Excellence. Over the current funding cycle BCP memberspublished 403 cancer-related papers of which 22% were intra-Programmatic collaborations 37% were inter-Programmatic collaborations and 72% were multi-institutional in nature. Supported by senior clinical leaderswithin the National Accreditation Program for Breast Centers-accredited Rowan Breast Center BCP generateshigh-impact practice-changing research moving the needle on breast cancer treatment and outcomes. +No NIH Category available Abbreviations;Academy;American;American Cancer Society;Androgen Receptor;Androgens;Antineoplastic Agents;Applied Research;Area;Arts;Award;Basic Cancer Research;Basic Science;Biological;Biological Assay;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Model;Catchment Area;Cells;Cellular biology;Chemoresistance;Chromatin;Clear cell renal cell carcinoma;Clinic;Collaborations;Community Outreach;Conventional (Clear Cell) Renal Cell Carcinoma;DNA Methylation;DNA Sequence;Dental Schools;Detection;Diagnostic;Direct Costs;Doctor of Philosophy;Drosophila genus;Early Diagnosis;Early treatment;Education;Endothelial Cells;Engineering;Environment;Epidermal Growth Factor Receptor;Epigenetic Process;Epithelium;Eye;Faculty;Fostering;Funding;Gene Expression;Glioblastoma;Goals;Grant;HMGB Family Gene;Heritability;High Mobility Group Proteins;High School Student;IFNAR1 gene;Image;Immune;Immune Evasion;In Vitro;Inflammation;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of prostate;Mass Spectrum Analysis;Medal;Medicine;Mentors;Mentorship;Mesenchymal;Metabolism;Methods;Molecular;Molecular Biology;Mutation;Pancreatic Ductal Adenocarcinoma;Paper;Pathway interactions;Peer Review;Pennsylvania;Philadelphia;Physicians;Play;Postdoctoral Fellow;Prevention strategy;Preventive;Process;Publications;Publishing;Radiobiology;Research;Resistance;Retinoblastoma;Role;Scholars Program;Schools;Science;Scientist;Signal Pathway;Signal Transduction;Societies;Stromal Cells;Technology;Therapeutic;Training;Transcriptional Regulation;Translating;Transposase;Tumor Biology;Tumor Escape;United States National Academy of Sciences;United States National Institutes of Health;Universities;Veterinary Medicine;Veterinary Schools;Viral;XCL1 gene;acronyms;anticancer research;cancer cell;cancer initiation;castration resistant prostate cancer;chimeric antigen receptor;clinical investigation;community engagement;doctoral student;drug sensitivity;environmental carcinogenesis;epigenetic regulation;epithelial to mesenchymal transition;genome integrity;health disparity;histone modification;imaging program;in vivo Model;innovation;insight;interest;medical schools;meetings;member;mimicry;novel;optogenetics;prognostic;programs;protein B;recruit;school district;success;symposium;tobacco carcinogenesis;tumor;tumor growth;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis;type I interferon receptor;undergraduate student Tumor Biology Program n/a NCI 10772981 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8304 1860700 "BERGER, SHELLEY L" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 74933 46112 28821 PROJECT SUMMARY Tumor Biology Program The Tumor Biology Program is one of two basic science Research Programs of the Abramson Cancer Center (ACC). This Program aims to catalyze research within the ACC to advance an understanding of mechanisms underlying tumorigenesis and to identify pathways that will enable novel preventive diagnostic prognostic and therapeutic approaches to cancer. Since its inception in the early 1970s the Tumor Biology Program has continued to respond to emerging areas and advances in cancer research. The Program is currently organized around three central Aims: 1) Elucidate the molecular and cellular basis underlying cancer; 2) Understand the epigenetics of cancer; and 3) Investigate the tumor microenvironment and metastatic progression. Members of Tumor Biology are highly interactive collaborating intra-Programmatically across scientific topics relevant to each Aim including genome integrity cell signaling metabolism and viral pathways with an eye on cancers of highest burden or health disparity in our catchment area. Ground-breaking discoveries in Tumor Biology uncovered novel mechanisms of epithelial-mesenchymal transition transcriptional control of cancer drug sensitivity epigenetic regulation of inflammation novel mechanisms of androgen-resistance in prostate cancer and immune evasion by viral mimicry. New targets were translated to the clinic in collaboration with other Programs for early detection and treatment. The Tumor Biology Program is led by new and energetic Program co-Leaders (PLs) Shelley Berger PhD and Sandra Ryeom PhD who together catalyze impactful intra- and inter-Programmatic collaborations by a variety of innovative methods. The PLs are instrumental in recruiting new members mentoring junior faculty stimulating interactions and meetings among faculty members and organizing conferences and symposia. Tumor Biology Program members play key roles in the training and mentorship of high school students PhD students MD/PhD students and MD or PhD postdoctoral fellows in cancer-related research through their leadership roles in the University of Pennsylvania Biomedical Graduate Studies (BGS) MD/PhD program (MSTP) and NIH T32 training grants. The continued success of the Tumor Biology Program is evidenced by the exceptional scientific progress of its members demonstrated through high-impact publications with multi-institutional inter- and intra-Programmatic collaborations offering key insights into the biology of cancer. Currently the Program has 53 members from 20 departments and five different schools with total funding of $25.7M (annual direct costs) of which 20.0M is peer-reviewed and $6.4M is NCI-funded. The Program has 67 R01-equivalents. Since 2015 Tumor Biology Program members published 617 cancer-related papers of which 15% were intra-Programmatic 29% were inter-Programmatic and 62% were multi-institutional. +No NIH Category available Abbreviations;Acceleration;Address;Advanced Malignant Neoplasm;Applications Grants;Area;Bioethics;Cancer Center;Cancer Center Support Grant;Clinical;Clinical and Translational Science Awards;Collaborations;Community Outreach;Data;Databases;Development;Discipline;Education;Educational Activities;Educational Status;Ensure;Evaluation;Faculty;Funding;Future;Genetic Counseling;Goals;Grant;Health Policy;Improve Access;Individual;Lead;Leadership;Malignant Neoplasms;Measures;Medical;Mentored Clinical Scientist Development Program;Mentors;Mentorship;Minority;Mission;NCI Center for Cancer Research;Outcome;Pediatric Hospitals;Peer Review;Pennsylvania;Philadelphia;Physics;Preparation;Professional Education;Radiation;Radiobiology;Research;Research Methodology;Research Personnel;Research Training;Resource Sharing;Role;Schedule;Schools;Science;Scientific Inquiry;Scientist;Students;Testing;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underrepresented Minority;Universities;Woman;Youth;acronyms;anticancer research;cancer care;cancer education;career;career development;clinical epidemiology;community engagement;continuing medical education;education research;environmental carcinogenesis;faculty mentor;faculty research;graduate medical education;high school;imaging program;improved;innovation;medical schools;member;operation;population based;post-doctoral training;programs;success;tobacco carcinogenesis;tool;training opportunity;translational medicine;translational therapeutics;undergraduate medical education;undergraduate student Cancer Research Training and Education Coordination n/a NCI 10772975 12/7/23 0:00 PAR-20-043 5P30CA016520-48 5 P30 CA 16520 48 1/15/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8302 1891470 "MANKOFF, DAVID A." Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 167971 103367 64604 PROJECT SUMMARY Cancer Research Training and Education Coordination (CRTEC)Education and training have been central to the mission of the Abramson Cancer Center (ACC) throughout itsexistence. The ACC Cancer Research Training and Education Coordination (CRTEC) component coordinatesACC cancer-related education training and career activities. In this role CRTEC integrates these activitiesacross the Penn campus including the ACC the Perelman School of Medicine (PSOM) and nine other PennSchools that have activities with cancer education and training content. A prime focus of CRTEC is to drive andpromote cancer education and training activities in the ACC and across the University of Pennsylvania with thegoals of delivering cancer-related education to students trainees faculty and other professionals andexpanding and diversifying the cancer workforce through targeted education training and mentorship. TheSpecific Aims of CRTEC are as follows: Aim 1: Coordinate cancer education training and career developmentactivities across the ACC and Penn; Aim 2: Provide cancer research-related education training andmentorship to individuals ranging from high school and undergraduate students to cancer professionals withan emphasis on ensuring a diverse and enduring pipeline of trainees and future cancer researchers; and Aim3: Evaluate the quality and impact of ACC CRTEC activities to improve ACC education/training and to guidenew CRTEC developments. CRTEC impacts students trainees and professionals with a goal to advancecancer research careers starting with entry-level professional training through faculty and cancer researchleadership roles. CRTEC is led by an ACC Associate Director for Education and Training senior support staffand an Operations Committee. It interacts with the Programs Shared Resources and Community Outreachand Engagement. CRTEC impacts the ACC by (1) coordinating the already diverse well-established andextensive cancer-related education and training activities at the ACC and Penn; (2) improving access tocancer-related education for students trainees staff and professionals; (3) sustaining cancer careerdevelopment through integrated cancer-related training and mentoring for faculty trainees and staff; and (4)enhancing diversity at all levels of education and training. CRTEC leverages formidable strengths at ACC andPenn in cancer education and training that include a compact accessible and highly integrated campus withextraordinary depth in all disciplines relevant to cancer research; longstanding cancer-focused education in theACC PSOM and other Schools; a uniquely large and diverse portfolio of GME and biomedical postdoctoraltraining programs many with decades of NCI and other funding; extensive ACC-directed professionaleducation; and expertise and national leadership in basic translational clinical and population-based cancerresearch. CRTEC provides ACC members with a central point of contact for innovations in cancer-relatededucation and training. +No NIH Category available Apoptosis;Apoptotic;B-Cell Leukemia;B-Cell Lymphomas;B-Lymphocytes;BCL2 gene;BCL2L1 gene;Biological Markers;Burkitt Lymphoma;Cancer Etiology;Cell Line;Cell Survival;Clinic;Clinical Trials;Combined Modality Therapy;Development;Diagnostic;FDA approved;Family;Family member;Family psychotherapy;Follicular Lymphoma;Genomic approach;Genomics;Hematologic Neoplasms;Human;Human Cell Line;Investigation;Knowledge;Link;Lymphoid;Lymphoma;Lymphoma cell;Lymphomagenesis;MCL1 gene;Malignant Neoplasms;Molecular;Monitor;Mus;Pathway interactions;Patients;Population;Protein Family;Proteins;Resistance;Role;Sampling;Scientist;Spermatogenesis;System;Testing;Therapeutic;Therapeutic Intervention;biomarker identification;cancer cell;cancer therapy;experimental study;improved;inhibitor;innovation;knowledge base;large cell Diffuse non-Hodgkin's lymphoma;leukemia;mouse model;non-genomic;novel;overexpression;patient derived xenograft model;pressure;prognostic;prognostic indicator;resistance mechanism;single cell analysis;targeted treatment;therapeutic target;therapy resistant;treatment response;tumor;tumorigenesis BCLW in lymphoma survival and resistance to targeted BCL2 family therapies NarrativeDysregulation of the anti-apoptotic BCL2 family of proteins allows cancer cells to survive. Results from theproposed studies will significantly increase understanding of an understudied BCL2 family member and itscontribution to lymphoma survival and resistance to targeted therapies. Our studies will ultimately lead toimproved therapeutic targeting for the treatment of lymphomas and likely other malignancies. NCI 10772969 11/29/23 0:00 PA-19-056 5R01CA236853-05 5 R01 CA 236853 5 "JHAPPAN, CHAMELLI" 12/1/19 0:00 11/30/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 1902443 "EISCHEN, CHRISTINE M." Not Applicable 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 336543 NCI 215733 120810 SummaryA prerequisite for tumor development is acquiring resistance to apoptosis. This can be accomplished throughmultiple mechanisms but a frequent alteration in human cancers that protects from apoptosis is theoverexpression of one or more of the anti-apoptotic BCL2 family members. BCL2 itself is frequentlyoverexpressed in multiple types of B cell lymphomas and many other lymphoid and non-lymphoid malignancies.Because of the perceived reliance of cancer cells on BCL2 for survival a targeted specific BCL2 inhibitor wasdeveloped ABT-199 (venetoclax). Although venetoclax has been FDA approved for the treatment of specificleukemias clinical trials with venetoclax have not been successful for B cell lymphomas with high levels of BCL2such as follicular lymphomas and diffuse large B cell lymphomas (DLBCL) that have translocated or amplifiedBCL2. The results indicate these lymphomas do not require BCL2 for their continued survival revealing asignificant gap in knowledge of what lymphomas use to protect themselves from apoptosis. Recently we madethe unexpected discovery that BCLW an unexplored anti-apoptotic BCL2 family member that was only thoughtto be important in spermatogenesis was overexpressed in six different types of B cell lymphomas includingfollicular lymphoma and DLBCL. We determined patients with DLBCL containing higher levels of BCLW hadreduced survival and BCLW was more highly expressed than BCL2 in higher grade follicular lymphoma. Wealso showed BCLW was necessary for the survival of Burkitt lymphoma cells and increased levels of BCLWprovided resistance to Burkitt lymphoma cells to an inhibitor that targets three anti-apoptotic BCL2 familymembers. Therefore we hypothesize BCLW overexpression is necessary for the survival of multiple types of Bcell lymphomas and confers resistance to lymphoma cells to venetoclax and other BCL2 family inhibitors. Wepropose two Aims to test this hypothesis. In Aim 1 we propose to evaluate the requirements of BCLW in multipledifferent B cell lymphomas in relationship to other BCL2 family members and mechanisms for its overexpression.In Aim 2 we propose to determine the contribution of BCLW to resistance to inhibitors of anti-apoptotic BCL2family members and ways to overcome this resistance. Completion of these Aims will significantly increaseknowledge into the BCL2 family of proteins and the contribution of BCLW to B cell lymphomas and resistance totargeted inhibitors of BCL2 family members. Results are also likely to lead to improved lymphoma clinical trialsdiagnostics prognostics and therapeutic interventions with knowledge based treatment combinations. 336543 +No NIH Category available Address;Cancer Institute of New Jersey;Clinical;Community Outreach;Development;Educational workshop;Environment;Funding;Goals;Grant;Healthcare;High School Faculty;Malignant Neoplasms;Medical Students;Mentors;New Jersey;Oncology;Parents;Physicians;Postdoctoral Fellow;Public Health;Research;Research Training;Schools;Science;Science Technology Engineering and Mathematics Education;Students;Training;Training Programs;Underrepresented Minority;Wood material;Youth;anticancer research;cancer health disparity;career;clinical training;cost;equity diversity and inclusion;experience;high school;improved;junior high school;medical schools;minority children;minority trainee;peer coaching;programs;role model;school district;science teacher;skills;success;teacher mentor;underrepresented minority student Rutgers Youth Enjoy Science (RUYES) program Project NarrativeThe proposed supplement to Rutgers Youth Enjoy Science (RUYES) project is relevant to public health becauseit will develop a more diverse biomedical cancer research and healthcare workforce to address cancer healthdisparities in New Jersey and nationally. The supplement will provide workshops that augment peer mentors andmentees skills to enhance the overall mentoring and training environment at the Rutgers Cancer Institute of NewJersey. It will support Teacher Mentors who will establish Science Clubs in middle and high schools to increasethe value of STEM education in the students. This project will also provide research and clinical training tounderrepresented medical students to pursue careers in oncology. In addition the medical students will serveas role models and pee-mentors to RUYES trainees. NCI 10772813 8/1/23 0:00 PA-20-272 3R25CA247785-03S1 3 R25 CA 247785 3 S1 "LOPEZ, BELEM G" 9/1/20 0:00 11/30/23 0:00 ZCA1(J2) 8936236 "CHAUDHARY, SUNITA " Not Applicable 10 SURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 310 Other Research-Related 2023 106232 OD 98363 7869 AbstractIn alignment with the strategic goals of Rutgers Cancer Institute and NCI the goal of thissupplement is to enhance an inclusive mentoring environment and promote the value ofdiversity equity and inclusion at Rutgers Cancer Institute. To achieve this goal we aim to: 1)enhance the mentoring skills of students and post-doctoral fellows who serve as peer-mentors atRutgers Cancer Institute; and support development of mentee skills required to managementoring relationships to succeed in research training (Mentoring Up); 2) organize oncologyrelated Science Clubs in middle/high schools by Teacher Mentors; and 3) provide mentoredclinical and research experience to under-represented minority (URM) medical students toencourage them to pursue oncology careers. Effective mentoring relationships are critical forsupporting mentees' continued professional development and for overcoming barriers to successparticularly for URM trainees. Formal training to improve mentor and mentee skills benefits boththe mentor and mentee. For Aim 1 we will initiate formal peer-mentor and mentee trainingprograms at Rutgers Cancer Institute. For Science Club Teacher Mentors initiative (Aim 2) wewill establish after-school Science clubs in 4 middle and high schools in school districts withhigh percentage of URM students. For Aim 3 the Oncology Physician Training Initiative toMaximize Diversity (OPTIM) we engage first year URM medical students (from Rutgers RobertWood Johnson Medical School (RWJMS)) in clinical shadowing cancer research and peermentoring of trainees in the Rutgers Youth Enjoy Science Program (RUYES). The supplementsupports costs associated with developing inclusive peer-mentor and mentee trainings;establishing Science Clubs in middle/high schools; and trainee slots for medical students in thenewly established Oncology Physician Training Initiative to Maximize Diversity (OPTIM). Thissupplement builds on the parent NCI funded R25 Training Grant (RUYES; 1R25CA247785)which engages high school science teachers and URM youth in mentored cancer researchprofessional development and community outreach activities to build a diverse oncologyworkforce. 106232 +No NIH Category available Achievement;Address;Affect;Age;Agriculture;Antineoplastic Agents;Area;Behavior;Biological Sciences;Biomedical Engineering;Businesses;California;Cancer Biology;Cancer Burden;Cancer Control;Cancer Model;Caring;Catchment Area;Cervical Cancer Education;Cervix Uteri;Cessation of life;Client;Clinic;Clinical;Clinical Services;Clinical Trials;Collaborations;Collection;Communication;Communities;Community Health;Community Health Aides;Community Outreach;Comprehensive Cancer Center;Country;County;Coupled;DNA Repair;Diagnosis;Diagnostic;Discipline;Disease;Disparity population;Dissemination and Implementation;Early Diagnosis;Education;Education and Outreach;Educational Models;Engineering;Enrollment;Environmental Science;Equity;Evidence based intervention;Federally Qualified Health Center;Funding;Geographic Locations;Goals;Grant;Health;Health Educators;Health behavior;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Image;Imaging Device;Immunology;Individual;Institution;Intervention;Intervention Studies;Journals;Knowledge;Leadership;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medical Imaging;Metabolism;Microscopic;Mission;Molecular;Multimedia;NCI-Designated Cancer Center;Oncology;Outcome;Palpable;Pap smear;Patients;Population;Positioning Attribute;Positron-Emission Tomography;Prevention;Prevention program;Prevention strategy;Primary Prevention;Productivity;Prunus persica;Publications;Publishing;Radio;Recording of previous events;Research;Resources;Rural;Science;Scientist;Screening for cancer;Secure;Services;Signal Transduction;Solid;System;Techniques;Technology;Testing;Time;Training;Underserved Population;United States National Institutes of Health;Universities;Vaccination;Veterinary Medicine;Vision;Vulnerable Populations;Woman;Workforce Development;cancer education;cancer health disparity;cancer risk;career development;cervical cancer prevention;community clinic;community engaged research;community engagement;community setting;comparative;disparity reduction;economic disparity;ethnic disparity;ethnic diversity;health care delivery;health equity;implementation outcomes;improved;innovation;insight;medical schools;member;neighborhood disadvantage;novel;outcome disparities;prevent;primary care team;programs;racial diversity;racial population;risk mitigation;satisfaction;screening;screening guidelines;screening program;social disparities;system-level barriers;tobacco control;treatment as usual;treatment trial;vaccine acceptance;women of color Healthy Cervix: A Clinic Community Health Educator-Based Cervical Cancer Education Prevention and Screening Program (HEALIX) PROJECT NARRATIVEProjections estimate that approximately 13960 women in the U.S will be diagnosed with cervical cancer in 2023and about 4310 women will die from the disease with most of these cases and deaths occurring among sociallyand economically disadvantaged women of color. Human papilloma virus vaccination coupled with earlydetection is the optimal primary prevention strategy against cervical cancer with potential to eliminate cervicalcancer disparities. To address the current dearth of effective preventative programs embedded within thecommunity health clinic system we propose to prepare for and implement the Healthy Cervix (a.k.a. HEALIX)program a community clinic health educator-based cervical cancer education prevention and screening effortthat addresses individual community and systems level barriers to achieve equity and eliminate cervical cancer. NCI 10772727 9/15/23 0:00 PA-20-272 3P30CA093373-21S1 3 P30 CA 93373 21 S1 "ROBERSON, SONYA" 7/1/02 0:00 6/30/26 0:00 ZCA1(M1) 6094231 "LARA, PRIMO N." Not Applicable 4 INTERNAL MEDICINE/MEDICINE 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 310 Research Centers 2023 197070 OD 140000 57070 PROJECT SUMMARYWidespread use of the human papilloma virus (HPV) vaccine coupled with early detection is expected to reducethe cervical cancer burden across all racial/ethnic groups and mitigate disparities as women of color aredisproportionately affected by cervical cancer. To address the current dearth of effective preventative programsembedded within the community health clinic system where most of the underserved populations receive carewe developed the Healthy Cervix program a community clinic health educator-based cervical cancer educationprevention and screening effort (HEALIX) built as a community engaged research collaboration between theUniversity of California Davis Comprehensive Cancer Center and Peach Tree Health (Peach Tree) a FederallyQualified Health Center (FQHC). HEALIX is grounded in a multilevel health equity framework merging acommunity health worker-led outreach and education model approach with cervical cancer training for primarycare teams and the option of both HPVself-collectionand clinical Papanicolaou (Pap) testing for clients/patients.The primary goal of this study is to evaluate the acceptability appropriateness and feasibility of implementingthis multilevel intervention which addresses individual community and systems level barriers on increasingHPV completion rates among patients ages 9-17 and Pap testing among women ages 21-65 in three of PeachTrees clinics compared to usual care. This will be accomplished through the following aims: Aim 1) Customizeand contextualize cervical cancer prevention communications education strategies and multi-media deliverymodes that will inform necessary adaptations to the proposed multilevel intervention; and Aim 2) Pilot theHEALIX multilevel intervention in three Peach Tree clinics evaluating selected implementation outcomes andexploring service (screening/vaccination rates) and client/patient (satisfaction) outcomes.The proposed research is significant because it will contribute to the field of multilevel intervention research tomitigate cervical cancer disparities and addresses the need for more scientifically rigorous evidence-basedinterventions that can be disseminated and implemented in diverse communities. Successful achievement of ourAims will significantly increase HPV vaccination and Pap testing rates over baseline advance our understandingof the utility of HPV self-collection kits in community settings; and will provide insights on strategies that can beutilized to address other cancer health disparities impacting women. Furthermore given the paucity of effectivemultilevel interventions to increase HPV vaccine uptake and Pap testing in understudied underrepresented andunderreported communities this study can guide effective dissemination and implementation of empiricallyderived evidence-based interventions for health care delivery systems serving rural racially/ethnically diverseand socially disadvantaged communities. 197070 +No NIH Category available ABCB1 gene;Abraxane;Address;Affinity;Antineoplastic Agents;Applications Grants;Binding;Biodistribution;Blood Circulation Time;Brain;Breast Cancer Cell;Breast Cancer Patient;Cell Surface Receptors;Clinical;Couples;Data;Development;Diameter;Doxorubicin;Drug Combinations;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug usage;Engineering;Epidermal Growth Factor Receptor;Equilibrium;Estrogen Receptors;Exhibits;Extracellular Matrix;Extravasation;FDA approved;Fibroblast Growth Factor;Formulation;Future;Goals;Human;In Vitro;Knowledge;Lung;MDA MB 231;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Methods;Modeling;Multi-Drug Resistance;Mus;Neoplasm Metastasis;Ovarian;Paclitaxel;Particle Size;Patient-derived xenograft models of breast cancer;Patients;Penetration;Pharmaceutical Preparations;Polyethylene Glycols;Primary Neoplasm;Progesterone Receptors;Prostate;Pump;Role;Surface Plasmon Resonance;Testing;Therapeutic;Tissues;Toxic effect;Translating;Treatment Efficacy;Tumor Necrosis Factor Receptor;Tumor Tissue;Vertebral column;Work;Xenograft procedure;aggressive breast cancer;cancer type;chemotherapy;cytotoxicity;drug distribution;drug resistance development;effective therapy;hormone therapy;improved;in vivo;innovation;insight;malignant breast neoplasm;member;molecular drug target;nanoparticle;nanoparticle drug;nanopolymer;neoplastic cell;novel;orthotopic breast cancer;particle;receptor internalization;surface coating;targeted agent;therapeutic nanoparticles;trafficking;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor xenograft;uptake Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer Project NarrativeTriple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer and managementof this cancer is challenging because it does not respond well to most of the FDA-approved breast cancer drugs.The goal of this study is to develop targeted tumor-penetrating nanoparticles to more effectively deliverchemotherapeutics to TNBC tumors and metastases. The proposed studies may in the long term have highclinical impact with respect to our current treatment options for TNBC patients. NCI 10772405 5/25/23 0:00 PA-16-160 4R37CA218617-06 4 R37 CA 218617 6 "SORG, BRIAN S" 3/1/18 0:00 2/28/25 0:00 Nanotechnology Study Section[NANO] 10117396 "KIM, ANTHONY J" Not Applicable 7 NEUROSURGERY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 340673 NCI 220500 120173 Project Summary and AbstractTriple-negative breast cancer (TNBC) - an aggressive subtype of breast cancer that is associated with increasedmetastatic potential and poor patient survival - is characterized by the lack of expression of estrogen receptor(ER) progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) and accounts for ~15-20% of invasive breast cancers. TNBC represents an important clinical challenge because these cancersrespond poorly to endocrine therapy or other available targeted agents; thus chemotherapy is currently thebackbone of standard therapy with a median survival of only ~13 months. Current FDA-approved nanoparticle-drug formulations of doxorubicin (Doxil) and paclitaxel (Abraxane) have been studied for the treatment of TNBChowever neither have been shown to significantly improve tumor control or patient survival. This is most likelydue to (i) limited extravasation from the tumor vasculature (ii) poor penetration within breast tumor tissue (iii)inability to efficiently target tumor cell drug uptake within the tumor microenvironment and (iv) development ofdrug resistance via expression of multidrug resistance (MDR) pumps such as P-glycoprotein. To address thesetherapeutic barriers we have recently: (1) engineered relatively large polymeric nanoparticles (between 63 to114 nm) that rapidly penetrate in breast tumor tissue with tumor-specific fibroblast growth factor-inducible 14(Fn14)-targeting to further improve particle dispersion drug distribution and tumor-specific cellular uptake withinthe tumor microenvironment and (2) developed a novel high-throughput method for quantitative characterizationof Fn14-specific and nonspecific binding (towards tumor ECM) of various nanoparticle formulations. Thus thecentral hypothesis of this grant proposal is that by modulating the Fn14-specific equilibrium binding affinities (KD)and minimizing the nonspecific binding to tumor ECM Fn14-targeted tumor penetrating nanoparticles will (1)provide well-dispersed sustained delivery into the tumor and regions of the tumor tissue that contain TNBC cellsand (2) specifically target to and efficiently traffic within Fn14-positive TNBC cells while sparing adjacent healthytissues from toxic effects. This strategy is likely to result in significant improvements in efficacy and reduce toxicityin TNBC primary tumors and disseminated metastases compared to free drugs and their clinical nanoparticleformulation counterparts which will generate new insights into the rate-limiting barriers and mechanisms oftumor-specific targeting for nanoparticle therapeutics. Future applications of the information obtained from thisproject may be applied to improve the delivery and therapeutic efficacy of molecularly targeted drugs and drugcombinations which has the potential to eventually translate into novel more effective treatment strategies.Importantly the successful development of effective nanoparticle therapeutics for TNBC should allow us toextend these findings to the treatment of other Fn14-positive cancer types (e.g. lung prostate ovarian brain). 340673 +No NIH Category available Address;Affect;Antibody-drug conjugates;Attention;Biosensor;Cancer Histology;Cancer Patient;Categories;Cells;Chemotherapy and/or radiation;Clinical;Cytotoxic Chemotherapy;DNA Damage;DNA Repair;Data;Diagnosis;Drug Delivery Systems;Drug Sensitization;Drug usage;Family;Foundations;Frustration;Goals;Heterogeneity;Human;Ionizing radiation;Label;Link;MEKs;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mus;Nonmetastatic;Normal tissue morphology;Oncogenes;Organ;Pathway interactions;Patient-Focused Outcomes;Patients;Penetration;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Process;Prodrugs;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Resistance;Role;Schedule;Serine;Signal Pathway;Signal Transduction;Techniques;Technology;Testing;Therapeutic;Therapeutic Index;Toxic effect;Translating;Treatment Efficacy;Tumor Cell Line;Tumor Tissue;Unresectable;Work;biomarker driven;cancer cell;cancer survival;cancer therapy;cell killing;chemotherapy;clinical translation;clinically relevant;curative treatments;cytotoxic;delivery vehicle;extracellular;flexibility;genetic approach;homologous recombination;improved;improved outcome;inhibitor;innovation;insight;kinase inhibitor;molecular targeted therapies;neoplastic cell;novel;novel therapeutics;p21 activated kinase;p21-activated kinase 1;patient derived xenograft model;peptide drug;pharmacologic;radiation resistance;radioresistant;response;side effect;small molecule;subcutaneous;tool;tumor;tumor microenvironment;tumor xenograft;tumorigenesis;tumorigenic Elucidation and therapeutic exploitation of PAK mediated radioresistance PROJECT NARRATIVEUnderstanding how tumors respond to radiotherapy is critical to producing new molecularly targeted treatmentsthat overcome radiation resistance and improve survival for cancer patients. Based on our preliminary data wepredict that p21 activated kinases cause resistance to radiotherapy and that by targeting these kinases we cansensitize tumors to radiotherapy. In this proposal we will investigate the mechanisms though which p21activated kinases produce resistance to radiotherapy which will allow us to develop biomarker driven treatmentapproaches to increase radiotherapy's ability to destroy tumors while decreasing side effects. NCI 10772404 2/27/23 0:00 PA-16-160 4R37CA215081-06 4 R37 CA 215081 6 "PRASANNA, PAT G" 12/18/17 0:00 11/30/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11182831 "ADVANI, SUNIL J" Not Applicable 50 RADIATION-DIAGNOSTIC/ONCOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 395 Non-SBIR/STTR 2023 354197 NCI 224175 130022 PROJECT SUMMARY/ABSTRACTTumor resistance to radiotherapy remains a critical barrier to improving outcomes for patients diagnosed withlocally advanced unresectable cancers. Cellular sensitivity to ionizing radiation (IR) is governed by intracellularand extracellular factors. To overcome tumor radioresistance drugs that sensitize tumor cells to ionizingradiation (IR) are used. Non-targeted cytotoxic chemotherapies given concurrently with radiotherapy havedemonstrated improved tumor control and overall survival in cancer patients. However since this paradigmshifting approach occurred in the 1980's there has been a shocking lack of progress in developing molecularlytargeted radiosensitization approaches. Improving the therapeutic ratio of IR in combination with systemicallydelivered drugs can be achieved by two general approaches 1) using drugs that block DNA damage repairresponses 2) delivering radiosensitizing drugs selectively to tumors. These two methods are orthogonaltechniques to achieve the same end goal of increasing IR induced tumor kill while reducing normal tissuetoxicities. To address both of these fundamental cancer therapy problems we have focused on targetdiscovery and tumor selective drug delivery vehicles. With regards to target discovery our recent studies onnon-canonical CRAF functions led to our discovery of an unexpected role for PAK in DNA damage repair andsensitivity to IR. PAK is comprised of a family of six kinases subdivided in Group I and II. Importantly PAK areinvolved in process central to oncogenesis tumor aggressiveness and patient survival. To tackle tumorselective drug delivery we are developing drug conjugated activatable cell penetrating peptides (ACPP) toselectively deliver potent radiosensitizers to tumors based on extracellular tumor protease activity. ACPPconsist of a drug conjugated polycationic cell penetrating peptide and an autoinhibitory polyanionic peptideseparated from each other by a flexible peptide linker. This peptide linker is specifically cleaved by proteasesenriched in the extracellular tumor microenvironment. While ACPP is intact the drug conjugated cellpenetrating peptide is neutralized (i.e. held in a pro-drug state) by the polyanionic peptide so that the drugcannot gain access to its intracellular target. Tumor microenvironment proteases cleave ACPP and release thedrug conjugated cell penetrating peptide which is then taken up by tumor cells. The goals of our proposal areto gain insight into how PAK governs radioresistance and then therapeutically exploit this with targeted PAKinhibitors. In Aim 1 we will genetically determine the mechanisms through which Group I and II PAKs governIR resistance. In Aim 2 we will pharmacologically test the ability to radiosensitize tumors with small moleculePAK inhibitors. In Aim 3 we will test if tumor targeted ACPP increase the therapeutic ratio of conjugated PAKinhibitors. Our approach has complementary innovations in both DNA damage target discovery and tumorselective drug delivery. Combining these approaches will lay a foundation for moving away from non-targetedcytotoxic radiosensitization to biomarker driven molecularly guided radiosensitization. 354197 +No NIH Category available Address;Affect;Androgen Receptor;Androgens;Area;Automobile Driving;Biological;Biological Models;Biology;Cell Culture Techniques;Clinical;Clinical Course of Disease;Clinical Trials;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Event;FRAP1 gene;Feedback;Foundations;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genomics;Heterogeneity;Hormonal;Human;In Vitro;Insulin-Like Growth Factor I;Interruption;Intervention;Malignant Neoplasms;Malignant neoplasm of prostate;Modeling;Molecular;Mus;Mutation;NCOA3 gene;Nature;Neoplasms;Newly Diagnosed;Oncogenic;Organoids;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Phosphatidylinositols;Phosphotransferases;Prostate;Proteome;Publications;Receptor Signaling;Recurrence;Regulation;Reporting;Role;Sampling;Signal Pathway;Signal Transduction;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Up-Regulation;cancer invasiveness;cancer subtypes;clinical investigation;clinically relevant;cohort;human disease;human model;in vitro Model;in vivo;in vivo Model;insight;mTOR Inhibitor;men;molecular subtypes;mouse model;mutant;novel;novel diagnostics;novel therapeutic intervention;pharmacologic;prostate carcinogenesis;receptor;targeted treatment;therapeutic target;translational impact;ubiquitin-protein ligase Coordinate Regulation of Oncogenic Signaling Pathways in SPOP Mutant Prostate Cancer NarrativeAbout 10% of prostate cancers have mutations in the SPOP gene roughly 20000 men will bediagnosed with SPOP mutant prostate cancer in the US each year. These cancers show distinctmolecular features and activation of specific signaling pathways. Successful completion of this projectwill provide insights into the biology underlying this subclass of prostate cancer define the ability tospecifically target these cancers and identify novel diagnostic and therapeutic approaches acrossprostate cancer classes. NCI 10772402 2/17/23 0:00 PA-16-160 4R37CA215040-06 4 R37 CA 215040 6 "HILDESHEIM, JEFFREY" 1/1/18 0:00 1/31/25 0:00 Tumor Cell Biology Study Section[TCB] 6710748 "BARBIERI, CHRISTOPHER E" Not Applicable 12 UROLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 2/13/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 360976 NCI 212965 148011 Project Summary / Abstract Prostate cancer (PCa) is a clinically heterogeneous disease with marked variability in patientoutcomes. Striking molecular heterogeneity may underlie the variable clinical course with distinct molecularsubtypes recently identified. However the biologic implications and translational impact of novel subtypes arelargely undefined and there is a critical need for new models to study the biology and therapeuticvulnerabilities of these novel subtypes of PCa. Recurrent mutations in SPOP occur in about 10% of PCa anddefine a distinct core molecular class of PCa. However the mechanisms by which SPOP mutation drivesprostate tumorigenesis in vivo remain unknown. Using multiple novel in vitro and in vivo models of SPOP mutant PCa preliminary data demonstratethat SPOP mutation drives neoplasia and invasive cancer in the mouse prostate. Furthermore preliminarystudies in models in vitro and in vivo support that SPOP mutation activates the phospho-inositide 3-kinase(PI3K) signaling pathway with evidence for this regulation in human PCa. Interestingly while PI3K activationnormally downregulates androgen receptor (AR) signaling we show that SPOP mutation interrupts thisnegative feedback by upregulating AR. These results suggest that SPOP mutation activates two known criticalsignaling pathways in PCa AR and PI3K signaling. Based on these preliminary findings we hypothesizethat SPOP mutation drives prostate tumorigenesis through coordinate regulation of AR and PI3Ksignaling pathways. To address this hypothesis we will utilize novel in vitro and in vivo models and humanPCa samples to establish the mechanistic basis of SPOP regulation of PI3K/mTOR signaling define therelative importance of PI3K/mTOR and AR signaling in driving formation and progression of SPOP mutantPCa and determine the potential for therapeutic targeting of AR and PI3K/mTOR signaling in SPOP mutantPCa. This project leverages unique in vivo and in vitro model systems to study a recently discovered keysubtype of PCa. Together these studies will establish the importance of PI3K signaling and AR signaling inPCa driven by SPOP mutations define the critical signaling events in SPOP mutant PCa and the broaderapplicability across PCa subtypes and provide the foundation for clinical trials targeting this subclass. 360976 +No NIH Category available Antibodies;Antibody Response;Antibody Therapy;Antigens;Antitumor Response;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;CCR;CD47 gene;CD47-SIRP;CTLA4 gene;Cells;Chemotherapy and/or radiation;Clinical;Clinical Pathways;Clinical Research;Clone Cells;Complement;Complement 3a;Complement 5a;Complement Activation;Critical Pathways;Data;Deposition;ERBB2 gene;Epitopes;Health;Human;Immune;Immune Tolerance;Immunity;Immunocompetent;Immunologics;Immunosuppression;Immunotherapy;Infiltration;Inflammation;Knockout Mice;Knowledge;Lymphoma;MS4A1 gene;Macrophage;Malignant Neoplasms;Mediating;Mediator;Mission;Modeling;Monoclonal Antibodies;Mus;Non-Hodgkin's Lymphoma;Oncology;Outcome;PD-1 blockade;PD-1/PD-L1;Pathway interactions;Phagocytes;Phagocytosis;Phase I Clinical Trials;Phase II Clinical Trials;Public Health;Publishing;Radiation therapy;Regulatory T-Lymphocyte;Reporting;Research;Resistance;Signal Transduction;Solid;Solid Neoplasm;T cell response;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Trastuzumab;Tumor Antigens;Tumor Immunity;United States National Institutes of Health;Vaccination;Vaccines;anti-CTLA4;anti-PD-1;anti-tumor immune response;antibody immunotherapy;antibody-dependent cellular phagocytosis;antigen-specific T cells;antitumor effect;cancer type;effector T cell;immune cell checkpoints;immune checkpoint blockade;improved;in vivo;innate immune checkpoint;innovation;insight;malignant breast neoplasm;neoantigens;patient response;patient subsets;polyclonal antibody;prevent;programmed cell death protein 1;recruit;resistance gene;response;standard of care;synergism;trafficking;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;vaccine strategy Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers Project NarrativeThe proposed research is relevant to public health because it seeks to mechanistically understand how best to combine targeted antibody and vaccine treatments with immune checkpoint blockade immunotherapies. This knowledge will ultimately improve the efficacy of existing targeted antibody therapies and immunotherapiesextend the range of these combinations to different tumor types and reduce the toxicity of these combinations.Thus the proposed research is relevant to the part of the NIHs mission that pertains to developing innovativeresearch strategies and their application to protect and improve human health. NCI 10771935 11/29/23 0:00 PA-19-056 5R01CA238217-05 5 R01 CA 238217 5 "SINGH, ANJU" 12/6/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 11624164 "HARTMAN, ZACHARY CONRAD" Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 364247 NCI 226241 138006 AbstractWhile immune checkpoint blockade (ICB) has emerged as a validated therapeutic axis in a variety of cancersinitial monotherapy strategies have proven beneficial only to a subset of patients. These studies havesuggested the importance of T-cells in responsive cancers thus strategies to improve T-cell stimulation andinfiltration have been prioritized. However our recent studies (Shuptrine et al. 2017) have identified theCD47/SIRP innate pathway which governs antibody dependent cell phagocytosis (ADCP) as one of themost critical potential mediators of anti-tumor immunity. This suggests that complementary innate anti-tumoreffector pathways involving antibodies particularly relating to ADCP may represent critical pathways toestablish effective anti-tumor responses. Recent positive results from the first clinical study using CD47 innateICB (with CD20 mAb in resistant lymphoma) strongly suggest that this may be a clinically effective means tostimulate immunity in cancers (Advani NEJM 2018). This may be best explored in solid cancers in HER2+Breast Cancer (BC) which are currently treated using HER2 mAbs that we recently determined functionthrough ADCP (Tsao et al. JCI-Insight in review). Additionally we have also recently published positiveresponses from a vaccine strategy targeting HER2 documenting the induction of polyclonal antibodies (pAbs)in HER2+ BC patients (Crosby et al. CCR 2019). We have now identified these HER2 pAbs to elicit anti-tumor effects through the activation of complement allowing our study of how pAbs (in contrast to monoclonalHER2-Abs) may differentially impact tumor immunity. Based on our recent adaptive ICB mechanistic studies(Crosby et al. 2018) our central hypothesis is that HER2-targeted mAbs or pAbs elicit antibody dependentphagocytosis (ADCP) that is enhanced by CD47 blockade to immunologically to recruit and prime effector T-cells that can be expanded through the use of CTLA4 adaptive ICB mAbs and functionally enhanced by theuse of PD1 ICB mAbs. Guided by our preliminary data this hypothesis will be tested by utilizing our uniqueHER2+ BC models that can be interrogated with the following combinations that comprise our specific aims: 1)HER2+CD47 mAbs 2) HER2/CD47 mAbs + CTLA4/PD1 ICB combinations and 3) HER2 vaccination + innateCD47 ICB and CTLA4/PD1 adaptive ICB combinations. These studies will be the first to determine how theseinnate and adaptive ICB combinations impact Ab-mediated anti-tumor immunity and mechanistically altertumor-specific and non-specific adaptive responses as well as determine how the HER2 pAb activation ofcomplement and direct T-cell stimulation can alter anti-tumor immunity in an endogenous HER2 immune-competent model that possesses few neoepitopes and is PD1 resistant. The proposed research is significantbecause if fundamental mechanisms and synergies are identified with minimal toxicities these approachescould be utilized with targeted mAbs and vaccines in other solid cancers to expand and enhance the potentialutility of immunotherapy as a therapeutic option for the majority of cancers. 364247 +No NIH Category available Administrative Supplement;Adolescent;Asian Americans;Clinical Research;Clinical Trials;Communities;Daughter;Doctor of Philosophy;Enrollment;Ethnic Origin;Female;Female Adolescents;Funding;Future;Gender;Gender Role;Goals;Interview;Knowledge;Mentors;Modeling;Mothers;Outcome;Parents;Participant;Physical activity;Population Group;Population Heterogeneity;Prevention Research;Principal Investigator;Randomized Controlled Trials;Research;Research Personnel;Research Subjects;Scientific Advances and Accomplishments;South Asian;Strategic Planning;Structure;United States National Institutes of Health;Woman;Women's Health;cancer prevention;disorder prevention;disparity reduction;evidence base;exercise intervention;experience;girls;health disparity;health equity;implementation strategy;improved;lens;male;moderate-to-vigorous physical activity;recruit;sex Administrative Supplement for A Multilevel Physical Activity Intervention for South Asian Women and Girls PROJECT NARRATIVELimited participation of diverse population groups in research threatens health equity. We seek funding toengage South Asian American women and adolescent girls in clinical research and to co-develop arecruitment and retention model responsive to the gender-related factors that influence women and girls'participation in PA and cancer prevention research. Our results will inform long overdue evidence-basedstrategies to enhance clinical trial participation and mitigate disparities of underrepresented women and girls. NCI 10771843 9/14/23 0:00 PA-20-272 3R01CA242520-05S1 3 R01 CA 242520 5 S1 "DEAN, DAVID WORTH" 8/1/19 0:00 7/31/24 0:00 Community-Level Health Promotion Study Section[CLHP] 8355312 "KANDULA, NAMRATHA R" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/13/23 0:00 7/31/24 0:00 310 Non-SBIR/STTR 2023 221291 OD 138307 82984 PROJECT SUMMARYWomen and adolescent girls of South Asian background experience multilevel barriers to physical activity (PA).The South Asians Active Together (SAATH) trial (R01CA242520) is an ongoing randomized controlled trial thathas enrolled 172 South Asian (SA) American mothers and adolescent daughters to evaluate the effects of adyadic physical activity (PA) intervention on moderate to vigorous PA in SA women and girls. The goal of thisadministrative supplement to the SAATH trial is to conduct new research to identify and develop replicablestrategies to overcome gender-specific barriers that South Asian women experience to clinical researchparticipation. Our team has extensive experience with community-engaged recruitment of South AsianAmericans in clinical research; however SA women and girls remain underrepresented in PA and cancerprevention research despite persistent health disparities. Even with community-engaged recruitmentapproaches there are strong differences between male and female participants regarding access toopportunities and multilevel influences on the decision to participate in clinical research. The researchproposed in this supplement targets knowledge gaps about the influence and intersection of gender andethnicity on implementation strategies to improve representation of SA women in clinical research.Specific Aims of this Administrative Supplement are to: 1) Identify how gendered roles experiences andidentities influence access participation and inclusion as research subjects by performing and analyzing semi-structured interviews with SA mothers and daughters who did and did not participate in the SAATH trial (n=15dyads); 2) Develop and evaluate replicable strategies using an intersectional lens and participatory actionmodel for enhancing access and inclusion of SA women and adolescent girls in PA and cancer preventionresearch. This administrative supplement is led by Principal Investigator (PI) Namratha Kandula MD MPH andincludes an early stage investigator Milkie Vu PhD who will be mentored by the Dr. Kandula to accomplish thescientific goals of the parent study and supplement. This administrative supplement will address Objective 1.2Objective 2.4 and Objective 3.1of the Trans-NIH Strategic Plan for Women's Health Research which seek toinvestigate the influence of sex and gender on disease prevention presentation management and outcomesimprove the recruitment and retention of women underrepresented in clinical research and disseminate andimplement evidence-based strategies to improve women's health. Resultsnewcommitmentfrom this supplement will provideknowledge about the intersection of gender and ethnicity to inform replicable strategies to improveof SA women and adolescents girls for future PA and cancer prevention studies. 221291 +No NIH Category available Acute Lymphocytic Leukemia;Adult;Affect;Affective;Age;Behavior;Behavioral;Brain;Brain Injuries;Brain Neoplasms;Buffers;Caring;Central Nervous System;Central Nervous System Diseases;Child;Child Rearing;Child Welfare;Childhood Cancer Treatment;Cognitive;Cranial Irradiation;Data;Development;Diagnosis;Distress;Early Diagnosis;Emotional;Employment;Ensure;Environment;Failure;Family;Female;Friends;Friendships;Goals;Happiness;Healthcare Systems;Hearing;Home visitation;Hospitalization;Human;Impairment;Individual;Intervention;Intrathecal Chemotherapy;Knowledge;Late Effects;Life;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Marriage;Mediating;Medical;Mission;Modeling;Morbidity - disease rate;Nature;Neuroblastoma;Neurocognitive;Neurocognitive Deficit;Nursery Schools;Organ;Outcome;Parents;Pediatric Oncology;Population;Positioning Attribute;Predictive Factor;Problem Solving;Public Health;Quality of life;Race;Research;Residual state;Resources;Retinoblastoma;Risk;Risk Factors;Role;School-Age Population;Schools;Second Primary Cancers;Site;Social Development;Social Values;Social isolation;Subgroup;Survivors;Time;Toxic effect;United States National Institutes of Health;Victimization;Vision;Vulnerable Populations;Work;burden of illness;childhood cancer survivor;cost;design;developmental psychology;disability;early onset;educational atmosphere;effective intervention;emotional distress;experience;heuristics;high risk;improved;improved outcome;informant;neurotoxic;peer;prevent;primary outcome;protective factors;psychosocial;psychosocial adjustment;resilience;sex;skills;social;social cognition;social neuroscience;success;survivorship;teacher;young cancer survivor Psychosocial Risk in Young Survivors of Early Onset Pediatric Cancer: The Role of Physical and Neurocognitive Late Effects This research is highly relevant to public health because of the rapidly growing population of childhood cancersurvivors and the increasing burden of late effects from therapy on survivors families and the healthcaresystem. Determining specific medical and neurocognitive late effects that increase psychosocial morbidity aswell as protective factors will inform more effective interventions to optimize quality of life in children affectedby early onset cancer. This is relevant to the part of NIHs mission that pertains to developing fundamentalknowledge that will extend human life and help to reduce the burdens of illness and disability. NCI 10771642 2/18/23 0:00 PA-19-056 3R01CA248103-03S2 3 R01 CA 248103 3 S2 "NELSON, WENDY" 2/9/21 0:00 1/31/27 0:00 "Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]" 2443084 "GERHARDT, CYNTHIA A" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 29006 NCI 18835 10171 Despite increased survival1 over two-thirds of children with cancer experience late effects such assecondary cancers sensorimotor deficits and neurocognitive impairment.23 Psychosocial late effectsparticularly social isolation and victimization difficulties forming and maintaining friendships and emotionaldistress are common for survivors of central nervous system (CNS) disease or those who receive CNS-directed therapy (e.g. cranial radiation intrathecal chemotherapy).4-6 Unfortunately interventions to improveoutcomes have had limited success.78 So why dont childhood cancer survivors have friends and feel happy?Our model posits that residual deficits in social cognition contribute to negative peer interactions and poorpsychosocial outcomes in children with brain injury.1011 However most work has focused on adult survivors ofpediatric cancer and not children diagnosed early in life (preschool). These young survivors may be at greatestrisk for difficulties for several reasons. First the peak onset of the most common pediatric cancers occursbefore age 6.1 Second their treatments have an especially harmful impact on brain development and a highrate of sensorimotor deficits.23 Third children are treated up to 3 years and isolated at a critical time for socialdevelopment. Fourth parents are at risk for distress which may impair their ability to buffer negative effects ontheir children.1718 Thus there is an urgent need to characterize psychosocial risk in children treated for earlyonset cancer and to evaluate the utility of our model to inform more effective targeted interventions. Our long-term goal is to reduce morbidity and improve the well-being of children with cancer. The objective of thiscontrolled multi-site study is to identify predictors of friendships and emotional distress in young cancersurvivors (i.e. diagnosed < age 6 >1 year off treatment). Using a rigorous matched control design we willassess peer interactions and friendships in the elementary classrooms (i.e. grades 3-5) of 200 survivors.Individual and family functioning will be assessed during home visits with families of survivors and 200matched classmates. We will identify deficits in social cognition and peer interactions as well as environmentalresources (e.g. parenting school climate) that predict long-term psychosocial adjustment (i.e. friendshipsdistress). The rationale is that deficits in social cognition and peer interactions contribute to psychosocial riskwhich could be mitigated by resources in the school and family environments. Aim 1. Compare the long-termpsychosocial adjustment of young survivors to matched peers and identify group differences in social cognitionand peer interactions that may predict poor adjustment. Aim 2. Identify specific social cognitive and peerinteraction factors that account for psychosocial adjustment in young survivors. Aim 3. Identify environmentalresources that protect psychosocial adjustment in young survivors. This research is significant as it willdelineate early risk and protective factors that predict long-term adaptation for young survivors and leave us ina prime position to develop interventions that will improve survivorship care and prevent long-term morbidity. 29006 +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Adolescent;Age;Biological Models;Biology;CBFA2T1 gene;Cancer Patient;Cells;Child Health;Childhood Acute Myeloid Leukemia;Chimeric Proteins;Clinical;Clinical Trials;Collection;Communities;Complex;Credentialing;Data;Development;Disease;Engineering;Fusion Oncogene Proteins;Future;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Enhancer Element;Genetic Heterogeneity;Genetic Transcription;Genetically Engineered Mouse;Genomics;Genotype;Goals;Hematopoietic stem cells;Histones;Human;Human Cell Line;Immunodeficient Mouse;In Vitro;Infrastructure;Institution;Investigation;Libraries;MLL gene;Malignant Childhood Neoplasm;Modeling;Mus;Mutation;Myeloproliferative disease;NUP214 gene;NUP98 gene;Oncoproteins;Outcome;Pathogenicity;Patients;Pattern;Personal Satisfaction;Phase I Clinical Trials;Phosphorylation;Preclinical Drug Development;Principal Investigator;Property;Proteome;Proteomics;Qualifying;RUNX1 gene;Recurrence;Research;Research Personnel;Resources;Saint Jude Children's Research Hospital;Sampling;Series;Specimen;Supportive care;Technology;Therapeutic;Treatment Protocols;Umbilical Cord Blood;Universities;Variant;Viral;Washington;acute myeloid leukemia cell;chemotherapy;disease heterogeneity;disorder subtype;driver mutation;drug sensitivity;epigenome;epigenomics;fetal;genetic approach;high risk;human model;improved;induced pluripotent stem cell;innovation;insight;interdisciplinary approach;leukemia;medical schools;molecular subtypes;mouse model;novel;novel strategies;novel therapeutics;patient derived xenograft model;patient population;pre-clinical;progenitor;programs;protein expression;rational design;response;risk stratification;skills;targeted treatment;transcription factor;transcriptome sequencing;transcriptomics Cross-species development and credentialing of pediatric AML models PROJECT NARRATIVE:Pediatric AML is a heterogenous group of myeloid neoplasms with over 20 distinct molecular subtypes manyof which are associated with a poor response to chemotherapy yet the majority of these subtypes lack robustmodel systems for the identification of therapeutic vulnerabilities. We will develop a series of models of high-risk pediatric AML using both human and murine approaches that capture disease heterogeneity withextensive transcriptomic epigenomic and proteomic credentialing against our large collection of primarysamples exploiting the unique expertise of each research team in this multi-PI proposal. The successfulcompletion of these studies will nominate new model systems for rare pediatric AML subtypes that can be usedby the scientific community to develop new therapeutics or establish mechanistic insights. NCI 10771589 12/11/23 0:00 PAR-20-131 1R01CA285272-01 1 R01 CA 285272 1 "KLAUZINSKA, MALGORZATA" 12/15/23 0:00 11/30/28 0:00 Special Emphasis Panel[ZRG1-CTH-E(55)R] 10650621 "MAGEE, JEFFREY ALAN" "KLCO, JEFFERY M" 1 RADIATION-DIAGNOSTIC/ONCOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/15/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 665385 NCI 526635 138750 PROJECT SUMMARY:The objective of this multi-principal investigator application is to leverage the complimentary expertise of theinvestigators to develop and credential multiple new mouse models of high-risk pediatric acute myeloid leukemia(AML). These will include both human and mouse AML with genotypes and cells of origin that are informed byreal-world patient data and represent understudied high-risk molecular subtypes of the disease. This proposalwill address a pressing clinical and scientific need. Children with AML continue to have an overall poor survivalrelative to other pediatric cancer patients. Advances in targeted therapies have been slow to develop and up-front treatment protocols have remained remarkably stagnant for the past 4 decades. Efforts to derive newtherapies have lagged in part due to the marked genetic heterogeneity of pediatric AML. Indeed we haveestablished that there are over 20 unique molecular subtypes of pediatric AML that reflect unique driver mutationsand expression signatures. Pediatric AML also harbor secondary mutations that further exacerbate geneticheterogeneity. Thus therapies that might benefit patients with one genetic subtype of pediatric AML could havelimited value in a different patient population. Unfortunately current models of pediatric AML do not reflect themarked genomic diversity observed in patients. Current approaches commonly focus on a limited subset ofmolecular subtypes typically avoiding rare high-risk subtypes and they either do not co-model secondarymutations or they implement mutational combinations that are not reflected in patients. Thus there remains aclear unmet need to advance pediatric AML modeling as a means to expand genetically informed therapeuticoptions. We will address this need through the completion of three Aims that exploit the unique skills of eachinvestigators independent research programs and the exceptional institutional infrastructures at both St. JudeChildrens Research Hospital and Washington University School of Medicine. Aim 1: Develop novel syngeneicmouse models of high-risk pediatric AML; Aim 2: Develop human models of rare pediatric AMLs with patient-informed cooperating mutations; Aim 3. Credential established and newly developed AML models against oneanother and primary human specimens. To create AML models we will deploy several innovative geneticstrategies including a novel approach to generate genetically complex murine AML from induced pluripotentstem cells and direct editing of human cord blood progenitors. Credentialing will involve a direct comparison ofprimary patient material with genetically matched murine and human models based on transcriptomicepigenomic and proteomic strategies. The high-risk pediatric AML models developed through thiscomprehensive cross-species proposal will provide the scientific community with an unparalleled collection ofextensively characterized specimens for future investigations into disease mechanisms and therapeuticvulnerabilities. 665385 +No NIH Category available Address;Analytical Chemistry;Anatomy;Architecture;Area;Bar Codes;Benchmarking;Biological;Biological Assay;Biological Markers;Biology;Biosensor;Blood;CRISPR/Cas technology;Cancer Etiology;Cancer Model;Career Mobility;Cause of Death;Characteristics;Clinic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Complement;Complex;DNA;Dependence;Detection;Development;Diagnosis;Diagnostic;Diagnostic Sensitivity;Diagnostic Specificity;Diffuse;Disease;Disease stratification;Early Diagnosis;Engineering;Enzymes;Evaluation;Excision;Exhibits;Extracellular Matrix;Fostering;Future;Generations;Genetic;Goals;Homing;Human;Image;Imaging Device;Imaging Techniques;Immune;Immunoglobulin Fragments;Implant;In Vitro;Injectable;Intervention;Invaded;Investigation;Lesion;Libraries;Light;Malignant Neoplasms;Medical;Medical Imaging;Mentors;Modality;Molecular;Molecular Profiling;Monitor;Mutation;Neoplasm Metastasis;Non-Invasive Detection;Nucleic Acids;Oligonucleotides;Oncology;Operative Surgical Procedures;Paper;Patients;Peptide Hydrolases;Peptides;Positron-Emission Tomography;Precision therapeutics;Primary Neoplasm;Property;Proteomics;Radiation;Recombinants;Reporter;Reporting;Research;Resource-limited setting;Sampling;Signal Transduction;Site;Specificity;Survival Rate;Testing;Therapeutic;Time;Training;United States National Institutes of Health;Urine;Validation;Visualization;X-Ray Computed Tomography;cancer cell;cancer diagnosis;cancer type;cell motility;colorectal cancer metastasis;colorectal cancer screening;delivery vehicle;design;detection sensitivity;diagnostic biomarker;diagnostic platform;disease classification;efficacy validation;empowerment;experience;improved;in vivo;innovation;interdisciplinary approach;metastatic colorectal;molecular imaging;mortality;nanobodies;nanosensors;novel;novel strategies;novel therapeutics;organoid transplantation;personalized approach;personalized diagnostics;point-of-care diagnostics;portability;pre-clinical;precision medicine;programs;rational design;response;scaffold;sensor;technology development;theranostics;therapy outcome;tool;trafficking;transcriptomics;translational potential;transplant model;treatment response;treatment strategy;tumor;tumor heterogeneity;tumor microenvironment;urinary Developing multiplexed microenvironmental sensors for precision diagnostics of cancer metastasis Narrative Efforts to improve oncology therapeutic outcomes will be greatly aided by the integration of early detection and new precision therapies reflected by the significantly improved survival rate of patients with metastatic colorectal cancer (CRC) that is detected at an early stage when resection is especially effective. In light of the lack of a generalizable approach accessing specific diagnostic biomarkers this proposed study seeks to leverage the molecular signatures in the tumor microenvironment to develop multiplexed in vivo sensors for precision diagnosis of cancer metastasis. Successful completion of the proposed research program will exhibit a preclinical framework of disease detection stratifying and monitoring and will provide rationale for extending this modular platform to the general context of cancer through tailored targets specificities. NCI 10771541 3/23/23 0:00 PA-19-130 4R00CA237861-03 4 R00 CA 237861 3 "OSSANDON, MIGUEL" 1/1/20 0:00 2/28/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15435816 "HAO, LIANGLIANG " Not Applicable 7 ENGINEERING (ALL TYPES) 49435266 THL6A6JLE1S7 49435266 THL6A6JLE1S7 US 42.349594 -71.099726 10001093 BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) BOSTON MA BIOMED ENGR/COL ENGR/ENGR STA 22151390 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 394 Non-SBIR/STTR 2023 249000 NCI 169030 79970 Summary More than 90% of all cancer-related deaths are caused by metastasis the spread of cancer from its origin. By the time most cancer metastases become clinically visible the disease has progressed too far to benefit from early-stage interventions such as surgery or radiation. Thus new approaches accessing specific diagnostic biomarkers are highly desired to improve therapeutic outcomes. Microenvironmental signatures such as extracellular matrix (ECM) alterations stromal composition or immune components exhibit critical determinants of metastatic dissemination broadly across cancers. Herein the main goal of this proposal is to converge the disease hall markers and rational design of biomolecular engineering to develop multidisciplinary approaches towards precision diagnostics of cancer metastasis. As metastases start to invade they alter the extracellular matrix through aberrant proteolytic activities that could be leveraged as biomarkers. The applicant set out to systematically identify proteases expressed in metastatic colorectal cancer (CRC) by transcriptomic and proteomic analysis. To improve the detection sensitivity it is proposed to integrate the proteolytic activity to formulate a library of enzyme activated sensors by reengineering the ECM targeting nanobody with extraordinarily tumor targeting efficacy for maximal on-target signal generation (Aim 1). To optimize the detection specificity the multiplexity of these activity-based sensors will be extensively expanded for disease classification using CRISPR-Cas-based nucleic acid barcode readout. Preliminary investigation into the in vivo DNA barcodes revealed that they could be detected noninvasively as a urinary reporter but could also enable portable detection on paper (Aim 2). Beyond initial diagnosis disease stratification and treatment monitoring are critical to establishing a robust therapy. The novel sensors will thus be evaluated for noninvasive tumor monitoring and imaging in disease recapitulating metastatic CRC models (Aim 3). Successful completion of these three aims would offer a tumoral activation responsive genetically encoded tracking (TARGET) platform can 1) unveil new biology at the metastasis-specific tumor microenvironment 2) provide a completely noninvasive way to track tumor metastasis and 3) offer a pipeline for validating novel therapies which are currently unachievable by single modality agents. This project requires innovative integration across several fields. The candidate has assembled an exceptional team to help her achieve the goals of technology development and career transition including her mentor Dr. Sangeeta Bhatia (MIT medical engineering) and Drs. Tyler Jacks (MIT tumor genetics) Dr. Richard Hynes (MIT extracellular matrix) Dr. Frank Gertler (MIT cell motility) and Dr. Shawn Chen (NIH theranostics) on the mentoring committee. This training period will allow the candidate to gain experience in tumor microenvironment network pre-clinical cancer models and analytical chemistry. In the future the principles of this modular platform could apply to other disease areas. The research program here aligns well with the candidates long-term goal to develop multi-scale engineered tools in the context of cancer. 249000 +No NIH Category available Affect;Benign;Biological Models;Cell Migration Induction;Cells;Clinical;Collagen;Coupled;Data;Development;Disease;Disease Progression;Distant;Endocrine;Endothelial Cells;Epithelium;Event;Extracellular Matrix;Extracellular Matrix Proteins;Fibroblasts;Follicular thyroid carcinoma;Genetic;Human;Immune;In Vitro;Incidence;MAP Kinase Gene;MAPK Signaling Pathway Pathway;Malignant Neoplasms;Malignant neoplasm of thyroid;Modeling;Modification;Molecular;Mutation;Neoplasm Metastasis;Non-Malignant;Oncogene Activation;Oncogenic;Outcome;PIK3CG gene;Papillary thyroid carcinoma;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patients;Pattern;Phenotype;Prevention;Prevention strategy;Primary Neoplasm;Proteins;RAS genes;Research Proposals;Role;Sampling;Signal Transduction;Site;Solid;Solid Neoplasm;Stromal Cells;Stromal Change;Therapeutic;Thyroid Diseases;Thyroid Gland;Tissues;Tumor Cell Line;Tumor Subtype;adenoma;anaplastic thyroid cancer;biomarker identification;cancer diagnosis;clinical practice;crosslink;efficacy evaluation;extracellular;human disease;in vitro Model;in vivo;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;permissiveness;predictive marker;recruit;response;thyroid neoplasm;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis MAPK pathway modulation in thyroid tumorigenesis PROJECT NARRATIVEThis proposal seeks to answer how activation of the same signaling pathway MAPK pathway via differentproteins in the cascade affects the molecular mechanisms of cancer development and can modify the tumormicroenvironment. The overall objective is to identify novel therapeutic targets within the microenvironmentwith a secondary objective to determine how how different activating mutations of the same pathway changesrecruitment and modulation of the tumor microenvironment. The outcome of the proposed studies can impactclinical practice paradigms and lead to the development of novel therapeutic and prevention strategies forthyroid cancer. NCI 10771325 2/17/23 0:00 PA-16-160 3R01CA214511-06S1 3 R01 CA 214511 6 S1 "HILDESHEIM, JEFFREY" 7/3/18 0:00 8/31/24 0:00 Molecular and Cellular Endocrinology Study Section[MCE] 9300777 "FRANCO, AIME T" Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 3/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 35642 NCI 35642 0 PROJECT SUMMARY/ABSTRACTThyroid cancer is the most common endocrine malignancy and incidences are rising. Thyroid cancers offollicular cell origin stand out among solid tumors because many of the tumor-initiating genetic events areknown. Activating mutations of effectors of the MAPK signaling pathway are associated with both follicular andpapillary thyroid cancer and occur throughout the spectrum of thyroid diseases from benign adenomasthrough therapeutically refractive poorly-differentiated disease. Despite sharing activation of the MAPKpathway activation via different effectors in the pathway results in distinct and unique pathological outcomesincluding metastasis to distinct distant sites. We do not understand how activation of a single pathway viadifferent mutations within the signaling cascade results in different pathological outcomes and recruitment ofdifferent tumor microenvironments. This paradigm is seen not only in thyroid cancer but in othermalignancies. We will utilize recently generated mouse models of thyroid cancer to model follicular andpapillary thyroid cancers to study how activation of the oncogene Hras versus Braf affects tumor developmentand can modify the tumor microenvironment. We hypothesize that mode of activation contributes to stromalrecruitment and extracellular matrix (ECM) modification thus contributing to the pathobiology of tumorformation and progression. The data generated in these studies will provide a better understanding of themechanisms by which different oncogenic events that activate the same pathway predisposes thedevelopment distinct pathological outcomes. We hope to use these data to develop novel therapeutic andprevention strategies for thyroid cancer. 35642 +No NIH Category available Address;Bioinformatics;Biometry;Cancer Etiology;Cancer Patient;Carcinoma;Clinical;Clinical Oncology;Clinical Trials;Complex;DNA Sequence Alteration;Data;Data Analyses;Epidermal Growth Factor Receptor;Epithelial Cells;Epithelium;Genetically Engineered Mouse;Heterogeneity;Histone Deacetylase Inhibitor;Human;Hylobates Genus;Immune;Immune checkpoint inhibitor;Immune signaling;Immunologic Tests;Immunotherapy;K-ras mouse model;KRAS2 gene;Knowledge;Lung Adenocarcinoma;MAP Kinase Gene;MAPK Signaling Pathway Pathway;MEKs;Malignant neoplasm of lung;Mediating;Mesenchymal;MicroRNAs;Mutate;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenic;Operative Surgical Procedures;PD-1/PD-L1;Pathway interactions;Patients;Phenotype;Pre-Clinical Model;Productivity;Publishing;Ras/Raf;Regulation;Research Personnel;Resected;Resistance;Resistance development;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;Testing;Therapeutic;Translating;Tumor-infiltrating immune cells;United States;Up-Regulation;anti-PD-L1;cancer subtypes;co-clinical trial;drug development;efficacy evaluation;efficacy testing;epithelial to mesenchymal transition;human model;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;in vivo evaluation;inhibitor;kinase inhibitor;member;molecular pathology;mortality;mouse model;multidisciplinary;mutant;neoplastic cell;novel;pre-clinical;response;response biomarker;small molecule;targeted agent;treatment response;tumor;tumor heterogeneity;tumor-immune system interactions The Role of Epithelial-Mesenchymal Transition in Re-Wiring KRAS Mutant Lung Cancer PROJECT NARRATIVEKRAS mutant lung cancer is a leading cause of cancer mortality in the United States and a lung cancersubtype for which targeted agents such as MEK inhibitors have not made significant clinical progress. Basedupon the preliminary data from the investigators we propose: 1) to study the role and reversibility of epithelial-mesenchymal transition (EMT) in KRAS mutant lung cancer to confer resistance to MEK inhibitors ii) evaluatethe effects of MEK inhibitors on the tumor immune microenvironment and the therapeutic vulnerabilities thatarise due to immune checkpoint upregulation in pre-clinical models and iii) characterize the immune-relatedmarkers associated with EMT/MAPK activation and investigate the markers of sensitivity/resistance tocombination anti-PD-L1 and MEK inhibitor treatment in patient tumor samples. NCI 10771308 12/20/23 0:00 PA-16-160 5R37CA214609-07 5 R37 CA 214609 7 "HENDERSON, LORI A" 1/1/18 0:00 12/31/24 0:00 Clinical Oncology Study Section[CONC] 10185817 "GIBBONS, DON LYNN" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 333517 NCI 205874 127643 PROJECT SUMMARY ABSTRACTSubstantial therapeutic advances have been made in NSCLC subsets harboring specific genomic alterationsand targetable with small molecule kinase inhibitors. Unfortunately a similar strategy has been unsuccessfulfor the ~30% of patients with mutated KRAS. Similarly immune checkpoint inhibitors of the PD-1/PD-L1 axisprovide durable response to ~20% of NSCLC patients but the majority of patients do not benefit from thissingle-agent approach. There is a knowledge gap about the regulation of MAPK pathway signaling in mutantKRAS tumors and the interplay between oncogenic signaling and the immunosuppressive microenvironmentwhich translates into a major unmet therapeutic need. The members of our multidisciplinary team (Gibbons Heymach Wistuba Draetta and Wang) have atrack record of productivity in studying KRAS mutant lung cancer and represent expertise in mouse modelingof human lung cancer clinical oncology immunotherapy molecular pathology of lung cancer drugdevelopment and bioinformatics. The Investigators have developed preliminary data from analysis of humanlung cancer specimens and preclinical Genetically Engineered Mouse Models (GEMMs) of KRAS mutantNSCLC that the epithelial-mesenchymal transition (EMT) status of tumor cells is critical to their therapeuticresponse to MEK inhibitors with the epithelial state producing profound sensitivity to MEK inhibitors and themesenchymal state producing resistance even in mutant KRAS tumors. Further we have published that themicroRNA-200-ZEB1 axis regulates EMT the immune microenvironment of tumors and subsequent responseto immune checkpoint inhibitors. Based upon preliminary data we hypothesize that: 1. Tumor cell EMT produces heterogeneity in KRASmutant tumors by suppressing MAPK pathway signaling 2. The altered tumor immune microenvironmentresulting from tumor cell EMT confers targetable vulnerabilities to new immune therapies 3. Combinationimmune checkpoint inhibitors and signaling pathway inhibitors will provide an effective complementarytargeting strategy for mutant KRAS NSCLC. We will address these hypotheses by: i) evaluating the role ofEMT in de novo and acquired resistance to MEK inhibitors in preclinical models of lung adenocarcinoma ii)determining the effects of MEK inhibitors on the tumor immune microenvironment and testing the efficacy oftheir combination with immune checkpoint inhibitors to enhance response in preclinical models of KRASmutant lung adenocarcinoma and iii) characterizing the relationship of EMT to MAPK pathway activation inhuman lung cancer samples and the markers of sensitivity/resistance to combination anti-PD-L1/MEK inhibitortreatment in clinical trial specimens. 333517 +No NIH Category available Address;Alleles;Androgen Receptor;BRCA1 gene;BRCA2 gene;Biological Assay;Blood;Blood specimen;Cancer Patient;Categories;Cells;Clinical;Clinical Management;Clinical Trials;DNA sequencing;Data;Development;Diagnosis;Disease;Drug Targeting;Evaluation;Event;FDA approved;Gene Expression;Genes;Genetic;Genomics;Goals;Inherited;Knowledge;Lesion;Life;Link;Local Therapy;Longitudinal cohort;Malignant neoplasm of prostate;Molecular;Mutation;Operative Surgical Procedures;Patient Selection;Patients;Pharmaceutical Preparations;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Prediction of Response to Therapy;Rationalization;Recurrence;Resistance;Resources;Role;Sampling;Selection for Treatments;Specimen;Systemic Therapy;Time;Tissues;Treatment outcome;Work;abiraterone;anticancer research;castration resistant prostate cancer;chemotherapy;cohort;docetaxel;enzalutamide;genetic predictors;genetic testing;genomic biomarker;homologous recombination;hormone therapy;improved;inhibitor therapy;liquid biopsy;men;molecular phenotype;mutational status;novel;patient oriented;patient population;predictive marker;prospective;recombinational repair;response;response biomarker;standard of care;targeted treatment;taxane;transcriptome sequencing;treatment comparison;treatment response;tumor;tumor DNA Genetic and genomic determinants of homologous recombination repair deficiency as treatment selection markers for lethal prostate cancer PROJECT NARRATIVEWe propose a resource-driven patient-centered study to determine the genetic/genomic drivers of homologousrecombination deficiency and their role as treatment selection markers for lethal prostate cancer. The focus onliquid biopsies in a vulnerable patient population facing difficult treatment decisions will directly lead totreatment selection strategies to improve clinical management as well as patient selection strategies for clinicaltrials. NCI 10771150 11/30/23 0:00 PA-19-056 5R01CA238284-05 5 R01 CA 238284 5 "DAEE, DANIELLE L" 12/3/19 0:00 11/30/24 0:00 Cancer Biomarkers Study Section[CBSS] 7730792 "LUO, JUN " Not Applicable 7 UROLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 337120 NCI 205875 131245 PROJECT SUMMARYHomologous recombination (HR) deficiency (HRD) particularly from biallelic mutational loss ofBRCA1/BRCA2/ATM (BRCA/ATM) is significantly enriched in men with metastatic castration-resistant prostatecancer (mCRPC). Such patients have multiple FDA-approved systemic life-prolonging therapies to choosefrom including abiraterone enzalutamide and taxane chemotherapies as well as the possibility of poly(ADP-ribose) polymerase (PARP) inhibitor therapy which currently remains investigational. A few recent studiessuggest that patients with germline and/or somatic HRD mutations may respond better (and for longerdurations of time) to novel hormonal therapies than their HRD-negative counterparts. These studies suggestthat in addition to PARP inhibition potent AR suppression is also synthetic lethal with HRD in mCRPC.However the genetic/genomic determinants of HRD and their role in treatment selection remain unknown. Wepropose a resource-driven patient-centered study to determine the genetic/genomic drivers of HRD predictingdeep response to abiraterone and enzalutamide. We hypothesize that mCRPC patients can be categorizedinto three groups according to HRD status defined by deleterious mutations in HRD genes: 1) germline/somaticHRD; 2) somatic-only HRD; 3) negative HRD; and that these groups are molecularly distinct and havedifferent clinical implications as predictive markers of response to AR-targeting therapies and taxanechemotherapies. To address the overall hypothesis it is necessary to establish clinical and tumor/normalspecimen cohorts that enable detailed molecular and clinical characterization of HRD in men with mCRPC. InSpecific Aim 1 we will seek to ascertain the HRD mutations status both somatic and germline in threeexisting advanced/lethal prostate cancer cohorts enriched for HRD using blood-based assays. In Specific Aim2 we will determine the association of HRD status defined by blood-based assays with treatment response tofirst-line AR-directed therapy (abiraterone/enzalutamide) and taxane chemotherapies in mCRPC patients bycomparing treatment outcomes of men in these three groups. In Specific Aim 3 we seek to determine theexpression correlates of HRD status defined by blood-based assays and further ascertained by tissue-basedassays by performing RNA-Seq in surgical specimens from men with lethal prostate cancer with: 1)germline/somatic HRD; 2) somatic-only HRD; and 3) negative HRD. The proposed work addresses an unmetneed due to focus on liquid biopsy markers in a vulnerable patient population facing difficult treatmentdecisions. Also our effort in defining the clinical and functional implications of HRD status in establishedcohorts of mCRPC patients will directly lead to treatment selection strategies to improve clinical managementas well as patient selection strategies for clinical trials. 337120 +No NIH Category available 4T1;Arachidonic Acids;Biological Assay;Biological Markers;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Cells;Collagen;Collagen Fiber;Development;Dextrans;Dinoprostone;Down-Regulation;Eicosanoids;Environment;Extracellular Matrix;Fiber;Fibroblasts;Flow Cytometry;Funding;Generations;Genetic Engineering;Glucose;Glutamates;Glutamine;Grant;Human;Image;Immune;Immune system;Immunocompetent;Immunohistochemistry;Immunologic Surveillance;Immunosuppression;Immunotherapy;Inbred BALB C Mice;Inflammation;Inflammation Mediators;Inflammatory Response;Intercellular Fluid;Invaded;MDA MB 231;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Metabolic;Metabolism;Microscopy;Modification;Molecular;Mus;Neoplasm Metastasis;Pattern;Physiological;Play;Production;Prognosis;Prostaglandin-Endoperoxide Synthase;Reaction;Regulation;Role;SCID Mice;Small Interfering RNA;Source;Spleen;Splenocyte;Structure;Time;Traction;Treatment outcome;Tumor Escape;Tumor Promotion;Tumor-Derived;Tumor-infiltrating immune cells;Western Blotting;Xenograft procedure;biomaterial compatibility;cancer cell;cell motility;cyclooxygenase 2;cytokine;image guided;immunoregulation;improved;in vivo;mRNA Expression;malignant breast neoplasm;mechanical force;mechanotransduction;nanomedicine;nanoparticle;nanoparticle delivery;novel;optical imaging;overexpression;photoimmunotherapy;protein expression;second harmonic;siRNA delivery;translatable strategy;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Hostile Environments Promote Invasion and Metastasis COX-2 is a critically important target in cancer that we found to influence mechanical force exerted by cancercells the extracellular matrix and cancer associated fibroblasts and tumor and spleen metabolism. Here weintend to focus on new directions that investigate the role of COX-2 in mechanobiology and in metabolism andimmune suppression to develop new translatable strategies to improve triple negative breast cancer treatmentoutcome. We will also deliver COX-2 siRNA using novel dextran nanoparticles that will also be modified toscavenge cytokines in the tumor microenvironment. NCI 10771139 11/6/23 0:00 PA-19-056 5R01CA082337-20 5 R01 CA 82337 20 "WOODHOUSE, ELIZABETH" 7/1/99 0:00 11/30/24 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 1878950 "BHUJWALLA, ZAVER M." Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 280013 NCI 171000 109013 Inflammation plays a major role in breast cancer development and progression.Cyclooxygenase (COX)-2 and its product prostaglandin E2 (PGE2) are major mediatorsof inflammation in cancer cells. In this competitive renewal application our newdirections are built on discoveries made during the previous funding period. Withimaging we uncovered the role of COX-2 in mechanotransduction its impact onattracting cancer associated fibroblasts (CAFs) altering collagen fiber structure andfunction and increasing metastasis. We found that COX-2 overexpression in tumorsimpacted tumor and spleen metabolism that opens the possibility of spleen dysregulationcontributing to tumors escaping immune surveillance. In our efforts to downregulateCOX-2 in tumors with siRNA delivery we found that most nanoparticles (NPs)significantly increased COX-2 until we developed a biocompatible translatable dextranNP that successfully delivered COX-2 siRNA to effectively decrease COX-2 and PGE2 incancer cells and tumors. These observations have resulted in our three new aims thatfocus on advancing our understanding COX-2 in cancer and in developing translatablestrategies to target COX-2 and CAFs. In Aim 1 will investigate the role of COX-2 inaltering extracellular matrix (ECM) stiffness and composition and the impact ofeliminating CAFs that are a source of COX-2 on the ECM and on tumor immune cellsand metastasis. In Aim 2 we will identify the causes of the metabolic changes in thetumor and spleen caused by COX-2 and the effects of eliminating CAFs on tumor andspleen metabolism and splenocytes. In Aim 3 we will downregulate COX-2 inestablished tumors with siRNA and determine the impact on the ECM metabolism andimmune cells. A small component of this Aim will include developing cytokinescavenging NPs that are based on the modified dextran NP we developed. We willevaluate the ability of these NPs to reduce cytokines in tumor interstitial fluid. Thestudies will be performed with triple negative breast cancer models geneticallyengineered to overexpress or downregulate COX-2 in immune suppressed and immunecompetent mice. These studies may lead to ECM modification strategies including CAFelimination to alter ECM stiffness to reduce cancer aggressiveness and may result innew metabolic targets and biomarkers for immunotherapy as well as new strategies toconvert an immune suppressive tumor microenvironment into an immune active one.! 280013 +No NIH Category available 3-Dimensional;Ablation;Adipocytes;Allografting;Anoikis;Antioxidants;Apoptosis;Apoptotic;Autophagocytosis;BRAF gene;Binding;Blood Vessels;CAV1 gene;Cells;Coculture Techniques;Collagen;Complex;DNA Sequence Alteration;Endothelial Cells;Endothelium;Equilibrium;Experimental Neoplasms;Exposure to;Extracellular Matrix;Fatty Acid Desaturases;Fatty Acids;Fibroblasts;Gene Expression;Genes;Genetic;Genetic Transcription;Growth;Heterogeneity;Human;Immunotherapy;Impairment;Inflammation;Integrins;Invaded;Knockout Mice;Link;Lymph;Mediating;Mediator;Melanoma Cell;Metastatic Neoplasm to the Lung;Modality;Modeling;Monounsaturated Fatty Acids;Mus;Neoplasm Metastasis;Non-Malignant;Nuclear;Oncogenes;Oncogenic;Output;Oxygen;Pathway interactions;Patients;Persons;Phenotype;Primary Neoplasm;Proliferating;Publishing;Recovery;Refractory;Reporting;Repression;Resistance;Role;Shapes;Signal Pathway;Signal Transduction;Stress;Testing;Therapeutic;Therapeutic Intervention;Translational Repression;Tumor Suppressor Proteins;Tumor-infiltrating immune cells;Xenograft procedure;angiogenesis;biological adaptation to stress;endoplasmic reticulum stress;gain of function;immune cell infiltrate;immune checkpoint blockade;improved;inhibitor;melanoma;microphthalmia-associated transcription factor;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;nutrient deprivation;pharmacologic;programs;response;targeted agent;targeted treatment;transcription factor;tumor;tumor growth;tumor microenvironment;tumorigenic;uptake The integrated stress response and the microenvironment in melanoma progression Project NarrativeWe will study the role of an adaptive stress response (termed Integrated Stress Response) and its effectorATF4 in progression and metastasis of malignant melanoma. We will examine how in non-malignant cells theISR shapes the microenvironment by remodeling blood vessels and the extracellular matrix and how in turnmelanoma cells respond to the microenvironment by using the ISR in combination with well-known pro-tumorigenic mediators to promote invasion and survival during metastatic dissemination. The long-term aimof these studies is to uncover new targets for therapeutic intervention. NCI 10771131 1/2/24 0:00 PA-20-185 5R01CA268597-03 5 R01 CA 268597 3 "WOODHOUSE, ELIZABETH" 1/1/22 0:00 12/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-D(02)M] 2090001 "KOUMENIS, CONSTANTINOS " "GODING, COLIN " 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 373164 NCI 274166 98998 SUMMARYDespite the emergence novel therapeutic modalities including BRAF inhibitors and immunotherapies over7100 people are expected to die each year from malignant melanoma primarily from metastatic disseminationand therapy resistance. The proposed studies leverage the expertise of the two co-PIs in tumormicroenvironment the Integrated Stress Response (ISR) and melanoma progression to test the overallhypothesis that as part of the adaptive response to tumor microenvironmental (TME) stress bi-directionalinteractions between melanoma cells and fibroblasts endothelial cells and adipocytes promote survivalmetastatic dissemination and therapy resistance. Preliminary results and published reports from the two PIsindicate that the ISR is activated in human melanomas and that genetic or pharmacological disruption of theISR severely impairs primary tumor growth and metastasis in multiple experimental tumors includingmelanomas. The studies will delineate the salient roles of the transcription factor ATF4 a major transcriptionaleffector of the Integrated Stress Response in a pro-survival and pro-metastatic program mediated by the non-canonical tumor suppressor BRN2 a transcription factor effector of multiple melanoma-associated signalingpathways. To test the central hypothesis we will pursue three specific aims: In Aim 1 we will use a novelconditional global ATF4 knockout mouse model as well as Fibroblast (FB)-specific and Endothelial (EC)-specific ATF4 knockout mice and cells to determine the role of ATF4 expression in each TME component onmelanoma progression and metastasis. Preliminary results with global or FB-specific deletion of ATF4 resultsin a severe deficiency in tumor growth of flank melanoma tumors. In Aim 2 we will study how SRC promotesmelanoma progression via ATF4-BRN2 cooperativity. Both BRN2 and ATF4 can repress anoikis/apoptosisand in preliminary studies we reveal that BRN2 interacts with ATF4. Therefore we will test the hypothesis thatExtracellular Matrix (ECM)-driven integrin signaling and monounsaturated fatty acid (MUFA) uptake fromadipocytes and lymph converge on SRC to impose a cooperative BRN2-ATF4 anti-apoptotic and pro-metastasis gene expression program driven in part by hippo signaling. Finally under Aim 3 we will determinehow MUFAs dictate melanoma phenotype. Here we will dissect a novel mechanism underpinning MUFA-mediated nuclear localization of -catenin and test the hypothesis that the resulting SRC-driven nuclear CAV1--catenin complex promotes a pro-metastasis gene expression program via BRN2-ATF4 and the contributionof ATF4 and BRN2 to melanoma phenotypic heterogeneity and tumor immune infiltration. By delineating howthe ISR uses ATF4 to coordinate the output of the TME to shape melanoma progression we will identifytherapeutically exploitable pathways for anti-melanoma approaches. 373164 +No NIH Category available Address;Aftercare;Axon;Behavioral;Bortezomib;Cancer Model;Cancer Patient;Cancer Survivor;Chemotherapy-induced peripheral neuropathy;Cisplatin;Clinic;Clinical;Cultured Cells;Dependovirus;Development;Disease;Dominant-Negative Mutation;Dose;Dose Limiting;Drops;Enzymes;Etiology;Health;Hematologic Neoplasms;Hyperalgesia;In Vitro;Injections;Intervention;Knock-out;Lead;Life;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methods;Multiple Myeloma;Mus;Nerve;Nerve Fibers;Neurodegenerative Disorders;Neurology;Neurons;Neuropathy;Niacinamide;Oncology;Other Genetics;Paclitaxel;Pain;Pathogenesis;Pathway interactions;Patients;Peripheral Nerves;Peripheral Nervous System Diseases;Pharmaceutical Preparations;Phosphotransferases;Plasma;Prevention;Prevention strategy;Process;Proteins;Quality of life;Safety;Spinal Puncture;Sterility;Symptoms;Therapeutic;Tissues;Toll-like receptors;Toxic effect;Translating;Translations;Vincristine;Virus;Wild Type Mouse;Work;analog;appropriate dose;axonal degeneration;cancer therapy;chemotherapeutic agent;chemotherapy;chemotherapy induced neuropathy;cofactor;cost;disability;effective therapy;effectiveness testing;evidence base;experimental study;functional outcomes;gene therapy;heart metabolism;improved;in vivo;leukemia;metabolomics;mouse model;multidisciplinary;neuroinflammation;neuronal cell body;neurotransmission;nicotinamide-beta-riboside;novel;oral supplementation;overexpression;oxaliplatin;prevent;programs;selective expression;side effect;success;treatment duration;treatment strategy;tumor progression Developing mechanism-based strategies to treat chemotherapy-induced peripheral neuropathy Project Narrative:Peripheral neuropathy is the main dose limiting side effect of many widely used and effective chemotherapeuticdrugs. Most chemotherapy-induced peripheral neuropathies are characterized by loss of nerve fibers (axons).Here we will explore several avenues to block this destructive process. If successful this project will identifynovel treatment strategies for the prevention and treatment of chemotherapy-induced peripheral neuropathywhich have the potential to be translated to the clinic. NCI 10771101 12/22/23 0:00 PAR-19-325 5R37CA267905-03 5 R37 CA 267905 3 "UMAR, ASAD" 1/13/22 0:00 12/31/26 0:00 Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT] 12111921 "GEISLER, STEFANIE " Not Applicable 1 NEUROLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 375638 NCI 241568 134070 Project Summary/AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a common frequently dose-limiting side-effect ofchemotherapeutic drugs. CIPN can be excruciatingly painful profoundly debilitating cause permanent disabilityand lead some patients to elect to end life-saving treatment. In contrast to other side effects CIPN frequentlylasts well beyond the duration of treatment and can cause permanent disability. Consequently therapies areurgently needed as they would not only enhance the quality of life of cancer patients both during and aftertreatment but also improve cancer therapy by permitting effective chemotherapeutic dosing. To address thisneed we have developed mechanism-based interventional strategies for CIPN.Chemotherapy-induced neuropathies are characterized by axonal degeneration which leads to the unpleasantsymptoms of neuropathies. We have shown that vincristine and bortezomib two widely used chemotherapeuticagents with different mechanisms of action act via the neuronal protein SARM1 the central executioner of agenetically encoded axon degeneration program. Activated SARM1 cleaves the metabolic cofactor NAD+leading to local NAD+ depletion followed by metabolic collapse and axon fragmentation. We here present severalnew strategies to block this final common pathway to axon degeneration. We generated a SARM1dominant/negative that potently inhibits SARM1 function and axon degeneration. We will utilize adeno-associated virus (AAV) -mediated expression of a SARM1 dominant-negative to block SARM1 activity and willassess the effect of SARM1-dominant/negative on axon degeneration neuroinflammation and functionaloutcomes. We have shown in vitro that boosting the synthesis of NAD+ strongly protects against vincristine andbortezomib-induced axon degeneration. We will use virus-mediated expression of enzymes of the NAD+ salvagepathway to boost NAD+ synthesis which counters the axon destructive effects of SARM1. As a further step totranslation to the clinic we will evaluate in mouse models of cancer whether our therapeutic strategies interactwith the cancer or chemotherapy and are effective in cancer-bearing mice. Success of our experiments will leaddirectly to clinically viable means to prevent and treat CIPN. 375638 +No NIH Category available Address;Advanced Malignant Neoplasm;Affect;Anxiety;Breast;Cancer Family;Caregivers;Caring;Communication;Comprehensive Cancer Center;Conflict (Psychology);Data;Decision Making;Development;Diagnosis;Distress;Effectiveness;Enrollment;Family;Family Caregiver;Feedback;Foundations;Friends;Future;Goals;Gynecologic;Health;Healthcare;Hospice Care;Individual;Intervention;Intervention Trial;Interview;Knowledge;Location;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Mental Depression;National Alliance for Caregiving;Newly Diagnosed;Oncology;Operative Surgical Procedures;Outcome;Pain;Palliative Care;Parents;Participant;Patient Care;Patients;Persons;Psychosocial Assessment and Care;Quality of life;Randomized;Reporting;Reproducibility;Research;Resources;Sex Behavior;Sexual Health;Social support;Surveys;Symptoms;Testing;Training;Training Support;cancer care;cancer diagnosis;cancer therapy;cancer type;care recipients;caregiving;coping;cost effective;disabling symptom;end of life;experience;follow-up;health care service utilization;improved;innovation;intimate behavior;malignant breast neoplasm;multiphase optimization strategy;novel;preference;primary endpoint;primary outcome;psychoeducation;psychoeducational;recruit;reproductive;sexual relationship;skills;telehealth;theories Decision Support Training for Advanced Cancer Family Caregivers: The CASCADE Factorial Trial PROJECT NARRATIVEA priority focus in oncology and palliative care is preparing the 3.2 million U.S. family caregivers of personswith cancer to effectively partner with patients in health-related decision-making from diagnosis to the end oflife particularly in underserved settings. Over 70% of patients with cancer involve relatives friends andpartners in healthcare decisions including choices about cancer treatments surgery transitions and locationof care accessing palliative and hospice care and many others. Patients making healthcare decisions withunprepared family caregivers may experience inadequate family decision support leading to heighteneddistress and receipt of care/treatments inconsistent with their values and preferences which may in turnincrease distress for family caregivers. NCI 10770967 9/19/23 0:00 PA-20-272 3R01CA262039-03S1 3 R01 CA 262039 3 S1 "MOLLICA, MICHELLE A" 7/15/21 0:00 6/30/26 0:00 Clinical Management in General Care Settings Study Section[CMGC] 10712991 "DIONNE-ODOM, JAMES N." Not Applicable 7 OTHER HEALTH PROFESSIONS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF NURSING 352940001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 204066 OD 137418 66648 A priority in oncology and palliative care is preparing the 3.2 million U.S. family caregivers of persons withcancer to effectively support patients in health-related decision-making from diagnosis to the end of lifeparticularly in underserved settings. Over 70% of patients with cancer involve family in health decisionsincluding choices about treatments surgery location of care accessing palliative care and many others.Patients making these decisions with unprepared family caregivers may experience inadequate family decisionsupport leading to heightened distress and receipt of care/treatments inconsistent with their values andpreferences. This in turn may increase distress for family caregivers. There is a critical need to train cancerfamily caregivers to effectively support patient decision-making; however few palliative care interventions havebeen tested to enhance caregiver skills in providing decision support. We have developed CASCADE (CAreSupporters Coached to be Adept DEcision partners) a lay navigator-led telehealth early palliative careintervention to train advanced cancer caregivers how to effectively partner with patients in health decisionmaking. Evolving out of our prior early palliative care caregiving interventions decision support relevantcontent for family caregivers includes principles of effective social support communication and OttawaDecision Guide training; however we do not know which of these components and component interactionsinfluences patient and caregiver decision-making outcomes. Traditional research approaches treatinterventions as bundled treatment packages making it difficult to assess definitively which interventioncomponents can be reduced eliminated or replaced to improve efficiency. Hence we propose a randomized23 (2x2x2) factorial trial the first such trial in oncology palliative care using the Multiphase OptimizationStrategy (MOST) to test components of CASCADE in order to assemble an optimized scalable version of theintervention. 352 family caregivers of persons with newly-diagnosed advanced cancer will be randomized toreceive one or more palliative care lay navigator-delivered decision partnering training components based onthe Ottawa Decision Support Framework and Social Support Effectiveness Theory: 1) psychoeducation onsocial support effectiveness in decision support (1 vs. 3 sessions); 2) decision support communication training(yes vs. no); and 3) Ottawa decision Guide training (yes vs. no). We will determine CASCADE components(main effects/interactions) that contribute meaningfully to patient and caregiver outcomes including patienthealthcare utilization (Aim 1) and use those results to build a version of the CASCADE intervention that ismaximally effective and scalable (Aim 2). To maximize recruitment we will recruit from two NCI-designatedcomprehensive cancer centers in Birmingham AL and Atlanta GA. Using the innovative MOST framework willyield a highly novel and cost effective version of CASCADE primed for confirmatory RCT testing scalabilityand reproducibility. 204066 +No NIH Category available Address;Alcohol consumption;Atlases;Automobile Driving;Bioinformatics;CD3 Antigens;CD8B1 gene;Cd68;Cells;Chromosomal Gain;Chromosomal Instability;Clinical;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Epidemiology;Epithelium;Evaluation;Event;Formalin;Gene Expression;General Population;Genetic;Genome;Genomics;HPV-negative head and neck cancer;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Histologic;Human Papillomavirus;Immune;Immunofluorescence Immunologic;Immunogenetics;Immunogenomics;Immunologic Surveillance;Infection;Intercept;Knowledge;Lesion;Leukoplakia;Malignant - descriptor;Malignant Conversion;Malignant Neoplasms;Maps;Mediation;Modeling;Molecular;Morphology;Mutation;Natural History;Oral;Oral Leukoplakia;Paraffin Embedding;Patients;Persons;Population;Prevention;Process;Prospective cohort;Records;Resolution;Risk;Risk Factors;Role;Sampling;Screening for Oral Cancer;Structure;Subgroup;Surveys;Tissues;Tobacco use;Tumor Immunity;Whole Blood;anti-cancer;biobank;bioinformatics pipeline;cancer initiation;cohort;driver mutation;exome;exome sequencing;genomic data;immunogenic;immunoregulation;malignant mouth neoplasm;molecular marker;mouse model;mouth squamous cell carcinoma;neoplastic;novel;oral carcinogenesis;oral premalignancy;oral tissue;predictive marker;premalignant;prognostication;programmed cell death ligand 1;transcriptome;transcriptome sequencing;transcriptomics Mapping immuno-genomic drivers of the head and neck precancer invasive-disease transition n/a NCI 10770868 9/15/23 0:00 RFA-DE-23-013 1U01CA290479-01 1 U01 CA 290479 1 "WANG, WENDY" 9/15/23 0:00 8/31/28 0:00 ZDE1-AC(01) 12479946 "ALEXANDROV, LUDMIL B" "GUTKIND, JORGE SILVIO ; LIPPMAN, SCOTT M" 50 OTHER BASIC SCIENCES 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 790000 NIDCR 120254 69746 PROJECT SUMMARYGlobally more than 900000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) eachyear with more that 250000 dying annually from this cancer. Infection with human papilloma virus (HPV) aknown risk factor for developing HNSCC significantly impacts clinical prognostication. Specifically for HPV-negative HNSCC the most lethal subtype of head and neck cancer less than 30% of those diagnosed survivefor more than five years. The most common and lethal HPV-negative HNSCC subtype is oral cavity squamouscell carcinoma (OSCC). Importantly most OSCCs are preceded by morphologically distinguishable pre-cancerous lesions which are readily accessible for histological and molecular evaluation. This provides a uniqueopportunity for intercepting this deadly cancer in the earliest stages of its development by halting the conversionof oral precancer into invasive OSCC. Oral leukoplakia the focus of this application represents the most frequenttype of oral premalignancy with one in every fifty people is expected to develop OL in their lifetime. OLs lowmalignant transformation rate of ~3.3% progressing to oral cancer and its highly variable natural history poses amajor challenge for surveying OLs and for intercepting their malignant conversion into invasive oral cancers.To address this challenge we hypothesize that the evolutionary transition from an OL into an OSCC is due tothe immuno-genomic interactions encompassing the acquisition of somatic driver events the gain ofchromosomal instability and the loss of effective immunosurveillance. We further hypothesize that the genomicand immune landscapes of OL in patients who subsequently develop oral cancer (progressors) will differ fromthose that do not develop oral cancer (non-progressors). The overall objective of this project is to elucidate themolecular and immune mechanisms by which OLs progress to OSCCs and to develop actionable and predictivebiomarkers. To achieve this objective we will leverage well-annotated OL cohorts to generate the largest whole-exome and whole-transcriptome atlas encompassing 300 OLs including at least 100 cancer progressors and100 non-progressors. Further by utilizing a spatial multiplex immuno-fluorescence platform and an unbiasedRNA-sequencing approach for immuno-profiling we will comprehensively map the immune landscapes of these300 OLs and associate distinct immuno-genetic features with likely progression to OSCC. Lastly our state-of-the-art oral carcinogenesis mouse model will be used to model the transition of OL to OSCC at the single cellresolution in order to understand the role of common genomic alterations and immune surveillance in thisprocess. Overall this project will reveal the compendium of immuno-genetic changes that drive the evolutionarytransition from an OL to an OSCC and elucidate a set of targetable immune cell population(s) and novel immunesurveillance mechanisms which can likely halt this malignant transformation. 190000 +No NIH Category available Address;Alcohol consumption;Atlases;Automobile Driving;Bioinformatics;CD3 Antigens;CD8B1 gene;Cd68;Cells;Chromosomal Gain;Chromosomal Instability;Clinical;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Epidemiology;Epithelium;Evaluation;Event;Formalin;Gene Expression;General Population;Genetic;Genome;Genomics;HPV-negative head and neck cancer;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Histologic;Human Papillomavirus;Immune;Immunofluorescence Immunologic;Immunogenetics;Immunogenomics;Immunologic Surveillance;Infection;Intercept;Knowledge;Lesion;Leukoplakia;Malignant - descriptor;Malignant Conversion;Malignant Neoplasms;Maps;Mediation;Modeling;Molecular;Morphology;Mutation;Natural History;Oral;Oral Leukoplakia;Paraffin Embedding;Patients;Persons;Population;Prevention;Process;Prospective cohort;Records;Resolution;Risk;Risk Factors;Role;Sampling;Screening for Oral Cancer;Structure;Subgroup;Surveys;Tissues;Tobacco use;Tumor Immunity;Whole Blood;anti-cancer;biobank;bioinformatics pipeline;cancer initiation;cohort;driver mutation;exome;exome sequencing;genomic data;immunogenic;immunoregulation;malignant mouth neoplasm;molecular marker;mouse model;mouth squamous cell carcinoma;neoplastic;novel;oral carcinogenesis;oral premalignancy;oral tissue;predictive marker;premalignant;prognostication;programmed cell death ligand 1;transcriptome;transcriptome sequencing;transcriptomics Mapping immuno-genomic drivers of the head and neck precancer invasive-disease transition n/a NCI 10770868 9/15/23 0:00 RFA-DE-23-013 1U01CA290479-01 1 U01 CA 290479 1 "WANG, WENDY" 9/15/23 0:00 8/31/28 0:00 ZDE1-AC(01) 12479946 "ALEXANDROV, LUDMIL B" "GUTKIND, JORGE SILVIO ; LIPPMAN, SCOTT M" 50 OTHER BASIC SCIENCES 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 790000 NCI 379746 220254 PROJECT SUMMARYGlobally more than 900000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) eachyear with more that 250000 dying annually from this cancer. Infection with human papilloma virus (HPV) aknown risk factor for developing HNSCC significantly impacts clinical prognostication. Specifically for HPV-negative HNSCC the most lethal subtype of head and neck cancer less than 30% of those diagnosed survivefor more than five years. The most common and lethal HPV-negative HNSCC subtype is oral cavity squamouscell carcinoma (OSCC). Importantly most OSCCs are preceded by morphologically distinguishable pre-cancerous lesions which are readily accessible for histological and molecular evaluation. This provides a uniqueopportunity for intercepting this deadly cancer in the earliest stages of its development by halting the conversionof oral precancer into invasive OSCC. Oral leukoplakia the focus of this application represents the most frequenttype of oral premalignancy with one in every fifty people is expected to develop OL in their lifetime. OLs lowmalignant transformation rate of ~3.3% progressing to oral cancer and its highly variable natural history poses amajor challenge for surveying OLs and for intercepting their malignant conversion into invasive oral cancers.To address this challenge we hypothesize that the evolutionary transition from an OL into an OSCC is due tothe immuno-genomic interactions encompassing the acquisition of somatic driver events the gain ofchromosomal instability and the loss of effective immunosurveillance. We further hypothesize that the genomicand immune landscapes of OL in patients who subsequently develop oral cancer (progressors) will differ fromthose that do not develop oral cancer (non-progressors). The overall objective of this project is to elucidate themolecular and immune mechanisms by which OLs progress to OSCCs and to develop actionable and predictivebiomarkers. To achieve this objective we will leverage well-annotated OL cohorts to generate the largest whole-exome and whole-transcriptome atlas encompassing 300 OLs including at least 100 cancer progressors and100 non-progressors. Further by utilizing a spatial multiplex immuno-fluorescence platform and an unbiasedRNA-sequencing approach for immuno-profiling we will comprehensively map the immune landscapes of these300 OLs and associate distinct immuno-genetic features with likely progression to OSCC. Lastly our state-of-the-art oral carcinogenesis mouse model will be used to model the transition of OL to OSCC at the single cellresolution in order to understand the role of common genomic alterations and immune surveillance in thisprocess. Overall this project will reveal the compendium of immuno-genetic changes that drive the evolutionarytransition from an OL to an OSCC and elucidate a set of targetable immune cell population(s) and novel immunesurveillance mechanisms which can likely halt this malignant transformation. 600000 +No NIH Category available Targeting autophagy to increase the sensitivity of LKB1-deficient lung tumors to angiogenesis inhibitor PROJECT NARRATIVEPatients harboring co-mutations of KRAS and LKB1 two of the most frequent mutations detected in non-smallcell lung cancer (NSCLC) develop aggressive lung tumors show a high frequency of metastases and areresistant to all standard therapeutics. Using pre-clinical mouse models of KRAS-mutant LKB1-deficient (KL)NSCLC we have demonstrated that autophagy is required for KL lung tumorigenesis by replenishment ofnutrient storage in response to energy crisis. In this proposal we will investigate the novel concept thatautophagy compensates for nutrient deprivation caused by angiogenesis inhibitor for the survival and growth ofKL lung tumors which will provide a new therapeutic strategy by autophagy inhibition combined withangiogenesis inhibitor to selectively and effectively treat lung cancer patients bearing co-mutations of KRAS andLKB1. NCI 10770658 4/11/23 0:00 PAR-20-292 7R21CA263136-02 7 R21 CA 263136 2 "CHEN, WEIWEI" 8/1/22 0:00 7/31/24 0:00 ZCA1-SRB-P(M1)S 11768709 "GUO, YANXIANG " Not Applicable 10 INTERNAL MEDICINE/MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 4/1/23 0:00 7/31/23 0:00 395 Non-SBIR/STTR 2022 220193 NCI 140250 79943 ABSTRACTLung cancer is the leading cancer killer worldwide with non-small cell lung cancer (NSCLC) accounting for morethan 85% of these cases. KRAS and LKB1 are the two most frequent mutations detected in lung cancer patients.Lung cancer patients bearing co-mutations of KRAS and LKB1 show increased aggressiveness a highfrequency of metastases and resistance to all standard therapies. Cancer cells acquire nutrients from circulatingblood. Angiogenesis inhibitors which block the growth of blood vessels have been used for lung cancertreatment. However multiple preclinical as well as clinical studies have reported that LKB1 depletion confersresistance to angiogenesis inhibitors regardless of whether or not receiving chemotherapy. One of acquiredresistance to antiangiogenics stems from tumor adaptations by induction of metabolic symbiosis. Autophagy isa process that cell eats itself to generate building blocks energy and redox homeostasis and for elimination ofwaste in response to metabolic stress such as nutrient depletion. Many studies including our group have provedthat in response to extracellular nutrient deprivation cancer cells can scavenge nutrients through autophagy-mediated intracellular recycling for tumor growth proliferation survival and malignancy. Thereforesimultaneously eliminating nutrient availability from both intracellular and extracellular sources could be aninnovative strategy for a successful cancer treatment. In particular we recently demonstrated that autophagy isupregulated in Kras-mutant Lkb1-deficient (KL) lung tumor and autophagy inhibition is synthetically lethal in KL-mediated tumorigenesis. Moreover anti-tumor effect by autophagy ablation is much more profound in Lkb1-deficient KL lung tumor than Lkb1 wild type (WT) KP (Kras-mutant p53-deficient) lung tumor. Based on aboverationale and preliminary studies we formed central hypothesis: autophagy-mediated intracellular recyclingcompensates for nutrient deprivation caused by angiogenesis inhibitor to support the survival and growth of KLlung tumor. We will: 1) determine the role and mechanism of cell-autonomous autophagy in conferring resistanceof KL lung tumor to angiogenesis inhibitor; and 2) Determine if targeting autophagy can sensitize Lkb1-deficientKL lung tumor but not Lkb1-WT KP lung tumor to angiogenesis inhibitor. Our study will determine if LKB1mutations could be explored as a predictive biomarker for precision lung cancer therapy using the combinationof autophagy inhibitor and angiogenesis inhibitor. Once our hypothesis is confirmed in preclinical mouse modelsthe novel therapy of autophagy inhibitor hydroxychloroquine combined with angiogenesis inhibitor Bevacizumabcan be naturally and immediately translated into clinical trials for treating lung cancer patients harboring co-mutations of KRAS and LKB1. 220193 +No NIH Category available Abbreviations;Address;Alternative Splicing;Area;Bioinformatics;Biomedical Research;Biometry;Bronchoalveolar Lavage Fluid;Budgets;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Cancer Survivorship;Capillary Electrophoresis;Categories;Cell Culture Techniques;Cells;Chemicals;Chemoprevention;Complex;Comprehensive Cancer Center;Computer software;Consultations;Core Facility;Cryo-electron tomography;Culture Media;Data Analyses;Data Analytics;Data Set;Detection;Development;Device or Instrument Development;Devices;Drops;Electron Microscopy;Engineering;Equipment;Experimental Designs;Flow Cytometry;Fluorescence;Formalin;Freezing;Funding;Genomics;Grant;High Pressure Liquid Chromatography;Immunologic Monitoring;Immunooncology;Informatics;Institution;Intramural Research Program;Label;Leadership;Liquid substance;Malignant Neoplasms;Mass Spectrum Analysis;Methods;Microscopy;Molecular Carcinogenesis;Mutation;NCI Center for Cancer Research;Ohio;Optics;Pediatric Hospitals;Peptide Sequence Determination;Pharmaceutical Chemistry;Post-Translational Protein Processing;Preparation;Price;Protein Analysis;Protein Truncation;Proteins;Proteomics;Proteomics Shared Resource;Publications;Published Comment;Research;Research Institute;Research Personnel;Research Priority;Resource Sharing;Resources;S10 grant;Saliva;Sampling;Scanning Electron Microscopy;Serum;Services;Site;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stable Isotope Labeling;Techniques;Time;Tissue imaging;Tissues;Training;Transmission Electron Microscopy;United States National Institutes of Health;Universities;Urine;Variant;Work;advanced analytics;biomedical informatics;cancer imaging;cancer prevention;cancer proteomics;college;differential expression;experience;experimental study;improved;innovation;instrument;instrumentation;ion mobility;leukemia;leukemia tissue bank;light microscopy;mass spectrometer;mass spectrometric imaging;member;method development;new technology;novel;operation;programs;protein crosslink;protein expression;protein protein interaction;reconstruction;recruit;senior faculty;software development;structural biology;timeline;tissue fixing;translational genomics;translational therapeutics Shared Resource 14: Proteomics (PSR) n/a NCI 10770539 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7791 6478319 "FREITAS, MICHAEL A." Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 202561 129847 72714 PROJECT SUMMARY PROTEOMICS SHARED RESOURCE (PSR)The PSR provides expertise and access to state-of-the-art instrumentation for proteomics experiments. The PSRis embedded within the OSU Campus Chemical Instrument Center offering competitive pricing and exceptionalservice by leveraging generous support from the Office of Research and Colleges and grants from the NIH.During the last review the PSR was rated Outstanding as part of the Analytics Shared Resource Group withthree addressable comments to reduce turn-around time a perceived drop in percent users actually due to anincrease of non-cancer users as an OSU facility and perceived duplicative services. Major services include: 1)consultation for sample preparation MS experiment design data analysis and timelines; 2) protein identificationusing state-of-the-art MS on a variety of sample matrices; 3) in depth protein characterization including but notlimited to post-translational modifications protein variant/mutations protein truncation sites detection alternatesplice form detection de novo protein sequencing protein cross-linking and protein-protein interactions; 4)protein quantification using label-free (spectral counts and/or relative intensity) or stable isotope label techniques(SILAC or ITRAQ/TMT) quantitative MALDI tissue imaging and targeted mass spectrometry; and 5) dataanalysis provided with the BISR using commercial and in-house developed software platforms. Major equipmenthas been enhanced in the past 5 years through three NIH S10 grants and a funded P41 Resource Center formethods development. PSR Specific Aims are to: 1) provide advanced mass spectrometry-based proteomicsservices; 2) provide innovative proteomic data analytics and bioinformatics platforms to facilitate userinterpretation; and 3) provide consultation on experimental design and training on self-operated MS instruments.Over the current funding cycle the PSR provided key services in support of 44 publications (5 > 10 impactfactor) 380 users and 8 NCI grants including 1 K22 1 P01 4 R01s 1 R33 and 1 U01. The PSR is critical tothe OSUCCC research priorities of immuno-oncology translational genomics cancer engineering and cancerprevention and survivorship. Advanced analytical platforms allow researchers to discover novel differentiallyexpressed proteins in serum urine BAL fluid saliva frozen tissues formalin fixed tissues cell culture mediaand cell lysates. Given the robust OSUCCC recruitment demand for services and new technologies willincrease. The GSR will expand its staff instrumentation and services before capacity is reached. To addressthis planned new services are being implemented or expanded (informatics services with BISR capillaryelectrophoresis and ion mobility methods tissue imaging and structural biology using native MS as developedby a P41 Resource grant). Over the next funding period the PSR will be a member of the Immune Monitoringand Discovery Platform. The annual budget of the PSR is $1993101 yet the CCSG request is $158381. Thusthe PSR leverages extensive institutional support and seeks only 7.9% support from CCSG funds. +No NIH Category available Abbreviations;Agriculture;Animal Experiments;Biological;Biological Assay;Biological Markers;Biometry;Budgets;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cancer Hospital;Cancer Survivorship;Carcinogens;Cell Culture Techniques;Chemoprevention;Clinical Treatment;Clinical Trials;Clinical Trials Network;Collaborations;Comparative Pathology;Comprehensive Cancer Center;Diet;Dietary Practices;Discipline;Environmental Science;Epidemiology;Excretory function;Faculty;Flow Cytometry;Food;Food Patterns;Funding;Future;Genetic Determinism;Genomics;Grant;Growth;High Pressure Liquid Chromatography;Human;Immunooncology;In Vitro;Individual;Informatics;Institution;Intake;Intervention;Intramural Research Program;Investigational Therapies;Investments;Laboratories;Lipids;Liquid Chromatography;Malignant Neoplasms;Mass Spectrum Analysis;Metabolism;Microscopy;Mission;Molecular Carcinogenesis;Molecular Epidemiology;NMR Spectroscopy;Nutrient;Ohio;Pathway Analysis;Pediatric Hospitals;Pharmaceutical Chemistry;Phytochemical;Preparation;Prevention;Proteomics;Publications;Published Comment;Reporting;Research;Research Institute;Research Personnel;Research Support;Resource Sharing;Role;Sampling;Schedule;Services;Source;Supercritical Fluid Chromatography;Surveys;Techniques;Technology;Tobacco;Tobacco use;Training;Translational Research;Universities;Validation;absorption;animal imaging;anti-cancer;base;biomedical informatics;cancer prevention;cancer risk;clinical translation;college;digital imaging;drug development;food science;food science/technology;improved;in vivo;innovation;insight;instrument;instrumentation;ion mobility;leukemia;leukemia tissue bank;lipidomics;liquid chromatography mass spectrometry;member;metabolomics;method development;microbiome;novel;pathology imaging;programs;recruit;senior faculty;survivorship;tobacco exposure;translational genomics;translational scientist;translational therapeutics Shared Resource 12: Nutrient and Phytochemical Analytics (NPASR) n/a NCI 10770535 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7789 1897233 "CLINTON, STEVEN K" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 94949 60865 34084 PROJECT SUMMARY NUTRIENT AND PHYTOCHEMICAL ANALYTICS SHARED RESOURCE (NPASR)The mission of the NPASR is to provide niche services supporting research with high quality assays forbiomarkers of tobacco exposure specific nutrients or a vast array of anti-cancer phytochemicals found in foodsources. NPASR primarily supports the Molecular Carcinogenesis and Chemoprevention (MCC) and the CancerControl (CC) Programs which have robust research examining the role of diet and tobacco in cancer etiologyprevention and survivorship. The NPASR co-Directors are Drs. Steven Clinton a translational researcher incancer prevention (interim co-Director Senior Faculty Advisor; MCC co-Leader) and Devin Peterson a seniorfood science chemist in the College of Food Agricultural and Environmental Sciences. The Specific Aims of theNPASR are to: 1) provide expert leading-edge bioanalytical method development and quantitative analysis ofnutrients and bioactive phytochemicals in foodstuffs; 2) conduct targeted quantitative analysis of nutrientsbioactive phytochemicals and their metabolites in biological samples generated from in vitro in vivo and humanstudies using HPLC-MS/MS techniques; and 3) perform untargeted metabolomics and lipidomics services forcancer-related studies. NPASR technologies include state-of-the-art ultra-high performance liquidchromatography (UHPLC) mass spectrometry (MS) and liquid chromatography triple quadrupole MS/MS (LC-MS/MS). NPASR has added several new analytical capabilities during the current funding cycle including: 1) ionmobility hardware facilitating a broad semi-quantitative lipidomics platform; 2) a second MS instrument to supportuntargeted metabolomics and lipidomics demand; and 3) a state-of-the-art MS/MS for utmost sensitivity. Duringthe current funding cycle the NPASR supported 49 publications (2 > 10 impact factor) 55 users and 6 NCIgrants including 1 P50 3 R01s 1 U19 and 1 U01 involving all five CCC programs. These efforts andpublications have contributed to defining biomarkers of exposure or intake and provided novel insight intophytochemical absorption distribution metabolism and excretion. More recently NPASR has expanded intotargeted and untargeted metabolomics supporting our understanding of individual cancer risk due to tobaccoexposure nutrients specific foods and dietary patterns. To meet future demands of OSUCC Investigatorsaligned with OSUCCC strategic priorities NPASR will further support for example studies of metabolomic-microbiome interactions genetic determinants of metabolism and tobacco use biomarkers. During the next grantcycle lipidomics and bioactive lipid analytic capabilities will be expanded to meet the needs of a growing userbase of all five programs. The NPASR provides a critical service for CCC members evaluating foods nutrientsand carcinogens that spans research disciplines from cell culture and experimental animal studies to humantrials and molecular epidemiology. The annual budget of the NPASR is $387249 yet the CCSG request is$74239. As such the NPASR leverages extensive institutional support and seeks only 19.2% support fromCCSG funds. +No NIH Category available Abbreviations;Address;Biocompatible Materials;Biometry;Biopsy;Blood;Bone Marrow;Budgets;CD34 gene;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Cancer Survivorship;Cell Survival;Chemoprevention;Clinic;Clinical;Clinical Data;Clinical Research Protocols;Clinical Treatment;Clinical Trials;Clip;Collaborations;Collection;Comparative Pathology;Comprehensive Cancer Center;Consent;Cryopreservation;DNA;Data;Electronics;Equipment and supply inventories;Evaluation;Experimental Hematology;Flow Cytometry;Fostering;Funding;Genetic;Genetic Materials;Genomics;Grant;Hematological Disease;Hematology;Hematopoietic stem cells;Immune;Immunologic Monitoring;Immunooncology;Immunophenotyping;Institution;Institutional Review Boards;Intervention;Intramural Research Program;Laboratories;Leukapheresis;Liquid substance;Location;Lymphoma;Marrow;Mentored Clinical Scientist Development Program;Microscopy;Molecular Carcinogenesis;Multiple Myeloma;NCI Center for Cancer Research;Nitrogen;Nutrient;Ohio;Oncology;Operative Surgical Procedures;Outcome;Pathologic;Pathology;Patients;Pediatric Hospitals;Pharmaceutical Chemistry;Phenotype;Phytochemical;Procedures;Process;Proteins;Proteomics;Protocols documentation;Publications;Published Comment;Quality Control;Research;Research Institute;Research Personnel;Research Priority;Resource Sharing;Resources;Sampling;Services;Source;Stromal Cells;Structure of nail of finger;Surveys;System;Techniques;Tissue Procurements;Translational Research;Umbilical Cord Blood;Universities;animal imaging;biobank;biomedical informatics;bone;cancer care;cancer prevention;clinical translation;digital imaging;genomic data;hip bone;improved;leukemia;leukemia tissue bank;lymph nodes;material transfer agreement;member;next generation sequencing;pathology imaging;population based;programs;recruit;sample collection;senior faculty;standard of care;translational genomics;translational therapeutics Shared Resource 09: Leukemia Tissue Bank (LTBSR) n/a NCI 10770525 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7786 10561693 "ALINARI, LAPO " Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 90104 57759 32345 PROJECT SUMMARY LEUKEMIA TISSUE BANK SHARED RESOURCE (LTBSR)The LTBSR is a longstanding biobank established in 1997 that procures processes and stores biologicmaterial from consenting patients with hematologic diseases. The LTBSR procures samples in two ways: 1) viaa general biobanking protocol for future research; and 2) via specific clinical research protocols with specialcollection needs. The major services of the LTBSR are consenting patients procuring samples (e.g. blood bonemarrow and leukapheresis products) as directed by the general or a specific IRB protocol assessing samplequality providing fresh samples to investigators or processing them for storage providing an oversight processfor use of samples and data and delivering samples and data to approved recipients. Investigators receivesamples identified phenotypically or genetically along with clinical data and available pathology data (includingstandard of care immunophenotyping and genetic sequencing panels). During the current cycle Dr. Lapo Alinari(LR) replaced the prior LTBSR Director (David Lucas who moved from Columbus) and Dr. Robert Baiocchi (LR)replaced Dr. Clara Bloomfield (LR) as the Senior Faculty Advisor. The Specific Aims of the LTBSR are to: 1)consent subjects and procure samples from patients with hematologic diseases; 2) uniformly processcharacterize and store biospecimens using state-of-the art procedures; and 3) provide biospecimens withassociated clinical pathological and genomic data to OSUCCC researchers and to outside institutions so thatthey can correlate findings from patient samples with clinical or population-based outcomes. Over the currentgrant cycle the LTBSR has supported 67 investigators (75% OSUCCC members) and all five of the OSUCCCresearch programs 45 publications (11 > 10 impact factor) and 19 NCI grants including 1 K12 1 K22 1 K23 1P01 13 R01s and 2 R35s. The OSUCCC has recently made a commitment to substantially increase samplesobtained by lymph node sampling from lymphoma patients. In addition the LTBSR has expanded services forcollecting discarded normal hipbone from replacement surgeries as a source of marrow stromal cells andumbilical cord blood as a source of CD34+ hematopoietic stem cells. In the next funding cycle the LTBSR willcontinue to expand its breadth of tissue procurement services addressing the OSUCCC research priorities ofimmuno-oncology translational genomics and cancer prevention and survivorship. The annual budget of theLTBSR is $664631 yet the CCSG request is $70451. Thus the LTBSR leverages extensive institutionalsupport and seeks only 10.6% support from CCSG funds. +No NIH Category available Abbreviations;Academic Medical Centers;Address;Agreement;Biometry;Budgets;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Cancer Research Project;Cancer Survivorship;Cell Separation;Cells;Chemicals;Chemoprevention;Clinical Treatment;Clinical Trials;Communication;Comparative Pathology;Complex;Comprehensive Cancer Center;Computer software;Consultations;Cytometry;Development;Disease;Education and Outreach;Educational workshop;Engineering;Equipment;Experimental Designs;Faculty;Fee-for-Service Plans;Flow Cytometry;Flow Cytometry Shared Resource;Funding;Genomics;Grant;Hour;Image Analysis;Immune system;Immunologic Monitoring;Immunooncology;Institution;Institutional Review Boards;Intervention;Intramural Research Program;Laboratories;Lasers;Magnetism;Malignant Neoplasms;Mentored Clinical Scientist Development Program;Methodology;Methods;Microscopy;Mission;Molecular Carcinogenesis;Names;Nutrient;Ohio;Pediatric Hospitals;Pharmaceutical Chemistry;Phytochemical;Positioning Attribute;Procedures;Proteomics;Publications;RNA;Research;Research Institute;Research Personnel;Resource Sharing;Resources;Services;Sorting;Supporting Cell;Surveys;System;Technical Expertise;Technology;Testing;Time;Training;Training Programs;Translational Research;United States National Institutes of Health;Universities;Work;animal imaging;anticancer research;assay development;base;biomedical informatics;cancer care;cancer prevention;cancer risk;clinical translation;commercialization;digital imaging;exosome;extracellular;extracellular vesicles;fluorescence microscope;industry partner;instrument;instrumentation;leukemia;leukemia tissue bank;magnetic cell separation;material transfer agreement;member;microbiome;microvesicles;new technology;operation;pathology imaging;programs;recruit;technology development;translational genomics;translational therapeutics Shared Resource 07: Flow Cytometry (FCSR) n/a NCI 10770520 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7784 1881179 "CHALMERS, JEFFREY JOHN" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 138461 88757 49704 PROJECT SUMMARY FLOW CYTOMETRY SHARED RESOURCE (FCSR)Flow cytometry services are critical for cancer research. Since flow cytometry instrumentation is expensive andtypically requires significant technical expertise a centralized resource is essential. The mission of the FCSR isto support OSUCCC members and high-impact cancer research projects with high quality cell analysis andsorting capabilities. The FCSR also provides training and regularly host technology-based seminars orworkshops to introduce new technology to OSUCCC members. The FCSR continues to strive to be a state-of-the-art cell analysis laboratory that has the following Specific Aims to: 1) provide state-of-the-art equipment andsupport for high-quality cancer research for OSUCCC members on a fee-for-service basis; 2) continuously workwith OSUCCC members to provide substantial technical expertise and training for state-of the-art cytometryinstruments to address fundamental questions in cancer research so that researchers can have 24-hour accessto flow cytometry instrumentation; and 3) introduce OSUCCC members to new instrumentation technology andmethodologies being developed at the FCSR through a variety of educational outreach activities. The FCSR co-Directors are Jeffrey Chalmers (Department of Chemical and Biomolecular Engineering) and recently appointedco-Director Kevin Weller Associate Director of the Pelotonia Institute of Immuno-Oncology (PIIO) andspecifically to develop the Immune Monitoring and Discovery Platform a cross-cutting shared-resource initiativethat integrates shared resources for complex immuno-oncology projects. Further Dr. Gregory Behbehani (LR)is a Faculty Advisor for the Helios mass cytometer (CyTOF) system. Over the current grant cycle major changesto the FCSR were to align with the establishment of the PIIO which will result in a substantial increase in theneed for flow cytometry services. To address this need new instrumentation was purchased including four newinstruments including a state-of-the-art Cytek Aurora flow cytometer and a Helios mass cytometer. During thistime period the FCSR contributed to 231 publications (39 >10 impact factor) had 296 users with 34118 hoursof service (83.7% to OSUCCC members) and supported 80 NCI grants (1 K12 1 K22 1 K24 6 P01s 1 P5052 R01s 1 R03 7 R21s 3 R35s 1 R37 1 T32 and 5 U01s). In the next funding cycle the FCSR will supportthe increasing needs of all OSUCCC strategic priorities including immuno-oncology translational genomicscancer engineering and cancer prevention and survivorship. The user base will substantially increased requiringnew staff and technologies for example by purchasing an additional Aurora instrument and increasing cellsorting cell isolation and exosome/microvesicle research. In addition new services under development includedevelopment of further exosome characterization and isolation technology. The annual budget of the FCSR is$518075 yet the CCSG request is $108261. As such the FCSR leverages extensive institutional support andseeks only 20.9% support from CCSG funds. +No NIH Category available Abbreviations;Address;Age;Algorithms;Anatomy;Animal Model;Animals;Antibodies;Biological Markers;Biomedical Research;Biometry;Board Certification;Breeding;Budgets;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Cancer Survivorship;Chemoprevention;Clinical Treatment;Clinical Trials;Comparative Pathology;Complement;Complex;Comprehensive Cancer Center;Computer software;Custom;Data Analyses;Development;Diagnostic;Engineering;Experimental Designs;Experimental Pathology;Flow Cytometry;Fostering;Funding;Genomics;Grant;Histology;Hour;Human;Human Pathology;IACUC;Image;Image Analysis;Immunofluorescence Immunologic;Immunohistochemistry;Immunologic Monitoring;Immunooncology;In Situ Hybridization;Informatics;Intervention;Intramural Research Program;Laboratories;Lesion;Machine Learning;Malignant Neoplasms;Medicine;Mentored Clinical Scientist Development Program;Microscopy;Minor;Molecular Carcinogenesis;Mus;NCI Center for Cancer Research;Names;Nutrient;Ohio;Pathologic;Pathologist;Pathology;Peer Review;Pharmaceutical Chemistry;Phenotype;Physiological;Phytochemical;Proteins;Proteomics;Publications;RNA;Research;Research Institute;Research Personnel;Resource Sharing;Sampling;Services;Slide;Stains;Surveys;Tissue Procurements;Tissues;Translational Research;Universities;Validation;Veterinary Medicine;Veterinary Pathology;Workload;animal imaging;animal tissue;biomedical informatics;cancer prevention;cancer therapy;carcinogenesis;clinical translation;college;comparative;digital imaging;experience;human tissue;improved;leukemia;leukemia tissue bank;meetings;member;open source;pathology imaging;pre-clinical;preclinical efficacy;preclinical toxicity;programs;quantitative imaging;recruit;tissue biomarkers;translational genomics;translational impact;translational study;translational therapeutics;treatment response;tumor progression Shared Resource 06: Comparative Pathology and Digital Imaging (CPDISR) n/a NCI 10770517 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7783 3086533 "LA PERLE, KRISTA MARIE DUBRAY" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 137316 88023 49293 PROJECT SUMMARY COMPARATIVE PATHOLOGY & DIGITAL IMAGING SHARED RESOURCE (CPDISR)The CPDISR provides expert readily available and affordable experimental pathology support to investigatorsconducting research for understanding the development and treatment of cancer using preclinical animal modelsand/or human tissues procured for translational research. During the current funding period a recent majordevelopment was the inclusion of complete histology services optimized for human tissues as well as expandedslide digitization and quantitative image analysis services for stained human and animal tissue slides. As a resultDr. Anil Parwani (MCC) has been named co-Director with Dr. Krista La Perle (CB) the name of the sharedresource (SR) has been changed to the Comparative Pathology & Digital Imaging Shared Resource and theSpecific Aims have been modified accordingly. The Specific Aims are to: 1) provide consultative services toOSUCCC investigators for optimal experimental design sample submission and data analysis and interactionswith other SRs; 2) provide support for preclinical efficacy and toxicity animal studies as well as translationalstudies that utilize human tissues; and 3) perform digitization and quantitative image analysis of stained slidesfrom animal and human tissues. During the current 5-year grant cycle a third board certified veterinarypathologist and seven additional technical staff have been added to anticipate usage in conjunction with therobust OSUCCC recruitment and strategic priorities. The CPDISR also acquired a Leica PELORIS 3 dual retorttissue processor after successful peer-reviewed funding through the OSUCCC Intramural Research Program.During this grant cycle the CPDISR contributed to 84 publications (12 > 10 impact factor) 537 investigatorsand 57 NCI grants including 1 K12 1 K22 1 K24 5 P01s 1 P50 35 R01s 7 R21s 2 R35s 1 T32 and 3 U01sinvolving members of all five OSUCCC research programs. For the next grant cycle the CPDISR will be a regularmember of the Immune Monitoring and Discovery Platform an overarching shared resource initiative fosteringcomplex immuno-oncology projects. In addition a major emphasis will be to continue to expand our availablemenu of antibodies optimized for immunohistochemistry immunofluorescence and in situ hybridization in tissuesof animal and human origin by various staining platforms including multiplexing according to the specific needsof OSUCCC members. We will also increase our support of image analysis projects allowing machine learningapproaches to be developed with the center for cancer engineering; and continue to evaluate available opensource and commercial image analysis software platforms/modules to complement our Aperio and Visiopharmsoftware in order to quantify biomarkers in animal and human tissues. The annual budget of the CPDISR is$1863254 yet the CCSG request is $107366. As such the CPDIR seeks only 5.8% budgetary support fromCCSG funds. +No NIH Category available Abbreviations;Adverse event;Area;Artificial Intelligence;Bioconductor;Biological;Biometry;Biostatistics Shared Resource;Budgets;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Cancer Survivorship;Center for Translational Science Activities;Chemoprevention;Clinical;Clinical Cancer Center;Clinical Data;Clinical Sciences;Clinical Treatment;Clinical Trials;Collaborations;Communities;Comparative Pathology;Comprehensive Cancer Center;Data;Data Analyses;Databases;Development;Disease;Education;Educational workshop;Electronic Health Record;Engineering;Ensure;FAIR principles;Faculty;Flow Cytometry;Funding;Future;Genomics;Grant;Guidelines;Health Insurance Portability and Accountability Act;Health Services Research;Hour;Immunologic Monitoring;Immunooncology;Individual;Informatics;Infrastructure;Institution;Institutional Review Boards;Intervention;Intramural Research Program;Logistics;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Methodology;Methods;Microscopy;Mission;Modeling;Molecular Carcinogenesis;Monitor;Multi-Institutional Clinical Trial;NCI Center for Cancer Research;Nutrient;Ohio;Oncology;Outcomes Research;Pediatric Hospitals;Persons;Pharmaceutical Chemistry;Phytochemical;Population Research;Population Study;Preparation;Procedures;Process;Proteomics;Protocols documentation;Publications;Publishing;Registries;Reporting;Reproducibility;Research;Research Activity;Research Design;Research Institute;Research Methodology;Research Personnel;Resource Sharing;Resources;Review Committee;Role;Safety;Science;Scientist;Services;Statistical Data Interpretation;Surveys;System;Technology;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;animal imaging;anticancer research;biomedical informatics;cancer care;cancer prevention;clinical translation;data quality;data visualization;design;digital imaging;epidemiology study;experimental study;genomic data;health disparity;innovation;leukemia;leukemia tissue bank;material transfer agreement;member;multidimensional data;next generation sequencing;pathology imaging;patient oriented;population based;professor;programs;query tools;recruit;research study;single-cell RNA sequencing;sound;tool;translational genomics;translational therapeutics;working group Shared Resource 03: Biostatistics (BSR) n/a NCI 10770506 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7780 8665590 "FERNANDEZ, SOLEDAD A" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 295772 189598 106174 PROJECT SUMMARY BIOSTATISTICS SHARED RESOURCE (BSR)The BSR provides a centralized resource of expertise in the biostatistical and design aspects ofclinical/translational basic and population-based cancer research. The specific aims of the BSR are to: 1)collaborate with OSUCCC investigators in all aspects of quantitative translational research including studydesign training and education reproducibility and scientific rigor statistical analysis data visualization andmanuscript and report preparation; 2) enable strong and consistent collaborations by providing a biostatisticalnavigator to all OSUCCC research programs and Disease Specific Research Groups (DSRGs) and byproviding education and biostatistical training to OSUCCC members; and 3) provide biostatistical andmethodological review of all cancer protocols submitted to the OSUCCC Clinical Scientific Review Committee(CSRC) and Data Safety Monitoring Committee (DSMC) and as needed for the Total Cancer Care (TCC)research committee for the BSSR. To bolster team science in cancer research BSR established a navigator-system in 2013 now expanded over the current cycle to 20 different groups at OSU and Nationwide Children'sHospital (NCH) whereby biostatisticians are embedded within each DSRG and are involved with all researchstudies from their inception. Navigators are intimately familiar with the clinical biological and statistical issuesthey support and serve as point persons for establishing collaborations between these groups and the broaderOSU community. Office hours were established within all five OSUCCC programs where the navigatorbiostatistician spends half a day every other week at a provided space. BSR also actively developed workshopsseminars and courses devoted to training biomedical investigators in the fundamentals of design analysis andscientific rigor. Over the current cycle BSR supported individual investigators using genomic data from the TCCprotocol the Oncology Research Information Exchange Network (ORIEN) Avatar program at OSU and theNational Patient-Centered Research Clinical Network (PaTH) by providing computational and programmingsupport data visualization graphical and query tools and data interpretation. BSR works together with othershared resources and the DSMC and CSRC in the development and implementation of protocols to ensureHIPAA compliant processes and high data quality by enforcing the application of Findable AccessibleInteroperable and Reusable (FAIR) guidelines. During the current cycle the BSR supported 405 publications(59 > 10 impact factor) and 98 NIH (53 NCI) grants including 26 R01s 35 R21s 1 R03 14 U01s 5 U24s 3U19s 3 U54s 8 P01s 2 P30s 1 P50. Over the next grant cycle the BSR's role in the new strategic priorities forthe OSUCCC including immuno-oncology translational genomics cancer engineering and cancer preventionand survivorship will substantially increase the BSR's contributions and will specifically include new recruits andtechnologies. The annual budget of the BSR is $4063515 yet the CCSG request is $231260. As such theBSR leverages extensive institutional support and seeks only 5.7% support from CCSG funds. +No NIH Category available Abbreviations;Accreditation;Address;American;Area;Biometry;Blood;Budgets;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Cancer Patient;Cancer Survivorship;Chemoprevention;Childhood;Clinical;Clinical Data;Clinical Treatment;Clinical Trials;Comparative Pathology;Comprehensive Cancer Center;Computerized Medical Record;Consent;Data;Diagnosis;Disease;Engineering;Enrollment;Equipment and supply inventories;Faculty Recruitment;Flow Cytometry;Funding;Future;Genomics;Goals;Grant;Health protection;Histology;Immunooncology;Institution;Institutional Review Boards;Intervention;Intramural Research Program;Laboratories;Leadership;Malignant Neoplasms;Management Information Systems;Mentored Clinical Scientist Development Program;Microscopy;Minor;Mission;Molecular Carcinogenesis;Normal tissue morphology;Nutrient;Ohio;Oncology;Online Systems;Pathologist;Pathology;Patients;Pediatric Hospitals;Pharmaceutical Chemistry;Phytochemical;Prevention;Procedures;Proteomics;Protocols documentation;Publications;Research;Research Institute;Research Personnel;Resource Sharing;Sampling;Services;Specimen;Specimen Handling;Surveys;Tablets;Time;Tissue Procurements;Tissues;Translational Research;Tumor Tissue;Universities;Visualization software;Work;analytical tool;animal imaging;biobank;biomedical informatics;cancer care;cancer prevention;cancer therapy;clinical translation;college;digital imaging;exome sequencing;genomic data;innovation;instrumentation;leukemia;leukemia tissue bank;material transfer agreement;member;new technology;next generation;pathology imaging;programs;prospective;recruit;square foot;translational genomics;translational therapeutics Shared Resource 02: Biospecimen Services (BSSR) n/a NCI 10770503 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7779 9733857 "HAMPEL, HEATHER L" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 229150 146891 82259 PROJECT SUMMARY BIOSPECIMEN SERVICES SHARED RESOURCE (BSSR)The mission of the BSSR is to support innovative translational research to advance the prevention diagnosisand treatment of cancer through the provision of biospecimens and clinical data. The Specific Aims are to: 1)collect data and specimens from OSUCCC cancer patients using the IRB-approved Total Cancer Care (TCC)universal consenting and biobanking protocol for future unspecified research; 2) prospectively procurebiospecimens for specific IRB-approved protocols; and 3) provide high quality centralized biorepository servicesfor IRB-approved grant-funded and large institutional projects in a CAP-accredited biorepository. Over thecurrent grant cycle the major changes for the BSSR include: a) implementation of TCC across all DiseaseSpecific Research Groups (DSRGs) covering all cancers - TCC now includes 57256 consented subjectsresulting in regular usage of biospecimens and data; and b) the ORIEN AVATAR program was initiatedproviding OSUCCC members with research grade next generation exome sequencing results on tumor andnormal tissue with clinical annotation from 3049 TCC subjects at OSU and 11500 across ORIEN (the OSUCCCis a major contributor of samples). During the current grant cycle the BSSR provided key services in support of122 publications (35 > 10 impact factor) 105 users and 24 NCI grants including 1 K01 1 K12 2 P01s 2 P50s11 R01s 4 R21s 1 U10 1 UH2 and 1 UM1. Over the next grant cycle BSSR will contribute to each of the newstrategic priorities for the OSUCCC by providing biospecimens and high quality genomic and clinical data asrequested by immuno-oncology translational genomics cancer engineering and cancer prevention andsurvivorship investigators. Each area will be supported by the TCC and given the robust faculty recruitment andregularly increasing patient volumes; there will be an increase in prospective procurement and biobanking aswell. Given the robust OSUCCC recruitment and increasing patient volumes demand for services and newtechnologies will increase. The BBSR will expand its staff instrumentation and services before capacity isreached. The annual budget of the BSSR is $2206277 yet the CCSG request is $179168. As such The BSSRleverages extensive institutional support and seeks only 8.1% support from CCSG funds. +No NIH Category available Abbreviations;Adverse event;Algorithms;Area;Bioinformatics;Bioinformatics Shared Resource;Biometry;Budgets;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Chemoprevention;Clinical Data;Clinical Treatment;Clinical Trials;Comparative Pathology;Complex;Comprehensive Cancer Center;Computational Biology;DNA;Data;Data Set;Data Storage and Retrieval;Dimensions;Disparate;Faculty;Flow Cytometry;Fostering;Funding;Future;GENIE;Gene Expression;Generations;Genomics;Genomics Shared Resource;Goals;Grant;Health protection;Immunologic Monitoring;Immunooncology;Informatics;Information Technology;Institution;Institutional Review Boards;Intervention;Intramural Research Program;Leadership;Left;Literature;Malignant Neoplasms;Medical center;Metagenomics;Microscopy;Molecular Carcinogenesis;Monitor;Ohio;Oncology;Participant;Patients;Pediatric Hospitals;Pharmaceutical Chemistry;Population Sciences;Process;Proteomics;Protocols documentation;Publications;Records;Reporting;Research;Research Institute;Research Personnel;Resource Sharing;Safety;Services;Source;Surveys;System;The Cancer Genome Atlas;Translational Research;Universities;Untranslated RNA;Visual;Work;animal imaging;anticancer research;arm;biobank;biomedical informatics;cancer care;clinical translation;data analysis pipeline;data de-identification;data integration;data management;data visualization;data warehouse;digital imaging;drug sensitivity;falls;genomic data;improved;instrumentation;leukemia;leukemia tissue bank;member;metabolomics;next generation sequencing;novel;pathology imaging;programs;recruit;single cell sequencing;technology platform;tool;translational therapeutics Shared Resource 01: Biomedical Informatics (BISR) n/a NCI 10770498 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7778 7811753 "COOMBES, KEVIN ROBERT" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 136730 87647 49083 PROJECT SUMMARY BIOINFORMATICS SHARED RESOURCE (BISR)The BISR is an essential shared resource that supports a wide range of studies with bioinformatics andcomputational biology needs ranging from next generation sequencing (NGS) to data management in populationscience studies. Housed within the Department of BMI the BISR's goal is to leverage a variety of informaticsservices ranging from analysis of omics datasets to patient/participant-centered data instrumentation accessand management tools and processes. The Specific Aims of the BSR are to: 1) Provide state of the artbioinformatics and computational biology services; and 2) Provide OSUCCC investigators with servicesexpertise and access to technology platforms in support of heterogeneous and multi-dimensional biomedicaldata management requirements. Over the current grant cycle Drs. Kevin Coombes (TT) and Lang Li (CB)assumed leadership of BISR replacing Drs. Philip Payne and Jeffrey Parvin. During the current funding cycle aMemorandum of Understanding (MOU) was established for the Department of Biomedical Informatics (BMI) andthe OSUCCC to support 5 faculty at 10% per year for 3 years within BISR as they transition to grant funding ona rolling basis to provide non-chargeable cancer focused bioinformatics work for OSUCCC membership and/orcancer focused researchers. Additional major changes for BISR include supporting the enhancement of theGenomics Shared Resource (GSR) to incorporate newly developed shared services with Nationwide Children'sHospital (NCH); and added capabilities to support studies involving data from single-cell sequencing long-read(third generation) sequencing metabolomics and metagenomics. BISR has added five new faculty to supportthe areas of (1) computational optimization for drug sensitivity prediction (Cheng) (2) proteomics and functionalannotation of DNA non-coding regions (Zhang) (3) metabolomics and metagenomics (Mathe) (4) single-cellsequencing (Ma) and (5) long-read sequencing (Au). BISR supported Biospecimen Services Shared Resource(BSSR) projects (Total Cancer Care [TCC] and the Oncology Research Information Exchange Network [ORIEN])by establishing a data warehouse of patient records with de-identified data. During the current funding cycle theBISR supported 115 publications (25 > 10 impact factor) 134 users and 32 NCI grants including 5 P01s 2 P50s13 R01s 3 R21s 1 R50 2 U01s 1 U10 1 UG1 involving members from all five programs. Over the next grantcycle BISR will enhance services for integromics e.g. the integration of disparate source of both omics andclinical data. BISR will be a critical part of the Immune Monitoring and Discovery Platform (IMDP) an overarchingapproach for fostering interactions among shared resources for complex immuno-oncology projects. The annualbudget of the BISR is $1122279 yet the CCSG request is $106905. As such the BISR leverages extensiveinstitutional support and seeks only 9.5% support from CCSG funds. +No NIH Category available Adherence;Adolescent and Young Adult;Age;Area;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Research Project;Cancer Therapy Evaluation Program;Cancer health equity;Catchment Area;Censuses;Cessation of life;Charge;Child;Childhood;Clinical;Clinical Cancer Center;Clinical Data;Clinical Investigator;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;Clinical Trials Network;Communities;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;Data;Dedications;Diagnosis;Disease;Doctor of Philosophy;Effectiveness;Elderly;Ensure;Female;Goals;Good Clinical Practice;Grant;Guidelines;Hispanic;Hispanic Populations;Individual;Infrastructure;Intervention;Intervention Studies;Investigational Therapies;Leadership;Longevity;Maintenance;Malignant Neoplasms;Measures;Methodology;Minority;Minority Enrollment;Mission;Monitor;Ohio;Patients;Pediatric Hospitals;Physician Executives;Physicians;Policies;Population;Population Heterogeneity;Population Sciences;Protocol Compliance;Protocols documentation;Provider;Quality Control;Reporting;Research;Research Activity;Research Personnel;Resources;Safety;Scientist;Serious Adverse Event;Services;Special Population;Strategic Planning;Therapeutic;Therapeutic Intervention;Time;Underserved Population;Universities;Vision;Woman;aging population;anticancer research;arm;cancer clinical trial;cancer diagnosis;cancer research center director;cost effective;data management;improved;investigator training;investigator-initiated trial;multidisciplinary;outreach;participant enrollment;patient safety;programs;quality assurance;racial minority;research clinical testing;sound;timeline Clinical Protocol and Data Management n/a NCI 10770489 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7776 12489762 "HAYS, JOHN L." Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 420268 269402 150866 PROJECT SUMMARY - CLINICAL PROTOCOL AND DATA MANAGEMENTPart I: Clinical Protocol and Data Management (CPDM). CPDM facilitates all clinical cancer research at TheOhio State University Comprehensive Cancer Center (OSUCCC) and is responsible for 14996 interventional(5648 interventional therapeutic) accruals over the reporting period. The CPDM has three major components:the Clinical Trials Office (CTO) the Quality Assurance (QA) Office and the OSUCCC Data and Safety MonitoringPlan (DSMP). Oversight is provided by the Associate Director for Clinical Research (ADCR) William CarsonMD who also is serving as the interim CTO Medical Director. Dr. Carson supervises the CTO AdministrativeDirector Angela Campbell MS assisted by the Executive Director for Administration David Gosky MA MBA.The CTO provides investigators with centralized expertise and support for the implementation coordination andexecution of cancer clinical trials. The CTO staff focuses on OSUCCCs mission vision and values to supportinvestigators in the highest quality clinical cancer research with adherence to all federal and state guidelines.Part II: Data and Safety Monitoring. All cancer clinical trials conducted by OSUCCC investigators includeoversight of data and safety monitoring. The OSUCCC Data and Safety Monitoring Plan (DSMP) approved bythe NCI and last revised August 1 2018 provides guidance for the conduct of cancer clinical trials in accordancewith NCI CCSG requirements. The Data and Safety Monitoring Committee (DSMC) chaired by Beth ChristianMD assures patient safety and protocol compliance by OSUCCC investigators and staff and has monitored 413trials during the reporting period. The independent control function for OSUCCC studies is provided by theQuality Assurance Oversight Committee (QAOC) which has audited 180 trials over the reporting period.Part III: Inclusion of Women and Minorities in Clinical Research. OSUCCC leadership investigators andstaff are committed to the inclusion of women and minorities in cancer clinical trials. Oversight of the inclusion ofdiverse populations in cancer clinical trials is the responsibility of Dr. Carson who is assisted by Electra PaskettPhD Associate Director for Population Sciences and Community Outreach and Director of the Center for CancerHealth Equity (CCHE). Outreach to women and minorities is led by CCHE staff who educate the communityabout OSUCCC programs services and the value of clinical trials.Part IV: Inclusion of Individuals Across the Lifespan in Clinical Research. The inclusion of individualsacross the lifespan in cancer clinical research is an important goal of the OSUCCC. Nationwide ChildrensHospital (NCH) is the pediatric arm of the OSUCCC and is committed to making clinical trials available to childrenwith a cancer diagnosis. It is the policy of the OSUCCC that individuals of all ages including children and olderadults are included in cancer clinical trials. In summary the OSUCCC facilitates clinical cancer research andprovides quality safety and monitoring of all trials with an emphasis on the inclusion of women minorities otherunderserved populations and individuals across the lifespan in its catchment area (the State of Ohio). +No NIH Category available Abbreviations;Accounting;Acute Myelocytic Leukemia;Advisory Committees;Area;Award;Basic Science;Bioinformatics;Biomedical Research;Biometry;Budgets;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Survivorship;Carcinogenesis Mechanism;Chemoprevention;Clinical Cancer Center;Clinical Sciences;Clinical Treatment;Clinical Trials;Comparative Pathology;Complex;Comprehensive Cancer Center;Cryoelectron Microscopy;Disease;Doctor of Pharmacy;Doctor of Philosophy;Drug Kinetics;Engineering;Ensure;Evaluation;Faculty;Faculty Recruitment;Flow Cytometry;Funding;Future;Genes;Genetically Engineered Mouse;Genomics;Goals;Grant;Growth;Image;Immunologic Monitoring;Immunooncology;Institution;Intervention;Intervention Studies;Intramural Research Program;Investments;Laboratories;Libraries;Malignant Neoplasms;Medicine;Methods;Microscopy;Molecular Carcinogenesis;Monitor;NCI Center for Cancer Research;National Cancer Institute;Nutrient;Ohio;Oncology;Pediatric Hospitals;Peer Review;Pharmaceutical Chemistry;Pharmacy facility;Phytochemical;Policies;Population Sciences;Productivity;Proteomics;Quality Control;Reporting;Research;Research Personnel;Research Priority;Resource Development;Resource Sharing;Services;Slide;Smoking;Speed;Surveys;System;Technology;Translational Research;United States National Institutes of Health;Universities;Validation;Vision;Visit;Work;animal imaging;anticancer research;biomedical informatics;cancer care;cancer prevention;cancer research center director;clinical translation;college;cost effective;cost effectiveness;digital imaging;drug development;exosome;instrumentation;leukemia;leukemia tissue bank;member;mouse model;new technology;operation;pathology imaging;pre-clinical;programs;recruit;satisfaction;screening;small molecule;translational genomics;translational therapeutics;working group Shared Resource Management n/a NCI 10770482 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7774 6904902 "BAKER, SHARYN D" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 252847 162081 90766 PROJECT SUMMARY SHARED RESOURCES MANAGEMENTThe Ohio State University Comprehensive Cancer Center (OSUCCC) manages and supports 16 CCSG-fundedShared Resources (SRs) and is proposing two developing shared resources in this application. The goals of theOSUCCC SRs are to support OSUCCC members by providing specialized technologies services and expertisethat maximize quality and speed of service while maintaining cost-effectiveness and quality control. The SRssupport all five Research Programs and are managed by faculty from seven different colleges and NationwideChildrens Hospital. Most of the SRs are centrally located and in close proximity to OSUCCC members. TheSpecific Aims for Shared Resource Management are to: 1) evaluate for need and establish new specializedtechnologies services and expertise that enhance scientific interaction and productivity; 2) ensure that the SRsprovide cost-effective reliable and quality-controlled technologies services and expertise; 3) support SRsthrough budget planning laboratory management systems and sustainability; and 4) establish policies for SRaccess and use. The OSUCCC directly manages 13 of the 16 SRs and the others are jointly managed asinstitutional SRs that follow NCI policies. Reporting to the OSUCCC Director the SRs are led by Sharyn BakerPharmD PhD Associate Director for Shared Resources. Dr. Baker works with Heather Hampel MS LGCAssociate Director for Biospecimen Research for integration of biospecimen services with the SRs. Dr. Bakerleads the Shared Resource Team Leader (SRTL) committee that oversees SR management and implementationof the scientific vision. The SRTL monitors quality and user satisfaction through user surveys and usercommittees. SR development and evaluation is provided to Dr. Baker from the Associate Directors CommitteeProgram Leaders and the External Scientific Advisory Board. Shared Resource Management operations includeensuring compliance with OSUCCC policies (prioritization of use and access budgets billing and quality control)and compliance with OSU Office of Research policies and the federal Uniform Guidance. For the evaluation ofnew instrumentation and services Dr. Baker manages the Intramural Research Program (IRP) that providesexternal peer review of SR applications evaluating scientific merit and planned usage ($3.4M awarded this grantcycle. Overall support to the SRs over the last grant cycle has been $18M allowing for all of the SRs to havebeen enhanced and offer new services. Future plans for each SR are accounting for planned increased usagedue to the OSUCCC strategic research priorities and planned recruitment. The OSUCCC provides over $9M inoverall support of the SRs annually The OSUCCC is requesting a total of $1971340 in CCSG funding 8.9%of the total support. +No NIH Category available Adenocarcinoma;Aggressive behavior;Anabolism;Androgen Receptor;Androgens;Animal Model;Biochemical;Biological Markers;Biopsy;Cancer Patient;Castrate sensitive prostate cancer;Castration;Cell Line;Cells;Cessation of life;Clinic;Clinical;Compensation;Data;Dependence;Disease;Enzymes;Glucose;Glutaminase;Glutamine;Glycolysis;Goals;Heterogeneity;Histologic;Hormones;Kidney;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolic;Minority;Molecular;Neoplasm Metastasis;Neuroendocrine Carcinoma;Neuroendocrine Cell;Nutrient;Outcome;Oxidative Phosphorylation;Pathologic;Patients;Prediction of Response to Therapy;Process;Prognosis;Prostate Cancer therapy;Prostatectomy;Protein Isoforms;Public Health;Receptor Inhibition;Recurrence;Resistance;Sampling;Specimen;Starvation;Testing;Warburg Effect;Work;advanced disease;advanced prostate cancer;androgen sensitive;cancer cell;castration resistant prostate cancer;cohort;differential expression;experience;hormone therapy;individual patient;novel marker;patient variability;potential biomarker;prostate cancer cell;targeted treatment;therapy resistant;treatment response;trend;tumor Glutaminase I isoforms as personalized biomarkers of prostate cancer Relevance to Public HealthProstate cancer is a heterogeneous disease. Different patients respond to therapiesdifferently and the prognosis varies significantly from patient to patient. The goal of theproposed work is to identify novel biomarkers to help guide treatment and predictprognosis which is an urgent unmet need. Successful completion of the project has thepotential to benefit a large number of patients. NCI 10770465 12/21/23 0:00 PA-20-185 5R01CA260726-03 5 R01 CA 260726 3 "MCKEE, TAWNYA C" 1/1/22 0:00 12/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 8029590 "HUANG, JIAOTI " Not Applicable 4 PATHOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 362661 NCI 225255 137406 Abstract Prostate cancer (PCa) is a heterogeneous disease. Responses to therapy and prognosis vary significantly from patient to patient and biomarkers that can predict therapy response and prognosis are urgently needed. In an attempt to identify metabolic mechanisms of hormonal therapy for PCa we discovered thatan important function of androgen receptor (AR) in advanced PCa is to upregulate the expression ofglutaminase 1 (GLS1) which is critical for glutamine utilization by cancer cells to compensate for theirinability to produce sufficient ATP and metabolic intermediates from glucose due to the Warburg effect.Hormonal therapy targeting AR inhibits GLS1 expression and glutamine utilization starving cells to death. GLS1 has two isoforms kidney-type glutaminase (KGA) and glutaminase C (GAC). Our workdemonstrates that early stage hormone-sensitive PCa mostly expresses kidney-type glutaminase (KGA)the weaker AR-dependent GLS1 isoform while late stage therapy-resistant PCa mostly expresses the morepotent and AR-independent glutaminase C (GAC). We have shown that this switch in the expression of GLS1isoforms is a molecular basis for the important clinical phenomenon including tumors initial sensitivity tohormonal therapy and the eventual therapy resistance. Importantly we also observed significant heterogeneityin the GLS1 isoform expression from case to case. For example while the majority of hormone sensitivecancers expresses KGA a minority expresses GAC. Similarly while most cases of late stage PCaexpress GAC a minority expresses KGA. The heterogeneous expression of GLS1 isoforms of differentenzymatic activities by PCa of various disease stages was intriguing and prompted us to determinetheir possible correlations with the heterogeneous clinical outcomes observed in PCa patients. We will studythe value of GLS1 isoforms as potential biomarkers with the hypothesis that tumors that predominantly expressKGA respond better to hormonal therapy and have better prognosis while those that predominantly expressGAC respond poorly to hormonal therapy and have worse prognosis. This hypothesis will be tested in largehighly valuable patient tumor cohorts of hormone sensitive prostate cancer and CRPC. Additionally we willtest if differential expression of the GLA isoforms is associated with the two histologic types of PCaadenocarcinoma that is AR dependent and usually has a protracted disease course vs small cell neuroendocrinecarcinoma which is AR-independent and rapidly lethal. 362661 +No NIH Category available Abbreviations;Adult;Award;Basic Science;Biological;Biometry;Cancer Biology;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Catchment Area;Cessation of life;Chemoprevention;Childhood;Clinical;Clinical Treatment;Clinical Trials;Collaborations;Colorectal Cancer;Comparative Pathology;Comprehensive Cancer Center;Decision Making;Diagnosis;Direct Costs;Discipline;Disease;Doctor of Philosophy;Exhibits;Flow Cytometry;Funding;Future;Genomics;Glioblastoma;Goals;Grant;Growth;Head and Neck Cancer;Immune checkpoint inhibitor;Immune system;Immunogenomics;Immunooncology;Immunotherapeutic agent;Institution;Intervention;Intramural Research Program;Journals;Longevity;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of thyroid;Medicine;Microscopy;Molecular;Molecular Biology;Molecular Carcinogenesis;Morbidity - disease rate;NCI Center for Cancer Research;National Cancer Institute;National Comprehensive Cancer Network;Non-Small-Cell Lung Carcinoma;Ohio;Oncology;Outcome;Patients;Pediatric Hospitals;Peer Review;Peer Review Grants;Pharmaceutical Chemistry;Pharmacy facility;Physicians;Prognosis;Proliferating;Proteomics;Publications;Publishing;Research;Research Personnel;Research Priority;Resistance;Resource Sharing;Scientist;Services;Signal Pathway;Solid Neoplasm;The Cancer Genome Atlas;Therapeutic;Tissues;Training;Translating;Translational Research;United States National Institutes of Health;Universities;Validation;Veterinary Medicine;animal imaging;biomedical informatics;cancer care;cancer cell;college;colon cancer prevention;digital imaging;drug development;host neoplasm interaction;improved;innovation;interest;investigator-initiated trial;leukemia;malignant breast neoplasm;meetings;member;mortality;multidisciplinary;pathology imaging;preclinical study;prognostic;programs;recruit;sarcoma;small molecule;therapeutic target;translational goal;translational therapeutics;treatment response;tumor;tumor heterogeneity;tumor progression Project 05: Translational Therapeutics (TT) n/a NCI 10770463 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7766 1885529 "CARBONE, DAVID P." Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 46756 35523 11233 PROJECT SUMMARY TRANSLATIONAL THERAPEUTICS (TT)The Translational Therapeutics (TT) Program at The Ohio State University Comprehensive Cancer Center(OSUCCC) co-led by David Carbone MD PhD Blake Peterson PhD and Elaine Mardis PhD unites anoutstanding team of 79 basic translational and/or clinical researchers from 18 departments within The OhioState University (OSU) Colleges of Medicine Pharmacy and Veterinary Medicine and Nationwide ChildrensHospital (NCH). The goal of the TT program is to translate advances in solid tumor molecular biology andpromising preclinical studies into innovative clinical trials to improve the state of the art in the diagnosis andtreatment of solid tumors. Solid tumors are by far the major causes of cancer death in our catchment area (thestate of Ohio) dominated by diseases of special interest in this program including lung breast colorectal headand neck thyroid and gynecologic cancers. As a result of existing expertise and collaborative scientific effortsas well as focused recruitments across a spectrum of disciplines the TT program exhibits strength in basic andtranslational research in lung cancer gastrointestinal malignancies breast cancer sarcoma and glioblastomaas well as newly enhanced capabilities in drug development. The Specific Aims of the TT program are to: 1)identify and therapeutically target alterations in solid tumor proliferation and survival signaling pathways; 2)identify tumor-host interactions and target them via small molecule and immunotherapeutic approaches; and 3)develop and improve upon approaches for determining prognosis selecting appropriate therapies andevaluating the response to treatment. During the current funding cycle the TT Program successfully recruited28 solid tumor clinicians basic scientists and physician-scientists. In addition TT investigators produced 1130peer-reviewed publications; 178 of these were published in high impact (10) journals 16% resulted from intra-programmatic collaborations and 31% from inter-programmatic collaborations; 74% were multi-institutional; atotal of 86% were collaborative publications. TT members collaborated on programmatic grant submissions andwere awarded one NCI P01 two U01s and two UG1s as well as two T32 training grants. The TT Program has$9.2M in current annual direct costs from peer-reviewed grants $6.6M (71%) of which is from the NCI. The TTProgram is well-integrated with the clinical teams via participation in the multidisciplinary Disease SpecificResearch Groups (DSRG) and organizes Pan-Disease Investigator-Initiated Trial meetings to catalyzeinteractions between DSRGs. As such there were 4070 accruals to interventional clinical trials during the lastfunding cycle of which 3351 (82%) were therapeutic including 1144 (28%) investigator-initiated trials. Futuredirections focused on the OSUCCC research priorities and cancers relevant to our catchment area and growthin cellular and checkpoint inhibitor research (adult and pediatric) immunogenomics tumor resistance and tumorheterogeneity and small molecule drug development. +No NIH Category available Abbreviations;Agriculture;Area;Arts;Automobile Driving;Award;Biological;Biometry;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Carcinogenesis Inhibition;Catchment Area;Cell model;Chemicals;Chemoprevention;Chemopreventive Agent;Clinic;Clinical Research;Clinical Treatment;Clinical Trials;Collaborations;Colorectal;Comparative Pathology;Complement;Comprehensive Cancer Center;Dentistry;Development;Diet;Diet and Nutrition;Dietary Assessment;Dietary Intervention;Dietary Practices;Doctor of Philosophy;Ecology;Education;Endogenous Factors;Endometrial;Engineering;Enrollment;Environment;Environmental Science;Exogenous Factors;Exposure to;Faculty;Flow Cytometry;Food;Foundations;Funding;Future;Genetic;Genetic Counseling;Genetic Predisposition to Disease;Genetic Screening;Genomics;Goals;Grant;Hormonal;Human;Immune Targeting;Immunology;Immunooncology;Immunotherapeutic agent;In Vitro;Incidence;Institution;Intervention Studies;Intervention Trial;Investments;K-Series Research Career Programs;Laboratory Study;Lesion;Life Style;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Manuscripts;Mediating;Mediator;Medicine;Mentors;Metabolic;Metabolism;Microscopy;Molecular;Molecular Carcinogenesis;Morbidity - disease rate;Natural Source;Neoplastic Cell Transformation;Nutrient;Nutritional;Ohio;Participant;Peer Review;Pharmacognosy;Pharmacologic Substance;Pharmacy facility;Phase;Phytochemical;Pre-Clinical Model;Prevention;Prevention program;Prevention strategy;Process;Program Sustainability;Proteomics;Public Health;Public Policy;Publications;Publishing;Research;Research Personnel;Resource Sharing;Risk;Safety;Science;Services;Structural Chemistry;System;Testing;Time;Tissue Engineering;Tobacco;Toxic effect;Training;Translational Research;Translations;Tumor Immunity;United States National Institutes of Health;Universities;Veterinary Medicine;animal imaging;anti-cancer;anticancer research;biochemical model;biomedical informatics;cancer care;cancer risk;cancer survival;carcinogenesis;clinical investigation;college;colorectal cancer prevention;dietary guidelines;digital imaging;early phase clinical trial;graduate student;high risk population;in vivo;innovation;laboratory experiment;leukemia;member;microbiome;microbiota;mortality;multimodality;novel;nutrition;nutritional guideline;pathology imaging;pre-clinical;premalignant;preventive intervention;programs;recruit;screening;translational therapeutics;tumor progression;undergraduate student Project 04: Molecular Carcinogenesis and Chemoprevention (MCC) n/a NCI 10770458 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7764 1897233 "CLINTON, STEVEN K" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 46937 30088 16849 PROJECT SUMMARY MOLECULAR CARCINOGENESIS AND CHEMOPREVENTION (MCC)The Molecular Carcinogenesis and Chemoprevention (MCC) Program at The Ohio State UniversityComprehensive Cancer Center (OSUCCC) led by Steven Clinton MD PhD and Richard Fishel PhD has48 members from 22 Departments and 8 OSU Colleges (Arts and Sciences Dentistry Education and HumanEcology Food Agriculture and Environmental Science Medicine Pharmacy Public Health and VeterinaryMedicine). The MCC Program examines cancer as an integrated and dynamic process over time with a majorfocus on the interface between genetics and the environment that collectively impacts the carcinogenesiscascade. This approach provides a foundation for chemoprevention and dietary interventions to reduce theburden of cancer in high-risk individuals as well as to decrease the incidence mortality and morbidity of cancer inour Ohio catchment area (CA) and the nation. Our expertise extends to defining standards for genetic screening andcounselling as well defining dietary and nutritional guidelines that impact cancer risk through public policy nationallyand globally. The Specific Aims of the MCC Program are: 1) Carcinogenesis: To characterize the geneticmolecular and cellular changes induced by germline chemical physical hormonal or microbiological mediatorsthat contribute to neoplastic transformation and multistage carcinogenesis; 2) Chemoprevention: To develop andcharacterize novel cancer chemopreventive agents and define their efficacy safety and mechanisms of actionusing biochemical cellular and preclinical models that ultimately lead to early phase human studies; and 3) DietNutrition and Metabolism: To identify dietary patterns nutritional components and lifestyle variables thatenhance or inhibit the carcinogenesis cascade across the continuum of cancer progression. MCC Programmembers published 547 cancer-relevant manuscripts between 12/01/14 and 11/30/19. Of these 14% were intra-programmatic (multiple authors from MCC Program) 31% were inter-programmatic (authors from multiple OSUCCCPrograms) and 72% were multi-institutional (authors from both CC and another institution). The total collaborativepublications is 83%. MCC Program funding stands at $7.9M in overall direct cancer-focused funding of which$7.0M is peer-reviewed including $6.8M direct funding from NIH ($3.4M from NCI). Over the last five years MCCProgram members have accrued 1487 participants to trials; 670 to interventional trials and 817 to non-interventionaltrials. MCC members serve as leaders of the Ohio Colorectal Cancer Prevention Initiative involving 3651participants (3310 colorectal and 341 endometrial) and ORIEN Total Cancer Care with enrollment of 50683.TheMCC program is fully integrated with the high priority crosscutting research initiatives of the OSUCCC and future planscomplement and enhance programmatic aims while promoting interactions with the other research Programs and focuson 1) metabolic signatures in carcinogenesis and prevention; 2) the microbiome and immunology interface withPelotonia Institute for Immuno-Oncology initiatives; and 3) collaborative efforts with the Center for Cancer Engineering. +No NIH Category available Abbreviations;Academy;Applications Grants;Award;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer health equity;Chemoprevention;Complement;Comprehensive Cancer Center;Development;Ecosystem;Education;Faculty;Faculty Recruitment;Fellowship;Fellowship Program;Fostering;Funding;Future;Grant;High School Student;Historically Black Colleges and Universities;Laboratories;Leadership;Learning;Malignant Neoplasms;Medical;Medicine;Mentors;Mentorship;Minority;Molecular Carcinogenesis;NCI Center for Cancer Research;Ohio;Oncology;Outcome;Paper;Population Sciences;Positioning Attribute;Postdoctoral Fellow;Process;Recommendation;Research;Research Personnel;Research Priority;Research Support;Rotation;STEM program;Science;Science Technology Engineering and Mathematics;Scientist;Students;System;Systems Integration;Teacher Professional Development;Training;Training Activity;Training Programs;Training Support;Training and Education;Underrepresented Minority;Universities;University resources;Woman;anticancer research;cancer education;career development;college;education research;experience;faculty mentor;high school;high school program;improved;leukemia;member;peer;physician-scientist training program;post-doctoral training;pre-doctoral;programs;recruit;summer student;training opportunity;translational therapeutics;undergraduate student;underrepresented minority student Cancer Research Training and Education Coordina n/a NCI 10770432 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7754 1928269 "KIRSCHNER, LAWRENCE S" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 114412 73341 41071 PROJECT SUMMARY CANCER RESEARCH TRAINING AND EDUCATION COORDINATIONThe Center for Cancer Mentoring Education Leadership and Oncology-related Training (CAMELOT) serves asthe centralized hub for the Ohio State University Comprehensive Cancer Center (OSUCCC) fostering cancerresearch and education and disseminating those opportunities. CAMELOTs efforts begin at the high schoollevel continue through undergraduate and graduate training and then extend through post-doctoral training andinto early faculty development and mentoring. CAMELOT is directed by Dr. Lawrence Kirschner the OSUCCCAssociate Director of Training and Education. He is assisted by Drs. Deepa Sampath Elizabeth Klein and RosaLapalombella. CAMELOT coordinates training and education programs through: 1) direct programs (e.g. forhigh school Pelotonia fellows external undergraduate student summer rotations including students from OhioHistorically Black Universities and Colleges); 2) integrating College of Medicine (COM) programs with OSUCCCactivities and opening them to trainees and junior faculty outside the COM; 3) supporting grant submissions byjunior faculty; and 4) supporting training grant submissions. The Pelotonia Fellowship Program (PFP) a majorcommitment by the OSUCCC to fellowship training has been in existence for 10 years and provides stipendsand research support to fellows from the undergraduate to the postdoctoral fellowship level. OSUCCC provides$2-3M/year to support the PFP. During the current grant cycle 251 pre- and postdoctoral fellowships awardedof which 155 had mentors who were OSUCCC members from all five of the OSUCCC research programs and10 of the 15 OSU Colleges. More than 90% of these trainees are currently active as cancer researchers. Newprograms developed by CAMELOT include two cancer research-focused pipeline programs one for localunderrepresented minority high school students and another for current OSU undergraduates. The SpecificAims are to: 1) provide integration and coordination of training opportunities for cancer research across theOSUCCC and university ecosystem and region including high schools and colleges; 2) enhance formalizedprogramming for cancer-based mentoring including both peer-to-peer and senior-to-junior mentoring; and 3)develop an integrated system to enable assessment and outcome tracking for trainees at all levels ofengagement with the OSUCCC (grants papers academic positions etc.) to foster continuous qualityimprovement in educational and career development activities. The OSUCCC is planning robust facultyrecruitment around strategic research priorities that will create new opportunities for education and training. Toaccommodate this a bigger pipeline for training is planned in the next funding cycle. The OSUCCC will: 1)expand graduate and postgraduate training slots and programs for high school students; 2) establish the YoungCancer Investigator Faculty Academy that focuses on OSUCCC wet-lab researchers to support development ofindependent research programs; 3) establish a uniform tracking system for trainees; and 4) foster submissionsof R25 and T32 training grants including supplements. +No NIH Category available Acceleration;Achievement;Administrator;Advisory Committees;Award;Basic Science;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Hospital;Catchment Area;Clinical;Clinical Data;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Colon Carcinoma;Communication;Community Outreach;Comprehensive Cancer Center;Dedications;Development;Doctor of Philosophy;Education;Endometrial Carcinoma;Engineering;Ensure;Evaluation;Evolution;Faculty;Faculty Recruitment;Floor;Fostering;Foundations;Funding;Future;Genes;Goals;Grant;Growth;Health;Height;Immunooncology;Infrastructure;Interdisciplinary Study;International;Intervention;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Mentors;Minority;Ohio;Oncology;Outcome;Paper;Policies;Population;Positioning Attribute;Postdoctoral Fellow;Productivity;Reporting;Research;Research Institute;Research Personnel;Resource Sharing;Resources;Role;Schedule;Science;Secure;Services;Strategic Planning;Students;System;Systems Integration;Tobacco;Training;Training Activity;Training and Education;Translational Research;Translations;Universities;Validation;Vision;Work;animal imaging;anticancer research;cancer education;cancer prevention;cancer research center director;career development;clinical translation;college;community engagement;data management;experience;improved;innovation;malignant breast neoplasm;meetings;member;patient navigator;patient outreach;programs;recruit;research facility;social media;success;symposium;synergism;translational genomics;web site Cancer Center Administration n/a NCI 10770427 12/12/23 0:00 PAR-20-043 5P30CA016058-48 5 P30 CA 16058 48 9/12/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 7753 9098327 "GOSKY, DAVID M" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 251733 161367 90366 PROJECT SUMMARY CANCER CENTER ADMINISTRATIONThe Ohio State University Comprehensive Cancer Center (OSUCCC) Administration provides efficient andeffective administrative support to the OSUCCCs Director Senior Leadership Research Program LeadersShared Resource (SR) Directors and OSUCCC members. The role of OSUCCC Administration is tooperationalize OSUCCCs most critical research functions by fulfilling the following Specific Aims: 1) AccelerateOSUCCCs remarkable evolution by leveraging resources and expanding OSUCCCs infrastructure; 2) PromoteOSUCCCs strategic planning and evaluation efforts; 3) Support OSUCCCs comprehensive basic scienceclinical and cancer control activities by fostering transdisciplinary and/or translational science; and 4) SupportOSUCCCs community outreach and engagement and education and training activities. The OSUCCC is a matrixcancer center with administrative staff providing support to 293 OSUCCC members from 48 departments in 11Ohio State University colleges with 108 members recruited in the last five years. OSUCCC Administrationleverages the expertise of its team members while operating in an innovative and efficient manner. New initiativessupported since the last grant cycle include: 1) developing the OSUCCC Pelotonia Institute for Immuno-Oncology (PIIO) in partnership with Pelotonia a major donor providing $65M for the PIIO; 2) supporting anincrease of direct cancer-related research funding from $64.8M to $75.4M between 2015-2020; 3) facilitatingrecruitment of key senior-level faculty; 4) enabling the seamless transition of a new OSUCCC Director andsupporting advisory committee restructuring; 5) providing full support for 18 PPG 6 SPORE and 14 other largemulti-investigator (e.g. UG1 UM1 U19 U54) applications resulting in six funded awards; 6) supporting thedevelopment of the Small Animal Imaging and the Clinical-Translational Science into full SRs in this application;7) initiating two developing SRs (Targeted Validation and Gene Editing); 8) fostering growth of the Clinical TrialsOffice from 130 FTE to 189 FTE to facilitate clinical research; 9) completing the entire fit-out and full occupancyof over 1.18M ft2 of space in The James Cancer Hospital and Solove Research Institute which opened inDecember 2014; 10) overseeing expansion of research space including new space for the OSUCCC Center forTobacco Research; 11) working with University leadership to obtain 100000 ft2 dedicated for cancer research;two floors will be in the new Interdisciplinary Research Facility scheduled to open in 2023; 12) creatingCAMELOT (Center for Cancer Mentoring Education Leadership and Oncology-related Training) to centralizecoordinate and manage all cancer education and training activities; 13) facilitating development of Ascendingto New Heights the 2020-2025 OSUCCC Strategic Plan; 14) implementing eRAMPv2 an OSUCCC onlineordering and billing system across SRs; 15) deploying $15M for new pilot grant opportunities; and 16) promotingresearch-relevant communication throughout the OSUCCC catchment area through additional social mediaplatforms cancer-focused symposia and development of a new website. +No NIH Category available Affect;Antigen-Presenting Cells;Antigens;Antitumor Response;Autoantigens;Autoimmunity;Blood;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCR6 gene;Cancer Remission;Cell Maintenance;Cell physiology;Cells;Data;Dendritic Cells;Dependence;Dermis;Disease-Free Survival;Excision;Future;Generations;Genetic Transcription;Growth;Hair follicle structure;ITGAX gene;Image;Immune checkpoint inhibitor;Immune response;Immunity;Immunologic Memory;Immunotherapy;Infection;Inflammation;Invaded;Knock-out;Laboratories;Location;Longevity;Lymph Node Subcapsular Sinus;Lymph Node Tissue;Lymphoid;Maintenance;Malignant Neoplasms;Memory;Modeling;Molecular;Mus;Myeloid Cells;Neoplasm Metastasis;Operative Surgical Procedures;Patients;Population;Positioning Attribute;Recurrent tumor;Reporting;Role;Sentinel;Signal Transduction;Site;Skin;Skin Tissue;Survivors;T memory cell;T-Cell Receptor;T-Lymphocyte;Testing;Tissues;Transcript;Tumor Cell Invasion;Tumor Immunity;Tumor Tissue;Virus Diseases;Vitiligo;Work;anti-melanoma immunity;chemokine;draining lymph node;lymph nodes;melanoma;memory recall;memory retention;mouse model;novel;receptor;residence;response;tissue resident memory T cell;tumor;tumor growth Sustaining Tissue Resident Memory T cells PROJECT NARRATIVELong-term cancer remission requires generation of tumor-specific immune memory. Memory T cells that residein primary sites of tumor growth and in sites prone to metastasis such as the lymph node are particularly critical.This application examines requirements for maintaining these tissue-resident memory T cells and theirimportance in durable anti-tumor responses. NCI 10770421 12/6/23 0:00 PA-20-185 5R01CA254042-03 5 R01 CA 254042 3 "ZAMISCH, MONICA" 1/1/22 0:00 12/31/26 0:00 "Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]" 9278084 "HUANG, YINA HSING" "TURK, MARY JO " 2 MICROBIOLOGY/IMMUN/VIROLOGY 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 483753 NCI 294972 188781 ABSTRACTDurable immunity to cancer is sustained by memory T cells. In contrast to circulating memory subsets whichtraffic in and out of the blood tissue-resident memory (TRM) cells are transcriptionally programed for prolongedresidence and recall function within tissue. Collaborative studies between our laboratories were among the firstto identify a requirement for TRM cells in immunity to cancer. Using a melanoma-associated vitiligo (MAV) mousemodel that closely mimics the vitiligo that develops in immune checkpoint inhibitor-treated melanoma patientswho benefit from prolonged disease-free survival we showed that skin TRM cells are necessary and sufficient forlong term protective immunity against melanoma in the dermis. However mechanisms for controlling TRM cellpersistence and identity as well as the contribution of TRM cells to tumor immunity at sites of frequent metastasisremain unclear. In this application we examine an unexpected mechanism for TRM cell maintenance in the skinand reveal a new subset of vitally important TRM cells that persist in tumor-draining lymph nodes.In the skin of mice with MAV as well as melanoma patients with vitiligo immunofluorescent imaging revealedthat TRM cells form lymphoid aggregates containing large populations of CD11c-expressing myeloid cells. Whileprior work indicates that CD11c+ dendritic cells (DCs) are critical for initiating immune responses but dispensablefor reactivating TRM we find that depletion of CD11c-expressing cells results in rapid disaggregation and loss ofCD8 TRM cells in the skin. We further show that the CXCR6/CXCL16 axis is required for TRM cell persistence andtumor protection in the skin. These findings identify a critical requirement for CXCL16-expressing myeloid cellsin coordinating the organization and retention of CXCR6-expressing TRM in the tissue which will be examined inSpecific Aim 1. The importance of the CXCR6/CXCL16 axis and persisting self antigen in controlling TRM cellfunction and plasticity will be tested in Specific Aim 2. Finally parallel mechanisms will be explored in lymphnodes (LNs) where our preliminary studies led us to discover a novel population of tumor-specific T cells that iscrucial for protection against melanoma growth in lymph nodes. The presence of LN TRM cells has not previouslybeen shown in the setting of cancer. A role for APCs and chemokines in maintaining such responses isessentially unknown and will be the focus of Specific Aim 3. This proposal will thus test the overarchinghypothesis that tumor-specific TRM cells both in skin and draining lymph nodesrely on key interactions withAPCs and chemokines for their proper positioning maintenance and anti-tumor function. 483753 +No NIH Category available Algorithms;Bilateral;Biological Markers;Blinded;Blood;Blood Proteins;Blood Screening;Blood Tests;Blood specimen;CA-125 Antigen;Cancer Etiology;Cancerous;Carcinoma;Carcinoma in Situ;Cells;Cessation of life;Clinical;Collecting Cell;Collection;Data;Detection;Development;Diagnosis;Disease;Early Detection Research Network;Early Diagnosis;Endoscopes;Endoscopy;Epithelial Cells;Epithelial ovarian cancer;Epithelium;Family;Fertility;Genetic;Goals;Greater sac of peritoneum;Health;High Risk Woman;Histology;Human;Hysterectomy;Image;Image Analysis;Imaging Techniques;Instruction;Lead;Learning;Lesion;Malignant Neoplasms;Malignant neoplasm of ovary;Mammalian Oviducts;Metastatic Malignant Neoplasm to the Ovary;Methods;Morbidity - disease rate;Neoplasm Metastasis;Operative Surgical Procedures;Ovarian;Ovarian Serous Adenocarcinoma;Ovary;Patients;Pilot Projects;Predictive Value;Procedures;Proteomics;Recommendation;Recording of previous events;Research;Resolution;Risk;Risk Reduction;Salpingo-Oophorectomy;Sampling;Screening for Ovarian Cancer;Sensitivity and Specificity;Serous;Serum;Serum Markers;Serum Proteins;Survival Rate;Symptoms;System;Target Populations;Techniques;Technology;Test Result;Testing;Thinness;Time;Tissues;Transvaginal Ultrasound;Woman;Work;biomarker validation;blood-based biomarker;cell preparation;classification algorithm;clinically actionable;fluorescence imaging;high resolution imaging;imaging biomarker;improved;in vitro Model;in vivo;miniaturize;minimally invasive;mortality;optical imaging;premalignant;protein biomarkers;prototype;screening;spectrograph Ovarian Cancer Detection with Blood- and Imaging-Based Biomarkers NARRATIVEThere is currently no acceptable screening method for ovarian cancer and most cases are detected when thedisease is widespread and likely to be deadly. We will develop a two-step blood-based biomarker followed by aminimally-invasive fallopian tube imaging and sampling technique as an effective method to detect ovariancancer at an early time when the disease is most curable. NCI 10770413 1/5/24 0:00 PAR-19-264 5R01CA260399-03 5 R01 CA 260399 3 "MARQUEZ, GUILLERMO" 1/1/22 0:00 12/31/26 0:00 Special Emphasis Panel[ZRG1-SBIB-A(59)R] 6525212 "BARTON, JENNIFER KEHLET" "FISHMAN, DAVID A.; LOKSHIN, ANNA E" 7 BIOMEDICAL ENGINEERING 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ BIOMED ENGR/COL ENGR/ENGR STA 857210158 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 676976 NCI 601225 75751 A central problem in ovarian cancer is late diagnosis which causes the 5-year survival rate to plummetbelow 50%. Ovarian cancer symptoms are vague and nonspecific and current screening is generally noteffective. Because ovarian cancer is so deadly risk-reducing salpingo-oophorectomy (RRSO) is oftenrecommended for women at high risk; however RRSO has fertility and health consequences. It is nowbelieved that ovarian high-grade serous carcinoma (HGSC) may begin in the fallopian tubes (FTs) as seroustubal intraepithelial carcinoma (STIC) and that precancerous changes are detectable before metastasis to theovary and peritoneal cavity occurs. Our preliminary data indicate that there are significant changes in serumprotein biomarkers in HGSC cases 12-84 months prior to diagnosis. Further we have also shown that changesoccur in multispectral fluorescence image markers of normal and cancerous ovaries and FTs and that we canbuild a thin falloposcope suitable for traversing the uterus and FT for imaging and cell collection. We will address the unmet clinical need for a minimally invasive test for STIC and early (stage I/II) ovariancancer. Currently no methods enable the detection of ovarian HGSC with a lead time of more than 12 months.Overall our work will meet the need to detect aggressive cancers at the earliest possible stage. Our initialtarget population is women at high risk for ovarian cancer who wish to delay or avoid RRSO. We will combineblood screening for protein markers with a minimally invasive falloposcopy for optical imaging and FT cellcollection. Our procedure will be tested in a study of women at high risk undergoing bilateral salpingo-oophorectomy with hysterectomy which will enable us to obtain and compare test results to gold standardhistology. The specific aims are to: 1) Develop and validate biomarkers that detect STIC and early epithelial ovarian cancer. We will improveupon our existing cut-off based algorithm with newly-discovered markers as well develop a velocity-basedbiomarker algorithm. The algorithm that detects disease 12-84 months prior to diagnosis will be confirmed inan independent blinded set of clinical blood samples. 2) Develop endoscopic imaging and pathomics markers. We will improve our prototype falloposcopesystem with higher resolution multispectral imaging and improved cell collection ability. We will developimaging and karyometric markers from the FT images and the cells collected and perform a pilot in vivo study. 3) Develop an actionable clinical strategy for early detection of epithelial ovarian cancer. A study will beperformed in women at high risk who are planning a RRSO. Those who test positive from our blood testdeveloped in Specific Aim 1 will have their tissue undergo a falloposcopy. Imaging and pathomics data will beused to develop a classifier which will be compared to gold standard histology findings of normal FT STIC oroccult HGSC. 676976 +No NIH Category available Adhesions;Age;Anatomy;Anoikis;Ascites;Biological;Biology;Biomimetics;Cell Aggregation;Cell-Cell Adhesion;Cells;Cellular Assay;Clinical;Computer Simulation;Data;Detection;Diagnosis;Disease;Elements;Engineering;Extracellular Matrix;Extracellular Matrix Proteins;Future;Greater sac of peritoneum;In Vitro;Individual;Integrins;Liquid substance;Malignant Neoplasms;Malignant neoplasm of ovary;Mechanics;Mesothelial Cell;Mesothelium;Methods;Modeling;Molecular;Motion;Movement;Mus;Neoplasm Metastasis;Ovary;Pathologic;Pathway interactions;Patients;Pelvis;Peritoneal;Peritoneal Fluid;Peritoneum;Primary Neoplasm;Process;Prognosis;Progression-Free Survivals;Quality of life;Race;Resistance;Respiratory Diaphragm;Role;Sampling;Selectins;Serous;Site;Solid Neoplasm;Survival Rate;System;Testing;Therapeutic;Tissues;Variant;Work;Xenograft Model;Xenograft procedure;cancer cell;cancer diagnosis;experimental study;improved;in vitro testing;in vivo;intraperitoneal;meter;mouse model;multidisciplinary;neoplastic cell;palliation;patient prognosis;patient variability;response;shear stress;simulation;surgery outcome;tumor;tumor growth;tumor microenvironment;tumor progression The role of multi-cellular aggregates vs. individual tumor cells in metastasis of high-grade serous ovarian cancer An improved understanding of different pathways used in metastasis will provide opportunities to slow thespread of high-grade serous ovarian cancer (HGSOC) improving patient prognosis and quality of life. InHGSOC metastasis results from individual cells and aggregates of cells that break free from a tumor sitefloat through the peritoneum and reattach in a new site. We hypothesize that single cell and aggregate-based metastasis are distinct processes and will test this hypothesis through analysis of patient samplescomputational simulations of single cell and aggregate movement through the peritoneum andexperimental tests in vitro and in vivo. NCI 10770405 12/21/23 0:00 PA-19-056 5R01CA240965-04 5 R01 CA 240965 4 "AULT, GRACE S" 8/7/20 0:00 12/31/25 0:00 Tumor Progression and Metastasis Study Section[TPM] 9854431 "KREEGER, PAMELA K" Not Applicable 2 BIOMEDICAL ENGINEERING 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI BIOMED ENGR/COL ENGR/ENGR STA 537151218 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 468230 NCI 305912 162318 Patients with high-grade serous ovarian cancer (HGSOC) are frequently diagnosed with extensive metastaticdisease resulting in a poor prognosis. In HGSOC metastasis occurs primarily by transcoelomic spread wheretumor cells detach from the primary tumor float through the peritoneal fluid and attach to the mesothelial layerto form new metastases. Tumor cells in patient ascites exist as single cells or in multi-cellular aggregatessimilar in size to experimental spheroids. We hypothesize that single cell and aggregate-based metastasis aredistinct processes in HGSOC transcoelomic spread. To test this hypothesis we will utilize a combination ofengineering-based approaches (in vitro culture systems multivariate modeling computational fluid dynamics)and biological methods (molecular and cellular assays analysis of patient samples xenograft models). Thisproposal leverages a diverse collaborative team that includes experts in engineering biology and the clinicalpresentation of HGSOC. Completion of the proposed studies will result in an improved understanding ofmechanisms regulating transcoelomic spread and identification of potential targets for future work to controlmetastatic spread. 468230 +No NIH Category available Abraxane;Adopted;Apoptosis;Apoptosis Inhibitor;BCL2 gene;Binding;Biodistribution;Biological;Blood Vessels;Carbonates;Cell Death;Cells;Chemoresistance;Clinical;Clinical Trials;Combined Modality Therapy;Cyclin D1;Desmoplastic;Development;Dodecanol;Dose Limiting;Down-Regulation;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Encapsulated;Epidermal Growth Factor Receptor;Epithelium;Erinaceidae;Extracellular Matrix;Extracellular Signal Regulated Kinases;FRAP1 gene;Failure;Family member;Feedback;Formulation;Genes;Glutathione;Glycolysis;Goals;Hepatotoxicity;In Vitro;Incubated;Inhibition of Cell Proliferation;Intervention;KPC model;KRAS2 gene;Laboratories;Ligands;MEK inhibition;MEKs;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mesenchymal;Metabolism;Mus;Mutate;Mutation;Neoplasm Metastasis;Oncogenic;Organ;Oxidation-Reduction;PI3K/AKT;PIK3CG gene;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Peptides;Pharmaceutical Preparations;Phosphatidylinositols;Phosphorylation;Phosphotransferases;Play;Polymers;Proliferating;Proteins;Proto-Oncogene Proteins c-akt;Ras/Raf;Reporting;Resistance;Role;SHH gene;Signal Transduction;Site;Surface;Survival Rate;TNF-related apoptosis-inducing ligand;TNFRSF10A gene;TNFRSF10B gene;Therapeutic;Toxic effect;Treatment Efficacy;Tumor Burden;Tumor Promotion;biological adaptation to stress;cancer cell;cancer stem cell;cancer therapy;carcinogenesis;chemotherapy;combinatorial;cost;density;ethylene glycol;gemcitabine;improved;in vivo;inhibitor;innovation;mouse model;mutant;nanomedicine;nanoparticulate;novel;novel strategies;novel therapeutics;overexpression;pancreatic cancer cells;pancreatic neoplasm;pancreatic stellate cell;propylene;resistance mechanism;side effect;stem cell biomarkers;stem cell proliferation;synergism;therapeutic evaluation;therapy development;treatment strategy;tumor;tumor growth;uptake Nanomedicine of Hedgehog and AKT/ERK Dual Inhibitors for Pancreatic Cancer PROJECT NARRATIVE Desmoplasia reduction using polymeric NPs containing Hh inhibitor MDB5 will effectively deliver EGFR-targeting NPs containing MEK and AKT targeting ONC201 and chemotherapeutic drug gemcitabine (GEM) tothe tumor site hence treat pancreatic cancer with reduced systemic and organ toxicity. NCI 10770383 1/3/24 0:00 PA-20-185 5R01CA266759-03 5 R01 CA 266759 3 "FU, YALI" 1/25/22 0:00 12/31/26 0:00 Nanotechnology Study Section[NANO] 6615593 "MAHATO, RAM I." Not Applicable 2 OTHER BASIC SCIENCES 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF PHARMACY 681987835 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 397900 NCI 267471 130429 PROJECT SUMMARY Gemcitabine (GEM) a frontline drug shows limited efficacy due to its rapid metabolism and inefficient deliveryto the desmoplastic pancreatic tumor site. Hedgehog (Hh) signaling activates pancreatic stellate cells (PSCs)and plays a critical role in the formation of desmoplasia and proliferation of cancer stem cells (CSCs). KRAS ispredominantly mutated in pancreatic cancer (PC) yet KRAS remains a difficult target. Since inhibition ofmTORC1/2 increases ERK phosphorylation we propose combination therapy of GEM with ONC201 which isan AKT/ERK dual inhibitor to effectively treat PC. ONC201 inhibits cell proliferation and induces TNF-relatedapoptosis inducing ligand (TRAIL)-mediated apoptosis. Further we have adopted a stroma depletion strategyby sequentially administrating Hh inhibitor MDB5 for reducing physical barrier of drug delivery to the tumor site.While sonic hedgehog (Shh)-deficient tumors have reduced stromal content such tumors are aggressive withincreased vascularity and metastatic potential. Therefore reduction of desmoplasia by inhibiting Hh pathway willallow efficient delivery of ONC201 and GEM loaded into EGFR targeted NPs to the pancreatic tumor site. Wehave identified an effective combinatorial treatment strategy using clinically viable inhibitors which can beapplied to PDAC tumors with different KRAS mutations. In our preliminary studies (i) compared to free GEMmPEG-co-PCC-g-GEM-g-DC NPs increased GEM accumulation in orthotopic tumor by 2.5-fold. To control GEMrelease into the tumor we synthesized mPEG-co-P(Asp)-g-DC-S-S-GEM with GEM payload of 14% w/w. Therewas 90% GEM release from the polymer upon incubation with L-glutathione (GSH). Combination of GEM withONC201 showed synergy in killing resistant PC cells in vitro and reduced tumor growth in vivo more effectivelythan their monotherapies. We also synthesized 2-chloro-N1-[4-chloro-3-(2-pyridinyl) phenyl]-N4 N4-bis(2-pyridinylmethyl)-14-benzenedicarboxamide (MDB5) which inhibited Hh ligands and CSC markers moreefficiently than vismodegib. Targeted NPs were prepared and optimized by decorating their surface with EGFRbinding peptide GE11 at different ligand density. Systemic administration of MDB5 loaded GE11-NPs into PCtumor bearing mice resulted in higher drug concentration in the tumor at 4h post administration compared tonon-targeted NPs. Therefore we hypothesize that sequential administration of MDB5 loaded NPs will increaseGEM and ONC201 delivery to the tumor and result in synergistic inhibition of PC by reversing resistance inducedby desmoplasia and CSC proliferation more efficiently. Our specific aims are to i) assess the effects of ONC201and GEM combination in GEM resistant PC cells in vitro and in vivo ii) development of targeted redox sensitivenanomedicine of MDB5 ONC201 and GEM and iii) nanoparticulate delivery of MDB5 ONC201 and GEMcombination in orthotopic PDX and spontaneous KPC mouse models. Long-term impact is to develop novelstrategies to reduce desmoplasia-induced chemoresistance in PC using multifunctional nanomedicine of MDB5GEM and ONC201. 397900 +No NIH Category available Ablation;Algorithms;Animal Model;Biological;Brain;Clinic;Clinical;Clinical Research;Clinical Trials;Data;Dose;Drug Delivery Systems;Elements;Failure;Fluorescence;Geometry;Goals;Gold;Human body;Illinois;Image;In Vitro;Investigation;Joint repair;Location;Malignant Neoplasms;Maps;Measurement;Measures;Mediating;Meditation;Metals;Methods;Modality;Modeling;Monitor;Monte Carlo Method;Mus;Noise;Organism;Penetration;Play;Positioning Attribute;Property;Radiation Dose Unit;Radiation therapy;Radiation-Sensitizing Agents;Radioactivity;Radiosensitization;Research;Resolution;Roentgen Rays;Role;Sampling;Scanning;Spatial Distribution;Specific qualifier value;Superficial Lesion;System;Techniques;Therapeutic;Thermal Ablation Therapy;Time;Tissues;Translating;Universities;Work;X-Ray Computed Tomography;X-Ray Medical Imaging;attenuation;cancer care;cancer therapy;clinical imaging;density;design;detector;fluorescence imaging;image reconstruction;imaging modality;imaging system;improved;in vivo;mouse model;nanoGold;novel;particle;phantom model;pre-clinical;reconstruction;side effect;tomography;transmission process;tumor X-ray fluorescence emission tomography for imaging trace gold in mouse models Project NarrativeThe goal of the proposed research is to optimize a novel x-ray fluorescence emission tomography systemcapable of directly imaging metal maps in biological samples and if desired jointly estimate the metal andattenuation maps. The proposed system will provide the spatial resolution sensitivity and tissue penetrationdepth needed to image gold nanoparticles in small animal models paving the way to in vivo guiding andmonitoring metal-mediated radiation therapy and photothermal ablation cancer therapy. NCI 10770355 12/18/23 0:00 PA-21-051 5F31CA275324-02 5 F31 CA 275324 2 "ODEH, HANA M" 1/6/23 0:00 1/5/26 0:00 Special Emphasis Panel[ZRG1-F15-P(20)L] 16136139 "DEBROSSE, HADLEY ANNA" Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 1/6/24 0:00 1/5/25 0:00 398 "Training, Individual" 2024 47694 NCI 47694 0 Project Summary In this project we propose to develop and optimize a novel X-ray fluorescence emission tomography systemand reconstruction algorithm to image trace gold in biological samples. Gold nanoparticles (GNPs) play animportant role in cancer therapy serving as radiosensitizers in metal-meditated radiation therapy and as criticalcomponents to photothermal ablation therapy. These therapies offer a promising treatment for superficial lesionsand are currently being explored in in vivo and clinical trials but could see improved efficacy and decreased sideeffects if the location and concentrations of GNPs could be mapped accurately. However current metal-mappingmethods do not provide the sensitivity or tissue penetration depth necessary to image relevant metalconcentrations. For these therapies to be translated to the clinic there needs to be a highly sensitive metal-mapping imaging modality that can image gold at the relevant concentrations and depths. In recent years X-ray fluorescence tomography has emerged as a promising modality for metal-mapping.Specifically X-ray fluorescence emission tomography (XFET) offers high sensitivity needed for imaging tracegold used in in vivo and clinical studies. Furthermore XFET offers advantages over other x-ray fluorescenceimaging modalities: it provides a direct measurement of the metal without noise-amplifying tomographic imagereconstruction and it does not require a full sinogram which limits the tissue penetration depth of othermodalities. In the proposed work we will optimize the hardware acquisition parameters of an existing XFETsystem to maximize gold detectability. We will also optimize an XFET image reconstruction algorithm to jointlyestimate metal maps as well as attenuation maps providing a novel method for obtaining an attenuation mapthat would otherwise be obtained by an additional dose-delivering computed tomography (CT) scan. The specific aims of this proposal are: 1) develop algorithms and a realistic forward model to jointlyreconstruct metal distributions and attenuation maps of objects 2) optimize XFET hardware acquisitionparameters to maximize gold detectability at specified radiation dose levels and 3) validate reconstructionmethods and optimization strategies in mouse phantom models assess minimum detectable gold concentrationand compare image quality metrics to CT. Upon completion aim 1 will provide a method to map metals at lowconcentrations and a novel method of obtaining an attenuation map using fluorescent emission data. Aim 2 willdesign a novel system geometry with parameters that maximize gold detectability. Aim 3 will demonstrate XFETsensitivity limits and compare image quality metrics to an existing system. These results will allow us to makepredictions about this preclinical systems capabilities in an eventual clinical scenario paving the way for XFETto be used as a clinical imaging system capable of mapping therapeutic GNPs for safer treatment and fewer sideeffects in cancer therapies. 47694 +No NIH Category available POLQ- and CtIP-regulated telomere fusions and translocations are involved in early events in carcinogenesis PROJECT NARRATIVEThe (dys)regulation of telomeres the terminal structures of linear chromosomes is associated withimmortalization aging and tumorigenesis. This fact is best exemplified by the bone marrow failure and cancerpredisposition syndrome dyskeratosis congenita where mutations in eleven genes all of which encode factorsrequired for telomere maintenance are known to cause the disease. Approbation of the belief that telomeremaintenance is an important area of investigation was provided by the 2009 Nobel Prizes in Physiology orMedicine which were awarded for the discovery of telomeres and telomerase. NCI 10770273 3/30/23 0:00 PA-21-268 7R01CA266524-02 7 R01 CA 266524 2 "WITKIN, KEREN L" 8/1/22 0:00 7/31/27 0:00 Cancer Etiology Study Section[CE] 1920949 "HENDRICKSON, ERIC A" Not Applicable 5 RADIATION-DIAGNOSTIC/ONCOLOGY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 1/27/23 0:00 7/31/23 0:00 393 Non-SBIR/STTR 2022 294462 NCI 214006 80456 PROJECT SUMMARYWe propose to investigate the mechanisms that regulate a cells ability to escape from the crisis caused bytelomere shortening. As normal human cells age their telomeres gradually shorten. When the telomeresshorten significantly the cell undergoes senescence which is a naturally occurring barrier to cancer. Ifhowever a cell should suffer a transforming mutation it can by-pass senescence and continue to proliferateuntil its telomeres become so short that they are non-functional. The resulting lack of end protection triggerscrisis a state that is highlighted by genomic instability as chromosomes engage in breakage:fusion:bridgingcycles that almost invariably result in the death of the cell. On rare occasions a cell can resolve its fusionsreestablish its telomeres and stabilize its genome. Such cells are said to be immortalized and it is likely thatthey are the progenitors of most human cancers. That the (dys)regulation of telomere maintenance is alsoassociated with aging immortalization and tumorigenesis in other experimental systems adds confidence tothe belief that these issues are conserved and important. Previously we have demonstrated that DNA ligase IIIand poly (ADP) ribose polymerase 1 are required for human cells to survive crisis. Here we propose to definethe role of DNA polymerase theta/Q (POLQ) which acts in the same pathway in this process. Unexpectedlywe show that deletion of POLQ causes telomere elongation and escape from crisis. We will uncover howPOLQ normally suppresses these events. Integral to surviving crisis is a requirement to resolve the chromosomal fusions/translocations that occurredduring crisis. One way to do this is to physically shear them apart by the application of tension (akabreakage). This process however is highly mutagenic and often leads to lethal outcomes. A secondresolution process more likely to ensure survival is to convert the chromosome fusions into ultra-fine bridges(UFBs) and then enzymatically in a process that is very poorly understood resolve these UFBs. Here wedemonstrate that the loss-of-function of the resection nuclease C-terminal interacting protein (CtIP) results ina high frequency of UFBs that are not resolved and we propose experiments to mechanistically unravel howthese bridges many of which involve telomeres are generated and why they are not resolved. In all of theseapproaches we utilize the strengths of the Hendrickson and Baird laboratories. The Hendrickson laboratoryexcels at the technology of gene targeting to study the impact of loss-of-function mutations of genes (POLQand CtIP in this instance) on telomere maintenance. The Baird laboratory is the worlds leader in analyzingtelomere fusion events in human cells undergoing crisis. Their ability to characterize the dynamics of singletelomeric ends has provided the fields deepest understanding of the mechanism of telomere fusions in humancells. In summary our proposed studies impact on DNA repair and telomere maintenance and the importanceof understanding these processes for cancer biology is clear. 294462 +No NIH Category available Ablation;Acidity;Amino Acids;Antitumor Response;Cancer Patient;Carbon Dioxide;Clinical;Cues;Data;Deubiquitination;Development;FOXP3 gene;Glucose;Growth Factor;Human;Hypoxia;Immune system;Immunosuppression;Immunotherapy;Infiltration;Malignant neoplasm of lung;Mediating;Metabolic;Modeling;Molecular;Mus;Neoplasm Metastasis;Peptide Hydrolases;Publications;Regulatory T-Lymphocyte;Role;Stress;Testing;Therapeutic;Treatment Efficacy;Tumor Escape;Tumor Immunity;Ubiquitin;Up-Regulation;anti-tumor immune response;cancer cell;cancer therapy;checkpoint receptors;cytokine;effector T cell;fitness;forkhead protein;immune checkpoint blockade;immunogenicity;improved;neoplasm immunotherapy;neoplastic cell;novel;programs;success;synergism;transcription factor;tumor;tumor microenvironment;ubiquitin isopeptidase A deubiquitination module controls Treg adaptation to tumor microenvironment Project NarrativeThis study identifies a deubiquitination module in controlling Treg adaptation to the harshtumor microenvironment and provides a rational for simultaneous targeting USP21 andUSP22 in antitumor immune therapy. NCI 10769773 11/27/23 0:00 PA-19-056 5R01CA257520-04 5 R01 CA 257520 4 "LIU, YIN" 1/1/21 0:00 12/31/25 0:00 "Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]" 7261033 "FANG, DEYU " "ZHANG, BIN " 5 PATHOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 505710 NCI 321304 184406 Project Summary:One of the recent advances in cancer treatment is the development of immunotherapy largelythrough targeting the checkpoint receptors. However attempts at immunotherapy to increaseantitumor immune responses have achieved very limited success. A major hurdle in tumorimmunotherapy is mediated by regulatory T (Treg) cells which suppress the function of antitumoreffector T cells. The lineage transcription factor Forkhead Box P3 (FoxP3) is known as aprogrammer for Treg adaptation in the harsh tumor microenvironment such as metabolic changesand hypoxia. However the factors that control FoxP3-mediated Treg fitness to orchestrate thesurvival and functions of intratumoral Treg cells have not been identified. Importantly our recentpublications and preliminary discoveries in the current application suggest that tumormicroenvironment factors possibly induce Treg fitness/adaptation through selectivelyupregulating a deubiquitinase module including USP21 and USP22 but not USP7 of FoxP3 tocontrol Treg adaptation. The current proposed studies will identify the tumor microenvironmentfactors that induce USP21 and USP22 expression in Tregs (Aim 1) and to test whether Tregswith simultaneous USP21 and USP22 deletion fail to adapt in the harsh tumor microenvironmentwhich consequently potentiates the antitumor immune therapy (Aim 2). Results from our proposedstudy will define a novel molecular cue in control Treg fitness to the tumor microenvironment andprovide a rationale for the combined USP21 and USP22 suppression in antitumor immune therapy. 505710 +No NIH Category available Address;Benign;Biological Markers;Blinded;Blood;Blood Plasma Volume;Blood Tests;CA-19-9 Antigen;Cancer Detection;Cancer Patient;Categories;Circulation;Clinic;Clinical;Cohort Studies;Collection;Cyst;Cytolysis;Data;Dependence;Detection;Development;Diagnosis;Diagnostic;Diagnostic Procedure;Disease;Endoscopic Ultrasonography;Evaluation;Financial cost;Fine needle aspiration biopsy;Frequencies;Health;High Resolution Computed Tomography;Hypoxia;Image;Imaging Techniques;Individual;Investigation;Knowledge;Label;Lesion;Lipids;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of pancreas;Methods;Microelectrodes;Microfluidic Microchips;Monitor;Necrosis;Organelles;Pancreas;Pancreatic Cyst;Pancreatic Diseases;Pancreatic Ductal Adenocarcinoma;Patients;Plasma;Probability;Procedures;Proteins;Recovery;Research;Research Personnel;Retrospective cohort;Risk;Sampling;Source;Symptoms;Techniques;Technology;Time;Translating;Tumor-Derived;Validation;Work;acute pancreatitis;biomarker panel;blood-based biomarker;cancer type;candidate marker;clinical development;cost;early detection biomarkers;efficacy evaluation;exosome;extracellular vesicles;follow-up;mortality;nanoparticle;novel;pancreatic cancer patients;particle;patient stratification;premalignant;protein biomarkers;screening;technology platform;tumor Distinguishing Pancreatic Cancer from Benign Pancreatic Disease using Nanoparticle-based Biomarkers Project NarrativeThis project evaluates biomarkers carried by tumor-derived extracellular vesicles for efficacy in stratifyingpatients with pancreatic cysts into categories of high-probability and low-probability for the presence ofpancreatic cancer thereby identifying patients who would benefit from an invasive fine needle aspiration biopsyof the pancreas. The use of label-free high conductance dielectrophoresis technology will enable simultaneousrecovery of these different nanoparticle types from plasma for biomarker detection. This research will generatenew knowledge supporting the development of a nanoparticle-based biomarker panel for the detection ofpancreatic cancer while also helping to enable the use of nanoparticle-based biomarkers for diagnosticapplications in the clinic. NCI 10769729 12/13/23 0:00 PAR-20-053 5R37CA258787-03 5 R37 CA 258787 3 "YOUNG, MATTHEW R" 1/1/22 0:00 12/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 8795495 "IBSEN, STUART DUNCAN" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 424508 NCI 276702 147806 Project SummaryThis project evaluates the efficacy of using biomarkers carried by tumor-derived exosomes and other organelle-derived extracellular vesicles to differentiate patients with pancreatic cancer from patients with benign pancreaticdisease. We will use high conductance dielectrophoresis-based technology to simultaneously recover differenttypes of these cancer-derived nanoparticles from individual samples of volume limited patient plasma. This willenable access to volume restricted early stage cancer samples. This research will generate new knowledgesupporting the development of a nanoparticle-based biomarker panel for early and late stage pancreatic cancerdetection and will support the rationale to bring nanoparticle-based diagnostics to the clinical setting.Pancreatic cysts are coincidently discovered with increasing frequency as the use of high resolution CT and MRIimaging increases with up to 9.3% of patients having an asymptomatic cyst. An invasive endoscopic ultrasoundguided fine needle aspiration biopsy (EUS/FNA) is traditionally used to determine if the cyst is pancreatic ductaladenocarcinoma (PDAC). This has a high financial cost and associated health risk where 1/100 patients willdevelop acute pancreatitis and 1/10 of these patients will die. Currently 60-76% of patients that undergoEUS/FNA do not have pancreatic cancer. This signifies the unmet clinical need to develop a blood test to stratifypatients with pancreatic cysts into categories of high-probability and low-probability for having PDAC wherehigh-probability would benefit from the EUS/FNA. Currently no blood based PDAC biomarkers exist. Tumor-derived nanoparticles offer a new source of potential PDAC related biomarkers. The challenge is that traditionalnanoparticle recovery methods for each nanoparticle type require plasma volumes that are too large to besupported with currently available PDAC patient plasma samples. Our preliminary data now suggest that highconductance dielectrophoresis (DEP) techniques can recover sufficient amounts of nanoparticle derivedbiomarkers to detect precancerous lesions as well as differentiate early and late stage PDAC from controls andrequires only 30 l of plasma. Each Aim will translate our DEP validation of individual biomarkers into a panelthat will be evaluated in a blinded cohort study consisting of patients with PDAC and benign pancreatic disease.We focus Aim 1 on particles actively released by tumors and Aim 2 on different cellular organelle fragments.Aim 3 evaluates these biomarkers and five from our preliminary data on stage 1 and 2 PDAC samples.The significance of this research is that the knowledge generated will lead to potential validation of a panel ofnanoparticle-associated biomarkers capable of differentiating PDAC from benign pancreatic disease. Theresearch proposed here may ultimately support the rationale for the clinical development of a nanoparticle-baseddiagnostic blood test to identify patients with pancreatic cysts that would benefit from the EUS/FNA procedure. 424508 +No NIH Category available Accountability;Address;African American;Cancer Burden;Cancer Center;Caring;Clinical;Clinical Services;Communities;Community of Practice;Complex;Country;Dedications;Development;Distance Learning;Education;Educational Curriculum;Educational workshop;Evaluation;Faculty;Feedback;Funding;Future;Genetic;Genomics;Goals;Health Professional;Hereditary Malignant Neoplasm;Hispanic;Hybrids;Income;Infusion procedures;International;Knowledge;Learning;Letters;Medical Education;Mission;Modeling;Participant;Patient Care;Patients;Precision therapeutics;Professional Education;Quality of Care;Resources;Risk Assessment;Risk Management;Self Direction;Self Efficacy;Services;Surveys;Technology;Testing;Therapeutic;Training;Underrepresented Minority;Update;cancer genetics;cancer genomics;cancer risk;cancer therapy;case-based;clinical practice;equity diversity and inclusion;evidence base;experience;genetic information;improved;member;multimodality;patient engagement;patient population;point of care;polygenic risk score;practice setting;precision medicine;programs;scale up;skill acquisition;skills;socioeconomics;success;tumor;workforce needs Cancer Genetics Professional Education in a Global Community of Practice Project NarrativeTo help address the significant global demand for cancer genomics education skills development andevidence-based patient care this project proposes to continue a successful multifaceted Intensive Course andglobal Clinical Cancer Genomics Community of Practice. The program leverages the expertise and resourcesof the academic center to prepare community-based clinicians with the knowledge and skills needed tointegrate genomic advances into best practices in cancer risk assessment personalized risk management andtargeted cancer treatment. Fulfillment of the activities outlined in this proposal will further our efforts to grow thenumber of clinicians with practitioner-level proficiency in genetic cancer genetics across the U.S. andinternationally. NCI 10769612 9/19/23 0:00 PAR-21-278 2R25CA171998-11 2 R25 CA 171998 11 "ZAHIR, NASTARAN" 9/19/13 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 10875074 "BLAZER, KATHLEEN " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 324000 NCI 300000 24000 The rapid and ongoing infusion of genomic information into clinical practice continues to fuel the need for askilled workforce to navigate genomically-informed patient care. National surveys document the continued gapbetween the need for and availability of clinicians equipped with the knowledge skills and resources tointegrate complex germline and tumor genetic information into practice. This R25 proposal outlines a plan to furtherthe mission of the Clinical Cancer Genomics and Community of Practice (CCGCoP) to help address thecontinuing demand for clinicians competent in evidence-based cancer genomics care. The CCGCoP is builton the theoretical framework of situated learning the resources and expertise of the academic cancer centerand a distinguished faculty of recognized thought leaders to deliver a multimodal inter-professional course ingenetic cancer risk assessment (GCRA) to clinicians practicing in communities with limited access to GCRAservices. Over the current project period 719 clinicians from diverse practice settings have completed the courseor are now in session exceeding our projected accrual by 43%. 18% are from underrepresented minorities(13% Hispanic 5% African American); 68% deliver all or part of their clinical services to socio-economicallyunderserved patient populations and 9% practice in low to middle income countries. The aims for thiscontinuation proposal are to: 1) Continue the established annual CCGCoP Intensive Course 2) Update thecurrent curriculum and learning assessments 3) Develop and pilot a Self-directed Review Course to addressthe need for course alumni to refresh their knowledge and skills with evidence-based cancer genomics contentand case-based activities 4) Evaluate the Intensive Course and Self-directed Review on participantengagement knowledge case-based skills learning experience and value to practice and incorporate intoiterative improvements in the self-directed model. Fulfillment of these aims will further our efforts to grow thenumber of clinicians with practitioner-level proficiency in genetic cancer genetics across the U.S. andinternationally. Additionally our plan to develop and pilot a self-directed cancer genetics review course willsupport ongoing quality improvement in GCRA for course alumni and will serve as a framework for our futuredevelopment of a fully self-directed version of the intensive course to reach a broader national and internationalaudience of healthcare professionals. 324000 +No NIH Category available Cancer Survivorship;Intervention;Malignant Childhood Neoplasm;Outcome;Training Training in Pediatric Cancer Survivorship Outcomes and Interventions PUBLIC HEALTH RELEVANCE - This application would support continued postdoctoral training to youngepidemiologists behavioral scientists geneticists and clinician-researchers who will become the nextgeneration of scientists in pediatric cancer survivorship research. The training focuses on pediatric cancersurvivorship and cancer control outcomes with research approaches informed by Global Health issues.Progress in these areas could have a major impact in reducing the burden of cancer and improving quality oflife in cancer survivors. NCI 10769595 9/14/23 0:00 PA-20-142 2T32CA225590-06A1 2 T32 CA 225590 6 A1 "BOULANGER-ESPEUT, CORINNE A" 4/1/18 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1954879 "KRULL, KEVIN R" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 214081 NCI 290764 22461 PROJECT SUMMARY/ABSTRACTRemarkable gains have been made in the treatment of pediatric cancers over the past 60 years resulting in agrowing population of long-term survivors of childhood cancer that is currently estimated to exceed 500000.Many long-term survivors experience chronic health conditions and poor health behaviors which significantlycontributes to medical burden and impacts functional outcomes and quality of life. Research on long-termsurvivors of pediatric cancer is continually informing the design of new treatment approaches for newlydiagnosed patients with the objective of minimizing long-term therapy-related morbidity and mortality. As themajority of children diagnosed with cancer will become long-term survivors and will be at risk for experiencingmultiple complications following treatment continued research is needed to enhance health and functionaloutcomes. Future research efforts will require well-trained independent investigators from the fields of oncologyepidemiology behavioral and social sciences biostatistics cancer biology and genetics health services andother allied health disciplines. While some T32-funded cancer training programs offer training opportunities incancer survivorship few academic institutions possess the resources and large multidisciplinary team that St.Jude does to provide in-depth post-doctoral research training focusing on pediatric cancer populations.Currently we have the only NIH-funded training program with a primary focus on pediatric cancer survivorship.The purpose of our training program is to develop the next generation of scientific leaders with theinterdisciplinary skills and knowledge that is necessary to become world-class competitive scientists in the areaof pediatric cancer survivorship. The key elements to the program includes: a Scholarship Oversight Teamcomprised of primary and secondary mentors and a clinical collaborator; a Management Committee to reviewprogram progress; an Advisory Committee; clinical and research training relating to cancer survivorship andpediatric oncology; a formal but flexible MSc curriculum in clinical investigation and a MPH curriculum inepidemiology biostatistics or health systems policy; training in scientific writing grant preparation and grantreview; and a detailed evaluation that will track the ongoing progress of the trainees in their subsequentcareers. We have just completed the 4th year of the new program and have graduated four postdoctoralfellows three of whom have gone into academia and one into industry. We have a new class of traineesprogressing well. Of note one of the former trainees and one of the current trainees are under-representedminorities Black and Hispanic respectively and one comes from an economically disadvantaged background.For this competing renewal we have significantly enhanced the program with required light and optionaldeep experiences in both Global Health which has been part of the program from the start but is notformalized. The innovation and uniqueness of the program includes its comprehensive focus on pediatriccancer survivorship across the lifespan of the survivor. 214081 +No NIH Category available Cancer Control;Grant;Training Training Grant in Precision Cancer Control PROJECT NARRATIVEThe ability to precisely target individuals with cancer and at-risk populations with evidence-based tools to addressindividual sociocultural or environmental factors is likely to lead to the greatest improvements in canceroutcomes and reductions in cancer risk. Thus this application for a new T32 postdoctoral training program atFox Chase Cancer Center is designed to prepare PhD and MD postdoctoral fellows to lead innovative andscientifically rigorous research in precision cancer control with diverse populations. NCI 10768785 9/14/23 0:00 PA-20-142 1T32CA278766-01A1 1 T32 CA 278766 1 A1 "LIM, SUSAN E" 9/14/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1866225 "FANG, CAROLYN Y." Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 9/14/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 155945 NCI 144764 11181 PROJECT SUMMARYIn the United States more than 40 percent of new cancer cases can be attributed to modifiable factors. Yetdespite advances in knowledge regarding the multilevel factors associated with cancer risk the annual numberof cancer cases is predicted to increase nearly 50% from 1.5 million new cases in 2015 to approximately 2.3million in 2050. Thus a greater emphasis on cancer risk reduction and cancer control along with a highlytrained workforce in this domain -- is needed to counter this projected increase. Recent advances in precisionmedicine have resulted in great optimism for potential therapeutic options and may provide a model for how toevolve the field of cancer control. To realize the full potential of precision cancer control it will be imperative tonot only assess biologic properties but to also consider individual variabilities in behavioral lifestyle andenvironmental factors. As a result precision cancer control research requires multidisciplinary approaches thatenable seamless integration and collaboration to inform our understanding of how to identify those individualswho are at elevated risk or who might benefit from specific effective and implementable interventions. Thusthere is a significant need to equip the next generation of cancer control scientists with skills required to: (1)precisely characterize the populations at increased risk for cancer or poor outcomes; (2) identify the multilevelfactors contributing to elevated risk or negative outcomes; and (3) develop and implement appropriateinterventions to effectively address those factors. This application for a new T32 postdoctoral training programat Fox Chase Cancer Center is designed to prepare PhD and MD postdoctoral fellows to conduct innovativeresearch in precision cancer control with diverse populations. The transdisciplinary training includes acomplementary program of didactic activities and intensive mentored research experiences which will equiptrainees to lead independent careers in precision cancer control. The Program Faculty include 25 mentors all ofwhom have established track records of obtaining peer-reviewed funding. We propose to enroll 2 postdoctoralfellows each year (for two-year terms) over the five-year award. All fellows will receive rigorous training in theprinciples of precision cancer control research design and methodology grant-writing responsible conduct ofresearch and career/professional skills development. T32 mentors are drawn from a broad base of exceptionalCancer Center faculty with a breadth of expertise ranging from molecular biology genetics epidemiologybiostatistics geospatial technology psychology public health and implementation science. The rich resourcesavailable at Fox Chase Cancer Center (FCCC) include comprehensive genomic biologic socioculturalbehavioral and environmental-level data combined with advanced geospatial and statistical tools that will enableour faculty and their trainees to apply precision cancer control methods in strategic efforts toward reducing cancerrisk and mortality across diverse populations. 155945 +No NIH Category available Acceleration;Address;Area;Award;Basic Science;Cancer Center;Catchment Area;Clinical Research;Collaborations;Creativeness;Crystallization;Dana-Farber Cancer Institute;Development;Discipline;Disease;Eligibility Determination;Faith;Funding;Grant;Incentives;Incubators;Investigation;Joints;Measures;Minority;Nodal;Peer Review;Pilot Projects;Population Sciences;Process;Reporting;Request for Proposals;Research Personnel;Strategic Planning;Strategic vision;Structure;Sum;Talents;Time;Training;Translations;Underrepresented Minority;anticancer research;cancer clinical trial;cancer health disparity;experience;inter-institutional;interdisciplinary collaboration;interest;member;minority patient;programs;response;success;underserved community Developmental Funds Project NarrativeNot applicable. NCI 10768702 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7167 1863889 "HOWLEY, PETER M" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 913332 513108 400224 Project Summary/AbstractNot applicable. +No NIH Category available Academy;Advanced Development;Age;Area;Award;Biological Models;CA-125 Antigen;Cancer Center;Cancer Center Support Grant;Cancer Vaccines;Caring;Catchment Area;Cervical;Clinical;Clinical Trials;Collaborations;Combined Vaccines;Correlative Study;Dana-Farber Cancer Institute;Department of Defense;Development;Diagnostic Procedure;Direct Costs;Disease;Disparity in diagnosis;Early Diagnosis;Endometrial;Endometrial Carcinoma;Environment;Faculty;Fellowship Program;Funding;Germ Cell Cancers;Germ cell tumor;Goals;Grant;Gynecologic;Histology;Human;Immunotherapy;Incidence;Infrastructure;Institution;Investigation;K-Series Research Career Programs;Laparotomy;Leadership;Link;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant Vaginal Neoplasm;Malignant neoplasm of cervix uteri;Malignant neoplasm of ovary;Malignant neoplasm of vulva;Massachusetts;Mentored Clinical Scientist Development Program;Mentors;Mirza;Mission;Mucinous;Mutate;Mutation;Operative Surgical Procedures;Organoids;Outcome;Ovarian;Paper;Patient-Focused Outcomes;Peer Review Grants;Pharmaceutical Preparations;Poly(ADP-ribose) Polymerase Inhibitor;Pregnancy;Prevention;Process;Publishing;Ras/Raf;Recommendation;Research;Research Personnel;Research Training;Resistance;Resource Sharing;Science;Scientist;Screening for cancer;Skates;Strategic Planning;Structure;Suggestion;Surgeon;Surgical Management;System;Teacher Professional Development;Techniques;Testing;Training;Translational Research;Translations;Tumor Immunity;Vagina;Vulva;Woman;anti-PD-1;anticancer research;biomarker discovery;cancer prevention;cancer risk;cancer surgery;cancer therapy;career;career development;combinatorial;community engagement;diagnostic technologies;improved;inter-institutional;investigator-initiated trial;member;minimally invasive;next generation;novel strategies;novel therapeutic intervention;oncology program;pre-clinical;prognostic method;programs;racial disparity;radical hysterectomy;resistance mechanism;response;restoration;screening;surgical disparities;translational scientist;trend;working group Program 02: Gynecologic Cancers Project NarrativeNot Applicable. NCI 10768698 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7165 1941071 "MATULONIS, URSULA ANNE" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 37759 26244 11515 Gynecologic Cancers ProgramProject Summary / AbstractThe mission of the Gynecologic (Gyn) Cancers Program is to improve patient outcomes by developing novelstrategies for early detection therapy and prevention through integrated translational research across theconsortium. A related mission is to train and educate the next generation of translational researchers clinicaltrialists outcomes researchers and basic scientists who focus on Gyn cancers. The Program encompassesinvestigation of all Gyn cancers including ovarian endometrial cervical vaginal vulvar and germ cell cancersas well as gestational trophoblastic disease. Moreover we respond to the increasing incidence of endometrialcancer (EnCa) in our catchment area (Massachusetts) as well as racial disparities in diagnosis and treatmentof cervical cancer and EnCa in Massachusetts.A previous DF/HCC Program in Gyn Cancers was not included in the last CCSG renewal (2016); the currentProgram is thoroughly revamped. Its 59 members (47 primary and 12 secondary) represent five DF/HCCinstitutions and 6 academic departments. In 2019 peer-reviewed grant funding attributed to the Program was$2.1 million in direct costs from the NCI and $1.2 million from other sponsors. During the current fundingperiod primary Program members published 629 cancer-relevant papers. Of these 20% were inter-institutional 27% were intra-programmatic and 34% were inter-programmatic collaborations between two ormore DF/HCC members.For the next CCSG funding period the Programs Specific Aims are to: 1) Develop and implement earlydetection prevention diagnostic and prognostic methods for Gyn cancers in Massachusetts and acrossthe US; 2) Develop and advance novel therapeutic strategies for Gyn cancers; and 3) Educate and mentorthe next generation of leaders for Gyn Cancers through fellowship programs junior faculty development andplacement of junior faculty on national committees. These goals align perfectly with the DF/HCC strategic planand will require the full suite of CCSG components: shared resources collaborative infrastructure an effectivesystem for clinical trial review and conduct and structured processes for community engagement and cancerresearch training. +No NIH Category available Address;American Society of Clinical Oncology;Award;Basic Science;Biological;Biology;CTLA4 gene;Cancer Center;Cancer Center Support Grant;Catchment Area;Cells;Classification;Clear cell renal cell carcinoma;Clinical Trials;Collaborations;Combined Modality Therapy;Community Health Education;Core Facility;Dana-Farber Cancer Institute;Development;Direct Costs;Disease;EZH2 gene;Early Diagnosis;Ensure;Funding;Future;Goals;Grant;Immunologics;Incidence;Infrastructure;Institution;International;Kidney Neoplasms;Malignant Neoplasms;Massachusetts;Medicine;Mission;Molecular;Nature;New Agents;Nivolumab;Nobel Prize;Oxygen;PD-1 blockade;Paper;Pathway interactions;Patient-Focused Outcomes;Patients;Peer Review Grants;Phenotype;Play;Population;Positioning Attribute;Pre-Clinical Model;Process;Prognosis;Publishing;Randomized;Renal carcinoma;Research Personnel;Research Training;Rewards;Role;Seminal;Series;Signal Transduction;Strategic Planning;Structure;Surrogate Markers;System;Testing;Training;Training and Education;Validation;Vascular Endothelial Growth Factors;Work;antagonist;anti-PD-1/PD-L1;anticancer research;bevacizumab;cancer infiltrating T cells;cancer prevention;clinical development;community engagement;disparity reduction;drug development;early detection biomarkers;effective therapy;genetic signature;improved;inhibitor;innovation;inter-institutional;member;new therapeutic target;novel;pembrolizumab;phase I trial;phase II trial;phase III trial;predictive marker;programmed cell death ligand 1;programmed cell death protein 1;programs;standard of care;symposium;treatment response;tumor Program 52: Kidney Cancer Project NarrativeNot Applicable. NCI 10768696 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7164 10412700 "CHOUEIRI, TONI " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 38146 34032 4114 Kidney Cancer ProgramProject Summary / AbstractThe DF/HCC Kidney Cancer Program performs innovative basic research into the molecular basis of kidneytumors. Scientific efforts within the current funding period focused on identifying meaningful biomarkers forearly detection and prognosis underlying mechanisms of disease biology novel therapeutic targets for thevarious kidney cancer populations and improved preclinical models for preliminary validation of these findings.The Program has made notable advances in mechanism-based classification and treatment of kidney cancersrewarded by marked improvements in patient outcomes and with the 2019 Nobel Prize in Medicine awarded tolongstanding SPORE co-leader W.KaelinDFCI for his seminal discovery of the mechanism by which cells senseoxygen. The Program is well positioned for a leading role in addressing critical questions that will be points ofincreasing emphasis in kidney cancers in the near future.The Programs 42 members (29 primary and 13 secondary) represent six DF/HCC institutions and 9 academicdepartments. In 2019 peer-reviewed grant funding attributed to the Program was $2.1 million in direct costsfrom the NCI and $1.7 million from other sponsors. During the current funding period primary Programmembers published 612 cancer-relevant papers. Of these 40% were inter-institutional 21% were intra-programmatic and 47% were inter-programmatic collaborations between two or more DF/HCC members.In order to achieve the Program mission we propose the following Specific Aims over the next CCSG fundingperiod: 1) Identify and validate novel targets in kidney cancer and establish preclinical models to test newagents; 2) Leverage Program infrastructure to facilitate drug development and to identify molecular andbiological predictors of prognosis and response to therapy; and 3) Ensure that the Program servesMassachusetts (our CCSG catchment area) and the nation through the development of cancer prevention andearly detection strategies community education and training of future leaders in the field. To execute theseAims we will take full advantage of DF/HCCs collaborative infrastructure core facilities clinical trial systemsand structured processes for community engagement and cancer research training. +No NIH Category available 18 year old;Acceleration;Address;Affect;BRAF gene;Basic Science;Behavior;Biological;Biology;Biopsy;Cancer Center;Cancer Center Support Grant;Catchment Area;Cells;Child;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Communities;Core Facility;Coupled;Dana-Farber Cancer Institute;Diagnosis;Direct Costs;Disease;Epigenetic Process;Foundations;Funding;Genetic Transcription;Genome;Genomics;Goals;Immune;Immune Targeting;Immunology;Institution;International;Journals;Knowledge;Laboratories;Leadership;Malignant Neoplasms;Massachusetts;Medical Oncologist;Medicine;Metabolic;Mission;Molecular;Molecular Evolution;Nature;Neoplasm Metastasis;New England;Outcome;Paper;Patients;Peer Review;Peer Review Grants;Play;Pre-Clinical Model;Prevention;Publications;Publishing;Reporting;Research;Research Personnel;Resistance;Resources;Risk;Role;Sampling;Science;Seminal;Shapes;Signal Transduction;Skin Cancer;Skin tanning;Specimen;Statutes and Laws;Structure;Surgical Oncologist;Technology;Therapeutic;Toxic effect;Training;Training and Education;Translating;Translations;Tumor Bank;anti-CTLA4;anti-PD-1;cancer risk;carcinogenicity;checkpoint inhibition;epigenomics;immune checkpoint;improved;inter-institutional;melanoma;melanomagenesis;member;metabolomics;novel;pre-clinical;preclinical study;programs;resistance mechanism;standard of care;targeted treatment;treatment optimization;treatment response;tumor;tumor microenvironment;tumor progression Program 35: Melanoma Project NarrativeNot Applicable. NCI 10768693 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7163 2044583 "HODI, FRANK S" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 37906 29680 8226 Melanoma ProgramProject Summary / AbstractThe Melanoma Program seeks to study all aspects of melanoma with the goal of advancing our understandingof the disease and translating the knowledge into improvements in diagnosis prevention and therapy toimprove or save the lives of melanoma patients. Its members include international leaders who have madeseminal contributions to both the basic understanding of melanoma and the management of patients withdirect impact on vastly improved clinical outcomes. Our collaborative research is embodied in part in apatient biopsy program coordinated by surgical and medical oncologists and dermatopathologists. Well-annotated tumor samples before during and after therapy enable deep understanding of genomic andmolecular evolution in melanoma and address questions related to treatment responsiveness; this tumorbank is widely shared with investigators within and well beyond the Cancer Center. Beyond this resourcethe Program has deep roots in basic research translation pivotal clinical trials and in training outstandingmelanoma researchers.The Programs 43 members (35 primary and 8 secondary) represent all seven DF/HCC institutions and 10academic departments. In 2019 peer-reviewed grant funding attributed to the Program was $2.4 million indirect costs from the NCI and $2.0 million from other sponsors. During the current funding period primaryProgram members published 564 cancer-relevant papers. Of these 26% were inter-institutional 18% wereintra-programmatic and 45% were inter-programmatic collaborations between two or more DF/HCC members.These numbers reflect the Programs deeply interactive and collaborative ethos.To achieve the Program mission our Specific Aims during the next CCSG funding period are to 1) Examinethe molecular underpinnings of melanoma comprised of genomics epigenomics and metabolomics withthe goal of leveraging the discoveries to optimize therapies for patients; 2) Investigate microenvironmentfeatures that modulate melanoma treatment responses; and 3) Study external factors that influencecarcinogenic risk behaviors relevant to melanoma-genesis and treatment accessibility. To realize theseAims Program members will take advantage of CCSG collaborative clinical trial and educational/trainingstructures and exceptional core facilities. +No NIH Category available Acceleration;Address;Authorship;BRAF gene;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Cellular biology;Clinic;Clinical;Clinical Research;Clinical Trials;Collaborations;Combination immunotherapy;DNA sequencing;Dana-Farber Cancer Institute;Development;Diagnosis;Direct Costs;Discipline;Drug resistance;Early Diagnosis;Elements;Epidermal Growth Factor Receptor;Evolution;Faculty;Funding;Genetic Predisposition to Disease;Genomics;Goals;Immunotherapeutic agent;Immunotherapy;Infrastructure;Institution;Investigation;KRAS2 gene;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thorax;Mentors;Methods;Mission;Molecular Analysis;Mutation;Oncogenes;Paper;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Peer Review Grants;Pharmaceutical Preparations;Play;Population;Postdoctoral Fellow;Predisposition;Prevention;Preventive;Process;Prognosis;Publishing;ROS1 gene;Research;Research Personnel;Resistance;Resource Sharing;Resources;Role;Screening for cancer;Seminal;Signal Pathway;Signaling Molecule;Stains;Strategic Planning;Strategic vision;Structure;Testing;Therapeutic Agents;Therapeutic Clinical Trial;Training;Underrepresented Minority;Underserved Population;Vaccines;cancer care;cancer cell;cancer genetics;cancer health disparity;cancer risk;cancer subtypes;career;chemotherapy;clinical development;community engagement;computed tomography screening;frontier;immune checkpoint blockade;improved;innovation;insight;inter-institutional;liquid biopsy;lung cancer screening;member;minority investigator;new technology;next generation;novel therapeutic intervention;novel therapeutics;preclinical study;programmed cell death ligand 1;programs;resistance mechanism;response;single cell analysis;smoking cessation;social;targeted agent;targeted treatment;tumor;tumor DNA;tumor immunology;tumor microenvironment Program 34: Lung Cancer Project NarrativeNot Applicable. NCI 10768690 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7162 2092519 "JOHNSON, BRUCE E." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 37906 29680 8226 Lung Cancer ProgramProject Summary / AbstractThe Lung Cancer Program conducts innovative research on lung cancer causes and pathogenesis focusingon discoveries that improve prevention diagnosis and therapy. The Program leverages expertise across allDF/HCC institutions in smoking cessation lung cancer screening genetic susceptibility genomic changes inlung cancer preclinical and clinical studies of novel therapies and molecular analysis of tumors before andafter targeted and immunotherapeutic agents. A core strength of the Program is an integral bidirectional linkbetween the laboratory and clinic which has enabled insights into drug resistance and accelerated clinicaldevelopment of agents to overcome newly identified vulnerabilities. Community engagement is embedded inthe Programs laboratory preventive cancer screening and clinical efforts.The Programs 69 members (51 primary and 18 secondary) represent six DF/HCC institutions and 11academic departments. In 2019 peer-reviewed grant funding attributed to the Program was $6.5 million indirect costs from the NCI and $2.6 million from other sponsors. During the current funding period primaryProgram members published 1004 cancer-relevant papers. Of these 27% were inter-institutional 27% wereintra-programmatic and 42% were inter-programmatic collaborations between two or more DF/HCC members.To achieve the Program mission we propose the following Specific Aims during the next CCSG fundingperiod: 1) Identify environmental social and genomic determinants of lung cancer risk and their role insusceptibility pathogenesis and prognosis of lung cancer both in underserved and broader populations; 2)Define pathogenic mechanisms that underlie the development and evolution of lung cancer; 3) Exploit thediscoveries in cell biology to characterize signaling pathway activated by driver oncogenes to develop noveltherapeutic approaches to thoracic malignancies; 4) Characterize the mechanisms of primary and acquiredresistance to targeted therapy and develop new methods to overcome resistance; and 5) Identify criticaltumor-intrinsic tumor microenvironment and host determinants of response to immunotherapy across lungcancer subtypes.Each of these Aims is intimately related to the DF/HCC strategic plan. To achieve them Program memberswill depend heavily on CCSG support in the form of shared resources a clinical trials infrastructureexceptional collaborative opportunities processes for community engagement and established structuresto train junior investigators. +No NIH Category available Achievement;Address;Adult;Adult Glioblastoma;Age;Anaplastic astrocytoma;Antibodies;Area;Astrocytoma;Award;Biology;Brain Neoplasms;Cancer Center;Cancer Center Support Grant;Cells;Central Nervous System;Central Nervous System Neoplasms;Chemicals;Child;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Childhood Malignant Brain Tumor;Chromatin;Chromatin Remodeling Factor;Classification;Clinical;Clinical Trials;Collaborations;Communities;Core Grant;Country;DNA Repair;Dana-Farber Cancer Institute;Dedications;Diagnostic tests;Direct Costs;Discipline;Disease;Environment;Ependymoma;Epidermal Growth Factor Receptor;Epigenetic Process;Faculty;Fostering;Funding;Genes;Glioblastoma;Glioma;Grant;Grant Review;Histones;Immunotherapy;Inherited;Institution;International;Laboratories;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of central nervous system;Mentored Clinical Scientist Development Program;Metabolic;Metabolic Pathway;Microglia;Mission;Molecular Genetics;Neoplasms;Nervous System;Neurilemmoma;Neurofibromin 2;Neurons;Neurosciences;Oncogenes;Oncogenic;Oncoproteins;Pediatric Oncology Group;Peer Review;Pharmaceutical Chemistry;Positioning Attribute;Prognosis;Proliferating;Protein Kinase;Publications;Published Comment;Reporting;Research;Research Personnel;Research Priority;Scholarship;Science;Services;Site;Strategic vision;Structure;Therapeutic;Training;Underrepresented Minority;Woman;Work;addiction;cancer care;career;career development;diffuse midline glioma;immune checkpoint blockade;improved;insight;inter-institutional;loss of function mutation;member;meningioma;molecular diagnostics;molecular pathology;mutant;neoantigen vaccine;neoplastic cell;neuro-oncology;novel therapeutics;programs;recruit;response;skills;standard of care;success;synthetic peptide;tenure track;therapeutic target;tool;tumor;tumor immunology;tumor metabolism;tumor microenvironment;young adult Program 30: Neuro-Oncology Project NarrativeNot Applicable. NCI 10768685 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7160 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 38917 38917 0 Neuro-Oncology ProgramProject Summary / AbstractNeuro-Oncology has been a CCSG disease-based Program since 2005 with the mission to improve standardsof care for cancers of the nervous system. The Program features a broad portfolio of research initiatives in thegeneral clinical disciplines and in therapeutically relevant scientific areas. Over the past two funding cycles weprioritized work on astrocytomas the most lethal brain tumor of adults and the most common brain tumor ofchildhood. Going forward we will extend our work on astrocytomas and broaden our clinical and translationalprofile with an initiative on hereditary and sporadic neoplasms driven by loss-of-function mutations in theNeurofibromin 2 (NF2) gene. We will also explore new therapeutic opportunities from the emerging field ofcancer neuroscience. In accord with the Directors Strategic Vision contemporary tools of medicinal chemistrywill be brought to bear upon undruggable oncogenic drivers and tumor-specific epigenetic and metabolicvulnerabilities will be exploited as therapeutic targets. The immunosuppressive glioma microenvironment willbe targeted with personalized synthetic peptide neoantigen vaccines and with bi-valent CART cells thatrelease anti-EGFR antibodies within the local environment of tumor cells.Skill sets of the leadership team (T. BatchelorBWH D. Haas-KoganDFCI/BCH/BWH S. PlotkinMGH and M. SuvaMGH)align with Program strategies and research priorities. The Programs 98 members (87 primary and 11secondary) draw from all seven DF/HCC institutions and 15 academic departments. Peer-reviewed funding in2019 was $13.1 M (direct costs representing an increase from $12.2M reported in 2014) of which $8.9 M wasfrom NCI. Components of the support package include a renewed SPORE grant on glioma a K12 training granton Neuro Oncology. From 2016 to 2019 Program primary members generated 955 peer-reviewedpublications. Inter-programmatic collaborations are reflected in 41% of these publications and intra-programmatic collaborations in 27% while 26% represent inter-institutional collaborations.Going forward we have five specific aims across the lifespan of central nervous system cancers. Aim onetargets epigenetic vulnerabilities for diffuse midline glioma (DMG) - a uniformly fatal pediatric brain cancer. Aimtwo exploits addictions to druggable chromatin modifiers and metabolic pathways in grade 4 IDH-mutantastrocytomas of young adults. Aim three is to advance immunotherapy for IDH WT adult glioblastoma beyondthe currently limited paradigm of immune checkpoint blockade. Aim four targets genetically validated proteinkinases that may serve as downstream effectors of proliferation in NF2-deficient CNS tumors includingmeningiomas schwannomas and ependymomas. Aim five targets gliomagenic functions of microglia andelectrically active neurons within the tumor microenvironment. +No NIH Category available Address;Advanced Malignant Neoplasm;Affordable Care Act;Area;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Survivor;Caregivers;Caring;Chronic;Clinical;Clinical Informatics;Clinical Investigator;Clinical Sciences;Clinical Trials;Collaborations;Communities;Dana-Farber Cancer Institute;Data Sources;Diagnosis;Direct Costs;Effectiveness;Ensure;Equity;Exercise;Family;Family Study;Fostering;Funding;Goals;Health Care Reform;Health Services Accessibility;Healthcare;Individual;Institute of Medicine (U.S.);Institution;Intervention;Investments;Malignant Neoplasms;Measures;Methods;Mission;Modeling;Oncology;Outcome;Palliative Care;Paper;Patient Outcomes Assessments;Patient-Centered Care;Patient-Focused Outcomes;Patients;Peer Review;Peer Review Grants;Phase;Population;Practice Guidelines;Prevention;Program Research Project Grants;Publishing;Reporting;Research;Research Methodology;Research Subjects;Screening for cancer;Services;Symptoms;System;Testing;Training;Translating;Translational Research;United States Agency for Healthcare Research and Quality;United States National Institutes of Health;Vulnerable Populations;Work;accountable care organization;cancer care;cancer diagnosis;cancer therapy;cancer type;care delivery;design;effective intervention;end of life care;ethnic minority;evidence base;experience;fitness;health care cost/financing;health related quality of life;hospice environment;improved;innovation;inter-institutional;knowledge translation;member;next generation;palliative;patient oriented;patient-clinician communication;precision medicine;programs;racial minority;routine practice;screening;socioeconomic disadvantage;symptom management;tool;treatment trial Program 10 Cancer Care Delivery Research Project NarrativeNot Applicable. NCI 10768672 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7155 7337203 "MACK, JENNIFER W" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 37069 30488 6581 Cancer Care Delivery Research ProgramProject Summary / AbstractThe mission of the Cancer Care Delivery Research (CCDR) Program is to facilitate and conduct research thatensures the delivery of high-quality patient-centered care to individuals with all types of cancer. Advances incancer diagnosis screening prevention and treatment are usually tested and reported in defined andrelatively small groups of research subjects. Members of the CCDR Program measure the extent to whichinterventions are effective when the reported advances are scaled population-wide. The Program developsrefines tests and implements strategies to maximize the impact of discoveries. A particular point of emphasisis the degree to which the benefits of research discoveries extend to patients from racial and ethnic minoritybackgrounds and to those who are socioeconomically disadvantaged.The Program has 66 members (56 primary and 10 secondary) representing all seven DF/HCC institutions and12 academic departments. In 2019 peer-reviewed grant funding attributed to the Program was $5.1 million indirect costs from the NCI and $7.7 million from other sponsors. During the current funding period primaryCCDR members published 1336 cancer relevant papers. Of these 25% were inter-institutional 23% wereintra-programmatic and 39% were inter-programmatic collaborations between two or more DF/HCC members.CCDRs emphasis on improving the experience efficiency and equity of cancer care ensures that innovationsin cancer treatment and care realize their full potential throughout populations and care settings. To meet theProgram mission CCDR members have built successful collaborations developed new research methodsconstructed data sources and trained the next generation of clinical investigators. Our Specific Aims for thenext CCSG funding period are to: 1) Assess the quality effectiveness and value of new and establishedinterventions to treat cancer with an emphasis on precision medicine by (a) designing clinical informaticsstrategies to improve cancer care delivery and (b) promoting capacity for delivering precision medicine; 2)Evaluate patient-centered outcomes of cancer care including health-related quality of life and symptom burdenby developing tools to assess the patient experience; 3) Assess the impact of healthcare reform includingalternative delivery coverage and reimbursement systems on cancer screening diagnosis treatment andoutcomes; and 4) Develop and test strategies to improve palliative and end of life care (EOL) experiences foradvanced cancer patients and their families. +No NIH Category available Acceleration;Address;Androgen Receptor;Area;Aspirin;Biological Markers;Blood;Breast;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Survivorship;Catchment Area;Clinical;Clinical Trials;Cohort Studies;Collaborations;Complex;Data;Diagnosis;Diet;Direct Costs;Discipline;Disease;Epidemiologist;Epidemiology;Etiology;Feces;Fostering;Funding;Genomics;Goals;Histology;Incidence;Individual;Inherited;Institution;Investments;Laboratory Study;Location;Longevity;Malignant Neoplasms;Mammographic Density;Massachusetts;Metabolic Marker;Metabolism;Mission;Molecular;National Cancer Institute;Obesity;Observational epidemiology;Outcome;Paper;Patient Outcomes Assessments;Patients;Peer Review;Peer Review Grants;Pharmaceutical Preparations;Phase;Physical activity;Postdoctoral Fellow;Predictive Cancer Model;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Productivity;Prognostic Marker;Publications;Publishing;Recording of previous events;Research;Research Methodology;Research Personnel;Risk;Risk Factors;Role;Science;Strategic Planning;Structure;Tissues;Training;Translating;Translations;Tumor Subtype;Underrepresented Minority;United States National Institutes of Health;Urine;Woman;biomarker identification;cancer epidemiology;cancer prevention;cancer subtypes;career;cohort;energy balance;epidemiology study;follow-up;gastrointestinal;genetic variant;genomic biomarker;improved;innovation;inter-institutional;lifestyle factors;malignant breast neoplasm;member;microbiome;modifiable risk;molecular marker;mortality;next generation;nonalcoholic steatohepatitis;novel;predictive marker;programs;prospective;randomized trial;screening;student mentoring;tool;tumor;understudied cancer Program 07 Cancer Epidemiology Project NarrativeNot Applicable. NCI 10768667 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7152 8692463 "ELIASSEN, A. HEATHER " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 36348 36348 0 Cancer Epidemiology ProgramProject Summary / AbstractThe mission of the Cancer Epidemiology Program (CEP) is to facilitate and conduct innovative epidemiologyresearch related to cancer and to support translation of the findings into meaningful advances in cancerprevention screening diagnosis and treatment. A key programmatic goal is the integration of cancerepidemiology research across the Cancer Centers disease- and discipline-based Programs. As a result inter-programmatic collaborations have led to the forward translation of epidemiologic findings into prospectiveclinical trials and reverse translation to laboratory studies that explore the cellular and molecular mechanismsunderlying epidemiologic observations. The Program is deeply invested in the mission of training andmentoring students and postdoctoral and clinical fellows who represent the next generation of cancerepidemiologists especially trainees from underrepresented minority backgrounds.The Programs 68 members (50 primary and 18 secondary) represent all seven DF/HCC institutions and 12academic departments. In 2019 peer-reviewed grant funding attributed to the Program was $11.5 million indirect costs from the NCI and $3.8 million from other sponsors. During the current funding period primary CEPmembers published 1093 cancer-relevant papers. Of these 47% were inter-institutional 46% were intra-programmatic and 40% were inter-programmatic collaborations between two or more DF/HCC members.These numbers reflect the breadth of interactivity promoted by the CCSG structure and senior leaders.Program members tackle etiological questions in cancer mortality including lifestyle factors as well aspredictive and prognostic biomarker studies. The Program emphasizes research goals in priority areas of ourcatchment area the DF/HCC strategic plan and scientific focus outlined in the NCIs 2022 Annual Plan(obesity and cancer; cancer survivorship). For the next CCSG funding period our Specific Aims are toaccelerate science collaboration translation and training in the following areas: (1) Energy balancemetabolism and cancer; (2) Risk factors and cancer subtypes; (3) Molecular and genomic biomarkers incancer; and (4) Factors associated with cancer mortality. +No NIH Category available Acceleration;African American population;B-Cell Antigen Receptor;B-Cell Lymphomas;Basic Science;Boston;Cancer Center;Cancer Center Support Grant;Caring;Catchment Area;Chronic Lymphocytic Leukemia;Clinic;Clinical Research;Clinical Trials;Collaborations;Core Facility;Dana-Farber Cancer Institute;Dedications;Development;Direct Costs;Disease;Early Intervention;Elements;Enhancers;FDA approved;Follicular Lymphoma;Funding;General Hospitals;Genetic;Genetic Predisposition to Disease;Genetic Transcription;Genomics;Guidelines;Hematologic Neoplasms;Hodgkin Disease;Hospitals;Immune response;Individual;Infrastructure;Institution;Israel;Laboratories;Lesion;Lymphoid;Lymphoid Cell;Lymphoma;Malignant Neoplasms;Malignant lymphoid neoplasm;Massachusetts;Mediastinal;Medical center;Mission;Molecular;Molecular Analysis;Molecular Profiling;Multiple Myeloma;Mutation;Natural History;New Agents;Nivolumab;Oncogenic;Paper;Participant;Pathogenicity;Patients;Pediatric Hospitals;Peer Review Grants;Plasma Cell Neoplasm;Plasma Cells;Play;Predisposing Factor;Prevention;Proteomics;Publishing;Receptor Signaling;Research;Research Personnel;Resources;Role;Structure;Testing;Thalidomide;Therapeutic;Therapeutic Agents;Training;Translating;Translational Research;Translations;Treatment outcome;Update;Woman;Work;anti-tumor immune response;base;bench-to-bedside translation;clinical development;disorder prevention;health disparity;immunoregulation;improved;inhibitor;innovation;insight;inter-institutional;interest;large cell Diffuse non-Hodgkin's lymphoma;lymphoid neoplasm;member;mouse model;multidisciplinary;next generation;novel strategies;novel therapeutic intervention;novel therapeutics;pembrolizumab;preclinical development;prognostic value;programs;tumor Program 06 Lymphoma and Myeloma Project NarrativeNot Applicable. NCI 10768665 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7151 8436435 "GHOBRIAL, IRENE M." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 37542 21091 16451 Lymphoma and Myeloma ProgramProject Summary / AbstractThe Lymphoma and Myeloma Program characterizes specific lymphoid and plasma cell malignancies at thecellular and molecular level using state-of-the-art approaches including informative murine models patienttumors and comprehensive analyses of molecular signatures. Program members then translate the emerginginsights into innovative clinical trials. Members include: 1) investigators with lymphoma and myeloma researchprograms that span basic translational and clinical research; 2) dedicated clinicians; 3) hematopathologists;and 4) computational biologists and biostatisticians with a focus on these diseases. Their historic and recentefforts have identified new rational treatment targets and moved promising targeted inhibitors from laboratoriesinto the clinic. Program members also have longstanding interest and contributions in the analysis andaugmentation of host immune responses to lymphoma and myeloma. Engagement with the Cancer Centerscatchment area (Massachusetts) and training of the next generation of Lymphoma and Myeloma researchersare integral Program elements.The Programs 74 members (47 primary and 27 secondary) represent five DF/HCC institutions and 9 academicdepartments. In 2019 peer-reviewed grant funding attributed to the Program was $5.4 million in direct costsfrom the NCI and $5.6 million from other sponsors. During the current funding period primary Programmembers published 933 cancer-relevant papers. Of these 27% were inter-institutional 23% were intra-programmatic and 36% were inter-programmatic collaborations between two or more DF/HCC members.For the next CCSG finding period our Specific Aims are to: 1) Elucidate pathogenic mechanisms underlyingspecific lymphoid/plasma cell neoplasms; 2) Develop novel therapeutic approaches to lymphoid and plasmacell neoplasms; and 3) Evaluate early intervention and prevention in patients with precursor conditions forhematologic malignancies. To realize these Aims Program members will avail of invaluable CCSG resources:core facilities collaborative structures the CCEE and OCRET functions and a clinical trials infrastructure thatis highly effective for bench-to-bedside translation. +No NIH Category available Acute leukemia;Adoptive Cell Transfers;Allogenic;Azacitidine;Bone Marrow;Boston;C2H2 Zinc Finger;CDK4 gene;CRISPR/Cas technology;Cancer Center;Cancer Center Support Grant;Cardiovascular Diseases;Caring;Cell fusion;Cells;Cellular biology;Chemicals;Childhood Acute Lymphocytic Leukemia;Childhood Leukemia;Clinic;Clinical;Clinical Trials;Collaborations;Communities;Community Outreach;Dana-Farber Cancer Institute;Dendritic Cells;Development;Direct Costs;Disease;Dominant-Negative Mutation;Dysmyelopoietic Syndromes;Education and Outreach;Epigenetic Process;Event;FLT3 gene;Funding;Genetic;Genome engineering;Goals;Grant;Hematopoiesis;Human;Immunologic Deficiency Syndromes;Immunologist;Immunotherapy;Infrastructure;Institution;International;Investigation;Journals;Laboratories;Lead;Leadership;Malignant Neoplasms;Massachusetts;Medicine;Mission;Modeling;Molecular Biology;Mutation;Myeloproliferative disease;Nature;New England;Paper;Pathogenesis;Patient-Focused Outcomes;Peer Review;Peer Review Grants;Population Sciences;Positioning Attribute;Precancerous Conditions;Preleukemia;Program Research Project Grants;Protocols documentation;Publishing;Relapse;Research;Research Personnel;Resource Sharing;Science;Scientist;Stem cell transplant;System;TP53 gene;Taxonomy;Thalidomide;Training;Translating;Translational Research;Translations;Universities;Vaccination;Zebrafish;analog;anticancer research;asparaginase;bench to bedside;cancer cell;chronic leukemia;early phase clinical trial;genetic predictors;improved;in vivo Model;inhibitor;innovation;inter-institutional;investigator-initiated trial;leukemia;meetings;member;mutant;new therapeutic target;next generation;novel;novel therapeutics;open source;outcome prediction;outreach;patient derived xenograft model;prognostic value;programs;single-cell RNA sequencing;standard of care;stem cells;tenure track;therapeutic target Program 04 Leukemia Project NarrativeNot Applicable. NCI 10768663 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7150 10504721 "LANE, ANDREW A" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 38124 34833 3291 Leukemia ProgramProject Summary / AbstractThe mission of the Leukemia Program is to improve patient outcomes through innovative translational researchon acute and chronic leukemias myelodysplastic syndromes myeloproliferative neoplasms and antecedentpremalignant states. Our longstanding objectives are to (a) discover cell-intrinsic and microenvironmentaldrivers of these conditions and (b) translate laboratory discoveries into investigator-initiated early-phaseclinical trials. To develop novel therapeutics Program members leverage effective and fruitful collaborationsbetween leukemia biologists chemists immunologists and clinicians. These interactions depend critically onthe Cancer Centers collaborative infrastructure shared resources outstanding systems for clinical trial reviewand conduct and the deep culture of bench-to-bedside investigation across the consortium. Communityoutreach and training in cancer research are deeply embedded in the Programs laboratory translational andclinical efforts.The Programs 89 members (69 primary and 20 secondary) represent six DF/HCC institutions and 10academic departments. In 2019 peer-reviewed grant funding attributed to the Program was $8.9 million indirect costs from the NCI and $8.3 million from other sponsors. During the current funding period primaryProgram members published 1129 cancer-relevant papers. Of these 27% were inter-institutional 26% wereintra-programmatic and 41% were inter-programmatic collaborations between two or more DF/HCC members.For the next CCSG funding period we propose the following two Specific Aims: 1) Identify novel mechanismsthat contribute to the pathogenesis of acute leukemias myelodysplastic syndromes myeloproliferativeneoplasms and premalignant states and 2) Advance therapeutics that target vulnerabilities in these diseases. +No NIH Category available AR gene;Acceleration;Acetates;Address;African American;Androgen Receptor;Androgens;Armenia;Attention;Biological Models;Biological Process;Biostatistics Core;CDK4 gene;Cancer Center;Cancer Center Support Grant;Cancer Patient;Castrate sensitive prostate cancer;Catchment Area;Cells;ChIP-seq;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Community Outreach;Data;Data Science;Detection;Development;Direct Costs;Early treatment;Elements;Enhancers;Epigenetic Process;Funding;Genes;Genets;Institution;International;Length;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Massachusetts;Mediating;Mission;Mutate;Mutation;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Nonmetastatic;PD-1 blockade;Paper;Patients;Peer Review Grants;Phenotype;Prostate;Publishing;RNA Splicing;Reporting;Repression;Research;Research Design;Research Personnel;Resistance;Resource Sharing;Resources;Sampling;Series;Signal Transduction;Structure;Surrogate Endpoint;Training;Tumor Suppressor Genes;Upstream Enhancer;Variant;abiraterone;androgen deprivation therapy;antagonist;biomarker driven;cancer biomarkers;cancer cell;cancer epidemiology;cancer genetics;castration resistant prostate cancer;clinical practice;clinical translation;collaborative trial;community engagement;constitutive expression;efficacy evaluation;enzalutamide;exome sequencing;gene repression;genome sequencing;genome wide association study;genome-wide;genomic biomarker;improved;improved outcome;in vivo;inhibitor;inter-institutional;member;men;multidisciplinary;next generation;novel;patient population;phase II trial;phase III trial;programmed cell death ligand 1;programs;prostate cancer risk;resistance mechanism;risk stratification;transcriptome;tumor;tumor progression;whole genome Program 03 Prostate Cancer Project NarrativeNot Applicable. NCI 10768660 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7149 1863884 "BALK, STEVEN P." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 37588 37588 0 Prostate Cancer ProgramProject Summary / AbstractThe Prostate Cancer Program seeks to improve outcomes for all prostate cancer patients by bringing togethera multidisciplinary team of investigators across the DF/HCC consortium to catalyze and accelerate researchleading to clinical benefit. A founding premise of the Program is that genuine progress in the management ofprostate cancer requires iterative fundamental discovery through research in model systems and in patient-derived samples clinical translation and subsequent analysis of patient-derived clinical samples to assessmechanisms of action and sensitivity or resistance in vivo. The Program harnesses CCSG structures andresources to achieve this iterative cycle. Additionally the Program addresses the diversity of our catchmentarea (Massachusetts) and pays particular attention to training the next generation of basic and clinicalinvestigators across the consortium.The Programs 66 members (42 primary and 24 secondary) represent seven DF/HCC institutions and 11academic departments. In 2019 peer-reviewed grant funding attributed to the Program was $2.6 million indirect costs from the NCI and $3.4 million from other sponsors. During the current funding period primaryProgram members published 840 cancer-relevant papers. Of these 27% were inter-institutional 30% wereintra-programmatic and 31% were inter-programmatic collaborations between two or more DF/HCC members.To achieve the Program mission our Specific Aims for the next CCSG funding period are to 1) Improvedetection and early treatment of aggressive prostate cancer; 2) Identify mechanisms of resistance tocurrent therapies and identify further targetable vulnerabilities; and 3) Exploit tumor specific vulnerabilitiesthrough biomarker driven clinical trials that include diverse patient populations. The disproportionate burdenof prostate cancer on African American men underlies key elements of each Aim which therefore depend inpart on the Community Outreach and Engagement (COE) functions of the Cancer Center. In additionProgram members rely heavily on Center collaborative and clinical trials structures and shared resources. +No NIH Category available Access to Information;Administrative Supplement;Award;Budgets;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Data;Clinical Protocols;Clinical Trials;Communication;Communities;Community Outreach;Contracts;Core Facility;Dana-Farber Cancer Institute;Data;Dedications;Dependence;Development;Education and Outreach;Ensure;Equity;Evaluation;Event;Funding;Funding Opportunities;Goals;Grant;Guidelines;Home;Informatics;Infrastructure;Institution;Institutional Review Boards;Leadership;Malignant Neoplasms;Manuals;Modeling;Monitor;Parents;Peer Review;Performance;Pilot Projects;Policies;Process;Protocols documentation;Publications;Reporting;Research;Resource Sharing;Resources;Safety;Services;Site;Strategic Planning;Structure;Surveys;System;Technology;Training;Training and Education;Work;active method;anticancer research;cancer health disparity;data management;member;news;operation;programs;satisfaction;service member;web site Administrative Core Project Narrative Not applicable. NCI 10768656 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7146 7907909 "GOFF, DEBORAH J" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 1538568 931614 606954 Project Summary/Abstract Not applicable. +No NIH Category available Acceleration;Advanced Malignant Neoplasm;Appointment;Awareness;Basic Science;Behavioral;Biological;Biology;Boston;Cancer Biology;Cancer Center;Cancer Etiology;Cancer Patient;Cancer health equity;Catchment Area;Cell Therapy;Clinic;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communities;Comprehensive Cancer Center;Dana-Farber Cancer Institute;Data Science;Development;Developmental Therapeutics Program;Diagnosis;Dreams;Early Diagnosis;Education;Educational Activities;Ensure;Environment;Equity;Faculty;Fostering;Funding;Future;Future Generations;General Hospitals;Genetic;Genetic Heterogeneity;Goals;Grant;Grooming;Health Sciences;Hospitals;Individual;Inequity;Infrastructure;Institution;Investigation;Israel;Laboratories;Laboratory Finding;Leadership;Learning;Lymphoma;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of prostate;Massachusetts;Medical center;Mentorship;Minority;Mission;Modeling;Molecular;Multiple Myeloma;Oncogenic;Outcome;Pathogenesis;Pathway interactions;Pediatric Hospitals;Phase;Phase III Clinical Trials;Population;Population Sciences;Prevention;Prevention strategy;Preventive;Primary Neoplasm;Public Health Schools;Renal carcinoma;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Risk Assessment;Risk Reduction;Schools;Science;Screening for cancer;Services;Societies;Specimen;Strategic Planning;Structure;Talents;Training;Training and Education;Transcend;Translational Research;Treatment outcome;Underserved Population;Universities;Woman;Work;anticancer research;base;bench-to-bedside translation;cancer care;cancer cell;cancer epidemiology;cancer genetics;cancer health disparity;cancer immunotherapy;cancer prevention;cancer risk;care delivery;clinical practice;community engagement;convict;disparity reduction;empowerment;first-in-human;high risk population;immune checkpoint blockade;improved;improved outcome;innovation;insight;inter-institutional;interdisciplinary approach;interdisciplinary collaboration;leukemia;malignant breast neoplasm;medical schools;melanoma;member;neuro-oncology;new technology;novel;novel strategies;novel therapeutics;operation;patient population;prevent;programs;synergism;therapy resistant;treatment strategy;tumor immunology Dana-Farber/Harvard Cancer Center OverallProject NarrativeThe primary goal of the Cancer Center is to promote collaborative interactions across seven consortiuminstitutions that will lead to new approaches to cancer prevention diagnosis and treatment. These advanceswill occur while also advancing the Centers mission to reduce disparities and to train future leaders in cancerresearch. NCI 10768654 11/22/23 0:00 PAR-20-043 5P30CA006516-59 5 P30 CA 6516 59 "PTAK, KRZYSZTOF" 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 1871771 "GLIMCHER, LAURIE HOLLIS" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 397 Research Centers 2024 11441846 NCI 7887346 3554500 OverallProject Summary / AbstractNow in its 22nd year of operation Dana-Farber/Harvard Cancer Center (DF/HCC) was the first consortiummodel NCI-designated Comprehensive Cancer Center. The consortium is comprised of 1100 members fromfive principal Harvard-affiliated hospitals and two Harvard health science schools: Beth Israel DeaconessMedical Center (BIDMC) Boston Childrens Hospital (BCH) Brigham and Womens Hospital (BWH) Dana-Farber Cancer Institute (DFCI) Harvard Medical School (HMS) Harvard T. H. Chan School of Public Health(HSPH) and Massachusetts General Hospital (MGH). Our overarching goals are to identify the geneticbiological environmental and behavioral bases of cancer and to develop effective strategies to reduce riskand improve preventive and treatment outcomes. Our catchment area is the Commonwealth of Massachusetts.Our steady progress over the last two decades has depended on the combined resources and talent at the 7institutions; the unique consortium structure that enables collaborative bench-to-bedside translational researchby population basic and clinical members; and well-coordinated Center leadership. DF/HCC embodies: 1) anintegrated structure that aspires to excellence in research and accelerates clinically effective discoveries 2) acohesive research community for cross-institutional and transdisciplinary collaborations and 3) a collectivelylarge patient population that expedites the conduct of innovative clinical trials. Our work occurs in 18 ResearchPrograms that cross scientific and institutional boundaries and span the gamut of population basic and clinicalcancer research; members excel in each sphere. Two entities a Center for Cancer Equity and Engagement(CCEE) and an Office for Cancer Research Education and Training (OCRET) help fulfill our responsibilities tothe catchment area and to train future leaders in cancer research. The Center supports 14 Shared Resourcesthat provide members with quality research services that cannot easily be duplicated in individual laboratoriesor institutions. A unified clinical research infrastructure serves all seven consortium institutions and makes itpossible for members to conduct innovative early-phase (proof-of-concept and Phase I/II) clinical trials acrossthe consortium. A portfolio of grants that transcend organizational and disciplinary boundaries (e.g. SPOREsProgram Projects SU2C Dream Teams) reflect our collective translational and collaborative ideals.Our next phase of work is guided by a multi-part Strategic Plan that emphasizes mechanistic understanding ofcancer early cancer detection equity new therapeutic avenues and a renewed commitment to education andmentorship. Underlying these goals are a culture and infrastructure streamlined for collaborative investigationof populations fundamental cellular and molecular mechanisms primary tumor specimens and the barriers toimproved cancer-related outcomes in all segments of society. 11441846 +No NIH Category available African American population;Appearance;B-Lymphocytes;BRCA1 gene;Breast;Breast Cancer Genetics;Breast conservation;Carcinoma;Cells;Chronology;Clonal Expansion;Collaborations;Data;Disease;Dissociation;Duct (organ) structure;Ecosystem;Endowment;Epithelial Cells;Event;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Predisposition to Disease;Genetic Transcription;Genetically Engineered Mouse;Genomics;Germ-Line Mutation;Gland;Goals;Heterogeneity;Human;Immune;Immune system;In Situ;In Situ Lesion;Individual;Intervention;Knock-out;Label;Lesion;Lymphoid Cell;Macrophage;Malignant Neoplasms;Mammary gland;Measures;Mediating;Methods;Mitosis;Molecular;Mus;Myeloid Cells;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Null Lymphocytes;Oncogenic;Organoids;Phenotype;Play;Premalignant Cell;Prevention;Preventive therapy;Prognosis;Puberty;Receptor Protein-Tyrosine Kinases;Role;Route;Signal Transduction;Somatic Mutation;Statistical Data Interpretation;Stress;T-Lymphocyte;TNF gene;TP53 gene;Testing;Tissues;Trees;Tumor Suppressor Proteins;Uncertainty;Variant;Visualization;Woman;Work;breast stem cell;breast tumorigenesis;cancer cell;cancer type;cell type;extracellular;functional loss;immune cell infiltrate;in vivo;innovation;lead candidate;malignant breast neoplasm;mammary;member;mosaic;mosaic analysis;mutant;neoplastic cell;novel;paracrine;pharmacologic;premalignant;progenitor;recruit;success;targeted treatment;tool;transcription factor;transcriptome;transcriptomics;tumor;tumor initiation;tumor progression;tumorigenesis A premalignant chronology of cell-state variability in basal-like breast cancer PROJECT NARRATIVEBasal-like breast cancer has the worst prognosis of all breast cancer types. One of the hurdles to identifyingeffective targeted therapies is the uncertainty about how the disease arises in the first place. By examiningcancer-prone tissues before tumor onset we hope to identify the path(s) that cells take en route to becoming abasal-like cancer. NCI 10768617 12/29/23 0:00 PA-20-185 5R01CA256199-03 5 R01 CA 256199 3 "KAI, MIHOKO" 1/1/22 0:00 12/31/26 0:00 Cancer Genetics Study Section[CG] 9677317 "JANES, KEVIN A" "ZONG, HUI " 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 589939 NCI 371472 218467 PROJECT SUMMARY/ABSTRACTBasal-like carcinoma is a rapidly-progressing and highly variable subtype of breast cancer that arisesspontaneously (often in African Americans) or in genetically predisposed women. Such tumors are believed toarise from the functional loss of the BRCA1 and TP53 tumor suppressors in uncommitted basoluminalprogenitors of the breast. However it has been challenging to dissect the origins of the disease for lack ofappropriate tools making it difficult to conceive of how the cell-state variability of premalignant mutants givesrise to basal-like breast cancer. The long-term goal of this work is to identify the critical cellular and moleculartransitions underlying basal-like breast cancer genetics. The current application deploys a novel geneticallyengineered mouse model called mosaic analysis of double markers (MADM) which randomly deletes murineBrca1Trp53 in transit-amplifying progenitors of the mammary gland. In MADM stochastic deletion isgenetically defined by coexpression of GFP allowing locally expanded premalignant lesions to be visualizedwithin the gland before the onset of basal-like disease. We found that premalignant expansion is accompaniedby extensive recruitment of specific immune subsets suggesting they play crucial roles in tumorigenesis. Ourobjective is to combine MADM with innovative methods for dissociation-free transcriptomics that will identifycell-state variabilities within mutant epithelial cells and the infiltrating immune lineages of a premalignancy.The hypothesis is that epithelial-cell plasticity and the stromal microenvironment coordinately diversify mutantlesions revealing premalignant transcriptional states that ultimately progress to basal-like cancer in the breastand mammary gland. The aims of the proposal are: 1) To define shared premalignant trajectories ofbasoluminal diversification triggered by BRCA1TP53 deficiency in mice and humans. 2) To deconvolve theimmune heterogeneities that are locally paired with specific premalignant ecosystems for basal-like breastcancer. 3) To functionally validate cell states important for progression by using genetic pharmacologic andparacrine perturbations that homogenize intrinsic or extrinsic variability of premalignant cells ex vivo. Co-PIsJanes and Zong are thought leaders in their respective fields of intratumor cell-state heterogeneity andgenetically engineered mouse modeling with a multi-year track record of collaboration. Together with a pair ofsenior clinicians the team is poised to have a significant overall impact on our understanding of basal-likebreast tumorigenesis. 589939 +No NIH Category available African American;African ancestry;American;Award;Biological;Cancer Etiology;Cessation of life;European;Funding;Genetic;Genetic Risk;Genomics;Goals;Incidence;Individual;Indolent;Investigation;Malignant neoplasm of prostate;Measures;Mediating;Mendelian randomization;Metabolic;Modeling;Parents;Phase;Population;Predictive Value;Preventive measure;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Research;Sampling;Screening for Prostate Cancer;Subgroup;Techniques;Training;anticancer research;cohort;genome wide association study;health disparity;high risk population;improved;men;metabolomics;mortality;multi-ethnic;novel;polygenic risk score;predictive modeling;prostate cancer model;prostate cancer risk;risk variant;screening;statistics Integrating Genomics and Metabolomics to Develop Predictive Models of Prostate Cancer in Multiethnic Men PROJECT NARRATIVEThis investigation is focused on identifying genetically regulated metabolomic factors that contribute to prostatecancer risk in men across multi-ancestry populations. Results from this research are expected to substantiallycontribute to our knowledge of the underlying genetic and metabolic mechanisms that contribute to prostatecancer risk and health disparities and improve predictive models of prostate cancer across populations. Thiswould improve our ability to detect high risk individuals who would benefit from earlier or more intensive screeningand provide novel biological mechanisms to target for preventative measures likely reducing prostate cancermortality and the number of indolent cases treated unnecessarily. NCI 10768434 9/20/23 0:00 PA-20-272 3R00CA246063-04S1 3 R00 CA 246063 4 S1 "DAEE, DANIELLE L" 2/1/20 0:00 6/30/25 0:00 ZCA1(O2) 14153859 "DARST, BURCU FRANCES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Non-SBIR/STTR 2023 87998 OD 49999 37999 PROJECT SUMMARY/ABSTRACT OF THE FUNDED PARENT AWARDProstate cancer (PCa) is the second leading cause of cancer death among American men with men of Africanancestry have the highest PCa incidence and mortality rates. While the causes of this notable health disparityare not fully understood growing evidence suggests that genetics is a contributing factor. However most PCaresearch has focused on men of European descent particularly genome-wide association studies (GWAS)which has resulted in polygenic models having poorer predictive value in non-Europeans. The overarching goalof this research is to identify genomic and metabolomic factors that contribute to PCa risk in men across multi-ancestry populations. In the R00 phase of this award Dr. Darst will initiate a new line of research that appliesintegrative techniques to investigate combined genomic and metabolomic factors influencing PCa risk. This willbuild directly upon the research and training received in the K99 period. She will identify genetically regulatedmetabolites that could be causally associated with PCa risk in multi-ancestry populations and/or indicatepotentially novel genetic risk loci (Aim 1). This will require developing a large multi-ancestry metabolomicimputation panel and performing two-sample Mendelian randomization for each metabolite and GWAS summarystatistics from the large and diverse PRACTICAL Consortium. Using a subset of 872 African American men fromthe Multiethnic Cohort (MEC) and the Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening TrialDr. Darst will investigate the biological mechanisms implicated by genetic risk of PCa as measured by a multi-ancestry polygenic risk score metabolites that could mediate the effects of genetic factors on overall andaggressive PCa and whether integrative techniques could be used to identify genomic and metabolomic factorsthat distinguish subgroups of individuals with high PCa risk (Aim 2). Results are expected to substantially improveour ability to detect high risk individuals who would benefit from earlier or more intensive PCa screening acrossmulti-ancestry populations and provide novel biological mechanisms to target for preventative measures likelyreducing PCa mortality and the number of indolent PCa cases treated unnecessarily. 87998 +No NIH Category available Cancer Biology;Training;Universities;programs Graduate Program in Cancer Biology Training at Emory University PROJECT NARRATIVEThis proposal is to support a unique program of predoctoral training in Cancer Biology at Emory University. Asuite of evidence-based learning approaches experienced research mentors and a unique ability to interactacross clinical and laboratory disciplines will enable the development of our Ph.D. level workforce in academicindustry and government-based research careers as well as other biomedical research-related careers toenhance understanding the biology of cancer and ultimately reach a cancer-free world. This proposal will ensureappropriate training in rigor and reproducibility methods to assessing student competencies and a focus oninclusive excellence to train a diverse cadre of Ph.D. scientists capable of cross-disciplinary communication. NCI 10768333 9/14/23 0:00 PA-20-142 1T32CA272392-01A1 1 T32 CA 272392 1 A1 "DAMICO, MARK W" 9/15/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9239753 "LESINSKI, GREGORY B." "KANG, SUMIN " 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 214374 NCI 203976 10398 PROJECT SUMMARYCancer represents a collection of diseases that remains the second leading cause of death in the United States.However several recent advances in cross-disciplinary research have improved patient outcomes and provideda tremendous opportunity for continued progress. In order to further the innovation and clinical impact of researchdiscoveries a Ph.D. workforce with broad conceptual knowledge across the field of cancer biology research isrequired. To ensure successful careers Ph.D. scientists need an acute awareness of rapidly evolvingtechnological approaches used in cancer biology research deep knowledge of specific areas and criticalthinking skills. To address the need for well-trained diverse cross-disciplinary Ph.D. scientists entering theworkforce we propose the Graduate Program in Cancer Biology Training at Emory University. This Programwill provide an exceptional interdisciplinary training program that is above and beyond Ph.D. programs at Emorywith opportunities for basic and translational research focused on cancer biology. It will be highly integratedwithin the environment at the Winship Cancer Institute the NCI-designated Comprehensive Cancer Center. Asuite of evidence-based learning approaches experienced research mentors focused on cancer in various Ph.D.Programs and unique ability to interact across clinical and laboratory disciplines will enable the development ofour trainees' success in academic- industry- and government-based research careers. The objective of thisProgram is to provide a diverse population of predoctoral students with effective training that culminates in 1)Ph.D. scientists with broad conceptual knowledge who are trained to think critically effectively and communicatetheir findings; 2) A Ph.D. workforce aware of how to conduct responsible rigorous and reproducible scientificstudies; and 3) A Ph.D. workforce with training in cross-disciplinary communication and exposure to clinicalapplication of research findings. To achieve this goal we will use a core curriculum that includes discussion-based active learning approaches to fundamental principles of cancer biology and the development ofpresentation skills through didactic classroom and seminar experiences. The importance of rigor andreproducibility in cancer research is emphasized during all phases of the training for both students and mentorswith a required course emphasizing this training as part of the courses seminars and journal clubs. This programwill have an environment focused on inclusive excellence to ensure the recruitment and retention of studentsfrom diverse and underrepresented backgrounds. Finally Ph.D. trainees will have unique training opportunitiesincluding the responsibility to organize and execute symposiums seminars rigorous training in ethical aspectsof research and ample opportunity for close interaction with clinical and research trainees undergoing post-doctoral fellowship training to invigorate communication-related to translational relevance in cancer. 214374 +No NIH Category available Adult;Advocate;Affect;Area;Authorization documentation;Behavioral Research;COVID-19;Cancer Patient;Cancer Survivor;Cigarette;Clinical;Clinical Research;Clinical Trials;Cohort Studies;Comprehensive Cancer Center;Data;Data Collection;Development;Diagnosis;Electronic Nicotine Delivery Systems;Electronic cigarette;Environment;Epidemiologist;Excision;Fostering;Funding;Future;General Population;Goals;Guidelines;Head Cancer;Health;Health Benefit;Institution;Interruption;Intervention;Intervention Studies;Investigation;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Measures;Mentors;Metabolism;National Comprehensive Cancer Network;Neck Cancer;Observational Study;Ohio;Operative Surgical Procedures;Outcome;Patient Recruitments;Patients;Perioperative complication;Policies;Population;Positioning Attribute;Professional Organizations;Public Health;Quality of life;Quasi-experiment;Reporting;Request for Proposals;Research;Research Activity;Research Design;Research Methodology;Research Personnel;Research Project Grants;Safety;Sample Size;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Surgeon;Surgical complication;Symptoms;Tobacco;Tobacco-Related Carcinoma;Toxic effect;Training;Treatment-related toxicity;United States;United States Food and Drug Administration;Universities;authority;cancer epidemiology;cancer survival;career development;chemotherapy;cigarette smoking;cohort;combustible cigarette;coronavirus disease;design;editorial;electronic cigarette use;evidence base;experience;exposure to cigarette smoke;follow-up;hospital utilization;improved;member;novel;patient population;randomized trial;response;safety assessment;skills;smoking cessation;sound;standard of care;symptomatology;tobacco control;tobacco products;tobacco regulatory science;tool;treatment as usual;treatment guidelines Electronic cigarette use in lung cancer patients PROJECT NARRATIVEElectronic cigarettes are increasingly used in cancer patients and despite marketing that suggests a healthbenefit almost no data exist to corroborate such claims. This K07 will provide strong career developmenttraining in tobacco control intervention study design and analysis and primary data collection through didacticcoursework and hands-on experiences. This training will support the implementation analysis andinterpretation of the proposed research aims of examining in head neck and lung cancer patients theassociations of electronic cigarette use with combustible cigarette smoking reduction and cessation as well asfor quality of life and treatment toxicities using complementary study designs and shared assessmentmeasures. NCI 10768042 5/5/23 0:00 PA-20-272 3K07CA215546-05S1 3 K07 CA 215546 5 S1 "BIAN, YANSONG" 2/1/23 0:00 1/31/24 0:00 10526564 "BRASKY, THEODORE M." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 398 Other Research-Related 2023 186616 NCI 172793 13823 TITLE: Electronic Cigarette Use in Head Neck and Lung Cancer PatientsPROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to facilitate Dr. Theodore Braskys development into an established andindependent investigator for tobacco control. For this research he will focus on cancer patients and the impactof electronic cigarettes (e-cigs) on cigarette smoking quitting and health outcomes. It is established thatcigarette smoking adversely affects the cancer patient in many ways. E-cigs have the potential to reducecigarette smoke exposures related toxicities and foster smoking cessation. However almost no researchexists to substantiate this hypothesis. Dr. Brasky is a cancer epidemiologist and member of the Ohio StateUniversity Comprehensive Cancer Center (OSUCCC) with considerable expertise in the analysis andinterpretation of longitudinal data. Due to a strong institutional environment he has been participating invarious tobacco-focused research projects over the past several years. Excited by this he wants to takeadvantage of the extraordinary opportunities in tobacco control related to e-cigs. The proposed training planwill enable him to obtain expertise and experience in tobacco research (e.g. coursework in tobacco regulatoryscience) intervention studies (e.g. coursework in clinical research methods and translational behavioralresearch) and primary data collection in complementary studies. This training will capitalize on the exceptionalinstitutional environment at OSU and an experienced mentor in tobacco control in Dr. Peter Shields DeputyDirector of the OSUCCC. Herein Dr. Brasky will address critical research gaps that will aid in theunderstanding for the impact of e-cigs on the cancer patient generally and specifically for the creation of soundpolicy decisions by the Food and Drug Administration. This proposal requests a funded extension to completeDr. Braskys research goals due to significant COVID-19 related interruptions. The Specific Aims are to: 1)analyze an observational cohort of 184 head neck and lung cancer patients and examine the associations ofe-cigs with smoking reduction smoking cessation quality of life and treatment toxicities; and 2) Evaluatefeasibility acceptability compliance and safety of a pilot patient-choice trial of a pod-based e-cig versusstandard of care in 40 head neck and lung cancer patients planning to undergo surgical resection. Thesecomplementary studies will be among the first to examine associations in patients with tobacco-related cancersand will share assessment measures. Results from this research will yield critical data in order to providesound and evidence-based decisions on e-cigs. 186616 +No NIH Category available Administrator;Anatomy;Blood;Budgets;Cancer Center Support Grant;Cells;ChIP-seq;Clinical;Clinical Data;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Collection;Consent;Databases;Dissociation;Ensure;Event;Faculty;Fresh Tissue;Future;Goals;Guidelines;Hospitals;Improve Access;Infrastructure;Institution;Leadership;Maintenance;Malignant Neoplasms;Methodology;Noise;Nucleic Acids;Operative Surgical Procedures;Pathologist;Pathology;Patients;Physician Executives;Plasma;Policies;Process;Protocols documentation;Research;Research Personnel;Resource Sharing;Resources;Sampling;Science;Services;Signal Transduction;Sister;Source;Specialist;Specimen;Speed;Strategic Planning;Surgical Pathology;Technology;Tissue Banks;Tissue Procurements;Tissues;Translational Research;Work;anticancer research;cost;data management;demographics;experience;experimental study;meetings;member;next generation;peer;programs;single cell sequencing;tissue processing;virtual Tissue Procurement Facility & Biospecimen n/a NCI 10767942 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6925 1875926 "KIM, HONG JIN " Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 308562 198432 110130 ABSTRACT: TISSUE PROCUREMENT FACILITY SHARED RESOURCEThe Tissue Procurement Facility (TPF) is the main conduit for access to protocol driven tissue-based research.As part of the 2019 strategic plan this SR was expanded and reorganized to provide additional services andwith a more robust pipeline for faculty conducting this type of clinical research. The expansion of this resourceled to enhanced services including: More timely fresh tissue collection. TPF has developed a pipeline to collect fresh tissue for next-generation research focusing on single-cell and chip sequencing. The fresh tissue infrastructure requires significant collaboration between Surgical Pathology Anatomic Pathology TPF and Clinical Protocol and Data Management (CPDM). For scRNA sequencing TPF has added an additional workflow to facilitate thismethodology. Tissue dissociation. TPF is equipped for single-cell dissociation to process tissue to single-cell for investigators that do not have the technology to do so and/or are investigating more robust experiments. Ultrapure plasma processing. Ultra highspeed plasma purification for downstream cfDNA analysis. Ultrapure plasma will produce a significantly cleaner signal-to-noise ratio for investigators looking at cfDNA.TPFis led by an experienced faculty and staff. Dr. Calhoun is Director of Surgical Pathology and AnatomicalPathology at UNC and serves as Pathology Director. He works closely with the surgical liaison co-leader HJKim to ensure responsible policies are in place for the procurement of research specimens following guidelinesestablished by the UNC Hospitals. Amy Garratt serves as the Facility Director for the SR and its translationalconsenting and collection component. This is a well-managed resource with an operating budget of $1.0M.TPF requests $229718 (21% of the total) for fiscal year 2020. LCCC members were more than 66% of theusers in fiscal year 2019 virtually all other users were performing cancer research. The Facility procured anddistributed 46091 specimens to support 154 different investigator-initiated studies. +No NIH Category available Appointment;Area;Basic Science;Big Data;Biometry;Biostatistics Shared Resource;Budgets;Cancer Center;Cancer Center Support Grant;Caregivers;Clinic;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Design;Computational Biology;Consultations;DNA Repair;Data;Data Analyses;Data Set;Detection;Dose;Evaluation;Experimental Designs;Faculty;Funding;Gene Expression;Generations;Genetic;Genomics;Grant;Growth;Heart Atrium;Human Resources;Image;Institution;International;Joints;Manuscripts;Maps;Methods;Methylation;Monitor;Patients;Population Sciences;Preparation;Process;Protocols documentation;Psychometrics;Public Health Schools;Publications;Reading;Research;Research Design;Research Personnel;Review Committee;Safety;Sample Size;Sampling;Science;Services;Signal Transduction;Source;Statistical Data Interpretation;Statistical Models;Students;Symptoms;System;Training;Translational Research;Universities;Walking;Work;Writing;circadian;cost;deep learning;design;experience;genomic predictors;graduate student;high dimensionality;innovation;malignant breast neoplasm;member;method development;novel;peer;procedure safety;programs;randomized clinical trials;senior faculty;skills;transcriptome sequencing;tumor;virtual Biostatistics n/a NCI 10767940 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6923 1901879 "IBRAHIM, JOSEPH G" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 321454 206723 114731 ABSTRACT: BIOSTATISTICS SHARED RESOURCEThe Biostatistics Shared Resource (BIOS) provides access for LCCC faculty across the basic clinicaltranslational and population science spectrum to an experienced staff and recognized national leaders instatistical modeling and analysis. The Centers breadth of science requires a broad range of expertiseavailable in BIOS and includes for example: population sciences psychometric analysis clinical trial designand analysis basic experimental science as well as big data omics. This range requires a core that can beaccessed by virtually all members on the front end for experimental design from small undertakings to largetrials. Access is encouraged through a weekly walk in clinic centrally located in the Lineberger atrium wherefaculty and students at all levels can discuss projects at their inception. The masters and doctoral level full timeBIOS SR staff operate this clinic and there is also a traditional appointment system for researchers withdefined problems. This team is supported by senior biostatisticians with a wide range of expertise from theSchool of Public Healths internationally recognized Biostatistics Department. These leaders also serve on theProtocol Review Committee and the Data and Safety Monitoring Committee. Senior faculty are fully engaged inLCCC research as collaborators and researchers in methods for example in the Biostatistics PO1 in clinicaltrials methods development. In addition both staff and faculty encourage the participation of graduate studentswho have the opportunity to engage faculty and peers in statistical review as part of their own training underthe guidance of the senior faculty-level statisticians. This facility is a LCCC exclusive SR and was well used byover 100 faculty in fiscal year 2019. BIOS requests $239374 which is approximately 20% of the totaloperating costs for this highly subsidized facility sustained by an annual LCCC contribution of ~$1M BIOS hasbeen a key partner in multiple grants and publications over the prior five years from Dr Rashids analysis ofNobel Laureate Aziz Sancars work on circadian timing of DNA repair processes to Dr Tans design for DrSongs project in caregivers management of patient symptoms. +No NIH Category available Accelerometer;Area;Award;Behavior Therapy;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Control Research;Caring;Clinical;Clinical Trials;Common Terminology Criteria for Adverse Events;Complex;Computer software;Consultations;Continuity of Patient Care;Contracts;Data;Data Analyses;Development;Explosion;Faculty;Foundations;Grant;Health Policy;Health behavior;Hospitals;Institution;Intervention;K-Series Research Career Programs;Leadership;Location;Malignant Neoplasms;Measures;Methodology;Methods;Oncology;Opioid;Outcomes Research;Participant;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Personal Satisfaction;Postoperative Period;Quality of Care;Quality of life;Registries;Research;Research Design;Research Institute;Research Personnel;Resource Sharing;Resources;Site;Source;Surveys;Symptoms;System;Treatment outcome;United States National Institutes of Health;Universities;Validation;Vertebral column;anticancer research;behavioral study;clinical care;comparative effectiveness;design;electronic data;fitbit;flexibility;health management;implementation evaluation;innovation;interest;malignant breast neoplasm;member;mid-career faculty;multi-site trial;neoplasm resource;novel therapeutics;peer;research study;response;skills;study population;tool;trend PRO-Core n/a NCI 10767922 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6916 10534616 "BENNETT, ANTONIA " Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 148996 95817 53179 ABSTRACT: PATIENT REPORTED OUTCOMES-CORE SHARED RESOURCEThe Patient Reported Outcomes-Core Shared Resource (PRO-core) was developed in response to a growingnumber of cancer center investigators who require methodological consulting related to survey developmentuse and analysis as well as use of a customizable electronic data capture tool for collecting informationdirectly from patients and other stakeholders. PRO Core provides a software platform and scientificconsultation to investigators conducting PRO research. This includes clinical trials of new drugs interventionswith symptom and quality of life endpoints and studies of the integration of PRO assessment into clinical care.Dr. Bennett is the faculty director and an Associate Professor of Health Policy and Management. Shecontributed as an investigator to the development and validation of the NCI Patient-Reported Outcomesversion of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). In fiscal year 2019 the SRwas used by 27 faculty 67% of whom were LCCC members. Importantly the SR supports highly sophisticatedmethodology and is a national leader in Patient Reported Outcomes. These skills and methods allow the SR tosupport external cancer collaborators at multi-site trial locations such as Duke Cancer Institute EmoryUniversity Georgetown and Moffit. PRO is requesting $111249 for this SR which is approximately 39% of itsfiscal year 2020 Operating budget. PRO Core has been a successful SR as demonstrated by the following metrics. PRO Core studies aresupported by 11 NIH grants (5 from NCI including 1 K award) and 3 Patient-Centered Outcomes ResearchInstitute (PCORI) contracts. Studies are also supported by Genentech the Breast Cancer ResearchFoundation and pilot awards from the Alliance for Clinical Trials in Oncology cooperative group. PRO Core issupporting a growing portfolio of: 1) studies evaluating the implementation of PRO assessment in oncologycare and 2) studies collecting both PRO data and wearable / activity tracker (e.g. Garmin Fitbit) data. PROCore has developed technical capability and expertise in these areas and the LCCC is now known forsubstantial scientific leadership in these two areas. In addition PRO Core is supporting studies that evaluatethe comparative effectiveness of new treatments and a new registry that tracks opioid need and use amongpost-operative patients. +No NIH Category available Basic Science;Bioinformatics;Biological Assay;Biological Sciences;Budgets;Cancer Center Support Grant;Cancer Research Project;Cell physiology;Center for Translational Science Activities;Clinical;Clinical Pathways;Clinical Trials;Collaborations;Complement;Computer Analysis;Consultations;DNA Resequencing;Data;Detection;Education;Environment;Equipment;Faculty;Future;Generations;Genome;Genomics;Genomics Shared Resource;Genotype;Glean;Heritability;Infrastructure;Institution;Intake;Investments;Knowledge;Laboratories;Malignant Neoplasms;Maps;Molecular;Molecular Epidemiology;Molecular Genetics;National Clinical Trials Network;North Carolina;Pathologist;Patient Care;Patients;Population Study;Precision Medicine Initiative;Preparation;Primary Neoplasm;Process;Production;Protocols documentation;Publications;RNA;RNA interference screen;Records;Repetitive Sequence;Reproducibility;Research;Research Personnel;Sampling;Services;Source;Specimen;System;Technical Expertise;Technology;Tennessee;Testing;The Cancer Genome Atlas;Universities;Validation;Variant;cancer genetics;cancer genomics;cancer predisposition;cancer type;clinical translation;computer infrastructure;data sharing;design;digital;epidemiology study;experience;genome sequencing;instrumentation;malignant breast neoplasm;member;nano-string;nanopore;next generation;peer;public database;technology platform;transcriptome;transcriptome sequencing;transcriptomics;translational cancer research;translational genomics;translational study;treatment arm;tumor;whole genome Sequencing and Genomics n/a NCI 10767918 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6914 8579946 "JONES, CORBIN D" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 261956 168461 93495 ABSTRACT: SEQUENCING AND GENOMICS SHARED RESOURCESequencing and Genomics (SEQ) provides an integrated platform of technology expertise education andinfrastructure to create an accessible environment for LCCC researchers to undertake cutting-edge genomicsprojects. The Core specializes in six major technologies: Next Generation short-read sequencing (Illumina)long-read sequencing and genomic mapping (Oxford Nanopore Technologies BioNano Inc.) NanoStringdigital RNA quantification Affymetrix microarrays Illumina bead array genotyping and RNAi screening forfunctional validation. Through reciprocity with North Carolina State University the SR also has access to thePacific Biosciences Sequel system. These are complemented by LCCC investments in computationalinfrastructure and analysis. Over the past five years LCCC has integrated two new units in partnership withTPF and CPDM to compliment SEQ specifically to facilitate translational cancer genomics to seamlesslysupport the coordination project management and tracking necessary to perform genomics studies on patientsamples from protocol-driven trials. In addition the Translational Genomics Laboratory (TGL) focuses solely oncancer sample preparation for downstream sequencing NanoString analysis or other molecular testing. Thislaboratory uses automated instrumentation and stable protocols optimized for limited input and degradedcancer specimens collected from clinical trials and translational studies. TGL initiates a pathway for clinicalgenomics projects through SEQ and subsequent analysis by the bioinformatics SR (BIOIN).SEQ SR requests $195591 3% of the total fiscal year 2019 budget. LCCC faculty were 43% of fiscal year2020 users. During the past five years SEQ supported the LCCC investigators involved in TCGA. This projectoversaw the molecular characterization of over 20000 primary tumor and matched normal samples across 33cancer types. Within the next year SEQ will acquire an ONT PromethION 24 system which uses a high-capacity long-read sequencing technology capable of high production whole genome sequencing andtranscriptomics. This technology allows for efficient resequencing of whole genomes including repetitiveelements structural variation and other problematic regions of the genome. ONT sequencing providesreproducible detection of small medium and large size structural variations and in the near future thedetection of 5mC. +No NIH Category available Advanced Malignant Neoplasm;Affinity;Budgets;Cancer Biology;Cancer Center Support Grant;Capital;Cells;Clinical;Clinical Trials;Collaborations;Consultations;Data;Data Analyses;Development;Drug Targeting;Epitopes;Equipment;Experimental Designs;Faculty;Fractionation;Funding;Gene Expression;High Pressure Liquid Chromatography;Individual;Informatics;Infrastructure;Institution;Investments;Kinetics;Label;Laboratories;Maintenance;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Metabolism;Methods;Modification;Pathway interactions;Phosphotransferases;Postdoctoral Fellow;Preparation;Privatization;Protein Analysis;Proteins;Proteome;Proteomics;Proteomics Shared Resource;Recombinant Antibody;Regulation;Research;Research Personnel;Resolution;Resource Sharing;Sampling;Services;Signal Transduction;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Students;Techniques;Technology;Therapeutic;Training and Education;anti-tumor immune response;anticancer research;cancer immunotherapy;cell transformation;chemoproteomics;chimeric antigen receptor T cells;cost;cost effective;data acquisition;discount;experience;innovation;insight;instrument;instrumentation;mass spectrometer;member;novel;novel therapeutic intervention;peer;protein complex;protein degradation;protein protein interaction;response;small molecule;student training;training opportunity;tumor progression Proteomics n/a NCI 10767901 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6906 1893668 "GRAVES, LEE M" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 181209 116533 64676 ABSTRACT: PROTEOMICS SHARED RESOURCEThe Proteomics SR (PROT) is a state-of-the-art facility that brings cutting edge proteomics research to LCCCfaculty. It is a well-established shared resource (SR) that provides consultation for the design of experimentssample preparation mass spectrometry (MS) and extensive data analysis for LCCC members. Directed by anexpert staff the SR is full service allowing users with projects but little experience to understand the range ofdata acquisition opportunities. The SR also has the instrumentation that allows more experienced users accessto expensive well maintained mass spectrometers. Core staff and expert users have extended the capabilitieswith innovative techniques such as the MIB/MS analysis of cell wide kinase activity. Contributions includevalidating and characterizing cancer-relevant drug targets quantifying proteome and signaling networkchanges in response to emerging therapeutics studying the dynamic regulation of the kinome describing howspecific pathways globally remodel cancer proteomes independent of changes in gene expression anddetermining how protein interaction networks are dysregulated in cancer.Instrumentation includes; state-of-the-art mass spectrometers include: Thermo Lumos Thermo QExactive HF-X Thermo QExactive Biopharma Thermo QExactive HF Thermo Orbitrap Velos and Sciex 5800MALDI/TOF/TOF. All were partially purchased or leased by LCCC including four within the last four years. Thepurchase and maintenance of the current PROT SR instruments are beyond the means of any individual lab.LCCC investments have made it possible for multiple labs to access high end technology. The cost of PROTSR services are generally lower by 25% than comparable private company or other academic institutions andLCCC members receive an additional discount making the facility quite cost effective. The LCCC is requesting$135301 from the CCSG which represents 21% of the total operating budget; 48% of the SR usage is byLCCC faculty. +No NIH Category available Animal Cancer Model;Animals;Area;Benchmarking;Budgets;Cancer Center;Cancer Center Support Grant;Cells;Charge;Confocal Microscopy;Core Facility;Cost Sharing;Drug Screening;Equipment;Faculty;Funding;Geography;Grant;Hour;Human Resources;Image;Image Analysis;In Situ;Institution;Investments;Journals;Laboratories;Leadership;Light;Maintenance;Malignant Neoplasms;Medicine;Microscope;Microscopy;Modality;Modeling;Modernization;Molecular;Nature;Needs Assessment;Organ;Peer Review;Publishing;Research Personnel;Resource Sharing;Resources;Services;Source;Stromal Cells;Students;System;Talents;Time;Tissue imaging;Tissues;Training Activity;Visual;Visualization;Work;anticancer research;cancer therapy;confocal imaging;cost;cost effective;cost effectiveness;experience;imaging modality;instrument;instrumentation;intravital imaging;light microscopy;live cell imaging;medical schools;member;multi-photon;new technology;peer;programs;response;screening;spectrograph;tumor;ultra high resolution Microscopy n/a NCI 10767897 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6904 1922923 "BEAR, JAMES E" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 191465 123129 68336 ABSTRACT: MICROSCOPY SHARED RESOURCEThe Microscopy Shared Resource (MICRO) combines two outstanding microscopy resources the MicroscopyServices Laboratory (MSL) and the Hooker Imaging Core (HIC). The MSL provides confocal imagingincluding spectral imaging spinning disk confocal standard wide-field imaging on both upright and invertedmicroscopes and light-sheet microscopy. The HIC provides confocal imaging on both inverted and uprightmicroscopes wide-field imaging and high-content imaging for visual drug screens. HIC also houses a multi-photon system for intravital imaging of tissues and organs at cellular scale within a living animal with the optionof re-imaging the same animal over time. Dr. James Bear (CCB program co-leader) oversees the SR asfaculty director and provides broad scientific direction. Dr. Pablo Ariel facility director brings experience inlive-cell imaging image analysis tissue clearing and light-sheet microscopy. He has 10 years of directexperience in imaging using multiple modalities (widefield confocal multiphoton super resolution light-sheet)in multiple subject areas. This is a cost-effective service to the members of LCCC. A useful benchmark forcomparing microscopy recharge rates is confocal microscopy use ranges from $16 to $32 per hour dependingon the specific model at the LCCC MICRO SR. Access to similar equipment at peer institutions ranges from~$30 to $50 per hour demonstrating the cost effectiveness of our SR. MICRO SR requests $142766 for thisfacility 21% of the total operating budget. MICRO is a well-established SR with use by 59 LCCC members ineight programs making up approximately 34% of overall users. +No NIH Category available Acceleration;Benchmarking;Biometry;Budgets;Cancer Center Support Grant;Charge;Complement;Comprehensive Cancer Center;Data;Ensure;Equipment;Faculty;Feedback;Fees;Funding;Human Resources;Individual;Infrastructure;Institution;Investments;Leadership;Maps;Pathology;Police;Process;Recording of previous events;Reproducibility;Research;Resource Sharing;Resources;Respondent;Schools;Science;Services;Source;Strategic Planning;Surveys;Technology;Tissues;Training;Training and Education;Work;biomedical resource;cost effective;equipment acquisition;experience;innovation;instrumentation;medical schools;meetings;member;new technology;operation;peer;programs;recruit;single cell analysis;statistics;technique development;tool;training opportunity Shared Resource Management n/a NCI 10767881 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6894 11642136 "DARR, DAVID " Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 95161 61196 33965 ABSTRACT: SHARED RESOURCE MANAGEMENTThe Lineberger Comprehensive Cancer Center has a strong history of providing high quality and cost-effectiveshared resources that offer innovative services and technologies to the membership. The oversight of the SRsinvolves the Director Deputy Director and Associate Directors of the Center. Program leaders also providevaluable input and guidance on the services offered. Center members provide feedback through surveys andserve on SR active internal advisory boards for each SR. Over the last five years this management processhas provided substantial new infrastructure for the faculty including: 1) an expanded and more robust tissue-based research pipeline for correlative work 2) new technologies such as single cell analysis mass speccytometer instrumentation and a CyroEM 3) expanded faculty SR leadership expertise in pathology andbiostatistics. The financial and administrative oversight is provided by the Associate Director of Administrationand his staff of 4 FTEs devoted to this endeavor. The SRs are well managed and are well used asdemonstrated by these statistics: 97% of 2018 user-survey respondents stated the SR overall experience was excellent or good. 81% of LCCC Members used a Shared Resource in FY19 82% of FY19 total LCCC managed-Shared Resource users were Center facultyImportantly the SRs are cost-effective and provide exceptional value to the members. The Center requests8% of the operating budget for the SRs from the CCSG. This is greatly leveraged through a sustained annualinstitutional commitment of over $10M in operational support 37% of the total SR operating budget. Theremaining SR operating budget approximately $14.3M is recovered by recharge mechanisms. As a result ofthe CCSG and institutional commitment members receive discounts on fees priority access and freeconsultative services. +No NIH Category available Adherence;Administrator;Association of American Cancer Institutes;Attention;Budgets;Cancer Center;Cancer Center Support Grant;Catchment Area;Center for Translational Science Activities;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;Contracts;Data;Dedications;Development;Discipline;Disease;Economically Deprived Population;Enrollment;Ensure;Equity;Faculty;Fostering;Frequencies;Funding;Future;Genomics;Image;Immunotherapy;Industry;Institutional Review Boards;Intervention;Intervention Trial;Knowledge;Leadership;Link;Longevity;Minority;Minority Health Research;Minority Recruitment;Mission;Monitor;Monitoring Clinical Trials;Multicenter Trials;National Clinical Trials Network;North Carolina;Observational Study;Patients;Performance;Phase;Physician Executives;Prevention;Preventive;Protocols documentation;Quality Control;Regulatory Affairs;Reporting;Research;Research Design;Research Personnel;Research Training;Resources;Retrieval;Review Committee;Risk;Safety;Science;Services;Site;Specialist;Time;Training;UNC Lineberger Comprehensive Cancer Center;Underserved Population;Woman;Work;Writing;cancer clinical trial;clinical development;clinical trial enrollment;community engagement;data management;design;drug development;ethnic minority;faculty mentor;improved;innovation;member;minority health disparity;novel;novel therapeutics;operation;participant enrollment;patient engagement;programs;protocol development;racial minority;socioeconomic disadvantage;treatment trial Clinical Protocoal and Data Management n/a NCI 10767864 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6885 12557327 "LEE, CARRIE B" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 765997 492603 273394 ABSTRACT: CLINICAL PROTOCOL AND DATA MANAGEMENTThe Clinical Protocol and Data Management (CPDM) component includes the Clinical Protocol Office (CPO)and the compliance committees (Compliance Data and Safety Monitoring). These groups provide centralizedmanagement and oversight for cancer clinical trials conducted by UNC Lineberger Comprehensive CancerCenter (LCCC) members. The CPDM delivers a full range of management and quality control services forinvestigator-initiated local and multi-center trials (IITs) industry or other sponsored trials as well as thoseoriginating in the NCI such as the National Clinical Trials Network groups. CPDM centralizes the protocolregistration regulatory affairs compliance committee work and management of clinical trials facilitatesefficient and effective training for research personnel and monitors timely activation of protocols in support ofLCCC investigators from all relevant disciplines. IIT development is facilitated by our Clinical DevelopmentTeam made up of dedicated specialists. Carrie Lee MD MPH serves as Medical Director of the CPO ClaireDees MD ScM is the Faculty Director of the Clinical Development Team and Matt Milowsky MD chairs theClinical Trials Executive Committee composed of the disease-specific Protocol Office Disease (POD) facultyand other leaders. In 2019 interventional trials accrued 2799 patients including 733 accrued to treatment trials.Observational studies enrolled 656 patients and 514 enrolled on ancillary/correlative trials. LCCC clinical trialsenroll patients from the entire state of North Carolina our catchment area.A unique feature of LCCCs CPDM is the Clinical Development Team that assists investigators developing IITsin study concept development and design funding applications protocol writing and adherence to regulatoryrequirements including IND support and management of FDA communications. With this team over the past 5years we have increased our IITs by 30% and nearly doubled our LCCC-held INDs to 42. Trial review isfacilitated by our PODs endorsed trials undergo review by the Resource and Feasibility Team (RAFT) toensure appropriate staffing and resources then review by the Protocol Review Committee (PRC).Budget andcontract development occur in parallel so that IRB review and contract execution can be as close as possible.The LCCC Data and Safety Monitoring Committee meets monthly to review trials with the frequency of reviewbased on risk and complexity as determined by the LCCC PRC. The CPDM supports independent audits of ourIITs conducted by an external entity the UNC Office of Clinical Trials (OCT). The Compliance Committeemeets monthly to review audit findings and corrective and preventive action (CAPA) plans.UNC LCCC conducts research on minority health disparities and seeks new ways to optimize trials acrossunderserved groups and the lifespan. Dr. Charlot the CPDM faculty advisor for minority accrual is activatingplans to improve clinical trial participation of racial/ethnic minorities and socioeconomically disadvantagedpopulations creating a valuable link between CPDM and COE. +No NIH Category available Advisory Committees;Area;Arts;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Survivor;Caregivers;Catchment Area;Cell Therapy;Clinical Research;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Data;Decision Making;Disease;Education;Ensure;Epigenetic Process;Ethnic Origin;Evaluation;Exhibits;Faculty;Faith-based organization;Funding;Geography;Group Meetings;Healthcare Systems;Hospitals;Immunotherapy;Inflammation;Infrastructure;Institution;Investments;Leadership;Malignant Neoplasms;Methods;Minority;Mission;North Carolina;Obesity;Pharmacy facility;Population Sciences;Population Study;Postdoctoral Fellow;Preparation;Prevention Research;Process;Public Health;Race;Reporting;Research;Research Priority;Resource Development;Resource Sharing;Resources;Risk Factors;Rural;Schools;Science;Scientist;Strategic Planning;Structure;Teacher Professional Development;Technology;Training;Translational Research;Underrepresented Minority;Universities;Workforce Development;anticancer research;cancer care;career;cohort;college;community college;community engagement;cost efficient;falls;high school;improved;medical schools;meetings;member;minority disparity;population based;programs;recruit;research and development;rural area;technology development;undergraduate student;urban area;urban disparity;working group Planning and Evaluation n/a NCI 10767857 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6882 6477317 "EARP, HENRY SHELTON" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 516845 332375 184470 ABSTRACT: PLANNING AND EVALUATIONThe LCCC internal and external advisory groups provided invaluable guidance in planning and evaluation of allthe major initiatives and includes: The Senior Leadership Team which is composed of the Director Deputy Director and Associate Directors and meets weekly to evaluate progress in strategic LCCC initiatives. The Program Planning Committee which meets monthly to evaluate progress of all important initiatives and includes institutional and Research Program Leaders as well as the Senior Leadership Team. The Internal Advisory Board comprised of institutional leaders including the Chancellor; Dean of the College of Arts and Sciences Deans of the Schools of Medicine Pharmacy and Public Health and external advisors and meets with the Director at least quarterly. The Scientific Advisory Board (SAB) which is comprised of expert external advisors and which was expanded with the addition of two new members in 2018/19 to provide additional expertise in specific areas such as community outreach and engagement and clinical trials. There are now 14 members on the SAB with complementary expertise in basic clinical translational and population sciences and administration. The SAB meets at least annually at the UNC LCCC. The Community Advisory Board (CAB) the 12 membered CAB meets quarterly with the Director and COE Leadership. The CAB is geographically racially and ethnically representative of our catchment area (the state of North Carolina) and offers a variety of important perspectives and constituencies including cancer survivors and caregivers community and faith-based organizations rural and urban areas state and non-profit agencies and under-represented minorities.These coordinated teams of advisors provide critical advice and guidance both annually in the fall and ad-hocas required ensuring that LCCC most effectively set priorities and pursues objectives that promote basicclinical prevention and translational research at the Center. With careful planning and critical input fromadvisory groups the Director initiated a new 5 year strategic planning process reorganized operatingcommittees continued significant recruitment launched new population-based studies strengthenedcommunity outreach efforts and expanded immunotherapy and GMP infrastructure. +No NIH Category available Address;Area;Attention;Authorization documentation;Award;Basic Science;Budgets;Cancer Center Support Grant;Catchment Area;Categories;Centers of Research Excellence;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Development;Discipline;Disease;Education;Educational Status;Expenditure;Extramural Activities;Faculty;Faculty Recruitment;Funding;Future;Grant;Growth;Guidelines;Institution;Interdisciplinary Study;Investments;Link;Malignant Neoplasms;Measures;Methodology;Mission;North Carolina;Pilot Projects;Population;Population Sciences;Population Study;Process;Publications;Quality of Care;Research;Research Priority;Resource Sharing;Resources;Schools;Scientist;Strategic Planning;Technical Expertise;Training and Education;Translating;Translational Research;Translations;UNC Lineberger Comprehensive Cancer Center;Universities;Work;Writing;anticancer research;authority;cancer health disparity;care delivery;community engagement;cost effective;fundamental research;high risk;innovation;malignant stomach neoplasm;neoplastic;new technology;novel strategies;programs;recruit;success Developmental Funds n/a NCI 10767852 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6881 6477317 "EARP, HENRY SHELTON" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 870561 559846 310715 ABSTRACT: DEVELOPMENTAL FUNDSDevelopmental Funds support the Lineberger Comprehensive Cancer Center (LCCC) mission directly throughthe provision of resources and indirectly by leveraging institutional and philanthropic assets. Collectively theseresources expand and enhance cancer research across LCCC in the basic clinical population andtranslational sciences. During the last five years these funds have been used to make key recruitments and tolaunch innovative ideas through pilot project funding. Through these expenditures the LCCC bolsteredinterdisciplinary and translational research efforts. By objective criteria such as extramural grants funded andjunior faculty garnering national awards LCCC recruitment efforts have been a stunning success. Thecompetition for pilot project awards occurs twice yearly both with a general call for innovative ideas andspecific RFAs devised by the Senior and Program Leaders to stimulate ideas arising from the LCCC planningprocesses. The awards have initiated new research across the clinical population translational and basicspectrums again yielding success in seeding extramural grant funding broad collaborations and cancerrelated publications. As has been the case over the last decade Developmental Funds have been a key togrowth innovation and the Centers scientific and clinical impact. The Center distributed over $14.0M over the5 year period and received a return on investment of $77M. LCCC requests $650000 in this category peryear in this renewal application justified by past success and needs for a growing Center. +No NIH Category available Address;Area;Arts;Big Data;Biological Markers;Bladder;Breast;Cancer Burden;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Caring;Catchment Area;Clinical;Clinical Research;Collaborations;Colon;Colon Carcinoma;Community Outreach;Comprehensive Cancer Center;Computers;Continuity of Patient Care;Data;Data Collection;Data Linkages;Data Science;Development;Dimensions;Direct Costs;Early Diagnosis;Endometrium;Epidemiologic Methods;Epidemiologist;Epidemiology;Etiology;Evidence based intervention;Extramural Activities;Faculty;Faculty Recruitment;Funding;Genetic;Genetic Research;Genomics;Grant;Head and Neck Cancer;Health Services;Heterogeneity;Human;Infrastructure;Institution;International;Intervention;Investments;Leadership;Lesion;Link;Lung;Malignant Neoplasms;Mentors;Methods;Molecular;Molecular Epidemiology;Monitor;North Carolina;Outcome;Pathology;Pattern;Peer Review;Pharmaceutical Preparations;Pharmacoepidemiology;Pilot Projects;Population;Population Sciences;Population Study;Prevention;Prevention approach;Prevention strategy;Productivity;Prostate;Public Health Schools;Publishing;Registries;Research;Research Personnel;Research Priority;Resource Sharing;Resources;Risk;Science;Scientist;Screening for cancer;Sociology;Specimen;Statistical Methods;Strategic Planning;Surveys;Training and Education;Wages;analytical method;cancer care;cancer epidemiology;cancer health disparity;cancer prevention;cancer risk;cancer site;cancer therapy;cohort;college;community engagement;computer science;data management;data sharing networks;deep learning;design;epidemiology study;genomic data;health disparity;health equity;improved;interdisciplinary collaboration;malignant breast neoplasm;medical schools;melanoma;member;method development;neoplasm registry;novel;population based;pre-clinical research;programs;public health priorities;racial diversity;recruit;screening;social;sociologist;surveillance data;survivorship;tumor Cancer Epidemiology Research Program n/a NCI 10767839 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6877 6970058 "HENDERSON, LOUISE " Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 40559 26083 14476 ABSTRACT: CANCER EPIDEMIOLOGY PROGRAMThe Cancer Epidemiology program studies environmental genetic and molecular risks for cancer and canceroutcomes to identify priorities for public health and clinical intervention. The program has three aims: (1) Risk-Based Prevention and Early Detection: To identify opportunities for risk-based prevention and early detectionof cancer; (2) Treatment Outcomes and Survivorship: To improve cancer treatment outcomes andsurvivorship through epidemiologic and clinical research that leads to evidence-based interventions; (3)Integrative Molecular Epidemiology: To deepen understanding of cancer etiology heterogeneity andsurvivorship through integrative human molecular and histopathologic studies of precursor lesions and tumors.A major cross-cutting theme is addressing the epidemiology of health disparities. As a comprehensive cancercenter in an economically socially and racially diverse state CE is well-poised to address health equity.Across these aims we use multidimensional North Carolina studies and conduct cross-program research toyield high impact findings. Members have expertise in population-based epidemiology data linkagepharmacoepidemiology survey research clinical research screening molecular and biomarker researchtranslational preclinical research sociology pathology genomics data science computer science andstatistical and epidemiologic methods. Research resources include population-based studies of breast colonprostate head and neck cancer as well as registries for breast and lung screening. Many of these studiesparticipate in large national and international data-sharing initiatives and consortia. The Program brings valueto the Center through study resources that collect exposure and outcome data and biospecimens a uniqueshared resource (Statewide Cancer Data) and expertise in epidemiologic methods. The Program is supportedby UNC Linebergers investments in faculty recruitments shared resources and developmental funds. TheUNC Lineberger strategic plan emphasis on optimizing cancer outcomes in North Carolina has led tosignificant investment across population sciences and is expanding in new areas in coming years includingendometrium and bladder with sustained support for ongoing data collection in breast cancer and head andneck cancers. The CE Program consists of 33 members who are associated with 9 departments at UNC-Chapel Hill and affiliated institutions. During the last funding period program members have published 776cancer-related articles 24% were inter-programmatic and 19% were intra-programmatic (34%collaborative). In 2019 our program members held grants totaling $10.0M (direct cost) in cancer-relevantextramural funding including $5.2M (direct costs) from the NCI and $3.0M other peer-reviewed funding. +No NIH Category available Address;Affect;Antibodies;Antigen Presentation;Antitumor Response;Bone Marrow;Breast Cancer Patient;CD8-Positive T-Lymphocytes;CTLA4 gene;Cell Communication;Cells;Chemotactic Factors;Combined Modality Therapy;Cross Presentation;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Diagnosis;Disease;Future;Gene Expression Profiling;Human;Immune;Immune response;Immunity;Immunoglobulins;Immunotherapeutic agent;Immunotherapy;Infection;Intervention;Location;Mammary Neoplasms;Masks;Measures;Mediating;Modality;Modeling;Mucins;Mus;Mutation;Paclitaxel;Pathway interactions;Patients;Phase;Population;Production;Publishing;Regulation;Research;Role;Scanning;Site;Survival Rate;T cell differentiation;T cell infiltration;T cell response;T-Lymphocyte;Techniques;Therapeutic;Treatment Efficacy;Tumor Antigens;Tumor Immunity;United States;Up-Regulation;Woman;adaptive immune response;anti-PD-L1;anti-tumor immune response;cancer diagnosis;chemokine;chemotherapy;combinatorial;cytokine;design;draining lymph node;effective therapy;epigenome;experimental study;immune checkpoint blockade;improved;in vivo imaging;lymph nodes;malignant breast neoplasm;migration;molecular subtypes;mouse model;phase 3 study;programmed cell death ligand 1;programmed cell death protein 1;response;secondary lymphoid organ;standard of care;treatment response;tumor;tumor microenvironment Targeting the Epigenome to Improve Responses to Immunotherapy PROJECT NARRATIVEBreast cancer is the most commonly diagnosed cancer among women in the United States meaning thatidentifying effective therapies and improving upon current standard-of-care treatment options is criticallyimportant. The research conducted during the F99 phase will explore how the function of dendritic cells isaltered during TIM-3 blockade while the K00 phase will focus on understanding how the location of immunecells within the tumor affects the induction of anti-tumor immunity. Both of these studies will increase ourunderstanding of the mechanisms behind the anti-tumor immune response and have the potential to informthe design of future immunotherapeutic interventions. NCI 10767837 1/3/24 0:00 RFA-CA-19-002 5K00CA245807-05 5 K00 CA 245807 5 "DAMICO, MARK W" 9/6/19 0:00 12/31/25 0:00 ZCA1-RTRB-R(A1) 14414232 "GARDNER, ALYCIA " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Other Research-Related 2024 101101 NCI 93612 7489 Project SummaryConventional dendritic cells (cDCs) are central regulators of the adaptive immune response and have beenshown to be required for the induction of T cell-mediated anti-tumor immunity. In particular a subset of cDCs(cDC1) is responsible for transporting tumor antigens to the lymph node and cross presenting antigen in orderto activate cytotoxic T lymphocytes thereby inducing an anti-tumor response. We have recently observed TIM-3 (T-cell immunoglobulin and mucin domain containing-3) expression on cDCs in human and murine mammarytumors and found that TIM-3 blockade improved response to standard-of-care paclitaxel chemotherapy inmodels of triple-negative and luminal B disease. This occurred through increased chemokine expression bycDCs without a corresponding in T cell infiltration leading me to hypothesize that the spatial localization ofcDCs and T cells within tumors is a critical determinant of successfully immunotherapy. In the F99 portion ofthis application I will therefore seek to determine if TIM-3 blockade alters the spatial organization of T cells andif this is responsible for therapeutic efficacy. In the K00 phase of this proposal I will expand these studies toevaluate whether cDC/T cell clustering is a prerequisite for response to immune checkpoint blockade and othertherapeutic modalities. 101101 +No NIH Category available Address;Adolescent;Area;Arts;Behavior Therapy;Behavioral;Behavioral Sciences;Biometry;Breast;Cancer Burden;Cancer Center Support Grant;Cancer Control;Cancer Control Research Program;Cancer Etiology;Cancer Survivor;Caregivers;Catchment Area;Cervical;Collaborations;Colon;Communication;Community Outreach;Comparative Effectiveness Research;Complex;Databases;Department chair;Development;Dietary Intervention;Direct Costs;Discipline;Discipline of Nursing;Disparity;Disparity population;Doctor of Philosophy;Education;Electronic cigarette;Evaluation;Evidence based intervention;Extramural Activities;Faculty;Faculty Recruitment;Fellowship;Fostering;Funding;Future;Grant;Health Promotion;Health Services;Health behavior;Health system;Healthcare Systems;Home;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Influentials;Infrastructure;Interactive Communication;Intervention;Intervention Studies;Investments;Journalism;Lead;Leadership;Link;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Marketing;Medical Oncologist;Medical Oncology;Mentors;Methodology;North Carolina;Obesity;Outcome;Outcome Study;Outcomes Research;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Pattern;Peer Review;Personal Satisfaction;Pharmacy facility;Physical activity;Policies;Policy Making;Policy Research;Population;Population Heterogeneity;Population Sciences;Positioning Attribute;Postdoctoral Fellow;Prevention;Prevention strategy;Productivity;Prostate;Provider;Public Health;Public Health Schools;Publications;Publishing;Quality of life;Recording of previous events;Research;Research Infrastructure;Research Personnel;Resource Sharing;Risk Factors;Sales;Schools;Science;Scientist;Screening for cancer;Survivors;Technology;Testing;Tobacco use;Training;access disparities;behavior change;cancer care;cancer epidemiology;cancer health disparity;cancer prevention;cancer risk;career;career development;cigarette warning label;college;community engagement;cost effective;design;digital;disparities in morbidity;disparity elimination;distinguished professor;electronic cigarette use;health application;health communication;health disparity;improved;medical schools;member;mortality disparity;multidisciplinary;novel;patient oriented;post-doctoral training;pre-doctoral;prevent;programs;public policy on tobacco;recruit;screening;support network;survivorship;symptom management Cancer Prevention and Control Research Program n/a NCI 10767833 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6876 8704946 "BASCH, ETHAN M." Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 41356 26595 14761 ABSTRACT: CANCER PREVENTION AND CONTROL PROGRAMThe UNC Lineberger Cancer Prevention and Control Program focuses on the development evaluation anddissemination of evidence-based interventions and policy approaches to improve cancer outcomes in NorthCarolina and beyond. Our program is comprised of 56 program members and fosters strong collaborationsbetween faculty from the six schools; Schools of Medicine Public Health Nursing Pharmacy Media andJournalism and the College of Arts and Sciences and 28 departments.The CPC program has four broad themes: (1) Implementing health promotion interventions to reduce cancerrisk factors; (2) Developing cancer communication strategies to improve cancer prevention and control; (3)Improving quality of cancer care and long-term outcomes for cancer survivors; and (4) Studying patterns ofcancer care screening and prevention to inform interventions and policy initiatives that improve canceroutcomes. Eliminating cancer health disparities is a cross-cutting theme of our program.Highlights of our nationally recognized research by program investigators include: tobacco control policyresearch on the design and efficacy of graphic cigarette warning labels that is guiding FDA policy; research onsales and marketing of electronic cigarettes including interventions to prevent adolescent e-cigarette use;research on digital and mobile interventions for diet obesity physical activity and symptom management withparticular focus on disadvantaged populations and cancer survivors; novel patient-reported outcomes studiesthat inform national policy; and implementing interventions in our Catchment area of North Carolina focused oneliminating disparities in access and outcomes.The Program is led by Dr. Kurt M. Ribisl a behavioral scientist and Dr. Ethan Basch a medical oncologistand health services researcher. Program members are PIs of three NCI funded pre- and post-doctoral traininggrants. The Program adds value in terms of integrative activities and opportunities for intra- and cross-programcollaboration; professional development and networking support for junior faculty CPC members; access toshared resources such as the Communications for Health Applications and Interventions Biostatistics andPatient-Reported Outcomes Core; as well as space seminars retreats training and education. Since our lastrenewal UNC Lineberger has benefited the Program through strong support for infrastructure facultyrecruitments extensive use of shared resources and providing developmental funds as befits one of threemajor UNC Lineberger strategic directions Optimizing Cancer Outcomes in North Carolina. During the lastfunding period program members have published 1359 cancer-related articles 26% were intra-programmaticand 19% were inter-programmatic (38% collaborative). In 2019 our program members held grants totaling$18.9M (direct cost) in cancer-relevant extramural funding including $6.8M (direct costs) from the NCI and$8.9M in other peer-reviewed funding. +No NIH Category available Address;Adherence;African American population;Animal Model;Autopsy;Award;Basic Science;Behavior;Bioinformatics;Biological;Biological Markers;Biology;Breast;Cancer Center Support Grant;Cancer Research Project;Catchment Area;Cells;Cellular Structures;Center for Translational Science Activities;Classification;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Country;County;DNA Integration;DNA analysis;DNA sequencing;Data;Direct Costs;Discipline;Disease;Disparity;ERBB2 gene;Elderly;Epidemiologist;Etiology;Exposure to;Extramural Activities;Faculty;Fostering;Funding;Gene Expression;Genetic;Genome Stability;Genomics;Goals;Grant;Growth;Health Sciences;Health Services;Health Services Accessibility;Health Services Research;Immune;Immunocompetent;Immunotherapeutic agent;Immunotherapy;Incidence;Infrastructure;Institution;Interdisciplinary Study;International;Intervention Trial;Investments;Leadership;Malignant Neoplasms;Metastatic breast cancer;Minority-Serving Institution;Molecular Analysis;Multicenter Trials;Mus;Neoplasm Metastasis;Neoplasm Transplantation;North Carolina;Oncogene Activation;Oncology;Organ;Outcome;Patients;Peer Review;Population Research;Population Study;Positioning Attribute;Primary Neoplasm;Proteomics;Public Health;Public Hospitals;Publishing;RNA;Regimen;Research;Research Design;Research Personnel;Research Support;Resources;Role;Science;Scientist;Seminal;Source;State Hospitals;Technology;Therapeutic;Tissues;Training;Translational Research;Tumor Subtype;Woman;Work;anticancer research;bench to bedside;cancer health disparity;cancer subtypes;cancer therapy;care outcomes;clinical care;clinical database;cohort;community engagement;design;epidemiology study;experience;genetic analysis;genetic manipulation;graduate student;hormone receptor-positive;human tissue;improved outcome;innovation;interest;intervention program;large datasets;malignant breast neoplasm;meetings;member;minority disparity;mouse model;new technology;novel;outreach;population based;predicting response;programs;prospective;racial disparity;recruit;response;senior faculty;single cell analysis;success;therapy adherence;tool;transcriptome sequencing;transcriptomics;translational oncology;transplant model;treatment optimization;treatment response;treatment trial;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor-immune system interactions;undergraduate student Breast Cancer Research Program n/a NCI 10767826 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6874 7071147 "CAREY, LISA A" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 42152 27107 15045 ABSTRACT: BREAST CANCER PROGRAMThe Breast Cancer Program (BC) was an outgrowth of the basic translational population and clinical researchof the LCCC Breast Cancer SPORE which has been continuously funded since 1992. LCCC investment infaculty and infrastructure supports one of the countrys premier clinical and research breast programsperforming important interdisciplinary research in the past decade with members rising to national leadershippositions. This knitting together of clinical basic and epidemiologic research is the hallmark of the BreastProgram and is reflected in the investment in faculty and resources fostered by including in the last 5 yearsover $10M in genomics/sequencing resources used for institutional as well as large multicenter trials. Thiscommitment is reflected in patient-facing institutional trials examining clinical implications of breast cancersubtypes as well as LCCC leadership of collaborative tissue-based studies through the Translational BreastCancer Research Consortium (TBCRC) and AURORA-US Project (https://auroraus.org) a multicentermultiplatform analysis of DNA RNA and other alterations in metastases compared with matched primarytumors. The longitudinal and exceptional investment in the Carolina Breast Cancer Studies (CBCS) representsthe largest and most heavily annotated population-based study ever performed addressing racial disparities inbreast cancer behavior and outcome. CBCS has received an additional $5M investment in this cycle and isproviding the community with an increased understanding of the full range of breast cancer research fromgenomics /genetics to health services. Program strategic goals include: 1) genomic and genetic analyses ofmetastatic and primary breast cancers 2) bench-to-bedside approaches using murine models 3) translationaldiscovery and strategies based on human tissue-based correlative science 4) clinical trials and population-based studies leveraging and applying UNC science and community input to address the root causes ofdisparities. BC members include clinicians basic researchers statisticians bioinformaticians epidemiologistsand health services scientists. BC has long-term interest in North Carolinas minority disparities following theprograms seminal discoveries of the high incidence of triple negative breast cancer (TNBC) in younger AfricanAmericans the subsequent molecular analysis showing the disparity is even more striking and the surprisingfinding that the largest racial disparity in survival is in women with hormone receptor-positive disease forwhom access to care and adherence to treatment are key. The BC Program consists of 21 members who areassociated with 10 basic science and 5 clinical departments at UNC-Chapel Hill and affiliated institutions.During the last funding period program members published 494 cancer-related articles of which 56% wereinter-programmatic and 15% were intra-programmatic (57% collaborative). In 2019 our program membersheld grants totaling $8.1M (direct cost) in cancer-relevant extramural funding including $4.0M (direct costs)from the NCI and $1.8M other peer-reviewed funding. +No NIH Category available Adoption;Age;Automobile Driving;Award;Basic Science;Behavioral;Bioinformatics;Biological Models;Biology;Businesses;Cancer Center Support Grant;Cancer Etiology;Catchment Area;Categories;Cells;Characteristics;Childhood;Chromatin;Clinical;Communities;Community Outreach;Complement;Comprehensive Cancer Center;Computational Biology;Constitution;Constitutional;Coupling;DNA;DNA Sequence;Data;Development;Developmental Therapeutics Program;Direct Costs;Disease Management;Educational Activities;Educational Curriculum;Educational process of instructing;Elements;Environment;Environmental Risk Factor;Epigenetic Process;Ethics;Evaluation;Extramural Activities;Faculty;Faculty Recruitment;Foundations;Funding;Gene Combinations;Gene Expression;Gene Expression Regulation;Generations;Genes;Genetic;Genetic Polymorphism;Genetic Research;Genetic Transcription;Genomics;Genotype;Grant;Growth;Health;Healthcare;Human;Individual;Informatics;Infrastructure;Institution;Investigation;Investments;Laboratories;Laboratory Organism;Large-Scale Sequencing;Leadership;Lesion;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medical Oncologist;Mus;Mutation;Outcome;Patient Care;Patients;Pediatric Oncologist;Peer Review;Pharmaceutical Chemistry;Phenotype;Policies;Population;Population Study;Precision Health;Precision therapeutics;Predisposition;Process;Program Reviews;Provider;Publishing;Recommendation;Regulator Genes;Renal carcinoma;Research;Research Personnel;Resources;Scientist;Secure;Shapes;Somatic Mutation;Structure;System;Target Populations;Technology;Therapeutic;Therapeutic Intervention;Toxic effect;Training and Education;Translational Research;UNC Lineberger Comprehensive Cancer Center;Variant;Vision;Yeasts;anticancer research;cancer care;cancer genetics;cancer genomics;cancer prevention;cancer therapy;clinical application;clinical care;clinical translation;community engagement;data handling;diagnostic tool;drug discovery;epigenomics;exome;experience;fly;genome-wide;genomic data;genomic variation;high throughput technology;improved;innovation;insight;interdisciplinary approach;melanoma;member;model organism;new technology;novel;post-doctoral training;precision oncology;prevent;programs;research clinical testing;synergism;transcriptome sequencing;transcriptomics;translational oncology;tumor;tumorigenesis;whole genome Cancer Genetics Research Program n/a NCI 10767816 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6870 14864296 "MAGNUSON, TERRY R" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 59084 37996 21088 ABSTRACT: CANCER GENETICS PROGRAMThe Cancer Genetics (CG) Program of the UNC Lineberger Comprehensive Cancer Center (LCCC) wasestablished in 2001 to facilitate an integrated multi-disciplinary approach to genetics research and itsapplication to clinical care. The program is comprised of laboratory-based investigators statistical geneticistsresearchers and clinicians all focused on improving our understanding of cancer etiology and the treatment ofcancer. By integrating the multiple strengths of UNC ranging from basic science to clinical genomic analysisthe LCCC Cancer Genetics Program has become a world leader in (i) mechanisms of cancer-associatedgenes; (ii) precision oncology and bioinformatics; and (iii) epigenetics/epigenomics. Cancer treatments areincreasingly tailored to an individuals genomic constitution and the genomic characteristics of the tumormitigating toxicity and enhancing efficacy by precisely targeting mutations that drive tumor propagation. Wehave developed a comprehensive program that includes: (i) integrating diverse experimental organisms fromyeast fly and mouse to cell-based systems and ultimately human populations to identify mechanisms thatresult in genomic and transcriptomic alterations and the specific lesions responsible for cancer phenotypes; (ii)use of Whole Genome Whole Exome and Whole Transcriptome Sequencing (WGS/WES/WTS) as effectivediagnostic tools; (iii) facilitating the meaningful use of genomic information by patients and providers throughstructured categorization of genomic variation based on clinical validity and utility; (iv) a state-of-the-artinformatics approach that incorporates generation analysis and management of genomic data couplinggenomic and clinical information to drive both clinical testing and translational research; (v) development ofethical and practical policies for the use of WGS data by clinicians for patient care; and (vi) exploration ofepigenomic mechanisms and strategies for therapeutic intervention.Our vision has been realized through value added LCCC resources for the strategic recruitment of faculty inemerging fields investment in cutting-edge technology including data handling enhanced organization forintegrative analyses and the securing of significant federal funding to enable the application of genomics todiverse aspects of cancer care and prevention. CG consists of 31 members who are associated with 10 basicscience and 3 clinical departments at UNC-Chapel Hill and affiliated institutions. During the last funding periodprogram members have published 544 cancer-related articles 39% were inter-programmatic and 16% wereintra-programmatic (45% collaborative). In 2019 our program members held grants totaling $15.2M (directcost) in cancer-relevant extramural funding including $5.7M (direct costs) from the NCI and $8.6M in otherpeer-reviewed funding. +No NIH Category available AIDS Malignancy Consortium;AIDS related cancer;Acquired Immunodeficiency Syndrome;Address;Africa;African American;Animal Model;Area;Basic Science;Bioinformatics;Biological Markers;Biological Products;Biology;Cancer Center Support Grant;Carcinogens;Catchment Area;Caucasians;Cell secretion;Cells;Clinical;Communities;Community Healthcare;Community Outreach;Development;Diagnosis;Direct Costs;Disparity;Doctor of Philosophy;Endogenous Retroviruses;Environment;Epidemic;Epigenetic Process;Extramural Activities;Faculty;Flowers;Funding;Gene Delivery;Genomics;Goals;Graduate Education;Grant;HIV;HIV Infections;Head Cancer;Hispanic;Home;Human;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Immune signaling;Immunity;Immunology;Immunotherapy;Incidence;Infectious Agent;Innate Immune Response;International Agency for Research on Cancer;Intervention;Investments;Leadership;Lentivirus;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;MicroRNAs;Microbiology;Minority;Modernization;Modification;Molecular;NCI-Designated Cancer Center;National Cancer Advisory Board;Neck Cancer;Neoplasms;North Carolina;Oncogenic Viruses;Oncology;Organoids;Patients;Pattern;Persons;Pharmaceutical Preparations;Postdoctoral Fellow;Prevention;Professional counselor;Proteomics;Publications;Reagent;Relative Risks;Research;Research Personnel;Research Project Grants;Role;Sampling;Series;Services;Shapes;Signal Pathway;Specimen;Systems Biology;Training;Training and Education;United States National Academy of Sciences;United States National Institutes of Health;Vaccines;Viral;Viral Cancer;Viral Genome;Viral Pathogenesis;Viral Vector;Virus;Virus-Cell Membrane Interaction;Vulnerable Populations;Woman;Work;adaptive immune response;analysis pipeline;biocontainment facility;cancer therapy;community engagement;delivery vehicle;demographics;distinguished professor;epigenome;exosome;extracellular vesicles;gene therapy;graduate student;humanized mouse;interest;malignant mouth neoplasm;medical schools;member;metabolomics;microbiome analysis;neoplastic cell;next generation sequencing;novel;novel therapeutics;peer;pre-clinical;prevent;professor;programs;recruit;single cell technology;small hairpin RNA;small molecule;training opportunity;translational study;tumor;tumorigenesis;vector;viral detection;virology;virus related cancer Virology Research Program n/a NCI 10767809 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6869 6691168 "DITTMER, DIRK P" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 40560 26084 14476 ABSTRACT: VIROLOGY PROGRAMApproximately 20% of all cancers result from infectious agents with the majority of these malignancies beingvirus-associated cancers. The Virology Program (VIR) focuses on deciphering the basic mechanisms by whichhuman tumor viruses are linked to the development of malignancy. The long-term goal of VIR is to understandviral perturbation sufficiently to generate new therapies including small molecules biologics and vaccines thattarget viruses and viral cancers. The aims for VIR are focused on five research areas. These includeunderstanding: (i) Viruses and Immunity (ii) Virus-Cell Interactions (iii) Viral Pathogenesis and Tumorigenesis(iv) Cancers impacted by HIV infection and (v) Clinical & Translational Virology which includes gene therapyimmune therapy and global oncology. Recent discoveries include the finding that virus-infected cells secreteexosomes or extracellular vesicles which modulate the tumor environment and the discovery that viral-encoded microRNAs contribute to the development of neoplasms. Additional findings focus on the modulationof innate immune signaling pathways by oncogenic viruses epigenetic modifications in the context of viralcancers and development of new therapies for AIDS-associated cancers. VIR also provides the scientificunderpinnings of the UNC Lineberger Global Oncology effort which is tightly integrated with other NCI-designated cancer centers NCI-funded collaborative groups including the AIDS Malignancy Consortium in theUS and Africa and the NIH global research agenda. There are 23 program members from 10 differentdepartments across campus. These faculty investigators have 39 research grants and $9.7 million (directcosts) in annual extramural support including $2.4 million from NCI and $5.5 million from other peer and otherNIH. Members authored a total of 407 cancer-relevant publications during the past 5 years; 13% were intra-programmatic and 16% were inter-programmatic. VIR is the administrative home of LCCC viral vector/genetherapy efforts and based on overlapping biology is working closely with the Immunology (IMM) researchprogram. LCCCs humanized mouse program is led by Victor Garcias work in VIR. There are extremelyaccomplished investigators in VIR including Dr. Jack Griffith elected to the National Academy of Sciences Dr.Raab-Traub National Cancer Advisory Board member and Dr. Damania who serves on the NCI Board ofScientific Counselors. Research in VIR is informed by the Office of Community Outreach and Engagementparticularly with respect to HPV-associated cancers with an emphasis on translational studies related to humanpapilloma virus (HPV) including recruitment of new faculty and investment of pilot funding. HPV-associatedcervical and oral cancers are of particular interest to LCCC as the incidence of HPV-associated cervical andoral cancer in our catchment area exceeds the national average. +No NIH Category available Acceleration;Address;Animal Model;Antineoplastic Agents;Area;Award;Basic Science;Biological Products;Biological Response Modifier Therapy;Biology;Breast;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Therapy;Chemicals;Clinical;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Communities;Community Outreach;Computer Assisted;Computer Models;Critiques;Cryoelectron Microscopy;Dedications;Development;Direct Costs;Discipline;Drug Delivery Systems;Drug Design;Drug Formulations;Drug Kinetics;Environment;Enzymes;Epigenetic Process;Extramural Activities;Faculty;Formulation;Funding;Future;Genetically Engineered Mouse;Genomics;Goals;Grant;Guanosine Triphosphate Phosphohydrolases;Home;Immunotherapy;Incidence;Infrastructure;Institution;Interdisciplinary Study;Intervention;Investments;Lead;Leadership;Lipids;Lung;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Minor;Molecular;Molecular Biology;Multiple Myeloma;Mus;Nanodelivery;Nanotechnology;Oncogenic;Pancreas;Paper;Pathway interactions;Patients;Pharmaceutical Chemistry;Pharmacodynamics;Pharmacology;Phase;Phospholipase;Phosphotransferases;Positioning Attribute;Postdoctoral Fellow;Productivity;Prostate;Protein Engineering;Proteins;Proteomics;Publishing;RNA interference screen;Research;Research Personnel;Resolution;Resource Sharing;Resources;Schools;Signal Transduction;Strategic Planning;System;Technology;Therapeutic;Therapeutic Research;Therapeutic Studies;Therapeutic Trials;Toxic effect;Training and Education;Translating;Translational trial;Translations;Viral;X-Ray Crystallography;animal resource;anticancer research;cancer therapy;cancer type;cheminformatics;cohort;community engagement;design;distinguished professor;drug development;drug discovery;health care disparity;high throughput screening;human model;imaging modality;improved;in vivo Model;innovation;interest;lead optimization;live cell imaging;macromolecule;malignant breast neoplasm;member;mortality;nanoparticle;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;peer;pharmacologic;pre-clinical assessment;programs;receptor;recruit;response;small molecule;structural biology;student training;tool;translational scientist Molecular Therapeutics Research Program n/a NCI 10767802 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6868 9485310 "FRYE, STEPHEN VERNON" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 40560 26084 14476 ABSTRACT: MOLECULAR THERAPEUTICS PROGRAMThe Molecular Therapeutics (MT) program is dedicated to evaluating cancer targets developing noveltherapies and devising more effective delivery systems via highly integrated basic science and translationalactivities. The Program is led by Stephen Frye Director of the Center for Integrative Chemical Biology andDrug Discovery (CICBDD) and Fred Eshelman Distinguished Professor and Gary Johnson KenanDistinguished Professor in the Department of Pharmacology. The MT Program consists of 42 members whoare associated with four schools and 16 departments. During the last funding period program members havepublished 675 cancer-related articles. MT is highly collaborative. 16% of these papers are intra-programmaticand 33% are inter-programmatic (43% collaborative). In 2019 our program members held grants totaling$20.9M (direct cost) in cancer-relevant extramural funding including $6.4M (direct costs) from the NCI and$13.0M other peer funding. The MT program is comprised of investigators with expertise in five broad areas:Chemical and Structural Biology; Drug Discovery and Development; Drug Delivery and Nanotechnology;Systems Pharmacology; and Oncogenic Signaling. Many investigators in the program have activecollaborations with other LCCC programs using and providing direction for LCCC's shared resources. Theseinteractions enable many of the scientific steps needed for the discovery and development of promisingtherapies. In 2015 MT was rated outstanding stating the minor weakness of this program is that relativelyfew of the promising therapeutics have moved into investigator initiated clinical trials at the LCCC. Since thisreview multiple clinical studies have been initiated at UNC and other institutions based on discoveries in MTas outlined in our response to the prior critique. Future plans build on unique translational resources availabledue to the creation of the Eshelman Institute for Innovation and Pinnacle Hill which bring more than $100million to progress UNC-based discoveries into patients. Cellular and biologic therapies will be an area offuture focus for MT members enabled by the expansion of the Clinical Immunotherapy Program's GMP facility.Through these efforts MT will continue to accelerate discovery of new cancer therapeutics and with theClinical Research and Breast Cancer Programs design and execute translational and therapeutic trials in ourpatients. +No NIH Category available Actins;Address;Apoptosis;Area;Basic Science;Biochemistry;Biology;Biophysics;Blood Vessels;Cancer Center Support Grant;Cancer Intervention;Catchment Area;Cell Cycle;Cell Cycle Regulation;Cell physiology;Cells;Cellular biology;Chromatin;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communities;Community Outreach;Complex;Core Facility;Cullin Proteins;Cytoskeleton;DNA;DNA Modification Process;DNA Repair;DNA biosynthesis;Development;Dioxygenases;Direct Costs;Disparity;Doctor of Philosophy;Education;Educational process of instructing;Electronic cigarette;Entrepreneurship;Environment;Enzymes;Epigenetic Process;Equipment;Event;Extramural Activities;Faculty;Faculty Recruitment;Family;Fostering;Funding;Genomics;Goals;Grant;Growth Factor;Institution;Intervention;Investments;Joints;Knowledge;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mentors;Mentorship;Metabolism;Modeling;Molecular;Multiple Myeloma;Neoplasm Metastasis;North Carolina;Output;Pancreas;Pathway interactions;Phase;Phenotype;Pilot Projects;Population;Population Sciences;Productivity;Program Development;Prostate;Publishing;RNA;Recording of previous events;Regulation;Research;Research Activity;Research Personnel;Resistance;Resource Sharing;Role;Scientist;Seminal;Signal Pathway;Signal Transduction;Structure;Talents;Technology;Testing;Therapeutic;Therapeutic Intervention;Tissues;Training;Transcriptional Regulation;Translating;Translations;Tumor Cell Invasion;Tumor Suppression;Ubiquitin;angiogenesis;anticancer research;cancer cell;cancer therapy;career;cell motility;commercialization;community engagement;drug discovery;effective therapy;high school;histone modification;improved;insight;interest;junior high school;malignant breast neoplasm;meetings;melanoma;member;migration;neoplastic cell;new therapeutic target;novel diagnostics;novel therapeutics;peer;pre-clinical;preclinical trial;professor;programs;receptor;research and development;response;small molecule inhibitor;symposium;targeted cancer therapy;therapeutic target;tumor;tumor initiation;tumor progression;tumorigenesis;ubiquitin-protein ligase Cancer Cell Biology Research Program n/a NCI 10767789 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6866 1922923 "BEAR, JAMES E" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 40560 26084 14476 ABSTRACT: CANCER CELL BIOLOGY PROGRAMThe overarching goals of the Cancer Cell Biology (CCB) Program are: (i) to understand at the molecular andcellular levels mechanisms underlying tumor initiation progression metastasis and resistance to therapeutictreatment and (ii) to identify and validate new targets for cancer therapy. Insight derived from these studieswhen integrated with research and development from other programs will provide targets and guidance for thedevelopment of strategies for therapeutic intervention of cancer. Toward these two goals the Program facultyinvestigate various aspects of cancer cell biology including growth factors and receptors; angiogenesis andvascular biology; apoptosis; cell cycle regulation; chromatin biochemistry and transcriptional regulation; cellmicrostructure and function; DNA replication and repair; metabolism; regulatory RNA; and signal transduction.Led by two co-leaders with complementary expertise Yue Xiong and James Bear the program organizesthese different areas into four major research aims: (1) Cell Cycle (2) Cell Signaling (3) Cell Movement andOrganization and (4) Chromatin Biology. The major emphasis of the Program is to foster integrated researchthat spans these inter-related themes enhancing the research and translational capabilities of programinvestigators through the establishment expansion and utilization of appropriate core facilities and promotinginteractions with investigators from other LCCC basic clinical and population sciences programs. CCB hasmade concerted and focused efforts to improve translational output by fostering inter-programmaticcollaboration directed towards translation of basic science discoveries engaging in entrepreneurship andbrining small molecule inhibitors to pre-clinical and clinical trials. The research of CCB addresses fundamentalbiology that applies to all cancers but has a particular impact on cancers relevant to our catchment area suchas multiple myeloma lung cancer and melanoma. In addition members of CCB have been active incommunity outreach and engagement activities such as advising state legislators on e-cigarette regulation.Finally the members of CCB are fully committed to education training and mentoring at levels ranging frommiddle schoolers through junior faculty at our own institution.The Cancer Cell Biology Program consists of 43 members who are associated with 12 basic science and 3clinical departments at UNC-Chapel Hill and affiliated institutions. During the last funding period programmembers published 740 cancer-related articles. Of these 23% were inter-programmatic and 10% were intra-programmatic (31% collaborative). In 2019 our program members held grants totaling $18.2M (direct cost) incancer-relevant extramural funding including $3.5M (direct costs) from the NCI and $13.6M other peer. +No NIH Category available Area;Award;Basic Science;Budgets;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Sciences;Committee Membership;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Contracts;Development;Education;Ensure;Equipment;Evaluation;Faculty;Fostering;Funding;Funding Opportunities;Grant;Human Resources;Informatics;Information Technology;Infrastructure;Institution;Leadership;Malignant Neoplasms;Mentors;Mission;Monitor;NCI Center for Cancer Research;North Carolina;Output;Patient advocacy;Population Sciences;Process;Recommendation;Recurrence;Reporting;Research;Research Activity;Resource Sharing;Resources;Services;Strategic Planning;Surveys;Training;Training and Education;Translational Research;UNC Lineberger Comprehensive Cancer Center;United States National Institutes of Health;Universities;Vision;Wages;Work;anticancer research;cancer education;career;community center;community engagement;computer network;experience;innovation;meetings;member;operation;programs;recruit;symposium;translational cancer research Admin-Core n/a NCI 10767778 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6864 6477317 "EARP, HENRY SHELTON" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 491442 316040 175402 ABSTRACT: ADMINISTRATIVE COREThe Lineberger Comprehensive Cancer Center (LCCC) Administrative Core includes the Senior LeadershipTeam (SLT) and Center Administration. The SLT establishes the overall strategic direction and researchmission for LCCC and center Adminstration operationalizes this vision. The SLT includes the Director DeputyDirector of Clinical Science and Associate Directors of Basic Translational and Population Science; Educationand Training; Community Outreach and Engagement; and Administration and meets weekly to consider allmatters impacting LCCC. Center Administration provides infrastructure to promote the cancer researchactivities of its 324 members with a particular focus on facilitating transdisciplinary and translational cancerresearch with relevance to the catchment area the State of North Carolina and informed by bi-directional inputfrom the community. The Administration supports the Director Senior Leaders Program Leaders SharedResources Directors and LCCC Members in carrying out the Center mission through effective strategicplanning and evaluation operational management and centralized resources.LCCC Administration (80 FTE/$6.3M) oversees the largest research operation at the University of NorthCarolina including a $165M budget (FY19) covering grant and fiscal management and other administrativeservices for faculty members and 13 Shared Resources. Many of these reside in center-controlled space(165000 nsf) which the administrative staff also manages. The administrative staff is responsible for humanresources and administering partial salary support for over 1200 FTEs. Administrative responsibilities include:management of Center finances personnel grants and contracts purchasing and philanthropy; providingadministrative and financial oversight for LCCC shared resources; overseeing space utilization and commonequipment; facilitating recruitment efforts; managing center membership; and coordinating pilot awardprograms. Additional activities involve coordinating Center planning and evaluation activities includingleadership and programmatic meetings seminars annual symposia and retreats and internal and externalboard meetings. The administrative staff also supports communication to the 324 LCCC members and theUniversity as a whole as well as educating citizens and legislators regarding Center activities across the state.The Administrative Core monitors and reports on member accomplishments funding cancer-related activity tothe membership committee and SLT as a part of the annual membership evaluation. The conduct of surveysand evaluation for planning is also a function of the central administrative staff. The Administrative Corefunctions are overseen by an Associate Director for Administration with more than 15 years of experience atUNC. +No NIH Category available Appointment;Arts;Authorization documentation;Award;Basic Cancer Research;Basic Science;Behavioral;Bioinformatics;Biology;Budgets;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Caregivers;Caring;Catchment Area;Chemicals;Clinic;Clinical Data;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Data;Development;Direct Costs;Discipline of Nursing;Disease;Disparity;Early Diagnosis;Education and Outreach;Epidemiology;Epigenetic Process;Evaluation Research;Facility Construction;Faculty;Fostering;Funding;Future;Genetic Research;Genomic approach;Government;Grant;Health;Health Resources;Health Services;Healthcare;Human;Incidence;Information Systems;Infrastructure;Institution;Insurance Carriers;Intervention;Intervention Trial;Investments;Leadership;Malignant Neoplasms;Measures;Medicaid;Medicare;Minority Groups;Mission;Molecular Epidemiology;Monitor;Morbidity - disease rate;Names;North Carolina;Oncology;Outcome;Patient Care;Patients;Performance;Pharmacologic Substance;Pharmacy facility;Policies;Population;Population Heterogeneity;Population Sciences;Prevention;Privatization;Productivity;Protocols documentation;Public Health;Publications;Publishing;Research;Research Personnel;Resource Sharing;Resources;Role;Rural Population;Schools;Science;Scientist;Services;Stretching;System;Talents;Technology;The Cancer Genome Atlas;Therapeutic;Training;Training and Education;Translating;Translations;United States;Universities;Urban Population;anticancer research;authority;cancer care;cancer epidemiology;cancer genetics;cancer research center director;cancer therapy;career;chimeric antigen receptor T cells;college;community based participatory research;community college;community engagement;data management;drug discovery;epidemiology study;imaging detection;innovation;malignant breast neoplasm;medical schools;member;minority disparity;mortality;multidisciplinary;neoplasm registry;operation;outreach;population based;population health;programs;public policy on tobacco;recruit;safety net;screening services;senior faculty;survivorship;undergraduate student Cancer Center Support Grant PROJECT NARRATIVEThe Lineberger Comprehensive Cancer Center (LCCC) forms the nexus for researchers focused onunderstanding and identifying the mechanisms leading to the prevention of and treatments for cancer. LCCCis an integral component of the research mission at The University of North Carolina (UNC) at Chapel Hillcoalescing the cancer research capabilities of the Schools of Medicine Public Health Pharmacy and Nursingand the College of Arts and Sciences. The LCCC strives to reduce cancer incidence morbidity and mortality inNorth Carolina the United States and across the globe through innovative research cutting-edge treatmentsmulti-disciplinary training education and outreach. NCI 10767776 12/4/23 0:00 PAR-20-043 5P30CA016086-48 5 P30 CA 16086 48 "SHAFIK, HASNAA" 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6477317 "EARP, HENRY SHELTON" Not Applicable 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 397 Research Centers 2024 7044854 NCI 4530453 2514401 ABSTRACTOver the past 5 years the Center sustained its upward trajectory in cancer research excellence and service toits catchment area the State of North Carolina. With Dr Sharplesss appointment to NCI Director inconsultation with University leadership and the Centers Scientific Advisors Dr Earp was re-appointed UNCLineberger Comprehensive Cancer Center (LCCC) Director for an additional term. The LCCC continued itsexceptional performance of the past decade with respect to all important metrics including state service. Directcost cancer research funding in 2019 increased to $161M of which over $54M comes from NCI; Centerresearch space under the Directors authority increased by ~10000nsf; participation in interventional trials wasover 11000 accruals for the 5 year period; 36% of the more than 6000 cancer related publication werecollaborative; construction of a GMP facility was begun and a CAR T program was initiated with multiple INDsand 8 trials opened; and the Office of Community Outreach Engagement expanded LCCCs traditional strengthin community-based participatory research and implementation .The Centers 324 members span the basic clinical and population sciences organized into 9 programs withsubstantial inter- and intra-programmatic productivity. Faculty additions in the physical and pharmaceuticalsciences created new opportunities in drug discovery delivery imaging and early detection. Substantialinvestment in faculty technology and bioinformatics dramatically expanded cancer genetics research includingleadership in the TCGA and expanded use of sequencing in clinical trials. LCCC population scientists initiatedsignificant new efforts in cancer outcomes with recruitment and infrastructure for analyzing all cancer cases inour catchment area as well as new endeavors in cancer communication health access survivorship andmolecular epidemiology. Groundbreaking observations in breast cancer minority disparity research emergedfrom Center programs. Our basic programs continue to publish high-impact observations that are beingtranslated into human therapeutics. A trans-Center Global Oncology effort received grants in each of the NCIsnew competitions. The Centers continued expansion is driven by remarkable institutional support includingdirect support for cancer research from the state legislature. The UNC Lineberger requests continued fundingfor: 9 scientific programs; 13 shared resources; Clinical Protocol and Data Management; Protocol Review andMonitoring System Developmental Funds Planning Leadership and Evaluation and Cancer Research andCareer Enhancement The CCSG budget supports technological and operational expansion for a talentedfaculty integrated through cancer center mechanisms towards making advancements in the prevention earlydetection and treatment of cancer in North Carolina and the nation. 7044854 +No NIH Category available ALCAM gene;African American population;Biopsy;CD44 gene;Cells;Characteristics;Chemicals;Chemoresistance;Clinical;Colon;Colonic Neoplasms;Colorectal Cancer;Cytometry;Data;Development;Disease;Early Diagnosis;Ephrins;Epithelium;Funding;Future;Gene Silencing;Genetic;Goals;Growth;Incidence;Joints;LGR5 gene;Malignant Neoplasms;Mediating;Molecular;Molecular Profiling;Mutation;Neoplasm Metastasis;Nonmetastatic;Oncogenic;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Phosphorylation;Phosphotransferases;Play;Proteins;Proto-Oncogenes;Relapse;Resistance;Role;Signal Pathway;System;Technology;Testing;Time;Tissues;United States;Western Blotting;Xenograft procedure;adenoma;aldehyde dehydrogenase 1;beta catenin;biomarker signature;cancer cell;cancer stem cell;cancer therapy;caucasian American;claudin-1 protein;clinical decision-making;clinical practice;colon cancer metastasis;colon cancer patients;colorectal cancer metastasis;colorectal cancer progression;colorectal cancer treatment;early onset colorectal cancer;effective therapy;efficacy testing;imaging system;improved;inhibitor;innovation;mortality;mouse model;multimodality;multiplexed imaging;novel;overexpression;parent grant;patient derived xenograft model;personalized decision;pre-clinical;racial difference;racial disparity;racial population;receptor;risk prediction;src-Family Kinases;stem cell biomarkers;targeted treatment;tool;treatment strategy;tumor;tumor growth Impact of CLDN1 inhibition on chemoresistance and metastasis of colon cancer Claudin-1 plays a key role in the aggressive features of CRC in AA patients. A claudin-1-associated signature and inhibitor will be invaluable tools for identifying aggressive CRCs andreducing CRC mortality in AA patients. NCI 10767698 8/15/23 0:00 PAR-22-114 3R01CA250383-03S1 3 R01 CA 250383 3 S1 "CHEN, WEIWEI" 2/12/21 0:00 1/31/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 8251450 "DHAWAN, PUNITA " "HOPKINS, COREY R." 2 BIOCHEMISTRY 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 395 Non-SBIR/STTR 2023 238397 NCI 174250 64147 Despite advances in colorectal cancer (CRC) treatment and early detection the burden of CRCon African Americans (AAs) remains high. AAs have the highest incidence of CRC among allracial groups in the United States. Compared with Caucasian Americans (CAs) AAs show ~25%higher CRC incidence and ~50% higher CRC mortality. Furthermore early CRC onset is relativelycommon in AAs and among patients with high-grade CRC the 5-year overall survival aftersurgery is three times lower in AAs than in CAs. Recent studies have shown that mutations inAPC and -catenin are associated with the high incidence in AAs. Nevertheless the mechanismsunderlying the racial differences in CRC aggressiveness are poorly understood.We and others have demonstrated that claudin-1 expression is frequently dysregulated in CRC.Additionally alterations in the APC/Wnt/-catenin pathway (which are known to promote CRC)are correlated with increased claudin-1 levels in CRC. Our preliminary data demonstrate that AApatients with CRC have higher claudin-1 expression than CA patients and colon tumors with highclaudin-1 expression have higher numbers of cancer stem cells (CSCs) contributing to tumoraggressiveness and relapse. Moreover recent studies have shown that CSCs specificallyCD44+CD166 cells may contribute to the higher incidence of CRC in AAs than in CAs. Thepurpose of this supplement is to evaluate the role of claudin-1 in racial disparities in CRCaggressiveness and to develop a protein signature in correlation with its molecular determinants.We also plan to test the efficacy of a novel claudin-1 inhibitor in aggressive patient-derivedxenografts (PDXs) from AA patients with aggressive CRC. The development and characterizationof this novel claudin-1 inhibitor are supported by an NCI parent grant (R01CA250383). The overallgoal of this joint project is to improve the prediction and treatment of aggressive CRC tumors inAA by targeting claudin-1. Our hypothesis is that claudin-1 plays a key role in the aggressivefeatures of CRC in AA patients. A claudin-1-associated signature and inhibitor will be invaluabletools for identifying aggressive CRCs and reducing CRC mortality in AA patients. Innovation liesin the novel concept of this study and the use of state-of-the-art and cutting-edge technologiesincluding HyperionTM Imaging System and PDX models. Specific Aim 1. Identify the moleculardeterminants of CRC modulated by claudin-1 in AA relative to that in CA patients. Specific Aim 2.Determine the effects of claudin-1 inhibition on PDXs from AA and CA patients with CRC. Thesuccessful completion of this project will yield a claudin-1-associated molecular signature topredict aggressive disease and a claudin-1-targeted therapy for CRC for AA patients. 238397 +No NIH Category available Administrative Supplement;Affect;Anoikis;Anxiety;Area;Automobile Driving;Biological;Biological Markers;Biological Process;Black Populations;Black race;Blood;Blood specimen;Brain;Cancer Patient;Cell Death;Cells;Chronic;Chronic stress;Couples;Data;Dedications;Detection;Disparity;Endosomes;Environment;Ethnic Origin;Exposure to;Extracellular Matrix;Fibroblasts;Fright;Functional disorder;Generations;Genetic Transcription;Geographic Locations;Glutamate Metabolism Pathway;Glutamates;Health Services Accessibility;Homeostasis;Housing;Immunosuppression;Individual;Institutional Racism;Link;Location;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mental Health;Modeling;Neighborhoods;Nutritional Support;Organ;Outcome;Pancreas;Pathway interactions;Patient-Focused Outcomes;Patients;Physiological;Poverty;Production;Proteins;Psyche structure;Psychosocial Factor;Race;Racial Segregation;Regulation;Reporting;Research;Research Personnel;Resources;Stress;Survival Rate;Synapses;Testing;Time;Tumor Promotion;Vesicle;cancer cell;cancer health disparity;cancer survival;circulating biomarkers;early detection biomarkers;environmental disparity;extracellular vesicles;forging;genetic signature;health disparity;multidisciplinary;novel;pancreatic cancer cells;pancreatic cancer patients;pancreatic neoplasm;parent grant;post-traumatic stress;prevent;prognostic;receptor;scaffold;socioeconomics;stressor;tumor;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Pancreatic Cancer-Associated Fibroblasts: Function Detection and Regulation PROJECT NARRATIVEThis study uniquely couples chronic stress endured by individuals residing within underserved geographiclocations (neighborhoods) with biological tumor-promoting markers generated by the non-cancer pancreaticcells during pancreatic cancer. The study hence aims to inform on key biologic basis of pancreatic cancerhealth disparities an understudied but NCI high priority area. NCI 10767490 9/11/23 0:00 PAR-22-114 3R01CA269660-02S1 3 R01 CA 269660 2 S1 "WOODHOUSE, ELIZABETH" 6/1/22 0:00 5/31/27 0:00 Tumor Microenvironment Study Section[TME] 7852640 "CUKIERMAN, EDNA " Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 254999 NCI 135638 119361 PROJECT SUMMARY/ABSTRACTPancreatic Cancer (PC) survival rates are very low and even lower for patients from low socioeconomicbackgrounds/circumstances (SES) often living in geographic locations with limited access to care. Oneexplanation for this disparity could be chronic stress. Several researchers including our CollaborativeInvestigator have shown that Black individuals and those living in neighborhoods with low SES endure sustainedexposure to stressful circumstances (e.g. systemic racism lack of resources) which impact mental health (e.g.anxiety fear) and augment PC. Neighborhood SES (nSES) hence serve as a macro-environmental indicator ofchronic stress independent of a patients SES and mental health. Low nSES can for example prevent cancercell death and promote its aggressiveness. If the biologic basis of PC health disparities is to be elucidatedstudies proposing to understand how for example nSES impacts PC are needed. The parent grant focuses onstudying the non-cancerous cells and natural scaffold units of the pancreas in PC. Of note the specific moleculesstudied are implicated in chronic stress. In fact some chronic stress features such as glutamate excess aresimulated by the non-cancerous units of the pancreas during PC. We reported that pro-tumorigenic activationof these units are indicative of unfavorable PC patient outcomes. Interestingly the same units also are implicatedin synapse stability in brain and in the generation of small membranous vesicles that are produced by these unitsand can be detected in blood. Building on this our parent grant proposes to: i) reveal how the natural scaffold ofthese units regulates pro tumoral unit functions; ii) assess whether detection of the unique unit-generatedmembranous vesicles inform on the pancreatic tumor-promoting vs. tumor-suppressing status of PC patientsorgan; and iii) question if the molecules relevant for driving pro-tumoral function of the units can be targeted.Here we plan to expand this scope by forging a multidisciplinary partnership with a disparity research expert Dr.Shannon Lynch in the form of 3 specific new aims:Aim 1: Measure biomarkers (high Glu & others) and macro-environmental measures of chronic stress (nSES;racial segregation) to determine if high levels of environmental stress correlate with biologic stress.Aim 2: Evaluate the correlation between chronic stress measures (biomarkers macro-environmentalmeasures) and pro-tumoral circulating biomarkers in vesicles informing on local stress-like microenvironments.Aim 3: Determine if microenvironment-indicative biomarkers are associated with PC patient survival timealone and after adjustment for comprehensive chronic stress measures and race/ethnicity in multivariableregression models. 254999 +No NIH Category available Advanced Malignant Neoplasm;Affect;Analgesics;Behavior Therapy;Behavioral;Behavioral Model;Cancer Intervention;Cancer Patient;Cellular Phone;Chronic Cancer Pain;Clinical Trials;Cognitive Therapy;Complication;Data;Distress;Doctor of Philosophy;Education;Feasibility Studies;Funding;Future;Goals;Health Technology;Intervention;Interview;Knowledge;Learning;Life;Malignant - descriptor;Malignant Neoplasms;Measures;Medical;Medication Management;Mentors;Mentorship;Methods;Mission;Mobile Health Application;Monitor;Opioid;Pain;Pain interference;Pain management;Palliative Care;Patients;Persons;Pharmacotherapy;Population;Psychology;Randomized;Research Activity;Research Personnel;Scientific Advances and Accomplishments;Secondary pain;Series;Structure;Symptoms;Target Populations;Technology;Testing;Training;Training Programs;United States National Institutes of Health;behavioral clinical trial;biopsychosocial;cancer pain;chronic pain;chronic pain patient;daily pain;design;digital healthcare;effective therapy;efficacy trial;improved;longitudinal analysis;mHealth;novel;pain outcome;pain self-management;patient subsets;pharmacologic;psychologic;randomized clinical trials;recruit;research faculty;retention rate;smartphone application;therapy design;therapy development;treatment as usual Admin Supplement: Integrating pain-CBT into an mHealth analgesic support intervention for patients with chronic pain from advanced cancers PROJECT NARRATIVEChronic pain a common and distressing complication of advanced cancer is commonly treated withanalgesics with minimal access to comprehensive biopsychosocial pain management approaches. Aligningwith NCI's mission to advance scientific knowledge to help patients live longer healthier lives this K08proposal seeks to improve cancer patients' pain self-management by adapting and integrating cognitivebehavioral therapy for pain into an existing mHealth intervention designed to optimize pharmacologicmanagement (e.g. daily pain/opioid monitoring and tailored advice) for patients with advanced cancer. Thisintegrated psychological and pharmacologic mHealth intervention has strong potential to improve cancer painoutcomes and to readily disseminate pain management support and alleviate pain for a wide range of patientswith advanced cancer. NCI 10767398 3/14/23 0:00 PA-20-272 3K08CA266937-01S1 3 K08 CA 266937 1 S1 "RADAEV, SERGEY" 7/1/22 0:00 6/30/27 0:00 15744827 "AZIZODDIN, DESIREE R" Not Applicable 5 FAMILY MEDICINE 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 398 Other Research-Related 2023 52021 NCI 48168 3853 PROJECT SUMMARY/ABSTRACTPain affects approximately two thirds of patients with advanced incurable cancers. Cognitive BehavioralTherapy for pain (pain-CBT) is an effective treatment for chronic pain from cancer. Unfortunately pain-CBT inits traditional format (60-minute in-person sessions) is often unrealistic for patients with advanced cancer.Behavioral treatments require substantial adaptation to meet advanced cancer patients' real-life needs andshould ideally integrate with their pharmacotherapy (e.g. opioid) plans. Mobile health (mHealth) technology is apromising strategy to deliver and ultimately disseminate brief pain-CBT interventions to cancer patients.The goal of Dr. Azizoddin's K08 proposal is to develop a novel mHealth application that integrates brief pain-CBT into an existing mHealth application designed to optimize opioid management for patients with chronicpain from advanced incurable cancers. Leveraging co-mentor's app (R21-funded) Smartphone Technology toAlleviate Malignant Pain (STAMP) is a patient-facing smartphone app that facilitates daily symptom and opioidmonitoring and delivers tailored pain education and advice. Following the NIH Stage Model for BehavioralIntervention Development (Stage:1A&1B) Dr. Azizoddin will create STAMP+CBT a novel intervention thatharmonizes psychological and medical support for advanced cancer pain. In AIM 1: the PI will develop andrefine STAMP+CBT by adapting pain-CBT for brief mHealth delivery through a series of iterative qualitativeinterviews and wireframe and user acceptability testing (AIM 1A). STAMP+CBT will be programmed andtested in a small pre-pilot with the target population to inform app refinements (AIM 1B). In AIM 2: 60 patientswith chronic pain related to advanced cancer will be randomized to the app or usual care + digital cancer paineducation for 6 weeks. Feasibility of the study will be determined by examining recruitment/retention rates andcompletion rates of app-delivered pain-CBT content. A subset of patients will complete qualitative debriefinginterviews to inform final app refinements. Measures will explore anticipated primary (pain interference) andsecondary pain outcomes to inform the design of a future (R01) efficacy trial of STAMP+CBT. Dr. Azizoddin'sresearch activities will be mentored by an interdisciplinary team of expert investigators in pain psychology(Robert Edwards PhD) palliative care clinical trials (Andrea Enzinger MD & James Tulsky MD) cancer pain(Christine Miaskowski PhD) and mobile health (Michael Businelle PhD & Daniel Gundersen PhD). This K08proposal will allow Dr. Azizoddin to acquire training in: 1) adapting psychological pain interventions for cancerpopulations 2) learning rigorous methods to develop/refine behavioral mHealth interventions 3) conductingrandomized clinical trials of behavioral interventions and 4) conducting longitudinal analysis of momentarypain/psychological mHealth data. This training program and structured mentorship under the guidance ofesteemed research faculty will provide Dr. Azizoddin with the support necessary to become a successfulindependent investigator specializing in effective and scalable behavioral treatments to improve cancer pain. 52021 +No NIH Category available Research Training;Surgical Oncology;Training Programs Surgical Oncology Research Training Program RELEVANCEThere remains a great need for research to prevent and treat cancer. Surgeons-scientists are uniquelypositioned to translate research findings associated with surgical diseases to the bedside and operating room.This program seeks to increase the number of surgeon-scientists that are committed to investigativeexcellence in academic surgical oncology. NCI 10767059 9/14/23 0:00 PA-20-142 2T32CA229102-06A1 2 T32 CA 229102 6 A1 "DAMICO, MARK W" 7/16/18 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1898868 "CHEN, HERBERT " "DUDEJA, VIKAS " 7 SURGERY 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 512949 NCI 485686 34548 PROJECT SUMMARY Cancer remains one of the most common causes of death in the United States second only tocardiovascular disease. Great need exists for continued research to prevent cancer and improve outcomes.Surgeon-scientists are uniquely positioned to translate research findings associated with surgical diseases tothe bedside and operating room. Despite their unique expertise and effectiveness in research the role of thesurgeon-scientist has historically been threatened for the last few decades. Surgeon-scientists are submittingfewer career development awards and have lower success rates in obtaining NIH funding. There has beenonly small growth in the percentage of surgeons funded by NIH in the past 10 years but surgical oncologistsrepresent the largest group of surgeon subspecialists receiving NIH grants. It is critical that we continue toexpand this pool of investigators and develop surgeon-scientists in the field of oncology. The overall program goal of the Surgical Oncology Research Training Program at the University ofAlabama at Birmingham (UAB) is to provide surgical residents who are strongly motivated toward a career insurgical oncology with a comprehensive mentored research and training experience that prepares them forsuccessful careers as surgeon-scientists. The program provides surgeon-scientists who intend to enter acareer in academic surgery particularly in surgical oncology with the opportunity for basic translational andhealth services research training in a mentored multidisciplinary collaborative environment. The programleverages the extensive resources of the UAB Department of Surgery UAB ONeal Comprehensive CancerCenter (CCC) the UAB Heersink School of Medicines Center for Clinical and Translational Science (CCTS)the Office of Postdoctoral Education (OPE) and an abundance of health services and disparities researchprograms and centers. The program includes a pool of outstanding extramurally funded trainers from a varietyof cancer-related disciplines. Seven trainees have completed the program; 1 has obtained a faculty positionwith NCI funding and 6 are continuing their clinical training in environments that will facilitate their continuedsuccess in developing independent academic careers. An additional 4 are currently appointed. Several haveobtained additional degrees to advance their scientific knowledge and several have been successful inobtaining additional funding to support their fellowship training or further career development. While this is anew program it has already been successful in developing its first NIH-funded surgeon-scientist. It hasalso attracted a diverse group of trainees including 27% African American and 82% female. Traineeshave demonstrated excellent productivity as evidenced by publications and national presentations.These early markers of success are clear indicators of the programs future ability to produceextramurally funded surgeon-scientists in the field of surgical oncology. 512949 +No NIH Category available ARNTL gene;Acceleration;Address;Administrative Supplement;Adult;Award;Biological Assay;Cell Proliferation;Circadian Dysregulation;Circadian Rhythms;Circadian gene expression;Code;Colorectal Cancer;Complex;Computer Analysis;Coupled;DNA Damage;Data;Death Rate;Development;Diagnostic Neoplasm Staging;Dietary Factors;Down-Regulation;Environmental Risk Factor;Enzymes;Funding;Genes;Genetic;Genome;Genome Stability;Genomic Instability;High Fat Diet;Human;Intestinal Polyps;Intestines;Link;Loss of Heterozygosity;Malignant Neoplasms;Maps;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;Mus;Mutation;Oncogenic;Organoids;Parents;Pathogenesis;Pathway interactions;Patients;Peroxisome Proliferator-Activated Receptors;Prevention strategy;Proliferating;Reporting;Research;Risk Factors;Signal Transduction;Stress;Surveys;Survival Rate;System;Testing;The Cancer Genome Atlas;Time-restricted feeding;WNT Signaling Pathway;biobank;c-myc Genes;cancer prevention;cancer type;cell growth regulation;circadian;circadian pacemaker;circadian regulation;colon cancer patients;dietary control;early onset colorectal cancer;exome sequencing;experimental study;human data;interdisciplinary approach;intestinal epithelium;knock-down;metaplastic cell transformation;mouse model;novel;nutrition;older patient;parent grant;pharmacologic;reconstitution;response;stable isotope;stemness;supplemental instruction;transcription factor;transcriptome;tumorigenesis Circadian Clock and Myc-dependent Regulation of Cellular Transformation The supplement instructions for PAR-22-114 state: At a minimum the Research Strategysection should be completed and must include a summary or abstract of the funded parentaward or project. Other sections should also be included if they are being changed by theproposed supplement activities.The original Project Narrative document has not changed as a result of the proposedsupplement activities. NCI 10767049 8/8/23 0:00 PAR-22-114 3R01CA259370-02S1 3 R01 CA 259370 2 S1 "LUO, RUIBAI" 8/1/23 0:00 7/31/25 0:00 10549858 "MASRI, SELMA " Not Applicable 47 BIOCHEMISTRY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 135445 NCI 93397 42048 The supplement instructions for PAR-22-114 state: At a minimum the Research Strategysection should be completed and must include a summary or abstract of the funded parentaward or project. Other sections should also be included if they are being changed by theproposed supplement activities.The original Project Summary / Abstract document has not changed as a result of theproposed supplement activities. 135445 +No NIH Category available Address;Antibodies;Antigen Targeting;Antigens;B-Cell Neoplasm;B-Lymphocytes;Binding;Binding Proteins;Biological Assay;Bispecific Antibodies;Bite;CD3 Antigens;CTLA4 gene;Cancer Center;Cancer Patient;Carbohydrates;Cell Surface Proteins;Cell surface;Cells;Clinical Trials;Combined Modality Therapy;Complex;Data;Detection;Development;Disease;Disease Progression;Dose;Drug Kinetics;FDA approved;Fc domain;Funding;Future;Half-Life;Human;Immune;Immune checkpoint inhibitor;Immune system;Immunoglobulin Fragments;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;In Vitro;Intravenous infusion procedures;Invaded;Investigational Therapies;Lectin;Malignant Neoplasms;Metastatic/Recurrent;National Cancer Institute;National Cancer Program;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Patients;Phase;Phase I Clinical Trials;Phosphatidylinositols;Phosphotransferases;Polysaccharides;Prognosis;Proteins;Receptor Protein-Tyrosine Kinases;Refractory;Regulatory T-Lymphocyte;Relapse;Safety;Sequential Treatment;Serum;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Specificity;Surface;Surface Antigens;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Toxic effect;Transgenic Mice;Tumor Antigens;Work;bi-specific T cell engager;cancer cell;cancer immunotherapy;cell motility;cost;driver mutation;first-in-human;humanized mouse;immune checkpoint blockade;in vitro activity;in vivo;manufacture;mouse model;neonatal Fc receptor;neonatal human;new technology;novel;novel therapeutics;overexpression;palliative;phase I trial;pre-clinical;preclinical development;prevent;programmed cell death protein 1;programs;safety assessment;stable cell line;sugar;tumor growth Extendedhalf-lifeGlyTR1 combined with checkpoint blockadefor Cancer Immunotherapy Project NarrativeDirecting the immune system to kill cancer cells is a highly potent way of treating cancer.Abnormal addition of carbohydrates to proteins is a near universal feature of cancer howevercurrent immunotherapies cannot readily target these. Here we propose to further develop a noveltechnology that directs immune cells to kill cancer cells based on expression of alteredcarbohydrates. NCI 10766646 9/20/23 0:00 PA-22-178 1R42CA285234-01 1 R42 CA 285234 1 "DJEMIL, SARRA" 9/21/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 7042327 "DEMETRIOU, MICHAEL " "ZHOU, RAYMOND WENHOU" 15 Unavailable 80209701 ZKQLT6S8LXY9 80209701 ZKQLT6S8LXY9 US 33.64852 -117.82136 10045711 "GLYTR THERAPEUTICS, INC." San Carlos CA Domestic For-Profits 94070 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 400000 NCI 374483 0 Abstract Treatment of non-resectable recurrent/metastatic solid cancers is currently palliative only and there is anurgent unmet need for novel mechanisms of action and additional paradigm shifting therapeutic options. Antigen-targeting cancer immunotherapies such as bi-specific antibodies (eg Bi-specific T cell engager or BiTEs) providea unique approach for cancer immunotherapy. However applying this therapeutic tactic to solid cancers hasbeen restricted by a limited number of protein antigens safe for targeting. Moreover even if safe cell-surfaceantigens are identified different bi-specific antibodies will likely be needed for each different antigen/cancer. Thiswould greatly increase development time and costs. Thus there remains a great need for additional safe antigen-specific immunotherapies particularly for those with refractory/metastatic solid cancers who have fewtherapeutic options. Many cell surface cancer-specific antigens are not proteins but rather complexcarbohydrates that have limited or no expression in normal tissues. For example 16GlcNAc-branched N-glycans constitute a small subset of the complex-type N-glycans expressed at the surface of normal human cellsbut are markedly up-regulated in diverse solid cancers by driver mutations in the receptor tyrosinekinase/RAS/phosphoinositide-3-kinase(PI3K) signaling pathway. Aberrant over-expression of 16GlcNAc-branched N-glycans in solid tumors drives RTK signaling tumor growth motility invasion and metastasis. Asboth a marker and driver of many diverse cancers 16 GlcNAc-branched N-glycans provide an excellent targetfor antigen-specific immunotherapies. However an antibody to 16GlcNAc-branched N-glycans has never beengenerated. To address this issue we generated a novel class of immunotherapeutics that readily target abnormalglycan antigens with high specificity. We have termed this technology Glycan-dependent T cell Recruiter(GlyTR pronounced glitter). With funding from the Biden Cancer Moonshot program of the National CancerInstitute we developed and optimized the GlyTR1 bi-specific protein that binds both 16GlcNAc-branched N-glycans and CD3 in T cells. The GlyTR1 bi-specific protein induces T cell-dependent killing of a wide diversity ofsolid cancers in vitro and in vivo with EC50s as low as ~50 femtomolar yet does not kill normal cells or triggeron-target off-cancer toxicity in humanized mouse models. GlyTR1 is undergoing late-stage IND-enablingstudies and upon FDA approval the UC Irvine Cancer Center will perform a dose-escalation Phase 1 clinicaltrial in relapsed/metastatic solid cancer. However as GlyTR1 has a short half-life of ~2.5hrs and requiresconstant intravenous infusion herein we propose to develop a longer half-life version of GlyTR1. We alsopropose to examine for potential additive/synergistic activity with checkpoint inhibitors. Data from thisproposal will be used to inform future clinical trials following confirmation of safety of GlyTR1 in our Phase 1 trialnamely whether a longer half-life GlyTR1 and/or co-treatment with checkpoint inhibitors should be pursued. 400000 +No NIH Category available Adult;Animals;Binding;Biological Assay;Biological Availability;Cancer Patient;Canis familiaris;Cell Culture Techniques;Cell Cycle Progression;Cell Death;Cell Line;Cell Proliferation;Cell physiology;Cellular Assay;Clinical;Clinical Trials;Colorectal Cancer;Dependence;Dissociation;Dominant-Negative Mutation;Dose;Dose Limiting;Drug Kinetics;Genes;Genetic Transcription;Grant;Growth;Guidelines;Homeostasis;Human;In Vitro;Intellectual Property;Lead;Legal patent;Liver Microsomes;MYC Family Protein;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Metabolic;Modeling;Molecular;Molecular Conformation;Monitor;Mus;Neuroblastoma;Oral;Patients;Peptides;Permeability;Pharmaceutical Preparations;Phase;Phosphotransferases;Play;Pre-Clinical Model;Proliferating;Property;Protein-Serine-Threonine Kinases;Proteins;Proto-Oncogene Proteins c-myc;Protocols documentation;Rattus;Research;Resistance;Role;Safety;Small Business Innovation Research Grant;Solubility;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Toxicokinetics;Toxicology;Transgenic Mice;Translations;Validation;Vendor;Xenograft Model;anti-cancer;aurora kinase A;c-myc Genes;cancer cell;cancer type;canine model;colon cancer cell line;drug candidate;efficacy evaluation;efficacy testing;functional group;improved;inhibitor;mouse model;multicatalytic endopeptidase complex;novel;overexpression;paralogous gene;preclinical development;preclinical safety;safety study;small molecule;tool;transcription factor;tumor growth;tumor xenograft;tumorigenesis Small Molecule MYC Degraders as Novel Cancer Therapeutic Agents PROJECT NARRATIVEThis proposal seeks to continue the pre-clinical development of novel MYC degraders to treat c-myc-dependentnon-small cell line cancers (NSCLCs) and colorectal cancers (CRCs). We show that our MYC degraders harborexcellent drug-like properties and are effective in inhibiting the growth of c-myc-dependent NSCLC and CRC inpre-clinical models. Our MYC degraders have potential to impact the lives of millions of cancer patients in U.S.and represent a significant market opportunity. NCI 10766504 9/22/23 0:00 PA-22-176 2R44CA268456-02 2 R44 CA 268456 2 "WEBER, PATRICIA A" 4/5/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 12682168 "FEI, DENNIS LIANG" "KNOWE, MATTHEW " 26 Unavailable 826941754 WVEMHJFUNJ97 826941754 WVEMHJFUNJ97 US 25.794577 -80.206744 10020810 "STEMSYNERGY THERAPEUTICS, INC." MIAMI FL Domestic For-Profits 331361104 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 939827 NCI 759217 119126 PROJECT SUMMARY/ABSTRACTThe MYC family proteins are comprised of three paralogs termed c-myc N-myc and L-myc. The MYC proteinsplay a fundamental role in cell proliferation and oncogenesis by regulating cellular processes such as genetranscription protein translation cell cycle progression and cell death. While N-myc and L-myc driveoncogenesis in a small number of cancer types the requirement of c-myc is widespread in a broad range ofhuman cancers. MYC protein levels are highly regulated by Aurora A: both c-myc and N-myc bind to Aurorakinase A to escape proteasomal degradation. With the support of SBIR Phase I we have successfully identifiednovel small molecules that 1). directly target the MYC:Aurora A binding interface 2). potently degrade bothendogenous N-myc and c-myc (henceforth MYC degraders) 3). are metabolically stable and orallybioavailable and 4). are efficacious in inhibiting the growth of tumors dependent on either N-myc or c-myc.For the SBIR Phase II period we plan to advance pre-clinical development of our MYC degraders with anemphasis on treating c-myc-dependent cancers. We propose two specific aims:Specific Aim 1: Test the efficacy of SSTA-315 across c-myc dependent cancers while in parallel developderivative c-myc degraders with improved potency and efficacy.Specific Aim 2: Evaluate the safety profile of SSTA-315 (or an alternative lead MYC degrader) in IND-enablingGLP toxicity studies.Successful completion of the proposed studies will complete IND-enabling safety studies for our lead MYCdegrader preparing for the IND registration with the FDA as the immediate next step. Given that MYC proteinsare deregulated in most human cancers our MYC degraders have potential to impact the lives of millions ofcancer patients in U.S. and represent a significant market opportunity. 939827 +No NIH Category available 2-tyrosine;ABL1 gene;ABL2 gene;Ablation;Animal Model;Biological;Brain;Cell Hypoxia;Cells;Cellular biology;Characteristics;Clinical Trials;Dasatinib;Data;Dependence;Development;Disseminated Malignant Neoplasm;Doctor of Philosophy;Environment;FDA approved;Fellowship;Foundations;Future;Genetic Transcription;Gleevec;HSF1;Hypoxia;Impairment;In Vitro;Intervention;Investigation;Luciferases;Lung Adenocarcinoma;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Mediating;Metastatic malignant neoplasm to brain;Modality;Nature;Neoplasm Metastasis;Oxygen;Patient-Focused Outcomes;Patients;Phosphoric Monoester Hydrolases;Phosphotransferases;Phosphotyrosine;Play;Postdoctoral Fellow;Principal Investigator;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;Proto-Oncogene Proteins c-abl;Reporter;Reporting;Research;Research Project Grants;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;Technology;Therapeutic;Time;Training;Translating;Trastuzumab;Tumor-Associated Process;Tyrosine Kinase Inhibitor;Tyrosine Phosphorylation;Work;anticancer research;autocrine;brain parenchyma;cancer cell;cancer therapy;career;effective therapy;efficacious treatment;high-throughput drug screening;improved;in vivo;inhibitor;leukemia;lung cancer cell;lung colonization;molecular targeted therapies;oxidation;pharmacologic;pre-clinical;pre-doctoral;preclinical study;programs;response;restraint;skills;small molecule;targeted treatment;trait;transcription factor;tumor;tumor hypoxia;tumor microenvironment;tumor progression;ubiquitin-protein ligase Understanding the impact that tumor representative oxygen tension has on phosphotyrosine-dependent signaling networks in solid tumors PROJECT NARRATIVELow oxygen tension despite being a distinguishing trait of solid tumors is rarely recapitulated in preclinicalcancer research leading to the investigation of less-representative signaling pathways and the omission ofhypoxia induced sensitivities and resistances to pharmalogical intervention. This proposal describes completedand ongoing pre-doctoral efforts to uncover actionable targets of tyrosine kinase signaling pathways that emergeduring hypoxia and in hypoxic metastatic niches as well as future post-doctoral efforts to investigate the impactof hypoxia induced tyrosine phosphatase (PTP) inactivation. Further since PTPs restrain cellular signalingidentification of emergent sensitivities due to the loss of PTP activity may result in the identification of biologicalmechanisms amenable to therapeutic exploitation that have been not captured in previous normoxic efforts. NCI 10765139 6/5/23 0:00 RFA-CA-20-048 4K00CA264162-03 4 K00 CA 264162 3 "ELJANNE, MARIAM" 9/1/21 0:00 5/31/27 0:00 ZCA1-SRB-H(M1) 15173399 "MAYRO, BENJAMIN JACOB" Not Applicable 30 BIOCHEMISTRY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Other Research-Related 2023 89100 NCI 82500 6600 PROJECT SUMMARY/ ABSTRACTThe perturbation of phospho-tyrosine mediated signaling networks is an essential occurrence during themultistep process of tumor development and progression. As a result the components of these phospho-tyrosinesignaling networks especially tyrosine kinases have been shown to be a key reservoir of actionable moleculartargets for the treatment of cancer. In recent years it has been revealed that the tumor microenvironment playsa critical role in modulating the signaling pathways that govern tumor progression and metastasis. The featuresof a tumor's microenvironment have been shown to produce unique sensitivities and resistances to differenttreatment modalities. One major aspect of the tumor microenvironment which is often overlooked in preclinicalstudies is oxygen tension. This proposal seeks to understand the impact that oxygen tension has onphosphotyrosine-dependent signaling networks in solid tumors and how the resultant vulnerabilities can betargeted to improve patient outcome. In Aim 1.1 (prior studies) we sought to identify alterations in signalingnetworks that occur when lung cancer cells colonize the brain a hypoxic environment. We showed that brain-metastatic lung cancer cells elevate and have an increased dependence on a non-canonical HSF1-E2Ftranscriptional program for survival. Importantly we identified that this transcriptional program is targetablethrough treatment with allosteric ABL2 tyrosine kinase inhibitors. In Aim 1.2 (proposed studies) using a smallmolecule screen I have identified previously unrecognized modulators of the cellular response to hypoxia atumor microenvironment feature associated with increased metastasis and lower overall survival in patients withsolid tumors. The top uncharacterized hit was the FDA-approved ABL1/2 tyrosine kinase inhibitor Dasatinib andmy preliminary investigation has shown that the ABL kinases are critical regulators of HIF-1 protein stability. Iwill continue mechanistic investigation of the ABL- HIF-1 axis in vitro and in vivo. Finally in Aim 2 (post-doctoralstudies) I will focus on understanding the impact that tumor representative- oxygen tension has on proteintyrosine phosphatase activity. Extensive investigation has demonstrated that tumor hypoxia induces activationof phospho-tyrosine signaling networks but current work has almost exclusively focused on the role of tyrosinekinases. I show that hypoxia induces inhibitory oxidation of protein tyrosine phosphatases (PTPs). Using mass-spectrometry based approaches I will identify the oxidized- PTP landscape (ox-PTPome) of tumor samples andcancer cells at oxygen levels observed in tumors. Further since PTPs restrain cellular signaling I will employhigh-throughput drug screening technologies in vitro to identify emergent sensitivities due to the loss of PTPactivity that would not have been captured in the numerous normoxically (tumor-unrepresentative oxygen level)performed screens. Overall the focus of my career is to understand how the different characteristics of the tumormicroenvironment such as hypoxia modulates the signaling networks co-opted by cancer cells and translatethis to the identification of biological mechanisms that may be amenable to therapeutic exploitation. 89100 +No NIH Category available Affect;Anabolism;Animal Model;Awareness;Biological Markers;Breast Cancer Cell;Cells;Cessation of life;Colorectal Cancer;Complex;Cytoprotection;Dependence;Distal;Drug Metabolic Detoxication;Endoplasmic Reticulum;Environment;Enzymes;Foundations;Functional disorder;Future;Genetic Engineering;Impairment;Malignant Neoplasms;Membrane;Metabolic;Modeling;Normal Cell;Normal tissue morphology;Oxidoreductase;Palmitates;Palmitoyl Coenzyme A;Pathway interactions;Patients;Play;Poison;Poisoning;Predisposition;Production;Property;Role;Serine;Shock;Sphingolipids;Therapeutic;Tissues;Toxic effect;Tumor Markers;Tumor Tissue;Ubiquitin;Work;cancer cell;cancer cell subtype;cancer subtypes;cancer therapy;cancer type;endoplasmic reticulum stress;inhibitor;insight;ketodihydrosphingosine;malignant breast neoplasm;misfolded protein;multicatalytic endopeptidase complex;novel;patient derived xenograft model;prevent;proteostasis;response;serine palmitoyltransferase;targeted cancer therapy;therapeutic target;triple-negative invasive breast carcinoma;tumor;uptake Targeting the detoxification function of the enzyme KDSR for cancer therapy PROJECT NARRATIVEThe studies in this project will explore the therapeutic potential of targeting KDSR a metabolic enzyme whichwe hypothesize plays and important role in preventing buildup of a toxic metabolite (3KDS) in multiple subtypesof cancer cells such as triple negative breast cancer cells. This toxic metabolite may be produced in higher levelsin cancer cells compared to normal cells and tissues making this a potentially cancer-selective therapy. We willidentify the factors that produce this toxic metabolite in cancer cells and compare/contrast their activities incancer cells versus normal cells. These efforts will help us develop effective strategies around this new targetsuch as how to identify the cancer subtypes that would respond well and what toxicities to normal cells to beaware of. NCI 10764824 11/30/23 0:00 PA-20-185 5R01CA269711-02 5 R01 CA 269711 2 "CHEN, WEIWEI" 1/16/23 0:00 12/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 10726637 "KIM, DOHOON " Not Applicable 2 ANATOMY/CELL BIOLOGY 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 349944 NCI 208922 141022 PROJECT SUMMARYIt is increasingly recognized that certain metabolic enzymes are required in cells not for what they producebut instead for processing and thus preventing the accumulation of their substrates which may have toxicproperties. Such enzymes can be attractive therapeutic targets as their inhibition can poison cancer cellswith self-produced toxic metabolites in a manner that is highly dependent on production of the toxicmetabolite. Here we investigate a new detoxifying enzyme ketodehydrosphinganine reductase (KDSR)which is part of the de novo sphingolipid biosynthesis pathway. We find that KDSR is not required toprovide sphingolipids as cancer cells can readily salvage them from their environment but instead isneeded to prevent accumulation of its substrate 3-ketodehydrosphinganine (3KDS). Accumulation of3KDS either via KDSR KO or by direct treatment of 3KDS to cells appears to disrupt the endoplasmicreticulum (ER) and cause an overload of misfolded proteins in cancer cells. This indicates KDSR as apotential cancer therapy target capable of impairing ER function and proteostasis in cancer cells whichwe will explore in this proposal. In Aim 1 we will examine the upstream steps that drive 3KDS productionwhich we hypothesize are elevated in multiple cancer subtypes and thus directly renders the cellsdependent on KDSR for 3KDS detoxification. These will be further considered as possible biomarkers fortumors that would respond to KDSR targeting. In Aim 2 we will examine how 3KDS accumulation disruptsthe ER and leads to death and the responses mounted by cancer cells to counter 3KDS toxicity. In Aim3 we will gauge the therapeutic potential of targeting KDSR by comparing 3KDS production capacitybetween tumor tissues and normal tissues from animal models and from deidentified patient tissues. Inthis manner we hope to provide a working blueprint for how to selectively target subtypes andsubpopulation of cancer cells based on their 3KDS producing activities provide biomarkers which predictwhether a tumor will respond to such a therapy and provide new insights into the endoplasmic reticulum-and proteostasis- related vulnerabilities of cancer cells. 349944 +No NIH Category available AIDS related cancer;Affect;Area;Behavior;Black race;Cancer Center Support Grant;Caring;Clinical;Consent;Coupled;Diagnosis;Discrimination;Disease remission;Ethnic Origin;Food;Future;Gender Identity;HIV;HIV diagnosis;Health;Healthcare;Homophobia;Housing;Income;Insurance Coverage;Intervention;Interview;Latinx;Malignant Neoplasms;Methods;Monitor;Outcome;Paper;Participant;Patients;Perception;Persons;Prevention;Primary Care;Provider;Quality of Care;Race;Risk Factors;Role;Screening for cancer;Sexual and Gender Minorities;Shapes;Societal Factors;Stage at Diagnosis;Structure;Surveys;Survival Rate;System;Time;Transportation;built environment;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer risk;cancer therapy;care outcomes;cohort;experience;follow-up;health care availability;improved;marginalized population;negative affect;poor health outcome;racism;resilience;screening;sexual identity;social determinants;social factors;social stigma;sociodemographic factors;structural determinants;structural health determinants;therapy design;therapy development;tool;treatment adherence;treatment and outcome Specialized CCSG supplement SODH and Quality of Cancer Care in HIV-associated Cancers PROJECT NARRATIVEMany social and societal factors have been identified which negatively impact the health of persons with HIVand cancer including cultural barriers access to healthcare stigma related to race ethnicity HIV status genderor sexual identity and more. However little is known about how these factors intersect to affect health outcomesfor persons with HIV and cancer. This project seeks to improve understanding of these social and societal factors- including patient provider and system-level drivers of cancer disparities among persons with HIV - in order toidentify future interventions aimed at eliminating cancer disparities in persons with HIV. NCI 10764695 9/13/23 0:00 PA-20-272 3P30CA023100-37S1 3 P30 CA 23100 37 S1 "BELIN, PRECILLA L" 7/1/96 0:00 4/30/24 0:00 ZCA1(J2) 1900169 "CALIFANO, JOSEPH A" Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 397 Research Centers 2023 247224 NCI 160280 86944 PROJECT SUMMARY/ABSTRACTPersons with HIV (PWH) experience worse cancer outcomes compared to those not living with HIV.Numerous social and structural determinants of health (SDOH) have been identified for PWH and for cancercare including cultural barriers stigma insurance status healthcare access the built environment and more.HIV stigma is associated with suboptimal engagement in care differential cancer risk and prevention behaviors.Further the cumulative burden of living with HIV compounded by a cancer diagnosis can negatively affect clinicaloutcomes. Few studies have explored the perspectives of PWH and cancer limiting development of interventionsdesigned to improve the treatment experience and outcomes. Additionally PWH from the most marginalizedgroups who are diagnosed with cancer have risk factors for poor health outcomes. Gender and sexual minoritiesas well as people who are Black or Latinx tend to have less access to health care poorer quality of care andgeneral health outcomes. However little is known about how SDOH risk factors intersect and affect HIV canceroutcomes.We seek to improve understanding of SDOH including patient provider and system-level drivers of cancerdisparities among PWH to identify the most critical and actionable areas for intervention. Our specific aims areto (1) Explore HIV care engagement and the cancer prevention diagnosis and treatment experiences ofPWH diagnosed with cancer focusing on (a) health care engagement and treatment adherence prior toand after cancer diagnosis and (b) the roles of social stigmas (e.g. HIV stigma cancer stigma racismhomophobia) in cancer screening and diagnosis; (2) Examine associations of SDOH with the cancerdiagnosis treatment and outcomes among PWH receiving care or follow-up of cancer at UCSD. This willbe accomplished using a mixed methods approach including (1) Semi-structured qualitative interviewsconducted with consenting UCSD patients undergoing cancer care or monitoring to better understand theexperience of PWH receiving cancer care and (2) quantitative methods to identify SDOH factors associated withhealth outcomes in UCSDs cohort of PWH and cancer via EMR abstraction coupled with a short quantitativesurvey. Identified factors will be associated with cancer outcomes including stage at diagnosis engagement incancer therapy remission and survival rates.Accomplishment of these aims will contribute to understanding the social and structural determinants ofcancer care outcomes among PWH and identify actionable areas for future interventions aimed atmitigation and elimination of cancer disparities in PWH. 247224 +No NIH Category available Address;Assessment tool;Award;Cancer Center;Cancer Control;Certification;Characteristics;Collaborations;Colorado;Communication;Competence;Cost Analysis;Data;Data Analyses;Databases;Dedications;Development;Dissemination and Implementation;Eligibility Determination;Evidence based program;Funding;Guidelines;Health;Infrastructure;Intervention;Link;Literature;Measures;Mentors;Metadata;Methods;Modeling;Names;National Cancer Institute;Outcome;Parents;Patients;Policies;Population;Practical Robust Implementation and Sustainability Model;Primary Care;Process;Provider;Publications;Published Comment;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Resources;Rural;Surveys;System;Testing;Training;Translating;Update;Vertebral column;cancer prevention;career;certificate program;contextual factors;cost;dissemination science;evidence base;human centered design;implementation measures;implementation science;implementation study;innovation;instrument;lung cancer screening;member;outreach;pilot test;practice setting;pragmatic implementation;preference;primary care practice;primary care setting;programs;public database;shared decision making;smoking cessation;theories;tool;web-based tool Expanding the Dissemination and Implementation Models webtool adding an assessment instrument for Implementation Science Project Narrative (from parent award P50 CA244688)We propose an Implementation Science Center for Cancer Control with a focus of developing validating andsharing innovative pragmatic models and methods related to the costs benefits and value of translatingevidence-based cancer control programs and guidelines into rural primary care practice settings. Our theme isPragmatic implementation science approaches to assess and enhance the value of cancer prevention andcontrol in rural primary care. These approaches will inform strategies to implement lung cancer screening andother cancer prevention and control interventions and advance implementation science by providing measuresreporting guides resources training and certification of competence. NCI 10764400 9/5/23 0:00 PA-20-272 3P50CA244688-05S2 3 P50 CA 244688 5 S2 "VANDERPOOL, ROBIN CLINE" 9/20/19 0:00 8/31/24 0:00 ZCA1(A1) 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 FAMILY MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 375995 NCI 173633 96367 Project Summary/Abstract (from parent award P50 CA244688)The theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. 270000 +No NIH Category available Address;Assessment tool;Award;Cancer Center;Cancer Control;Certification;Characteristics;Collaborations;Colorado;Communication;Competence;Cost Analysis;Data;Data Analyses;Databases;Dedications;Development;Dissemination and Implementation;Eligibility Determination;Evidence based program;Funding;Guidelines;Health;Infrastructure;Intervention;Link;Literature;Measures;Mentors;Metadata;Methods;Modeling;Names;National Cancer Institute;Outcome;Parents;Patients;Policies;Population;Practical Robust Implementation and Sustainability Model;Primary Care;Process;Provider;Publications;Published Comment;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Resources;Rural;Surveys;System;Testing;Training;Translating;Update;Vertebral column;cancer prevention;career;certificate program;contextual factors;cost;dissemination science;evidence base;human centered design;implementation measures;implementation science;implementation study;innovation;instrument;lung cancer screening;member;outreach;pilot test;practice setting;pragmatic implementation;preference;primary care practice;primary care setting;programs;public database;shared decision making;smoking cessation;theories;tool;web-based tool Expanding the Dissemination and Implementation Models webtool adding an assessment instrument for Implementation Science Project Narrative (from parent award P50 CA244688)We propose an Implementation Science Center for Cancer Control with a focus of developing validating andsharing innovative pragmatic models and methods related to the costs benefits and value of translatingevidence-based cancer control programs and guidelines into rural primary care practice settings. Our theme isPragmatic implementation science approaches to assess and enhance the value of cancer prevention andcontrol in rural primary care. These approaches will inform strategies to implement lung cancer screening andother cancer prevention and control interventions and advance implementation science by providing measuresreporting guides resources training and certification of competence. NCI 10764400 9/5/23 0:00 PA-20-272 3P50CA244688-05S2 3 P50 CA 244688 5 S2 "VANDERPOOL, ROBIN CLINE" 9/20/19 0:00 8/31/24 0:00 ZCA1(A1) 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 FAMILY MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 375995 NHLBI 19293 10707 Project Summary/Abstract (from parent award P50 CA244688)The theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. 30000 +No NIH Category available Address;Assessment tool;Award;Cancer Center;Cancer Control;Certification;Characteristics;Collaborations;Colorado;Communication;Competence;Cost Analysis;Data;Data Analyses;Databases;Dedications;Development;Dissemination and Implementation;Eligibility Determination;Evidence based program;Funding;Guidelines;Health;Infrastructure;Intervention;Link;Literature;Measures;Mentors;Metadata;Methods;Modeling;Names;National Cancer Institute;Outcome;Parents;Patients;Policies;Population;Practical Robust Implementation and Sustainability Model;Primary Care;Process;Provider;Publications;Published Comment;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Resources;Rural;Surveys;System;Testing;Training;Translating;Update;Vertebral column;cancer prevention;career;certificate program;contextual factors;cost;dissemination science;evidence base;human centered design;implementation measures;implementation science;implementation study;innovation;instrument;lung cancer screening;member;outreach;pilot test;practice setting;pragmatic implementation;preference;primary care practice;primary care setting;programs;public database;shared decision making;smoking cessation;theories;tool;web-based tool Expanding the Dissemination and Implementation Models webtool adding an assessment instrument for Implementation Science Project Narrative (from parent award P50 CA244688)We propose an Implementation Science Center for Cancer Control with a focus of developing validating andsharing innovative pragmatic models and methods related to the costs benefits and value of translatingevidence-based cancer control programs and guidelines into rural primary care practice settings. Our theme isPragmatic implementation science approaches to assess and enhance the value of cancer prevention andcontrol in rural primary care. These approaches will inform strategies to implement lung cancer screening andother cancer prevention and control interventions and advance implementation science by providing measuresreporting guides resources training and certification of competence. NCI 10764400 9/5/23 0:00 PA-20-272 3P50CA244688-05S2 3 P50 CA 244688 5 S2 "VANDERPOOL, ROBIN CLINE" 9/20/19 0:00 8/31/24 0:00 ZCA1(A1) 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 FAMILY MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 375995 OD 48872 27123 Project Summary/Abstract (from parent award P50 CA244688)The theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. 75995 +No NIH Category available AIDS related cancer;Address;Adult;Age;Aging;Area;Biological Factors;CD4 Lymphocyte Count;Cancer Control;Cancer Patient;Caring;Categories;Cessation of life;Characteristics;Clinical;Clinical Data;Clinical Research;Collaborations;Communities;Complex;Coupled;Data;Data Sources;Databases;Dedications;Development;Diagnosis;Disparity;Electronic Health Record;Epidemiology;Equity;Ethnic Origin;Face;Florida;Foundations;Funding;Future;General Population;Geography;Goals;HIV;HIV diagnosis;Health system;Healthcare Systems;Incidence;Individual;Inequity;Infrastructure;Insurance Coverage;Intervention;Knowledge;Link;Machine Learning;Malignant Neoplasms;Mediation;Methods;Morbidity - disease rate;Muslim religion;Natural Language Processing;Not Hispanic or Latino;Oncology;Outcome;Pathway interactions;Patients;Persons;Play;Policies;Population;Population Heterogeneity;Provider;Race;Research;Research Infrastructure;Research Personnel;Resources;Role;Social Environment;Stage at Diagnosis;Survival Rate;Transportation;United States;Work;barrier to care;cancer care;cancer invasiveness;cancer therapy;cancer type;care delivery;care outcomes;cohort;data repository;data resource;ethnic diversity;ethnic minority population;experience;health care availability;improved;innovation;insight;intervention delivery;lens;low socioeconomic status;mortality;novel;palliative;patient population;racial diversity;racial minority;rurality;social;social factors;social health determinants;social stigma;therapy development;tool;treatment comparison;treatment disparity;treatment pattern;trend;underserved area Harnessing EHR to develop a Florida-based Coalition on Cancer Care Inequities among PHIV (Social Determinants of Health and Quality of Cancer Care in HIV-associated Cancers) PROJECT NARRATIVEAlthough cancer is a leading cause of morbidity and mortality among people with HIV (PWH) they are less likelyto receive any treatment compared to their HIV-seronegative counterparts even after considering importantclinical factors such as cancer type and cancer stage at diagnosis. Despite the documented inequities in generalhealthcare access PWH experience limited prior work has investigated the role of multi-level social factorscollectively known as social determinants of health (SDoH) that may impact PWHs receipt of equitable high-quality cancer care. Through the present one-year proposal we set out to develop the necessary infrastructureto address this gap in scientific knowledge leveraging a novel electronic health record-based linkage of multiplehealth systems throughout Florida called OneFlorida+ (19 million patients) to gain real world insights into therole SDoH play in cancer treatment receipt among PWH in the US and facilitate the development of future patientor provider-level interventions tailored to the HIV oncology care context. NCI 10764381 8/16/23 0:00 PA-20-272 3P30CA076292-25S3 3 P30 CA 76292 25 S3 "PTAK, KRZYSZTOF" 2/18/98 0:00 1/31/27 0:00 Cancer Centers Study Section (A)[NCI-A] 1877243 "CLEVELAND, JOHN L." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 397 Research Centers 2023 249906 NCI 203465 46441 PROJECT SUMMARYIn the US people with HIV (PWH) experience elevated mortality and morbidity due to cancer compared to thegeneral population. Factors contributing to the disproportionate burden of poor cancer outcomes among PWH islikely multi-factorial including inter-connected clinical and social factors. Among other factors inequities incancer treatment delivery to PWH is likely a contributor to low cancer-specific survival rates PWH face in the US.It is known that PWH are less likely to receive cancer treatment compared to their HIV-seronegative counterpartseven after factoring important clinical factors such as cancer type and cancer stage at diagnosis. Althoughsignificant prior research demonstrates PWH experience many social barriers to health care a largelyunexplored area is the role social determinants of health (SDoH) play in inequitable cancer treatment delivery toPWH. Insights into cancer treatment inequities among PWH in the context of multi-level SDoH specificallyindividual-level factors such as insurance status and race/ethnicity as well as contextual SDoH based on anindividuals geographic social environment will provide a critical opportunity to facilitate patient- and provider-level intervention development tailored to PWH. To address this gap in scientific knowledge we propose toleverage a novel electronic health record (EHR)-based linkage of multiple health care systems across the stateof Florida covering 19 million patients and 70% of adults living in Florida called OneFlorida+. OneFlorida+presents a novel unprecedented context to characterize cancer treatment trends in the context of SDoHimpacting PWH given Florida has among the highest rates of cancer in the US a racially and ethnically diversepopulation and one of the highest HIV incidence rates in the US. Our aims include: Aim 1: Enhance electronichealth record data of patients with HIV and any invasive cancer with individual and contextual-level SDoHthrough developing novel NLP tools and linking external exposome databases; and Aim 2: Examine trends andsocial inequities in cancer treatment delivery to PWH diagnosed with invasive cancer. The present proposal willlead to three important outcomes: (1) the development of an interdisciplinary team of investigators dedicated toimproving cancer care delivery and outcomes among PWH a vulnerable priority cancer patient population inFlorida 16; (2) establishment of the necessary research infrastructure to inform the development of paradigmshifting interventions; and (3) the discovery of novel insights into the interplay between SDoH race/ethnicityHIV and cancer outcomes in FLs context. Taken together this one-year project provides a necessary foundationand the opportunity to apply an innovative lens to view important inequities in cancer control and will providetimely critical policy relevant findings to facilitate interventions for delivery of equitable high-quality cancertreatment to PWH in the US. 249906 +No NIH Category available Pleiotropic functions of FOXC2 in EMT stem cells and breast cancer progression Currently there are no treatment options available to kill cancer stem cells (CSCs) which are responsible forbreast tumor recurrence development of resistance to therapy and metastatic progression. We have identifieda novel CSC-specific signaling pathway. Modulation of this signaling pathway components with selective inhibitorwill help cure aggressive metastatic breast cancer. This proposal aims to define and characterize this clinically`targetable' signaling pathway that is indispensable for the generation maintenance and function of the breastCSC pool. NCI 10764124 7/26/23 0:00 PA-16-160 7R01CA155243-11 7 R01 CA 155243 11 "YASSIN, RIHAB R" 3/16/11 0:00 7/31/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 9340088 "MANI, SENDURAI AYYAVOO" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF MEDICINE 29034202 UNITED STATES N 12/2/22 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2022 321099 NCI 201316 119783 Development of resistance to therapies tumor relapse and metastasis pose significant risks to breast cancerpatients and are responsible for the majority deaths among these cancer patients. Recent studies havedemonstrated that the developmental process is known as epithelial-mesenchymal-transition (EMT) as well asa subpopulation of cancer cells termed cancer stem cells (CSC) in these various processes. We and othershave shown that the EMT program and stem cell properties are interconnected and specifically cancer cellsare capable of acquiring stem cell attributes through the activation of EMT. This suggested that targeting EMTprogram may reduce the disease burden and will decrease death among cancer patients. However the dearthof signaling pathways emanating from the tumor microenvironment capable of inducing EMT - includinginflammatory cytokines and transforming growth factor -1 (TGF1) makes it impossible to therapeutically targetEMT. Cumulative studies from our laboratory over the last 9 years have resulted in the seminal identification ofthe transcription factor FOXC2 as a key player in metastasis and also as a common downstream effector ofmultiple EMT-signaling pathways and indispensable for the procurement of CSC properties. A characteristicfeature of CSCs is their capability to self-renew via asymmetrical or symmetrical self-renewal type of cell divisionsthereby enabling the continued existence and expansion of the CSC pool. The current proposal willsystematically test the role of FOXC2 as a critical element of the molecular switch facilitating CSC self-renewaland expansion and investigate if aberrant activation of FOXC2 leads to increase in CSC populations via Notchsignaling resulting in tumor progression and metastasis. We will use a combination of in vitro- and in vivo tumormodels and patient-derived xenografts as well as genetically engineered mouse models to tease out thisprocess. We will also examine the function of TGF1 a physiologically relevant inducer of EMT in dictatingFOXC2-induced CSC expansion. Also we will evaluate FOXC2-regulated mitotic bookmarking in maintainingthe identity of the CSCs following stem cell division. Finally we will test select small molecule inhibitors capableof modulating FOXC2-function in selectively preventing CSC expansion during EMT. Significance: In summaryour proposal will not only help clarify the fundamental processes regulating CSC self-renewal and expansion ofCSCs during EMT but will also contribute to designing novel strategies that would provide an opportunity to shiftthe balance of CSC towards more differentiated cells and exhaust therapy-resistant metastasis-prone CSCs. 321099 +No NIH Category available Affect;Affinity;Binding;Biochemical;Biochemistry;Biological Assay;Brain;Catalysis;Cell Differentiation process;Cell Proliferation;Cells;Childhood Glioma;Chromatin;Clinical;Complex;CpG Islands;Data;Development;Elements;Ependymoma;Exhibits;Foundations;Future;Gene Expression;Gene Silencing;Genes;Genetic;Genomics;Glioma;Goals;Health;Histone H3;Histones;Human;Investigation;Knowledge;Lysine;Malignant - descriptor;Malignant Neoplasms;Methionine;Methods;Methylation;Molecular;PRC1 Protein;Pathogenesis;Phenotype;Phosphorylation;Play;Polycomb;Positioning Attribute;Post-Translational Protein Processing;Post-Translational Regulation;Posterior Fossa;Prognosis;Proliferating;Proteins;Regulation;Repression;Research Proposals;Residual state;Resistance;Role;Site;Surface;Testing;Therapeutic;Therapeutic Intervention;Tumor Suppressor Genes;Work;antitumor effect;diffuse midline glioma;effective therapy;genome-wide;histone modification;insight;interdisciplinary approach;loss of function mutation;mutant;neoplastic cell;novel;oncohistone;pre-clinical;programs;promoter;recruit;targeted treatment;theories;therapeutic target;tumor;tumorigenesis;tumorigenic Understanding the regulation of PRC2 activity by EZHIP and the K27M oncohistone in pediatric gliomas PROJECT NARATIVEThe misregulation of proteins involved in gene silencing is proposed to play a causative role in a subset ofpediatric gliomas associated with poor prognosis. This research proposal will define the mechanisms of howthese proteins affect gene expression to promote tumorigenesis. Findings from our project will facilitate thedevelopment of targeted therapies for these clinically challenging tumors that lack effective therapies. NCI 10763885 12/11/23 0:00 PA-20-185 5R01CA266861-02 5 R01 CA 266861 2 "WEINREICH, MICHAEL DALE" 1/12/23 0:00 12/31/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 9035743 "LEWIS, PETER W" Not Applicable 2 BIOCHEMISTRY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 303682 NCI 205875 97807 PROJECT SUMMARYPost-translational regulation of histones and other chromatin-associated proteins is a major means by whichgene expression is modulated during normal and malignant development. Polycomb group proteins are essentialfor proper development and are frequently altered in human cancers. The Polycomb Repressive Complex 2(PRC2) functions in a collaborative chromatin-based crosstalk with PRC1 and H3K27me3 to initiate and maintaingene silencing. We have found that PRC2 catalysis of H3K27me3 is inhibited in pediatric gliomas by twosuspected tumor drivers: histone H3 K27M and EZHIP. Inhibition of PRC2 activity by K27M and EZHIP can resultin aberrant gene expression cellular differentiation and cell proliferation. Despite a substantial reduction inH3K27 methylation levels caused by EZHIP or K27M our work has revealed residual H3K27me3 at CpG islandsnear promoters of known and suspected tumor suppressor genes. Furthermore evidence suggests that thisresidual PRC2 activity plays a critical role in supporting tumorigenesis. This proposal seeks to leverage andextend our preliminary findings to define the mechanisms by which K27M and EZHIP misregulate PRC2 topromote tumorigenesis by employing a multi-disciplinary approach that integrates biochemical genetic andgenomic methods. Specifically we will (1) define the role of aberrant PRC2 activity in promoting K27M andEZHIP-containing tumors (2) determine the mechanism of targeting PRC2 to CpG islands in gliomas and (3)define the mechanism of PRC2 inhibition by EZHIP. Expected results will help us formulate novel theories andprovide crucial mechanistic basis underlying the pathogenesis by oncohistones. The knowledge generated inthe course of this study will motivate future therapeutic efforts for treating pediatric gliomas. 303682 +No NIH Category available 3-Dimensional;Abdomen;Abscopal effect;Address;Adhesions;Animal Model;Animals;Antibody Activation;Artificial nanoparticles;Ascites;Biodistribution;Biometry;Cancer Biology;Cancer Patient;Carboplatin;Carcinomatosis;Cause of Death;Cell Death;Cell Line;Cell physiology;Cells;Characteristics;Chemoresistance;Chemosensitization;Cisplatin;Clinic;Clinical;Cytoskeleton;DNA;Development;Diffuse;Disease Resistance;Dose;Drug Kinetics;Effectiveness;Engineering;Epidermal Growth Factor Receptor;Female Genital Neoplasms;Goals;Greater sac of peritoneum;Gynecologic Oncology;Image;Immune;Immune mediated destruction;Immunocompetent;Immunoconjugates;Knowledge;Leadership;Light;Liquid substance;Malignant Neoplasms;Malignant neoplasm of ovary;Mitochondria;Modeling;Modification;Molecular;Molecular Profiling;Monitor;Mus;Nanotechnology;Neoplasm Metastasis;Nodule;Operative Surgical Procedures;Optics;Outcome;Ovarian;Pathway interactions;Patients;Perfusion;Peritoneal;Peritoneal Fluid;Pharmaceutical Preparations;Phenotype;Photosensitizing Agents;Physiological;Platinum;Platinum Compounds;Play;Proliferating;Recurrence;Regimen;Research;Residual state;Resistance;Role;Route;Safety;Signal Transduction;Stress;Surface;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic Index;Time;Tissues;Tumor Burden;Tumor Debulking;Tumor Immunity;Tumor-associated macrophages;Xenograft procedure;anti-tumor immune response;cancer cell;cancer therapy;cancer type;chemotherapy;density;design;dosimetry;fluorescence imaging;image guided;image-guided drug delivery;immunogenic cell death;immunoregulation;improved;in vivo;individual patient;insight;intraperitoneal;light dosimetry;malignant ascites;migration;mouse model;multidisciplinary;nano;nanoparticle;nanoscale;nanotechnology platform;ovarian neoplasm;patient derived xenograft model;patient prognosis;photoimmunotherapy;receptor;response;safety assessment;shear stress;standard care;targeted biomarker;targeted delivery;targeted treatment;taxane;three-dimensional modeling;tumor;tumor immunology;uptake Targeting Fluid Stress-induced Chemoresistance in a 3D Carcinomatosis Perfusion Model Using Mechanism-based Photo-immunoconjugate Nanoparticles NARRATIVEAdvanced stage ovarian cancer often spreads along currents of abdominal fluid and remains the leading causeof deaths from gynecologic tumors in the US. These currents confer fluid shear stress on ovarian cancermetastases which changes the molecular characteristics of the tumors and makes them more resistant tochemotherapy. This proposal will develop a light-activatable nanotechnology to improve photoimmunotherapyand overcome fluid shear stress-induced chemoresistance in ovarian cancer. NCI 10763877 12/15/23 0:00 PA-20-185 5R01CA256710-02 5 R01 CA 256710 2 "SALVADOR MORALES, CAROLINA" 1/12/23 0:00 12/31/27 0:00 Radiation Therapeutics and Biology Study Section[RTB] 12005600 "HUANG, HUANG CHIAO " "RIZVI, IMRAN " 4 BIOMEDICAL ENGINEERING 790934285 NPU8ULVAAS23 790934285 NPU8ULVAAS23 US 38.992333 -76.952986 820102 "UNIV OF MARYLAND, COLLEGE PARK" COLLEGE PARK MD BIOMED ENGR/COL ENGR/ENGR STA 207420001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 494356 NCI 409883 84473 ABSTRACTThe prognosis for patients with advanced stage and recurrent ovarian cancer has remained dismal fordecades. The poor response rates result in part from resistance to chemotherapy particularly platinum- andtaxane-based agents. Ovarian cancer often metastasizes via transcoelomic routes along currents of asciticfluid in the peritoneal cavity. We have engineered a 3D adherent perfusion model to mimic ovarian nodulesthat stud peritoneal surfaces and recapitulate resistant disease thereby providing a unique platform to developtargeted therapies. Our studies showed that physiologically relevant fluid shear stress (FSS) induces a pro-metastatic phenotype and confers resistance to platinum agents. Photoimmunotherapy (PIT) has shownpromise in selectively imaging and treating disseminated tumors and it can resensitize chemoresistant cancercells to platinum agents. However the high thresholds of intracellular photoimmunoconjugate required for celldeath have hindered the effectiveness of PIT in physiologically relevant models. Therefore the main goal ofthis proposal is to develop a multi-purpose nanoplatform that breaks the selectivity-uptake trade-off ofphotoimmunoconjugates and enables multi-tier cancer targeting under peritoneal FSS. We have recentlyshown that successful conjugation of photoimmunoconjugates onto nanoparticles can effectively enhanceintratumoral photoimmunoconjugate delivery and improve PIT outcomes in mice. We hypothesize thatnanoscale engineering enables high-payload co-delivery of photoimmunoconjugate and chemotherapy in amanner that is safe and efficacious in overcoming FSS-induced chemoresistance. This approach willsignificantly enhance the therapeutic index of platinum agents for ovarian cancer patients. In Aim 1 a panel ofphotoimmunoconjugate-nanoconstructs (PICNC) will be developed to target biomarkers altered by FSS in a 3Dperfusion model of ovarian cancer. In Aim 2 we will assess the effects on chemosensitization T cell sparingand destruction of immune supporting tumor-associated macrophages following PICNC-PIT under FSS in 3Dperfusion models. In Aim 3 to improve the safety and consistency of the treatment we will develop image-guided strategies to inform the timing and dosing of PICNC-PIT in mouse models. In Aim 4 the anti-tumorefficacy of PICNC-PIT will be evaluated in cell line-based syngeneic (immunocompetent) and xenograft mousemodels as well as PDX models for ovarian cancer. The PIs envision a simple and feasible modification to thestandard treatment framework where PICNC will be delivered intraperitoneally after surgical debulking andactivated by light triggering PIT and releasing chemotherapy. The knowledge gained could play atransformative role in the development of improved therapeutic regimens tailored to the molecular profile ofdisseminated tumors in individual patients. To accomplish these aims we will deploy our multi-disciplinaryteam of nanoparticle engineering 3D tumor perfusion model cancer biology tumor immunology biostatisticsand gynecologic oncology experts to examine the impact of our technology on ovarian cancer treatment. 494356 +No NIH Category available American;Architecture;Binding;Binding Proteins;Binding Sites;Biological;Biological Assay;Biological Markers;Blood;Cause of Death;Cell Survival;Cells;Cessation of life;Chromatin;Chromatin Remodeling Factor;Chromosomes;Clinical;Complex;DNA;DNA Binding;Data;Development;Evaluation;Evolution;Follow-Up Studies;Future;Genomics;Goals;Invaded;Knowledge;Laboratories;Lead;Libraries;Ligands;Longterm Follow-up;Malignant neoplasm of prostate;Maps;Mass Spectrum Analysis;Metastatic Prostate Cancer;Modeling;Molecular;Neoplasm Metastasis;New Agents;Oncogenic;Oncology;Outcome;Patient-Focused Outcomes;Pharmaceutical Preparations;Phenotype;Primates;Process;Proliferating;Prostate;Prostate Cancer therapy;Proteins;RNA;Resistance;Role;SWI/SNF Family Complex;Scaffolding Protein;Site;Structure;Therapeutic;Therapeutic Agents;Transcript;Untranslated RNA;Urine;Work;cancer cell;cell motility;enzalutamide;exosome;hormone therapy;improved;in vivo;insight;intermolecular interaction;knock-down;liquid biopsy;men;migration;mortality;multiple datasets;novel;novel therapeutic intervention;novel therapeutics;overexpression;precision medicine;prevent;prostate cancer progression;protein complex;screening;small molecule;standard of care;success;therapeutic target;therapeutically effective;therapy resistant;tool;validation studies Therapeutic Targeting of The Long Noncoding RNA SCHLAP1 in Aggressive Prostate Cancer PROJECT NARRATIVETreatment-resistant prostate cancer negatively impacts thousands of men every year and newtherapeutic strategies are urgently needed to improve patient outcomes. This work will evaluatetherapeutic opportunities for the long noncoding RNA (lncRNA) SChLAP1 an underexploreddriver of aggressive prostate cancer with the objective of validating drug-like small molecules thatinhibit its oncogenic functions. The long-term goal of this work is to yield a precision medicine-based strategy for aggressive and treatment-resistant prostate cancer while helping to establishlncRNA targeting as a therapeutic paradigm in oncology. NCI 10763875 1/4/24 0:00 PAR-20-292 5R21CA277305-02 5 R21 CA 277305 2 "COVELL, DAVID G" 1/12/23 0:00 12/31/24 0:00 ZCA1-TCRB-5(O1)S 10297815 "HARGROVE, AMANDA E" "SOMARELLI, JASON ANDREW" 4 CHEMISTRY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF ARTS AND SCIENCES 277054673 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 162638 NCI 105188 57450 Prostate cancer (PCa) is a leading cause of death among American men. Nearly all of these deaths are due to theevolution of therapy resistance and metastatic spread. As such there is an urgent unmet need to develop new agentsto treat therapy-resistant metastatic PCa. The long noncoding RNA (lncRNA) Second Chromosome Locus Associatedwith Prostate 1 (SChLAP1) has been identified as the top RNA associated with prostate cancer-specific mortality andmetastasis from multiple datasets with long-term follow up. Knockdown/overexpression of SChLAP1 is associatedwith changes to pro-metastatic phenotypes such as invasion and colony formation. Targeting this critical cellularregulator has been elusive however and its mechanism of action in promoting PCa therapy resistance and metastasishas not been fully elucidated. For example an interaction between SChLAP1 and the SWI/SNF complex has beenimplicated in PCa progression in some studies but not in others. This gap in knowledge regarding the molecularfunction of SChLAP1 prevents effective therapeutic targeting of SChLAP1. Recent work by our team and others hasrevealed a complex RNA architecture within SChLAP1 as well as protein binding regions localized to highly structuredand primate-conserved regions of the transcript. This compelling evidence for functional RNA structures combinedwith the availability of SChLAP1 as a biomarker in urine and blood renders targeting of lncRNA SChLAP1 a promisingprecision medicine-based treatment approach for men with aggressive PCa. The overall objectives of the proposed work are to: 1) identify and characterize protein interactors andchromatin-binding sites critical to SChLAP1 oncogenic activity and 2) validate drug-like ligands identified in recentscreens as tool molecules for targeting structured regions of SChLAP1 including inhibition of these interactions andSChLAP1-driven phenotypes. The central hypothesis is that the mechanism of SChLAP1 involves interactions withboth protein and chromatin and that targeting these interactions will inhibit SChLAP1-driven phenotypes and revealnovel therapeutic avenues to treat metastatic treatment-resistant PCa. In Aim 1 unbiased sequencing and massspectrometry-based approaches will identify chromatin regions and proteins bound by SChLAP1 in cells and theseinteractions will be interrogated in an array of phenotypic assays to evaluate their role in proliferation cancer cellsurvival migration/invasion and resistance to standard-of-care hormone therapy. In Aim 2 ligands of conservedSChLAP1 substructures will be validated in phenotypic assays and their effects on molecular interactions will beinterrogated. Expected outcomes of this work will be as follows: 1) comprehensive biological insight into targetableintermolecular interactions for SChLAP1 and 2) identification of small molecules that inhibit SChLAP1:proteininteractions and subsequent phenotypes in PCa. This work will set the stage for a future R01 proposal focused on invivo validation studies for small molecules targeting SChLAP1 and the development of an exosome-based liquidbiopsy for SChLAP1 with the ultimate goal of yielding a precision medicine-based strategy for aggressive andtreatment-resistant PCa while also helping to establish lncRNA targeting as a therapeutic paradigm in oncology. 162638 +No NIH Category available Accounting;Address;Androgen Receptor;Attention;Cessation of life;Chronic Disease;Clinical;Collaborations;Complex;Data;Development;Disease;Event;Failure;Goals;Hormonal Risk Factor;Knowledge;Life Expectancy;Life Style;Mean Survival Times;Measurement;Measures;Methodology;Methods;Modeling;Nurses' Health Study;Outcome;Patients;Performance;Prognostic Factor;Prognostic Marker;Proportional Hazards Models;Prospective cohort study;Receptor Signaling;Recurrence;Recurrent Malignant Neoplasm;Research;Research Personnel;Residual state;Risk Factors;Role;Statistical Data Interpretation;Statistical Methods;Structure;Time;Woman;anticancer research;breast cancer diagnosis;breast cancer progression;breast cancer survival;cancer recurrence;cancer subtypes;cancer survival;clinically significant;conditioning;epidemiology study;flexibility;genetic risk factor;hazard;implementation facilitation;innovation;malignant breast neoplasm;novel;prognostic value;receptor expression;simulation;targeted treatment;tool Statistical methods for breast cancer survival using the restricted mean survival time NarrativeWe propose novel statistical tools to elucidate the clinical signicance of prognostic factors in breast cancersurvival and to summarize the residual survival time after breast cancer recurrence. Through the applicationof the proposed methods we expect to gain new knowledge about the progression of heterogeneous breastcancer which will lead to better targeted therapies for patients and advances in breast cancer survival. Whilethe proposed research focuses on breast cancer research the proposed statistical methods will have a broadapplicability for other chronic diseases. NCI 10763853 12/28/23 0:00 PAR-20-052 5R03CA267343-02 5 R03 CA 267343 2 "MARIOTTO, ANGELA B" 1/12/23 0:00 12/31/24 0:00 ZCA1-SRB-1(O1)S 12425150 "LEE, CHI HYUN " Not Applicable 2 BIOSTATISTICS & OTHER MATH SCI 153926712 VGJHK59NMPK9 153926712 VGJHK59NMPK9 US 42.386914 -72.521131 850904 UNIVERSITY OF MASSACHUSETTS AMHERST HADLEY MA SCHOOLS OF PUBLIC HEALTH 10359450 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 75041 NCI 50000 25041 SummaryBreast cancer is a complex and heterogeneous disease where the roles of many prognostic factors includingandrogen receptor (AR) which is an emerging potential prognostic biomarker remain unclear in its clinical pro-gression. The Nurses' Health Studies (NHS) which motivated this application are large prospective cohortstudies conducted to investigate the risk factors for major chronic diseases in women including breast cancer.The data from the NHS contain invaluable information for breast cancer research such as lifestyle hormonaland genetic risk factors as well as clinical outcomes such as breast cancer diagnosis recurrence and death. Inmany epidemiologic studies on breast cancer survival including the NHS the hazard ratio (HR) which is esti-mated based on the proportional hazards (PH) model has been the most routinely used effect measure despiteits limitations. In the NHS data the PH assumption in the association between AR expression and breast cancersurvival was found to be violated. The interpretation of HR is challenging and the result is often misleading if thePH assumption is violated which makes it difcult to assess AR's prognostic values. Recently summary metricsbased on the restricted mean survival time (RMST) which is dened as the life expectancy up to a specic timepoint have attracted substantial attention as useful alternatives to the HR. The RMST has many advantageousfeatures such as its straightforward interpretation and robustness. Specically we can assess the prognosticfactor's effects in terms of absolute effect which is clinically more interpretable than the HR without assumingPH using the RMST-based regression model. In this project we propose to develop novel statistical methodsbased on RMST to fully utilize the rich data from the NHS and to gain a better understanding of the complexeffect of AR on breast cancer progression and survival. Under Aim 1 we will develop a exible regressionmethod based on RMST that estimates the varying covariate effects across a range of time. The proposedregression method will be used to elucidate the clinical signicance of AR in survival by different subtypes ofbreast cancers. Under Aim 2 we will develop a model-free approach to summarize the bivariate survivaldata (i.e. time from an initial event to an intermediate event and from the intermediate event to a failureevent). The metrics developed under Aim 2 will be used to study residual survival after breast cancer recurrenceand facilitate comparisons between groups by AR status for different breast cancer subtypes. These novel sta-tistical approaches will be applied to data from the NHS to obtain new knowledge about the prognostic values ofAR and potentially lead to better targeted therapies. 75041 +No NIH Category available Address;Aqueous Humor;Ascites;Biological Assay;Biological Markers;Blood;Blood Volume;Blood specimen;Bone Marrow Aspiration;Cardiovascular system;Cells;Cerebrospinal Fluid;Clinical;Collaborations;Companions;Complement;Data;Detection;Development;Diagnosis;Diagnostic;Diagnostic Imaging;Early treatment;Endoscopic Ultrasonography;Endothelium;Epithelium;Evolution;FDA approved;Genomics;Immune;Immunofluorescence Immunologic;Industry;Intervention;Laboratory Research;Malignant Neoplasms;Malignant neoplasm of pancreas;Mammography;Mesenchymal;Metastatic breast cancer;Methods;Monoclonal gammopathy of uncertain significance;Morphology;Multiple Myeloma;Neoplasm Circulating Cells;Newly Diagnosed;Patient Recruitments;Patients;Plasma;Population;Portal vein structure;Procedures;Proteomics;Protocols documentation;Publishing;Research;Research Design;Research Project Grants;Resources;Sampling;Science;Screening procedure;Slide;Specificity;Technology;Testing;Time;Ultrasonography;Work;automated algorithm;automated analysis;burden of illness;candidate identification;clinical care;clinical implementation;clinical practice;clinically significant;cohort;diagnostic assay;diagnostic strategy;extracellular vesicles;imaging platform;improved;liquid biopsy;malignant breast neoplasm;multimodality;multiple omics;novel;pancreatic neoplasm;patient population;peripheral blood;prospective;routine screening;screening;standard of care;technological innovation;technology validation;tumor Multi-modal Liquid Biopsy Early Assessment of Breast Cancer Pancreatic Cancer and Multiple Myeloma Project NarrativeThis Liquid Biopsy Research Laboratory (LBRL) partnership team led by PI Peter Kuhn (academic) and Co-IRick Wenstrup (industry) of Epic Sciences is advancing biologically informed liquid biopsy (LBx) technology tofill gaps in current clinical practice of early cancer assessment. The three scenarios addressed by the LBx are1) peripheral blood LBx as a companion to mammography for the early assessment of breast cancer 2)enhanced screening and diagnostic workup for pancreatic cancer through multi-omic capabilities to create amulti-modal LBx using peripheral blood and portal vein blood and 3) a peripheral blood LBx as a substitute tobone marrow aspirate to diagnose myeloma precursor states and detect the transition to multiple myeloma toeasily identify candidates for early treatment intervention. NCI 10763336 9/18/23 0:00 RFA-CA-23-018 1U01CA285013-01 1 U01 CA 285013 1 "HODGES, NICHOLAS AARON" 9/18/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(A1)R 1861452 "KUHN, PETER " Not Applicable 37 SOCIAL SCIENCES 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF ARTS AND SCIENCES 900894304 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 695450 NCI 420000 275450 AbstractThis Liquid Biopsy Research Laboratory (LBRL) will address specific unmet clinical needs in the earlyassessment of cancer by developing and validating multi-analyte liquid biopsy (LBx) technologies in distinctclinical contexts to maximize patient benefit by bringing together clinical research and industry experts. TheLBRL proposed research is motivated by preliminary work published by us and others that indicate tumors leakdetectable levels of multiple analytes potentially early in tumor evolution into the circulatory system. Here wepropose three research projects that will address current clinical gaps in the early assessment of cancer usingLBx technologies to maximally leverage resources toward gaining sufficient evidence for clinical implementationof at least one project by the end of the initial period. Clinical utilities will be explored in both screening anddiagnostic workup in the early assessment of cancer with a focus on refining and validating technologiesmethods and assays for LBx and a particular emphasis on integrating the genomics and proteomics of singlecells as well as oncosomes along with plasma genomics and proteomics to configure a final clinically impactfulassay. Aim 1 will focus on developing a comprehensive LBx-based companion to mammography for the earlyassessment of breast cancer (BC) with a focus on the `intent to treat' population of patients undergoing screening.Subaims include technology refinement for (1) a fit for purpose test consisting of previously validatedimmunofluorescence (IF) assays to characterize rare epithelial endothelial mesenchymal and immune cells aswell as oncosomes; and (2) existing comprehensive tests adapted for the requirements of low disease burdenusing multi-omic multi-analyte approach for diagnostic workup following a positive mammogram or following apositive LBx screening test. Aim 2 will focus on developing enhanced screening and diagnostic workup forpancreatic cancer (PANC) through multi-omic capabilities on cells and plasma to create a multi-modal LBx aimedat a fit for purpose test appropriate as a screening tool prior to diagnostic imaging or an information-rich adjunctto an EUS procedure. Aim 3 is focused on the development of a PB LBx as a substitute to bone marrow aspirate(BMA) to diagnosed myeloma precursor states (MGUS and SMM) and detect the transition to multiple myelomato easily identify candidates for early treatment intervention. The overall partnership team of the LBRL isleveraging established collaborations with a track record of identifying the clinical gap designing studies thathave a high likelihood of timely recruitment of patients and successful procurement of samples technologicalinnovation and refinement compliant and scalable commercial solution development and deployment intoclinical care. 695450 +No NIH Category available Abraxane;Adult;Affinity;Albumins;Azoles;Binding;Biopsy;Breast;Cell Line;Clinical;Clinical Research;Clinical Trials;Cytotoxic agent;Detection;Development;Dose;Drug Targeting;End Point Assay;EphA2 Receptor;Esters;Evaluation;FDA approved;Formulation;Future;Invaded;Investigational Therapies;Letters;Ligands;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Measurement;Names;Neoplasm Metastasis;Normal tissue morphology;Oncogenic;Oncologist;Organ;Paclitaxel;Pancreas;Patient Selection;Patients;Penetration;Pharmaceutical Preparations;Phase;Primary Neoplasm;Prognosis;Property;Prostate;Protocols documentation;Receptor Cell;Receptor Protein-Tyrosine Kinases;Reporting;Research Personnel;Serum;Side;Signal Transduction;Site;Small Business Innovation Research Grant;Solid Neoplasm;Surface;Surrogate Endpoint;Testing;Therapeutic;Tissues;Toxic effect;Tumor Markers;Xenograft Model;anti-cancer;cancer cell;cell motility;chemotherapeutic agent;chemotherapy;circulating cancer cell;design;diagnostic strategy;efficacy study;first-in-human;gemcitabine;imaging study;in vivo;in vivo Model;in vivo imaging;innovation;neoplastic cell;novel;novel diagnostics;novel therapeutic intervention;overexpression;pancreatic cancer cells;pancreatic cancer model;pancreatic neoplasm;pharmacologic;receptor;receptor internalization;standard of care;targeted agent;targeted treatment;tumor Targeting pancreatic cancer metastases with Targefrin PROJECT NARRATIVEWe propose to target a specific tumor marker EphA2 expressed on the surface of aggressive pancreaticcancers. We propose to develop our potent and effective EphA2 targeting agent Targefrin that effectivelyinhibits tumor metastases. We will also probe Targefrin as an effective drug deliver agent to target chemotherapyselectively to the tumor and circulating cancer cells. Hence the proposed therapeutic strategy wouldsimultaneously eliminate the primary tumor and suppress pancreatic cancer metastases. NCI 10763331 9/14/23 0:00 PA-22-176 1R43CA277917-01A1 1 R43 CA 277917 1 A1 "FRANCA-KOH, JONATHAN C" 9/14/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 14550749 "BAGGIO, CARLO " Not Applicable 50 Unavailable 117950976 DXNPA5VKJM96 117950976 DXNPA5VKJM96 US 10066265 "ARMIDA LABS, INC." SAN DIEGO CA Domestic For-Profits 921222844 UNITED STATES N 9/14/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 400000 NCI 312000 78000 ABSTRACTWe intend to devise a novel therapeutic strategy based on a specific cancer cell receptor named EphA2 whichis abundant on the surface of metastatic pancreatic cancers. Over the past several years our studies focused ontesting the anti-cancer potential of agents targeting the receptor in suppressing cell migration and invasion incellular studies as well as in inhibiting tumor metastases using in vivo models. Very recently we have derivedthe most effective agonistic agent reported to date that potently targets the EphA2 receptor and causes itsdegradation. In preliminary studies the agent is remarkably effective in inhibiting pancreatic cancer cellmigration. The agent also causes the internalization of the receptor; hence we intend to probe whether we canuse this agent also to deliver chemotherapy selectively to pancreatic tumors. 400000 +No NIH Category available Address;Adoption;Adverse event;Autoantibodies;Autoimmune;Autoimmune Diseases;Autoimmune Process;Autoimmunity;B-Lymphocytes;Biological;Blood;Blood specimen;CD19 gene;CD4 Positive T Lymphocytes;Cancer Patient;Cardiac;Cardiopulmonary;Cells;Chest;Clinical;Clinical Research;Collaborations;Combined Modality Therapy;Complement;Diagnosis;Diagnostic tests;Discipline;Early Diagnosis;Excess Mortality;Exposure to;Foundations;Goals;Heart;Humoral Immunities;IL17 gene;Immune;Immunologist;Immunotherapy;Inflammatory;Injury;Innate Immune Response;Institution;Intervention;Investigation;Knockout Mice;Laboratories;Lead;Life;Link;LoxP-flanked allele;Lung;Malignant neoplasm of lung;Measures;Mediating;Modeling;Monitor;Mus;Natural Immunity;Outcome;PD-1 blockade;Patients;Pre-Clinical Model;Production;Quality of life;Radiation Oncologist;Radiation therapy;Role;Sampling;Serum;Structure of parenchyma of lung;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Toxicity Attenuation;Universities;Validation;Wild Type Mouse;Work;adaptive immune response;adaptive immunity;anti-CD20;anti-PD-1;anti-PD1 therapy;autoimmune toxicity;bench to bedside;cytokine;humoral immunity deficiency;immune checkpoint;improved;improved outcome;inhibitor;irradiation;mouse model;neutrophil;new therapeutic target;novel;novel diagnostics;novel marker;pharmacologic;pre-clinical;predictive marker;prevent;programmed cell death protein 1;prospective;response;therapeutic target;translational study Autoimmunity in Cardiopulmonary Toxicities from Radiotherapy andImmunotherapy Project NarrativeIn this proposal we will investigate autoimmune mechanisms of cardiac and lung toxicities from thoracicirradiation in the presence of PD-1 blockade. Outcomes of the proposed studies will help to identify novelbiomarkers for early diagnosis of serious and fatal adverse events and novel therapeutic targets for managingthe toxicities and improving therapeutic ratio. NCI 10763129 8/29/23 0:00 PA-21-268 7R01CA252484-04 7 R01 CA 252484 4 "SOMMERS, CONNIE L" 8/1/20 0:00 5/31/26 0:00 Radiation Therapeutics and Biology Study Section[RTB] 1943281 "LU, BO " Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 153890272 SZPJL5ZRCLF4 153890272 SZPJL5ZRCLF4 US 38.948231 -92.327335 578002 UNIVERSITY OF MISSOURI-COLUMBIA COLUMBIA MO SCHOOLS OF MEDICINE 652110001 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 606856 NCI 426554 180302 SummaryCardiopulmonary toxicities following thoracic radiotherapy and PD-1 blocking immunotherapy have a majorimpact on quality of life and survival. Therefore there is an unmet need to have early diagnostic test andintervention for fatal toxicities. Our proposal aims to understand immune mechanisms that modulatepotentially life-threatening cardiopulmonary toxicities. We propose to study the toxicities in both mouse modelsand patients by analyzing blood samples. To achieve our goals we have assembled a collaborative teamacross three institutions with a group of expert consultants in order to identify biological correlates andtherapeutic targets to ameliorate these autoimmune toxicities. Our prior studies showed excessive mortality inmice simultaneously exposed to radiotherapy and PD-1 inhibition which we show is dependent on both thecytokine IL-17A and the B-cell. Since both Th17/IL-17A and humoral immunity are implicated in autoimmunediseases we hypothesize that toxicities result from the unchecked adaptive Th17 response due to PD-1blockade combined with autoantibodies against heart and lung tissues generated by the pro-inflammatory B-lymphocytes. We will employ mouse models and pharmacological inhibitors to dissect the underlyingautoimmune mechanisms and measure key components of Th17 and B-cell response in prospectivelycollected blood samples from lung cancer patients undergoing combine radiotherapy and immunotherapy.Aim 1: To determine whether IL-17A/Th17 responses mediate the toxicities. We hypothesize that bothinnate and adaptive immunity contributes to the toxicities through the link of IL-17A. We will generate KO miceunable to produce IL-17A through either neutrophils or CD4 T cells. We expect that the toxicities areattenuated when Th17/IL-17A are blunted in these mouse models. To determine whether IL-17A/Th17 can beused as predictive biomarkers for the toxicities we will examine dynamic changes of Th17/IL-17A in serumsamples from our patients. Aim 2: To determine the role of humoral response in mediating thetoxicities. We hypothesize that pro-inflammatory Tbet+ B-lymphocytes drive autoantibody production whichresults in the toxicities. We will use Tbetflox/flox CD19cre mice as our model in which mature Tbet+ B cells areabsent. This approach will be complemented by pharmacological depletion of B cells using anti-CD20 or byneutralizing autoantibodies with IVIg in wild-type mice. We expect that the toxicities are attenuated in thesemodels. Furthermore we will test whether pharmacological inhibitors of Th17/IL-17A reduce Tbet+ B cells andautoantibodies. Finally the rise of autoantibodies in blood will be captured in mice and patients as a surrogatefor the toxicities. Our study of basic mechanisms in preclinical models combined with analysis of patientsamples will lead to novel diagnostics for early detection and improved therapies for severe cardiopulmonarytoxicities. 606856 +No NIH Category available AKT3 gene;Automobile Driving;Binding;Biological Assay;Cancer Biology;Cancer Etiology;Cell Line;Cell Survival;Cells;Cessation of life;Chemoresistance;Chronic;DNA Repair;DNA Sequence Alteration;Data;Development;Disseminated Malignant Neoplasm;Distant;Epithelium;Exhibits;Fibroblasts;Gene Amplification;Genetic Transcription;Glioma;Goals;Human;Immunofluorescence Immunologic;Immunoprecipitation;Invaded;KRAS2 gene;Location;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mesenchymal;Molecular;Mutation;Neoplasm Metastasis;Oncogenes;Organ;Organoids;Pancreatic Ductal Adenocarcinoma;Paracrine Communication;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Postdoctoral Fellow;Process;Prognosis;Protein Isoforms;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Receptor Protein-Tyrosine Kinases;Relapse;Research;Resistance;Role;TANK-binding kinase 1;Techniques;Technology;Therapeutic;Tissues;Work;axl receptor tyrosine kinase;cancer cell;cancer therapy;cancer type;cell motility;combat;effective therapy;epithelial to mesenchymal transition;experimental study;gain of function;in vivo;loss of function;malignant breast neoplasm;migration;mutant;neoplastic cell;novel;novel strategies;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pharmacologic;programs;protein expression;response;single cell sequencing;slug;transcription factor;tumor;tumor microenvironment;tumor progression;tumorigenesis Deciphering molecular mechanisms of Epithelial Plasticity Project NarrativeTANK-binding kinase 1 (TBK1) a critical downstream effector of mutant active KRAS is central to Axl-driven epithelial-mesenchymal transition (EMT) in KRAS-mutant Pancreatic Cancer (PDA); howeverthe mechanism of how TBK1 drives EMT has yet to be elucidated. I hypothesize that Axl-mediatedTBK1 drives EMT via direct activation of AKT3 and the stability of downstream transcriptionalnetworks. Despite significant research efforts the function of EMT in metastasis has yet to be fullyelucidated and metastatic cancers and relapse remain the primary cause of cancer related deaths;therefore my postdoctoral studies will be focused on understanding the molecular mechanismsunderlying cellular plasticity EMT and metastasis to reveal novel strategies to target these programsfor effective therapy for metastatic cancer.. NCI 10763026 11/14/23 0:00 RFA-CA-19-057 5K00CA253718-05 5 K00 CA 253718 5 "DAMICO, MARK W" 12/1/21 0:00 11/30/25 0:00 ZCA1-SRB-H(M1) 15532527 "ARNER, EMILY NICOLE" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Other Research-Related 2024 97217 NCI 90016 7201 Project Summary/Abstract Cellular plasticity a feature associated with epithelial-to-mesenchymal transition (EMT) contributesto tumor cell survival migration invasion and therapy resistance. Across human cancer tumors that are highgrade poorly differentiated and have undergone EMT carry a worse prognosis with a high likelihood ofmetastasizing to distant organs. EMT is a common feature associated with tumor progression and is thoughtto be critical to cancer cell dissemination in some tumors such as pancreatic ductal adenocarcinoma(PDA). PDA is a lethal and poorly understood human malignancy that is characterized by an activatingmutation in KRAS. Additionally AXL a receptor tyrosine kinase (RTK) has been implicated in tumorprogression metastasis therapy resistance and EMT in multiple cancer types including PDA. During mydissertation studies I have found that TANK-binding kinase 1 (TBK1) a critical downstream effector ofmutant active KRAS is central to AXL-driven EMT in KRAS-mutant PDA. However the mechanism of howTBK1 drives EMT has yet to be elucidated. We hypothesize that TBK1 drives EMT via activation of AKT3and the stability of downstream transcriptional networks. My data demonstrate that AKT3 is activateddownstream of TBK1 in response to stimulation of AXL which leads to the binding of AKT3 and Slug in anAXL-TBK1 dependent manner. To complete my dissertation I will establish the function of AKT3 in driving EMTdownstream of Axl and TBK1 with the following goals: 1) Establish the necessity of AKT3 for Axl and TBK1 drivenEMT; 2) Evaluate EMT transcription factors engaged downstream of TBK1 and 3) Determine the effect of AKT3activation on the stability of EMT transcription factors. Despite significant evidence that EMT directly contributes to tumor progression several studies havesuggested EMT is not required for the metastatic spread of PDA and breast cancer. For example mostmetastatic lesions are known to exhibit epithelial features an observation that seems to be at odds withEMT as a prerequisite for metastasis. As such the importance of EMT in cancer biology h as beenquestioned. I hypothesize that the chronic activation of an EMT program within a tumor may depend onparacrine signals within the tumor microenvironment dictating whether the tumor cells undergo EMT orMET. Because these cells exist in a plastic state it is possible that these tumor cells readily revert theirphenotype based on a microenvironment-specific context and factors. Additionally current in vivo lineage-tracing technology has not settled the debate between the importance of collective m igration and/or EMTfor metastatic dissemination. During my postdoctoral research I aim to investigate the role of EMT inmetastasis using in vivo lineage tracing single-cell sequencing and organoids to better understandepithelial plasticity in an oncogene- and tissue-specific manner. Understanding this process will aid in thedevelopment of effective metastatic cancer therapies and will direct future research directions in metastasis. 97217 +No NIH Category available Acceleration;Antibody-drug conjugates;Basic Science;Biological Markers;Biopsy;Breast Cancer Cell;Breast Cancer Patient;CRISPR screen;Cell model;Cells;Clinical;Clinical Sciences;Clinical Trials;Combined Modality Therapy;Complement;Complex;Coupled;DNA Damage;DNA Repair;Data;Disease;Dose;Drug Combinations;Drug Targeting;Exhibits;FDA approved;Funding;Immunohistochemistry;Lead;Link;Mediating;Modeling;Molecular Analysis;Morbidity - disease rate;Organoids;PARP inhibition;PIK3CG gene;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phase Ib/II Clinical Trial;Preclinical Testing;Prediction of Response to Therapy;Prognosis;Progression-Free Survivals;Refractory;Research Personnel;Resistance;SN-38;Sampling;Schedule;Series;Testing;Therapeutic;Therapeutic Trials;Therapeutic Uses;Topoisomerase;Toxic effect;Translational Research;Treatment-related toxicity;Triplet Multiple Birth;Tumor Antigens;Validation;Work;cancer subtypes;chemotherapy;clinical biomarkers;clinical development;clinical trial analysis;clinically relevant;combinatorial;druggable target;exome sequencing;experience;homologous recombination;humanized monoclonal antibodies;improved;improved outcome;in vivo;in vivo evaluation;inhibitor;innovation;irinotecan;malignant breast neoplasm;mortality;new combination therapies;new therapeutic target;next generation;novel;novel therapeutic intervention;objective response rate;optimal treatments;patient derived xenograft model;patient subsets;pharmacodynamic biomarker;predicting response;repaired;resistance mechanism;response;success;synergism;transcriptome sequencing;translational goal;treatment response;triple-negative invasive breast carcinoma;tumor Synergistic combinatorial DNA damage response/repair inhibition and Sacituzumab Govitecan in triple-negative breast cancer Project NarrativeOur team recently led the clinical development of Sacituzumab Govitecan (SG aka Trodelvy) the first FDA-approved antibody-drug conjugate (ADC) for triple-negative breast cancer (TNBC) leading to substantiallyimproved outcomes for this most aggressive and poor-prognosis breast cancer subtype. Here we propose tobuild on this success by testing a new targeted drug combination incorporating SG for resistant tumors and bydeveloping biomarkers and additional combinations to guide rational use of this new treatment approach. Weseek to move potentially transformative new combination therapies rapidly into clinical trials. NCI 10763002 12/29/23 0:00 PA-20-185 5R01CA260890-03 5 R01 CA 260890 3 "SONG, MIN-KYUNG H" 1/1/22 0:00 12/31/26 0:00 Developmental Therapeutics Study Section[DT] 1980799 "ELLISEN, LEIF W" "BARDIA, ADITYA " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 503805 NCI 299884 203921 Project SummaryThe long-term objective of this project is to identify new more effective and less toxic therapeutic approachesfor triple-negative breast cancer (TNBC) the most aggressive and poor-prognosis breast cancer subtype. Ourteam recently led the clinical development of the first antibody-drug conjugate (ADC) for metastatic TNBC(mTNBC) Sacituzumab Govitecan (SG aka Trodelvy) achieving dramatically improved objective responserates (ORRs) progression-free survival (PFS) and overall survival (OS) and resulting in accelerated FDAapproval in 2020. SG comprises the topoisomerase 1 (TOP1) inhibitor SN-38 (the active metabolite ofirinotecan) coupled to a humanized monoclonal antibody targeting Trop-2 a tumor antigen expressed in >90%of mTNBC. While it represents a paradigm-changing therapy only approximately 30% of mTNBC patientsexperience a therapeutic response to SG highlighting the need to identify combination therapies with SG thatwill uniquely complement and enhance its efficacy. Our preliminary data lead to the hypothesis that PARPinhibition (PARPi) is synergistic with SG in mTNBC. Accordingly we are carrying out a funded investigator-initiated phase 1b/2 clinical trial (NCT04039230) of SG and PARPi (talazoparib) for mTNBC notably deliveredvia a sequential dosing schedule to minimize toxicity and improve the therapeutic window. Here our team ofclinical translational and basic science investigators seeks to move forward the rational therapeutic use of SGand SG/PARPi and to discover new combinatorial therapies incorporating SG. Our aims are: i) to establish theassociation of therapeutic response with pre-treatment and pharmacodynamic markers of DNA damage andrepair with SG/talazoparib versus SG alone for mTNBC through analysis of clinical trial and other patientsamples; ii) to determine mechanisms of resistance to SG monotherapy and SG/PARPi through CRISPRscreens and analysis of post-progression patient samples and to test select druggable targets to overcomethem; and iii) to optimize drug scheduling and in vivo efficacy for novel combinations to overcome SG/PARPiresistance. Collectively these studies will enable and inform the next generation of mechanism-basedtherapeutic trials investigating SG-based combinatorial therapy for patients with mTNBC. 503805 +No NIH Category available ASCL1 gene;African Caribbean;Anus;Biological Markers;Biopsy;Black Populations;Caribbean region;Caring;Cells;Central America;Cervical;Clinical;Consumption;Cytology;DNA Methylation;Data;Development;Diagnosis;Discrimination;Disease;Disparity;Dysplasia;Early Diagnosis;Environment;Epigenetic Process;Expert Opinion;Goals;Guidelines;HIV;HPV-High Risk;Health;High Risk Woman;Human papilloma virus infection;Immune;Immune Targeting;Immune response;Immunologics;Immunotherapeutic agent;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Latino Population;Latinx;Lesion;Literature;Longitudinal Studies;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of anus;Measures;Methods;Methylation;Minority;Minority Groups;Minority Men;Minority Women;Neighborhoods;Oncogenic;Outcome;Patient Triage;Patients;Performance;Persons;Play;Population Heterogeneity;Poverty;Precancerous Conditions;Prevalence;Recommendation;Reduce health disparities;Research;Resolution;Risk;Risk Factors;Role;Sample Size;Sampling;Screening for cancer;Sensitivity and Specificity;Site;South America;Squamous intraepithelial lesion;Stimulus;Time;Translating;Universities;Viral;Vulva;Woman;advanced disease;biomarker identification;black men;burden of illness;cancer invasiveness;cancer risk;carcinogenesis;chronic infection;cost;design;disparity reduction;ethnic diversity;evidence base;food insecurity;health disparity;high risk;high risk population;housing instability;immunological intervention;immunoregulation;improved;men who have sex with men;men who have sex with men and women;methylation biomarker;mortality;overtreatment;racial disparity;recruit;risk stratification;screening;screening guidelines;side effect;social determinants;social health determinants;tumor progression;tumor-immune system interactions Screening strategies and social determinants of health among people with high risk of anal cancer PROJECT NARRATIVE:Anal cancer is particularly high among certain groups; health disparity further contributes to this high riskamong minorities. The proposed research will examine performance of emerging screening methods foraHSIL (precancerous condition of anal cancer) among minorities with a high risk of anal cancer as well ascharacterize DNA methylation immunologic response and social determinants associated with aHSIL mostlikely to progress to cancer. Findings will provide much-needed evidence for anal cancer screening strategiesto reduce health disparities improve screening outcomes and decrease the incidence of anal cancer amonghigh-risk minorities. NCI 10762863 9/12/23 0:00 PAR-21-035 1R01CA285198-01 1 R01 CA 285198 1 "SAHASRABUDDHE, VIKRANT V" 9/12/23 0:00 8/31/28 0:00 HIV Comorbidities and Clinical Studies Study Section[HCCS] 1872503 "FLOWERS, LISA C." "ROSA-CUNHA, ISABELLA ; XIAO, CANHUA " 5 OBSTETRICS & GYNECOLOGY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/12/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1046509 NCI 756504 290005 Abstract:The incidence of anal cancer has almost doubled during the past decades along with increased advanceddisease and mortality. Persistent high-risk human papillomavirus (hrHPV) infection leads to anal high-gradesquamous intraepithelial lesion (aHSIL) the precursor for anal cancer. Anal cancer risk is also exceptionallyhigh among certain groups: people living with HIV men having sex with men (MSM) and women with lowerhigh-grade anogenital tract diseases. Health disparity further contributes to this high rate as minorities suchas Black MSM have a significantly higher rate of aHSIL and cancer. Thus early detection of aHSILparticularly among high-risk minorities is crucial to reduce cancer incidence and disease burden. Howeverthe current recommendation for aHSIL screening is based on expert opinions and research on high-riskminorities is scarce. Thereby we propose this large multisite study to investigate potential screening markersfor aHSIL with a specific focus on high-risk minorities. Furthermore only a small portion of those diagnosedwith aHSIL will develop cancer yet the treatment recommendation is for all aHSIL resulting in significant over-treatment leading to unnecessary side effects and increased cost. It is crucial to develop reliable markers tostratify risks of aHSIL progression and regression. Given the importance of local DNA methylation and theimmune environment to viral stimulus and carcinogenesis hence we will examine DNA methylation andimmunological profiles to identify markers for cancer risk stratification after aHSIL. Examining local immuneresponses may also shed light on targeted immunotherapeutic approaches and for better outcomes.Additionally given the disparities in anal cancer incidence and outcomes and the increasingly recognizedimpact of social determinants on health including in HIV care HPV infection and cancer screening we willexamine whether social determinants play a pivotal role in aHSIL prevalence and clearance. We will recruit500 minority men and women at high risk for anal cancer from Emory University and the University of Miamiwhere we have a large portion of diverse populations including US born Blacks Caribbean Blacks Latinx andMSM. We will follow them yearly for up to two years. Overall the proposed study provides a uniqueopportunity to examine the much-needed evidence on early aHSIL screening among high-risk minorities. Themethylation results will be crucial to stratify risks of screen-detected aHSIL and could be translated toscreening. The immune and inflammatory profile will identify alterations associated with neoplastic progressionand subsequently inform targeted immune interventions for better outcomes. Documenting the importance ofsocial determinants will provide invaluable recommendations to reduce health disparities improve screeningoutcomes and decrease the incidence of anal cancer among high-risk minorities. 1046509 +No NIH Category available Acquired Immunodeficiency Syndrome;Antiviral Therapy;Basic Science;Binding;Cell Proliferation;Cells;Cellular Metabolic Process;Citric Acid Cycle;Coupling;Enzymes;Episome;Etiology;Event;G1 Phase;Genome;Glutamine;Herpesviridae;Herpesviridae Infections;Human;Human Herpesvirus 4;Human Herpesvirus 8;IKKepsilon;Immune;Immune response;Individual;Integration Host Factors;Interferons;Investigation;Kaposi Sarcoma;Knowledge;Lymphoma;Lymphoma cell;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Oncogenic Viruses;Outcome;Patients;Phosphorylation;Phosphotransferases;Post-Translational Protein Processing;Proliferating;Protein-Serine-Threonine Kinases;Proteins;Purines;Pyrimidine;Research;Role;Serine;System;Testing;Thymidine Kinase;Tumor Biology;Tumor Cell Biology;Vaccines;Viral;Viral Physiology;Work;anti-viral efficacy;cancer cell;chronic infection;clinical application;deamidation;drug-like compound;effective therapy;efficacy evaluation;gammaherpesvirus;immunodeficient mouse model;insight;interest;mortality;neoplastic cell;novel;nucleotide metabolism;organ transplant recipient;pathogen;primary effusion lymphoma;programs;small molecule;small molecule inhibitor;targeted treatment;tumor;tumor metabolism;virus host interaction Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma Project NarrativeHuman Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi'ssarcoma primary effusion lymphoma (PEL) and multicentric Castleman's disease. Wediscovered that KSHV exploits an innate immune kinase to promote the proliferation of KSHV-infected PEL cells. This study will develop small molecule inhibitors to target the innate immunekinase thus impeding the proliferation of KSHV-infected PEL cells. NCI 10762816 6/30/23 0:00 PA-20-185 1R01CA285192-01 1 R01 CA 285192 1 "READ-CONNOLE, ELIZABETH LEE" 7/1/23 0:00 6/30/28 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 8067784 "FENG, PINGHUI " Not Applicable 37 NONE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF DENTISTRY/ORAL HYGN 900894304 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 378581 NCI 228750 149831 AbstractTitle: Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphomaHuman gamma herpesviruses including Kaposi's sarcoma-associated herpesvirus (KSHV) andEpstein-Barr virus (EBV) are causative agents of diverse malignancies in immune-compromised individual including AIDS patients and organ transplant recipients. In addition toKS KSHV is invariably associated with two types of lymphoma primary effusion lymphoma(PEL) and multicentric Castleman's disease (MCD). No vaccine or effective treatment isavailable for KSHV-associated malignancies though antiviral therapy targeting viral thymidinekinase is an option with limited efficacy.We have an outstanding interest in virus-host interaction involving innate immune defensesystem. Recently we discovered that KSHV exploits the IKKepsilon kinase to reprogrammetabolism in KSHV latently-infected PEL cells. Specifically KSHV activates IKKepsilon to fuelde novo nucleotide synthesis via activating key metabolic enzymes known as glutamineamidotransferases. In doing so IKKepsilon promotes the proliferation of KSHV-infected PELcells and depletion of IKKepsilon arrests these cells at G0/G1 phase. This study will delineatethe molecular interaction that KSHV activates IKKepsilon in metabolic reprogramming to supportimmortal proliferation of PEL cells. We have developed novel small-molecule inhibitors ofIKKepsilon and glutamine amidotransferases. We will explore these drug-like molecules totarget IKKepsilon and glutamine amidotransferase to impede PEL cell proliferation. Our workwill not only elucidate fundamental mechanism governing PEL cell metabolism and proliferationbut also provide proof-of-concept that targets host factors to treat KSHV-associatedmalignancies. 378581 +No NIH Category available AIDS related cancer;Acquired Immunodeficiency Syndrome;Actins;Address;Adherens Junction;Adhesions;Automobile Driving;Binding;Blood Vessels;Cell Culture Techniques;Cell Cycle;Cell Cycle Arrest;Cell Proliferation;Cell Shape;Cells;Complex;Contact Inhibition;Cyclin-Dependent Kinase Inhibitor;Cytoskeleton;Data;Endothelial Cells;Genome;Gentian Violet;Herpesviridae Infections;Human;Human Herpesvirus 8;Individual;Infection;Kaposi Sarcoma;Knowledge;Left;Lymphatic Endothelial Cells;Lytic;Malignant Neoplasms;Measures;Mediating;Mentored Clinical Scientist Development Program;Messenger RNA;MicroRNAs;Modeling;Normal Cell;Oncogenic;Pathway interactions;Phenotype;Process;Proliferating;Proliferation Marker;Proteins;Protocols documentation;Public Health;Repression;Role;Solid Neoplasm;Stains;Study models;Supporting Cell;Testing;Therapeutic;Therapeutic Intervention;Transcript;Viral;Viral Genes;Work;cadherin 5;cell type;gene product;improved;inhibitor;innovation;monolayer;mutant;neoplastic cell;trafficking;tumor;tumorigenesis Mechanisms of KSHV-induced endothelial cell loss of contact inhibition of proliferation PROJECT NARRATIVEKaposis Sarcoma-associated herpesvirus (KSHV) is a major cause of AIDS-associated cancers and thusrepresents a significant public health burden. The proposed work seeks to establish how KSHV triggers cellularproliferation in an improved cell culture model of the KSHV-associated cancer Kaposis sarcoma. Results will beimpactful because they will improve our understanding of mechanisms underlying Kaposis Sarcoma and ourability to develop therapeutic strategies for this cancer. NCI 10762813 6/22/23 0:00 PA-20-185 1R01CA285193-01 1 R01 CA 285193 1 "READ-CONNOLE, ELIZABETH LEE" 7/1/23 0:00 6/30/28 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 9354245 "GOTTWEIN, EVA HENRIETTE" Not Applicable 5 MICROBIOLOGY/IMMUN/VIROLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 494501 NCI 314253 180248 SUMMARYKaposis Sarcoma-associated herpesvirus (KSHV) causes the AIDS-defining cancer Kaposis Sarcoma (KS).The KSHV-infected KS tumor cells (KSCs) express proliferation markers indicating a loss of contact inhibitionof proliferation (CIP). CIP is considered a tumor suppressive pathway and loss of CIP is a crucial feature ofoncogenic transformation in solid tumors. How KSHV antagonizes CIP is not known. The KS tumor cells mostlikely originate from microvascular lymphatic endothelial cells (LECs). While LECs therefore represent arelevant model for studies of KS KSHV-induced proliferation after de novo infection of primary human LECshas not been demonstrated. We have developed a protocol for KSHV infection of primary human LECs thatallows us to measure KSHV-induced loss of CIP. The central hypothesis underlying this application is thatKSHV-induced loss of CIP is a critical driving feature of oncogenesis in KS. Our preliminary work shows thatthe KSHV miR-K10 miRNAs contribute substantially to the KSHV-induced loss of CIP in LECs but are not theonly viral determinants of this phenotype. Our results furthermore implicate viral repression of p27 disruptionof adherens junctions (AJs) and deregulation of the cytoskeleton and vesicular trafficking in KSHV-mediatedloss of CIP. To test our hypothesis and elucidate the mechanisms underlying KSHV-induced loss of CIP wepropose three Specific Aims. In Specific Aim 1 we will determine the expression of the four miR-K10 miRNAsin KSHV-infected LECs and KS. We will also define their individual contributions to the KSHV-induced loss ofCIP. In Specific Aim 2 we will identify the mechanisms underlying the miR-K10-induced loss of CIP in KSHV-infected LECs. In Specific Aim 3 we will identify other viral genes that promote the KSHV-induced loss of CIP.The proposed study is innovative because our model provides rigorously defined experimental settings thatenable the analysis of KSHV-induced loss of CIP after infection of a primary human cell type with relevance toKS. This work is significant because it will establish the viral determinants of KSHV-induced LEC proliferationthereby explaining oncogenic mechanisms in KS. Results will be impactful since CIP is a tumor-suppressivemechanism. Understanding how KSHV overcomes CIP will help us to explain how KSHV causes KS and couldpotentially be exploited for therapeutic intervention in KS. 494501 +No NIH Category available Address;Affect;Africa;Africa South of the Sahara;Age;Algorithms;COVID-19;Cancer Etiology;Cancerous;Caring;Cervical Cancer Screening;Cessation of life;Clinical;Cold Therapy;Cost Analysis;Country;Data;Diagnosis;Disease Outcome;Early Diagnosis;Early treatment;Electrocoagulation;Eligibility Determination;Excision;Female;Goals;Government;Guidelines;HIV;HIV diagnosis;Health Status;Hospital Referrals;Hospitals;Hysterectomy;Incidence;Infant;Information Systems;Infrastructure;Intervention;Invasive Lesion;Kenya;Lesion;Letters;Life;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Monitor;Morbidity - disease rate;National Cancer Institute;Online Systems;Outcome;Patients;Pilot Projects;Population;Procedures;Provider;Public Health;Quality-Adjusted Life Years;Randomized Controlled Trials;Recommendation;Resource-limited setting;Risk;Running;Screening Result;Service provision;Services;Site;System;Treatment Efficacy;Visual;Woman;Work;World Health Organization;acceptability and feasibility;antenatal;cancer care;cancer therapy;cervical cancer prevention;chemotherapy;comorbidity;cost;cost effective;cost effective intervention;cost effectiveness;design;eHealth;efficacy evaluation;experience;follow-up;high risk;human centered design;implementation strategy;implementation/effectiveness;improved;innovation;interoperability;mortality;patient retention;patient-level barriers;premalignant;prevent;primary outcome;public health relevance;reproductive;reproductive tract;scale up;screening;secondary outcome;social stigma;standard of care;system-level barriers;tool;treatment site;uptake Implementing and Evaluating the Cancer Tracking System (CATSystem): A systems level intervention to improve Cervical Cancer screening treatment referral and follow up in Kenya PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCEThis trial will evaluate the CATSystem - a web-based system-level intervention that addresses persistent gapsin cervical cancer care by facilitating guideline-adherent services to optimize the cervical cancer screening andtreatment cascade of care. This study is designed to evaluate intervention efficacy implementationoptimizations and assess cost-effectiveness to inform larger scale-up. Cervical cancer is preventable thusinnovative approaches are critically needed in Kenya to improve cervical cancer outcomes. NCI 10762689 8/14/23 0:00 PAR-21-035 1R01CA278617-01A1 1 R01 CA 278617 1 A1 "CHOLLETTE, VERONICA" 8/15/23 0:00 6/30/28 0:00 Population and Public Health Approaches to HIV/AIDS Study Section[PPAH] 8321888 "KESSLER, SARAH FINOCCHARIO" "MABACHI, MARIANNE NATABHONA" 3 FAMILY MEDICINE 16060860 YXJGGNC5J269 16060860 YXJGGNC5J269 US 39.026584 -94.636347 1484303 UNIVERSITY OF KANSAS MEDICAL CENTER KANSAS CITY KS SCHOOLS OF MEDICINE 661608500 UNITED STATES N 8/15/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 583607 NCI 474915 108692 AbstractIn Kenya cervical cancer (CC) contributes to over 80% of female reproductive-tract cancers4 yet only 16.4%of eligible women are screened for CC.5 This is far below the World Health Organization's (WHO) target if 70%screening coverage; prioritizing access among women living with HIV given their higher risk of developing CC.Women who are screened and referred for treatment onsite (precancerous lesions) or off-site (cancerouslesions) experience high rates of loss to follow up (30-60%) during treatment. Many system and patient levelbarriers continue to exist resulting in significant morbidity and mortality that could be prevented. Innovative andfeasible eHealth strategies have improved clinical outcomes and patient retention in low resource settings andcould be key to reaching global targets for CC screening and treatment coverage in Kenya. To help addresssystem level barriers to CC screening treatment and follow-up our team worked with end-users (providers andpatients) to develop the Cancer Tracking System (CATSystem) a web-based algorithm generated tool topromote guideline adherent CC screening and retention through treatment. We piloted the CATSystem in aKenyan hospital and found that rates of onsite treatment for precancerous lesions and referral for treatment forwomen with positive screens were higher (2.5 to 5-fold improvement) during the pilot compared to serviceprovision six months prior. The goal of this project is to rigorously evaluate the efficacy implementation andcost-effectiveness of the CATSystem to improve rates of screening treatment referral and follow-up care in amatched cluster randomized controlled trial in 10 Kenyan government hospitals (5 intervention 5 standard ofcare (SOC)). Specific aims (SA) of the study are to (1) Implement and evaluate the efficacy of CATSystem toimprove guideline adherent CC screening treatment referral and follow up (2) Assess feasibility andacceptability of implementation of CATSystem in government run facilities using a human centered designapproach and (3) Calculate the costs and cost-effectiveness of the CATSystem to increase quality adjusted lifeyears gained. CC cancer deaths can be prevented with early detection and treatment. This study will evaluatethe public health impact of the CATSystem in improving CC screening treatment referral follow-up and thefeasibility of scale up to other low resource settings. 583607 +No NIH Category available Acceleration;Address;Adoption;Ascites;Automation;Benign;Biological Assay;Biological Markers;Blood;Blood Tests;Blood specimen;CA-125 Antigen;Cancer Model;Cancer Patient;Cells;Chromatography;Circulation;Clinical;Clinical Research;Complement;Diagnostic;Diameter;Disease;Early Diagnosis;Epithelial ovarian cancer;Excision;General Hospitals;Genetic Risk;Germ-Line Mutation;Goals;Gynecologic;Hospitals;Image;Industry;Intervention;Lesion;Liquid substance;Malignant - descriptor;Malignant Female Reproductive System Neoplasm;Malignant neoplasm of ovary;Massachusetts;Messenger RNA;Methods;Molecular;Molecular Analysis;Monitor;Mus;Nanotechnology;Nucleic Acids;Operative Surgical Procedures;Organoids;Ovarian;Pathogenesis;Pathology;Patients;Performance;Perinatal;Plasma;Proteins;Quality Control;Research;Resources;Sampling;Screening for Ovarian Cancer;Screening for cancer;Serous;Site;Standardization;Statistical Data Interpretation;System;Systems Biology;Technology;Testing;Thinking;Time;Translating;Tumor Burden;United States;Update;Validation;Woman;advanced disease;assay development;biobank;biomarker panel;cancer biomarkers;cancer care;cancer diagnosis;cancer imaging;cancer subtypes;circulating biomarkers;clinical translation;cohort;comparative;design;diagnostic value;early detection biomarkers;exosome;extracellular vesicles;high risk;high risk population;insight;instrument;liquid biopsy;minimal risk;minimally invasive;molecular dynamics;multidisciplinary;nanoplasmonic;novel;patient derived xenograft model;peripheral blood;prophylactic;prospective;protein biomarkers;protein profiling;screening;success;tool;tumor progression;tumorigenesis Expanding early cancer detection with high throughput OCEANA - Ovarian Cancer Exosome Analysis with Nanoplasmonic Array NARRATIVEWe propose to translate a novel liquid biopsy platform for early cancer detection. Specifically we willapply a forward-thinking nano-plasmonic platform for comprehensive high-throughput molecularanalyses of extracellular vesicles (EVs). We will rigorously address EVs' clinical utility to detect high-grade serous ovarian cancer in high-risk patient cohorts. NCI 10762488 9/19/23 0:00 RFA-CA-23-018 1U01CA284982-01 1 U01 CA 284982 1 "HODGES, NICHOLAS AARON" 9/19/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(A1)R 9797123 "LEE, HAKHO " "CASTRO, CESAR M" 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 877641 NCI 649022 228619 Ovarian cancer (OvCa) remains the most lethal gynecologic cancer in the United States. Earlydetection through screening particularly of high-risk populations is an appealing strategy for timelyintervention yet conventional efforts have not improved survival. Extracellular vesicles (EVs; 30-200nm in diameter) are actively released by cells into circulation carrying diverse molecular cargo.Capturing this information could provide a real-time window to monitor tumor burden and dynamicmolecular changes and potentially OvCa precursor lesions. We aim to advance our translational EVassay for early OvCa diagnosis with a focus on its most lethal subtype high-grade serous ovariancancer (HGSOC). We formed a powerful strategic academic-industry alliance betweenMassachusetts General Hospital Brigham and Women's Hospital and Exosome Diagnostics andhave laid out two primary objectives. Technology renement. We will implement an automated andhigh-throughput platform OCEANA (Ovarian Cancer Exosomal Analysis with Nanoplasmonic Array).We will also construct an EV marker panel to enhance the diagnostic power of EV assays. Expandedclinical validation. We will rigorously evaluate OCEANA and EV biomarkers using patient-derivedorganoids and samples across the clinical spectrum (e.g. benign early advanced stages) from aworld-class and gynecologic-focused biorepository. We have four Specic Aims to achieve theseobjectives. Aim 1. We will develop a disk-based cartridge for fast automated total EV isolation. Theunderlying technology will be our dual-mode chromatography (DMC) which has demonstratedsuperior EV extraction from plasma. Aim 2. We will establish an expanded EV-marker panel forHGSOC detection informed by patient-derived organoids and EVs. Specically EV protein and mRNAresults will be combined to make a multi-analyte marker panel. Aim 3. We will analyze EVs from micehosting HGSOC patient-derived xenografts to study the relationship between tumor progression andcirculating EVs. Aim 4. We will screen circulating EVs in women with benign or malignant ovarianconditions rigorously evaluating OCEANA's clinical performance. Impact. This project will establishOCEANA as a transformative tool for comprehensive EV analyses. The clinical study will also validateEVs as a potent circulating biomarker for early detection of HGSOC. Ultimately we envisiontranslating the technology as a monitoring tool for cancer care across research and clinical settings. 877641 +No NIH Category available African American population;Amino Acids;Asia;Asian ancestry;Asian population;Biological;Biological Assay;Biological Markers;Blood specimen;California;Cancer Etiology;Caucasians;Cessation of life;Clinical;Clinical Data;Cohort Studies;Data;Databases;Diagnosis;Diagnostic;Disease;Early Diagnosis;Epidemiology;Ethnic Origin;Ethnic Population;Etiology;Europe;European;European ancestry;Evaluation;Functional disorder;Gastrointestinal Diseases;Genetic;Genomics;Health;Hospitals;Incidence;Individual;Japanese American;Life Style;Malignant Neoplasms;Malignant neoplasm of pancreas;Medicare claim;Mentors;Metabolic;Metabolic syndrome;Minority;Minority Groups;Modeling;Native Hawaiian;Organ;Pancreas;Participant;Pathogenesis;Pathway interactions;Pattern;Performance;Phase;Population;Population Heterogeneity;Prevention;Prognosis;Prospective cohort;Questionnaires;Race;Research;Research Design;Resources;Risk;Risk Factors;Running;Sampling;Screening for cancer;Standardization;Subgroup;Survival Rate;Symptoms;Systems Biology;Techniques;United States;associated symptom;biobank;cancer risk;cohort;comorbidity;data integration;design;epidemiologic data;gastrointestinal symptom;genetic variant;genome-wide;genomic data;high risk;high risk population;improved;insight;metabolomics;mortality;multi-ethnic;neoplasm registry;novel;pancreatic cancer model;predictive modeling;racial diversity;risk prediction model;risk stratification;sex Integrating epidemiologic clinical genomic and metabolomic profiles to predict pancreatic cancer risk in a multiethnic population PROJECT NARRATIVEPancreatic cancer is a significant health problem in the United States with very poor survival and disproportionateburden across race/ethnicity. Our objective is to apply an integrative systems biology approach incorporatingepidemiologic clinical genetic and metabolomic data to improve the prediction of pancreatic cancer risk in aracially heterogeneous population. By refining the identification of high-risk individuals our study will help toestablish new strategies for targeted prevention and early detection and reduce the overwhelming burden of thislethal disease. NCI 10762478 1/2/24 0:00 RFA-CA-20-014 5R00CA256525-04 5 R00 CA 256525 4 "ROTUNNO, MELISSA" 1/9/23 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 14485373 "HUANG, BRIAN " Not Applicable 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 Non-SBIR/STTR 2024 224100 NCI 135818 88282 ABSTRACTPancreatic cancer is a highly lethal malignancy that has a very poor prognosis in the United States. It has a 5-year survival rate of only 9% and is projected to become the second most common cancer death by 2030.Pancreatic cancer also has a disproportionate burden across race/ethnicity with higher incidence rates observedamong minority groups such African Americans Japanese Americans and Native Hawaiians. Past predictionmodels have been developed to identify high-risk individuals and improve the earlier detection of this disease.However these models were designed in individuals of primarily European or Asian ancestry and have not beenvalidated in multiethnic populations. In addition these models included mainly known epidemiologic risk factorsand only a few incorporated data on genetic variants or health conditions. Thus a model that employs moregranular data such as comorbidities/symptoms genomics and metabolomics for the prediction of pancreaticcancer across multiple races/ethnicities does not exist. In this study we seek to apply an integrative systemsbiology approach to enhance the prediction of pancreatic cancer risk using data from the Multiethnic Cohort(MEC) Study. The MEC is a long-standing prospective cohort of over 215000 racially diverse individuals thathas comprehensive lifestyle environmental clinical and genetic data. We will use data from existing resourcesof the MEC including epidemiologic risk factors from questionnaires clinical health conditions from Medicareclaims genetic data from a large biorepository of blood samples and cancer incidence and mortality informationfrom SEER Cancer registries and state and national mortality databases. We will also generate new metabolomicdata for a subset of MEC participants. Our specific aims are: 1) to identify clusters or patterns of clinical conditionsassociated with pancreatic cancer risk; 2) to validate existing prediction models in a multiethnic population anddevelop an enhanced prediction model that incorporates epidemiologic clinical and genomic data; 3) to identifymetabolites associated with pancreatic cancer in a multiethnic population; and 4) to integrate epidemiologicclinical genomic and metabolomic data to identify individuals at high risk of pancreatic cancer. Results from thisstudy are expected to elucidate etiologic mechanisms and improve the prediction of pancreatic cancer risk forheterogeneous populations. This will have significant implications for improving strategies for earlier detectionand reducing the overwhelming burden of this fatal cancer. 224100 +No NIH Category available Aneuploidy;Apoptosis;Award;Base Pairing;Binding;Biological Assay;Cell Aging;Cell Survival;Cell division;Cells;Centromere;Chromosomal Breaks;Chromosome 16;Chromosome Deletion;Chromosomes;Clinical;Complex;DNA Damage;DNA Double Strand Break;DNA Primase;Data;Development;Dicentric chromosome;Distal;Doctor of Philosophy;Double Strand Break Repair;Doxycycline;Ectopic Expression;Environment;Event;Frequencies;Genes;Genome;Genome Stability;Genomic Instability;Genomics;Germ Cells;Goals;Gonadal structure;Haploidy;Hela Cells;Human;In Vitro;Institution;Length;Link;Malignant Neoplasms;Mediating;Medical;Methods;Molecular;Neoplasms;Pathologic;Pathway interactions;Patient Care;Patients;Physicians;Physiological;Polymerase;Process;Proliferating;Regulation;Reporter;Repression;Role;Running;Rupture;Scientist;Signal Transduction;Somatic Cell;TP53 gene;Telomerase;Telomerase Inhibitor;Telomerase RNA Component;Telomerase inhibition;Telomere Maintenance;Telomere Shortening;Testing;Trees;alpha-Thalassemia;cancer cell;cancer diagnosis;cancer prevention;carcinogenesis;career;cell transformation;chromosome fusion;chromothripsis;design;detection assay;expectation;experimental study;genetic approach;healing;improved;mortality;neoplastic cell;novel strategies;p53-binding protein 1;prevent;programs;reconstitution;recruit;repaired;response;senescence;stem cells;telomere;tumor;tumorigenesis Telomerase-Mediated Healing of Double-Strand Breaks in Human Cells PROJECT NARRATIVETelomere shortening impedes uncontrolled cell division either by triggering replicative senescence or apoptosisor by running transformed cells into telomere crisis in which rampant end-to-end telomere fusions andchromosome rupture restrict cell viability. This project aims to identify the molecular mechanism andphysiologic repressors of telomerase-mediated DNA double-strand break repair which may enabletransformed cells to escape telomere crisis and emerge as clinical tumors. My anticipated findings willilluminate another facet of genomic instability in early tumorigenesis and may lead to novel strategies forcancer diagnosis and prevention. NCI 10762339 11/21/23 0:00 PA-19-191 5F30CA257419-04 5 F30 CA 257419 4 "DAMICO, MARK W" 1/1/21 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-F08-M(20)L] 14621309 "KINZIG, CHARLES GUNNAR" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTTelomereswhich define and protect the ends of humans linear chromosomesserve as a natural check oncarcinogenesis. Genome stability requires cells to differentiate telomeres from perilous DNA double-strandbreaks (DSBs) to block inappropriate DSB repair and DNA damage response (DDR) signaling which humansaccomplish with the shelterin complex. Telomerase maintains telomere length in the gonads and some stemcells but telomeres in somatic cells shorten with each cell division due to developmental silencing oftelomerase. Unfettered cell division in early neoplasms eventually leads to a few telomeres becoming criticallyshort and activating persistent DDR signaling which causes cells with functional p53 and Rb pathways toundergo senescence or apoptosis. Cells defective in these pathways continue to divide until multiple telomeresbecome de-protected and then enter telomere crisis defined by poor cell viability due to intolerable genomicinstability as chromosomes repeatedly fuse at their ends and break. Clinical tumors emerge from crisis withrearranged aneuploid genomes and a telomere maintenance mechanism. To escape from telomere crisis Ipredict that malignant cells must reconstitute their telomeres and that telomerase may accomplish this bydirectly repairing non-telomeric chromosome ends with neotelomeres. The objective of the proposed project is to identify and mechanistically characterize telomerase-mediated DSB repair in human cells. In vitro telomerase can add TTAGGG repeats to a non-telomericbreakpoint sequence derived from a patient with -thalassemia due to a terminal chromosomal truncation.Using this sequence I have designed a PCR-based reporter assay to detect neotelomere formation in cells atan inducible DSB and have gathered evidence that suggests that telomere healing occurs in human cells in atelomerase-dependent manner. I will improve this assay with TaqMan probes on a qPCR platform to rigorouslyquantify telomere healing events and will perform further experiments to demonstrate that telomerase isresponsible for TTAGGG repeat addition. Because telomerase-mediated repair threatens to convert DSBs intoterminal chromosome deletions I hypothesize that human cells have evolved mechanisms to block telomeraseactivity at DSBs. I will implement a genetic approach with my telomere healing assay to identify the physiologicrepressors of this aberrant mode of DSB repair. Ultimately I aim to unveil a new role for telomerase in enablingincipient cancers to traverse the bottleneck of telomere crisis. This leap in our understanding of genomicinstability in early tumorigenesis may lead to unexpected ways to detect and prevent cancer in patients. Withthe aid of this award and the stimulating environment of the Tri-Institutional MD/PhD Program I will growscientifically medically and professionally in ways that will enable me to advance toward my long-term careergoal of leading a cancer-centric lab while providing patient care as a transformative physician-scientist. 52694 +No NIH Category available Academy;Adult;Advisory Committees;Advocacy;Advocate;African American;Benchmarking;Black American;Black Populations;Black church;Black race;California;Cancer Survivor;Caring;Church;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Country;Data;Development;Diagnosis;Diffusion of Innovation;Education;Educational Activities;Educational Materials;Evaluation;Feedback;Florida;Funding;General Population;Goals;Health;Health Professional;Hispanic;Human;Individual;Institution;Knowledge;Latino;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Measures;Mission;Modeling;Multimedia;Pancreas;Persons;Policy Maker;Population;Population Heterogeneity;Prostate;Reporting;Research;Research Personnel;Research Project Grants;Resources;Risk;Scientist;Technology;Theoretical model;Training;Training Programs;Universities;University of Southern California Norris Cancer Center;Voice;Work;Writing;anticancer research;behavior change;cancer health disparity;cancer risk;catalyst;community center;community engaged research;design;education research;evidence base;experience;handbook;health belief;health equity;improved outcome;innovation;low socioeconomic status;member;men;outreach;programs;theories;tool;web site;webinar Outreach Core n/a NCI 10762323 9/20/23 0:00 PAR-22-249 2U54CA233465-06 2 U54 CA 233465 6 9/20/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5729 1910369 "BAEZCONDE-GARBANATI, LOURDES A." Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 201966 121973 79993 ABSTRACT COMMUNITY OUTREACH COREThe goal of the Community Outreach Core (COC) is to continue supporting the Florida-California CancerResearch Education and Engagement Health Equity (CaRE2) Center by sharing scientific data and resultsfrom ongoing projects with throughout our communities promoting clinical research education and trainingcommunity members to be advocates and community influencers on cancer. Our Community Outreach Core(COC) team has over 20 years of experience working in bicoastal community engagement research withdiverse populations including but not limited to Black African American (B/AA) and Hispanic/Latinox (H/L)individuals of various country origins and of low socioeconomic status. We will continue supporting Centerinvestigators conducting prostate pancreatic and now lung cancer research. Building on COCs prior workfour (4) aims to accomplish are to 1) Create and implement a Community Advocacy Academy designed totrain support and measure the impact of 600 community advocates in sharing information about cancercancer research and the CaRE2 Center and its projects 2) Develop and deliver to 5000 community membersevidence-based multimedia educational materials maximizing the use of technology and media tailored to B/AA and H/L audiences focusing on pancreatic and lung cancer information cancer research and clinical trialsparticipation and biospecimens donation for cancer research. 3) Partner with CaRE2 investigators to hosteducational activities to inform and educate B/AA and H/L diverse populations and other key stakeholdersabout cancer research advances and CaRE2 center discoveries. 4) Partner with the CaRE2 Planning andEvaluation Core to evaluate the effects of the COC program and activities. +No NIH Category available Address;African American population;Black Bear;Black race;California;Cancer Etiology;Caring;Cells;Cessation of life;Cytidine Deaminase;DCK gene;Data Set;Deoxycytidine Kinase;Diagnosis;Drug Kinetics;Drug usage;Education;Epidermal Growth Factor Receptor;Epigenetic Process;Exposure to;Fc Receptor;Florida;Fluorouracil;Formulation;Gene Expression;Genetic;Goals;High Prevalence;Human;Incidence;Investigation;Leucovorin;Malignant Neoplasms;Measures;Metabolism;Modeling;Mus;Nucleoside Transporter;Operative Surgical Procedures;Organoids;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Phosphorylation;Pilot Projects;Population Heterogeneity;Proteins;Publishing;RNA;Resistance;Risk;SNP genotyping;Safety;Sampling;Solubility;Surface;Survival Rate;Systemic Therapy;Testing;Toxic effect;Treatment Efficacy;Variant;Wild Type Mouse;anticancer activity;anticancer research;chemotherapy;cohort;design;efficacy evaluation;efficacy testing;enzyme activity;ethnic diversity;experience;experimental study;gemcitabine;health equity;improved;in vivo;irinotecan;lipophilicity;mortality;mouse model;multi-ethnic;nanoparticle;oxaliplatin;pancreatic PDX models;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;patient derived xenograft model;patient stratification;personalized chemotherapy;protein expression;racial difference;racial diversity;response;subcutaneous;targeted delivery;therapy outcome;treatment choice;tumor;tumor growth;tumor xenograft;uptake Pilot Project 5 n/a NCI 10762320 9/20/23 0:00 PAR-22-249 2U54CA233465-06 2 U54 CA 233465 6 9/20/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5726 9113801 "HAN, BO " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 55330 33415 21915 ABSTRACT Pilot Project 5Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and the survivalrate remains stagnant with a 5-year survival rate of only 5-8%. Black/African Americans (B/AA) individualsexperience the highest prevalence and lowest overall survival rates of PDAC compared to their Whitecounterparts. FOLFIRINOX (5-fluorouracil leucovorin oxaliplatin and irinotecan) is often the preferredchemotherapy treatment choice for patients with PDAC but considerable toxicities have limited its use. Thedecreased expression of nucleoside transporters due to genetic and epigenetic reasons appeared to account forGem resistance. In addition deoxycytidine kinase (dCK) which is responsible for Gem phosphorylation into theactive form is postulated to correlate with Gem efficacy. To address these challenges we have modified Gemto 4-(N)- stearoylGem (4NSG) to: i) block the CDA attack on Gem and ii) increase Gem transport into PDACcells. Our recent results revealed highly expressed epidermal growth factor receptors (EGFR) in pancreatictumor samples. Guided by our recently published and unpublished results we hypothesize that optimized 4NSGnanoparticles with surface-modified anti-EGFR antibody (4NSGnpcetu) will improve the therapeutic efficacy ofGem. We propose the following specific aims to address this hypothesis. Aim 1: Test the efficacy of 4NSGnpcetuin B/AA and White patient-derived organoid models (PDOs) with stroma and in primary PDAC cells. Aim 2:Evaluate the therapeutic efficacy of 4NSGnpcetu in PDAC PDX mouse models bearing subcutaneous tumors fromB/AA and White patients. Aim 3: Measure dCK RNA/protein expression in PDAC PDX tumor models and SNPgenotypes in PDAC cases and controls in the MultiEthnic dataset. Our studies will determine whether racialdifferences in dCK variant gene expression and protein activity can correlate with improved Gem efficacy inB/AA and /or White PDAC patients. The valuable information obtained will significantly advance the overall goalof improving the response and survival rate in PDAC patients. +No NIH Category available 3-Dimensional;ATAC-seq;Acinar Cell;Acinus organ component;Address;African American;African American population;Black Populations;Black race;California;Cancer cell line;Caring;Cell Line;Cell Reprogramming;Cells;Chronic;Coculture Techniques;Collagen;Conditioned Culture Media;Data;Development;Disease;Disparity;Duct (organ) structure;Ductal Epithelial Cell;Early Diagnosis;Early treatment;Education;Event;Experimental Models;Extracellular Matrix;Fibronectins;Florida;Funding;Gender;Gene Expression;Genes;Goals;Heterogeneity;Hispanic;Hispanic Populations;Histone Deacetylase Inhibitor;Human;Immune;Immunofluorescence Immunologic;In Situ;Incidence;Individual;Inflammation;Inflammatory;Institution;Latino;Latino Population;Lesion;Link;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Metabolic stress;Metaplasia;Methods;Microscopic;Molecular;Normal Range;Outcome;Oxidative Stress;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Penetration;Peptide Hydrolases;Pharmaceutical Preparations;Phenotype;Pilot Projects;Process;Prognosis;Publishing;Race;Role;Sampling;Stains;Stromal Cells;System;Tissues;Trichostatin A;anticancer research;biophysical properties;biophysical techniques;cancer health disparity;chronic pancreatitis;combat;comorbidity;effective therapy;health equity;improved;inhibitor;irritation;mortality;mouse model;novel;pancreas development;pancreatic ductal adenocarcinoma model;pancreatic metaplasia;pancreatic stellate cell;pharmacologic;prevent;racial disparity;stellate cell;therapeutic target;transcriptome sequencing;treatment response;tumor microenvironment Full Project 3 n/a NCI 10762318 9/20/23 0:00 PAR-22-249 2U54CA233465-06 2 U54 CA 233465 6 9/20/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5724 9113801 "HAN, BO " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 125234 75632 49602 ABSTRACT FULL PROJECT 3 ADMPancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancers with poor prognosisand rising incidence. To combat this deadly disease we should direct our efforts towards preventing PDAC orhalting the progression of precursor lesions to invasive disease parallel to developing novel treatments. One ofthe earliest known initiating events for PDAC is the process of acinar-to-ductal metaplasia (ADM). Understandingand reduction of ADM formation may reduce early PDAC development and progression. Blacks display asignificantly increased incidence and mortality from PDAC compared to other races for unknown reasons. Therole of race on pancreatic ADM and its contributions to the development and progression of PDAC need to beaddressed. In our previously funded CaRE2 Pilot Project we used normal pancreatic acinar tissues from BlackWhite and Hispanic donors to study the impact of race on acinar-to-ductal metaplasia (ADM) and found thatBlacks undergo ADM to a greater extent than Whites or Hispanics. In this proposed Full Project as part of theCaRE2 renewal we will expand on and extend our previous pilot project by including diseased tissues from CPand PDAC from White Black and Hispanic donors since accumulating evidence suggest that chronicpancreatitis (CP) is a major precursor to the development of PDAC. We will investigate the impact of race on thecellular and molecular events regulating the interplay between ADM and the microenvironment. Guided by ourpublished and unpublished results we hypothesize that the racial disparities seen in PDAC are related todifferences in how the pancreas microenvironment develops during ADM which means that ADM and itssurrounding microenvironment can be used as a target to treat PDAC. We propose the following specific aimsto address this hypothesis: Aim 1: The influence of race on ADM of healthy pancreas CP and PDAC-associatedacinar tissues. Aim 2: The roles of pancreatic stellate cells and macrophages in ADM and ADM reversal Aim 3:Contributions of the race to ADM reversal and cell heterogeneity. The proposed studies will impact the field ofpancreatic cancer by providing a missing link between disparities ADM tumor microenvironment and potentialtreatments for CP and PDAC. The specific focus on the racial contributions of microenvironment remoldingduring pancreatic metaplasia aligns with the Florida-California Cancer Research Education and Engagement(CaRE2) Health Equity Centers overall goal to eliminate cancer health disparities among Black and Latinoindividuals in California Florida and across the U.S. +No NIH Category available Address;African;African American;African Caribbean;Award;Benchmarking;Black race;California;Cancer Center;Cancer Science;Career Mobility;Caring;Central American;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Cuban American;Data;Development;Doctor of Philosophy;Education;Education and Outreach;Educational Activities;Ensure;Evaluation;Event;Exhibits;Extramural Activities;Florida;Foundations;Funding;Goals;Grant;Growth;Health;Health Disparities Research;Hispanic;Human Resources;Individual;Infrastructure;Institution;International;Intranet;Knowledge;Latina;Latino;Latinx population;Lead;Leadership;Link;Mexican;Minority Groups;Mission;Modeling;Monitor;Office of Administrative Management;Online Systems;Outcome;Prevention Research;Principal Investigator;Program Evaluation;Publications;Puerto Rican;Research;Research Personnel;Research Project Grants;Resource Sharing;Scanning;Scientist;Series;South American;Strategic Planning;Structure;Supervision;Underrepresented Minority;United States National Institutes of Health;Universities;University of Southern California Norris Cancer Center;Vision;Woman;Work;anticancer research;cancer health disparity;cancer prevention;education research;ethnic diversity;gender diversity;health equity;implementation strategy;improved;interest;minority engagement;minority scientist;programs;racial diversity;sharing platform;success;symposium;web site;webinar Administrative Core n/a NCI 10762315 9/20/23 0:00 PAR-22-249 2U54CA233465-06 2 U54 CA 233465 6 9/20/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5721 6367572 "CARPTEN, JOHN D." Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 182265 110075 72190 ABSTRACT ADMINISTRATIVE COREThe Florida-California Cancer Research Education & Engagement (CaRE2) Health Equity is a partnershipamong the University of Florida (UF) Florida A&M University (FAMU) and University of Southern California(USC) to eliminate cancer health disparities in Florida California and nationally. Building on the strong foundationand Center accomplishments that met or exceeded the benchmarks set for the first 5-year funding cycle wepropose another 5 years of support for our cutting edge work. The Administrative Core of the CaRE2 Center willserve as the hub of the CaRE2 Centers activities including the management coordination supervision andpromotion of the Centers activities. The administrative leadership will be primarily responsible for the Centersstrategic planning including: defining and upholding its mission and objectives conducting environmentalscanning for strategy development directing and managing strategy implementation and ensuring adjustmentsare made for continuous quality improvement (CQI) based on program evaluation. The established benchmarksfor the success of the Administrative Core are: (1) Integrated research efforts focused on cancer disparitiesresearch by a minimum of 12 UF-FAMU-USC collaborative teams. Three research projects are submitted aspart of this application and we anticipate making three additional awards between Years 2 and 4 and sixprojects supported with a Developmental Research Program and leverage funds (with additional extramuralprojects anticipated); (2) Integrated research education efforts focused on increasing the pool ofunderrepresented minorities focused on cancer research; (3) Integrated community outreach efforts focusedon engaging minority populations to collaborate on cancer research that reflects mutual interests; (4)Successful dissemination efforts that address cancer disparities in sub-populations of Black/African Americanand Hispanic/Latinx individuals via the Centers websites publications webinars conference presentationscommunity outreach events and educational activities; and (5) Submission of NIH K-series T-series andR-series grants led or co-led by a FAMU investigator and led by early stage investigators. +No NIH Category available Address;Advocate;Affect;Articulation;Awareness;Basic Science;California;City of Hope Comprehensive Cancer Center;Clinic;Clinical;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Data;Decentralization;Democracy;Disparity;Dissemination and Implementation;Education;Ensure;Environment;Evaluation;Faculty;Fostering;Grant;Human;Infrastructure;Institution;Intelligence;Knowledge;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Outcome;Population;Process;Recording of previous events;Research;Research Activity;Research Methodology;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Scientific Inquiry;Scientist;Services;Training;Training and Education;Translational Research;Translations;Universities;Writing;cancer health disparity;clinical trial enrollment;community engagement;community partnership;community setting;data access;drug development;ethnic minority;evidence base;experience;innovation;member;minority communities;outreach;racial minority;skills;success;tool;translational impact;translational potential;usability;web site Outreach n/a NCI 10762295 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5720 1864164 "LO, DAVID D" Not Applicable 39 Unavailable 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA Domestic Higher Education 925210001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 188000 124499 63501 Our U54 Outreach Core will facilitate the successful translation implementation and dissemination of researchfindings developed by U54 investigators. We build on the community relationships strategies and partnershipdeveloped during the P20 Planning period. Success of our P20 planning was due to the leadership of Dr.Christopher Sistrunk City of Hope Comprehensive Cancer Center (CoHCCC) and Dr. David Lo leader of theU54 Center for Disparities at University of California Riverside (UCR). Together these investigators usedreverse translation to bring community engagement to the bench scientists. Traditionally shared resourcecores support research activities by providing cutting-edge tools facilities and well-skilled faculty to advanceresearch. Yet there is often a gap in resources and knowledge on how research teams can ensure the translationof their findings from the basic science level (the bench) to the community and also from the community tothe bench. Thus the bidirectional potential of translational research has rarely been fully optimized. Building onthe success of our P20 and U54 UCR Center for Disparities we aim for our UCR-CoHCCC U54 partnership tooptimize the bidirectional potential of true community partnership. Community needs as articulated byengagement is typically not directly obtained by bench scientists and may explain the limited translation ofresearch findings to communities that are most adversely affected by cancer.1-2 Subsequently there is a markedlack of access and awareness of scientific data by community members and limited knowledge of communityneed and context by scientists. This inadequate dissemination lack of data access and increasing gap betweenscientists and communities limits the impact of scientific discoveries particularly in racial/ethnic minoritycommunities. Our U54 Outreach Core moves beyond traditional community engagement to foster rigorous bi-directional evidence-based strategies to narrow the divide. Aim 1 will facilitate the integration of the communityengagement across UCR-CoHCCC U54 research projects/pilots and cores. Aim 2 will provide technicalassistance and training to community stakeholders so they can engage UCR-CoHCCC U54-sponsored researchprojects and cores. Aim 3 will facilitate the translation and dissemination of UCR-CoHCCC U54 findings toaddress knowledge gaps across the cancer health disparities continuum. +No NIH Category available Award;California;City of Hope Comprehensive Cancer Center;Clinical Trials;Collaborations;Communities;Comprehensive Cancer Center;Contractor;Databases;Education;Educational process of instructing;Educational workshop;Effectiveness;Equity;Evaluation;Feedback;Funding;Future;Goals;Grant;Individual;Joints;Knowledge;Leadership;Measures;Mentors;Mentorship;Modeling;Monitor;Outcome Measure;Performance;Pilot Projects;Play;Process;Program Evaluation;Progress Reports;Publications;Recommendation;Reporting;Research;Research Personnel;Resources;Structure;Surveys;Therapeutic;Training;Training Programs;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;anticancer research;cancer health disparity;career;career development;drug development;equity diversity and inclusion;health disparity;improved;insight;meetings;outreach;programs;success;webinar Planning & Evaluation n/a NCI 10762293 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5718 14892770 "DAVIS, KENDRICK " Not Applicable 39 Unavailable 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA Domestic Higher Education 925210001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 111118 70551 40567 The goals of the Planning and Evaluation Core (PEC) are to monitor evaluate and assess the progress of ourU54 Partnerships in meeting its milestones objectives and goals. The Core supports our University of CaliforniaRiverside (UCR) City of Hope Comprehensive Cancer Center (CoHCCC) U54 Partnerships goals of capacity-building education and training. Together in this U54 UCR and CoHCCC aim to develop the collaborationstranslational resources and training programs to enhance diversity in cancer research and achieve equity indrug development - throughout the entire drug development pipeline. To achieve our PECs goals we are guidedby four boards the Internal Advisory Board (IAB) External Advisory Board (EAB) Community Advisory Board(CAB) and Diversity Equity and Inclusion Board (DEI). Our IAB and EAB have served a key role in guiding ourP20 planning grant; in our proposed U54 these two boards will be joined by our newly created CAB and DEI.The inclusion of these two new boards underscores our U54s commitment to 1) serving the diverse individualsthat live in our Southern California communities and 2) to mentor and train a diverse early-stage investigatorswho are committed to eliminating our current disparities in cancer therapeutics drug development and accessto clinical trials. Through the activities and oversight of the PEC our four advisory boards will 1) conductevaluation tracking and reporting of the progress of projects and cores and 2) provide focused feedback toprogram U54 leadership and investigators. As in our P20 planning grant the U54 PEC will work with the IAB toprovide a structured and rigorous review process to select new Full and Pilot projects as well as Mini-Pilots forthe Capacity Core. The PEC will assess all components of our U54 partnership. The PEC will assure that the1) Research and Evaluation Core training and education programs are effective in providing education andbuilding capacity 2) Outreach Core works with investigators to be inclusive of the communities we serve and 3)Capacity Core identifies provides early-stage investigators (ESI) with mentorship in target identification drugdevelopment and clinical trials. We anticipate that together our Cores will play a key role in developing futureU54 projects that build UCRs capacity in drug development and clinical trials. +No NIH Category available ATAC-seq;Acetyl Coenzyme A;Acetylation;African American;African ancestry;Biological Markers;Black race;Blood;Blood Vessels;Breast Cancer survivor;California;Cardiovascular Diseases;Cell Aging;Cell Separation;Cells;ChIP-seq;Chemoprevention;Chromatin;City of Hope Comprehensive Cancer Center;Clinical Trials;Code;Collection;Comprehensive Cancer Center;Cytotoxic Chemotherapy;Data;Diabetic Nephropathy;Doctor of Medicine;Eating;Epigenetic Process;Estrogen receptor negative;Failure;Gene Abnormality;Genes;Genetic Transcription;Grant;Growth;Health;Heart;Histone Acetylation;Human Resources;Hyperinsulinism;IRF1 gene;Inflammation;Inflammatory;Institutional Review Boards;Insulin;Insulin Resistance;Interferon-beta;Interleukin-6;Joints;Kidney;Latina;Latina Population;Leukocytes;Link;Malignant Neoplasms;Mentors;Mentorship;Metabolic;Metformin;Mitochondria;Muscle Cells;NF-kappa B;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Organ;Patients;Phase;Phenotype;Pilot Projects;Premature aging syndrome;Production;Proteins;Regulation;Reproducibility;Research;Research Personnel;Respiration;Risk;Running;Serum;Supervision;Surveys;TNF gene;Testing;Therapeutic Trials;Time;Training;Transplantation;Universities;Woman;clinical biomarkers;cohort;community center;cytokine;drug development;drug repurposing;experience;fighting;follow-up;malignant breast neoplasm;medical schools;mouse model;outreach;pilot trial;recruit;senescence;standard of care;stem cells;transcriptomics Pilot-Project 1 n/a NCI 10762292 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5717 12161030 "LEFKOWITZ, DEBORAH " Not Applicable 39 Unavailable 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA Domestic Higher Education 925210001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 52288 33199 19089 University of California Riverside (UCR) has never implemented a therapeutic trial. Building therapeutic trialcapacity at UCR was our biggest challenge and the biggest failure - of our P20 planning grant. City of HopeComprehensive Cancer Center (CoHCCC) runs hundreds of therapeutic trials (Phase 0 to 4) ranging fromchemoprevention to Phase 1 CAR-Tcell therapy. In our P20 planning grant we leveraged an on-going CoHCCCoutreach trial testing in women with insulin-resistance testing the ability of metformin to reduce 1) production ofinflammatory cytokines and 2) circulating senescent inflammatory cells. While CoHCCC has implemented thistrial in community centers the trial rapidly ran into problems at UCR. Key issues were 1) lack of experience ofthe UCR Institutional Review Board (IRB) and 2) a need for greater mentorship of UCR investigators. In this U54grant we are determined to help UCR open therapeutic trials; however first we need to build capacity. U54 PilotProject 1 uses state-of-the-art single cell-transcriptomics and -ATACseq in the context of a simple therapeutictrial. This trial tests the ability of standard-of-care metformin to reduce inflammation in insulin-resistant breastcancer survivors. Under the oversight of David Lo M.D. Dean of Research at UCR Medical School the trial willbe conducted at CoH using CoH patients personnel and IRB. CoH will provide hands-on training in 1)therapeutic trials and 2) rigor and reproducibility of clinical biomarkers. CoHs IRB will use this opportunity tomentor UCRs IRB. In Year 3 the trial will be opened for accrual at UCR. Metformin is known to reverse insulin-resistance and remove senescent cells. In this capacity building trial we aim to test in insulin-resistant Latinaand African American/Black breast cancer survivors the hypothesis that metformin can 1) restore metabolichealth (reverse insulin-resistance) 2) reduce H3K9ac-chromatin opening of genes coding forIL6/TNF/INF and 3) reduce inflammation and circulating SASP cells. Aim 1 will build UCR clinical-trialscapacity by conducting a UCR-CoH partnered trial at CoH in a diverse cohort. Aim 2 will provide capacity buildingin biospecimen collection biomarker analysis and rigor and reproducibility. In Aim 3 CoH IRB continues itsmentorship (started during P20) of UCR IRB in regulations for therapeutic trials. +No NIH Category available Acetylation;Acylation;Affect;African;African ancestry;Arginine;Automobile Driving;Binding;Biological;Biological Markers;Biology;Biopsy Specimen;Breast Cancer Cell;Breast Epithelial Cells;Cell Proliferation;Cell physiology;Cells;Complex;Data;EP300 gene;ERBB2 gene;Epigenetic Process;Estrogen receptor positive;European;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Goals;Histone Acetylation;Histone H3;Histones;Human;Individual;Invaded;Isomerism;Lysine;MCF10A cells;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic Activation;Molecular;Mutation;Neoplasm Metastasis;Oncogenic;PIK3CA gene;PIK3CG gene;Pathway interactions;Peptidylprolyl Isomerase;Prognosis;Publishing;Reader;Recurrence;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Site;Testing;Therapeutic;Tissue Banks;Transactivation;Transcriptional Activation;Tumor Cell Biology;Woman;Writing;XCL1 gene;cancer cell;cell immortalization;cell transformation;cell type;cofactor;determinants of treatment resistance;drug development;druggable target;improved;malignant breast neoplasm;mammary;new therapeutic target;notch protein;overexpression;programs;promoter;recruit;stem;stem cell self renewal;therapeutic target;therapy resistant;tumor Full Project 1 n/a NCI 10762290 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5715 6870042 "MARTINEZ, ERNEST " Not Applicable 39 Unavailable 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA Domestic Higher Education 925210001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 220682 145250 75432 Most luminal B breast cancers (LBBC; ER+ HER2-wt Ki67>14%) carry a good prognosis. Howeverapproximately 20% of LBBC are highly aggressive and resistant to current therapies. Poor-prognosis LBBCdisproportionally impact women of African descent; the majority are MYC-activated. There have been manyfailed attempts to therapeutically target MYC. These attempts have failed in part due to our current inability toseparate the cancer-promoting activities of MYC mechanistically or therapeutically from its normal essentialcellular functions. In preliminary data we show that the cancer-transforming ability of MYC is dependent on threelysine (K) residues of MYC (K149 K158 and K323) that are major substrates for acetylation by the histoneacetyltransferases (HATs) p300 and GCN5; individual substitutions of these specific sites block the ability ofMYC to transform human mammary cells. Guided by our preliminary data here we aim to dissect the cofactorsand molecular mechanisms by which these MYC acetyl-K (AcK) residues promote cell transformation andinitiation and progression of LBBC. Our long-term goal is to identify new druggable targets to improve survivalof women most affected by aggressive LBBC; consequently our studies will focus on women of African-descent.Guided by our preliminary data we hypothesize that a gene-selective MYC-AcK signaling pathway drives theaggressive tumor cell biology of therapy-resistant LBBC and involves transcription cofactors and epigeneticcoregulators that write and/or read AcK marks on MYC and histones perhaps including cofactors co-overexpressed with MYC in LBBC such as PIN1 GCN5 p300 and/or YEATS2. Here we will investigate therole of MYC-AcK dependent signaling in luminal mammary cell transformation and aggressive progression ofluminal cancer cells and LBBC tumors as well as identify the cofactors and mechanisms involved.Characterization of this new MYC oncogenic signaling pathway may provide biomarkers and/or therapeutictargets for LBBC in women of African descent. Aim 1 will test the impact of MYC-AcK dependent signaling inmammary epithelial cell transformation and in the aggressive biology of LBBC in women of African-descent. Aim2 will characterize the molecular mechanisms of MYC-AcK dependent gene regulation in transformed mammaryepithelial cells and in LBBC cells and tumors from women of African-descent. +No NIH Category available Award;Basic Science;California;Cancer Center Planning Grant;City of Hope Comprehensive Cancer Center;Clinical Trials;Collaborations;Comprehensive Cancer Center;Development;Disparity;Engineering;Evaluation;Funding;Genomics;Goals;Grant;Institution;Instruction;Joints;Mentors;Mentorship;Monitor;Pharmaceutical Preparations;Pilot Projects;Qualifying;Research;Research Personnel;Resource Development;Resources;Schedule;Structure;Tissue Banks;Translational Research;United States National Institutes of Health;Universities;Writing;drug development;education research;experience;medical schools;meetings;success;translational impact Capacity Development Core n/a NCI 10762289 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5714 6870042 "MARTINEZ, ERNEST " Not Applicable 39 Unavailable 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA Domestic Higher Education 925210001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 196087 124500 71587 It is challenging to build successful research collaborations. Successful collaborations are even more challengingwhen working across institutions and with early-stage investigators (ESIs). To overcome these challenges wedeveloped the Capacity Building Core. The Core's goal is to provide resources and mentorship to build jointcollaborations between City of Hope Comprehensive Cancer Center (CoHCCC) and University of CaliforniaRiverside (UCR) ESI. We aim to build collaborations that 1) increase UCR capacity for drug developmentcapacity - at all stages of the drug-develop pipeline and 2) result in independent NIH-funding. The CapacityCore will match UCR ESIs with senior CoHCCC and UCR investigators. Senior CoHCCC investigators will beselected based on their prior proven ability to 1) successfully mentor ESIs and 2) help them attain independentNIH funding. U54 PI Drs. Ernest Martinez (UCR) and Victoria Seewaldt (CoH) have extensive mentorshipexperience and will lead the Capacity Core. Under the Capacity Core UCR-CoH Mini-Pilots will be 1) crafted byESIs under senior mentorship 2) competed and 3) teams awarded $100000 for one year. Our P20 planninggrant shows us that success of a pilot project is increased when ESI have senior mentors from both CoH andUCR; therefore UCR ESI applying for Mini-Pilots are required to have a CoH and UCR mentor. In Years 1 and2 a total of 3 Mini-Pilots will be funded/year. These 6 Mini-Pilots will be an important opportunity for us to buildjoint UCR ESI-CoH grants and capacity at UCR. In Years 3-5 $200000 originally allocate to the CapacityBuilding Core will be re-allocated to support two new Pilots Pilots 3 and 4. In Years 3-5 we will offer 1 Mini-Pilot/year. CoH discretionary funds ($100000/year) will allow us to either supplement Pilot Projects or increasethe number of Mini-Pilots offered in Years 3-5. +No NIH Category available Address;Advocate;Antelopes;California;Catchment Area;Cellular biology;City of Hope Comprehensive Cancer Center;Clinical;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;County;Data;Development;Disparity;Doctor of Medicine;Doctor of Philosophy;Economics;Ensure;Environment;Evaluation;Farm;Fostering;Funding;Grant;Growth;Incubators;Individual;Latina;Lead;Leadership;Los Angeles;Mentors;Mentorship;Mission;Monitor;National Cancer Institute;Neighborhoods;New York City;Pilot Projects;Policies;Policy Developments;Politics;Principal Investigator;Publications;Reporting;Research;Research Personnel;Resources;Safety;Science;Therapeutic;Time;Toxicology;Training;Translational Research;United States;United States National Institutes of Health;Universities;Work;cancer health disparity;career;chimeric antigen receptor T cells;disparity elimination;diversity and inclusion;drug development;education research;experience;frontier;health disparity;human subject protection;meetings;member;minority communities;next generation;outreach;professor;programs;rural area;timeline Administrative Core n/a NCI 10762288 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5713 6870042 "MARTINEZ, ERNEST " Not Applicable 39 Unavailable 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA Domestic Higher Education 925210001 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 235307 149401 85906 The Administrative Core is led by the U54s Principal Investigators Ernest Martinez Ph.D. (PI University ofCalifornia Riverside [UCR]) and Victoria Seewaldt M.D. (PI City of Hope Comprehensive Cancer Center[CoHCCC]). The overall mission of the Administrative Core is to facilitate the U54 UCR CoH ComprehensiveCancer Center (CoHCCC) U54 partnership by providing high-quality scientific leadership administrative supportand fiscal management. The Administrative core supports U54 planning priority-setting and implementation.The Core will support the ability of the External Advisory Board (EAB) Internal Advisory Board (IAB) andCommunity Advisory Board (CAB) to guide and provide advice and oversight of our U54. Our EAB members arenational leaders and lead their own P20 and U54 grants focusing on eliminating disparities. EAB leaders includeRobert Winn M.D. (Massey Comprehensive Cancer Center) Laura Fejerman Ph.D. (UC Davis) Lucio MieleM.D. (LSU) and Melissa Simon Ph.D. (Lurie Comprehensive Cancer Center). Our IAB members are seniorleaders at both UCR and CoHCCC. IAB leaders from UCR include Dr. Kelechi Kalu Ph.D. and Vice Provost andProfessor of Political Science; Dr. Frances Sladek Professor of Cell Biology and Toxicology. IAB leaders fromCoHCCC include Steven Forman Ph.D. CoHCCC leader of CAR-T cell therapeutics program and BeckmanTherapeutic Director; Linda Malkas Ph.D. Dean of Translational Science and External Affairs. To ensurementorship of the next generation of U54 leaders we include on our IAB two early-stage investigators (ESIs)serve on our IAB this includes Jernej Murn Ph.D. a basic investigator from UCR and Ana Tergas M.D. apromising clinical trialist and Latina researcher from CoHCCC. Together we will work with the Planning andEvaluation Core (PEC) and serve as the U54s oversight body. The IAB will meet with U54 leaders twice-year -or more frequently if needed - to provide strategic direction policy development and evaluation of our U54Partnership Projects and Cores. The PEC IAB and EAB will perform yearly review of Full and Pilot projects andCores. The CAB will evaluate projects and cores particularly our Community Outreach Core and assess ourability to mentor and promote the careers of URM ESI. The EAB IAB and CAB will meet jointly with U54 projectand core leaders to assess overall progress and ability to impact cancer health disparities and disparities in drugdevelopment and clinical trials. +No NIH Category available Address;Affect;African;African American;African American population;American;Award;Bioinformatics;Black race;California;Cancer Center Planning Grant;Catchment Area;Cell Line;City of Hope Comprehensive Cancer Center;Clinical;Collaborations;Communities;Comprehensive Cancer Center;Conduct Clinical Trials;Core Facility;County;Crowding;Disparity;Drug Design;Drug Targeting;Economics;Education;Engineering;Ensure;Equity;European;FDA approved;Faculty;Fellowship;Fostering;Funding;Goals;Grant;Growth;Hispanic Americans;Incubators;Individual;Infrastructure;Institution;Investments;Joints;Laboratories;Latino;Latino Population;Los Angeles;Malignant Neoplasms;Master of Science;Mentors;Mentorship;Minority;Neighborhoods;Not Hispanic or Latino;Pharmaceutical Preparations;Phase;Physicians;Population;Population Heterogeneity;Postdoctoral Fellow;Prognosis;Reporting;Research Personnel;Resources;Scientist;Section 8;Site;Societies;Students;System;Testing;Therapeutic Agents;Therapeutic Trials;Toxic effect;Training;Training Programs;Translations;United States;United States National Institutes of Health;Universities;Work;anticancer research;cancer health disparity;clinical trial participant;commercialization;disparity elimination;disparity reduction;drug development;drug discovery;malignant breast neoplasm;manufacturing facility;medical schools;men;minority communities;news;next generation;novel therapeutics;phase 1 testing;programs;screening;small molecule inhibitor;success;synergism;therapeutic development;women of color 2/2 Drug Development and Capacity Building: A UCR/CoH-CCC Partnership In this U54 partnership UCR and CoHCCC aim to develop the collaborations resources and training programsto reduce disparities in drug development throughout the entire drug development pipeline. Our goal is for thisprogram to become a focal point for UCR and CoHCCC to mentor and train a diverse force of cancer biologistsand address the disparities in cancer therapeutics and drug development. Our goal is for this program to mentorand train a diverse force of cancer biologists and address the disparities in cancer therapeutics and drugdevelopment. NCI 10762287 9/22/23 0:00 PAR-22-249 1U54CA285114-01 1 U54 CA 285114 1 "VAHEDI, SHAHROOZ" 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 6870042 "MARTINEZ, ERNEST " "SEEWALDT, VICTORIA L." 39 BIOCHEMISTRY 627797426 MR5QC5FCAVH5 627797426 MR5QC5FCAVH5 US 33.972585 -117.350361 577506 UNIVERSITY OF CALIFORNIA RIVERSIDE RIVERSIDE CA EARTH SCIENCES/RESOURCES 925210001 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 397 Research Centers 2023 1358485 NCI 875651 482834 The United States (U.S.) has led the world in drug discovery for over 50 years. While this is a significantaccomplishment U.S. drugs have been almost exclusively optimized and tested in non-Hispanic European-Americans and been minimally evaluated in men- or women-of-color. As a result drugs that work well in non-Hispanic European-Americans (Anglos) may have unexpected toxicity or decreased efficacy in most of theworlds population. Disparities in U.S. drug development occur throughout the entire drug discovery pipeline.Only a small number of basic scientists are Latino/Hispanic- or African-American. Initial drug development andoptimization takes place in cell lines derived from Anglos. Less than 2% of physicians conducting clinical trialsare Latino/Hispanic- or African-American6. Most clinical trials participants are Anglos. Yet new drugs are FDAapproved for Latinos/Hispanics- and African-Americans/Africans without sufficient testing. It is unacceptable thatdrugs are developed by and optimized for only a fraction of our citizens. In this U54 partnership we aim todevelop the resources infrastructure and training to mentor the next generation of researchers that reflect thediversity of our Catchment Area. Building on our successful P20 grant here in this U54 partnership UCR andCoHCCC aim to develop the collaborations resources and training programs to reduce disparities in drugdevelopment throughout the entire drug development pipeline. Our goal is for this program to become a focalpoint for UCR and CoHCCC to mentor and train a diverse force of cancer biologists and address the disparitiesin cancer therapeutics and drug development. Already our P20 has fostered joint R01 grants K01 grants andpre-/post-doctoral fellowships. Both institutions are highly committed - CoHCCC contributed over $800K to ourP20 grant and will contribute $250K/year to ensure the success of this U54 partnership. Aim 1 will strengthenUCRs cancer research capacity and develop the resources to increase UCR/CoHCCCs ability to jointly developtherapeutic agents optimized for the diverse populations in our catchment area. Aim 2 will increase the capacityof UCR and CoHCCC to jointly develop drugs that target disparities in survival affecting the diverse individualsliving in our Southern California communities. Aim 3 will provide the training opportunity and mentorship toensure that the next generation of therapeutic scientists and clinical trialists reflect the diversity of SouthernCalifornia. 1358485 +No NIH Category available Achievement;Address;Adolescent and Young Adult;Advanced Malignant Neoplasm;Advisory Committees;Area;California;Cancer Patient;Cancer Survivor;Cancer health equity;Career Choice;Catchment Area;Clinical Trials;Communities;County;Data;Development;Disparity;Documentation;Evaluation;Feedback;Female Adolescents;Future;Goals;Healthcare Systems;Hispanic;Inequity;Institution;Lead;Leadership;Logic;Malignant Neoplasms;Medical Students;Methods;Modeling;Modification;Outcome;Outcome Assessment;Pancreatic Ductal Adenocarcinoma;Patients;Pilot Projects;Policy Maker;Principal Investigator;Provider;Reproductive Health;Research;Research Personnel;Research Project Grants;Resource Sharing;Resource-limited setting;Resources;Rural;Scholars Program;Services;System;Testing;Universities;anticancer research;black patient;cancer education;cancer health disparity;care delivery;community engaged research;disparity reduction;education research;experience;graduate student;health equity;improved;improved outcome;innovation;member;multi-component intervention;multidisciplinary;novel;novel therapeutic intervention;programs;telehealth;undergraduate student;underserved community Planning and Evaluation Core n/a NCI 10762276 9/14/23 0:00 PAR-22-249 1U54CA285115-01 1 U54 CA 285115 1 9/15/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5710 1971389 "MARTINEZ, MARIA ELENA" Not Applicable 50 Unavailable 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA Domestic Higher Education 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 93021 58874 34147 PROJECT SUMMARY/ ABSTRACT PLANNING AND EVALUATION COREThe Planning and Evaluation (P&E) Core of the Cancer Research and Education to Advance HealTh Equity(CREATE) Partnership will implement a comprehensive mixed-method and outcome-oriented evaluation of allCREATEs activities and components. Using innovative evaluation methods that are integrated into allPartnership components the P&E Core addresses its overarching goal: To develop implement and sustain aframework that drives rigorous ongoing evaluation to support the scientific and programmatic goals of thePartnership. To accomplish this the Partnership proposes the following Specific Aims: 1) Leverage existinginternal expertise within both institutions by engaging the Internal Advisory Committee (IAC) in internalplanning and assessing research core and shared resource activities; 2) Implement an innovative efficientand rigorous mechanism for soliciting and evaluating new pilot projects and evaluating the progress of existingPartnership-sponsored projects; 3) Utilize the external evaluation expertise provided by highly experiencedunbiased multidisciplinary experts of CREATEs Program Steering Committee (PSC) and Community AdvisoryBoard (CAB) to achieve the Partnerships stated goals and objectives; 4) Build and maintain a continuousplanning evaluation and tracking system using a approach to provide CREATE Partnership leadership withmetrics to make data driven decisions throughout all Partnership activities and components. To achieve P&ECore aims internal and external experts will be engaged including: 1) a collaborative Multiple PrincipalInvestigator group (MPI); 2) a larger Executive Committee made up of the MPIs Program Managers CREATEUndergraduate Scholars Program director Core and Shared Resource Leads and an Evaluation Lead; 3) amultidisciplinary IAC; 4) a PSC composed of external members with appropriate scientific expertise; and 5) anexternal CAB made up of community partners organizations. CREATE MPIs will lead the planning componentand an evaluation lead will direct all evaluation efforts independently of the MPIs. The expected impact is to: 1)advance cancer health equity in underserved communities in the Southern Border Region of California; 2)further increase SDSUs cancer research capacities 3) expand SDSUs and UCSDs cancer health disparitiesand community-engaged research 4) build a pipeline of a diverse biomedical workforce largely focused onundergraduate graduate and medical students and early stage investigators underrepresented in thebiomedical workforce. Based on the goals of the selected full and pilot projects included in this applicationCREATE expects major advancements in reducing disparities related to the following areas: 1) contribute tothe development of a novel therapeutic strategy to be tested in future clinical trials 2) provide actionableinformation to stakeholders regarding inequity in cancer patients access to telehealth and; 3) generate a novelmulticomponent intervention that adapts care delivery to address reproductive health among rural and Hispanicfemale adolescent and young adult cancer survivors. +No NIH Category available Address;Adverse event;COVID-19 pandemic;California;Cancer Patient;Caring;Catchment Area;Cohort Studies;Communication;Complement;County;Data;Data Set;Databases;Development;Disparity;Elderly;Emergency department visit;Environment;Equity;Ethnic Origin;Future;Health Services Accessibility;Health system;Healthcare;Healthcare Systems;Hospitalization;Hospitals;Household;Improve Access;Income;Individual;Inequality;Inequity;Internet;Intervention;Knowledge;Language;Link;Logistic Regressions;Low income;Malignant Neoplasms;Medicare;Medicare claim;Medicare/Medicaid;Methods;Modeling;Oncology;Outcome;Patient Care;Patient-Focused Outcomes;Patients;Perception;Persons;Policies;Policy Maker;Population;Populations at Risk;Positioning Attribute;Provider;Quality of Care;Race;Research;Risk;Safety;Secondary to;Socioeconomic Status;Surveys;Technology;Telecommunications;Testing;Visit;Vulnerable Populations;access disparities;adverse outcome;anticancer research;beneficiary;cancer care;cancer education;cancer health disparity;cancer risk;care delivery;care outcomes;disparity reduction;ethnic minority;experience;health disparity;health equity;improved;interest;marginalized population;neoplasm registry;older patient;pandemic disease;patient population;patient-level barriers;population based;post-COVID-19;provider-level barriers;racial minority;response;telehealth Full Project 2: The Intersection of Telehealth and Health Disparities in At-Risk Older Patients with Cancer n/a NCI 10762274 9/14/23 0:00 PAR-22-249 1U54CA285115-01 1 U54 CA 285115 1 9/15/23 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5708 78426082 "JAVIER-DESLOGES, JUAN FRANCISCO" Not Applicable 50 Unavailable 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA Domestic Higher Education 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 180318 114125 66193 PROJECT SUMMARY/ ABSTRACT PROJECT 2Telehealth utilization increased rapidly across the US healthcare system in response to the COVID-19pandemic. As we emerge from the pandemic telehealth has become a new option for communication betweenpatients and providers. Cancer care delivery appears well positioned to incorporate telehealth into the standardworkflow of patient care. Furthermore equitable implementation of telehealth could potentially increase accessto care among vulnerable patients. However emerging data suggest disparities with telehealth utilizationaccess among non-White low income and non-English speaking individuals. Inequitable implementation oftelehealth could inadvertently create barriers among our most vulnerable patients which could paradoxicallyincrease cancer health disparities. Large-scale rigorous research evaluating disparities in telehealth utilizationwithin the post-COVID-19 cancer care environment is lacking. Furthermore research has not addressed howtelehealth utilization influences safety and quality of care compared to conventional in-person visits particularlyamong our at-risk populations with higher baseline risks of poor outcomes and adverse events. Finally acomprehensive understanding of telehealth disparities requires an understanding of patient perceptions andprovider biases towards telehealth which represent important unaddressed questions. To fill these criticalknowledge gaps we propose a comprehensive population-based cohort study among Medicare beneficiarieswith cancer incorporating linkages to secondary datasets providing data on providers hospitals and regionalfactors. We will assess the impact of telehealth on vulnerable cancer populations through the following aims: 1)identify and characterize disparities in telehealth during and after the COVID-19 pandemic; 2) assess theimpact of telehealth on efficacy and safety of cancer delivery among at-risk populations; and 3) defineactionable patient-level barriers and provider biases with telehealth utilization. This proposed study will helpdefine the national landscape of telehealth among cancer patients and will provide a framework for thedevelopment of future interventions to optimize telehealth among at-risk patients. This timely project will deliveractionable information to providers healthcare systems and policymakers. Overall equitable safe andeffective telehealth delivery stands to increase access to care and reduce cancer health disparities among ourmost vulnerable cancer patients. +No NIH Category available 3-Dimensional;Acetylation;Actins;Adherence;Adhesions;Adhesiveness;Affect;African American;American;Behavior;Binding;Biochemical;Biology;Biophysics;Cause of Death;Cell Adhesion;Cell Cycle Progression;Cell Nucleus;Cell Proliferation;Cell model;Cells;Chemotherapy-Oncologic Procedure;Collaborations;Cytoplasm;Cytoskeleton;Cytosol;Data;Development;Disease;Disease Progression;Enhancers;Environment;Excision;Extracellular Matrix;F-Actin;Flavins;G Actin;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Goals;Hispanic;Hospitals;Human;Impairment;Incidence;Insurance;Integrins;Invaded;Knowledge;Laboratories;Life;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Mechanics;Mixed Function Oxygenases;Morbidity - disease rate;Myosin ATPase;Neoplasm Metastasis;Not Hispanic or Latino;Nuclear;Nuclear Export;Nucleic Acid Regulatory Sequences;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pattern;Phenotype;Play;Pre-Clinical Model;Primary Neoplasm;Property;Proteins;Reporting;Role;Serum Response Factor;Signal Induction;Signal Transduction;Socioeconomic Status;Stromal Cells;Structure;Testing;Transcription Coactivator;Transcriptional Regulation;alpha Actin;anticancer research;biophysical properties;cancer cell;cancer education;cell motility;depolymerization;effective therapy;experience;extracellular;health equity;high risk population;human disease;improved;improved outcome;in vivo;mechanical properties;migration;mortality;myocardin;new therapeutic target;novel therapeutic intervention;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic stellate cell;patient population;screening;therapeutic target;therapeutically effective;transcription factor;tumor growth;tumor microenvironment Full Project 1: Defining Mechanisms of MICAL-dependent Pancreatic Cancer Cell Migration n/a NCI 10762273 9/14/23 0:00 PAR-22-249 1U54CA285115-01 1 U54 CA 285115 1 9/15/23 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5707 1886399 "LOWY, ANDREW M" Not Applicable 50 Unavailable 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA Domestic Higher Education 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 180319 114126 66193 PROJECT SUMMARY/ ABSTRACT PROJECT 1Pancreatic duct adenocarcinoma (PDAC) takes the life of an American approximately every 12 minutes anddisproportionately affects African American and Hispanic patients who experience higher rates of morbidityand mortality compared to non-Hispanic white patients. Since the incidence of PDAC is relatively modest evenamong higher risk groups screening is not feasible. Thus improvements in outcomes require an improvedunderstanding of PDAC biology to guide development of effective therapies. Here the partnering PIscomplementary expertise in PDAC biology and modeling cellular biophysical properties converge to investigatemechanisms of PDAC cell migration and metastasis the primary cause of death in this patient population.The Lowy laboratory focused on identifying therapeutic targets by performing unbiased discovery in PDAC vs.normal pancreas. They hypothesized that super enhancer associated genes which define cell identity wouldbe effective therapeutic targets for PDAC. One differentially acetylated enhancer region was mapped to theMICAL2 gene that encodes a flavin monooxygenase. This protein drives F-actin depolymerization that in thecytosol can restructure the actin myosin machinery used to migrate and respond to external mechanical andbiochemical signals. MICAL2 also plays a role in linking nuclear actin dynamics to serum response factor(SRF) transcription. Myocardin-related transcription factors (MTRFs) are co-activators of SRF; when nuclearactin depolymerization is induced by MICAL2 globular actin is targeted for nuclear export freeing MTRF tobind SRF and activate transcription of genes important for cell adhesion and migration. Studies in PDAC cellsreveal that silencing MICAL2 expression impairs cell migration and metastasis.The Katira laboratory in collaboration with Dr. Englers group have reported that cell adhesiveness serves as abiophysical marker for metastatic potential and both adhesiveness and contractility enable adurotaxis theability of cells to migrate regardless of a stiffness gradient. To goal of this project is to define how MICAL2influences properties of adhesiveness and durotaxis and how it may regulate properties not only of the cancercell but of the tumor microenvironment through regulation of gene expression. We hypothesize that MICAL2promotes PDAC cell invasion and metastasis by cell autonomous and non-cell autonomousmechanisms. We will test this hypothesis in three specific aims; 1) Determine how MICAL2 modulatesadherence and durotaxis in pancreatic cancer cells 2) Determine how MICAL2 promotes pancreatic cancercell migration and metastasis and 3) Determine how MICAL2 related signaling from cancer an stromal cellsmodulates the tumor microenvironment. As a putative therapeutic target our goal is to determine how MICAL2functionally regulates cell migration and metastatic capacity during PDAC progression. This knowledge will bekey to understanding how and when MICAL2 activity can be targeted in PDAC. +No NIH Category available Administrative Efficiency;Advisory Committees;Asian Americans;California;Cancer Center;Catchment Area;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Ensure;Environmental Health;Equity;Faculty;Feedback;Funding;Future;Glues;Goals;Grant;Health Disparities Research;Hispanic-serving Institution;Infrastructure;Institution;Leadership;Malignant Neoplasms;Mediation;Medical Students;National Cancer Institute;Native Americans;Pacific Island Americans;Pathway interactions;Peer Review;Persons;Population;Positioning Attribute;Principal Investigator;Provider;Recording of previous events;Research;Research Personnel;Resource Sharing;Resources;Role;Schools;Scientist;Services;Structure;System;Teacher Professional Development;United States National Institutes of Health;Universities;Work;anticancer research;base;cancer education;cancer health disparity;career;career development;college;education research;evidence base;experience;graduate student;health equity;meetings;member;mid-career faculty;operation;outreach;programs;recruit;synergism;undergraduate student Administrative Core n/a NCI 10762271 9/14/23 0:00 PAR-22-249 1U54CA285115-01 1 U54 CA 285115 1 9/15/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5705 1971389 "MARTINEZ, MARIA ELENA" Not Applicable 50 Unavailable 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA Domestic Higher Education 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 353527 223752 129775 PROJECT SUMMARY/ ABSTRACT ADMINISTRATIVE COREThe goal of the Administrative Core of the Cancer Research and Education to Advance HealTh Equity(CREATE) Partnership is to provide strategic leadership and administrative oversight to advance theoverarching goal of the Partnership. This includes providing an efficient infrastructure to support all scientificadministrative and fiscal activities of the Partnership to ensure effective synergy within and across San DiegoState University (SDSU) and the UC San Diego (UCSD) Moores Cancer Center (MCC). Additional goalsinclude developing cancer research opportunities and pathways for undergraduate graduate and medicalstudents as well as early-stage investigators (ESIs) which will lead to a future workforce that is more diverseand reflective of the catchment-area population. As a single unit the Administrative Core provides strategicleadership and administrative oversight to advance Partnership goals. The Core is the glue that keeps thePartnership together and due to its extensive experience and history it is able to provide necessary servicesto support an efficient administrative system and infrastructure under the leadership of multiple PrincipalInvestigators. The Administrative Core is structured so that the Partnership leaders can establish andimplement a highly integrated operation that ensures exponential benefit from the collaboration of the twoinstitutions. The Core works synergistically to effectively implement the CREATE Partnership activities incancer research research education early-stage faculty career development and community outreach. Toaccomplish Partnership goals the CREATE leadership proposes the following Specific Aims: 1) Provideleadership coordination and management to the scientific administrative and fiscal components of theCREATE Partnership. 2) Promote evidence-based and sustainable interactions and build new researchcollaborations across the Partnership. 3) Procure scientific and strategic feedback and guidance from internaland external advisors. 4) Assist in recruitment of ESIs and work with the Transforming fAcuLty dEvelopmeNTfor Equity (TALENT) Shared Resource to support their career development. The AC is positioned to buildstrong institutional commitment to cancer research and cancer disparities research while growing thePartnerships research education programs and increasing outreach to the communities and their providers inthe Southern Border Region of California. By the end of this project period the Partnership intends to grow thecancer research base at SDSU by at least 25% and the number of peer reviewed funded cancer disparitiesand/or community-engaged grants by at least 20%. +No NIH Category available Advanced Malignant Neoplasm;Alaska Native;American Indians;Asian;Automobile Driving;Behavior;Black Populations;Border Community;Breast;California;Cancer Burden;Cancer health equity;Caring;Catchment Area;Cause of Death;Colorectal;Communities;County;Dissemination and Implementation;Education;Equity;Ethnic Population;Evaluation;Evidence based intervention;Fostering;Funding;Future;Goals;Health Disparities Research;Hispanic Populations;Incidence;Institution;Leadership;Linguistics;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of prostate;Medical Students;Mentors;Minority;Names;Neighborhood Health Center;Pancreas;Pathway interactions;Pilot Projects;Population;Race;Research;Research Personnel;Research Project Grants;Resource Sharing;Risk Factors;Rural;Screening for cancer;Teacher Professional Development;Underrepresented Students;Universities;agricultural community;anticancer research;cancer education;cancer health disparity;career;career development;community engaged research;community engagement;design;education research;ethnic diversity;experience;gastrointestinal;graduate student;health assessment;health equity;improved;insight;inter-institutional;outreach;population based;programs;racial population;recruit;screening;survivorship;undergraduate student;underserved community 2/2 Cancer Research and Education to Advance HealTh Equity (CREATE) Partnership PROJECT NARRATIVE - OVERALLThe purpose of this new inter-institutional U54 application between San Diego State University (SDSU) andthe University of California San Diego (UCSD) is to advance cancer health equity in underserved communitiesthroughout the southern California border communities of San Diego and Imperial Counties. Under a newname the Cancer Research and Education to Advance HealTh Equity (CREATE) Partnership theoverarching goals are to further increase SDSUs cancer research capacities and expand SDSUs and UCSDsemphasis on cancer health disparities research. Additional goals include developing cancer researchopportunities and pathways for undergraduate graduate and medical students as well as early-stageinvestigators (ESIs) which will lead to a future workforce that is more diverse and reflective of the catchment-area population. NCI 10762270 9/14/23 0:00 PAR-22-249 1U54CA285115-01 1 U54 CA 285115 1 "WALI, ANIL" 9/15/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 1971389 "MARTINEZ, MARIA ELENA" "CRIPPS, RICHARD MATTHEW; MADANAT, HALA ; MURPHY, JAMES D" 50 FAMILY MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 397 Research Centers 2023 1311403 NCI 830002 481401 PROJECT SUMMARY/ABSTRACT OVERALLThe Cancer Research and Education to Advance HealTh Equity (CREATE) Partnerships overarching goalsare to further increase SDSUs cancer research capacities and expand SDSUs and UCSDs emphasis oncancer health disparities research. Bi-directional community engagement is also a principal feature that isintegrated across every organizational component in the CREATE Partnership and is a strength that SDSUhas built over the last 30 years. Additional goals include developing cancer research opportunities andpathways for undergraduate graduate and medical students as well as early-stage investigators (ESIs)which will lead to a future workforce that is more diverse and reflective of the catchment-area population. Tomeet these overarching goals the following Specific Aims are proposed: 1) Recruit and support diverse ESIswho have chosen an intentional career goal to become independent cancer-focused researchers(Administrative Core and Transforming fAcuLty dEvelopmeNT for Equity [TALENT] Shared Resource); 2)Conduct catchment-area relevant research and pilot research projects aligned with identified cancer prioritiesfor the underserved communities in the region (Research and Research Pilot Projects and Planning andEvaluation Core); 3) Expand and implement cancer cancer disparities and community-engaged researcheducation with a focus on under-represented students across SDSU and UCSD undergraduate graduateprograms and medical students (Research Education Core); and 4) Integrate community engagement into allCREATE Partnership activities (Outreach Core). To achieve these aims the CREATE Partnership requests theinitial support for two Full Research Projects and one Pilot Research Project designed to provide insight intothe mechanisms (or behaviors) underlying cancer health disparities. All three projects will be jointly led bySDSU and UCSD Co-Leads; Project 2 is co-led by two under-represented researchers. The Research Projectswill be integrated with the Research Education Core providing expanded research experiences in cancercancer disparities and community-engaged research to under-represented undergraduate graduate andmedical students. A TALENT Shared Resource will foster the career development of Partnership ESIs. TheOutreach Core will develop new and strengthen existing community-academic partnerships to foster cancerresearch education and tailored outreach efforts with a focus on the dissemination and implementation ofevidence-based interventions that can reduce the cancer burden. The Partnership is notably bolstered bystrong institutional commitment an Administrative Core composed of investigators with demonstratedleadership and organizational capabilities and a strong Planning and Evaluation Core guided by an externalProgram Steering Committee an Internal Advisory Board and a Community Advisory Board. 1311403 +No NIH Category available Address;Advertisements;Awareness;Biomedical Research;Career Choice;Career Mobility;Clinical;Clinical Research;Collaborations;Communication;Communities;Complex;Comprehensive Cancer Center;Core Facility;County;Dedications;Development;Disparity;Education;Education and Outreach;Educational Activities;Educational Curriculum;Effectiveness;Environment;Event;Faculty;Fellowship;Future;Goals;Health Disparities Research;Health Services;Healthcare;Historically Black Colleges and Universities;Hour;Incidence;Infrastructure;Institution;Knowledge;Laboratories;Malignant Neoplasms;Mass Media;Medical center;Medicine;Mentors;Mentorship;Minority Groups;Morbidity - disease rate;NCI-Designated Cancer Center;Pharmacology;Pharmacy facility;Pilot Projects;Postdoctoral Fellow;Printed Media;Process;Records;Research;Research Infrastructure;Research Personnel;Residencies;Science;Students;Technology;Texas;Training;Underrepresented Minority;Universities;anticancer research;cancer education;cancer health disparity;career;cohort;college;community engagement;design;education research;experience;health disparity populations;improved;innovation;interest;member;minority trainee;mortality;novel;outreach;programs;racial diversity;recruit;skills;social media;summer program;summer research;symposium;undergraduate student;underrepresented minority student;university student BCM-TSU CURED Cancer Research Education Program (C-REP) CURED C-REP Project NarrativeThe CURED C-REP will provide an 8-weeks mentored cancer research experience that integrates BaylorCollege of Medicine (BCM) and Texas Southern University (TSU) infrastructures every summer followed by year-long culturally congruent outreach education activities that will increase the awareness knowledge andunderstanding of research concepts processes and careers in cancer research/cancer health disparities acohort of 20 underrepresented minority students from TSU. The proposed CURED C-REP will enhance cancerresearch education capacity at TSU promote the diversity of the cancer research workforce and improve BCMseffectiveness in developing and sustaining research programs focused on cancer health disparities. NCI 10762269 9/21/23 0:00 PAR-22-239 1P20CA284971-01 1 P20 CA 284971 1 9/21/23 0:00 8/31/27 0:00 ZCA1-SRB-2(A1) 5704 8391596 "HUANG, SHIXIA " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 120049 75000 45049 CURED C-REP Summary/AbstractThe Collaborative Cancer Research Education Program (C-REP) of the Baylor College of Medicine (BCM)/ DanL Duncan Comprehensive Cancer Center (DLDCCC) and Texas Southern University (TSU) P20 CollaborativeUnion for Cancer Research Education and Disparities (CURED) project will train 20 TSU underrepresentedminority students in cancer research cutting edge technologies and career pathway. The cohort of 20 CUREDscholars will participate in an 8-weeks mentored cancer research experience that integrates BCM and TSUinfrastructures every summer followed by year-long culturally congruent outreach education activities that willincrease the awareness knowledge and understanding of research concepts processes and careers in cancerresearch/cancer health disparities. The goal of our proposed CURED C-REP is to promote novel and effectivevenues to attract URM students into biomedical research and career pathways specifically in cancer and topromote comprehensive outreach education focused on cancer disparities and community engagement that willbenefit the students faculty and staff at both comprehensive cancer centers and ISUPSs as well as thecommunity. We are certain that the proposed CURED C-REP will enhance cancer research education capacityat TSU promote the diversity of the cancer research workforce improve BCM/DLDCCCs effectiveness ofdeveloping and sustaining research programs focused on cancer health disparities while increasing the numberof investigators conducting cancer health disparities research. +No NIH Category available Address;Adherence;Affect;African American;American;Atlases;Awareness;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer cell line;Breast Cancer therapy;CDK4 gene;Cancer Etiology;Cessation of life;Clinical;Code;Computer Models;Data;Databases;Death Rate;Decision Making;Disparity;Documentation;Drug resistance pathway;Early Diagnosis;Education;Electronic Health Record;Environmental Risk Factor;Epidermal Growth Factor Receptor;Epigenetic Process;Ethnic Origin;European;FAT gene;Female Breast Carcinoma;Financial Hardship;Frequencies;Genes;Genetic;Genetic Predisposition to Disease;Genetic Variation;Genomics;Head and Neck Cancer;Hispanic;Hispanic Populations;Human;In Vitro;Interview;Malignant Neoplasms;Messenger RNA;Metastatic breast cancer;Mutation;Not Hispanic or Latino;Oral;Outcome;Patients;Pattern;Pharmaceutical Preparations;Population;Population Study;Prevalence;Progression-Free Survivals;Quality of life;RB1 gene;Race;Resistance;Resistance development;Social support;Surveys;Testing;The Cancer Genome Atlas;Treatment outcome;United States;Variant;Woman;anticancer research;cancer genomics;design;differential expression;genomic data;hormone receptor-positive;hormone therapy;improved;individual patient;information gathering;inhibitor;inhibitor therapy;mRNA Expression;malignant breast neoplasm;markov model;medication compliance;mortality;novel therapeutic intervention;outcome disparities;patient population;racial disparity;resistance mechanism;screening;side effect;social determinants;social health determinants;statistics;targeted treatment;therapy resistant;treatment site;tumor;verbal Impact of race and ethnicity on outcomes in patients with hormone receptor-positive breast cancer treated with CDK4/6 inhibitors Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have recently emerged as a new treatment strategy forhormone receptor (ER/PR) positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative(HR+/Her2-) subtype ofbreast cancer (BC) patients. Recent studies suggest that their benefit may be restrictedonly to non-HispanicEuropean American (EA) BC patients without significant improvement inAfrican American(AA) or Hispanics patients. Using patient interviews computational modeling and functional studies this projectwill analyze thesocial determinants and genetic aspects contributing to CDK4/6i therapy resistance in AA BCpatients. NCI 10762267 9/21/23 0:00 PAR-22-239 1P20CA284971-01 1 P20 CA 284971 1 9/21/23 0:00 8/31/27 0:00 ZCA1-SRB-2(A1) 5702 10027528 "KAIPPARETTU, BENNY ABRAHAM" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 40016 25000 15016 Breast cancer (BC) is the most common cancer in women worldwide and is the second leading cause of cancerdeath in women. However the advances in outcomes of BC patients have been limited to a subset of the affectedpopulation namely European American (EA) women compared to their African American (AA) womencounterparts. Despite various hormone therapies the hormone receptor (ER/PR) positive (HR+) humanepidermal growth factor receptor 2 (HER2)-negative (HR+/Her2-) subtype of BC remains difficult to treat. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have recently emerged as a new treatment strategy.Interestinglya 2022 population-based study confirmed that while the outcomes for HR+/Her2- metastatic BC have improvedsince CDK4/6i were introduced in 2015 this effect is primarily driven by the improved overall survival (OS) innon-Hispanic EApatients without significant improvement in AA or Hispanics patients.The relative contributionof genetic factors vs. medication adherence or social determinants of health (SDOH) on such outcomes is lessunderstood. Recent efforts to address this gap include databases such as All of Us designed to betterunderstand the interplay between genetic factors and social determinants. From a functional point ourpreliminary analysis ofThe Cancer Genomic Atlas (TCGA) data shows decreased mRNA expression of FAT1FAT4 and RB1 the major genes involved in resistance to CDK4/6i in AA compared to EA HR+/Her2- BC.Thusthis project will do preliminary analysis of two aspects of BC therapy resistance in AA BC patients. Aim-1 of thisproject will assess the impact of medication adherence and various social determinants on clinical outcomes offemale BC patients treated with CDK4/6i. Aim-2 will analyze the impact of genetic variations and low expressionof FAT1 FAT4 and RB1 genes on the development of resistance to CDK4/6i in AA women with BC. We will usesurveys verbal medication review and EHR documentation of medication possession to gather informationrelated to medication adherence and social determinants that may impact compliance. We will also analyze theprevalence of germline and somatic variations and epigenetic status of FAT1 FAT4 and RB1 genes in BCpatients of EA and non-EA ancestry. Using computational modeling we will predict the functional networking ofFAT1 FAT4 and RB1 low expression in AA BC patients. Using established databases clinical informationobtained from the electronic health record (EHR) and surveys exploring SDOH and medication adherencepatterns this pilot aims to generate preliminary data exploring the impact of these factors on treatment outcomesin AA vs. EA patients receiving oral targeted therapy including CDK4/6i. Discovery of AA-centric geneticvariations and the impact of low expressed FAT1 FAT4 and RB1 genes in the functional networking will becritical in pre-selecting AA BC patients that may benefit from CDK4/6i therapy. +No NIH Category available Address;African American population;Black Bear;Black race;California;Cancer Etiology;Caring;Cells;Cessation of life;Cytidine Deaminase;DCK gene;Data Set;Deoxycytidine Kinase;Development;Diagnosis;Drug Kinetics;Drug usage;Education;Epidermal Growth Factor Receptor;Epigenetic Process;Exposure to;Fc Receptor;Florida;Fluorouracil;Formulation;Gene Expression;Genetic;Goals;High Prevalence;Hispanic;Human;Incidence;Investigation;Knowledge;Latinx;Latinx population;Leucovorin;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metabolism;Modeling;Mus;Nucleoside Transporter;Operative Surgical Procedures;Organoids;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Pattern;Phosphorylation;Pilot Projects;Population;Population Heterogeneity;Proteins;Publishing;RNA;Resistance;SNP genotyping;Safety;Sampling;Solubility;Surface;Survival Rate;Systemic Therapy;Testing;Toxic effect;Treatment Efficacy;Variant;Wild Type Mouse;anticancer activity;anticancer research;chemotherapy;cohort;design;efficacy evaluation;efficacy testing;enzyme activity;ethnic diversity;experience;experimental study;gemcitabine;health equity;improved;in vivo;irinotecan;lipophilicity;mortality;mouse model;multi-ethnic;nanoparticle;novel;oxaliplatin;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;patient derived xenograft model;patient stratification;personalized chemotherapy;protein expression;racial difference;racial diversity;response;subcutaneous;targeted delivery;therapy outcome;treatment choice;tumor;tumor growth;tumor xenograft;uptake Development and Testing of a Novel Biospecific using modified Gemcitibine to target and treat Pancreatic Cancer n/a NCI 10762216 9/19/23 0:00 PAR-22-249 2U54CA233396-06 2 U54 CA 233396 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5687 11735026 "AGYARE, EDWARD KWASI" Not Applicable 2 Unavailable 623751831 W8LKB16HV1K5 623751831 W8LKB16HV1K5 US 30.428914 -84.289766 513802 FLORIDA AGRICULTURAL AND MECHANICAL UNIV TALLAHASSEE FL Domestic Higher Education 323073105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 49136 33200 15936 ABSTRACT Pilot Project 5Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies and the survivalrate remains stagnant with a 5-year survival rate of only 5-8%. Black/African Americans (B/AA) individualsexperience the highest prevalence and lowest overall survival rates of PDAC compared to their Whitecounterparts. FOLFIRINOX (5-fluorouracil leucovorin oxaliplatin and irinotecan) is often the preferredchemotherapy treatment choice for patients with PDAC but considerable toxicities have limited its use. Thedecreased expression of nucleoside transporters due to genetic and epigenetic reasons appeared to account forGem resistance. In addition deoxycytidine kinase (dCK) which is responsible for Gem phosphorylation into theactive form is postulated to correlate with Gem efficacy. To address these challenges we have modified Gemto 4-(N)- stearoylGem (4NSG) to: i) block the CDA attack on Gem and ii) increase Gem transport into PDACcells. Our recent results revealed highly expressed epidermal growth factor receptors (EGFR) in pancreatictumor samples. Guided by our recently published and unpublished results we hypothesize that optimized 4NSGnanoparticles with surface-modified anti-EGFR antibody (4NSGnpcetu) will improve the therapeutic efficacy ofGem. We propose the following specific aims to address this hypothesis. Aim 1: Test the efficacy of 4NSGnpcetuin B/AA and White patient-derived organoid models (PDOs) with stroma and in primary PDAC cells. Aim 2:Evaluate the therapeutic efficacy of 4NSGnpcetu in PDAC PDX mouse models bearing subcutaneous tumors fromB/AA and White patients. Aim 3: Measure dCK RNA/protein expression in PDAC PDX tumor models and SNPgenotypes in PDAC cases and controls in the MultiEthnic dataset. Our studies will determine whether racialdifferences in dCK variant gene expression and protein activity can correlate with improved Gem efficacy inB/AA and /or White PDAC patients. The valuable information obtained will significantly advance the overall goalof improving the response and survival rate in PDAC patients. +No NIH Category available 3-Dimensional;Address;Affect;African American;African American population;Alveolar;Amides;Angiogenesis Inhibition;BAY 54-9085;BRAF gene;Bioinformatics;Biological;Biological Factors;Biological Models;Biomedical Engineering;Black American;Black Populations;Black race;Bronchiolo-Alveolar Adenocarcinoma;California;Carcinogens;Caring;Cell Line;Cell Survival;Cells;Collection;Combined Modality Therapy;DNA;Data Analyses;Development;Disparity;Doctor of Philosophy;Drug Combinations;Education;Epidermal Growth Factor Receptor;Epithelial Cells;Erlotinib;Ethnic Origin;Ethnic Population;Florida;Formalin;Funding;Gel;Gelatin;Gene Mutation;Genes;Genetic;Growth;In Vitro;Individual;Inhalation;Invaded;KRAS2 gene;Knowledge;Leukocytes;Lung Adenocarcinoma;MAP Kinase Gene;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medicine;Metabolism;Metastatic Neoplasm to the Bone;Methodology;Methods;Modeling;Molecular;Mutate;Mutation;Neoplasm Metastasis;Nicotine;Organoids;PIK3CG gene;Paraffin Embedding;Pathway interactions;Patients;Pattern;Perfusion;Pharmaceutical Preparations;Porosity;Printing;Race;Resources;Risk Factors;STK11 gene;Sampling;Site;Source;System;TP53 gene;Testing;Therapeutic;Time;Tissue Model;Tobacco smoke;Treatment Efficacy;Variant;Vascular Endothelial Cell;Woman;Work;alpelisib;alveolar epithelium;anti-cancer therapeutic;anticancer research;black men;black women;bone;cancer cell;cancer health disparity;cytotoxicity;driver mutation;drug development;effective therapy;exome sequencing;exposure to cigarette smoke;follow-up;health disparity;health equity;high risk;in vitro Model;inhibitor;innovation;interdisciplinary collaboration;member;men;migration;mutant;neoplasm registry;novel;novel therapeutics;osteogenic;progenitor;racial difference;racial population;response;targeted treatment;therapeutic evaluation;therapeutic target;tool;treatment response;two-dimensional Full Project 2 - An Organoid System Tailored to Study Lung Cancer in Blacks n/a NCI 10762215 9/19/23 0:00 PAR-22-249 2U54CA233396-06 2 U54 CA 233396 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5686 6871503 "LAMANGO, NAZARIUS SAAH" Not Applicable 2 Unavailable 623751831 W8LKB16HV1K5 623751831 W8LKB16HV1K5 US 30.428914 -84.289766 513802 FLORIDA AGRICULTURAL AND MECHANICAL UNIV TALLAHASSEE FL Domestic Higher Education 323073105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 110556 74700 35856 ABSTRACT FULL PROJECT 4 LUNGLung cancer is a prominent source of cancer health disparity particularly in Black men. While they have lowerexposure to cigarette smoke the most common risk factor for lung cancer Black men have a 37% higher riskfor lung cancer than White men. In addition the 5-year survival of Black men and women is below that of Whitesubjects. Numerous causes likely underlie these differences including genetic differences. The latter may affectthe metabolism of nicotine/tobacco smoke components responses to therapy and differences in cancer drivergene mutations. To understand the effects of the genetic differences between racial/ethnic groups on lung cancerdevelopment and treatment we need to characterize the driver mutations in lung adenocarcinoma (LUAD themost common type of lung cancer) in Black Americans and develop in vitro lung cancer model systems thatreflect the relevant mutations in the correct genetic background. There is a notable lack of cell line models forlung adenocarcinoma from Black Americans with no Black cell lines from alveolar epithelial cells (the LUADprogenitors) and only 5 known LUAD cell lines (compared to 67 White cell lines). While targeted therapies areavailable for a subset of LUAD in vitro systems to test therapeutics in Black Americans are sorely lacking. Wehypothesize that due to genetic differences LUAD in Blacks will have a unique repertoire of cancer driver genesand will respond to targeted therapies distinctly from white LUAD. This proposal represents an interdisciplinarycollaboration in which a medicinal (bio)chemist from FAMU (Dr. Lamango) a biomedical engineer from UF (Dr.Huang) and a molecular geneticist from USC (Dr. Offringa) combine their innovative resources to tackle thepronounced health disparities in lung cancer in Black Americans. We will do so through three Specific Aims: InAim 1 we will identify the main driver mutational signatures of lung adenocarcinoma from 100 Black Americanswho are 5-fold underrepresented in mutational studies. In Aim 2 we will develop new immortalized alveolar andlung adenocarcinoma cell lines from Black subjects and use these and existing cell lines to develop 2-dimensional (2D) and 3-dimensional (3D) in vitro models. We will test promising drugs (polyisoprenylatedcysteinyl amide inhibitors (PCAIs)) developed by the Lamango lab that target the KRAS pathway which isfrequently mutated in LUAD. As time allows we will also test other targeted therapeutics and combinations ofdrugs. In Aim 3 we will develop a novel 3D-printed bone cancer metastasis model to study the differential efficacyof PCAIs and other targeted therapeutics on cancer cell cytotoxicity migration and invasion. Bone is the mostcommon metastatic site of LUAD. The three proposed Specific Aims address the lack of knowledge about cancerdriver genes in Black American lung adenocarcinoma generate a collection of normal alveolar and lungadenocarcinoma cell lines from Black subjects that will be used to establish race-appropriate models and will bea great resource for others and allow the testing of therapeutics on cells from Black Americans using 2D 3Dand bone metastasis models. +No NIH Category available 3-Dimensional;ATAC-seq;Acinar Cell;Acinus organ component;Address;African American;African American population;Black Populations;Black race;California;Cancer cell line;Caring;Cell Line;Cell Reprogramming;Cells;Chronic;Coculture Techniques;Collagen;Conditioned Culture Media;Data;Development;Disease;Disparity;Duct (organ) structure;Ductal Epithelial Cell;Early Diagnosis;Early treatment;Education;Event;Experimental Models;Extracellular Matrix;Fibronectins;Florida;Funding;Gender;Gene Expression;Genes;Goals;Heterogeneity;Hispanic;Hispanic Populations;Histone Deacetylase Inhibitor;Human;Immune;Immunofluorescence Immunologic;In Situ;Incidence;Individual;Inflammation;Inflammatory;Institution;Latino;Latino Population;Lesion;Link;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Metabolic stress;Metaplasia;Methods;Microscopic;Molecular;Normal Range;Outcome;Oxidative Stress;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Penetration;Peptide Hydrolases;Pharmaceutical Preparations;Phenotype;Pilot Projects;Process;Prognosis;Publishing;Race;Role;Sampling;Stains;Stromal Cells;System;Tissues;Trichostatin A;anticancer research;biophysical properties;biophysical techniques;cancer health disparity;chronic pancreatitis;combat;comorbidity;effective therapy;health equity;improved;inhibitor;irritation;mortality;mouse model;novel;pancreas development;pancreatic ductal adenocarcinoma model;pancreatic metaplasia;pancreatic stellate cell;pharmacologic;prevent;racial disparity;stellate cell;therapeutic target;transcriptome sequencing;treatment response;tumor microenvironment Racial contributions of microenvironment remolding during pancreatic metaplasia n/a NCI 10762214 9/19/23 0:00 PAR-22-249 2U54CA233396-06 2 U54 CA 233396 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5685 16567215 "ALI, JAMEL " Not Applicable 2 Unavailable 623751831 W8LKB16HV1K5 623751831 W8LKB16HV1K5 US 30.428914 -84.289766 513802 FLORIDA AGRICULTURAL AND MECHANICAL UNIV TALLAHASSEE FL Domestic Higher Education 323073105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 79951 74700 5251 ABSTRACT FULL PROJECT 3 ADMPancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancers with poor prognosisand rising incidence. To combat this deadly disease we should direct our efforts towards preventing PDAC orhalting the progression of precursor lesions to invasive disease parallel to developing novel treatments. One ofthe earliest known initiating events for PDAC is the process of acinar-to-ductal metaplasia (ADM). Understandingand reduction of ADM formation may reduce early PDAC development and progression. Blacks display asignificantly increased incidence and mortality from PDAC compared to other races for unknown reasons. Therole of race on pancreatic ADM and its contributions to the development and progression of PDAC need to beaddressed. In our previously funded CaRE2 Pilot Project we used normal pancreatic acinar tissues from BlackWhite and Hispanic donors to study the impact of race on acinar-to-ductal metaplasia (ADM) and found thatBlacks undergo ADM to a greater extent than Whites or Hispanics. In this proposed Full Project as part of theCaRE2 renewal we will expand on and extend our previous pilot project by including diseased tissues from CPand PDAC from White Black and Hispanic donors since accumulating evidence suggest that chronicpancreatitis (CP) is a major precursor to the development of PDAC. We will investigate the impact of race on thecellular and molecular events regulating the interplay between ADM and the microenvironment. Guided by ourpublished and unpublished results we hypothesize that the racial disparities seen in PDAC are related todifferences in how the pancreas microenvironment develops during ADM which means that ADM and itssurrounding microenvironment can be used as a target to treat PDAC. We propose the following specific aimsto address this hypothesis: Aim 1: The influence of race on ADM of healthy pancreas CP and PDAC-associatedacinar tissues. Aim 2: The roles of pancreatic stellate cells and macrophages in ADM and ADM reversal Aim 3:Contributions of the race to ADM reversal and cell heterogeneity. The proposed studies will impact the field ofpancreatic cancer by providing a missing link between disparities ADM tumor microenvironment and potentialtreatments for CP and PDAC. The specific focus on the racial contributions of microenvironment remoldingduring pancreatic metaplasia aligns with the Florida-California Cancer Research Education and Engagement(CaRE2) Health Equity Centers overall goal to eliminate cancer health disparities among Black and Latinoindividuals in California Florida and across the U.S. +No NIH Category available Address;African American;Archives;Basic Science;Biocompatible Materials;Bioinformatics;Black race;California;Caring;Cell Line;Chemistry;Collaborations;Collection;Complex;Conscious;Data;Databases;Development;Development Plans;Disparity;Education;Ensure;Evaluation;FDA approved;First Independent Research Support and Transition Awards;Florida;Funding;Future;Genomics;Goals;Hispanic;Human;Implant;Individual;Institution;Latinx;Latinx population;Lead;Leadership;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Medical Research;Mentorship;Methodology;Mission;Modeling;Molecular;Normal tissue morphology;Organoids;Outcome;Pathologic;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pilot Projects;Plasma;Population;Prostate;RNA;Race;Research;Research Personnel;Research Project Grants;Residual state;Resource Sharing;Resources;Role;Sampling;Scientist;Serum;Specimen;Technology;Testing;Tissue Banks;Tissue Model;Tissue Sample;Tissues;Translational Research;Tumor Tissue;Universities;anticancer research;biobank;cancer health disparity;cancer type;career development;clinical database;clinical translation;crosslink;drug development;drug discovery;ethnic diversity;experience;genomic data;health equity;member;neoplasm registry;novel;pancreatic cancer patients;patient derived xenograft model;patient population;racial diversity;recruit;repository;research and development;response;skills;success;technology development;tumor;virtual Tissue Modeling and Drug Discovery Core n/a NCI 10762213 9/19/23 0:00 PAR-22-249 2U54CA233396-06 2 U54 CA 233396 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5684 10648034 "FLORES-ROZAS, HERNAN ALCIDES" Not Applicable 2 Unavailable 623751831 W8LKB16HV1K5 623751831 W8LKB16HV1K5 US 30.428914 -84.289766 513802 FLORIDA AGRICULTURAL AND MECHANICAL UNIV TALLAHASSEE FL Domestic Higher Education 323073105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 221957 149971 71986 ABSTRACT TISSUE MODELING & DRUG DEVELOPMENT CORE (SHARED RESOURCE)The goal of the Florida-California Cancer Research Education & Engagement (CaRE2) Health Equity CentersTissue Modeling and Drug Development Core (TMDDC) is to provide a growing archive of fixed and living tissuesthat will support the mission of the CaRE2 Center. In the first funding period (Cycle 1) we were highly successfulin gaining access for FAMU and CaRE2 researchers to annotated tissues from Black/African American (B/AA)and Hispanic/Latinx (H/L). In total the TMDDC now has regulatory compliant access across the partnership tocancer cases including pancreatic cancer blocks (295 B/AA 306 H/L) pancreatic cancer plasma/serum (136B/AA 53 H/L) prostate cancer blocks (548 B/AA 195 H/L) and prostate plasma/serum (595 B/AA 92 H/L).Also the TMDDC facilitated creation or identification of 4 new patient-derived xenografts (PDX) from B/AApatients with pancreatic cancer for studies at FAMU and USC. The TMDDC will continue to develop a robustwell-annotated biorepository of fixed and living tissue samples from a racially and ethnically diverse Florida andCalifornia patient population and make them available to the CaRE2 investigators. The TMDDC will consist ofexisting institutional nationally shared and future-conscious biorepository resources. The short-term goals ofthe TMDDC are to provide the necessary tissue samples for the three projects included in this application whilepreparing for the future needs of the existing and upcoming CaRE2 Center projects. The TMC will address thechallenge of recruiting B/AA and H/L individuals in medical research and the limited supply of qualitybiospecimens and genomic data for these populations. Our specific aims are to: Aim 1. Advance our existingvirtual and physical repositories that will increasingly provide biospecimens from diverse tumor repositoriesthrough a single access point provided by the CaRE2 Center. Many cancer types and many tissue models arerelevant to outcomes in disparities research. The broad types of tissues and data required to study these complexissues make acquisition of a fully satisfactory repository beyond the scope of any single institution. Thereforewe will develop capabilities to collect or acquire novel diverse and well annotated specimens through ourinstitutional resources and other resources. Aim 2. Acquire living tumor tissue for drug development. PDXshave proven to better predict human drug responses than historically used cell-line derived studies. Developmentof these PDXs has the potential to facilitate rapid drug development including testing response as a function ofrace/ancestry. The TMDDC will advance the existing Cycle 1 developed tissue repository at FAMU. The TMDDCwill advance on the existing living tissue repository at FAMU. By achieving these aims we will: (1) enhancecancer disparities tissue-modeling research; (2) expand cancer disparities resources for CaRE2 researchersand (3) ensure a sustained focus on transferring know-how technology and collaborations with FAMU.Evaluation will be based on adequate provision of project-required specimens/resources and by success intransferring drug development technology and knowhow to FAMU. +No NIH Category available Achievement;Address;Advanced Malignant Neoplasm;African American;Bioinformatics;Biological;Biometry;Black American;California;Cancer Research Project;Cancer health equity;Caring;Clinical;Communities;Community Outreach;Comprehensive Cancer Center;Data;Data Analyses;Data Collection;Data Management Resources;Data Science;Data Set;Data Storage and Retrieval;Databases;Development;Doctor of Philosophy;E-learning;Education;Educational Materials;Educational workshop;Ensure;Environmental Exposure;Evaluation;Event;Florida;Funding;Future;Gene Expression Profiling;Goals;Grant;Health;Health Disparities Research;High-Throughput Nucleotide Sequencing;Hispanic;Individual;Institution;Laboratories;Malignant Neoplasms;Manuscripts;Methodology;Methods;Mutation;Mutation Analysis;Occupations;Pilot Projects;Population;Preparation;Procedures;Publications;Quality Control;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Schedule;Science;Series;Services;Source;System;Techniques;Tissue Model;Training;Training Support;Triage;Underserved Population;Universities;University of Southern California Norris Cancer Center;Work;anticancer research;cancer health disparity;computerized data processing;computing resources;data cleaning;data management;data repository;data sharing;design;drug development;education research;exome sequencing;experimental study;federated data;genomic data;health equity;high dimensionality;human data;innovation;lectures;meetings;member;mortality;novel;outreach;public database;single cell sequencing;software as a service;software development;transcriptome sequencing;web site Bioinformatics Statistical and Methodological Core n/a NCI 10762212 9/19/23 0:00 PAR-22-249 2U54CA233396-06 2 U54 CA 233396 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5683 11628050 "KIROS, GEBRE-EGZIABHER " Not Applicable 2 Unavailable 623751831 W8LKB16HV1K5 623751831 W8LKB16HV1K5 US 30.428914 -84.289766 513802 FLORIDA AGRICULTURAL AND MECHANICAL UNIV TALLAHASSEE FL Domestic Higher Education 323073105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 34494 23307 11187 ABSTRACT BIOINFORMATICS STATISTICAL AND METHODOLOGICAL COREThe primary goal of the Bioinformatics Statistical and Methodological (BSM) Core at the Florida-CaliforniaCancer Research Education & Engagement (CaRE2) Health Equity Center is to provide the data managementdata cleaning data storage and data release to public databases for all information generated by our Center. Inaddition it will provide bioinformatics statistical and methodological support for all the cancer research projectsproposed as well as future projects that will build upon them and disseminate to all CaRE2 Center members andthe scientific community at large in a timely fashion. We will reach these goals through three aims: First we willprovide bioinformatics statistical and methodological support. This first aim established the job scheduling andinterfaces to meet the needs of all CaRE2 Health Equity Center investigators. We will support bioinformatics andstatistical issues across the projects and cores. Bioinformatics support will include in-depth quality control andassessment of all high-throughput sequencing data from multiple platforms and facilitate access to publiclyavailable datasets. Statistical and methodological support will consist of all aspects from collecting to state-of-the-art data analysis and interpretation and abstract manuscript and grant preparation. The second aim will beenhancing and maintaining a federated data repository resource that enables the interaction of CaRE2 members.This second aim ensures that all data are of high quality and disseminated to all CaRE2 Center members andthe scientific community promptly. In the third aim we will provide bioinformatics statistical and methodologicalsupport and educational opportunities to the CaRE2 Center. This third aim focuses on developing onlineeducational materials that BSMC's members and guest experts will present through the core events such asseminar series and interactive lectures among all CaRE2 Center members. +No NIH Category available Award;California;City of Hope Comprehensive Cancer Center;Clinical Trials;Collaborations;Communities;Comprehensive Cancer Center;Contractor;Databases;Education;Educational process of instructing;Educational workshop;Effectiveness;Equity;Evaluation;Feedback;Funding;Future;Goals;Grant;Individual;Joints;Knowledge;Leadership;Measures;Mentors;Mentorship;Modeling;Monitor;Outcome Measure;Performance;Pilot Projects;Play;Process;Program Evaluation;Progress Reports;Publications;Recommendation;Reporting;Research;Research Personnel;Resources;Structure;Surveys;Therapeutic;Training;Training Programs;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;anticancer research;cancer health disparity;career;career development;drug development;equity diversity and inclusion;health disparity;improved;insight;meetings;outreach;programs;success;webinar Core 1: Planning and Evaluation n/a NCI 10762163 9/22/23 0:00 PAR-22-249 1U54CA285116-01 1 U54 CA 285116 1 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5671 1877351 "ANN, DAVID K" Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 124168 70550 53618 The goals of the Planning and Evaluation Core (PEC) are to monitor evaluate and assess the progress of ourU54 Partnerships in meeting its milestones objectives and goals. The Core supports our University of CaliforniaRiverside (UCR) City of Hope Comprehensive Cancer Center (CoHCCC) U54 Partnerships goals of capacity-building education and training. Together in this U54 UCR and CoHCCC aim to develop the collaborationstranslational resources and training programs to enhance diversity in cancer research and achieve equity indrug development - throughout the entire drug development pipeline. To achieve our PECs goals we are guidedby four boards the Internal Advisory Board (IAB) External Advisory Board (EAB) Community Advisory Board(CAB) and Diversity Equity and Inclusion Board (DEI). Our IAB and EAB have served a key role in guiding ourP20 planning grant; in our proposed U54 these two boards will be joined by our newly created CAB and DEI.The inclusion of these two new boards underscores our U54s commitment to 1) serving the diverse individualsthat live in our Southern California communities and 2) to mentor and train a diverse early-stage investigatorswho are committed to eliminating our current disparities in cancer therapeutics drug development and accessto clinical trials. Through the activities and oversight of the PEC our four advisory boards will 1) conductevaluation tracking and reporting of the progress of projects and cores and 2) provide focused feedback toprogram U54 leadership and investigators. As in our P20 planning grant the U54 PEC will work with the IAB toprovide a structured and rigorous review process to select new Full and Pilot projects as well as Mini-Pilots forthe Capacity Core. The PEC will assess all components of our U54 partnership. The PEC will assure that the1) Research and Evaluation Core training and education programs are effective in providing education andbuilding capacity 2) Outreach Core works with investigators to be inclusive of the communities we serve and 3)Capacity Core identifies provides early-stage investigators (ESI) with mentorship in target identification drugdevelopment and clinical trials. We anticipate that together our Cores will play a key role in developing futureU54 projects that build UCRs capacity in drug development and clinical trials. +No NIH Category available Acetylation;Acylation;Affect;African;African ancestry;Arginine;Automobile Driving;Binding;Biological;Biological Markers;Biology;Biopsy Specimen;Breast Cancer Cell;Breast Epithelial Cells;Cell Proliferation;Cell physiology;Cells;Complex;Data;EP300 gene;ERBB2 gene;Epigenetic Process;Estrogen receptor positive;European;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Goals;Histone Acetylation;Histone H3;Histones;Human;Individual;Invaded;Isomerism;Lysine;MCF10A cells;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic Activation;Molecular;Mutation;Neoplasm Metastasis;Oncogenic;PIK3CA gene;PIK3CG gene;Pathway interactions;Peptidylprolyl Isomerase;Prognosis;Publishing;Reader;Recurrence;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Site;Testing;Therapeutic;Tissue Banks;Transactivation;Transcriptional Activation;Tumor Cell Biology;Woman;Writing;XCL1 gene;cancer cell;cell immortalization;cell transformation;cell type;cofactor;determinants of treatment resistance;drug development;druggable target;improved;malignant breast neoplasm;mammary;new therapeutic target;notch protein;overexpression;programs;promoter;recruit;stem;stem cell self renewal;therapeutic target;therapy resistant;tumor Project 1 n/a NCI 10762160 9/22/23 0:00 PAR-22-249 1U54CA285116-01 1 U54 CA 285116 1 9/22/23 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5668 6870042 "MARTINEZ, ERNEST " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 146078 82999 63079 Most luminal B breast cancers (LBBC; ER+ HER2-wt Ki67>14%) carry a good prognosis. Howeverapproximately 20% of LBBC are highly aggressive and resistant to current therapies. Poor-prognosis LBBCdisproportionally impact women of African descent; the majority are MYC-activated. There have been manyfailed attempts to therapeutically target MYC. These attempts have failed in part due to our current inability toseparate the cancer-promoting activities of MYC mechanistically or therapeutically from its normal essentialcellular functions. In preliminary data we show that the cancer-transforming ability of MYC is dependent on threelysine (K) residues of MYC (K149 K158 and K323) that are major substrates for acetylation by the histoneacetyltransferases (HATs) p300 and GCN5; individual substitutions of these specific sites block the ability ofMYC to transform human mammary cells. Guided by our preliminary data here we aim to dissect the cofactorsand molecular mechanisms by which these MYC acetyl-K (AcK) residues promote cell transformation andinitiation and progression of LBBC. Our long-term goal is to identify new druggable targets to improve survivalof women most affected by aggressive LBBC; consequently our studies will focus on women of African-descent.Guided by our preliminary data we hypothesize that a gene-selective MYC-AcK signaling pathway drives theaggressive tumor cell biology of therapy-resistant LBBC and involves transcription cofactors and epigeneticcoregulators that write and/or read AcK marks on MYC and histones perhaps including cofactors co-overexpressed with MYC in LBBC such as PIN1 GCN5 p300 and/or YEATS2. Here we will investigate therole of MYC-AcK dependent signaling in luminal mammary cell transformation and aggressive progression ofluminal cancer cells and LBBC tumors as well as identify the cofactors and mechanisms involved.Characterization of this new MYC oncogenic signaling pathway may provide biomarkers and/or therapeutictargets for LBBC in women of African descent. Aim 1 will test the impact of MYC-AcK dependent signaling inmammary epithelial cell transformation and in the aggressive biology of LBBC in women of African-descent. Aim2 will characterize the molecular mechanisms of MYC-AcK dependent gene regulation in transformed mammaryepithelial cells and in LBBC cells and tumors from women of African-descent. +No NIH Category available Address;Adopted;Advanced Malignant Neoplasm;Alaska Native;American Indians;Area;Asian population;Black Populations;California;Cancer health equity;Caring;Catchment Area;Collaborations;Communities;Community Health Systems;County;Data;Development;Diagnosis;Diffusion;Disparity;Early Diagnosis;Education;Education and Outreach;Educational workshop;Ensure;Ethnic Population;Evaluation;Evidence based practice;Fostering;Geographic Locations;Goals;Hispanic Populations;Individual;Infusion procedures;Institution;Intervention;Investments;Leadership;Linguistics;Malignant Neoplasms;Medical Students;Methodology;Mexico;Minority;Mission;Modeling;NCI-Designated Cancer Center;Native-Born;Needs Assessment;Neighborhood Health Center;Not Hispanic or Latino;Pacific Islander;Pathway interactions;Patients;Population;Positioning Attribute;Prevention;Race;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Resource Sharing;Resources;Risk Factors;Rural;Screening for cancer;Teacher Professional Development;Training;Underserved Population;Voice;Work;agricultural community;anticancer research;cancer care;cancer education;cancer health disparity;collaborative approach;community building;community engaged research;community engagement;community organizations;community partnership;design;education research;ethnic diversity;experience;graduate student;health equity;implementation science;improved;innovation;medically underserved;multidisciplinary;outreach;programs;racial population;screening;student participation;survivorship;undergraduate student;underserved community;web platform Outreach Core n/a NCI 10762149 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5665 8828287 "CRESPO, NOE CUAUHTEMOC" Not Applicable 51 Unavailable 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA Domestic Higher Education 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 171758 114125 57633 PROJECT SUMMARY/ ABSTRACT OUTREACH COREThe Cancer Research and Education to Advance HealTh Equity (CREATE) Partnerships geographic area iscomposed of San Diego and Imperial Counties the two U.S.-Mexico border counties in California whichinclude ~3.5 million residents. This region is a majority-minority area with extensive cultural linguistic andracial/ethnic diversity. Disparities in cancer risk factors screening treatment and survivorship continue topersist nationally and within the Partnerships region particularly among underserved groups. Generallymedically underserved individuals are diagnosed with cancer at a later stage and have poorer survivalcompared to individuals who are more affluent. Reducing these cancer disparities requires capacitydevelopment for evidence-based practice and community-engaged research and practice dissemination. Thereis also a need for greater engagement and training of researchers from under-represented backgrounds tocollaborate with community organizations that serve this population. Further communities rarely haveopportunities to develop research programs and implement evidence-based practices in collaboration withexpert clinicians and researchers. Using innovative approaches that are integrated into all Partnershipcomponents the Outreach Core addresses these gaps through its overarching goal: To integrate communityengagement principles into all CREATE Partnership activities. To accomplish this the Outreach Core willadopt the Community-to-Bench model which provides an intentional effort to ensure community engagementand bi-directional dialogue. The following Specific Aims are proposed: 1) Advance cancer health equity byfacilitating and supporting catchment area-relevant research and community-engaged research including butnot limited to Partnership-sponsored research projects; 2) Provide support to community health centers forscreening early detection linkage to care and referral pathways; 3) Foster community engagement byconducting needs assessments disseminating evidence-based practices and resources and implementingeducational and outreach activities; and 4) Contribute to the Partnerships educational mission by providingeducational opportunities to undergraduate graduate and medical students as well as early-stageinvestigators in areas of community-engaged research and cancer disparities. Working closely with theCommunity Advisory Board the OC will build upon existing community partnerships to further expand thePartnerships outreach activities with underserved communities and to support research in catchment areapriority cancers. To conduct this work the Core has assembled a multidisciplinary team with expertise incancer disparities research prevention multilevel interventions and community health system interventions.The Cores collaborative approach is responsive to community needs and will improve cancer health equity inthe Partnerships region and beyond. +No NIH Category available Achievement;Advisory Committees;Area;Awareness;California;Cancer Biology;Cancer Center;Clinical;Collaborations;Communication;Communities;Complement;Coupled;Dedications;Degree program;Development;Doctor of Philosophy;Education;Educational Activities;Ensure;Environment;Ethnic Population;Evaluation;Exposure to;Faculty;Fellowship;Financial Support;Funding;Future;Goals;Grant;Health;Health Disparities Research;Human Resources;Individual;Joints;Laboratory Research;Leadership;Malignant Neoplasms;Manuscripts;Medical Students;Mentors;Mentorship;Modeling;Molecular Chaperones;Neighborhood Health Center;Participant;Physicians;Preparation;Provider;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Resource Sharing;Scholars Program;Schools;Science;Scientist;Students;Time;Training;Travel;Trinidad;Underrepresented Minority;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Work;anticancer research;cancer education;cancer health disparity;career;career development;cohort;community clinic;community engagement;community organizations;doctoral student;education research;effectiveness evaluation;experience;follow-up;graduate student;health equity;improved;interest;medical schools;multidisciplinary;operation;peer;peer coaching;pre-clinical;programs;public health research;racial population;recruit;social determinants;student participation;success;summer research;undergraduate student Research Education Core n/a NCI 10762148 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5664 6380746 "CRIPPS, RICHARD MATTHEW" Not Applicable 51 Unavailable 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA Domestic Higher Education 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 171758 114125 57633 PROJECT SUMMARY/ABSTRACT RESEARCH EDUCATION COREThe goal of the Cancer Research and Education to Advance HealTh Equity (CREATE) Research Education(RE) Core is to provide critical educational and career development opportunities to current and futureunderrepresented cancer scientists and professionals. The RE Core will build upon its achievements tosupport students at three important inflection points in the cancer education pipeline: in Aim 1 CREATEUndergraduate Scholars will be paired with world-class cancer disparities researchers and clinicians andcomplete a summer research and education program coupled with follow-up research during the academicyear. Scholars will be supported and mentored in their applications to graduate and professional schools tofurther their development as cancer disparities scholars. Undergraduates will benefit from near-peermentoring by CREATE Medical Student Scholars who in Aim 2 will carry out cancer disparities researchand participate during their first year of medical school in a newly-developed elective focused upon thesocial determinants of cancer health. In Aim 3 CREATE Graduate Scholars recruited as underrepresentedsecond-year PhD students working in cancer research laboratories will be supported to assure theirretention and success in their PhD programs. Graduate Scholars will receive research and financial supportwill gain expertise in fellowship grant preparation and submission and will receive education in culturalawareness to enable successful participation in a diverse scientific workforce. These activities will directlyand positively increase the number of individuals engaged in cancer disparities research promote retentionin their selected degree programs and will ultimately increase the participation of underrepresentedminorities in this critical research area. The RE Core will be co-led by an established team of investigatorswho have significant experience in leading NIH-supported educational programs. Co-leads Drs. RichardCripps (SDSU) and James Murphy (UCSD) and will work with Drs. Ricardo Zayas (SDSU) and DennisTrinidad (UCSD) to develop new activities and direct Core progress. The CREATE Partnerships InternalAdvisory Committee will oversee operations and RE Core personnel will collaborate with the Planning andEvaluation Core to assess the effectiveness of each aim and to guide program improvement. Theopportunities offered through the RE Core will engage and support the development of students from racialand ethnic groups that are underrepresented in the biomedical sciences. The education that will be providedin cancer-related research will guide participants towards successful careers in this area and enable them todevelop research programs focused upon cancer disparities. +No NIH Category available Achievement;Address;Adolescent and Young Adult;Advanced Malignant Neoplasm;Advisory Committees;Area;California;Cancer Patient;Cancer Survivor;Cancer health equity;Career Choice;Catchment Area;Clinical Trials;Communities;County;Data;Development;Disparity;Documentation;Evaluation;Feedback;Female Adolescents;Future;Goals;Healthcare Systems;Hispanic;Inequity;Institution;Lead;Leadership;Logic;Malignant Neoplasms;Medical Students;Methods;Modeling;Modification;Outcome;Outcome Assessment;Pancreatic Ductal Adenocarcinoma;Patients;Pilot Projects;Policy Maker;Principal Investigator;Provider;Reproductive Health;Research;Research Personnel;Research Project Grants;Resource Sharing;Resource-limited setting;Resources;Rural;Scholars Program;Services;System;Testing;Universities;anticancer research;black patient;cancer education;cancer health disparity;care delivery;community engaged research;disparity reduction;education research;experience;graduate student;health equity;improved;improved outcome;innovation;member;multi-component intervention;multidisciplinary;novel;novel therapeutic intervention;programs;telehealth;undergraduate student;underserved community Planning and Evaluation Core n/a NCI 10762147 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5663 9786952 "MADANAT, HALA " Not Applicable 51 Unavailable 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA Domestic Higher Education 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 73053 49800 23253 PROJECT SUMMARY/ ABSTRACT PLANNING AND EVALUATION COREThe Planning and Evaluation (P&E) Core of the Cancer Research and Education to Advance HealTh Equity(CREATE) Partnership will implement a comprehensive mixed-method and outcome-oriented evaluation of allCREATEs activities and components. Using innovative evaluation methods that are integrated into allPartnership components the P&E Core addresses its overarching goal: To develop implement and sustain aframework that drives rigorous ongoing evaluation to support the scientific and programmatic goals of thePartnership. To accomplish this the Partnership proposes the following Specific Aims: 1) Leverage existinginternal expertise within both institutions by engaging the Internal Advisory Committee (IAC) in internalplanning and assessing research core and shared resource activities; 2) Implement an innovative efficientand rigorous mechanism for soliciting and evaluating new pilot projects and evaluating the progress of existingPartnership-sponsored projects; 3) Utilize the external evaluation expertise provided by highly experiencedunbiased multidisciplinary experts of CREATEs Program Steering Committee (PSC) and Community AdvisoryBoard (CAB) to achieve the Partnerships stated goals and objectives; 4) Build and maintain a continuousplanning evaluation and tracking system using a approach to provide CREATE Partnership leadership withmetrics to make data driven decisions throughout all Partnership activities and components. To achieve P&ECore aims internal and external experts will be engaged including: 1) a collaborative Multiple PrincipalInvestigator group (MPI); 2) a larger Executive Committee made up of the MPIs Program Managers CREATEUndergraduate Scholars Program director Core and Shared Resource Leads and an Evaluation Lead; 3) amultidisciplinary IAC; 4) a PSC composed of external members with appropriate scientific expertise; and 5) anexternal CAB made up of community partners organizations. CREATE MPIs will lead the planning componentand an evaluation lead will direct all evaluation efforts independently of the MPIs. The expected impact is to: 1)advance cancer health equity in underserved communities in the Southern Border Region of California; 2)further increase SDSUs cancer research capacities 3) expand SDSUs and UCSDs cancer health disparitiesand community-engaged research 4) build a pipeline of a diverse biomedical workforce largely focused onundergraduate graduate and medical students and early stage investigators underrepresented in thebiomedical workforce. Based on the goals of the selected full and pilot projects included in this applicationCREATE expects major advancements in reducing disparities related to the following areas: 1) contribute tothe development of a novel therapeutic strategy to be tested in future clinical trials 2) provide actionableinformation to stakeholders regarding inequity in cancer patients access to telehealth and; 3) generate a novelmulticomponent intervention that adapts care delivery to address reproductive health among rural and Hispanicfemale adolescent and young adult cancer survivors. +No NIH Category available Adolescent and Young Adult;Aftercare;California;Cancer Patient;Cancer Science;Cancer Survivor;Cancer Survivorship;Caring;Catchment Area;Clinic;Clinical;Communities;Community Clinical Oncology Program;Consult;Consultations;Continuity of Patient Care;Contraceptive methods;County;Data;Diagnosis;Discipline of Nursing;Distress;Effectiveness;Effectiveness of Interventions;Evaluation;Faculty;Female Adolescents;Fertility;Focus Groups;Future;Geography;Health;Health Insurance;Health Personnel;Health Professional;Healthcare;Hispanic;Hispanic Populations;Infertility;Intervention;Interview;Latina;Learning;Linguistics;Malignant Neoplasms;Menopausal Symptom;Methods;Mexico;Newly Diagnosed;Nursing Faculty;Oncology;Outcome;Parents;Pathway interactions;Patients;Pilot Projects;Premature Ovarian Failure;Quality of Care;Quality of life;Reporting;Reproductive Health;Reproductive Medicine;Research;Research Personnel;Resource-limited setting;Resources;Risk;Rural;Rural Community;Social Work;Social Workers;Specialist;Structure;Survivors;Underserved Population;Universities;Work;adverse pregnancy outcome;anticancer research;arm;cancer care;cancer education;care delivery;clinical care;community engagement;design;effectiveness evaluation;experience;feasibility testing;health care delivery;health disparity;health equity;health literacy;high risk;hybrid type 1 trial;implementation measures;implementation outcomes;implementation science;improved;low health literacy;medically underserved;multi-component intervention;multi-site trial;neoplasm resource;novel;oncofertility;outreach;patient navigation;pilot test;primary outcome;psychosocial;remote communities;reproductive;rural Hispanic;rural area;rural healthcare;screening;shared decision making;survivorship;telehealth;uptake Pilot Project 1: Creating Bridges to Reproductive Health Care for Rural Adolescent and Young Adult Cancer Survivors n/a NCI 10762146 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5662 14924877 "HOYT, HELINA " Not Applicable 51 Unavailable 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA Domestic Higher Education 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 71831 47728 24103 PROJECT SUMMARY/ ABSTRACT PILOT PROJECTReproductive health care in cancer patients is an unmet need in Imperial County a medically underservedrural region of the Cancer Research and Education to Advance HealTh Equity (CREATE) Partnershipscatchment area with a predominantly Hispanic population. Reproductive health is a major issue for adolescentand young adult (AYA) cancer survivors because they can experience higher risks of infertility adversepregnancy outcomes and unmet informational needs. Reproductive health care effectively reduces risks butuptake is low because there are no scalable interventions to support the implementation of routine reproductivehealth care in underserved geographically remote communities. Guided by the Cancer Survivorship CareQuality Framework this pilot proposal seeks to adapt and pilot test a multi-component intervention to improvereproductive health care uptake by female AYA cancer survivors. The intervention has three componentsderived from our prior work: 1) a reproductive risk summary (RS) and survivorship care plan on reproductivehealth (SCP-R) 2) navigation and 3) telehealth reproductive consults. In Aim 1 we will adapt the RS andSCP-R in English and Spanish to be responsive to the cultural health literacy and socio-ecological needs ofLatina AYA survivors through focus groups with AYA survivors and parents/guardians and semi-structuredinterviews with healthcare providers. We will also systematically evaluate barriers and facilitators toreproductive health care in Imperial County and examine how to fit the multi-component intervention to thissetting through focus groups with survivors and parents/guardians and interviews with healthcare providersand clinic staff. In Aim 2 we will conduct feasibility testing of the multicomponent intervention in a single armpilot hybrid type 1 trial (evaluating effectiveness and observing implementation). The primary outcome isengagement in reproductive health care by 15 newly diagnosed and 15 post-treatment AYA survivors.Secondarily we will qualitatively assess effectiveness fit and implementation outcomes with AYA survivorshealthcare providers and health clinic staff. The proposal directly targets a critical health disparity faced byfemale AYA survivors in our catchment area and need for partnership between rural community healthprofessionals and urban specialists to deliver quality reproductive survivorship care. We will generate a novelscalable intervention and preliminary data to support a future multi-site trial on intervention effectiveness inincreasing reproductive care in rural medically underserved oncology settings. The partnership betweenSDSU CRCD and UCSD researchers will be strengthened with collaborative learning communityengagement and increased capacity of trainees to support future cancer research in Imperial County. +No NIH Category available 3-Dimensional;Acetylation;Actins;Adherence;Adhesions;Adhesiveness;Affect;African American;American;Behavior;Binding;Biochemical;Biology;Biophysics;Cause of Death;Cell Adhesion;Cell Cycle Progression;Cell Nucleus;Cell Proliferation;Cell model;Cells;Chemotherapy-Oncologic Procedure;Collaborations;Cytoplasm;Cytoskeleton;Cytosol;Data;Development;Disease;Disease Progression;Enhancers;Environment;Excision;Extracellular Matrix;F-Actin;Flavins;G Actin;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Goals;Hispanic;Hospitals;Human;Impairment;Incidence;Insurance;Integrins;Invaded;Knowledge;Laboratories;Life;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Mechanics;Mixed Function Oxygenases;Morbidity - disease rate;Myosin ATPase;Neoplasm Metastasis;Not Hispanic or Latino;Nuclear;Nuclear Export;Nucleic Acid Regulatory Sequences;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pattern;Phenotype;Play;Pre-Clinical Model;Primary Neoplasm;Property;Proteins;Reporting;Role;Serum Response Factor;Signal Induction;Signal Transduction;Socioeconomic Status;Stromal Cells;Structure;Testing;Transcription Coactivator;Transcriptional Regulation;alpha Actin;anticancer research;biophysical properties;cancer cell;cancer education;cell motility;depolymerization;effective therapy;experience;extracellular;health equity;high risk population;human disease;improved;improved outcome;in vivo;mechanical properties;migration;mortality;myocardin;new therapeutic target;novel therapeutic intervention;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic stellate cell;patient population;screening;therapeutic target;therapeutically effective;transcription factor;tumor growth;tumor microenvironment Project 1: Defining Mechanisms of MICAL-dependent Pancreatic Cancer Cell Migration n/a NCI 10762144 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5660 10966413 "KATIRA, PARAG " Not Applicable 51 Unavailable 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA Domestic Higher Education 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 169580 112678 56902 PROJECT SUMMARY/ ABSTRACT PROJECT 1Pancreatic duct adenocarcinoma (PDAC) takes the life of an American approximately every 12 minutes anddisproportionately affects African American and Hispanic patients who experience higher rates of morbidityand mortality compared to non-Hispanic white patients. Since the incidence of PDAC is relatively modest evenamong higher risk groups screening is not feasible. Thus improvements in outcomes require an improvedunderstanding of PDAC biology to guide development of effective therapies. Here the partnering PIscomplementary expertise in PDAC biology and modeling cellular biophysical properties converge to investigatemechanisms of PDAC cell migration and metastasis the primary cause of death in this patient population.The Lowy laboratory focused on identifying therapeutic targets by performing unbiased discovery in PDAC vs.normal pancreas. They hypothesized that super enhancer associated genes which define cell identity wouldbe effective therapeutic targets for PDAC. One differentially acetylated enhancer region was mapped to theMICAL2 gene that encodes a flavin monooxygenase. This protein drives F-actin depolymerization that in thecytosol can restructure the actin myosin machinery used to migrate and respond to external mechanical andbiochemical signals. MICAL2 also plays a role in linking nuclear actin dynamics to serum response factor(SRF) transcription. Myocardin-related transcription factors (MTRFs) are co-activators of SRF; when nuclearactin depolymerization is induced by MICAL2 globular actin is targeted for nuclear export freeing MTRF tobind SRF and activate transcription of genes important for cell adhesion and migration. Studies in PDAC cellsreveal that silencing MICAL2 expression impairs cell migration and metastasis.The Katira laboratory in collaboration with Dr. Englers group have reported that cell adhesiveness serves as abiophysical marker for metastatic potential and both adhesiveness and contractility enable adurotaxis theability of cells to migrate regardless of a stiffness gradient. To goal of this project is to define how MICAL2influences properties of adhesiveness and durotaxis and how it may regulate properties not only of the cancercell but of the tumor microenvironment through regulation of gene expression. We hypothesize that MICAL2promotes PDAC cell invasion and metastasis by cell autonomous and non-cell autonomousmechanisms. We will test this hypothesis in three specific aims; 1) Determine how MICAL2 modulatesadherence and durotaxis in pancreatic cancer cells 2) Determine how MICAL2 promotes pancreatic cancercell migration and metastasis and 3) Determine how MICAL2 related signaling from cancer an stromal cellsmodulates the tumor microenvironment. As a putative therapeutic target our goal is to determine how MICAL2functionally regulates cell migration and metastatic capacity during PDAC progression. This knowledge will bekey to understanding how and when MICAL2 activity can be targeted in PDAC. +No NIH Category available Administrative Efficiency;Advisory Committees;Asian Americans;California;Cancer Center;Catchment Area;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Ensure;Environmental Health;Equity;Faculty;Feedback;Funding;Future;Glues;Goals;Grant;Health Disparities Research;Hispanic-serving Institution;Infrastructure;Institution;Leadership;Malignant Neoplasms;Mediation;Medical Students;National Cancer Institute;Native Americans;Pacific Island Americans;Pathway interactions;Peer Review;Persons;Population;Positioning Attribute;Principal Investigator;Provider;Recording of previous events;Research;Research Personnel;Resource Sharing;Resources;Role;Schools;Scientist;Services;Structure;System;Teacher Professional Development;United States National Institutes of Health;Universities;Work;anticancer research;base;cancer education;cancer health disparity;career;career development;college;education research;evidence base;experience;graduate student;health equity;meetings;member;mid-career faculty;operation;outreach;programs;recruit;synergism;undergraduate student Administrative Core n/a NCI 10762142 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5658 9786952 "MADANAT, HALA " Not Applicable 51 Unavailable 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA Domestic Higher Education 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 303732 201815 101917 PROJECT SUMMARY/ ABSTRACT ADMINISTRATIVE COREThe goal of the Administrative Core of the Cancer Research and Education to Advance HealTh Equity(CREATE) Partnership is to provide strategic leadership and administrative oversight to advance theoverarching goal of the Partnership. This includes providing an efficient infrastructure to support all scientificadministrative and fiscal activities of the Partnership to ensure effective synergy within and across San DiegoState University (SDSU) and the UC San Diego (UCSD) Moores Cancer Center (MCC). Additional goalsinclude developing cancer research opportunities and pathways for undergraduate graduate and medicalstudents as well as early-stage investigators (ESIs) which will lead to a future workforce that is more diverseand reflective of the catchment-area population. As a single unit the Administrative Core provides strategicleadership and administrative oversight to advance Partnership goals. The Core is the glue that keeps thePartnership together and due to its extensive experience and history it is able to provide necessary servicesto support an efficient administrative system and infrastructure under the leadership of multiple PrincipalInvestigators. The Administrative Core is structured so that the Partnership leaders can establish andimplement a highly integrated operation that ensures exponential benefit from the collaboration of the twoinstitutions. The Core works synergistically to effectively implement the CREATE Partnership activities incancer research research education early-stage faculty career development and community outreach. Toaccomplish Partnership goals the CREATE leadership proposes the following Specific Aims: 1) Provideleadership coordination and management to the scientific administrative and fiscal components of theCREATE Partnership. 2) Promote evidence-based and sustainable interactions and build new researchcollaborations across the Partnership. 3) Procure scientific and strategic feedback and guidance from internaland external advisors. 4) Assist in recruitment of ESIs and work with the Transforming fAcuLty dEvelopmeNTfor Equity (TALENT) Shared Resource to support their career development. The AC is positioned to buildstrong institutional commitment to cancer research and cancer disparities research while growing thePartnerships research education programs and increasing outreach to the communities and their providers inthe Southern Border Region of California. By the end of this project period the Partnership intends to grow thecancer research base at SDSU by at least 25% and the number of peer reviewed funded cancer disparitiesand/or community-engaged grants by at least 20%. +No NIH Category available Advanced Malignant Neoplasm;Alaska Native;American Indians;Asian;Automobile Driving;Behavior;Black Populations;Border Community;Breast;California;Cancer Burden;Cancer health equity;Caring;Catchment Area;Cause of Death;Colorectal;Communities;County;Dissemination and Implementation;Education;Equity;Ethnic Population;Evaluation;Evidence based intervention;Fostering;Funding;Future;Goals;Health Disparities Research;Hispanic Populations;Incidence;Institution;Leadership;Linguistics;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of prostate;Medical Students;Mentors;Minority;Names;Neighborhood Health Center;Pancreas;Pathway interactions;Pilot Projects;Population;Race;Research;Research Personnel;Research Project Grants;Resource Sharing;Risk Factors;Rural;Screening for cancer;Teacher Professional Development;Underrepresented Students;Universities;agricultural community;anticancer research;cancer education;cancer health disparity;career;career development;community engaged research;community engagement;design;education research;ethnic diversity;experience;gastrointestinal;graduate student;health assessment;health equity;improved;insight;inter-institutional;outreach;population based;programs;racial population;recruit;screening;survivorship;undergraduate student;underserved community 1/2 Cancer Research and Education to Advance HealTh Equity (CREATE) Partnership PROJECT NARRATIVE - OVERALLThe purpose of this new inter-institutional U54 application between San Diego State University (SDSU) andthe University of California San Diego (UCSD) is to advance cancer health equity in underserved communitiesthroughout the southern California border communities of San Diego and Imperial Counties. Under a newname the Cancer Research and Education to Advance HealTh Equity (CREATE) Partnership theoverarching goals are to further increase SDSUs cancer research capacities and expand SDSUs and UCSDsemphasis on cancer health disparities research. Additional goals include developing cancer researchopportunities and pathways for undergraduate graduate and medical students as well as early-stageinvestigators (ESIs) which will lead to a future workforce that is more diverse and reflective of the catchment-area population. NCI 10762141 9/19/23 0:00 PAR-22-249 1U54CA285117-01 1 U54 CA 285117 1 "WALI, ANIL" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 9786952 "MADANAT, HALA " "CRIPPS, RICHARD MATTHEW; MARTINEZ, MARIA ELENA; MURPHY, JAMES D" 51 NONE 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA GRADUATE SCHOOLS 921821901 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1206257 NCI 832615 373642 PROJECT SUMMARY/ABSTRACT OVERALLThe Cancer Research and Education to Advance HealTh Equity (CREATE) Partnerships overarching goalsare to further increase SDSUs cancer research capacities and expand SDSUs and UCSDs emphasis oncancer health disparities research. Bi-directional community engagement is also a principal feature that isintegrated across every organizational component in the CREATE Partnership and is a strength that SDSUhas built over the last 30 years. Additional goals include developing cancer research opportunities andpathways for undergraduate graduate and medical students as well as early-stage investigators (ESIs)which will lead to a future workforce that is more diverse and reflective of the catchment-area population. Tomeet these overarching goals the following Specific Aims are proposed: 1) Recruit and support diverse ESIswho have chosen an intentional career goal to become independent cancer-focused researchers(Administrative Core and Transforming fAcuLty dEvelopmeNT for Equity [TALENT] Shared Resource); 2)Conduct catchment-area relevant research and pilot research projects aligned with identified cancer prioritiesfor the underserved communities in the region (Research and Research Pilot Projects and Planning andEvaluation Core); 3) Expand and implement cancer cancer disparities and community-engaged researcheducation with a focus on under-represented students across SDSU and UCSD undergraduate graduateprograms and medical students (Research Education Core); and 4) Integrate community engagement into allCREATE Partnership activities (Outreach Core). To achieve these aims the CREATE Partnership requests theinitial support for two Full Research Projects and one Pilot Research Project designed to provide insight intothe mechanisms (or behaviors) underlying cancer health disparities. All three projects will be jointly led bySDSU and UCSD Co-Leads; Project 2 is co-led by two under-represented researchers. The Research Projectswill be integrated with the Research Education Core providing expanded research experiences in cancercancer disparities and community-engaged research to under-represented undergraduate graduate andmedical students. A TALENT Shared Resource will foster the career development of Partnership ESIs. TheOutreach Core will develop new and strengthen existing community-academic partnerships to foster cancerresearch education and tailored outreach efforts with a focus on the dissemination and implementation ofevidence-based interventions that can reduce the cancer burden. The Partnership is notably bolstered bystrong institutional commitment an Administrative Core composed of investigators with demonstratedleadership and organizational capabilities and a strong Planning and Evaluation Core guided by an externalProgram Steering Committee an Internal Advisory Board and a Community Advisory Board. 1206257 +No NIH Category available Academy;Achievement;Address;Admission activity;Advanced Malignant Neoplasm;African American;Applications Grants;Applied Research;Award;Basic Science;Behavioral;Behavioral Research;Benchmarking;Bioinformatics;Biomedical Research;Biometry;Black Populations;Black race;California;Cancer health equity;Career Choice;Caring;Clinical;Clinical Research;Collaborations;Communities;Complement;Comprehensive Cancer Center;Data;Discipline;Discipline of Nursing;Doctor of Philosophy;Education;Educational Activities;Engineering;Ensure;Environment;Ethnic Origin;Evaluation;Fellowship;Florida;Funding;Genomics;Goals;Government;Grant;Health;Health Disparities Research;Health Professional;Healthcare Systems;Hispanic;Historically Black Colleges and Universities;Immersion;Impact evaluation;Individual;Institution;International;K-Series Research Career Programs;Knowledge;Latino;Latino Population;Malignant Neoplasms;Manuscripts;Medicine;Mentors;Mentorship;Minority Graduate Student;Minority Groups;Modeling;Monitor;Native Americans;Oncology;Outcome;Outcomes Research;Patients;Persons;Pharmacy facility;Population;Population Research;Postbaccalaureate;Postdoctoral Fellow;Process;Program Evaluation;Public Health;Publishing;Publishing Peer Reviews;Race;Research;Research Personnel;Research Training;Science;Scientist;Site;Structure;Students;Training;Training Programs;Training Support;Tribes;Underrepresented Minority;United States National Academy of Sciences;United States National Institutes of Health;Universities;University of Southern California Norris Cancer Center;anticancer research;cancer health disparity;career;career development;cost;education research;ethnic diversity;experience;graduate student;health care disparity;health equity;higher education;improved;interest;medical schools;meetings;minority trainee;multidisciplinary;peer;posters;pre-clinical;pre-doctoral;programs;racial diversity;recruit;response;success;training opportunity;undergraduate student Research Education Core n/a NCI 10762130 9/19/23 0:00 PAR-22-249 2U54CA233444-06 2 U54 CA 233444 6 9/17/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5656 16054449 "ALLEN, JOHN M" Not Applicable 3 Unavailable 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL Domestic Higher Education 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 117219 76865 40354 ABSTRACT RESEARCH EDUCATION COREDisparities in health care based on race/ethnicity represent a mutable factor that costs the U.S. governmentbillions of dollars annually. According to the National Academy of Science Board on Higher Education BlacksLatinos and Native American tribal people together represent approximately 25% of the nations populations yetthey represent only 8% of the total science and engineering PhD recipients. The Florida-California CancerResearch Education & Engagement (CaRE2) Health Equity Center is a collaboration among Florida A&MUniversity (FAMU a Historically Black College and University {HBCU}) University of Florida (UF) and Universityof Southern California (USC) that will advance cancer research to better meet the needs of Black and Latinocommunities. In response to the Comprehensive Partnerships to Advance Cancer Health Equity (CPACHE) U54PAR the CaRE2 Health Equity Center Research Education Core (REC) is proposed to meet the cancerresearch education needs of underrepresented minorities (URM) in Florida and California especially Blacks andLatinos. The REC will: (1) support the training of 30 URM post-bac students in a one-year mentored researchand training program (Postbac-CaRE2); and (2) provide academic career development mentorship and tailoredresearch training opportunities to increase the competitive research capacity for a total of 90 URM graduatestudents post-doctoral fellows and early-stage investigators and 40 ongoing trainees(CaRE2-Grad+); (3)Evaluation of CaRE2 Research Education activities. Post-baccalaureate trainees at each partner site will havea year-long immersion in research working with multidisciplinary teams to build their knowledge of research andto promote their academic career paths in cancer-related health disparities. Graduate students post-doctoralfellows and ESIs at each site will receive intensive mentoring academic career development and tailoredresearch training opportunities to promote their successful attainment of research-related and academicmilestones. Program outcomes of the REC will be monitored with Planning and Evaluation Core support todevelop a robust long-term tracking and evaluation program of the REC activities across the diverse CaRE2training pipelines. The Administrative Core will use data gathered via assessment activities to implementprogram changes as needed to promote the success of the trainees. +No NIH Category available Accountability;Achievement;Advocate;African American;Annual Reports;Award;Benchmarking;Black race;California;Career Mobility;Caring;Collaborations;Communities;Community Health Education;Community Outreach;Data;Decision Making;Development;Doctor of Pharmacy;Doctor of Philosophy;Documentation;Education;Education and Outreach;Educational workshop;Effectiveness;Ensure;Evaluation;Exhibits;Extramural Activities;Faculty;Florida;Fostering;Funding;Goals;Grant;Health Disparities Research;Hispanic;Individual;Investments;Latino;Leadership;Measures;Mentors;Monitor;Online Systems;Outcome;Outcome Assessment;Pathway Analysis;Peer Review;Population;Process;Program Evaluation;Publications;Quantitative Evaluations;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resource Allocation;Resource Sharing;Resources;Scholarship;Science;Scientist;Social Network;Surveys;Training;Underrepresented Minority;Universities;anticancer research;cancer health disparity;career development;design;education research;health equity;implementation evaluation;improved;inter-institutional;meetings;member;minority trainee;multidisciplinary;programs;recruit;success;symposium;webinar Planning and Evaluation Core n/a NCI 10762129 9/19/23 0:00 PAR-22-249 2U54CA233444-06 2 U54 CA 233444 6 9/17/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5655 8694196 "EZENWA, MIRIAM OMELEBELE" Not Applicable 3 Unavailable 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL Domestic Higher Education 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 44033 28874 15159 ABSTRACT PLANNING AND EVALUATION COREIn line with our long-term goal to eliminate cancer health disparities in Florida California and nationally theUniversity of Florida (UF) Florida A&M University (FAMU) and University of Southern California (USC)have formed a triad partnership to establish the Florida-California Cancer Research Education &Engagement (CaRE2) Health Equity Center. The Planning and Evaluation Core (PEC) of the CARE2 HealthEquity Center will implement a systematic planning and assessment plan that guides program improvementand document accountability and effectiveness. The specific aims of the PEC are to: (1) provide operativeplanning of internal and external partnership activities for CaRE2 Centers cores and projects (2) prioritize andsupport three additional collaborative research projects to expand cancer disparities research nationally; (3) Tofoster continuous quality improvement and demonstrate the impact of the partnership the PEC will continue totrack monitor and evaluate all partnership activities; and (4) To provide independent assessment andguidance the PEC will continue to foster the tracking monitoring and evaluation of partnership activities by theProgram Steering Committee (PSC) and the External Evaluator. Using clear metrics to assess the outcomes ofeach core and project PEC will support the aims of the CaRE2 Center by providing the guidance and oversightto ensure continuous quality improvement. The expected outcomes for the PEC are: (1) evidence documentingthe success of scholarship activities and tracking processes among UF FAMU and USC scientists; (2)documentation of the effectiveness of the bi-monthly web-based partnership meetings and annual face-to-faceretreat; (3) findings from the social network analysis that documents changes in scientific collaborations acrossthe CaRE2 Center; and (4) assessment of the congruence between objectives activities and outcomes acrossthe cores. +No NIH Category available 3-Dimensional;Address;Affect;African American;African American population;Alveolar;Amides;Angiogenesis Inhibition;BAY 54-9085;BRAF gene;Bioinformatics;Biological;Biological Factors;Biological Models;Biomedical Engineering;Black American;Black Populations;Black race;Bronchiolo-Alveolar Adenocarcinoma;California;Carcinogens;Caring;Cell Line;Cell Survival;Cells;Collection;Combined Modality Therapy;DNA;Data Analyses;Development;Disparity;Doctor of Philosophy;Drug Combinations;Education;Epidermal Growth Factor Receptor;Epithelial Cells;Erlotinib;Ethnic Origin;Ethnic Population;Florida;Formalin;Funding;Gel;Gelatin;Gene Mutation;Genes;Genetic;Growth;In Vitro;Individual;Inhalation;Invaded;KRAS2 gene;Knowledge;Leukocytes;Lung Adenocarcinoma;MAP Kinase Gene;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medicine;Metabolism;Metastatic Neoplasm to the Bone;Methodology;Methods;Modeling;Molecular;Mutate;Mutation;Neoplasm Metastasis;Nicotine;Organoids;PIK3CG gene;Paraffin Embedding;Pathway interactions;Patients;Pattern;Perfusion;Pharmaceutical Preparations;Porosity;Printing;Race;Resources;Risk Factors;STK11 gene;Sampling;Site;Source;System;TP53 gene;Testing;Therapeutic;Time;Tissue Model;Tobacco smoke;Treatment Efficacy;Variant;Vascular Endothelial Cell;Woman;Work;alpelisib;alveolar epithelium;anti-cancer therapeutic;anticancer research;black men;black women;bone;cancer cell;cancer health disparity;cytotoxicity;driver mutation;drug development;effective therapy;exome sequencing;exposure to cigarette smoke;follow-up;health disparity;health equity;high risk;in vitro Model;inhibitor;innovation;interdisciplinary collaboration;member;men;migration;mutant;neoplasm registry;novel;novel therapeutics;osteogenic;progenitor;racial difference;racial population;response;targeted treatment;therapeutic evaluation;therapeutic target;tool;treatment response;two-dimensional Project 4 LUNG n/a NCI 10762127 9/19/23 0:00 PAR-22-249 2U54CA233444-06 2 U54 CA 233444 6 9/17/18 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5653 9837699 "HUANG, YONG " Not Applicable 3 Unavailable 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL Domestic Higher Education 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 116025 76082 39943 ABSTRACT FULL PROJECT 4 LUNGLung cancer is a prominent source of cancer health disparity particularly in Black men. While they have lowerexposure to cigarette smoke the most common risk factor for lung cancer Black men have a 37% higher riskfor lung cancer than White men. In addition the 5-year survival of Black men and women is below that of Whitesubjects. Numerous causes likely underlie these differences including genetic differences. The latter may affectthe metabolism of nicotine/tobacco smoke components responses to therapy and differences in cancer drivergene mutations. To understand the effects of the genetic differences between racial/ethnic groups on lung cancerdevelopment and treatment we need to characterize the driver mutations in lung adenocarcinoma (LUAD themost common type of lung cancer) in Black Americans and develop in vitro lung cancer model systems thatreflect the relevant mutations in the correct genetic background. There is a notable lack of cell line models forlung adenocarcinoma from Black Americans with no Black cell lines from alveolar epithelial cells (the LUADprogenitors) and only 5 known LUAD cell lines (compared to 67 White cell lines). While targeted therapies areavailable for a subset of LUAD in vitro systems to test therapeutics in Black Americans are sorely lacking. Wehypothesize that due to genetic differences LUAD in Blacks will have a unique repertoire of cancer driver genesand will respond to targeted therapies distinctly from white LUAD. This proposal represents an interdisciplinarycollaboration in which a medicinal (bio)chemist from FAMU (Dr. Lamango) a biomedical engineer from UF (Dr.Huang) and a molecular geneticist from USC (Dr. Offringa) combine their innovative resources to tackle thepronounced health disparities in lung cancer in Black Americans. We will do so through three Specific Aims: InAim 1 we will identify the main driver mutational signatures of lung adenocarcinoma from 100 Black Americanswho are 5-fold underrepresented in mutational studies. In Aim 2 we will develop new immortalized alveolar andlung adenocarcinoma cell lines from Black subjects and use these and existing cell lines to develop 2-dimensional (2D) and 3-dimensional (3D) in vitro models. We will test promising drugs (polyisoprenylatedcysteinyl amide inhibitors (PCAIs)) developed by the Lamango lab that target the KRAS pathway which isfrequently mutated in LUAD. As time allows we will also test other targeted therapeutics and combinations ofdrugs. In Aim 3 we will develop a novel 3D-printed bone cancer metastasis model to study the differential efficacyof PCAIs and other targeted therapeutics on cancer cell cytotoxicity migration and invasion. Bone is the mostcommon metastatic site of LUAD. The three proposed Specific Aims address the lack of knowledge about cancerdriver genes in Black American lung adenocarcinoma generate a collection of normal alveolar and lungadenocarcinoma cell lines from Black subjects that will be used to establish race-appropriate models and will bea great resource for others and allow the testing of therapeutics on cells from Black Americans using 2D 3Dand bone metastasis models. +No NIH Category available Achievement;Address;Advanced Malignant Neoplasm;African American;Bioinformatics;Biological;Biometry;Black American;California;Cancer Research Project;Cancer health equity;Caring;Clinical;Communities;Community Outreach;Comprehensive Cancer Center;Data;Data Analyses;Data Collection;Data Management Resources;Data Science;Data Set;Data Storage and Retrieval;Databases;Development;Doctor of Philosophy;E-learning;Education;Educational Materials;Educational workshop;Ensure;Environmental Exposure;Evaluation;Event;Florida;Funding;Future;Gene Expression Profiling;Goals;Grant;Health;Health Disparities Research;High-Throughput Nucleotide Sequencing;Hispanic;Individual;Institution;Laboratories;Malignant Neoplasms;Manuscripts;Methodology;Methods;Mutation;Mutation Analysis;Occupations;Pilot Projects;Population;Preparation;Procedures;Publications;Quality Control;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Schedule;Science;Series;Services;Source;System;Techniques;Tissue Model;Training;Training Support;Triage;Underserved Population;Universities;University of Southern California Norris Cancer Center;Work;anticancer research;cancer health disparity;computerized data processing;computing resources;data cleaning;data management;data repository;data sharing;design;drug development;education research;exome sequencing;experimental study;federated data;genomic data;health equity;high dimensionality;human data;innovation;lectures;meetings;member;mortality;novel;outreach;public database;single cell sequencing;software as a service;software development;transcriptome sequencing;web site Bioinformatics Statistical and Methodological Shared Resources Core n/a NCI 10762124 9/19/23 0:00 PAR-22-249 2U54CA233444-06 2 U54 CA 233444 6 9/17/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5650 8240680 "LEE, JI-HYUN " Not Applicable 3 Unavailable 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL Domestic Higher Education 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 83631 54840 28791 ABSTRACT BIOINFORMATICS STATISTICAL AND METHODOLOGICAL COREThe primary goal of the Bioinformatics Statistical and Methodological (BSM) Core at the Florida-CaliforniaCancer Research Education & Engagement (CaRE2) Health Equity Center is to provide the data managementdata cleaning data storage and data release to public databases for all information generated by our Center. Inaddition it will provide bioinformatics statistical and methodological support for all the cancer research projectsproposed as well as future projects that will build upon them and disseminate to all CaRE2 Center members andthe scientific community at large in a timely fashion. We will reach these goals through three aims: First we willprovide bioinformatics statistical and methodological support. This first aim established the job scheduling andinterfaces to meet the needs of all CaRE2 Health Equity Center investigators. We will support bioinformatics andstatistical issues across the projects and cores. Bioinformatics support will include in-depth quality control andassessment of all high-throughput sequencing data from multiple platforms and facilitate access to publiclyavailable datasets. Statistical and methodological support will consist of all aspects from collecting to state-of-the-art data analysis and interpretation and abstract manuscript and grant preparation. The second aim will beenhancing and maintaining a federated data repository resource that enables the interaction of CaRE2 members.This second aim ensures that all data are of high quality and disseminated to all CaRE2 Center members andthe scientific community promptly. In the third aim we will provide bioinformatics statistical and methodologicalsupport and educational opportunities to the CaRE2 Center. This third aim focuses on developing onlineeducational materials that BSMC's members and guest experts will present through the core events such asseminar series and interactive lectures among all CaRE2 Center members. +No NIH Category available Address;Awareness;Behavior;Biologic Characteristic;Cancer Burden;Cancer Center;Cancer health equity;Characteristics;Collaborations;Communication;Communities;Community Health Education;Community Outreach;Community Participation;Cuban;Early Diagnosis;Education and Outreach;Educational Activities;Educational Curriculum;Equity;Ethnic Population;Event;Evidence based program;Feedback;Florida;Genetic Counseling;Genetic Risk;Goals;Health;Health Disparities Research;Health Sciences;Hispanic;Individual;Knowledge;Latino;Latino Population;Malignant Neoplasms;Mexican;Participant;Patient Recruitments;Persons;Pilot Projects;Population;Prevention;Puerto Rican;Puerto Rico;Reporting;Research;Research Activity;Research Personnel;Research Priority;Research Project Grants;Research Support;Screening for cancer;Skin Cancer;Source;Training;Translational Research;Underserved Population;United States;Universities;Woman;Work;bilingualism;biobank;cancer education;cancer health disparity;cancer prevention;cancer risk;community based participatory research;community engagement;community organizations;ethnic minority population;evidence base;high risk;improved;interest;intervention refinement;member;outreach;preference;programs;promoter;racial minority population;recruit;research data dissemination;screening;social culture;success;telephone based;tool;training opportunity;virtual Outreach Core n/a NCI 10762086 9/19/23 0:00 PAR-22-249 2U54CA163068-11 2 U54 CA 163068 11 9/24/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5644 11289246 "CHRISTY, SHANNON MARIE" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 117452 69705 47747 ABSTRACT | OUTREACH COREThe Outreach Core (OC) of the Ponce Health Sciences University-Moffitt Cancer Center (PHSU-MCC)Partnership provides community outreach and education to improve cancer screening behaviors in underservedpopulations. Currently over 60 million persons identify as Hispanic/Latino (H/L) comprising almost 18% of thecontinental United States (US) population with an additional 3.1 million US citizens residing in Puerto Rico (PR).Despite unique socio-cultural and biological characteristics in sub-ethnic groups H/L populations tend to beviewed in aggregate. Mexicans Puerto Ricans and Cubans are the largest sub-ethnic groups among US H/Ls.Efforts to achieve equity require an approach rooted in the knowledge and incorporation of both thecharacteristics and preferences of the specific communities. Indeed one-third of H/Ls report that they obtain atleast some health information from community-based organizations. The overall goal of the OC is to increasecommunity cancer awareness community engagement and participation in cancer health disparities researchand outreach in H/L communities. Working closely with other Partnership cores and investigators the teamproposes to elevate and expand its activities to facilitate reciprocal communication between community membersand partnership researchers through OC educational activities training opportunities supporting participantrecruitment efforts and incorporation of the Community Advisory Panel (CAP) feedback on partnership researchprojects. Together with community members and Partnership researchers the OC will increase cancerawareness community engagement and participation in cancer health disparities research in the H/Lcommunities served by MCC (in FL) and PHSU (in PR) through the following three Specific Aims: 1) To developdeliver and disseminate cancer education and outreach activities to H/L community members to reduce cancerhealth disparities. The team will deliver cancer education to H/L communities in PR and FL using evidence-based programs through multiple delivery strategies and reflecting partnership research priorities and topics ofinterest identified by community members. 2) To enhance capacity for mutually beneficial research engagementto address cancer health disparities. The team will facilitate communication between community members andpartnership investigators (e.g. CAP Research Corner) support partnership research that is responsive tocommunity needs (translational research) promote community participation in the partnerships researchactivities/projects to reduce cancer health disparities and train researchers and community members incommunity engagement principles. 3) To expand the capacity to train community members as lay healthpromoters to deliver evidence-based cancer education programs in their communities. The team will traincommunity members and community partners/organizations to deliver evidence-based cancer education (e.g.Cancer 101 OC activities) in their local communities to address cancer health disparities. +No NIH Category available Accountability;Advanced Malignant Neoplasm;Advisory Committees;Area;Cancer Center;Cancer health equity;Collaborations;Collection;Communication;Community Outreach;Data;Development;Education and Outreach;Elements;Ensure;Evaluation;Evolution;Feedback;Florida;Funding;Goals;Grant;Growth;Health Sciences;Hispanic;Information Systems;Institution;Journals;Knowledge;Latino Population;Logic;Modeling;Monitor;National Cancer Institute;Online Systems;Outcome;Output;Process;Progress Reports;Publications;Puerto Rico;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Science;Strategic Planning;Structure;Surveys;Time;Universities;Update;Work;cancer health disparity;effectiveness evaluation;flexibility;improved;innovation;meetings;member;novel;programs;special interest group;success Planning and Evaluation Core n/a NCI 10762084 9/19/23 0:00 PAR-22-249 2U54CA163068-11 2 U54 CA 163068 11 9/24/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5642 7745732 "GWEDE, CLEMENT K." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 105988 62901 43087 ABSTRACT | PLANNING AND EVALUATION CORE (PEC)The Planning and Evaluation Core (PEC) of the Ponce Health Sciences University-Moffitt Cancer Center(PHSU-MCC) Partnership monitors and evaluates progress toward the implementation of the goals andobjectives of the Partnership across all areas including research education and community outreach. The PECserves as a central node for accountability and ensures that the Partnership is completing proposed aims andobjectives through its evaluative framework. The PEC evaluation processes allow for the Administrative Core(AC) to maximize resources identify novel directions for the Partnership and report the progress of Partnershipcores and investigators to institutional leaders and the National Cancer Institute (NCI). The PEC maintainsinternal and external advisory groups to support strategic planning monitoring and evaluation of Partnershipactivities by assessing the relationships between aims activities outputs and expected outcomes. The twoessential PEC advisory groups are the Internal Advisory Committee (IAC) and the Program Steering Committee(PSC). The IAC and PSC work closely together within the PEC to provide guidance and recommendations tothe AC. The PEC establishes Logic Models for each Partnership component and provides continual updating toreflect the new aims activities and evolution of the Partnership. The PEC in collaboration with the QuantitativeSciences Core (QSC) implemented the use of REDCap to track grants and publications (including journal impactfactors) submitted and obtained by the Partnership researchers to streamline tracking. The PEC is a member ofthe Partnerships to Advance Cancer Health Equity Evaluators Special Interest Group (PACHE SIG) which worksto identify common elements for the evaluation of PACHE programs at the national level. The PEC will build onprior successes with the necessary flexibility to adapt and respond to emerging challenges innovations anddevelopments. The specific aims of the PEC are: 1) Coordinate collection tracking and analysis of evaluationdata for Partnership components processes and activities. This provides the AC with critical data needed toinitiate terminate or modify new and ongoing initiatives to achieve the Partnership goals and objectives. ThePEC incorporates Logic Models web-based relational data systems for tracking outcomes and annualPartnership member surveys to monitor and evaluate the effectiveness of communications interactions andintegration between/across Partnership components at both institutions. 2) Conduct internal evaluations ofPartnership components through the activities of the IAC. The IAC will review quarterly progress reports for theCores and research projects and provide summative feedback. The IAC will also collaborate with the AC to solicitand evaluate new research projects. 3) Implement external evaluations of Partnership components through theactivities of the PSC and an external evaluation consultant. The PSC provides unbiased rigorous and expertevaluation of the progress of the Partnership annually and recommends improvements throughout the grantperiod via quarterly meetings with the AC. +No NIH Category available Address;Admixture;Area;Big Data;Bioinformatics;Biometry;Cancer Center;Cell Line;Collaborations;Communication;Consent;DNA;Data;Data Analyses;Data Collection;Data Scientist;Development;Disparity;Education;Ensure;Environment;Evaluation;Future;Genetic;Genome;Genomics;Grant;Health Disparities Research;Health Sciences;Hispanic;Hispanic-serving Institution;Improve Access;Informatics;Infrastructure;Institution;Latino;Latino Population;Lead;Life Cycle Stages;Molecular;Molecular Profiling;Oncology;Online Systems;Participant;Phase;Physicians;Proteomics;Puerto Rico;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Sample Size;Sampling;Science;Services;Students;System;The Cancer Genome Atlas;Tissues;Training;Translations;Universities;Vision;Visualization software;analytical tool;ancestry analysis;biobank;cancer health disparity;cohort;data integration;data management;design;education research;experience;genomic data;high dimensionality;improved;infrastructure development;innovation;member;novel;online resource;precision medicine;research study;skills;software infrastructure;statistics;synergism;tool;transcriptome sequencing Shared Resource Core: Quantitative Sciences Core n/a NCI 10762080 9/19/23 0:00 PAR-22-249 2U54CA163068-11 2 U54 CA 163068 11 9/24/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5638 8696935 "ESCHRICH, STEVEN ALLEN" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 182034 108032 74002 ABSTRACT | QUANTITATIVE SCIENCES COREThe Quantitative Sciences Core (QSC) of the Ponce Health Sciences University-Moffitt Cancer Center (PHSU-MCC) Partnership provides resources and expertise for generating managing and analyzing big data. It is thefocal point for expertise in quantitative approaches to address the underrepresentation of Hispanic/Latino (H/L)populations in omics studies and to incorporate ancestry analysis in Partnership research approaches. Byjoining PHSU's expertise in genetic ancestry with the MCC bioinformatics team the QSC combines a unique setof skills required to address the molecular components of cancer disparities in admixed H/L populations. TheQSC provides expertise in bioinformatics biostatistics and informatics and participates in every phase of theresearch life cycle. The QSC supports data provisioning study design analysis plans and power estimates todemonstrate the feasibility and improve rigor and reproducibility in all Partnership research projects and grantsubmissions. In addition the QSC contributes to the dissemination of high-throughput molecular data bydeveloping web-based visualization tools. As a central resource for research projects the QSC also facilitatescollaboration thereby leveraging the data gathered by the Partnership investigators. The QSC analyzed the firstH/L genomic data generated in collaboration with the Puerto Rico BioBank (PRBB)/Oncology ResearchInformation Exchange Network (ORIEN) Avatar and implemented the H/L Bioportal (GLOBAL) a web-basedresource. The QSC develops tools for visualizing and interpreting data pipelines to estimate genetic ancestryand has built expertise in genomics bioinformatics at the Hispanic-Serving Institution (HSI) including hiringtraining and the acquisition of computing and storage infrastructure. The Specific Aims of the QSC will be: 1)Provide research project support for biostatistics and bioinformatics from study design endpoint definitionsample size estimation power calculation and data analysis. Regular interactions between lead data scientistsand project members will allow for the continuing development of novel analytic tools to address emergingquestions aligned with the Partnerships needs. 2) Provide data integration and management services forPartnership projects and cores. Projects needing tissue/data collection systems will leverage the existingsoftware infrastructure from PRBB Biospecimen Management System (BMS). The QSC/PRBB Data Conciergeprovisions data and linkages from these systems. Other supported services include the H/L Bioportal EstimatedCell Line Ancestry (ECLA) tool and the Partnership Continuous Quality Improvement System for the Planning& Evaluation Core. 3) Provide quantitative sciences expertise in support of the Partnership. The QSC aims todevelop expertise in statistics at the HSI; characterize publicly available molecular signatures in Partnershipcohorts; develop analytics for PRBB optimization of consent and participant communications; expand the omicsexperience for students (collaboration with the Research Education Core) and enhance the use of ancestry inquantitative studies. +No NIH Category available Acceleration;Address;Awareness;Blood;Breast;Breast Cancer Genetics;Cancer Center;Caribbean region;Clinical;Clinical Data;Clinical Trials;Collaborations;Colon;Colorectal Cancer;Communities;Community Health;Community Health Education;Community Outreach;Consent;DNA;Data;Data Set;Databases;Dedications;Demographic Survey;Development;Education;Education and Outreach;Funding;Future;Genetic;Genome;Grant;Gynecologist;Health Disparities Research;Health Educators;Health Sciences;Historical Survey;Hospitals;Individual;International;Island;Latin America;Latin American;Latino;Logistics;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Medical Students;Minority Participation;Molecular;Molecular Profiling;Oncologist;Organoids;Ovarian;Patient Education;Patient Recruitments;Patient Selection;Patients;Physicians;Physicians' Offices;Play;Population;Prevalence;Principal Investigator;Process;Prostate;Publications;Puerto Rican;Puerto Rico;RNA;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Science;Services;Specimen;Surgeon;System;Techniques;Tissue Donations;Tissue Microarray;Tissues;Training;Translation Initiation;Underrepresented Minority;Universities;Urologist;anticancer research;biobank;breast cancer genomics;cancer diagnosis;cancer health disparity;cancer therapy;cancer type;data registry;education research;health disparity;improved;innovation;malignant breast neoplasm;medical schools;molecular phenotype;neoplasm registry;novel;outreach;patient derived xenograft model;precision medicine;recruit;targeted treatment;transcriptome sequencing;translational cancer research Shared Resource Core: Puerto Rico BioBank n/a NCI 10762079 9/19/23 0:00 PAR-22-249 2U54CA163068-11 2 U54 CA 163068 11 9/24/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5637 1896485 "CRESS, WILLIAM DOUGLAS" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 227999 135311 92688 ABSTRACT | PUERTO RICO BIOBANKThe Puerto Rico BioBank (PRBB) Shared Resource of the Ponce Health Sciences University-Moffitt CancerCenter (PHSU-MCC) Partnership collects processes annotates stores and distributes biospecimens andclinical-demographic data for investigator-initiated translational cancer research. As of August 2022 the PRBBhas consented 4097 subjects representing 42 different cancer types and healthy individuals. From thesesubjects 1899 clinical history and demographic surveys were completed and 8453 biospecimens werecollected. Tissues derivative analytes (e.g. DNA/RNA) data and tissue microarrays have been distributed toresearch projects supporting publications and grant submissions. The PRBB contributed to the development ofa Biobanking clerkship for medical students in collaboration with the Research Education Core (REC) andcontributed to education efforts in H/L communities in both Tampa and Ponce in collaboration with the OutreachCore (OC). Together with the Quantitative Sciences Core (QSC) the PRBB has consented 142 H/L patients tothe ORIEN-Avatar network (https://www.oriencancer.org) improving the representation of H/L tissues in thisnetwork dedicated to accelerating the discovery of novel targeted cancer treatments that is currently only 7.2%.The PRBB participates in international consortia including REBLAC (Latin American and Caribbean Biobankingnetwork) PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in theGenome) LAGENO-BC (Latin America Genomics of Breast Cancer Consortium) the Latino Colorectal CancerConsortium (LC3) the Confluence Project for Breast Cancer Genetics. The objective of the PRBB is to addressthe critical unmet need in cancer health disparities of a lack of representation of H/L patients in comprehensivemolecular datasets at levels that align with the prevalence of cancer in this population. The aims are: 1) Supportresearch projects by targeted recruitment of patients of selected cancer types along with non-cancer controls.Recruitment is both broad to build a comprehensive database for future projects and focused on the currentlyproposed full research projects in prostate and ovarian cancer. We will continue to optimize the logistics of patienteducation and consenting at collaborating physicians offices and San Lucas Hospital (SLH) and by maintainingconstant contact with Project PIs. 2) Support research by developing innovative resources and services. We willfocus on developing new research resources and services that can be rapidly accessed by researchers. Thisincludes building well-annotated tissue microarrays representing cancer types that significantly impact H/Ls(prostate ovarian) expanding molecular phenotyping (exomeSeq RNAseq ancestry) in collaboration withORIEN tapping into the potential for identifying clinical trials that are matched to a patients molecular profileand leverage our emerging expertise in organoid and patient-derived xenografts models to support projects. 3)Collaborate with partnership components in education outreach and community education on the importanceof tissue donation and improving data availability with the QSC. +No NIH Category available Address;Adherence;Affect;African American;American;Atlases;Awareness;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer cell line;Breast Cancer therapy;CDK4 gene;Cancer Etiology;Cessation of life;Clinical;Code;Computer Models;Data;Databases;Death Rate;Decision Making;Disparity;Documentation;Drug resistance pathway;Early Diagnosis;Education;Electronic Health Record;Environmental Risk Factor;Epidermal Growth Factor Receptor;Epigenetic Process;Ethnic Origin;European;FAT gene;Female Breast Carcinoma;Financial Hardship;Frequencies;Genes;Genetic;Genetic Predisposition to Disease;Genetic Variation;Genomics;Head and Neck Cancer;Hispanic;Hispanic Populations;Human;In Vitro;Interview;Malignant Neoplasms;Messenger RNA;Metastatic breast cancer;Mutation;Not Hispanic or Latino;Oral;Outcome;Patients;Pattern;Pharmaceutical Preparations;Population;Population Study;Prevalence;Progression-Free Survivals;Quality of life;RB1 gene;Race;Resistance;Resistance development;Social support;Surveys;Testing;The Cancer Genome Atlas;Treatment outcome;United States;Variant;Woman;anticancer research;cancer genomics;design;differential expression;genomic data;hormone receptor-positive;hormone therapy;improved;individual patient;information gathering;inhibitor;inhibitor therapy;mRNA Expression;malignant breast neoplasm;markov model;medication compliance;mortality;novel therapeutic intervention;outcome disparities;patient population;racial disparity;resistance mechanism;screening;side effect;social determinants;social health determinants;statistics;targeted treatment;therapy resistant;treatment site;tumor;verbal Impact of race and ethnicity on outcomes in patients with hormone receptor-positive breast cancer treated with CDK4/6 inhibitors Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have recently emerged as a new treatment strategy forhormone receptor (ER/PR) positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative(HR+/Her2-) subtype ofbreast cancer (BC) patients. Recent studies suggest that their benefit may be restrictedonly to non-HispanicEuropean American (EA) BC patients without significant improvement inAfrican American(AA) or Hispanics patients. Using patient interviews computational modeling and functional studies this projectwill analyze thesocial determinants and genetic aspects contributing to CDK4/6i therapy resistance in AA BCpatients. NCI 10762047 9/21/23 0:00 PAR-22-239 1P20CA284967-01 1 P20 CA 284967 1 9/21/23 0:00 8/31/25 0:00 ZCA1-SRB-2(A1) 5623 78943867 "HUNTER, RODNEY " Not Applicable 18 Unavailable 50298975 HYYJJ5ZP7CR9 50298975 HYYJJ5ZP7CR9 US 29.724646 -95.362731 8280201 TEXAS SOUTHERN UNIVERSITY HOUSTON TX Domestic Higher Education 770044501 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 38075 25000 13075 Breast cancer (BC) is the most common cancer in women worldwide and is the second leading cause of cancerdeath in women. However the advances in outcomes of BC patients have been limited to a subset of the affectedpopulation namely European American (EA) women compared to their African American (AA) womencounterparts. Despite various hormone therapies the hormone receptor (ER/PR) positive (HR+) humanepidermal growth factor receptor 2 (HER2)-negative (HR+/Her2-) subtype of BC remains difficult to treat. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have recently emerged as a new treatment strategy.Interestinglya 2022 population-based study confirmed that while the outcomes for HR+/Her2- metastatic BC have improvedsince CDK4/6i were introduced in 2015 this effect is primarily driven by the improved overall survival (OS) innon-Hispanic EApatients without significant improvement in AA or Hispanics patients.The relative contributionof genetic factors vs. medication adherence or social determinants of health (SDOH) on such outcomes is lessunderstood. Recent efforts to address this gap include databases such as All of Us designed to betterunderstand the interplay between genetic factors and social determinants. From a functional point ourpreliminary analysis ofThe Cancer Genomic Atlas (TCGA) data shows decreased mRNA expression of FAT1FAT4 and RB1 the major genes involved in resistance to CDK4/6i in AA compared to EA HR+/Her2- BC.Thusthis project will do preliminary analysis of two aspects of BC therapy resistance in AA BC patients. Aim-1 of thisproject will assess the impact of medication adherence and various social determinants on clinical outcomes offemale BC patients treated with CDK4/6i. Aim-2 will analyze the impact of genetic variations and low expressionof FAT1 FAT4 and RB1 genes on the development of resistance to CDK4/6i in AA women with BC. We will usesurveys verbal medication review and EHR documentation of medication possession to gather informationrelated to medication adherence and social determinants that may impact compliance. We will also analyze theprevalence of germline and somatic variations and epigenetic status of FAT1 FAT4 and RB1 genes in BCpatients of EA and non-EA ancestry. Using computational modeling we will predict the functional networking ofFAT1 FAT4 and RB1 low expression in AA BC patients. Using established databases clinical informationobtained from the electronic health record (EHR) and surveys exploring SDOH and medication adherencepatterns this pilot aims to generate preliminary data exploring the impact of these factors on treatment outcomesin AA vs. EA patients receiving oral targeted therapy including CDK4/6i. Discovery of AA-centric geneticvariations and the impact of low expressed FAT1 FAT4 and RB1 genes in the functional networking will becritical in pre-selecting AA BC patients that may benefit from CDK4/6i therapy. +No NIH Category available Address;Advanced Malignant Neoplasm;Advisory Committees;Annual Reports;Area;Budgets;Career Choice;Catchment Area;Clinical Research;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Disparity;Disputes;Education;Education and Outreach;Educational Activities;Educational Curriculum;Ensure;Ethics;Evaluation;Faculty;Funding;Goals;Grant;Guidelines;Health Disparities Research;Historically Black Colleges and Universities;Human Resources;Infrastructure;Institution;Leadership;Malignant Neoplasms;Medical center;Medicine;Minority Groups;National Cancer Institute;Pharmacology;Pilot Projects;Policies;Productivity;Recommendation;Reporting;Research;Research Activity;Research Personnel;Research Support;Resources;Scientist;Structure;Students;Texas;Training;Underrepresented Minority;Underserved Population;United States National Institutes of Health;Universities;Veronica;Work;anticancer research;cancer care;cancer education;cancer health disparity;college;data management;data sharing;education research;empowerment;equity diversity and inclusion;experience;health disparity;innovation;meetings;member;outreach;programs;recruit;synergism BCM/TSU P20 Collaborative Union for Cancer Research Education and Disparities (CURED) Administrative Core (AC) NARRATIVE CURED Administrative CoreThe goal of the Administrative Core in the BCM-TSU P20 Collaborative Union for CancerResearch Education and Disparities (BCM-TSU P20 CURED) program will be to ensurecontinuity of the strong and productive ongoing partnership between BCM and TSU enhancecancer research and education capacity at both BCM and TSU while promoting the diversity ofthe cancer research workforce. The CURED proposes to not only provide integratedadministrative support promote recruitment and increase diversity but also provide scientificoversight and promote sustainable collaborations in the areas of research education andcommunity outreach. NCI 10762046 9/21/23 0:00 PAR-22-239 1P20CA284967-01 1 P20 CA 284967 1 9/21/23 0:00 8/31/27 0:00 ZCA1-SRB-2(A1) 5622 15897276 "AJEWOLE, VERONICA B" Not Applicable 18 Unavailable 50298975 HYYJJ5ZP7CR9 50298975 HYYJJ5ZP7CR9 US 29.724646 -95.362731 8280201 TEXAS SOUTHERN UNIVERSITY HOUSTON TX Domestic Higher Education 770044501 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 Research Centers 2023 95188 62500 32688 ABSTRACT CURED Administrative CoreAdministrative Core of the proposed BCM-TSU P20 CURED program will serve as a primary administrative unitthat oversees the collaborative research education and associated outreach efforts between the two institutions.The goal of Administrative Core is to ensure continuity of the strong and productive ongoing partnership betweenBCM and TSU to enhance cancer research and education capacity at both BCM and TSU while promoting thediversity of the cancer research workforce. This is to be accomplished through activities such as administrativeoversight operational support communications as well as regulatory and financial oversight. The two objectivesof Administrative Core are: (1) To provide integrated administrative support promote recruitment and increasediversity: The pilot projects and cores will benefit from centralized activities regarding budgetary activity includingdispensing monies overseeing budgets generating interim and final financial reports and resolving disputes. Inaddition the administrative core with input from the IAC will use the discretionary funds it receives each year tosupport new pilot projects in both institutions. It will collaborate with the Education core (C-REP) to promotesustainable cancer research and education capacity in P20 program. It will also facilitate C-REP to developsystematic curriculum and educational research programs between the institutions. It will conduct planning andevaluation of the P20 partnership ensure the partnership follows NIH policies and guidelines and submit theannual financial and scientific reports to the IAC EAC and NIH. (2) To provide scientific oversight and promotecollaborations: The core will provide scientific oversight by arranging internal meetings of investigatorsassessing research progress and providing project management support to ensure that milestones areaccomplished in a timely manner. It will also coordinate internal and external advisory committee meetings andimplement the recommendations received. It will ensure frequent interactions and promote collaborationsbetween members of both the institutions by conducting regular seminars and monthly meetings. It will work withinstitutional leaders to promote recruitment of new workforce to ensure diversity equity and inclusion (DEI). Weexpect this BCU-TSU P20 CURED program will evolve to be a highly collaborative systematic and sustainablepartnership between the two institutions that synergizes strengths of faculty and students in cancer researcheducation and community outreach. +No NIH Category available Address;Advisory Committees;African American;Area;Cancer Center;Career Choice;Collaborations;Communities;Community Health Education;Community Outreach;Comprehensive Cancer Center;Cost Allocation;Data;Degree program;Development;Disparity;Education;Education and Outreach;Educational Curriculum;Effectiveness;Emerging Technologies;Ensure;Environment;Evaluation;Exposure to;Facilities and Administrative Costs;Faculty;Fostering;Funding;Funding Agency;Goals;Health Disparities Research;Historically Black Colleges and Universities;Infrastructure;Institution;Joints;Lead;Leadership;Malignant Neoplasms;Medical center;Medicine;Mentors;Minority Health Research;National Cancer Institute;Pilot Projects;Prevention;Process;Program Development;Research;Research Peer Review;Research Personnel;Resources;Schools;Science;Students;Texas;Training;Training Support;Underrepresented Students;Underserved Population;United States National Institutes of Health;Universities;anticancer research;cancer education;cancer health disparity;career;career development;college;cost;design;education research;empowerment;ethnic diversity;experience;graduate student;higher education;improved;innovation;member;outreach;outreach program;programs;research and development;summer student;undergraduate student;university student 2/2 Collaborative Union for Cancer Research Education and Disparities (CURED) CURED OVERALL: Project NarrativeThe BCM-TSU P20 Collaborative Union for Cancer Research Education and Disparities (CURED) Proposalwill establish a formal collaborative alliance between BCM and TSU for cancer research education andcommunity outreach. Our multipronged approach will maximize the strengths of each institution and leverageexisting collaborative relationships to create a shared infrastructure between BCM and TSU that will provide anoptimal environment for cancer research education community outreach and opportunities for careerdevelopment and pathway enhancement focused on diversifying the biomedical workforce. BCM-TSU P20CURED will also develop sustainable research capacity and obtain preliminary data through pilot projects thatwill develop into independent investigator research applications and collaborative applications to the NIH/NCIand/or other Federal/Non-federal funding agencies. NCI 10762045 9/21/23 0:00 PAR-22-239 1P20CA284967-01 1 P20 CA 284967 1 "RODRIGUEZ, LARITZA MARIA" 9/21/23 0:00 8/31/27 0:00 ZCA1-SRB-2(A1) 15897276 "AJEWOLE, VERONICA B" "ROUCE, RAYNE HELEN" 18 OTHER HEALTH PROFESSIONS 50298975 HYYJJ5ZP7CR9 50298975 HYYJJ5ZP7CR9 US 29.724646 -95.362731 8280201 TEXAS SOUTHERN UNIVERSITY HOUSTON TX SCH ALLIED HEALTH PROFESSIONS 770044501 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 397 Research Centers 2023 285563 NCI 187500 98063 CURED Overall AbstractDan L Duncan Comprehensive Cancer Center (DLDCCC) at Baylor College of Medicine (BCM) and TexasSouthern University (TSU) are jointly submitting a P20 application to build a collaborative partnership in cancerresearch education and outreach. DLDCCC is a National Cancer Institute (NCI) designated cancer center. TSUis one of the nations largest Historically Black Colleges and Universities (HBCU) serving underservedpopulations and underrepresented students (ISUPSs). BCM and TSU have had several successfulcollaborations. This relationship was strengthened recently through TSUs U54 Center for Biomedical andMinority Health Research where BCM faculty have partnered closely on collaborative cancer disparitiescommunity education and outreach. This P20 program provides an excellent opportunity for TSU and BCM toexpand collaborations. We propose a BCM-TSU P20 program Collaborative Union for Cancer ResearchEducation and Disparities (CURED) that will foster strong collaborations utilizing our complementary strengths.Overall objectives are to create a shared infrastructure that will provide an optimal environment for cancerresearch education community outreach and career development and diversify the biomedical workforce.CURED was established under the direction of senior leadership at each institution reflected in the significantinstitutional support for this partnership. BCM has committed $160000/year for four years in cost matching funds$ 50000 for Pilot project 2 for one year and committed funds to support the training of TSU summer studentsin the Cancer Research Education Program. TSU has committed to return the Indirect Cost allocation amountingto $98000 each year. All TSU investigators are members of the DLDCCC. Leaders of each institution are thuscommitted to empower the P20 partnership to address cancer health disparities among URM and underservedpopulations in Houston. Our goals are to (1) establish a collaborative alliance between BCM and TSU for cancerresearch education and community outreach. We will (a) establish CURED offices in both institutions that willprovide coordination for relevant activities evaluate progress of current projects and ensure a pipeline ofinnovative pilot projects; (b) centralize institutional resources for faculty/trainee research needs (c) lead a cancerresearch and career development program for TSU students that includes mentored cancer research aneducational curriculum hands-on training in emerging technologies and professional development; (d) build aBCM/TSU comprehensive outreach program to address cancer disparities at the bench bedside and within thecommunity; and (2) to support a pipeline of collaborative innovative cancer research pilot projects.Overall Impact: We are certain that the proposed CURED will enhance cancer research education capacity atTSU promote a diverse research workforce and improve BCM/DLDCCCs effectiveness in developing andsustaining research programs focused on cancer health disparities. We will develop sustainable researchcapacity leading to independent and collaborative applications to the NIH/other Federal/Non-federal agencies. 285563 +No NIH Category available Acceleration;Acquired Immunodeficiency Syndrome;Address;B lymphoid malignancy;B-Cell Lymphomas;Binding;Biology;Cell Line;Cell Survival;Cells;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;DNA biosynthesis;Data;Epigenetic Process;Gene Expression;Gene Silencing;Genes;Genetic Transcription;Genome;Goals;HIV/AIDS;Hand;Human Herpesvirus 8;Kaposi Sarcoma;Left;Length;Life Cycle Stages;Lymphoma;Lymphoma cell;Lytic;Lytic Phase;Maintenance;Malignant Neoplasms;Modeling;Mutation;Oncogenic;Patients;Proliferating;Proteins;Public Health;RNA;RNA replication;Replication Origin;Research;Role;Site;Transcript;Untranslated RNA;Viral;Viral Genes;Viral Genome;Virus;Virus Latency;Work;histone modification;knock-down;latent gene expression;lytic replication;neoplastic cell;primary effusion lymphoma;programs;reactivation from latency;recruit;transcriptome;transcriptome sequencing;tumor;viral DNA Role of a latent OriLyt RNA in KSHV latency in primary effusion lymphoma Project NarrativeThe proposed research is relevant to public health because it focuses on defining mechanisms of how theKaposi's sarcoma-associated herpesvirus (KSHV) maintains latency in tumor cells. Because latency control isfundamental to the viral life cycle our research significantly impacts studies in AIDS-defining malignanciescaused by KSHV including primary effusion lymphoma. NCI 10761865 8/1/23 0:00 PA-20-195 1R21CA285135-01 1 R21 CA 285135 1 "READ-CONNOLE, ELIZABETH LEE" 8/1/23 0:00 7/31/25 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 11738429 "MANZANO, MARK " Not Applicable 2 MICROBIOLOGY/IMMUN/VIROLOGY 122452563 VDFYLZPJEAV6 122452563 VDFYLZPJEAV6 US 34.749005 -92.320097 1471106 UNIV OF ARKANSAS FOR MED SCIS LITTLE ROCK AR SCHOOLS OF MEDICINE 722057101 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 214583 NCI 140250 74333 Project SummaryThe Kaposi's sarcoma-associated herpesvirus (KSHV) causes the AIDS-defining B cell malignancy primaryeffusion lymphoma (PEL). KSHV is found in all tumor cells and is tightly latent in >95% of infected cells. Latencyis an intricately organized program that highly restricts gene expression to a handful of genes (i.e. latency genes).PEL cell lines require these latency genes to be constitutively expressed while the lytic genes are silenced forsurvival. Thus both expression of the latency genes and maintenance of the latency program are critical for PELcells. However the contributions of most viral genes to the survival and proliferation of PEL-derived cell linesare unknown. Our long-term goal is to accelerate our understanding of the biology of this AIDS-defininglymphoma by comprehensively analyzing viral factors required for PEL tumor cell survival. We thereforeperformed an RNA-targeting CRISPR/CasRx tiled screen to identify KSHV transcripts required for the survivalof PEL cells. Our results reveal that the left-hand origin of lytic replication (OriLytL) encodes a previouslyunannotated RNA critical for the survival of PEL cell lines. The OriLytL serves as one of two initiation sites crucialfor viral DNA replication during reactivation from latency. In this lytic phase the OriLytL produces two longnoncoding RNAs required for lytic viral DNA replication. However our data suggest that the latency-specificOriLytL (OriLytLlat) RNA is distinct and functions differently from the lytic OriLytL RNAs. Our central hypothesisis that the OriLytLlat RNA acts to maintain the latency program. Since latency is crucial for the survival of tumorcells the OriLytLlat RNA is a critical oncogenic driver of KSHV-associated cancers. The over-all objective is tocharacterize this latency-specific OriLytLlat RNA and determine its role in latency maintenance in PEL. In Aim 1we will characterize the latent viral transcriptome including the full-length OriLytLlat RNA using long-read RNAsequencing. In Aim 2 we will define the role of the OriLytLlat RNA in the recruitment of chromatin binding factorsand resulting epigenetic changes in the viral genome that contribute to establish and maintain the latencyprogram. Together this work will provide a new model on how viral latency is influenced by a latent RNA fromthe lytic origin of replication. Importantly our studies will also shed light on the biology of other KSHV-associatedmalignancies including Kaposis sarcoma. 214583 +No NIH Category available ABL1 gene;Acute Myelocytic Leukemia;Address;Affinity;Alleles;Allosteric Site;American;Binding;Binding Sites;Biochemical;Biophysics;Blast Phase;Bypass;Cessation of life;Chronic Myeloid Leukemia;Chronic-Phase Myeloid Leukemia;Clinical;Clinical Trials;Communication;Complex;Crystallography;Dasatinib;Dependence;Distant;Dose;Enzyme Inhibition;Event;Exhibits;FDA approved;Foundations;Gatekeeping;Imatinib;Knowledge;Laboratory Study;Leukemic Cell;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medicine;Methods;Molecular Conformation;Mutation;Non-Small-Cell Lung Carcinoma;Patient-Focused Outcomes;Patients;Ph+ ALL;Pharmaceutical Preparations;Philadelphia Chromosome;Philadelphia Chromosome Positive Chronic Myelogenous Leukemia;Phosphotransferases;Physiological;Prevalence;Probability;Protac;Proto-Oncogene Proteins c-abl;Protocols documentation;Rationalization;Recurrent disease;Refractory;Regulatory Element;Reporting;Residual state;Resistance;Sampling;Signal Transduction;Site;Site-Directed Mutagenesis;System;Technology;Testing;Therapeutic;Treatment Failure;Tyrosine Kinase Inhibitor;Work;Xenograft procedure;clinical development;effective therapy;improved;inhibitor;leukemia;melanoma;mouse model;mutant;novel therapeutic intervention;optimal treatments;research clinical testing;resistance mechanism;resistance mutation;targeted treatment Strategies to target BCR-ABL1 compound mutants in CML and Ph+ ALL PROJECT NARRATIVEIn patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemiaemergence of BCR-ABL1 compound mutations (two mutations in the same BCR-ABL1 molecule) confers high-level clinical resistance to tyrosine kinase inhibitors (TKIs) and leads to disease relapse. Currently these patientslack any suitable treatment options defining an unmet medical need. Our work will mechanistically define threecomplementary approaches for controlling BCR-ABL1 compound mutation-based TKI resistance and use thisknowledge to develop rational strategies to improve patient outcomes. NCI 10761798 12/29/23 0:00 PA-19-056 5R01CA257602-04 5 R01 CA 257602 4 "O'HAYRE, MORGAN" 11/10/21 0:00 12/31/25 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 8093590 "DEININGER, MICHAEL W." Not Applicable 4 Unavailable 57163172 JZDRNT166LE4 57163172 JZDRNT166LE4 US 43.037892 -87.935338 5304801 "VERSITI WISCONSIN, INC." MILWAUKEE WI Research Institutes 532332121 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 339694 NCI 205875 133819 Abstract: Philadelphia chromosome-positive (Ph+) leukemia is caused by BCR-ABL1 a constitutively activefusion kinase. Tyrosine kinase inhibitors (TKIs) targeting the ATP site of BCR-ABL1 are effective in treatingchronic-phase chronic myeloid leukemia (CP-CML) yet minimally effective at treating blast-phase CML and Ph+acute lymphoblastic leukemia. In the 20 years since the approval of the first TKI in all of medicine imatinib TKIshave dramatically improved survival of patients with CP-CML resulting in a projected increase of CMLprevalence from 70000 Americans in 2010 to 180000 in 2050. Despite this progress TKI-resistant CML remainsa challenge with >1000 deaths annually in the U.S. At least 50% of TKI treatment failure arises throughmutations in BCR-ABL1. Laboratory studies on the five FDA-approved BCR-ABL1 TKIs have established theirmutational profiles against the >30 mutations observed in patients. In aggregate these TKIs cover the clinicalspectrum of BCR-ABL1 single point mutants. Ponatinib is the only TKI that is clinically effective against the T315Igatekeeper mutant. However BCR-ABL1 compound mutants defined as 2 mutations in the same BCR-ABL1allele that include T315I with any second mutation are resistant to all approved TKIs including ponatinib leavingthese patients with no further treatment options. Asciminib is the first inhibitor in clinical development that bindsthe BCR-ABL1 myristoyl site an allosteric site distant from the ATP site to enforce an autoinhibited inactiveconformation. We established that asciminib like ponatinib is not effective against T315I-inclusive compoundmutants yet combining ponatinib (but not nilotinib or dasatinib) with asciminib is extremely effective at inhibitingmany T315I-inclusive compound mutant forms of BCR-ABL1. This discovery provides the basis for a noveltherapeutic strategy to address an entirely unmet medical need and is the foundation of this proposal. In Aim 1we will use computational biophysical and crystallographic methods to decipher how ponatinib re-sensitizescompound mutant BCR-ABL1 to asciminib. We will test the combination in relevant mouse models and in primaryleukemia samples. In Aim 2A we will develop a therapeutic strategy for clinically resistant BCR-ABL1 compoundmutants that are not inhibited by the combination of ponatinib with asciminib. Instead we will target these mutantsfor proteasomal degradation using an asciminib proteolysis targeting chimera (PROTAC) strategy. Unlike TKIsPROTACs are effective even upon transient or weak binding. We will test the hypothesis that ponatinib-inducedstabilization of the myristoyl site is the initiating event that allows subsequent binding of an asciminib-PROTACand proteasomal degradation of compound mutant BCR-ABL1. In Aim 2B we will develop a ponatinib-PROTACstrategy for compound mutants carrying a myristoyl site resistance mutation. Our work will provide a rationalefor clinical evaluation of ponatinib combined with asciminib as a therapy for currently untreatable BCR-ABL1compound mutant leukemia. Compound mutations are also a major cause of resistance in acute myeloidleukemia melanoma and lung cancer and our study will provide a blueprint for treating these malignancies. 339694 +No NIH Category available Address;Awareness;Behavior;Biologic Characteristic;Cancer Burden;Cancer Center;Cancer health equity;Characteristics;Collaborations;Communication;Communities;Community Health Education;Community Outreach;Community Participation;Cuban;Early Diagnosis;Education and Outreach;Educational Activities;Educational Curriculum;Equity;Ethnic Population;Event;Evidence based program;Feedback;Florida;Genetic Counseling;Genetic Risk;Goals;Health;Health Disparities Research;Health Sciences;Hispanic;Individual;Knowledge;Latino;Latino Population;Malignant Neoplasms;Mexican;Participant;Patient Recruitments;Persons;Pilot Projects;Population;Prevention;Puerto Rican;Puerto Rico;Reporting;Research;Research Activity;Research Personnel;Research Priority;Research Project Grants;Research Support;Screening for cancer;Skin Cancer;Source;Training;Translational Research;Underserved Population;United States;Universities;Woman;Work;bilingualism;biobank;cancer education;cancer health disparity;cancer prevention;cancer risk;community based participatory research;community engagement;community organizations;ethnic minority population;evidence base;high risk;improved;interest;intervention refinement;member;outreach;preference;programs;promoter;racial minority population;recruit;research data dissemination;screening;social culture;success;telephone based;tool;training opportunity;virtual Outreach Core n/a NCI 10761659 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5532 9609318 "JIMENEZ CHAVEZ, JULIO CESAR" Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144604 92222 52382 ABSTRACT | OUTREACH COREThe Outreach Core (OC) of the Ponce Health Sciences University-Moffitt Cancer Center (PHSU-MCC)Partnership provides community outreach and education to improve cancer screening behaviors in underservedpopulations. Currently over 60 million persons identify as Hispanic/Latino (H/L) comprising almost 18% of thecontinental United States (US) population with an additional 3.1 million US citizens residing in Puerto Rico (PR).Despite unique socio-cultural and biological characteristics in sub-ethnic groups H/L populations tend to beviewed in aggregate. Mexicans Puerto Ricans and Cubans are the largest sub-ethnic groups among US H/Ls.Efforts to achieve equity require an approach rooted in the knowledge and incorporation of both thecharacteristics and preferences of the specific communities. Indeed one-third of H/Ls report that they obtain atleast some health information from community-based organizations. The overall goal of the OC is to increasecommunity cancer awareness community engagement and participation in cancer health disparities researchand outreach in H/L communities. Working closely with other Partnership cores and investigators the teamproposes to elevate and expand its activities to facilitate reciprocal communication between community membersand partnership researchers through OC educational activities training opportunities supporting participantrecruitment efforts and incorporation of the Community Advisory Panel (CAP) feedback on partnership researchprojects. Together with community members and Partnership researchers the OC will increase cancerawareness community engagement and participation in cancer health disparities research in the H/Lcommunities served by MCC (in FL) and PHSU (in PR) through the following three Specific Aims: 1) To developdeliver and disseminate cancer education and outreach activities to H/L community members to reduce cancerhealth disparities. The team will deliver cancer education to H/L communities in PR and FL using evidence-based programs through multiple delivery strategies and reflecting partnership research priorities and topics ofinterest identified by community members. 2) To enhance capacity for mutually beneficial research engagementto address cancer health disparities. The team will facilitate communication between community members andpartnership investigators (e.g. CAP Research Corner) support partnership research that is responsive tocommunity needs (translational research) promote community participation in the partnerships researchactivities/projects to reduce cancer health disparities and train researchers and community members incommunity engagement principles. 3) To expand the capacity to train community members as lay healthpromoters to deliver evidence-based cancer education programs in their communities. The team will traincommunity members and community partners/organizations to deliver evidence-based cancer education (e.g.Cancer 101 OC activities) in their local communities to address cancer health disparities. +No NIH Category available Address;American Society of Clinical Oncology;Basic Cancer Research;Biometry;Bone Marrow Transplantation;Cancer Center;Career Choice;Career Mobility;Caring;Clinical;Clinical Oncology;Clinical Trials;Communities;Development;Diagnosis;Doctor of Philosophy;Education;Educational workshop;Effectiveness;Evaluation;Exposure to;Faculty;Feedback;Fellowship Program;Florida;Goals;Grant;Health Disparities Research;Health Sciences;Hematology;Hispanic;Immersion;Industry;Interest Group;Island;Latino;Latino Population;Malignant Neoplasms;Medical;Medical Students;Mentors;Mentorship;Needs Assessment;Oncologist;Oncology;Operative Surgical Procedures;Outcome;Participant;Population;Positioning Attribute;Postdoctoral Fellow;Prevention;Puerto Rican;Puerto Rico;Research;Research Personnel;Residencies;Rotation;Scholarship;Science Technology Engineering and Mathematics;Scientist;Series;Site;Students;Surgical Oncology;Training;Universities;Urology;Vision;Writing;anticancer research;cancer clinical trial;cancer health disparity;cancer therapy;career;career development;clinical practice;clinical training;cultural competence;design;doctoral student;education research;experience;faculty mentor;graduate school;health disparity;improved;interest;investigator training;minority health;patient engagement;peer coaching;post-doctoral training;pre-doctoral;programs;recruit;senior faculty;success;summer research;tumor;undergraduate student Research Education Core n/a NCI 10761658 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5531 6131384 "APPLEYARD, CAROLINE B" Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144604 92222 52382 ABSTRACT | RESEARCH EDUCATION COREThe Research Education Core (REC) of the Ponce Health Sciences University and Moffitt Cancer CenterPartnership has built an educational program that supports participants across the career continuum preparingthem for basic or clinical oncology-related careers. The long-term goal of the REC is to increase the recruitmentadvancement and quality of cancer research scientists and oncologists from the Puerto Rican andHispanic/Latino (H/L) population while advancing health disparities research focused on this population. Throughongoing interactions with all components of the Partnership the RECs educational framework (2007-2022) hasresulted in: 125 participants obtaining faculty medical or industry/federal/academic positions with 30 inhematology-oncology clinical practice; completion of 137 research rotations by PhD MD or PsyD students;guidance of 22 Early-Stage Investigators (ESIs); and the creation of new courses clerkships and robust cancerand health disparities seminar series. Leveraging our prior successes the REC strategy is designed to jointlyengage participants across career levels and institutes to create a lasting peer mentoring network which will beaccomplished under the following aims: Aim 1 engages H/L undergraduate students at both PHSU and MCCeight total per year in a new two-year-plus program with year-round mentoring and research experiencescombined with intensive summer research immersion to promote conceptual change in preconceived ideas oflimited opportunities and fit for STEM and cancer research. Aim 2 establishes two-year diversity post-doctoralscholarships at MCC for H/L fellows to support career success with a focus on cancer health disparities andminority health; and also establishes career development scholarships for late-stage PHSU PhD students tosupport career enhancement activities and successful transition to post-doctoral training. Two rolling scholarshipslots are available at each site. The scholarships are interwoven with training in cultural competencyprofessionalism scientific writing and health disparities to successfully promote a path toward independence.Aim 3 addresses the need to increase the number of H/L medical residents and medical students entering anoncology career track. REC will facilitate the creation of the first urology residency program in PR enable surgicaloncology training at MCC for two PR surgical residents per year and immerse eight medical students per yearin a summer cancer research experience alongside PhD students. Aim 4 enhances the career development ofESIs by providing individualized support for each ESI through collaborative interactions health disparitiestraining grant/scientific writing workshops career development activities identifying networking opportunitiesand tracking and evaluating ongoing mentorship and sponsorship. In sum REC trainees will gain cancerresearch and health disparities experience through exposure to Partnership projects and Cores. The RECoutcomes will support the overall Partnership objectives by building and strengthening trainee career pathwaysat critical career transition points resulting in a more diverse pool of oncologists and research scientists. +No NIH Category available ADRB2 gene;Adrenergic Receptor;Anxiety;Aspirin;Attenuated;Biological;Biological Assay;Black race;Cancer Biology;Cancer Center;Carcinoma;Case Series;Case/Control Studies;Chronic stress;Clinical;Data;Development;Diagnosis;Disease;Distress;Dose;Emotional;Enzyme-Linked Immunosorbent Assay;Epithelial ovarian cancer;Ethnic Origin;Evaluation;Future;Gene Expression;Genes;Goals;Health Sciences;Hispanic;Hormones;Hospitals;Human;Immune;Immune response;Immunity;Immunosuppression;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Intervention;Latina;Lead;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Mediating;Mental Depression;Mus;Norepinephrine;Not Hispanic or Latino;Outcome;Pathway interactions;Patient Self-Report;Patients;Pharmacotherapy;Population Heterogeneity;Population Intervention;Population Study;Prevention strategy;Process;Prospective cohort;Prostaglandins;Puerto Rico;Race;Reporting;Research;Research Project Grants;Resources;Risk;Role;Sampling;Science;Serous;Services;Stress;Sympathetic Nervous System;Time;Tissues;Tumor Immunity;Tumor Tissue;Tumor-associated macrophages;Universities;Up-Regulation;Woman;Work;adaptive immunity;biobank;biobehavior;bisphosphonate;cancer risk;cancer survival;carcinogenicity;education research;epidemiologic data;ethnic disparity;ethnic diversity;exome;experience;high risk;immune function;improved;innovation;mouse model;novel;outreach;ovarian cancer prevention;ovarian neoplasm;pharmacologic;population based;prevent;prospective;psychosocial;racial disparity;racial diversity;response;restraint stress;systemic inflammatory response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor progression;tumorigenesis The impact of biobehavioral factors and aspirin on ovarian cancer biology n/a NCI 10761655 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5528 8645671 "ARMAIZ-PENA, GUILLERMO N" Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144604 92222 52382 ABSTRACT | FULL RESEARCH PROJECT 2Growing evidence indicates that the biological response to chronic stress and subsequent distress canpromote the progression of epithelial ovarian cancer via prolonged activation of the sympathetic nervoussystem and sustained norepinephrine release. Downstream consequences of norepinephrine exposureinclude increased prostaglandin-related inflammation and an immunosuppressive landscape. Converselyincreasing evidence supports the role of aspirin use in ovarian cancer prevention and survival. Yet keyquestions remain about the underlying biological mechanism of action of chronic stress/distress and aspirinuse (considering low and standard doses separately) and their interrelationship with ovarian cancer biology.Specifically we propose to evaluate the hypothesis that distress enhances ovarian cancer progression bypromoting inflammatory and immune processes and that aspirin abrogates these effects. Our innovative studyuses unique population-based and experimental resources. Aim 1 will use data from four long-termprospective cohorts in diverse populations a population-based case-control study a hospital case series thatcollected self-reported measures of chronic stress and distress (e.g. depression) and ovarian tumor tissue.Aim 1 will measure gene expression in bulk high grade serous tumor samples (to capture the full tumormicroenvironment) using whole exome RNASeq. We hypothesize that distress is associated with the up-regulation of inflammation-related and immune suppression gene expression pathways that is normalizedamong aspirin users. We will also assess if the association of distress with ovarian cancer risk is attenuatedamong aspirin users. Notably we are leveraging racially and ethnically diverse studies that have highlycharacterized ovarian cancer cases allowing assessment of differences in association by race (BlackWhite) and ethnicity (Hispanic non-Hispanic) as well as the examination of associations between distress-related gene expression profiles and clinical outcomes. Using an orthogonal and interactive approach Aim 2will use experimental ovarian cancer mouse models to characterize the progressive effect over time of dailyrestraint stress on tumor inflammation and immunity as well as ovarian tumor growth using RNASeq andstress hormones measured via ELISA assays. We also will examine if aspirin (recapitulating equivalents oflow and standard dose aspirin in humans) counteracts the effects of chronic stress on tumor progression andinflammatory and immune gene expression networks. This project will leverage the scientific services ofseveral cores including the Puerto Rico BioBank (PRBB) and the Quantitative Science Core (QSC) withsubstantial interaction with the Outreach Core the Planning and Evaluation Core and working with trainees inthe Research Education Core. This innovative application will inform future work to develop novel immuno-preventive strategies pharmacotherapies and psychosocial interventions to prevent and treat invasiveovarian cancer in women who experience chronic stress and distress. +No NIH Category available Address;Admixture;Affect;Aftercare;Androgen Receptor;Automobile Driving;Biological Markers;Black Populations;Black race;Blood specimen;Cancer Center;Cancer Patient;Castration;Cell Line;Cells;Cessation of life;DNA Methylation;DNA Methylation Inhibition;Data;Development;Disease Progression;Disparity;Drug Modelings;Drug resistance;Drug usage;Epigenetic Process;Failure;Florida;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;Goals;Health Sciences;Hispanic;Hispanic Populations;Incidence;Indolent;Latino;Latino Population;Malignant Neoplasms;Malignant neoplasm of prostate;Methylation;Molecular;Molecular Probes;Not Hispanic or Latino;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Plasma;Play;Population;Populations at Risk;Prediction of Response to Therapy;Prostate;Prostate Cancer therapy;Puerto Rican;Reporting;Research Project Grants;Resistance;Risk;Role;Sampling;Selection for Treatments;Series;Socioeconomic Status;The Cancer Genome Atlas;Tissues;Treatment Failure;Tumor Biology;Universities;Validation;Work;androgen deprivation therapy;biobank;black men;cancer health disparity;cancer initiation;cancer type;chemotherapy;clinical risk;clinically relevant;cohort;data registry;differential expression;disease phenotype;docetaxel;drug sensitivity;enzalutamide;epigenetic variation;gene therapy;health care availability;high risk;improved;liquid biopsy;men;methylation biomarker;methylation pattern;mortality;neoplasm registry;novel;outcome disparities;patient oriented;potential biomarker;prostate cancer cell line;racial disparity;racial population;response;risk stratification;targeted agent;taxane;therapy resistant;treatment response;tumor;tumor DNA Epigenetic variations associated with aggressiveness in prostate cancer among Puerto Rican men n/a NCI 10761654 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5527 78066806 "D?AZ OSTERMAN, CARLOS JOEL" Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144604 92222 52382 ABSTRACT | FULL RESEARCH PROJECT 1Puerto Rican (PR) Hispanic/Latino (H/L) men have the highest prostate cancer (PCa) mortality among Hispanicpopulations. According to the recent PR Cancer Registry data PCa is the leading cancer type in terms ofincidence (35% of all cancer cases) and mortality (17% of all cancer deaths) in PR H/L men. They havesignificantly higher PCa-specific mortality than non-Hispanic white (NHW) and non-Hispanic Black (NHB) men;addressing this gap constitutes our central efforts. While socioeconomic status and access to healthcare arecontributors manifest differences in molecular features between racial groups highlight the role of tumor biologyin racially disparate outcomes in PCa. Our long-term goal is to identify DNA methylation biomarkers driving geneexpression changes that underly PCa therapy resistance and aggressiveness in at-risk populations particularlyPR H/L men. The central hypothesis is that differences in tumor DNA methylation patterns and populationadmixture are associated with drug response and aggressiveness in PCa in PR H/L men. The rationale is thatidentifying the molecular basis of PCa disparities will serve to reduce the burden of lethal PCa disparities affectingPR H/L men. Our goals will be accomplished through two Specific Aims: Aim 1) Investigate associations betweenaggressiveness and methylated genes in PCa among the PR H/L population and the impact of methylation ontheir expression. (1a) Investigate differentially methylated genes associated with drug resistance andaggressiveness among PR H/L PCa patients and compare with methylation data from NHB from the Florida PCabiobank NHW PCa patients from MCC and TCGA. (1b) Evaluate differential DNA methylation on geneexpression patterns. We will establish comparisons with previous data obtained from NHW men from MCC andTCGA. (1c) Evaluate whether population admixture will modify the methylation level of PR-specific methylatedgenes. Further we will investigate whether genes that contain ancestry determinants are associated with theaggressiveness of PCa and disparity. Aim 2. Assess the contribution of DNA methylation to PCa resistance tostandard therapies using drug-resistant PCa sublines and liquid biopsies from PCa patients progressing aftertreatment. (2a) Identify differentially methylated genes associated with drug-resistant phenotypes using cell-based models of drug resistance including castration resistance enzalutamide resistance and docetaxelresistance. (2b) Evaluate the expression of differentially methylated genes in resistant sublines compared tosensitive cell lines. (2c) Assess the effect of DNA methylation inhibition on drug sensitivity in resistantphenotypes. (2d) As an exploratory aim we will evaluate resistance-associated methylation profiles in bloodsamples from PR and MCC patients previously treated with androgen deprivation therapy androgen receptor-targeting agents or taxane-based chemotherapy. The identification and validation of novel DNA methylationsignatures associated with aggressive and drug-resistant PCa in PR men have the potential to improve riskstratification and treatment selection in this high-risk understudied population. +No NIH Category available Address;Admixture;Area;Big Data;Bioinformatics;Biometry;Cancer Center;Cell Line;Collaborations;Communication;Consent;DNA;Data;Data Analyses;Data Collection;Data Scientist;Development;Disparity;Education;Ensure;Environment;Evaluation;Future;Genetic;Genome;Genomics;Grant;Health Disparities Research;Health Sciences;Hispanic;Hispanic-serving Institution;Improve Access;Informatics;Infrastructure;Institution;Latino;Latino Population;Lead;Life Cycle Stages;Molecular;Molecular Profiling;Oncology;Online Systems;Participant;Phase;Physicians;Proteomics;Puerto Rico;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Sample Size;Sampling;Science;Services;Students;System;The Cancer Genome Atlas;Tissues;Training;Translations;Universities;Vision;Visualization software;analytical tool;ancestry analysis;biobank;cancer health disparity;cohort;data integration;data management;design;education research;experience;genomic data;high dimensionality;improved;infrastructure development;innovation;member;novel;online resource;precision medicine;research study;skills;software infrastructure;statistics;synergism;tool;transcriptome sequencing Quantitative Sciences Core n/a NCI 10761653 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5526 8899935 "DUTIL, JULIE " Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144604 92222 52382 ABSTRACT | QUANTITATIVE SCIENCES COREThe Quantitative Sciences Core (QSC) of the Ponce Health Sciences University-Moffitt Cancer Center (PHSU-MCC) Partnership provides resources and expertise for generating managing and analyzing big data. It is thefocal point for expertise in quantitative approaches to address the underrepresentation of Hispanic/Latino (H/L)populations in omics studies and to incorporate ancestry analysis in Partnership research approaches. Byjoining PHSU's expertise in genetic ancestry with the MCC bioinformatics team the QSC combines a unique setof skills required to address the molecular components of cancer disparities in admixed H/L populations. TheQSC provides expertise in bioinformatics biostatistics and informatics and participates in every phase of theresearch life cycle. The QSC supports data provisioning study design analysis plans and power estimates todemonstrate the feasibility and improve rigor and reproducibility in all Partnership research projects and grantsubmissions. In addition the QSC contributes to the dissemination of high-throughput molecular data bydeveloping web-based visualization tools. As a central resource for research projects the QSC also facilitatescollaboration thereby leveraging the data gathered by the Partnership investigators. The QSC analyzed the firstH/L genomic data generated in collaboration with the Puerto Rico BioBank (PRBB)/Oncology ResearchInformation Exchange Network (ORIEN) Avatar and implemented the H/L Bioportal (GLOBAL) a web-basedresource. The QSC develops tools for visualizing and interpreting data pipelines to estimate genetic ancestryand has built expertise in genomics bioinformatics at the Hispanic-Serving Institution (HSI) including hiringtraining and the acquisition of computing and storage infrastructure. The Specific Aims of the QSC will be: 1)Provide research project support for biostatistics and bioinformatics from study design endpoint definitionsample size estimation power calculation and data analysis. Regular interactions between lead data scientistsand project members will allow for the continuing development of novel analytic tools to address emergingquestions aligned with the Partnerships needs. 2) Provide data integration and management services forPartnership projects and cores. Projects needing tissue/data collection systems will leverage the existingsoftware infrastructure from PRBB Biospecimen Management System (BMS). The QSC/PRBB Data Conciergeprovisions data and linkages from these systems. Other supported services include the H/L Bioportal EstimatedCell Line Ancestry (ECLA) tool and the Partnership Continuous Quality Improvement System for the Planning& Evaluation Core. 3) Provide quantitative sciences expertise in support of the Partnership. The QSC aims todevelop expertise in statistics at the HSI; characterize publicly available molecular signatures in Partnershipcohorts; develop analytics for PRBB optimization of consent and participant communications; expand the omicsexperience for students (collaboration with the Research Education Core) and enhance the use of ancestry inquantitative studies. +No NIH Category available Acceleration;Address;Awareness;Blood;Breast;Breast Cancer Genetics;Cancer Center;Caribbean region;Clinical;Clinical Data;Clinical Trials;Collaborations;Colon;Colorectal Cancer;Communities;Community Health;Community Health Education;Community Outreach;Consent;DNA;Data;Data Set;Databases;Dedications;Demographic Survey;Development;Education;Education and Outreach;Funding;Future;Genetic;Genome;Grant;Gynecologist;Health Disparities Research;Health Educators;Health Sciences;Historical Survey;Hospitals;Individual;International;Island;Latin America;Latin American;Latino;Logistics;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Medical Students;Minority Participation;Molecular;Molecular Profiling;Oncologist;Organoids;Ovarian;Patient Education;Patient Recruitments;Patient Selection;Patients;Physicians;Physicians' Offices;Play;Population;Prevalence;Principal Investigator;Process;Prostate;Publications;Puerto Rican;Puerto Rico;RNA;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Science;Services;Specimen;Surgeon;System;Techniques;Tissue Donations;Tissue Microarray;Tissues;Training;Translation Initiation;Underrepresented Minority;Universities;Urologist;anticancer research;biobank;breast cancer genomics;cancer diagnosis;cancer health disparity;cancer therapy;cancer type;data registry;education research;health disparity;improved;innovation;malignant breast neoplasm;medical schools;molecular phenotype;neoplasm registry;novel;outreach;patient derived xenograft model;precision medicine;recruit;targeted treatment;transcriptome sequencing;translational cancer research Puerto Rico BioBank Core n/a NCI 10761652 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5525 7364827 "FLORES, IDHALIZ " Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144606 92223 52383 ABSTRACTThe Puerto Rico BioBank (PRBB) Shared Resource of the Ponce Health Sciences University-Moffitt CancerCenter (PHSU-MCC) Partnership collects processes annotates stores and distributes biospecimens andclinical-demographic data for investigator-initiated translational cancer research. As of August 2022 the PRBBhas consented 4097 subjects representing 42 different cancer types and healthy individuals. From thesesubjects 1899 clinical history and demographic surveys were completed and 8453 biospecimens werecollected. Tissues derivative analytes (e.g. DNA/RNA) data and tissue microarrays have been distributed toresearch projects supporting publications and grant submissions. The PRBB contributed to the development ofa Biobanking clerkship for medical students in collaboration with the Research Education Core (REC) andcontributed to education efforts in H/L communities in both Tampa and Ponce in collaboration with the OutreachCore (OC). Together with the Quantitative Sciences Core (QSC) the PRBB has consented 142 H/L patients tothe ORIEN-Avatar network (https://www.oriencancer.org) improving the representation of H/L tissues in thisnetwork dedicated to accelerating the discovery of novel targeted cancer treatments that is currently only 7.2%.The PRBB participates in international consortia including REBLAC (Latin American and Caribbean Biobankingnetwork) PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in theGenome) LAGENO-BC (Latin America Genomics of Breast Cancer Consortium) the Latino Colorectal CancerConsortium (LC3) the Confluence Project for Breast Cancer Genetics. The objective of the PRBB is to addressthe critical unmet need in cancer health disparities of a lack of representation of H/L patients in comprehensivemolecular datasets at levels that align with the prevalence of cancer in this population. The aims are: 1) Supportresearch projects by targeted recruitment of patients of selected cancer types along with non-cancer controls.Recruitment is both broad to build a comprehensive database for future projects and focused on the currentlyproposed full research projects in prostate and ovarian cancer. We will continue to optimize the logistics of patienteducation and consenting at collaborating physicians offices and San Lucas Hospital (SLH) and by maintainingconstant contact with Project PIs. 2) Support research by developing innovative resources and services. We willfocus on developing new research resources and services that can be rapidly accessed by researchers. Thisincludes building well-annotated tissue microarrays representing cancer types that significantly impact H/Ls(prostate ovarian) expanding molecular phenotyping (exomeSeq RNAseq ancestry) in collaboration withORIEN tapping into the potential for identifying clinical trials that are matched to a patients molecular profileand leverage our emerging expertise in organoid and patient-derived xenografts models to support projects. 3)Collaborate with partnership components in education outreach and community education on the importanceof tissue donation and improving data availability with the QSC. +No NIH Category available Advisory Committees;Affect;Area;Brassicaceae;Budgets;COVID-19 pandemic;Cancer Center;Career Mobility;Categories;Collaborations;Committee Members;Communication;Communities;Community Health;Development;Doctor of Philosophy;Earthquakes;Ensure;Faculty;Fostering;Funding;Funding Agency;Future;Goals;Grant;Growth;Guidelines;Health Disparities Research;Health Educators;Health Sciences;Hispanic;Hurricane;Incubators;Infrastructure;Institution;Knowledge;Latino;Leadership;Learning;Mentors;Persons;Preparation;Productivity;Progress Reports;Publications;Puerto Rico;Recruitment Activity;Research;Research Activity;Research Personnel;Research Project Grants;Resource Development;Resource Sharing;Resources;Scientist;Source;Supervision;Training Activity;Underrepresented Minority;United States National Institutes of Health;Universities;Work;anticancer research;cancer health disparity;career;career development;conflict resolution;driving force;education research;expectation;experience;innovation;member;minority engagement;minority health;pandemic disease;programs;recruit;resilience;success;virtual Administrative Core n/a NCI 10761651 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5524 7890165 "MATTA, JAIME L" Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 144606 92223 52383 ABSTRACT | ADMINISTRATIVE COREThe Administrative Core (AC) of the Ponce Health Sciences University-Moffitt Cancer Center (PHSU-MCC)Partnership serves as its central coordinating component. The AC manages all aspects of the Partnershipincluding day-to-day administrative and financial supervision recruitment and retention of memberscommunications coordination of activities logistical support and charting the Partnerships present and futuredirections. Administration occurs jointly at Ponce Health Sciences University (PHSU) and Moffitt Cancer Center(MCC) with continuous communication by the AC co-leaders. The AC supports the growth stability andinfrastructure of the Partnership and actively recruits and promotes Early-Stage Investigators (ESIs). The AChas facilitated a significant increase in Partnership research grant funding and publications while providingsupport and continuity for the Partnership investigators and the communities during multiple major hurricanesearthquakes and the pandemic. The AC leadership has worked closely together for the last 16 years andpossesses a wealth of institutional Partnership and NCI knowledge providing long-term stability. The AC willcontinue to support all projects cores and shared resources and act as the incubator for innovative efforts toreduce cancer disparities in Hispanic/Latino (H/L) communities. The goals of the AC are to support growth andinnovation which is accomplished by the following specific aims: 1) Provide infrastructure for the Partnership.The AC will provide oversight and support related to scientific leadership fiscal oversight and managementrecruitment and retention of faculty and Partnership staff productivity oversight preparation of non-competingprogress reports and conflict resolution. The AC will accomplish this aim by establishing clear expectationssetting the overall direction of the Partnership and developing new leaders to promote its sustainability. 2)Facilitate communication and integration throughout all levels of the Partnership by ensuring the disseminationof activities opportunities challenges and accomplishments to all members of the Partnership Institutionalleadership and the broader institutional members. 3) Manage and advance the portfolio of Partnership researchprojects from initial solicitation through acquiring independent external funding. The AC will stimulate scientificdiscussions set the guidelines and timing of all new project solicitations and manage the selection and activationof high-impact projects. The AC will provide support for scientific publications submission of research grants toexternal funding agencies and identify additional resources for project success. 4) Support the advancement ofEarly-Stage Investigator (ESI) careers. The AC will identify and recruit promising ESIs to the Partnership fostertheir development and oversee their progress collaborating with the Research Education Core (REC) to providecareer development resources mentoring and sponsorship tailored to each ESI. The overall goals are topromote the career advancement of a diverse junior faculty pool and to attract young investigators to focus oncancer health disparities and minority health. +No NIH Category available Accreditation;Achievement;Address;Admixture;Advocate;Affect;Basic Cancer Research;Basic Science;Bay Region;Biological;COVID-19 pandemic;Cancer Center;Cancer Patient;Caregivers;Clinical;Clinical Research;Collaborations;Communication;Communities;Community Developments;Community Health;Community Health Education;Community Outreach;Complex;Comprehensive Cancer Center;Development;Direct Costs;Doctor of Philosophy;Earthquakes;Education;Educational Materials;Ensure;Environment;Evaluation;Evaluation Research;Evolution;Faculty;Florida;Fostering;Funding;Genetic;Genomics;Goals;Grant;Growth;Health;Health Disparities Research;Health Educators;Health Sciences;Health Services Accessibility;Hematology;Hispanic;Hurricane;Infrastructure;Institution;Intervention;Joints;Language;Latino;Latino Population;Learning;Malignant Neoplasms;Medical;Medical Students;Minority Participation;NCI-Designated Cancer Center;Natural Disasters;Oncology;Operative Surgical Procedures;Outcome;Peer Review;Population;Postdoctoral Fellow;Poverty;Preparation;Process;Productivity;Psychological Factors;Publications;Puerto Rico;Reduce health disparities;Research;Research Personnel;Research Project Grants;Research Support;Residencies;Resources;Science;Specimen;Tissue Microarray;Training;Universities;anticancer research;biobank;cancer clinical trial;cancer education;cancer health disparity;career;catalyst;community engagement;disparity gap;doctoral student;empowerment;experience;forging;genomic data;graduate medical education;health disparity;improved;innovation;inter-institutional;novel;outreach;outreach program;programs;recruit;resilience;social factors;social media;translational cancer research;undergraduate student (1/2) Ponce Health Sciences University-Moffitt Cancer Center Partnership # The Partnership between Ponce Health Sciences University (PHSU) in Puerto Rico and the Moffitt CancerCenter (MCC) in Tampa is focused on reducing cancer disparities in the Hispanic/Latino (H/L) communities andcontributing to the elimination of health disparities in the H/L population at large. The Partnership aims to providethe means to expand research capabilities of the ISUPS (PHSU) and enhance research on cancer healthdisparities at the NCI-designated Cancer Center (MCC). The joint programs have resulted in successfuloutcomes in cancer research education training community outreach and in biobanking. NCI 10761650 9/22/23 0:00 PAR-22-249 2U54CA163071-11 2 U54 CA 163071 11 "SAN MIGUEL-MAJORS, SANDRA L" 9/25/12 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 7890165 "MATTA, JAIME L" "DUTIL, JULIE ; MONTEIRO, ALVARO N" 98 PHARMACOLOGY 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR SCHOOLS OF MEDICINE 7327004 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 397 Research Centers 2023 1301440 NCI 830000 471440 ABSTRACT | OVERALLThe Hispanic/Latino (H/L) communities in the Ponce and Tampa Bay regions experience both shared and uniquechallenges associated with poverty access to care and language. The Ponce Health Sciences University(PHSU) in Puerto Rico (PR) and the Moffitt Cancer Center (MCC) in Florida have forged a strong relationshipand leveraged their respective strengths and resources to address these needs with the ultimate goal ofeliminating cancer health disparities. The 15-year Partnership has established joint programs for basic andclinical research cancer outreach cancer education and training and biobanking building networks ofinvestigators focused on cancer disparities and infrastructure for sustained long-term collaboration. Combinedwith the establishment and growth of a unique biobanking resource for H/L and the integration of quantitativesciences expertise this dynamic environment is a catalyst for the recruitment of new faculty at PHSU in basicand translational cancer research increases the health disparities research focus at MCC and stimulatesinnovative cancer research. To ensure a durable impact the Partnership fosters the development of cancerresearchers and clinicians through an exchange of research and medical trainees between institutions andsupporting the successful advancement of Early-Stage Investigators (ESIs). The Partnership and our outreachactivities continue to be integral in promoting cancer health in our H/L communities and has provided vital supportfor overcoming two major hurricanes devastating earthquakes and the COVID pandemic. The challengesachievements and lessons learned to provide a strong basis to guide the evolution and further expansion of thisPartnership whose primary goals are to reduce cancer disparities in the Hispanic/Latino (H/L) communities andto contribute to the elimination of health disparities in the population at large. The specific aims for the U54Partnership renewal are (1) Increase Partnership investigators and collaborations committed to innovativecancer health disparities research creating long-term sustainability. This will be accomplished through theengagement of faculty and ESIs with resources to support collaborations grant preparations publications andnetworking. (2) Identify and foster the growth of diverse trainees for a career in cancer research and healthdisparities. We will support the recruitment and development of trainees from diverse backgrounds across thecareer continuum with an emphasis on H/L. (3) Support novel research projects that will contribute to theidentification and elimination of cancer health disparities in H/L. We will foster the development of projectsthat investigate the biological basis psychological and social factors of cancer disparities through a rigorousevaluation of research projects that have the potential to reduce specific disparity gaps. (4) Increase communityengagement in cancer health disparities research. This will be accomplished by fostering communityengagement including bi-directional activities education increased social media presence and dialogue withthe research component and activities of our Community Health Educator. 1301440 +No NIH Category available 3-Dimensional;Abscopal effect;Animals;Applications Grants;Area;Brain Neoplasms;Cadaver;Cancer Model;Canis familiaris;Cell Death;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Computer software;Data;Development;Devices;Diagnostic Imaging;Dose;Effectiveness;Engineering;Europe;European;Feedback;Future;Glioblastoma;Goals;Grant;Head;Heating;Human;Image;Imaging technology;Immune response;Immunologic Stimulation;In Vitro;Intensity-Modulated Radiotherapy;Lesion;Magnetic fluid hyperthermia;Magnetic nanoparticles;Magnetism;Malignant neoplasm of prostate;Measurement;Measures;Modeling;Monitor;Normal tissue morphology;Oils;Penetration;Performance;Phase;Preparation;Radiation therapy;Radio;Recurrence;Resolution;Scanning;Shapes;Signal Transduction;Small Business Innovation Research Grant;System;Technology;Temperature;Temperature Sense;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Universities;Visualization;Water;Width;Work;attenuation;brain size;cancer therapy;chemotherapy;clinical imaging;commercialization;cytotoxic;design;dosimetry;experience;hyperthermia treatment;image guided;imager;imaging system;immunogenic cell death;in vivo;in vivo Model;innovation;insight;interest;magnetic field;millimeter;nanoparticle;neoplastic cell;new technology;particle;pre-clinical;preclinical trial;prototype;quality assurance;theranostics;time use;tomography;treatment planning;tumor Development of a prototype clinical theranostic platform combining Magnetic Particle Imaging (MPI) and Magnetic Fluid Hyperthermia (MFH) for the treatment of brain tumors NARRATIVEMagnetic Particle Imaging (MPI) is an emerging imaging technology that directly quantitates magneticnanoparticle (MNP) concentration in tissue while Magnetic Fluid Hyperthermia (MFH) can activate those sameMNPs causing local tissue heating and killing of tumor cells. In this grant we will advance MFH by building thefirst clinical-scale localized MFH system incorporating realtime MPI tomographic temperature monitoring toenable thermal dosimetry in the target during treatment. Successful completion of the objectives will provide asystem ready for future large animal and clinical trial testing. NCI 10761630 6/29/23 0:00 PA-22-176 1R44CA285064-01 1 R44 CA 285064 1 "POND, MONIQUE ADRIANNE" 7/1/23 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-CTH-E(11)B] 10603749 "GOODWILL, PATRICK " Not Applicable 12 Unavailable 78791637 HY76TZ1Z48X4 78791637 HY76TZ1Z48X4 US 37.509276 -121.998181 10026310 "MAGNETIC INSIGHT, INC." Alameda CA Domestic For-Profits 94502 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 SBIR/STTR 2023 1011684 NCI 714019 231480 SUMMARY/ABSTRACTIn this SBIR grant proposal Development of a prototype clinical theranostic platform combining MagneticParticle Imaging (MPI) and Magnetic Fluid Hyperthermia (MFH) for the treatment of brain tumors we will developa human brain-sized integrated localized MFH/MPI system. We will develop an imaging-guided MFH treatmentdevice capable of closed-loop localized heating and tomographic temperature monitoring during treatment. MFH relies on the delivery of magnetic nanoparticles to tumors followed by application of alternating magneticfields which causing local heating of tissue and killing of tumor cells. Cell death occurs due to the heat or byenhancing the cytotoxic effects of radio/chemotherapy. MFH offers considerable potential for numerousbiomedical applications especially as an adjunct to radiation therapy in the clinical treatment of recurrentglioblastoma. However MFH currently suffers from limitations that persist after nearly four decades of clinicalexperience and regulatory approval in Europe. Following delivery the nanoparticle distribution within the tumorcan be heterogeneous and unpredictable leading to undertreatment in areas of low MNP concentration andexcessive heating near normal tissues. These issues are compounded by a limited ability to accurately monitortissue temperature in 3D and in realtime. The technology developed in this SBIR constitutes a paradigm shift for MFH by developing the first human-sized localized MFH system. Localized MFH is a new technology that uses strong magnetic field gradients toconfine MNP heating to a small region. Particles within the region can generate heat while those outside theregion cannot. Our technology will transition clinical MFH from the current state of the art of loosely targetedregional heating to mm-accurate localized heating of target tissues. We believe this transition from regional toprecisely targeted is comparable to the transition of early loosely targeted radiation therapy to the present day3D-targeted intensity-modulated radiation therapy. In this Direct to Phase II SBIR proposal we will add MFH to our existing clinical-scale MPI prototype to enablelocalized MPI/MFH with integrated temperature sensing and validate the performance in animal cadaversthrough the following specific aims: Aim 1. Build a clinical RF heating head coil for simultaneous MFH and imaging and integrate it into ourprototype clinical imager Aim 2. Integrate MPI-based temperature sensing with heating to control MFH to a treatment plan. Aim 3. Test overall system in phantoms and animal cadavers in preparation for preclinical trials in dogs At the end of this Direct to Phase II proposal we will have demonstrated integrated MPI/MFH for preciselylocalized image-guided therapeutic heating in a prototype that is suitable for clinical studies. In our future workwe plan to test this system in a large animal trial at JHU for treatment of spontaneous canine GBM. 1011684 +No NIH Category available 3-Dimensional;Abnormal Epithelial Cell;Acute;Address;Advocate;Africa;Africa South of the Sahara;African;Area;Award;Biological Assay;Biopsy;Cancer Center;Cervical Cancer Screening;Cervix Neoplasms;Cervix Uteri;Cessation of life;Clinical;Clinical Research;Clinical Trials;Color;Colposcopy;Computer software;Confidence Intervals;Country;Data;Data Collection;Data Set;Developed Countries;Developing Countries;Devices;Diagnosis;Disease;Dysplasia;Effectiveness;Eligibility Determination;Epidemiology;Face;Factor Analysis;Friends;Future;Head;Health Care Costs;Human;Human Papillomavirus;Image;Imaging Device;Imaging Techniques;Imaging technology;Incidence;Income;Infrastructure;International;Intervention;Kenya;Laboratories;Malawi;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Measurable;Measurement;Measures;Medical;Oncology;Optics;Pap smear;Patient imaging;Patient-Focused Outcomes;Patients;Persons;Phase;Positioning Attribute;Poverty Areas;Predisposition;Procedures;Property;Recommendation;Reproducibility;Reproductive Health;Research;Resolution;Resource-limited setting;Shapes;Site;Small Business Innovation Research Grant;Sterility;Support Groups;Surveys;Technology;Telemedicine;Testing;Three-Dimensional Imaging;Uninsured;United States National Aeronautics and Space Administration;United States National Institutes of Health;Virginia;Visit;Visual;Visualization;Woman;World Health Organization;cancer care;cervical cancer prevention;cost;falls;follow-up;high resolution imaging;imaging system;improved;innovation;interest;longitudinal analysis;low and middle-income countries;marginalization;medical schools;mortality;new technology;novel;phase 2 study;portability;programs;reconstruction;research clinical testing;response;screening;screening program;socioeconomic disadvantage;socioeconomics;statistics;technology development;tool;treatment program;usability;virtual A Novel Low-Cost Handheld 3D Imaging System for Improved Screening of Cervical Neoplasia in Resource Limited Settings Project NarrativeCervical cancer is one of the most preventable and treatable forms of cancer yet nearly 90% of cases in low-to middle-income countries result in death. To address this crisis we recently developed a portable low-costsimple-to-use telemedicine- and patient-friendly innovative imaging system that can help advance toward thescreen-and-treat strategy for cervical cancer prevention advocated by the World Health Organization. In thisphase II study we will establish the feasibility of our screening protocols through a multisite international studyand advance the overall technology. NCI 10761604 9/19/23 0:00 PA-22-176 2R44CA254586-02 2 R44 CA 254586 2 "ZHAO, MING" 8/1/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 16301082 "CARSON, JOSEPH " Not Applicable 51 Unavailable 80049233 FX8MZJECT715 80049233 FX8MZJECT715 US 32.894418 -117.193011 10043018 "PENSIEVISION, INC." SAN DIEGO CA Domestic For-Profits 921212965 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1116921 NCI 859717 184134 AbstractCervical cancer is one of the most preventable and treatable forms of cancer reflected by the fact that itsincidence has significantly fallen in most of the developed world over the past 30 years largely due to effectivescreening and treatment programs. In developing countries and also in socio-economic disadvantaged areasof developed countries many women lack convenient access to affordable and high-quality programs to savetheir lives. Currently more than a million women worldwide have cervical cancer. Most of these women do nothave access to diagnoses and treatments that could cure them or prolong their lives. In 2012 >500000 newcases of cervical cancer were diagnosed worldwide and >250000 of these women died of the disease --nearly 90% in low- to middle-income countries. Deaths due to cervical cancer are projected to rise by almost25% over the next 10 years without proper interventions. New technological developments offer the potential tomake comprehensive cervical cancer care feasible and affordable in low- and middle-income countries and tomitigate the skyrocketing healthcare costs in the developed world. In response we have recently developed(through support from an NSF-SBIR and NIH-SBIR award) a portable low-cost simple-to-use telemedicine-and patient-friendly innovative imaging system that can help advance toward the screen-and-treat strategy forcervical cancer prevention advocated by the World Health Organization. In this phase II study we will establishfeasibility of our screening protocols through a multisite international study and advance the overall technology. 1116921 +No NIH Category available Acceleration;Address;Adoption;Antibodies;Bar Codes;Biological Markers;Biopsy Specimen;CTLA4 gene;Cancer Diagnostics;Cell Communication;Cells;Clinical;Complement;Complex;Computer software;Data;Development;Diagnostic;Diagnostics Research;Disease Progression;Epidermal Growth Factor Receptor;Fibroblasts;Fluorescent in Situ Hybridization;Gene Order;Genes;Genomics;Geographic Distribution;Geography;Glioblastoma;Hypoxia;Image;Immune;Immune Targeting;Immunofluorescence Immunologic;In Situ;Mammary Neoplasms;Maps;Marketing;Medical Research;Messenger RNA;Methods;Molecular;Molecular Profiling;Neighborhoods;Neuroblastoma;Nucleic Acids;Oligonucleotides;Pathology;Phase;Population;Population Heterogeneity;Post-Translational Protein Processing;Process;Processed Genes;Proliferating;Proteins;RNA;Reagent;Research;Research Personnel;Resolution;Sampling;Scanning;Signal Pathway;Signal Transduction;Slice;Slide;Spatial Distribution;System;Technology;Testing;Time;Tissues;Transcript;Tumor Subtype;Tumor Tissue;Validation;Visualization;antibody conjugate;cancer biomarkers;cancer imaging;cell type;clinical diagnostics;commercialization;cytokine;exhaustion;experimental study;flexibility;human imaging;in-vitro diagnostics;instrument;instrumentation;malignant breast neoplasm;molecular marker;multiple omics;neoplastic cell;programmed cell death protein 1;ratiometric;receptor;single molecule;tool;tumor;tumor growth;tumor microenvironment Spatial genomics analysis of tumor samples NARRATIVEUnderstanding cell-to-cell interactions in tumors is critical for clinical diagnostics and medicalresearch. Spatial Genomics has developed a technology to map cell populations and molecularstates of single cells in the native tumor microenvironment. This technology can identify celltypes and the spatial interactions between immune cells and tumors cells in the tissue togenerate a spatial map with molecular information. NCI 10761582 9/1/23 0:00 PA-22-176 1R44CA285121-01 1 R44 CA 285121 1 "LOU, XING-JIAN" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-MCST-G(15)B] 14880077 "FRIEDA, KIRSTEN " Not Applicable 28 Unavailable 80426411 C2CPGG8RZLV9 80426411 C2CPGG8RZLV9 US 34.137044 -118.09741 10044764 "SPATIAL GENOMICS, INC." Pasadena CA Domestic For-Profits 91107 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 SBIR/STTR 2023 998481 NCI 698875 244606 SUMMARYImaging the tumor microenvironment (TME) is key to understanding tumor growth diseaseprogression and therapy options. The TME often consists of a complex neighborhood of diversepopulations of immune cells fibroblasts and tumors cells. Little is known about the geographyof the tumors and the spatial organization of the distinct cell types. The ability to rapidly identifydifferent cell types and tumor subtypes using molecular markers will be transformative for cancerdiagnostics.At Spatial Genomics we are commercializing technology that allows transcript profiling in tumorsamples. With this technology cell types in situ and spatial organizations can be directly identifiedand visualized in tumor tissue slices. These capabilities provide a powerful tool for examining thedifferent cell types and their interactions in the tumor microenvironment. In this proposal we willdevelop the reagents instrumentation and the associated software that will allow researchers toperform spatial mapping experiments in tumor slices. 998481 +No NIH Category available 3-Dimensional;Address;Adoptive Cell Transfers;Adult;Anti-Inflammatory Agents;Area;Biological Assay;Blood Vessels;Brain;Cell Line;Cell Proliferation;Cells;Coculture Techniques;Combined Modality Therapy;Complex;Data Set;Development;Drug Screening;Effectiveness;Environment;Excision;Extracellular Matrix;Flow Cytometry;Funding;Gene set enrichment analysis;Genes;Genetic Transcription;Glioblastoma;Glioma;Goals;Heterogeneity;Human;Human Biology;Hydrogels;Image Cytometry;Immune;Immune Evasion;Immune response;Immunofluorescence Immunologic;Immunological Models;Immunologics;Immunosuppression;Immunotherapy;In Vitro;Infiltration;Invaded;Life Expectancy;Link;Macrophage;Macrophage Activation;Malignant Neoplasms;Microglia;Modeling;Myelogenous;National Institute of Environmental Health Sciences;Nature;Operative Surgical Procedures;Organoids;Parents;Pathway interactions;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Population;Pre-Clinical Model;Primary Brain Neoplasms;Proliferating;Radiation;Reproducibility;Research Personnel;Risk;Role;Sampling;Scientist;Shapes;Small Business Innovation Research Grant;Survival Rate;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Tissues;Universities;Validation;Wisconsin;Work;Xenograft Model;cancer cell;cell motility;cell type;chemotherapy;chimeric antigen receptor T cells;cytokine;drug discovery;effectiveness evaluation;experience;human model;human tissue;immune checkpoint blockade;in vitro Model;individual patient;innovation;interest;migration;neural;novel;novel therapeutic intervention;novel therapeutics;personalized medicine;phase 2 study;response;screening;sex;single-cell RNA sequencing;small molecule;standard of care;stem;therapeutic target;tumor;tumor microenvironment;tumor-immune system interactions Neural organoid models of the immunological microenvironment of glioblastoma for drug discovery applications This project will apply Stem Pharms human neural organoids for the development ofglioblastoma models that are amenable to screening for drug discovery applications. Throughinclusion of patient-derived glioblastoma cancer cells microglia and peripherally derivedmacrophages we aim to develop a model that better represents the immunosuppressiveenvironment of glioblastoma tumors for evaluating emerging therapeutics to eliminate cancers. NCI 10761235 7/11/23 0:00 PA-22-178 1R41CA281533-01A1 1 R41 CA 281533 1 A1 "FRANCA-KOH, JONATHAN C" 7/11/23 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 12640532 "LEBAKKEN, CONNIE S" Not Applicable 2 Unavailable 79733405 YTLQLAJ53CB7 79733405 YTLQLAJ53CB7 US 43.078624 -89.371462 10038710 "STEM PHARM, INC." MADISON WI Domestic For-Profits 537116434 UNITED STATES N 7/11/23 0:00 6/30/24 0:00 396 SBIR/STTR 2023 406500 NCATS 213592 48255 Project Summary/AbstractGlioblastoma (GBM) is the most prevalent primary brain tumor in adults with extremely poorsurvival rates and largely unchanged standard of care. While there are many challenges todeveloping better GBM treatments one of the major challenges is the immune-suppressiveenvironment commonly found within GBM tumors. This immune-suppressive nature results in atumor that is not suitable for mounting an immune response to GBM cells rendering emergingimmunotherapies ineffective. To address this issue suitable models that can interrogate thecomplex interactions between GBM cancer cells and microglia and peripherally derivedmacrophages would be invaluable for target identification screening of novel therapeutics and formode of action studies. Tumor-associated microglia and macrophages are of particular interestdue to their primary role in shaping the immunological environment of GBM tumors. Humanorganoid technology is well-suited for modeling complex multicellular interactions in a humantissue-like environment. Stem Pharms hydrogel-enabled neural organoids allow for incorporationof non-neural populations such as microglia and macrophages in a reproducible 96-well plateformat amenable to screening applications. Therefore work in this proposal will develop andvalidate a human in vitro glioblastoma organoid model through incorporation of microgliamacrophages and patient derived GBM cells in our neural organoids. Specific aims will 1)characterize organoids incorporating GBM evaluate GBM survival invasion and proliferation;and characterize cell-type specific transcriptional responses to GBM and compare them to parenttumors and publicly available data sets. 2) demonstrate immunosuppressive activation ofmicroglia and macrophages within the neural organoid in response to infiltrating GBM cells.Multiplex cytokine panels co-stimulatory and checkpoint molecule expression and a directimmunosuppression assay with peripheral blood mononuclear cell-derived T-cells will be used toevaluate microglia and macrophage immunosuppression. Finally treatment with three smallmolecules known to modulate macrophage activation will be assessed within the organoids todemonstrate the ability to regulate the microglial and macrophage response to GBM cells.Successful completion of these specific aims will result in a robust in vitro organoid model withnovel capabilities to interrogate GBM invasion and subsequent microglia and macrophageimmunosuppression. This will provide pharma partners with the ability to study therapies thatpreviously failed due to this immunosuppressive environment and test new therapeuticapproaches. Phase II studies will expand the number of available patient-derived samples tobetter capture the diversity and heterogeneity of GBM tumors explore sex-linked differences andevaluate the effectiveness of CAR-Ts and combination therapies within the GBM model with thegoal of bringing better treatment options to patients for this devastating condition. 280000 +No NIH Category available 3-Dimensional;Address;Adoptive Cell Transfers;Adult;Anti-Inflammatory Agents;Area;Biological Assay;Blood Vessels;Brain;Cell Line;Cell Proliferation;Cells;Coculture Techniques;Combined Modality Therapy;Complex;Data Set;Development;Drug Screening;Effectiveness;Environment;Excision;Extracellular Matrix;Flow Cytometry;Funding;Gene set enrichment analysis;Genes;Genetic Transcription;Glioblastoma;Glioma;Goals;Heterogeneity;Human;Human Biology;Hydrogels;Image Cytometry;Immune;Immune Evasion;Immune response;Immunofluorescence Immunologic;Immunological Models;Immunologics;Immunosuppression;Immunotherapy;In Vitro;Infiltration;Invaded;Life Expectancy;Link;Macrophage;Macrophage Activation;Malignant Neoplasms;Microglia;Modeling;Myelogenous;National Institute of Environmental Health Sciences;Nature;Operative Surgical Procedures;Organoids;Parents;Pathway interactions;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Population;Pre-Clinical Model;Primary Brain Neoplasms;Proliferating;Radiation;Reproducibility;Research Personnel;Risk;Role;Sampling;Scientist;Shapes;Small Business Innovation Research Grant;Survival Rate;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Tissues;Universities;Validation;Wisconsin;Work;Xenograft Model;cancer cell;cell motility;cell type;chemotherapy;chimeric antigen receptor T cells;cytokine;drug discovery;effectiveness evaluation;experience;human model;human tissue;immune checkpoint blockade;in vitro Model;individual patient;innovation;interest;migration;neural;novel;novel therapeutic intervention;novel therapeutics;personalized medicine;phase 2 study;response;screening;sex;single-cell RNA sequencing;small molecule;standard of care;stem;therapeutic target;tumor;tumor microenvironment;tumor-immune system interactions Neural organoid models of the immunological microenvironment of glioblastoma for drug discovery applications This project will apply Stem Pharms human neural organoids for the development ofglioblastoma models that are amenable to screening for drug discovery applications. Throughinclusion of patient-derived glioblastoma cancer cells microglia and peripherally derivedmacrophages we aim to develop a model that better represents the immunosuppressiveenvironment of glioblastoma tumors for evaluating emerging therapeutics to eliminate cancers. NCI 10761235 7/11/23 0:00 PA-22-178 1R41CA281533-01A1 1 R41 CA 281533 1 A1 "FRANCA-KOH, JONATHAN C" 7/11/23 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 12640532 "LEBAKKEN, CONNIE S" Not Applicable 2 Unavailable 79733405 YTLQLAJ53CB7 79733405 YTLQLAJ53CB7 US 43.078624 -89.371462 10038710 "STEM PHARM, INC." MADISON WI Domestic For-Profits 537116434 UNITED STATES N 7/11/23 0:00 6/30/24 0:00 396 SBIR/STTR 2023 406500 NCI 96499 21800 Project Summary/AbstractGlioblastoma (GBM) is the most prevalent primary brain tumor in adults with extremely poorsurvival rates and largely unchanged standard of care. While there are many challenges todeveloping better GBM treatments one of the major challenges is the immune-suppressiveenvironment commonly found within GBM tumors. This immune-suppressive nature results in atumor that is not suitable for mounting an immune response to GBM cells rendering emergingimmunotherapies ineffective. To address this issue suitable models that can interrogate thecomplex interactions between GBM cancer cells and microglia and peripherally derivedmacrophages would be invaluable for target identification screening of novel therapeutics and formode of action studies. Tumor-associated microglia and macrophages are of particular interestdue to their primary role in shaping the immunological environment of GBM tumors. Humanorganoid technology is well-suited for modeling complex multicellular interactions in a humantissue-like environment. Stem Pharms hydrogel-enabled neural organoids allow for incorporationof non-neural populations such as microglia and macrophages in a reproducible 96-well plateformat amenable to screening applications. Therefore work in this proposal will develop andvalidate a human in vitro glioblastoma organoid model through incorporation of microgliamacrophages and patient derived GBM cells in our neural organoids. Specific aims will 1)characterize organoids incorporating GBM evaluate GBM survival invasion and proliferation;and characterize cell-type specific transcriptional responses to GBM and compare them to parenttumors and publicly available data sets. 2) demonstrate immunosuppressive activation ofmicroglia and macrophages within the neural organoid in response to infiltrating GBM cells.Multiplex cytokine panels co-stimulatory and checkpoint molecule expression and a directimmunosuppression assay with peripheral blood mononuclear cell-derived T-cells will be used toevaluate microglia and macrophage immunosuppression. Finally treatment with three smallmolecules known to modulate macrophage activation will be assessed within the organoids todemonstrate the ability to regulate the microglial and macrophage response to GBM cells.Successful completion of these specific aims will result in a robust in vitro organoid model withnovel capabilities to interrogate GBM invasion and subsequent microglia and macrophageimmunosuppression. This will provide pharma partners with the ability to study therapies thatpreviously failed due to this immunosuppressive environment and test new therapeuticapproaches. Phase II studies will expand the number of available patient-derived samples tobetter capture the diversity and heterogeneity of GBM tumors explore sex-linked differences andevaluate the effectiveness of CAR-Ts and combination therapies within the GBM model with thegoal of bringing better treatment options to patients for this devastating condition. 126500 +No NIH Category available Adverse event;Agonist;Antigen Presentation;Binding;Biopsy;Capital;Clinical Research;Colorectal Cancer;Complement;Consensus;Development;Dose;Dose Limiting;Drug Kinetics;Effectiveness;Epidermal Growth Factor Receptor;Food;Foundations;Funding;Future;Genomics;Goals;Immune checkpoint inhibitor;Immunooncology;In Vitro;In complete remission;Integrin alpha4beta1;Integrins;Maintenance;Malignant neoplasm of lung;Mediating;Medical;Metastatic Melanoma;Mismatch Repair Deficiency;Modeling;Nivolumab;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Oral;Orphan Drugs;Overdose;Patients;Phase;Pleural Mesothelioma;Primary carcinoma of the liver cells;Privatization;Progressive Disease;Recommendation;Regimen;Renal Cell Carcinoma;Resistance;Safety;Sampling;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Solid Neoplasm;Stable Disease;T cell infiltration;T cell response;T-Cell Activation;T-Lymphocyte;Toxic effect;anaplastic lymphoma kinase;anti-CTLA4;anti-PD-1;anti-PD1 therapy;autoimmune toxicity;checkpoint therapy;design;first-in-human;immune checkpoint blockade;immunotoxicity;improved;in vitro activity;ipilimumab;melanoma;migration;novel;objective response rate;partial response;pembrolizumab;pharmacologic;phase 1 study;response;risk mitigation;safety study;standard of care;trafficking;tumor 7HP349 an Integrin Activator to Treat Patients With anti-PD-1 Resistant Solid Tumors PROJECT NARRATIVEA significant proportion of solid tumor patients are resistant to anti-PD-1 immune checkpoint therapy largelydue to insufficient priming and trafficking of tumor-targeted T cells. 7HP349 is an allosteric agonist of 41 andL2 integrins that has shown enhanced T cell priming and activation antitumor efficacy and survival in tumormodels with increased T cell infiltration into tumors and has the potential to significantly increase response ratesin patients resistant to anti-PD-1 immune checkpoint therapy. This proposal is for a Phase Ib clinical study toevaluate 7HP349 in combination with anti-CTLA-4 followed by anti-PD-1 immune checkpoint blockade in solidtumor patients with secondary resistance to anti-PD-1. NCI 10761171 9/19/23 0:00 PA-22-177 1R44CA285207-01 1 R44 CA 285207 1 "TRIPURANI, SWAMY KRISHNA" 9/19/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 9297425 "MARATHI, UPENDRA " "LEWIS, LIONEL DAVID; SCHARY, WILLIAM " 7 Unavailable 79364082 CJJ6DE7APKY6 79364082 CJJ6DE7APKY6 US 29.707269 -95.408671 10037533 "7 HILLS PHARMA, LLC" HOUSTON TX Domestic For-Profits 770302108 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 999200 NCI 768615 230585 PROJECT SUMMARY/ABSTRACTImmuno-oncology (IO) therapies particularly immune checkpoint inhibitors (ICIs) such as nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) have made rapid advances in inducing remarkable response rates in patientsin a variety of solid tumors. However over 40% of melanoma patients develop secondary resistance to aPD-1-based therapy and have limited treatment options.Integrins 41 and L2 are crucial for antigen presentation T cell priming and trafficking. 7HP349 is an oralallosteric agonist of 41 and L2 integrins that may potentially reverse anti-PD-1 resistance and increase ICIeffectiveness in these patients without elevating toxicity. 7HP349 shows augmented T cell activity in vitro andenhanced antitumor efficacy and survival in tumor models with increased T cell infiltration into tumors but notto normal tissues. We have made significant progress with 7HP349 development including approval of OrphanDrug Designation (ODD) and Fast-Track Designation for melanoma and completion of a first-in-human (FIH)Phase I study of the safety tolerability and pharmacokinetics of 7HP349 with the optimal pharmacokinetic dose(OPD) defined for Phase Ib/IIa.Our hypothesis is that the augmentation of T cell responses with a standard regimen of ipilimumab incombination with 7HP349 followed by a maintenance regimen of nivolumab monotherapy will improveresponses without added toxicity in solid tumor patients with secondary aPD-1 resistance. Here we propose aPhase Ib dose escalation study (7HP-111a) with 7HP349 to evaluate the safety tolerability and PK of 7HP349 incombination with ipilimumab followed sequentially by nivolumab monotherapy in solid tumor patients(melanoma pleural mesothelioma renal cell carcinoma MSI-high or mismatch repair-deficient colorectal cancerhepatocellular carcinoma and non-small cell lung cancer with no EGFR or anaplastic lymphoma kinase (ALK)genomic tumor aberrations) who have secondary aPD-1 resistance. T cell activation studies will also beperformed on patient samples and biopsies collected as part of this study. The proposed Phase Ib study will notonly enable the subsequent design and conduct of a future Phase IIa dose expansion study to evaluate thepreliminary efficacy of 7HP349 in combination with ipilimumab followed sequentially by nivolumab monotherapyin melanoma patients with secondary resistance to aPD-1 therapy but potentially lay the foundation for noveltreatment options in such patients. 999200 +No NIH Category available Address;Adjuvant;Animals;Biodistribution;Biological Assay;Biotechnology;Cause of Death;Cell Death;Characteristics;Cisplatin;Clinical;Collaborations;Combined Modality Therapy;Cytotoxic agent;Darkness;Data;Deglutition;Development;Disease;Disease model;Distant;Dose;Dose Limiting;Drug Kinetics;Drug Targeting;Economic Burden;Effectiveness;Esophageal carcinoma;Fluorescence;Foundations;Generations;Goals;Grant;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Histologic;Human Papillomavirus;In Vitro;Incidence;Investigation;Kidney;Kinetics;Lasers;Legal patent;Licensing;Light;Lighting;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Maximum Tolerated Dose;Measures;Medical Technology;Morbidity - disease rate;Mouth Neoplasms;Mucositis;Mus;Outcome;Oxygen;PUVA Photochemotherapy;Patients;Penetration;Pennsylvania;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Phototherapy;Platinum;Prodrugs;Publications;Radiation;Recurrent disease;Regimen;Research;Safety;Singlet Oxygen;Site;Skin Carcinoma;Small Business Technology Transfer Research;Solid Neoplasm;Squamous cell carcinoma;Survivors;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Treatment Protocols;Tumor Volume;Universities;Virginia;Work;advanced disease;analog;animal imaging;anti-tumor immune response;chemotherapy;commercialization;compare effectiveness;cytotoxic;disability;dosage;drug candidate;effective therapy;efficacy evaluation;improved;in vivo;mouse model;novel;novel therapeutic intervention;novel therapeutics;preclinical development;side effect;skin squamous cell carcinoma;systemic toxicity;targeted treatment;time interval;treatment strategy;tumor;tumor hypoxia;uptake Light-directed therapy of squamous cell head and neck cancer with a novel dual-acting chemotherapeutic. PROJECT NARRATIVEHead and neck cancer is the sixth leading cancer worldwide and ninth leading cause of death. A standardchemotherapy for head and neck cancer is cisplatin; however systemic administration of cisplatin causessevere side effects that limit its use dosage and effectiveness. In order to reduce these side effects andmaximize effective treatment of head and neck cancer we propose a new therapeutic agent thatdelivers a potent dose of activated cisplatin and toxic oxygen species selectively to the site of the tumorwith light. NCI 10761072 8/3/23 0:00 PA-22-178 1R41CA281440-01A1 1 R41 CA 281440 1 A1 "POND, MONIQUE ADRIANNE" 8/3/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-E(11)B] 8856326 "HARTMAN, MATTHEW C" "HARADA, HISASHI " 4 Unavailable 117161580 JY3LRMUPFQW9 117161580 JY3LRMUPFQW9 US 37.547136 -77.447015 10059652 "LIGHT SWITCH BIO, LLC" Richmond VA Domestic For-Profits 23298 UNITED STATES N 8/3/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 406186 NCI 316066 63967 PROJECT SUMMARY. In this Phase I STTR project Light Switch Bio will collaborate with VirginiaCommonwealth University and the University of Pennsylvania for the early-stage development of IR-Platin afirst-in-class photoactivated chemotherapy for treatment of head and neck squamous cell carcinoma (HNSCC)the sixth leading cancer worldwide. Most patients with HNSCC present with advanced disease and needmultimodal therapy incorporating cisplatin which has shown to be effective in controlling locoregional disease.However the use of cisplatin is plagued by issues with dose-limiting toxicities that are potentially lethal andcontribute to long-term disability. For many patients these toxicities mean that they cannot receive prolongedtreatment of cisplatin and as a result suffer worse outcomes. When combined with radiation cisplatin is alsoknown to exacerbate radiation-induced mucositis that creates a spectrum of long-term swallowing disabilities.These challenges present an opportunity for strategies that can deliver cisplatin locally avoiding the disablingmorbidities and potentially lethal side effects of systemically active cisplatin. Our strategy to address this needis IR-Platin: an inactive prodrug of cisplatin that releases activated platinum(II) species and singlet oxygen in thepresence of near-infrared (nIR) light. The dual mode of activation is expected to lead to effective treatment oflarge and hypoxic tumors two of the main limitations of photodynamic therapy. Moreover because the releaseof activated platinum species is directed with light the systemic toxicity associated with platinum chemotherapyin HNSCC should be strongly diminished. Further the demonstrated tendency for phototherapies to induce anantitumor immune response in combination with the adjuvant capacity of active platinum(II) species grants IR-Platin the potential to provide control of distant disease and recurrent disease. Our publications and preliminarydata have established the dual mechanisms of action of IR-Platin its in vitro stability its low toxicity in mice andimproved tumor control in mice bearing HNSCC tumors treated with IR-Platin plus nIR light compared to cisplatin.The goal of this proposal is to establish the feasibility and therapeutic potential of IR-Platin for the treatment ofHNSCC in orthotopic mouse models. The results of the proposed investigation are anticipated to help obtaincritical preliminary data to support larger IND-enabling studies and our Phase II STTR application. Specific Aim1 focuses on IR-Platins tumor uptake toxicity efficacy and mechanism of action for treatment in orthotopicmouse models of HNSCC. Specific Aim 2 investigates the pharmacokinetics of IR-Platin. These studies willprovide critical data to evaluate the therapeutic potential of IR-Platin for the treatment of HNSCC and will lay thefoundation for its use in the targeted treatment of other light accessible cancers (e.g. non-resectable squamouscarcinomas of the skin and esophagus; lung cancer; bladder cancer). As a first-in-class treatment strategy IR-Platin will also pave the way for Light Switch Bios development of other light-targeted drugs that mitigate off-target toxicities by physically targeting their activity. 406186 +No NIH Category available Animals;Antibody Therapy;Antibody-drug conjugates;Antigens;Apoptotic;Aptamer Technology;Binding;Biodistribution;Bypass;Cancer Etiology;Canis familiaris;Cell Line;Cell Proliferation;Cell Surface Receptors;Cells;Cessation of life;Chemistry;Chemotherapy-Oncologic Procedure;Clinical;Clinical Research;Clinical Trials;Confocal Microscopy;Cysteine;Cytotoxic agent;Data;Derivation procedure;Development;Drug Kinetics;Engineering;Enzyme-Linked Immunosorbent Assay;Event;FDA approved;Fc Immunoglobulins;Flow Cytometry;High Pressure Liquid Chromatography;Homing;Human;IgG1;Immune checkpoint inhibitor;Immunoglobulin G;In Vitro;Inbred BALB C Mice;Ketones;Label;Maleimides;Malignant Neoplasms;Malignant neoplasm of pancreas;Maximum Tolerated Dose;Mediating;Monoclonal Antibodies;Mus;N-terminal;Neoplasm Metastasis;Normal Cell;Nucleic Acids;Paclitaxel;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathology;Patients;Penetration;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Primates;Process;Prognosis;Proteomics;Quantitative Reverse Transcriptase PCR;RNA;Reaction;Recombinants;Regulation;Reporting;Reproducibility;Scheme;Services;Side;Site;Small Business Innovation Research Grant;Solid Neoplasm;Specificity;Sulfhydryl Compounds;Surface;Surface Antigens;Survival Rate;Technology;Testing;Therapeutic;Time;Tissue Sample;Tissues;Toxic effect;Treatment Efficacy;Trypsin;Tumor Antigens;Validation;Vascularization;anti-cancer;antigen binding;aptamer;biophysical properties;cancer cell;cancer type;chemical synthesis;cytotoxic;drug candidate;effective therapy;efficacy study;gemcitabine;human tissue;in vivo;in vivo evaluation;innovation;interest;interstitial;manufacturing cost;mouse model;nanoparticle;neoplastic cell;next generation;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;phase 2 study;precision medicine;preclinical study;product development;receptor;response;success;technology platform;transamination;tumor;tumor progression An Aptamer-directed IgG1-Fc Drug Conjugate (AFDC) for Treating Pancreatic Cancer Project NarrativeThis SBIR Phase I project is directed at developing an innovative precision medicine based on Aptamer-directed IgG1-Fc Drug Conjugate (AFDC) for the treatment of pancreatic cancer. NCI 10761053 9/22/23 0:00 PA-22-176 1R43CA281460-01A1 1 R43 CA 281460 1 A1 "EVANS, GREGORY" 9/22/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 78599482 "GAO, XIANG " Not Applicable 9 Unavailable 80344566 KX22VNNMBYZ3 80344566 KX22VNNMBYZ3 US 35.938902 -79.040688 10045918 "ONCOTRAP, INC." CHAPEL HILL NC Domestic For-Profits 275176165 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 400000 NCI 284373 95749 Abstract Pancreatic ductal adenocarcinoma (PDAC) ranks the seventh in causing cancer-related death among allhuman cancers with very poor prognosis and horrendous survival rate. Despite the use of gemcitabine/nab-paclitaxel and FOLFIRINOX the median survival rates for patients with metastatic PDAC are still less than oneyear. Immune checkpoint inhibitor had little responses against PDAC in clinical trials. Currently there is an urgentunmet need to develop precision medicine that can be used for more effective treatment of PDAC. One exciting strategy to specifically kill solid tumors is by using antibody-drug conjugate (ADC) whichhas achieved remarkable success both clinically and commercially. Unfortunately the development of ADC fora specific cancer type such as PDAC is significantly limited by the lack of tumor surface antigens that bind onlyto cancer cells of interest but not normal cells. In this SBIR Phase I project we propose to develop an Aptamer-directed IgG-Fc Drug Conjugate (AFDC) platform by integrating the unique aptamer highly specific to PDAC cellswith the Fc fragment of human IgG1 that is well-known to have prolonged circulating time and exposable cysteineresidues for efficient conjugation with cytotoxic warhead. Two specific aims will be pursued. The first aim is tovalidation of APTPDAC-mediated killing of PDAC cells and development of a potent Aptamer-directed IgG1-FcDrug Conjugate (AFDC) highly specifically against human PDAC cells. The second aim is to perform in vivoevaluation assess anti-tumor efficacy of AFDC in orthotopic PDAC mouse models and identify the putative cellsurface receptor(s) on PDAC cells that is recognized by APTPDAC. The success of this proof-of-concept Phase Iproject will result in an innovative drug conjugate platform with unique features and a drug candidate that can befurther developed for the treatment of PDAC. In the Phase II studies we will perform extensive mechanistic studies on the identified target(s) for tissuespecificity and possible side toxicities. We will more accurately determine the drug conjugation sites the ratiosof aptamer Fc and vcMMAE in the final product by trypsin digest/MOTI-TOF and trypsin digest/HPLC. The invivo stability of aptamer can be further enhanced by using the 2-fully modified RNA aptamer technology the Liulab reported. We will further engineer additional cysteine residues to the N-terminal region of IgG1-Fc and testthe upper limit of drug-to-Fc ratios that can be achieved to evaluate the consequences in terms of toxicity andtherapeutic efficacy in human PDAC PDX mouse models. When we have generated sufficient data in CMC andpreclinical studies we will seek for CRO to generate materials under the GMP regulations and get ready for PKand toxicity studies in dogs and in primates. These studies will pave the road for an IND application for a phaseI human clinical trial. 400000 +No NIH Category available Acute;Address;Antigens;Apoptosis;Australia;Award;Biochemical;Biological Assay;Blood;Body Weight Changes;Bortezomib;CA-125 Antigen;Cancer Model;Cancer Patient;Cancer cell line;Canis familiaris;Carboplatin;Cardiotoxicity;Chemotherapy-Oncologic Procedure;Cisplatin;Clinical;Clinical Trials;Country;Data;Deubiquitination;Development;Dose;Dose Limiting;Drug Targeting;Drug resistance;Effectiveness;Epithelial ovarian cancer;Exhibits;Female;Formulation;Goals;Greater sac of peritoneum;Gynecologic Pathology;Half-Life;Human;Improve Access;Industry;Lead;Legal patent;Licensing;Liquid substance;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Mantle Cell Lymphoma;Marketing;Medical;Medical Oncologist;Molecular Weight;Monitor;Multiple Myeloma;Mus;Neutropenia;Normal Cell;Normal tissue morphology;Nucleosome Core Particle;Operative Surgical Procedures;Organ;Ovarian;Paclitaxel;Patients;Peptides;Peripheral Nerves;Peripheral Nervous System Diseases;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Platinum;Platinum Compounds;Poly(ADP-ribose) Polymerase Inhibitor;Predisposition;Process;Property;Proteasome Inhibition;Proteasome Inhibitor;Proteins;Rattus;Recurrence;Regimen;Resistance;Safety;Scientist;Solid;Solid Neoplasm;Speed;Stress;Structure;Survival Rate;Symptoms;TP53 gene;Testing;Therapeutic;Therapeutic Index;Thrombocytopenia;Tissues;Toxic effect;Toxicology;Treatment Efficacy;Tumor Debulking;Tumor Tissue;Ubiquitin;Universities;Validation;Vascular Endothelial Growth Factors;Vertebral column;analog;anticancer activity;behavior test;cancer cell;cancer therapy;cell killing;chemotherapy;design;drug candidate;endoplasmic reticulum stress;experience;improved;improved outcome;in vitro activity;in vivo;inhibitor;manufacture;method development;misfolded protein;mouse model;multicatalytic endopeptidase complex;neoplastic cell;neurophysiology;neurotoxicity;novel;novel therapeutics;patient derived xenograft model;peptide drug;pharmacokinetics and pharmacodynamics;preclinical development;protein aggregation;protein metabolism;proteotoxicity;receptor;refractory cancer;response;safety study;side effect;small molecule;small molecule inhibitor;standard of care;targeted agent;therapeutic evaluation;treatment response;tumor;tumor xenograft;ubiquitin isopeptidase Development of a novel small molecule RPN13 inhibitor and therapeutic for advanced ovarian cancer patients Project Narrative:Three new proteasome-targeting chemotherapeutic drugs reached the market in the past decade. Althoughthese peptide-based proteasome inhibitors are effective against multiple myeloma unfortunately they have notproven useful to treat solid tumors (e.g. Ovarian Cancer). Up Therapeutics is developing novel small moleculeinhibitors that are not peptide-based and target a different component of the proteasome (RPN13) as drugcandidates for the treatment of solid tumors notably ovarian cancer. NCI 10760824 8/30/23 0:00 PA-22-176 1R44CA278176-01A1 1 R44 CA 278176 1 A1 "POND, MONIQUE ADRIANNE" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 14879826 "ANCHOORI, RAVI KUMAR" Not Applicable 6 Unavailable 80370789 KVFLK2JVJST8 80370789 KVFLK2JVJST8 US 39.186076 -76.788341 10043401 "UP THERAPEUTICS, INC." Frederick MD Domestic For-Profits 21704 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 868417 NCI 736575 75030 Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy despite aggressive surgery andtoxic chemotherapies. More effective and safer targeted drugs are urgently needed to address this unmetmedical need. Compared to normal tissues EOC exhibits aberrant proteasome function that triggersaccumulation of high molecular weight polyubiqutinated and misfolded protein aggregates. Because of thisunresolved proteotoxic stress EOC cell lines are highly susceptible to proteasome inhibitors. While highlyeffective against liquid cancers like multiple myeloma unfortunately the licensed 20S proteasome inhibitorssuch as bortezomib have proven ineffective against solid tumors including EOC. This reflects limited tissueaccess for these peptide-based drugs and dose-limiting toxicities notably peripheral neuropathythrombocytopenia and neutropenia. Up284 is a proprietary upstream (19S) proteasome inhibitor with a noveltarget and mechanism RPN13 inhibition and a structure designed to overcome the limitations of the licenseddrugs with respect to limited potency (Up284 blocks substrate recognition and deubiquitination by the 19Srather than just one of the three 20S catalytic activities) poor activity against solid tumors (Up284 has anovel spiro structure with improved drug-like properties compared to peptide-based 20S inhibitors andpromotes antigen-representation by tumor cells) key toxicities of peripheral neuropathy (Not clinicallyapparent with Up284 in initial murine studies) and thrombocytopenia and neutropenia (Up284 spares theimmunoproteasome and lacks these side effects). Up284 shows broad anticancer activity in vitro includingagainst EOC lines selected for platinum resistance with a robust therapeutic index and a promising safety profileand the ability to control xenograft tumor in an orthotopic mouse model of EOC. This promising data reflects ourextensive medicinal chemistry effort to achieve drug-like properties and a patent has been awarded in US(pending in other countries) to cover the novel backbone and lead compounds. Murine data indicate Up284 hasfavorable pharmacodynamics and confirm the novel mechanism of action in vivo. By inhibiting proteasomeubiquitin receptor RPN13 function and its associated deubiquitinase activity Up284 produces more rapidaccumulation of larger molecular weight polyubiquinated protein aggregates than the 20S inhibitors. These toxicmisfolded protein aggregates produce an unresolved ER stress activate the canonical Unfolded ProteinResponse (UPR) and thus Up284 more rapidly triggers p53-independent apoptosis than 20S inhibitor. To supportan IND application to FDA we propose: Aim 1: Assessing toxicity & Peripheral Neuropathy (PN) in mice treatedIP vs IV with Up284 vs. bortezomib (months 1-3). Aim 2: Mouse clinical trial: Testing therapeutic efficacy ofUp284 delivered IP vs IV against 13 ovarian PDX models (months 3-7); Aim 3: Process development GLPmanufacture formulation stability & GLP bioanalytical method development of Up284 (months 7-24); Aims 4 &5: GLP toxicology and safety studies of Up284 in rats & dogs (months 15-24). 868417 +No NIH Category available Adolescent;Adult;American Cancer Society;Antibodies;Antibody-drug conjugates;Antineoplastic Agents;Behavior;Biological Assay;Body Weight Changes;Body Weight decreased;Bypass;Canis familiaris;Cell Line;Cells;Cessation of life;Child;Clinic;Clinical;Clinical Research;Data;Disease;Dose;Doxorubicin;Drug Design;Ewings sarcoma;Excretory function;Female;Goals;Good Manufacturing Process;Guidelines;Histologic;Human;Ifosfamide;Insurance Carriers;Investigational Drugs;Lead;Ligand Binding;Ligands;Liquid Chromatography;Macrophage;Malignant Fibrous Histiocytoma;Malignant Neoplasms;Mass Spectrum Analysis;Maximum Tolerated Dose;Measures;Metabolism;Methodology;Methods;Modeling;Mus;Nude Mice;Oncology;Operative Surgical Procedures;Patients;Pharmacotherapy;Phase;Price;Process;Property;Radiation;Rattus;Receptor Cell;Recovery;Renal function;Resistance;Rodent;Science;Small Business Innovation Research Grant;Soft tissue sarcoma;Solid Neoplasm;Survival Rate;Therapeutic;Toxic effect;Toxicokinetics;Toxicology;Toxin;Treatment outcome;Tumor-associated macrophages;United States;Validation;Vertebral column;Work;absorption;anti-cancer;cancer cell;cancer subtypes;cancer therapy;cancer type;chemical substitution;chemotherapy;clinical development;cost;dosage;effectiveness evaluation;efficacy study;improved;innovation;leiomyosarcoma;liver function;male;manufacture;molecular subtypes;mouse model;novel;novel strategies;patient derived xenograft model;pharmacokinetics and pharmacodynamics;pre-Investigational New Drug meeting;pre-clinical;programs;research clinical testing;response;sarcoma;soft tissue;subcutaneous;success;synovial sarcoma;targeted treatment;therapeutic target;tumor;tumor heterogeneity;validation studies Targeting Macrophages to Treat Soft Tissue Sarcomas PROJECT NARRATIVESoft tissues sarcomas (STS) is a broad term for multiple subtypes of cancer that start in soft tissues. There iscurrently no unifying treatment for STS subtypes beyond surgery chemotherapy and radiation. ResoluteScience Inc. is developing novel STS therapy by using tumor-associated macrophages (TAMs) to process anddeliver anti-cancer agents to solid tumors. NCI 10760719 7/26/23 0:00 PA-22-176 1R44CA285036-01 1 R44 CA 285036 1 "EVANS, GREGORY" 8/1/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 78495902 "BARNETT, FAITH H" Not Applicable 50 Unavailable 117780091 VRZMU2PG3G24 117780091 VRZMU2PG3G24 US 10067443 "RESOLUTE SCIENCE, INC." RANCHO SANTA FE CA Domestic For-Profits 92067 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 398976 NCI 266339 106536 PROJECT SUMMARYSoft tissues sarcomas (STS) is a broad term for multiple subtypes of cancer that start in soft tissues. Most STSare treated in the same way in the clinic regardless of the subtype. STS encompasses over 50 histologic andmolecular subtypes with each displaying variable clinical behavior. There is currently no unifying treatmentfor STS subtypes beyond surgery chemotherapy and radiation.Resolute Science Inc. is developing novel STS therapy by using TAMs to process and deliver anti-cancer agentsto solid tumors. Targeting TAMs to kill the associated cancer has the advantage of being tumor-agnosticcompared to that of targeting a specific cancer cell receptor. This approach bypasses concerns of tumorheterogeneity and evolved resistance associated with therapeutics that target specific properties of each cancertype. Our lead therapeutic RS-5 is well-tolerated and demonstrated strong anti-cancer efficacy across multiplemurine sarcoma tumor models including the subcutaneous (sc) and intracranial (ic) HT1080 sarcoma cell linemodel and a doxorubicin-resistant patient derived xenograft (PDX) sarcoma model. Resolutes modular drugdesign allows for straightforward chemical substitutions of ligand backbone linker and payloads. Finally thecost of commercial manufacturing will be significantly lower than that of antibodies and antibody-drug conjugates(ADCs) which could significantly reduce the price of this cancer treatment for patients and insurers.The overall goal of the Fast-Track program is to conduct studies that further show the efficacy of Resolutesplatform molecule as therapy for different STS subtypes and perform pre-Investigational New Drug (IND) andIND-enabling studies. Our Phase I goal for this SBIR Fast-Track proposal is to validate the choice of one subtypeof STS Undifferentiated Pleomorphic Sarcoma (UPS) as an initial clinical indication for RS-5. The measure ofsuccess to advance to Phase II is 1) establish dose response of RS-5 in a doxorubicin-resistant UPS model 2)establish anti-cancer efficacy equal or better than doxorubicin in a doxorubicin-naive PDX model 3) demonstrateanti-cancer efficacy in both male and female mice 4) establish contribution of MTM to anti-cancer efficacy fromthat of RS-5. In Phase II we will perform pre-Investigational New Drug (IND) and IND-enabling studies withpotential expansion into other STS subtypes through additional efficacy studies. The measure of success forPhase II is 1) demonstrate comparable or better anti-cancer efficacy of RS-5 at a well-tolerated dose to that ofdoxorubicin at a well-tolerated dose in at least 1 additional PDX model 2) the successful validation of bio-analytical methods for nonclinical toxicology species and humans and 3) conduct IND-enabling studies.Completion of this Fast-Track proposal will result in validation of STS as our first clinical indication for RS-5 andcompletion of the IND-enabling studies to support the clinical development of RS-5. Once completed the PhaseI and II work will provide a rapid path for RS-5 to obtain approval for Phase I clinical testing. 398976 +No NIH Category available Acute;Age;Animal Model;Antibodies;Antibody-drug conjugates;Antimitotic Agents;Apoptosis;Attention;Autologous Stem Cell Transplantation;Binding;Biological;Biological Assay;Biological Sciences;Blood;Brain;Carcinoma;Cell Proliferation;Cell Survival;Cell model;Cells;Central Nervous System;Central Nervous System Neoplasms;Cerebellum;Chemotherapy-Oncologic Procedure;Child;Childhood Brain Neoplasm;Childhood Malignant Brain Tumor;Chromatin Remodeling Factor;Chronic;Clinical;Consensus;Cytotoxic agent;Diagnosis;Disease;Dose;Drug Administration Routes;Drug Delivery Systems;Drug Exposure;Drug Kinetics;Drug Targeting;Engraftment;Epigenetic Process;Excision;Exhibits;FDA approved;Failure;Genetic;High Dose Chemotherapy;Histone Acetylation;Histone Deacetylase Inhibitor;Human;Immunofluorescence Immunologic;In Vitro;Injections;Insulin-Like-Growth Factor I Receptor;Intravenous;Invaded;Laboratories;Lead;Link;Luciferases;Malignant Neoplasms;Maximum Tolerated Dose;Medicine;Microtubules;Modality;Modeling;Mus;Neurosecretory Systems;Operative Surgical Procedures;Organ;Pathogenesis;Patients;Penetration;Peptides;Pharmaceutical Preparations;Phase;Positioning Attribute;Pre-Clinical Model;Primary Neoplasm;Prognosis;Radiation therapy;Research;Rhabdoid Tumor;Risk;Route;SMARCA4 gene;SMARCB1 gene;Sampling;Site;Small Business Technology Transfer Research;Standardization;Subgroup;Surface;Systemic Therapy;Testing;Therapeutic;Therapeutic Effect;Tissues;Toxic effect;Toxin;Treatment Efficacy;Treatment Protocols;Tumor Cell Line;Tumor Volume;Western Blotting;Xenograft Model;anti-cancer;blood-brain barrier penetration;cell motility;chemotherapy;chromatin remodeling;cytotoxicity;early childhood;efficacy evaluation;implantation;improved;in vivo;meter;mouse model;neoplastic cell;novel;peptide drug;rare cancer;response;side effect;systemic toxicity;targeted treatment;treatment strategy;tumor;tumor growth;tumorigenesis An IGF-1R-targeting peptide drug conjugate for targeted treatment of atypical teratoid/rhabdoid tumors NARRATIVEAtypical teratoid/rhabdoid tumors (AT/RT) are rare but lethal childhood brain cancers that lack effective andsafe targeted therapies. NightHawk Biosciences Inc. has developed an anti-IGF-1R peptide-drug conjugate(PDC) to link an AT/RT-targeting peptide to strong cytotoxic drugs for enhanced delivery and tumor specifictreatment. NightHawk has partnered with N. Dahmanes laboratory at Weill Cornell Medicine examine thepotential of this therapeutic approach for AT/RT. NCI 10760549 9/19/23 0:00 PA-22-178 1R41CA285172-01 1 R41 CA 285172 1 "DJEMIL, SARRA" 9/19/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 10198431 "GOLDSTEIN, NEIL " Not Applicable 4 Unavailable 828572292 HQUBBMC377D4 828572292; 957834133 HQUBBMC377D4 US 35.888104 -78.889749 10020622 "NIGHTHAWK BIOSCIENCES, INC." Morrisville NC Domestic For-Profits 275606847 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 399110 NCI 350833 22167 PROJECT SUMMARYAtypical teratoid/rhabdoid tumors (AT/RT) are rare embryonal central nervous system malignancies that occurin early childhood and are lethal. Current treatment strategies for children diagnosed with AT/RT are limited tosurgery radiation and chemotherapy but to date none of these have successfully improved survival beyond18 months and most are associated with significant toxicities given the young age of patients. Geneticinactivation of the SWI/SNF chromatin remodeling complex underlies AT/RT tumorigenesis; thus targetedtherapies that can correct the epigenetic dysregulation in AT/RT present a compelling therapeutic strategy ifthese agents can be selectively delivered to tumor cells in the brain. Peptide-drug conjugates (PDCs) are onetreatment modality that can accomplish this by linking target-specific peptides to strong cytotoxic drugs toenhance site-specific delivery and tumor-specific therapeutic effects while limiting exposure of the drug tohealthy surrounding tissues. To leverage this approach for AT/RT NightHawk Biosciences Inc. has developeda PDC strategy that combines a novel binding peptide (429) against the Insulin-like Growth Factor 1 Receptor(IGF-1R) which is highly expressed on the surface of AT/RT cells with potent cytotoxic drugs for targetedtreatment of AT/RT. In this Phase I STTR NightHawk will partner with Dr. Nadia Dahmanes laboratory at WeillCornell Medicine to test two investigational anti-IGF-1R PDCs one conjugated to the antimitotic toxinmonomethyl auristatin E (MMAE) and a second conjugated to the pan-HDAC inhibitor panobinostat in cell andanimal models of AT/RT. In preliminary studies anti-IGF-1R PDCs are efficacious against IGF-1R-expressingand AT/RT cell lines in vitro. Further a single intratumoral injection of 429-MMAE significantly reduced tumorvolumes following flank implantation of A431 an IGF-1R-expressing epithelial carcinoma. To validate thepotential of this approach for AT/RT and define the optimal drug to be used in the final PDC format we proposeto examine anti-IGF-1R PDCs for therapeutic efficacy against human AT/RT cells and in an in vivo orthotopictumor model. In Aim 1 anti-IGF-1R PDC candidates will be tested against an expanded panel of human AT/RTcell lines for effects on cell viability apoptosis cytotoxicity and cell migration and invasion. In Aim 2 systemic(intravenous) and direct (intratumoral) drug delivery strategies will be explored to define dose-exposure responserelationships and to determine the maximum tolerated dose. Aim 3 will evaluate in vivo efficacy of the anti-IGF-1R PDCs on tumor inhibition and survival in an established orthotopic mouse model of AT/RT. We expect thatcompletion of the proposed aims will determine potential for achieving therapeutic benefit in AT/RT and identifya lead PDC candidate to advance to IND-enabling studies. 399110 +No NIH Category available Address;Adjuvant;Antibodies;Antigens;Antitumor Response;Blood;CD8-Positive T-Lymphocytes;Cancer Vaccines;Cells;Clinical;Clinical Trials;Cryopreservation;DNA;DNA Maintenance;DNA Vaccines;DNA delivery;Delivery Rooms;Development;Devices;Disadvantaged;Dose;Dryness;Effectiveness;Electroporation;Epidermis;Formulation;Freeze Drying;Future;Genetic;Goals;Gold;Human;Immune Targeting;Immune response;Immunization;Immunotherapeutic agent;Immunotherapy;Intramuscular;Intramuscular Injections;Jet Injections;Lead;Malignant Neoplasms;Mediating;Melanoma Vaccine;Methods;Modality;Modeling;Mucous Membrane;Mus;Muscle;Natural Killer Cells;Needles;Nucleic Acid Vaccines;Nucleic Acids;Pain;Painless;Phase;RNA;RNA delivery;RNA vaccine;Regimen;Research;Site;Skin;Small Business Innovation Research Grant;T cell response;Technology;Temperature;Testing;Therapeutic;Time;Tissues;Treatment Efficacy;Tumor-Infiltrating Lymphocytes;Vaccination;Vaccines;Work;cancer immunotherapy;cancer therapy;clinical development;comparative efficacy;efficacy evaluation;gene gun;gp100 Antigen;immunogenicity;improved;individual patient;lipid nanoparticle;melanoma;mouse model;nanoparticle delivery;neoantigen vaccine;neoantigens;neoplastic cell;next generation;novel;nucleic acid delivery;particle;preclinical development;protective efficacy;prototype;response;therapeutic evaluation;trafficking;tumor;vaccine delivery Next Generation Gene-Gun Delivered DNA and RNA Immunotherapeutic Vaccines for Melanoma. PROJECT NARRATIVEOrlances Gene Gun uniquely enables needle-free delivery of DNA and RNA vaccines into the epidermis of theskin. We hypothesize that the ability of the gene gun to directly deliver DNA and RNA into cells in the epidermiswill make it more effective than conventional intramuscular delivery of DNA and RNA vaccines in targeting tumorcells localized in the skin. Here we will optimize gene gun delivery of DNA or RNA to identify a regimen thatinduces strong tumor specific immune responses and protection from melanoma in a mouse model. NCI 10760452 9/21/23 0:00 PA-22-176 1R43CA281585-01A1 1 R43 CA 281585 1 A1 "REGMI, SAROJ GOPAL" 9/21/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CDPT-V(13)B] 16307527 "FRIZZELL, HANNAH " Not Applicable 7 Unavailable 80337564 KH6YJYH55G53 80337564 KH6YJYH55G53 US 47.567886 -122.313367 10042809 "ORLANCE, INC." SEATTLE WA Domestic For-Profits 981950008 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 200000 NCI 153885 33032 PROJECT SUMMARYOrlance has developed a next-generation Gene Gun (MACH-1 GG) that efficiently delivers DNA and RNA intoepidermal cells leading to robust immune responses. Sequencing of tumors from individual patients has led tothe identification of personalized neoantigens that could be targeted with cancer vaccines. Howevertechnologies that can effectively deliver these cancer neoantigens and promote the induction of localized tumorspecific T cell responses are still needed. Nucleic acid (NA; DNA and RNA) vaccines administered using specificformulations or delivery technologies that achieve intracellular delivery offer considerable promise to achievethis goal. These include electroporation (EP) or jet injection for IM delivery of DNA or lipid nanoparticles (LNPs)for IM delivery of RNA. These delivery modalities however have different drawbacks including a requirementfor high doses (1-5 mg of DNA) ultra-cold storage due to limited stability (RNA/LNPs) reactogenicity or painpost-administration and a limited ability to target immune responses to specific tissues. The GG entails thedelivery of room temperature stable lyophilized DNA or RNA vaccines on gold microparticles. It achieves painlessand direct intracellular delivery into skin cells with very low doses (1-4 g) that results in systemic mucosal andlocalized skin immune responses that could provide a benefit for treatment of cancers and in particularmelanoma. The MACH-1 GG is based on a previous successful GG that induced strong antibody and T cellresponses in phase I human clinical trials. The MACH-1 provides significant improvements over this earlierdevice. Here we will investigate the feasibility of using MACH-1 to deliver DNA or RNA cancer vaccines in miceand test the hypothesis that MACH-1 will offer advantages in immunogenicity and efficacy over other DNA/RNAdelivery technologies for melanoma. We will first determine if co-delivering a novel set of genetic adjuvants willincrease the ability of MACH-1 DNA and RNA vaccines to induce melanoma-specific T cell responses. Next wewill determine if combining DNA and RNA in the same dose or in a prime-boost regimen offers synergistic effects.We will then compare MACH-1 delivery of DNA and/or RNA melanoma vaccines to DNA delivery by EP or RNAdelivery by LNPs for immunogenicity and protective efficacy in mice. This work will be accomplished in two Aims:Aim 1: Investigate the impact of genetic adjuvants on the immunogenicity and efficacy of GG delivered DNA andRNA melanoma vaccines. Aim 2: Determine if combining the optimized adjuvanted DNA and RNA vaccines inthe same dose or in a prime-boost regimen enhances immunogenicity and efficacy compared to EP delivery ofDNA and LNP delivery of RNA in a mouse model of melanoma. Successful completion of these Aims willestablish MACH-1 as an effective device to deliver cancer vaccines. 200000 +No NIH Category available Address;Benchmarking;Biological Assay;Biological Markers;Biological Specimen Banks;Blood;Blood Tests;Budgets;Cancer Patient;Characteristics;Circulation;Clinical;Clinical Sensitivity;Clinical Trials;Complex;DNA Probes;Data;Detection;Development;Epigenetic Process;Gene Silencing;Genome;Genomic Segment;Genomics;Goals;Hypermethylation;Immune;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotherapy;Kinetics;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Measures;Methods;Methylation;Monitor;Mutation;Non-Small-Cell Lung Carcinoma;Outcome;Paper;Patients;Pattern;Performance;Phase;Plasma;Prediction of Response to Therapy;Publishing;Reproducibility;Scanning;Screening for cancer;Sensitivity and Specificity;Signal Transduction;Small Business Innovation Research Grant;Somatic Mutation;Specific qualifier value;Specificity;Surveys;Technology;Therapeutic;Therapeutic Equivalency;Treatment Efficacy;Tumor Tissue;Universities;Validation;Work;cancer genome;cancer immunotherapy;cancer type;cell free DNA;checkpoint therapy;chemotherapy;clinical practice;clinical predictors;commercialization;density;disorder control;effective therapy;exome sequencing;immune cell infiltrate;improved;ineffective therapies;liquid biopsy;mutant;patient subsets;promoter;radiological imaging;responders and non-responders;response;serial imaging;side effect;survival outcome;tumor;tumor DNA;validation studies;virtual Monitoring Immunotherapy Response via Gene Silencing Landscapes in Cell-Free DNA PROJECT NARRATIVE:Some lung cancer patients have robust and durable tumor responses to immunotherapy whereas othersderive no benefit from such treatment. A blood test that monitors for changes in the amount of tumor DNA inthe circulation could help to distinguish responders from non-responders thereby improving clinical outcomesin such patients. NCI 10760450 8/28/23 0:00 PA-22-176 1R43CA285041-01 1 R43 CA 285041 1 "BOZZA, WILLIAM PATRICK" 9/1/23 0:00 2/29/24 0:00 Special Emphasis Panel[ZRG1-CDPT-V(13)B] 8783320 "BARRETT, MICHAEL T" "PATEL, ABHIJIT " 2 Unavailable 117513847 FVZKKWHC58Q6 117513847 FVZKKWHC58Q6 US 41.290358 -72.63544 10061767 "BINARY GENOMICS, INC." MADISON CT Domestic For-Profits 64432172 UNITED STATES N 9/1/23 0:00 2/29/24 0:00 394 SBIR/STTR 2023 398040 NCI 281714 90286 ABSTRACT:Immunotherapies produce remarkable long-term responses in subsets of patients with non-small cell lungcancer but unfortunately most patients do not respond to such treatment. Current biomarkers to predict whichpatients will benefit have limited accuracy and decisions to continue or suspend treatment are mainly guided bymonitoring of radiographic changes in tumor size. However unusual immune-related response patterns suchas pseudo-progression mixed response and delayed response can make scans difficult to interpret. Circulatingtumor DNA (ctDNA) has emerged as a highly promising biomarker for monitoring immunotherapy efficacy.Several studies involving various immunotherapy agents and multiple types of cancer have demonstrated thatearly reduction in ctDNA levels during treatment are predictive of tumor response and improved survivaloutcomes. However existing technologies that measure ctDNA by probing for common somatic mutations willfail patients whose tumors lack these mutations. This limitation is being addressed by creating customizedassays based on patient-specific tumor mutation profiles; but this approach is complex expensive and slow.We have developed a ctDNA assay technology based on detection of epigenetic features that are found invirtually all cancer cell genomes. Preliminary data indicate that our approach has broad patient coverage andcan be applied to multiple types of cancer without requiring tumor profiling and assay customization. As proofof concept we aim to establish the utility of our assay technology for monitoring of lung cancer immunotherapyresponse. In this Phase I SBIR application we will evaluate the analytical and baseline clinical performancecharacteristics of the assay technology with a plan for a larger follow-on clinical utility study in Phase II. Theanalytical validation and baseline clinical performance metrics will be benchmarked against existing commercialmutation-based ctDNA assays to justify further development and commercialization of our technology. 398040 +No NIH Category available Agonist;Animal Model;Antigen-Presenting Cells;Autologous;Blood;CD8-Positive T-Lymphocytes;Cell physiology;Clinical;Clone Cells;Coculture Techniques;Cross Presentation;Cross-Priming;Dendritic Cells;Disease remission;Distant;FLT3 ligand;Genetic;Goals;Hepatitis B Surface Antigens;Hodgkin Disease;Immune system;Immunologic Monitoring;Immunology;Immunotherapy;Indolent;Infiltration;Knowledge;Lymphoma;Measures;Mediating;Methods;Minority;Modeling;Molecular;Mus;Mutation;Non-Hodgkin's Lymphoma;Oncology;Outcome;PD-1 blockade;Patient Monitoring;Patients;Phenotype;Pre-Clinical Model;Production;Radiation therapy;Resistance;Sampling;Site;Sorting;T cell receptor repertoire sequencing;T cell response;T cell therapy;T-Cell Activation;T-Lymphocyte;Techniques;Testing;Therapeutic Effect;Tumor Antigens;Tumor Suppression;Work;anti-PD-1;anti-PD1 therapy;antigen-specific T cells;antitumor effect;cancer therapy;chemokine;clinical remission;cross reacting material 197;cytokine;immune checkpoint blockade;improved;in situ cancer vaccination;in situ vaccination;insight;mouse model;non-Hodgkin's lymphoma patients;novel;patient subsets;pembrolizumab;predict clinical outcome;preservation;prevent;programmed cell death ligand 1;programmed cell death protein 1;recruit;resistance mechanism;response;tumor;tumor microenvironment;usability Potentiating Checkpoint Blockade by Cross-Priming Tumor-Reactive T cells with In Situ Vaccination PROJECT NARRATIVE: Checkpoint blockade immunotherapy has been a great advance in oncology but still onlybenefits a minority of patients. We have developed a novel immunotherapy in situ vaccination(ISV) which induces clinical remissions in patients with lymphoma and greatly increases theefficacy of PD1-blockade in a pre-clinical model. This prompted a new recently opened trialcombining ISV with PD1 blockade. Here we will perform basic immunology studies to improveour understanding of the ISV and PD1-blockade in previously banked and unidentified patientsamples and in the animal model. NCI 10760305 11/13/23 0:00 PA-19-056 5R37CA246239-05 5 R37 CA 246239 5 "SOMMERS, CONNIE L" 12/6/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 9049556 "BRODY, JOSHUA D" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 348958 NCI 205875 143083 PROJECT SUMMARY: Checkpoint blockade has had tremendous impact on cancer therapy but onlya subset of patients respond. While non-response may be due to lack of tumor-associated antigen(TAA) our group and others have shown that as important as having TAA is the immune systemscapacity to present TAA on antigen presenting cells specifically a subset of cross-presenting Batf3-expressing dendritic cells (DC). Without Batf3-DC anti-tumor effects of PD1 blockade are lost.Therefore we hypothesize that increasing cross-priming DC will improve the efficacy of PD1 blockade. To increase cross-priming we developed an in situ vaccination (ISV) combining (i) Flt3L to recruitDC (ii) radiotherapy (XRT) to load DC with TAA and (iii) a TLR agonist to activate the TAA-loaded DCs.We tested this novel ISV (Flt3L/XRT/polyIC) in advanced stage lymphoma patients and observeddramatic systemic remissions in some patients. To improve the ISV we developed a murine ISV modelwhich recapitulated the clinical findings and also increased cure rates of PD1 blockade from 0% to~75% which prompted a new trial using ISV plus pembrolizumab opened in 02/19. Still the unmet clinical need is great to understand and improve upon our ISV and PD1 blockadewe will develop methods to measure cross-priming using sophisticated mouse models (Aim 1) anddeep immune monitoring of patient samples from the two trials (Aim 23). In Aim 1 we will determine how ISV enhances PD1 blockade in mouse models in which we preserveonly cross-priming or only direct-priming (by the tumor) or both. Specifically we will: (a) determine ifcross-priming is necessary for ISV anti-tumor effects (b) define a signature of cross-primed T cellsincluding their expression of checkpoint molecules and (c) characterize resistance mechanisms. In Aim 2 we will demonstrate that ISV cross-primes patients tumor-reactive T cells by analyzingbanked samples from our ISV-treated patients. Specifically we will: (a) use ex vivo autologous tumor:Tcell co-cultures flow-sorting and immunoSEQ to identify anti-tumor T cells and (b) use 5 scRNAseq/TCRseq to quantify and characterize those T cells and then correlate them with clinical responses. In Aim 3 we will analyze banked samples from our ongoing ISV plus pembrolizumab trial which alsoincludes administration of a surrogate Ag at the ISV site. Specifically we will: (a) assess whethersurrogate Ag cross-presentation is improved by ISV and PD1 blockade and whether it predicts clinicaloutcomes and (b) determine mechanisms of tumoral suppression of cross-priming. Lymphomas kill ~21000 patients annually in the U.S. The most common lymphomas are incurablewith standard therapies and minimally responsive to checkpoint blockade. Improving our understandingof ISV and PD1 blockade will improve their efficacy and thereby improve the lives of our patients. 348958 +No NIH Category available Address;Animal Model;Auxins;B-Cell Leukemia;Bromodomain;Cancer Etiology;Carcinoma;Cell Culture System;Cell Line;Cells;Chimeric Proteins;Chromosomal translocation;Chromosomes;Clinical;Clinical Research;Clinical Trials;Complex;Development;Drug Targeting;Ectopic Expression;Effectiveness;Engineering;Environment;Female;Future;Gene Fusion;Genes;Genetic Models;Genetically Engineered Mouse;Genomics;Human;In Vitro;Knowledge;Link;Malignant Epithelial Cell;Malignant Neoplasms;Methods;Modeling;Mus;Mutation;Neoplasms;Normal Cell;Nuclear Protein;Nuts;Oncogenic;Patients;Physiological;Population;Property;Proteins;Recurrence;Reporter Genes;Research;Resources;Solid Neoplasm;System;Technology;Testing;Testis;Time;Tissues;Toxic effect;Transgenic Mice;cell type;clinically relevant;cytotoxic;drug candidate;effective therapy;experimental study;fusion gene;genome editing;genomic data;in vivo;in vivo Model;in vivo imaging;innovation;insight;male;mouse model;novel strategies;pre-clinical;progenitor;protein degradation;side effect;small molecule;stem;targeted treatment;therapeutic development;tool;treatment strategy;tumor;tumorigenesis Developing a clinically-relevant genetically engineered mouse model for Nut carcinoma Project Narrative:Nut Carcinoma (NC) is an aggressive cancer with no effective treatment. We will build a genetically engineeredmouse model of NC that will transform understanding of early-stage NC and potentially other cancers caused byNUTM1 gene fusions. The results of our studies will also contribute significant insights needed to developeffective NC treatments without intolerable side effects. NCI 10760244 12/18/23 0:00 PAR-21-038 5R37CA269076-02 5 R37 CA 269076 2 "WITKIN, KEREN L" 1/5/23 0:00 12/31/27 0:00 Molecular Oncogenesis Study Section[MONC] 16611662 "GU, BIN " Not Applicable 7 OBSTETRICS & GYNECOLOGY 193247145 R28EKN92ZTZ9 193247145 R28EKN92ZTZ9 US 42.653979 -84.492032 5245901 MICHIGAN STATE UNIVERSITY EAST LANSING MI SCHOOLS OF MEDICINE 488242600 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 396540 NCI 238276 158264 Title: Developing a Clinically-Relevant Genetically Engineered Mouse Model of NUT CarcinomaProject Summary:A testis-specific gene called Nuclear protein in testis (NUTM1) has emerged as a recurrent fusion partner ofoncogenic fusion genes in poorly understood neoplasms. Among these neoplasms NUT carcinoma (NC) is themost aggressive and is the paradigm for the study of NUTM1 fusion gene-associated cancers. The majority ofNCs are associated with a chromosome translocation that joins together gene fragments of the Bromodomain-containing protein 4 (BRD4) and the NUTM1 protein. Clinical research and experimental research based on invitro cell culture systems has established the BRD4-NUTM1 fusion protein as the sole driver of NC. This projectwill address two vital current issues in NC research:Issue 1: Paradoxically although BRD4-NUTM1 suffices to drive NC ectopic expression of BRD4-NUTM1 innon-NC cells is unequivocally cytotoxic. Whether there is a specific cell type in which NCs originate and howthese cells are able to circumvent the cytotoxic effects of BRD4-NUTM1 is a mystery.Issue 2: As the driver of NC oncogenesis BRD4NUTM1 is the most promising drug target for treating NC.However targeted therapy strategies directed against the BRD4 fragment of BRD4-NUTM1 have beendisappointing largely because of intolerable side effects that are due to endogenous BRD4 being broadlyexpressed. Targeting the testis-specific NUTM1 protein has the potential to circumvent most systematic sideeffects in male patients and all side effects in female patients yet this strategy has not been explored in aphysiological context.Building on our expertise in genome editing technology and unique resources in genetically engineered mouselines we will address these two vital NC issues by building the first genetically engineered mouse model thatcan recapitulate the tissue and physiological context of NC. Aim 1 will build and characterize an induciblechromosome translocation mouse model for NC. Our model mice will express reporter genes for tracing andisolating NC cells that express BRD4-NUTM1. Aim 2 will identify the NC cell type of origin by analyzing genomicdata from NC-originating normal cell populations and cells in early stages of NC development. Aim 3 will leveragein vivo inducible BRD4-NUTM1 protein degradation to model NUTM1 targeting in order to establish a targetingstrategy for treating NC with minimal side effects.Overall Impact. This project will produce a genetically engineered mouse model of Nut Carcinoma as an entirelynew experimental tool for studying oncogenic mechanisms of BRD4-NUTM1. Our studies will transformunderstanding of early-stage NC and spur therapeutic development to treat NC without intolerable side effects.This project will also shed light on mechanisms and treatment strategies for other poorly understood cancerswith NUTM1 fusion genes. 396540 +No NIH Category available 4T1;Affinity;Amino Acids;Antineoplastic Agents;Binding;Biological Markers;Body Weight decreased;Breast Cancer Patient;Carcinoma;Clinical;Contrast Media;Detection;Development;Diagnostic;Diffuse;Diffusion;Dose;Doxorubicin;Drug Delivery Systems;Drug Kinetics;Drug Targeting;Epidermal Growth Factor Receptor;Estrogen Receptors;Extracellular Matrix;Fibronectins;Goals;High Pressure Liquid Chromatography;Human;Imaging technology;Immunocompetent;In Vitro;Injections;Invaded;Life;Magnetic Resonance Imaging;Malignant Neoplasms;Modeling;Molecular;Mus;Neoplasm Metastasis;Normal tissue morphology;Oncoproteins;Outcome;Patients;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Phenotype;Positron-Emission Tomography;Precision therapeutics;Progesterone Receptors;Property;Proteins;Quality of life;Signal Transduction;Small Business Innovation Research Grant;Solid Neoplasm;System;Testing;Therapeutic;Toxic effect;Treatment Efficacy;Tumor Angiogenesis;anti-cancer therapeutic;black women;cancer cell;cancer clinical trial;cancer diagnosis;cancer imaging;cancer therapy;cellular targeting;chemotherapy;clinical application;clinical development;clinical practice;commercialization;cytotoxicity;design;drug efficacy;effective therapy;efficacious treatment;epithelial to mesenchymal transition;hydrophilicity;image guided;image guided therapy;improved;in vivo;malignant breast neoplasm;meter;migration;molecular imaging;mouse model;nanosized;novel;novel therapeutics;overexpression;patient derived xenograft model;peptide drug;personalized cancer therapy;pre-clinical assessment;side effect;systemic toxicity;targeted treatment;theranostics;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor specificity;uptake;young woman Development of peptide drug conjugates for cancer therapy Project NarrativeThe project will focus on development and commercialization of a novel peptide drug conjugate with highlyefficient tumor specific drug delivery for effective treatment of triple negative breast cancer. Comprehensivepreclinical assessments of the peptide drug conjugate will be performed to enable clinical development.Successful outcome will result in effective treatment of triple negative breast cancer. NCI 10760236 7/26/23 0:00 PA-22-176 1R43CA281488-01A1 1 R43 CA 281488 1 A1 "REGMI, SAROJ GOPAL" 8/1/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 15835051 "HALL, RYAN CHRISTOPHER" Not Applicable 11 Unavailable 79282660 L1VLYM9HZNK3 79282660 L1VLYM9HZNK3 US 41.489266 -81.490318 10035907 "MOLECULAR THERANOSTICS, LLC" BEACHWOOD OH Domestic For-Profits 441221765 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 265179 NCI 190639 57192 Abstract The ultimate goal of this project is to develop and commercialize peptide drug conjugates to treat life-threatening triple negative breast cancer. Triple negative breast cancer (TNBC) is a high aggressivesubtype of breast cancer with poor survival. TNBC patients do not respond well to currently availableclinical therapies including targeted therapy. Chemotherapy is commonly used to treat TNBC. We willdevelop novel peptide conjugates of chemotherapeutics for highly efficient and tumor-specific delivery ofthe anticancer drugs into triple negative breast cancer. Various drug delivery systems includingnanosized delivery systems have been tested for delivery of anticancer therapeutics for treating TNBC.However these delivery systems are unable to provide efficient drug delivery in solid tumors due to thephysical barrier of dense tumor extracellular matrix (ECM). Previously we have designed and developeda small peptide targeted MRI contrast agent ZD2-N3-Gd(HP-DO3A) (MT218) to target an ECMoncoprotein extradomain B fibronectin (EDB-FN) for accurate detection of TNBC. MT218 is able todeliver the contrast agent at micromolar concentrations in aggressive tumors including TNBC resultingin robust signal enhancement for accurate detection of triple negative breast cancer in mice with MRI.Currently MT218 is in phase II clinical development for cancer diagnosis. In this project we will designand develop ZD2 peptide targeted drug conjugates for efficacious treatment of TNBC. The specific aimsare: 1) to synthesize and characterize a peptide drug conjugate to treat triple negative breast cancer; 2)to determine in vivo therapeutic efficacy of the drug conjugate to treat TNBC in mouse models. Afterfurther demonstrating the feasibility of the peptide drug conjugate in tumor models including a PDXmodel in this phase 1 SBIR project we will then further perform comprehensive preclinical assessmentof its physicochemical properties pharmaceutical properties and therapeutic efficacy for further clinicaldevelopment. The peptide drug conjugate has a great potential to achieve highly efficient tumor-specificdrug delivery and efficacious treatment of triple negative breast cancer and to improve the quality of thelife and survival of the patients. 265179 +No NIH Category available Affect;Alabama;Amino Acids;Automobile Driving;Beds;Biology;CRISPR/Cas technology;Cancerous;Cell Nucleus;Cell Proliferation;Cells;Chromogranin A;Clinical;Complex;Data;Dependence;Development;Diagnosis;Diarrhea;Disease;Disease Progression;Disease remission;Epithelium;Exanthema;Excision;Flushing;Foundations;Future;Gene Targeting;Genes;Genomics;Goals;Growth;Heart failure;Histone Deacetylase Inhibitor;Hormone secretion;Hormones;Human;In Vitro;Incidence;Islet Cell Tumor;Knock-out;Ligand Binding;Maintenance;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Measurement;Mentors;Mesenchymal;Metastatic Neoplasm to the Liver;Modeling;Mus;NOTCH3 gene;Neoplasm Metastasis;Neoplasms;Neuroendocrine Tumors;Non-Small-Cell Lung Carcinoma;Notch Signaling Pathway;Nude Mice;Oncogenic;Oncology;Operative Surgical Procedures;Organ;Outcome;Outcome Measure;Palliative Care;Pancreatic Ductal Carcinoma;Pathway Analysis;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Phenotype;Physicians;Play;Primary Neoplasm;Primary carcinoma of the liver cells;Production;Progression-Free Survivals;Proliferating;Proteins;Recurrence;Research;Role;Sampling;Scanning;Scientist;Seminal;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;Symptoms;Systemic Therapy;Testing;Time;Tissue Microarray;Training;Transfection;Tumor Biology;Tumor Cell Line;Universities;Widespread Disease;Work;Xenograft Model;career;cell growth;cell motility;clinically relevant;curative treatments;disabling symptom;effective therapy;experience;gastrointestinal;gene network;improved;in vivo;insight;knock-down;lung Carcinoma;medulloblastoma;microCT;migration;mortality;mouse model;neoplastic cell;notch protein;novel;novel therapeutics;overexpression;patient prognosis;public health relevance;reduce symptoms;response;side effect;targeted treatment;treatment strategy;tumor;tumor growth;tumor progression;tumor xenograft;tumorigenesis Characterizing the Role of NOTCH2 in Neuroendocrine Tumors PUBLIC HEALTH RELEVANCE STATEMENT (PROJECT NARRATIVE)Patients with pancreatic neuroendocrine tumors (pNETs) often have few symptoms before tumors havemetastasized hence most patients are diagnosed with late-stage disease for which there are few effectivetherapies. The incidence of pNETs increases yearly but the development of newer and more effective therapiesis still limited by our understanding of the biology of pNET tumorigenesis and progression. Modulation of theNotch2 signaling pathway is a promising approach for treating pNETs and further characterization of the role ofthe Notch2 pathway in pNETs may deepen our understanding of NETs while facilitating the development of noveltherapies. NCI 10760205 9/6/23 0:00 PA-21-052 5F31CA260945-02 5 F31 CA 260945 2 "DIBELLO, ANTHONY THOMAS" 9/1/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15097375 "HERRING, BRENDON ROBERT" Not Applicable 7 SURGERY 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 41349 NCI 41349 0 PROJECT SUMMARYPancreatic neuroendocrine tumors (pNETs) are the second most common malignancy of the pancreas with anoverall survival of 3.6 years and successful surgery the only treatment offering potential for cure. Howeveraround 40-95% of pNETs are metastatic at the time of initial diagnosis with local recurrence within theresection bed as the norm. Furthermore patients with liver metastases from pNETs often have debilitatingsymptoms such as uncontrollable diarrhea flushing skin rashes and heart failure. There are few systemictherapies that have proven to be clinically useful and those that have still bear widely variable response ratesand have poor side effect profiles. The goal of this proposal is to determine the role of Notch2 in theproliferation metastasis and hormone-secreting phenotype of NETs and evaluate Notch2 as apredictor of patient outcomes. Preliminary data from our lab suggests that overexpression of Notch2 resultsin an increase of the proliferative rate of NET cells while decreasing their hormone secretion. Our data alsosuggest that Notch2 is upregulated in metastatic pNETs compared to primary tumors. Seminal data from oneof the largest genomic studies to date on pNETs has also identified Notch2 as a key master-regulator of pNETmetastasis representing a key convergence of dependencies required for disease progression and theestablishment of metastasis. Therefore it is my hypothesis that Notch2 functions in an oncogenic role inNETs and drives tumor progression resulting in a more aggressive phenotype and portending worsepatient prognosis. To evaluate this hypothesis we will conduct phenotypic characterization (proliferationhormone production migration) on Notch2-overexpressing pNET cell lines that have been transiently andstably transfected. We will similarly evaluate pNET cell lines with Notch2 knockdown via siRNA as well asstable knockout pNET cell lines generated using CRISPR-Cas9. We will then conduct similar studies in vivousing a liver metastasis mouse model whereby Notch2-overexpressing and Notch2 pNET cell lines are injectedinto athymic mice. Using this model we will evaluate tumor growth and metastasis via microCT in addition tohormone secretion over a 16-week period. We will then conduct endpoint analysis of tumors and mouseorgans. Lastly we will immunohistochemically analyze the expression of Notch2 using pNET tissuemicroarrays derived from human patients that have undergone surgical resection at the University of Alabamaat Birmingham and evaluate the relationships between the expression of Notch2 Notch2 pathwaycomponents and various patient outcome measures. This study will yield valuable information on the effects ofNotch2 in pNETs that can help to guide future targeted therapeutic efforts and inform an understanding ofpNET biology. 41349 +No NIH Category available Address;Biological Markers;Biopsy;Cell Line;Cell Survival;Characteristics;Chromatin;Chromosome abnormality;Chromosomes;Clinical;Commercial grade;Complex;Cytogenetics;DNA;Data;Data Set;Decision Making;Detection;Development;Diagnosis;Diagnostic;Formaldehyde;Formalin;Freezing;Funding;Future;Genomic DNA;Genomic Segment;Genomics;Goals;Grant;Hi-C;Hydration status;Industrialization;Investigation;Karyotype determination procedure;Letters;Libraries;Ligation;Liquid substance;Malignant Neoplasms;Maps;Methodology;Methods;Modernization;Molecular Weight;Nature;Online Systems;Optics;Organic solvent product;Paraffin Embedding;Performance;Phase;Process;Prognostic Marker;Protocols documentation;Recovery;Reporting;Reproducibility;Research;Research Personnel;Resolution;Resources;Sampling;Services;Signal Transduction;Single Nucleotide Polymorphism;Small Business Innovation Research Grant;Solid Neoplasm;Specimen;Stratification;System;Technology;Testing;Time;Tissue Embedding;Validation;biomarker discovery;blood neoplasm;chromosome conformation capture;clinically relevant;cohort;computational platform;cost;design;diagnostic biomarker;genome analysis;improved;informatics tool;insertion/deletion mutation;next generation sequencing;novel strategies;pre-clinical;preservation;prognostic;success;tumor;virtual Chromosomal aberration detection in FFPE tissue using proximity ligation sequencing NARRATIVEFor decades chromosomal aberrations have been useful biomarkers for mechanistic investigations of diagnosisand treatment decision making for liquid tumors. The utility of chromosomal aberration in diagnosis andstratification of solid tumor treatment options is limited by the fact that virtually all solid tumor samples are storedas formalin-fixed paraffin embedded (FFPE) tissue. In this proposal we describe a scalable proximity ligationsequencing method and analysis platform that can overcome limitations presented by the highly fragmentedDNA found in FFPE tissue to identify chromosomal aberrations in solid tumors in FFPE blocks enabling researchand diagnostic applications. NCI 10759887 9/25/23 0:00 PA-22-176 1R44CA281528-01A1 1 R44 CA 281528 1 A1 "FRANCA-KOH, JONATHAN C" 9/25/23 0:00 8/30/25 0:00 Special Emphasis Panel[ZRG1-CDPT-V(13)B] 8860440 "EACKER, STEPHEN MATTHEW" Not Applicable 7 Unavailable 79752735 TQ67ST6YELX5 79752735 TQ67ST6YELX5 US 47.67118 -122.285148 10038678 "PHASE GENOMICS, INC." SEATTLE WA Domestic For-Profits 981052218 UNITED STATES N 9/25/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 858324 NCI 666354 135818 ABSTRACTThe detection of chromosomal aberrations is a frontline diagnostic for the spectrum of blood neoplasms.Chromosomal aberrations such as translocations inversions deletions and insertions have been historicallyidentified using cytogenetic methods or more recently through application of long read sequencing or opticalmapping technologies. These methods have been less applicable in solid tumor research and diagnosticsbecause they require either viable cells or high-molecular weight DNA. The vast majority of solid tumorbiopsies are stored in formalin-fixed paraffin-embedded (FFPE) blocks a process that highly fragmentsgenomic DNA. In this proposal we describe a low-cost and scalable method compatible with FFPE tissue thatenables the detection of chromosomal aberration using proximity ligation sequencing.Proximity ligation methods such as chromosome conformation capture (3C) and Hi-C can be used to order andorient segments of genomes reconstructing end-to-end chromosome sequences. When a sequence deviatesfrom the expected order or orientation such as is in the case of chromosomal aberrations the sequenceappears as an obvious off-diagonal signal on a Hi-C heatmap making identification of chromosomalabnormalities an automatable process.We propose to apply proximity ligation as a cytogenomic method to detect the breadth of chromosomalaberrations at high resolution and low cost. This proposal outlines a path to a commercially available productand service which will establish a highly validated method for use in research and eventually in a diagnosticsetting. This will be accomplished by 1) designing an easy to use FFPE Hi-C protocol amenable to multiwellplate handling 2) building a robust automated platform to reproducibly call chromosome aberrations from Hi-Cdata and 3) proving the validity and reproducibility of these methods on real world sample. The result of theseefforts will be a new cancer cytogenetics methodology called Karyotyping by SequencingTM (KBS). 858324 +No NIH Category available Abbreviations;Address;Antioxidants;Automobile Driving;Biodistribution;Blood Cell Count;CCL2 gene;CCL7 gene;CD8B1 gene;Cells;Cessation of life;Chemistry;Chemotaxis;Clinical Chemistry;Combined Modality Therapy;Data;Diagnosis;Diameter;Disease;Disease Progression;Dose;Environment;Excision;Extravasation;Formulation;Future;Goals;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immuno-Chemotherapy;In Vitro;In complete remission;Incidence;Intravenous;KPC model;KRASG12D;Legal patent;Licensing;Malignant Neoplasms;Malignant neoplasm of pancreas;Maximum Tolerated Dose;Medical;Modeling;Mus;Oncology;Organ;Pathway interactions;Patients;Penetration;Peptide Hydrolases;Pharmaceutical Chemistry;Pharmacotherapy;Phase;Phenotype;Pilot Projects;Polymers;Pre-Clinical Model;Prodrugs;Production;Reporting;Research;Resistance;Small Business Innovation Research Grant;Solid Neoplasm;Survival Rate;Therapeutic;Tissues;Toxic effect;Toxicokinetics;Toxicology;Treatment Efficacy;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Tumor-associated macrophages;Universities;Up-Regulation;antagonist;cancer cell;cancer therapy;checkpoint therapy;chemokine;chemokine receptor;clinically relevant;cytotoxic;cytotoxicity;efficacy evaluation;efficacy testing;gemcitabine;immune modulating agents;immunoregulation;in vivo;innovation;monocyte;mortality;mouse model;nanomedicine;nanoparticle;neoplastic cell;novel;pancreatic cancer model;pancreatic cancer patients;phase 1 study;pre-Investigational New Drug meeting;prognostic;receptor;recruit;standard of care;success;therapy resistant;tumor;tumor growth;tumor microenvironment A novel dual-carrier ultrasmall nanomedicine for the treatment of stroma-rich pancreatic cancer Project Narrative:Pancreatic cancer is one of the deadliest solid tumor malignancies. With DUO-307 Duo Oncology combines achemotherapeutic and an immunomodulatory agent to kill cancer cells and stimulate the bodys immuneresponse to recognize and kill the cancer. This therapy is delivered as an ultrasmall nanomedicine that canpenetrate the dense stroma tissue surrounding the tumor. NCI 10759720 9/14/23 0:00 PA-22-178 1R41CA285174-01 1 R41 CA 285174 1 "POND, MONIQUE ADRIANNE" 9/15/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 14647836 "EICHINGER, KATHERINE MARIE" Not Applicable 12 Unavailable 117619495 QK2QNS6KHHM5 117619495 QK2QNS6KHHM5 US 40.440683 -79.956021 10063170 DUO ONCOLOGY INC PITTSBURGH PA Domestic For-Profits 15207 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 394967 NCI 316520 52608 AbstractPancreatic cancer (PC) has an annual worldwide incidence of more than 495000 cases and anannual mortality rate of almost 460000 cases. Most patients are diagnosed late and cannotundergo resection and therefore rely on pharmacotherapy to extend their lives. Currenttherapies offer only limited benefit due in large part to the dense stroma tissue that surroundsand protects the tumor. Duo Oncology is developing an ultra-small nanoparticle containinggemcitabine and an immunomodulatory chemokine receptor type 2 antagonist to kill cancercells and invigorate anti-tumor immunity. These small nanoparticles less than 30nm indiameter show enhanced extravasation and tissue penetration particularly in the PC tumorsenriched with dense stroma. Further research proposed herein will prepare DUO-307 for futureIND-enabling studies with formulation optimization toxicology and therapeutic efficacy using acutting edge ex vivo tumor explant model and a clinically-relevant mouse model of PC withdense stroma. 394967 +No NIH Category available Ablation;Acceleration;Address;Animals;Antioxidants;Biliverdine;Biochemical;Biochemistry;Biological Assay;Biological Availability;Blood Cells;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer therapy;Cancer Biology;Cell Death;Cell Survival;Cell model;Characteristics;Chemoresistance;Chronic;Coupled;Coupling;Cytoprotection;Data;Dependence;Development;Enzymes;Equilibrium;Feasibility Studies;Generations;Genetic;Genetic Models;Genetic study;Goals;Heme;Human;Human Genetics;In Vitro;Infrastructure;Inhibition of Cancer Cell Growth;Intellectual Property;Intervention;Laboratories;Lead;Lipid Peroxidation;Malignant Neoplasms;Metabolic;Mitochondria;Modeling;Mus;Names;Normal Cell;Oral;Outcome;Oxidation-Reduction;Oxidative Stress;Oxidoreductase;Pathway interactions;Pharmaceutical Chemistry;Phase;Phenotype;Pre-Clinical Model;Proliferating;Radiation therapy;Reactive Oxygen Species;Reagent;Reproducibility;Research Design;Research Support;Resistance;Structure;Technology;Therapeutic;Time;Tissues;Toxic effect;Translational Research;Treatment Efficacy;Validation;Work;anti-cancer therapeutic;antioxidant enzyme;cancer cell;cellular targeting;chemotherapy;clinically relevant;commercialization;conventional therapy;gene complementation;human model;implantation;in vitro Assay;in vivo;in vivo Model;inhibitor;innovation;malignant breast neoplasm;mouse model;novel;orthotopic breast cancer;oxidative damage;pharmacologic;pre-clinical;preclinical development;preclinical efficacy;protoporphyrin IX;standard of care;tumor growth Development of a new class of BLVRB-targeted redox therapeutics in breast cancer The goals of this proposal are 1) to validate in mouse models BLVRB (biliverdin IX reductase)as a new cellular target in breast cancer and 2) to develop new BLVRB inhibitors as a novelbreast cancer therapy with the predicted minimal toxicity to normal cells. If successful our studywould be pre-clinical validation of first-in-class BLVRB redox inhibitors in breast cancerrepresenting a potential paradigm shift for cancer therapeutics. NCI 10759653 9/14/23 0:00 PA-22-176 1R43CA284999-01 1 R43 CA 284999 1 "FRANCA-KOH, JONATHAN C" 9/14/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 10374336 "MARCHENKO, NATALIA " Not Applicable 1 Unavailable 79478502 HH9LT9M9B3N4 79478502 HH9LT9M9B3N4 US 40.945115 -73.107309 10037989 "BLOOD CELL TECHNOLOGIES, LLC" Stony Brook NY Domestic For-Profits 11790 UNITED STATES N 9/14/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 285200 NCI 205032 61510 SUMMARYEnhanced metabolic and mitochondrial activity inherent in actively proliferating cancer cells generates anexcessive amount of reactive oxygen species (ROS) associated with intracellular redox imbalance that impactscellular viability.To survive chronic oxidative stress cancer cells evolve to activate scavenging/anti-oxidantenzymes to restore redox balance. This differential activation of antioxidant pathways compared to normal cellsprovides a therapeutic window for novel cellular targets. Moreover the effects of chemo- and radiotherapy (inpart) are attributed to oxidative stress that causes irreversible oxidative damage and cell death and activationof redox-regulating pathways is thought to promote resistance to such therapies. The obligatory dependence ofcancer cells on antioxidant defense pathways as a fundamental pro-survival mechanism suggests the broadtranslational utility of their targeting in breast cancer. Modulation of redox-adaptation mechanisms represents afeasible strategy to eradicate cancer cells and/or restore chemosensitivity to conventional therapies.For the first time we identified the heme (Fe2+-protoporphyrin IX) catabolic enzyme BLVRB (biliverdinIX reductase) as a new cellular target in breast cancer. We demonstrated the requisite and non-redundant pro-survival antioxidant function of BLVRB in breast cancer cells coupled with therapy resistance and poor outcomesin breast cancer patients. The primary hypothesis of this application is that BLVRB functions in a redox-regulated pathway of antioxidant handling and cytoprotection in breast cancer cells. The secondary hypothesisis that BLVRB-selective inhibitor(s) may be developed as a novel and potentially non-toxic strategy for breastcancer treatment with minimal predicted off-target effects in normal cells. Using (1) BLVRB/inhibitor co-crystalstructures (2) computational RMSD matrices for SARs and (3) extensive ADME/T and PK studies we identifiedtwo lead compounds with excellent bioavailability and oral PK characteristics that selectively block BLVRB redoxcoupling.The objectives of this proposal are (1) to extend initial proof-of-principle studies for BLVRB pre-clinical targetvalidation using in vivo breast cancer models and (2) to characterize first-in-class BLVRB-selective inhibitors forin vitro and in vivo efficacy. Study Design: We will apply in vivo genetic models for target validationsimultaneously addressing redox-dependent mechanisms by gene complementation studies using BLVRB+/+ andBLVRB-/- breast cancer isogenic lines: (1) to confirm requisite functions in tumor growth and metastatic burden;(2) to establish redox-dependent phenotype (Aim 1). Aim 2 will validate the pre-clinical efficacy of leadcompounds using well-established phenotypic read-outs in vitro and in orthotopic breast cancer implantationmodels. We will also address synthetic lethality BLVRB inhibitors with standard-of-care chemotherapy in vivo.Impact: If successful the proposed work would be first-in-class pre-clinical validation of redox inhibitors in breastcancer representing a potential paradigm shift for cancer therapeutics. 285200 +No NIH Category available Address;Adult;Age;American Society of Clinical Oncology;Automobile Driving;Back;Body Size;Body Surface Area;Body mass index;Breast;Breast Cancer Patient;California;Cancer Patient;Cardiotoxicity;Cardiovascular Diseases;Characteristics;Clinical Management;Cytotoxic agent;Data;Data Sources;Diabetes Mellitus;Diagnosis;Disease;Dose;Epidemiology;Ethnic Origin;Fright;Gender;Guidelines;Health;Hepatic;Hormone Receptor;Impairment;Integrated Delivery of Health Care;Intervention;Investigation;Kidney;Kidney Diseases;Knowledge;Link;Mediating;Mediator;Medical Oncology;Meta-Analysis;Modification;Morbid Obesity;Neuropathy;Neutropenia;Nodal;Non obese;Obesity;Outcome;Patients;Pharmaceutical Preparations;Pharmacology;Positioning Attribute;Prevalence;Prognosis;Provider;Race;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Reporting;Research;Risk;Role;System;Toxic effect;Treatment-related toxicity;Uncertainty;United States;Weight;Woman;adverse outcome;breast cancer survival;cancer recurrence;cancer survival;chemotherapy;clinically relevant;comorbidity;data integration;epidemiology study;experience;follow-up;improved;malignant breast neoplasm;mortality;novel;obese patients;optimal treatments;provider factors;study population Obesity chemotherapy dosing and breast cancer outcomes PROJECT NARRATIVEEpidemiologic studies have linked obesity to poor breast cancer outcomes and it has been suggested thatobese women may experience poorer outcomes in part due to dose reductions of chemotherapy drugs; thisis because most cytotoxic agents are dosed according to body size and clinicians may scale back the highdoses administered to obese women due to concern about inducing toxicity. Given persisting uncertaintyabout dosing obese women in a study population of nearly 34000 women with breast cancer who werediagnosed and treated in two integrated healthcare delivery systems Kaiser Permanente Northern Californiaand Group Health we propose to: i) examine the relationship between body size and dose intensity and willfurther examine how the factors contributing to dose reductions vary by body size ii) evaluate whetherchemotherapy dose reductions mediate the associations between obesity and adverse breast canceroutcomes and iii) evaluate the association between body size and toxicity among women identified asreceiving the full body-size determined dose of chemotherapy. Addressing these questions will provide theevidence needed to better inform clinicians treating the 102000 obese women diagnosed with breast cancereach year in the United States. NCI 10759611 2/2/23 0:00 PA-16-160 4R37CA222793-06 4 R37 CA 222793 6 "SHELBURNE, NONNIEKAYE F" 1/1/18 0:00 12/31/24 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 11112095 "KANTOR, ELIZABETH DAVID" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 2/2/23 0:00 12/31/23 0:00 393 Non-SBIR/STTR 2023 592632 NCI 415246 177386 ABSTRACT Epidemiologic studies have linked obesity to poor breast cancer outcomes and it has been suggested thatobese women may experience poorer outcomes in part due to inadequate dosing of cytotoxic agents amongobese women. Specifically most cytotoxic agents are dosed according to body surface area and therefore thelarger the woman the higher the absolute dose. However evidence shows that clinicians are more likely todepart from recommended dosing among heavier women for fear of inducing chemotherapy-associated toxicity.In 2012 the American Society of Clinical Oncology (ASCO) released guidelines stating that obese womenshould be dosed according to their full body surface area largely based on evidence that suggested that fully-dosed obese women do not appear to experience more toxicity than fully-dosed normal-weight women.However the guidelines acknowledge that data are extremely limited with regard to more severe obesity and inthe real-world context of comorbidities. Furthermore these guidelines cite that this practice of `dose reducing'obese women may be one reason contributing to the poorer outcomes observed in this group. However todate no empirical investigations have sought to determine if and to what extent dose-reduced chemotherapymay explain differences in breast cancer survival. These guidelines were met with some criticism citing theneed for further evidence and data suggest continuing uncertainty about proper dosing of obese cancerpatients. Understanding the drivers of dose reductions may help better inform our understanding of thispractice and efforts to disseminate guidelines; however we know little about factors driving dose intensity andhow these factors may vary by body size. We therefore propose to address these gaps using data on nearly 34000 Stage I-IIIA breast cancerpatients diagnosed and treated at Kaiser Permanente Northern California and at Group Health. Specifically wewill use the rich data from these integrated healthcare delivery systems to examine the relationship betweenbody size and dose intensity and will further examine how the factors contributing to dose reductions vary bybody size (Aim 1). We will also evaluate if and to what extent dose reductions mediate the associationbetween obesity and breast cancer recurrence and survival (Aim 2). Lastly we will evaluate the associationbetween body size and toxicity among women identified as receiving the full BSA-determined dose ofchemotherapy (Aim 3). Our findings will provide critical and timely information to support or to warrantmodification of current recommendations for chemotherapy dosing for obese breast cancer patients. Given thehigh and increasing prevalence of obesity in the United States it is critical that we improve our understanding ofchemotherapy dosing. The knowledge gained from this study can be used to better inform optimal treatment forthe estimated 102000 obese women diagnosed with breast cancer each year in the United States. 592632 +No NIH Category available Adjuvant;Agonist;Antineoplastic Agents;Antitumor Response;Bacteria;Barbering;Binding;Biological Assay;CAR T cell therapy;Cell Nucleus;Cells;Chemicals;Clinical Trials;Collaborations;Cyclic GMP;Cytotoxic T-Lymphocytes;DNA;Data;Dinucleoside Phosphates;Drug Kinetics;Endoplasmic Reticulum;Epigenetic Process;Evaluation;Event;Exhibits;Family;Gene Activation;Generations;Genetic Transcription;Golgi Apparatus;Half-Life;Host Defense;Human;IRF3 gene;Immune;Immune checkpoint inhibitor;Immune system;Immunocompetent;Immunologic Stimulation;Immunotherapy;Infection;Inflammatory;Innate Immune System;Interferon Type I;Intravenous;Knock-in;Laboratories;Lead;Luciferases;MDA MB 231;Malignant Neoplasms;Modeling;Mus;Nucleic Acids;Oral Administration;Pathway interactions;Periodicity;Pharmaceutical Preparations;Predisposition;Production;Property;Proteins;Radiation;Route;Safety;Signal Transduction;Stimulator of Interferon Genes;T cell response;T-Lymphocyte;TANK-binding kinase 1;Therapeutic;Toll-like receptors;Tumor Immunity;Universities;Vaccines;adaptive immunity;analog;anti-PD-1;antimicrobial drug;antitumor agent;cancer cell;cancer therapy;chemotherapeutic agent;clinical development;cytokine;design;dosage;ds-DNA;effective therapy;efficacy evaluation;experimental study;high throughput screening;immunoregulation;in vivo;innate immune pathways;medical schools;melanoma;microbial;novel;pathogen;pembrolizumab;phase I trial;phosphoric diester hydrolase;programmed cell death protein 1;screening;sensor;small molecule;transcription factor;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Human specific STING agonists for the treatment of cancer PROJECT NARRATIVEStimulation of the immune system has been shown to be a powerful approach for the treatment of cancer. Wehave found that stimulation of an immune pathway controlled by a cellular molecule referred to as STING caneffectively trigger anti-tumor responses. Here we have generated a new array of STING-dependent compoundsthat we intend to evaluate as anti-cancer drugs. NCI 10759593 7/10/23 0:00 PA-22-178 1R41CA275637-01A1 1 R41 CA 275637 1 A1 "REGMI, SAROJ GOPAL" 8/1/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 15943806 "BARBER, GLEN N" "AHN, JEONGHYUN " 26 Unavailable 2058614 PJV5A55KF6T5 2058614 PJV5A55KF6T5 US 25.79466 -80.206795 10055061 "STINGINN, LLC" MIAMI FL Domestic For-Profits 331361128 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 399812 NCI 301754 71902 PROJECT SUMMARYCellular innate immune sensors such as STING (STIMULATOR OF INTERFERON GENES) have evolved todetect microbial infection of the cell (1-3). STING controls the potent cytosolic DNA-stimulated innate immunepathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted byintracellular bacteria following infection. Alternatively STING can be activated by cyclic GMP-AMP (cGAMP)generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNAspecies which can include microbial DNA or self-DNA leaked from the nucleus (4). Association with CDNsenables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines whichfacilitate adaptive immunity (3). Aside from being critical for the protection against microbial infection STINGsignaling has been shown to be essential for facilitating robust anti-tumor immunity. Regulation of theimmune system to stimulate anti-tumor cytotoxic T cell responses is proving to be a powerful approach for theeffective treatment of a variety of cancers. For example STING agonists based on synthetic CDNs have beenshown to exert potent anti-tumor properties likely by stimulating APCs and are now being evaluated in Phase Itrials for the treatment of cancer. However such CDNs are highly labile and do not exert potent activity whengiven systemically. This has limited their use/evaluation to intratumoral and oral administration. Here wedescribe a new generation of novel small STING agonists that activate STING signaling that appear superior toexisting CDNs for evaluation in anti-tumor therapeutic strategies. The compounds have been generated bySTINGINN LLC based in Miami in collaboration with the University of Miami School of Medicine FL. 399812 +No NIH Category available 3-Dimensional;Acceleration;Acquired Immunodeficiency Syndrome;Amino Acids;Anabolism;Animals;Biological Models;Biological Process;Carbon;Carbon nanoparticle;Cell Communication;Cell Culture System;Cell Proliferation;Cell model;Cells;Citric Acid Cycle;Clinic;Diphosphates;Enzymes;Funding;Genes;Glutamine;Goals;Growth;Herpesviridae Infections;Human;Human Herpesvirus 8;Kaposi Sarcoma;Ligase;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Mutagenesis;Nitrogen;Nucleotides;Pathogenesis;Pathway interactions;Patients;Prevention;Proliferating;Proteins;Purines;Pyrimidine;Ribose-Phosphate Pyrophosphokinase;Role;Small Interfering RNA;Societies;Spindle Cell Neoplasm;System;Technology;Testing;Therapeutic Agents;Translating;Up-Regulation;Viral;Viral Genes;Warburg Effect;aerobic glycolysis;cancer cell;cancer type;carcinogenesis;cell transformation;effective therapy;effectiveness evaluation;expectation;experimental study;genetic manipulation;in vivo;innovation;knock-down;locked nucleic acid;metabolome;metabolomics;metaplastic cell transformation;mortality;multidisciplinary;new technology;new therapeutic target;novel;novel therapeutics;nucleotide metabolism;primary effusion lymphoma;reverse genetics;therapeutic target;three dimensional cell culture;tumor;tumorigenesis Cell model for KSHV infection and genetic manipulation Project NarrativeKaposis sarcoma-associated herpesvirus (KSHV) causes several human cancers including Kaposissarcoma primary effusion lymphoma and multicentric Castlemans disease. These malignancies inflictmorbidity and mortality to the society in US and worldwide. This project will investigate the mechanismsmediating the metabolic pathways supporting the growth and survival KSHV-induced cancer cells and identifypotential therapeutic targets for developing novel prevention and treatment approaches. NCI 10759522 7/6/23 0:00 PA-20-185 2R01CA096512-16 2 R01 CA 96512 16 "READ-CONNOLE, ELIZABETH LEE" 1/13/03 0:00 6/30/28 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 11026736 "GAO, SHOU-JIANG " Not Applicable 12 GENETICS 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/6/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 584851 NCI 398557 186294 Cancer cells depend on reprogrammed metabolic pathways for anabolic proliferation. Discovering these cancermetabolic vulnerabilities can reveal novel targets for therapy. Kaposis sarcoma-associated herpesvirus (KSHV)is the causal agent of Kaposis sarcoma (KS) and several other cancers. Despite intensive studies for severaldecades there is currently no effective therapy for KS. Our long-term goal is to delineate the pathogenesis ofKSHV-induced cancers providing a scientific basis for developing novel therapies. Toward this goal we havepreviously developed an efficient system of KSHV-induced cellular transformation of primary cells and a reversegenetics system for KSHV mutagenesis. Using these powerful systems in the current funding period we havedelineated viral and cellular genes that are essential for KSHV-induced cellular transformation and identifiednovel therapeutic targets and agents that have the potentials for translating into clinics. In particular we haverecently discovered that KSHV-transformed cells are addicted to glutamine. Unlike other types of cancer cellsthat utilize glutamine to replenish the TCA cycle glutamine is primarily shunted to nucleotides syntheses byproviding the critical g-nitrogen in addition to amino acids. KSHV hijacks numerous rate-limiting enzymes in thesepathways including phosphoribosyl pyrophosphate amidotransferase (PPAT) and phosphoribosylpyrophosphate synthetases 1 (PRPS1) which is upregulated in KS spindle tumor cells. Significantly knockdownof these enzymes suppresses the proliferation of KSHV-transformed cells but has no effect on theprimary/uninfected cells. Our hypothesis is that KSHV encodes specific gene(s) to hijack the nucleotidesynthesis pathways to support the proliferation and survival of KSHV-transformed cells and hencetargeting these pathways is effective for therapy of KSHV-induced tumors. We have developed 3D Culturesystems that closely representing in vivo metabolic changes an innovative nanoparticles carbon-dots (Cdots)-mediated delivery approach for locked nucleic acid (LNA)-siRNAs and cutting-edge technology of metabolomicsfor tracing the carbon and nitrogen flows. We will determine the essential roles of the dysregulated nucleotidesynthesis pathways for KSHV-induced cellular transformation and tumorigenesis (Aim 1); determine themechanisms by which KSHV hijacks the nucleotide synthesis pathways for supporting the proliferation andsurvival of KSHV-transformed cells (Aim 2); and target vulnerable genes in the nucleotide pathways using theCdots-mediated delivery approach for treating KSHV-induced tumorigenesis (Aim 3). The proposed project ishighly significant as it will test a novel hypothesis of KSHV manipulation of key cellular metabolic pathwaysusing multidisciplinary innovative approaches and model systems. It is our expectation that theaccomplishment of this project will lead to the identification of novel cancer vulnerabilities of KSHV-inducedcancers which could provide a scientific basis for developing novel therapies. 584851 +No NIH Category available Acceleration;Adherence;Adipocytes;Adult;Adverse effects;Affect;Age;Antiestrogen Therapy;Attention;Attenuated;Behavior Therapy;Behavioral;Biological;Biological Markers;Body Weight decreased;Breast Cancer Patient;Breast Cancer Prevention;Breast Cancer Risk Factor;Breast Cancer survivor;Caloric Restriction;Cancer Control;Cells;Cessation of life;Characteristics;Clinical;Clinical Research;Data;Development;Dietary Intervention;Disease;Disease susceptibility;Estrogen receptor positive;Estrogens;Extracellular Matrix;Face;Fibroblasts;Foundations;Future;Growth;Health;Health Benefit;Human;Immune;Incidence;Individual;Inflammatory;Intermittent fasting;Intervention;Intervention Studies;Intervention Trial;Lead;Life Style;Malignant Neoplasms;Mammary Neoplasms;Mediator;Medical Oncology;Menopausal Status;Metabolic;Metabolic Diseases;Metabolic dysfunction;Modality;Modeling;Neoplasm Metastasis;Newly Diagnosed;Obesity;Outcome;Overweight;Patient-Focused Outcomes;Patient-derived xenograft models of breast cancer;Patients;Persons;Phase;Play;Postmenopause;Predisposition;Premenopause;Prognosis;Protein Secretion;Quality of life;Randomized;Research Personnel;Resistance development;Risk;Role;Science;Specific qualifier value;Stromal Cells;Structure;Thinness;Time;Time-restricted feeding;Translating;Tumor Promotion;Tumor Subtype;Weight;Woman;Work;breast cancer diagnosis;breast cancer progression;cancer risk;cancer subtypes;circulating biomarkers;clinically relevant;common treatment;dietary;efficacy trial;epidemiology study;hormone therapy;improved;improved outcome;innovation;interdisciplinary collaboration;intervention delivery;intervention refinement;malignant breast neoplasm;mammary;novel;novel therapeutic intervention;nutrition;obesity treatment;patient derived xenograft model;patient population;preclinical study;therapy outcome;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor progression;weight loss intervention Novel dietary interventions for reducing obesity-associated breast cancer PROJECT NARRATIVEThe incidence of obesity and metabolic dysfunction continues to rise particularly among women; a detrimentalconsequence is increased breast cancer risk and worse patient outcome. This proposal will 1) advance ourunderstand of obesitys impact breast cancer; 2) examine if a novel weight loss strategy intermittent energyrestriction can eliminate obesity-associated tumor progression; and 3) investigate if this intervention will bevaluable for helping breast cancer patients improve outcomes. NCI 10759457 1/4/24 0:00 PAR-21-035 5R01CA258766-03 5 R01 CA 258766 3 "KIM, YOUNG S" 1/1/22 0:00 12/31/26 0:00 Cancer Prevention Study Section[CPSS] 7747809 "MACLEAN, PAUL S." "CATENACCI, VICTORIA A; KABOS, PETER " 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 580275 NCI 373167 207108 PROJECT SUMMARYDespite new treatment modalities the incidence of breast cancer has remained steady in recent years with>250000 new diagnoses and >40000 deaths annually in the US. Concurrently the proportion of US womenwith overweight or obesity continues to rise and is approaching 70%. Obesity and metabolic disease (whichoccurs in lean and obese women) increase breast cancer incidence and worsen patient outcomes in women ofall ages. Premenopausal women with obesity are at increased risk of triple negative (TN) breast cancer (lackingany targetable factors). Postmenopausal women with obesity incur more estrogen receptor (ER) positive breastcancer and are more likely to develop resistance to endocrine therapies. While estrogen is clearly an importantpart of this relationship two key observations suggest that there may be estrogen-independent mechanisms atplay: 1) obesity is accompanied by worse prognosis for estrogen-independent triple negative breast cancer; and2) anti-estrogen therapies are less effective against ER+ breast tumors in women with obesity. Regardless oftumor subtype and menopausal status excess weight is associated with poor outcomes for breast cancerpatients. Weight loss is known to improve breast cancer outcomes but most people cannot sustain the standarddietary weight loss strategies and weight regain is common. Intermittent energy restriction (IER) is a novel dietaryweight loss strategy that may have more beneficial effects on metabolic health and on breast cancer risk andtumor progression. The work in this proposal will employ preclinical clinical and interventional studies toexamine a novel mechanism of obesity-associated tumor progression and the value and feasibility of innovativedietary interventions for eliminating obesitys adverse effects on breast cancer.We have merged expertise in nutrition obesity and medical oncology to: 1) examine a novel role that cancer-associated fibroblasts (CAFs) and the tumor microenvironment (TME) may be playing in obesity-associatedtumor progression; 2) investigate if the novel dietary weight loss strategy of IER can eliminate obesity-associatedtumor progression; and 3) perform an ORBIT Phase IIa proof-of-concept study examining the ability of an IER-based weight loss intervention to reach meaningful clinical milestones in breast cancer patients afflicted withoverweight and obesity and refine the intervention for delivery in a future randomized efficacy trial.If the objectives of this proposal are achieved we will have:* Advanced our understanding of the obesity breast cancer relationship with evidence of a novel role for CAFs and the TME in obesity-associated tumor promotion for TN and ER+ breast cancer;* Established the foundation for IER weight loss trials in breast cancer survivors with data that will help us adapt these strategies to the unique characteristics and needs of this patient population; and* Identified novel circulating biomarkers of a pro-metastatic TME which may help identify patients most susceptible to metastatic disease. 580275 +No NIH Category available Acute Lymphocytic Leukemia;Affinity;Amino Acids;Apoptosis;Apoptotic;Area;Bcr-Abl tyrosine kinase;Binding;Biology;Blood Circulation;Bypass;Cell Line;Cell physiology;Cells;Charge;Chemicals;Chromosomal translocation;Chromosome abnormality;Chronic Myeloid Leukemia;Clinical;Clinical Trials;Collaborations;Combination Drug Therapy;Combined Modality Therapy;Computer Models;Dimerization;Disease;Drug resistance;Event;Experimental Leukemia;Genes;Genetic Diseases;Goals;Growth;Heterodimerization;Homo;Homodimerization;Hydrophobicity;Individual;Inflammatory;Intravenous;Lead;Length;Leukemic Cell;Ligation;Location;Malignant Neoplasms;Mediating;Modeling;Oncogenic;Pain;Patients;Penetration;Peptide Synthesis;Peptides;Permeability;Phase;Phosphotransferases;Physiological Processes;Production;Protein Tyrosine Kinase;Proteins;Proteolysis;Recurrence;Research Personnel;Resistance;Sampling;Serum;Shapes;Signal Transduction;Solid;Specificity;Technology;Tertiary Protein Structure;Testing;Therapeutic;Therapeutic Intervention;Translations;Tyrosine Kinase Inhibitor;Variant;Viral;cell killing;chronic myeloid leukemia cell;clinically relevant;design;dimer;drug discovery;improved;in vitro testing;in vivo;inhibitor;leukemia;leukemia treatment;mouse model;mutant;mutational status;new technology;novel;novel therapeutic intervention;pre-clinical;protein oligomer;resistance mutation;solid state;standard of care;stapled peptide;success;targeted agent;targeted treatment;therapeutic protein;tumorigenesis A Leukemia Cell-Specific Coiled-Coil Protein for Treatment of Chronic Myeloid Leukemia Project NarrativeThe long-term goal of this proposal is to develop a protein inhibitor against Bcr-Abl the causativeagent of chronic myeloid leukemia (CML) and 30% of acute lymphoblastic leukemia (ALL) thatcircumvents current problems with Bcr-Abl targeted therapy. Computationally designed coiled-coil proteins will be synthetically made and will be tested for ability to inhibit dimerization of Bcr-Abl. These peptides are designed to specifically enter leukemia cells be resistant to degradationbe stable in the bloodstream and show efficacy in blocking the activity of Bcr-Abl thus providinga new type of therapy for these leukemias. NCI 10759390 12/15/23 0:00 PA-19-056 5R01CA244583-04 5 R01 CA 244583 4 "BOURCIER, KATARZYNA" 1/1/21 0:00 12/31/25 0:00 Gene and Drug Delivery Systems Study Section[GDD] 1922826 "LIM, CAROL S." Not Applicable 1 PHARMACOLOGY 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF PHARMACY 841129049 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 313959 NCI 205875 108084 Project Summary/AbstractThe long-term goals of this proposal are to explore the protein dimerization interface as an area for therapeuticintervention. Protein dimerization/oligomerization is a recurring theme in biology representing the mechanismby which hundreds of proteins regulate key cellular processes such as enzymatic activity and signal transduction.This non-covalent protein homo- or heterodimerization is mediated by hydrophobicity and both shape and chargecomplementarity. Once thought to be undruggable dimer interfaces are emerging as an area for powerfultherapeutic intervention for inflammatory diseases pain genetic diseases cancer and other diseases. The goalof this proposal is to develop a clinically relevant small protein dimerization inhibitor. As a model we will useour dimerization coiled-coil (cc) inhibitor of Bcr-Abl. Bcr-Abl is an example of a protein that must dimerize toenable its oncogenic activity. Bcr-Abl results from an abnormal chromosomal translocation manifests as aconstitutively active tyrosine kinase and causes of 95% of chronic myeloid leukemias (CML). We build on ournovel computationally designed Bcr coiled-coil mutant (ccmut) that selectively dimerizes with Bcr-Abl and inhibitsits activity. When virally delivered as a gene ccmut is effective against wild-type and mutant forms of Bcr-Abl.Our ccmut specifically favors heterodimerization with Bcr-Abl to disrupt Bcr-Abl dimerization a necessary step foroncogenesis and thus represents a novel therapeutic strategy. We have also fused ccmut to a non-toxic cell-penetrating peptide with known leukemia cell specificity and showed that it disrupts Bcr-Abl dimerization andenters and kills leukemia cells. For this proposal we will explore peptide stapling technologies (to increaseproteolytic stability) and native chemical ligation to synthesize 2 shorter stapled peptides into a longer therapeuticprotein domain. We will first computationally model possible staple locations that maintain target affinity. Thesestapled versions (CPP-St-ccmut) are predicted to enter cells resist serum proteolysis bind to Bcr-Abl and inhibitits activity. We will then test the activity of our constructs with and without TKI ponatinib to test multidomaintargeting of Bcr-Abl in CML cell lines CML patient samples and a CML animal model. Aims are as follows: Aim1: Computationally design and synthesize with solid state peptide synthesis and native chemical ligation aleukemia-specific stapled cc inhibitor (CPP-St-ccmut) against Bc-Abl. Aim 2: Determine cell internalizationbinding and apoptotic ability of CPP-St-ccmut candidates in leukemic cell lines including those with clinicallyrelevant mutations that are resistant to TKIs and cells derived from patient samples alone and in combinationwith ponatinib. Aim 3: Demonstrate efficacy of CPP-St-ccmut with and without ponatinib in a simple pre-clinicalmouse model of CML (syngeneic mouse model using intravenously injected BaF/3 cells expressing drug-resistant Bcr-Abl variants including compound mutants). Our goal is to develop a stapled protein domaintargeting the protein-protein dimerization interface Bcr-Abl kinase. 313959 +No NIH Category available Accounting;Address;Adipose tissue;Algorithms;American;Architecture;Area;Artificial Intelligence;Breast;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Risk Factor;Caring;Cause of Death;Clinical;Computer software;Data;Databases;Detection;Development;Diagnosis;Early Diagnosis;Ensure;Feasibility Studies;Funding;Grant;Health care facility;High Risk Woman;Hospitals;Image;Incidence;Infrastructure;Legal patent;Life Style;Link;Machine Learning;Malignant Neoplasms;Mammary Gland Parenchyma;Mammography;Manuals;Measurement;Measures;Medical;Medical Device;Medical Imaging;Medical Records;Methods;Modeling;Patient risk;Patient-Focused Outcomes;Patients;Performance;Phase;Population;Positioning Attribute;Predictive Factor;Preventive care;Process;Prognostic Factor;Protocols documentation;Questionnaires;ROC Curve;Reader;Recommendation;Research;Risk;Risk Assessment;Risk Estimate;Risk Factors;Risk Reduction;Scanning;Screening procedure;Secure;Small Business Technology Transfer Research;Teaching Method;Technology;Technology Assessment;Time;Tissues;Validation;Visit;Visualization;Woman;Work;aged;automated analysis;breast density;breast pathology;cancer diagnosis;cancer invasiveness;clinical practice;cyber security;density;design;digital;high risk;imaging modality;improved;innovation;innovative technologies;malignant breast neoplasm;novel;novel strategies;phase 1 study;prevent;risk stratification;routine screening;screening;supplemental screening;timeline;tumor;young woman Image-based risk assessment to identify women at high-risk for breast cancer 8. PROJECT NARRATIVETraditional breast cancer risk assessments remain insufficient for identifying women at high-risk prior todiscovery even when accounting for high breast density since most diagnosed cases do not have an identifiablerisk factor. WAVED Medicals image-based risk assessment technology identifies high-risk women by quantifyingthe amount of risky dense mammographic tissue in a screening setting to provide a more accurate and objectiverisk estimation. Medical professionals can proactively stratify risk and recommend preventive care rather thanreactive treatments to improve patient outcomes. NCI 10759110 7/5/23 0:00 PA-22-178 1R41CA285182-01 1 R41 CA 285182 1 "REGMI, SAROJ GOPAL" 9/1/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 78348388 "BATCHELDER, KENDRA " "KHALIL, ANDRE " 2 Unavailable ZLJQKJ5J1948 ZLJQKJ5J1948 US 10071946 WAVED MEDICAL LLC ORONO ME Domestic For-Profits 44733610 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 SBIR/STTR 2023 405950 NCI 276862 102919 7. PROJECT SUMMARYBreast cancer is the most common cancer worldwide and the most common cancer diagnosed in Americanwomen. While there has been good progress regarding detection and treatment methods breast cancer remainsthe primary cause of death from malignant tumors. Hence there is a critical need for the development of novelpredictive and prognostic factors. Risk assessments are currently performed by medical professionals to identifywomen that could benefit from enhanced breast surveillance or risk reduction methods. Unfortunately mostdiagnosed cases do not have an identifiable risk factor making it a challenge to identify high risk women prior toonset using classical risk assessments. This medical difficulty has resulted in the development of several artificialintelligence and machine learning approaches being applied to screening mammograms to identify breast cancerearlier. However these approaches search for abnormalities that indicate an existing cancer and have beenfound to not be generalizable to the entire screening population. It is becoming more common for younger womento be diagnosed with breast cancer and the cancers tend to be more aggressive. This Phase I proposes tocreate a risk assessment product for mammography that is not based on machine learning but rather a novelmeasurement of risky dense tissue. Alteration in the architecture and composition of microenvironment is a well-recognized component of breast pathologies and some changes may occur prior to tumor onset. WAVEDMedicals measurement is sensitive to these alternations in identifying areas of dense tissue that is tumor prone.This feasibility study seeks to demonstrate that the novel measurement of risky dense breast tissue has thepotential to be implemented into classical risk models. Phase I specific aims are to 1) improve efficiency inidentifying risky dense tissue on mammograms by creating a secure database that contains preprocessed datafor optimized analysis and 2) establish risky dense tissue as a better predictor of breast cancer than traditionalmammographic percent density (MPD) by showing risky dense tissue is more accurate in predicting breastcancer than MPD. Follow-on Phase II efforts will include developing a platform and integrating WAVED intohospital infrastructure for evaluating mammograms. These improvements will create a risk assessment productthat increases the accuracy of medical professionals at identifying high-risk patients and ensures patients arereceiving additional medical care such as supplemental screening or risk reduction methods to prevent invasivecancer. Successful completion of the project has potential to advance state-of-the-art breast cancer assessmentsto provide quantification of risky dense tissue to identify high-risk patients needing preventive care. 405950 +No NIH Category available Anions;Anti-Inflammatory Agents;Anticoagulants;Bile fluid;Biliary;Biological Markers;Biological Response Modifiers;Blood Circulation;Blood flow;Chromatography;Clinical;Coagulation Process;Collaborations;Communication;Complication;Cryopreservation;Data;Development;Diagnosis;Disease;Dose;Effectiveness;Flushing;Future;Glycocalyx;Goals;Heart Arrest;Heparin;Histology;Hypoxia;Infiltration;Inflammation;Ischemia;Legal patent;Letters;Liver;Liver neoplasms;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Methods;Modeling;Morbidity - disease rate;Neoplasm Circulating Cells;Nitrogen Dioxide;North Carolina;Oligosaccharides;Organ;Organ Preservation;Organ Procurements;Organ Transplantation;Orphan;Orphan Drugs;Outcome;Patients;Perfusion;Phase;Polysaccharides;Portal Pressure;Predisposition;Primary carcinoma of the liver cells;Procedures;Process;Production;Publishing;Pump;Rattus;Recommendation;Recurrent Malignant Neoplasm;Recurrent tumor;Recycling;Regional Perfusion;Regulatory Pathway;Reperfusion Injury;Reperfusion Therapy;Retrospective Studies;Risk Reduction;Small Business Technology Transfer Research;Structure;Surgical Models;Surgical complication;Technology;Testing;Therapeutic;Thrombophilia;Time;Tissues;Transplantation;Universities;Warm Ischemia;adverse outcome;animal data;cancer recurrence;cohort;curative treatments;effective therapy;experience;experimental study;graft function;improved;in vivo;in vivo Model;inflammatory marker;ischemic injury;liver cancer patient;liver function;liver injury;liver ischemia;liver preservation;liver transplantation;mortality;mouse model;natural hypothermia;neutrophil;novel;pharmacokinetics and pharmacodynamics;post-transplant;pre-clinical;preservation;product development;success;transplant model Development ofsynthetic heparin to protect liver graft from ischemia reperfusion injury duringtransplantation Project NarrativeFor some liver cancer patients a liver transplantation represents a cure yet this procedureinvolves ischemia reperfusion injury which effects graft function and leads to tumor recurrence.Glycan Therapeutics in collaboration with the University of North Carolina Chapel Hill willinvestigate the use of dekaparin to reduce transplant associated ischemia reperfusion injury. Thesuccess of this project will offer a way to mitigate a common complication which has no existingtherapeutics available. NCI 10759102 6/27/23 0:00 PA-22-178 1R41CA285005-01 1 R41 CA 285005 1 "TRIPURANI, SWAMY KRISHNA" 7/1/23 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1-MBBC-G(10)B] 14461672 "ARNOLD, KATELYN " Not Applicable 2 Unavailable 78778864 KYG3DZSMH4R7 78778864 KYG3DZSMH4R7 US 35.906622 -79.049867 10034629 GLYCAN THERAPEUTICS CORPORATION Raleigh NC Domestic For-Profits 27606 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 SBIR/STTR 2023 400000 NCI 267023 106809 Project Summary/AbstractAccording to the most recent data published by the Global Cancer Observatory over 900000patients worldwide were diagnosed with liver cancer in 2020. For patients with hepatocellularcarcinoma the most common type of liver cancer liver transplantation is the only potentiallycurative treatment option. Liver transplantation inevitably involves periods of time where the liveris removed from blood circulation during procurement. When the liver is connected to the recipientand blood flow is restored the ischemia phase damage causes inflammation and coagulationcomplications. This ischemia reperfusion (IRinj)ury is a key factor in morbidity and mortalityafter transplantation. Furthermore there is preclinical and clinical evidence that IR injuryleads to cancer recurrence in over 20% of patients within 3 years. Despite these poor outcomesthere are no approved therapeutics available targeting IR injury during liver transplantation.Potential therapeutics could improve post-transplant organ function and reduce the risk ofcancer recurrence. This phase I STTR is focused on developing a therapeutic strategy todecrease IR injury during liver transplantation. We have identified a novel syntheticoligosaccharide structure called dekaparin produced exclusively by Glycan Therapeutics with adual mechanism of action. IR injury leads to a hypercoagulable state with a flux of immunemediators primarily neutrophils infiltrating reperfused tissue resulting in tissue damage.Dekaparin has anticoagulant and anti-inflammatory activity and is effective in reducing warm IR-mediated liver injury in a mouse model that mimics surgical complication. The necessity of dualactivity was demonstrated using other oligosaccharides that have only anticoagulant or anti-inflammatory activity. Single activity oligosaccharides decreased liver injury when combinedbut not when used separately. In this current application we propose to evaluate dekaparinstherapeutic potential against ischemia injury happening during graft procurement andpreservation using an ex vivo model of rat liver perfusion after cold storage. Five tasks areplanned to support this single aim: 1) Complete 10 g synthesis of dekaparin for ex vivo studies; 2)Establish ex vivo model of isolated perfused rat liver; 3) Evaluate effect of dekaparin on IR injury inex vivo model; 4) Use extended criteria liver grafts in ex vivo model with dekaparin; 5) Purifydekaparin from spent perfusate to recycle material for future use. In Phase II we will use the exvivo model to explore different doses of dekaparin. We will conduct the in vivo orthotopic livertransplantation model in rats. Lastly we will evaluate the metastatic ability of circulating tumorcells in the transplant model with dekaparin treatment to determine tumor recurrence potential. 400000 +No NIH Category available Acceleration;Address;Advocacy;Aftercare;Age;CLIA certified;Cancer Patient;Cancer Survivor;Capital;Characteristics;Cholangiocarcinoma;Colorectal Cancer;Communication;Communities;Complex;Creativeness;Development;Disadvantaged;Discipline;Disparity;Ensure;Environment;Evaluation;Family;Fostering;Genomics;Goals;Health Benefit;Health system;Investments;Knowledge;Leadership;Malignant Neoplasms;Methodology;Multiple Myeloma;Participant;Patient advocacy;Patients;Persons;Population;Positioning Attribute;Provider;Research;Research Personnel;Resources;Rural Population;Science;Technology;Testing;Underserved Population;Universities;Vision;Washington;anticancer research;cancer genomics;cancer health disparity;career;evidence base;follow-up;genome sequencing;improved;innovation;interdisciplinary collaboration;member;outreach;patient engagement;patient oriented;patient population;rare cancer;recruit;success;synergism;tumor;understudied cancer Washington University Participant Engagement and Cancer Genomic Sequencing Center (WU-PE-CGS) PROJECT NARRATIVEThe goal of the WU-PE-CGS is to build a rigorous scientific evidence base for approaches direct engagementof cancer patients and post-treatment cancer survivors from rural and underserved populations as participantsin cancer research. Our Center will provide a significant return on the scientific investment resulting ininnovations to advance participant engagement outreach and communication in genomic characterizationstudies. NCI 10759096 9/8/23 0:00 RFA-CA-19-045 3U2CCA252981-03S1 3 U2C CA 252981 3 S1 "MECHANIC, LEAH E" 9/1/21 0:00 8/31/26 0:00 ZCA1-TCRB-O(M1) 2110411 "COLDITZ, GRAHAM A." "DING, LI ; DRAKE, BETTINA F.; FIELDS, RYAN C" 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 4382 NCI 2818 1564 PROJECT SUMMARYVision. Participant engagement and sequencing research from the Washington University ParticipantEngagement and Cancer Genomic Sequencing Center (WU-PE-CGS) will fill critical gaps in knowledgemethodology and characterization of understudied cancer populations leading to optimal approaches toparticipant engagement outreach and communication in genomic characterization studies.Goal. The overall goal of the WU-PE-CGS is to build a rigorous scientific evidence base for approaches directengagement of cancer patients and post-treatment cancer survivors as participants in cancer research. Ourfocus is on rare and understudied cancer populations with significant disparities including cholangiocarcinomamultiple myeloma and colorectal cancer under age 50. Participant engagement strategies are most effectivewhen they are adapted and implemented in real-world settings in partnership with community and patientadvocacy stakeholders.Setting. Our Center will be housed in an exceptional environment that fosters transdisciplinary collaborationcatalyzes new ideas in patient engagement and ensures support for patient engagement and genomesequencing that finds solutions for complex recruitment and engagement challenges in real-world settings withunderrepresented patient populations. Significant matching contributions from Washington University will allowus to quickly and strategically invest in ideas.Aims. The specific aims of the Center are to: (1) Advance the field of participant engagement to study cancerdisparities and rare cancers by conducting innovative and impactful direct stakeholder engagement withcontinuous evaluation and research; (2) Expand an exceptional diverse team of investigators patients andadvocacy stakeholders; (3) Address cancer disparities by understanding barriers to and improving the abilityfor disadvantaged and understudied populations to encounter use and benefit from genomic sequencing andanalysis; (4) Organize and integrate Center units to facilitate transdisciplinary team science within our Centerand across the PE-CGS Network.Innovations and impact. The WU-PE-CGS builds on a long and outstanding record of leadership in both cancerdisparities and genomic research across the cancer continuum. We will be particularly innovative and allow fora significant return on the scientific investment in several ways. First our Center has distinctive features thatinclude a combined focus on cancer disparities the application of strategies to increase participantengagement in research success in biospecimen acquisition and exceptional genomic sequencing expertise.Second we have assembled a diverse world class team with strong linkages to multiple rare and understudiedcancers. Third we engage investigators from different disciplines and invest in the development of earlycareer scholars. Fourth we will strategically and creatively disseminate products in ways that will benefitresearchers practitioners and community members. Fifth we will partner with exceptional patient-centeredand wide-reaching advocacy groups to engage patients optimize recruitment and seamlessly return results.Input from these groups patients and their families is a key strength that will leverage our track record ofstakeholder-engaged research. And finally we have developed a focused strategy for collective integration ofour units. These synergies will allow our Center to become a national resource for optimal approaches toparticipant engagement outreach and communication in genomic characterization studies and other studiesas technologies advance that will accelerate progress for both the scientific community patients and theircommunities. In summary we are uniquely situated to advance a network of participant engagement and sequencingresearchers integrate research with patients and their stakeholders build intellectual capital and significantlyenhance the capacity for participant engagement and genomic characterization studies. This Center willultimately benefit health systems providers and people with rare cancers and lead to a reduction in cancerdisparities. 4382 +No NIH Category available Address;African American;African American population;African ancestry;Area;Bioinformatics;Biological;Biological Factors;Biometry;Cancer Gene Mutation;Cancer Patient;Cells;Characteristics;Clinical;Clinical Management;Cohort Studies;DNA;DNA Sequence Alteration;Data;Databases;Development;Diagnosis;Discrimination;Disease;Ensure;Epithelial Cells;Exposure to;Frequencies;Genetic;Genetic Predisposition to Disease;Genetic study;Genomics;Geography;Goals;Health behavior;Immune;Immunity;Incidence;Individual;Indolent;Inflammation;Inflammatory;Investigation;Life Cycle Stages;Life Style;Malignant neoplasm of prostate;Molecular;Neighborhoods;Oncogenic;PSA screening;Pathology;Pathway interactions;Prevalence;Prevention strategy;Process;Program Research Project Grants;Prospective cohort;Prostate;Prostatic Neoplasms;Public Health;Recording of previous events;Records;Research;Research Personnel;Research Project Grants;Resources;Risk;Risk Factors;Role;Sampling;Scientist;Social Environment;Sociology;Somatic Mutation;Stress;Subgroup;Surveys;Susceptibility Gene;Time;Tumor Tissue;Variant;anticancer research;built environment;cell type;cohort;contextual factors;data management;design;disease prognosis;early life adversity;epidemiologic data;exome sequencing;genome wide association study;genome-wide;high risk;improved;individualized prevention;lifestyle factors;men;mortality;multidisciplinary;neoplasm registry;non-genetic;novel;patient stratification;perceived stress;personalized medicine;poor health outcome;population based;programs;prostate cancer risk;recruit;sample collection;segregation;social;social factors;social stress;social stressor;stressor;success;synergism;treatment choice;treatment strategy;tumor;tumor microenvironment Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics Immunity and Stress (RESPOND) Project Narrative Program Project OverviewThe overarching goal of this Program Project is to uncover the social and biological factors related to diseaseaggressiveness and poor health outcomes that contribute to the high prostate cancer mortality rates in AfricanAmerican men. To address this goal we propose to establish a large national population-based cohort study(RESPOND) comprised of 10000 AA men with incident prostate cancer identified through nine SEER and NPCRU.S. cancer registries. Leveraging this resource and investigator expertise we have designed four highly-integrated Projects that are supported by four Cores which are all focused on the central theme of identifyingfactors that contribute to aggressive prostate cancer in African American men. NCI 10759094 9/1/23 0:00 PAR-16-457 3U19CA214253-06S1 3 U19 CA 214253 6 S1 "DAEE, DANIELLE L" 7/5/18 0:00 6/30/24 0:00 ZCA1-RPRB-6(O1) 8474689 "HAIMAN, CHRISTOPHER ALAN" Not Applicable 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 73392 NCI 44480 28912 Abstract Program Project OverviewAfrican American (AA) men have a >60% higher incidence and are more likely to be diagnosed with aggressivePCa than white men. Reasons for the greater burden of aggressive disease in AA men are unknown but arelikely to include a multitude of factors including social factors such as lifetime stress inherited susceptibility andtumor-related features such as somatic alterations and local inflammation in the microenvironment. Theoverarching goal of this Program Project is to uncover the social and biological factors that are related to PCaaggressiveness in AA men. To accomplish this objective we will establish a large national population-basedcohort study RESPOND (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles ofGenetics Immunity and Social Stress) of 10000 AA men with incident PCa identified through nine SEER andNPCR U.S. cancer registries from states that include 38% of all AA PCa cases in the U.S.. The cohort will providecomprehensive information on multilevel stressors over the lifecourse such as discrimination early-life adversityand neighborhood disorder including geospatial neighborhood data over time and degree of perceived stress;2) lifestyle factors and health behaviors; 3) disease-specific factors including PSA screening history andtreatment choice; 4) germline DNA to study genetic susceptibility and 5) tumor block samples forcharacterization of somatic variation and immune profiling of the tumor microenvironment. No previous studyhas attempted to obtain information across these domains in a single large sample in order to understand therelative contribution of each and relationships between molecular and non-genetic components. In order toaddress these goals we have assembled a multi-disciplinary team of scientists and clinicians with establishedtrack records in PCa research. Leveraging the RESPOND resource and investigator expertise we havedesigned a Program Project composed of four Projects that are supported by four Cores which are all focusedon the central theme of identifying social and biological factors related to PCa disease aggressiveness in AAmen. These Projects include: the investigation of multilevel social stressors across the lifecourse in relationshipwith aggressive PCa (Project 1); genome-wide discovery efforts of germline susceptibility loci for aggressivePCa and examination of the relationship between germline and somatic variation (Project 2); the identificationof underlying somatic alterations in PCa tumors and biological pathways that are related to aggressive disease(Project 3); and a detailed assessment of inflammation in the tumor microenvironment as it relates to PCaaggressiveness in AA men (Project 4). Each of the four Projects address a distinct research domain howeverwhen studied together create scientific synergy and a far more comprehensive picture of the major factors thatcontribute to aggressive PCa in AA men. The information we will discover is likely to have immediate clinicalimplications in the areas of improved patient stratification and personalized medicine. Hence this study hasbroad reaching significance and addresses numerous challenges in the clinical management of PCa in AA men. 73392 +No NIH Category available Address;Bar Codes;Big Data;Biological Specimen Banks;Breast Cancer Cell;Calibration;Cancer Biology;Cell Count;Cell Line;Cell Survival;Cells;Chemoresistance;Clinical;Communities;Data;Developmental Therapeutics Program;Diagnosis;Dimensions;Disease Progression;Doxorubicin;Drug resistance;Experimental Models;Fluorouracil;Future;Gene Expression;Genomics;Goals;Growth;Heterogeneity;Human;Individual;Link;Malignant Neoplasms;Maps;Measurement;Measures;Methods;Modeling;Molecular;Paclitaxel;Patients;Phenotype;Play;Population;Prediction of Response to Therapy;Regimen;Resistance;Role;Sampling;Schedule;System;Systems Biology;Technology;Testing;Texas;Therapeutic;Therapeutic Agents;Time;Treatment Failure;Universities;Variant;austin;behavior prediction;cancer therapy;cell dimension;cell growth;chemotherapeutic agent;chemotherapy;clinically relevant;cost;epigenetic variation;experimental study;high dimensionality;improved;individualized medicine;mathematical model;medical schools;model development;multidimensional data;neoplastic cell;new technology;novel;predictive modeling;response;single-cell RNA sequencing;standard of care;therapy resistant;transcriptome;transcriptomics;translational potential;treatment response;triple-negative invasive breast carcinoma;tumor;tumor heterogeneity Systems Approaches to Understanding Subpopulation Heterogeneity in Therapeutic Resistance PROJECT NARRATIVETreatment of cancer is complicated by intratumor variation in which individual cells and groupsof cells within a single tumor respond differently to therapeutic agents. The high degree ofintratumor heterogeneity in triple-negative breast cancers confounds treatment efforts. Here wedevelop a linked set of experiment-computational workflows to measure track and predict thebehavior of heterogeneous triple-negative breast cancer cells. NCI 10759093 9/4/23 0:00 PAR-19-287 3U01CA253540-04S1 3 U01 CA 253540 4 S1 "DUECK, HANNAH RUTH" 9/8/20 0:00 8/31/25 0:00 ZCA1-RTRB-U(M1) 10352775 "BROCK, AMY " "YANKEELOV, THOMAS E" 37 BIOMEDICAL ENGINEERING 170230239 V6AFQPN18437 170230239 V6AFQPN18437 US 30.291188 -97.737568 578403 UNIVERSITY OF TEXAS AT AUSTIN AUSTIN TX BIOMED ENGR/COL ENGR/ENGR STA 787121139 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 79365 NCI 54696 24669 PROJECT SUMMARYIn recent years improvements in diagnosis and treatment have extended the lives of many patients with triplenegative breast cancer but resistance to treatment remains a major clinical and scientific challenge. Whilestandard-of-care treatment and chemotherapy is effective in many TNBC patients approximately 40% ofpatients display resistance leading to poor overall survival. TNBC are characterized by significant intratumorheterogeneity which further complicates treatment. Mechanisms of chemoresistance in TNBC patientsremain poorly understood in part due to a lack of available methods and models to measure intratumorheterogeneity and track changes in heterogeneous tumor compositions over time. Here we propose to use anew technology to track individual cells and clones as they respond to different chemotherapeutic agents; thismore detailed information about the tumor cell population will be used to build mathematical models betterpredict and optimize therapeutic response. We first measure individual cell gene expression changes inresponse to treatment and then assemble these measurements into cell subpopulation trajectories takingadvantage of a barcoding technology developed in our lab to quantify clonally-resolved single celltranscriptomes. These Aim 1 studies will build a compendium of gene expression cell growth and survivaldata that describes how each of the heterogeneous cells in major experimental models of subtypes of triplenegative breast cancer responds to clinically-relevant therapeutic agents. The new ability to layer clonalidentifier information on single cell gene expression data reveals the detailed trajectories of individual cellsthat escape therapy. It also distinguishes subpopulations with pre-existing treatment resistance from thosein which a resistant state is induced. At a higher conceptual level this proposal seeks to also address a broadpractical challenge: the high-dimensional omics data collected in many large-scale efforts points often pointsto correlations in disease progression but not been informative for building mechanistic models to aid in thepredictive of tumor response. Often other types of data are more readily available-- lower dimensional datawith more frequent measurements. We therefore next ask: How can these distinct data types be integratedinto a useful framework to build predictive models of tumor cell response to therapy? This seems a fitting goalfor the systems biology of cancer community. We propose to tackle this challenge with our barcode trackingtechnology; relative fractions of sensitive and resistance phenotypes along with separate longitudinalmeasurements of cell number (low dimension data) become the inputs for a mechanistic model to predicttherapeutic response and resistance (Aim 2). In Aim 3 we will perform trajectory-mapping and model testingusing patient-derived triple negative breast cancer cells towards understanding the potential for translationalutility. By integrating different data types into a cohesive framework we aim to describe how sensitive andresistant subpopulations in TNBC grow die and transition in response to treatment. 79365 +No NIH Category available 3-Dimensional;Actins;Actomyosin;Affect;Automobile Driving;Biological Models;Biomedical Engineering;Breast Cancer Cell;Breast Cancer cell line;Breast cancer metastasis;Cancer Biology;Cancer Patient;Cancerous;Cell Cycle;Cell Separation;Cell Volumes;Cell membrane;Cell surface;Cells;Cellular biology;Cessation of life;Clinical;Complement;Confined Spaces;Cytoplasm;Cytoskeleton;Data;Dissociation;Distant;Elements;Event;Extracellular Matrix;Fatty acid glycerol esters;Fiber;Gel;Goals;Growth;Image;Imaging Device;In Vitro;Individual;Integrins;Intracellular Transport;Ion Channel;Ions;Light;Mediating;Metastatic breast cancer;Microfluidic Microchips;Microtubules;Modeling;Molecular;Molecular Biology;Mus;Myosin Type II;Neoplasm Metastasis;Optics;Organ;Organoids;Osmosis;Patients;Phase;Primary Neoplasm;Regulation;Research Personnel;Role;Solid Neoplasm;Swelling;Testing;Tissues;Traction;Transplantation;Travel;Tumor Cell Migration;Water;Work;Zebrafish;cancer cell;cell motility;combat;experimental study;fluid flow;in vivo;in vivo Model;innovation;interdisciplinary approach;interstitial;intravital microscopy;live cell imaging;malignant breast neoplasm;mammary;mathematical model;migration;mouse model;multiphoton microscopy;neoplastic cell;new therapeutic target;novel;optogenetics;patient derived xenograft model;targeted treatment;therapeutic target;tool;triple-negative invasive breast carcinoma;tumor;tumorigenic;water channel The interplay of ion transporters and cytoskeleton in breast cancer migration and metastasis The inability to clinically treat cancer metastasis is responsible for the majority of patient deaths from solid tumorsincluding breast cancer. Cell migration is a pivotal step in the metastatic dissemination of cancerous cells froma primary tumor to distant organs in the body. We herein employ a multidisciplinary approach which integratesstate-of-the-art bioengineering and imaging tools quantitative analysis and in vivo models to offer acomprehensive understanding of the mechanisms driving breast cancer cell migration in physically-confinedspaces and identify novel therapeutic targets to reduce breast cancer metastasis. NCI 10759092 2/24/23 0:00 PA-19-056 3R01CA254193-03S1 3 R01 CA 254193 3 S1 "AULT, GRACE S" 2/2/21 0:00 1/31/26 0:00 Tumor Progression and Metastasis Study Section[TPM] 7108207 "KONSTANTOPOULOS, KONSTANTINOS " "MARTIN, STUART S" 7 ENGINEERING (ALL TYPES) 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD BIOMED ENGR/COL ENGR/ENGR STA 212182680 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 77642 NCI 51769 25873 The inability to clinically treat tumor metastasis is responsible for the majority of cancer patientdeaths. Cell migration is a pivotal step in the metastatic dissemination of cancer cells from a primary tumor todistant organs in the body. Cell motility is governed by cell-matrix interactions the actomyosin cytoskeleton andcell volume regulation via the involvement of ion transporters such as the Na+/H+ exchanger 1 (NHE1) asexplained by the Osmotic Engine Model (OEM). The roles of cytoskeleton and ion transporters in cell locomotionhave been typically studied in isolation. The overarching goal of this project is to employ a multidisciplinaryapproach involving state-of-the-art bioengineering and imaging tools quantitative analysis and in vivo models todefine the relative roles and potential crosstalk between ion transporters and the cytoskeleton in breast cancercell migration and metastasis in vivo. This application will test the hypothesis supported by intriguing preliminarydata that the coordinated action of local isosmotic swelling at the leading edge and shrinkage at the trailing edgemediated by NHE1 and SWELL1 respectively supports migration in confinement. We further hypothesize thatNHE1 and SWELL1 act in concert with cell cytoskeleton to mediate efficient migration and metastasis. Given thelack of targeted therapies for triple negative breast cancer (TNBC) we will prioritize TNBC cell lines and patient-derived xenograft (PDX) tumor cells as models. In Aim 1 we will establish the functional roles of NHE1 andSWELL1 in cell migration inside confining -channels of different stiffnesses in 3D gels and in cell disseminationfrom 3D breast cancer cell organoids. We will also elucidate the mechanism responsible for the polarizeddistribution of NHE1 and SWELL1 at the cell front and rear respectively and use novel optogenetic tools to altertheir spatial polarization and test how these alterations affect the direction and efficiency of cell migration. Inparallel we will develop an innovative mathematical model to identify the key variables that enable OEM-mediated cell motility. In Aim 2 we will delineate the interplay between OEM and the various cytoskeletalconstituents including b1 integrins myosin II actin and microtubules. Importantly we will define the intracellulartransport mechanisms responsible for NHE1 and SWELL1 shuttling along the longitudinal cell surface. We willalso introduce a comprehensive mathematical model to decipher the crosstalk of OEM and cytoskeletalcomponents in regulating migration efficiency. In Aim 3 we will demonstrate the effects of NHE1 and SWELL1silencing on cell migration in natural mammary tissue tracks in vivo and examine their roles in breast cancergrowth and metastasis using TNBC cell lines and PDXs orthotopically transplanted to the 4th mammary fat padof mice. We will complement mouse studies with experiments in zebrafish which enables us to image its entirevasculature at exceptional optical clarity in order to delineate the roles of ion transporters in different steps ofthe metastatic cascade. This application brings together a team of investigators with expertise in bioengineeringimaging cell & molecular biology quantitative analysis PDXs in vivo studies and breast cancer biology. 77642 +No NIH Category available Address;Adverse event;Biochemical;Biological Markers;Biology;Biopsy;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Clinic;Clinical;Code;Data;Diagnosis;Disease;Disease Progression;Distant Metastasis;Early Diagnosis;Genes;Genetic;Genetic Determinism;Genetic study;Genomic approach;Genomics;Hematopoietic Neoplasms;Heritability;Hospitals;Image;Impairment;Indolent;Inherited;Kininogenase;Knowledge;Length;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Modeling;Mutation;PF4 Gene;PSA screening;Pathway interactions;Play;Price;Prognostic Factor;Prostate;Prostate Cancer therapy;Quality of life;Recurrence;Reflex action;Risk;Role;Screening for Prostate Cancer;Screening procedure;Signal Transduction;Single Nucleotide Polymorphism;Testing;Time;Transcription Alteration;Translating;Twin Studies;United States;Variant;Work;biomarker panel;cancer diagnosis;cancer survival;clinical risk;clinical translation;clinically significant;cohort;cost;exome sequencing;follow-up;genetic information;genetic predictors;genetic risk factor;genetic testing;genetic variant;genome wide association study;high risk;high risk men;improved;insight;kallikrein 4;men;middle age;model design;novel;peripheral blood;population based;predictive marker;prostate cancer progression;rare variant;risk stratification;screening;trait;transcriptome;unnecessary treatment Genetic Predictors of Prostate Cancer Survival Project NarrativeWhile prostate cancer screening reduces death from prostate cancer it does so at the cost of unnecessarytreatment of men with nonaggressive disease. To address this we propose to identify inherited geneticchanges that influence survival time after a diagnosis of prostate cancer and incorporating such geneticinformation into prostate cancer screening tools. If successful this will enable more precise prostate cancerscreening reducing both death from prostate cancer and unnecessary treatment. NCI 10759024 3/14/23 0:00 PA-19-056 3R01CA244948-03S1 3 R01 CA 244948 3 S1 "MCKEE, TAWNYA C" 1/15/21 0:00 12/31/25 0:00 Cancer Biomarkers Study Section[CBSS] 8876972 "KLEIN, ROBERT J." Not Applicable 13 GENETICS 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 394 Non-SBIR/STTR 2023 222600 OD 131716 90884 Project Summary / AbstractEven though most men diagnosed with prostate cancer will not die of the disease prostate cancer is still thesecond leading cause of cancer death among men in the United States. While screening for prostate cancerreduces death from disease this comes at the price of both unnecessary biopsies that reveal no evidence ofcancer and treatment of otherwise indolent cancer resulting in unnecessary adverse events. Therefore thereis an unmet need for improved screening tools for prostate cancer. To address this need we have previouslydeveloped a four-kallikrein biomarker panel that is now commercially available as a reflex test for use after aninitial PSA screening; found that the four kallikrein model improves the prediction prior to any diagnosis ofprostate cancer of which men may die of prostate cancer; and identified SNPs associated with survival timeafter diagnosis independent of known prognostic factors. Combining these SNPs and the four kallikrein panelimproves our ability to identify men at risk of dying from prostate cancer even further. Based on these findingswe propose here a germline genomic approach to identify men at risk of dying from prostate cancer. Byleveraging recent computational advances in genomic analysis we will take a gene-centered approach toidentify genes for which genetically controlled transcriptional alterations and/or functional coding mutationsinfluence survival time in prostate cancer. Using these genes along with known genetic risk factors for prostatecancer and the four kallikrein panel we will build and test models designed to identify men at risk for clinicallysignificant prostate cancer in order to better stratify men in the screening context prior to biopsy. Specificallywe will: 1) Identify genes for which genetically controlled expression level changes and/or rare coding variantsalter the risk of dying from prostate cancer; 2) Determine at what stage(s) of disease progression these geneticchanges operate; and 3) Improve our 4-kallikrein biomarker predictor of lethal prostate cancer throughincorporation of genetic data. This will be achieved by conducting both a transcriptome-wide association study(TWAS) with prostate specific models and a whole exome sequencing study in a set of well-annotated cohortswith long follow-up time after prostate cancer diagnosis. Successful completion of these aims will enablebetter risk stratification of men prior to prostate cancer diagnosis. We envision these findings being useful inthe screening context enabling more precise identification of men at high risk of dying from prostate cancer inthe next two decades thereby reducing death from prostate cancer due to the benefits of early detection whileavoiding unnecessary biopsies and unneeded treatment of otherwise indolent cancers. Furthermore thesefindings will be useful in understanding the biology of lethal prostate cancer as we anticipate these findings willpinpoint new genes and pathways that play important roles in prostate cancer progression. 222600 +No NIH Category available Adherence;Adult;Behavior;Body Composition;Body Weight decreased;Cancer Prevention Intervention;Chronic Disease;Colon Carcinoma;Complex;Data;Ecological momentary assessment;Education;Endometrial Carcinoma;Engineering;Event;Fatty acid glycerol esters;Feedback;Glycosylated hemoglobin A;Goals;Guidelines;Health;Hip region structure;Human;Individual;Intervention;Literature;Maintenance;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mathematics;Measurement;Measures;Mental Health;Methods;Modeling;Monitor;Nature;Obesity;Outcome;Overweight;Pain;Participant;Patient Outcomes Assessments;Persons;Physical activity;Positive Reinforcements;Public Health;Randomized Controlled Trials;Recommendation;Renal carcinoma;Research;Resolution;Risk;Risk Reduction;Sequential Multiple Assignment Randomized Trial;Smoking;Stress;Substance abuse problem;System;Techniques;Testing;Time;Walking;Weight maintenance regimen;Work;actigraphy;adaptive intervention;aged;behavior change;cancer prevention;cancer risk;cancer type;cost effectiveness;digital health;digital platform;exercise intervention;fitbit;global health;high risk;high risk population;improved;innovation;mHealth;malignant breast neoplasm;malignant stomach neoplasm;multiphase optimization strategy;pilot test;prevent;randomized trial;response;simulation;social cognitive theory;tool;treatment arm;vigorous intensity;wearable device Optimizing Individualized and Adaptive mHealth Interventions via Control Systems Engineering Methods Physical activity can reduce risk for a variety of chronic diseases including several types of cancer butunfortunately many individuals try but fail to be active (e.g. think New Years Resolutions). The purpose of thisproject is to evaluate if an intervention that uses methods from control systems engineering to adjust support toeach persons changing needs will promote increased physical activity compared to another intervention thatdoes not use these methods. NCI 10759023 7/6/23 0:00 PAR-18-559 3R01CA244777-04S1 3 R01 CA 244777 4 S1 "BLAKE, KELLY D" 7/14/20 0:00 6/30/25 0:00 Psychosocial Risk and Disease Prevention Study Section[PRDP] 8576782 "HEKLER, ERIC " "RIVERA, DANIEL E" 50 FAMILY MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 107917 OD 68302 39615 Background: Strong evidence indicates physical activity (PA) reduces risk of bladder breast colonendometrium esophagus gastric and renal cancer and there is moderate evidence for lung cancer. Individualsaged 40+ who are inactive are at high risk of developing cancers 5865 but only 1/3 meet guidelines for PA;5-15thus they are an important group to target. While effective PA interventions exist interventions often workonly for some individuals or only for a limited time16-18 thus establishing the need for interventions that canaccount for dynamic idiosyncratic PA determinants in order to support each persons PA. In response wedeveloped JustWalk a modular adaptive mobile health (mHealth) intervention that makes daily N-of-1adjustments to support PA for each person. JustWalk is based on Social Cognitive Theory (SCT) with N-of-1adaptation driven by a mathematical dynamical model of SCT which we have developed and validated. JustWalkcan perform N-of-1 adaptation based on our innovative use of control engineering methods which we call acontrol optimization trial (COT). We have a digital platform and empirical justification for our next step: toevaluate in a randomized controlled trial (RCT) whether using a COT approach to continuously optimize a PAintervention to each individual is superior to an intervention that is identical but lacks the COT methods. Primarypurpose: Evaluate differences in minutes/week of moderate-to-vigorous intensity PA (MVPA) among the COT-optimized vs. non-COT groups at 12 months. Hypotheses: We hypothesize significantly higher minutes/weekof MVPA in the intervention arm (COT) relative to control (non-COT) as measured via ActiGraph (powered foreffect size of 0.32). Methods: We will conduct this RCT with 386 adults aged 40+ who are inactive andoverweight/obesity. This is a high-risk group who would benefit from a PA intervention for cancer prevention andwho would benefit from an adaptive intervention because of the idiosyncratic and dynamic nature of PA that ispronounced within this group. Assessments will be conducted at baseline 6 and 12-months using a hip-wornActiGraph for assessing minutes/week of MVPA as justified by guidelines. Implications: This research is highlysignificant because our intervention would be the first scalable PA intervention squarely grounded in SCT withN-of-1 adaptation driven by a mathematical dynamical model version of SCT. Further favorable results wouldjustify use of our COT methods for other complex and highly idiosyncratic and dynamic behaviors such as weightmanagement smoking or substance abuse. Finally our work should improve understanding of engagementwith digital health tools. This research is highly innovative as we would be the first to conduct a COT and toempirically evaluate its utility in an RCT. 107917 +No NIH Category available Adult;Affect;Anabolism;Antineoplastic Agents;Behavioral;Brain;Brain region;Cancer Survivor;Cell division;Cell physiology;Cisplatin;Clinical Trials;Coenzymes;Cognitive;Cognitive deficits;Confocal Microscopy;DNA Repair;Data;Dendrites;Dendritic Spines;Development;Enhancers;Ensure;Enzymes;Functional disorder;Gliosis;Glycolysis;Goals;Hippocampus;Impaired cognition;Impairment;Laboratories;Learning;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Medical;Memory;Memory impairment;Metabolic;Metabolic Pathway;Metabolism;Molecular;Morphology;Mus;Neuronal Dysfunction;Neurons;Niacinamide;Nicotinamide Mononucleotide;Nicotinamide adenine dinucleotide;Pathway interactions;Patients;Pharmaceutical Preparations;Platinum;Play;Process;Quality of life;Role;Safety;Supplementation;Testing;Therapeutic;Transferase;Translational Research;United States;Work;age related neurodegeneration;aged;behavior test;cancer therapy;chemobrain;chemotherapy;clinically relevant;cognitive function;cohort;comorbidity;drug development;effective therapy;enzyme activity;healthspan;improved;insight;mouse genetics;mouse model;myelination;neurogenesis;neurotoxicity;novel;novel therapeutic intervention;older patient;overexpression;patient derived xenograft model;pharmacologic;prevent;side effect;stem;therapeutic target;therapeutically effective PQ#12; Targeting Nampt-mediated NAD+ metabolism in chemobrain PROJECT NARRATIVE In the United States cognitive dysfunction stemming from chemotherapy is a major adverse conditionaffecting approximately 14 million cancer survivors. Unfortunately the underlying pathophysiologicalmechanisms remain unknown. The findings of this proposal are crucial towards elucidating a role for theNampt-mediated NAD+ metabolic pathway in improving neuronal and cognitive dysfunction resulting fromchemobrain. This understanding will provide insight into development of novel therapeutic interventions thattarget chemotherapy-induced cognitive dysfunction. NCI 10759020 7/21/23 0:00 RFA-CA-18-019 3R01CA242158-06S1 3 R01 CA 242158 6 S1 "CHEN, WEIWEI" 8/8/19 0:00 7/31/24 0:00 ZCA1-SRB-2(M2)S 10001078 "JANG, MI-HYEON " Not Applicable 10 NEUROSURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 136017 NCI 86635 49382 PROJECT SUMMARY Chemotherapy-induced cognitive dysfunction (referred to as chemobrain) negatively impacts cancersurvivors and has emerged as a significant medical problem. To date no effective treatment exists due to thelimited understanding of the mechanisms that drive chemotherapy-induced cognitive impairments. To provideeffective therapeutic strategies for this emergent medical problem this application aims to answer ProvocativeQuestion #12: What are the molecular and cellular mechanisms that underlie the development of cancertherapy-induced severe adverse sequelae? While the underlying molecular pathways vulnerable tochemotherapy-induced neurotoxicity are not well understood recent results from our laboratory indicate theNampt-mediated NAD+ pathway is a promising therapeutic target for chemobrain. Using the platinum-basedchemotherapy compound cisplatin we demonstrate its efficacy in suppressing the nicotinamide phosphoribosyltransferase (Nampt)-mediated NAD+ metabolic pathway. Cisplatin-mediated suppression of Nampt-NAD+metabolism leads to neurogenic dysfunction of the adult mouse hippocampus and memory impairments.Remarkably we found that by increasing NAD+ levels via administration of the NAD+ precursor nicotinamidemononucleotide (NMN) we can effectively reverse cisplatin-induced deficits in neuronal dendrite morphologyand memory function thus emphasizing the therapeutic potential of NAD+ metabolism in amelioration ofchemobrain. Based on these observations our central hypothesis is that increasing Nampt or NAD+ levelsprevent cisplatin-induced impairments in neuronal and cognitive function. Our findings represent a noveltherapeutic strategy for chemobrain. To test this novel hypothesis Aim 1 will determine whether increasingNAD+ levels through NMN supplementation can improve cisplatin-induced deficits in neuronal and cognitivefunction in both young and aged mice. In addition our translational proposal will ensure the safety of NMN as wewill determine if NMN has a detrimental impact on anti-neoplastic activity of cisplatin using patient-derivedxenograft (PDX) mouse models. Subsequently Aim 2 will elucidate if genetically increasing Nampt levels canprevent impairments in neuronal morphology and cognitive function. We will also evaluate if P7C3 a Namptenzyme activity enhancer can improve cisplatin-induced chemobrain in young and aged mice. Our proposedwork will provide critical pathophysiological mechanisms and improve our understanding of the Nampt-mediatedNAD+ metabolic pathway in order to improve chemotherapy-induced cognitive dysfunction. Ultimately thefindings will provide a framework by which safe and effective therapeutic strategies may be utilized in patientsundergoing cancer treatment so as to minimize or reverse neuronal and memory dysfunction. 136017 +No NIH Category available ASCL1 gene;Acetates;Address;Androgen Metabolism;Androgen Receptor;Androgens;Automobile Driving;CYP17A1 gene;Cancer Patient;Cells;Characteristics;Clinical;Collection;Combined Modality Therapy;DNA Methyltransferase Inhibitor;DNA Sequence Alteration;Data;Development;Disease Resistance;Drug Modulation;EZH2 gene;Engineering;Epigenetic Process;Epithelium;Experimental Models;Genetic;Goals;Human;Human Cell Line;Incidence;Knowledge;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Mediating;Metastatic Prostate Cancer;Modeling;Molecular;Mouse Cell Line;Mutation;Neuroendocrine Prostate Cancer;Neurosecretory Systems;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Positioning Attribute;Prostate;Prostate Adenocarcinoma;Prostate Cancer therapy;Publishing;RB1 gene;Receptor Signaling;Relapse;Research;Resistance;Science;Signal Transduction;Specimen;TP53 gene;Testing;Therapeutic;Time;Tissues;Tumor Suppressor Genes;Variant;Work;abiraterone;androgen deprivation therapy;androgen independent prostate cancer;androgen sensitive;antagonist;cancer cell;castration resistant prostate cancer;cell transformation;derepression;design;effective therapy;enzalutamide;improved;individual patient;inhibitor;molecular targeted therapies;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;phenotypic biomarker;prostate cancer cell;receptor expression;relapse patients;response;single cell analysis;therapeutically effective;therapy resistant;treatment response NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer PROJECT NARRATIVEMany cancers including metastatic prostate cancer resist molecularly targeted therapy by altering theirphenotype from one that is dependent on the target to one that is not. Here we characterize genetic mutationsand epigenetic mechanisms that drive transformation from androgen dependent prostate cancer to androgenindependent prostate cancer. The goal is to identify new approaches for treating lethal prostate cancers. NCI 10759015 4/25/23 0:00 PA-18-484 3R01CA234162-05S1 3 R01 CA 234162 5 S1 "JOHNSON, RONALD L" 5/22/19 0:00 4/30/25 0:00 Tumor Cell Biology Study Section[TCB] 1898849 "GOODRICH, DAVID W." Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 8020 NCI 4768 3252 Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC) but allpatients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent onandrogen receptor (AR) signaling but a significant fraction lack AR expression become AR signalingindependent and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of NEPCvariants among CRPC has increased as more patients benefit from improved ADTs like enzalutamide andabiraterone acetate. This suggests increasingly stringent AR signaling blockade is driving development ofNEPC. This is an important clinical problem because NEPC is aggressive and lethal; development of effectivetherapies is hampered by limited understanding of relevant molecular mechanisms. NEPC clearly arises fromARpos CRPC as they share clonal origin in patients that harbor both. We have determined that geneticinactivation of the RB1/TRP53 tumor suppressor genes cooperate to facilitate transformation of ARpos PADC toNEPC through derepression of epigenetic reprogramming factors. Inhibiting these reprogramming factorsreverses NEPC transformation and restores ADT sensitivity demonstrating that epigenetic changes areinvolved. We hypothesize that a change in NOTCH-ASCL1 signaling triggers the epigeneticreprogramming underlying NEPC transformation. This hypothesis has clinical ramifications as the pathwaycould conceivably be manipulated therapeutically to delay or reverse NEPC transformation extending theduration of beneficial ADT clinical responses in some patients. We propose three specific aims using novelprostate cancer mouse models and unique human clinical specimens to test this hypothesis characterize howPADC cells transform into NEPC cells and explore novel therapeutic approaches for the treatment of thislethal form of prostate cancer. We will: 1) Test if NOTCH signaling is sufficient to maintain an androgendependent PADC phenotype; 2) Characterize how prostate cancer cells transition from PADC to NEPC; 3)Determine whether epigenetic modulating drugs reverse NEPC transformation and ADT resistance viaNOTCH-ASCL1 signaling. The long term goal of this project is to improve prostate cancer therapy byadvancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic resistance. 8020 +No NIH Category available Adoptive Cell Transfers;Adoptive Transfer;Anatomy;Angiogenesis Inhibition;Angiogenic Factor;Angiogenic Proteins;Attenuated;Biology;Blood Circulation;Blood Vessels;CD8-Positive T-Lymphocytes;Cancer Patient;Cell physiology;Cells;Cellular Immunology;Clinical;Collaborations;Color;Cytokine Signaling;Data;Disease;Dose;Down-Regulation;Effectiveness;Endothelial Cells;Endothelium;Engineering;Feedback;Flow Cytometry;Generations;Hemorrhage;Homing;Hypoxia;Imaging Techniques;Immune;Immunity;Immunosuppression;Immunotherapy;Infiltration;Inflammatory;Knowledge;Ligands;Liquid substance;Mediating;Modeling;Molecular;Neoplasms in Vascular Tissue;Outcome;Patients;Pattern;Perfusion;Peripheral;Phage Display;Physiological;Play;Population;Process;Proliferating;Proteins;Publishing;Research Personnel;Role;Signal Transduction;Solid Neoplasm;Source;Starvation;Structure;T cell infiltration;T-Lymphocyte;Technical Expertise;Technology;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor-Associated Vasculature;Tumor-infiltrating immune cells;Up-Regulation;Vaccination;Vascular Endothelial Growth Factors;Vegf inhibition;Work;anergy;angiogenesis;bevacizumab;cell motility;chimeric antigen receptor T cells;cytokine;immune cell infiltrate;immune checkpoint blockade;immunoregulation;improved;improved outcome;in vivo imaging;knock-down;migration;novel;overexpression;pleiotropism;prognostic indicator;receptor;receptor expression;response;single cell analysis;success;tool;trafficking;tumor;tumor growth;tumor immunology;tumor microenvironment;tumor-immune system interactions Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors CD8 T cell infiltration into tumors is a positive prognostic indicator of patient survival and recent successes incontrolling tumors by adoptive transfer of activated tumor-specific T cells validate its importance. Indeed it hasbecome clear that the patients who respond clinically to new generation immunotherapies are those in whichan immunological infiltrate is already evident prior to treatment. Thus limited infiltration of immune cellsrepresents a major barrier to tumor control above the hurdle created by immunosuppression. T cells entertumors by leaving the bloodstream and crossing the wall of the tumor blood vessel. To do so T cells mustengage with molecules that are expressed on the blood vessel wall that function like a molecular Velcro. Intumors the function of this Velcro is suboptimal. The work proposed in this application is directed towardsunderstanding how to improve its fuctionality and improve the infiltration of T cells into tumors. We believe thatthis understanding will lead to strategies that can be used to enhance this process and that this will extend therange and effectiveness of many kinds of immunotherapy for improved outcomes in cancer patients. NCI 10759011 8/18/23 0:00 PA-18-484 3R01CA233716-05S1 3 R01 CA 233716 5 S1 "LIU, YIN" 6/1/19 0:00 5/31/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 1946902 "ENGELHARD, VICTOR H" "KELLY, KIMBERLY A." 5 MICROBIOLOGY/IMMUN/VIROLOGY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 31373 NCI 19426 11947 The presence of CD8 T cells (TCD8) in tumors is a positive prognostic indicator of patient survival butrepresentation of TCD8 in many tumors is poor. While this could be a consequence of poor intratumoralproliferation it is also the case that only a very small fraction of adoptively transferred TCD8 or CAR-T entertumors. Our published and preliminary data indicates that homing receptor ligand (HRL) expression on tumorvasculature is suboptimal and that entry of TCD8 into tumors can be enhanced by relief of immunosuppression.Our work also suggests a positive feedback model in which intratumoral effector activity from newly enteringTCD8 is needed to maintain HRL expression and sustain entry of newly arising effectors. Work conducted byothers has suggested that pro-angiogenic factors such as VEGF may limit TCD8 infiltration by multiplemechanisms including disorganized vascular structure interference with cytokine signaling in endothelial cellsto induce HRL upregulation and suppression of intratumoral immunity. However how these different aspectsof angiogenesis influence direct TCD8 effector entry into tumors remains to be determined. There is also stilllittle understanding of the roles that innate immune cells and intratumoral Ag play in augmenting entry of TCD8effectors. This multi-PI R01 application is a collaboration between two investigators with complementaryexpertise. The Engelhard lab has identified: subpopulations of TCD8 effectors based on homing receptor (HR)expression pattern; the patterns of HRL expression on tumor vasculature; and the HR/HRL pairs that mediateTCD8 effector migration into tumors. The Kelly lab has focused on developing tools and using engineeringapproaches to study the role of the endothelium in disease. Using phage display technology they identifiedhornerin a novel non-VEGF induced protein overexpressed on tumor vasculature. Hornerin knockdown leadsto vessel normalization and increased perfusion without loss of blood vessels. Hornerin may be an idealmolecule to attenuate in order to promote vessel normalization without the confounding pleiotropic effectsobserved when inhibiting VEGF. These two investigators will use these novel tools and expertise to understandhow the direct entry of TCD8 into tumors is regulated by intratumoral Ag tumor vasculature and tumormicroenvironment. Aim 1 will determine the impact of intratumoral immunoregulatory mechanisms on HRLexpression on tumor vasculature and on exogenous TCD8 effector trafficking. Aim 2 will determine the impact ofpro-angiogenic factors and tumor vessel normalization on HRL expression on tumor vasculature and onexogenous TCD8 effector trafficking. Aim 3 will determine the role of innate immune cells and intratumoral Ag inpromoting TCD8 effector trafficking into tumors. Overall this work will illuminate factors that limit the migration oftumor-specific T cells into tumors after vaccination or adoptive transfer and suggest approaches to enhancetheir infiltration and subsequent therapeutic efficacy. This information may be used in conjunction with activevaccination or adoptive transfer-based immunotherapies to enhance their efficacy in a broader spectrum ofcancer patients. 31373 +No NIH Category available Biology;Cell Cycle Regulation;Cell Line;Cells;Childhood Solid Neoplasm;Clinical;Complication;DNA Methylation;Data;Development;Epigenetic Process;Family;Gene Expression Alteration;Genes;Genetic Transcription;Goals;Health;Histone Acetylation;Human;In Vitro;Incidence;Invaded;Knock-out;Knockout Mice;Laboratories;Link;Malignant Neoplasms;Mediating;Metastatic Neoplasm to the Lung;Mus;Mutation;Neoplasm Metastasis;PHD Finger;Pathogenesis;Pathway interactions;Patients;Phenotype;Play;Primary Bone Osteosarcoma;Prognosis;Promoter Regions;Proteins;Research;Research Proposals;Ring Finger Domain;Role;Site;Structure of parenchyma of lung;TP53 gene;Testing;Therapeutic;Therapeutic Intervention;Ubiquitin;Ubiquitination;Work;anticancer treatment;cancer therapy;cell motility;chemotherapy;design;effective therapy;epigenetic regulation;epigenome;gain of function;genetic corepressor;histone methylation;improved;in vivo;inhibitor;inhibitor therapy;knock-down;loss of function;migration;mortality;mouse model;next generation;novel;novel therapeutic intervention;osteosarcoma;overexpression;preservation;recruit;response;therapeutic target;tumor;tumor progression;tumorigenesis;tumorigenic;virtual Role of UHRF1 in osteosarcoma and its relationship to RB Metastasis remains the most significant complication of osteosarcoma. Among the patients who developmetastasis less than 1 in 5 survive. Thus there is a pressing clinical need to determine the factors responsiblefor metastasis in osteosarcoma in order to facilitate the development of new therapeutic strategies. Our limitedunderstanding of the biology which drives the spread of osteosarcoma from primary bone sites into lungtissue has limited our ability to accomplish this. We identified UHRF1 as a protein overexpressed inosteosarcoma that plays a significant role in osteosarcoma metastasis. This project aims to further ourunderstanding of the role of UHRF1 in tumor formation progression and metastasis and further investigate itspotential as therapeutic target for anti-cancer treatment. Given that UHRF1 is overexpressed in multiplecancers this research proposal has the potential to impact human health beyond osteosarcoma. NCI 10759010 9/20/23 0:00 PA-18-484 3R01CA229696-05S1 3 R01 CA 229696 5 S1 "HILDESHEIM, JEFFREY" 6/1/19 0:00 5/31/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 10405896 "BENAVENTE, CLAUDIA ANDREA" Not Applicable 47 PHARMACOLOGY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF PHARMACY 926970001 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 121681 NCI 77504 44177 Metastasis remains the most significant fatal complication in the treatment of osteosarcoma. Among thepatients who develop metastasis less than 1 in 5 survive. Genetic alterations at the RB transcriptionalcorepressor 1 (RB1) gene have been associated with increased mortality metastasis and poor response tochemotherapy in osteosarcoma. However the precise mechanism through which this occurs remains to beelucidated. Studies in our laboratory identified UHRF1 (Ubiquitin-like containing PHD and RING Fingerdomains 1) as a gene that is upregulated and its protein overexpressed in osteosarcoma. UHRF1 is amultifunctional protein involved in epigenetic regulation that has been shown to interact with RB. Further theRB/E2F pathway directly regulates UHRF1 expression. Our data indicates that targeting UHRF1overexpression dramatically increases survival in mice bearing osteosarcoma tumors and reduces the rate andnumber of metastases. The goal of this proposal is to determine the mechanism(s) through which UHRF1contributes to tumor progression to help design novel therapeutic interventions for the treatment ofosteosarcoma. These studies also evaluate whether UHRF1 is a valid target for most osteosarcomas or onlythose bearing RB1 mutations. For this we will define the role of UHRF1 in osteosarcoma pathogenesis andprogression focusing on its relationship with RB1 and define the roles of each of the UHRF1 functionaldomains in the UHRF1-associated migration and invasion in osteosarcoma. This proposal tests the hypothesisthat gene expression alterations driven by UHRF1 underlie tumor progression and poor survival inosteosarcoma. Successful completion of this work is likely to directly influence the development of UHRF1inhibitors relevant for therapeutic intervention for osteosarcoma and other cancers with UHRF1overexpression. 121681 +No NIH Category available 3-Dimensional;Address;Adjuvant;Adult;Adult Glioblastoma;Adult Glioma;Age;Agreement;Astrocytoma;Award;BRAF gene;Basic Science;Biology;Biometry;Boston;Brain;Brain-Derived Neurotrophic Factor;CDK4 gene;Cancer Center;Cancer Etiology;Cell Cycle Arrest;Cell Cycle Progression;Cells;Cessation of life;Child;Child Care;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Clinical;Clinical Trials;Collaborations;Complement;Computational Biology;Cyclin D1;Dana-Farber Cancer Institute;Daphne plant;Development;Diagnosis;Doctor of Medicine;Doctor of Philosophy;Enzymes;Excision;Fostering;Funding;General Hospitals;Genetic;Genetically Engineered Mouse;Glioblastoma;Glioma;Growth;Hospitals;Human;Image;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotherapy;Independent Living;International;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Massachusetts;Metabolic;Methods;Modality;Molecular;Mutation;Nature;Neurons;Neurosurgeon;Oncologist;Operative Surgical Procedures;Pathology;Patient-Focused Outcomes;Patients;Pediatric Hospitals;Persons;Pharmaceutical Preparations;Pharmacology;Phosphorylation;Primary Brain Neoplasms;Protein Isoforms;Protein Kinase;Protein-Serine-Threonine Kinases;Quality of life;Recurrence;Reproducibility;Research Personnel;Research Project Grants;Resected;Science;Scientist;Signal Transduction;Structural Biologist;Survivors;Talents;Teaching Hospitals;Testing;Therapeutic;Time;Tumor Immunity;Tumor Tissue;Universities;Variant;Woman;Work;alpha ketoglutarate;antagonist;brain tissue;career;cell type;childhood cancer mortality;clinical imaging;efficacy study;flexibility;humanized mouse;imaging study;improved;in vivo;inhibitor;innovation;leukemia;medical schools;melanoma;mouse model;mutant;neuro-oncology;neuroligin 3;novel;novel strategies;novel therapeutics;professor;programmed cell death protein 1;programs;response;single cell sequencing;skills;small molecule;standard of care;targeted treatment;tool;translational scientist;tumor;tumor growth;tumor microenvironment;young adult SPORE: Targeted Therapies for Glioma NarrativePrimary cancers of the brain have surpassed leukemias as the number one cause of cancer-related death inchildren and low-grade astrocytomas are the most common brain tumor of childhood. Pediatric low-gradeastrocytomas (PLGAs) are survivable with current standard of care. However the quality of life for long-termPLGA survivors and their capacity for independent living is compromised to a significant degree. Targetedtherapeutics for PLGA are urgently needed. The work proposed for Project One has the potential to deliverbrain-penetrant targeted therapies for these tumors. Primary brain tumors including high-grade gliomas arethe third most common cause of cancer-related death in persons ages 15-39 years (http://www.CBTRUS.org).In the fullness of time the work proposed for Projects Two and Three could change the standard of care andimprove patient outcomes for these tumors via highly selective synthetic lethal therapeutic modalities(Project Two) or small molecule adjuvants to immunotherapy (Project Three). Project Four addresses aunique feature in the biology of high-grade gliomas. These tumors occur within the context of the brainmicroenvironment. Preliminary studies have shown that neuronal activity within the glioma microenvironmentsecrete a factor (NLGN3) that promotes the growth of these tumors in adults and also in children. The studyplan for this project will explore a novel therapeutic opportunity embedded within the NLGN3 requirement. NCI 10759007 9/11/23 0:00 PAR-18-313 3P50CA165962-10S1 3 P50 CA 165962 10 S1 "HUBBARD, LEAH" 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J(M1) 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 234721 NCI 131129 103592 This is the competing renewal of a SPORE initiative on glioma at Dana-Farber/Harvard Cancer Center. Ourobjective is to improve the standard of care for children young adults and adults with these tumors throughthe use of targeted therapies. Towards this end basic scientists from Harvard Medical School and the BroadInstitute join with clinical/translational investigators from Boston Childrens Hospital Brigham and WomensHospital Dana-Farber Cancer Institute and Massachusetts General Hospital. There are four projects: Project One targets pediatric low-grade astrocytomas (PLGAs). Nearly 75% of PLGAs are driven byactivating mutations in the BRAF protein kinase. Clinician/scientists Daphne Haas-Kogan M.D. and KarenWright M.D. together with structural biologist Michael Eck M.D. Ph.D. will develop and test brain-penetranttargeted therapeutics for BRAF-mutant PLGAs. Project Two targets IDH-mutant gliomas which presenttypically in young adults. IDH-mutant gliomas produce extraordinarily high levels of the oncometabolite R-2-hydroxyglutarate (2-HG). However therapeutic exploitation of the differential 2-HG content between normaland malignant brain tissue has yet to be realized. Neurosurgeon Daniel Cahill M.D. Ph.D. and cancerbiologist William Kaelin M.D. will address this therapeutic lacuna. Project Three targets adult gliomas.Recent studies by basic scientist Jean Zhao Ph.D. show that in addition to suppressing cell cycle progressionCDK4/6 antagonists promote anti-tumor immunity and synergistically enhance the response to checkpointinhibitors. Going forward Dr. Zhao together with neuro-oncologist Patrick Wen M.D. will test the hypothesisthat brain penetrant CDK4/6 inhibitors can augment immunotherapeutic approaches to GBM. Project Fourtargets the neuronal microenvironment of adult and pediatric gliomas. Neuro-oncologist and developmentalneurobiologist Michelle Monje M.D. Ph.D. has shown that neurons promote glioma growth through activity-regulated secretion of neuroligin-3 (NLGN3) into the tumor microenvironment. Basic scientist Mario SuvaM.D Ph.D. has refined methods for single cell sequencing of the multiple cell types within themicroenvironment of freshly resected human gliomas. Working together Monje and Suva will define themolecular mechanisms whereby microenvironmental NLGN3 modulates formation and progression of gliomasand explore a novel therapeutic opportunity embedded within the NLGN3 requirement. Rigor and reproducibility of work conducted in the four projects will be fostered by cores for Pathologyand for Biostatistics and Computational Biology. An Administration core will enable and manage themultiple consortium agreements and collaborative interactions between Harvard Medical School the fourparticipating Harvard teaching hospitals and facilitate clinical trials and imaging studies. Intellectual vigorwithin the program is sustained and refreshed by annual Career Enhancement Awards to young investigatorsand by annual Developmental Project Awards. 234721 +No NIH Category available 8q24;African American;Area;Aromatase Inhibitors;Automobile Driving;Binding;Biological;Breast Cancer Model;Breast Cancer Patient;Cell Proliferation;Cell Survival;Cell Therapy;Cell physiology;Cessation of life;Chicago;Cholesterol;Chromosomes;Collection;Data;Development;Diagnosis;Disease;Enzymes;Epoxy Compounds;Estrogen Receptors;Estrogen receptor positive;Estrogens;Freezing;Genomics;Goals;Incidence;Mammary Neoplasms;Messenger RNA;Methods;Molecular;Normal tissue morphology;Not Hispanic or Latino;Organoids;Outcome;Patient-Focused Outcomes;Patients;Pre-Clinical Model;Prevention strategy;Production;Prognosis;Prognostic Factor;Race;Recurrence;Relapse;Resistance;Risk;Role;Squalene;Stage at Diagnosis;Sterol Biosynthesis Pathway;Sterols;Survival Rate;Tamoxifen;Testing;Tumor Promotion;Tumor Subtype;Up-Regulation;Woman;Work;breast cancer survival;cancer type;cohort;epoxidase;health equity;hormone therapy;improved;inhibitor;innovation;insight;mRNA Expression;malignant breast neoplasm;mortality risk;novel;outcome disparities;protein expression;racial disparity;racial diversity;relapse risk;response;statistics;survival disparity;targeted treatment;therapeutic target;treatment strategy;triple-negative invasive breast carcinoma;tumor SQLE and Sterols Contribute to Racial Disparity in ER+ Breast Cancer Patient Survival PROJECT NARRATIVEThe proposed work will investigate SQLE as well as SQLE-regulated sterols as novel players in the survivaldisparity observed in patients with ER+ breast cancer. This work has the potential to increase health equity byimproving survival for AA women with ER+ breast cancer through the development of novel preventive andtreatment strategies that target underlying molecular mechanisms contributing to disparate outcomes. NCI 10758961 12/21/23 0:00 PAR-21-323 5R21CA276820-02 5 R21 CA 276820 2 "WALLACE, TIFFANY A" 1/3/23 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-OBT-Y(55)R] 8737070 "FRASOR, JONNA " "HOSKINS, KENT " 7 PHYSIOLOGY 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL SCHOOLS OF MEDICINE 606124305 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 168144 NCI 112698 55446 ABSTRACTThe racial disparity in breast cancer survival rates has largely been attributed to late-stage diagnoses andincreased incidence of triple negative breast cancer in African American (AA) compared to non-Hispanic White(white) women. However the latest statistics indicate that more than 50% of tumors in AA women are estrogenreceptor positive (ER+). ER+ tumors are considered less aggressive and are typically treated effectively withendocrine therapies that target ER activity (i.e. tamoxifen) or estrogen production (i.e. aromatase inhibitors).Despite a generally favorable prognosis for women with ER+ breast cancer AA women still have a greater riskthan white women of dying from ER+ disease. We have found that AA women in the Chicago area have a 4 to5-fold greater risk of death from ER+ breast cancer than white women even after controlling for stage atdiagnosis treatment and other known prognostic factors. This finding implies that biologic mechanisms areactivated in ER+ breast cancer from AA women resulting in resistance to endocrine therapy and a greater riskof relapse and death. Our overarching goal is to identify biological and molecular mechanisms contributing tothe racial survival disparity in ER+ breast cancer patients. The goal of this proposal is to investigate the role ofSQLE (squalene epoxidase) a key enzyme in the biosynthesis of sterols cholesterol and oxysterols as apotential driver of poor outcome in AA women with ER+ tumors. We hypothesize that elevated SQLE in ER+tumors of AA women leads to an accumulation of biologically active sterols that function to promote tumor cellproliferation and survival. Mechanistically we expect these sterols to function by altering ER activity and reducingresponsiveness to endocrine therapies. To investigate this we propose 3 aims: 1) to define the mechanism bywhich SQLE is up-regulated in ER+ breast tumors in AA women; 2) to identify SQLE-regulated sterols that areassociated with race in ER+ breast tumors and 3) to assess the cellular function and therapeutic potential ofSQLE in ER+ tumors of AA women. To accomplish these aims we will utilize newly generated tumor collectionsand novel preclinical models from AA women as well as an innovative method we developed to detect andanalyze multiple sterol species. Overall we expect to establish SQLE as a critical player in the racial disparityobserved in survival of patients with ER+ breast cancer. Importantly we expect to uncover two new mechanismsthat may explain i) how SQLE contributes to early relapse and ii) why SQLE expression is elevated in ER+tumors of AA women. Ultimately this work has the potential to increase health equity by improving survival forAA women with ER+ breast cancer through the development of novel preventive and treatment strategies thattarget underlying molecular mechanisms contributing to disparate outcomes. 168144 +No NIH Category available BAY 54-9085;Biological Markers;Breeding;CD8-Positive T-Lymphocytes;Cancer Etiology;Cell Death;Cell Survival;Clinical;Combined Modality Therapy;Cystine;Cytotoxic T-Lymphocytes;Data;Development;Down-Regulation;Drug Metabolic Detoxication;Electrons;Future;Genes;Genetic study;Genetically Engineered Mouse;Glutathione;Goals;Hepatocarcinogenesis;Hepatocyte;Homeostasis;Human;Hydroxyl Radical;Immune checkpoint inhibitor;Immunotherapy;Infiltration;Iron;Knock-out;Knockout Mice;LCN2 gene;Link;Lipid Peroxides;Liver;Liver neoplasms;Malignant neoplasm of liver;Mediating;Molecular;NR0B2 gene;Oncogenes;Organ;PD-1/PD-L1;Pathologic;Pathway interactions;Patients;Pharmaceutical Preparations;Physiological Processes;Prediction of Response to Therapy;Primary carcinoma of the liver cells;Process;Production;Proliferating;Proteins;Reaction;Receptor Inhibition;Repression;Resistance;Role;Signal Transduction;Sleeping Beauty;Systemic Therapy;T cell infiltration;T-Cell Proliferation;T-Lymphocyte;TRAF6 gene;Therapeutic;Therapeutic Studies;Toxic effect;Tumor Suppressor Proteins;Ubiquitination;Unresectable;Up-Regulation;Work;anti-PD-1;anti-PD-L1;bevacizumab;cancer cell;cancer therapy;cell growth regulation;cell type;clinical development;cytokine;derepression;glutathione peroxidase;immune cell infiltrate;immune checkpoint;improved;in vivo;insight;iron deficiency;leukemia inhibitory factor receptor;liver cancer model;mortality;neoplastic cell;neutralizing antibody;novel drug combination;overexpression;patient derived xenograft model;patient subsets;predicting response;predictive marker;receptor binding;receptor expression;receptor function;role model;targeted cancer therapy;therapeutic target;timeline;treatment response;tumor;tumor progression Targeting the LIFR-LCN2 pathway to improve liver cancer therapy PROJECT NARRATIVEThe current systemic therapies for liver cancer including sorafenib and the combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) have limited therapeutic benefits with no predictive biomarkers available.Our preliminary studies uncovered roles for a targetable LIFRNF-BLCN2 pathway in regulating livertumorigenesis sorafenib-induced ferroptotic cell death and tumor infiltration by cytotoxic T cells. The goal of thisproject is to provide new insights into the mechanisms of therapeutic targeting of an iron-sequestering pathwaywhich has significant clinical implications in regard to the biomarkers and therapeutic targets for liver cancer. NCI 10758777 12/12/23 0:00 PA-20-185 5R01CA269140-02 5 R01 CA 269140 2 "VENKATACHALAM, SUNDARESAN" 1/1/23 0:00 12/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 9385371 "MA, LI " Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 432117 NCI 266739 165378 PROJECT SUMMARY/ABSTRACTIron is vital for many physiological processes but excessive iron causes toxicity. Dysregulated iron homeostasis(either iron deficiency or overload) is a harbinger of pathological conditions. The liver stores iron in hepatocytesand is the major organ that controls systemic iron homeostasis. Liver cancer primarily hepatocellular carcinoma(HCC) is highly lethal with limited treatment options and no biomarkers to predict therapy response. Leukemiainhibitory factor receptor (LIFR) is frequently downregulated in human HCC; however in vivo and genetic studiesof LIFRs functions in liver cancer development and therapy response were lacking. Recently by constructingand characterizing hepatocyte-specific and inducible Lifr-knockout mice we found that loss of Lifr promoted livertumorigenesis and conferred resistance to sorafenib-induced ferroptosis a non-apoptotic type of cell deathcharacterized by the iron-dependent accumulation of lipid hydroperoxides. Our data also pointed to a role forLIFR in inhibiting NF-B signaling in the liver which in turn downregulates lipocalin 2 (LCN2) an iron-sequestering cytokine. In parallel our data revealed that in oncogene-induced liver tumors overexpression ofLIFR increased while knockout of Lifr decreased CD8+ T cell infiltration which may be mediated by LCN2-dependent downregulation of iron levels viability and proliferation of T cells. Altogether these data support ahypothesis that loss or downregulation of LIFR in liver cancer leads to upregulation of LCN2 which on one handconfers resistance to ferroptosis on liver tumor cells and on the other hand deprives T cells of iron that isessential for T cell viability proliferation and effector function; both mechanisms contribute to liver cancerprogression and therapy resistance. In the proposed work we will elucidate the molecular mechanisms by whichLIFR inhibits NF-B signaling in liver cells (Specific Aim 1). Further we will investigate whether LCN2 can serveas a therapeutic target for enhancing sorafenib efficacy in HCC (Specific Aim 2). Finally we will study whetherLIFR or therapeutic LCN2 neutralization can sensitize HCC to immunotherapy (Specific Aim 3). Geneticallyengineered mouse models Sleeping Beauty transposon-mediated oncogene-induced liver cancer models andHCC patient-derived xenograft models will be used to study the therapeutic potential and mechanisms of actionof two novel drug combinations which will illuminate how to improve liver cancer therapy by targeting an iron-sequestering pathway. We envision that low LIFR expression and high LCN2 expression could be used to selectHCC patients who will likely benefit from the combination therapy with the LCN2-neutralizing antibody plussorafenib or immune checkpoint inhibitors. 432117 +No NIH Category available Acceleration;Address;Agonist;Antitumor Response;Benchmarking;Biodistribution;Biological;Biopsy Specimen;Blood Chemical Analysis;Breast Cancer Patient;Cancer Patient;Cell membrane;Cells;Characteristics;Clinical;Clinical Research;Clinical Trials;Complex;Contracts;Cytosol;Data;Dendritic Cells;Development;Dinucleoside Phosphates;Disseminated Malignant Neoplasm;Dose;Drug Kinetics;Encapsulated;Ensure;Enzymes;Exclusion;Excretory function;Exhibits;Filtration;Formulation;Funding;Future;Gene Activation;Generations;Half-Life;Haplotypes;Head and Neck Squamous Cell Carcinoma;Human;Immune checkpoint inhibitor;Immune response;Immunotherapy;Incubated;Inflammation;Injections;Interferon-beta;Interferons;Knowledge;Lead;Legal patent;Liver;Macrophage;Malignant Neoplasms;Manganese;Mediating;Metabolism;Methods;Michigan;Microfluidics;Modeling;Mus;Myeloid Cells;Nanotechnology;Natural Killer Cells;Nature;Neoplasm Metastasis;Oryctolagus cuniculus;Pathway interactions;Patient-Focused Outcomes;Patients;Penetration;Periodicity;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I Clinical Trials;Pilot Projects;Plasma;Population;Preparation;Process;Production;Public Health;Reproducibility;Research;Rights;Safety;Sampling;Small Business Innovation Research Grant;Solid Neoplasm;Stimulator of Interferon Genes;System;T-Lymphocyte;Technology;Technology Transfer;Therapeutic;Time;Tissues;Toxicology;Universities;Variant;Work;anti-tumor immune response;cancer immunotherapy;cancer type;cell type;clinic ready;clinical development;comparative efficacy;design;drug development;experience;healthy volunteer;immune activation;immune checkpoint blockade;improved;improved outcome;large scale production;lead candidate;manufacture;manufacturing organization;manufacturing scale-up;monocyte;nano;nanoformulation;nanoparticle;nonhuman primate;novel;novel therapeutics;pharmacokinetics and pharmacodynamics;pre-clinical;preclinical study;response;safety study;scale up;success;technology platform;therapeutic candidate;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;uptake Process Development and Preclinical Advancement of a Novel Nanoparticle Formulation for Immune Activation Narrative:The proposed research is most relevant to public health as these studies will generate new fundamentalknowledge in the development of a novel cancer immunotherapy and will advance one promising new therapyin preparation for clinical trials. The SNP nanoparticle formulation will improve the transformation of cold intohot tumors by prolonging stimulation of the STING pathway leading to a robust immune response in the tumormicroenvironment. This approach may be efficacious as a monotherapy in some cancers and will also augmentthe activity of other immunotherapies particularly immune checkpoint inhibitors. NCI 10758714 9/19/23 0:00 PA-22-176 1R44CA281497-01A1 1 R44 CA 281497 1 A1 "POND, MONIQUE ADRIANNE" 9/19/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-BBBT-F(10)B] 78787481 "JOHNSON, RICHARD " Not Applicable 10 Unavailable HGU2SLP22BK2 HGU2SLP22BK2 US 10070665 SAROS THERAPEUTICS INC RIVERWOODS IL Domestic For-Profits 60015 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1196731 NCI 921230 197210 SummaryDespite the success of immune checkpoint inhibitors for some types of cancer the overall response rate remainssuboptimal. The majority of solid tumors exclude T-cells (termed cold) thus presenting a key limiting factor forcancer immunotherapy. Activation of the cGAS-STING pathway has been demonstrated to induce anti-tumorimmune responses with impressive efficacy in preclinical studies. However clinical stage STING agonists basedon cyclic dinucleotides (CDNs) suffer from major limitations including: 1) Administration via intratumoralinjection. STING agonists administered intratumorally are cleared rapidly and intratumoral injection reduces theirutility against metastatic cancer. 2) Conventional STING agonists do not readily cross the cell membrane failingto maximize activation of STING located within the cytosol. 3) Cell penetration of conventional STING agonistsis not biased to the dendritic cells and macrophages which is the cell type needed to drive an anti-tumor immuneresponse. 4) Conventional STING agonists do not work across the human population due to variations in STINGhaplotypes. Indeed in recent phase I clinical trials STING agonists given intratumorally exhibited only marginalefficacy. Hence a potent platform for systemic delivery of STING agonists is urgently needed to improve patientoutcomes. Saros Therapeutics is developing a novel nanotechnology (referred to as SNP) that addresses eachof these limitations by: 1) Incorporating manganese along with CDA a CDN-based STING agonist in the nano-formulation. We have shown that Mn augments the activation of STING by CDA lowering the dose necessaryto achieve a significant biologic (Type I IFN expression) and therapeutic (tumor growth/survival) benefit. 2)Incorporating the Mn-CDA complex in a nanoparticle protects the CDA from degradation extending half-life andfacilitating uptake by myeloid cells (DC macrophages) that drives a Type I IFN response by the immune cells inthe TME. The combination of Mn+CDA incorporated into a nanoparticle formulation also improves the safetyprofile of this therapy and allows administration by IV ensuring systemic exposure and improved responses insettings of multiple tumors and metastasis. Based on our compelling data we will examine the potency of SNPpreparations in human patient biopsy samples. We will assess pharmacokinetic and tissue retentioncharacteristics of SNP in both mice and non-human primates and benchmark against other STING agonists. Wewill develop microfluidic methods for large scale production of SNP in anticipation of transfer to a contractdevelopment and manufacturing organization (CDMO). Results from these studies will accelerate thedevelopment of our novel nanotechnology with the aim of quickly bringing immunotherapys benefits to morepatients with cancer. 1196731 +No NIH Category available 1 year old;Acceleration;Acute Myelocytic Leukemia;Adolescent;Brain Stem Glioma;Canada;Cancer Center;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Trials;Clinical Trials Design;Collection;Complication;Country;Development;Diagnosis;Disease;Eligibility Determination;Enrollment;Family;Foundations;Functional disorder;Hormonal;Immunotherapy;Institution;Interdisciplinary Study;Laboratories;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Mission;Molecular;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;Organ;Outcome;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Prognosis;Progress Reports;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Tissues;Universities;Work;anticancer research;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;novel therapeutic intervention;operation;reproductive;small molecule;translational study COG NCTN Year 10 BIQSFP Supplement & Progress Report PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcomes for all children with cancer. NCI 10758682 4/12/23 0:00 PA-20-272 3U10CA180886-10S1 3 U10 CA 180886 10 S1 "MOONEY, MARGARET M" 4/11/14 0:00 2/28/25 0:00 ZCA1(O1) 10871228 "HAWKINS, DOUGLAS S." Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 2432383 NCI 2914519 172562 PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhoodcancers many of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a numberof childhood cancers however has been limited with approximately 50% of children with acute myelogenousleukemia 50% of children with high-risk neuroblastoma and more than 90% of children with brainstem gliomastill succumbing to their disease. In the US cancer remains the leading cause of death from disease in childrengreater than one year of age. Moreover the late effects of cancer treatment including permanent organ andtissue damage hormonal and reproductive dysfunction and second cancers are of special concern with morethan 40% of the 500000 survivors of childhood cancer (estimated as of 2020) experiencing a significant healthrelated quality of life complication from childhood cancer and its treatment. Thus despite our advancesdevelopment of new therapeutic approaches must be a priority for childhood cancer basic translational andclinical researchers. The Childrens Oncology Group (COG) the worlds largest organization devotedexclusively to childhood and adolescent cancer research was founded 20 years ago. The COGsmultidisciplinary research team comprised of more than 9000 members conducts research at more than 220leading childrens hospitals universities and cancer centers. This proposal is for COG as part of the NationalCancer Institutes (NCI) National Clinical Trials Network (NCTN) to continue its collaborative research workthat supports the mission of improving the outcome for all children with cancer. The COG will design andconduct clinical-translational studies for children with cancer that builds on an increasing understanding of themolecular basis for pediatric malignancies and has the highest potential to improve the outcome. Usinginnovative clinical trial designs suitable for the study of rare diseases we will study novel therapeuticapproaches including but not limited to targeted small molecule drugs immunotherapies and cellular therapies.The COG research portfolio importantly also includes clinical trials focused on improving the quality of life forchildren with cancer and childhood cancer survivors. As more than 90% of children diagnosed with cancer inthe US are treated at COG member institutions COG has the ability to offer a diverse population of childrenwith cancer and their families the opportunity to participate in innovative research. This research effort includesallowing for collection and annotation of biospecimens from all children with cancer providing the foundationfor discovery and accelerating the most promising research efforts conducted in laboratories around the world.The proposal is for support of the COG Network Operations Center clinician-scientists who develop andconduct research and for member sites to participate through enrollment of eligible subjects. 2432383 +No NIH Category available Address;Animal Model;Automation;Cancer Patient;Clinic;Clinical;Clinical Protocols;Clinical Research;Computer software;Coupling;Custom;Data;Data Analyses;Data Collection;Data Reporting;Decision Making;Development;Devices;Diagnostic;Documentation;Electron Spin Resonance Spectroscopy;Engineering;Evaluation;Generations;Good Manufacturing Process;Guidelines;Human;Linear Accelerator Radiotherapy Systems;Magnetic Resonance Imaging;Malignant Neoplasms;Marketing;Measurement;Measures;Medical Device;Medical Technology;Monitor;Morphologic artifacts;Motivation;Movement;National Cancer Institute;Oncology;Oxygen;Oxygen saturation measurement;Patients;Performance;Peripheral Vascular Diseases;Physiologic pulse;Prognosis;Program Research Project Grants;Radiation Oncology;Radiation therapy;Research;Resource-limited setting;Resources;Role;Safety;Site;Speed;System;Technology;Testing;Therapeutic;Time;Tissues;Translating;Treatment outcome;Underserved Population;Work;achievement test;cancer care;cancer therapy;clinical care;clinical research site;cohort;college;commercialization;data acquisition;design;design and construction;diabetic;digital;effective therapy;efficacy evaluation;ergonomics;flexibility;healthy volunteer;heart motion;human subject;image guided;image guided radiation therapy;improved;in vivo;industry partner;innovation;innovative technologies;instrumentation;light weight;manufacture;medical schools;novel;operation;phantom model;prototype;respiratory;response;safety and feasibility;success;therapy outcome;tissue phantom;tool;treatment strategy;tumor;usability;user-friendly EPR scanner for tumor oximetry in the clinic PROJECT NARRATIVEWe propose to build an innovative first-in-clinic easy-to-use oxygen scanner for repeated monitoring of tumoroxygen levels in cancer patients. The scanner will be built using the advanced in vivo electron paramagneticresonance (EPR) technology developed at Dartmouth College and in partnership with ViewRay a pioneer inthe development of MRI image-guided linear accelerator for radiation therapy. The new oxygen scanner canprovide potentially important and previously unavailable information on tumor oxygen status which is importantfor accurate prognosis and development of effective treatment strategies for cancer therapy. NCI 10758625 11/28/23 0:00 PAR-21-166 5R01CA269234-02 5 R01 CA 269234 2 "SORG, BRIAN S" 1/1/23 0:00 12/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-S(57)R] 1986495 "KUPPUSAMY, PERIANNAN " Not Applicable 2 ENGINEERING (ALL TYPES) 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH BIOMED ENGR/COL ENGR/ENGR STA 37551421 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 580625 NCI 381706 198919 PROJECT SUMMARYThis academic-industrial partnership (AIP) proposal seeks to develop a robust and easy-to-use clinical scannerfor tumor oxygen measurement (oximetry) in cancer patients. By knowing quantitative tumor oxygen levels inreal time radiotherapy could be better planned and delivered at times when there will be an optimal therapeuticratio thus significantly improving cancer care. The proposed approach seeks to leverage the unique capabilitiesof the in vivo electron paramagnetic resonance (EPR) oximetry technology that we have developed formeasurement in human subjects into a medical device that is ready for routine clinical use. The scanner canmake direct and repeated measurements of tumor oxygen by typical end-users in a clinical setting. The EPRresearch team at the Geisel School of Medicine (Dartmouth College) has successfully demonstrated the clinicalfeasibility and safety of EPR oximetry for measuring tumor oxygen in the clinic and now seeks to expand uponthat success through a collaborative partnership with ViewRay a medical-device company that is engaged inMRI image-guided radiation therapy. The clinical scanner will be designed to make it easier to operate by clinicalstaff and sufficiently robust and reliable for its intended use in a variety of clinical settings. The following specificaims are proposed to achieve the overall objective of developing an advanced EPR scanner for oximetry that isready to be manufactured and used in routine clinical care to enhance cancer therapy: (Aim 1) Design andconstruct a 600-MHz pulse EPR system for clinical oximetry; (Aim 2) Fabricate a new class of compactlightweight and advanced resonator designs specifically optimized for pO2 measurements in human tumors;(Aim 3) Develop hardware and software interface with advanced measurement capabilities and user-friendlyoperation suitable for use in the clinic; (Aim 4) Assemble test and evaluate the scanner for repeatedmeasurements of oxygen concentration using tissue phantoms and animal models of tumor; and (Aim 5)Evaluate the efficacy usability and safety of the oxygen scanner as a medical device and validate its use tomake oxygen measurements in cancer patients and human factors engineering. The EPR scanner fullyintegrated with the hardware and software modules will be evaluated in relation to its ability to meet or exceedregulatory standards and for its practicality as a clinical device. The new first-in-clinical scanner will be a veryvaluable tool in the clinic for accurate prognosis and development of effective treatment strategies for cancertherapy. It can also be a valuable clinical tool for other clinical conditions where tissue oxygen is a critical variablefor decision making e.g. patients with diabetic peripheral vascular disease. 580625 +No NIH Category available Acceleration;Area;Autoimmune;Autonomic nervous system;Cancer Model;Cell Therapy;Cells;Cellular biology;Clinical;Communication;Elements;Endothelial Cells;Exclusion;Extracellular Matrix;Fibroblasts;Human;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immune system;Immunocompetent;Immunooncology;Immunosuppression;Immunotherapy;Inflammatory;Invaded;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Multiple Sclerosis;NGFR Protein;Natural regeneration;Neoplasm Metastasis;Nerve;Neurodegenerative Disorders;Neuroglia;Neurons;Neuropathy;Neuropeptides;Neurotransmitters;Pain;Patients;Peripheral;Peripheral Nervous System;Play;Process;Property;Publishing;Regulation;Reporting;Research;Role;Schwann Cells;Signal Transduction;Spinal cord injury;Syndrome;Testing;Tissues;Transgenic Organisms;Treatment Failure;Tumor Immunity;Tumor-Associated Vasculature;Tumor-infiltrating immune cells;Wallerian Degeneration;Work;anti-CTLA-4 therapy;anti-CTLA4;anti-PD-1;anti-tumor immune response;cancer cell;cancer therapy;cancer type;clinically relevant;evidence base;expectation;falls;immune cell infiltrate;immunoregulation;improved;malignant breast neoplasm;melanoma;mouse model;nerve repair;nerve supply;novel;novel strategies;novel therapeutic intervention;perineural;pharmacologic;prevent;promoter;repaired;response;synergism;targeted treatment;tertiary lymphoid organ;tissue repair;translational oncology;treatment strategy;tumor;tumor growth;tumor microenvironment;tumor progression The Role of Schwann Cells in the Progression of Melanoma Project NarrativeThe immune system is capable of slowing or preventing cancer progression; however theimmune tolerance of cancer significantly hinders protective anti-tumor immune responses andleads to treatment failures and poor patient survival. We uncovered that melanoma-associatedSchwann cells inhibit the formation of the tertiary lymphoid structures in tumors and promoteimmunosuppression favoring immune tolerance and cancer progression. We will determine themolecular mechanism of tumor immunity regulation by the Schwann cells and target themgenetically and pharmacologically as a novel therapeutic strategy aimed at breaking the immunetolerance and synergizing with anti-PD-1 and anti-CTLA4 immune checkpoint inhibitors. NCI 10758618 12/26/23 0:00 PA-20-185 5R01CA266529-02 5 R01 CA 266529 2 "BERA, TAPAN K" 1/1/23 0:00 12/31/27 0:00 Cellular and Molecular Biology of Glia Study Section[CMBG] 10569986 "BUNIMOVICH, YURI " Not Applicable 12 DERMATOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 403740 NCI 253925 149815 Project SummaryClinical and experimental evidence demonstrate that cancer progression depends on the interactions ofmalignant cells with other elements of the tumor microenvironment (TME). Functions of cancer-associatedfibroblasts endothelial cells tumor-infiltrating immune cells and other stromal elements in regulating tumorgrowth and progression have been intensively investigated. Peripheral neurons are now also recognized asimportant constituents of the tumor milieu. The degree of tumor innervation is directly correlated with cancerprogression and metastasis and inversely correlated with patient survival. Several mechanisms responsiblefor nerve-mediated cancer progression have been proposed including regulatory activity of neurotransmittersand neuropeptides on tumor-associated vasculature and immune infiltrate. Thus far work in this area largelyfocused on the role of the autonomic nervous system in promoting cancer with several reports also implicatingthe somatic afferent innervation. However the role of the neuroglia of the peripheral nervous system inpromoting cancer progression remains unclear. Specifically excluding the process of perineural invasion theextent to which Schwann cells (SCs) principal glia of the peripheral nervous system modulate TME andfacilitate cancer progression has not been investigated. We demonstrated that SCs are present in humanmelanoma tissue and that they accelerate tumor growth and metastasis in several melanoma mouse models.We discovered that this effect is due to the activation of repair SCs and their inhibition of tertiary lymphoidstructure (TLS) formation and protective anti-tumor immune responses. However the mechanism of SCimmunomodulation in TME remains unknown. We hypothesize that melanoma-associated repair SCspromote immune tolerance to melanoma and their targeting is a novel immunotherapy approach againstcancer. To test our hypothesis we will pursue two Specific Aims: 1) determine the mechanism ofimmunomodulation by repair SCs in melanoma and 2) target repair SCs in melanoma as a novel approachto therapy. In Aim 1 we will examine how SCs promote immune tolerance of cancer and impede TLSformation in tumors focusing on Slit2 MAG and p75NTR signaling mechanisms. Transgenicimmunocompetent autochthonous BrafCA melanoma and slow Wallerian degeneration WldS mouse modelswill be utilized. In Aim 2 we will test whether targeting melanoma-associated repair SCs to break immunetolerance synergizes with current anti-PD-1 and anti-CTLA4 therapies. The primary impact of the proposalwill be mechanistic verification of SC-dependent maintenance of the immune tolerance a major challengein the current treatment of advanced malignancies. We expect that our results will validate a novelimmunotherapy approach for melanoma based on targeting tumor-associated glia an approach which willlikely be applicable to other types of cancer. 403740 +No NIH Category available ABL1 gene;Acute;Acute leukemia;Affect;Aggressive-Phase Myeloid Leukemia;Apoptosis;Attenuated;Blast Phase;Blood;Bone Marrow Transplantation;CD34 gene;Cell Cycle;Cell Differentiation Induction;Cells;Chronic Myeloid Leukemia;Chronic-Phase Myeloid Leukemia;Clinical;Constitution;Constitutional;Cytokine Receptors;Cytokine Signaling;Data;Dependence;Endocytosis;Family;Fluorouracil;Granulocyte-Macrophage Colony-Stimulating Factor;Hematopoiesis;Hematopoietic;Hematopoietic System;Human;IL3 Gene;Image;In Vitro;Knock-out;Leukemic Cell;Malignant - descriptor;Maps;Mass Spectrum Analysis;Mediating;Membrane;Messenger RNA;Mouse Strains;Mus;Myelogenous;Myeloid Cells;Normal Cell;Outcome;Pathway interactions;Patients;Phase;Phenotype;Philadelphia Chromosome;Phosphotransferases;Physiological;Prevalence;Printing;Protein Array;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-abl;Publishing;Recurrence;Relapse;Reporting;Residual state;Resistance;Role;Signal Pathway;Signal Transduction;Signaling Protein;Stress;Testing;Therapeutic Agents;Tumor Suppressor Proteins;Tyrosine Kinase Inhibitor;Undifferentiated;Work;Xenograft procedure;biological adaptation to stress;chronic myeloid leukemia cell;cofactor;cytokine;drug sensitivity;improved;in vivo;inhibitor;inhibitor therapy;knock-down;leukemia;leukemic stem cell;leukemogenesis;live cell imaging;member;nanoparticle;novel;overexpression;prevent;receptor;response;single-cell RNA sequencing;stem;stem cells;therapy resistant;transcriptome The function of MS4A3 in normal and malignant hematopoiesis PROJECT NARRATIVEMost patients with chronic myeloid leukemia (CML) require life-long therapy with BCR-ABL1 tyrosine kinaseinhibitors (TKIs) to avoid relapse. CML cells minimize expression of membrane-spanning four A (MS4A3) toescape TKIs. We will identify the underlying mechanism and whether re-expression of MS4A3 can be harnessedto increase response to TKIs. NCI 10758614 12/21/23 0:00 PA-20-185 5R01CA268496-02 5 R01 CA 268496 2 "JHAPPAN, CHAMELLI" 1/1/23 0:00 12/31/27 0:00 Special Emphasis Panel[ZRG1-OBT-Y(02)M] 8093590 "DEININGER, MICHAEL W." Not Applicable 4 Unavailable 57163172 JZDRNT166LE4 57163172 JZDRNT166LE4 US 43.037892 -87.935338 5304801 "VERSITI WISCONSIN, INC." MILWAUKEE WI Research Institutes 532332121 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 561224 NCI 397146 164078 Chronic myeloid leukemia (CML) is caused by BCR-ABL1 a constitutively active tyrosine kinase generated fromthe Philadelphia chromosome. In the chronic phase of CML (CP-CML) myeloid cells are expanded but maintainterminal differentiation. Most CP-CML patients achieve durable responses to BCR-ABL1 tyrosine kinaseinhibitors (TKIs) and their extended survival is reflected by a steep rise in CML prevalence. Unfortunately TKIsfail to eliminate quiescent CML stem cells (LSCs) whose survival is independent of BCR-ABL1 necessitatinglifelong TKI therapy to prevent CML recurrence. In 5-10% of patients a differentiation block converts CP-CMLinto blast phase CML (BP-CML) an aggressive acute leukemia that is often BCR-ABL1-independent and TKIresistant. Our overarching hypothesis is that blocked differentiation is central to the BCR-ABL1 independencethat characterizes the extremes of the clinical CML spectrum: Persistence of residual leukemia despite TKItherapy and TKI-resistant BP-CML. We have discovered that expression of MS4A3 a member of the MS4A(membrane-spanning four A) family of signaling proteins is profoundly reduced in quiescent TKI resistant andBP CML cells and that low MS4A3 correlates with shorter survival. MS4A3 knockdown (KD) in CML CD34+ cellsinhibits myeloid differentiation and promotes TKI resistance while ectopic MS4A3 expression has oppositeeffects (Zhao et al. Blood. 2021;Epub ahead of print. PMID: 34780648). Our preliminary data suggest that MS4A3promotes IL-3 and GM-CSF signaling in CML CD34+ cells by promoting endocytosis of their cognate commonchain (c) receptors. We hypothesize that MS4A3 promotes myeloid differentiation by enhancing response to ccytokines in leukemic stem and progenitor cells (LSPCs). TKI resistant CML cells downregulate MS4A3 to bluntresponse to differentiation-inducing cytokines thereby maintaining a primitive therapy-resistant state. Re-establishment of MS4A3 expression will enforce differentiation and enhance drug sensitivity. In Aim 1 we willdelineate how MS4A3 regulates endocytosis and signaling of c cytokine receptors. We will track endocytosisby high-throughput immunofluorescent and confocal live cell imaging identify MS4A3 cofactors by massspectrometry and MS4A3-regulated signaling pathways by reverse phase protein array. In Aim 2 we willdetermine the function of MS4A3 in normal hematopoiesis. We will generate mouse strains with hematopoietic-specific conditional Ms4a3 knockout or inducible overexpression and characterize their hematopoietic system atsteady state and under stress. In Aim 3 we will delineate the role of MS4A3 in CML hematopoiesis and as atherapeutic agent in CML. We will test whether modulating MS4A3 expression in LSPCs affects leukemogenesisand TKI response and whether MS4A3-loaded nanoparticles attenuate BP-CML in xenografts. If successful wewill establish MS4A3 as a novel master regulator of c cytokine signaling that governs signal strength bymodulating endocytosis. BP-CML remains mostly incurable and most CP-CML patients require lifelong TKItherapy. Our work may provide proof of concept for using forced MS4A3 expression to overcome TKI resistance. 561224 +No NIH Category available Affect;Animal Model;Apoptosis;Bacteria;Bacterial Genes;Bioinformatics;Biological;Biological Models;Biopsy;Cancer Detection;Chronic;Clinical;Clinical Research;Colitis associated colorectal cancer;Colon;Colorectal Cancer;DNA Damage;Development;Disease;Enzymes;Epithelium;Event;Genes;Genomic Instability;Gut Mucosa;Human;Immune response;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Integration Host Factors;Intestinal Cancer;Investigation;Knowledge;Laboratories;Light;Longitudinal Studies;Malignant Neoplasms;Metabolism;Modeling;Molecular;Mucous Membrane;Mus;Organoids;Oxidative Stress;Pathogenesis;Pathway interactions;Patients;Proliferating;Proteome;Proteomics;Rectum;Research;Resources;Risk;Role;Sampling;Signal Pathway;Specimen;Structure;Study models;Surface;System;Systems Biology;Taxonomy;Techniques;Technology;Ulcerative Colitis;Work;cancer therapy;carcinogenesis;colitis associated cancer;colorectal cancer prevention;colorectal cancer risk;design;dextran sulfate sodium induced colitis;dysbiosis;fecal microbiota;gut microbes;gut microbiome;gut microbiota;human microbiota;in vivo;innovation;interest;metaproteomics;microbial;microbial community;microbiome;microbiome composition;microbiota;microbiota profiles;mouse model;mucosal microbiota;new technology;novel diagnostics;novel strategies;novel therapeutic intervention;phosphoproteomics;protein expression;rectal;response;statistics;tool;translational potential;tumor progression;tumorigenic Elucidating the role of gut microbiota in colitis-associated colorectal cancer Project NarrativeHuman gut microbiome composition has recently been associated with a wide array of diseases includinginflammatory bowel disease (IBD) and colorectal cancer. We propose to study the structure and function of thegut microbiota in the development of IBD associated colorectal cancer. Our proposed study may lead to betterunderstanding of the interplay between gut microbiota and colon mucosa and could shed light to noveldiagnostic and therapeutic approaches to IBD and associated colorectal cancer. NCI 10758607 1/5/24 0:00 PA-20-185 5R01CA276173-02 5 R01 CA 276173 2 "DASCHNER, PHILLIP J" 1/1/23 0:00 12/31/27 0:00 Cancer Prevention Study Section[CPSS] 7284983 "CHEN, RU " "PAN, SHENG " 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 554291 NCI 395448 158843 AbstractPatients with ulcerative colitis (UC) an inflammatory bowel disease (IBD) have an increased risk of developingcolitis-associated colorectal cancer (CAC). Human gut microbiome composition has recently been associatedwith a wide array of diseases including IBD and colorectal cancer. Studies have shown that gut microbiotacould influence colon epithelium to initiate or promote colorectal cancer development directly or indirectly.However little is known on the structure and function of the microbiota in CAC and how they implicate thedevelopment of CAC at the molecular level. In this study we will investigate the role of microbiota in thedevelopment of CAC as well as the molecular events underlying the interplay of microbiota and host response.The project builds upon our previous studies in examining the genomic instabilities and proteome alterations inthe colon epithelium during the pathogenesis of IBD-CAC and will focus on the mechanistic and functionalinvolvement of the microbiome and their components in the modulation (by protective bacteria) or activation(by tumorigenic bacteria) of CAC development. Specifically we will investigate the implication of mucosa-associated microbiota in CAC by an integrated approach using three model systems including clinicalspecimens (Aim 1) in vitro microbial cultivation and organoid models (Aim 2) and in vivo mouse model (Aim3). Our integrative state-of-the-art approach will characterize the composition functional genes and pathwaysof the microbiome implicated in CAC and the impact of microbiota on colon mucosa. By studying the gutmicrobiota and its interplay with the colon host using novel approaches and cutting-edge technology our studyhas significant translational potential that could lead to establishing the gut microbiome as predictors of CACrisk and aid in developing approaches for CAC prevention and detection in IBD patients. 554291 +No NIH Category available Alleles;American Cancer Society;Animal Model;Apoptotic;Cancer Patient;Cancer cell line;Cell Death;Cell Death Induction;Cell Proliferation;Cell Separation;Cell model;Cells;Cessation of life;Data;Dependence;Genes;Genetic;Genetic Transcription;Goals;Growth;Human;Immunocompromised Host;Implant;Lung;Lung Neoplasms;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Mus;Mutation;Normal Cell;Oncogenic;Patients;Phenotype;Prognosis;Proliferating;Property;Publishing;Reporting;Sampling;Specificity;Squamous Cell;TP53 gene;Testing;Therapeutic;Transactivation;Transcriptional Activation;Translating;cancer cell;cancer therapy;carcinogenesis;cell growth;design;detection platform;experimental study;gain of function;genome-wide analysis;inhibitor;lung cancer cell;lung xenograft;mouse model;mutant;neoplastic cell;new therapeutic target;novel;patient derived xenograft model;radioresistant;small molecule inhibitor;subcutaneous;tumor;tumor growth;tumor xenograft;tumorigenesis;tumorigenic Novel inhibitors of oncogenic p53 mutants for lung cancer therapy. Gain-of-function (GOF) p53 mutations are very frequent in all types of chemo- and radio-resistant intractablelung cancers with poor prognosis and are required for their tumorigenic phenotype. The proposed project isdesigned to identify and validate small molecule inhibitors that specifically inactivate the oncogenic function ofGOF p53 in tumors sparing normal cells. Thus the identified inhibitors should have a cancer cell-specificefficient therapeutic property for lung cancers with p53 mutation. NCI 10758594 11/30/23 0:00 PAR-20-292 5R21CA267971-02 5 R21 CA 267971 2 "COVELL, DAVID G" 12/30/22 0:00 11/30/24 0:00 ZCA1-TCRB-Q(O1)S 1864795 "DEB, SWATI P." "WINDLE, BRAD E." 4 BIOCHEMISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 163304 NCI 105188 58116 Project Summary Gain-of-function (GOF) p53 mutations are very frequent in all types of chemo- and radio-resistant intractablelung cancers with poor prognosis. Depletion of endogenous mutant p53 eliminates the tumorigenic phenotype ofmany human lung cancer cell lines. Therefore small molecule inhibitors that specifically inactivate the oncogenicfunction of GOF p53 should have a cancer cell-specific efficient impact on many lung cancer patients. Using genome wide analyses of lung cancer cells we have traced the oncogenic properties of GOF p53 to itsability to transcriptionally activate expression of cell proliferative genes. Our published genetic data showed thattransactivation deficient GOF p53 is defective in tumor formation and proliferation of lung cancer cells. Here wepropose to test a hypothesis that small molecule inhibitors of GOF p53-specific transcriptional activation (GOFp53TAIn) specifically inhibit proliferation of lung cancer cells and tumors with GOF p53 mutation. Our short-term goal is to test this hypothesis in cellular and animal models of lung cancer. Our long-term goal is to translateour findings into novel targeted therapies for human lung cancer. In support of our hypothesis our preliminary studies have identified novel small molecule inhibitors (GOFp53TAIns) that specifically inhibit GOF p53-driven transcriptional activation sparing Wild-type (WT) p53-induced transcription and basal transcription. Pilot experiments identified GOF p53TAIns that preferentiallyinhibited growth of lung cancer cells with GOF p53 over p53-null lung cancer cells or lung cancer cells with WT53. One of the GOF p53TAIns Gloxazone specifically inhibits GOF p53-induced transcription and cell growthand in addition specifically inhibits growth of tumors from xenografts of lung cancer cells with mutant p53 butnot from that of WT p53. The proposed hypothesis will be further tested via the following specific aims: Aim 1: Examine identified GOF p53TAIns for their ability to specifically inhibit GOF p53-inducedgrowth of lung cancer cells inducing cell death. Human lung cancer cell lines spanning different subtypes (non-small cell small cell squamous cell) with or without various GOF p53 mutation (a) matched sets of gene-editedlung cancer cell lines with GOF p53 WT p53 and p53-null alleles (b) and tumor cells isolated from primary orpassaged patient lung cancer samples (c) will be employed. Ability of GOF p53TAIns to alter GOF p53 stabilitywill be determined and analysis of mechanism of growth inhibition for selected compounds will be initiated. Aim 2: Examine identified GOF p53TAIns for their ability to specifically inhibit GOF p53-driventumor growth and induce tumor cell death using mouse models. Three mouse models tumors from (a)xenograft of lung cancer cells implanted subcutaneously or orthotopically and (b) patient-derived xenografts(PDX) in immunocompromised mice will be used and (c) inducible GOF p53-dependent lung cancer mousemodels will be examined. 163304 +No NIH Category available Address;Affect;Biological;Celiac Disease;Cell Differentiation process;Cell physiology;Cells;Clinical;DNA Damage;DNA Repair;Development;Disease;Disease model;Exhibits;Exons;Frequencies;Gene Silencing;Generations;Genes;Genetic;Genetic Transcription;Genomics;Histone H3;Intestinal Neoplasms;Intestines;Knock-out;Knockout Mice;Knowledge;Lead;Lymphocyte;Lymphoma;Lymphomagenesis;Lysine;Malignant Neoplasms;Measures;Messenger RNA;Methylation;Modeling;Modification;Molecular;Mutate;Mutation;Oncogene Activation;Oncogenes;Outcome;Pathogenesis;Pathway interactions;Patients;Phenotype;Population;Premalignant Cell;Process;Prognosis;RNA Splicing;Rag1 Mouse;Recording of previous events;Role;STAT5B gene;Site;T-Cell Development;T-Cell Lymphoma;T-Lymphocyte;T-cell receptor repertoire;Techniques;Testing;Therapeutic;Treatment Protocols;V(D)J Recombination;Work;cell transformation;design;effective therapy;genotoxicity;histone methyltransferase;improved;innovation;intraepithelial;mouse model;novel;novel therapeutic intervention;overexpression;premalignant;recruit;response;single-cell RNA sequencing;standard of care;tumor; T cells Clinical and Genetic Origins of Monomorphic Epitheliotropic Intestinal T Cell Lymphoma PROJECT NARRATIVEMonomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare but lethal disease with a mediansurvival of 1 year. The molecular role of SETD2 (the most frequently silenced gene in MEITL) and its interactionwith activated oncogenes in MEITL pathogenesis is largely unknown. In this proposal we develop novel mousemodels of this disease to define the role of SETD2 in MEITL pathogenesis. NCI 10758565 12/22/23 0:00 PA-20-185 5R01CA277192-02 5 R01 CA 277192 2 "JHAPPAN, CHAMELLI" 1/1/23 0:00 12/31/27 0:00 Molecular Oncogenesis Study Section[MONC] 9339838 "DAVE, SANDEEP " Not Applicable 4 INTERNAL MEDICINE/MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 374942 NCI 232883 142059 ABSTRACTMonomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare but lethal disease with a mediansurvival of 1 year. There is no current effective standard-of-care. Previous MEITL sequencing efforts performedby our group and others have revealed SETD2 as one of the most frequently altered genes in this disease.SETD2 directs trimethylation of the lysine 36 residue on histone H3 (H3K36me3) which in turn is associatedwith active transcription of genes. SETD2 has been implicated in DNA damage repair and mRNA splicing.However the molecular role of SETD2 and its interaction with activated oncogenes in MEITL pathogenesis islargely unknown.In this proposal we will utilize a conditional mouse model to determine how SETD2 loss contributes to thecreation of a premalignant pool of intestinal intraepithelial cells (IELs) the cell of origin of MEITL. We will alsoinvestigate how the combination of SETD2 loss and activation of the oncogenes STAT5B or MYC lead to IELtransformation. Finally we will determine the extent to which SETD2 deficiency sensitizes T lymphoma cells toa variety of genotoxic chemotherapeutics. We anticipate that the results of this work will have immediate impacton the design of effective treatment regimens that target MEITL and other SETD2-deficient lymphomas. 374942 +No NIH Category available Acute;Address;Aftercare;Algorithms;Biochemical;Businesses;Cancer Center;Cancer Patient;Caring;Case Management;Classification;Clinic;Clinical Decision Support Systems;Collaborations;Communities;Computer Models;Consult;Cost Savings;Data;Electronics;Ensure;Explosion;Future;Guidelines;Health Insurance Portability and Accountability Act;Health Services Accessibility;Health system;Ingestion;Knowledge;Malignant Neoplasms;Malignant neoplasm of prostate;Manuals;Marketing;Medical;Medical Records;Modeling;Monitor;New York;Nurse Practitioners;Oncologist;Oncology;Operative Surgical Procedures;PSA screening;Patient Education;Patient Preferences;Patient-Focused Outcomes;Patients;Performance;Persons;Phase;Physicians;Population;Preparation;Probability;Process;Production;Protocols documentation;Provider;Publishing;Recommendation;Recurrence;Reporting;Research;Resource Allocation;Resources;Retrieval;Retrospective cohort;Running;Sampling;Skin Cancer;Survival Rate;Symptoms;Test Result;Testing;Time;Training;Triage;Urology;Visit;Visual;Visualization;Woman;active method;cancer care;cancer diagnosis;cancer type;care providers;clinical decision support;clinical decision-making;cloud based;cohort;commercialization;dashboard;design;follow-up;improved;individual patient;insight;men;novel;patient health information;patient population;performance tests;pilot test;prostate cancer risk;screening;software as a service;tool;usability;virtual VIPCare: Virtual Predictive Care workflow with integrated surveillance for optimal care protocol selection and management in at-risk prostate cancer patients NarrativeProstate cancer is the leading cancer diagnosis in men (not including skin cancer) and has high survival rates(98% at 5 years) resulting in an estimated 3.2M US men currently living with prostate cancer. However datashows follow up among prostate cancer patients remains a significant challenge. This project will create a cloud-based clinical decision support system to automatically monitor track and optimally classify prostate cancercases for triage by applying advanced algorithms to curated medical data. NCI 10758350 8/29/23 0:00 PA-22-176 1R43CA281547-01A1 1 R43 CA 281547 1 A1 "WEBER, PATRICIA A" 9/1/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-HSS-J(10)B] 77809785 "HENSLEY ALFORD, SHARON " Not Applicable 17 Unavailable 116905433 N1EMHHVX3F35 116905433 N1EMHHVX3F35 US 41.208817 -73.776778 10060891 VIZLITICS INC. CHAPPAQUA NY Domestic For-Profits 105141000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 SBIR/STTR 2023 406500 NCI 273218 106689 AbstractProstate cancer is the leading cancer diagnosis in men (not including skin cancer) and has high survival rates(98% at 5 years) resulting in an estimated 3.2M US men currently living with prostate cancer. However datashows follow up among prostate cancer patients remains a significant challenge. A recent study at Dana-Farber/Brigham and Womens Cancer Center (DF/BCC) demonstrated its novel Virtual Prostate Cancer Clinic(VPCC) increased access to care for new patients by 1110% and expanded revenue by 174% in four years.Leveraging knowledge gained by the VPCCs preliminary studies and to address this challenge in the marketVizlitics will develop a Software-as-a-Service product on top of its existing Cancer Insights (CI) platform incollaboration with its research partners at DF/BCC to serve US cancer centers and community oncologists.Known as VIPCare this new CDSS will automatically monitor track and optimally classify prostate cancer casesfor triage by applying advanced algorithms to curated medical data. The cloud-based platform will ingest andcurate cancer patient medical records including unstructured notes and apply Markov Decision Process (MDP)modeling of patient longitudinal data onto published surveillance guidelines. VIPCare will automatically retrievenew medical record data to keep models current with the latest tests and encounters and then compute aclassification probability for a patient being in each care protocol (active surveillance active treatment or post-treatment surveillance) and the probability of moving from one care protocol to another. In addition the modelwill provide a recommendation for whether the patient should be followed by an electronic virtual or in-personvisit with an APP or physician. This approach will: 1) improve follow-up of surveillance patients by scaling analready validated approach 2) leverage MDP to reduce the need for manual data entry medical record reviewand hands-on patient management and 3) improve allocation of clinic resources. Phase I Specific Aims are to:1. Develop a MDP model by incorporating prostate cancer guidelines on longitudinal patient data. Usingretrospective patient data the team will apply the MDP model to compute probabilities for current and future carebased on latest tests and medical record data. 2. An optimization algorithm will use the probability scores createdin Aim 1 patient preferences and provider constraints to compute the triage recommendation for each patient.The dashboard will give the overview status of each patient individually and the entire patient population globally.3. In lab usability testing will be run as well as accuracy testing of the classification and optimization algorithms.At the end of Phase I the company will have demonstrated feasibility of VIPCare achieving acceptable usertesting and computation model accuracy 80%. Phase II will be a real-time test pilot of VIPCare at a prostatecancer clinic with additional technical enhancements in preparation for commercialization. Significant marketopportunities exist for a tool like VIPCare that can offer demonstrated cost savings increased practice efficiencyand improved patient outcomes. 406500 +No NIH Category available Acids;Adjuvant;Adopted;Aminolevulinic Acid;Anatomy;Area;Augmented Reality;Biopsy;Brain;Brain Neoplasms;Brain region;Clinical;Clinical Research;Computer software;Correlation Studies;Darkness;Data;Data Display;Detection;Disease;Emerging Technologies;Excision;FDA approved;Fiber;Fluorescence;Glioblastoma;Goals;Image;Imaging Device;Imaging technology;Infiltration;Light;Lighting;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of brain;Manufacturer;Measurement;Measures;Metabolism;Methods;Microinvasive;Microscope;Monitor;Nature;Neuronavigation;Neurosurgical Procedures;Newly Diagnosed;Normal tissue morphology;Operative Surgical Procedures;Optics;Patient imaging;Patients;Pharmaceutical Preparations;Physiologic pulse;Positioning Attribute;Postoperative Period;Process;Prognosis;Prospective Studies;Real-Time Systems;Resectable;Resected;Residual Neoplasm;Sampling;Scanning;Signal Transduction;Surface;Surgeon;Surgical margins;Surgically-Created Resection Cavity;System;Techniques;Technology;Time;Tissues;Tumor Burden;Tumor Tissue;Visual;Visualization;Work;brain based;brain tumor resection;clinical application;clinically significant;fluorescence imaging;fluorescence lifetime imaging;fluorescence-guided surgery;imaging system;improved;neoplastic cell;neurosurgery;novel;optical imaging;prospective;protoporphyrin IX;radiological imaging;software development;spatial integration;tool;tumor;virtual Integration of 5-ALA Fluorescence Lifetime Imaging with Stereotactic Surgical Navigation for Quantitative Real-Time Spatial Localization of Tumor During Neurosurgical Procedures PROJECT NARRATIVEFluorescence guided surgery using the exogenous agent 5-ALA has been increasingly utilized to enhance theability to detect residual tumor and improve the extent of resection for glioblastoma. As currently implementedintensity-based detection by the surgeon viewing fluorescence through the operating microscope is non-quantitative and background light-sensitive requiring the surgeon to work in a dark field. Our novel opticalimaging FLIm system captures and analyzes tissue fluorescence quantitatively and successful integration ofthis technology with existing stereotactic neuronavigation for spatial annotation of FLIm data and visualizationis expected to generate a new tool for improved tumor detection and resection while overcoming the currentlimitations of 5-ALA use. NCI 10758281 12/22/23 0:00 PAR-20-155 5R01CA277380-02 5 R01 CA 277380 2 "PEREZ, J MANUEL" 1/1/23 0:00 12/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-S(57)R] 9801007 "BLOCH, ORIN " "MARCU, LAURA ; VALCU, BOGDAN " 4 NEUROSURGERY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 491858 NCI 340897 150961 PROJECT SUMMARY/ABSTRACTMaximal surgical resection of the most common primary brain cancer glioblastoma (GBM) has been shown toimprove overall survival in a highly morbid disease. However delineation of residual tumor at the margins ofsurgical resections can be challenging using conventional techniques and therefore the use of fluorescenceguided surgery (FGS) has emerged as an adjuvant tool for tumor detection. At present only one agent 5-aminoleveulinic acid (5-ALA) is approved for detection of GBM during surgery. Metabolism of 5-ALA intoprotoporphyrin IX (PpIX) is detected qualitatively by wide-field fluorescence imaging through the surgicalmicroscope. This intensity-based detection is non-quantitative and background light-sensitive requiring thesurgeon to work in a dark field. We have developed a fiber-based pulse-excitation time-resolved method forFluorescence Lifetime Imaging (FLIm) to detect quantitative PpIX fluorescence in real-time under fullillumination conditions. Our goal in this study is to integrate the point-scanning FLIm technology with anexisting intraoperative stereotactic neuronavigation system produced by BrainLab to spatially co-register FLImdata across the surgical field for applicable surgical guidance. We aim to develop new software and tissueclassifiers based on primary patient data and to apply the integrated technology in a prospective clinical studyto demonstrate the benefits for surgical navigation.To achieve the overall goal of developing a new integrated technology which is immediately applicable forroutine use in brain tumor resections we will undertake the following aims: Aim 1) To develop new software forintegration of the FLIm device with the BrainLab neuronavigation system for real-time acquisition of spatialpositioning of FLIm data and display of the data overlaid on the patients imaging in the navigation space. Aim2) To develop classifiers for surgically resectable tumor based on PpIX fluorescence lifetime thresholdsdetermined through a prospective study correlating FLIm data to tissue biopsies. Aim 3) To validate theaccuracy of integrated FLIm-based navigation in identifying residual tumor tissue to facilitate a greater extent ofresection in a prospective clinical study. 491858 +No NIH Category available Ablation;Affect;Antibodies;Antigen-Presenting Cells;Antitumor Response;B-Lymphocytes;Binding;Biochemical;Biopsy;CD8-Positive T-Lymphocytes;CD80 gene;CD8B1 gene;Cancer Patient;Cells;Clinical Trials;Cytoplasmic Tail;Detection;Development;Genes;Human;Immune;Immune system;Immunologics;Immunosuppression;Immunotherapy;Individual;Infiltration;Knowledge;Ligands;Macrophage;Malignant Neoplasms;Mediating;Memory;Modeling;Molecular;Molecular Profiling;Mus;Neurotransmitters;Outcome;PD-1 blockade;Pathway interactions;Patients;Pattern;Phosphotyrosine;Physiological;Production;Property;Proteins;Regulatory T-Lymphocyte;Shapes;Signal Induction;Signal Transduction;T cell response;T memory cell;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Tyrosine;Work;anti-cancer therapeutic;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cancer therapy;cell type;checkpoint therapy;exhaustion;fatty acid oxidation;immune activation;improved outcome;inhibitor;lipid metabolism;monocyte;novel;outcome prediction;peripheral blood;prognostic significance;programmed cell death ligand 1;programmed cell death protein 1;receptor;response;success;transcriptomics;tumor;tumor growth;tumor microenvironment Detection of PD-1 inhibitory signaling and its molecular relays in T cells: Implications for cancer immunotherapy Project NarrativeActivation of the immune system by immunotherapy can be used for the treatment of cancer but major gapsin our knowledge compromise optimal outcomes. This project will study how immunotherapy affects theproperties of CD8+ T effector and T regulatory cells and their crosstalk with other immune components of thetumor microenvironment. This work may significantly improve the outcome of immunotherapy and provide amajor benefit to cancer patients. NCI 10758274 12/22/23 0:00 PA-20-185 5R01CA257672-02 5 R01 CA 257672 2 "ZAMISCH, MONICA" 1/1/23 0:00 12/31/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 2206318 "BOUSSIOTIS, VASSILIKI A" "VLACHOS, IOANNIS " 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 640414 NCI 384727 255687 PD-1 blocking agents have achieved significant success as anti-cancer therapeutics. The mechanism(s) of howPD-1 compromises anti-tumor function remain poorly understood. Although in trans engagement of PD-1expressed in T cells by its ligands expressed on APC or cancer cells inhibits T cell activation evolving discoveriesprovide evidence that PD-L1:B7-1(CD80) in cis and PD-1:PD-L1 in cis non-canonical interactions occur whenthese molecules are co-expressed on APC and disrupt the canonical interaction between PD-1 and PD-L1 intrans and T cell inhibitory signaling. Thus expression of PD-L1 in the tumor microenvironment (TME) is notsynonymous with PD-1-mediated T cell inhibition. We generated an antibody that recognizes PD-1pY248 (pPD-1)which is required for PD-1 inhibitory signaling and detected pPD-1 in mouse and human. We found pPD-1+ Tcells in cultures in mouse tumor models and patient biopsies but also in CD8+ T central memory (TCM) cells inthe peripheral blood of healthy individuals. In tumor bearing mice pPD-1 was expressed in tumor infiltrating CD8+T lymphocytes but mostly in Treg. We generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) andselectively eliminated PD-1 in Treg (Pdcd1f/fFoxP3cre). In tumor-bearing Pdcd1f/fFoxP3cre mice Treg displayedenrichment in pathways regulating lipid metabolism fatty acid oxidation and production ofmonocyte/macrophage chemotactic protein-1 (MCP-1) and GABAergic neurotransmitter with knownimmunosuppressive function. These features correlated with a significant increase of B cells and M2-likemacrophages diminished activation of tumor infiltrating T cells and increased tumor growth. Our results reveala previously unappreciated network by which Treg-selective blockade of PD-1 signaling reshapes theimmunological landscape and suggest that abrogation of PD-1 signaling in distinct cell types differentially impactsthe TME. Our findings indicate that pPD-1 is a powerful marker to identify T cells subjected to PD-1 inhibitorysignaling and support the novel hypothesis that cell-specific detection of PD-1 signaling by pPD-1 might predictthe outcome of checkpoint immunotherapy. To investigate these we will pursue the following specific aims:1. To identify the immunological and biochemical properties of pPD-1+ T cells in the context of cancer.We will characterize pPD-1+ CD8+ TIL and Treg by single cell immunoprofiling and investigate how T cell subset-specific PD-1 signaling reshapes the TME by using our Pdcd1f/fCD8cre and Pdcd1f/fFoxP3cre mice.2. To identify the molecular and functional properties of pPD-1+ cells in healthy individuals. We willexamine how PD-1 signaling shapes the properties of T cells in healthy individuals and in cancer patients anduncover why only cancer-mediated PD-1 signaling induces TEX.3. To determine expression function and prognostic significance of pPD-1+ TIL in cancer patients. Wewill examine cell-specific PD-1 expression and signaling in patient biopsies co-expression of PD-1/pPD-1 PD-L1 and CD80 and determine their prognostic significance. 640414 +No NIH Category available Address;Adherence;Adult;Affect;Android;Antineoplastic Agents;Behavioral;Caregivers;Caring;Cellular Phone;Clinic;Communication;Complex;Computers;Continuity of Patient Care;Data;Development;Dose;Drug toxicity;Elderly;Food-Drug Interactions;Frequencies;Funding;Future;Glean;Goals;Grant;Health Insurance;Health Personnel;Health Technology;Home;Home environment;Incidence;Income;Instruction;Internet;Intervention;Intervention Studies;Interview;Knowledge;Malignant Neoplasms;Managed Care;Medication Management;Methods;Mobile Health Application;Modeling;Monitor;Motivation;Oncology;Online Systems;Oral;Outcome;Ownership;Palliative Care;Patient Outcomes Assessments;Patients;Perception;Personal Computers;Pharmaceutical Preparations;Pharmacologic Substance;Polypharmacy;Problem Solving;Program Acceptability;Provider;Questionnaires;Randomized Controlled Trials;Regimen;Reporting;Research;Self Efficacy;Self Management;Social support;Solid Neoplasm;Symptoms;Tablets;Technology;Theory of Change;Time;United States Food and Drug Administration;behavior change;cancer care;cancer therapy;care providers;chemotherapy;comorbidity;coping;design;efficacy testing;financial toxicity;flexibility;health literacy;human old age (65+);improved;insight;literacy;mHealth;medication administration;programs;response;satisfaction;side effect;symptom management;technology platform;tool;treatment comparison;usability;web-based assessment Exploring the Use of a Web-Based Program for Older Adults Receiving Oral Anticancer Agents to Improve Communication and Self-Management Oral anticancer agents (OAAs) account for over half of the new cancer treatments approved by the Food andDrug Administration. For older adults who are taking OAAs and self-managing care in the home environmentresearch is crucial for the development of supportive interventions to improve communication informationexchange and self-efficacy in the management complex OAA and related symptoms/side effects. This studywill explore concordance of the timing frequency and continuity of information sharing communication andknowledge gaps between patients caregivers and oncology health care providers specific to OAA treatment;examine patient-reported outcomes associated with OAA self-management; and to explore perceptions ofsupportive web-based program design features that may assist with the development of future intervention tool. NCI 10758263 12/14/23 0:00 PAR-20-052 5R03CA262908-02 5 R03 CA 262908 2 "D'ANGELO, HEATHER" 1/1/23 0:00 12/31/24 0:00 ZCA1-SRB-1(O1)S 12541941 "MARSHALL, VICTORIA KATE" Not Applicable 15 NONE 69687242 NKAZLXLL7Z91 69687242 NKAZLXLL7Z91 US 28.074039 -82.395963 513807 UNIVERSITY OF SOUTH FLORIDA TAMPA FL SCHOOLS OF NURSING 33612 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 74750 NCI 50000 24750 Oral anticancer agents (OAAs) are increasingly being prescribed and now account for over half of the newcancer treatments approved by the Food and Drug Administration. Older adults have the highest incidence ofmost solid tumor cancers and are often prescribed OAAs. Despite the speculated convenience of OAAspatients and their caregivers have steep literacy needs specific to information regarding this complex treatmentand are often met with numerous challenges. They must demonstrate self-efficacy in the management ofcomplex OAA regimens adherence symptom/side effect management monitoring and reporting of drugtoxicities potential drug-drug or food-drug interactions and polypharmacy in the home environment.Both patients and caregivers report that OAA information is inadequate potentially affecting safe treatmentadministration and management. Today oncology care is shifting from oncology clinics to home environmentsresulting in implications for how care is delivered and communicated to patients given the decreasedfrequency of face-to face contact with oncology providers. Older adults have reported worse communicationwith oncology providers related to chemotherapy treatment compared with their younger counterparts leavingolder adults vulnerable to worse outcomes. Web-based programs offer a potential solution to increasecommunication and generate new ways to support self-management of cancer care.The specific aims of this mixed methods study are to: 1a) Explore concordance of the timing frequency andcontinuity of information sharing and communication regarding OAA treatment between patients caregiversand oncology health care providers 1b) Identify patient and caregiver OOA knowledge gaps; 2) Evaluatepatient-reported outcomes associated with the self-management of OOA treatment including health literacysatisfaction with OAA information symptoms self-efficacy for managing medication social support for takingmedications medications taken for other comorbid conditions palliative care referraland technologyownership/use via quantitative questionnaires; ad 3) Assess web-based program design features that willassist in the development of a future intervention tool to manage OAA treatment and to evaluate customizedconsiderations needed for older adult oncology patients using technology.Findings will inform future research with aims geared towards; 1) development of a supportive web-basedprogram for older adults receiving OAAs and their caregivers that is theoretically driven and rooted inbehavioral change and technology use in older adults and 2) evaluating the web-based program foracceptability usability feasibility and user engagement. The long-term goal is to inform a larger RCT to testthe efficacy of the web-based program to improve OAA-specific outcomes of older adult patients. 74750 +No NIH Category available Area;Authorization documentation;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer health equity;Clinical;Clinical Research;Clinical Research Protocols;Clinical Trials;Committee Members;Complement;Data;Discipline;Ensure;Institutional Review Boards;Malignant Neoplasms;Mission;Monitor;Pharmacology;Process;Protocols documentation;Research;Research Design;Research Personnel;Research Support;Resources;Role;Safety;Support System;System;Time;anticancer research;authority;community engagement;human subject protection;interest;medical specialties;metabolomics;multidisciplinary Protocol Review and Monitoring System n/a NCI 10758258 12/1/23 0:00 PAR-20-043 5P30CA022453-42 5 P30 CA 22453 42 8/8/97 0:00 11/30/25 0:00 ZCA1-RTRB-C 8825 1885004 "FLAHERTY, LAWRENCE E" Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 97865 63549 34316 PROTOCOL REVIEW AND MONITORING SYSTEM (PRMS) ABSTRACTThe Protocol Review and Monitoring System (PRMS) at KCI ensures rigorous review of the scientific merit ofresearch protocols prioritization of protocols across the Cancer Center and monitors progress of all clinicalresearch. Prior to submission to the PRMC a first stage review is conducted within each of the Multi-Disciplinary Teams (MDT) who prioritize protocols within their respective area of expertise and practice. Withrespect to prioritization of protocols the MDT conducts a pre-review of potential protocols for activation todetermine whether they complement the current portfolio of open protocols and whether they should moveforward for submission to the PRMC. The MDT also reviews the protocols for scientific interest and thelikelihood of attaining adequate accrual. This process eliminates redundant reviews by the PRMC and reducessubmission of competing protocols. Although the MDT identifies the prioritization it is reviewed and confirmedby the Protocol Review and Monitoring Committee (PRMC). The PRMC fulfills the primary role of the PRMS.The PRMC is composed of a broad array of complementary expertise with an emphasis on senior investigatorsfrom various disciplines and specialties as well as representatives from the Biostatistics and BioinformaticsCore Pharmacology and Metabolomics Core the Clinical Trials Office (CTO) the KCI Network and theOffice of Cancer Health Equity & Community Engagement. The members of the committee represent asufficient size and breadth of expertise to conduct a critical and fair scientific review of all clinical researchprotocols involving cancer patients at KCI. The PRMC provides internal oversight of the scientific merit of thecancer trials in addition to assuring that its clinical resources are engaged to ensure the best practices forscientific endeavors and applications. The function of the PRMC is complementary to that of the IRB whichfocuses on the protection of human subjects. The PRMC is not intended to duplicate or overlap theresponsibilities of the IRB nor is it intended to perform an auditing or data and safety monitoring function.Scientific review takes into account the specific rationale study design duplication of studies already inprogress elsewhere and at the Cancer Center adequacy of biostatistical input and feasibility for completion ofthe study within a reasonable time frame. Additionally the PRMC is responsible for accrual monitoring;protocols are reviewed regularly to evaluate scientific progress including accrual rates to ensure that thescientific aims of the study are on track for completion in the estimated timeframes indicated at initialsubmission. +No NIH Category available Administrator;Advocate;Affordable Care Act;Age;Behavior;Black Populations;Characteristics;Cigarette;Colorado;Counseling;Data;Data Set;Decision Making;Disparity;Drug Prescriptions;Ensure;Grant;Health;Health Policy;Healthcare;Hispanic Populations;Income;Insurance;Insurance Carriers;Knowledge;Low Income Population;Low income;Managed Care;Medicaid;National Cancer Institute;Nicotine;Patients;Pattern;Persons;Pharmaceutical Preparations;Population;Process;Public Health;Public Policy;Recommendation;Research;Research Priority;Smoke;Smoker;Smoking;System;Testing;Tobacco Use Cessation;cost effective;design;evidence base;improved;insight;low socioeconomic status;prior authorization;programs;reduce tobacco use;sex;smoking cessation Examining the Impact of Medicaid's Prior Authorization Requirements for Tobacco Cessation Medications on Tobacco Cessation Medication Prescriptions PROJECT NARRATIVE RELEVANCEIncreasing access to tobacco cessation medications is a key part of U.S. health policys strategy for reducingsmoking rates especially for smokers with low incomes. The central objectives of this project are to estimatethe impact of prior authorization requirements for tobacco cessation medications in Medicaid programs on theuse of cessation-related health care treatment and to understand prior authorizations implications fordisparities in the use of tobacco cessation medications and for potentially contraindicated prescriptions. Thefindings from this study will provide public health stakeholders with information that can be used when makingdecisions about whether to require prior authorization for tobacco cessation medications and conditional onrequiring prior authorization to set up systems and rules that improve the prior authorization process fortobacco cessation medications. NCI 10758252 12/28/23 0:00 PAR-20-052 5R03CA270451-02 5 R03 CA 270451 2 "PRUTZMAN, YVONNE M" 1/1/23 0:00 12/31/24 0:00 ZCA1-SRB-1(O1)S 12078669 "DILLENDER, MARCUS OWEN" Not Applicable 5 MISCELLANEOUS 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN SCHOOLS OF ARTS AND SCIENCES 372032408 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 79250 NCI 50000 29250 PROJECT SUMMARY/ABSTRACTIncreasing access to tobacco cessation medications is a key part of U.S. health policys strategy for reducingsmoking especially for low-income smokers who are less likely to use tobacco cessation medications thanhigh-income smokers are. Given that the Affordable Care Act requires Medicaid programs to cover tobaccocessation medications Medicaid coverage grants enrollees access to tobacco cessation medications inprinciple but over two-thirds of state Medicaid programs require doctors to obtain prior authorization fromprogram administrators before prescribing tobacco cessation medications. While prior authorizationrequirements advocates argue that requiring prior authorization can ensure appropriate and cost-effectiveprescribing without reducing access to helpful medications even small prescribing hurdles have the potentialto have large impacts on prescribing behavior and medication access. Public health leaders call for removingbarriers in access to tobacco cessation medications but it is not currently known if requiring prior authorizationmeaningfully reduces overall use of these medications or if it instead ensures appropriate use without reducingaccess more generally as its advocates argue. This project proposes to estimate the impact of priorauthorization requirements in Medicaid on the use of tobacco cessation medications by using detailed data onhealth care claims to study Colorados Medicaid program removing its prior authorization requirement fortobacco cessation medications in 2018. A primary objective of the proposed project is to estimate the impact ofColorado removing its prior authorization requirement on overall tobacco cessation prescriptions and relatedtreatments. A second objective is to estimate heterogeneous impacts of removing prior authorizationrequirements for different demographic groups. The project then proposes to use the estimates to conductadditional analyses to assess the national implications of Medicaid programs requiring prior authorization fortobacco cessation medications. In addition the project proposes to test for heterogeneous effects of priorauthorization requirements based on prior health conditions to assess the claim that the main effect of priorauthorization requirements is to avoid prescriptions that Medicaid programs could identify as potentially beinginappropriate. Achieving these aims will provide stakeholders with information that can be used when makingdecisions about whether to require prior authorization for tobacco cessation medications and conditional onrequiring prior authorization to set up systems and rules that improve the prior authorization process fortobacco cessation medications. Achieving the aims of this study will address multiple research priorities of theNational Cancer Institute by increasing knowledge about barriers in access to evidenced-based cessationtreatments by identifying strategies to increase the use of cessation treatments for people with lowsocioeconomic status and by providing insights into how insurers can contribute to tobacco cessation. 79250 +No NIH Category available Acceleration;Address;Admixture;Adult;Affect;African American;American;Arabs;Area;Automobile Driving;Behavioral;Cancer Center Support Grant;Cancer Survivor;Cancer Survivorship;Catchment Area;Characteristics;Childhood;Clinic;Clinical;Cohort Studies;Collaborations;Colon Carcinoma;Communication;Communication Research;Communities;Comprehensive Cancer Center;Custom;Data;Development;Diagnosis;Discrimination;Disease Progression;Disparity;Endometrial Carcinoma;Epigenetic Process;Ethnic Origin;Evidence based intervention;Family member;Funding;Future;Genetic;Goals;Grant;Health;Immunity;Incidence;Individual;Inflammation;Institution;Intervention;Investigation;Lesbian Gay Bisexual Transgender;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Manuscripts;Metabolic syndrome;Michigan;Minority;Minority Groups;Mission;Molecular;Molecular Epidemiology of Cancer;Obesity;Onset of illness;Outcome;Participant;Patient-Focused Outcomes;Patients;Peer Review;Physical activity;Physicians;Population;Population Heterogeneity;Population Study;Prognosis;Publishing;Quality of Care;Race;Reduce health disparities;Research;Research Project Grants;Resources;Risk;Risk Behaviors;Risk Factors;Risk Reduction;Role;Rural;Rural Population;SEER Program;Schools;Sexual and Gender Minorities;Site;Smoking;Survivors;Susceptibility Gene;System;Targeted Research;Technology;Testing;Underserved Population;United States;Universities;Work;analytical method;biomarker discovery;cancer diagnosis;cancer epidemiology;cancer health disparity;cancer prevention;cancer risk;clinical practice;clinical research site;cohort;community based research;comorbidity;defined contribution;design;disparity elimination;disparity reduction;eHealth;end of life;epidemiology study;ethnic diversity;experience;family genetics;gender minority group;health equity;heritability pattern;high risk;high risk population;improved;interest;malignant breast neoplasm;medically underserved;member;metropolitan;mortality;neoplasm registry;novel;outreach;patient-clinician communication;population based;population health;preclinical study;programs;provider behavior;psychosocial;racial bias;racial disparity;racial diversity;recruit;risk stratification;screening;social;survivorship;symptom management;theories;treatment choice;tumor Population Studies and Disparities Research n/a NCI 10758233 12/1/23 0:00 PAR-20-043 5P30CA022453-42 5 P30 CA 22453 42 8/8/97 0:00 11/30/25 0:00 ZCA1-RTRB-C 8819 7932759 "BEEBE-DIMMER, JENNIFER L" Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 27033 17554 9479 POPULATION STUDIES AND DISPARITIES RESEARCH ABSTRACTThe Population Studies and Disparities Research (PSDR) Program is committed to identifying key geneticand behavioral risk factors underlying disease onset and progression and developing and testing novelintervention strategies to reduce risk and improve diagnosis treatment and outcomes with an emphasis onreducing and/or eliminating cancer health disparities among populations contained within our catchment area.This interactive Program includes 28 members from 11 departments and 3 schools at Wayne State Universityand $6936093 in peer reviewed cancer-related funding of which $5793590 is from the NCI. The PSDRProgram has two overarching scientific themes. The first theme is to investigate the distribution anddeterminants of cancer risk survivorship and outcomes in a racially and ethnically diverse population. Majorscientific investigations under this theme use emerging advances in genetics to address our highly-diversecatchment area population that is approximately 25% African American includes the largest Arab-Americancommunity in the US; developing projects target both sexual and gender minority cancer survivors and ruralpopulations within our expanded catchment area. The work is supported by the Detroit area population-basedcancer registry a founding participant in the SEER Program a resource that is well-leveraged for extensivepopulation-based studies of the epidemiology of lung breast prostate colon ovarian and endometrial cancersin diverse populations. The second theme is to develop and test evidence-based interventions focused onpatient family member and physician behaviors to reduce disparities in cancer prevention treatmentsurvivorship and end-of-life outcomes. The main focus of this theme is modifying social and behavioral factorsdriving risk behaviors screening and treatment choices the quality of physician-patient-family membercommunication symptom management and survivorship in racially and ethnically diverse adult and pediatricpopulations. The work is supported by a unique custom-designed video data capture system installed in multipleclinic sites to study the ways racial bias and poor communication give rise to unequal treatment decisions andhealth outcomes. Future directions include the development of multi-PI grants focused on African Americancancer survivors leveraging the Detroit Research on Cancer Survivors (Detroit ROCS) cohort study. The DetroitROCS study is the largest single cohort conducted exclusively among African American cancer survivors with agoal of understanding the determinants of poorer outcomes in this population. eHealth technologies to enhancepatient-provider communication are also being developed. PSDR Program members actively collaborate withmembers of the MI MT and TBM Programs at KCI. Of the 409 manuscripts published from December 2015to November 2019 43% and 25% were intra- and inter-programmatic respectively and 74% were multi-institutional collaborations. +No NIH Category available African American;African American population;Anatomy;Benchmarking;Biological;Biological Markers;Cancer Center;Cancer Center Support Grant;Catchment Area;Classification;Clinic;Clinical;Clinical Drug Development;Clinical Investigator;Clinical Trials;Clinical effectiveness;Collaborations;Communities;Conduct Clinical Trials;Disparity;Dose;Drug Combinations;Drug Design;Enrollment;Family;Funding;Genetic;Genetic Transcription;Genomics;Goals;Immunologic Markers;Incidence;Industry;Institution;International;Intervention;Laboratories;Laboratory Finding;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Manuscripts;Michigan;Minority Groups;Mission;Molecular;NCI Center for Cancer Research;New Agents;Nuclear;Pathway interactions;Patients;Peer Review;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Population Study;Prediction of Response to Therapy;Process;Publishing;Research;Research Personnel;Research Project Grants;Schools;Scientist;Signal Pathway;Stromal Cells;Stromal Neoplasm;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Traditional Medicine;Translating;Tumor Biology;Tumor Markers;Tumor-infiltrating immune cells;Universities;Work;base;cancer health disparity;cancer therapy;cancer type;chemotherapy;clinical translation;clinical trial enrollment;clinically relevant;drug development;drug discovery;early phase trial;effectiveness validation;follow-up;genomic biomarker;high throughput screening;improved;interest;malignant breast neoplasm;member;molecular imaging;molecular marker;multidisciplinary;novel;novel strategies;novel therapeutic intervention;novel therapeutics;patient oriented;personalized medicine;pharmacodynamic biomarker;pharmacokinetics and pharmacodynamics;phase 2 study;phase II trial;phase III trial;programs;psychosocial;racial difference;response;small molecule libraries;structural biology;translational cancer research;translational study;treatment response;treatment trial;tumor;tumor metabolism;tumor microenvironment Molecular Therapeutics n/a NCI 10758226 12/1/23 0:00 PAR-20-043 5P30CA022453-42 5 P30 CA 22453 42 8/8/97 0:00 11/30/25 0:00 ZCA1-RTRB-C 8818 9609623 "AZMI, ASFAR S" Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 41624 27028 14596 MOLECULAR THERAPEUTICS ABSTRACTThe mission of the Molecular Therapeutics (MT) Program is to translate laboratory findings to the clinic and tofacilitate collaborations between basic and clinical scientists to improve the lives of patients with cancer byidentifying new molecules targets and strategies for treating cancer. This highly interactive Program includes50 members from 11 departments and 4 schools at Wayne State University and the Karmanos Cancer Institute(KCI) Network and $3031514 in peer reviewed cancer-related funding of which $971206 is from the NCI.Additionally industry-sponsored clinical trial funding is $29599781. Program membership includes a crosssection of laboratory-based and clinical investigators in the KCI who interact through programmatic activities andcollaborate on research grants and investigator-initiated clinical trials. The scientific themes of the MT Programare to: 1) identify and validate novel therapeutics targets and pathways for selective tumor targeting; 2) identifycellular/molecular determinants and biomarkers of tumor response; and 3) validate effectiveness of new agentsin interventional treatment trials. The MT Program focuses on new approaches for treating cancer ranging fromdrug discovery to mechanism-based efforts emphasizing mechanisms-of-action of novel tumor-targeted andstandard agents and critical signaling pathways all with the goal of clinical translation. The interests of MTmembers include tumor metabolism nuclear transporters transcriptional targets and signaling pathways andextend to the impact of therapy on tumor-infiltrating immune cells. Biomarker research includes pharmacokineticsand pharmacodynamics cellular and molecular biomarkers and molecular/genetic profiles predictive ofresponses to therapy and/or that lead to actionable therapies. A particular emphasis is on biomarkers relevantto cancer disparities between African American and white patients as treatment targets and for personalizedtreatment trials. Research in the MT Program draws from our nationally/internationally recognized clinical trialsprogram at KCI which employs tumor profiling (including genomic profiling) to facilitate enrollment on phase Iand early phase II trials and to identify patients most likely to respond to particular treatments. Phase II clinicaltrials draw from basic laboratory findings culminating in investigator-initiated clinical trials. MT members leadphase III trials often working with multi-center teams and cooperative groups. MT Program members study allmajor cancer types including those that occur at high incidence in the KCI catchment area. These initiatives havehelped define cancer health disparities in our catchment area identify racial differences in tumor biology andled to enrollment of large numbers of African Americans in clinical trials. The overriding goal of the MT Programis to conduct and deliver patient-centered cancer research and treatment to benefit patients in the catchmentarea. MT Program members extensively collaborate with members of the MI TBM and PSDR Programs atKCI. Of the 935 manuscripts published between December 2015 and November 2019 34% and 32% were intra-and inter-programmatic respectively and 62% were multi-institutional collaborations. +No NIH Category available Address;Age;Antigen-Presenting Cells;Autoimmune;B-Cell Activation;Cell Communication;Cell Compartmentation;Cells;Clinical;Clonality;Combination immunotherapy;Combined Modality Therapy;Complementary DNA;Computing Methodologies;Cytometry;Data;Data Set;Dendritic Cell Vaccine;Development;Ethnic Origin;Evolution;Expression Profiling;Foundations;Gender;Gene Expression;Genes;Genetic;Genetic Transcription;Genomics;Goals;Heterogeneity;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Monitoring;Immunologic Stimulation;Immunology;Immunotherapy;Infusion procedures;Learning;Length;Lymphoid;Lymphoid Cell;Malignant neoplasm of prostate;Microsatellite Instability;Mismatch Repair Deficiency;Modeling;Monitor;Morbidity - disease rate;Multiplexed Ion Beam Imaging;Myelogenous;Myeloid Cells;Oncology;Participant;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phenotype;Physicians;Play;Prostate-Specific Antigen;Protein Analysis;Proteomics;Protocols documentation;Provenge;Role;Sampling;Scientist;Solid Neoplasm;T cell response;T-Cell Receptor;T-Lymphocyte;Testing;Time;Tissue Sample;Transcript;Tumor Burden;Tumor Tissue;Urogenital Cancer;Work;anti-CTLA4;cancer immunotherapy;cancer type;career;castration resistant prostate cancer;clinical predictors;clinical training;clinical trial participant;cohort;high dimensionality;immunogenic;improved;in vivo;ipilimumab;method development;mortality;novel;patient subsets;predicting response;predictive signature;programs;protein expression;response;response biomarker;single cell proteins;skills;success;targeted treatment;tool;treatment response;tumor;tumor microenvironment Discovery of myeloid immune features predictive of response to cancer immunotherapy in prostate cancer PROJECT NARRATIVECancer immunotherapy is a promising antitumor therapy but the success in solid tumors especially prostatecancer has been limited. While current immunotherapies focus on targeting the T cell compartmentcombination therapies that incorporate activation of the myeloid compartment could increase the efficacy ofimmunotherapy in solid tumors. I have profiled single cell transcript and protein expression in peripheralimmune cells in a prostate cancer cohort during combined immunotherapy treatment and I will use this datasetto investigate the heterogeneity of the myeloid compartment and how that heterogeneity relates to treatmentresponse. NCI 10758215 12/18/23 0:00 PA-19-191 5F30CA257291-04 5 F30 CA 257291 4 "ODEH, HANA M" 1/1/21 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-F09C-Q(20)L] 14636842 "MCCARTHY, ELIZABETH " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTCancer immunotherapy has been a revolutionary antitumor treatment and is approved to treat a plethora ofcancer types. However in solid tumors the response has been limited with only approximately 20 percent ofpatients responding except for patients with high tumor burden as evidenced by microsatellite instability (MSI)or mismatch repair deficiency (MMRD). The limited response is especially pronounced for prostate cancer. Inprostate cancer the only currently approved therapy (except for MSI/MMRD patients) is sipuleucel-T adendritic cell vaccine. Sipuleucel-T activates antigen presenting cells ex vivo before reinfusion where in vivoactivation of B and T cell responses are associated with response to the therapy. This immunogenic myeloidand lymphoid cell interaction is just one example of a plethora of interactions which can be either immunogenicor tolerogenic. Improved understanding of the role of myeloid compartment in pro- or anti-tumor activity willallow for improved targeting of the myeloid compartment in combination immunotherapy strategies.Immunosuppressive myeloid states can be observed both in the periphery and in the tumor microenvironment.Peripheral monitoring of the immune system holds incredible potential due to the ease of monitoring and theability for longitudinal repeated sampling. To characterize the heterogeneity of the circulating myeloidcompartment I used a genetic multiplexing strategy to simultaneously profile gene and protein expressionon single cells from ~700000 peripheral blood mononuclear cells (PBMCs) from longitudinal samplingof a metastatic castration resistant prostate cancer (mCRPC) cohort undergoing combinedimmunotherapy. In my first aim I propose to use this dataset to describe novel myeloid cell states in theperiphery and to investigate which states recapitulate in the tumor microenvironment and which states predictclinical response to the immunotherapy. In my second aim I will investigate how these myeloid cell statesinteract with the lymphoid compartment to create an immunogenic or tolerogenic tumor response. My sponsorDr. Jimmie Ye has extensive expertise in single cell omics for profiling the immune system in both auto-immune and tumor contexts. My co-sponsor Dr. Lawrence Fong has made foundational discoveries in thefield of cancer immunotherapy with a particular focused on the mechanisms behind response to cancerimmunotherapy in genitourinary cancers including prostate cancer. My co-sponsor Dr. Matthew Spitzer hasextensive expertise in the understanding the systemic response of the immune system to a tumor with aparticular focus in using mass cytometry for high dimensional single cell protein expression profiling. I will beundergoing longitudinal clinical training in cancer immunotherapy with Dr. Lawrence Fong who is the directorof the Cancer Immunotherapy Program at UCSF. Overall this work will lay the foundation for improvedprediction of response to cancer immunotherapy and the identification of novel targets within the myeloid targetto improve clinical response in solid tumors. 52694 +No NIH Category available Active Sites;Agreement;Antineoplastic Agents;Biology;Bypass;CRISPR screen;Cell Cycle Inhibition;Cell Cycle Progression;Cell Death;Cell Proliferation;Cell Survival;Cells;Chromatin;Chromosome Segregation;Complex;DNA;DNA Adduction;DNA Adducts;DNA Damage;DNA Repair;DNA Topoisomerases;DNA lesion;DNA strand break;Ensure;Enzymes;Etoposide;Eukaryota;Excision;Fission Yeast;Genes;Genetic Transcription;Human;Knock-out;Lesion;Link;Literature;Mammalian Cell;Mediating;Pathway interactions;Poison;Process;Prokaryotic Cells;Proteins;Reaction;Regulation;Research Personnel;Resistance;Role;Rotation;SPO11 gene;Signal Transduction;Somatic Cell;Stress;Superhelical DNA;TOP1 gene;TOP2A gene;Testing;Therapeutic;Topoisomerase;Topoisomerase II;Topoisomerase III;Type I DNA Topoisomerases;Tyrosine;Vertebral column;Work;cancer therapy;experimental study;follow-up;neoplastic cell;protein protein interaction;repaired;response;treatment response;whole genome Deciphering pathways involved in topoisomerase II turnover PROJECT NARRATIVEType II topoisomerases are essential for the relief of topological tensions during transcription replication andchromosome segregation. This proposal aims to elucidate the mechanisms by which several specificregulators act together to ensure proper turnover of these topoisomerases which is critically important for DNAdamage avoidance and cell survival.. NCI 10758213 11/29/23 0:00 PA-20-185 5R01CA275712-02 5 R01 CA 275712 2 "OKANO, PAUL" 1/1/23 0:00 12/31/27 0:00 Cancer Etiology Study Section[CE] 1980054 "CHEN, JUNJIE " Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 452669 NCI 279425 173244 PROJECT SUMMARYDNA topoisomerases are types of enzymes that can specifically resolve topological stresses by transientlyintroducing strand breaks into DNA molecules and enabling the rotation of the supercoiled DNA strand.Mammalian cells encode two types of topoisomerases: type I topoisomerases (TOP1 TOP1mt TOP3A andTOP3B) which introduce single strand breaks into DNA and type II topoisomerases (TOP2A TOP2B andSPO11) which introduce double strand breaks (DSBs) into DNA. This proposal focuses on type IItopoisomerases i.e. TOP2A/2B in human somatic cells. During cleavage reaction the tyrosine in the catalytic active site of TOP2 is covalently linked to theDNA backbone and forms the so-called topoisomerase II cleavage complex (TOP2cc). Under normalconditions TOP2cc forms transiently and is not detectable. However a wide variety of topoisomerase poisonsincluding etoposide have been developed and used as chemotherapeutic drugs for cancer treatment.Mechanistically etoposide acts to stabilize TOP2cc which eventually lead to DNA strand breaks and kill tumorcells. While many investigators including us investigated TOP2-induced DNA lesions and how they can berepaired by different repair pathways this proposal focuses on a new concept that cells have evolved distinctpathways to avoid and limit DNA lesions induced by TOP2. In this proposal we will determine mechanisticallyhow several unique TOP2 regulators act together to avoid DNA damage and therefore promote cell survival.Results from these studies are critically important for the understanding of therapeutic response to etoposideand other anti-cancer agents.. 452669 +No NIH Category available African American;American;Arabs;Area;Award;Awareness;Cancer Biology;Cancer Center Support Grant;Cancer health equity;Career Mobility;Catchment Area;Clinical;Collaborations;Communities;Community Health;Community Healthcare;Comprehensive Cancer Center;Dedications;Development;Direct Costs;Education;Educational process of instructing;Educational workshop;Enrollment;Ensure;Event;Faculty;Fellowship;Female;Fostering;Foundations;Funding;Funding Mechanisms;Future;Gerontology;Goals;Health Personnel;Health Professional;High School Student;Hispanic;Infrastructure;Internships;Leadership;Malignant Neoplasms;Medical;Medical Students;Mentors;Molecular Genetics;Molecular Medicine;Not Hispanic or Latino;Patient Care;Physics;Policies;Postdoctoral Fellow;Race;Reproducibility;Research;Research Personnel;Resources;Schools;Services;Solid;Students;Training;Training Activity;Training Programs;Training Support;Training and Education;Translational Research;United States National Institutes of Health;Universities;Update;Work;anticancer research;cancer care;cancer education;cancer initiation;career;career development;career networking;clinical care;community engagement;continuing medical education;effectiveness evaluation;environmental stressor;graduate student;high school;leadership development;medical schools;member;next generation;novel;programs;recruit;response;skills;success;symposium;tenure track;training project;undergraduate student Cancer Research Training and Education Coordination n/a NCI 10758206 12/1/23 0:00 PAR-20-043 5P30CA022453-42 5 P30 CA 22453 42 8/8/97 0:00 11/30/25 0:00 ZCA1-RTRB-C 8815 8462233 "COTE, MICHELE L" Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 65786 42718 23068 CANCER RESEARCH TRAINING AND EDUCATION COORDINATION (CRTEC) ABSTRACTKarmanos Cancer Institute (KCI) provides extensive cancer research training and educational programs thatspan all career stages. Dr. Michele Cote (PSDR) Associate Center Director for Education leads KCIs CRTECefforts. In addition to identification promotion and support of University-sponsored training activities Dr. Cote(PSDR) coordinates the cancer-specific programs at KCI. With the support of CRTEC Education AdvisoryCouncil members each with expertise in a particular field or window of training Dr. Cote (PSDR) serves as themain point of contact for trainees across the career trajectory. A key component of the CRTEC is to evaluatethe effectiveness of the supported training activities and identifying gaps and opportunities to enhance KCItraining efforts across the spectrum.KCIs education efforts span the education and training continuum including efforts focused on high schoolstudents undergraduate students graduate and medical students post-doctoral trainees residents and fellowsjunior faculty tenured faculty and community healthcare providers. CRTEC efforts are supported by ten activetraining projects totaling $895210 direct costs. Several have grown out of a T32 led by Dr. Matherly (MT)(T32CA009531). This training program in the biology of cancer that has been continuously funded for over threedecades. Since 2015 24 students have been supported via the T32 five of whom were also awardedsubsequent F30 or F31 support. Novel efforts at KCI include the launch of focuSStem in 2019 a programdeveloped by a high school student for high school students with support from KCI leadership. In its inauguralyear five schools and 149 students have participated in the day-long program (37% African American 30% non-Hispanic white 27% Arab American 4% Hispanic and 2% other races; over 50% females). A recent addition toour efforts in reaching high school students is the Discovery to Cure High School Internship Program (DTCHIP)(R25HD072591) led by Dr. Gil Mor (TBM) which will begin recruiting in the summer of 2020. +No NIH Category available Aftercare;Alleles;Anchorage-Independent Growth;Apoptosis;Breast Carcinoma;Candidate Disease Gene;Cell Cycle Arrest;Cell Differentiation process;Cells;Chemoresistance;Colon Carcinoma;Comet Assay;DNA;DNA Damage;DNA Repair;DNA Replication Timing;DNA Sequence Alteration;DNA biosynthesis;Development;Embryo;Embryonal Carcinoma;Embryonal Carcinoma Cell;Embryonic Development;Enterobacteria phage P1 Cre recombinase;Event;Exercise;Fiber;Fibroblasts;Generations;Genes;Genetic Recombination;Genetically Engineered Mouse;Genome;Germ Cells;Human;In Situ;In Vitro;Lesion;Malignant - descriptor;Malignant Neoplasms;Measures;Modeling;Mus;Mutagens;Mutate;Mutation;Nature;Neoplasms;Oncogene Activation;Oncogenes;Oncogenic;Pathology;Pathway interactions;Phenotype;Pluripotent Stem Cells;Proliferating;Property;Risk;Risk Reduction;Role;Signal Transduction;Somatic Cell;Spermatocytes;Structure of primordial sex cell;System;Teratocarcinoma;Teratoma;Testicular Germ Cell Tumor;Testicular Neoplasms;Testicular malignant germ cell tumor;Therapeutic;Tissue-Specific Gene Expression;Tissues;Tumor Suppressor Genes;Tumorigenicity;Undifferentiated;cell transformation;cell type;chemotherapy;experience;experimental study;genotoxicity;improved;in vitro Model;in vivo;induced pluripotent stem cell;lung Carcinoma;mouse model;neoplastic cell;pressure;prevent;repaired;replication stress;response;stem cell biomarkers;stem cell therapy;therapy development;transcriptome sequencing;treatment response;tumor;tumor initiation;tumor progression;tumorigenesis;young man The role of the DNA damage response in the development and therapeutic sensitivity of malignant testicular germ cell tumors. Project NarrativeThis proposal will elucidate the DNA damage response properties of testicular germ cell tumors (TGCTs) andthe cells from which they arise which will inform the mechanisms underlying their remarkable sensitivity toconventional genotoxic chemotherapy. Understanding the basis of TGCT chemosensitivity will apply broadly tothe development of treatments for the many other cancers that do not respond favorably to chemotherapy.Additionally investigating the malignant transformation of pluripotent cells will be important for improving stem-cell based therapies which carry the risk of tumorgenicity. NCI 10758203 12/21/23 0:00 PA-19-192 5F30CA247458-05 5 F30 CA 247458 5 "PURI, ANU" 1/1/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 15096462 "LOEHR, AMANDA " Not Applicable 19 OTHER BASIC SCIENCES 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 Project SummaryTesticular germ cell tumors (TGCTs) are exceptionally sensitive to conventional genotoxic chemotherapy. Thisis likely due to the distinct DNA damage response (DDR) features of TGCTs and the germ cells from which theyarise. Unlike somatic cells which often respond to DNA damage by arresting the cell cycle and conducting DNArepair germ cells as well as long-lived pluripotent stem cells typically avoid the use of error-prone repairmechanisms and favor apoptosis reducing the risk of genetic alterations in subsequent generations. Similarlythe TGCT precursor lesion germ cell neoplasia in situ does not show activation of a DDR whereas precursorlesions of most somatic cancers express markers of an activated DDR in response to oncogene activation whichserves as a barrier to tumor progression. To study TGCTs our lab has developed the first genetically engineeredmouse model of malignant TGCTs by conditional activation of Kras an oncogene and inactivation of Pten atumor suppressor gene in germ cells. The malignant teratocarcinomas generated in these mice are composedof pluripotent embryonal carcinoma (EC) and differentiated teratoma tissue. Interestingly EC cells both in vivoand cultured in vitro express stem cell markers have tumor propagating activity and are readily killed followingchemotherapy treatment. Using cells derived from this model the experiments proposed here will elucidate theDDR properties of TGCTs and the cells from which they arise which will inform the mechanisms underlying theirexceptional chemosensitivity. Specifically this proposal aims to: understand how the cells that give rise toTGCTs respond to oncogenic events apparently avoiding DDR activation (Aim 1) and determine the mechanismunderlying the chemosensitivity of the embryonal carcinoma components of TGCTs and the chemoresistance oftheir differentiated counterparts (Aim 2). Aim 1 will be investigated by generating primordial germ cell-like cells(PGCLCs) and embryonic germ cell-like cells (EGCLCs) from induced pluripotent stem cells (iPSCs) derivedfrom mouse embryonic fibroblasts (MEFs) with conditional Pten and Kras alleles and assessing malignanttransformation the degree of DNA replication stress the extent of DNA damage and the nature of the DDR inuntransformed and transformed cells. For Aim 2 I will analyze differential gene expression in EC anddifferentiated cells before and after treatment with genotoxic chemotherapy and investigate the role ofdifferentially regulated pathways in the chemosensitivity phenotype. It is critically important to study this curablecancer because understanding the basis of TGCT chemosensitivity will apply broadly to the development oftreatments for the many other cancers that do not respond favorably to conventional chemotherapy. Additionallyunderstanding the malignant transformation of pluripotent cell types including embryonic germ cells and iPSCswill be important for the improvement of stem-cell based therapies which carry the risk of tumorgenicity. 52694 +No NIH Category available Adopted;Aerobic;Anti-Inflammatory Agents;Cancer Etiology;Cancer Prognosis;Categories;Cell physiology;Cessation of life;Characteristics;Classification;Complex;Data;Development;Diagnosis;Disease;Drug resistance;Electron Transport;Elements;Endocrine;Environment;Etiology;Female;Foundations;Gene Expression;Gene Expression Profile;Genes;Glycolysis;Goals;Growth;Human;Immune;Immunotherapy;Impairment;In Vitro;Inflammatory;Longevity;Macrophage;Mediating;Metabolic;Metabolism;Methods;Mitochondria;Modeling;Molecular;Mus;Neoplasm Metastasis;Oxidative Phosphorylation;Pathway interactions;Patients;Periodicity;Phenotype;Population;Positioning Attribute;Prognosis;Regulation;Resistance;Role;Structure;T-Lymphocyte;Testing;Therapeutic;Tumor stage;Tumor-associated macrophages;Tumor-infiltrating immune cells;Work;angiogenesis;breast cancer survival;cancer subtypes;chemotherapy;cytotoxic;cytotoxicity;drug-sensitive;experience;flexibility;immune cell infiltrate;immune checkpoint blockade;immunogenic;immunogenicity;in vivo;innovation;insight;malignant breast neoplasm;mammary;novel;preference;programs;protein expression;respiratory;success;therapeutic target;transplant model;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Combating the Immunosuppressive Tumor Microenvironment in Triple Negative Breast Cancer: The Role of Mitochondrial Dynamics in the Polarization of Tumor-Associated Macrophages PROJECT NARRATIVETriple Negative Breast Cancer (TNBC) is an aggressive disease with limited treatment options and less than30% of patients with TNBC will survive beyond five years after diagnosis. This project seeks to prove thatmitochondrial manipulation is an effective strategy to repolarize macrophages into an anti-tumor state. Theresults may provide insights towards strengthening and advancing the use of immune therapies in a poor-prognosis cancer. NCI 10758195 12/5/23 0:00 PA-21-049 5F30CA268872-03 5 F30 CA 268872 3 "BIAN, YANSONG" 1/1/22 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 15252295 "CHAN, HILDA LYN" Not Applicable 9 NONE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 Project Summary/AbstractTriple Negative Breast Cancer (TNBC) is a devastating disease with aggressive growth and frequent metastases.Less than 30% of patients with metastatic TNBC survive beyond five years after their diagnosis. While otherbreast cancer subtypes have well-defined endocrine markers TNBC tumors lack such specific therapeutictargets making cyclic chemotherapy the mainstay of treatment. Immune checkpoint blockade therapy aims toleverage TNBCs inherent yet limited immunogenicity though success has been restricted by otherimmunosuppressive elements in the tumor environment. The overarching goal is to find alternative and/orsynergistic methods to enhance immune-mediated cytotoxicity in the TNBC tumor microenvironment. The overallobjective of this proposal is to enhance tumor microenvironment immunogenicity by repolarizing macrophagesout of a pro-tumor state and into a cytotoxic anti-tumor state. The central hypothesis is that mitochondrial fusiongoverns tumor associated macrophages (TAM) pro-tumor functions within the tumor microenvironment. Therationale for this project is that macrophage metabolism defines polarization fate. Particularly anti-tumormacrophages upregulate glycolysis while pro-tumor macrophages depend on oxidative phosphorylation. Asmitochondria house oxidative phosphorylation-associated pathways and as mitochondrial structure impactsoxidative phosphorylation efficiency manipulating mitochondrial structure could determine polarization fate. Thisproposal consists of proof-of-principle studies to demonstrate macrophages are flexible and that repolarizationcan be achieved by manipulating mitochondrial structure in vitro and in vivo. Along this trajectory the centralhypothesis will be tested by pursuing two specific aims. Aim 1 will determine the role of mitochondrial dynamicsin macrophage polarization. For this aim we will culture TNBC tumor macrophages in vitro manipulatemitochondrial dynamics and then evaluate polarization. Aim 2 will determine whether TAM pro-tumor functionswithin the tumor microenvironment are dependent on mitochondrial fusion. In this aim we will evaluate the effectof macrophages with altered mitochondrial dynamics on T cell cytotoxicity metastasis and angiogenesis. Theproposed studies are innovative because they will evaluate direct causation between mitochondrial dynamicsand macrophage polarization and will also define a relevant in vivo macrophage phenotype. The project issignificant because it sets the foundation for manipulation of macrophage mitochondria as a therapeutic strategyto enhance tumor microenvironment immunogenicity for TNBC. Collectively these studies will lend insight intothe mechanisms that govern macrophage fate and make progress towards novel immune therapies for TNBC. 52694 +No NIH Category available Acetic Acids;Advocacy;Algorithms;Area;California;Cancer Prevention Intervention;Cancer Prevention Trial;Caring;Cervical;Cervical Cancer Screening;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Clinical Trials Unit;Cold Therapy;Collaborations;Communities;Country;Cytology;DNA;Data;Dedications;Development;Diagnosis;Eligibility Determination;Enrollment;Ensure;Equity;Funding;Genotype;Guidelines;Gynecologic Oncologist;HIV;HIV/AIDS;HPV-High Risk;Health;Health Policy;High Prevalence;Human Papillomavirus;Human papilloma virus infection;Incidence;Infrastructure;Intervention;Laboratories;Leadership;Lesion;Life Cycle Stages;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;Mission;Multi-Institutional Clinical Trial;Outcome;Participant;Pathogenesis;Performance;Persons;Phase;Policies;Population Density;Population Heterogeneity;Pragmatic clinical trial;Prevalence;Prevention;Procedures;Protocols documentation;Public Health;Publications;Regulation;Research;Research Activity;Research Infrastructure;Research Personnel;Resource-limited setting;Resources;Risk;San Francisco;Scientist;Screening for cancer;Seminal;Site;System;Testing;Thermal Ablation Therapy;Training;Training and Education;Treatment Efficacy;United States National Institutes of Health;Universities;Virus Diseases;Visual;Woman;World Health Organization;Zimbabwe;advanced disease;aged;antiretroviral therapy;base;cancer epidemiology;cancer prevention;cancer therapy;cervical cancer prevention;clinical infrastructure;clinical research site;clinically significant;eligible participant;experience;innovation;insight;investigator training;low and middle-income countries;migration;multimodality;next generation;point of care;premalignant;preventive intervention;primary care clinic;primary health center;programs;public health intervention;recruit;retention rate;scale up;screening;therapeutic HPV vaccine;treatment duration;treatment optimization;trial planning Implementing HIV/Cervical Cancer Prevention CASCADE Clinical Trials in Zimbabwe (ZIM-CASCADE) Project NarrativeTo optimize cervical cancer (CXCA) screening and the pre-cancer treatment cascade for women living withHIV (WLWH) in Zimbabwe and in other lower middle income countries (LMIC) the University of California SanFrancisco and University of ZimbabweClinical Trials Research Centre (UZ-CTRC) in collaboration with localPEPFAR-funded implementation partners Organization for Public Health Interventions and Development(OPHID) and the Zimbabwe Technical Assistance Training and Education Center for Health (Zim-TTECH)(collectively ZIM-CASCADE) propose to serve as a LMIC CASCADE UG1 Clinical Site. ZIM-CASCADE willcontribute critical evidence to inform optimization implementation and scale-up of effective CXCA preventioninterventions for WLWH in resource-limited settings and the multi-modal CASCADE data will inform publichealth policy in Zimbabwe and globally. NCI 10758129 8/4/23 0:00 RFA-CA-22-051 1UG1CA284918-01 1 UG1 CA 284918 1 "FRECH, MARIA SILVINA" 8/4/23 0:00 5/31/27 0:00 ZCA1-SRB-F(M3) 8378936 "CHIRENJE, ZVAVAHERA MIKE" "GUZHA, BOTHWELL " 11 OBSTETRICS & GYNECOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 8/4/23 0:00 5/31/24 0:00 399 Other Research-Related 2023 275910 NCI 209341 66569 Project Summary/AbstractZimbabwe is a resource-constrained country with a high burden of HIV and cervical cancer (CXCA).Zimbabwean women with CXCA present with advanced disease and two-thirds die within a year of diagnosis.CXCA screening has low coverage (13%) and is conducted largely through visual inspection with acetic acid(VIA) with plans to migrate to human papillomavirus (HPV) deoxyribonucleic acid (DNA) testing. Precancertreatment is mostly cryotherapy or thermal ablation but is only accessed by 53% of women screen positive. Tomeet the WHO 2030 target of eliminating CXCA by 2120 Zimbabwe needs new interventions that areacceptable affordable point-of-care scalable and clinically proven. To optimize CXCA screening and the pre-cancer treatment cascade for women living with HIV (WLWH) University of California San Francisco (UCSF)and the University of ZimbabweClinical Trials Research Centre (CTRC) in collaboration with local PEPFAR-funded implementation partners Organization for Public Health Interventions and Development (OPHID) andthe Zimbabwe Technical Assistance Training and Education Center for Health (Zim-TTECH) (collectivelyZIM-CASCADE) propose to serve as a LMIC CASCADE UG1 Clinical Site. ZIM-CASCADE draws onextensive experience in conducting clinical research and CXCA screening and treatment among WLWH withaccess to 95000 WLWH of whom >44000 are currently receiving comprehensive CXCA screening andtreatment through the OPHID and Zim-TTECH programs located in Zimbabwes high-density populationcenters of Harare and Chitungwiza. ZIM-CASCADE will be led by 2 gynecological oncologists with globallyrecognized expertise in CXCA screening and treatment and will utilize research personnel and infrastructurefrom dedicated clinical research sites and community-based primary care clinics whose experience has beendeveloped over nearly 3 decades of continuous research activities. ZIM-CASCADE will participate in all 4scientific focus areas of the CASCADE Network and will complete the following Specific Aims: (1) Provideinsight as to clinical significance and feasibility of planned trials by drawing on extensive clinical expertise inCXCA prevention among WLWH; (2) Utilize the expansive pluripotent infrastructure and research managementsystems developed over 28 years to conduct high quality pragmatic clinical trials; (3) Accrue and retain eligibleWLWH through effective and equitable engagement with community partners; and (4) Ensure compliance withall protocol procedures and applicable research regulations. Completion of the Aims will contribute criticalevidence to inform optimization implementation and scale-up of effective cervical cancer preventioninterventions for WLWH in resource-limited settings and the multi-modal CASCADE data will inform publichealth policy in Zimbabwe and globally. 275910 +No NIH Category available Activities of Daily Living;Address;Adult;Affect;Age;Aging;Anus;CD4 Lymphocyte Count;Cancer Patient;Caring;Cessation of life;Client satisfaction;Clinical;Colorectal Cancer;Complement;Data;Data Collection;Data Linkages;Data Reporting;Development;Diagnosis;Discrimination;Elderly;Esophagus;Face;Female Breast Carcinoma;Florida;Future;General Population;Goals;HIV;HIV Seronegativity;HIV Seropositivity;HIV diagnosis;Head and neck structure;Health;Health Surveys;Highly Active Antiretroviral Therapy;Hospitalization;Immunosuppression;Intervention;Larynx;Life Expectancy;Liver;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measurement;Measures;Medicare;Medicare claim;Mental Health;Methods;Morbidity - disease rate;NCI-Designated Cancer Center;Older Population;Oral cavity;Outcome;Outcome Assessment;Pain;Pancreas;Patient Monitoring;Patient Outcomes Assessments;Patient Self-Report;Patient-Centered Care;Patients;Persons;Pharyngeal structure;Physical Function;Population;Quality of life;Reporting;Research;Risk;Role;SEER Program;Solid Neoplasm;Stomach;Supportive care;Surveys;Survival Analysis;Symptoms;United States Centers for Medicare and Medicaid Services;Upper digestive tract structure;Veterans;Vulnerable Populations;Work;cancer care;cancer diagnosis;cancer risk;cancer therapy;care delivery;comorbidity;data registry;experience;financial toxicity;hazard;health related quality of life;improved;innovation;lens;marginalization;mortality;neoplasm registry;older patient;outcome disparities;patient population;patient-clinician communication;physical conditioning;social;social factors;social stigma;survival disparity;symptom management;symptomatic improvement;therapy design;treatment response;tumor progression;understudied cancer Health-related quality of life and patient reported outcomes among people living with HIV and cancer PROJECT NARRATIVEPeople with HIV (PWH) with a cancer diagnosis experience elevated cancer-specific mortality and worse canceroutcomes compared to their HIV-negative counterparts. Poor symptom management may contribute to lowersurvival among PWH with cancer however limited research exists evaluating patient-reported outcomes(PROs). By utilizing an existing unique linkage stewarded by the NCI called SEER-MHOS complemented byprimary data collection characterizing PROs and related HIV-specific social barriers among HIV positive cancerpatients treated at an NCI-designated cancer center the current study will explore PROs among cancer patientswith HIV to inform the development of future large-scale R01-level research opportunities focused on improvingmulti-faceted symptom control among PWH with cancer to ultimately reduce preventable cancer deaths amongU.S. PWH. NCI 10758118 8/16/23 0:00 PAR-20-052 1R03CA278603-01A1 1 R03 CA 278603 1 A1 "JENSEN, ROXANNE ELAINE" 8/16/23 0:00 7/31/25 0:00 ZCA1-RTRB-C(M1) 12095480 "ISLAM, JESSICA YASMINE" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 8/16/23 0:00 7/31/25 0:00 393 Non-SBIR/STTR 2023 168500 NCI 100000 68500 PROJECT SUMMARYAdvances in HIV treatment have improved life expectancy among people with HIV (PWH). As PWH live longerthey are at increased risk for cancer and cancer-related mortality compared with the general population.However it remains unclear what factors may contribute to persistent survival disparities and poor canceroutcomes among PWH in the US. Integrating measurement of patient-reported outcomes (PROs) into routineand supportive cancer care is a potential strategy to improve PWHs quality of life cancer outcomes and survival.PROs encompass data reported directly by patients to describe how they feel and function such as symptomsphysical function and health-related quality of life. In the general (i.e. HIV-uninfected) cancer patient populationPRO scores are associated with several adverse cancer clinical outcomes including poor response to therapycancer progression and shorter survival. Given that PWH are also more likely to be diagnosed with non-AIDSdefining cancers at later stages and experience elevated mortality it is urgent to investigate opportunities suchas the role of PROs to improve survival and ultimately reduce preventable cancer deaths among PWH. Howeverto our knowledge no research exists in the context PROs and overall health-related quality of life among PWHwith cancer. To address this research gap our objective is to evaluate physical and mental health symptomology(PROs) throughout the cancer diagnosis trajectory and associations with cancer outcomes among HIV-positivecancer patients. We propose a two-pronged approach: we will leverage an existing NCI-sponsored data linkagebetween the Surveillance Epidemiology and End Results (SEER) cancer registry data and Centers for Medicareand Medicaid Services (CMS) Medicare Health Outcomes Survey (MHOS) (Aims 1 and 2) and conduct primarydata collection among HIV positive cancer patients treated at an NCI-designated cancer center (Aim 3). We willcarry out the following specific aims: Aim 1: Compare changes in patient reported outcomes (PROs) after acancer-diagnosis among non-AIDS defining cancer patients living with and without HIV; Aim 2: Estimateassociations of PROs (pre-diagnosis post-diagnosis and change in PROs) with overall survival among olderpatients diagnosed with non-AIDS defining cancers with HIV; and Aim 3: Explore the role of HIV-specific clinicaland social factors in patient reported outcome assessments among a broad age range of HIV positive cancerpatients treated at one NCI-designated cancer center. Findings from this research will provide preliminary datato inform the development of future large-scale R01-level research opportunities focused on improving symptomcontrol among PWH with cancer and evaluating the integration of tailored patient-reported outcome datacollection into routine supportive care of this vulnerable population. 168500 +No NIH Category available Amino Acid Sequence;Animals;Arizona;Back;Binding;Binding Sites;Biological;Biotechnology;Bone Marrow;Cancer Biology;Cancer Patient;Cell Adhesion;Cell Mobility;Cells;Cessation of life;Chemicals;Chemotaxis;Clinic;Collaborations;Compensation;Complex;Development;Disease;Drug Kinetics;Drug resistance;Enhancers;Epithelial Cells;Generations;Goals;Growth;Hepatotoxicity;Hormonal;Hormones;Human;Immunotherapy;Invaded;Investigation;Lead;Malignant Neoplasms;Malignant neoplasm of prostate;Maximum Tolerated Dose;Messenger RNA;Metabolic;Modality;Modeling;NCI-Designated Cancer Center;Normal Cell;Operative Surgical Procedures;Organ;Organoids;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacology and Toxicology;Phase;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Production;Property;Prostate;Prostate Cancer therapy;Protein Kinase;Protein Phosphorylation Inhibition;Protein-Serine-Threonine Kinases;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Quality of life;RNA;RNA Degradation;Radiation;Regulation;Resistance;Scaffolding Protein;Serine;Signal Transduction;Structure;Structure-Activity Relationship;Techniques;Testing;Therapeutic;Tumor Cell Invasion;Universities;analog;anticancer activity;bone;cancer therapy;cell growth;chemotherapy;clinical candidate;cytokine;design;drug discovery;experimental study;improved;in silico;in vivo;inhibitor;lymph nodes;men;migration;mouse model;neoplastic cell;nephrotoxicity;novel;novel strategies;prevent;professor;prostate cancer cell line;proto-oncogene protein pim;research clinical testing;side effect;small molecule;synergism;tool;tumor;tumor growth Regulation of RNA Decapping and Degradation: A novel approach to prostate cancer therapy NarrativeProstate cancer (PCa) is the most common cancer of men and once spread it is incurable. The centralpremise of this application is that it is possible to develop highly potent and selective competitive inhibitors thatregulate RNA decapping and thus stimulate the destruction of specific RNAs in tumor cells inhibiting tumorgrowth and invasion. The goal of this proposal is to develop a novel second generation small molecule drugthat can be used in the clinic to regulate RNA destruction and thus block PCa growth. NCI 10758110 7/11/23 0:00 PA-22-176 1R43CA281394-01A1 1 R43 CA 281394 1 A1 "DJEMIL, SARRA" 8/1/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 1863635 "KRAFT, ANDREW S" Not Applicable 6 Unavailable 827435749 HLEQZTL74FF1 827435749 HLEQZTL74FF1 US 32.804808 -79.946292 10019577 VORTEX BIOTECHNOLOGY CORPORATION CHARLESTON SC Domestic For-Profits 294034279 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 397168 NCI 289721 81464 Prostate cancer (PCa) is the most frequent killer of men with over 34000 deaths per year. If PCa is not curedby initial definitive surgery and/or radiation and spreads to lymph nodes bones or other organs current therapiesare not curative. Hormone blockade chemotherapy and immunotherapy have significant side effects thatimpact the patients quality of life. Thus novel treatments are needed for those who fail standard therapy. Thegoal of this proposal is to develop a new first-in-class small molecule regulator of RNA destruction as a PCacancer treatment. Preliminary results demonstrate that small molecules can be created which regulate RNAdecapping and thus enhance RNA destruction. Experiments demonstrate that the scaffold protein needed forRNA decapping Enhancer of Decapping 3 (EDC3) is heavily phosphorylated by the Pim 1 and 3 serine proteinkinases in PCa and this phosphorylation inhibits its ability to regulate decapping. Blocking the ability of EDC3to bind Pim1 and 3 reverses this inhibition and leads to the destruction of specific set of RNAs regulators of celladhesion cytokine production and cell mobility. Inhibiting EDC3 phosphorylation with a novel small moleculeVBT-34 blocks PCa growth and invasion. This first-generation of compounds was identified in a screen thatincluded high levels of ATP thus allowing the identification of potential allosteric inhibitors. Modeling the Pim1and 3 structure demonstrates that the current lead compound VBT-34 fits into a newly identified pocket in thePim 1 and 3 kinase. No significant evidence of compensatory EDC3 phosphorylation particularly by the AKTkinase which is highly activated in PCa has been identified. The Specific Aims of this application are toimprove the drug-like properties of VBT-34: 1- Designing synthesizing and testing VBT analogs to i) increasethe potency of the compound for the inhibition of EDC3:Pim1/3 complex formation ii) improve thephysicochemical and pharmacokinetic properties of the lead compound. The novel VBT analogs will be optimizedby iterative studies guided by in silico modeling and structure-activity relationship (SAR) investigation. 2-Determine lead compound maximum tolerated dose and antitumor efficacy using animal tumor models.Investigate whether the newly synthesized lead compound inhibit(s) PCa growth invasion and RNAdegradation. Strict go/no go criteria for compound advancement to each level of testing will be met. This effortwill be carried out by Vortex Biotechnology Corporation headed by Dr. Andrew S. Kraft a past Director of twoNCI-designated Cancer Centers collaborating with Dr. Wei Wang Co-Director of the University of Arizona Centerfor Drug Discovery and Professor of Pharmacology and Toxicology. This team will use state-of-the-art drugdiscovery tools to develop second generation inhibitors that can be transitioned into the clinic. Regulation ofdecapping and thus the stimulation of specific RNA degradation is a first-in-class approach to inhibiting cancerinvasion and growth. This team has the expertise to synthesize evaluate and advance compounds into a phaseII application and human clinical testing. 397168 +No NIH Category available Ablation;Acceleration;Achievement;Address;Anatomy;Animal Model;Animals;Autopsy;BAY 54-9085;Biological Markers;Biopsy;CRISPR/Cas technology;Cirrhosis;Clinic;Clinical;Clinical Trials;DNA Sequence Alteration;DNA sequencing;Data;Development;Devices;Diagnosis;Diagnostic;Disease;Disease Management;Drug Delivery Systems;Early Diagnosis;Enrollment;Etiology;Excision;Failure;Family suidae;Fibrosis;Future;Genes;Genetic;Genetic Induction;Hepatic;Histopathology;Human;Image;Imaging technology;Immunity;Immunologics;Injections;Intervention;Knock-out;Life;Liver;Liver diseases;Liver neoplasms;Malignant Neoplasms;Malignant neoplasm of liver;Measurement;Medical Device;Metabolism;Methods;Miniature Swine;Modeling;Molecular;Molecular Profiling;Monitor;Nature;Oncogenes;Operative Surgical Procedures;Outcome;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physiological;Physiology;Pre-Clinical Model;Preclinical Testing;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Process;Radiation therapy;Recurrence;Refractory;Reproducibility;Research Personnel;Risk;Rodent;Safety;Solid;Stage at Diagnosis;Steatohepatitis;Survival Rate;Systemic Therapy;Techniques;Technology;Testing;Therapeutic;Therapeutic Embolization;Time;Translating;Transplantation Surgery;Tumor Burden;Tumor Suppressor Genes;Tumor Tissue;Unresectable;Variant;Virus Diseases;Work;advanced disease;beta catenin;biliary tract;biomarker identification;biomarker validation;cancer diagnosis;chemotherapy;clinically relevant;commercialization;comorbidity;cost effective;effective therapy;global health;imaging modality;improved;improved outcome;innovation;liver cancer model;liver function;molecular modeling;molecular phenotype;molecular subtypes;molecular targeted therapies;mortality;novel;optimal treatments;overexpression;palliative;patient population;patient subsets;pharmacokinetics and pharmacodynamics;porcine model;precision medicine;preclinical study;prevent;response;somatic cell gene editing;specific biomarkers;standard of care;success;targeted treatment;therapeutic development;therapeutic evaluation;therapeutically effective;tool;tumor;tumor heterogeneity;tumor microenvironment;tumorigenesis;two-arm study;ultrasound An Inducible Swine Hepatocellular Carcinoma Platform for Enhanced Therapeutic Development PROJECT NARRATIVEHepatocellular carcinoma (HCC) is the most common form of liver cancer and the second deadliest cancer inthe world with a 5-year survival rate between 5-14%. Therapies for HCC especially in advanced stages arelimited and insufficient due in part to tumor heterogeneity underlying comorbidities in human patients and alack of known biomarkers for optimal treatment approaches. Taking advantage of the unique genetic anatomicaland physiological similarities between minipigs and humans we will induce genetic mutations in the minipig liverto accurately model specific subtypes of human HCC and use this platform for developing targeted therapiesspecific to subsets of HCC patients. NCI 10758109 8/23/23 0:00 PA-22-176 1R43CA284940-01 1 R43 CA 284940 1 "FRANCA-KOH, JONATHAN C" 9/1/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CDPT-R(12)B] 12592224 "KORPELA, DEREK MATTHEW" Not Applicable 2 Unavailable 829874523 L99NWZNZ7K57 829874523 L99NWZNZ7K57 US 44.955424 -93.152857 10022488 "RECOMBINETICS, INC." Eagan MN Domestic For-Profits 55121 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 342154 NCI 252400 67370 PROJECT SUMMARYHepatocellular carcinoma (HCC) is a global health burden ranking as the fourth most common and seconddeadliest cancer in the world. Effective therapeutic strategies for HCC especially at advanced stages are limiteddue to tumor heterogeneity underlying patient comorbidities and lack of identified biomarkers for diseasemanagement. Overall survival rates for advanced disease are just 5-14% indicating that improved therapies areneeded. Historically rodents have served as the predominant preclinical model but results in these studies havenot translated to successful human application. Limitations of these and other models include variations in thegenetic and molecular mechanisms of tumorigenesis inconsistencies in immunity and tumor microenvironmentsand marked differences in size anatomy and physiology. Shortcomings of these models create barriers toidentifying targetable biomarkers developing device and imaging technologies pharmaceutical treatments andtechniques for biopsy and surgery all of which are necessary to improve outcomes for HCC patients. To createa platform whose preclinical testing will translate to innovation in these fields of HCC management we havedeveloped methods to induce HCC in the liver of minipigs using somatic cell gene editing. Our minipig platformis ideal for therapeutic development as the size physiology anatomy and metabolism of minipigs are closelyrelated to humans. Moreover liver function segmental anatomy biliary tree and hepatic vasculature aremarkedly similar to humans. To date we have proven the feasibility of this approach in developing solid livertumors rapidly and reproducibly with induced molecular changes identified in HCC patients. In this proposal weaim to advance our HCC platform for use in precision medicine innovation by refining our HCC minipig modelsto recapitulate the molecular phenotype specific to the most common subtype of human HCC. We will conducta drug study with the standard of care systemic therapy sorafenib to determine if our swine model respondscomparably to human patients. Achievement of these aims will help validate our novel minipig platform andsegway into future studies (1) evaluating the safety and efficacy of molecularly targeted therapies drug deliverydevices and tumor embolization ablation and cryotherapeutic technologies (2) developing novel imagingmethods (3) studying processes of tumorigenesis and (4) identifying biomarkers for early diagnosis andtherapeutic strategies. The minipig HCC platform will bring innovative approaches to HCC translating resultspreclinical studies to improved patient outcomes in the clinic by bolstering clinical trial success rates in a cost-effective and time-efficient manner. In Phase II work these models will be refined and developed in the contextof relevant co-morbidities such as underlying liver disease and validated in clinical trial-like scenarios as proof ofconcept for commercialization. 342154 +No NIH Category available Attention;Binding;Binding Sites;Biogenesis;Cell Aging;Cell Proliferation;Chromatin;Chromatin Structure;Development;Drosophila genus;Epigenetic Process;Event;Future;Gene Expression;Gene Expression Regulation;Gene Silencing;Genetic;Genetic Transcription;Genomic DNA;Genomics;Goals;Growth;Heterochromatin;Histone H3;Histones;Homologous Gene;Human;Hypermethylation;Inhibition of Cell Proliferation;Investigation;Knowledge;Lysine;Malignant Neoplasms;Mediating;Methods;Methylation;Mitosis;Molecular;Mutation;Oncogenic;Oncoproteins;Organ;Organ Size;Organism;Output;Pathway interactions;Play;Proliferating;Proteins;RAS inhibition;RNA Interference;Regulation;Reporting;Research;Resistance;Role;Sequence Homology;Signal Transduction;Small RNA;System;Therapeutic;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;Untranslated RNA;chromatin modification;epigenetic regulation;fly;histone methyltransferase;histone modification;novel;overexpression;recruit;response;restraint;tumorigenesis Functions of a novel suppressor of oncogenic Ras Project NarrativeEpigenetic alterations including heterochromatin changes are important for cancer development as well astumor suppression but the mechanisms remain unclear. The current project focuses on a novel suppressor ofRas CRIF which may provide an inroad leading to understanding how oncogenic Ras reorganizes chromatinto induce cell proliferation and how heterochromatin formation functions in epigenetic tumor suppression.Understanding how CRIF regulates heterochromatin and counteracts oncogenic signals to resist tumorigenesismay lead to novel epigenetic cancer therapeutics. NCI 10757911 12/22/23 0:00 PAR-20-052 5R03CA277213-02 5 R03 CA 277213 2 "SHARMAN, ANU" 1/1/23 0:00 12/31/24 0:00 ZCA1-TCRB-V(O1)S 1965260 "LI, WILLIS X" Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 79000 NCI 50000 29000 Functions of a novel suppressor of oncogenic RasOncogenic Ras accounts for more than 30% of all human cancers. Ras normally controls mitogenic pathwaysand functions as an on/off switch controlling cell proliferation. Heterochromatin appears to be a form of cellularrestraint in both flies and humans that oncogenic Ras has to overcome to induce cell proliferation. Many tumorsuppressors such as Rb and BRCAs play a role in heterochromatin formation and an inability to formheterochromatin formation itself permits tumorigenesis in response to oncogenic Ras. However howheterochromatin formation counteracts oncogenic Ras and how Ras can overcome heterochromatin-mediatedtumor suppression remain unclear. Understanding how heterochromatin counteracts oncogenic signals andhow oncogenic pathways overcome heterochromatin to induce growth and proliferation may lead to novelepigenetic cancer therapeutics. To investigate the connection from oncogenic mutations to epigenetic alterations we have used Drosophilagenetics to identify new players mediating cellular responses to oncogenic Ras with a particular attention tononconventional Ras signaling components. Among the novel suppressors of oncogenic Ras we found thatCRIF regulates both cell proliferation and heterochromatin formation. The objective of this project is tounderstand the mechanism by which the putative tumor suppressor CRIF antagonizes the effects of oncogenicRas on cell proliferation. The long-term goal of the research is to elucidate how heterochromatin formationfunctions in epigenetic tumor suppression and how oncoproteins reorganize chromatin to induce cellproliferation and tumorigenesis. We hypothesize that CRIF counteracts oncogenic Ras by inhibiting cellproliferation and increasing heterochromatin formation an epigenetic tumor suppression system. In thisproposal we plan to elucidate the molecular functions CRIF in counteracting oncogenic Ras-inducedproliferation and in heterochromatin regulation. Specifically we will investigate how CRIF resist oncogenic Rasin controlling proliferation and the role of CRIF in regulating heterochromatin. Results from these studies willbreak new grounds for investigating the molecular mechanisms underlying the epigenetic effects of oncogenicRas the role of epigenetic dysregulation in cancer development and the role heterochromatin in tumorsuppression. 79000 +No NIH Category available Leveraging implementation science to accelerate adoption of shorter-course radiation for breast and prostate cancer PROJECT NARRATIVEThe proposed research is relevant to public health because it addresses the appropriate use of shorterradiation treatments (called hypofractionation) for breast and prostate cancer a critical step to improvingaccess to high-value patient-centered cancer care. This research proposal will assess variation across theUnited States in adoption of hypofractionation and methodically evaluate and pilot test implementationstrategies to improve adoption of hypofractionation in a community-based clinical practice setting. The resultsof this work will generate fundamental knowledge to inform healthcare leaders and policymakers abouteffective methods to facilitate adoption of evidence-based cancer care thereby improving access to shorterradiation treatments that improve quality of life and reduce the burden of cancer treatment for patients. NCI 10757868 8/8/23 0:00 PA-21-268 7K08CA252640-04 7 K08 CA 252640 4 "RADAEV, SERGEY" 12/1/22 0:00 11/30/25 0:00 Career Development Study Section (J)[NCI-J] 10442558 "GILLESPIE, ERIN FAYE" Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 398 Other Research-Related 2022 263032 NCI 243548 19484 PROJECT SUMMARY/ABSTRACT The overall goal of this NCI K08 career development proposal is to facilitate Dr. Erin Gillespiesdevelopment into an independent investigator in cancer health services research focusing on strategies toenhance quality and evidence-based care in radiation oncology. This proposal focuses on shortening thecourse of radiation from 7-9 weeks to 3-5 weeks (called hypofractionation) which is associated withequivalent cancer control improved patient-reported outcomes and decreased costs in patients with breastand prostate cancer. Nonetheless adoption has been slow. Dr. Gillespies prior work has revealed that theindividual radiation oncologist is highly influential in whether patients with breast cancer receivehypofractionation or a longer course of radiation. The overall hypothesis is that radiation oncologists are the linchpin in radiation treatment decision-making and that implementation strategies that harness behavioral economics will be most likely to impactpractice change. My primary objectives are to 1) identify and characterize positive deviant radiation oncologists(high users of hypofractionation) that will 2) elucidate implementation strategies and associate them withadoption of hypofractionation across various settings and 3) pilot test a multi-pronged strategy that promotesuse of hypofractionation in preparation for a large pragmatic multi-center controlled trial. The rationale thatunderlies the proposed research and training plan is that with new knowledge about the levers that drivephysician decision-making (beyond knowledge gaps) healthcare leaders and policymakers can optimallydesign and implement systems that evoke change. Dr. Gillespie will harness the resources and expertise atMemorial Sloan Kettering Cancer Center where she is a faculty member in the Department of RadiationOncology and the Center for Health Policy and Outcomes. She is also engaged in research in the community-based setting through the MSK Cancer Alliance. Her training plan has a foundation of implementation sciencethat incorporates large dataset analysis mixed methods and behavioral economic theory. In Aim 1 of the proposed study the investigators will analyze a Medicare dataset that includes claimslinked to prescribing radiation oncologist and organization and is supplemented by the AMA Masterfile. Theywill systematically conduct the first-ever evaluation of implementation strategies in radiation oncology usingmixed methods. Lastly in Aim 3 the investigators will develop and pilot test a multi-pronged strategy informedby Aims 1-2 and including audit and feedback. This proposal together with the new skills Dr. Gillespie willacquire will generate new knowledge about the impact of implementation strategies on de-implementation oflong-course radiation key parameters necessary to design optimal strategies to encourage physicians toadopt high value radiation. This will specifically support the development of an implementation strategy that willbe tested in a subsequent prospective randomized trial to assess real world efficacy. 263032 +No NIH Category available 3-Dimensional;Address;Adjuvant Chemotherapy;Adjuvant Therapy;Anthracycline;Automobile Driving;Biopsy;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Cancer Patient;Carbon;Cell Cycle;Cells;Cessation of life;Chemoresistance;Data;Disease;Equilibrium;Face;Generations;Genetic;Goals;Guanosine Triphosphate Phosphohydrolases;Human;Immune system;Immunocompetent;In Vitro;Life;Machine Learning;Maintenance;Malignant Neoplasms;Mathematics;Measures;Mediating;Medical Oncology;Metabolic;Metabolism;Mitochondria;Mus;Neoadjuvant Therapy;Oncogenic;Optic atrophy 1;Organelles;Organoids;Oxidative Phosphorylation;Patient-Focused Outcomes;Patients;Phenotype;Platinum;Play;Population;Process;Protein Dynamics;Proteins;Recurrence;Refractory;Regulation;Residual Neoplasm;Residual state;Role;Scanning Electron Microscopy;Signal Pathway;Structure;Testing;Therapeutic;Tissue imaging;Transmission Electron Microscopy;Transplantation;Tumor Burden;Visualization;chemotherapy;high risk;improved;in vivo;inhibitor;insight;knock-down;malignant breast neoplasm;mitochondrial genome;mitochondrial metabolism;mouse model;mutant;neoplastic cell;novel;patient derived xenograft model;pharmacologic;preference;response;targeted treatment;taxane;therapeutic target;therapy resistant;transcriptomics;treatment response;triple-negative invasive breast carcinoma;tumor;tumor-immune system interactions;tumorigenic Metabolic adaptation in residual triple negative breast cancer following chemotherapy PROJECT NARRATIVEChemoresistance in triple negative breast cancer (TNBC) leads to extremely poor patient outcomes and thereare no approved targeted therapies with which to treat residual tumors that persist following chemotherapy.Based on our preliminary findings that TNBCs rely on mitochondrial metabolism to evade chemotherapy wenow aim to delineate the functional role of mitochondrial structural dynamics in TNBC metabolic adaptations andchemoresistance. Our long-term goal is to therapeutically target regulators of mitochondrial structure in chemorefractory TNBCs. NCI 10757746 11/16/23 0:00 PA-20-185 5R37CA269783-02 5 R37 CA 269783 2 "WILLIS, KRISTINE AMALEE" 12/27/22 0:00 11/30/27 0:00 Tumor Cell Biology Study Section[TCB] 9605655 "ECHEVERRIA, GLORIA VITTONE" Not Applicable 9 NONE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX OVERALL MEDICAL 770303411 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 380311 NCI 252086 128225 ABSTRACTOxidative phosphorylation (oxphos) a mitochondrial energy generation process promotes chemotherapeuticresistance in breast and other cancers. In fact transplantation of mitochondria from tumorigenic cells into non-tumorigenic cells demonstrated these organelles are necessary and sufficient for aggressive phenotypes of triplenegative breast cancer (TNBC) cells. Nearly 50% of TNBC patients treated with neoadjuvant (pre-surgical)chemotherapy (NACT; combined anthracyclines platinums and/or taxanes) will harbor substantial residualtumor burden leading to extremely high risk of recurrence and death4. There are no approved targeted therapiesfor neoadjuvant treatment of non-BRCA-mutant TNBC. Thus there is an urgent need to find ways to eradicateresidual tumor cells. Furthermore the mechanisms driving metabolic reprogramming in chemoresistant TNBCare unclear. Our comparisons of serial pre- and post-NACT patient-derived xenograft (PDX) and human TNBCbiopsies revealed heightened oxphos signatures in residual tumor cells and we demonstrated oxphos is aunique therapeutic vulnerability of residual TNBC. We observe significantly higher protein levels of themitochondrial fusion-driving GTPase optic atrophy 1 (OPA1) in post- vs. pre-NACT TNBC biopsies. Furthermorehigh expression of mitochondrial fusion-driving proteins in breast cancer is associated with poor survival. Theimpact of mitochondrial structure dictated by the balance of mitochondrial fission and fusion on metabolismvaries highly across tumor types. Despite the importance of mitochondria to metabolism no studies haveaddressed how mitochondrial structure impacts metabolic states driving TNBC therapeutic responses. Ourpreliminary data provide evidence that NACT increases mitochondrial fusion and metabolism in vitro and in vivo.We can increase oxphos and NACT resistance in TNBC cells by genetically or pharmacologically perturbingmitochondrial fission with Mdivi-1 a Drp1 inhibitor. Conversely perturbation of mitochondrial fusion withMYLS22 an OPA1 inhibitor decreased oxphos and NACT resistance. We hypothesize OPA1-drivenmitochondrial fusion mediates an NACT-induced metabolic switch to promote chemoresistance in TNBC cells.To address this our specific aims are to: 1) Determine if mitochondrial fusion is responsible for chemotherapy-induced oxphos in TNBC and 2) Target and quantify mitochondrial fusion in residual TNBC mouse models andserial patient biopsies. These results will increase our mechanistic understanding of regulation of themitochondrial life as well as mechanisms driving metabolic adaptations in TNBC. Furthermore our findings willprovide additional metabolic therapeutic targets to overcome chemoresistance in residual TNBCs. 380311 +No NIH Category available 90Y;Applications Grants;CD8-Positive T-Lymphocytes;Cancer Patient;Canis familiaris;Cells;Clinical;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Data;Dendritic Cells;Development;Disease;Disseminated Malignant Neoplasm;Dose;Dose Limiting;Exhibits;External Beam Radiation Therapy;Foundations;Goals;Half-Life;Head and Neck Squamous Cell Carcinoma;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immune response;Immunologics;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Incidence;Infiltration;Interferon Activation;Interferon Type I;Ligands;Linear Energy Transfer;Location;Lymphocyte;Lymphopenia;Malignant Neoplasms;Methods;Micrometastasis;Microscopic;Modality;Modeling;Mus;Mutation;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Positioning Attribute;Predisposition;Production;Property;Proteins;Public Health;Radiation;Radiation therapy;Radioisotopes;Radionuclide therapy;Recurrence;Resources;Site;Spatial Distribution;Stimulator of Interferon Genes;Surface;T cell infiltration;T-Lymphocyte;Therapeutic;Tissues;Toxic effect;Training;Translations;Treatment Cost;Treatment Protocols;Tumor Immunity;Tumor Promotion;Universities;Wisconsin;analog;anti-CTLA4;anti-PD-L1;anti-tumor immune response;cancer therapy;cancer type;checkpoint therapy;chelation;comparative;exhaust;exhaustion;experimental study;immune cell infiltrate;immunoregulation;improved;insight;melanoma;mouse model;neoantigens;neoplastic cell;novel;novel strategies;particle;physical property;preclinical study;prevent;professor;radiation delivery;radiological imaging;receptor;recruit;research clinical testing;response;synergism;treatment response;tumor;tumor heterogeneity;tumor microenvironment Targeted radionuclide therapy for tumor immunomodulation and enhancing immunotherapy response Project NarrativeCancer is increasingly becoming a larger public health burden with rising incidence of many cancer types andrapidly rising treatment costs worldwide necessitating development of new effective cancer therapies. We aredeveloping a new approach representing a dramatic shift in the treatment of metastatic cancer utilizing immuneresponses to recognize and destroy cancer (known as immunotherapy) in combination with systemicallyadministered radiation therapy known as targeted radionuclide therapy (TRT). This grant application proposesexperiments that will deepen our mechanistic understanding of the dynamic radionuclide-specific effects of TRTon tumor cells immune cells and anti-tumor immunity with potential for the results to expand treatment optionsfor metastatic cancers in the U.S. and abroad. NCI 10757706 12/1/23 0:00 PA-21-049 5F30CA268780-03 5 F30 CA 268780 3 "BIAN, YANSONG" 1/1/22 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 14090025 "KERR, CAROLINE PAULA ANNE" Not Applicable 2 RADIATION-DIAGNOSTIC/ONCOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 44425 NCI 44425 0 Project Summary/AbstractWe aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modalityapproach to stimulate and diversify an endogenous anti-tumor immune response at all tumor sites to recognizeand destroy tumor cells in a manner that will prevent recurrence and enable long-term cancer free survival.Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1) are a class of immunotherapies that modulate immunetolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells andthereby overcoming T cell inhibition or exhaustion. In patients with immunologically hot tumors characterizedby a pre-existing but exhausted anti-tumor immune response ICIs can restore efficacy to the anti-tumor immuneresponse sometimes resulting in complete and durable tumor regression. However ICIs have not shown clinicalbenefit in the treatment of immunologically cold cancers that are characterized by low levels of T cell infiltrateand low mutation burden resulting in few mutation-created neo-antigens. To overcome immunotherapy treatmentbarriers posed by immunologically cold tumors we propose to combine systemic delivery of ICIs with systemicdelivery of radiation by targeted radionuclide therapy (TRT). To date nearly all approaches to combiningradiation and immunotherapy have used external beam radiotherapy (EBRT) which promotes tumor immunecell infiltration through activation of type I interferon (IFN) responses. Administration of EBRT to multiple tumorsites or to the whole body (to target radiographically occult or microscopic disease) would result in prohibitivetoxicity including lymphopenia. TRT is a systemic method of delivering a therapeutic radionuclide to a tumorwhich poses an alternative option for delivery of immunomodulatory radiation to metastatic tumor sites withoutcausing immunosuppression. The Weichert lab at the University of Wisconsin-Madison has developed a novelclass of TRT known as NM600 an alkylphosphocholine analog that is selectively taken up and retained in nearlyany tumor type in any location. Our broad hypothesis is that unique physical properties of radionuclides (e.g.emission type linear energy transfer half-life tissue range) differentially impact immunomodulation by TRT. Inthis study the immunomodulatory capacity of alpha- (225Ac) and beta- (90Y) particle emitting radionuclides will becompared directly. In a project that builds upon the ongoing collaborative progress of the Morris and Weichertlabs we will now determine the radionuclide-specific potency of combining TRT with immunotherapy to enhancethe immune response against immunologically cold tumors. In murine models we will: 1) expand on preliminarydata showing potent synergy with the combination of TRT and ICI 2) evaluate therapeutic mechanisms of TRTand ICI using the intrinsic properties of 225Ac- and 90Y-NM600 focusing on type I IFN response activation and 3)investigate potential enhanced tumor responses with the combination of two distinct radionuclides with ICI. Theinsights and treatment regimens developed in these studies should enable rapid translation to clinical testing inpatients and potentially for any type of metastatic cancer. 44425 +No NIH Category available Aftercare;Alleles;BRAF gene;Biological Models;Blood;Cancer Detection;Cancer Patient;Clinical;Codon Nucleotides;DNA;DNA Mutational Analysis;DNA Sequence;Detection;Development;Diagnostic tests;Dideoxy Chain Termination DNA Sequencing;Drug Targeting;Effectiveness;Eligibility Determination;Epidermal Growth Factor Receptor;FDA approved;Foundations;Future;KRAS2 gene;Malignant Neoplasms;Managed Care;Medicine;Methods;Monitor;Mutate;Mutation;Mutation Analysis;Mutation Detection;Patients;Performance;Pharmaceutical Preparations;Phase;Plasma;Recovery;Reproducibility;Sampling;Serum;Small Business Innovation Research Grant;Specificity;Specimen;System;Systems Analysis;Technology;Testing;Tissue Sample;Tissues;Tumor Tissue;Validation;Work;cancer care;clinical application;commercialization;companion diagnostics;cost;detection test;digital;improved;innovation;liquid biopsy;novel;success;targeted treatment;technology platform;tumor;validation studies Development of An Innovative TEE Technology for Mutation Detection NarrativeThe objective of this SBIR Phase II project is to further develop a breakthroughTEE technology and validate TEE-based tests for clinical use. NCI 10757697 9/18/23 0:00 PA-22-176 1R44CA284965-01 1 R44 CA 284965 1 "LOU, XING-JIAN" 9/18/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CDPT-V(13)B] 79538945 "DENG, QIPAN " "GUO, BAOCHUAN " 13 Unavailable 144259343 ETKMDA959PF6 144259343 ETKMDA959PF6 US 41.358354 -81.416503 10000553 "GLC BIOTECHNOLOGY, INC." Hudson OH Domestic For-Profits 44236 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1071571 NCI 470173 531295 Abstract The objective of this project is to further develop a breakthrough Toehold-Enrichment-Extraction (TEE) technology and validate TEE-based tests for use in cancer detection and caremanagement. TEE is a novel DNA extraction method. Unlike conventional extraction methodsTEE extracts mutated DNA while enriching it with high recovery. Moreover unlike current PCR-based enrichment methods TEE enriches mutated DNA without altering original DNA sequences.We have shown that TEE could enrich mutated DNA by as much as 1000 fold. Therefore whenTEE is used to extract DNA for a mutation detection test it significantly increases analyticalsensitivity of the test leading to accurate detection of mutated DNA at a much lower concentrationlevel which could not be achieved if a conventional method is used to extract DNA. To illustratewhen a conventional method is used to extract DNA Sanger sequencing cannot detect mutatedDNA if its concentration is less than 20%. In contrast when TEE is used to extract mutated DNAit enables Sanger sequencing to detect 0.1% mutated DNA. In other words Sanger-sequencingbecomes as sensitive as digital PCR or NGS when we incorporate TEE into Sanger sequencing(we term this combination TEE-Sanger sequencing) for mutation analysis. Furthermore we havedemonstrated that TEE-Sanger sequencing could detect mutated DNA from clinical specimen likeFFPE tumor tissue and blood (serum) samples indicating that TEE-based testing is compatiblewith clinical applications. Since TEE is a DNA extraction method it can replace conventional methods to extractDNA for mutation analysis. Moreover TEE is not only a breakthrough technology but also aplatform on which various TEE-based tests can be developed for different clinical applications.Inspired by the success of our preliminary study and potential of the TEE technology we proposethis SBIR Phase II project to further study the TEE technology providing a strong foundation forits commercialization. This project has four specific aims. 1071571 +No NIH Category available Affect;Binding;Breast Cancer Cell;Breast Cancer cell line;Breast cancer metastasis;Cell Nucleus;Cells;Cellular biology;Characteristics;Clinical;Communication;Core Facility;DNA Methylation;Data;Dependence;Disabled Persons;Down-Regulation;Drug resistance;Enzymes;Epigenetic Process;Excision;Fatty Acids;Focal Adhesion Kinase 1;Funding;Genes;Genetic Transcription;Glucose;Glutamine;Histone Deacetylase;Histone Deacetylase Inhibitor;Laboratories;Leptin;Malignant Neoplasms;Mechanics;Mediating;Messenger RNA;Metabolic;Metabolic Activation;Mitochondria;Modeling;Modification;Molecular;Molecular Biology;Mus;Mutation;Neoplasm Metastasis;Nuclear;Outcome;Oxidative Phosphorylation;PTK2 gene;Pancreas;Pathway interactions;Patient-derived xenograft models of breast cancer;Phosphorylation;Phosphotransferases;Play;Post-Translational Regulation;Prognosis;Protein Dephosphorylation;Protein Kinase;Proteins;Proto-Oncogenes;Publications;Publishing;Regulation;Reporting;Research;Research Personnel;Resources;Role;SH3 Domains;SRC gene;Secure;Signal Pathway;Signal Transduction;Squamous cell carcinoma;Subgroup;Transcriptional Regulation;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;United States National Institutes of Health;Validation;Xenograft procedure;cancer subtypes;clinically significant;epigenetic regulation;experience;fatty acid oxidation;histone modification;hormone receptor-positive;in vivo;inhibitor;knock-down;malignant breast neoplasm;metabolomics;ovarian neoplasm;oxidation;patient derived xenograft model;predict clinical outcome;promoter;small hairpin RNA;src-Family Kinases;translational study;triple-negative invasive breast carcinoma;tumor;tumor progression;tumor xenograft;tumorigenesis;v-src Oncogenes Disabled-2 in the metabolic regulation of oncopathways Disabled 2 (DAB2) is one of the few proteins that are known for removing the phosphorylation of c-Srcprotooncogene and Src pathway is frequently activated in triple negative breast cancer (TNBC). We havepreviously reported that mitochondrial reprogramming to fatty acid oxidation (FAO) is a key regulator ofSrc activation in TNBC but the mechanism of regulation is not understood. Since our current preliminarydata suggest that FAO regulates DAB2 expression in TNBC this project will evaluate the significanceDAB2 in the metabolic activation of Src in TNBC. NCI 10757684 1/3/24 0:00 PAR-20-052 5R03CA277079-02 5 R03 CA 277079 2 "LUO, RUIBAI" 1/9/23 0:00 12/31/24 0:00 ZCA1-SRB-2(O1)S 10027528 "KAIPPARETTU, BENNY ABRAHAM" "PARK, JUNHYOUNG " 9 GENETICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 80000 NCI 50000 30000 Abstract: Compared to hormone receptor (HR) positive breast cancer (BC) basal or triple negative BC (TNBC)suffers a poor prognosis and limited treatment options because of the lack of understanding of its driver signalingpathways. Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus.We have previously published that TNBC has energy dependency to mitochondrial FA -oxidation (FAO). FAOinduces tumor and metastatic potential of TNBC. Src oncopathway is one of the most frequently upregulatedpathways in TNBC and a critical player of TNBC metastasis. Like most protein kinases Src family kinases (SFKs)require phosphorylation within a segment of the kinase for its full catalytic activity. Src is mainly phosphorylated(pSrc) at either Y419 (active state) or Y530 (inactive state). Compared to most BC subgroups pSrc (Y419) issignificantly upregulated in TNBC subgroups. However how pSrc oncopathway is activated in TNBC was largelyunknown. In this context our lab made a breakthrough discovery that in TNBC FAO regulates thephosphorylation of Src at Y419 without any major impact on the phosphorylation of Y530. Though we haveshown that FAO inhibition decreases the pSrc (Y419) so far the mechanism of this critical regulation is not fullyunderstood. Only very fewer proteins have been proposed for the removal of phosphorylation from pSrc (Y419).Disabled-2 (DAB2) is known to bind at SH3 domain of Src and directly suppress the Y419 phosphorylation. Thisdephosphorylation results in the inactivation for Src without affecting the phosphorylation at Y530. Previousstudies have suggested that the epigenetic transcriptional downregulation of DAB2 is a major determinant ofcancer progression and clinical outcome. FA and FAO metabolites are known to epigenetically modify nucleargenes. Our strong preliminary data using different models suggest that the FAO downregulate the DAB2 mRNAin TNBC. Moreover HDAC inhibitors activate DAB2 mRNA in TNBC cells. All these suggest that FAO may beepigenetically regulating DAB2. Thus in this project we will evaluate how FAO-mediated retrograde signalingepigenetically modify the tumor suppressor DAB2. We will also analyze if such regulation of DAB2 is critical inthe FAO-mediated activation of Src oncopathway in TNBC. In Aim-1 FAO-mediated transcriptional regulation ofDAB2 will be confirmed using TNBC cell lines and already available tumor tissues collected after long-termtreatment with FAO inhibitors in mice bearing TNBC patient-derived xenograft (PDX) models. We also haveTNBC cells after stably knocking down FAO rate-limiting enzymes. Aim-2 will analyze the epigeneticmodifications of DAB2 promoter after metabolic modulation. Overall this will be one of the first mechanicalstudies in TNBC to show how the mitochondrial retrograde regulation modulate a tumor suppressor gene tocontrol a major oncopathway via its post-translational regulation. The investigator team is well experienced inthe proposed studies and supported by other core facilities. Strong preliminary data and previous publicationssupport the feasibility of this project. 80000 +No NIH Category available Acetylation;Adjuvant Therapy;Biological Markers;Biology;Breast;Breast Cancer Cell;Cell physiology;Cells;Cellular Metabolic Process;ChIP-seq;Chemicals;Cisplatin;Clustered Regularly Interspaced Short Palindromic Repeats;Compensation;Complex;Data;Doxorubicin;Drug Metabolic Detoxication;Endocrine;Equilibrium;Estrogen receptor positive;Event;Exhibits;Exposure to;Fatty acid glycerol esters;Fulvestrant;Genes;Grant;Knock-out;Lead;Link;Lysine;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Measurement;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Modeling;Nature;Oncogenic;Pathway interactions;Peroxidases;Phenotype;Physiological;Post-Translational Protein Processing;Property;Publications;Reactive Oxygen Species;Recurrence;Reporter;Resistance;Risk;SOD2 gene;Selective Estrogen Receptor Modulators;Signal Transduction;Sirtuins;Stains;Subgroup;Superoxides;Systemic Therapy;T47D;Tamoxifen;Techniques;Testing;Time;Tissue Microarray;Tumor Promoters;Woman;Work;Xenograft Model;breast malignancies;cancer cell;high risk;hormone therapy;in vivo;knock-down;mammary;mimetics;mitochondrial metabolism;monomer;mouse model;mutant;neoplastic cell;new therapeutic target;novel;patient derived xenograft model;permissiveness;prevent;programs;public database;response;small hairpin RNA;stem;stem cell biomarkers;stem-like cell;stemness;targeted treatment;therapy resistant;tissue culture;transcriptome sequencing;tumor;tumorigenesis;tumorigenic MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies NARRATIVEWe have identified a mitochondrial signaling axis centered on MnSOD-K68 which when its normalacetylation status is altered disrupts cell metabolism leading to aberrant-ROS levels and a tumorpermissive phenotype (Zhu et al 2019). Interestingly emerging data suggests that the disruptionof mitochondrial metabolism including aberrant ROS levels is an increasingly acceptedmechanism of oncogenicity due to an enrichment of stem-like cells. Thus it is proposed that whenMnSOD-Ac exists outside of its normal physiological context it disrupts cellular and mitochondrialmetabolism and promotes lineage plasticity properties (or tumor cell stemness) leading to anoncogenic permissive and TamR phenotype and is a potential target for new therapies. NCI 10757655 11/20/23 0:00 PA-19-056 5R01CA253678-04 5 R01 CA 253678 4 "WILLIS, KRISTINE AMALEE" 1/9/21 0:00 12/31/25 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7573491 "GIUS, DAVID " Not Applicable 20 RADIATION-DIAGNOSTIC/ONCOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 331347 NCI 213772 117575 SUMMARYThe dysregulation of mitochondrial networks responsible for maintaining normal metabolism is anestablished hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolismleads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling thatdisrupts metabolic balance which can establish a tumorigenic and/or therapy resistant phenotype.In this regard a subgroup of estrogen receptor-positive (ER+) breast malignancies which exhibitincreased ROS levels and a high risk of recurrence due to endocrine therapy has been identified.We recently found a novel mitochondrial signaling axis centered on manganese superoxidedismutase (MnSOD) which when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered disruptscell metabolism leading to aberrant ROS levels (Zhu Nature Commun. 2019). In addition breastcancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2(known to promote stemness-like properties) increased SOX2 and Oct4 (two established stem cellbiomarkers) leading to oncogenicity and pan resistance phenotype (PanR) to agents commonlyused in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumorsto exhibit a lineage plasticity phenotype. Based on our new data our recent publication (Zhu et alNature Commun. 2019) and work by others it is hypothesized that dysregulated MnSOD biologydue to aberrant/increased MnSOD-K68-Ac levels disrupts normal cellular and mitochondrialmetabolism. This initiates metabolic reprogramming via increased levels of HIF2 leading to a cellstemness-mediated tumor-permissive and/or PanR phenotype. Thus we seek to further explore howMnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype leading tooncogenicity and/or PanR. Finally will GC4419 exposure a chemical SOD detoxification mimicreverse the oncogenic and/or PanR phenotypes? 331347 +No NIH Category available 3-Dimensional;Acids;Address;African American;Air;Antibodies;Biological Markers;Blood Tests;Blood specimen;CA-125 Antigen;Cancer Control;Carcinoma;Chemicals;Clinical;Collection;Colonoscopy;Colorectal Cancer;Cryopreservation;Detection;Development;Devices;Diagnosis;Diagnostic Procedure;Disease;Disparity;Early Diagnosis;Eligibility Determination;Ensure;Enzymes;Exclusion;Fecal occult blood;Feces;Fingers;Geographic Locations;Goals;Guaiac;Guidelines;Heme;Hemoglobin;Hemorrhage;Hispanic Populations;Home;Hygiene;Immunoassay;Incidence;Income;Intestines;Investigation;Life;Low Income Population;Low income;Malignant Neoplasms;Mass Spectrum Analysis;Medical;Methods;Microfluidic Microchips;Minority;Modernization;Monitor;Neighborhood Health Center;Neoplasms;Outcome;Paper;Pathology;Patients;Performance;Persons;Plasma;Play;Polymers;Population;Predisposition;Preventive;Preventive service;Proteins;Public Health;Race;Reaction;Recommendation;Reporting;Research;Research Project Grants;Role;Sampling;Screening procedure;Sensitivity and Specificity;Serum;Signal Transduction;Specific qualifier value;Specificity;Statistical Algorithm;System;Techniques;Technology;Testing;Time;Tumor Antigens;Underserved Population;Uninsured;United States;Vulnerable Populations;Whole Blood;accurate diagnostics;biobank;biomarker selection;cancer biomarkers;cancer care;cancer health disparity;care systems;catalyst;colon cancer patients;colorectal cancer screening;cost;design;detection platform;diagnostic strategy;diagnostic value;experience;improved;innovation;interest;mass spectrometer;method development;minimally invasive;models and simulation;mortality;multiplex detection;novel;novel strategies;operation;outreach;outreach program;photosystem;point of care testing;polymerization;portability;programs;protein biomarkers;prototype;regenerative;screening;screening program;self testing;survival outcome;underserved community Multiplexed Paper-Based Blood Test for Early-Stage Colorectal Cancer Screening Project NarrativeThis project proposes to develop a paper-based blood test through the multiplexed analysis of five colorectalcancer biomarkers which are expected to provide accurate early detection when combined with our signalamplification strategy. The proposed research project is relevant to public health because it seeks to develop amore sensitive low-cost and minimally invasive blood test to improve colorectal cancer screening rates inminorities uninsured and low-income patients. Upon completion this project will provide community healthcenters with unique preventive and diagnostic capability that will enable them to expand their reach to all eligiblepatients. NCI 10757644 11/30/23 0:00 PAR-20-292 5R21CA270727-02 5 R21 CA 270727 2 "ZHU, CLAIRE" 12/26/22 0:00 11/30/24 0:00 ZCA1-SRB-X(O1)S 12410769 "BADU-TAWIAH, ABRAHAM " Not Applicable 3 CHEMISTRY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF ARTS AND SCIENCES 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 160508 NCI 105188 55320 Project SummaryPreventive services have been emphasized as essential components of the medical care system. However thedisparities in cancer incidence and mortality rates experienced by vulnerable populations are evident in rates ofscreening for colorectal cancer (CRC). While community health centers can play an important role in addressingthese disparities their current operations are not set up to ensure that every eligible patient receives timely CRCscreening. The current patient self-test relies on a fecal immunochemical test that is plagued with low rates ofpositive early cancer identification and difficulty in excluding non-neoplastic causes of intestinal bleed. Until alow-cost simple and highly accurate diagnostic method is developed screening rates in minorities uninsuredand low-income populations will likely remain low. The long-term goal of this project is to improve the accessibilityof CRC screening through the development of a new on-demand diagnostic approach that has potential toenable self-testing at home followed by signal development and diagnosis after sending the test to a centralfacility (for example by mail). The objective of the current R21 application is to pre-validate a set of five CRCcancer antigen biomarkers through their multiplexed detection on a 3D paper-based microfluidic device in CRCpatients as well as to test the possibility of using a self-regenerative photo-catalyst to amplify mass spectrometry(MS) signals for early CRC detection. The test is designed to be stable enabling storage under ambientconditions a condition critical for successful remote sampling. The test is also rapid enough to enable point-of-care testing on a portable mass spectrometer. Although the proposed detection strategy is based onimmunoassay the use of a photoredox catalyst to amplify MS signal is novel. Traditional immunoassay tests usecolorimetric detection via enzyme amplification necessitating both cold storage and analysis of the once-initiatedcolorimetric signal within a specified time to ensure the validity of the test. This research program will follow threespecific aims: (1) using 356 CRC patient biorepository samples to validate the five selected biomarkers CEACA199 CA242 CA125 CA153 and to optimize their multiplexed detection via paper-based immunoassay (2)investigation and selection of a photosystem for mass spectrometry signal amplification and (3) using anindependent set of patient samples collected in the field to validate proposed method through the developmentof a prototype 3D paper-based microfluidic device for CRC detection in whole blood samples. The project isinnovative because it combines new levels of simplicity and practicality modest levels of cost and a centralizeddetection strategy which will redefine the breadth of application and performance/cost ratio for accurate CRCdetection in underserved communities. The proposed research is significant because it has potential to improvecancer care among all populations irrespective of their race geographic location or income. 160508 +No NIH Category available Address;Affect;Aging;Amino Acids;BRCA1 gene;Base Excision Repairs;Brain;Brain Injuries;Catalytic Domain;Cell Aging;Cell Death;Cell Line;Cell Survival;Cells;DNA;DNA Binding;DNA Damage;DNA Repair Pathway;DNA lesion;DNA replication fork;Dangerousness;Development;Dimerization;Divalent Cations;EXO1 gene;Electrostatics;Environment;Enzymes;Eukaryota;Excision;Excision Repair;Exposure to;Face;Genome;Genome Stability;Genomic Instability;Glioblastoma;Glioma;Human;Hypoxia;Leisures;Length;Lesion;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Minority;Mutation;Neoplastic Cell Transformation;Nucleotides;Organ;Organism;Oxidative Stress;Oxygen;Pathway interactions;Physiological;Play;Proteins;Reporting;Resected;Role;Site;Stress;Structure;Structure-Activity Relationship;Testing;X-Ray Crystallography;base;chelation;differential expression;dimer;endonuclease;homologous recombination;in vitro Assay;in vivo;inhibitor;insight;monomer;new therapeutic target;nuclease;oxidation;oxidative DNA damage;oxidative damage;public health relevance;rational design;recombinational repair;recruit;repaired;replication stress;stressor;tumor EEPD1 Repair of Stressed Replication Forks PUBLIC HEALTH RELEVANCE STATEMENTJust by using oxygen to generate energy cells sustain daily oxidative DNA damage. This oxidative DNAdamage is especially dangerous at replication forks where the damage must be repaired before replicationmakes the oxidative mutations permanent. EEPD1 mediates a unique pathway for the cell to repair thisdamage that brain cancers subvert for their survival. NCI 10757643 12/8/23 0:00 PA-20-185 5R01CA205224-07 5 R01 CA 205224 7 "WEINREICH, MICHAEL DALE" 6/1/16 0:00 12/31/27 0:00 Radiation Therapeutics and Biology Study Section[RTB] 1872740 "HROMAS, ROBERT A" Not Applicable 20 INTERNAL MEDICINE/MEDICINE 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 348750 NCI 225000 123750 PROJECT SUMMARYSince DNA bases are continuously damaged by oxidation cells have evolved a robust pathway to repair thistype of DNA base damage termed base excision repair (BER). Most oxidative damage can be repaired at thecells leisure except at a replication fork where oxidative damage can cause replication fork collapse.Collapsed forks are a far greater danger to the cell than oxidative damage elsewhere in the genome but themechanism of BER at oxidatively damaged replication forks is less well understood compared to BERelsewhere. The 5 abasic endonuclease APE1 plays a key role in BER repair at oxidatively stressed replicationforks. However there is significant evidence for an alternative pathway; some cancers lack APE1 yet replicatewithout difficulty and several aging organs lose expression of APE1 without deleterious effects. We previouslyfound that the 5 endonuclease EEPD1 can initiate homologous recombination (HR) repair of stressedreplication forks by cleaving the lagging parental strand of a stalled fork and loading EXO1 for 5 end resectionin a BRCA1-indepednent manner. In further characterization of EEPD1 we found that it has 5 abasicendonuclease activity similar but not identical to APE1. EEPD1 can replace APE1 in BER assays in vitro and invivo. EEPD1 depletion also harmed the repair and restart of oxidatively damaged replication forks. EEPD1depletion or deletion also resulted in significantly decreased cell survival in the presence of oxidative oralkylative stressors which cause DNA lesions repaired by BER. EEPD1 has a high differential expression inglioblastoma (GBM) compared to adjacent normal brain or other cancers. GBM exist in a hypoxic environmentand are sensitive to oxidative injury and EEPD1 is required for the survival in every GBM cell line tested. OurSEC-MALS studies found that EEPD1 exists as a dimer in physiologic solution. We resolved the X-raycrystallographic structure of the EEPD1 nuclease domain to 3.0 . The tertiary structure of the EEPD1monomer is similar to the AlphFold2-predicted EEPD1 nuclease domain structure. The EEPD1 crystalstructure also has similarities to and distinctions from the APE1 structure. Thus EEPD1 represents a uniqueopportunity to gain insight into the structural basis for abasic endonuclease activity and how this activitypromotes repair of oxidatively-stressed replication forks. Understanding the structure-function relationship ofEEPD1 will lead to regions to target for development of rationally designed inhibitors for which we havecandidate compounds. This is especially important in GBM for which new therapeutic targets are sorelyneeded. This renewal application will assess how the structure of EEPD1 functions to repair of replication forksstressed by oxidative DNA damage in GBM cells by addressing three questions: 1) Is EEPD1 dimerizationessential for its activity? 2) What EEPD1 domains mediate its 5 abasic endonuclease activity? 3) Whatare the distinct roles for EEPD1 versus APE1? 348750 +No NIH Category available Address;Adverse event;Biological Markers;Blood;Bone Marrow;Cancer Patient;Cell Separation;Cells;Clinical;Clone Cells;Comprehensive Cancer Center;Cryopreservation;DNA;DNA Methylation;Data;Development;Disease;Disease remission;Drug Costs;Epigenetic Process;Evaluation;Fingerprint;Funding;Generations;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Hematopoiesis;Human;Immune;Immune response;Immune system;Immunologic Markers;Immunologic Techniques;Immunologics;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Individual;Inflammation;Knowledge;Leukocytes;Libraries;Lymphocyte;Malignant Neoplasms;Measures;Mediating;Methodology;Methylation;Mutation;Myeloid-derived suppressor cells;Myelopoiesis;Nature;Nivolumab;Patient-Focused Outcomes;Patients;Pattern;Peripheral;Phenotype;Population;Prediction of Response to Therapy;Predictive Value of Tests;Production;Prognosis;Prognostic Marker;Property;Prospective Studies;Recurrence;Recurrent disease;Reproducibility;Retrospective Studies;Risk;Role;Site;Standardization;Stratification;Therapeutic Agents;Time;Tumor Immunity;Unresectable;Work;biomarker identification;blood treatment;cancer type;cell type;checkpoint therapy;chemotherapy;clinical application;clinical decision-making;cohort;cost effective;epigenome-wide association studies;granulocyte;immune checkpoint blockade;immune modulating agents;immunological status;immunomodulatory therapies;improved;in vivo;innovation;methylomics;monocyte;neutrophil;novel;novel marker;novel therapeutics;patient response;pembrolizumab;peripheral blood;phenotypic biomarker;predictive marker;prognostic;prognostic value;programmed cell death ligand 1;prospective;response;response biomarker;survivorship;tool;treatment duration;treatment response;tumor;tumor microenvironment DNA-based Immune Phenotyping in HNSCC for Biomarkers of Response to Immunotherapy PROJECT NARRATIVEThis application seeks to develop biomarkers of response to immunotherapy in head and neck cancers. Wepropose to develop unique biomarkers that identify the cells that inhibit the immune attack of the cancer andpredict which patients will and will not benefit from immune therapy as well as guide development of noveldrugs based on detailed knowledge of immune phenotypes in patients who respond poorly to treatment. NCI 10757635 12/22/23 0:00 PA-19-056 5R01CA253976-04 5 R01 CA 253976 4 "BHARTI, SANITA" 1/1/21 0:00 12/31/25 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 1934274 "KELSEY, KARL TIMOTHY" "CHRISTENSEN, BROCK CLARKE" 1 PUBLIC HEALTH & PREV MEDICINE 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF PUBLIC HEALTH 29034202 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 598303 NCI 493382 104921 PROJECT SUMMARY/ABSTRACTHead and Neck Squamous Cell Carcinomas (HNSCCs) are devastating upper airway tumors that are associatedwith an immunosuppressive network impacting the tumor microenvironment bone marrow and the peripheralblood compartments. The development of novel biomarkers of cancer immunity have not kept pace withbreakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormalhematopoiesis and the production of immunosuppressive leukocyte populations. Nor have biomarkers kept pacewith clinical indications for use of immunomodulatory therapies. Here we address the gap in clinically applicableimmune biomarkers by first developing unique immuno-methylomic tools to identify aberrant peripheral immunecell populations followed by the application of such tools for studying HNSCC survivorship. The FDA recentlyapproved pembrolizumab with or without chemotherapy as a first-line treatment for metastatic or unresectablerecurrent disease which is poised to dramatically increase the number of patients receiving immunotherapy forHNSCC further underscoring the critical need to identify biomarkers of response to treatment even before defacto issues of drug cost. Further recent successful trials of immunomodulatory agents treating late stageHNSCC reveal that there is a crucial role for the immune system in disease survival and prognosis. Tounderstand and quantify immune status we propose to apply novel DNA methylation-based immunephenotyping biomarkers that will define the immune suppressive state and allow us to intensively study itsrelationship to immunotherapy treatment response in HNSCC. The proposed study will draw from twoindependent comparable prospectively collected patient cohorts at NCI-designated Comprehensive CancerCenters. Results from single cell tracing approaches to follow clones of cells in-vivo in cancer patients showeddramatic evidence that the intrinsic ability to attract new immune cells to the tumor results in improved checkpointblockade activity. This finding strongly supports our approach to identifying biomarkers of checkpoint blockaderesponse through measures in the peripheral blood. As new immunotherapies are developed for HNSCC it iscrucial to mediate the effects of the hosts compromised immune system. The new generation of epigenetictechniques for immune profiling will provide biomarkers that are useful both in assessing immune status and inaddressing mechanisms of immune modifiers. 598303 +No NIH Category available Address;Admission activity;Award;Basic Science;Biomedical Research;CCL7 gene;Career Mobility;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Community Networks;Community Outreach;Complement;Comprehensive Cancer Center;Core Facility;Data;Development;Diverse Workforce;Doctor of Philosophy;Education Projects;Educational Activities;Educational process of instructing;Enrollment;Environment;Ethnic Origin;Faculty;Feedback;Fellowship;First Generation College Students;Fostering;Fox Chase Cancer Center;Funding;Goals;Grant;Growth;Health;Health Disparities Research;Health Promotion and Education;Inequity;Institution;Interdisciplinary Study;Malignant Neoplasms;Measurable;Medical;Mentors;Mentorship;Minority Groups;Minority Health Research;Minority-Serving Institution;Pathway interactions;Pilot Projects;Population;Population Sciences;Positioning Attribute;Postdoctoral Fellow;Qualifying;Research;Research Infrastructure;Research Institute;Research Personnel;Research Project Grants;Research Project Summaries;Research Support;Research Training;Rotation;Science;Special Population;Students;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;Work;anticancer research;cancer education;cancer health disparity;career;career development;cohort;college;community based participatory research;community engaged research;community partnership;design;education research;experience;graduate student;health disparity;innovation;inter-institutional;medical schools;minority communities;multidisciplinary;novel;population based;pre-doctoral;professional students;programs;racial minority;skills;student mentoring;systemic barrier;training opportunity;undergraduate student;underrepresented minority student;underserved community;underserved minority;university student Research Education Core n/a NCI 10757597 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 9/18/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5088 2084863 "KLEIMAN, FRIDA E" Not Applicable 12 Unavailable 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY Domestic Higher Education 100655024 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 207168 132800 74368 PROJECT SUMMARY Research Education Core TUFCCC: Dr. Carolyn Fang (Co-Leader) HC: Dr. Olorunseun Ogunwobi The Research Education Core (REC) builds upon our successful 5-year U54 Partnership and rigorous multidisciplinary training environment at Temple University-Fox Chase Cancer Center (TUFCCC) and Hunter College (HC). The overarching goal of the REC is to promote inclusive excellence in the training and professional and scientific development of Early-Stage Investigators (ESIs) and students through intensive mentored experiences in cancer health disparities research. The REC leverages exceptional institutional strengths in training and research education across TUFCCC and HC the outstanding core facilities of an NCI- designated Comprehensive Cancer Center our combined interdisciplinary research infrastructure in population clinical translational and basic sciences and a diverse student population across both institutions. In addition to research training the Research Education Core will nurture and mentor students throughout their studies infuse 21st century skills of collaboration and communication and develop professional career opportunities. The overarching goal of the Research Education Core is to support educational activities that complement and enhance the training of a diverse workforce to meet the nations cancer research needs. To achieve this goal the Research Education Core will address the following specific aims: Aim 1. Provide mentorship and research support for 8 diverse ESIs to enhance career development and facilitate their transition to independent investigators in cancer disparities research. The two-year fellowship will culminate with an application for external funding to support the trainees transition into an independent investigator. Aim 2. Implement an enhanced 10- week Summer Cancer Research Institute (SCRI) for 15 undergraduate and graduate students in biomedical or population cancer research per year (75 students over 5 years). Our successful SCRI program which offers unique training opportunities for undergraduate and graduate students in biomedical clinical or population- based cancer research will be expanded from 10 to 15 trainees per year (a 50% increase). Aim 3. Facilitate academic-community research opportunities to support the conduct of culturally appropriate cancer research in partnership with underserved minority communities and populations. In collaboration with the COC and key community partners the REC will establish a semester-long rotation for ESIs and other trainees to foster greater skills in conducting community-engaged research to address health disparities. These novel training opportunities offered through collaborative academic-community partnerships will provide innovative hands-on fieldwork experiences for trainees. In sum the Research Education Core will promote inclusive excellence in building a diverse workforce by breaking systemic barriers (including structural inequities and limited access to mentored training) building a sense of community and offering a sustainable pathway for impacting change and advancing the careers of ESIs and other trainees working in cancer health disparities. +No NIH Category available Address;Adopted;Advanced Malignant Neoplasm;Area;Benchmarking;Cancer health equity;Clinical;Collaborations;Communication;Communities;Community Outreach;Consensus;Consensus Development;Data;Data Collection;Development;Doctor of Philosophy;Education and Outreach;Ensure;Equity;Evaluation;Feedback;Foundations;Fox Chase Cancer Center;Funding;Goals;Grant;Grant Review;Health Disparities Research;Health Policy;Health system;Impact evaluation;Individual;Information Dissemination;Infrastructure;Institution;Leadership;Logic;Measures;Mentors;Mentorship;Methods;Minority Groups;Modeling;Monitor;Online Systems;Outcome;Peer Review;Phase;Play;Policies;Positioning Attribute;Procedures;Process;Productivity;Publications;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;System;Technology;Training;United States National Institutes of Health;Universities;Vision;Work;cancer care;cancer health disparity;college;community based research;community engagement;cost;design;experience;formative assessment;functional independence;health equity;improved;innovation;member;population health;preservation;programs;repository;senior faculty;sharing platform;social;success;systemic barrier;underserved minority Planning and Evaluation Core n/a NCI 10757596 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 9/18/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5087 9857651 "DODD, SARAH JANE " Not Applicable 12 Unavailable 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY Domestic Higher Education 100655024 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 103584 66400 37184 PROJECT SUMMARYPlanning and Evaluation CoreTU FCCC: Grace X. Ma PhD (Co-Leader) HC: Sarah Jane Dodd PhD MSW (Co-Leader) Lin Zhu PhD (Co-Leader ESI)The overall goal of Planning and Evaluation Core (PEC) is to build on the infrastructure created and continue to: 1)improve the foundation to support planning monitoring and evaluation of the impact of research projects coresand shared resources of Temple University Fox Chase Cancer Center (TUFCCC) and Hunter College (HC)Partnership on reducing cancer health disparities and advancing health equity; and 2) maximize resources identifynew directions and actively facilitate by bringing senior faculty early-stage investigators and trainees together todesign and pursue cutting-edge cancer health disparities research through rigorous solicitation evaluation andselection of new projects using NIH grant review criteria. Guided by the TUFCCC/HC Partnership Logic Model thePEC team will collaborate with each Core/Project leaders to develop specific evaluation plans; implementprocedures to collect all necessary evaluation data with the least cost and burden to Partnership leadersresearchers and community members. The PEC team will introduce new features to enhance our capacity forevaluating the scientific integration and collaboration across the Partnership bi-directional community engagementand institutional changes both qualitatively and quantitatively. The PEC will leverage the innovativeComprehensive and Dynamic e-Platform (CDEP) established during current TUFCCC/HC Partnership 1.0 to furtherstrengthen the support for planning process outcome and impact evaluation of all Core/Projects and the overallPartnership. Building on the robust process the PEC team with support of the AC IAC PSC and NCI will solicitevaluate and select new research projects to increase the competitive research capacity among TUFCCC/HCpartners and promote cutting-edge basic clinical translational and community-based research initiatives in cancercare for underserved minority populations. The PEC will use the NCI Grid-Enabled Measures (GEM) Platform toorganize and facilitate consensus building within and across the Partnership in shared program priorities sharedcommon metrics measures benchmarks analysis and dissemination. Broadly this evaluation will include a three-tier strategy focused on individual Cores/projects the overall Partnership and the broader collaboration betweenthe TUFCCC/HC Partnership and communities served by other NCI/CRCHD funded Partnerships. The PECrenewal application is designed to center around breaking systemic barriers and promote inclusive excellencethrough identifying resources and improving infrastructure in Four Pillars: research projects training/mentorshipand community outreach/engagement as well as research capacity building. The PEC will be guided by the IEframework and the Partnerships Vision to monitor progress and evaluate impact of U54 components and theoverall Partnership towards advancing cancer health equity in the PNN region and beyond. +No NIH Category available Address;Affect;African American;African American population;African ancestry;American;Animals;BRCA mutations;BRCA1 gene;Basic Research Breast Cancer;Bioinformatics;Biological;Biological Markers;Biological Specimen Banks;Biology;Biometry;Black American;Black race;Breast Cancer Cell;Breast Cancer Patient;Cancer Biology;Cancer health equity;Cell Culture Techniques;Cell Line;Cells;Chromosomes;Clinical;Collaborations;Communities;Community Outreach;Complex;DNA Damage;DNA Repair Pathway;DNA biosynthesis;Data Analyses;Detection;Diagnosis;Disparity;Doctor of Philosophy;Educational workshop;Eligibility Determination;Ethics;Ethnic Origin;European;Exposure to;Fox Chase Cancer Center;Gene Amplification;Genetic Engineering;Genetic Screening;Goals;Health Fairs;Human;Imaging technology;Immunohistochemistry;Informed Consent;Institution;Learning;MDM2 gene;Malignant Neoplasms;Mentors;Microarray Analysis;Molecular Biology;Morbidity - disease rate;Mutation;Neoplasm Circulating Cells;Outcome;Participant;Pathology;Pathway interactions;Patients;Pilot Projects;Play;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Population;Probability;Proliferating;Proteins;Race;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Sampling;Scientist;Signal Transduction;Specimen;Stains;Students;TP53 gene;Testing;Tissue Microarray;Tissues;Training;Tumor Tissue;Underrepresented Minority;Underrepresented Students;Universities;Woman;Work;Xenograft procedure;aggressive breast cancer;animal imaging;biological research;cancer biomarkers;cancer health disparity;cancer subtypes;cohort;college;data acquisition;education research;empowerment;follower of religion Jewish;health disparity;improved;inhibitor therapy;insight;malignant breast neoplasm;minority engagement;minority trainee;mortality;mouse model;mutant;mutation carrier;next generation;novel;patient derived xenograft model;protein expression;replication stress;reverse genetics;screening;systemic barrier;targeted treatment;temozolomide;therapeutic target;triple-negative invasive breast carcinoma;tumor;university student Pilot Research Project: Evaluating Black and African American Breast Cancer Populations for Therapeutic Targeting of Aberrant p53 MDM2 MDMX and PARP signaling n/a NCI 10757595 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 9/18/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5086 1884552 "BARGONETTI, JILL E." Not Applicable 12 Unavailable 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY Domestic Higher Education 100655024 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 112184 71913 40271 Project SummaryEvaluating Black and African American Breast Cancer Populations for Therapeutic Targeting of Aberrant p53 MDM2 MDMX and PARP signalingHC: Jill Bargonetti PhD (Co-Leader)TUFCCC: Denise Connolly PhD (Co-Leader)Partnerships are needed to break the systemic barriers that have limited systematic and ethicalbiological research on the underpinnings of aggressive triple negative breast cancer (TNBC) inBlack Americans of African Ancestry (AA). Our U54 partnership increases the ability to studyunderstudied biomarkers in order to improve screening and treatment options. This U54 pilotproject brings together teams of established scientists at Hunter College (HC) and TempleUniversity Fox Chase Cancer Center (TUFCCC) to analyze already available AA patient breastcancer samples for screening highly probable aggressive breast cancer biomarkers that mayfacilitate targeted treatments for AA TNBCs. Moreover the team will mentor underrepresentedstudents from HC with cross-institutional exposure to different state of the art scientific platformto Address Cancer Health Equity in training as well as research objectives. The primary goal ofthis project is to determine if PARP inhibitor (PARPi) therapeutics can be expandedbeyond the mutant BRCA1 cohorts to Black/AA cohorts with mtp53/MDM2/MDMX/PARPbiomarkers. We will educate the Black/AA community about breast cancer biomarkers and willempower them to ask biomarker-based questions during diagnosis and treatment. The aims arethe following. 1) To compare the expression of MDM2 MDMX mtp53 and PARP in breast cancer(BC) tumors from AA and EA patients. We will construct (BC) tissue microarrays (TMAs) fromretrospectively collected tumors from 125 AA and 125 EA patients. TMAs will be stained forMDM2 MDMX p53 and PARP. 2) We will test the driver roles of the MDM2/MDMX-mtp53-PARPfor targeting BCs with PARPi therapies in cell culture and xenograft mouse models. We will workwith the Community Outreach Core to educate community about breast cancer biomarkersBreak Systemic Barriers to Inclusion: This study directly addresses systemic barriers of AAwomen as an understudied cohort for biological determinants of TNBC. We are collating TUFCCCBC AA samples with the goal of identifying potential targeted therapeutic options to reduce breastcancer disparities. Completion of this work will provide insights on critical breast cancerbiomarkers mtp53/MDM2/MDMX/PARP in Black/AAs and will educate the next generation ofunder-represented scientists. +No NIH Category available Address;Affect;African;African American population;African ancestry;Biological;Biological Markers;Black race;Blood specimen;Cancer Detection;Cancer Etiology;Caucasians;Cessation of life;Characteristics;Colon;Colon Carcinoma;Colonoscopy;Colorectal Cancer;Community Outreach;Consent;DNA Markers;DNA Methylation;Data;Development;Diet;Doctor of Philosophy;Early identification;Endoscopy;Environment;Environmental Risk Factor;Epigenetic Process;Exhibits;Fecal occult blood;Frequencies;Gene Expression;Genes;Genetic;Incidence;Individual;Intervention;Malignant Neoplasms;Measures;Methylation;Modeling;Molecular;Mucous Membrane;Neighborhoods;Organoids;Outcome;Patients;Phenotype;Pilot Projects;Polyps;Population;Positioning Attribute;Prevalence;Prevention;Preventive treatment;Procedures;Quantitative Trait Loci;Questionnaires;Recording of previous events;Research Project Grants;Risk;Saliva;Scientist;Screening for cancer;Screening procedure;Subgroup;Testing;Time;United States;University Hospitals;Variant;Woman;adenoma;biobank;cancer health disparity;cancer risk;caucasian American;college;colon cancer patients;colorectal cancer risk;colorectal cancer screening;disparity elimination;disparity reduction;early detection biomarkers;epigenome;experience;genetic variant;high risk;high risk population;improved outcome;in vitro Model;men;methylation pattern;mortality;mortality risk;negative affect;patient population;patient subsets;peripheral blood;pre-clinical;predictive marker;racial disparity;randomized trial;research study;saliva sample;screening;social determinants;socioeconomics;systemic barrier;tool;tumorigenesis;uptake Full Research Project 2: Changes in DNA methylation phenotype in CRC n/a NCI 10757594 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 9/18/18 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5085 2084863 "KLEIMAN, FRIDA E" Not Applicable 12 Unavailable 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY Domestic Higher Education 100655024 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 18553 11893 6660 Project SummaryFull Research Project 2 Colon CancerChanges in DNA methylation phenotype in CRC associated with racial disparitiesTUFCCC: Carmen Sapienza PhD (Co-Leader) and Jayashri Ghosh PhD (Co-Leader ESI) HC: Frida E. Kleiman PhD (Co-Leader)Colorectal cancer (CRC) incidence and mortality rates are disproportionately higher in African Americans (AA)compared to Caucasian Americans (CA). Current non-invasive screening tools such as fecal occult blood tests(FOBT) or fecal DNA markers detect cancer after it occurs. More effective tools for prevention and treatment ofhigher risk individuals such as colonoscopy or endoscopy are invasive less popular and subjective and currentuptake of these screening tools is lower among AA compared to CA. Therefore identification of early andobjective biomarkers that distinguish normal colon mucosa of individuals at high risk for CRC from individuals atlow risk might decrease racial disparities in CRC. In our previous U54 Pilot project (Cycle 1) we have identifieda subgroup of patients having highly disrupted epigenomes displaying abnormal DNA methylation patterns intheir normal mucosa identified as Outlier Methylation Phenotype (OMP). We have been able to significantlyassociate this phenotype with CRC patients over healthy controls. Furthermore AA CRC patients appear morethan twice as likely as CA patients to have OMP. In the current cycle we propose to determine the prevalenceof OMPs in a larger group of patients in Specific Aim 1A both AA (150 CRC and 200 controls) and CA (150 CRCand 200 Controls). In Specific Aim 1B we will elucidate biological mechanisms for the contribution of OMP toCRC tumorigenesis using patient derived organoids (PDO). In Specific Aim 2 we will also determine whetherOMP - affected genes in AA patients are enriched in Black/Ancestry-informative genetic variants. In Specific Aim3 we will determine whether environmental factors and social determinants influence the frequency of OMP inAA groups. Break Systemic Barriers to Inclusion: Our Hunter College/Temple/Fox Chase interdisciplinaryteam of bench scientists clinicians and community outreach scientists is in a unique position to reduce systemicbarriers that lead to underrepresentation of the AA population in epigenetic research studies. This projectaddresses data gaps by including AAs in the epigenetic studies and by developing quantitative and less invasivescreening tests that will potentially enable AAs to increase the uptake of CRC screening and reduce coloncancer disparities. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;African;Algorithms;American;Applications Grants;Artificial Intelligence;Asian;Bioinformatics;Biometry;Biostatistics Core;Cancer Biology;Cell division;ChIP-seq;Clinical;Clinical Informatics;Clinical Trials;Collaborations;Collection;Communities;Consultations;DNA sequencing;Data;Data Analyses;Data Protection;Data Set;Database Management Systems;Development;Diverse Workforce;Doctor of Philosophy;Education;Environment;Epigenetic Process;Equity;Experimental Designs;Fostering;Funding;Future;Genetic;Genomics;Goals;Grant;Health Disparities Research;High Performance Computing;Informatics;Infrastructure;Institution;Investigation;Knowledge Extraction;Laboratories;Latinx;Leadership;Link;Machine Learning;Malignant Neoplasms;Manuscripts;Medical Genetics;Methods;Mission;Molecular;Multiomic Data;New Jersey;New York City;Phase;Philadelphia;Pilot Projects;Play;Population Sciences;Productivity;Proteins;Proteomics;Publishing;Qualitative Research;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Research Proposals;Research Support;Research Training;Resource Sharing;Retrieval;Ribosomal RNA;Role;Science;Secure;Services;Students;Surface;System;Technology;Training;Underrepresented Minority;Writing;artificial intelligence algorithm;biological systems;cancer genetics;cancer health disparity;cancer prevention;career;clinical application;computer infrastructure;cost effective;data resource;epigenomics;ethnic minority population;experience;graph neural network;innovation;instrument;interest;member;minority investigator;minority trainee;novel;preclinical study;protein function;protein protein interaction;racial minority population;single-cell RNA sequencing;skills;software development;statistics;systemic barrier;tool;transcriptome sequencing Biostatistics and Bioinformatics Core (BBC) n/a NCI 10757592 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 9/18/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5083 10812477 "KRAMPIS, KONSTANTINOS " Not Applicable 12 Unavailable 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY Domestic Higher Education 100655024 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 64810 41545 23265 Project SummaryBiostatistics and Bioinformatics Core (Shared Resource)TUFCCC: Eric A. Ross PhD (Co-Leader) HC: Konstantinos Krampis PhD (Co-Leader)The goal of the Biostatistics and Bioinformatics Core (BBC) is to enhance cancer health disparities research inunderserved African- Asian- and Latinx American communities in Philadelphia New Jersey and New York Cityby providing expertise in experimental design biostatistics bioinformatics genomics clinical cancer geneticsmixed methods research machine learning and artificial intelligence. BBC members were selected based ontheir substantial expertise in quantitative science qualitative research high performance computing and softwaredevelopment laboratory investigations and clinical cancer genetics. Its members provide the capacity to createinnovative methods and systems to address new problems and technologies that surface in a rapidly changingscientific environment. BBC activities will leverage the collaborations and tools developed during the currentfunding cycle to accelerate future high-quality cancer disparities research throughout the TUFCCC/HC CancerPartnership. This highly interactive Core will play fundamental roles in all phases of study design/execution and allPartnership projects and cores will interact with the BBC. The specific goals of the Biostatistics and BiostatisticsCore are to: (1) Provide expert consultation in the rigorous design of experiments and studies including researchproposal development. (2) Support U54-supported research by analyzing study results with appropriatequantitative mixed methods and computing approaches developed in-house or current best practices in thefield. Assist investigators with the interpretation and presentation of results and the writing of statistical andbioinformatics components of manuscripts. (3) Develop novel Machine Learning/Artificial Intelligence (ML/AI)algorithms to facilitate cancer disparities research by enhancing knowledge extraction from multi-omic dataresources. Provide training in the latest ML/AI research tools for cancer applications. (4) Provide expert clinicalcancer genetics advice and cost-effective high-throughput genomic and epigenetic services to meet the criticalmolecular laboratory needs of the proposed research projects as well as future U54-supported investigations.Maintain the computational infrastructure for the collection storage and analysis of data generated by U54-supported investigations. By providing diverse expertise and informatics and laboratory tools the BBC willsupport the Partnerships mission of advancing cancer equity among underserved and underrepresentedracial/ethnic minority populations while breaking systemic barriers that under-represented minorities (URM)encounter in the research workforce through research training support and infrastructure that helps enable thecareers of URM investigators and trainees. +No NIH Category available Accountability;Address;Advanced Malignant Neoplasm;Advisory Committees;African;African American;American;Asian;Asian Pacific American;Black race;Cancer Research Project;Collaborations;Communication;Communities;Community Outreach;Decision Making;Doctor of Philosophy;Education;Education and Outreach;Ensure;Equity;Evaluation;Faculty;Fostering;Foundations;Fox Chase Cancer Center;Goals;Grant;Health Disparities Research;Health Sciences;Health system;Hispanic Americans;Infrastructure;Institution;Joints;Latinx;Leadership;Letters;Localized Malignant Neoplasm;Mentors;Mission;New Jersey;New York City;Organization administrative structures;Outcome Measure;Performance;Philadelphia;Productivity;Regional Cancer;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resource Sharing;Science;Services;Structure;Underserved Population;Universities;Vision;Work;anticancer research;cancer health disparity;cancer prevention;career;college;community organizations;design;equity diversity and inclusion;ethnic minority population;experience;implementation outcomes;improved;inter-institutional;medical schools;meetings;member;multidisciplinary;operation;organizational structure;population health;programs;racial minority population;systemic barrier TUFCCC/HC Regional Comprehensive Cancer Health Disparities Partnership n/a NCI 10757591 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 9/18/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5082 1971441 "ERBLICH, JOEL " Not Applicable 12 Unavailable 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY Domestic Higher Education 100655024 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 311530 199698 111832 PROJECT SUMMARY Administrative Core TUFCCC: Grace X. Ma PhD (Contact PI) and Camille Ragin PhD MPH (MPI) HC: Olorunseun Ogunwobi MD PhD (Contact PI) and Joel Erblich PhD MPH (MPI) The Administrative Core (AC) of the TUFCCC/HC Regional Comprehensive Cancer Health Disparities Partnership 2.0 (aka: SPEECH 2.0) builds on an established effective leadership governance infrastructure and foundation of productivity and impact. Over the past 5 years the Partnership directly supported 84 investigators 56 cancer disparities research projects mentored 180 trainees (61% received career or education advancements) and engaged 50 diverse community-based organization partners in cancer prevention activities. The overall goal of the AC for SPEECH 2.0 is to further enhance cancer health disparities research infrastructure and our administrative leadership to provide vigorous scientific/programmatic oversight and integration of research projects education/training and community outreach and engagement activities to be conducted by the Partnership ensuring high-quality standards of excellence and impact on advancing cancer equity in underserved Black/African American (AA) Asian Pacific Americans (APA) and Hispanic American/Latinx (HA) communities in the Philadelphia NJ and NYC (PNN) region. The ACs functions include but are not limited to providing leadership oversight fiscal management coordination integration and communication to support the Partnerships day-to-day operations. The AC will ensure the efficient effective and synergistic performance of the proposed Partnerships aims throughout all of the projects cores and shared resources. The aims of the integrated TUFCCC/HC Administrative Core are as follows: Aim 1. Leverage the established organizational structure to enhance operational capacity and provide robust administrative and fiscal support for overall program activities of TUFCCC/HC Partnership cores and research projects. Aim 2. Facilitate and enhance communication and collaboration opportunities to promote team science among Partnership faculty trainees investigators and program coordinators. Aim 3. Strengthen and maintain leadership infrastructure to ensure the integration of cores projects shared resources as well as inter-institutional initiatives across Partnership and beyond. Aim 4. Establish and maintain sustainable infrastructure to support and ensure the competitiveness of the Partnership's research project portfolio. Aim 5. Direct and support continuous quality improvement using multiple metrics to inform decision-making in planning and evaluation across all cores and projects of the Partnership. Both institution leaders have and will continue to provide exceptional commitments to SPEECH 2.0. AC has been well established and integrated and will continue to be jointly led by experienced multidisciplinary cancer research leaders. The AC team demonstrated not only synergistic accomplishments during SPEECH 1.0 but also strong long-term commitments to the shared vision of advancing cancer equity among underserved populations. Inclusive Excellence will serve as our guiding principle across all cores and projects. In practice the AC core will be committed to addressing systemic barriers and incorporating diversity equity and inclusion efforts into all aspects of our Partnership for the proposed next U54 grant period. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;African American;Area;Asian Americans;Asian Pacific American;Basic Science;Bioinformatics;Biometry;Black race;COVID-19 pandemic;Cancer Intervention;Cancer health equity;Career Mobility;Clinical Sciences;Collaborations;Communities;Community Health Aides;Community Outreach;Competence;Comprehensive Cancer Center;County;Data;Diagnosis;Discipline;Doctor of Philosophy;Education;Equity;Evaluation;Faculty;Feedback;Fostering;Foundations;Fox Chase Cancer Center;Funding;Grant;Health;Health Disparities Research;High Prevalence;Hispanic Americans;Hispanic-serving Institution;Individual;Infrastructure;Institution;Interdisciplinary Study;Intervention;Malignant Neoplasms;Mentors;Mentorship;Methods;Minority;Modeling;Monitor;Needs Assessment;Neighborhoods;Outcome;Pilot Projects;Population;Population Sciences;Positioning Attribute;Poverty;Publications;Recommendation;Research;Research Infrastructure;Research Institute;Research Personnel;Research Project Grants;Research Support;Resources;Risk Factors;Schools;Science;Scientist;Societies;Strategic Planning;Students;Target Populations;Training;Underrepresented Populations;Underrepresented Students;Underserved Population;Universities;Vision;Workforce Development;advanced disease;anticancer research;aspirate;bench to bedside;cancer education;cancer health disparity;cancer prevention;cancer risk;career development;college;community based participatory research;community engagement;community organizations;education research;ethnic minority;evidence base;experience;improved;innovation;member;mortality;multidisciplinary;next generation;outreach;outreach program;programs;racial minority;recruit;screening;skills;social determinants;structural determinants;success;systemic barrier;translational approach;undergraduate student;underserved community (2/2) TUFCCC/HC Regional Comprehensive Cancer Health Disparities Partnership PROJECT NARRATIVEOverallThe underserved vulnerable African American Asian-Pacific American and Hispanic American populations inthe PA-NJ-NYC region experience significant cancer-related health disparities across the cancer continuumfrom a higher prevalence of cancer risk factors to delayed screening and diagnoses experiencing moreadvanced disease and poorer outcomes. SPEECH has made significant strides toward transforming cancerhealth disparities research and education; research infrastructure and platforms that enabled investigators toadvance cancer health equity in these underrepresented and underserved populations. In the next five yearsour Partnership aims to advance cancer health disparities research training/workforce development andcommunity-informed interventions by breaking structural systemic barriers and promoting inclusiveexcellence across disciplines among basic clinical and population science researchers trainees and diverseunderserved communities NCI 10757590 9/19/23 0:00 PAR-22-249 2U54CA221704-06 2 U54 CA 221704 6 "SAN MIGUEL-MAJORS, SANDRA L" 9/18/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 1971441 "ERBLICH, JOEL " "FORD, JENNIFER S; MA, GRACE X.; RAGIN, CAMILLE C." 12 BIOLOGY 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY SCHOOLS OF ARTS AND SCIENCES 100655024 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1035402 NCI 663719 371683 PROJECT SUMMARYOverall TUFCCC: Grace X. Ma PhD (Contact PI) and Camille Ragin PhD MPH (MPI)HC: Olorunseun O. Ogunwobi MD PhD (Contact PI) and Joel Erblich PhD MPH (MPI)The Synergistic Partnership for Enhancing Equity in Cancer Health (SPEECH) is a highly collaborative andmutually beneficial Partnership between Temple University/Fox Chase Cancer Center (TUFCCC) and HunterCollege (HC) and the only NCI-funded U54 CPACHE in PA and NJ and one of two in NYC. Our establishedrobust research infrastructure has made significant contributions to addressing substantial cancer healthdisparities (CHD) in underserved African American Asian-Pacific American and Hispanic American populations.These target populations have higher cancer mortality rates compared to others in the U.S. and majority live inneighborhoods with medium-very high and persistent poverty. In the past five years SPEECH directly supported84 investigators mentored 180 trainees funded 56 cancer disparities projects facilitated 93 publications anddirectly stimulated $45 million externally funded grants. Additionally 14 minority ESIs received careeradvancement we engaged 50 community-based organizations trained 41 community health workers andeducated 1200 members of diverse communities in cancer prevention. Leveraging this momentum of successour Vision is to Promote Inclusive Excellence and break systemic barriers to close gaps in cancer healthdisparities research education community outreach and engagement and achieve infrastructure capacitybuilding. Through exceptional institutional commitments two full projects a pilot project and integrated cores ofAdministrative Research Education Biostatistics/Bioinformatics Planning and Evaluation and CommunityOutreach we propose to achieve the following specific aims. Aim 1: Accelerate TUFCCC-HC Partnershiptransdisciplinary cancer disparities research collaborations and advance cancer health equity across thespectrum of basic clinical and population sciences. Aim 1a: build strengthen and sustain cancer researchcapacities and infrastructure at HC. Aim 1b: advance CHD research to maximize impact at TUFCCC. Aim 1c:foster community-driven research to address cancer disparities in the PA-NJ-NYC region. Aim 2. Train the nextgeneration of CHD scientists and workforce leaders for a pipeline of diverse and underrepresented studentsproviding them with multidisciplinary cancer disparities research education experiences and mentorship andcareer development opportunities through the implementation of enhanced Summer Cancer Research Instituteand newly established Hunter/Temple HEAL Program. Aim 3. Recruit mentor and retain diverse ESIs especiallyURM groups to enhance career development and facilitate their transition to independent investigators. Aim 4.Use bidirectional community engagement approaches to implement a robust community outreach program thatbuilds bridges between diverse communities and researchers to support: a) cancer education and interventionsb) cancer disparities research projects and c) CBPR competencies for investigators and trainees. Aim 5.Conduct a mixed-method evaluation aimed at monitoring progress providing feedback and summative impactdata on all Partnership programing for promoting sustainable solutions to improved cancer health equity. 1035402 +No NIH Category available Investigating the metastatic drive in pancreas cancer PROJECT NARRATIVEUnderstanding the fundamental mechanisms behind the metastatic drive of pancreas cancer and finding waysto intercept this process has great potential to impact survival. This information would also help evaluate theimmediate and the longer-term risks of local vs. distant relapse of disease which would immediately impactpatient management using already existing therapies. The investigations proposed here will rigorously test theprinciples underlying a mechanistic framework to explain the metastatic process in pancreas cancer and howbest to apply the insights to the clinic. NCI 10757574 6/29/23 0:00 PA-21-268 7R01CA223483-07 7 R01 CA 223483 7 "AULT, GRACE S" 8/9/18 0:00 11/30/24 0:00 Tumor Cell Biology Study Section[TCB] 1926329 "HINGORANI, SUNIL R" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 6/29/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2022 327136 NCI 213118 114018 PROJECT SUMMARYThe unusually high metastatic proclivity of pancreas cancer is life-limiting for a majority of patients includingthose diagnosed at early stages. A minority of patients nevertheless present with and succumb to locallydestructive disease. These distinct disease presentations and predilections for distant spread versus primarytumor growth also suggest that the appropriate application of systemic versus local therapies might increasetheir efficacy and prolong survival even as we await the development of more effective targeted therapies. Wehave undertaken a systematic effort to dissect the pathophysiologic mechanisms underlying the extremelethality of pancreatic ductal adenocarcinoma (PDA) primarily through the generation and study of geneticallyengineered mouse models (GEMMs) of the disease that faithfully recapitulate the clinical syndromehistopathology molecular features and response and resistance to treatments seen in the human disease. Wehave recently developed model systems that manifest the two disease phenotypes described above and usedthese systems to uncover a metastatic program orchestrated by the Runx3/RUNX3 transcription factor thatgoverns the balance between cell division and dissemination. This program slows the proliferation of tumorcells while increasing their ability to disseminate and successfully colonize distant sites. Runx3 acting inconcert with point-mutant Trp53 and distinct gene dosages of Dpc4/Smad4 suppresses local growth at theexpense of distant spread. In this proposal we seek to further unravel the mechanisms underlying this decisionnode in pancreas cancer disease behavior and the influences that distinct combinations of tumor suppressorgene mutations can have on both the tumor epithelial cells and the metastatic niche. These aims will beaccomplished through the generation and characterization of novel GEMMs of PDA; identification of thecomposition target gene occupancy and transcriptional outputs of Runx3-associated transcriptionalcomplexes; and characterization of extracellular vesicles that mediate cell behaviors promoting metastasis.Collectively these investigations will reveal the mechanisms underlying the extraordinary competency of PDAsto metastasize identify new potential targets to disrupt this capability and help inform the appropriate selectionof local vs. systemic treatment modalities already in use in the clinic. 327136 +No NIH Category available Adoptive Transfer;Adult;Adverse effects;American;Antigen Targeting;Antigens;Biological;Brain Neoplasms;CAR T cell therapy;CBLB gene;CD276 gene;CD28 gene;CRISPR screen;CRISPR/Cas technology;Cell Cycle;Cell surface;Cells;Cellular immunotherapy;Chemotherapy and/or radiation;Childhood;Childhood Brain Neoplasm;Clinical;Clinical Research;Core Facility;Disease;Down-Regulation;Engineering;Generations;Genes;Genetic;Glioma;Goals;Hematologic Neoplasms;Heterogeneity;Homing;IL3RA gene;Image;Immune;Immune response;Immunocompetent;Immunology;Immunotherapy;Impaired cognition;Impairment;In Vitro;Inflammatory;Intervention;Life;Macrophage;Mediating;Mediator;Memory;Modeling;Modification;Molecular;Mus;Mutate;Operative Surgical Procedures;Outcome;Patients;Penetration;Performance;Persons;Phase;Phenotype;Play;Positioning Attribute;Pre-Clinical Model;Primary Brain Neoplasms;Proliferating;Receptor Signaling;Research;Research Personnel;Resistance;Role;Safety;Saint Jude Children's Research Hospital;Shapes;Subgroup;T-Cell Activation;T-Cell Homing Receptors;T-Cell Receptor;T-Lymphocyte;TCR Activation;Techniques;Testing;Training;Transmembrane Domain;Tumor Antigens;Tumor-associated macrophages;Xenograft Model;antigen-specific T cells;antitumor effect;career;chimeric antigen receptor;chimeric antigen receptor T cells;cytokine;cytotoxicity;design;engineered T cells;exhaustion;extracellular;genome wide screen;human disease;immune cell infiltrate;improved;improved outcome;in vitro activity;in vivo;innovative technologies;interest;motor impairment;mouse model;neoplastic cell;novel;prototype;receptor;research clinical testing;success;targeted treatment;tool;trafficking;transcriptomics;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions Improving CAR T cell therapy for brain tumors using immune competent models PROJECT NARRATIVEAccording to the American Brain Tumor Association over 16000 people are estimated to die from brain tumorsthis year while the currently available therapies cause motor and cognitive impairments and only extend life by2 years. CAR T cell immunotherapy has the potential to improve outcomes in adult and pediatric brain tumorpatients; however optimized CAR design must be evaluated in models that closely mimic human disease andbarriers for therapy. In this study I propose using immune competent brain tumor models to enhance CAR T cellefficacy for brain tumors by optimizing CAR costimulatory domains silencing negative T cell regulators andtargeting suppressive effectors of the brain tumor microenvironment including tumor associated macrophages. NCI 10757469 12/15/23 0:00 RFA-CA-20-014 5R00CA256262-04 5 R00 CA 256262 4 "HU, ZHANG-ZHI" 1/1/21 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 12419173 "HAYDAR, DALIA " Not Applicable 98 Unavailable 143983562 M3KHEEYRM1S6 143983562 M3KHEEYRM1S6 US 38.927274 -77.014396 1518602 CHILDREN'S RESEARCH INSTITUTE WASHINGTON DC Research Institutes 200102916 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 224100 NCI 127187 96913 PROJECT SUMMARY/ABSTRACTThe overall objective of this study is to engineer a potent CAR T cell therapy for high grade glioma (HGG)a subgroup of brain tumors for which outcomes remain poor. CAR T cell therapy is an innovative technologybased on adoptive transfer of antigen-specific T cells engineered to elicit a clinically effective and specificimmune response against tumor cells. Early clinical studies in HGG patients demonstrated safety of CAR T celltherapy for brain tumors; yet only limited benefits were observed. Lack of efficacy is most likely multifactorialand include heterogenous antigen expression limited homing to and penetration of tumors T cell exhaustionand limited persistence as well as the immunosuppressive tumor microenvironment (TME). Therefore thecentral hypothesis of this proposal is that optimized design and additional genetic modifications of CART cells will improve their antitumor effects and that these interventions will be evaluated in immunecompetent mouse models that closely mimic human disease. Three interrelated research aims are proposedto test this hypothesis and the rationale of each is outlined below. First CAR design has to be optimized andevaluated in immune competent glioma models. In Aim 1 I will generate CAR T cells containing different co-stimulatory domains (CD28. 41BB. CD28.mut and 41BB.mut) and compare their activity in vitro and invivo. Second a genome wide screen in primary T cells has identified key regulators of T cell activation post T-cell receptor (TCR) stimulation. Identified genes belong to molecules that regulate cell cycle proliferation anddownstream TCR signaling including SOCS1 RASA2 or CBLB. In Aim 2 I will therefore explore if CRISPR-Cas9 mediated silencing of Socs1 Rasa2 and/or Cblb enhances the effector functions of CAR T cells. Theindependent Aim 3 will then explore a dual CAR targeting approach in which I will not only target glioma cellsbut also immunosuppressive cells within the glioma microenvironment. These studies are focused on tumorassociated macrophages (TAMs) since they are abundantly present in gliomas and play a critical role in shapingthe TME. To support the feasibility of this project I have adapted the well-established immune competent GL261glioma model to study CAR T cell therapies targeting the relevant tumor antigen B7-H3 which is not onlyexpressed by GL261 cells but also in a broad range of pediatric and adult brain tumors. In addition mypreliminary studies indicate that `prototype' B7- H3 CAR T-cells readily recognize and kill GL261 cells in vitroand have antitumor activity in vivo highlighting that the developed model is well suited for the proposed aims ofthis project. State of the art technique will be used in all three Aims to not only study the function and in vivo fateof CAR T-cells but also their antitumor activity and how CAR T-cells interact with glioma- infiltrating immunecells. Completion of this study will define the most optimal CAR design that best controls HGG tumors andpersists longer in the context of inflammatory brain tumors. Additionally results will illustrate if targeting TAMswill overcome the suppressive effects of TME on B7-H3 CAR T cells. 224100 +No NIH Category available Abdomen;Adverse event;Alloantigen;Allogenic;Anesthesia procedures;Autoimmune Responses;Biological Markers;Biopsy;Body Weight decreased;Caring;Categories;Clinical;Clinical Research;Clinical Trials;Colitis;Collagen;Colonoscopy;Complication;Contrast Media;Crohn's disease;Data;Deposition;Diagnosis;Diagnostic tests;Disease;Dose;Endoscopy;Feces;Genetic Diseases;Goals;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Hemoglobin;Human;Image;Immune;Immune system;Immunocompromised Host;Immunologic Deficiency Syndromes;Infectious colitis;Intervention;Intestines;Liver;Methods;Modality;Molecular;Mus;Muscular Dystrophies;Non-Neoplastic Hematologic and Lymphocytic Disorder;Output;Oxyhemoglobin;Pathologic;Patient risk;Patients;Pharmaceutical Preparations;Phase;Physicians;Pilot Projects;Refractory;Risk;Schedule;Skin;Skin Temperature;Solid Neoplasm;Steroids;Symptoms;T-Lymphocyte;Testing;Therapeutic;Time;Transplant Recipients;Weight Gain;chemotherapy;clinical diagnosis;clinical efficacy;deoxyhemoglobin;diagnostic accuracy;experience;gastrointestinal;graft vs host disease;high risk;histological stains;improved;individual patient;mortality;optoacoustic tomography;patient stratification;personalized medicine;photoacoustic imaging;safe patient;safety assessment;safety testing Non-invasive assessment of graft vs host disease using optoacoustic imaging Currently diagnosis of graft vs host disease (GVHD) is often complicated by the potential ofchemotherapy/infectious colitis in patients that have undergone allogeneic hematopoietic stemcell transplant.This proposal seeks to evaluate Multispectral optoacoustic tomography (MSOT)imaging as a method to separately detect and stratify patients with GVHD from patients withchemotherapy/infectious colitis. NCI 10757461 12/21/23 0:00 PAR-20-292 5R21CA271218-02 5 R21 CA 271218 2 "BEIER, HOPE THOMAS" 1/1/23 0:00 12/31/24 0:00 ZCA1-TCRB-9(O1)S 8734007 "HOLTER CHAKRABARTY, JENNIFER LIN" "MCNALLY, LACEY R" 5 RADIATION-DIAGNOSTIC/ONCOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 183026 NCI 126225 56801 Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative modality forpatients with aggressive hematologic malignancies and many nonmalignant hematologicdisorders (genetic disorders and immunodeficiency disorders). Graft vs host disease (GVHD) isthe major complication and cause of non-relapse mortality in allogeneic HSCT. GVHD isattributable to donor T cell recognition of recipient alloantigen presenting commonly in skin liverand gastrointestinal (GI-GVHD). Initial clinical suspicion of GI-GVHD is made by symptoms ofsevere weight loss and increased stool output >500cc (500->1500)per day without other causeidentified. Clinical diagnosis of GI-GVHD separately from chemotherapy/infectious colitis (CI-Colitis) requires colonoscopy/endoscopy followed by biopsy but has < 60% intra-expertvariability of pathological diagnosis. To overcome these limitations in diagnosis of GI-GVHD wepropose to: 1) test the safety of Clinical MSOT detecting oxy-/deoxy-hemoglobintotal hemoglobin and collagen contrast in patients with GI-GVHD and to 2) evaluate thepotential of clinical MSOT to differentiate GI-GVHD from chemotherapy/infectious colitis(CI-Colitis) to ultimately increase diagnostic accuracy decrease patient risk and decrease timeto therapy.Building upon our experience in HSCT and autoimmune responses in patients as well asexperience with multispectral optoacoustic tomography these proposed studies aim to assessthe potential of MSOT imaging to differentiate GVHD from CI-Colitis with the ultimate goalto provide patients a transabdominal non-invasive accurate and objective method toidentify disease for individual patients in support of personalized medicine. Wehypothesize that clinical MSOT imaging is safe for patients with compromised immunesystems and that clinical MSOT can distinguish GVHD from CI-Colitis based upon acombination of oxy- and deoxy-hemoglobin and collagen. We will test this hypothesis bythe following Aims: 1) Assess safety of clinical features of MSOT in patients with GI-GVHDor CI-Colitis; and 2) Evaluate potential of clinical MSOT to identify and stratify GI-GVHD inHSCT patients. Our study will be the first to test clinical MSOT in HSCT patients and the firstproposed study to use MSOT differentiate diseases of similar clinical presentation butradically different therapies. 183026 +No NIH Category available Androgen Receptor;Antibody-drug conjugates;Bioinformatics;Biology;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer cell line;Cancer Cell Growth;Cell Line;Cell Proliferation;Cessation of life;Cisplatin;Clinical;Data;Data Set;Dimerization;Disease;Drug Combinations;Drug resistance;ERBB2 gene;ERBB3 gene;Epidermal Growth Factor Receptor;Epigenetic Process;Estrogen Receptors;Foundations;Genetic Transcription;Goals;Heregulin;Histones;Immunotherapy;In Vitro;Invaded;Ligands;Light;Lysine;Mediating;Mediator;Messenger RNA;Metastatic Neoplasm to the Lung;MicroRNAs;Modeling;Molecular;Monoclonal Antibodies;Neoplasm Metastasis;Outcome;PHD Finger;Paclitaxel;Patient-derived xenograft models of breast cancer;Patients;Play;Poly(ADP-ribose) Polymerase Inhibitor;Post-Transcriptional Regulation;Progesterone Receptors;Prognosis;Proteins;Receptor Protein-Tyrosine Kinases;Recurrent tumor;Relapse;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Agents;Up-Regulation;anti-PD-1/PD-L1;anti-PD-L1 antibodies;breast cancer progression;cancer subtypes;chemotherapeutic agent;chemotherapy;effective therapy;gain of function;histone demethylase;in vivo;inhibitor;insight;knock-down;loss of function;malignant breast neoplasm;migration;molecular targeted therapies;neutralizing antibody;novel;novel therapeutics;overexpression;receptor expression;research and development;targeted treatment;therapeutically effective;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression HER3-PHF8 signaling axis in triple-negative breast cancer progression We aim to define the molecular basis of HER3 signaling promotion of triple negative breast cancer(TNBC) progression and metastasis via upregulation of PHF8 a key histone lysine demethylase. Theproposed studies will shed a new light on our understanding of epigenetic promotion of HER3-driven TNBC.Data generated will provide compelling evidence to develop novel therapeutic agents/strategies inhibitingHER3 or PHF8 either alone or in combination with chemotherapy for the patients with TNBC especiallythose with the subtypes of Basal-like 1 (BL1) Luminal-Androgen receptor (LAR) or Basal-like 2 (BL2). NCI 10757442 11/28/23 0:00 PA-20-185 5R01CA266269-02 5 R01 CA 266269 2 "KONDAPAKA, SUDHIR B" 12/23/22 0:00 11/30/27 0:00 Tumor Progression and Metastasis Study Section[TPM] 7923651 "LIU, BOLIN " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 782627814 M7KCJ79FAVH5 782627814 M7KCJ79FAVH5 US 29.957378 -90.082793 577902 LSU HEALTH SCIENCES CENTER NEW ORLEANS LA SCHOOLS OF MEDICINE 701127021 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 369829 NCI 251585 118244 Triple-negative breast cancer (TNBC) is defined as a breast cancer (BC) subtype lack of estrogenreceptor (ER) and progesterone receptor (PR) expression and HER2 amplification/overexpression. Itrepresents a significant clinical challenge because the patients with TNBC have a poor prognosis andaccount for a disproportionate number of BC deaths. Although targeted therapies including PARP inhibitorsand a Trop-2-directed antibody (Ab)-drug conjugate as well as immunotherapy (anti-PD-1/PD-L1 Abs) havebeen approved to treat advanced/metastatic TNBC chemotherapy currently remains the mainstay for a largepart of TNBC patients and initially effective. However drug resistance and tumor recurrence frequently occursuggesting that TNBC is highly heterogenerous and it is in urgent need to develop more effective molecular-based therapies for this aggressive disease. We recently discovered an elevated expression of HER3 (orerbB3) in about half of the TNBC clinical samples and cell lines examined. Bioimformatics analyses of TCGAdatasets revealed that high erbB3 expression significantly associated with poorer outcomes in TNBCpatients especially those with the subtypes of Basal-like 1 (BL1) Luminal-Androgen receptor (LAR) orBasal-like 2 (BL2). We then identified PHF8 (PHD finger protein 8 or KDM7B a histone lysine demethylase)as one of the most downregulated epigenetic modifiers upon silencing of erbB3 in a BL2-TNBC cell line. Thepositive correlation of erbB3 and PHF8 was further supported via analysis of BC clinical samples and celllines. Moreover studies with gain-of-function and loss-of-function approaches indicated that PHF8 played acrucial role in HER3-mediated promotion of BL1/2-TNBC cell growth migration and invasion. Thus wehypothesize that PHF8 functions as a key downstream mediator of HER3 signaling in BL1/2-TNBCprogression and metastasis; and inhibition of HER3 or PHF8 will significantly enhance the efficacy ofchemotherapy against TNBC. We intend to define the molecular basis of HER3 signaling-mediatedupregulation of PHF8 in TNBC and subsequent tumor progression and metastasis and to determine thetherapeutic potential of inactivation of HER3 or PHF8 in combination with chemotherapy against TNBC. 369829 +No NIH Category available Acceleration;Adolescent;Adolescent and Young Adult;Binding;Biochemical;Biological Models;Bone Tissue;CRISPR interference;Cell Differentiation process;Cell Proliferation;Cell physiology;Cells;Characteristics;Child;Chimeric Proteins;Chromatin;Chromosomal Rearrangement;Chromosomal translocation;Common Neoplasm;Dependence;Development;ETS Domain;EWS-FLI1 fusion protein;EWSR1 gene;Enabling Factors;Enhancers;Environment;Epigenetic Process;Ewings sarcoma;FLI1 gene;Family member;Fostering;Fusion Oncogene Proteins;Generations;Genes;Genetic;Genetic Transcription;Genomics;Growth;Heterogeneity;Histologic;Histones;Human;Impact evaluation;In Vitro;Label;Link;Malignant Bone Neoplasm;Malignant Childhood Neoplasm;Malignant Neoplasms;Mass Spectrum Analysis;Mediator;Mesenchymal Cell Neoplasm;Mesenchymal Differentiation;Mesenchymal Stem Cells;Microsatellite Repeats;Oncogenic;Oncoproteins;Operative Surgical Procedures;PAX7 gene;Patients;Pluripotent Stem Cells;Post-Translational Protein Processing;Process;Proliferating;Proteins;Proteomics;RNA;Radiation;Regulation;Regulatory Pathway;Research Personnel;Site;Testing;Untranslated RNA;Variant;Work;cancer cell;chemotherapy;cofactor;embryonic stem cell;epigenomics;histone modification;hybrid gene;induced pluripotent stem cell;insight;neoplastic cell;new therapeutic target;novel;novel strategies;permissiveness;protein function;recruit;sarcoma;small hairpin RNA;soft tissue;stem cell differentiation;stem cell model;stem cells;transcription factor;transcriptome;transcriptomics;tumor;young adult Developmental control of chromatin states in cancer NARRATIVECancers of children and young adults result from the interplay between genetic and epigenetic factorsand the cellular states that accompany a period of developmental progression and accelerated growth.We propose a project that explore this relationship through the bone and soft tissue cancer Ewingsarcoma. How the critical oncoprotein that leads to Ewing sarcoma influences and is itself influencedby an evolving chromatin environment will be studied. NCI 10757436 12/5/23 0:00 PA-20-185 5R01CA276663-02 5 R01 CA 276663 2 "WITKIN, KEREN L" 1/1/23 0:00 12/31/27 0:00 Cancer Genetics Study Section[CG] 1951105 "DAVIS, IAN J" Not Applicable 4 PEDIATRICS 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 392693 NCI 270616 122077 SUMMARYEwing sarcoma a cancer of the bone and soft tissue of children and young adults remains a highly lethal cancerdespite the use of aggressive chemotherapy radiation and surgery. The tumor is dependent on the developmentof a hybrid gene that brings together parts of two different genes EWSR1 and FLI1 through chromosomaltranslocation or chromoplexy. The resulting EWS-FLI1 fusion oncoprotein acts as a transcriptional and chromatinregulator. Building from the work of our lab and others demonstrating that EWS-FLI1 gains neomorphic activityto regulates chromatin state at microsatellite coopted to become enhancers in tumor cells. However we haveshown that the activity and genomic targeting of EWS-FLI1 is influenced by the underlying epigenomic state ofthe cell. We demonstrated that primary and in vitro differentiated mesenchymal stem cells offer a chromatin statesimilar to that of Ewing sarcoma. We hypothesize that during stem cell differentiation a unique permissivechromatin state develops that enables EWS-FLI1. Further we hypothesize that this permissive state is madeup of chromatin regulators characteristically modified histones and specific RNAs. In this project we willemploy cancer cell (Aim 1) and stem cell developmental approaches (Aim 2) to identify the protein and RNAinteractors and the posttranslational modifications of histones that create a favorable environment. We predictthat critical features will be shared between both model systems. We will test the impact of these factors byevaluating the activity of EWS-FLI1 on chromatin states and transcription when these factors are modulated.The generation of Ewing sarcoma patient derived stem cells will enable us to evaluate the impact of EWS-FLI1across the process of cellular differentiation. Integrated single cell analytics of chromatin accessibility and thetranscriptome will enable direct evaluation of the impact of EWS-FLI1 on chromatin and reciprocally chromatinon EWS-FLI1. We will specifically study the biochemical interaction and functional relationship betweenEWS-FLI1 and the transcriptional regulator PAX7 one of the interactors identified during pilotexperimentation. 392693 +No NIH Category available Address;Anatomy;Biological;Biological Markers;Blood;Blood Vessels;Brain;Breast;Cellularity;Clinical;Clinical Trials;Clonal Evolution;Collection;Data;Data Set;Disease;Genes;Genetic Heterogeneity;Goals;Histology;Image;Immune system;Immunotherapy;Inflammation;Leptomeninges;Location;MRI Scans;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metastatic Neoplasm to the Central Nervous System;Metastatic malignant neoplasm to brain;Monitor;Mutation;PD-1 inhibitors;Pathway interactions;Patients;Pattern;Perfusion;Pharmaceutical Preparations;Physiological;Play;Resistance;Role;Shapes;Tissue Sample;Tissues;Tumor Burden;Vertebral column;Work;brain magnetic resonance imaging;burden of illness;chemotherapy;contrast enhanced;genetic evolution;immune activation;immunotherapy trials;improved;improved outcome;insight;interest;novel therapeutics;patient population;patient subsets;pembrolizumab;radiological imaging;responders and non-responders;response;response biomarker;survival prediction;targeted treatment;tool;treatment response;trial enrollment;tumor;tumor DNA;tumor growth;tumor microenvironment;tumor progression Using MRI and circulating tumor DNA to improve the interpretation of response to immunotherapy and targeted therapy in CNS metastases Project Narrative There is increasing interest in using immunotherapy or targeted therapy to treat brain metastasesincluding leptomeningeal disease from cancer. However it can be challenging to interpret response totreatment or to understand patterns of response or resistance to treatment since serial tissue samples aredifficult to obtain from brain metastases. The goal of this proposal is to use circulating tumor DNA andsophisticated MRI scans to characterize the biological response of brain metastases to immunotherapy andtargeted therapy by monitoring circulating tumor DNA burden and clonal evolution during treatment andcomparing these to changes on MRI. NCI 10757395 11/20/23 0:00 PA-18-629 5R01CA244975-05 5 R01 CA 244975 5 "WANG, YISONG" 12/15/19 0:00 11/30/24 0:00 Cancer Biomarkers Study Section[CBSS] 9577741 "GERSTNER, ELIZABETH " "BRASTIANOS, PRISCILLA KALIOPI; CARTER, SCOTT " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 612337 NCI 403865 208472 Project Summary/Abstract There is increasing interest in using immunotherapy or targeted therapy to treat brain metastasesincluding leptomeningeal disease from cancer. However it can be challenging to interpret response totreatment or to understand patterns of response or resistance to treatment since serial tissue samples aredifficult to obtain from the brain. Thus there is a critical need to identify noninvasive makers of response orresistance to new therapies being evaluated in this understudied patient population. In this proposal Aim 1 will combine circulating tumor DNA with sophisticated MRI scans to improve ourability to interpret response of brain metastases patients treated with pembrolizumab a PD-1 inhibitor. Withpembrolizumab increase in contrast enhancement on MRI can be tumor progression or inflammation fromsuccessful re-activation of the immune system with treatment. We hypothesize that by combining a quantitativemeasure of tumor burden specifically circulating tumor DNA with MRI scans we will be able to disambiguatetrue progression from pseudoprogression and moreover to understand mechanisms of response/resistance.Aim 2 will use circulating tumor DNA to shed light on the clonal evolution of brain metastases in response totargeted therapy allowing for noninvasive means to understand response and resistance patterns. Aim 3 willaddress the clinical challenge of accurately determining radiographic response in patients with leptomeningealdisease from cancer. Similar to our hypothesis for parenchymal brain metastases we expect that addingctDNA to MRI will improve our ability to more reliably measure LMD response to treatment. 612337 +No NIH Category available Affect;Binding;Biological;Biology;CDC2 gene;Cancer Biology;Cancer Etiology;Cancer Model;Cancer Patient;Carcinogens;Cell Cycle;Cell Death;Cell Death Induction;Cell Survival;Cells;Cessation of life;Cisplatin;Development;Diagnosis;Diagnostic;Epigenetic Process;Future;Genetic;Genetic Transcription;Growth;Helicobacter Infections;Helicobacter pylori;Human;Infection;Link;Mediating;Molecular;Mus;NF-kappa B;Oncogenic;Oncology;Organoids;Outcome;Pathology;Persons;Phosphorylation;Play;Population;Positioning Attribute;Preventive;Property;Refractory;Reporting;Resistance;Risk Factors;Role;Signal Pathway;Signal Transduction;Stimulus;Stomach Carcinoma;Survival Rate;Technology;Therapeutic;Therapeutic Intervention;Time;Tissue Sample;Transcriptional Regulation;United States;Work;cancer cell;cancer statistics;carcinogenesis;chemotherapeutic agent;chemotherapy;clinically significant;design;empowerment;experience;gastric carcinogenesis;gastric tumorigenesis;genotoxicity;human tissue;improved;in vitro Model;malignant stomach neoplasm;mouse model;neoplastic cell;novel;novel therapeutic intervention;overexpression;pharmacologic;prognostic;refractory cancer;response;self-renewal;therapy resistant;transcription factor;transcriptional reprogramming;translational potential;translational study Molecular Functions of CDK1 in Gastric Tumorigenesis Project Narrative Gastric cancer is the third most common cause of cancer-related death world-wide causing more than700000 death each year. We plan to characterize the molecular function(s) of CDK1 in gastric carcinogenesisin order to identify its biological diagnostic prognostic and possibly therapeutic significance. NCI 10757380 1/5/24 0:00 PA-19-056 5R01CA249949-04 5 R01 CA 249949 4 "YASSIN, RIHAB R" 1/12/21 0:00 12/31/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 7001109 "EL-RIFAI, WAEL " Not Applicable 27 SURGERY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 416925 NCI 271613 145312 ABSTRACT/SUMMARY: Gastric cancer is the third leading cause of cancer-related death worldwide. The 2018global cancer statistics report indicates an estimated over 1000000 new cases and an estimated 783000deaths in 2018. Gastric cancers are poorly responsive to therapy and have an unfavorable outcome with anestimated overall 5-year survival rate of approximately 20%. In response to genotoxic stimuli cancer cellsundergo rewiring and reprogramming of transcription and signaling networks to drive adaption and survivalproperties. This reprogramming leads to the development of acquired adaptive properties that promote survivaland expansion of neoplastic cells. Comprehensive analysis approaches have enabled us to identify a biologicallyrelevant novel signaling axis in gastric cancer. We detected aberrant cytosolic overexpression of CDK1 in humanand mouse gastric cancers. While CDK1 is a well-established cell cycle regulator we have discovered previouslyunreported functions in neoplastic cells in gastric cancer the focus of this proposal. We found that in responseto genotoxic stimuli such as infection and chemotherapeutics the surviving pool of neoplastic cells develop anacquired adaptive pro-survival response that includes induction of CDK1 and SOX9 transcription factor. Wedemonstrate for the first time that CDK1 is induced in response to activation of NF-kB transcription activity. Atthe same time CDK1 induces SOX9 through epigenetic mechanisms that include activation of DNMT1 andsuppression of miR-145. Inhibition of CDK1 by genetic or pharmacologic approaches decreased SOX9 level andactivity and induced cancer cell death. Based on novel preliminary results we hypothesize that activation ofCDK1-SOX9 axis promotes cell survival and expansion of neoplastic cells in response to H. pylori infection andchemotherapeutic interventions. We have developed three specific aims that include mechanistic functionaland translational studies using in vitro models organoid cultures mouse models and de-identified human tissuesamples. In aim 1 we plan to investigate the role of H. pylori infection and NF-kB transcription factor in regulatingCDK1-SOX9 axis. We will also investigate a novel epigenetic link that includes CDK1 and DNMT1 in regulatingSOX9 transcription factor levels and activity. Our second aim will focus on investigating molecular functions andoncogenic transcription network of CDK1-SOX9 axis. The translational significance will be studied in aim 3 byinvestigating therapeutic potential and clinical significance of CDK1-SOX9 functional axis in gastric cancer. Wehave assembled a highly collaborative team with experience in advanced molecular technologies cancermodels and oncology making us in a unique position to perform the proposed studies. Upon completion of thiswork we expect to unveil a novel druggable paradigm of cross-talk between CDK1 and SOX9 signaling pathwaysin gastric tumorigenesis. These molecular interactions not only provide a novel understanding of the biology ofgastric cancer but also offer future translational opportunities for the design of new therapeutic interventions forgastric cancer. 416925 +No NIH Category available Adenocarcinoma;Alveolar;Alveolar Cell;Applications Grants;BCL2L1 gene;Biological;Biological Markers;Cancer Etiology;Cancer Patient;Cell Survival;Cells;Clinical;Clinical Trials;Companions;Data;Disease Outcome;Disease Reservoirs;Drug Tolerance;Drug resistance;ERBB2 gene;Epidermal Growth Factor Receptor;Evolution;FGFR1 gene;Funding;Future;Gene Expression Profile;Genetic Transcription;Goals;Growth;Histologic;In Vitro;KRAS2 gene;Link;Lung Adenocarcinoma;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Non-Small-Cell Lung Carcinoma;Nuclear;Oncogenes;Oncogenic;Oncoproteins;Outcome;Output;PTPN11 gene;Pathway interactions;Patients;Phenotype;Play;Pre-Clinical Model;Proteins;Ras Inhibitor;Regimen;Residual Cancers;Residual Neoplasm;Resistance;Role;Safety;Sampling;Signal Pathway;Signal Transduction;Specimen;Switch Genes;System;Testing;Therapeutic;Up-Regulation;Work;cancer cell;cell type;clinical development;clinical translation;clinically relevant;cohort;efficacy evaluation;improved;inhibitor;innovation;insight;molecular marker;mortality;multidisciplinary;mutant;neoplastic cell;novel;pharmacologic;precision medicine;primitive cell;response;single-cell RNA sequencing;small molecule;small molecule inhibitor;success;survival outcome;targeted treatment;therapeutic target;therapy resistant;tumor Characterization of YAP as a rational companion target in lung cancer PROJECT NARRATIVE. Precision medicines that specifically target proteins that drive cancer growth areleading to improved responses in many advanced-stage cancer patients. However this clinical success is limitedbecause treatment resistance occurs. The studies in this grant proposal focus on the characterization of amechanism of tumor cell persistence and resistance to signaling pathway targeted therapies in lung cancer withthe overall goal of enhancing survival outcome for cancer patients through improved precision medicinestrategies. NCI 10757349 12/15/23 0:00 PA-20-185 5R01CA204302-08 5 R01 CA 204302 8 "FORRY, SUZANNE L" 3/1/17 0:00 12/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 9547125 "BIVONA, TREVER G" Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 345206 NCI 213750 131456 PROJECT ABSTRACT. Lung cancer is the leading cause of cancer mortality worldwide with non-small cell lungcancer (NSCLC) the predominant histologic subtype of lung cancer and lung adenocarcinoma the major subsetof NSCLC. Despite clinical progress with the use of targeted therapies drug resistance remains a problem thatlimits patient survival. A less well understood aspect of the evolution of drug resistance is the drug tolerantpersister cell state in which a subpopulation of cancer cells survives initial targeted treatment to form a minimalresidual disease (MRD) reservoir that is a precursor to acquired resistance. We propose an innovativemultidisciplinary and collaborative project to hopefully improve the survival of NSCLC patients by defining therole that the Hippo-YAP pathway plays in promoting drug tolerance and MRD to current pathway targetedtherapies. Extending work that we completed in the first funding cycle of this R01 we aim to capitalize on ourdiscovery of the Hippo-YAP signaling pathway as a critical molecular circuit and therapeutic target in the manycancers driven by hyperactivation of RTK-RAS-MAPK signaling. Our data suggest an emerging paradigm inwhich YAP activation is a key functional feature of the drug tolerant state during RTK-RAS-MAPK targetedinhibition in NSCLC. We observed YAP activation during therapy in multiple oncogene-driven NSCLC preclinicalmodels treated with EGFR ALK KRAS and SHP2 inhibitors. YAP upregulation promoted the expression ofseveral survival factors including BCL-xL and RTKs such as FGFR1 and ErbB2. Furthermore through single-cell RNA sequencing (scRNAseq) performed longitudinally in clinical specimens obtained from patients treatedwith targeted inhibitors we discovered that residual cancer cells often show lineage plasticity and a transition toan alveolar type (AT)1/2-like transcriptional state that is a novel phenotype of slow cycling drug tolerant cancercells. We verified this occurred in bona fide cancer cells (i.e. not from misannotated normal alveolar cells) andwas distinct from therapy-nave adenocarcinoma or normal AT1/2 cells. Our data suggest a role for YAP inpromoting drug tolerance and this novel form of lineage plasticity. Inhibition of YAP signaling with YAP/TEADsmall molecule inhibitors that are in clinical development suppressed drug tolerant cancer cell survival andexpression of molecular markers of the AT1/2-like lineage switch. We propose to further test the hypothesis thatYAP signaling is a key molecular switch that regulates the biological and clinical response to RTK-MAPK pathwayinhibitors. In Aim 1 we define the role of YAP in promoting drug tolerance and the AT1/2-like lineage plasticitypresent in drug tolerant cancer cells in RTK-RAS-MAPK-driven NSCLCs. We also test whether pharmacologicinhibition of YAP/TEAD can thwart MRD and enhance response to RTK-RAS inhibitors in preclinical models. InAim 2 we study molecular features of YAP/TEAD activation and the AT1/2-like lineage switch as biomarkers ofMRD and clinical outcomes using tumors from patients before and on treatment. This project offers insight intothe role of YAP and lineage plasticity in therapy tolerance and MRD with potential for future clinical translation. 345206 +No NIH Category available Address;Animals;Basic Science;CD8B1 gene;Cell Differentiation process;Cell physiology;Cells;Clinical;Clinical Trials;Confusion;Consumption;Custom;DNA;DNA methyltransferase inhibition;Data;Development;Diet;Dietary Factors;Dietary Fatty Acid;Epigenetic Process;Epithelial Cells;Epithelium;Exhibits;Experimental Designs;Fatty acid glycerol esters;Fish Oils;Funding;Growth;Health;High Fat Diet;Human;Immune;Immunity;Immunologic Surveillance;Immunophenotyping;In Vitro;Interferons;Knockout Mice;Knowledge;Life Style;Linoleic Acids;Malignant Neoplasms;Mediating;Metabolic;Modeling;Molecular;Morbidity - disease rate;Mus;Non obese;Obese Mice;Obesity;Oleic Acids;Olive oil preparation;Omega-3 Fatty Acids;Persons;Play;Population;Prevention;Production;Reactive Oxygen Species;Role;STAT3 gene;Safflower Oil;Saturated Fatty Acids;Signal Transduction;T cell differentiation;T-Lymphocyte;Therapeutic;Toxic effect;Tumor-Derived;Tumor-infiltrating immune cells;Vitamin D;World Health Organization;aldehyde dehydrogenase 1;antitumor effect;cancer prevention;cancer risk;cancer therapy;carcinogenesis;cocoa butter;conditional knockout;demethylation;dietary;dietary supplements;dosage;fatty acid-binding proteins;good diet;improved;in vivo;insight;mortality risk;mouse model;neoplastic cell;novel;preclinical study;prevent;protein expression;response;sensor;tumor;tumor growth; T cells E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function PROJECT NARRATIVEData from this study are expected to establish E-FABP as a novel molecular sensor mediating n-3 FA-inducedanti-tumor effects. This proposal will not only have basic science ramifications for understanding molecularmechanisms by which n-3 FAs epigenetically enhance immune cell differentiation but will also have significanttranslational implications for the role of healthy diets in cancer prevention. NCI 10757341 11/30/23 0:00 PA-19-056 5R01CA180986-10 5 R01 CA 180986 10 "EMENAKER, NANCY J" 9/1/21 0:00 12/31/25 0:00 Cancer Prevention Study Section[CPSS] 9620088 "LI, BING " Not Applicable 1 PATHOLOGY 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF MEDICINE 522421320 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 312864 NCI 202501 110363 PROJECT SUMMARY/ABSTRACTDespite therapeutic advances over 600000 people in the US will die from cancer in 2019. Preventing cancereliminates the risk of mortality and/or morbidity that may occur with the development of cancer. Thus cancerprevention represents the most effective way for addressing cancer challenges. Healthy diet is considered beessential to reduce cancer risk by maintaining and improving immunity but recent VITAL trials did not showbeneficial effects of these supplements. The negative results reflect the mechanistic knowledge gap of howdietary factors modulate health. The objectives of this renewal application are to determine cellular andmolecular mechanisms by which epithelial fatty acid binding protein (E-FABP) promotes n-3 fatty acid-mediated tumor prevention by enhancing immune cell differentiation and anti-tumor activity. Data collected inthe last funding cycle have successfully established E-FABP as a new host-derived cancer prevention factor innon-obese subjects. During our studies we observed that different types of high fat diets (HFD 45% fat)including cocoa butter (rich in saturated fatty acids FAs) safflower oil (rich in 18:2 linoleic acid) fish oil (rich inn-3 FAs) all induced similar degree of obesity in mouse models. However tumor growth in these obese micewas dramatically different with the fastest growth in cocoa butter group and slowest in the fish oil group. Inanalyzing the immunophenotype of these obese mice we found an atypical population of CD8+ T cells thatwas specifically upregulated in the fish oil group. More interestingly fish oil diet-induced CD8+ Tdifferentiation and anti-tumor effects were blunted in mice lacking E-FABP suggesting a novel molecularmechanism mediated by E-FABP. Thus we hypothesized that host expression of E-FABP plays a critical rolein n-3 FA-induced immune cell differentiation and anti-tumor function. Three specific aims are proposed toaddress the central hypothesis in this renewal application. Specific Aim 1 will determine the mechanisms bywhich E-FABP promotes n-3 FA-induced immune cell differentiation. Experiments are designed to elucidatemolecular mechanisms by which consumption of dietary n-3 FAs regulate CD8+ T cell differentiation via E-FABP-dependent epigenetic reprogramming. Specific Aim 2 will delineate how E-FABP mediates n-3 FA-induced anti-tumor activity. Results of Aim 2 are expected to reveal that E-FABP promotes host anti-tumoractivity through targeting both immune cells and tumor-derived epithelial cells. Specific Aim 3 will evaluatewhether targeting E-FABP with optimized n-3 FA diets results in effective tumor prevention. In summarysuccessful completion of this proposal will offer E-FABP as a new cancer prevention target and havesignificant mechanistic and clinical implications for healthy diet-mediated cancer prevention. 312864 +No NIH Category available Address;Admission activity;Award;Basic Science;Biomedical Research;CCL7 gene;Career Mobility;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Community Networks;Community Outreach;Complement;Comprehensive Cancer Center;Core Facility;Data;Development;Diverse Workforce;Doctor of Philosophy;Education Projects;Educational Activities;Educational process of instructing;Enrollment;Environment;Ethnic Origin;Faculty;Feedback;Fellowship;First Generation College Students;Fostering;Fox Chase Cancer Center;Funding;Goals;Grant;Growth;Health;Health Disparities Research;Health Promotion and Education;Inequity;Institution;Interdisciplinary Study;Malignant Neoplasms;Measurable;Medical;Mentors;Mentorship;Minority Groups;Minority Health Research;Minority-Serving Institution;Pathway interactions;Pilot Projects;Population;Population Sciences;Positioning Attribute;Postdoctoral Fellow;Qualifying;Research;Research Infrastructure;Research Institute;Research Personnel;Research Project Grants;Research Project Summaries;Research Support;Research Training;Rotation;Science;Special Population;Students;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;Work;anticancer research;cancer education;cancer health disparity;career;career development;cohort;college;community based participatory research;community engaged research;community partnership;design;education research;experience;graduate student;health disparity;innovation;inter-institutional;medical schools;minority communities;multidisciplinary;novel;population based;pre-doctoral;professional students;programs;racial minority;skills;student mentoring;systemic barrier;training opportunity;undergraduate student;underrepresented minority student;underserved community;underserved minority;university student Research Education Core n/a NCI 10757263 9/19/23 0:00 PAR-22-249 2U54CA221705-06 2 U54 CA 221705 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5044 1866225 "FANG, CAROLYN Y." Not Applicable 2 Unavailable 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA Domestic Higher Education 191226003 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 270400 246813 23587 PROJECT SUMMARYResearch Education CoreTUFCCC: Dr. Carolyn Fang (Co-Leader) HC: Dr. Olorunseun OgunwobiThe Research Education Core (REC) builds upon our successful 5-year U54 Partnership and rigorousmultidisciplinary training environment at Temple University-Fox Chase Cancer Center (TUFCCC) and HunterCollege (HC). The overarching goal of the REC is to promote inclusive excellence in the training andprofessional and scientific development of Early-Stage Investigators (ESIs) and students through intensivementored experiences in cancer health disparities research. The REC leverages exceptional institutionalstrengths in training and research education across TUFCCC and HC the outstanding core facilities of an NCI-designated Comprehensive Cancer Center our combined interdisciplinary research infrastructure in populationclinical translational and basic sciences and a diverse student population across both institutions. In addition toresearch training the Research Education Core will nurture and mentor students throughout their studies infuse21st century skills of collaboration and communication and develop professional career opportunities. Theoverarching goal of the Research Education Core is to support educational activities that complement andenhance the training of a diverse workforce to meet the nations cancer research needs. To achieve this goalthe Research Education Core will address the following specific aims: Aim 1. Provide mentorship and researchsupport for 8 diverse ESIs to enhance career development and facilitate their transition to independentinvestigators in cancer disparities research. The two-year fellowship will culminate with an application for externalfunding to support the trainees transition into an independent investigator. Aim 2. Implement an enhanced 10-week Summer Cancer Research Institute (SCRI) for 15 undergraduate and graduate students in biomedical orpopulation cancer research per year (75 students over 5 years). Our successful SCRI program which offersunique training opportunities for undergraduate and graduate students in biomedical clinical or population-based cancer research will be expanded from 10 to 15 trainees per year (a 50% increase). Aim 3. Facilitateacademic-community research opportunities to support the conduct of culturally appropriate cancer research inpartnership with underserved minority communities and populations. In collaboration with the COC and keycommunity partners the REC will establish a semester-long rotation for ESIs and other trainees to foster greaterskills in conducting community-engaged research to address health disparities. These novel trainingopportunities offered through collaborative academic-community partnerships will provide innovative hands-onfieldwork experiences for trainees. In sum the Research Education Core will promote inclusive excellence inbuilding a diverse workforce by breaking systemic barriers (including structural inequities and limited access tomentored training) building a sense of community and offering a sustainable pathway for impacting change andadvancing the careers of ESIs and other trainees working in cancer health disparities. +No NIH Category available Address;Adopted;Advanced Malignant Neoplasm;Area;Benchmarking;Cancer health equity;Clinical;Collaborations;Communication;Communities;Community Outreach;Consensus;Consensus Development;Data;Data Collection;Development;Doctor of Philosophy;Education and Outreach;Ensure;Equity;Evaluation;Feedback;Foundations;Fox Chase Cancer Center;Funding;Goals;Grant;Grant Review;Health Disparities Research;Health Policy;Health system;Impact evaluation;Individual;Information Dissemination;Infrastructure;Institution;Leadership;Logic;Measures;Mentors;Mentorship;Methods;Minority Groups;Modeling;Monitor;Online Systems;Outcome;Peer Review;Phase;Play;Policies;Positioning Attribute;Procedures;Process;Productivity;Publications;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;System;Technology;Training;United States National Institutes of Health;Universities;Vision;Work;cancer care;cancer health disparity;college;community based research;community engagement;cost;design;experience;formative assessment;functional independence;health equity;improved;innovation;member;population health;preservation;programs;repository;senior faculty;sharing platform;social;success;systemic barrier;underserved minority Planning and Evaluation Core n/a NCI 10757262 9/19/23 0:00 PAR-22-249 2U54CA221705-06 2 U54 CA 221705 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5043 6255019 "MA, GRACE X." Not Applicable 2 Unavailable 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA Domestic Higher Education 191226003 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 171021 107900 63121 PROJECT SUMMARYPlanning and Evaluation CoreTU FCCC: Grace X. Ma PhD (Co-Leader) HC: Sarah Jane Dodd PhD MSW (Co-Leader) Lin Zhu PhD (Co-Leader ESI)The overall goal of Planning and Evaluation Core (PEC) is to build on the infrastructure created and continue to: 1)improve the foundation to support planning monitoring and evaluation of the impact of research projects coresand shared resources of Temple University Fox Chase Cancer Center (TUFCCC) and Hunter College (HC)Partnership on reducing cancer health disparities and advancing health equity; and 2) maximize resources identifynew directions and actively facilitate by bringing senior faculty early-stage investigators and trainees together todesign and pursue cutting-edge cancer health disparities research through rigorous solicitation evaluation andselection of new projects using NIH grant review criteria. Guided by the TUFCCC/HC Partnership Logic Model thePEC team will collaborate with each Core/Project leaders to develop specific evaluation plans; implementprocedures to collect all necessary evaluation data with the least cost and burden to Partnership leadersresearchers and community members. The PEC team will introduce new features to enhance our capacity forevaluating the scientific integration and collaboration across the Partnership bi-directional community engagementand institutional changes both qualitatively and quantitatively. The PEC will leverage the innovativeComprehensive and Dynamic e-Platform (CDEP) established during current TUFCCC/HC Partnership 1.0 to furtherstrengthen the support for planning process outcome and impact evaluation of all Core/Projects and the overallPartnership. Building on the robust process the PEC team with support of the AC IAC PSC and NCI will solicitevaluate and select new research projects to increase the competitive research capacity among TUFCCC/HCpartners and promote cutting-edge basic clinical translational and community-based research initiatives in cancercare for underserved minority populations. The PEC will use the NCI Grid-Enabled Measures (GEM) Platform toorganize and facilitate consensus building within and across the Partnership in shared program priorities sharedcommon metrics measures benchmarks analysis and dissemination. Broadly this evaluation will include a three-tier strategy focused on individual Cores/projects the overall Partnership and the broader collaboration betweenthe TUFCCC/HC Partnership and communities served by other NCI/CRCHD funded Partnerships. The PECrenewal application is designed to center around breaking systemic barriers and promote inclusive excellencethrough identifying resources and improving infrastructure in Four Pillars: research projects training/mentorshipand community outreach/engagement as well as research capacity building. The PEC will be guided by the IEframework and the Partnerships Vision to monitor progress and evaluate impact of U54 components and theoverall Partnership towards advancing cancer health equity in the PNN region and beyond. +No NIH Category available Address;Affect;African American;African American population;African ancestry;American;Animals;BRCA mutations;BRCA1 gene;Basic Research Breast Cancer;Bioinformatics;Biological;Biological Markers;Biological Specimen Banks;Biology;Biometry;Black American;Black race;Breast Cancer Cell;Breast Cancer Patient;Cancer Biology;Cancer health equity;Cell Culture Techniques;Cell Line;Cells;Chromosomes;Clinical;Collaborations;Communities;Community Outreach;Complex;DNA Damage;DNA Repair Pathway;DNA biosynthesis;Data Analyses;Detection;Diagnosis;Disparity;Doctor of Philosophy;Educational workshop;Eligibility Determination;Ethics;Ethnic Origin;European;Exposure to;Fox Chase Cancer Center;Gene Amplification;Genetic Engineering;Genetic Screening;Goals;Health Fairs;Human;Imaging technology;Immunohistochemistry;Informed Consent;Institution;Learning;MDM2 gene;Malignant Neoplasms;Mentors;Microarray Analysis;Molecular Biology;Morbidity - disease rate;Mutation;Neoplasm Circulating Cells;Outcome;Participant;Pathology;Pathway interactions;Patients;Pilot Projects;Play;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Population;Probability;Proliferating;Proteins;Race;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Sampling;Scientist;Signal Transduction;Specimen;Stains;Students;TP53 gene;Testing;Tissue Microarray;Tissues;Training;Tumor Tissue;Underrepresented Minority;Underrepresented Students;Universities;Woman;Work;Xenograft procedure;aggressive breast cancer;animal imaging;biological research;cancer biomarkers;cancer health disparity;cancer subtypes;cohort;college;data acquisition;education research;empowerment;follower of religion Jewish;health disparity;improved;inhibitor therapy;insight;malignant breast neoplasm;minority engagement;minority trainee;mortality;mouse model;mutant;mutation carrier;next generation;novel;patient derived xenograft model;protein expression;replication stress;reverse genetics;screening;systemic barrier;targeted treatment;temozolomide;therapeutic target;triple-negative invasive breast carcinoma;tumor;university student Pilot Research Project: Evaluating Black and African American Breast Cancer Populations for Therapeutic Targeting of Aberrant p53 MDM2 MDMX and PARP signaling n/a NCI 10757261 9/19/23 0:00 PAR-22-249 2U54CA221705-06 2 U54 CA 221705 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5042 1939293 "CONNOLLY, DENISE C" Not Applicable 2 Unavailable 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA Domestic Higher Education 191226003 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 342926 216357 126569 Project SummaryEvaluating Black and African American Breast Cancer Populations for Therapeutic Targeting of Aberrant p53 MDM2 MDMX and PARP signalingHC: Jill Bargonetti PhD (Co-Leader)TUFCCC: Denise Connolly PhD (Co-Leader)Partnerships are needed to break the systemic barriers that have limited systematic and ethicalbiological research on the underpinnings of aggressive triple negative breast cancer (TNBC) inBlack Americans of African Ancestry (AA). Our U54 partnership increases the ability to studyunderstudied biomarkers in order to improve screening and treatment options. This U54 pilotproject brings together teams of established scientists at Hunter College (HC) and TempleUniversity Fox Chase Cancer Center (TUFCCC) to analyze already available AA patient breastcancer samples for screening highly probable aggressive breast cancer biomarkers that mayfacilitate targeted treatments for AA TNBCs. Moreover the team will mentor underrepresentedstudents from HC with cross-institutional exposure to different state of the art scientific platformto Address Cancer Health Equity in training as well as research objectives. The primary goal ofthis project is to determine if PARP inhibitor (PARPi) therapeutics can be expandedbeyond the mutant BRCA1 cohorts to Black/AA cohorts with mtp53/MDM2/MDMX/PARPbiomarkers. We will educate the Black/AA community about breast cancer biomarkers and willempower them to ask biomarker-based questions during diagnosis and treatment. The aims arethe following. 1) To compare the expression of MDM2 MDMX mtp53 and PARP in breast cancer(BC) tumors from AA and EA patients. We will construct (BC) tissue microarrays (TMAs) fromretrospectively collected tumors from 125 AA and 125 EA patients. TMAs will be stained forMDM2 MDMX p53 and PARP. 2) We will test the driver roles of the MDM2/MDMX-mtp53-PARPfor targeting BCs with PARPi therapies in cell culture and xenograft mouse models. We will workwith the Community Outreach Core to educate community about breast cancer biomarkersBreak Systemic Barriers to Inclusion: This study directly addresses systemic barriers of AAwomen as an understudied cohort for biological determinants of TNBC. We are collating TUFCCCBC AA samples with the goal of identifying potential targeted therapeutic options to reduce breastcancer disparities. Completion of this work will provide insights on critical breast cancerbiomarkers mtp53/MDM2/MDMX/PARP in Black/AAs and will educate the next generation ofunder-represented scientists. +No NIH Category available 3-Dimensional;Acculturation;Address;Affect;African American;American Society of Clinical Oncology;Bass;Biostatistics Core;Black race;Cancer Center;Cancer Patient;Cervical;Communication;Communities;Community Outreach;Comparison arm;Conflict (Psychology);Country;Data;Decision Aid;Decision Making;Devices;Dimensions;Doctor of Philosophy;Educational Materials;Effectiveness;Family;Funding;Gallbladder;Gender;Genes;Genetic;Genetic Counseling;Genetic Risk;Genetic study;Genomics;Goals;Grant;Health;Health Promotion;Health behavior change;High-Risk Cancer;Hispanic Americans;Information Management;Intervention;Knowledge;Language;Latinx;Latinx population;Link;Liver;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Maps;Marketing;Medical;Medical Genetics;Methods;Modeling;Mutation;New York City;Not Hispanic or Latino;Oncologist;Oncology;Patient Preferences;Patient Recruitments;Patients;Perception;Philadelphia;Policies;Population;Population Heterogeneity;Provider;Public Health;Readiness;Reporting;Research Personnel;Research Project Grants;Risk;Risk Assessment;Site;Stomach;Tablets;Test Result;Testing;Underserved Population;Vision;Work;Writing;arm;cancer health disparity;cancer risk;cancer therapy;cultural values;eHealth;education research;efficacy evaluation;efficacy testing;ethnic diversity;falls;genetic information;genetic testing;health equity;hereditary risk;improved;innovation;intervention participants;mortality;precision oncology;preference;primary outcome;provider communication;racial diversity;randomized trial;recruit;secondary outcome;support tools;systemic barrier;tool;treatment arm;tumor;vector Full Research Project 1: Testing the Efficacy of an eHealth Decision Support Tool to Help Latinx Cancer Patients Make Informed Decisions About Tumor Genomic Testing n/a NCI 10757259 9/19/23 0:00 PAR-22-249 2U54CA221705-06 2 U54 CA 221705 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5040 6597778 "BASS, SARAH B" Not Applicable 2 Unavailable 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA Domestic Higher Education 191226003 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 66675 52050 14625 Project SummaryFull Research Project 1 Genomic TestingTesting the Efficacy of an eHealth Decision Support Tool to Help Latinx Cancer Patients Make Informed Decisions About Tumor Genomic TestingTU FCCC: Sarah Bauerle Bass PhD MPH (Co-Leader) and Michael Hall MD MS (Co-Leader)HC: Tracey A. Revenson PhD (Co-Leader) and Ana F. Abrado-Lanza PhD (Latinx Culture Leader)The use of tumor genomic profiling (TGP) to identify potential cancer treatments can also identify secondaryhereditary risks the patient was unaware of. ASCO policy mandates communication of TGP risks and elicit patientpreferences for managing these types of results. Latinx patients have increased cancer risk and mortality but areespecially vulnerable to barriers that would impede optimal decision making about secondary genetic risksincluding language and acculturation barriers access and affordability deportation risks medical mistrust and lowgenetic knowledge. The primary goal of this study is to evaluate the efficacy of an electronic health (eHealth)decision support tool (DST) to increase informed decision making among Latinx patients. This proposal builds oncurrent RCT results of testing an eHealth DST called Gene Pilot with Black cancer patients and formative workwith Latinx patients funded by the pilot mechanism of the current U54 Partnership. These studies use innovativecommercial marketing methods to address TGP concerns promote informed decision making and increasecommunication with providers about preferences for secondary genetic information. Grounded in the OttawaFramework the study will determine the efficacy of a revised DST Gene PilotLX compared to traditional decisionsupport. Specific aims are: 1. Revise the Gene Pilot DST to reflect formative work with Latinx cancer patients toincorporate specific cultural values and language needs. We will use formative results and establish Communityand Scientific Advisory Boards to revise content to make it culturally-anchored. We will then conduct user testingwith 25 Latinx cancer patients; 2. Test the impact of Gene PilotLX in a randomized trial. We will conduct a fullypowered RCT with 232 Latinx cancer patients at four oncology sites. Intervention participants will have access toGene PilotLX via a tablet or personal device; the comparison arm will receive non-targeted education materialsabout TGP. Primary outcomes include decision preparedness decisional conflict and communication ofpreferences with a doctor. Secondary outcomes include communication of preferences with family and changes inperceptions of TGP. H1: Those in the Gene PilotLX arm will have greater reduced decisional conflict and higherdecision preparedness compared to the non-targeted decision aid. H2: Those in the Gene PilotLX arm will reportcommunicating TGP preferences with their oncologist more when compared to the non-targeted information arm;and 3. Determine whether the effects of Gene PilotLX on primary and secondary outcomes are moderated byLatinx cultural values and acculturation. H3: Gene PilotLX will have a larger effect on primary outcomes for thoseholding stronger values of familismo and those who are more acculturated than those with lower values. Thereverse will occur with the Latinx value of fatalismo. Break Systemic Barriers to Inclusion: In line with the U54sInclusive Excellence vision this study addresses systemic barriers by focusing on Latinx-specific challenges toengaging and communicating about TGP thereby reducing potential cancer health disparities by improvinginformed decision making in an under-studied population at high risk of cancer. +No NIH Category available Accountability;Address;Advanced Malignant Neoplasm;Advisory Committees;African;African American;American;Asian;Asian Pacific American;Black race;Cancer Research Project;Collaborations;Communication;Communities;Community Outreach;Decision Making;Doctor of Philosophy;Education;Education and Outreach;Ensure;Equity;Evaluation;Faculty;Fostering;Foundations;Fox Chase Cancer Center;Goals;Grant;Health Disparities Research;Health Sciences;Health system;Hispanic Americans;Infrastructure;Institution;Joints;Latinx;Leadership;Letters;Localized Malignant Neoplasm;Mentors;Mission;New Jersey;New York City;Organization administrative structures;Outcome Measure;Performance;Philadelphia;Productivity;Regional Cancer;Research;Research Infrastructure;Research Personnel;Research Priority;Research Project Grants;Resource Sharing;Science;Services;Structure;Underserved Population;Universities;Vision;Work;anticancer research;cancer health disparity;cancer prevention;career;college;community organizations;design;equity diversity and inclusion;ethnic minority population;experience;implementation outcomes;improved;inter-institutional;medical schools;meetings;member;multidisciplinary;operation;organizational structure;population health;programs;racial minority population;systemic barrier Administrative Core n/a NCI 10757257 9/19/23 0:00 PAR-22-249 2U54CA221705-06 2 U54 CA 221705 6 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5038 6255019 "MA, GRACE X." Not Applicable 2 Unavailable 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA Domestic Higher Education 191226003 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 263108 176833 86275 PROJECT SUMMARYAdministrative CoreTUFCCC: Grace X. Ma PhD (Contact PI) and Camille Ragin PhD MPH (MPI) HC: Olorunseun Ogunwobi MD PhD (Contact PI) and Joel Erblich PhD MPH (MPI)The Administrative Core (AC) of the TUFCCC/HC Regional Comprehensive Cancer Health DisparitiesPartnership 2.0 (aka: SPEECH 2.0) builds on an established effective leadership governance infrastructure andfoundation of productivity and impact. Over the past 5 years the Partnership directly supported 84 investigators56 cancer disparities research projects mentored 180 trainees (61% received career or educationadvancements) and engaged 50 diverse community-based organization partners in cancer prevention activities.The overall goal of the AC for SPEECH 2.0 is to further enhance cancer health disparities research infrastructureand our administrative leadership to provide vigorous scientific/programmatic oversight and integration ofresearch projects education/training and community outreach and engagement activities to be conducted bythe Partnership ensuring high-quality standards of excellence and impact on advancing cancer equity inunderserved Black/African American (AA) Asian Pacific Americans (APA) and Hispanic American/Latinx (HA)communities in the Philadelphia NJ and NYC (PNN) region. The ACs functions include but are not limited toproviding leadership oversight fiscal management coordination integration and communication to support thePartnerships day-to-day operations. The AC will ensure the efficient effective and synergistic performance ofthe proposed Partnerships aims throughout all of the projects cores and shared resources. The aims of theintegrated TUFCCC/HC Administrative Core are as follows: Aim 1. Leverage the established organizationalstructure to enhance operational capacity and provide robust administrative and fiscal support for overallprogram activities of TUFCCC/HC Partnership cores and research projects. Aim 2. Facilitate and enhancecommunication and collaboration opportunities to promote team science among Partnership faculty traineesinvestigators and program coordinators. Aim 3. Strengthen and maintain leadership infrastructure to ensure theintegration of cores projects shared resources as well as inter-institutional initiatives across Partnership andbeyond. Aim 4. Establish and maintain sustainable infrastructure to support and ensure the competitiveness ofthe Partnership's research project portfolio. Aim 5. Direct and support continuous quality improvement usingmultiple metrics to inform decision-making in planning and evaluation across all cores and projects of thePartnership. Both institution leaders have and will continue to provide exceptional commitments to SPEECH 2.0.AC has been well established and integrated and will continue to be jointly led by experienced multidisciplinarycancer research leaders. The AC team demonstrated not only synergistic accomplishments during SPEECH 1.0but also strong long-term commitments to the shared vision of advancing cancer equity among underservedpopulations. Inclusive Excellence will serve as our guiding principle across all cores and projects. In practicethe AC core will be committed to addressing systemic barriers and incorporating diversity equity and inclusionefforts into all aspects of our Partnership for the proposed next U54 grant period. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;African American;Area;Asian Americans;Asian Pacific American;Basic Science;Bioinformatics;Biometry;Black race;COVID-19 pandemic;Cancer Intervention;Cancer health equity;Career Mobility;Clinical Sciences;Collaborations;Communities;Community Health Aides;Community Outreach;Competence;Comprehensive Cancer Center;County;Data;Diagnosis;Discipline;Doctor of Philosophy;Education;Equity;Evaluation;Faculty;Feedback;Fostering;Foundations;Fox Chase Cancer Center;Funding;Grant;Health;Health Disparities Research;High Prevalence;Hispanic Americans;Hispanic-serving Institution;Individual;Infrastructure;Institution;Interdisciplinary Study;Intervention;Malignant Neoplasms;Mentors;Mentorship;Methods;Minority;Modeling;Monitor;Needs Assessment;Neighborhoods;Outcome;Pilot Projects;Population;Population Sciences;Positioning Attribute;Poverty;Publications;Recommendation;Research;Research Infrastructure;Research Institute;Research Personnel;Research Project Grants;Research Support;Resources;Risk Factors;Schools;Science;Scientist;Societies;Strategic Planning;Students;Target Populations;Training;Underrepresented Populations;Underrepresented Students;Underserved Population;Universities;Vision;Workforce Development;advanced disease;anticancer research;aspirate;bench to bedside;cancer education;cancer health disparity;cancer prevention;cancer risk;career development;college;community based participatory research;community engagement;community organizations;education research;ethnic minority;evidence base;experience;improved;innovation;member;mortality;multidisciplinary;next generation;outreach;outreach program;programs;racial minority;recruit;screening;skills;social determinants;structural determinants;success;systemic barrier;translational approach;undergraduate student;underserved community (1/2) TUFCCC/HC Regional Comprehensive Cancer Health Disparities Partnership PROJECT NARRATIVEOverallThe underserved vulnerable African American Asian-Pacific American and Hispanic American populations inthe PA-NJ-NYC region experience significant cancer-related health disparities across the cancer continuumfrom a higher prevalence of cancer risk factors to delayed screening and diagnoses experiencing moreadvanced disease and poorer outcomes. SPEECH has made significant strides toward transforming cancerhealth disparities research and education; research infrastructure and platforms that enabled investigators toadvance cancer health equity in these underrepresented and underserved populations. In the next five yearsour Partnership aims to advance cancer health disparities research training/workforce development andcommunity-informed interventions by breaking structural systemic barriers and promoting inclusiveexcellence across disciplines among basic clinical and population science researchers trainees and diverseunderserved communities NCI 10757256 9/19/23 0:00 PAR-22-249 2U54CA221705-06 2 U54 CA 221705 6 "SAN MIGUEL-MAJORS, SANDRA L" 9/19/18 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 6255019 "MA, GRACE X." "ERBLICH, JOEL ; OGUNWOBI, OLORUNSEUN O; RAGIN, CAMILLE C." 2 INTERNAL MEDICINE/MEDICINE 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA SCHOOLS OF MEDICINE 191226003 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1763950 NCI 1275578 488372 PROJECT SUMMARYOverall TUFCCC: Grace X. Ma PhD (Contact PI) and Camille Ragin PhD MPH (MPI)HC: Olorunseun O. Ogunwobi MD PhD (Contact PI) and Joel Erblich PhD MPH (MPI)The Synergistic Partnership for Enhancing Equity in Cancer Health (SPEECH) is a highly collaborative andmutually beneficial Partnership between Temple University/Fox Chase Cancer Center (TUFCCC) and HunterCollege (HC) and the only NCI-funded U54 CPACHE in PA and NJ and one of two in NYC. Our establishedrobust research infrastructure has made significant contributions to addressing substantial cancer healthdisparities (CHD) in underserved African American Asian-Pacific American and Hispanic American populations.These target populations have higher cancer mortality rates compared to others in the U.S. and majority live inneighborhoods with medium-very high and persistent poverty. In the past five years SPEECH directly supported84 investigators mentored 180 trainees funded 56 cancer disparities projects facilitated 93 publications anddirectly stimulated $45 million externally funded grants. Additionally 14 minority ESIs received careeradvancement we engaged 50 community-based organizations trained 41 community health workers andeducated 1200 members of diverse communities in cancer prevention. Leveraging this momentum of successour Vision is to Promote Inclusive Excellence and break systemic barriers to close gaps in cancer healthdisparities research education community outreach and engagement and achieve infrastructure capacitybuilding. Through exceptional institutional commitments two full projects a pilot project and integrated cores ofAdministrative Research Education Biostatistics/Bioinformatics Planning and Evaluation and CommunityOutreach we propose to achieve the following specific aims. Aim 1: Accelerate TUFCCC-HC Partnershiptransdisciplinary cancer disparities research collaborations and advance cancer health equity across thespectrum of basic clinical and population sciences. Aim 1a: build strengthen and sustain cancer researchcapacities and infrastructure at HC. Aim 1b: advance CHD research to maximize impact at TUFCCC. Aim 1c:foster community-driven research to address cancer disparities in the PA-NJ-NYC region. Aim 2. Train the nextgeneration of CHD scientists and workforce leaders for a pipeline of diverse and underrepresented studentsproviding them with multidisciplinary cancer disparities research education experiences and mentorship andcareer development opportunities through the implementation of enhanced Summer Cancer Research Instituteand newly established Hunter/Temple HEAL Program. Aim 3. Recruit mentor and retain diverse ESIs especiallyURM groups to enhance career development and facilitate their transition to independent investigators. Aim 4.Use bidirectional community engagement approaches to implement a robust community outreach program thatbuilds bridges between diverse communities and researchers to support: a) cancer education and interventionsb) cancer disparities research projects and c) CBPR competencies for investigators and trainees. Aim 5.Conduct a mixed-method evaluation aimed at monitoring progress providing feedback and summative impactdata on all Partnership programing for promoting sustainable solutions to improved cancer health equity. 1763950 +No NIH Category available Acquired Immunodeficiency Syndrome;Address;Adverse event;Advocacy;Affect;Area;Cancer Center;Caring;Cervical Cancer Screening;Client;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Clinical effectiveness;Collaborations;Colposcopy;Communicable Diseases;Communities;Community Networks;Diagnosis;Eligibility Determination;Enrollment;Ensure;Environmental Risk Factor;Equity;Feedback;Funding;Geographic Locations;Goals;Gynecologist;Gynecology;HIV;HIV Infections;HIV diagnosis;Health Services Accessibility;Health system;Healthcare Systems;Hospitals;Human Papillomavirus;Infrastructure;Institution;Interdisciplinary Study;Intervention;Leadership;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Mentors;Morehouse School of Medicine;Outcomes Research;Participant;Persons;Population;Population Heterogeneity;Positioning Attribute;Poverty;Pragmatic clinical trial;Prevalence;Prevention;Procedures;Protocols documentation;Reporting;Research;Research Infrastructure;Research Personnel;Resources;Risk;Rural;Rural Community;Services;Site;Socioeconomic Factors;Structure;Training;Travel;Treatment outcome;Universities;Urban Community;Woman;Women's Health;Women's Interagency HIV Study;Work;black women;cancer risk;cervical cancer prevention;clinical care;clinical infrastructure;clinical research site;clinical trial protocol;community clinic;community engagement;community organizations;community partnership;cultural competence;data quality;deprivation;design;diversity and equity;ethnic minority;experience;follow-up;health care availability;health communication;health disparity;human subject;implementation science;improved;indexing;innovation;mHealth;malignant breast neoplasm;member;mortality;multidisciplinary;participant retention;patient navigation;prevention service;programs;racial minority;recruit;reproductive outcome;research study;retention rate;rural area;rural counties;rural setting;screening;screening guidelines;screening program;social health determinants;underserved area;urban setting Georgia Consortium to Eliminate Cervical Cancer in Women Living with HIV (GaCECC-WLWH) PROJECT NARRATIVEHIV and cervical cancer severely impact racial and ethnic minorities in Georgia particularly Black women livingwith HIV (WLWH). The Georgia Consortium to Eliminate Cervical Cancer in Women Living with HIV maximizesthe collaborative strengths of Emorys high-impact HIV research and clinical network and Morehouse School ofMedicines strong community and clinical partnerships by engaging a diverse array of community memberswho serve WLWH. This unique setting of multidisciplinary partners will provide the CASCADE Network withvaluable information on the clinical effectiveness and scalability of interventions aimed at improving cervicalcancer prevention in WLWH. NCI 10757203 8/10/23 0:00 RFA-CA-22-051 1UG1CA284884-01 1 UG1 CA 284884 1 "FRECH, MARIA SILVINA" 8/15/23 0:00 5/31/27 0:00 ZCA1-SRB-F(M3) 1872503 "FLOWERS, LISA C." "SHETH, ANANDI NAYAN" 5 OBSTETRICS & GYNECOLOGY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 8/15/23 0:00 5/31/24 0:00 399 Other Research-Related 2023 324621 NCI 207425 117196 PROJECT SUMMARY/ABSTRACTWomen living with HIV (WLWH) have a substantially increased risk for cervical cancer when compared to womenwithout HIV infection (1). Georgia has the second largest population of people living with HIV in the US with aprevalence of 1.9 times the national rate (2). Simultaneously Georgias rates of cervical cancer are notablyhigher than the national average with 8.0 per 100000 women diagnosed between 2015-2019 (3). Black womenare disproportionately impacted by HIV(4) and cervical cancer in Georgia (5) and have significantly higher ratesof being lost to follow-up and not undergoing colposcopy or treatment after an abnormal cervical cancer screenwhen compared to white women (6). It is thus imperative that Georgia is a focal point of pragmatic clinical trialsto address cervical cancer screening and treatment among WLWH who face health disparities. The GeorgiaConsortium to Eliminate Cervical Cancer in Women Living with HIV (GaCECC) encompasses established well-funded programs in Georgia that service WLWH and are primed to conduct the CASCADE Network clinicaltrials. The GaCECC includes Emory University HIV research and clinical networks urban and rural Ryan Whitefunded clinics Morehouse School of Medicines (MSMs) extensive community networks Georgia Cancer Centerfor Excellence at Grady Health System (GCCE) and respected HIV and womens health community-basedorganizations in Georgia. The GaCECC has access to thousands of WLWH through various clinical sites thatserved over 9000 WLWH and performed over 5000 cervical cancer screenings between 2020-2021 in bothurban and rural settings across Georgia. These sites serve high proportions of Black women who aredisproportionately affected by social determinants of health. The GaCECCs experienced client navigationservices will work to optimize participant access to and completion of recommended screening and treatmentsequences. The GaCECC recruitment and retention team will assure seamless linkage of care between positivescreens at community clinics and colposcopy at the GCCE. Grady Memorial Hospital will provide its Grady MobileHealth Center Vehicle to bring colposcopy to women who are unable to travel to the GCCE. Emory UniversityMSM and AAPHC partner gynecologists will deliver CASCADE Network protocol-based treatment at theGCCE Ponce Infectious Disease Clinic and rural gynecology offices associated with AAPHC. Experiencedinvestigators and research staff in HIV and HPV clinical trials will proficiently implement clinical trials protocolsand ensure optimal retention. The GaCECC will use the strengths and resources leveraged by each collaboratorin this consortium to address cervical cancer prevention for WLWH. In sum the GaCECC will harness its clinicaland research leadership in HIV care and cervical cancer prevention (Aim 1) to advance research in cervicalcancer prevention among WLWH through the CASCADE Network clinical trial (Aim 2) to implement pragmaticclinical trials in cervical cancer prevention across all four scientific focus areas (Aim 3) and to utilize its networkof community partnerships to enroll and retain WLWH with an emphasis on equity and diversity. 324621 +No NIH Category available Address;African American;Age;Age of Onset;Alcohol abuse;Area;Artificial Intelligence;Baltimore;Caring;Cervical;Cervical Cancer Screening;Characteristics;Cities;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Clinical effectiveness;Collaborations;Colposcopy;Communicable Diseases;Communities;Community Outreach;Comprehensive Cancer Center;County;Cytopathology;Data;Data Science;Development;Disadvantaged;Disease;Early Diagnosis;Emerging Technologies;Enrollment;Ethnic Origin;Evaluation;Evidence based intervention;Excision;Failure;Gender;Gynecologic Oncology;HIV;Health;Health Services Accessibility;Heterogeneity;High Prevalence;Home;Housing;Human Papillomavirus;Human Resources;Incidence;Informatics;Infrastructure;Intervention;Laboratories;Leadership;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maryland;Mental Health;Methods;Neighborhoods;Outcome;Patients;Population;Population Sciences;Poverty;Pragmatic clinical trial;Prevalence;Prevention;Protocols documentation;Race;Recurrent disease;Research;Resources;Risk;Risk Factors;Sampling;Services;Site;Substance abuse problem;Technology;Translational Research;Transportation;Universities;University resources;Viral Load result;Visualization;Woman;cervical cancer prevention;cervicovaginal;chronic infection;clinically significant;community engagement;comorbidity;computerized;data management;economic disparity;effectiveness clinical trial;effectiveness evaluation;ethnic disparity;health care availability;health care service;health illiteracy;high risk;immune reconstitution;implementation science;implementation strategy;improved;inner city;insight;medical schools;molecular diagnostics;mortality;new technology;novel;oncology service;patient navigation;peer support;population based;pragmatic implementation;premalignant;preventive intervention;programs;protocol development;racial disparity;recruit;screening;screening guidelines;sex;social disparities;social health determinants;uptake Baltimore CASCADE Study Site (BaCSS Project) Baltimore CASCADE Study Site (BaCSS Project)Project Narrative African American Women living with HIV in disadvantaged regions of the US have an increased risk ofcervical cancer and require focused prevention interventions using novel and emerging technologies. In theBaCSS Project we engage the population science and clinical trials expertise and resources of the University ofMaryland School of Medicine (UMSOM) to establish a clinical study site for the CASCADE network. The projectprovides operational leadership and pluripotent infrastructure in support of the implementation science studiesand pragmatic clinical trials of evidence-based interventions for the prevention and early diagnosis of cervicalcancer and supports the development of concepts and protocols to overcome barriers and reduce failures incervical cancer prevention in WLWH. NCI 10757186 9/15/23 0:00 RFA-CA-22-051 1UG1CA284883-01 1 UG1 CA 284883 1 "FRECH, MARIA SILVINA" 9/15/23 0:00 5/31/27 0:00 ZCA1-SRB-F(M3) 9180528 "ADEBAMOWO, CLEMENT ADEBAYO" "TAYLOR, GREGORY H" 7 PUBLIC HEALTH & PREV MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/15/23 0:00 5/31/24 0:00 399 Other Research-Related 2023 308998 NCI 199999 108999 Baltimore CASCADE Study Site (BaCSS Project)Project summary Women living with HIV (WLWH) have a higher risk of cervical cancer because of incomplete immunereconstitution and high prevalence of risk factors for cervical cancer. The risk is greater among African American(AA) WLWH in economically and socially disadvantaged areas such as West Baltimore because of intersectionwith race gender social determinants of health (SDOH) and HIV co-morbidities including substance abuse.Despite the widespread availability of population-based cervical cancer screening in the US AA-WLWH living indisadvantaged areas have lower rates of screening uptake. Strategic evaluations of recently developed andemerging methods and technologies for cervical cancer prevention in intended use settings are urgently neededto address the cervical cancer prevention needs of this population. In the BaCSS project we engage the clinical and population science resources of the University ofMaryland School of Medicine (UMSOM) to establish a clinical study site for the CASCADE network. The site willenroll AA-WLWH into implementation science studies and clinical trials of evidence-based interventions for theprevention and early diagnosis of cervical cancer. The project provides operational leadership and pluripotentinfrastructure for these studies in the CASCADE network and supports the development of concepts andprotocols for pragmatic clinical trials of the effectiveness of clinically proven interventions to overcome barriersand reduce failures in cervical cancer prevention in WLWH. 308998 +No NIH Category available Attention;Award;Blood Transfusion;Breast;Breast Cancer Prevention;Breast Cancer Risk Factor;Breast Feeding;Cell Proliferation;Child;Circulation;Clinical;Clinical Trials;DDR2 gene;Data;Duct (organ) structure;Exposure to;Female;Future;Goals;Grant;Harvest;Hormone secretion;Hormones;Human;Immune Evasion;Incubated;Inflammation;Insulin-Like Growth Factor Binding Protein 4;Insulin-Like Growth Factor Binding Protein 5;Insulin-Like Growth Factor Receptor;Lactation;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Mediator;Messenger RNA;Modeling;Molecular;Monitor;Mothers;Mouse Mammary Tumor Virus;Mus;Neoplasm Metastasis;Oncogenes;Ovarian;Ovary;Peptide Hydrolases;Postpartum Period;Pregnancy;Pregnancy-Associated Plasma Protein-A;Procedures;Proliferating;Proliferation Marker;Protease Inhibitor;Proteins;Reporting;Risk;Role;STC1 gene;STC2 gene;Schedule;Serum;Signal Pathway;Signal Transduction;Testing;Time;Tissues;Transfusion;Transgenic Mice;Translating;Trees;Trust;Wild Type Mouse;Work;design;experimental study;forging;in vitro activity;inhibitor;malignant breast neoplasm;migration;mouse model;overexpression;prevent;protective effect;theories;tumor Exploring ovarian-derived hormone STC1 as the mediator of the protective effect of breast feeding against breast cancer. Breastfeeding is protective against breast cancer but the mechanism underlying this protective effect isunknown. This application focuses on the ovarian derived hormone STC1 as the driver of the protective effectof breastfeeding. NCI 10757058 12/22/23 0:00 PAR-20-292 5R21CA270702-02 5 R21 CA 270702 2 "PERLOFF, MARJORIE" 1/1/23 0:00 12/31/24 0:00 ZCA1-SRB-2(O1)S 7616499 "GERMAIN, DORIS A" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 213320 NCI 126225 87095 Pregnancy imposes remarkable changes to the breast; 1- during pregnancy impressive cellular proliferationand differentiation of the ductal tree is observed 2- during lactation the ultimate function of breast and 3- duringpost-lactation involution that is associated with tissue remodeling and inflammation. Interestingly both theproliferation during pregnancy and the inflammation during involution engage signaling pathways associated withcancer and indeed the risk of breast cancer increases following pregnancy. However extended lactationreduces that risk but the molecular mechanism of the protective effect of breastfeeding remains unknown. Basedon our preliminary data we postulate that the ovarian-derived hormone stanniocalcin 1 (STC1) is the potentialmediator of the protective effect of breastfeeding. STC 1 is a secreted hormone produced mainly by the ovariesduring lactation. It has been found to act as an inhibitor of the protease PAPP-A Pregnancy-Associated PlasmaProtein A. PAPP-A is a secreted protease that promotes proliferation through IGF signaling by degrading IGFBP-5 during involution promotes immune evasion and we reported takes advantage of the microenvironment ofinvolution to promote metastasis. PAPP-A is frequently overexpressed in the breast cancers and we havegenerated the first mouse model of PAPP-A driven mammary tumors. Importantly for this application we foundthat long lactation prevents the formation of PAPP-A-driven tumors. Our hypothesis is that ovarian-derived STC1produced during lactation reach the mammary gland through the circulation saturates and inhibits PAPP-A andis the mechanism underlying the protective effect of long lactation. We present preliminary data thatincubation of PAPP-A with serum taken from lactating females but not from non-lactating femalesinhibits its ability to degrade IGFBP-5. Further depletion of STC1 from lactating -female serum blocksthis effect. The goal of this exploratory award is to test if transfusions of blood from lactating donors into non-lactating recipients during post-partum involution can mimic the protective effect of lactation in these recipientfemales. In order to test this possibility we propose the following aims; Specific aim 1: Characterize potentialfluctuations in the serum concentration and activity of STC1 throughout lactation and determine if transfusionsof blood from lactating females can mimic the protective effect of long lactation in wild-type non-lactating mice.Specific aim 2: Testing the protective effect of ovarian STC1 against PAPP-A driven mammary tumors. In thisaim we will perform the same experiment described in aim 1 but in the MMTV-PAPP-A transgenic mice with twoexceptions. First since this model is much more aggressive than normal involution without prior lactation wewill use a more intense scheduling of transfusions. Second since 75% of PAPP-A transgenic mice develop post-partum mammary tumors when females do not lactate we will monitor tumor formation. 213320 +No NIH Category available Address;Altruism;Apoptosis;Apoptotic;B-Cell Lymphoma 6 Protein;B-Cell Lymphomas;B-Lymphocytes;BCL6 gene;Binding;Biology;Cancer Biology;Cancer Center;Cancer Etiology;Cell Death;Cell Death Induction;Cell Line;Cells;Characteristics;Chemicals;Chemistry;Chemotherapy-Oncologic Procedure;Clinical;Collaborations;Complex;Consult;DNA biosynthesis;Dana-Farber Cancer Institute;Data;Defect;Development;Diffuse;Dominant Genetic Conditions;Epigenetic Process;Estrogen Receptors;Foundations;Genes;Genetic Transcription;Genomics;Hematopoietic Neoplasms;Histone Deacetylation;Human;Lead;Lymphoma;Lymphoma cell;Maintenance;Malignant Neoplasms;Mediating;Modeling;Mutation;Neoplasm Metastasis;Normal Cell;Organism;Pathway interactions;Polycomb;Proliferating;Proteins;Publishing;Reporting;Repression;Research Personnel;Role;Side;Solubility;Specificity;TP53 gene;Testing;Therapeutic;Toxic effect;Transcription Coactivator;anticancer research;blood treatment;cancer cell;cancer genomics;cancer therapy;cell suicide;clinical development;derepression;effectiveness evaluation;gain of function;gain of function mutation;inhibitor;interdisciplinary approach;invention;novel;off-target site;overexpression;patient derived xenograft model;personalized medicine;promoter;recruit;small molecule;therapeutic development;transcription factor HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL RelevanceCancer researchers have identified genes and molecules that directly drive the proliferationsurvival and metastasis of cancer cells. In addition genes have been identified that can directan altruistic form of cellular suicide that protects the organism from mistakes in development orDNA replication. We are developing small molecules which we call TCIPs (TranscriptionalChemical Inducers of Proximity) that rewire the cancer cell to kill itself with its own driver andmay enable an entirely new less toxic and more effective approach to the treatment of bloodcancers. NCI 10757014 11/7/23 0:00 PA-20-185 5R01CA276167-02 5 R01 CA 276167 2 "O'HAYRE, MORGAN" 12/22/22 0:00 11/30/27 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1891587 "CRABTREE, GERALD R." "GRAY, NATHANAEL SCHIANDER" 16 PATHOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 483597 NCI 313210 170387 Project SummaryThe past two decades of cancer research have identified one or more drivers for most humanmalignancies. In addition multiple cell death genes and pathways have been identified thatnormally protect the organism against developmental mutations or defects in genomicmaintenance. These observations suggest that one might be able to rewire the transcriptionalcircuitry to cause the cancer cell to kill itself with its own driver. We have invented a new classof molecules that use Chemically Induced Proximity (CIP) to rewire the cancer cell such that thecancer driver activates proapoptotic pathways. We call these molecules TranscriptionalChemical Inducers of Proximity or TCIPs because they induce proximity or recruit a cancerdriver to the promoters of proapopotic genes. For development of these two-sided bifunctionalmolecules we will focus on Diffuse Large Cell B Cell Lymphoma (DLBCL) using the masterinhibitor of cell death BCL6 as an anchoring transcription factor on the promoters ofproapoptotic genes. For an activator we use any of several aberrantly-expressed transcriptionor epigenetic activators to simultaneously derepress and activate proapoptotic genes. We havesynthesized bifunctional small molecules that recruit transcriptional activators over-expressed inDLBCL to the promoters of proapoptotic genes normally bound and repressed by BCL6. In ourpreliminary studies these molecules lead to rapid and robust killing of DLBCL that is superior tothe best-in-class inhibitors and also specific for cells that over-express the targets of thebifunctional molecule. Using a strategy similar to genetic dominant gain-of-function mutationsTCIP can engage cancers with multiple drivers thereby going beyond conventional inhibitorsand degraders. Because bifunctional molecules rely on two separately overexpressed proteinsTCIP takes advantage of the natural fundamental basis of transcriptional specificity to provideprecise predictable and selective killing of cancer cells. To further develop this approach wewill first optimize these molecules for stability solubility and specificity of killing of DLBCL.Secondly we will define the mechanism by which they produce robust and rapid killing. Finallywe will test them in established PDX models. Our studies will involve a multidisciplinaryapproach drawing on expertise in chemistry clinical lymphoma treatment cancer biology andgenomic biology. If successful we will lay the foundation for a new concept in the treatment oflymphoma and more broadly cancer chemotherapy that is more specific than many existingapproaches. The use of a novel dominant gain-of-function strategy by TCIPs addresses theissue of treatment of cancers such as DLBCL that have multiple concurrent drivers. 483597 +No NIH Category available 3' Untranslated Regions;Acute Myelocytic Leukemia;Acute Promyelocytic Leukemia;Acute leukemia;Adult;Affect;Apoptosis;Binding;Binding Proteins;CRISPR screen;CRISPR/Cas technology;Cell Differentiation process;Cell physiology;Cells;Child;Data;Differentiation Therapy;Elements;Enhancers;Epigenetic Process;Family;Gene Expression;Genetic Diseases;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Human;Human Genetics;In Vitro;Intervention;Laboratories;Length;Leukemic Cell;Maintenance;Malignant - descriptor;Malignant Neoplasms;Maps;Messenger RNA;Modification;Mus;Myelogenous;Myeloid Leukemia;Patients;Pattern;Pharmaceutical Preparations;Poly(A) Tail;Post-Transcriptional Regulation;Proteins;RNA;RNA Recognition Motif;RNA Splicing;RNA-Binding Proteins;Regulator Genes;Regulon;Role;Shapes;Spliceosomes;Surface Antigens;Survival Rate;Testing;Transcript;Undifferentiated;Yin;ZFP36L2 gene;Zinc Fingers;acute myeloid leukemia cell;cell growth;epigenomic profiling;gain of function;genome-wide;in vivo;leukemia;leukemic stem cell;leukemic transformation;mRNA Stability;mRNA Transcript Degradation;mRNA Translation;member;monocyte;neoplastic cell;novel;overexpression;paralogous gene;posttranscriptional;progenitor;screening;self-renewal;stem;stem cell differentiation;stem cells;stemness;targeted treatment;tumor initiation;tumor progression mRNA stability and its impact on hematopoiesis and acute leukemia NarrativeThis application focuses on a family of RNA-binding proteins (ZFP36/TIS11) identified in ourscreens are able to control stemness and differentiation of acute myeloid leukemia (AML) cells.It tests the hypothesis that 3UTR targeting of key hematopoiesis-regulating mRNAs by theZFP36/TIS11 family represents a novel posttranscriptional mechanism of stem cell differentiationand leukemic transformation. NCI 10756984 12/21/23 0:00 PA-20-185 5R01CA266212-03 5 R01 CA 266212 3 "KLAUZINSKA, MALGORZATA" 1/1/22 0:00 12/31/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 7647769 "AIFANTIS, IANNIS " Not Applicable 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 486121 NCI 286797 199324 AbstractThis application focuses on acute myeloid leukemia (AML) a blood cancer that is characterized by lowsurvival rates and few available targeted therapies. The five-year overall survival rate for AML is below30 percent in adults and around 65% in children. Interestingly one type of intervention that has beensuccessful for a subtype of AML (acute promyelocytic leukemia APL) is a differentiation therapywhere drugs can induce tumor cell differentiation and apoptosis. Here we present surface antigen-guided CRISPR/CAS9 differentiation screens in AML and study one of the most prominent hits in thesescreens the RNA binding protein (RBP) ZFP36L2. RBPs can modify RNA at multiple levels includingsplicing processing modification and degradation. Considering that RBPs are key regulators of geneexpression alterations of these proteins are also implicated in several human genetic diseasesincluding cancer. Our laboratory has recently presented CRISPR/CAS9 screening of RBPs in severaltypes of human leukemia and identified novel regulators of the spliceosome machinery in blood cancers.Our CRISPR screens identified ZFP36L2 a member of the TIS11/TTP zinc-finger containing family ofRBPs that also includes the ZFP36 and ZFP36L1 paralogs. We were able to show that ZFP36L2 bindsAU-rich elements on 3 untranslated regions (UTRs) of a number of mRNAs that that control earlyhematopoietic and myeloid differentiation. This interaction promotes target mRNA degradation and themaintenance of an undifferentiated state. These studies showed that ZFP36L2 can bind and degradethe two other members of the TIS11/TTP family ZFP36 and ZFP36L1 creating a potential additionallevel of post-transcriptional regulation of differentiation. Inhibition of ZFP36L2 restores mRNA stabilityof targeted transcripts and triggers leukemia cells to undergo myeloid differentiation and eventualapoptosis. Epigenomic profiling of a number of primary AML patients revealed enhancer modulesnearby ZFP36L2 that associated with distinct AML cell states establishing a coordinated epigeneticand post-transcriptional mechanism that shapes leukemic differentiation. In this application we initially(Aim 1) focus on the in vivo role of ZFP36L2 in AML and identify mRNAs direct targets that can controlAML cell differentiation and growth. In Aim 2 we study all three members of the ZFP36/TIS11 familyand study in detail their roles in hematopoiesis and myeloid leukemia. 486121 +No NIH Category available Acidity;Acidosis;Acute;Address;Angiogenic Factor;Animal Cancer Model;Anti-Bacterial Agents;Anti-Inflammatory Agents;Area;Award;Blood Vessels;Bone Marrow;Breast Cancer Model;Breast Cancer Patient;Chemotherapy and/or radiation;Chronic;Development;Dichloromethylene Diphosphonate;Disparate;Effectiveness;Electron Spin Resonance Spectroscopy;Elements;Endothelium;Event;Functional disorder;Homeostasis;Hypoxia;Image;Image Guided Biopsy;Imaging technology;Immunologics;Knockout Mice;Label;Liposomes;Location;Macrophage;Magnetic Resonance;Magnetic Resonance Imaging;Mammary Neoplasms;Maps;Methodology;Modality;Mus;Occupations;Oxygen;Particulate;Perfusion;Play;Population;Prognosis;Progress Reports;Protein Tyrosine Kinase;Receptor Protein-Tyrosine Kinases;Regulation;Reporting;Role;Sampling;Scanning;Shapes;Site;Solid Neoplasm;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Treatment outcome;Tumor Promotion;Tumor Tissue;Tumor-associated macrophages;United States National Institutes of Health;Vascular Endothelial Growth Factors;Work;acute infection;angiogenesis;cancer therapy;chemokine receptor;chemotherapy;clinical efficacy;clinically relevant;cohort;docetaxel;extracellular;imaging modality;improved;in vivo;in vivo monitoring;innovation;insight;monocyte;mouse model;normoxia;parent grant;polyoma middle tumor antigen;recruit;repaired;residence;response;transcription factor;tumor;tumor hypoxia;tumor microenvironment;tumor progression;wound healing In vivo monitoring of tumor microenvironment regulation for macrophages PROJECT NARRATIVEThis project aims to test the hypothesis that bi-directional interaction between tumor microenvironment andregion-specific macrophages plays a role in tumor progression thru regulation of hypoxia and acidosis. In vivomapping of tumor hypoxia using innovative magnetic resonance technology in mice deficient in specificmacrophage populations or lacking hypoxia-regulated macrophage functions in a mouse model of breast cancermay provide new insight into a macrophage/tumor microenvironment axis that suppresses the efficacy ofclinically-relevant anti-cancer therapies. NCI 10756978 12/5/23 0:00 PA-20-185 5R01CA194013-08 5 R01 CA 194013 8 "LIN, CHARLES" 4/1/15 0:00 12/31/26 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(03)M] 1995004 "KHRAMTSOV, VALERY V" "EUBANK, TIMOTHY D" 2 BIOCHEMISTRY 191510239 M7PNRH24BBM8 191510239 M7PNRH24BBM8 US 39.618877 -79.973319 9163701 WEST VIRGINIA UNIVERSITY MORGANTOWN WV SCHOOLS OF MEDICINE 265066845 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 324900 NCI 213750 111150 Hypoxia and macrophages drive tumor aggressiveness and treatment outcome leading to worse prognosis forbreast cancer patients. Contrary to acute hypoxia where tissue homeostasis is vital for development and repairchronic hypoxia observed in solid tumors stimulate unproductive angiogenesis by excessive vascular endothelialgrowth factor expression leading to dysfunctional vessels that perpetuate hypoxia and acidic extracellularpH; factors that limit effective perfusion of treatment modalities like chemotherapies and radiotherapies andpromote tumor aggressiveness. Macrophages are intimately involved in regulating unproductive angiogenesisthru secretion of soluble factors that support this activity. In the parent grant we advanced electron paramagneticresonance (EPR)-based techniques towards in vivo real-time tumor microenvironment (TME) profiling in animalcancer models. Using these approaches we showed macrophage hypoxia-inducible transcription factors (HIF)-1 and HIF-2 had disparate roles in regulating TME parameters like oxygen and pHe through structural andfunctional alterations in vessels that dictated docetaxel efficacy. We showed that HIF-1 augments expressionof endothelial tyrosine kinase (TIE2) receptor on macrophages called TIE2-expressing macrophages (TEMs)previously-reported to be pro-angiogenic but now better defined as pro-hypoxic by dysregulating vesselsleading to poor perfusion. The overall objective of the renewal is to investigate macrophage location and functionthat perpetuates a hypoxic TME detrimental to perfusion of therapeutic modalities. To achieve this centralobjective we propose these specific aims: (SA1): To optimize magnetic resonance imaging modalities forin vivo multifunctional mapping of local tumor tissue parameters. Advances in paramagnetic probes andimaging technologies such as rapid scan EPR imaging and Overhauser-enhanced MRI allow for mappingspecific areas of hypoxia and acidosis and characterizing their relationship to tumor macrophage locoregionalpopulations. (SA2): Elucidate tumor macrophage location-specific functions in regulating hypoxia andacidosis in a mouse model of breast cancer. We will sample tumor origin and regions of hypoxia in PyMTbreast cancer models using image-guided biopsy to understand the bi-directional shaping of TME andmacrophages that contribute to poor vessel perfusion and hypoxia. (SA3): Investigate recruited and tissue-resident macrophage populations and their respective roles in contributing to tumor hypoxia andacidosis that dictate chemotherapy effectiveness. We will track fluorescent bone marrow monocytes to tumororigin and generate conditional macrophage-deficient breast tumor mice to systematically determine a causalrole of specific macrophage populations. Summarizing in vivo mapping of tumor hypoxia and acidosis usinginnovative magnetic resonance technology in mice deficient in specific macrophage populations or lackinghypoxia-regulated macrophage functions in a mouse model of breast cancer may provide new insight into amacrophage/TME axis that suppresses the efficacy of clinically-relevant anti-cancer therapies. 324900 +No NIH Category available Acute Myelocytic Leukemia;Address;Allogenic;Animals;B-Lymphocytes;Behavior;Blast Phase;Blood Vessels;Bone Marrow;Bone marrow failure;Cell Differentiation process;Cell Respiration;Cell Survival;Cells;Chromosome abnormality;Chronic;Chronic Myeloid Leukemia;Chronic Phase;Chronic-Phase Myeloid Leukemia;Clinical;Clinical Trials;Clonal Evolution;Clonal Hematopoietic Stem Cell;Compensation;Data;Development;Disease;Dose;Down-Regulation;Drug Kinetics;Dysmyelopoietic Syndromes;Endothelial Cells;Ensure;Erythroid;Exclusion;Experimental Designs;FLT3 gene;Gene Expression;Goals;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Hemorrhagic Thrombocythemia;Homeostasis;Human;Impairment;In Vitro;Institution;Knock-out;Lymphoid;Lymphoma;Malignant Neoplasms;Megakaryocytes;Messenger RNA;Metabolism;MicroRNAs;Mitochondria;Molecular;Molecular Abnormality;Mononuclear;Mus;Mutate;Mutation;Myelodysplastic/Myeloproliferative Disease;Myelofibrosis;Myelogenous;Myeloproliferative disease;Names;Output;Oxidative Phosphorylation;PECAM1 gene;Pathogenesis;Patient-Focused Outcomes;Patients;Peripheral;Pharmaceutical Preparations;Pharmacodynamics;Play;Polycythemia Vera;Prognosis;Proteins;Reactive Oxygen Species;Reporting;Risk;Role;Safety;Sampling;Schedule;Secondary acute myeloid leukemia;Secondary to;Splenomegaly;Stem cell transplant;T-Lymphocyte;Testing;Therapeutic;Time;Untranslated RNA;Zebrafish;acute myeloid leukemia cell;arteriole;chronic myeloid leukemia cell;density;design;effective therapy;fatty acid oxidation;gene conservation;in vivo;knock-down;leukemia;leukemic stem cell;leukemic transformation;manufacture;molecular targeted therapies;mouse model;novel;novel therapeutics;precursor cell;prevent;progenitor;prognostic;programs;risk stratification;self-renewal;stem cells;stemness;therapeutically effective The Role of miR-142 in the Transformation of Clonal Hematopoietic Disorders into AML Project narrative (relevance):Despite appropriate treatments chronic blood disorders such as myeloproliferative neoplasms (MPN) andchronic myelogenous leukemia (CML) (called here collectively MPD) can transform respectively into secondaryacute myeloid leukemia (sAML) or blast crisis (BC) CML which are very poorly responsive to currently availabletreatments. This proposal seeks to understand the mechanisms through which deficit of a molecule called miR-142 confers to the MPD cells a more aggressive clinical behavior that transforms them into sAML/BC CML cells.To address the unmet need for effective therapies for these conditions we will also develop a novel drug calledCpG-M-miR-142 designed to restore levels of miR-142 and hopefully to lead to a cure in these otherwise poor-risk patients. NCI 10756961 12/18/23 0:00 PA-20-185 5R01CA258981-03 5 R01 CA 258981 3 "KLAUZINSKA, MALGORZATA" 1/1/22 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 7766595 "MARCUCCI, GUIDO " "ZHANG, BIN " 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 488601 NCI 277614 210987 Chronic clonal blood disorders such as myeloproliferative neoplasms (MPN) and chronic phase (CP) chronicmyelogenous leukemia (CML) may over time transform respectively into secondary (s) acute myeloid leukemia(AML) and blast crisis (BC) CML which are poorly responsive to currently available therapies includingallogeneic stem cell transplantation. Thus the availability of novel and more effective treatments is a true unmetneed for these patients.MicroRNAs (miRNAs) are small non-coding RNAs that target messenger RNAs and regulate the correspondingprotein levels. MIR142 encoding miR-142 is a highly conserved gene expressed at high levels inhematopoietic cells and is involved in the development and function of myeloid lymphoid and megakaryocyte-erythroid progenitors. MIR142 has been found mutated and/or downregulated both in lymphoma and AML.Furthermore miR-142 knock-out (KO) causes impaired hematopoiesis in zebra fish and mice with expansion ofhematopoietic stem and progenitor cells (HSPCs) and decreased hematopoietic output.We recently demonstrated that miR-142 KO in mouse models with clonal myeloproliferative disorders (MPDs;i.e. FLT3-ITD+ MPN or CP CML) prompts transformation into an AML-like disease and confers a significantlyshorter survival to these animals. Our data support a role of miR-142 deficit in deregulation of the metabolism ofclonal hematopoietic stem cells (HSCs) with a switch to higher levels of oxidative phosphorylation (OxPhos) viaincreased fatty acid oxidation (FAO); these changes likely play a key role in the transformation of clonal HSCsinto leukemic stem cells (LSCs). We demonstrated that rescue of miR-142 deficit with a novel miR-142 mimiccompound (CpG-M-miR-142) reduced OxPhos levels and viability of LSCs decreased LSC burden and activityand prolonged survival of treated BC CML mice. Thus the central hypothesis of this proposal is that theunderstanding of the cellular and molecular basis of miR-142 downregulation and its impact on thetransformation of clonal MPD into aggressive AML-like disease will allow us to design and optimize noveltreatments to compensate for the miR-142 deficit and prevent and cure MPD transformation. We propose thefollowing Specific Aims (SAs): SA#1: To define the role of miR-142 deficit in the sAML/BC CML transformation.SA#2: To dissect the molecular mechanisms through which miR-142 deficit contributes to sAML/BC CMLtransformation. SA#3: To investigate the pharmacokinetic (PK) pharmacodynamic (PD) and therapeutic impactof a synthetic CpG-M-miR-142 that will rescue miR-142 deficit in sAML/BC CML. 488601 +No NIH Category available Affect;Algorithms;Appearance;Artificial Intelligence;Base Sequence;Benign;Bladder;Bladder Neoplasm;Cancer Detection;Cancer Diagnostics;Cancer Patient;Cancerous;Cessation of life;Clinic;Clinical;Communities;Complex;Computer Vision Systems;Cystoscopy;Data;Data Set;Detection;Diagnosis;Diagnostic;Diagnostic Sensitivity;Ensure;Environment;Equipment;Excision;Future;Goals;Healthcare;Histologic;Hospitals;Human;Image;Image Analysis;Inflammatory;Intervention;Knowledge;Learning;Lesion;Light;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Medical Imaging;Medical center;Modeling;Morbidity - disease rate;Morphology;Newly Diagnosed;Operating Rooms;Operative Surgical Procedures;Outcome;Papillary;Pathologic;Patients;Performance;Physician Assistants;Predictive Value;Process;Protocols documentation;Provider;Recurrence;Recurrent Malignant Neoplasm;Research;Role;Site;Specificity;Staging;Standardization;Surgeon;Technology;Testing;The Cancer Imaging Archive;Time;Training;Translating;Transurethral Resection;United States;Universities;Urologist;Urology;Validation;Washington;Work;annotation system;augmented intelligence;automated segmentation;body system;cancer diagnosis;cancer imaging;cancer recurrence;cancer risk;cancer surgery;care burden;cloud based;convolutional neural network;cost effective;deep learning algorithm;deep neural network;demographics;design;experience;high risk;image guided;image processing;improved;improved outcome;indexing;millisecond;mortality;multidisciplinary;neural;novel;patient stratification;prospective;recruit;recurrent neural network;risk stratification;screening;segmentation algorithm;tool;tumor;tumor progression Intraoperative integration of artificial intelligence during cystoscopic surgery PROJECT NARRATIVEIn this study we will develop and apply an artificial intelligence image processing algorithm based onconvolutional neural networks for real time detection of bladder tumors during cystoscopy and transurethralresection. Our long-term objective is to improve bladder cancer detection and resection to improve canceroutcomes. NCI 10756939 12/11/23 0:00 PAR-19-158 5R01CA260426-03 5 R01 CA 260426 3 "DARDZINSKI, BERNARD JOSEPH" 1/1/22 0:00 12/31/26 0:00 Clinical Translational Imaging Science Study Section[CTIS] 7594907 "LIAO, JOSEPH C" "XING, LEI " 16 UROLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 502446 NCI 331009 171437 PROJECT SUMMARYBladder cancer is the sixth most common cancer in the U.S. has one of the highest recurrence rates of allcancers and is the most expensive cancer to treat from diagnosis to death. Current standard for bladdercancer diagnosis relies on clinic-based white light cystoscopy for initial screening followed by transurethralresection of bladder tumor in the operating room for pathologic diagnosis and local staging. White lightcystoscopy has several well recognized shortcomings particularly incomplete detection thereby leading tosuboptimal resection and contributing to cancer recurrence and progression. Our goal is to improve outcomesfor bladder cancer patients through integration of a deep learning algorithm to improve cystoscopic detectionand enhance surgical resection.Artificial intelligence (AI)-based on deep neural networks have demonstrated remarkable capacity to learncomplex relationships and incorporate existing knowledge into the inference model. We hypothesize that AI-augmented detection of bladder tumor will improve diagnostic cystoscopy in the clinic setting to identifysuspicious lesions and improve the quality of transurethral resection in the operating room thereby reducingoverall cancer recurrence and outcome. Towards the goal of establishing a paradigm of AI-based frameworkfor augmented detection of bladder cancer we will leverage our strong preliminary data and outstandingenvironment in AI research. We propose three specific aims: 1) To curate a high-quality annotated cystoscopyimaging dataset to optimize deep neural network CystoNet; 2) To design and optimize CystoNet for real-timecystoscopic navigation and cancer detection; and 3) To conduct a prospective multicenter validation ofCystoNet during bladder cancer surgery.Successful completion of the studies proposed here will serve to translate deep learning algorithm to thedynamic environment of cystoscopic surgery without the need for specialized instrumentaitons. We foreseeour approach will improve the outcome of a major cancer and genearlizable to other organ systems amenablefor endsocopic interventions. 502446 +No NIH Category available Mechanistic characterization of the cell cycle-dependent DNA repair pathway- Resubmission PROJECT NARRATIVEPrecise regulation of the DNA repair machinery is essential to protect our genetic material from DNAdamage and prevent genome instability which is a hallmark of cancer. Therefore understanding theregulations how cells control the choice of DNA repair pathway is essential for devising a therapeuticstrategy for cancer treatment. Our goal is to elucidate the molecular mechanism on the cell cycle-regulated DNA repair by identifying a key histone mark reader that potentially regulates repair proteinshomeostasis at damaged chromatin. NCI 10756874 3/22/23 0:00 PA-21-268 7R01CA244261-03 7 R01 CA 244261 3 "WITKIN, KEREN L" 3/1/21 0:00 2/28/27 0:00 Radiation Therapeutics and Biology Study Section[RTB] 12563666 "LEUNG, JUSTIN WAI CHUNG" Not Applicable 20 RADIATION-DIAGNOSTIC/ONCOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 12/7/22 0:00 2/28/23 0:00 393 Non-SBIR/STTR 2022 103877 NCI 67018 36859 PROJECT SUMMARYChromatin-based DNA damage response (DDR) pathway is fundamental for protecting cells from genomeinstability which is a hallmark of cancer. The DDR pathway is tightly regulated throughout the cell cycle to ensurespatiotemporal control of DNA repair. Cell cycle-regulated chromatin modification is crucial for orchestrating DNArepair. Notably H4K20 methylation is a cell cycle-dependent histone mark that is involved in DNA double-strandbreak (DSB) repair pathway choice. Newly incorporated unmodified H4 recruits TONSL to replicated damagedchromatin to execute homologous recombination (HR) repair; whereas H4K20me2 recruits 53BP1 to damagedchromatin predominately at G1 phase to promote non-homologous end joining (NHEJ). The knowledge gap forthe current model comes from the unclear role and regulation of H4K20me1 and DSB repair pathway choice.Identifying histone H4K20me readers provides important insights into how chromatin modifications executecellular functions by recruiting downstream effector proteins to damaged chromatin at the right time. We identifiedZMYM3 (Zinc finger myeloproliferative and mental retardation type-3) as an HR promoting factor whichspecifically binds to the H4K20 methylation mark. The overall objective of this project is to elucidate themechanistic regulatory role of ZMYM3 on cell cycle-regulated H4K20 methylation and how it translates into DNADSBs repair pathway choice on post-replicative chromatin. Specifically we propose to 1) determine theconnection between ZMYM3 and H4K20 methylation by biochemical assays and genetic studies; 2) characterizethe ZMYM3 functional complex(es) on post-replicative damaged chromatin; and 3) elucidate the mechanism ofhow ZMYM3 regulates cell cycle-regulated DSB repair pathway choice and. We will focus on investigatingDYNLL1/LC8 a recently characterized DNA repair protein and its physical genetic and functional connectionswith ZMYM3 in DSB repair regulation. Our long-term goal is to dissect the detail of how cells orchestrate DNArepair via chromatin modifications. These studies are poised to provide critical insights into how H4K20me1 andH4K20me2 dictate the choice between HR and NHEJ on post-replicative chromatin repair. It will also decipherhow ZMYM3 shapes the post-replicative chromatin epigenome and recruits DDR proteins at damaged chromatin.Although inherited DDR defects predispose in cancer development the vulnerability is therapeutically exploitedto preferentially kill tumor cells. Thus DNA damaging agents are a major class of therapeutic agents that includeradiotherapy. Since chromatin directly regulates DNA repair proteins accrual at damaged chromatin theepigenome is an attractive target for drug discovery for cancer treatment. This work exploits a combination ofbiochemical genetic epigenetics and cellular approaches to dissect the detailed mechanism of cell cycle-regulated epigenome on genome integrity maintenance that can translate to potential biomarkers and drugdiscovery for cancer treatment. 103877 +No NIH Category available Accountability;Address;Advanced Malignant Neoplasm;Advisory Committees;American;Assessment tool;Cancer Center;Cancer health equity;Collaborations;Communication;Communities;Community Actions;Consensus;Consultations;Data;Data Analyses;Decision Making;Education;Effectiveness;Ensure;Environment;Equity;Evaluation;Evaluation Methodology;Evaluation Research;Faculty;Faculty Recruitment;Familiarity;Funding;Goals;Grant;Impact evaluation;Individual;Institution;Interview;Lead;Logic;Malignant Neoplasms;Measures;Modeling;New Mexico;Outcome;Outcome Assessment;Outcome Measure;Pacific Northwest;Participant;Policies;Process;Productivity;Program Evaluation;Publications;Questionnaires;Recommendation;Regional Cancer;Reporting;Request for Applications;Research;Research Project Grants;Science;Scientist;Southwestern United States;Students;Study Section;Suggestion;Surveys;Techniques;Training;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;Washington;Work;anticancer research;cancer health disparity;career;community engagement;data collection methodology;equity diversity and inclusion;evidence base;health equity;implementation evaluation;improved;innovation;instrument;meetings;member;outreach;programs;success;synergism;translational health science Planning & Evaluation Core n/a NCI 10756866 9/19/23 0:00 PAR-22-249 2U54CA132383-16 2 U54 CA 132383 16 9/30/07 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5017 14484930 "BOREN, RACHEL " Not Applicable 2 Unavailable 173851965 J3M5GZAT8N85 173851965 J3M5GZAT8N85 US 32.279041 -106.755696 5895702 NEW MEXICO STATE UNIVERSITY LAS CRUCES LAS CRUCES NM Domestic Higher Education 880031045 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 28690 19993 8697 ABSTRACTThe Planning & Evaluation Core (P&E Core) of the Partnership for the Advancement of Cancer Researchbetween New Mexico State University (NMSU) and Fred Hutchinson Cancer Center (Fred Hutch) coordinatescritical functions necessary for the determination of the impact and effectiveness of Partnership activities in theattainment of its goals and objectives. P&E Core Leads Dr. Rachel Boren at NMSU and Dr. Julian Simon atFred Hutch have extensive expertise in program evaluation methodologies. Dr. Boren is Director of theSouthwest Outreach Academic Research (SOAR) Evaluation and Policy Center at New Mexico StateUniversity and has been an evaluator for over 10 years. She has previously worked as an evaluator for theInstitute of Translational Health Sciences (ITHS) based at the University of Washington. Fred Hutch is affiliatedwith the University of Washington and participates in the ITHS thus giving Dr. Boren a unique familiarity withboth institutions. Dr. Simon has served as Research Project and Core Lead as well currently serving as MPI forthe Partnership. His nearly 20-year involvement with the Partnership gives him a historical perspective on theculture of the collaboration. The five Specific Aims of the P&E Core are to: 1. Provide assessment tools toevaluate track and report on progress in all aspects of the Partnership; 2. Release Requests for Applicationsfor new pilot and full Research Projects and conduct rigorous review of proposals; 3. Engage communitymembers and community action boards to evaluate impact of the Partnership on advancing regional cancerhealth equity; 4. Convene IAC and PSC to review progress of Cores and Research Projects and facilitatecommunication between the advisory bodies NCI and Core and Project Leads and; 5. Evaluate theimplementation and impact of the Guiding Principles (described in detail in Overall). In order to accomplishthese Aims the P&E Core will work with the MPIs (Drs. Graciela Unguez and Julian Simon) as well asResearch Project and Core Leads to develop appropriate evaluation instruments to inform on the effectivenessof the Partnerships activities. Quantitative and qualitative measure of outcomes will be collected and assessedbased on the metrics described in the Logic Model (see P&E Core). New Research Projects will be solicitedevaluated and implemented through the P&E Core. Current Research Projects and Cores will be evaluatedand if necessary revised in consultation with the Internal Advisory Committee the Program SteeringCommittee and NCI Program Staff. Rigorous review of the effectiveness of projects and activities will enableprogress to meeting the Partnerships goal of advancing health equity in the communities served. +No NIH Category available 11 year old;18 year old;Accelerometer;Address;Adolescence;Adult;Advanced Malignant Neoplasm;Age;American;Behavior;Body mass index;Cancer Center;Cellular Phone;Child;Childhood;Chronic Disease;Clinical;Collaborations;Colorectal Cancer;Communities;Computers;County;Diabetes Mellitus;Diet Habits;Disease;Disparity;Education;Electronics;Environment;Epidemic;Evaluation;Facebook;Family;Family member;Fostering;Fruit;Funding;Goals;Guidelines;Health;Health Food;Healthy Eating;Heart Diseases;Hispanic;Hodgkin Disease;Home;Hour;Household;Institution;Intake;Leisures;Life;Life Style;Long-Term Effects;Malignant Neoplasms;Mentorship;New Mexico;Obesity;Overweight;Parents;Physical activity;Pilot Projects;Play;Preparation;Prevalence;Prevention program;Privatization;Protocols documentation;Recommendation;Recreation;Reduce health disparities;Reporting;Research;Research Project Grants;Risk;Schools;Science;Scientist;Site;Sleep;Stroke;Students;Surveys;Teenagers;Television;Testing;Time;Universities;Update;Video Games;Washington;Writing;Yakima Valley;active lifestyle;after-school program;anticancer research;behavior change;cancer risk;cancer type;career development;community engaged research;cost;design;education research;efficacy evaluation;feasibility testing;fifth grade;fruits and vegetables;graduate student;health disparity;health equity promotion;healthy lifestyle;high body mass index;improved;innovation;leukemia;low socioeconomic status;malignant breast neoplasm;mortality;nutrition;obesity in children;obesity prevention;obesity risk;oral communication;outreach;physical inactivity;pilot test;programs;recruit;school district;sedentary lifestyle;skills;social;tv watching;undergraduate student;underserved community Pilot Project 1: H-PACE: Promoting Healthy Living Through Behavior Change n/a NCI 10756865 9/19/23 0:00 PAR-22-249 2U54CA132383-16 2 U54 CA 132383 16 9/30/07 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5016 78529790 "MAGOC, DEJAN " Not Applicable 2 Unavailable 173851965 J3M5GZAT8N85 173851965 J3M5GZAT8N85 US 32.279041 -106.755696 5895702 NEW MEXICO STATE UNIVERSITY LAS CRUCES LAS CRUCES NM Domestic Higher Education 880031045 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 86107 60005 26102 ABSTRACTIn New Mexico 15.2% of children between the ages of 6-15 are obese ranking New Mexico 23rd among allU.S. states. Obesity prevalence also increases with age. In 2018 only 13% of New Mexico children ages 2-4years were obese compared with 32% of adults 18 years of age and older. Likewise for Washington in 201612% of children ages 2-4 years were obese compared to 29% of adults. To address the prevalence of obesityand related diseases such as diabetes heart disease stroke and several types of cancer programs focusingon increasing opportunities for active living and healthy eating are necessary. Multi-component school-basedobesity prevention programs have demonstrated increases in PA and improvement in dietary habits; howevermost afterschool programs are short term; evidence is needed to confirm long-term effects. Moreoverprograms that involve parents have shown to be more successful in helping children choose healthierbehaviors. Therefore the purpose of this proposal is to pilot test the Healthy Parents and ChildrenEnhancement (H-PACE) program -- a community-engaged research project through an existing after-schoolprogram in Las Cruces NM and a new partnership in Sunnyside WA among children 8-11 years of age (3rd-5th grade). It is expected that implementing the H-PACE program will be feasible and demonstrate clinicallyimportant changes in improving childrens lifestyle behaviors. In addition to participating in after-schoolactivities which will include structural active play as well as educational lessons and activities children willtake home family-based engaging activities such as fruits and veggies for fun preparation at home withparents. Parents will also be connected to each other and program staff via a private invitation-only Facebookgroup which will provide regular updates on after-school activities and particular family-based weeklyassignments. The life skill portion of this program is designed to have lasting impact on children fromhouseholds of lower socioeconomic status (SES) and their family members. The current pilot project will alsoenhance the community-academic partnerships between the local school district New Mexico State Universityand Fred Hutchinson Cancer Center to deliver an after-school program that is low cost mutually beneficialand sustainable. Proper nutrition and physical activity (PA) are essential parts of overall health. Together theycan decrease the risk of developing obesity as well as related diseases such as diabetes heart diseasestroke and several types of cancer. Health disparities associated with active living have led the CDC to call forgreater active living programing for children. The current project will address this need in southern NM and theLower Yakima Valley of Washington by implementing an active living after-school program at four school sites. +No NIH Category available Adult;Advanced Malignant Neoplasm;Ascorbic Acid;Back;Behavioral Research;Biological Availability;Biological Markers;Blood;Cancer Center;Cardiometabolic Disease;Carotenoids;Chlorophyll;Chronic Disease;Collaborations;Communities;Community Actions;Computer software;Consumption;County;Cross-Over Trials;Diet;Dietary Intervention;Dietary Practices;Digestion;Dryness;Educational Curriculum;Educational Intervention;Effectiveness;Environment;Evaluation;Exclusion;Folic Acid;Food;Funding;Future;Health;Health Sciences;Hispanic;In Vitro;Information Systems;Infrastructure;Intake;Intervention;Knowledge;Latinx;Low income;Malignant Neoplasms;Measurable;Mentors;Methods;Mexican;Modeling;Modernization;New Mexico;Outcome;Outcome Measure;Participant;Phytochemical;Pilot Projects;Plants;Prevention education;Preventive;Process;Program Evaluation;Public Health;Public Health Education;Randomized;Recipe;Recurrent Malignant Neoplasm;Research;Research Personnel;Resources;Risk;Scientist;Self Efficacy;Services;Spottings;Students;Testing;Time;Tocopherols;Training;Translating;Universities;Variant;Vitamin B Complex;Vulnerable Populations;Waiting Lists;anticancer research;cancer health disparity;cancer prevention;cancer recurrence;cancer risk;career;community based research;comorbidity;cooking;design;dietary;education research;effectiveness testing;evidence base;experience;faculty mentor;fruits and vegetables;graduate student;human centered design;improved;meetings;member;meter;nutrition;outreach;population health;portion control;primary outcome;programs;recruit;secondary outcome;success;systems research;trial design;vulnerable community Project 3: A Transdisciplinary Approach to Increasing Phytonutrients in New Mexican Diets: A Kitchen-to-Lab-to-Table Model n/a NCI 10756863 9/19/23 0:00 PAR-22-249 2U54CA132383-16 2 U54 CA 132383 16 9/30/07 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5014 15028886 "GUZMAN, IVETTE " Not Applicable 2 Unavailable 173851965 J3M5GZAT8N85 173851965 J3M5GZAT8N85 US 32.279041 -106.755696 5895702 NEW MEXICO STATE UNIVERSITY LAS CRUCES LAS CRUCES NM Domestic Higher Education 880031045 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 117542 83468 34074 ABSTRACTIt is well established that phytonutrient-rich foods are cancer preventive and that diets high in phytochemicalssuch as carotenoids tocopherols and chlorophylls are associated with decreased cancer risk and recurrence.Historically traditional dietary patterns across multiple cultures have been plant-based and phytonutrient-rich.As dietary patterns have westernized they have become less plant-based and thus less phytonutrient-rich. Inparallel communities that previously consumed plant-based diets have experienced increased risks of cancerand cardiometabolic disorders. The Hispanic/Latinx community in southern New Mexico has been particularlyimpacted by cancer health disparities making it imperative to develop effective and sustainable strategies toimprove diet quality. This Full Project builds upon an ongoing collaboration between investigators at NewMexico State University (NMSU) and the Fred Hutchinson Cancer Center (Fred Hutch) to develop andimplement a kitchen-to-lab-to-table research model. Here we extend our research by partnering with theNMSU Cooperative Extension Service. We will create new content focused on prevention of cancer and otherchronic diseases by increasing fruits and vegetables improving diet quality and improving portion controlusing culturally congruent materials. We will create a Community Action Board comprised of communitymembers served by NMSU Cooperative Extension in southern New Mexico. Specific Aims are: Aim 1: Tooptimize carotenoid tocopherol and chlorophyll content and bioavailability by changing cooking methods andingredients in 15 culturally congruent southern New Mexican recipes. Aim 2: To develop and test the effects ofa culturally adapted 6-session curricula delivered through the NMSU Cooperative Extension Service in twoSouthern New Mexico counties using a randomized waitlist-controlled crossover trial design (n=60). Theresearch will build upon our kitchen-to-lab-to-table research model of working with communities with lowincomes and limited resources with high cancer health disparities to identify culturally appropriate methods toimprove diet intake and quality. Study results will be used to continue to develop evidence-based methods toinform culinary practices to disseminate to communities and to design community-based dietary interventionsto improve the health of vulnerable communities. The research will establish a new kitchen-to-lab-to-tablemodel to collaborate with Hispanic/Latinx communities in southern New Mexico with high cancer healthdisparities and to identify culturally appropriate methods to improve diet quality. Study results will be used tocontinue to develop evidence-based methods to inform culinary practices to disseminate to communities andto design community-based dietary interventions to improve the health of vulnerable communities. +No NIH Category available Acute;Address;Advanced Malignant Neoplasm;Aspartate;Automobile Driving;Bioinformatics;Biological;Biometry;Cancer Model;Cancer Patient;Cell Proliferation;Cell physiology;Cells;Cellular Metabolic Process;Characteristics;Chronic;Citric Acid Cycle;Collaborations;Community Health;Complex;Data;Data Analyses;Data Set;Defect;Dependence;Educational Status;Educational workshop;Electron Transport;Environment;Enzymes;Epigenetic Process;Ethnic Origin;Face;Fostering;Gene Expression Process;Genetic Transcription;Genotype;Health;Human;Hypoxia;Impairment;Institution;Interdisciplinary Study;Intervention;Intrinsic factor;Joints;Knowledge;Machine Learning;Malignant Neoplasms;Measurement;Mentors;Metabolic;Metabolism;Metadata;Mitochondria;Modeling;Mutation;Nutrient;Oncogenic;Outcome;Oxygen;Pathway Analysis;Patients;Pilot Projects;Process;Proliferating;Proteins;Proteomics;Race;Reactive Oxygen Species;Reproducibility;Research;Research Personnel;Research Support;Resources;Science;Scientist;Statistical Methods;Students;Succinate Dehydrogenase;Succinate dehydrogenase (ubiquinone);Supporting Cell;System;Techniques;Time;Tissues;Training;Tumor Suppressor Proteins;Underrepresented Students;anticancer research;cancer cell;cancer type;career;career development;community engagement;design;education research;epigenomics;experience;health disparity;improved;improved outcome;inhibitor;loss of function mutation;machine learning model;meetings;member;metabolic abnormality assessment;metabolic phenotype;multidisciplinary;mutant;next generation;novel;novel therapeutic intervention;outreach;pressure;prevent;protein expression;proteostasis;research data dissemination;response;restoration;statistics;student training;success;targeted cancer therapy;transcriptomics;tumor;tumor metabolism;tumor progression;tumorigenesis;underserved community Project 2: Systemic Understanding of Cellular Mechanisms of Metabolic Adaptations in Cancer n/a NCI 10756862 9/19/23 0:00 PAR-22-249 2U54CA132383-16 2 U54 CA 132383 16 9/30/07 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5013 14597269 "JEON, SOYOUNG " Not Applicable 2 Unavailable 173851965 J3M5GZAT8N85 173851965 J3M5GZAT8N85 US 32.279041 -106.755696 5895702 NEW MEXICO STATE UNIVERSITY LAS CRUCES LAS CRUCES NM Domestic Higher Education 880031045 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 115222 81851 33371 ABSTRACTCancers are characterized by alterations to cellular metabolism that promote tumorigenesis however ourunderstanding of how these metabolic changes are enacted and how they mechanistically support cancer cellfunction remains lacking. While some metabolic changes reproducibly occur as a direct result of oncogenicmutations other metabolic alterations occur over time through adaptive metabolic protein expression changesthat allow cells to surmount metabolic deficiencies during cancer progression. Notably this latter group ispredicted to be enriched for functionally important metabolic changes suggesting that their identification wouldhave particularly relevance for cancer research. However detailed understanding of which metabolicalterations are the result of adaptations is hampered by the lack of models for directly studying reproduciblemetabolic adaptations in cancer. Additionally data on differences in cancer-related adaptations based on raceor ethnicity that contribute to health disparities are lacking. Here we propose to address this knowledge gapby investigating the mechanisms of metabolic adaptation system that we have recently established where lossof function mutations in the tumor suppressor succinate dehydrogenase (SDH) selects for cells withconcordant expression of components of mitochondrial electron transport chain complex I which ultimatelysupports cell metabolism and cell proliferation. Using this system we will investigate the metabolic drivers ofcomplex I adaptations in SDH deficient cells (Aim 1) and use polyomics measurements of gene expressionprocesses such a epigenetics transcription and proteostasis to identify the cellular processes that enactadaptive changes to complex I expression (Aim 2). We will also take a systematic approach using state-of-the-art statistical methods to leverage publicly available patient tumor datasets containing polyomic measurementsand patient metadata in order to identify adaptive changes to metabolic protein expression during cancerprogression (Aim 3). This multidisciplinary Full Project also addresses the Partnerships Guiding Principles(see Overall section) for inclusive mentoring of diverse research teams and for research dissemination tounderserved communities helping to educate and provide opportunities for next generation of researchers. +No NIH Category available Active Learning;Address;Advanced Malignant Neoplasm;Affect;American Indians;Behavior;COVID-19;COVID-19 outbreak;COVID-19 pandemic;Cancer Control;Cancer Etiology;Collaborations;Communities;Community Actions;Community of Practice;Country;Decision Making;Detection;Development;E-learning;Education;Educational workshop;Elements;Ensure;Environment;Equity;Evaluation;Evidence based program;Faculty;Fostering;Funding;Geographic Locations;Health Insurance;Healthy Eating;Hispanic;Individual;Inequity;Infrastructure;Intervention;Knowledge;Latinx;Learning;Low income;Malignant Neoplasms;Measures;Medically Underserved Area;Mexico;Navajo;New Mexico;Outcome;Outreach Research;Persons;Pilot Projects;Policy Making;Population;Poverty;Prevention;Prevention education;Process;Research;Research Activity;Research Methodology;Research Project Grants;Research Training;Science;Series;Services;Students;Training;Training and Education;Trust;Underserved Population;Vaccination;Voice;Washington;Work;anticancer research;cancer education;cancer prevention;colorectal cancer screening;community based participatory research;community center;community engaged research;community engagement;community organizations;community partnership;diversity and inclusion;evidence base;experience;health equity;healthy lifestyle;high school;improved;lens;low health literacy;marginalized community;member;outreach;research in practice;rural underserved;screening program;social;social media Outreach Core n/a NCI 10756840 9/19/23 0:00 PAR-22-249 2U54CA132381-17 2 U54 CA 132381 17 9/30/07 0:00 8/31/28 0:00 ZCA1-SRB-2(A1) 5010 7706911 "CEBALLOS, RACHEL M." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 254309 144494 109815 ABSTRACTThe Outreach Core is based on the premise that the US-Mexico border and Indian Country in thenorthwestern regions of New Mexico (NM) as well as the Central region of Washington State (WA) are largelyrural and medically underserved areas where inequities are severe especially among Hispanic/LatinxAmerican Indian (AI) and LGBTQAI+ populations. These geographical areas are the foci of the OutreachCores work. Long term the Partnership aspires to increase the health equity in these regions. To do so theSpecific Aims are: 1) To integrate community engagement activities and practices within the Partnership forAdvancing Cancer Research (PACR); 2) To increase capacity for community-academic partnerships tosuccessfully use community-based participatory research (CBPR); and 3) To build on and use evidence-basedprograms (EBPs) to promote cancer equity in Latinx AI and LGBTQIA+ populations. The Outreach Core wasvery successful in the U54-III reaching 4631 individuals in NM and 3287 in WA. Since the outbreak of theCOVID-19 pandemic in-person cancer prevention education and other Outreach Core activities were adaptedto online platforms in English and Spanish. At the request of the Community Action Boards (CABs) informationon COVID-19 and vaccination was disseminated through social media with positive results. For this U54-IV wewill follow the Partnership Guiding Principles of 1) restructuring scientific environments; 2) restructuring scientificprocesses; and 3) restructuring scientific engagement and will work collaboratively with our CABs to foster mutualunderstanding of the Partnership and the community organizations represented by the CABs to ensure that NMSUand Fred Hutch equitably engage communities in all the activities. CAB discussions about the various ResearchProjects and Cores will be initiated as well as bi-directional discussions on community-based participatoryresearch (CBPR). The Partnership will also endeavor to establish community organization expertise in researchinitiatives by providing training and education in research. The expected end result will be community-orientedPilot and Pre-Pilot projects funded by the Partnership. Five modules fostering inclusion of community members inresearch practices will provide opportunities for historically marginalized communities to voice their strengths andways of knowing through collaborative experiences. Finally the Outreach Core will continue to collaborate with theCABs and communities on evidence-based programs such as Screen-to-Save (a colorectal cancer screeningprogram) Yego (a Navajo healthy eating project) e-Learning by the Cooperative Extension Services (on healthylifestyle behaviors) and Cancer 101 (a series on cancer causes prevention and detection). The Planning &Evaluation Core (P&E Core) will evaluate the formative and summative outcomes of the activities. +No NIH Category available Abstinence;Accounting;Address;Adult;Advanced Malignant Neoplasm;Biochemical;Cancer Research Project;Cessation of life;Cigarette;Communities;Counseling;Data;Development;Disparity;Disparity population;Electronic Nicotine Delivery Systems;Environment;Equity;Ethnic Origin;Evaluation;Feedback;Future;Gender Identity;Health;High Prevalence;Intervention;Interview;Language;Latinx;Lead;Malignant Neoplasms;Media Intervention;Methods;Modification;National Cancer Institute;New Mexico;Nicotine;Pharmacotherapy;Pilot Projects;Population;Prevalence;Preventable cancer cause;Process;Randomized Controlled Trials;Readiness;Reduce health disparities;Research;Research Personnel;Research Training;Resources;Risk;Science;Sex Orientation;Sexual and Gender Minorities;Smoke;Smoker;Smoking treatment;Structure;Students;Testing;Tobacco;Tobacco Use Cessation;Tobacco use;Training;Treatment outcome;United States National Institutes of Health;Work;anticancer research;arm;career development;community organizations;comparison group;design;diaries;digital;digital intervention;education research;effectiveness testing;efficacy outcomes;empowerment;experience;flexibility;follow-up;gender minority community;gender minority group;individualized medicine;innovation;mHealth;member;mortality;nicotine user;novel;novel strategies;outreach;pilot trial;primary outcome;programs;psychologic;queer;recruit;satisfaction;secondary outcome;smoking cessation;smoking prevalence;social media;success;theories;tobacco abstinence;tobacco cessation intervention;tobacco control;tobacco products;tobacco user;treatment effect;treatment group;treatment research;trend;user centered design;young adult Project 4: CulturallyTailored AvatarLed mHealth Intervention to Aid Smoking Cessation Among Sexual and Gender Minority Young Adults in New Mexico n/a NCI 10756836 9/19/23 0:00 PAR-22-249 2U54CA132381-17 2 U54 CA 132381 17 9/30/07 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5006 9496052 "HEFFNER, JAIMEE " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 183853 104462 79391 ABSTRACTSmoking prevalence among sexual and gender minority (SGM) adults in New Mexico is more than twice ashigh as non-SGM adults suggesting that existing SGM-related disparities in tobacco use will persist well intothe foreseeable future unless sustained efforts are undertaken to address them. Helping young adult tobaccousers to quit is a critical piece of SGM-directed tobacco control interventions yet there have been few efforts todevelop tailored treatments specifically for this population. This is a critical gap given that this is a populationwhose access to and use of traditional cessation treatments involving counseling and pharmacotherapy ispoor. SGM young adults in New Mexico (NM) are likely to experience unique influences on tobacco use andcessation tied to both their ethnic and SGM identities in addition to other aspects of their identity. Anintersectional focus is critical for developing interventions to address high rates of tobacco use among SGMyoung adults in New Mexico that are acceptable accessible and effective. To address these needs we haveadapted an avatar-led digital Acceptance and Commitment Therapy (ACT) program for SGM young adultsmokers at all stages of readiness to quit. This program (called Empowered Queer Quitting and Living orEQQUAL) showed great promise in a single-arm pilot trial: 93% satisfaction and a 23% biochemically-confirmed quit rate. In this study we propose to develop a version of the program that is culturally tailored toSGM young adults in New Mexico (EQQUAL-NM) and conduct a pilot randomized controlled trial (n=120) topreliminarily evaluate acceptability and efficacy of EQQUAL-NM relative to the National Cancer InstitutesQuitGuide program. We hypothesize that compared with QuitGuide EQQUAL-NM will show a trend towardgreater satisfaction number of logins biochemically confirmed 7-day point prevalence nicotine and tobaccoabstinence and psychological flexibility (i.e. ACTs theory-based change mechanism). We will also explorereadiness to quit sexual orientation gender identity and Latinx ethnicity as moderators of treatment effects.This project is significant: (1) it focuses on an NIH-defined disparities group with a high prevalence of tobaccouse that has been underserved in treatment research; (2) it addresses SGM individuals desire for a programtailored to their unique needs and challenges in a readily scalable and accessible format; (3) if proveneffective EQQUAL-NM would be highly disseminable online and via SGM community-serving organizations inNM. It is also innovative: (1) it is the first self-guided digital cessation treatment culturally tailored for SGMyoung adults in New Mexico (2) there are currently no other SGM-tailored treatments available in Spanish (3)its novel treatment approach advances the science of ACT for tobacco cessation by testing effectiveness forusers at all stages of readiness to quit; and (4) use of avatars and interactive games as engagementstrategies is substantially different than existing treatments. This project will generate all the pilot data neededto support an R01-level project testing the effectiveness of EQQUAL-NM in a fully-powered trial. +No NIH Category available Adult;Advanced Malignant Neoplasm;Ascorbic Acid;Back;Behavioral Research;Biological Availability;Biological Markers;Blood;Cancer Center;Cardiometabolic Disease;Carotenoids;Chlorophyll;Chronic Disease;Collaborations;Communities;Community Actions;Computer software;Consumption;County;Cross-Over Trials;Diet;Dietary Intervention;Dietary Practices;Digestion;Dryness;Educational Curriculum;Educational Intervention;Effectiveness;Environment;Evaluation;Exclusion;Folic Acid;Food;Funding;Future;Health;Health Sciences;Hispanic;In Vitro;Information Systems;Infrastructure;Intake;Intervention;Knowledge;Latinx;Low income;Malignant Neoplasms;Measurable;Mentors;Methods;Mexican;Modeling;Modernization;New Mexico;Outcome;Outcome Measure;Participant;Phytochemical;Pilot Projects;Plants;Prevention education;Preventive;Process;Program Evaluation;Public Health;Public Health Education;Randomized;Recipe;Recurrent Malignant Neoplasm;Research;Research Personnel;Resources;Risk;Scientist;Self Efficacy;Services;Spottings;Students;Testing;Time;Tocopherols;Training;Translating;Universities;Variant;Vitamin B Complex;Vulnerable Populations;Waiting Lists;anticancer research;cancer health disparity;cancer prevention;cancer recurrence;cancer risk;career;community based research;comorbidity;cooking;design;dietary;education research;effectiveness testing;evidence base;experience;faculty mentor;fruits and vegetables;graduate student;human centered design;improved;meetings;member;meter;nutrition;outreach;population health;portion control;primary outcome;programs;recruit;secondary outcome;success;systems research;trial design;vulnerable community Project 3: A Transdisciplinary Approach to Increasing Phytonutrients in New Mexican Diets: A Kitchen-to-Lab-to-Table Model n/a NCI 10756835 9/19/23 0:00 PAR-22-249 2U54CA132381-17 2 U54 CA 132381 17 9/30/07 0:00 8/31/26 0:00 ZCA1-SRB-2(A1) 5005 6771929 "GREENLEE, HEATHER " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 207904 118127 89777 ABSTRACTIt is well established that phytonutrient-rich foods are cancer preventive and that diets high in phytochemicalssuch as carotenoids tocopherols and chlorophylls are associated with decreased cancer risk and recurrence.Historically traditional dietary patterns across multiple cultures have been plant-based and phytonutrient-rich.As dietary patterns have westernized they have become less plant-based and thus less phytonutrient-rich. Inparallel communities that previously consumed plant-based diets have experienced increased risks of cancerand cardiometabolic disorders. The Hispanic/Latinx community in southern New Mexico has been particularlyimpacted by cancer health disparities making it imperative to develop effective and sustainable strategies toimprove diet quality. This Full Project builds upon an ongoing collaboration between investigators at NewMexico State University (NMSU) and the Fred Hutchinson Cancer Center (Fred Hutch) to develop andimplement a kitchen-to-lab-to-table research model. Here we extend our research by partnering with theNMSU Cooperative Extension Service. We will create new content focused on prevention of cancer and otherchronic diseases by increasing fruits and vegetables improving diet quality and improving portion controlusing culturally congruent materials. We will create a Community Action Board comprised of communitymembers served by NMSU Cooperative Extension in southern New Mexico. Specific Aims are: Aim 1: Tooptimize carotenoid tocopherol and chlorophyll content and bioavailability by changing cooking methods andingredients in 15 culturally congruent southern New Mexican recipes. Aim 2: To develop and test the effects ofa culturally adapted 6-session curricula delivered through the NMSU Cooperative Extension Service in twoSouthern New Mexico counties using a randomized waitlist-controlled crossover trial design (n=60). Theresearch will build upon our kitchen-to-lab-to-table research model of working with communities with lowincomes and limited resources with high cancer health disparities to identify culturally appropriate methods toimprove diet intake and quality. Study results will be used to continue to develop evidence-based methods toinform culinary practices to disseminate to communities and to design community-based dietary interventionsto improve the health of vulnerable communities. The research will establish a new kitchen-to-lab-to-tablemodel to collaborate with Hispanic/Latinx communities in southern New Mexico with high cancer healthdisparities and to identify culturally appropriate methods to improve diet quality. Study results will be used tocontinue to develop evidence-based methods to inform culinary practices to disseminate to communities andto design community-based dietary interventions to improve the health of vulnerable communities. +No NIH Category available Authorization documentation;Biostatistics Shared Resource;Businesses;Calendar;Cancer Center Support Grant;Clinical Data;Clinical Protocols;Clinical Trials;Development;Ensure;Exclusion;Human;Institution;Institutional Review Boards;Investments;Malignant Neoplasms;Mission;Monitor;Policies;Process;Protocols documentation;Research;Resources;Review Committee;Special Population;Structure;System;Time;Update;authority;cancer clinical trial;clinical trial protocol;data management;design;meetings;operation;patient population;sound Protocol Review and Monitoring System Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756567 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7855 8864897 "GOPAL, AJAY " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 121179 121179 0 PROJECT SUMMARY: PROTOCOL REVIEW AND MONITORING SYSTEM (PRMS)A single Protocol Review and Monitoring System (PRMS) governs all oncology clinical trial protocols acrossthe Consortium partner institutions and assures that cancer-relevant human research is (1) scientificallyimportant and statistically sound; (2) designed appropriately without excluding special populations for non-scientific reason; (3) feasible with reasonably attainable accrual targets given the available patient population;and (4) supportive of the research mission of the Consortium. The central feature of the PRMS is the ScientificReview Committee (SRC). The PRMS committee structure is responsible for approving protocols that meet itsstringent and well-defined criteria. A Research Group Review is required prior to submission to the SRC aspart of a two-stage review process and assures that Consortium protocols are of high scientific merit andfeasible prior to investing additional institutional resources in development.The SRC evaluates scientific merit feasibility prioritization and progress of all Consortium clinical trialprotocols. As part of the Consortiums trial activation process SRC approval is required prior to IRB review.Efficient operations and weekly SRC meetings have resulted in a median overall process time of 14 calendardays (10 business days) which has remained consistent since 2015. The PRMS further ensures that duringaccrual the scientific rationale for the protocol has remained relevant and that accrual is sufficient to meet thescientific aims of the trial. Since implementation of the updated Low Accrual Policy in FY 2015 the number ofreviews and closures increased from 25 trials reviewed and three closures to 74 reviewed and 24 closed in FY2018. All protocols approved by PRMS have access to CCSG-supported centralized resources includingClinical Protocol and Data Management (CPDM) and the Biostatistics Shared Resource (BSR). PRMS has theultimate authority to close trials that do not demonstrate scientific progress. +No NIH Category available Area;Back;Cancer Center Support Grant;Cessation of life;Communication;Evaluation;Feedback;Goals;Individual;Institution;Investments;Leadership;Malignant Neoplasms;Methods;Mission;Monitor;Outcome;Process;Reporting;Resources;Structure;Time;Universities;Vision;Washington;member;response Leadership Planning and Evaluation Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756563 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7853 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 645904 385463 260441 PROJECT SUMMARY: LEADERSHIP PLANNING & EVALUATION Dr. Gary Gilliland the Consortium Director creates the overarching vision for the Fred Hutch/University of Washington Cancer Consortium. To accomplish this he engages internal and external leaders committees and individuals to help define this vision and to chart the short and long-term steps needed to move towards this goal. Structures have been created to help assure that the plans of the Consortium are congruent with those of the member institutions. With the help of Consortium Administration methods have been developed to monitor the activities of the Consortium as directed by the planning process and to help assure that these activities are communicated to Consortium members. Robust processes have been created to evaluate progress made in achieving the goals set out in the planning process report the results of the evaluations back to involved members review responses to the evaluations and evaluate the outcomes of those responses. The specific aims for Leadership Planning & Evaluation are (1) with input from internal and external experts to identify those areas where investments of time and resources are most likely to assist the Consortium in achieving its mission to eliminate cancer as a cause of suffering and death; (2) to create a structure that engages all Consortium partners in planning so that individual institutional objectives are well aligned with Consortium objectives (3) to continuously monitor and communicate Consortium activities to all stakeholders and (4) to create an iterative process for evaluating Consortium activities providing feedback reviewing responses to feedback and revaluating subsequent outcomes. +No NIH Category available Address;Area;Award;Biology;Cancer Center Support Grant;Cancer Research Project;Catchment Area;Child;Collaborations;Community Outreach;Data;Development;Emerging Technologies;Faculty;Funding;Future;Grant;Growth;Health Disparities Research;Health Service Area;Human Resources;Individual;Institution;Laboratories;Lead;Malignant Neoplasms;Modeling;Outcomes Research;Pilot Projects;Pre-Clinical Model;Productivity;Publications;Research;Research Personnel;Research Support;Resource Development;Resource Sharing;Resources;Risk Reduction;Science;Solid Neoplasm;Special Population;Technology;Translational Research;Underserved Population;Universities;Washington;cancer health disparity;community engagement;disparity reduction;innovation;member;mouse model;new technology;pathogen;recruit;tumor immunology Development Funds Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756562 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7852 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 1869759 1064697 805062 PROJECT SUMMARY: DEVELOPMENTAL FUNDS Developmental funds were used in the last cycle for recruiting new investigators supporting developmental projects creating new shared resources and helping fund several key staff investigators. Several outstanding investigators who received recruitment funds during the project period would not have come to Seattle without the extra support that was offered through the availability of CCSG New Investigator Awards distributed to faculty from Fred Hutch (FH) University of Washington (UW) and Seattle Childrens (SC). The availability of CCSG Pilot Award funding provides investigators a very tangible benefit of Cancer Consortium membership and has stimulated new initiatives and collaborations that would otherwise not have occurred particularly in transdisciplinary science cancer health disparities and catchment area health. Funds to catalyze new Shared Resource development have afforded Consortium members access to technologies and expertise that would otherwise not be sustainable in an individual laboratory or even on an institutional basis. Finally developmental funds help support staff investigators focused on enhancing our community outreach and engagement efforts. During the last grant period Developmental Funds supported the recruitment of 33 productive Consortium faculty members in areas of strategic growth and funded 45 Pilot Award projects. Together these faculty members and pilot projects gave rise to a total of 439 publications and over $28M in new follow-on funding. In the last cycle Developmental Funds were instrumental in the formation of the Hutch Data Commonwealth and supported two Special Populations Staff Investigators both of whom continue to lead efforts to reduce disparities in underserved populations and one of whom has become the new Director of our Office of Community Outreach & Engagement. In this application we are requesting funds to support future Pilot and New Investigator Awards two new Special Populations Staff Investigators and a Preclinical Models Shared Resource. +No NIH Category available Address;Adopted;Area;Bioinformatics;Biological;Biology;Biomedical Research;Biometry;Cancer Burden;Cancer Center Support Grant;Clinical Trials;Collaborations;Communicable Diseases;Companions;Computational Biology;Computing Methodologies;Data;Data Analyses;Data Science;Data Set;Development;Educational Status;Environment;Environmental Exposure;Evaluation;Funding;Future;Growth;Growth and Development function;Health;Human;Immune;Immune response;Immunotherapy;Informatics;Institution;International;Knowledge;Leadership;Life Style;Machine Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Mathematics;Measures;Medicine;Methodology;Methods;Mission;Molecular Biology;Natural History;Penetration;Positioning Attribute;Prevention;Productivity;Publications;RNA Processing;Reproducibility;Research;Research Methodology;Research Personnel;Research Project Grants;Science;Software Tools;Statistical Methods;Technology;Therapeutic;Therapeutic Trials;Training;Translating;Work;anticancer research;biological research;biomarker discovery;biomedical data science;cancer diagnosis;cancer genomics;colorectal cancer screening;computational platform;computer science;design;diagnostic biomarker;diagnostic tool;experimental study;genome analysis;genome-wide;handheld mobile device;high throughput technology;leukemia treatment;mathematical methods;member;method development;microbiome;molecular diagnostics;multidimensional data;novel;novel diagnostics;novel therapeutics;personalized approach;personalized medicine;precision medicine;precision oncology;predictive marker;programs;recruit;response;risk stratification;statistics;tumor Research Program: Biostatistics & Computational Biology Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756559 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7850 1861221 "KOOPERBERG, CHARLES L" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 73738 40542 33196 PROJECT SUMMARY: BIOSTATISTICS & COMPUTATIONAL BIOLOGY (BCB)Quantitative and data sciences have penetrated nearly all aspects of biomedical research. With that comeschallenges and opportunities to develop the methods needed to make valid and efficient use of these data forinference on human health and medicine. The Biostatistics & Computational Biology (BCB) Program providesthe intellectual environment for advancing these efforts.Our research program portfolio spans a broad range of activities from statistical methods development tobiological research that uses experimental studies in conjunction with computational methods. Our statisticalresearch emphasizes analytic approaches to genome-scale data sets molecular diagnostics development andapplications of objective measures of lifestyle and environmental exposures and methods for clinical trials.Highlights include breakthroughs in prostate and colorectal cancer screening analysis new methods for designand analysis of therapeutic trials and the development of new statistical approaches for precision medicineand biomarker discovery. Biological research is concentrated on cancer-relevant aspects of quantitativeimmune profiling infectious disease/microbiome and basic molecular biology. BCB members have identifiednew therapeutic avenues for treatment of leukemias and novel predictive markers of immunotherapy response.Our research is characterized by a productive interplay between applied work and methods development.Our specific aims are to develop rigorous statistical and mathematical methods relevant to predictive andpersonalized medicine; to develop and use experimental technological and companion computational ormathematical methods to gain understanding of the natural history of cancer and to develop and disseminatestatistical and computational methods in cancer research.A substantial portion of our research is in areas of emphasis such as high-dimensional data analysis immuneprofiling mobile device data and machine learning that were not a major focus 5 years ago. The ongoinggrowth and development of high-throughput technologies for acquiring biological data provides greatopportunities and challenges for statisticians and computational researchers to make impactful contributions incancer research. BCB members are well-positioned to capitalize on these exciting opportunities: we have awide range of quantitative methodological training augmented by cancer-relevant domain knowledge; we haveoutstanding collaborations; we are strongly committed to translating our methods research into new diagnostictools and therapies; and we are attentive to emerging opportunities in biomedical data science. +No NIH Category available Adoptive Immunotherapy;Adult;Antibodies;Antigen Targeting;Appointment;Blood;Cancer Center Support Grant;Cell Therapy;Cell physiology;Cell surface;Cells;Cellular immunotherapy;Center Core Grants;Child;Clinical;Clinical Trials;Complex;Coupled;Development;Direct Costs;Down-Regulation;Engineering;Evaluation;Faculty;Funding;Genetic Engineering;Grant;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Immune;Immune Evasion;Immune system;Immunity;Immunologics;Immunology;Immunotherapeutic agent;Immunotherapy;Institution;Investigation;Investments;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Metabolic;Modality;Modeling;Myelogenous;Nanotechnology;Nature;Neoplasm Metastasis;Paper;Patients;Pediatric Hematology;Peer Review;Peptide/MHC Complex;Pre-Clinical Model;Property;Publishing;Regulatory T-Lymphocyte;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resource Sharing;Resources;Role;Safety;Sampling;Science;Signal Transduction;Solid Neoplasm;Specimen;T cell therapy;T-Cell Receptor;T-Lymphocyte;Therapeutic;Translating;Transplantation;Tumor Tissue;Turtles;Universities;Washington;Work;cancer cell;cancer immunotherapy;chimeric antigen receptor;clinical application;clinical infrastructure;design;effector T cell;engineered T cells;first-in-human;genetic manipulation;humanized mouse;immune checkpoint blockade;improved;insight;meetings;member;neoplastic cell;next generation;novel;pre-clinical;programs;receptor;recruit;response;small molecule;success;synthetic biology;therapeutically effective;tumor;tumor eradication;tumor immunology;tumor progression;vaccine strategy Research Program: Cancer Immunology Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756555 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7847 10337758 "BLEAKLEY, MARIE " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 74662 58065 16597 PROJECT SUMMARY: CANCER IMMUNOLOGY (CI) Over the past decade immunotherapy has emerged as an established modality that is revolutionizing the treatment of many cancers. The Cancer Immunology (CI) Research Program has focused on genetically manipulating T cells applying new principles of synthetic biology and combining engineered T cells with small molecules and antibodies to broaden the applications and improve the safety and efficacy of adoptive immunotherapy. Despite the success achieved with immunologic approaches in treating some malignancies major gaps exist in our current understanding of the complex relationship between progressing tumors and host immunity and these must be understood and overcome to achieve the potential of immunotherapy in many common cancers. The CI program will focus on systematically tackling these barriers to eradicating tumors using a variety of immunotherapeutic modalitie alone and in combination. The specific aims of CI are (1) to develop effective and safe cellular immunotherapies for adult and pediatric hematologic malignancies and solid tumors (2) to identify and overcome the barriers to immune-mediated tumor eradication using clinical specimens and preclinical models (3) to translate discoveries in basic immunology and synthetic biology to novel clinical applications in cancer immunotherapy. The Cancer Immunology (CI) program currently has 39 members from 11 departments and divisions and 4 Consortium institutions. Nineteen members have primary appointments at Fred Hutch 12 members at University of Washington and 8 members at Seattle Childrens. Fourteen new faculty members joined this program in the last cycle. The current research support of CI members is $23.4M (direct costs) in research grant funding of which $4.4M (19%) is from the NCI and $7.8M (33%) is peer reviewed. The Cancer Immunology program published a total of 470 papers in the last grant period of which 14% were intra- programmatic 49% were inter-programmatic and 50% had external co-authors. Program members have utilized all 12 of the Consortium Shared Resources. This P30 grant also assists this program by providing administrative and logistical support for CI meetings pilot funding for new research projects and recruitment resources for new faculty. +No NIH Category available Achievement;Animal Model;Antibody Therapy;Antibody-drug conjugates;Architecture;Bioinformatics;Biological;Biology;Biostatistics Shared Resource;Bone Marrow Transplantation;CRISPR/Cas technology;Cancer Center Support Grant;Cell model;Cells;Center Core Grants;Child;Collaborations;Defect;Development;Diagnosis;Dimensions;Direct Costs;Disease;Emerging Technologies;Faculty;Fanconi's Anemia;Flow Cytometry;Funding;Gene Expression Profiling;Genes;Genetic Engineering;Genomics;Grant;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Immune system;Immunocompetent;Immunologic Monitoring;Individual;Intervention;Knowledge;Laboratories;Malignant Neoplasms;Medicine;Methods;Modeling;Monitor;Morbidity - disease rate;Mutation;Mutation Analysis;Paper;Pathology;Patients;Peer Review;Phenotype;Publishing;Radioimmunotherapy;Research;Research Project Grants;Research Support;Resource Sharing;Resources;Safety;Speed;T-Lymphocyte;Technology;Therapeutic;Translating;Transplantation;Universities;Virus Diseases;Washington;Work;antibody engineering;cell community;comparative;curative treatments;digital;effective therapy;gene therapy;hematopoietic cell transplantation;improved;induced pluripotent stem cell;insight;laboratory development;leukemia;manufacture;meetings;member;mortality;new technology;novel strategies;programs;recruit;stem cell biology;stem cell function Research Program: Hematologic Malignancies Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756552 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7846 1878414 "APPELBAUM, FREDERICK " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 73738 40542 33196 PROJECT SUMMARY: HEMATOLOGIC MALIGNANCIES (HM)Members of the Hematologic Malignancies Program (HM) are committed to advancing knowledge of thebiologic basis of hematologic malignancies and exploiting this knowledge to reduce the morbidity and mortalitycaused by these disorders. The HM Program is led by Drs. Frederick R. Appelbaum and Geoffrey Hill withDrs. Janice Abkowitz and Hans-Peter Kiem serving as Associate Leaders. The Program has four specific aims:(1) to develop and use emerging technologies to study the abnormalities that result in hematologicmalignancies; (2) to better understand how normal blood stem cells function and how selected abnormalitiesmight be corrected using gene therapy; and to develop improved treatments for hematologic malignanciesusing both non-transplant (Aim 3) and hematopoietic cell transplant-based (Aim 4) approaches.The HM Program currently has 113 members with 62 based at Fred Hutch 42 based at University ofWashington and 9 based at Seattle Childrens. Since the prior cycle HM has gained a net of 38 members.The current research support of HM members is $22.4M (direct costs) of which $11.8M is peer-reviewedfunding including $4.3M from the NCI. HM Program members published a total of 1194 papers over thecurrent grant period of which 32% were intra-programmatic 30% were inter-programmatic and 53% hadexternal co-authors. All 12 Consortium Shared Resources were utilized by HM members in the course of theirwork with major contributions coming from Comparative Medicine Therapeutic Manufacturing Genomics &Bioinformatics Research Pathology Immune Monitoring & Flow Cytometry and Biostatistics SharedResources. This P30 grant also assists this program by providing administrative and logistical support for HMmeetings pilot funding for new research projects and recruitment resources for new faculty. +No NIH Category available Abbreviations;Address;Affect;Anogenital cancer;Appointment;B-cell receptor repertoire sequencing;Back;Bacteria;Biology;Burkitt Lymphoma;Cancer Biology;Cancer Burden;Cancer Center Support Grant;Cancer Etiology;Carcinoma;Center Core Grants;Child;Clinical;Collaborations;Computational Biology;Country;Development;Diagnosis;Direct Costs;Epidemiologist;Epidemiology;Faculty;Funding;Genital;Genitalia;Grant;Helicobacter pylori;Helicobacter pylori induced gastric cancer;Hepatitis B Virus;Hepatitis C virus;Hepatitis Viruses;Human Herpesvirus 4;Human Herpesvirus 8;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immunology;Kaposi Sarcoma;Lymphoma;Malignant Neoplasms;Malignant neoplasm of liver;Measures;Merkel Cells;Merkel cell carcinoma;Modality;Modeling;Natural History;Oncology;Paper;Peer Review;Play;Polyomavirus;Prevention;Prevention strategy;Public Health;Publishing;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Study models;T cell receptor repertoire sequencing;T-Cell Receptor;Therapeutic;Transgenic Organisms;Universities;Virus;Virus-like particle;Washington;Work;anticancer research;carcinogenesis;chimeric antigen receptor T cells;clinical translation;design;improved;inter-institutional;low income country;malignant oropharynx neoplasm;meetings;member;microbiome;novel;oncology program;pathogen;pre-clinical;prevent;programs;recruit;translational study;treatment guidelines;treatment response;treatment strategy;tumor immunology;vaccine acceptance;vaccine development;virus development Research Program: Pathogen Associated Malignancies Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756551 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7845 1863891 "GALLOWAY, DENISE A." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 72846 56249 16597 PROJECT SUMMARY: PATHOGEN ASSOCIATED MALIGNANCIES (PAM)The overall focus of this program is to study pathogen-associated malignancies (PAM) to better preventdiagnose and treat these cancers. We will place an emphasis on studying host-pathogen interactions toidentify novel vulnerabilities caused by the pathogens and will use this information to design prevention ortreatment strategies. We will focus on anogenital and oropharyngeal cancers caused by humanpapillomaviruses (HPV) Merkel cell carcinoma (MCC) caused by Merkel cell polyomavirus (MCPyV) gastriccancers caused by Helicobacter pylori (H. pylori) Kaposi sarcoma and other lymphomas caused by Kaposisarcoma herpesvirus (KSHV) liver cancers caused by hepatitis B and C viruses (HBV HCV) and bothlymphomas and epithelial cancers caused by Epstein Barr virus (EBV). Additionally we will study the role thatspecific bacteria or the microbiome play in promoting cancer and in modifying response to treatmentmodalities. The specific aims of the program are (1) to study host-pathogen interactions of PAMs to identifymechanisms of cancer induction and exploitable vulnerabilities (2) to support translational studies of PAMs inpreclinical and clinical settings that can inform the design of better prevention or therapeutic strategies and (3)to implement effective public health measures to eliminate PAMs and adapt the advances in cancer researchmade in resource-rich countries to address the cancer burdens of low income countries.The PAM Program currently has 37 members with 14 members having primary appointments at Fred Hutch22 members at University of Washington and 1 member at Seattle Childrens. The current research support ofPAM members is $26.4M (direct costs) of which $7.6M is peer-reviewed funding including $2M from the NCI.The PAM program published a total of 377 papers in the last grant period of which 16% were intra-programmatic 44% were inter-programmatic 52% were inter-institutional and 45% had external co-authors.Program members have utilized all 12 of the Consortium Shared Resources. This P30 grant also assists thisprogram by providing administrative and logistical support for PAM meetings pilot funding for new researchprojects and recruitment resources for new faculty. +No NIH Category available Affect;Appointment;Area;Behavioral;Behavioral Sciences;Biometry;Cancer Burden;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Catchment Area;Center Core Grants;Child;Clinical;Collaborations;Communities;Cost Effectiveness Analysis;Data;Development;Direct Costs;Discipline;Disease;Early Diagnosis;Economics;Endogenous Factors;Environmental and Occupational Exposure;Epidemiology;Etiology;Evaluation;Faculty;Funding;General Population;Generations;Genetic;Genome;Genomics;Goals;Grant;Health;Health Policy;Health Promotion;Health Services;Home;Incidence;Individual;Inequity;Integrated Health Care Systems;Intervention;Knowledge;Laboratories;Leadership;Life Style;Malignant Neoplasms;Medical Oncology;Methodology;Methods;Mission;Morbidity - disease rate;Neoplasm Metastasis;Obesity;Observational Study;Outcome;Outcomes Research;Paper;Peer Review;Pharmaceutical Preparations;Physical activity;Play;Population;Population Sciences;Prevention;Prevention strategy;Prevention trial;Productivity;Prognosis;Proteome;Psychology;Publishing;Quality of life;Randomized Controlled Trials;Recording of previous events;Recurrence;Registries;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Risk Reduction;Role;Screening for cancer;Second Primary Cancers;Special Population;Surveillance Methods;System;Target Populations;Testing;Training;Translating;Treatment Failure;Underserved Population;Universities;Washington;Work;administrative database;biobank;cancer care;cancer epidemiology;cancer prevention;cancer risk;care delivery;clinical practice;cohort;comorbidity;dissemination science;health determinants;health economics;high risk population;implementation science;improved;meetings;member;metabolome;microbiome;mortality;neoplasm registry;new technology;next generation;novel;novel strategies;nutrition;obesity prevention;programs;recruit;risk prediction model;risk stratification;screening;shift work;smoking cessation;survivorship;uptake Research Program: Cancer Epidemiology Prevention & Control Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756548 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7844 1896638 "MALONE, KATHLEEN E" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 73738 40542 33196 PROJECT SUMMARY: CANCER EPIDEMIOLOGY PREVENTION & CONTROL (CEPC)The mission of the Cancer Epidemiology Prevention & Control (CEPC) Program is to reduce the populationburden of cancer through the generation of knowledge of factors that contribute to cancer incidence morbidityand mortality and the development of effective and as needed tailored primary secondary and tertiarycancer prevention strategies. To accomplish this mission our faculty conduct clinical and community-basedstudies in the general population as well as in targeted and underserved populations. Program Leadershipincludes Drs. Kathleen Malone and Marian Neuhouser as Co-Leaders and Drs. Margaret Peggy Hannon andScott Ramsey as Associate Program Leaders.CEPC has 84 members from 21 departments across the Consortium representing multiple scientificdisciplines including epidemiology health services health economics health outcomes behavioral sciencesmedical oncology nutrition psychology and genetics. Thirty-six members have primary appointments at theFred Hutch 47 have primary appointments at University of Washington and 1 has a primary appointment atSeattle Children's. Twenty-eight members joined CEPC in this grant period. In FY 2018 CEPC had $27.5M(direct costs) in research funding of which $17.4M (63.3%) is peer-reviewed including $10.6M from NCI. Inaddition CEPC is the home of several large coordinating centers (not counted in research funding) which areassociated with an additional $9.3M in funding. CEPC program members published 1871 papers in this grantperiod of which 23% reflected intra-programmatic collaborations 28% reflected inter-programmaticcollaborations and 50% reflected external collaborations. Eleven of 12 Consortium Shared Resources wereutilized by CEPC members in the course of their work over the last cycle. This P30 grant assists this programby providing administrative and logistical support for CEPC meetings pilot funding for new research projectsand recruitment resources for new faculty.Key program resources include: the Cancer Surveillance System (CSS) our SEER Cancer Registry; theHutchinson Institute for Cancer Outcomes Research (HICOR); the UW Health Promotion Research Center(HPRC); the Institute for Health Metrics and Evaluation (IHME); large well-characterized cohorts with extensivedata and biospecimens; national coordinating centers; and nationally-recognized cancer expertise that spansthe cancer control continuum. CEPC plays an important role in training the next generation of cancerresearchers. The CEPC research portfolio is focused on populations problems and inequities in ourcatchment area and beyond. +No NIH Category available Adopted;Affinity;Animal Model;Area;Basic Science;Belief;Biology;Biomedical Engineering;Brain;Cancer Biology;Cancer Center Support Grant;Cancer Detection;Cancer Etiology;Catchment Area;Cell Cycle;Cell Separation;Cells;Cellular biology;Center Core Grants;Child;Chromatin Structure;Chromosome Segregation;Clinical;Clinical Research;Collaborations;Computational Biology;DNA Repair;DNA analysis;Data;Development;Direct Costs;Disease;Engineering;Epigenetic Process;Faculty;Fostering;Foundations;Funding;Gene Expression;Gene Expression Profile;Genome;Genomics;Goals;Grant;Image;Incentives;Institution;Knowledge;Laboratories;Leadership;Learning;Lung;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Mentors;Methods;Microfluidics;Mission;Monitor;Morbidity - disease rate;Mutagenesis;Nature;Normal Cell;Organ;Outcome;Paper;Peer Review;Phenotype;Play;Population;Postdoctoral Fellow;Preparation;Productivity;Protein Chemistry;Protein Engineering;Proteins;Publications;Publishing;RNA;Recruitment Activity;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Sampling;Science;Scientist;Signal Transduction;Site;Specific qualifier value;Structure;Subgroup;Techniques;Technology;Tissues;Training;Training Programs;Translational Research;Universities;Washington;Work;biological research;cancer cell;cancer diagnosis;cancer genomics;cancer therapy;cancer type;cell behavior;cell free DNA;cell motility;epigenomics;forging;fundamental research;graduate student;high throughput screening;improved;inhibitor;innovation;meetings;member;mortality;nanomolar;next generation;nuclease;pre-clinical;preclinical study;programs;protein structure prediction;recruit;stem cells;structural biology;three dimensional structure;tool;transcriptome;translational potential;translational study;variant of unknown significance Research Program: Cancer Basic Biology Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756546 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7843 1888671 "COOPER, JONATHAN A" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 68565 51967 16598 PROJECT SUMMARY: CANCER BASIC BIOLOGY (CBB)Cancer Basic Biology (CBB) is the sole fundamental science program in the Cancer Consortium. Its mission isthree-fold: to conduct basic biological research related to cancer; to enable and conduct translational researchthat brings basic research findings to preclinical and clinical studies; and to train and mentor the nextgeneration of cancer researchers. Scientifically CBB research has three Specific Aims: (1) to elucidate thefundamental mechanisms that drive normal and cancer cell biology; (2) to use advanced genomics andepigenomics technologies to understand gene expression and phenotype in normal and cancer cells; and (3)to develop and apply new tools to facilitate basic science and cancer cell analyses. Each of these aims has abasic (discovery) and a translational (preclinical) component. The CBB Program leadership represents all threeacademic institutions and the breadth of fundamental research on cancer. Program Co-Leaders JonathanCooper and Ray Monnat take responsibility for cell biology and genomics/epigenomics respectively. AssociateProgram Leaders David MacPherson and Barry Gumbiner add strength in animal models and cell/structuralbiology. All four CBB leaders are united in the goals of fostering research on the basic biology of normal andcancer cells and in promoting the development and application of new tools to improve cancer diagnosis andtherapy. The program benefits the catchment area through research on lung brain and other cancer types thatcause significant mortality and morbidity in our area. Our program structure and leadership work to foster highquality cutting edge science within CBB and across Research Programs by providing opportunities to meetshare ideas and develop new collaborative opportunities. We actively recruit new members with cancer-specific expertise and identify new ways to promote both collaborative and translational science. CBBmembers play an additional key role in training the next generation of cancer scientists.The CBB Program currently has 105 members with 38 based at Fred Hutch 63 based at University ofWashington and 4 based at Seattle Childrens. Since the prior cycle CBB has gained a net of 32 members.The current research support of CBB members is $43.2M (direct costs) of which $27.3M is peer-reviewedfunding including $9M from the NCI. CBB Program members published a total of 1057 papers over thecurrent grant period of which 12% were intra-programmatic 16% were inter-programmatic and 48% hadexternal co-authors. Eleven of the 12 Consortium Shared Resources were utilized by CBB members in thecourse of their work. This P30 grant assists this program by providing administrative and logistical support forCBB meetings pilot funding for new research projects and recruitment resources for new faculty. +No NIH Category available Affect;Anthropometry;Behavior;Behavioral;Biology;Biometry;Biopsy;Body Composition;Breast;Cancer Center Support Grant;Cancer Etiology;Cancer Survivor;Certification;Clinic;Clinical;Clinical Research;Clinical assessments;Collection;Communities;Complement;Computational Biology;Data Collection;Development;Diet;Dietary Intervention;Dual-Energy X-Ray Absorptiometry;Equipment;Exercise;Exercise Test;Exercise Tolerance;Fine needle aspiration biopsy;Food;Food production;Goals;Gynecologic;Health Personnel;Health Services Research;Hematologic Neoplasms;Human;Human Resources;Indirect Calorimetry;Individual;Intake;Intervention;Intervention Studies;Knowledge;Laboratories;Life Style;Life Style Modification;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Measurement;Monitor;Nutritional;Nutritional Study;Nutritional Support;Obesity;Participant;Physical activity;Postdoctoral Fellow;Preventable cancer cause;Prevention;Privacy;Procedures;Prognosis;Protocols documentation;Quality of life;Research;Research Personnel;Resource Sharing;Resources;Science;Services;Specimen;Specimen Handling;Spirometry;Students;Testing;Training;VO2max;abdominal fat;biological research;cancer epidemiology;cost;design;epidemiology study;exercise physiologist;exercise program;exercise training;feeding;flexibility;improved;interest;malignant breast neoplasm;minimally invasive;nutrition;programs;research facility;research study;survivorship;tumor immunology Shared Resource: Prevention Center Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756545 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7842 8441297 "CHOW, ERIC JESSEN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 192368 105765 86603 PROJECT SUMMARY: PREVENTION CENTER SHARED RESOURCE (PCSR)The goal of the Prevention Center Shared Resource (PCSR) is to facilitate transdisciplinary collaborativeresearch within the Consortium focused on better understanding the contributions of behavior/lifestylemodification nutrition physical activity and obesity to cancer development prognosis and survivorship.Centrally located at Fred Hutch (FH) the PCSR accomplishes this by providing Consortium investigatorsaccess to well-trained staff and a full-service research facility (over 10000 nsf) that contains a Research Clinic(RC) Exercise Research Center (ERC) and Human Nutrition Lab (HNL). The RC is staffed with medicalpersonnel who can perform clinical assessments collect biospecimens (including various biopsies) and obtaindetailed anthropometry. The ERC conducts exercise training and testing including VO2 max spirometry andindirect calorimetry. Trained exercise physiologists are available to help investigators design tailored exerciseprograms and to oversee exercise sessions for study participants. The HNL provides comprehensive supportfor the conduct of human feeding studies as well as the food component of behavioral and community nutritionintervention studies. Services include study diet design food production and delivery meal service datacollection and study participant management and monitoring according to diet intake protocols. The PCSRalso provides training and certification for technical staff and serves as a support resource and training facilityfor investigators post-doctoral and clinical fellows and students interested in exercise science and nutritionresearch.Given the increasing number of individuals in the US affected by cancer it is of great importance to identifycauses of cancer that are preventable and ways to improve the quality of life among cancer survivors. Thelong-term goal of the PCSR is to maintain itself as a unique cutting-edge resource for the Consortium tofacilitate advances in our knowledge of the behavioral/lifestyle nutritional physical activity and obesity-relatedcontributors to cancer development prognosis and survivorship. +No NIH Category available Advisory Committees;Area;Biological Specimen Banks;Biomedical Research;Cancer Center Support Grant;Client;Clinical;Data;Data Science;Data Storage and Retrieval;Databases;Development;Enrollment;Epidemiologist;Faculty;Funding;Goals;Health Sciences;Individual;Infrastructure;Interview;Interviewer;Maintenance;Malignant Neoplasms;Manuscripts;Mission;Outcome;Participant;Patient Recruitments;Peer Review;Process;Public Health Applications Research;Publications;Research;Research Activity;Research Project Grants;Resource Sharing;Resources;Secure;Services;Support System;Surveys;Systems Integration;Techniques;Technology;Training;Translational Research;Universities;Washington;base;biomedical resource;cost effective;cost effectiveness;data infrastructure;data management;data sharing;design;electronic data;innovation;member;new technology;novel;operation;personalized approach;population health;programs;recruit;research study;tool Shared Resource: Collaborative Data Services Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756544 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7841 10283600 "DUGGAN, CATHERINE ROSE" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 207659 114173 93486 PROJECT SUMMARY: COLLABORATIVE DATA SERVICES SHARED RESOURCE (CDSSR)The mission of Collaborative Data Services Shared Resource (CDSSR) at the Fred Hutch/University ofWashington Cancer Consortium is to provide strategic service in the design oversight and implementation ofscientific studies by Consortium faculty members. CDSSR is comprised of two units Programming andInterviewing & Data Operations which are managed by unit managers with expertise in these areas and isdirected by Dr. Catherine Duggan with guidance from a 14-member faculty oversight committee which meetsbiannually. CDSSR services support Consortium goals by (1) providing access to programming services andexpertise; (2) providing access to a research call center and to a highly trained team of research interviewers;(3) providing data management solutions encompassing data entry remote secure data capture and securedata storage; (4) developing novel tailored approaches to individual projects needs including workflow designcustomized programming and application of new technologies; (5) educating and training Consortium facultyand staff on data capture programming data science and interviewing techniques; and (6) providinginfrastructure support to maintain programmatic functions for example design of biospecimen repositoriescall center management and database maintenance. CDSSR supports multiple studies that are recruitingparticipants capturing data surveying study participants designing and managing biospecimen repositoriesand implementing funded research studies. Since 2015 CDSSR has supported 232 projects from 66Consortium members across all 8 Consortium research programs; increased its client base by an average of63% over 4 years (FY 2015-FY 2018); supported the publication of over 60 manuscripts; held over 40 trainingclasses in electronic data capture technologies and scientific programming; and increased cost-effectivenessand efficiency of multiple studies. Priority is given to Consortium faculty with peer-reviewed projects and juniorfaculty seeking peer-reviewed funding. The resource continues to expand upon its technical collaborative andadministrative expertise by providing access to current technologies adapted for research use and expandingits client base. +No NIH Category available Address;Advisory Committees;Applications Grants;Award;Awareness;Biological;Biological Markers;Biometry;Biostatistics Shared Resource;Budgets;Cancer Center Support Grant;Cancer Survivorship;Clinical;Clinical Trials Design;Collaborations;Data;Data Analyses;Dedications;Development;Diagnostic tests;Differential Equation;Ensure;Faculty;Feedback;Funding;Genetic;Genomics;Grant;Laboratory Scientists;Methods;Modeling;Pathway Analysis;Phase;Population;Probability;Proteomics;Research;Research Contracts;Research Personnel;Research Project Grants;Resource Sharing;Risk;Series;Services;Statistical Methods;Survival Analysis;Time;United States National Institutes of Health;anticancer research;data integration;experience;improved;innovation;kernel methods;member;metabolomics;microbiome;multidimensional data;multiple omics;predictive modeling;programs;satisfaction;skills Shared Resource: Biostatistics Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756542 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7840 10244881 "GOOLEY, TED " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 314857 173111 141746 PROJECT SUMMARY: BIOSTATISTICS SHARED RESOURCE (BSR)The Biostatistics Shared Resource (BSR) provides collaborative statistical support to Consortium membersacross each of the Research Programs. We emphasize the importance of establishing ongoing and continuingcollaboration with biostatisticians as a means of maximizing scientific collaborations that lead to impactfulcancer research. The BSR aids members with projects that do not have dedicated funding for biostatisticalsupport. In addition the BSR assists members across all Programs in the development of grant proposals. It isexpected that such proposals will have biostatistical support built into the budget in which case if a grant isawarded a funded collaboration with a biostatistician would subsequently take place outside the auspices ofthe BSR. In this sense the BSR frequently spawns NIH-funded research. The BSR is composed of six faculty-level statisticians and three masters-level statisticians and the CCSG currently funds roughly 1.1 FTE. Thelevel of support for each biostatistician of the BSR ranges from 5-20% as each biostatistician is primarilyfunded by research grants and contracts independent of their BSR activities. The CCSG-supported effortensures that a stable staff of highly skilled biostatisticians is available to Consortium investigators. Themembers of the BSR have many years of experience working collaboratively with clinical population andlaboratory scientists and possess a wide range of expertise in statistical methods that are relevant to theConsortium including clinical trial design (Phase I through Phase III) survival analysis (including competingrisks) longitudinal data diagnostics testing biomarkers prediction models microbiome genomic proteomicmetabolomic high-dimensional data analysis multi-omic and data-integration methods analysis of nonlineartime series including modeling and inference with ordinary differential equations cancer survivorship inverse-probability weighting statistical genetics biological pathway analysis mixed model and kernel methodsquantile regression and causal inference. +No NIH Category available Adherence;Area;Bar Codes;Biological;Biological Products;Cancer Center Support Grant;Cell Therapy;Cells;Clinic;Clinical;Clinical Management;Clinical Research;Clinical Trials;Collaborations;Communication;Complex;Computer software;Detection;Development;Diagnosis;Employee;Ensure;Equipment;Equipment and supply inventories;Evaluation;Faculty;Future;Goals;Good Manufacturing Process;Human Resources;Institution;Investments;Malignant Neoplasms;Modality;Modernization;Output;Patient-Focused Outcomes;Performance;Phase;Process;Production;Provider;Qualifying;Quality Control;Research;Research Personnel;Resource Development;Resource Sharing;Resources;Safety;Scientific Advances and Accomplishments;Scientist;Services;Structure;System;Talents;Technology;Testing;Therapeutic;Training;Training Programs;Translating;Universities;Update;Vision;Washington;anticancer research;cancer prevention;cancer therapy;clinical practice;cost effective;gene therapy;improved;manufacture;manufacturing facility;member;next generation;patient safety;pre-clinical;prevent;process optimization;programs;quality assurance;recruit;satisfaction;success;technology platform;translational potential Shared Resource: Therapeutic Manufacturing Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756539 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7838 14767057 "ADAMS, JAMES B" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 397466 218530 178936 PROJECT SUMMARY: THERAPEUTIC MANUFACTURING SHARED RESOURCE (TMSR)The Fred Hutch/University of Washington Cancer Consortium a world leader in the detection diagnosis andprevention of cancer has built a state-of-the-art clinical manufacturing center of excellence within theTherapeutic Manufacturing Shared Resource (TMSR) located at Fred Hutch (FH). This resource providestranslational services that enable complex cancer research treatments to progress from the lab to the bedside.TMSR provides clinical manufacturing services for a multitude of products for Consortium investigators thatspan from traditional biologics to advanced cell and gene therapy applications. Utilizing the TMSR Consortiummembers have initiated a range of Phase I and II clinical trials that have advanced the scientific understandingof cancer therapies. The services provided by TMSR follow current Good Manufacturing Practices (cGMP) andinclude personnel that are highly trained in the field of clinical manufacturing. Additionally the facilities andequipment are maintained in a qualified cGMP manner and all products are subject to quality control testingand quality assurance systems that ensure the safe manufacture and release of clinical trial materials. TheTMSR also provides project management and process development resources to both improve manufacturingsuccess rates and help to translate projects from faculty labs into the cGMP manufacturing facility efficientlyand effectively. Taken together these services are critical for Consortium member who wish to quickly andsafety translate with research directly into the clinic in order to conduct Phase I and II clinical studies in a cost-effective compliant and timely manner for complex cell and gene therapy modalities. The TMSR effectivelyconsolidates the development and production of highly complex biological and living cellular and genetherapies into a single shared resource. The TMSR ensures FDA compliance and provides regulatory supportthat enables the translation of potential therapeutic products from the benchtop to the bedside therebyproviding direct impact on patient outcomes. +No NIH Category available Adherence;Advisory Committees;Biological Assay;Biology;Cancer Center Support Grant;Cell physiology;Cells;Clinical;Clinical Immunology;Clinical Research;Clinical Trials;Communicable Diseases;Communities;Complex;Custom;Data;Data Set;Development;Equipment;Evaluation;Experimental Designs;Faculty;Feedback;Flow Cytometry;Flow Cytometry Shared Resource;Funding;Genetic Engineering;Goals;Group Meetings;Immune;Immune response;Immunologic Monitoring;Immunotherapy;Individual;Institution;Laboratory Research;Laboratory Study;Lasers;Maintenance;Major Histocompatibility Complex;Malignant Neoplasms;Manufacturer;Measures;Molecular;Monitor;Patients;Peptides;Personal Satisfaction;Phenotype;Procedures;Proteins;Protocols documentation;Qualifying;Reagent;Reproducibility;Research;Research Personnel;Resource Sharing;Sampling;Services;Shapes;Staff Development;Surveys;T-Lymphocyte;Technology;Therapy trial;Training;Transplantation;Universities;Washington;Work;antigen-specific T cells;cancer immunotherapy;cytokine;engineered T cells;immunotherapy trials;improved;instrument;instrumentation;laser cell sorter;meetings;member;research study;skills;symposium;technology platform;tumor immunology;vaccine development Shared Resource: Immune Monitoring & Flow Cytometry Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756535 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7836 10229272 "CAO, JIANHONG " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 254217 139771 114446 PROJECT SUMMARY: IMMUNE MONITORING & FLOW CYTOMETRY SHARED RESOURCE (IM&FCSR)The Immune Monitoring and Flow Cytometry Shared Resource (IM&FCSR) provides investigators withservices and research expertise supporting a wide range of laboratory and clinical studies in cancerimmunology and immunotherapy transplant biology infectious disease and vaccine development. TheIM&FCSR produces custom-made tetramer complexes of specific peptide and major histocompatibilitycomplex molecules as unique reagents for assessing antigen-specific T cells and isolating these T cells fortherapy trials. Our flow cytometry service offers a wide range of instrumentation from single-laser benchtopanalyzers to complex multi-laser cell sorters. We provide protocol-specific flow cytometric immune monitoringto support immunotherapy trials. We quantify cytokine proteins as a measure of immune and other cellularfunction at technology platforms of high multiplicity single cell and/or ultrasensitivity. We perform specificcellular and molecular assays of native and genetically engineered T cells for laboratory research studies andfor monitoring clinical samples. Technical assistance is available for data evaluation and interpretation as isassistance in optimal experimental design. The different dataset we can provide enable the characterization ofimmune cells phenotypes and functionality determining immune responses and tracking and monitoring ofimmune cell products during immunotherapies. +No NIH Category available Affect;Alternative Splicing;Apoptosis;Awareness;Biological;Biological Assay;Biological Process;Biopsy;Biopsy Specimen;Brain;Brain Neoplasms;Cell Separation;Data;Development;Event;Excision;Exons;Future;Genes;Genetic Transcription;Glioblastoma;Glioma;Goals;Growth;Invaded;Investigation;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Methodology;Methods;Molecular;Molecular Analysis;Molecular Weight;Normal tissue morphology;Operative Surgical Procedures;Pathogenesis;Pathway interactions;Patients;Pattern;Process;Prognosis;Protein Isoforms;Proteins;Proteomics;RNA;RNA Splicing;Radiation therapy;Research;Resolution;Reverse Transcriptase Polymerase Chain Reaction;Sampling;Source;Spliced Genes;Survival Rate;Techniques;Technology;Testing;Time;Tissues;Transcript;Tumor Antigens;Validation;Variant;Western Blotting;Work;biobank;cancer survival;cancer type;candidate identification;chemotherapy;diagnostic biomarker;differential expression;experimental study;follow-up;large scale data;mRNA sequencing;neoplastic cell;new therapeutic target;novel;novel marker;novel strategies;personalized medicine;potential biomarker;precision medicine;protein folding;proteogenomics;public database;side effect;small hairpin RNA;standard of care;stem cells;therapeutic target;transcriptome sequencing;transcriptomics;translational study;tumor;tumor initiation;variant detection Using proteogenomics to assess the functional impact of alternative splicing events in glioblastoma PROPOSAL NARRATIVEGlioblastoma (GBM) is the most aggressive type of glioma characterized by fast growth and poor prognosiswith an average survival of 15 months. Here we will apply a systematic molecular analysis to identifyalternatively spliced genes in GBMs and then validate the biological function of those splice forms in patient-derived glioma stem cells. Our main goal is to identify putative alternative splicing genes as therapeutic targetsfor future studies in personalized medicine. NCI 10756532 11/22/23 0:00 PAR-20-292 5R21CA267394-02 5 R21 CA 267394 2 "GANGULY, ANIRUDDHA" 1/1/23 0:00 12/31/24 0:00 ZCA1-SRB-P(O1)S 7320385 "COBBS, CHARLES S" "SEARLE, BRIAN CHIH-SENG" 9 Unavailable 79264420 GZ5WW5GZY2A5 79264420 GZ5WW5GZY2A5 US 47.608392 -122.322135 10001759 "SWEDISH MEDICAL CENTER, FIRST HILL" SEATTLE WA Independent Hospitals 981224307 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 207100 NCI 148600 58500 PROJECT ABSTRACTGlioblastoma (GBM) is the most malignant type of brain tumor with a median survival time of 15 months.Despite advances in cancer survival for many malignancies GBM survival rates still remain low and have notsignificantly changed over the last 30 years emphasizing the urgent need for new treatment options. One ofthe common hallmarks of cancer is splicing perturbations and alternatively spliced genes are an interestingnew source for potential diagnostic biomarkers and therapeutic targets. Current methodologies to characterizesplicing in tumors using mRNA sequencing can only indicate that alternative exons are transcribed butadditional validation is needed to verify that these spliceforms produce functional proteins. Our preliminaryresults comparing paired tumor/normal samples indicate that alternative splicing in GBM affects many moregenes than previously expected both at the transcript and protein levels. Based on these data we hypothesizethat a set of alternatively spliced genes are involved in tumor initiation and GBM pathogenesis. In this proposalwe will use a combination of precision medicine approaches to detect and quantify tumor-specific alternativesplicing events in GBMs. We will verify that these events produce distinct proteoforms using splicing-awareproteogenomics experiments. Finally we will functionally characterize differentially expressed splice isoformcandidates for their effects on growth apoptosis and invasion in patient-derived glioma stem cells. Ifsuccessful this work will lead to new understanding of the biological impact of novel GBM proteoforms andpotentially lead to novel approaches to treatment of GBM based on unique tumor antigens and molecularpathways. 207100 +No NIH Category available Analytical Biochemistry;Analytical Chemistry;Area;Awareness;Bile Acids;Bioinformatics;Biological;Biological Assay;Cancer Biology;Cancer Center Support Grant;Cancer Patient;Chromatography;Clinical;Coenzymes;Consult;Consultations;Data;Data Analyses;Dedications;Development;Digestion;Education;Educational Materials;Educational workshop;Equipment;Experimental Designs;Feedback;Fractionation;Future;Gel;General Population;Grant;High Pressure Liquid Chromatography;Human Resources;Individual;Informatics;Infrastructure;Isotopes;Lipids;Liquid substance;Major Histocompatibility Complex;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Methodology;Methods;Mission;Modernization;Modification;Molecular;NMR Spectroscopy;Nuclear Magnetic Resonance;Pathway Analysis;Peptides;Policies;Post-Translational Protein Processing;Preparation;Process;Productivity;Proteins;Proteomics;Proteomics Shared Resource;Research;Research Personnel;Research Support;Resource Sharing;Resources;Sampling;Services;Slice;Statistical Data Interpretation;Technology;Testing;Time;Tissues;Tracer;Training;Training and Education;Translating;Universities;Volatile Fatty Acids;Washington;advanced analytics;cancer care;cancer immunotherapy;cancer prevention;complex data;cost effective;design;education resources;effective therapy;experience;experimental study;improved;instrument;interest;knowledge base;lipidomics;liquid chromatography mass spectrometry;member;metabolic abnormality assessment;metabolomics;metabolomics resource;new technology;operation;programs;response;skills;small molecule;stable isotope;statistics;symposium;tool;tumor immunology Shared Resource: Proteomics & Metabolomics Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756531 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7834 10082895 "GAFKEN, PHILIP R" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 337300 233893 103407 PROJECT SUMMARY: PROTEOMICS & METABOLOMICS SHARED RESOURCE (P&MSR)The Proteomics and Metabolomics Shared Resource (P&MSR) consists of the Fred Hutch (FH)-basedProteomics Facility and the University of Washington South Lake Union (UW-SLU) Metabolomics Facility. TheP&MSR Proteomics Facility was formed in 2002 and has been under the direction of Dr. Phil Gafken since itsinception. The P&MSR Metabolomics Facility was formed in 2013 and has been under the direction of Dr.Daniel Raftery. The mission of the P&MSR is (1) to provide high-quality cost-effective and reliable service in atimely manner for proteomics and metabolomics experiments; (2) to develop and implement new omicsexperiments assays and tools to uncover the molecular details influencing cancer biology; and (3) to supportthe development of translatable and clinical tests. The P&MSR operates and maintains chromatography massspectrometry and nuclear magnetic resonance instruments and offers services such as experimental designand consultation sample preparation and chromatography protein or metabolite identification andquantification protein modification characterization targeted protein or metabolite quantification metabolic fluxanalysis and data analysis and informatics support. New technologies and services are continually beingevaluated based on feedback from Consortium members. Over the next granting period areas of interest thatwill be investigated include the analysis of major histocompatibility complex peptides to support cancerimmunology and immunotherapy research. For metabolomics we will add to our over 20 current assays byexpanding our capabilities to measure metabolic flux provide the capability to investigate real-time metabolismstudies using stable isotope tracers and develop higher throughput global profiling assays to support researchin cancer biology. With well-established operation policies Consortium users have cost-effective reliable andimmediate access to the P&MSR. The research supported by the P&MSR demonstrates that it is an importantpart of the critical Shared Resources infrastructure needed to support the Fred Hutch/University of WashingtonCancer Consortium. +No NIH Category available ATAC-seq;Adopted;Atmosphere;Attention;Bar Codes;Bioinformatics;Bioinformatics Shared Resource;Biological Assay;Biological Sciences;CRISPR/Cas technology;Cancer Center Support Grant;Caring;Chromium;Collaborations;Communities;Creativeness;DNA-Protein Interaction;Data;Data Analyses;Development;Dideoxy Chain Termination DNA Sequencing;Education;Ensure;Environment;Equipment;Experimental Designs;Expression Profiling;Faculty;Feedback;Future;Generations;Genetic Fingerprintings;Genomics;Genomics Shared Resource;Goals;Growth and Development function;Hi-C;Housing;Individual;Malignant Neoplasms;Messenger RNA;Methodology;Methods;MicroRNAs;Peer Review;Persons;Phase;Postdoctoral Fellow;Publications;Reagent;Research;Research Personnel;Research Project Grants;Resource Sharing;Ribosomes;Sampling;Savings;Scientist;Seasons;Services;Students;Sum;System;Targeted Resequencing;Technology;Time;Training;Training and Education;Transact;Transcend;Universities;Untranslated RNA;Washington;Work;bead chip;deep sequencing;digital;epigenomics;exome sequencing;experience;genome sequencing;graduate student;instrumentation;interest;member;methylome;nano-string;new technology;sound;success;training opportunity;trend;whole genome Shared Resource: Genomics & Bioinformatics Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756530 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7833 10229275 "DELROW, JEFFREY " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 430471 236677 193794 PROJECT SUMMARY: GENOMICS & BIOINFORMATICS SHARED RESOURCE (G&BSR)The Genomics & Bioinformatics Shared Resource (G&BSR) is a state-of-the-art facility that has continued toevolve over the past 20 years providing Cancer Consortium members with access to sophisticated genomics based technologies and a team consisting of a highly experienced scientist expert technical staff andseasoned bioinformaticians. This team provides a seamless experience for the researcher supporting allphases of technology selection experimental design sample QC data generation and analysis. The broadportfolio of massively parallel deep sequencing services offered through the G&BSR includes whole genomesequencing; whole exome sequencing; expression profiling of mRNAs miRNAs and non-coding RNAs;ribosome sequencing; and numerous targeted resequencing applications. Additionally epigenomics servicesincluding the profiling of the DNA methylome ATAC-seq and Hi-C sequencing assays are performed. TheG&BSR was also an early adopter of CRISPR-Cas9 pooled screens and supported the development ofCUT&RUN a protein-DNA interaction assay developed by Fred Hutch investigators led by Dr. StevenHenikoff CBB with both technologies now implemented as high-throughput pipelines available to the broaderConsortium community through the G&BSR. In addition the G&BSR routinely employs NanoString digitalbarcoding technology conducts Sanger sequencing and provides training on and access to qPCRinstrumentation. Major equipment includes an Illumina NovaSeq 6000 sequencer an lllumina HiSeq 2500sequencer two Illumina MiSeq sequencers a Pacific Biosciences Sequel sequencer an Illumina BeadChipsystem a NanoString nCounter system a 10x Genomics Chromium controller two ABI 3730xl sequencers aPerkinElmer Sciclone NGSx Workstation and four ThermoFisher Scientific QuantStudio 5 real-time PCRsystems. Peer-reviewed studies accounted for 66% of the work performed in the G&BSR during 2017 and staffcontributed to over 30 publications (July 2017 June 2018). +No NIH Category available Antibodies;Biological Assay;Cancer Center Support Grant;Complex;Consultations;Custom;DNA;Detection;Development;Experimental Designs;Fostering;Funding;Generations;Histopathology;Image;Image Analysis;Immunohistochemistry;In Situ Hybridization;Individual;Industry Standard;Learning;Malignant Neoplasms;Pathologic;Pathologist;Pathology;Phase;Phenotype;Process;Production;RNA;Reagent;Research;Research Personnel;Resource Sharing;Resources;Scientist;Services;Slide;Social Network;Tissue Microarray;Tissues;Training;Translating;Universities;Validation;Washington;assay development;cancer therapy;cost;cost effective;density;design and construction;digital imaging;experience;improved;innovation;laser capture microdissection;programs;quantitative imaging;screening;tool;translational goal;tumor Shared Resource: Research Pathology Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756529 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7832 10927652 "CHANTHAPHAVONG, RATSAMY SAVANH" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 397875 218756 179119 PROJECT SUMMARY: RESEARCH PATHOLOGY SHARED RESOURCE (RPSR) The Research Pathology Shared Resources (RPSR) provides a suite of cutting-edge tools to enable the analysis of complex cancer phenotypes in a spatially-resolved manner. Understanding the complex pathologic social network within tumors is essential to further develop our mechanistic understanding of cancer and translate those learnings into effective cancer treatments. The RPSR offers capabilities ranging from routine histopathology services to custom immunohistochemical antibody and assay development to cutting-edge multiplex immunohistochemistry (mIHC). In addition the RPSR Lab Directors and staff scientists provide wide- ranging expertise extending from the experimental design phase to downstream quantitative image analysis. The RPSR is committed to fostering a culture of continuous improvement and providing innovative high- quality cost-effective and expeditious services to the Fred Hutch/University of Washington Cancer Consortium in order to broadly contribute to the basic and translational mission of the Consortium. +No NIH Category available Address;Adopted;Adoption;Algorithms;Area;Cancer Etiology;Cessation of life;Colon;Colon Carcinoma;Colonoscopes;Colonoscopy;Color;Complex;Data Analyses;Detection;Development;Diamond;Economic Burden;Engineering;Evaluation;Excision;Goals;Growth;Image;Imaging technology;Incidence;Lesion;Location;Malignant Neoplasms;Methods;Modeling;Morbidity - disease rate;Optics;Patients;Performance;Physicians;Polyps;Precancerous Polyp;Published Comment;Screening for cancer;Screening procedure;Side;Societies;Surface;System;Time;Training;United States;Woman;burden of illness;cancer prevention;clinical practice;contrast imaging;cost;design;experience;fabrication;image processing;imaging capabilities;imaging system;improved;lens;men;mortality;novel;premalignant;prevent;screening Single viewpoint panoramic imaging technology for colonoscopy Project NarrativeColonoscopy is a common cancer screening procedure that is far from perfect and one of its major flaws is thatthe physician is unable to view large areas of the colon hidden behind folds which leads to missed pre-cancerousgrowths and the unexpected early development of cancer. We will develop and demonstrate a unique singleviewpoint panoramic imaging technology which can be either integrated to the new colonoscope or added as anattachment to the standard colonoscopes providing a wide-field forward view and 360-degree side-view. Amore thorough colonoscopy will lead to fewer missed polyps longer screening intervals and a substantialreduction in the economic burden of colonoscopy NCI 10756524 12/15/23 0:00 PAR-22-090 5R21CA277667-02 5 R21 CA 277667 2 "SALVADOR MORALES, CAROLINA" 1/1/23 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-BST-P(81)S] 11101636 "LIANG, RONGGUANG " Not Applicable 7 NONE 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF OPTOMETRY/OPHT TECH 857210158 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 156013 NCI 105188 50825 AbstractColon cancer is a leading cause of cancer death in the United States and worldwide. Colonoscopy is thepreferred screening method at an estimated annual cost of about $24 billion in the US. Unfortunately manylesions are missed because they can remain hidden from view behind folds and flexures of the colon. Currentmethods of increasing the field of view are ineffective and some are very expensive preventing the adoption ofthese methods into clinical practice.In this proposal we propose to develop a single viewpoint panoramic imaging technology which can provide360-degree side-view of the colon. The proposed panoramic imaging system consists of an array of imagingsystems which share the same viewpoint addressing the key barrier in reconstructing the panoramic image frommultiple imaging systems. We will develop a unique monolithic opto-mechanical design to integrate allsubsystems precisely without active alignment. The proposed single viewpoint panoramic imaging system canbe either integrated to the new colonoscope so that the colonoscope will have standard forward view and 360-degree panoramic side-view or built as a snap-on attachment for the current commercial colonoscopes toprovide 360-degree panoramic side-view.To demonstrate the imaging capability of the proposed single viewpoint panoramic system we will first developand characterize a single viewpoint panoramic attachment for the standard colonoscope and then evaluate theperformance in detecting polyps and compare to a standard colonoscope.The proposed single viewpoint panoramic imaging system will maximize the detection of polyps and substantiallyreduce the incidence of colon cancer. It will benefit the patients and society in five-fold: reducing incidence ofcolon cancer reducing the chance of interval cancer decreasing overall morbidity and mortality increasing theinterval between colonoscopies and reducing the economic burden of this disease. 156013 +No NIH Category available Administrator;Area;Attention;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Trials;Collaborations;Community Outreach;Data;Development;Ensure;Equity;Evaluation;Faculty;Feedback;Funding;Goals;Grant;Guidelines;Heart;Infrastructure;Institution;Interdisciplinary Study;Intervention Trial;Journals;Leadership;Maintenance;Malignant Neoplasms;Measures;Mind;Monitor;Philanthropic Fund;Process;Publications;Recommendation;Research;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Secure;Strategic Planning;Training and Education;Universities;Vision;Washington;Work;anticancer research;career;community engagement;design;equity diversity and inclusion;improved;innovation;meetings;member;mouse model;operation;pre-clinical;programs;success;symposium;tumor;underserved community Cancer Center Administration Not applicable to P30 CCSG as stated in the FOA PAR-17-095. NCI 10756523 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7829 1862283 "LAW, WENDY " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 Research Centers 2024 665228 452863 212365 PROJECT SUMMARY: ADMINISTRATIONThe Consortium Administration provides high quality efficient and effective support to Fred Hutch/University ofWashington Cancer Consortium leaders Research Programs Shared Resources and members.Administration owns and drives the processes that Consortium scientific leaders use to define theConsortium's vision and strategic goals implement initiatives monitor progress in achieving objectives andsecure needed resources to develop and maintain the requisite infrastructure. Consortium Director Dr. GaryGilliland and senior leaders developed a strategic plan through a process started when he arrived in 2015. Theprocess is ongoing by design with annual internal and external evaluations of milestones. Throughout theprocess Administration ensures that CCSG guidelines are integral to the strategic goals and activities. As aresult of these activities Consortium membership has grown by >170 members; cancer-relevant grant fundingfor the Consortium is at $242M of which $50M is from the NCI; interventional trials have 5424 accruals andnon-interventional trials have 5292 accruals (increases of 83% and 20% respectively from FY 2014 to FY2018); and members have over 6600 cancer-related publications as authors and co-authors with 11% of themin journals with impact factors greater than 20.New in this cycle of the CCSG are the components for Community Outreach & Engagement (COE) andCancer Research Career Enhancement (CRCE). Administration has been pivotal to establishing offices forboth of these new components to oversee their respective areas of activity. Other new Consortium initiativesinclude the formation of three Integrated Research Centers (IRCs) the continued development of the SeattleTranslational Tumor Research initiative (STTR) and major enhancements of clinical trials infrastructure.Administration has interfaced with initiative leaders and their respective administrators in order to leveragestrengths and resources toward supporting Research Programs and members. Finally as a result of facultyfeedback a new developing Shared Resource for preclinical mouse models was developed by Administrationto further Consortium science.` +No NIH Category available Alaska;Area;Biology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Detection;Cancer Etiology;Carcinogenesis Mechanism;Caregivers;Catchment Area;Cause of Death;Cessation of life;Child;Childhood;Clinical;Clinical Research;Collaborations;Communities;Comprehensive Cancer Center;Computational Biology;County;Development;Diagnosis;Diagnostic;Discipline;Disease;Educational process of instructing;Enrollment;Ensure;Equation;Equity;Exposure to;Faculty;Faculty Recruitment;Fostering;Funding;Genomics;Goals;Grant;Health;Health Sciences;Hematopoietic Stem Cell Transplantation;Idaho;Immunology;Immunotherapeutic agent;Individual;Institution;Intervention;Investments;Knowledge;Laboratories;Laboratory Research;Leadership;Malignant Neoplasms;Measures;Mentors;Mission;Molecular;Montana;Outcome;Patients;Peer Review;Population Research;Postdoctoral Fellow;Prevention;Prevention strategy;Primary Prevention;Public Health;Quality of Care;Research;Research Infrastructure;Research Personnel;Resources;Risk Factors;Risk Marker;Science;Secondary Prevention;Students;Therapeutic;Training;Training and Education;Translating;Translational Research;Translations;Transplantation;Underrepresented Populations;United States;Universities;Washington;Work;Wyoming;anticancer research;base;cancer care;cancer diagnosis;cancer therapy;carcinogenesis;clinical care;clinical practice;computer studies;epigenomics;graduate student;host neoplasm interaction;improved;insight;inter-institutional;interdisciplinary collaboration;interest;member;mortality;multidisciplinary;next generation;outreach;pathogen;profiles in patients;programs;synthetic biology;targeted treatment;therapy development;treatment center;treatment trial;tumor;tumor metabolism;tumor progression Cancer Center Support Grant PROJECT NARRATIVE: OVERALLThere were an estimated 1.7 million new cases of cancer in the United States in 2018 and an estimated609000 deaths from the disease. Cancer is the second leading cause of the death in the U.S. The goal of theFred Hutchinson/University of Washington Cancer Consortium is the elimination of cancer as a cause ofsuffering and death through more effective prevention diagnosis and treatment deriving from fundamentalinsights into the biology of the disease. NCI 10756522 12/22/23 0:00 PAR-17-095 5P30CA015704-49 5 P30 CA 15704 49 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 397 Research Centers 2024 9081129 NCI 5732981 3348148 PROJECT SUMMARY: OVERALLThe Fred Hutchinson/University of Washington Cancer Consortium (the Consortium) brings together morethan 600 members with research interests in basic clinical and public health sciences related to cancer. Thegoal of the Consortium is the elimination of cancer as a cause of suffering and death through more effectiveprevention diagnostics and treatment deriving from fundamental insights into the biology of the disease. Theextensive interdisciplinary collaboration among the partner institutions in the cancer research disciplines ofbasic clinical and public health sciences affords new opportunities to reduce suffering and mortality fromcancer.The Consortium was established in 2002 to build upon the complementary strengths and resources of threepartner institutions: the Fred Hutch which has been an NCI-designated Comprehensive Cancer Center since1976; the University of Washington which has significant strength in cancer research clinical care andteaching; and Seattle Childrens the major pediatric academic center in the region. In 2008 the Seattle CancerCare Alliance the cancer treatment center founded and equally co-owned by the three founding institutionswas formally added to the cancer center designation.The Consortiums total funding base (direct dollars) is $242M of which $117M is peer-reviewed including$50M from the NCI. During the last grant period over 170 new faculty members joined the Consortium addingbreadth and depth to our research and clinical capabilities. In the most recent year we enrolled 1338 patientsonto interventional treatment trials of which more than 50% were investigator-initiated. The ratio of accruals tonewly registered patients was 28%.The Consortium serves a catchment area of 13 counties in western Washington. This equates to the region inwhich 83 percent of our patients reside. As the only NCI-designated comprehensive cancer center in a five-state region (Washington Wyoming Alaska Montana and Idaho) we not only seek to serve the health needsof the catchment area through research training and outreach but also to ensure high impact throughout thelarger region.The Consortium continues to build upon historic strengths in basic cancer biology immunology andtransplantation pathogen associated malignancies tumor specific translational research computationalbiology and studies of cancer etiology prevention and outcomes. The Consortium is well poised to continue itsexceptional level of research in these areas. The CCSG continues to have a high impact on the Consortiumfostering new inter-institutional collaborations strengthening the translational research platform andintensifying research efforts on problems of the catchment area. Partner institutions contributed nearly $1.2billion in institutional support during the last project period including investments in our laboratory and clinicalresearch infrastructure as well as in faculty recruitment and trainee support. 9081129 +No NIH Category available Affect;Alleles;Antibodies;Antigen Targeting;Antigens;Apoptosis;Apoptotic;Attention;BCL1 Oncogene;Biological Assay;CAR T cell therapy;CD19 Antigens;CD19 gene;CD8B1 gene;Cell Death;Cell Death Induction;Cell Death Signaling Process;Cell-Mediated Cytolysis;Cells;Cessation of life;Data;Drug Combinations;Drug resistance;Engineering;Epidermal Growth Factor Receptor;Genes;Genetic;Genetic Engineering;Genomic approach;Glioblastoma;Goals;Granzyme;Hematopoietic Neoplasms;Immune system;Immunology;Immunotherapy;In Vitro;Laboratories;Lead;Life;Liquid substance;Lymphoma;Malignant Neoplasms;Malignant lymphoid neoplasm;Mediating;Mitochondria;Multiple Myeloma;Mus;Mutation;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacogenetics;Plasma Cells;Predisposition;Proteins;Receptor Signaling;Resistance;Signal Transduction;Solid;Solid Neoplasm;Surface;T-Lymphocyte;Techniques;Testing;Tumor Biology;Tumor Cell Line;Xenograft Model;Xenograft procedure;cancer cell;cancer type;cell killing;chimeric antigen receptor T cells;cytotoxicity;density;drug candidate;effector T cell;engineered T cells;functional genomics;gain of function;genetic approach;in vivo;inhibitor;innovation;invention;knockout gene;loss of function;lymphoid neoplasm;mouse model;mutant;neoplastic cell;perforin;pharmacologic;resistance mechanism;response;small molecule;standard care;tool;tumor Understanding and manipulating programmed cell death (PCD) pathways to facilitate lymphoid tumor killing by CAR T cells PROJECT NARRATIVEImmune therapy has become a standard treatment for multiple types of cancers and ultimately relies on T cellsto kill tumor cells; however we dont yet fully understand the relationship between how T cells kill tumors andhow cell death pathways in tumors lead to their death. CAR T cells are engineered T cells that kill lymphoidtumors by targeting a specific protein on their surface and are now standard treatment for lymphoid cancers.We propose to examine the mechanisms by which CAR T cells kill tumors and define the programmed celldeath pathways in tumor cells that enable susceptibility and resistance to CAR T cell killing with the goal ofusing specific combinations of drugs and engineering approaches to enhance T cell-mediated tumor killing. NCI 10756502 12/29/23 0:00 PA-19-056 5R01CA249062-04 5 R01 CA 249062 4 "SOMMERS, CONNIE L" 1/7/21 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 10066497 "MAUS, MARCELA VALDERRAMA" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 632838 NCI 514420 118418 PROJECT SUMMARYRecent advances using CAR T cells in lymphoid malignancies have made it clear that manipulation of the hostimmune system can radically alter the course of a cancer. Although there have been lifesaving responses insome patients all too many patients have inadequate responses. Some patients and tumor types have beenmore amenable to CAR T cell therapies than others despite similar levels of antigen expression uniformityand density. The exact mechanisms by which CAR T cells induce tumor cell death are unknown and may bedue to a combination of multiple T cell effector functions that ultimately result in cell death potentially bytriggering programmed cell death in tumor cells. Our overall hypothesis is that CAR T cells mediate tumor celldeath by inducing programmed cell death (PCD) pathways in target cells. A logical corollary of this hypothesisis that one potential mechanism of resistance which has received scant attention is genetic or functionalresistance to PCD in the target tumor cells. Furthermore we hypothesize that the state of PCD constituents intumor cells confers sensitivity or resistance to T-cell mediated killing and that this relative resistance can beovercome with drugs that enhance PCD signaling in tumor cells. Finally because systemically administereddrugs that enhance PCD signaling may also affect CAR T cells we propose genetic engineering approaches torender CAR T cells resistant to candidate PCD-enhancing drugs. This is a collaborative project between anexpert in CAR T cells and immunology and an expert in programmed cell pathways and tumor biology.Together we aim to define the effector functions of T cells that induce tumor cell death (Aim 1) define theprogrammed cell death pathways in tumors that confer sensitivity or resistance to CAR T cell mediated killing(Aim 2) and use innovative strategies to enhance CAR T cell killing of tumor cells by manipulating PCDpathways using small molecule drugs in combination with genetic engineering of the CAR T cells. 632838 +No NIH Category available Affect;Astrocytes;Automobile Driving;Autopsy;Biological Assay;Biological Markers;Blood;Brain;CD44 gene;Cell Line;Cell Proliferation;Cell Separation;Cell surface;Cells;Cerebrospinal Fluid;Clinical;Clinical Trials;Complement;Country;Cytology;Dedications;Development;Diagnosis;Diagnostic;Disease;Drug usage;Extracellular Matrix;Flow Cytometry;Fright;Gene Expression;Gene Expression Profiling;Goals;Growth;Heparan Sulfate Proteoglycan;Heparanase inhibitors;Heparitin Sulfate;Homing;Human;In Vitro;Incidence;Invaded;Knowledge;Lead;Leptomeninges;Ligands;Link;Magnetic Resonance Imaging;Malignant Neoplasms;Mediating;Melanoma Cell;Metastatic Melanoma;Metastatic malignant neoplasm to brain;Modeling;Morbidity - disease rate;NGFR Protein;Neoplasm Circulating Cells;Neoplasm Metastasis;Nerve Growth Factor Receptors;Neurofibromatosis 2;Neurofibromin 2;Neuroglia;Oncogenic;PAK-1 kinase;Pathway interactions;Patient Isolation;Patients;Phenotype;Phosphorylation;Positioning Attribute;Prevention;Primary Neoplasm;Prognosis;Property;Proteomics;Reporting;Role;Sampling;Selection for Treatments;Series;Signal Transduction;Technology;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Tumor Markers;Variant;Work;Xenograft procedure;biomarker development;cancer therapy;clinical development;clinical predictors;cohort;combat;combinatorial;diagnostic value;drug discovery;effective therapy;heparanase;improved;in vivo;melanoma;mortality;neoplastic cell;neurotrophic factor;novel;novel therapeutics;prevent;prognostic;promoter;small molecule;syndecan;targeted biomarker;targeted treatment;therapeutic target;tool;transcriptional coactivator p75;transcriptomics;tumor Mechanisms of melanoma brain metastasis by CTCs isolated from patients' blood and CSF Melanoma brain metastasis (MBM) associates with high morbidity and mortality and is still extremely difficult totreat. An improved in-depth understanding of properties and mechanisms of brain-homing and brain-extrudedCirculating Tumor Cells (CTCs) are urgently needed and considered fundamental pre-requisites for thedevelopment of new and effective therapies targeting MBM. NCI 10756467 11/21/23 0:00 PA-16-160 5R01CA216991-07 5 R01 CA 216991 7 "YOUNG, MATTHEW R" 12/15/17 0:00 11/30/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 1948620 "MARCHETTI, DARIO " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM SCHOOLS OF MEDICINE 871310001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 153000 NCI 100990 52010 Melanoma Brain Metastasis (MBM) carries a dismal prognosis with a median overall survival of only 4-6 months.If patients develop leptomeningeal disease the overall survival is even lower. The incidence of MBM has beenreported to be up to 43% in clinical settings and up to 75% in the autopsy series. Although notions that CirculatingTumor Cells (CTCs) act as seeds of intractable metastasis are established there is no knowledge characterizingMBM-colonizing CTCs. Single-cell CTC transcriptional profiling has also demonstrated that CTCs isolated frompatients are very distinct from cell lines that are widely used for drug discovery. This is even more compellingconsidering that significant discrepancies of biomarkers among CTCs and corresponding primary and metastatictumors have been observed. Moreover while the presence of CTCs in the cerebrospinal fluid (CSF) remains thegold standard the sensitivity of cytology is only 50-56% at time of the first CSF analysis. Therefore thedevelopment of effective therapy approaches - CTC-based tests - could have a tremendous clinical impact to treatMBM. We hypothesize that the neurotrophin receptor p75NTR and Heparanase (HPSE) two markers implicatedin MBM models are novel CTC biomarkers to predict clinical MBM and potential therapeutic targets to preventMBM. The objective of this application is to demonstrate that the p75NTR/HPSE axis is diagnostic in clinicalMBM; and that p75NTR and HPSE are novel therapeutic CTC targets to combat MBM. In aim 1 we will: a) isolateand characterize p75NTR/HPSE CTC subsets from blood and CSF (multiparametric flow cytometry andDEPArrayTM technologies among others) and compare the expression of p75NTR/HPSE combinations in CTCsof melanoma patients diagnosed either with or without MBM; b) directly link patient-isolated CTC subsetspossessing p75NTR/HPSE expression and combinations to clinical MBM. In aim 2 we will assess effects ofregulating functions of p75NTR/HPSE CTC subsets on MBM development by using small-molecule p75NTR andnew HPSE inhibitors along with CTC xenografts; and complement these effects with regulatory p75NTR/HPSEgene expression (pINDUCER lentiviral toolkit). In aim 3 we will: a) determine roles of CTC-expressed Merlin asan important integrator of p75NTR/HPSE pathways altering CTC proliferation vs. growth arrest; b) delineateHPSE-induced syndecan-mediated modulation of Merlin/Hippo signaling to affect CTC properties driving MBM.Uncovering MBM CTC phenotypes offers the opportunity to modify treatment by extending studies directly tohuman melanoma. This project lead by an inter-disciplinary and well-integrated team will study and validate newand specific CTC biomarkers responsible for CTC-induced MBM. It has high therapeutic impact and is paradigm-shifting. We are uniquely positioned to perform this study not only for having access to an extensive cohort ofblood/CSF samples from melanoma patients but also for the extensive expertise interrogating the entire CTCspectrum by combining multiple and complementary CTC technologies unlike other groups in the country. 153000 +No NIH Category available Address;Benign;Benign Prostatic Hypertrophy;Biological Markers;Biopsy;Blood;Blood Tests;Cancer Patient;Classification;Clinical;Data;Diagnosis;Diagnostic;Diffusion;Disease Progression;Extraprostatic;General Population;Gleason Grade for Prostate Cancer;Goals;Histology;Hospitalization;Image;Indolent;Interdisciplinary Study;Invaded;Liquid substance;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Modeling;Monitor;Nomograms;Non-Invasive Detection;Operative Surgical Procedures;PSA screening;Pathologic;Pathology;Patient Selection;Patients;Periodicals;Procedures;Prostate;Prostate-Specific Antigen;Prostatectomy;Prostatic Diseases;Protocols documentation;Radiation;Radical Prostatectomy;Rectum;Reference Standards;Risk;Seminal Vesicles;Sensitivity and Specificity;Sepsis;Testing;Tissues;Training;United States;Update;Urine;Visualization;accurate diagnosis;artificial intelligence algorithm;cancer diagnosis;clinical care;clinical imaging;clinical risk;clinical translation;clinically significant;cohort;disorder risk;high risk;improved;magnetic resonance imaging biomarker;men;non-invasive monitor;noninvasive diagnosis;novel;overtreatment;patient screening;patient subsets;performance tests;prospective;prostate biopsy;prostate cancer risk;prostatitis;recruit;rectal;research clinical testing;risk prediction;risk stratification;screening;spectrograph;standard of care;tool;tumor Diffusion Histology Imaging: A Clinical Tool to Non-Invasively Diagnose and Manage Prostate Cancer PROJECT NARRATIVEMany of the invasive transrectal prostate biopsies performed for PSA screening are unnecessary50% of themen undergoing a biopsy do not have prostate cancer. Although biomarkers and magnetic resonance imaging(MRI) has been used more often to help better select men for biopsy these tools are not accurate enough toreplace biopsy. We have developed a new way of analyzing the MRI images called diffusion histology imaging(DHI) that can accurately and non-invasively diagnose prostate cancer which has the potential to reduceifnot eliminateunnecessary prostate biopsies. NCI 10756449 12/6/23 0:00 PA-20-185 5R01CA258690-03 5 R01 CA 258690 3 "AVULA, LEELA RANI" 1/1/22 0:00 12/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 15210658 "KIM, ERIC HWAN" "IPPOLITO, JOSEPH EDWARD" 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 506137 NCI 325490 180647 PROJECT SUMMARYThere are clear limitations to the current approach to prostate cancer (PCa) diagnosis. Approximately half ofthe men who undergo a transrectal prostate biopsyan extremely uncomfortable invasive procedure withsignificant risk including sepsisare not found to have PCa. For those who have PCa many have indolentcancers that are best managed with active surveillance (AS) which requires annual repeat biopsies due to alack of accurate noninvasive tools. Biomarkers and prostate magnetic resonance imaging (MRI) have beenincreasingly used to attempt to address this problem. However the currently available tools are not accurateenough alone or in combination to forgo biopsy.We have developed a new MRI sequence (diffusion basis spectrum imaging) and a method of analyzing theseimaging metricsdiffusion histology imaging (DHI)that may overcome the limitations of conventional MRIinterpretation. Preliminary data demonstrates high accuracy of DHI to predict prostate biopsy results(presence of cancer and grade of cancer when present). We aim to apply DHI to patients in two distinct clinicalsettings: Aim 1 initial biopsy for PSA screening and Aim 2 repeat biopsy for known indolent PCa managedwith AS. We also plan for Aim 3 to update our DHI model based on the data obtained in these aims thenrecruit and test the updated DHI model in an independent group of patients undergoing PSA screening. Wehypothesize that DHI will allow for accurate and non-invasive diagnosis of PCa and thus reduce unnecessarybiopsies.In our proposed studies the men will have had biomarker testing then receive a clinical prostate MRI(conventional sequences) with the DBSI imaging protocol added onto it prior to biopsy. The DBSI imaging willbe analyzed post-acquisition by our DHI model. Note that the DBSI protocol will add just a few minutes to thetotal duration of the clinical MRI and will not significantly impact the patient or the clinical imaging workflow. Inparallel to conventional MRI interpretation and biopsy per clinical care our team will perform DHI analysis onthe MRI images. By comparing DHI to biomarkers and conventional MRI against the histopathologic goldstandard (biopsy) in a prospective manner we will determine if DHI can be used to noninvasively diagnose andmonitor PCa; therefore supporting the clinical translation of DHI to be used as an alternative to invasivebiopsies. 506137 +No NIH Category available Adoption;Algorithms;Area;Artificial Intelligence;Attention;Benign;Biopsy;Biopsy Specimen;Cells;Cellularity;Clinical;Code;Collaborations;Colorado;Computer software;Cytology;Data;Detection;Development;Diagnosis;Diagnostic;Evaluation;Evolution;Excision;Face;Fine needle aspiration biopsy;Funding;Future;Glass;Goals;Grant;Hospitals;Image;Incidence;Label;Literature;Location;Lung;Methods;Microscope;Microscopic;Microscopy;Modality;Modeling;Nightmare;Operative Surgical Procedures;Optics;Pathologist;Pathology;Patient Care;Patients;Phase;Physicians;Procedures;Reporting;Research;Resources;Risk;Sampling;Scanning;Schools;Site;Slide;Specimen;Stains;Stream;Surface;System;Technology;Telepathology;Thick;Thyroid Gland;Thyroid Nodule;Thyroidectomy;Time;Training;Unnecessary Surgery;algorithm training;artificial intelligence algorithm;blind;clinical application;commercialization;computer aided detection;digital;digital imaging;experience;imaging platform;innovation;interest;live stream;novel;point of care;point-of-care diagnostics;prototype;rapid detection;risk mitigation;robotic microscopy;standard of care;transfer learning;usability;validation studies Leveraging Label-Free Digital Imaging to Enable Rapid On-Site Evaluation (ROSE) During Thyroid Biopsy Procedures Project NarrativeThyroid nodules have a high incidence rate and assessment via fine-needle aspiration (FNA) biopsy is often anintegral step in the diagnostic pipeline. Unfortunately in up to 30% of the procedures insufficient cellularityresults in repeat biopsies or unnecessary surgical resections both of which may be avoided by employing RapidOn-Site Evaluation (ROSE) for specimen adequacy. Pathwares goal is to make ROSE available for allphysicians and their patients regardless of location by developing a novel point-of-care microscope for remoteAI-assisted biopsy analysis. NCI 10756316 7/3/23 0:00 PA-22-176 1R43CA285170-01 1 R43 CA 285170 1 "ZHAO, MING" 7/3/23 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 78592999 "HOLSING, TROY " Not Applicable 7 Unavailable 54749447 NC5PBWCNX956 54749447 NC5PBWCNX956 US 47.618262 -122.357741 10056539 PATHWARE INC. Golden CO Domestic For-Profits 80401 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 394 SBIR/STTR 2023 399994 NCI 325950 56463 Project Summary/AbstractPathware is developing Bioptic an imaging platform to analyze biopsy samples at the point-of-care. Thesystem will rapidly digitize unstained biopsy samples and utilize computer-aided detection/diagnostics to enablequick and efficient evaluations by pathologists. Typical barriers to point-of-care diagnostics are overcome bycombining novel computational microscopy with AI (Artificial Intelligence) algorithms to direct on-site or remotepathologists to regions of clinical interest. This proposed research's broad long-term objective is to enable real-time diagnostics of pathology samples at the point-of-care.Thyroid nodules have a high incidence rate and assessment via fine-needle aspiration (FNA) biopsy is often anintegral step in the diagnostic pipeline. The biopsy samples are frequently inadequate for diagnosis resulting inrepeat biopsies or unnecessary surgical resections. Rapid On-Site Evaluation (ROSE) for sample adequacy isideal for patient care because it mitigates the risk of inadequate samples by verifying diagnostic quality at thepoint-of-care. Despite the high incidence of inadequate biopsies ROSE is performed in less than 25% of thyroidbiopsy procedures due to financial and operational barriers including pathologist availability. The currentalternatives to ROSE (telepathology robotic microscopy and live-streaming microscopy) are plagued by barriersto adoption due to the requirement of staining samples technical challenges and regulatory limitations. AI-assisted ROSE has the potential to overcome these barriers and provide a superior standard-of-care.The immediate goals of the proposed project are to 1) demonstrate non-destructive imaging of unstained thyroidcytology smears with a novel microscopy modality and 2) train AI algorithms on the acquired images for futuredevelopment of computer-aided detection algorithms for ROSE adequacy assessments. 399994 +No NIH Category available Address;Bioinformatics;Biometry;Cancer Etiology;Cancer Patient;Carcinoma;Clinical;Clinical Oncology;Clinical Trials;Complex;DNA Sequence Alteration;Data;Data Analyses;Epidermal Growth Factor Receptor;Epithelial Cells;Epithelium;Genetically Engineered Mouse;Heterogeneity;Histone Deacetylase Inhibitor;Human;Hylobates Genus;Immune;Immune checkpoint inhibitor;Immune signaling;Immunologic Tests;Immunotherapy;K-ras mouse model;KRAS2 gene;Knowledge;Lung Adenocarcinoma;MAP Kinase Gene;MAPK Signaling Pathway Pathway;MEKs;Malignant neoplasm of lung;Mediating;Mesenchymal;MicroRNAs;Mutate;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenic;Operative Surgical Procedures;PD-1/PD-L1;Pathway interactions;Patients;Phenotype;Pre-Clinical Model;Productivity;Publishing;Ras/Raf;Regulation;Research Personnel;Resected;Resistance;Resistance development;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;Testing;Therapeutic;Translating;Tumor-infiltrating immune cells;United States;Up-Regulation;anti-PD-L1;cancer subtypes;co-clinical trial;drug development;efficacy evaluation;efficacy testing;epithelial to mesenchymal transition;human model;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;in vivo evaluation;inhibitor;kinase inhibitor;member;molecular pathology;mortality;mouse model;multidisciplinary;mutant;neoplastic cell;novel;pre-clinical;response;response biomarker;small molecule;targeted agent;treatment response;tumor;tumor heterogeneity;tumor-immune system interactions The Role of Epithelial-Mesenchymal Transition in Re-Wiring KRAS Mutant Lung Cancer PROJECT NARRATIVEKRAS mutant lung cancer is a leading cause of cancer mortality in the United States and a lung cancersubtype for which targeted agents such as MEK inhibitors have not made significant clinical progress. Basedupon the preliminary data from the investigators we propose: 1) to study the role and reversibility of epithelial-mesenchymal transition (EMT) in KRAS mutant lung cancer to confer resistance to MEK inhibitors ii) evaluatethe effects of MEK inhibitors on the tumor immune microenvironment and the therapeutic vulnerabilities thatarise due to immune checkpoint upregulation in pre-clinical models and iii) characterize the immune-relatedmarkers associated with EMT/MAPK activation and investigate the markers of sensitivity/resistance tocombination anti-PD-L1 and MEK inhibitor treatment in patient tumor samples. NCI 10756186 1/30/23 0:00 PA-16-160 4R37CA214609-06 4 R37 CA 214609 6 "HENDERSON, LORI A" 1/1/18 0:00 12/31/24 0:00 Clinical Oncology Study Section[CONC] 10185817 "GIBBONS, DON LYNN" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 395 Non-SBIR/STTR 2023 363165 NCI 224176 138989 PROJECT SUMMARY ABSTRACTSubstantial therapeutic advances have been made in NSCLC subsets harboring specific genomic alterationsand targetable with small molecule kinase inhibitors. Unfortunately a similar strategy has been unsuccessfulfor the ~30% of patients with mutated KRAS. Similarly immune checkpoint inhibitors of the PD-1/PD-L1 axisprovide durable response to ~20% of NSCLC patients but the majority of patients do not benefit from thissingle-agent approach. There is a knowledge gap about the regulation of MAPK pathway signaling in mutantKRAS tumors and the interplay between oncogenic signaling and the immunosuppressive microenvironmentwhich translates into a major unmet therapeutic need. The members of our multidisciplinary team (Gibbons Heymach Wistuba Draetta and Wang) have atrack record of productivity in studying KRAS mutant lung cancer and represent expertise in mouse modelingof human lung cancer clinical oncology immunotherapy molecular pathology of lung cancer drugdevelopment and bioinformatics. The Investigators have developed preliminary data from analysis of humanlung cancer specimens and preclinical Genetically Engineered Mouse Models (GEMMs) of KRAS mutantNSCLC that the epithelial-mesenchymal transition (EMT) status of tumor cells is critical to their therapeuticresponse to MEK inhibitors with the epithelial state producing profound sensitivity to MEK inhibitors and themesenchymal state producing resistance even in mutant KRAS tumors. Further we have published that themicroRNA-200-ZEB1 axis regulates EMT the immune microenvironment of tumors and subsequent responseto immune checkpoint inhibitors. Based upon preliminary data we hypothesize that: 1. Tumor cell EMT produces heterogeneity in KRASmutant tumors by suppressing MAPK pathway signaling 2. The altered tumor immune microenvironmentresulting from tumor cell EMT confers targetable vulnerabilities to new immune therapies 3. Combinationimmune checkpoint inhibitors and signaling pathway inhibitors will provide an effective complementarytargeting strategy for mutant KRAS NSCLC. We will address these hypotheses by: i) evaluating the role ofEMT in de novo and acquired resistance to MEK inhibitors in preclinical models of lung adenocarcinoma ii)determining the effects of MEK inhibitors on the tumor immune microenvironment and testing the efficacy oftheir combination with immune checkpoint inhibitors to enhance response in preclinical models of KRASmutant lung adenocarcinoma and iii) characterizing the relationship of EMT to MAPK pathway activation inhuman lung cancer samples and the markers of sensitivity/resistance to combination anti-PD-L1/MEK inhibitortreatment in clinical trial specimens. 363165 +No NIH Category available Address;Adoption;Attitude;Awareness;BRCA mutations;Behavioral Model;Cancer Patient;Cancer Survivor;Clinic;Cognition;Community Health;Consolidated Framework for Implementation Research;Counseling;Data;Disparity;Education;Elements;Eligibility Determination;Emotional;Emotions;Ethnic Origin;Evidence based intervention;Exhibits;Face;Future;General Population;Genetic Counseling;Genetic Enhancement;Genomics;Goals;Guidelines;Happiness;Health education;Health system;Healthcare;Healthcare Systems;Hereditary Breast and Ovarian Cancer Syndrome;Hour;Hybrids;Intervention;Knowledge;Language;Latina;Latina Population;Latinx population;Linguistics;Malignant Neoplasms;Minority Groups;Outcome;Participant;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research;Research Design;Risk;Risk Management;Schedule;Screening procedure;Self Efficacy;Services;Site;Speed;Survivors;Telephone;Testing;Training;Translation Process;Translations;Transportation;Visual Aid;Woman;acceptability and feasibility;arm;behavior prediction;cancer risk;community clinic;cost;design;disparity reduction;efficacy evaluation;efficacy study;efficacy testing;ethnic minority;evidence base;genetic counselor;genetic predictors;genetic testing;health literacy;hereditary risk;implementation outcomes;implementation research;improved;innovation;interest;literacy;minority patient;optimism;preference;primary outcome;process evaluation;psychosocial;racial minority;response;satisfaction;success;testing services;testing uptake;tool;underserved minority;uptake Testing a culturally targeted narrative video to reduce disparities in the use of genetic counseling and testing in Latina women at-risk of HBOC NarrativeParticipating in genetic counseling and testing (GCT) can inform treatment and risk management decisions forwomen at-risk of hereditary breast and ovarian cancer but Latina women underuse GCT services. This studywill test the efficacy of a culturally targeted narrative video in enhancing GCT uptake and psychosocial outcomesin at-risk Latina women through a RCT. We will conduct an Implementation Focused Process Evaluation togather implementation outcomes that will ultimately enhance the speed and quality of the translational process. NCI 10756145 12/29/23 0:00 PAR-18-559 5R01CA248543-04 5 R01 CA 248543 4 "SHELBURNE, NONNIEKAYE F" 1/1/21 0:00 12/31/25 0:00 Health Disparities and Equity Promotion Study Section[HDEP] 11086716 "HURTADO DE MENDOZA CASAUS, ALEJANDRA " Not Applicable 98 INTERNAL MEDICINE/MEDICINE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200570001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 504874 NCI 369432 135442 ABSTRACTNational guidelines recommend that women at increased risk for Hereditary Breast and Ovarian Cancer (HBOC)due to BRCA1/2 mutations be referred for genetic counseling and consider genetic testing. Awareness of apositive result can inform treatment decisions for cancer patients and risk management plans in both cancersurvivors and women unaffected with cancer. The slow translation of guidelines into practice particularly impactsminority populations who receive services in community health clinics. Latina women have lower awarenessand use of genetic counseling and testing (GCT) than non-Latina Whites. Latinas face multiple health carepragmatic and psychosocial barriers to GCT uptake. Latinas prefer culturally targeted interventions in Spanishwith plain language visual aids and a narrative format. We developed a culturally targeted narrative video inSpanish for at-risk Latinas. Piloted in a single-arm trial (N=40) Latinas reported high satisfaction and exhibiteda significant increase in knowledge from pre- to post-test. Nearly all participants (95%) reported an interest inGCT and 62% completed genetic counseling. We will use an innovative hybrid research design that combineselements of traditional efficacy studies as well as best practices from implementation research to enhance thequality and speed of the translational process. Guided by an expanded Integrated Behavioral Model we willconduct a RCT to evaluate the efficacy of our video vs. the FORCE fact sheet on enhancing GCT uptake andpsychosocial outcomes. To maximize the potential for implementation in community clinics we will train clinicstaff to administer the Referral Screening Tool (RST) a validated tool to identify women at-risk of HBOC. Guidedby the Consolidated Framework for Implementation Research we will conduct an Implementation FocusedProcess Evaluation to gather data on clinic implementation outcomes for use of the Referral Screening Tool andthe video. We will refer participants to free Spanish telephone genetic counseling. We will randomize 300 at-riskLatinas at four sites with large Latinx populations. Our primary outcome is genetic counseling uptake.Aim 1. Evaluate the impact of our video vs. fact sheet on GCT uptake. Participants in the video arm will havehigher genetic counseling uptake (H1.1.) and higher genetic testing uptake (H1.2.) at 4 months.Aim 2. Evaluate the impact of our video vs. fact sheet on psychosocial and process evaluation outcomes. H2.1:Video participants will have higher knowledge positive attitudes subjective norms self-efficacy and positiveanticipatory emotions. H2.2. Video participants will have higher acceptability and feasibility ratings.Exploratory aim: Evaluate mechanisms of the video's impact on genetic counseling uptake (knowledge attitudesnorms self-efficacy anticipatory emotions). If counseling uptake does not differ by arm then we will evaluatepredictors of uptake.Aim 3. Examine key implementation outcomes of feasibility acceptability adoption fidelity and futuresustainability of using the Referral Screening Tool and the video at the community clinics. 504874 +No NIH Category available Acute Myelocytic Leukemia;Aerobic;Affect;Biological Models;CRISPR interference;CRISPR/Cas technology;Cancer Etiology;Cell Line;Cell model;Cell physiology;Cells;Cellular Metabolic Process;Characteristics;Citric Acid Cycle;Clear Cell;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Correlative Study;DNA;DNA Modification Process;Data;Data Set;Disease;Elderly;Endocrine;Enzyme Inhibition;Enzymes;Epithelium;Eukaryotic Cell;Familiarity;Family;Family member;Fumarate Hydratase;Future;Gastrointestinal Stromal Tumors;Generations;Genes;Genetic;Glioblastoma;Glioma;Hereditary Paraganglioma;Histones;Human;Hydroxylation;In Vitro;Inherited;Investigation;Isocitrate Dehydrogenase;Knowledge;Lead;Lesion;Light;Localized Disease;Malate Dehydrogenase;Malignant Neoplasms;Malignant neoplasm of thyroid;Mediating;Metabolic;Missense Mutation;Mitochondrial Proteins;Mixed Function Oxygenases;Modeling;Molecular;Mutation;Neoplasms;Nuclear;Oncogenic;Operative Surgical Procedures;Oxygenases;Paraganglioma;Patients;Phenotype;Pheochromocytoma;Process;Production;Property;Protein Isoforms;Proteins;Quality of life;RNA;Reactive Oxygen Species;Renal Cell Carcinoma;Renal carcinoma;Reporting;Research Project Grants;Role;Somatic Mutation;Source;Structural Protein;Study models;Succinate Dehydrogenase;Succinates;Survival Rate;Syndrome;System;Thyroid Gland;Time;Tissues;Tumor Promotion;United States;United States National Institutes of Health;Validation;Variant;Work;aldehyde dehydrogenases;alpha ketoglutarate;cofactor;gene repression;high risk;histone demethylase;in silico;in vivo;in vivo Model;knock-down;leukemia;member;mouse model;mutant;neoplastic;small hairpin RNA;stem;stem cell biomarkers;stem cells;therapy development;transcription factor;tumor;tumorigenesis Identification of enzymes inhibited by oncometabolites in Succinate Dehydrogenase mutant tumors PROJECT NARRATIVEGenes encoding enzymes in the tricarboxylic acid cycle (TCA cycle also known as the Krebs cycle) are causativegenetic lesions in human cancers including both inherited tissue-specific tumor syndromes and a variety ofsporadic cancers. These tumors are associated with the accumulation of oncometabolites which interfere withan enzyme family of ~70 members that use alpha-keto-glutarate (aKG also known as 2-oxo-glutarate) as acofactor. In this application we will use a CRISPRi-based screen to identify and perform pilot validation of theaKG-dependent enzyme(s) whose inhibition by oncometabolites leads to the acquisition of the neoplasticphenotype. NCI 10756126 12/13/23 0:00 PAR-20-052 5R03CA277217-02 5 R03 CA 277217 2 "LUO, RUIBAI" 1/1/23 0:00 12/31/24 0:00 ZCA1-TCRB-V(O1)S 1928269 "KIRSCHNER, LAWRENCE S" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 78750 NCI 50000 28750 PROJECT SUMMARYThe tricarboxylic acid cycle (TCA cycle also known as the Krebs cycle) is a fundamental process in eukaryoticcells serving as the source for ATP generation and producing reducing equivalents for cell metabolism underaerobic conditions. In recent years it has become clear that genes encoding the enzymes in the TCA cycle canbe causative genetic lesions in human cancers including in inherited tumor syndromes associated with renalcancer paragangliomas/pheochromocytomas (PPGL) and Gastrointestinal Stromal Tumors (GISTs) amongothers including epithelial thyroid cancer. They are also well described in sporadic tumors from these sametissues as well as in a spectrum of other cancers including acute myeloid leukemia (AML) and glioblastoma.Mutations in Krebs cycle enzymes and their related cofactors are thought to cause tumor formation through theoncogenic effects of excess metabolite accumulation (oncometabolites). These intermediate metabolites act byinterference with the function of enzymes requiring the metabolic cofactor alpha-ketoglutarate (aKG also knownas 2- oxoglutarate). There are approximately 70 aKG-dependent enzymes in humans and they perform a varietyof essential cellular functions including mediating modification of DNA RNA and histone proteins. Enzymes ofthis class are also responsible for oxidative hydroxylation of proteins including the structural protein collagen.We have previously demonstrated using both in vitro and in vivo models for thyroid neoplasia that loss of theSuccinate Dehydrogenase D subunit (SDHD) causes phenotypic changes indicative of early stages of cancer.Further this genetic changes causes cells to gain a stem-like phenotype as evidenced by expression of thestem cell associated transcription factors Nanog and Oct4 and production of the stem cell marker AldehydeDehydrogenase (ALDH). Despite the fact that interference with aKG-dependent oxygenases has been proposedas a neoplastic mechanism no prior efforts have been made to identify family members which are responsiblefor the neoplastic change. To fill this knowledge gap we propose to use a high throughput CRISPR-basedtranscriptional repression screen to identify aKG-dependent enzymes whose inhibition leads to a recapitulationof the stem-like phenotype. Identified hits will be validated using a combination of cellular models and in silicoanalysis of tumor-based omics data. The Aims for this R03 pilot proposal are as follows:1) To use a CRISPRi screen to identify alpha-ketoglutarate (aKG) dependent enzyme(s) whose inhibitionleads to the acquisition of a stem-like phenotype2) To validate identified enzymes in cell line models and in human tumor datasetsIdentification of the enzymes whose functions are affected by accumulation of the oncometabolite succinate willshed important new light on the molecular mechanism of disease associated with Sdhx and other TCA cyclemutations and will provide a stepping stone for future research grants that will allow detailed delineation ofgenetic and/or protein targets that drive tumor formation in the thyroid and other tissues (e.g. glioma leukemia). 78750 +No NIH Category available Acceleration;Affect;Aging;Allogenic;Antibodies;Azacitidine;Biological;Biopsy;Cancer Model;Cancer Survivor;Categories;Cell surface;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Clonality;DNA Sequence Alteration;DNA sequencing;Data;Data Set;Decitabine;Dendritic Cells;Development;Diagnosis;Diagnostic;Disadvantaged;Disease Progression;Dose;Dysmyelopoietic Syndromes;Engraftment;Epigenetic Process;Erythroid;Frequencies;Future;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genomics;Genotype;Hematologic Neoplasms;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Histologic;Human;Incidence;Individual;Interleukin-15;Libraries;Link;Macrophage;Macrophage Colony-Stimulating Factor;Marrow;Measures;Modeling;Modification;Molecular;Mus;Mutation;Osteoclasts;Patients;Pharmacodynamics;Phenotype;Physiological;Population;Preclinical Testing;Production;Proto-Oncogene Protein c-kit;Publishing;Reproducibility;Research;Resistance;Risk;Sampling;Stem cell transplant;Technology;Therapeutic;Therapeutic Agents;Transitional Cell;Work;Xenograft Model;Xenograft procedure;aging population;cell type;comparative;conditioning;curative treatments;cytokine;epigenome;high risk;human data;humanized mouse;improved;irradiation;leukemia;monocyte;mouse model;multiple omics;mutant;new therapeutic target;novel therapeutics;pre-clinical;programs;repaired;response;single cell analysis;single cell technology;standard of care;stem;stem cells;targeted treatment;transcriptome;treatment response Modeling myelodysplasia NARRATIVEMyelodysplastic Syndromes (MDS) are blood cancers with increasing incidence with aging and in cancersurvivors and limited therapeutic options. The field lacks adequate MDS models to facilitate hypothesis- andpreclinical-testing. The proposed work utilizes a breakthrough humanized mouse recipient to build xenograftmodels and then validate both the engrafting material and its response to standard therapy. NCI 10756120 12/29/23 0:00 PAR-17-245 5R01CA253981-04 5 R01 CA 253981 4 "WATSON, JOANNA M" 1/1/21 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-N(55)R] 1868623 "GRIMES, H. LEIGHTON" "HALENE, STEPHANIE " 1 Unavailable 71284913 JZD1HLM2ZU83 71284913 JZD1HLM2ZU83 US 39.140663 -84.501007 615001 CINCINNATI CHILDRENS HOSP MED CTR CINCINNATI OH Independent Hospitals 452293039 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 525320 NCI 437174 88146 PROJECT SUMMARYMyelodysplastic Syndromes (MDS) are a cancer of the hematopoietic stem cell (HSC) on the rise in the agingpopulation and cancer survivors. The only curative treatment for MDS is allogeneic stem cell transplantationwith marked limitations in the majority of MDS patients. As a result standard-of-care focuses onhypomethylating agents (HMA) azacytidine (AZA) and decitabine (DAC) which invariably result in resistanceand disease progression. There is a dire need for new therapeutics; however there are no robust models ofMDS to accelerate preclinical testing. We have generated a breakthrough humanized xenograft-recipientmouse model which eliminates conditioning and facilitates engraftment of primary MDS. We will validate themodel by single-cell genetic and genomic characterization of diagnostic MDS patient material before therapyand of the same cells engrafted in humanized mice clearly dellineating the transcriptional impact ofxenografting. Next we will establish pharmacodynamic endpoints for AZA within the mouse model and applythe empirically-derived dose of AZA to the model. Human MDS material will be captured for single cellanalyses post-AZA therapy from both patients and xenografts. The multi-omics comparative analyses willincisively determine the utility of MISTRG-W41 for MDS preclinical testing by illustrating the extent to whichAZA-affected programs in patients are similarly changed in the xenograft. This deep molecular genotypic andphenotypic understanding of HMA effects on subclonal and hierarchical cellular compositions of MDS will buildthe basis for comparison of novel-targeted-therapeutic agents as alternatives concurrent or post-HMAtherapeutic approaches. 525320 +No NIH Category available Agonist;Antitumor Response;Back;Biological Assay;Breast Cancer Model;Bypass;CXCL10 gene;Cell Differentiation process;Cell Shape;Cells;Chromosomal Instability;Chronic;Clustered Regularly Interspaced Short Palindromic Repeats;Cyclic GMP;Cytoplasm;Cytosol;DNA;Data;Dependence;Development;Double-Stranded RNA;Embryonic Development;Epithelium;Gene Activation;Gene Silencing;Gene Targeting;Genetic Transcription;Genetically Engineered Mouse;Genomic Instability;Human;Immune;Immune response;Immune system;Immunotherapy;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interferon Type I;Interferons;Invaded;Knock-out;Link;Logic;Malignant Neoplasms;Malignant neoplasm of lung;Mammalian Cell;Maps;Mediating;Mediator;Medicine;Mus;Mutagenesis;Nature;Neoplasm Metastasis;Normal Cell;Nucleic Acids;Output;Pathway interactions;Phenotype;Predisposition;Process;Production;Reporter;Resistance;Role;STING1 gene;Signal Transduction;Source;Stimulator of Interferon Genes;Stimulus;System;Testing;Therapeutic;Thinking;Transplantation;Tumor Immunity;Tumor Promotion;Viral;Work;anti-tumor immune response;autoinflammatory;cancer cell;cancer cell differentiation;combinatorial;cytokine;ds-DNA;early phase clinical trial;experimental study;genetic manipulation;immune activation;immune checkpoint blockade;immune resistance;in vivo;innate immune pathways;interest;mouse model;neoplastic cell;novel;pancreatic cancer model;progenitor;programs;resistance mechanism;response;sensor;single cell sequencing;stem;stem cells;synergism;therapeutically effective;therapy development;tissue regeneration;transcription factor;tumor;tumor heterogeneity;type I interferon receptor;vector;wound healing Probing cytosolic nucleic acid sensing pathways in cancer NARRATIVEThe aberrant presence of double-stranded nucleic acids in the cytoplasm promotes a robust inflammatory re-sponse which has galvanized interest in developing therapies that can sensitize cancer cells to the immunesystem. However we found that cancer cells with chronic inflammation - fueled by genomic instability haveadapted resistance to a key innate immune pathway called cGAS-STING redirecting a normally lethal outputtowards alternative pathways that promote metastasis. Motivated by the discovery that these resistant cellscan still be sensitized to immune attack in a manner independent of cGAS-STING we aim to unravel the con-text-dependence of this versatile signaling cascade to test if restoring normal responses to inflammation canbe used as an effective therapeutic strategy to sensitize tumors to immune therapy. NCI 10756115 12/13/23 0:00 PA-19-056 5R01CA256188-04 5 R01 CA 256188 4 "WATSON, JOANNA M" 1/1/21 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 11441179 "LAUGHNEY, ASHLEY MARIE" "BAKHOUM, SAMUEL F" 12 PHYSIOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 647795 NCI 517699 130096 ABSTRACTThe ability of mammalian cells to elicit inflammation is central to many processes including embryogenesiswound healing tissue regeneration and cancer metastasis. A major source of inflammatory signaling is theaberrant presence of double-stranded (ds) nucleic acids in the cytoplasm. Mammalian cells have evolved high-ly conserved mechanisms to detect cytosolic nucleic acids as an anti-viral defense. In normal cells cGAS (cy-clic GMP-AMP synthase) and its downstream signaling effector STING (stimulator of interferon genes) havebeen proposed as essential mediators of type I interferon (IFN) signaling and downstream immune activation.We have shown however that in cancer cells with chromosomal instability (CIN) there is no evidence of type IIFN signaling despite the presence of cytosolic DNA and constitutive activation of cGAS and STING. Insteadcancer cells rewire their signaling downstream of STING to selectively suppress IFN signaling and enable oth-er pro-metastatic pathways such as NF-B. Three important pieces of evidence bring into question the essen-tiality of the cGAS-STING pathway in promoting anti-tumor immunity and suggest heretofore unappreciatedredundancies and context dependence of nucleic acid sensing in cancer: 1) chromosomally unstable cancercells retain IFN-responsiveness to cytosolic dsRNA. 2) Cancer cells with CIN can still elicit a robust anti-tumorimmune response to cytosolic dsDNA in a manner independent of cGAS-STING and type I IFN. 3) Expressionof nucleic acid sensors and downstream inflammatory pathways is highly variable across tumor subpopulationsand metastatic cell states in which a continuum of stem-like to more committed epithelial progenitors is ob-served. Together these findings challenge the current view that cGAS-STING signaling is the universal media-tor of inflammation in response to cytosolic dsDNA. Herein we aim to understand functional redundancies andinteractions across cytosolic nucleic acid sensing pathways and how their transcriptional outputs vary with tu-mor cell differentiation status. We will systematically interrogate key nucleic acid sensors and their downstreameffectors in three syngeneic mouse models characterized by increased metastatic potential and high levels ofCIN. We will experimentally manipulate CIN rates to identify cytosolic nucleic acid-dependent but cGAS-STING-independent mechanisms of immune activation (Aim 1). We will then couple high-throughput single-cellsequencing with combinatorial CRISPR-mediated gene inactivation of key cytosolic nucleic acid sensors andeffectors in metastasis-initiating stem cells distinguished by SOX2 expression versus their more differentiatedcounterparts to map the cell state-specific regulatory logic of this pathway (Aim 2). Unraveling the context-dependence of this extremely important and versatile signaling cascade has the potential to transform ourthinking about chronic inflammation in cancer and to reveal therapeutic vulnerabilities in chromosomally unsta-ble cancer cells that are otherwise resistant to cGAS-STING signaling. 647795 +No NIH Category available African American population;Ameloblastoma;Autophagocytosis;Autophagosome;BRAF gene;Bioenergetics;Biological;Biological Markers;Black Populations;Black race;CD34 gene;Caucasians;Cell Line;Cell Survival;Cells;Characteristics;Clinical;Colorectal Cancer;Complex;Cysteine-Rich Domain;Cytoprotection;DNA Sequence Alteration;Disparity;Drosophila pros protein;ENG gene;Epithelium;GTF2H1 gene;Growth;Head and Neck Neoplasms;Hypoxia;Hypoxia Inducible Factor;Incidence;Knowledge;MAP Kinase Gene;Mediating;Mesenchymal;Modeling;Mus;Mutation;Neoplasm Metastasis;Nutrient;Odontogenic Tumors;Oncogenes;Oncogenic;Operative Surgical Procedures;Oxidative Stress;PECAM1 gene;Pathway interactions;Patients;Pattern;Phagocytosis;Phenotype;Phosphotransferases;Prevalence;Prognostic Marker;Property;Protein-Serine-Threonine Kinases;Proteins;Proto-Oncogene Proteins B-raf;Race;Recurrence;Recycling;Residual state;Running;Sampling;Signal Pathway;Stress;Testing;Tissues;Treatment outcome;Tumor Promotion;Variant;angiogenesis;cancer stem cell;cohort;comparative;density;disparity reduction;in vivo;migration;mortality;neoplastic;neoplastic cell;prognostic indicator;prognostic value;racial disparity;racial diversity;racial health disparity;racial population;stem-like cell;survival outcome;therapy resistant;trafficking;tumor;tumor microenvironment Biological Indicators of Racial Disparity in Ameloblastoma Recurrence Project NarrativeAfrican-Americans have a five-fold incidence of ameloblastoma than Caucasians. One quarter of all post-surgicalameloblastoma recurrence occur in the Black racial group. Full understanding of mechanisms promotingameloblastoma recurrence are needed to mitigate disparities in ameloblastoma treatment outcomes. NCI 10756111 12/1/23 0:00 PAR-18-654 5R01CA259307-03 5 R01 CA 259307 3 "WOODHOUSE, ELIZABETH" 12/14/21 0:00 11/30/26 0:00 Special Emphasis Panel[ZRG1-OBT-Y(55)R] 7618421 "AKINTOYE, SUNDAY O" Not Applicable 3 DENTISTRY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF DENTISTRY/ORAL HYGN 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 334547 NCI 205875 128672 Project SummaryAmeloblastoma accounts for 14% of all odontogenic tumors and African-Americans are five times more likely todevelop ameloblastoma compared to Caucasians. Despite radical surgery 10% of ameloblastomas recur and25% of recurrent ameloblastomas occur in the black racial group. The biological determinants of ameloblastomaracial disparity are unclear and there are no specific biological markers to predict recurrence. Mostameloblastomas display genetic mutations of BRAF that encodes the serine/threonine protein kinase B-Raf anactivator of MAPK/ERK-signaling pathway. BRAF oncogenes induce the expression of key autophagic markersthat include LC3 p62 and BECLIN1. High expressions of p62 ATG7 and LC3 have been identified in all variantsof ameloblastoma and our in vivo mouse ameloblastoma tumor model displayed elevated LC3 and p62 levels.These suggest ameloblastoma recurrence can be attributed to autophagic cell survival mechanisms of residualinvasive neoplastic odontogenic epithelium. Interplay of autophagic regulator BECNLIN1 with RUBICON [Rundomain Beclin-1-interacting and cysteine-rich domain-containing protein] a component of LC3-associatedphagocytosis (LAP) dysregulates autophagosomal maturation and endocytic trafficking to promote tumormigration and invasiveness. Our hypothesis is that autophagy reactivates residual invasive odontogenicepithelium by LAP-mediated entosis and recycling of bioenergetic cellular components. Our collaborative grouphas a relatively large cohort of ameloblastoma tissues and have generated epithelial-derived (EP-AMCs) andmesenchymal-derived (MS-AMCs) ameloblastoma cell lines from BRAF V600E+ multicystic/follicularameloblastomas. To elucidate biological mechanisms contributing to racial disparity in Black versus White racialgroups we will determine prognostic biomarkers of ameloblastoma recurrence and assess how LC3-mediatedautophagic cargo processing orchestrate recurrence disparity. In Aim 1 we will determine whether autophagicproteins are pro-oncogenic adaptors associated with ameloblastoma racial disparity aggressive phenotype andpropensity for recurrence. In Aim 2 we will assess whether residual invasive ameloblastic epithelium survive usingLAP-mediated entosis and recycling of bioenergetic cellular components. While ameloblastoma is relatively rareunderstanding the interplay of two converging cytoprotective pathways in ameloblastoma growth pattern andrecurrence has the potential to lead to new prognostic biomarkers and precision-guided therapies to alleviateracial disparities in BRAF+ tumors like ameloblastoma. 334547 +No NIH Category available Address;Attention;Breast Cancer survivor;Cancer Survivor;Caring;Classification;Clinical;Cognitive Therapy;Data;Diagnosis;Distress;Enrollment;Equilibrium;Experimental Designs;Feedback;Future;General Population;Goals;Health;Human;Individual;Intervention;Interview;Longterm Follow-up;Malignant Neoplasms;Mental Health;Methods;Outcome;Participant;Patient Education;Pattern;Perception;Personal Satisfaction;Pilot Projects;Population;Precision Medicine Initiative;Psychosocial Assessment and Care;Public Health;Publishing;Randomized;Reporting;Research;Research Design;Sequential Multiple Assignment Randomized Trial;Step Tests;Structure;Survivors;Testing;Time;Training;Woman;adaptive intervention;anxiety symptoms;arm;cancer diagnosis;clinically significant;cost;depressive symptoms;design;digital health;digital intervention;efficacious intervention;efficacy evaluation;efficacy testing;experience;experimental study;follow-up;improved;improved outcome;innovation;mHealth;malignant breast neoplasm;member;mobile application;mood symptom;patient engagement;personalized approach;post intervention;prevent;psychological distress;psychosocial;reduce symptoms;skills;smartphone application;social stigma;survivorship;symptom treatment;therapy design Evaluating a mobile application to reduce distress in breast cancer survivors using an adaptive design Project NarrativePsychological distress presented through symptoms of depression and anxiety is very common among breastcancer survivors and it is critical that easily accessible helpful and engaging interventions are madeavailable. IntelliCare an app-delivered intervention has been shown to be highly effective in reducingsymptoms of depression and anxiety in the general population suggesting strong potential for public impactamong breast cancer survivors. This proposal will evaluate the efficacy of IntelliCare to reduce symptoms ofdepression and anxiety for breast cancer survivors as well as the added value of human coaching to increaseengagement resulting in an adaptive intervention design for breast cancer survivors that is low cost easilyaccessible and highly efficient. NCI 10756103 12/6/23 0:00 PAR-18-559 5R37CA248434-04 5 R37 CA 248434 4 "GRIMES, GENEVIEVE M" 12/1/20 0:00 11/30/24 0:00 Adult Psychopathology and Disorders of Aging Study Section[APDA] 10584614 "CHOW, PHILIP " Not Applicable 5 PSYCHIATRY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 441005 NCI 284455 156550 Project Summary/AbstractPsychological distress in breast cancer survivors is highly prevalent significant and costly. Studies show thatnearly half of all breast cancer survivors will experience clinically significant symptoms of depression and/oranxiety in the first five years after their cancer diagnosis. There is robust evidence that cognitive behavioraltherapy (CBT) is an efficacious intervention for distress in cancer survivors. Unfortunately access issignificantly limited by a lack of trained clinicians and expense. To overcome these barriers smartphoneapplications (`apps') have emerged as a feasible and effective method to provide low-cost delivery of healthinformation and treatment. To our knowledge there are no publicly available mental health apps that havebeen rigorously tested with cancer survivors. Members of our research team previously developed andvalidated a publicly available fully automated app-delivered mental health intervention IntelliCare which isbased on tenants of CBT. We recently conducted a pilot of the IntelliCare app suite in breast cancer survivorsand found that its use led to a significant reduction in symptoms of depression and anxiety with particularlyrobust effects among those with a moderate level of distress or greater upon study enrollment. The positiveresult from our single-arm pilot leads us to the next logical step of testing the efficacy of the IntelliCare appsagainst a robust control in a randomized study with long-term follow-up. The goals of this project are: (1) toevaluate the efficacy of the IntelliCare apps in reducing symptoms of depression and anxiety in breast cancersurvivors and (2) to test the impact of human coaching as a way to increase engagement with the intervention.Using an innovative experimental design called the Sequential Multiple Assignment Randomized Trial(SMART) 313 breast cancer survivors with elevated symptoms of depression and anxiety will be randomizedto initially receive the IntelliCare apps or app-delivered Patient Education. We will test the effects of theIntelliCare apps on symptoms of depression and anxiety at post intervention 6 and 12 month follow-up (Aim1). During the first week of app use we will identify participants that are low-engagers of the IntelliCare apps.These low-engagers will be re-randomized to receive coaching in addition to the apps vs. no change (i.e.continue using the apps naturally) to test the added value of coaching on engagement (Aim 2). Finally we willconduct semi-structured exit interviews with participants who receive the IntelliCare apps. Interviews willcapture survivors' perceptions about the extent to which and how tailoring the apps and coaching specificallyfor breast cancer survivors may improve intervention outcomes and engagement. (Aim 3). Adaptiveapproaches to promoting engagement such as added coaching for those who struggle to engage will balancethe competing needs for scalability and individualized attention to address rapidly expanding survivorship careneeds. 441005 +No NIH Category available AXIN1 gene;AXIN1 protein;Address;Adverse effects;Biological;CTNNB1 gene;Cells;Classification;Collaborations;Complement;Development;Disease;Disparate;Enterobacteria phage P1 Cre recombinase;Event;Exons;FDA approved;Gene Expression;Genes;Genetic Variation;Glucose;Glutamate-Ammonia Ligase;Glutamine;Hepatocarcinogenesis;Human;Immune checkpoint inhibitor;Impairment;In Vitro;Injections;Isotope Labeling;Lead;Ligands;Liver;LoxP-flanked allele;Malignant Neoplasms;Malignant neoplasm of liver;Metabolic;Metabolism;Minor;Modeling;Molecular;Mus;Mutation;Oncogenic;Pathogenesis;Pathway interactions;Placebos;Play;Porcupines;Pre-Clinical Model;Primary carcinoma of the liver cells;Productivity;Role;Sampling;Scaffolding Protein;Signal Pathway;Signal Transduction;Sleeping Beauty;Tail;Tankyrase;Testing;Therapeutic;Transposase;Universities;Unresectable;Veins;beta catenin;cancer therapy;gain of function;gain of function mutation;hepatocellular carcinoma cell line;inhibitor;liver cancer model;loss of function;loss of function mutation;molecular subtypes;molecular targeted therapies;mouse model;mutant;overexpression;precision medicine;receptor;response;tumor Investigating multifactorial beta-catenin activation in hepatocellular cancers Project NarrativeLiver cancer is a deadly form of malignancy with limited treatment options. This project seeks to understand howdifferent mutations in Wnt/-Catenin pathway contribute to liver cancer development. The results will elucidatethe distinct signaling pathways induced by -catenin activation due to distinct mechanisms; and will pave a wayfor precision medicine for liver cancer treatment. NCI 10756066 12/25/23 0:00 PA-19-056 5R01CA250227-05 5 R01 CA 250227 5 "XU, WANPING" 3/1/22 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-DKUS-J(05)] 6960544 "CHEN, XIN " "MONGA, SATDARSHAN SINGH" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 441198 NCI 346236 94962 AbstractHepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options and lacks molecular-targeted therapies. Activation of Wnt/-catenin cascade has been shown to play a major role during HCCpathogenesis. Mutations in CTNNB1 the gene encoding for -catenin interfere with its degradation leading toits gain-of function (GOF) and activation and are implicated in 20-35% of all HCCs. A mutually exclusive groupof additional around 8% of HCCs is the one with the loss-of-function (LOF) mutations in AXIN1 which encodesfor a scaffolding protein AXIN1 essential for -catenin degradation. Our previous studies also showed that -catenin activation alone is insufficient for HCC development. Based on the concomitant presence of CTNNB1mutations and c-MET activation in ~11% of human HCC and the presence of LOF mutations in AXIN1 and c-MET activation together in ~4% of human HCC we established two murine HCC models c-Met/-catenin andc-Met/sgAxin1 using sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HDTVI).These models recapitulate the respective human HCC subsets based on gene expression studies. Intriguinglyusing these mouse models and human HCC samples we discovered that AXIN1 LOF mutant HCC does notshow activation of canonical liver-specific -catenin target genes such as glutamine synthetase (Gs) and Tbx3which was evident in CTNNB1-mutant HCCs. In contrast Hippo cascade is inactivated in LOF mutations inAXIN1 mutant but not in CTNNB1-mutant HCCs. Based on the above observations our overarching hypothesisis that despite -catenin being the common downstream effector mutations in CTNNB1 and AXIN1 lead todistinct molecular subtypes of HCC and tumor development in these two classes requires participation of distinctsignaling pathways. We propose the following three specific aims to address our highly relevant hypothesis. InAim 1 we plan to define whether ligand dependent activation of Wnt/-catenin is required for c-Met/sgAxin1induced HCC formation in mice. In Aim 2 we will investigate Gs dependent and independent metabolic andsignaling cascades in mouse HCC development. And in Aim 3 we will characterize the functional contribution ofHippo cascade in Ctnnb1 GOF and Axin1 LOF mutant HCCs. Altogether our studies will elucidate the distinctsignaling pathways induced by -catenin activation due to two distinct mechanisms and how we may effectivelytarget these tumors based on genetic variations. The proposal represents an ongoing & productive collaborationbetween Dr. Xin Chen from UCSF and Dr. Paul Monga from University of Pittsburgh. The results may pave away for precision medicine in HCC. 441198 +No NIH Category available 3-Dimensional;Antineoplastic Agents;Apoptotic;Applications Grants;Biochemical;Biological;Carcinomatosis;Cells;Cellularity;Cessation of life;Characteristics;Chimeric Proteins;Classification;Combined Modality Therapy;Consensus;Disease;Drug Kinetics;Engraftment;FDA approved;Fc Immunoglobulins;Fc domain;Goblet Cells;Granulocyte-Macrophage Colony-Stimulating Factor;Greater sac of peritoneum;Growth;Half-Life;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Hepatotoxicity;Human;Hyperthermia;Immune system;Immunity;Induction of Apoptosis;Interleukins;Intestinal Obstruction;Intravenous Bolus;Ligands;Malignant Neoplasms;Medical center;Microscopic;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Mucinous;Mucins;Mus;Non obese;Normal Cell;Nutritional;Operative Surgical Procedures;Organoids;Outcome Study;Patients;Peritoneal;Persons;Plasma;Positioning Attribute;Postoperative Period;Procedures;Prognosis;Proteins;Pseudomyxoma Peritonei;Recurrence;Recurrent disease;Regimen;Reporting;Resected;Residual Neoplasm;Residual state;Risk;Serum;Severe Combined Immunodeficiency;Signal Pathway;Stem Cell Factor;Study models;System;TNF gene;Techniques;Testing;Therapeutic;Therapeutic Agents;Transgenic Organisms;Treatment Efficacy;Tumor Debulking;Tumor Tissue;Universities;Xenograft procedure;advanced disease;anti-cancer;artesunate;biological adaptation to stress;cancer cell;chemotherapy;clinical efficacy;combinatorial;cytotoxicity;diabetic;endoplasmic reticulum stress;gastrointestinal system;improved;in vitro activity;in vivo;intraperitoneal;intraperitoneal therapy;mortality;mouse model;multimodality;novel;novel strategies;partial response;patient derived xenograft model;preclinical efficacy;pressure;prevent;rare cancer;receptor;reconstitution;response;sensor;tumor;tumor xenograft Application of in vivo humanized PDX mouse model and ex vivo organoid model to assess the therapeutic efficacy of combinatorial therapy for pseudomyxoma peritonei NARRATIVEPseudomyxoma peritonei (PMP) is a rare malignancy reported in one to two people per 1000000 annually.The accumulation of intraperitoneal mucin in PMP often exerts pressure on the digestive system andculminates in nutritional compromise which in advanced disease may also lead to intestinal obstructioncausing significant morbidity and mortality. In this grant application we propose developing a combinatorialtherapy comprising the ferroptosis-inducing agent artesunate and chimeric TRAIL to be used in addition toconventional hyperthermic intraperitoneal chemotherapy to treat PMP patients after cytoreductive surgery. Webelieve that the combinatorial treatment may effectively prevent recurrence of this disease. NCI 10756057 3/30/23 0:00 PA-21-268 7R21CA259243-02 7 R21 CA 259243 2 "CHEN, WEIWEI" 12/20/21 0:00 11/30/24 0:00 ZCA1-TCRB-V(O1)S 1881799 "LEE, YONG J" Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 3/30/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2023 191278 NCI 114538 76740 ABSTRACT Pseudomyxoma peritonei (PMP) of appendiceal origin is an insidious lethal malignancy that respondspoorly to systemic chemotherapy and frequently recurs despite aggressive morbid locoregional surgicaltherapy. Although encouraging treatment results have been reported with the combination of cytoreductivesurgery and hyperthermic intraperitoneal chemotherapy (HIPEC) PMP recurrence is common. In this grantapplication we hypothesize that a multimodal approach (a combination of the biochemical agent Fc-TRAIL(immunoglobulin Fc domain fused tumor necrosis factor-related apoptosis-inducing ligand) and the ferroptoticagent artesunate) will effectively prevent recurrence of PMP by promoting apoptotic death. The specific aims ofthis project are to: (1) examine the preclinical efficacy of the combinatorial treatment using Fc-TRAIL andartesunate (ART) in mouse intraperitoneal patient-derived xenograft (PDX) models of PMP; and (2) investigatethe mechanism of synergistic induction of cytotoxicity by the combinatorial treatment of Fc-TRAIL and ART inorganoids of PMP. The proposed studies in the first aim will employ humanized PDX mouse models to assessthe effect of the multimodal treatment on the growth and regression of PDX tumors from PMP patients inhumanized triple transgenic NSGTM-SGM3 mice (nonobese diabetic/severe combined immunodeficiencygamma mice expressing human interleukin-3 granulocyte-macrophage colony-stimulating factor and stem cellfactor). NSGTM-SGM3 mice engrafted with human hematopoietic stem cells (HSC) are cutting-edge models forstudying the clinical efficacy of combinatorial treatment on PMP tumor in an in vivo setting without placingpatients at risk. In the second aim we will employ biochemical and molecular techniques to investigate themechanism of apoptotic death. Since NSG-SGM3 mice are a proven host for engraftment of human tumorsas well as the establishment of human immunity following HSC transplantation we expect that humanizedPDX mouse models will retain most of the characteristics of the original tumors and reconstituted humanimmune system. Thus the successful outcome of this study will support the application of the humanized PDXmouse model to assess a novel combinatorial therapy for patients with PMP. 191278 +No NIH Category available Adverse effects;Affect;Animal Model;Attention;Biological Process;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer therapy;Cancer Patient;Cells;Cessation of life;Chemotherapy and/or radiation;Code;Combined Modality Therapy;Cytoplasm;Development;Diagnosis;Disease;Drug Sensitization;Drug resistance;Effectiveness;Epidermal Growth Factor Receptor;Epigenetic Process;Estrogen Receptors;Evaluation;Extracellular Matrix;Formulation;Gene Expression Regulation;Gene Silencing;Genetic Transcription;Goals;Growth;Hormones;In Vitro;Injections;Invaded;Lead;Life;Lipids;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic breast cancer;Multi-Drug Resistance;Neoplasm Metastasis;Normal tissue morphology;Nucleotides;Oncogenes;Oncogenic;Outcome;Patients;Phenotype;Play;Process;Progesterone Receptors;Prognosis;Proliferating;RNA;RNA Interference;Radiation therapy;Refractory;Regimen;Relapse;Resistance development;Role;Signal Pathway;Small Interfering RNA;Survival Rate;Therapeutic;Tissues;Transcript;Untranslated RNA;Up-Regulation;WNT Signaling Pathway;Woman;Xenograft Model;aggressive breast cancer;beta catenin;cancer cell;cancer drug resistance;cancer subtypes;cancer survival;chemotherapy;clinical development;colorectal cancer progression;design;effective therapy;efficacy evaluation;environmental change;improved;in vivo;ineffective therapies;malignant breast neoplasm;migration;mortality;mouse model;nanoparticle;new therapeutic target;novel;novel therapeutics;overexpression;preclinical development;self assembly;siRNA delivery;side effect;standard of care;stemness;targeted treatment;therapeutic nanoparticles;therapeutic siRNA;therapeutic target;triple-negative invasive breast carcinoma;tumor;tumorigenesis Smart nanoparticles regulating oncogenic IncRNA for breast cancer therapy This project is aimed at developing safe and effective smart multifunctionalnanoparticles to regulate long noncoding RNAs (lncRNAs) associated with cancermetastasis and drug-resistance in triple negative breast cancer patients. Tumor-specific silencing of cancer-promoting lncRNAs with the nanoparticles offers a noveltherapy to treat metastatic breast cancer with minimal side-effects to enhance theefficacy of chemotherapy and to eventually eradicate the disease and improve thesurvival of cancer patients. A lead smart nanoparticle formulation will be identified atthe end of the project for preclinical and clinical development. NCI 10755865 1/10/23 0:00 PA-18-484 3R01CA235152-05S1 3 R01 CA 235152 5 S1 "FU, YALI" 12/12/18 0:00 11/30/23 0:00 Nanotechnology Study Section[NANO] 6899678 "LU, ZHENG-RONG " Not Applicable 11 BIOMEDICAL ENGINEERING 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH BIOMED ENGR/COL ENGR/ENGR STA 441061712 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 395 Non-SBIR/STTR 2023 75403 NCI 54180 21223 The goal of this project is to develop smart dual-targeted lipid ECO/siRNA self-assemblynanoparticles to target oncogenic long non-coding RNAs (lncRNAs) as a novel therapy totreat metastatic and drug-resistant triple negative breast cancer (TNBC). Metastasis and drugresistance are the main causes for high mortality rate of women diagnosed with TNBCworldwide. Although targeted therapies have been developed to treat some subtypes ofbreast cancer the TN subtype is particularly refractory to these therapies. OncogeniclncRNAs play a critical role in tumorigenesis stemness invasion metastasis and drugresistance of cancer by simultaneously manipulating multiple cancer-associated signalingpathways. Hence lncRNAs are promising novel therapeutic targets for TNBC. We willdevelop smart dual-targeted lipid ECO/siRNA nanoparticles to regulate the expression of anidentified lncRNA associated with cancer EMT stemness metastasis and drug resistance asa novel therapy for TNBC. This oncogenic lncRNA is highly expressed in TNBC tumors butnot in normal tissues making this smart nanoparticle therapy a highly feasible and promisingapproach to effectively treating TNBC without any adverse effects in healthy tissues. We havedemonstrated the feasibility of silencing the oncogenic lncRNA for suppressing the survivaland aggressiveness of TNBC cells and for completely inhibiting tumor proliferation in a TNBCmouse model. In this project we will optimize and develop the smart ECO/siRNAnanoparticles to improve tumor-specific cytosolic delivery of therapeutic siRNAs and toeffectively silence the cancer-promoting lncRNA in treating TNBC. We will also explore thecombination therapy of silencing lncRNA with the smart nanoparticles and chemotherapy tohave the synergistic effects of inhibiting metastasis alleviating multidrug resistance andenhancing chemotherapy to achieve curative outcomes and to eventually eradicate TNBC.The specific aims of this project are 1) to design and optimize smart dual-targetedECO/siRNA nanoparticles for efficient and specific gene silencing in cancer cells via systemicadministration; 2) to determine the effects of silencing oncogenic lncRNA with the smart dual-targeted ECO/siRNA nanoparticles on the invasiveness and drug-resistance of TNBC cells invitro; 3) to determine the efficacy of the smart dual-targeted ECO/siRNA nanoparticles aloneand in combination with chemotherapy for TNBC therapy in animal models. Our long-termgoal is to develop a novel and feasible therapy based on the smart nanoparticles to treat life-threatening metastatic and drug-resistant breast cancer. 75403 +No NIH Category available 3D Print;Address;Adoption;Algorithms;Anatomy;Appearance;Beauty;Behavior;Biological Models;Clinic;Clinical;Complex;Data;Databases;Dependence;Derivation procedure;Development;Diagnostic;Dictionary;Digital Libraries;Dimensions;Dose;Ensure;Evaluation;Image;Image Analysis;Imaging Techniques;Lead;Lesion;Libraries;Lung;Lung CAT Scan;Lung nodule;Machine Learning;Measures;Medical Imaging;Methods;Modeling;Nodule;Noise;Non-linear Models;Outcome;Output;Patients;Performance;Play;Predictive Analytics;Property;Protocols documentation;Radiation Dose Unit;Research;Role;Sampling;Scanning;Scheme;Shapes;Signal Transduction;Source;Statistical Models;System;Techniques;Technology;Texture;Training;Transcend;Work;X-Ray Computed Tomography;clinical application;clinical translation;clinically relevant;data-driven model;deep learning;deep learning algorithm;deep neural network;design;flexibility;imaging system;improved;insight;interest;low dose computed tomography;lung cancer screening;lung lesion;machine learning method;neural network;novel;predicting response;public database;quantitative imaging;radiomics;reconstruction;response;screening;shape analysis;simulation;success;targeted imaging Nonlinear performance analysis and prediction for robust low dose lung CT PROJECT NARRATIVEMajor research efforts have been devoted to the development of nonlinear reconstruction algorithms frommodel-based reconstruction to deep learning these algorithms have demonstrated many advantages such asimproved image quality reduced radiation dose and additional diagnostic information that are not achievablewith traditional linear reconstructions. However only a disproportionately small number has reach the clinicdue to the lack of a predictive image quality analysis framework to quantify diagnostic performance controlalgorithm behavior and ensure consistent performance for robust clinical deployment. The propose effort usea combination of analytic and machine learning approaches to drive much-needed quantitative assessmentstandards that directly relate image quality to diagnostic performance and establish optimal strategies forrobust reliable clinical deployment of nonlinear algorithms. NCI 10755743 12/29/23 0:00 PA-19-056 5R01CA249538-05 5 R01 CA 249538 5 "TANDON, PUSHPA" 1/1/22 0:00 12/31/24 0:00 Imaging Technology Development Study Section[ITD] 14318598 "GANG, JIANAN GRACE" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 459797 NCI 384369 75428 1PROJECT SUMMARY / ABSTRACT 2 Nonlinear algorithms such as model-based reconstruction (MBR) and deep learning (DL) reconstruction have 3 sparked tremendous research interest in recent years. Compared to traditional linear approaches the nonline- 4 arity of these algorithm transcends traditional signal-to-noise requirement and offer flexibility to draw information 5 from a variety of sources (e.g. statistical model prior image dictionary training data). MBR has enabled numer- 6 ous advancements including low-dose CT and advanced scanning protocols. Deep learning algorithms are rap- 7 idly emerging and have demonstrated superior dose vs. image quality tradeoffs in research settings. However 8 widespread clinical adoption of nonlinear algorithms has been impeded by the lack of a lack of systematic quan- 9 titative methods for performance analysis. Nonlinear methods come with numerous dependencies on the imag-10 ing techniques the imaging target and the prior information and the data itself. The relationship between these11 dependencies and image quality is often opaque. Furthermore improper selection of algorithmic parameters can12 lead to erroneous features (e.g. smaller lesions texture) in the reconstruction. Therefore methods to quantify13 and predict performance permit efficient and quantifiable performance evaluation to provide the robust control14 and understanding of imaging output necessary for reliable clinical application and regulatory oversight.15 We propose to establish a robust predictive framework for performance assessment and optimization that can16 be generalized to any reconstruction method. We quantify performance in turns of the perturbation response and17 covariance as a function of imaging techniques system configurations patient anatomy and importantly the18 perturbation itself. The perturbation response quantifies the appearance (e.g. biases blurs distortions) and19 together with the covariance allows the computation of more complex metrics such as task-based performance20 and radiomic measures including size shape and texture information. We illustrate utility of the approach in lung21 imaging with the following specific aims: Aim 1: Develop a lesion library and generate perturbations encom-22 passing clinically relevant features. We will extract lesions from public databases and develop methods lesion23 emulation in for realistic CT simulation and physical data via 3D printing technology. Aim 2: Develop a gener-24 alized prediction framework for perturbation response and covariance. Using analytical and neural network25 modeling we will establish a framework that predicts perturbation response and covariance across imaging26 scenarios for classes of algorithms with increasing data-dependence including MBR with a Huber penalty MBR27 with dictionary regularization and a deep learning reconstructor. Aim 3: Develop assessment and optimiza-28 tion strategies to drive robust low dose lung screening CT methods. We will optimize and adapt nonlinear29 algorithms and protocols for lung cancer screening to achieve faithful representations of clinical features. This30 work has the potential to drive much-needed quantitative assessment standards that directly relate image quality31 to diagnostic performance and optimal strategies for robust reliable clinical deployment of nonlinear algorithms.32 459797 +No NIH Category available Acetylation;Address;Angiogenesis Inhibitors;Antigens;Automobile Driving;Cell physiology;Cells;Chromatin;Chronic;Clinical Trials;Complex;Consumption;Cytotoxic T-Lymphocytes;Data;Environment;Epigenetic Process;Functional disorder;Gene Expression;Genes;Genetic Transcription;Goals;Histones;Hypoxia;Immune;Immunologic Memory;Immunology;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Vitro;Infiltration;Knowledge;Ligands;Link;Machine Learning;Malignant Neoplasms;Mediating;Metabolic;Metabolic stress;Metabolism;Metformin;Methylation;Minority;Mitochondria;Modeling;Modification;Monoclonal Antibodies;Mus;Non-Insulin-Dependent Diabetes Mellitus;Oxidative Stress;Oxygen;PD-1 blockade;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Proliferating;Reactive Oxygen Species;Regimen;Research Personnel;Resistance;Role;Signal Transduction;Site;Solid Neoplasm;Starvation;System;T cell differentiation;T cell infiltration;T-Lymphocyte;Tumor Immunity;angiogenesis;anti-PD-1;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cancer therapy;cell type;cofactor;demethylation;epigenome;exhaust;exhaustion;experience;functional outcomes;histone methylation;histone modification;immune cell infiltrate;immune checkpoint blockade;in vivo;inhibitor;melanoma;mouse model;neoplastic cell;novel;patient subsets;programmed cell death protein 1;receptor;resistance mechanism;response;stem;stressor;success;synergism;transcription factor;transcriptional reprogramming;tumor;tumor hypoxia;tumor metabolism;tumor microenvironment Dissecting the role of hypoxia in T cell differentiation in cancer PROJECT NARRATIVEWhile immunotherapy for cancer can have remarkable effects at prolonging patients' lives it only is successfulin a minority of patients. This is because patients need functional immune cells within their tumors to respondto these immune boosting therapies. We and others have shown that the capacity of tumor cells to consumemetabolites can starve infiltrating immune cells although the mechanisms are unclear. We will use preclinicalmodels to understand how cancer immunity is regulated by metabolism as well as analyze immune cells frompatients treated with immunotherapy in combination with metabolism altering drugs. NCI 10755738 12/11/23 0:00 PA-20-185 5R01CA277473-02 5 R01 CA 277473 2 "LIU, YIN" 1/1/23 0:00 12/31/27 0:00 "Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]" 10043437 "DELGOFFE, GREG M." "NAJJAR, YANA ; POHOLEK, AMANDA CATHERINE" 12 MICROBIOLOGY/IMMUN/VIROLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 553015 NCI 372725 180290 PROJECT SUMMARY/ABSTRACTImmunotherapeutic treatments for cancer especially the use of monoclonal antibody mediated blockade of`checkpoint' molecules like PD-1 has changed the treatment paradigm for patients with solid tumors likemelanoma. However only a subset of patients benefit from these therapies due to several resistancemechanisms concentrated within the tumor microenvironment (TME) the site of action of cytotoxic T cells. Tcells must contend with physical barriers to infiltration immunosuppressive cell types the expression of co-inhibitory ligands on target cells and a harsh metabolic environment produced by cancer cells. In addition to Tcell-extrinsic immunosuppression T cells within tumors have a distinct differentiation trajectory resulting inacquisition of an alternative dysfunctional fate termed exhaustion. Exhausted T cells are terminallydifferentiated hypofunctional upon stimulation and possess poor capacity to proliferate a crucial componentof immune memory. We and others have shown that exhausted T cells have severe metabolic deficienciesand that metabolic stress within the TME most notably hypoxia exposure potentiates differentiation towardsexhaustion. In line with this we and others have shown that melanoma patients with more oxidative hypoxictumors are more likely to progress on anti-PD1. Thus the hypoxic TME and the intrinsic functional deficiencyof exhausted T cells are linked. However how hypoxia and resultant oxidative stress alter T cell differentiationremain unclear. Our hypothesis is that hypoxia exposure promotes T cell exhaustion by driving aberrantchromatin bivalency and loss of transcription such that hypoxia mitigation treatments will alter T celldifferentiation and support increased T cell function. AIM 1: How does hypoxia drive epigenetic changes thatbias T cell differentiation and function? Hypoxia drives several cellular adaptations including transcriptionalreprogramming via HIF-1 induction of reactive oxygen species (ROS) and metabolic shifts. We will A) use invitro systems to identify mechanisms of hypoxia contributing to altered histone methylation and bivalency inmurine T cells; and B) determine contributions of hypoxia to the T cell epigenome and explore potentialmitigation strategies in murine tumor models. AIM 2: How do hypoxia reducing regimens alter intratumoral Tcell differentiation in melanoma patients? We and other have shown that targeting tumor cell metabolism orangiogenesis can increase the oxygen tension within tumors in both mouse models and melanoma patients. Inthis Aim we will take advantage of two investigator-initiated clinical trials in melanoma utilizing metformin oraxitinib in combination with anti-PD-1 and deeply explore transcriptional epigenetic metabolic and functionaloutcomes associated with reduction of hypoxia coincident with anti-PD-1. We expect these studies to addressknowledge gaps in the fields of epigenetics immunology and cancer immunotherapy uncovering how tumorhypoxia can bias T cell differentiation and response to anti-PD-1 with the goal of identifying novel targets thatmitigate hypoxia driven T cell exhaustion and overcome barriers to immunotherapy for cancer. 553015 +No NIH Category available 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol;4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;Alleles;Asian;Biological Markers;Black race;Blood specimen;Cancer Burden;Cancer Etiology;Carcinogens;Cells;Cessation of life;Chemopreventive Agent;Chinese;Cohort Studies;Communities;Complex;Copy Number Polymorphism;Cytochrome P450;Cytosol;Data;Development;Drug Metabolic Detoxication;Enzymes;Exhibits;Genes;Genetic Markers;Genetic Polymorphism;Genetic Variation;Genotype;Glucuronides;Glucuronosyltransferase;Goals;Health;Human;Isomerism;Liver;Lung;Malignant neoplasm of lung;Mediating;Metabolic;Metabolism;Microsomes;Nicotine;Nitrosamines;Oxidoreductase;Pathway interactions;Pattern;Phenotype;Play;Population;Predisposition;Prevention strategy;Prospective cohort;Prospective cohort study;Protein Isoforms;Risk;Role;SNP genotyping;Singapore;Smoker;Smoking;Tissues;Tobacco;Tobacco smoke;Tobacco-Associated Carcinogen;Urine;Validation;Variant;Women's Health;cancer risk;carcinogenesis;carcinogenicity;cigarette smoking;cohort;cost effective;enantiomer;genetic variant;genome wide association study;genome-wide;high risk;improved;insight;lung cancer prevention;lung cancer screening;lung carcinogenesis;lung development;mortality;novel;novel strategies;phenotypic biomarker;precision cancer prevention;prospective;protective pathway;recruit;sample collection;screening;smoking cessation;targeted sequencing;urinary Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention Project NarrativeThe major mode of metabolism of NNK a major contributor to the induction of lung cancer in smokers is viathe formation of its pro-carcinogenic metabolite NNAL. Two enantiomers of NNAL are formed -- (R)-NNAL and(S)-NNAL with (R)-NNAL the major isoform formed in the lung and both enantiomers detoxified byglucuronidation. We provide novel preliminary data demonstrating a strong and statistically significant inverseassociation between the ratio of urinary (R)-NNAL-glucuronide (Gluc)/(S)-NNAL-Gluc and lung cancer risk insmokers from two independent large cohort studies and this novel stable biomarker of lung cancer riskreflects the potential importance of (R)-NNAL in the carcinogenicity of NNK and strongly supports the goals ofthis proposal which is to evaluate the importance of different NNAL enantiomers and glucuronides in lungcancer carcinogenesis and to elucidate novel urinary biomarkers of lung cancer risk focusing on the NNALformation and elimination pathways. NCI 10755737 11/7/23 0:00 PA-20-185 5R01CA269223-02 5 R01 CA 269223 2 "SIMONDS, NAOKO ISHIBE" 12/16/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 1901170 "LAZARUS, PHILIP " "YUAN, JIAN-MIN " 5 PHARMACOLOGY 41485301 XRJSGX384TD6 41485301 XRJSGX384TD6 US 46.728892 -117.155742 9082001 WASHINGTON STATE UNIVERSITY PULLMAN WA SCHOOLS OF PHARMACY 991641060 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 573416 NCI 462803 110613 The tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is considereda major contributor to the induction of lung cancer in smokers. The metabolism of NNK is complex with itscarcinogenic effects likely via the formation of its major pro-carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Two enantiomers of NNAL are formed: (R)- and (S)-NNAL both of which areextensively detoxified by glucuronidation in humans. Our novel preliminary data demonstrate a strong andstatistically significant inverse association between the ratio of urinary (R)-NNAL-glucuronide (Gluc)/(S)-NNAL-Gluc and lung cancer risk in two independent prospective cohort studies. Furthermore smokers homozygousfor the deletion polymorphism of the major NNAL-glucuronidating enzyme UGT2B17 had a significant 3-foldhigher risk for lung cancer than those with at least one functional UGT2B17 allele in both cohorts. These datastrongly support our hypothesis that (R)-NNAL plays a key role in tobacco-induced lung carcinogenesis andsuggests that we have identified novel important phenotypic and genetic markers of lung cancer risk. The goalof this proposal is to evaluate the importance of NNAL enantiomers and glucuronides in lung cancercarcinogenesis and to elucidate novel phenotypic and genetic markers of NNAL formation and eliminationpathways and lung cancer risk in multiple populations. Our goals are to prospectively evaluate whether thelevels or ratios of specific urinary NNAL isomers or glucuronides are associated with lung cancer risk in: (1)Chinese smokers from three cohort studies from Shanghai and Singapore and (2) White and Black smokersfrom the Southern Community Cohort Study and to subsequently screen and validate genetic variantsassociated with the variability in NNAL enantiomer and glucuronide formation. These studies should providecrucial insight for understanding variability and establishing phenotypes and genotypes important in lungcancer risk and will assist in identifying smokers at high risk for lung cancer for the development ofchemopreventive strategies targeting the NNK metabolism pathway. 573416 +No NIH Category available Affinity;Antineoplastic Agents;Binding;Binding Proteins;Biochemical;Biological Assay;Biophysics;Cell Extracts;Complex;Cryoelectron Microscopy;Data;Defect;Development;Discrimination;Drug Targeting;Drug resistance;Eukaryota;Eukaryotic Initiation Factor-1;Eukaryotic Initiation Factors;Event;Exhibits;FDA approved;Fluorescence Microscopy;Future;Gene Expression;Hand;Human;In Vitro;Individual;Initiator Codon;Initiator tRNA;Label;Laboratories;Length;Letters;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Messenger RNA;Modeling;Molecular;Neoplasm Metastasis;Oncogenic;Pathogenesis;Physiological;Positioning Attribute;Preparation;Principal Investigator;Process;Proteins;Reagent;Recombinants;Regulation;Resolution;Ribosomal Proteins;Ribosomes;Role;Saccharomyces cerevisiae;Series;Signal Transduction;Site;Specificity;Structure;System;Text;Therapeutic;Time;Translating;Translation Initiation;Translations;Tumor-Derived;Yeasts;anti-cancer therapeutic;cancer therapy;data exchange;eukaryotic initiation factor-5B;fluorophore;mutant;overexpression;polyadenosine;public health relevance;reconstitution;recruit;single molecule;single-molecule FRET;time use;tumor growth;tumorigenesis The mechanism and regulation of mRNA recruitment during eukaryotic translation initiation PUBLIC HEALTH RELEVANCE STATEMENT (PROJECT NARRATIVE)The efficiency with which messenger RNAs (mRNAs) are recruited to the ribosome for translation intro proteinsis a carefully controlled aspect of gene expression in eukaryotes whose dysregulation has been causally linkedto tumorigenesis tumor growth drug resistance and metastasis in many human cancers. Using a powerfulcombination of reagents and experimental approaches that are unique to the principal investigators andcollaborators laboratories this project will elucidate the molecular mechanisms that drive and control mRNArecruitment during eukaryotic translation initiation. The results of these studies will deepen our understanding ofthe mechanisms that control gene expression and the molecular pathogenesis of various cancers as well asidentify targets for the development of anticancer therapeutics. NCI 10755732 11/20/23 0:00 PA-20-185 5R01CA277727-02 5 R01 CA 277727 2 "MAAS, STEFAN" 12/19/22 0:00 11/30/27 0:00 Molecular Genetics Study Section[MG] 1971251 "GONZALEZ, RUBEN L" Not Applicable 13 CHEMISTRY 49179401 F4N1QNPB95M4 49179401 F4N1QNPB95M4 US 40.81207 -73.954377 1833202 COLUMBIA UNIV NEW YORK MORNINGSIDE NEW YORK NY GRADUATE SCHOOLS 100276900 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 327507 NCI 202930 124577 PROJECT SUMMARYThe efficiency with which messenger RNAs (mRNAs) are translated into proteins by the ribosome is afundamental determinant of gene expression. This efficiency is often determined during the mRNA recruitmentstep of translation by the ribosome. Consequently this step is a crucial point of control for gene expression. Ineukaryotes mRNA recruitment is an elaborate multi-step and highly regulated process that depends upon theactivities of ~13 eukaryotic initiation factors (eIFs). Dysregulation of eIF activity and mRNA recruitment has beencausally linked to tumorigenesis tumor growth drug resistance and metastasis in an increasing list of humancancers. Consequently several eIFs and their roles in mRNA recruitment are emerging as very attractiveanticancer drug targets with an existing FDA-approved eIF-targeting compound already having beensuccessfully repurposed as an anticancer therapy. In order to expand and fully exploit this therapeutic potentialhowever it is necessary to understand the molecular events that underlie eIF function and mRNA recruitment. Here we will use a highly purified fluorophore-labeled Saccharomyces cerevisiae in vitro translationsystem that we developed and that includes a full-length site-specifically labeled eIF4G and a fully reconstitutedsite-specifically labeled eIF3 reagents that have been difficult to generate. With these reagents in hand we willuse state-of-the-art single-molecule fluorescence microscopy and cryogenic electron microscopy (cryo-EM)including a pioneering time-resolved cryo-EM approach developed by our collaborator Dr. Joachim Frank todirectly observe and characterize the dynamics of mRNA recruitment during eukaryotic translation initiation. In Aim 1 we will investigate the mechanism through which the multi-component eIF4F complex activatesdifferent classes of mRNAs for loading onto ribosomal 43S pre-initiation complexes (PICs) and how changes tothe composition of the eIF4F complex can alter which classes of mRNAs are activated. We hypothesize that thestructural dynamics of the activated mRNA complex are critical for mRNA loading and will quantify how thesedynamics contribute to mRNA selection. In Aim 2 we will investigate how the multi-component eIF3 complexinteracts with different classes of mRNAs and/or the 43S PIC in order to facilitate mRNA activation and/or loadingonto a 43S PIC as well as how biologically active subcomplexes of eIF3 can modulate these activities. A large-scale structural rearrangement of 43S PIC-bound eIF3 is thought to control its mRNA loading activity and we willtherefore characterize how this rearrangement facilitates formation of the 48S PIC on mRNAs of differentclasses. In Aim 3 we will investigate the mechanism through which eIF1A and eIF5B mediate mRNA start-codonrecognition within a 48S PIC. Start-codon recognition by eIF1A has recently been associated with a large-scalerearrangement of the 48S PIC in which eIF5B and initiator transfer RNA (Met-tRNAi) are repositioned inpreparation for joining of the large subunit to the 48S PIC to form the elongation-competent 80S IC. We willcharacterize these 48S PIC dynamics and determine their role in start-codon recognition and subunit joining. 327507 +No NIH Category available Affinity;Allosteric Regulation;Avidity;Binding;Binding Sites;Biological;Complex;DNA Binding;DNA Binding Domain;DNA Damage;Development;Disease;Drug Targeting;Generations;Genetic Transcription;Gymnastics;Homologous Gene;Human;In Vitro;Knowledge;Length;MDM2 gene;Malignant Neoplasms;Maps;Measurement;Mediating;Modeling;Molecular;Molecular Biology;Molecular Conformation;NMR Spectroscopy;Nuclear Translocation;Pathway interactions;Phosphorylation;Phosphorylation Inhibition;Phosphorylation Site;Play;Proteins;Regulation;Relaxation;Role;Signal Transduction;Spectrometry;Stress;Structure;Surface;TP53 gene;Testing;Therapeutic;Work;biophysical techniques;cancer therapy;experimental study;flexibility;in vivo;inhibitor;insight;intermolecular interaction;novel;novel strategies;overexpression;resistance mechanism;response;small molecule;tumor Allosteric Regulation of MDMX by Protein Disorder MDMX is a key regulator of p53 DNA binding and transcriptional activity. Elucidating thestructure and regulation of MDMX is essential for development of novel cancertherapeutics. Our recent work revealed that phosphorylation sites in intrinsicallydisordered regions of MDMX play important roles in regulating MDMX interaction withp53 and other cellular proteins and are important for efficient activation of p53 duringDNA damage response. This proposal will further investigate how MDMXphosphorylation sites in disordered regions regulate its structure and function usingmolecular biology and NMR spectrometry. These experiments will advance theunderstanding of how stress signals activate p53 by regulating MDMX-p53 interactionand may reveal novel strategy for targeting MDMX. NCI 10755705 12/19/23 0:00 PA-20-185 5R01CA141244-13 5 R01 CA 141244 13 "AMIN, ANOWARUL" 9/1/09 0:00 12/31/26 0:00 Tumor Cell Biology Study Section[TCB] 1972427 "CHEN, JIANDONG " "DAUGHDRILL, GARY W" 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 304497 NCI 222750 81747 MDMX and MDM2 are homologues that regulate the p53 tumor suppressor using differentmechanisms. While MDM2 is responsible for controlling p53 degradation MDMX regulates p53 DNAbinding and transcriptional activities. MDMX overexpression occurs in a subset of human tumors leadingto inactivation of p53. Efficient p53 response to stress and DNA damage involves phosphorylation ofMDMX followed by release of p53. Successful targeting of the p53 pathway for cancer therapy requiresunderstanding how MDMX regulates p53 function. MDMX contains an ordered p53 binding domain andRING domain and two long disordered regions that regulate p53 and CK1 binding in a phosphorylation-dependent manner. Our work identified intra- and intermolecular interactions essential for MDMXfunctions: (1) MDMX/p53 interaction inhibits p53 DNA binding. (2) MDMX/MDM2 interaction promotesMDMX degradation. (3) MDMX/14-3-3 interaction promotes MDMX nuclear translocation. (4)MDMX/CK1 interaction promotes MDMX/p53 binding and inhibition of p53. (5) MDMX intramolecularinteraction regulates p53 binding. Importantly these interactions are regulated by two phosphorylationsites (S289 S367) located in intrinsically disordered regions (IDR) of MDMX. We hypothesize that thecoordinated control is mediated by intramolecular interactions between ordered and disordered regions ofMDMX. The IDRs regulate the switching of intra/inter-molecular contacts in a phosphorylation-dependentmanner. We propose integrated molecular biology and biophysics approach to elucidate the mechanismof MDMX regulation: (1) Determine how the length and flexibility of MDMX IDR1 regulates auto-inhibition of p53 binding. (2) Investigate how CK1 phosphorylation switches MDMX to an openconformation that inhibits p53 DNA binding. (3) Determine how Chk2 phosphorylation of IDR2S367 regulates multiple MDMX interactions. These experiments will significantly advance theunderstanding of how stress signals activate p53 by targeting disordered regions of MDMX which isessential to develop MDMX inhibitors for cancer therapy. 304497 +No NIH Category available 3-Dimensional;Abdomen;Accounting;Adopted;Affect;Algorithms;Arizona;Benign;Breathing;Cessation of life;Chelating Agents;Clinic;Clinical;Clinical Trials;Colorectal;Colorectal Cancer;Country;Data;Detection;Diagnosis;Diagnostic;Discrimination;Disease;Drops;Early Diagnosis;Engineering;Excision;Gadolinium;Goals;Image;Image Analysis;Image Enhancement;Imaging Techniques;Incidence;Industry;Knowledge;Lesion;Life;Liver;Liver neoplasms;Location;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Maps;Medical;Metastatic Neoplasm to the Liver;Methods;Motion;Neoplasm Metastasis;Operative Surgical Procedures;Outcome;Patient Selection;Patients;Phase;Physiological;Population;Precision therapeutics;Radial;Reproducibility;Research;Resectable;Resolution;Scanning;Scheme;Scientist;Sensitivity and Specificity;Techniques;Technology;Test Result;Translations;Treatment outcome;Universities;Unresectable;Variant;Work;accurate diagnosis;alternative treatment;cancer imaging;clinical practice;clinical translation;colon cancer patients;contrast enhanced;contrast imaging;cost;data acquisition;deep neural network;design;diagnostic accuracy;diagnostic value;efficacy evaluation;flexibility;image processing;image reconstruction;imaging facilities;imaging modality;improved;industry partner;liver imaging;new technology;next generation;novel;personalized care;reconstruction;research clinical testing;soft tissue;spatiotemporal;tumor;tumor specificity Advancing MRI technology for early diagnosis of liver metastases Project NarrativeLiver metastases are common in colorectal cancer and knowledge of number location and sizeimpacts precision of therapy survival and overall costs. Magnetic Resonance Imaging (MRI) iscommonly used for evaluating liver metastases but detection and diagnosis of small tumorsremains challenging. Our proposal is based on a collaborative integrated team of universityscientists clinician-scientists and industry engineers to develop and clinically trial new MRItechnology that overcomes limitations related to imaging small liver tumors in patients. NCI 10755679 11/22/23 0:00 PAR-18-009 5R01CA245920-05 5 R01 CA 245920 5 "AVULA, LEELA RANI" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 1955101 "ALTBACH, MARIA I." "MARTIN, DIEGO R" 7 RADIATION-DIAGNOSTIC/ONCOLOGY 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 354576 NCI 266736 87840 AbstractLiver is commonly involved in metastatic disease in colorectal cancer (CRC) and knowledge aboutthe presence and location of these tumors affects treatment decisions. In patients with CRCsurgical or ablative treatment of liver metastases improves overall survival. Early diagnosis ofcolorectal metastases (i.e. while lesions are small) is expected to improve treatment outcomes byincreasing the number of subjects that can undergo surgical resection or by identifying subjectsearly on when non-surgical options are an alternative treatment. Magnetic Resonance Imaging(MRI) is regarded as the most effective imaging modality for the detection and characterization ofliver neoplasms; T2-weighted (T2w) and T1-weighted (T1w) images - combined withadministration of a gadolinium chelate agent and multi-phase dynamic contrast enhancement(DCE) - are the foundational acquisitions used for the detection and characterization of livertumors. However challenges remain for the detection and characterization of small lesions dueto factors including inadequate spatial resolution partial volume effects physiological motion andvariations in timing of contrast arrival in DCE imaging. In this academic-industrial partnership thescientific and engineering teams at the University of Arizona and Siemens Medical Solutions arecoming together to develop robust radial MRI techniques for T2w/T2 mapping and DCE imagingof the liver to improve detection and characterization of small tumors with the goal of bringingthese techniques to routine clinical practice. The proposed work is based on a radial turbo spin-echo technique pioneered by the team at the University of Arizona for abdominal imaging and aradial stack-of-stars technique with continuous acquisition for DCE imaging. The specific aims ofthe partnership are: Aim 1: To develop radial T2w acquisition and reconstruction techniques withefficient full coverage of the liver for small tumor detection and accurate T2 quantification for tumorcharacterization. Aim 2: To implement a self-navigated 3D radial stack-of-stars technique forcontinuous acquisition of DCE data and retrospective reconstruction of the dynamic phases. Aim3: To conduct a clinical evaluation of the techniques from Aims 1 and 2 against conventional T2wand DCE techniques. Aim 4: To streamline translation of the new radial methods to the clinic bydeveloping a computationally efficient reconstruction pipeline. The endpoints of our study includetechnical advances in MRI acquisitions that markedly overcome limitations of current liver MRI forthe diagnosis of early metastases. We expect our proposal to yield technology improvementsthat will increase precision of care and outcomes in patients with metastatic malignancies inparticular those with colorectal cancer. 354576 +No NIH Category available Animal Model;Attenuated;Bacteria;Cancer Patient;Cell Wall;Cells;Chemicals;Disease;Disseminated Malignant Neoplasm;Endopeptidases;Engineered Probiotics;Engineering;Enterococcus;Enterococcus durans;Enterococcus faecium;Enzymes;Growth;Health;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune signaling;Immunity;Immunotherapy;Individual;Laboratories;Large-Scale Sequencing;Link;Livestock;Malignant Neoplasms;Malignant neoplasm of lung;Metastatic Melanoma;Molecular;Pathway interactions;Patients;Pattern recognition receptor;Peptidoglycan;Pharmaceutical Preparations;Population;Probiotics;Renal carcinoma;Resistance;Role;Signal Pathway;Therapeutic;Therapeutic Agents;Translating;Translations;Work;analog;anti-CTLA4;anti-PD-1/PD-L1;anti-PD-L1 therapy;anti-PD1 therapy;cancer immunotherapy;cancer therapy;checkpoint therapy;clinical efficacy;commensal bacteria;enteric infection;enteric pathogen;gut inflammation;host microbiota;human model;immunoregulation;improved;in vivo;intestinal barrier;lactic acid bacteria;melanoma;microbiota;mouse model;novel;novel therapeutic intervention;novel therapeutics;patient response;pet animal;protective factors;response;small molecule;therapy outcome Translation of commensal bacteria mechanism for immunotherapy PROJECT NARRATIVEThe microbiota of cancer patients is correlated with their response to immunotherapy drugs but the mechanismsof specific commensal bacteria strains have not been elucidated and limit their translation into new therapeutics.The Hang laboratory recently discovered that beneficial Enterococci strains have unique peptidoglycancomposition and remodeling enzymes. These exciting findings reveal fundamental microbiota mechanisms incancer immunotherapy and afford new opportunities to engineer probiotic bacteria and synthesizeimmunomodulatory metabolite analogs to improve cancer immunotherapy. NCI 10755660 11/30/23 0:00 PA-18-876 5R01CA245292-06 5 R01 CA 245292 6 "XI, DAN" 12/2/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 9076601 "HANG, HOWARD C" Not Applicable 50 Unavailable 781613492 PHZJFZ32NKH4 781613492 PHZJFZ32NKH4 US 32.903062 -117.243592 7375802 "SCRIPPS RESEARCH INSTITUTE, THE" LA JOLLA CA Other Domestic Non-Profits 920371000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 499794 NCI 281574 218220 PROJECT SUMMARYMicrobiota are associated with remarkable effects on host health and disease. Notably discrete species ofcommensal bacteria have been correlated with improved patient responses to cancer immunotherapy. Howeverthe molecular mechanisms underlying the functions of these beneficial bacteria remain poorly understood. Inparticular specific strains of Enterococci have been linked with improved response to anti-PD-1/PD-L1 treatmentin patients with metastatic melanoma lung and kidney cancers but their mechanism of action has not beenelucidated nor employed to improve cancer immunotherapy. Recent work from the Hang laboratory hasdemonstrated that these beneficial strains of Enterococci have unique peptidoglycan composition andremodeling enzymes. Based on these studies this project hypothesizes that specific strains of Enterococci mayprime innate immune signaling pathways and enhance anti-PD-1/PD-L1 immunotherapy against metastaticcancers. To evaluate the activity and mechanism(s) of Enterococci during immunotherapy as well as co-opt theirprotective factors for cancer immunotherapy this proposal will examine how specific Enterococci strains altercancer growth immune cell populations and microbiota composition in mouse models of cancer immunotherapy.In addition the Hang laboratory will identify Enterococci protective factors and engineer them into existing humanprobiotics to translate our basic microbiota-cancer immunotherapy findings into novel therapeutic agents. Finallythe Hang laboratory will also synthesize novel immunomodulatory small molecules that activate host pathwaysused by Enterococci to enhance cancer immunotherapy. These studies will reveal fundamental microbiota-cancer immunotherapy mechanisms and develop new therapeutic strategies and agents to enhance cancerimmunotherapy. 499794 +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Acute T Cell Leukemia;Cells;Center for Translational Science Activities;Child;Childhood;Childhood Leukemia;Clinical;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Country;Data;Data Analyses;Defect;Disease;Funding;Future;Genome;Genomics;Immunotherapy;Investments;Label;Laboratories;Liquid Chromatography;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Mass Spectrum Analysis;Molecular;National Cancer Institute;Pacific Northwest;Pathway interactions;Pediatric Research;Phenotype;Phosphorylation;Post-Translational Protein Processing;Proteins;Proteome;Proteomics;Relapse;Resistance;Resources;Sampling;Signal Pathway;Standardization;Toxic effect;United States National Institutes of Health;anticancer research;cancer type;driver mutation;genome analysis;high risk;insight;instrumentation;leukemia;malignant breast neoplasm;multiple omics;novel;novel therapeutics;open source;precision oncology;programs;proteogenomics;tandem mass spectrometry;targeted treatment;tumor Center for Advanced Multi-Omic Characterization of Cancer PROJECT NARRATIVECancer is a disease that often originates in genomic abnormalities; however these genome-level defects exertits functional significance at the level of proteins. Coordinating with the National Institute of Health CommonFund Kids First program the Clinical Proteomic Tumor Analysis Consortiums Proteome CharacterizationCenter at the Pacific Northwest National Laboratory will comprehensively characterize the protein- andphosphorylation-level changes in cancer and healthy states by combing proteome- and genome-levelinformation. This will help identify dysregulated signaling pathways for novel therapies for high-risk pediatricleukemias who do not respond well to current treatment options and have high rates of relapse. NCI 10755578 6/9/23 0:00 PA-20-272 3U24CA271012-02S1 3 U24 CA 271012 2 S1 "HILTKE, TARA" 6/1/22 0:00 5/31/27 0:00 ZCA1(J1) 10219185 "LIU, TAO " Not Applicable 4 Unavailable 32987476 CWKJEXDG79A7 32987476 CWKJEXDG79A7 US 46.280405 -119.290503 685903 BATTELLE PACIFIC NORTHWEST LABORATORIES RICHLAND WA Research Institutes 993520999 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 310 Other Research-Related 2023 516800 OD 309311 207489 PROJECT SUMMARYThe National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium (CPTAC) is a national effort toaccelerate the understanding of the molecular basis of cancer through the application of large-scale proteomeand genome analysis or proteogenomics. Launched in 2011 CPTAC pioneered the integrated proteogenomicanalysis of colorectal breast and ovarian cancer to reveal new insights into these cancer types such asidentification of proteomic-centric subtypes prioritization of driver mutations by correlative analysis of copynumber alterations and protein abundance and understanding cancer-relevant pathways through post-translational modifications.In this project CPTAC will collaborate with the NIH Common Fund Gabriella Miller Kids First PediatricResearch Program (Kids First) to comprehensively characterize pediatric leukemia samples (such as T-cellacute lymphoblastic leukemia T-ALL and acute myeloid leukemia AML) using mass spectrometry-basedproteomics. This project will fully integrate proteogenomic information of such leukemia samples to capture andreplicate specific cancer phenotype better understand the interconnection of cancer pathways identify novelprotein targets for targeted therapies and immunotherapies and to stimulate future pediatric cancer researchand precision oncology.The PNNL PCC will perform comprehensive integrated global proteome and phosphoproteome analyses of atotal of 272 pediatric leukemia samples provided by the Kids First collaborators in various forms (such as cellpellets and surfaceome samples) using state-of-the-art liquid chromatography-tandem mass spectrometryinstrumentation highly multiplexed isobaric mass-tag labeling (TMT 18-plex) and integrated sampleworkflows. The resulting molecular data will become a community resource available at CAVATICA. 516800 +No NIH Category available Acceleration;Address;Adoptive Cell Transfers;Adverse event;Antigens;Biological;CD28 gene;CRISPR interference;CRISPR-mediated transcriptional activation;CRISPR/Cas technology;CTLA4 gene;Cancer Model;Cell Therapy;Cell physiology;Cells;Cellular immunotherapy;Chromatin;Chronic;Clustered Regularly Interspaced Short Palindromic Repeats;Cues;DNA Sequence;Development;Engineering;Environment;Evaluation;Face;Functional disorder;Genes;Genetic;Genetic Complementation Test;Genetic Engineering;Genetic Screening;Genetic Transcription;Genetic study;Genome;Goals;Human;In Vitro;Interferon Type II;Interleukin-2;Knock-out;Learning;Libraries;Locales;Malignant Neoplasms;Methods;Pre-Clinical Model;Preclinical Testing;Production;Regulation;Regulator Genes;Repression;Resistance;Safety;Science;Site;Synthetic Genes;T cell therapy;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Transgenic Organisms;Translating;Treatment Efficacy;Tumor Antigens;VAV1 gene;Xenograft Model;Xenograft procedure;antigen-specific T cells;cancer immunotherapy;cancer therapy;candidate validation;chimeric antigen receptor T cells;cytokine;design;engineered T cells;fitness;functional genomics;gain of function;gene discovery;gene network;genetic element;genome wide screen;genome-wide;high throughput technology;improved;in vivo;insight;knock-down;loss of function;member;mouse model;next generation;novel;overexpression;pre-clinical;programs;promoter;rational design;receptor;response;single-cell RNA sequencing;small hairpin RNA;synthetic biology;synthetic construct;therapeutic gene;tool;transcription factor;tumor;tumor microenvironment Decoding and reprogramming T cells through synthetic biology for cancer immunotherapy NARRATIVEThe next generation of genetically engineered T cell therapies for cancers will depend on synthetic programsthat enhance their potency and persistence. We recently performed high-throughput studies to discover genesthat enhance T cell stimulation-dependent responses and enhance their functional persistence. Here we willuse a systematic approach to evaluate how these genes and synthetic DNA constructs that integrate theminto novel circuits that respond to stimulation by cancer targets alter the ability of engineered T cells to treatcancer in multiple preclinical models. NCI 10755371 12/6/23 0:00 PA-20-185 5R01CA276368-02 5 R01 CA 276368 2 "LIU, YIN" 1/1/23 0:00 12/31/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 8358199 "MARSON, ALEXANDER " "ROYBAL, KOLE T" 11 Unavailable 99992430 KH6NJ6ND8737 99992430 KH6NJ6ND8737 US 37.767618 -122.394315 1567601 J. DAVID GLADSTONE INSTITUTES SAN FRANCISCO CA Research Institutes 941582261 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 674325 NCI 442000 232325 ABSTRACTEngineered T cell-based cancer therapies are a major advancement in cancer treatment; however the majorityof cancers still do not respond to adoptive cellular therapy. We need to design new T cell therapies withincreased potency and we need to overcome cell dysfunction that occurs as T cells face chronic tumor antigenstimulation. We and others have screened for genes that can be knocked out in antigen-specific T cells toenhance their functions but enormous opportunities still remain to knock-in new synthetic DNA sequences attargeted genome sites. This proposal is focused on detailed evaluation of genes and inducible gene programsthat will enable next-generation cellular therapies for cancer. We have developed several complementarytechnologies to discover synthetic gene programs that can be inserted into T cell genomes to enhancetherapeutic functions. We developed a CRISPR technology for high throughput pooled knock-ins toaccelerate discovery of synthetic knock-in programs (Roth et al. Cell 2020) and have now have conductedtwo screens with ~100-member libraries that include transcription factors and synthetic chimericreceptors (switch receptors) to discover programs that make chronically stimulated T cells resistant todysfunction. In addition we have optimized a complementary robust platform for genome-wide CRISPRactivation (CRISPRa) gain-of-function forward genetic screens in human T cells and have already completedsystematic discovery of factors that regulate stimulation-dependent cytokine production (Schmidt andSteinhart et al. Science 2022). We propose to translate insights from these high-throughput discoveryefforts into preclinical testing of novel knock-in designs with screen hits in vivo using xenotransplanted mousemodels. In this proposal we will test validated candidates from gain-of-function CRISPR PoKI (Aim 1) andCRISPRa (Aim 2) screens to discover new components of knock-in constructs that improve cell-based T celltherapies. We also recognize that these genetic components may be more beneficial if they are not expressedconstitutively. In Aim 3 we draw on the power of synthetic biology to engineer synthetic circuits that caninduce or repress genetic programs in response to antigen stimulation. This precise and dynamicregulation of genetic elements has great potential to further enhance efficacy and safety of next-generationimmune cell therapies. Taken together we present a proposal that leverages recent discoveries fromCRISPR discovery platforms and deep expertise in synthetic biology to engineer powerful knock-in circuitsthat we will validate and study in preclinical cancer models. We leverage functional genomics CRISPRengineering and synthetic cell program design expertise to address insufficient T cell potency and T celldysfunction which remain significant barriers to adoptive cell therapy for cancer. 674325 +No NIH Category available Abnormal Cell;Adaptor Signaling Protein;Address;Adoption;Affect;Agammaglobulinaemia tyrosine kinase;Age;Amino Acid Substitution;Artificial Intelligence;Artificial Intelligence platform;Attenuated;B-Cell Activation;B-Cell NonHodgkins Lymphoma;B-Lymphocytes;Binding Sites;Biochemical Reaction;Biological Assay;Blood typing procedure;Body part;Cancer Biology;Cell Survival;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Collaborations;Cultured Cells;Data;Drug Kinetics;Extranodal;Genes;Growth;Hematopoietic Neoplasms;Hodgkin Disease;Immune response;Immune system;Immunity;In Vitro;In complete remission;Indolent;Industrialization;Inflammation;Innate Immune Response;Investigational Drugs;Knowledge;Leucine;Link;Lymphocyte;Lymphoma;Lymphoma cell;Lysine;Malignant Neoplasms;Mediating;Medicine;Missense Mutation;Mutate;Mutation;Myelogenous;Natural Immunity;Non-Hodgkin's Lymphoma;Nuclear;Oncogenes;Oncogenic;Oncoproteins;Outcome;Pathogenesis;Patients;Phosphotransferases;Physiological;Polyubiquitin;Positioning Attribute;Proline;Proteins;Publishing;Reed-Sternberg Cells;Ring Finger Domain;Signal Transduction;Site;Solid;Structure;Technology;Testing;Therapeutic Agents;Toll-like receptors;Toxic effect;Transgenic Organisms;Ubiquitination;United States;Waldenstrom Macroglobulinemia;Work;Xenograft procedure;adaptive immune response;adaptive immunity;cancer therapy;causal variant;college;deep learning;drug candidate;drug development;drug discovery;in vivo;inhibitor;large cell Diffuse non-Hodgkin's lymphoma;mouse model;multicatalytic endopeptidase complex;neural network;novel therapeutics;precision medicine;protein degradation;response;screening;small molecule;success;therapeutic development;therapeutic target;tumorigenesis;virtual Therapeutic Targeting a Non-Hodgkin Lymphoma Driver Using AI PROJECT NARRATIVEThis project engages the expertise of its academic and industrial partners to develop therapeutic agents forundruggable oncoproteins. Artificial intelligence (AI) will advance small molecule discovery for cancer driversinto investigational new drug-enabling studies and clinical trials. The success of this project will catalyze theadoption of AI in drug discovery to target a wide range of high-priority oncoproteins in the era of precisionmedicine. NCI 10755367 11/13/23 0:00 PAR-21-166 5R01CA271546-02 5 R01 CA 271546 2 "AGYIN, JOSEPH KOFI" 12/16/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-SBIB-S(57)R] 8146758 "LI, YONG " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 590477 NCI 369048 221429 Therapeutic Targeting a Non-Hodgkin Lymphoma Driver using AIPROJECT SUMMARYBaylor College of Medicine (BCM) and Atomwise Incorporation have partnered to discover optimize and testinhibitors to undruggable oncoproteins using artificial intelligence (AI). Both Hodgkin lymphoma and non-Hodgkin lymphoma (NHL) are cancers that start in lymphocytes which are part of the bodys immune system.The main difference between Hodgkin lymphoma and NHL is in the specific lymphocyte each involves: in thepresence of abnormal cells called Reed-Sternberg cells the lymphoma is classified as Hodgkins; otherwise itis classified as NHL. NHL is the most common blood cancer and causes over 20000 deaths every year in theUnited States. There are about 90 types of NHL which usually develop when mutations occur within alymphocyte. The gene MYD88 encodes myeloid differentiation primary response 88 protein a critical universaladapter with essential functions in inflammation and immunity. Following stimulation of toll-like receptorsMYD88 transduces the signal to activate genes responsible for innate and adaptive immune responses.MYD88 is a driver oncogene that is frequently mutated in B-cell NHLs. The most frequent missensemutation is L265P which changes leucine at position 265 to proline and accounts for ~90% of all MYD88mutations. MYD88 L265P is found in ~90% of Waldenstrm macroglobulinemia (WM a rare NHL) >50% ofprimary extranodal lymphomas and ~29% of activated B-cell diffuse large B-cell lymphomas (DLBCL). WM isconsidered incurable. DLBCL can be cured in about 40% of the patients but those with MYD88 L265P havepoorer survival than those without. BCM collaborates with Atomwise the inventor of the first deep learning AItechnology based on neural networks and a leader in AI-assisted drug discovery to virtually screen 2.7 millioncompounds. We identified scores of AI-selected compounds targeting a binding site near L265P in MYD88. Wevalidated these hits by evaluating their inhibition of MYD88 L265P ubiquitination and xenograft tumorigenesis.One compound attenuated lymphoma growth from NHL cells with MYD88 L265P but not that with WT MYD88.We hypothesize that adaptor oncoproteins such as MYD88 L265P can be targeted by AI. In thisapplication we propose two specific aims to develop drug candidates that target MYD88 L265P for NHLtherapy. In Aim 1 we will use AI to virtually screen billions of compounds to discover novel drug candidatestargeting a binding site near L265P in MYD88. In Aim 2 we will optimize validated hit compounds targetingMYD88 L265P. Data generated from this partnership will provide a solid scientific platform for therapeuticdevelopment targeting the oncogenic MYD88 L265P while sparing WT MYD88 which is critical for both innateand adaptive immunity. This work addresses the unmet clinical need to target MYD88 L265P directly andadvances drug development against mutation-specific drivers. 590477 +No NIH Category available Ablation;Agreement;Animal Model;Apoptosis;Autologous;Automobile Driving;Autophagocytosis;Biological Assay;Bone Diseases;Bone Marrow;Bortezomib;Bromodomain;Bromodomains and extra-terminal domain inhibitor;Cell Line;Cell Survival;Cells;Chloroquine;Clinic;Clustered Regularly Interspaced Short Palindromic Repeats;Coin;Data;Data Set;Development;Disease;Disease Progression;Disease Resistance;Drug resistance;Evolution;Flow Cytometry;Generations;Genetic;Growth;Half-Life;Human;Immunocompetent;Immunohistochemistry;Impairment;In Vitro;Malignant Neoplasms;Mediating;Medicine;Melphalan;Modeling;Multiple Myeloma;Mus;Newly Diagnosed;Newly Diagnosed Disease;Oncogenic;Osteoblasts;Osteocalcin;Osteoclasts;Osteolysis;Pathway interactions;Patient Isolation;Patients;Phosphotransferases;Plasma Cells;Program Sustainability;Proliferation Marker;Proteasome Inhibitor;Proteins;Reagent;Refractory;Refractory Disease;Resistance;Roentgen Rays;Role;Stress;Testing;Therapeutic;Time;Tissue Microarray;Tissues;Toxic effect;Translations;Work;bone;c-myc Genes;clinically relevant;clinically significant;cohort;cytochemistry;defined contribution;efficacy evaluation;efficacy testing;genetic approach;improved;in vivo;inhibition of autophagy;inhibitor;lenalidomide;multicatalytic endopeptidase complex;neoplastic cell;novel;programs;resistance mechanism;response;skeletal;small molecule inhibitor;standard of care;synergism;targeted treatment;tartrate-resistant acid phosphatase;transcriptome sequencing;tumor growth;tumorigenic Role of ULK3 in Sensitive and Refractory Multiple Myeloma NARRATIVEAnalysis of multiple myeloma (MM) patients (n=815) from across the disease spectrum reveals Unc-51 LikeKinase-3 (ULK3) as being significantly expressed in newly diagnosed and refractory MM and our emergingstudies define ULK3 as a key regulator of autophagy and MM cell viability in vitro. Excitingly our team hasdeveloped novel ULK3 inhibitors (SG3/MA9) that rapidly inhibit autophagy and can also block the activity of thebromodomain containing protein 4 (BRD4) which is also expressed in refractory MM and is an important driverof the MYC oncogenic program. Based on preliminary in vitro and in vivo studies demonstrating the efficacy ofSG3/MA9 for the treatment of nave and refractory MM the proposed studies herein for the first time will definethe role of ULK3 in MM progression and test the efficacy of novel dual BRD4/ULK3 inhibitors in treating MM andresensitizing resistant disease to standard of care therapies using in vitro and in vivo approaches. NCI 10755362 11/3/23 0:00 PA-20-185 5R01CA269721-02 5 R01 CA 269721 2 "O'HAYRE, MORGAN" 12/16/22 0:00 11/30/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 8846677 "LYNCH, CONOR C" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 482202 NCI 286173 196029 SUMMARYMultiple myeloma (MM) is an incurable and fatal disease. Reagents such as the proteasome inhibitorbortezomib have significantly extended overall survival but resistance can rapidly arise. To generate therapiesthat can provide durable responses especially in the context of refractory disease a deeper understanding ofthe genetics driving the disease and the evolution of therapy resistance is required. To this end our team hasperformed RNASeq analysis of CD138+ MM cells derived from patients across the disease spectrum (n=815)and identified that Unc-51 Like Kinase-3 (ULK3) is highly expressed in newly diagnosed and refractory MM. Ouremerging studies demonstrate a novel role for ULK3 in regulating autophagy in MM a key program that sustainscell survival under times of stress and has been implicated as a major mechanism of proteasome inhibitorresistance. Of note MM is known to be highly dependent on autophagy. Currently specific ULK3 inhibitors arelacking. As a strategy to overcome resistance to single agents our team has focused on the development ofnovel inhibitors such as SG3 that target multiple kinases including ULK3 (EC50 90nM) as well bromodomainprotein 4 (BRD4)(3). BRD4 is a known driver of MYC and analysis of our patient RNASeq data again revealsincreased BRD4 expression in refractory MM. The BRD4 inhibitor JQ1 effectively impairs the tumorigenicpotential of MM but resistance has also been noted with this reagent. Our agent SG3 inhibits BRD4 activity inthe nM range (27 nM) similar to that of JQ1 (20 nM) and consistent with our ULK3 studies SG3 treatment rapidlyinhibits autophagy in MM cells. In vivo we found SG3 significantly inhibits MM progression and induced bonedisease. Excitingly our team has already developed a 2nd generation SG3 derivative coined MA9 that is just aseffective as SG3 in vitro and in vivo but has superior stability. We also show that MA9 can resensitize proteosomeinhibitor resistant MM cells to bortezomib. The central hypothesis of this proposal is that ULK3 is a key regulatorof autophagy in MM and represents a novel target for treatment of refractory disease and it will be testedwith three Aims. Aim 1 will take a genetic approach and delete ULK3 to its role in regulating autophagy in MMas well in the progression of the disease in vivo using clinically relevant animal models. Aim 2 will interrogatethe impact of our dual ULK3/BRD4 compound MA9 in MM progression and overall survival in vivo compared toJQ1 and the autophagy inhibitor chloroquine (CQ). Aim 3 will examine the efficacy of MA9 for the treatment ofCD138+ MM isolated from nave and refractory patients using a novel ex vivo high throughput platform developedat Moffitt. Here we will also define the contribution of ULK3 in mediating proteasome inhibitor resistance usingbortezomib resistant MM cell lines. Importantly in each Aim we will also determine the role of ULK3 in MMinduced bone destruction - a clinically significant aspect of this disease. We expect our anticipated results willprovide strong rationale for the translation of our novel dual ULK3/BRD4 inhibitors to the clinic. 482202 +No NIH Category available Amino Acid Transporter;Amino Acids;Anthelmintics;Attention;Automobile Driving;Biochemical Pathway;Breast Cancer Cell;Breast Cancer cell line;Cancer Cell Growth;Carbon;Cell Line;Cell Proliferation;Cells;Clinical Trials;Coupled;DNA Methylation;Data;Drug Targeting;Epigenetic Process;Essential Amino Acids;Estrogen receptor positive;Evaluation;FDA approved;Future;Genetic;Genetic Transcription;Glutamine;Glycine;Goals;Growth;Growth and Development function;Human;In Vitro;Knockout Mice;Logic;Lysine;Malignant Neoplasms;Mammary Neoplasms;Mediating;Metabolic Pathway;Metabolism;Methionine;Methylation;Molecular;Mus;Normal Cell;Nude Mice;Pathway interactions;Pharmaceutical Preparations;Pre-Clinical Model;Proliferating;Protein Biosynthesis;Purines;Pyrimidine;Role;Serine;Specificity;System;Testing;Therapeutic;Up-Regulation;WNT Signaling Pathway;Xenograft procedure;addiction;amino acid metabolism;anti-cancer;cancer cell;cancer therapy;carcinogenesis;chemotherapy;drug repurposing;druggable target;in vivo;inhibitor;malignant breast neoplasm;meter;mouse model;neoplastic cell;novel;nucleotide metabolism;patient derived xenograft model;pharmacologic;pre-clinical;small hairpin RNA;targeted treatment;tool;triple-negative invasive breast carcinoma;tumor;tumor growth;uptake Amino acid transporter SLC38A5 as a drug target for TNBC: Evaluation with genetic and pharmacologic approaches Tumor cells rely upon glutamine-dependent metabolic pathways as well as serine/glycine/methionine-drivenone-carbon metabolic pathway for their proliferation and growth; the amino acid transporter SLC38A5supplies these four amino acids to triple-negative breast cancer (TNBC) cells. As TNBC has no effectivetargeted therapy our goal is to show using in vitro studies with cell lines and in vivo studies with appropriatepreclinical mouse models that pharmacologic blockade of SLC38A5 is a logical approach for targetedtreatment of TNBC. NCI 10755350 11/22/23 0:00 PAR-20-292 5R21CA277140-02 5 R21 CA 277140 2 "KONDAPAKA, SUDHIR B" 12/16/22 0:00 11/30/24 0:00 ZCA1-SRB-2(O1)S 1861006 "GANAPATHY, VADIVEL " Not Applicable 19 BIOCHEMISTRY 609980727 E4Z2NUYUMHF9 609980727 E4Z2NUYUMHF9 US 33.592746 -101.898787 8285902 TEXAS TECH UNIVERSITY HEALTH SCIS CENTER LUBBOCK TX SCHOOLS OF MEDICINE 794306271 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 160938 NCI 105188 55750 Amino acid metabolism in tumor cells is very different from that in normal cells. The tumor-specific metabolicpathway glutaminolysis focuses on glutamine. Recently another fundamental pathway was discovered forcancer cell proliferation: the serine-glycine-methionine-one-carbon pathway. Tumor cells upregulatespecific amino acid transporters to satisfy their increased need for glutamine glycine serine and methionineto fuel these pathways. Blocking the entry of these amino acids into tumor cells has potential for cancertherapy. Recently we provided evidence for this approach by identifying SLC6A14 an amino acid transporterwith broad specificity that is induced in ER-positive (ER+) breast cancer (BC) and by showing that blockadeof this transporter reduces ER+ BC. But SLC6A14 is not expressed in triple-negative breast cancer (TNBC).TNBC must rely upon a different transporter as a fix to its addiction to glutamine/serine/glycine/methionine.We have now identified this transporter as SLC38A5 a Na+-coupled uptake system exclusively for these fouramino acids. SLC38A5 is upregulated in TNBC by WNT/DVL1. Furthermore SLC38A5 promotesmacropinocytosis a unique feature essential for tumor growth. Here we will show that SLC38A5 drives theglutamine- and one-carbon metabolic pathways in TNBC and evaluate in preclinical models the potential ofthis transporter as a logical drug target for TNBC. We have identified the FDA-approved drug niclosamide asa potent inhibitor of SLC38A5 function and expression. This drug can be used pharmacologically to interrogatethe role of SLC38A5 in TNBC. We also have Slc38a5-null mice as a genetic tool for these studies.Hypothesis: SLC38A5 drives the glutamine-dependent and one-carbon metabolic pathways in TNBC; assuch pharmacologic inhibition or genetic deletion of SLC38A5 will block TNBC. We will test this hypothesiswith two aims: (Aim 1) Demonstrate that SLC38A5 is obligatory for glutaminolysis and one-carbon metabolicpathway to promote cell proliferation and remodeling of the epigenetic landscape in TNBC cells and elucidatethe molecular mechanisms by which WNT/DVL1 induces SLC38A5 in these cells. Here we will use classicalas well as patient-derived xenograft TNBC cell lines. (Aim 2) Evaluate the impact of SLC38A5 loss on tumorgrowth in mouse models of TNBC using Slc38a5-/- mice and niclosamide as a proof-of-concept for future useof this transporter as a selective drug target for TNBC. Here we will use xenografts of human TNBC cell linesin nude mice to evaluate the anticancer efficacy of niclosamide and also compare the development/growthof spontaneous mammary tumors in a TNBC mouse model [C3(1)-TAg mouse] with and without niclosamidetreatment (pharmacologic) and on Slc38a5+/+ and Slc38a5-/- backgrounds (genetic). Impact: With no knowntargeted therapy chemotherapy is the only option for TNBC. Establishment of SLC38A5 as a drug targetwould aid future use of pharmacologics (e.g. niclosamide) to block its expression and transport function as atargeted therapy for TNBC either as a monotherapy or in combination with standard chemotherapeutics. 160938 +No NIH Category available Adjuvant;Affect;Autoimmune;Autoimmune Responses;Bioinformatics;Biological;Biological Assay;Biology;Cancer Patient;Cells;Clinical;Data;Dendritic Cells;Deoxyribonucleases;Detection;Development;Dose;Encapsulated;Environment;Enzymes;Fractionation;Future;Genes;Goals;Immune;Immune response;Immunobiology;In Vitro;Infection;Innate Immune Response;Investigation;Knock-out;Link;Macrophage;Malignant Neoplasms;Measures;Modeling;Molecular;Mus;Myelogenous;Myeloid Cells;Nucleic Acids;Outcome;Patients;Polynucleosome;Pre-Clinical Model;Radiation therapy;Reagent;Regimen;Regulation;Repression;Research Design;Risk;Role;Sampling;Series;Signal Transduction;Stimulus;T cell response;Testing;Tumor Immunity;adaptive immune response;adaptive immunity;anti-tumor immune response;cancer cell;cancer immunotherapy;cancer therapy;combinatorial;conditional knockout;drug development;high reward;immunogenic;improved;in vivo;innovation;microvesicles;new therapeutic target;novel;pancreatic cancer model;radiation response;response;therapeutic target;treatment effect;tumor DNASE1L3 regulation of anti-tumor immune responses following radiation therapy Project NarrativeThe fact that two different cancer patients can respond differently to the same therapy represents animportant problem in cancer treatment. Using in depth analysis of responsive and unresponsive tumors wehave identified a novel target with the potential to help those with non-responsive tumors. We use unique andhigh quality preclinical models to evaluate the impact of this target on outcome and use advanced analysis oftumors to understand the molecular regulation of the target. NCI 10755344 11/29/23 0:00 PAR-20-292 5R21CA277250-02 5 R21 CA 277250 2 "SOMMERS, CONNIE L" 1/1/23 0:00 12/31/24 0:00 ZCA1-TCRB-9(O1)S 10127825 "GOUGH, MICHAEL JAMES" Not Applicable 9 Unavailable 79611840 H3R1MLL2VLT7 79611840 H3R1MLL2VLT7 US 45.533688 -122.617301 10061009 PROVIDENCE HEALTH & SERVICES - OREGON Renton WA Other Domestic Non-Profits 980543368 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 175664 NCI 105188 70476 Project SummaryThe critical preliminary data for this proposal relates to dendritic cells a critical immune cell that links innatedetection of infection to adaptive immune responses that can uniquely target and destroy targets. These sameprinciples apply to initiate and control immune responses to cancer. We discovered that in tumors that areunable to generate adaptive immunity to assist in tumor cure following radiation therapy dendritic cells fail tomature. These dendritic cells that fail to mature express a novel target gene called Dnase1l3 which has beenshown to negatively regulate innate stimuli and to negatively regulate autoimmune responses. This proposal isan innovative investigation into the role of this gene in anti-tumor immunity and the mechanisms by which it isregulated in dendritic cells in tumors.We hypothesize that DNAse1l3 represses innate and adaptive immune responses in the tumor environment.The specific aims of this study are to 1: Determine the consequence of myeloid expression of Dnase1l3 onthe immune response to radiation therapy; 2: Unbiased analysis of the consequence of myeloid expression ofDnase1l3 on the tumor immune environment following radiation therapy. Our study design incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using a range of RT doses andfractionations. These are combined with unique knockouts and assays that allow us to identify divergentresponses in vitro and in vivo. Our analyses of clinical samples use high quality bioinformatic approaches thatallow us to evaluate effect of the tumor environment on the biological response to innate adjuvants in patientsamples. 175664 +No NIH Category available Address;Adjuvant;Adjuvant Chemotherapy;Affect;Agonist;Antibodies;Architecture;Biological;Biological Markers;Biological Models;Biology;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer cell line;Cancer Etiology;Cell Line;Cessation of life;Characteristics;Chemoresistance;Chemotherapy-Oncologic Procedure;Chromatin;Clinical;Clinical Management;Complex;DNA Binding;Data;Development;Disease;Disease Management;ERBB2 gene;EZH2 gene;Enhancers;Epidermal Growth Factor Receptor;Epigenetic Process;Estradiol;Estradiol Receptors;Estrogen Receptor alpha;Estrogen Receptor beta;FDA approved;Foundations;Gene Expression Profile;Genetically Engineered Mouse;Goals;Histones;In Vitro;Individual;Invaded;Knowledge;Ligands;Malignant Neoplasms;Mammary Neoplasms;Mediating;Modeling;Modification;Molecular;Morbidity - disease rate;NF-kappa B;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Newly Diagnosed;Oncogenic;Organoids;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Phenotype;Primary Neoplasm;Progesterone Receptors;Prognosis;Prognostic Marker;Proliferating;Proteins;Recurrence;Recurrent disease;Refractory;Resistance;Retrospective cohort;Role;Signal Pathway;Signal Transduction;Specimen;Testing;Therapeutic;Treatment Protocols;Tumor Promotion;United States;Validation;Woman;anti-cancer;cancer diagnosis;cancer type;chemotherapy;clinically significant;combat;effective therapy;efficacy evaluation;genetic corepressor;genome-wide;genomic locus;improved;improved outcome;in vitro Model;in vivo;innovation;malignant breast neoplasm;migration;molecular subtypes;mortality;neoplastic cell;new therapeutic target;novel;novel strategies;participant enrollment;patient derived xenograft model;patient stratification;phase II trial;predict responsiveness;prevent;prospective;receptor;response;standard of care;targeted agent;targeted treatment;therapy outcome;tool;treatment response;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression ER repurposes EZH2 to suppress oncogenic NFB signaling in TNBC PROJECT NARRATIVETriple negative breast cancer (TNBC) is an aggressive form of the disease with few treatment options highrecurrence rates and disproportionately higher mortality rates. This proposal involves elucidating themechanisms by which estrogen receptor beta (ER) elicits potent anti-cancer effects in TNBC and determiningthe utility of specifically targeting this receptor alone and in combination with established chemotherapyregimens for therapeutic purposes. Results of the proposed study are expected to contribute to thedevelopment of a new class of therapies and allow for better stratification of patients to specific forms ofchemotherapy ultimately resulting in improved outcomes for thousands of patients each year. NCI 10755315 12/28/23 0:00 PA-19-056 5R01CA249116-04 5 R01 CA 249116 4 "HILDESHEIM, JEFFREY" 1/1/21 0:00 12/31/25 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 8084551 "HAWSE, JOHN R." Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 451760 NCI 294457 157303 PROJECT SUMMARY/ABSTRACTBreast cancer remains the most commonly diagnosed cancer in women and is the second leading cause ofcancer-related deaths among women. Triple Negative Breast Cancer (TNBC) affects approximately 15-20% ofall breast cancer patients is the most aggressive sub-type of breast cancer and accounts for adisproportionately higher fraction of cancer-related morbidities and mortalities. Treatment options areextremely limited for TNBC patients and the most commonly employed neoadjuvant and adjuvantchemotherapy drugs have existed for decades. De novo and acquired chemotherapy resistance remains amajor problem and disease recurrence results in breast cancer-related death for the large majority of patients.Further complicating the clinical management of TNBC is the lack of FDA-approved targeted therapies that canbe utilized to prevent disease recurrence in the adjuvant setting. Thus the identification and validation of noveldrug targets and more effective treatment options continues to represent a major unmet clinical need. We havedemonstrated that Estrogen Receptor Beta (ER) is expressed in approximately 20% of TNBCs and haveshown that patients with ER positive tumors have improved long-term prognosis. In addition we have shownthat ligand-mediated activation of ER by estradiol or ER selective agonists inhibits TNBC cell line andpatient derived xenograft proliferation invasion and migration in vitro as well as primary tumor growth andmetastatic spread in vivo. Importantly we provide the first evidence that estradiol can elicit clinical benefit in apatient with ER positive metastatic and chemo-refractory TNBC. Mechanistically we demonstrate that ERpotently suppresses the nuclear factor kappa B (NFB) pathway in TNBC cells effects that are mediatedthrough association of ER with EZH2/PRC2 leading to epigenetic modifications to histone residues at NFBtarget gene loci. Furthermore we have demonstrated that ER modifies chemotherapy responsiveness ofTNBC cell line models and patient derived organoids and inhibits chemo-resistant cell lines. Based on thesedata the central hypothesis of this proposal is that ER repurposes EZH2 to inhibit NFB signaling in TNBCthereby eliciting anti-cancer effects and enhancing chemotherapeutic responsiveness. To test this hypothesisthe following Specific Aims are proposed: 1). Determine the molecular mechanisms by which ER suppressesNFB signaling in TNBC and 2). Elucidate the biological importance and clinical significance of ER-mediatedsuppression of NFB signaling in TNBC using novel genetically engineered mice PDX/PDO models andpatient specimens. To conduct these Aims we will utilize multiple model systems innovative approaches andmolecular tools to comprehensively address our focused hypothesis. Given the extremely poor outcomes inwomen with TNBC the proposed studies are of critical importance towards the goal of improving treatmentstrategies to more effectively manage this disease. 451760 +No NIH Category available Address;Antibodies;Autologous Stem Cell Transplantation;Autophagocytosis;B lymphoid malignancy;B-Lymphocytes;Binding;Biochemical;Biological Assay;Blood Vessels;Bone Marrow;Bone Surface;Catabolism;Cell Separation;Cell Survival;Cells;Clinical;Clinical Treatment;Complex;Cytolysis;DNA Sequence Alteration;Dependence;Deubiquitination;Development;Drug resistance;Endothelium;Family;Family member;Gene Expression Profiling;Gene Silencing;Goals;Heterogeneity;High Dose Chemotherapy;Human;Link;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Methods;Molecular;Multiple Myeloma;Neoplasms;Neoplastic Plasma Cell;Pathogenesis;Pathology;Pathway interactions;Patients;Plasma;Play;Predisposition;Process;Proliferating;Proteasome Inhibition;Proteasome Inhibitor;Protein Biosynthesis;Protein Family;Proteins;Recurrence;Recurrent tumor;Refractory;Relapse;Reporting;Resistance;Resistance development;Role;Sampling;Signal Pathway;Signal Transduction;Stress;System;TRIM Motif;Testing;Tracer;Ubiquitin;Xenograft procedure;bone;cell growth;chemotherapy;clinically relevant;improved;improved outcome;in vivo;inhibitor;member;misfolded protein;mouse model;multicatalytic endopeptidase complex;new therapeutic target;novel;pre-clinical;prevent;protein aggregation;protein complex;protein degradation;protein function;protein protein interaction;proteostasis;proteotoxicity;receptor;screening;stem;stem cell survival;stem cells;stem-like cell;survival outcome;therapy resistant;treatment response;ubiquitin isopeptidase Analyzing protein homeostasis pathways in multiple myeloma stem-like cells Proposal Description:In this project we will delineate functions for TRIM44 and its interacting molecules in MM stem-like cells usingbiochemical and molecular methods. The long-term goal is to establish TRIM44 as a new therapeutic targetand ultimately develop inhibitors to eradicate MM stem-like cells in the bone marrow and improve patientsurvival. NCI 10755287 11/6/23 0:00 PA-19-056 5R01CA181319-09 5 R01 CA 181319 9 "HOWCROFT, THOMAS K" 7/2/14 0:00 11/30/25 0:00 Tumor Cell Biology Study Section[TCB] 7314495 "MCCARTY, NAMI " Not Applicable 18 BIOCHEMISTRY 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF MEDICINE 770305400 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 333450 NCI 213750 119700 Abstract:Multiple myeloma (MM) is an incurable B cell malignancy that is characterized by the growth of neoplasticplasma cells within the bone marrow microenvironment. Despite progress in the clinical treatment of MMincluding the use of high-dose chemotherapy and autologous stem cell transplantation a considerableproportion of patients develop resistance and become refractory to therapies. Drug resistance in MM isenabled by evolving genomic alterations as well as by contributions from stromal components in the bonemarrow microenvironment. Specifically the bone marrow provides a protective niche for slowly cycling/quiescent stem-like MM cells that are not killed by chemotherapies. We have discovered sub-populations ofMM stem-like cells that preferentially localize to osteoblastic niches of the bone marrow. Gene expressionprofiling revealed that a novel tripartite motif factor TRIM44 is upregulated in MM stem-like cells isolated fromthe osteoblastic niche. TRIM family proteins function as autophagy-regulatory receptors and TRIM44 genesilencing decreases autophagy. In this project we will investigate roles for TRIM44 and its links to proteinhomeostasis control during MM initiation progression and resistance to therapy. Our working hypothesis is thatTRIM44 plays integral roles in promoting quiescent MM stem cell survival within the bone marrow niche byregulating pathways involved in proteotoxic stress. Furthermore we propose that targeting TRIM44 or itsinteracting proteins will result in diminished MM survival and improved outcome in response to therapy. To testthis hypothesis we will (i) analyze signaling pathways regulated by TRIM44 and determine how components ofthese pathways promote cell survival under proteotoxic stress; (ii) characterize novel substrates (from a recentmass spectrometry screen) that selectively bind to TRIM44 and determine the functional significance of theseinteractions in primary MM cells; and (iii) delineate the clinical relevance of these TRIM44-dependent pathwaysin MM pathogenesis and relapse using xenograft mouse models. Our long-term goal is to selectively inhibitTRIM44-dependent signaling pathways to benefit patients by reducing MM progression and/or blocking tumorrecurrence after therapy. 333450 +No NIH Category available Abdomen;Activities of Daily Living;Address;Adult;Allografting;Biological Assay;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cell physiology;Chest;Child;Childhood;Chronic;Clinical;Communicable Diseases;Complication;DNA;Data;Detection;Development;Elements;Epstein-Barr Virus Infections;Epstein-Barr Virus-Related Malignant Neoplasm;Evaluation;Exposure to;Flow Cytometry;Functional disorder;Generations;Goals;Heart;Hodgkin Disease;Human;Human Herpesvirus 4;Immune;Immune response;Immunocompetent;Immunocompromised Host;Immunologics;Immunology;Immunosuppression;Immunotherapy;Individual;Inflammatory;Intervention;Intestines;Kidney;Knowledge;Liver;Lung;Lymphoma;Lymphoproliferative Disorders;Malignant - descriptor;Memory;NK Cell Activation;Natural Killer Cells;Non-Hodgkin's Lymphoma;Normal Statistical Distribution;Nucleic Acid Amplification Tests;Oncology;Organ Transplantation;Outcome;Pathway interactions;Patients;Pediatric Hospitals;Phase;Phenotype;Plasma;Population;Primary Infection;Prospective cohort;Publishing;Recovery;Sampling;Solid;Standardization;T cell therapy;T memory cell;T-Lymphocyte;Time;Transplant Recipients;Viral;Viral Load result;Viral load measurement;Virus;Virus Replication;Whole Blood;chemokine;co-infection;cytokine;exhaust;exhaustion;experimental study;functional status;high risk;immune function;member;organ transplant recipient;patient subsets;peripheral blood;post-transplant;prevent;programs;prospective;receptor;response;rituximab;translational approach;transplant centers;tumorigenesis;viral DNA;young adult Understanding the immune response changes to clinical interventions for Epstein-Barr virus infection prior to lymphoma development in children after organ transplants (UNEARTH) NARRATIVEPost-transplant lymphoproliferative disease (PTLD) is a group of rare malignant complications of solid organtransplant that include Hodgkin disease and non-Hodgkin lymphoma. About 50-80% are associated withEpstein-Barr virus (EBV) infection yet the T cell and Natural Killer cell immune responses in primary EBVinfection in children or during progression to PTLD are not well characterized. By performing detailedprospective immunological phenotyping through the first year after 278 pediatric organ transplants we willunearth pathways that may inform EBV oncogenesis progression in immunocompromised populations. NCI 10755205 8/31/23 0:00 PAR-21-348 1U01CA275304-01A1 1 U01 CA 275304 1 A1 "READ-CONNOLE, ELIZABETH LEE" 9/1/23 0:00 8/31/28 0:00 ZCA1-TCRB-D(M1) 7042785 "DHARNIDHARKA, VIKAS R." Not Applicable 1 PEDIATRICS 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 987185 NCI 762075 225110 Abstract/SummaryAmong the Epstein-Barr virus associated cancers is post-transplant lymphoproliferative disease (PTLD) a rarebut major complication of pediatric solid organ transplants (SOT). Many children are EBV-seronegative at timeof SOT leading to primary EBV infection from the allograft under intense immunosuppression and a higherchance of a chronic high viral load (CHVL) state or PTLD. Longitudinal peripheral blood EBV DNA nucleic acidtesting (NAT) has not improved the individual prediction of PTLD occurrence likely due to variable SOT recipientimmune responses. Further these patients receive clinical interventions for EBV DNAemia with incompleteresponses for unknown reasons. Our team of SOT infectious disease and immunology professionals will bringnew and complimentary expertise to close these knowledge gaps. We will perform longitudinal T and NK cellimmune function assays in conjunction with local and central EBV and anellovirus NAT in 1390 samples across5 time points in the first year after 278 SOT (kidney liver heart lung or intestine) at 3 major children's hospitals.We will accomplish the following Specific Aims comparing thoracic and abdominal SOT recipients with primaryEBV infection or CHVL state: 1. Assess the prospective phenotypic and functional features of T cellexhaustion and correlate with EBV infection outcomes and NK cell profile. Hypothesis: SOT recipients'that develop CHVL state display distinct phenotypic memory differentiation and exhausted CD8+ and CD4+ Tcell profiles that are regulated by distinct inflammatory circuits. We will accomplish this aim by performing multi-spectral flow cytometry to characterize T cell phenotype and function as well as Meso Scale Discovery platformto assess distinct viral control-relevant plasma cytokines/chemokines during the phases of initial replicationexpansion progression CHVL or recovery states. 2. To prospectively define the number phenotype andfunctional status of NK cells and correlate with EBV infection outcomes. Hypothesis: NK cell activationwill coincide with primary infection and will correlate positively with clearance vs. negatively with persistent EBVreplication. NK cell dysfunction will develop in patients with CHVL who are at highest risk of PTLD. We willleverage our established multi-spectral flow cytometry panel and analyze patients with primary EBV infectionafter SOT and answer questions related to the activation status NK receptor repertoire and functional capacity.3. Determine the association of peripheral blood torquetenovirus (TTV) DNA loads to EBV outcomes Tand NK cell profiles. Hypothesis: TTV loads reduce with clinical reductions in immunosuppression and predictEBV clearance. We will accomplish this aim using longitudinal whole blood NAT assays for both viruses atcommon time points performed centrally to minimize lab variability. By study end we will know the T and NKimmune responses to EBV across multiple clinical situations. We expect to find key immune mechanisms thatwill predict poor or delayed EBV clearance despite clinical interventions which may lead to new translationalimmunotherapy approaches to prevent PTLD or inform EBV oncogenesis in other populations. 987185 +No NIH Category available AIDS-Related Lymphoma;Age;Autopsy;Baltimore;Biological Assay;Biological Markers;Burkitt Lymphoma;CD4 Lymphocyte Count;Cause of Death;Chicago;DNA;DNA Methylation;DNA analysis;Data;Development;Diagnosis;Diagnostic;Epigenetic Process;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Lymphoma;Epstein-Barr Virus-Related Malignant Neoplasm;Evaluation;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;HIV;Hodgkin Disease;Human Herpesvirus 4;Investigation;Large-Cell Immunoblastic Lymphoma;Lymphoma;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Methylation;Modeling;Modification;Organ;Pathway interactions;Patients;Pattern;Persons;Plasma;Plasma Cells;Population;Prevalence;Saliva;Sampling;Screening for cancer;Source;Specificity;System;Testing;Training;Validation;Viral;Viral Genes;Viral Genome;Virus Latency;bisulfite sequencing;cell free DNA;cohort;cost;design;epigenome;health care availability;improved;large cell Diffuse non-Hodgkin's lymphoma;latent infection;liquid biopsy;low and middle-income countries;lymphoblastoid cell line;methylation pattern;methylome;novel;point of care;primary effusion lymphoma;rapid test;sample collection;screening;sex;transcriptome;transcriptome sequencing;tumor Investigating the EBV methylome in PLWH: Discovery and Development of Novel EBV Diagnostics in Plasma and Saliva PROJECT NARRATIVEThis project seeks to study EBV gene regulation and the relationship between the EBV epigenome and EBV andcellular transcriptome in EBV(+) lymphoma in the setting of HIV. The study will also characterize EBV methylationin cfDNA from plasma and saliva in order to define and develop novel EBV diagnostics for HIV-associatedlymphoma.1 NCI 10755171 9/8/23 0:00 PAR-21-348 1U01CA284811-01 1 U01 CA 284811 1 "LIDDELL HUPPI, REBECCA" 9/8/23 0:00 8/31/28 0:00 ZCA1-TCRB-D(M1) 1942371 "AMBINDER, RICHARD FREDERICK" "XIAN, RENA " 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/8/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 713651 NCI 468529 245122 ABSTRACTEBV(+) lymphomas are an important cause of death in people living with HIV (PLWH). Different patterns of viraland cellular gene expression have been found to characterize different subtypes of EBV(+) lymphomas. CpGmethylation of EBV DNA is an important epigenetic regulator of viral and cellular gene expression. At presentwe have a very limited understanding of CpG methylation in EBV(+) lymphomas in PLWH and how this maydetermine patterns of viral gene expression. Although we are very successful in treating some EBV(+) lymphomain HIV patients many cases are diagnosed very late after organ function has been compromised or only onpost-mortem exam. This is especially true in populations with limited access to health care in the US as well asin low- and middle-income countries (LMIC) with high HIV prevalence. Assessment of cell-free DNA (cfDNA) inplasma is increasingly recognized as useful in early cancer detection. Plasma cell-free EBV DNA has beenshown to be useful in screening for nasopharyngeal cancer. However high levels of EBV DNA in some PLWHreduce the specificity of EBV DNA quantitation as a diagnostic maker of lymphoma. Evidence is emerging thatEBV CpG methylation or patterns of methylation could accurately identify EBV(+) malignancies. The proposedstudies should improve the collective understanding of epigenetic modification of EBV and viral and cellular geneexpression and enable discovery of novel EBV liquid biopsy diagnostics for early cancer detection in PLWH. Inaim 1 we will characterize lymphoma transcriptomes by RNA-Seq and EBV methylomes by high throughputbisulfite sequencing (bs-Seq) to investigate the relationship between the cellular and viral transcriptome andEBV methylation. In aim 2 we will systematically investigate the plasma EBV DNA methylome in PLWH withEBV(+) lymphoma and PLWH controls so as to identify differentially methylated regions of the viral genome thatare most informative for lymphoma. These results will guide design and evaluation of methylation-specific PCRprimer sets that can enable rapid assessment of EBV methylation states. The results from the qMSP studies willbe used to develop and train an automated qMSP classifier for the presence of EBV(+) lymphoma. In aim 3 wepropose to establish a new plasma (and saliva) specimen collection from PLWH with EBV(+) lymphoma andmatched controls. We will validate the plasma classifier developed in this independent cohort. We will also applythis qMSP classifier to saliva to explore the possibility that saliva cfDNA may be a useful surrogate for plasmacfDNA. At the conclusion of our studies we anticipate having an improved understanding of the interplaybetween lymphoma gene expression EBV gene expression and EBV CpG methylation. Our results will aid inthe development of the first plasma EBV qMSP PCR assay for EBV(+) lymphoma in PLWH and will enableexploration of saliva as an alternate source for cfDNA for future liquid biopsy applications in PLWH. We anticipatethat our findings will pave the way for the development of point of care multiplex PCR assay systems appropriatefor future investigations of low-cost screening assays in the US and in LMICs.1 713651 +No NIH Category available Activities of Daily Living;Allografting;B-Cell Lymphomas;B-Lymphocytes;Blood;Cell Proliferation;Cell Survival;Cell physiology;Cells;Characteristics;Custom;Cytometry;Development;Epithelium;Epstein Barr Virus B cell lymphoma;Epstein Barr Virus B lymphoma cell;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr pathogenesis;FOS gene;Genes;Genetic Variation;Goals;HIV;Herpesviridae;Human Herpesvirus 4;Immune;Immune response;Immunity;Immunocompromised Host;Immunosuppression;Impairment;Individual;Infection;Life;Link;Lymphoid;Lymphomagenesis;Lymphoproliferative Disorders;Lytic Phase;Lytic Virus;MAP Kinase Gene;Malignant Neoplasms;Membrane Proteins;MicroRNAs;Modeling;Molecular;Morbidity - disease rate;Multi-Institutional Clinical Trial;Mutation;NCAM1 gene;Natural Killer Cells;Oncogenes;Organ Transplantation;Pathogenesis;Patients;Peptides;Peripheral Blood Mononuclear Cell;Persons;Phenotype;Plasma;Population;Predisposing Factor;Proliferating;Proteins;Risk;Role;Sampling;Signal Pathway;Solid;T cell response;T-Lymphocyte;Testing;Therapeutic;Transcription Factor AP-1;Transplant Recipients;Variant;Viral;Viral Genes;Viral Pathogenesis;Viral Proteins;Virus;Work;adaptive immune response;antiviral immunity;biobank;cell transformation;extracellular vesicles;gain of function mutation;gene function;genome sequencing;high dimensionality;immunoregulation;immunosuppressed;infected B cell;innovation;mortality;novel;organ transplant recipient;post-transplant;prevent;prospective;response;transforming virus;tumor;virus genetics;whole genome Epstein Barr Virus Driven Mechanisms of Post Transplant Lymphoproliferative Disease PROJECT NARRATIVEEpstein Barr virus (EBV) infection is associated with significant morbidity and mortality in solid organ transplantrecipients including the development of EBV+ B cell lymphomas and post-transplant lymphoproliferative disease(PTLD). The goal of our study is to determine how EBV genetic diversity leading to alterations in viral genefunction and immune recognition contributes to the pathogenesis of EBV+ PTLD. NCI 10755055 8/24/23 0:00 PAR-21-348 1U01CA275305-01A1 1 U01 CA 275305 1 A1 "READ-CONNOLE, ELIZABETH LEE" 9/1/23 0:00 8/31/28 0:00 ZCA1-TCRB-D(M1) 1888109 "MARTINEZ, OLIVIA M" "KRAMS, SHERI M." 16 SURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 627903 NCI 406673 221230 PROJECT SUMMARY/ABSTRACTEpstein Barr virus (EBV) is a broadly disseminated gammaherpes virus that in immunosuppressed orimmunocompromised individuals can cause serious life-threatening B cell lymphomas. In solid organ transplant(SOT) recipients these EBV+ B cell lymphomas are the most serious manifestation of the group ofheterogeneous lymphoproliferations termed post-transplant lymphoproliferative disease (PTLD). Predisposingfactors for PTLD include primary EBV infection reactivation of EBV in recipient B cells and impaired T cellimmunity due to immunosuppression. There are major gaps in our understanding of how specific viral genescontribute to lymphomagenesis in the context of EBV+ PTLD and whether there are specific alterations in theimmune response to EBV in SOT that develop EBV+ PTLD compared to those that do not. Prior work from ourgroup has focused on latent membrane protein 1 (LMP1) the major oncogene of EBV to better understandEBV+ PTLD pathogenesis. In a recent prospective multicenter clinical trial in SOT recipients we demonstratedthat specific gain of function mutations in LMP1 significantly correlate with the development of EBV+ PTLD.Weve also demonstrated that EBV alters the host cell microRNA profile and that this has direct effects on survivalof EBV+ B lymphoma cells. Building on our previous innovative studies of the bidirectional interactions betweenEBV and host immunity and using our unique Biorepository of samples from SOT recipients that developedEBV+ PTLD and matched SOT controls that did not develop EBV+ PTLD we propose to define the impact ofviral genetic diversity on protective immune responses to EBV. We hypothesize that EBV genetic diversity leadsto alterations in viral gene function and immune recognition that contribute to the pathogenesis of EBV+ PTLD.To test this hypothesis we propose the following Specific Aims:1) Determine the genetic diversity of EBV in PTLDand the impact on host cell function 2) Determine the effect of EBV+ PTLD-associated genetic diversity on hostimmunity to EBV and 3) Determine how extracellular vesicles and microRNA contribute to the development ofEBV+ PTLD. We anticipate these studies will identify novel mechanisms underlying the EBV-drivenpathogenesis of B cell lymphomas in PTLD and will reveal new opportunities for therapeutic strategies to preventand treat EBV+ B cell lymphomas in immunosuppressed and immunocompromised individuals. 627903 +No NIH Category available Address;Affect;Animals;Behavior;Biological;Breast Cancer Model;Carcinogens;Cell physiology;Cells;Chronic;Circadian Dysregulation;Circadian Rhythms;Cytometry;Data;Detection;Development;Epidemiology;Exhibits;Exposure to;Future;Gene Expression;Gene Expression Profiling;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Growth;Health;Heat Stress Disorders;Helicobacter pylori;Hour;Incidence;International Agencies;Investigation;Jet Lag Syndrome;K-ras mouse model;KRAS oncogenesis;KRAS2 gene;KRASG12D;Kinetics;Knowledge;Light;Lighting;Link;Location;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Metabolic Diseases;Molecular;Mus;Nuclear;Oncogenic;Outcome;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Periodicity;Peripheral;Persons;Physiological;Physiology;Play;Probability;Public Health;RAS driven cancer;Research;Resolution;Risk;Role;Schedule;Signal Transduction;Skin Cancer;Source;Stimulus;Stress;System;Testing;Time;Travel;Tumor Burden;Vulnerable Populations;Work;anticancer research;biological adaptation to stress;cancer risk;cancer type;cell type;circadian;circadian pacemaker;design;digital;disorder risk;experience;experimental study;genome-wide;heat shock transcription factor;heat-shock factor 1;in vivo;insight;lung tumorigenesis;malignant stomach neoplasm;mouse model;mutant;nervous system disorder;proteostasis;proteotoxicity;response;shift work;temporal measurement;transcription factor;transcriptome sequencing;transcriptomics;tumor;tumor barcoding and sequencing;tumor microenvironment;tumorigenesis Establishing a mechanistic basis for enhanced tumorigenesis under chronic circadian disruption 8. Project NarrativeEnvironmental disruption of circadian rhythms caused by altered timing of light exposure asoccurs in shift work increases the risk of several types of cancer including lung cancer. Wefound that an altered lighting schedule that mimics the circadian disruption experienced by shiftworkers enhances tumor formation in a mouse model of KRAS-driven lung adenocarcinoma.This project tests the hypothesis that increased tumor formation in response to chronic circadiandisruption is caused by perturbation of normal daily cycles in signaling through the transcriptionfactor heat shock factor 1 (HSF1) which leads to chronic activation of a molecular proteotoxicstress response pathway. NCI 10754969 11/14/23 0:00 PA-20-185 5R01CA271500-02 5 R01 CA 271500 2 "LUO, RUIBAI" 12/15/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-CB-L(02)M] 2094046 "LAMIA, KATJA A" Not Applicable 50 Unavailable 781613492 PHZJFZ32NKH4 781613492 PHZJFZ32NKH4 US 32.903062 -117.243592 7375802 "SCRIPPS RESEARCH INSTITUTE, THE" LA JOLLA CA Other Domestic Non-Profits 920371000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 537153 NCI 296769 240384 PROJECT SUMMARY (DESCRIPTION)Circadian rhythms coordinate behavior and physiology with predictable daily environmental cycles. The timingof circadian cycles is primarily determined by the timing of light exposure. Chronic disruption of circadianrhythms such as that experienced during shift work or travel across time zones increases the risk of severaltypes of cancer in people. A handful of studies has shown that exposure to altered light cycles designed torecapitulate so-called chronic jet lag experienced by shift workers enhances tumorigenesis in geneticallyengineered mouse models of breast liver and lung cancers. We have established that exposure to a lightingschedule that mimics chronic jet lag increases tumor formation in a mouse model of KRAS-driven lungadenocarcinoma. Furthermore we found that tumors from mice exposed to chronic circadian disruptionexpress higher levels of genes that are activated by the heat stress response factor HSF1.HSF1 has been shown to facilitate tumorigenesis in several systems and may be particularly pathogenic inRAS-driven cancers. We hypothesize that chronic circadian disruption causes elevated activity of HSF1 thusleading to aggravated oncogenic activity of KRASG12D and increased tumorigenesis. This proposal willexamine whether HSF1 is required for increased formation of KRASG12D-driven lung tumors in response tocircadian disruption.In Aim 1 of this project we will use genetic deletion of Hsf1 either throughout the animal or exclusively withintumors to investigate its role in increased tumorigenesis caused by circadian disruption in KrasLSLG12D mice(a.k.a. Krastm4TyJ). In Aim 2 of this project we will use a combination of bulk RNA sequencing digital cytometrydetection of differential rhythmicity and location-barcoded sequencing of tumor-bearing lung sections to revealadditional molecular mechanisms that could contribute to enhanced tumorigenesis in response toenvironmental disruption of circadian rhythms. 537153 +No NIH Category available Animals;Binding;Biological Markers;Biological Process;Blood Circulation;Blood Vessels;Body Fluids;Calibration;Cancer Detection;Cancerous;Cells;Clinical;Collection;Detection;Development;Diagnostic;Diagnostic Neoplasm Staging;Diagnostic tests;Disease;Disease Progression;Engineering;Exposure to;Extracellular Fluid;Extracellular Space;Genetically Engineered Mouse;Health;Image;In Vitro;Investigation;Label;Luciferases;Malignant Neoplasms;Membrane;Methods;Modeling;Molecular Profiling;Monitor;Mus;Mutation;Normal Cell;Normal tissue morphology;Oncogenes;Organ;Pancreas;Pancreatic Ductal Adenocarcinoma;Physiological;Preparation;Procedures;Proteins;Proteomics;Reproducibility;Research;Retrieval;Role;Sampling;Sensitivity and Specificity;Signal Transduction;Source;Standardization;Structure;Surface;Survival Rate;System;Techniques;Testing;Tissues;Transgenic Mice;Tumor Burden;Tumor-Derived;Vascularization;Visualization;Work;analytical tool;cancer biomarkers;cancer cell;cancer diagnosis;cell transformation;cell type;cellular engineering;clinical application;clinical diagnostics;clinically relevant;comparative;design;diagnostic strategy;diagnostic tool;disease diagnostic;efficacy evaluation;extracellular vesicles;flexibility;in vitro Model;in vivo;innovation;intercellular communication;minimally invasive;mouse model;neoplastic;neoplastic cell;novel;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;prevent;prognostic;prognostic tool;single molecule;specific biomarkers;standard of care;tool;transcriptomics;treatment response;tumor;tumor progression;vesicular release;virtual A SYNTHETIC BIOMARKER TO UNIVERSALLY ASSESS THE RELATIVE CONTRIBUTION OF HEATHY AND CANCEROUS TISSUE TO CIRCULATING EV POOL PROJECT NARRATIVESince Extracellular Vesicles (EVs) are shed by virtually all cells into bodily fluids they are relatively easy tocollect and might be considered the ultimate source of biomarkers for disease diagnostics. However the clinicalutility of EVs is limited by a lack of reliable and reproducible methods to identify and evaluate EV-associatedbiomarkers. This proposal will utilize a flexible platform based on detection of an innovative EV-marker whichwill be combined with mouse models to rigorously validate the potential of EVs as biomarkers for the detectionand staging of cancer. NCI 10754958 11/29/23 0:00 PAR-20-053 5R01CA270251-02 5 R01 CA 270251 2 "YOUNG, MATTHEW R" 12/15/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 10264856 "COCUCCI, EMANUELE " Not Applicable 3 OTHER HEALTH PROFESSIONS 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF PHARMACY 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 390578 NCI 247986 142592 PROJECT SUMMARY / ABSTRACTExtracellular vesicles (EVs) are cell-derived membrane-bound structures released into extracellular spaces thatnavigate the bodily fluids and appear to support intercellular communication. Cancer cells release significantlyhigher numbers of EVs then their normal counterparts. Because the EV contents are derived from the cell oforigin molecular profiling of circulating EVs are being scrutinized as a non-invasive means for early cancerdiagnosis monitoring disease progression and assessing response to treatment. However EV-based clinicaldiagnostics have been limited by inadequate rigor and reproducibility of samples to specifically discriminateisolate and characterize normal and disease-associated EVs.Three analytical and conceptual challenges have prevented the identification of specific and reproducible EV-associated cancer biomarkers with clinical relevance: 1) no unbiased strategy has been developed to evaluatethe limits of cancer detection using EVs; 2) the relative contribution of healthy tissues to the pool of circulatingEVs is not known; and 3) a systematic analysis of the number and composition of circulating cancer-derived EVsduring tumor development has not been performed.These complications have prompted us to design a general platform capable of evaluating the contribution ofspecific tissues to the pool of circulating EVs in otherwise health animals compared to animals undergoing cancerdevelopment. The system is based on an engineered EV marker developed from the tetraspanin protein CD63(enCD63) which facilitates collection visualization and quantification of EVs released by specific cells andtissues.By restricting the expression of enCD63 to specific normal or neoplastic cells and tissues of geneticallyengineered mouse models we will unambiguously examine the efficacy of EVs as biomarkers. We propose touse our innovative platform to: 1) perform an unbiased calibration correlating the number of EVs with their cellsof origin (Aim 1); 2) define the relative contribution of healthy tissues to the pool of circulating EVs (Aim 2); and3) to assess the specificity and sensitivity of EVs in cancer detection (Aim 3).This application focuses on Pancreatic Ductal Adenocarcinoma (PDAC) a deadly neoplastic disease with lowsurvival rate that lacks specific and sensitive diagnostic tests. Completion of the proposed studies will contributeto the development of standardized procedures for the preparation selection and analysis of EV-basedbiomarkers. 390578 +No NIH Category available Adolescent;Adolescent and Young Adult;Adult;Age;Biological Markers;Cigarette;Clinical;Complement;Cotinine;Data;Data Reporting;Dimensions;Education;Electronic cigarette;Ethnic Origin;Future;Generations;Goals;Health;Health Policy;Heterogeneity;High Prevalence;High School Student;Individual;Investigation;Knowledge;Longitudinal Studies;Measurement;Measures;Modeling;Monitor;Nicotine;Nitrosamines;Outcome;Patient Self-Report;Pattern;Policies;Policy Maker;Population Assessment of Tobacco and Health;Prevalence;Prevention;Public Health;Race;Reporting;Research;Research Methodology;Risk;Risk Factors;Role;Sampling;Sex Differences;Sex Orientation;Statistical Methods;Surveys;Symptoms;Time;Tobacco;Tobacco Use Cessation;Tobacco Use Disorder;Tobacco use;Vulnerable Populations;Work;cigarette smoking;clinical practice;clinically relevant;cohort;effective intervention;electronic cigarette use;epidemiology study;experience;health data;health knowledge;high risk;improved;longitudinal analysis;nicotine use;physical conditioning;prospective;protective factors;secondary analysis;sex;social;sociodemographics;substance use;tobacco products;twelfth grade;young adult E-Cigarette Use among U.S. Adolescents and Young Adults: Longitudinal Associations with Tobacco Use and Health and Dimensions of Risk and Protection PROJECT NARRATIVEAlthough one in every three U.S. high school seniors used e-cigarettes in the past year the long-termtrajectories and consequences of e-cigarette use and longitudinal associations with other nicotine/tobaccouse tobacco cessation tobacco use disorder symptoms and other health consequences beyond 1-3 yearsremain largely unknown especially among vulnerable populations. This study will address these critical gaps inpublic health knowledge by improving estimates of e-cigarette use trajectories investigating the long-termhealth consequences associated with trajectories of e-cigarette use among adolescents and young adults andidentifying important risk and protective factors and subpopulations most vulnerable to e-cigarette use and itsconsequences. Findings from the proposed longitudinal study will be widely disseminated to help guide clinicalpractice inform public health policies and enhance future longitudinal research to reduce tobacco-relatedharms. NCI 10754952 11/10/23 0:00 PA-20-185 5R01CA270546-02 5 R01 CA 270546 2 "RODITIS, MARIA LEIA" 12/15/22 0:00 11/30/25 0:00 Addiction Risks and Mechanisms Study Section[ARM] 11885269 "EVANS-POLCE, REBECCA J" Not Applicable 6 NONE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI GRADUATE SCHOOLS 481091276 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 320831 NCI 214904 105927 PROJECT SUMMARY/ABSTRACTOne-third of U.S. adolescents and young adults (AYAs) report e-cigarette (EC) use making it the leadingnicotine/tobacco product used by AYAs. Most longitudinal studies of e-cigarette use only focus on short-termoutcomes 1-3 years later do not fully examine newer vs. older generation e-cigarette products and do notconsider potential differences by sex age race/ethnicity educational attainment or sexual orientation.Potential bias in e-cigarette estimates over time is not well understood. These gaps warrant longer-termprospective investigations with clinically relevant measures in diverse national samples of AYAs. This projectwill identify longitudinal trajectories of e-cigarette use and their relationships with cigarette smoking othernicotine/tobacco products other substance use tobacco use disorder (TUD) symptoms nicotine/tobaccocessation and health consequences related to nicotine/tobacco use among U.S. AYAs. Our study aims to: (1)Compare state-of-the-art statistical approaches for reducing nonresponse bias in estimates of trajectories andsurvival models for EC use due to differential attrition and evaluate the reporting bias associated with self-reports of EC use using biomarker data; (2) Examine the initiation of e-cigarette use and transitions with othernicotine/tobacco product use and other substance use in AYAs over 4- and 7-year time periods of longitudinaldata; (3) Identify the trajectories of EC cigarette and other tobacco use and their longitudinal relationshipswith adverse health consequences (e.g. TUD symptoms health problems) measured with survey andbiomarker data in AYAs over 4- and 7-year time periods and determine if trajectories or consequences differby age sex race/ethnicity education sexual orientation or newer vs. older e-cigarette products; and (4)Based on the Social Ecological Model assess multiple levels of risk and protective factors (and interactionsacross levels) for EC use trajectories and their associations with other nicotine/tobacco use tobacco cessationand health consequences over 4- and 7-year time periods and examine if EC use trajectories and theirassociations with other nicotine/tobacco use tobacco cessation and health consequences differ by age sexrace/ethnicity education sexual orientation or newer vs. older EC products. An experienced team will conductsecondary analyses of longitudinal data from the Monitoring the Future (MTF) and Population Assessment ofTobacco and Health (PATH) studies. These two epidemiological studies are the most recent and largestnationally representative longitudinal studies that allow for the identification of long-term trajectories andconsequences of EC use among AYAs. This project will use longitudinal data from a nationally representativesample of 9800 secondary students measured between 2014 and 2020 in the MTF study and a prospectivenationally representative sample of 13651 adolescents (12-17 years) 9802 young adults (18-25 years) and22506 adults (26 and older) measured across six waves in the PATH study (2013/2014-2020). 320831 +No NIH Category available 21 year old;Acute Myelocytic Leukemia;Adult;Adult Acute Myeloblastic Leukemia;Age;Ara-C;Azacitidine;Biological;Biology;CRISPR/Cas technology;Cell Line;Characteristics;Childhood;Childhood Acute Myeloid Leukemia;Childhood Leukemia;Classification;Clinical;Clinical Data;Clinical Trials;Collaborations;Collection;Creatinine;Custom;Cytarabine;DNA Sequence Alteration;DNMT3B gene;Data;Daunorubicin;Decitabine;Development;Diagnosis;Diagnostic;Elderly;Enrollment;Environment;Etoposide;Evaluation;Exposure to;Florida;Genome;Genomics;Glucose;Guidelines;Knock-out;Leukemic Cell;Malignant Neoplasms;Methods;Methylation;Molecular;Molecular Disease;Multi-Institutional Clinical Trial;Multiomic Data;Mutation;Outcome;Pathway interactions;Patient risk;Patients;Pediatric Oncology Group;Pediatric cohort;Pharmaceutical Preparations;Pharmacology;Phosphotransferases;Positioning Attribute;Procedures;Prognosis;Prognostic Factor;Prognostic Marker;Proteins;Proteome;Proteomics;Qualifying;Randomized;Rare Diseases;Recommendation;Recurrence;Reporting;Research;Research Personnel;Risk;Saint Jude Children's Research Hospital;Sample Size;Sampling;Series;System;Systems Biology;Therapeutic Intervention;Translating;Translational Research;Transplantation;Universities;Work;acute myeloid leukemia cell;amino acid metabolism;cancer genomics;chemotherapy;clinical prognosis;clinical translation;clinically relevant;cohort;demethylation;effective therapy;epigenomics;genome wide methylation;improved;innovation;meetings;metabolome;metabolomics;methylome;methylomics;novel;novel therapeutics;pharmacologic;prognostic;repository;risk stratification;screening;success;transcriptome;transcriptomics Integrated Systems Biology of Pediatric AML Relevance Statement:Acute myeloid leukemia (AML) is the second most common childhood leukemia and has a dismal prognosis. For over 40years AML chemotherapy has changed little with the continued reliance on ara-C daunorubicin and etoposide asfrontline agents. The proposed research seeks to define the impact of proteomic and metabolomics landscape ofleukemic cells on patient risk stratification and revealing additional layers of the molecular basis of AML prognosisto guide the development of more effective treatments for AML. NCI 10754933 11/15/23 0:00 PA-20-185 5R01CA270120-02 5 R01 CA 270120 2 "AGRAWAL, LOKESH" 12/15/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 8666845 "LAMBA, JATINDER K." "POUNDS, STANLEY BARRETT" 3 PHARMACOLOGY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF PHARMACY 326115500 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 602894 NCI 501794 101100 ABSTRACT: Acute myeloid leukemia (AML) is a rare devastating and understudied malignancy with ~2000 new casesand around 61000 cases in US. Though intensive chemotherapy primarily consisting of ara C (also known as cytarabine)daunorubicin and etopside have been used to treat AML for over 4 decades only 65% 40% and 10% of pediatric (age<21) adult (age 21-65) and elderly (age > 65) patients survive 5 years after diagnosis respectively. Application co-PIsDrs. Lamba (pharmacology) and Pounds (biostatistician specializing in cancer genomics) have successfully collaboratedfor over a decade to develop methods and discover molecular prognostic factors for AML. We and other investigators fromChildrens Oncology group have recently characterized the genome methylome and transcriptome of pediatric AML andassociated each of these with prognosis in pediatric AML. Dr. Pounds developed the innovative integrative analysisprocedure canonical correlation with projection onto the most interesting statistical evidence (CC-PROMISE) thatdramatically increases statistical power for meaningful biological discovery in a rare-disease small sample size setting;using CC-PROMISE we discovered that reduced methylation and increased expression of the DNMT3B associates withgreater genome-wide methylation burden and worse prognosis; translating the DNMT3B discovery into evaluation ofdemethylating agents in the ongoing AML16 clinical trial (NCT03164057). These genomic epigenomic and transcriptomicfeatures along with microenvironmental and other factors must impact the proteome and metabolome of AML in clinicallyrelevant ways which unfortunately are not well understood. There has been essentially no study focused on comprehensiveevaluation of the proteome and metabolome of pediatric AML in a reasonable cohort of uniformly treated patients. Notingthe marked genomic transcriptomic methylomic and prognostic differences between pediatric and adult AML it is notplausible to extrapolate finding from adult AML patients to pediatric. Thus an integrated systems-level understanding ofthe molecular disease biology is needed to develop effective strategies and improve the prognosis of pediatric AML. Aspioneers in the collection and integrated analysis of the pediatric AML genome methylome and transcriptomeapplication co-PIs Drs. Lamba and Pounds are uniquely positioned to characterize the proteome and metabolomeof pediatric AML and integrate them with our large repository of previously collected molecular treatment andoutcome data for a series of multi-center clinical trials. Thus in this application we propose to characterize globalmetabolome (aim 1) and proteome (aim 2) the leukemic cell obtained at diagnosis for risk stratification and prognosis byevaluating impact on outcome in three St Jude led multi-institute clinical trials (AML02 AML08 and AML16 total patientsn=400). In aim 3 we plan to develop a comprehensive integrated view of the genome methylome transcriptomeproteome metabolome and clinical prognosis of pediatric AML using novel methods. These innovative andexceptionally rigorous studies will be the first comprehensive evaluation of the pediatric AML metabolome and proteomeand develop an innovative integrated analysis method to perform the first integrated analysis of five forms of omic data withmultiple clinical endpoints to obtain the most complete understanding of pediatric AML systems biology to date. 602894 +No NIH Category available Address;Adoption;Affect;Appearance;Attention;Body Image;Cancer Intervention;Cancer Survivor;Cancer Survivorship;Caring;Chronic;Cognitive Therapy;Compassion;Consensus;Coping Skills;Data;Deglutition;Disease Management;Distress;Dose;Effectiveness;Elements;Empathy;Evaluation;Future;General Population;Head Cancer;Head and Neck Cancer;Image;Impairment;Intervention;Interview;Life;Manuals;Measures;Mediating;Mediator;Mental Depression;Methods;Modeling;Morbidity - disease rate;Neck Cancer;Oncology;Population;Psychosocial Assessment and Care;Psychotherapy;Quality of life;Randomized;Randomized Controlled Trials;Site;Site Visit;Smiling;Social Well-Being;Social isolation;Source;Structure;Supportive care;Surveys;Therapeutic;Therapeutic Intervention;Time;Transact;Treatment Efficacy;arm;attentional control;cancer therapy;clinical care;clinical practice;clinically significant;coping;effective therapy;efficacy evaluation;efficacy testing;evidence base;expectation;follow-up;functional disability;improved;novel;post intervention;primary endpoint;psychologic;psychosocial;routine care;suicide mortality;theories;treatment strategy A Randomized Controlled Trial to Evaluate a Novel Treatment Strategy for Body Image-Related Distress Among Head and Neck Cancer Survivors PROJECT NARRATIVEHead and neck cancer survivors suffer high rates of body image-related distress which results in significantpsychosocial morbidity and decreased quality of life. However effective therapies to manage this disorder amonghead and neck cancer survivors are lacking. We have developed a novel scalable tele-cognitive behavioraltherapy intervention for head and neck cancer survivors with body image-related distress that could provide thefirst effective treatment in this population thereby minimizing psychosocial morbidity improving quality of lifeand developing new standards of clinical care. NCI 10754928 11/14/23 0:00 PAR-21-035 5R37CA269385-02 5 R37 CA 269385 2 "NELSON, WENDY" 12/15/22 0:00 11/30/27 0:00 Lifestyle Change and Behavioral Health Study Section[LCBH] 14865589 "GRABOYES, EVAN MICHAEL" Not Applicable 6 OTOLARYNGOLOGY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 568482 NCI 464915 103567 PROJECT SUMMARY/ABSTRACTThis R01 proposal aims to test the efficacy of a tele-cognitive behavioral therapy (CBT) intervention as a noveltreatment paradigm for body image-related distress (BID) among head and neck cancer (HNC) survivorsexamine its underlying mechanism of change and characterize factors affecting its future adoption into clinicalpractice. Treatment of HNC results in substantial life-altering morbidity related to disfigurement challengesspeaking and difficulty swallowing. As a result 75% of HNC survivors express body image concerns and 28%meet criteria for BID. BID is a source of devastating psychosocial morbidity as HNC survivors with BID have asix-fold increase in depression high rates of social isolation decreased quality of life (QOL) and a 2-fold higherrate of suicide mortality relative to other cancer survivors. To date evidence-based strategies to manage HNC-related BID are lacking. To address this gap we developed BRIGHT (Building a Renewed ImaGe after Head &neck cancer Treatment) a 5-session manualized tele-CBT intervention based on a transactional coping modelof HNC-related BID. Findings from our single-arm and pilot randomized controlled trial (RCT) showed thatBRIGHT was feasible acceptable and resulted in a statistically and clinically significant reduction in BID relativeto dose- and delivery-matched controls at 1- and 3-month follow-up. Our preliminary data suggest that BRIGHTreduces HNC-related BID by enhancing adaptive body image coping skills (reducing avoidance increasingpositive rational acceptance [i.e. rational appearance related self-talk]). Based on these promising preliminaryefficacy and mechanistic data we propose a multi-site RCT in which HNC survivors with clinically significant BID(N=180) will be randomized to BRIGHT or attention control (AC) a manualized tele-supportive care interventionthat controls for time professional attention and common factors. HNC survivors will complete measures ofHNC-related BID psychological and social well-being QOL and measures of theory-derived mechanisms ofchange underlying CBT. We will conduct semi-structured interviews and in-depth site visits to develop animplementation toolkit to enhance the adoption of BRIGHT into clinical care. Specific Aim 1 will evaluate theefficacy of BRIGHT relative to AC on (a) HNC-related BID and (b) psychological and social well-being and QOL.Specific Aim 2 will examine the mechanism of change underlying BRIGHT for HNC-related BID. Specific Aim3 will characterize key determinants that will affect the future adoption of BRIGHT into routine clinical practice.Findings from our study may support BRIGHT as the first evidence-based strategy to manage BID among HNCsurvivors thereby developing new standards of care and improving psychosocial morbidity and QOL in thispopulation. Theory-driven mechanism of change data may help identify specific therapeutic elements to optimizethe effectiveness of CBT for BID as well as advance our understanding of the underlying theory of CBT. Finallyfindings may enhance the implementation of psychosocial interventions for cancer survivors in diverse settings. 568482 +No NIH Category available 3-Dimensional;Accounting;Adhesions;Affect;Architecture;Binding;Biological Assay;Biopsy;Breast Cancer Detection;C-terminal;CDH1 gene;Cadherins;Calcium;Carcinogenicity Tests;Cell membrane;Cell physiology;Cells;Clinical Management;Clinical Research;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Collection;Cytoplasmic Tail;Data;Development;Diffuse;Diffuse gastric cancer;Dysplasia;E-Cadherin;Enrollment;Event;Family;Family history of;Family member;Gastric Tissue;Generations;Genes;Genotype;Germ-Line Mutation;Goals;Heritability;Histology;Homeostasis;Individual;Inherited;Laboratories;Lobular;Malignant Neoplasms;Mediating;Medical;Medical History;Modeling;Molecular;Morphology;N-terminal;Organoids;Participant;Pathogenicity;Patients;Penetrance;Penetrance analysis;Phenotype;Proliferation Marker;Proteins;Recording of previous events;Regulation;Reporting;Risk;Risk Estimate;Risk Management;Serial Passage;Syndrome;TP53 gene;Time;Tissues;Tumor Markers;Uncertainty;Variant;Work;cancer risk;cohort;data collection methodology;gastric organoids;gastric tumorigenesis;genetic panel test;genetic pedigree;genomic profiles;improved;indexing;loss of function;malignant breast neoplasm;malignant stomach neoplasm;prospective;protein function;recruit;risk variant;screening;tool;tumor progression;tumorigenic;variant detection Defining the phenotype and cancer penetrance of CTNNA1 loss-of-function germline variants PROJECT NARRATIVEHereditary loss-of-function variants in the CTNNA1 gene may be associated with increased risk of gastric and/orbreast cancer however the breadth and magnitude of the cancer risks associated with this gene remain poorlyunderstood. This study will define the cancer penetrance in CTNNA1 loss-of-function variant carriers and willdevelop laboratory assays to further refine these cancer risks in a variant-specific manner. The combined resultsfrom this work will enable variant-specific CTNNA1 cancer risk determination which will lay importantgroundwork to allow for appropriate clinical management of cancer risk in CTNNA1 loss-of-function variantcarriers as well as their family members. NCI 10754926 11/30/23 0:00 PAR-20-292 5R21CA267949-02 5 R21 CA 267949 2 "UMAR, ASAD" 12/15/22 0:00 11/30/24 0:00 ZCA1-SRB-X(O1)S 11486226 "KATONA, BRYSON WILLIAM" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 209957 NCI 129204 80753 PROJECT SUMMARYHereditary diffuse gastric cancer syndrome (HDGC) is a hereditary condition associated with increased risk ofdiffuse gastric cancer and lobular breast cancer. While HDGC is classically caused by germline mutations in theCDH1 gene recent evidence has identified the CTNNA1 gene coding for -E-catenin as a new putative HDGCrisk gene. We previously showed that 12% and 67% of individuals with a CTNNA1 loss-of-function (LOF) variantidentified on multigene panel testing had a personal history of diffuse gastric cancer or breast cancerrespectively. However given limitations of previously collected data the extent and magnitude of the cancerrisks associated with LOF variants in CTNNA1 remain uncertain at this time. Elucidating accurate cancer riskestimates for CTNNA1 LOF variant carriers is critical to allow for proper cancer risk management of this affectedcohort as well as their family members. Our preliminary data demonstrates that CTNNA1 LOF variant carrierscan be successfully recruited as study participants enabling collection of detailed personal and family historywith creation of three-generation pedigrees that can be used for cancer penetrance analyses. Furthermore weshow that CTNNA1 LOF variant carriers may have differing variant-specific cancer risks with potentially reducedgastric cancer risk associated with C-terminal LOF variants. Finally we demonstrate that patient-derived gastricorganoids including from CTNNA1 LOF variant carriers can be successfully established. Taken together wehypothesize that CTNNA1 LOF variant-specific cancer risks can be established through a combinationof improved cancer penetrance estimates and patient-derived gastric organoid models. We willinvestigate this hypothesis by first defining the cancer penetrance of CTNNA1 LOF variant carriers through theprospective CTNNA1 Family Expansion (CAF) Study enabling collection of detailed personal and familymedical history with subsequent creation of three-generation pedigrees that will be utilized for cancerpenetrance analysis. Secondly we will determine CTNNA1 variant-specific gastric tumorigenesis using patient-derived gastric organoids which are invaluable tools for recapitulating gastric cancer development. We willutilize these patient-derived gastric organoids to test the carcinogenic potential of different CTNNA1 LOFvariants. Together the study results from this proposal will be critical for establishing variant-specific cancerrisks for CTNNA1 LOF variants which will ultimately help inform cancer risk management decisions for theseaffected patients and their families. 209957 +No NIH Category available Acceleration;Acquired Immunodeficiency Syndrome;Acute;Affect;Africa South of the Sahara;Age;Age Years;Aging;Biological;Biological Aging;Biological Assay;Biological Clocks;Biological Factors;Biological Markers;Blood;Cancer Center;Cancer Etiology;Cancer Patient;Cells;Cervical Cancer Screening;Chemotherapy and/or radiation;Chronic;Chronology;Clinical;Clinical Data;Clinical Research;Collaborations;DNA;DNA Methylation;DNA analysis;Data;Diagnosis;Disease;Disparity;Elderly;Epidemiology;Epigenetic Process;Flow Cytometry;Future;Geographic Locations;HIV;HIV Infections;HIV Seronegativity;HIV Seropositivity;Hematology;Hospitals;Human Papillomavirus;Immune;Immune Evasion;Immune System Diseases;Immunity;Immunologics;Immunology;Immunosuppression;Incidence;Income;Individual;Inferior;Knowledge;Life Expectancy;Link;Location;Longevity;Maintenance;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measurable;Measures;Mediating;Morbidity - disease rate;Oncogenic;Oncology;Outcome;Patients;Peripheral Blood Mononuclear Cell;Persons;Phenotype;Play;Population;Premature aging syndrome;Prevalence;Process;Radiation Oncology;Recurrence;Regimen;Relapse;Resistance;Role;Sampling;Site;Swab;T-Lymphocyte;Testing;Time;Toxic effect;Translating;Translational Research;Treatment outcome;Treatment-related toxicity;Tumor-infiltrating immune cells;United States;Virus Diseases;Whole Blood;Woman;Work;Zambia;aged;aging population;antiretroviral therapy;bead chip;cancer diagnosis;cancer health disparity;cancer therapy;chemoradiation;clinically relevant;comorbidity;exhaust;health disparity;immune function;low and middle-income countries;methylation pattern;methylome;mortality;mortality risk;multidisciplinary;novel therapeutics;older women;outcome disparities;peripheral blood;receptor;response;side effect;socioeconomics;standard of care;tumor;tumor progression;tumorigenesis;underserved community;women of color The Impact of Biologic Aging on Immunity-Related Cervical Cancer Outcome Disparities Among Women Living with HIV in Zambia Project NarrativeHuman papillomavirus (HPV)-associated cervical cancer remains one of the leading causes of cancer mortalityin People Living with Human Immunodeficiency Virus ([HIV] PLWH) in underserved low- and middle-incomecountries. PLWH have evidence of premature aging which could contribute to cervical cancer progression andresponses to chemoradiation therapy (CRT). To identify potential biological biomarkers of aging the proposedproject will focus on measuring differences in epigenetic changes between HIV-positive vs HIV-negative cervicalcancer patients before and after CRT and correlating these changes with immunological phenotype for use infuture clinical studies. NCI 10754783 9/19/23 0:00 RFA-CA-22-056 1R01CA284623-01 1 R01 CA 284623 1 "LIDDELL HUPPI, REBECCA" 9/19/23 0:00 8/31/28 0:00 ZCA1-TCRB-D(M1) 9862098 "LIN, LILIE LEMING" "COGHILL, ANNA ; MSADABWE, SUSAN CITONJE" 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 666443 NCI 464198 202245 Project Summary/AbstractCervical cancer disproportionately affects women of color from low-socioeconomic geographical locations.Locations such as sub-Saharan Africa can also have a high incidence of Human Immunodeficiency Virus (HIV)infection and access to cervical cancer screening is generally limited for women living in these underservedcommunities. Furthermore People Living with Human Immunodeficiency Virus (PLWH) have evidence ofpremature aging which could contribute to cervical cancer progression and responses to chemoradiation therapy(CRT). CRT is the standard of care for locally advanced cervical cancer and older women (52 years of age)treated with CRT have worse side effects than younger (<52 years) women suggesting that advanced age mayinfluence clinical outcomes from CRT for cervical cancer. Many of the hallmarks of cancer includingtumorigenesis tumor maintenance therapy resistance and immune evasion are regulated by epigeneticchanges in DNA (e.g. DNA methylation). DNA methylation levels are correlated with (1) chronological clockswhich estimate the age of a sample/patient or (2) biological clocks a widely accepted measure of where anindividual is in their lifespan regardless of chronological age which can be reflective of disease morbidity andmortality risk. Indeed the biological age of PLWH (i.e. HIV-mediated epigenetic age) is advanced up to 20 yearsbeyond chronological age; however studies examining epigenetic aging in PLWH have not evaluated prematureaging in PLWH with cervical cancer nor the contribution if any of oncologic therapy on premature aging.Preliminary data comparing women living with HIV(WHIV) vs. HIV-negative cervical cancer patients indicate thatbiological aging defined using patterns of methylation that accumulate on host DNA over time was significantlyaccelerated in WHIV vs. HIV-negative cervical cancer patients and this accelerated aging was significantlyassociated with mortality after cancer diagnosis. The proposed study will test the hypothesis that a biomarker ofaging can be identified and will correlate with systemic and tumor immunologic phenotype and function that canbe used in the future to select WHIV and cervical cancer for novel therapeutic regimens. In Aim 1 differencesin DNA methylation will be compared between WHIV vs. HIV-negative patients with cervical cancer. Aim 2 willfocus on measuring systemic and tumor immune cell phenotype function and repertoire that will be correlatedwith biologic age at pre-CRT and 1 year post-CRT. Furthermore Aim 3 will focus on determining an associationof longitudinal (pre-CRT and 1-year post-CRT) biologic age changes with clinical outcomes. Results from theproposed work are expected to elucidate how oncologic treatment in the setting of immunosuppression due toHIV infection impacts the aging process and through detailed interrogation of immune cells to link aging tounderlying biological features that may exacerbate disparities in clinical outcomes observed in women living withHIV and cervical cancer. 666443 +No NIH Category available 3-Dimensional;Address;Algorithms;Artificial Intelligence;Benign;Big Data;Biometry;Biopsy;Breast;Breast Cancer Detection;California;Characteristics;Clinical;Code;Collaborations;Community Practice;Computer software;Computers;DNA Sequence Alteration;Data;Data Science;Data Set;Data Storage and Retrieval;Databases;Diagnosis;Diagnostic;Digital Breast Tomosynthesis;Digital Mammography;Equilibrium;Goals;Grant;Health;Human;Image;Imaging Device;Imaging technology;Institution;International;Lead;Link;Machine Learning;Malignant Neoplasms;Mammographic screening;Mammography;Medicine;Metadata;Methods;Modality;Modeling;Molecular;Nature;Oncology;Outcome;Output;Participant;Pathology;Performance;Population;Positioning Attribute;Publications;Radiology Specialty;Randomized Controlled Trials;Registries;Reverse engineering;Risk;Seminal;Series;Supervision;Techniques;Technology Assessment;Testing;Time;Training;Translating;Universities;Validation;Washington;Woman;algorithm development;algorithmic methodologies;artificial intelligence algorithm;augmented intelligence;breast imaging;clinical implementation;clinical risk;clinical translation;clinically relevant;clinically significant;cloud based;computer aided detection;crowdsourcing;deep learning;digital;experience;genetic risk factor;improved;industry partner;innovation;long short term memory;malignant breast neoplasm;molecular subtypes;mortality;multidisciplinary;novel;novel strategies;patient population;population based;prospective;radiologist;routine screening;screening;tool;tumor Artificial Intelligence for Improved Breast Cancer Screening Accuracy: External Validation Refinement and Clinical Translation PROJECT NARRATIVECurrent interpretation of screening mammography suffers from human limitations leading to approximately30000 missed cancers and 3.8 million false positives exams every year in the U.S. alone. Our multidisciplinaryteam of experts on breast cancer screening machine and deep learning data science and imagingtechnology assessment will validate our highly accurate 2D mammography artificial intelligence (AI) algorithmthat was the best performer in an international competition with >1200 participants and then further enhance itwith novel AI augmentation methods. We will then apply innovative techniques to scale the AI algorithm from2D to 3D mammography addressing the issue of a 50-to-100-fold increase in volumetric data with 3D examsand then clinically translate our optimized AI 3D mammography tool through a series of interpretive accuracystudies involving experienced and inexperienced radiologists from both academic and community practices. NCI 10754552 12/7/23 0:00 PAR-18-009 5R37CA240403-05 5 R37 CA 240403 5 "SALVADOR MORALES, CAROLINA" 1/1/20 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 11373261 "LEE, CHRISTOPH I" Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 471836 NCI 436919 34917 PROJECT SUMMARYScreening mammography saves lives but human interpretation alone is imperfect and is associated withsignificant harms including ~30000 missed breast cancers and ~3.8 million false-positives exams each yearin the U.S. alone. Traditional computer-aided detection failed to improve screening accuracy in part due tothe static nature of software trained and tested on small datasets decades ago. Recent advances in improvedcomputer processing power cloud-based data storage capabilities and availability of large imaging datasetshave led to renewed excitement for applying artificial intelligence (AI) to mammography interpretation.We propose a unique academic-industry partnership to validate refine scale and clinically translate ourproven 2D mammography AI algorithm to 3D mammography interpretation. Our team helped organize andlead the Dialogue for Reverse Engineering Assessments and Methods (DREAM) Digital MammographyChallenge an open crowdsourced AI algorithmic challenge that provided >640000 digital 2D mammogramimages and associated clinical metadata to >1200 coding teams worldwide. Our industry partner for thisgrant DeepHealth Inc. was the top performing team in the DREAM Challenge. With >50% of U.S. facilitiesnow offering 3D mammography for screening the 50-to-100-fold increase in imaging data represents a newcritical barrier for both radiologists and AI algorithm developers. To date there have been few publicationsaddressing AI-enhanced interpretation of 3D mammography the emerging screening exam of choice.We will validate our post-DREAM algorithm for 2D mammography (which currently rivals human interpretationalone) using UCLA's Athena Breast Health Network one of the largest population-based breast imagingregistries. We will enhance our 2D AI algorithm with expert radiologist supervision and examine the impact ofadding novel non-imaging data parameters including genetic mutation and tumor molecular subtype data tohelp train the AI model to identify more clinically significant cancers. We will use several novel technicalalgorithmic approaches to scale from 2D to 3D mammography which in our preliminary studies have shownimproved accuracy beyond radiologist interpretation alone. Finally we will perform a series of interpretivestudies to identify the optimal interface between black box outputs and radiologist interpreters whichremains an understudied topic. With >40 million U.S. women undergoing screening each year seeminglysmall improvements in overall accuracy would still imply significantly improved population-based outcomes.In summary we have assembled an unparalleled multidisciplinary team with expertise in machine/deeplearning breast cancer screening accuracy medicine oncology radiology imaging technology assessmentand biostatistics. We have a proven track record of strong collaboration and are well positioned to validateenhance scale and translate our proven 2D AI algorithm for improved 3D mammography accuracy. Our newend user tool will help tip the balance of routine screening towards greater benefits than harms. 471836 +No NIH Category available 3-Dimensional;Ablation;Binding;Biological Assay;Biological Markers;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer gene;CCND1 gene;Cell division;Cell physiology;Cells;Chemoresistance;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNA;Data;Disease;Dominant-Negative Mutation;Drug resistance;Enhancers;Epigenetic Process;Frequencies;Future;Gene Activation;Gene Expression;Genes;Genetic Transcription;Genome;Goals;Histones;Homeostasis;Hyperactivity;Individual;Kinetics;Knowledge;Maps;Mediating;Molecular;Molecular Conformation;Mutate;Neoplasm Metastasis;Oncogenic;Patients;Pharmaceutical Preparations;Population;Positioning Attribute;Process;Proteins;Proto-Oncogenes;Regulation;Regulator Genes;Research;Resistance;Resolution;Role;SP1 gene;Signal Transduction;Subgroup;Survival Rate;Technology;Testing;Therapeutic;Therapeutically Targetable;Tumor Promotion;Zinc Fingers;cancer genome;disease heterogeneity;disorder subtype;functional genomics;genome editing;genome-wide;improved;inhibitor;malignant breast neoplasm;notch protein;novel;programs;promoter;protein expression;secretase;success;targeted treatment;therapeutically effective;therapy resistant;transcription factor;triple-negative invasive breast carcinoma;tumor growth Notch-driven Epigenetic Program of MYC and CCND1 in Triple-Negative Breast Cancer Project NarrativeFrequently mutated or hyperactivated Notch receptors dysregulate transcription of genes with key functions intriple-negative breast cancer (TNBC) a heterogenous disease lacking targetable therapeutic options. Myresearch elucidates precise epigenetic mechanisms by which Notch transcription complexes regulate their TNBCtarget genes. This mechanistic knowledge constitutes an important step toward selective epigenetic targeting offunctionally important but undruggable genes such as MYC CCND1 and SOX9 in the Notch-addicted TNBC.! NCI 10754544 11/30/23 0:00 PA-19-056 5R01CA230800-05 5 R01 CA 230800 5 "FINGERMAN, IAN M" 12/1/19 0:00 11/30/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 12159130 "FARYABI, ROBERT BABAK" Not Applicable 3 PATHOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 373497 NCI 232887 140610 Project SummaryTriple-negative breast cancer (TNBC) accounts for ~10% of all the breast cancer cases but its survival rate islower due to the lack of effective targeted treatments. This underscores the importance of finding newtreatments for therapy-resistant TNBC which is further complicated by the disease heterogeneity.Unfortunately success of targeted therapies in TNBC has been limited partly due to the lack of a detailed andmechanistic understanding of the drivers of each disease subgroup. An important contributor to the TNBCpathobiology is Notch signaling. Hyperactive Notch signaling promotes tumor growth increases chemotherapyresistance decreases survival and increases the chance of metastases. Although the biomarkers of theNotch-active TNBC subgroup and drugs to target Notch signaling have been recently developed treatingpatients with Notch inhibitory agents has been ineffective to date partly due to the limited understanding ofhow the Notch signaling controls these fundamental processes. An important direct consequence of Notch signaling is to activate key TNBC genes including MYCCCND1 and SOX9. MYC is one of the most important proto-oncogenes promoting tumor growth and survival.CCND1 controls cell division among other cellular processes. SOX9 increases metastatic potential. Despitetheir importance existing drugs fail to directly target these proteins. We propose to leverage the regulatoryrelationships between Notch and its target genes to selectively and efficiently target them. In order to achievethis goal we first need to understand the mechanisms by which Notch regulates MYC CCND1 and SOX9 inTNBC. We propose to use cutting-edge functional genomics and chromatin conformation assays to elucidatetheir Notch-directed regulatory mechanisms at population and single-cell resolutions. To develop more potenttherapeutic options we plan to use the latest single-cell resolution technologies to discover how drug-resistantcells circumvent the effect of Notch inhibitory drugs and maintain the expression of these critical Notch targets.We plan to use this knowledge in the future to tailor therapeutic strategies for individual TNBC patients withactivated Notch signaling and in the process hope to improve the survival of patients with this aggressive anddifficult to treat form of breast cancer.! 373497 +No NIH Category available Adult;Binding;Biochemical;Biological Assay;Cell Count;Cell Density;Cell Hypoxia;Cell Survival;Cells;Cellular Metabolic Process;Chemicals;Clinical Research;Colon;Colorectal Cancer;Consumption;Data;Development;Dietary Factors;Dose;Drug Design;Drug Targeting;Eating;Ensure;Enzyme Kinetics;Enzymes;Exposure to;Food;Fructose;Future;Gene Activation;Generations;Genes;Genetic;Genetic Models;Glucose;Goals;Growth;Human;Hypoxia;Incidence;Ingestion;Intake;Intestines;Isoenzymes;Isotopes;Ketohexokinase;Kinetics;Link;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mediator;Metabolic;Metabolic syndrome;Metabolism;Modality;Modeling;Molecular;Mus;Mutation;Nutrient;Obesity;Oral;Organ;Organoids;Oxygen;Patients;Physiology;Placebos;Play;Process;Prospective cohort study;Protein Biochemistry;Protein Isoforms;Proteins;Public Health;Publications;Pyruvate Kinase;Recombinant Proteins;Recombinants;Role;Science;Structure;Sucrose;Testing;Time;Tracer;Transactivation;Tumor Promotion;Variant;Woman;cancer cell;clinical development;colon cancer cell line;colorectal cancer progression;colorectal cancer risk;combat;cost;dietary;experimental study;fructose-1-phosphate;hypoxia inducible factor 1;improved;inhibitor;intestinal adenoma;men;metabolomics;microbiota;middle age;mortality;mouse model;mutant;new therapeutic target;novel therapeutics;pharmacologic;pre-clinical;programs;small molecule;sugar;tumor;tumor growth;tumor metabolism Molecular Mechanisms of Fructose-induced Colorectal Cancer Cell Survival Project NarrativeColorectal cancer (CRC) is the third most common cancer in men and the second in women with a worldwidetotal of over 1.8 million new cases per year. Dietary factors play an important role in CRC because thesetumors develop adjacent to the intestinal lumen and receive direct exposure to ingested nutrients chemicalsand microbiota throughout the day. Fructose consumption is associated with CRC risk and CRC-specificmortality so this proposal will test how the major fructose metabolite fructose 1-phosphate alters cellularmetabolism to promote tumor cell survival. NCI 10754511 12/15/23 0:00 PA-20-185 5R01CA258697-03 5 R01 CA 258697 3 "KUMAR, AMIT" 1/10/22 0:00 12/31/26 0:00 Cancer Prevention Study Section[CPSS] 8791247 "GONCALVES, MARCUS DASILVA" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 552192 NCI 335226 216966 Project SummaryClear associations have been established between the food we eat and the development and progression ofcolorectal cancer (CRC). For example the consumption of fructose increases the risk for CRC developmentand CRC-specific mortality. However the mechanism underlying this association is unknown. We have shownthat moderate daily exposure to oral high fructose corn syrup (HFCS a mix of fructose and glucose) leads tolarger and more aggressive intestinal adenomas in mice. These effects were absent in mice with geneticdeficiency of ketohexokinase (KHK) the enzyme that converts fructose to fructose 1-phosphate (F1P). Ametabolomic analysis of these tumors showed that F1P is highly abundant following HFCS exposure and thisincrease correlates with a reduction in pyruvate kinase (PK) activity. Therefore we hypothesize that F1P theproduct of KHK enhances tumor growth by acting as an allosteric inhibitor of PK to promote anabolicmetabolism and cell survival. We will test this hypothesis using mouse physiology and organ metabolism celland human organoid culture and recombinant protein biochemistry. In Aim 1 we will genetically andpharmacologically manipulate the M2 isozyme of PK (PKM2) in mice to interrogate its role as a mediator ofHFCS-induced tumor growth. In Aim 2 we will define the mechanistic linkage between fructose exposure andcancer cell survival. We have found that cells in culture do not grow faster when exposed to fructose howeverwe observed a significant improvement in cell viability especially under conditions of high cell density andhypoxia with fructose in the media. Therefore we hypothesize that F1P inhibits PKM2 to promote hypoxic cellsurvival. We will test this hypothesis using cell and organoid culture models exposed to fructose and hypoxia.We will genetically and pharmacologically manipulate KHK and PKM2 expression and activity in these modelsto determine the specific effects of these proteins on cell metabolism and survival. In Aim 3 we will assess theeffects of F1P on recombinant PK isoforms with a particular focus on PKM2. We hypothesize that fructose-derived F1P binds to and inhibits PKM2. We will perform biochemical activity and structural assays todetermine the kinetic parameters and oligomeric state of PK isoforms in the presence of F1P. Theseexperiments will reveal the molecular mechanisms of how F1P binds and inhibits PKM2. Together these aimswill change our fundamental understanding of how fructose alters tumor cell metabolism define thefructose/F1P/PKM2 axis as a metabolic vulnerability of CRC and provide pre-clinical evidence for PKM2activators as a novel therapeutic modality to combat CRC. 552192 +No NIH Category available Biological Markers;Cancer Research Network;Funding;Image;Progress Reports;Quality of life;Reporting;Southwest Oncology Group;programs SWOG BIQSFP Projects GY10 This is a supplement application for Biomarker Imaging and Quality of Life Studies FundingProgram (BIQSFP) funding for the following SWOG Cancer Research Network studies: S1608S1803 S1827 S2114 and S2212.Additionally this request contains the progress reports for the following additional studies:S1500 S1612 S1929 S1418 and S1826.The report for S1314 is a final progress report. NCI 10754459 5/16/23 0:00 PA-20-272 3U10CA180888-10S1 3 U10 CA 180888 10 S1 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 ZCA1(O1) 6765159 "BLANKE, CHARLES D." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Other Research-Related 2023 1336498 NCI 1090765 245733 This is a supplement application for Biomarker Imaging and Quality of Life Studies FundingProgram (BIQSFP) funding for the following SWOG Cancer Research Network studies:S1608 S1803 S1827 S2114 and S2212.Additionally this request contains the progress reports for the following additional studies:S1500 S1612 S1929 S1418 and S1826.The report for S1314 is a final progress report. 1336498 +No NIH Category available Ablation;Antineoplastic Agents;Automobile Driving;Binding;Biochemical;Biological Assay;CRISPR/Cas technology;Cell Fractionation;Clinical;Cultured Cells;Data;Data Set;Dependence;Disease;Drug Targeting;Enhancers;Future;Genes;Genetic;Genetically Engineered Mouse;Genotype;Goals;Grant;Homeostasis;Human;Immunotherapy;K-ras mouse model;KRAS oncogenesis;KRAS2 gene;Label;Libraries;Lipids;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator;Membrane;Mining;Mutate;Mutation;Nature;Oncogenes;Oncogenic;Oncoproteins;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pancreas;Pathway interactions;Pentosephosphate Pathway;Pharmaceutical Preparations;Phase;Phosphatidylinositol Phosphates;Phosphatidylinositols;Phosphotransferases;Prevalence;Process;Protein Isoforms;Proteins;RAS driven cancer;RAS genes;RAS inhibition;Ras Inhibitor;Research;Research Personnel;Role;Signal Transduction;Signaling Protein;Stress;Systems Biology;Techniques;Testing;Therapeutic;Training;Validation;Xenograft procedure;cancer cell;cell growth;cell transformation;experimental study;inhibitor;inorganic phosphate;mouse model;mutant;new therapeutic target;novel;novel therapeutics;pancreatic cancer model;pharmacologic;phosphoproteomics;ras Oncogene;ras Proteins;response;small molecule inhibitor;therapeutic target;tumor growth;tumor xenograft;tumorigenesis;tumorigenic Interrogating the RAS interactome for therapeutic vulnerabilities Project NarrativeThe RAS genes are mutated in a third of human cancers in the USA including in some of the most intractablecancers like pancreatic. Despite this prominence the encoded oncoproteins are extremely difficult topharmacologically target. I therefore propose to identify the proteins RAS oncoproteins interact with to drivetumorigenesis as a way to unveil potential new drug targets to treat a huge proportion of human cancers. NCI 10754299 12/22/23 0:00 PA-19-130 5R00CA248495-04 5 R00 CA 248495 4 "XU, WANPING" 3/10/20 0:00 12/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 14158826 "ADHIKARI, HEMA " Not Applicable 1 BIOCHEMISTRY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 224100 NCI 144116 79984 PROJECT SUMMARY AND ABSTRACTThe RAS genes KRAS NRAS or HRAS are commonly mutated in human cancers. Clinicallyinhibiting RAS has proven challenging and RAS-mutant cancers remain some of the mostintractable diseases even to immunotherapies. It is thus critical to elucidate oncogenic RASsignaling not only to better understand the tumorigenic process but also to identify new potentialtherapeutic targets. To this end I exploited the novel technique of BirA-mediated proximitylabeling to identify proteins within the immediate vicinity (interactome) of each RAS isoform. I thenscreened an sgRNA library targeting interactome components for genes promoting RAStransformed cell growth identifying the druggable phosphatidylinositol phosphate lipid kinasePIP5K1A as specifically driving KRAS oncogenesis. PIP5K1A represents an entirely newtherapeutic target in KRAS-mutant cancers and suggests that other proteins in the RASinteractome may similarly mediate RAS oncogenesis. I will capitalized on these discoveries inthree aims. As PIP5K1A is a druggable kinase it provides a way to specifically inhibit KRASoncogenesis which could be exploited to enhance the antineoplastic activity of drugs targetingRAS effector pathways. Thus in aim 1 I will elucidate the role and therapeutic potential oftargeting PIP5K1A in KRAS-mutant cancers. The identification of PIP5K1A promoting KRASoncogenesis suggests that other interactome proteins may similarly mediate RAS function. Thusin aim 2 I will mine the RAS interactome for novel modifiers of RAS oncogenesis focusing on theinteractome protein EFR3A as a potential general mediator of oncogenic RAS-driventumorigenesis. Finally the RAS interactome is most certainly dynamic varying under differentconditions. Determining the content of the RAS interactome under distinct settings may thusidentify new vulnerabilities specific to diverse cellular conditions. Thus in aim 3 I will probe theRAS interactome in response to cellular perturbations. In sum I will expand upon my discoverythat PIP5K1A promotes KRAS oncogenesis to explore this kinase as a new therapeutic target andidentify other novel therapeutic vulnerabilities that exists within the RAS interactome. The K99segment of this grant will complete my training in RAS signal transduction extend my traininginto phosphoproteomics xenograft and genetically engineered mouse models of tumorigenesis.The R00 segment will capitalize on the use of proximity labeling to study the dynamicnature of oncogenic RAS signaling. My long-term goal is to transition into an independentinvestigator and apply systems biology approaches to uncover the signaling circuitry ofoncogene drivers with the objective of identifying novel therapeutic vulnerabilities in RAS-mutantcancers. 224100 +No NIH Category available ATAC-seq;Affect;Androgen Receptor;Androgen Response Element;Androgens;Benign;Binding;Biological Assay;Biotin;Bypass;Cell Survival;Cell physiology;Cessation of life;ChIP-seq;Chromatin;Clinical;Complex;DNA Binding;Development;Disease Progression;Environment;Event;Foundations;Funding;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Growth;Human;Impairment;Knowledge;Laboratories;Left;Ligands;Ligation;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Mass Spectrum Analysis;Mediating;Metastatic Prostate Cancer;Mission;Modality;Modeling;Molecular;Monomeric GTP-Binding Proteins;Nucleic Acid Regulatory Sequences;Oncogenes;Outcome;Output;Patients;Phenotype;Phosphorylation;Phosphotransferases;Prostate;Prostate Cancer therapy;Protein Analysis;Protein Kinase;Proteome;Public Health;RNA;Receptor Signaling;Regulation;Remission Induction;Research;Resistance;Role;Sampling;Serum Response Factor;Signal Pathway;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tissues;United States National Institutes of Health;Work;Xenograft procedure;androgen deprivation therapy;androgen sensitive;cancer survival;castration resistant prostate cancer;clinical application;clinically relevant;deprivation;improved;inhibitor;innovation;insight;knock-down;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;patient derived xenograft model;pharmacologic;prevent;prostate cancer cell;prostate cancer model;prostate cancer prevention;prostate cancer progression;receptor binding;recruit;response;response biomarker;targeted treatment;transcription factor;transcriptome;transcriptome sequencing;treatment strategy Toward Selective Androgen Deprivation by Targeting Androgen Activation of SRF PROJECT NARRATIVEThe proposed research is relevant to public health because insights into the specific molecular mechanismsby which androgens control prostate cancer (CaP) progression are ultimately expected to provide the foundationto develop novel treatment options that are tailored to the specific AR-dependent events that underlie the lethalphenotype of CaP a malignancy that causes more than 30000 deaths annually in the US. Thus the proposedresearch is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that willhelp reduce the burdens of human cancer. NCI 10754236 12/20/23 0:00 PA-19-056 5R01CA166440-11 5 R01 CA 166440 11 "HILDESHEIM, JEFFREY" 6/19/14 0:00 12/31/24 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10368792 "HEEMERS, HANNELORE " Not Applicable 11 OTHER BASIC SCIENCES 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 318384 NCI 201035 117349 Project summary/AbstractDespite the central role of androgen receptor (AR) in prostate cancer (CaP) progression insights into the specificmolecular mechanisms by which AR controls the cellular processes that drive CaP progression remain largelyelusive. Lack of this knowledge is an important problem because without it development of novel therapeuticapproaches that target specifically AR-dependent events underlying the lethal phenotype is unlikely. The long-term goal is to understand how the mechanism(s) by which AR controls clinically relevant gene expression inCaP cells can be manipulated for therapeutic intervention. The objective here is to determine the therapeuticpotential of disrupting AR-responsive PKN1-SRF interactions. The central hypothesis is that targeting PKN1will prevent CaP progression mediated by AR-responsive SRF action. This hypothesis is formulated based onpreliminary work produced in the applicant's laboratory. The rationale for the proposed studies is that once it isunderstood how AR regulation of SRF action in CaP occurs select targeting of AR action that is relevant todisease progression will be possible. The central hypothesis is tested by pursuing 3 specific aims: 1) determinethe role of PKN1 in the AR-responsive SRF transcriptional complex; 2) define the substrate for PKN1's kinaseaction in the AR-dependent SRF transcriptional complex; and 3) determine therapeutic potential of targeting AR-responsive PKN1-SRF interactions. Aim 1 will determine the impact of genetic or pharmacological inactivationof PKN1 on the composition and function of AR-dependent SRF complex at target genes using a combination ofRNA-Seq ChIP-Seq and ATAC-Seq assays. In Aim 2 state-of-the-art biotin-based proximity ligation assaysand mass spectrometry in CaP models that express wild-type or kinase-dead PKN1 or in which PKN1 action ispharmacologically inhibited will define PKN1-dependent phosphorylation of SRF the SRF transcriptionalcomplex and its chromatin environment. Aim 3 will determine the therapeutic potential of inhibiting PKN1-SRFinteractions in clinically relevant PDXs and fresh ex vivo explants of CaP tissue obtained from patients. Clinicallyapplicable biomarkers of response to such treatment will be sought using gene expression and proximity ligationassays. The proposed research is innovative because it focuses on an entirely different approach to target ARaction in CaP: unraveling and targeting an AR-dependent signaling pathway downstream of AR that controls theexpression of genes that are relevant for CaP progression. This contribution is significant because is it the firststep in a continuum of research that is expected to lead to the development of novel treatment modalities thattarget specifically AR-mediated gene expression that underlies the lethal CaP phenotype. With respect toexpected outcomes the proposed studies will identify the molecular mechanisms by which PKN1 introduces atherapeutic vulnerability in the AR-PKN1-SRF signaling cascade that gives rise to the aggressive CaPphenotype. These results will have an important positive impact because they will fundamentally advanceknowledge about AR action in CaP in general and provide new targets for CaP therapy specifically. 318384 +No NIH Category available Angiogenesis Inhibitors;Apoptosis;Apoptotic;Award;Biology;Cell Death;Cell membrane;Cells;Ceramides;Chemoresistance;Chemosensitization;Clinical Trials;Cytidine;DC101 Monoclonal Antibody;Data;Diffusion;Dose;Endothelial Cells;Endothelium;Engineering;Equilibrative Nucleoside Transporter 1;Etoposide;Extracellular Space;Failure;Gene Delivery;Grant;Histology;Hydrolase;Hydrolysis;Implant;Investigation;KDR gene;Lysosomes;Mammalian Cell;Manufacturer;Mediating;Membrane;Memorial Sloan-Kettering Cancer Center;Mus;Nucleoside Transporter;Nucleosides;Outcome;Paclitaxel;Pharmaceutical Preparations;Proliferating;Proteins;Radiation;Radiation therapy;Reagent;Resistance;Rights;Role;Schedule;Services;Signal Transduction;Site;Soft tissue sarcoma;Sphingolipids;Sphingomyelins;Testing;Therapeutic;Tyrosine Kinase Inhibitor;Validation;Vascular Endothelial Growth Factors;Vegf inhibition;Xenograft procedure;acid sphingomyelinase;analog;antagonist;anti-cancer;bevacizumab;cancer therapy;cell injury;chemotherapy;derepression;design;follow-up;gemcitabine;gene therapy;improved;in vivo;inhibitor;nanoliposome;neoplastic cell;pharmacologic;phase II trial;preclinical study;prevent;programs;response;sarcoma;symposium;synergism;technology development;treatment response;tumor;uptake Ceramide-Rich Platforms Functionalize Gemcitabine Uptake Transport of nucleoside chemotherapeutic drugs is primarily accomplished in mammalian cells throughEquilibrative Nucleoside Transporter 1 (ENT1) considered constitutively on redistributing drugs across abilayer via facilitated diffusion. Preliminary evidence however indicates that ENT1 transport of thechemotherapeutic gemcitabine in endothelial cells requires gemcitabine-induced acid sphingomyelinase(ASMase) activation formation of ceramide-rich platforms (CRPs) on the external plasma membrane andENT1 insertion into CRPs for optimized transport function. We propose the existence of a previously-unrecognized form of chemoresistance involving suppression of ENT1 function reversible by pharmacologicactivation of ASMase/Ceramide Signaling. NCI 10754234 12/12/23 0:00 PA-19-056 5R01CA255336-04 5 R01 CA 255336 4 "KONDAPAKA, SUDHIR B" 1/1/21 0:00 12/31/25 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 1878821 "KOLESNICK, RICHARD N" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 364399 NCI 205875 158524 Our data indicate that in select settings activation of acid sphingomyelinase (ASMase)/ceramide signaling intumor endothelial cells by radiation and certain chemotherapies synergizes with direct tumor cell damage toimpact outcome. ASMase is a lysosomal hydrolase preferentially expressed in endothelial cells up to 20-foldcompared with other mammalian cells. Mechanistically endothelial ASMase activation leads within min toformation of plasma membrane ceramide-rich platforms (CRPs) macrodomains that organize apoptotic signalingprograms. Support for our concept derives from studies showing xenografts of all histologies when implanted inasmase-/- host mice become resistant to gemcitabine paclitaxel etoposide and high single dose radiotherapyeffects reversed by exclusive adenoviral asmase gene delivery to tumor microvasculature. We recentlydiscovered VEGF is the principal inhibitor of endothelial ASMase and that anti-angiogenic drugs de-repressASMase amplifying tumor responses to anti-cancer therapies but only under specific conditions. We foundirrespective of t1/2 or anti-angiogenic class these drugs enhance endothelial apoptosis and tumor response onlyif scheduled at 1-2h preceding chemotherapy as ASMase can be de-repressed for only 1-2h. Based on thesedata the MSK Sarcoma Service performed a Phase II trial that showed sphingolipid-based timing ofbevacizumab vs. conventional synchronous timing improved metastatic sarcoma response to the cytidineanalogue gemcitabine from 38 to 93% (p=0.0024; Tap and Kolesnick unpublished). The current application willhelp establish the mechanism by which temporal delivery of a short-acting anti-angiogenic drug simultaneouslyenhances gemcitabine-induced endothelial and tumor cell apoptosis. The overarching hypothesis of thisapplication is that the principal nucleoside transporter in mammalian cells ENT1 required for gemcitabineuptake is not constitutively on as generally accepted but must insert into CRPs on endothelial and tumor cellsfor functionalization. This new membrane-based mechanism of gemcitabine action will be explored in 3 aimsdesigned to examine mechanism of ENT1 functionalization via CRPs in both endothelial and sarcoma cellsVEGF inhibition of ASMase-generated CRPs and pharmacologic strategies to enhance endothelial ASMase-ceramide signaling in vivo to improve ENT1-mediated gemcitabine uptake and cell death. A major concept to beexplored is that gemcitabine-induced ASMase secreted by endothelium triggers bystander gemcitabine uptakevia ENT1 in tumor cells. As such these investigations potentially define failure to stimulate ASMase/ceramidesignaling as mediating a new form of chemoresistance. It is anticipated that information derived from studiesproposed here will inform a planned follow up clinical trial for advanced sarcoma to be performed by the SarcomaService at MSK. 364399 +No NIH Category available Address;Advanced Malignant Neoplasm;Alaska Native;American Association of Cancer Research;Antidotes;Area;Association of American Cancer Institutes;Attitude;Award;Awareness;COVID-19 impact;Caliber;Cancer Science;Clinical;Collaborations;Development;Economics;Exhibits;Exposure to;Faculty;Funding;Funding Mechanisms;Future;Goals;Grant;Growth;Health Disparities Research;Health Status;Hispanic-serving Institution;Historically Black Colleges and Universities;Institution;International;Knowledge;Laboratories;Lead;Malignant Neoplasms;Medical;Minority;Minority Groups;Minority-Serving Institution;National Cancer Institute;Native Hawaiian;Outcome;Participant;Public Health;Publications;Race;Research;Research Personnel;Resources;Science;Students;Study Subject;Time;Training;Travel;Trust;Underrepresented Minority;anticancer research;career;distrust;ethnic minority;expectation;experience;health equity;health inequalities;innovation;interest;knowledge base;meetings;member;minority health disparity;minority investigator;minority student;next generation;peer;professor;programs;racial minority;recruit;skills;social;symposium;tribal college Minority and Minority Serving Institution Faculty in the Field of Cancer Research Public HealthThis project is a pivotal initiative by the American Association for Cancer Research since racial and ethnicminorities remain underrepresented as faculty in the field of cancer research. It is imperative tocontinue to increase the diversity and visibility of faculty members in the field. One of the mostimportant aims of this award program is to facilitate networking and collaboration opportunities forminority faculty and faculty at Minority-Serving Institutions with the wide range of cancer researchersthroughout the world. This is not just a necessity for minority faculty but also essential for faculty atminority-serving institutions. Beyond the direct benefits to Scholar Awardees the program haspotentially wider implications for the health status of the minority population in general resultingfrom the formation of a larger pool of experienced minority basic cancer researchers andclinicians to contribute thrive and gain health equity in the field. The enhancement of the MSI facultymembers research program enriches the experience of the minority students he or she trains.Additionally minority investigators are more likely to explore the issues relating to minorityhealth disparities as well as to have a better prospect of recruiting and collaborating withminority study subjects and a significant increase in the number and visibility of minority cancerresearchers might serve as an effective antidote to attitudes of distrust on the part of studyparticipants and help lead to greater trust on the part of minorities in the medical and researchinstitutions. NCI 10754222 8/23/23 0:00 PA-21-151 2R13CA076526-24 2 R13 CA 76526 24 "LIU, JIEXIN" 9/25/97 0:00 8/31/28 0:00 ZCA1-PCRB-9(M1) 8011666 "FOTI, MARGARET " Not Applicable 2 Unavailable 139203590 K4LZTWHBSGN6 139203590 K4LZTWHBSGN6 US 39.949341 -75.150986 210901 AMERICAN ASSOCIATION FOR CANCER RESEARCH PHILADELPHIA PA Other Domestic Non-Profits 191064404 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 54350 NCI 54350 0 AbstractThe American Association for Cancer Research (AACR) requests renewal of support for the projectentitled MSI Faculty in the Field of Cancer Research. The funds for this project will provide supportfor the participation of full-time minority faculty and faculty from Minority-serving Institutions (MSIs)[Historically Black Colleges & Universities (HBCUs) Hispanic Serving institutions (HSIs) Alaska Native andNative Hawaiian Serving Institutions Tribal Colleges and Universities (TCUs) and other relevantinstitutions] in high-caliber national scientific conferences organized by the AACR. The AACR AnnualMeeting exposes faculty (primarily junior faculty at the level of Assistant Professor) to the broad rangeof ongoing cancer research in basic translational and clinical areas and AACR Special Conferencesallows them to participate in those scientific sessions that are especially relevant to their researchinterests and professional growth. Overall AACR conferences present unique opportunities to interactwith the worlds leading experts and discus the latest findings in rapidly developing areas of cancerresearch.This project is an essential component of a multi-level program instituted by the AACR to address theproblem of underrepresentation of minorities working in cancer research and biomedical science. Thebroad objective of the project is to increase the scientific knowledge base of faculty scholars and toencourage them and their students to pursue careers in cancer research. The project aims to facilitatefaculty scholars professional relationships and networking and sponsorship possibilities with nationaland international cancer researchers and to further their careers and enhance their recognition byprofessional peers through providing the opportunity to present and discuss their own research findingsbefore international audiences.These awards have been generously supported through this R13 funding mechanism from 1997-2021.The AACR is deeply appreciative to the National Cancer Institute (NCI) for 24 years of supportingminority faculty scholars and faculty scholars at MSIs in cancer research their research programs andby extension to the next generation of minority cancer researchers they train in the laboratory and inthe classroom. With the generous support of the NCI the AACR can assure that it remains innovativeand essential to the future of cancer research. 54350 +No NIH Category available Achievement;Address;Advanced Malignant Neoplasm;American Association of Cancer Research;Area;Association of American Cancer Institutes;Award;Awareness;Behavior Therapy;COVID-19 impact;Caliber;Cancer Science;Career Choice;Clinical;Clinical Trials;Collaborations;Dedications;Development;Economics;Education;Exposure to;Funding;Funding Mechanisms;Future;Goals;Grant;Growth;Health Disparities Research;Institution;International;Knowledge;Learning;Location;Malignant Neoplasms;Medical Students;Medicine;Mentors;Minority;Minority Graduate Student;Minority Groups;Minority Health Research;National Cancer Institute;Outcome;Patients;Play;Postdoctoral Fellow;Public Health;Publications;Race;Research;Research Personnel;Role;Science;Scientist;Target Populations;Time;Training;Travel;Trust;Underrepresented Minority;United States National Institutes of Health;Voice;anticancer research;career;career development;expectation;experience;field study;health equity;health inequalities;improved outcome;innovation;knowledge base;medically underserved;meetings;minority children;minority communities;minority investigator;minority scientist;minority student;outreach;programs;skills;social;success;symposium Young Minority Scientists in the Field of Cancer Research Public HealthThis project is a pivotal initiative by the American Association for Cancer Research to address thechallenges of minority underrepresentation in cancer research to support an increasing number ofminority investigators to contribute thrive and to gain health equity in the field of cancer research.Minority cancer researchers have many unique roles to play in cancer research including adding adiverse voice to this field of study with the promise of producing innovation and mentoringopportunities for future minority students. One of the most important results of the program is toimprove outcomes for minority and medically underserved patients. Minority research scientists havethe potential to be more successful in balancing the diversity of clinical trial subjects and moresuccessful in inspiring the trust of subjects. Because of sensitivity to cultures and even the locations oftargeted populations dedicated minority researchers also hold promise for succeeding with behavioralinterventions that require outreach to minority communities. NCI 10754218 8/16/23 0:00 PA-21-151 2R13CA040577-35 2 R13 CA 40577 35 "LIU, JIEXIN" 3/15/85 0:00 8/31/28 0:00 ZCA1-PCRB-9(M1) 8011666 "FOTI, MARGARET " "HAIT, WILLIAM N." 2 Unavailable 139203590 K4LZTWHBSGN6 139203590 K4LZTWHBSGN6 US 39.949341 -75.150986 210901 AMERICAN ASSOCIATION FOR CANCER RESEARCH PHILADELPHIA PA Other Domestic Non-Profits 191064404 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 73683 NCI 68225 5458 AbstractThe American Association for Cancer Research (AACR) requests renewal of support for the projectYoung Minority Scientists in the Field of Cancer. These funds will provide Minority Scholar in CancerResearch Awards to support the participation of early-career underrepresented scientists from NIH-recognized minority populations at high-caliber national scientific conferences organized by the AACR.AACR conferences present unique opportunities to interact with the worlds leading experts and discussthe latest findings in rapidly developing areas of cancer research. By attending an AACR conferenceattendees will advance their understanding of cancer and be exposed to the most cutting-edge researchin the field. This project is an essential component of a multi-level program instituted by the AACR toaddress the problem of underrepresentation of minorities working in cancer research and biomedicalscience.The Minority Scholar in Cancer Research Awards program exposes early-career minority scientists to themost current groundbreaking cancer science and medicine through their participation in AACR AnnualMeetings and Special Conferences. In addition to their exposure to cancer research scholar awardeesalso gain access to mentoring and networking opportunities with experienced investigators career-building showcases of their achievements and important professional development guidance. Theseawards are given annually to minority graduate students medical students residents and clinical andpostdoctoral fellows to support their participation at AACR Annual Meetings or Special Conferences.These awards have been generously supported through this R13 funding mechanism from 1985-2022.The AACR is deeply appreciative to the National Cancer Institute (NCI) for 37 years of supportingminority investigators in cancer research and looks forward to continuing the success of this program forthe period 2023-2028. 73683 +No NIH Category available Address;Adjuvant;Age;Anus;Apoptosis;Biological Markers;Blood;Cancer Center;Cancer Model;Cancer Patient;Cervix Uteri;Chemotherapy and/or radiation;Clinical;Clinical Research;Clinical Trials;Cohort Studies;Colorectal Cancer;DNA Damage;Data;Diagnosis;Disease;Dose;Enzyme Inhibition;Excision;Experimental Models;Failure;Feces;Gender;Goals;Growth;Height;Immune;Immunity;Immunooncology;Immunosuppression;Immunotherapy;In complete remission;Incidence;Infrastructure;Institution;Intestines;Kynurenine;Lead;Local Therapy;Malignant Neoplasms;Mediating;Mediator;Mismatch Repair;Morbidity - disease rate;Mus;Neoadjuvant Therapy;Neoplasm Metastasis;Oncology;Operative Surgical Procedures;Organoids;Outcome;PD-1 inhibitors;PI3K/AKT;Pathologic;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmacodynamics;Phase;Phase II Clinical Trials;Phase III Clinical Trials;Positioning Attribute;Pre-Clinical Model;Radiation;Radiation Protection;Radiation therapy;Randomized;Rectal Cancer;Rectum;Regimen;Resistance;Safety;Sampling;Site;Small Intestines;Solid Neoplasm;Statistical Models;Therapeutic;Toxic effect;Treatment Efficacy;Treatment-related toxicity;Tryptophan;Tryptophan 23 Dioxygenase;Tryptophan Metabolism Pathway;Tumor Immunity;Tumor Suppressor Proteins;Tumor Tissue;Universities;Washington;Work;arm;beta catenin;biobank;biomarker identification;cancer therapy;chemoradiation;chemotherapy;clinical diagnosis;cohort;efficacy evaluation;experience;genotoxicity;improved;inhibitor;novel;novel therapeutic intervention;novel therapeutics;overexpression;patient population;phase 1 study;phase II trial;phase III trial;precision medicine;predicting response;programmed cell death protein 1;radiation delivery;rectal;repair function;response;standard of care;synergism;therapy resistant;treatment response;treatment strategy;tumor Targeting Tryptophan Metabolism in Rectal Cancer Project Narrative:More than 40000 new rectal cancers occur annually in the US and current treatment strategies (chemotherapyradiation and surgery) provide a 5-year disease survival of only 65%. Therefore there is an unmet need for newtreatment approaches that improve LARC clinical outcomes and reduce morbidity. We propose to examineadding a new therapy (inhibition of the enzyme IDO1) to rectal cancer therapy that may improve overall curerates and reduce treatment related toxicity. NCI 10754178 9/21/23 0:00 PAR-21-033 1R01CA278197-01A1 1 R01 CA 278197 1 A1 "VIKRAM, BHADRASAIN" 9/21/23 0:00 8/31/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 9963291 "CIORBA, MATTHEW AARON" "PARK, HAESEONG " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 513828 NCI 354660 159168 Project Summary/Abstract:More than 40000 new rectal cancers occur annually in the US and the majority are locally advanced whendiagnosed (LARC). Current total neoadjuvant therapy (TNT) with chemoradiation followed by surgery providesmodest outcomes with a 20-25% pathologic complete response (pCR) rate and 5-year disease survival of only65%. Therefore there is an unmet need for new treatment approaches that improve LARC clinical outcomesand reduce morbidity. Using LARC patient samples and pre-clinical modeling we recently identified a rationalefor combining short course radiation therapy (SCRT) with inhibitors of the immuno-oncology target IDO1.Indoleamine 23 dioxygenase 1 (IDO1) metabolizes tryptophan along the kynurenine pathway and is recognizedas a potent suppressor of tumor reactive immunity. Our robust findings identify IDO1 overexpression as apathologic response in LARC therapy leading to immune-independent treatment resistance and animmunosuppressive TME. We found that: 1) Radiation induces IDO1 overexpression universally across LARCpatients and in colorectal cancer (CRC) models regardless of MSI status. 2) IDO1 activity directly promotescritical mediators of CRC growth and treatment resistance (-catenin and PI3K/AKT; 3) In mice the potent IDO1inhibitor epacadostat (EPA) sensitizes CRC to simulated SCRT radiation by relieving immune suppression andaugmenting radiation induced CRC apoptosis. We have conducted a Phase I dose escalation study ofepacadostat in combination with SCRT/chemotherapy and identified EPA 400mg BID to be safe and showspreliminary evidence of efficacy. These findings lead us to conclude with following central hypothesis: IDO1inhibition is a rationally selected adjunctive immunotherapy in CRC that enhances anti-tumor immunitysynergizes with DNA damaging therapy and protects the normal small intestine. Project goals include:Defining efficacy of EPA/SCRT/chemotherapy as TNT for LARC and a pharmacodynamic basis for EPA in abiospecimen accruing Phase II trial with a randomized biomarker cohort (Aim 1). Defining biomarkers andidentifying precision medicine approaches to support the further clinical study of this combination (Aim 2). Wewill leverage institutional experience and expertise our established clinical trial infrastructure (NCT03516708)and a standard-of-care cohort to address this central hypothesis Impact: If successful we will take thisapproach to a potentially practice-changing randomized phase III clinical trial using precision medicineapproaches to address the unmet need to improve LARC patient outcomes. As IDO1 is also upregulated inother solid tumors treated by RT (cervix anal etc) the approach of combining EPA with genotoxic therapiesmight be expanded to other solid tumor types. 513828 +No NIH Category available Acute;Address;Age;American Cancer Society;Anxiety;Attenuated;Blood;Cancer Patient;Cancer Survivor;Cannabidiol;Cannabinoids;Cannabis;Chemicals;Cognitive deficits;Data;Diagnosis;Disease;Dose;Effectiveness;Encapsulated;Hemp;Hour;Impaired cognition;Individual;Legal;Literature;Long-Term Effects;Malignant Neoplasms;Marketing;Measures;Memory;Mental Depression;Mental Health;Moods;Outcome;Pain;Pain intensity;Pain interference;Palliative Care;Patients;Pharmaceutical Preparations;Pilot Projects;Placebo Control;Placebos;Plants;Polypharmacy;Prevalence;Prevention;Proliferating;Quality of life;Radiation;Randomized;Reporting;Research;Review Literature;Risk;Role;Scientist;Sleep;Sleep Disorders;Sleep disturbances;Standardization;Stress;Surveys;Symptoms;Task Performances;Testing;Tetrahydrocannabinol;United States;Variant;Work;active method;affective disturbance;cancer diagnosis;cancer therapy;chemobrain;chemotherapy;cognitive function;cognitive task;design;efficacy evaluation;experience;experimental study;improved;interest;marijuana use;multiple drug use;pain reduction;pilot trial;placebo group;prescription opioid;psychologic;psychological distress;randomized placebo controlled trial;reduce symptoms;side effect;sleep quality;synthetic cannabinoid;trend Cannabis for Palliative Care in Cancer: A Placebo-controlled Randomized Trial of Full Spectrum Hemp-derived CBD/THC Project NarrativeMany cancer patients suffer from pain sleep and mood problems and are using cannabis to relieve thesesymptoms. Cannabis may provide such relief but may also produce negative side effects including cognitiveimpairment an especially problematic issue for cancer patients indicating more research on cannabis use inthe cancer context is required. In this endeavor the present study seeks to compare the use of hemp-derivedCBD with and without THC versus placebo on measures of sleep pain mood subjective and objectivecognitive functioning and quality of life within 185 cancer patients. NCI 10754176 7/31/23 0:00 PAR-21-035 1R01CA284860-01 1 R01 CA 284860 1 "STRECK, BRENNAN PARMELEE" 8/1/23 0:00 7/31/28 0:00 Biobehavioral Medicine and Health Outcomes Study Section[BMHO] 9036273 "BRYAN, ANGELA " "HUTCHISON, KENT E." 2 PSYCHOLOGY 7431505 SPVKK1RC2MZ3 7431505 SPVKK1RC2MZ3 US 40.013296 -105.251932 1199902 UNIVERSITY OF COLORADO Boulder CO SCHOOLS OF ARTS AND SCIENCES 803031058 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 650978 NCI 439671 211307 Project SummaryProblems with pain sleep and mood are common among individuals diagnosed with cancer (i.e. cancersurvivors/patients) and many are turning to cannabis for symptom relief/palliative care. Recent reviews of theliterature suggest that cannabis use can indeed provide benefit for symptoms including pain interference painintensity and aspects of mood disturbance (i.e. anxiety). Cannabis may also prove less harmful/morebeneficial than other palliative care options like opiate medications and may reduce the use of multipledrugs (i.e. polypharmacy). Despite these promising benefits it is also important to consider the potentialnegative effects cancer patients may experience from cannabis use including compromised cognitive function.Research clearly demonstrates that cannabis compromises objective functioning immediately after usebut there is mixed evidence regarding its effects long-term. This equivocation may be due to cannabinoidcontent as the main psychoactive constituent of cannabis 9-tetrahydrocannabinol (THC) is associatedwith memory and other cognitive impairment but cannabidiol (CBD) a non-psychoactive cannabinoid mayattenuate these negative effects. Such effects are especially important to consider among cancer patients whoare particularly vulnerable to cognitive deficits. Differential effectiveness of CBD versus THC versus acombination is also evident for outcomes of sleep disturbance anxiety and pain. Overall as cannabiscontinues to become legally available across the US and cancer patients look to cannabis for relief morestudies are needed to better determine the efficacy of cannabis use the role of different cannabinoid ratiosand what side effects may arise from its use. Existing research examines synthetic cannabinoids which arechemically homogenous and THC/CBD isolates which are unrepresentative of the whole-plant products thatare now widely available in the United States. As such it is increasingly necessary to conduct rigorousexperimental research using more ecologically valid forms of cannabis among cancer patients. The presentproposal seeks to utilize a rigorous placebo-controlled randomized trial to understand the effects of fullspectrum hemp-derived CBD (fsCBD; CBD that contains a small amount of THC) and broad spectrum hemp-derived CBD (bsCBD; CBD that contains no THC) versus placebo on measures of sleep pain mooddisturbance subjective and objective cognitive functioning and quality of life. These CBD products can belegally purchased and used over the counter across the U.S. so the results of this study have immediateapplication to and importance for cancer patients and their clinicians. The project aims are to 1) compare theeffects of fsCBD vs bsCBD vs placebo on sleep quality pain intensity/interference mood disturbance (anxietydepression) cognitive functioning and quality of life over 8 weeks of sustained use and 2) compare the acuteeffects of fsCBD vs bsCBD vs placebo one and two hours after use on pain intensity current mood andobjective cognitive task performance. 650978 +No NIH Category available Adenocarcinoma;Biopsy;Cancer Detection;Cancer Etiology;Caring;Cessation of life;Clinical;Clinical Research;Data;Decision Making;Detection;Development;Devices;Diagnosis;Diagnostic;Disease;Evaluation;Excision;Freezing;Frequencies;Frozen Sections;Hand;Hematoxylin and Eosin Staining Method;Histologic;Histopathology;Lobectomy;Lung;Lung nodule;Lymph Node Dissections;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Medicine;Metals;Molecular;Molecular Diagnosis;Morphology;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Observational Study;Operating Rooms;Operative Surgical Procedures;Pathologist;Patient Care;Patient-Focused Outcomes;Patients;Performance;Procedures;Process;Reporting;Reproducibility;Retrospective Studies;Robotics;Scientist;Segmental Mastectomy;Side;Slide;Specificity;Specimen;Squamous Cell;Stains;Sterility;Structure of parenchyma of lung;Surgeon;Surgical complication;Surgical margins;System;Techniques;Technology;Testing;Thoracic Surgeon;Time;Tissue Banks;Tissue Sample;Tissues;Translating;Translations;United States;Validation;Water;accurate diagnosis;cancer diagnosis;cancer subtypes;cancer surgery;clinical care;clinical decision-making;college;handheld equipment;improved;improved outcome;in vivo;in vivo evaluation;innovation;innovative technologies;lung cancer screening;malignant breast neoplasm;minimally invasive;new technology;next generation;operation;prospective;prototype;rapid diagnosis;research and development;seal;specific biomarkers;standard of care;surgical risk;technology validation;tumor;tumor diagnosis Validation and Translation of MasSpec Pen Technology for Intraoperative Evaluation of Non-small Cell Lung Cancer NARRATIVENon-small cell lung cancer (NSCLC) is a devasting disease and the leading cause of cancer-related death in theUnited States for which surgery is a critical treatment option. During surgical procedures for patients withNSCLC many important decisions are made by the surgeons to define the diagnosis of the tumor and the extentof tissue resection however the clinical technologies that currently exist to support surgeons in these difficultassessments are outdated slow and prone to many errors leading to dire consequences for patients. In ourstudy we propose to refine and validate a groundbreaking new technology that allows tissues to be accuratelyidentified in the patient and on excised specimens providing surgeons with new capabilities in obtaining real-time and molecular-based information to guide their surgical decisions and improve outcome for patients. NCI 10753977 6/2/23 0:00 PAR-21-206 1R01CA284742-01 1 R01 CA 284742 1 "MCKEE, TAWNYA C" 6/2/23 0:00 5/31/28 0:00 Special Emphasis Panel[ZRG1-ISB-J(57)R] 8559273 "BURT, BRYAN MICHAEL" "SCHIAVINATO EBERLIN, LIVIA ; WISEMAN, JUSTIN " 9 SURGERY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 6/2/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 601550 NCI 428814 172736 SUMMARYNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States for whichsurgery remains a critical treatment option. The appropriate extent of resection for NSCLC is highly dependenton intra-operative decision-making. Specifically the diagnosis of NSCLC is often determined intra-operativelyby a limited resection of a suspicious pulmonary nodule and intraoperative diagnosis is required beforeproceeding to a larger cancer-specific resection during the same procedure. Further intraoperative evaluationof resection margins is required in NSCLC surgeries to assure complete cancer removal before leaving theoperating room (OR). Thus the ability to accurately diagnose NSCLC and determine surgical margins in the ORis critical in the care for patients with NSCLC. However the current technology used for intraoperative evaluationof NSCLC diagnosis and margins is frozen section analysis a century-old technique that is labor-intensive andprone to error. Frozen section analysis also extends operative time subjecting patients to increased risks ofsurgical complications. New technologies that can provide surgeons with the ability to rapidly and accuratelydiagnose NSCLC in the OR and evaluate surgical margins with high accuracy are critically needed to improvesurgical care and outcomes for patients. We have reported the development of an innovative technology theMasSpec Pen (MSPen) for rapid and non-destructive diagnosis of cancer tissues. The MSPen deploys a singledroplet of water to gently extract molecules from tissues which are then analyzed by mass spectrometry (MS)and statistical classifiers to provide diagnosis in seconds. We have demonstrated that the MSPen can accuratelydiagnose NSCLC using banked tissues with 97% accuracy. We have also shown that the MSPen system canbe translated to the OR for use by surgeons for rapid in vivo and ex vivo tissue analysis. Through a collaborativepartnership between academic scientists and surgeons at Baylor College of Medicine and the R&D team atMSPen Technologies Inc. we now propose to refine and validate the MSPen for intraoperative diagnosis andsurgical margin evaluation in NSCLC. Our objective is to optimize and translate new MSPen technology forNSCLC detection test its functionality and validate its performance in the OR setting thus delivering a potentiallyimproved platform for intraoperative lung tissue analysis to surgeons - the end users. Our specific aims are: Aim1. Optimize the MSPen Technology for intraoperative use in NSCLC operations. We will develop a next-genMSPen platform for use in open and robotic NSCLC surgeries; Aim 2. Validate the MSPen for NSCLC diagnosis.We will conduct a prospective observational study allowing thoracic surgeons to validate the technology forNSCLC diagnosis in the OR; Aim 3. Validate the MSPen for intraoperative surgical margin evaluation in NSCLC.We will validate the MSPen technology for surgical margin evaluation in vivo and ex vivo including the mostrepresentative tissue margins that are currently disregarded in clinical care. Our propose has the potential tooffer transformative benefits to surgeons in advancing the surgical standard of care for patients with lung cancer. 601550 +No NIH Category available Acceleration;American;Award;Basic Science;Biology;Cancer Biology;Cancer Control;Cells;Cities;Clinical;Clinical Research;Collaborations;Communication;Development;Diagnosis;Diagnostic tests;Disease;Education;Educational workshop;Ensure;Epigenetic Process;Ethnic Origin;Experimental Pathology;Faculty;Feedback;Fostering;Functional disorder;Gender;Goals;Homeostasis;Human Papillomavirus;Immune;Immune Evasion;Individual;Institution;Interest Group;Knowledge;Malignant Neoplasms;Mentors;Neoplasm Metastasis;Participant;Pathogenesis;Pathology;Postdoctoral Fellow;Prevention;Research;Research Personnel;Role;Scientific Societies;Scientist;Seasons;Secure;Societies;Sodium Chloride;Special Event;Suggestion;Systems Biology;Technology;Therapeutic;Tissues;Transcriptional Regulation;Translational Research;Underrepresented Populations;Visual;Woman;Work;biomarker development;body system;cancer prevention;career;career development;design;diversity and inclusion;extracellular vesicles;graduate student;gut inflammation;human disease;insight;interest;lectures;malignant breast neoplasm;meetings;member;mid-career faculty;posters;pre-doctoral;prognostic assays;programs;racial population;skills;social;symposium;targeted treatment;tissue injury;tumor metabolism;tumor progression;verbal 2023 Annual Meeting of the American Society for Investigative Pathology The Annual Meeting of the American Society for Investigative Pathology offers a unique forum for the sharing oforiginal research results related to a wide spectrum of human diseases and disorders with particular emphasison the development treatment and prevention of cancer. Such sharing fosters more rapid advances in theunderstanding of human diseases such as cancer and accelerates the rate at which this knowledge can beapplied to the development of diagnostic and prognostic tests as well as targeted therapies. A major goal of themeeting is to provide educational and career support to young investigators who are interested in cancer biologyand experimental pathobiology. NCI 10753942 8/23/23 0:00 PA-21-151 1R13CA284830-01 1 R13 CA 284830 1 "WANG, WENDY" 9/1/23 0:00 8/31/24 0:00 ZCA1-PCRB-9(M1) 15646248 "COLEMAN, WILLIAM B" Not Applicable 8 Unavailable 876862772 XYLCK58MST41 876862772 XYLCK58MST41 US 39.013531 -77.101138 10004881 AMERICAN SOCIETY/INVESTIGATIVE PATHOLOGY ROCKVILLE MD Other Domestic Non-Profits 20852 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 15000 NCI 15000 0 The 2023 Annual Meeting of the American Society for Investigative Pathology (ASIP) will be held in conjunctionwith the Tissue Matrix and Pathobiology conference from October 22-25 at The Grand America Hotel in SaltLake City UT. This scientific conference is a collaboration between The Histochemical Society the AmericanSociety for Matrix Biology and the ASIP. The Annual Meeting of the ASIP provides a unique forum forpresentation and sharing of cutting-edge research in experimental pathology. The target audience and subjectmatter for the meeting are diverse but united by a common focus on mechanisms of disease. Reflecting theinterests of the ASIP membership the four-day scientific program for the 2023 Annual Meeting is comprised ofplenary sessions major symposia award lectures workshops guest society symposia and special sessionscovering disease pathogenesis biomarker development prevention diagnosis and therapeutics advancedtechnologies organ systems and systems biology. This program contains strong components in cancerpathobiology. Major cancer-related sessions will focus on: (i) Cancer Metabolism Metastasis and TherapeuticImplications; (ii) Transcriptional Control in Cancer; (iii) Tissue Injury and Cancer Biology Extracellular Vesiclesin Disease; (iv) The Intersection Between Breast Cancer and the Matrix; (v) Cancer Progression and Metastasis.In addition four meritorious award lectures will have a cancer-focus: (a) HPV and Cancer; (b) Diverse Functionsand Fates of Innate Immune Cells in Gut Inflammation and Cancer; (c) Epigenetic Control of Cancer Metastasisand Immune Evasion; and (d) TIMPs: Emerging Roles in Tissue Homeostasis and Cancer Progression.Additional opportunities for presentation of cancer-focused research will include abstract-driven minisymposiaand poster discussion sessions which will intentionally feature young investigators and trainee scientists. Theprogram further provides a number of sessions focused on education and career development. These sessionsare designed for trainees and young investigators but are open to all attendees. Education and careerdevelopment topics for 2023 include navigating challenging conversations and enhancement of verbal andvisual communication skills. The ASIP regards promotion of the career development of trainee and younginvestigators as an extremely important aspect of the Annual Meeting. Accordingly the meeting provides notonly special events designed for their needs but also sessions that highlight/showcase their work. Similarly theProgram Committee works hard to ensure diversity among the participants with respect to gender ethnic/racialgroup stage of career and institutional affiliation. For 2023 among invited speakers: 39% are women 39% areAssistant/Associate Professors (or equivalent) and 100% of sessions include speakers that are women orunderrepresented. The sole specific aim of this application is to promote the participation of trainees and younginvestigators in the 2023 Annual Meeting through provision of a Scholar Award program targeted to graduatestudents postdoctoral fellows clinical residents/fellows and junior faculty members. 15000 +No NIH Category available Acquired Immunodeficiency Syndrome;Address;Affect;Africa;African;Animal Model;Antibodies;Bacteria;Biology;Blood;CD14 gene;Cell Communication;Cell Proliferation;Cells;Clinical;Clinical Research;Clinical Sciences;Complex;Computational Biology;Data;Development;Disease Outcome;Epidemiology;Flagellin;Gene Expression Profile;Genes;Goals;HIV;HIV Infections;Herpesviridae Infections;Human;Human Herpesvirus 8;Immune;Immune response;Immunocompromised Host;Immunologics;In Situ;Infection;Inflammation;Inflammatory;Innate Immune Response;Kaposi Sarcoma;Laboratories;Lipopolysaccharides;Longitudinal cohort;Machine Learning;Malignant Neoplasms;Methods;Modeling;Molecular;Morbidity - disease rate;Oral;Outcome;Palate Kaposi's Sarcoma;Pathogenesis;Patients;Population;Poverty;Predictive Factor;Prevention;Preventive;Prognostic Marker;Research Personnel;Role;Societies;Specimen;TLR4 gene;Technology;Therapeutic;Therapeutic Agents;Time;Tobacco use;Translational Research;Underrepresented Populations;Validation;Visceral;Work;antiretroviral therapy;cancer specimen resource;case control;co-infection;cohort;comorbidity;complement pathway;cytokine;dysbiosis;health disparity;innovation;insight;lipopolysaccharide-binding protein;longitudinal analysis;machine learning algorithm;metaplastic cell transformation;microbial;microbiome;microbiota;mortality;novel;pre-clinical;predictive marker;prognostic;prognostic value;response;single cell sequencing;skin organogenesis;statistics;therapeutic target;therapeutically effective;therapy outcome;tumor;tumorigenesis Impact of microbiota on AIDS-Kaposis sarcoma development and therapy Project NarrativeKaposis sarcoma-associated herpesvirus (KSHV) causes several human cancers including Kaposissarcoma the most common cancer in AIDS patients. KSHV infection and Kaposis sarcoma inflict morbidityand mortality to the society in US and worldwide which particularly affect underrepresented people living withHIV (PLWH) and cancer. This project will identify the factors that contribute to the development andtherapeutic outcome of Kaposis sarcoma thus providing the scientific basis for developing novel preventionand treatment approaches to benefit the patients. NCI 10753890 9/8/23 0:00 RFA-CA-22-056 1R01CA284554-01 1 R01 CA 284554 1 "READ-CONNOLE, ELIZABETH LEE" 9/8/23 0:00 8/31/28 0:00 ZCA1-TCRB-D(M1) 11026736 "GAO, SHOU-JIANG " Not Applicable 12 GENETICS 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/8/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 793089 NCI 526007 267082 Project AbstractMicrobiota imbalance impacts the development and therapeutic outcome of cancer by altering host immuneresponse and inflammation. Kaposis sarcoma (KS) is the most common cancer in HIV-infected patients causedby infection of Kaposis sarcoma-associated herpesvirus (KSHV). Despite antiretroviral therapy KS remainscommon among HIV-infected patients. It remains unclear what factors might influence the development andtherapeutic outcome of AIDS-KS? In response to RFA-CA-22-056 entitled: Basic/Translational Research onHealth Disparities in Underrepresented People Living with HIV (PLWH) and Cancer this application specificallyaddresses the underserved African populations that have high numbers of new HIV infections with the long-term goal is to delineate the pathogenesis of AIDS-associated KS (AIDS-KS) and identify effective therapeutictargets and agents as well as prognostic biomarkers. We have recently shown the impoverishment of oralmicrobial diversity and enrichment of specific microbiota in oral AIDS-KS and demonstrated that bacteria andtheir products lipopolysaccharide and flagellin promote KSHV-induced tumorigenesis by enhancing inflammationin a preclinical KSHV-induced KS animal model. Our hypothesis is that specific microbiota regulatesinflammation to impact KS development and therapeutic outcome in AIDS-KS patients. We haveassembled a strong collaborative team with diverse expertise in HIV infection KSHV biology microbiome clinicalsciences epidemiology statistics computational biology and machine learning. We will take advantage of thelong-term clinical studies in Africa with well-defined cross-sectional case-control and longitudinal cohorts of largeHIV-infected and AIDS-KS populations directed by investigators of this project. We will determine the impact ofspecific microbiota on inflammation and AIDS-KS development by performing case-control analyses in naveAIDS-KS and HIV/KSHV patients without KS (Aim 1); and examine the impact of specific microbiota on thetherapeutic outcome of KS by case-control longitudinal analyses of AIDS-KS patients undergoing anti-retroviraltherapy followed by validation analyses in an independent cohort (Aim 2). This interdisciplinary project willanalyze the molecular virological microbial immunological single cell spatial omics and clinical features ofAIDS-KS patients using advanced machine learning approaches. We expect to identify factors that influence thedevelopment and therapeutic outcome of AIDS-KS patients. The proposed work is highly significant and willhave prognostic preventive and therapeutic impacts on AIDS-KS patients. This will be the first time that the roleof microbiota will be systematically examined in AIDS-KS patients from well-characterized cohorts. The proposedinnovative approaches such as spatial single cell sequencing and machine learning will generate unique andunprecedented results providing novel insights into the pathogenesis and therapeutic outcome of AIDS-KS. 793089 +No NIH Category available Bromodeoxyuridine;Cancer Patient;Cancer cell line;Cell Death;Chemoresistance;Chromatin;Cisplatin;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNA Damage;Data;Etoposide;Family member;Gene Targeting;Genes;Genetic;Genetic Transcription;Genomics;Histone H3;Human;In Situ Nick-End Labeling;In Vitro;Kinetics;Knowledge;Libraries;MYCL1 gene;MYCN gene;Malignant neoplasm of lung;Modeling;Molecular;Mus;Mutation;Neurosecretory Systems;Parents;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Process;Proliferating;Proteins;Proteomics;RNA analysis;Refractory;Relapse;Resistance;Role;SAGA;System;Testing;Tissues;cancer type;chemotherapy;epigenetic silencing;established cell line;genetic manipulation;histone modification;in vivo;insight;lentivirally transduced;lung cancer cell;member;mutant;novel;overexpression;patient derived xenograft model;patient response;prevent;response;screening;small cell lung carcinoma;tissue culture;transcriptome sequencing;treatment response;tumor growth Identifying and understanding drivers of chemoresistance in small cell lung cancer Project NarrativeSmall cell lung cancer (SCLC) patients tend to respond remarkably well to chemotherapy but through largelyunknown mechanisms chemoresistance rapidly emerges. We found that single gene perturbation ofchemosensitive patient derived xenograft models of SCLC can confer switch to chemoresistance and we tookadvantage of this finding to perform in vivo functional screens. This proposal is focused on understanding apathway that emerged from our screens that when suppressed potently drive SCLC chemoresistance in vivo. NCI 10753857 7/1/23 0:00 PA-20-185 1R01CA281133-01A1 1 R01 CA 281133 1 A1 "JOHNSON, RONALD L" 7/1/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 9856130 "MACPHERSON, DAVID " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 545661 NCI 314261 231400 SUMMARYSmall cell lung cancer (SCLC) is an aggressive and lethal neuroendocrine lung cancer type. Most patients initiallyrespond to chemotherapy but relapse occurs within months and genetic alterations that drive chemoresistanceare poorly understood. Beyond amplification of MYC family members and epigenetic silencing of SLFN11 thefield has an extremely poor understanding of genes that promote SCLC chemoresistance. We developed a novelsystem in which we genetically alter highly chemosensitive patient derived xenograft (PDX) models of SCLC toidentify perturbations that confer resistance to cisplatin/etoposide (CIS-ETO) in vivo. Lentiviral overexpressionof either MYCN or MYCL caused complete switch to chemoresistance (Grunblatt et al 2020). To systematicallyidentify SCLC chemoresistance drivers we expanded use of this PDX lentiviral transduction system to performin vivo CRISPR inactivation screens. We identified sgRNAs targeting multiple components of the SAGA (Spt-Ada-Gcn5 acetyltransferase) chromatin modifying complex as screen hits and confirmed that deleting the SAGAmember USP22 a deubiquitylase indeed confers chemoresistance in two SCLC PDX models while return ofUSP22 to a USP22-null SCLC PDX model re-sensitizes to chemotherapy. Our overarching hypothesis is thatsuppressing the expression of USP22 and SAGA complex members drives chemoresistance in SCLC and thattranscriptional changes caused by SAGA suppression are critical. Aim 1 we will interrogate how geneticallyperturbing multiple SAGA complex members including USP22 and TADA1 in PDX models alters the in vivoresponse to chemotherapy. Aim 2 employs genomic and proteomic approaches to develop a deep molecularunderstanding of the USP22-regulated genes and pathways that contribute to chemotherapy response in SCLCand uses human patient data to prioritize key SAGA targets for functional study. Decades of studyingchemotherapy response in SCLC cell lines grown in vitro have provided little insight into how chemoresistanceemerges suggesting that key aspects of this process are not recapitulated under tissue culture conditions. Ournovel system prioritizes the study of chemoresistance using in vivo approaches with potential to providefoundational knowledge to help prevent chemoresistance or re-sensitize chemoresistant SCLC to chemotherapy. 545661 +No NIH Category available Affect;Antioxidants;Biological;Biological Assay;Biological Markers;Biology;Breast Cancer Cell;Breast Cancer cell line;Cancer Patient;Cancer cell line;Cell Line;Cells;Cessation of life;Chemistry;Clinic;Clinical;Clinical Trials;Complement;Complex;Cysteine;Disease;Electrons;Endocrine;Enzymes;Evaluation;Glutathione;Growth;In Vitro;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of prostate;Metabolic;Modality;Modeling;Molecular;NADPH Oxidase;Neoplasm Metastasis;Oncogenic;Organoids;Oxidation-Reduction;Pathway interactions;Patients;Phenotype;Proteins;Proteome;Regulation;Relapse;Reporting;Repression;Resistance;Role;Sentinel;Signal Transduction;Signaling Protein;Techniques;Testing;Therapeutic;Treatment Efficacy;Up-Regulation;acetovanillone;acquired treatment resistance;anti-cancer;cancer subtypes;cancer type;candidate identification;candidate marker;cysteinesulfenic acid;disulfide bond;ebselen;epigenetic regulation;epigenetic silencing;glutathione S-transferase pi;in vivo;inhibitor;insight;interest;mRNA Expression;malignant breast neoplasm;molecular marker;novel;novel marker;overexpression;oxidation;patient derived xenograft model;pharmacodynamic biomarker;predictive marker;prognostic;protein expression;protein function;protein protein interaction;protein structure;sensor;small molecule;transcriptomics;tumor;tumorigenesis Investigating GSTP1 as a novel regulator of the cysteine redoxome in breast cancer and maker of vulnerability to redox-based therapy Project NarrativeGSTP1 is uniquely downregulated in luminal and some Her2-positive breast cancers. This proposal willexplore whether epigenetic silencing of GSTP1 makes BRCA sensitivity redox-based therapy anddelineate the molecular consequences of its repression. NCI 10753588 11/29/23 0:00 PAR-20-292 5R21CA270876-02 5 R21 CA 270876 2 "KONDAPAKA, SUDHIR B" 12/12/22 0:00 11/30/24 0:00 ZCA1-SRB-2(O1)S 6938270 "HELD, JASON M." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 196280 NCI 126225 70055 Project SummaryGlutathione S-transferase Pi 1 (GSTP1) is an enzyme that conjugates glutathione to smallmolecule electrophiles. GSTP1 has been implicated in promoting the growth of many cancertypes where GSTP1 overexpression is proposed to promote metabolic re-wiring or sequestercancer-related signaling proteins through protein-protein interactions. In contrast to the modest upregulation of GSTP1 in cancer reported by these studies oursystematic evaluation of cancer cell lines patient-derived xenografts and patient tumors finds thatGSTP1 expression is uniquely and dramatically silenced by many orders of magnitude in luminalbreast cancer going from one of the most abundant cellular proteins to barely express. Her2positive (Her2+) breast cancers have a bimodal GSTP1 expression distribution with a significantproportion also silencing GSTP1. Decreased GSTP1 expression in breast cancer allowed us to discover a novel non-canonicalregulatory function of GSTP1: re-directing the flux of cysteine oxidation to structurally remodel theproteome via allosteric disulfide bonds. These changes are critical for breast cancertransformation since re-expression of GSTP1 and inhibition of redox signaling decreases thetransformation capacity of GSTP1-silenced breast cancer cells. This proposal focuses on two Specific Aims. First is GSTP1 silencing a therapeuticvulnerability in BRCA? Second what are the molecular and redoxomic consequences of GSTP1silencing? Together these Aims will provide new mechanistic insight into how GSTP1 expressiondrives redox signaling in breast cancer and determine if GSTP1 silencing is a therapeuticallyactionable vulnerability. 196280 +No NIH Category available 3-Dimensional;Address;Aminolevulinic Acid;Binding;Biopsy;Brain Neoplasms;Brain scan;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Computer software;Consumption;Country;Development;Diagnosis;Drops;Ensure;Environment;Excision;Fingerprint;Future;Glioblastoma;Glioma;Goals;Healthcare;Image;Image Analysis;Imaging Device;Imaging Techniques;Infiltration;Institution;Licensing;MRI Scans;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Marketing;Measurement;Measures;Multi-Institutional Clinical Trial;Neurosurgeon;Newly Diagnosed;Operative Surgical Procedures;Pathologic;Pathology;Patient Care;Patient-Focused Outcomes;Patients;Performance;Physicians;Physiological;Property;Radiation Dose Unit;Radiation Oncologist;Radiation therapy;Radiogenomics;Radiology Specialty;Recurrence;Relaxation;Reproducibility;Research;Sampling;Scanning;Site;Standardization;System;Techniques;Testing;Therapy trial;Time;Tissue Sample;Tissues;Translating;Travel;Validation;Variant;Vendor;brain tumor imaging;cancer imaging;clinical application;clinical care;clinical imaging;clinical implementation;clinical research site;clinical translation;computerized data processing;digital;experience;imaging biomarker;imaging platform;improved;improved outcome;industry partner;interest;neurosurgery;next generation;novel;outcome prediction;performance site;personalized medicine;predictive modeling;predictive tools;prospective;quantitative imaging;radiologist;radiomics;reconstruction;recruit;synergism;targeted treatment;tool;treatment planning;trial comparing;trial planning;tumor;volunteer MR Fingerprinting based Quantitative Imaging and Analysis Platform (MRF-QIA) for brain tumors. Project Narrative:Almost all clinical magnetic resonance imaging (MRI) scans are inherently qualitative which leads to subjectiveanalysis and poor center-to-center reproducibility. This project is to develop and clinically translate a novelquantitative MR scan called MR Fingerprinting and a quantitative image analysis software called MRF-QIA intothe clinical workflow through an academic and industry partnership. We will also clinically validate a specializedapplication for predicting tumor infiltration in glioblastoma patients that will eventually allow personalizedtreatment planning to improve patient outcomes. NCI 10753556 1/3/24 0:00 PAR-20-155 5R01CA269604-02 5 R01 CA 269604 2 "KIM, BOKLYE" 1/1/23 0:00 12/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-S(57)R] 12566494 "MA, DAN " "BADVE, CHAITRA ; DAVATZIKOS, CHRISTOS " 11 BIOMEDICAL ENGINEERING 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 503308 NCI 335049 168259 Abstract The clinical utility of MR images is largely as a qualitative tool without in-built standardizationwhich requires subjective interpretation and time-consuming analysis. Importantly thesequalitative MRI approaches have demonstrated poor tissue characterization and poor center-to-center reproducibility greatly limiting their use in clinical trials. Availability of a robust quantitativeimaging tool with high tissue discriminability can directly impact clinical care by offering actionableinformation to end-user clinicians. As an example availability of accurate tumor infiltration mapsin Glioblastomas a highly aggressive brain tumor can pave the way for novel multisite clinicaltrials in personalized radiation therapy and neurosurgery for improved outcomes. None of thecurrent MRI techniques offer this capability in an accurate and reproducible manner. MRF is aquantitative imaging scan that can address the limitations of qualitative MRI by providingreproducible and physiologically meaningful measurements of tissue properties. We have alsoshown that utilizing the underlying physical/physiological bounds of the quantitative MRF valuesimproves the reproducibility of the image analysis techniques. Integration of MRF and advancedquantitative analytics could fundamentally address the well-recognized low-reproducibility inqualitative MRI approaches and allow broad clinical translation. In this proposal we haveestablished an academic-industrial partnership among MRF developers (CWRU) image analysisand AI experts (UPenn) Brain tumor imaging experts (UHCMC) and leading healthcare company(Siemens) to ensure successful clinical translation of the MRF-QIA into the clinical workflow. Wewill achieve our goal with the following aims: Aim 1: Establish a high throughput MRF scan andassess multisite performance for FDA approval; Aim 2: Fully integrate the MRF-QIA imageanalytics software into the clinical system for brain tumor analysis; Aim 3: Clinical validation of theMRF-QIA application for infiltration prediction in Glioblastoma patients. This project will add newcapabilities to the clinical flow directly impacting the end-user experience and patient care: 1) FDAapproval of MRF product scan will allow any Siemens clinical site to add it to their routine patientscans. 2) The MRF-QIA software will be distributed globally through Siemens Global DigitalMarket and will be available for broad clinical and multisite research applications. 3) Thespecialized application for GB infiltration prediction will lead to new clinical trials for planningtargeted biopsy extended resections and personalized radiotherapy by neurosurgeons andneuro-oncologists to eventually provide targeted treatment plans for GB patients. 503308 +No NIH Category available Acute;Acute Lymphocytic Leukemia;Adult;Affect;Age;Antibodies;Antigens;B cell differentiation;B cell therapy;B lymphoid malignancy;B-Lymphocytes;Blood;Blood Tests;CAR T cell therapy;CD19 gene;Cell Lineage;Cell Maturation;Cells;Characteristics;Childhood;Childhood Leukemia;Clinical;Communicable Diseases;Data;Dedications;Development;Diphtheria;Disease remission;Ensure;Epidemiology;Epitopes;FDA approved;Frequencies;Goals;Guidelines;Haemophilus influenzae;Hepatitis A;Hepatitis B;Humoral Immunities;Immunity;Immunocompetence;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Immunologic Markers;Immunooncology;Immunotherapy;Individual;Infection;Infection prevention;Influenza B Virus;Institution;Intravenous Immunoglobulins;Kinetics;Knowledge;Laboratories;Long-Term Effects;Medicine;Memory B-Lymphocyte;Methods;Minority;Modeling;Multiple Myeloma;Non-Hodgkin's Lymphoma;Non-Malignant;Observational Study;Outcome;Patients;Pertussis;Plasma Cells;Population;Recovery;Relapse;Research Personnel;Research Proposals;Sampling;Scanning;Streptococcus pneumoniae;Subgroup;T cell therapy;T-Lymphocyte Subsets;Testing;Tetanus;Time;Vaccinated;Vaccination;Vaccines;Viral;Virus;cancer immunotherapy;cancer therapy;cost effective;cytokine release syndrome;evidence base;high risk population;immune-related adverse events;improved;improved outcome;indexing;infection risk;innovation;neurotoxicity;novel;observational cohort study;pathogen;pathogenic virus;pragmatic intervention;preservation;programs;prophylactic;prospective;response;risk stratification;selective expression;statistics;success;targeted treatment;time use;tumor;vaccination strategy;vaccine response Humoral immunity after CAR-T cell therapy for B cell malignancies: The HICAR Study PROJECT NARRATIVEThe long-term effects of CAR-T cell therapies (CARTx) on pathogen-specific humoral immunity and infection riskare poorly understood. There are no data to guide evidence-based approaches to prophylactic strategies suchas vaccination or immunoglobulin replacement to prevent infections in this rapidly growing high-risk population.This proposal will characterize antibody levels and vaccine responses after CARTx and how these results varyby treatment and clinical characteristics to improve long-term outcomes after CARTx. NCI 10753555 12/21/23 0:00 RFA-CA-19-044 5U01CA247548-05 5 U01 CA 247548 5 "LIU, YIN" 1/1/20 0:00 12/31/24 0:00 ZCA1-RTRB-Y(O1) 11706357 "HILL, JOSHUA AIDEN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 353 Non-SBIR/STTR 2024 592029 NCI 343665 248364 PROJECT SUMMARY/ABSTRACTThe development of chimeric antigen receptor T cell therapies (CARTx) for B cell malignancies is a majormilestone in cancer immunotherapy with high rates of durable complete remissions. Although cytokine releasesyndrome and neurotoxicity are the earliest and most dramatic immune related adverse events (irAEs) afterCARTx severe manifestations are transient and only affect a minority of patients. In contrast on-target off-tumor depletion of non-malignant B lineage cells affects the majority of patients and all long-term responders.CD19 expression declines as B cells differentiate into plasma cells whereas BCMA is selectively expressed byplasma cells. Since plasma cells are responsible for maintaining long-lived antibodies and nave/memory B cellsare important for generating new immunity CD19 versus BCMA-CARTx may differentially affect preexistingimmunity and vaccine responses. Dr. Hills goal is to understand the long-term effects of CARTx on humoralimmunity. This proposal incorporates the expertise of an outstanding group of researchers in infectious diseasesimmuno-oncology epidemiology laboratory medicine and statistics who are dedicated to ensuring the successof this innovative research proposal. They will leverage their expertise and high-volume immunotherapyprograms to achieve the following aims.The first Aim involves a prospective observational cohort study of 130 CARTx recipients (50 adult CD19 50pediatric CD19 30 adult BCMA) with relapse-free survival 6 months. Dr. Hill will use a novel systematic viralepitope scanning method (VirScan) to longitudinally characterize the antivirome to 206 viral pathogens. Theseresults will describe and identify correlates of antivirome diversity metrics at 6- and 12-months post-CARTx.VirScan will allow for a nuanced assessment of the differential impacts of CARTx on humoral immunecompetence. The second Aim will utilize samples from Aim 1 to determine the effect of CARTx on the durabilityof preexisting humoral immunity to vaccine-preventable infections and the proportion of patients lackingseroprotection after CARTx. These data will expand on Aim 1 to inform vaccination strategies. In the third AimDr. Hill will perform a prospective observational study of 95 CARTx recipients (50 adult CD19 25 pediatric CD19and 20 adult BCMA) to define the frequency and correlates of positive vaccine responses 6 months afterCARTx. Patients will be vaccinated for S. pneumoniae tetanus diphtheria pertussis H. influenza b andhepatitis A and B according to institutional guidelines.This proposal will address critical knowledge gaps by employing innovative methods to elucidate the scope ofpathogen-specific deficits in humoral immunity and whether vaccination can mitigate these irAEs after CARTx.The findings will guide evidence-based strategies for infection prevention such as vaccination or immunoglobulinreplacement to improve outcomes in this rapidly growing population of high-risk individuals. 592029 +No NIH Category available Address;Adjuvant;Adoptive Cell Transfers;Adoptive Transfer;Albumins;Animals;Antigen Presentation;Antigen-Presenting Cells;Antigens;Binding;Biodistribution;Biological Models;Blood;Blood Circulation;Cancer Vaccines;Cell Count;Cell Culture Techniques;Cell Therapy;Cell membrane;Cells;Clinical;Clinical Trials;Disease remission;Dose;Engraftment;Ensure;Exhibits;Face;Fluorescein-5-isothiocyanate;Hematologic Neoplasms;Human;Immune system;Immunization;Immunocompetent;Immunotherapy;Injections;Investments;Language;Licensure;Ligands;Lipids;Lymph;Membrane;Memory;Molecular;Molecular Chaperones;Molecular Target;Patients;Peptide Vaccines;Peptides;Phenotype;Phospholipids;Polymers;Population;Property;Public Health;Regimen;Rejuvenation;Research;Role;Safety;Secondary Immunization;Solid Neoplasm;Surface Antigens;System;T cell response;T cell therapy;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Vaccinated;Vaccination;Vaccine Adjuvant;Vaccines;amphiphilicity;booster vaccine;cancer immunotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;design;draining lymph node;genetically modified cells;in vivo;leukemia/lymphoma;lymph nodes;melanoma;mouse model;neoplastic cell;peptide amphiphiles;receptor;response;safety assessment;success;synthetic biology;technology platform;tumor;uptake Enhancing CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor Project Narrative: Using no more than two or three sentences describe the relevance ofthis research to public health. In this section be succinct and use plain language thatcan be understood by a general lay audience.Immunotherapy using the transfer of a patients own T cells genetically modified to attacktumors is showing great promise in clinical trials but faces several challenges to reach its fullpotential in the treatment of solid tumors. In this project we propose to develop a strategy tovaccinate transferred T cells boosting their expansion and function in patients to increase thesafety and efficacy of this promising cancer immunotherapy. NCI 10753531 12/15/23 0:00 PAR-19-158 5R01CA247632-05 5 R01 CA 247632 5 "SOMMERS, CONNIE L" 1/1/20 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-H(02)M] 7368895 "IRVINE, DARRELL J" Not Applicable 7 ENGINEERING (ALL TYPES) 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA BIOMED ENGR/COL ENGR/ENGR STA 21421029 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 304886 NCI 210713 94173 Project Summary/Abstract 30 lines or less:Adoptive cell therapy (ACT) with chimeric antigen receptor (CAR) T cells has shown dramaticclinical responses in hematologic cancers with a high proportion of durable completeremissions elicited in leukemias and lymphomas. This success has led to a strong commercialinvestment establishing adoptive cell therapy as a viable clinical therapy and the first licensureof CAR-T therapy by the FDA in 2017. However achieving the full promise of CAR-T ACTespecially in solid tumors will require further advances in this form of cellular therapy. A keychallenge is maintaining a sufficient pool of functional CAR-T cells in vivo. In addition even inhematologic tumors treated effectively with CAR T cells chemotherapeutic lymphodepletionregimens with high toxicity are often required to ensure the engraftment and initial expansion ofthe donor cells. We recently discovered an efficient strategy for molecularly targeting peptidevaccines and vaccine adjuvants to lymph nodes through the use of albumin-bindingphospholipid-polymer linkers conjugated to antigens/molecular adjuvants. Albumin constitutivelytraffics from blood to lymph and serves as an effective chaperone to concentrate theseamphiphile-vaccine (amph-vax) components in lymph nodes that would otherwise be rapidlydispersed in the bloodstream following parenteral injection. However these lipid-polymerconjugates also exhibit the property that they insert in cell membranes on arrival in lymphnodes. We propose here to exploit these dual lymph node targeting and membrane-decoratingproperties of amph-vax molecules to create a booster vaccine for CAR T cells which can beused to repeatedly expand and rejuvenate CAR-T directly in vivo- in native lymph nodes and/ortumors. To evaluate this approach in the presence of a complete host immune system we willtest this concept both with human T cells and with an immunocompetent syngeneic mousemodel of melanoma recently developed by our lab. Our specific aims are to (1) Characterizethe biology of synthetic antigen presentation of amphiphile-ligands from the surface of antigenpresenting cells to CAR T cells in vivo (2) to demonstrate an amph-vax design generalizable toany CAR (3) to evaluate the capacity of a CAR-T vaccine to expand T cells with enhancedfunctionality and persistence in vivo and (4) to test the utility of intratumoral amph-vax deliveryto enhance CAR-T and endogenous T cell priming in tandem. These studies will establish arobust technology platform to transform multiple aspects of adoptive cell therapy and addresskey limitations in existing ACT therapeutic strategies. 304886 +No NIH Category available Acute;Anabolism;Antineoplastic Agents;Biological Assay;Cancer cell line;Carbon;Cell membrane;Cells;Characteristics;Clinical Trials;Collaborations;Colon Carcinoma;Colorectal Cancer;Coupled;Cytosol;Development;Disease;Disease remission;Dose;Drug Delivery Systems;Drug Kinetics;Drug Transport;Enzymes;Epithelial Cells;Epithelial ovarian cancer;Equilibrium;Evaluation;Exhibits;FDA approved;FRAP1 gene;Genetically Engineered Mouse;Glutathione;Glycine;Glycine Hydroxymethyltransferase;Human;Hydroxymethyltransferases;Hypoxia;In Vitro;In complete remission;KPC model;KRAS2 gene;Lead;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Molecular;Mus;Non-Small-Cell Lung Carcinoma;Nucleotide Biosynthesis;Nutrient;Oxidation-Reduction;Pancreas;Partial Remission;Pathway interactions;Pemetrexed;Pharmaceutical Chemistry;Pharmacology;Pharmacy (field);Prognostic Factor;Proliferating;Protons;Purines;Pyrimidine;Reactive Oxygen Species;Recovery;Regulation;Research;Respiration;Ribonucleotides;Role;SLC19A1 gene;Series;Serine;Severe Combined Immunodeficiency;Signal Transduction;Source;Structure;Survivors;Testing;Time;Toxic effect;Transplantation;X-Ray Crystallography;Xenograft Model;Xenograft procedure;advanced disease;analog;antitumor agent;cancer care;cancer cell;clinical care;clinically relevant;drug discovery;drug metabolism;efficacy trial;gemcitabine;glycine amide;in vivo;in vivo evaluation;inhibitor;lead optimization;metabolomics;mouse model;mutant;nanomolar;new therapeutic target;novel;novel strategies;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;patient derived xenograft model;preclinical study;prototype;standard of care;structural biology;therapeutic target;thymidylate;tumor;tumor growth;tumor microenvironment;uptake Therapeutic Targeting Mitochondrial C1 Metabolism PROJECT NARRATIVEWe discovered novel compounds targeting a critical mitochondrial enzyme (SHMT2) with secondary inhibitionof cytosolic nucleotide biosynthesis that represent an entirely new approach for treating cancer. Our objective isto optimize lead structures for tumor targeting and inhibition of mitochondrial and cytosolic metabolism atmodest doses with minimal toxicity. This collaboration between experts in medicinal chemistry molecularpharmacology of anti-cancer drugs x-ray crystallography and structural biology pharmaceutics in vivo mousemodels of cancer and clinical care of patients with pancreatic cancer is rare in academic research into targetedcancer drug discovery. Our proposed studies will provide the important groundwork for further preclinicalstudies leading to an IND application for these novel molecules. NCI 10753524 12/22/23 0:00 PA-19-056 5R01CA250469-04 5 R01 CA 250469 4 "GREENBERG, WILLIAM A" 1/1/21 0:00 12/31/25 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1955379 "MATHERLY, LARRY H" "DANN, CHARLES E.; GANGJEE, ALEEM " 13 RADIATION-DIAGNOSTIC/ONCOLOGY 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 552994 NCI 459714 93280 ABSTRACTMetabolic reprogramming is an important hallmark of cancer. Of the altered metabolic pathways associatedwith malignancy one-carbon (C1) metabolism is particularly notable. The 3-carbon of serine is the major C1donor for de novo synthesis of purines and thymidylate in the cytosol and the primary catabolic pathway forserine and synthesis of glycine occurs in the mitochondria. The mitochondrial C1 pathway also generatesreducing equivalents and is an important source of ATP. The first enzyme of the mitochondrial C1 pathwayserine hydroxymethyltransferase (SHMT) 2 is an oncodriver which is upregulated in a substantial number ofcancers. Growing evidence suggests that SHMT2 could be an independent prognostic factor and an importanttherapeutic target for cancer. We discovered novel 5-substituted pyrrolo[32-d]pyrimidine compounds AGF291AGF347 and AGF359. Following their internalization by the proton-coupled folate transporter (PCFT) thesecompounds inhibit mitochondrial C1 metabolism at SHMT2 with direct secondary inhibitions of cytosolictargets in de novo purine (DNP) biosynthesis (at 5-aminoimidazole-4-carboxamide ribonucleotideformyltransferase and glycinamide ribonucleotide formyltransferase) and SHMT1. Our compounds inhibitproliferation of epithelial ovarian cancer non-small cell lung cancer colorectal cancer and pancreatic cancer(PaC) cells suggesting their potential as broad-spectrum anti-tumor agents. AGF347 exhibited significant invivo antitumor efficacy with potential for complete responses against both early and upstage PaC xenograftmodels. We posit that our novel compounds offer an entirely new approach for treating cancer. Our objectiveis to optimize our lead structures for tumor targeting via PCFT and inhibition of mitochondrial and cytosolicC1 metabolism at modest doses with minimal toxicity. We will use PaC as a disease prototype for furtherdevelopment of our novel multi-targeted inhibitors. In Aim 1 we will synthesize up to 100 compounds basedon lead compounds to optimize uptake by tumors and inhibition of SHMT2 and cytosolic pathways includingDNP biosynthesis. In Aim 2 we will test analogs from Aim 1 for antitumor potencies toward clinically relevantPaC cell lines tumor selectivity and plasma membrane and mitochondrial drug transport drug metabolism andinhibition of SHMT2 and cytosolic pathways including DNP biosynthesis. We will measure downstream impactson mTOR signaling mitochondrial respiration glutathione pools and reactive oxygen species. In Aim 3 wewill evaluate pharmacokinetics tolerability and in vivo antitumor activities of compounds from Aims 1 and 2 bytoxicity/efficacy trials with human PaC cell line xenograft and PDX models and with the KPC mouse PaC model.Our lead analogs are first-in-class and our proposed studies will afford optimized compounds with the bestbalance of selective tumor targeting and anti-tumor efficacy resulting from inhibition of SHMT2 anddownstream anabolic pathways. We anticipate developing SHMT2/DNP-targeted compounds for INDsubmission and clinical trials based on our studies. 552994 +No NIH Category available Ablation;Address;Affect;American;Animal Model;Animals;Anti-Inflammatory Agents;Apoptosis;Area;Autoimmune Diseases;Biological Assay;Biomedical Engineering;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Coculture Techniques;Colitis;Colon;Colon Carcinoma;Combined Modality Therapy;Complementary and alternative medicine;Crohn's disease;DNA;DNA Damage;Dangerousness;Disease;Dose;Drug Kinetics;Economic Burden;Effectiveness;Europe;Exposure to;FDA approved;Fractionation;Functional disorder;Genetically Engineered Mouse;Genome;Ginseng Preparation;Goals;Immune;Induction of Apoptosis;Infiltration;Inflammatory;Inflammatory Bowel Diseases;Intestines;Knowledge;Lead;Life Style;LoxP-flanked allele;Macrophage;Malignant Neoplasms;Mediating;Modeling;Molecular;Mus;Myeloid Cells;Natural Compound;Natural Source;Nature;North America;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Plants;Prevalence;Property;Research;Resveratrol;SIRT1 gene;Sepsis;Signal Pathway;Signal Transduction;Standardization;TNF gene;TP53 gene;Testing;Toxic effect;Treatment outcome;Ulcerative Colitis;anti-cancer;anticancer activity;cancer chemoprevention;cell type;cellular targeting;colon cancer prevention;colon cancer risk;conditional knockout;conventional therapy;cost;dextran sulfate sodium induced colitis;efficacy testing;experimental study;improved;in vivo;innovation;microbiota;murine colitis;novel;p53 Signaling Pathway;pharmacologic;replication stress;response;sex;side effect;single molecule;small molecule;sound;treatment strategy Harnessing the power of p53 with Panaxynol from American Ginseng to suppress colitis and prevent colon cancer NARRATIVE The purpose of this project is to address the issue of alternative and impactful options for patients withInflammatory Bowel Disease (IBD) to both treat their disease and prevent colon cancer that can result from long-standing and uncontrolled IBD. In comparing innovative treatment strategies panaxynol (PA; isolated fromAmerican Ginseng) stands out as our most potent molecule tested; and we are exploring a unique mechanismthat might not only elucidate colitis mechanisms and cures but branch into other diseases driven by dysregulatedm function. The results of this project will lead to clinical trials and the standardization of PA as a stand-aloneproduct or as part of a synergistic combination therapy for patients with IBD. NCI 10753523 12/7/23 0:00 PA-19-056 5R01CA246809-05 5 R01 CA 246809 5 "PERLOFF, MARJORIE" 1/1/20 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-T(02)M] 7955996 "HOFSETH, LORNE J" "MURPHY, ELIZABETH ANGELA" 6 PHARMACOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF PHARMACY 292080001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 306754 NCI 205875 100879 PROJECT SUMMARY Affecting upwards of 4 million people in North America and Europe with an economic burden of $30 -$45 billion Inflammatory Bowel Diseases (IBDs) are debilitating significantly affect life-style and carry a highcolon cancer risk. Because conventional treatment outcomes are modest with dangerous side effects about halfof IBD patients turn to complementary and alternative medicines (CAMs). Although CAMs have been used forthousands of years there is a gap in our knowledge of the mechanisms supporting their effectiveness.Understanding these mechanisms will lead to standardized treatment for IBD outside of toxic FDA-approveddrugs. This will lower their colon cancer risk. Over the past decade we have shown that American Ginseng (AG)suppresses colitis and prevents colon cancer in mice. Using scientifically rigorous Bioassay-GuidedFractionation we have isolated a polyacetylene called panaxynol (PA) that has anti-inflammatory and anti-cancerproperties. PA (compared to the100's of other CAMs being tested) comes from a natural source and is a singleingredient allowing it to be standardized on its own or in a cocktail. What makes this molecule particularlyinteresting and innovative is the mechanism - it is a single molecule extracted from AG with a unique capacityto target macrophages (m) for apoptosis. Our long-term goal is to identify the primary component(s) of AGresponsible for the robust anti-inflammatory and chemopreventive properties of AG we have observed over thepast decade; and to determine their mechanism of action. The overall objective of this application is to gain adeeper understanding of both: (a) the broad treatment potential of PA (i.e. multiple pharmacologic andbioengineered animal models of colitis and colon cancer); and (b) the underlying mechanism(s) behind theobservation that PA targets m for apoptosis. We focus here on a DNA-damage independent p53 signalingpathway as a mechanism toward m apoptosis. The scientific premise underlying the proposed research isrobust. Comparing nine FDA-approved drugs small molecules and CAMs PA is the most efficacious atsuppressing colitis in a DSS mouse model. Our central hypothesis is that PA isolated after a decade of rigorousbioassay-guided fractionation has anti-inflammatory and anti-cancer activity in the colon because it activatesp53- mediated apoptosis in infiltrating m; mitigating colitis; and preventing colon cancer associated with colitis.Furthermore PA acts as an anti-inflammatory in these models because it induces p53 through a DNA damage-like signaling response in m that is independent of detectable DNA damage. To address this hypothesis wewill test the efficacy of PA in three mouse models of colitis and in genetically engineered mice. Because itappears that PA is taking advantage of a unique p53 mechanism in m we will test PA in mice with p53conditionally knocked out in colonic m. A DNA damage-independent mechanism is explored. Resultsconsistent with our hypothesis would identify an innovative low cost safe specific and natural compound withanti-inflammatory and cancer chemopreventive properties that could quickly be implemented clinically. 306754 +No NIH Category available Acute;Address;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer cell line;Cell Death;Cell Survival;Cells;Clinical;Clinical Investigator;Collaborations;Collection;Combined Modality Therapy;Disease;Disease Progression;Drug Combinations;Drug Screening;Drug Synergism;Epidermal Growth Factor Receptor;Estrogen Receptors;Excision;Experimental Models;FDA approved;Family;Goals;Growth;Human;Impairment;In Vitro;Life;Liquid substance;Malignant Neoplasms;Mammary Neoplasms;Multiple Myeloma;Oncogenic;Oncoproteins;Operative Surgical Procedures;Outcome;Outcomes Research;Oxidative Stress;PIM1 gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase;Phosphotransferases;Pre-Clinical Model;Progesterone Receptors;Proteasome Inhibition;Proteasome Inhibitor;Protein Inhibition;Protein Isoforms;Proteins;Radiation;Reactive Oxygen Species;Recurrent tumor;Reporting;Research;Resistance;Sampling;Solid;Solid Neoplasm;Stress;Testing;Translating;Up-Regulation;Validation;Xenograft Model;antitumor effect;biological adaptation to stress;cancer stem cell;cancer subtypes;cancer type;chemotherapy;clinical development;clinically relevant;cytotoxicity;drug testing;druggable target;early experience;efficacy evaluation;efficacy study;human model;in vivo;inhibitor;kinase inhibitor;malignant breast neoplasm;misfolded protein;molecular targeted therapies;mortality;mouse model;multicatalytic endopeptidase complex;neoplastic cell;novel;overexpression;oxidative damage;pre-clinical;proteotoxicity;proto-oncogene protein pim;rational design;receptor;research clinical testing;resistance mechanism;screening;small molecule inhibitor;standard of care;stem-like cell;targeted treatment;therapy resistant;tool;transcription factor;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor xenograft Investigating Rational Combination Therapies for Triple-Negative Breast Cancer PROJECT NARRATIVETriple-negative breast cancer (TNBC) which accounts for ~20% of all breast cancer cases represents a breastcancer subtype with the poorest outcome. No molecularly targeted therapy has been FDA-approved to treat thevast majority of patients with TNBC and approximately 35% of whom are expected to succumb to the diseaseeach year. Our proposed study will utilize highly robust experimental approaches and is focused on preclinicalidentification and validation of novel and potentially life-saving targeted therapies for patients with TNBC. NCI 10753515 1/3/24 0:00 PA-20-185 5R01CA258833-03 5 R01 CA 258833 3 "KONDAPAKA, SUDHIR B" 1/1/22 0:00 12/31/26 0:00 Developmental Therapeutics Study Section[DT] 10806199 "HORIUCHI, DAI " Not Applicable 5 PHARMACOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 309112 NCI 193195 115917 PROJECT SUMMARY/ABSTRACTTriple-negative breast cancer (TNBC) refers to a collection of heterogeneous breast tumors that lack expressionof immediately druggable molecules such as the estrogen and progesterone receptors and human epidermalgrowth factor receptor 2. No targeted therapy is currently approved for the vast majority of TNBC patients. TNBCpatients who have received the current standard of care consisting of chemotherapy radiation and surgeryoften experience early tumor recurrence and a significantly worse mortality rate. Therefore it is critical to identifyand validate clinically viable life-saving targeted therapies for patients with TNBC. We previously reported thatthe oncogenic MYC pathways were activated in ~50% of TNBC cases compared with non-TNBC cases and thatMYC levels were associated with poor outcomes among TNBC patients. Unfortunately clinical development ofinhibitors that directly target MYC activity has remained challenging. To overcome this challenge we previouslytook an alternative approach known as the synthetic lethal screening approach to identify readily druggabletargets required for MYC-driven tumor viability but that are not essential in non-tumor cells. Our screen identifiedthe PIM family of kinases which is composed of the closely related nonessential kinase isoforms PIM1 -2 and-3 (PIM hereafter) as a promising target in MYC-driven TNBC. We found that PIM expression was elevated intriple-negative (TN) tumors in clinical samples and was associated with poor patient outcomes. Clinically relevantpan-PIM inhibitors showed activity in various experimental models of TNBC. However our single-agent efficacystudies using preclinical PIM inhibitors showed that although PIM inhibition significantly slowed the growth of TNtumors it induced only modest in vivo tumor cell death and regression suggesting the need for combinationtherapies. We have taken robust drug screening approaches and have unexpectedly found that the drugcombination that targets PIM kinases and the proteasome can acutely induce toxic levels of proteotoxic stressselectively in MYC-overexpressing TNBC cells. Mechanistically our preliminary observations indicate that PIMinhibition which elevates the levels of reactive oxygen species when combined with proteasome inhibitionoverwhelms the capacity of TNBC cells to continuously degrade damaged proteins resulting in proteotoxic crisis.Thus our observations raise the possibilityand our study will test the hypothesisthat PIM inhibitionrepresents a unique and clinically viable tool to sensitize TNBC tumors to proteasome inhibition. The successfulexecution of this research will allow for the identification and interrogation of clinically exploitable vulnerabilitiesin MYC-driven solid-cancer types such as TNBC. The outcomes of this research could also encourage the FDA-approved proteasome inhibitors (e.g. carfilzomib) which have not been successfully used outside of liquid tumortypes to be rapidly evaluated in combination with pan-PIM kinase inhibitors in early-stage MYC-driven solid-tumor trials. 309112 +No NIH Category available Address;Adoption;Adult;Benchmarking;Biological Markers;Biological Models;Cancer Biology;Cancer Model;Cataloging;Catalogs;Cell Line;Cell Signaling Process;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Combination immunotherapy;Combined Modality Therapy;Communities;Credentialing;DNA sequencing;Data;Dependence;Development;Disease Progression;Electroporation;Engineering;Epigenetic Process;Epithelium;Evaluation;FGFR1 gene;Flow Cytometry;Genes;Genetic;Genetic Annotation;Genetic Diseases;Genetic Variation;Genetically Engineered Mouse;Genome;Genome engineering;Genomics;Genotype;Goals;Human;Human Biology;Immune;Immunocompetent;Immunooncology;Laboratories;Lesion;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mediating;Methods;Minor;Modeling;Molecular;Molecular Analysis;Mus;Mutation;Myeloid-derived suppressor cells;Oncogenes;Oncology;Organ;Patient-Focused Outcomes;Patients;Phenotype;Physiological;Physiology;Pre-Clinical Model;Property;Reagent;Regulatory T-Lymphocyte;Role;Series;Testing;Therapeutic;Tissues;Toxic effect;Translational Research;Treatment Protocols;Tumor Suppressor Genes;Variant;anticancer research;cancer cell;cancer diagnosis;cancer genome;cancer initiation;cell type;checkpoint therapy;cohort;efficacy evaluation;efficacy testing;flexibility;genetic element;genome sequencing;host neoplasm interaction;human cancer mouse model;human disease;human model;immune cell infiltrate;immunoregulation;in vivo;in vivo Model;insight;malignant stomach neoplasm;mouse model;new therapeutic target;next generation;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;portability;pre-clinical;precision oncology;preclinical study;prostate cancer model;response;standard of care;targeted treatment;therapeutic target;therapy development;tool;transcriptome sequencing;translational study;treatment response;tumor;tumor behavior;tumor microenvironment;tumor progression;tumorigenesis;wasting;whole genome Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies The cataloging of mutations in human cancers has produced new insights into oncology but functional studiesin relevant model systems are needed to interpret and exploit this information. Herein we propose to develop arapid and inexpensive platform based on electroporation of genetic elements into specific tissues of adult miceto study cancer drivers and the dependencies they create in an immunocompetent and physiological context.Our approach will contribute to our understanding of cancer mechanisms and provide a suite of genetically-engineered mouse models that will facilitate evaluation of targeted therapies and immune oncology agents. NCI 10753498 12/15/23 0:00 PAR-17-245 5R01CA233944-05 5 R01 CA 233944 5 "WATSON, JOANNA M" 1/1/20 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-J(55)R] 1928317 "LOWE, SCOTT W." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 439281 NCI 244588 194693 Genome characterization has enabled the cataloging of genes altered in human tumors and stimulated thedevelopment of therapies that exploit these alterations. Still functional studies are ultimately needed to interpretand exploit the genetic variation that exists in human cancers. Furthermore it is now apparent that cancerphenotypes and responses to therapy are dramatically influenced by the tissue microenvironment and hence itis necessary to have in vivo models that accurately recapitulate both the genetics and physiology of cancers inpatients. Although existing genetically engineered mouse models (GEMMs) have been instrumental in validatingcancer-promoting mutations and developing therapeutic concepts in a physiological and relevant context thesemodels are simply too slow and expensive to be broadly useful and only recapitulate a minor fraction of thegenetic lesions associated with human cancer. Driven by the need for more accurate and facile models thisproject combines CRISPR genome engineering and in vivo organ electroporation with the goal of producing thefirst-in-kind collection of genetically-defined mouse models of three major epithelial malignancies. We refer tothese models as electroporation-based genetically engineered mouse models (EPO-GEMMs). EPO-GEMMshave a range of advantages over traditional GEMMs in that they are fast affordable modular highly portableand avoid the substantial waste associated with GEMMs produced by strain intercrossing. These models arefully somatic enable focal tumor development and importantly enable the study of tumor-host interactions byallowing tumors to be rapidly engineered in hosts of different genetic backgrounds. Based on substantialpreliminary data to validate the EPO-GEMM concepts our project will produce and characterize EPO-GEMMsof stomach prostate and pancreatic cancer - three common human cancers for which existing mouse modelsdo not exist or are tedious. We will then perform a series of demonstration projects to evaluate and illustrate theunique potential of the EPO-GEMM approach ranging from testing the efficacy and toxicity of target inhibitionexploring the effects of specific immune cell types on cancer initiation and progression and using synchronouscohorts of genetically defined cancer models to test new targeted therapies and immune oncology approaches.Therefore our project is of direct relevance to the overarching goals of the Oncology Models Forum as EPO-GEMMs constitute translational research models that are robust representations of human biology areappropriate to test questions of clinical importance and provide reliable information for patients benefit. Eachof these models will be credentialed with the Oncology Model Fidelity Score and all reagents will be madeavailable through the NCIP Hub. We believe that the development and detailed characterization of rapid flexibleand immunocompetent EPO-GEMMs and the adoption of these models for pre-clinical studies will be critical forthe functional annotation of genetic variation in human cancer and greatly contribute to the implementation ofprecision oncology. 439281 +No NIH Category available Adverse effects;Affect;Affective;Amputees;Analgesics;Bilateral;Biomimetics;Bionics;Breast;Breast Cancer Risk Factor;Breast Cancer survivor;Case Study;Chest;Communication;Complex;Conscious;Cutaneous;Data;Deafferentation procedure;Development;Devices;Distress;Electric Stimulation;Electrodes;Electronics;Esthesia;Fascicle;Feeling;Frequencies;Future;Goals;Hand;Human;Implant;Implanted Electrodes;In Situ;Injury;Intervention;Limb structure;Location;Mammaplasty;Mammary Gland Parenchyma;Mastectomy;Measures;Nerve;Nipples;Numbness;Operative Surgical Procedures;Pain;Participant;Patients;Phantom Limb Pain;Phase 0 Trial;Physiologic pulse;Probability;Procedures;Process;Psychophysics;Quality of life;Reconstructive Surgical Procedures;Recovery;Research;Residual state;Risk;Risk Reduction;Safety;Sensory;Signal Transduction;Simple mastectomy;Structure of radial nerve;Structure of ulnar nerve;Surgical complication;Symptoms;Technology;Testing;Time;Tissues;Touch sensation;United States Food and Drug Administration;Ventral thoracic nerve structure;Woman;bench to bedside;chronic neuropathic pain;chronic pain;cost;design;experience;foot;implantation;improved;limb amputation;malignant breast neoplasm;median nerve;nerve supply;neural patterning;neural stimulation;neuroprosthesis;novel;pain reduction;pressure;primary outcome;reconstruction;sensor;somatosensory;success;surgical risk Bionic Breast Project: A Neuroprosthesis to Restore Touch Sensation and Reduce Chronic Pain After Mastectomy PROJECT NARRATIVESimple mastectomy amputates all of the breast tissue including the third through sixth intercostal nerves leavingthe breast numb. The resulting deafferentation leads to major adverse effects including a disembodiment of thebreasts loss of touch-based affective communication abolition of breast-centered erogenous touch and inmany women the development of chronic pain. Our objective is to lay the groundwork for a neuroprostheticsolution to the negative sensory sequelae of mastectomy by establishing that touch sensation can be restoredto the breast via bionics. NCI 10753314 7/27/23 0:00 PAR-21-035 1R01CA281301-01A1 1 R01 CA 281301 1 A1 "PERLOFF, MARJORIE" 8/1/23 0:00 7/31/28 0:00 "Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section[BNVT]" 7744804 "LINDAU, STACY TESSLER" Not Applicable 1 OBSTETRICS & GYNECOLOGY 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 844117 NCI 610623 233494 PROJECT SUMMARY/ABSTRACTMillions of women worldwide have undergone mastectomy and breast reconstruction procedures. Simple (alsocalled total) mastectomy the most common mastectomy procedure for women with breast cancer amputatesall of the breast tissue including the third through sixth intercostal nerves leaving the breast numb. Loss ofsensation is a distressing symptom (affecting more than 60%) that leads to major adverse effects includingelevated risk of injury disembodiment (a feeling that the breasts no longer are part of one's body) loss of touch-based affective communication (e.g. the feel of an embrace) and loss of erogenous sensation. Mastectomyalso often results in chronic neuropathic pain (25-60%) a costly and burdensome condition that standardinterventions cannot reliably alleviate. Our solution the Bionic Breast Device (BBD) combines a neuralstimulation approach (successfully deployed to restore touch in bionic hands and feet in limb amputees) with anovel tissue-like stretchable sensor that detects pressure applied to the nipple-areolar complex. The BBD willtrigger stimulation of intercostal nerves evoking a sensation experienced on the otherwise insensate breast. Theobjective of the present Phase 0 trial is to characterize for the first time the sensory consequences of electricallyactivating the intercostal nerves that innervate the breast in women who have recently undergone a mastectomy.In this study we will implant cuff electrodes on intercostal nerves T3 and T4 in women during their mastectomyprocedure. Participants will all be women undergoing bilateral mastectomy with two stage alloplastic (implant)reconstruction for early breast cancer (unilateral in situ or T1N0 <2cm) or breast cancer risk reduction. Followinga 4-6 week recovery period after mastectomy with electrode implantation participants will undergo twice-weeklypsychophysical testing sessions during which electrical stimulation will be applied to the nerves through theelectrodes via percutaneous leads. Participants will have the electrodes and percutaneous leads removed duringtheir planned second stage reconstructive surgery 12-20 weeks after mastectomy. The specific aims of thisresearch are to: (1) Establish the parameters of electrical stimulation of the intercostal nerves that evokeperceptible and distinguishable sensations and characterize the projected fields on the body; (2) Characterizethe features of the sensations evoked via activation of the intercostal nerves including their quality and perceivednaturalness; and (3) Gauge the short (during implantation) and longer-term (6 months following explantation)impact of intermittent electrical stimulation of the intercostal nerves on post-mastectomy pain. This trial willestablish that touch sensation can be restored to the breast via neural stimulation. Data will also be obtained toinform future feasibility (including safety) efficacy and acceptability trials. The Bionic Breast Project proposesenormous benefit at relatively low cost and risk and thus has the potential to be truly transformative. 844117 +No NIH Category available Adult;Affect;Autocrine Communication;Binding;Biochemical;Biological Assay;Carrier Proteins;Cell membrane;Cell surface;Cells;Chimera organism;Complex;Coupled;Cryoelectron Microscopy;Cysteine-Rich Domain;Data;Dedications;Destinations;Development;Diffusion;Dissociation;Endoplasmic Reticulum;Fab Immunoglobulins;Family;G-Protein-Coupled Receptors;Heterodimerization;Histidine;Homeostasis;Human;Hydrophobicity;In Vitro;Intestinal Cancer;Intestines;Kidney;Lateral;Ligands;Lipid Bilayers;Lipids;Location;Membrane;Membrane Proteins;Membrane Transport Proteins;Modeling;Modification;Molecular;Molecular Conformation;Morphogenesis;Movement;Mutagenesis;Pattern;Polysaccharides;Proteins;Proteoglycan;Publishing;Resolution;Route;Signal Transduction;Site;Structure;Surface;System;Technology;Testing;Tissues;Transferase;Transmembrane Domain;exosome;experience;experimental study;glycosylation;inhibitor;insight;intestinal homeostasis;migration;molecular dynamics;palmitoleate;particle;prevent;protein protein interaction;receptor;stem cell division;stem cell niche Molecular Mechanisms of Wnt Transport NARRATIVEWnts are evolutionarily conserved ligands that signal at short range to regulate morphogenesiscell fate and stem cell renewal. This application will provide a molecular understanding of the howWnts are secreted from the endoplasmic reticulum to the cell surface by binding their dedicatedtransporter protein WLS. We have determined the atomic resolution structure of Wnt in complexwith WLS using cutting-edge single-particle cryo-electron microscopy and we propose tocontribute additional structures as well as employ a range of biochemical and cell-basedexperiments to study how Wnts bind to WLS are transported and dissociate from WLS to reachtheir target cells for signaling. NCI 10753139 9/18/23 0:00 PA-20-185 1R01CA275005-01A1 1 R01 CA 275005 1 A1 "AMIN, ANOWARUL" 9/18/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-MBBC-P(02)M] 9815330 "MANCIA, FILIPPO " "VIRSHUP, DAVID M" 13 PHYSIOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 480139 NCI 319929 160210 ABSTRACTWnts are a family of evolutionary conserved secreted ligands that act at short range to coordinate morphogeneticmovements and cell fate decisions. Secretion of Wnt and subsequent recognition by its cognate receptor requireits O-palmitoleation in the endoplasmic reticulum. This modification is carried out by PORCN that then transfersWnt to WLS its dedicated integral membrane transporter. How WLS associates with Wnt in the ER andsubsequently delivers it to the receptor Frizzled on the receiving cell remains largely unknown and is the focusof this Application.Currently there is a limited understanding of how WLS binds Wnts and transport them to the cell membrane.Here we present as recently published data the structure of human WLS in a complex with WNT8A determinedusing single-particle cryo-electron microscopy to 3.2 resolution. The WLS membrane domain resembles a Gprotein-coupled receptor (GPCR) albeit with one additional transmembrane helix. The O-palmitoleated Wnthairpin loop 2 inserts into a conserved central cavity of the GPCR-related domain with the attached palmitoleateprotruding out into the lipid bilayer. Highly conserved patches on the outward-facing surfaces of thetransmembrane domain of WLS adjacent to a hydrophobic gateway suggest potential mechanisms for Wnttransfer from PORCN and to Frizzled.We propose to further study the interaction between WLS and Wnt using the available structural information asstarting point. First we will investigate how Wnt associate with WLS. We propose to determine the structure ofWLS in its apo absent Wnt state as well as probe the putative site of entrance of Wnt into WLS by structure-guided mutagenesis and biochemical assays. Our preliminary results suggest a direct interaction between WLSand PORCN. Second we will test how changes in sequence and glycosylation pattern can affect Wnt secretionand destination as well as the effect of pH on the interaction between the two proteins using structure-guidedmutagenesis as well as Wnt transport and delivery assays in primary intestinal cells. Third we propose to studythe release of Wnt to subsequent receptors. Our preliminary results suggest a direct interaction between WLSand the Frizzled receptor and we will test this hypothesis using detailed structure function analyses. 480139 +No NIH Category available Metabolic reprogramming to improve EGFRvIII CAR T cell persistence NARRATIVEAdoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been successful against some liquidtumors but has failed to cure solid tumors; a key reason for CAR T cell failure against solid tumors is antigenheterogeneity. However pre-clinical studies of CAR T cells against solid tumors in animal models show somepromise; in a brain tumor mouse model of glioblastoma CAR T cells recognizing the EGFRvIII tumor-specificantigen are successful in eliminating tumor but only against homogeneous tumor and only when mice firstreceive lymphodepletive host conditioning prior to CAR T cell infusion. In this R21 application we propose toutilize metabolic reprogramming of EGFRvIII CAR T cells to improve CAR T cell persistence with the goal toeliminate the need for lymphodepletive host conditioning; and we will test if EGFRvIII CAR T cells delivered inthe absence of lymphodepletive host conditioning preserves the endogenous immune system and improvesheterogeneous tumor killing. NCI 10753084 1/19/23 0:00 PA-21-268 7R21CA253163-03 7 R21 CA 253163 3 "SINGH, ANJU" 7/1/21 0:00 6/30/24 0:00 ZCA1-SRB-A(M1)P 8647178 "MACIVER, NANCIE " Not Applicable 4 PEDIATRICS 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/3/22 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2022 217753 NCI 154157 63596 ABSTRACTAdoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been successful against some liquidtumors but has failed to cure solid tumors. A key reason for CAR T cell failure against solid tumors is antigenheterogeneity. However pre-clinical studies of CAR T cells against solid tumors in animal models show somepromise; in a brain tumor mouse model of glioblastoma CAR T cells recognizing the EGFRvIII tumor-specificantigen are successful in eliminating tumor but only against homogeneous tumor and only when mice firstreceive lymphodepletive host conditioning (via total body irradiation) prior to CAR T cell infusion. Althoughlymphodepletive host conditioning provides immunological space for CAR T cell expansion it is problematic inthe context of heterogeneous solid tumors as it impairs endogenous host immunity which is critical for targetingalternative antigens found within the solid tumor. For that reason successful CAR T cell treatment against solidheterogeneous tumors will require innovative methods to improve CAR T cell persistence to eliminate the needfor host lymphodepletive conditioning and allow for preservation of host endogenous immunity. To achieve thiswe propose to utilize metabolic reprogramming of EGFRvIII CAR T cells. Many studies over the last decadehave now clearly demonstrated a link between T cell differentiation function and metabolism. A predominantlyoxidative metabolism supports T cell surveillance survival and memory whereas a predominantly glycolyticmetabolism supports biosynthesis to promote effector T cell proliferation and function but is associated withdecreased longevity. The objectives of this R21 proposal are to (1) utilize metabolic reprogramming of EGFRvIIICAR T cells to improve CAR T cell persistence in vitro and in vivo and (2) test the ability of modified EGFRvIIICAR T cells delivered in the absence of lymphodepletive host conditioning to preserve the endogenous immunesystem and improve heterogeneous tumor killing. We hypothesize that methods that increase oxidativemetabolism will improve CAR T cell persistence eliminating the need for lymphodepletive host conditioningmaintaining host endogenous immunity and ultimately improving heterogeneous tumor killing. To test ourhypothesis we will perform the following specific aims: 1) Identify genetic and pharmacological strategies tomodify EGFRvIII CAR T cells for enhanced metabolic fitness to support persistence; and 2) Test if metabolicallyfit murine EGFRvIII CAR T cells delivered in the absence of lymphodepletive host conditioning preserveendogenous immunity. If successful these approaches can be partnered in future studies with strategies toenhance endogenous host immunity against heterogeneous tumors and overcome a hostile immunosuppressivetumor environment. This work while performed in a brain tumor model would be relevant for CAR T cell therapyagainst multiple solid tumors. 217753 +No NIH Category available Address;Aging;Amino Acids;BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like;BNIP3L gene;Binding;Biological Markers;Cancer Etiology;Cessation of life;Clinic;Data;Detection;Development;Disease;Disease Management;Disease Progression;Etiology;FRAP1 gene;Fatty Liver;Genes;Glucagon;Grant;Growth;Guanosine Triphosphate Phosphohydrolases;Hepatocyte;Homeostasis;Human;Incidence;Knock-out;Link;Lipids;Liver;Lobule;Lysosomes;Malignant neoplasm of liver;Metabolic;Mitochondria;Molecular;Nutrient;Nutrient availability;Obesity Epidemic;Overnutrition;Patient-Focused Outcomes;Pattern;Phosphotransferases;Primary carcinoma of the liver cells;Process;Proteomics;Regulation;Research;Role;Sampling;Signal Transduction;Societies;Testing;Tumor Suppressor Proteins;United States;Work;cell growth;fatty acid metabolism;fatty acid oxidation;fatty liver disease;hepatocellular carcinoma cell line;improved;inhibitor;insight;lipid metabolism;liver cancer model;liver function;liver metabolism;mTOR Inhibitor;mTOR Signaling Pathway;mTOR inhibition;mitochondrial dysfunction;mouse model;neoplastic cell;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;nutrient deprivation;prevent;receptor;response;tumor growth;tumorigenic BNIP3 and BNIP3L (NIX) in lipid homeostasis and growth control in the liver Project NarrativeThe proposed research examines the role of BNIP3 BNIP3L and mitophagy in control of lipid metabolismin the liver de-regulation of which has significance for understanding the link between fatty liver diseaseand hepatocellular carcinoma. NCI 10752932 5/24/23 0:00 PA-20-185 2R01CA200310-06A1 2 R01 CA 200310 6 A1 "WILLIS, KRISTINE AMALEE" 3/1/16 0:00 5/31/28 0:00 Cancer Cell Biology Study Section[CCB] 7375165 "MACLEOD, KAY F" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 402418 NCI 249782 152636 Project SummaryFatty liver disease has emerged as a major contributing factor to the increased incidence of hepatocellularcarcinoma (HCC) in western societies in the past several years and rates of HCC in the US are projectedto increase further in the years ahead due to over-nutrition and the obesity epidemic. Thus anunderstanding of how lipid levels in the liver are regulated and the underlying mechanistic basis of lipidaccumulation in disease states is important to developing improved ways to prevent and treat fatty liverand HCC. The proposed research sets out to define the role of the BNIP3 and BNIP3L mitochondrialcargo receptors in lipid metabolism in normal liver and in preventing fatty liver disease and hepatocellularcarcinoma. In the past cycle of this grant we showed that BNIP3 is essential for mitophagy induced bynutrient deprivation and that this in turn promotes lipid droplet turnover. Further we showed that BNIP3-dependent mitophagy sets up metabolic zonation in the liver through control of mitochondrial mass. Wealso showed that loss of BNIP3 promoted HCC due to lipid accumulation in both mouse models of livercancer and in human liver where loss of BNIP3 expression predicted HCC patient outcomes whencombined with expression levels of genes involved in fatty acid metabolism. In this renewal applicationour work aims to develop further our understanding of the mechanistic basis of how BNIP3 promotes lipiddroplet turnover in concert with the turnover of mitochondria how a second novel role for BNIP3 inmodulating the mTOR signaling pathway contributes to progression of NAFLD and NASH to HCC andhow BNIP3 and BNIP3L (NIX) interact functionally in the liver. Specifically in Aim 1 we seek to fullyunderstand the role of BNIP3 in lipid droplet turnover and liver metabolism by investigating: (1) whetherBNIP3 interacts with Rheb or other molecular partners at the lysosome and lipid droplet; and/or (2) howthe Rheb-BNIP3 interaction modulates BNIP3-LC3 interactions and mitophagy. The key objective in Aim2 is to define how BNIP3 suppresses steatosis and HCC via modulation of mTOR pathway signaling. InAim 3 we propose to determine how BNIP3 and BNIP3L (NIX) differ in their role in hepatic steatosis andhow this contributes to control of steatosis mTOR activity tumor cell growth and liver cancer. Throughoutthis renewal proposal we make use of novel mouse models human HCC cell lines and primary humanliver samples to explain the role of BNIP3 and BNIP3L in lipid homeostasis and growth control in the liver. 402418 +No NIH Category available Adopted;Age;Alabama;American Society of Clinical Oncology;Body Weight decreased;Cancer Etiology;Cancer Intervention and Surveillance Modeling Network;Cancer Patient;Catalogs;Cessation of life;Characteristics;Chest Pain;Clinical;Clinical Research;Clinical Trials;Collaborations;Community Networks;Community Practice;Community of Practice;Coughing;Data;Data Sources;Decision Analysis;Decision Making;Detection;Diagnostic Imaging;Electronic Health Record;Ethnic Origin;European;Excision;Florida;Funding;Future;Geography;Goals;Guidelines;Image;Infrastructure;Knowledge;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Natural Language Processing;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;Patients;Pattern;Policies;Population;Population Heterogeneity;Prognosis;Prospective cohort;Public Health;Race;Radiology Specialty;Recommendation;Recurrence;Registries;Reporting;Research;Retrospective cohort;Scanning;Shortness of Breath;Smoking Status;Socioeconomic Status;Survival Rate;Symptoms;System;Thoracic Radiography;X-Ray Computed Tomography;black patient;clinical trial enrollment;comorbidity;comparative effectiveness;compare effectiveness;data integration;electronic health data;electronic structure;evidence based guidelines;improved;innovation;lung cancer screening;models and simulation;mortality;multimodality;participant enrollment;patient oriented;patient population;pulmonary function;randomized clinical trials;repository;rurality;screening;social health determinants;sociodemographics;socioeconomics;study population;surveillance data;surveillance imaging;surveillance strategy;unstructured data;uptake Advancing Precision Lung Cancer Surveillance and Outcomes in Diverse Populations (PLuS2) NARRATIVECurrently it is unclear whether guideline-recommended CT imaging surveillance among patients with early-stagelung cancer improves survival. Our proposed study has direct value for advancing public health by examiningreal-world timely data on the outcomes of lung cancer surveillance. The project will combine multimodal real-world data with simulation modeling to fill critical clinical and policy gaps regarding lung cancer surveillance. NCI 10752848 7/5/23 0:00 PA-20-185 1R01CA284646-01 1 R01 CA 284646 1 "MARCUS, PAMELA M" 7/5/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-HSS-P(90)S] 9623464 "BRAITHWAITE, DEJANA K" "BIAN, JIANG ; GOULD, MICHAEL K; JEON, JIHYOUN " 3 SURGERY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 7/5/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 556496 NCI 388879 167617 Due in part to recent advances in screening and treatment the 5-year relative survival rate for patients with early-stage non-small cell lung cancer (NSCLC) the leading cause of cancer death worldwide continues to increase each year. The uptake of guideline-recommended computed tomography (CT) imaging surveillance semiannually for 2 years and annually for up to 5 years following curative-intent therapy is increasing rapidly in the U.S. despite unclear evidence regarding its benefit in reducing mortality. Furthermore clinical trials of CT imaging surveillance have not been reported among U.S. populations with NSCLC. This gap in research is alarming and portends a low quality of evidence in clinical guidelines. Currently no comprehensive lung cancer surveillance data source exists that catalogs real-world lung cancer surveillance utilization patterns and downstream outcomes both of which are necessary to develop evidence-based recommendations for surveillance following curative-intent therapy. This project Advancing Precision Lung Cancer Surveillance and Outcomes in Diverse Populations (PLUS2) will create this unique data source to study understand and optimize lung cancer surveillance and downstream outcomes. Building on the extant infrastructure and preliminary data from the lung cancer screening registry of the PCORI- and NCI-funded OneFlorida+ Clinical Research Consortium a network of community practices that serve Florida Georgia and Alabama PLUS2 will leverage multilevel data from electronic health records claims and system-level factors for patients with early-stage NSCLC who have completed curative-intent therapy (n~27217; median age 70) from 2012-2022 (retrospective cohort) and 2022-2025 (prospective cohort). The overarching goal of the project is to evaluate the comparative effectiveness of lung cancer surveillance strategies principally semi-annual versus annual CT surveillance in relation to long-term outcomes among diverse patients with early-stage NSCLC within the U.S. population. By generating previously unavailable real-world data from NCIs Lung Cancer Intervention and Surveillance Modeling Network (CISNET) for use in validated simulation models this proposal responds directly to calls to improve patient-centered decision-making in lung cancer surveillance candidates for whom the net benefits of surveillance are currently uncertain. This study is foundational for lung cancer surveillance practice change. 556496 +No NIH Category available Defining clinically relevant transcriptional networks in gastrointestinal stromal tumor Project NarrativeFor patients with gastrointestinal stromal tumor (GIST) our clinical capacity to predict the risk of recurrencefollowing resection or the course of metastatic disease is limited and leads to significant uncertainties in patientcare. The oncogenic program underlying GIST is driven by a core group of lineage-specific transcription factorsand epigenetic regulators with resulting disease behavior being dictated by additional disease state-specificaccessory transcription factors. This proposal aims to understand the core transcriptional output of GIST andhow accessory transcription factors modify this central program to inculcate disease behavior with implicationsfor treatment strategies in this disease. NCI 10752803 2/27/23 0:00 PA-21-268 7K08CA245235-04 7 K08 CA 245235 4 "LIM, SUSAN E" 8/1/20 0:00 7/31/25 0:00 Career Development Study Section (J)[NCI-J] 14304164 "HEMMING, MATTHEW " Not Applicable 2 RADIATION-DIAGNOSTIC/ONCOLOGY 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 3/1/23 0:00 7/31/23 0:00 398 Other Research-Related 2022 223535 NCI 206977 16558 Project SummaryGastrointestinal stromal tumor (GIST) is a common form of soft tissue sarcoma and our limited ability to predictthe course of metastatic disease or the risk of recurrence following resection creates significant uncertainties inpatient care. These critical unresolved problems underscore the deficit in biological understanding of factorsinvolved in GIST oncogenesis and clinical behavior. We have previously characterized the enhancer andtranscriptional landscape of GIST using this information to identify a transcription factor (TF) network withelements predictive of patient outcomes. Within this network are core TF members present in all GIST subtypesand responsible for establishing basal GIST transcriptional output. Additional accessory TFs are present in adisease state-specific manner being found exclusively in indolent or aggressive disease. Supporting the TFnetwork the MOZ histone acetyltransferase complex is uniquely responsible for establishing enhancers in GIST.Our central hypothesis is that core TFs and the MOZ chromatin regulatory complex generate the GISTtranscriptional program which is modified by state-specific accessory TFs to instruct disease behaviorand determine clinical outcomes. Understanding how core TFs function to control the GIST epigenome and how accessory TFs modulatethis oncogenic framework is of chief relevance to understanding the biology of this disease. Aim 1 of thisproposal seeks to characterize how the core TF network members interact with enhancers and othertranscriptional regulators to exert gene regulation. Because defined accessory TFs are expressed exclusively ina disease state-specific fashion Aim 2 will determine how these factors modify the core TF network andinfluence transcriptional output through genetic disruption and accessory TF expression in clinical samples willbe used to associate their expression with clinical outcomes. Finally Aim 3 will define the role of the MOZcomplex a unique dependency in GIST in collaborating with TFs to generate the GIST transcriptional state.These studies will define the transcriptional machinery that underlies GIST advance our understanding ofmolecular determinants of indolent and aggressive disease and develop a biological framework for novelapproaches to predicting clinical behavior that may impact the care of patients suffering from this disease. As a physician-scientist dedicated to understanding and treating sarcoma my long-term goal is todevelop an independent research program to generate a detailed understanding of GIST biology that willtransform patient care. During my proposed training period I will perform mentored research in the laboratory ofDr. Scott Armstrong at DFCI with supportive co-mentorship from Dr. George Demetri; my outstanding advisorycommittee will further guide my research and career development. This mentorship together with my exceptionalinstitutional environment access to superb educational programs and myriad training opportunities will enableme to advance my career goals and contribute to meaningful sarcoma research. 223535 +No NIH Category available Address;Aging;American;Biochemistry;Biology;Cells;Cellular biology;Collaborations;Communities;Creativeness;Dedications;Development;Developmental Therapeutics Program;Disease;Educational workshop;Ensure;Environment;Epigenetic Process;Equilibrium;Feedback;Fostering;Future;Gene Expression;Generations;Genetic;Goals;Hematologic Neoplasms;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Housing;Immune;Individual;Inflammation;International;Interpersonal Relations;Lighting;Lightning;Malignant - descriptor;Mentors;Metabolism;Molecular;Oral;Pharmaceutical Chemistry;Postdoctoral Fellow;Productivity;Regulation;Relaxation;Request for Proposals;Research;Research Personnel;Science;Scientist;Societies;Talents;Techniques;Time;Underrepresented Minority;Woman;Work;career;career development;catalyst;cost;design;educational atmosphere;graduate student;hematopoietic differentiation;innovation;interest;lectures;meetings;next generation;novel;novel therapeutic intervention;peer;posters;professor;programs;stem cell biology;symposium;therapeutic target;tumor;tumorigenesis The Hematologic Malignancies Conference NARRATIVEThe FASEB Scientific Research Conference on Hematologic Malignancies is the premier scientific conferencefocused on the biology and therapeutic targeting of hematological disorders. It brings together a critical mass ofleaders in the field with exceptionally talented trainees in an intimate setting that is highly conducive to formaland informal scientific mentoring and interpersonal interactions. The goal of this proposal is to leverage thethriving intellectual environment at this conference in order to catalyze the career development of trainees intofuture independent investigators who will lead the next generation of transformative advances in the field. NCI 10752784 6/22/23 0:00 PA-21-151 1R13CA284792-01 1 R13 CA 284792 1 "DUGLAS TABOR, YVONNE" 8/1/23 0:00 7/31/24 0:00 ZCA1-PCRB-9(M1) 9011036 "GUTIERREZ, ALEJANDRO " Not Applicable 8 Unavailable 74816851 CLHCSTHHSX25 74816851 CLHCSTHHSX25 US 39.013531 -77.101138 2604901 FEDERATION OF AMER SOC FOR EXPER BIOLOGY Rockville MD Other Domestic Non-Profits 20852 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 38900 NCI 38900 0 SUMMARY/ABSTRACTThe goal of this R13 application is to provide partial support to the 2023 Scientific Research Conference onHematologic Malignancies administered by the Federation of American Societies for Experimental Biology(FASEB). This biannual conference is the premier meeting in the field and provides invaluable opportunities forearly-career scientists to interact with peers and leading established investigators in the field in a highly collegialand intimate setting. Numerous established investigators in the field see their attendance at this conferencewhen they were trainees as pivotal to their career development and the ability to help catalyze the careerdevelopment of young investigators is a major draw for established scientists to this conference. The provisionalscientific program highlights the most exciting science at the cutting edge of diverse sub-fields of hematologicmalignancies of deep interest to the scientific community. Major topics include 1) malignant hematopoietic stemcell biology 2) normal hematopoietic development 3) clonal hematopoiesis and aging 4) inflammation andhematopoiesis 5) the hematopoietic niche 6) regulation of leukemogenic gene expression programs 6)metabolism and epigenetics and 7) novel therapeutic strategies. Two keynote lectures from internationallyrecognized leaders in the field bookend the conference. A number of presentation slots are specifically dedicatedto oral presentations by to junior investigators to be selected from abstracts. Poster Lighting Rounds provide anopportunity for trainees to introduce the audience to their work during oral sessions and ensure that the postersessions are one of the most interactive parts of the conference. The sole budgetary request in this R13application is for 50% support of the registration and housing costs for all trainees (graduate students andpostdoctoral fellows) who will present oral or poster presentations at this conference. 38900 +No NIH Category available Address;Adenosine;Antibodies;Artificial nanoparticles;Biological Assay;Blocking Antibodies;COVID-19;Cancer Patient;Cell physiology;Cells;Characteristics;Chemotaxis;Cytotoxic T-Lymphocytes;Disease model;Effectiveness;Electrophysiology (science);Failure;Formulation;Goals;Head and Neck Squamous Cell Carcinoma;Immune;Immune checkpoint inhibitor;Immunologic Surveillance;Immunotherapy;In Vitro;Infiltration;Investigational Therapies;Ion Channel;Laboratories;Liposomes;Malignant Neoplasms;Mediating;Membrane Potentials;Messenger RNA;Methods;Mus;Nature;Oncologist;Operative Surgical Procedures;Organoids;Patients;Peptides;Potassium Channel;Production;Property;Purinergic P1 Receptors;RNA vaccine;Radiation therapy;Relapse;Research;Resistance;Resistance development;Shapes;Signal Pathway;Solid;Solid Neoplasm;Specificity;Survival Rate;T cell infiltration;T cell therapy;T-Lymphocyte;Testing;Toxic effect;Tumor Burden;Up-Regulation;anti-PD1 therapy;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cell motility;chemotherapy;combinatorial;cytokine;cytotoxicity;design;fighting;high risk;humanized mouse;immune cell infiltrate;improved;in vivo;interest;lipid nanoparticle;melanoma;migration;mortality;mouse model;nanoparticle;novel therapeutic intervention;overexpression;patch clamp;programmed cell death protein 1;response;side effect;targeted delivery;trafficking;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Liposome-based mRNA cancer immunotherapy targeting ion channels PROJECT NARRATIVEThe body fights solid tumors by engaging immune cells called T lymphocytes that kill cancer cells.As these cells need Kv1.3 ion channels to perform this function in this proposal we aim to developnew cancer immunotherapy treatments that increase the number of Kv1.3 channels in Tlymphocytes from cancer patients. NCI 10752680 11/16/23 0:00 PAR-20-292 5R21CA277341-02 5 R21 CA 277341 2 "SOMMERS, CONNIE L" 12/9/22 0:00 11/30/24 0:00 ZCA1-TCRB-9(O1)S 2105384 "CONFORTI, LAURA " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 41064767 DZ4YCZ3QSPR5 41064767 DZ4YCZ3QSPR5 US 39.129719 -84.520554 1523902 UNIVERSITY OF CINCINNATI CINCINNATI OH SCHOOLS OF MEDICINE 452210001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 204485 NCI 126225 78260 PROJECT SUMMARYImmune checkpoint inhibitors like monoclonal blocking antibodies against programmed cell death 1 (PD1) haverevolutionized the way solid malignancies are treated. However despite a dramatic response in some patientsthe majority either have no response or develop resistance. The focus of our research is on head and necksquamous cell carcinoma (HNSCC) an aggressive cancer with high mortality rates and high resistance tocheckpoint inhibitors. Our goal is to develop new treatment options that improve immunosurveillance and reducethe resistance to PD1 therapy in HNSCC patients.The efficacy of immunotherapy in cancer relies on the therapy's capability to increase their migration of tumor-specific T cells into the tumor and sustain their cancer killing capacity despite the immunosuppressive tumormicroenvironment (TME). Improving the ability of the T cells to infiltrate the tumor and to function in the hostileTME remains the greatest challenge of immunotherapy. These functions of T lymphocytes rely on Kv1.3 andKCa3.1 potassium channels that control the membrane potential and facilitate the Ca2+ influx necessary forcytokine production cytotoxicity and chemotaxis. We have discovered that these channels contribute to thefailure of immune surveillance and the resistance to immunotherapy in HNSCC. KCa3.1 channels are inhibitedby adenosine an immunosuppressive molecule present in the TME and this mechanism limits T cell infiltrationinto the tumors. In addition Kv1.3 channels are reduced in tumor infiltrating T cells and contribute to inefficientcytotoxicity. Lastly we observed that cytotoxic T cells of HNSCC patients that respond to PD1 blockadedisplay a characteristic increase in Kv1.3 and loss of response to adenosine. Therefore a therapy that enhancesKv1.3 and confer resistance to adenosine selectively in T cells would be highly beneficial in HNSCC.We will develop lipid nanoparticles (LNPs) for targeted delivery to T cells of a messenger RNA (mRNA) encodingKv1.3 and a peptide that confers resistance to adenosine through liposomal nanoparticles. The adenosine-blocking peptide blocks the signaling pathway downstream to the adenosine receptor. Herein will test thehypothesis that a cell-targeted liposomal mRNA formulation that induces overexpression of Kv1.3channels and loss of adenosine-sensitivity in T lymphocytes can reduce the resistance to anti-PD1therapy in HNSCC patients. In Aim 1 we will produce LNPs that carry an mRNA encoding Kv1.3 and a peptidethat blocks the effect of adenosine and are decorated with antibodies for targeted delivery to T lymphocytes. InAim 2 we will determine the impact of these LNPs on tumors utilizing HNSCC patient-derived organoids andhumanized mice. These studies will establish the feasibility of a new formulation that can improve the T cellcytotoxicity and confer resistance to the TME and its validity for single-agent or combinatorial cancerimmunotherapy. 204485 +No NIH Category available Address;Affinity;Antineoplastic Agents;Antitumor Response;Bacterial Toxins;Binding;Biopsy;Blood;Brain;Canis familiaris;Catheters;Cell Separation;Cells;Clinical;Combination immunotherapy;Complement;Convection;Cytotoxic agent;Cytotoxin;Development;Disease Management;Dose;Dose Limiting;Doxorubicin;Drug Monitoring;EPHA3 gene;EphA2 Receptor;EphB2 Receptor;Ephrins;Excision;Genotype;Glioblastoma;Glioma;Heterogeneity;IL13RA1 gene;IgG1;Immune response;Immune system;Immunologics;Infiltration;Interleukin-13;Intravenous;Ligand Binding;Long-Term Survivors;Macrophage;Magnetic Resonance Imaging;Medicine;Microtubules;Modality;Molecular;Molecular Target;Mus;Newly Diagnosed;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase I Clinical Trials;Phenotype;Play;Primary Brain Neoplasms;Primary Neoplasm;Property;Pseudomonas aeruginosa toxA protein;Quality of life;Recurrence;Recurrent tumor;Reflux;Research;Resistance;Rodent;Role;Stains;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Toxic effect;Tumor Volume;Tumor-associated macrophages;Tumorigenicity;antitumor effect;assault;design;drug distribution;effective therapy;experimental study;human disease;human model;improved;in situ vaccination;interest;malignant breast neoplasm;monocyte;mutant;neoplastic cell;neovasculature;novel;overexpression;receptor;response;scaffold;self-renewal;stem cells;stem-like cell;success;therapy resistant;transcriptome sequencing;translational model;tumor;tumor heterogeneity;tumor microenvironment;tumor progression;tumor-immune system interactions Combinatorial Immunotherapy using a Multivalent Drug Conjugate for GBM Treatment NARRATIVEGlioblastoma (GBM) is an incurable primary brain tumor of high heterogeneity. This heterogeneity is one of themajor obstacles to GBM treatment. To this end we identified four molecular targets that are over-expressedcollectively in all patients with GBM but not normal brain. This is a unique development and we generatedcytotoxic drug conjugates targeting these receptors simultaneously with an increased access to tumors toproduce effective molecular resection with long-lasting anti-tumor response. In addition we will also inflamethese immunologically cold tumors with a targeted conjugate so they can mount more effective immuneresponses to complement the direct killing action of the cytotoxins. This approach has a great potential ofsignificantly improving the management of the disease. NCI 10752675 12/15/23 0:00 PA-20-185 5R01CA276233-02 5 R01 CA 276233 2 "CARDONE, MARCO" 12/9/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-OTC1-A(80)S] 1861015 "DEBINSKI, WALDEMAR " "ROSSMEISL, JOHN HENRY" 5 BIOLOGY 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 536182 NCI 426186 109996 SUMMARYTreatment of glioblastoma (GBM) represents an unmet need in medicine. We have been pursuing atherapeutic approach of delivering potent targeted and specific cytotoxins using continuously evolvingconvection-enhanced delivery. Patients with GBM over-express interleukin 13 receptor alpha 2 (IL-13RA2)EphA2 EphA3 and EphB2 receptors that are present in various pathophysiological compartments of GBMand all four are expressed in tumor cells of the core of tumor and in locally-infiltrating tumor cells while EphA2is also found in tumor neovasculature. Further IL-13RA2 EphA2 and EphA3 are associated with and playcrucial roles in the pathobiology of glioma stem-like cells. Finally the EphA3 receptor are found in M2 GBM-associated macrophages. Thus collectively IL-13RA2 EphA2 EphA3 and EphB2 are over-expressed inprincipal GBM compartments shown to be involved in tumor progression and/or resistance to therapies. In afirst-of-kind approach we performed Phase I clinical trial in dogs with spontaneous gliomas which representsa faithful model of human disease using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. Weobserved exceptional anti-tumor responses including several near complete regressions prolongation ofsurvival and excellent quality of life in this dose-finding trial at no toxicity. In addition we found evidence forimmune system activation during the therapy. Encouraged by these results we pursued the novel idea oftargeting all four receptors instead of two with one pharmaceutical compound. One of the Eph receptor ligandsephrinA5 (eA5) binds EphA2 EphA3 and EphB2 receptors. We have thus generated an agent based on eA5and IL-13 mutants targeting all four receptors using an IgG1 scaffold (QUAD). In our initial experiments theQUAD was conjugated to derivatives of Doxorubicin (Dox) or a derivative of Pseudomonas exotoxin APE38QQR to generate single pharmaceutical agents and these drug conjugates retained their bindingaffinities towards the targeted receptors while demonstrating prominent killing activity on GBM cells. QUAD-Dox and QUAD-PE38QQR conjugates have already shown prominent long-lasting anti-tumor effects in dogswith spontaneous glioma at no toxicity: 60 88 and 91% of tumor volume regression in the treated dogsrespectively. Recently we have conjugated QUAD to DM1 a microtubule-disrupting agent. The QUAD-DM1 isextremely potent on GBM cells with IC50s in low femtomolar range ~50x better than the Dox/PE conjugates.Therefore we will continue this exciting line of research through Specific Aims as follows. In Specific Aim 1 wewill treat dogs with spontaneous newly diagnosed and recurrent high-grade gliomas with QUAD-DM1. InSpecific Aim 2 we will examine immune responses and the phenotype and genotype of recurring tumors in thecourse of QUAD-DM1 therapy. Our approach addresses crucial issues of inter- and intra-tumoral heterogeneityand evokes an in situ vaccination or so called tumor inflaming effect. We envision that this all-out assaulttermed by us molecular resection will result in a more effective management of GBM. 536182 +No NIH Category available 3-Dimensional;Affinity;Antineoplastic Agents;Apoptosis;Apoptotic;Binding;Binding Sites;Biochemical;Biological;Biological Assay;Biological Availability;Biophysics;Breast;C-terminal;CD47-SIRP;Cell Adhesion;Cells;Cellular Assay;Chemicals;Clinical;Clinical Trials;Colorectal;Colorectal Cancer;Complex;Cytostatics;DCC gene;Data;Development;Dimethyl Sulfoxide;Dominant-Negative Mutation;Drug Kinetics;Drug Screening;Drug Targeting;Engineering;Epithelium;Fluorescence Resonance Energy Transfer;Focal Adhesion Kinase 1;Focal Adhesions;Future;Glioblastoma;Hydrocarbons;Induction of Apoptosis;Invaded;Knockout Mice;Label;Laboratories;Lead;Libraries;Ligands;Lymphangiogenesis;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Maps;Measures;Mediating;Melanoma Cell;Mesenchymal;Morphologic artifacts;Mutation;N-terminal;Neoplasm Metastasis;Normal Cell;Oncogenic;Oral;Ovarian;PI3K/AKT;Pancreas;Pathway interactions;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phosphotransferases;Proliferating;Protein Isoforms;Protein Tyrosine Kinase;Proteins;Regional Cancer;Reporting;Research;Research Project Grants;Role;Scaffolding Protein;Series;Signal Pathway;Signal Transduction;Solid Neoplasm;System;Technology;Tertiary Protein Structure;Testing;Therapeutic;Transfection;alpha helix;analog;angiogenesis;anti-cancer;beta catenin;biophysical techniques;cancer cell;cancer therapy;cell motility;comparative efficacy;counterscreen;cytotoxicity;design;experimental study;genetic manipulation;improved;in vivo;inhibitor;innovation;kinase inhibitor;knock-down;leupaxin;melanoma;meter;migration;mutant;myristoylation;novel;novel therapeutics;overexpression;paxillin;peptide drug;peptidomimetics;pharmacologic;protein protein interaction;recruit;response;scaffold;screening;small molecule;stapled peptide;targeted cancer therapy;targeted treatment;tumor growth;tumor progression Discovery of PPI inhibitors for the FAK FAT domain PROJECT NARRATIVEThis R21 research project will identify innovative small molecule compounds that target alternative regions ofthe cancer protein focal adhesion kinase (FAK). This project will help identify a new class therapeutics for multiplesolid tumors; including breast pancreatic melanoma ovarian colorectal and lung cancers. Furthermore it willdevelop advanced drug screening technologies to target protein-protein interactions in cancer cells and improveupon current therapies that target FAK. NCI 10752664 11/28/23 0:00 PAR-20-292 5R21CA267285-02 5 R21 CA 267285 2 "FORRY, SUZANNE L" 12/9/22 0:00 11/30/24 0:00 ZCA1-TCRB-V(O1)S 11543338 "MARLOWE, TIMOTHY A" "THATCHER, GREGORY R. J" 7 EMERGENCY MEDICINE 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 161464 NCI 105188 56276 PROJECT SUMMARY/ABSTRACTFocal adhesion kinase (FAK) or protein tyrosine kinase 2 (PTK2) is a 125 kDa non-receptor tyrosine kinaseand scaffolding protein that is overexpressed or amplified in many cancers including ovarian breast colorectalmelanoma glioblastoma and pancreatic cancers. FAK is involved in multiple biological pathways that cancontribute to cancer progression including cell migration invasion lymphangiogenesis anti-apoptosismetastasis epithelial-mesenchymal transition (EMT) and signaling pathways mediated by PI3K/AKT and -catenin. FAK has been validated as a target in cancer therapy by genetic manipulation and FAK knockdownresults in robust activation of apoptosis in cancer cells with minimal effects in normal cells. Many ATP-competitive FAK kinase domain inhibitors have been reported; however these are only cytostatic and/ormoderately selective for FAK and have shown limited efficacy in clinical trials. Kinase-independent roles of FAKare not blocked by kinase inhibition; in particular the scaffolding function of the C-terminal focal adhesiontargeting (FAT) domain. The FAK FAT domain is the major modulator of FAK-dependent anti-apoptosis and isthe domain regulated by the endogenous dominant-negative FAK isoform termed FAK-related non-kinase(FRNK). Specifically the FAT-paxillin protein-protein interaction (PPI) localizes FAK to the focal adhesion andmutation of residues at the FAT domain interface perturbs focal adhesion turnover cell adhesion migration andinvasion. Thus a major unmet need is the discovery of small molecule chemical probes that block FAK FATdomain scaffolding. In order to target the FAK FAT domain we have previously explored fragment screening bySPR/NMR and hydrocarbon-stapled peptides. These approaches led to FAT fragment-based hits withmicromolar affinity and the lead stapled peptide probe UA-1907 (KD = 1 M) that induces apoptosis in melanomacells. For this project we will develop novel drug screening assays leveraging chemical probe UA-1907 to identifysmall molecule FAT ligands that disrupt the anti-apoptotic scaffolding functions of FAK. Specifically we will: 1)design a TR-FRET biochemical assay to screen a 35000 compound PPI-biased library for hits that inhibit UA-1907 binding to FAT; 2) confirm biochemical hits as FAT ligands using SPR and HSQC-NMR approaches; and3) develop a NanoBiT cellular assay measuring FAK-paxillin binding to validate hits. In all we expect this projectto identify the first described small molecule-based inhibitors of the FAT-paxillin interaction that will serve as thebasis for future medicinal chemistry optimization studies. 161464 +No NIH Category available Anaphase;Automobile Driving;Biochemical;Cell Nucleus;Cell division;Cells;Cellular biology;Chromatin;Chromosomal Instability;Chromosome Segregation;Chromosomes;Chronic;Collaborations;Complex;Crows;Cytoplasm;DNA;DNA Binding;DNA Damage;DNA Sequence Rearrangement;DNA-Binding Proteins;Data;Defect;Digestion;Disease;Docking;Electron Transport Complex III;Endoplasmic Reticulum;Environment;Etiology;Evolution;Exhibits;Functional disorder;Gene Rearrangement;Genes;Genome;Genomic DNA;Genomic Instability;Goals;Health;Human;Immune;Immune System Diseases;Immune signaling;Incentives;Individual;Inflammatory;Interphase;Laboratories;Lead;Letters;Malignant Neoplasms;Membrane;Methods;Missense Mutation;Mitosis;Modeling;Molecular;Mutagenesis;Mutate;Mutation;N-terminal;Nuclear;Nuclear Envelope;Numerical Chromosomal Abnormality;Pathway interactions;Pattern;Penetration;Phase;Play;Positioning Attribute;Process;Prognosis;Proteins;Proteomics;Resected;Role;Rupture;Site;Source;Stimulator of Interferon Genes;Structural Chromosomal Abnormality;Structure;TREX1 gene;TREX2 gene;Testing;Therapeutic;Three Prime Repair Exonuclease 1;Topoisomerase;Tumor Immunity;Vesicle;Viral;Work;anti-tumor immune response;cancer genome;chromosome missegregation;chromothripsis;endonuclease;genome integrity;immune activation;immunoregulation;improved;insight;micronucleus;mutation carrier;novel;polyproline;prevent;protein protein interaction;pseudotoxoplasmosis syndrome;recruit;repaired;sensor;therapy resistant;tumor Immune control and genomic instability at micronuclei PROJECT NARRATIVEMicronuclei are aberrant nuclear compartments that can form as a result of chromosome mis-segregation.Frequent loss of micronuclear envelope integrity exposes DNA to the cytoplasm leading to genomic DNA re-arrangements and immune activation. Building on our prior work we now propose to determine the mecha-nisms of DNA damage and immune activation at micronuclei. NCI 10752663 12/6/23 0:00 PA-20-185 5R37CA261183-03 5 R37 CA 261183 3 "WEINREICH, MICHAEL DALE" 1/1/22 0:00 12/31/26 0:00 Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section[NCSD] 9072090 "MACIEJOWSKI, JOHN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 424822 NCI 240013 184809 PROJECT SUMMARYChromosomal instability (CIN) is a hallmark of cancer characterized by high rates of chromosome mis-segre-gation during cell division. CIN can generate nuclear aberrations termed micronuclei when a chromosome orchromosome fragment lags during anaphase and fails to join the main chromatin mass that will form the prima-ry nucleus. Micronuclei recruit nuclear envelopes but defects in construction lead to frequent rupturing loss ofcompartmentalization and an unregulated exchange of proteins and small vesicles with the cytoplasm. Mi-cronuclear envelope rupturing causes broad dysfunction and is associated with extensive DNA damage andgenomic rearrangements including clustered mutational phenomena such as chromothripsis and kataegiswhich are commonly observed in cancer genomes. Ruptured micronuclei can also activate the pro-inflammato-ry cGAS-STING pathway which plays essential roles in anti-tumor immunity. These observations suggest thatmicronuclei may represent key platforms for genome evolution and immune activation in cancer. The mecha-nisms driving DNA damage and immune activation at micronuclei are poorly understood. The laboratory dis-covered that the endoplasmic reticulum (ER)-associated exonuclease TREX1 which is mutated in a variety ofhuman immune diseases including Aicardi-Goutires Syndrome accumulates at micronuclei upon micronu-clear envelope rupture where it resects micronuclear DNA and limits cGAS-STING activation. ThereforeTREX1 occupies central positions in key pathways with diverse roles in human health and disease. Conse-quently there is strong rationale to understand mechanisms of TREX1 activity and engagement with cytosolicDNA. The long-term goals of the laboratory are to determine mechanisms of DNA damage clustered mutage-nesis and immune activation at sites of nuclear envelope rupture. The specific Aims of this proposal are to 1)Elucidate mechanisms of TREX1 structure and function 2) Determine how TREX1 is recruited to micronucleiand 3) Dissect pathways of micronuclear DNA damage. Each objective is supported by extensive preliminarydata. Aim 1 will focus on a previously uncharacterized region in TREX1 which is essential for its ability to de-grade cytosolic DNA and inhibit cGAS activation. Aim 2 will build on results showing that TREX1 DNA bindingfunction is dispensable for its localization to micronuclei while its association with the ER is essential. Aim 3will use a new method to purify micronuclei to dissect sources of micronuclear DNA damage. Taken togetherthese data will provide fundamental insights into cancer genome evolution explain how previously uncharac-terized TREX1 mutations cause Aicardi-Goutires syndrome and may identify new strategies to improve anti-tumor immunity. 424822 +No NIH Category available Adaptor Signaling Protein;Address;Binding;Binding Proteins;Biochemical;Biological;Biological Assay;Biological Availability;CRISPR interference;Cancer Model;Cancer Patient;Cancer cell line;Carboxylic Acids;Cell Line;Cells;Clinic;Clinical;Complex;Data;Down-Regulation;Drug resistance;Epidermal Growth Factor Receptor;Generations;Genes;Goals;Growth Factor;Immunotherapy;Impairment;KRAS2 gene;Lead;Length;Ligands;Link;Malignant neoplasm of lung;Maps;Mediating;Membrane;Mutation;Oncogenic;Pathway interactions;Patients;Permeability;Pharmaceutical Preparations;Pilot Projects;Protac;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Recurrent disease;Relapse;Resistance;Signal Pathway;Signal Transduction;Structure;Systems Biology;Testing;Tyrosine Kinase Inhibitor;acquired drug resistance;anaplastic lymphoma kinase;cellular targeting;design;efficacy evaluation;experience;genome-wide;genome-wide analysis;immune checkpoint blockade;improved;inhibitor;innovation;kinase inhibitor;knock-down;lung cancer cell;molecular targeted therapies;mutant;new growth;new therapeutic target;pharmacologic;protein protein interaction;response;small hairpin RNA;success;targeted treatment;therapy development;tumor;ubiquitin-protein ligase;vector Developing GRB2-PROTACs for Treatment of Lung Cancer Project Narrative Drug resistance due to activation or reactivation of alternative RTK signal pathways has been amajor clinical challenge for the treatment of lung cancer. Successful completion of this project will offereffective GRB2-targeting degraders as lead compounds for a new targeted therapy to address thisdifficult problem. NCI 10752662 12/1/23 0:00 PAR-20-292 5R21CA267283-02 5 R21 CA 267283 2 "FORRY, SUZANNE L" 12/9/22 0:00 11/30/24 0:00 ZCA1-TCRB-Q(O1)S 10198795 "JI, HAITAO " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 177242 NCI 105188 72054 Project Summary Pharmacological targeting of driver receptor tyrosine kinases (RTKs) can yield strong clinical responses butlung cancer patients treated with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)inhibitors inevitably experience disease recurrence due to acquired resistance. More and better generations of RTK-targeting molecular therapies are developed but still acquired resistance remains as a major and persistent clinicalchallenge. Checkpoint blockade immunotherapies are used to treat lung cancer yet lung cancer patients with EGFRmutations and ALK rearrangements have low response rates. We have mapped the protein networks in EGFR-mutant and ALK-rearranged lung cancers and shown growth factor bound protein 2 (GRB2) is a key oncogenicdriver that causes acquired resistance to EGFR or ALK targeted therapies. The recent discovery of covalenttargeted therapies for KRAS G12C offers an unprecedented opportunity to target KRAS directly. However theresistance against KRAS G12C drugs is being observed in the treatment of KRAS-mutant lung cancer patients. Agenome-wide analysis shows the activation of RTK signaling pathways and that GRB2 is a crucial gene for KRASG12C drug resistance. To overcome this problem we will develop the first drug that selectively degrades GRB2and disrupts GRB2 interactions with driver RTKs. In preliminary studies we have obtained a potent GRB2 binderTX-1-124 and solved the crystal structure of GRB2 bound with this compound. In this R21 application we willdesign and synthesize the first-in-class cell-permeable proteolysis-targeting chimeras (PROTACs) to degradeintracellular GRB2 and evaluate potency of new GRB2-PROTACs against EGFR-mutant ALK-rearranged andKRAS G12C lung cancer cells including those cells resistant to first-line EGFR- ALK- and KRAS G12C targetedtherapies. The success of this project will offer the proof-of-concept that pharmacological downregulation of GRB2using GRB2-PROTACs will block oncogenic RTK signaling and overcome acquired resistance mediated by RTKpathway activation or reactivation. The Specific Aim is the design synthesis and characterization of GRB2-PROTACs based on GRB2 binder TX-1-124. 177242 +No NIH Category available Address;American;Antimalarials;Autophagocytosis;Benchmarking;Cancer cell line;Cell Line;Cell Survival;Cell surface;Cells;Cessation of life;Chemotherapy and/or radiation;Clinic;Combination immunotherapy;Curative Surgery;Cyclic AMP-Dependent Protein Kinases;DNA Binding;Data;Dependence;Development;Diagnosis;Disease;Disease Progression;Environment;Excision;Extracellular Matrix Proteins;Face;Fibroblasts;Genetic;Genetic Complementation Test;Genetic Engineering;Genetically Engineered Mouse;Half-Life;Human;Hydroxychloroquine;Immune;Immune Evasion;Immune system;Immunotherapy;Impairment;Investigation;KRAS oncogenesis;KRAS2 gene;KRASG12D;Laboratories;MEKs;Major Histocompatibility Complex;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metabolic;Modeling;Mus;Mutation;NOD/SCID mouse;Nutrient;Oncogenic;Organ;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Phosphotransferases;Play;Pre-Clinical Model;Predisposition;Process;Qualifying;Radiation therapy;Recycling;Refractory;Reporting;Role;Site;Specificity;Starvation;Stress;Stromal Cells;Survival Rate;TP53 gene;Technology;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;Tumor Burden;Tumor Immunity;Tumor Suppressor Proteins;Tumor Tissue;United States;Xenograft procedure;anti-PD-1;cancer cell;cancer therapy;chemoproteomics;drug testing;efficacy evaluation;immune checkpoint blockade;improved;in vivo;inhibition of autophagy;inhibitor;innovation;mouse model;mutant;neoplastic cell;novel;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;pancreatic stellate cell;pharmacologic;pre-clinical;preclinical development;side effect;small molecule inhibitor;synergism;targeted agent;therapy resistant;tumor;tumor growth;tumor hypoxia;tumor microenvironment;tumor progression ULK1 Inhibitor in Combination with Immune Checkpoint Blockade in PancreaticCancer PROJECT NARRATIVECancer cells use autophagy a cellular recycling process that plays an essential role in treatment resistance andallows cancer cells to survive nutrient and oncogenic stress. As such targeting autophagy has become a criticaltherapeutic strategy in cancer and our laboratory has discovered the most selective and potent autophagyinhibitor to date: ULK-101. This proposal will evaluate the efficacy of ULK-101 in mouse models of pancreaticcancer with dual immune checkpoint blockade which will provide critical data to support autophagy inhibitors asa viable pancreatic cancer treatment option. NCI 10752658 11/6/23 0:00 PAR-20-292 5R21CA270588-02 5 R21 CA 270588 2 "CHEN, WEIWEI" 12/9/22 0:00 11/30/24 0:00 ZCA1-TCRB-V(O1) 8751162 "MACKEIGAN, JEFFREY PAUL" Not Applicable 7 OBSTETRICS & GYNECOLOGY 193247145 R28EKN92ZTZ9 193247145 R28EKN92ZTZ9 US 42.653979 -84.492032 5245901 MICHIGAN STATE UNIVERSITY EAST LANSING MI SCHOOLS OF MEDICINE 488242600 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 164619 NCI 105188 59431 PROJECT SUMMARYPancreatic cancer is responsible for the third most cancer-related deaths in the United States and >60000Americans will be diagnosed in 2022. Further patients with pancreatic ductal adenocarcinoma (PDAC) face a5-year survival rate of less than 5%. Although the genetic drivers of PDAC have been well established thesecancers remain largely refractory to treatment. To survive PDACs depend on autophagy an intracellular nutrientrecycling process. Autophagy provides an internal nutrient pool for tumor cell survival and pancreatic stellatecells also use autophagy to support their metabolic demands. Further autophagy contributes to immune evasiona well-known therapeutic challenge in PDAC. Consistent with these roles genetic autophagy inhibition has beenshown to reduce PDAC tumor growth; however the translation of these discoveries is limited by a lack ofpharmacologic autophagy inhibitors available for preclinical use.To address this problem our lab developed a potent and selective small molecule inhibitor of ULK1 (ULK-101)a protein kinase that controls autophagy induction. Importantly we have shown that starved cancer cells arehighly sensitive to ULK1 inhibition consistent with autophagy-dependent survival during stress. While severalULK1 inhibitors exist we have demonstrated that ULK-101 is the most potent and selective to date and the idealcandidate for preclinical investigations. Therefore we propose to evaluate the effects of ULK-101 in mousemodels of pancreatic cancer. We hypothesize that ULK-101 will suppress autophagy through ULK1 inhibitionand thereby reduce pancreatic tumor growth and improve therapeutic efficacy.Aim 1 will use an orthotopic tumor model using human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1)to test whether ULK-101 treatment reduces tumor progression in vivo. We will then use these orthotopic modelsto assess target engagement and ULK-101 selectivity by measuring ULK1 inhibition using chemoproteomics.These orthotopic models will also be used to evaluate the effect of ULK-101 on tumor progression which we willbenchmark against hydroxychloroquine an approved lysosomal inhibitor. For Aim 2 we will use a syngeneicorthotopic tumor model with 7940b murine cells and the established pancreatic KPC mouse (LSL-KrasG12D/+LSL-Trp53R172H/+ Pdx1-cre model) to test whether ULK-101 will decrease tumor burden. Because autophagyinhibition sensitizes PDACs to immunotherapy we will also evaluate ULK-101 in combination with dual immunecheckpoint blockade (anti-CTL4 and anti-PD-1). The genetically engineered mouse model in Aim 2 features afunctional immune system tumors at the appropriate site and disease progression that parallels humanpancreatic cancer.Through these thorough in vivo studies we will examine ULK1 inhibition as a strategy for treating pancreaticcancer and may provide evidence for further development of ULK-101 and novel autophagy inhibitors. 164619 +No NIH Category available Address;Adoption;Adverse event;Biopsy;Cancer Patient;Cancer Research Network;Caring;Case Mixes;Characteristics;Classification;Clinical;Data;Databases;Diagnostic;Diagnostic Errors;Disease;Electronic Health Record;Eligibility Determination;Evaluation;Expenditure;Funding;Goals;Guidelines;Health Expenditures;Health Services Accessibility;Hospitals;Image;Infrastructure;Injury;Investigation;Learning;Level of Evidence;Life;Link;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Modeling;National Cancer Institute;Network Infrastructure;Nodal;Non-Small-Cell Lung Carcinoma;Observational Study;Operative Surgical Procedures;Outcome;Pathologic;Patient Care;Patient Selection;Patient-Focused Outcomes;Patients;Patterns of Care;Pilot Projects;Practice Guidelines;Procedures;Process;Recommendation;Research Design;Risk;Risk Estimate;Selection Criteria;Selection for Treatments;Serious Adverse Event;Site;Specialist;Staging;Survival Rate;Techniques;Testing;Time;Translating;Uncertainty;Unnecessary Surgery;Variant;Vital Status;Work;care costs;chemotherapy;cohort;comparative effectiveness;comparative effectiveness study;cost;data sharing;design;effectiveness evaluation;follow-up;high risk;implementation strategy;improved;lung cancer screening;lymph node biopsy;lymph nodes;models and simulation;neoplasm registry;novel;novel strategies;predictive modeling;radiological imaging;treatment optimization;trial comparing;tumor Comparative-Effectiveness of Pretreatment Lung Cancer Nodal Staging PROJECT NARRATIVEOur goal is to reduce diagnostic and treatment errors improve survival and increase the value of care for lungcancer patients by improving our ability to select patients who benefit from a lymph node biopsy prior tostarting treatment. This study determines the effectiveness of guideline recommended selection criteria for apretreatment lymph node biopsy and it tests whether a novel approach to selecting patients for lymph nodebiopsy is equivalent to guideline recommended strategy in terms of survival but superior in terms of lowerbiopsy-related severe adverse events and health expenditures. Findings from this study will lead to: 1)developing and testing implementation strategies designed to increase guideline-concordant lymph nodeevaluation 2) alternative guideline recommendations for lymph node evaluation and/or 3) justifying trialscomparing outcomes between different lymph node evaluation strategies. NCI 10752631 1/4/24 0:00 PA-20-185 5R01CA258352-03 5 R01 CA 258352 3 "HALPERN, MICHAEL TOUBER" 1/17/22 0:00 6/30/26 0:00 Health Services: Quality and Effectiveness Study Section[HSQE] 8385865 "FARJAH, FARHOOD " Not Applicable 7 SURGERY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 539713 NCI 466234 73479 ABSTRACTOur goal is to reduce diagnostic and treatment errors improve survival and increase the value of care for lungcancer patients by improving our ability to select patients who benefit from a pretreatment lymph node biopsy.Accurately determining whether cancer has spread to lymph nodes and the extent of spread (a process callednodal staging) is critical for appropriate treatment selection. Understaging can lead to omission ofchemotherapy or unnecessary surgery. Overstaging can lead to unnecessary chemotherapy and omission ofsurgery. Diagnostic and treatment errors negatively impact survival. These errors commonly occur when usingimaging alone for nodal staging. A biopsy can reduce the chances of error but it can also result in rare life-threatening adverse events. Each biopsy costs ~$5000. Practice guidelines recommend selectively performinga biopsy when imaging findings suggest nodal disease. However national biopsy rates are less than half ofwhat they should be. Moreover there is 25-fold facility-level variability not explained by access to care case-mix or clinician or facility characteristics. These findings along with the low levels of evidence underlyingguideline recommendations suggest true clinical and scientific uncertainty over the indications for lymph nodebiopsy. We conducted a pilot study to better understand how well guideline recommendations select patientsfor biopsy and learned that guideline-concordant nodal staging selects all patients with true nodal disease forbiopsy and two-thirds of patients without true nodal disease for biopsy. Additionally we developed andvalidated an alternative risk-based nodal staging strategy that uses a prediction model to stratify and selectpatients for lymph node biopsy. Preliminary data show that it identifies nearly all patients with true nodaldisease for biopsy but selects fewer patients without nodal true nodal disease for biopsy. However therelationship between selection strategies for lymph node biopsy and patient outcomes remains unknown. Wehypothesize that guideline-concordant nodal staging is associated with higher 5-year survival rates comparedwith guideline-discordant nodal staging (Aim I) and that risk-based nodal staging is equivalent to guideline-concordant nodal staging in terms of survival but superior in terms of lower biopsy-related adverse events andhealthcare expenditures (Aim II). Testing these hypotheses will require ~4000 patients; therefore a trial is notfeasible at this time. We will create a novel cohort of lung cancer patients using the Cancer Research Networkinfrastructure to conduct Aim I using an observational comparative-effectiveness study design with advancedregression techniques and machine learning to minimize confounding. Additionally we will use patient-leveldata from this cohort as model inputs in a comparative-effectiveness simulation model that we will develop toconduct Aim II. Findings from this study will lead to: 1) developing and testing implementation strategiesdesigned to increase guideline-concordant nodal staging 2) alternative guideline recommendations for nodalstaging and/or 3) justifying trials comparing outcomes between different nodal staging strategies. 539713 +No NIH Category available Address;Androgens;Biological Assay;Clinical;Data;Diagnosis;Disease;Event;Exposure to;Face;Freedom;Gene Expression Profile;Genes;Genomics;Goals;Guidelines;High-Throughput DNA Sequencing;Local Therapy;Localized Disease;Malignant Neoplasms;Malignant neoplasm of prostate;National Comprehensive Cancer Network;Operative Surgical Procedures;PSA level;Pathologic;Patient Care;Patient-Focused Outcomes;Patients;Pelvic lymph node group;Performance;Phase III Clinical Trials;Positioning Attribute;Postoperative Period;Prognostic Marker;Prostatectomy;Publishing;Radiation;Radiation Therapy Oncology Group;Radiation therapy;Radical Prostatectomy;Randomized;Recurrence;Recurrent Malignant Neoplasm;Research;Resources;Retrospective cohort;Sampling;Technology;Therapeutic;Tissue Therapy;Tissues;United States;Vertebral column;androgen deprivation therapy;arm;biobank;cancer recurrence;clinical translation;cohort;disorder control;follow-up;high risk;improved;men;molecular marker;novel;patient subsets;personalized medicine;phase III trial;predicting response;predictive marker;predictive modeling;predictive signature;prognostic;progression risk;prospective;prostate cancer risk;randomized trial;response;serum PSA;side effect;standard care;standard of care;transcriptome;transcriptome sequencing;transcriptomics;treatment strategy;tumor Molecular Biomarkers of Long-Term Response to Androgen Deprivation Therapy and Radiation in Prostate Cancer PROJECT NARRATIVEThe vast majority of PCa patients present with clinically localized disease for which radical prostatectomy (RP)represents a standard treatment option. Although RP is performed with curative intent a significant proportionof surgically treated patients face the risk of PCa recurrence and require further treatment. Therefore the long-term goal of this project is to develop and validate prognostic and predictive biomarkers through the analysis oftumor samples from two completed landmark phase III trials to personalize PCa patient care following surgery. NCI 10752617 12/21/23 0:00 PA-20-185 5R01CA260066-03 5 R01 CA 260066 3 "MCKEE, TAWNYA C" 1/1/22 0:00 12/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 9231962 "MAHER, CHRISTOPHER A" "LUO, JINGQIN ; SIMKO, JEFF P" 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 576462 NCI 442623 133839 Of the 33330 men who died from prostate cancer in United States last year over 80% of these patientspresented with localized disease. Thus a majority of PCa patients are diagnosed at a potentially curable stageand are often treated with radical prostatectomy (RP). Following RP patients with aggressive disease face therisk of prostate cancer recurrence which manifests as persistently elevated or increasing serum PSA. Whilesalvage radiation therapy (RT) represents a standard treatment option for post-surgical recurrences it results inlong-term disease control in only 30-40% of patients. Thus the post-surgical recurrence state presents multipleopportunities to improve patient care by addressing three critical challenges: (1) determining which patients willbenefit from the addition of androgen deprivation therapy (ADT) (2) identifying which patients treated with RTand ADT will require further treatment intensification and (3) identifying the appropriate treatment intensificationstrategy for RT and ADT treated patients. Since androgen-directed therapies represent the backbone oftreatment for PCa (that have progressed through local therapies) the RTOG 96-01 and RTOG 05-34 phase IIIclinical trials represent a unique resource of banked prostatectomy cohorts from patients that were randomizedto the presence or absence of treatment with ADT. For patients whose clinical and pathologic features placethem at highest risk of dying from PCa these landmark trials have defined the standard of care by showing thatthe addition of ADT to RT resulted in significant improvements to patient survival compared to RT alone. Thispresents an unparalleled opportunity to develop and validate predictive and prognostic biomarkers addressingmultiple unmet clinical needs throughout patient care following surgery. Aim 1 will focus on using high-throughputDNA and RNA sequencing to develop a predictive classifier for identifying which patients would benefit from ADTusing patients from RTOG 96-01 and 05-34. In Aim 2 we will develop and validate a prognostic classifier thatintegrates genomic and clinicopathologic data for PCa patients treated with RT+ADT that may benefit fromtreatment intensification. Aim 3 will focus on identifying RT+ADT patients requiring treatment intensification thatcould benefit from receiving pelvic lymph node radiation therapy using patients from RTOG 05-34. The proposedstudy would have significant impact by developing and optimizing prognostic and predictive biomarkers thatcould have enormous potential for rapid clinical translation to personalize therapy and transform themanagement of PCa patients following surgery. 576462 +No NIH Category available Address;Adopted;Adult;Antigen Presentation;Antitumor Response;Architecture;Biology;Brain;Brain Injuries;CD4 Positive T Lymphocytes;CSF1R gene;CTLA4 blockade;CTLA4 gene;Cells;Clinical Research;Clinical Trials;Collaborations;Communication;Cues;Data;Dependence;Development;Diffuse astrocytoma;Environment;Exposure to;Failure;Genetic Transcription;Glioblastoma;Glioma;Human;Immune;Immune Evasion;Immune Targeting;Immune checkpoint inhibitor;Immune system;Immunosuppression;Immunotherapy;Infiltration;Inflammatory Infiltrate;Inflammatory Response;Interdisciplinary Study;Intervention;Ligands;Long-Term Care;Macrophage;Malignant Neoplasms;Malignant neoplasm of brain;Mentorship;Methods;Microglia;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Natural Immunity;Nature;Neuroglia;Other Genetics;Pathway interactions;Patients;Peripheral;Phagocytes;Phagocytosis;Phase II Clinical Trials;Physicians;Population;Receptor Protein-Tyrosine Kinases;Recurrence;Regulation;Regulatory T-Lymphocyte;Repression;Research;Role;Scientist;Shapes;Signal Pathway;Signal Transduction;Source;T cell infiltration;T-Lymphocyte;Techniques;Th1 Cells;Therapeutic;Tissue Preservation;Training;Tumor Promotion;Tumor Subtype;Work;anti-CTLA4;anti-tumor immune response;checkpoint therapy;effector T cell;genetic approach;innovation;insight;mouse genetics;mouse model;neuroinflammation;novel;novel therapeutics;older patient;patient engagement;polarized cell;preclinical study;programmed cell death protein 1;programs;receptor;recruit;response;skills;standard of care;targeted treatment;transcriptomics;tumor;tumor growth;tumor microenvironment Elucidating the distinct roles of T cell-polarized microglia in glioblastoma suppression and progression Project NarrativeGlioblastoma is the most common adult brain cancer and has remained incurable since it was first identified overtwo centuries ago. A central reason for this failure in treatment lies in the heterogenous and immunosuppressivenature of these malignancies and its ability to evade the immune system from destruction. This proposal willidentify how microglia and macrophages the largest non-tumor component of the microenvironment can adoptopposing tumor killing/tumor promoting activation states and how manipulation of these different states mayredirect progressing glioblastoma toward regression. NCI 10752583 7/18/23 0:00 PA-21-052 1F31CA284773-01 1 F31 CA 284773 1 "DIBELLO, ANTHONY THOMAS" 8/1/23 0:00 6/30/27 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)Q] 15039603 "GARCIA-RIVERA, LIZMARIE " Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 40186 NCI 40186 0 Project Summary/AbstractGlioblastoma is a grade IV diffuse astrocytoma the deadliest and most common form of adult brain cancer.Standard of care extends survival by approximately 1-18 months with the poorest benefits being seen by elderlypatients (>70yrs). New forms of immune-based therapies including immune checkpoint inhibitors (ICI) may turnthe corner in treatments for primary and recurrent glioblastoma. Unfortunately no clinical trial so far has shownmajor benefits in either survival or immune engagement for these patients. Recent findings suggest that gliomasharbor multiple and intertwined cellular sources of immune suppression that dampen ICI-initiated responses.Thus one solution may be to not only enhance effector T cells by blocking checkpoints such as CTLA-4 and PD-1 but to also target the immune suppressive niches in glioblastoma the largest of which is comprised of glioma-associated microglia and macrophages (GAMs). In fact GAMs are a highly attractive target and have beendepleted in pre-clinical and clinical studies via CSF1R inhibition (PLX3397). This approach however yieldedmixed responses in models and no response in patients. Another path may be to reprogram GAMs but we lackinsights into the pathways that promote anti-tumor GAMs. Therefore identifying the cellular and molecularregulators of pro- and anti-tumor GAM states is the next step in unlocking new therapeutic avenues. Recent workby the Kaech lab showed that CTLA-4 blockade in orthotopic mouse models of glioblastoma reduced regulatoryT cell (Treg) infiltration increased helper Th1 cell infiltration and microglia exposed to Th1 cell-derived IFNgwere reprogrammed into an antigen presenting (MHCII+) tumor-phagocytosing (AXL+/MER+) state; in concertthese effects significantly increased survival. This proposal will investigate how GAMs especially the brainresident microglia acquire and maintain distinct functional states with the hypothesis that Treg-specific signalingsustains tumor-promoting GAMs during glioblastoma progression while Th1 T cells induce tumor-killing GAMsduring an effective ICI-initiated response. Two specific aims are proposed to interrogate this hypothesis. The firstaim will employ single-cell spatial transcriptomics to address whether Tregs and Th1 cells are extrinsic regulatorsof GAM states through direct contact and/or secretory signaling and whether these interaction axes exist inhuman glioblastoma. The second aim will define the intrinsic AXL/MER and related pathways regulating GAMstate switching. In summary this work will better inform GAM-targeting interventions by defining how infiltratingT cells and GAM-intrinsic signaling pathways coordinate the dynamic biology underlying pro- and anti-tumorGAM states. This application outlines the applicants proposed training plan which includes diverse andmultidisciplinary research mentorship training in cutting-edge and advanced techniques and development ofbroader scientific skills such as collaboration and effective communication. The research and training outlined inthis proposal will prepare the applicant to conduct innovative rigorous and impactful research. 40186 +No NIH Category available Acute Myelocytic Leukemia;Adverse effects;Aftercare;Allogenic;Biopsy;Blood Vessels;Bone Marrow;Bone marrow biopsy;CD8-Positive T-Lymphocytes;CD8B1 gene;Cause of Death;Cell Death;Cell Death Induction;Cell Differentiation process;Cell Survival;Cell Transplantation;Cells;Clinical;Clinical Research;Clinical Trials;Combined Modality Therapy;DNA;DNMT3a;Development;Effector Cell;Epigenetic Process;FDA approved;Feedback;Flow Cytometry;Gene Expression;Gene Silencing;Generations;Genetic Transcription;Goals;Growth;Human;Immune;Immune Evasion;Immune response;Immunocompetent;Immunodeficient Mouse;Immunophenotyping;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Inflammasome;Interleukin-6;Intravenous;Leukemic Cell;Macrophage;Malignant Neoplasms;Marrow;Mediating;Mediator;Modeling;Molecular;Mus;Myeloid Cells;NF-kappa B;Normal tissue morphology;Oligonucleotides;Oncogenes;Organ;Patient-Focused Outcomes;Patients;Positioning Attribute;Pre-Clinical Model;Property;Radiation;Radiation Dose Unit;Radiation Protection;Radiation therapy;Radiation-Induced Cancer;Radioimmunotherapy;Recurrence;Recurrent disease;Refractory;Refractory Disease;Regimen;Regulator Genes;Regulatory T-Lymphocyte;Relapse;Reporting;Research;Resistance;Role;Secondary acute myeloid leukemia;Signal Transduction;Small Interfering RNA;Solid Neoplasm;Stat3 protein;Sting Injury;Structure;Survival Rate;System;T cell infiltration;T-Lymphocyte;TLR9 gene;Testing;Therapeutic;Time;Tissues;Toxic effect;Treatment Efficacy;Tumor Debulking;Tumor-associated macrophages;Vascularization;acute myeloid leukemia cell;cancer cell;cancer therapy;cell mediated immune response;clinical biomarkers;clinically relevant;combinatorial;comparative efficacy;conditioning;cytokine;cytotoxic;cytotoxicity;design;efficacy evaluation;efficacy study;epigenomics;experience;hematopoietic cell transplantation;image guided;image-guided radiation;immune checkpoint;immunogenic;immunogenic cell death;immunogenicity;immunotoxicity;improved;in vivo;in vivo Model;inhibitor;innovation;leukemia;leukemia relapse;leukemia treatment;leukemic stem cell;lymphoid irradiation;neovascularization;novel;nuclease;personalized approach;potential biomarker;preclinical study;radiation resistance;recruit;sensor;small molecule;synergism;timeline;trafficking;transcriptomics;translational goal;treatment comparison;tumor;tumor microenvironment;uptake Myeloid cell-selective oligonucleotide-based STAT3 inhibition combined with total marrow and lymphoid irradiation for immunotherapy of acute myeloid leukemia PROJECT NARRATIVEThe improvement of long-term outcomes for patients with treatment-refractory acute myeloid leukemia (AML)represents one of the highest unmet need for cancer therapy in general. Based on the initial preclinical andclinical studies we propose to combine new image-guided AML radiotherapy which spares normal organs witha novel oligonucleotide-based immunotherapeutic agent CpG-STAT3 inhibitor to stimulate patients ownimmune responses against leukemia. The overarching goal is to develop a paradigm-shifting effective and safercombinatorial treatment for relapsed and recurrent AML patients. NCI 10752538 7/19/23 0:00 PAR-22-198 1R01CA284593-01 1 R01 CA 284593 1 "VIKRAM, BHADRASAIN" 7/19/23 0:00 6/30/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 10354880 "KORTYLEWSKI, MARCIN " "HUI, SUSANTA K" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 7/19/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 711258 NCI 404124 307134 PROJECT SUMMARYThere has been little or no long-term improvement in outcomes for patients with treatment-refractory acutemyeloid leukemia (AML). The recently developed image-guided radiation strategy total marrow and lymphoidirradiation (TMLI) delivers high radiation doses to major leukemia reservoirs while sparing normal tissues.Although TMLI prior to allogeneic hematopoietic cell transplantation (HCT) improved patients 2-year overallsurvival (OS) rate from <10% to 48% relapses remained common. Such radiation resistance is a consequenceof both intrinsic cancer cell properties and the extrinsic influence of the tumor microenvironment. It was previouslydemonstrated that radiation-induced cell death causes the release of danger signals recruiting Toll-like Receptor-9 (TLR9)-positive myeloid cells which jump-start tumor vascularization and regrowth. These cancer-promotingrather than immunostimulatory effects are mediated by TLR9-mediated secretion of cytokines such as IL-6thereby leading to activation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 is amultifaceted oncogene and a central immune checkpoint regulator operating in AML cells as well as in tumor-associated myeloid cells in patients. However it remains an elusive target with no FDA-approved direct smallmolecule STAT3 inhibitors. To overcome this challenge we previously developed a strategy to deliveroligonucleotide STAT3 inhibitors such as siRNA or decoy DNA specifically into commonly TLR9-positive AMLand normal myeloid cells. The nuclease-resistant second-generation CpG-STAT3 decoy inhibitor (CSI-2)injected intravenously showed efficacy in targeting STAT3 suppressing leukemia cell survival and/or inducingimmune responses against moderate burden of human and mouse AML in vivo. The hypothesis is that combiningthe immunostimulatory CSI-2 strategy with conditioning TMLI treatments will improve treatment efficacy againstAML even at high burden (>50% leukemic blasts in the bone marrow) by providing time for the generation ofadaptive T-cell driven immune responses. The preliminary results demonstrated that the TMLI regimen canimprove uptake of CSI-2 by AML thereby reducing leukemia-initiating potential augmenting AMLimmunogenicity and thereby inducing potent CD8+ T cell-mediated antileukemic immune responses. Wepropose to: 1. elucidate the molecular mechanisms of TMLI/CSI-2 effect on AML cell differentiation; 2. optimizeTMLI to maximize the effect on leukemic bone marrow vascular structure CSI-2 delivery leukemogenicpotential and immunogenicity; 3. assess the efficacy and cellular mode-of-action of the TMLI/CSI-2 combinationtreatment compared to either treatment alone in human or mouse AML models in humanized or syngeneic micerespectively. The overarching goal of this interdisciplinary proposal is to produce a clinically relevant effectiveand safe combinatorial radiation-immunotherapy for patients with relapsed/recurrent AML representing thehighest unmet need in cancer therapy. 711258 +No NIH Category available ATAC-seq;Acute;Adaptive Immune System;Affect;Antigen Presentation Pathway;Antioxidants;Antitumor Response;Autoimmune;CD8-Positive T-Lymphocytes;CRISPR screen;Cellular Metabolic Process;ChIP-seq;Chromatin;Chronic;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Data;Dependence;Development;Down-Regulation;Effectiveness;Electron Transport;Event;Expression Profiling;Fatty Acids;Fluorescence Microscopy;Heart;Immune Evasion;Immune response;Immune system;Immunosuppression;Immunotherapy;In Vitro;Innate Immune System;Interferon Type I;Interferon Type II;Interferon alpha;Interferon-beta;Interferons;Knock-out;Link;Major Histocompatibility Complex;Malignant Neoplasms;Mediating;Melanoma Cell;Membrane Potentials;Metabolic;Metabolism;Mitochondria;Mus;Oxidative Phosphorylation;Pathway interactions;Phenotype;Phosphorylation;Play;Process;Production;Proteins;RNA;Reaction;Reactive Oxygen Species;Regulation;Role;Screening Result;Signal Pathway;Signal Transduction;Skin Cancer;Surface;Testing;Therapeutic;Transcriptional Activation;Tumor Immunity;Up-Regulation;Western Blotting;Work;anti-tumor immune response;cancer cell;cancer immunotherapy;cancer therapy;cell type;desensitization;fatty acid metabolism;fatty acid oxidation;improved;in vivo;insight;melanoma;metabolomics;mitochondrial membrane;mitochondrial metabolism;neoplastic cell;novel;pharmacologic;programmed cell death ligand 1;response;therapy development;transcription factor;transcriptomics;tumor;tumor metabolism;tumor microenvironment;tumor progression;tumor-immune system interactions Mitochondrial Regulation of Interferon Response in Melanoma PROJECT NARRATIVEReduced interferon (IFN) signaling is major way tumor cells evade the immune system. Mitochondria are centralplayers in cell metabolism but their role in regulating anti-tumor immune responses is less well understood. Thisproject examines the link between mitochondria and IFN signaling which may provide new ways to target tumormetabolism to bolster anti-tumor immune responses and the effectiveness of immunotherapy. NCI 10752523 7/14/23 0:00 PA-21-051 1F31CA278581-01A1 1 F31 CA 278581 1 A1 "PURI, ANU" 8/1/23 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 78269514 "JOHNSON, MELISSA " Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 40516 NCI 40516 0 PROJECT SUMMARYInterferons (IFNs) are central orchestrators of tumor immunity and can elicit both pro-tumor and anti-tumorresponses depending on the cancer cell type the type of IFN produced (e.g. a b or g) duration of the signaland other factors in the tumor microenvironment (TME). In their anti-tumor role IFNs induce expression of majorhistocompatibility complex I (MHC-I) on the surface of tumor cells that mediates CD8+ T cell recognition andkilling. Paradoxically IFNs also upregulate expression of CD8+ T cell inhibitory surface molecules such asprogrammed death ligand 1 (PD-L1) to temper the immune response and avoid an autoimmune reaction. ThusIFNs play a dual and opposing role in cancer development making a more complete understanding of thecontexts in which their pro- or anti-tumor functions predominate important for effective cancer therapydevelopment. Immune evasion can occur when malignant cells lose MHC-I and antigen processing andpresentation (APP) machinery or otherwise become desensitized to IFN signaling. Thus finding ways toreinvigorate these pathways has significant therapeutic potential. Interestingly recent work from the sponsorslab and others has shown that mitochondrial electron transport chain activity is required for IFN-induced MHC-Iexpression. In addition preliminary data show that chronic IFN stimulation in vitro reduces mitochondrialoxidative phosphorylation (OXPHOS) in melanoma cells suggesting that IFN signaling can also influence tumormitochondrial metabolism. To probe this novel regulatory link between the metabolic state of tumor cells andtheir responses to IFN a metabolism-targeted CRISPR knock-out screen was performed in mouse melanomacells. Results from this screen not only confirmed a requirement for mitochondrial OXPHOS in regulating IFNsignaling but also implicated fatty acid metabolism and ROS. Based on these preliminary data it is proposedthat mitochondrial OXPHOS specifically mitochondrial fuel utilization and ROS production can directly regulatekey IFN signaling steps and that chronic IFN exposure leads to changes in mitochondrial metabolism thatfacilitate immune evasion in melanoma. This overall hypothesis will be tested through completion of two specificaims. Aim 1 is to determine which steps in the IFN signaling pathway are subject to mitochondrial OXPHOS-mediated regulation and the precise mitochondrial metabolic signals involved. Aim 2 is to determine how reducedmitochondrial OXPHOS and/or increased mitochondrial ROS are generating a suppressive tumormicroenvironment and if chronic type I IFN signaling elicits similar immunosuppressive effects as chronic type IIIFN exposure. This project will provide important new insights into the relationship between mitochondrialmetabolism and IFN responses during tumor progression that might be exploited to improve or reactivate anti-tumor immune responses for better cancer treatment and augment cancer immunotherapy. 40516 +No NIH Category available Address;Adult;Affect;Anti-Inflammatory Agents;Biological Assay;Cancer Etiology;Cell Differentiation process;Cell Line;Cell Proliferation;Cells;Cellular Morphology;Cessation of life;Color;Confocal Microscopy;Data;Development;Diagnosis;Differentiation and Growth;Disease;Disease Progression;Doxycycline;Duct (organ) structure;Epithelial Cells;Epithelium;Etiology;Event;Family member;Gene Expression;Genes;Goals;Histologic;Homeostasis;Human;Immunofluorescence Immunologic;Immunohistochemistry;In Vitro;Interleukin-12;Invaded;KRAS oncogenesis;Kinetics;Knowledge;Lesion;Lesion by Stage;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mesenchymal;Metaplastic Cell;Metaplastic Epithelial Cell;Modeling;Molecular Biology Techniques;Mucins;Mucous Membrane;Mus;Neoplasm Metastasis;Operative Surgical Procedures;Organoids;Pancreas;Pancreatic Diseases;Pancreatic Ductal Adenocarcinoma;Pathological Staging;Pattern;Phenotype;Play;Population;Proteins;Regulation;Reporting;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Source;Specific qualifier value;Staging;Stains;Stomach;Surface;Survival Rate;System;TFF1 gene;TP53 gene;Testing;Therapeutic Intervention;Training;Tumor Subtype;Tumor Volume;Tumor Weights;United States;Up-Regulation;Western Blotting;Woman;Work;axon guidance;biomarker development;cancer cell differentiation;cancer initiation;cytokine;differential expression;experimental study;gastric foveola;histological stains;immunocytochemistry;in vivo;inducible gene expression;inhibitor;insight;interleukin-23;knock-down;loss of function;malignant stomach neoplasm;men;molecular subtypes;mutant;neoplastic;neoplastic cell;pancreatic cancer cells;pancreatic neoplasm;pancreatic tumorigenesis;patient prognosis;premalignant;programs;protein expression;single-cell RNA sequencing;small hairpin RNA;statistics;transcriptome sequencing;treatment response;tumor;tumor growth;tumor progression;tumorigenic Role of Gastrokine 2 in pancreatic cancer development Project NarrativePancreatic cancer is an aggressive disease that is frequently diagnosed in late stages after metastasis hasoccurred highlighting the need for a better understanding of early transformation events and tumorigenicmechanisms. Completion of this research proposal will help address this gap in knowledge by revealing thefunctional contribution of a de novo expressed gastric protein Gastrokine 2 which is hypothesized to play atumor suppressive role in pancreatic tumor progression. Knowledge gained from studies could impact biomarkerdevelopment with the potential for therapeutic intervention. NCI 10752479 6/23/23 0:00 PA-21-051 1F31CA278589-01A1 1 F31 CA 278589 1 A1 "SCHMIDT, MICHAEL K" 7/12/23 0:00 7/11/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 77803699 "BELL, WHITNEY JEAN" Not Applicable 4 PHYSIOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/12/23 0:00 7/11/24 0:00 398 "Training, Individual" 2023 39211 NCI 39211 0 AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest adult cancers with a 5-year survival rate ofonly 11% and is one of the top five leading causes of cancer-related deaths for men and women in the UnitedStates. These dire statistics underscore the need for a better understanding of the mechanisms that promotepancreatic cancer initiation and progression. Recent studies have begun to show that metaplastic epithelialdifferentiation in pancreatic cancer can significantly impact disease progression. Our preliminary data fromongoing studies investigating the role of cytokines IL-12/IL-23 in pancreatic cancer cell differentiation showedthat gain of aggressive epithelial to mesenchymal-like phenotype is associated with the concurrent loss of gastriclineage genes including Gastrokine 2 (Gkn2). Gkn2 is abundantly expressed by normal stomach epithelial cellsplays an anti-inflammatory role in gastric epithelial homeostasis. Recently Gkn2 and its family member Gkn1have been shown to be de novo upregulated in metaplastic epithelial cells in pancreatic cancer. However thefunctional roles of gastrokines in pancreatic tumorigenesis remain unclear. The goals of this proposal are toelucidate the kinetics cellular source and driver(s) of de novo Gkn2 expression in pancreatic neoplasia as wellas determine the functional role of Gkn2 in pancreatic cancer development. To achieve these goals in Aim 1we will determine the expression pattern and cellular identity of Gkn2-positive cells as well as understand howoncogenic Kras and/or Src signaling may contribute to the expression of Gkn2 in pancreatic epithelial cells. InAim 2 we will investigate the functional role of Gkn2 in pancreatic tumor growth tumor cell differentiation andinvasion. Specifically we will utilize reversible Gkn2 knockdown systems to determine its contribution to thegrowth and differentiation of Kras-transformed epithelial cells in pancreatic cancer. Our proposed research willutilize state-of-the art models to provide an understanding of how a gastric identity gene program emerges earlyin transformed pancreatic epithelium and acts as a potential impediment to the aggressive progression of cancer. 39211 +No NIH Category available Activities of Daily Living;Animal Cancer Model;Antioxidants;Biogenesis;Body Surface Area;Body Weight;Body mass index;C26 tumor;Cachexia;Cancer Patient;Cancer Prognosis;Cancer Survivorship;Colorectal;Data;Dependence;Development;Diet;Dietary Practices;Dihydropyrimidine Dehydrogenase;Disease;Dose;Drug toxicity;Enzymes;Epidemiology;Fatigue;Fluorouracil;Functional disorder;Goals;Half-Life;Health;Knowledge;Literature;Liver;Maintenance;Malignant Neoplasms;Metabolic;Metabolic dysfunction;Metabolism;Mitochondria;Modeling;Morbidity - disease rate;Morphology;Mus;Muscle Mitochondria;Muscle function;Natural Compound;Natural Products;Obese Mice;Obesity;Pathology;Patients;Pharmaceutical Preparations;Phenotype;Positioning Attribute;Postdoctoral Fellow;Process;Publishing;Quality Control;Quality of life;Quercetin;Recommendation;Recording of previous events;Regimen;Research;Respiration;Role;Skeletal Muscle;Source;Testing;Therapeutic;Thinness;Toxic effect;Training;Transgenic Mice;Treatment Efficacy;Treatment outcome;Weight;anti-cancer;cancer cachexia;cancer risk;cancer therapy;carcinogenesis;chemotherapy;dietary;dietary antioxidant;dietary approach;improved;insight;loss of function;mitochondrial dysfunction;muscle form;novel;obese person;obesity treatment;pharmacologic;prevent;protein degradation;tumor Impact of obesity on chemotherapy-induced muscle mitochondrial dysfunction PROJECT NARRATIVEObesity increases the risk of cancer; thus individuals that are obese are more likely to undergo chemotherapyin their lifetime. While it is common practice to apply a dosing cap current recommendations for the treatmentof obese cancer patients is full body surface area chemotherapy dosing regimens despite some evidencesuggesting that these patients may have exacerbated drug toxicities including perturbations to skeletal musclemitochondrial function. The primary goal of my proposed F31 is to 1) understand the impact of obesity onchemotherapy-induced skeletal muscle mitochondrial dysfunction and 2) provide mechanistic and therapeuticinsights aimed at better improving chemotherapy tolerance with obesity. NCI 10752436 6/30/23 0:00 PA-21-051 1F31CA278490-01A1 1 F31 CA 278490 1 A1 "BOULANGER-ESPEUT, CORINNE A" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F10B-C(20)L] 78444772 "CARDACI, THOMAS " Not Applicable 6 PATHOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF MEDICINE 292080001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 37073 NCI 37073 0 PROJECT SUMMARYObesity increases the risk of cancer; thus individuals that are obese are more likely to undergo chemotherapyin their lifetime. However there is a dearth of literature on the impact of weight status on cancer patient lifequality and functional capacity throughout treatment. For instance our knowledge of the impact of obesity oncancer and chemotherapy-induced cachexia - the unintentional loss of lean mass which directly contributes tofunctional dependency poor treatment outcomes and decreased survival is incomplete. An obesityparadox has been postulated; however the epidemiology remains equivocal on the benefits/detriments of ahigh pre-treatment body weight and body mass index. While obesity and cachexia are diseases at oppositeends of the weight spectrum these pathologies share some underlying perturbations (e.g. mitochondrialdysfunction) that may exacerbate functional decrements when these morbidities co-occur. Our lab made thenovel and significant discovery that obese mice dosed for lean mass were unable to survive 2-3 cycles of thechemotherapeutic 5 fluorouracil (5FU). Indeed contrary to what has been suggested we discovered thatobese mice are not protected against chemotherapy-induced cachexia and show exacerbated skeletal muscletoxicities. Disruptions to mitochondria are 1) central to chemotherapy-induced skeletal muscle mass loss and2) are known to be existent with obesity and metabolic dysfunction; however mitochondrial dysfunction andresultant functional deficits have not been assessed when these morbidities co-occur. Antioxidants have beenshown to improve mitochondrial function. Indeed we have shown that the antioxidant dietary compoundquercetin can reduce cancer cancer cachexia and chemotherapy-induced fatigue and can increasemitochondrial function in healthy mice. Thus quercetin may hold promise as a dietary strategy to treatcachexia associated with cancer and its therapies in the obese condition. The primary goal of my proposedF31 is to 1) understand the impact of obesity on 5FU-induced skeletal muscle dysfunction and 2) providemechanistic and therapeutic insights aimed at better improving 5FU tolerance with obesity. My centralhypothesis is that 5FU-induced mitochondrial loss and dysfunction is exacerbated with an obese phenotypeand intervening with quercetin will mitigate the deleterious effects of 5FU on skeletal muscle. To test thishypothesis I propose three related but independent specific aims: 1) Examine the impact of obesity on cancerand 5FU-induced cachexia and function loss; 2) Determine the role of mitochondria in obesity-exacerbated5FU toxicities; and 3) Explore the utility of dietary quercetin on improving 5FU treatment tolerance and off-target toxicities with obesity. The proposed studies align with my training aims and will provide me with theopportunity to gain expertise in obesity phenotyping and natural compounds as therapeutics mitochondrialhealth and dynamics cachexia and functional testing. Further the professional development training willpromote advancement to the next step in my path to research independence. 37073 +No NIH Category available Area;Benign;Binding;Biodistribution;Blood;Cell Line;Cells;Clinical;Contrast Media;Cytoskeleton;Data;Derivation procedure;Detection;Development;Disease;Drug Kinetics;Elements;Eligibility Determination;Excision;Fibrosis;Fluorescence;Fluorescent Dyes;Goals;Hemorrhage;Human;Image;Image-Guided Surgery;Imaging Techniques;Incidence;Indocyanine Green;Knock-out;Local Therapy;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mesentery;Microscopic;Modality;Modernization;Molecular;Mus;Neoadjuvant Therapy;Operating Rooms;Operative Surgical Procedures;Pancreas;Pancreatectomy;Pancreatic Ductal Adenocarcinoma;Pancreatic duct;Pancreatitis;Patients;Peptides;Performance;Perfusion;Perioperative Care;Predisposition;Procedures;Reporter;Reporting;Resectable;Resected;Resolution;Scientist;Signal Transduction;Specificity;Surface;Surgeon;Systemic Therapy;Techniques;Testing;Time;Tissue imaging;Tissues;Toxic effect;Toxicity Tests;Translating;Visualization;base;extracellular;fluorescence imaging;image guided;imaging modality;imaging probe;improved;in vivo;interest;minimally invasive;novel;optoacoustic tomography;pancreatic ductal adenocarcinoma cell;plectin;prototype;response;skill acquisition;targeted agent;tumor;tumor specificity;ultrasound Pancreas Cancer Specific Probe for Image Guided Resection Pancreatic cancer has poor negative resection margin rates with modern intraoperative imaging.We will develop a plectin-1 peptide probe to specifically target pancreatic cancer with near infraredfluorescent imaging to improve visualization in the operating room. NCI 10752431 9/1/23 0:00 PA-20-272 3P30CA225520-06S2 3 P30 CA 225520 6 S2 "SHAFIK, HASNAA" 5/1/18 0:00 4/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 2488117 "MANNEL, ROBERT S." Not Applicable 5 OBSTETRICS & GYNECOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 9/1/23 0:00 4/30/24 0:00 397 Research Centers 2023 132191 NCI 91166 41025 Pancreas Cancer Specific Probe for Image Guided ResectionThis application is being submitted in response to the Notice of Special Interest (NOSI) identifiedas NOT-CA-21-100. The incidence of pancreatic ductal adenocarcinoma (PDAC) continues torise as does the number of patients eligible for surgical resection due to improvements inneoadjuvant therapy. Surgical resection with negative resection margins remains the onlyopportunity for cure for patients with this disease. However microscopically positive resectionmargins have been reported in up to 75% of patients undergoing resection for curative intent.Clinically available imaging techniques lack the ability to detect microscopic tumor involvement ofmesenteric vessels or differentiate between fibrosis and live tumor representing an unmet clinicalneed. Development of a PDAC specific near infrared (NIR) contrast agent that can be detectedby multispectral optoacoustic tomography (MSOT) would improve intraoperative detection ofresection margin. This proposal will synthesize a NIR reporter agent that targets plectin-1 peptidewhich is aberrantly located on the surface of PDAC cells. Our synthesized probe will be optimizedfor binding with human PDAC. Specificity of the probe will be tested on human PDAC cell linesand tissue collected from resected PDAC. The most efficiently performing probe will then betested for toxicity and performance in vivo in mice. Successful completion of this proposal willgenerate a PDAC-specific contrast probe to improve detection of viable PDAC and adjacentfibrosis in vivo using MSOT and NIR fluorescence. 132191 +No NIH Category available Area;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Catchment Area;Clinical Trials;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;County;Data;Development;Diverse Workforce;Exclusion;Funding;Genomics;Grant;Health Services Accessibility;Hematopoietic;Hospitals;Illinois;Imaging technology;Immunology;Immunotherapy;Incidence;Institution;Interdisciplinary Study;Intervention;Malignant Neoplasms;Methods;Mission;Missouri;Molecular;Neoplasm Metastasis;Pathway interactions;Patient Care;Patients;Prevention;Prevention strategy;Publications;Regional Cancer;Research;Research Personnel;Resource Sharing;Risk Factors;Risk Reduction;Schools;Science;Screening for cancer;Solid Neoplasm;Speed;Strategic Planning;Talents;Therapeutic;Time;Tissues;Training and Education;Translating;Translational Research;Underserved Population;Universities;Washington;anticancer research;bench to bedside;burden of illness;cancer care;cancer diagnosis;cancer imaging;cancer therapy;clinical care;community partnership;disparity reduction;follower of religion Jewish;imaging science;implementation science;innovation;malignant breast neoplasm;member;mortality;multidisciplinary;novel;patient population;personalized medicine;prevent;programs;success;tumor immunology;tumor progression Cancer Center Support Grant OVERALL: PROJECT NARRATIVEThe Alvin J. Siteman Cancer Center (SCC) at Washington University and Barnes-Jewish Hospital is a NCIdesignated Comprehensive Cancer Center whose mission is to prevent cancer in the community and transformcancer patient care through scientific discovery. SCC accomplishes this mission through strong researchprograms shared resource support education and training pilot funding programs and community outreach.The translational research and scientific discovery facilitated by our seven multidisciplinary research programsand 10 shared resources (11th requested in this application) is driven by the needs of patients in our 82-countycatchment area throughout Missouri and southern lllinois. NCI 10752347 7/14/23 0:00 PA-20-272 3P30CA091842-22S1 3 P30 CA 91842 22 S1 "ROBERSON, SONYA" 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 194375 NCI 125000 69375 OVERALL: PROJECT SUMMARYThe Alvin J. Siteman Cancer Center (SCC) at Washington University and Barnes-Jewish Hospital is a NCIdesignated Comprehensive Cancer Center whose mission is to prevent cancer in the community and transformcancer patient care through scientific discovery. SCC accomplishes this mission through strong researchprograms shared resource support education and training pilot funding programs and community outreach.The translational research and scientific discovery facilitated by our seven multidisciplinary research programsand 10 shared resources (11th requested in this application) is driven by the needs of patients in our 82-countycatchment area throughout Missouri and southern Illinois. The center applies the exceptional talent among our 230 members from four schools and 23 departmentsto further understand the mechanisms of cancer pathways speed the conduit from bench to bedside andimplement prevention strategies that impact cancer screening incidence and mortality in our catchment area. SCCs Breast Cancer Research Hematopoietic Development and Malignancy Mechanisms of CancerBiology Oncologic Imaging Prevention and Control Solid Tumor Therapeutics and Tumor ImmunologyResearch Programs promote novel multidisciplinary cancer research and encourage intra inter and cross-institution collaboration. Success is evidenced by SCCs key metrics in the project period; data below are currentas of this application and each represents an all-time high for the center: NCI funding $41.0M direct excluding CCSG dollars Number of large collaborative grants 72 Interventional clinical trial accruals 5071 in 2018 Total cancer-focused publications 1148 in 2018; 35% intra- or inter-programmatic High Impact Publications 201 in 2018 (> 10.0 IF) In the next five years SCC will advance its mission through exceptional research and clinical care withspecial emphasis on four overarching scientific themes chosen to optimally harness and magnify the centersimpact on cancer in the field and in our catchment. These scientific pillars are: genomics and its application toclinical care; innovation in imaging technologies and their use in cancer diagnosis and treatment; immunologyand the enhancement of patient care using unique immune therapies; and prevention to reduce the burden ofdisease in the population of patients we serve. These core strengths align with SCCs current strategic plan andinform research program aims objectives and initiatives. 194375 +No NIH Category available Acute Myelocytic Leukemia;Acute leukemia;Adult;Affect;African ancestry;Algorithms;American;Architecture;Archives;Assessment tool;Biological;Biological Assay;Biological Testing;Biology;Cell surface;Cells;Classification;Clinical;Clinical Pathways;Clonality;Cytogenetics;DNA Resequencing;Data;Disease;European;European ancestry;Exhibits;FLT3 gene;Frequencies;Gene Mutation;Genes;Genetic;Genetic Risk;Genetic Transcription;Genetically Engineered Mouse;Genome;Genomics;Genotype;Goals;Human;Human Genetics;Incidence;Knowledge;Malignant Neoplasms;Medical Genetics;Modality;Modeling;Molecular;Mutate;Mutation;Oncogenic;Open Reading Frames;Outcome;Patients;Population;Prediction of Response to Therapy;Prognosis;Prognostic Marker;Publications;Publishing;RNA Splicing;RNA analysis;Recurrence;Relapse;Residual Neoplasm;Resistance;Risk;Risk Adjustment;Role;Sampling;Somatic Mutation;Testing;Therapeutic;Variant;XCL1 gene;Xenograft Model;Xenograft procedure;acute myeloid leukemia cell;cancer genetics;chemotherapy;clinical practice;clinical risk;cohort;driver mutation;drug development;exome;exome sequencing;genetic panel test;genetic risk assessment;in vivo;in vivo evaluation;leukemia;leukemic stem cell;leukemogenesis;multimodality;multiple omics;mutant;novel;precision oncology;prognostic;prognostic significance;response;risk stratification;therapy development;tool;transcriptome sequencing;treatment response;treatment stratification;tumor progression Towards an inclusive genomic risk classification for acute myeloid leukemia (AML) B. PROJECT NARRATIVEThis project studies the cancer genetics of human acute myelogenous leukemia. The overarching goal of thisproposal is to delineate genetic and genomic contributors that are currently missing in clinical risk stratificationtools and in the growing landscape of potential druggable and disease-modifying targets. Our results will informthe needed complexity of clinical genetic testing panels inclusive genetic risk assessment tools and identifyexemplars of thus-far unrecognized leukemic drivers. NCI 10752188 9/18/23 0:00 PA-20-185 1R01CA284595-01 1 R01 CA 284595 1 "CAGA-ANAN, EMILIE CHARLISSE F" 9/18/23 0:00 7/31/28 0:00 Cancer Genetics Study Section[CG] 14857366 "EISFELD, ANN-KATHRIN " "GRIMES, H. LEIGHTON; MARDIS, ELAINE R" 3 MISCELLANEOUS 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF EDUCATION 432101016 UNITED STATES N 9/18/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 687428 NCI 566236 121192 A. PROJECT SUMMARYAcute myeloid leukemia (AML) is the most common adult acute leukemia. Molecular features such ascytogenetics and somatic mutations are essential components of risk stratification; used in daily clinicalpractice to determine treatment modality and intensity. Our knowledge of recurrent genetic AML-associatedfeatures survival associations subsequent genetic risk classification and clinical practice is informed by large-scale genomic studies performed over the past decade on patients of Central-European ancestry. Thuscurrent clinical practice is predicated on the supposition that adequate testing has been performed and thatgenetic background should not affect the known AML-associated genetic and genomic landscape and genesthat associate with treatment response and/or that drive AML-genesis. However our published and preliminarydata reveal that ancestry affects not only the frequencies and impact of known AML-associated genemutations but also multiple recurrent variants in genes thus-far not implicated in AML-genesis. Wehypothesize that: a) known AML-associated drivers may carry different prognostic significance and might needto be adjusted in clinical risk classifications depending on ancestry and b) some unrecognized molecularfeatures are ancestry-associated drivers of AML-genesis and/or therapy resistance. We propose to extend ourinitial studies of AML genomes and genomics to provide statistical confidence around frequently mutatedgenes and a more inclusive molecularly-adjusted risk and treatment stratification for AML patients. Next wewill focus on NPM1c a genotype which confers favorable outcome in AML patients with Central-Europeanancestry but poor outcomes in other ancestries. We will use cutting-edge single-cell multiomic assays todelineate bystander clonal mutations from potential driver mutations then we will biologically test their role inclonality/leukemia-stem-cell frequency and treatment response. We expect to provide an inclusivecharacterization of the genetic and genomic landscape of AML identify those variants with prognosticsignificance and provide exemplars of here-to-fore unrecognized drivers of treatment response and survival.The overall goal is to enable precision oncology approaches which accommodate the effects of underlyinghuman genetics. 687428 +No NIH Category available Academic Detailing;Adherence;Adverse effects;Anatomy;Applications Grants;Area;Artificial Intelligence;Blood coagulation;California;Cancer Patient;Caring;Cause of Death;Characteristics;Clinic;Clinical;Clinical Data;Clinical Decision Support Systems;Computerized Medical Record;Coupled;Data;Day Surgery;Disparity;Education;Educational Intervention;Equity;Event;Geography;Goals;Guideline Adherence;Guidelines;Gynecologic;Health;Health system;Hospitals;Inequity;Inpatients;Institution;Intervention;Interview;Knowledge;Learning;Length of Stay;Low-Molecular-Weight Heparin;Malignant Neoplasms;Medical;Medical Societies;Mentorship;Methodology;Morbidity - disease rate;Multi-Institutional Clinical Trial;Naloxone;Nonmetastatic;Oncology;Outcome;Patient Discharge;Patients;Pharmaceutical Preparations;Population;Postoperative Period;Poverty;Prevention;Procedures;Professional Organizations;Prophylactic treatment;Qualitative Research;Race;Randomized Controlled Trials;Recommendation;Recovery;Research;Research Methodology;Research Personnel;Resources;Risk;Risk Reduction;Role;Side;Site;Socioeconomic Status;South Carolina;Stratification;Surgeon;Surveys;Testing;Universities;Work;black patient;cancer care;cancer health disparity;cancer site;cancer surgery;cancer therapy;clinical infrastructure;compliance behavior;cost;data registry;disparity reduction;evidence based guidelines;gastrointestinal;health equity;health literacy;improved;informant;inpatient service;interest;lens;mortality;multi-component intervention;multidisciplinary;neoplasm registry;opioid overdose;patient population;practice setting;racial disparity;randomized trial;risk stratification;social health determinants;structural determinants;support tools;urologic;venous thromboembolism NCI ESSP: An Equity Focused Intervention to Improve Utilization in Guideline Concordant Extended Venous Thromboembolism Prophylaxis After Major Cancer Surgery Project NarrativeWhile blood clots after major cancer surgery are common and harmful to patients the medications available todecrease blood clot risk are seldom used. Blood clots may play a role in observed racial disparities for cancerpatients though little is known about this. We will perform a multi-faceted educational intervention to improvesurgeon and patient use of these medications to reduce the risk of blood clots after major cancer surgery andpotentially reduce disparities in cancer outcomes. NCI 10752125 8/10/23 0:00 PA-20-272 3P30CA138313-15S1 3 P30 CA 138313 15 S1 "ROBERSON, SONYA" 4/1/09 0:00 3/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 1860729 "DUBOIS, RAYMOND N." Not Applicable 6 BIOCHEMISTRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 8/1/23 0:00 3/31/24 0:00 397 Research Centers 2023 186902 NCI 125000 61902 Project Summary/AbstractVenous thromboembolism (VTE) following major cancer surgery is a significant contributor to morbidity andmortality. Extended VTE prophylaxis (ePpx) following major cancer surgery decreases the risk of post-hospitalVTE and is recommended by professional societies. However utilization of ePpx remains limited. Moreoverracial disparities exist for cancer associated outcomes including VTE and mortality. These inequities in broadercancer care suggest that disparities may exist related to the utilization of ePpx. This aspect of cancer care hasnot been studied through a lens of cancer health disparities. The reasons for low utilization of ePpx remain asignificant knowledge gap. Electronic medical record (EMR)-based clinical decision support systems (CDSS)have been effective in improving adherence to inpatient VTE prophylaxis though has not been studied for ePpx.The overall objective of this work is to identify barriers and facilitators related to ePpx guideline adherence andconvene stakeholders to develop and implement a multi-faceted educational intervention including an EMR-based CDSS for increasing guideline adherence in a diverse oncology population. Our central hypothesis is thatmodifiable patient and surgeon factors exist which provide an explanatory mechanism for poor adherence toePpx guidelines (both by the surgeon and patient) and that these factors may be overcome by the equity focusedintervention described below. We will test our hypotheses through these specific aims:Specific Aim 1: Characterize barriers and facilitators to ePpx guideline adherence as perceived by stakeholdersvia key informant interviews with a diverse group of patients and surgeons at three hospitals within the MUSCHealth system that routinely perform abdominopelvic cancer surgery. Hypothesis 1: Barriers and facilitators related to ePpx use exist that are not forthcoming from clinical data; once uncovered these factors will inform the educational interventions in Aims 2.1 and 2.2.Specific Aim 2.1: Conduct a stepped-wedge randomized trial including multi-faceted surgeon-focusededucation and academic detailing to evaluate the impact of an EMR-based CDSS to increase adherence to ePpxguidelines at the three selected hospitals. Hypothesis 2.1: The intervention will increase ePpx following abdominopelvic cancer surgery.Specific Aim 2.2: Evaluate the impact of VTE related pre-discharge education on patient adherence to ePpxvia a pre-post study of patients undergoing abdominopelvic cancer surgery at the three selected hospitals. Hypothesis 2.2: Focused VTE related education will improve patient adherence.The application of rigorous qualitative research methodology to this clinical context will elucidate mechanisms toimprove administration of guideline concordant ePpx. Pairing these data with a multi-faceted stakeholderinformed educational intervention this work has the potential to significantly impact cancer care and mitigatecancer health disparities. 186902 +No NIH Category available Acceleration;Alternative Splicing;Area;Biology;Cancer Biology;Career Mobility;Cell physiology;Clinical;Collaborations;Creativeness;Defect;Development;Discipline;Education;Event;Fostering;Future;Goals;Immune response;Immune system;Industry;Intention;Knowledge;Learning;Malignant Neoplasms;Modification;Molecular;Oncology;Outcome;Pathogenesis;Pharmaceutical Preparations;Pharmacologic Substance;Physical condensation;Physicians;Postdoctoral Fellow;Process;RNA;RNA Processing;RNA Splicing;RNA-targeting therapy;Research;Research Personnel;Resources;Role;Schedule;Scholarship;Science;Scientist;Series;Site;Therapeutic;Translations;Underrepresented Minority;Woman;anticancer research;bench to bedside;cancer clinical trial;cancer initiation;career;career development;collaborative environment;drug development;graduate student;high throughput technology;interest;lectures;meetings;next generation;novel;novel strategies;novel therapeutic intervention;posters;pre-doctoral;preclinical trial;programs;recruit;response;social;symposium;targeted cancer therapy;therapeutic target;tumorigenesis RNA Processing in Cancer Conference: From Bench to Bedside PROJECT NARRATIVEThe FASEB 'RNA processing in cancer: from bench to bedside' conference is focused onexploring how RNA processing contributes to cancer and how this process can be targeted forthe development of novel cancer therapeutics. The proposed conference will cross-pollinate thefields of RNA biology and cancer biology seed new collaborations across disciplines andfacilitate the next generation of scientists to implement novel strategies towards targeting RNA inoncology. NCI 10752111 8/10/23 0:00 PA-21-151 1R13CA284796-01 1 R13 CA 284796 1 "LUO, RUIBAI" 9/1/23 0:00 8/31/24 0:00 ZCA1-PCRB-9(M1) 10300099 "ANCZUKOW-CAMARDA, OLGA " Not Applicable 8 Unavailable 74816851 CLHCSTHHSX25 74816851 CLHCSTHHSX25 US 39.013531 -77.101138 2604901 FEDERATION OF AMER SOC FOR EXPER BIOLOGY Rockville MD Other Domestic Non-Profits 20852 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 10900 NCI 10900 0 SUMMARYAlterations in RNA processing have recently emerged as a new cancer hallmark and a promising target forcancer therapies. The fields of cancer and RNA biology have traditionally been studied in isolation; however anintegrated approach between these fields is needed to prepare the next generation of scientists and physiciansto uncover the mechanisms of their relationship. Currently no conference in the cancer field incorporates RNAbiology. To fill this gap we propose the unique and timely interdisciplinary conference FASEB RNA processingin cancer: from bench to bedside to foster future collaborations and research advances. The main objectivesof this meeting are to define the role of RNA processing in cancer initiation progression and drug responsesand to identify novel therapeutic strategies to target RNA processing defects in cancer. This 5-day longconference to be held in Houston TX in November 2023 will bring together scientists including graduatestudents postdoctoral fellows and junior and senior investigators as well as clinicians and physicians andscientists from industry and pharmaceutical companies from the fields of RNA biology and cancer. While puttingtogether the speakers list the organizing committee made a commitment to increased diversity. The conferenceprogram will include invited lectures short talks from trainees and educational/professional sessions featuringleading scientists with distinct expertise yet shared interest in understanding the role of RNA processing in cancerpathogenesis and developing novel cancer therapeutics. Our specific aims are to (1) Organize aninterdisciplinary conference on RNA processing and cancer; (2) Promote interactions to foster collaborativeresearch and career advancement; (3) Foster the recruitment and development of diverse junior investigators inRNA biology and cancer research fields; (4) Accelerate translation of fundamental advances into novel clinicalcancer therapeutics. The proposed conference will cross-pollinate the fields of RNA biology and cancer biologyseed new collaborations across disciplines and facilitate the next generation of scientists to implement novelstrategies towards targeting RNA processing in oncology. 10900 +No NIH Category available Address;Attenuated;Award;Basic Science;Biological Markers;CCL17 gene;Cancer Biology;Cancer Burden;Cancer Center;Cancer Control;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Development;Direct Costs;Early Diagnosis;Education;Environment;Fostering;Funding;Health care facility;Healthcare;Intervention;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medical center;Medicine;Metastatic malignant neoplasm to brain;Mission;Modeling;NCI-Designated Cancer Center;Names;Nebraska;Organoids;Patients;Pharmaceutical Chemistry;Physicians;Population Sciences;Positioning Attribute;Prevention;Prognosis;Reporting;Research;Research Infrastructure;Research Peer Review;Research Support;Resource Sharing;Resources;Risk;Role;Scientific Advances and Accomplishments;Synthesis Chemistry;Teacher Professional Development;Tissue Microarray;Training and Education;Translational Research;Universities;anticancer research;cancer care;cancer education;cancer health disparity;cancer initiation;clinical care;community engagement;computational chemistry;health disparity;innovation;interdisciplinary collaboration;malignant breast neoplasm;member;metabolomics;multidisciplinary;novel therapeutic intervention;outreach;patient oriented;preclinical imaging;programs;recruit;research facility;translational cancer research;tumor progression;underserved community Blocking CCR4/CCL17 Axis Attenuates Breast Cancer Brain Metastasis PROJECT NARRATIVEThe Fred & Pamela Buffett Cancer Center (BCC) the only NCI-designated cancer center in Nebraska is a matrixcancer center at the University of Nebraska Medical Center and our affiliated healthcare network NebraskaMedicine. The Mission of the BCC is to promote innovative translational cancer research excellence in cancereducation and training and outstanding patient-centered cancer care and to reduce the burden of cancer andcancer health disparities across Nebraska and beyond. NCI 10751912 9/12/23 0:00 PA-20-272 3P30CA036727-37S1 3 P30 CA 36727 37 S1 "BELIN, PRECILLA L" 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 2401856 "COWAN, KENNETH H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 191875 NCI 125000 66875 PROJECT SUMMARYThe Fred & Pamela Buffett Cancer Center (Buffett Cancer Center or BCC) an NCI-designated Cancer Centersince 1984 is committed to basic translational clinical and population science research comprehensiveeducational programs and outreach to underserved communities in our catchment area (Nebraska). The newBCC integrated cancer research and care facility increased Cancer Center-controlled research space 1.7-fold(total 400000 sq ft) creating an environment which fosters scientific innovation and transdisciplinarycollaborations. The Cancer Center is fully integrated into the university and its affiliated healthcare networkNebraska Medicine (NM) with the Director reporting directly to the UNMC Chancellor and CEO NM andappointed BCC Physician-in-Chief. Two Cancer Center leadership positions were established since the lastreview Deputy Director and Associate Director for Community Outreach and Engagement (COE) with the latterleading efforts to reduce cancer burden and disparities in diverse communities across Nebraska. The BCC alsoappointed four new senior leaders and eliminated dual leadership roles to promote clinical and translationalresearch. The centralization expansion and reorganization of the BCC Clinical Trials Office was completed anda new CTMS (OnCore) installed culminating in a 1.8-fold increase in accrual to interventional clinical trials.Research infrastructure was enhanced by the addition of a new Preclinical Imaging Shared Resource as well asseveral new resources (e.g. Metabolomics Organoids Patient-Derived Models Tissue Microarrays Syntheticand Medicinal Chemistry and Computational Chemistry). The BCC has three Research Programs: CancerBiology Program (CBP); Targets Modulators and Delivery Program (TMDP); and GI Cancer Program (GICP).Two programs CBP and TMDP changed names reflecting the strategic realignment of their missions themesand memberships. With 28 Members recruited during the current funding period the BCC has a robust trackrecord of clinical and translational research supported by 14 multidisciplinary awards (P01 P50 P20s U awards;6 from NCI) and 16 new MPI awards (11 from NCI). Cancer-relevant peer-reviewed research funding in the BCCincreased 1.4-fold to $25.3M (Annual Direct Costs) and NCI funding increased 1.3-fold to $12.5 M (Annual DirectCosts) since our last review. 191875 +No NIH Category available Alternative Therapies;Anaphylatoxins;Animals;Area;Biological Assay;Bone Marrow;C3AR1 gene;Cancer Etiology;Carbon ion;Cell Membrane Alteration;Cell model;Cells;Cessation of life;Coculture Techniques;Complement;Complement 3a;Complement 3b;Complement 5a;Complement Activation;Complement Membrane Attack Complex;Complement Receptor;Curative Surgery;Data;Dendritic Cells;Dendritic cell activation;Deposition;Development;Disease;Effector Cell;Exclusion;Fibroblasts;Fibrosis;Flow Cytometry;Generations;Goals;Growth;Histologic;Histology;Histopathologic Grade;Human;Immune;Immune Tolerance;Immunofluorescence Immunologic;Immunologics;Immunomodulators;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In Vitro;Infiltration;Irradiated tumor;KRASG12D;Knock-out;Knockout Mice;Linear Energy Transfer;LoxP-flanked allele;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mannose Binding Lectin;Measures;Mediating;Modality;Modeling;Mus;Mutation;Neoplasm Metastasis;PET/CT scan;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phagocytes;Photons;Population;Production;Proliferating;Protons;Radiation;Radiation therapy;Regulatory T-Lymphocyte;Reporting;Research;Roentgen Rays;Role;Serum;Signal Transduction;Sirius Red F3B;Source;Stains;Survival Rate;T-Lymphocyte;Tamoxifen;Testing;Therapeutic;Treatment Efficacy;Tumor Immunity;Tumor Promotion;Unresectable;Western Blotting;X-Ray Computed Tomography;cancer therapy;complement deficiency;complement pathway;complement system;fluorodeoxyglucose;immune cell infiltrate;immunomodulatory therapies;improved;in vivo imaging system;inhibitor;insight;irradiation;knock-down;migration;mouse model;neoplastic cell;neutralizing antibody;novel;novel therapeutic intervention;pancreatic cancer model;pancreatic ductal adenocarcinoma model;pancreatic tumorigenesis;proton therapy;receptor;receptor expression;response;restraint;single-cell RNA sequencing;small hairpin RNA;small molecule inhibitor;therapy development;translational study;translational therapeutics;tumor;tumor growth;tumor microenvironment;tumorigenesis Anti-Complement Immunotherapy for Pancreatic Cancer PROJECT NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer deathby 2030 due to a dearth of therapeutic options which could extend survival. Using novel mouse models weaim to understand how complement activation in the tumor microenvironment promotes oncogenesis bysignaling to immune cells and cancer-associated fibroblasts. We further aim to study translational therapeuticswhich blockade complement signaling both alone and in combination with radiotherapy as an ablative andimmunomodulatory therapy to demonstrate novel immunotherapeutic strategies for PDAC. NCI 10751872 6/30/23 0:00 PA-21-049 1F30CA278322-01A1 1 F30 CA 278322 1 A1 "BIAN, YANSONG" 1/1/24 0:00 12/31/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(22)L] 16054390 "BELL, BRETT I" Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY / ABSTRACTPancreatic Ductal Adenocarcinoma (PDAC) is an almost uniformly lethal disease with an overall survival under10%. Despite therapeutic advances in all arenas of cancer treatment including immunotherapy overall survivalhas not significantly improved in PDAC representing a critical need for the development of novel therapeuticstrategies for this disease. The tumor microenvironment (TME) in PDAC is characterized by animmunosuppressive infiltrate causing T-cell exclusion and dense stromal desmoplasia. The complementcascade is activated in the PDAC TME and may promote this uniquely challenging TME by signaling to immunecells and fibroblasts expressing complement receptors. Complement activation has previously beendemonstrated to promote infiltration of immune cells which contribute to T-cell exclusion in multiple tumor typesin a context-dependent fashion. The long-term objectives of this project are to understand microenvironmentalmechanisms by which complement promotes oncogenesis in PDAC and to elucidate the interactions betweenradiotherapy (RT) and complement blockade in PDAC. A novel autochthonous mouse model of PDAC wasgenerated and crossed with complement deficient C3 knockout (KO) mice to allow for studies which define therole of complement in PDAC. Tumor growth in complement-proficient wild type (WT) PDAC mice and C3 KOPDAC mice will be tracked using serial PET/CT imaging. Tumors will be assessed histologically from 3-6 monthsafter induction with tamoxifen to determine histologic grade normal acinar area and fibrotic area. Flow cytometrywill be used to determine the impact of complement on infiltrating immune cells while single-cell RNA-sequencingwill provide insight into the development and activation of cancer-associated fibroblasts. We will also assess therole of tumor cell vs. stromally derived C3 with shRNA depletion of C3 in YFP-expressing KPC cells (KPCY) inflank tumor growth studies in WT and C3 KO mice as a second model to confirm these results. To assess theimpact of photon proton and carbon ion RT on complement activation and immune tolerance we will irradiateKPCY using each radiation modality. Complement deposition assays will be performed by culturing irradiatedand non-treated tumor cells in the presence of serum as a complement source before measuring activation byflow cytometry. Next dendritic cells will be co-cultured with irradiated and non-irradiated KPCY cells with serumto determine if complement deposition on irradiated tumor cells reduces dendritic cell activation markersmeasured by flow cytometry. Translational studies will be performed using neutralizing antibodies and smallmolecule inhibitors to blockade complement signaling alone and with RT in an orthotopic KPCY model. Mice willbe treated with neutralizing antibodies and inhibitors to blockade complement signaling and irradiated with an X-strahl Small Animal Radiation Research Platform or a Varian ProBeam proton therapy machine and growth willbe tracked by IVIS. Complement activation will be assessed by western blot and immunofluorescence and flowcytometry will assess differences in infiltrating immune cells post-irradiation. 52694 +No NIH Category available Agonist;Antibodies;Bar Codes;Biochemical;Candidate Disease Gene;Carcinoma;Cell Line;Cell Lineage;Cells;Characteristics;Chemoresistance;Combined Modality Therapy;Computer Models;Computing Methodologies;Data;Data Science;Data Set;Development;Developmental Process;Disease Progression;Epithelium;Exhibits;Gene Expression Profile;Genetic;Genetic Transcription;Growth Factor;Heterogeneity;Human;Hypoxia;Image;Immunofluorescence Immunologic;Indirect Immunofluorescence;Individual;Infection;Information Theory;Lead;Libraries;Maintenance;Malignant Neoplasms;Measures;Mediating;Mesenchymal;Methods;Modeling;Molecular;Neoplasm Metastasis;Oxygen;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Phenotype;Phosphoproteins;Phosphotransferases;Population;Process;Protocols documentation;Regulation;Resistance;Signal Pathway;Signal Transduction;Small Interfering RNA;Sorting;Systems Biology;Testing;Transcript;Treatment Factor;Uncertainty;Variant;Work;cell population study;cell transformation;chemotherapy;cytokine;design;differential expression;epithelial to mesenchymal transition;experimental study;fluorescence imaging;human imaging;information model;insight;interest;knock-down;novel;overexpression;pancreatic ductal adenocarcinoma cell;predictive modeling;prevent;programs;response;single cell analysis;single-cell RNA sequencing;small molecule inhibitor;transcription factor;transcriptome sequencing;transcriptomic profiling;tumor;wound healing Assessing the Transcriptional and Signaling Basis of Heterogeneity in the Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma PROJECT NARRATIVEEpithelial-mesenchymal transition (EMT) is a normal cellular program involved in development and woundhealing that occurs aberrantly in carcinomas to promote metastasis and chemotherapy resistance. Within cellpopulations and tumors EMT occurs with a high degree of heterogeneity with some cells undergoing thetransition and others remaining in an epithelial state. This project will develop integrated experimental andcomputational methods for quantifying the degree to which EMT heterogeneity is regulated transcriptionally orvia biochemical signaling processes in pancreatic ductal adenocarcinoma (PDAC) with anticipated resultshaving important implications for developing novel combination therapies for PDAC. NCI 10751834 6/16/23 0:00 PA-21-051 1F31CA275364-01A1 1 F31 CA 275364 1 A1 "ODEH, HANA M" 7/1/23 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16557794 "BARBEAU, MICHELLE C" Not Applicable 5 NONE 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA UNIVERSITY-WIDE 229044195 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 39135 NCI 39135 0 PROJECT SUMMARYThe epithelial-mesenchymal transition (EMT) is a developmental process that is aberrantly reactivated inpancreatic ductal adenocarcinoma (PDAC) to promote disease progression and chemoresistance. PDAC tumorsand cell lines typically contain a heterogeneous mixture of transformed cells displaying epithelial or mesenchymalcharacteristics complicating efforts to understand the regulatory mechanisms that govern this importantphenotypic switching. The observation that EMT can be initiated by a variety of different growth factors lowoxygen tension and matrix-mediated signaling strongly suggests that multiple signaling pathways cooperate todrive robust EMT and raises the possibility that EMT heterogeneity is explained by the ability of only some cellsto activate robustly the pathways that cooperate to drive EMT. Another potential but not necessarily mutuallyexclusive explanation for phenotypic heterogeneity is that some PDAC cells are primed to undergo EMT due totranscriptional differences that enable utilization of specific transcription factors or signaling pathways. Based onour preliminary data we hypothesize that certain PDAC cells are transcriptionally primed to undergo EMTand that EMT heterogeneity further depends upon cell-to-cell variations in kinase-regulated signalingprocesses within cell populations. The objective of the work proposed here is to test these hypotheses throughthe development of quantitative systems biology methods to study the basis of EMT heterogeneity regulation viatranscriptional and kinase-mediated signaling processes. In Aim 1 an iterative immunofluorescence imagingpipeline will be developed to gather multiplexed signaling data on populations of PDAC cells treated with differentEMT agonists. Based on preliminary studies we propose to measure markers for seven distinct signalingpathway nodes and two EMT markers to create a dataset with nine features measured for thousands of cells foreach experimental condition. We will then apply a mutual information data science approach for the quantitativeidentification of the signaling pathways that cooperate to drive robust EMT. Model predictions will be tested usingsmall molecule inhibitors and siRNA-mediated knockdowns. In Aim 2 we will use genetic barcoding for thetranscriptomic profiling of EMT-resistant or -compliant lineages within cell populations. Single-cell RNAsequencing data from cells before and after EMT induction will be analyzed to identify transcriptional states thatpreferentially enable PDAC cells to undergo the mesenchymal transition. The relevance of candidate transcriptsfor explaining EMT priming will be tested through knockdown experiments. The methods developed in this workwill be broadly applicable to the study of EMT in other cancer settings and to the study of alternative types ofphenotypic switching. Moreover the specific results will have implications for the design of novel combinationtherapies for PDAC based on the objective of suppressing EMT to promote responsiveness to chemotherapy. 39135 +No NIH Category available Acute Myelocytic Leukemia;Adult;Automobile Driving;Blood Cells;Cell Line;Cell Maturation;Cell Separation;Cell physiology;Cells;Chromatin;Clinical;Cre lox recombination system;DNA Methylation;Data;Defect;Development;Diagnosis;Epigenetic Process;FOS Protein;Family;Gene Expression Profiling;Genetic Transcription;Hematologic Neoplasms;Homeostasis;Human;Immune;Immune Evasion;Immunologic Surveillance;Immunotherapeutic agent;Impairment;In Vitro;Interferon Type II;Lymphoid Cell;MAPK8 gene;MEK inhibition;MEKs;Mediating;Mus;Myelogenous;Natural Killer Cells;Outcome;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Play;Post-Translational Protein Processing;Precursor Natural Killer Cell;Production;Proteins;Regulation;Role;Series;Signal Pathway;Signal Transduction;Survival Rate;Testing;Therapeutic;Transcriptional Activation;Treatment Efficacy;Work;Xenograft Model;activating transcription factor;acute myeloid leukemia cell;cancer cell;checkpoint receptors;design;dimer;epigenetic profiling;exhaustion;functional disability;immune checkpoint;in vivo;in vivo Model;inhibitor;leukemia;leukemia relapse;mouse model;novel;p38 Mitogen Activated Protein Kinase;pharmacologic;preservation;prevent;programs;small molecular inhibitor;stem cells;targeted treatment;therapeutic target;therapeutically effective;transcription factor;transcriptome sequencing The roles of AP-1 pathway activation in NK cell development and exhaustion programming in AML PROJECT NARRATIVEThe studies outlined in this proposal aim to determine the mechanisms by which activating protein-1 (AP-1)influences natural killer (NK) cell development and function in the setting of acute myeloid leukemia (AML). Ourcomprehensive approach will allow for a deeper understanding of the developmental and functionalconsequences of AP-1 pathway signaling in NK cell precursors and mature NK cells in the setting of AML. Thestudies outlined in this proposal will reveal novel mechanisms that hinder NK cell development and function inAML. NCI 10751755 8/3/23 0:00 PA-21-049 1F30CA284896-01 1 F30 CA 284896 1 "BIAN, YANSONG" 9/1/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-F09C-Z(22)L] 16564581 "JEREMY, ERIN G." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 42007 NCI 42007 0 PROJECT SUMMARY/ABSTRACTThe 5-year overall survival rate for acute myeloid leukemia (AML) is less than 35% making it the most fatalleukemia in adults. Natural killer (NK) cells are a type of innate lymphoid cell (ILC) capable of recognizing andkilling malignant cells. We have previously demonstrated that NK cells are developmentally and functionallyimpaired in AML. These impairments correlate to worse overall survival and clinical outcomes highlighting theimportance of understanding the mechanisms by which AML alters NK cell development and function. To betterunderstand these defects we assessed the transcriptional and epigenetic landscape of NK cells in AML anddiscovered that mature NK cells from AML patients are globally hypomethylated when compared to normalcontrols and have abnormal activation of activating protein-1 (AP-1). AP-1 which is a set of transcription factor(TF) dimers primarily composed of Jun and Fos family proteins has been shown to regulate ILC developmentand homeostasis chromatin accessibility and immune cell exhaustion. The activity of AP-1 is regulated byupstream mitogen activated protein kinases p38 JNK and ERK through transcription activation and post-translational modifications. In this proposal we will determine how the MEK/ERK signaling branch of the AP-1signaling pathway contributes to NK cell defects in AML and whether development and function can be restoredthrough AP-1 pathway inhibition. We hypothesize that AP-1 signaling is a critical regulator of NK cell developmentand function that becomes dysregulated in AML. These studies will first describe the mechanism(s) by which theAP-1 pathway influences NK cell development in the setting of AML (Aim 1). We will use pharmacologic agentsas well as CRISPRcas9 editing to understand how aberrant AP-1 signaling skews human NK cell development.We will also determine the functional consequences of aberrant AP-1 activation in mature NK cells (Aim 2).Finally we will assess the therapeutic efficacy of AP-1 pathway regulation in multiple in vivo models of AML (Aim3). Results from these studies will further our mechanistic understanding of NK cell development in AML to betterinform therapeutic strategies. 42007 +No NIH Category available Accidents;Alternative Splicing;Apoptosis;Apoptotic;BCL2 gene;Bcl-2 Homology Domain;Binding;CRISPR screen;Cancerous;Candidate Disease Gene;Cell Death;Cell Death Induction;Cell Nucleus;Cell physiology;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Consensus;Cytoplasm;DNA Polymerase II;Data;Death Rate;Drug Design;Experimental Genetics;Family member;Gene Expression;Genes;Genetic Transcription;Goals;Immunoprecipitation;Knock-out;Knowledge;Measures;Messenger RNA;Methods;Mitochondria;Modeling;Normal Cell;Nuclear;Nuclear Export;Nuclear Protein;Patient Selection;Patients;Pharmaceutical Preparations;Phenotype;Process;Production;Protein Isoforms;Proteins;RNA;RNA Splicing;RNA immunoprecipitation sequencing;RNA-Binding Proteins;Regulation;Regulator Genes;Resistance;Role;Series;Signal Transduction;Testing;Time;Toxic effect;Transcript;Work;cancer cell;cell growth;cell killing;cell type;design;drug mechanism;experimental study;genetic regulatory protein;genome-wide;improved;inhibitor;inhibitor therapy;insight;interest;live cell imaging;live cell microscopy;mRNA Expression;mRNA Precursor;novel;novel drug combination;pre-clinical;response;treatment strategy Mechanism of cell lethality following loss of gene expression. PROJECT NARRATIVEWe currently lack the ability to predict how cancer cells will respond to transcriptional inhibitorsa drug class ofmajor clinical and pre-clinical interest. This proposal aims to characterize an unexpected mechanism by whichtranscriptional inhibition induces cell death. Rational drug design and patient selection depends oncomprehensively understanding how transcriptional inhibitors activate regulated cell death. NCI 10751723 7/17/23 0:00 PA-21-051 1F31CA284879-01 1 F31 CA 284879 1 "ODEH, HANA M" 8/1/23 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-F05-Q(20)L] 77854474 "HARPER, NICHOLAS WADE" Not Applicable 2 GENETICS 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 32478 NCI 32478 0 PROJECT SUMMARYThe goal of this project is to determine the mechanism by which cell death results from transcriptional inhibition.The consensus model in the field posits that cell death following transcriptional inhibition results from the loss ofspecific mRNA species and subsequent loss of protein. By targeting such a core cellular process transcriptionalinhibition is thought to overwhelm cellular control and lead to unavoidable cell death. This death process definedas Accidental Cell Death (ACD) is not controlled by the cell and does not result from the use of defined effectormolecules. Contrary to the conventional model we found that rather than induce ACD cell death followingtranscriptional inhibition results from a previously undescribed regulated apoptotic signal. Furthermore we foundthat RNA Pol II degradation rather than loss of mRNA production resulted in cell death. Our data suggests anew model whereby degradation of Pol II induces a signal that leaves the nucleus and is received by themitochondria to initiate apoptosis. To identify genes that regulate a pro-apoptotic signal following transcriptionalinhibition we performed a genome-wide CRISPR screen. Genome-wide CRISPR screens often fail to identifydeath regulatory genes making it difficult to elucidate mechanisms of cell death. To overcome this we developeda novel experimental strategy that allowed us to identify genes whose knockout modulated the cell death ratefollowing transcriptional inhibition. Based on the results of our screen in Aim 1 we will test the hypothesis thatthe alternative splicing regulator PTBP1 facilitates altered splicing and nuclear export of regulatory pre-mRNAand that this activity is required for cell death following transcriptional inhibition. We will use live cell microscopyto establish the functional role of PTBP1 nuclear export. We will use SLAM-seq and RIP-seq to quantify PTBP1activity following transcriptional inhibition. Our screen also identified BCL2L12 as the critical apoptotic effectorgene for transcriptional inhibition. In Aim 2 we will test the hypothesis that BCL2L12 activates apoptosis followingtranscriptional inhibition in an isoform-specific manner. We will perform a series of functional geneticsexperiments to characterize the role of BCL2L12 in the apoptotic response. By describing a new mechanisticmodel by which transcriptional inhibition induces cell death we will improve our understanding of how toeffectively use transcriptional inhibitors therapeutically. Ultimately we hope our work will improve our ability topredict which patients will best respond to transcriptional inhibitors and help identify novel treatment strategies. 32478 +No NIH Category available 3-Dimensional;Address;Aftercare;Age;Anatomy;Biopsy;Blood specimen;Brain imaging;Cessation of life;Chemotherapy and/or radiation;Clinical;Clinical Medicine;Data;Data Set;Detection;Diffusion;Disease;Disease Progression;Early treatment;Edema;Evolution;Excision;Frustration;Future;Glioblastoma;Goals;Habitats;Image;Immune system;Inflammation;Intervention;Laboratories;Machine Learning;Magnetic Resonance Imaging;Malignant neoplasm of brain;Manuals;Maps;Medial;Methods;Modification;Molecular;Monitor;Necrosis;Neoplasm Circulating Cells;Neuroanatomy;Oncology;Operative Surgical Procedures;Patient Monitoring;Patient-Focused Outcomes;Patients;Performance;Performance Status;Perfusion;Physicians;Physiological;Population;Process;Prognosis;Protocols documentation;Radiation Oncology;Radiation therapy;Research;Resolution;Scanning;Scientist;Statistical Data Interpretation;Surgically-Created Resection Cavity;System;Techniques;Texture;Training;Translating;Treatment outcome;Tumor Volume;aggressive therapy;anatomic imaging;automated segmentation;brain volume;career;chemotherapy;clinical practice;convolutional neural network;deep learning;disability;feature selection;image processing;imaging biomarker;improved;improved outcome;learning network;molecular marker;neovascularization;neuroimaging;novel;novel strategies;predictive modeling;prognostic;quantitative imaging;radiomics;risk stratification;segmentation algorithm;serial imaging;skills;standard care;tool;treatment response;treatment strategy;tumor;tumor growth Machine Learning and Radiomics Techniques for Analysis of Daily MRI in Glioblastoma Patients PROJECT NARRATIVEGlioblastoma is the most common primary brain cancer worldwide and urgent treatment strategiesare needed since it is almost a universally fatal disease. The focus of this project is to address unmetneeds by developing tools that identify and monitor patients with significant anatomic and/orphysiologic tumor changes much earlier than current methods so that in the future promptaggressive and early therapy adaption can be implemented. This project will translate directly to thepractice of clinical medicine and advance the field of glioblastoma treatment. NCI 10751672 8/10/23 0:00 PA-21-049 1F30CA278357-01A1 1 F30 CA 278357 1 A1 "BIAN, YANSONG" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F10C-D(20)L] 16056632 "CULLISON, KAYLIE " Not Applicable 27 RADIATION-DIAGNOSTIC/ONCOLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARYGlioblastoma is the most common primary brain cancer worldwide. Novel treatment strategies areurgently needed since glioblastoma is nearly universally fatal with a median overall survival of only 1.5-2 years. A frustrating aspect of glioblastoma is that approximately half of all patients will have whatlooks to be tumor growth on their post-treatment MRI termed progression. Although half of patientswith progression will turn out to have pseudoprogression which is a not-fully understood phenomenonbelieved to be edema and inflammation caused by the immune system and represents a good responseto treatment. In fact patients with pseudoprogression tend to do better than the general glioblastomapopulation and have a median overall survival of up to 3 years. On the other hand patients with trueprogression of disease (tumor growth and poor/nonresponse to treatment) tend to do worse than thegeneral glioblastoma population and have a medial overall survival of only 10 months. The frustratingpart for clinical team and the patients themselves is that true progression and pseudoprogression arenot discernable from one another during treatment or even on initial post-treatment imaging (1-monthpost-treatment). Instead the current gold-standard to distinguish between true and pseudoprogressionis to watch and wait continue monitoring with serial imaging and see if the patient clinically worsensor stabilizes. Thus there is an unmet need for techniques that reliably and accurately determine if tumorgrowth/progression is occurring during treatment and predict/determine which sub-type of progression(true progression or pseudoprogression) a patient has. My laboratory focuses on responding to thisunmet need through a variety of methods: serial multiparametric MRI (anatomic perfusion diffusionspectroscopic etc.) quantitative MRI analysis machine learning and molecular research includinganalyzing blood samples of glioblastoma patients to look for circulating tumor cells and other molecularmarkers. This proposal focuses on auto-detection of tumors on MRI based on machine learning (Aim1) and analysis of anatomic and physiologic changes (Aim 2) from daily multiparametric MRI to addressthis issue by creating techniques that can detect enlarging tumors during treatment and predict betweentrue and pseudoprogression months earlier than current methods. The goal of this proposal is to developtools that identify and monitor patients with significant anatomic and/or physiologic tumor changes muchearlier than current methods so that in the future prompt aggressive and early therapy adaption canbe implemented. This project will translate directly to the practice of clinical medicine and advance thefield of glioblastoma treatment. Additionally it will allow me to gain hands-on skills and expertise inmachine learning radiomics MRI neuroimaging neuro-anatomy radiation therapy and oncology andaid in preparing me for a career as an academic physician scientist in the field of radiation oncology. 52694 +No NIH Category available Adenocarcinoma;Affect;Aging;Anatomy;Architecture;Benign;Biological;Biopsy;Cadaver;Cancer Etiology;Cell Proliferation;Cells;Cessation of life;Clinical;Colon;Colonic Diseases;Colonoscopy;Colorectal;Colorectal Cancer;Consensus;Detection;Development;Disease;Disease Management;Disease Progression;Dissection;European ancestry;Event;Frequencies;Genetic Predisposition to Disease;Hindgut;Incidence;Individual;Inflammatory Bowel Diseases;Institutional Review Boards;Investigation;Lasers;Left;Length;Link;Location;Malignant Neoplasms;Maps;Metadata;Methodology;Midgut;Monitor;Morbidity - disease rate;Mosaicism;Mutagenesis;Mutation;Mutation Analysis;Normal tissue morphology;Organ;Organism;Outcome;Pathogenesis;Pathologic Mutagenesis;Pathology;Patients;Pattern;Play;Polyps;Precision therapeutics;Predisposition;Reporting;Research;Resolution;Risk;Role;Sampling;Somatic Mutation;Space Perception;Standardization;Structure;Syndrome;Testing;Tissues;Universities;Utah;Variant;adenoma;biobank;body system;causal variant;cohort;colonic crypt;disorder risk;early onset colorectal cancer;fitness;gastrointestinal;genome sequencing;human disease;human tissue;improved;innovation;insight;microbiome;mortality;mosaic;screening;spatiotemporal;whole genome SEMIColon: Somatic Exploration of Mosaicism in Colon Project NarrativeDiseases of the colon are widespread with colorectal cancer the 2nd leading cause of cancer death in the USand inflammatory bowel disease highly prevalent and rising in incidence across the globe. These pathologieshave distinct presentations and outcomes across the length of the colon but the genetic etiologies of thesedifferences are poorly understood and limit precision treatment. By understanding how somatic mosaicismdiffers throughout the colon and disease development we will be better equipped to treat these pathologiesbetter prepared to identify at-risk individuals and better able to study tissue-specific disease progression inother organ systems. NCI 10751575 8/11/23 0:00 PA-21-050 1F30CA284847-01 1 F30 CA 284847 1 "DAMICO, MARK W" 9/1/23 0:00 10/31/27 0:00 Special Emphasis Panel[ZRG1-F08-A(20)L] 78499408 "HIATT, LAUREL " Not Applicable 1 GENETICS 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 48972 NCI 48972 0 Project Summary/Abstract If we understand the somatic mosaicism of healthy tissues and how this changes throughpathogenesis we will be better equipped to screen for monitor and treat disease. Somatic mutationsplay a central role in disease pathogenesis from developmental syndromes to cancer and there is growingconsensus that somatic mosaicism in healthy tissue influences fitness and disease predisposition. Newmethodological breakthroughs enable the accurate detection of somatic mutations mutation rates andmutational signatures. Establishing a biological baseline of mosaic profiles in healthy and diseased tissue canfacilitate the prediction of genetically-driven disease states and the optimization of disease management. By studying somatic mosaicism in healthy and diseased colon I will gain insight into colorectalpathogenesis and establish a research framework to apply to other tissues. The colon is ideal for mosaicresearch given its monoclonal crypts elevated mutation rate and well-studied architecture. There are alsosignificant associations between somatic mosaicism and colorectal disease: somatic mutations are causativein colorectal cancer (CRC) and are proposed to contribute to inflammatory bowel disease (IBD). Thesediseases have well-established regional presentations with distinct pathologies along the length of the colonsuch as right and left CRC and differently-clustered subtypes of IBD. However the genetic etiologiesunderlying these pathologies are unknown given previous limitations in mosaic research. This proposal willexamine the spatiotemporal dynamics of colonic mosaicism in the context of healthy tissue and pathogenesis.Evaluating mosaicism across the length of the colon will provide insight into whether region-specificmutagenesis either endogenous or exogenous explains variation in regional pathogenesis. A preliminary study by Lee-Six et al. reported variation in mutational signature proportions across thecolon. However this analysis was limited by its low sequencing coverage (~15x) and examination of a smallnumber of colonic subregions in a small cohort. By leveraging access to cadaver tissue and colonoscopysamples in tandem with biological and computational advances I will quantify mosaicism with greaterresolution and capacity for hypothesis testing. This proposal will determine individual and cohort-basedmutational rates by anatomic subsite of the colon and extract mutational signatures that indicatemutagenic processes such as cellular proliferation or microbiome variation. I hypothesize that midgut-and hindgut-derived colonic structures will harbor distinct mutational signatures from unique mutagenesis andregionally distinct mutation rates. These mutational landscapes will likely overlap regionally with thespatially-linked findings of CRC and IBD suggesting a role in pathogenesis. Completion of this proposal willthen serve as an ideal framework to examine regional variation and pathogenesis in other tissues. 48972 +No NIH Category available Affect;Antigens;Automobile Driving;Bioinformatics;CD8-Positive T-Lymphocytes;Cancer Model;Cancer Patient;Caring;Cessation of life;Clinical Trials;Collaborations;Computer software;Development;Epigenetic Process;Flow Cytometry;Funding;Future;Genetic;Genitourinary system;Genomics;Growth;HDAC1 gene;Histone Deacetylase Inhibitor;Human;Immune checkpoint inhibitor;Immunofluorescence Immunologic;Immunologics;Immunology;In Vitro;Knowledge;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Measures;Migration Assay;Modeling;Mus;Oncology;Patients;Physicians;Population;Positioning Attribute;Prognosis;Regulatory T-Lymphocyte;Research;Sampling;Scientist;Single Nucleotide Polymorphism;Source;Specificity;Stains;Statistical Models;Survival Rate;T cell response;T-Cell Immunologic Specificity;T-Lymphocyte;Testing;Training;Translational Research;Tumor Antigens;Tumor Biology;Tumor Volume;United States;Work;anti-PD-1;cancer diagnosis;cancer immunobiology;career;effective therapy;enzyme linked immunospot assay;experience;immune checkpoint blockade;immunogenic;immunogenicity;improved;in vivo;men;migration;mouse model;neoantigen vaccination;neoantigens;response;single-cell RNA sequencing;subcutaneous;transcriptome sequencing;transcriptomics;treatment effect;tumor;tumor immunology;tumor microenvironment;ultrasound Effects of entinostat and neoantigen vaccination on bladder cancer Project NarrativeAdvanced bladder cancer has a poor prognosis and only 20-30% of patients respond to immune checkpointblockade. Response to the immune checkpoint inhibitor PD-1 can be improved by adding the histonedeacetylase inhibitor entinostat but it is unknown how modulation of M-MDSCs and the neoantigen landscapecan be leveraged to augment response. We hypothesize that entinostat-induced changes in M-MDSCs andneoantigen expression drive response to the combination of entinostat and PD-1 and we seek to improveresponse through neoantigen vaccination. NCI 10751492 6/30/23 0:00 PA-21-049 1F30CA278317-01A1 1 F30 CA 278317 1 A1 "BIAN, YANSONG" 8/1/23 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 15642892 "BECKABIR, WOLFGANG " Not Applicable 4 MICROBIOLOGY/IMMUN/VIROLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 46129 NCI 46129 0 Project Summary/AbstractBladder cancer is a prevalent and deadly cancer with over 80000 new cases and 17000 deaths annually in theUnited States. Advanced bladder cancer has only a 15% 5-year survival rate. One of the most effectivetreatments for advanced bladder cancer is immune checkpoint blockade (ICB) but only 20-30% of patients withadvanced bladder cancer respond and most responses are not enduring. A promising new treatment identifiedby our group to improve bladder cancer ICB response is the selective class 1 histone deacetylase inhibitorentinostat. In a mouse model entinostat plus anti-PD-1 (PD-1) ICB induced complete enduring responses in67% of mice. Entinostat decreased intratumoral M-MDSC and Treg populations decreased tumor single-nucleotide variant (SNV) neoantigen burden in vivo increased expression of some SNV neoantigens in vitroand increased T cell specificity for these neoantigens in vivo. However much of the mechanism behind responseto entinostat plus PD-1 is unknown particularly how entinostat decreases immunosuppressive populations andaffects expression of the neoantigen landscape. Understanding this mechanism is important to predict whichpatients will respond and to potentially improve responses through antigen-directed therapy. We hypothesizethat entinostat-induced ICB response is driven by increased M-MDSC differentiation decreased M-MDSCmigration and increased expression of suppressed immunogenic neoantigens augmenting response toneoantigen vaccination. I will investigate two components driving response to entinostat plus PD-1: M-MDSCsand neoantigens. The training in computational and wet lab immunology tumor biology and genetics orthotopicmurine tumor models and translational research with a clinical trial will assist me in becoming an independentlyfunded physician-scientist leading a cancer immunology research lab and caring for bladder cancer patients.In our M-MDSC-focused Aim 1 I will perform flow cytometry and transwell migration assays with M-MDSCs fromorthotopic bladder cancer model tumors to assess whether M-MDSC differentiation and migration are affectedby entinostat treatment. I will conduct immunofluorescence staining of human tumors from the LCCC1827entinostat window trial (NCT03978624) to assess whether adding entinostat to ICB treatment decreases M-MDSCs in humans. The Vincent Lab has developed LENS a software platform to identify neoantigens frommultiple genomic sources. In our neoantigen expression-focused Aim 2 I will use LENS to identify all theneoantigens in 3 murine bladder cancer lines developed by the Kim Lab test T cell neoantigen specificity byhigh-throughput ELISPOT and use statistical modeling to predict neoantigens immunogenicity. I will alsovalidate whether entinostat-induced immunoediting occurs in human tumors from LCCC1827. In our neoantigenvaccination-focused Aim 3 I will test whether neoantigen vaccination improves tumor response to entinostatplus PD-1. I will treat orthotopic tumors measure their growth and perform flow cytometry and single cellRNAseq to measure non-exhausted neoantigen-specific CD8+ T cell abundance. 46129 +No NIH Category available Adhesions;Affect;Agonist;Antigen Presentation;Antigen Presentation Pathway;Antigens;Autoimmunity;Automobile Driving;Biological;Biological Assay;Biological Markers;Blood;Bone Marrow;Castration;Cell Cycle Kinetics;Cell Differentiation process;Cell Line;Cell Survival;Cell physiology;Cells;Cellular biology;Chimera organism;Circulation;Clinical Trials;Coculture Techniques;Data;Dendritic Cells;Dependence;Disease;Dose;Endosomes;Estradiol;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Estrogens;FLT3 ligand;Female;Flow Cytometry;Fluorescent Antibody Technique;Genetic;Genetically Engineered Mouse;Goals;Gonadal Steroid Hormones;Head and Neck Cancer;High Endothelial Venule;Homing;Hormones;Human;Immune;Immune response;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Vitro;Incidence;Inflammation;Knockout Mice;Label;Lymphocyte;Macrophage;Male Castration;Mediating;Mediator;Menopausal Status;Migration Assay;Modeling;Molecular;Mus;Nodal;Outcome;Ovalbumin;Ovariectomy;Patients;Phenotype;Play;Population;Postmenopause;Premenopause;Process;Proteomics;Receptor Signaling;Regulatory T-Lymphocyte;Reporting;Research;Risk;Role;Selection for Treatments;Sex Preselection;Signal Transduction;Site;System;T cell differentiation;T-Cell Activation;T-Lymphocyte;Target Populations;Testing;Testosterone;Therapeutic;Time;Toll-like receptors;Tomatoes;Tumor Antigens;Up-Regulation;Woman;antagonist;antigen-specific T cells;cancer cell;cancer therapy;cellular targeting;density;draining lymph node;effector T cell;experimental study;head and neck cancer patient;immunoregulation;improved;in vitro Assay;in vivo;lymphatic vessel;male;men;menopausal hormone therapy;mouse model;negative affect;novel marker;novel therapeutics;pharmacologic;pre-clinical;programmed cell death protein 1;receptor;response;restraint;sex;sexual dimorphism;therapy resistant;trafficking;treatment response;tumor;tumor microenvironment;tumor progression;uptake Sexual dimorphism and the immuno-modulatory role of estrogen signaling in HNSCC NARRATIVEThe outcomes and treatment response of head and neck cancer varies by sex and menopausal status withpremenopausal women demonstrating the best response to therapy including immunotherapy. Our preclinicaldata identified regulatory T cells (Tregs) dendritic cells (DCs) and high endothelial venules (HEVs) as targetpopulations mediating estrogen's response to therapy. In this proposal we examine how estrogen regulatesthese cellular targets to modulate the sexually dimorphic effect of therapy. NCI 10751465 7/3/23 0:00 PA-20-185 1R01CA284651-01 1 R01 CA 284651 1 "ZAMISCH, MONICA" 7/3/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 6491204 "KARAM, SANA " Not Applicable 6 RADIATION-DIAGNOSTIC/ONCOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 646344 NCI 414544 231800 ABSTRACTHead and neck cancer (HNSCC) afflicts mostly men. Female patients who develop HNSCC tend to bepostmenopausal with menopausal hormone therapy lowering their risk of developing the disease. We show thatpremenopausal female HNSCC patients have an improved response to therapy including immunotherapy (IO).Using clinical trial data we show no difference in response to IO from testosterone. Similarly our preclinical datashow no IO response effect from gonadal castration. But 0.1 mg estradiol (E2) improves response in castratedmale mice to that of female mice. Our overall objective is to understand how the premenopausal female hormoneE2 contributes to progression and treatment resistance. Our data show that E2 had no effect on cancer cellviability suggesting the tumor microenvironment (TME) as the site of action. E2 is known to play a major role inautoimmunity and inflammation where it modulates dendritic cell (DC) and regulatory T cells (Treg)differentiation and function and lymphatic vessel maturation. These immune cell populations regulate responseto immunotherapy in HNSCC but how they are affected by sex hormones remains largely uncharacterized. Ourpreclinical data also show that compared to male mice females have increased DCs less suppressive Tregsand respond better to immunotherapeutic strategies with enhanced Teff function. Such response is removedwith oophorectomy (OVX) but rescued with E2 of 0.1mg. OVX also changes the TME towards animmunosuppressive one with enhanced immunosuppressive Treg activity similar to that of male mice. Finallywithin the TME OVX reduces the formation of high endothelial venules (HEVs) in the TME and draining lymphnodes (dLN) which enhance Teff cell priming and subsequent trafficking into the TME. We hypothesize thatthe sexually dimorphic response is driven by E2 acting via its receptors on Tregs and DCs to enhanceantigen presentation and increase Teff activation thus selectively determining response toimmunotherapy. We also hypothesize that E2 will increase homing and trafficking of antigen specific Tcells by enhancing HEV formation and maturation. In Aim1 we will interrogate the regulatory mechanismsof E2's effects on the DC biology by using genetically engineered mouse models (GEMMS) in vitro assays andproteomic analysis to examine receptor subtypes and molecular mediators of DC differentiation maturation andantigen presentation. Aim 2 will dissect mechanisms of how E2's effect on Tregs can drive response andselection of sex-specific immunotherapies. We will test this with GEMMS mouse chimeras and pharmacologicalmanipulation in in vivo and in vitro co-culture experiments to identify signaling and downstream effectors.Focusing on T cell trafficking in Aim 3 we will examine E2's effect on HEV formation and T cell egress from thedLN to the TME and systemic circulation using a combination of flow and immunofluorescence techniques inGEMMs and in vitro systems. These studies will collectively elucidate the basic mechanisms for advancing sex-directed novel biomarkers and therapeutics in HNSCC. 646344 +No NIH Category available Address;Affect;Animal Housing;Animal Model;Animals;Basal metabolic rate;Biomedical Research;CD28 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Caring;Chronic;Clinic;Clinical;Data;Development;Down-Regulation;Flow Cytometry;Genetically Engineered Mouse;Goals;Guidelines;Harvest;House mice;Housing;Human;Immune;Immune checkpoint inhibitor;Immunologics;Immunotherapy;Impairment;In Vitro;Institution;Knockout Mice;Knowledge;Laboratories;Laboratory Animal Science;Laboratory Animals;Malignant Neoplasms;Measures;Mediating;Medical;Modeling;Molecular;Molecular Target;Mus;Nerve;Norepinephrine;Outcome;Pathway interactions;Patients;Phenotype;Physiological;Play;Pre-Clinical Model;Process;Publishing;Receptor Signaling;Reproducibility;Research;Research Proposals;Rodent;Role;Signal Induction;Signal Transduction;Standardization;Surface;Sympathetic Nervous System;T-Cell Activation;T-Lymphocyte;Temperature;Testing;Thermogenesis;Training;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Work;adrenergic stress;anti-PD-1;anti-tumor immune response;anticancer research;beta-adrenergic receptor;cancer therapy;career;cold stress;design;effector T cell;environmental stressor;experience;falls;functional disability;guide for the care and use of laboratory animals;human disease;human model;improved;in vivo;insight;mRNA Expression;melanoma;mouse model;novel therapeutics;pre-clinical;preclinical study;protein expression;receptor;response;success;therapy development;translational potential;treatment response;tumor;tumor growth;tumor immunology Examining the impact of laboratory housing temperature on murine CD28 and the response to anti-PD-1 Project NarrativeThe data generated in preclinical cancer research are often unreproducible and not translatable to the clinic.The goal of this proposal is to better understand the full impact of housing conditions on the animal models werely on for studying cancer and the anti-tumor immune response by studying the influence of laboratory rodenthousing temperature on murine CD8+ T cell anti-tumor immunity and response to immunotherapy. Theknowledge gained from these studies will have direct implications on the role of laboratory housing conditionsas a variable in murine models of cancer and immunotherapy. NCI 10751424 8/10/23 0:00 PA-21-051 1F31CA288029-01 1 F31 CA 288029 1 "PURI, ANU" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 77897817 "JAMES, CAITLIN M" Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 32512 NCI 32512 0 Project Abstract/SummaryFor decades animals in biomedical research have yielded significant scientific and medical breakthroughs bygenerating the essential preclinical data that ultimately support the discovery and development of treatmentsfor human diseases including cancer. However while we to rely on animal models to investigate thecomplexity of cancer and cancer therapies these preclinical studies have alarmingly low success inreproducibility and even lower preclinical-to-clinical success rates. As per the Guide for the Care and Use ofLaboratory Animals 8th Edition research institutions have standardized minimum guidelines for the housinghusbandry and overall care for laboratory animals that they must adhere to. A mildly cool ambienttemperature is a critical aspect of animal housing that has been shown to elicit significant physiologicalchanges to research rodents driven by the activation of the sympathetic nervous system and increased -adrenergic receptor (-AR) signaling as a result of the systemic release of norepinephrine. This is due to thecompensatory response known as non-shivering thermogenesis employed by rodents housed attemperatures that fall below their thermoneutral zone (which is the range of ambient temperatures at whichheat generated by basal metabolism is sufficient for maintaining homeostatic core temperature. ) Our lab haspreviously established that standard (ST) subthermoneutral laboratory housing temperatures result insignificant impairment to the murine CD8+ T cell-dependent anti-tumor immune response compared to micehouse at thermoneutral temperatures (TT). Additionally we have shown that the immune checkpoint inhibitorPD-1 an immunotherapy that has recently seen success as a front-line approach to treating cancers likemelanoma has improved efficacy in treating tumor-bearing mice housed at TT in a -AR-dependent manor.Although published and preliminary data indicate a role for the co-receptor CD28 in the diminished anti-tumorfunction of CD8+ T cells as a result of increased -AR signaling a gap exists in our understanding of themechanisms underlying the reduced CD8+ T cell activation and effector function in mice housed at ST.Therefore we propose using genetically engineered mouse models to precisely interrogate CD28 signalingand test hypothesis that standard housing temperatures impairs CD8+ T cell anti-tumor immunity and the invivo efficacy of PD-1 via impaired CD28 co-stimulation. We will use in vitro and in vivo approaches toexamine the effects of housing temperature on CD8+ T cell CD28 expression and signaling as well as tumor-infiltrating lymphocytes in mice treated with PD-1 therapy. The studies outline in this proposal have thepotential to identify a previously undefined mechanism by which subthermoneutral laboratory animal housingtemperatures influence experimental outcomes of cancer and immunotherapy models while alsocharacterizing a widely underappreciated variable that exists in our animal models. 32512 +No NIH Category available ATAC-seq;Acute Myelocytic Leukemia;Adenocarcinoma;Affect;Affinity;Apoptosis;Automobile Driving;Binding;Biological Assay;Cancer cell line;Cell Culture Techniques;Cell Line;Cell Proliferation;Chemotherapy and/or radiation;Chromatin;Chromatin Remodeling Factor;Co-Immunoprecipitations;Combined Modality Therapy;Complex;Data;Enhancers;Epigenetic Process;Flow Cytometry;Future;Gene Expression Regulation;Genes;Genetic Transcription;Glycerol;Goals;Histones;Human;Immunoprecipitation;In Vitro;Knowledge;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mediating;Mentors;Missense Mutation;Modeling;Molecular;Mutation;Nonsense Mutation;Normalcy;Nucleic Acid Regulatory Sequences;Nucleosomes;Oncogenic;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Pediatric Oncology;Phenotype;Play;Positioning Attribute;Prognosis;Proteasome Inhibition;Proteins;Reader;Recurrence;Regulator Genes;Rhabdoid Tumor;Role;SMARCB1 gene;Scientist;Sedimentation process;Stains;Survival Rate;Testing;Therapeutic;Toxic effect;Training;Transcriptional Regulation;Tumor Suppressor Proteins;Urea;Western Blotting;Work;beta-Galactosidase;genome-wide;improved;improved outcome;in vivo;insight;loss of function;mutant;mutation screening;new therapeutic target;novel;overexpression;posttranscriptional;recruit;senescence;success;targeted treatment;therapeutic target;transcriptome sequencing;treatment and outcome;tumor The role of DPF2 stability in SMARCB1-deficient cancers PROJECT NARRATIVELoss of SMARCB1 has been identified as the sole mutation in a number of rare pediatric cancers most of whichhave a poor prognosis despite intensive therapies including surgery radiation and chemotherapy. Thus a morerobust understanding of the mechanisms driving this set of cancers is vital to improving patient treatment andoutcomes. This study aims to generate knowledge that will set the stage for new therapeutic targets andimproving patient outcomes. NCI 10751414 7/10/23 0:00 PA-21-051 1F31CA278008-01A1 1 F31 CA 278008 1 A1 "SCHMIDT, MICHAEL K" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16516570 "COOPER, GARRETT " Not Applicable 5 PEDIATRICS 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARYRhabdoid tumors are one of the most aggressive and lethal cancers in pediatric oncology with overall 5-yearsurvival rates of ~20-25%. Loss of SMARCB1 is the primary recurrent genetic alteration found in over 90% ofcases. Recent advances have implicated SMARCB1 loss in a number of other cancers broadly referred to asSMARCB1-deficient cancers. SMARCB1 is a critical component of the BAF chromatin remodeling complex acomplex which controls gene transcription by positioning nucleosomes at gene regulatory regions. Targetedlocalization of the BAF complex to enhancers has largely been attributed to SMARCB1 yet no domain has beenidentified on SMARCB1 that is able to recognize and bind specific histone marks. Instead SMARCB1 is only ableto nonspecifically bind to nucleosomes. This raises a key question: how does the BAF complex recognizeregulatory regions such as enhancers and bind. Recent work has shown that deletion of SMARCB1 depletes anadjacent BAF subunit DPF2 which is able to recognize and bind histone marks associated with enhancers. Re-expression of SMARCB1 in a SMARCB1-deficient cell line leads to a robust accumulation of DPF2. The histonereader protein DPF2 has previously been implicated in the recruitment of the BAF complex to regulatoryregions. Through deep mutational scanning of SMARCB1 we have identified four missense mutations inSMARCB1 that seem to mimic an oncogenic loss of function nonsense mutation. These residues are predictedto directly interact with DPF2 which suggests SMARCB1 mediates its tumor suppressor role at least partiallythrough its interaction with DPF2. Moreover we have identified a novel tumor suppressor role of DPF2 in thecontext of constitutive overexpression in two SMARCB1-deficient cancers cell lines. For this reason wehypothesize that depletion of DPF2 is required in SMARCB1-deficient cancers. In Aim 1 I will test the hypothesisthat reduced DPF2 association with the BAF complex is driving this observed loss of function phenotype byassessing the phenotypic structural and regulatory effects of each proposed SMARCB1 mutant. In Aim 2 I willtest the hypothesis that stabilization of DPF2 may be a promising therapeutic strategy to restore transcriptionnormalcy despite the loss of SMARCB1. In this aim I will characterize the phenotypic structural and regulatoryconsequences of DPF2 overexpression in SMARCB1-deficent cell lines and determine if this is occurring througheither a BAF-dependent or BAF-independent mechanism. Together these aims will provide fundamental insightinto the mechanisms through which SMARCB1 exerts its tumor suppressor function as well as expand ourunderstanding of DPF2 in SMARCB1-deficient cancers as a potential therapeutic target. 47694 +No NIH Category available Acute Myelocytic Leukemia;Alternative Splicing;Apoptosis;Biological Assay;Biological Markers;Biological Models;Bone Marrow;Cancer cell line;Cell Death;Cell Line;Cell Survival;Cells;Chronic Myelomonocytic Leukemia;Clinical;Clonal Hematopoietic Stem Cell;Combined Modality Therapy;Congenic Mice;DNA;DNA Damage;DNA Repair;Data;Development;Disease;Dose;Drug Combinations;Dysmyelopoietic Syndromes;Dysplasia;Engraftment;Future;Gene Mutation;Genes;Genetically Engineered Mouse;Genomic Instability;Goals;Hematologic Neoplasms;Heterozygote;Hybrids;Hypersensitivity;In Vitro;Ineffective Hematopoiesis;Lead;Malignant Neoplasms;Mammals;Measures;Mediating;Messenger RNA;Modeling;Molecular;Molecular Target;Mus;Mutant Strains Mice;Mutation;Myeloproliferative disease;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacodynamics;Pharmacological Treatment;Phosphorylation;Poly(ADP-ribose) Polymerase Inhibitor;Prevalence;Process;Production;Proliferating;Protein Isoforms;Protein Kinase;Proteins;RNA;RNA Decay;RNA Helicase;RNA Splicing;Recurrence;Reporting;Resolution;Role;SRSF2 gene;Sampling;Single-Stranded DNA;Spliceosomes;Structure;Terminator Codon;Testing;Therapeutic;Transcript;Translating;acute myeloid leukemia cell;attenuation;cancer cell;cancer therapy;candidate identification;cell type;cytopenia;efficacy study;experimental study;gene repair;genetically modified cells;in vivo;in vivo Model;inhibitor;innovation;mutant;novel;novel strategies;novel therapeutic intervention;peripheral blood;pharmacologic;pre-clinical;premature;resistance mechanism;side effect;targeted treatment;therapeutic evaluation;transcriptome sequencing Targeting Nonsense-Mediated RNA Decay in Splicing Factor Mutant Myeloid Malignancies. PROJECT NARRATIVEExpression of mutant U2AF1(S34F) SF3B1(K700E) or SRSF2(P95H) alters RNA splicing ingenetically-engineered mouse models and primary clinical samples including increasedproduction of nonsense transcripts that rely on nonsensemediated RNA decay (NMD) forclearance. Our preliminary data suggest that spliceosome mutant cells are more sensitive to NMDinhibition than wild-type cells and the differential sensitivity is partially dependent on excessive Rloop formation and DNA damage. Ongoing pre-clinical in vivo efficacy studies will test the potentialfor SMG1i to treat hematologic malignancies that have splicing factor mutations. NCI 10751386 8/16/23 0:00 PA-21-052 1F31CA284751-01 1 F31 CA 284751 1 "DIBELLO, ANTHONY THOMAS" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 14237171 "CABRERA, CLAUDIA " Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 33646 NCI 33646 0 Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorderscharacterized by peripheral blood cytopenias bone marrow dysplasia and ineffective hematopoiesis.Approximately 50% of MDS 60% chronic myelomonocytic leukemia (CMML) 20% of acute myeloid leukemia(AML) harbor heterozygous mutations in spliceosome factor genes such as SF3B1 U2AF1 SRSF2 and ZRSR2.Although many studies have shown that mutations in splicing factor genes lead to distinct patterns of aberrantsplicing no specific alternatively spliced isoform has been demonstrated to directly cause MDS. Howeveraberrations in splicing induced by splicing factor gene mutations create a vulnerability in MDS cells. Our groupand others showed that cells harboring spliceosome gene mutations have increased sensitivity topharmacological perturbation of the spliceosome by splicing modulator drugs. The sensitivity of spliceosomemutant cells to further splicing perturbations raises the possibility that they are vulnerable to accumulation ofmisspliced transcripts. A large portion of the misspliced RNAs caused by spliceosome mutations or splicingmodulator treatment are nonsense mRNAs that harbor premature termination codons (PTCs). These nonsensemRNAs which may cause deleterious effects if translated are normally degraded by a RNA surveillancepathway called nonsense-mediated RNA decay (NMD). The prevalence of nonsense mRNAs in cancer cells withspliceosome mutations leads us to hypothesize that mutant cells will be more sensitive to NMD attenuation dueto the role of NMD in the clearance of nonsense mRNAs that can be detrimental. Preliminary data from our groupindicate that NMD disruption (using a SMG1 inhibitor [SMG1i]) preferentially kills cancer cells expressing differentsplicing factor gene mutations. This cell death is associated with the induction of R-loops and DNA damage.Building on preliminary studies we propose to test the therapeutic potential of NMD inhibition in selective killingof spliceosome mutant cancer cells using in vivo models and define the underlying mechanism for thehypersensitivity of spliceosome mutant cells to NMD attenuation. In Specific Aim 1 we will test the therapeuticpotential of NMD inhibition to selectively kill spliceosome mutant cancer cells using in vivo models. We will engraftprimary mouse AML cells in congenic mice and test whether in vivo treatment with a highly specific inhibitor ofSMG1 (SMG1i) the only known protein kinase that regulates the NMD pathway can selectively kill cancer cellswith spliceosome mutations. We will further establish the therapeutic potential of targeting NMD by combiningSMG1i with ATR or PARP inhibitors DNA damage repair proteins that are activated in splicing factor mutantcells. In Specific Aim 2 we will define the molecular mechanism for the sensitivity of spliceosome mutant cellsto NMD attenuation. We will identify candidate NMD targets whose levels are modulated by SMG1i or mutantsplicing factors potentially nominating downstream functional targets that could be modulated for cancertreatment. Collectively this project will nominate therapies to treat MDS and AML with splicing factor mutations. 33646 +No NIH Category available Actins;Address;Adipocytes;Adipose tissue;Adopted;Adult;Biogenesis;Biological Assay;Biological Markers;Biophysics;Biopsy;Body mass index;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer cell line;Cancer Prognosis;Cell Proliferation;Cell Separation;Cells;Chemoresistance;Clinic;Clinical;Coculture Techniques;Communication;Cues;Cytoskeleton;Data;Data Analyses;Diameter;Exhibits;Experimental Designs;Frequencies;Genes;Goals;Hypertrophy;In Vitro;Incidence;Inguinal lymph node group;Injections;Institution;Intervention;Invaded;Lipids;Malignant Neoplasms;Mammaplasty;Mammary Duct;Mass Spectrum Analysis;Mediating;Mediator;Mentors;Mentorship;Metabolic Diseases;Metabolic dysfunction;Methods;MicroRNAs;Microfluidics;Molecular;Mus;Obese Mice;Obesity;Obesity Epidemic;Organ;Organoids;Patient-Focused Outcomes;Patients;Phenotype;Prognosis;Prognostic Marker;Proliferating;Research;Research Personnel;Risk Factors;Science;Smoking;Sorting;Techniques;Thinness;Tissues;Training;Transcriptional Regulation;Tumor Promotion;United States;Vesicle;Weight;Weight Gain;Woman;Work;behavior in vitro;breast cancer progression;cell behavior;cell motility;cell type;cohort;experimental study;extracellular vesicles;fatty acid oxidation;genetic inhibitor;humane endpoint;imaging study;implantation;improved;in vivo;interest;malignant breast neoplasm;mammary;migration;mortality;nanoparticle;neoplastic cell;obese person;pharmacologic;precursor cell;skills;targeted treatment;transcriptome sequencing;tumor;tumor metabolism;tumor progression;vesicular release Hypertrophic adipocytes as biophysical mediators of breast cancer progression PROJECT NARRATIVEBreast cancer is the most common cancer in the United States and its incidence and mortality increase withobesity. This proposal aims to investigate if hypertrophic expansion of mammary adipocytes upon weight gaincontributes to the poor prognosis of obese breast cancer patients via vesicle-mediated alterations to tumor cellmetabolism. Collectively this proposal will identify molecular mechanisms between adipocytes and tumor cellsthat can be targeted in the clinic and indicate if mammary adipocyte hypertrophy could serve as a prognosticbiomarker for breast cancer patients. NCI 10751284 7/10/23 0:00 PA-21-052 1F31CA278410-01A1 1 F31 CA 278410 1 A1 "DIBELLO, ANTHONY THOMAS" 8/21/23 0:00 8/20/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 15963720 "BEEGHLY, GARRETT F" Not Applicable 19 NONE 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY UNIVERSITY-WIDE 148502820 UNITED STATES N 8/21/23 0:00 8/20/24 0:00 398 "Training, Individual" 2023 46574 NCI 46574 0 PROJECT SUMMARYOver 40% of adult women in the U.S. are obese and obesity will soon overtake smoking as the leading risk factorfor cancer. For breast cancer obese women demonstrate both a higher incidence and higher rate of cancer-related mortality compared to normal weight women. While many studies focus on potential systemicconnections behind this observation the breast is rich in white adipose tissue (WAT) which is highly remodeledin the context of obesity and thus local tissue-resident cues must also be considered. At the cellular level whiteadipocytes are the functional units of WAT and secrete extracellular vesicles (EVs) that promote tumorprogression. Recent studies indicate that adipocyte-derived EVs contain lipids and other metabolites for fattyacid oxidation that modulate tumor cell metabolism to increase migration proliferation and chemoresistance. Inobese individuals adipocytes become hypertrophic with known consequences for metabolic disease. Whetheradipocyte hypertrophy similarly impacts breast cancer risk and prognosis is less clear. Preliminary data in thisproposal indicate that hypertrophic adipocytes promote the proliferation and migration of co-cultured tumor cellsto a greater extent than donor-matched non-hypertrophic control adipocytes. Moreover I found that hypertrophicadipocytes secrete more EVs and exhibit remodeled cortical actin. Given that the actin cytoskeleton mediatesthe biogenesis of EVs by other cell types this proposal aims to investigate if hypertrophy remodeled corticalactin and increased EV secretion are interconnected. Moreover the proposed research also aims to discern ifthese differences impact breast cancer progression by altering tumor cell metabolism. In Specific Aim 1 I willcharacterize the concentration size distribution and cargo of EVs released by hypertrophic vs. controladipocytes via nanoparticle tracking analysis and mass spectrometry. In Specific Aim 2 I will expose breastcancer cells to EVs secreted by hypertrophic vs. control adipocytes to assess how treatment impacts tumor cellbehavior in vitro and in vivo. Moreover I will perform pharmacological and genetic inhibitor studies to determineif altered fatty acid oxidation underpins any observed differences in tumor cell phenotypes. Collectively this workwill help discern if hypertrophic adipocytes constitute a distinct subpopulation of cells conducive to tumorprogression and thus contribute to the poor prognosis of obesity-associated breast cancer. In the clinic identifiedmolecular mechanisms between adipocytes and tumor cells could be targeted therapeutically and the degree ofmammary adipocyte hypertrophy could serve as a prognostic biomarker for patient outcomes. Beyond researchI will develop skills around experimental design data analysis mentorship and science communication throughmy training goals and team of mentors outlined in this proposal. These skills will be essential to achieve my long-term professional goal of becoming an independent investigator at a research-focused institution. 46574 +No NIH Category available Ablation;Acute Myelocytic Leukemia;Adult;Apoptosis;Apoptotic;Architecture;BCL1 Oncogene;Biochemical;Bioinformatics;Blood;CRISPR interference;CRISPR screen;CRISPR/Cas technology;Caspase;Cell Death Induction;Cell Line;Cells;Clinical;Collaborations;Combined Modality Therapy;Complex Analysis;Crista ampullaris;Data;Development Plans;Drug resistance;Electron Microscopy;Ensure;Equipment;Event;Genes;Genetic;Goals;Growth;Hematopoietic Neoplasms;Hematopoietic stem cells;Homeostasis;Human;In Vitro;Induction of Apoptosis;Laboratories;Lead;Malignant Neoplasms;Mediating;Mentors;Microscopy;Mitochondria;Molecular;Morphology;OPA1 gene;Organelles;Pathogenesis;Pathology;Pathway interactions;Patients;Peptide Hydrolases;Pharmaceutical Preparations;Phase;Physiological;Process;Prognosis;Proteins;Proteolysis;Proteolytic Processing;Regulation;Research;Research Personnel;Resistance;Resistance development;Resources;Role;Sampling;Scientist;Shapes;Stress;Structure;Survival Rate;System;Techniques;Testing;Therapeutic;Training;United States Food and Drug Administration;Xenograft procedure;acquired drug resistance;acute myeloid leukemia cell;cancer cell;career development;chaperonin;course development;cytochrome c;drug resistance development;efficacy evaluation;electron tomography;experimental study;genome-wide;in vivo;inhibitor;innovation;leukemia;mimetics;mitochondrial dysfunction;mortality;mouse model;novel;pharmacologic;post-doctoral training;pre-clinical;prevent;programs;protein complex;research and development;response;skills;small molecule;spatiotemporal;success;superresolution imaging;superresolution microscopy;targeted treatment;treatment strategy;tumor Targeting mitochondrial dynamics in drug-resistant acute myeloid leukemia PROJECT NARRATIVE Mitochondria are dynamic organelles that actively change their shape to accommodate cellular requirements. Cancer cells can exploit this adaptation to support their energy demands or resist to drug-induced cell death. This proposal aims to 1) determine the precise molecular mechanisms cancer cells alter their mitochondrial morphology during acquisition of drug-resistance and 2) evaluate the therapeutic potential of combining small molecules targeting mitochondrial structure with cell death-inducing agents in acute myeloid leukemia. NCI 10751235 3/3/23 0:00 PA-19-130 4R00CA252602-03 4 R00 CA 252602 3 "KLAUZINSKA, MALGORZATA" 3/3/23 0:00 2/28/26 0:00 Transition to Independence Study Section (I)[NCI-I] 16063478 "GLYTSOU, CHRISTINA " Not Applicable 10 BIOLOGY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PHARMACY 71073001 UNITED STATES N 3/3/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 249000 NCI 158599 90401 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) is the second most common leukemia in adults and typically has a dismal prognosis and high mortality which is exemplified by a 28% five-year overall survival rate. Venetoclax a selective inhibitor of the anti-apoptotic protein BCL-2 has received FDA approval for the treatment of AML. Despite promising early responses of AML patients to venetoclax drug resistance ensues after prolonged treatment andhighlights the urgency for a deep understanding of the underlying mechanisms. Recently I discovered that mitochondria in AML cells undergo a morphological change upon venetoclax resistance. Using a genome-wide CRISPRi screen in human AML I identified genes involved in mitochondrial structure as synthetic lethal vulnerabilities for venetoclax in AML. Mitochondria of venetoclax-resistant AML cells actively modify their architecture and function to prevent apoptosis. Supporting this OPA1 the master regulator of mitochondrial cristae structure and CLPB a mitochondrial chaperonin were strikingly upregulated in venetoclax-resistant AML cells relative to the sensitive cells. CLPB directly interacts with OPA1 to maintain the physiological mitochondrial morphology. Promisingly genetic CLPB or OPA1 ablation enhances venetoclax-induced apoptosis of AML cells by promoting cristae remodeling and mitochondrial stress. This proposal aims to leverage these observations by 1) delineating the mechanistic details by whichmitochondrial dynamics and homeostasis lead to acquisition of drug resistance in AML using super-resolution microscopy electron tomography and biochemical techniques and 2) assessing the therapeutic potential of perturbing mitochondrial structure to augment venetoclax action in preclinical AML mouse models. This research stands to have significant clinical impact because it can serve as a basis for developing new combinational targeted therapies for patients with AML.In addition this proposal outlines my career development plan for obtaining the requisite training to transition into a successful independent investigator. This includes 1) guidance from my esteemed mentor Dr. IannisAifantis expert in blood malignancies and mouse models; 2) scientific training by an expert advisory panel consisting of Drs. Raoul Tibes Hans-Willem Snoeck Kivanc Birsoy and Evripidis Gavathiotis all in top institutes of NYC; 3) hands-on training using state-of-art equipment including super-resolution microscopy with Dr. Eli Rothenberg; 4) collaboration with experts in microscopy and bioinformatics; and 5) career development courses sponsored by NYU. The laboratory of Dr. Aifantis and NYU Department of Pathology will provide the resources critical to my training and research ensuring my success. This extensive professional growth program will guide me during the mentored phase excelling as an independent academic scientist. Collectively the proposed research and career development plans are expected to generate data with significant impact on circumventing targeted-therapy resistance in AML and setting the basis of my future research as an independent researcher. 249000 +No NIH Category available Affect;Anoikis;Apical;Apoptosis;Automobile Driving;Behavior;Binding;Biochemical;Biological Assay;Blood Circulation;Blood Platelets;Breast;Breast Cancer Cell;Breast Cancer Treatment;Breast Cancer cell line;Breast cancer metastasis;Cell Communication;Cell Survival;Cells;Cessation of life;Chemicals;Circulation;Development;Disease;Distant Metastasis;ERBB2 gene;Epidermal Growth Factor;Epithelial Cells;Face;Feedback;Gene Expression;Genes;Genetic Transcription;Glycoproteins;Goals;Immune;In Vitro;Intervention;Link;Lubricants;Maintenance;Mediating;Mediator;Membrane Glycoproteins;Metastatic breast cancer;Methods;Modeling;Molecular;Morphology;Mucins;Neoplasm Circulating Cells;Neoplasm Metastasis;Outcome;P-Selectin;Patient-Focused Outcomes;Patients;Platelet Activation;Platelet aggregation;Play;Prevention;Primary Neoplasm;Proteins;Publishing;Regulation;Research;Resistance;Role;Signal Transduction;Surface;Survival Rate;Tail;Techniques;Testing;Therapeutic Intervention;Transcript;Transforming Growth Factor beta;Tumor Promotion;Up-Regulation;Veins;cell behavior;epithelial to mesenchymal transition;glycosylation;improved;in vivo;in vivo Model;malignant breast neoplasm;mouse model;neoplastic cell;new therapeutic target;novel;receptor;recruit;standard of care;success;tumor;tumor xenograft The TGF-Beta/MUC4 Signaling Axis in Circulating Tumor Cells of Metastatic Breast Cancer PROJECT NARRATIVEThe proposed studies aim to determine the role of the Mucin-4 cell-surface glycoprotein in platelet-tumor cellinteractions in breast cancer metastasis. Successful completion of these studies will reveal a novel method ofplatelet-tumor cell crosstalk which enhances survival of metastasizing tumor cells. Characterization of thisrelationship will advance understanding of metastasis and reveal a novel target for metastatic intervention. NCI 10751169 5/26/23 0:00 PA-21-051 1F31CA278419-01A1 1 F31 CA 278419 1 A1 "ODEH, HANA M" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 78514660 "FREE, SAVANNAH R" Not Applicable 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 40288 NCI 40288 0 PROJECT SUMMARYMetastasis is responsible for the majority of breast cancer deaths and standard-of-care treatments fail toeffectively target metastasizing cells. Circulating tumor cells (CTCs) in the bloodstream rely on the physicalprotection and chemical signals of platelets to survive and seed metastatic lesions. One such chemical signal istransforming growth factor beta (TGF-) which after secretion by platelets has been shown to modulate CTCgene expression and behavior. TGF- has also been shown to upregulate expression of the cell-surfaceglycoprotein Mucin-4 (MUC4) in various cellular contexts. MUC4 has been implicated in tumor development andmaintenance and was recently observed to contribute to platelet-CTC interactions. This raises the question ofwhether platelet-secreted TGF- may be upregulating CTC-MUC4 enhancing platelet-CTC interaction andgenerating a positive feedback loop. The hypothesis driving the proposed studies is that platelet-TGF-upregulates CTC-MUC4 reinforcing CTC-platelet binding and enhancing metastatic cell survival. Specific Aim 1will determine the effects of platelet-derived TGF- on tumor cell MUC4 expression using cellular molecularand biochemical techniques and assess MUC4-dependent cellular aggressiveness in vitro. Specific Aim 2 willcharacterize the role of MUC4 in platelet-tumor cell interactions using in vitro binding assays. Specific Aim 3 willassess the effects of platelet-TGF- and CTC-MUC4 crosstalk in vivo using tail vein and orthotopic xenografttumor mouse models of metastasis. Successful completion of this research will reveal a novel form of platelet-CTC crosstalk exposing an important means by which metastasizing cells survive and illuminating a potentialnew therapeutic target for breast cancer metastatic prevention. 40288 +No NIH Category available 4T1;Bioinformatics;Biological Assay;Biology;Bone Marrow;Bone Marrow Transplantation;Bone neoplasms;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Breeding;Bypass;Cancer Patient;Cell Separation;Cells;Circulation;Colony-Forming Units Assay;Color;Communication;Complex;Development;Disease Progression;EO771;Environment;Female;Flow Cytometry;Fostering;Frequencies;Generations;Genetic;Goals;Grant;Hematology;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Human;Immune;Immune Evasion;Immune response;Immune system;Immunoglobulin G;Immunologic Surveillance;Immunology;Immunotherapy;Injections;Knowledge;Laboratories;Lymphopoiesis;Modeling;Mouse Mammary Tumor Virus;Mus;Myelogenous;Myelopoiesis;Natural Killer Cells;Osteoblasts;Output;Play;Population;Primary Neoplasm;Prognosis;Proliferating;Property;Proteins;Regulation;Research;Role;Sampling;Site;Source;T-Lymphocyte;Testing;Time;Training;Tumor Promotion;Tumor stage;anti-tumor immune response;beta catenin;bone;bone cell;breast cancer progression;cancer type;career;effective therapy;exhaustion;experience;experimental study;granulocyte;hematopoietic stem cell self-renewal;immunoregulation;improved;inhibitor;interest;irradiation;malignant breast neoplasm;monocyte;mouse model;neoplastic cell;neutralizing antibody;novel;overexpression;polyoma middle tumor antigen;reconstitution;single-cell RNA sequencing;skills;training opportunity;transcriptome;transplant model;tumor;tumor growth;tumor immunology;tumor progression Regulation of hematopoiesis during tumor progression Project NarrativeAltered hematopoiesis and myeloid biased skewing promotes the expansion of immune suppressive myeloidpopulations a phenomenon that is observed in cancer patients regardless of the tumor type and/or disseminationto bone. Currently the impact of a primary tumor on bone marrow hematopoietic stem and progenitor cells(HSPCs) as well as the factors involved in changing their frequency and/or functionality remain unclear. Theaims proposed here will broaden our understanding of the effects of tumor progression on hematopoiesis andimportantly the role of the bone in generating the immune suppressive environment. NCI 10751146 7/26/23 0:00 PA-21-051 1F31CA284858-01 1 F31 CA 284858 1 "PURI, ANU" 8/1/23 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(22)L] 77843782 "EUL, EMILY M" Not Applicable 1 ORTHOPEDICS 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 Project Summary/AbstractThe immune system plays an important role during tumor progression having the ability to recognize and killtumor cells (T cells and NK cells) [1]. Unfortunately these immune responses can be bypassed through a varietyof mechanisms including creating an immune suppressive environment that alters the ability of T cells and NKcells to inhibit tumor growth [2]. Major players in suppressing anti-tumor immune responses are immaturemyeloid populations originating in the bone marrow. Several lines of evidence indicate a correlation betweenincreased numbers of immature myeloid populations in bone marrow circulation and at tumor site with diseaseprogression and reduced survival [3 4]. Altered bone marrow hematopoiesis with skewing towardsmyelopoiesis is indeed observed in cancer patients regardless of the tumor type and/or dissemination to bone.However the impact of a primary tumor on bone marrow hematopoietic stem cells (HSC) and the factors involvedin changing their frequency and/or functionality remain to be elucidated.Dkk1 a Wnt/-catenin inhibitor exerts immune suppressive effects in various cancer types by either supportingmyeloid suppressor populations or inhibiting anti-tumor immune responses [5-7]. However the mechanisms bywhich Dkk1 induces the changes in immune populations during tumor progression are not fully understood andevidence of direct effects of Dkk1 on mature immune cells are sparse. Interestingly Dkk1 is required forhematopoietic stem cell (HSC) regeneration [8] and over expression can promote long-term HSC exhaustion intransplantation models [9]. Currently the role of Dkk1 on hematopoietic stem and progenitor cells (HSPCs)during cancer progression has not been investigated. My preliminary studies show Dkk1-dependent increasesin HSPC frequencies following orthotopic injection of EO771 breast cancer cells demonstrating systemic effectsof a primary tumor on bone marrow hematopoiesis.Based on these observations this training opportunity will allow me to test the hypothesis that bone derived Dkk1alters HSPCs frequency and function to increase myelopoiesis and transform the immune landscape duringtumor progression. Thus I propose the following aims: Aim 1: To uncover alterations to HSPCs during breastcancer progression; and Aim 2: To investigate the role of bone derived Dkk1 on HSPCs.These aims will reveal the impact of tumor progression on hematopoiesis and the role of the bone in orchestratinga tumor-conducive immune suppressive environment. The training received through this proposal will allow meto pursue my interests in bone biology and hematology strengthen my research skills and allow me to developthe skill set necessary for an Academic career at the intersection of bone biology hematology and immunology. 47694 +No NIH Category available Adult;Affect;Brain;Brain Neoplasms;Breathing;Caring;Cementation;Childhood;Clinical Investigator;Clinical Trials;Collaborations;Communities;Computational Biology;Development;Diagnostic;Disabled Persons;Discipline;Disease;Environment;Epigenetic Process;Event;Gene Fusion;Generations;Genetic;Genomics;Glioblastoma;Glioma;Goals;Human;Image;Immunotherapy;International;Knowledge;Laboratories;Malignant Neoplasms;Mediating;Mentors;Metabolism;Minority;Modality;Molecular;Neurons;Newly Diagnosed;Oncolytic viruses;Participant;Pathway interactions;Patient Care;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Regimen;Research;Research Personnel;Science;Scientist;Therapeutic;Translating;Tumor Subtype;Woman;chimeric antigen receptor T cells;clinical phenotype;genome-wide;improved;innovation;mathematical model;medulloblastoma;meetings;molecular subtypes;multidisciplinary;new technology;next generation;novel;novel strategies;novel therapeutics;prognostic;single cell sequencing;stem cells;symposium;tool;tumor growth;tumor initiation;tumor microenvironment;tumor-immune system interactions 2023 Basic Mechanisms to Clinical Trials in Brain Tumors Gordon Research Conference Project NarrativeThe goal of the inaugural Basic Mechanisms to Clinical Trials in Brain Tumors Gordon Research Conferencemultidisciplinary international meeting is to discuss and debate cutting-edge concepts and breakthroughs in thebrain tumor field to help develop innovative mechanism-based diagnostic prognostic and therapeuticapproaches that will significantly advance the care of brain tumor patients in an all-inclusive environment. Wewill also strive to provide inspiration and opportunities to the next generation of scientists and emphasizediversity in science. NCI 10751111 6/22/23 0:00 PA-21-151 1R13CA284781-01 1 R13 CA 284781 1 "SHARMAN, ANU" 6/22/23 0:00 5/31/24 0:00 ZCA1-PCRB-9(M1) 1883032 "MAJUMDER, SADHAN " Not Applicable 2 Unavailable 75712877 XL5ANMKWN557 75712877 XL5ANMKWN557 US 41.480003 -71.569648 2988701 GORDON RESEARCH CONFERENCES East Greenwich RI Domestic For-Profits 28183465 UNITED STATES N 6/22/23 0:00 5/31/24 0:00 398 Other Research-Related 2023 16000 NCI 16000 0 Project SummaryBrain tumors are among the most lethal and devastating human cancers. Despite decades of advances in thefield patient outcomes for brain tumors remain poor. However there has been a recent surge ofmultidisciplinary discoveries in this field that are likely to impact patient care in a momentous way. The goal ofthe inaugural Basic Mechanisms to Clinical Trials in Brain Tumors Gordon Research Conference (GRC)multidisciplinary international meeting is to discuss and debate cutting-edge concepts and breakthroughs in thebrain tumor field to help develop innovative mechanism-based diagnostic prognostic and therapeuticapproaches that will significantly advance the care of brain tumor patients. The meeting will cover bothpediatric and adult brain tumors and will focus on (1) deciphering the mechanisms that control normal braindevelopment and how aberrations of such mechanisms produce disease (2) studying how alterations inmolecular pathways (including genetic and epigenetic events) result in clinical phenotypes (3) understandinghow the brain and immune microenvironment affect tumor initiation and growth and (4) investigating how suchknowledge can be translated into improved patient care. Emphasis would be placed on new concepts in braintumor research new technological and computational biology approaches and new therapeutic modalities andtheir challenges. Laboratory and clinical investigators would develop novel strategies to translate new findingsinto novel clinical trials. Further an important feature of the meeting will be bringing together eminent leadersand women minorities persons with disabilities early stage and early established investigators in the field inorder to build relationships and provide mentoring and networking opportunities to cement the commitment ofthe new generation of scientists and clinicians to the field and provide them with the tools to make a differencein the lives of brain tumor patients and create opportunities to explore potential collaborations. The meetingwill be extensively evaluated by participants and their ideas and opinions will be discussed in an open meetingand will be taken into consideration in planning for subsequent years. 16000 +No NIH Category available AIDS related cancer;Acquired Immunodeficiency Syndrome;Affect;Africa South of the Sahara;Antiviral Response;Apoptosis;Apoptotic;Autoimmune Diseases;Biology;CASP8 gene;Caspase;Cell Death;Cells;Cessation of life;Communicable Diseases;Complex;Cytoplasm;DNA;Data;Development;Disease;Enzymes;Genetic Transcription;Herpesviridae;Herpesviridae Infections;Human Herpesvirus 8;Immune Evasion;Immune response;Infection;Innate Immune Response;Interferon Type I;Interferons;Kaposi Sarcoma;Lytic Phase;Maintenance;Mediating;Mediator;Molecular;Nature;Oncogenic Viruses;Pathway interactions;Peptide Hydrolases;Production;Proteins;Receptor Signaling;Regulation;Regulatory Pathway;Reporting;Role;Signal Transduction;Stimulus;TLR3 gene;Testing;Toll-Like Receptor Pathway;Toll-like receptors;Tumor Immunity;Up-Regulation;Viral;Virus;Virus Replication;Work;cancer type;druggable target;experience;inhibitor;insight;mutant;new therapeutic target;overexpression;pathogen;prevent;reactivation from latency;receptor;response;targeted treatment;tumor;virus host interaction Determining how Kaposis sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses PROJECT NARRATIVEDuring replication the AIDS-associated tumor virus Kaposis sarcoma-associated herpesvirus (KSHV)strongly blocks cellular responses to replicate efficiently. Since replication is needed for developmentand maintenance of Kaposis sarcoma and other KSHV-induced tumors KSHV immune evasion couldbe exploited to treat these diseases. In this project we will investigate the role of a cellular enzymecaspase-8 in KSHV inhibition of cellular response to understand immune evasion by this virus andpotentially identify new druggable targets against KSHV infection. NCI 10751037 12/14/23 0:00 PA-20-185 5R01CA268976-03 5 R01 CA 268976 3 "READ-CONNOLE, ELIZABETH LEE" 12/1/21 0:00 11/30/26 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 10791399 "GAGLIA, MARTA MARIA" Not Applicable 2 MICROBIOLOGY/IMMUN/VIROLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI GRADUATE SCHOOLS 537151218 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 352662 NCI 231075 121587 Project summary. During lytic infection the AIDS-associated tumor virus Kaposis sarcoma-associatedherpesvirus (KSHV) blocks cells from activating the anti-viral type I interferon (IFN) responses. This block ofthe innate immune response facilitates efficient viral replication which in turn contributes to development ofKaposis sarcoma. Thus elucidating the mechanisms by which KSHV evades the host innate immuneresponse may provide insights on how to target this and other KSHV-induced tumors. However because ofthe complex and redundant nature of the type I IFN induction pathway how KSHV blocks this early antiviralresponse is still incompletely understood. In a previous study we found that the host protease caspase-8 is amajor mediator of type I IFN inhibition by KSHV. KSHV reactivation from latency only triggers minimal type IIFN induction but there is a much stronger transcriptional induction and secretion of type I IFNs whencaspase-8 is also inhibited. This stronger IFN induction in turn reduces KSHV reactivation. These resultsindicate that caspase-8 activity is necessary to inhibit IFN induction and thus promotes KSHV replication.This finding was surprising because caspase-8 activation is generally considered antiviral as it inducesapoptotic cell death. However we do not detect wide-spread cell death during reactivation from latencydespite caspase-8 activation suggesting that caspase-8 is hijacked and repurposed by KSHV to inhibit type IIFN responses. At present the molecular mechanisms that lead to caspase-8 activity and the pathways thatare targeted by caspase-8 to control type I IFN during KSHV infection remain unclear. We have newpreliminary data suggesting that caspase-8 is activated by a pathogen sensing pathway the Toll-like receptor(TLR) pathway as a cellular response to infection. Caspase-8 then proceeds to inhibit a different pathogensensing pathway cGAS-mediated DNA sensing. Therefore we hypothesize that KSHV is taking advantageof a TLR-mediated cellular response to infection that activates caspase-8. KSHV is then able to redirect thisactivity to inhibit DNA sensing instead of activating apoptosis. We will test this hypothesis and determine howcaspase-8 is activated by TLR signaling in KSHV-infected cells without triggering cell death (Aim 1) andwhich host protein(s) are cleaved by caspase-8 to block cGAS-induced type I IFN responses (Aim 2).Moreover we will also investigate whether and how caspase activity is connected to other previouslydescribed mechanisms of immune evasion by KSHV (Aim 3). As caspase-8 is a druggable targetunderstanding how caspase-8 is used by KSHV to regulate type I IFNs and promote its replication will revealwhether and how this enzyme could be exploited for KSHV therapy. This is important as there are no targettherapies for this virus and Kaposis sarcoma remains one of the leading types of cancers in sub-SaharanAfrica and the second most common AIDS-associated malignancy in the US. This project will also uncoverfundamental aspects of caspase signaling that may play a role in other diseases connected to IFN. 352662 +No NIH Category available 3-Dimensional;Area;Biopsy;Breast;Breast Cancer Detection;Breast Cancer Risk Factor;Breast Magnetic Resonance Imaging;Cancer Detection;Clinical;Consult;Data Set;Development;Digital Breast Tomosynthesis;Digital Mammography;Financial cost;Future;Goals;Image;Imaging Techniques;Individual;Lateral;Laws;Lead;Left;Letters;Magnetic Resonance Imaging;Malignant Neoplasms;Mammary Gland Parenchyma;Mammographic screening;Mammography;Methods;Modality;Modeling;Notification;Physicians;Process;ROC Curve;Radon;Recommendation;Research;Research Personnel;Risk;Scanning;Sensitivity and Specificity;Signal Transduction;Slice;Specificity;Target Populations;Techniques;Testing;Thick;Three-Dimensional Imaging;Tissues;Training;Translating;Validation;Woman;artificial intelligence method;base;biomarker validation;breast density;breast imaging;convolutional neural network;cost;digital;high risk;imaging biomarker;imaging facilities;malignant breast neoplasm;novel;screening;supplemental screening;tomosynthesis;ultrasound Detecting Mammographically-Occult Cancer in Women with Dense Breasts Using Digital Breast Tomosynthesis Over ten million women each year receive a notification letter informing them that they have dense breasttissue and that they should consider having supplemental screening with ultrasound or MRI. Unfortunatelythere is insufficient information available to help women determine whether the benefits for them as anindividual outweigh the known harms of getting supplemental screening. Our research goal is to develop atechnique that can detect breast cancers missed on screening digital breast tomosynthesis images in womenwith dense breast tissue and thus giving women additional information to help them make better informeddecisions regarding supplemental screening. NCI 10751019 12/1/23 0:00 PA-20-185 5R01CA269540-02 5 R01 CA 269540 2 "ABRAMS, NATALIE" 12/8/22 0:00 11/30/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 14162892 "LEE, JUHUN " Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 313455 NCI 197142 116313 Most women in the USA who have dense breasts at screening mammography receive a letter notifying themthat mammography is less effective for them and having dense breasts increases the risk of breast cancer.The letter advises women to talk with their physician whether they should have additional screening withultrasound or magnetic resonance imaging (MRI). The possible benefit of additional screening is detecting amammographically occult (MO) cancer. However the likelihood that a woman has a missed cancer is notknown. Thus women are left with a difficult decision balancing the uncertain potential benefit of additionalscreening against the known costs. These known costs are financial (as some states do not cover thesupplemental screen) and the risk of an unnecessary biopsy as the specificity of ultrasound and MRI are lowerthan mammography. We have developed a novel technique using a Radon Cumulative Distribution Transform(RCDT) to detect MO cancers. The RCDT can highlight subtle suspicious signals by detecting asymmetriesbetween the left and right mammograms. Our technique achieved an area under the ROC curve of 0.81 usingscreening mammograms. Digital breast tomosynthesis (DBT) a pseudo-3D imaging technique is replacingmammography in the USA because of its higher sensitivity and specificity. However MO cancers still exist inDBT. The goal of our research is to develop imaging biomarkers for MO cancers on screening DBT of womenwith dense breasts. This would allow women to know the likelihood that they have an MO cancer and therebyallow them to make a more informed choice regarding supplemental screening. The key difference betweenDBT and standard 2D mammography is the available information in the z-direction. Such additional informationprovides advantages for cancer detection but it also adds technical complexity when applying RCDT on DBTimages. There are three ways to process DBT exams for RCDT: 1) applying RCDT on 2D DBT slices 2)applying RCDT on synthetic mammograms from DBT and 3) applying the 3D RCDT on DBT volumes. Todevelop imaging biomarkers for MO cancer in screening DBT we need to investigate the optimal method toprocess DBT for RCDT. We will develop imaging biomarkers for the three methods using a developmentaldataset of 900 MO cancer cases (clinical cases read as normal but the woman has breast cancer detected onher next screening DBT) and 1800 cases (clinical cases read as normal and the woman does not have breastcancer detected on her next two screening DBTs). We will utilize a 2D convolutional neural network (CNN) anda 3D CNN as robust classifiers to analyze the RCDT processed DBT for MO cancer detection. Using a 5-foldcross-validation we will train CNNs for each method and find the optimal method to process DBT for MOcancer detection. Finally we will use an independent dataset of 100 cases to validate the classifier. If we aresuccessful then up to 15 million women each year who have dense breasts will have needed information uponwhich to base their decision for getting supplemental screening. 313455 +No NIH Category available ATAC-seq;Address;Biological;Breast Cancer Cell;Breast Cancer Model;Cells;Characteristics;Clinical;Clonality;Computer Analysis;Data;Development;Event;Genes;Genetic Counseling;Genetic Models;Genetic Models for Cancer;Genetic Transcription;Germ-Line Mutation;Human;Image;Immune;Incidence;Malignant Neoplasms;Modeling;Molecular;Mutation;Nature;Oncogene Activation;Oncogenes;Oncogenic;Patient-derived xenograft models of breast cancer;Patients;Pattern;Phenotype;Predisposition;Process;Prognosis;Proteins;Proteomics;Renal Cell Carcinoma;Renal carcinoma;Resolution;Role;Sampling;Signal Transduction;Somatic Mutation;Susceptibility Gene;Testing;Tissue-Specific Gene Expression;Tissues;Transcend;Tumor Suppressor Proteins;Variant;brca gene;cancer cell;cancer predisposition;cancer type;cell stroma;differential expression;experience;human imaging;improved;mouse genetics;mouse model;multiple omics;multiplexed imaging;neoplastic cell;patient derived xenograft model;personalized cancer therapy;pressure;response;single cell analysis;single nucleus RNA-sequencing;transcriptomics;translational impact;treatment choice;treatment response;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis Impact of cancer predisposition on oncogenic process microenvironment and treatment The promise of personalized cancer therapy will only be realized when the full impact of each patient's variantscan be fully understood. Our proposal aims at taking advantage of the recent rapid accumulation of omics dataand leveraging our expertise in PDX and genetic models along with experience in single cell omics toaddress a number of unanswered questions related to cancer predisposition. Results from this project willimpact both the fundamental biological questions regarding cancer predisposition and practical clinicalquestions regarding genetic counseling and treatment choices with considerations to the origins of variants/mutations in the cancer driver genes. NCI 10751015 12/25/23 0:00 PA-20-185 5R01CA260112-03 5 R01 CA 260112 3 "LI, JERRY" 1/1/22 0:00 12/31/26 0:00 Cancer Genetics Study Section[CG] 9766169 "DING, LI " "CHEN, FENG " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 427827 NCI 275130 152697 Our previous study of more than 10 thousand tumors across 33 cancer types identified over 800 germlinepredisposition variants in both tumor suppressors and oncogenes. Although the impact of some of thesevariants on cancer onset incidence rate and clonality have been documented the effects of these variants(especially when compared to somatic mutations) on molecular characteristics of cancer cells contributions ofnon-cancer cells having germline variants and treatment responses are far less studied. Our recent singlecell(sc) /single nucleus(sn) RNA-seq analyses of cancer samples provided comprehensive expression profilesat a single cell resolution and revealed the expression of key cancer predisposition genes such as BRCA 112VHL BAP1 and c-MET in many non-cancer stromal and immune cells in the tumor microenvironment (TME).Our pilot analyses also revealed significant differential gene expression in cancer and non-cancer cells basedon the nature of the driver event being germline or somatic. We hypothesize that tumors with certain germlinepredisposition variants in tumor suppressors and oncogenes may show differences in tumor progression andtreatment responses from those tumors with somatic mutations in the same genes due to differentialinfluence on mutational transcriptomic and proteomic profiles of the cancer cells and potentially distinctivecontributions from non-cancer cells having those germline changes. To take advantage of the considerableprogress over the last few years namely newly accumulated cancer sequencing data advances in single cellomics patient-derived xenografts (PDX) and tumor genetic models we propose to test these hypotheses byperforming the following: compare germline predisposition variants and somatic mutations to dissect theirdifferential biological impacts and interactions using computational analysis (Aim 1); perform singlenucleus RNA-seq/ATAC-seq spatial transcriptomics and multiplex imaging analysis of human cancersamples to reveal the differential roles of germline predisposition variants and somatic mutations in tumorcells and the TME (Aim 2); use PDX and genetic cancer models to investigate potential functionaldifferences between germline predisposition variants and somatic mutations in tumor cells TME andtreatment responses (Aim 3). Results from this study will advance our understanding of the uniquecontributions of germline variants to cancer cells and TME alike improve genetic counseling and prognosisand provide guidance for differential treatment of tumors carrying germline variants vs somatic mutations in keycancer driver genes. 427827 +No NIH Category available Acute Myelocytic Leukemia;Basic Cancer Research;Biological Assay;Biological Markers;Breast;Cancer Patient;Cancer Prognosis;Clinical;Collection;Communities;Computer software;Data;Data Analyses;Data Set;Development;Disease;Drug Targeting;Effectiveness;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Estrogen receptor positive;Event;Frequencies;Gene Deletion;Gene Expression;Gene Expression Alteration;Genes;Genomics;Glioblastoma;Goals;Immunotherapy;Joints;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Metadata;Methods;Modeling;Mutate;Mutation;Names;Non-Small-Cell Lung Carcinoma;Oncogenic;Output;Pathway interactions;Patient Selection;Patient-Focused Outcomes;Patients;Pilot Projects;Probability;Recurrence;Research;Resources;Risk;Sampling;Somatic Mutation;Source Code;TP53 gene;The Cancer Genome Atlas;Therapeutic;Transfusion;Translating;Treatment Efficacy;Work;actionable mutation;cancer genomics;cancer type;clinical application;clinical phenotype;clinical predictive model;cohort;computer framework;design;driver mutation;genetic signature;genomic aberrations;genomic biomarker;immune cell infiltrate;improved;innovation;interest;malignant breast neoplasm;melanoma;mutational status;oncotype;patient biomarkers;patient prognosis;patient stratification;personalized cancer therapy;personalized medicine;precision oncology;predict clinical outcome;predictive modeling;prognostic;prototype;response;targeted treatment;tool;transcriptome sequencing;transcriptomics;translational cancer research;tumor;tumor progression An innovative integrated computational framework using gene signatures for patient stratification PROJECT NARRATIVEIn this project we will develop a new statistical framework to integrate genomic and transcriptomic data todefine gene signatures that recapitulate the downstream oncogenic pathways underlying driver genomicaberrations in cancer. This framework will be utilized to perform secondary data analysis using a vastamount of existing cancer data generated from previous studies. Accomplishment of this project will lead toa comprehensive list of cancer-specific gene signatures and prediction models that can be used to stratifypatients for directing personalized treatment in multiple cancer types especially early-stage lung cancer. NCI 10750994 11/29/23 0:00 PAR-20-276 5R01CA269764-02 5 R01 CA 269764 2 "OSSANDON, MIGUEL" 12/8/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 10225324 "CHENG, CHAO " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 405626 NCI 253516 152110 Project Summary/AbstractCancer is a very heterogeneous disease with each patient being driven by a specific set of genomicaberrations. As such personalized treatment has been intensively investigated as a promising strategyfor further improving patient prognosis. To aid personalized treatment both genomic and expression-based biomarkers have been investigated. Somatic mutations and amplification/deletions of genesespecially driver genes have been used to predict cancer prognosis and to preselect patients fortargeted treatment. Despite some successful examples the overall effectiveness of these genomicbiomarkers remains unclear. Similarly many gene expression-based biomarkers have been proposedbut only a few of them are translated into clinical applications. In this project we propose a new strategy:develop an innovative statistical framework that integrates genomic and transcriptomic data to definegene signatures by modeling the quantitative relationships between genomic aberrations and geneexpression alterations. These signatures recapitulate the downstream oncogenic pathways underlyingdriver genomic events and importantly can capture pathway de-regulation caused by othermechanisms. We will use this framework to leverage a vast amount of existing cancer data created fromprevious studies. Specifically we will utilize the TCGA ICGC and TARGET data to define acomprehensive list of gen signatures to characterize all driver genomic aberrations in 6 cancer typesincluding lung breast and pancreatic cancer glioblastoma melanoma and acute myeloid leukemia.These gene signatures will then be combined to build integrative models to predict clinical outcomesincluding patient prognosis and sensitivity to therapeutic treatment. We will further incorporate immuneinfiltration scores and clinical factors to maximize the prediction power of these models. Following thatwe will utilize a collection of 85 cancer datasets with matched gene expression profiles and survivalinformation to develop prognostic prediction models. Outputs from these models can be used to stratifypatients for advising personalized treatment. In line with our long-term research interest we will integratein-house and existing lung cancer data to develop an optimized model for predicting post-surgicalrecurrence risk of patients with early-stage non-small cell lung cancer. The resulting software sourcecode gene signatures prediction models and other resources from this project will be released in atimely manner. These resources will benefit a broad scientific community in the filed of basic andtranslational cancer research. 405626 +No NIH Category available 20 year old;Adolescent and Young Adult;Alveolar;Alveolar Rhabdomyosarcoma;Animals;Automobile Driving;Avil;Biological Assay;Biological Availability;Biological Markers;Breeding;Cell Death;Cell Line;Cell Proliferation;Cells;Childhood;Collection;Combined Modality Therapy;Cytoskeleton;Data;Development;Disease;Drug Kinetics;F-Actin;FOXM1 gene;Fibroblasts;Gene Fusion;Gene Knock-Out Model;Gene Silencing;Genes;Genetically Engineered Mouse;Goals;Histology;Housekeeping Gene;Housing;In Vitro;Injections;Intravenous;Investigation;Knockout Mice;Knowledge;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Mesenchymal Stem Cells;Metabolism;Modeling;Molecular;Mus;Muscle;Muscle Development;Oncogenes;Oncogenic;Oral;Patient-Focused Outcomes;Patients;Permeability;Pharmaceutical Preparations;Phenocopy;Planet Mars;Predisposition;Prognosis;Property;Proteins;RNA;RNA Interference;Rhabdomyosarcoma;Role;Safety;Series;Solubility;Testing;Tetanus Helper Peptide;Tissues;Transgenic Mice;Transgenic Organisms;Xenograft Model;Xenograft procedure;absorption;cell motility;chemotherapy;efficacy evaluation;efficacy testing;follow-up;in vitro testing;in vivo;inhibitor;mouse model;mutant;nanomolar;new therapeutic target;novel;novel strategies;novel therapeutic intervention;overexpression;patient derived xenograft model;pharmacodynamic biomarker;sarcoma;screening;small hairpin RNA;small molecule;small molecule inhibitor;soft tissue;targeted treatment;therapeutic biomarker;therapeutic target;therapeutically effective;transcriptome;tumorigenesis;tumorigenic;virtual Targeting AVIL a novel oncogene in rhabdomyosarcoma PROJECT NARRATIVEDespite collaborative national trials of multimodal therapy and chemotherapy intensification the outcome forpatients with advanced stage rhabdomyosarcoma (RMS) has not improved in two decades. We have identifieda cancer-driving factor to which RMS cells are addicted. In this application we propose the systematicinvestigation of targeting this factor as a novel approach against RMS. NCI 10750987 12/15/23 0:00 PA-20-185 5R01CA269594-02 5 R01 CA 269594 2 "FORRY, SUZANNE L" 1/1/23 0:00 12/31/27 0:00 Special Emphasis Panel[ZRG1-OTC1-A(80)S] 9223112 "LI, HUI " Not Applicable 5 PATHOLOGY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 453284 NCI 283488 169796 Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue cancer. Despite treatment intensificationthe outcome for patients with advanced stage RMS has remained dismal. As of now no targeted therapy isavailable. Better understanding and treatment are clearly needed. In our preliminary study we identified a noveloncogene AVIL in RMS. We found that 1) AVIL forms a fusion with a house-keeping gene MARS in some RMS;2) AVIL is overexpressed in the majority of remaining RMS we tested yet hardly detectable in mesenchymalstem cells or normal muscle tissues; 3) RMS cells are addicted to AVIL dysregulation in that silencing MARS-AVIL (in RMS cells that harbor the fusion) or silencing AVIL (in AVIL overexpressed RMS) nearly eradicated thecells and dramatically inhibited in vivo xenografts but had no effect on control cells; 4) converselyoverexpressing AVIL promoted cell proliferation and migration enabled fibroblasts to form foci and transformedmesenchymal stem cells; 5) sarcoma patients with increased AVIL expression have worse prognosis; and 6)RMS cells are sensitive to our small molecules inhibiting AVIL. Based on these observations our long-termhypothesis is that AVIL is an Achilles heel of RMS and targeting it may be an effective approach for treating thedisease. In this application we propose the systematic investigation of AVIL as a novel target against RMS. Aim1: Determine the efficacy of targeting AVIL in vitro. We will investigate its role in an expanded list of cell linesand short-term explants of RMS PDX cultures. We will test the efficacy of tet-inducible shRNAs targeting AVILand small molecule compounds we identified through small molecule screen. Since last submission we alsogenerated over 70 novel compounds derivative of the initial hit compounds. We will test their efficacy in vitro. Inaddition we will determine whether AVIL expression serves as a biomarker for sensitivity to AVIL inhibition. Aim2: Determine the efficacy of targeting AVIL in animal RMS models. We will use shRNA and small-moleculeinhibitors in xenograft models to test both the efficacy and safety of targeting AVIL in vivo. In addition we havegenerated both Avil transgenic and knockout models. We will cross Avil transgenic with various Cre strains totest whether Avil overexpression is sufficient for RMS tumorigenesis. We will also use Avil knockout mousemodel by crossing them with RMS mouse models to test whether Avil expression is necessary for RMStumorigenesis in mouse. Aim 3: Investigate the downstream targets and mechanisms of AVIL inhibition andidentify potential pharmacodynamic biomarkers. We will investigate molecular mechanism under which AVILregulates FOXM1 stability and determine the domain and exact activity on F-actin that are responsible for itsoncogenic activity. Aim 4: Assess AVIL-targeting lead compounds for optimal ADME (absorption distributionmetabolism elimination) bioavailability and pharmacokinetic properties. The proposed study will have asignificant impact on the understanding and treatment of RMS. The findings will pave ways to target AVIL as anovel oncogene and lead to the development of novel therapeutic approaches for the desperate disease. 453284 +No NIH Category available Address;Allografting;Alzheimer's Disease;Automobile Driving;Bar Codes;Breast Cancer Cell;CRISPR interference;CRISPR screen;Candidate Disease Gene;Cell Line;Cell model;Cells;Chromaffin Cells;Citric Acid Cycle;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;Data Analyses;Defect;Diabetes Mellitus;Dioxygenases;Disease;Electron Transport;Enzymes;Estrogen Receptor alpha;Estrogen Receptor beta;Family;Gastrointestinal Stromal Tumors;Gene Expression;Gene Targeting;Genes;Genomic DNA;Growth;Guide RNA;Heart Diseases;Hereditary Paraganglioma;Histones;Hypoxia;Inherited;Lethal Genes;Link;Malignant Neoplasms;Measures;Metabolic;Methods;Mitochondria;Modeling;Molecular;Monitor;Mus;Mutation;Paraganglioma;Pathologic;Pathway interactions;Patients;Pheochromocytoma;Positioning Attribute;Pre-Clinical Model;RNA library;Recipe;Renal carcinoma;Resistance;Running;Signal Transduction;Succinate Dehydrogenase;Succinates;Synthetic Genes;Testing;Therapeutic;Time;Tissues;Transcription Repressor;Tumor Suppressor Genes;Validation;Work;candidate identification;cell growth;cell type;clinical application;deep sequencing;demethylation;experimental study;gene repression;genome-wide;hormone therapy;insight;knock-down;molecular pathology;neoplastic cell;neuroendocrine cancer;novel;novel therapeutics;promoter;rare cancer;screening;targeted treatment;tumor;tumorigenesis Genome-wide synthetic lethal screening for vulnerabilities in a cell model of succinate dehydrogenase-loss paraganglioma NarrativeParaganglioma and pheochromocytoma are rare cancers that can run in families and can spread and killpatients. We are studying the unusual errors in gene recipes that cause these tumors. The current projectuses a method to identify additional gene recipes required only by the tumor cells as clues to possible newtherapies. NCI 10750986 11/22/23 0:00 PAR-20-292 5R21CA266999-02 5 R21 CA 266999 2 "O'HAYRE, MORGAN" 12/8/22 0:00 11/30/24 0:00 ZCA1-SRB-P(O1)S 1864697 "MAHER, LOUIS JAMES" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 167249 NCI 105188 62061 Abstract: Genome-wide synthetic lethal screening for vulnerabilities in a cell model of succinatedehydrogenase-loss paragangliomaThis proposal focuses on the molecular pathology of familial paraganglioma (PGL). Paradoxically thisremarkable neuroendocrine cancer is caused by inherited mutations that inactivate succinatedehydrogenase (SDH) an enzyme of the mitochondrial tricarboxylic acid (TCA) cycle. A fundamental scientificunderstanding of the molecular basis of this tumor is lacking limiting powerful approaches that might beidentified to exploit unique vulnerabilities due to the fundamental metabolic defect in this cancer. The linksbetween SDH loss and tissue-specific tumorigenesis remain unknown and conventional preclinicalmodels have been unavailable. The current hypothesis for PGL tumorigenesis invokes loss or inactivation ofboth parental copies of any of the four SDH subunit genes (A-D). The subsequent accumulation of succinatecompetitively inhibits the activities of several dioxygenase enzymes that normally suppress hypoxic signalingand demethylate histones and DNA. Despite this general mechanistic model other mechanisms are possibleand it is unclear what unique vulnerabilities may be present in SDH-loss cells that could permit targetedtherapies. We hypothesize that an unbiased genome-wide lentiviral CRISPR screen will identify geneswhose loss displays synthetic lethality with SDH loss. This hypothesis is supported by previous successfulwork in our labs identifying genes whose loss confers resistance to multiple forms of endocrine therapy inER+ and ER+ breast cancer cells. Important new PGL cell models have become available in the form ofSdhblox/lox and Sdhb-/- immortalized mouse chromaffin cells (imCC). This positions us ideally to conduct andanalyze an unbiased genome-wide synthetic lethal screen using an available CRISPR single guide RNA(sgRNA) library. Aim 1 will undertake a paired unbiased lentiviral CRISPR screen in matched normal andSDH-loss imCC lines. Aim 2 will complete data analysis to identify candidate synthetic lethal genes. Aim 3 willcomplete independent validation of representative synthetic lethal genes and pathways. Finally Aim 4 willimplement a mouse allograft tumor model to monitor selective inhibitory effects of nominated target geneknockdown in Sdhb-/- vs. Sdhblox/lox imCC. This project is unique in being the first unbiased syntheticlethal screen addressing the unmet cancer needs of SDH-loss familial PGL patients. Because SDHgenes are tumor suppressors in other cancers including gastrointestinal stromal tumor (GIST) and somekidney cancers identifying potential vulnerabilities in SDH-loss cells may be broadly applicable clinically. 167249 +No NIH Category available Achievement;Address;Aftercare;Alanine;Animal Model;Arterial Embolization;Ascorbic Acid;BAY 54-9085;Biology;Cancer Etiology;Carbon;Cell Survival;Clinic;Clinical Trials;Common Neoplasm;Data;Dehydroascorbic Acid;Dependence;Detection;Development;Diagnosis;Disease;Functional Imaging;Glucose;Image;Imaging technology;Inferior;Ischemia;Laboratories;Lactate Dehydrogenase;Life Expectancy;Liver;Magnetic Resonance Imaging;Malignant Epithelial Cell;Malignant Neoplasms;Measurement;Measures;Metabolic;Metabolism;Methodology;Methods;Molecular and Cellular Biology;NADP;Nuclear;Oxidation-Reduction;Oxidoreductase;Pathologic;Patients;Physiologic pulse;Positron-Emission Tomography;Primary carcinoma of the liver cells;Prognosis;Pyruvate;Pyruvate Metabolism Pathway;Recurrence;Reproducibility;Residual Neoplasm;Residual state;Resolution;Selection for Treatments;Sensitivity and Specificity;Shunt Device;Signal Transduction;Specificity;Stress;Technology;Testing;Therapeutic;Time;Tissues;Translating;Tumor Burden;United States;Work;aerobic glycolysis;anatomic imaging;cancer cell;cancer imaging;clinical application;clinical imaging;contrast enhanced;detection sensitivity;diagnostic accuracy;genome editing;imaging biomarker;imaging probe;improved;in vivo;liver cancer model;magnetic resonance spectroscopic imaging;metabolic imaging;metabolomics;molecular imaging;mortality;novel;patient prognosis;response;spectroscopic imaging;standard of care;targeted imaging;targeted treatment;treatment response;treatment stratification;tumor;tumorigenesis;uptake Dynamic Nuclear Polarization MR Spectroscopic Imaging for Diagnosis and Treatment Response Assessment in Hepatocellular Carcinoma PROJECT NARRATIVEThe diagnosis of HCC and assessment of its response to treatment rely primarily on imagingbiomarkers which have replaced tissue-based measures. Recent studies demonstrate significantlimitations of standard-of-care imaging paradigms for: (i) distinguishing HCCs from other tumorscommonly observed in the liver (ii) informing on the molecular and cellular biology required tofacilitate treatment stratification and (iii) assessing treatment response. The development of thefunctional imaging strategies required to address these deficiencies has been limited by theabsence of methodologies that can tailor imaging probe selection to the relevant HCC biology aswell as a dearth of representative animal models. Using genome editing and metabolomics ourlaboratory has demonstrated fundamental enzymatic dependencies of HCC cells to be promisingimaging targets for diagnosis and treatment response assessment using Dynamic NuclearPolarization 13Carbon Magnetic Resonance Spectroscopic Imaging a novel and emergingimaging technology. The proposed project will build on this prior work to assess the accuracy ofthis technology for diagnosing and characterizing HCC and for treatment response assessmentusing unique translational animal models developed in our laboratory. NCI 10750967 12/11/23 0:00 PA-20-185 5R01CA258715-03 5 R01 CA 258715 3 "WU, YICONG" 1/5/22 0:00 12/31/26 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 11044822 "GADE, TERENCE P" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 509806 NCI 313727 196079 Hepatocellular carcinoma (HCC) is the most rapidly rising cause of cancer mortality in the United States. Themajority of patients with HCC present with incurable disease at diagnosis and despite the approval of targetedtherapies life expectancy remains less than 20 months. The diagnosis of HCC as well as its response totreatment rely primarily on imaging biomarkers which have replaced tissue-based methods. Recent studiesdemonstrate that the dismal prognosis for these patients issues at least in part from deficiencies of currentclinical imaging paradigms in diagnosing HCC as well as in identifying residual or recurrent HCC after treatment.Clinical imaging paradigms for HCC diagnosis and the assessment of treatment response are based on anatomicimaging features that often fail to identify HCCs or provide functional measures of response to targeted therapies.Indeed the sensitivity of standard-of-care (SOC) contrast-enhanced (CE) MRI for small HCCs can be as low as20%. Similarly SOC imaging provides inadequate assessments of response to therapies. Addressing thisdeficiency requires the development of new imaging paradigms that provide functional measures of HCC biologyto improve accuracy sensitivity and specificity as well as inform the application of therapeutics.The development of novel functional imaging strategies for HCC has been limited by the absence ofmethodologies that can tailor imaging probe selection to the relevant HCC biology as well as a dearth ofrepresentative animal models. Using genome editing and metabolomics our laboratory has demonstrated thefundamental dependence of HCC cells on lactate dehydrogenase and NADPH-dependent reductases to bepromising imaging targets for Dynamic Nuclear Polarization 13Carbon Magnetic Resonance SpectroscopicImaging (DNP-13C-MRSI) an emerging imaging technology. The proposed project will build on this prior work tostudy the ability of DNP-13C-MRSI to: 1) improve the accuracy of diagnosis and treatment response assessmentof HCC following SOC therapies as compared to conventional imaging and 2) inform treatment selection.We hypothesize that DNP-13C-MRSI provides a unique technology through which to leverage fundamentalenzymatic dependencies of HCC cells and enable functional molecular imaging for diagnosis and treatmentresponse assessment. To test this hypothesis the proposed project will use unique animal models of HCCdeveloped in our lab to pursue three aims: (1) to optimize a DNP-13C-MRSI pulse sequence that enablessensitive accurate and reproducible measurements of regional pyruvate metabolism in autochthonous HCCsat high spatial resolution; (2) to determine the sensitivity specificity and accuracy of DNP-13C-MRSI of HP 1-13C-pyruvate uptake and metabolism for identifying HCCs; and (3) to determine the accuracy of DNP-13C-MRSI ofHP 1-13C-pyruvate and/or 1-13C-dehydroascorbic acid (DHA) for identifying and characterizing residualdisease/local recurrence following TAE as compared to SOC imaging. The achievement of the proposed aimsholds the potential to transform the imaging and treatment of patients with HCC a devastating disease. 509806 +No NIH Category available Accounting;Acidity;Address;Affect;Anatomy;Area;Biological;Biological Markers;Biopsy;Blood - brain barrier anatomy;Blood Vessels;Blood Volume;Cell Density;Cell Proliferation;Cellularity;Characteristics;Classification;Clinical;Clinical Management;Codon Nucleotides;Diffusion;Diffusion Magnetic Resonance Imaging;Disease;Early identification;Enzymes;Event;Extravasation;Functional Imaging;Glioma;Glycolysis;Goals;Histologic;Histology;Human;Hypoxia;Hypoxia Inducible Factor;Image;Indolent;Intervention;Isocitrate Dehydrogenase;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Glioma;Measurable;Measurement;Metabolic;Microvascular Proliferation;Modality;Molecular;Mutation;Nature;Operative Surgical Procedures;PECAM1 gene;Patients;Perfusion;Physiological;Positron-Emission Tomography;Process;Prognosis;Recurrence;S-Phase Fraction;Signal Transduction;Therapeutic;Therapeutic Intervention;Tissues;Treatment Failure;World Health Organization;anatomic imaging;angiogenesis;cerebral blood volume;contrast enhanced;density;fluorodeoxyglucose;follow-up;gain of function;image guided;imaging biomarker;improved;inhibitor;inhibitor therapy;insight;lactate dehydrogenase A;longitudinal analysis;magnetic resonance imaging biomarker;malignant phenotype;metabolic imaging;mutant;mutational status;neoplastic cell;new therapeutic target;non-invasive imaging;patient population;response;serial imaging;standard of care;targeted treatment;theories;treatment response;tumor;tumor growth;tumor microenvironment;uptake Molecular MR-PET to characterize malignant transformation and identify therapeutic vulnerabilities in human IDH-mutant gliomas PROJECT NARRATIVEIsocitrate dehydrogenase (IDH)-mutant gliomas have distinct metabolic characteristics and therapeuticvulnerabilities. However advanced imaging biomarkers of IDH-mutant glioma remain limited for malignanttransformation and new IDH inhibition therapy. Our proposed studies will utilize molecular MR-PET imaging toidentify imaging biomarkers that could improve the clinical management of IDH-mutant gliomas. NCI 10750893 7/21/23 0:00 PA-21-049 1F30CA284809-01 1 F30 CA 284809 1 "PURI, ANU" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F10C-D(20)L] 16056454 "CHO, NICHOLAS S." Not Applicable 36 RADIATION-DIAGNOSTIC/ONCOLOGY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 40079 NCI 40079 0 PROJECT SUMMARY/ABSTRACT The World Health Organization (WHO) classification of gliomas has been steadily shifting from a histologicalclassification towards a molecular classification. For example isocitrate dehydrogenase (IDH) mutational statusis a critical feature of the recent 2021 WHO classification. Compared to IDH-wild-type (IDH-wt) gliomas IDH-mutant (IDH-m) gliomas have distinct clinical characteristics such as accounting for most low-grade gliomas(LGGs; grade 2) having better prognosis growing slower and affecting a younger patient population comparedto IDH-wt gliomas. However all WHO grade 2 IDHm gliomas are expected to eventually become malignanthigher-grade (WHO grades 3-4) gliomas in a process known as malignant transformation. Upon malignanttransformation patients with IDHm gliomas have a significantly worse prognosis. Thus early non-invasiveimaging biomarkers of IDHm glioma malignant transformation may allow for earlier identification of treatmentfailure and appropriate therapeutic interventions. Magnetic resonance imaging (MRI) is critical for the management of patients with IDHm gliomas. Currentlyidentification of malignant transformation in patients with IDHm gliomas involves the emergence of contrast-enhancing areas on T1-post-contrast MRI in previously non-enhancing grade 2 gliomas. However advancedMRI biomarkers sensitive to acidity perfusion and cellular density may provide earlier identification of the tumormicroenvironment changes associated with malignant transformation and earlier identification of treatmentfailure. Furthermore combining our labs pH-sensitive MRI with metabolic positron emission tomography (PET)imaging may yield deeper insights into the tumor microenvironment particularly for metabolic shifts associatedwith malignant transformation and new IDH inhibitor targeted therapies that inhibit the mutant IDH enzyme. Asa result this proposal seeks to identify molecular MR-PET biomarkers associated with malignant transformationand successful IDH inhibition of IDHm gliomas. In Specific Aim 1 we will establish a sequential order of advanced MRI biomarkers in IDHm gliomasundergoing malignant transformation using pH-sensitive perfusion diffusion and anatomical MRI and thenvalidate MR-PET biomarkers of IDHm gliomas with histopathological markers from targeted surgical biopsies. InSpecific Aim 2 we will utilize pH-sensitive MRI and PET to evaluate metabolic perturbations in IDHm gliomasfollowing successful IDH inhibitor therapy. The proposed studies may improve IDHm glioma management byestablishing imaging biomarkers of malignant transformation and successful IDH inhibitor treatment response. 40079 +No NIH Category available 16S ribosomal RNA sequencing;APC gene;APC mutation;Acceleration;Adherence;Area;Attention;Automobile Driving;Benign;Biology;Cancer Etiology;Carcinoma;Cessation of life;Characteristics;Chronology;Colitis;Colon;Colorectal Cancer;Colorectal Neoplasms;DNA Damage;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Early identification;Environment;Epithelial Cells;Epithelium;Event;Future;Gene Expression Regulation;Genetic;Germ-Free;Goals;Habitats;Hand;Histopathology;Human;Individual;Inflammatory Bowel Diseases;Laboratory Finding;Lesion;Malignant Neoplasms;Measures;Metabolic Pathway;Microbe;Microbiology;Modeling;Mucositis;Mucous Membrane;Mus;Mutate;Mutation;Pathogenesis;Pathogenicity;Patient Care;Prevention;Proliferating;Research;Spatial Distribution;Testing;Therapeutic;Time;Tissues;Tumor Suppressor Genes;Woman;adenoma;anticancer research;cancer risk;cancer therapy;carcinogenesis;colon cancer patients;colon microbiota;colon tumorigenesis;colorectal cancer prevention;colorectal cancer progression;driver mutation;dysbiosis;fecal microbiome;host microbiome;innovation;insight;member;men;metabolomics;microbial;microbial colonization;microbial composition;microbiome;microbiome composition;microbiota;mortality;mouse model;novel;novel strategies;pathogen;permissiveness;time use;transcriptome sequencing;transcriptomics;tumor;tumor microbiome;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Defining the changing microbiome composition and host-microbe mechanistic effects following Apc inactivation during colorectal cancer pathogenesis Project NarrativeColorectal cancer (CRC) is the second leading cause of cancer mortality globally and understanding themicrobiota contributions to disease development is predicted to lead to new approaches to CRC preventionand therapy. In this proposal using a murine model I will define how genetic loss of adenomatous polyposiscoli (Apc) a CRC driver mutation present in at least 80% of CRC modulates the microbiome throughout thetime course of colorectal tumor development. I expect my results to provide support in the future for innovationin CRC patient care. NCI 10750676 7/17/23 0:00 PA-21-051 1F31CA284760-01 1 F31 CA 284760 1 "ODEH, HANA M" 9/16/23 0:00 9/15/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 78865657 "DZIEROZYNSKI, LINDSEY " Not Applicable 7 BIOCHEMISTRY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF PUBLIC HEALTH 212182680 UNITED STATES N 9/16/23 0:00 9/15/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 Project SummaryGlobally colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and womenand is projected to increase by 70% in the next 20 years. One of the earliest initiating events of CRC ismutation of adenomatous polyposis coli (APC) a tumor suppressor gene. This mutation initiates the gradualprogression from normal proliferating colon epithelial cells (CECs) to dysplastic lesions to the eventualformation of tumors known as adenomas. Somatic APC mutations occur in >80% of sporadic CRCs. Growingevidence demonstrates that factors within the local microenvironment can significantly influence cancer riskand onset. One key characteristic of the colon adenomatous environment is an imbalanced microbiome.Disruption in the makeup of these microbiota known as dysbiosis is related to many diseases includingcolitis inflammatory bowel disease and CRC. While dysbiosis contributes to promoting adenoma progressionand CRC whether APC mutation triggers changes in the local microenvironment to facilitate tumor progressionand microbiome dysbiosis remains largely unknown. Using an inducible murine model of CEC Apc truncationour lab found that Apc inactivation and subsequent colon tumorigenesis results in microbiome dysbiosis andoutgrowth of pathogenic species further associated with increased bacterial mucosal adherence. Thisproposal aims to define the timing and mechanisms by which the early microbiome changes following Apcinactivation. We hypothesize that Apc loss alters the microenvironment to cause early loss of commensalspecies and provides a habitat for pathogenic outgrowth and pro-carcinogenesis. We will test our hypothesisthrough the following aims. Aim 1: Defining the effects of Apc inactivation on the composition spatial/temporaldynamics and tumorigenic potential of the host microbiome. Using 16S rRNA amplicon sequencing andmicrobiology I will identify early microbiome changes following Apc loss during gradual colon tumorigenesisand will determine if this differs by colon region. I will use germ-free models to evaluate if the changingmicrobiome is sufficient to induce colon tumorigenesis. Aim 2: Identifying the mechanism(s) by which Apcinactivation contributes to microbiome dysbiosis and the expansion of pathogenic species. I will utilizetranscriptomics and metabolomics to examine changes in metabolic pathways and gene regulation inassociation with changes in microbiome composition and timing of Apc inactivation. This research will providenovel insights into the events occurring upon Apc mutation and the crosstalk between mutated CECs and thelocal microbiome. 47694 +No NIH Category available Auxins;Biochemical;CRISPR/Cas technology;Cancer Biology;Cancer cell line;Cell Line;Cellular biology;Chromatin;Chromosomes;Clupeidae;Complex;Cyclic GMP;Cytosol;DNA;DNA Binding;DNA Repair Pathway;DNA-Binding Proteins;Data;Data Analyses;Dedications;Defect;Electron Microscopy;Endosomes;Enzyme-Linked Immunosorbent Assay;Exposure to;Fluorescence Microscopy;Gene Expression;Genes;Genetic;Genomic DNA;Genomic Instability;Goals;Home;Immune signaling;Immunofluorescence Immunologic;Immunotherapeutic agent;Individual;Innate Immune Response;Interferons;Interphase;Intervention;Learning;Malignant Neoplasms;Measures;Membrane Proteins;Mitosis;Modeling;Molecular;Nuclear;Nuclear Envelope;Nuclear Inner Membrane;Outcome;Pathway interactions;Phosphorylation;Production;Productivity;Proteins;Publishing;Regulation;Role;Rupture;Scientist;Signal Transduction;Site;Sorting;Source;Stimulator of Interferon Genes;System;Testis;Training;Transcript;Transfection;Tumor Promotion;Western Blotting;Work;cancer cell;career;chromosome missegregation;design;env Gene Products;experimental study;innate immune pathways;insight;light microscopy;live cell imaging;micronucleus;novel;recruit;response;seal;sensor;spatiotemporal;synergism;tumor;tumor growth Determining the role of nuclear envelope reformation proteins in regulating the cGAS/STING innate immune response in cancer PROJECT NARRATIVE:Cancer cells are prone to genomic instability that can lead to exposure of genomic DNA to the cytosol where itcan be recognized by cytosolic DNA sensors and trigger an innate immune response. However themechanisms by which cytosolic DNA sensors such as cGAS are regulated especially in response to aberrantexposures of self DNA in cancer is unclear. Therefore this proposal intends to define the role of novelregulators of the cGAS/STING innate immune response to inform targeted interventions to cancer. NCI 10750669 6/30/23 0:00 PA-21-051 1F31CA278423-01A1 1 F31 CA 278423 1 A1 "ODEH, HANA M" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F05-D(21)L] 78576149 "ISENHOUR, ANTHONY WAYNE" Not Applicable 3 ANATOMY/CELL BIOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARY/ABSTRACT:In cancer cells exposure of self DNA to the cytosol is driven by a variety of genomic instabilities such asmicronuclei chromatin bridges and nuclear ruptures. This cytosolic DNA can be recognized by cytosolic DNAsensors such as cGAS (cyclic GMP-AMP synthase) which triggers a downstream innate immune response.Interestingly and confoundingly the activation of the cGAS/STING innate immune pathway can protect orsensitize tumors to immunotherapeutic interventions depending on the specific context. Therefore insight intothe ways in which cGAS/STING signaling is regulated in cancer can inform targeted intervention. Sources ofcytosolic DNA in cancer cells arise primarily from defects in mitosis that lead to the enclosure of chromosomesin micronuclei that are prone to rupture. These ruptured micronuclei recruit cGAS and nuclear envelopereformation (NER) factorssuch as LEM2 CHMP7 and BAFbut it remains unknown how or if these NERfactors impact cGAS/STING signaling but there is emerging evidence in published and in our preliminary datathat there is potential crosstalk between cGAS/STING signaling and NER proteins. The goal of this proposalis to provide key insights into the regulation of the innate immune response to cytosolic DNA in cancercells by nuclear envelope reformation factors. In order to achieve this goal I will use transfected herringtestes (HT) DNA and transfected DNA-coated beads as models for cytosolic DNA as this can be more readilycontrolled compared to the stochastic formation of micronuclei only some of which are unstable and prone torupture. With this model I will use CRISPR/Cas9 gene-editing and the auxin-inducible-degron (AID) conditionaldegradation system to probe the roles of NER factors in cGAS/STING signaling in response to transfected HTDNA and DNA beads. This proposal will address fundamental aspects of cell biology and innate immunesignaling that will shed light on immunotherapeutic targets for cancer. 47694 +No NIH Category available Adrenergic Agents;Adrenergic Receptor;Adrenergic beta-Agonists;Affect;Antitumor Response;Ants;Binding;Breast Cancer Model;Cancer Biology;Cancer Patient;Cancer Prognosis;Cell Differentiation process;Cells;Chronic stress;Common Lymphoid Progenitor;Cytotoxic T-Lymphocytes;Data;Development;EO771;Ensure;Enzyme-Linked Immunosorbent Assay;Event;Exhibits;Fellowship;Flow Cytometry;GATA3 gene;Goals;Helper-Inducer T-Lymphocyte;Immune;Immune response;Immunity;Immunosuppression;Immunotherapy;In Vitro;Infiltration;Isoproterenol;Knock-out;Knockout Mice;Knowledge;Literature;Lymphoid Cell;Lymphoid Tissue;Malignant Neoplasms;Mediating;Methodology;Methods;Molecular;Moon;Mus;Myeloid-derived suppressor cells;Natural Killer Cells;Nature;Nerve;Norepinephrine;Pathway Analysis;Pathway interactions;Patients;Phenotype;Physicians;Play;Population;Pre-Clinical Model;Proteins;Publishing;Receptor Signaling;Regulation;Role;Scientist;Signal Transduction;Site;Sorting;Stress;Surface;T cell differentiation;T-Lymphocyte;Techniques;Testing;Training;Treatment outcome;Tumor Immunity;Tumor Promotion;Tumor Volume;Work;adrenergic stress;anti-tumor immune response;beta-2 Adrenergic Receptors;breast cancer progression;catalyst;comparison control;conditional knockout;cytotoxic;experience;improved;improved outcome;in vivo Model;melanoma;nerve supply;novel;patient prognosis;prevent;response;single-cell RNA sequencing;skills;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Understanding the role of 2AR-signaling on ILC2 differentiation/plasticity and its implications in cancer progression Project NarrativeInnate lymphoid cells (ILCs) are highly plastic cells that can exert both enhancing and regulatory activity in tumormicroenvironment depending on the type of signals they receive. Our hypothesis is that the suppressor functionsof ILC2s are enhanced by stress through 2 adrenergic signaling and thus contributes to the known tumorpromoting effects of stress. The work proposed here will investigate how adrenergic stress affects ILC2 plasticityand immune-inhibitory functionality in the tumor site with the long-term intent of improving outcomes ofimmunotherapy in patients. NCI 10750348 7/21/23 0:00 PA-21-050 1F30CA284763-01 1 F30 CA 284763 1 "BIAN, YANSONG" 9/1/23 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-F09C-Z(22)L] 78410963 "CHOI, JEE EUN " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 32512 NCI 32512 0 Project Summary / Abstract:In preclinical models norepinephrine released by sympathetic nerves during chronic stress have beendemonstrated to promote an immunosuppressive tumor microenvironment (TME) through activation of the 2-adrenergic receptor (2AR) on various cells including immune cells. This sequence of events could bedetrimental to the treatment outcome in cancer patients who are experiencing increased levels of stress. Innatelymphoid cells (ILCs) specifically type II ILCs (ILC2s) have been demonstrated as a small but critical cellpopulation within the TME. However there is little known about the mechanisms that regulate ILC plasticity andfunction in the TME. Even though ILC2s express high levels of 2AR how stress impacts ILC2 activity within theTME is not yet known. In new preliminary data we have observed a correlation between increased ILC2s anddecreased tumor volume in knock out mice lacking the 2AR. Furthermore our data suggests a shift in ILC2plasticity toward an anti-tumor phenotype upon loss of 2AR signaling by single-cell RNA sequencing. Thereforewe hypothesize that 2AR signaling activated by chronic stress drives the immunosuppressive function of ILC2ssuppressing the anti-tumor immune response within the tumor microenvironment. We will interrogate the role2AR signaling plays as a rheostat in ILC development and plasticity into the helper ILC subsets by the two aimsproposed here. In Aim 1 we will determine the effect of 2AR signaling on common lymphoid progenitors (CLPs)differentiation into ILC2s and ILC2 plasticity. Utilizing in vitro cultures of wildtype and 2AR-/- CLPs and ILC2swith a -AR agonist treatment we will analyze the changes in ILC subset ratios due to 2AR signaling. We willalso elucidate the molecular mechanism by which these changes occur using both targeted and high-throughputmethodologies. In Aim 2 we will determine the impact of 2AR signaling on ILC2-mediated tumor progressionusing IL-5cre2-ARfl/fl conditional knockout mice. The changes in the TME and tumor growth in mice with aconditional 2AR knock out in ILC2 will be analyzed using spectral flow cytometry. Overall this project will utilizein vitro and in vivo models and other state-of-the-art techniques to understand how chronic stress through 2-AR signaling hampers effective ant-tumor immune response in tumor microenvironment. 32512 +No NIH Category available ADP ribosylation;Acrylamides;Active Sites;Adenosine Diphosphate Ribose;Alkynes;Automobile Driving;Binding;Binding Proteins;Biological Assay;Biology;Cell Death;Cell Survival;Cells;Chemicals;Chemistry;Chimeric Proteins;Comparative Study;Cysteine;Diazomethane;Disease;Drug Targeting;Endoplasmic Reticulum;Environment;Enzymes;Exhibits;FDA approved;Family;Genetic;Goals;Growth;Human;Hydrogen Peroxide;Knock-out;Label;Lead;Length;Light;Link;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Maps;Mass Spectrum Analysis;Mediating;Methods;Nicotinamide adenine dinucleotide;Oncology;Phenotype;Phosphotransferases;Physiology;Poly(ADP-ribose) Polymerase Inhibitor;Post-Translational Protein Processing;Process;Protac;Protein Biosynthesis;Proteins;Proteome;Proteomics;Research Personnel;Role;Signal Transduction;Stress;Technology;Testing;Translations;Ubiquitin;Ultraviolet Rays;Western Blotting;cancer cell;cancer subtypes;cross reactivity;crosslink;drug candidate;inhibitor;insight;interest;knock-down;lung cancer cell;member;nanomolar;new therapeutic target;novel;paralogous gene;pomalidomide;pre-clinical;preservation;protein degradation;protein protein interaction;proteostasis;proteotoxicity;small cell lung carcinoma;small molecule;tandem mass spectrometry;tool;tumor progression;ubiquitin-protein ligase;ultraviolet irradiation Chemical Biology-Based Tools to Uncover the Function of PARP16 in cancer PROJECT NARRATIVEPARP16 is emerging as a novel cancer driver in ovarian and lung cancer however the role of PARP16enzymatic activity in cancer is not fully understood. We have recently developed the first potent and selectivecovalent PARP16 inhibitor called DB008 and have observed that the non-catalytical activity of PARP16 is moreimportant for ovarian and lung cancer growth than PAR16 enzymatic activity. The goal of this proposal is todevelop new chemical tools based on DB008 that will validate PARP16 as an oncology drug target provide alead preclinical candidate and identify PARP16 interactors in order to understand the mechanism of action ofPARP16 in cancer. NCI 10750279 7/17/23 0:00 PA-21-052 1F31CA284712-01 1 F31 CA 284712 1 "DIBELLO, ANTHONY THOMAS" 7/17/23 0:00 7/16/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15624440 "BEJAN, DANIEL " Not Applicable 1 PHYSIOLOGY 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 7/17/23 0:00 7/16/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARY/ABSTRACTPARP16 a member of the PARP family of enzymes responsible for carrying out the post-translationalmodification known as ADP-ribosylating is emerging as a novel therapeutic target in two cancer subtypes. Inovarian cancer PARP16 was shown to negatively regulate protein translation in order to maintain proteostasis.Genetic deletion (i.e. knockout or knockdown) of PARP16 resulted in an increase in global protein translationforcing ovarian cancer cells to enter a state of proteotoxic stress that ultimately leads to cancer cell death. Insmall cell lung cancer (SCLC) PARP16 was identified as an off-target to the recently FDA-approved PARP1inhibitor talazoparib suggesting that the efficacy of talazoparib in SCLC may be due to dual targeting ofPARP1 and PARP16. However knockdown of PARP16 alone also decreased SCLC viability. Both of thesecancer studies point to PARP16 as actionable oncology target however the role of PARP16 catalytic activityin cancer has not been fully characterized. Our group has recently developed the first cysteine-targetedcovalent PARP inhibitor called DB008 that displays excellent proteome-wide selectivity for PARP16 in thecovalent binding mode. While DB008 inhibits PARP16 catalytic activity with nanomolar potency neither of theaforementioned PARP16 knockout/knockdown phenotypes were observed with DB008 treatment in ovariancancer and SCLC suggesting that the non-catalytic activity (i.e. protein-protein interactions) ofPARP16 may regulate protein homeostasis and cancer growth as opposed to PARP16 enzymaticactivity. To test this hypothesis I aim to develop two novel chemical probes based on DB008 to evaluate thenon-catalytic functions of PARP16 in cancer. In Aim 1 I will synthesize a PARP16 proteolysis targetingchimera (PROTAC) that will chemically knockdown PARP16 in ovarian cancer and SCLC. The PARP16PROTAC will evaluate whether depletion of PARP16 and its protein-protein interactions reduces cancer cellviability as observed with genetic knockdown methods. Completion of this aim will validate PARP16 as a newcancer target and provide a lead preclinical drug candidate. In Aim 2 I introduce a novel proximity labelingstrategy for identifying interactors of endogenous PARP16 in cancer. This is done by converting DB008 into acaged photo-crosslinkable probe that uses UV light to uncage and release a reactive crosslinking species thatwill covalently tag interacting proteins which can then be enriched using click chemistry and identified by massspectrometry. Completion of this aim will provide understanding for how PARP16 regulates translation and cellviability in cancer. The technology described in Aim 2 presents a new use case for covalent inhibitors that isgeneralizable to other enzymes families beyond PARPs. In summary this proposal will generate invaluablechemical biology tools for uncovering the mechanism of action of PARP16 in cancer while also providing apotential lead drug candidate for combating PARP16-mediated diseases. 47694 +No NIH Category available Achievement;Arts;Authorization documentation;Award;Basic Science;Businesses;Cancer Burden;Cancer Center Support Grant;Cancer Patient;Cancer Science;Caring;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Health;Community Outreach;Complex;Development;Direct Costs;Discipline of Nursing;Duke Comprehensive Cancer Center;Education;Engineering;Enrollment;Environment;Faculty;Faculty Recruitment;Fellowship;Funding;Future;Goals;Grant;Health;Health system;Hepatic;Immunity;Infrastructure;Interdisciplinary Study;Intervention;Investigation;Investments;Laboratories;Leadership;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Medicine;Metastatic Neoplasm to the Liver;Mission;Oncology;Paper;Patient Care;Patients;Peer Review;Pilot Projects;Population;Population Research;Population Sciences;Process;Public Policy;Publishing;Recommendation;Research Activity;Research Infrastructure;Research Personnel;Research Technics;Resource Allocation;Resource Sharing;Schools;Science;Scientist;Series;Signal Transduction;Strategic Planning;Structure;Testing;Therapeutic;Time;Training;Training and Education;Translational Research;Translations;Universities;University Hospitals;Work;anticancer research;authority;cancer care;cancer genomics;career development;clinical care;community based participatory research;community engagement;cost;design;health disparity;innovation;medical schools;member;multidisciplinary;new technology;next generation;novel;outpatient facility;population based;programs;recruit;therapeutic development;therapeutic evaluation;training opportunity;translational study Deciphering Mechanisms of Hepatic Immunity Governing Pancreatic Cancer Liver Metastasis PROJECT NARRATIVE (RELEVANCE STATEMENT) OVERALLThe Duke Cancer Institute which has authority and responsibility for all cancer-related activities at DukeUniversity and in the Duke University Health System provides support and promotes collaborations betweenfaculty and staff involved in cancer research education and patient care. This Cancer Center Support Grantfacilitates oversight and integration of all cancer-related research activities from basic research to translationalstudies to clinical and population investigation to community outreach to global cancer. Building upon anextensive strategic planning process priority activities to maximize local regional and national impact havebeen identified. NCI 10750243 9/6/23 0:00 PA-20-272 3P30CA014236-49S2 3 P30 CA 14236 49 S2 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 1865395 "KASTAN, MICHAEL B" Not Applicable 4 PHARMACOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 397 Research Centers 2023 201250 NCI 125000 76250 PROJECT SUMMARY/ABSTRACT OVERALLThe Duke Comprehensive Cancer Center was founded as a matrix center within the Duke University School ofMedicine in 1972 and the Duke Cancer Institute (DCI) was created as a new administrative entity within DukeHealth in October 2010 with authority and responsibility for all cancer-related activities at Duke University andin the Duke University Health System. The DCI was started with significant investments from Duke Healthincluding a new $243M clinical care outpatient facility over $60 million of new funds available to support newinitiatives and a commitment for ongoing annual investment by the Duke Health System. DCI faculty includewell-established and funded experts spanning the full spectrum of cancer research fields from intracellularsignaling to cancer genomics to therapeutic development and testing to population science. DCI programmaticactivities support the career development of the next generation of cancer experts and provide platforms formulti-disciplinary scientific teams to develop and test new hypotheses. During the most recent funding periodthe DCI structure has continued to evolve and mature currently consisting of 304 members from 34 departmentswithin 7 schools at Duke University (Medicine Nursing Arts and Sciences Engineering Public PolicyEnvironment and Business) and organized as 8 multi-disciplinary research programs (2 basic discovery 1population science and 5 translational/clinical) whose work is supported by 14 Shared Resources (8 lab-basedand 6 supporting translational/clinical/population research activities). In addition to Program and SharedResource leaders DCI senior leadership which includes an Executive Director Deputy Director 7 AssociateDirectors and 8 other key leaders provides oversight and direction of DCI initiatives. DCI members are currentlysupported by over $111M of external cancer-related grant support (direct costs) over $63M of which is peer-reviewed including 32 peer-reviewed multi-investigator grants (involving 81 subprojects/cores) and 61 trainingand fellowship awards. DCI members published over 5750 cancer-focused papers during the past fundingperiod ~40% of which represent collaborative efforts between DCI investigators. On average ~7000 newcancer patients are seen each year at the Duke University Hospital. In 2018 DCI Programs enrolled over 4000patients on clinical trials including nearly 2000 interventional accruals and 770 therapeutic accruals. DCI isheavily engaged in both community outreach/engagement and educating the next generation of cancer cliniciansand scientists. Duke Health support of the DCI included a total of over $65M of additional investment in the mostrecent funding period including support for recruitment retention and protected academic time for DCI faculty.The DCI completed an extensive 5-year Strategic Planning process identifying strategic goals and priorities thatenable the DCI mission to Discover Develop and Deliver the future of cancer carenow resulting in a seriesof discrete recommendations that are serving as a guide for determining current and future resource allocationrecruiting priorities and infrastructure changes required to achieve DCI goals. 201250 +No NIH Category available Acetylation;Affect;Behavior;Binding;Biological Assay;Biological Models;Cell Line;Cell Nucleus;Cells;Chromatin;Complex;DNA;DNA Polymerase II;Defect;Development;Disease;Elements;Embryo;Engineering;Ensure;GAS41 gene;Gene Activation;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Genomics;Goals;Health;Histone Acetylation;Human;Image;Imaging Techniques;Kinetics;Link;MLLT3 gene;Malignant Neoplasms;Measurable;Mediating;Messenger RNA;Methods;Modeling;Molecular;Molecular Conformation;Monitor;Mutagenesis;Mutation;Nature;Nephroblastoma;Oncogenic;Organism;Outcome;Output;Pathogenicity;Pathologic;Pattern;Phosphorylation;Physical condensation;Positioning Attribute;Process;Production;Property;Protein Overexpression;Proteins;Proteomics;RNA;Reader;Regulation;Regulator Genes;Resolution;Role;Series;Site;Specificity;System;Techniques;Technology;Testing;Time;Transcription Elongation;Transcription Regulatory Protein;Transcriptional Activation;Transcriptional Regulation;Variant;Visualization;Work;cellular imaging;gain of function;gene correction;genetic regulatory protein;human disease;in vivo;in vivo imaging;insight;interest;kidney cell;leukemia;molecular dynamics;molecular imaging;molecular scale;mutant;novel;novel therapeutic intervention;recruit;residence;single molecule;virulence gene Mechanisms of pathogenic gene activation by aberrant transcriptional hubs formed by mutant ENL PROJECT NARRATIVEAberrant transcriptional hub formation defined by high local concentrations of proteins has been associatedwith disease including cancers and human expansion repeat disease yet the exact functional consequence ofhub formation remains unknown. Oncogenic mutations in the chromatin reader protein ENL are linked totranscriptional hub formation and are required for hyper-transcriptional activation of target genes. Thesemutations are a powerful system in which to understand hub-mediated transcription and the effect of hubformation the molecular kinetics of incorporated proteins genome organization and alter transcriptionaldynamics. NCI 10750194 7/12/23 0:00 PA-21-052 1F31CA284714-01 1 F31 CA 284714 1 "DIBELLO, ANTHONY THOMAS" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F08-A(20)L] 78264411 "MATHIAS, KAELI MARIE" Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARYTranscription is an essential and tightly regulated process that requires the coordination of many factors toensure proper gene expression. Current models of transcription are predicated on stable hierarchicalinteractions. These models have been challenged through recent developments in in vivo imaging which haverevealed that many transcriptional regulatory proteins interact transiently with chromatin. Instead of relying onstability occupancy at target loci is achieved through more frequent interactions resulting from the formation ofhigh local-concentration assemblies within nuclei called hubs. Little is known about the functional impacts ofhub formation on transcription how hubs alter the kinetics of regulatory proteins and how hubs function in cancerhuman expansion repeat disease and other diseases. Previous studies largely rely on the ectopicoverexpression of proteins of interest and qualitative assays to study hub function and there is a of lack of bothspecific strategies to perturb hub formation/properties with a measurable functional output and application ofsuitable technologies to look at protein kinetics in vivo. The goal of this project is to use oncogenic mutationsfound in the chromatin reader protein ENL to elucidate the mechanisms by which hubs impact transcription.ENL mutations are among the first examples of pathogenic mutations that result in aberrant hub formation.Importantly such hub formation is functionally required for hyper-activation of target genes. The high specificityand gain-of-function nature of ENL mutations make them a powerful system to study both the mechanisms ofhub formation as well as how aberrant hubs contribute to human disease. I hypothesize that ENL mutant proteinspromote the clustering of multiple elements both genomic and proteomic to alter transcription at target loci. InAim 1 I will combine advanced imaging techniques including single molecule tracking and live imaging oftranscription to determine the effect of hub formation on the molecular kinetics of incorporated proteins andtranscription dynamics. In Aim 2 I will investigate the effect of hub formation on the spatial proximity of targetgenes using DNA-FISH and live imaging to determine if hubs drive genome reorganization for coordinatedexpression of target loci. Completion of this project will offer novel insights as to how pathogenic mutations resultin aberrant hub formation and affect transcriptional dynamics to drive disease. More broadly this work willadvance our understanding of hub-mediated gene regulation revealing the potential for novel therapeuticstrategies to target gene dysregulation in disease. 47694 +No NIH Category available Affect;Astrocytes;BCL10 gene;Biological Response Modifiers;Blood - brain barrier anatomy;Brain;Brain Stem;Brain region;Categories;Cell Survival;Cells;Childhood;Childhood Brain Neoplasm;Childhood Brain Stem Neoplasm;Clinical Trials;Coculture Techniques;Complex;Cytoplasmic Protein;Data;Development;Diagnosis;Excision;Fostering;Genes;Genetic Transcription;Glioblastoma;Glioma;H3 K27M mutation;Histone H3.3;Immune;Immunity;Immunofluorescence Immunologic;In Vitro;Individual;Infiltration;Invaded;Laboratories;Location;Lymphocyte Depletion;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Mentorship;Microglia;Midbrain structure;Modeling;Molecular;Mucosa- associated lymphoid tissue lymphoma translocation protein-1;Mus;Myelogenous;NF-kappa B;Nature;Neoplasms;Operative Surgical Procedures;Pathogenesis;Patients;Peptide Hydrolases;Pharmacologic Substance;Phenothiazines;Physicians;Play;Point Mutation;Pontine structure;Proliferating;Protease Inhibitor;Proteins;Radiation;Radiation therapy;Research Personnel;Research Training;Role;Sampling;Scientist;Series;Signal Transduction;Structure;Techniques;Testing;Therapeutic;Training;Tumor Immunity;Tumor-associated macrophages;Tumor-infiltrating immune cells;Wild Type Mouse;cancer cell;cancer type;career;cell killing;cell motility;diffuse midline glioma;effective therapy;epigenome;experience;experimental study;immune activation;immune cell infiltrate;improved;inhibitor;migration;mouse model;new therapeutic target;novel;novel therapeutic intervention;pediatric patients;pharmacologic;protein complex;response;scaffold;single-cell RNA sequencing;standard care;translational therapeutics;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions MALT1 protease as a regulator of anti-tumor immunity and tumor progression in diffuse midline glioma PROJECT NARRATIVEDecades of clinical trials have not improved overall survival of pediatric patients diagnosed with H3K27M-mutant diffuse midline glioma (DMG). H3K27M-mutant DMG is one of the most challenging cancers to treat dueto its location within delicate regions of the brain and its highly aggressive nature. We outline in this proposal aseries of studies that will evaluate a new therapeutic target for the treatment of H3K27M-mutant DMG. NCI 10750167 6/20/23 0:00 PA-21-049 1F30CA284607-01 1 F30 CA 284607 1 "BIAN, YANSONG" 7/1/23 0:00 6/30/27 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16052731 "BUTTERFIELD, HANNAH " Not Applicable 12 PEDIATRICS 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTH3K27M-mutant diffuse midline glioma (DMG) is a devastating pediatric brain tumor. Surgical resection is difficultbecause these tumors are in delicate midbrain/brainstem locations and infiltrate into critical structures. Despitedecades of clinical trials H3K27M-mutant DMG is considered uniformly fatal with a median overall survival of9-11 months. Radiation therapy which itself is highly toxic to the developing pediatric brain extends survival by2-3 months. Therefore the development of safe and effective therapies for DMG is of utmost importance.I propose to evaluate the effect of inhibiting MALT1 on the pathogenesis of H3K27M-mutant DMG. MALT1 is theeffector molecule of the CARMA/CARD-BCL10-MALT1 (CBM) signalosome a cytoplasmic protein complex thatdrives downstream pro-survival NF-kB transcriptional activity. MALT1 possesses both scaffolding and proteaseactivities. Our laboratory and others have demonstrated that MALT1 protease activity promotes cancer cellviability proliferation and migration/invasion in multiple cancer types. In addition to its role within cancer cellsMALT1 is also a critical regulator of immune cell responses and our laboratory is investigating the impact ofMALT1 protease in the tumor microenvironment (TME) of high-grade glioma. Based on my preliminary data Ihypothesize that inhibiting MALT1 proteolytic activity could provide dual benefit in H3K27M-mutant DMG bothvia the direct effects of inhibiting MALT1 within the cancer cells and via the effects of inhibiting MALT1 proteasewithin immune cells of the TME to promote anti-tumor immune activation.In Aim 1 of this proposal we will evaluate the influence of MALT1 protease activity on the H3K27M-mutant DMGTME. Experimental techniques utilized in this aim will include use of murine models single cell RNA sequencingand multispectral immunofluorescence. In Aim 2 of this proposal we will evaluate the impact of MALT1 proteaseinhibition on malignant features of H3K27M-mutant DMG cells using a series of in vitro analyses. Finally in Aim3 we will analyze the impact of MALT1 protease inhibition with or without radiation in our orthotopic/syngeneicH3K27M-mutant DMG model.Overall this project evaluates inhibition of MALT1 protease as a potential therapeutic approach for H3K27M-mutant DMG. Completion of this proposal will provide me with exceptional research training by an outstandingteam of scientists and physician-scientists. This training experience will prepare me for a career as a physician-scientist who studies the molecular underpinnings of pediatric cancers to develop new and improved treatments. 52694 +No NIH Category available Adjuvant Therapy;Animals;Binding;Bioinformatics;Biologic Characteristic;Biological;Biological Factors;Biology;Cancer Patient;Cell Cycle;Cell Death;Cell Proliferation;Cell Survival;Cells;Cellular biology;Cessation of life;Characteristics;Chemoresistance;Combined Modality Therapy;Data;Devices;Disease;Disease Resistance;Exhibits;FDA approved;Follistatin;Gene Expression Profile;Genetic Transcription;Goals;Human;Immunotherapy;Knock-out;Link;Malignant neoplasm of ovary;Mediating;Messenger RNA;Microfluidics;Molecular;Pathway interactions;Patient Care;Patient-Focused Outcomes;Phenotype;Proliferating;Proteasome Inhibitor;Proteins;RNA analysis;Recurrent disease;Refractory;Relapse;Residual Cancers;Residual state;Role;Route;Sea;System;Testing;Therapeutic;Tumor Tissue;Ubiquitin;Up-Regulation;Work;Yeasts;cancer cell;cancer type;chemotherapy;differential expression;effective therapy;genetic approach;improved;improved outcome;in vivo;inhibitor;knock-down;multicatalytic endopeptidase complex;neutralizing antibody;new therapeutic target;novel;novel strategies;novel therapeutics;pharmacologic;prevent;recruit;senescence;small molecule inhibitor;targeted treatment;therapeutic target;therapy resistant;transcriptome sequencing Evaluating unique aspects of quiescent ovarian cancer cell biology for therapeutic targets Cancer cell quiescence is an understudied mechanism of chemotherapy resistance and drives poor outcomesfor patients with ovarian cancer. We will study the unique biology of quiescent ovarian cancer cells to identifytherapeutic vulnerabilities of quiescent cells. Based on our findings we will test novel therapeutic combinationsto eradicate quiescent cells to overcome chemotherapy resistance and increase disease cure rates. NCI 10750118 7/6/23 0:00 PA-20-185 1R01CA278100-01A1 1 R01 CA 278100 1 A1 "GHOSH-JANJIGIAN, SHARMISTHA" 7/15/23 0:00 6/30/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 9076039 "BUCKANOVICH, RONALD J" Not Applicable 12 Unavailable 119132785 J3Z5MNJJ3FZ4 119132785 J3Z5MNJJ3FZ4 US 40.437078 -79.96154 3840801 MAGEE-WOMEN'S RES INST AND FOUNDATION Pittsburgh PA Other Domestic Non-Profits 152134572 UNITED STATES N 7/15/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 438083 NCI 374114 63969 Most ovarian cancer (OvCa) patients develop fatal chemotherapy-resistant disease. Elucidating mechanismsof chemoresistance in OvCa may identify therapeutic targets to prevent or treat relapsed OvCa. Oneunderstudied mechanism of chemotherapy resistance in OvCa is quiescence. Quiescent cells are transientlynon-proliferating and thus refractory to standard therapies which target rapidly proliferating cells. The over-arching hypothesis of this project is that hypothesis is that understanding the biology of quiescentOvCa cancer cells will identify critical new therapeutic targets to improve patient outcomes. We haveused multiple novel approaches to identify and characterize the transcriptional signature of quiescent OvCacells. This work indicates that quiescent OvCa (qOvCa) cells have several unique characteristics including: (i)a unique Quiescence Associated Secretory Phenotype (QuASP) which drives chemotherapy resistance in non-quiescent cancer cells and (ii) altered expression of select components of the ubiquitin-proteosome system(UPS) including induction of UBL7. Indeed our preliminary data indicate that induction of UBL7 is sufficient todrive a quiescent cell phenotype including the expression of the QuASP. Bio-informatic analysis of quiescentOvCa cell RNAseq data identified the SRF/MRTF transcription pathway as being inversely correlated with theOvCa quiescent signature. Consistent with this a small molecule inhibitor of SRF/MRTF-mediatedtranscription CCG081 (i) induces UBL7 (ii) drives cells into a dense quiescent state and (iii) indicating acritical role for the UPS in quiescent cell viability CCG081 sensitizes OvCa cells to proteasome inhibitors.Based on these discoveries we propose: SA 1: To characterize the OvCa QuASP. We hypothesize thatcharacterizing the QuASP will identify critical biologic factors related to quiescence. We will identify QuASPfactors validate the expression of QuASP factors in ovarian cancer and other cancer types and useknockdown and neutralizing antibodies to evaluate the function of these factors in quiescent OvCa cells.SA 2:To determine the role of the UPS and UBL7 in quiescent cancer cells. We hypothesize that UPS changescontribute to the quiescent cell state and are essential for quiescent cell viability. We will identify whichcomponents of the UPS contribute to the quiescent phenotype including expression of the QuASP anddetermine if the proteosome is essential to maintain quiescent OvCa cell viability. Finally we will SA 3:Evaluate the impact of targeting the proteosome quiescent cells in vivo. We hypothesize that the ability topharmacologically force these residual cells into a quiescent state and then eliminate these quiescent cells viaproteosome inhibition will increase cure rates. We will evaluate the therapeutic potential of combined CCG081and FDA-approved proteosome inhibitors as consolidative therapy after chemotherapy to eradicate residualquiescent cells. Impact: We will define the regulators of OvCa cell quiescence providing therapeutic targetseradiate to improve patient outcomes. 438083 +No NIH Category available Alternative Splicing;Amino Acid Sequence;Antigen Targeting;Antigens;Automobile Driving;Binding;Binding Sites;Biological Assay;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Patient;Cancer Vaccines;Cancer cell line;Cell surface;Cells;Cessation of life;Coculture Techniques;Code;Cytomegalovirus;Data;Databases;Development;Disease;Exons;Flow Cytometry;Frequencies;Genes;Genomics;Genotype-Tissue Expression Project;Goals;Human;Human Herpesvirus 4;Immune checkpoint inhibitor;Immune response;Immunology;Immunoprecipitation;Immunotherapy;In Vitro;Influenza;Interferon Type II;Introns;Knock-out;Lead;Length;MHC Class I Genes;Malignant Neoplasms;Maps;Measurement;Measures;Mediating;Messenger RNA;Methods;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Pathway interactions;Patient Care;Patients;Peptides;Peripheral Blood Mononuclear Cell;Physicians;Physiologic pulse;Primary Neoplasm;Process;Production;Proliferating;Protein Isoforms;Proteins;RNA Splicing;RNA-Binding Proteins;Research;Sampling;Scientist;Solvents;Sorting;Source;Surface;T cell response;T-Cell Activation;T-Lymphocyte;Techniques;Testing;The Cancer Genome Atlas;Training;Transcription Process;Translating;Tumor Antigens;Tumor Expansion;United States;Vaccines;Viral;Work;anti-PD-1;anti-tumor immune response;bioinformatics pipeline;cancer cell;cancer type;candidate identification;career;cohort;crosslink;cytokine;experimental study;genetic approach;immunogenic;immunogenicity;improved;in silico;insight;lung cancer cell;mRNA Expression;mRNA Precursor;mortality;neoantigens;neoplastic cell;novel;overexpression;posttranscriptional;protein aminoacid sequence;public database;response;transcriptome sequencing;tumor;tumor specificity Alternate splicing as a source of shared neoantigens in a non-small cell lung cancer PROJECT NARRATIVEAlternative splicing is a post-transcriptional regulatory process that is dysregulated in cancer and may generateunique peptides called neoantigens that can be recognized by antitumor CD8+ T cells. We have built abioinformatic pipeline that has identified 21 candidate alternative splicing-derived neoantigens in non-small celllung cancer a deadly cancer type. The experiments outlined in this proposal will determine how these moleculescontribute to the immunogenicity of non-small cell lung cancer which may facilitate the development of newimmunotherapies for this devastating disease. NCI 10750090 6/22/23 0:00 PA-21-050 1F30CA278494-01A1 1 F30 CA 278494 1 A1 "BIAN, YANSONG" 9/1/23 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 78122306 "ENGLANDER, RYAN " Not Applicable 5 MICROBIOLOGY/IMMUN/VIROLOGY 22254226 H6D6JMXJXDE6 22254226 H6D6JMXJXDE6 US 41.734182 -72.793791 1506603 UNIVERSITY OF CONNECTICUT SCH OF MED/DNT FARMINGTON CT SCHOOLS OF MEDICINE 60305335 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTNon-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the United States. Immunecheckpoint inhibitors (ICIs) like anti-PD-1 have increased overall survival in NSCLC but most patients still donot respond to treatment. Cancer vaccines that target tumor-specific antigens known as neoantigens mayincrease the efficacy of ICIs and other immunotherapies by expanding neoantigen-reactive CD8+ T cells thatcan recognize and destroy tumor cells. Alternative splicing is a ubiquitous post-transcriptional regulatory processthat allows cells to produce different mRNA and protein sequences from the same gene. Alternative splicing isbroadly dysregulated in many cancer types including NSCLC and may generate novel peptide sequences absentfrom normal tissue that can be recognized as neoantigens by CD8+ T cells. To identify alternative splicing-derived neoantigens in NSCLC we used long-read RNA sequencing to comprehensively map full-length mRNAisoforms in NSCLC tumors and predict the proteins they encode with high accuracy. We found 145914 predictedpeptides that were specific to tumors and shared by up to 70% of NSCLC patients. To identify which of thesepeptides might be immunogenic we used immunopeptidomics to directly sequence peptides bound to MHCClass I in three NSCLC cell lines. We identified 21 peptides that are bound to MHC Class I on NSCLC cells andare encoded by tumor-specific alternatively spliced mRNA isoforms. These splicing-derived peptides arepotentially shared neoantigens that might represent vaccine targets for NSCLC. Therefore Aim 1 will testwhether any of these 21 splicing-derived peptides can be recognized by CD8+ T cells from NSCLC patients. Wewill examine whether patient CD8+ T cells can proliferate secrete cytokines like interferon-gamma and lysetarget cells in response to these peptides. The experiments proposed in Aim 1 will provide crucial insight into thefrequency and immunogenicity of alternative splicing-derived neoantigens in NSCLC. Aim 2 will examine whichregulators of alternative splicing are driving production of these peptides. To this end we will leverage publiclyavailable databases to identify splicing factors whose expression in tumors or target binding sites suggest anassociation with the mRNA isoforms that code for the 21 splicing-derived peptides. We will use targeted geneticapproaches to study whether candidate splicing factors directly regulate peptide-coding isoform splicing in vitro.This work will highlight mechanisms that can drive the production of tumor-specific splicing-derived peptides andmay reveal novel targets that can be exploited to enhance NSCLC immunogenicity. Altogether these studiesmay identify candidates for new immunotherapies including personalized NSCLC cancer vaccines that can beused to treat multiple patients who share expression of immunogenic splicing-derived neoantigens. This proposalwill provide me excellent training that will facilitate my career goals as a physician-scientist who leveragesadvances in genomics and immunology to improve care for patients with cancer. 52694 +No NIH Category available Academia;Agreement;Area;Atmosphere;Behavior;Biology;Biomedical Research;Career Mobility;Centromere;Chromatin;Chromosome Segregation;Chromosome Structures;Chromosome abnormality;Chromosomes;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Counseling;Curiosities;DNA;DNA Sequence Alteration;Development;Discipline;Disease;Elements;Environment;Enzymes;Epigenetic Process;Feedback;Fostering;France;Future Generations;Genome;Goals;Health;Homeostasis;Human;Image;Immune system;Interdisciplinary Study;International;Investigation;Italy;Life;Malignant Neoplasms;Meiosis;Mentors;Mentorship;Microscopy;Mind;Mission;Mutation;Organism;Participant;Physical condensation;Postdoctoral Fellow;Prevention;Process;Productivity;Prokaryotic Cells;Research;Research Personnel;San Francisco;Science;Scientist;Structure;Students;Switzerland;System;Technology;Twin Multiple Birth;Universities;Woman;Work;Xenopus;anticancer research;biophysical analysis;biophysical techniques;cancer therapy;career;chromosome replication;cohesin;cohesion;condensin;coral;daughter cell;egg;genome editing;insight;interdisciplinary collaboration;lectures;meetings;men;molecular dynamics;molecular scale;multidisciplinary;peer;posters;prevent;repaired;segregation;single molecule;symposium;telomere;transmission process;tumorigenesis;ultra high resolution 2023 Chromosome Dynamics Gordon Research Conference and Seminar Project NarrativeChromosome aberrations including DNA mutation and altered chromosome number are a hallmark ofcancer but our understanding of the basic biology of chromosomes is incomplete. In order to beaccurately transmitted to daughter cells the DNA on chromosomes must be replicated and partitionedand all damage to chromosomes repaired to prevent mutations. This meeting brings togetherresearchers from all areas of chromosome biology to discuss their research exchange ideas andestablish collaborations that will enable the prevention and treatment of cancer. NCI 10750086 6/22/23 0:00 PA-21-151 1R13CA284570-01 1 R13 CA 284570 1 "SHARMAN, ANU" 6/16/23 0:00 5/31/24 0:00 ZCA1-PCRB-9(M1) 11418424 "BELL, STEPHEN DAVID" Not Applicable 2 Unavailable 75712877 XL5ANMKWN557 75712877 XL5ANMKWN557 US 41.480003 -71.569648 2988701 GORDON RESEARCH CONFERENCES East Greenwich RI Domestic For-Profits 28183465 UNITED STATES N 6/16/23 0:00 5/31/24 0:00 398 Other Research-Related 2023 16000 NCI 16000 0 AbstractThe 2023 Gordon Research Conference on Chromosome Dynamics organized by Camilla Bjorkegren andStephen D Bell will present cutting edge research on chromosome biology. Chromosomes carry theblueprint of life and aberrations in their structure and function is central to the development of cancer. Thisinternational meeting will be held in Il Ciocco Italy from June 25-30 2023. The twin objectives of thisconference are to foster exchange of the information and ideas and to encourage new interdisciplinarycollaborations. Approximately 175 researchers from the various chromosome sub-disciplines will bebrought together. The meeting will feature 3 keynote speakers including two well-established leaders inthe field: Dr. Susan Gasser (ISREC Switzerland) and Dr. Geeta Narlikar (UC San Francisco USA) as wellas an emerging leader Dr. Romain Koszul (Inst. Pasteur France). Podium presentations will featureinvited internationally-renowned experts as well as younger scientists whose work will be selected fromthe submitted abstracts. Eight additional platform sections covering all major aspects of chromosomes willbe held including chromosome structure and organization cohesion and condensation centromeres andtelomeres chromosome segregation meiosis and chromosome replication and repair. This meeting isrelevant to the NCI mission because of its emphasis on basic chromosome biology many aberrations ofwhich are central to the development of cancer. Junior scientists will also have the possibility to attend atwo-day Gordon Research Seminar (GRS) preceding the GRC organized by Coral Zhou. The GRS willfeature a keynote lecture by Dr. Wendy Bickmore (University of Edinburgh) two sessions with 16 talks bytrainees selected from abstracts and two poster sessions. There will also be an additional mentorshipsession where invited mentors representing a broad range of scientific careers will provide counsel fortrainees through self-selected small group discussions. We anticipate that the intense scientific andmentoring interactions during both the GRS and GRC will impact cancer research in many significant waysand help establish productive multidisciplinary research collaborations and further the careers of trainees. 16000 +No NIH Category available Address;Animal Model;Astrocytes;Astrocytoma;Biological;Biological Assay;Cell Line;Cell Proliferation;Cells;Central Nervous System Neoplasms;ChIP-seq;Characteristics;Citric Acid Cycle;Clinical Trials;CpG Islands;Critiques;DNA;DNA Methylation;DNA methylation profiling;Data;Decarboxylation;Dioxygenases;Disadvantaged;Electroporation;Enzyme Inhibition;Enzymes;Epigenetic Process;FRAP1 gene;Funding;Gene Expression;Genes;Genetic;Genomics;Glioma;Glucose;Glutamine;Goals;Grant;Histones;Human;Hypermethylation;In Vitro;Isocitrate Dehydrogenase;Isocitrates;Isotopes;Knowledge;Link;Loss of Heterozygosity;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Mediating;Medical;Metabolic;Metabolic Pathway;Metabolism;Methylation;Modeling;Molecular;Mus;Mutate;Mutation;Newly Diagnosed;Outcome;PIK3CG gene;PTEN gene;Phenotype;Physicians;Prognosis;Proteins;Proto-Oncogene Proteins c-akt;Published Comment;Regulation;Research;Role;Scientist;Signal Transduction;Testing;Therapeutic;Training;Translating;Tumor Suppressor Proteins;Tumorigenicity;Work;alpha ketoglutarate;bisulfite;career;cell type;cellular engineering;clinical heterogeneity;curative treatments;demethylation;effective therapy;epigenome;experimental study;genome-wide;histone demethylase;histone methylation;in utero;in vivo;inhibitor;knock-down;mutant;nervous system disorder;new therapeutic target;next generation sequencing;novel;prognostic;programs;protein expression;targeted treatment;therapeutic candidate;therapeutic development;transcriptome sequencing;tumor;tumor growth The role of PTEN in epigenetic and metabolic regulation of IDH-mutant gliomas PROJECT NARRATIVEAstrocytomas are a deadly and intractable form of brain cancer that frequently bear mutations in the TCAcycle-related gene isocitrate dehydrogenase 1 (IDH1m). A subset of these tumors bears grim prognoses anddemonstrate lowered levels of DNA methylation. This study aims to (1) determine how epigenetic andmetabolic processes are altered in IDH1m astrocytomas and (2) develop targeted strategies for more efficienttreatment of these tumors. NCI 10750036 7/10/23 0:00 PA-21-051 1F31CA278378-01A1 1 F31 CA 278378 1 A1 "SCHMIDT, MICHAEL K" 8/1/23 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15156924 "HAGGERTY-SKEANS, JAMES ROBERT" Not Applicable 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 40384 NCI 40384 0 ABSTRACTAstrocytic tumors of the central nervous system (CNS) are intractable tumors and harbor dismal outcomes dueto a lack of targeted treatment options. More than 70% of astrocytic tumors bear mutations in the TCA cycle-related gene isocitrate dehydrogenase 1 (IDH1). Wildtype IDH1 catalyzes the oxidative decarboxylation ofisocitrate to generate -Ketoglutarate (KG) while mutated IDH1 (IDH1m) metabolizes KG into theoncometabolite D-2-hydroxyglutarate (D2HG). Several epigenetic dioxygenases including histone and DNAdemethylases require KG to demethylate histone residues and DNA CpG islands. D2HG competitivelyinhibits these enzymes due to its structural similarity to KG. This results in an increase in histone and DNAmethylation referred to as the glioma-CpG island methylation phenotype (G-CIMP). However DNA methylationG-CIMP levels are not uniform in IDH1m astrocytomas. IDH1m astrocytomas with low versus high levels of G-CIMP bear a particularly grim prognosis. My preliminary data identifies PTEN loss of heterozygosity (LOH) asthe top genetic alteration in G-CIMP low versus G-CIMP high tumors. Moreover PTEN LOH independentlyrelated with a poor prognosis. However it remains unknown how PTEN LOH drives tumorigenicity in IDH1mastrocytomas. Our premise is based on the observation that PTEN is a critical tumor suppressor. In othercancers PTEN LOH activates PI3-kinase (PI3K)/AKT-mTOR signaling to drive tumor growth through variousmechanisms including metabolic reprogramming. My preliminary data demonstrates increased cell proliferationin IDH1m astrocytic cell lines with partial PTEN knockdown (KD) accompanied by a reduction in D2HG levels.Based on my premise and preliminary data I hypothesize that PTEN LOH activates PI3K/AKT-mTOR signalingto metabolically reprogram IDH1m astrocytomas to reduce D2HG levels and thereby mediate lowered DNAmethylation and G-CIMP levels. Subsequently targeting PI3K/AKT-mTOR signaling represents a promisingcandidate for therapeutic development. To test this hypothesis I propose two specific aims. Aim 1 will mapalterations in metabolic pathways that generate D2HG in human and murine-derived IDH1m astrocytomas withor without PTEN reduction using a novel in-utero electroporation (IUE) Pten +/- IDH1m model. In parallel I willassess corresponding genome wide epigenetic alterations including DNA methylation using next generationsequencing-based epigenetic assays in relation to changes in gene expression. Aim 2 will determine iftargeting PTEN LOH-driven PI3K/AKT-mTOR activation is therapeutic in vitro and proof-of-principle in animalmodels. Together my work will address a critical gap in our knowledge by defining how PTEN LOH drives asubset of aggressive IDH1m astrocytomas via metabolic reprograming and lay the groundwork for developingtargeted and effective therapies for malignant IDH1m astrocytomas. 40384 +No NIH Category available Address;American Cancer Society;Area;Attention;Award;Awareness;Back;Cancer Center;Cancer Control;Cancer Patient;Cancer Science;Cancer Survivorship;Cancer health equity;Caregivers;Collaborations;Communities;Community Actions;Complex;Consensus;Data;Data Collection;Diagnosis;Disparity;Epidemiology;Fees;Funding;Future;Gender Identity;Geography;Health;Individual;Infrastructure;Intervention;Lesbian Gay Bisexual Transgender;Lesbian Gay Bisexual Transgender Intersex;Level of Evidence;Los Angeles;Malignant Neoplasms;Medical center;Mentorship;Minority;Modeling;Modification;Names;National Cancer Institute;National Institute on Minority Health and Health Disparities;New York;New York City;Participant;Patients;Peer Review;Persons;Policies;Population;Populations at Risk;Professional Organizations;Publications;Recording of previous events;Research;Research Methodology;Research Personnel;Research Priority;Risk Factors;Safety;Science;Scientist;Screening for cancer;Sex Orientation;Sexual and Gender Minorities;Structure;Survivors;Techniques;Training;Travel;United States National Institutes of Health;Universities;Work;anticancer research;cancer diagnosis;cancer health disparity;cancer prevention;cancer risk;community engagement;community organizations;cost;disparity reduction;experience;gender minority community;gender minority group;innovation;interest;intersectionality;lifetime risk;meetings;member;minority stress;novel;novel strategies;posters;social;symposium;transgender The Science of Cancer Health Equity for Sexual and Gender Minority Communities NARRATIVESexual and gender minority people experience many disparities before during and after a diagnosis of cancer.New research is needed to reduce these disparities and new scientists need to be trained and supported inconducting this research. We will host a two-and-a-half day conference to bring together experiencedresearchers trainees and early-stage investigators interested in working to address sexual and gender minoritycancer disparities so that we can chart a course forward for research in this area. NCI 10749970 9/22/23 0:00 PA-21-151 1R13CA284572-01 1 R13 CA 284572 1 "DEAN, DAVID WORTH" 9/22/23 0:00 8/31/24 0:00 ZCA1-PCRB-9(M1) 10552100 "KAMEN, CHARLES STEWART" "QUINN, GWENDOLYN P" 25 SURGERY 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 32500 OD 15000 0 ABSTRACTSexual and gender minority people (SGM) experience multiple cancer-related disparities including higher ratesof cancer risk factors lower rates of cancer screening higher lifetime risk of cancer and unmet needs duringcancer survivorship. Although many national organizations including the National Cancer Institute (NCI) and theAmerican Cancer Society (ACS) have stated the need for more cancer research among SGM communitiesthere is currently no consensus about the highest research priorities promising research models or mechanismsfor collaboration between geographically dispersed scientific teams. To address this gap we propose a two-and-a-half day conference focused on the Science of Cancer Health Equity for SGM Communities. Thisconference will bring together researchers trainees early-stage investigators and community stakeholders toreview the current science on cancer health equity for SGM persons identify high-priority research topics anddevelop novel approaches to engage communities and influence policy. The conference will be held at the NewYork University (NYU) Langone Medical Center Campus in New York City from October 5-7 2023. It is structuredaround a transdisciplinary framework: looking within across and between areas of scientific expertise andcommunity wisdom to establish priorities. In line with this framework we have convened a conference organizingcommittee comprising two MPIs representatives from 7 cancer centers and a SGM Community Action Boardwith strong support from SGM community organizations such as the National LGBT Cancer Network.Support from the NCI R13 mechanism (PA-21-151) is needed to cover speaker fees as well as travel costsfor trainees early-stage investigators patients and community participants. The aims of this conferenceare: 1) to examine the current level of evidence informing research across the cancer control continuum forSGM cancer patients survivors and caregivers; 2) to establish future research priorities across the cancercontrol continuum for SGM cancer patients survivors and caregivers; 3) to promote the research of traineesand early stage investigators especially those from minoritized backgrounds interested in research acrossthe cancer control continuum for SGM communities; 4) to develop a transdisciplinary network of scholarswith a focus on mentorship and on shared research methods that can address cancer health equity across thecancer control continuum; 5) to disseminate findings from this conference including priorities for future SGMcancer health equity research through a publicly available executive summary and a peer-reviewed openaccess publication. If funded this conference will produce: (a) a publicized list of SGM cancer health equityresearch priorities and (b) a network of transdisciplinary researchers and community members ready tocollaborate on projects addressing these priorities. This R13 award will also help us create an infrastructurefor future conferences to continue this work with the next hosted by Cedars Sinai in Los Angeles in 2024. 15000 +No NIH Category available Address;American Cancer Society;Area;Attention;Award;Awareness;Back;Cancer Center;Cancer Control;Cancer Patient;Cancer Science;Cancer Survivorship;Cancer health equity;Caregivers;Collaborations;Communities;Community Actions;Complex;Consensus;Data;Data Collection;Diagnosis;Disparity;Epidemiology;Fees;Funding;Future;Gender Identity;Geography;Health;Individual;Infrastructure;Intervention;Lesbian Gay Bisexual Transgender;Lesbian Gay Bisexual Transgender Intersex;Level of Evidence;Los Angeles;Malignant Neoplasms;Medical center;Mentorship;Minority;Modeling;Modification;Names;National Cancer Institute;National Institute on Minority Health and Health Disparities;New York;New York City;Participant;Patients;Peer Review;Persons;Policies;Population;Populations at Risk;Professional Organizations;Publications;Recording of previous events;Research;Research Methodology;Research Personnel;Research Priority;Risk Factors;Safety;Science;Scientist;Screening for cancer;Sex Orientation;Sexual and Gender Minorities;Structure;Survivors;Techniques;Training;Travel;United States National Institutes of Health;Universities;Work;anticancer research;cancer diagnosis;cancer health disparity;cancer prevention;cancer risk;community engagement;community organizations;cost;disparity reduction;experience;gender minority community;gender minority group;innovation;interest;intersectionality;lifetime risk;meetings;member;minority stress;novel;novel strategies;posters;social;symposium;transgender The Science of Cancer Health Equity for Sexual and Gender Minority Communities NARRATIVESexual and gender minority people experience many disparities before during and after a diagnosis of cancer.New research is needed to reduce these disparities and new scientists need to be trained and supported inconducting this research. We will host a two-and-a-half day conference to bring together experiencedresearchers trainees and early-stage investigators interested in working to address sexual and gender minoritycancer disparities so that we can chart a course forward for research in this area. NCI 10749970 9/22/23 0:00 PA-21-151 1R13CA284572-01 1 R13 CA 284572 1 "DEAN, DAVID WORTH" 9/22/23 0:00 8/31/24 0:00 ZCA1-PCRB-9(M1) 10552100 "KAMEN, CHARLES STEWART" "QUINN, GWENDOLYN P" 25 SURGERY 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 32500 NCI 17500 0 ABSTRACTSexual and gender minority people (SGM) experience multiple cancer-related disparities including higher ratesof cancer risk factors lower rates of cancer screening higher lifetime risk of cancer and unmet needs duringcancer survivorship. Although many national organizations including the National Cancer Institute (NCI) and theAmerican Cancer Society (ACS) have stated the need for more cancer research among SGM communitiesthere is currently no consensus about the highest research priorities promising research models or mechanismsfor collaboration between geographically dispersed scientific teams. To address this gap we propose a two-and-a-half day conference focused on the Science of Cancer Health Equity for SGM Communities. Thisconference will bring together researchers trainees early-stage investigators and community stakeholders toreview the current science on cancer health equity for SGM persons identify high-priority research topics anddevelop novel approaches to engage communities and influence policy. The conference will be held at the NewYork University (NYU) Langone Medical Center Campus in New York City from October 5-7 2023. It is structuredaround a transdisciplinary framework: looking within across and between areas of scientific expertise andcommunity wisdom to establish priorities. In line with this framework we have convened a conference organizingcommittee comprising two MPIs representatives from 7 cancer centers and a SGM Community Action Boardwith strong support from SGM community organizations such as the National LGBT Cancer Network.Support from the NCI R13 mechanism (PA-21-151) is needed to cover speaker fees as well as travel costsfor trainees early-stage investigators patients and community participants. The aims of this conferenceare: 1) to examine the current level of evidence informing research across the cancer control continuum forSGM cancer patients survivors and caregivers; 2) to establish future research priorities across the cancercontrol continuum for SGM cancer patients survivors and caregivers; 3) to promote the research of traineesand early stage investigators especially those from minoritized backgrounds interested in research acrossthe cancer control continuum for SGM communities; 4) to develop a transdisciplinary network of scholarswith a focus on mentorship and on shared research methods that can address cancer health equity across thecancer control continuum; 5) to disseminate findings from this conference including priorities for future SGMcancer health equity research through a publicly available executive summary and a peer-reviewed openaccess publication. If funded this conference will produce: (a) a publicized list of SGM cancer health equityresearch priorities and (b) a network of transdisciplinary researchers and community members ready tocollaborate on projects addressing these priorities. This R13 award will also help us create an infrastructurefor future conferences to continue this work with the next hosted by Cedars Sinai in Los Angeles in 2024. 17500 +No NIH Category available ATP Synthesis Pathway;Acute;Antidiabetic Drugs;Biochemical;Biochemistry;Bioenergetics;Biological Assay;Biomass;Cancer cell line;Carbon;Cell Proliferation;Cells;Chemicals;Citric Acid Cycle;Clinical;Complex;Consumption;Data;Development Plans;Doctor of Philosophy;Electron Transport;Environment;Enzymes;Equilibrium;FDA approved;Genetic;Glucose;Glycolysis;Goals;Growth;Image;In Vitro;Knock-out;Knowledge;Laboratory Research;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Memorial Sloan-Kettering Cancer Center;Mentorship;Metabolic;Metabolism;Methods;Mitochondria;Nutrient;Organelles;Oxidative Phosphorylation;Permeability;Phenformin;Phosphorylation Inhibition;Physicians;Postdoctoral Fellow;Production;Proliferating;Proteins;Pyruvate;Regulation;Reporter;Research;Scientist;Serum;Source;Therapeutic;Training;Universities;Warburg Effect;aerobic glycolysis;cancer cell;cancer therapy;career development;clinical training;design;extracellular;imaging modality;in vivo;inhibitor;insight;liquid chromatography mass spectrometry;medical schools;metabolomics;novel;oxidation;patient derived xenograft model;research and development;response;skills;tumor;tumor metabolism;tumor microenvironment Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer PROJECT NARRATIVECancer cells are addicted to glucose but only to secrete the majority as lactate (also known as aerobicglycolysis or Warburg effect) thereby creating an inhospitable glucose-poor and lactate-rich microenvironmentthat would otherwise be lethal to most cells. This application is designed to mechanistically investigate howlactate regulates cancer cell glucose utilization and to assess the therapeutic potential of targeting cancerlactate oxidation. The results from this study will provide knowledge in the regulation of central carbonmetabolism and insight into the targeting lactate oxidation as a cancer therapy. NCI 10749952 11/20/23 0:00 RFA-CA-20-014 5R00CA256505-04 5 R00 CA 256505 4 "O'HAYRE, MORGAN" 1/1/23 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 15340094 "CAI, XIN " Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 169777 NCI 143671 80429 PROJECT SUMMARY/ABSTRACTGlucose is an essential fuel for cancer cell proliferation in serving both as a substrate for ATP production andas an irreplaceable carbon source for biomass accumulation. Cancer cells are especially addicted to glucosebut only to secrete the majority as lactate (known as aerobic glycolysis or Warburg effect) thereby creating aninhospitable glucose-poor and lactate-rich microenvironment that would otherwise be lethal to most cells.However cancer cells can efficiently use the limiting glucose and excess lactate for unlimited growth throughunclear mechanisms. My preliminary data revealed that in low glucose conditions extracellular lactateenhances cancer cell proliferation. Mechanistically I found that lactate preferentially enters the mitochondriaTCA cycle over glucose to increase oxidative phosphorylation (OXPHOS) activity which in turn suppressesglycolysis to conserve extracellular glucose suggesting cancer cells rely on lactate-induced OXPHOS foroptimal growth. The proposed studies are aimed at mechanistically dissecting the metabolic interplay betweenlactate-mediated mitochondrial OXPHOS and glycolysis (Aim 1 & 3) and assessing therapeutic potential oftargeting lactate oxidation in cancer (Aim 2). The following specific aims are being pursued: Aim 1. Determinehow lactate-mediated increase in OXPHOS suppress glycolysis; Aim 2. Assess the in vivo therapeuticpotential of targeting lactate oxidation using Phenformin; Aim 3. Mechanistically dissect how cells distinguishand preferentially use extracellular lactate over glucose for entry into TCA cycle. The knowledge and scientificexpertise gained through these studies will facilitate my transition to independence with my long-term goal tostudy and target metabolic vulnerabilities in cancer as a physician scientist.In addition to the scientific goals I have also outlined a detailed career development plan in this application toobtain skills that are necessary for leading an independent research laboratory. The proposed research andtraining plan will be conducted under the mentorship of Dr. Craig Thompson. Memorial Sloan-KetteringCancer Center along with the nearby Rockefeller University and Weill Cornell Medical College will provide theideal academic environment to achieve these goals for me to transition to independence. 169777 +No NIH Category available Address;Aftercare;Biological Models;Biopsy;Blood Banks;CRISPR library;Cancer Patient;Cancer cell line;Candidate Disease Gene;Cause of Death;Cell Line;Cervical;Chemotherapy and/or radiation;Clinic;Clinical;Clonal Expansion;Custom;DNA Library;DNA Sequence Alteration;Data;Databases;Dimensions;Drug Screening;Evolution;Fistula;Freezing;Fresh Tissue;Future;Gene Pool;Genes;Hemorrhage;Immune;In Vitro;Institution;Laboratories;Libraries;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Modeling;Mutate;Mutation;Organoids;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Population;Precision therapeutics;Prognostic Marker;Publishing;Qualifying;Radiation-Sensitizing Agents;Radiosensitization;Recording of previous events;Relapse;Resistance;Risk;Sampling;Swab;Techniques;Testing;Tissue Banks;Tissues;Translating;Treatment outcome;Woman;biobank;candidate validation;cell bank;chemoradiation;clinical translation;cohort;computational pipelines;driver mutation;exome sequencing;experience;genetic testing;high risk;human tissue;improved;in vitro testing;large-scale database;microbiome;new therapeutic target;novel;patient population;predictive marker;radiation resistance;radiation response;research clinical testing;response;risk variant;screening;single-cell RNA sequencing;standard of care;targeted agent;targeted treatment;therapeutically effective;tumor;tumorigenesis Identifying Novel Radiation Sensitizers in Cervical Cancer Project NarrativeThis project aims to validate potential targets for chemoradiation sensitization in patients with cervical cancerundergoing chemoradiation for cure. This will be accomplished by testing previously identified potential targetsin cervical cancer cell lines and organoid models and by computationally validating mutations that expandduring CRT in patients undergoing treatment. This proposal uses a novel non-invasive swab-based biopsymethod to collect serial data without harm or discomfort to patients which is the first approach in cervicalcancer. NCI 10749921 11/15/23 0:00 PAR-20-292 5R21CA277332-02 5 R21 CA 277332 2 "PRASANNA, PAT G" 12/7/22 0:00 11/30/24 0:00 ZCA1-TCRB-9(O1)S 11517691 "COLBERT, LAUREN ELIZABETH" Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 170405 NCI 105188 65217 Project SummaryCervical cancer remains a significant global cause of death in women and 40% of women with cervical cancerwill relapse and die despite chemoradiation treatment. There is an urgent need to identify prognostic andpredictive biomarkers for chemoradiation response. We have developed and optimized a novel non-invasiveswab-based biopsy approach to collect tissue before during and after chemoradiation without patient discomfortor risks of serial biopsies such as bleeding or fistula. Despite low tumor purity we have also developed a customcomputational pipeline to optimize mutation calling and identify clonally expanded mutations duringchemoradiation. Developing a deep understanding of genomic alterations during and after CRT to these findingswill help fast-track clinical translation of targeted therapies. To this end we have used our pipeline in a pilot studyof 70 patients to reconstruct the evolution of mutations during CRT and identify proliferatively advantageousdriver mutations and pathways. This proposal aims to validate the candidate driver mutation lists in multipledimensions and develop a patient-derived organoid platform to test potential targeted therapies. First we willvalidate the preliminary identified clonally expanded genes and pathways in a larger population of alreadycollected but yet-to-be-sequenced samples. Second we will perform a CRISPR/Cas9 library screen of thesepreliminarily identified drivers in available cervical cancer cell lines. Simultaneously we will develop a cervicalcancer organoid biobank to perform single-cell RNA sequencing before and after CRT and validate thesepreliminarily identified genes. This platform will be used in the future to test targeted agents. When we completethe aims of this R21 we will have validated ideal targets developed testing platforms and set the stage fortesting clinically impactful therapies in a future R01. 170405 +No NIH Category available Active Sites;Address;Adhesives;Adoptive Cell Transfers;Adoptive Transfer;Advanced Malignant Neoplasm;Agonist;Antibodies;Antigens;Antineoplastic Agents;Apoptosis;Biological Markers;Blood;Blood flow;Breast Cancer Model;Breast Melanoma;CD3 Antigens;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cell Communication;Cells;Cellular immunotherapy;Clinical;Clinical Trials;Cluster Analysis;Coculture Techniques;Complex;Cytotoxic T-Lymphocytes;Data;Destinations;Disseminated Malignant Neoplasm;Effector Cell;Equilibrium;Exclusion;Foundations;Genetic;Home;Homing;Human;ICAM2 gene;Immune;Immune checkpoint inhibitor;Immunity;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Integrins;Intercellular adhesion molecule 1;L-Selectin;Laboratories;Leukocytes;Ligands;Liver X Receptor;Lymphocyte;Lymphocyte Homing Receptors;Malignant Neoplasms;Mammary Neoplasms;Mediating;Memory;Metastatic breast cancer;Modeling;Mus;Myeloid Cell Suppression;Myeloid Cells;Myeloid-derived suppressor cells;Natural Immunity;Natural Killer Cells;Outcome;Patient Selection;Patients;Population;Pre-Clinical Model;Publishing;Regimen;Research;Residual state;Resistance;Site;Solid;Solid Neoplasm;Spleen;Splenectomy;Structure;Suppressor-Effector T-Lymphocytes;System;T cell response;T cell therapy;T memory cell;T-Lymphocyte;Testing;Therapeutic;Tissues;Travel;Treatment Efficacy;Tumor Immunity;Work;adaptive immunity;anti-cancer;blood-based biomarker;cancer immunotherapy;cancer therapy;checkpoint inhibition;chemokine;clinically relevant;cytotoxic CD8 T cells;defined contribution;fitness;genetic approach;human cancer mouse model;improved;in vivo;insight;interest;lymph nodes;lymphoid organ;melanoma;microscopic imaging;mouse model;new therapeutic target;novel;patient response;preconditioning;predicting response;predictive signature;prevent;prognostic indicator;prognostication;programs;receptor;recruit;resistance mechanism;response;stem cells;therapy resistant;trafficking;tumor;tumor microenvironment Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity Project NarrativeImmunosuppressive myeloid cells are recognized as a significant barrier to the efficacy of immunotherapies incancer patients although their precise site of action is not fully understood. Our laboratory discovered thatmyeloid cells interact with anticancer immune cells directly within the blood forming previously unrecognizedcirculating myeloid cell (CMC) clusters that we propose instigate global immune suppression. Our proposedresearch has the potential to define CMC clusters as a novel mechanism of immune suppression therebyimplicating these cellular conjugates as a blood-based biomarker to guide treatment decisions to improve patientresponses to anticancer agents. NCI 10749915 12/18/23 0:00 PA-19-056 5R01CA250412-04 5 R01 CA 250412 4 "KUO, LILLIAN S" 1/1/21 0:00 12/31/25 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 1899932 "EVANS, SHARON S" "ABRAMS, SCOTT I." 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 627450 NCI 376452 250998 Durable outcomes in subsets of solid cancer patients treated with immune checkpoint inhibitors (ICI) or adoptivecell transfer (ACT) immunotherapy has driven interest in gaining a better understanding of resistancemechanisms that could identify novel druggable targets. Myeloid-derived suppressor cells (MDSC) haveemerged as one such barrier based on their ability to inhibit innate and adaptive immunity. While elevated bloodMDSC are recognized as a poor prognostic indicator in cancer patients it is widely thought that the main effectorsite for MDSC is within the tumor microenvironment (TME). This is in line with the well-documented contact-dependent mechanisms involving short-lived intermediates that underlie known mechanisms of T cellsuppression by MDSC. Our published and preliminary studies enlarge on this view showing that MDSC alsofunction outside the TME through an unprecedented mechanism of intravascular immune suppression. Theproposed study builds on our discovery that circulating MDSC initiate contact-dependent cleavage of the L-selectin homing receptor on target T cells that substantially reduces antigen-driven expansion of cytotoxic T cellsin lymph nodes. We further found that L-selectin loss coincides with the formation of stable MDSC clusters in theblood of murine tumor models and advanced cancer patients. We term these new structures circulating myeloidcell (CMC) clusters. These observations led us to hypothesize that CMC clusters are an unrecognized functionalniche for systemic immune suppression in cancer. To test this hypothesis we will first determine if blood-borneMDSC target not only nave T cells but more broadly attack stem cell memory and central memory T cells andnatural killer cells that each require L-selectin for their antitumor activity. Secondly we will determine if CMCclusters are the active site of L-selectin cleavage by using a multipronged genetic approach to examine L-selectinfate following disruption of MDSC-T cell conjugate formation in vivo. These mechanistic studies center on 2integrins that are highly expressed by MDSC but are normally inactive on leukocytes in fast-flowing blood undernon-pathological conditions. Thirdly we will examine the translational relevance of CMC clusters during ICI orACT therapy in a preclinical model in which blood is the primary effector site for MDSC due to their exclusionfrom the TME (by blocking chemokine-directed trafficking) and spleen (by splenectomy). We will depletecirculating MDSC in this model using antibodies or a clinically relevant liver-X-receptor agonist that inducesMDSC-intrinsic apoptosis to establish if blood-borne MDSC contribute to therapeutic resistance. Complementarystudies will test the hypothesis that combining the analysis of circulating MDSC with CMC clusters and/or T cellL-selectin will formulate an immunosuppressive signature that predicts response to first-line therapy in metastaticcancer patients. The proposed studies will provide new insights into an unprecedented function of circulatingmyeloid cells and could lead to the consideration of CMC clusters as a functional biomarker for prognosticationor preselection of patients that would benefit from MDSC-depleting regimens during cancer immunotherapy. 627450 +No NIH Category available Acetoacetates;Acids;Adult;Agonist;Antibodies;Apoptosis;Attenuated;BRAF gene;Binding;Binding Proteins;Blood;Breast Cancer Cell;Butter;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cancer Patient;Cell Proliferation;Cell Survival;Chemicals;Chondroitin Sulfates;Clinical;Colon Carcinoma;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cyclic AMP-Responsive DNA-Binding Protein;DNA sequencing;Dairy Products;Data;Diet;Dietary Proteins;Eating;Elements;Enhancers;Epigenetic Process;Exhibits;FFAR2 gene;Foundations;G-Protein-Coupled Receptors;Genetic Transcription;Hippophae;Human;Human Milk;Immune;Immune checkpoint inhibitor;Immune response;Immunologics;Immunotherapy;In Vitro;Ketone Bodies;Knockout Mice;Lewis lung carcinoma cell;Libraries;Link;Lipids;MC38;Malignant Neoplasms;Milk;Mus;Nude Mice;Nutrient;Nutrition Therapy;Oils;Outcome;PD-1/PD-L1;Pathway interactions;Periodicity;Population;Recovery;Research Activity;Signal Transduction;Signaling Molecule;Single-Stranded DNA;Stereoisomer;Structure;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;Testing;Trans Fatty Acids;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Volatile Fatty Acids;Work;Xenograft procedure;cancer infiltrating T cells;cancer initiation;cancer risk;cancer therapy;checkpoint therapy;chemotherapy;design;diet and cancer;dietary;dietary supplements;exhaustion;extracellular;immunodeficient mouse model;immunogenic;improved;insight;interest;kethoxal;lung cancer cell;melanoma;meter;multidisciplinary;next generation sequencing;novel;programmed cell death ligand 1;programmed cell death protein 1;response;transcriptome;transcriptome sequencing;treatment response;tumor;tumor growth Dietary trans-vaccenic acid enhances anti-tumor immunity Project Narrative:Despite extensive studies on relationships between diets and cancer risk or many balanced nutrition therapieswith hope to keep cancer patients healthy and strong for treatment and recovery little is known about how dietarysubstances influence cancer and anti-cancer therapies. We thus constructed a blood chemical (BC) compoundlibrary which contains circulating diet-derived nutrients including inorganics organic metabolites lipids anddietary supplements and performed screens to identify BCs that influence responses to immune checkpointinhibitors (ICIs). In this proposal we hypothesize that dietary trans-vaccenic acid (TVA) the predominant formof trans fatty acids in human milk enhances activation of CD8+ T cells and consequent anti-tumor immunity. NCI 10749906 11/13/23 0:00 PA-20-185 5R01CA276568-02 5 R01 CA 276568 2 "XI, DAN" 12/7/22 0:00 11/30/27 0:00 Cancer Prevention Study Section[CPSS] 8238758 "CHEN, JING " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 337635 NCI 205875 131760 Project Summary/Abstract:Despite extensive studies on relationships between diets and cancer risk or many balanced nutrition therapieswith hope to keep cancer patients healthy and strong for treatment and recovery little is known about how dietarysubstances influence cancer. Our recent work supports a novel concept that acetoacetate a diet-derivedcirculating ketone body and chondroitin sulfate a dietary supplement function as signaling molecules andselectively promote BRAF V600E-expressing tumor growth. This lays the foundation for our central questionthat is: which circulating diet-derived substances - defined as blood chemicals commonly containing diet-derived nutrients including inorganics organic metabolites lipids dietary supplements and proteins - potentiateor attenuate cancer initiation progression or responses to anti-cancer therapies and how? We thus constructeda blood chemical (BC) compound library and performed two preliminary screens to identify BCs that influenceresponses to immune checkpoint inhibitors (ICIs). We identified trans-vaccenic acid (TVA; a.k.a. (11E)-octadec-11-enoic acid) as an overlapping top candidate from both screens which not only enhances activation of Tcells but also rescues PD-L1/PD-1-dependent exhaustion of T cells. TVA is the predominant form of trans-fatty acids enriched in human milk while cis-vaccenic acid (CVA) a stereoisomer of TVA is found in SeaBuckthorn oil. TVA is also commonly found in dairy products including milk and butter. TVA is relatively stableand naturally only ~19% or 12% of dietary TVA is converted to rumenic acid in human or mice respectively.Using diverse immunogenic and immunodeficient mouse models we found that TVA but not CVA enhancesanti-tumor immunity via CD8+ T cells. Mechanistically TVA exhibits extracellular signaling function andenhances CD8+ T cell activation through a G-protein-coupled receptor (GPCR)-cAMP-responsive elementbinding protein (CREB) pathway. Moreover we identified immunosuppressive GPR43 a short chain fatty acid(SCFA)-binding GPCR as a target of TVA. Taken together we hypothesize that dietary TVA functions as asignaling molecule to potentiate activation of CD8+ T cells by attenuating GPR43 leading to enhanced anti-tumorimmunity. Thus TVAs effects on T cells are independent of the PD-L1/PD1 axis providing a perfect rationale toevaluate potentially synergistic efficacy of TVA in combination with immune checkpoint therapy for an improvedimmunotherapy. Three specific aims include: (1) To test the hypothesis that dietary TVA enhances CD8+ T cellactivity and consequent anti-tumor immunity as a single agent and has synergistic effects in combination withICIs; (2) To test the hypothesis that dietary TVA exhibits extracellular signaling function through a GPCR-CREBaxis for CD8+ T cell activation and explore the underlying signaling and epigenetic mechanisms by temporalintegrated mechanistic studies; and (3) To test the hypothesis that TVA attenuates GPR43 by competing with itsSCFA agonists and perform structure-activity research (SAR) to design TVA-derivatives with improved efficacyto target GPR43 and consequently activate CD8+ T cells. 337635 +No NIH Category available AXIN2 gene;BRAF gene;CRISPR interference;CTNNB1 gene;Cancer Biology;Cancer Etiology;Cancer Model;Cell Culture Techniques;Cell Line;Cell Proliferation;Cells;Cessation of life;Cholangiocarcinoma;Clinical Data;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal;Colorectal Cancer;Combined Modality Therapy;Complex;Data;Dependence;Development;Down-Regulation;Drug Combinations;Drug resistance;Engineering;Exposure to;Feedback;Gene Expression;Genes;Genetic Transcription;Genomic approach;Human;In Vitro;Individual;Inferior;KRAS oncogenesis;KRAS2 gene;LGR5 gene;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediator;Mitogen-Activated Protein Kinases;Modeling;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenes;Oncogenic;Organoids;Outcome;Output;PIK3CA gene;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphotransferases;Porcupines;Proliferating;Proteomics;Recurrence;Refractory;Regimen;Regulation;Resistance;Role;Signal Transduction;Skin;Tankyrase;Testing;Tissues;Toxic effect;Translations;Tumor Cell Line;United States;WNT Signaling Pathway;Work;cancer cell;cancer genomics;colon cancer cell line;colon cancer patients;colorectal cancer treatment;functional genomics;genomic data;improved;in vivo;inhibitor;interest;knock-down;melanoma;metastatic colorectal;mutant;new technology;novel strategies;novel therapeutics;patient derived xenograft model;patient population;programs;resistance mechanism;response;small molecule;small molecule inhibitor;synergism;systemic toxicity;targeted agent;targeted treatment;tool;transcription factor;treatment strategy;tumor;tumor growth Understanding intrinsic resistance to direct KRAS inhibition in colorectal cancers PROJECT NARRATIVECancers driven by the oncogene KRAS are responsible for more than 70000 deaths in the United Statesannually. Recently developed small molecules directly targeting the KRASG12C mutation have produced highresponse rates in patients with lung cancer but only show limited benefit for patients with colorectal cancer. Inthis proposal we study the signaling links between KRAS and the transcription factor CTNNB1 to understandthe mechanisms of resistance to KRAS inhibition in colorectal cancer and find new therapeutic combinations. NCI 10749899 12/14/23 0:00 PA-20-185 5R37CA266549-03 5 R37 CA 266549 3 "CHEN, WEIWEI" 1/1/22 0:00 12/31/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 11457512 "GORDAN, JOHN D" Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 471981 NCI 292248 179733 PROJECT SUMMARY/ABSTRACTMetastatic colorectal cancers (CRC) are the second leading cause of cancer death in the US. While advancesin targeted therapies have transformed the treatment of many cancers CRC has proven largely refractory to thisapproach. Thus while agents targeting BRAFV600E and the KRASG12C mutation have dramatically improved thetreatment of lung cancer and melanoma they have only shown limited impact in CRC.CTNNB1 transcription is upregulated in >75% of CRC via APC inactivation and other mutations. As CTNNB1 isa common mediator of drug resistance and has been shown to be sufficient to maintain CRC proliferation wehypothesize that it is a key mediator of intrinsic resistance to KRAS inhibition in CRC. Although multiple agentstarget CTNNB1 regulation via the WNT pathway these have proven too toxic for human use to date.Thus we have used proteomics to map the signaling response to KRASG12C inhibition in CRC cell lines andkinome-wide knockdown to identify kinases whose suppression synergizes with KRASG12C inhibition. Byintegrating these two approaches we were able to uncover several kinases that function as signaling linksbetween KRAS and CTNNB1 and whose inhibition synergizes with direct KRAS inhibition to reduce CTNNB1target gene expression. As KRASG12C inhibitors do not impact normal KRAS signaling this exciting preliminarydata suggests that we may be able to preferentially downregulate CTNNB1 in tumors without systemic toxicity.We will build on this key preliminary data in this project: In Aim 1 we will expand our analysis of the kinaseresponse to KRASG12C inhibition to additional CRC cell lines and the assess the impact of key kinases onCTNNB1 transcription. In Aim 2 we will use CRISPR in patient-derived xenografts (PDX) to circumvent thelimitations of available small molecules to validate the role of CTNNB1 in APC-mutant CRC PDX. We will furtheruse CRISPR or small molecules (when available) to test kinases already found to modulate CTNNB1 or emergingfrom Aim 1 in CRC treatment models and to determine their role in in vivo CRC biology. Finally in Aim 3 we willdevelop KRASG12C CRC organoid and cell line models with mutations in PIK3CA a common CRC mutation thatco-occurs with KRAS mutations and is likely to cause resistance to KRASG12C inhibitors but for which there areno models currently available. These tools will allow us to stratify the impact of PIK3CA mutation on our currenttreatment strategies and to optimize a regimen engineered specifically for this combination of mutations.This rigorous study of KRAS-driven signaling in CRC leverages new small molecules and robust quantitativeapproaches to unmask links between KRAS and the mechanisms that support CRC after KRAS inhibition.Uncovering the basis of resistance to direct KRAS inhibition in CRC will yield rational combination strategiesprimed for translation into clinical trials. 471981 +No NIH Category available Address;Amides;Anabolism;Antibiotics;Area;Bacterial Antibiotic Resistance;Bacterial Infections;Binding;Biological;Cell Wall;Cell surface;Clinic;Clinical;Cyclic Peptides;DNA Sequence Alteration;Development;Drug usage;Fermentation;Foundations;Glycopeptide Antibiotics;Gram-Negative Bacteria;Gram-Positive Bacteria;Grant;Guanidines;Improve Access;Ligands;Measures;Metabolic;Modeling;Modification;Molecular;Multi-Drug Resistance;Natural Products;Organism;Pathway interactions;Peripheral;Preparation;Public Health;Reaction;Reporting;Resistance;Resistance development;Series;Structure;Time;Vancomycin;Vancomycin Resistance;Vancomycin resistant enterococcus;Vancomycin-resistant S. aureus;Work;analog;antimicrobial;bacterial resistance;chloropeptin I;clinically significant;design;efflux pump;enzyme substrate;improved;in vivo;innovation;methicillin resistant Staphylococcus aureus;next generation;novel strategies;novel therapeutics;pathogen;pathogenic bacteria;preclinical evaluation;ramoplanin;rational design;resistance mechanism;therapy resistant Biologically Active Cyclic Peptides NarrativeFundamental new approaches and new therapeutics for the treatment of resistant bacterialinfections (MRSA VRSA and VRE) will emerge from the studies including the rational designof remarkably potent broad spectrum and especially durable antibiotics that possess multipleindependent synergistic mechanisms of action acting on a common pathway. A fundamentalunderstanding of the mechanism of action and the interaction of glycopeptide antibiotic naturalproducts and their analogs with their biological targets will be defined. NCI 10749893 11/30/23 0:00 PA-19-056 5R01CA041101-39 5 R01 CA 41101 39 "FU, YALI" 7/1/85 0:00 11/30/24 0:00 Synthetic and Biological Chemistry B Study Section[SBCB] 1865676 "BOGER, DALE L" Not Applicable 50 Unavailable 781613492 PHZJFZ32NKH4 781613492 PHZJFZ32NKH4 US 32.903062 -117.243592 7375802 "SCRIPPS RESEARCH INSTITUTE, THE" LA JOLLA CA Other Domestic Non-Profits 920371000 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 413606 NCI 213750 199856 Abstract. The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistantbacterial infections including methicillin-resistant S. aureus (MRSA). In fact even after 60 years of clinical usevancomycin administration in the clinic is still steadily increasing. Consequently the emergence of resistantGram-positive pathogens including vancomycin-resistant Enterococci (VRE) and vancomycin-resistant S.aureus (VRSA) presents a serious public health problem at a time few new antibiotics are being developed.These two pathogens rank 4th and 5th on the WHO global priority list of antibiotic-resistant bacteria for whichthere is an urgent need for new treatments. The only clinically significant mechanism of vancomycin resistanceis its induced late stage remodeling of the bacterial cell wall precursor termini from D-Ala-D-Ala (the target ofvancomycin) to D-Ala-D-Lac. Objectives of the work have included the redesign of vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding capable of treating both sensitive and vancomycin-resistant bacterial infections anddirectly addressing the underlying molecular basis of vancomycin resistance. The exciting results with bindingpocket analogs designed for dual D-Ala-D-Ala/D-Lac binding and subsequently with their peripherally modifiedderivatives that incorporate synergistic second and third mechanisms of action (MOAs) independent of D-Ala-D-Ala/D-Lac binding chart a compelling path forward for the development of potent and especially durableantibiotics not prone to eliciting resistance for treatment of deadly vancomycin-resistant and multidrug-resistantbacterial infections. The studies in the last grant period have produced analogs worthy of comprehensivepreclinical evaluation and the challenges for the work have returned to those of their preparation. This is an areawhere the PI and his group are well equipped and excited to address. The proposed studies will improve accessto the analogs through development of an innovative next generation total synthesis or semisynthetic approachand lay a foundation for fermentation access to the pocket modified glycopeptide antibiotics. The immediatetarget of the next generation synthetic studies which are at an advanced stage is the synthesis of an analogthat is projected to be the most active compound in the series examined to date bearing the most effectivepocket modification and two key peripheral modifications. A well-conceived stereochemical simplification in thetarget structures will also be examined that will substantially improve synthetic access to the aglycon corestructure without compromising antimicrobial activity. Optimization of activity derived from a new third MOAdiscovered in the last grant period will be conducted and such efforts have already improved on the impressiveactivity reported to date. In vivo assessments of key compounds will be conducted that build on the stunningresults to date structural characterization of pocket analogs bound to model ligands will be pursued to confirmthe fundamental basis of the remarkable dual D-Ala-D-Ala/D-Lac binding and a breakthrough discovery forachieving antimicrobial activity against Gram-negative as well as Gram-positive bacteria will be examined. 413606 +No NIH Category available Ablation;Acceleration;Affect;Antibodies;Binding;Binding Proteins;Binding Sites;CRISPR interference;CRISPR-mediated transcriptional activation;Cancer Etiology;Cells;Cessation of life;ChIP-seq;Chromatin;Chromosomes;Cyclin D1;DNA Sequence Alteration;Data;Defect;Dependence;Diagnosis;Disease;Drug resistance;Ectopic Expression;Elements;Enhancers;Epigenetic Process;Event;Gene Expression;Genes;Genetic;Genome;Genomics;Goals;Growth;Heavy-Chain Immunoglobulins;Imides;Immunotherapy;In Situ;Individual;Infection;Light-Chain Immunoglobulins;Location;Lymphocyte;Malignant Neoplasms;Measures;Mediating;Modality;Molecular;Molecular Target;Multiple Myeloma;Mutation;Newly Diagnosed;Oncogenes;Outcome;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Plasma Cells;Positioning Attribute;Proliferating;Proteasome Inhibitor;Proto-Oncogenes;Refractory;Regulator Genes;Regulatory Element;Research;Resistance;Resistance development;Role;Running;Scientist;Specimen;Testing;Thalidomide;Therapeutic;Therapeutic Effect;Translating;Trisomy;Tumor Suppressor Genes;Validation;Variant;Work;analog;career;cell growth;drug sensitivity;drug-sensitive;epigenome;experimental study;gene repression;genomic data;histone methyltransferase;histone modification;immunoregulation;improved;in vivo Model;innovation;insight;molecular subtypes;mortality;next generation sequencing;novel strategies;overexpression;prognostic;programs;promoter;response;therapeutic target;transcription factor;transcriptome sequencing;treatment response Revealing the cis-Regulatory Function of IMiDs in Multiple Myeloma. Project NarrativeMultiple myeloma patients benefit from several therapeutic options including immunomodulatory imide drugs(IMiDs) but most patients eventually acquire disease that is refractory to treatment and succumb to myeloma.This project will investigate the molecular targets of IMiDs the transcription factors IKAROS and AIOLOS todetermine their function and role in IMiD resistance. Results will inform the mechanisms by which IMiDs functionor fail to function in myeloma where IMiD-resistance is a major driver of mortality. NCI 10749870 11/3/23 0:00 PAR-21-128 5K22CA266739-02 5 K22 CA 266739 2 "JAKOWLEW, SONIA B" 12/7/22 0:00 11/30/25 0:00 ZCA1-RTRB-R(M1) 11050427 "BARWICK, BENJAMIN GABRIEL" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 187448 NCI 173563 13885 Project SummaryMultiple myeloma is a cancer of plasma cells resulting in over 12000 U.S. deaths each year. Genetic alterationsin myeloma include trisomy of most odd-numbered chromosomes translocations that result in ectopic expressionof oncogenes as well as structural variants and mutations in oncogenes and tumor suppressor genes. Thesedistinct genetic alterations manifest as unique molecular subtypes. Significant improvements in outcomes havebeen made using therapies including proteasome inhibitors thalidomide-analogs collectively known asimmunomodulatory imide drugs (IMiDs) and immunotherapies. Unfortunately most patients still developdisease that is refractory to treatment and succumb to myeloma. These frontline therapies are used regardlessof myeloma subtype and whether they are equally effective in all myelomas is not fully understood. This isunderscored by our recent study identifying Immunoglobulin Light Chain Lambda (IGL) translocations aspredictive of poor IMiD responses. IMiDs mediate the degradation of the lymphocyte transcription factorsIKAROS and AIOLOS. Interestingly the IGL enhancer was bound by some of the highest levels of IKAROS inthe myeloma epigenome. This suggests that location and levels of IKAROS and AIOLOS activity in the genomedictate IMiD responses. To test the hypothesis that the genomic elements bound by IKAROS and AIOLOSdetermine IMiD response and that these regions vary between myeloma genetic subtypes the following aims areproposed. 1) IKAROS and AIOLOS genomic binding sites will be determined and compared between IMiD-sensitive and -resistant myeloma cells to see if these factors localize to distinct regions of the genome in IMiD-resistant myeloma. In conjunction the epigenetic program of IKAROS- and AIOLOS-bound regions will becharacterized under baseline and IMiD-treated conditions to identify how IKAROS and AIOLOS depletion affectsthese elements as well as the resultant impact on gene expression. 2) IKAROS and AIOLOS will each beinhibited using CRISPR interference and the resultant phenotypic and molecular impact will be assessed todetermine the contribution of each factor to IMiD responses. 3) IKAROS- and AIOLOS-bound genomic elementswill be systematically disrupted to test the function of these regulatory elements in mediating IMiD resistance. The long-term goals of the candidate are to run an independent research program investigating the etiologyof cancer and translate findings into better therapeutic targeting and patient outcomes. The above aims willprovide a framework for establishing an independent research program. The above aims will also applyinnovative new approaches to discover the mechanism by which IMiDs exert their therapeutic effects and whysome myelomas become IMiD resistant a major cause of multiple myeloma mortality. 187448 +No NIH Category available B-Cell Lymphomas;B-Cell Neoplasm;B-Lymphocytes;Biological Models;Burkitt Lymphoma;Cell Culture Techniques;Cell Line;Cells;DNA Methylation;DNA Methylation Inhibition;DNMT3B gene;Development;EBNA2 protein;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Lymphoma;Gene Mutation;Genes;Genetic Transcription;Growth;HIV Infections;Hodgkin Disease;Human;Human Herpesvirus 4;Immune response;Immunocompetent;Immunocompromised Host;In Vitro;LMP1;Lymphoma;MYC gene;Mediating;Modeling;Mus;Oncogenic Viruses;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Proteins;RNA;Retroviral Vector;Retroviridae;Role;Structure of germinal center of lymph node;System;T cell response;T-Lymphocyte;TNFSF5 gene;Testing;Time;Tonsil;Umbilical Cord Blood;Viral;Viral Proteins;Virus Latency;anti-tumor immune response;experimental study;humanized mouse;immunogenic;immunosuppressed;in vitro Model;in vivo;in vivo Model;infected B cell;interleukin-21;large cell Diffuse non-Hodgkin's lymphoma;mouse model;mutant;neoplastic cell;novel;overexpression;promoter;public health relevance;restoration;small molecule;stable cell line;transcription factor;transforming virus;tumor;viral RNA Roles of LMP1 and MYC in EBV-induced B-cell tumors PUBLIC HEALTH RELEVANCEEpstein-Barr virus (EBV) is an important cause of human lymphomas such as Burkitt lymphomas (BLs) anddiffuse large B cell lymphomas (DLBCLs) that have stringent forms of viral latency (types I and II) that cannottransform B cells in vitro. We have recently developed a new model system that allows us to obtain EBV-infectedBL-like lymphomas with type I latency and EBV-infected DLBCLs with type II latency in nave B cells. In thisproposal we will extend this model into primary human GC B cells define the specific EBV genes and/or RNAsrequired to form each tumor type and identify pathways that restore expression of the EBV LMP1 protein in BL-like tumors thereby enhancing the T cell response to BL-like tumors in humanized mice. NCI 10749776 8/31/23 0:00 PAR-21-348 1U01CA284614-01 1 U01 CA 284614 1 "READ-CONNOLE, ELIZABETH LEE" 9/1/23 0:00 8/31/28 0:00 ZCA1-TCRB-D(M1) 1860327 "KENNEY, SHANNON CELESTE" Not Applicable 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 451228 NCI 290179 161049 PROJECT SUMMARY/ABSTRACTEpstein-Barr virus (EBV) is an important cause of human lymphomas in both immunocompetent andimmunosuppressed humans including Burkitt lymphomas (BLs) Hodgkin lymphomas (HLs) and diffuse large Bcell lymphomas (DLBCLs). There are three different types of EBV latency (types I II and III) that differ in thenumber of latent viral proteins expressed and transforming ability. Only type III viral latency (in which all 9 latentviral proteins are expressed) can transform primary human B cell in vitro but because type III latency is highlyimmunogenic EBV+ tumors with type III latency in humans are relatively rare and largely found inimmunosuppressed hosts. EBV+ HLs and DLBCLs in humans commonly have type II latency (characterized byexpression of EBNA1 LMP1 and LMP2A) while EBV+ BLs which contain MYC translocations have type Ilatency (in which EBNA1 is the only viral protein expressed). However there is currently no in vivo or in vitromodel available to study how EBV infection causes lymphomas with type I or type II latency since this form ofviral latency is not transforming in vitro and wild-type EBV-induced lymphomas in humanized mouse modelsinevitably support type III latency. EBNA2 transcriptionally activates each of the latent viral promoters usedduring type III latency. Using a newly constructed EBNA2-deleted EBV mutant (EBNA2 EBV) made by our labwe have developed a novel culture system that allows us to stably infect primary nave B cells in vitro with thismutant and to examine the effect of MYC over-expression. Our exciting preliminary results show that B cellsinfected with EBNA2 EBV form DLBCL-like and HL-like tumors with type II viral latency at late time points inNSG mice and that over-expressing the MYC gene (using a retroviral vector) in EBNA2 EBV-infected B cellsresults in rapid onset of aggressive tumors that resemble human BLs and support type I EBV latency. In contrastexpression of MYC alone does not cause tumors in this model. As human BLs DLBCLs and HLs are derivedfrom germinal center (GC) B cells in Aim 1 we will use this new model to examine the ability of EBNA2 EBV-infected primary GC B cells (with or without MYC over-expression) to form lymphomas in NSG mice. In Aim 2we will identify the specific EBV genes (and/or viral RNAs) required for the development of EBNA2 EBV-induced tumors (with or without MYC) in nave versus GC B cells. In Aim 3 we will define mechanisms by whichMYC turns off LMP1 expression in EBNA2 EBV-induced lymphomas and determine if small molecules that canrestore LMP1 expression enhance the immune response to tumors in humanized mice. The proposedexperiments will provide the first model system to define how types I and II EBV latency cause lymphomas inhuman GC B cells and to ask if restoration of LMP1 expression in BLs enhances the host immune response. 451228 +No NIH Category available 20 year old;Acute leukemia;Address;Adolescent;Adult;Age Years;All of Us Research Program;Alleles;Alternative Splicing;Automobile Driving;Birth;Cause of Death;Child;Child Care;Choanal Atresia;Chromosome abnormality;Chronic;Clinical;Congenital Abnormality;Congenital Heart Defects;Data;Data Set;Defect;Development;Diagnosis;Disease;Down Syndrome;Epidemiology;Evaluation;Gene Expression;Gene Fusion;General Population;Genes;Genetic;Genetic Counseling;Genetic Variation;Genome;Genomic approach;Genomics;Genotype;Germ-Line Mutation;Health;Individual;Joints;Knowledge;Lead;Link;Live Birth;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Mutation;Neuroblastoma;Nucleic Acid Regulatory Sequences;Outcome;Pathogenicity;Patients;Pattern;Pediatric Research;Phenotype;Population;Populations at Risk;Predisposition;Quality Control;Registries;Reporting;Risk;Risk Factors;Survivors;Susceptibility Gene;Syndrome;Testing;United States;Variant;Work;cancer epidemiology;cancer genomics;cancer predisposition;cancer risk;carcinogenesis;case control;cohort;congenital anomaly;congenital heart disorder;data registry;de novo mutation;epidemiologic data;genetic architecture;genetic association;genome sequencing;genome wide association study;genomic data;improved;insight;large datasets;leukemia;neoplasm registry;novel;population based;proband;programs;rare variant;response;secondary analysis;therapeutic target;transcriptome sequencing;trend;tumor;whole genome Integrating Epidemiologic and Genomic Data to Elucidate the Genetic Overlap Between Congenital Anomalies and Pediatric Cancer NARRATIVEIn our prior work we have identified multiple novel congenital anomaly-cancer associations by linking datafrom population-based birth-defects and cancer registries from four states. Here we propose to expand thisstudy to seven additional states to analyze a cohort representing >25 million live births and approximately 35%of the US population. We will also search for genetic mechanisms driving these associations through theanalysis of whole-genome sequencing data in 20000 children with congenital anomalies or pediatric cancerincluding 2000 sequenced tumors. NCI 10749761 9/19/23 0:00 PAR-20-276 1R01CA284531-01 1 R01 CA 284531 1 "DAEE, DANIELLE L" 9/19/23 0:00 8/31/28 0:00 Cancer and Hematologic Disorders Study Section[CHD] 10854751 "HUFF, CHAD DANIEL" "LUPO, PHILIP J." 9 PUBLIC HEALTH & PREV MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 483022 OD 185536 55000 ABSTRACTIn the United States cancer remains the leading cause of death by disease in those <20 years of age andapproximately 80% of survivors have at least one chronic health condition by 45 years of age. One of thestrongest risk factors for cancer in children and adolescents is being born with a congenital anomalythis istrue both for chromosomal abnormalities (e.g. Down syndrome) and non-chromosomal birth defects (e.g. non-syndromic congenital heart defects) as recently validated in our registry linkage study of over 10 million livebirths. By linking data from population-based birth defects and cancer registries in four states included in theGenetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study we identified multiple novelcongenital anomaly-cancer associations that are not part of known cancer predisposition syndromes includingchoanal atresia-acute leukemia (HR=9.2 95% CI: 3.8-22.1) and CHD-neuroblastoma (HR=3.4 95%: 2.6-4.5).Furthermore consistent with our epidemiologic findings our genomic assessments have led to theidentification of a novel leukemia predisposition disorder characterized by multiple congenital anomalies(including choanal atresia) and pathogenic germline variants in USP9X. In this application we propose toexpand our integrated epidemiologic and genomic approach to address our central hypothesis thatpleiotropic genetic variation generates specific congenital anomaly-pediatric cancer (CA-PC) patternswith increased risk conferred to each co-occurring phenotype. Our overall objective is to elucidate theoverlap between congenital anomalies and pediatric cancer by leveraging and integrating existing datasetsincluding 1) the Gabriella Miller Kids First Pediatric Research Program with 44 congenital anomaly andpediatric cancer cohorts representing 20000 patients and 48000 genomes; 2) the All of Us ResearchProgram with WGS data on >90000 individuals; and 3) the GOBACK Registry Linkage Birth Cohort whichincludes population-based data on >25 million live births. In Aim 1 we will analyze an expanded population-based cohort of >25 million children to identify new CA-PC patterns and confirm previously reported patterns.In Aim 2 we will analyze germline whole-genome sequencing (WGS) data from 2000 children with bothcongenital anomalies and pediatric cancer and over 20000 children with either congenital anomalies orpediatric cancer to identify novel pleiotropic genes harboring rare pathogenic variants responsible for specificCA-PC patterns. In Aim 3 we will describe the landscape of somatic alterations in pediatric cancers that resultfrom pathogenic CA-PC variants through the analysis of tumor-normal WGS and RNA-Seq data in 2000children. This work will generate novel insights into cancer predisposition and subsequently lead to improvedcare for children with congenital anomalies who comprise 120000 births every year in the United States. Inaddition insights into cancer development among at-risk populations could provide clinical utility (e.g. geneticcounseling or therapeutic targets) for children and adults with cancer in the general population. 240536 +No NIH Category available 20 year old;Acute leukemia;Address;Adolescent;Adult;Age Years;All of Us Research Program;Alleles;Alternative Splicing;Automobile Driving;Birth;Cause of Death;Child;Child Care;Choanal Atresia;Chromosome abnormality;Chronic;Clinical;Congenital Abnormality;Congenital Heart Defects;Data;Data Set;Defect;Development;Diagnosis;Disease;Down Syndrome;Epidemiology;Evaluation;Gene Expression;Gene Fusion;General Population;Genes;Genetic;Genetic Counseling;Genetic Variation;Genome;Genomic approach;Genomics;Genotype;Germ-Line Mutation;Health;Individual;Joints;Knowledge;Lead;Link;Live Birth;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Mutation;Neuroblastoma;Nucleic Acid Regulatory Sequences;Outcome;Pathogenicity;Patients;Pattern;Pediatric Research;Phenotype;Population;Populations at Risk;Predisposition;Quality Control;Registries;Reporting;Risk;Risk Factors;Survivors;Susceptibility Gene;Syndrome;Testing;United States;Variant;Work;cancer epidemiology;cancer genomics;cancer predisposition;cancer risk;carcinogenesis;case control;cohort;congenital anomaly;congenital heart disorder;data registry;de novo mutation;epidemiologic data;genetic architecture;genetic association;genome sequencing;genome wide association study;genomic data;improved;insight;large datasets;leukemia;neoplasm registry;novel;population based;proband;programs;rare variant;response;secondary analysis;therapeutic target;transcriptome sequencing;trend;tumor;whole genome Integrating Epidemiologic and Genomic Data to Elucidate the Genetic Overlap Between Congenital Anomalies and Pediatric Cancer NARRATIVEIn our prior work we have identified multiple novel congenital anomaly-cancer associations by linking datafrom population-based birth-defects and cancer registries from four states. Here we propose to expand thisstudy to seven additional states to analyze a cohort representing >25 million live births and approximately 35%of the US population. We will also search for genetic mechanisms driving these associations through theanalysis of whole-genome sequencing data in 20000 children with congenital anomalies or pediatric cancerincluding 2000 sequenced tumors. NCI 10749761 9/19/23 0:00 PAR-20-276 1R01CA284531-01 1 R01 CA 284531 1 "DAEE, DANIELLE L" 9/19/23 0:00 8/31/28 0:00 Cancer and Hematologic Disorders Study Section[CHD] 10854751 "HUFF, CHAD DANIEL" "LUPO, PHILIP J." 9 PUBLIC HEALTH & PREV MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 483022 NCI 187040 55446 ABSTRACTIn the United States cancer remains the leading cause of death by disease in those <20 years of age andapproximately 80% of survivors have at least one chronic health condition by 45 years of age. One of thestrongest risk factors for cancer in children and adolescents is being born with a congenital anomalythis istrue both for chromosomal abnormalities (e.g. Down syndrome) and non-chromosomal birth defects (e.g. non-syndromic congenital heart defects) as recently validated in our registry linkage study of over 10 million livebirths. By linking data from population-based birth defects and cancer registries in four states included in theGenetic Overlap Between Anomalies and Cancer in Kids (GOBACK) Study we identified multiple novelcongenital anomaly-cancer associations that are not part of known cancer predisposition syndromes includingchoanal atresia-acute leukemia (HR=9.2 95% CI: 3.8-22.1) and CHD-neuroblastoma (HR=3.4 95%: 2.6-4.5).Furthermore consistent with our epidemiologic findings our genomic assessments have led to theidentification of a novel leukemia predisposition disorder characterized by multiple congenital anomalies(including choanal atresia) and pathogenic germline variants in USP9X. In this application we propose toexpand our integrated epidemiologic and genomic approach to address our central hypothesis thatpleiotropic genetic variation generates specific congenital anomaly-pediatric cancer (CA-PC) patternswith increased risk conferred to each co-occurring phenotype. Our overall objective is to elucidate theoverlap between congenital anomalies and pediatric cancer by leveraging and integrating existing datasetsincluding 1) the Gabriella Miller Kids First Pediatric Research Program with 44 congenital anomaly andpediatric cancer cohorts representing 20000 patients and 48000 genomes; 2) the All of Us ResearchProgram with WGS data on >90000 individuals; and 3) the GOBACK Registry Linkage Birth Cohort whichincludes population-based data on >25 million live births. In Aim 1 we will analyze an expanded population-based cohort of >25 million children to identify new CA-PC patterns and confirm previously reported patterns.In Aim 2 we will analyze germline whole-genome sequencing (WGS) data from 2000 children with bothcongenital anomalies and pediatric cancer and over 20000 children with either congenital anomalies orpediatric cancer to identify novel pleiotropic genes harboring rare pathogenic variants responsible for specificCA-PC patterns. In Aim 3 we will describe the landscape of somatic alterations in pediatric cancers that resultfrom pathogenic CA-PC variants through the analysis of tumor-normal WGS and RNA-Seq data in 2000children. This work will generate novel insights into cancer predisposition and subsequently lead to improvedcare for children with congenital anomalies who comprise 120000 births every year in the United States. Inaddition insights into cancer development among at-risk populations could provide clinical utility (e.g. geneticcounseling or therapeutic targets) for children and adults with cancer in the general population. 242486 +No NIH Category available 3-Dimensional;Accounting;Antigen Presentation;Antineoplastic Agents;Antitumor Response;Biology;CDC2 gene;CXCL10 gene;Cancer Etiology;Cells;Cessation of life;Clinical;Commuting;Cytoprotection;Defect;Diagnosis;Dinucleoside Phosphates;Disease;Epigenetic Process;Excision;Extravasation;Fellowship;Foundations;Gene Expression;Generations;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immunologics;Immunosuppression;Immunotherapy;Induced Mutation;Interferon Type I;KRAS2 gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Medical;Messenger RNA;Methods;Microfluidics;Mitochondrial DNA;Modeling;Modernization;Mutate;Mutation;Natural Immunity;Non-Small-Cell Lung Carcinoma;Oncogenic;Operative Surgical Procedures;PDL1 inhibitors;Pathway interactions;Patient-Focused Outcomes;Patients;Peptides;Periodicity;Phosphotransferases;Physicians;Physiologic pulse;Protein Isoforms;Proteins;Public Health;Quality of life;RNA Splicing;Radiation therapy;Refractory;Research;Resistance;Role;STAT1 gene;STK11 gene;Sampling;Scientist;Secondary to;Source;Spliceosomes;Stimulator of Interferon Genes;Stimulus;Subgroup;Survival Rate;System;T-Lymphocyte;Technology;Therapeutic;Thoracic Surgical Procedures;Training;Tumor Immunity;United States;United States Food and Drug Administration;Validation;aggressive therapy;anti-tumor immune response;cancer cell;cancer immunotherapy;cytokine;cytotoxicity;derepression;ds-DNA;epigenetic silencing;experience;immune checkpoint blockade;immunogenic;immunogenicity;improved;inhibitor;micronucleus;mutant;neoantigens;novel strategies;novel therapeutic intervention;novel therapeutics;patient subsets;pharmacologic;post-doctoral training;promoter;recruit;refractory cancer;standard of care;success;therapeutically effective;therapy outcome;treatment strategy;tumor Dual targeting of cGAS-STING and splicing to prime lung cancer immunogenicity Project NarrativeWith a focus on post-doctoral training this proposal aims to advance a novel approach for the treatment of ahighly aggressive form of lung cancer. In addition to enhancing the pool of highly trained physician-scientiststhe results of this study will validate a novel approach to enhance cancer immunogenicity. This may be usefulin treating many forms of cancer thus improving public health and quality of life for patients. NCI 10749760 7/17/23 0:00 PA-21-048 1F32CA284615-01 1 F32 CA 284615 1 "JAKOWLEW, SONIA B" 7/17/23 0:00 7/16/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 12216727 "GEDEON, PATRICK C" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/17/23 0:00 7/16/24 0:00 398 "Training, Individual" 2023 76052 NCI 76052 0 Project SummaryLung cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer(NSCLC) is the most common type of lung cancer and despite aggressive treatment strategies that includemedical therapy surgical resection and radiation therapy 5-year survival rates for patients with lung cancerremain dismal. Recently the US Food and Drug Administration (FDA) approved several immune checkpointinhibitor-based therapies for the treatment of NSCLC establishing immunotherapy as an effective therapeuticoption and standard-of-care treatment for NSCLC. Despite this many patients fail to respond to immunecheckpoint blockade (ICB) and the subgroup of patients with KRAS and STK11 commutations (KL) hasemerged as a particularly aggressive immunosuppressive form of NSCLC resistant to ICB. Our group hasrecently discovered that by treating KL-mutated NSCLC with epigenetic de-repressing agents expression of akey protein in the immune response against lung cancer stimulator of interferon genes (STING) is restored.When stimulus for the STING pathway is subsequently provided through pulsed inhibition of a spindleassembly checkpoint protein monopolar spindle 1 (MPS1) potent anti-tumor responses occur restoringsensitivity to ICB. While these findings have yet to be validated in clinical samples of KL-mutated NSCLCthese samples are now available to use for study. Validation of this therapeutic strategy will show that it ispossible to overcome KL-mutation induced immunosuppression though it does not generate neoantigens todrive durable anti-neoplastic immune responses. Fortunately MPS1 shares kinase homology with CDC2-likekinase (CLK2) a key regulator of mRNA splicing and dual MPS1/CLK2 inhibitors have been developed. Thisprovides the unique opportunity to additionally dive durable anti-tumor immune responses throughsimultaneous pharmacological disruption of mRNA splicing. Indeed pharmacological modulation of splicingwas recently demonstrated as a definitive untapped method to generate neoantigens that elicit anti-tumorimmune responses. The overall goal of this fellowship proposal is therefore to provide advanced post-doctoraltraining in translational cancer immunotherapy research while evaluating a novel approach to enhanceimmunogenicity in a highly aggressive and resistant form of NSCLC. We will accomplish this by (1) validatingthe effect of epigenetic de-repression of STING and pulsed MPS1 inhibition in clinical samples of ICB-resistantKL-mutated NSCLC and (2) examining mRNA splice disruption and neoantigen generation in dual MPS1/CLK2inhibitor treated KL-mutated NSCLC. Together these aims will seek to improve therapeutic outcomes forpatients with NSCLC while enhancing the pool of highly trained physician-scientists. 76052 +No NIH Category available Acids;Acute;Adenocarcinoma;Adenocarcinoma Cell;Adjuvant;Adjuvant Study;Administrative Supplement;Africa;Alcohols;Architecture;Asia;Barrett Esophagus;Bile fluid;Biochemical Pathway;Bioenergetics;Biological Assay;Biopsy Specimen;Cancer Etiology;Cancer cell line;Carbon;Carboplatin;Cell Differentiation process;Cell Line;Cell Proliferation;Cessation of life;Chemotherapy and/or radiation;Chromatin;Chronic;Citric Acid Cycle;Country;Data;Data Set;Dependence;Development;Development Plans;Disease;Distant;Early Diagnosis;Embryonic Development;Enzymes;Epithelial Cells;Esophageal Adenocarcinoma;Esophageal Squamous Cell;Esophageal Squamous Cell Carcinoma;Esophagectomy;Esophagus;Excision;Future;Gastroesophageal reflux disease;Gene Expression;Gene Expression Profiling;Genes;Genomics;Glucose;Glucose Intolerance;Glutamine;Glycolysis;High Prevalence;Histologic;Histology;Homeostasis;Human;Immunotherapy;Inflammation;Inflammatory;K-Series Research Career Programs;Knowledge;Large Intestine Carcinoma;Liquid substance;Lye;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mediator;Metabolic;Metabolic Pathway;Metabolic stress;Metabolic syndrome;Metabolism;Methanol;Mission;Modality;Modeling;Molecular;Multiomic Data;NADP;Neoadjuvant Therapy;Neoplasm Metastasis;Obesity;Organoids;Oxidation-Reduction;Oxidative Phosphorylation;Oxidative Stress;Paclitaxel;Pathway interactions;Patients;Phenotype;Physiology;Principal Investigator;Process;Protein Isoforms;Protocols documentation;Public Health;Radiation;Recurrence;Regimen;Research Personnel;Residual Neoplasm;Resistance;Role;Scientific Advances and Accomplishments;Scientist;Signal Pathway;Squamous Cell;Squamous Cell Neoplasms;Squamous Differentiation;Squamous cell carcinoma;Starvation;Stress;Surgeon;System;Temperature;Testing;The Cancer Genome Atlas;Tissue Sample;Training;Treatment Protocols;Work;Writing;cancer subtypes;career development;cell growth;chemoradiation;chemotherapy;data integration;differential expression;effective therapy;esophageal squamous cell cancer;established cell line;fatty acid oxidation;functional genomics;histone modification;improved;individualized medicine;insight;interest;knock-down;liquid chromatography mass spectrometry;metabolic phenotype;metabolome;metabolomics;multiple omics;new therapeutic target;next generation;novel;overexpression;personalized medicine;programs;response;stable isotope;standard of care;surgery outcome;three dimensional cell culture;tobacco exposure;transcription factor;transcriptomics;treatment strategy Administrative Supplements to Participate in the NCI Early-stage Surgeon Scientist Program (ESSP) This project is relevant to public health because improved molecular understanding ofesophageal cancer focusing separately on esophageal adenocarcinoma and squamous cellcarcinoma subtypes is necessary to develop more effective treatment strategies for thisdisease which has only 20% 5-year survival. Our work will identify new targets that are uniqueto esophageal cancer subtypes based on their underlying metabolism. This project is thereforedirectly relevant to the NCIs mission to advance scientific knowledge that will improve patientsurvival and train the next generation of cancer researchers through this career developmentaward. NCI 10749648 6/23/23 0:00 PA-20-272 3P30CA006516-58S1 3 P30 CA 6516 58 S1 "PTAK, KRZYSZTOF" 3/10/97 0:00 11/30/26 0:00 Cancer Centers Study Section (A)[NCI-A] 1871771 "GLIMCHER, LAURIE HOLLIS" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 3/1/23 0:00 11/30/23 0:00 397 Research Centers 2023 208750 NCI 208750 0 "PROJECT SUMMARY ABSTRACTThis application is being submitted in response to the Notice of Special Interest (NOSI) identified as ""NOT-CA-21-100."" Esophageal cancer (EC) is the sixth most common cause of cancer deaths worldwide with 5-year survival of 20%. The two primary subtypes of EC esophageal squamous cell carcinoma (ESCC) andesophageal adenocarcinoma (EAC) demonstrate markedly different sensitivities to standard-of-careneoadjuvant regimens including chemotherapy and chemoradiation prior to esophagectomy and adjuvantimmunotherapy protocols for residual disease. Given their differential sensitivities to treatment there is acritical need to identify the unique vulnerabilities of ESCC and EAC and develop tailored treatment regimensfor each histology which historically have been treated as a single disease. The transcription factor p63 is amarker of squamous cell differentiation and our preliminary data have shown that it is highly expressed inESCC cell lines and absent in EAC cell lines. P63 is a known regulator of cellular metabolism withestablished roles in promoting glycolysis and redox homeostasis in both embryonic development andsquamous cell tumors while the absence of p63 results in glucose intolerance and metabolic syndrome. Weaim to determine the role of p63 in defining metabolic programs that underlie ESCC and EAC histologies inorder to define their unique metabolic vulnerabilities and identify novel therapeutic targets towards a morepersonalized treatment approach for esophageal cancers. Through the proposed Specific Aims and CareerDevelopment Plan we will quantify the flux through metabolic pathways that define ESCC and EAC anddetermine their dependence on p63 isoform expression correlating these results with markers of squamousand glandular differentiation. Furthermore we will validate these results against metabolome profiles oftreatment-nave ESCC and EAC tissue samples. In Aim 2 we will define direct and indirect metabolic targetsof p63 isoforms in esophageal cancer cell lines and organoids using CUT-and-RUN and transcriptomicsanalyses and integrate these datasets using multi-omics approaches to define the metabolic networkdownstream of p63. Studies will be performed in 2D and 3D cultures using established cell lines and patient-derived organoids as well as patient-derived biopsy samples and utilize functional genomics high throughputmetabolomics and multi-omics integration in novel 3D culture models that recapitulate the native architectureand physiology of human esophagus and esophageal cancers. The results of these studies will provide novelinsight into the unique metabolic vulnerabilities of ESCC and EAC that underlie their sensitivity and resistancephenotypes and will provide the basis for future studies to establish new metabolic targets for treatment ofthis deadly disease." 208750 +No NIH Category available Academic Medical Centers;Affect;Amino Acids;Anticodon;Archives;Basic Science;Biochemical;Biological;Biological Markers;Biology;Cancer Biology;Cell Line;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cellular biology;ChIP-seq;Chemicals;Chemoresistance;Classification;Clinical;Clinical Sciences;Codon Nucleotides;Colorectal Neoplasms;Complement;Couples;Cox Proportional Hazards Models;Cysteine;Data;Data Set;Dependence;Development;Diagnosis;Disease;Disease Management;Disease Progression;Doctor of Philosophy;Epithelium;Exhibits;Fostering;Gene Targeting;Genes;Genetic Transcription;Half-Life;High-Throughput Nucleotide Sequencing;Histologic;Histology;Human;In Situ Hybridization;In Vitro;Investigation;Knock-out;Label;Lead;Link;Literature;Logistics;Lung;Maintenance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mediator;Medical;Messenger RNA;Metabolic;Metastatic Neoplasm to the Lung;Methods;Modality;Modeling;Modification;Molecular Disease;Nature;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Nucleotides;Nutrient availability;Oncogenic;Outcome;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Patients;Phenotype;Physicians;Pilot Projects;Production;Prognosis;Proteins;RNA;RNA Polymerase III;Regulation;Regulator Genes;Reporting;Research;Research Personnel;Ribosomes;Role;Sampling;Scientist;Severity of illness;Site;Solid;Structure;Survival Rate;Survivors;Training;Transcript;Transfer RNA;Transfer RNA Aminoacylation;Translations;Tumor stage;Untranslated RNA;Validation;Work;amino acid metabolism;biobank;career development;cell type;chemoradiation;clinical decision-making;clinical practice;cohort;deprivation;disorder subtype;experimental study;innovation;mRNA Decay;mRNA Stability;molecular marker;molecular subtypes;neoplastic cell;novel;novel marker;pancreatic ductal adenocarcinoma model;patient prognosis;pharmacologic;pressure;prognostic;programs;screening;skills;tissue culture;transcriptome;transcriptomics;tumor;tumorigenic Investigating tRNA biology as a prognostic and oncogenic feature in pancreatic adenocarcinoma PROJECT NARRATIVEPancreatic ductal adenocarcinoma is one of the deadliest solid malignancies with well-defined transcriptomicsubtypes and amino acid dependencies. The study proposed here offers an innovative approach to investigatetransfer RNAs as regulators of these phenotypes and robust molecular markers of disease progression. Thesefactors along with its capacity to elucidate broader mechanisms of cancer biology underlie the proposalssignificance. NCI 10749469 8/9/23 0:00 PA-21-049 1F30CA284534-01 1 F30 CA 284534 1 "DAMICO, MARK W" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16083071 "KAWALERSKI, RYAN " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARYPancreatic ductal adenocarcinoma (PDAC) is uniquely difficult to treat due to late diagnosis and limited medicalmanagement options for a majority of patients. This is despite a wealth of watershed studies on disease drivermechanisms over the past decade highlighting a need for alternative approaches to studying this disease. It isnow clear that PDACs present along a bimodal continuum of transcriptomic subtypes that exhibit distinctprognoses and additional work on advanced PDAC models has uncovered that these tumors though highlychemoresistant are sensitive to external amino acid supply through metabolic dysregulation. Transcripts thatdefine known PDAC molecular subtypes present unique codon biases suggesting that PDACs are subject tobiologically deterministic codon-level selective pressures. Work from our lab and others has shown that theabundance of properly aminoacylated transfer RNAs (tRNAs) highly structured and chemically modified non-coding RNAs is highly deterministic of mRNA half-life. This mechanism acts through codon-anticodonrecognition and ribosome elongation rate and alterations of functional tRNA abundance can dictate cellularfunctions via concomitant regulation of mRNA stability. Furthermore a wealth of literature evidence in diversecell types across species demonstrates that tRNA regulation can be disease-specific. Thus tRNAs may likelyserve a key regulatory role in PDAC subtype expression and amino acid sensitivity given their function inbridging codon-amino acid pairings during protein production.As proof of concept I have strong preliminary evidence that tRNA expression can be highly predictive of diseasestage in a limited cohort of primary colorectal tumor samples. Furthermore a pilot study of PDACs revealedwidespread tRNA dysregulation with increased use of cysteine-decoding transcripts matching existing literaturethat PDACs are specifically sensitive to deprivation of this amino acid. In this proposal I seek to interrogatelinked roles of tRNAs as regulators of mRNA and nutrient availability phenotypes in PDAC. My central hypothesisis that PDACs specifically regulate tRNA expression to confer cell survival and proliferation advantages and thattRNA profiling can reveal novel biomarkers for use in clinical decision-making. I will address this hypothesisthrough the following aims: Aim 1: Characterize tRNA expression and modifications in primary patient PDACs;Aim 2: Investigate PDAC tRNA regulation as a driver of tumor cell survival. These aims will be achieved througha combination of biochemical and high-throughput sequencing approaches using archived patient samples andestablished in vitro cell lines. Beyond biological interrogation this proposal involves novel technical developmentin the experimental and analytical application of tRNA sequencing for large patient sample cohorts. This projectwould be the first to analyze tRNA gene-specific regulation in cancer and will be significant in that it may revealnovel targetable mechanisms of PDAC maintenance and a potent set of disease-associated clinical features thatare likely to inform fundamental cancer biology. 52694 +No NIH Category available 4D MRI;Ablation;Animals;Automobile Driving;Blood flow;Cancer Etiology;Cancer Patient;Caring;Cessation of life;Child;Cirrhosis;Clinical;Complication;Dedications;Excision;Exclusion;Family suidae;Fellowship;Foundations;Future;Goals;Growth;Guidelines;Hepatectomy;Hepatic;Hepatic Insufficiency;Hepatobiliary;Hyperemia;Hypertrophy;Image;Liver;Liver Dysfunction;Liver Failure;Liver Regeneration;Liver diseases;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Mentors;Methods;Operative Surgical Procedures;Outcome;Partial Hepatectomy;Patient Care;Patient Selection;Patients;Phase;Portal System;Portal Venous System;Postoperative Period;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Records;Research;Research Personnel;Research Project Grants;Research Training;Risk;Scientist;Series;Surgeon;Surgical Oncologist;Surgical complication;Survival Rate;Time;Training;United States;Universities;Unresectable;Wisconsin;cancer care;candidate identification;career;career development;curative treatments;experimental study;improved;liver function;liver transplantation;magnetic resonance imaging biomarker;mortality;multidisciplinary;nonalcoholic steatohepatitis;novel;radiologist;reconstruction;sham surgery;translational scientist Predicting Future Liver Remnant Function and Growth Trajectory Using Novel MR Imaging Biomarkers PROJECT NARRATIVEPost-hepatectomy liver failure is the most severe surgical complication with a mortality rate ranging from 1.2 to33.8%. My proposed research project will use a novel Magnetic Resonance (MR) Imaging sequence toanalyze portal blood flow and correlate the results with existing MR sequences for liver volume and function.By predicting future liver remnant function after partial hepatectomies through novel parameters our projectwill improve patient selection pre-operative surgical planning and outcomes in patients with liver cancer. NCI 10749468 7/26/23 0:00 PA-21-048 1F32CA284535-01 1 F32 CA 284535 1 "ODEH, HANA M" 7/26/23 0:00 7/25/24 0:00 Special Emphasis Panel[ZRG1-F10C-D(20)L] 78583883 "JOSHI, DEVASHISH " Not Applicable 2 SURGERY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 7/26/23 0:00 7/25/24 0:00 398 "Training, Individual" 2023 75437 NCI 75437 0 PROJECT ABSTRACTHepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths in the world. In fact HCCis the fastest growing cause of all cancer deaths in the United States with a poor 5-year survival rate of 18%.The only curative therapies for HCC are liver transplantation or liver resection (partial hepatectomy) and fornon-surgical candidates ablation. Malignant tumors within the liver whether primary or secondary are the mostcommon indication for curative partial hepatectomies. However many patients with HCC have underlyingcirrhosis or some degree of liver dysfunction. As a result the most severe complication after surgery remainspost-hepatectomy liver failure with a mortality rate between 1.2 to 33.8%.Successful curative partial hepatectomy requires sufficient liver regeneration and function to avoid post-operative hepatic insufficiency. Currently potential surgical candidates are identified by determining future liverremnant (FLR) volume. There are no clear guidelines for FLR volume in mild-moderate liver disease. It isknown that portal blood flow is a key parameter driving liver hypertrophy but is not well understood.We hypothesize that there is a relationship between portal blood flow FLR growth trajectory and liver function.To investigate we will perform partial hepatectomies in 7 healthy pigs with 3 controls undergoing a shamsurgery. All 10 pigs will undergo magnetic resonance (MR) Imaging at 4 separate time points (pre-operativepost-operative day [POD] 0 between POD 6-8 and between POD 26-30) to evaluate for portal blood flowusing a novel 4D flow MR method liver volume and liver function. Our imaging time points will help assessthe first two aims demonstrating the utility of quantitative MR imaging biomarkers in predicting FLR functionand growth trajectory and also determining the relationship between FLR function and volume over time.Finally we aim to determine the effects of portal hyperemia via a meal challenge to assess portal systemaccommodation and compliance as a predictive parameter. Our goal is to predict FLR function and growth toimprove patient selection pre-operative surgical planning and outcomes through a series of three aims.The applicant Devashish Joshi MD is a general surgery resident at the University of Wisconsin-Madisonpursuing a career as a surgical oncologist and independent investigator. This fellowship would support hissecond year of dedicated research time with minimal clinical responsibilities. His sponsor radiologist Dr. ScottReeder and co-sponsor hepatobiliary surgical oncologist Dr. Sharon Weber have significant track records ofmentoring surgical trainees. They will guide and mentor Dr. Joshi in completing the proposed project toimprove care in patients with liver cancer and build his foundations towards becoming a surgeon-scientist. 75437 +No NIH Category available AKT2 gene;Affect;Automobile Driving;Back;Biochemical;Biological Markers;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer therapy;Breast Epithelial Cells;Breast cancer metastasis;Cell Adhesion;Cell Line;Cell secretion;Cells;Clone Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Collagen Type I;Deposition;Development;Disease;Distant;Down-Regulation;Environment;Evaluation;Extracellular Matrix;Extracellular Matrix Proteins;Fibronectins;Generations;Genes;Goals;Human;In Vitro;Invaded;KRAS2 gene;Knock-out;Knowledge;Link;Lung;MCF10A cells;Mammary Neoplasms;Mediating;Membrane Proteins;Metastatic Neoplasm to the Lung;Modeling;Mus;Muscle;Mutation;Neoplasm Circulating Cells;Neoplasm Metastasis;Oncogene Activation;Oncogenes;Organ;PIK3CG gene;Pathway interactions;Patients;Phenotype;Population;Prevention;Primary Neoplasm;Probability;Process;Production;Proteins;Published Comment;Pulmonary artery structure;Reporting;Research;Risk;Role;Sarcomeres;Smooth Muscle Myocytes;Stromal Cells;Structure of parenchyma of lung;Testing;Therapeutic;Tumor Markers;Tumor Suppressor Proteins;Tumor-Derived;Up-Regulation;Vacuum;Vascular Smooth Muscle;Work;cell motility;diagnostic biomarker;exosome;extracellular;improved;lung colonization;lung metastatic;malignant breast neoplasm;mammary epithelium;metastasis prevention;migration;neoplastic cell;new therapeutic target;novel;novel therapeutics;obscurin;response;restoration;transcription factor;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumorigenesis;vascular smooth muscle cell proliferation Obscurin-Deficient Breast Epithelia Generate Secreted Factors that Prime Lung Vascular Smooth Muscle Cell Pre-metastatic Microenvironment Formation PROJECT NARRATIVE:Although breast cancer patient survival has improved in the last two decades metastatic stage disease remainsthe highest killer of breast cancer patients. Successful metastasis relies on the earliest stages of pre-metastaticmicroenvironment formation in which vascular smooth muscle cell-derived extracellular fibronectin and collagen1a1 proteins fill the organ parenchyma yet no biomarker of the primary tumor can predict or identify the probableor ongoing coordination of this process nor is there a defined tumor target to therapeutically block pre-metastaticmicroenvironment formation. The aim of this project is to investigate the first ever probable link between breastepithelial cell metastasis suppressor obscurin loss and pre-metastatic microenvironment formation highlightinga potential novel tumor biomarker and target for incoming or ongoing metastatic disease. NCI 10749467 7/31/23 0:00 PA-21-049 1F30CA278384-01A1 1 F30 CA 278384 1 A1 "PURI, ANU" 7/15/23 0:00 7/14/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(90)L] 15615727 "EASON, MATTHEW KENT" Not Applicable 7 BIOCHEMISTRY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 7/15/23 0:00 7/14/24 0:00 398 "Training, Individual" 2023 45811 NCI 45811 0 Project Summary/Abstract: New therapies blocking metastatic spread are greatly needed to improve breast cancer patient survival.Pre-metastatic niche development has been identified as a key milestone to successful metastasis generatedin response to a growing tumors release of secreted factors. Critical to the pre-metastatic niche is the pre-metastatic microenvironment (PMM) composed of extracellular matrix (ECM) proteins deposited by residentstromal cells that enhance metastasis. To date PMM development has been studied solely in the context ofhighly metastatic tumor models using cell lines rich in tumor suppressor and oncogene mutations however nodirect mechanistic connections between metastatic driver genes and PMM formation have yet been deciphered.Obscurins have recently been pinned as potent metastasis suppressors in breast cancer. Biochemical evidencefrom our group has mechanistically linked obscurin loss to PI3K/Akt2 activation in breast epithelial cells drivingoncogenesis and metastatic spread. However no study has yet drawn the connection between the loss ofobscurin in breast epithelia and PMM development. This study will test the novel hypothesis that loss of obscurinin breast epithelia primes vascular smooth muscle cell (vSMC)-derived fibronectin and collagen 1a1 depositionin the PMM through secreted factors potentiating metastasis. The goal of my application is to investigate the potential of obscurin-deficient breast epithelia secretedfactors (OBEFs) to drive vSMC ECM fibronectin and collagen 1a1 deposition. OBEFs will be isolated fromOBSCN knock-out (KO) MCF10A cell clones while the human pulmonary artery smooth muscle cell (HPASMC)line will be the representative PMM cell population for the following reasons: 1) Lung PMM development isdependent on phenotypically activated lung vSMC-derived ECM production and 2) Pre-metastatic lung vSMC-derived ECM has been shown to enhance metastatic lung seeding in the pre-metastatic lung parenchyma. Inparticular I will investigate potential changes in OBEF-driven vSMC-derived ECM fibronectin and collagen 1a1and their connection to enhanced lung metastatic seeding (Aim 1). Then I will identify the responsible secretedfactors (Aim 2) that drive the subsequent vSMC ECM fibronectin and collagen 1a1 production in the lung PMM.Together these studies will connect our knowledge of PMM development back to a major suppressor of primarytumor metastasis indicating the first targetable tumor biomarker linked to the stromal component of PMMgeneration. 45811 +No NIH Category available Antigen Presentation;Automobile Driving;Award;BAY 54-9085;Binding;Bioinformatics;Biological Response Modifiers;CTNNB1 gene;Cancer Biology;Cancer Etiology;Cell Proliferation;Cells;Clinical;Combined Modality Therapy;Data;Development;Disease;Education;Exclusion;Future;Gene Expression;Genes;Growth;Immune;Immune System Diseases;Immune Targeting;Immune checkpoint inhibitor;Immune response;Immunohistochemistry;Immunooncology;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Incidence;Inflammatory Response;Injections;Interferon Regulatory Factor 2;K-Series Research Career Programs;Knock-out;Lead;Link;Liver;Lymphocyte;Lymphocyte Activation;Lymphocyte Function;Lymphoid;MET gene;Malignant Neoplasms;Malignant neoplasm of liver;Modality;Modeling;Monitor;Mutate;Oncogenes;Patients;Phenotype;Physicians;Population;Predisposition;Primary carcinoma of the liver cells;Proto-Oncogenes;Receptor Protein-Tyrosine Kinases;Regimen;Regulation;Repression;Research Training;Residencies;Resistance;Role;Scientist;Signal Transduction;Sleeping Beauty;Survival Rate;System;Tail;Techniques;Testing;Therapeutic;Therapeutic Effect;Training;Transposase;Tumor Burden;Tumor Immunity;Tumor-infiltrating immune cells;United States;Unresectable;Veins;adaptive immune response;anti-PD1 therapy;beta catenin;biomarker driven;career;cell type;chronic liver disease;clinically relevant;combinatorial;differential expression;driver mutation;end stage disease;immunoregulation;improved;in vivo;inhibitor;liver cancer model;molecular subtypes;mortality;mouse model;mutant;mutant mouse model;neoplastic cell;novel;nuclear factor-erythroid 2;objective response rate;precision medicine;response;response biomarker;single-cell RNA sequencing;standard of care;synergism;synthetic biology;transcription factor;treatment stratification;tumor;tumor-immune system interactions;tumorigenesis Investigating Immunosuppression in Beta-catenin-mutated Hepatocellular Carcinoma for Improved Precision Medicine Therapeutics PROJECT NARRATIVEHepatocellular carcinoma (HCC) is increasing in incidence due to the sequalae of chronic liver disease with nosignificant recent improvement in patient survival due to a lack of biomarker-driven therapeutics. -catenin-activation (mutated CTNNB1 oncogene) represents a molecular subset of HCC cases which are resistant tocurrent immunotherapies. This proposal will investigate mechanisms of -catenin activation drivingimmunosuppression in the tumor immune microenvironment with our results paving the way for precisionmedicine therapeutics for -catenin-mutated HCC. NCI 10749344 6/22/23 0:00 PA-21-049 1F30CA284540-01 1 F30 CA 284540 1 "BIAN, YANSONG" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16533174 "LEHRICH, BRANDON " Not Applicable 12 PATHOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTHepatocellular carcinoma (HCC) is the 6th leading cause of cancer-associated mortality in the United States andis rising due to chronic liver disease and its associated sequalae. Currently the response rates to currenttherapeutic paradigms consisting of immune checkpoint inhibitors (ICIs) remain low and there exist an urgentneed for novel combinatorial therapies to improve patient mortality. Lack of response to current ICIs is mainlydue to a poor understanding of the tumor immune microenvironment (TIME) and how various HCC drivermutations lead to specific immune phenotypes. Additionally there currently exist no biomarker-driventherapeutics for patient treatment stratification. -catenin-active (encoded by mutated CTNNB1 oncogene) HCCsrepresent approximately 26-35% of HCCs and respond poorly to ICIs due to -catenin driving animmunosuppressive TIME and limiting the effector function of lymphocytes important for anti-tumor immunity.We have developed novel -catenin-mutated HCC mouse models where mutant CTNNB1 is co-expressed witheither the proto-oncogene MET (-catenin/hMet) or nuclear factor erythroid 2related factor 2 (Nrf2) (-catenin/Nrf2). These models represent 11% and 10% of all clinical HCC cases respectively. Our preliminarystudies demonstrate that -catenin potentiates tumorigenesis in -catenin-mutated HCC and that directlytargeting -catenin promotes an inflammatory response driving anti-tumor immunity. Based on theseobservations our overarching hypothesis is that -catenin actively suppresses the adaptive immune responsein the TIME and targeting -catenin or its downstream immunomodulatory factors may improve susceptibility toICIs. To investigate I propose the following specific aims which will uncover novel mechanisms of -cateninsignaling in the HCC TIME aimed at developing precision medicine therapeutics. Specific Aim 1: We willdetermine the immune cells activated following -catenin inhibition and investigate whether there is in vivosynergy combining -catenin inhibition and ICIs through single-cell RNA-sequencing (scRNA-seq) and multipleximmunohistochemistry. Thus we will identify mechanisms of immunosuppression caused by -catenin activationin -catenin-mutated HCC. Specific Aim 2: Based on our preliminary data showing interferon regulatory factor-2 (IRF2) repression in -catenin-mutated HCC we hypothesize that -catenin-mutated HCCs may be sensitizedto ICIs or even show spontaneous tumor regression upon re-expression of IRF2 as a result of enhancedimmune response. We will use synthetic biology approaches to selectively induce IRF2 expression at varioustimepoints in tumorigenesis and monitor tumor burden. We will then use scRNA-seq on the lymphoid populationto identify cell types and states regulated by IRF2 and test combination of IFNg (which induces IRF2) + ICI as atherapeutic modality. Contribution to Training: This proposal combines rigorous research training in livercancer biology immuno-oncology and advanced bioinformatic analyses with an excellent clinical education toaid my development as a future academic physician-scientist at the forefront of immune dysfunction in cancer. 52694 +No NIH Category available Acceleration;Antibody-drug conjugates;Automobile Driving;Breast;Cadherins;Cell Line;Characteristics;Clinical;Clinical Management;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Complement;Data;Dependence;Disease;Drug resistance;E-Cadherin;ERBB2 gene;Engineering;Environment;Epidermal Growth Factor Receptor;Estrogen receptor positive;Evolution;Exhibits;FDA approved;Future;Genes;Genetic Transcription;Genomics;Goals;Growth;Growth Factor Receptors;HSP 90 inhibition;Heat-Shock Proteins 90;Histologic;IGF1R gene;In Vitro;Inferior;Investigation;Knock-out;Learning;Lobular Carcinoma;Malignant Epithelial Cell;Mediating;Messenger RNA;Metastatic breast cancer;Molecular;Molecular Chaperones;Mutation;Nature;Nuclear;Null Lymphocytes;Oncogenic;Organoids;Outcome;Patients;Phenotype;Physicians;Plasma;Pre-Clinical Model;Prevalence;Prognosis;Receptor Protein-Tyrosine Kinases;Recurrence;Regulation;Reporting;Repression;Research Personnel;Resistance;Role;Sampling;Scientist;Signal Pathway;Signal Transduction;Specimen;Testing;The Cancer Genome Atlas;Therapeutic;Training;Tyrosine Kinase Inhibitor;Woman;Xenograft procedure;breast cancer progression;clinically relevant;clinically significant;effective therapy;experimental study;gain of function;genome editing;hormone therapy;in vitro Model;infiltrating duct carcinoma;innovation;mRNA Expression;malignant breast neoplasm;mutant;overexpression;patient subsets;permissiveness;protein expression;response;targeted treatment;therapy resistant;transcriptome sequencing;translational cancer research;tumor;tumor progression Characterizing and Targeting ERBB2 Mutations in Invasive Lobular Carcinoma PROJECT NARRATIVEActivating ERBB2 mutations are enriched in invasive lobular carcinoma (ILC) of the breast suggesting acrosstalk between ERBB2 mutations and the characteristic loss of CDH1 in ILC. Clinical trials havedemonstrated promising efficacy using anti-HER2 tyrosine kinase inhibitors in patients with ERBB2 mutant ILC.The ultimate goal of the proposed studies is to characterize the functional roles of recurrent ERBB2 mutationsin ILC vs IDC using innovative preclinical models and provide rationale for specific combination targetedtherapy in patients with ERBB2 mutant ILC in order to enhance anti-tumor activity and/or delay drugresistance. NCI 10749213 6/16/23 0:00 PA-21-049 1F30CA278319-01A1 1 F30 CA 278319 1 A1 "PURI, ANU" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16052505 "LIU, JIE BIN " Not Applicable 12 PHARMACOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARYAlthough invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer there remains much to belearned about the unique nature of this disease. Compared to invasive ductal carcinoma (IDC) ILC isunderstudied with distinct histological genomic and clinical characteristics. Despite key differences womenwith estrogen receptor-positive (ER+) ILC will most likely receive the same treatment as women with ER+ IDCthough often show inferior long-term outcomes.Recently the Lee-Oesterreich Lab and others have identified enrichment of ERBB2 mutations in ILC comparedto IDC. As ILC is characterized by loss of CDH1 (E-cadherin) our findings may suggest a potential interactionbetween loss of CDH1 and mutations in ERBB2 in driving ILC tumor progression. As ERBB2 mutations usuallyoccur in the absence of ERBB2 amplification there are currently no FDA-approved therapies targeting ERBB2mutant ILC. Several clinical trials have reported promising efficacy of anti-HER2 tyrosine kinase inhibitorsincluding neratinib in patients with ERBB2 mutant ILC. However resistance to these therapies is inevitable. Inorder to identify the most effective combination therapies the functional role of these recurrent ERBB2mutations in ILC requires further investigation. Using a combination of clinical specimens innovative in vitromodels and CRISPR-based genome editing our proposal will determine the prevalence of ERBB2 mutations inctDNA collected from plasma samples of patients with metastatic breast cancer and investigate how thesemutations influence HER2 activation and downstream signaling pathways and sensitivity/resistance toavailable anti-HER2 agents (Aim 1). We will also evaluate the effects of CDH1 knockout and re-expression onHER2 signaling and degradation in order to understand the cooperation between loss of CDH1 and mutationsin ERBB2 in ILC and explore potential mechanisms of HER2 regulation by E-cadherin (Aim 2).Results of this and future research will help inform clinicians and researchers of the mechanisms clinicalrelevance and targetability of recurrent ERBB2 mutations and complement findings from ongoing clinical trialsto identify the most effective therapy combinations for patients with ERBB2 mutant ILC. 52694 +No NIH Category available Mechanisms of non-genetic variation in melanoma Project NarrativeFor many patients with melanoma treatment with targeted therapies initially shows great promise onlyfor the disease to return often without any new mutations that explain why the treatment stoppedworking. This proposal aims to define non-genetic mechanisms that explain how cancers likemelanoma become resistant to therapy. By understanding these mechanisms we can unlock newtherapeutic strategies to overcome treatment failure. NCI 10749208 2/10/23 0:00 PA-21-268 7K08CA237856-04 7 K08 CA 237856 4 "LIM, SUSAN E" 9/1/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 14749029 "GARG, SALIL " Not Applicable 3 PATHOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 10/2/22 0:00 8/31/23 0:00 398 Other Research-Related 2022 160672 NCI 148771 11901 Project Summary/AbstractThis proposal details a five year training plan for the development of a research program focused onnon-genetic mechanisms of therapy resistance in melanoma. Therapies that target the MAPK pathwayin melanoma have remarkable success in shrinking patients initial tumors but disease recurs oftenwithout new mutations that explain therapy failure. This appears to be due to a small population of rarecells present in the initial tumor that display high levels of resistance genes such as epidermal growthfactor receptor (EGFR) and are not killed by initial MAPK targeted therapy. The mechanisms that driveformation of these rare pre-resistant cells are unknown though preliminary studies implicate generegulation by enhancers. The goals of this research proposal are to characterize the key geneticpathways that define pre-resistant cells in patient tumors identify enhancers that drive expression ofresistance genes and cellular variation and to identify pharmacologic targets for preventing therapyresistance. Since EGFR plays an important role in many cancers and non-genetic variation appears toundergird treatment failure in many different malignancies the implications of this work for humandisease may be far-reaching. The work will be mentored by Phillip A. Sharp at the MassachusettsInstitute of Technology a leader in understanding gene regulation in cancer and whose laboratory hasproduced numerous distinguished alumni.I am a practicing molecular pathologist at the Massachusetts General Hospital interested in howvariation arises naturally within biological systems. In diagnostic pathology we are attempting toachieve ever greater personalized medicine in cancer treatment using sequencing. To achieve thebest precision medicine possible we must understand the mechanisms by which tumors evade therapythat go beyond genetic changes such as mutations. This will allow us to build better more accuratediagnostics and give our oncologist colleagues the best actionable information. My career objectiveduring the proposal period is to obtain a tenure-track position at an academic medical center continuingwork as a Principal Investigator. Specifically during the proposal period I will gain experience withmelanoma model systems enhancer biology genomics and systems biology approaches. My longterm objective is to define how variation and heterogeneity arise within biological systems and how wecan diagnose and manipulate these processes in human disease. 160672 +No NIH Category available Acceleration;Antigen Presentation;Apoptotic;Autoimmunity;Biological Availability;Blood;CD4 Positive T Lymphocytes;Cancer Etiology;Cell physiology;Cells;Cessation of life;Chronic;Circulation;Clinical Trials;Complex;Cues;Cytotoxic Chemotherapy;Data;Diagnosis;Disease;Elements;Family;Fibroblasts;Frequencies;Frustration;Gene Expression;Gene Expression Profile;Genetic;Goals;Growth;Heterogeneity;Human;Immune;Immune response;Immunity;Immunologic Monitoring;Immunologics;Immunotherapy;Incidence;Infiltration;Inflammation;Inflammatory Response;Interferons;Ligands;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metastatic Neoplasm to the Liver;Modeling;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Neoplasms;Operative Surgical Procedures;Oral;Outcome;PD-1 blockade;Paclitaxel;Pancreatic Ductal Adenocarcinoma;Patients;Phenotype;Phosphotransferases;Play;Pre-Clinical Model;Radiation therapy;Receptor Protein-Tyrosine Kinases;Regulation;Research;Resistance;Role;Signal Transduction;T cell infiltration;T-Cell Proliferation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;Therapeutic Uses;Time;Tumor Immunity;Wild Type Mouse;Work;anti-PD-1;anti-PD1 therapy;attenuation;axl receptor tyrosine kinase;chemotherapy;clinical application;druggable target;effector T cell;efficacy testing;immune cell infiltrate;immunogenic cell death;inhibitor;kinase inhibitor;knockout animal;lymph nodes;monocyte;mouse model;neoplasm immunotherapy;neoplastic cell;novel;pancreatic ductal adenocarcinoma model;paracrine;phase I trial;pre-clinical;prevent;programs;response;restraint;single cell sequencing;small molecule inhibitor;success;synergism;targeted treatment;therapy resistant;trafficking;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;tumorigenic Divergent Roles of MerTKTyro3 and Axl in Pancreatic Cancer and Metastasis PROJECT NARRATIVEThe dismal outcomes of pancreatic cancer and its unresponsiveness to immunotherapy is in part due to thepro-tumorigenic immunosuppressive tumor microenvironment engendered by infiltrating myeloid and fibroblasticcells. We have identified MerTK Tyro3 and Axl receptor tyrosine kinases as important but distinct regulators ofimmunosuppressive myeloid cells and potentially cancer-associated fibroblasts. This research will elucidatemechanisms by which these kinases hinder the immune response and will evaluate novel clinically applicabletherapeutic agents that could magnify the response to current immunotherapies. NCI 10749044 11/14/23 0:00 PA-20-185 5R01CA270792-02 5 R01 CA 270792 2 "WATSON, JOANNA M" 12/1/22 0:00 11/30/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6477317 "EARP, HENRY SHELTON" "PYLAYEVA-GUPTA, YULIYA " 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 483544 NCI 314111 169433 ABSTRACTPancreatic Ductal Adenocarcinoma (PDAC) is perhaps the most recalcitrant human neoplasm. With 10% overall5-year survival and an increasing incidence PDAC will be the second leading cause of cancer deaths within adecade. The constellation of chemo- and targeted therapy resistant tumor cells and a tumor microenvironmentfeaturing suppressive innate immune cells and fibroblasts frustrates therapeutic success. PDAC and preclinicalPDAC models both show a massive myeloid and fibroblast cell infiltration which suppresses effector T cells andpromotes metastases. Our data implicate a family of receptor tyrosine kinases Tyro3 Axl MerTK (TAM RTKs)in directing pro-tumorigenic polarization of CAFs and myeloid cells in PDAC. The homeostatic role of myeloidcell TAM RTKs is to coordinate suppression of innate immune inflammatory responses to apoptotic materialpreventing chronic inflammation and autoimmunity. Our preliminary data show that TAM RTKs play non-redundant and sometimes opposing functions in the PDAC tumor microenvironment (TME) leading topolarization of myeloid cells and fibroblasts. Clinical trials of TAM RTK inhibition are beginning; thus our work tounderstand the consequences and mechanism of inhibition for each TAM RTK is both timely and significant.Host MerTK and Tyro3 in wild type mice promote PDAC growth and contribute to lack of responsiveness to anti-PD1 therapy as germline MerTK or Tyro3 deletion slow PDAC growth markedly reduces liver metastasis andpromotes anti-PD-1 efficacy. However in the Axl-/- mice there is an unexpected increase in metastaticoutgrowth. Our group has synthesized orally bioavailable selective MerTK kinase inhibitors which recapitulateaspects of MerTK and/or Tyro3 genetic loss. Lastly our preliminary studies in patients identify MerTK+ and Tyro3+myeloid cells and document an increase in MerTK+/Tyro3+ MDSCs in the blood of PDAC patients.Hypothesis. MerTK+ and/or Tyro3+ monocytes macrophages MDSCs and Tyro3+ fibroblasts are expanded inPDAC and have at least some separate roles in the suppressive TME and metastasis promotion. Our SpecificAims are: Aim 1: To determine how MerTK and Tyro3 act in the innate immune compartment to acceleratePDAC growth and metastasis and how Axl has the opposite effect. Aim 2: To determine the role of Tyro3 inPDAC cancer associated fibroblasts and Aim 3: To evaluate the therapeutic potential of targeting TAM RTKs inPDAC in preclinical PDAC models (using UNC inhibitors one of which is in Phase 1 trials) in combination withother cytotoxic and immune therapies. We will quantify functionally characterize and study gene expressionsignature of MerTK+ and Tyro3+ myeloid cells in the circulation tumors and lymph nodes and fibroblast cells inthe PDAC patient tumors before and during therapy. Success would represent a significant advance towardunderstanding how to make immunologically cold PDAC tumors hot and responsive to immunotherapy. 483544 +No NIH Category available Address;Adverse effects;Adverse event;Affect;Aftercare;Artificial Intelligence;Brain;Brain Stem;Caring;Clinic;Clinical;Clinical Trials;Cranial Irradiation;Data;Dedications;Development;Distant;Dose;Ensure;Feedback;Foundations;Functional disorder;Goals;Infrastructure;Interdisciplinary Study;Knowledge;Learning;Life;Life Expectancy;Malignant Neoplasms;Maximum Tolerated Dose;Medical;Metastatic malignant neoplasm to brain;Morbidity - disease rate;Neoplasm Metastasis;Neurocognitive;Neurocognitive Deficit;Neurologic;Optic Nerve;Organ;Patients;Performance;Phase;Phase I/II Clinical Trial;Prediction of Response to Therapy;Procedures;Quality of life;Radiation;Radiation Oncologist;Radiation Therapy Oncology Group;Radiation Toxicity;Radiation necrosis;Radiation therapy;Radiosurgery;Relapse;Research;Retrospective Studies;Site;Solid;System;Technology;Therapeutic Intervention;Tissues;Translating;Treatment Protocols;Treatment outcome;United States;automated segmentation;brain size;clinical practice;design;effective therapy;falls;follow-up;imaging Segmentation;improved;innovation;irradiation;learning progression;nervous system disorder;novel;novel therapeutic intervention;outcome prediction;patient population;preservation;prospective;response;spatiotemporal;targeted treatment;technology development;tool;treatment planning;treatment strategy;tumor An artificial intelligence-driven distributed stereotactic radiosurgery strategy for multiple brain metastases management PROJECT NARRATIVEPatients with multiple brain metastases a cancer which has spread to multiple places in the brain have poorsurvival or quality of life after single fraction stereotactic radiosurgery or whole brain radiotherapy. We willdevelop and study a new treatment strategy for multiple brain metastases using spatial and temporalfractionated stereotactic radiosurgery by frameless GammaKnife. The new procedure uses artificialintelligence to optimize and manage the treatment to improve patients survival and quality of life after thetreatment. NCI 10749026 11/23/23 0:00 PAR-18-560 5R01CA235723-06 5 R01 CA 235723 6 "OBCEMEA, CEFERINO H" 1/1/19 0:00 12/31/24 0:00 Biomedical Computing and Health Informatics Study Section[BCHI] 10291010 "GU, XUEJUN " "LU, WEIGUO ; WARDAK, ZABIHULLAH " 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 498609 NCI 314464 184145 PROJECT SUMMARYBrain metastases (BMs) are a life-threatening neurological disease but current treatment regimens cannotmanage multiple (>4) BMs (mBMs) without causing strong adverse effects. Stereotactic radiosurgery (SRS)utilizing potent dose to irradiate BMs and quick dose falloff to spare nearby tissues has proven to be an effectivetreatment regimen for limited-number and small-size BMs. However SRS could not avoid high toxic dose whenBMs are multiple clustered or adjacent to critical organs. To safe and effectively treat mBMs with SRS requiresaddressing these urgent needs: 1) to identify the maximum tolerable SRS dose; 2) to study neurocognitivedecline and design strategies to preserve patients post-treatment quality of life; and 3) to develop and implementhigh-quality streamlined mBMs SRS treatment and follow-up care.To address mBMs SRS management needs we aim to develop and implement an artificial intelligence (AI)-driven treatment planning system (TPS) and conduct a therapeutic intervention clinical trial both dedicated toimprove mBMs SRS treatment quality and efficiency. The AI-driven TPS namely AimBMs will have three AI-based computational modules including AI-Segtor for automatic segmentation AI-Predictor for treatmentoutcome prediction and AI-Planner for spatiotemporal distributed SRS plan optimization. AimBMs is initiallydeveloped based on retrospective data and facilitate the mBMs distributed SRS prospective phase I/II clinicaltrials while the clinical trial will provide critical clinical knowledge and evidence as feedback to improve AimBMsperformance. The ultimate goal of the project is to translate the AimBMs to routine clinical practice to improvemBMs SRS treatment quality patients post-treatment QoL and clinical facility workflow.In response to PAR-18-560 we have formed a multidisciplinary collaboration between radiation oncologists andmedical physicists to develop a novel AI-driven distributed SRS technology and conduct a cancer-targetedtherapeutic intervention for managing mBMs. The projects innovations include: 1) novel SRS treatment planningtechnological capability enabled by AI-based auto-segmentation treatment outcome prediction andspatiotemporal plan optimization; 2) novel AI learning capability to improve developed AI tools performancethrough the coherent clinical trial. The technology development will support the therapeutic intervention clinicaltrial while the clinical trial is designated to improve the developed system performance. This seamlesslyintegrated development mode ensures the developed system is clinically practical. Upon completion our newlydeveloped AimBMs will lay a solid foundation for mBMs SRS management and benefit a wide population ofpatients with BMs. Moreover the AI-based treatment planning and treatment delivery infrastructure built formBMs SRS can be transferred to other tumor sites to generate an even broader clinical impact. 498609 +No NIH Category available Adopted;Alleles;Bacteria;Cell Communication;Cell Nucleus;Cell division;Cells;Chromosome Segregation;Chromosomes;Coculture Techniques;Complex;Cytogenetics;Cytoplasm;DNA;DNA Damage;DNA Sequence;DNA Sequence Rearrangement;DNA sequencing;Data;Defect;Development;Drug resistance;Ecosystem;Environment;Event;Exhibits;Exposure to;Female;Fluorescence;Fluorescent in Situ Hybridization;Frequencies;Genetic;Genetic Materials;Genetic Polymorphism;Genome;Genomic Instability;Genomics;Goals;Human;Immune response;Innate Immune Response;Knowledge;Label;Lateral;Lipids;Malignant Neoplasms;Mammalian Cell;Maps;Measures;Mediating;Messenger RNA;MicroRNAs;Mitochondria;Mitosis;Mitotic;Modeling;Monitor;Mutate;Mutation;Nuclear Envelope;Nuclear Structure;Nucleic Acids;Oncogenes;Organelles;Pathway interactions;Phenotype;Predisposition;Process;Proteins;Reporter;Research;Resistance;Resolution;Role;Signal Transduction;Single Nucleotide Polymorphism;Site;Stimulator of Interferon Genes;Structure;System;Testing;Visualization;Y Chromosome;acquired drug resistance;cancer cell;cancer genome;cell type;chromosome missegregation;chromothripsis;digital;extracellular;genome sequencing;live cell imaging;male;micronucleus;next generation;response;sensor;trafficking;tumor microenvironment;uptake;whole genome Non-cell autonomous consequences of cytoplasmic DNA PROJECT NARRATIVEChromosomally unstable cancer cells frequently harbor cytoplasmic DNA that activates a cell-intrinsic innateimmune response. We currently do not understand whether these cytoplasmic DNAs are capable of elicitingnon-cell autonomous effects to surrounding cells in the tumor microenvironment. The proposed research seeksto elucidate whether and how fragmented chromosomes entrapped in the cytoplasm can undergo lateral transferbetween cells in a shared environment which will advance our understanding of cell-to-cell interactions in thetumor microenvironment. NCI 10748962 6/28/23 0:00 PA-21-051 1F31CA284510-01 1 F31 CA 284510 1 "ODEH, HANA M" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F05-D(21)L] 78916242 "MAURAIS, ELIZABETH " Not Applicable 30 PATHOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 38431 NCI 38431 0 PROJECT SUMMARY/ABSTRACTGenomic instability is a hallmark of cancer and can drive high rates of chromosome segregation errors duringmitotic cell division which can generate abnormal structures called micronuclei that entrap mis-segregatedchromosomes. Micronuclei are susceptible to massive DNA damage triggering the catastrophic pulverization ofthe entrapped chromosome into small DNA fragments a process termed chromothripsis. In addition togenerating genomic rearrangements that drive cancer development DNA fragments from micronuclei can alsomis-accumulate and persist in the cytoplasm. These cytoplasmic DNAs are detected by the cytosolic DNA sensorcGAS resulting in the cell-autonomous activation of the STING pathway to trigger an innate immune response.Although the cGAS-STING signaling mechanisms are well defined the fate of cytoplasmic DNAs followingrecognition by cGAS remains a critical knowledge gap. Here I propose to investigate non-cell autonomous rolesof cytoplasmic DNAs which hold critical implications in how genomically unstable cancer cells can elicit inter-cellular responses with the tumor microenvironment. I hypothesize that cytoplasmic DNAs derived fromfragmented chromosomes in micronuclei become exported for uptake by neighboring cells. To test thishypothesis I will leverage an experimental system enabling chromosome-specific induction of micronuclei andcytoplasmic DNA followed by tracking of specific cytoplasmic DNA fragments that harbor a selectable marker.In Aim 1 I will determine whether and how cytoplasmic DNAs are released into the extracellular environment tofacilitate non-cell autonomous activation of the cGAS-STING pathway in adjacent cells. I will further determinewhether extracellular DNA derived from the cytoplasm of host cells can be taken up by recipient cells which willbe monitored by live-cell imaging using a dCas9-based cytoplasmic DNA reporter. In Aim 2 I will track theincorporation of cytoplasmic DNAs into recipient cell nuclei and determine whether these fragments can integrateinto the host genome. This will be studied using a combination of cytogenetics and whole-genome sequencingto investigate the possibility of lateral DNA transfer between human cells. Despite occurring frequently inbacteria inter-cellular DNA transfer has been a longstanding challenge to test in the context of human cancer.These studies have potential for broad impact by advancing our understanding of cancer cell interactionsincluding the transfer of oncogenes and/or mutations from chromosomally unstable cancer cells to non-cancercells in the tumor microenvironment. 38431 +No NIH Category available A549;Actins;Adenocarcinoma Cell;Affect;Aging;Antineoplastic Agents;Apoptosis;Autoimmune;Automobile Driving;CD8-Positive T-Lymphocytes;CDKN2A gene;Cancerous;Cause of Death;Cells;Chronic;Cicatrix;Collagen;Connective Tissue Diseases;Cyclin-Dependent Kinase Inhibitor;Data;Deposition;Diagnosis;Disease;Engraftment;Enzymes;Epithelial Cells;Etiology;Extracellular Matrix;Fibroblasts;Fibrosis;Goals;Growth;Growth Factor;Human;Hypertrophy;Immunofluorescence Immunologic;In Vitro;Inflammation;Knowledge;Light;Link;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Monitor;Morbidity - disease rate;Mus;Myofibroblast;Neoplasms;Organ;Organoids;Outcome;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Patients;Phenotype;Play;Production;Publishing;Pulmonary Fibrosis;Reporting;Research;Rheumatism;Risk;Risk Factors;Role;Scleroderma;Signal Transduction;Skin;Smooth Muscle;Stains;Stromal Cells;Sudan Black B;System;Systemic Scleroderma;TNF gene;Technology;Testing;Time;Transforming Growth Factor beta;Translating;Trichrome stain method;Tumor Immunity;Tumor Promotion;aged;airway remodeling;bench to bedside;beta-Galactosidase;cell growth;cell injury;cell type;cytokine;gain of function;high voltage electron microscopy;human disease;idiopathic pulmonary fibrosis;in vivo;innovation;insight;knock-down;loss of function;lung development;member;muscle hypertrophy;novel;novel therapeutics;permissiveness;receptor;senescence;therapeutic candidate;transcriptome sequencing;tumor;tumor growth;tumorigenesis;tumorigenic;validation studies Targeting fibrosis to change cancer outcomes PROJECT NARRATIVEPatients diagnosed with Scleroderma (SSc) a disease resulting in the progressive scarring of the skin and lungshave a significantly increased risk of lung cancer or Cancerous Scleroderma (CSc). The main cell type that isresponsible for this severe scarring promotes the development of lung cancer in SSc patients hence thisresearch aims to uncover ways to target these pathogenic cells to resolve CSc. There is no currently establishedtreatment to reverse scarring in any organ therefore the impact of the novel insights gained from this researchwill be tremendous. NCI 10748730 7/27/23 0:00 PA-21-052 1F31CA284547-01 1 F31 CA 284547 1 "DIBELLO, ANTHONY THOMAS" 8/15/23 0:00 8/14/28 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 78937833 "BRECKENRIDGE, JOEY EMERY" Not Applicable 1 Unavailable 71284913 JZD1HLM2ZU83 71284913 JZD1HLM2ZU83 US 39.140663 -84.501007 615001 CINCINNATI CHILDRENS HOSP MED CTR CINCINNATI OH Independent Hospitals 452293039 UNITED STATES N 8/15/23 0:00 8/14/24 0:00 398 "Training, Individual" 2023 47680 NCI 47680 0 PROJECT SUMMARYScleroderma (SSc) patients have more than a 300% increased risk of lung cancer or Cancerous Scleroderma(CSc). SSc is a chronic autoimmune connective tissue disease of unknown etiology and has the highestmorbidity of all rheumatologic diseases. Moreover aging is a key risk factor in SSc patients for pathologicalairway remodeling or idiopathic pulmonary fibrosis (IPF) the leading cause of death in SSc patients. Intriguinglyaging is associated with increased senescent cells likely contributing to increased fibrosis. Published reportsshow that fibroblasts from IPF patients are senescent and produce a pro-tumorigenic senescence associatedsecretory phenotype (SASP) suggesting a potential key role for senescent myofibroblasts the key cell typeresponsible for fibrosis in driving the pathogenesis of CSc. Although it is evident that there is a tight linkbetween fibrosis and cancer in CSc the directionality of this progression and molecular circuits linking the twoare unknown. Published data by our lab show that the TNF superfamily member 14 LIGHT signals throughLTR expressed on myofibroblasts to drive collagen deposition and -smooth muscle actin hypertrophy thehallmarks of fibrosis. Our novel preliminary data suggests that senescent myofibroblasts drive cancer in aLIGHT dependent manner: In gain-of-function studies intratracheal (I.T.) LIGHT led to enhanced fibrosis andsenescent myofibroblasts in aged mice while in loss-of-function studies comparing aged to young mice givenlung adenocarcinoma cells I.T. LIGHT deletion abrogated cancer engraftment in aged mice while young WTand LIGHT-/- mice were protected from cancer engraftment. Additionally in a mouse lung organoid system weshowed that senescent myofibroblasts expressing LTR increase tumor growth. Therefore we hypothesizethat senescent myofibroblasts are responsible for driving pulmonary fibrosis in scleroderma andpromote lung cancer through expression of a SASP. Notably in a novel model we established of CSc LIGHTdeletion decreased fibrosis cancer engraftment and senescent myofibroblasts. One key question is how LIGHTaffects senescent myofibroblasts to drive cancer therefore we will address this through the following SpecificAims: 1) To identify the molecular circuits that LIGHT uses to drive cancerous scleroderma and 2) To directlyinvestigate the role of senescent myofibroblasts in promoting cancer ex vivo. For aim 1 we will modulate LIGHTsignaling and fibrosis in mice and induce our novel model of CSc monitoring disease. For aim 2 we will useRNA-sequencing and human lung organoids to identify the molecular pathways that drive CSc downstream ofLIGHT in senescent myofibroblasts to translate findings from mouse to human. The research described in aim 1will provide an understanding as to how LIGHT signaling drives CSc pathogenesis while the research describedin aim 2 will establish the role of senescent myofibroblasts as the key players in CSc and provide key insightson how to target these cells. Upon completion of these aims this project has the potential to identify a noveltherapeutic candidate targeting senescent myofibroblasts to reverse CSc. 47680 +No NIH Category available Address;African;African American;African American population;African ancestry;Age;Asian;Asian ancestry;Asian population;Assessment tool;Breast Cancer Detection;Breast Cancer Genetics;Breast Cancer Model;Breast Cancer Risk Factor;Case/Control Studies;Clinical;Cohort Studies;Complex;Data;Data Pooling;Data Set;Development;Elasticity;Epidemiology;Estrogen Receptors;Estrogen receptor negative;Estrogen receptor positive;Ethnic Population;European ancestry;Family history of;Funding;Gene Frequency;Genes;Genetic;Genetic Counseling;Genetic Diseases;Incidence;Individual;Investigation;Knowledge;Lasso;Left;Life Style;Linkage Disequilibrium;Mammographic screening;Maps;Methods;Modeling;Mutation;Noise;Outcome;Penetrance;Performance;Population;Predisposition;Prevention;Public Domains;Quantitative Trait Loci;RNA Splicing;Race;Racial Equity;Reproductive History;Risk;Risk Assessment;Risk Factors;Sample Size;Scoring Method;Signal Transduction;Statistical Methods;Susceptibility Gene;Target Populations;Testing;Training;Translating;Variant;Veterans;Woman;access disparities;ancestry analysis;black women;cancer subtypes;causal variant;clinical practice;cohort;early onset;genetic predictors;genetic variant;genome wide association study;genome-wide;genome-wide analysis;genomic locus;high risk;improved;innovation;malignant breast neoplasm;mortality;multi-ethnic;non-genetic;novel;polygenic risk score;precision medicine;racial disparity;racial population;risk prediction;risk prediction model;risk stratification;risk variant;screening;statistics;tool;transcriptome;transcriptome sequencing;transcriptomics;translational impact;triple-negative invasive breast carcinoma Polygenic Risk Prediction of Breast Cancer for Women of African Descent PROJECT NARRATIVEThere is an urgent need to reduce the persistent racial disparities in breast cancer outcomes in the U.S and theadvances in precision medicine have left African Americans behind. The primary objective of this study is tobuild a risk assessment tool for women of African descent from genetic alterations in genes that contribute toincreased breast cancer risk and combine this tool with environmental and lifestyle risk factors of breastcancer. We also wish to find the causal risk factors for breast cancer that share across populations. NCI 10748724 7/24/23 0:00 PAR-20-276 2R01CA228198-05A1 2 R01 CA 228198 5 A1 "NELSON, STEFANIE A" 4/19/18 0:00 7/1/28 0:00 Special Emphasis Panel[ZRG1-EPH-C(02)M] 8472867 "HUO, DEZHENG " Not Applicable 1 PUBLIC HEALTH & PREV MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 515299 NCI 390831 124468 PROJECT ABSTRACT African Americans have the highest breast cancer mortality rate highest incidence rate of early-onsetbreast cancer and highest incidence rate of triple-negative breast cancer in the U.S. More than 220susceptibility loci for breast cancer have been identified by genome-wide association studies (GWAS) mainlyin population of European ancestry. Polygenic risk scores (PRS) which aggregate common genetic variantsidentified by GWAS have been developed to predict genetic risk of breast cancer for European ancestrywomen and used in clinical practice but the PRS for African American women has suboptimal accuracy.Therefore we propose a comprehensive analytical study that leverages several types of existing geneticdatasets for breast cancer available to us and in public domains to address three specific aims. First we aimto conduct cross-ancestry fine-mapping analysis to identify a credible set of causal variants in 237 breastcancer susceptibility loci. Then we will develop parsimonious and robust PRS from the credible set of variants.We have compiled and harmonized genetic data from breast cancer GWASs in women of African ancestryincluding 18034 cases and 22104 controls and leverage the association results from European ancestry(>133000 cases and >291000 controls) and Asian (>22000 cases and >22000 controls) populations.Second we aim to develop precise PRS using genome-wide data with several novel cross-ancestry statisticalmethods. We will develop PRS models for overall breast cancer and its subtypes (estrogen receptor positiveand negative and triple-negative breast cancer). Then we will validate the models generated in aims 1-2 inindependent datasets (>14000 cases and >82000 controls) from case-control studies ongoing cohort studiesand an ongoing risk-adaptive breast cancer screening trial. Third we will integrate the best performed PRSwith existing risk prediction models that are based on non-genetic risk factors. The resulting absolute riskmodels have a good potential to translate knowledge from GWAS to inform the practice of genetic counselingbreast cancer screening and prevention for African Americans. It has good potential to advance racial equity inbreast cancer. 515299 +No NIH Category available 3-Dimensional;Anatomy;Animal Model;Animals;Brain;Brain Diseases;Brain Mapping;Brain Neoplasms;Brain imaging;Cell Proliferation;Cell membrane;Cells;Choline;Clinic;Clinical;Clinical Research;Data;Deoxyglucose;Detection;Deuterium;Development;Disease Management;Disease Progression;Dose;Evaluation;Future;Glioblastoma;Glioma;Goals;Growth;Human;Hydrogen;Imaging Device;Imaging Techniques;Label;Lesion;Longitudinal Studies;MRI Scans;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Measures;Medical Imaging;Metabolic;Metabolism;Methods;Modeling;Mus;Normal tissue morphology;Nutrient;Oligodendroglioma-Astrocytoma;Patients;Phospholipids;Positioning Attribute;Positron-Emission Tomography;Primary Brain Neoplasms;Prognosis;Proliferating;Radioactive;Research Project Grants;Resolution;Rodent Model;Scanning;Signal Transduction;Solid;Specificity;Techniques;Testing;Therapeutic;Tissues;Tracer;Translating;Translations;Tumor Tissue;Tumor Volume;brain size;brain tissue;brain tumor imaging;cancer type;chemotherapeutic agent;clinical translation;contrast imaging;detection sensitivity;dietary supplements;early detection biomarkers;experimental study;glucose analog;glucose metabolism;glucose uptake;imaging detection;imaging modality;imaging probe;improved;in vivo;insight;magnetic resonance spectroscopic imaging;membrane synthesis;metabolic abnormality assessment;metabolic imaging;mouse model;novel;response;stable isotope;standard of care;temozolomide;treatment effect;treatment response;tumor;tumor growth;tumor metabolism;tumor specificity;uptake Mapping of choline uptake and metabolism in brain tumors with deuterium metabolic imaging (DMI) PROJECT NARRATIVEDeuterium metabolic imaging (DMI) is a novel 3D method that can noninvasively map metabolism of non-radioactive deuterium-labeled substrates in healthy or diseased brain. Choline is an essential nutrient that isoften taken up and metabolized at a higher level in tumors than in normal tissue. Deuterium-labeled choline is apromising imaging probe that can be combined with DMI to map choline uptake and metabolism in brain tumorsin vivo and inform on tumor aggressiveness and treatment response. NCI 10748411 11/3/23 0:00 PAR-20-052 5R03CA267438-02 5 R03 CA 267438 2 "ZHANG, HUIMING" 12/5/22 0:00 11/30/24 0:00 ZCA1-TCRB-9(O1)S 10309744 "DE FEYTER, HENK " Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 83750 NCI 50000 33750 PROJECT SUMMARYWhile neuro-oncologists rely heavily on medical imaging particularly magnetic resonance imaging (MRI) fordetection and sizing of brain tumors they do not have access to a robust method that shows the activemetabolism of tumor lesions. Positron emission tomography (PET) detection of the radioactive glucose analog18F-deoxyglucose (FDG) is widely used for metabolic imaging of many solid cancers outside of the brain. FDG-PET detects high glucose uptake which is often a sign of active and growing tissue such as in proliferatingtumors. However when used for scanning tumors in the brain FDG-PET has shown to be often inconclusive.This is not due to any technical limitation but merely the consequence of the high glucose uptake of normalbrain leading to high background signal and thus low metabolic image contrast between brain and tumor. Choline is an essential nutrient and proliferating cells need choline for phospholipid and membranesynthesis. As a result many types of cancer have evolved with a high capacity for choline uptake andmetabolism. In contrast choline uptake in normal brain is in comparison very low. Our preliminary data indicatethat the detection of deuterated choline uptake and metabolism using the novel technique Deuterium MetabolicImaging (DMI) can provide high brain tumor-specific image contrast with surrounding brain. DMI of deuterium(2H)-labeled choline allows detection of choline uptake and/or choline metabolism simply by varying the timingof the scan in relation to the start of the choline administration. These features make choline DMI a very promisingmetabolic imaging technique for use in brain tumors. The overall objective is to investigate the potential of choline DMI as a metabolic imaging method for braincancer. In this R03 research project we propose to investigate the value of mapping choline uptake andmetabolism with DMI as correlate for brain tumor grade and prognosis (Aim 1) and evaluating treatment effect(Aim 2). We will use two established mouse models of brain tumor grade 3 and grade 4 glioma and test theeffect of temozolomide the standard of care chemotherapeutic on tumor choline uptake and metabolism. Choline is an essential nutrient and used as a nutritional supplement within and outside of clinical settingsat very high but safe doses. Deuterium is a stable isotope and commonly used as a tracer for metabolic studies.Finally DMI is a highly translatable imaging technique already applied in clinical research settings. Therefore ifthe potential of mapping of choline uptake and metabolism is established in these rodent models rapidtranslation of DMI for detection of deuterium-labeled choline in human patients is relatively straightforward. 83750 +No NIH Category available Acute T Cell Leukemia;Adult;Adult Precursor B Lymphoblastic Leukemia;Adult Precursor T Lymphoblastic Leukemia;Apoptosis;Automobile Driving;BCL2L1 gene;Binding;Biological Assay;Biological Process;CRISPR/Cas technology;Cell Death;Cell Proliferation;Cell Survival;Cells;Central Nervous System;Chemoresistance;Chemotherapy-Oncologic Procedure;Child;Childhood Precursor T Lymphoblastic Leukemia;Clinical;Combined Modality Therapy;Coupled;DNA Methylation;DNA Modification Methylases;DNMT3a;DNMT3a mutation;Development;Disease-Free Survival;Dose;Down-Regulation;Enhancers;Enzymes;Gene Expression;Generations;Genetic;Genetic Enhancer Element;Genetic Models;Genome;Genome engineering;Genomics;Goals;Hematologic Neoplasms;Hematopoietic Neoplasms;Human;Hypersensitivity;IL7 gene;Impairment;Inferior;Interleukin-6;Link;Maintenance;Malignant - descriptor;Malignant Neoplasms;Modeling;Molecular;Molecular Abnormality;Mus;Mutant Strains Mice;Mutate;Mutation;NOTCH1 gene;Neoplasms;Oncogenic;Outcome;PTPN6 gene;Pathogenesis;Pathology;Patient-Focused Outcomes;Patients;Phenotype;Positioning Attribute;Prognosis;Reagent;Recurrence;Relapse;Research;Resistance;Role;Sampling;Signal Transduction;Stat5 protein;Stress;Survival Rate;System;T-Cell Lymphoma;T-Cell Transformation;T-Lymphocyte;Testing;Time;Treatment Side Effects;Treatment outcome;Tumor Suppressor Proteins;Up-Regulation;White Blood Cell Count procedure;acute T-cell lymphoblastic leukemia cell;chemotherapeutic agent;chemotherapy;clinical prognosis;cytokine;gain of function mutation;genome sequencing;high risk;high risk population;in vivo;inhibitor;leukemia;loss of function;lymphadenopathy;mouse genetics;mouse model;mutant;novel;novel therapeutic intervention;patient derived xenograft model;patient population;precision medicine;programs;rational design;relapse patients;standard of care;stem cells;tool;treatment strategy;virulence gene JAK/STAT signaling in the pathogenesis of DNMT3A mutant T-ALL PROJECT NARRATIVE In adults T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic cancer with a pooroverall survival high relapse rate and significant treatment-related side effects due to intense chemotherapyregimens. Using mouse genetic models and primary T-ALL patient samples this project will study theimportance of JAK/STAT signaling in the pathology of T-ALL driven by loss-of-function DNMT3A mutations.The main goal of these research efforts is the development of precision medicine approaches for DNMT3A-mutant adult T-ALL patients a group with poor clinical outcomes and no established standard-of-care forrelapsed patients. NCI 10748361 11/9/23 0:00 PA-19-056 5R01CA236819-05 5 R01 CA 236819 5 "JHAPPAN, CHAMELLI" 12/12/19 0:00 11/30/24 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 9640952 "CHALLEN, GRANT ANTHONY" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 329411 NCI 209150 120261 ABSTRACT Like other cancers T-cell acute lymphoblastic leukemia (T-ALL) arises from the accumulation of geneticabnormalities that impair function of immature T-cell progenitors. DNMT3A which encodes a de novo DNAmethyltransferase enzyme that catalyzes the establishment of new DNA methylation marks on the genome isrecurrently mutated in 10-18% of adult T-ALL cases and confers a poor clinical prognosis. We recentlyshowed using genetic mouse models that Dnmt3a acts as a T-cell tumor suppressor. Introduction of anactivating Notch1 mutation into a Dnmt3a loss-of-function genetic background (a common genetic combinationin patients) generated a lethal T-ALL with half the latency period compared to T-ALL with wild-type Dnmt3a.Dnmt3a-mutant T-ALL blasts are resistant to cell death both in vivo and under different stress conditions. Thissuggests a major biological function of DNMT3A mutations in T-ALL cells is to make them harder to kill andthe inferior clinical outcomes of these patients may be due to resistance to standard chemotherapy regimens.We have now uncovered a potential mechanism to explain this which is conserved in both Dnmt3a-mutantmouse T-ALL models and primary human DNMT3A-mutant T-ALL patient samples. DNMT3A-mutant T-ALLcells are hypersensitive to cytokines such as IL-6 and IL-7 which results in elevated JAK/STAT signalingtriggering a pro-survival gene expression program. Specifically we hypothesize that DNMT3A-mutant T-ALL cells are resistant to apoptosis due to pSTAT5-dependent upregulation of BCL-xL. The goals ofthis proposal are to understand the molecular mechanisms driving these phenotypes and exploit them for noveltherapeutic interventions. We will test this hypothesis with the following Specific Aims; Determine the role of STAT5 and BCL-xL in the pathogenesis of DNMT3A-mutant T-ALL Define the role of JAK/STAT signaling in chemoresistance of DNMT3A-mutant T-ALL. Identify molecular mechanisms underpinning the functional phenotypes of Dnmt3a-mutant T-ALL. We will leverage preliminary findings to interrogate this hypothesis using a complementary combination ofgenetic mouse models human patient-derived xenografts and CRSIPR/Cas9 genome engineering. In Aim 1we will evaluate the importance of STAT5 and BCL-xL for the development and maintenance of DNMT3A-mutant T-ALL (both mouse and human) using state-of-the-art genetic tools. In Aim 2 we will use genomicassays to understand how DNMT3A-mutant T-ALL cells are resistant to chemotherapy and if JAK/STATinhibition can resensitize these cells to chemotherapeutic agents in vivo. In Aim 3 we will determine theimportance of DNA methylation at enhancers in the generation of pathogenic gene expression programs forthis T-ALL subtype and evaluate the role of SHP-1 in conferring cytokine hypersentivity to DNMT3A-mutant T-ALL cells. We will use the results of this project to inform design of rationally-targeted precision medicinestrategies for the treatment of T-ALL patients based on their underlying genetics. 329411 +No NIH Category available Acceleration;Acute;Address;Advanced Malignant Neoplasm;Adverse event;Affect;Aftercare;Antineoplastic Agents;Arthralgia;Back;Chills;Clinical;Clinical Treatment;Colitis;Combination immunotherapy;Combined Modality Therapy;Community Clinical Oncology Program;Coupled;Data;Decision Making;Detection;Deterioration;Development;Diarrhea;Disease;Dizziness;Dose;Early Diagnosis;Early Intervention;Early identification;Ensure;Event;Fatigue;Fever;Headache;Heart;Immune;Immune checkpoint inhibitor;Immunotherapy;Institution;Intervention;Knowledge;Late Effects;Malignant Neoplasms;Measures;Mission;Monitor;Moon;Myalgia;National Cancer Institute;Nausea;New Agents;Nivolumab;Outcome;Palpitations;Patient Outcomes Assessments;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Public Health;Publishing;Pulmonary Inflammation;Quality of life;Recommendation;Reporting;Research;Research Personnel;Risk;Safety;Shortness of Breath;Supportive care;Swelling;Symptoms;Therapeutic;Therapy trial;Time;Toxic effect;United States Food and Drug Administration;University of Texas M D Anderson Cancer Center;Vomiting;Work;cancer immunotherapy;cancer therapy;checkpoint therapy;cohort;compliance behavior;disabling symptom;drug development;early phase clinical trial;early phase trial;experience;gastrointestinal symptom;immune-related adverse events;improved;ipilimumab;optimism;pembrolizumab;precision medicine;prevent;side effect;standard of care;survival outcome;symptom cluster;symptom management;targeted treatment;treatment response Use of Patient-Reported Outcomes in Understanding Symptomatic Adverse Events in Early-Phase Trials of Combination Treatments that Include Immune Checkpoint Inhibitors and Targeted Therapy PROJECT NARRATIVE This project will utilize patient report to examine the short-term and long-term symptomatic adverseevents associated with combination therapies that include immune checkpoint inhibitors in early-stage clinicaltrials. Early assessment of the patient's perspective on personal harms and benefits of these combinationimmunotherapies will allow for proactive intervention inform decisions about therapies that might havesimilar survival outcomes but different symptomatic consequences and provide timely empirical data for drugdevelopers about the symptomatic effects of their products. This research is relevant to public health and to theNational Cancer Institute's mission in that it will lead to a better understanding of the largely unknown short-term and long-term side effects of combination therapies that include immune checkpoint inhibitors. NCI 10748312 11/17/23 0:00 PAR-18-869 5R01CA242565-05 5 R01 CA 242565 5 "FILIPSKI, KELLY" 6/5/19 0:00 11/30/25 0:00 Nursing and Related Clinical Sciences Study Section[NRCS] 14523326 "GEORGE, GOLDY C" "HONG, DAVID S." 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 323350 NCI 202094 121256 PROJECT SUMMARY Breakthroughs in cancer immunotherapy have excited patients and clinicians and have brought optimismback into the oncology community. However these therapies are often effective for only a percentage of patientsand some patients may even be at risk for serious and sometimes fatal toxicities related to the therapy. Unlikethe toxicities induced by standard therapies immune-related adverse events (irAEs) are just becoming appreci-ated and side effect profiles for new immunotherapies are often poorly understood. Further contributing to thisissue is the increasing use of therapies that combine immune checkpoint inhibitors approved by the US Foodand Drug Administration (eg nivolumab pembrolizumab) with other checkpoint inhibitors or targeted thera-pies. The unique toxicities of such combination therapies remain largely unknown and need to be tracked sothat their immune-related safety profiles can be characterized and adequately managed. Researchers at The Uni-versity of Texas MD Anderson Cancer Center propose to use patient-reported outcomes (PROs) to capturesymptomatic irAEs of combination therapies that include checkpoint inhibitors taking advantage of the largenumber of early-phase trials of these therapies already in place in the institution's Department of InvestigationalTherapeutics coupled with the expertise in longitudinal symptom assessment in the Department of SymptomResearch. The Specific Aims of the study are: (1) to identify track and evaluate emerging symptomatic toxic-ities and symptom burden during early-phase clinical trials of treatments that include immune checkpoint in-hibitors in combination with other checkpoint inhibitors or targeted therapies; and (2) to investigate relation-ships between longitudinal patient-reported symptoms and clinical outcomes (eg development of moderate-to-severe irAEs time to treatment discontinuation time to deterioration) in early-phase trials of combination treat-ments that include checkpoint inhibitors and to investigate whether moderate to severe irAEs are predicted byincreases in relevant symptoms prior to the event. The study's clinical impact will be early detection of irAEs associated with combination therapies thatinclude checkpoint inhibitors to facilitate proactive intervention. Worsening symptoms may presage the emer-gence of their clinical manifestations and allow for appropriate supportive care or for other treatment decisionsto be made. PROs are an essential component of cancer drug development without which clinicians and regu-lators have an incomplete picture of how patients are affected by a new agent. PROs will provide invaluable pa-tient perspectives on the symptomatic effects of combination treatments that include immune checkpoint in-hibitors to multiple stakeholders in early drug development (eg patients sponsors regulators and payers). This project addresses Recommendation F in the Cancer Moon Shot Blue Ribbon Panel 2016 reportwhich calls for accelerated research to monitor and manage patient-reported symptoms not only for improvingquality of life but also for ensuring patient adherence to treatments that will improve therapeutic response.1 323350 +No NIH Category available Adopted;Amino Acids;Anabolism;Aspartate;Aspartate Transaminase;Award;Biological Assay;CRISPR screen;Cancer Cell Growth;Cancer Etiology;Cell Hypoxia;Cell Line;Cell Proliferation;Cell Respiration;Cell membrane;Cessation of life;Chemicals;Clinic;Collaborations;Conversion disorder;Cytoplasm;Dependence;Distant;Drops;Electron Transport;Environment;Enzymes;Exposure to;Foundations;GOT2 gene;Genetic;Glutamine;Growth;Hypoxia;In Vitro;Injections;Isotope Labeling;KRAS2 gene;KRASG12D;Knock-out;Knockout Mice;Libraries;Liver;Magnetic Resonance;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mitochondrial Aspartate Aminotransferase;Modeling;NADH;Natural regeneration;Neoplasm Metastasis;Nutrient;Organ;Organoids;Oxygen;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic enzyme;Pathway interactions;Patients;Phase;Pre-Clinical Model;Primary Neoplasm;Process;Proliferating;Protein Biosynthesis;Refractory;Resistance;Role;Route;Starvation;Stress;Supplementation;Survival Rate;TP53 gene;Testing;Therapeutic;United States;Vascular blood supply;Work;cancer cell;carboxylate;carboxylation;cell growth;deprivation;experimental study;gene synthesis;improved;in vivo;inhibitor;metabolic imaging;metabolomics;mutant;mutant mouse model;novel strategies;nucleotide metabolism;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;patient derived xenograft model;pharmacologic;pre-clinical;programs;tool;tumor;tumor growth;tumor metabolism;tumor xenograft;uptake Targeting aspartate biosynthesis in pancreatic tumors Project Narrative Pancreatic ductal adenocarcinoma frequently subjected to oxygen-limiting environments is highlyrefractory to all forms of treatment and novel approaches to inhibit their primary growth and colonization ofdistant organs are urgently needed. In this proposal as a potential therapeutic strategy we will identify andinhibit the metabolic route and enzyme that pancreatic cancers rely on to synthesize aspartate a metabolitethat we previously found to be limiting under hypoxia and whose supplementation increases primary tumorgrowth and metastatic potential of pancreatic cancer cells. Additionally the analysis of which metabolicchanges pancreatic cancer cells undergo during metastasis will increase understanding of the metabolicrewiring this process triggers and will identify potential metabolic liabilities of metastasis. NCI 10748311 11/17/23 0:00 PA-19-130 5R00CA248838-04 5 R00 CA 248838 4 "SALNIKOW, KONSTANTIN" 7/1/20 0:00 11/30/24 0:00 Transition to Independence Study Section (I)[NCI(B)-I] 14727428 "GARCIA BERMUDEZ, JAVIER " Not Applicable 30 PEDIATRICS 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 224099 NCI 136646 87453 Pancreatic ductal adenocarcinomas (PDACs) are the second leading cause of cancer death in theUnited States with a survival rate of 3% once it spreads to distant organs. PDAC cells within a tumor arefrequently starved for oxygen due to their high proliferation rate and insufficient vasculature. This degree ofhypoxia in the tumor triggers strong metabolic adaptations on cancer cells that allow their survival andproliferation. Among these adaptations are altered uptake and utilization of major nutrients such as glutamine.However the precise mechanisms through which pancreas cancer metabolism adapts to hypoxia and whetherthis could be exploited for therapy remain unknown. In preliminary studies we found that when pancreatic and lung cancers are exposed to low levels ofoxygen the amino acid aspartate required for protein and nucleotide synthesis becomes limiting. Simplyincreasing the uptake of exogenous aspartate by expression of a plasma membrane aspartate transporterstrongly promoted the growth rate of cancer cells under hypoxia and in tumors as well as enhanced theirmetastatic potential. These findings provide evidence that aspartate can be a cancer growth-limiting metabolitein vivo. Furthermore a CRISPR/Cas9 screen using a library of sgRNAs targeting rate-limiting metabolicenzymes revealed that GOT2 one of the two enzymes that de novo synthesizes cellular aspartate fromglutamine is essential for in vitro proliferation under hypoxia of a KRAS/TP53 mutant PDAC cell line. Buildingupon these results I propose to test the hypothesis that targeting de novo aspartate synthesis may havetherapeutic potential in pancreatic tumors at the level of primary tumor growth and metastasis. Throughout the initial phase of this award we will define the essentiality of GOT2-mediated aspartatesynthesis in a panel of PDAC cell lines upon being exposed to low tensions of oxygen and importantly whengrown as tumors and during colonization of distant organs. Additionally we will determine the contribution andimpact on cancer proliferation of the two divergent metabolic routes of glutamine conversion into aspartate:oxidative and reductive metabolism. Building upon the obtained results we will target aspartate synthesis inpre-clinical patient-derived models and KRAS/TP53 mutant mouse models and by using isotope-labelingmetabolomic analysis we will show which aspartate synthesis route is used by pancreatic tumors in vivo. Finally by using in vivo metabolomics and mitochondrial pull-downs in primary and metastatic tumors Ipropose to define whether hypoxia-triggered metabolic rewiring is a determinant of the metastatic potential ofPDAC cells. These analysis will identify which metabolic changes PDAC cells undergo during metastasisunveiling potential liabilities that could be targeted in order to decrease spread of PDAC to distant organs. Altogether the proposed experiments will define the role of aspartate synthesis in PDAC tumor growthand metastasis and will test whether any other metabolic changes are required for PDAC cells to metastasize. 224099 +No NIH Category available ASCL1 gene;Acute;Anabolism;Arginine;Arginine deiminase;Aspartate;BETA2 protein;Cancer Biology;Cancer Model;Carbon;ChIP-seq;Clinic;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Computer Analysis;Consumption;Data;Data Analyses;Data Set;Dependence;Development;Disease;Disease model;Environment;Enzymes;Family member;Folic Acid Antagonists;Genes;Genetic Transcription;Genetically Engineered Mouse;Glean;Goals;Health;Human;Huntsman Cancer Institute at the University of Utah;In Vitro;Isotopes;Knowledge;Lung Neuroendocrine Neoplasm;MYCL1 gene;MYCN gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;Metabolism;Mission;Modeling;Neoplasm Metastasis;Neuroendocrine Tumors;Nucleotide Biosynthesis;Oncogenic;Patients;Pharmaceutical Preparations;Physiological;Platinum;Play;Process;Regulator Genes;Research;Resistance;Resistance development;Resources;Role;Secondary to;Serine;Specific qualifier value;Starvation;Stress;System;Testing;Therapeutic;Time;Training;United States National Institutes of Health;activating transcription factor;activating transcription factor 4;argininosuccinate synthase;base editing;cancer subtypes;chemotherapy;chromatin immunoprecipitation;deprivation;desensitization;effective therapy;experimental study;gene synthesis;human model;improved;in vivo;inhibitor;lung cancer cell;metabolomics;molecular subtypes;mouse model;novel;nucleotide metabolism;overexpression;preclinical study;preclinical trial;prevent;programs;rapid growth;resistance mechanism;response;single-cell RNA sequencing;small cell lung carcinoma;standard of care;targeted treatment;therapeutically effective;therapy resistant;transcription factor;transcriptomics;treatment strategy;tumor;tumor metabolism;urea cycle Investigating and targeting metabolic vulnerabilities of MYC-driven small cell lung cancer PROJECT NARRATIVESmall cell lung cancer (SCLC) is the deadliest and most difficult-to-treat subtype of lung cancer with astandard-of-care that has remained largely unchanged for decades. Arginine deprivation by pegylated argininedeiminase (ADI-PEG20) is the most effective targeted therapy in preclinical studies of MYC-driven SCLC buttumors eventually become resistant to ADI-PEG20. In accordance with NIHs mission to advance humanhealth this study will interrogate mechanisms of ADI-PEG20 resistance to identify therapeutic strategies thatprolong the efficacy of ADI-PEG20 and improve survival of patients with SCLC. NCI 10748278 8/23/23 0:00 PA-21-051 5F31CA275295-02 5 F31 CA 275295 2 "ODEH, HANA M" 9/1/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 77976312 "IRELAND, ABBIE SHAYE" Not Applicable 4 PHARMACOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT ABSTRACT Small cell lung cancer (SCLC) is a fatal neuroendocrine lung tumor that is challenging to treat due toearly metastasis rapid growth and a lack of easily targetable driver alterations. For the last ~40 years SCLChas been treated primarily as a single disease in the clinic with combination platinum-based chemotherapy thatoffers a median survival of only ~10-12 months. It is imperative to better understand SCLC biology to enabledevelopment of novel treatment strategies that effectively prolong patient survival. SCLC tumors amplify oroverexpress one oncogenic MYC family member: MYC MYCL or MYCN. MYC-high SCLCs are metabolicallydistinct from MYC-low and have specific and targetable metabolic vulnerabilities. The most effective therapeuticstrategy for treatment of MYC-high SCLCs in preclinical trials is deprivation of circulating arginine by pegylatedarginine deiminase (ADI-PEG20). MYC-high SCLCs are particularly sensitive to ADI-PEG20 because they lackthe enzyme argininosuccinate synthetase 1 (ASS1) that catalyzes de novo synthesis of arginine by the ureacycle. Still SCLC tumors eventually develop resistance to ADI-PEG20 (ADIR) that corresponds with re-expression of ASS1. Upon ADIR tumors acquire secondary metabolic dependencies that may be targeted toprolong ADI-PEG20 response and patient survival. Preliminary data show that ADIR SCLC depends on serineand one-carbon (1C) metabolism which can be targeted with anti-folates. Preliminary data also delineatecandidate transcriptional regulators that may govern ADIR in SCLC. Activating transcription factor 4 (ATF4) astress-responsive transcription factor is one predicted upstream regulator of gene programs enriched in ADIRvs nave SCLCsdetermined by bulk and single-cell RNA sequencing. ATF4 is induced upon acute argininedeprivation in SCLC and continues to be expressed with its target genes during ADIR. Here the applicant willemploy a single-cell RNA-seq-derived model of SCLC response to ADI-PEG20 metabolite profiling in vivoisotope tracing and CRISPR-based gene editing to interrogate whether ATF4 governs ADIR. The hypothesis forthis research is that ATF4 drives ADIR by enhancing serine and 1C metabolism in an ASS1-dependent manner.Experiments will be performed in two specific aims to test whether ATF4 governs: 1) the sensitivity of MYC-highSCLCs to ADI-PEG20 and/or 2) the sensitivity of ADIR SCLCs to 1C metabolism inhibitors. Knowledge gleanedfrom this research will inform combination treatment strategies that improve the efficacy of ADI-PEG20 andextend survival of patients with SCLC and other ASS1-low tumors. The proposed research will provide uniqueopportunities for the applicant to gain expertise in cancer biology cancer metabolism and computationalanalysis of -omics datathree major goals of the applicants training plan. The proposed research will occurover three years of training at Huntsman Cancer Institute and the University of Utah a collaborative andresource-rich training environment in the lab of Dr. Trudy Oliver. 47694 +No NIH Category available 3-Dimensional;Apoptosis;Architecture;Atomic Force Microscopy;Biomimetics;Breast Cancer Cell;Breathing;Cancer Biology;Cancer Cell Growth;Cell Death;Cell model;Cell secretion;Cells;Cessation of life;Clinical;Communication;Complex;Coupled;Desmoplastic;Development;Disease;Doctor of Philosophy;Educational process of instructing;Endocrine;Engineering;Epithelium;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Flow Cytometry;Foundations;Glycoproteins;Goals;Growth;Lead;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mechanics;Mentors;Mesenchymal;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Methods;Modeling;Morbidity - disease rate;Neoplasm Metastasis;Nonmetastatic;Output;Pathway interactions;Patients;Periodicity;Phenotype;Positioning Attribute;Postdoctoral Fellow;Primary Neoplasm;Production;Proliferating;Proteins;Proteomics;Research;Research Personnel;Role;Signal Transduction;Site;Stretching;Stromal Cells;Structure of parenchyma of lung;Survival Rate;Testing;Tissue Engineering;Tissues;Training;Tumor Cell Migration;Universities;Vesicle;Western Blotting;Woman;Work;cancer cell;cancer diagnosis;cancer subtypes;cell type;conditioning;defined contribution;effective therapy;experimental study;extracellular;extracellular vesicles;improved;in vivo;insight;interest;lung volume;malignant breast neoplasm;mechanical force;mechanical load;mechanical properties;mechanotransduction;metabolic rate;migration;mortality;neoplastic;neoplastic cell;novel;paracrine;phenotypic biomarker;prevent;single-cell RNA sequencing;skills;targeted treatment;therapy development;three dimensional cell culture;three-dimensional modeling;transmission process;tumor microenvironment Matrix Accumulation in the Metastatic Niche Project NarrativeAfter metastasis to the lungs breast cancer cells are exposed to unique forces and matrix proteins that are notpresent at the primary tumor. My previous findings indicate that cyclic stretching mimicking breathing dynamicswithin a 3D model of the early metastatic niche can drive tumor cells into a state of growth arrest withoutwidespread cell death. Because stromal cells are the key contributor of matrix composition and architecture mygoal is to evaluate the unique fibroblast subtypes conditioned by breast cancer cells at different stages of themetastatic cascade and characterize how the tissue changes they produce alter the metastatic progression ofdisseminated breast cancer cells. NCI 10747988 11/16/23 0:00 RFA-CA-20-048 5K00CA264734-04 5 K00 CA 264734 4 "DAMICO, MARK W" 9/1/21 0:00 11/30/26 0:00 ZCA1-SRB-H(M1) 15315991 "LIBRING, SARAH " Not Applicable 5 BIOMEDICAL ENGINEERING 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN BIOMED ENGR/COL ENGR/ENGR STA 372032408 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 88695 NCI 82125 6570 Project SummaryBreast cancer (BC) is the most frequently diagnosed cancer in women. In addition metastatic BC has a 5-yearsurvival rate of only 27% and metastases are associated with the vast majority of cancer-related deaths. Recentresearch has highlighted a complex dynamic between cancer cells and the tumor microenvironment as essentialfor the formation of macrometastases. Within this field tissue stiffening through matrix accumulation and alteredmatrix organization were recently linked with sustained proliferation and increased migration of tumor cells.Elevated levels of the glycoprotein fibronectin (FN) have been correlated to poor patient survival in BC and arelinked to enhanced seeding of disseminated tumor cells at metastatic sites. My previous work has indicatedseveral mechanisms through which accumulated FN impacts the metastatic potential of BC cells. Foremost Ihelped identify a transient increase in extracellular FN in the lungs which peaked before overt metastasiscoupled with a non-transient increase in total lung volume. I further found that cyclic mechanical force acted asa suppressor of cancer cell growth in a biomimetic lung model implicating the accumulation of extracellularmatrix (ECM) as an attempt by the cancer cells to alter the mechanical properties of the lung tissue and resistentering dormancy. However my results showed that BC cells could not organize FN into ECM independently.Instead BC cells altered the accumulation and architecture of FN by conditioning resident fibroblasts throughsoluble factors and extracellular vesicles. I observed that the FN produced by conditioned fibroblasts varied notonly based on the phenotype of the BC cell but also from the method of conditioning which tested paracrine andendocrine signaling. These preliminary results indicate that unique subtypes of cancer associated fibroblasts(CAFs) may develop based on the BC cell conditioning mechanism where unique subtypes may be associatedwith the specific needs of the various stages of the metastatic cascade. Therefore Aim 1 of the proposed studiesduring my Ph.D. research will define the contribution of cyclic strain on BC cell phenotype and dormancy usingour novel actuating platform. Aim 2 which I will undertake during my postdoctoral research will seek to betterdefine the varied roles of CAFs in metastatic progression through the development of a foundation of subtypesafter conditioning with media isolated extracellular vesicles and contact from BC cancer cells includingmetastatic and non-metastatic BC cells with epithelial and mesenchymal phenotypes. These findings will enableadvanced interaction studies and promote the development of novel targets for fibroblasts which may be a moreconsistent target than genetically unstable cancer cells and lead to more effective treatment. In addition theproposed studies and training plan will expand my current tissue engineering skillset to include advancedunderstanding of mechanotransduction pathways and CAF formation as well as improve my communicationmentoring and teaching. Together these skills will place me as a competitive candidate for an independentprinciple investigator position in a research university at the intersection of cancer biology and engineering. 88695 +No NIH Category available Antibodies;Attenuated;Biological Assay;Cancer cell line;Cell Line;Cell Proliferation;Cell Survival;Cell surface;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinical;Coupled;DNA biosynthesis;Data;Dihydrofolate Reductase;Dose;Down-Regulation;Enzymes;FGFR1 gene;FGFR3 gene;Failure;Fibroblast Growth Factor Receptors;Folic Acid;Folic Acid Antagonists;Human;In Vitro;Libraries;Link;Lung Adenocarcinoma;MAP Kinase Gene;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;Modeling;Molecular;Mus;Non-Small-Cell Lung Carcinoma;Oncogenic;Pathway interactions;Patients;Pemetrexed;Phosphotransferases;Protein Isoforms;Protein Kinase;Protein-Serine-Threonine Kinases;Proteome;RNA interference screen;Regulation;Relapse;Research;Resistance;Resistance development;Ribosomal Protein S6 Kinase;Ribosomes;Role;Scaffolding Protein;Series;Serine;Signal Pathway;Signal Transduction;Therapeutic;Treatment Efficacy;Treatment outcome;Variant;Xenograft procedure;cancer cell;cancer therapy;cancer type;chemotherapy;clinical application;clinical efficacy;combinatorial;folic acid metabolism;improved;in vivo;inhibitor;insight;interest;kinase inhibitor;mouse model;novel;patient derived xenograft model;pharmacologic;response;screening;small hairpin RNA;therapeutic target;therapy outcome;tumor;tumor growth;tumor progression Dissecting pemetrexed resistance in non-small cell lung carcinoma PROJECT NARRATIVEThe treatment of non-small cell lung carcinoma (NSCLC) with pemetrexed-based chemotherapy often leads tothe development of resistance and therapeutic failure but the mechanism responsible for the resistance remainslargely unclear. Through a customized RNAi screening we identified FGFR3 signaling as a critical factor ofpemetrexed resistance perhaps by mediating activation of a pemetrexed target enzyme in the folate metabolismand MAPK pathway. In this proposal we will newly uncover the mechanism by which FGFR3 activates folatemetabolism and MAPK pathway to drive pemetrexed resistance and validate the therapeutic efficacy of targetingFGFR3 signaling and pemetrexed as a novel combinatorial therapy for pemetrexed-resistant NSCLC. NCI 10747983 11/6/23 0:00 PAR-20-292 5R21CA277103-02 5 R21 CA 277103 2 "FORRY, SUZANNE L" 12/1/22 0:00 11/30/24 0:00 ZCA1-TCRB-Q(O1)S 8600225 "KANG, SUMIN " Not Applicable 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 197542 NCI 126225 71317 PROJECT SUMMARY Despite the existence of various therapeutic approaches chemotherapy is a mainstay of cancer treatment.Pemetrexed-based chemotherapy a multitargeted antifolate that inhibits folate metabolism is extensively usedto treat non-small cell lung carcinoma (NSCLC) which is the most common type of lung cancer. Howeverpatients often relapse due to the development of resistance leading to therapeutic failure. Many studies haveinvestigated possible chemoresistance models yet the precise mechanism is still largely elusive. Oncogenic kinases are well implicated in human cancers and of great clinical interest due to their role incancer. To better understand the link between kinase-mediated metabolic regulation and pemetrexed resistancewe performed a customized RNAi screen to identify a clinically applicable target kinase that is critical forpemetrexed resistance. We found that inhibition of one of the fibroblast growth factor receptors (FGFR) familyFGFR3 selectively sensitizes NSCLC cells to pemetrexed leading to decreased cancer cell survival andproliferation. Coupled kinase and metabolic assays revealed that FGFR3 may indirectly activate one of thepemetrexed target enzymes dihydrofolate reductase (DHFR) in the folate metabolism. Furthermore globalproteome profiling and phospho-signaling array suggested that FGFR3 may be involved in regulating expressionor activity of factors in the MAPK pathway including KSR2 and RSK1/2. These suggest that FGFR may providepemetrexed resistance through modulating folate metabolism and MAPK pathway and is a promising therapeutictarget to improve the pemetrexed response. Indeed pharmacological inhibition of FGFR3 significantly sensitizedpemetrexed-resistant NSCLC cell lines to pemetrexed treatment in vitro and in vivo. Our central hypothesis is that FGFR3 confers pemetrexed resistance in NSCLC by regulating the metabolicenzyme DHFR and MAPK pathway. Therefore FGFR3 inhibitors may represent potent pemetrexed sensitizingagents in NSCLC. Two specific aims are proposed: (1) To decipher the molecular mechanism underlying FGFR3-mediated activation of folate metabolism and MAPK pathway which confers pemetrexed resistance in NSCLC;(2) To validate FGFR3 signaling as a therapeutic target in treatment of pemetrexed-resistant NSCLC usingvarious NSCLC cell lines and patient-derived xenograft and syngeneic mouse models of lung cancer. Thisproposal will not only provide information about the role of FGFR3 in pemetrexed resistance but also a newactionable approach to improve the treatment outcome of lung cancer that is not responsive to pemetrexed-based chemotherapy. 197542 +No NIH Category available Acceleration;Address;Alkylating Agents;Animal Model;Animals;Automobile Driving;Behavior;Benchmarking;Biocompatible Materials;Biological Assay;Biophysics;Blood Vessels;Brain;Brain Neoplasms;Cancer Model;Cell Line;Cells;Clinic;Clinical;DNA;DNA Modification Process;DNA Repair;Diffuse;Dimensions;Disparate;Drug resistance;Engineering;Evaluation;Excision;Failure;Gelatin;Generations;Glioblastoma;Glioma;Goals;Human;Hyaluronic Acid;Hydrogels;Imaging Device;Invaded;Libraries;Link;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Meta-Analysis;Metabolic;Methyltransferase;Microfluidics;Modeling;Molecular Weight;Operative Surgical Procedures;Outcome;Patients;Pattern;Pericytes;Physiological;Play;Process;Proliferating;Proteins;Recurrence;Resistance;Resources;Role;Signal Transduction;Specimen;Surgical margins;Survival Rate;Technology;Tissue Engineering;Tissue Model;Variant;Work;Xenograft procedure;anti-cancer;bioinformatics tool;detection limit;drug candidate;in vivo;insight;migration;mimetics;miniaturize;mortality;neurovascular;novel;novel therapeutics;pressure;programs;repaired;response;standard of care;stem;temozolomide;therapeutic evaluation;therapy resistant;tumor Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma NARRATIVEGlioblastoma is the most aggressive and deadly form of brain cancer whose poor clinical outcome stems fromits diffuse invasion throughout the brain and drug resistance. This project will develop and thoroughlycharacterize a tissue engineering platform to investigate pathophysiological processes responsible for invasivespreading therapeutic resistance and poor survival. NCI 10747926 11/21/23 0:00 PAR-19-113 5R01CA256481-04 5 R01 CA 256481 4 "BECKER, STEVEN" 12/1/20 0:00 11/30/25 0:00 Cellular and Molecular Technologies Study Section[CMT] 9109865 "HARLEY, BRENDAN A." Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 450043 NCI 330131 119912 ABSTRACTGlioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgical resectionfollowed by treatment with the alkylating agent temozolomide (TMZ). However two major challenges make GBMcurrently untreatable: 1) its diffuse invasion beyond the surgical margin; and 2) TMZ resistance that is tightlylinked to expression of the DNA damage repair protein MGMT. While perivascular niches (PVNs) extending fromthe tumor into the surrounding parenchyma are believed to regulate invasion recurrence and poor survival themajority of animal glioma models are sensitive to TMZ and most do not express MGMT making it difficult toassess novel therapeutics in animal models that dont display TMZ resistance. This Cancer Tissue EngineeringCollaborative project will develop and thoroughly characterize a multidimensional engineered PVN biomaterialstudy pathophysiological processes driving GBM invasion and TMZ resistance and accelerate the evaluation ofnovel TMZ derivatives created to target diffuse GBM cells regardless of MGMT status. We will use advancedmicrofluidics to create libraries of miniaturized gelatin hydrogels containing margin-mimetic hyaluronic acid (HA)and an embedded perivascular network. We also use a novel synthetic pipeline to create TMZ derivatives thatgenerate alternate DNA modifications that cannot be removed by MGMT that we hypothesize work in an MGMT-independent fashion. Merging these technologies we will benchmark an engineered PVN platform formed usingprimary brain neurovascular cells for rapid evaluation of GBM invasion MGMT expression and TMZ resistanceamenable to analysis of cell lines and patient-derived GBM specimens with disparate MGMT profiles. To do thiswe will first construct and thoroughly characterize an engineered perivascular niche (Aim 1). We will use thisnovel biomaterial to benchmark patterns of invasion and MGMT expression in GBM cell lines (Aim 2). Finallywe will establish predictive efficacy of TMZ variants in an engineered perivascular niche (Aim 3). Together wewill develop characterize and benchmark a tissue engineered PVN to examine the role of microenvironmentalselection pressures in the tumor margin on behaviors related to invasion MGMT-mediated TMZ resistancerecurrence and poor survival. Consistent with score-driving criteria of the CTEC program we will develop andthoroughly characterize an engineered PVN biomaterial show it fits within the continuum of existing cancermodels use it to examine phenomena underlying the failure to achieve durable survival and gain actionableinsight regarding novel TMZ derivatives with potential to effectively target GBM cells in the margins independentof MGMT status. 450043 +No NIH Category available Ablation;Acceleration;African American;African American population;American;Antibodies;Biology;Cancer Biology;Cancer Etiology;Cancer Patient;Cell Communication;Cell Line;Cell membrane;Cell model;Cells;Cessation of life;Clinical;Combined Modality Therapy;Data;Data Set;Death Rate;Development;Diagnosis;Disease;Ectopic Expression;Epithelial Cells;European;Exhibits;GPI Membrane Anchors;Genes;Genetic;Glycolates;Goals;Human;Immune;Immune Evasion;Immune response;Immunosuppressive Agents;Inflammatory;Macrophage;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Membrane Glycoproteins;Messenger RNA;Metastatic Prostate Cancer;Molecular;Monoclonal Antibodies;Mus;Mutation;Neoplasm Metastasis;Oncogenes;Oncogenic;Outcome;Oxidation-Reduction;Patients;Phagocytosis;Pharmaceutical Preparations;Polymers;Prognosis;Prostate;Repression;Resources;Role;Sampling;TP53 gene;Testing;Therapeutic;Tumor-associated macrophages;United States;Work;Xenograft Model;Xenograft procedure;advanced prostate cancer;antibody conjugate;cancer health disparity;cancer immunotherapy;cancer type;castration resistant prostate cancer;effective therapy;high risk;improved;improved outcome;in vivo;inducible gene expression;innate immune checkpoint;knock-down;malignant breast neoplasm;men;mouse model;mutant;nanoparticle;nanopolymer;neoplastic cell;new therapeutic target;novel therapeutics;overexpression;palliative;prostate cancer cell;prostate cancer metastasis;racial disparity;racial population;sialic acid binding Ig-like lectin;small molecule;systemic toxicity;targeted delivery;targeted treatment;therapeutic target;treatment strategy;tumor Targeted delivery of multimodal therapy for reducing prostate cancer disparity Project NarrativeOur proposed work will develop the targeted delivery of multimodal therapy for reducing racial disparities ofAfrican American prostate cancer. Our proposed study will move beyond an incremental advance acceleratethe development of new therapeutics against metastatic prostate cancer and improve clinical outcomes inAfrican American patients with prostate cancer. NCI 10747924 11/3/23 0:00 PAR-18-654 5R01CA265937-03 5 R01 CA 265937 3 "VENKATACHALAM, SUNDARESAN" 12/9/21 0:00 11/30/26 0:00 Special Emphasis Panel[ZRG1-OBT-Y(55)R] 10315507 "LIU, RUNHUA RUNA" "ZHOU, JIANGBING " 7 GENETICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 345094 NCI 276380 68714 Project SummaryAmong all racial groups African American men have the highest rate of prostate cancer and their cancers exhibita more aggressive biology leading to higher rates of death. Although systemic treatments have been developedfor this disease these are primarily palliative; additional treatment strategies need to be developed. The majorobjective of this proposed project is to develop new targeted therapeutics to improve treatment of patients withadvanced prostate cancer including African American patients who have a particularly worse prognosis andwhose tumors harbor more of an inflammatory and immune signature. CD24 a cell-surface glycoprotein is notexpressed in normal prostate epithelial cells but is expressed in approximately 50% of prostate cancers and in60-66% of African American prostate cancers. For humans and mice CD24 expression is associated withprostate cancer metastasis and for patients with prostate cancer over-expression of CD24 is associated withtumor metastasis and poor prognosis. Notably a CD24-p53 axis contributes to African American prostate cancerdisparities. In addition CD24 is the dominant innate immune checkpoint in human cancers and is a promisingtarget for cancer immunotherapy. Thus CD24 may have dual functions as a cell-intrinsic oncogene and animmune suppressor and it is a potential therapeutic target for patients with metastatic castration-resistantprostate cancers. We hypothesize that targeting the CD24-p53 axis is an effective therapy for African Americanswith metastatic castration-resistant prostate cancer. In this application we propose a) to synthesize andcharacterize multifunctional nanoparticles for targeted delivery of anti-CD24 antibody and PRIMA1 (a p53inducer) b) to evaluate targeted delivery of CD24/p53 targeted multimodal therapy to reduce prostate cancerracial disparities and c) to determine the molecular mechanisms of the targeted therapy. Our proposed work isexpected to establish CD24 as a new therapeutic target and to demonstrate a new therapy that meets the needsof African American patients with metastatic castration-resistant prostate cancer. 345094 +No NIH Category available Address;Affect;Age;Alleles;Apoptosis;Asbestos;Binding;Calcium;Calcium Channel;Calcium Signaling;Carcinogens;Cell Culture Techniques;Cell Death;Cell Differentiation process;Cell Nucleus;Cell Survival;Cells;Cessation of life;Citric Acid Cycle;Collaborations;Complement;Cutaneous Melanoma;Cytoplasm;Cytosol;DNA;DNA Damage;DNA Repair;Data;Development;Disease;Dose;Endoplasmic Reticulum;Environment;Environmental Carcinogens;Enzymes;Exposure to;Family;Family member;General Population;Genes;Genetic;Genetic Transcription;Germ-Line Mutation;Growth;HMGB1 gene;Heterozygote;High Prevalence;Human;Hypoxia;Impairment;Incidence;Individual;Induced Mutation;Inherited;Inositol;Lead;Link;Malignant - descriptor;Malignant Neoplasms;Malignant mesothelioma;Mesothelioma;Metabolic;Metabolic Pathway;Metabolism;Mineral Fibers;Mitochondria;Multiprotein Complexes;Mus;Mutate;Mutation;Names;Nature;Nuclear;Pathogenesis;Pathway interactions;Penetrance;Phenotype;Plasma;Predisposition;Prevalence;Primary Cell Cultures;Proliferating;Reagent;Regulation;Resistance;Risk;Role;Skin Cancer;Skin Carcinoma;Somatic Mutation;Syndrome;Testing;Therapeutic Intervention;Time;Tumor Promotion;UV induced;Ultraviolet Rays;Uveal Melanoma;Warburg Effect;Wild Type Mouse;aerobic glycolysis;cancer cell;cancer type;carcinogenesis;carcinogenicity;cell transformation;cohort;environmental carcinogenesis;erionite;in vivo;inorganic phosphate;ionization;irradiation;melanoma;metaplastic cell transformation;mitochondrial metabolism;mouse model;mutation carrier;novel;receptor;response;sarcoma;sex;stem;synergism;tripolyphosphate;tumor;tumor growth;uptake;volunteer Mechanisms of BAP1 activity in human cancer development PROJECT NARRATIVEWe discovered that germline BAP1 mutations are associated with high susceptibility to multiple tumor types:among them the prevalence of malignant mesothelioma (MM) predominates upon exposure to low amounts ofasbestos that do not normally cause disease. Here we propose to determine the mechanisms by which BAP1mutations modulate cancer penetrance in carriers of germline BAP1 mutations including the effects of BAP1 oncellular metabolism and how these mechanisms relate to cancer penetrance and mesothelioma. NCI 10747923 11/16/23 0:00 PA-19-056 5R01CA237235-05 5 R01 CA 237235 5 "SALNIKOW, KONSTANTIN" 12/13/19 0:00 11/30/24 0:00 Cancer Etiology Study Section[CE] 1869066 "CARBONE, MICHELE " "YANG, HAINING " 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 400659 NCI 260168 140491 PROJECT SUMMARYThis application investigates mechanisms of gene and environment interaction in carcinogenesis.Malignant mesothelioma (MM) is frequent in individuals continuously exposed to carcinogenic mineralfibers such as asbestos and erionite but it is very rare in those with limited or no exposure. Geneticsinfluences susceptibility to MM. We have recently demonstrated that carriers of germline BAP1 mutationshave increased incidence of multiple cancer types including MM (we named this condition the BAP1cancer syndrome). In some BAP1-mutation carrying families MM accounts for more than 50% ofdeaths and we found that this may be due to increased susceptibility to MM from exposure to modestamounts of asbestos that would normally not cause MM in the general population. We also found thatheterozygous BAP1 germline mutations in addition to asbestos also increase susceptibility to malignanttransformation following exposure to Ionizing Irradiation and ultraviolet (UV) light which may account forthe high prevalence of melanomas and skin carcinomas in carriers of BAP1 mutations. BAP1 is the first andso far the only gene shown to regulate environmental carcinogenesis. The mechanism(s) by whichmutated BAP1 causes MM pathogenesis are being elucidated. Inositol 145-trisphosphate (IP3) binds andactivates the IP3 receptors (IP3Rs). We demonstrated that BAP1 is present in the endoplasmic reticulum(ER) where it regulates the activity of the IP3-Receptor-3 (IP3R3) the main ER channel that controls Ca2+release from the ER to the cytoplasm to the mitochondria regulating apoptosis. We discovered that reducedlevels of BAP1 in carriers of heterozygous BAP1 mutations impair apoptosis and favor cellular transformationof cells that accumulated DNA damage following exposure to asbestos IR and UV-light. We also discoveredthat normal primary cells of carriers of heterozygous germline BAP1 mutations derive energy from aerobicglycolysis known as Warburg effect which so far had been considered a hallmark of cancer cells. Weidentified a specific metabolic signature associated with the Warburg effect by studying the metabolites presentin the plasma of carriers of heterozygous germline BAP1 mutations. Our central hypothesis is that changes inCa2+ concentration lead to increased resistance of cells containing BAP1 mutations to apoptosis and tochanges in metabolic pathways that in turn are responsible for the very high cancer penetrance observed inBAP1 mutation carriers. To address this hypothesis we will examine the following specific Aims:AIM 1: To study the mechanisms by which BAP1 mutations induce a Warburg effect.AIM 2: To study the hypothesis that the Warburg effect is HIF-1-independent in BAP1+/- cells.AIM 3: To study the contributions of calcium signaling and metabolic alterations due to germline BAP1mutations to MM development.To elucidate the activity of BAP1 on the I P 3 R 3 and the related effects on cancer penetrance we haveassembled a unique cohort of families carrying germline BAP1 mutations and have access to uniquereagents derived from volunteers from these families. These unique reagents include: primary cell culturesderived from family members that inherited germline BAP1 mutations as well as from sex- and age-matched controls from the same families sera and plasma from germline BAP1 mutation carriers andmatched controls and a heterozygous BAP1 mouse model and derived cell cultures. In addition weassembled a unique sets of heterozygous BAP1 and IP3R3 mice that recapitulate the human conditionand that allow us to study the effects of BAP1 mutations in vivo upon exposure to carcinogens.Collaborations with some of the leading experts in the field Drs. Pinton and Giorgi experts in Ca2+signaling and mitochondrial metabolism; and Dr. Mikoshiba expert in IP3R3 activities complement andsynergize with the expertise of the two MPIs. These studies will be relevant to the multiple malignanciesassociated with the BAP1 cancer syndrome in both carriers of BAP1 mutations and those who developsomatic mutations of BAP1 during tumor development. 400659 +No NIH Category available 3D ultrasound;Address;Aftercare;Biology;Carbon ion;Cell Death;Cell Line;Cell Proliferation;Cells;Cessation of life;Charge;Clinical;Collimator;Combined Modality Therapy;Complex;Custom;Cysteine;Cystine;DNA Damage;Dependence;Deposition;Development;Distant Metastasis;Dose;Drug Metabolic Detoxication;Engineering;Generations;Genetically Engineered Mouse;Glutathione;Goals;Heavy Ions;Helium;High-LET Radiation;Hospitals;Human;Immune response;Ionizing radiation;Ions;KPC model;Knowledge;Laboratories;Linear Energy Transfer;Link;Lipid Peroxidation;Local Therapy;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Microscopic;Modality;Molecular;Mus;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Physics;Protons;Radiation;Radiation therapy;Radiobiology;Radiology Specialty;Reactive Oxygen Species;Relative Biological Effectiveness;Reporting;Research;Resistance;Resolution;Roentgen Rays;Signal Transduction;Therapeutic;Time;Tumor Markers;United States National Aeronautics and Space Administration;advanced pancreatic cancer;animal imaging;anti-cancer;anticancer research;cell killing;clinically relevant;cost effective;gemcitabine;high-LET heavy ion therapy;imaging capabilities;immune cell infiltrate;improved;improved outcome;in vivo;irradiation;laboratory facility;meter;mouse model;neoplastic cell;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;particle beam;pharmacologic;pre-clinical;radiation response;relative effectiveness;serial imaging;tumor;tumor growth;x-ray irradiation Linear energy transfer (LET) dependencies for understanding pancreatic tumor control and relevant molecular endpoints in support of RBE-based heavy-ion radiotherapy Despite decades of research pancreatic ductal adenocarcinoma remains one of the deadliest of cancers butrecent advances in heavy-ion radiotherapy and in ferroptosis-inducing drugs may begin to change this. Thisproposal will investigate the relationship of linear energy transfer with tumor killing and associated endpointsas well as how these interact with the induction of ferroptosis. The knowledge gained will help to developoptimized approaches to heavy ion radiotherapy potentially making it both more clinically effective and morecost effective to improve outcomes for pancreatic cancer and other hard-to-treat tumors. NCI 10747913 12/28/23 0:00 RFA-CA-20-032 5R01CA256840-04 5 R01 CA 256840 4 "BUCHSBAUM, JEFFREY" 1/1/21 0:00 12/31/25 0:00 ZCA1-SRB-2(O2) 1942267 "AMUNDSON, SALLY A." Not Applicable 13 RADIATION-DIAGNOSTIC/ONCOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 465865 NCI 287571 178294 This proposal brings together a unique interdisciplinary team with complementary expertise in high-LETradiobiology pancreatic cancer research and high-LET physics. It leverages the engineered PDA (pancreaticductal adenocarcinoma) mouse models and imaging capabilities at our PDA Mouse Hospital together with thehigh-LET charged particle beams generated at Brookhavens NSRL and our Radiological ResearchAccelerator Facility (RARAF) at Columbia to address the central hypothesis that heavy ion radiotherapy(HIRT) effects in PDA are LET dependent and can be enhanced by pharmacological induction of ferroptosis. HIRT represents a promising therapeutic opportunity for improving (PDA) survival with very encouragingsurvival results reported after combined carbon-ion and gemcitabine therapy for locally advanced PDA.Compared with other radiotherapy modalities the high-LET radiations deposit energy far more denselyresulting in complex DNA damage clustered reactive oxygen species (ROS) formation and altered damagesignaling. The generation of clustered ROS by HIRT is clearly linked to cell killing however PDA upregulatesROS detoxification pathways potentially leading to mitigation of tumor cell killing by radiation. Our labs haverecently shown that pharmacological inhibition of cystine import counters PDA resistance to endogenous ROStriggering ferroptotic death in PDA cell lines and tumors and resulting in significantly improved survival ofautochthonous PDA tumor bearing mice. The efficiency of lipid peroxidation upon which ferroptosis dependsvaries with LET suggesting that overcoming ferroptosis resistance in combination with optimized HIRT mayprove a powerful approach for PDA treatment. Thus our central hypothesis is that HIRT effects in PDA are LET dependent and can be enhanced bypharmaceutical induction of ferroptosis. The goal is to understand and quantify PDA-HIRT relevant endpointsusing state-of-the art PDA mouse models in extended heavy-ion beams customized for mouse tumorexposure with and without pharmacological induction of ferroptosis. Our second goal is understanding the LETdependencies of PDA-HIRT relevant endpoints: First to find the optimal dose-averaged LET (LETD)corresponding to these endpoints and second to assess whether clinical helium ion beams may induce similaryields of these endpoints a conclusion that would potentially revolutionize heavy ion radiotherapy. Our mouse irradiations will use custom extended heavy-ion beams at Brookhavens NSRL facility.However the LETD distributions within the irradiated mouse tumors cover a much smaller LET range than intypical human tumors treated with HIRT. We will assess whether the conclusions drawn from these studies arestill valid at the higher LETs and lower LETs respectively of relevance for clinical carbon-ion and helium-ionHIRT by recapitulating relevant endpoints at RARAF our preclinical heavy-ion irradiation facility where mono-LET beams for cellular irradiations are available from 10 to 200 keV/m. 465865 +No NIH Category available Affect;Alcohols;Behavior;Bioinformatics;Biological Markers;Cancer Patient;Cell Line;Clinical;Diagnosis;Disease;Disease-Free Survival;Epidemiology;Etiology;Exhibits;Genes;Genetic Transcription;Heterogeneity;Human;Human Papillomavirus;Human papilloma virus infection;Immunologic Surveillance;In Vitro;Incidence;Individual;Infection;Inflammatory Response;Life;Malignant Neoplasms;Methods;MicroRNAs;Molecular;Morbidity - disease rate;Mutation;Oncogenes;Oncogenic;Oropharyngeal Squamous Cell Carcinoma;Outcome;Pathway interactions;Patients;Physicians;Pilot Projects;Population;Population Study;Predisposition;Prevalence;Prevention;Preventive vaccine;Prognosis;Prognostic Marker;Public Health;Quality of life;Radiation Tolerance;Radiation therapy;Risk;Serum;Smoking;Tissues;Tobacco;Tumor Markers;Tumor Suppressor Proteins;University of Texas M D Anderson Cancer Center;Untranslated RNA;Vaccination;cohort;functional outcomes;human papilloma virus oropharyngeal squamous cell carcinoma;improved;individualized medicine;interest;knock-down;malignant oropharynx neoplasm;novel;novel marker;patient biomarkers;patient prognosis;patient screening;patient stratification;personalized medicine;predictive modeling;prognostic;prognostication;recruit;reduce tobacco use;response;screening;smoking prevalence;surveillance strategy;survival prediction;treatment response;treatment strategy;trend;tumor;young adult Immuno-inflammatory Response Non-coding RNAs as Predictors of HPV Status & Outcome of Oropharyngeal Cancer Patients PROJECT NARRATIVEDespite declining smoking rates in the U.S the incidence of squamous cell carcinoma of the oropharynx(SCCOP) continues to increase dramatically largely attributed to an increase in HPV prevalence; and as suchour public health SCCOP prevention paradigm must expand beyond tobacco and alcohol control. Identificationof serum noncoding RNA-related biomarkers for patients with tumor HPV(+) SCCOP would have a majorpublic health impact; and such novel noncoding RNA-related biomarkers could refine the prognostication ofHPV(+) SCCOP allowing for better selection of SCCOP patients for treatment deintensification and potentiallyother HPV-associated diseases. This has implications for our understanding of the molecular mechanism ofHPV(+) SCCOP as well as an opportunity to significantly impact the screening and more personalizedtreatment of HPV(+) SCCOP for better survival and quality of life. NCI 10747865 11/28/23 0:00 PA-19-056 5R01CA236859-05 5 R01 CA 236859 5 "FILIPSKI, KELLY" 12/1/19 0:00 11/30/24 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 8583024 "LI, GUOJUN " Not Applicable 9 SURGERY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 239590 NCI 147895 91695 PROJECT SUMMARYSquamous cell carcinoma of the oropharynx (SCCOP) is a highly morbid life-threatening disease. Despitedeclining smoking prevalence the incidence of SCCOP is increasing particularly among younger adults. Thistrend is the result of the rising prevalence of oncogenic human papillomavirus (HPV) infection in the population.The majority (approximately 70-80%) of SCCOP patients are HPV-positive [HPV(+)]. HPV(+) SCCOP is distinctfrom HPV-negative [HPV(-)] SCCOP in terms of epidemiologic clinical and molecular features and especiallyin terms of clinical behavior response to treatment and survival. Therefore in patients with SCCOPdetermination of HPV status is critical for defining prognosis and tailoring therapy. Unfortunately there iscurrently no effective screening method to identify patients with tumor HPV(+) SCCOP. Further among patientswith HPV(+) SCCOP there remains heterogeneity in clinical outcomes. Identification of patients with SCCOPneeding treatment intensification and those able to benefit from reduction of treatment intensity is critical to moreeffective and less morbid treatment. Noncoding RNAs (ncRNAs) that affect the immuno-inflammatory responsecontrol HPV clearance and escape of immune surveillance and may contribute to tumor HPV status and relatedclinical outcomes of SCCOP patients. NcRNAs exhibit stable expression in human serum. We hypothesize thatpretreatment serum expression profiles of immuno-inflammatory response ncRNAs are associated with tumorHPV(+) SCCOP and related clinical outcomes. The specific aims for this project are as follows: Aim 1: Todetermine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs aremarkers of tumor HPV status in a cohort of 1500 patients with incident SCCOP recruited treated and followedat The University of Texas MD Anderson Cancer Center. Aim 2: To determine if pretreatment serum expressionprofiles of selected immuno-inflammatory response ncRNAs predict disease-specific survival disease-freesurvival and overall survival among HPV(+) SCCOP patients from the cohort described for Aim 1. Aim 3: Tovalidate significant associations found in Aims 1 and 2. We will use an independent cohort of 625 SCCOP casesto control for potential false-positive or unbiased estimates of associations. Aim 4: To characterize functions ofimmuno-inflammatory response ncRNAs on tumor radiosensitivity in vitro. We will screen a panel of HPV(+)SCCOP cell lines for ncRNAs of interest in a clinical setting in order to further validate these prognostic ncRNAsfound in Aim 2. This functional study will validate 1 or more of these ncRNAs as biomarkers that can beincorporated into prognostic prediction models to permit more personalized treatment. Identifying novelbiomarkers for tumor HPV status and prognosis of patients with HPV(+) SCCOP will allow physicians to moreeffectively tailor screening for patients at risk of HPV(+) SCCOP as well as treatment and surveillance strategiesthat optimize survival and quality of life for patients with HPV(+) SCCOP. 239590 +No NIH Category available Adult;Antitumor Response;Autologous;Biology;CTLA4 blockade;Cancer Etiology;Cause of Death;Cells;Clinical;Colon Carcinoma;Colonic Neoplasms;Colorectal;Combination immunotherapy;Combined Modality Therapy;Data;Disease;Engineering;Environment;Goals;Human;Immune;Immune response;Immune system;Immunologic Stimulation;Immunotherapy;Incidence;Infiltration;Knowledge;Ligands;Liver;Lymphocyte;Lymphocyte Activation;Lymphocyte Function;Lymphocytic Infiltrate;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Metastatic Neoplasm to the Liver;Methods;Microsatellite Repeats;Mission;Mus;Neoplasm Metastasis;Oncolytic;Operative Surgical Procedures;Outcome;Paper;Patient-Focused Outcomes;Patients;Pre-Clinical Model;Proliferating;Public Health;Publishing;Quality of life;Reproducibility;Research;Resected;Signal Transduction;Site;System;T cell infiltration;T-Lymphocyte;Technology;Testing;Therapeutic;Translating;Treatment Protocols;Tumor Expansion;Tumor Promotion;United States National Institutes of Health;Viral;Woman;anti-CTLA-4 therapy;anti-CTLA4;anti-tumor immune response;cancer cell;clinically relevant;colon cancer metastasis;colon cancer patients;cytotoxic;humanized mouse;immune checkpoint blockade;improved;in vivo Model;innovation;lymphocyte proliferation;men;metastatic colorectal;mortality;mouse model;neoplastic cell;novel;novel strategies;oncolysis;overexpression;patient derived xenograft model;pre-clinical;reconstitution;response;stem;therapeutically effective;therapy resistant;trafficking;translational impact;tumor;tumor microenvironment Stimulating Lymphocyte Activation Combined with Inhibition of Immunosuppressive Signals in Colon Cancer Metastases Project NarrativeOver the last decade colon cancer and CRLM have increased in young U.S. men and womenresulting in a 1% annual increase in mortality. The proposed research is relevant to publichealth because the discovery of strategies to optimize anti-tumor immune responses in this dis-ease is ultimately expected to improve patient outcomes compared to the best current thera-pies. Despite the exciting results of immunotherapy and checkpoint blockade in many previouslytherapy-resistant malignancies the field is currently stymied in how to utilize this technology tobattle microsatellite stable (>95%) colon cancer and as a result the proposed research is rele-vant to the NIH's mission to develop improved immunotherapy approaches of novel combina-tions to define how immunosuppressive tumor promoting environments can be overcome. NCI 10747856 12/22/23 0:00 PA-19-056 5R37CA238435-06 5 R37 CA 238435 6 "ZAMISCH, MONICA" 1/22/20 0:00 12/31/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 9849504 "MAKER, AJAY V." Not Applicable 11 SURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 340135 NCI 210610 129525 Project Summary/AbstractColon cancer and colorectal liver metastases (CRLM) are a significant and increasingly lethal disease. Thoughthere is a strong scientific premise to harness the immune system to treat this cancer there remains a funda-mental gap in understanding of how immunotherapies can be utilized for the majority of these tumors particu-larly microsatellite stable cancers. The central hypothesis is that the tumor microenvironment can be manipu-lated to enhance cytotoxic lymphocyte infiltration and activation and that checkpoint blockade can be simulta-neously utilized to incite a clinically relevant immune response. This one-two punch hypothesis has beenformulated on the basis of preliminary data produced by the applicant where increased T-cell trafficking to tu-mors when combined with CTLA4 blockade resulted in complete CRLM regressions. The rationale for theproposed research is that once it is known how to enhance immunostimulatory signals in the microenvironmentand simultaneously suppress inhibitory influences a new strategy for the management of colon cancer is pos-sible. Supported by a very strong scientific premise based on published papers and robust preliminary datathis hypothesis will be tested by pursuing three specific aims: 1) Determine mechanisms to enhance lympho-cyte proliferation and anti-tumor specific immune responses in colon cancer by manipulating immunosuppres-sive signals 2) Examine mechanisms that supply immunostimulatory influences directly into the tumor; and 3)Combine checkpoint blockade with selective delivery of human LIGHT to treat surgically resected tumors andhuman CRLM in a pre-clinical autologous system. Under the first aim we expect to increase lymphocyte infiltra-tion proliferation and activation while simultaneously curbing immunosuppressive signals/cells in the microen-vironment utilizing a validated pre-clinical model established by the applicants. In the second aim a clinicallyrelevant method to safely increase LIGHT expression within colon cancer tumors using novel tumor-specificviral delivery mechanisms engineered by the applicants will be analyzed. Under the third aim patient tumorswill be utilized in an autologous humanized mouse model and treated with CTLA4 blockade combined with on-colytic viral delivery mechanisms to increase LIGHT expression. The proposed research is innovative becausethe multi-combination therapy of LIGHT expression in CRLM with tumor-specific oncolysis and checkpointblockade will deliver an inventive approach that will be universally applicable from patient to patient. New hori-zons that will stem from this innovative strategy include a better understanding of anti-CTLA4 biology that maynot only enhance response rates but also vastly increase indications for its use in previously cold tumorsincluding microsatellite stable gastrointestinal cancer. This contribution will be significant because it will estab-lish a synergistic combination of immunotherapies that will have direct translational impact on one of the dead-liest cancers worldwide. The implications of our results may improve patient quality of life and provide survivaladvantages over the best current surgical and chemotherapeutic strategies for this disease. 340135 +No NIH Category available Address;Adopted;Affect;Antigen Presentation;Arachidonic Acids;Area;CD36 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Biology;Cell Proliferation;Cell Survival;Cell physiology;Cells;Characteristics;Clinical;Combined Modality Therapy;Complement;Development;Dimensions;Dinoprostone;Disease;Environment;Equilibrium;Fatty Acids;Frequencies;Functional disorder;Glucose;Glutamine;Goals;Heterogeneity;Homeostasis;Hyperlipidemia;Hypoxia;Immune;Immunity;Immunologic Surveillance;Immunosuppression;Immunotherapy;Impairment;Infiltration;Influentials;Intervention;Learning;Lipids;Lipolysis;Lipoproteins;Lymphocyte Function;Lymphocytic Infiltrate;MHC antigen;Malignant Neoplasms;Metabolic;Metabolic Control;Metabolic Pathway;Metabolism;Modeling;Nature;Nutrient;Nutrient availability;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phenotype;Production;Proliferating;Prostaglandin D2;Proteins;Resistance;Resources;Seminal;Signal Transduction;Source;Stress;T cell infiltration;T cell response;T-Lymphocyte;Testing;Therapeutic;Time;Tumor Immunity;Tumor-Derived;Tumor-Infiltrating Lymphocytes;Up-Regulation;War;Work;aerobic glycolysis;anti-tumor immune response;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cancer therapy;cell growth;combat;cost;eicosanoid metabolism;exhaust;exhaustion;flexibility;immune cell infiltrate;immune checkpoint;immunogenicity;immunoregulation;improved;lipid biosynthesis;melanoma;neoplastic cell;novel;nutrient deprivation;oxidized low density lipoprotein;programmed cell death ligand 1;programmed cell death protein 1;programs;response;stem;trait;tumor;tumor immunology;tumor metabolism;tumor microenvironment;tumor progression;tumor-immune system interactions Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity Project Narrative: A cardinal trait of the tumor microenvironment is that it is immuno-suppressive and converting it to onethat is immuno-supportive is the key to developing effective immunotherapies that can combat cancer. Thisproposal focuses on a largely unexplored area of tumor immunology the metabolic control of T cell functionand survival in tumors and seeks to determine if the deregulated metabolic states of tumor cells directlycontribute to the development of an immunosuppressive tumor microenvironment by altering the functionphenotype and metabolic states of tumor infiltrating T cells. This work has the potential to open up a newdimension of immunoregulation in tumors and determine if T cell metabolic reprogramming offers newopportunities for cancer immunotherapy. NCI 10747827 4/13/23 0:00 PA-21-071 3R01CA240909-04S1 3 R01 CA 240909 4 S1 "ZAMISCH, MONICA" 3/1/20 0:00 2/28/25 0:00 Special Emphasis Panel[ZRG1(55)-R] 6138391 "KAECH, SUSAN M" "WAHL, GEOFFREY MYLES" 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 81092 NCI 42680 38412 Project Summary: Metabolic transformation is a hallmark feature of cancer cells that allows sustained anabolic metabolism tofuel cell growth and proliferation and when distilled to its core cancer is ultimately a disease of uncheckedanabolic metabolism. Yet it is not well understood how the aberrant metabolic activity of tumor cells affects thefunction phenotype and metabolic states of neighboring immune cells in the tumor microenvironment. Thedevelopment of new immunotherapies that stimulate anti-tumor T cell responses to control or eradicate canceris a revolutionary and promising area of cancer therapy but the immunosuppressive nature of the tumormicroenvironment remains the biggest obstacle to increasing the frequency of patients that respond toimmunotherapy. We propose that a major component dictating whether the tumor microenvironment (TME) isimmuno-supportive or immuno-suppressive is the metabolic state of tumor cells. This model is based on the factthat like tumor cells tumor infiltrating lymphocytes (TILs) also require high rates of aerobic glycolysis andglutaminolysis to proliferate and perform tumoricidal effector functions. It is well documented that CD8+ T cellsare functionally suppressed or exhausted in tumors and perhaps a primary source of this suppression is simplynutrient deprivation stemming from competition between metabolically active tumor and immune cells for thesame nutrients. This model of a metabolic tug-of-war between tumor and immune cells over nutrients such asglucose and glutamine presents an entirely different perspective on how an immunosuppressive TME may form. To bridge this gap in cancer immunology we will determine how metabolic pathways particularly thoseinvolved in lipid homeostasis utilized by melanoma and pancreatic ductal adenocarcinoma (PDAC) affect thequality and function of infiltrating immune cells. Specifically in Aim 1 we will investigate the balance betweenlipogenesis and lipolysis in tumor cells to determine how this affects the composition of lipids and lipoproteins inthe TME and the types of TILs present. We will test if CD8+ TILs metabolically adapt to changes in tumor cellmetabolism and learn how this affects their anti-tumor immune response. In Aim 2 we will investigate if TILsrespond to hyperlipidemia and Ox-LDL in the TME via upregulation of the transporter CD36 and elucidate howOx-LDL-CD36 signaling suppresses CD8+ TIL effector functions (this work is the first to explore this pathway inCD8+ T cells to our knowledge). Lastly we found arachidonic acid (AA) metabolism correlates with TIL infiltrationand in Aim 3 we will explore a new model that the balance of PGD2 and PGE2 changes as tumors progressconverting an immuno-supportive TME to one that is more immuno-suppressive. In all three Aims we will targetthese metabolic pathways to discover novel combinations of therapies that enhance the efficacy ofimmunotherapies currently in clinical use today. This work has great potential to uncover several new dimensionsof immunosuppression in the tumor microenvironment and interventions to stimulate anti-tumor immunity. 81092 +No NIH Category available Architecture;Brain;Breast;Breast Cancer Patient;Clinical Research;Environment;Ethnic Origin;Exhibits;Formalin;Genes;Immune;Immune Tolerance;In Situ;Incidence;Infiltration;Interruption;Macrophage;Malignant Neoplasms;Maps;Metastatic malignant neoplasm to brain;Molecular;Multiplexed Ion Beam Imaging;Neoplasm Metastasis;Neuroimmune;Paraffin Embedding;Pathology;Patient-Focused Outcomes;Patients;Primary Neoplasm;Proteins;Race;Resolution;Socioeconomic Factors;Technology;Tissue Microarray;Tissue Sample;Up-Regulation;Variant;Woman;black patient;black women;breast cancer progression;density;differential expression;high dimensionality;immunoregulation;malignant breast neoplasm;mortality;neoplastic cell;neuropathology;preclinical study;prognostication;racial population;targeted treatment;tumor;tumor microenvironment;tumor-immune system interactions Deconvolution and interruption of the cancer-neuro-immune axis facilitating brain metastases Black women exhibit a significantly higher incidence and mortality from breast-to-brainmetastasis that cannot be solely explained by cultural and socioeconomic factorsnecessitating the need to identify molecular mechanisms governing these differences.We hypothesize that increased incidence and progression of breast cancer in Blackwomen is in part due to race-based differences in tumor-immune interactions. This projectseeks to examine how the spatial architecture of the tumor microenvironment reflectsdistinct tumor-immune interactions and how these interactions prime systemic immunetolerance of disseminated tumor cells enabling brain-specific metastases. NCI 10747824 9/11/23 0:00 PA-21-071 3U54CA261717-02S1 3 U54 CA 261717 2 S1 "GRIL, BRUNILDE M" 3/1/23 0:00 8/31/25 0:00 10312066 "HAYDEN GEPHART, MELANIE " Not Applicable 16 NEUROSURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 3/1/23 0:00 8/31/23 0:00 397 Research Centers 2023 76446 NCI 49225 27221 Black women exhibit a significantly higher incidence and mortality from breast-to-brainmetastasis. This difference in cancer incidence and patient outcomes cannot be solelyexplained by cultural and socioeconomic factors necessitating the need to identifymolecular mechanisms governing these differences. Preclinical and clinical studies havediscovered differences in tumor microenvironment (TME) composition and architecturethat are distinct in breast cancers from Black patients. Microvessel density macrophageinfiltration and upregulation of immune-related genes have been shown to exist in Blackwomen compared to White women supporting the idea that ethnic variation can contributeto distinct changes in the TME. Little is known about the immune environment in breastcancer brain metastases especially in Black patients. We hypothesize that increasedincidence and progression of breast cancer in Black women is in part due to race-baseddifferences in tumor-immune interactions. This proposal will examine how the spatialarchitecture of the TME reflects distinct tumor-immune interactions and how theseinteractions prime systemic immune tolerance of disseminated tumor cells enablingbrain-specific metastases.Stanford Pathology and Neuropathology departments have constructed a tissuemicroarray (TMA) containing brain metastases and primary tumors from a diverse groupof breast cancer patients. We will characterize the spatial architecture of these TMAsusing multiplexed ion beam imaging (MIBI). MIBI is a cutting -edge technology thatenables simultaneous quantification of up to 39 proteins in formalin-fixed paraffin-embedded tissue samples to create high dimensional tumor-immune maps at subcellularresolution. Using MIBI we will construct in-situ subcellular protein spatial maps of bothprimary breast cancer and breast cancer brain metastases TME. We will subsequentlyidentify features of the primary and brain metastases TMEs that are differentiallyexpressed between Black women and other racial groups. We will focus on identifyingfeatures of the tumor-immune microenvironment (immune composition spatialarchitecture tumor-immune interactions) that vary based on patient race. The results fromthis project will be instrumental in developing appropriate prognostication and targetedtherapies for Black women with breast cancer. 76446 +No NIH Category available Address;Adolescence;Adolescent and Young Adult;Adverse effects;Aftercare;Age;Age Months;Award;Back;Behavioral;Cannabinoids;Cannabis;Characteristics;Chronic;Cigarette;Community Health;Cross-Sectional Studies;Data;Decision Making;Dedications;Dependence;Development;Disease;Drug usage;Education;Electronics;Emotional;Environment;Epidemic;Expectancy;Female;Flavoring;Freedom;Friends;Future;Gender;Health;Individual;Inhalation;Intervention;Interview;JUUL;Left;Life Experience;Malignant Neoplasms;Marijuana Smoking;Measures;Modeling;Moods;Motivation;Nicotine;Oils;Oral;Outcome;Parents;Participant;Pattern;Persons;Plants;Play;Policies;Population;Predisposition;Prevention;Prevention strategy;Problem behavior;Proliferating;Public Health;Relapse;Reporting;Research;Rewards;Risk;Risk Factors;Role;Schools;Self Administration;Smoking;Social Environment;Stress;Students;Surveys;Technology;Testing;Tobacco;Tobacco use;Tobacco-Related Carcinoma;Uncertainty;Variant;Waxes;Women's Health;Youth;adverse outcome;aged;biopsychosocial;catalyst;cigarette smoking;cohort;combustible tobacco;coping;craving;design;deviant;electronic cigarette use;emerging adult;emotion regulation;empowerment;experience;experimental study;flexibility;habituation;health goals;heated tobacco products;high-risk adolescents;insight;intergenerational;male;marijuana use;marijuana vaping;multiple drug use;nicotine exposure;nicotine use;ninth grade;novel;parent grant;parent project;pleasure;polysubstance use;prevent;programs;progression risk;public health priorities;recruit;response;self esteem;smoking initiation;social;substance use;theories;therapy design;tobacco products;trend;uptake;vaping;vaping nicotine;young adult Vaping Nicotine and Cannabis Across Adolescence and Young Adulthood PROJECT NARRATIVE (PARENT AWARD R01CA229617)Vaping-the inhalation of vaporized substances from electronic devices-has increased in adolescents and young adults (AYAs) including vaping of flavors only nicotine and cannabis products. This study will provide new essential information about whether low-risk AYAs begin nicotine and cannabis use via vaping and whether vaping may lead to adverse consequences including cigarette and cannabis smoking. This study will provide public health officials with data regarding the potential adverse public health impact of AYA vaping and clear targets for intervention to reduce AYA vaping and the health consequences that may follow. NCI 10747805 5/5/23 0:00 PA-21-071 3R01CA229617-04S2 3 R01 CA 229617 4 S2 "RODITIS, MARIA LEIA" 9/20/19 0:00 8/31/24 0:00 9227137 "LEVENTHAL, ADAM MATTHEW" "BARRINGTON-TRIMIS, JESSICA LOUISE" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 4/1/23 0:00 8/31/23 0:00 393 Non-SBIR/STTR 2023 130723 NCI 79226 51497 "PROJECT SUMMARY (PARENT AWARD R01CA229617)In 2015 evidence that e-cigarette use (""vaping"") in adolescents and young adults (AYAs) had increased and was associated with increased risk of cigarette smoking initiation generated concern in the public health community. Subsequent research has left the field with several critical questions including: (1) whether vaping truly has a causal effect on smoking or merely reflects a common liability toward deviancy among 'high-risk' AYAs with emotional or behavioral problems (2) whether an emerging wave of new vaping products including new nicotine products such as JUUL and an increasingly diverse class of products dedicated to vaping cannabis plant oils and waxes may increase the appeal and addictive potential of vaping and (3) whether there exist particular characteristics of vaping products and biopsychosocial mechanisms that underlie the risk of AYA vaping initiation progression and transition to other forms of drug use that could be targeted in prevention efforts. The uncertainties regarding the impact of AYA vaping have left policy officials with little evidence to determine if AYA vaping should be prioritized in public health programs and if so the most effective strategies for prevention.To address the evidence needs and provide a flexible framework for future study of the impact of various vaping products on the AYA tobacco product and cannabis use burden we will test a novel 'catalyst model' of AYA vaping. The catalyst model proposes two steps which we will evaluate in Aims 1 and 2 of this proposal. Step 1 (AIM 1 ). To determine whether (a) AYAs with fewer emotional-behavioral risk factors who have been previously deterred from drug use in traditional (non-vaporized) forms are at risk of vaping initiation (b) the unique qualities and product features of vaping (e.g. concealability flavors appealing technology social acceptability low perceived harm) increase risk of AYA vaping and (c) features of vaping products disproportionately increase the risk of vaping initiation for low-risk AYAs. Step 2 (AIM 2). To determine whether (a) vaping increases the risk of cross-product transitions involving initiation of other vaping products or combustible nicotine or cannabis as well as increases risk of progression to problematic drug use outcomes including dependence poly-drug use and chronic drug use through early adulthood (b) rewarding effects from exposure to nicotine cannabinoids and other product components (e.g. flavorings) increases risk of cross-product transitions and problematic drug use outcomes and (c) product characteristics modify this association. To test the model we will leverage data collected from participants from age 14-19 (2013-2018) from our existing cohort and follow participants into early adulthood (20-23 from 2019-2023; N-2000). We will also recruit a new cohort of 9th grade students at age 14 (N=2500) at the same schools as part of a cohort-sequential design that will apply causal inference analytic approaches to determine whether observed associations are likely causal. Collectively this project will provide critical information regarding the priority and potential targets of public health efforts aimed at reducing the potential adverse public health effects resulting from AYA vaping including tobacco-related cancer." 130723 +No NIH Category available Antiviral Agents;Area;Brain Neoplasms;Clinical Trials;Cytomegalovirus;Cytomegalovirus Infections;Data;Diagnosis;Doctor of Philosophy;Glioblastoma;Goals;Human;Immunocompetent;Immunotherapy;Jasminum;Link;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Modeling;Molecular;Mus;Parents;Patient-Focused Outcomes;Patients;Population;Resistance;Role;Therapeutic;Valganciclovir;Virus;blood-brain tumor barrier;design;effective therapy;human model;improved;irradiation;mouse model;response;standard of care;therapy resistant;tumor growth Defining the role of cytomegalovirus in glioblastoma therapies Narrative:Glioblastoma is a devastating brain cancer with no effective treatments. Data from our lab and others suggeststhat cytomegalovirus which is widespread in human populations has an impact on tumor growth and patientoutcomes. The goal of this study is identify mechanisms underlying therapeutic resistance caused bycytomegalovirus and to design new and more effective approaches. NCI 10747768 5/1/23 0:00 PA-21-071 3R01CA263324-02S1 3 R01 CA 263324 2 S1 "DASCHNER, PHILLIP J" 4/11/22 0:00 3/31/27 0:00 Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] 8662619 "LAWLER, SEAN EDWARD" "COOK, CHARLES H" 1 PATHOLOGY 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF MEDICINE 29034202 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 89342 NCI 60484 28858 Summary:Glioblastoma (GBM) is an incurable brain tumor for which improved therapies are badly needed. There areroughly 10000 cases diagnosed in the US each year and median survival is ~14 months. Evidence has beenaccumulating over recent years linking cytomegalovirus (CMV) to GBM and other cancers. However the roleof CMV in GBM remains poorly defined. CMV is a prevalent virus in humans where it resides lifelong in a latentstate but can be reactivated under certain conditions. Several clinical trials targeting CMV using diverseapproaches including immunotherapies and the anti-viral drug valganciclovir have shown very promisingresponses in GBM patients but the underlying mechanisms are not clear. To improve our understanding of thisarea we have developed an immunocompetent murine model of intracranial GBM grown in the context of asystemic latent CMV infection. This consistently leads to significantly shortened survival compared with mockinfected controls in multiple distinct murine GBM models. These effects can be reversed by treatment with anti-viral drugs.The goal of this study is to investigate the role of cytomegalovirus in therapeutic resistance in glioblastomabuilding from our parent RO1 to design new combination approaches. As part of her PhD studies in the lab of DrLawler Jasmine Clark will: 1) Identify anti-viral drugs for the most effective combination with standard of care(chemoirradiation) 2) investigate the role of altered vasculature/blood tumor barriers in therapeutic resistanceand 3) find molecular mechanisms involved in mediating resistance using our mouse and human models ofglioblastoma with CMV. Our goal is to develop improved therapeutic combinations. 89342 +No NIH Category available Acceleration;Acids;Address;Area;Bacteria;Barrett Esophagus;Bile Acids;Cell Differentiation process;Clinical;Collaborations;Colon;Colon Carcinoma;Communities;Data;Deoxycholic Acid;Development;Dysplasia;Enrollment;Enterobacteriaceae;Environment;Epithelium;Esophageal Adenocarcinoma;Esophageal Neoplasms;Esophageal Tissue;Feedback;Future;Gastroesophageal reflux disease;Goblet Cells;Helicobacter Infections;Helicobacter pylori;Homeostasis;Incidence;Inflammation;Intestines;Knowledge;Lesion;Logistic Regressions;Microbial Biofilms;Minority;Modeling;Mucins;Mucous body substance;Mutagens;NF-kappa B;Neoplasms;Obesity;Oral;Oral health;Organoids;Parents;Pathway interactions;Patients;Population;Prevalence;Production;Prognosis;Prospective cohort;Research;Risk;Risk Factors;Role;Salivary;Sampling;Series;Signal Transduction;Stomach;Streptococcus;Structure;Study models;Testing;Thinness;Time;Tissue Sample;Tissues;Upper digestive tract structure;Work;aspirate;carcinogenesis;carcinogenicity;cohort;experimental study;gastric microbiome;gastrointestinal;gastrointestinal epithelium;gut microbiome;infection rate;member;microbial;microbiome;microbiome alteration;microbiome composition;modifiable risk;mouse model;neoplastic;notch protein;oral microbial community;oral microbiome;parent grant;prospective;trend;tumor progression The Role of the Microbiome and Notch Signaling in Esophageal Adenocarcinoma PROJECT NARRATIVEThe purpose of this NCI Diversity Supplement is to explore the relationship between bacterial metabolites andneoplastic progression in Barretts esophagus. Additionally the work will assess how these metabolites relate toNotch signaling and the development of esophageal adenocarcinoma. NCI 10747759 9/19/23 0:00 PA-21-071 3R01CA255298-03S1 3 R01 CA 255298 3 S1 "DASCHNER, PHILLIP J" 1/1/21 0:00 12/31/25 0:00 Cancer Prevention Study Section[CPSS] 9047196 "ABRAMS, JULIAN " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 7/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2023 70807 OD 43044 27763 PROJECT SUMMARYThe incidence of esophageal adenocarcinoma (EAC) has risen 10-fold over the past half century and continuesto have a dismal prognosis. Modeling studies suggest that only a minority of EAC cases are attributable to obesityor gastric esophageal reflux. Helicobacter pylori infection rates have plummeted since the mid-20th century andabsence of H. pylori is associated with ~two-fold increased risk of Barretts esophagus (BE) the EAC precursorlesion and of EAC itself. Dramatic changes in the upper GI microbiome in western populations likely occurredwhile BE and subsequently EAC began to rise in incidence. Our groups prior work has discovered correlationsbetween the microbiome BE and EAC. In BE weve described tissue-associated microbiome alterations withprogression to EAC with notably increased Enterobacteriaceae and Streptococcus. Oral microbiome alterationshave been associated with future risk of EAC and we also previously described differences in the oralmicrobiome of a small group of BE patients. Alterations in the oral microbiome have also been associated withpoor oral health which was itself associated with increased risk of EAC in a recent analysis. In this proposal weseek to clarify how oral microbiome and metabolite alterations may drive progression of esophageal neoplasia.In particular we seek to understand how specific oral community members enriched or depleted in abnormalstates may shift metabolite production and lead to pro-carcinogenic changes in the upper gastrointestinalenvironment. We hypothesize that specific alterations of the oral microbiome can promote the development ofEAC and that the pro-neoplastic effects of bacteria are due in part to metabolite production. This hypothesis willbe pursued through the following inter-related specific aims: 1) To assess the oral microbial community structureassociated with progression from BE to EAC by identifying key bacterial taxa and 2) To isolate salivary microbialmetabolites associated with progression from BE to EAC while describing the totality of metabolites within theoral microbiome more deeply than any prior work. The parent grant addresses the hypothesis that deoxycholicacid (DCA) in gastro-esophageal refluxate induces Notch signaling in BE decreasing goblet cell differentiationand mucus production. However the parent R01 does not address the relationship between key bacterialmetabolites and their relationship to Notch signaling and neoplastic progression to EAC. This proposal addressesthis critical gap. 70807 +No NIH Category available Adult;African Burkitt's lymphoma;Animal Model;Apoptosis;B-Cell Lymphomas;B-Lymphocytes;C-Myc Translocation;Cell Cycle Progression;Cell Differentiation process;Cell Proliferation;Cell Survival;Cells;Chromosomal translocation;DNA Repair;DNA Sequence Alteration;Data;Dependence;Development;Disease;Epstein-Barr Virus-Related Lymphoma;Event;Funding;Genetic;Genome;Genomic Instability;Heavy-Chain Immunoglobulins;Human;Human Herpesvirus 4;Incidence;Infection;Integration Host Factors;Lymphoma;Malaria;Malignant Neoplasms;Molecular;Mus;Mutate;Mutation;Parasites;Pathogenesis;Pathway interactions;Plasmodium;Process;Proliferating;Proteins;Resistance;Risk;Structure of germinal center of lymph node;System;Systems Analysis;TP53 gene;Viral;Viral Genes;Viral Proteins;Virus;Work;c-myc Proto-Oncogenes;chronic infection;co-infection;experimental study;gammaherpesvirus;infected B cell;latent infection;metaplastic cell transformation;novel therapeutic intervention;prevent;promoter;synergism;targeted treatment;tumorigenesis Defining mechanisms of gammaherpesvirus-driven genomic instability in B cells PROJECT NARRATIVEGammaherpesviruses (GHVs) are ubiquitous viruses that establish lifelong chronic infections that can lead tocancer especially lymphoma. We identified a host protein p53 as being critical for limiting mutations and cellulartransformation due to GHV infection. Experiments are proposed to further define mechanisms of geneticmutations and tumorigenesis that are restricted by p53 during GHV infection which could identify targets fortherapies to prevent or treat GHV-associated lymphomas. NCI 10747707 3/24/23 0:00 PA-21-071 3R01CA167065-07S1 3 R01 CA 167065 7 S1 "READ-CONNOLE, ELIZABETH LEE" 4/4/14 0:00 2/28/27 0:00 Cancer Etiology Study Section[CE] 6484493 "FORREST, JAMES CRAIG" Not Applicable 2 MICROBIOLOGY/IMMUN/VIROLOGY 122452563 VDFYLZPJEAV6 122452563 VDFYLZPJEAV6 US 34.749005 -92.320097 1471106 UNIV OF ARKANSAS FOR MED SCIS LITTLE ROCK AR SCHOOLS OF MEDICINE 722057101 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 62560 NCI 44540 18020 PROJECT SUMMARYGammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerouscancers. During chronic infection GHVs express viral gene products that stimulate host-cell proliferation anddifferentiation processes thought to facilitate long-term latent persistence and contribute to tumorigenesis.However GHVs are not acutely transforming and cancer is rare given the high incidence of infection amongadult humans estimated at more than 95% for Epstein-Barr virus (EBV). This suggests that host cells areequipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization. In work performedduring the previous funding period we identified the tumor suppressor p53 as a protein that is activated duringthe establishment of GHV latent infection. p53 is frequently considered a guardian of the genome workingdownstream of multiple mutagenic pathways to halt cell-cycle progression stimulate DNA repair or promoteapoptosis. p53 is frequently mutated in human cancers including endemic Burkitt lymphoma an EBV-associatedlymphoma that is characterized by a chromosomal translocation between the immunoglobulin heavy-chainpromoter and cellular proto-oncogene c-myc. It is hypothesized that EBV synergizes with malaria to promotethe survival of cells that harbor IgH/c-myc translocations. Using murine gammaherpesvirus 68 (MHV68) infectionof mice as a small animal model to enable a multi-system analysis GHV pathogenesis we demonstrated thatp53 limits cellular proliferation especially of germinal center (GC) cells. We also found that p53 inhibits IgH/c-myc translocations in B cells of infected mice an event that correlates with enhanced B cell lymphomadevelopment in p53-deficient mice infected with MHV68. Moreover we provide preliminary data indicating thatco-infection of mice with MHV68 and a murine malaria parasite also promotes IgH/c-myc translocations.Experiments proposed in this competing renewal will build on our previous progress harnessing the powerfulmouse and MHV68 genetic systems to (i) define viral genes and molecular pathways that promote genomicinstability and lymphoma development (ii) identify viral and host-factor dependencies in GHV-driven lymphomasand (iii) determine the mechanisms through which MHV68 and murine Plasmodium parasites facilitatechromosomal translocations. In addition to providing a better understanding of how GHVs cause disease weanticipate that results of this work will inform new therapeutic approaches that target lymphoma dependenciesand reduce the mutagenic potential of GHVs and related co-infections. 62560 +No NIH Category available Aftercare;American Joint Committee on Cancer;Beds;Biological;Biological Markers;Cancer Biology;Cancer Patient;Cellularity;Cetuximab;Cisplatin;Clinical;Clinical Data;DNA;DNA Damage;Data;Defect;Deglutition;Deglutition Disorders;Diffusion;Diffusion Magnetic Resonance Imaging;Disease;Dose;Double Strand Break Repair;Eligibility Determination;Ensure;Excision;Functional disorder;Gene Expression;Gene Expression Profiling;Genes;Genomics;Goals;HPV oropharyngeal cancer;Human Papillomavirus;Hypoxia;Image;In complete remission;Individual;Inferior;Left;Lesion;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of anus;Measures;Mediating;Methods;Molecular;Monitor;Morbidity - disease rate;Motion;Mucositis;Mutation;Nature;Neck Dissection;Nodal;Normal tissue morphology;Operative Surgical Procedures;Oxygen;PET/CT scan;Pathologic;Pathway interactions;Patient Selection;Patients;Pilot Projects;Positron-Emission Tomography;Postoperative Period;Primary Neoplasm;Process;Prognosis;Progression-Free Survivals;Radiation;Radiation Dose Unit;Radiation Tolerance;Radiation therapy;Research;Resolution;Statistical Models;Structure;Survival Rate;Tissues;Toxic effect;Treatment outcome;Treatment-related toxicity;Virus Integration;Virus Replication;Work;biomarker discovery;cancer classification;candidate identification;chemoradiation;chemotherapy;cohort;disorder control;experience;fluorodeoxyglucose positron emission tomography;genome sequencing;genomic signature;imaging biomarker;non-invasive imaging;novel;overtreatment;patient stratification;pilot trial;pre-clinical;primary endpoint;quantitative imaging;radiation resistance;randomized trial;response;side effect;tool;treatment response;tumor;tumor hypoxia;tumor microenvironment;whole genome Dose de-escalation of HPV-associated oropharynx cancers: Exploration of HPV mediated radiation sensitivity Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) treated with a high dose of radiation (70Gy) has an excellent chance to be cured but the high radiation dose has significant side effects. The goal ofthis proposal is to evaluate how well a significantly reduced dose of radiation (30 Gy) can control and curecancer in certain patients with HPV-positive OPC. These patients will be selected based on the level ofoxygen in their tumors as tumors with low levels of oxygen (hypoxia) often do not respond as well to radiationtreatment as those with higher levels of oxygen; and in patients without hypoxic tumors evidence has shownthat the reduced dose of radiation may work just as well and without the severe side effects. NCI 10747663 4/5/23 0:00 PA-21-071 3R01CA238392-04S1 3 R01 CA 238392 4 S1 "VIKRAM, BHADRASAIN" 3/3/20 0:00 2/28/25 0:00 Radiation Therapeutics and Biology Study Section[RTB] 10411987 "LEE, NANCY Y" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 4/4/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 243191 NCI 137396 105795 The prognosis of HPV+ oropharyngeal cancer (OPC) treated with standard radiation at 70 Gy is excellent.However 80% of these patients experience grade 2 mucositis and 30% have permanent swallowingdysfunction. Clinical data suggest that 70 Gy may be overtreatment for some HPV+ OPCs. A modestreduction of 10-16 Gy for an unselected cohort with HPV+ OPC showed a 2-year progression-free survival(PFS) of 80% but 40% of patients still had difficulty swallowing at 1 year. The proposed research will employimaging (PET/MRI) biomarkers to identify patients with HPV+ OPC who may benefit from a major dosereduction to 30 Gy a dose based on experience in HPV+ anal cancer with the goal of maintaining tumorcontrol and cure while substantially reducing treatment-related toxicity. A pilot trial of 19 HPV+ OPC patientstreated at 30 Gy followed by neck dissection was encouraging with a 2-year PFS of 93%. Significant toxicityreduction was observed. The proposed research will expand on the initial findings of the proof- of-principlestudy to a larger cohort of patients. The proposed imaging metrics to select patients for major dose de-escalation will include baseline and early intra-treatment [18F]-FMISO PET imaging which will provideinformation on tumor hypoxia a marker of radioresistance (Aim 1). Eligible patients will have no evidence ofhypoxia on baseline imaging or have resolution of hypoxia during treatment which will portend tumorradiosensitivity. We will interrogate the tumor microenvironment (Aim 2) by deriving quantitative imagingbiomarkers (QIBs) from multi-parametric diffusion-weighted MRI (DW-MRI) consisting of non-Gaussianintravoxel incoherent motion (NG-IVIM) as well as [18F]-FMISO) PET imaging to select appropriate 30 Gycandidates to avoid neck dissection with the goal of further toxicity reduction. The change in intra-treatment diffusion (D surrogate of tumor cellularity) and kurtosis (K surrogate of tissue microstructure) frombaseline DW-MRI will guide which patients de-escalated to 30 Gy can avoid neck dissection. HPV is known todysregulate the DNA damage response (DDR) and double-strand break (DSB) repair pathways to facilitateviral replication. Preclinical work suggests that this dysregulation accounts for the radiosensitivity of HPV+OPC although there are conflicting data regarding the precise nature of the responsible defect. For Aim 3whole-genome sequencing (WGS) with mutational signature analyses will be used to identify DDR andDSB repair defects in individual HPV tumors and characterize the clinical influence on radiosensitivity. Therelationship between genomic signatures and non-invasive imaging of tumor hypoxia and tumor cellularity thatportend radiobiological sensitivity also will be explored. The proposal's central hypothesis is that PET/MRI ofHPV+ OPC classification with the underpinnings of a molecular characterization of the cancer biology willyield a robust decision tool to stratify patients for whom dose de-escalation to 30 Gy will provide aclinical benefit and significantly reduced toxicity without compromising treatment outcome. 243191 +No NIH Category available Acute Myelocytic Leukemia;Biological Models;Biological Process;Bladder;Breast;Breast Melanoma;CRISPR/Cas technology;Cancer Patient;Cell Line;Cell Respiration;Cell model;Characteristics;Clinical;Core Facility;Cutaneous Melanoma;Data;Databases;Dependence;Development;Electron Transport Complex III;Ensure;Evaluation;Event;Foundations;Future;Generations;Genes;Genetic Models;Genus Hippocampus;Glucose;Human;Impairment;Incidence;Individual;Invaded;Knock-in;Knock-out;Lead;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mediator;Melanoma Cell;Metabolic;Metabolic Pathway;Mitochondria;Modeling;Molecular;Molecular Genetics;Mutate;Mutation;Oncogenes;Oncogenic;Oncology;Outcome;Pancreas;Pathologic;Pathway interactions;Phenotype;Production;Prognosis;Proliferating;Property;Proteins;Public Health;Publishing;RNA;RNA Splicing;Recording of previous events;Resources;Respiration;Role;Series;Site;Solid;Solid Neoplasm;TP53 gene;Technical Expertise;Testing;Therapeutic;Tissues;Transcript;Tumor Cell Line;Tumor Subtype;Tumorigenicity;Universities;Warburg Effect;Work;cancer type;career;cell type;genome editing;improved;innovation;insight;leukemia;malignant breast neoplasm;melanoma;metabolomics;migration;mutant;novel;personalized strategies;therapeutic target;transcriptome;transcriptome sequencing;transcriptomics;treatment strategy;tumor;tumorigenesis;tumorigenic Harnessing hotspot specific differences among SF3B1 mutations to define novel mechanisms of tumorigenicity and targetability in solid malignancies PROJECT NARRATIVESF3B1 is the most commonly mutated splicing factor in cancer so identifying resultant therapeutic vulnerabilitiescan significantly impact the many cancers harboring these mutations (breast melanoma pancreatic bladderetc.). Development and use of novel genetic models of SF3B1 will allow us to delineate its mutation-specificroles in tumorigenesis and define potential therapeutic strategies. Additionally key mechanistic insight will begained from the observation that TP53 and SF3B1 mutations are mutually exclusive in cancer and therefore arelikely to have overlapping roles in tumorigenesis. NCI 10747548 6/22/23 0:00 PA-21-049 1F30CA268325-01A1 1 F30 CA 268325 1 A1 "DAMICO, MARK W" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15976138 "BERGMAN, RILEY " Not Applicable 5 INTERNAL MEDICINE/MEDICINE 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN SCHOOLS OF MEDICINE 372032408 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 32884 NCI 32884 0 PROJECT SUMMARYSF3B1 is the most commonly mutated splicing factor in cancer occurring in thousands of cancer patientsannually. Mutations in SF3B1 result in a neomorphic protein that causes aberrant splicing of hundreds oftranscripts including known cancer associated genes. While the mechanisms by which these alterations promotetumorigenesis are incompletely understood our lab has previously shown SF3B1 mutations are attractivetherapeutic targets. SF3B1 mutations are prevalent in many cancers (breast melanoma bladder pancreaticleukemias) so improving our ability to target these mutations could have major public health implications. To dothis there is a fundamental need to better understand how SF3B1 mutations drive tumorigenesis. Recent workin acute myeloid leukemia shows differences in missplicing oncogenic effects and prognosis among variousSF3B1 hotspot mutations yet there are no studies to date investigating these in solid malignancies. To determinepotential therapeutic strategies novel model systems are required. An innovative genome editing approach willallow us to study the mutations at the most common hotspots from breast cancer and melanoma K700 andR625 respectively in several representative cell line models. Changes in the transcriptome and phenotypicdifferences in proliferation migration and invasion will determine whether there are specific alterations inSF3B1 that lead to distinct oncogenic phenotypes. Additionally preliminary systematic analysis of onlinecancer databases shows SF3B1 mutations and TP53 alterations are mutually exclusive in cancer. This oftensuggests either synthetic lethality or a lack of selection for co-occurrence due to shared roles in tumorigenesis.Successful generation of dual SF3B1 mutant and TP53 mutant or TP53 knock out cell lines demonstrates thatthe mutations are unlikely to be synthetic lethal. Instead this relationship likely demonstrates a shared roleand will allow us to determine novel mechanisms of SF3B1-mediated tumorigenesis. Previous findings inSF3B1 mutants demonstrate dysfunctional cellular respiration due to missplicing and degradation of a UQCC1a component of mitochondrial complex III. There is a resultant increase in glucose similar to p53s well knownrole in promoting the Warburg effect. Further studying the relationship between mutant SF3B1 and TP53 mayidentify therapeutic vulnerabilities that can be additionally leveraged against the large subset of cancers withTP53 mutations. The sponsors robust history of utilizing genome editing strategies to study individual mutationsin breast cancer in conjunction with the abundant resources and core facilities at Vanderbilt University makethese Aims achievable. Completion of these aims provide an excellent foundation in cancer molecular genetics.This will allow the PI to acquire the technical skills to build toward an independent investigational career inoncology specifically studying novel pathologic features of cancers that lead to uniquely targetablevulnerabilities. 32884 +No NIH Category available Address;Adhesions;Antibody-drug conjugates;Antigen Presentation;CD4 Positive T Lymphocytes;Cells;Clinical;Cues;Data;Disease;Drug Delivery Systems;Embryo;Epithelial Cells;Exclusion;Extracellular Matrix;Fibroblasts;Fibrosis;Genes;Immune Evasion;Immunosuppression;Immunotherapy;Impairment;In Vitro;Inflammatory;Interleukin-1;Invaded;Malignant Neoplasms;Membrane;Mesenchymal;Mesoderm;Mesothelial Cell;Mesothelium;Monoclonal Antibodies;Myocardial Infarction;Operative Surgical Procedures;Organ;Outcome;Pancreatic Ductal Adenocarcinoma;Pathologic;Peripheral;Peritoneal;Phase;Phenotype;Physiological;Population;Preclinical Testing;Process;Reporting;Resistance;Signal Pathway;Solid Neoplasm;Source;Surface;Survival Rate;System;T cell infiltration;T cell regulation;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Training;Transforming Growth Factor beta;Tumor Volume;Vaccines;anti-cancer;cancer cell;chemotherapy;chimeric antigen receptor T cells;combat;immune checkpoint blockade;immune resistance;in vivo Model;lipid biosynthesis;mesothelin;mouse genetics;neglect;novel;novel strategies;prevent;single-cell RNA sequencing;targeted cancer therapy;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;wound healing Function of mesothelial cells in the tumor microenvironment of pancreatic ductal adenocarcinoma Project NarrativePancreatic ductal adenocarcinoma (PDA) is characterized by extensive desmoplasia caused by differentcancer-associated fibroblast (CAF) populations. As a major source of fibroblasts in other pathologicalconditions such as wound healing peritoneal fibrosis and surgical adhesions mesothelial cells have beenhistorically neglected as a potential functional constituent of the PDA microenvironment. This project aims toinvestigate the contribution of mesothelial cells to CAF formation and the function of mesothelial-fibroblastictransition in PDA which will elucidate a novel mesothelial cell-CAF system and has the potential to result in theidentification of novel strategies to target CAFs in PDA. NCI 10747452 11/10/23 0:00 PA-20-188 5R00CA252009-04 5 R00 CA 252009 4 "LIU, YIN" 12/1/22 0:00 11/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 15233515 "HUANG, HUOCONG " Not Applicable 30 SURGERY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Non-SBIR/STTR 2024 224100 NCI 136647 87453 Project Summary/AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by extensive desmoplasia causedby the rapid expansion of cancer-associated fibroblasts (CAFs) resulting in the formation of dense stroma.CAFs stimulate cancer progression by secreting a variety of factors that support cancer cells and facilitateimmunosuppression. In addition they also secrete extracellular matrix (ECM) that provides survival andinvasion cues to cancer cells and impairs drug delivery. Recently several populations of CAFs with distinctfunctions have been characterized in PDA by our group and others using single cell RNA sequencing (scRNAseq). One population is characterized as myofibroblastic CAFs (myCAFs) another population is characterizedas inflammatory CAFs (iCAFs) the third population was first identified as antigen-presenting CAFs (apCAFs)which express MHC II molecules and can effectively present antigen to T cells. My preliminary datademonstrated that apCAFs are mesothelial cells. Mesothelial cells form a continuous layer of epithelial cellsknown as mesothelium. The mesothelium is traditionally thought to be a membrane providing a non-adhesivesurface covering organs and tissues. However until the description of apCAF population mesothelial cellshave been neglected as a potential functional constituent of the tumor microenvironment. My preliminary datasuggest that during PDA progression mesothelial cells go through a mesothelial-fibroblastic transition (MFT)in which they down-regulate MHC II molecules that are required for CD4+ T cells activation and up-regulatefibroblast genes that have been known to prevent T cell infiltration and activation. Peripheral T cell exclusion isa major immune evasion phenotype in PDA and my preliminary data show that this exclusion occurs at theregion where mesothelial cells are transitioning to CAFs. Therefore MFT might be an important mechanism ofimmune evasion and understanding this process is critical. In this proposal I will test the hypothesis that thefibroblastic transition of mesothelial cells promotes immune evasion in PDA and identify potentialstrategies to inhibit this process. I propose the following two aims: Aim 1. Determine the fate of mesothelialcells during PDA progression. Aim 2. Determine the functions of MFT on immune evasion. The outcomeof the proposed study has the potential to shift the paradigm of tumor microenvironment studies identify novelstrategies to target CAFs and overcome resistance of immune therapies in PDA and other tumor types. 224100 +No NIH Category available Adipose tissue;Asian;Asian Americans;Biological Markers;Black race;Body Composition;Body fat;Body mass index;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer Treatment;California;Cancer Prognosis;Cells;Cessation of life;Complex;Computerized Medical Record;Data;Detection;Development;Diagnosis;Drug or chemical Tissue Distribution;ERBB2 gene;Ethnic Origin;Ethnic Population;Exhibits;Fatty acid glycerol esters;Female;Gene Expression;Genes;Genetic Transcription;Hip region structure;Hispanic;Hispanic Americans;In Situ Hybridization;Incidence;Inequity;Intervention;LEPR gene;Leptin;Link;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Measures;Modeling;Modification;Muscle;Nonmetastatic;Not Hispanic or Latino;Obesity;Outcome;Pacific Islander;Phenotype;Physiological;Precision therapeutics;Prevalence;Prognosis;RNA;Race;Receptor Gene;Recurrence;Recurrent Malignant Neoplasm;Research;Resources;Risk;Risk Reduction;Role;Sampling;Scanning;Skin;Specimen;Testing;Transcript;Tumor Markers;Tumor Subtype;Tumor Tissue;Variant;Visceral;Woman;X-Ray Computed Tomography;adipokines;adiponectin;black women;cancer recurrence;cancer risk;cell type;cohort;ethnic diversity;genetic signature;high body mass index;hormone receptor-negative;hormone receptor-positive;improved;indexing;individualized prevention;insight;leptin receptor;malignant breast neoplasm;mortality;novel;outcome prediction;predictive modeling;predictive signature;preventive intervention;programs;prospective;protein expression;racial difference;racial diversity;racial population;receptor;receptor expression;risk prediction;subcutaneous;transcriptome sequencing;transcriptomics;tumor;tumor microenvironment;waist circumference Understanding the role of adiposity and adipokine-related RNA expression in the tumor microenvironment on breast cancer outcomes in a racially and ethnically diverse sample PROJECT NARRATIVEExcess adiposity is independently associated with recurrence risk and death in hormone receptor-positive breastcancer but among non-Hispanic Black women and hormone-receptor negative breast cancer casesassociations are less clear. We will test the central hypothesis that adipose tissue depots (visceral vs.subcutaneous) measured using computed tomography scans have differing associations with adipokine andadipokine receptor gene expression profiles and related gene signatures in the breast tumor microenvironmentwhich can be used to develop outcome predictive models. This high impact study will advance the field byyielding new data on how adipose tissue distribution impacts (1) gene expression profiles in the breast tumormicroenvironment and (2) breast cancer outcomes with an emphasis on the interplay among race and ethnicityand tumor subtype. NCI 10747436 11/30/23 0:00 PA-20-185 5R01CA277862-02 5 R01 CA 277862 2 "GALLICCHIO, LISA M" 12/1/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 10513738 "LLANOS WILSON, ADANA A.M." "FELICIANO, ELIZABETH MARJORIE CESPEDES" 13 PUBLIC HEALTH & PREV MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF PUBLIC HEALTH 100323725 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 635699 NCI 527026 108673 ABSTRACTThe mechanisms linking adiposity with breast cancer and how variation in adipose tissue distribution contributeto inequities in breast cancer recurrence and mortality remain to be determined. Untangling the complexinteractions among adiposity race and ethnicity and breast tumor phenotype is a first step which requiresprecise adiposity measures and identification and refinement of adiposity-associated biomarkers within breasttumor tissues that can predict breast cancer outcomes. Our preliminary research has shown that the distributionof visceral adipose tissue and subcutaneous adipose tissue assessed by computed tomography (CT) scansdiffer by race and ethnicity and outperforms body mass index (BMI) in predicting cancer outcomes. Our priorresearch also showed that gene and protein expression of the adipokines leptin and adiponectin and theirreceptors vary in breast tumor tissues and generally lower expression is associated with more aggressive tumorfeatures (e.g. higher grade larger size hormone receptor negative status and triple-negative subtype). Furtherwe found that increased body fatness measures general obesity (BMI) body fat distribution (waistcircumference hip circumference WHR) and body composition (fat mass index percent body fat) areassociated with higher leptin receptor protein expression in breast tumor tissues with evidence of effectmodification by race. Building on these preliminary studies we hypothesize that adipose tissue depots (visceralvs. subcutaneous) have differing associations with adipokine and adipokine receptor expression profiles andrelated gene signatures in the breast tumor microenvironment (TME). Using multiplex RNA in situ hybridizationto characterize the abundance of adipokine and adipokine receptor expression in the breast TME CT scans toassess adipose tissue distribution and RNA-seq for transcriptomic analysis in a large diverse cohort of 1600women with breast cancer we will: (1) Test whether adiposity is associated with cell type-specific RNAexpression profiles of leptin adiponectin and their receptors in breast tumors and the adjacent breast TME; (2)Define associations between RNA expression profiles of leptin adiponectin and their receptors in the breastTME with tumor clinicopathology; and (3) Characterize RNA expression profiles associated with leptinadiponectin and their receptors in the breast TME to predict breast cancer recurrence and mortality. This studywill yield novel insights on how adipose tissue distribution impacts gene expression profiles in the breast TMEand new information about potential differences by race and ethnicity and tumor subtype. Such data are criticalfor efforts to integrate tumor markers and systemic factors into breast cancer risk and outcome prediction modelsand to informing the development of precision prevention interventions and precision therapeutics for diversebreast cancer patients. 635699 +No NIH Category available Address;Adhesions;Affinity;Aggressive behavior;Apoptosis;Area;Automobile Driving;Biological Assay;Biological Markers;Breast;Breast Cancer Patient;Breast cancer metastasis;Cancer Patient;Cell Culture Techniques;Cell Proliferation;Cells;Cessation of life;Clinical;Communities;Cooperative Behavior;Data;Data Set;Diagnosis;Disease;Distant;Environment;Epidermal Growth Factor Receptor;Event;Feedback;Fos-Related Antigens;Frequencies;Genetic Transcription;Growth;Hematopoietic Neoplasms;Human;In Situ;In Vitro;Individual;Laboratories;Learning;Life;Ligands;Ligation;Light;Lung;Malignant Neoplasms;Mammary Neoplasms;Metastatic breast cancer;Metastatic/Recurrent;Methods;Micrometastasis;Modeling;Molecular;Mus;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;Organoids;Outcome;Patient-Focused Outcomes;Patients;Play;Positioning Attribute;Privatization;Prognosis;Proliferating;Prostate;Protein Tyrosine Kinase;Receptor Activation;Receptor Signaling;Recurrence;Recurrent Malignant Neoplasm;Research;Resistance;Resistance development;Role;Sampling;Signal Induction;Signal Transduction;Site;Survival Rate;Testing;Therapeutic;Transcriptional Activation;Woman;Work;anticancer research;breast cancer survival;burden of illness;cancer recurrence;cancer type;early phase trial;epidemiology study;epigen;human data;improved;in vivo;innovation;malignant breast neoplasm;metastatic process;mortality;mouse model;multidisciplinary;neoplastic cell;novel therapeutic intervention;pre-clinical;prevent;programs;success;targeted treatment;transcription factor;tumor;tumor progression Role of tumor cell cluster-induced signaling in breast cancer metastasis The ultimate cause of most breast cancer-related deaths is metastasis the spread of cancer to distant organs.Recent research indicates that in breast cancer as well as many other tumor types circulating clusters oftumor cells are associated with therapy resistance widespread metastases and significantly worse prognosis.By learning more about these micrometastases this proposal seeks to identify molecular vulnerabilities thatcan be used to eradicate them thereby extending survival in patients with metastatic breast cancer. NCI 10747405 11/22/23 0:00 PA-19-056 5R37CA234488-06 5 R37 CA 234488 6 "GRIL, BRUNILDE M" 12/1/19 0:00 11/30/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 10214765 "CHEUNG, KEVIN JON" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 362340 NCI 205875 156465 The root cause of most breast cancer deaths is metastasis. By dissecting the molecular events driving it theresearch community can develop new therapeutic approaches to eradicate and prevent metastatic disease.One promising avenue of research involves the cooperative behavior of tumor cells. Conventionallymetastasis is conceptualized as the dissemination of individual tumor cells to distant organs. However recentstudies by the Cheung research group and others have established that clusters of tumor cells metastasize todistant organs more efficiently than single cells in mouse models and that circulating tumor cell clusters areassociated with poor patient outcomes and therapy resistance in humans. The molecular mechanismsresponsible for aggression in tumor cell clusters and the optimal therapeutic strategies to eliminate clustershave remained obscure. Recently the Cheung laboratory has found that clustered tumor cells displayheightened levels of apoptosis resistance cell proliferation and changes in molecular expression that indicatethat the cells are cooperating with one another. These studies reveal that the tyrosine kinase EGFR isactivated at cell-cell contacts in clustered tumor cells and they establish that EGFR and the low-affinity EGFRligand Epigen are necessary for cluster-dependent proliferation and metastatic colonization. The proposedproject will test the hypothesis that tumor cell clusters are highly metastatic because they contain a privatesignaling environment involving EGFR Epigen and the transcription factor Fra-1 and that disrupting thissignaling environment will neutralize clusters metastatic potential. The Cheung lab has already developedtechnically innovative organoid and murine models to study cluster-based signaling and its impact onmetastasis in vivo. Using these models the lab will first determine whether cluster-induced metastaticefficiency depends specifically on local activation by Epigen. Second the lab will determine the impact of Fra-1transcriptional programs and signaling feedback loops on metastatic processes specific to tumor cell clustersas well as whether this program depends on the presence of Epigen. Third the lab will supplement itsexperimental findings by studying the association between EGFR Epigen and long-term recurrence andmortality data from human breast cancer datasets. Through this integrated approach the Cheung lab willdevelop an understanding of the cooperative molecular mechanisms that underlie the propensity of tumor cellclusters to metastasize. As described in the proposal this understanding is likely to reveal molecularvulnerabilities that can be exploited to develop new anti-metastatic therapies. Although the work proposed herefocuses on uncovering therapeutic strategies to target tumor cell clusters in breast cancer the findings willpotentially be relevant to a wide range of tumor types. 362340 +No NIH Category available ASCL1 gene;ATAC-seq;Ablation;Advisory Committees;Atlases;Automobile Driving;BETA2 protein;Cancer Center;Cancer Histology;Cancer Model;Cell Nucleus;Cells;Chemoresistance;Classification;Clinical;Collaborations;Computing Methodologies;Doctor of Philosophy;Drug Targeting;ELF3 gene;Environment;Epidermal Growth Factor Receptor;Epigenetic Process;Faculty;Funding;Genes;Genetic Transcription;Genomics;Goals;Histologic;Histology;Human;In Vitro;Knock-out;Lasers;Libraries;Lung;Lung Adenocarcinoma;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Medical Oncology;Memorial Sloan-Kettering Cancer Center;Mentors;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;Neurosecretory Systems;Non-Small-Cell Lung Carcinoma;Oncogenic;Patient Care;Patients;Phenotype;Physicians;Play;Population;Pre-Clinical Model;Preparation;Process;RB1 gene;RNA;Recurrence;Regulator Genes;Relapse;Research;Research Proposals;Resistance;Resources;Risk;Role;Sampling;Scientist;Signal Transduction;TP53 gene;Therapeutic;Training;Validation;Variant;biomarker identification;cancer cell;cancer subtypes;cancer type;career;career development;cell transformation;cohort;epigenetic regulation;experience;experimental study;genetic manipulation;in vivo;in vivo Model;innovation;laboratory experience;molecular marker;notch protein;novel drug class;overexpression;patient derived xenograft model;pre-clinical;preclinical study;pressure;prevent;programs;research and development;single cell sequencing;single-cell RNA sequencing;skills;small cell lung carcinoma;targeted treatment;tenure track;therapeutic target;therapy resistant;transcription factor;transcriptomics;tumor;tumor heterogeneity;whole genome Uncovering Epigenetic and Transcriptional Drivers of Neuroendocrine Plasticity at Single-Cell Level in Patients with Small Cell Lung Cancer Transformation PROJECT NARRATIVEHistological transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC)and subsequent diversification into more aggressive SCLC subtypes are examples ofneuroendocrine lineage plasticity a process that promotes metastasis and treatment resistancein lung cancer. This proposal uses 1) single-cell sequencing in patient tumors of combinedLUAD/SCLC histology and 2) functional experiments in preclinical models of SCLC transformationto identify transcriptomic and epigenetic changes driving lineage plasticity. These moleculardrivers may identify a novel class of drug targets that ablate lineage plasticity with therapeuticimplications in not just lung cancer but also any cancer type where small cell transformation mayarise. NCI 10747402 12/1/23 0:00 PA-20-203 5K08CA259161-03 5 K08 CA 259161 3 "BIAN, YANSONG" 12/15/21 0:00 11/30/26 0:00 Career Development Study Section (J)[NCI-J] 15624212 "CHAN, JOSEPH MINHOW" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 197198 NCI 182591 14607 PROJECT SUMMARY/ABSTRACTResearch: In lung adenocarcinoma (LUAD) neuroendocrine (NE) transformation to small cell lung cancer(SCLC) is associated with metastasis and resistance to targeted therapies. This lineage plasticity often leads toLUAD and SCLC admixed in the same tumor. We demonstrated that laser-microdissected LUAD and SCLCintratumoral components share truncal mutations confirming NE transformation. SCLC itself is classified asclassical variant and non-NE subtypes. Preclinical studies demonstrate that variant and non-NE subtypes haveincreased risk for metastasis and chemoresistance. It is poorly understood what gene regulatory mechanismdrives SCLC transformation and SCLC subtype switching. Single-cell RNA and ATAC sequencing (scRNA-seqsnATAC-seq) in samples of combined LUAD/SCLC histology present an ideal platform to characterize theintratumoral heterogeneity of NE plasticity. As a control reference we completed scRNA-seq in a cohort of denovo SCLC (Chan et al. bioRxiv under review at Cancer Cell). We performed scRNA-seq in an initial cohort ofcombined LUAD/SCLC and found significantly increased intratumoral subtype diversity in transformed SCLC (T-SCLC). We found Notch suppression in T-SCLC and reactivation with subsequent SCLC subtype diversification.We observed overexpressed SOX2 and ELF3 in pre-transformed vs classical LUAD and PHOX2B and ELF3 inT-SCLC vs de novo SCLC. We hypothesize that under RB1 and TP53 loss key transcription factors (SOX2PHOX2B ELF3) epigenetic regulators and modulation of Notch signaling all contribute to NE transformationand subtype diversification. We will leverage scRNA-seq and snATAC-seq in samples of combined LUAD/SCLChistology to 1) identify molecular markers of subclonal populations 2) reconstruct the regulatory network and 3)validate transcriptomic and epigenetic drivers of NE plasticity in preclinical in vitro and in vivo models includingan EGFR+ LUAD patient-derived xenograft undergoing NE transformation after osimertinib treatment.Candidate: Dr. Joseph Chan MD PhD is a Medical Oncology Fellow at MSKCC. He aims to become anindependent tenure-track physician-scientist investigating lineage plasticity in metastasis and treatmentresistance in cancer. His mentors Drs. Charles Rudin and Dana Peer are leading experts in lung cancer andsingle-cell sequencing respectively. Dr. Chan proposes a five-year period of mentored training to acquire wetlab and advanced computational skills. His wet lab training will include 1) single-cell library preparation and 2)genetic manipulation of preclinical models for functional validation. His computational training will include 1)snATAC-seq analysis and 2) advanced machine learning. His advisory committeeDrs. Charles SawyersHelena Yu Ronan Chalign and Christina Lesliewill guide his training and research.Environment: MSKCC is a cancer center renowned for patient care innovative research and training for juniorfaculty seeking careers as independent physician-scientists. MSKCC houses the Single Cell Research Initiativethat advances single-cell sequencing which will support this proposal for research and career development. 197198 +No NIH Category available Architecture;Atomic Force Microscopy;Behavior;Binding;Biochemical;Biochemistry;Biological Assay;Biological Models;Biology;Biophysical Process;Biophysics;Breast Cancer Patient;Breast Cancer cell line;Breast cancer metastasis;CRISPR interference;Cancer cell line;Cell Line;Cell Nucleus;Cell physiology;Cells;Characteristics;Chromatin;Chromatin Fiber;Chromatin Structure;Chromosome Segregation;Complex;Confocal Microscopy;Coupled;DNA;DNA-Protein Interaction;Development;Disease;Distal;Down-Regulation;Electron Microscopy;Estrogen receptor positive;Exhibits;Fluorescence Microscopy;Gene Expression Regulation;Gene Silencing;Gene Structure;Genes;Genetic Transcription;Genome;Goals;Heterochromatin;Histologic;Histone H3;In Vitro;Individual;Injections;Integral Membrane Protein;Intermediate Filament Proteins;Invaded;Label;Lamin Type B;Lamins;Length;Liquid substance;Lysine;MCF7 cell;Malignant Neoplasms;Mechanics;Mediating;Mediator;Membrane;Metastatic/Recurrent;Methylation;Modification;Molecular;Monitor;Morphology;Mus;Neoplasm Metastasis;Nuclear;Nuclear Envelope;Nuclear Inner Membrane;Nuclear Pleomorphism;Nucleosomes;Organism;Output;Patient-Focused Outcomes;Phase;Physiological;Play;Pleomorphism;Postdoctoral Fellow;Proliferating;Protein Region;Proteins;Research;Research Project Grants;Role;Severities;Shapes;Sum;System;T47D;Techniques;Tertiary Protein Structure;Testing;Time;Trophoblast Cancer;Tumor Markers;Up-Regulation;Variant;Visualization;Work;biophysical properties;cancer cell;diagnostic biomarker;disease phenotype;experimental study;gene repression;heterochromatin-specific nonhistone chromosomal protein HP-1;histone methylation;histone modification;in vivo;lamin B receptor;malignant breast neoplasm;micronucleus;migration;mouse model;neoplastic cell;novel;overexpression;physical model;programs;protein expression;public health relevance;receptor binding;reconstitution;recruit;restoration;single molecule;targeted cancer therapy;therapy development;tumor progression;ultra high resolution Dissecting the mechanistic role of multinucleation in breast and trophoblast cancers Project Narrative and Public Health Relevance StatementSilencing large regions of the genome is essential for proper cell function and these heterochromatic regionsare organized at the nuclear periphery. A diagnostic marker of tumor severity and patient outcome aredistortions to the size and shape of the nucleus termed pleomorphism. The research program proposed aimsto develop a fundamental understanding of heterochromatin formation at the nuclear envelope which willprovide tangible targets for cancer therapies that aim to restore proper regulation of gene expression andnuclear morphology. NCI 10747383 12/29/23 0:00 RFA-CA-19-002 5K00CA245719-07 5 K00 CA 245719 7 "DAMICO, MARK W" 1/1/21 0:00 12/31/24 0:00 ZCA1-RTRB-R(A1) 14207598 "KEENEN, MADELINE " Not Applicable 4 ANATOMY/CELL BIOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Other Research-Related 2024 95046 NCI 88103 6943 Project Summary/Abstract A key driver of cancer is the global deregulation of transcription networks in the cell. Transcriptional outputis dependent on chromatin structure and topology; repressed genes are sequestered from active genes intoregions of compacted DNA near the nuclear membrane. Dense chromosomal domains termed heterochromatinare associated with Heterochromatin Protein-1 (HP1) and are tethered to the periphery via an interaction withthe nuclear transmembrane protein Lamin Binding Receptor (LBR) and the intermediate filament protein LaminB. Consequently cancer cells that undergo global rewiring of transcription also often exhibit aberrant proteinexpression of Lamin B LBR and HP1. The physical manifestation of the misregulation of these proteins isdistortion in the size and shape of the nuclear envelope. Indeed this nuclear pleomorphism is used as ahistological marker of tumor progression. In estrogen receptor positive (ER+) breast cancer patientsdownregulation of HP1 and upregulation of Lamin B and LBR is strongly correlated with earlier occurrence ofdistal metastasis. Understanding the biophysical properties that govern the assembly of heterochromatin at thenuclear periphery will facilitate the development of therapies aimed at restoring proper gene regulation. HP1 wasrecently found to concentrate DNA and chromatin into liquid-liquid phase separated (LLPS) droplets in vitro. Thissuggests a potential mechanism of DNA organization in vivo. To investigate the molecular details of HP1-mediated compaction and phase separation I utilized DNA curtains and confocal microscopy. I identified keyregions of HP1 required for multivalentLLPS interactions and DNA compaction. This preliminary researchfocused on DNA and the graduate work in Aim 1 will build on these studies by evaluating HP1 interactions withcomplex nucleosomal substrates. Heterochromatin in vivo is distinguished by evenly spaced nucleosomes andthe trimethylation of histone H3 lysine 9 (H3K9me3). I will make chromatin substrates that range from mono-nucleosomes to 50kb chromatin fibers with variations in spacing and methylation modification. I will monitor thebinding oligomerization and phase separation of HP1 on these substrates by a combination of bulk biochemicalassays and a novel single molecule chromatin assay. The proposed postdoctoral research in Aim 2 will focuson determining a physical model of the nuclear periphery. I will reconstitute the interactions between chromatinand the lamina with single molecule studies in vitro and super resolution studies in cells. I will use cell lines andmouse models of breast cancer metastasis to determine the molecular mechanism guiding metastatic recurrenceof ER+ breast cancer patients with high expression of Lamin B and LBR. This research program will propel metoward my ultimate goal of leading my own lab studying how nuclear topology is coupled to cell fate determinationin development and the misregulation that leads to disease. 95046 +No NIH Category available Acceleration;Accounting;Adult;Adverse effects;Antigens;Antisense Oligonucleotides;B cell differentiation;B lymphoid malignancy;B-Cell Activation;B-Cell Acute Lymphoblastic Leukemia;B-Cell Antigen Receptor;B-Cell Lymphomas;B-Cell NonHodgkins Lymphoma;B-Lymphocytes;BCL2 gene;Binding;Bone Marrow;Burkitt Lymphoma;Cells;Cellular biology;Chromatin;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;DNA Binding;Data;Dependence;Development;Diagnosis;Disease Progression;Embryonic Development;Exposure to;FRAP1 gene;Family;Family member;Future;Genes;Genetic;Genetic Transcription;Glycolysis;Goals;Health;Hematologic Neoplasms;Hematopoiesis;Homeostasis;Human;IGF1R gene;INSR gene;Immune signaling;Incidence;Lesion;Lymphocyte Activation;Lymphoma;Lymphomagenesis;Maintenance;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Modeling;Mus;Oncogenic;PAX5 gene;PI3K/AKT;Pathway interactions;Pharmaceutical Preparations;Physiological;Process;Proteins;Receptor Activation;Resistance;Risk;Role;Signal Transduction;Structure of germinal center of lymph node;TCF3 gene;Therapeutic;Therapeutic Intervention;Tumor Promotion;Up-Regulation;Work;Zinc Fingers;immune activation;in vivo;large cell Diffuse non-Hodgkin's lymphoma;mTOR inhibition;member;multidisciplinary;new therapeutic target;novel;novel therapeutics;overexpression;premalignant;programs;protein structure;reconstitution;response;side effect;standard of care;targeted treatment;therapeutic target;transcription factor;tumor;tumor growth;tumor initiation DISSECTING THE ROLE OF PRDM15 IN NORMAL HEMATOPOIESIS AND B-CELL MALIGNANCIES NARRATIVERecent work from our groups has demonstrated that PRDM15 a member of the PRDM family of transcriptionregulators is essential in early embryogenesis but dispensable for adult homeostasis. Given the upregulationof PRDM15 expression in different types of human B cell lymphomas here we propose to investigate thefunction of PRDM15 in both normal hematopoiesis under conditions of B cell activation and duringlymphomagenesis.This study aims at understanding the mechanism of PRDM15-driven metabolic rewiring and explore futureopportunities for therapeutic intervention in PRDM15 overexpressing B cell lymphomas. NCI 10747364 11/28/23 0:00 PA-19-056 5R01CA248984-04 5 R01 CA 248984 4 "JHAPPAN, CHAMELLI" 12/9/20 0:00 11/30/25 0:00 Molecular Oncogenesis Study Section[MONC] 14078747 "GUCCIONE, ERNESTO " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 441059 NCI 261450 179609 SUMMARY B cell non-Hodgkin Lymphoma (B-NHL) is the 7th most common cancer in the US and the predominanttype of hematologic malignancies accounting for ~50% of all diagnosed cases. Despite a betterunderstanding of their genetic repertoire the factors governing the unique transcriptional and signalingdependencies of different B-NHL subclasses remain incompletely understood. As such clinical responses tostandard-of-care therapies are highly heterogeneous. There is therefore an urgent need to identify noveltailored therapeutic strategies that provide more effective and durable responses. Here we show that a member of the PRDM family of lineage determining transcription factors(PRDM15) is abnormally upregulated in B cell malignancies and propose to assess its potential as a noveldrug target. Our preliminary data strongly support that PRDM15 can be depleted without major adverse effectsin vivo. A targeted depletion in pre-malignant B-cell cells will however strongly delay lymphomagenesis.Mechanistically PRDM15 acts by transcriptionally regulating tumor-promoting metabolic pathways (e.g.PI3K/AKT glycolysis). Interestingly while dispensable for B cell differentiation under steady state conditionsPRDM15 plays a role during B-cell activation that notably results in metabolic changes equivalent to thoseoccurring in lymphomas. We hypothesize that PRDM15 modulates transcription and consequently the expression of proteins(e.g. IGF1R INSR HK3) involved in the essential metabolic changes imposed by physiological B cell immuneactivation or oncogenic transformation. This project aims to better define PRDM15 as a key regulator ofmetabolic rewiring during these processes. We propose to investigate this central hypothesis in the followingSpecific Aims: In Aim1 we will assess the mechanistic role of PRDM15 in tumor initiation and maintenance andto assess the therapeutic potential of targeting PRDM15 in specific tumor subsets. Specifically we will focuson downstream genes and pathways ultimately regulated by PRDM15 in B cells lymphomas. In Aim 2 we willcharacterize PRDM15s role in normal hematopoiesis and B cell responses both at steady state and uponexternal challenges (e.g. exposure to foreign antigens bone marrow reconstitution). This will be relevant bothto understand the role of PRDM15 in the context of normal B cell differentiation and to evaluate the potentialrisks or side effects of therapies targeting PRDM15 functions. The significance of these studies is that given the importance of PRDM15 for metabolic rewiring ofactivated and transformed B cells understanding the mechanism of action of PRDM15 will allow targeting itsdegradation or inhibiting its function and may be of future therapeutic relevance. The health relatedness is that our studies may identify new therapeutic opportunities for a variety of B-cell lymphomas that have high energetic demands. 441059 +No NIH Category available Aggressive behavior;Automobile Driving;BRAF gene;Cancer Patient;Cell Culture Techniques;Cell Line;Cell Proliferation;Cell Survival;Cessation of life;Chemotherapy and/or radiation;Clinical;Combined Modality Therapy;Complex;Critical Pathways;Cytotoxic Chemotherapy;Data;Development;Disease;Disease Progression;Disease model;Drug Combinations;Emergency Situation;Endocrine;Epithelial Cells;Event;FRAP1 gene;Feedback;Foundations;Genetic;Genetically Engineered Mouse;Goals;In Vitro;Incidence;Knowledge;MEKs;Malignant Neoplasms;Malignant neoplasm of thyroid;Maps;Mediating;Molecular;Molecular Analysis;Mutate;Mutation;Neoplastic Cell Transformation;Neurofibromin 2;Oncogenes;Oncogenic;Operative Surgical Procedures;PIK3CG gene;Palliative Care;Pathway interactions;Patients;Physiological;Process;Prognosis;Protein Kinase;Radioactive Iodine;Recurrence;Refractory;Resistance;Resistance development;Role;Sgk protein;Signal Pathway;Signal Transduction;TP53 gene;Testing;Therapeutic;Thyroid Gland;Time;Unresectable;Woman;anaplastic thyroid cancer;cancer diagnosis;clinically relevant;combinatorial;design;effective therapy;genetic approach;in vivo;in vivo Model;inhibitor;mouse genetics;mouse model;mutant;novel;overexpression;patient population;patient subsets;prototype;radioiodine therapy;rational design;resistance mechanism;response;targeted treatment;therapeutic target;therapy resistant;tumor;tumor growth;tumor progression Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer Approximately 2000 patients with thyroid cancer die each year in the U.S. and many more suffer from progressive symptomatic disease. The limited number of advanced thyroid cancer patients has been a major obstacle to our understanding of the molecular mechanisms involved in disease progression as well as to the development of effective therapies. Furthermore even when the driving oncogenic insults are known and targeted inhibitors are available cancers invariably develop resistance to them.In this application we leverage the power of mouse genetics and in vivo disease modeling to characterize novel pathways that are critical for thyroid cancer development and to define novel paradigms for rationally designed combinatorial therapies. Successful completion of the proposed studies will help map novel signaling pathways and design effective therapies providing benefit not only to advanced thyroid cancer patients but also to those with other tumor types sharing the same genetic alterations. NCI 10747360 11/29/23 0:00 PA-19-056 5R01CA128943-17 5 R01 CA 128943 17 "GHOSH-JANJIGIAN, SHARMISTHA" 2/1/09 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-EMNR-E(02)M] 6981843 "DI CRISTOFANO, ANTONIO " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 380260 NCI 227701 152559 Thyroid cancer is the most common endocrine malignancy and ranks as the sixth most common cancer diagnosed in women. Rising incidence of thyroid cancer is reflected by the projected 52000 new cases in 2019. A majority of patients have differentiated thyroid cancer and are managed successfully with a combination of surgery and radioiodine (RAI) therapy. However tumors may present or recur as RAI-refractory or metastatic in which case they have a poorer prognosis and death is common. Among these anaplastic thyroid cancer (ATC) although relatively rare represents a true clinical emergency: ATC is typically unresectable at presentation highly resistant to therapy RAI-resistant and associated with a median survival of less than 9 months when patients are treated with multimodal therapy and less than 3 months with palliative care. Cytotoxic chemotherapy and radiation are generally ineffective in prolonging survival of ATC patients. Thus ATC remains one of the most lethal tumors and needs novel effective and especially rational therapeutic approaches. The major obstacle to this goal is the lack of a detailed understanding of the pathways altered both in the early stages (drivers) and during progression of ATC. As the patient population is small our mechanistic knowledge is based on the retrospective analysis of patient material and on cell lines often of dubious origin. We now know that TP53 is lost or mutated in 70% of ATCs and that in almost 40% the PI3K cascade is constitutively activated. Additional common drivers include BRAF (40%) and RAS (27%) activating mutations. Despite this knowledge it is increasingly clear that we are still missing a comprehensive wiring chart depicting all theinteractions between different cooperating driver pathways. Such detailed map is of paramount importance to design effective multidrug combinations that consider less known signaling conduits mechanisms of resistance and feedback pathway activation. The current application has two broad long-term objectives. The first goal is to utilize a combination of in vivo ex vivo and in vitro approaches to test the hypothesis that activation and/or overexpression of the SGK1 protein kinase are integral and essential components of the neoplastic transformation process initiated by constitutive activation of PI3K RAS and SRC in thyroid epithelial cells and that SGK1 targeting is essential for effective inhibition of tumor growth. The second objective is to use genetically engineered mouse models as well as cell culture approaches to test the hypothesis that mutations in mTORC1-activating pathways including loss of NF2 and activation of PI3K signaling cooperate with oncogenic RAS by contributing crucial signals needed for RAS-mediated transformation of thyroid epithelial cells. This genetic interaction opens a window of opportunity for targetedtherapeutic approaches. 380260 +No NIH Category available Address;Advisory Committees;Award;Biological Models;Bromodomain;CRISPR screen;CRISPR/Cas technology;Cancer Etiology;Cessation of life;Clinical;Clinical Trials;Complement;Data;Dependence;Development;Development Plans;Disease;Disease Outcome;Disseminated Malignant Neoplasm;Electroporation;Epigenetic Process;Evaluation;Expenditure;Fracture;Genes;Genetically Engineered Mouse;Genomics;Goals;Histone Acetylation;Human;Indolent;Knock-out;Knowledge;Lead;Localized Disease;Malignant Neoplasms;Malignant neoplasm of prostate;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Modeling;Molecular;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Oncogenes;Pain;Patient Care;Patients;Penetrance;Pharmaceutical Preparations;Phenotype;Physiological;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Reader;Research;Resistance;Signal Transduction;Signaling Molecule;Site;Survival Rate;Techniques;Therapeutic;Training;Treatment Side Effects;Tropism;Universities;Whole Organism;androgen deprivation therapy;bone;career;career development;castration resistant prostate cancer;drug development;effective therapy;epigenomics;genome-wide;improved;in vivo;in vivo Model;inhibitor;innovation;interest;men;mortality;mouse genome;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;nuclease;overexpression;pre-clinical;precision medicine;preclinical study;prostate cancer metastasis;prostate cancer model;prostate cancer progression;small molecule;small molecule inhibitor;somatic cell gene editing;spinal cord compression;standard of care;targeted agent;targeted treatment;therapeutic development;therapy resistant;tool;transcription factor;treatment as usual;treatment response;treatment strategy;tumor;tumor microenvironment;tumor progression Identification of therapeutic vulnerabilities in prostate cancer bone metastasis Project Narrative Metastatic prostate cancer is the second-leading cause of cancer-related deaths in men ranks third innational cancer expenditures and represents significant morbidity to patients due to bone metastasis and sideeffects of treatment. This proposal will perform preclinical studies to identify previously unrecognized therapeuticvulnerabilities of prostate cancer bone metastasis and treatment-resistant tumors. These studies may ultimatelyresult in novel treatments that can potentially improve survival and reduce morbidity of this lethal disease. NCI 10747354 12/1/23 0:00 PAR-18-366 5K22CA258806-03 5 K22 CA 258806 3 "VAHEDI, SHAHROOZ" 1/1/22 0:00 12/31/24 0:00 Career Development Study Section (J)[NCI-J] 14304891 "ARRIAGA, JUAN MARTIN" Not Applicable 13 UROLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 Other Research-Related 2024 192456 NCI 178200 14256 Project Summary/Abstract Prostate cancer lethality is mainly due to metastasis which occurs most frequently in bone and isassociated with high morbidity. Despite recent progress current treatments are not curative and therefore newtherapeutic strategies are urgently needed. Given that both metastatic progression and therapeutic resistanceoccur in the context of a whole organism and are influenced by the tumor microenvironment one significantchallenge to our current understanding of metastatic progression is the paucity of models in which to studymetastasis in its physiological context and especially models that recapitulate the bone tropism of humanprostate cancer. The overarching goal of this proposal is to understand how the molecular alterations present in lethalprostate cancers contribute to disease outcome and how to use this knowledge to develop more effectivetherapies. In particular my preliminary data strongly suggests MYC as a driver of bone metastasis progression.Given that MYC has traditionally been hard to target therapeutically this proposal will leverage unique mousemodels of bone metastasis to address specific therapeutic vulnerabilities to target MYC signaling dependenciesin prostate cancer. Specifically in Aim 1 I will study small molecule inhibition of the ATAD2-bromodomain as astrategy to inhibit metastasis and therapy resistance. In Aim 2 I will use CRISPR screens to identify syntheticlethal vulnerabilities of prostate tumors with high MYC activation. In Aim 3 I will exploit CRISPR technology tosomatically edit the genomes of mouse prostates in order to streamline the study of the phenotypicconsequences of genetic alterations for prostate cancer progression. The career development plan outlined in this award leverages my training at Columbia University and anoutstanding advisory committee into an innovative research plan to steer my career into specific precisionmedicine approaches for the treatment of prostate cancer bone metastasis. This proposal will provide theconceptual groundwork preliminary data and experimental tools for a competitive R01 submission thuslaunching my independent career. If successful this award will provide proof-of-principle for a new class of targeted agents and uncovernew therapeutic vulnerabilities in metastatic prostate cancer as occurs in vivo. This proposal will advance thefield by potentially leading to novel clinically testable hypotheses that may guide clinical trials. Ultimately theseresults will impact patient care by reducing the morbidity and mortality associated with metastatic prostatecancer. 192456 +No NIH Category available AKT inhibition;AKT1 gene;AKT2 gene;AKT3 gene;BRAF gene;Biological Models;Brain;CDKN2A gene;Cell Line;Cessation of life;Clinical Management;Clinical Trials;Collaborations;Collection;Data;Development;Diagnosis;Disease;Disease Resistance;Distant;Distant Metastasis;Drug resistance;FDA approved;Focal Adhesion Kinase 1;Focal Adhesions;Gene Combinations;Gene Delivery;Genetically Engineered Mouse;Genomics;Goals;Growth;Histologic;Human;Incidence;Invaded;Knowledge;Lipids;Lung;MAP Kinase Gene;MEK inhibition;MEKs;Malignant Neoplasms;Melanoma Cell;Metastatic Melanoma;Metastatic Neoplasm to the Lung;Metastatic malignant neoplasm to brain;Modeling;Molecular;Mus;Neoplasm Metastasis;Nonmetastatic;Organ;PI3K/AKT;PTEN gene;PTK2 gene;Pathologist;Pathway interactions;Patient-Focused Outcomes;Patients;Penetrance;Phosphoric Monoester Hydrolases;Phosphorylation;Pre-Clinical Model;Process;Productivity;Prognosis;Protein Dephosphorylation;Proteomics;Proto-Oncogene Proteins c-akt;Research;Resistance;Resources;Risk;Sampling;Scientist;Signal Transduction;Site;Skin Cancer;Talents;Testing;Time;Toxic effect;Translations;Treatment Failure;Xenograft Model;clinically relevant;effective therapy;high risk;human data;human disease;improved;improved outcome;in vivo;inhibitor;interest;melanocyte;melanoma;mouse model;mutant;next generation sequencing;novel;novel therapeutics;patient derived xenograft model;pharmacologic;postnatal;prevent;response;standard of care;targeted treatment;therapeutic target;therapeutically effective;tool;tumor A High-Throughput Model for Human Melanoma Recently approved therapies have shown unprecedented promise in advanced stages of melanoma but clinicalmanagement of brain metastases remains challenging. This project strives to understand the mechanisms bywhich melanomas metastasize to the brain such that more effective therapies can be developed to improve theoutcomes for these patients. NCI 10747339 11/6/23 0:00 PA-19-056 5R01CA121118-14 5 R01 CA 121118 14 "SNYDERWINE, ELIZABETH G" 4/13/07 0:00 11/30/25 0:00 Tumor Progression and Metastasis Study Section[TPM] 6257820 "HOLMEN, SHERI L" Not Applicable 1 SURGERY 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 260775 NCI 171000 89775 Significant advances in melanoma research have resulted in new therapies that have remarkably improved themanagement and overall survival of melanoma. However many patients still succumb to the disease and morethan half of all melanoma deaths are due to brain metastases. As a means to overcome this challenge wedeveloped a novel mouse model that allows postnatal delivery of genes of interest to melanocytes. Usinggenomic and proteomic data from human melanoma samples we tested several gene combinations for theirability to induce metastatic melanoma in vivo. Hyperactivation of the PI3K/AKT pathway in the context of mutantBRAF and CDKN2A loss resulted in the development of spontaneous melanoma with full penetrance and amean survival of only 6 weeks. The majority of these mice also developed multiple metastases to the lungs andbrain. This model mimics the human disease genetically histologically and by sites of metastasis. Importantlythis model system provides a powerful platform to further study the mechanisms of melanoma metastasis.Elucidation of this network will allow the identification of key pathway nodes that represent potential therapeutictargets to disrupt this process. We used next generation sequencing and proteomics analysis of non-metastaticand metastatic tumor samples to identify downstream targets of AKT1 implicated in melanoma brain metastasis.Our data showed that tumors expressing activated AKT1 displayed elevated levels of focal adhesion (FA) factorsand phosphorylated focal adhesion kinase (P-FAK). In addition mutant AKT1 expression increased invasion andthis was reduced by pharmacological inhibition of either AKT or FAK. Moreover loss of PTEN which also resultsin increased FAK activity cooperated with activated AKT1 to further enhance brain metastasis in vivo. Despitethese promising preliminary findings a critical gap still remains in understanding whether and how FAK promotesmelanoma brain metastasis and whether the AKT1-FAK-PTEN axis can be exploited as a therapeutic target inthis disease. Our long-term goal is to use this knowledge to develop novel melanoma therapies and improvepatient outcomes. Pursuant to this goal we have generated a diverse collection of state-of-the-art research toolsand assembled a talented team of scientists and clinicians with a track record of productive collaboration to carryout and critically evaluate the results of the proposed aims. Using these unique resources we propose to testthe following hypotheses: 1) AKT1 FAK signaling is essential for the development of melanoma brainmetastases; 2) Combined inhibition of BRAFV600E MEK and FAK is superior to standard of care targeted therapyand; 3) Loss of PTEN expression results in sustained FAK phosphorylation which enhances the developmentof melanoma brain metastases. Successful completion of the aims in this proposal will significantly impact thefield by laying the groundwork for translation into clinical trials leading to new and better treatments for patientswith brain metastases and those who are at high risk of developing brain metastases. 260775 +No NIH Category available 3-Dimensional;Animal Model;Architecture;Basic Science;Biological;Biological Assay;Blood Vessels;Breast cancer metastasis;Cells;Cellular Structures;Cellular biology;Cessation of life;Classification;Clinical;Complex;Cytometry;Data;Data Set;Diameter;Disease;Distant;Ensure;Evaluation;Extracellular Matrix;Extravasation;Fibroblasts;Gene Expression;Genetic Transcription;Human;Image;Immune;Immunofluorescence Immunologic;Immunohistochemistry;In Vitro;Individual;Invaded;Malignant Neoplasms;Malignant neoplasm of pancreas;Mammary Neoplasms;Masks;Measurement;Mechanics;Microfluidic Microchips;Microfluidics;Modeling;Molecular;Mus;Neoplasm Metastasis;Organ;Organoids;Pancreatic Adenocarcinoma;Patients;Phenotype;Pre-Clinical Model;Process;Proteome;Proteomics;Publishing;Research;Resolution;Sampling;Series;Signal Transduction;Site;Stains;Structure;Techniques;Technology;Testing;Three-Dimensional Imaging;Tissues;Training;Tumor Tissue;Validation;Venous;Visualization;Wood material;Work;cancer cell;candidate identification;candidate validation;cell behavior;cell type;classification algorithm;deep learning algorithm;imaging approach;in vivo;in vivo evaluation;innovation;insight;malignant breast neoplasm;metastatic process;molecular marker;mouse model;multiple omics;novel;real-time images;reconstitution;reconstruction;response;segmentation algorithm;single-cell RNA sequencing;spatial relationship;synergism;targeted treatment;transcriptome;transcriptome sequencing;tumor;tumor microenvironment RTB 2 n/a NCI 10747318 12/1/23 0:00 RFA-CA-21-002 5U54CA268083-03 5 U54 CA 268083 3 12/1/21 0:00 11/30/26 0:00 ZCA1-SRB-X 9000 9719315 "EWALD, ANDREW JOSEF" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 313311 191335 121976 Metastasis requires fundamental changes in cell behavior and causes most cancer deaths. Metastasis is alsoan inherently 3D process involving interactions among diverse cancer cells and with the tumor microenvironment(TME). We developed innovative 3D assays to model each step in metastasis ex vivo. We use these assays togenerate hypotheses about how cancer cells accomplish metastasis and which molecular signals should betargeted therapeutically. In vivo validation of these hypotheses is rate limiting technically and conceptually. Wecan compare the effects of many perturbations in vitro with real-time imaging and molecular readouts. Incontrast in vivo validation is generally limited to measurements of tumor diameter CTC and metastasis numbersand a few molecular markers in 2D sections. There is an urgent need to achieve a 3D understanding ofmetastasis including the complex interactions among cell types and transitions between cell states. The3D imaging and spatial multi-omics approaches in TECH1 and TECH2 are ideally suited to allow us tounderstand vascular invasion the key transition from local to metastatic disease. Prior studies generallyevaluated single cell types or a few markers largely in 2D. CODA (TECH1) will enable us to classify cell typesand their spatial relationships in 3D. DBiT-seq (TECH2) enables us to reconstruct the transcriptome and selectproteome of high-resolution regions (~10 micron) across whole sections of human tumors. We will combine thesetechniques to achieve spatial multi-omics and resolve cancer cell state changes during breast cancer metastasis.Aim 1: Adapt CODA to murine models and human breast tumors focusing on venous invasion. We willfirst supply archival human breast tumors to enable TECH to adapt their 3D deep learning algorithms to breastcancer. We will start with a existing series of 250 human breast tumors with digitized serial sections. We will thencollect fix and section fresh human breast tumor samples stained with immune and cancer cell markers. Wewill use CODA to reconstruct the 3D architecture of vascular invasion and associated stromal responses. Wewill also adapt CODA techniques for use with murine preclinical models. We will then leverage these insights toreconstitute the vascular invasion niche in vitro by adapting a novel microfluidic platform we developed.Aim 2: Adapt DBiT-seq for murine and human breast tumors focusing on cancer cell state transitions.We will adapt DBiT-seq to 3D human breast tumor samples to understand spatial relationships among cancercell states during vascular invasion. This analysis will be led from cell states and inferred state transitions wedefined in vitro using single cell RNA-seq in our 3D metastasis assays. We will then collect a staged series oftumors and distant organs from GEMMs to define cell state transitions spatially across metastatic processes thatare difficult to sample in humans. We will then use the transcriptional and signaling dynamics identified in vivousing DBiT-seq to identify candidate molecular regulators for functional validation in vascular invasionmicrofluidic devices in vitro. Validated candidates will then be tested in vivo in breast cancer GEMMs. +No NIH Category available Acceleration;Activities of Daily Living;Aerobic;Affect;Age;Aging;Area;Behavior Therapy;Body Composition;Body Weight decreased;Cancer Survivor;Clinical;Clinical Trials;Cohort Studies;Control Groups;Creatine;Creatinine;Data;Diet;Dietary Intervention;Dual-Energy X-Ray Absorptiometry;Elderly;Enrollment;Exercise;Fasting;Fatty acid glycerol esters;Fracture;Funding;Gait speed;Health;Home;Hour;Individual;Ingestion;Intervention;Intervention Trial;Longevity;MRI Scans;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Medical Research;Methods;Minority;Muscle;Obesity;Older Population;Outcome;Overweight;Participant;Patients;Performance;Physical Function;Physical Performance;Physical activity;Physical assessment;Populations at Risk;Prevalence;Program Research Project Grants;Quality of life;Risk;Rural;Sampling;Schedule;Skeletal Muscle;Surveys;Testing;Thinness;Time;Urine;Venous blood sampling;Visiting Nurse;Woman;X-Ray Computed Tomography;arm;cancer diagnosis;cancer survival;capsule;comparative efficacy;design;diet and exercise;disability;disability risk;effective intervention;exercise intervention;exercise program;falls;health assessment;high risk population;improved;intervention effect;lean body mass;lifestyle intervention;men;muscle form;novel;older men;older women;preservation;programs;reduced muscle mass;response;rural setting;sarcopenia;tool;validation studies;wasting;weight loss intervention AMPLIFIed muscle mass in older cancer survivors enrolled in a diet-exercise program We will measure muscle mass and changes in muscle mass in the funded program project theAdapting MultiPLe behavior Interventions that eFfectively Improve (AMPLIFI) CancerSurvivor Health (1P01CA22997 using a novel accurate and non-invasive method the D3-Creatine dilution method. This project will assess for the first time how diet exercise andaging affects skeletal muscle mass in this at-risk population of older cancer survivors and testthe hypothesis that muscle mass and changes in muscle mass are strongly related to changesin functional capacity and physical activity. NCI 10747310 11/30/23 0:00 PAR-18-869 5R01CA246695-05 5 R01 CA 246695 5 "AGURS-COLLINS, TANYA" 12/9/19 0:00 11/30/24 0:00 "Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]" 7747865 "EVANS, WILLIAM J" "CAWTHON, PEGGY MANNEN; DEMARK-WAHNEFRIED, WENDY " 12 NUTRITION 124726725 GS3YEVSS12N6 124726725 GS3YEVSS12N6 US 37.870017 -122.268624 577502 UNIVERSITY OF CALIFORNIA BERKELEY BERKELEY CA EARTH SCIENCES/RESOURCES 947101749 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 230688 NCI 178461 52227 We propose to add the measurement of muscle mass to an already funded program projectgrant. Rapid declines in physical functioning often occur after the diagnosis of cancerespecially among older cancer survivors; however a handful of diet and exercise interventionshave been found to ameliorate these losses. The contribution of muscle mass and changes inmuscle mass in older men and women particularly those who have survived cancer is not wellcharacterized partly due to the inability to directly and accurately quantify skeletal muscle massand reliance on assessments of lean mass as a surrogate. The Adapting MultiPLe behaviorInterventions that eFfectively Improve (AMPLIFI) Cancer Survivor Health (1P01CA22997)is aimed at testing three distinct lifestyle interventions among 652 older inactive overweight orobese cancer survivors a large proportion of whom will be minority and rural. The interventionsinclude: 1) a 6-month dietary intervention aimed at improving diet quality and weight loss aswell as preserving lean body mass; 2) a 6-month intervention that is aimed at promotingaerobic physical activity; and 3) a 12-month diet and exercise intervention that combines bothdiet and exercise simultaneously (and effects will be evaluated against the combination ofinterventions 1 and 2 in sequence). Visiting nurses will assess physical function and performphlebotomy at home health assessments scheduled at baseline and every six months;participants also will complete surveys that assess diet physical activity and overall quality oflife. We propose to measure the effects of these interventions on muscle mass usingthe novel D3-creatine (D3Cr) dilution method. We have demonstrated that this non-invasive method can be implemented in a large cohort study (MrOS) and that D3Cr musclemass is strongly associated with functional capacity and risk of disability and that age-associated decreases in muscle mass are associated with slower gait speed and decreasedstrength. These associations were not observed using DXA derived lean mass. Subjects willingest a 60 mg capsule of D3Cr and produce a fasting urine sample 48 96 hours later forthe assessment of D3-Creatinine enrichment to determine creatine pool size and because98% of total body creatine is found in muscle muscle mass. For the first time therelationship between changes in muscle mass resulting from exercise and weight loss andfunctional capacity and physical activity will be assessed in this at-risk population of oldercancer survivors. 230688 +No NIH Category available A549;Acetylation;Acetyltransferase;Active Sites;Address;Affinity;Antibodies;Apoptosis;Binding;Biochemical;Biological;Biological Assay;Biological Process;CASP9 gene;Calorimetry;Cancer Patient;Cancer cell line;Cell Proliferation;Cell Survival;Cell physiology;Cells;Chemicals;Chromatin Structure;Clinical;Coenzyme A;Collection;Colon;Colorectal Cancer;Complex;Development;Epigenetic Process;Fibroblasts;Fluorescence;Fluorescence Polarization;Fluorescent Probes;Foundations;Genomics;Goals;H1299;HCT116 Cells;HT29 Cells;Histone Acetylation;Histone H2A;Histone H4;Human;Invaded;Investigation;Knowledge;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Mission;Mitochondria;Molecular;Monitor;N-terminal;Outcome;Pathway interactions;Peptides;Physiological;Play;Process;Proteins;Public Health;Radioactive;Reporting;Reproducibility;Research;Resources;Roentgen Rays;Role;Sampling;Series;Slug protein;Structure;Structure-Activity Relationship;System;TP53 gene;Testing;Tetracyclines;Therapeutic;Tissues;Titrations;Up-Regulation;Xenograft procedure;adduct;analog;cancer cell;cell motility;chromatin remodeling;cyanine dye 5;drug discovery;epithelial to mesenchymal transition;fluorophore;gene repression;high throughput screening;human disease;inhibitor;knock-down;lung cancer cell;member;meter;mouse model;novel;novel therapeutic intervention;pharmacologic;pharmacophore;prevent;redshift;response;screening;small hairpin RNA;small molecule;small molecule inhibitor;small molecule libraries;stable cell line;success;therapeutic target;tumor growth;tumor progression Discovery of small molecule inhibitors for protein N-terminal acetyltransferase D There are no small molecule inhibitors in existence to target NatD. This application is the firststudy that seeks to discover novel small molecules targeting NatD. The proposed research isrelevant to public health because the developed NatD inhibitors will increase our understandingof how NatD contributes to cancer progression and its value as a therapeutic target which isrelevant to the mission of NCI. NCI 10747309 11/16/23 0:00 PAR-20-271 5R01CA258887-03 5 R01 CA 258887 3 "FORRY, SUZANNE L" 12/1/21 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-BST-F(55)R] 11406053 "HUANG, RONG " Not Applicable 4 PHARMACOLOGY 72051394 YRXVL4JYCEF5 72051394 YRXVL4JYCEF5 US 40.41872 -86.910361 1481402 PURDUE UNIVERSITY WEST LAFAYETTE IN SCHOOLS OF PHARMACY 47906 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 470343 NCI 319238 151105 Emerging evidence implies that protein acetyltransferases play a crucial role in diversebiological processes and various human diseases including cancer. Protein N-terminalacetyltransferase D (NatD) also known as Naa40 Nat4 or Patt1 is a unique member of proteinN-terminal acetyltransferases because it only acetylates histones H2A and H4 that share theidentical N-terminal sequence of SGRGK. NatD has been reported to play an important role in avariety of processes including remodeling of chromatin structure cell migration and invasion andapoptosis. The elevated level of NatD in human lung and colorectal cancer tissues correlates withpoor clinical outcomes. Moreover loss of NatD suppresses human lung cancer cell invasion anddecreases the tumor growth in colorectal cancer xenograft mice models. Hence we hypothesizethat NatD is a compelling target for the development of novel cancer therapeutics for lung andcolorectal cancers. However there are no specific small molecule probes available for NatD todecipher the functions of NatD acetyltransferase activity in cancer. To fill this gap our long-termgoal is to discover novel potent and selective small molecule NatD inhibitors. For this applicationwe will employ a series of facile and reproducible high-throughput screening (HTS) assays withorthogonal readouts to screen 400000 diverse compounds from selected chemical libraries atthe Chemical Genomics Facility at Purdue Institute for Drug Discovery. Then we will characterizeactive compounds in structural mechanistic selectivity and cell-based studies. Upon completionof this project we expect to identify potent and selective first-in-class NatD small moleculeinhibitors as chemical probes for NatD function in cells. The knowledge gained from this projectwould expedite the development of NatD modulators and our understanding of NatD-regulatedpathways in cancer patients. 470343 +No NIH Category available Adaptive Immune System;Agonist;Androgen Analogues;Androgen Receptor;Androgen Therapy;Androgens;Apoptosis;Autophagocytosis;Autophagosome;Biopsy;CRISPR/Cas technology;Cancer Biology;Cancer Patient;Castration;Cell model;Cells;Chronic;Clinical;Clinical Management;Clinical Research;Cytoplasm;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Disorder;DNA Repair Gene;Data;Defect;Disease;Dose;Environment;Exposure to;FDA approved;Gene Amplification;Genes;Goals;Growth;Hormonal;Hormones;Hour;Human;Immune;Immune response;Immune signaling;Immunotherapeutic agent;In Vitro;Infiltration;Injections;Innate Immune System;Interferons;Knock-out;Left;Ligands;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Prostate Cancer;Molecular;Mutation;NF-kappa B;Nature;Nucleic Acids;PSA level;Pain;Pathway interactions;Patients;Positioning Attribute;Prediction of Response to Therapy;Process;Production;Prostatic Neoplasms;Quality of life;Receptor Signaling;Recurrence;Resistance;Resolution;Resources;Role;Serum;Sex Functioning;Signal Transduction;Stimulator of Interferon Genes;TP53 gene;Testing;Testosterone;Therapeutic;Treatment Efficacy;Variant;Work;Xenograft Model;Xenograft procedure;advanced prostate cancer;androgen deprivation therapy;antitumor effect;biomarker development;cancer immunotherapy;castration resistant prostate cancer;chemokine;digital;ds-DNA;empowerment;exposed human population;genetic signature;humanized mouse;immune activation;immune checkpoint blockade;immunoregulation;improved;in vivo;innate immune pathways;innovation;insight;men;mouse model;novel;overexpression;pain relief;palliative;patient subsets;pre-clinical;preclinical study;prostate biopsy;prostate cancer cell;prostate cancer cell line;response;sensor;synergism;tool;translational approach;treatment duration;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Androgen Activation of Innate Immune Signaling to Enhance Prostate Cancer Immune Response We have recently developed a novel and paradoxical approach to treat castration resistant prostate cancerpatients by using supraphysiologic testosterone (SupraT) termed bipolar androgen therapy (BAT) as a therapyfor this disease. The proposed work will provide mechanistic insights into how SupraT works at the molecular andcellular level. Successful completion of the project will inform us whether SupraT involves immune activation andimmune editing of prostate tumors an insight which could transform the clinical management of patients withmetastatic castration-resistant prostate cancer in the immediate term. NCI 10747302 12/12/23 0:00 PA-20-185 5R01CA243184-03 5 R01 CA 243184 3 "KUO, LILLIAN S" 12/1/21 0:00 11/30/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8775288 "KACHHAP, SUSHANT KRISHNA" "DENMEADE, SAMUEL R" 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 472615 NCI 288620 183995 Bipolar androgen therapy (BAT) is a paradoxical approach for the treatment of castration-resistant prostate cancer(CRPC) whereby testosterone levels are rapidly cycled between supraphysiologic and castrate concentrations.Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT withother agents to achieve increased efficacy and tumor responses. Previous observations suggest thatsupraphysiological testosterone (SupraT) induce DNA double strand breaks (DSB). It has been speculated that ifleft unrepaired DSBs may lead to cellular crisis and apoptosis. In this proposal we provide novel evidence thatunrepaired DSBs induced by SupraTs are routed to the autophagosomes where they activate cytoplasmic nucleicacid sensors that trigger the downstream interferon stimulated genes (ISGs) and innate immune pathways. Basedon our preliminary data we propose a novel idea that: i) Unrepaired DSBs induced by SupraTs are routed forspecialized autophagic degradation termed nucleophagy; ii) SupraTs induced autophagosomal DNA can activatecytoplasmic DNA sensing pathways~ specifically the nucleic acid sensing pathway (cGAS-STING and RIG-Ipathway); iii) Activation of nucleic acid sensing pathway by SupraTs would be more pronounced in prostate tumorsthat have DNA repair defect; and iv) BAT might activate innate and adaptive immune cells specially in a subset ofpatients having DNA repair defect. In this proposal we will determine the role of nucleic acid sensors in mediatingimmune signaling by SupraTs in PCa. Utilizing tumor biopsies from PCa patients receiving BAT we will evaluatewhether nucleic acid sensor mediated innate immune signaling serves as a molecular determinant of treatmentresponse. To test our hypothesis we will utilize several innovative tools and resources including CRISPR-Cas9generated knockout cellular models GeoMx Digital Spatial profiling of immune landscape in the tumormicroenvironment unique patient derived prostate cancer xenografts models a humanized mouse models that hasfunctional innate and adaptive immune cells and serum and tumor biopsies from patients receiving BAT. We thinkthese unique resources position us well to undertake the proposed work with immediate clinical impact. We haveassembled a team of experts in basic and clinical prostate cancer biology and immunotherapy who will provide theirunique expertise to successfully accomplish our goals. Successful completion of the proposed work will generate:a) mechanistic insights into modulation of immune response by SupraTs b) valuable clinical insights into activationof immune cells by BAT c) novel tumor- and serum-based markers that can be utilized for the development ofbiomarkers predictive of therapy response and d) provide a rationale for strategically utilizing BAT to activateimmune response and combine it with immunotherapeutics that empower the adaptive immune system such asimmune checkpoint blockade and T-cell therapeutics to achieve synergy. 472615 +No NIH Category available Acute Lymphocytic Leukemia;Adherence;Age;Behavior assessment;Behavioral;Biological Markers;Cancer Relapse;Cause of Death;Cessation of life;Child;Child Behavior;Child Rearing;Child health care;Childhood;Classification;Code;Conflict (Psychology);Data;Data Collection;Deglutition;Disease;Dose;Drops;Drug Prescriptions;Education;Educational process of instructing;Electronics;Enrollment;Ensure;Equation;Family;Goals;Health Care Costs;Home;Hospitalization;Ingestion;Intervention;Learning;Life;Malignant Childhood Neoplasm;Measurement;Measures;Medical;Medication Management;Medicine;Methodology;Methods;Modeling;Monitor;Morbidity - disease rate;Nurses;Oral;Parents;Participant;Patient Self-Report;Patients;Pediatric Oncology Group;Pediatrics;Pharmaceutical Preparations;Procedures;Public Health;Randomized Controlled Trials;Research;Resistance;Risk;Schedule;Scheme;Shapes;Specific qualifier value;Stress;Surveys;Techniques;Testing;Time;Treatment Failure;Treatment outcome;United States National Institutes of Health;behavior measurement;biomarker validation;cancer care;cancer risk;caregiving;chemotherapy;clinical care;clinically significant;diaries;efficacy evaluation;experience;health disparity;improved;innovation;medication administration;medication compliance;medication nonadherence;mortality;novel;pharmacologic;pill;programs;recruit;restraint;retention rate;risk prediction;satisfaction;screening;secondary outcome;side effect;skills;translational impact;treatment as usual;usability Behavioral Parenting Skills as a Novel Target for Improving Pediatric Medication Adherence Public Health SignificanceRecent landmark studies from the Childrens Oncology Group (COG) highlight adherence to home-based oralchemotherapy as an enduring problem in pediatric cancer care. Yet little is known about why some familieshave difficulty adhering to their childs home-based oral chemotherapy while others do not. Through the novelexamination of how behavioral parenting skills shape adherence at the episode and daily levels the proposedprogram of research has potential to lead to a paradigm shift in pediatric cancer adherence risk prediction andinterventions moving away from blunt demographic-based risk prediction and identifying behavioral parentingskills that are easily amenable to screening modifiable and may be more precise predictors of non-adherencerisk. NCI 10747297 12/1/23 0:00 PA-18-722 5R01CA258337-03 5 R01 CA 258337 3 "NELSON, WENDY" 12/15/21 0:00 11/30/26 0:00 Clinical Management in General Care Settings Study Section[CMGC] 10654598 "BOUCHARD, ELIZABETH " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 588984 NCI 397684 191300 In pediatric health care non-adherence to medications is a significant driver of avoidable suffering and death.Over half of children do not adhere to prescribed medications and non-adherence is the leading cause oftreatment failure in pediatrics. Non-adherence can lead to worsening illness death preventable hospitalizationincreased health care cost and morbidity. Even in pediatric cancer when the consequences of non-adherenceto chemotherapy are potentially life threatening over 40% of patients have clinically significant non-adherence.For the most common pediatric cancer Acute Lymphoblastic Leukemia (ALL) children who miss just 10% ofchemotherapy doses have a nearly 4-fold risk of cancer relapse. Despite decades of research we do not haveeffective strategies to meaningfully increase pediatric medication adherence. The goal of the proposedresearch is to reduce preventable pediatric morbidity and mortality through testing a novel target behavioralparenting skills as a modifiable mechanism to improve medication adherence in young children (ages 3-9).Based upon our preliminary data we have begun to develop CareMeds a parenting skills-focused adherenceintervention. The goal of this project is to use stages 0 and 1 of the NIH Stage Model to further develop andevaluate the feasibility of the CareMeds intervention. Evidence is converging on family functioning andparenting style as critical factors that shape child medication adherence. Yet previous studies typically rely onone-time global measures making it difficult to discern the precise parenting skills that improve medicationadherence. For example we know very little about what exactly supportive or cohesive families are doing topromote medication adherence. In Aim 1 we will use direct observation of medication administration at home tounderstand common episode-level barriers and identify the behavioral parenting skills that are most successfulin achieving medication administration in young children. In Aim 2 we will use daily diary data collection toexamine how daily parenting experiences influence the risk of medication non-adherence. We will use datafrom Aims 1 and 2 and input from diverse parents to refine the final CareMeds intervention package. In Aim 3we will conduct a pilot RCT of the intervention versus usual care with 100 families of young children ages 3-9with ALL within 1 month of initiation of oral chemotherapy prescription. Findings from this program of researchwill make significant conceptual contributions through providing nuanced understanding of the aspects ofparenting at the episode and daily levels that shape medication adherence in young children. It will makeinnovative methodological advances through use of direct observation of medication administration daily diarydata on transient parenting experiences and rigorous measurement of adherence through objective behavioralmeasures (electronic pill bottle monitoring) and pharmacological measures (validated biomarkers of drugmetabolites). Finally it will have significant translational impact through setting the stage for a full-scale multi-center RCT to examine the efficacy of the CareMeds intervention. 588984 +No NIH Category available African American population;Blood specimen;California;Chronic Disease;Cohort Studies;Computerized Medical Record;Cost efficiency;Cultural Diversity;Data;Diagnosis;Diagnostic;Ensure;Environment;Environmental Risk Factor;Ethnic Origin;Ethnic Population;Etiology;Genetic;Genomics;Geographic Locations;Grant;Hawaii;Hospitals;Infrastructure;Japanese American;Latino Population;Leadership;Life Style;Maintenance;Malignant Neoplasms;Medical;Native Hawaiian;Paper;Participant;Planning Techniques;Postdoctoral Fellow;Publishing;Race;Research;Research Methodology;Research Personnel;Resources;Risk Factors;Sampling;Science;Specimen;Structural Racism;Students;Testing;Training;United States National Institutes of Health;Urine;Vital Statistics;Woman;biobank;climate change;cohort;computerized;data sharing;design;dietary;disorder prevention;epigenomics;ethnic difference;ethnic disparity;ethnic diversity;ethnic health disparity;ethnic minority;follow-up;genetic risk factor;indexing;innovation;men;metabolomics;microbiome research;multi-ethnic;neoplasm registry;novel strategies;nutrition;parent grant;programs;prospective;racial disparity;racial diversity;racial health disparity;racial minority;racial population;social health determinants;tumor;willingness Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study - Diversity Supplement Project Narrative Parent GrantThis renewal application seeks support for the infrastructure maintenance of the Multiethnic Cohort (MEC) Studyestablished in 1993-1996 to continue a well-integrated program of research testing innovative hypotheses aimedat ensuring that racial/ethnic disparities are investigated and progress in disease prevention applies to major USracial/ethnic minorities. By including 215251 men and women mostly of 5 racial/ethnic populations (AfricanAmericans Japanese Americans Latinos Native Hawaiians and Whites) the MEC is the most racially andethnically diverse cancer cohort and its value for etiologic research on chronic diseases is widely recognized.Leadership of the MEC entails a highly interactive team-science approach; investigators have amplydemonstrated willingness to share data and samples. NCI 10747120 6/5/23 0:00 PA-21-071 3U01CA164973-11S1 3 U01 CA 164973 11 S1 "MAHABIR, SOMDAT" 6/1/23 0:00 8/31/27 0:00 1898900 "LE MARCHAND, LOIC " "HAIMAN, CHRISTOPHER ALAN" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 6/1/23 0:00 8/31/23 0:00 393 Non-SBIR/STTR 2023 38586 NCI 38586 0 Abstract Parent GrantThis renewal application seeks support for the infrastructure of the Multiethnic Cohort (MEC) Study which wasestablished in Hawaii and southern California in 1993-1996 to study risk factors for cancer and other chronicdiseases. The study was designed to take advantage of the ethnic and cultural diversity of the two geographicareas as well as the expertise of the investigators in nutrition ethnic/racial disparities studies and genetics. Itis the most ethnically diverse cancer cohort in existence. It achieves high cost-efficiency by significantlysupplementing active follow-up information with computerized linkages to SEER cancer registries vital statisticshospital-discharge diagnoses medical claim data electronic medical records and geospatial information. Atbaseline the cohort included information on 215000 men and women comprised almost entirely of fiveethnic/racial populations: Japanese Americans Latinos Whites African Americans and Native Hawaiians. Theresource was later expanded to include a prospective biorepository of blood specimens from ~70000 of theparticipants and urine specimens on a large subset. Leadership of the MEC entails a highly interactive team-science approach and the investigators have amply demonstrated their willingness to share data/samples andto participate actively in consortia. Research accomplishments include significant contributions to understandingboth genetic and environmental risk factors for cancer. Over 291 papers describing our findings have beenpublished during the current grant cycle. In addition over the last 28 years 129 NIH grants/supplements havebeen built around the MEC (77 were active in the current cycle) and more than 136 students and postdoctoralfellows have been trained on the study. This application describes our aims over the next 5 years for maintainingand enhancing the infrastructure of the MEC as well as plans for methodological research. We project adding7253 incident cancer cases in the new 5 years to the current 48064 cases; 2670 of these cases will have pre-diagnostic blood samples to be added to the current 10957 cases. We will add 6K FFPE tumor samples to thecurrent ~13K. In addition this grant renewal will make possible the continuation of a well-integrated program ofresearch aimed at evaluating lifestyle environmental and genetic risk factors and social determinants of healthfor cancer and other common chronic diseases taking advantage of new approaches such as dietary qualityindices exposomics genomics epigenomics microbiomics metabolomics and multilevel exposures includingspatial environment structural racism and climate change. The MEC will allow the testing of innovative researchhypotheses aimed at ensuring that racial/ethnic health disparities are investigated and that progress in diseaseprevention applies to all major US racial/ethnic minorities. 38586 +No NIH Category available Acute Lymphocytic Leukemia;Address;Behavior;Behavioral;Cancer Patient;Caregivers;Child;Child Rearing;Childhood;Code;Conflict (Psychology);Data;Diagnosis;Disparity;Distress;Ensure;Family Caregiver;Funding;Goals;Home;Intervention;Knowledge;Malignant Childhood Neoplasm;Oral;Outcome;Parents;Patient-Focused Outcomes;Pattern;Pharmaceutical Preparations;Population;Research;Scheme;Science;Shapes;Video Recording;cancer health disparity;career;caregiving;chemotherapy;disparity reduction;experience;health literacy;improved;medication administration;medication compliance;novel;outcome disparities;parent grant;parent project;skills;sociodemographics;training opportunity;trait Behavioral Parenting Skills as a Novel Target for Improving Pediatric Medication Adherence Project NarrativeThe purpose of this supplement application is to extend and enhance research from parent grant(R01CA258337-01A1) examining parental and family caregivers experiences in ensuring medicationadherence in pediatric cancer patients. Findings from the supplements proposed activities will fill gaps inknowledge about modifiable factors that can be addressed via targeted interventions to improve patientoutcomes. This training opportunity will allow the candidate to pursue their career goal of developinginterventions to mitigate disparities in cancer populations. NCI 10747094 4/13/23 0:00 PA-21-071 3R01CA258337-02S1 3 R01 CA 258337 2 S1 "NELSON, WENDY" 12/15/21 0:00 11/30/26 0:00 Clinical Management in General Care Settings Study Section[CMGC] 10654598 "BOUCHARD, ELIZABETH " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 3/1/23 0:00 11/30/23 0:00 393 Non-SBIR/STTR 2023 178929 NCI 103129 75800 AbstractThis parent grant (R01CA258337-01A1) for this supplement focuses on the relationship between parentingskills and medication adherence in young children diagnosed with acute lymphoblastic leukemia (ALL) themost common pediatric cancer. Parents are tasked with giving daily medications for oral chemotherapy athome an experience that can be marked by parent-child conflict logistical difficulties and distress. In order todevelop an intervention to minimize barriers to successful medication administration it is critical to understandparental skills behaviors and experiences with giving pediatric cancer patients medication at-home. One ofthe aims of this parent grant-funded study uses direct observation of medication administration via videorecording in the home to collect objective data to characterize the specific parenting experiences at the dailyand episode levels that shape medication administration in young children. Initial reviews of video-recordeddirect observations of parents administering medications point to an opportunity to augment the existingquantitative coding schemes with newly developed qualitative coding schemes. The candidate for thissupplement will benefit from the opportunity to expand her existing research expertise in caregiving science bycreating a qualitative coding scheme that captures nuanced contextual data about medication administration inthe home setting. The candidate for this supplement will also build on the parent project by analyzingassociations between parents' sociodemographic data and medication administration in order to identifypotential patterns of disparities in medication adherence outcomes thus contributing to her goal to strengthenher experience in disparities research. Finally in order to fulfill the candidate's goal of broadening herexpertise in health literacy she will extend the parent project's aim of considering parental health literacy as apotential correlate of medication adherence experiences by conducting additional analysis of the health literacyvariable to identify potential associations with parental caregiver's sociodemographic traits. Findings fromthese activities will fill gaps in knowledge about modifiable factors (caregiver behaviors and health literacyskills) that can be addressed via targeted interventions to improve patient outcomes and mitigate disparities. 178929 +No NIH Category available Acceleration;Achievement;Acute Myelocytic Leukemia;Ara-C;Biological;Childhood Leukemia;Clinical;Clinical Trials;Collaborations;DNMT3B gene;Daunorubicin;Development;Diagnosis;Disease;Disease Resistance;Etoposide;Evaluation;Failure;Foundations;Funding;Gene Expression;Genes;Genomics;International;Legal patent;Leukemic Cell;Methods;Methylation;Molecular;Outcome;Patients;Pharmacology;Procedures;Productivity;Prognosis;Prognostic Factor;Publications;Rare Diseases;Recurrent disease;Research;Resistance;Sample Size;Translating;Translations;Validation;Variant;cancer genomics;chemotherapy;clinical practice;clinically significant;cohort;demethylation;effective therapy;epigenomics;genome wide association study;genome wide methylation;innovation;leukemia treatment;leukemic stem cell;molecular domain;older patient;pediatric patients;prognostic;risk stratification;sound;symposium;transcriptomics Genomics of AML Prognosis Relevance Statement:Acute myeloid leukemia (AML) is the second most common childhood leukemia and has a dismal prognosis. For over 40years AML chemotherapy has changed little with the continued reliance on ara-C daunorubicin and etoposide asfrontline agents. The proposed research seeks to prepare a sound scientific rationale to incorporate prognostic geneexpression scores into the risk stratification of AML patients and revealing additional layers of the molecular basisof AML prognosis to guide the development of more effective treatments for AML. NCI 10747046 7/14/23 0:00 PA-21-071 3R01CA132946-14S1 3 R01 CA 132946 14 S1 "AGRAWAL, LOKESH" 4/1/08 0:00 6/30/26 0:00 Xenobiotic and Nutrient Disposition and Action Study Section[XNDA] 8666845 "LAMBA, JATINDER K." "POUNDS, STANLEY BARRETT" 3 PHARMACOLOGY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF PHARMACY 326115500 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 79819 NCI 58312 21507 1. ABSTRACT: Acute Myeloid Leukemia (AML) is a heterogeneous disease with a dismal outcome; fewer than20% of elderly patients and only 50-65% of pediatric patients are cured and survive more than 3 years followingdiagnosis. Despite this the standard therapy for AML treatment has relied primarily on an intensive combination of ara-C daunorubicin and etoposide (ADE) for over 40 years. Relapsed and resistant disease following treatment withstandard therapy (ADE: ara-C daunorubicin and etoposide) are the most common clinical failures that occur intreating this disease. Application co-PIs Drs. Lamba (pharmacology) and Pounds (biostatistician specializing incancer genomics) have successfully collaborated for over a decade to develop methods and discover molecularprognostic factors for AML. During our recently completed second funding cycle we were very productive with 13scientific publications 53 conference presentations and two pending patents. Our second-cycle scientificachievements include the development of an ara-C SNP score that predicts leukemic cell intracellular levels of ara-CTP the active form of ara-C the development of the innovative integrative analysis procedure; canonicalcorrelation with projection onto the most interesting statistical evidence (CC-PROMISE) that dramatically increasesstatistical power for meaningful biological discovery in a rare-disease small sample size setting; using CC-PROMISE to discover that reduced methylation and increased expression of the DNMT3B associates with greatergenome-wide methylation burden and worse prognosis; translating the DNMT3B discovery into evaluation ofdemethylating agents in the ongoing AML16 clinical trial; the development and initial validation of the six-genepediatric leukemia stem cell (pLSC6) score (patent pending) and five-gene ADE resistance score (ADE-RS5) scorethat predict prognosis. In this renewal application we propose to accelerate our exciting progress by extensivelyvalidating the pLSC6 and ADE-RS5 scores to provide a robust scientific foundation to translate them into clinicalpractice and further developing our understanding of the biological basis of AML development and prognosis intoother molecular domains. In the current proposal we seek to accelerate our exciting progress by extensively validatingthe pLSC6 and ADE-RS5 scores in ~ 4000 patients across 10 independent national and international AML cohortstreated on intensive chemotherapy to provide a robust scientific foundation for its translation into clinical practice.In aim 2 we propose to perform a clinical outcome-GWAS (CO-GWAS) and establish prognostic genes and variantswith a constellation of genomic epigenomic and transcriptomic features that associate with clinical outcomes whichwill undergo thorough mechanistic validation in aim 2. The successful completion of these studies will bescientifically and clinically significant by preparing a sound scientific rationale to incorporate prognostic geneexpression scores into the risk stratification of AML patients and revealing additional layers of the molecular basisof AML prognosis to guide the development of more effective therapies. 79819 +No NIH Category available Role of SerpinB3 in glioblastoma cancer stem cells Project Narrative ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLSGlioblastoma (GBM) is the most common primary malignant brain tumor and a population of cancer stem cells(CSCs) allows the tumor the tumor to quickly regrow after aggressive standard-of-care treatment. The objectiveof my project is to determine the mechanism through which GBM CSCs signal through junctional adhesionmolecule-A (JAM-A) via Serpin B3 a serine/cysteine protease inhibitor that interacts with JAM-A and has beenshown to signal through TGF- in other cancers. The successful completion of this proposal will further ourunderstanding of the signaling networks used by GBM CSCs for their self-renewal identify new therapeutictargets and provide essential training toward my development as a physician scientist. NCI 10747021 5/22/23 0:00 PA-21-268 7F30CA250254-03 7 F30 CA 250254 3 "DAMICO, MARK W" 7/1/22 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16036969 "LAUKO, ADAM " Not Applicable 11 PATHOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 7/1/22 0:00 12/31/22 0:00 398 "Training, Individual" 2022 31200 NCI 31200 0 Project Summary ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLSGlioblastoma (GBM) is the most aggressive primary malignant brain tumor with a median survival of 18-20months. Despite therapeutic interventions including surgery radiation and chemotherapy multiple clones ofchemo- and radiotherapy-resistant cells repopulate the tumor resulting in recurrence and a high rate of patientmortality. These cells are referred to as cancer stem cells (CSCs) due to their ability to self-renew and generatethe cellular heterogeneity present in the tumor. Our lab identified junctional adhesion molecule-A (JAM-A) onCSCs and through functional studies demonstrated that JAM-A is both necessary and sufficient for self-renewaland tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcriptionfactor activity; however the intermediate signaling network is yet to be fully elucidated. To further delineate thispathway we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry to determine theproteins to which JAM-A directly binds. This analysis led to the identification of the serine/cysteine proteaseinhibitor SerpinB3 as a binding partner. Interestingly SerpinB3 does not contain the conserved PDZ domain thatis present on nearly every other known JAM-A binding partner. Although multiple pro-tumorigenic mechanismsincluding regulation of TGF-1 and inhibition of apoptosis have been proposed for SerpinB3 in the context ofother cancers very little is known about the function of the protein in GBM CSCs and its relationship to JAM-Ais yet to be elucidated. Using in vitro CSC functional assays I have accumulated evidence that SerpinB3 isnecessary for the maintenance of CSCs and that reduction of SerpinB3 attenuates TGF-1 expression. Basedon these observations I hypothesize that SerpinB3 interaction with JAM-A is essential for the maintenance ofGBM CSCs through regulation of TGF-1 and inhibition of apoptosis. Aim 1 will test the hypothesis that SerpinB3maintains the CSC state through inhibition of apoptosis and upregulation of TGF-1. I will disrupt the lysosomalmembrane with siramesine to elucidate the role of SerpinB3 in the inhibition of apoptosis. Additionally I willinvestigate the role of SerpinB3 in the regulation of TGF-1 signaling in CSCs. Aim 2 will test the hypothesis thattargeting the JAM-A/SerpinB3 interaction will compromise self-renewal and GBM growth. I will utilize DSSOcrosslinking to determine the region of interaction between the two proteins. Finally I will determine theconsequence of disrupting the JAM-A/SerpinB3 interaction on the CSC state with small interfering peptides.Successful completion of this project will advance our understanding of how the CSCs state is maintained inGBM via specific JAM-A intracellular binding domains bridging cellular communication and cell signaling. Thestudies outlined in this fellowship will provide me an opportunity to gain experience in brain tumor research andallow me to continue my training though scientific meetings and mentorship opportunities preparing for a careeras a physician scientist. 31200 +No NIH Category available Address;Adolescent;Adoption;Age;COVID-19 pandemic effects;COVID-19 vaccine;Cancer Control;Caring;Case Management;Clinic;Cluster randomized trial;Communication;Community Healthcare;Complex;Data;Decision Making;Dose;Effectiveness;Evaluation;Event;Exposure to;Goals;Grant;Hispanic;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Infrastructure;Intervention;Malignant Neoplasms;Manuscripts;Methods;Modeling;Outcome;Parents;Penetration;Pennsylvania;Preparation;Provider;Randomized;Recommendation;Research Activity;Research Personnel;Rural;Rural Population;Source;System;Testing;Training;Training Activity;Vaccination;Vaccines;Work;Writing;arm;boys;cancer prevention;care outcomes;career;career development;comparison intervention;cost;doctoral student;evidence base;experience;follow-up;girls;health inequalities;implementation framework;implementation outcomes;implementation strategy;improved;innovation;meetings;parent grant;prevent;primary care clinic;primary care practice;primary care provider;primary outcome;rural health clinic;skills;social media;vaccine acceptance HPV ECHO: Increasing the adoption of evidence-based communication strategies for HPV vaccination in rural primary care practices Project NarrativeThis diversity supplement will promote the career development of Miss Josheili Llavona-Ortiz a Hispanicdoctoral student with the long-term goal of becoming an independent cancer researcher. The proposedsupplemental work is a mixed-methods study to assess the impact of the COVID-19 pandemic and theapproval of COVID-19 vaccines on both HPV vaccination rates in primary care clinics and the way providersrecommend the HPV vaccine to parents of adolescents. The research and training activities of this supplementwill allow Miss Llavona-Ortiz to achieve the following short-term career goals: 1) To expand her contentexpertise in HPV vaccine communication and cancer prevention; 2) To help her acquire practical experience inmixed methods; 3) To help her continue to develop scientific writing skills as applied to manuscript and grantpreparation; and 4) To improve her presentation skills by participating in national scientific meetings andcancer control planning events. NCI 10746991 9/22/23 0:00 PA-21-071 3R37CA253279-04S1 3 R37 CA 253279 4 S1 "KOBRIN, SARAH" 8/10/20 0:00 4/30/25 0:00 Dissemination and Implementation Research in Health Study Section[DIRH] 10084455 "CALO, WILLIAM ALEXIS" Not Applicable 10 PUBLIC HEALTH & PREV MEDICINE 129348186 TNKGNDAWB445 129348186 TNKGNDAWB445 US 40.264414 -76.674014 1524204 PENNSYLVANIA STATE UNIV HERSHEY MED CTR HERSHEY PA SCHOOLS OF MEDICINE 170332360 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 99246 NCI 59371 39875 Abstract of the Parent Grant (5R37CA253279-03; William Calo PI)Despite the availability of the human papillomavirus (HPV) vaccine that can prevent over 34800 HPV-relatedcancers in the US every year only 51% of girls and boys were up-to-date by 2018. Rural populations are themost impacted by HPV-related cancers. Best practices like the Announcement Approach training and systemscommunication have proven effective in increasing HPV vaccination but rural providers struggle to access andimplement such best practices. These data prompt the question: How can academic centers support HPVvaccination in rural primary care practices? Although never tested for HPV vaccination the ECHO (Extensionfor Community Healthcare Outcomes) Model is a promising implementation strategy (practice facilitation) thatallows experts at academic centers to connect with primary care providers to discuss best practices in careand complex cases managed within local practices. The objective of this R01 is to test two ECHO-deliveredHPV vaccination communication interventions in rural primary care clinics. The first will provide AnnouncementApproach training (HPV ECHO); the second will provide this approach plus systems strategies to communicatewith parents who initially decline vaccination (HPV ECHO+). The rationale for the project is that ECHO is arobust highly-accessible platform to deliver best practices to rural providers and address the context-specificcommunication needs of parents. Our long-term goal is to improve HPV vaccination rates in rural clinics andreduce the health inequity rural populations experience in cancer outcomes. Aim 1 is to evaluate the impact ofHPV ECHO and HPV ECHO+ on HPV vaccination among adolescents. We will conduct a 3-arm clusterrandomized trial with 36 primary care clinics in rural Pennsylvania. Clinics will be randomized to: HPV ECHOHPV ECHO+ or control. Our primary outcome will be change in HPV vaccine initiation (1 doses) amongadolescents ages 11-14 at 12-month follow-up. Aim 2 is to evaluate the impact of HPV ECHO and HPVECHO+ on implementation outcomes. Guided by implementation science frameworks we will conduct amixed-methods evaluation to compare interventions on acceptability adoption cost penetration andsustainability. Aim 3 is to evaluate the impact of interventions vaccine information on secondary acceptance ofHPV vaccination at the clinic level. We will also follow a subset of 200 vaccine-declining parents for up to 12months to assess exposure to and impact of vaccine information from study arms versus naturally-occurringsources (e.g. social media) on secondary acceptance. Our expected outcome is to demonstrate theeffectiveness of a highly efficient and scalable implementation strategy ECHO to support HPV vaccination inrural clinics. This study is innovative in leveraging existing infrastructure at academic centers to deliver bestpractices for HPV vaccination where they are needed most and in developing a greater understanding of theinfluences on decision making among vaccine-declining parents. We expect the project to have a significantimpact on HPV vaccine uptake as we address the communication needs of both rural providers and parents. 99246 +No NIH Category available Adhesions;Architecture;Automobile Driving;Biological Models;Breast Cancer Cell;Breast Cancer Patient;Cell Nucleus;Cell Survival;Chromosomal Instability;Collection;Coupled;Cytotoxic Chemotherapy;Data;Defect;Disease;Drug Targeting;ERBB2 gene;Ensure;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Estrogens;Event;Family;Family member;Functional disorder;Gamma-H2AX;Genome Stability;Genomic Instability;Genomics;Goals;Growth;Heat-Shock Proteins 70;Heterogeneity;Individual;Malignant Neoplasms;Mediating;Metastatic/Recurrent;Mitosis;Mitotic;Molecular;Molecular Chaperones;Nuclear;Oncogenic;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphotransferases;Play;Precision therapeutics;Process;Progesterone;Proliferating;Protein Tyrosine Kinase;Proteins;Receptor Signaling;Reporting;Resistance;Role;Signal Pathway;Signal Transduction;Testing;Therapeutic;Toxic effect;Work;YES1 gene;cancer initiation;cell growth;cell motility;chemotherapy;differential expression;drug efficacy;expectation;extracellular;improved;inhibitor;innovation;insight;live cell imaging;malignant breast neoplasm;micronucleus;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;receptor;receptor expression;refractory cancer;response;restoration;src-Family Kinases;survivorship;targeted treatment;taxane;therapeutic target;transcription factor;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor progression Discovering the role of YES1 in triple negative breast cancer PROJECT NARRATIVETriple Negative Breast Cancer (TNBC) is a highly aggressive disease that has limited treatment options. Thisproposal focuses on determining if a protein called YES1 may underlie the malignancy associated with TNBCand the molecular pathways it uses to cause poor patient outcomes. This work will also provide a proof-of-concept in model systems testing the possibility of inhibiting YES1 with drugs that may ultimately lead to a moreeffective approach for treating TNBC. NCI 10746980 9/13/23 0:00 PA-21-071 3R01CA257502-03S1 3 R01 CA 257502 3 S1 "XU, WANPING" 2/1/21 0:00 1/31/26 0:00 Tumor Cell Biology Study Section[TCB] 1924151 "KERI, RUTH A." Not Applicable 11 OTHER BASIC SCIENCES 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 31315 NCI 21377 9938 PROJECT SUMMARY/ABSTRACTSRC Family Kinases (SFKs) are a group of 9 non-receptor tyrosine kinases that mediate the effects of manyextracellular and intracellular signaling pathways. While these proteins have often been considered to befunctionally similar to SRC the founding member of the family it is now clear that they have non-redundant andunique activities. In cancer these proteins are differentially expressed and their roles can even be antagonistic.This project launches from our discovery that one of these family members YES1 is selectively overexpressedin Triple Negative Breast Cancer (TNBC) is associated with poor outcomes and is necessary for sustainedgrowth of TNBC cells. TNBC is a collection of highly aggressive diseases with limited therapeutic optionsprimarily involving cytotoxic chemotherapy. While many patients initially respond to these treatments resistanceis common resulting in poor patient outcomes. Thus identifying vulnerabilities in this group of diseases isessential to yield approaches for improving survivorship. We propose that YES1 is one of these vulnerabilities.In preliminary data we show that YES1 is essential for maintaining expression of Epidermal Growth FactorReceptor (EGFR) as well as ensuring mitotic fidelity. EGFR is a major driver of TNBC growth. When YES1 isdepleted EGFR is degraded and its signaling is lost. In addition we report that YES1 silencing causes severalnuclear defects including micro- multi- and dysmorphic nuclei indicating that YES1 is essential for accuratecompletion of mitosis. We hypothesize that these two functions of YES1 are essential for cellular viability inTNBC. Moreover we propose that YES1 may be a useful therapeutic target to improve the efficacy of drugstargeting EGFR and mitosis. In Aim 1 we will determine how YES1 controls EGFR degradation and assesswhether YES1 overexpression underlies resistance to EGFR inhibitors in TNBC. Aim 2 will focus on identifyingspecific events in mitosis that are impacted by YES1 and the mechanisms involved. It will also discern whethermodulating YES1 can impact response to taxanes mainstay chemotherapies for TNBC. Lastly in Aim 3 we willdetermine if EGFR and YES1 participate in a feedforward loop that controls mitosis. This will involve interrogatingthe role of EGFR in mediating the effects of YES1 on mitosis and determining if EGFR is also an upstreamregulator of YES1. Major innovations of this project include the identification of YES1 as a new oncogenic driverof TNBC the discovery that YES1 and EGFR may control the genomic complexity that is associated with thisdisease the therapeutic assessment of a novel inhibitor of YES1 in PDX models of TNBC and the potential forimproving the efficacy of EGFR inhibitors and taxanes in a disease that requires new therapeutic approaches toimprove patient outcomes. 31315 +No NIH Category available 3-Dimensional;ARID1A gene;Air;Anatomy;Automobile Driving;Biological;Biology;CRISPR interference;CRISPR-mediated transcriptional activation;CRISPR/Cas technology;Cancer Patient;Candidate Disease Gene;Cells;Chromosomal Instability;Coculture Techniques;Coupled;Cytotoxic Chemotherapy;Data;Detection;Disease;Early Diagnosis;Ecosystem;Engineering;Epithelium;Event;Evolution;Exhibits;Experimental Models;Gene Expression;Generations;Genes;Genetic;Genetic Engineering;Genome Stability;Genomic approach;Genomics;Genotype;Goals;Human;Human Herpesvirus 4;Immune;Immune Evasion;Immune response;Immune system;Immunologic Deficiency Syndromes;Immunology;Immunooncology;Immunotherapeutic agent;Immunotherapy;In Vitro;Infiltration;Inflammatory;Liquid substance;MLH1 gene;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Measures;Mediating;Mentors;Methodology;Methods;Microsatellite Instability;Modeling;Molecular;Monitor;Mutate;Mutation;Natural Immunity;Natural Killer Cells;Normal tissue morphology;Oncogenes;Oncogenic;Oncology;Organoids;Patients;Phase;Phenotype;Physiological;Population;Predisposition;Proteins;Reaction;Regulation;Research;Research Personnel;Resistance;Resistance development;Role;Series;Shapes;Somatic Mutation;System;T-Lymphocyte;TP53 gene;Technology;Testing;The Cancer Genome Atlas;Therapeutic;Training;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Work;Xenograft procedure;adaptive immunity;cancer cell;cancer immunotherapy;cancer subtypes;cancer surgery;cancer therapy;career;cell killing;conventional therapy;gastric organoids;gastric tumorigenesis;genetic approach;genetic manipulation;genome editing;immune cell infiltrate;immune checkpoint blockade;immunoregulation;improved;in vitro Model;in vivo;insight;malignant stomach neoplasm;mouse model;multimodality;mutant;neoantigens;neoplasm immunotherapy;neoplastic cell;next generation;novel;novel therapeutics;patient subsets;pharmacologic;preservation;response;skills;success;tool;treatment response;tumor;tumor immunology;tumor microenvironment;tumor-immune system interactions;tumorigenesis Functional characterization of novel oncogenic loci driving progression and immune response in gastrointestinal cancer PROJECT NARRATIVEDiverse cancers can now be treated by modulating the immune system to recognize and destroy tumor cells;however only subsets of patients respond to such immunotherapies and tumors often progress despite theseefforts. I propose to apply a coupled set of cutting-edge next-generation in vitro and in vivo methodologies todefine the role of somatic mutations in response to cancer immunotherapies in human gastrointestinal cancers.My data will elucidate fundamental biological principles of the tumor-immune interaction providing a mechanisticframework to inform immunotherapeutic strategies and targets. NCI 10746908 7/21/23 0:00 PA-20-188 4R00CA263014-03 4 R00 CA 263014 3 "KUO, LILLIAN S" 9/1/21 0:00 8/31/26 0:00 Transition to Independence Study Section (I)[NCI-I] 14376485 "LO, YUAN-HUNG " Not Applicable 9 MICROBIOLOGY/IMMUN/VIROLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 249000 NCI 153704 95296 PROJECT SUMMARY/ABSTRACT Gastric cancer (GC) is one of the most common and lethal cancers worldwide. GC surgery is highly morbidand responses to the limited array of treatment options are poor. There is hope that recent genomic sequencingdata can be leveraged to develop newer improved molecular therapies for GC but rigorous mechanistic testingis still needed to validate the therapeutic potential of targeting any newly proposed oncogenes. Immunotherapy is an exciting new therapy that has revolutionized oncology and shows tremendouspotential. In contrast to cytotoxic chemotherapies which exhibit fractional killing invariably leading to resistanceimmune cells can infiltrate almost all anatomic sites to recognize and completely eliminate malignant cells inprimary and wide-spread metastatic disease. However the immune systems full anti-tumor killing potential canbe restricted by evasive measures by the tumor and/or intrinsic immunosuppressive mechanisms that limitcollateral damage to normal tissues during anti-tumor inflammatory reactions. In GC little is known about howcancer cells evade the system and studies investigating the molecular mechanisms underlying tumor-immune interactions have been limited by a lack of physiologically relevant in vitro human systemswhere state-of-the-art genetic approaches can be applied. These mechanisms are important because theywould be essential to our understanding of GC tumorigenesis and the regulation of immunotherapeuticresponses. Such mechanistic insight on the immune system to GC is fundamental and significant to advanceand improve GC therapies. In this proposal we utilize a series of CRISPR/Cas9 genome editing tools to createnovel forward genetically engineered models of the four major GC subtypes as defined by The Cancer GenomeAtlas project including chromosomal instability (CIN) genomic stability (GS) microsatellite instability (MSI) andEpstein-Barr virus-associated (EBV) in primary 3D human gastric organoids (Aim1 and Aim2). In a paralleltranslational aim we propose to use a second-generation patient-derived organoid model that allows tumor andstroma to be preserved alongside each other to study interactions between tumor cells and their veritableecosystem of cohabiting immune cells in primary human gastric cancer (Aim 3). The overall goal of this projectis to investigate how genetic alterations contribute to gastric tumorigenesis and immunotherapeutic responsesusing synergistic next-generation in vivo and in vitro models. Collectively the results of this project will providenew insights into fundamental aspects of the molecular mechanisms underlying the tumor-immune interactionand enhance current GC immunotherapies. A team of expert mentors advisors and collaborators will train Dr. Lo in new methods that are critical tothe success of this research. The combination of mentoring support skills and data obtained in the K99 phasewill provide Dr. Lo a springboard to achieving independence as an investigator in the R00 phase and beyond. 249000 +No NIH Category available Accounting;Automobile Driving;Award;Basic Science;Biochemical;Biological Assay;Biological Process;Breast;Breast Cancer Treatment;Cancer Biology;Cancer Diagnostics;Cell Polarity;Cell physiology;Colorectal Cancer;Data;Deubiquitinating Enzyme;Deubiquitination;Development;Drosophila genus;Ectopic Expression;Endometrial Carcinoma;Family;Family member;Female Breast Carcinoma;Future;Genetic Status;Genetically Engineered Mouse;Glioma;Goals;Growth;Human;In Vitro;Individual;Knock-in Mouse;LATS1 gene;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mammals;Mammary Neoplasms;Mediating;Metabolism;Modification;Molecular;Molecular and Cellular Biology;Mouse Mammary Tumor Virus;Mus;Natural regeneration;Newly Diagnosed;Oncogenes;Organ Size;Orthologous Gene;Pathway interactions;Phase;Phosphorylation;Phosphotransferases;Physiological;Polyubiquitination;Problem Solving;Process;Protein-Serine-Threonine Kinases;Proteins;Regulation;Role;Scientist;Serine;Signal Pathway;Signal Transduction;Site;Time;Tissues;Training;Transcription Coactivator;Translational Research;Tumor Burden;Tumor Suppressor Proteins;Ubiquitination;Woman;breast tumorigenesis;cancer therapy;career;cell growth;design;druggable target;experimental study;fly;in vivo;insight;malignant breast neoplasm;mammary;novel;novel therapeutic intervention;novel therapeutics;polyoma middle tumor antigen;sarcoma;skills;targeted treatment;tumor;tumorigenesis;ubiquitin isopeptidase Elucidating a Novel Mechanism for LATS1/2 in Suppressing Tumorigenesis Project narrative:Dysregulation of the tumor suppressors LATS1/2 core components of Hippo pathway is common in manyhuman tumors including breast cancer but its upstream regulator and physiological role in breasttumorigenesis remains unclear. This proposal aims to elucidate how LATS1/2 kinase activity and tumorsuppressive function is regulated by upstream deubiquitinase OTUD3 as well as to examine how LATS1/2 arecritically involved in breast tumorigenesis through phosphorylating Raptor at Ser606 which in turn suppressesmTORC1 kinase activity. NCI 10746905 8/15/23 0:00 PA-20-188 4R00CA259329-03 4 R00 CA 259329 3 "LUO, RUIBAI" 3/1/21 0:00 2/28/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15440312 "DAI, XIAOMING " Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 249000 NCI 144014 104986 Abstract:The Hippo pathway is an evolutionarily conserved signaling cascade regulating numerous biological processesincluding cell growth and fate decision organ size control and regeneration. The core of the Hippo pathway inmammals consists of a kinase cascade LATS1/2 and MST1/2 that controls various cellular processes throughorchestrating the phosphorylation of downstream substrates including YAP and TAZ. In keeping with apossible tumor suppressive role of the Hippo signaling pathway it has been found that Hippo pathwaydysregulation is common in many human tumors including breast glioma lung colorectal cancer andendometrial cancer. However although a few of upstream regulators and downstream substrates wereidentified the exact molecular mechanisms underlying how upstream signaling pathways control LATS1/2kinase activity and its physiological functions in breast cancer have not yet been fully elucidated. Hence themajor goal of this proposal is to explore the upstream regulator of LATS1/2 as well as to uncover a novel tumorsuppressor role of LATS1/2 in controlling tumorigenesis in the breast cancer setting. To this end I haveobtained preliminary data showing that the deubiquitinating enzyme OTUD3 but not other OTUD familymember specifically interacts and deubiquitinates LATS1. More importantly I identified Raptor one of the corecomponents of mTORC1 which is a central cell growth regulator governing cellular metabolism as a novelphosphorylation substrate of LATS1/2. In this proposal I plan to: 1) characterize OTUD3 as a novel upstreamregulator that positively regulates LATS1/2 kinase activity largely through deubiquitination of LATS1/2; 2)determine the physiological role of LATS1/2 in suppressing breast tumorigenesis largely throughphosphorylating Raptor at Ser606 site which in turn inhibits the kinase activity of mTORC1; 3) determinewhether and how Raptor phosphorylation at Ser606 by LATS1/2 regulates breast cancer development in vivo.The long-term goals of my career are to apply the insights of molecular and cellular biology studies tounderstand the physiological significance of deregulated Hippo/mTORC1 signaling pathways that are importantin the development of human malignancies especially in breast cancer and to search for proper druggabletargets for better anti-breast cancer treatment. This K99/R00 award will provide protected time for me topursue the novel hypotheses of this proposal obtain new skill sets to execute experiments and solve problems.In addition the K99 award will allow me to focus my efforts on independently conducting basic andtranslational research and to train future young scientists in the cancer biology field. 249000 +No NIH Category available Acceleration;Activities of Daily Living;Advisory Committees;Biological Assay;Biology;Bypass;Cancer Biology;Cancer Model;Cancer Patient;Cell Line;Cell Proliferation;Cell Survival;Chimeric Proteins;Classification;Clinical;Collaborations;Communication;Complement;Dana-Farber Cancer Institute;Data;Dependence;Development;Dimerization;ERBB2 gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Family;Generations;Genes;Genetic Screening;Genomics;Goals;Grant;Heterodimerization;Homo;Human;Immunofluorescence Immunologic;In Vitro;Injections;Investigation;Laboratories;Leadership;Learning;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mentors;Mentorship;Methods;Missense Mutation;Modeling;Molecular Biology;Molecular Target;Mutagenesis;Mutate;Mutation;Nude Mice;Oncogenes;Oncogenic;Organoids;Patient Care;Patients;Phase;Point Mutation;Postdoctoral Fellow;Receptor Protein-Tyrosine Kinases;Relapse;Reporting;Research;Resistance;Role;STAT1 gene;Science;Signal Transduction;Stains;Techniques;Therapeutic;Training;Tyrosine Kinase Inhibitor;Validation;Variant;Writing;Xenograft procedure;cancer genomics;cancer imaging;career;career development;clinical investigation;design;functional genomics;genetic approach;image processing;improved;in vivo;in vivo Model;inhibitor;inhibitor therapy;lapatinib;member;mortality;mouse model;mutant;novel therapeutic intervention;patient subsets;pharmacologic;pre-clinical;receptor;resistance mutation;structural biology;targeted treatment;tissue processing;tumor;tumor growth;tumor initiation;tumor xenograft;tumorigenesis;variant of unknown significance Functional Characterization of HER Family Variant Biology and Resistance in Cancer Project NarrativeCancer can be caused by activating alterations in receptor tyrosine kinases such as EGFR or HER2. Thisproposal aims to improve our understanding of the functional consequences of EGFR and HER2 activation andresistance to HER-targeted inhibitors thereby accelerating the development of new therapeutic strategies fortreating patients with alterations in these genes. NCI 10746883 9/11/23 0:00 PA-19-130 4R00CA248836-03 4 R00 CA 248836 3 "KONDAPAKA, SUDHIR B" 9/15/21 0:00 8/31/26 0:00 Transition to Independence Study Section (I)[NCI-I] 11406263 "HAYES, TIKVAH K" Not Applicable 36 PHARMACOLOGY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 248999 NCI 158514 90485 Project Summary/AbstractDr. Tikvah Hayes is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-FarberCancer Institute and the Broad Institute. Her long-term career goal is to reduce cancer-associated mortality andsuffering by determining the mechanisms of cancer development and identifying attractive therapeutic strategiesfor better patient care. To accomplish this goal Dr. Hayes uniquely leverages both functional genomics andmolecular biology methods to answer fundamental questions related to cancer biology.The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTK) is frequently alteredin cancer. Targeted panel sequencing of patient tumors has revealed a number of activating alterations in bothEGFR and HER2. As a consequence several generations of molecularly targeted EGFR and HER2 therapieshave been designed and have proved efficacious for some patients with either EGFR- or HER2-mutant cancers.However a subset of patient-observed HER family variants lacking a reported function persist and in the absenceof functional data are classified as variants of unknown significance. It remains unknown whether all EGFR andHER2 missense mutations are oncogenic drivers and are sensitive to clinical EGFR or HER2-targeted therapies.This proposal aims to functionally and mechanistically characterize the role of EGFR and HER2 missensevariants in promoting oncogenesis and resistance to tyrosine kinase inhibitor (TKI) therapies. Aim 1 will seek tonominate alternative strategies for patients harboring rare EGFR mutations where no clinically approved EGFR-targeted therapy exists. Aim 2 will evaluate the oncogenic capacity of rare EGFR variants. Finally in Aim 3HER2 variant oncogenic capacity and TKI sensitivity will be interrogated. The proposed research will greatlyimprove our understanding of how RTK missense variants promote cancer development and resistance totargeted therapies.Dr. Hayes will learn new techniques which will include organoid culturing in vivo cell line xenografts intrathoraciclung injections tumor imaging and tissue processing/staining while simultaneously enhancing her careerdevelopment through training in grant-writing science communication and leadership. During the K99 phaseDr. Hayes research and training will be carried out under the primary mentorship of Dr. Matthew Meyerson aleader in cancer genomics and will be additionally complemented by collaborations with experts in high-throughput genetic screening clinical genomics structural biology and in vivo mouse modeling as well asmentoring from an advisory committee consisting of Drs. Michael Eck William Hahn Pasi Janne and Carla Kim. 248999 +No NIH Category available Accounting;Address;Adoptive Transfer;Attenuated;Behavior;Biological;Blood Vessels;Bone Marrow;CAR T cell therapy;Cancer Vaccines;Cell Lineage;Cell Proliferation;Cells;Chimera organism;Circulation;Clinical Trials;Complement;Development;Disease;Disease Outcome;Female;Foundations;Frequencies;Gene Expression Profile;Generations;Germ Cells;Glioblastoma;Growth;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immunity;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;In Vitro;Incidence;Individual;Infiltration;Interleukin-1 beta;Intervention;Knock-out;Laboratories;Left;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Mediator;Mus;Myeloid-derived suppressor cells;OX40;Oncolytic viruses;Pathogenesis;Pathway Analysis;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Pharmaceutical Preparations;Phase;Play;Population Heterogeneity;Pre-Clinical Model;Predisposition;Primary Brain Neoplasms;Production;Prognosis;Regulation;Reporting;Research;Role;Serum;Sex Differences;T-Cell Activation;T-Lymphocyte and Natural Killer Cell;Testing;Therapeutic;Tumor Immunity;Tumor-associated macrophages;Variant;antagonist;anti-CTLA4;anti-PD-1;anti-tumor immune response;autocrine;cancer stem cell;chemotherapy;clinical efficacy;clinically relevant;complement system;density;drug candidate;drug repurposing;efficacy evaluation;experimental study;fludarabine;genetic signature;granulocyte;immune activation;immune checkpoint;improved;in vitro activity;in vivo;inhibitor;insight;male;monocyte;neoplastic cell;novel;pharmacologic;polarized cell;programs;receptor;response;sex;standard of care;stem cell self renewal;success;therapeutic target;therapy outcome;therapy resistant;transcriptome;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenesis Role of myeloid-derived suppressor cells in local and systemic immunosuppression in glioblastoma PROJECT NARRATIVESuppression of anti-tumor immune response is a major mechanism facilitating the progression and therapeuticresistance of glioblastoma (GBM) the most malignant primary brain tumor. The objective of this project is to gainmechanistic insight into how differential accumulation and function of myeloid-derived suppressor cell (MDSC)subtypes in males versus females contribute to persistent GBM growth via suppression of local and systemicimmunity regulation of the complement system and re-programing the tumor microenvironment. The successfulcompletion of this proposal will elucidate novel interventions targeting MDSC subset variation and account forsex as a biological variable for improved immunotherapy response which will further be developed as part of myindependent research program. NCI 10746880 3/7/23 0:00 PA-19-130 4R00CA248611-03 4 R00 CA 248611 3 "FORRY, SUZANNE L" 3/7/23 0:00 2/28/26 0:00 Transition to Independence Study Section (I)[NCI-I] 15337100 "BAYIK WATSON, DEFNE " Not Applicable 27 PHARMACOLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 3/7/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 248997 NCI 169184 79813 PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary malignant brain tumor with a mediansurvival of up to 20 months. Males have a 1.6-fold higher incidence of GBM compared to females and worsedisease outcome. Standard-of-care treatment and immunotherapies which are currently in clinical trials havehad limited success improving patient outcome. An immunosuppressive microenvironment facilitating tumorprogression and restricting anti-tumor immune response likely underlies therapeutic resistance. Althoughmyeloid-derived suppressor cell (MDSCs) accumulate in patients with malignancies and play a critical role in theestablishment of this immunosuppressive milieu the mechanisms by which individual MDSC subsets promotetumorigenesis remain poorly defined. In pre-clinical models I demonstrated that monocytic MDSCs (mMDSCs)infiltrated tumor at higher rates in males while granulocytic MDSCs (gMDSCs) were more abundant in theperipheral circulation of females. Furthermore there were more immunosuppressive myeloid cells in the tumorsof male patients and gMDSC gene signature associated with poor prognosis of female patients. MDSC subsetvariation also determined sex-specific therapeutic response in preclinical models including to fludarabine andanti-IL-1. I also established that complement component 1q (C1q) is highly expressed by gMDSCs and elevatedin females. Based on these observations I hypothesize that MDSC subsets promote GBM progression viadistinct mechanisms in a sex-specific manner and that their targeting will improve the efficacy of T cell-activatingstrategies. Specific Aim 1 will test the hypothesis that mMDSCs and gMDSCs have distinct roles in local andsystemic immunosuppression in a sex-specific manner. This aim will investigate the changes in tumor growthvascular density and immune activation status by adoptively transferring MDSC subsets and selectively depletingMDSCs in bone marrow chimeras. Specific Aim 2 will test the hypothesis that the unique gene expressionsignatures of MDSC subsets makes them susceptible to distinct drugs that can be combined with checkpointmodulators. Sub-Aim 2A will examine the efficacy of drug candidates on MDSC activity in vitro and in vivo whileSub-Aim 2B will attempt to achieve durable anti-tumor immune response by combining MDSC targetingstrategies with anti-PD-1 anti-CTLA-4 and anti-OX40. Specific Aim 3 will test the hypothesis that gMDSC-derived C1q promotes MDSC lineage commitment and systemic immunosuppression by evaluating tumorprogression and checkpoint response in the absence of C1q. Sub-Aim 3A will use C1qa knockout bone marrowand C1q receptor inhibitors to determine MDSC fate. Sub Aim 3B will use pharmacological inhibitors combinedwith checkpoint modulators. These studies lay the foundation for my future research program and thedevelopment of novel immunotherapies for GBM by addressing variations in anti-tumor immunity repurposingdrugs and defining targetable pathways. These results are broadly applicable to other cancers and can lead toadvanced treatment opportunities and improved patient outcome. 248997 +No NIH Category available Antibodies;Antibody-drug conjugates;Binding;CD8-Positive T-Lymphocytes;Cancer Model;Cancer Patient;Carcinogens;Cell Surface Receptors;Cell membrane;Cells;Cetuximab;Clinical;Coupled;Cytotoxic Chemotherapy;Cytotoxic agent;Cytotoxin;DNA Damage;DNA Repair;Data;Dose Limiting;ERBB2 gene;Epidermal Growth Factor Receptor;Goals;Grant;Immune;Immune checkpoint inhibitor;Immune response;Immuno-Chemotherapy;Immunocompetent;Immunotherapy;Implant;Ionizing radiation;Irradiated tumor;Link;Locally Advanced Malignant Neoplasm;Modeling;Molecular;Morbidity - disease rate;Mus;Normal tissue morphology;Organ;Pathway interactions;Patients;Pharmaceutical Preparations;Quality of life;Radiation induced damage;Radiation therapy;Radiation-Sensitizing Agents;Radio;Radiosensitization;Role;Schedule;Systemic Therapy;Techniques;Technology;Testing;Therapeutic;Therapeutic Index;Time;Tissues;Toxic effect;Trastuzumab;Treatment-related toxicity;Tubulin;adaptive immune response;anti-tumor immune response;antibody conjugate;carcinogenesis;checkpoint inhibition;chemoradiation;chemotherapy;clinically relevant;curative treatments;cytotoxic;cytotoxicity;delivery vehicle;design;drug development;efficacy testing;immune cell infiltrate;immunogenic;improved;improved outcome;inhibitor;innovation;interest;mouse model;neoplastic cell;novel therapeutics;pre-clinical;precision medicine;programmed cell death protein 1;receptor;receptor binding;response;success;systemic toxicity;targeted delivery;tool;tumor;tumor specificity;tumor xenograft;tumor-immune system interactions Spatially precise radio-chemo-immunotherapy using antibody conjugates PROJECT NARRATIVEPatients with locally advanced cancers continue to be treated with radiotherapy and decades old conventionalchemotherapies that sensitize tumors to radiation damage however tumor control is suboptimal and treatmenttoxicity high. Based on preliminary data we hypothesize that highly potent antibody drug conjugatesspecifically radiosensitize tumor cells avoid normal tissue and engage tumor immune responses. In thisproposal we will investigate the interplay of antibody conjugated radiosensitizers and radiotherapy within thecontext of the tumor immune microenvironment to develop precision radio-chemo-immunotherapy strategies. NCI 10746862 12/15/23 0:00 PA-20-185 5R01CA268513-02 5 R01 CA 268513 2 "PRASANNA, PAT G" 12/1/22 0:00 11/30/27 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11182831 "ADVANI, SUNIL J" Not Applicable 50 RADIATION-DIAGNOSTIC/ONCOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 479773 NCI 303654 176119 PROJECT SUMMARY/ABSTRACTLocally advanced cancers remain a therapeutic challenge to eradicate. The most successful treatments forsuch patients continue to combine decades old classical cytotoxic chemotherapies with radiotherapy. Whilechemo-radiotherapy improves tumor control using non-targeted drugs increases normal tissue damage in theirradiated field along with systemic toxicities precluding further treatment intensification. Targeted deliveryapproaches can improve the chemo-radiotherapy paradigm by restricting highly potent radiosensitizersspecifically to irradiated tumor targets that activate anti-tumor immune responses while simultaneouslyavoiding normal tissues. To test this hypothesis we leveraged antibody drug conjugate (ADC) technology forreceptor-restricted radiosensitization. ADCs split the roles of tumor targeting and killing into two distinctmolecular tasks. Targeting is achieved by the antibody portion recognizing cell surface receptors preferentiallyfound on tumor cells. Following cell surface receptor binding ADCs are endocytosed and the attached drugpayload warhead intracellularly released specifically within target cells. ADCs have been exclusively built bylinking cytotoxic drugs to tumor targeting antibodies. The potent anti-tubulin drug monomethyl auristatin E(MMAE) is the most common ADC warhead. We discovered MMAE could also radiosensitize. Advancing tosyngeneic murine models using our novel drug delivery vehicles we have now provided the first demonstrationthat MMAE produces durable irradiated tumor control which is dependent on CD8 T cells and is enhanced byimmune checkpoint inhibition. While antibody coupled MMAE is target restricted. However once releasedMMAE has dose limiting toxicities. To achieve increasingly precise tumor radiosensitization we usedorthogonal strategies and rationally constructed a first-in-class radiosensitizing ADC designed to inhibit DNAdamage repair. As proof of concept we conjugated anti-EGFR antibody cetuximab to ATM inhibitor AZD0156(cetux-AZD0156). Cetux-AZD0156 specifically bound and delivered drug to EGFR+ tumors while avoidingadjacent peri-tumoral normal tissue. Moreover cetux-AZD0156 radiosensitized and increased irradiated tumorcontrol. Based on these findings we hypothesize that anti-ErbB ADCs coupled to radiosensitizing warheadsimprove spatial precision of radiosensitization and engage the tumor immune microenvironment (TIME). Thegoals of this proposal are to methodically test this hypothesis by evaluating radiosensitizing ADC warheads inmurine tumor models using our innovative toolbox of tumor-targeted radiosensitizing ADC warheads. In Aim 1we will test the ability of auristatins to sculpt the irradiated TIME and promote immunogenic tumor control. InAim 2 we will test if immunotherapies potentiate radiosensitizing auristatins to achieve durable tumor control.In Aim 3 we will test first-in-class ADCs with ATM inhibitor warheads for tissue selective radiosensitization.Rigorously testing radiosensitizing ADCs in advanced murine models will provide rationale for moving awayfrom non-targeted chemo-radiotherapy toward molecularly guided precision radio-chemo-immunotherapies. 479773 +No NIH Category available Animals;Apoptosis;Biological Markers;Biopsy;Blinded;Blood;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Neoplasms;Cancer Detection;Cancer Patient;Cardiovascular system;Cells;Cephalic;Classification;Clinic;Clinical;Clinical Management;Clinical Research;Clinical Trials;DNA;Data;Data Analyses;Development;Devices;Diagnosis;Diagnostic;Disease;Drug Delivery Systems;Edema;Enrollment;Evaluation;Excision;Family suidae;Focused Ultrasound;Foundations;Frequencies;Future;Genetic;Genomics;Glioblastoma;Goals;Green Fluorescent Proteins;Hemorrhage;Histologic;Histology;Image;Injury;Intervention;Intravenous;Knowledge;Location;Magnetic Resonance Imaging;Malignant neoplasm of brain;Measurement;Medical;Methods;Microbubbles;Modeling;Molecular;Molecular Diagnosis;Molecular Profiling;Molecular Target;Monitor;Morbidity - disease rate;Mutation;Mutation Detection;Necrosis;Neuronavigation;Operative Surgical Procedures;Patients;Plasma;Procedures;Property;Public Health;Quality of Care;Quality of life;RNA;Randomized;Research;Resected;Risk;Rodent;Safety;Sampling;Schedule;Site;Sonication;Specimen;Stains;System;Techniques;Therapeutic;Time;Tissues;Transfection;Translations;Tumor Markers;Tumor-Derived;Variant;anatomic imaging;blood-brain barrier disruption;blood-brain barrier permeabilization;circulating biomarkers;clinical practice;clinically significant;detection sensitivity;genetic information;genetic signature;human data;implantation;improved;inflammatory marker;innovation;liquid biopsy;minimally invasive;molecular marker;mouse model;novel;personalized care;porcine model;prospective;protein biomarkers;radiological imaging;safety and feasibility;targeted treatment;therapeutically effective;tissue injury;tool;treatment response;tumor;tumor DNA;tumor progression Sonobiopsy for Noninvasive Genetic Evaluation of Glioblastoma Patients PROJECT NARRATIVEThe proposed research is relevant to public health because developing a noninvasive capability of diagnosing and monitoring brain tumors in the brain will fundamentally advance personalized care for patients with malignant brain tumors. In addition to the standard diagnostics of anatomic imaging and surgical histology the proposed technique has the potential to become the third pillar for brain tumor management by radically advancing the ability to easily and regularly acquire tumor genetic and molecular signatures. NCI 10746860 12/12/23 0:00 PAR-21-033 5R01CA276174-02 5 R01 CA 276174 2 "PEREZ, J MANUEL" 12/1/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 2084466 "LEUTHARDT, ERIC CLAUDE" "CHEN, HONG " 1 NEUROSURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 580791 NCI 373499 207292 ABSTRACTThere is an unmet critical need for noninvasive methods to interrogate the genetic and molecular properties of the malignant brain tumor known as glioblastoma (GBM). Our group was the first to introduce the focused ultrasound (FUS)-enabled liquid biopsy technique for noninvasive and spatially targeted molecular diagnosis and characterization of brain tumors which we term sonobiopsy. The current barrier to the widespread use of sonobiopsy in clinical practice is the lack of human data that rigorously characterizes the safety and feasibility of this technique. Our long-term goal is to transform the clinical management of GBM patients by providing genetic signatures of the disease using sonobiopsy. The overall obiective of this proposal is to perform a randomized blinded double-armed single-center prospective clinical trial to validate the safety and diagnostic feasibility of sonobiopsy. We have strong preliminary data that demonstrated the feasibility and safety of sonobiopsy in rodent and porcine GBM models and also developed a neuronavigation-guided FUS system for performing sonobiopsy in patients. The proposed clinical trial will accomplish two specific aims: 1) Demonstrate enrichment of GBM plasma circulating tumor DNA (ctDNA) to a detectable level with sonobiopsy and 2) Define the safety profile of sonobiopsy in GBM patients. Under the first aim we will enroll forty presurgical GBM patients who will be randomized (1 :1) for sonobiopsy versus sham. Immediately prior to surgical resection sonobiopsy or sham will be performed and plasma will be collected pre- and post-sonication. Genetic sequencing will be performed on plasma samples as well as surgically resected sonicated tumor samples. We will compare: 1) the frequency of GBM-specific variants in the blood pre- and post-sonobiopsy 2) the differences in ctDNA enrichment between sonobiopsy and sham and 3) the concordance in mutation detection between post-sonobiopsy plasma samples and standard sequencing of tumor samples. For the second aim because the sonobiopsy or sham intervention will be performed in an intraoperative MRI surgical suite prior to resection we will use MR imaging to define the blood-brain barrier permeability changes and detect tissue injury or edema/hemorrhage at the surrounding healthy tissue and sonicated sites if they occur Histological analysis of surgically resected sonicated and un-sonicated tumors will be performed to define the safety profile of sonobiopsy by staining for hemorrhage necrosis apoptosis and inflammation markers. This project is innovative because it is a substantial departure from the status quo by using FUS in a novel fashion to substantially increase the presence of tumor biomarkers in the blood. The proposed research is significant because it will establish the foundation of knowledge to enable the translation of this innovative technique and ultimately advance the diagnosis and monitoring of brain cancer patients by identifying genetic signatures of the tumor without surgery. In addition to the standard diagnostics of anatomic imaging and surgical histology sonobiopsy has the potential to become the third pillar for brain tumor management which will have a dramatic impact on patient survival and quality of life. 580791 +No NIH Category available Alzheimer's Disease;Biological Assay;CD34 gene;Cells;Clinical Trials;Combined Modality Therapy;Development;Dose;Engraftment;Future;Glioblastoma;Glioma;Growth;Hematopoietic stem cells;Human;Immune;Immune checkpoint inhibitor;Immunosuppression;Immunotherapy;Infiltration;Label;Low Dose Radiation;Macrophage;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Metastatic malignant neoplasm to brain;Modeling;Molecular;Molecular Target;Mus;Nature;Outcome;Patients;Phagocytosis;Primary Brain Neoplasms;Prognosis;Resistance;T-Lymphocyte;Therapeutic;Treatment Efficacy;Tumor Promotion;Tumor-associated macrophages;Xenograft procedure;beta-site APP cleaving enzyme 1;cancer therapy;checkpoint inhibition;cytokine;design;drug candidate;humanized mouse;immune checkpoint blockade;improved;induced pluripotent stem cell;inhibitor;novel therapeutic intervention;pharmacologic;preclinical study;programs;screening;small molecule;stem cells;synergism;therapeutic target;therapeutically effective;therapy resistant;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Macrophage-based Therapy and Immune Checkpoint Blockade for Glioblastoma Project NarrativeGlioblastoma (GBM) is the most frequent and lethal type of primary brain tumor that is highly resistant tocurrent treatments including immune checkpoint blockade (ICB) indicating that development of new effectivetherapeutic approaches is urgently needed. Because GBM harbors abundant tumor-associated macrophages(TAMs) that mainly augment malignant growth promote therapeutic resistance and mediate immunesuppression that negatively impacts current immunotherapy reprograming tumor-promoting macrophages(pTAMs M2-like) into tumor-suppressive macrophages (sTAMs M1-like) not only activates macrophagephagocytosis of glioma cells to suppress malignant growth but may also remodel the immunemicroenvironment to facilitate current ICB. In this proposal we will assess whether reprograming pTAMs intosTAMs through BACE1 inhibition by MK-8931 synergizes with current ICB to significantly improve therapeuticefficacy for GBM which will inform further clinical trials to potentially benefit patients with GBM or othermalignant brain tumors including brain metastases. NCI 10746856 11/6/23 0:00 PA-20-185 5R01CA277966-02 5 R01 CA 277966 2 "SINGH, ANJU" 12/1/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-OTC-D(08)F] 8662503 "BAO, SHIDENG " Not Applicable 11 OTHER BASIC SCIENCES 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 331459 NCI 205875 125584 Project SummaryGlioblastoma (GBM) the most lethal primary brain tumor with poor prognosis is highly resistant to currenttreatments including immune checkpoint blockade (ICB) partially due to the immune suppressivemicroenvironment. GBM harbors abundant tumor-associated macrophages (TAMs) that are critical immunecells in the tumor microenvironment (TME). Because the majority of TAMs are tumor-promoting macrophages(pTAMs M2-like) that augment malignant growth promote therapeutic resistance and mediate immunesuppression reprograming pTAMs into tumor-suppressive macrophages (sTAMs M1-like) represents apromising therapeutic strategy. As pTAMs establish the immunosuppressive microenvironment that negativelyimpacts current immunotherapy redirecting pTAMs into sTAMs not only activates macrophage phagocytosis ofglioma cells but may also remodel the immune microenvironment to facilitate current ICB. To identify smallmolecules that can reprogram pTAMs into sTAMs to promote macrophage phagocytosis of glioma cells wedesigned a cell-based fluorescent screening assay using GFP-labeled iPSC-derived macrophages andtdTomato-expressing glioma cells including glioma stem cells (GSCs) to discover drug candidates andcorresponding molecular targets. To this end we found that several specific inhibitors of BACE1 (-siteamyloid precursor protein cleaving enzyme 1) could effectively stimulate macrophage phagocytosis to engulfglioma cells including GSCs and thus identified BACE1 as a therapeutic target to reprogram pTAMs intosTAMs. We demonstrated that BACE1 is preferentially expressed by pTAMs in human GBMs and is requiredfor maintaining pTAM polarization. Importantly pharmacological inhibition of BACE1 by its inhibitor MK-8931(Verubecestat) potently redirected pTAMs into sTAMs and promoted macrophage phagocytosis of glioma cellsto inhibit GBM growth. Furthermore we found that low doses of radiation (IR) markedly enhanced TAMinfiltration and synergized with MK-8931 treatment to suppress GBM tumor growth. As several BACE1inhibitors including MK-8931 initially developed for Alzheimer's disease have been demonstrated to be safefor humans in clinical trials repurposing these inhibitors for the macrophage-based cancer therapy shouldstraightforward and promising. As abundant pTAMs largely contribute to the immune suppressivemicroenvironment reprograming pTAMs into sTAMs through BACE1 inhibition may remodel the TME tofacilitate current ICB. Thus we hypothesize that reprograming pTAMs into sTAMs throughpharmacological inhibition of BACE1 synergizes with current immune checkpoint inhibition to improvetherapeutic efficacy for GBM. We will accomplish our objectives through the following aims: (1) We willassess the effect of reprograming pTAMs into sTAMs on the immune microenvironment in GBM; and (2) Weevaluate the therapeutic impact of TAM-based therapy in combination with current ICB for GBM. The outcomeswill inform future clinical trials to improve treatment for GBM and potentially brain metastases. 331459 +No NIH Category available Ablation;Biochemical;Biological;Bypass;Cell Survival;Cells;Chronic;Clinical;Colorectal Cancer;Combined Modality Therapy;Data;Development;Dose Limiting;Genes;Genetic;Genetically Engineered Mouse;HSF1;Heat-Shock Response;Human;Individual;KRAS oncogenesis;KRAS2 gene;KRASG12D;Laboratory Study;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mediating;Membrane;Molecular;Monitor;Mutate;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenic;PIK3CG gene;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phase II Clinical Trials;Phosphorylation;Phosphorylation Site;Post-Translational Protein Processing;Pre-Clinical Model;Protein Secretion;Proteins;Proteome;Proto-Oncogene Proteins c-akt;Quality Control;Regulation;Relapse;Research;Resistance;Ribonucleases;Signal Pathway;Signal Transduction;Specificity;Stress;Therapeutic;Toxic effect;Treatment Efficacy;Ubiquitination;cancer cell;clinically relevant;improved;in vivo;inhibitor;insight;mutant;novel therapeutic intervention;pancreatic cancer model;patient derived xenograft model;patient response;pharmacologic;pre-clinical;preclinical trial;prevent;protein aggregation;proteostasis;proteotoxicity;refractory cancer;resistance mechanism;response;therapy resistant;tumor;tumor growth;tumorigenesis Proteostasis Reprogramming in Mutant KRAS-Driven Cancers NARRATIVEMutant KRAS is frequent driver of lung pancreatic and colorectal cancers. Our research will establish a noveltherapeutic strategy to target the proteostasis reprogramming in KRAS-mutant cancers and improvepatient response to KRAS inhibitor. NCI 10746855 11/27/23 0:00 PA-20-185 5R01CA270240-02 5 R01 CA 270240 2 "XU, WANPING" 12/1/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-OTC1-A(80)S] 12011233 "CHEN, XI " Not Applicable 9 ANATOMY/CELL BIOLOGY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 463840 NCI 289900 173940 ABSTRACTKRAS is one of the most frequently mutated genes in human cancers. Despite advances in the development ofinhibitors that directly target mutant KRAS and the FDA approval of KRASG12C inhibitor sotorasib for KRASG12C-mutant non-small cell lung cancer (NSCLC) cancer cell adaptation and resistance to KRAS inhibitors are almostinevitable and remains a major challenge that limits their clinical benefits. Our preliminary data establishproteostasis reprogramming as an essential mechanism that mediates tumor resistance to KRAS inhibitor.Inactivation of oncogenic KRAS rapidly downregulates both the heat shock response (HSR) and IRE1a branchof the unfolded protein response (UPR). However only IRE1a is selectively reactivated in KRASi-resistanttumors. Genetic or pharmacologic suppression of IRE1a substantially sensitizes KRASG12C-mutant tumors tosotorasib leading to complete and durable responses in preclinical NSCLC and pancreatic cancer models.Mechanistically we found that oncogenic KRAS-MAPK signaling promotes IRE1a protein stability through directERK-IRE1a interaction. In contrast multiple mechanisms of resistance to KRASi including reactivated ERK andhyperactivated AKT converge to re-activate IRE1a in resistant tumors. These findings provide a framework toseek biological insight into the proteostasis reprogramming in KRAS-mutant cancers and to further explore theeffects of pharmacological inhibition of proteostasis reprogramming as an anti-tumor approach for KRAS-mutantcancers. We hypothesize that IRE1a-mediated proteostasis reprogramming facilitates tumor resistance tooncogenic KRAS inhibition and that multiple resistance pathways converge with IRE1a to restore proteostasisand promote therapy resistance to KRAS inhibitors. This proposal will determine the molecular mechanisms ofdifferential IRE1a regulation in response to mutant KRAS inhibition (Aim 1) define proteostasis machinerycrosstalk between HSR and UPR in KRAS-mutant cancers (Aim 2) and evaluate the therapeutic efficacy oftargeting proteostasis reprogramming to overcome KRASi resistance in KRAS-mutant cancers (Aim 3).Accomplishing these aims will establish the biological significance and biochemical basis of oncogenic signalingregulated proteostasis network in KRAS-mutant human cancers leading to development of more effective andwell-tolerated therapeutic strategy to reverse KRASi resistance and bypass the on-target toxicity of targetingmultiple resistance signaling pathways. 463840 +No NIH Category available Acute;Address;Aftercare;Antitumor Response;Biological;Biomedical Engineering;Cancer Etiology;Catheterization;Cessation of life;Chemoembolization;Cirrhosis;Clinic;Compensation;Consumption;Curative Surgery;Data;Deterioration;Development;Diagnosis;Disease;Docosahexaenoic Acids;Dose;Effectiveness;Engineering;Etiology;Extensive Necrosis;Fluoroscopy;Funding Opportunities;Goals;Growth;Hepatic;Hepatic artery;Hepatocyte;High Dose Chemotherapy;Histopathology;Human;Hypoxia;Incidence;Injury;Intervention;Ischemia;Light;Lipoprotein (a);Liver;Liver Cirrhosis;Liver diseases;Liver neoplasms;Low-Density Lipoproteins;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Measures;Mediating;Medicine;Metabolism;Methods;Modeling;Molecular;Necrosis;Omega-3 Fatty Acids;Palliative Care;Parents;Patients;Perfusion;Population Heterogeneity;Primary carcinoma of the liver cells;Process;Property;Radiology Specialty;Rattus;Recurrent tumor;Research Proposals;Residual Neoplasm;Resolution;Risk Reduction;Rodent;Safety;Signal Transduction;Solid Neoplasm;Surveillance Program;Survival Rate;Technology;Testing;Therapeutic;Toxic effect;Treatment Efficacy;Tumor Burden;United States;United States National Institutes of Health;Unresectable;Vascular Endothelial Growth Factors;Work;angiogenesis;anti-cancer;biomaterial compatibility;clinical practice;dietary;effective therapy;efficacy evaluation;epithelial to mesenchymal transition;feeding;hepatoprotective;high risk population;image guided;improved;in vivo;innovation;ischemic injury;liver cancer model;liver function;liver injury;liver preservation;nanoparticle;neoplastic cell;novel;novel therapeutics;patient derived xenograft model;patient population;reconstitution;response;treatment strategy;tumor;tumor eradication;tumor growth;uptake Docosahexaenoic Acid Loaded Low-density Lipoproteins: A Novel Biologic Intervention for Hepatocellular Carcinoma. PROJECT NARRATIVELocoregional delivery of docosahexaenoic acid (DHA) loaded lipoproteins a completely natural engineered biologic isable to selectively kill liver tumor cells at doses that do not harm surrounding normal liver. In the present proposal weaim to leverage the selectivity of this agent to treat liver cancer without injury to the surrounding liver in the settingliver cirrhosis. In addition we will assess the efficacy of this biologic to provide sustained tumor eradication overconventional locoregional therapies. This project is in response to the parent NIH R01 funding opportunityannouncement PA20-185. NCI 10746850 12/14/23 0:00 PA-20-185 5R01CA271496-02 5 R01 CA 271496 2 "FU, YALI" 12/1/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-OTC1-A(80)S] 10840231 "CORBIN, IAN RONALD" Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 393281 NCI 243358 149923 PROJECT SUMMARY/ ABSTRACTHepatocellular carcinoma (HCC) is ranked as the second most common cause of cancer-related death globally.Transarterial chemoembolization (TACE) remains the only first-line treatment for unresectable intermediate-stage HCC despite the fact that this stage is comprised of a heterogeneous group of patients with a wide rangeof liver function variable tumor number and size. In clinical practice only 50-60% of patients with intermediatedHCC benefit from TACE thus repeated rounds of TACE therapy are performed to achieve maximum tumorrecession. The critical factors that impact the effectiveness of TACE therapy are the worsening of liver functionand tumor recurrence. The former arises from progressive off-target embolic ischemic injury to the liver whilethe latter results from hypoxia-induced angiogenesis epithelial-to-mesenchymal transition (EMT) and tumorgrowth triggered by TACE. These processes inevitably dominate the course of this disease resulting in poor longterm survival with a 5-year survival rates <12%. Novel therapies against HCC are urgently needed as theincidence of HCC is steadily increasing in the United States. In recent years the natural omega-3 fatty aciddocosahexaenoic acid (DHA) has been shown to possess promising anticancer properties and its consumptionhas been implicated in reducing the risk of HCC. The effects of dietary DHA on established solid tumors isnominal. To address this issue our lab has engineered a novel low-density lipoprotein (LDL) based biologic thatis reconstituted with unesterified DHA (herein referred to as LDL-DHA). Therapeutically we have shown in asyngeneic rat model of HCC that transarterial delivery of LDL-DHA is able to induce extensive necrosis (>80%)of HCC tumors and impede the tumor growth (3 fold) without injury to surrounding normal liver. Moreoverrepeated intra-arterial LDL-DHA treatments was shown to provide sustained regression of HCCs. Furthermorethe uptake of LDL-DHA in the normal liver was shown to be not only safe but potentially hepatoprotective. Inaddition recent preliminary data from our group has documented that LDL-DHA is able to downregulate HIF-1and EMT signaling in HCC cells thus inhibiting tumor angiogenic/regrowth activity. The goal of the presentproposal is to evaluate the utility image-guided locoregional LDL-DHA therapy for intermediate-stage HCC. Toaddress this goal we will examine the following specific aims: 1) evaluate the safety of intra-arterial LDL-DHAdelivery in rat models of cirrhosis; and 2) compare the therapeutic efficacy of LDL-DHA versus conventionalTACE methods to provide sustained tumor control in a patient derived-xenograft rat model of HCC. We expectthat the combined work of these Aims will validate the safety of LDL-DHA treatment in preserving liver functionin settings of cirrhosis and demonstrate the efficacy of this therapy to provide sustained tumor eradication overTACE. The LDL-DHA treatment strategy will be significant because it offers a new method of effectively treatingHCC while preserving liver function. Ultimately it is our endeavor to bring this technology to the clinic where it isanticipated to provide safe and efficacious approach to managing of unresectable HCC. 393281 +No NIH Category available Address;Adjuvant Chemotherapy;Adult;Aftercare;Award;Beds;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cell Line;Cell Proliferation;Cells;Central Nervous System Diseases;Clinical;Data;Development;Diagnosis;Disease;Drug Delivery Systems;Encapsulated;Engineering;Ensure;Epidermal Growth Factor Receptor;Etiology;Excision;Extracellular Matrix;Flow Cytometry;Ganciclovir;Glioblastoma;Goals;Growth;Immune;Immune response;Immune system;Immunity;Implant;In Vitro;Kinetics;Knowledge;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Mentors;MicroRNAs;Modeling;Molecular;Mus;Operative Surgical Procedures;Pathway interactions;Patients;Phase;Positron-Emission Tomography;Primary Brain Neoplasms;Prognosis;Proliferating;Proto-Oncogene Proteins c-akt;Publishing;Radiation therapy;Regimen;Resected;Role;STAT3 gene;Safety;Signal Transduction;Simplexvirus;Small RNA;Surgically-Created Resection Cavity;Survival Analysis;System;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;Thymidine Kinase;Time;Treatment Efficacy;Tumor Burden;Tumor Debulking;Tumor Volume;Up-Regulation;Validation;cell growth;chemotherapy;clinical care;clinical translation;effective therapy;exosome;fluorescence imaging;image guided;imaging agent;immune activation;immune clearance;implantation;in vivo;induced pluripotent stem cell;migration;mouse model;neoplastic cell;nerve stem cell;novel;promoter;response;restoration;stem cells;success;suicide gene;synergism;therapeutic miRNA;therapy development;treatment strategy;tumor;tumor microenvironment microRNA therapies for advanced brain tumors NARRATIVEThis proposal emphasizes on evaluating the therapeutic potential use of induced pluripotent stem cell derivedneural stem cells to deliver microRNA to advanced brain tumors. Once validated this therapeutic strategy hasa great potential to be integrated into the clinical care regimen for brain tumor therapy. NCI 10746847 12/1/23 0:00 PA-19-130 5R00CA245030-04 5 R00 CA 245030 4 "MAAS, STEFAN" 4/1/20 0:00 12/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 11728143 "BHERE, DEEPAK " Not Applicable 6 PATHOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF MEDICINE 292080001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 224097 NCI 150401 73696 ABSTRACTEach year upwards of 14000 patients are diagnosed with Glioblastoma (GBM) the most malignant form ofprimary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options forGBM but patients generally succumb to the disease. MicroRNAs (miR) are emerging as key regulators ofcellular differentiation and proliferation; have been implicated in the etiology of a variety of cancers includingGBM. Our exciting preliminary studies show great promise for exosomes shed from induced pluripotent stemcell derived - neural stem cells (iNSC) expressing miR-124 to target brain tumors. In the mentored (K99)phase of this study I will evaluate the immune effects mediated by miR-124 delivered locally into the tumorbed via encapsulated neural stem cells following tumor debulking. We hypothesize that miR-124 modulation byexosomes enriched in miR-124 from NSC when delivered into the tumor resection cavity will target tumor cellproliferation and enhance T-cell mediated immune clearance of GBM cells. Once these effects are validated inthe R00 phase of the award the potential synergy between the modulation of miR-7 and miR-124 which targetAKT and STAT3 respectively will be studied to develop a sECM encapsulated iNSC delivered miR-7/ miR-124therapeutic approach to target resected GBM. In order to ensure safety of iNSC implantation the herpes simplexvirus thymidine kinase suicide gene system will be incorporated. The efficacy of iNSC-miR-7/miR-124/HSV-TKwill be evaluated in mouse models of GBM resection. We hypothesize that dual modulation of miR-124 and miR-7 will target the AKT-STAT3 signaling that is critical to tumor cell growth and together with the activation of hostimmune system medicated tumor clearance will present therapeutic benefit. Upon validation this microRNAbased therapeutic strategies will pave path to much needed novel treatments to target GBM. 224097 +No NIH Category available 3-Dimensional;Ablation;Address;Adoption;Adverse event;Agreement;American;Blinded;Blood Vessels;Cancer Detection;Cicatrix;Clinical;Clinical Research;Contrast Media;Contrast Sensitivity;Data;Data Set;Deposition;Detection;Development;Diagnosis;Early identification;Encapsulated;Fat necrosis;Follow-Up Studies;Gases;Granulation Tissue;Hepatic;Image;Image Analysis;Imaging Techniques;Incidence;Inflammation;Inflammatory;Institution;Kidney;Lipids;Longterm Follow-up;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Microbubbles;Modality;Monitor;Multimodal Imaging;Operative Surgical Procedures;Pathology;Patient Recruitments;Patients;Performance;Pilot Projects;Predictive Value;Proteins;Protocols documentation;Reader;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Reference Standards;Relapse;Renal Cell Carcinoma;Renal carcinoma;Renal function;Residual state;Resolution;Retreatment;Safety;Sample Size;Site;Specificity;Techniques;Testing;Time;Tissues;Ultrasonography;anatomic imaging;calcification;cancer recurrence;clinical application;clinically actionable;contrast enhanced;contrast enhanced computed tomography;cost;design;dosage;experience;follow-up;imaging approach;imaging detection;imaging modality;improved;kidney cortex;multimodality;portability;preservation;quantitative imaging;radiologist;real-time images;screening;sensor;standard of care;surveillance imaging;temporal measurement;tumor;ultrasound Multi-modality detection of RCC Recurrence Post Ablation Project Narrative:Localized ablation is a recommended treatment for T1a renal cancers and increasingly used as a non-surgicaltreatment option. Detection of cancer recurrence by CT or MRI (the current clinical standard) can be problematicdue to patient contraindications low temporal resolution and cost. We propose multi-modality contrast-enhanced ultrasound to detect recurrent renal cancer following ablation and propose to compare its performanceto contrast-enhanced cross-sectional imaging in a fully powered clinical study. NCI 10746846 11/30/23 0:00 PA-20-185 5R01CA269750-02 5 R01 CA 269750 2 "TANDON, PUSHPA" 12/1/22 0:00 11/30/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 11944169 "EISENBREY, JOHN " "TRABULSI, EDOUARD JOHN; WALLACE, KIRK DENNIS" 2 RADIATION-DIAGNOSTIC/ONCOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 526094 NCI 337240 188854 Project Summary: Renal cell carcinoma (RCC) accounts for 3-5% of all cancers. Localized ablation is arecommended treatment for T1a renal cancers (approximately 25% of all RCC) and particularly important for thetreatment of patients who are poor surgical candidates due to diminished renal function or with a solitary kidney.Post-ablation imaging protocols for detection of recurrence vary but mainly rely on contrast-enhanced computedtomography (CECT) or contrast-enhanced magnetic resonance imaging (CEMRI) at 3-12 months intervals.However detection of relapse based on detection of contrast enhancement within the ablation cavity can bechallenging on both modalities due to most imaging findings of recurrence being nonspecific because ofchanges in tumor size enhancement from fat necrosis and scarring and the development of calcificationsfollowing therapy. Additionally these techniques can be problematic due to modality and contrast agentcontraindications. As an alternative to CECT and CEMRI contrast-enhanced ultrasound (CEUS) has gainedacceptance for a variety of clinical applications. In small pilot studies our group has demonstrated the ability ofCEUS to monitor for both residual and recurrent RCC following percutaneous ablation with 100% sensitivity andno adverse events. While encouraging our findings were based on a relatively small sample size and with anoverall specificity of the technique that ranged from 75-96% primarily due to an inability to properly identify theboundaries of the ablation cavity from the surrounding renal cortex. To assess the clinical promise of CEUS wepropose a larger fully powered study recruiting patients across multiple institutions and using multi-modalityimaging techniques to overcome these limitations and enable clinical adoption. In our first specific aim we willcharacterize the sensitivity specificity positive and negative predictive value and inter-reader agreement of both2D CEUS and contrast-enhanced cross-sectional imaging for detecting recurrent RCC following ablation; we willuse a combination of long-term follow-up imaging and tissue pathology as a reference standard instead of relyingon CECT or CEMRI. At each site blinded radiologists with varying experience levels in CEUS will interpretexams enabling us to define these parameters while also quantifying reader variability. In the second aim wewill evaluate the potential improvement to the qualitative assessments of 2D CEUS when fused with the patient'spre-treatment cross-sectional imaging which we hypothesize will provide better delineation of the initial tumorboundary. In the third aim we will assess the potential added value of using multi-modality volumetric CEUS fordetecting RCC recurrence post ablation and also an advanced Doppler non-contrast technique as an exploratorysub-aim. Finally we will explore use of quantitative parameters extracted from 2D/3D CEUS exams to determineif this improves the overall performance of CEUS. At the study's conclusion we hope to address the currentlimitations in RCC recurrence surveillance imaging with fully powered CEUS study to support clinical adoptionwhile also addressing prior limitations through the use of multi-modality and quantitative imaging. 526094 +No NIH Category available Address;Adjuvant Chemotherapy;Alternative Therapies;Anatomy;Bilateral;Biological Markers;Blood Vessels;Breast Cancer Model;Breast Cancer Patient;Breast Cancer therapy;Breast Magnetic Resonance Imaging;Breast-Conserving Surgery;Cancer Center;Carboplatin;Cell Death;Cell Survival;Cellularity;Chemotherapy-Oncologic Procedure;Clinical;Complement;Computer software;Consumption;Contralateral Breast;Custom;Cyclophosphamide;Data;Diffusion Magnetic Resonance Imaging;Disease;Doxorubicin;Drug Kinetics;Early identification;Early treatment;FDA approved;Fatty acid glycerol esters;Fingerprint;Gadolinium;Goals;Homeostasis;Image;In complete remission;Ions;Longitudinal Studies;MRI Scans;Magnetic Resonance Imaging;Mammography;Maps;Measures;Membrane;Metabolic;Methods;Modeling;Monitor;Neoadjuvant Therapy;Noise;Nuclear;Paclitaxel;Pathologic;Patient Care;Patient Monitoring;Patients;Perfusion;Permeability;Physiologic pulse;Prediction of Response to Therapy;Prognosis;Property;Protocols documentation;Protons;Scanning;Signal Transduction;Sodium;Standardization;Structure;System;Testing;Time;Tissues;Toxic effect;Treatment Protocols;Variant;Water;alternative treatment;breast imaging;cancer cell;cell injury;cohort;contrast enhanced;design;extracellular;imaging biomarker;imaging modality;improved;individualized medicine;insight;malignant breast neoplasm;novel;pembrolizumab;prognostic model;radio frequency;responders and non-responders;response;therapy outcome;treatment response;triple-negative invasive breast carcinoma;tumor;ultrasound Multinuclear MRI to Monitor Breast Cancer Therapy Project NarrativeNeoadjuvant chemotherapy (NACT) is administered to treat locally advanced invasive breast cancer by shrinkinginoperable tumors and to enable breast-conserving surgery. It offers the opportunity to evaluate tumor responseto treatment in aggressive disease and early identification of responders versus non-responders can aid theidentification of patients who could benefit from additional trials. We propose to implement a novel quantitativemultinuclear MRI protocol based on simultaneous acquisitions of sodium and proton MR fingerprinting data todevelop an imaging biomarker model of early response of breast cancer to NACT. NCI 10746832 11/13/23 0:00 PA-20-185 5R01CA266345-02 5 R01 CA 266345 2 "SALVADOR MORALES, CAROLINA" 12/1/22 0:00 11/30/27 0:00 Clinical Translational Imaging Science Study Section[CTIS] 10786031 "MADELIN, GUILLAUME " "BROWN, RYAN " 12 RADIATION-DIAGNOSTIC/ONCOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 625153 NCI 368822 256331 Project SummaryNeoadjuvant chemotherapy (NACT) is administered to treat locally advanced invasive breast cancer by shrink-ing inoperable tumors and to enable breast-conserving surgery. About 30% of patients have inadequate NACTresponse but are not immediately identified by standard imaging such as mammography ultrasound or struc-tural magnetic resonance imaging (MRI) and are therefore subjected to unnecessary toxicity and thwarted fromcustomized treatment. An imaging method for early assessment of tumor response to NACT is still needed toidentify non-responders that may be candidates for alternative therapy. Our hypothesis is that in responding pa-tients cancer cell damage induced by NACT can be characterized by loss of ion homeostasis through changesin pH membrane depolarization and dysregulation of transmembrane ion transporters. This loss of homeostasisimmediately manifests as variations in the intracellular sodium concentration and cellular volume fraction and po-tentially the cellular microenvironment itself. We therefore propose to implement a new quantitative multinuclearMRI (QMM) protocol where structural information from proton (1H) MR fingerprinting (MRF) acquired with bothCE (T1 pre/post contrast) and dynamic CE (pharmacokinetics) methods and metabolic information from sodium(23Na) MRF will be acquired simultaneously on a clinical system at 3 T. We will also develop a QMM-basedimaging biomarker model that combines the metabolic metrics related to ion homeostasis with the structural andpharmacokinetic metrics to assess changes in cancer cell viability during early NACT as a predictor of therapyresponse. Specific aim 1: Quantitative multinuclear MRI (QMM) protocol for breast imaging at 3 T. (1.a) To build a1H/23Na multichannel RF coil for bilateral breast MRI at 3 T. (1.b) To optimize a multinuclear fingerprinting (MNF)which consists of a simultaneous 1H/23Na MRF acquisition. MNF will be acquired with 2 echo times to separatewater and fat signals using the Dixon method (Dixon MNF) before and after Gadolinium contrast enhancement(CE MNF) and also during dynamic CE (DCE MNF). (1.c) Optimization of the QMM protocol which includesdiffusion tensor imaging (DTI) CE MNF DCE MNF and Dixon MNF. Specific aim 2: Longitudinal application ofQMM in patients with breast cancer during NACT. (2) Longitudinal study in patients with triple negative breastcancer (TNBC) that undergo standard clinical NACT regimen who will be scanned: (1) baseline (pre-NACT)(2) within 1 week of the 1st cycle (3) within 1 week of the 2nd cycle. Specific aim 3: To develop biomarkermodel for prognosis of therapy efficiency from QMM data. (3.a) To develop an imaging biomarker model of breastcancer response to therapy based on the combination of metabolic pharmacokinetic and structural metrics fromthe QMM protocol. (3.b) To determine which combinations of biomarkers from the model are best predictor ofpathological response after NACT. 625153 +No NIH Category available Acceleration;Adjuvant;Affect;Antigens;Biophysics;Blood;Blood Pressure;Blood Vessels;Brain Neoplasms;Cancer Model;Cell Hypoxia;Cell Respiration;Cells;Cerebrovascular Spasm;Characteristics;Chimeric Proteins;Chronic;Clinical;Complex;Data;Dose;Drops;Drug usage;Effectiveness;Equilibrium;Erectile dysfunction;FDA approved;Flow Cytometry;Gastrointestinal tract structure;Heterotopic Transplantation;Human;Hypoxia;Immune;Immune Evasion;Immunocompetent;Immunophenotyping;Immunotherapy;Kinetics;Lead;Luciferases;Malignant Neoplasms;Measures;Metabolic;Mitochondria;Modality;Modeling;Mus;Muscle relaxants;Mutation;Normal tissue morphology;Oxygen;Oxygen Consumption;PD-1 blockade;Papaver;Papaverine;Parents;Perfusion;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Phosphodiesterase Inhibitors;Proteins;Publishing;RNA analysis;Radiation;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Radio;Radiosensitization;Relaxation;Reporter;Reporting;Resistance;Rodent;Safety;Smooth Muscle;Solid Neoplasm;Structure;T-Lymphocyte;Testing;Theft;Transplantation;Tumor Oxygenation;Vascular resistance;Vasospasm;anti-PD1 therapy;anticancer treatment;cancer infiltrating T cells;cancer therapy;cardiovascular effects;cell killing;chemotherapy;design;drug-like compound;effective therapy;exhaustion;immune cell infiltrate;immune checkpoint blockade;improved;in vivo;inhibitor;insight;mammary epithelium;mouse model;neoplastic cell;novel;novel therapeutics;orthotopic breast cancer;phosphoric diester hydrolase;programmed cell death protein 1;radiation response;small molecule;stemness;theories;tumor;tumor hypoxia;tumor microenvironment;vascular bed Overcoming hypoxic resistance to anti-cancer therapy NARRATIVELow levels of oxygen (hypoxia) within a tumor is a barrier to effective therapy with radiation and immunecheckpoint blockade. We have developed some new drug like compounds that can reduce the consumption ofoxygen within the tumor and reduce hypoxia. We now propose to test these in model tumors to see if theysensitize to treatment with radiation or PD1 blockade. NCI 10746805 11/15/23 0:00 PA-19-056 5R01CA255334-04 5 R01 CA 255334 4 "AGYIN, JOSEPH KOFI" 12/15/20 0:00 11/30/25 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1933683 "DENKO, NICHOLAS C." "LI, ZIHAI " 3 RADIATION-DIAGNOSTIC/ONCOLOGY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 524443 NCI 337980 186463 ABSTRACTTumor hypoxia reduces the effectiveness of anti-cancer treatment with radiotherapy some chemotherapy andimmune checkpoint blockade therapy. For radiotherapy biophysical measures show that hypoxic cells require2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For immunotherapyhypoxia has been shown to contribute to immune evasion and even accelerate T cell exhaustion. For thesereasons many groups have tried to deliver more oxygen to tumors as an adjuvant to increase tumor sensitivity.Unfortunately this approach has met with disappointing clinical results.We have looked at tumor oxygenation differently as a supply and demand mismatch with the supply beinginadequate to meet the demand of the growing tumor mass. Therefore if we could reduce oxygen demandrather than increase supply we could effectively reduce hypoxia and sensitize tumors. Because mitochondriaare the major sink for oxygen within a cell we propose that novel mitochondria inhibitors would reduce oxygendemand to match the limited supply. We have identified papaverine (PPV) as an FDA-approved molecule withthe ability to inhibit mitochondrial function at clinical doses. Published studies from our group showed that inmouse tumors that papaverine can radiosensitize through inhibition of mitochondrial function producingMetabolic Radiosensitization. Papaverine was originally isolated from the poppy and used as a smooth musclevasorelaxant presumably due to inhibition of phosphodiesterase 10A. This activity makes it an effective drug forcerebral vasospasm but causes a systemic drop in blood pressure and potential adverse cardiovascular effects.We therefore propose in this application to synthesize and evaluate new small molecule derivatives of papverinethat we have designed to remove its activity as a phosphodiesterase inhibitor but retain its activity as amitochondrial complex 1 inhibitor. Using these PPV derivatives and sophisticated mouse models of cancer weintend to prove that inhibition of mitochondrial function is an effective strategy for removing hypoxia in solidtumors without affecting well oxygenated normal tissue. Preliminary data supports the overall theory thatmitochondrial inhibitors increase tumor oxygenation and sensitivity to radiotherapy and immune checkpointblockade therapy. 524443 +No NIH Category available Address;Algorithms;Amino Acid Sequence;Binding;Biological Process;Biophysics;Cell Nucleus;Cell Proliferation;Cells;Childhood Leukemia;Chromatin;Clinical;Code;Computer Analysis;DNA;Data;Disease;Distal;EWS-FLI1 fusion protein;Elements;Enhancers;Fusion Oncogene Proteins;Future;Gene Abnormality;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Fusion;Genes;Genetic Transcription;Genomic Segment;HOXA9 gene;Hematopoietic;Homeobox Genes;Hybrids;In Vitro;Information Resources;Link;Liquid substance;Malignant Neoplasms;Mediating;Membrane;Molecular Conformation;Morphology;NUP98 gene;Nuclear;Nucleic Acids;Oncogenes;Oncogenic;Optics;Organelles;Parents;Phase;Phenotype;Process;Property;Protein Region;Proteins;RNA Polymerase II;Recurrence;Role;Saint Jude Children's Research Hospital;Source;Structure;Testing;Transcriptional Regulation;Translating;cell transformation;gene translocation;genomic data;lens;novel;promoter;protein function;protein protein interaction;sarcoma;submicron;transcription factor;tumorigenesis Role of Phase separation by fusion oncoproteins in oncogenesis NARRATIVEGene translocations often create fusion oncoproteins (FOs) that cause uncontrolled cell proliferation andoncogenesis in a wide variety of cancers. Our preliminary results show that gene fusions often create FOs thatare abnormal transcription factors that we hypothesize drive oncogenesis by forming aberrant transcriptioncenters and other aberrant functional bodies through the process of liquid-liquid phase separation (LLPS). Ourstudies are addressing open questions regarding the oncogenic mechanisms associated with myriad FOs andmay enable mechanistic interpretation of clinical genomics data on novel fusion oncogenes in the future. NCI 10746795 11/23/23 0:00 PA-19-056 5R01CA246125-05 5 R01 CA 246125 5 "AMIN, ANOWARUL" 12/6/19 0:00 11/30/24 0:00 Macromolecular Structure and Function B Study Section[MSFB] 1923544 "KRIWACKI, RICHARD W" "DENIZ, ASHOK A; MOHAN, MADAN " 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 560279 NCI 451601 108678 SUMMARYGene translocations that fuse segments of two different genes (termed parents) are known to driveoncogenesis in myriad cancers. Expression of in-frame translocations yields fusion oncoproteins (FOs) withhybrid functional properties that aberrantly control critical biological processes and ultimately causeunchecked cell proliferation and oncogenesis. FOs are often abnormal transcription factors that fuseunstructured segments of one parent that function as activation domains to a DNA or chromatin bindingdomain of the other. These FOs result in abnormal gene expression that transforms cells and drivesoncogenesis. Our preliminary computational results show that FOs often contain intrinsically disorderedregions (IDRs) that display sequence features associated with the ability to undergo liquid-liquid phaseseparation (LLPS) a process now appreciated to mediate the formation and function of numerous cellularbodies including membrane-less organelles and importantly nuclear transcription centers with punctatemorphology. Our computational analyses of thousands of clinically documented fusion oncogenes show that asignificant portion of the associated FOs contain LLPS-prone IDRs. Based on this observation we hypothesizethat a set of FOs transform cells by forming aberrant transcription centers through phase separation; other FOscontaining LLPS-prone IDRs may form aberrant cellular puncta that host different functions. Further wehypothesize that FOs represent a rich source of proteins which through analysis in cells and in vitro andthrough computational analyses will reveal novel sequence and conformational features associated withphase separation. These hypotheses will be tested through three specific aims. 560279 +No NIH Category available 4T1;Animal Model;Anti-CD47;Antibodies;Antibody-drug conjugates;Antigens;Biodistribution;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer cell line;CD276 gene;CD47 gene;Cell Death;Cell surface;Cells;Clinical;Clinical Trials;Cytotoxic Chemotherapy;Dose;Doxorubicin;Drug Kinetics;Drug Synergism;Drug resistance;Epidermal Growth Factor Receptor;Evaluation;Experimental Designs;Extracellular Domain;Future;Goals;Human;Imaging Techniques;Immune response;In Vitro;Investigation;Laser Scanning Confocal Microscopy;Luciferases;MDA MB 231;MDA-MB-468;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Medical;Modeling;Monoclonal Antibodies;Mus;Neoplasm Metastasis;Normal Cell;Operative Surgical Procedures;Paclitaxel;Patients;Pharmaceutical Preparations;Positron-Emission Tomography;Pre-Clinical Model;Procedures;Production;Prognosis;Protocols documentation;Quality of life;Recurrence;Recurrent tumor;Relapse;Residual state;Safety;Sampling;Solid Neoplasm;Specificity;Surface;Survival Rate;Testing;Therapeutic;Toxic effect;Tumor Angiogenesis;Tumor Suppression;Xenograft Model;Xenograft procedure;anti-cancer;antibody-dependent cell cytotoxicity;cancer subtypes;chemotherapy;chimeric antigen receptor;curative treatments;cytotoxic;cytotoxicity;design;dosage;effective therapy;engineered T cells;folate-binding protein;gemcitabine;glycosylation;immune activation;improved;in vivo;in vivo imaging system;inhibitor;innovation;malignant breast neoplasm;microscopic imaging;neoplastic cell;novel;overexpression;pre-clinical;preclinical evaluation;prevent;rapid growth;receptor;response;side effect;small molecule;small molecule inhibitor;synergism;systemic toxicity;targeted treatment;translational applications;translational potential;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor xenograft Synergistic Targeted Therapy of Antibody-Drug Conjugates for Triple-Negative Breast Cancer The triple negative breast cancer (TNBC) which is characterized by rapid growth metastasis and recurrencecomprises about 15% of all breast cancers and often regrows after primary treatment leading to poor prognosisin TNBC patients. It is highly desired to develop an effective therapy for elimination of TNBC. Therefore thecombined antibody-drug conjugates (ADCs) that integrate the advantages of specific targeting and antibody-dependent cellular cytotoxicity of a novel tumor-specific monoclonal antibody and the direct cytotoxicity of theantibody-delivered payloads will be developed and characterized for TNBC treatment. NCI 10746794 12/15/23 0:00 PA-19-056 5R01CA238273-05 5 R01 CA 238273 5 "BOURCIER, KATARZYNA" 1/1/20 0:00 12/31/25 0:00 Developmental Therapeutics Study Section[DT] 10315507 "LIU, RUNHUA RUNA" "LIU, XIAOGUANG MARGARET" 7 GENETICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2024 438502 NCI 298801 139701 Triple negative breast cancer (TNBC) comprises 10-20% of all breast cancers and is characterized by rapidgrowth metastasis and recurrence. Furthermore human TNBC often regrows after primary treatment leadingto poor prognosis in patients with TNBC. The standard cytotoxic chemotherapies for TNBC have the poor clinicalbenefit and severe side effects. Targeted therapies such as monoclonal antibodies (mAbs) antibody-drugconjugates (ADCs) chimeric antigen receptor engineered T cells and small molecule inhibitors have beendeveloped to treat solid tumors while minimizing the side effects on normal cells but none of these therapieshas been applied to treat TNBC. Thus targeted therapy remains an unmet medical need to effectively treatTNBC. Our preliminary studies identified the targeting surface receptors (such as CD276 and CD47) in TNBCdeveloped novel tumor-specific mAbs that target TNBC but not to normal cells tested multiple small moleculesshowing high toxicity established the construction and evaluation procedures of anti-CD276/CD47 ADCs andevaluated the potential safety and anticancer efficacy of our ADCs in vitro and in vivo. Our central hypothesis isthat the ADCs-based therapy can effectively eliminate TNBC with a limited side effect via integrated anti-cancermechanisms. In this study we propose to develop targeted therapies for curative treatment of TNBC. In Aim 1we aim to build an effective platform of ADC therapies to treat CD276+ TNBC and identify the most efficienttreatment strategy by investigating the targeting specificity ADC payloads-mediated anti-TNBC efficacy andanti-CD276 mAb-induced immune cell activation and suppression of tumor angiogenesis. In Aim 2 we willdevelop anti-CD47 ADC-based targeted therapies to eliminate CD47+ TNBC especially chemotherapy-inducedCD47+ TNBC and prevent tumor recurrence and metastasis. We will investigate the anti-tumor efficacy usingmultiple TNBC cell lines and xenograft tumors and delineate the anti-TNBC mechanisms including ADC-mediated drug cytotoxicity anti-CD47 mAb-dependent cellular cytotoxicity and synergistic action of ADC drugand anti-CD47 mAb. In Aim 3 we plan to use our established protocols of maximal tolerated dosepharmacokinetics biodistribution and anti-tumor efficacy to evaluate the therapeutic values of our combined dualCD276 and CD47 targeting ADCs in our metastatic syngeneic TNBC xenograft models after surgery and/orchemotherapy. If the anti-cancer efficacy is confirmed in the preclinical models this will be the first combinedADCs-based targeted therapy for TNBC treatment which may overcome drug resistance enhance cytotoxicityto tumor cells with low dose limit systemic toxicities and prevent antigen-loss relapse. Importantly our designswill model clinical therapies for potential translational application which would improve life quality and thesurvival rate of TNBC patients in combination with surgery and/or chemotherapy. 438502 +No NIH Category available Biological Assay;Biological Markers;CD8-Positive T-Lymphocytes;Cancer Control;Cells;Cessation of life;Clinical;Clinical Trials;Combination Drug Therapy;Combined Modality Therapy;Complex;Consensus;Data;Development;Disease;Early Intervention;Enrollment;External Beam Radiation Therapy;Financial Hardship;Future;Glycolysis;Image;Immune;Immune checkpoint inhibitor;Immune response;Immuno-Chemotherapy;Immunologic Markers;Immunophenotyping;Immunotherapy;Intervention;Lesion;Ligands;Link;Malignant neoplasm of lung;Metabolic;Monitor;Newly Diagnosed;Non-Small-Cell Lung Carcinoma;Observational Study;Outcome;Patient Selection;Patient-Focused Outcomes;Patients;Pattern;Peripheral;Phenotype;Positron-Emission Tomography;Precision Medicine Initiative;Precision therapeutics;Progression-Free Survivals;Progressive Disease;Proteins;Radiation;Radiation therapy;Radio;Risk;Site;Standardization;Systemic Therapy;Systemic disease;T-Cell Receptor;Therapeutic;Toxic effect;Treatment Efficacy;Treatment-related toxicity;Tumor Volume;United States National Institutes of Health;Validation;X-Ray Computed Tomography;anti-PD-1;biomarker identification;biomarker signature;burden of illness;cancer survival;chemotherapy;circulating biomarkers;clinical imaging;cytokine;disorder control;fluorodeoxyglucose positron emission tomography;high risk;imaging biomarker;improved;improved outcome;individual patient;individual response;irradiation;learning strategy;monocyte;multidisciplinary;outcome prediction;patient stratification;peripheral blood;phase II trial;predictive marker;prognostic value;prognostication;programmed cell death ligand 1;prospective;quantitative imaging;radiation response;radiomics;randomized trial;response;response biomarker;risk stratification;standard of care;support tools;survival outcome;synergism;treatment response;tumor;uptake Biomarkers of Response to Immuno-chemotherapy & oliGometastatic Hypofractionated radioTherapy (BRIGHT) for Lung Cancer: Synergy of PET/CT Imaging and Peripheral Blood Assays NARRATIVEPatients with metastatic non-small cell lung cancer undergo complex combinations of treatments includingchemotherapy immunotherapy and radiation therapy; and while some patients have prolonged cancer controlfrom therapy others develop rapid progression. We propose to assess and monitor treatment response withpositron emission tomography imaging and circulating immunologic biomarkers to improve patient outcomes byquickly detecting patients who are not benefiting from standard of care chemo-immunotherapy and selecting forpatients whose outcomes can be improved with the addition of radiation therapy. Development and validationof combined imaging and circulating biomarkers can support treatments that are adapted to the response ofindividual patients with metastatic non-small cell lung cancer and improve clinical outcomes. NCI 10746779 11/27/23 0:00 PAR-19-363 5R01CA258997-03 5 R01 CA 258997 3 "VIKRAM, BHADRASAIN" 12/20/21 0:00 11/30/26 0:00 Clinical Translational Imaging Science Study Section[CTIS] 11513463 "BOWEN, STEPHEN R." "ZENG, JING " 7 RADIATION-DIAGNOSTIC/ONCOLOGY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 547570 NCI 385770 161800 ABSTRACTManagement of patients with metastatic non-small cell lung cancer (NSCLC) requires navigation of anincreasingly diverse therapeutic landscape. Although immune checkpoint inhibitors (ICI) of anti-programmedcell death 1 (PD1) and its ligand PDL1 in combination with chemotherapy (chemoICI) are standard of care formetastatic NSCLC and have improved survival in some patients the majority are subject to treatment-relatedtoxicity at significant financial burden with little clinical benefit. Radiation therapy can prolong survival inpatients with limited sites of metastatic disease (oligometastatic) or limited sites of progressive disease(oligoprogression) on systemic therapy but no consensus exists on which patients and lesions would benefitfrom irradiation. Patient selection and treatment adaptation through early response assessment is an unmetneed to increase the effective combination of chemotherapy immunotherapy and radiation therapy inmetastatic NSCLC and improve outcomes. Biomarkers are critical to our understanding of complex responsepatterns to chemoICI and radiation. In patients with newly diagnosed metastatic NSCLC starting chemoICI perstandard of care we propose to assess and monitor treatment response by combining positron emissiontomography (PET) imaging of macroscopic disease burden and circulating immunologic biomarkers of occultsystemic disease burden in support of precision therapy through the following aims: (1) construct clinical PETimaging and circulating immunologic biomarker signatures of chemoICI response patterns to risk stratifypatients into (a) early widespread progression (b) oligoprogression and (c) responsive disease; (2) constructclinical PET imaging and circulating immunologic biomarker signatures of oligoprogressive radiation therapyresponse patterns to identify patients and lesions that benefit from ablative radiation; and (3) correlate localizedclinical PET imaging and global circulating immunologic biomarkers with survival outcomes.Fluorodeoxyglucose (FDG) PET scans and peripheral blood draws will be performed prior to chemoICI 3weeks into chemoICI and 12 weeks into chemoICI. For patients who develop oligoprogressive disease we willacquire FDG PET scans and peripheral blood prior to and 1-month post radiation therapy. We will developcombined quantitative PET imaging and circulating immunologic biomarker signatures of chemoICI andradiation response that stratify patients into the following groups: (i) high-risk patients predicted to developrapid widespread progressive disease who require aggressive second-line systemic therapy (ii) moderate-riskpatients predicted to develop oligoprogressive disease who require consolidation radiation to high-risk lesiontargets (iii) low-risk patients predicted to have durable long-term response to first-line therapy. Successfulcompletion of this project will support the launch of a clinical trial on biomarker response-adaptive chemoICIand radiation therapy in patients with metastatic non-small cell lung cancer in order to improve cancer controland survival. 547570 +No NIH Category available Acinar Cell;Biological;Cancer Etiology;Cell Line;Cell Reprogramming;Cells;Cessation of life;Cytoplasm;Data;Development;Diagnosis;Disease;Duct (organ) structure;Genetic;Genetic Transcription;Growth;Heterozygote;Human;In Vitro;Intervention;KRAS oncogenesis;KRAS2 gene;KRASG12D;Knockout Mice;Lesion;Life Expectancy;LoxP-flanked allele;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediator;Metaplasia;Molecular;Mus;Mutation;Outcome Study;PTK2B gene;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pathway interactions;Patients;Phosphorylation;Phosphotransferases;Pre-Clinical Model;Protein Tyrosine Kinase;Proteins;Role;Serine;Signal Pathway;Signal Transduction;Solid;Survival Rate;Testing;Text;Therapeutic Intervention;Tissues;Tyrosine;United States;Validation;Xenograft Model;Xenograft procedure;anticancer activity;anticancer research;antitumor effect;beta catenin;cancer therapy;carcinogenesis;chemotherapy;cofactor;druggable target;gain of function;improved;improved outcome;inhibitor;interest;intestinal tumorigenesis;knock-down;mortality;mouse model;mouse tyrosine kinase 2;mutant;novel;novel strategies;novel therapeutic intervention;p65;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;patient derived xenograft model;pharmacologic;pre-clinical;preclinical evaluation;premalignant;ras Oncogene;research clinical testing;small hairpin RNA;targeted treatment;therapeutic target;therapeutically effective;tumor growth Targeting PYK2 for the treatment of PDAC Development of new treatment strategies that interfere with RAS oncogene-dependent signalingpathways could greatly improve the outcome of PDAC patients. Successful completion of thisstudy will validate PYK2 as a new functionally relevant and pharmacologically actionable targetfor PDAC and PYK2targeted therapy as a novel effective approach to treating PDAC. NCI 10746761 11/14/23 0:00 PA-19-056 5R01CA236965-05 5 R01 CA 236965 5 "XU, WANPING" 12/16/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-MCT2-C(01)S] 7927236 "HU, JING " Not Applicable 12 PHARMACOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 322194 NCI 205875 116319 Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancersand is the third and soon to be the second leading cause of cancer-related deaths in the UnitedStates. The average life expectancy after diagnosis with metastatic disease is just three to sixmonths. There obviously is an urgent and unmet need for novel effective therapeuticapproaches but identifying therapeutic targets that will increase survival rates of PDAC patientsremains one of the greatest challenges in current cancer research. Since nearly 100% ofpancreatic ductal adenocarcinoma (PDAC) carried mutational activation of KRAS KRAS istheoretically ideal candidate for PDAC therapeutic intervention. But targeting KRAS directly hasbeen unsuccessful. As a result there is significant interest in identifying novel downstreameffectors of oncogenic KRAS signaling that could be amenable to pharmacologic intervention.PYK2 (proline-rich tyrosine kinase 2) is a non-receptor cytoplasmic tyrosine kinase which isexpressed at a very low level in normal pancreas. We found that PYK2 was drastically inducedin mouse PanIN (pancreatic intraepithelial neoplasia non-invasive precursor lesions of PDAC)and human PDAC tissues and that PYK2 elevation required KARS and occurred at thetranscriptional level. Functionally our results showed that whole-body deletion of PYK2 evenheterozygous deletion remarkably suppressed PanIN formation in the Pdx1-Cre KRASG12Dmouse model. Further we found that shRNA knockdown of PYK2 abrogated tumor growth in aPDAC cell line xenograft model suggesting that PYK2 is required for PDAC maintenance.Mechanistically our data revealed that PYK2 regulates two cancer-related pathways: the Wnt/-catenin pathway and the NF-B pathway both pathways are known important for PDACgenesis and progression. Overall our preliminary results strongly suggested that PYK2 is a newfunctionally relevant and druggable target for PDAC. Our central hypothesis of this study is thatPYK2 is a novel downstream effector of mutant KRAS signaling essential for PDACcarcinogenesis and maintenance and a new actionable target for treating PDAC. We will test ourhypothesis through the following Specific Aims. Aim 1 will validate the role of PYK2 in mutantKRAS-driven PDAC carcinogenesis. Aim 2 will unravel how PYK2 is hard-wired among mutantKRAS-activated signaling networks. Aim 3 will validate PYK2 inhibition as an actionable andeffective approach to treating PDAC in preclinical models of PDAC. Successful completion of theaims could prove that PYK2-targeted therapy represents an exciting and potentially promisingnew approach to treating pancreatic cancer. 322194 +No NIH Category available Achievement;Adolescence;Adolescent;Affect;Alternative Splicing;Binding;Biological Markers;Biological Models;Brain Neoplasms;CRISPR/Cas technology;CUL9 gene;Cancer Etiology;Cells;ChIP-seq;Child;Clinical;Data;Detection;Development;Disease;Disease model;Down-Regulation;Etiology;Fibroblasts;Future;Gene Expression;Genes;Genetic;Genome;Germ-Line Mutation;Goals;Hereditary Retinoblastoma;Histologic;Human;Impairment;Incidence;Individual;Inherited;Knockout Mice;Li-Fraumeni Syndrome;Link;Lung;Malignant Bone Neoplasm;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Methodology;Missense Mutation;Modeling;Molecular;Mus;Mutation;Non-Hematologic Malignancy;Nonmetastatic;Operative Surgical Procedures;Osteoblasts;Pathologic;Pathway interactions;Patients;Pharmaceutical Preparations;Phenocopy;Proteins;Proteolysis;RB1 gene;RNA Splicing;Research;Research Personnel;Retinoblastoma;Role;Specimen;Spliceosomes;Survival Rate;System;TP53 gene;Technology;Testing;Therapeutic;Tumor Suppressor Genes;Tumor Suppressor Proteins;Ubiquitin;Variant;anticancer research;autosome;bone;cancer genetics;chemotherapy;clinical application;disorder control;exome sequencing;experimental study;genome-wide analysis;human disease;human model;improved;in vitro Model;induced pluripotent stem cell;inhibitor;insight;leukemia;mortality;multicatalytic endopeptidase complex;mutant;new therapeutic target;novel;novel therapeutic intervention;osteosarcoma;pharmacologic;precise genome editing;prevent;promoter;transcriptome;tumor initiation;ubiquitin-protein ligase Dissecting and Targeting RB1-Mutant Osteosarcoma PROJECT NARRATIVE In vitro modeling of human disease has recently become possible due to the remarkable achievements ofhuman induced pluripotent stem cells (iPSCs) and precise genome editing technologies. We propose to applyhereditary retinoblastoma (RB) iPSCs to dissect the pathological mechanisms triggered by RB1 mutation. Thisresearch will have the potential to reveal novel therapeutic targets to treat RB1-mutant osteosarcoma. NCI 10746741 2/3/23 0:00 PA-19-056 5R01CA246130-03 5 R01 CA 246130 3 "MAAS, STEFAN" 3/1/21 0:00 2/28/26 0:00 Skeletal Biology Development and Disease Study Section[SBDD] 11718725 "LEE, DUNG-FANG " Not Applicable 18 BIOLOGY 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF MEDICINE 770305400 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 404808 NCI 281297 123511 PROJECT SUMMARY/ABSTRACT Bone cancer is one of the most common primary malignancies in children and adolescents. Osteosarcomacomprises almost 60% of the common histological subtypes of bone sarcoma. While the five-year survival rate ofnon-metastatic disease hovers at approximately 70% metastatic disease most often to the lungs is associatedwith survival rates of 15% to 30%. Despite advances in surgery and multi-agent chemotherapy lack ofunderstanding of the molecular mechanisms of osteosarcomagenesis has prevented significant improvement inthe survival of patients over the past 40 years. This malignancy makes osteosarcoma one of the leading causesof cancer mortality among children and adolescents. Therefore elucidation of the function of individualosteosarcoma-associated genes (e.g. RB1 and p53 tumor suppressor genes) to explore the possible pathologicalmechanisms involved in osteosarcoma initiation development and progression is critical for future osteosarcomadetection and treatment. Induced pluripotent stem cells (iPSCs) is one of the most promising platforms recognized by cancerresearchers. Recently several groups including us successfully apply patient-derived iPSCs to phenocopy cancerfeatures explore disease mechanisms and screen therapeutic drugs. These findings strongly suggest patient-derived iPSCs is a feasible system to model and dissect cancer etiology. Patients with hereditary retinoblastoma(RB) an inherited autosomal dominant cancer disorder caused by germline mutations/deletions in the RB1 tumorsuppressor gene have increased >400 fold incidence of osteosarcoma which provides a perfect model systemto study the role of RB1 in osteosarcomagenesis. Our preliminary studies revealed that an increase of spliceosome genes in RB iPSC-derived osteoblasts.These results lead to our central hypothesis that an altered spliceosome function is important for facilitating tumorinitiation and development in RB1-mutant osteosarcoma. Guided by strong preliminary data we plan to utilize RBpatient-derived iPSC disease model to pursue three Specific Aims to elucidate the pathological mechanismsinvolved in RB1-mutant osteosarcoma: (1) To elucidate how loss of RB1 contributes to upregulated spliceosomegene expression. (2) To evaluate the therapeutic potential of splicing modulators for osteosarcoma treatment. (3)To define the role of CUL9 in regulating RB1 function. Collectively our proposed research will broadly impact the osteosarcoma field by characterizing theessential role of spliceosome in regulating RB1-mutant osteosarcoma development. These studies will also havepotential to uncover novel molecular mechanisms regulating RB1 proteolysis controlled by CUL9 tumorsuppressor. Successful completion of the proposed experiment will add valuable and novel insights to a broadrange of fields including cancer genetics dysregulation of spliceosome gene expression and ubiquitin-proteasome proteolytic pathway each of which bears potential clinical applications for osteosarcoma treatment. 404808 +No NIH Category available Antibody-drug conjugates;Automobile Driving;Biography;Biological Markers;Biological Products;Bladder;Breast Cancer Patient;Cancer Patient;Chemotherapy and/or radiation;Cisplatin;Clinic;Clinical;Combined Modality Therapy;DNA Damage;Data;Disease;Event;Foundations;Gene Expression;Genetic;Genetic Transcription;Genomics;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Immune;Immune checkpoint inhibitor;Immune system;Immunologic Factors;Immunologics;Immunotherapy;International;Malignant neoplasm of urinary bladder;Modality;Molecular;Mutation;Oncology;Outcome;Pathogenesis;Patients;Radiation;Radiation Tolerance;Radiation therapy;Radiobiology;Research;Research Personnel;Resistance;Robin bird;Roentgen Rays;Testing;Therapeutic;Treatment Efficacy;Work;antitumor effect;cancer therapy;cancer type;checkpoint therapy;chemotherapy;immune checkpoint blockade;improved;improved outcome;innovation;insight;multidisciplinary;multimodality;next generation;preservation;programs;radiation effect;radiation resistance;radiation response;radiomics;response;standard of care;treatment strategy;tumor Genomic and Microenvironmental Determinants Temporal Dynamics and Treatment Efficacy of Radiation-Based Combination Therapies PROJECT NARRATIVEOverall Section This proposal focuses on elucidating the genomic and microenvironmental determinants and temporaldynamics underlying efficacy of radiation-based combination therapies. We will use an innovative molecularcharacterization trial testing radiation plus antibody-drug conjugate in bladder cancer and radiation plusimmunotherapy in head and neck cancer to characterize the mechanistic drivers underlying these nextgeneration RT-based therapies. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. NCI 10746700 3/20/23 0:00 PA-21-071 3U54CA274513-01S1 3 U54 CA 274513 1 S1 "VIKRAM, BHADRASAIN" 2/1/23 0:00 1/31/25 0:00 9306964 "CHAN, TIMOTHY AN-THY" "YU, DAVID SUNG-WEN" 11 INTERNAL MEDICINE/MEDICINE 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 2/1/23 0:00 7/31/23 0:00 397 Research Centers 2023 36982 NCI 22970 14012 PROJECT SUMMARYOverall Section Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants andtemporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT) alone orin combination with other treatments is used to treat about two-thirds of all cancer patients. Despite thewidespread use of radiation therapy in oncology our understanding of the mechanisms driving response andresistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy andresistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus onusing combination therapies in which radiation is used with systemic agents highlighting the urgent need tounderstand the drivers of efficacy. Among the most promising new biologics being studied for use withradiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use aninnovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI inhead and neck cancer to characterize the mechanistic drivers underlying these next generation RT-basedcombinations. The central hypothesis of this U54 application is that specific genetic and immunologicmechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will addressthese questions through 3 specific aims. In Aim 1 we will work to understand the molecular mechanisms thatunderlie efficacy of treatment with radiation plus ADC. Here our working hypothesis is that specific genetic andimmunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage ourmolecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservationtherapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT +SG. In Aim 2 we will improve identification of patients who are sensitive or resistant to RT-based therapiesbased on new insights into transcriptional dynamics and temporal reprogramming during treatment withradiation-based therapies. Here we will leverage our molecular characterization trial treating head and necksquamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG orICI. We will build on recent experimental and clinical breakthroughs led by our research groups which haveidentified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim3 we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT +immune checkpoint blockade. Here using our head and neck trial (Part B) we will uncover the unique geneticand immunologic factors that govern response to RT when combined with these two classes of agents. Wewill elucidate the differential molecular effects of the two approaches immune reprogramming andmechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. 36982 +No NIH Category available Achievement;Antibodies;Biocompatible Materials;CAR T cell therapy;CD28 gene;CD3 Antigens;Cell Therapy;Cells;Clinical;Clinical Data;Cytotoxic T-Lymphocytes;Development;Disease Progression;Engraftment;Hematopoietic Neoplasms;Hour;Immune system;In Situ;In Vitro;Methods;Patients;Phenotype;Population;Procedures;Production;Public Health;Research;Specificity;Techniques;Time;Training;Translating;bioscaffold;career;chimeric antigen receptor;chimeric antigen receptor T cells;cost;experimental study;health disparity;improved;manufacture;manufacturing facility;manufacturing process;programs;success;tumor Biomaterial Scaffolds for Ex Vivo and In Situ CAR-T Cell Production RELEVANCE TO PUBLIC HEALTHCAR-T cell therapy drafts a patients immune system (cytotoxic T cells) to target and kill tumors and itscombination of pin-point specificity and broad efficacy has translated into exciting clinical data and revolutionarytreatment for certain blood cancers. The major impediment to widespread use of CAR-T therapy remains its costwhich approaches $500K a slow manufacturing process and huge regulatory hurdles for facilities thatmanufacture CAR-T cells. We will develop biomaterial approaches to CAR-T cell therapy including improvedmethods to reprogram cells to release cells quickly to tumors and even to generate the CAR-T cells entirelywithin a patients own body. NCI 10746676 4/5/23 0:00 PA-21-071 3R37CA260223-03S1 3 R37 CA 260223 3 S1 "SALOMON, RACHELLE" 4/16/21 0:00 3/31/26 0:00 Biomaterials and Biointerfaces Study Section[BMBI] 11876861 "BRUDNO, YEVGENY " Not Applicable 2 ENGINEERING (ALL TYPES) 42092122 U3NVH931QJJ3 42092122 U3NVH931QJJ3; XRPPWZ3TK937 US 35.784675 -78.677233 578204 NORTH CAROLINA STATE UNIVERSITY RALEIGH RALEIGH NC BIOMED ENGR/COL ENGR/ENGR STA 276957514 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 85053 NCI 60710 24343 PROJECT SUMMARYDespite unprecedented clinical success of chimeric antigen receptor (CAR)-T cell therapy against tumorswidespread application is limited by lengthy and labor-intensive ex vivo manufacturing procedures that result in:(i) very high costs of therapy of up to half of a million dollars; (ii) delays of weeks or months to infuse CAR-T cellsto patients with rapidly progressing disease; and (iii) heterogeneous composition and terminal differentiation ofinfused CAR-T cells as a result of ex vivo culture that limit CAR-T cell engraftment and persistence. Despitesignificant achievements in this space reducing the time costs and regulatory burden remains a deep unmetneed in CAR-T cell therapy and significant reducing or eliminating ex vivo procedures remains a critical unmetneed. The research outlined in this proposal develops new biomaterials approaches to reduce the time and effortto produce CAR-T cells in vitro to enhance CAR-T cell phenotype and function. We propose that a short (~hour)pre-activation step with anti-CD3/CD28 antibodies can be immediately followed by transduction and deliveryusing a biomaterial scaffold. This diversity supplement will support Dr. Trey Davis and allow him to participate innew experiments to extend the scope of Aim 1 studies and will allow him to receive robust training in associatedtechniques professional development and career planning. We expect that our results will provide a basis for ageneral cellular therapeutic strategy and promote widespread patient access especially to populations that havebeen the victims of health disparities. 85053 +No NIH Category available Award;Malignant neoplasm of lung;Parents;Research;novel therapeutics Understanding and exploiting novel therapeutic vulnerabilities of RIT1-driven lung cancer PROJECT NARRATIVEPer the FOA this section is not required. The research supplement proposal does not change the activities ofthe parent award. NCI 10746645 3/31/23 0:00 PA-21-071 3R37CA252050-03S2 3 R37 CA 252050 3 S2 "XU, WANPING" 4/1/21 0:00 3/31/26 0:00 Molecular Oncogenesis Study Section[MONC] 11639678 "BERGER, ALICE " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 77845 NCI 44230 33615 PROJECT SUMMARY/ABSTRACTPer the FOA this section is not required. The research supplement proposal does not change the activities ofthe parent award. 77845 +No NIH Category available Academia;Address;Artificial Intelligence;Biodistribution;Biological;Cell Death;Cell Nucleus;Cells;Clinic;Clinical;Computational Technique;Computer Models;Cytoplasm;DNA Double Strand Break;Data;Dimensions;Disparate;Dose;Double Strand Break Repair;Elements;Foundations;Geometry;Goals;Gold;Grant;High-LET Radiation;Home;Human;Immune;Immunotherapy;In Vitro;Industry;Injections;Intestines;Investigation;Kinetics;Knowledge;Literature;Mediating;Mitochondria;Modeling;Molecular;Monte Carlo Method;Nanotechnology;Normal tissue morphology;Operative Surgical Procedures;Pathologic;Prediction of Response to Therapy;Publications;Radiation;Radiation Dose Unit;Radiation Oncology;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Rectal Cancer;Recurrence;Research Infrastructure;Resolution;Roentgen Rays;Solid;Structure;Techniques;Testing;Time;Tissue Model;Toxic effect;Translating;Translations;Transmission Electron Microscopy;Tumor Tissue;chemoradiation;chemotherapy;clinical implementation;clinical translation;clinically relevant;dosage;experience;fluorescence imaging;high resolution imaging;improved;in vivo;innovation;ionization;irradiation;mathematical model;multidisciplinary;nano;nanoGold;nanoscale;novel;novel imaging technique;pharmacologic;predictive modeling;radiation response;receptor internalization;receptor mediated endocytosis;response;synergism;treatment strategy;tumor;tumor DNA Rational translation of gold nanoparticle mediated radiosensitization to the clinic Increasing the radiation dose delivered to rectal cancers treated preoperatively can improvepathological response at the time of surgery and possibly even obviate the need for surgery butthis has been challenging to implement in the clinic due to the limited radiation tolerance of thesurrounding normal intestinal loops. Gold nanoparticles that preferentially accumulate in tumorsoffer the possibility to increase radiation dose within the tumor without damaging adjacentnormal tissues. To amplify this radiation dose enhancement we propose to advance clinicaltranslation of a paradigm using gold nanoparticles that home to the tumor get internalized byreceptor-mediated endocytosis disperse in the cytoplasm via co-administered pharmacologicalagents and can be modeled by mathematical techniques that predict the biologicalconsequences of tumor accumulation. NCI 10746610 1/26/23 0:00 PA-21-268 7R01CA257241-03 7 R01 CA 257241 3 "PRASANNA, PAT G" 1/13/21 0:00 12/31/25 0:00 Nanotechnology Study Section[NANO] 8547492 "KRISHNAN, SUNIL " "CHO, SANG HYUN" 18 NEUROSURGERY 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF MEDICINE 770305400 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 395 Non-SBIR/STTR 2023 640366 NCI 493568 146798 The use of high atomic number (Z) elements as radiosensitizers of tumors has been well documented in theliterature over the last few decades. In particular gold nanoparticles (GNPs) typically defined as high-Z goldstructures with the longest dimension smaller than 100 nm have been the subject of active investigation for thesame purpose for the past 15 years. Early in vivo demonstration of GNP-mediated radiosensitization (GMR)effect was based on passive accumulation of GNPs within tumors (passive targeting). While resulting in aremarkable level of GMR this approach generally requires clinically less relevant radiation quality (low energykilovoltage x-rays) and clinically unachievable (without direct injection) gold concentration (up to 7mg gold pergram of tumor). To overcome these difficulties we have been investigating an alternative approach based onactive targeting which shows a promising outlook for clinical translation in the near term. This proposal seeksto surmount the remaining challenges associated with our active targeting-based approach before embarkingon clinical translation of GMR. Specifically we aim to identify the molecular mechanism of GMR biodistributionand kinetics of GNPs developed for clinical translation their fate at the tumor and cellular levels and thecorrelation between GNP-mediated dose enhancement and GMR. Despite abundant data and publications onGMR accumulated over the years critical knowledge gaps still exist in terms of the aforementioned aspectshindering clinical translation of GMR. As demonstrated in our preliminary data we propose to address suchissues that hold the key for clinical translation of GMR through concerted multidisciplinary efforts. Uponachieving this goal a pilot human trial of GNP-enhanced radiation therapy (RT) will also be conducted withinthis project for the management of recurrent rectal cancer. Overall we will pursue three Specific Aims shownbelow to achieve the goals of this project. (1) To determine the molecular mechanism of GMR thebiodistribution/kinetics of GNPs in vitro and in vivo and the radiosensitization efficacy in clinically relevanttreatment scenarios (2) To correlate GNP-mediated dose enhancement and GMR using high resolutionimage-based cell/tissue models and nanoscale computational techniques and (3) To conduct a pilot humantrial of GNP-enhanced RT for previously radiated recurrent rectal cancers. Ultimately this project would lay thefoundation for widespread applications of the currently envisioned RT paradigm that enables more potent andtumor-specific RT with less toxicity. 640366 +No NIH Category available Aftercare;Animals;Apoptotic;Award;BCL1 Oncogene;Breast Cancer Cell;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Characteristics;Chemotherapy and/or radiation;Cytolysis;Disease;Effectiveness;Exposure to;Goals;Growth;Immune;Immune response;Immune system;Malignant Neoplasms;Mammary Neoplasms;Mediating;Modeling;Natural Killer Cells;Nature;Parents;Patients;Phenotype;Population;Property;Protein Family;Recovery;Recurrent Malignant Neoplasm;Recurrent disease;Residual Neoplasm;Residual state;Sequential Treatment;Site;Sorting;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Treatment Protocols;Tumor-infiltrating immune cells;Xenograft procedure;anti-tumor immune response;cancer recurrence;cell growth;chemotherapy;design;immunogenic cell death;in vivo;mortality;mouse model;neoplastic cell;prevent;senescence;therapeutic effectiveness;treatment response;tumor A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells Parent Award Narrative Statement (R01CA260819)This project is designed to evaluate the capacity of senolytic agents to eliminate breast tumor cells induced intosenescence by chemotherapy and radiation with studies in both cell culture and tumor bearing animals and toidentify the contribution(s) of the immune system to the effectiveness of this therapeutic strategy. NCI 10746519 9/21/23 0:00 PA-21-071 3R01CA260819-03S1 3 R01 CA 260819 3 S1 "VENKATACHALAM, SUNDARESAN" 3/1/21 0:00 2/28/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 1884001 "GEWIRTZ, DAVID A." "HARADA, HISASHI ; LANDRY, JOSEPH WILLIAM" 4 PHARMACOLOGY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 43892 NCI 30144 13748 Parent Award Abstract/Summary (R01CA260819)Chemotherapy and radiation can induce breast tumors to enter a prolonged state of growth arrest withcharacteristics of senescence. A senescent-like state is also characteristic of residual tumor cells that surviveafter chemotherapy and/or radiation have eliminated the bulk of a tumor cell population. Tumor cells survivingtherapy-induced senescence have the capacity to recover proliferative capacity subsequent to their prolongedgrowth arrest. Recovery and re-emergence of tumor cells from this growth-arrested state could contribute todisease recurrence months or years after the patient has apparently been cured of the primary disease. Several agents have recently been identified as having senolytic properties [e.g. ABT-263 (navitoclax)]which can selectively kill senescent cells. Given that disease recurrence and consequent cancer mortality isfrequently associated with the re-emergence of proliferative tumor cells either at the primary disease site ormetastatic sites a primary goal of this project will be to test the hypothesis that senolytic agents can eliminatetherapy induced senescent breast tumor cells to prevent or at least significantly suppress cancer recurrence. Aim 1 will examine the hypothesis that the senolytic agent ABT-263 can efficiently eliminate cellsinduced into senescence by chemotherapy or radiation when used sequentially (and potentially repeatedly) afterthe initial therapy. Sensitivity to senolytics will be assessed in senescence-sorted breast tumor cells prior tosenescence and during the course of recovery and in residual populations surviving after the bulk of the tumorpopulation has been eliminated by therapeutic agents. The effectiveness of a sequential treatment schedule willalso be assessed in vivo using xenograft and PDX tumor models. Aim 2 will interrogate the mechanisms whereby the senolytic ABT-263 promotes cell death in senescentbreast tumor cells with a focus on the contributions of pro- and anti-apoptotic BCL-2 family proteins. Aim 3 will examine the immune response to therapy-induced senescent cells alone and after treatmentwith senolytics. A phenotypic assessment of tumor infiltrating immune cells and studies with selective immunecell depletion in mouse models will define the nature (adaptive and innate) of the antitumor immune response.Ex vivo studies will further determine NK- and T cell-mediated lysis of senescent cells in the absence or presenceof ABT-263. The ability of senolytics to induce immunogenic cell death will be a focus. Toxicity to the host willbe compared for exposure to senolytics concomitant with chemotherapy (i.e. prior to entry into senescence) andsubsequent to induction of senescence. 43892 +No NIH Category available Ablation;Amino Acids;Antioxidants;Cancer Intervention;Catabolism;Cysteine;Cystine;Data;Dipeptides;Gamma-glutamyl transferase;Glutathione;Glycine;Goals;Growth;Malignant Neoplasms;Mammary Neoplasms;Mediating;Plasma Cells;Research;Source;Supplementation;Testing;Therapeutic;Tissues;Tumor Promotion;Work;cancer cell;cancer subtypes;cancer therapy;cell growth;cysteinylglycine;experimental study;extracellular;in vivo;interest;novel;therapeutic target;triple-negative invasive breast carcinoma;tumor;tumor growth;tumorigenesis Impact of extracellular glutathione catabolism on triple-negative breast cancer Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. We havemade the surprising discovery that the antioxidant glutathione (GSH) functions extracellularly not intracellularlyto support TNBC growth. Our research will challenge the paradigm of antioxidant function in cancer by describinga novel mechanism of GSH function as a circulating source of amino acids and has the potential to reveal acompletely new set of therapeutic targets for TNBC intervention. NCI 10746501 3/31/23 0:00 PA-21-071 3R01CA269813-02S1 3 R01 CA 269813 2 S1 "WILLIS, KRISTINE AMALEE" 4/18/22 0:00 1/31/27 0:00 Tumor Cell Biology Study Section[TCB] 12481152 "HARRIS, ISAAC SPENCER" Not Applicable 25 GENETICS 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 3/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 59863 NCI 38872 20991 Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited treatment options. There isan emerging interest in blocking antioxidants for cancer therapy but how antioxidants promote cancer growth isunclear. Glutathione (GSH) is the most abundant antioxidant in the body and our previous work has shown thatGSH promotes tumorigenesis of triple-negative breast cancers (TNBC). It is generally assumed that GSH actsintracellularly as an antioxidant in cancer cells. However our preliminary studies show that blocking intracellularGSH synthesis does not impede TNBC growth. These surprising results suggest an alternative mechanismwhere extracellular GSH supports breast tumor growth. The overarching goal of this proposal is to determinehow extracellular GSH promotes tumor growth. It is known that extracellular GSH is present in plasma but cellscannot import GSH. Instead GSH is metabolized by gamma-glutamyl transferase (GGT1) to produce a glutamyl-dipeptide and cysteinylglycine which yields cystine and glycine. Indeed we find that ablation of GSH synthesisin vivo not only lowers circulating GSH but also reduces the levels of cysteinylglycine cysteine and glycine intissues. Further we show that supplementation with GSH and cysteinylglycine can rescue TNBC growth uponcystine depletion in GGT1-dependent and -independent manners respectively. Together these preliminary datasuggest an alternative mechanism where GSH functions as a circulating source of metabolites rather than as adirect antioxidant. In this proposal we describe experiments that will test the hypothesis that the catabolism ofextracellular GSH by tumor GGT1 supports TNBC growth. In Aim 1 we will elucidate the impact of extracellularGSH on TNBC growth. In Aim 2 we identify the reliance of TNBC on GGT1-mediated GSH catabolism. In Aim3 we will determine the mechanisms by which cysteinylglycine supplies cysteine for TNBC growth. Our researchwill challenge the paradigm of antioxidant function in cancer by describing a novel mechanism of GSH functionas a circulating source of amino acids. Further these studies have the potential to reveal a completely new setof unrealized targets and therapeutic strategies for TNBC. 59863 +No NIH Category available Anatomy;Automobile Driving;BCL6 gene;Biological;Biological Markers;Biology;CD4 Positive T Lymphocytes;Cells;Cellular immunotherapy;Clinical;Clinical Management;Collection;Cutaneous;Cutaneous Lymphoma;Cutaneous T-cell lymphoma;D Cells;DNA sequencing;Data;Dermal;Dermis;Development;Disease;Disease Management;Enzymes;Epidermis;Fatty acid glycerol esters;Functional disorder;Future;Gene Mutation;Genes;Genetic;Genetic Markers;Genetic Transcription;Genomics;Goals;Hemophagocytic Lymphohistiocytoses;Homing;Human;Immunologics;Immunology;Immunophenotyping;Inflammatory;Institution;Interferon Type II;Knowledge;Life;Lymphocyte;Lymphoma;Lymphomagenesis;MAP Kinase Gene;Malignant Neoplasms;Molecular;Molecular Analysis;Morbidity - disease rate;Mutation;Non-Hodgkin's Lymphoma;Organ;Patients;Pattern;Phenotype;Physiological;Prognosis;RHOA gene;Research;Sampling;Skin;Skin Cancer;Somatic Cell;Somatic Mutation;Southern Blotting;Stimulus;Syndrome;T-Cell Lymphoma;Testing;Time;Tissues;Tumor Burden;Visceral;antibody mimetics;clinical heterogeneity;clinical phenotype;clinically actionable;cohort;cytokine;disease phenotype;disease prognosis;effective therapy;familial hemophagocytic lymphohistiocytosis;high dimensionality;mortality;mutant;new therapeutic target;novel;receptor;therapeutic target;transcription factor;transcriptome sequencing; T cells Mechanisms of Lymphomagenesis of Skin Resident Gamma Delta T cells PROJECT NARRATIVEWe propose to study a large multi-institutional cohort of gamma delta T cell lymphomas to identify the biologicalbasis of this disease. NCI 10746459 12/15/23 0:00 PA-20-185 5R01CA260064-03 5 R01 CA 260064 3 "JHAPPAN, CHAMELLI" 12/13/21 0:00 11/30/26 0:00 "Arthritis, Connective Tissue and Skin Study Section[ACTS]" 10995631 "CHOI, JAEHYUK " Not Applicable 5 DERMATOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 412288 NCI 301445 110843 PROJECT SUMMARYPrimary cutaneous gamma delta T cell lymphomas (PCGDTLs) are a collection of highly aggressive incurablenon-Hodgkin lymphoma of the skin-homing T cell. Median survival is 31 months. Five-year survival is 19.9%.Without a fundamental understanding of disease pathophysiology there has been little progress in the last fewdecades. A critical unmet need is to uncover novel therapeutic targets via elucidation of basic diseasemechanisms. Lymphoma phenotypes are determined by a combination of somatic mutations and cell of origin.To elucidate the genomic transcriptional and cellular origins of PCGDTLs we have assembled a large multi-institutional cohort of samples representing diverse clinical phenotypes. By analyzing high-dimensional genomicand immunological data we hypothesize that we can identify the molecular basis of this disease. Importantlythese studies represent a serendipitous opportunity to elucidate the biology of skin-resident gamma delta T cellsa poorly understood but likely important lymphocyte in human skin. 412288 +No NIH Category available Acute Myelocytic Leukemia;Address;Adoptive Transfer;Affect;Agonist;Area;Aryl Hydrocarbon Receptor;Biological Assay;Biology;Cell Line;Cell Lineage;Cell Maturation;Cell physiology;Clinical;Clinical Research;Coculture Techniques;Data;Defect;Detection;Development;Disease;Disease Progression;Family;Future;Genes;Goals;Growth;Hematologic Neoplasms;Homeostasis;Human;Hyperactivity;Immune;Immune Evasion;Immunologic Surveillance;Immunotherapy;Interleukin-2;Knockout Mice;Knowledge;Label;Leukemic Cell;Ligands;Lymphoid Cell;Maintenance;Malignant - descriptor;Malignant Neoplasms;Measures;Modeling;Mus;Myeloid Cells;Natural Killer Cells;Outcome;Pathologic;Pathway interactions;Patients;Phenotype;Play;Population;Proliferating;Publishing;Receptor Activation;Receptor Inhibition;Receptor Signaling;Regulatory T-Lymphocyte;Relapse;Research;Role;Solid Neoplasm;Support Groups;Survival Rate;T-Cell Development;T-Cell Proliferation;Testing;Therapeutic;Tissues;Transgenic Mice;Treatment Efficacy;acute myeloid leukemia cell;aryl hydrocarbon receptor ligand;cancer cell;cell type;conditional knockout;cytokine;cytotoxic;design;improved;in vivo;inhibitor;innovation;leukemia;member;mouse model;novel;older patient;patient derived xenograft model;pharmacologic;stem cells;targeted treatment;transcription factor;tumorigenic Group 1 Innate Lymphoid Cell Dysregulation in Acute Myeloid Leukemia PROJECT NARRATIVEThe aims described in this application seek to determine novel mechanisms of group 1 ILC dysregulation inacute myeloid leukemia (AML). We propose an innovative approach to discover the mechanism(s) leading toexpanded ILC1 populations in AML and to determine the functional significance of these expanded populationson overall disease progression. Successful completion of these studies will address critical knowledge gaps inour understanding of how ILCs function in disease states especially the setting of AML. NCI 10746445 12/5/23 0:00 PA-21-049 5F30CA250244-03 5 F30 CA 250244 3 "BIAN, YANSONG" 1/3/22 0:00 12/31/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 14669028 "LORDO, MATTHEW " Not Applicable 3 PATHOLOGY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 "Training, Individual" 2024 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) is a common and aggressive hematologic malignancy caused by a pathologicexpansion of immature myeloid cells. Despite significant research efforts spanning 50 years the 5-year survivalrate in AML has remain relatively unchanged at <27.4% underscoring the need for innovative approaches totreatment. Natural killer (NK) cells are a member of the group 1 innate lymphoid cell (ILC) family that play apivotal role in the detection and elimination of leukemic cells. However we and others have previously shownthat AML is able to inhibit NK cell maturation promoting disease progression. Mechanistically we have shownthat AML blasts are capable of secreting agonists for the aryl hydrocarbon receptor (AHR) transcription factorwhich inhibits NK cell maturation and function. Accumulating evidence suggests that AHR is required for themaintenance of a related group 1 ILC subset termed an ILC1. Notably ILC1s have been shown to be pro-tumorigenic in solid tumor mouse models. Therefore we hypothesize that AML is able to skew ILC populationsto suppress immune-surveillance by NK cells while promoting ILC1s. Preliminary data from our group supportthis hypothesis by demonstrating that AML is capable of expanding ILC1 populations in a tissue-specific mannerin an AML mouse model. Furthermore we predict that these ILC1s are functionally hyperactive in the setting ofAML and promote disease progression. Our long-term goal in this project is to determine how AML leads todysregulation of group 1 ILCs and to elucidate the downstream consequences on AML progression. Thus ouraims are 1) to identify and characterize the mechanism(s) which promote ILC1 expansion in AML and 2) todetermine the functional consequences of expanded ILC1 populations in AML. To address these aims we willuse a combination of ex vivo and in vivo studies. First we will determine whether AML promotes ILC1 expansionthrough interconversion from NK cells skewing of ILC progenitors towards an ILC1 phenotype and/or from directproliferation of ILC1s. We will also use transgenic mouse models to assess the contribution of Ahr and ILC1-derived cytokines in promoting AML progression. By identifying these mechanisms we will be able to bettertarget these pathways to restore group 1 ILC homeostasis and inform the development of future immune-basedtherapies. This project represents a novel and innovative approach to targeted therapy in AML by focusing onhow leukemia targets ILC populations an area which has been understudied to date. Successful completion ofthese studies will fill in critical knowledge gaps of how ILCs are dysregulated in AML and how these cells can betargeted therapeutically to improve patient survival. 52694 +No NIH Category available Capsid;Cell membrane;Cell surface;Cell-Matrix Junction;Cells;Chimeric Proteins;Collaborations;Coupled;Cryoelectron Microscopy;Crystallography;Cytosol;Data;Dengue Virus;Detection;Dimensions;Double Stranded RNA Virus;E protein;Electron Microscopy;Electrons;Elements;Event;Experimental Designs;Flavivirus;Fluorescence Microscopy;Foundations;Goals;Grant;In Vitro;Infection;Ions;Label;Light;Lipid Bilayers;Liposomes;Mediating;Membrane;Membrane Fusion;Membrane Proteins;Methods;Microscopy;Modeling;Molecular;Molecular Conformation;Mutation;Outcome Study;Pathogenesis;Pathway interactions;Penetration;Perforation;Process;Productivity;Property;Proteins;RNA Viruses;RNA chemical synthesis;Recombinant Proteins;Recombinants;Resolution;Rhesus;Rotavirus;Site;Structure;System;Testing;Time;Tropism;Viral;Viral Proteins;Virion;Virus;Virus Assembly;Virus-like particle;Visualization;West Nile virus;Work;cell type;design;experimental study;human pathogen;imaging study;live cell imaging;movie;novel strategies;particle;recombinant virus;reconstitution;single molecule;uptake Structure and Assembly of Viruses NarrativeThe mechanism by which viruses enter cells determines crucial aspects of cell tropism host range andultimately pathogenesis. We combine advanced methods in cryo-EM and live-cell imaging to determinemolecular mechanisms of entry for broad classes of viruses using two groups of major human pathogens --flaviviruses and rotaviruses -- as models. NCI 10746443 11/14/23 0:00 PA-19-056 5R01CA013202-51 5 R01 CA 13202 51 "AMIN, ANOWARUL" 6/1/75 0:00 11/30/24 0:00 Macromolecular Structure and Function C Study Section[MSFC] 1857787 "HARRISON, STEPHEN COPLAN" Not Applicable 7 Unavailable 76593722 Z1L9F1MM1RY3 76593722 Z1L9F1MM1RY3 US 42.337481 -71.104964 1504801 BOSTON CHILDREN'S HOSPITAL BOSTON MA Independent Hospitals 21155724 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 378338 NCI 213750 164588 "SummaryThe structure of a virus particle must conform to the mechanism by which it enters and infects a cell. We seekto relate structures of virus particles and viral surface proteins to mechanisms of the steps in cell attachmentuptake and penetration that initiate a productive infection. The proposed experiments take advantage of recentadvances in electron cryomicroscopy (cryo-EM) and live-cell imaging to define these mechanisms for both non-enveloped and enveloped viruses taking rotaviruses and flaviviruses (West Nile and dengue viruses inparticular) as specific examples. Previous live-cell imaging studies defined the cellular entry pathway forrhesus rotavirus (RRV). We can now relate structures we have determined for distinct conformations of thespike-like viral protein 4 (VP4) which mediates cell entry to stages of plasma-membrane remodeling in theentry pathway. We will extend on-going analyses by cryo-EM of VP4 conformations at the membrane interfaceboth on cells and in an in vitro-reconstituted system for early steps to determine how RRV deforms and thendisrupts a membrane bilayer. A mechanism for RRV membrane perforation suggested by preliminary datamay help unify observations made with several other RNA viruses. Proposed experiments will connect high-resolution structures with direct analyses (by electron cryotomography and potentially by high-resolutiontemplate matching) of VP4 conformations during cell entry and with sequences of events in time (by lattice-light-sheet microscopy). For the flavivirus fusion protein (the ""E protein"") completing a structure for thepostfusion conformation of the intact protein will enable design of experiments to trap fusion intermediates andthus to define the fusion mechanism more completely than hitherto possible. The intended outcomes of thestudies for both rotaviruses and flaviviruses are structurally and mechanistically accurate ""molecular movies""of viral entry." 378338 +No NIH Category available Age;Apoptosis;BCL1 Oncogene;BCL2 gene;Back;Binding;Biology;Bromodomain;C-terminal;CRISPR screen;Cell Line;Cell model;Cells;Chromatin;Complex;Core-Binding Factor;Coupled;DNA Binding;DNA Polymerase II;Dependence;Dysmyelopoietic Syndromes;Engraftment;Enhancers;Exhibits;Exons;Familial Platelet Disorder;Genes;Genetic Transcription;Germ-Line Mutation;Growth;Hematopoiesis;Hematopoietic stem cells;Heterozygote;Homologous Transplantation;In Vitro;Induction of Apoptosis;Introns;Length;Libraries;Malignant - descriptor;Maps;Mediating;Messenger RNA;Mus;Mutation;Myeloproliferative disease;Network-based;Oncogenes;Outcome;Patients;Prognosis;Protac;Protein Isoforms;Proteins;RNA;RUNX1 gene;Reader;Recurrent disease;Repression;Residual state;Resistance;Risk;Somatic Mutation;Time;Transcriptional Activation Domain;Transcriptional Regulation;antagonist;autosome;chemotherapy;chromatin protein;cofactor;epigenome;graft vs host disease;homoharringtonine;improved;in vivo;inhibitor;knock-down;loss of function mutation;mutant;new therapeutic target;novel;novel therapeutics;patient derived xenograft model;pre-clinical;preclinical efficacy;recruit;small hairpin RNA;stem cells;targeted treatment;transcription factor;transcriptome Biology and novel therapy of AML expressing somatic or germline mutant RUNX1 Narrative:Studies proposed will elucidate impact of mutant RUNX1 on epigenome/transcriptome as wellas efficacy of novel BETP antagonist-based combinations against AML expressing somaticRUNX1 mutation. These studies will also interrogate the efficacy of novel expression mimickers(EMs) of RUNX1 knockdown alone or in designated rational combinations against in vitro andin vivo cellular models of AML expressing somatic or germline mtRUNX1. NCI 10746429 11/15/23 0:00 PA-19-056 5R01CA255721-04 5 R01 CA 255721 4 "KONDAPAKA, SUDHIR B" 12/1/20 0:00 11/30/25 0:00 Developmental Therapeutics Study Section[DT] 1863849 "BHALLA, KAPIL " "DINARDO, COURTNEY ; FISKUS, WARREN CAMPBELL" 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 447219 NCI 276061 171158 Project Summary:RUNX1 is the DNA-binding subunit of the core binding factor (CBF) complex and a master-regulatortranscription factor which is involved in normal and malignant hematopoiesis. Somatic heterozygous RUNX1mutations commonly occur in Myelodysplastic Syndrome (MDS) (10%) as well as in secondary (s) or de novoAML (~10%). Germline mutations in RUNX1 cause the highly penetrant (~40%) autosomal dominant FamilialPlatelet Disorder (FPD) which can evolve into myeloid malignancy (FPD-MM). Majority of mutant (mt) RUNX1behave mostly as loss of function mutations conferring relative therapy-resistance and poorer survival inpatients with AML. Consequently there is a strong unmet need to develop novel therapies for AML expressingsomatic or germline mtRUNX1. Our preliminary studies have demonstrated for the first time that shRNA-mediated knockdown of RUNX1 (mutant and wild-type) or disruption of its binding to CBF induces greaterlethality in AML progenitor cells (HPCs) expressing mtRUNX1 compared to wild-type (wt) RUNX1. We alsofound that the +24kb enhancer (eR1) within the intragenic super-enhancer (SE) of RUNX1 regulates itstranscription in AML cells. The chromatin reader BET (Bromodomain Extra-terminal) protein (BETP) BRD4promotes transcription of RUNX1 and its targets. BRD4 degradation or eviction from chromatin or gene-editingof the +24kb RUNX1 eR1 induces lethality in AML cells. By determining and utilizing the mRNA signature fromRUNX1-depleted (by shRNA) AML cells we queried through LINCS1000-CMap (Connectivity Mapping)analysis for expression mimickers (EMs). We identified novel EMs that repress RUNX1 and its targets andinduce significantly more apoptosis of AML cells expressing mtRUNX1 versus wtRUNX1. Therefore thehypothesis motivating our studies is that knocking down of levels of RUNX1 and its targets will induce lethalitynot only in AML blasts expressing somatic mtRUNX1 but also in FPD/MM HPCs expressing germlinemtRUNX1. The specific aims of studies proposed are: AIM 1: To determine impact on active enhancerstranscriptome and pre-clinical in vitro and in vivo efficacy of BETP antagonist along with its co-repression ofRUNX1 BCL2 and CDK6 alone or in combination with BCL2 or CDK6 inhibitor in AML blasts and patient-derived xenograft (PDX) models expressing somatic mutant RUNX1. Additionally we will evaluate pre-clinicalefficacy of co-targeting CRISPR-Cas9 screen-discovered top druggable dependencies along with BETPantagonist against AML blasts expressing somatic mtRUNX1. AIM 2: To elucidate pre-clinical in vitro and invivo efficacy of the EMs homoharringtonine (omacetaxine) or fedratinib alone and in combination with BETPantagonists against patient-derived AML blasts and PDX models expressing somatic mtRUNX1. AIM 3: Todetermine pre-clinical in vitro and in vivo efficacy of selected EMs that repress RUNX1 and its targets againstpatient-derived HPCs from FPD-MM expressing germline mtRUNX1 and other somatic co-mutations versusHPCs from RUNX1-FPD expressing only germline mtRUNX1. 447219 +No NIH Category available Apoptosis;B-Cell Lymphomas;Biochemical;Biological;Biology;Biomechanics;Cells;Coculture Techniques;Data;Dependence;Development;Engraftment;Event;Extracellular Matrix;Fibroblasts;Generations;Genetic;Genetic Transcription;Genotype;Goals;Growth;Immune;Immune Evasion;Immune response;Immunity;Immuno-Chemotherapy;Immunosuppression;In Vitro;Knockout Mice;Lead;Lymphoma;Lymphoma cell;Lymphomagenesis;Malignant Neoplasms;Mediating;Mesenchymal;Molecular;Mus;Mutation;Oncogenic;Pathogenesis;Pathway interactions;Patients;Phenotype;Population;Privatization;Process;Proliferating;Regulatory T-Lymphocyte;Research;Role;Solid Neoplasm;Spontaneous Remission;Stromal Neoplasm;Testing;Therapeutic;Translating;Treatment-related toxicity;biomechanical test;cancer cell;cancer infiltrating T cells;heat-shock factor 1;human disease;implantation;insight;large cell Diffuse non-Hodgkin's lymphoma;mechanical properties;molecular subtypes;mouse model;novel;novel therapeutic intervention;novel therapeutics;permissiveness;pre-clinical;prognostic value;programs;supportive environment;trait;transcription factor;transcriptomics;tumor;tumor eradication;tumor growth;tumor microenvironment;tumorigenesis Role of the stromal microenvironment in B-cell lymphoma progression and immune escape Project NarrativeThe purpose of our studies is to identify novel therapeutic vulnerabilities for a common type of aggressivelymphoma (diffuse large B-cell lymphoma) by understanding the role of lymphoma associated fibroblasts thatare part of the tumor microenvironment. We will determine the mechanisms that fibroblasts utilize to sustainlymphoma cell grow and to decrease the lymphoma immune response. If successful these studies will launchthe development of specific and likely low-toxicity treatments that could benefit patients with incurablelymphomas. NCI 10746427 11/17/23 0:00 PA-19-056 5R01CA242069-05 5 R01 CA 242069 5 "JHAPPAN, CHAMELLI" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-MCT2-C(01)S] 9987337 "CERCHIETTI, LEANDRO C" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 471597 NCI 324320 147277 PROJECT SUMMARY/ABSTRACTThis project focus in the biology of diffuse large B-cell lymphoma (DLBCL) that are common aggressivemalignancies with a curability rate of 65% despite intensive chemoimmunotherapy. DLBCLs display an array ofgenetic alterations that define molecular subtypes and strong dependence on the microenvironment for survival.We hypothesize that reprogramming of the stromal microenvironment is critical for the oncogenicity of hallmarkmutations that mediate lymphoma progression and immune evasion. We propose to elucidate the roles of thecancer-associated fibroblasts (CAF) and extracellular matrix (ECM) components of the lymphomamicroenvironment to identify therapeutic vulnerabilities. CAFs are derived from healthy fibroblasts that have beenreprogrammed by cancer cells into a novel biological entity. Our long-term goal is to therapeutically exploitreprogrammed CAFs with consideration of genetically-defined DLBCLs. For this reason it is critical to elucidatethe mechanisms involved in CAF reprogramming. Not all CAFs are reprogrammed in the same way. Moreoverrather than a terminal effect CAF reprogramming as a transcriptionally dynamic process that allows theestablishment of a variety of adaptive phenotypes. Our preliminary data suggest the activation of shared andprivate pathways in the reprogramming of CAFs. We specifically identify and studied the role of HSF1 one ofthe shared transcription factors in CAFs. CAFs without HSF1 failed to produce an ECM with the biochemicalcomposition and mechanical properties required for lymphoma progression. Concomitantly lack of HSF1 in theTME allowed the establishment of an effective lymphoma immune response leading to tumor eradication. Weplan to test our central hypothesis and accomplish the objective of this application by pursuing these specificaims: Aim 1. Elucidate mechanisms of CAFs reprogramming that sustain genetically diverse DLBCLs:We will identify CAFs sub-populations and ECM composition in genetic DLBCL subtypes; and identify molecularpathways and reprogramming factors across and within CAFs sub-populations using HSF1 as lead effector. Aim2. Elucidate the role of CAFs in functionalizing the ECM for immune evasion. We will characterizebiomechanical and biochemical constraints imposed by CAFs to an effective lymphoma immunity. Aim 3.Determine the therapeutic impact of targeting CAFs in genetic DLBCL subtypes. We will determine theanti-lymphoma effect of co-targeting CAFs and lymphoma cells in molecularly-defined pre-clinical DLBCL murinemodels. The studies that we propose will provide significant insights on the mechanisms of stromal TMEreprogramming for the establishment of genetically defined DLBCLs and will contribute towards development ofnovel therapeutic strategies focused on targeting the stromal TME in these entities to increase curability. 471597 +No NIH Category available Adjuvant;Anti-Inflammatory Agents;Apoptotic;Bioinformatics;Biological;Biological Assay;Cell Maturation;Cells;Cessation of life;Chemotherapy and/or radiation;Clinical;Collection;Cross Presentation;Cytotoxic Chemotherapy;Data;Data Set;Dendritic Cells;Dose;Environment;Exposure to;Failure;Fractionation;Gene Expression Profile;Genes;Genetic Transcription;HMGB1 gene;Heat shock proteins;IRF3 gene;Immune;Immunity;Immunologic Adjuvants;Immunotherapy;In Vitro;Inflammatory;Interferons;Intervention;Knock-out;Link;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Myelogenous;Myeloid Cells;NF-kappa B;Necrosis;Outcome;Pancreas;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Pre-Clinical Model;Process;RNA;Radiation therapy;Regulation;Research Design;Residual Neoplasm;Sampling;Signal Transduction;Stimulator of Interferon Genes;T cell response;T-Lymphocyte;Testing;Therapeutic;Toll-like receptors;Transcriptional Regulation;Treatment Failure;Tumor Biology;Tumor Immunity;Tumor-associated macrophages;cancer cell;cancer type;checkpoint therapy;chemotherapy;environmental enrichment for laboratory animals;extranuclear DNA;immune function;immunogenic;improved;improved outcome;in vivo;novel;pancreatic cancer model;patient population;patient response;patient subsets;prevent;response;sensor;success;tumor Rewiring the myeloid cell response to adjuvants to improve tumor control Macrophage suppression of T cell responses in the tumor immune environment represents an importantproblem limiting cure of residual disease following radiation therapy. We use high quality preclinical models ofradiation therapy and immunotherapy to understand the mechanisms of success and failure in myeloidsuppression of the T cell control of tumors. This is combined with analysis of clinical samples to explore how anovel mechanistic interaction between immune cells determines immune mediated tumor control. NCI 10746426 11/29/23 0:00 PA-19-056 5R01CA244142-05 5 R01 CA 244142 5 "BUCHSBAUM, JEFFREY" 12/2/19 0:00 11/30/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 10127825 "GOUGH, MICHAEL JAMES" Not Applicable 3 Unavailable 99142093 C11KXJTP6ED1 99142093 C11KXJTP6ED1 US 45.527846 -122.613886 2574706 PROVIDENCE PORTLAND MEDICAL CENTER PORTLAND OR Independent Hospitals 972132933 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 339694 NCI 205875 133819 The critical preliminary data for this proposal is that contrary to the accepted dogma following exposure toendogenous immune adjuvants MyD88 delivers a negative signal to macrophages that limits tumor control byradiation therapy. We demonstrate that in poorly immunogenic tumors macrophages are rewired followingexposure to dying cancer cells such that they suppress multiple features of the tumor immune environment.This includes the ability of T cells to control residual disease and dendritic cell maturation. The aim of thisproposal is to understand the mechanisms by which this suppression occurs identify the regulation ofmacrophage suppression and use this to identify patient populations that will respond poorly to currenttherapies. We hypothesize that exposure to dying cells rewires macrophage signaling such that innateactivation of MyD88 suppresses local tumor immunity. The specific aims of this study are to 1: Test thehypothesis that loss of MyD88 prevents NFKB driven-anti-inflammatory gene transcription and results inincreased IRF3 driven IFN transcription; 2: Test the hypothesis that signaling through Mertk-mediated rewiringof macrophages changes the response to adjuvants limiting immune function in the tumor environment; and 3:Test the hypothesis that MyD88 patterns of gene expression are linked to poor patient outcome. Our studydesign incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using arange of RT doses and fractionations. These are combined with unique knockouts and assays that allow us toidentify divergent myeloid responses in vitro and in vivo. Our analyses of clinical samples use high qualitybioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological responseto innate adjuvants in patient samples. 339694 +No NIH Category available ATAC-seq;Address;Affect;American;Antibodies;Benign;Binding;CRISPR/Cas technology;Cell Line;Cell Nucleus;Cell Proliferation;Cells;ChIP-seq;Chimeric Proteins;Chromatin;Chromosome inversion;Complex;Data;Data Correlations;Data Set;Development;Diagnostic;Distal;EP300 gene;Enhancers;Fibroblasts;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Fusion;Gene set enrichment analysis;Genes;Genetic Transcription;Genomics;Growth;HL-60 Cells;HL60;Histones;Individual;Lung;Malignant - descriptor;Malignant Neoplasms;Measurement;Measures;Mesenchymal;Mesenchymal Cell Neoplasm;Micro Array Data;Modeling;Molecular;Multiprotein Complexes;Mutation;Nuclear;Oncogene Deregulation;Oncogenes;Oncogenic;Pathogenesis;Play;Positioning Attribute;Process;Proliferating;Proteins;RNA;RNA Polymerase II;RNA analysis;Recurrence;Repression;Resources;Role;STAT6 Transcription Factor;STAT6 gene;Solitary Fibrous Tumor;Stains;System;Testing;Time;Transactivation;Transcription Coactivator;Tumor Suppressor Genes;Work;cytokine;differential expression;genetic corepressor;inducible gene expression;novel diagnostics;novel therapeutics;programs;rare cancer;recruit;response;therapeutic target;transcription factor;transcriptome sequencing;tumor;tumorigenesis The molecular function of the oncogenic NAB2-STAT6 fusion protein Project NarrativeSolitary Fibrous Tumors (SFTs) are an understudied tumor with an unclear pathogenesis about a fifth of casesbecome malignant and unresponsive to treatments. There are no known recurring mutations in SFTs other thanan intra-chromosomal inversion that leads to a gene fusion between NAB2 and STAT6 which produces achimeric protein with an unknown function. Understanding the role the NAB2-STAT6 fusion protein plays in geneexpression will lead to greater understanding of SFTs development and progression to malignancy and mayelucidate therapeutic targets for the treatment of SFTs. NCI 10746424 12/7/23 0:00 PA-21-051 5F31CA265257-03 5 F31 CA 265257 3 "SCHMIDT, MICHAEL K" 12/1/21 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16482191 "HILL, CONNOR MACKENZIE" Not Applicable 3 GENETICS 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 "Training, Individual" 2024 35133 NCI 35133 0 Project Summary Solitary Fibrous Tumors (SFTs) are a mesenchymal tumor type that affects an estimated 10000Americans each year. 10-20% of these tumors become malignant and unresponsive to treatments. Thepathogenesis of SFTs is currently unknown as there are no recurring mutations in known tumor suppressorsgenes or oncogenes. The only recurring mutation identified in SFTs is a gene fusion between NAB2-STAT6 thatresults in a fusion protein. NAB2 and STAT6 are both transcription regulators. NAB2 is repressor of early growthresponse transcription factors (EGR1/2) and STAT6 is an activator of transcriptional programs in response tocytokines. Both proteins also contribute to enhancer activation. Despite both proteins' known functions howNAB2-STAT6 affects gene expression in SFTs is unknown. Using the gene set enrichment analysis (GSEA) of a large microarray data set of SFTs we have foundthat the expression of both NAB2 and EGR1 targets were significantly upregulated in SFTs. However theexpression of STAT6 targets was unchanged. We expressed NAB2-STAT6 and performed ChIP-seq analysisand found that NAB2-STAT6 localizes to distal active transcriptional enhancers. Lastly we analyzed RNA-seqand saw that almost 2000 genes were differentially expressed in Malignant tumors vs Benign tumors includingseveral genes which are regulated by well characterized transcriptional enhancers. We hypothesize that NAB2-STAT6 aberrantly activates EGR1 targets to increase proliferation and highjacks the activity of transcriptionalenhancers to promote malignancy. We have generated the intra-chromosomal inversion responsible for NAB2-STAT6 expression in thebenign lung fibroblast IMR90 cell line which replicates the mesenchymal origin of SFTs using CRISPR-Cas9. InAim 1 we will establish NAB2-STAT6s role in directing aberrant gene expression. We will characterize thegenomic binding profile of NAB2-STAT6 as well as its effect on gene expression and proliferation. In Aim 2 wewill investigate the ability of NAB2-STAT6 to reprogram transcriptional enhancers to promote malignancy. Firstwe will develop an inducible NAB2-STAT6 system to measure the ability of NAB2-STAT6 to reprogramtranscriptional enhancers. Then we will validate our results in primary SFTs and examine differences inmalignant vs benign tumors. Finally we will examine the ability of transcriptional enhancer changes to affectgene expression through analysis of RNA-seq of primary SFTs. Overall these aims will establish the function ofNAB2-STAT6 in promoting tumorigenesis in SFTs 35133 +No NIH Category available Address;Adjuvant Therapy;Adult;Affinity;Allogenic;Antigens;Autologous;Autologous Dendritic Cells;Avidity;Binding;CD8 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cells;Cessation of life;Cetuximab;Chimeric Proteins;Clinical Trials;Clone Cells;Cross Reactions;Data;Dendritic Cells;Disease;Engineering;Epidermal Growth Factor Receptor;Epitopes;Excision;FDA approved;Future;Goals;HLA-A2 Antigen;Haplotypes;Health;HepG2;Hepatocyte;Human;Human Engineering;Hybridomas;Immunization;Immunotherapy;In Vitro;Incidence;Interleukin-15;Lesion;Libraries;Light;Liver;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Memory;Methods;Mus;Normal Cell;Normal tissue morphology;Operative Surgical Procedures;PIK3CG gene;Patients;Peptides;Pharmaceutical Preparations;Physiologic pulse;Primary carcinoma of the liver cells;Process;Protocols documentation;Recurrence;Research;Safety;Scanning;Signal Transduction;Specificity;System;T-Cell Activation;T-Cell Proliferation;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;T-cell receptor repertoire;Testing;Tissues;Toxic effect;Transgenic Organisms;Tumor Tissue;Vaccines;Xenograft Model;alpha-Fetoproteins;antitumor effect;clinical trial readiness;cross reactivity;cytotoxicity;effective therapy;hepatocellular carcinoma cell line;in vivo;man;neoplasm immunotherapy;neoplastic cell;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;response;safety study;single cell sequencing;stem;stemness;success;tumor;vaccination strategy TCR engineering of human T cells for immunotherapy of hepatocellular carcinoma Project narrative Liver cancer especially hepatocellular carcinoma (HCC) is the fastest growing cancer in US with noeffective treatment. We are conducting research to identify HCC-specific T cell receptor (TCR) that can beused to engineer human T cell to become highly effective TCR-Ts to kill tumor cells without causing significanttoxicity to normal cells. This proposal allows us to gather sufficient data to apply for clinical trials and eventuallyleads to new immunotherapy for hepatocellular carcinoma. NCI 10746423 11/20/23 0:00 PA-18-484 5R01CA235159-06 5 R01 CA 235159 6 "BOURCIER, KATARZYNA" 12/7/18 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6181802 "HE, YUKAI " Not Applicable 12 BIOCHEMISTRY 966668691 N4WWJC8T2593 966668691; 809593387 JJJNQAJY5RN6; N4WWJC8T2593 US 33.470962 -81.991405 676605 AUGUSTA UNIVERSITY AUGUSTA GA SCHOOLS OF MEDICINE 309120004 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 308632 NCI 200411 108221 Project Summary Liver cancer is the 6th most common cancer and the 4th most common cause of cancer death in theworld. According to CDC the incidence rate of liver cancer has doubled over last 20 years making it thefastest growing cancer in US. It is estimated that there will be 42220 new cases and 30200 death of livercancer in 2018. Thus we are addressing an increasing health problem in US. Although liver resection iscurative the lack of adjuvant therapy becomes a critical barrier to the success of surgery resulting in ~70%5yr recurrence rate. Thus novel therapies are urgently needed and immunotherapy has a great potential.Majority (80-90%) of liver cancer is hepatocellular carcinoma (HCC) which re-express alpha fetoprotein (AFP).Engineering patients autologous T cells with AFP epitope-specific T cell receptor (TCR) genes offers a specificimmunotherapy for HCC. Currently one AFP158-specific high-affinity TCR just got approved for clinical trial inMay of 2017. But high-affinity TCRs may cause severe on- and off-target toxicity. We reason that it will requirea panel of TCRs with different affinity to find the optimal TCRs that enable human T cells to kill HCC tumorcells without toxicity. Thus we propose to identify multiple AFP-specific TCRs and test their antitumor efficacyand toxicity. We hypothesize that an effective in vivo immunization strategy will induce potent human AFP(hAFP)-specific CD8 response with diverse TCR repertoire in HLA-A2 mice. This large number of CD8 cellsenables us to directly study their antitumor function and identify a panel of TCRs with different affinityincreasing the chance of finding the optimal TCRs to create TCR-Ts of potent antitumor effect without toxicity.To test this hypothesis we have developed a concrete research strategy with three specific aims. A1: IdentifyhAFP158-specific TCRs to create TCR-Ts of different functional avidity; A2: Identify the hAFP158-specific TCRswithout or with minimal cross-reactivity; and A3: Create expandable and removable TCR-Ts with stemness toachieve potent in vivo antitumor effect. The goals are to obtain the optimal TCR genes that can engineerprimary human T cells to become effective TCR-Ts capable of killing human HCC cells without harming normalcells and to establish protocol for generating safe and effective TCR-Ts that are ready for clinical trials. In theend applications for an investigative new drug and clinical trial will be filed. This will eventually lead to newtherapeutic approach for HCC. In addition the methodical approach of creating AFP-specific TCR library andidentifying optimal TCRs with potent antitumor effect and no toxicity will serve as a platform for other antigensand HLA haplotypes which will greatly impact the field of tumor immunotherapy. 308632 +No NIH Category available 3-Dimensional;Address;Algorithms;Benign;Biopsy;Blood;Blood flow;Breast;Breast Cancer Detection;Breast Cancer Model;Breast Cancer Risk Factor;Breast Magnetic Resonance Imaging;Clinical;Clutterings;Complement;Contrast Media;Data;Data Science;Data Set;Dedications;Detection;Development;Diagnostic Factor;Diagnostic Imaging;Engineering;Fatty acid glycerol esters;Floor;Frequencies;Functional Imaging;Goals;Hemoglobin;Human body;Hypoxia;Image;Individual;Lasers;Lesion;Literature;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Maps;Methods;Modeling;Morphology;Motor;Mus;Noise;Optics;Partner in relationship;Patient imaging;Performance;Population;Predictive Value;Prognostic Factor;Radiation;Real-Time Systems;Recommendation;Reporting;Resolution;Risk;Rodent Model;Rotation;Scanning;Sensitivity and Specificity;Signal Transduction;Site;Specificity;Speed;System;Techniques;Technology;Testing;Time;Tissues;Transducers;Ultrasonic Tomography;Ultrasonography;Update;Visualization;Woman;absorption;angiogenesis;breast imaging;breast lesion;breast scanner;contrast enhanced;contrast imaging;convolutional neural network;cost;design;human study;imaging modality;imaging system;improved;interest;intravenous injection;malignant breast neoplasm;mammary;mouse model;optoacoustic tomography;photoacoustic imaging;premalignant;real-time images;screening;standard of care;structural imaging;technology development;technology validation;tomography;transmission process;tumor;ultrasound;vector;volunteer Quantitative volumetric ultrasonic and photoacoustic tomography NarrativeWe will develop an ultrafast and very high resolution system for tomographic ultrasound and photoacousticimaging. This system can enhance the sensitivity of breast lesion detection and will be used to reduce benignbiopsies through the methods developed here. NCI 10746408 11/10/23 0:00 PA-20-185 5R01CA258807-03 5 R01 CA 258807 3 "WANG, YISONG" 12/15/21 0:00 11/30/26 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 1872588 "FERRARA, KATHERINE W" "POPLACK, STEVEN " 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 587692 NCI 373269 214423 AbstractOur central goal is to create a volumetric real-time system combining ultrasound (US) and photoacoustic (PA)tomography (USPAT) for high resolution structural and functional imaging. The recent development of highchannel count ultrafast US systems creates the opportunity to capture volumes at a high frame rate.Tomography defined as a technique for displaying a representation of a cross section through a human bodyfacilitates high resolution (lamba/2) imaging by effectively rotating the US point spread function to reduce theeffect of diffraction. We have developed an ultrafast US capability mated to a tomographic ring of transducersand scanned in depth by motorized acquisition. Leveraging the ultrafast capability provides the opportunity foracquisition of volumetric functional breast images within 1 minute. The acquisition is controlled by 1024 coherentchannels of Verasonics imaging systems (to be increased to 2048) and includes embedded GPUs for real-timeimaging and analysis. When operated at 5 MHz the resulting spatial resolution is nearly isotropic in plane withresolution of ~ half a wavelength (in this case ~150 microns). Compared to US images acquired withconventional imaging the image quality is far improved. Ultrasound methods are attractive for integration intobreast management due to their utility in guiding biopsy and the very highsensitivity (97.3%) that can be achieveby combining ultrasound with conventional screening.Both transmission and reflection tomography modes willbe evaluated in order to facilitate both high resolution reflective modes and highly quantitative transmissionimaging. PA imaging (PAI) is particularly well suited to complement US and improve diagnostic imaging of thebreast. Our immediate goal is to reduce the number of biopsies required in women undergoing breast screening.Photoacoustic tomography (PAT) enhances the signal to noise ratio and visualization of morphology overconventional PAI. Healthy breast tissue has low optical absorption and US scattering allowing for highly efficientPAT. Since abnormally increased vasculature and hemoglobin at tumor sites produces strong intrinsicphotoacoustic contrast PAT is ideally suited for visualizing angiogenesis. Further PAT can assess the relativeoxygenation of a region. With our combined strategy we will evaluate characterization algorithms based oneach feature blood flow oxygenation and structural changes assessing the sensitivity of individual andcombined imaging features. With a first study of this technique in a mouse model of premalignant to malignanttransformation and a human study of lesion characterization we will determine whether USPAT can add to thesensitivity and specificity of lesion characterization by MRI. Our resulting specific aims are to: 1) implement andintegrate blood mapping US tomography and PAT for breast imaging 2) assess the sensitivity and specificityof the resulting system in a rodent model of breast cancer and 3) apply these new capabilities to image patientswith MRI detected abnormalities recommended for biopsy. 587692 +No NIH Category available 3-Dimensional;ATAC-seq;Address;Automobile Driving;Back;Beds;Biological;Cancer Model;Cell Differentiation process;Cells;ChIP-seq;Chemoresistance;Chromatin;Chromatin Structure;Complex;Computer Analysis;Computer Models;Coupled;Coupling;Data;Disease;Environment;Epigenetic Process;Event;Feedback;Frequencies;Gene Expression;Genetic Transcription;Genome Mappings;Genomics;Goals;Hi-C;Image;Imaging Device;Imaging Techniques;Imaging technology;Knowledge;Malignant Neoplasms;Malignant neoplasm of ovary;Maps;Modality;Modeling;Modification;Molecular;Molecular Analysis;Molecular Computations;Molecular Conformation;Outcome;Pathway interactions;Pattern;Phenotype;Platinum;Pluripotent Stem Cells;Population;Property;Recurrence;Relapse;Repression;Research;Resistance;Resolution;Resources;Science;Source;Technology;Testing;Theoretical model;Tissues;Universities;Work;cancer cell;cancer stem cell;chemotherapy;conventional therapy;epigenome;epigenomics;frontier;genome-wide;genomic profiles;high resolution imaging;histone modification;imaging modality;imaging platform;in vivo;inhibitor;innovation;nanoimaging;nanomaterials;nanoscale;physical property;pressure;programs;refractory cancer;self-renewal;single cell mRNA sequencing;stem cell therapy;stem cells;stemness;stressor;superresolution imaging;targeted agent;technology development;technology research and development;transcription factor;transcriptional reprogramming;transcriptome;transcriptomics;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenic Research Test-Bed Unit n/a NCI 10746400 12/20/23 0:00 RFA-CA-21-002 5U54CA268084-03 5 U54 CA 268084 3 12/10/21 0:00 11/30/26 0:00 ZCA1-SRB-X 8881 6681816 "MATEI, DANIELA E" Not Applicable 5 Unavailable 160079455 EXZVPWZBLUE8 160079455 EXZVPWZBLUE8 US 42.050479 -87.680046 6144601 NORTHWESTERN UNIVERSITY Chicago IL Domestic Higher Education 606114579 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 502023 557078 241428 Research Test-Bed Unit: PROJECT SUMMARYThe overall goal of the U54 Northwestern University Center for Chromatin Nanoimaging in Cancer (NU-CCNIC)is to develop and deploy a multi-scale chromatin nanoimaging platform together with molecular analyses andcomputational modeling to characterize chromatin structure and transcriptional patterns associated with thecancer stem cell (CSC) and chemoresistance phenotype. The immediate application of the proposed studies willbe ovarian cancer a malignancy of unmet need. It has been speculated that CSCs represent the reservoir fromwhich recurrent chemotherapy-resistant tumors arise. The key biological question addressed by this Center iswhether reprogramming of the transcriptome through epigenetic and chromatin organization-regulatedmechanisms leads to significant transcriptional plasticity which is critical for CSCs to withstand and survivestressors in the tumor environment driving tumor initiation and progression. As part of NU-CCNIC the ResearchTest-Bed Unit (RTB) will provide source materials for the nanoimaging technologies developed by theTechnology Development Unit (TECH). These resources include cells and tissues at various transition pointsbetween stem cell and non-stem cell phenotypes and between chemotherapy-sensitive and resistant states. Thestudies conducted by the RTB will test the applicability of the Nanoscale Chromatin Imaging and Analysis (nano-ChIA) platform and provide feedback to optimize its use. In addition the RTB will perform state-of-the-artcomputational genomic analyses of CSCs and chemotherapy-resistant cells including single-cell mRNAsequencing and genome mapping (e.g. Hi-C ATAC-sequencing and ChIP-sequencing). The specificobjectives of this unit are: 1) To identify CSC-specific epigenomic features and 3D chromatin packingconformations by integrating genome-wide maps of chromatin accessibility contact frequency and geneexpression networks with high resolution nano-scale chromatin imaging features. 2) To identify whether thetransition to a chemotherapy-resistant state promotes stemness-like chromatin packing and conformation. Locusspecific epigenetic manipulations will be coupled with high resolution imaging technologies to investigateresistant-state specific 3D chromatin packing and its relation to the CSC state. 3) To discover how globalepigenome manipulations induced by small enzymatic inhibitors block stemness and chemo-resistance throughalterations of chromatin packing. In all the integrated interrogation of cancer through chromatin nanoimagingmethods (TECH) and genome-wide mapping (RTB) will discover how transcriptional plasticity of CSCs andchemo-resistant cancer cells is regulated. The project is at the forefront of the field by using highly innovativemolecular and nanometer-scale chromatin imaging technologies to better understand the relationship betweenhigher level chromatin structure and key drivers of stemness and chemo-resistance in a disease that remainslethal and difficult to treat. +No NIH Category available Adenoviruses;Antibodies;Binding;Binding Proteins;Binding Sites;Bioinformatics;Biological;Biological Assay;Biological Process;Capsid;Capsid Proteins;Cell Differentiation process;Cells;Central Nervous System;Clinic;Communication;Computational Biology;Cre lox recombination system;Dependovirus;Development;Disease;Dose;Engineering;Environment;Epitopes;Evolution;Gene Delivery;Gene Transduction Agent;Gene Transfer;Generations;Genes;Genetic;Genetic Diseases;Goals;Homologous Gene;Human Genome;Immune response;Immune system;Immunity;Immunoprecipitation;In Vitro;Inflammation;Innate Immune Response;Investigation;Knock-in;Knock-out;Learning;Lentivirus;Maps;Measures;Mediating;Mentorship;Messenger RNA;Methods;Molecular Biology;Monitor;Mus;Nucleic Acid Binding;Nucleic Acids;Organ;Pathogenicity;Patients;Protein Secretion;Proteins;RNA;RNA Binding;Reporter;Research;Research Personnel;Retroelements;Retrotransposon;Retroviridae;Risk;Role;Serum;Structure;System;T cell response;Techniques;Technology;Tertiary Protein Structure;Therapeutic;Tissues;Tropism;Validation;Viral;Viral Vector;Virus;Work;bioluminescence imaging;body system;candidate identification;cell type;cytokine;delivery vehicle;design;env Gene Products;extracellular vesicles;gene therapy;genome sequencing;human embryonic stem cell line;immunogenic;immunogenicity;in vivo;intercellular communication;interest;mammalian genome;mutant;nanoparticle;nervous system disorder;nucleic acid delivery;programs;response;self assembly;side effect;skills;stem cells;therapeutic gene;tool;vector Interrogation of retroelement-derived proteins for functional gene transfer Project NarrativeThe goal of gene therapy is to precisely treat diseases by delivering nucleic acids that strike at the genetic root of thedisease. However a key bottleneck in the application of these technologies are appropriate delivery vehicles that do notinitiate strong immune responses. Here we propose to utilize mammalian virus-like proteins to engineer fully endogenousvectors that have the potential for efficient modular and non-immunogenic nucleic acid delivery for eventual applicationsin neurological disease treatment. NCI 10746395 8/30/23 0:00 PA-21-051 5F31CA275339-02 5 F31 CA 275339 2 "ODEH, HANA M" 9/1/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F05-D(21)L] 78099172 "LASH, BLAKE " Not Applicable 7 ENGINEERING (ALL TYPES) 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA BIOMED ENGR/COL ENGR/ENGR STA 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 43631 NCI 43631 0 Project Summary and AbstractGene therapy enables the treatment of a large number of genetic diseases through delivery of nucleic acids striking at theroot of the disease. This is advantageous because it is highly modular allowing for a number of different cargo nucleicacids to be delivered depending on the disease cause. As such the ideal gene therapy delivery vector would be able tocarry a variety of cargo deliver this in a targeted manner and accommodate a range of cargo sizes. There are a number oftechniques utilized to deliver nucleic acids including viral systems like adenovirus adeno-associated virus (AAV) andlentivirus as well as non-viral methods including nanoparticles. Although these therapies can be successful a keylimitation to currently used vectors is the immune response which can lead to ineffective delivery of nucleic acid cargo.There is currently a need to develop effective and non-immunogenic delivery vehicles for gene therapy for a wide range ofdiseases including neurological disease for which effective delivery vehicles have yet to be designed.To this end mammalian genomes contain numerous virus-like genes some of which have been co-opted by their hostcells for important functions. Among these are homologs of gag which encodes the capsid protein. We hypothesize thatendogenous genes encoding a capsid domain have the ability to self-assemble into capsids and mediate intercellularcommunication by binding secreting and delivering nucleic acid cargos. We propose to explore and re-engineerendogenous capsid-containing proteins for use as gene therapy vectors. We hypothesize that delivery vehicles composedentirely of self proteins will be more effective than standard vectors as they could be non-immunogenic. Here we proposeto use an approach combining in vitro characterization re-engineering and in vitro and in vivo validation to identifycandidate proteins and learn how they can be re-engineered. These systems will ideally be modular having bothprogrammable cargo and tropism to treat a range of diseases. We hope that by identifying and re-engineering thesesystems the resulting fully endogenous delivery vehicle will be useful for efficient reprogrammable andnon-immunogenic gene delivery.With the goal of becoming an independent investigator this project will also support development of computationalbiology skills molecular biology expertise as well as mentorship and scientific communication skills. These will besupported by the excellent research environment at the Broad Institute and MIT. 43631 +No NIH Category available Administrator;Advocate;Award;Back;Beds;Biomedical Engineering;Biomedical Research;Cancer Biology;Cancer Center;Cancer Patient;Chromatin;Collaborations;Communication;Communities;Comprehensive Cancer Center;Decision Making;Development;Educational workshop;Engineering;Ensure;Equity;Evaluation;Event;Fostering;Funding;Goals;Human Resources;Image;Imaging Techniques;Infrastructure;Knowledge;Leadership;Malignant Neoplasms;Mission;Modeling;Monitor;Patients;Process;Program Evaluation;Publications;Quality Control;Recommendation;Records;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resource Allocation;Resource Sharing;Resources;Schedule;Schools;Site Visit;Specialist;Techniques;Testing;Training;Underrepresented Minority;Universities;Validation;Veterans;Work;anticancer research;cancer imaging;cancer stem cell;cancer therapy;data quality;data sharing;design;diversity and equity;diversity and inclusion;equity diversity and inclusion;experience;graduate school;improved;innovation;medical schools;meetings;member;minority health;molecular modeling;nanoimaging;programs;recruit;research data dissemination;synergism;technology development;technology research and development;tumor progression;web site Administration and Coordination Core n/a NCI 10746394 12/20/23 0:00 RFA-CA-21-002 5U54CA268084-03 5 U54 CA 268084 3 12/10/21 0:00 11/30/26 0:00 ZCA1-SRB-X 8879 7125025 "BACKMAN, VADIM " Not Applicable 5 Unavailable 160079455 EXZVPWZBLUE8 160079455 EXZVPWZBLUE8 US 42.050479 -87.680046 6144601 NORTHWESTERN UNIVERSITY Chicago IL Domestic Higher Education 606114579 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 207846 340848 163482 Administrative and Coordination Core: PROJECT SUMMARYThe proposed Northwestern University Center for Chromatin NanoImaging in Cancer (NU-CCNIC) will bringtogether leading cancer research biologists from the Robert H. Lurie Comprehensive Cancer Center in theFeinberg School of Medicine and world-renowned imaging and molecular modeling specialists from theMcCormick School of Engineering with the goal of facilitating innovation and application of cutting-edge imagingtechniques to help solve some of the most pressing problems in cancer biology research. The Administrativeand Coordination Core (ACC) will be led by PI Vadim Backman. The day-to-day administration of the NU-CCNICwill be managed by the Center Administrator who will be responsible for maintaining all records relative to thisaward and ensuring communication synergy and resource sharing across the NU-CCNIC. Additionally Centeradministration will be supported by a Program Manager who in collaboration with the Center Administrator willbe responsible for the development of the NU-CCNIC website scheduling meetings and events facilitating thesharing of resources determine whether there will be pre-publication data sharing across the NU-CCNIC andaid in conversations about data quality control cross validation and reproducibility. An External Advisory Panel(EAP) will be formed bringing together investigators with expertise in fields related to cancer stem cell plasticityand chromatin nanoimaging. The EAP is envisioned as a group of highly active members engaged to advise theNU-CCNIC leadership on scientific direction and review progress evaluation research strategies andimplementation leadership and dissemination all in the effort to maximize the impact of the NU-CCNIC. TheNU-CCNIC will enhance the translational value and potential impact of its research by engaging a CancerResearch Advocate who will be a member of the EAP and will be invited to attend NU-CCNIC workshops andsite visits. The ACC will support weekly bi-weekly monthly and quarterly research meetings to fostercommunication collaboration and integration of the NU-CCNIC and will further support communication and wide-reaching knowledge dissemination through bi-annual workshops with outside speakers. In Aim 1 theAdministrative Core will promote and ensure clear and effective communication across the TechnologyDevelopment (TECH) and Research Test-Bed (RTB) Units. In Aim 2 we will plan and establish regular Centermeetings and research workshops to foster communications within the NU-CCNIC and to the broader communitythat are critical to our research mission and dissemination. In Aim 3 we will work to increase representation andtraining of underrepresented minorities in the biomedical research workforce of the NU-CCNIC. In Aim 4 we willpartner with the cancer research advocate to ensure the critical importance of the patient perspective in the NU-CCNIC. In Aim 5 we will work with the EAP and Cancer Research Advocate on NU-CCNIC evaluation programsto ensure Center progress is accomplished on a timely basis and that resources are allocated judiciously. +No NIH Category available 3-Dimensional;Address;Aftercare;Biological Assay;Cancer Biology;Cell Nucleus;Cell physiology;Cells;Chromatin;Chromatin Structure;Complex;Computing Methodologies;Cytotoxic Chemotherapy;DNA;Data;Data Set;Development;Diameter;Disease remission;Disparate;Electron Microscopy;Epigenetic Process;Event;Feedback;Fostering;Future;Genes;Genetic;Genetic Transcription;Genome Mappings;Genomics;Growth;Heterogeneity;Image;Imaging Techniques;Imaging technology;Knowledge;Label;Length;Link;Malignant Neoplasms;Methods;Microscopy;Mission;Molecular;Molecular Conformation;Molecular Target;Nanoscopy;Oncology;Optics;Pathway interactions;Pattern;Physics;Play;Population;Process;Relapse;Research;Resistance;Resistance development;Resolution;Role;Scanning;Series;Solid;Stem Cell Research;Techniques;Technology;Testing;Therapeutic;Time;Translating;Transmission Electron Microscopy;Universities;Vision;Visualization;anti-cancer therapeutic;anticancer research;cancer cell;cancer stem cell;cellular imaging;chemotherapy;data modeling;electron tomography;epigenomics;follow-up;frontier;imaging capabilities;imaging platform;insight;live cell microscopy;molecular imaging;molecular modeling;molecular scale;nanoimaging;nanoscale;nanosensors;new technology;novel therapeutic intervention;novel therapeutics;pressure;prevent;programs;quantitative imaging;single molecule;spatiotemporal;stem;stem cell biology;stressor;technology development;temporal measurement;therapeutically effective;therapy resistant;three dimensional structure;transcriptional reprogramming;tumor;tumor progression;ultra high resolution Northwestern University Center for Chromatin NanoImaging in Cancer (NU-CCNIC) U54 CENTER NARRATIVEDespite rapid advances in new anti-cancer therapeutics for many solid cancers complete remission is still rare.In many cases tumors eventually develop resistance to treatments. One of the major barriers to effectivetherapeutics is likely to be potentiated by highly transcriptionally plastic cancer stem cells. In this U54Northwestern University Center for Chromatin Nanoimaging in Cancer we will develop optimize test anddeploy new nanoimaging technologies integrated with state-of-the-art molecular and computational methods toaddress some of the long-standing questions related to the origin of cancer stem cells and their ability to adaptto chemotherapies. Addressing these fundamental knowledge and technology gaps may help identify newtherapeutic strategies that prevent tumor resistance to therapeutics and relapse after treatment. NCI 10746393 12/20/23 0:00 RFA-CA-21-002 5U54CA268084-03 5 U54 CA 268084 3 "BECKER, STEVEN" 12/10/21 0:00 11/30/26 0:00 ZCA1-SRB-X(O1) 7125025 "BACKMAN, VADIM " "MATEI, DANIELA E; ZHANG, HAO F" 5 BIOMEDICAL ENGINEERING 160079455 EXZVPWZBLUE8 160079455 EXZVPWZBLUE8 US 42.050479 -87.680046 6144601 NORTHWESTERN UNIVERSITY Chicago IL BIOMED ENGR/COL ENGR/ENGR STA 606114579 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 397 Research Centers 2024 1491008 NCI 1629160 751299 Overall: PROJECT SUMMARYCancer stem cells (CSCs) play a critical role in fostering tumor resistance to therapies and relapse aftertreatment. This presents a crucial barrier to the development of successful anti-cancer therapeutics.Transcriptional reprogramming and plasticity play a critical role in and out of the CSC state which in turn areinterdependent on the regulatory function of the three-dimensional (3D) structure of chromatin epigenetic statesand other molecular events. Our understanding of fundamental CSC biology has been hampered by the needfor cellular nanoscale imaging technologies that provide both highly detailed structural information regarding 3Dchromatin organization and highly multiplexed molecular imaging of the many molecular regulators and eventsinvolved in CSC processes. We propose to establish the Northwestern University Center for ChromatinNanoimaging in Cancer (NU-CCNIC) to address this fundamental technology gap in cellular nanoscale imagingand deploy the new technologies to address the fundamental knowledge gap in CSC biology. The Centerconverges experts in cellular nanoscale imaging computational imaging molecular modeling computationalgenomics CSC biology and oncology. The Center will develop test validate iterate and deploy an integratedand co-registered Multi-scale Chromatin Nanoimaging Platform that will comprise three nested-doll imagingtechniques: chromatin scanning transmission electron microscopy optical spectroscopic super-resolutionnanoscopy and optical spectroscopic nanosensing. The Nanoimaging Platform will enable quantitative imagingof chromatin structure and highly multiplexed molecular and gene-specific localization at the most fundamentallength-scale approaching 1 nm resolution including the imaging of statistically significant cell populations andlive cells with high temporal resolution over prolonged temporal follow-up times. The Nanoimaging Platform willbe bridged to computational genomics epigenomics genome mapping and predictive transcriptional modelingdatasets. These technologies will be deployed to answer several long-standing open questions in CSC biology.We will elucidate whether CSCs can originate from non-CSCs via transcriptional reprogramming test the role ofchromatin structure in fostering transcriptional plasticity in CSC processes and explore the possibility oftranscriptionally reprogramming CSCs to exit the stem-state as a new therapeutic strategy. All aspects of thetechnology development will be guided by the needs of the CSC biology testbed through a series of researchfeedback loops. In the long term such single-cell nanoimaging technologies will help comprehensiveunderstanding of the complex interplay between structural physico-chemical and molecular genomic events.We anticipate that these convergence studies will provide new insights into CSC biology which are impossibleto reveal with the use of any single method and open new opportunities for identifying therapeutic strategies. 1491008 +No NIH Category available Award;Malignant neoplasm of lung;Parents;Research;novel therapeutics Understanding and exploiting novel therapeutic vulnerabilities of RIT1-driven lung cancer PROJECT NARRATIVEPer the FOA this section is not required. The research supplement proposal does not change the activities ofthe parent award. NCI 10746367 3/22/23 0:00 PA-21-071 3R37CA252050-03S1 3 R37 CA 252050 3 S1 "XU, WANPING" 4/1/21 0:00 3/31/26 0:00 Molecular Oncogenesis Study Section[MONC] 11639678 "BERGER, ALICE " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 135696 NCI 77100 58596 PROJECT SUMMARY/ABSTRACTPer the FOA this section is not required. The research supplement proposal does not change the activities ofthe parent award. 135696 +No NIH Category available Angiopoietin-2;Binding;Blocking Antibodies;Blood Vessels;CD8-Positive T-Lymphocytes;Clinical Management;Diagnosis;Disease;Excision;Extravasation;Functional disorder;Genetic;Growth;Human;Immune Evasion;Immune checkpoint inhibitor;Immunosuppression;Impairment;Incidence;Inflammatory;Islet Cell Tumor;Liver;Mediating;Metastatic Neoplasm to the Liver;Mus;Neoplasm Metastasis;Operative Surgical Procedures;Patients;Perfusion;Plasma;Primary Neoplasm;Prognosis;Receptor Protein-Tyrosine Kinases;Regulation;Resistance;Role;Signal Transduction;Signaling Molecule;T cell infiltration;TIE-2 Receptor;Therapeutic;Tumor Escape;Tumor Markers;Work;anti-PD1 therapy;cancer biomarkers;checkpoint therapy;immune cell infiltrate;immunoregulation;improved;insight;liver function;mouse model;objective response rate;potential biomarker;prognostic;receptor;response;tumor;tumor growth;tumor progression;tumor-immune system interactions Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pancreatic neuroendocrine tumors PROJECT NARRATIVENearly half of patients with pancreatic neuroendocrine tumors (PanNET) present with liver metastases atdiagnosis which correlates with poor prognosis and the immunosuppressive microenvironment of PanNETlimits the efficacy of immune checkpoint inhibitors (ICI) for metastatic PanNET patients with a less than 10%objective response rate. Emerging evidence suggests that increased vascular leakage and poor vascularperfusion resulting from vascular destabilization impair immune cell infiltration into tumors thus facilitatingtumor immune evasion and consequent tumor progression. In this work we propose to study role ofangiopoietin-2/Tie2 signaling which regulates vascular destabilization and dysfunction in liver metastaticprogression and in ICI therapy resistance of metastatic PanNET as well as the potential of Tie signalingmolecules as sensitive cancer biomarkers for PanNET patients. NCI 10746299 9/19/23 0:00 PA-21-071 3R37CA266270-01A1S1 3 R37 CA 266270 1 A1S1 "SNYDERWINE, ELIZABETH G" 3/1/23 0:00 6/30/27 0:00 11781381 "KIM, MINAH " Not Applicable 13 PATHOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 3/1/23 0:00 6/30/23 0:00 396 Non-SBIR/STTR 2023 32125 NCI 20549 11576 Liver metastases are found in nearly half of PanNET patients at diagnosis while many others develop livermetastasis after surgical resection of the primary tumor. Though the incidence of pancreatic neuroendocrinetumors (PanNET) has increased steadily over recent decades there are only limited therapeutic options formetastatic PanNET patients. Furthermore immune checkpoint inhibitors (ICI) showed the limited efficacy inpatients with metastatic PanNET due to the immunosuppressive microenvironment. Therefore understandingthe mechanisms underlying liver metastasis immune evasion and their convergence on ICI therapy resistancein PanNET is urgently necessary to improve the clinical management of advanced PanNET. Vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Angiopoietin-2(Ang2) which binds to the receptor tyrosine kinase Tie2 is a potent vascular destabilizing factor. Wedemonstrated that under inflammatory conditions Ang2 suppresses Tie2 signaling and promotes vasculardestabilization and leakage. Importantly emerging evidence suggests that vascular destabilization facilitatestumor immune evasion by impairing immune cell infiltration. In preliminary studies using a spontaneousPanNET mouse model we found that Ang2 inhibition suppresses liver metastatic growth and improves thesurvival. Ang2 inhibition also reduced vascular leakage and increased CD8+ T-cell infiltration in metastases.We previously showed that suppression of Tie2 signaling is accompanied by ectodomain cleavage of the Tie2coreceptor Tie1 resulting in increased circulating levels of soluble Tie1 (sTie1). Our preliminary studies showthat elevated plasma sTie1 levels in PanNET patients have significant prognostic implications. In this project we will elucidate the mechanisms underlying Ang2-mediated liver metastatic progressionimmunosuppression and anti-PD-1 therapy resistance in metastatic PanNET. In Aim 1 we will determine thecontribution of Ang2-mediated vascular destabilization to liver metastatic progression in PanNET by usinghuman liver metastases and function-blocking antibodies or genetic Ang2 deletion in spontaneous andexperimental PanNET mouse models. Mechanistically in Aim 2 we will determine whether Ang2-mediatedvascular leakage impairs CD8+ T-cell infiltration in liver metastases serving as the basis for assessing theeffects of Ang2 inhibition combined with anti-PD-1 therapy in metastatic PanNET. We will determine if Ang2blockade sensitizes PanNET liver metastases to anti-PD-1 therapy by promoting vascular stabilization andCD8+ T-cell infiltration in PanNET mice. Finally Aim 3 will identify circulating levels of sTie1 at diagnosis as apotential biomarker for tumor aggressiveness in PanNET patients. Successful completion of this project whichelucidates the mechanisms underlying vascular regulation of the immune evasion could significantly enhancethe clinical management of metastatic PanNET as well as provide insights for the treatment of metastaticdisease deriving from other tumor types especially those with poor response to ICI therapy. 32125 +No NIH Category available Affinity;Anchorage-Independent Growth;Androgen Receptor;Androgens;Automobile Driving;Basal Cell;Benign;Biology;Biopsy;Castration;Cell Line;Cell Lineage;Cells;Cessation of life;ChIP-seq;Chromatin;Classification;Clinical;Clinical Trials;Data;Data Set;Development;Disease;ERBB2 gene;Endocrine;Epithelial Cells;Epithelium;Event;Gene Expression Regulation;Genes;Genetic Transcription;Genomic approach;Genomics;Growth;In Vitro;Knockout Mice;Ligands;Malignant Neoplasms;Malignant neoplasm of prostate;Modeling;Neurosecretory Systems;Oncogenes;Oncogenic;Organoids;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Prevention;Process;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Recurrence;Resistance;Resistance development;Role;Specific qualifier value;Stains;Stanolone;Stress;Testing;Testosterone;Therapeutic;Tissues;Tumor Biology;Tumor Suppressor Proteins;United States;Up-Regulation;War;abiraterone;addiction;advanced disease;advanced prostate cancer;androgen deprivation therapy;androgen sensitive;antagonist;castration resistant prostate cancer;cell type;clinical development;drug sensitivity;effective therapy;efficacy testing;enzalutamide;genome-wide;hormone therapy;in vivo;inhibitor;knock-down;male;migration;novel therapeutic intervention;patient derived xenograft model;pharmacologic;pressure;prevent;programs;prostate cancer cell;spatiotemporal;standard of care;stem cells;synergism;targeted treatment;therapeutic evaluation;therapeutic target;therapeutically effective;therapy resistant;transcription factor;transcriptome sequencing;treatment strategy;tumor Targeting early events in prostate cancer lineage plasticity PROJECT NARRATIVEStandard-of-care prostate cancer treatments targeting the androgen receptor transcription factor exertselective pressures that can lead to the emergence of lineage plasticity phenotypes that are difficult to treatand poorly-understood. This proposal seeks to understand the role and therapeutic potential of a stem celltranscription factor that is up-regulated by prostate cancer treatments and promotes early events in prostatecancer lineage plasticity. We will test the efficacy of blocking this stem cell transcription factor as well asinhibiting its downstream targets to treat prevent or reverse the emergence of lineage plasticity in prostatecancer. NCI 10746139 11/30/23 0:00 PA-20-185 5R01CA270539-02 5 R01 CA 270539 2 "BERA, TAPAN K" 12/1/22 0:00 11/30/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 9594633 "DEHM, SCOTT M." Not Applicable 5 PATHOLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 414876 NCI 290273 124603 PROJECT SUMMARY/ABSTRACTProstate cancer is the most common non-cutaneous cancer in males. Prostate cancer cells are dependent ona transcription factor called the androgen receptor (AR) which is activated by the androgens testosterone anddihydrotestosterone. Accordingly an effective treatment for patients with advanced prostate cancer isandrogen deprivation therapy which blocks the effects of androgens inhibits the AR and halts the growth ofprostate cancer cells. Although this form of treatment is very effective for advanced prostate cancer the stressof this therapy will eventually lead to the prostate cancer cells developing resistance. In approximately 25-30%of cases the stress of prostate cancer therapy will cause the prostate cancer cells to transform into cellularstates where they no longer resemble the original disease. These prostate cancer cells take on features ofalternative cell types through a process called lineage plasticity. These lineage plastic prostate cancers arevery difficult to treat because they do not contain AR and there are no effective therapeutics available.Additionally the processes by which standard prostate cancer therapies can cause prostate cancer lineageplasticity is poorly understood. This proposal seeks to understand the biology of prostate cancer lineageplasticity and develop new therapeutic strategies to treat prevent or reverse this disease stage. Ourpreliminary data demonstrates the stem cell transcription factor KLF5 is up-regulated by standard prostatecancer therapies that inhibit the AR. Up-regulation of KLF5 enhances androgen-independent growth ofprostate cancer cells as well as migration and colony formation phenotypes. Functionally the transcriptionalprogram initiated by up-regulated KLF5 clashes with the transcriptional program activated by the AR. Becausethe AR transcriptional program controls prostate cancer cell identity KLF5 up-regulation breaks down thisidentity and promotes very early steps in lineage plasticity of prostate cancer cells. We hypothesize thattargeting this early step in therapy-induced prostate cancer lineage plasticity will block later events that lead tovery aggressive treatment-resistant manifestations of the disease. We have identified ERBB2 as a focal pointof this tug-of-war between AR and KLF5 and shown that ERBB2 inhibitors can block the oncogenic effects ofKLF5. To advance these findings and identify additional therapeutic vulnerabilities in this pathway we propose2 Specific Aims. In Aim 1 we will study induction of KLF5 and lineage plasticity phenotypes in CRPC. In Aim 2we will test therapeutic potential of blocking early steps in CRPC lineage plasticity. A successful outcome canlead to rapid development of clinical trials testing these therapeutic strategies for treatment or prevention oflineage plastic prostate cancer. 414876 +No NIH Category available 18q;Automobile Driving;B-Cell Antigen Receptor;B-Cell Development;B-Cell Lymphomas;B-Lymphocytes;BCL2 gene;Biology;Bromodomains and extra-terminal domain inhibitor;Cell Death;Cell Line;Cells;Chromosome 18;Chromosome Arm;Chronic;Clinical;Combination immunotherapy;Complex;DNA copy number;Development;Disease;Down-Regulation;Event;Genes;Genetic;Genus Mentha;Hematopoietic Stem Cell Transplantation;Immunoglobulins;Immunophenotyping;Inhibition of Apoptosis;Investigation;Link;Lymphoma;Lymphomagenesis;MYC gene;Malignant - descriptor;Measures;Mediating;Molecular;Monitor;Mus;Mutation;Non-Hodgkin's Lymphoma;Oncogenes;Oncogenic;Outcome;Patient-Focused Outcomes;Patients;Phenotype;Play;Population;Pre-Clinical Model;Prognosis;Property;Proteins;Public Health;Receptor Signaling;Recurrence;Refractory;Relapse;Role;Signal Transduction;Structure of germinal center of lymph node;Subgroup;TCF7L2 gene;Testing;Therapeutic;Transgenic Mice;Work;activated B cell like;anergy;clinical heterogeneity;improved outcome;inhibitor;large cell Diffuse non-Hodgkin's lymphoma;molecular marker;molecular phenotype;molecular subtypes;mouse model;mutant;novel;overexpression;patient derived xenograft model;pre-clinical;precision medicine;prevent;receptor expression;resistance mechanism;risk stratification;rituximab;single-cell RNA sequencing;synergism;therapeutic target;tositumomab;transcription factor;tumor Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma Project NarrativeDiffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma andencompasses molecular subtypes with contrasting biology and clinical outcome. Conventional chemo-and immuno-therapy combinations fail to cure approximately 40% of DLBCL patients and thisrelapsed/refractory population has a very poor prognosis. Investigating the molecular drivers of pooroutcome and how these may be targeted with rational therapeutic strategies is likely to improve theoutcome of these patients and have a substantial impact on public health. NCI 10746128 11/14/23 0:00 PA-19-056 5R01CA240839-04 5 R01 CA 240839 4 "JHAPPAN, CHAMELLI" 12/1/20 0:00 11/30/25 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 12257403 "GREEN, MICHAEL RICHARD" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 396838 NCI 244962 151876 Project SummaryDiffuse large B-cell lymphoma (DLBCL) is the most common form lymphoma and is conventionallytreated with a combination of chemotherapeutics with the anti-CD20 antibody Rituximab. Although morethan half of patients can be cured with this approach the remainder have a dire prognosis with a shortsurvival. Despite the variability in patient outcome there are currently no routinely utilized molecularbiomarkers that can be employed for risk stratification or to direct a specific therapy. That is precisionmedicine does not currently exist for DLBCL.We have identified a genetic alteration on the q-arm of chromosome 18 (18q) that is associated with anaggressive subtype of DLBCL and defined the TCF4 and BCL2 genes as critical targets at this locus.The BCL2 gene encodes an important oncogene that prevents cell death and can be targeted with theinhibitor Venetoclax. The TCF4 gene encodes a transcription factor protein that we have found to drivekey malignant properties of lymphoma such as promoting the expression of the MYC oncogene and theB-cell receptor. In addition we have defined a way to eliminate TCF4 expression using a novel type ofprotein-degrader molecules that are directed towards BET proteins. This therefore provides an excitingrational therapeutic avenue for targeting TCF4. We hypothesize that combining this with an inhibitor ofBCL2 will target both genes that are activated by 18q alterations and provide a precision medicineapproach for treating this aggressive subset of DLBCL.Here we are proposing to investigate the function of 18q alterations in DLBCL and validate themechanism by which we believe this genetic event leads to lymphoma. We will also perform pre-clinicalinvestigation of combinations of BET and BCL2 inhibitors for the specific therapeutic targeting of 18qalterations. Together this work will advance our understanding of DLBCL disease biology and may leadto advances in precision medicine for this disease. 396838 +No NIH Category available Attenuated;Binding;Binding Proteins;CD8-Positive T-Lymphocytes;CDC2 gene;CDC7 gene;CHEK1 gene;Cancer Model;Cell Lineage;Cell Nucleus;Cell division;Cells;Chromosomal Instability;Chromosome 1;Chromosomes;Clinic;Clinical Trials;Complement;Conformal Radiotherapy;DNA Damage;DNA biosynthesis;DNA replication fork;DNA replication origin;Data;Eukaryota;Fire - disasters;Fluorescence;Fluorescence Resonance Energy Transfer;Genome;Genome Stability;Half-Life;Human;Human Chromosomes;Human Genome;Immune response;Immunotherapy;In Vitro;Irradiated tumor;Length;Licensing;Medical Oncology;Molecular;Molecular Conformation;Mus;Normal Cell;Pattern;Phosphorylation;Phosphotransferases;Proliferating;Protein phosphatase;Radiation;Radiation Oncology;Regulation;Replication Initiation;Replication Origin;Replicon;Reporter;Reporting;Role;S phase;Signal Transduction;Stress;T-Lymphocyte;Testing;Time;adaptive immune response;cancer cell;helicase;in vivo;innovation;insight;kinase inhibitor;lymph nodes;mouse model;novel;radiation response;superresolution microscopy;treatment response;tumor DNA damage signaling to dormant origins of replication We will identify a fundamental mechanism that determines the distance between origins of DNA replication inhuman cells. This mechanism is a key determinant of genome stability and the rate of cell division andaccordingly it is a key determinant of therapeutic response in the medical and radiation oncology clinic. NCI 10746122 11/6/23 0:00 PA-19-056 5R01CA236367-05 5 R01 CA 236367 5 "WEINREICH, MICHAEL DALE" 12/1/19 0:00 11/30/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 8581860 "BAKKENIST, CHRISTOPHER J." Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 322194 NCI 205875 116319 Higher eukaryotes evolved with mechanisms that initiate DNA replication at multiple origins on multiplechromosomes. Activation of the replicative helicase at a single origin in each of ~50000 replicons is sufficientto replicate the human genome in the absence of stress. These ~50000 origins are selected from a five- totenfold excess of licensed origins. Activation of additional replicative helicases at origins that would otherwisebe passively replicated is observed after stress. This plasticity in origin use is a simple mechanism to recoverDNA replication between stalled and collapsed replication forks. The mechanism(s) that limits origin firing to oneper replicon in the absence of stress is not known. We recently reported that the DNA damage signaling kinasesATR and Chk1 inhibit activation of the replicative helicase in the absence of stress. In preliminary studies weshow that Chk1 kinase activity is strictly associated with ATR kinase-dependent phosphorylations on Chk1 andthat these have an astonishingly short half-life in cells. We propose that this is a highly innovative mechanismthat localizes Chk1 kinase activity to the immediate vicinity of ATR at active replicative helicases. We also showthat Rif1 which has been implicated in the regulation of replication timing previously is phosphorylated and thatphosphorylated Rif1 binds protein phosphatase 1 (PP1). Based upon these findings we hypothesize thatChk1 kinase activity generates a ring of Rif1-PP1 around active replicative helicases and that this limits Cdc7kinase-dependent origin firing across a replicon. In Aim 1 we will investigate a new mechanistic paradigm forlocalizing DNA damage signaling to a small volume of the nucleus in the absence of stress. In Aim 2 we willinvestigate the molecular mechanism that limits activation of the replicative helicase across a replicon in theabsence of stress. In Aim 3 we will investigate the impact of ATR kinase inhibition and conformal radiation onimmune responses in tumor bearing mice. These studies are highly impactful as they will identify a fundamentalmechanism that determines inter-origin distance genome stability and the rate of cell division in highereukaryotes. Since this mechanism may be attenuated in T cells these studies will provide fundamental insightsinto adaptive immune responses. Our studies may have an immediate impact as the ATR and Chk1 kinaseinhibitors used here are in clinical trials. 322194 +No NIH Category available Acetylation;Achievement;Acute leukemia;Affect;Animals;Arginine;Binding;Biochemical;Bromodomain;CRISPR library;CRISPR screen;Cell Line;Cells;Classification;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Combined Modality Therapy;Complex;Elements;Epigenetic Process;Future;Gene Expression;Gene Expression Regulation;Gene Rearrangement;Genes;Genetic;Genetic Screening;Goals;Histone Acetylation;Histone Deacetylation;Histone H3;Histones;Human;Infant Leukemia;Lead;Left;Lysine;MLL gene;MLL-AF9;MLL-rearranged leukemia;Maintenance;Malignant Neoplasms;Mediating;Methylation;Methyltransferase;Monitor;Nature;Oncogenes;Oncogenic;Pathway interactions;Patients;Pharmacologic Substance;Phase I Clinical Trials;Positioning Attribute;Prognosis;Proteins;Publishing;Reader;Regimen;Reporting;Research;Role;SAGA;SIRT1 gene;Scanning;Signal Transduction;Surface;Survival Rate;Tail;Technology;Therapeutic;Toxic effect;Transcriptional Activation;Work;World Health Organization;cancer type;chromatin modification;clinically relevant;combinatorial;drug discovery;genetic approach;genome-wide;histone acetyltransferase;histone methylation;improved;in vivo;inhibitor;innovation;insight;leukemia;leukemogenesis;multiple omics;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;pharmacologic;pre-clinical;programs;protein folding;recruit;response;targeted treatment;treatment response Mechanism and therapeutic opportunities of targeting the Tudor domain PROJECT NARRATIVEMLL-rearrangement (MLL-r) affects about 10% acute leukemia patients and is associated with poorprognosis. This proposal has immediate clinical relevance in developing a more advanced treatment toMLL-r leukemias and will contribute to a broader understanding of how the dynamic epigenetic networkscontrol oncogene expression in cancers and therapeutic responses. The technology developed in thisproject will facilitate functional domain discovery for future targeted therapies. NCI 10746121 11/29/23 0:00 PA-20-185 5R01CA278050-02 5 R01 CA 278050 2 "JHAPPAN, CHAMELLI" 12/1/22 0:00 11/30/27 0:00 Special Emphasis Panel[ZRG1-OTC1-A(80)S] 12422169 "CHEN, CHUN-WEI DAVID" Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 460153 NCI 261451 198702 PROJECT SUMMARY/ABSTRACT MLL-rearranged (MLL-r) leukemias account for 5-10% of human acute leukemia and is associated withpoor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the MLL-rleukemias emphasize the need for novel regimens. Recent cancer epigenetics studies discovered a centralrole for the histone H3 lysine 79 (H3K79) methyltransferase DOT1L in MLL-r leukemogenesis. Importantclinical responses have been noted with DOT1L inhibitor treatment as a single agent however it is expectedthat combination treatments will be necessary. Our preliminary studies based on a Tudor domain focused CRISPR screen in MLL-r leukemia identifiedSGF29 as a novel vulnerability in MLL-r leukemia. The objective of this application is to determine the criticalepigenetic mechanisms that mediate the availability of KAT2A/B to maintain H3K9ac and oncogene expressionin MLL-r leukemia. Our central hypothesis is that SGF29 an H3K4me3 reader protein mediates recruitmentof KAT2A/B to maintain histone H3K9ac and MYC oncogenic program in MLL-r leukemia. We will dissect theSGF29-mediated epigenetic mechanisms (Aim 1) and investigate the efficacy of SGF29 targeting (alone or incombination with DOT1L inhibition) as a novel therapy in MLL-r leukemia (Aim 2). This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiplecomponents of an epigenetic network to efficiently suppress the cancer programs and (2) it establishes abrand new genetic screen approach for a sub-protein level functional pocket and drug discovery. The impactof this research will be of significance because (1) it immediately provides novel therapeutic opportunitiesagainst the difficult-to-treat MLL-r leukemias and (2) it will help identify novel functional elements inepigenetic regulators for future pharmaceutical targeting. 460153 +No NIH Category available ARID1A gene;Animal Model;Biology;Bladder;Cancer Patient;Cell Maintenance;Chromatin;Complex;Conflict (Psychology);Coupled;DNA Damage;Data;Disease;Elongation Factor;Epithelial Cells;Epithelial Physiology;Epithelium;Gene Expression;Genes;Genetic;Genetic Transcription;Genotype;Goals;Homeostasis;Human;Impairment;In Vitro;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Messenger RNA;Modality;Modeling;Molecular;Mus;Mutate;Mutation;Natural History;Nucleotides;Oncogenic;Organoids;PTEN gene;Pathogenesis;Patient-Focused Outcomes;Patients;Peptide Elongation Factor 2;Phenotype;Population;Process;Production;Proliferating;Protein Biosynthesis;Proteins;Regulation;Research;Specimen;System;TP53 gene;Therapeutic;Transcript;Translational Repression;Translations;Tumor Suppressor Proteins;Urothelial Cell;Urothelium;Work;cancer genome;carcinogenesis;cell transformation;chromatin protein;chromatin remodeling;clinical application;clinically significant;fitness;genome sequencing;improved;in vivo;in vivo Model;loss of function mutation;mRNA Translation;mouse model;novel;novel therapeutic intervention;parity;patient derived xenograft model;pharmacologic;polysome profiling;precision medicine;prevent;prognostic;programs;response;restoration;restraint;transcriptome;translational impact;tumor;tumor progression;tumorigenesis Transcriptional-translational conflict in bladder epithelial homeostasis and cancer PROJECT NARRATIVEWe have uncovered a new functional link between the ARID1A chromatin remodeler and the process of mRNAtranslation elongation important for urothelial cell maintenance and cancer pathogenesis. This discovery isclinically significant as ARID1A-deficient cancers are exquisitely sensitive to inhibition of translation elongationinitiation. Our goal is to definitively investigate the functional link between chromatin remodeling and proteinsynthesis control as well as determine the therapeutic implications of targeting this interface. NCI 10746112 12/6/23 0:00 PAR-19-183 5R01CA276308-02 5 R01 CA 276308 2 "MAAS, STEFAN" 1/1/23 0:00 12/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10807181 "HSIEH, ANDREW CALEB" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 396 Non-SBIR/STTR 2024 512155 NCI 302384 209771 ABSTRACTChromatin remodeling and protein synthesis are tightly regulated processes that impact gene expression andcellular phenotypes. However it is unknown to what extent these two regulatory mechanisms may be linked orindependent in controlling normal epithelial physiology and disease states. We have uncovered a new functionalrelationship between the chromatin remodeler ARID1A and mRNA translation elongation. This link is involved inmaintaining cellular fitness in the context of bladder carcinogenesis and represents a new tumor suppressivemechanism we call transcriptional-translational conflict. Loss of ARID1A triggers a simultaneous increase inoncogenic transcripts but also inhibition of the translation elongation factor eEF2 which results in a reduction inprotein synthesis and prevents cancer pathogenesis. However this process can be reversed by restoringtranslation elongation which enables the efficient synthesis of oncogenic mRNAs and cancer progression. Thisfinding provides a unified gene expression model which explains why ARID1A is a context specific tumorsuppressor. Importantly ARID1A deficient tumors retain a sensitivity to pharmacologic inhibition of translationelongation initiation. Recently our laboratory has developed and characterized new in vitro and in vivo modelsof both human and murine ARID1A deficient bladder cancer where we can also toggle translation elongation.We have used these models to discover a critical link between ARID1A and the process of mRNA translationelongation that is vital for urothelial homeostasis and bladder cancer progression. We hypothesize thattranscriptional-translational conflict in urothelium lacking ARID1A is mediated through decreased eukaryoticelongation factor 2 (eEF2) activity which when reversed unleashes a poised druggable oncogenic programsufficient to drive cancer progression. Our long-term objective is to utilize state-of-the-art mouse models andprimary organoid systems whole transcriptome polysome profiling and patient derived xenografts to definitivelyinvestigate the fundamental link between ARID1A and protein synthesis regulation in a highly relevant populationof bladder cancer patients. To do so we will address the following aims: 1) Determine the relevance andmechanism of transcriptional-translational conflict in urothelial cell transformation and carcinogenesis; and 2)Elucidate how gene expression parity enables cancer progression and represents a context specific therapeuticvulnerability. This research will help us gain a deeper understanding of the biology of bladder cancer and opena new paradigm for treating patients with lethal disease. Our work is particularly important for the progress ofprecision medicine because it seeks to mechanistically tie a highly prevalent bladder cancer genotype (ARID1Aloss) to a new treatment modality that holds therapeutic promise for bladder cancer patients. 512155 +No NIH Category available Adoptive Transfer;Antigen-Presenting Cells;Antigens;Automobile Driving;Binding Proteins;Cells;Chemicals;Clinical;Cross Presentation;Cross-Priming;Data;Dendritic Cells;Development;Event;Evolution;Foundations;Generations;Genetic Polymorphism;HIV;Heat shock proteins;Hematopoietic;Human;Immune;Immune response;Immune system;Immunity;Immunologic Surveillance;Immunologics;Immunology;In Situ;Individual;Knockout Mice;Knowledge;Laboratories;Lead;Ligands;Malignant Neoplasms;Mediating;Modeling;Molecular;Molecular Chaperones;Mus;Mutation;NK Cell Activation;Natural Killer Cells;Outcome;Pathway interactions;Patients;Peptides;Population;Positioning Attribute;Predisposition;Productivity;Publishing;Qualifying;Research;Resistance;Role;Shapes;Signal Transduction;Stimulus;T cell response;T-Lymphocyte;Tumor Antigens;Tumor Escape;Tumor-Derived;Vaccination;Virus Diseases;Wild Type Mouse;Work;anti-tumor immune response;conditional knockout;cytokine;insight;melanoma;neoantigens;novel;prevent;prognostic;receptor;response;tool;tumor;tumor immunology CD91 and cancer immunosurveillance NarrativeWe have identified a role for the heat shock protein (HSP) receptor CD91 in initiation of immuneresponses against nascent emerging tumors. These immune responses are central forimmunosurveillance of cancer a concept proposed over a hundred years ago. In this proposalwe aim to examine the interaction of CD91 with its ligands the HSPs on hematopoietic cells insitu as the mechanism that leads to productive anti-tumor immune responses. By understandingthis immunological pathway we will solve an outstanding question that is central to cancerimmunology and also be better able to predict individuals that have poor CD91 function and aremore susceptibility to developing cancer. NCI 10746105 11/6/23 0:00 PA-19-056 5R01CA233803-05 5 R01 CA 233803 5 "HOWCROFT, THOMAS K" 12/16/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 9043933 "BINDER, ROBERT J" Not Applicable 12 MICROBIOLOGY/IMMUN/VIROLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 319403 NCI 205875 113528 The immune system recognizes aberrant cells and eliminates them prior to emergence of nascent tumors. Thisprevents progression of many malignancies. In the absence of such immunity in mice or humans multiple andfrequent tumors are generated. Current immunosurveillance model involves the priming of T cell and NK cellimmunity. The gap in knowledge in this model is raised in two questions; (1) What is the molecular mechanismfor cross-priming T cell responses in the context of the negligible amount of antigen available at the earlystages of nascent tumor development? (2) What is the stimuli for co-stimulation of T cell priming and activationof NK cells. Our work has demonstrated that tumor-derived heat shock proteins (HSPs) introduced duringvaccination are super-efficient at cross-presentation of limited amounts of their chaperoned tumor (peptide)antigen. HSPs are also capable of initiating signals for co-stimulation. Both events require the HSP receptorCD91 expressed on dendritic cells and together allow for priming potent tumor-specific T cells. The release ofcytokines by DCs stimulated with HSPs enhances the T cell responses and activates NK cells. Our hypothesisis that when tumor antigen levels are limiting as in nascent emerging tumors the HSP-CD91 pathway isessential for cross-priming of anti-tumor immune responses. In humans immune responses to cancer areinfluenced by variable expression levels of CD91 and its polymorphism driving the clinical and translationalrelevance of this proposal. In this application we will determine how CD91 serves as an essential conduit forinitiating responses for cancer immunosurveillance. 319403 +No NIH Category available Binding;Biochemical;Biological;Biological Assay;Biological Process;Biophysics;CRISPR/Cas technology;Cancer Biology;Cancer Cell Growth;Cell Differentiation process;Cells;ChIP-seq;Chimeric Proteins;Chromatin;Core Protein;Development;Developmental Process;Disease;EP300 gene;Engineering;Enhancers;Gene Expression;Genes;Genetic Transcription;Genomics;Histones;Homologous Gene;Human;Impairment;In Vitro;Kabuki Make-Up Syndrome;Liquid substance;Malignant Neoplasms;Mediating;Methylation;Methyltransferase;Missense Mutation;Molecular;Mus;Mutate;Mutation;Neurodevelopmental Disorder;Patients;Phase;Physical condensation;Physiological;Process;Property;Protein Dynamics;Proteins;Publications;RNA Splicing;Regulation;Role;Stem Cell Development;System;Transcription Initiation Site;Tumor Suppression;Tumor Suppressor Proteins;Variant;Work;Y Chromosome;biophysical analysis;biophysical properties;cancer cell;chromatin modification;demethylation;embryonic stem cell;genome editing;insight;mutant;neoplastic cell;novel;programs;protein purification;reconstitution;recruit;stem cell differentiation;tumor;tumorigenesis Role of UTX condensation in chromatin regulation PROJECT NARRATIVECertain proteins can regulate cancer and development by regulating gene expression onchromatin. This project will study a fundamental biophysical property of an important protein thatis critical in regulating gene expression in cancer and stem cell development. Results from thiswork will provide important mechanistic insights into how this fundamental property protects usfrom cancer and also supports development. NCI 10746103 11/30/23 0:00 PA-20-185 5R01CA259573-03 5 R01 CA 259573 3 "OKANO, PAUL" 1/1/22 0:00 12/31/26 0:00 Molecular Genetics A Study Section[MGA] 11376371 "JIANG, HAO " Not Applicable 5 BIOCHEMISTRY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 303581 NCI 187976 115605 PROJECT ABSTRACTUTX/KDM6A is an important tumor suppressor and developmental regulator and is frequentlymutated in human cancers and certain neurodevelopmental disorders including Kabukisyndrome. Though UTX is a histone H3K27 demethylase the demethylase activity is oftendispensable in mediating tumor suppression and developmental regulation and the key molecularactivity of UTX in these processes remains elusive. UTX is thought to regulate chromatin activityby associating with and coordinating the function of MLL3/KMT2C and MLL4/KMT2D the majorH3K4 mono-methylase at enhancers and the p300 histone acetyltransferase all of which arealso frequently mutated in human cancers. In our preliminary studies we found that the tumorsuppressive activity of UTX requires its phase separation property conferred by its coreIntrinsically Disordered Region (cIDR). Endogenous UTX forms dynamic condensates in mouseembryonic stem cells (ESCs) and its cIDR is important for ESC differentiation. UTX and MLL4form co-condensates that enhance the H3K4 mono-methylation activity. We also found that UTYthe Y chromosome homolog of UTX has weaker tumor suppressive activity that is associatedwith formation of less dynamic condensates. These results let us formulate our central hypothesisthat UTX needs to be in condensates with appropriate biophysical properties to be active inregulating gene expression on chromatin in regulating tumorigenesis and stem cell differentiation.We proposal two Specific Aims.Aim 1. Determine the mechanisms by which UTX condensation regulates chromatinactivity. We will determine how UTX condensation regulates chromatin modification activities bybiochemical reconstitution and also through integrative analyses of multiple levels of chromatinactivity in both transduced cancer cells and endogenous Utx-edited ESCs.Aim 2. Determine how biophysical properties of the UTX condensates regulate itsbiological activities. We will study biophysical properties of UTX WT and variant condensatesand its associated co-activators. We will determine impacts of condensate properties on biologicalactivities at different levels in in both transduced cancer cells and endogenous Utx-edited ESCs.We will also examine effect of disease-associated missense mutations of UTX on condensateproperties. 303581 +No NIH Category available Acute Myelocytic Leukemia;Binding;Binding Sites;Biological;Cell Line;ChIP-seq;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;DNA;Data;Data Set;Disease;Enhancers;Epigenetic Process;Gene Expression Profile;Gene Mutation;Genetic Transcription;Genome;Genomics;Goals;Hematopoietic stem cells;Hi-C;Homeobox Genes;Hybrids;MLL-rearranged leukemia;Mediating;Modeling;Molecular;Mutation;Output;Pathogenesis;RNA;RNA immunoprecipitation sequencing;Regulation;Role;Sampling;Site;Structure;Testing;Transcriptional Regulation;Transgenic Organisms;Untranslated RNA;Work;acute myeloid leukemia cell;beta catenin;cell behavior;chromatin isolation by RNA purification sequencing;cohesin;cohesion;genomic locus;hematopoietic stem cell self-renewal;improved;leukemia;leukemic transformation;leukemogenesis;mouse model;novel;overexpression;programs;promoter;success;transcriptome sequencing;transgene expression Role of lncRNA mediated R-loops in CTCF boundary function and AML genome organization Narrative:The goal of this project is to understand the role of HOTTIP mediated aberrant R-loops in CTCFboundary function leukemic TAD formation and pathogenesis of AML. Our studies will unveilthe mechanisms by which HOTTIP lncRNA and CTCF boundary fine-tune WNT/-catenin targetTAD formation and transcription to modulate HSC behavior and leukemogenesis. Our projectwill define novel function of R-loops in lncRNA mediated CTCF boundary activity and AMLgenome organization. NCI 10746097 11/14/23 0:00 PA-20-185 5R01CA260729-03 5 R01 CA 260729 3 "KLAUZINSKA, MALGORZATA" 12/3/21 0:00 11/30/26 0:00 Special Emphasis Panel[ZRG1-OBT-H(02)M] 8836835 "HUANG, SUMING " "XU, MINGJIANG " 10 PEDIATRICS 129348186 TNKGNDAWB445 129348186 TNKGNDAWB445 US 40.264414 -76.674014 1524204 PENNSYLVANIA STATE UNIV HERSHEY MED CTR HERSHEY PA SCHOOLS OF MEDICINE 170332360 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 563725 NCI 447268 116457 Abstract: Acute myeloid leukemia (AML) is a heterogeneous disorder of hematopoietic stem and progenitor cells(HSPCs) associated with sequential acquisition of driver gene mutations. These mutations often lead to alteredgenome organization and transcriptional programs that perturb HSC self-renewal and differentiation. Recentlywe discovered that HOTTIP a posterior HOXA-associated long non-coding RNA (lncRNA) remodels CTCF-defined topologically associated domains (TADs). This remodeling regulates the homeotic gene-associatedleukemic transcription program and facilitates AML leukemogenesis driven by MLL rearrangement (MLLr+) orNMP1 mutation (NPM1C+). One of the top HOTTIP-regulated transcription motifs in AML is CTCF-binding sites(CBSs) suggesting a novel function of HOTTIP in regulating CTCF-mediated genome organization and AMLpathogenesis. Indeed combined RNA-seq ChIRP-seq and CTCF ChIP-seq analyses revealed that HOTTIPco-occupied with CTCF in a subset of the AML genome including HOXA and WNT/-catenin target gene locifor their activation. However it remains unknown whether and how HOTTIP lncRNA directly regulates CTCF-directed genome organization to promote leukemic transcription networks and leukemogenesis. Our preliminarydata showed that HOTTIP is capable of directly interacting with key TAD boundary CBSs in the HOXA and WNTtarget loci via formation of an R-loop structure. We hypothesize that HOTTIP activation mediates aberrant R-loop formation in CBSs to stratify CTCF chromatin boundary for reprograming AML TADs and leukemictranscription networks leading to HSPC perturbation and leukemogenesis. To test this hypothesis we will focuson the impact of the altered CTCF TAD boundary and R-loop formation upon HOTTIP activation on AML genomeregulation and gene transcription output. In this proposal we will test the importance of the HOTTIP activation-mediated aberrant R-loop formation in modulating the CTCF boundary activity and transcriptional regulation inAML. Specifically we will identify and characterize critical HOTTIP-regulated CTCF chromatin boundaries in theAML genome. We will then define the novel role of R-loops in HOTTIP-mediated CTCF chromatin boundarydefinition and genome organization. Finally we will assess the impact of the HOTTIP-mediated aberrant R-loopformation at specific TAD boundaries on leukemogenesis and HSPC regulation. 563725 +No NIH Category available Address;Adjuvant Chemotherapy;Animal Model;Appearance;Autophagocytosis;Behavior;Biochemistry;Biological Assay;Cancer Etiology;Cancer Patient;Cell division;Cells;Centrosome;Centrosome Pathway;Clinic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Colon;Colorectal Cancer;DNA;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Epithelium;Evolution;Failure;Fluorouracil;Frameshift Mutation;Gene Mutation;Genes;Genetic;Goals;Hereditary Nonpolyposis Colorectal Neoplasms;Human;Image;Individual;Induced Mutation;Invaded;Knowledge;Lesion;Link;Lymphocytic Infiltrate;Malignant - descriptor;Malignant Neoplasms;Mediating;Microsatellite Instability;Microsatellite Repeats;Mismatch Repair;Mismatch Repair Deficiency;Mismatch Repair Gene Inactivation;Modeling;Modification;Molecular;Molecular Biology;Mucinous Differentiation;Mus;Mutagenesis;Mutation;Mutation Detection;Oncogenes;Organoids;Pathogenesis;Pathologist;Pathway interactions;Patients;Penetrance;Pharmaceutical Preparations;Phenotype;Physiological;Play;Productivity;Prognostic Marker;Proteins;Qualifying;Recurrence;Research Personnel;Risk;Risk Marker;Role;Structure;System;Translations;Tumor Suppressor Proteins;Tumor-Associated Process;Validation;cancer genetics;carcinogenesis;cell motility;cell transformation;cohort;colon cancer patients;colon carcinogenesis;colorectal cancer treatment;early onset colorectal cancer;effectiveness evaluation;in vivo;inhibition of autophagy;innovation;live cell imaging;mortality;multidisciplinary;mutant;mutant mouse model;novel;personalized medicine;predictive marker;single molecule;therapeutic target;three dimensional cell culture;tumor;tumor initiation;tumor progression;tumorigenesis A cancer-derived truncating mutation in disease penetrance and progression of MSI CRC Project NarrativeIndividuals with DNA mismatch repair (MMR) gene inactivation have up to three orders of magnitude ofincreased risk of developing colorectal cancer and other malignancies with microsatellite instability (MSI).However the genetic basis and underlying mechanisms that determine the rate of disease penetrance ispoorly understood. This project will identify the mechanism by which MSI-derived target gene mutation drivesCRC tumorigenesis and progression through the centrosome pathway and potentially identify new target topredict and/or treat MSI-associated malignancies. NCI 10745933 11/15/23 0:00 PA-19-056 5R01CA238457-06 5 R01 CA 238457 6 "OKANO, PAUL" 8/6/20 0:00 11/30/24 0:00 Cancer Genetics Study Section[CG] 9614628 "LIANG, CHENGYU " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 519657 NCI 302671 216986 Project SummaryColorectal cancer (CRC) ranks as the 2nd most common cause of cancer mortality. Nearly allpatients suffering from Lynch Syndrome as well as 15-20% of patients with sporadic early CRChave microsatellite instability (MSI) due to DNA mismatch repair (MMR) deficiency. Notablydefective MMR by itself is not sufficient to drive cell transformation and tumorigenesis butmicrosatellite mutations in a limited number of target genes might be positively selected duringtumor development underlying MSI-associated pathogenesis. Unfortunately relatively little isknown about the molecular underpinnings of MSI target genes and their mechanism of action inMSI-associated disease penetrance. This project will fill this gap capitalizing on our recentdiscovery of a strong correlation between the MSI phenotype and recurrent frameshift (FS)mutation in the autophagy tumor suppressor UVRAG. The protein product of this FS mutationfunctions as an oncogene and a bona fide trigger of centrosome amplification (CA) in CRC. Wenow bring within this proposal a collaboration of leaders in CRC genetics and molecular biologyalong with clinicians and pathologists to understand the molecular mechanism by which CAaugments the expressivity of MMR mutations contributing to human colonic carcinogenesis. Toachieve this goal we propose three Specific Aims including (1) identifying the molecularmechanism of CA in MSI CRC associated with UVRAGFS expression; (2) examining the impactof CA on the differentiation and metastatic capacity of MSI patient-derived colonic organoids;and (3) investigating the in vivo role of MSI-derived UVRAGFS in disease penetrance and cancerprogression using targeted mutant mouse models. These aims will be addressed usingmultidisciplinary innovative approaches that integrate state-of-the-art genetic biochemistry live-cell imaging and physiological assays in cells and in mice with targeted mutations in genesrelated to MMR deficiency and centrosome deregulation. We have access to the right cohort ofpatients and our use of patient-derived colonic organoids will maximize the relevance of ourfindings for eventual translation to cancer patients in the clinic. Together we anticipate that ourstudies will delineate a novel mechanism underlying MSI-associated disease penetrance andprovide compelling in vivo validation of CA as a novel prognostic and predictive biomarker and atherapeutic target for personalized treatment of MSI CRC including Lynch Syndrome. 519657 +No NIH Category available Advisory Committees;Bioinformatics;Bypass;Cancer Center;Cell Maintenance;Cell Survival;Cells;Chemicals;Clinical;Co-Immunoprecipitations;Collaborations;Complex;Data;Data Set;Dependence;Doxycycline;Environment;Epigenetic Process;Faculty;Genetic;Goals;HDAC5 gene;Head;Heterogeneity;Human;Immunology;Immunosuppression;Immunotherapy;Impairment;In Vitro;Infiltration;Institution;K22 Award;KRAS oncogenesis;KRAS2 gene;KRASG12D;Knock-out;Laboratories;MADH3 gene;MADH4 gene;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Medical Research;Mentors;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncogenes;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pharmacologic Substance;Phenotype;Physicians;Pilot Projects;Play;Positioning Attribute;Postdoctoral Fellow;Publications;Recruitment Activity;Recurrent disease;Regulation;Relapse;Research;Research Personnel;Resistance;Role;S100A8 gene;Scientist;Signal Transduction;Students;TP53 gene;Therapeutic;Transforming Growth Factor beta;Tumor-associated macrophages;Up-Regulation;Writing;Xenograft Model;antitumor effect;cancer therapy;career development;clinical development;cytokine;dimensional analysis;disorder control;gain of function;improved;in vivo;independency;inhibitor;insight;loss of function;mouse model;mutant;neoplastic cell;novel;novel strategies;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;patient derived xenograft model;preclinical development;prevent;programs;receptor;recruit;response;screening;single-cell RNA sequencing;skills;synergism;targeted cancer therapy;targeted treatment;transcriptome;translational study;tumor;tumor growth;tumor heterogeneity;tumor progression Tumor-TAMs crosstalk enables bypass of oncogenic KRAS dependency in pancreatic cancer Project NarrativeTumor associated macrophages (TAMs) play an important role in tumor progression metastasis immunesuppression and therapy resistance but their function in oncogenic KRAS inhibition resistance is largelyunknown. Preliminary study suggests that forced expression of HDAC5 in pancreatic cancer cells promotesactive recruitment of TAMs which provide TGF to support oncogenic KRAS independent tumor growth. Thisproposal aims to investigate the necessity of tumor-TAMs crosstalk in the bypass of KRAS dependency andexplore the therapeutic potentials by co-targeting KRAS and HDAC5-TAM-TGF axis in pancreatic cancer. NCI 10745920 11/3/23 0:00 PAR-18-467 5K22CA251491-03 5 K22 CA 251491 3 "JAKOWLEW, SONIA B" 12/1/21 0:00 11/30/24 0:00 Transition to Independence Study Section (I)[NCI(B)-I] 12480666 "HOU, PINGPING " Not Applicable 10 MICROBIOLOGY/IMMUN/VIROLOGY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 200281 NCI 185445 14836 Project Summary/AbstractThe proposed study is to explore novel strategies to prolong disease control of cancer targeted therapy.Oncogenic KRAS (KRAS*) is the key driver of pancreatic cancer and pharmaceutical inhibition of KRAS usingchemical and other approaches is extensively developed in recent years. Utilizing a doxycycline inducibleKRASG12D mouse model with conditional p53 knockout in pancreas (iKPC) our previous publication indicatesthat 70% PDAC tumors relapsed 0.5-1 year after KRAS* depletion. I identified that the crosstalk between tumorcells and tumor associated macrophages (TAMs) promotes KRAS* depletion resistance in PDAC. Myunpublished data shows that forced expression of HDAC5 in iKPC cells leads to upregulation of Ccl2 and Ccl7and recruitment of TAMs. S100A8+ TAMs express abundant TGF that enables KRAS*-independent tumorgrowth. I hypothesize that the HDAC5-TAMs-TGF axis may serve as a general mechanism for therapyresistance after KRAS* depletion in PDAC. In this proposal I will evaluate the therapeutic potential of targetingHDAC5 TAMs and TGF pathway in several human and mouse PDAC models by loss-of-function study.Specifically In Aim 1 I will determine the essentiality of HDAC5 in KRAS* bypass and the regulation of TAMrecruitment by endogenous HDAC5. In Aim 2 I will utilize multi-dimensional analysis to illustrate the phenotypicdynamics and heterogeneity of TAMs after KRAS* depletion and demonstrate the essentiality of TAMs fortumors to bypass KRAS* dependency. In Aim 3 I will utilize SMAD4 deficient models to access the essentialityof TGF/SMAD4 pathway activation in KRAS* bypass and delineate the molecular mechanisms of TGF-drivenKRAS* bypass. The proposed research program will help me to launch an independent faculty position in anacademic/medical research institution. Meanwhile I will keep expanding my research skills in bioinformaticsimmunology epigenetics and translational studies. In terms of my career development I will devote to improvemy skills on managing lab mentoring postdocs and students scientific writing and presentation and seeking forcollaborations among others. MD Anderson Cancer Center and Dr. Ronald DePinhos laboratory provide anexcellent environment for me to achieve these goals. I have also formed an extraordinary advisory committeecomposed of Drs. Giulio Draetta Raghu Kalluri and Anirban Maitra. They will not only provide me technicalsupport for my proposed study but also assist me to seek a faculty position and succeed as an independentinvestigator. With the help of K22 award I will have a good start to achieve my long-term goals which are tocontinue basic and translational studies in pancreatic cancer as a lab head including but not limited to targetedtherapy resistance and to contribute to developing novel cancer therapies with other scientists physicians andpharmaceutical companies as a team player. 200281 +No NIH Category available Affect;Alleles;BRCA1 gene;BRCA2 gene;Biochemical;Biological Assay;Biotinylation;Bypass;Cancer Etiology;Cells;Cisplatin;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Complex;Cytoprotection;DNA;DNA Binding;DNA Crosslinking Agent;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Replication Factor;DNA Sequence Rearrangement;DNA analysis;DNA biosynthesis;DNA lesion;DNA replication fork;Defect;Deoxyribonucleases;Development;Double Strand Break Repair;Electron Microscopy;Endometrial Carcinoma;Ensure;Event;Excision;Exhibits;Female;Gastric Adenocarcinoma;Gene Conversion;Genetic;Genetic Recombination;Genome Stability;Genomic DNA;Genomic Instability;Goals;Head and Neck Squamous Cell Carcinoma;Human Cell Line;In Vitro;Individual;Invaded;Knowledge;Lesion;Longevity;Malignant Neoplasms;Malignant neoplasm of ovary;Mass Spectrum Analysis;Meiosis;Meiotic Recombination;Metabolism;Methodology;Methods;Mitotic;Molecular;Monitor;Mus;Mutation;Myeloproliferative disease;Predisposition;Primary carcinoma of the liver cells;Property;Prostate Adenocarcinoma;Proteins;Proteomics;Regulation;Reporting;Resistance;Role;Site;Squamous cell carcinoma;Sterility;Structure;Syndrome;Technology;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;Visualization;Woman;cancer genomics;cancer type;crosslink;genome editing;genome integrity;helicase;homologous recombination;innovation;insight;malignant breast neoplasm;novel;preservation;primary ovarian insufficiency;recruit;repaired;replication stress;reproductive;response;single molecule;spatiotemporal;superresolution imaging;superresolution microscopy;tool;tumor;tumorigenesis Regulation of DNA synthesis in response to DNA damage PROJECT NARRATIVEDefective repair of DNA lesions causes the accumulation of mutations and genomic rearrangements thatpredispose to cancer development. MCM8 and MCM9 are tumor suppressor genes that promote DNA repair.Understanding the impact of MCM8 and MCM9 cancer-associated mutations on genomic instability will providenovel and important insights into the molecular events that drive tumorigenesis. NCI 10745914 12/5/23 0:00 PA-19-056 5R01CA197774-09 5 R01 CA 197774 9 "WEINREICH, MICHAEL DALE" 12/1/15 0:00 11/30/25 0:00 Cancer Etiology Study Section[CE] 10922131 "CICCIA, ALBERTO " Not Applicable 13 GENETICS 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 364500 NCI 225000 139500 PROJECT SUMMARYGenomic DNA is constantly challenged by DNA damage either spontaneously induced during cellularmetabolism or generated by exogenous DNA damaging agents. During DNA replication DNA lesions cancause the stalling or collapse of replication forks. Fork collapse results in the formation of DNA double-strandbreaks (DSBs). MCM8 and MCM9 (MCM8-9) form a helicase complex that promotes the repair of DSBs byhomologous recombination. We recently identified MCM8IP as a novel interactor of MCM8-9 that maintainsgenomic integrity after replication stress. In particular we showed that MCM8IP promotes DSB repair byhomologous recombination facilitates the restart of replication forks arrested by DNA lesions and protects cellsfrom DNA damage generated by replication stress-inducing agents. Despite these important preliminaryfindings the precise mechanisms of action exhibited by MCM8IP MCM8 and MCM9 during DNArecombination and replication remain to be elucidated. MCM8 or MCM9 have been reported to act as tumorsuppressors and recent cancer genomic analyses have evidenced mutations in MCM8 MCM9 and MCM8IP inmultiple cancer types. The goals of this proposal are to define the precise biochemical and cellular activitiesdisplayed by the MCM8IP-MCM8-9 complex for suppressing genomic instability and to examine how theseactivities are affected by mutations in MCM8IP MCM8 and MCM9 identified in tumors. In particular wepropose 1) to define the biochemical activities and physical interactions exhibited by the MCM8IP-MCM8-9complex for preserving genomic integrity; 2) to elucidate the mechanisms by which MCM8IP-MCM8-9promotes DSB repair and ensures replication fork progression in response to DNA damage; 3) to evaluate thecontribution of MCM8IP MCM8 and MCM9 cancer-associated mutations to genomic instability. Our approachwill utilize innovative proteomic methods state-of-the-art genome editing technologies single-moleculeanalyses of replication dynamics electron microscopy and super-resolution imaging. We anticipate that ourstudies will define the unique mechanisms employed by the MCM8IP-MCM8-9 complex to suppress genomicinstability and will provide insights into the potential contribution of MCM8IP MCM8 and MCM9 cancer-associated mutations to cancer etiology. 364500 +No NIH Category available Academic Medical Centers;Agreement;Animals;Breast;Breast-Conserving Surgery;Cancerous;Carcinoma;Cessation of life;Clinical;Clinical Trials;Cosmetics;Cyclic GMP;Cytology;Data;Detection;Development;Diffusion;Distant;Dose;Drug Kinetics;European;Evaluation;Excision;FDA approved;Fluorescence;Fluorescent Probes;Formalin;Frozen Sections;Goals;Health Care Costs;Home;Hour;Human;Image;Imaging Device;Infiltration;Malignant Neoplasms;Mammaplasty;Mammary Neoplasms;Mastectomy;Maximum Tolerated Dose;Methods;Microscopic;Molecular Probes;Morbidity - disease rate;Noninfiltrating Intraductal Carcinoma;Operative Surgical Procedures;Paraffin Embedding;Pathologic;Pathology;Patients;Peptide Hydrolases;Performance;Phase;Postoperative Period;Procedures;Process;Prognostic Factor;Quality of life;Radiation therapy;Recurrence;Recurrent disease;Repeat Surgery;Residual Cancers;Risk;Risk Factors;Safety;Sampling;Savings;Signal Transduction;Specimen;Surface;Surgeon;Survival Rate;Techniques;Technology;Testing;Time;Tissue Sample;Tissues;Topical application;Touch sensation;Toxicology;Translating;Translational Research;Translations;Tumor Tissue;Vascularization;Woman;acute toxicity;breast lumpectomy;cancer cell;clinical application;clinical imaging;clinical translation;experience;first-in-human;healthy volunteer;image guided;imager;imaging agent;imaging probe;imaging study;in vivo;industry partner;malignant breast neoplasm;manufacturing capabilities;manufacturing facility;molecular imaging;mortality risk;next generation;novel;novel strategies;optical imaging;pharmacokinetics and pharmacodynamics;photonics;preclinical imaging;preclinical study;prevent;sample fixation;screening;standard of care;success;tumor Fluorescence-guided resection of breast tumors using a topically-applied molecular probe Project Narrative:The purpose of this academic/industrial partnership project is to translate an integrated imaging solution for thedetection of residual cancer on or near the surface of the surgical cavity after standard-of-care BreastConservation Surgery (BCS or lumpectomy). Consisting of a quenched fluorescent probe applied topically invivo to the surgical cavity and an FDA-approved imaging instrument (the PDE neo Hamamatsu Photonics)this technology has the potential to reduce repeat procedure rates due to incomplete resection (currentlybetween 8% and 86%) The final approved platform will have the potential to significantly reduce healthcarecosts due to repeat surgeries with associated reductions in risks of mortality/morbidity and enhancement inpatient quality-of-life. NCI 10745913 12/22/23 0:00 PAR-18-560 5R01CA246678-05 5 R01 CA 246678 5 "GRODZINSKI, PIOTR" 1/1/20 0:00 12/31/25 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 8479886 "BASILION, JAMES PETER" Not Applicable 11 RADIATION-DIAGNOSTIC/ONCOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 394 Non-SBIR/STTR 2024 388350 NCI 284928 103422 Project Summary/Abstract: Breast cancer is the most common cancer in women with an estimated 246660cases (and 40450 deaths) in the US during 2015. Due to better screening techniques cancers are caught earlierand 75% of patients are candidates for breast conserving surgery (BCS) to remove the cancer. BCS iscosmetically preferable to the alternative (mastectomy) and long-term survival rates are equivalent [1]. Thesuccess of BCS is assessed post-operatively by pathology. The status of the microscopic margins of excision ofthe lumpectomy specimen is still the most important prognostic and risk factor for local recurrence [23]. Apositive margin indicates that invasive carcinoma or ductal carcinoma in situ is touching a tissue edge of alumpectomy specimen. Among patients treated by BCS and radiation therapy positive margins are associatedwith a 2-fold increase in the risk of local recurrence when compared with negative margins [4]. A finding ofpositive margins is estimated to occur between 8% to 86% of the time requiring patients to return for furthertreatment often associated with poorer cosmetic results and increases in local and distant recurrence of thedisease. Current pathology methods only assess about 1/10 of 1% of the entire volume of the removed specimen.A consequence of margin undersampling is that local recurrence occurs in 5-16% of patients with pathologicallyclean margins suggesting that one or more regions of tumor had not been sampled during pathological analysisresulting in tumor remaining in the patient. In addition there is still no universal agreement among breastsurgeons on what constitutes an adequate negative margin for patients undergoing BCS [5]. Together thesedata demonstrate the unmet clinical need for technologies that rapidly and globally identify cancerous tissues inthe surgical cavity and can be used to guide their surgical resections during the procedure. Molecular imagingguided resections of tumors during surgeries are now being developed. However most approaches employ IVadministration of optical imaging agents which require hours or days to highlight tumor tissues. Moreoverinfiltrating cancer cells in tissues surrounding the main mass may not have developed a vasculature and likelywould not be identified using injected agents. Finally illuminating the entire cancer mass may create a highbackground signal from tumor that is not at the margin of the lumpectomy. Exploiting increased proteaseexpression at the edge of breast cancers we introduce the novel concept of in vivo topical administration ofquenched fluorescent molecular imaging probes to identify cancer that may remain in the surgical cavity afterstandard-of-care resection. This builds on years of preclinical studies and seeks to characterize performtoxicology and finally a Phase 1A & B clinical trial to demonstrate the utility of this novel approach. It has thepotential to reduce re-excisions as well as the false negative rate from pathology undersampling with aconsequent savings in healthcare costs and enhancement in patient life quality. 388350 +No NIH Category available Alleles;Automobile Driving;Biogenesis;Biological Models;Buffers;CRISPR/Cas technology;Carbon;Cell Proliferation;Cell Respiration;Cell division;Cells;Chromatin;Clinical;Consumption;Data;Defect;Development;Dietary intake;Disease;Drug Targeting;Enzymes;Frequencies;Gene Expression;Genes;Genetic Transcription;Global Change;Goals;Growth;Histone H3;Histones;Human;Human Cell Line;Hypoxia Inducible Factor;In Vitro;Isotope Labeling;KRAS2 gene;KRASG12D;Link;Lipids;LoxP-flanked allele;Lung Adenocarcinoma;Lysine;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolic Pathway;Metabolism;Methionine;Methylation;Methyltransferase;Mitochondria;Molecular;Molecular Abnormality;Mus;Mutate;Mutation;Oncogenic;Oxidative Phosphorylation;PPAR gamma;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Post-Translational Protein Processing;Protein Biosynthesis;Proteomics;Publishing;Regulation;Regulator Genes;S-Adenosylhomocysteine;S-Adenosylmethionine;Serine;Signal Transduction;Supporting Cell;System;Testing;Therapeutic;Tumor Promotion;Tumor Suppressor Proteins;Work;cancer cell;cancer type;cell growth;clinical efficacy;dietary;dietary restriction;efficacy evaluation;enzyme mechanism;histone methyltransferase;in vivo;inhibitor;lipidomics;loss of function;metabolomics;mouse model;neoplastic cell;novel therapeutic intervention;patient derived xenograft model;pre-clinical;programs;rational design;synthetic lethal interaction;transcription factor;tumor;tumor progression Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma PROJECT NARRATIVEMutations in chromatin regulating enzymes are a common feature of many cancer typesincluding lung adenocarcinoma. Our poor understanding of the mechanistic consequences thatthese mutations have on tumor progression hampers our development of new treatmentstrategies that exploit molecular vulnerabilities that may exist in these tumors. The overall goalof our project is to identify the molecular aberrations and potential therapeutic vulnerabilities incancers where SETD2 a chromatin regulating enzyme and tumor suppressor is inactivated. NCI 10745910 11/17/23 0:00 PA-20-185 5R01CA262619-03 5 R01 CA 262619 3 "WILLIS, KRISTINE AMALEE" 12/10/21 0:00 11/30/26 0:00 Tumor Cell Biology Study Section[TCB] 10328995 "FELDSER, DAVID " Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 389015 NCI 239394 149621 PROJECT SUMMARY SETD2 is mutationally inactivated in many cancer types including lung adenocarcinoma. In publishedwork we demonstrated that Setd2 inactivation has potent tumor promoting effects in an autochthonous mousemodel of KRASG12D-driven lung adenocarcinoma. SETD2 uniquely catalyzes histone H3 lysine 36trimethylation (H3K36me3) which marks actively transcribed gene bodies facilitating chromatin resetting aftergene transcription. In the current project we aim to understand the provocative observation that SETD2inactivation potently drives tumor cell proliferation due to a defect in one-carbon metabolism and activation ofmTORC1 signaling. We demonstrate that SETD2 loss is associated with an enrichment in the abundance of S-adenosyl methionine (SAM) and multiple other metabolites that are part of SAM-adjacent metabolic pathways.We will test the hypothesis that the disuse of SAM that results from the lost activity of the SETD2methyltransferase leads to SAM accumulation enhanced one-carbon metabolism and activation of mTORC1signaling all supporting cell growth and proliferation. Consistent with this hypothesis we demonstrate thatlimiting dietary intake of methionine reduces KRAS-driven lung adenocarcinoma growth and reverses theeffects of SETD2 inactivation. Thus we will assess the efficacy of clinical and pre-clinical drugs that target themethionine cycle for potential synthetic lethal interactions with SETD2 deficiency. Finally downstream ofactivated mTORC1 signaling we observe prominent transcriptional programs of hypoxia inducible factors(HIFs) and peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC1). Consistently weobserve multiple pathophysiological changes that are associated with increased activation of HIF and PGC1transcription such as alterations in mitochondrial biogenesis and the co-enhancement of oxidativephosphorylation and glycolytic pathways. Thus we will test the requirement of these master transcriptionfactors for effectuating phenotypes downstream of SETD2 inactivation. 389015 +No NIH Category available Affinity;African American;Antineoplastic Agents;Area;Binding;Biochemistry;Biophysics;Calorimetry;Complex;Computational Biology;Computer Analysis;Data Analyses;Development;Generations;Grant;Health;Ligands;Lysine;MLL-rearranged leukemia;New York;Parents;Patients;Pharmacology;Prognosis;Protac;Proteins;Public Health;Reporting;Research;Resolution;Site-Directed Mutagenesis;Statistical Data Interpretation;Structure;System;Techniques;Titrations;Training;Translational Research;Ubiquitin;X-Ray Crystallography;design;doctoral student;drug discovery;elongin B;elongin C;improved;insight;interest;medical schools;multicatalytic endopeptidase complex;novel therapeutic intervention;protein expression;protein protein interaction;protein purification;standard care;structural biology;training opportunity;translational medicine;treatment strategy;ubiquitin-protein ligase Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias PROJECT NARRATIVEMLL-rearranged leukemia patients have a dismal prognosis and respond very poorly to standard treatments.The proposed studies will facilitate design and development of effective WDR5 degraders as a novel therapeuticstrategy for the treatment of MLL-rearranged leukemias. Thus the proposed research is directly relevant topublic health. NCI 10745902 4/25/23 0:00 PA-21-071 3R01CA268384-02S1 3 R01 CA 268384 2 S1 "O'HAYRE, MORGAN" 5/1/22 0:00 4/30/27 0:00 Developmental Therapeutics Study Section[DT] 9738898 "JIN, JIAN " "WANG, G GREG " 13 PHARMACOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 97018 NCI 58026 38992 Project SummaryThis is an application for a Research Supplement to Promote Diversity in Health-Related Research (PA-21-071).The parent R01 grant associated with this application is entitled Discovery of First-in-class WDR5 PROTACsas a Novel Therapeutic Strategy for MLL-rearranged Leukemias and supported by the NCI(1R01CA268384-01). Jerrel Catlett is the diversity candidate. He is a US citizen of African-American descentand is currently an MD/PhD student at the Icahn School of Medicine at Mount Sinai New York. In this projectthe candidate will conduct structural biology biochemistry biophysics and computational biology studies tocharacterize PRORAC-induced WDR5-PROTAC-E3 ligase ternary complexes and to provide new structuralinsights for the PROTAC-induced ternary complex formation and guide design and development of moreeffective WDR5 degraders. 97018 +No NIH Category available Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen Project NarrativeHigh-risk Acute Myeloid Leukemia and Myelodysplastic Syndrome are aggressive hematologic cancersassociated with a very poor prognosis with less than 20% of patients surviving beyond 1 year. Venetoclax aBCL-2 inhibitor is one of the most exciting drugs in AML therapy. In this project we designed a Phase II clinicaltrial combining venetoclax with an optimized 10-day decitabine regimen in unfavorable risk categories of AMLand MDS with goals to improve outcomes of these patients by accelerating molecular responses and to furthercharacterize molecular determinants of response and resistance. NCI 10745877 3/1/23 0:00 PA-21-268 7R01CA235622-05 7 R01 CA 235622 5 "HENDERSON, LORI A" 6/17/19 0:00 5/31/24 0:00 Clinical Oncology Study Section[CONC] 7847414 "KONOPLEVA, MARINA Y" "SPENCER, DAVID H" 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 12/1/22 0:00 5/31/23 0:00 395 Non-SBIR/STTR 2022 270880 NCI 236667 34213 PROJECT SUMMARYThe outcomes of elderly patients and relapsed/refractory patients with either acute myeloid leukemia (AML) ormyelodysplastic syndromes (MDS) remain poor. Venetoclax is a selective BCL-2 inhibitor that recentlydemonstrated impressive activity when combined with hypomethylating agents decitabine or 5-azacitidine;however outcomes remained more modest among patients with unfavorable risk cytogenetics or with TP53mutations. Building on recent findings that increasing the schedule of decitabine from days 1-5 to days 1-10 of28 day cycles was associated with improved overall responses and survival among patients with unfavorable-risk cytogenetics and TP53 mutations we hypothesize that concomitant use of venetoclax and 10-daydecitabine will improve the response and survival rates especially in patients with high-risk karyotypes or TP53mutations. We designed a Phase II trial that will enroll four parallel open-label cohorts each with 40 patientsconsisting of high-risk AML or MDS patients either with advanced age or with relapsed/refractory disease. Theprimary objective is to determine the composite overall response rate; secondary objectives include determiningdisease-free and overall survival and the impact of high-risk karyotypes on response and survival. In additiontwo molecular hypotheses will be tested. First that clearance of exome-defined founding clone mutations fromthe peripheral blood provides a consistent and quantified response end-point that circumvents many sources ofinter-patient response variability and that combination venetoclax and decitabine will be associated withincreased rate and depth of mutation clearance vs. single-agent decitabine. Determining whether ahypomethylating doublet has improved outcomes vs. single-agent has been challenging for all but largerandomized studies partially due to clinical confounders such as hemodilute aspirates and poor count recoveryin older and heavily pre-treated patients. This novel approach to response determination isolates anti-leukemicactivity from other factors thus improving statistical power of the study. Second we will determine whetherresponses to combination venetoclax and decitabine correlate with leukemic dependence on BCL-2 activity oron other anti-apoptotic proteins. We will apply dynamic BH3 profiling to determine the dependence of AML blastson BCL-2 BCL-XL or MCL-1 and correlate these results with response survival and mutation patterns. Furtherwe will apply CyTOF analysis to serial bone marrow samples obtained during therapy and at relapse. We willquantify leukemia stem cell subpopulations and the expression of BCL-2 family proteins within bulk AML cellsvs. leukemia stem cells. These data will determine whether combination venetoclax and decitabine leads toelimination of both bulk and leukemia stem cell populations and whether sensitivity within subpopulationscorresponds with intracellular levels of BCL-2 family proteins. Collectively these studies will evaluate clinicalresponses and molecular outcomes of a novel combination therapy and will identify prognostic biomarkers andresistance mechanisms. 270880 +No NIH Category available Targeting mitochondrial complex I in acute lymphoblastic leukemia PROJECT NARRATIVEA leukemia called T-ALL cannot be cured by current treatments in more than half of adult patients. This projectwill test novel experimental drug affecting tumor metabolism alone and in combinations for suppression of ALLdisease development in laboratory models. Phase I/II clinical trial will examine safety and efficacy ofcombinations with standard chemotherapy in relapsed/refractory ALL. NCI 10745872 3/3/23 0:00 PA-21-268 7R01CA231364-05 7 R01 CA 231364 5 "HENDERSON, LORI A" 6/14/19 0:00 5/31/25 0:00 Developmental Therapeutics Study Section[DT] 7847414 "KONOPLEVA, MARINA Y" Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 12/1/22 0:00 5/31/23 0:00 395 Non-SBIR/STTR 2022 287375 NCI 221374 66001 ABSTRACT T-cell acute lymphocytic leukemia (T-ALL) is an aggressive hematological malignancy. Despitesuccesses in curing pediatric T-ALL with intensive chemotherapy the majority of adult T-ALL patients will relapseand die of their disease. We and others have demonstrated that in T-ALL oxidative phosphorylation (OxPhos)generates energy and metabolic intermediates necessary to promote growth and support survival by regulationof mitochondrial Complex I (CI). This unique metabolic and mitochondrial biology makes T-ALL vulnerable tostrategies that target OxPhos. We have identified a first-in-class nanomolar-potent inhibitor of OxPhos (OxPhosi) IACS-010759 thatinhibits CI of the OxPhos respiratory chain blocks oxygen consumption and destabilizes Hypoxia-InducibleFactor 1 (HIF-1). Our data demonstrated profound growth-inhibitory effects of this agent in T-ALL cell linesand primary ALL cells at low nM concentrations with minimal toxicity against normal BM cells. OxPhos blockadein vivo was tolerable as a single agent yet had only a modest therapeutic benefit. However targeting theOxPhos-driven biology of T-ALL is likely to be effective in the right combinations. We have demonstrated synergyof IACS-010759 with standard chemotherapy agents used in T-ALL both in vitro and in the in vivo T-ALL PDXmodels. We will translate these findings in our Aim 3 by a Phase I/II clinical trial of IACS-010759 combined witha modified hyperCVAD/L-asparaginase regimen in relapsed/refractory ALL patients using the recommendedPhase 2 dose of IACS-010759 from the ongoing AML trial. Matching pre-clinical studies on T-ALL PDX modelsin Aim 1 will develop biomarkers of response in ways not possible in human subjects. We have further identifieda synthetically lethal combination in T-ALL cells of OxPhosi with an inhibitor of the lactate transporter MCT1(AZD3965 now in Phase 2 trials) and in Aim 2 will investigate mechanisms of this synergy. We will alsocharacterize the effect of HIF-1 blockade by IACS-010759 on T-ALL cells using in vivo two-photon imaging ofmetabolic NADH and oxygen sensing by phosphorescence lifetime microscopy. Finally we will conduct furtherscreening with a novel high-content metabolomic drug library to identify other combinations with IACS-010759that are toxic to T-ALL cells but not normal cells for future therapeutic applications. We believe that the proposed studies will provide mechanistic insights into the newfound vulnerability ofT-ALL to OxPhosi; identify candidate predictive biomarkers for the combination of IACS-010759 withchemotherapy or MCT1 inhibitor; and develop combinations for the next generation of OxPhosi trials for T-ALL. 287375 +No NIH Category available Affect;Breast Cancer Cell;Butyrates;Cells;Colon Carcinoma;Colorectal;Data;Diagnostic Neoplasm Staging;Diet;Endocrine;Energy-Generating Resources;Fasting;Fatty Acids;Fatty acid glycerol esters;Healthcare;Histone Deacetylase Inhibitor;Immune checkpoint inhibitor;Ketoses;Ketosis;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolic;Metabolism;Metastatic Neoplasm to the Liver;Metastatic to;Mission;Modeling;Neoplasm Metastasis;Neurodegenerative Disorders;Nicotinic Acids;Nutritional;Organ;Pancreatic Ductal Adenocarcinoma;Patient Care;Patients;Primary Neoplasm;Prostate;Reporting;Research;Role;Signal Transduction;Signaling Molecule;Site;Stress;Tumor Suppressor Proteins;United States National Institutes of Health;Warburg Effect;cancer stem cell;cancer therapy;cancer type;carcinogenesis;improved;innovation;ketogenesis;ketogenic diet;ketogentic;metastatic colorectal;receptor;tumor progression The paradoxical roles of beta hydroxy butyrate in the liver pro-metastatic niche Project Narrative: The paradoxical roles of beta hydroxy butyrate in the liver pro-metastaticniche.The proposed research aims to elucidate the role of ketogenesis in the liver microenvironment for apro-metastatic niche. This study will be applied to prostate and colorectal cancer metastatic modelswhich are incurable once metastasized and will provide new targetable mechanisms to improve patientcare. Therefore this research pertains to the NIH mission to innovate and advance health carestrategies. NCI 10745869 3/30/23 0:00 PA-21-071 3P01CA233452-04S2 3 P01 CA 233452 4 S2 "WATSON, JOANNA M" 1/21/20 0:00 12/31/24 0:00 ZCA1(O1) 1895258 "LU, SHELLY CHI-LOO" "BHOWMICK, NEIL A." 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 3/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2023 140891 NCI 84366 56525 Project Summary/AbstractLiver metastasis is a steep obstacle for curative cancer treatment. Several cancers including prostate (PCa)colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC) commonly metastasize to this site. Data showsthat liver metastasis is promoted by endocrine signaling from the primary tumor which can transform the livermicroenvironment. Nonetheless this pre-metastatic to post-metastatic niche transformation can also beinfluenced by therapy and diet. The ketogenic diet (KD) is a high-fat carb-restrictive diet that mimics fasting bymaking fatty acids the main source of energy and promoting beta hydroxy butyrate (HB) synthesis (ketosis).KD has been successfully used to aid patients with neurodegenerative diseases. Additionally it has beenproposed to ameliorate different types of cancer by inducing a reverse-Warburg effect and sensitizing cells tocheckpoint inhibitors. However reports show that HB enables adaptability to nutritional stress in cancer stemcells and is associated with tumor progression and staging of prostate cancer. Nevertheless HB is also areported tumor suppressor being a known HDAC inhibitor and a signaling molecule through the niacin receptorGPR109a in colon and breast cancer cells. Understanding that the liver is the main HB synthesis organ in thisstudy we aim to elucidate the effects of a ketogenic metabolism affecting the liver premetastatic niche and itsparadoxical roles with PCa and CRC in their distinct metabolic reprogramming. 140891 +No NIH Category available Antineoplastic Agents;Biological Assay;Biological Process;Cell Cycle;Cell Line;Cells;Cellular biology;Chemicals;Communities;DNA Damage;DNA biosynthesis;Diabetes Mellitus;Disease;Disease Progression;Drug Targeting;Environment;Etiology;FDA approved;Family;Family member;Free Will;Health;Human;Individual;Inflammatory Bowel Diseases;Link;Malignant Neoplasms;Measures;Medicine;Mitosis;Molecular;Neurons;Oncology;Output;Pathologic;Pathway interactions;Pharmaceutical Chemistry;Phosphotransferases;Physiological;Play;Process;Proliferating;Protein Family;Protein Kinase;Proteins;Proteome;Reagent;Reporter;Research;Research Personnel;Resources;Role;Scientist;Signal Pathway;Signal Transduction;System;cancer therapy;chronic inflammatory disease;ciliopathy;cilium biogenesis;drug discovery;druggable target;inhibitor;kinase inhibitor;knock-down;member;migration;new therapeutic target;response;success;supplemental instruction;tool Identification and characterization of chemical probes for interrogation of the NEK family of kinases in cancer (Diversity Supplement - Belgodere) PROJECT NARRATIVEThe Never in mitosis A-related kinase (NEK) family of protein kinases is an important yet understudied kinasefamily that has recently been implicated in a variety of disorders including numerous cancers ciliopathieschronic inflammatory diseases and neuronal disorders. The lack of reliable tools to study NEK function hasmade it difficult to determine the specific role(s) that NEK family members play in the etiology and progressionof these diseases. In the proposed project we will use a generalizable family-based strategy to develop a suiteof tools including high quality chemical probes that will be made freely available to the biomedical researchercommunity and enable researchers to build a firm understanding of how these understudied kinases contributeto health and disease and validate new druggable targets for cancer drug discovery. NCI 10745843 5/17/23 0:00 PA-21-071 3R01CA273095-01S1 3 R01 CA 273095 1 S1 "FORRY, SUZANNE L" 9/1/22 0:00 8/31/26 0:00 14608541 "DREWRY, DAVID HAROLD" "BUROW, MATTHEW E." 4 NONE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PHARMACY 275995023 UNITED STATES N 3/1/23 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2023 110183 NCI 96308 13875 ABSTRACT / PROJECT SUMMARYKinases a class of proteins with more than 500 members in the human proteome are important regulators ofbiological processes in health and disease. Kinases have proven to be excellent drug targets with more than 70FDA approved medicines that target kinases. Despite this success most kinases are understudied and detailsof their functions are poorly understood. The NEK family of 11 kinases (NEK1 through NEK11) is a particularlyunderstudied set of kinases that play roles in key biological processes like the cell cycle ciliogenesis and theDNA damage response (DDR) all with relevance to cancer and human health. These kinases have emerginglinks to numerous cancers diabetes inflammatory bowel disease ciliopathies and ALS. In this project we willuse an efficient kinase systems-based approach to create an enabling suite of chemical probes assaysreagents and molecular tools to identify NEK family members that have key roles in cancer. These high-qualitycompounds and reagents we generate which we will freely share will allow scientists to build a deepunderstanding of the physiological and pathological roles members of the NEK family play. In Aim 1 we willcreate potent and selective inhibitors of each NEK using iterative medicinal chemistry and state of the art in celltarget engagement assays. In a complementary effort for this aim we will also create inducible NEK knockdowncell lines. In Aim 2 using compounds and the NEK knockdown lines we will evaluate the role and importance ofeach NEK in a suite of NEK and oncology-relevant cell health and cell biology signaling assays measuringeffects on proliferation migration the cell-cycle DNA replication and ciliogenesis. In Aim 3 we willexperimentally determine the substrates of each NEK locate the NEKs in broader kinase-dependent signalingpathways and develop genetically targetable kinase activity reporters for tracking NEK activity within theendogenous cellular environment. Output from this project will include potent and selective NEK inhibitors NEKfamily-wide assays details on the impact of NEK inhibition and knockdown on key cancer processes moleculartools and NEK substrate and pathway information. Successful completion will provide a framework and theresources needed to validate individual NEKs as high quality druggable targets for the treatment of cancer. 110183 +No NIH Category available Acetic Acids;Africa South of the Sahara;Carbon Dioxide;Cervical;Coagulation Process;Collaborations;Colposcopy;Development;Devices;Disadvantaged;Engineering;Excision;Failure;Gases;In Vitro;Laboratories;Malignant neoplasm of cervix uteri;Medical;Medical Device;Methods;Modeling;Normalcy;Performance;Randomized;Randomized Controlled Trials;Scanning;Testing;Time;Utah;Visual;Woman;Zambia;arm;compare effectiveness;cost;efficacy evaluation;field study;handheld equipment;histopathological examination;improved;in vivo;light weight;low and middle-income countries;novel;overtreatment;portability;premalignant;prevent;programs;public health relevance;satisfaction;screening program;standard care;success;trial comparing Development field testing and evaluation of the efficacy of a hand-held portable and affordable thermo-coagulator to prevent cervical cancer in low- and middle-income countries PUBLIC HEALTH RELEVANCE: This project will develop test and produce a lightweight cordless battery driven and rechargeable hand-held device for treating cervical precancer (Liger Thermal Coagulator). The study will evaluate its effectiveness compared to the current standard treatment (cryocautery) when used as part of a screen and treat programme using Visual Inspection with Acetic acid (VIA) in Sub Saharan Africa. NCI 10745754 12/2/22 0:00 RFA-CA-15-001 3UH3CA202721-05S3 3 UH3 CA 202721 5 S3 "LIDDELL HUPPI, REBECCA" 7/7/16 0:00 2/29/24 0:00 ZCA1-TCRB-6(A2) 14639587 "BASU, PARTHA " Not Applicable n/a Unavailable 279551881 HSMZYXZ7M358 279551881 HSMZYXZ7M358 FR 45.74846 4.84671 337706 INTERNATIONAL AGENCY FOR RES ON CANCER LYON Unavailable 69007 FRANCE N 12/1/22 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 442901 NCI 432137 10764 DESCRIPTION (provided by applicant): Successful cervical precancer screening programmes have not been replicated widely in Low and Middle Income Countries (LMICs) for a variety of reasons but largely due to the expense of laboratory based tests and colposcopy. Instead screen and treat programmes have been established relatively widely. These programmes are not trouble or cost free but are relatively inexpensive and successful. The most commonly used combination is Visual Inspection with Acetic acid (VIA) to screen and cryocautery to treat. Both of these have disadvantages. VIA overcalls abnormality relatively frequently and cryocautery is fraught with difficulties in gas (CO2 or N2O) supply both because it is variably expensive variably available and difficult to transport. Furthermore the long treatment time of cryocautery (11minutes in total) is perceived as a relative problem compared to Thermal Coagulation (1 - 2 mins) or LLETZ (1-2 minutes). Aims : This project aims to improve screen and treat programmes by discovering the best method of treatment and by reducing the treatment of normal women. The specific aims are 1. To develop test and produce 200 novel lightweight hand-held cordless portable battery driven and rechargeable Thermal Coagulators (Liger Medical Utah). 2. To evaluate the success / failure rate of Thermal Coagulation in a randomised controlled trial comparing thermal coagulation to the existing current standard cryocautery and to Large Loop Excision of the Transformation Zone (LLETZ aka LEEP) as part of a screen and treat programme in Zambia. 3. To evaluate the user satisfaction scores of the Liger Thermal Coagulator cryocautery as part of a screen and treat programme in Zambia. 4. To determine the rate of over treatment of VIA positive women as revealed by histopathological examination of the randomly assigned excised treatment cases. 5. To determine the value of Z scan to predict normality and abnormality in VIA positive women randomly assigned to excisional therapy Methods : In collaboration with a medical devices company in Utah we will develop and test the engineering performance of the Liger Thermal Coagulator in vitro and in vivo. We will produce 200+ Liger units and undertake a randomised controlled trial of the device compared to cryocautery and LLETZ using efficacy and user friendliness as endpoints. The inclusion of a study arm of excisional therapy will allow us to quantify the rate of overtreatment in VIA programmes and using the Z scan may allow for a non invasive method of accurately predicting normality and abnormality in VIA positive women 442901 +No NIH Category available ADP ribosylation;Action Potentials;Address;Affect;Antineoplastic Agents;Cancer cell line;Catalysis;Cause of Death;Cell Proliferation;Cells;Cessation of life;Chemicals;Colon;Colorectal Cancer;Complex;DNA Sequence Alteration;Development;Dimerization;Epithelial Cells;Genetic;Goals;Hand;Homeostasis;Human;Hyperactivity;Imaging Techniques;Intercept;Investigation;Link;Liquid substance;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Methods;Molecular;Mus;Mutation;Neoplasm Metastasis;Oncogenic;Outcome;Pathway interactions;Penetration;Pharmaceutical Preparations;Phase;Phenocopy;Polymerase;Population;Property;Protac;Protein Dynamics;Protein Family;Proteins;Proteome;Proteomics;Reporting;Research;Residual state;Resistance;Series;Signal Pathway;Signal Transduction;Site;Specificity;Tankyrase;Therapeutic;Therapeutic Agents;Time;Toxic effect;Validation;WNT Signaling Pathway;Work;Writing;anti-cancer;beta catenin;cancer cell;clinical investigation;colon cancer cell line;drug action;improved;in vivo;inhibitor;interest;knock-down;live cell imaging;new technology;novel therapeutic intervention;novel therapeutics;potential biomarker;preclinical study;prevent;programs;protein degradation;response;scaffold;small molecule;therapeutic target;tool;tumorigenesis Therapeutic targeting of Wnt signaling in cancer Project NarrativeDrugging the oncogenic Wnt/-catenin pathway is a prominent yet unsolved problem. We have previouslyfound targeting tankyrases a viable approach and now present a solution to address the unexpected resistanceissue. This study will cover the development of a new therapeutic agent a thorough investigation of its mode ofaction and the validation of its anticancer potential in mice. NCI 10745732 11/3/23 0:00 PA-20-185 5R01CA269377-02 5 R01 CA 269377 2 "GREENBERG, WILLIAM A" 12/1/22 0:00 11/30/27 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 8576057 "CHEN, CHUO " Not Applicable 30 BIOCHEMISTRY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 583848 NCI 356005 227843 Project Summary/AbstractThe overarching goal of our research program is to develop small-molecule anticancer drugs. We focus hereinon a new chemical method to control aberrant Wnt/-catenin signaling that drives tumorigenesis andmetastasis of many cancers in particular colorectal cancer (CRC). CRC affects about 4% of the populationand caused ~60000 deaths in 2021. Despite decades of effort drugging this oncogenic pathway has not beensuccessful. In 2009 we reported for the first time that Wnt/-catenin signaling can be intercepted by smallmolecules. Catalytic inhibition of tankyrases prevents the turnover of the Axin which leads to a rapidaccumulation of Axin. The accumulated Axin then stabilizes the -catenin destruction complex (DC) to facilitatethe degradation of -catenin. However using this strategy to treat cancer has not been successful. Recentstudies suggest that tankyrases can paradoxically support Wnt/-catenin signaling through molecularscaffolding. The unexpected dichotomous mode of action potentially explains the unsatisfactory outcomes ofvarious preclinical studies of tankyrase inhibitors. Although the mechanism by which tankyrases sustain Wnt/-catenin signaling is not clear mounting evidence suggests that the tankyrase aggregation is responsible for it.In this study we will develop a chemical strategy to control the catalysis-independent function of tankyrases.We will then use this new tool to study how tankyrases affect the dynamic assembly of DC. We will further usea proteomic approach to delineate the catalytic and scaffolding functions of tankyrases with detailedcharacterization of their mode of action. This work will help us understand how tankyrases control multiplesignaling pathways important to cancer. Additionally we will compare the responsiveness of a large panel ofimmortalized human colonic epithelial cell lines and CRC cell lines toward tankyrase inhibition and depletion.We will then corroborate the results with in vivo studies. Correlating the cellular sensitivity with their geneticbackground will provide potential biomarkers and inform therapeutic strategies for cancers. Overall this projectwill address the unsolved issue in drugging the Wnt/-catenin pathway and improve our understanding of howtankyrases control Wnt/-catenin signaling. 583848 +No NIH Category available 3-Dimensional;Acceleration;Actins;Animals;Apoptotic;Autoimmune;BRAF gene;Biology;Blood Vessels;Bromodeoxyuridine;Cells;Characteristics;Critical Pathways;Dermal Neoplasm;Dermis;Distant;Endothelial Cells;Epidermis;Focal Adhesions;Genes;Genetically Engineered Mouse;Genomics;Growth;Hair follicle structure;Health;Histologic;Human;Image;Immunotherapy;In Vitro;Invaded;Label;Lymphangiogenesis;Lymphatic;Lymphatic Endothelial Cells;Malignant Neoplasms;Measures;Melanoma Cell;Metastatic Melanoma;Metastatic Neoplasm to Lymph Nodes;Metastatic Neoplasm to the Lung;Modeling;Molecular;Monomeric GTP-Binding Proteins;Neoplasm Metastasis;Nevi and Melanomas;Nevus;Nutrient;Oncogenes;Organ;Patients;Play;Prognosis;Publishing;Role;Secondary to;Signal Transduction;Skin;Stress;Stress Fibers;Testing;Therapeutic;Therapeutic Agents;Tissues;Transgenic Mice;Tumor Angiogenesis;Tumor Biology;Tumor Promotion;Tumor stage;Tumor-Associated Process;Vascular Endothelial Cell;Vascularization;Work;Xenograft Model;angiogenesis;cell growth;human model;in vivo;in vivo imaging;inhibitor;kinase inhibitor;lymph nodes;lymphatic development;lymphatic vessel;melanocyte;melanoma;migration;mouse model;mutant;neoplastic cell;novel;novel therapeutic intervention;pharmacologic;prevent;recruit;side effect;small molecule;stem cells;therapeutic target;three-dimensional modeling;tumor;tumor growth;tumor initiation;tumor progression;unpublished works Identifying Therapeutic Targets for Stage III Melanoma While immunotherapies and kinase inhibitors can successfully treat metastatic melanoma they are notroutinely used to treat melanomas that have not yet disseminated systemically secondary to their sideeffects. Our recent work suggests that RhoJ plays a dual role in tumor biology- it promotes tumorformation while also controlling the ability of endothelial cells to form vessels in and around tumors. Herewe propose that RhoJ plays a selective role in tumor formation tumor angiogenesis andlymphangiogenesis. We test this hypothesis using genetically engineered mice advanced imaging andgenomics and newly developed RhoJ inhibitors. Completion of these studies will identify a newtherapeutic strategy that can be used to treat early stage melanoma and other cancers. NCI 10745698 12/14/23 0:00 PA-19-056 5R01CA244571-05 5 R01 CA 244571 5 "WOODHOUSE, ELIZABETH" 12/4/19 0:00 11/30/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 8584215 "GANESAN, ANAND K" Not Applicable 47 DERMATOLOGY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 376161 NCI 244283 131878 During the process of tumor progression melanoma cells must exit the epidermis to form a dermal tumorrecruit lymphatic vessels and then migrate to lymph nodes before metastasizing to distant organs.Melanoma prognosis directly correlates with tumor depth and lymph node metastasis. Therefore idealtherapeutic agents for early stage melanoma would not only block melanoma invasion but alsoprevent tumor cells from accessing lymphatic vessels. Published work from our group determined thatRhoJ a gene that allows melanoma cells to resist BRAF oncogene-induced stress is highly expressed inmelanoma tumors that metastasize to the lymph node. RhoJ deletion stalled the growth of BRAF mutantmelanoma tumors and inhibited the formation of BRAF mutant nevi in vivo. In addition to its selective rolein controlling the growth of BRAF mutant melanocytes RhoJ plays a specific role in tumor angiogenesis.RhoJ signaling in peritumoral endothelial cells induces them to generate vessels that serve as conduits forboth nutrients to enter tumors and metastasizing cells to exit tumors. Recent yet unpublished worksuggested that RhoJ deletion inhibited the ability of lymphatic endothelial cells to form vessels aroundtumors. Moreover small molecules that inhibit RhoJ signaling seemed to not only block the growth ofmelanoma tumors in vivo but also blocked the ability of endothelial cells to generate vessels to feed tumorcells in vitro. Here we propose that RhoJ has a dual role in tumor biology- it acts within the melanocyte topromote the formation of tumors and within the endothelial cells to promote the formation of lymphaticvessels around tumors in the skin and blood vessels around tumors in distant organs. We use acombination of state of the art single cell genomics in vivo imaging novel pharmacologic agents andtransgenic mouse models to: 1) determine how RhoJ acts in the melanocyte to promote the growth of earlystage tumors; 2) establish whether RhoJ acts in lymphatic endothelial cells to control tumorlymphangiogenesis; 3) assess the relative contributions of RhoJ to tumor growth andlymphanigogenesis/angiogenesis in vivo and in 3D models of human tumors. Completion of these studieswill define a new therapeutic strategy that halts cancer progression by simultaneously targeting both tumorcells and the vessels that feed them. 376161 +No NIH Category available Address;Advanced Malignant Neoplasm;Area;Award;Biometry;Cancer Patient;Caring;Chronic Care;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Communities;Complex;Data;Development;Diagnosis;Discipline of Nursing;Disparity;Dissemination and Implementation;Distress;Environment;Equity;Evaluation;Evidence based intervention;Family;Fatigue;Feedback;Focus Groups;Foundations;Funding;Geriatrics;Goals;Grant;Health Disparities Research;Health Services;Healthcare Systems;Individual;Institution;Internal Medicine;Intervention;Knowledge;Latinx population;Leadership;Malignant Neoplasms;Medicine;Mentors;Metastatic breast cancer;Methods;Modeling;Morbidity - disease rate;NCI-Designated Cancer Center;Neuropathy;New York City;Not Hispanic or Latino;Nurses;Oncologist;Oncology;Pain;Palliative Care;Palliative Medicine;Patient Care;Patients;Population Heterogeneity;Preparation;Randomized Controlled Trials;Recommendation;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Research Support;Rural;Scholarship;Screening for cancer;Self Management;Solid;Symptoms;Testing;Time;Training;Training Activity;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Woman;Writing;attentional control;black women;cancer health disparity;care delivery;care outcomes;career development;cognitive interview;community engaged research;community organizations;design;disparities in morbidity;disparity reduction;end of life;ethnic diversity;evidence base;experience;health disparity;health equity;improved;improved outcome;innovation;intervention delivery;malignant breast neoplasm;medical schools;minority patient;mortality;multidisciplinary;physical symptom;primary outcome;programs;psychologic;psychological symptom;racial disparity;racial diversity;racial minority;skills;social;social culture;social determinants;social health determinants;symptom management;therapy development;treatment arm The Development and Evaluation of a Community-Based Early Palliative Care Intervention for Black Women with Metastatic Breast Cancer PROJECT NARRATIVEMetastatic breast cancer substantially contributes to persistent health disparities in morbidity and mortality. Thegoal of this study is to develop a socio-culturally sensitive community-based early palliative care interventionto mitigate disparities in distress and symptom burden in Black women with metastatic breast cancer and totest its preliminary impact through a pilot randomized controlled trial. These findings will inform better equitypromotion of palliative care delivery and improved outcomes for underserved and underrepresented patientswith advanced cancer. NCI 10745669 11/15/23 0:00 PA-20-202 5K08CA267309-03 5 K08 CA 267309 3 "RADAEV, SERGEY" 12/20/21 0:00 11/30/26 0:00 Career Development Study Section (J)[NCI-J] 11953668 "MAZOR, MELISSA " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 193123 NCI 178818 14305 PROJECT SUMMARY/ABSTRACTResearch: Early palliative care (PC) for patients with advanced cancer is an understudied area of healthequity. Black women with metastatic breast cancer (MBC) disproportionality suffer from the psychological andphysical impacts of living with this serious condition. The purpose of this study is to develop and evaluate acommunity-engaged lay-navigator (LN) led early PC intervention (ACCEPT-PC) that targets distress andsymptom burden in Black women with MBC. The specific aims are to: 1) Conduct focus groups to assess theearly PC needs and preferred content format and delivery of a LN led community-based PC intervention; 2)Iteratively develop and refine the ACCEPT-PC intervention; 3) Conduct a pilot randomized controlled trial(RCT) of ACCEPT-PC to determine feasibility including preliminary impact in preparation for a fully poweredtrial. To accomplish these aims we will employ a sequential embedded mixed method community-engageddesign. Qualitative findings from focus groups with patients and stakeholders will guide the development ofACCEPT-PC which will be iteratively refined using cognitive interviews and evaluated for feasibility andpreliminary impact in a pilot RCT. Candidate: The primary objective of this application is to support Dr. MelissaMazors career development from a mentored researcher to an independent nurse-investigator focused onimproving disparities in PC for underserved women with advanced cancer. This K08 award will provide her withadvanced training in the following four areas: 1) PC intervention development; 2) health disparities research; 3)clinical trial design leadership and evaluation; and 4) R01 grant writing leadership and professionaldevelopment. To achieve these goals she has assembled a multidisciplinary mentoring team. Dr. Lin herprimary mentor is an accomplished clinician-investigator focused on breast cancer self-management. Dr.Wisnivesky her co-primary mentor is a disparities health services researcher with formal training inbiostatistics. Dr. Smith an oncologist trained in PC will provide expertise in community-engaged research andsocial determinants of PC disparities. Her scientific advisors include Dr. Goldstein a health servicesresearcher in the area of community-based PC and Dr. Dionne-Odom a nurse researcher who will provideadvanced training in LN coaching for cancer patients and clinical trials. Environment: The Icahn School ofMedicine at Mount Sinai has a strong tradition of outstanding research and is one of the top 20 medicalschools in NIH funding. The Division of General Internal Medicine is the largest division in the Department ofMedicine and has a well-established section of research and exceptional research infrastructure. The TischCancer Institute is an NCI-designated cancer center with well-established research and serves a largepopulation of diverse patients throughout New York City. The Brookdale Department of Geriatrics andPalliative Medicine is one of the leading palliative care institutions with unparalleled research support. 193123 +No NIH Category available Binding Proteins;Biological;Breast Cancer Cell;Breast Cancer Model;Breast Cancer cell line;Cancer Biology;Cancer Model;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;ChIP-seq;Consumption;DNA;DNA Modification Process;Data;Development;Epigenetic Process;Eukaryota;Excretory function;Exhibits;Exposure to;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Histones;Human;Hypoxia;In Vitro;Individual;Link;MDA MB 231;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Messenger RNA;Methylation;Methyltransferase;Modeling;Modernization;Modification;Mus;Neoplasm Metastasis;Niacinamide;Nicotinamide N-Methyltransferase;Oncogenic;Pathology;Pathway interactions;Patients;Phenotype;Physiology;Play;Polymerase;Postdoctoral Fellow;Process;Proteome;RNA;RNA methylation;Rattus;Regulator Genes;Relapse;Research;Research Project Grants;Role;S-Adenosylhomocysteine;S-Adenosylmethionine;Small Interfering RNA;Sprague-Dawley Rats;Stimulus;Systemic Therapy;Testing;Therapeutic Agents;Transcript;Translational Regulation;Urine;cancer cell;cancer gene expression;cancer stem cell;cancer therapy;differential expression;epitranscriptomics;genetic regulatory protein;histone modification;in vivo;knock-down;malignant breast neoplasm;methylome;mouse model;novel;nutrient deprivation;patient derived xenograft model;pharmacologic;posttranscriptional;prevent;protein expression;response;single-cell RNA sequencing;stem-like cell;stressor;trait;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression Biological and cancer-associated role of epitranscriptomic gene expression regulation PROJECT NARRATIVENicotinamide N-methyltransferase (NNMT) is a likely master regulator of triple-negative breast cancer (TNBC)gene expression through its hypomethylating effect on DNA histones and mRNA; however a link between NNMT expression and mRNA hypomethylation has not previously been established as a mechanism contributing to cancer progression. In my dissertation project I am testing the hypothesis that NNMT activity in TNBC cells results in 1) reduced m6A mRNA modification associated with altered protein expression of pathways mediating cellular stress response and 2) cancer stem cell-like traits associated with survival metastatic potential and increased in vivo tumor-forming capacity. As accumulating research has been highlighting the biological relevance of RNA modifications both in terms of normal physiology and pathology including cancer I plan to pursue my post-doctoral research on the biological and cancer-associated role of epitranscriptomic gene expression regulation with a translational focus as an endpoint to develop novel modulators of RNA modifications as potential cancer therapeutic agents. NCI 10745523 2/8/23 0:00 RFA-CA-19-002 4K00CA245784-03 4 K00 CA 245784 3 "ELJANNE, MARIAM" 9/11/19 0:00 11/30/26 0:00 ZCA1-RTRB-R(A1) 15839373 "DOLCEN, DENIZ NESLI" Not Applicable 16 GENETICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 393 Other Research-Related 2023 86725 NCI 80360 6365 PROJECT SUMMARY My lab discovered that NNMT is a direct GR transcriptional target gene in TNBC. I then observed relatively high NNMT expression in several aggressive patient-derived TNBC cell lines. NNMT consumes the universal methyl donor S-adenosyl methionine (SAM) for methylation of nicotinamide. High NNMT activity depletes SAM; as a result methyltransferase targets are hypomethylated in cells with high NNMT expression. NNMT-induced DNA and histone hypomethylation have been shown to result in oncogenic gene expression in cancer cells but NNMT mechanism of action in TNBC biology remains unclear. A link between NNMT expression and mRNA hypomethylation has not previously been established as a mechanism contributing to cancer progression. N 6 - methyladenosine (m6A) is an abundant and reversible RNA modification in eukaryotes. Our collaborator Dr. Chuan He discovered that m6A-binding proteins mediate translational regulation by altering stability and translational efficiency of m6A-modifed mRNAs. Importantly altered m6A mRNA methylation is implicated in the progression of several human cancers via causing changes in post-transcriptional gene expression of cancer pathways. To our knowledge I am the first to characterize the m6A methylome of a patient-derived TNBC cell line model (MDA-MB-231): ~ 7000 m 6A-modified transcripts are significantly enriched for pathways involved in cellular stress response cell death and cell survival. In addition I have data suggesting that NNMT activity in the MDA-MB-231 TNBC cell line results in 1) reduced m6A modification of mRNAs regulating key cancer pathways and 2) increased in vivo tumor-growth. In my dissertation research I am testing the hypothesis that NNMT activity in TNBC cells results in 1) reduced m6A mRNA modification associated with altered protein expression of pathways mediating cellular stress response and 2) cancer stem cell-like traits associated with survival metastatic potential and increased in vivo tumor-forming capacity. During my postdoctoral research I aim to test whether epitranscriptomic gene expression regulates dynamic cellular phenotypes including adaptation to the changing microenvironment. I will first characterize the actively transcribed genes with polymerase ChIPseq and perform whole proteome quantification with mass spectrometry in cells exposed to distinct microenvironmental stressors (e.g. nutrient deprivation hypoxia). I will then determine whether differential transcription of genes correlate with protein expression in different cellular states. If there is not a strong correlation I will perform individual siRNA knockdown of all known m6A-regulatory genes and determine the effect on protein expression. I will then utilize patient-derived xenograft mouse models and the Sprague Dowley rat model of spontaneous breast cancer to determine whether the m 6A-regulatory proteins are differentially expressed in distinct tumor regions with single-cell RNA sequencing. 86725 +No NIH Category available Address;Animal Model;Area;Bladder;Cancer Center Support Grant;Cancer Patient;Cell Therapy;Cellular biology;Clinic;Clinical;Clinical Research;Clinical Trials;Code;Collaborations;Colorectal Cancer;Communication;Dedications;Development;Discipline;Faculty;Funding;Grant;Growth;Head Cancer;Head and Neck Cancer;Immune;Immune Targeting;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunobiology;Immunologic Monitoring;Immunologist;Immunooncology;Immunotherapy;Inflammation;Infrastructure;Institution;Lead;Link;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mission;Modeling;Neck Cancer;PD-1/PD-L1;PDL1 pathway;Patient-Focused Outcomes;Patients;Phase;Play;Prevention;Property;Protocols documentation;Publications;Recording of previous events;Research;Research Personnel;Resistance;Resource Sharing;Resources;Role;Sampling;Seminal;Specimen;T-Lymphocyte;Testing;Therapeutic;Therapeutic Trials;Translations;Tumor Escape;Tumor Immunity;Tumor-infiltrating immune cells;Work;arm;cancer immunotherapy;cancer therapy;design;experience;human tissue;immune checkpoint blockade;immune resistance;improved;improved outcome;insight;malignant stomach neoplasm;melanoma;member;novel;novel strategies;patient derived xenograft model;programs;response;targeted treatment;tumor;tumor growth;tumor immunology Cancer Immunology Research Program n/a NCI 10745454 9/15/23 0:00 PAR-17-095 3P30CA016359-43S5 3 P30 CA 16359 43 S5 "HE, MIN" 7/1/97 0:00 7/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 8748 6483185 "BOSENBERG, MARCUS W" Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2023 4530485 2704767 1825718 CANCERIMMUNOLOGYRESEARCHPROGRAMPROGRAMCODE:CIPROJECTSUMMARY/ABSTRACTTheoverarchingmissionoftheCancerImmunology(CI)ResearchProgramistoimproveunderstandingofthehostresponsetocancerandtodiscoverandtestnovelapproachestoharnessthatresponsetoimprovepatientoutcomes.Theprogramwasrankedoutstandinginthelastrenewal.Drs.DhodapkarandChenleadtheCIprogramandareexperiencedinvestigatorswitha>15-yearhistoryofsustainedNCIfundingandmultiplecontributionsincancerimmunology.Dr.ChenpioneeredthetargetingofthePD-1/PD-L1pathwayincancerwhichhastransformedcancerimmunotherapy.CIconsistsof33membersfrom8differentdepartmentswhoseworkrevolvesaroundfourmajoraims:1)understandthemechanismsunderlyingthecapacityoftheimmunesystemtoinhibittumorgrowthaswellasmechanismsthatdrivetumorimmuneresistance;?2)discoverandtestnewapproachesforpromotinganti-tumorimmunity;?3)studythemechanisticlinksbetweeninflammationandcancer;?and4)undertaketargetedtherapeutictrialsthatutilizenovelendpointassessmentandbuildonthefundamentaldiscoveriesofAims1-3.CIexperienceda15%increaseintotalfunding($12Mdirect)aswellasa21%increaseinNCIfunding($2.3Mdirect).Collaborationsremainstrongwith17%intra-and30%inter-programmaticpublications.TranslationaleffortsintheCIprogramareabundantinparticularwithourtumorimmuno-oncology(TIL)lab.MajorcollaborationsexistwiththeLungCancerSPOREandSU2Cefforts(DT)theGU/Bladdergroup(ST)thePhaseIteam(DT)HeadandNeckCancers(DT)andthecolorectalcancerSU2Ccollaborative(CPC).SamplesarebeinganalyzedinnumerousCIclinicaltrialstoinvestigatethemechanismsunderlyingresistanceandresponsetoimmunetherapies.Humantissuehasbeencollectedundermultipleprotocolsandusedforpatient-derivedxenograft(PDX)andhumanizedmodels.Duringthelastfundingperiodimmunecheckpointblockadeforcancertreatmenthasemergedasoneofthemostexcitingandpromisingnewapproachestotreatcancerindecades.CIhasplayedaleadingroleinbringingthisrevolutionaryapproachintotheclinicwithseveralseminalstudiesthatintroducedcheckpointblockadetargetingthePD1/PD-L1pathwayinthetherapyofmelanomalunggastrichead/neckandbladdercancer.YCChasbeenattheforefrontoftheimmuno-oncologyrevolutionplayingleadrolesintheearlieststudiesandeventuallyFDAapprovalsofimmunecheckpointblockadeandcombinationblockadetheidentificationofnewcheckpointinhibitortargetsthedevelopmentofuniqueanimalmodelsandimportantadvancesinbasicimmunobiologyespeciallyinT-cellbiology.OverthelastfiveyearsthegrowthofourclinicaltrialeffortsinthisareahasenabledreversetranslationusingclinicalspecimenswhichbolstersSPOREandothermulti-PIgrants.CIwillcontinueasahighlyinteractiveprogramdedicatedtoimprovingunderstandingofthehostresponsetocanceranddevelopingnovelapproachestoimproveoutcomes. +No NIH Category available Adenocarcinoma;Androgen Receptor;Appearance;Applications Grants;Automobile Driving;Back;CD44 gene;Carcinoma;Cell Reprogramming;Cells;Classification;Clinical;Cues;Data;Desmoplastic;Development;Developmental Process;Epithelial Cells;Epithelium;Event;Extracellular Matrix;Feedback;Generations;Genes;Goals;Human;Hyaluronan;Hyaluronidase;Hybrids;In Vitro;Laboratories;Ligands;Malignant neoplasm of prostate;Mesenchymal;Metabolism;Modeling;Molecular;Neoplasm Metastasis;Neoplasms;Neuroendocrine Tumors;Neurosecretory Systems;Pathway interactions;Patient Selection;Phenotype;Population;Predisposition;Property;Prostate;Prostatic Neoplasms;Publishing;Regulation;Resistance;Role;Signal Transduction;Testing;Therapeutic;Tumor Cell Invasion;Tumor Promotion;Up-Regulation;Work;atypical protein kinase C;cancer cell;cancer type;castration resistant prostate cancer;design;effective therapy;enzalutamide;in vivo;neoplastic cell;non-oncogenic;novel;novel therapeutics;pressure;programs;prostate cancer cell;prostate cancer progression;response;stem;stem cells;stem-like cell;stemness;targeted treatment;therapeutic target;therapy design;therapy resistant;trait;tumor;tumor microenvironment;tumor progression Role of the CD44/Hyaluronan axis in mesenchymal prostate cancer The goal of this proposal is to investigate the role of the stroma and its crosstalk with the cancer cell in lineageplasticity and therapy resistance and to identify new non-oncogenic vulnerabilities to be targeted therapeutically.We will test the hypothesis that the loss of PKC/ upregulates a CD44/Hyaluronan axis that induces themesenchymal phenotype characterized by epithelial EMT and the generation of a desmoplastic tumor stromaboth critical events for tumor progression and therapy resistance. NCI 10745413 7/31/23 0:00 PA-20-185 1R01CA277857-01A1 1 R01 CA 277857 1 A1 "KAI, MIHOKO" 8/1/23 0:00 7/31/28 0:00 "Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]" 8800373 "DIAZ MECO CONDE, MARIA TERESA" Not Applicable 12 PATHOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 549768 NCI 324347 225421 Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer thatresults into multiple different tumor states. Recent classifications efforts have revealed that besides the androgenreceptor pathway positive adenocarcinomas (CRPC-AD) and the terminal neuroendocrine tumors (NEPC) thereare also tumors enriched in a hybrid state characterized by the expression of mesenchymal and stem cell traits.This phenotype is termed mesenchymal and stem-like prostate cancer (MSPC). The overarching goal of thisapplication is to identify novel molecular mechanisms underlying the MSPC phenotype that can be targetedtherapeutically. Our hypothesis is that the loss of PKC/ (encoded by PRKCI gene) by upregulating theCD44/Hyaluronan (HA) axis induces the mesenchymal phenotype characterized by the activation of epithelialEMT and the generation of desmoplastic tumor stroma both critical events for tumor progression and therapyresistance. We postulate that the detailed characterization of the mechanisms whereby PKC/ controls theCD44/HA axis will provide critical new information on the molecular pathways leading to MSPC progression andwill offer a rationale for the selection of patients susceptible to respond to new therapies designed atmesenchymal/stromal targets. Our preliminary data demonstrate that (1) human MSPC has low PRKCI levelsand a highly desmoplastic stroma; (2) PKC/ loss in the prostate epithelium in vivo induces EMT and promotesa desmoplastic response that remodels the tumor microenvironment; (3) Low PRKCI levels correlate withupregulation of the CD44/HA axis in human PCa supporting the human relevance of these findings. Based onthese premises in this proposal we will address the following specific Aims: Aim 1A: Determine how interferingwith CD44 or its ligands (OPN/SPP1 HA) block MSPC and enzalutamide resistance promoted by PKC/ -deficiency in the epithelium; Aim 1B: Determine the role of the CD44/HA axis in stromal activation and thestromal-epithelial feedback crosstalk; Aim 1C: Determine the molecular mechanism whereby PKC/ regulatesCD44; Aim 2A: Determine the role of prostate epithelial CD44 in driving MSPC in vivo; Aim 2B: Determine therole of prostate stromal CD44 in driving MSPC in vivo; Aim 3A: Determine the therapeutic potential of PEGPH20in combination with enzalutamide in the treatment of MSPC tumors and Aim 3B: Investigate its mechanism ofaction at a single-cell level. The results of this proposal will contribute to a more comprehensive understandingof the mechanisms driving the MSPC type of PCa and will be key for the design of new more selective andeffective therapies for this type of aggressive neoplasia. 549768 +No NIH Category available Affect;Biological Markers;Bone Marrow;Cancerous;Cessation of life;Classification;Clinic;Clinical;Development;Disease;Ensure;Future;General Population;Genomics;Image;Knowledge;Laboratories;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Modeling;Monoclonal Gammapathies;Monoclonal gammopathy of uncertain significance;Morbidity - disease rate;Multiple Myeloma;Nature;Oncogenic;Pathogenesis;Patients;Phase;Plasma;Plasma Cells;Prevention strategy;Research Proposals;Resources;Risk;Risk Assessment;Systemic Therapy;Testing;United States National Institutes of Health;biobank;c-myc Genes;diagnostic strategy;experimental study;extracellular;member;metabolomics;mortality;novel marker;novel strategies;premalignant;prevent;progression risk;risk stratification Assessment of Metabolites Among Asymptomatic Precursor and Malignant Monoclonal Gammopathies PROJECT NARRATIVEMultiple myeloma (MM) is an incurable cancer of plasma cells that is always preceded by an asymptomaticphase comprised of pre-cancerous plasma cells such as in monoclonal gammopathy of undeterminedsignificance (MGUS) or smoldering multiple myeloma (SMM). Given the incurable nature of MM this projectaims to measure the levels of select metabolites in the bone marrow plasma of patients with a spectrum ofplasma cell disorders via mass-spectrometry-based approaches so as to distinguish between pre-cancerousand cancerous plasma cells. Ultimately the knowledge gained from this study will help lower the risk ofmorbidity and mortality in the general population who remain at risk of developing MM from entities with pre-cancerous plasma cells such as MGUS and SMM; this study will also lay the basis of developing novelstrategies in the future to prevent this progression of pre-cancerous plasma cells to MM. NCI 10745371 4/24/23 0:00 PA-21-071 3R01CA254961-03S1 3 R01 CA 254961 3 S1 "WILLIS, KRISTINE AMALEE" 3/1/21 0:00 2/28/25 0:00 Cancer Biomarkers Study Section[CBSS] 14511069 "GONSALVES, WILSON " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 74489 NCI 46152 28337 PROJECT SUMMARYMultiple myeloma (MM) is a devastating clonal plasma cell (cPC) malignancy responsible for over 13000deaths in the US per year. It is always preceded by pre-malignant asymptomatic plasma cell disorders such asmonoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM).Despite the availability of various clinical genomic and imaging-based risk stratification models accurateclassification of precursor cPC disorders and their risk of progression to MM remains elusive. The fundamentalroadblock remains in the inability of existing clinical and laboratory-based biomarkers to distinguish betweenthe presence of premalignant or malignant cPCs in patients. In contrast recent advances in mass-spectrometry based metabolomics offers new opportunities to characterize intra- and extracellular metabolitesthat could serve as novel biomarkers reflective of the presence of malignant cPCs. This is especially promisingsince oncogenic drivers of progression of premalignant to malignant cPCs such as c-Myc has knowndownstream effects on multiple intracellular metabolic pathways resulting in altered extracellular metabolitelevels. These resultant metabolite profiles can be exploited to more accurately assess the risk of progression ofprecursor cPC disorders to MM in the future and ultimately affect management and treatment. Thus thisresearch proposal will test the hypothesis that the levels of select metabolites within the bone marrow (BM)plasma are reflective of the qualitative and quantitative presence of c-Myc-activated malignant cPCs in patientswith PC disorders. This research proposal will specifically validate the presence of differences in the levels ofselect metabolites in the BM plasma between MGUS and MM patients (Aim 1). It will also evaluate the effect ofc-Myc activation in cPCs on their extracellular levels of these select metabolites (Aim 2). Finally it will evaluatehow depleting the malignant cPCs with systemic therapy affects the BM plasma levels of these selectmetabolites in MM (Aim 3). These studies will provide an opportunity to advance our understanding of themetabolic rewiring associated with the pathogenesis of MM. This could allow us to better determine thetransition from MGUS to symptomatic MM for the development of potential early diagnostic or preventativestrategies. The expertise and resources of the members of the team the availability of the Myeloma SPOREbiobank and a NIH-designated comprehensive metabolomics core at the Mayo Clinic ensures the viability andexecution of the proposed experiments. 74489 +No NIH Category available African American population;Amino Acids;Asia;Asian ancestry;Asian population;Biological;Biological Assay;Biological Markers;Blood specimen;California;Cancer Etiology;Caucasians;Cessation of life;Clinical;Clinical Data;Cohort Studies;Data;Databases;Diagnosis;Diagnostic;Disease;Early Diagnosis;Epidemiology;Ethnic Origin;Ethnic Population;Etiology;Europe;European;European ancestry;Evaluation;Functional disorder;Gastrointestinal Diseases;Genetic;Genomics;Health;Hospitals;Incidence;Individual;Japanese American;Life Style;Malignant Neoplasms;Malignant neoplasm of pancreas;Medicare claim;Mentors;Metabolic;Metabolic syndrome;Minority;Minority Groups;Modeling;Native Hawaiian;Organ;Pancreas;Participant;Pathogenesis;Pathway interactions;Pattern;Performance;Phase;Population;Population Heterogeneity;Prevention;Prognosis;Prospective cohort;Questionnaires;Race;Research;Research Design;Resources;Risk;Risk Factors;Running;Sampling;Screening for cancer;Standardization;Subgroup;Survival Rate;Symptoms;Systems Biology;Techniques;United States;associated symptom;biobank;cancer risk;cohort;comorbidity;data integration;design;epidemiologic data;gastrointestinal symptom;genetic variant;genome-wide;genomic data;high risk;high risk population;improved;insight;metabolomics;mortality;multi-ethnic;neoplasm registry;novel;pancreatic cancer model;predictive modeling;racial diversity;risk prediction model;risk stratification;sex Integrating epidemiologic clinical genomic and metabolomic profiles to predict pancreatic cancer risk in a multiethnic population PROJECT NARRATIVEPancreatic cancer is a significant health problem in the United States with very poor survival and disproportionateburden across race/ethnicity. Our objective is to apply an integrative systems biology approach incorporatingepidemiologic clinical genetic and metabolomic data to improve the prediction of pancreatic cancer risk in aracially heterogeneous population. By refining the identification of high-risk individuals our study will help toestablish new strategies for targeted prevention and early detection and reduce the overwhelming burden of thislethal disease. NCI 10745361 1/9/23 0:00 RFA-CA-20-014 4R00CA256525-03 4 R00 CA 256525 3 "ROTUNNO, MELISSA" 1/9/23 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 14485373 "HUANG, BRIAN " Not Applicable 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 1/9/23 0:00 12/31/23 0:00 398 Non-SBIR/STTR 2023 249000 NCI 150909 98091 ABSTRACTPancreatic cancer is a highly lethal malignancy that has a very poor prognosis in the United States. It has a 5-year survival rate of only 9% and is projected to become the second most common cancer death by 2030.Pancreatic cancer also has a disproportionate burden across race/ethnicity with higher incidence rates observedamong minority groups such African Americans Japanese Americans and Native Hawaiians. Past predictionmodels have been developed to identify high-risk individuals and improve the earlier detection of this disease.However these models were designed in individuals of primarily European or Asian ancestry and have not beenvalidated in multiethnic populations. In addition these models included mainly known epidemiologic risk factorsand only a few incorporated data on genetic variants or health conditions. Thus a model that employs moregranular data such as comorbidities/symptoms genomics and metabolomics for the prediction of pancreaticcancer across multiple races/ethnicities does not exist. In this study we seek to apply an integrative systemsbiology approach to enhance the prediction of pancreatic cancer risk using data from the Multiethnic Cohort(MEC) Study. The MEC is a long-standing prospective cohort of over 215000 racially diverse individuals thathas comprehensive lifestyle environmental clinical and genetic data. We will use data from existing resourcesof the MEC including epidemiologic risk factors from questionnaires clinical health conditions from Medicareclaims genetic data from a large biorepository of blood samples and cancer incidence and mortality informationfrom SEER Cancer registries and state and national mortality databases. We will also generate new metabolomicdata for a subset of MEC participants. Our specific aims are: 1) to identify clusters or patterns of clinical conditionsassociated with pancreatic cancer risk; 2) to validate existing prediction models in a multiethnic population anddevelop an enhanced prediction model that incorporates epidemiologic clinical and genomic data; 3) to identifymetabolites associated with pancreatic cancer in a multiethnic population; and 4) to integrate epidemiologicclinical genomic and metabolomic data to identify individuals at high risk of pancreatic cancer. Results from thisstudy are expected to elucidate etiologic mechanisms and improve the prediction of pancreatic cancer risk forheterogeneous populations. This will have significant implications for improving strategies for earlier detectionand reducing the overwhelming burden of this fatal cancer. 249000 +No NIH Category available ATP Synthesis Pathway;Acute;Antidiabetic Drugs;Biochemical;Biochemistry;Bioenergetics;Biological Assay;Biomass;Cancer cell line;Carbon;Cell Proliferation;Cells;Chemicals;Citric Acid Cycle;Clinical;Complex;Consumption;Data;Development Plans;Doctor of Philosophy;Electron Transport;Environment;Enzymes;Equilibrium;FDA approved;Genetic;Glucose;Glycolysis;Goals;Growth;Image;In Vitro;Knock-out;Knowledge;Laboratory Research;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Memorial Sloan-Kettering Cancer Center;Mentorship;Metabolic;Metabolism;Methods;Mitochondria;Nutrient;Organelles;Oxidative Phosphorylation;Permeability;Phenformin;Phosphorylation Inhibition;Physicians;Postdoctoral Fellow;Production;Proliferating;Proteins;Pyruvate;Regulation;Reporter;Research;Scientist;Serum;Source;Therapeutic;Training;Universities;Warburg Effect;aerobic glycolysis;cancer cell;cancer therapy;career development;clinical training;design;extracellular;imaging modality;in vivo;inhibitor;insight;liquid chromatography mass spectrometry;medical schools;metabolomics;novel;oxidation;patient derived xenograft model;research and development;response;skills;tumor;tumor metabolism;tumor microenvironment Mechanistically Dissecting Glycolysis Regulation by Lactate and Its Therapeutic Potential in Cancer PROJECT NARRATIVECancer cells are addicted to glucose but only to secrete the majority as lactate (also known as aerobicglycolysis or Warburg effect) thereby creating an inhospitable glucose-poor and lactate-rich microenvironmentthat would otherwise be lethal to most cells. This application is designed to mechanistically investigate howlactate regulates cancer cell glucose utilization and to assess the therapeutic potential of targeting cancerlactate oxidation. The results from this study will provide knowledge in the regulation of central carbonmetabolism and insight into the targeting lactate oxidation as a cancer therapy. NCI 10745359 12/7/22 0:00 RFA-CA-20-014 4R00CA256505-03 4 R00 CA 256505 3 "O'HAYRE, MORGAN" 1/1/23 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 15340094 "CAI, XIN " Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 395 Non-SBIR/STTR 2023 249000 NCI 191478 57522 PROJECT SUMMARY/ABSTRACTGlucose is an essential fuel for cancer cell proliferation in serving both as a substrate for ATP production andas an irreplaceable carbon source for biomass accumulation. Cancer cells are especially addicted to glucosebut only to secrete the majority as lactate (known as aerobic glycolysis or Warburg effect) thereby creating aninhospitable glucose-poor and lactate-rich microenvironment that would otherwise be lethal to most cells.However cancer cells can efficiently use the limiting glucose and excess lactate for unlimited growth throughunclear mechanisms. My preliminary data revealed that in low glucose conditions extracellular lactateenhances cancer cell proliferation. Mechanistically I found that lactate preferentially enters the mitochondriaTCA cycle over glucose to increase oxidative phosphorylation (OXPHOS) activity which in turn suppressesglycolysis to conserve extracellular glucose suggesting cancer cells rely on lactate-induced OXPHOS foroptimal growth. The proposed studies are aimed at mechanistically dissecting the metabolic interplay betweenlactate-mediated mitochondrial OXPHOS and glycolysis (Aim 1 & 3) and assessing therapeutic potential oftargeting lactate oxidation in cancer (Aim 2). The following specific aims are being pursued: Aim 1. Determinehow lactate-mediated increase in OXPHOS suppress glycolysis; Aim 2. Assess the in vivo therapeuticpotential of targeting lactate oxidation using Phenformin; Aim 3. Mechanistically dissect how cells distinguishand preferentially use extracellular lactate over glucose for entry into TCA cycle. The knowledge and scientificexpertise gained through these studies will facilitate my transition to independence with my long-term goal tostudy and target metabolic vulnerabilities in cancer as a physician scientist.In addition to the scientific goals I have also outlined a detailed career development plan in this application toobtain skills that are necessary for leading an independent research laboratory. The proposed research andtraining plan will be conducted under the mentorship of Dr. Craig Thompson. Memorial Sloan-KetteringCancer Center along with the nearby Rockefeller University and Weill Cornell Medical College will provide theideal academic environment to achieve these goals for me to transition to independence. 249000 +No NIH Category available 3-Dimensional;Acidosis;Address;Algorithms;Animal Model;Animals;Bicarbonates;Biometry;Blood Vessels;Breast Cancer Model;Cancer Model;Cancer Patient;Clinic;Combretastatin A4 Phosphate;Contrast Media;Development;Dictionary;Dose;Drug Kinetics;Early Diagnosis;Environment;Esomeprazole;Evaluation;Fingerprint;Goals;Histopathology;Hypoxia;Image;Injections;Lead;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Maps;Measurement;Measures;Metformin;Methodology;Methods;Microelectrodes;Modeling;Monitor;Mus;Patients;Perfusion;Preparation;Quantitative Evaluations;Radiation therapy;Radiology Specialty;Recovery;Relaxation;Reporting;Reproducibility;Research;Research Personnel;Rodent Model;Series;Solid Neoplasm;Techniques;Therapeutic;Translating;Validation;Variant;Xenograft procedure;anticancer treatment;cancer diagnosis;cancer therapy;clinical translation;clinically relevant;contrast enhanced;design;experience;experimental study;extracellular;human model;imaging modality;improved;in vivo;innovation;metaiodobenzylguanidine;novel strategies;pancreas xenograft;pancreatic neoplasm;preclinical imaging;response;temporal measurement;treatment response;tumor;tumor diagnosis;tumor microenvironment Magnetic Resonance Fingerprinting of Tumor Vascular Perfusion and Acidosis PROJECT NARRATIVEOur long-term goal is to improve cancer diagnoses and the early response to anti-cancer treatments usingMagnetic Resonance Fingerprinting (MRF). To meet our goal we will develop and validate new dynamic 3DMRF and methods to accurately and precisely measure tumor vascular perfusion in rodent models of humancancers that are treated with established cancer therapies. We will also develop a new pHe-MRF method thatcan accurately measure extracellular tumor pH (pHe) in different tumor types and to monitor changes in tumorpHe in response to therapy using two co-administered MRI contrast agents. NCI 10745351 11/8/23 0:00 PAR-19-158 5R01CA269354-02 5 R01 CA 269354 2 "ZHANG, HUIMING" 12/1/22 0:00 11/30/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 8569494 "FLASK, CHRISTOPHER A" "PAGEL, MARK DAVID" 11 RADIATION-DIAGNOSTIC/ONCOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 597290 NCI 492988 104302 PROJECT DESCRIPTION As a major limitation in contrast enhanced MRI studies is that current MRI methods lack the combination ofaccuracy precision and temporal resolution to quantitatively measure contrast agents in vivo. We haveaddressed this problem by developing dynamic Magnetic Resonance Fingerprinting (MRF) methods that canrapidly measure T1 or T2 relaxation times with outstanding accuracy and precision (Radiology 2021). Our keyMRF innovations include a combination of highly undersampled spiral trajectories low flip angles and multiplemagnetization preparations to avoid errors from B1 inhomogeneities and limited T2 sensitivity. Our MRF methodscan also be adapted to simultaneously detect one or two MRI contrast agents. We have recently demonstrated that a new T1-MRF method can be used to dynamically generatequantitative T1 maps with very fast temporal resolution (~2.5 seconds) during an in vivo Dynamic ContrastEnhanced (DCE) MRF experiment. In Aim 1 we will first optimize a new 3D T1-MRF method to evaluate tumorvascular perfusion (ktrans) with high accuracy and precision in mouse cancer models. We will then evaluate thisDynamic Contrast Enhanced (DCE) MRF method by measuring changes in vascular perfusion in mouse cancermodels treated with either a vascular disrupting agent or radiotherapy. Our objective is to demonstrate that DCE-MRF provides superior precision in comparison to standard DCE-MRI methods providing the opportunity to moresensitively detect the early response to treatment which can then be translated to the clinic. We have also demonstrated that a similar dynamic MRF method can be used to simultaneously measure theconcentration of a T1 contrast agent and a T2 contrast agent within an in vivo tumor model with outstandingaccuracy and precision (Scientific Reports 2017 and 2019). In Aim 2 we will develop a similar two-agent MRFmethod to simultaneously detect a pH-dependent T1 contrast agent and a pH-independent T2 contrast agent tomeasure extracellular pH (pHe) in tumor models. We will apply our pHe-MRF approach to monitor changes intumor pHe after administering treatments that raise and lower tumor acidosis to validate our methodology. Our deliverable for this project is a new adaptable dynamic 3D MRF approach to quantitative measure oneor two MRI contrast agents in vivo. These new 3D DCE-MRF and pHe-MRF methods are the key innovation ofour research. We have developed a rigorous research approach with an emphasis on quantitative evaluationsand validations using multiple established mouse cancer models and therapeutic strategies. We have alsoassembled a team of strong and highly experienced investigators and we have an exceptional researchenvironment for our studies. Importantly this successful preclinical imaging project will immediately lead toclinical translation of the DCE-MRF method for use in cancer patients and will provide the opportunity for effectivepHe assessments in animal models and eventually in patients. 597290 +No NIH Category available 3-Dimensional;Area;Binding Sites;CRISPR/Cas technology;Cancer Biology;Cell Maintenance;Cell Separation;Cells;ChIP-seq;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Data;Derivation procedure;Development;Disease;Drug resistance;Epigenetic Process;Equilibrium;Exhibits;Foundations;Funding;Genes;Genetic;Genomics;Glycolysis;Goals;Human;Implant;KPC model;Knock-out;Knockout Mice;Knowledge;Link;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Mediating;Mentors;Messenger RNA;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Molecular Biology;Mus;Neoplasm Metastasis;Nude Mice;Oncogenes;Organoids;Oxidative Phosphorylation;Pancreas;Pathogenesis;Pathway interactions;Phase;Phenotype;Play;Polymerase;Population;Postdoctoral Fellow;Protein Dynamics;Proteins;Proteomics;Pyruvate;RNA Polymerase II;Recurrence;Research;Research Personnel;Research Project Grants;Research Proposals;Role;Techniques;Therapeutic;Tissues;Training;Transcription Elongation;Transgenic Mice;Tumor Burden;Tumor Tissue;United States;Work;cancer cell;cancer cell differentiation;cancer drug resistance;cancer stem cell;career;cell type;combinatorial;conventional therapy;effective therapy;embryonic stem cell;experimental study;improved;in vivo;islet stem cells;knock-down;knockout gene;lipidomics;metabolic phenotype;metabolic profile;metabolomics;neoplastic;neoplastic cell;novel;overexpression;oxidation;pancreatic cancer cells;pancreatic cancer model;pancreatic differentiation 2 protein;pancreatic tumorigenesis;post-doctoral training;pre-doctoral;programs;self-renewal;skills;stem cell biomarkers;stem cell self renewal;stem cells;stem-like cell;stemness;targeted treatment;therapeutic target;transcription factor;transcriptome sequencing;tumor heterogeneity;tumor metabolism;tumor progression;tumorigenesis Pancreatic cancer stem cells: PD2-mediated novel mechanistic link and metabolomic alterations PROJECT NARRATIVEThis research proposal outlines a training plan for becoming an independent cancer researcher with a focus incancer stem cells (CSCs) and pancreatic cancer (PC). In F99 predoctoral training I will investigate the role ofPancreatic Differentiation2 (PD2) in pancreatic CSCs and CSC-mediated PC progression with the goal ofdeciphering the mechanism of PD2-dependent CSC maintenance. In K00 postdoctoral training I will focus oninvestigating the mechanisms that promote the acquisition of different metabolic programs by CSCs anddifferentiated tumor cells; the molecular biology behind and the contribution of metabolism to CSC-mediateddrug resistance; and development of novel combinatorial therapeutics based on metabolic targeting to treatcancer. NCI 10745341 11/16/23 0:00 RFA-CA-18-001 5K00CA234962-06 5 K00 CA 234962 6 "DAMICO, MARK W" 9/13/18 0:00 11/30/24 0:00 ZCA1-TCRB-T(O1) 12480817 "KARMAKAR, SASWATI " Not Applicable 16 GENETICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Other Research-Related 2024 97077 NCI 89886 7191 PROJECT SUMMARY / ABSTRACTThis research proposal is intended to provide predoctoral and postdoctoral training to develop the necessaryskills for a career as an independent investigator in cancer biology. The long-term research focus is developmentof effective therapy for pancreatic cancer (PC) through 1) determining the contribution of cancer stem cells(CSCs) to PC progression and metastasis 2) understanding the mechanism of CSC maintenance and CSC-mediated drug resistance 3) identifying genetic epigenetic and metabolic factors essential for CSCmaintenance with the aim of identifying novel epigenetic and metabolic targets that can be exploited forcombinatorial therapy against PC. The objective of my dissertation research (F99 phase) is to define the roleof Pancreatic Differentiation 2 (PD2) in pancreatic CSCs and CSC-mediated PC progression with the goal ofdeciphering the mechanism of PD2-dependent CSC maintenance. PD2 is a ubiquitous multifunctional protein acore component of human RNA Polymerase II-Associated Factor 1 complex (PAF1C) that functions intranscription elongation and mRNA processing. We discovered that PD2 is a novel pancreatic CSC marker andmediates drug resistance of CSCs. Knowledge of the molecular mechanism of PD2-dependent CSCmaintenance and drug resistance is critical. We have recently made several discoveries relevant to this concept.First knockdown of PD2 significantly reduces the levels of established CSC and self-renewal markers.Importantly PD2 depletion significantly reduces tumor burden in vivo. Moreover RNA-sequencing andtranscription factor PCR array analyses revealed that several stemness and metastasis genes were significantlydownregulated following PD2 depletion. Based on aforementioned information and additional data wehypothesize that PD2 functions as a master-regulator of stem cell maintenance and thereby mediatesPC progression. Our research will utilize high throughput genomic techniques such as chromatinimmunoprecipitation sequencing and RNA-sequencing in presence and absence of PD2 to define downstreamtargets of PD2 and identify the pathway for PD2-dependent maintenance of pancreatic CSCs. We will alsodetermine the role of PD2 in CSC-mediated PC progression using a novel CRISPR- based PD2 knockout modelcrossed with KPC model of PC progression. To expand upon the future research direction and to build thefoundation for independence I will pursue postdoctoral training in cancer metabolism. The goal of the proposedK00 postdoctoral training is to gain expertise on :1) the current metabolomic strategies; 2) understand themechanisms that promote acquisition of different metabolic programs by CSCs and differentiated tumor cells; 3)contribution of metabolism to CSC-mediated drug resistance; and 4) development of novel combinatorialtherapeutics based on metabolic targeting to treat cancer. Ultimately the proposed F99/K00 training will providea strong intellectual foundation for R01 funding that will establish my independence and will provide professionaltraining in the skills required to be an effective PI and mentor. 97077 +No NIH Category available Attenuated;Binding;Biological Markers;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;Breast cancer metastasis;CRISPR/Cas technology;CXCL10 gene;Cell Line;Cell Migration Induction;Cell model;Cells;Clinical Trials;Co-Immunoprecipitations;Coupled;Data;Data Set;Disease;Disease-Free Survival;Fatty acid glycerol esters;Future;GNB1 gene;GTP-Binding Proteins;Gene Deletion;Gene Expression;Genes;Goals;Grant;Human Genome;Immune;Immune response;Immunotherapy;Implant;In Vitro;Inflammation;Inflammatory;Knowledge;Laboratories;Leukocytes;Libraries;Lung;Malignant Neoplasms;Mammary Neoplasms;Maryland;Mediating;Metastasis Induction;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Migration Assay;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncogenic;Pathway interactions;Patient-Focused Outcomes;Patients;Positive Lymph Node;Prognostic Marker;Public Health;Repression;Research;Role;Signal Pathway;Signal Transduction;Site;Specificity;Testing;Therapeutic Intervention;Tumor Promotion;Tumor Suppressor Proteins;Tumor-infiltrating immune cells;cancer cell;cancer therapy;cell motility;chemokine;clinically relevant;cytotoxic;gallein;gene repression;hormone receptor-negative;improved;inhibitor;innovation;malignant breast neoplasm;mammary;migration;molecular subtypes;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;programs;receptor;relapse patients;targeted treatment;therapeutic target;treatment response;tumor;tumor progression Targeting CXCL10 Chemokine Signaling in Breast Cancer Metastasis Project NarrativeThis proposal is relevant to public health because more than 30% of breast cancer patients relapse withmetastatic disease often fatal due to limited treatment options presenting an urgent need for innovativestrategies to improve patient outcomes. The proposed Cxcl10/Cxcr3/Gbg signaling axis is a novel mechanism oftumor metastasis in the context of breast cancers deficient in the ING4 tumor suppressor. Delineation of themechanism will offer new therapeutic targets and opportunities for biomarker-guided therapy. NCI 10745331 11/3/23 0:00 PAR-20-052 5R03CA270486-02 5 R03 CA 270486 2 "GRIL, BRUNILDE M" 12/1/22 0:00 11/30/24 0:00 ZCA1-SRB-2(O1)S 8138745 "KIM, SUWON " Not Applicable 7 OTHER BASIC SCIENCES 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 76750 NCI 50000 26750 Project Summary/AbstractCxcl10 is a chemokine that mediates leukocyte migration during normal immune response. In cancers Cxcl10has been considered as a good prognostic marker correlated with tumor immune infiltrates and therapyresponse consistent with its normal function in cytotoxic immune response. As such Cxcl10 has been utilizedas an indicator of robust immune response to therapy in clinical trials and Cxcl10-based cancer therapy hasbeen proposed. Paradoxically Cxcl10 is associated with metastasis and poor patient survival in severalcancers including breast cancer suggesting that Cxcl10 may have a function of promoting cancer progression.The molecular context of this Cxcl10 oncogenic role is not well understood. This research team has identifiedCXCL10 as one of the inflammatory genes repressed by the ING4 tumor suppressor which suggested apotential inverse functional relationship. Preliminary studies from the PIs laboratory analyzed breast tumorgene expression datasets including METABRIC and found that CXCL10-high/ING4-low expression wassignificantly associated with reduced disease-free survival in patients. These data suggested that Cxcl10 mayexert an oncogenic effect in the context of ING4 deficiencies. Corroborating this Cxcl10 induced in vitromigration of ING4-deleted cells but not of ING4-intact cells. The use of inhibitors demonstrated that Cxcl10-induced cell migration required Cxcr3 (the receptor for Cxcl10) and the Gbg subunits downstream of Cxcr3 Gprotein-coupled protein receptor (GPCR) but not Gai. These data indicated a novel mechanism of theCxcl10/Cxcr3/Gbg axis that mediated migration of ING4-deleted cells and potentially metastasis. Based onthese data the hypothesis that Cxcl10/Cxcr3/Gbg signaling mediates metastasis of ING4-deficient cancerwas generated. The overall goal of the study is to unravel the mechanism of Cxcl10 oncogenic signaling. Totest the hypothesis for this Small Grants Program R03 proposal the specific aims will focus on Gbg signalingas it may present novel therapeutic opportunities. The specific aims are: 1) to identify the specific Gbgsubunits responsible for mediating Cxcl10-induced migration of ING4-deleted breast cancer cells in vitro and 2)to determine the role of Gbg in Cxcl10-induced metastasis of mammary tumors using mouse models. In mousemodels gallein (a Gbg inhibitor) and Gb/Gg gene deletion will be evaluated for inhibitory effects on Cxcl10-induced tumor metastasis. Impact: Up to 34% of breast cancers have been identified as ING4-deficient which iscorrelated with lymph node positivity and poor patient survival. Thus delineation of the Cxcl10/Cxcr3/Gbg/ING4signaling mechanism may have a broad impact on breast cancer treatment. If the proposed hypothesis is provencorrect the cell and mouse models in the study can further be used to test novel therapeutic agents targeting thepathway. 76750 +No NIH Category available Acute Lymphocytic Leukemia;Affect;Apoptosis;Apoptotic;B lymphoid malignancy;B-Cell Lymphomas;Blood specimen;CAR T cell therapy;CD19 gene;COVID-19;COVID-19 patient;Cell Death Induction;Cell Therapy;Cell physiology;Cells;Clinical;Clinical Trials;Collaborations;Data;Development;Etiology;Functional disorder;Funding;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Granulocyte-Macrophage Colony-Stimulating Factor Receptors;Hematopoietic;Impairment;In Vitro;Interleukin 6 Receptor;Interruption;Knock-out;Laboratories;Life;Mediating;Mediator;Multi-Institutional Clinical Trial;Multicenter Studies;Myelogenous;Myeloid Cells;Outcome;Outpatients;Pathway interactions;Patients;Phase;Phase I/II Clinical Trial;Pre-Clinical Model;Prevention;Publishing;Receptor Cell;Refractory;Relapse;Resistance;Resolution;Role;Sampling;Severities;Site;T-Lymphocyte;Testing;Therapeutic;Toxic effect;United States;Work;Xenograft Model;cancer therapy;cell behavior;chimeric antigen receptor;cohort;cytokine;cytokine release syndrome;first-in-human;improved;in vivo;insight;laboratory experiment;large cell Diffuse non-Hodgkin's lymphoma;monocyte;monocyte colony stimulating factor;neurotoxicity;neutralizing antibody;novel;novel strategies;post-COVID-19;pre-clinical;prevent;receptor;response;severe COVID-19;tocilizumab;tool;transcription activator-like effector nucleases;tumor Towards Safer and More Effective CART Cell Therapy Through the Modulation of Myeloid Cytokines Project NarrativeOur goal is to develop novel strategies to prevent toxicities enhance efficacy and modulate themicroenvironment after chimeric antigen receptor T (CART) cell therapy for the treatment of cancer. We haveidentified GM-CSF and as a key cytokine in mediating CART cell toxicity and impairing their functions. We areplanning to study these interactions in lab experiments preclinical models and in a first-in-human clinical trialof GM-CSF neutralization with CART cell therapy to prevent neurotoxicity. NCI 10745321 12/15/23 0:00 PA-20-185 5R37CA266344-03 5 R37 CA 266344 3 "HU, ZHANG-ZHI" 12/9/21 0:00 11/30/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 15738149 "KENDERIAN, SAAD J." Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 568795 NCI 362093 206702 PROJECT SUMMARYDespite the impressive activity of chimeric antigen receptor (CART) T cell therapy in the treatment of B-cellmalignancies the therapy is limited by the development of cytokine release syndrome (CRS) and neurotoxicityas well as by lower rates of durable responses. While CRS is related to extreme elevation of cytokinesassociated with T cell expansion the exact etiology of neurotoxicity is unknown and no options for treatment ofneurotoxicity are available. It has however become apparent that inhibitory myeloid cells and cytokinescontribute to both CART cell toxicities and resistance. We have identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as a dominant driver for CART cell toxicity and inhibition of their functions. Ourrobust preclinical data indicate that GM-CSF inhibition reduces monocyte activation enhances CART cellfunctions and prevents the development of both CRS and neurotoxicity in a novel xenograft model for CARTcell-associated toxicities. Our additional studies suggest that GM-CSF disruption in CART cells amelioratestheir apoptosis independent of its effect on myeloid cells. These findings were corroborated when we utilizedGM-CSF depletion as a therapeutic strategy in patients with cytokine storm and severe Coronavirus Disease2019 COVID-19. Based on this work a Phase 1/2 multi-center study of GM-CSF neutralization after CART19cell therapy was launched. Our central hypothesis is that depletion of GM-CSF results in modulation of myeloidcell behavior amelioration of CART cell activation reduction of CART cell associated toxicities andenhancement of their efficacy. We will leverage our laboratory tools novel preclinical models and samplesfrom this clinical trial to test our hypothesis. In Aim 1 of this project we will examine the interactions betweenGM-CSF and monocytes after CART cell therapy. In Aim 2 of this project we will study the effect of GM-CSFdirectly on CART cells and Aim 3 will test how these changes affect toxicity and efficacy of CART19 celltherapy in the novel Phase 1/2 clinical trial. Completion of these Aims will identify novel insights into the toxicityand activity of CART cells and will develop a new strategy to prevent CART cell associated neurotoxicity andCRS potentially enabling the outpatient administration of CART cell therapy. 568795 +No NIH Category available 5' Untranslated Regions;Address;Affect;Age;Apoptosis;Binding Sites;Biological Assay;CRISPR/Cas technology;Cancer Biology;Cancer Model;Cells;Cellular biology;Characteristics;Co-Immunoprecipitations;Complementary DNA;Complex;Data;Diagnosis;Enzymes;Fibroblasts;Future;Gene Expression;Genes;Genetic Transcription;Genotype;Goals;Human;Immunohistochemistry;In Vitro;Inhibition of Cancer Cell Growth;Invaded;Investigation;KRASG12D;Lentivirus;Lentivirus Vector;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Measures;Messenger RNA;Methods;Methyltransferase;Modeling;Modification;Molecular;Monitor;Mus;Mutagens;Normal tissue morphology;Oncogenes;Oncogenic;Organoids;Pathway interactions;Persons;Phosphorylation;Positioning Attribute;Primary Neoplasm;Proteins;Proteomics;RNA;RNA immunoprecipitation sequencing;RNA methylation;RNA Messenger Splicing;Regulation;Regulator Genes;Reporter;Research;Role;Sampling;Survival Rate;Terminator Codon;Testing;Time;Transgenic Organisms;Translations;Woman;Xenograft procedure;cohort;effective therapy;epitranscriptome;experience;experimental study;gain of function;in vivo;inducible Cre;insight;knock-down;loss of function;lung cancer cell;lung tumorigenesis;metaplastic cell transformation;mouse model;mutant;novel;novel therapeutic intervention;overexpression;posttranscriptional;protein expression;ribosome profiling;small hairpin RNA;therapeutic target;transcriptome;transcriptome sequencing;tumor;tumor growth;tumor initiation;tumor progression;tumorigenesis Role of METTL3 and the m6A Epitranscriptome in cancer Project NarrativeThis study will characterize messenger RNA (mRNA) methylation in lung tumors and explore the oncogenicrole of the RNA methyltransferase METTL3 in lung cancer. This investigation could lead to novel therapeuticstrategies to control oncogene expression in lung adenocarcinoma and other tumor types.1 NCI 10745319 11/6/23 0:00 PA-19-056 5R01CA233671-05 5 R01 CA 233671 5 "MAAS, STEFAN" 12/11/19 0:00 11/30/24 0:00 Cancer Genetics Study Section[CG] 8793150 "GREGORY, RICHARD I." "KIM, CARLA F." 7 Unavailable 76593722 Z1L9F1MM1RY3 76593722 Z1L9F1MM1RY3 US 42.337481 -71.104964 1504801 BOSTON CHILDREN'S HOSPITAL BOSTON MA Independent Hospitals 21155724 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 578243 NCI 326691 251552 Lung adenocarcinoma accounts for about 40% of all lung cancers and is the most common form of lungcancer found in women and in people under the age of forty-five. Strikingly the 5-year survival rate for lungcancer overall is only about 18 percent and more than half of people with lung cancer die within one year ofdiagnosis. This highlights the need for more effective treatment options and underscores the importance ofresearch focused on uncovering and understanding new molecular and cellular pathways that contribute tolung cancer biology. Messenger RNAs (mRNAs) are subject to various posttranscriptional modificationsincluding N6-Methyladenosine (m6A). m6A is the most abundant mRNA modification and is emerging as animportant regulator of gene expression that can affect mRNA splicing export stability and translation. m6Ais catalyzed the METTL3 methyltransferase complex and occurs at a characteristic sequence motif at aposition close to the translation stop codon of a large subset of mRNAs. The goal of this proposal is to testthe central hypothesis that METTL3 is a novel oncogenic factor in lung cancer. The global m6A mRNA`epitranscriptome' will be mapped and measured in a cohort of primary human lung tumor samples. Relativelevels of METTL3 in tumors will be measured by immunohistochemistry and correlated with the m6A levelsand transcriptome-wide distribution. Loss- and gain-of-function experiments will address the widespreadimpact of METTL3 (and METTL3-interacting proteins) in controlling target mRNA expression and will helpuncover the molecular and cellular role of METTL3 METTL3-interacting proteins and a selection ofdownstream targets mRNAs in lung cancer cell biology. Finally the effects of METTL3 manipulation in lungtumor initiation and progression will be explored using a mouse lung cancer model as well as a novel lungorganoid model and a panel of assays will be deployed to examine the underlying molecular mechanism.Successful completion of the proposed studies will help establish METTL3 as a possible future therapeutictarget for lung adenocarcinoma and other cancers. 578243 +No NIH Category available Affect;Area;Biochemical;Biometry;Biopsy;Brain;Brain Neoplasms;Cauterize;Characteristics;Classification;Clinical;Clinical Research;Clinical Trials;Complement;Complex;Comprehensive Cancer Center;Conventional Surgery;Craniotomy;Data;Data Display;Databases;Diagnostic;Diagnostic Imaging;Diagnostic Procedure;Discrimination;Engineering;Environment;Epilepsy;Equipment;Excision;Fluorescence;Glioma;Goals;Harvest;Hemostatic function;Histopathology;Human;Image;Image-Guided Surgery;Imaging Device;Imaging Techniques;Imaging technology;Intervention;Label;Letters;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of brain;Manufacturer;Measurement;Metabolic;Microscope;Necrosis;Neoplasm Metastasis;Neurodegenerative Disorders;Neurologic;Neuronavigation;Neurosurgeon;Neurosurgical Procedures;Normal tissue morphology;Operative Surgical Procedures;Optics;Outcome;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Predictive Value;Procedures;Property;Protocols documentation;Qi;Radiation necrosis;Resources;Scanning;Signal Transduction;Specimen;Surgeon;Surgical Oncology;Surgically-Created Resection Cavity;System;Techniques;Technology;Testing;Time;Tissue Sample;Tissues;Tumor Tissue;Validation;Visual;Visualization;brain abnormalities;brain tissue;brain tumor resection;cohort;data acquisition;diagnostic value;feature detection;flexibility;fluorescence lifetime imaging;image processing;imaging system;improved;instrumentation;learning progression;multidisciplinary;nervous system disorder;neuro-oncology;neuropathology;neurosurgery;novel;optical imaging;pragmatic implementation;prospective;real-time images;standard of care;success;temporal measurement;tool;tumor Label-free fluorescence lifetime imaging for intraoperative real-time guidance of neurological procedures PROJECT NARRATIVEThe success of brain tumor resection and biopsy is limited by the surgeon's ability to distinguish pathologic fromnormal tissue intraoperatively and in real-time. Our novel optical imaging FLIm system captures and analyzestissue autofluorescence to identify distinct brain tissue types (tumor necrotic normal) and integrates thisinformation with standard of care neurosurgical technologies for convenient display onto the surgeon's field-of-view providing a means to better acquire a robust diagnostic biopsy and achieve maximal tumor resection. Thesuccessful validation of FLIm as an intraoperative adjunct for tumor tissue identification will improve brain cancerpatient outcomes and generate a paradigm for the use of FLIm in multiple areas of surgical oncology (othercancers) as well as guided interventions for treatment of functional neurologic diseases. NCI 10745303 12/1/23 0:00 PA-19-056 5R01CA250512-04 5 R01 CA 250512 4 "PEREZ, J MANUEL" 12/15/20 0:00 11/30/26 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 6647839 "MARCU, LAURA " "BLOCH, ORIN " 4 BIOMEDICAL ENGINEERING 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA BIOMED ENGR/COL ENGR/ENGR STA 956186153 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 74218 NCI 49313 24905 PROJECT SUMMARY/ABSTRACTThe outcome of brain tumor surgery is critically dependent on the neurosurgeon's ability to distinguish betweenabnormal and normal tissue in real-time. Our goal is to enhance this discrimination by using label-freeFluorescence Lifetime Imaging (FLIm) to detect tissue biochemical and metabolic characteristics that distinguishamong different tissue types and by integrating FLIm into the neurosurgical workflow to provide this informationin a real-time visual format useful for guiding tumor biopsy and resection. FLIm-derived tissue fluorescencefeature information will be co-registered with the preoperative-MRI (pMRI) and projected onto the conventionalsurgical microscope field-of-view (FOV). This should improve delineation of tumor margins and thus increaseboth the diagnostic yield of brain biopsy and the extent of tumor resection.The proposed FLIm technique will incorporate the following features: (1) Safe rapid and simultaneousmeasurement of time-resolved fluorescence decays in multiple spectral emission bands that will acquireextensive information in one scanning measurement of a large area of tissue selected by the surgeon; and (2)Fast analysis display and augmentation of fluorescence parameters that enable real-time visualization of opticaldata encoding diagnostic information onto the surgical FOV. The proposed clinical studies using FLIm as a stand-alone tool will establish classifiers to correlate FLIm parameters with specific tissue pathologies an importantstep in demonstrating FLIm's diagnostic value. The proposed integration of FLIm as an adjunct to theneuronavigation system and surgical microscope will provide data for combined analysis to validate the benefitof FLIm diagnostics in neurosurgical procedures. Three aims are proposed: Aim 1) Construct and integrate aFLIm device as a diagnostic adjunct with conventional neurosurgical tools. Aim 2) Clinically evaluate therelationship between FLIm parameters and distinct tissue pathologies and develop classifiers for different tissuetypes. Aim 3) Validate FLIm for real-time intraoperative guidance through a prospective analysis.In summary this study will demonstrate the clinical feasibility and utility of FLIm for intraoperative real-timeassessment of neurosurgical margins and the resulting improvement in neuropathologic diagnostic yield. Theacquired FLIm parameter database will enable subsequent clinical trials for automated tissue classification anddiagnostic prediction. The new FLIm instrumentation characterized by simple fast and flexible data acquisitionand display and its seamless integration with existing neurosurgical imaging will provide a less expensivealternative to intraoperative MRI and a valuable complement to current standard-of-care diagnostic procedures.Success in this area will warrant a more generalized use of FLIm in surgical oncology (other cancers) as well asguided interventions for treatment of functional neurologic diseases (e.g. epilepsy neurodegenerative diseases). 74218 +No NIH Category available 3-Dimensional;Affect;Alleles;Behavior;Bioinformatics;Biological Assay;Biological Models;Biology;Biometry;Cancer Diagnostics;Cancer Model;Cell Line;Cell model;Cells;Chromatin;Chromatin Structure;Chromosomal Loss;Chromosomal Rearrangement;Chromosomal Stability;Chromosome 15;Chromosome 6;Chromosome Condensation;Chromosome Deletion;Chromosome Structures;Chromosome abnormality;Chromosomes;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Communities;DNA Replication Timing;DNA analysis;DNA biosynthesis;DNA replication fork;Data Set;Development;Elements;Event;Family;Fluorescent in Situ Hybridization;Future;Gene Expression;Genes;Genetic Nondisjunction;Genetic Transcription;Genome;Genome Stability;Genomic Instability;Genomics;Haplotypes;Health;Human;Human Characteristics;Human Chromosomes;In Vitro;Knowledge;Laboratory Finding;Lead;Learning;Link;Maintenance;Malignant Neoplasms;Measures;Medical;Methods;Mitotic;Mitotic Chromosome;Modeling;Molecular;Names;Normal Cell;Nucleotides;Operative Surgical Procedures;Patient-Focused Outcomes;Phase;Phenotype;Physical condensation;Population;Postdoctoral Fellow;Prognosis;Progress Reports;Proteins;Public Speaking;RNA;Regulator Genes;Research;Role;Route;Sampling;Single Nucleotide Polymorphism;Testing;The Cancer Genome Atlas;Tissues;Training;Transcript;Translating;Untranslated RNA;Visualization;Work;articular cartilage;autosome;cancer cell;cancer genome;cancer risk;cancer type;chromosome conformation capture;chromosome missegregation;chromosome replication;clinically significant;genome wide association study;genome-wide;insight;interest;lymphoblastoid cell line;member;micronucleus;novel diagnostics;novel therapeutic intervention;novel therapeutics;pre-doctoral;progenitor;programs;risk variant;skill acquisition;skills;stem cells;targeted cancer therapy;tool;tumor;tumor progression;virtual Integrative Analysis of DNA Replication Timing in Cancer Project NarrativeGenome instability is a near ubiquitous characteristic of human cancer and is associated with worse patientoutcomes but when and how it arises in tumor development is not completely understood. The proposed workaims to uncover the role of the recently discovered cis-acting ASAR long non-coding RNA elements(ASynchronously Replicating Autosomal RNA) in the maintenance of normal chromosome stability and thepotentially widespread effects of ASAR disruption in cancer. The results of this proposal will contribute to abetter fundamental understanding of how chromosomes function in normal and cancer cells and ultimatelyhelp to fill the desperate need for new diagnostic and therapeutic options targeting unstable genomes inhuman cancer. NCI 10745301 11/22/23 0:00 RFA-CA-19-002 5K00CA245677-05 5 K00 CA 245677 5 "DAMICO, MARK W" 12/10/21 0:00 11/30/25 0:00 ZCA1-RTRB-R(A1) 14629033 "HESKETT, MICHAEL B" Not Applicable 16 GENETICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 87043 NCI 80595 6448 Project Summary/Abstract: Genome instability is the most significant feature associated with poor prognosisin many cancers. But despite being a near-universal characteristic of human cancer our knowledge of howgenome instability initiates and contributes to tumor development is lacking. Because of its wide presence andclose association with aggressive tumors insight into the possible mechanisms and consequences of genomeinstability is crucial in the search for new and targeted cancer therapies and diagnostics.Here a new model is proposed backed by significant preliminary findings for the maintenance of genomicstability by cis-acting long non-coding RNA (lncRNA) elements that regulate multiple aspects of large-scalechromosome function. The main hypothesis of this project is that the recently discovered cis-acting ASARlncRNAs (ASynchronously Replicating Autosomal RNA) are expressed by normal cells on all autosomes toregulate fundamental chromosome behavior such as DNA replication timing monoallelic gene expression 3-dimensional chromosome localization and mitotic chromosome condensation but are frequently disrupted incancer leading to genomic instability. Expression of the first two members of the ASAR family (ASAR6ASAR15) is required for stability on chromosome 6 and 15 respectively and disruption of either lncRNA leadsto aberrant chromosomes through increased stalling of replication forks and mis-segregation of chromosomes.The long-term objective of this research is to identify all ASARs on human autosomes validate their functionalrole in genome stability and use ASARs as a tool to understand and ultimately identify and treat cancers withgenomic instability. In Aim 1 a genome wide search for expression of putative ASARs will be performedutilizing a single-cell derived haplotype-resolved human primary cell model system followed by assessment ofthe functional qualities of potential ASARS with nucleotide sequencing assays that measure DNA replicationtiming allele specific RNA expression and 3D chromosome localization. To probe the potential effects ofASARs on human health a search for significant disruption of ASARs in a dataset of ~10000 human tumorsamples will be performed.The research will be conducted as part of a comprehensive training plan involving advanced skill developmentin bioinformatics and biostatistics professional development such as public speaking and networking and willtake place within an extensive intellectual community composed of cancer biologists at the Knight CancerInstitute molecular and medical geneticists and computational biologists at OHSU. The post-doctoral researchdirection will translate the knowledge of chromosome biology and skillsets in genomics developed during thepre-doctoral period to study the mechanisms of action of non protein-coding germline risk loci in humancancer. The successful results of the proposed research will reveal basic functions of chromosomes andprovide new insight towards understanding genomic instability a common abnormality in cancer. 87043 +No NIH Category available Ablation;Address;Adhesions;Breast;Breast Cancer Cell;Breast Cancer cell line;Breast Epithelial Cells;Breast cancer metastasis;CDH1 gene;CRISPR screen;Cell Adhesion;Cell Cycle;Cell Differentiation process;Cell-Cell Adhesion;Cells;Cessation of life;Complex;DNA Sequence Alteration;Data;Deletion Mutation;Development;Disease;EZH2 gene;Endogenous Retroviruses;Epigenetic Process;Estrogen Receptors;Estrogen receptor positive;Exhibits;Failure;GATA3 gene;Gene Mutation;Genes;Genetic Models;Genetic Transcription;Genetic study;Genome;Genomics;Heritability;Histone H2A;Histones;Human;Immune;Immune response;Impairment;Injections;Invaded;KDM1A gene;KLRD1 gene;Knowledge;Ligands;Lysine;Malignant Neoplasms;Mammary Neoplasms;Maps;Mediating;Mediator;Metastasis Suppression;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Modeling;Molecular;Molecular Abnormality;Monoubiquitination;Mouse Mammary Tumor Virus;Mus;Mutation;Natural Killer Cells;Neoplasm Metastasis;Oncogenic;Oncoproteins;Organ;Pathway interactions;Patients;Play;Point Mutation;Polycomb;Primary Neoplasm;Proliferating;Qa-1 Antigen;Regulation;Repression;Role;Scientist;Specificity;System;Testing;The Cancer Genome Atlas;Translating;Up-Regulation;Work;cancer genome;cancer initiation;cancer type;cell type;driver mutation;epigenetic regulation;gene repression;genetic approach;genome sequencing;histone demethylase;in vivo;inhibitor;malignant breast neoplasm;methyl group;migration;mortality;mouse model;neoplastic cell;new therapeutic target;non-genetic;novel strategies;polyoma middle tumor antigen;prevent;programs;protein complex;receptor;targeted treatment;transcription factor;transplant model;tumor microenvironment;tumor-immune system interactions;ubiquitin ligase Mechanism of LSD1 in breast cancer metastasis suppression As gene mutations found in cancers that spread to other organs (i.e. metastasis) are not too much differentfrom those found in primary tumors from the same patients scientists have proposed that non-geneticheritable mechanisms referred to as epigenetic mechanisms may be the real driver for metastasis. Thepurpose of this project is to study how loss of LSD1 an epigenetic regulator contributes to increased breastcancer metastasis by both cell-intrinsic (i.e. via its regulation of key target genes in breast epithelial cells)and extrinsic (e.g. immune cell-related) mechanisms. The knowledge from this project may translate intonovel therapeutic targets and strategies to treat and/or prevent the metastatic disease. NCI 10745297 11/15/23 0:00 PA-19-056 5R01CA248306-04 5 R01 CA 248306 4 "SNYDERWINE, ELIZABETH G" 12/1/20 0:00 11/30/25 0:00 Tumor Progression and Metastasis Study Section[TPM] 8656796 "LI, ZHE " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 342494 NCI 205875 136619 Comparisons of genetic mutations found in primary tumors and their corresponding metastatic lesions haveso far failed to define genetic mutations that lead to metastasis. This raises a notion that it is the epigeneticmechanisms working together with cancer type-specific oncogenic and/or cell type-specific lineage programsthat may drive metastatic progression. In breast cancer how epigenetic abnormalities drive metastaticprogression remains largely elusive. A better understanding of this may lead to novel strategies to blockbreast cancer metastasis. LSD1 (KDM1A) is the first identified histone demethylase. In human cancersgenetic abnormalities of LSD1 mainly include deletions and mutations. Such deletions/mutations have alsobeen found in metastatic breast cancer raising a possibility that LSD1 is a breast cancer metastasissuppressor. Indeed in preliminary studies we found induced loss of LSD1 in luminal mammary tumor cellsor LSD1 inhibitor treatment in the MMTV-PyMT mouse model led to a dramatic increase in lung metastasis.Mechanistically in luminal breast cells we found LSD1 interacts with GATA3 a key luminal-specifictranscription factor to control their common programs related to cell-cell adhesion and cell cycle. LSD1positively regulates GATA3 expression and represses that of TRIM37 a common target of both LSD1 andGATA3 which encodes a histone H2A ubiquitin ligase involved in gene repression. Importantly TRIM37 maycontribute to increased invasion and migration of luminal breast cancer cells with LSD1-loss via repression ofseveral cell adhesion genes (e.g. CDH1 VCL CTNNA1). Such expression changes were also observed inmurine PyMT tumor cells with LSD1-loss. Together these data suggest that LSD1 may suppress breastcancer metastasis via regulation of its target genes (e.g. TRIM37) in luminal cells in a demethylase activity-dependent manner. Intriguingly PyMT tumor cells with LSD1 ablation also exhibited a profound change inimmune-related genes suggesting that LSD1 may also suppress breast cancer metastasis by a cell-extrinsicimmune-related mechanism. To test these we will continue to establish mouse intraductal injection (MIND)transplantation models for PyMT tumor cells and human estrogen receptor+ breast cancer cell lines as our invivo system. In Aim 1 we will perform CRISPR-based screens to map functional domain(s) of LSD1responsible for its metastasis suppression vs. proliferation/survival-supporting roles and test if LSD1mutations found in patients impair its metastasis suppression function via disruption of the demethylaseactivity. In Aim 2 we will determine roles of LSD1 targets (e.g. TRIM37 and its partner EZH2 and others) ofluminal cells at different steps of the metastatic cascade in various MIND models. In Aim 3 we will determinethe immune mechanism mediating increased PyMT metastasis associated with LSD1 ablation in particularNK cells and MHC-I molecules as LSD1-loss in PyMT tumor cells led to a profound upregulation of variousclassic and non-classic MHC-Is which serve as ligands for inhibitory receptors in NK cells. 342494 +No NIH Category available 3' Untranslated Regions;Acute Myelocytic Leukemia;Address;Advanced Malignant Neoplasm;Arginine;Binding;Binding Proteins;Binding Sites;Blood;Blood Cells;CD34 gene;CRISPR screen;Cell fusion;Cells;Clinical;Communication;Cytotoxic agent;Data;Dependence;Development;Disease;Enzymes;Epigenetic Process;Equilibrium;Exhibits;Family;Family Study;Family member;Frequencies;Genetic Models;Hematologic Neoplasms;Hematopoietic stem cells;Human;Knockout Mice;Laboratories;Leukemic Cell;Link;Lymphoma cell;Malignant Neoplasms;Mammalian Cell;Maps;Measures;Mediating;Medicine;Messenger RNA;Methylation;Molecular;Mus;Mutation;Myeloid Leukemia;Nature;Normal Cell;Outcome;Pathogenesis;Pathway interactions;Patients;Post-Translational Protein Processing;Prognostic Marker;Proteins;RNA Binding;RNA Editing;RNA Recognition Motif;RNA Splicing;RNA-Binding Proteins;Reagent;Regulation;Relapse;Resistance;Role;Sampling;Site;Solid Neoplasm;System;Therapeutic;Time;Transferase;Translations;cell growth;chemotherapy;epigenome;genome-wide;inhibitor;leukemia;leukemia/lymphoma;leukemic stem cell;leukemogenesis;molecular targeted therapies;mouse model;myeloid leukemia cell;novel;novel strategies;novel therapeutic intervention;programs;protein function;response;stem;stem cell biology;stem cell function;stem cells;synergism;therapeutic target;transcriptome sequencing Characterizing the MSI2 network in leukemia PROJECT NARRATIVEAlthough molecular targeted therapy has dramatically changed how we treat cancer the treatment for acutemyeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsingwith their disease. Our studies have uncovered that the MUSASHI (MSI) family is required in AML. Thisproposal studies this family in both mouse models and in human AML in order to identify novel strategies fortargeting the stem cell program in leukemia. NCI 10745291 11/15/23 0:00 PA-19-056 5R01CA193842-09 5 R01 CA 193842 9 "KLAUZINSKA, MALGORZATA" 4/1/15 0:00 11/30/25 0:00 Molecular Oncogenesis Study Section[MONC] 9603277 "KHARAS, MICHAEL " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 371921 NCI 210125 161796 PROJECT SUMMARY/ABSTRACTAn evolutionary conserved developmental program is carefully maintained in hematopoietic stem cells (HSCs).Genetic alterations and epigenetic mechanisms can alter the balance of normal blood development resulting inhematological malignancies. Our laboratory and others have found that the MUSASHI2 (MSI2) RNA bindingproteins is highly expressed in the most aggressive cancers and predicts a poor clinical outcome in acutemyeloid leukemia (AML) patients. Genetic models have found that MSI2 is required for leukemia stem cellfunction. Utilizing a new way to identify mRNA targets of RNA binding proteins we have found that MSI2activity is increased in leukemia stem cells compared to normal stem and progenitor cells. This surprisingfinding suggests that RNA binding protein function can be dysregulated beyond just expression differences.We hypothesize that the MSI family of RNA binding protein have differential activity in AML compared tonormal cells and that MSI enhances the dysregulated epigenome in AML. We propose two possiblemechanisms for this intriguing finding 1) MSI2 associated RBPs compete for MSI2-binding sites and 2) Post-translation modifications can modulate MSI2 activity. Our preliminary data has uncovered that MSI2 canmediate resistance to PRMT5 and that PRMT1 and PRMT5 can directly methylate MSI2. PRMT5 inhibitors arebeing investigated as therapeutic targets and our proposal suggests a novel link to this pathway and mayexplain cell context MSI2 activity. Our proposal will utilize new genetic models to characterize MSI2 targets inspecific cellular contexts and explore the MSI2 associated program to identify new therapeutic strategies inAML. 371921 +No NIH Category available Address;Bypass;Cancer Patient;Cell Line;Clinical;Clinical Research;Clinical Trials;Collaborations;DNA Sequence Alteration;Data;Development;Drug resistance;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Erlotinib;Evaluable Disease;Exons;FDA approved;Future;Gefitinib;Generations;Genetically Engineered Mouse;Genomics;Goals;In Vitro;Induced Mutation;Insertion Mutation;Lead;Letters;Location;Malignant neoplasm of lung;Maps;Mediating;Medical Oncology;Medicine;Modeling;Molecular;Mutation;Nature;Non-Small-Cell Lung Carcinoma;Outcome;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Point Mutation;Population;Pre-Clinical Model;Productivity;Proteomics;Publications;Regimen;Reporting;Research Personnel;Resistance;Resources;Retrospective Studies;Role;Signal Pathway;Signal Transduction;Structure;Structure-Activity Relationship;Study models;Testing;Therapeutic;Treatment Protocols;Tyrosine Kinase Inhibitor;aurora kinase A;combat;drug sensitivity;effective therapy;efficacy evaluation;experience;improved;in silico;in vivo;inhibitor;molecular modeling;molecular pathology;mouse model;multidisciplinary;mutant;objective response rate;partial response;patient population;phase II trial;pre-clinical;preclinical study;prevent;resistance mechanism;resistance mutation;response;screening;targeted agent;targeted treatment;treatment strategy;tumor;virtual Therapeutic strategies against EGFR exon 20 mutant lung cancer PROJECT NARRATIVEConsiderable progress has been made in developing effective targeted therapies for NSCLC patients harboringtypical EGFR mutations (L858R and exon 19 deletions) but no advancements had been made for NSCLCpatients bearing atypical EGFR exon 20 insertion mutations who are inherently resistant to the same treatmentregimens. For this population we recently identified poziotinib as a potent and clinically active compound butcritical questions remain regarding mechanisms of resistance to this agent and other tyrosine kinase inhibitors(TKIs) targeting EGFR exon 20 insertions. This project addresses a critical unmet need to define mechanismsof resistance in this patient population and to identify therapeutic strategies to overcome resistance. NCI 10745273 11/15/23 0:00 PA-19-056 5R01CA234183-05 5 R01 CA 234183 5 "FORRY, SUZANNE L" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-MCT2-C(01)S] 1894553 "HEYMACH, JOHN V." "WONG, KWOK KIN " 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 501734 NCI 399844 101890 PROJECT SUMMARYApproximately 10-12% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor in-framemutations or insertions within exon 20 of EGFR. Unlike NSCLC patients bearing typical EGFR mutations(L858R or exon 19 deletions) these patients with exon 20 mutations are highly resistant to FDA-approved first-generation tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib with an objective response rate ofapproximately 4-8% and a median PFS of 2 months; by comparison first-generation TKIs lead to an objectiveresponse rate of ~60% and a PFS of ~10 months in patients with typical EGFR mutations. The populationimpacted by EGFR exon 20 mutations is sizable: approximately 2000-3000 patients per year in the US andapproximately 27000 patients per year worldwide. Until recently no treatment strategies had been identifiedthat were tailored for this patient population. We recently reported the results of a detailed structure-functionanalysis and screening effort that led to the identification of the TKI poziotinib as a potent and clinically activeinhibitor of EGFR exon 20 mutant tumors. Based on our preclinical data we have conducted a phase II trial ofpoziotinib. Initial results indicate high anti-tumor activity with best objective response of PR (partial response) in55% of 44 evaluable patients. However some patients do not initially respond to treatment (primary resistance)and for the patients who do respond initially acquired resistance is a clinical challenge. Our goals are toelucidate the mechanisms of primary and acquired resistance to poziotinib and other potential EGFR exon 20-targeted therapies. We find that in preclinical models primary resistance may be associated with size andlocation of the specific insertion with a greater distance of the insertion from the -c-helix associated with a lowersensitivity to poziotinib. Moreover we have generated evidence from preclinical models and NSCLC patientsindicating that acquired resistance may be mediated through multiple mechanisms some EGFR-dependent (e.g.additional EGFR alterations) and others EGFR-independent (e.g. activation of alternate signal bypasspathways). We hypothesize that a) the sensitivity of different exon 20 insertions/mutations to specific TKIs willbe dictated by the insertion size and location and treatment may be tailored based on this information; and b)that acquired resistance occurs through both EGFR-dependent and independent mechanisms that can betargeted. We will test these hypotheses through an integrative multidisciplinary effort involving preclinicalstudies molecular modeling and ongoing clinical studies. In Aim 1 we will investigate primary resistance andthe structure-function relationship between specific insertions and drug response; in Aim 2 we will investigatethe mechanisms of EGFR-dependent acquired resistance and in Aim 3 we will investigate EGFR-independentmechanisms. These studies will help guide the selection of TKIs based on a patients mutation and will providea road map for the future development of improved TKIs and more effective combinations to delay or preventthe emergence of drug resistance in this group of patients for which no targeted treatments currently exist. 501734 +No NIH Category available Acetylation;Area;Attention;Basal Cell;Binding;Biochemistry;Biological;Biology;Cell Aging;Cells;Cessation of life;Complex;Coupled;Disease;Doctor of Philosophy;Faculty;Foundations;Gene Expression;Genes;Genetic;Genetic Transcription;Genome;Genomics;Goals;Growth;HDAC3 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;Immune;In Vitro;Investigation;Link;Lung;Lung Neoplasms;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Mutate;Mutation;NCOR1 gene;NF-kappa B;Non-Small-Cell Lung Carcinoma;Nuclear Receptors;Outcome Study;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Play;Positioning Attribute;Regulation;Repression;Research;Resistance;Role;STK11 gene;Signal Pathway;Signal Transduction;Source;Specificity;TP53 gene;Therapeutic;Tumor Biology;Tumor Promotion;Tumor Suppressor Proteins;Tumor-infiltrating immune cells;United States;Work;anticancer research;cancer cell;career;experimental study;in vivo;inhibitor;insight;interest;lung cancer cell;lung tumorigenesis;mutant;mutational status;neoplastic cell;novel;p65;pharmacologic;post-doctoral training;pre-clinical;programs;protein complex;recruit;senescence;targeted treatment;tenure track;therapeutic evaluation;transcription factor;treatment response;tumor;tumor growth The HDAC3 pathway in LKB1-mutant lung cancer and senescence Project NarrativeLung cancer remains the most common source of cancer deaths annually in the United States and worldwideand the tumor suppressor LKB1 is one of the most frequently mutated genes in this disease. We recentlydiscovered that Histone Deacetylase 3 (HDAC3) is required for lung tumor growth in vivo and we identified twospecific mechanisms involved. This proposal aims to further investigate these mechanisms by 1) identifying themolecular explanations for LKB1 specific HDAC3 function and 2) defining how HDAC3 represses theSenescence-Associated Secretory Phenotype (SASP) and immune cell recruitment. NCI 10745269 11/2/23 0:00 PAR-18-467 5K22CA251636-02 5 K22 CA 251636 2 "JAKOWLEW, SONIA B" 12/1/22 0:00 11/30/25 0:00 ZCA1-RTRB-R(O2) 11726877 "EICHNER, LILLIAN J." Not Applicable 5 BIOCHEMISTRY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 191052 NCI 176900 14152 Project Summary/AbstractThe STK11/LKB1 tumor suppressor is mutated in ~15% of Non-Small Cell Lung Cancer (NSCLC)cases making it the third most frequent genetic alteration. LKB1 is frequently co-mutated with Kras andLKB1-mutant tumor biology is becoming increasingly of interest to the cancer field as the uniquenessof the underlying tumor biology coupled with the lack of targeted therapy options is gaining attention.Recent work identified a potent tumor promoting function of the HDAC3 complex in Kras-driven NSCLCand revealed that HDAC3 cooperates with the lung cancer lineage transcription factor NKX2-1 to drive aunique transcriptional program in lung cancer cells with LKB1 mutation. Interestingly regardless of LKB1mutational status HDAC3 was also found to directly repress the Senescence-Associated SecretoryPhenotype (SASP) via p65 NF-kB. The work outlined in this proposal aims to (1) elucidate themechanistic explanations for the observed transcriptional vulnerabilities unique to LKB1 mutant tumorsand to (2) define how the HDAC3 protein complex regulates the SASP and immune cell recruitment toimpact lung tumor growth control. Experiments will determine HDAC3 and NKX2-1 genomic bindingpatterns and interacting partners specific to LKB1-mutant cells whether Class IIa HDACs contribute tothe LKB1 specificity of HDAC3 function and therapeutic response to HDAC3 inhibition in LKB1-mutanttumors. These studies will also define how HDAC3 impacts p65 genome binding and activity identify whichNuclear Receptors are required for HDAC3 repression of the SASP and profile the HDAC3-dependentintratumoral immune infiltrate and its contribution to growth control in vivo. Insights gained from this workwill contribute to the understanding of key LKB1-specific transcriptional pathways and how they may beimpinged upon therapeutically. This research also aims to define the mechanism mediating HDAC3control of the SASP which will facilitate exploration of key questions about SASP involvement in tumorgrowth control more broadly. The candidate holds a Ph.D. in Biochemistry and is currently completing herpost-doctoral training with Dr. Reuben Shaw at the Salk Institute for Biological Studies. The candidatescareer goal is to obtain a tenure-track faculty position studying transcriptional deregulation in cancer.These studies will provide the foundation for a continued research program in this important emergingarea of cancer research. 191052 +No NIH Category available Ablation;Address;Adjuvant;Affect;Aromatase Inhibitors;Binding;Biological Markers;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;CDK4 gene;Cell Cycle;Cell Line;Cell Survival;Cell secretion;Cells;Clinical;Disease;Dose;Down-Regulation;ERBB2 gene;Early treatment;Endocrine;Enrollment;Estrogen receptor positive;Evaluable Disease;Gene Expression Profile;Genetic;Genomics;Goals;Growth;Growth Factor;Homodimerization;IL-6 inhibitor;Immune checkpoint inhibitor;Inflammatory;Interleukin-6;Interleukins;Knockout Mice;MCF7 cell;Mammospheres;Mediating;Modeling;Molecular Analysis;Mus;Neoadjuvant Therapy;Neoplasm Metastasis;Operative Surgical Procedures;Oral;Organoids;Pathway interactions;Patient Care;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phase Ib Trial;Phase Ib/II Clinical Trial;Phenotype;Phosphorylation;Population;Primary carcinoma of the liver cells;Proteomics;Qualifying;Recurrence;Resistance;Resistance development;Retinoblastoma Protein;Risk;Role;STAT3 gene;Safety;Serious Adverse Event;Serum;Solid Neoplasm;T47D;Testing;Time;Transgenic Mice;Transgenic Model;Transgenic Organisms;Treatment Protocols;Tumor Promotion;Tumor Volume;Tyrosine Phosphorylation;Up-Regulation;adjuvant endocrine therapy;advanced breast cancer;autocrine;biomarker identification;breast cancer progression;checkpoint therapy;chemotherapy;cytokine;efficacy testing;epithelial to mesenchymal transition;estrophilin;experience;high-throughput drug screening;hormone therapy;improved;in vivo;inhibitor;inhibitor therapy;malignant breast neoplasm;mortality;mouse model;novel;novel therapeutic intervention;paracrine;patient derived xenograft model;pharmacologic;phase II trial;pre-clinical;preclinical trial;predictive marker;programs;research clinical testing;resistance mechanism;response;senescence;small molecule inhibitor;src Homology Region 2 Domain;standard of care;stem;targeted treatment;transcriptomics;translational study;treatment strategy;tumor;tumor growth;tumor xenograft;tumor-immune system interactions;tumorigenesis;virtual Targeting STAT3 for the Treatment of CDK4/6 Inhibitor Resistant Advanced Estrogen Receptor Positive Breast Cancer Patients NARRATIVECDK4/6 inhibitors in combination with endocrine therapy are currently considered standard of care for patientswith advanced estrogen receptor positive breast cancer but virtually all patients will eventually acquire clinicalresistance to CDK4/6 inhibitor therapy. We have discovered a novel mechanism of resistance which is mediatedby high levels of IL-6 and activation of STAT3 targetable by an orally available small molecule inhibitor (TTI-101). The proposed translational studies will be testing the efficacy of TTI-101 clinically to treat those patientswho are likely to be unresponsive to CDK4/6 inhibitors. NCI 10745268 11/3/23 0:00 PAR-18-560 5R01CA255960-03 5 R01 CA 255960 3 "SONG, MIN-KYUNG H" 12/9/20 0:00 11/30/26 0:00 Clinical Oncology Study Section[CONC] 1859727 "KEYOMARSI, KHANDAN " Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 534225 NCI 329769 204456 ABSTRACTEstrogen receptor-positive (ER+)/HER2-negative breast cancer represents 70% of all breast cancer cases.Surgery and adjuvant/neo-adjuvant endocrine therapy (ET) are mainstays of treatment in early stage disease.However some patients receiving ET for early stage ER-positive breast cancer only have a partial reduction intheir risk of recurrence and mortality and those with advanced breast cancer (ABC) either progress shortly afterinitiating therapy (intrinsic resistance) or ultimately experience progression over time (acquired resistance).CDK4/6 inhibitors (CDK4/6is) with ET are currently considered standard of care for patients with advanced ER+/HER2 negative breast cancer. A key feature of CDK4/6 inhibition is the cell cycle inhibitory response it elicitsthrough induction of senescence which can be escaped resulting in cells readily re-entering the cell cycle assoon as drug is withdrawn. Senescent cells secrete interleukins inflammatory cytokines and growth factorswhich comprise the senescence-associated secretory phenotype (SASP) that affects surrounding cells andpromotes tumor growth. The most prominent SASP cytokine is interleukin-6 (IL-6) which is associated withmetastasis tumor aggressiveness and decreased survival. IL-6 activates STAT3 which is associated with amore aggressive phenotype and resistance to many therapies [chemotherapy targeted therapy and immunecheckpoint inhibitor therapy]. We developed CDK4/6i (i.e. palbociclib) resistant breast tumor cell line models andtheir molecular analysis showed that resistant cells adapt to palbociclib treatment by upregulation of IL-6 andactivation of STAT3 (phosphorylation of STAT3 on Y705 pY-STAT3). Treatment of the resistant cells with anoral small-molecule inhibitor of STAT3 (TTI-101) decreased cell viability by >25-fold and resulted in decreasedlevels of pY-STAT3 with concomitant decreases in (i) stem-like (CD44high/CD24low) population (ii) primary andsecondary mammosphere formation (iii) the EMT pathway. Furthermore TTI-101 treatment of mice bearingpatient derived xenografts (PDX) that express a similar gene expression signature as palbociclib-resistant celllines resulted in a marked decrease in tumor volume prolonged tumor-free survival and downregulation of serumIL-6 levels. We hypothesize that inhibition of IL-6 and/or STAT3 can reverse acquired CDK4/6i resistance in vivotransgenic and PDX models and in patients who have progressed on CDK4/6i based therapy. We propose acoordinated mechanistic preclinical and early phase clinical testing strategy to develop biomarker-qualifiedtherapy for the clinical need to overcome CDK4/6i resistance. To address these goals we will 1): Determine themechanism of IL-6 induction by long term CDK4/6 inhibition in vivo and the impact of IL-6 on tumorigenesis intransgenic mouse models; 2) Conduct pre-clinical trials in palbociclib resistant PDX and transgenic mousemodels to determine if inhibition of STAT3 and IL-6 can improve the survival of mice with CDK4/6i resistanttumors; and 3) Perform a Phase IB/II clinical trial of adding TTI-101 to standard of care palbociclib and aromataseinhibitor upon progression. 534225 +No NIH Category available Targeting Radiation-Induced Myeloid Cells to Promote T cell Immunity in Undifferentiated Pleomorphic Sarcoma PROJECT NARRATIVEPatients with undifferentiated pleomorphic sarcoma (UPS) the most common cancer of soft tissue in olderadults frequently suffer from incurable disease recurrence. Immunotherapy combined with radiation is apromising alternative for these patients but its efficacy is impeded by myeloid cells that infiltrate UPS tumors.Using mouse models and a clinical trial the candidate will study a virus-like compound to redirect thesemyeloid cells addressing a major obstacle to the success of immunotherapy and radiation for patients withUPS. NCI 10745266 4/18/23 0:00 PA-21-268 7K08CA245181-04 7 K08 CA 245181 4 "RADAEV, SERGEY" 6/1/20 0:00 11/30/25 0:00 Career Development Study Section (J)[NCI-J] 14677764 "KALBASI, ANUSHA " Not Applicable 16 NONE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA UNIVERSITY-WIDE 943052004 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 398 Other Research-Related 2022 141413 NCI 130938 10475 PROJECT SUMMARYDespite chemotherapy radiation and surgery patients with undifferentiated pleomorphic sarcoma (UPS)frequently suffer incurable disease relapse. Immune checkpoint blockade is a promising new therapeuticapproach for patients with UPS which promotes T cell mediated anti-tumor immunity. Still the majority ofpatients do not benefit. Radiation therapy (RT) a cornerstone of preoperative treatment of UPS can instigateT cell anti-tumor responses and synergize with immune checkpoint blockade. But RT can also result in therecruitment of immunosuppressive pro-tumor myeloid cells that restrain anti-tumor T cell responses. This isparticularly relevant in UPS which is characterized by a brisk myeloid cell infiltrate. The candidatehypothesizes that reprogramming RT-induced myeloid cells toward an antigen-presenting pro-inflammatoryphenotype will promote T cell mediated anti-tumor immunity in UPS.To investigate the hypothesis the candidate proposes studies using BO-112 a synthetic nanoplexed version ofpoly I:C that activates double-stranded RNA sensing pathways which are highly active in myeloid cells. Thesestudies will be conducted in murine models of UPS (Aim 1) as well as in UPS patients (Aim 2). In Aim 1 thecandidate will determine the impact of BO-112 on the fate phenotype and immunomodulatory function of RT-induced myeloid cells. In Aim 2 the candidate evaluates the capacity of BO-112 RT and anti-PD1 immunecheckpoint blockade to remodel the myeloid compartment and instigate anti-tumor T cell responses in UPSpatients enrolled on a window of opportunity phase 1 clinical trial. These studies will provide key insight intoplasticity of RT-induced myeloid subsets and their role in T cell mediated anti-tumor immunity especially inresponse to BO-112.The candidate is an Assistant Professor in Radiation Oncology at UCLA specializing in the treatment ofsarcoma. His scientific track record in tumor immunology and cancer immunotherapy highlights hiscommitment to an academic career in this field. The candidate's time is protected for research and careerdevelopment (80% effort) and he has the space equipment personnel and resources necessary to completethe proposed studies. Along with his mentor Dr. Antoni Ribas and co-mentor Dr. William McBride thecandidate has developed a comprehensive career development and training plan that will build expertise infour areas: (1) myeloid cell biology and plasticity (2) genetic mouse models as tools to study sarcoma and theimmune system (3) analysis and interpretation of high-dimensional single cell phenotyping and transcriptomicdata and (4) conduct of a translational phase 1 clinical trial. These career development activities will supportcompletion of the proposal and facilitate the transition to an independent scientific career conducting bench-to-bedside research with an emphasis on leveraging translational immunology to transform the care of patientswith sarcoma. 141413 +No NIH Category available Acute Renal Failure with Renal Papillary Necrosis;Affect;Animal Model;Antitumor Response;Biological;Biological Markers;Biological Products;Biology;Biopsy;CD34 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CTLA4 gene;Cancer Center;Cancer Model;Cancer Patient;Cancer Survivor;Cells;Chronic Kidney Failure;Clinical;Clinical Oncology;Combined Modality Therapy;Creatinine;Data;Detection;Development;Diagnostic;Drug Exposure;Drug Kinetics;Drug Modelings;Evaluation;Exhibits;Glomerular Filtration Rate;Glomerulonephritis;Goals;Guidelines;Hematopoietic;Histopathology;Human;Immune;Immune Sera;Immune checkpoint inhibitor;Immune system;Immunologic Surveillance;Immunological Models;Immunology;Immunomodulators;Immunophenotyping;Immunotherapy;Implant;Inbred BALB C Mice;Infiltration;Inflammation;Infusion procedures;Injury;Injury to Kidney;Interstitial Nephritis;Intervention;Kidney;Kinetics;Ligands;Lymphocyte;Malignant Neoplasms;Masks;Measures;Mediating;Modeling;Monitor;Mus;NCI-Designated Cancer Center;Nephrology;Newborn Infant;Nivolumab;Pathology;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phenotype;Pre-Clinical Model;Preclinical Testing;Proteomics;Regimen;Renal function;Research;Risk;Serum;Signal Transduction;System;T-Lymphocyte;Therapeutic;Time;Toxic effect;Toxicology;Vasculitis;acute toxicity;anti-CTLA4 antibodies;anti-PD1 antibodies;anti-cancer;cancer therapy;checkpoint therapy;circulating biomarkers;clinical practice;drug development;drug disposition;feasibility testing;follow-up;humanized mouse;immune modulating agents;immune-related adverse events;immunotoxicity;improved;innovation;ipilimumab;kidney biopsy;kidney dysfunction;mouse model;multidisciplinary;nephrotoxicity;novel;novel marker;pharmacodynamic model;pharmacokinetics and pharmacodynamics;pharmacologic;pre-clinical;pre-clinical assessment;preservation;prevent;programmed cell death protein 1;receptor;reconstitution;renal damage;response;restoration;translational impact;treatment response;tumor;urinary Preclinical and Clinical Models of Drug Induced Kidney Injury PROJECT NARRATIVEImmunotherapies are new medications used treat a variety of cancers. Treatment with immunotherapies suchas checkpoint inhibitors result in toxicity to the kidneys by activating the immune system. We plan to study howimmunotherapies affect the immune system and damage the kidneys and ways to identify this toxicity early incancer treatment. NCI 10745197 7/7/23 0:00 PAR-21-329 1R01CA277313-01A1 1 R01 CA 277313 1 A1 "SONG, MIN-KYUNG H" 7/7/23 0:00 6/30/28 0:00 Drug and Biologic Disposition and Toxicity Study Section[DBDT] 6791440 "JOY, MELANIE S" "ALEKSUNES, LAUREN M" 6 PHARMACOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF PHARMACY 800452571 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 636550 NCI 509700 126850 PROJECT SUMMARY/ABSTRACTImmune checkpoint inhibitors (ICIs) are biologic drugs that have revolutionized cancer treatment by targetingspecific inhibitory receptors or their ligands on T lymphocytes and thereby restoring immune systemsurveillance. Despite significant improvements in therapeutic responses ICIs cause immune-related adverseevents (irAEs). ICI-induced immune-mediated damage to the kidneys exhibits two phenotypes includingglomerulonephritis and acute kidney injury with interstitial nephritis. These kidney toxicities were not anticipatedin preclinical testing but now occur in patients receiving ICIs at a mean of 3 months of therapy. Within 5 yearsof receiving ICI therapy new onset chronic kidney disease and declines in glomerular filtration rate have beenobserved in 20% of cancer patients. Several issues mask our understanding of ICI nephrotoxicity: 1) the abilityto predict which patients will exhibit the toxicity 2) how to sensitively detect subclinical injury prior to significantelevations in serum creatinine and 3) poorly elucidated relationships between drug disposition the immunesystem kidney biology and antitumor responses to inform nephrotoxicity mechanisms. There is an urgent needto develop preclinical models and assessments that can inform irAEs as ICIs are becoming the primarytherapeutics for some cancers. This proposal will advance a novel mouse cancer model with a humanizedimmune system to identify mechanisms of kidney immunotoxicities associated with ICIs. Pharmacologicalinterventions will evaluate the contributions of 1) tumor type 2) drug exposure kinetics 3) on-target versus off-target responses and 4) human CD8+ and CD4+ lymphocyte signaling in the mouse model of ICI nephrotoxicity.The animal model will bridge preclinical testing and clinical practice in that the proposal will also evaluate cancerpatients prescribed ICI biologics for kidney toxicities. For patients mechanistic evaluations will be performedusing quantitative systems pharmacology (QSP) and pharmacokinetic approaches. The central hypothesis ofthis proposal is that a novel humanized animal model recapitulates the renal pathology observedclinically with ICIs and in combination with human biospecimens from cancer patients prescribed ICIsand novel QSP modeling can inform relationships between drug disposition the immune system andkidney biology antitumor responses and nephrotoxicity to understand mechanisms of ICI renal irAEs.The proposal consists of two independent Specific Aims to systematically evaluate kidney irAEs in an animalmodel and clinical patients receiving ICIs. We have assembled a multidisciplinary team with expertise in clinicaloncology nephrology immunology pharmacokinetic and pharmacodynamic modeling proteomics andtoxicology across two NCI-designated cancer centers to complete the proposed studies. The proposed researchhas high translational impact due to the current unmet need to predict detect and monitor kidney injury causedby ICIs and other immunomodulatory drugs with the goal of preventing long-term chronic kidney disease. 636550 +No NIH Category available Ablation;Adoptive Cell Transfers;Attention;Autoimmunity;CD8-Positive T-Lymphocytes;CD8B1 gene;CTLA4 gene;Cell physiology;Cells;Clinical;Clinical Trials;Data;Defect;Development;Equilibrium;Funding;Generations;Growth;Head and Neck Cancer;Human;Immune;Immune Tolerance;Immune response;Immune system;Immunity;Immunotherapy;In complete remission;Infection;Knock-out;Ligands;Logic;Maintenance;Malignant Neoplasms;Mediating;Metabolic;Modality;Modeling;Molecular Profiling;Monoclonal Antibodies;Mus;Organ;Outcome;PD-1 blockade;PD-1 pathway;PD-1/PD-L1;PD-L1 blockade;Patients;Peripheral;Phenotype;Proteins;Publishing;Regulatory T-Lymphocyte;Role;Sea;Signal Transduction;Solid Neoplasm;T cell infiltration;T cell receptor repertoire sequencing;T cell therapy;T-Cell Depletion;T-Cell Development;T-Lymphocyte;Testing;Therapeutic;Time;Tissues;Translations;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Work;cancer therapy;cancer type;cell type;checkpoint therapy;exhaust;exhaustion;immune checkpoint blockade;improved;in vivo;inhibitor;mouse model;neoantigens;neoplasm immunotherapy;novel;novel strategies;programmed cell death protein 1;response;restraint;success;synergism;targeted treatment;trafficking;tumor;tumor microenvironment Mechanisms of PD-1 and Tim-3 crosstalk in tumor-infiltrating lymphocytes Project NarrativeThe immune system must be carefully balanced to allow for elimination of infections while at the same timeavoiding unwanted or overly vigorous immune responses that can result in autoimmunity or immune-mediatedorgan damage. Immune balance is maintained in part by a type of immune cell known as the regulatory T cell(Treg). Here we will explore the possibility that a specific protein known as Tim-3 is an important regulator ofTreg function. We will also seek to identify specific intracellular molecules that are used by Tim-3 to control thefunction of Treg. These studies may lead to better therapies for treating cancer by enhancing a patients ownimmune response to the cancer. NCI 10745167 7/3/23 0:00 PA-20-185 2R01CA206517-06 2 R01 CA 206517 6 "ZAMISCH, MONICA" 4/1/16 0:00 6/30/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 1868435 "KANE, LAWRENCE P." "FERRIS, ROBERT L" 12 MICROBIOLOGY/IMMUN/VIROLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 541414 NCI 351420 189994 PROJECT SUMMARYThe past twenty years have seen a sea change in the treatment of many types of cancer with immunotherapy-based approaches including checkpoint blockade and adoptive cell therapy yielding remarkable results in somepatients. The inability thus far to achieve more complete responses in more patients has set off a widespreadeffort to identify novel targets for improving rates and duration of response either as single agents or togetherwith first-generation immunotherapies like PD-1/PD-L1 blockade. One of the second-generation checkpointtargets that has attracted attention from many groups including our own is the protein Tim-3. Thus far mAbstargeting Tim-3 have under-performed in clinical trials for solid tumors likely due in part to the fact that whileTim-3 is expressed at high levels on exhausted T cells it is not expressed on the TpEx cells. Obtaining a betterunderstanding of Tim-3 function in these various cell types may lead to more selective and efficacious Tim3-targeting therapies either as single agents or critically in combination with PD-1 pathway blockade. Work from our groups and others have revealed that Tim-3 appears to be particularly important for thesuppressive function of regulatory T cells (Treg) that are present in high numbers in tumors in particular effectorTreg (eTreg) which are a particularly suppressive subset of Treg. These cells are enriched within solid tumorsrelative to their proportions in normal peripheral tissues suggesting that they could be attractive targets for morespecific augmentation of immune responses within tumors. Since a significant proportion of Treg express Tim-3 and the function of this molecule in vivo is still being elucidated we generated a knockout model to study Tim-3 on these cells. Thus we found that inducible Treg-specific Tim-3 deletion results in a dramatic decrease inboth the growth of syngeneic tumors and the number of Treg infiltrating those tumors. However Treg-specificTim-3 deletion did not detectably impact Treg development or immune tolerance under homeostatic conditions. Based on published and preliminary data we hypothesize that Tim-3 is a critical regulator of effector Treg inthe tumor microenvironment. We will test this hypothesis with three Specific Aims. In Aim 1 we will determinewhy there are fewer eTreg in the tumors of mice with Treg-specific Tim-3 KO. In Aim 2 we will define the effectsof loss of Treg Tim-3 on the tumor microenvironment. Finally in Aim 3 we will determine how the loss of Tim-3on Treg impacts the response to PD-1 checkpoint blockade in both mouse models with an extension towardthe role of the interaction in the response to PD-1 blockade therapy in patients with head and neck cancer.Together these studies will provide the basis for more rational translation of Tim-3 as a target in the treatmentof solid tumors in the context of existing checkpoint targets like PD-1. As such these studies represent a logicalextension of work carried out in the previous cycle of this funded project. 541414 +No NIH Category available Affect;Age Years;Arkansas;Bioinformatics;Clinical;Collaborations;Communication;Communities;Data;Dedications;Development;Ensure;Funding;Genetic;Genomics;Hematological Disease;Hematology;Hematopoietic Neoplasms;Human Resources;Immune;Immunoglobulin M;Intercept;Knowledge;Laboratories;Leadership;Logistics;Malignant Neoplasms;Medical;Medicine;Mentors;Molecular;Monoclonal gammopathy of uncertain significance;Oncology;Patients;Persons;Population;Precancerous Conditions;Prevention;Productivity;Program Evaluation;Progress Reports;Quantitative Evaluations;Reagent;Research;Research Activity;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Scientist;Site;Site Visit;Specialized Center;Specimen;Training;Universities;Work;cancer prevention;career;college;community engagement;genomic data;interest;meetings;member;novel strategies;operation;outreach;precision cancer prevention;prevent;programs;success;tool;web site Administrative Core n/a NCI 10745011 8/18/23 0:00 RFA-CA-22-055 1U54CA272691-01A1 1 U54 CA 272691 1 A1 9/1/23 0:00 8/31/27 0:00 ZCA1-SRB-K(M3) 8722 8146758 "LI, YONG " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 255469 163812 91657 Project Summary The Administrative Core at the Cancer Prevention-Interception against MGUS Progression(CAP-MGUS) Center will provide administrative scientific fiscal and logistic oversight over the wholeCenter. The Core will also provide clerical support coordinate interactions between the Bioinformatics Coreand Research Projects and organize regular investigator meetings inside and outside the CAP-MGUS Center.It will bridge the research activities within the CAP-MGUS Center and the NCI CAP-IT program officials topromote collaboration ensure that the CAP-MGUS Centers work contributes effectively to issues relevant tothe CAP-IT mandates and maximize dissemination and application of Center discoveries. The AdministrativeCore has five primary objectives. First the Core will manage and communicate the research activities withinthe CAP-MGUS Center. Second the Administrative Core will promote collaborations on MGUS prevention andinterception between the Research Projects and the Bioinformatics Core within the CAP-MGUS Center andcollaborations between the Center members and outside investigators. Third the Administrative Core willorganize annual meetings and other network activities. Fourth the Administrative Core will conduct effectiveand contextually appropriate outreach. Fifth the Administrative Core will evaluate existing Research Projectsand develop new ones. The CAP-MGUS Center will be one of the few national research consortium centersdedicated to both IgM-MGUS and non-IgM MGUS prevention and interception. The Administrative Core willbring together top experts in MGUS and related cancers and other blood disorders provide scientific andlogistic oversight to Center activities disseminate scientific knowledge and discoveries and liaise betweenCenter members and outside stakeholders. +No NIH Category available Affect;Age Years;American;Amyloid;Automobile Driving;Blood;Bone Marrow;Bone Marrow Cells;Cancer Center;Chemicals;Chemoprevention;Chronic Lymphocytic Leukemia;Communication;Consensus;DNA Vaccines;Dedications;Development;Diagnosis;Diagnostic;Disease;Funding;Ganciclovir;Goals;Hematological Disease;IgE;Immunoglobulin A;Immunoglobulin D;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Immunologics;Immunoprevention;In Vitro;Infrastructure;Intercept;Intervention;Investigation;Life Expectancy;Light;Light-Chain Immunoglobulins;Lymphoid;Malignant Neoplasms;Molecular;Monoclonal gammopathy of uncertain significance;Multiple Myeloma;Mutate;Network Infrastructure;Non-Hodgkin's Lymphoma;Oncogenic;Oncoproteins;Patients;Persons;Plasmacytoma;Population;Population Control;Precancerous Conditions;Prevention;Preventive;Process;Protein Secretion;Proteins;Recommendation;Research;Research Personnel;Research Project Grants;Risk;Risk Factors;Role;Specialized Center;Syndrome;Testing;Waldenstrom Macroglobulinemia;cancer diagnosis;cancer invasiveness;cancer prevention;cancer risk;clinical practice;early phase clinical trial;efficacy evaluation;follow-up;high risk;in vivo;innovation;multiple myeloma M Protein;novel;precision cancer prevention;precision oncology;prevent;primary amyloidosis of light chain type;programs;progression risk;research and development;senescence;small molecule;targeted agent;tumor initiation;tumor progression;ubiquitin-protein ligase Cancer Prevention-Interception Against MGUS Progression Project NarrativeMonoclonal gammopathy of undetermined significance (MGUS) is a precancerous condition affecting ~3.5million Americans. Other than active surveillance there is no treatment to prevent MGUS from progressing intocancers the vast majority of which are incurable. The proposed CAP-MGUS Center will be one of the few inthe nation to facilitate the development of innovative agents against high-value targets in MGUS patients andthereby establish a foundational infrastructure to fast-track precision medicines for cancer prevention andinterception. NCI 10745010 8/18/23 0:00 RFA-CA-22-055 1U54CA272691-01A1 1 U54 CA 272691 1 A1 "GUNASEKHARAN, VIGNESH KUMAR" 9/1/23 0:00 8/31/27 0:00 ZCA1-SRB-K(M3) 8146758 "LI, YONG " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 1166056 NCI 900789 265267 Project SummaryMonoclonal gammopathy of undetermined significance (MGUS) is a precancerous condition in which a personhas moderately elevated levels of an abnormal immunoglobulin (Ig) protein (called M protein) in the blood.MGUS patients have a cancer risk ~6.5 times as high as the control population. MGUS may progress tomultiple myeloma (MM) Waldenstrm macroglobulinemia (WM) non-Hodgkin lymphoma (NHL) chroniclymphocytic leukemia (CLL) amyloid light-chain (AL) amyloidosis or plasmacytoma. MM WM a large portionof NHL and AL amyloidosis are incurable diseases. CLL and plasmacytoma are rarely cured. The significanceof MGUS calls for a cancer prevention-interception U54 Specialized Center dedicated to this precancerouscondition MGUS affects ~1% of the population MGUS progresses to cancer or other associated blooddisorders persistently at a rate of ~1% per year and ~90% cancer/disorder that progressed from MGUS areincurable. All patients with MGUS are potential candidates for cancer prevention and interception. Wehypothesize that cancer-driving molecules and the bone marrow microenvironment promoting MGUSprogression are suitable targets for precision cancer prevention and interception. We propose to establish theCancer Prevention-Interception against MGUS Progression to Cancer (CAP-MGUS) Center as an agile andeffective network infrastructure dedicated to preventing MGUS progression. This Center will undertakecollaborative research focusing on immunologically and chemically targeted agents that prevent or interceptthe oncogenic process in patients with MGUS or smoldering diseases. We propose three aims to achieve theCAP-MGUS Centers overarching goal. In Aim 1 we will functionally validate several oncotargets in tumorinitiation and progression to invasive cancer and ascertain their suitability for targeted intervention strategies.In Aim 2 we will discover innovative immuno- and chemo-prevention and interception agents through in vitroand in vivo efficacy evaluation. In Aim 3 we will develop new projects by identifying novel targets for cancer-preventive or interceptive interventions against MGUS progression. Collectively we expect to obtainchemoprevention and immunoprevention agents for further development or earlier phase clinical trials. 1166056 +No NIH Category available Adherens Junction;Adhesions;Adhesives;Anoikis;Basic Science;Binding;Biological Assay;Blood;Blood Circulation;Blood specimen;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;Cell Communication;Cell Survival;Cell model;Cell-Cell Adhesion;Cells;ChIP-seq;Characteristics;Chromatin;Chromatin Loop;Clinical Data;Data;Data Analyses;Data Set;Deposition;Development;Disease Progression;Distant;E-Cadherin;Electron Microscopy;Enzymes;Epigenetic Process;Exhibits;Extracellular Matrix;Future;Genetic Transcription;Goals;Hi-C;Histone-Lysine N-Methyltransferase;Homeobox;Hyaluronic Acid;In Vitro;Incidence;Intercellular Junctions;Licensing;Mammary Neoplasms;Mediating;Mediator;Metastatic breast cancer;Morbidity - disease rate;Multiomic Data;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;Patients;Physiological;Polysaccharides;Primary Neoplasm;Production;Prognosis;Proteins;Regulation;Research;Role;Shapes;Signal Transduction;Stress;Testing;Therapeutic;Transmission Electron Microscopy;Travel;Tumor Promotion;Work;cancer cell;cancer subtypes;clinically relevant;epigenetic regulation;experimental study;gain of function;improved;in vivo;in vivo Model;innovation;insight;loss of function;malignant breast neoplasm;mortality;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;pre-clinical;prevent;promoter;receptor;shear stress;transcription factor;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor diagnosis Mechanisms of tumor cell clustering in breast cancer metastasis Triple negative breast cancer (TNBC) exhibits the highest potential to metastasize and clustered circulatingtumor cells are associated with a significantly higher incidence of breast cancer metastasis. The primary goalof this proposal is to investigate a novel mechanism of cell-cell interaction that promotes tumor cell clusteringand metastasis in TNBC. Successfully accomplishing the proposed study will inspire the development of newstrategies for the treatment of metastatic TNBC. NCI 10744976 7/28/23 0:00 PA-20-185 1R01CA276432-01A1 1 R01 CA 276432 1 A1 "AULT, GRACE S" 7/28/23 0:00 6/30/28 0:00 "Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]" 7893348 "CHENG, CHONGHUI " Not Applicable 9 GENETICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 7/28/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 462861 NCI 289288 173573 Metastasis is the primary cause of breast cancer-related morbidity and mortality. During metastasis cells fromprimary tumors shed into the bloodstream as circulating tumor cells (CTCs). CTCs travel to distant organs toestablish secondary tumors. CTCs that form clusters exhibit a drastic increase in metastatic potential comparedto single CTCs. While previous studies have described E-cadherin as a key mediator of adhesion in CTC clustersand metastasis many breast tumors including tumors of the highly metastatic triple negative breast cancer(TNBC) express little to no E-cadherin. Thus an alternative E-cadherin-independent mechanism must exist tomediate clustering between CTCs thereby promoting metastasis and disease progression. To investigate CTCclustering mechanisms we developed an in vitro tumor cell clustering assay that incorporates physiologicalshear force and mimics in vivo conditions. Using this assay we found that E-cadherin-negative metastatic breastcancer cells can form cellular interactions with characteristics similar to cell adherens junctions. Speculating thatextracellular matrix (ECM) components from tumor cells may contribute to CTC clustering we analyzed ECMcomponents by breast cancer subtypes. We found that hyaluronic acid synthase 2 (HAS2) which is the primaryenzyme responsible for hyaluronic acid (HA) production in breast cancer cells is significantly upregulated inTNBC. We further observed that HA mediates clustering between TNBC tumor cells and confers them with theability to overcome insults present in the bloodstream including shear forces. Importantly we detected HAenrichment at the cell-cell junction of interacting CTCs in TNBC patient blood specimens. Mechanistically ourpreliminary results suggest that metastatic TNBC cells upregulate HAS2 expression in a chromatin loopingmechanism mediated by PRDM6 a transcriptional regulator and putative histone lysine methyltransferase.Collectively these preliminary findings lead us to hypothesize that in aggressive TNBC high levels of HAaugment CTC clustering via HA-dependent adhesive interactions between neighboring cells. We furtherhypothesize that the PRDM6 upregulates HA levels through epigenetic modulation of HAS2 expressionincluding chromatin looping interactions. We propose to study our hypotheses through two specific aims: 1)determine the role of HA in TNBC tumor cell clustering and metastasis and 2) elucidate the epigenetic regulationof HAS2 that impacts breast tumor cell clustering. To investigate our hypotheses we will utilize novel in vitroclustering assays and in vivo mouse models along with electron microscopy to reveal the structuralcharacteristics of CTC clusters. In addition we will utilize integrative multi-omics data analysis to elucidate theco-regulatory network governing HAS2 expression during CTC clustering. Importantly our results will beextensively validated in blood specimens from metastatic TNBC patients. Consequently successful completionof our proposed work will not only identify a novel mechanism that mediates strong cell-cell interactions but alsopave the mechanistic groundwork for identifying novel therapeutic options to suppress CTC clustering. 462861 +No NIH Category available Alpha Cell;Angiogenic Factor;Animal Model;Antibodies;Autocrine Communication;Binding;Bone Diseases;Bone Marrow;Bortezomib;Cell Communication;Cells;Clinical;Coculture Techniques;Cytokine Receptors;Development;Dexamethasone;Disease;Disease Progression;Drug resistance;Endocrine;Fibroblast Growth Factor Receptors;Foundations;Funding;Genes;Genetic;Goals;Growth;Growth Inhibitors;Homeostasis;Human;In Vitro;Kidney;Knowledge;Malignant - descriptor;Malignant Neoplasms;Marrow;Mediating;Mediator;Mining;Molecular;Multiple Myeloma;Mus;Musculoskeletal;Osteocytes;Osteogenesis;Osteolytic;Outcome;Paracrine Communication;Pathogenesis;Pathologic;Pathologic Neovascularization;Patient-Focused Outcomes;Patients;Phenotype;Plasma Cells;Play;Proliferating;Proteasome Inhibitor;Quality of life;Refractory;Refractory Disease;Regimen;Research;Resistance;Role;Serum;Signal Transduction;Source;Stromal Cells;TRANCE protein;Testing;VEGFA gene;Work;Xenograft procedure;absorption;angiogenesis;autocrine;bone;bone health;clinical database;data mining;design;effective therapy;efficacy evaluation;fibroblast growth factor 23;fracture risk;heparanase;improved;in silico;in vivo;inhibitor therapy;innovation;inorganic phosphate;lenalidomide;mouse model;novel;novel therapeutic intervention;paracrine;pharmacologic;receptor;relapse patients;repaired;response;stem;targeted treatment;therapy resistant;tool;treatment response;tumor;tumor growth;tumor microenvironment Contribution of osteocytes to the musculoskeletal effects of Multiple Myeloma NarrativeThe proposed research will examine previously unknown cellular and molecular mechanisms in the multiplemyeloma (MM) tumor microenvironment supporting disease progression and will produce important informationto guide the development of novel therapeutic approaches to improve clinical outcomes in MM patients. NCI 10744924 6/23/23 0:00 PA-20-185 2R01CA209882-07A1 2 R01 CA 209882 7 A1 "NADEAU, CHRISTINE FRANCES" 3/15/17 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 14271885 "DELGADO-CALLE, JESUS " "BELLIDO, TERESITA M." 2 PHYSIOLOGY 122452563 VDFYLZPJEAV6 122452563 VDFYLZPJEAV6 US 34.749005 -92.320097 1471106 UNIV OF ARKANSAS FOR MED SCIS LITTLE ROCK AR SCHOOLS OF MEDICINE 722057101 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 449805 NCI 293990 155815 SummaryMultiple myeloma (MM) is characterized by the growth of malignant plasma cells in the bone marrow supportedby increased angiogenesis. Despite significant advances in treatments MM remains incurable due to frequentrelapses originating from MM cells refractory to therapy. Further MM induces a devastating bone diseaseincreasing fracture risk and decreasing quality of life. The long-term goal of this proposal is to improve clinicaloutcomes in MM by defining targetable mechanisms underlying MM growth responses to therapy and bonedestruction. The rationale stems from work from the previous funding period demonstrating that osteocytes (Ots)are an abundant and long-lived source of signals in the MM tumor microenvironment (TME) that supports MMgrowth and promote bone destruction; and that targeting Ot-MM cell interactions decreases MM growth andimproves bone health. In studies leading to this application we found that MM cells upregulate the expressionof Fibroblast growth factor (FGF) 23 in Ots and discovered that Ots support angiogenesis and promote resistanceto Bortezomib-based therapies. The specific goal of this proposal is to evaluate the efficacy of targeting localFGF23 derived from Ots to decrease tumor growth repair damaged bone and improve responses to therapy inMM. The central hypothesis is that Ot-derived FGF23 promotes MM progression bone destruction andrefractory disease via local TME autocrine and paracrine signals mediated by the FGF23 co-receptor -Klotho(KL). This hypothesis will be tested in three specific aims: (1) Determine the contribution of Ot-derived FGF23to MM tumor growth and bone disease by interfering with paracrine and/or autocrine FGF23-KL signaling; (2)Determine the impact of Ot-derived Vascular endothelial growth factor A (VEGFA) a downstream target ofFGF23 and other osteocyte-derived pro-angeogenic factors on the pathological angiogenesis in the MM-TME;and (3) Determine the role of FGF23 and the FGF23 target gene Heparanase (HPSE) on TME-inducedresistance to Bortezomib-based therapies in MM cells. These aims will be pursued using a combination ofinnovative in vitro in vivo and in silico approaches including cell-specific genetic tools pharmacologicalapproaches human MM xenograft and immunocompentent mouse models of MM primary cells from MMpatients scRNAseq analysis and mining of MM patient genetic/clinical databases. 449805 +No NIH Category available Accelerometer;Acculturation;African American;African American population;Applications Grants;Area;Assessment tool;Behavioral;Budgets;California;Cancer Burden;Cancer Center Support Grant;Cancer Control Research;Cancer Control Research Program;Catchment Area;Center Core Grants;Charge;Child;Clinical;Clinical Investigator;Clinical Research;Clinical Sciences;Collection;Communities;Comprehensive Cancer Center;Consult;Consultations;Data;Data Collection;Data Element;Data Science Core;Development;Diabetes Mellitus;Direct Costs;Disparity;Doctor of Philosophy;Ecological momentary assessment;Ensure;Environmental Risk Factor;Epidemiology;Evaluation;Feedback;Funding;Grant;Hispanic;Hispanic Populations;Hospitals;Human Papilloma Virus Vaccination;Incidence;Individual;Institution;Intervention;Last Name;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Manuscripts;Medical;Medicare;Mission;Monitor;Moods;NCI Center for Cancer Research;Names;Neighborhoods;Obesity;Outcomes Research;Peer Review;Pesticides;Phase;Physical activity;Population Heterogeneity;Population Research;Preparation;Process;Publications;Research;Research Personnel;Resource Sharing;Risk;Risk Factors;Role;Running;Science;Services;Strategic Planning;Surveys;Technology;Tobacco;Tobacco-Related Carcinoma;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underserved Population;Universities;University of Southern California Norris Cancer Center;cancer epidemiology;cancer health disparity;cancer risk;data registry;data resource;data standards;dosimetry;early onset;effectiveness evaluation;feasibility research;health determinants;improved;intervention effect;malignant breast neoplasm;melanoma;member;men;mortality;neoplasm registry;novel;novel strategies;nutrition;obesity prevention;operation;population based;programs;recruit;research study;response;secondary analysis;smoking prevalence;sociodemographics;surveillance data;surveillance study;survivorship;tobacco prevention;tool;trend;tumor microenvironment;vaccine hesitancy Population Research Core n/a NCI 10744820 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8700 7854892 "COCKBURN, MYLES G" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 156703 94973 61730 PROJECT SUMMARY Population Research Shared ResourceThe mission of the newly proposed USC Norris Comprehensive Cancer Center (NCCC) Population ResearchShared Resource (PRC) is to maximize the impact of NCCC's research on priority cancer burdens and disparitiesin the catchment area and beyond by consultation and coordinated access to unique local and nationalpopulation-based data resources and assessment tools. The NCCC strategic planning process and 2018 annualcore survey identified member needs for a state-of-the-art Shared Resource (SR) to provide consultationaccess and support for leveraging population-based data resources. To respond to this need NCCC createdPRC in February 2019 overseen by NCCC Administration and led by Myles Cockburn PhD recruited to NCCCand appointed Director of PRC. As PRC Director Cockburn advertises to and ensures access by NCCCmembers; oversees and evaluates the effectiveness timeliness and impact of PRC services; and ensuresintegration with other NCCC SRs. Key services provided by PRC this grant cycle include: 1) surveillance studyconsultation and access to data on catchment area cancer burdens; 2) geospatial linkage and analysis to assessrecruitment feasibility target interventions and monitor intervention effects at individual/neighborhood level; 3)access to and interpretation of medical claims data (in SEER Medicare) and California's prescription and hospitaldischarge data (linked to LA CSP); and 4) consultation on collection preparation and analysis of novel individual-level naturalistic data (ecological momentary assessment (EMA) accelerometry and UV dosimetry). In responseto feedback from NCCC members and aligned with the NCCC Strategic Plan in the next grant cycle PRC willrun training sessions for clinical investigators on the use of EMA and other technologies in clinical researchstudies including studies to improve survivorship (i.e. physical activity reducing obesity and assessing mood).Since its inception in 2019 33 NCCC members in Cancer Control Research (CCR) Cancer Epidemiology (CE)and Translational and Clinical Sciences (TACS) research programs utilized PRC with 60 publications resultingfrom PRC engagement. PRC also contributed to 19 grant submissions resulting in five newly funded grantstotaling $1.8M in direct costs including three NCI R01 grants and two funded CCSG P30 supplements. Theanticipated annual budget of PRC in the first year of the next grant cycle is $435646 yet the CCSG request is$108485. Accordingly PRC leverages extensive institutional and recharge support and seeks only 25% fromCCSG funds. +No NIH Category available African ancestry;Algorithms;Animal Experimentation;Animal Model;Artificial Intelligence;Basic Science;Big Data;Bioinformatics;Biological Assay;Biometry;Biostatistical Methods;Biostatistics Shared Resource;Black Populations;Blood;Budgets;California;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Etiology;Cells;Charge;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Comprehensive Cancer Center;Custom;DNA;Data;Data Analyses;Data Science;Data Science Core;Databases;Development;Doctor of Philosophy;Electronic Health Record;Elements;Evaluation;Evolution;Experimental Designs;Fostering;Funding;Gene Expression Profile;Genets;Genomics;Grant;Image;Individual;Informatics;Infrastructure;Institution;Laboratory Study;Last Name;Latino Population;Leadership;Machine Learning;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maps;Medidata;Methodology;Methods;Mission;Modeling;Monitor;Mosses;Multiomic Data;Mutation;NCI Center for Cancer Research;Names;Neuroblastoma;Observational Study;Outcome;Patient Outcomes Assessments;Patients;Pediatric Oncology Group;Phenotype;Play;Population;Prognosis;Protocols documentation;Publications;Quality Control;Questionnaires;RNA;Regulation;Reporting;Research;Research Design;Research Personnel;Resource Sharing;Review Committee;Risk;Risk Factors;Role;Safety;Sampling;Serous;Services;Source;Specimen;Statistical Methods;Strategic Planning;Structure;System;Techniques;Tissues;Training Activity;Training and Education;Translational Research;Tumor Tissue;Universities;University of Southern California Norris Cancer Center;Work;anticancer research;cancer epidemiology;cancer health disparity;clinical trial protocol;computerized data processing;data acquisition;data integration;data quality;design;electronic health information;epigenomics;genome wide association study;immune cell infiltrate;improved;inquiry-based learning;insight;liquid biopsy;member;men;monitoring device;multi-ethnic;novel;novel strategies;ovarian neoplasm;programs;recruit;risk stratification;tool;trait;tumor;tumor microenvironment;wireless sensor Data Science Core n/a NCI 10744819 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8699 15034152 "LI, MING " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 502676 332019 170657 PROJECT SUMMARY Data Science Shared ResourceThe mission of the Data Science Shared Resource (DSC) of the USC Norris Comprehensive Cancer Center(NCCC) is to provide integrated state-of-the-art biostatistics and clinical research informatics support for cancerresearch spanning basic and translational science to clinical studies and cancer etiology to cancer control. DSCmembers work with investigators on the design conduct analysis and reporting of cancer research and play akey role in clinical trials protocol review and study monitoring in the NCCC. As such the DSC serves as a keyfoundational element in the Data Science component of the Strategic Plan enabling infrastructure and dataplatforms for all NCCC Research Programs. NCCC recruited Ming Li PhD as DSC Director and David BirtwellMSE as Co-Director with oversight of DSC by NCCC Administration. A major development in this grant periodDSC now expands beyond traditional biostatistics services to include clinical research informatics services tointegrate data from electronic health records to -omics platforms for analysis. DSC applies advanced and novelstatistical methods to these data including artificial intelligence/machine learning for discovery of underlying riskfactors prediction of population level risk and clinical decision algorithms and tools. During the current grantperiod (2015-2020) 88 NCCC members representing all five programs utilized the DSC resulting directly in 278publications and 13 funded cancer-related P and U grants. The anticipated annual budget of DSC in the firstyear of the next grant cycle is $1548658 yet the CCSG request is $379255. Accordingly DSC leveragesextensive institutional and recharge support and seeks only 24% from CCSG funds. +No NIH Category available Academia;Address;American Association of Cancer Research;American Society of Clinical Oncology;Atlases;Award;Biological Assay;Biological Markers;Blood;Blood specimen;Budgets;California;Cancer Center Support Grant;Cancer Detection;Cell Count;Cell Separation;Cells;Charge;Clinical;Clinical Sciences;Collaborations;Communities;Comprehensive Cancer Center;Core Biopsy;DNA Library;DNA amplification;DNA methylation profiling;Development;Direct Costs;Disease Management;Emerging Technologies;Expression Profiling;Extramural Activities;Extramural Funding Mechanisms;Faculty;Foundations;Funding;Gene Dosage;Generations;Genomics;Goals;Grant;High-Throughput Nucleotide Sequencing;Hour;Immune checkpoint inhibitor;Immunofluorescence Immunologic;Industry;Institution;Institutional Review Boards;International;Last Name;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Methodology;Methods;Methylation;Microfluidics;Microscopy;Mission;Molecular;Mutation;Names;Neoplasm Circulating Cells;Nucleic Acids;Occupational activity of managing finances;Oral;Paper;Patients;Peer Review;Phase;Phenotype;Plasma;Plasma Cells;Primary carcinoma of the liver cells;Process;Prognosis;Prostate Cancer therapy;Protocols documentation;Publishing;RNA;RNA amplification;Recovery;Regulation;Research;Research Personnel;Resource Sharing;Role;Seminal;Services;Slide;Southwest Oncology Group;Strategic Planning;System;TACSTD1 gene;Technology;Time;Translational Research;Universities;University of Southern California Norris Cancer Center;Update;X-Ray Computed Tomography;anticancer research;cell free DNA;commercialization;cost effective;empowerment;epigenomics;hormone therapy;improved;industry partner;insight;instrument;liquid biopsy;malignant breast neoplasm;member;men;multiple omics;new technology;new therapeutic target;novel;operation;precision medicine;predictive signature;prognostic;programs;prospective;radiomics;research and development;response;sample collection;therapeutic biomarker;timeline;transcriptome sequencing;transcriptomic profiling;translational research program;tumor;tumor DNA;tumor microenvironment;user-friendly;whole genome Liquid Biopsy Core n/a NCI 10744817 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8697 10702563 "GOLDKORN, AMIR " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 194588 117934 76654 PROJECT SUMMARY Liquid Biopsy Shared ResourceThe mission of the USC Norris Comprehensive Cancer Center (NCCC) Liquid Biopsy Shared Resource (LBC)is to provide a state-of-the-art multi-platform facility for capture and analysis of circulating tumor cells (CTCs)and matched plasma nucleic acids for cancer research. NCCC Administration oversees LBC with Amir GoldkornMD continuing in his role as the faculty Director and founder in 2015. Goldkorn provides the strategic directionfor LBC overseeing technology operations and financial management. LBC is located in NCCC wet labresearch space. During the current grant cycle noteworthy enhancements include: 1) expanded CTC enrichmentplatforms from 5 to 12; 2) added new microfluidic cell separation systems an automated slide stainer andRareCyte high-content CTC analysis and recovery system; 3) developed new workflows to combine recovery ofsingle CTCs for whole genome amplification and gene copy number analysis rapid enrichment of live CTCs forRNAseq chip array profiling of plasma cfDNA methylation and CTC immunofluorescence assays; 4) addedparallel cell-free DNA banking and non-EpCAM-dependent CTC enrichment for EpCAM-poor tumors; and 5)developed cost-effective workflows. In the next grant cycle LBC will be expanding research partnerships withR&D teams at various industry partners to co-develop exciting new liquid biopsy biomarker assays with strongpotential for commercialization. During the current grant period from 2015-2020 LBC served 23 full NCCCmembers in 3 research programs Translational and Clinical Sciences (TACS) Tumor Microenvironment (TME)and Genomic and Epigenomic Regulation (GER) resulting in 20 intramural and extramural funding applications15 of which were funded for $6.75M in direct costs. Since 2015 LBC has contributed to 5 published papers and11 abstracts and processed 5396 blood samples. The anticipated annual budget of LBC in the first year of thenext grant cycle is $400712 yet the CCSG request is $134712. Accordingly LBC leverages extensiveinstitutional and recharge support and seeks only 34% from CCSG funds. +No NIH Category available Adjuvant Therapy;African American;Basic Science;Bioinformatics;Biological Assay;Biology;Breast Cancer therapy;Budgets;CLIA certified;California;Cancer Center;Cancer Center Support Grant;Catchment Area;Cells;Charge;Clinical;Clinical Research;Clinical Sciences;Collaborations;Comprehensive Cancer Center;Consult;Cytometry;DNA Methylation;DNA copy number;Data;Data Science;Data Science Core;Development;Direct Costs;Disseminated Malignant Neoplasm;Doctor of Philosophy;Elements;Emerging Technologies;Ensure;Epigenetic Process;Faculty;Fostering;Funding;Gene Expression;Generations;Genetic;Genomics;Genomics Shared Resource;Grant;Heterogeneity;High-Throughput Nucleotide Sequencing;Image;Industry Standard;Infrastructure;Institution;Laboratories;Last Name;Leadership;Los Angeles;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Methods;Methylation;Mission;Molecular;Molecular Profiling;NCI Center for Cancer Research;Names;National Cancer Institute;Patients;Pediatric Hospitals;Pituitary Gland Adenoma;Population Sciences;Predisposition;Process;Publications;Regulation;Reporting;Research;Research Design;Research Personnel;Residual Neoplasm;Resource Sharing;Robotics;SNP genotyping;Services;Strategic Planning;Technology;Training;Translational Research;Universities;University of Southern California Norris Cancer Center;Variant;Woman;Work;anticancer research;arm;biomedical informatics;cancer cell;cancer epidemiology;cancer genome;cancer genomics;cancer health disparity;computerized data processing;design;epidemiology study;epigenomics;exome sequencing;industry partner;informatics tool;investigator training;large scale production;liquid biopsy;malignant breast neoplasm;member;men;multiple omics;nano-string;patient population;programs;recruit;research study;screening;symposium;transcriptome sequencing;transcriptomics;translational genomics;tumor;tumor microenvironment Molecular Genomics Core n/a NCI 10744816 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8696 8146152 "CRAIG, DAVID W" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 561998 400933 161065 PROJECT SUMMARY Molecular Genomics Shared ResourceThe mission of the Molecular Genomics (MGC) Shared Resource (SR) of the USC Norris Comprehensive CancerCenter (NCCC) is to provide services for industry-standard and state-of-the-art molecular and genomic assaysin support of NCCC investigators working across the continuum of basic translational clinical and populationsciences. Overseen by NCCC Administration and under the leadership of John Carpten PhD and David CraigPhD both newly recruited to NCCC in the current cycle the MGC serves as a foundational element with industry-standard technologies and field-leading expertise in large-scale SNP genotyping DNA methylation arraysintegrated genomic sequencing at the somatic transcriptomic and epigenetic landscape as well as state-of-the-art single-cell and spatial molecular profiling. Major developments this cycle include access to larger production-scale sequencing ensuring early access to transformative emerging technologies and implementation ofbioinformatic processes integration into other SRs. Specifically MGC: 1) added a high-throughput sequencingarm built from the ground up with advanced robotics and Illumina NovaSeq to enable large-scale projects; 2)established new collaborations with industry partners to ensure availability and early access to advanced state-of-the-art single-cell and spatial molecular profiling including 10X Genomics Agilent and Nanostring; and 3)implemented automated APIs bioinformatics and data processing for tight coordination with the Data ScienceShared Resource (DSC) in large-scale Novaseq sequencing. In alignment with the NCCC Strategic Plan in thenext grant cycle MGC plans to perform comprehensive molecular profiling with linkage to curated patient dataincluding single-cell genomics liquid biopsies for screening and residual disease and imaging mass cytometryand spatial transcriptomics to capture tumor and tumor microenvironment interactions applied to NCCC's diversepatient population. During the current grant period (2015-2020) 122 NCCC members representing all fiveprograms utilized the MGC resulting in 233 publications and $58.4M in direct cost grant funding as a direct resultof usage. The anticipated annual budget of the MGC in the first year of the next grant cycle is $2875229 yetthe CCSG request is $457972. Accordingly the MGC leverages extensive institutional and recharge supportand seeks only 16% from CCSG funds. +No NIH Category available Antibodies;Basic Cancer Research;Basic Science;Biological Markers;Breast;Breast Cancer Model;Breast Melanoma;Budgets;CD8B1 gene;California;Cancer Center Support Grant;Cancer Patient;Cancer Vaccines;Cell Separation;Cell Therapy;Cell surface;Cells;Charge;Chromatin Loop;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Cooperative Group;Clustered Regularly Interspaced Short Palindromic Repeats;Color;Complex;Comprehensive Cancer Center;Consultations;Copy Number Polymorphism;Correlative Study;Cytometry;Data;Diagnostic;Diet;Direct Costs;Disease Outcome;Doctor of Philosophy;ENG gene;Education;Equipment;Faculty;Fasting;Feedback;Flow Cytometry;Fluorescence;Foundations;Funding;Genome;Genomics;Genomics Shared Resource;Grant;Gynecologic Oncology Group;Immune;Immune checkpoint inhibitor;Immunologic Monitoring;Immunologics;Immunotherapy;Institution;Laboratories;Last Name;Local Therapy;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mediating;Methods;Mission;Molecular;Names;Natural Killer Cells;Neoplasm Circulating Cells;Neuroblastoma;Oncology;Pathogenesis;Pathology;Patients;Peer Review;Phenotype;Population;Proteins;Publications;Regulation;Reporting;Research;Research Design;Research Personnel;Research Support;Resolution;Resource Sharing;Role;Services;Sorting;Surveys;System;T cell clonality;Technology;Therapeutic;Training and Education;Translational Research;Tropism;Tumor-Infiltrating Lymphocytes;Universities;University of Southern California Norris Cancer Center;anticancer research;cancer cell;cancer clinical trial;cancer immunotherapy;cancer prevention;chemoradiation;chemotherapy;cost;cost effective;cytotoxic;epigenomics;high throughput analysis;immune function;immunological status;immunoregulation;immunotherapy clinical trials;improved;instrument;ipilimumab;member;mesenchymal stromal cell;mutant;pre-clinical;programs;prostate cancer risk;response;satisfaction;transcriptome sequencing;translational cancer research;tumor heterogeneity;tumor microenvironment;tumor-immune system interactions;vector Flow Cytometry Core n/a NCI 10744815 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8695 1972649 "KAST, WIJBE MARTIN" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 206871 125378 81493 PROJECT SUMMARY Flow Cytometry and Immune Monitoring Shared ResourceThe mission of the USC Norris Comprehensive Cancer Center (NCCC) Flow Cytometry and Immune MonitoringShared Resource (FCIM) is to provide advanced multi-parameter flow cytometry cell sorting capabilities andimmune monitoring services for advancing basic translational and clinical research with options for full-servicetechnical support for cancer clinical trial immune-monitoring correlative studies. NCCC Administration overseesFCIM with Martin Kast PhD (continuing in the role) and Rong Lu PhD (new in the role in 2015) as the faculty Co-Directors. Kast and Lu have extensive and complementary scientific expertise; they meet monthly to provideexecutive oversight for core services and to promote user access and satisfaction. In response to annual NCCCsurveys of Shared Resources (SR) and feedback from the NCCC External Advisory Board FCIM significantlyenhanced services and new equipment during the current grant cycle including: 1) expanded sorting and highthroughput analysis capabilities with 3 new instruments offering more available colors 2) increased post-sortviability 3) added services for mass cytometry (CyTOF)-assisted projects; and 4) lowered costs due to improvedefficiencies. In the next grant cycle based on user feedback FCIM will expand its services to include T cellreceptor (TCR) clonality determination and other single cell omics using a newly acquired Illumina MiSeq Systemin the Molecular Genomics SR and spatial immune profiling with the recently acquired Vector Polaris system inthe Translational Pathology SR. During the current grant period (2015-2020) 70 NCCC members representingall five programs utilized FCIM resulting in 53 publications and $15.9M in direct cost grant funding as a directresult of usage. The anticipated annual budget of FCIM in the first year of the next grant cycle is $632453 yetthe CCSG request is $143215. Accordingly FCIM leverages extensive institutional and recharge support andseeks only 23% from CCSG funds. +No NIH Category available California;Cancer Center Support Grant;Catchment Area;Clinical Protocols;Clinical Sciences;Clinical Trials;Committee Members;Comprehensive Cancer Center;Consultations;Development;Disease;Documentation;Ensure;Evaluation;Faculty;Female;Future;Grant;Institution;Institutional Review Boards;Intervention Studies;Intervention Trial;Last Name;Leadership;Longevity;Malignant Neoplasms;Medial;Mentorship;Minority;Minority Recruitment;Monitor;NCI Center for Cancer Research;Names;Patients;Peer Review;Policies;Process;Protocols documentation;Research Design;Review Committee;Speed;Standardization;System;Systems Development;Time;Training;Translational Research;Universities;University of Southern California Norris Cancer Center;Update;Woman;Writing;clinical investigation;cohort;design;early phase trial;flexibility;improved;investigator-initiated trial;meetings;member;molecular subtypes;multidisciplinary;phase 1 study;process improvement;programs;rare cancer;timeline Protocol Review and Monitoring System n/a NCI 10744814 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8694 7368239 "IQBAL, SYMA " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 143678 87079 56599 PROJECT SUMMARY - Protocol Review and Monitoring System (PRMS)At the USC Norris Comprehensive Cancer Center (NCCC) PRMS functions are performed by the ClinicalInvestigations Committee (CIC) which serves as the Center's scientific review committee. The CIC is co-chairedby Drs. Syma Iqbal (TACS) and Ann Mohrbacher (TACS). All cancer protocols undergo a two-step review priorto submission to IRB. Step 1 is a standardized Disease Team (DT) review coordinated by the ClinicalInvestigations Support Office (CISO) DT managers. In the current grant period we revamped the Stage 1process to standardize the reviews and enhance interactions between DTs and NCCC Research Programsparticularly the Translational and Clinical Sciences (TACS) Program. If the protocol is approved by the DT itproceeds to Step 2 the scientific review by the CIC. Only protocols that receive approval by the CIC can besubmitted and reviewed by IRB. The accrual of women minorities and patients across the lifespan is consideredat each step of the process as an evaluation criterion as is catchment area relevance. In 2019 CIC reviewed117 clinical trials 25 of which were institutional or externally peer-reviewed. Important new PRMS developmentsin the current cycle include: a new mandatory design and feasibility consultation meeting for investigator-initiated trials (IITs) which ensures early input from biostatisticians and CISO leadership; usage of a newlyupdated standardized protocol template; and more rigorous DT oversight. In addition a rapid activation pilotprogram for select high priority early phase trials was instituted in 2018-2019 with time to activation of 8-10weeks. Once protocols are activated they are monitored for accrual and scientific progress by the ScientificProgress and Accrual Monitoring Subcommittee of the CIC based on an established NCCC accrual monitoringpolicy. Key accomplishments resulting from these process improvements include: 1) activation timelines havedecreased by 57% from 42 weeks in 2015 to 18 weeks in 2019; 2) average time from new protocol CIC reviewmeeting to completion of CIC review decreased by 80% (from 5 weeks in 2015 to 1 week in 2019); and 3) adramatic increase in the number of interventional trials closed for poor accrual (from 11 in 2015 to 20 in 2019and 40 in 2020). Low accruing studies that were permitted to remain open met specific criteria such as anadequate remedial plan that resulted in improved accrual on subsequent monitoring or prior strong overallaccrual that slowed down due to cohort closures. Future plans include: a) further efforts to reduce time toactivation; b) expansion of support for IITs including protocol writing support (initiated in 2020) to enhance thequality and speed of trial development; and c) a new CIC mentorship program to train junior faculty to becomeCIC members and reviewers. +No NIH Category available Administrator;Asian;Black race;COVID-19 pandemic;California;Cancer Center Support Grant;Case Report Form;Catchment Area;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Data;Data Science;Databases;Development;Disease;Education and Outreach;Eligibility Determination;Employee;Ensure;Environment;Evaluation;Faculty;Generations;Grant;Institution;Intervention Trial;Last Name;Leadership;Longevity;Malignant Neoplasms;Medidata;Minority;Minority Groups;Mission;Monitor;Names;Operations Research;Participant;Patients;Phase;Physician Executives;Procedures;Process;Protocols documentation;Regulation;Reporting;Research;Research Personnel;Resource Sharing;Role;Safety;Services;Site;Standardization;Supervision;System;Time;Training;Underrepresented Populations;Universities;University of Southern California Norris Cancer Center;Update;Woman;Work;cancer clinical trial;clinical investigation;community engagement;data management;design;education planning;financial toxicity;improved;investigator-initiated trial;meetings;member;minority patient;multidisciplinary;programs;protocol development;quality assurance;service coordination;skills;therapy development;tool Clinical Protocol and Data Management n/a NCI 10744813 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8693 10806747 "EL-KHOUEIRY, ANTHONY BOUTROS" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 656287 442253 214034 PROJECT SUMMARY - Clinical Protocol and Data Management (CPDM)At the USC Norris Comprehensive Cancer Center (NCCC) the Clinical Investigations Support Office (CISO)serves as the centralized clinical trials office for all cancer trials independent of originating department or diseaseteam. The senior CISO leadership includes Anthony El-Khoueiry MD who serves as the Medical DirectorKevin Kelly MD who serves as the Assistant Medical Director and Zeno Ashai MBBS MPH who was appointedas Associate Director in 2019. CISO has three units: the Quality Assurance and Compliance Unit the RegulatoryUnit and the Research Operations Unit. CISO also supports the four clinical research oversight committees(Clinical Investigations Committee Data Safety and Monitoring Committee Quality Assurance Committee andPhase I Committee). In the current period CISO created a role for Disease Team Managers who superviseresearch staff and support the ten Disease Teams in Step 1 of Disease Team protocol reviews. Notably CISOalso expanded and enhanced services to support investigator initiated trials (IITs) over this grant periodincluding: new protocol development support (design and feasibility consultation meetings) addition of a protocolwriter Medidata Rave database development for interventional protocols and multisite coordination services(enabling NCCC to serve as a coordinating site for multi-site IITs when appropriate; 14 such trials coordinatedin 2019). Additional accomplishments over the grant period include: 1) an extensive CISO reorganization withaddition of 20 full time employees (FTEs) enabling expansion of services cited above; 2) full implementation ofthe OnCore clinical trials management system; 3) a 43.5% increase in interventional trial accruals from 816patients in 2015 to 1171 in 2019 (of which 223 (29%) were IITs); 4) a 57% decrease in time to activation from42 weeks in 2015 to 18 weeks in 2019; 5) improvement in the quality of IITs that reduced the disapproval rate atthe initial PRMS review from 35% in 2015 to 17% in 2019; and 6) substantial accrual of minorities in interventionaltrials (61.6% of 2019 accruals are from minority groups underrepresented in clinical trials). Despite the COVID-19 pandemic 659 patients were accrued to interventional trials from 1/1/2020 to 11/30/2020. +No NIH Category available Acceleration;Acute Lymphocytic Leukemia;Address;Administrator;Area;Award;Basic Science;Bioinformatics;Biology;Biostatistics Core;Breast;California;Cancer Burden;Cancer Center Support Grant;Cancer Science;Catchment Area;Cervical Cancer Screening;Clinical;Clinical Research;Colorectal;Communities;Comprehensive Cancer Center;Coupled;Data Science;Decision Making;Development;Direct Costs;Disparity;Doctor of Philosophy;Faculty;Faculty Recruitment;Fostering;Funding;Future;Genomics;Grant;Human Papillomavirus;Immunooncology;Institution;Intervention;Investments;Last Name;Lung;Malignant Neoplasms;Medicine;Molecular;NCI Center for Cancer Research;Names;Obesity;Pediatric Oncology;Peer Review;Pilot Projects;Population Research;Process;Prostate;Records;Research;Research Institute;Resource Sharing;Resources;Review Committee;Risk Factors;Science;Seasons;Services;Shapes;Societies;Strategic Planning;Tobacco;Translational Research;Universities;University of Southern California Norris Cancer Center;anticancer research;biomarker development;cancer health disparity;cancer research center director;drug development;epigenomics;faculty support;health equity;improved;innovation;interdisciplinary collaboration;member;population based;programs;recruit;research and development;success;therapeutic development;translational genomics Developmental Funds n/a NCI 10744811 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8691 1875698 "LERMAN, CARYN " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 397233 240751 156482 PROJECT SUMMARY Developmental FundsDevelopmental Funds (DFs) add significant value to the USC Norris Comprehensive Cancer Center (NCCC)members who conduct basic translational clinical and population research. Specifically we utilized CCSG DFsin the current grant period to recruit 11 new faculty members to support seven CCSG pilot projects and tocatalyze a restructuring of our bioinformatics platform leading to the expansion of the NCCC Biostatistics Coreinto a full-service Data Science Shared Resource (SR). Notably DFs were utilized in part to support the clusterrecruitment of John Carpten PhD and colleagues from the Translational Genomics Research Institute (TGen)who competed successfully for several new grants including a new NCI U54 Center for Health Equity whichintegrates faculty across all five NCCC Programs. CCSG DFs were augmented by substantial institutionalinvestments to foster high impact collaborative research with emphasis on addressing cancer burdens anddisparities in our catchment area. The return on investment (ROI) for CCSG DFs in the current period is 21:1and contributed to the increase in NCI funding by 22% peer-reviewed funding by 11% and overall cancerrelated funding by 18% (direct costs). The process for awarding DFs is led by Administration with finaldecisions made by the NCCC Director with input from Senior and Program Leaders. There are notableimprovements in this process during the current grant period. First based on the NCCC Strategic Plantargeted areas for DF-supported faculty recruitments are identified by the Executive Committee and facultyare recruited through a systematic search process. Second the new Director refreshed the ScientificReview Committee for DF-supported pilot projects; this committee reviews and scores all applications forinternally-funded pilot award opportunities. Further the new Associate Director for Administration enhancedthe pilot awards process from the distribution of RFAs to review and decision-making and finally to thetracking of metrics of success for DF-supported members. Tracking of metrics of success for faculty recruitsand pilot grants has been enhanced substantially through the recruitment of a seasoned researchadministrator. In this application we request ($1375000) to support strategic faculty recruitments ($1M)and developmental pilot projects ($375K) to be supplemented by institutional investments as we did in thecurrent project period. The new NCCC Strategic Plan Shaping the Future of Cancer Science 2020-2025will guide these future investments with a focus on specific priorities: interventions to reduce cancerdisparities cancer therapeutics/drug and biomarker development and translational and clinicalresearch in immune-oncology. As in the current period we will maintain a sharp focus on recruiting facultywho are underrepresented in medicine. +No NIH Category available Acceleration;Achievement;Acute Lymphocytic Leukemia;Address;Advisory Committees;Applications Grants;Area;Asian population;Benchmarking;Bioinformatics;Biological Markers;COVID-19;COVID-19 pandemic;California;Cancer Burden;Cancer Center Support Grant;Cancer Science;Catchment Area;Cell Line;Cervical Cancer Screening;Clinical Trials;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Comprehensive Cancer Center;County;Cyclic GMP;Data Science;Decision Making;Development;Direct Costs;Disparity;Doctor of Philosophy;Education;Education and Outreach;Ensure;Epidemiology;Evaluation;Feedback;Fostering;Funding;Genome;Genomics;Goals;Grant;Growth;Height;Hispanic Populations;Human Papillomavirus;Immunotherapy;Incidence;Infrastructure;Institution;Intervention;Intervention Trial;Investments;Last Name;Lead;Leadership;Los Angeles;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medicine;Minority Enrollment;Mission;Modeling;Molecular;Monitor;NCI Center for Cancer Research;Names;Obesity;Patients;Peer Review;Population Research;Process;Protocols documentation;Research;Research Personnel;Resource Allocation;Resource Sharing;Resources;Rest;Risk Factors;Role;SARS-CoV-2 transmission;Schools;Science;Scientist;Services;Strategic Planning;Talents;Testing;Therapeutic Clinical Trial;Tobacco use;Training;Training and Education;Universities;University of Southern California Norris Cancer Center;Vertebral column;Virus Diseases;Vision;Work;anticancer research;biobank;cancer care;cancer genomics;cancer health disparity;cancer prevention;cohesion;community engagement;ethnic disparity;ethnic diversity;genomic platform;improved;innovation;interdisciplinary collaboration;malignant breast neoplasm;member;mortality disparity;mouse model;multidisciplinary;novel;patient oriented;programs;racial disparity;racial diversity;recruit;therapeutic target Leadership Planning and Evaluation n/a NCI 10744810 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8690 1875698 "LERMAN, CARYN " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 895353 572309 323044 PROJECT SUMMARY Leadership Planning and EvaluationAt the USC Norris Comprehensive Cancer Center (NCCC) overall responsibility for planning and evaluationrests with the Director Caryn Lerman PhD who sets the vision and strategic processes to intensify the growthand impact of NCCCs cancer research training and community impact. Lerman transformed the SeniorLeadership team with well-defined roles and responsibilities enhancing the culture of engagement input andcontinuous improvement. Advisory bodies include the Executive Committee Research Leadership CouncilStrategic Planning Steering Committee External Core Advisory Committee (new) Community Advisory Board(new) and the External Advisory Board. Program Cross-Program and Center retreats foster team science anddrive the impact of NCCC research to address the cancer burden and disparities in our highly diverse catchmentarea. Informed by these committees Senior Leaders led several evaluation and transformation processes duringthis cycle including: 1) development of a new NCCC Strategic Plan (SP); 2) reassessment of NCCC membershipto improve cancer focus; 3) restructuring of Research Programs to achieve the goals of the SP and fostertransdisciplinary collaboration and impact; 4) evaluation of Shared Resources resulting in closure of threefacilities and addition of two new Shared Resources (one newly implemented and one in development); 5)creation of new Offices for Community Outreach and Engagement (COE) and Cancer Research Training andEducation Coordination (CRTEC); and 6) introduction of a Cancer Service Line Executive Committee and a newFunds Flow model to NCCC. Building upon the prior strategic plan Senior Leaders led a Center-wide processculminating in the NCCC Strategic Plan (2020-2025). Selected achievements in aligned initiatives include: 1)recruitment of 40 new leading scientists in the current grant period; 2) greater Senior Leadership involvement inclinical trials with growth in interventional accruals to 1171 in 2019 (increased from 816 in 2015) and strongenrollment of minorities (61.6% of interventional trial accruals); 3) integration of catchment-relevant research intoall NCCC research programs and attainment of $10M of funding for cancer disparities research; 4) investmentof $8M in a new Translational Team Science Accelerator Program to catalyze paradigm-changing cancerscience; 5) deployment of a process to prioritize advancement of novel potential targets and biomarkers withten novel potential therapeutic targets now in various stages of development; 6) procurement of a $20M+investment to construct and staff a cGMP facility to fuel immunotherapy research; 7) development of a newPopulation Research Shared Resource and expansion of the Data Science Shared Resource to includebioinformatics; and 8) creation of a new translational cancer genomics platform and enhancements to theMolecular Genomics Core now an NCI-designated Genome Characterization Center. These processeshave catalyzed the NCCCs strategic growth (18% increase in overall cancer research funding and 11%in peer reviewed funding) cancer focus (22% increase in NCI funding direct costs) and capability toreduce cancer burdens in our catchment area and beyond. +No NIH Category available Achievement;Acute Lymphocytic Leukemia;Address;Advocacy;African American;African American population;Age;American Indians;Amerindian;Appearance;Area;Asian;Asian population;Award;California;Cancer Burden;Cancer Center Support Grant;Cancer Patient;Caring;Catchment Area;Center Core Grants;Cigarette;Cities;Clinical Trials;Colorectal Cancer;Communities;Community Health;Community Outreach;Comprehensive Cancer Center;County;Data;Disease;Disparity;Doctor of Philosophy;Education;Educational Materials;Electronic cigarette;Enrollment;Event;Exhibits;Fostering;Foundations;Funding;Genomics;Government;Grant;Hispanic;Hispanic Populations;Home;Human Papilloma Virus Vaccination;Human Papillomavirus;Incidence;Individual;Language;Last Name;Leadership;Longevity;Los Angeles;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Mission;Monitor;Monograph;NCI Center for Cancer Research;Names;Needs Assessment;Not Hispanic or Latino;Obesity;Patient-Centered Care;Patients;Peer Review Grants;Persons;Policies;Population;Population Research;Public Policy;Research;Resource Sharing;Risk;Scanning;Science;Screening for cancer;Services;Smoke;South America;Strategic Planning;Surveillance Program;Television;Therapeutic;Tobacco;Tobacco use;Tribes;Underrepresented Minority;United States;Universities;University of Southern California Norris Cancer Center;behavior change;bilingualism;cancer health disparity;cervical cancer prevention;colon cancer patients;combustible cigarette;community engagement;community organizations;financial toxicity;health equity;malignant breast neoplasm;member;men;mortality;outreach;participant enrollment;patient navigation;patient oriented;programs;recruit;sedentary lifestyle;social media;tobacco control;vaping Community Outreach and Engagement n/a NCI 10744809 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8689 1910369 "BAEZCONDE-GARBANATI, LOURDES A." Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 370230 224384 145846 PROJECT SUMMARY Community Outreach and Engagement (COE)The Office of Community Outreach and Engagement (COE) at the USC Norris Comprehensive Cancer Center(NCCC) addresses the cancer-related community health needs for our catchment area of Los Angeles County(LAC) where 84% of NCCC patients reside. COE supports NCCCs mission to reduce the cancer burden inour catchment area and beyond through research education outreach and dissemination. To establishand align NCCC strategic priorities with the cancer burdens and unique disparities in our catchment area COEleveraged data from the NCI-funded Cancer Surveillance Program (CSP) our ongoing Community NeedsAssessment a community environmental scan and input from our Community Advisory Board (CAB). NCCCpriorities include: prostate breast lung liver and colorectal cancers and acute lymphoblastic leukemiaas well as behavior change priorities including obesity tobacco/vaping and HPV/cervical cancerprevention. NCCC COE has the following Specific Aims: 1) to define assess and monitor cancer-relevantneeds of our catchment area; 2) to foster catchment-relevant research education and outreach; 3) to enhanceenrollment of diverse underrepresented community members across the lifespan in cancer-related researchincluding clinical trials; 4) to elevate the impact of NCCC research through policy/advocacy for our catchmentarea; and 5) to extend our reach beyond the catchment area. Signature achievements include: 1) in 2019alone we partnered on initiatives with 30 community-based organizations and disseminated educationalmaterials to 290 community-based patient-centered and government organizations throughout LAC; 2) led orparticipated in 162 events reaching a total of 519782 individuals; ~80000 individuals were engaged throughsocial media and over 600000 were reached through Univision COE Spanish language televisionappearances; 3) fostered the new NCI U54 CaRE2 Health Equity Center (U54CA233465) as co-director of aCOE Core; 4) contributed to the new NCI U19 prostate cancer RESPOND study in African American men byfostering recruitment (U19CA214253); 5) catalyzed and contributed to several cancer-related R01-level peer-reviewed grants and seven of eight NCI CCSG P30 supplements awarded in the current grant period; 6)developed six cancer-specific mini-monographs to monitor the cancer burden in the catchment area; 7) fosteredrecent major NCI grant submissions including an NCI Moonshot grant on engagement of Hispanic colorectalcancer patients in genomics research and an NCI P20 on liver cancer disparities in Hispanics (October 2020);8) fostered strong accrual of underrepresented minorities and individuals across the lifespan to clinical trials;and (9) impacted public policy by participating in tobacco control coalitions in Los Angeles Long Beach andPasadena testifying to pass bills on restricting electronic cigarette flavors and on prohibiting access to electroniccigarettes where combustible cigarettes are prohibited. COE extended its reach to the Toiyabe Tribe in MonyoCounty (CCSG Supplement) and to Amerindian tribes living in Los Angeles and the Central Valley. +No NIH Category available Acceleration;Acute Lymphocytic Leukemia;Affinity;Antibodies;Antigens;Area;Asian population;B-Cell Lymphomas;Basic Science;Biological Assay;Biological Models;Biological Products;Body Weight;California;Cancer Burden;Cancer Center Support Grant;Cancer Control Research;Cancer Control Research Program;Catchment Area;Cell Communication;Cell Therapy;Cells;Cellular Metabolic Process;Child;Childhood Acute Lymphocytic Leukemia;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Colorectal Cancer;Communication;Community Outreach;Comprehensive Cancer Center;Computer Models;County;Cyclic GMP;Development;Direct Costs;Disparity;Doctor of Philosophy;ENG gene;Effector Cell;Ensure;Epigenetic Process;Etiology;FDA approved;Faculty;Fostering;Funding;Funding Mechanisms;Grant;Hepatitis C virus;Hepatology;Hispanic;Human;Human Herpesvirus 8;Human Papillomavirus;Immune;Immune signaling;Immunooncology;Immunosuppression;Immunotherapy;Inflammation;Institution;Journals;Langerhans cell;Last Name;Liver diseases;Liver neoplasms;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medicine;Mission;Modeling;NCI Center for Cancer Research;Names;Natural Killer Cells;Nature;Neoplasm Metastasis;Neuroblastoma;Oncology;Paper;Pathogenesis;Pathogenicity;Pathway interactions;Peer Review;Pilot Projects;Population;Publishing;Research;Research Personnel;Resistance;Risk Factors;Role;Schools;Science;Strategic Planning;Students;Systems Biology;T-Cell Receptor;T-Lymphocyte;Therapeutic Intervention;Toxic effect;Training and Education;Translating;Translational Research;Tumor Biology;Tumor Escape;Underrepresented Minority;Universities;University of Southern California Norris Cancer Center;Vesicle;Viral;Virus;Woman;Work;angiogenesis;anticancer research;antitumor effect;cancer cell;cancer education;cancer epidemiology;cancer health disparity;cancer immunotherapy;cancer therapy;cell stroma;cervical cancer prevention;chimeric antigen receptor;chimeric antigen receptor T cells;clinical investigation;clinical translation;community engagement;design;elementary school;faculty mentor;interest;investigator-initiated trial;malignant breast neoplasm;meetings;member;minority trainee;nano;neoplastic cell;non-alcoholic fatty liver disease;novel;novel strategies;programs;receptor expression;recruit;stem-like cell;targeted treatment;technology platform;three-dimensional modeling;tool;tumor;tumor immunology;tumor initiation;tumor microenvironment;virology;virus related cancer Tumor Microenvironment n/a NCI 10744808 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8688 1972649 "KAST, WIJBE MARTIN" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 73302 44426 28876 PROJECT SUMMARY Tumor Microenvironment (TME) ProgramThe Tumor Microenvironment (TME) Program at the USC Norris Comprehensive Cancer Center (NCCC) wascreated in 2003 and received a merit rating of Outstanding to Exceptional in 2015.The mission of this programis to discover basic mechanisms that control the interactions between cancer cells of viral and non-viraletiology and their microenvironment leading to the identification of molecules or pathways that can betargeted for therapeutic interventions. The program has three scientific aims: 1) To investigate thefundamental mechanisms underlying cancer cell immune cell and stroma cell interactions & communications;2) To investigate the pathogenesis of cancer viruses and their immune escape mechanisms; and 3) Toinvestigate the mechanisms underlying tumor immune escape and develop new approaches for cancerimmunotherapy. The TME Program continues to be co-led by W. Martin Kast PhD who brings expertise incancer virology & cancer immunology. The strategic recruitment of new co-leader Rongfu Wang PhD in 2019expanded expertise in cancer immunotherapy innate immune signaling and immune cell epigenetics. Togetherthey promote intra- and inter-programmatic collaborations through Program meetings retreats seminars andpilot funding mechanisms. The TME Program brings together 35 members from 10 departments in four schoolsat USC with expertise and research interest in tumor-stroma interactions metastasis inflammationangiogenesis cancer computational modeling cancers induced by viruses (HPV KHSV HCV) and cancerimmunology and immunotherapy. A unique aspect of this basic science Program is its commitment to clinicaltranslation. In the current funding period basic science discoveries by TME members led to four investigator-initiated clinical trials in the TACS and CCR programs. Research by the members has a unique impact on specificpopulations of the LA County catchment area particularly children (neuroblastoma and childhood acutelymphoblastic leukemia (ALL)) Asians (liver cancer) and Hispanic women (breast cancer & HPV-inducedcervical cancer). Also noteworthy is the collaboration with NCCCs Cancer Research Training and EducationCoordination (CRTEC) Program to provide TME-led cancer education of a very diverse group of students rangingfrom elementary school to junior faculty mentoring. During the current funding period Program members havepublished 283 papers of which 23% are intra-programmatic 27% are inter-programmatic 34% are multi-institutional and 29% are published in high impact journals including Nature Medicine J. Clinical InvestigationNature Communications PNAS JAMA Oncology Cancer Discovery Cell Metabolism Hepatology J ExtracellVesicles ACS Nano Cancer Res and Clinical Cancer Res. Program members hold $13.1M in cancer-relatedfunding (direct costs); $11.2M is peer reviewed of which $4.4M is from NCI representing increases of 34% foroverall and 49% for peer-reviewed (NCI funding remains strong and stable in this grant period). +No NIH Category available 3-Dimensional;Achievement;Acute Lymphocytic Leukemia;Address;Affinity;Animal Model;Antibodies;Antiviral Response;Basic Science;Behavior;Binding Sites;Biological Markers;Biological Models;Blocking Antibodies;California;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control Research;Cancer Detection;Catchment Area;Cell Death Induction;Cell Survival;Cell surface;Childhood;Chromatin;Clinic;Clinical Sciences;Clinical Trials;Collaborations;Colon Carcinoma;Colorectal Cancer;Community Outreach;Comprehensive Cancer Center;Cytoplasm;DNA Methylation;DNA biosynthesis;Data Science;Direct Costs;Disease;Disparity;Doctor of Philosophy;Education and Outreach;Epigenetic Process;Evolution;Fostering;Funding;GRP78 gene;Gene Expression;Genes;Genetic Enhancer Element;Genetic Recombination;Genome;Genome Stability;Genomics;Glucocorticoids;Goals;Grant;Growth;Immunologic Monitoring;Immunotherapy;In Vitro;Investigation;Last Name;Lead;Leadership;Link;Location;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mentors;Methods;Molecular;Molecular Chaperones;Monitor;Names;Neoplasm Metastasis;Normal Cell;Pathology;Pathway interactions;Peer Review;Phenotype;Phosphotransferases;Process;Prognosis;Protamine Kinase;Publications;Publishing;Regulation;Relapse;Research;Resistance;Resource Sharing;Role;Science;Signal Pathway;Signal Transduction;Strategic Planning;Therapeutic Agents;Training Programs;Training and Education;Transcriptional Regulation;Translating;Translational Regulation;Translational Research;Translations;Universities;University of Southern California Norris Cancer Center;Viral Genes;Work;anticancer research;antitumor effect;biodemography;bioinformatics pipeline;cancer biomarkers;cancer cell;cancer epidemiology;cancer type;cell growth regulation;circadian regulation;community engagement;drug development;epigenome;epigenomics;genome integrity;health equity;hormonal signals;inhibitor;kinase inhibitor;leukemia;malignant breast neoplasm;meetings;member;mouse model;multimodality;novel;overexpression;patient response;population health;pre-clinical;predictive marker;programs;recruit;research and development;response biomarker;small molecule;steroid hormone;steroid hormone analog;therapeutic biomarker;therapeutic target;transcription factor;transcriptomics;translational genomics;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;working group Genomic and Epigenomic Regulation n/a NCI 10744807 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8687 8652218 "DOU, YALI " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 73302 44426 28876 PROJECT SUMMARY Genomic and Epigenomic Regulation (GER) ProgramThe Genomic and Epigenomic Regulation (GER) Program is a basic science program with an overarching goalof discovering basic mechanisms of genomic and epigenomic regulation involved in growth and behavior ofnormal and cancer cells and translating basic findings into cancer detection prognosis and treatment incollaboration with other NCCC Programs. GER is led by Michael Stallcup PhD who has made breakthroughdiscoveries in steroid hormone signaling and transcriptional regulation and Yali Dou PhD renowned fortranslation of epigenetic discoveries into novel inhibitors. Aligned with the NCCC Strategic Plan priorities focusedon multi-modal biomarkers of cancer evolution and translational drug development research the Program'sSpecific Aims are to: 1) Define the genomic epigenomic and transcriptomic features that are distinct incancer cells relative to normal cells and 2) Characterize regulatory mechanisms and signaling pathwaysresponsible for cancer phenotypes to identify and validate novel potential therapeutic targets. In thecurrent grant period GER members made major discoveries of critical genes and pathways leveraging the newsystematic process at identifying and prioritizing potential targets to advance in a go-no-go pipeline under thenew Center for Cancer Drug Development at NCCC. Signature achievements include: 1) identifying antiviralgene expression as a marker of response to DNA methylation inhibitors in leukemia; 2) creating novelbioinformatics pipelines that define tumor-specific enhancer elements linked transcription factors and targetgenes as drivers of breast and prostate cancer; 3) identifying mechanisms by which GRP78 and HSP90 escapeto the cancer cell surface and drive cell survival and demonstrating that antibodies against GRP78 and HSP90have anti-tumor effects in animal models of various cancers; 4) establishing small molecule modulators oftranscriptional regulation of the cellular circadian clock as new potential therapeutic agents; and 5) identifying anew inhibitor of a histone kinase that eliminates multiple types of cancer cells. With support from NCCC GERfosters member interactions and drives novel collaborations through weekly and annual Program meetingsjunior member mentoring cancer-focused PhD programs and participation in NCCC-organized DiseaseResearch Affinity Groups and the Targets to Therapies Steering Committee. GER has 40 full members who hold$12.1M in total cancer research funding (direct costs) of which $9.9M is peer reviewed and $3.5M is from NCIrepresenting significant increases of 114% 94% and 134% respectively since the 2015 review. During thecurrent grant period members published 244 cancer-relevant publications of which 27% are intra-programmatic28% are inter-programmatic and 31% are high impact (IF >9). GER leaders promote a sharp focus on catchmentarea cancer burdens including acute lymphoblastic leukemia and prostate breast liver colorectal andlung cancer. +No NIH Category available ARID1A gene;Address;Adjuvant Therapy;Adult;Affinity;African American;Area;Award;Basic Science;Biological Assay;Biological Markers;Biological Response Modifier Therapy;California;Cancer Burden;Cancer Center Support Grant;Cancer Control Research Program;Cancer Patient;Catchment Area;Chest;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Combined Modality Therapy;Community Outreach;Companions;Comprehensive Cancer Center;County;DNA Methylation;Data;Development;Disease;Disparity;Disseminated Malignant Neoplasm;Doctor of Philosophy;Drug Targeting;Dysmyelopoietic Syndromes;Early Diagnosis;Enrollment;Epigenetic Process;Evolution;Ewings sarcoma;Fostering;Funding;GRP78 gene;Genitourinary system;Genomics;Gills;Grant;Hematologic Neoplasms;Hematology;Immune checkpoint inhibitor;Immunologics;Immunotherapy;Institution;Intervention Trial;Investigational Therapies;Journals;Last Name;Lead;Leadership;Liver diseases;Los Angeles;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Malignant neoplasm of prostate;Methods;Minority;Mission;Molecular;Monitor;Mutation;NCI Center for Cancer Research;Names;National Clinical Trials Network;Outcome;Paper;Patients;Peer Review;Pharmacodynamics;Phase;Pre-Clinical Model;Predictive Cancer Model;Process;Prognostic Marker;Publishing;RNA;Regulation;Research;Research Project Grants;Resource Sharing;Science;Signal Transduction;Solid;Strategic Planning;Therapeutic Intervention;Tissues;Translational Research;Underrepresented Minority;Universities;University of Southern California Norris Cancer Center;Validation;Woman;Work;anticancer research;artemis;cancer biomarkers;cancer diagnosis;cancer epidemiology;cancer genome;cancer health disparity;cancer risk;cancer therapy;candidate validation;cell free DNA;circulating biomarkers;community engagement;design;diagnostic biomarker;diagnostic strategy;dietary restriction;drug development;epigenomics;faculty mentor;gastrointestinal;genome sciences;health equity;improved;in vivo;inhibitor;innovation;investigator-initiated trial;leukemia;liquid biopsy;malignant breast neoplasm;meetings;member;men;metastatic colorectal;multidisciplinary;new therapeutic target;novel;novel marker;novel therapeutic intervention;preclinical efficacy;predictive marker;programs;prostate cancer model;repository;therapeutic biomarker;therapeutic candidate;therapeutic target;translational progress;treatment response;tumor;tumor microenvironment Translational and Clinical Sciences n/a NCI 10744805 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8686 6545166 "LENZ, HEINZ JOSEF " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 109954 66639 43315 PROJECT SUMMARY - Translational and Clinical Sciences ProgramThe Translational and Clinical Sciences Program (TACS) at the USC Norris Comprehensive Cancer Center(NCCC) is co-led by John Carpten PhD Parkash Gill MD and Heinz-Josef Lenz MD. The Specific Aims of theTACS Program are to: 1) Discover novel targets and develop new therapeutic approaches with emphasis onhigh priority cancers in our catchment area; 2) Design and conduct innovative high impact clinical trials withemphasis on early phase and investigator-initiated trials (IITs); and 3) Develop and validate innovative diagnosticapproaches and biomarkers of cancer evolution and therapeutic response. During the current grant period theTACS Program's 54 full members have made significant advances in novel therapeutic approaches including(but not limited to) the development of lead compounds targeting Artemis in leukemia through the NCIExperimental Therapeutics (NExT) program and the identification of a novel immunological mechanism of actionof EphrinB4/EphB2 therapies towards novel combination treatments for cancer. TACS members also lead inNCI-funded clinical trials through the Experimental Therapeutics Clinical Trials Network (ETCTN) and NationalClinical Trials Network (NCTN). TACS members also design and lead novel trials combining epigenetic inhibitorswith immunotherapies in adult cancers with funding from Stand Up to Cancer and are national leaders in thedevelopment of circulating biomarker research including a new NCI R01 in the area of cell free DNA methylation.Through the new NCI-funded U54 Center for Health Equity TACS members lead major efforts in translationalcancer disparities research engaging the Office of Community Outreach and Engagement and members acrossall five NCCC Research Programs. The exceptional progress of the TACS Program in the current period isevident in its metrics: members hold $30.4M in cancer research funding with $12.3M in peer reviewed fundingof which $6.8M is from NCI; this represents dramatic increases of 170% 194% and 198% respectivelycompared to the 2015 review. Members also lead or participate significantly (e.g. project or core leader) in 15collaborative P and U grants. Of the 971 scientific papers published in this grant period 21% are intra-programmatic 26% are inter-programmatic 48% are multi-institutional and 30% are in high impact journals (IF>9). From 2015-2019 TACS members enrolled 3641 patients to interventional trials of which 2983 wereinterventional therapeutic accruals; 57% of interventional trial accruals are underrepresented minorities. Thusthe TACS program is addressing cancer needs in our catchment area through high impact research projects incancer disparities through drug development and innovative trials and faculty mentoring. +No NIH Category available Acceleration;Achievement;Acute Lymphocytic Leukemia;Address;Adolescent and Young Adult;Adolescent and young adult cancer patients;Adopted;Adoption;Adult;Behavior;Behavior Therapy;Breast Cancer Genetics;California;Cancer Burden;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Control Research Program;Cancer Patient;Cancer Survivor;Cancer Survivorship;Career Mobility;Caring;Catchment Area;Center Core Grants;Cervical Cancer Screening;Clinical Sciences;Collaborations;Colorectal Cancer;Community Outreach;Comprehensive Cancer Center;County;Data;Data Science Core;Direct Costs;Disparity;Disparity population;Doctor of Philosophy;Ecological momentary assessment;Electronic cigarette;Environmental Risk Factor;Ethnic Origin;Evaluation;Faculty;Flavoring;Fostering;Funding;Goals;Grant;Grant Review;Health Benefit;Health Services Accessibility;Health behavior;Hispanic Populations;Human Papilloma Virus Vaccination;Institution;Intervention;Investigation;Last Name;Lead;Leadership;Link;Los Angeles;Maintenance;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Marketing;Media Intervention;Mentors;Names;Obesity;Outcome;Peer Review;Physical activity;Policies;Population Research;Poverty;Prevention program;Publishing;Race;Research Personnel;Resource Sharing;Risk Behaviors;Risk Factors;Schools;Science;Screening for Skin Cancer;Screening for cancer;Services;Strategic Planning;Sun Exposure;Surveillance Program;Technology;Teenagers;Tobacco;Tobacco use;Training;Training and Education;Translating;Translational Research;Underrepresented Minority;Underserved Population;United States National Institutes of Health;Universities;University of Southern California Norris Cancer Center;Woman;Work;Youth;anticancer research;behavior change;cancer care;cancer epidemiology;cancer health disparity;cancer risk;cancer therapy;cohort;combustible tobacco;community engagement;electronic cigarette use;ethnic disparity;financial toxicity;follow-up;genetic testing;health disparity;health equity;implementation science;improved;individualized prevention;innovation;mHealth;malignant breast neoplasm;member;multi-ethnic;multilevel analysis;obesity risk;obesity treatment;preventive intervention;programs;protective factors;school district;skin cancer prevention;social media;telehealth;tobacco products;tumor;vaping Cancer Control Research n/a NCI 10744804 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8685 7854892 "COCKBURN, MYLES G" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 73302 44426 28876 PROJECT SUMMARY - Cancer Control Research (CCR) ProgramThe Cancer Control Research (CCR) Program of the USC Norris Comprehensive Cancer Center (NCCC) seeksto understand and modify cancer risk behaviors improve cancer screening and enhance cancer survivorship.CCR has two new co-leaders in this grant cycle: Jennifer Unger PhD an expert on tobacco-related healthdisparities cultural risk and protective factors for cancer-related behaviors and Myles Cockburn PhD whodevelops evaluates and translates skin cancer prevention programs in the catchment area. Under theirleadership CCR has developed new intra- and inter-programmatic collaborations with a sharp focus on the newNCCC Strategic Plan priorities to develop multi-level models of cancer risk for precision prevention and to reducecancer disparities and risk behaviors in our catchment area. The Specific Aims of CCR are: 1) To understandand modify cancer risk behaviors and improve cancer screening with emphasis on cancer disparitiesand 2) To assess and improve cancer outcomes with emphasis on cancer disparities. Indeed the CCR's33 members include national leaders in tobacco and vaping obesity and physical activity cancer screening andadolescent and young adult (AYA) cancers all with a focus on reducing cancer burdens and disparities in ourcatchment area of Los Angeles County (LAC). CCR members are PIs/MPIs on major collaborative grants thatdirectly address catchment relevant cancer risk factors and behavior change including: NCI U54 Tobacco Centerfor Regulatory Science (TCORS); NIH U01 to develop mHealth interventions; NIH P30 on environmental risksfor obesity in Hispanics; and NIH U01 on health behavior adoption and maintenance. Transformativeachievements in the current period include: (1) among the first to link e-cigarette use with initiation of combustibletobacco products in teens and to document the impact of flavoring; CCR members testified to inform the newlysigned bill in California (2020) banning sweet flavoring; 2) documenting the marketing of e-cigarettes to youthwith claims of health benefits leading to implementation of new policies to limit youth access to e-cigarettes usein Los Angeles County; 3) developing an efficacious skin cancer prevention intervention for underserved youthwhich has been adopted by schools in Southern California; 4) revealing significant financial toxicity and ethnicdisparities in follow-up care among AYA cancer survivors; and 5) documenting under-utilization of breast cancergenetic testing that might otherwise improve treatment options for women. During the current grant period CCR's33 full members published 630 cancer-relevant articles (28% intra-program 26% inter-program 41% multi-institutional 12% high impact). They hold $15.5M in cancer research funding (direct costs) with increases inoverall (+39%) peer-reviewed (+34%) and NCI funding (+13%) since the 2015 CCSG review. +No NIH Category available Advisory Committees;California;Cancer Burden;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Sciences;Collaborations;Communities;Community Health;Community Health Education;Community Outreach;Complex;Comprehensive Cancer Center;Coordination and Collaboration;Data Scientist;Databases;Direct Costs;Discipline;Ecosystem;Education;Educational Activities;Engineering;Ensure;Evaluation;Evolution;Faculty;Feedback;Fostering;Funding;Goals;Graduate Education;Grant;Health;Health Educators;Health Professional;Hispanic;Individual;Last Name;Leadership;Malignant Neoplasms;Mentorship;Minority Groups;Mission;Modeling;NCI Center for Cancer Research;Names;Outcome;Peer Review;Peer Review Grants;Population;Postdoctoral Fellow;Principal Investigator;Productivity;Research;Research Personnel;Research Project Grants;Science;Scientist;Strategic Planning;Training;Training and Education;Translational Research;Underrepresented Minority;Underrepresented Populations;Universities;Work;anticancer research;cancer health disparity;career;career development;central database;clinical care;college;continuing medical education;design;elementary school;graduate student;health empowerment;innovation;medical schools;member;multidisciplinary;next generation;programs;success;tumor microenvironment;undergraduate student Cancer Research Training and Education Coordination n/a NCI 10744802 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8683 8756967 "DECLERCK, YVES A" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 237218 143770 93448 PROJECT SUMMARY Cancer Research Training and Education Coordination (CRTEC)Established in August 2017 the University of Southern California (USC) Norris Comprehensive Cancer Center(NCCC) Office of Cancer Research Training and Education Coordination (CRTEC) coordinates 19 differentcancer training and education initiatives within the NCCC: nine (47%) programs are NCI funded. While allprograms foster participation of diverse trainees four (21%) programs focus solely on underrepresented minority(URM) populations and three (16%) programs focus on training in cancer disparities research. CRTEC initiativesstart in elementary school and span the training continuum from undergraduate students to junior faculty. CRTECis led by the NCCC Associate Director for Training and Education Yves DeClerck MD and relies on the adviceof an Internal CRTEC Advisory Committee of nine members and a T32 grant coordinating committee of four T32Principal Investigators all of whom are NCCC members. CRTEC's mission is To prepare the next generationof basic translational clinical and population scientists with a focus on convergent science inclusionand diversity. This mission is achieved with four specific aims: 1) to train the next generation of researchersin the conduct of cancer convergent science; 2) to create a pipeline of integrated training and educationalprograms with an emphasis on underrepresented populations; 3) to develop innovative education programs forhealth care professionals and community cancer educators; and 4) to evaluate the impact of these programs ontrainees' career evolution in the cancer field. Notable is the newly created Cancer Research Education andTraining Evaluation (CREATE) centralized database at NCCC. During this grant period CRTEC reached 77undergraduate students (36.4% URM) 214 graduate students (19.2% URM) 51 post-graduate trainees (37.3%URM) and 26 junior faculty members (61.5% URM). Jointly with COE CRTEC trained an additional 147community health educators in our catchment area (predominantly Hispanic) over the last 2 years. Notably NCItraining grant funding (direct costs DC) increased by 37% over the current grant period (from $1.19M to $1.63M)and peer-reviewed funding increased by 14% (from $2.77M to $3.17M). The K-R Grant Club for junior facultysubmitting their first grants led directly to $8.5M in peer-reviewed cancer research funding (DC) of which $6.1Mis from NCI; four K-R Club trainees have received a score below the 10th percentile on their recent submissionsand await funding decisions. +No NIH Category available Administrative Coordination;Award;Basic Science;Biostatistics Shared Resource;Budgets;Businesses;COVID-19 pandemic;California;Cancer Center;Cancer Center Support Grant;Cancer Science;Catchment Area;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Complement;Complex;Comprehensive Cancer Center;County;Data;Data Science;Dedications;Doctor of Philosophy;Education;Educational Activities;Electronic Mail;Ensure;Equipment;Evaluation;Event;Faculty;Faculty Recruitment;Fostering;Funding;Future;Gifts;Goals;Grant;Guidelines;Human Resources;Informatics;Information Technology;Infrastructure;Investments;Last Name;Leadership;Los Angeles;Malignant Neoplasms;Mission;NCI Center for Cancer Research;Names;Outcome;Patients;Peer Review;Policies;Population Research;Positioning Attribute;Preparation;Process;Productivity;Publications;Ramp;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Science;Services;Shapes;Strategic Planning;Structure;System;Training and Education;Translational Research;Universities;University adminstration;Writing;anticancer research;cancer research center director;clinical investigation;community engagement;design;drug development;improved;innovation;meetings;member;operation;pre-clinical;programs;recruit;social media;square foot;tool;web site Administrative Core n/a NCI 10744799 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C 8682 1875698 "LERMAN, CARYN " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 Research Centers 2024 479929 294475 185454 PROJECT SUMMARY - NCCC Administration (NCCC-A)The University of Southern California (USC) Norris Comprehensive Cancer Center (NCCC) is a matrix cancercenter with a longstanding tradition of exceptional science across the spectrum of basic clinical translationaland population research. NCCC Administration (NCCC-A) provides the critical infrastructure to support theDirector Associate Directors Program Leaders Shared Resources (SRs) 187 members and NCCC officesand external stakeholders engaged in cancer research community outreach and engagement and training andeducation. Over this grant period NCCC-A has undergone a major transformation to completely reshapeadministrative support for NCCC in order to improve its impact value efficiency and alignment with CCSGguidelines. Under the strong leadership of new NCCC Director Caryn Lerman PhD and Associate Director forAdministration Christopher Loertscher MA NCCC-A achieved many accomplishments over this grant periodincluding to: 1) help develop and implement a new Strategic Plan; 2) coordinate a major reorganization of thefive NCCC Research Programs and the six SRs presented in this application; 3) reorganize and expand theadministrative staff structure with three new senior administrative managers to expand expertise in finance SRsmanagement grants administration research informatics and communications; 4) revamp NCCC membershipand space policies to enhance cancer focus; 5) implement new tools to improve reporting on grants publicationspilot awards and clinical trials; 6) provide support to recruit and onboard 40 new external faculty; and 7)coordinate ramp-down and resumption of NCCC activities during the COVID-19 pandemic. NCCC-A managesall finances pilot awards grants space and SRs including NCCC's annual operating budget of $37 million(FY2020). It supports all governance and programmatic meetings and retreats to propel the NCCC researchenterprise to greater collaboration and innovation. NCCC-A manages NCCC's 300000 sq. ft. of space acrossthe three NCCC-dedicated buildings under the control of the Director. In the next grant period NCCC-A willcontinue to execute the initiatives within the new NCCC 2020-2025 Strategic Plan by providing critical supportto: hasten the pace of cancer discovery; recruit new high impact collaborative faculty; increase the impact ofcommunity outreach and engagement as well as training and education; and foster new team science grantsthrough targeted RFAs and administrative activities that foster new collaborations. The efforts of NCCC-Acontributed to a 18% increase in total cancer research funding (11% increase in peer-reviewed fundingincluding a 22% increase in NCI funding) over this grant period. +No NIH Category available Accounting;Achievement;Address;Applications Grants;Basic Science;Biological Markers;COVID-19;COVID-19 pandemic;California;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Science;Caring;Catchment Area;Cell Line;Cities;Clinic;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;County;Cyclic GMP;Data Science;Decision Making;Detection;Development;Direct Costs;Economically Deprived Population;Education;Education and Outreach;Enrollment;Ensure;Epidemiology;Evaluation;Fostering;Funding;Genome;Genomics;Geographic Locations;Goals;Grant;Growth;Height;Immunotherapy;Infrastructure;Institution;International;Intervention;Intervention Trial;Investments;Laboratories;Lead;Leadership;Longevity;Los Angeles;Malignant Neoplasms;Minority;Mission;Modeling;Molecular;Monitor;NCI Center for Cancer Research;Oncology;Patients;Peer Review;Persons;Population;Population Heterogeneity;Population Research;Population Sciences;Process;Productivity;Protocols documentation;Publications;Request for Applications;Research;Research Personnel;Resource Sharing;Resources;Schools;Science;Scientist;Services;Special Population;Strategic Planning;Talents;Technology;Textiles;Therapeutic Clinical Trial;Therapeutic Intervention;Training;Training Programs;Training and Education;Translations;Underrepresented Populations;Universities;Vision;anticancer research;biobank;biomedical informatics;cancer care;cancer clinical trial;cancer genomics;cancer health disparity;cancer prevention;cohesion;community engagement;genomic platform;improved;innovation;interdisciplinary collaboration;member;mouse model;neoplasm resource;next generation;novel;patient oriented;pre-clinical;programs;recruit;socioeconomic disadvantage;success;survivorship;underserved community University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG) PROJECT NARRATIVE Overall ComponentAs one of the first eight Comprehensive Cancer Centers to receive the NCI designation in 1973 the Universityof Southern California Norris Comprehensive Cancer Center (NCCC) is a leader in cancer research educationand patient-centered oncology care. A central priority for NCCC is to serve the unique cancer-related needs ofour multicultural catchment area Los Angeles County. Our geographic location in the 4th most diverse city in thenation affords opportunities for NCCC to lead in bi-directional community engagement innovative trainingprograms and high impact research to address cancer burdens and disparities among diverse communities. NCI 10744798 12/22/23 0:00 PAR-20-043 5P30CA014089-48 5 P30 CA 14089 48 "HE, MIN" 12/1/96 0:00 11/30/26 0:00 ZCA1-RTRB-C(O1) 1875698 "LERMAN, CARYN " Not Applicable 37 INTERNAL MEDICINE/MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 397 Research Centers 2024 5921659 NCI 3796858 2124801 PROJECT SUMMARY Overall ComponentThe USC Norris Comprehensive Cancer Center at the University of Southern California (NCCC) has beencontinuously funded as an NCI-designated Comprehensive Cancer Center since 1973. NCCC has a rich traditionof collaborative research and serves as a major regional and international resource for cancer researcheducation community outreach and engagement and patient-centered oncology care. Our vision is to reducethe burden of cancer for all people. A central priority for NCCC is to serve the unique cancer-related needs ofour multicultural catchment area Los Angeles County (LAC). To achieve this goal our 187 full members formcollaborative teams and are organized into five impactful Research Programs served by six valuable SharedResources (SRs). NCCCs Cancer Research Training and Education Coordination (CRTEC) programs are partof the fabric of these efforts creating a diverse pipeline for the next generation of exceptional cancer scientistsand clinicians. The NCCC Office of Community Outreach and Engagement (COE) is the primary vehicle by whichwe understand engage and serve the needs of the underserved communities in our catchment area. Ourgeographic location in the 4th most diverse city in the nation affords opportunities for NCCC to lead in researchthat addresses cancer burdens and disparities among diverse communities and special populations. IndeedNCCC is distinguished by exceptional success in recruiting diverse populations to clinical trials with minoritiesaccounting for more than 61% of interventional therapeutic accruals. This application requests: 1) support forfive interactive Research Programs; 2) partial support for six SRs and one Developing Preclinical SR that providetechnologies services and scientific consultation that will enhance member interaction and productivity; 3)support for Leadership Planning and Evaluation; 4) support for Developmental Funds to foster pursuit of newpriorities strengthen science and explore new collaborations and technologies all aligned with the new NCCCStrategic Plan; 5) support for Cancer Center Administration; and 6) support centralized scientific oversightof cancer clinical trials. Members currently hold grants totaling $101.3M (direct costs) with $37.7M from NCIand have authored landmark publications representing high intra-programmatic (26%) inter-programmatic(25%) and multi-institutional (45%) cancer research. Continued funding from the Cancer Center Support Grant(CCSG) will allow us to build on our strengths in basic population and clinical sciences and to facilitatediscovery and its translation into direct benefit to patients and diverse communities. 5921659 +No NIH Category available Affect;Antigens;Antitumor Response;Bioinformatics;Biological Process;CD8-Positive T-Lymphocytes;CD8B1 gene;CRISPR screen;CRISPR/Cas technology;CTLA4 gene;Cancer Patient;Cell physiology;Cells;Chronic;Clinic;Clinical;Clonal Expansion;Combined Modality Therapy;Databases;Decision Modeling;Development;Disease remission;Drug Targeting;Effector Cell;Epigenetic Process;Foundations;Future;Gene Expression;Gene Expression Profiling;Genetic;Genetic Transcription;Goals;Heterogeneity;Human;Immune;Immune System Diseases;Immune response;Immunotherapy;Infection;Knockout Mice;Knowledge;Macrophage;Malignant Neoplasms;Memory;Modeling;Molecular;Mus;Outcome;Pathologic;Patients;Phase;Play;Population;Population Heterogeneity;Postdoctoral Fellow;Process;Regulatory T-Lymphocyte;Reporter;Research;Role;System;T cell differentiation;T cell response;T-Cell Development;T-Lymphocyte;Technology;Therapeutic;Training;Viral;Virus Diseases;Work;anti-PD-1;anti-tumor immune response;cancer type;cell type;chronic infection;clinical remission;conditional knockout;cytokine;cytotoxic;design;effector T cell;enhancing factor;exhaust;exhaustion;experience;genomic platform;high dimensionality;high throughput screening;immune checkpoint;immune checkpoint blockade;improved;in vivo;mouse model;new therapeutic target;novel;overexpression;pre-doctoral;prevent;progenitor;programmed cell death protein 1;programs;receptor;response;single-cell RNA sequencing;stem cells;success;transcription factor;tumor;tumor microenvironment;tumor progression Investigating molecular mechanism of immune response during cancer progression Project NarrativeT cell exhaustion is one of the main reasons that lead to immune dysfunction in chronic infection or cancer.Investigating the molecular mechanisms of T cell exhaustion will increase our understanding of T cells responseduring chronic infection or cancer progression. This will potentially lead to the development of optimaltherapeutic strategies for the patients under immune therapies or the discovery of new drug targets that canenhance T cell response in clinic. NCI 10744797 11/14/23 0:00 RFA-CA-18-001 5K00CA234842-07 5 K00 CA 234842 7 "DAMICO, MARK W" 9/8/18 0:00 11/30/24 0:00 ZCA1-TCRB-T(O1) 15316432 "CHEN, ZEYU " Not Applicable 7 NONE 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA ORGANIZED RESEARCH UNITS 22155450 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Other Research-Related 2024 97605 NCI 90375 7230 Project SummaryT cell exhaustion is a dysfunctional T cell state after chronic antigen exposure and this exhausted T cells(TEX) are often developed in chronic infection or tumor microenvironment. One of the key features of TEX isincreased expression of inhibitory molecules such as Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) andProgrammed Death 1 (PD-1). These molecules work as immune checkpoints to suppress T cell function inorder to prevent pathological damage from T cell hyper-activation. However in the tumor microenvironmentthese molecules limit the cytotoxic effect of T cells to kill tumor. Blocking these immune checkpoints hasbeen shown to achieve significant clinical benefits in multiple cancer types. Despite of these successes themajority of the patients do not achieve long-term tumor remission. Thus it is crucial to study the underlyingmolecular mechanism of T cell exhaustion development and seek for potential combination strategies withimmune checkpoint blockade (ICB) to enhance and sustain T cell response in clinic.During my doctoral research I focus on investigating the transcriptional mechanisms of T cell exhaustiondevelopment and how transcription factors control T cell reinvigoration after PD-1 blockade. In Specific Aim1.1 I focused on the transcriptional mechanisms of effector T cell loss and TEX progenitor establishmentduring chronic antigen exposure. Using single cell RNA sequencing (sc-RNA-Seq) we found two distincttranscriptional networks in the chronic effector T cells and the TEX progenitors and we systematicallydescribed the molecular mechanism of TEX development. In Specific Aim 1.2 I focus on establishing a T cellbased in vivo CRISPR-Cas9 screening system (RetroCRISPR) to functionally study transcriptionalmechanisms during T cell reinvigoration by PD-1 blockade. These studies will not only discover novelmechanisms of T cell exhaustion but also provide high dimensional profiling or high throughput screeningsystems for the field to study T cell response. In Specific Aim 2 I plan to extend my RetroCRISPR systeminto dissecting the complexity of tumor microenvironment and I will search for potential combinationstrategies with ICB to enhance T cell response. The overall goal for my current projects and future plans isto discover cell intrinsic and extrinsic mechanisms affecting T cell response and design optimal immunetherapeutic strategies for long-term tumor remission. 97605 +No NIH Category available Acidity;Activities of Daily Living;Affinity;Antibody Response;B-Lymphocytes;Cancer Patient;Cell physiology;Cells;Clinical;Coupled;Deposition;Development;Economics;Evolution;FOXP3 gene;Flow Cytometry;Freezing;Frequencies;Goals;Human;Hydrogen;Hypoxia;IgE;Immune system;Immunofluorescence Immunologic;Impairment;Macrophage;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Mediating;Modeling;Mus;NHE1;Neoplasm Metastasis;Outcome;PD-1 blockade;PRDM1 gene;Peripheral Blood Mononuclear Cell;Population;Positron-Emission Tomography;Prognostic Marker;Public Health;Regulation;Regulatory T-Lymphocyte;Reporting;Repression;Risk;Role;Secondary to;Self Tolerance;Serum;Shapes;Sodium;Specimen;Stains;Structure of germinal center of lymph node;T-Lymphocyte Subsets;T-cell receptor repertoire;Testing;Tissues;Tumor Escape;Tumor Expansion;Tumor Immunity;Tumor Promotion;Tumor-Infiltrating Lymphocytes;Tumor-associated macrophages;Up-Regulation;X-Ray Computed Tomography;adaptive immunity;biobank;cancer immunotherapy;cell type;clinically significant;contrast enhanced;defined contribution;digital;effector T cell;fluorescence molecular tomography;immune checkpoint blockade;immunogenicity;improved;insight;melanoma;neoplasm immunotherapy;new therapeutic target;patient prognosis;predictive marker;programs;receptor;response;single-cell RNA sequencing;spatial relationship;tertiary lymphoid organ;therapeutically effective;therapy outcome;tomography;transcription factor;tumor;tumor growth;tumor immunology;tumor microenvironment;tumor progression Follicular Regulatory T-cells Promote Cancer Project NarrativeThis study aims to reveal the previously unappreciated cell type TFR cells as a cancer prognostic marker andthe IgE response as a predictor to the disrupted TFR cell function. This study will also illustrate how adaptiveimmunity interplays with innate responses contributing to tumor evolution. If successful this study would advanceour fundamental mechanistic understanding of tumor immunology and lead to a new direction for cancerimmunotherapy. NCI 10744792 11/30/23 0:00 PA-20-185 5R01CA276190-02 5 R01 CA 276190 2 "KUO, LILLIAN S" 12/1/22 0:00 11/30/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 10360944 "LEAVENWORTH, JIANMEI WU" Not Applicable 7 NEUROSURGERY 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 356835 NCI 240293 116542 Project SummaryEfforts to amplify the bodys immune system against cancer has faced a barrier due to the bodys ownimmunosuppressive tumor-promoting mechanisms as commonly present for many cancers. We are dissectingthese shared mechanisms by focusing on specific immunosuppressive cells in the tumor with the goal ofdeveloping effective therapeutic approaches by targeting these cells to treat cancer. In this proposal weinvestigate the potential tumor-promoting role of a specific regulatory T (Treg) cell subset called follicularregulatory T (TFR) cells. TFR cells are known to regulate follicular helper T (TFH) cells B-cells and germinal center(GC) antibody responses while the intensity of TFH cells B-cells and tertiary lymphoid structures (TLS) in manycancers predict improved clinical outcomes and responses to cancer immunotherapy. However the contributionof TFR cells and humoral antibody responses to the regulation of anti-tumor immunity and tumor progressionremains to be largely unexplored. Our recent study of TFR cells has revealed that these cells accumulate inmurine and human melanoma. The functional stability and suppressive activity of TFR cells in the tumor requirethe expression of the transcription factor Blimp1. Deletion of Blimp1 in Treg cells not only results in impairedsuppressive activity but also leads to the expansion of TIL TFH cells and GC B-cells and enhanced tumoral IgEdeposition secondary to TFR dysregulation. Further analysis revealed that higher tumoral TFR signatures alongwith PRDM1 expression indicated increased malignancy and risk of metastasis in various cancers. IncreasedIgE was associated with the activation and polarization of tumor-associated macrophages (TAMs) via the IgEhigh affinity receptor FcRI potentially remodeling the tumor microenvironment (TME). These unexpectedfindings lead us to hypothesize that intratumoral TFR cells negatively impact the TME and promote tumorprogression by repressing IgE-mediated anti-tumor immunity and disrupting intratumoral TFR suppressiveactivity improves tumor control. Using genetically-modified mice and various tumor models we will define thefunctional capacity and mechanistic action of TFR cells in the regulation of tumor progression define thecontribution of IgE to anti-tumor immunity and the TME remodeling. Finally we will validate the TFR-IgE/FCERIAaxis in human tumors. Completion of this study will reveal the previously unappreciated cell type TFR cells as acancer prognostic biomarker and the IgE response as a predictor to the TIL TFR cell function. Insights gainedfrom this project will facilitate the identification of new therapeutic targets and predictive markers to therapeuticoutcome and the development of effective approaches to treat a broad spectrum of cancers. 356835 +No NIH Category available Affect;Aftercare;Age;Aging;Anti-Inflammatory Agents;Aspirin;BRCA1 gene;Bioinformatics;Biology;Blood;Bone Marrow;Breast Cancer Patient;Breast Cancer Risk Factor;Cell model;Cells;Characteristics;Chimera organism;Chronic;Clinical;Communities;Data;Development;Distal;Dose;Event;Exhibits;Germ-Line Mutation;Goals;Histologic;Hodgkin Disease;Immune;Immune system;Immunotherapy;Infiltration;Inflammation;Lymphocyte;Lymphocytic Infiltrate;Macrophage;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Methods;Modeling;Mus;Myeloid Cells;Natural Immunity;Nature;Non-Malignant;Obesity;Outcome;Parabiosis;Pattern;Phenotype;Plasma;Population;Publishing;Radiation;Radiation therapy;Recording of previous events;Reporter;Role;Second Primary Cancers;Signal Transduction;Spleen;Stress;Syndrome;T cell infiltration;Testing;Tissues;Transforming Growth Factor beta;Transplantation;Tumor Escape;Tumor Immunity;Tumor Subtype;Tumor-Infiltrating Lymphocytes;Virus Diseases;Woman;adaptive immunity;anti-tumor immune response;biobank;cancer immunotherapy;carcinogenesis;clinically significant;conditional knockout;cyclooxygenase 2;cytokine;deep learning;deep learning model;experimental study;high risk population;immune cell infiltrate;immunoregulation;innovation;malignant breast neoplasm;mammary;molecular modeling;monocyte;neoplasm resource;novel;pregnancy-associated breast cancer;response;systemic inflammatory response;treatment response;tumor;tumor-immune system interactions Investigating the Genesis of Tumor Immune Microenvironment (TIME) as a function of Inflammation NARRATIVEThe type and pattern of immune cell infiltrate in breast cancer is of growing clinical importance as they associatewith response to therapy and are the specific target of immunotherapy. However the factors that influence thegenesis of the type of tumor immune microenvironment (TiME) have yet to be defined. Our proposed systematicmechanistic high content analysis and modeling of the cellular and molecular mechanisms by which breastcancers evade the immune system focuses on will elucidate key factors that govern the origins of the TiME. NCI 10744790 12/1/23 0:00 PA-20-185 5R01CA270332-02 5 R01 CA 270332 2 "KUO, LILLIAN S" 12/1/22 0:00 11/30/27 0:00 Tumor Microenvironment Study Section[TME] 1940223 "BARCELLOS-HOFF, MARY HELEN" Not Applicable 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 459316 NCI 332104 127212 ABSTRACTThe type and pattern of immune cell infiltrate in breast cancer is of growing clinical importance as they associatewith response to therapy and are the specific target of immunotherapy. `Cold' cancers that lack infiltrating T cellsexhibit pronounced transforming growth factor (TGF) activity and predict poor outcomes in breast cancerpatients. However the factors that influence the genesis of the type of tumor immune microenvironment (TiME)have yet to be defined. We found that radiation-preceded breast cancers in women treated with radiation therapyfor Hodgkin's lymphoma are significantly enriched for TiME devoid of lymphocytes and rich in myeloid cellsTGF and cyclooxygenase 2. We used a Trp53 null mammary chimera model to determine the factorsunderpinning of this unexpected difference. Tumors with an immunosuppressive TiME lacking lymphocytesarose only in irradiated mice even when the transplant was not irradiated indicating host biology was key aswell as in mice lacking functional adaptive immunity pointing to a role for innate immunity. Strikingly transientaspirin treatment before cancer developed blocked the development of cold tumors. We hypothesize thatsystemic inflammation provokes the development of tumors with immunosuppressive cold TiME. Chronic low-level inflammation from aging obesity stress and chronic syndromes following viral infection is common. Herewe will test the specific hypothesis that inflammation-induced TGF during carcinogenesis alters tissue-residentmyeloid cells to promote the genesis of cancers with an immunosuppressive TiME. AIM 1 will use state-of-the-art analysis of cytokines and immune characteristics that correlate with the development of tumors with coldTiME using a novel biobank of blood plasma bone marrow spleen and nonmalignant mammary glands andtheir associated cancers as a function of inflammation or anti-inflammatory aspirin conditions at 4- 8- and 18-months post-treatment. The relevance of these findings will be tested by immunoprofiling women with breastcancer. AIM 2 will use parabiosis to test whether factors circulating during systemic inflammation contribute anduse macrophage depletion and a mouse in which myeloid cells cannot signal through TGF to test whethercirculating TGF elicits monocyte activation to promote the development of cold TiME. AIM 3 will analyze theresulting high-content data using deep learning and bioinformatics methods to identify tumor subtypes and toinfer key events. The main goal of our study is to test the innovative hypothesis that inflammation-induced TGFpromotes cold tumors by altering tissue-resident myeloid cells during carcinogenesis. Our proposal to conductsystematic high content analysis and modeling of the mechanisms by which breast cancers develop with animmunosuppressive TiME is highly significant in view of the growing clinical importance of the TiME. 459316 +No NIH Category available Antibodies;Antibody Formation;Antigen Presentation;Antitumor Response;B-Lymphocytes;Bacteria;Behavior;C57BL/6 Mouse;CD4 Positive T Lymphocytes;Cancer Etiology;Cell Communication;Cells;Cessation of life;Colitis associated colorectal cancer;Colon;Colonic Neoplasms;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Dendritic Cells;Development;Disease;Epithelium;Failure;Genes;Growth;Helicobacter;Helicobacter hepaticus;Helper-Inducer T-Lymphocyte;Home;Human;Immune;Immune response;Immunity;Immunotherapy;Incidence;Inflammation;Intestines;Invaded;Knock-out;Location;MHC Class II Genes;Malignant Neoplasms;Measures;Mediator;Microsatellite Instability;Modeling;Mucous body substance;Mus;NK Cell Activation;Natural Killer Cells;Outcome;Patient-Focused Outcomes;Patients;Persons;Property;Rectal Cancer;Rectal Neoplasms;Sampling;Shapes;Structure;Structure of germinal center of lymph node;T cell differentiation;T-Lymphocyte;Taxon;Testing;Therapeutic;Tumor Antigens;Tumor Burden;Tumor Immunity;anti-tumor immune response;cancer type;colon bacteria;colon cancer patients;colon microbiota;colorectal cancer treatment;gut microbiome;immunogenic;improved;intestinal epithelium;melanoma;microbiome;microbiome composition;microbiota;model development;mouse model;murine colitis;neoplasm immunotherapy;tertiary lymphoid organ;tumor;tumor growth Identifying the mechanism of anti-colorectal immunity induced by mucoinvasive colonic bacteria Project NarrativeColorectal cancer remains a common and deadly disease that is on the rise amongst young people worldwide.Colon tumors grow adjacent to the intestinal microbiome and bacteria from the microbiome can both drivetumor growth and also support the activation of anti-tumor immunity. Our proposal seeks to identify colonicbacteria that most activate colonic immune cells and define how immune cells become activated to kill tumors. NCI 10744789 11/8/23 0:00 PAR-22-061 5R01CA269902-02 5 R01 CA 269902 2 "DASCHNER, PHILLIP J" 12/1/22 0:00 11/30/27 0:00 "Digestive System Host Defense, Microbial Interactions and Immune and Inflammatory Disease Study Section[DHMI]" 8628273 "HAND, TIMOTHY WESLEY" Not Applicable 12 PEDIATRICS 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 507316 NCI 351502 155814 AbstractColorectal cancer (CRC) is a leading cause of cancer-related death and its incidence is on the rise in youngpeople. Colorectal tumors are often detected at late stages where therapy often fails. Immunotherapy isrevolutionizing the treatment of many types of cancer but is only effective for a very small subset of CRC patients.Thus there is a critical need for improved therapies for CRC. Colorectal tumors grow from the intestinalepithelium and interact with the colonic microbiota. CRC has been associated with shifts in the composition ofthe microbiota that promote inflammation and tumor growth. The microbiota can also shape colonic T and B cellimmune responses and is a critical modulator of the efficacy of tumor immunotherapy. Using a mouse model ofCRC (AOM/DSS) we show that colonization with a single bacterial taxon: Helicobacter hepaticus after tumorshave already developed leads to a reduction in tumor burden and size. H. hepaticus also increased the numbersize and organization of Tertiary lymphoid structures (TLS) next to colorectal tumors. The presence of TLS isassociated with positive outcomes in CRC patients but how they act to increase anti-tumor immunity is notknown. H. hepaticus-dependent tumor reduction depended upon CD4 T cells and B cells but not CD8 T cells.Most H. hepaticus-specific CD4+ T cells differentiated into T Follicular Helper (TFH) cells and localized in TLS.Importantly CD4cre Bcl6flox mice that cannot form TFH cells also failed to either form TLS or control CRC growthbut transfer of H. hepaticus-specific CD4+ T cells completely restored the anti-tumor response. Our hypothesisis that the distinct mucus colonization properties of Hhep leads to activation of anti-Hhep TFH that interact with Bcells to induce peri-tumoral TLS formation. Colonic TLS then act as platforms for the activation of anti-tumorCD4+ T cells NK cells and B cells which invade the tumor to support effective anti-tumor immunity. We will testthis hypothesis in two aims. First we will identify the genes and behavior (such as mucus/epithelial colonization)associated with Helicobacter-associated control over CRC. Next we will correlate the presence of TLS TFH andB cells in human CRC patients with specific mucus and tumor resident bacteria. Finally we will use our mousemodels to identify whether TLS serve as platforms for more effective activation of anti-tumor T and B cells.Together our proposal has the potential to identify the key bacterial components that should be targeted toaugment anti-tumor immunity and colonic TLS. Further we may identify mechanisms by which TLS support anti-tumor immune responses which could be used to formulate therapeutic anti-CRC approaches. If successful wecould identify mechanisms to rationally modify the microbiome to increase anti-tumor immunity. 507316 +No NIH Category available 3-Dimensional;Adhesions;Affinity;Architecture;Area;Binding;Biological Markers;Biology;Brain;Brain Neoplasms;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;Breast cancer metastasis;Carcinoma;Cell Adhesion;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cell-Cell Adhesion;Cells;Central Nervous System;Complex;Cues;Detection;Development;Diagnostic Imaging;Disparate;Drug Delivery Systems;Engineering;Exhibits;Gold;Growth;Growth Factor;Human;Image;Image Analysis;Individual;Invaded;Invasive Lesion;Knowledge;Label;Ligands;Malignant Neoplasms;Mammary Neoplasms;Mediating;Metastatic breast cancer;Metastatic malignant neoplasm to brain;Modeling;Molecular;Multimodal Imaging;Mus;Neoplasm Metastasis;Nerve;Nervous System;Neural Crest Cell;Neurites;Neurons;Neurosciences;Patient-Focused Outcomes;Patient-derived xenograft models of breast cancer;Peptide Hydrolases;Peripheral Nervous System;Post-Translational Protein Processing;Process;Prognosis;Protein Tyrosine Phosphatase;Proteolysis;Radiation;Radiation Dose Unit;Radiation therapy;Radiosensitization;Regulation;Research;Resistance;Resolution;Route;Signal Transduction;Solid Neoplasm;Structure;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Cell Invasion;Tumor Cell Migration;Tumor Markers;Tumor Promotion;Tumor Tissue;X-Ray Computed Tomography;Xenograft Model;axon guidance;brain tissue;cancer cell;cell motility;chemokine;effective therapy;extracellular;fluorescence imaging;fluorophore;imaging biomarker;imaging capabilities;imaging modality;imaging system;improved;in vivo;insight;malignant breast neoplasm;migration;mouse model;nanoGold;nanoparticle;neoplastic cell;neural;neurodevelopment;novel;novel marker;orthotopic breast cancer;patient derived xenograft model;perineural;receptor;standard of care;stem;targeted agent;targeted biomarker;targeted treatment;theranostics;therapy outcome;tumor;tumor growth;tumor microenvironment;white matter Detection Radiosensitization and Theranostic Targeting of Metastatic Breast Cancer by PTPmu When cancer cells grow invade and migrate along nerves in either the central (CNS) or peripheral nervoussystem (PNS) it results in the worst outcomes for patients yet there is very little knowledge about this processand no effective treatments. We hypothesize that a biomarker resulting from proteolysis of a cell-cell adhesionmolecule can be utilized to detect and treat cancer growth along nerves in both the CNS and PNS. Here weseek to enhance detection and treatment by developing a tumor-specific biomarker targeted theranostic agentthat selectively enhances radiosensitization of primary invasive and metastatic breast cancer to the brain forimproved radiation therapy. NCI 10744786 11/2/23 0:00 PA-20-185 5R01CA269816-02 5 R01 CA 269816 2 "ESPEY, MICHAEL G" 12/1/22 0:00 11/30/27 0:00 Radiation Therapeutics and Biology Study Section[RTB] 1939905 "BRADY-KALNAY, SUSANN M" "BASILION, JAMES PETER" 11 BIOCHEMISTRY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 601330 NCI 373497 227833 Both inside the central nervous system and outside in the peripheral nervous system cancer cells grow alongnerves as routes of invasion and metastasis called neural invasion. This growth is common in several carcinomasincluding breast cancer and is associated with poor prognosis. Proteolysis of cell adhesion molecules (CAMs)occurs in development and growing evidence suggests this post-translational modification may promote tumormigration and invasion on nerves that ultimately leads to metastasis to the brain in various tumor types includingbreast cancer. The receptor protein tyrosine phosphatase PTP is a CAM that is proteolyzed in cancer cells togenerate an extracellular fragment that is a unique imaging biomarker of the tumor microenvironment. The PTP-targeted agents we developed bind to this biomarker and recognize human brain tumors as well as invasiveprimary breast cancer and breast cancer that has metastasized to the brain. Systemic delivery of the PTP-targeted agent results in binding to tumor cells within minutes in xenograft models. Using a 3D cryo-imagingsystem we analyzed the extent of cell migration and dispersal within the brain. We found that the PTP-targetedagent labels 99% of all dispersing tumor cells far away from the main tumor mass on nerves in mouse models.This proposal represents the convergence of our expertise in neuroscience cell adhesion imaging and cancerto test if the PTP biomarker can be used to detect tumor growth along nerves leading to brain metastases. Gold nanoparticles (AuNPs) have shown outstanding versatility in biomedical applications includingimaging diagnostics drug delivery and radiation therapy. In this proposal we describe the development oftheranostic AuNPs for the detection and treatment of breast cancer metastases. We will achieve more sensitivedetection and treatment of invasive and metastatic lesions through the use of a three component theranosticnanoparticle containing: 1) a highly specific targeting agent of the PTP biomarker in the tumormicroenvironment; 2) a protease-sensitive quenched near infrared fluorophore for fluorescent imaging; and 3) agold nanoparticle (AuNP) for sensitization to radiotherapy. We will test whether the PTP-targeted agents detectsnerve associated growth using 3D single cell resolution cryo-imaging that precisely tracks migration of individualcancer cells on nerves. We will utilize our established human patient-derived xenograft models of metastaticbreast cancer and models that metastasize from the breast to the brain. Metastatic tumors are resistant to almostall chemotherapeutics so physical killing strategies like radiation must be improved and employed for bettertherapeutic outcomes. By delivering PTP-targeted conjugated AuNPs directly to primary and metastatic breastcancer we will exploit the radiosensitization of AuNP to reduce the required dose of radiation needed forradiotherapy thereby reducing collateral damage to normal surrounding tissues. We expect that these studieswill yield targeted nanoparticles that detect and treat nerve associated tumor growth while implicating CAMproteolysis as a generalizable mechanism for detecting and treating tumor invasion on nerves. 601330 +No NIH Category available Accounting;Agammaglobulinaemia tyrosine kinase;Alleles;Animals;B lymphoid malignancy;B-Cell Antigen Receptor;B-Cell Lymphomas;B-Lymphocytes;BCL6 gene;Binding;Biological;Bortezomib;Cancer Etiology;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemicals;Clinical;Complex;Coupled;Cyclophosphamide;Data;Development;Doxorubicin;Drug resistance;FDA approved;Gene Expression;Genes;Genetic Transcription;Glues;Goals;Growth;Hematological Disease;Human;Impairment;Inflammation;Investigation;Knock-out;Knockout Mice;Link;Lymphoma;Lymphoma cell;Lymphomagenesis;Lymphoproliferative Disorders;Malignant Neoplasms;Mature B-Lymphocyte;Membrane;Modeling;Molecular;Mus;Mutate;Mutation;NOTCH1 gene;Neoplasms;Non-Hodgkin's Lymphoma;Oncogenic;Pathogenesis;Pathway interactions;Patients;Penetrance;Phenotype;Prednisone;Proliferating;Proteasome Inhibitor;Receptor Inhibition;Receptor Signaling;Recurrence;Refractory;Regimen;Regulation;Relapse;Reporting;Resistance;Role;Series;Signal Pathway;Signal Transduction;Therapeutic;Treatment Efficacy;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tyrosine Kinase Inhibitor;Ubiquitin;Up-Regulation;Vincristine;Xenograft procedure;aged;cancer cell;cell transformation;gain of function mutation;gamma secretase;genetic signature;in vivo;inhibitor;large cell Diffuse non-Hodgkin's lymphoma;mouse model;multicatalytic endopeptidase complex;novel;patient derived xenograft model;personalized therapeutic;programs;protein degradation;rituximab;scaffold;success;tumor;tumorigenesis;ubiquitin ligase;ubiquitin-protein ligase Role of KLHL6 inactivation in mature B-cell malignancies Project NarrativeThe completion of this proposal will lead to a better understanding of ubiquitin-based regulation of B-celllymphoma onset and progression. Defining the molecular mechanism that links ubiquitin signaling pathwaywith protein degradation and gene expression and establishing the importance of such regulation in cancerwill be critical for generating effective personalized therapeutic approaches. NCI 10744779 11/30/23 0:00 PA-20-185 5R01CA207513-08 5 R01 CA 207513 8 "JHAPPAN, CHAMELLI" 8/1/16 0:00 11/30/26 0:00 Molecular Oncogenesis Study Section[MONC] 10912061 "BUSINO, LUCA " Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 365625 NCI 225000 140625 Project SummaryDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma accounting forabout 32000 new cases per year and leading to death in over 40% of cases. This proposal seeks toinvestigate the biological significance of KLHL6 a gene mutated in mature B-cell cancers with DLBCLdisplaying the highest rate of mutations. KLHL6 assembles into a functional CULLIN-RING Ubiquitin ligase(CRL) complex and cancer-associated mutations inhibit KLHL6 interaction to CULLIN3 resulting in loss ofactivity to transfer ubiquitin chains. In this proposal we investigate KLHL6 as a master regulator and tumorsuppressor of the NOTCH signaling. An investigation of the cell autonomous and drug resistance in murinemodel of DLBCL as well as patient derived DLBLC xenotransplants will be pursed. Building up on our datathe central hypothesis of this proposal is that deregulation of the KLHL6 function is crucial to lymphomagenesisand impacts therapy. Thus we aim in modeling loss of Khll6 in a mouse model of DLBCL (Aim1) and we willstudy how impairment of the NOTCH pathway impacts the therapeutic efficacy of B-cell receptor inhibition inDLBCL (Aim2). Overall this proposal investigates the mechanisms of DLBCL pathogenesis and treatment. Theclinical success of proteasome inhibitors bortezomib and E3 ubiquitin ligase glues for the treatment ofhematologic diseases has made the Ubiquitin pathway a bona fide target for cancer therapeutics. Thusdefining how novel E3 ligases function at a molecular level and investigating their role in inflammation is criticalin order to develop more specific therapeutic avenues. 365625 +No NIH Category available Acetylmuramyl-Alanyl-Isoglutamine;Address;Affinity;Animal Model;Antibodies;Antigens;Applications Grants;Bacteria;Biochemical;Biological Models;CD47 gene;Cancer Model;Cancer Patient;Caring;Cell Wall;Cells;Chemicals;Chemosensitization;Clinic;Clinical;Clinical Research;Collaborations;Communication;Complement;Data;Development Plans;Disease;Drug Targeting;Eligibility Determination;Endopeptidases;Enterococcus;Environment;Enzymes;Foundations;Funding;Genetic;Glycopeptides;Glycoside Hydrolases;Goals;Health;Human;Hydrolase;Hydrolysis;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunologics;Immunotherapy;Intrinsic factor;K22 Award;KPC model;Knock-out;Laboratories;Malignant Neoplasms;Mediating;Methods;Microbe;Modeling;Molecular;Muramidase;Myelogenous;N-Acetylmuramoyl-L-alanine Amidase;Non-Small-Cell Lung Carcinoma;Orthologous Gene;Outcome;PTPRC gene;Patient-Focused Outcomes;Patients;Pattern;Peptidoglycan;Phagocytosis;Pharmaceutical Preparations;Phenotype;Polysaccharides;Population;Postdoctoral Fellow;Probiotics;Production;Proteins;Reporter;Research;Research Personnel;Residual state;Role;Science;Signal Transduction;T-Cell Activation;Tissues;Training;Work;antimicrobial;antimicrobial peptide;cancer immunotherapy;cancer therapy;cancer type;career;career development;checkpoint therapy;chemoproteomics;experimental study;gastrointestinal epithelium;gut microbiota;host-microbe interactions;immune checkpoint blockade;immunoregulation;improved;in vivo Model;insight;melanoma;member;microbial;microbial colonization;microbial host;microorganism;mouse model;next generation;oral supplementation;pancreatic ductal adenocarcinoma model;patient response;patient subsets;pre-clinical;precision oncology;rapid test;response;skill acquisition;skills;small molecule;synergism;targeted treatment;therapy outcome;tool;tool development;transgene expression;triple-negative invasive breast carcinoma;tumor;tumor immunology Augmenting cancer checkpoint immunotherapies via microbially-derived metabolites PROJECT NARRATIVECancer immunotherapies including checkpoint inhibitors have revolutionized the treatment of multiple cancertypes yet these drugs are only effective in a small subset of patients. Although specific members of the gutmicrobiota have been positively correlated with patient outcomes the mechanisms underlying these clinicalobservations remain largely unknown. Using a combination of chemical tools biochemical characterization andin vivo model systems this proposal will examine enzymatic mobilization of microbial glycans from the gut as acommon mechanism to prime host immune responses during checkpoint blockade with the goal of augmentingthe efficacy of current and next-generation checkpoint immunotherapies. NCI 10744766 11/28/23 0:00 PAR-21-128 5K22CA272915-02 5 K22 CA 272915 2 "JAKOWLEW, SONIA B" 1/1/23 0:00 12/31/25 0:00 ZCA1-RTRB-R(M1) 12193549 "GRIFFIN, MATTHEW EVERETT" Not Applicable 47 CHEMISTRY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF ARTS AND SCIENCES 926970001 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 398 Other Research-Related 2024 142625 NCI 132060 10565 PROJECT SUMMARY/ABSTRACTImmune checkpoint inhibitors (ICIs) have significantly improved long-term survival across diverse cancer typesincluding melanoma non-small cell lung cancer triple negative breast cancer and others. However ICI efficacyrelies on multiple cancer host and environmental variables and only a small fraction of patients will respond tothese antibody drugs. Methods to improve ICI responsiveness are therefore a highly desirable unmet clinicalneed. Human-associated microbes are critical regulators of host health and disease including cancer treatment.Clinical studies have shown that specific gut bacterial species correlate with improved patient outcomes of ICItherapy and colonization by these active microbes can directly elicit antitumor activity in preclinical animalmodels. These observations raise a fundamental question: what are the microbial mechanisms that dictate ICIefficacy? My previous work has demonstrated that a secreted bacterial peptidoglycan hydrolase is sufficient tobroadly improve ICI therapy in murine models of cancer. Moreover this phenotype could be recapitulated simplyby coadministration of a synthetic fragment that mimics the product of the peptidoglycan hydrolase. Thesefindings raise the exciting hypothesis that the production of microbial metabolites can directly improve ICIefficacy. The main objective of my proposal is to examine enzymatic mobilization of bacterial PG metabolites asa general mechanism of immune modulation during cancer ICI therapy. Aim 1 will explore host enzymes as newfactors that determine ICI efficacy. Aim 2 will produce chemical probes to discover ICI-activating bacterialenzymes. Aim 3 will examine PG mobilization as a broad-spectrum strategy to potentiate ICI response in newindications and against new checkpoint targets. To accomplish these goals I have built a broad andinterdisciplinary skill set from my graduate work in chemical tool development with Dr. Linda Hsieh-Wilson atCaltech and my postdoctoral work in host-microbial communication and cancer immunology with Dr. HowardHang at Scripps Research. To complement these strengths I have established collaborations with leaders in thefields of cancer immunotherapy and host-microbial interactions to provide training in new cancer model systemsand access to critical human-derived isolates which will greatly aid in my efforts to establish the generality andhuman relevance of PG mobilization during ICI treatment. In addition I have proposed a comprehensive careerdevelopment plan to address any residual gaps in my abilities to effectively manage a laboratory disseminateour findings and obtain independent funding. The acquisition of these skills during the K22 period will fuelprogress towards the completion of my proposal providing key preliminary data needed for my first NCI R01grant application. My scientific and career development enabled by the K22 award will help me to achieve mylong-term career goal to become a successful independent investigator at the intersection of host-microbialcommunication and cancer immunotherapy. Moreover these efforts may yield mechanistic insights andtranslational avenues to understand and augment differential ICI responses in the clinic. 142625 +No NIH Category available 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;Accounting;Adult;Age;Amino Acids;Animal Model;Biological Markers;Cancer Burden;Cancer Etiology;Carcinogen exposure;Carcinogens;Cause of Death;Cells;Cessation of life;Cigarette;Cigarette Smoker;Clinical Research;Consumption;Country;DNA;DNA Adduction;DNA Adducts;DNA Binding;DNA Damage;DNA biosynthesis;Dangerousness;Data;Development;Disease;Electronic cigarette;Esophagus;Evaluation;Exposure to;Female;Genes;Goals;Growth;Guanine;High-Risk Cancer;Human;International Agency for Research on Cancer;Label;Laboratories;Laboratory Animals;Link;Lung;Lung nodule;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Marketing;Mass Spectrum Analysis;Metabolic Activation;Metabolism;Methodology;Mutation;N'-nitrosonornicotine;Nitrosamines;Oral;Oral cavity;Persons;Predisposition;Preventive measure;Property;RNA;Rattus;Regulation;Research;Resolution;Risk;Sampling;Site;Smokeless Tobacco;Smoker;Source;Structure of parenchyma of lung;System;Techniques;Testing;Tissues;Tobacco;Tobacco Industry;Tobacco smoke;Tobacco use;Tobacco-Associated Carcinogen;Tobacco-Related Carcinoma;Uncertainty;Urine;Woman;Work;adduct;analytical method;biobank;biomarker development;cancer prevention;cancer risk;carcinogenesis;carcinogenicity;cigarette smoke;cigarette smoking;environmental tobacco smoke exposure;epidemiology study;exposure to cigarette smoke;genetic information;heated tobacco products;male;malignant mouth neoplasm;men;programs;smokeless tobacco user;specific biomarkers;tobacco control;tobacco exposure;tobacco products;tobacco user;urinary Metabolism of Carcinogenic Tobacco-Specific Nitrosamines Tobacco products are major causes of lung cancer and oral cavity cancer which together will kill more than140000 people in the U.S. in 2019. The goals of this project are to quantify metabolites and DNA damageoriginating from specific carcinogens in tobacco products and use this information to identify people who maybe particularly susceptible to their carcinogenic effects so that intensive cancer prevention efforts can beinitiated. NCI 10744764 11/8/23 0:00 PA-19-056 5R01CA081301-25 5 R01 CA 81301 25 "JOHNSON, RONALD L" 4/1/99 0:00 11/30/24 0:00 Cancer Etiology Study Section[CE] 1865674 "HECHT, STEPHEN S" Not Applicable 5 PATHOLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 472542 NCI 306846 165696 Lung cancer is the leading cause of cancer death in the U.S with 142670 deaths expected in 2019 90%caused by cigarette smoking. Worldwide there are 1 billion smokers and 1.6 million lung cancer deaths peryear. Smokeless tobacco a cause of oral cavity esophagus and pancreas cancer is another deadly tobaccoproduct. The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are among the most important carcinogens in tobacco products considered by theInternational Agency for Research on Cancer to be carcinogenic to humans. Here we extend our researchon NNN and NNK by developing new urinary biomarkers from interactions of their metabolites with amino acidsand DNA. We also propose unique new methodology which can determine which oral cell DNA adducts inaddition to those derived from tobacco-specific nitrosamines result from exposure to compounds in cigarettesmoke. This will be accomplished using high resolution DNA adductomics techniques to identify DNA adductsin oral cells of people who have smoked cigarettes containing [13C]-labelled tobacco. We will use our biomarkerand DNA adduct data to analyze oral cell DNA lung DNA and urine samples in our Lung Cancer andPulmonary Nodule Biorepository with the goal of using readily obtainable samples (e.g. oral cells or urine) topredict DNA adduct levels in smokers' lungs. The specific aims are:1. Develop human urinary biomarkers of NNN exposure based on interactions of its metabolites with amino acids. These will be the first metabolite biomarkers specific to exposure to this powerful oral cavitycarcinogen.2. Develop an analytical method for quantitation of 7-[4-(3-pyridyl)-4-hydroxybutyl]guanine (7-PHB-G) as a human urinary DNA/RNA adduct biomarker of tobacco-specific nitrosamine exposure plus metabolic activation. 7-PHB-G will be the first urinary biomarker of specific DNA adduct formation by NNN and NNK.3. Prepare cigarettes from specially grown fully [13C]-labelled tobacco and use high resolution mass spectrometry-based DNA adductomics techniques to specifically identify which oral cell DNA adducts originate from tobacco in people who smoke these cigarettes. This aim promises to resolve longstanding uncertainty about which DNA adducts result from cigarette smoke exposure.4. Compare tobacco-specific and tobacco-related DNA adduct formation in lung tissue and oral cells from cigarette smokers and relate to urinary biomarkers of tobacco exposure.These specific aims can result in new biomarkers of tobacco-related exposures and cancer risk and ultimatelytest our overall hypothesis that biomarkers combined with certain genetic information can identify thosetobacco users at highest risk for cancer so that effective preventive measures can be initiated. The biomarkersdeveloped in this program also have potential application in tobacco product evaluation and regulation. 472542 +No NIH Category available Address;Biochemical;Cell Lineage;Cell model;Cells;Cicatrix;Complex;Copy Number Polymorphism;DNA Damage;DNA Repair;Data;Development;Disease;Distal;Elements;Etiology;Event;Failure;Fibrosis;Functional disorder;Genomic Instability;Goals;Hepatic Stellate Cell;Hepatic Tissue;Hepatocyte;Human;Impairment;In Vitro;Knockout Mice;Knowledge;Length;Link;Liver;Liver Failure;Liver Fibrosis;Malignant neoplasm of liver;Methylation;Modeling;Molecular;Mutation;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Physiological;Positioning Attribute;Primary carcinoma of the liver cells;Process;Promoter Regions;Protocols documentation;RNA-Directed DNA Polymerase;Risk Factors;Role;Signal Pathway;Somatic Mutation;System;TP53 gene;Telomerase;Telomere Maintenance;Telomere Shortening;Time;cell growth regulation;cell injury;connective tissue growth factor;end stage liver disease;hepatocyte nuclear factor;human embryonic stem cell;human pluripotent stem cell;in vivo;liver function;loss of function mutation;molecular modeling;mutant;novel;paracrine;prevent;promoter;response;stellate cell;stem cell biology;stem cell differentiation;targeted treatment;telomere;tool;transcription factor Telomere dysfunction and telomerase reactivation in the etiology and progression of liver cancer NARRATIVEMutations in telomerase and telomere dysfunction are implicated in the pathogenesis of a growing number ofhuman disorders including end-stage liver disease and cancer. In this proposal we will determine the molecularmechanisms behind hepatic cell failure and transformation in settings of impaired telomerase and elucidate newpathways involved in the progression of this response after telomere damage. We will use a unique combinationof molecular and cellular models to significantly increase current knowledge on hepatocyte function andtransformation in settings of short telomeres DNA damage and mutant telomerase. NCI 10744736 11/7/23 0:00 PA-20-185 5R01CA258386-03 5 R01 CA 258386 3 "WITKIN, KEREN L" 12/13/21 0:00 11/30/26 0:00 Cancer Etiology Study Section[CE] 10972665 "BATISTA, LUIS FRANCISCO ZIRNBERGER" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 324253 NCI 205875 118378 PROJECT SUMMARY/ABSTRACT Mutations in telomerase and telomere attrition are major risk factors for liver fibrosis and its progressionto hepatocellular carcinoma (HCC). However due to a lack of adequate models and intrinsic difficulties instudying human telomerase in physiologically relevant cells the molecular mechanisms responsible for liverfibrosis and cancer in settings of DNA damage arising from short telomeres remain elusive. While telomeraseknockout mice corroborate the importance of telomere maintenance and DNA repair for liver function themolecular mechanisms that govern liver abnormalities in patients with damaged telomeres are still unknown.Likewise the specific signaling pathways that trigger failure of hepatic cells following telomere shortening andaccumulation of DNA damage remain to be determined. In addition mutations in the promoter region of thetelomerase reverse transcriptase component (TERT) have been described as the initial and most prevalentmutation in HCC. While these mutations have been shown to reactivate telomerase the functional relevance ofthis process during failure and transformation of hepatic cells has yet to be interrogated. The focus of this proposal is to use human pluripotent stem cells as a novel platform to understand thedetrimental effects of mutant telomerase telomere shortening and accumulation of DNA damage in differenthepatic cell lineages. We have previously generated isogenic hPSC lines harboring several disease-specificmutations in telomerase and have successfully derived telomerase-mutant human hepatocytes and hepaticstellate cells in vitro following established protocols that recapitulate the in vivo development of these lineages. Here two specific aims are proposed that utilize this platform to understand the molecular consequencesof telomere erosion DNA damage and telomerase impairment for the function of hepatic cells and to determinetheir role during early stages of transformation. In Aim 1 we will determine the role of telomere shortening andDNA damage accumulation during fibrotic failure of different hepatic cell lineages with impaired telomerase. Wewill determine the extent to which mitigation of DNA damage reactivation of HNF4 and modulation p53 preventfibrotic triggering in telomerase-mutant hepatocytes with variable telomere lengths. As liver fibrosis and itsprogression to HCC are multicellular responses we will determine the role of progressive telomere shorteningduring the direct and the paracrine fibrotic activation of hepatic stellate cells. In Aim 2 we will investigate themolecular consequences of mutations in the TERT promoter region during progression of HCC in settings ofexacerbated DNA damage due to eroded telomeres. Specifically we will analyze the biochemical and functionalconsequences of mutations in the TERT promoter region for hepatocyte function and immortalization. These studies will determine the molecular mechanisms of liver fibrosis and its progression to HCC insettings of mutant telomerase and DNA damage. Our unique tools combined with our expertise in telomeraseDNA repair and stem cell biology puts us in an ideal position to make a significant impact in this field. 324253 +No NIH Category available Affect;Area;Aryl Hydrocarbon Receptor;Automobile Driving;Biology;Cell membrane;Cells;Data;Detection;Distant;Elements;Enzymes;Family;Focal Adhesion Kinase 1;Focal Adhesions;G-Protein-Coupled Receptors;GTP-Binding Proteins;Genetic;Genetic Transcription;Goals;Guanosine;Guanosine Triphosphate;Guanosine Triphosphate Phosphohydrolases;Incidence;Inositol;Invaded;Kruppel-like transcription factors;Lesion;MDA MB 231;Malignant Neoplasms;Mediating;Mediator;Membrane;Metabolic;Metabolic Pathway;Metabolism;Metastatic breast cancer;Molecular;Monitor;Monomeric GTP-Binding Proteins;Mutation;Neoplasm Metastasis;Oncogenic;Organ;Oxidoreductase;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmacological Treatment;Physiological;Play;Prevention;Process;Production;Proteins;Regulation;Reporter;Reporting;Research;Role;Signal Transduction;Site;Stains;Structure;Supplementation;Testing;Therapeutic;Therapeutic Intervention;Transcriptional Regulation;Tumor Cell Invasion;Work;breast cancer progression;cancer cell;cancer invasiveness;cancer type;cell motility;design;experimental study;ezrin;gain of function;improved;in vivo;insight;loss of function;malignant breast neoplasm;mortality;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;pharmacologic;prevent;protein activation;rho GTP-Binding Proteins;sensor;small hairpin RNA;targeted treatment;transcription factor;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression;tumorigenesis;virtual Leveraging the GTP Biosynthetic Pathway for Anti-Tumor Therapies Triple negative breast cancer (TNBC characterized by lack of expression of ER PR and Her2) is one of themost aggressive and deadliest types of cancer with high incidence of metastatic progression. Despitesignificant progress the molecular mechanisms that lead to the acquisition of metastatic ability in cancer cellsare not fully elucidated. The aim of our proposed research is to identify novel metabolic vulnerabilities that canbe leveraged therapeutically to suppress TNBC invasiveness and metastasis. NCI 10744732 11/8/23 0:00 PA-19-056 5R37CA248018-04 5 R37 CA 248018 4 "SNYDERWINE, ELIZABETH G" 12/10/20 0:00 11/30/25 0:00 Tumor Progression and Metastasis Study Section[TPM] 11757957 "BIANCHI-SMIRAGLIA, ANNA " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 345207 NCI 213232 131975 Invasion is one of the most detrimental features of all cancers including breast cancer as it allows cells toescape the primary site and form metastases at distant organs. Despite progress in prevention and earlylesions detection the mortality associated with metastatic breast cancer is still extremely high. This isespecially true for patients presenting with triple negative breast cancer (TNBC characterized by lack ofexpression of ER PR and Her2 ) which is the most aggressive and deadliest subtype of breast cancer andthe one that so far lack specific targets for therapeutic intervention. Understanding the mechanisms thatfacilitate the invasion of tumor cells will enable us to design more efficient therapeutic strategies to prevent orreduce metastasis.Our group has established a fundamental connection between GTP metabolism and tumor cell invasiveness;we have unveiled GTP and its metabolic enzymes (GME) as key players in tumor progression and metastaticpotential. We have developed unique fluorescent reporters for intracellular GTP that have allowed us todetermine that in live cells the intracellular GTP distribution is not uniform and brought forward the hypothesisthat local concentration of GTP can influence GTP-dependent processes. In particular we have previouslyshown that genetic or pharmacological modulation of the GTP metabolic pathway deeply affected theactivation status of small GTPases of the RHO-family and with it the tumor cells' invasive capability. Thus inAim 1 we will explore a novel mechanism of G-proteins activation based on GME subcellular localization.Our preliminary results showed that the rate-limiting enzyme for GTP de novo production inositolmonophosphate dehydrogenase 2 (IMPDH2) enriches at cell membrane sites that are critical for cell migrationand invasion (namely focal adhesion FA and invadopodia). The role of IMPDH2 at these sites is virtuallyuncharacterized. Thus in Aim 2 we will assess the catalytic and structural role of IMPDH2 in FA andinvadopodia formation as well as in focal adhesion kinase (FAK)-directed oncogenic motility.The understanding of GTP metabolic enzymes transcriptional regulation is far from complete. Identification oftranscriptional master regulators of the GTP biosynthetic pathway that could be pharmacologically targetedwould offer a more efficient way of suppressing this pathway. Our preliminary results suggest that Kruppel-likefactor 9 (KLF9) and aryl hydrocarbon receptor (AHR) play antagonistic roles in the transcriptional regulation ofGTP metabolic enzymes with KLF9 suppressing whereas AHR inducing GTP production. Thus in Aim 3 wewill elucidate this regulation and explore pharmacological treatments to regulate the activity of thesetranscription factors. 345207 +No NIH Category available Acceleration;Adenocarcinoma Cell;Age;Binding;Blood Vessels;Breast Cancer Model;Breast Cancer Patient;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Model;Cell Death;Cells;Cessation of life;Childbirth;Complex;Data;Data Set;Development;Diagnosis;Distant Metastasis;Ductal Carcinoma;Ductal Epithelial Cell;Future;Genomics;Goals;Grant;Immune;Immune Evasion;Immune Tolerance;Immune system;Immunosuppression;Immunotherapy;In Vitro;Integrins;Intercellular Junctions;Invaded;Knowledge;Laboratories;Link;Lymphangiogenesis;Lymphatic;Lymphatic Endothelial Cells;Macrophage;Malignant Neoplasms;Mammary gland;Mediating;Meditation;Mentors;Mining;Modeling;Monoclonal Antibodies;Myeloid Cells;Neoplasm Metastasis;Nulliparity;PD-1 blockade;Pancreatic Ductal Adenocarcinoma;Pancreatic Ductal Carcinoma;Pancreatic carcinoma;Pancreatic duct;Patients;Postdoctoral Fellow;Probability;Prognosis;Proliferating;Proteins;Proteomics;Recurrence;Renal Cell Carcinoma;Renal carcinoma;Research;Research Training;Resistance;Semaphorins;Signal Transduction;Signaling Molecule;T cell infiltration;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Tumor Cell Invasion;Tumor Cell Migration;Tumor Immunity;Tumor Promotion;Tumor-associated macrophages;Tumor-infiltrating immune cells;Woman;Work;angiogenesis;anti-tumor immune response;breast cancer diagnosis;breast cancer progression;career;density;design;experience;immune cell infiltrate;immunosuppressive macrophages;improved;insight;intercalation;interest;lymphatic vessel;malignant breast neoplasm;mouse model;neoplastic cell;novel;pancreatic ductal adenocarcinoma cell;podoplanin;postpartum breast cancer;pre-clinical;prevent;programmed cell death ligand 1;programmed cell death protein 1;recruit;reproductive;skills;targeted treatment;tumor;tumor growth;tumor heterogeneity;tumor immunology;tumor microenvironment;tumor progression;tumor-immune system interactions Discerning mechanisms of semaphorin 7A-mediated tumor progression via immunoevasion Project NarrativeWe have shown that SEMA7A promotes multiple aspects of breast cancer progression including proliferationsurvival invasion and immune evasion. The F99 portion of this proposal (Aim 1) aims to investigate SEMA7A-mediated alterations to TAMs and T cells in the TME responsible for suppressing anti-tumor immunity and iftargeting SEMA7A directly can impede tumor growth and immunoevasion. The K00 aspect of this application(Aim 2) proposes to identify novel mechanisms of immunoevasion in renal cell carcinoma and pancreaticductal carcinoma which may reveal novel targets for treatment to prevent metastases and prolong patientsurvival. NCI 10744585 8/15/23 0:00 RFA-CA-22-041 1F99CA284276-01 1 F99 CA 284276 1 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 12346407 "ELDER, ALAN MICHAEL" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 36666 NCI 36666 0 ProjectWeSummary/Abstracthave identified that semaphorin 7a (SEMA7A)a signaling molecule that activates integrin-1 signaling incanceris upregulated in postpartum breast cancer (PPBC) and is associated with increased lymphaticvesseldensity (LVD) tumor-associated macrophages (TAMs) and metastasis. Additionally SEMA7A+ tumorsrecapitulate the accelerated tumor progression observed in PPBC and high SEMA7A expression correlates withdecreased survival. As such PPBCs likely only represent a subset of SEMA7A+ cancers; there are currently notherapies targeting SEMA7A.cellareSEMA7A+BCSEMA7A+ breast cancers exemplify four key hallmarks of cancer: 1) resistance todeath 2) angiogenesis and lymphangiogenesis 3) immune evasion and 4) invasion and metastasis; TAMsimplicated n each and in creating a pro-tumor microenvironment (TME). As TAMs and LVD are amplified in it is probable that they contribute to the worse prognosis of PPBC.the F99 portion of this grant my goalsiIn are to: 1) investigate SEMA7A-mediated alterations immunecells of the TME in relation to mechanisms of antitumor immunity 2) dissect SEMA7A-induced mechanisms thatgovern tumor cell migration and 3) determine if monoclonal antibody-induced inhibition of SEMA7A impedestumor growth and immune suppression. I will define the mechanisms of SEMA7A-induced effects on immunecells of the TME that promote immunoevasion. I will also establish whether monoclonal antibody-inducedinhibition of SEMA7A impedes tumor growth and immune suppression. The results of these studies will identifyhow SEMA7A promotes tumor progression immunosuppression and lymphatic-meditated metastasis as wellas offer insight for future therapies to target SEMA7A+ breast cancers and provide insight to mechanisms ofimmunoevasion in similar cancers such as (PDAC) and advanced stage renal cell carcinomas (RCC).RCCtoendureimmunotherapyexpertiseimmuneprogressthe K00 portion of this grant will expand my interest in mechanisms of immunoevasion to PDAC andwhich are highly aggressive cancers with elevated tumor heterogeneity therapy resistance and resistance antitumor immune responses. The mechanisms by which PDAC and RCC evade the immune system andimmunotherapy remain to be discovered. I propose to identify novel mechanisms of immunoevasion andresistance in PDAC and RCC with an initial focus on SEMA7A. I will seek K00 laboratories with in tumor immunology immunotherapy ex vivo models and knowledge of dysregulated signaling withincells. These studies will provide crucial insight into how highly aggressive tumors like PDAC and RCCresulting in dismal prognoses and identify potential cells and mechanisms for future immunotherapies.In I 36666 +No NIH Category available Alanine;Anatomy;Animal Model;Animals;Area;Biochemical;Biological Markers;Biology;Cancer Center;Cancer Detection;Cancer Etiology;Cessation of life;Clinical;Contrast Media;Cyst;Data Analyses;Detection;Development;Diagnosis;Disease;Disease Progression;Doctor of Medicine;Doctor of Philosophy;Early Diagnosis;Educational process of instructing;Fellowship;Future;Genetic Models;Genetically Engineered Mouse;Genomics;Goals;Histological Techniques;Image;Imaging Techniques;Immunoprevention;Immunotherapy;Indolent;Inflammation;Institution;Laboratories;Learning;Lesion;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mentors;Metabolic;Metabolism;Methodology;Methods;Modality;Modeling;Monitor;Morphology;Non-Invasive Detection;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pattern;Phase;Positron-Emission Tomography;Postdoctoral Fellow;Prevalence;Prevention;Prevention Measures;Prevention strategy;Production;Public Speaking;Pyruvate;Recommendation;Research;Research Project Grants;Research Proposals;Scientist;Sensitivity and Specificity;Signal Transduction;Specificity;Survival Rate;Symptoms;Techniques;Time;Tissues;Training;Translating;United States;Warburg Effect;Work;Writing;cancer imaging;cancer prevention;cancer type;chronic pancreatitis;detection method;efficacy evaluation;efficacy testing;extracellular;high risk;human subject;imaging approach;imaging modality;imaging system;in vivo;in vivo imaging;innovation;metabolic imaging;metabolomics;molecular imaging;mouse model;neoplastic;non-invasive imaging;non-invasive monitor;novel;overtreatment;pancreatic cancer model;pancreatic ductal adenocarcinoma model;pre-clinical;premalignant;prevent;skills;specific biomarkers;success;tool;transcriptomics;tumor;tumor microenvironment Real Time Metabolic Imaging to Interrogate Early Detection and Prevention of Pancreatic Cancer Project Narrative Early detection of pancreatic cancer is one of the foremost priorities of the NCI. The overarching goal ofthis F99/K00 proposal is to develop the capability of non-invasively detecting advanced pancreatic intraepithelialneoplasia (PanIN) precursor lesions in pancreas prior to invasive disease using two magnetic resonance imagingbased tools: a) hyperpolarized metabolic imaging (HP MRI) and b) acidoCEST MRI and test the efficacy ofimmunoprevention in animal models employing these techniqies. The success of this proposal has the potentialfor leading to practice changing recommendations for non-invasively detecting and monitoring advanced PanINlesions and incipient pancreatic cancer as well as to prevent over-diagnosis and over-treatment in cysts thatharbor indolent biology. NCI 10744576 8/25/23 0:00 RFA-CA-22-041 1F99CA284365-01 1 F99 CA 284365 1 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 12563626 "ENRIQUEZ, JOSE S" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 37180 NCI 37180 0 Project Summary Pancreatic ductal adenocarcinoma (PDAC) has a median 5-year survival of only 11% and earlydiagnosis of PDAC is recognized as one of the highest priority areas by the NCI with a focus on identification ofmore sensitive and specific biomarkers and imaging strategies in discernible preneoplastic lesions. Theoverarching goal of this proposal is to develop the capability of non-invasively detecting advanced pancreaticintraepithelial neoplasia (PanIN) precursor lesions in pancreas prior to invasive disease in human subjects usingtwo magnetic resonance imaging-based tools: a) hyperpolarized metabolic imaging (HP MR) and b) acidoCESTMRI. Hyperpolarization increases the signal of conventional MRI by over 10000-fold. AcidoCEST MRI uses aclinically approved contrast agent to quantitatively measure the extracellular pH (pHe) in the tumormicroenvironment. The application of dual acidoCEST and HP MR is innovative as they interrogate two differentbut related biochemical features of PanINs: extracellular pH (pHe) and dynamic metabolic flux (HP lactate-to-pyruvate and HP alanine-to-pyruvate ratios) respectively. Together this approach provides an excitingopportunity to identify and understand early metabolic aberrations and biomarkers associated with these earlylesions to enable detection of advanced pancreatic preneoplastic lesions as well as pancreatic cancer at thesmallest size for which no methods of detection currently exist. This is a transitional research proposal with multiple sponsors for the F99 phase. Including thelaboratories of Pratip Bhattacharya Ph.D. in the Department of Cancer Systems Imaging and FlorenciaMcAllister M.D. in the Department of Clinical Cancer Prevention both at MD Anderson Cancer Center with thefollowing two aims. Aim 1 the F99 phase is to demonstrate and validate the sensitivity and specificity of dynamichyperpolarized metabolic biomarkers in the detection and monitoring the progression of pancreatic premalignantlesions to PDAC and compare these to a chronic pancreatitis model. Aim 2 the K00 phase research directionis to demonstrate detection of PanIN with a combination of HP MR and acidoCEST and to determine the efficacyof immunoprevention on PanIN models. The success of this proposal has the potential for leading to practicechanging recommendations for non-invasively detecting and monitoring advanced PanIN lesions and incipientpancreatic cancer as well as to non-invasively assess the immunopreventive measures for cancer prevention. Also included in this proposal is a fellowship training plan to be conducted in both the F99 and K00phases. They include additional training in metabolomic data analysis research skills in small animal handlinghistological and imaging techniques public speaking and scientific writing during the F99 phase. For the K00phase the training plan include establishing dual-imaging modalities develop immunopreventative strategiesmentoring and teaching future scientists and inter-departmental or institutional networking. 37180 +No NIH Category available Address;Affect;African American;African ancestry;Biological;Biological Factors;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Categories;Cells;Cessation of life;Collection;Data;Databases;Diagnosis;Diglycerides;Disease;Disease Progression;Disparity;Distant Metastasis;Epithelium;Etiology;European;Event;Exhibits;Foundations;Gene Expression;Generations;Genes;Genetic;Genetic Engineering;Genetic Transcription;Genetically Engineered Mouse;Gleason Grade for Prostate Cancer;Goals;Growth;Human;Human Resources;Hyperactivity;Immune;Immunocompetent;Immunohistochemistry;Impairment;Implant;Incidence;Inflammation Mediators;Inflammatory;Intrinsic factor;Invaded;Malignant neoplasm of prostate;Mediating;Mediator;Mesenchymal;Metastatic/Recurrent;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;Oncogenic;Organoids;Outcome;Pathway interactions;Phenotype;Phosphotransferases;Play;Population;Primary Neoplasm;Production;Prostatic Neoplasms;Protein Kinase C;RNA Interference;Race;Recurrent disease;Refractory;Regulation;Research Design;Resources;Role;Shapes;Signal Pathway;Signal Transduction;Socioeconomic Factors;Stains;Testing;Time;Tumor-infiltrating immune cells;Variant;cancer cell;cancer health disparity;castration resistant prostate cancer;cohort;cytokine;early onset;epithelial to mesenchymal transition;in vivo;insight;lifestyle factors;men;mortality;mouse model;neoplastic cell;novel marker;outcome disparities;overexpression;patient derived xenograft model;pharmacologic;programs;prostate cancer cell;prostate cancer cell line;prostate cancer model;prostate cancer progression;prostate carcinogenesis;racial difference;racial disparity;racial diversity;racial population;therapeutic target;transcriptome;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumorigenesis;tumorigenic Protein kinase C signaling in prostate cancer health disparities NARRATIVE The main goal in this application is to establish whether the PKCa signaling pathway contributes to outcomedisparities observed in PCa in AA men. Our studies identified the kinase PKCa as an essential player in prostatecancer cell growth tumorigenesis and invasion. We speculate that cancer cell PKCa plays a major role in theregulation of cytokine production and tumor immune cell populations which contributes to PCa racial disparities.1 NCI 10744533 6/8/23 0:00 PAR-21-322 1R01CA276082-01A1 1 R01 CA 276082 1 A1 "GRIL, BRUNILDE M" 6/8/23 0:00 5/31/28 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 1878620 "KAZANIETZ, MARCELO G." Not Applicable 3 PHARMACOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 6/8/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 488027 NCI 300324 187703 ABSTRACT Prostate cancer (PCa) the second leading cause of cancer-related deaths among men in the USdisproportionally affects men of African American (AA) descent who exhibit greater incidence faster diseaseprogression and higher rate of mortality than men of European descent (EA). AA men are more likely to presenthigh-grade disease and distant metastasis at the time of diagnosis. The drivers of this disparity are multifactorialand include socioeconomic lifestyle and biological factors. Current evidence suggests genetic alterations - suchas changes in oncogenic and tumor suppressive genes associated with PCa progression - and the presence ofa more inflammatory tumor microenvironment (TME) in prostate tumors from men of African descent as majorunderlying causes of this racial disparity. However there is still a limited understanding of the molecular/signalingfoundations behind the racial differences in PCa. Here we identified the diacylglycerol-regulated kinase PKCaas a potential contributor towards racial disparities in PCa. We found PKCa to be aberrantly overexpressed inaggressive PCa cell lines as well as in human PCa. Interestingly silencing PKCa expression from PCa cellsimpairs their invasive capacity as well as their ability to form tumors in mice. An in-depth RNA-Seq transcriptomeanalysis integrated with existing database inquires established PKCa as a crucial determinant for the expressionof cytokines known to be dysregulated in prostate tumors from AA men. Most remarkably expression analysisin patient-derived xenografts (PDXs) revealed higher PKCa levels in AA relative to EA prostate tumors whichassociates with the expression of epithelial-to-mesenchymal transition (EMT) markers. This led us to hypothesizethat excessive activation of PKCa signaling may contribute to racial disparities in PCa. In Aim 1 we will takeadvantage of a large collection of primary and metastatic human PCa tumors both from AA and EA men to testthe hypothesis that there is disproportionate PKCa expression and/or activation in AA PCa. We will establishpotential correlations with Gleason score disease recurrence and metastatic disease in the available cohorts ofAA and EA prostate tumors. In Aim 2 we will use both genetically engineered and syngeneic models towards thegoal of establishing the in vivo functional relevance of PKCa in prostate tumorigenesis and metastasis. Racial-related cell/tumor growth differences will be established using EA vs. AA PDXs and organoids derived from theseracially diverse set of PDXs. In Aim 3 we will pursue a thorough profiling of immune cell populations and cytokineexpression in mouse prostate tumors upon inducible silencing of PKCa. Transcriptome signatures will beestablished both in mouse models as well as in EA vs. AA PDXs to identify racial differences in PKCa-drivengene expression. This will provide a comprehensive perspective on how tumor cell PKCa contributes to thegeneration of a pro-inflammatory tumorigenic state and an immunosuppressive landscape and unearthassociated differences based on racial distinction. Our studies should provide exceptionally valuable informationon the oncogenic and metastatic pathways leading to racial disparities in PCa. 488027 +No NIH Category available Address;Adopted;Attention;Back;Behavior;Binding;Bypass;Cancer Model;Cancerous;Cell Differentiation process;Cell Fraction;Cell Reprogramming;Cell Separation;Cells;DNA Binding Domain;Diagnosis;Disease;Early Diagnosis;Ectoderm;Endoderm;Engineering;Epigenetic Process;Epithelial Cells;Epithelium;Event;Fibroblasts;Frequencies;Generations;Genes;Genetic Transcription;Genomics;Human;Human Development;Immune;Investigation;Lead;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Mammalian Oviducts;Mammary Gland Parenchyma;Maps;Mediating;Mesoderm;Modeling;Molecular;Motor Neurons;Mus;Mutate;Mutation;Neoplasm Metastasis;Neurons;Oncogenes;Oncogenic;Organism;Organoids;Outcome;Patient-Focused Outcomes;Phase;Phenotype;Pluripotent Stem Cells;Point Mutation;Postdoctoral Fellow;Process;Proliferating;Proteins;Regulation;Reporter;Reporting;Research;Role;Sampling;Skin;Somatic Cell;Stains;Synthetic Genes;System;TP53 gene;Therapeutic;Tissues;Tumor Suppressor Proteins;Work;cancer initiation;carcinogenesis;cell type;design;effective therapy;enhancing factor;gain of function;improved;induced pluripotent stem cell;mutant;overexpression;prevent;programs;sensor;small hairpin RNA;stem cell differentiation;stem cell fate;stem cell fate specification;stem cells;success;targeted treatment;three-dimensional modeling;transcription factor;trend;tumor;tumor initiation;tumor progression;tumorigenesis Mapping p53 dynamics to cell-fate outcomes in reprogramming and oncogenesis Project NarrativeThe objective of this proposal is to understand the role of the tumor suppressor protein p53 in aiding cell fatetransitions including cancer. As p53 mutants dominate the mutational landscape of cancer it is important tounderstand what functions of normal p53 are co-opted and enhanced by mutants to promote cell fatetransitions in order to establish effective therapies that target cells harboring these oncogenes. By studying therole of p53 and p53 mutants during transitions this work will shed light on early-stage cancers aiding early-detection of the disease and improving patient outcomes. NCI 10744532 8/11/23 0:00 RFA-CA-22-041 1F99CA284280-01 1 F99 CA 284280 1 "ODEH, HANA M" 8/11/23 0:00 7/31/25 0:00 ZCA1-RPRB-7(M1) 78672260 "BEITZ, ADAM MATTHEW" Not Applicable 7 ENGINEERING (ALL TYPES) 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA BIOMED ENGR/COL ENGR/ENGR STA 21421029 UNITED STATES N 8/11/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 Project Summary Cell fates are decided as an organism develops. In human development pluripotent stem cellsdifferentiate into the three layers of ectoderm mesoderm and endoderm. These classes of tissue furtherdifferentiate into specific cell types with specific functions including neurons immune cells and skin cells. Theseidentities are stable; once a cell differentiates into its final state it will not revert back to a stem cell state nor willit transform into another cell type. A skin cell will not spontaneously become a neuron even if the neuron isdamaged. However Takahashi and Yamanaka demonstrated that cells have the potential to revert back to astem cell fate when they reprogrammed mouse fibroblasts into induced pluripotent stem cells (iPSCs) by forcedoverexpression of stem cell-specifying transcription factors. In 2010 Vierbuchen and colleagues demonstratedthat fibroblasts could be reprogrammed directly to neurons using neuron-specific transcription factors bypassingthe need for an iPSC-intermediate. However reprogramming efficiencies in each of these systems was low; veryfew cells are actually capable of changing their cellular identity. In 2019 Babos and Galloway greatly improve reprogramming efficiencies in direct motor neuronreprogramming demonstrating improved reprogramming yields 100 times greater than the original process.They drew upon factors that enhanced another cell fate transition: cancer. Genes that promote a healthy cellstransition to cancer also improved the ability of a cell to change its cell type. Thus reprogramming can serve asa model of cancer initiation. By understanding the molecular mechanisms by which these oncogenes promotereprogramming we can understand how oncogenes evade cellular barriers to cancer and establish tumors.In the F99-phase of the proposed research I will investigate the role of the tumor suppressor protein p53 inoncogene-mediated reprogramming. p53 is the most frequently mutated gene in cancer. Rather than p53expression being lost in cancer it is most often mutated to create a protein unable to perform its designatedfunctions and accumulates to abnormally high levels. As a synthetic biologist I will design synthetic gene circuitsthat track and report p53 levels during reprogramming. I will isolate cells that accumulate p53 and investigatetheir ability to reprogram. In the K00-phase of the proposed research I will extend my investigations of p53 to three-dimensionalmodels of ovarian cancer. Ovarian cancer is often diagnosed at late stages after the cancer has metastasizedleading to poor patient outcomes. 3D models of tumor initiation can shed light on the early stages of ovariancancer and enable clinicians to catch the cancer early when the disease is most easily treated. By inducingcancer initiation in 3D models of ovarian cancer and tracking cancer progression using p53-sensors I will identifythe drivers of tumor establishment and factors associated with early-stage disease. 49194 +No NIH Category available Alternative Splicing;Award;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Cancer Biology;Cell Cycle Regulation;Cell Line;Cell physiology;Cells;Characteristics;Data;Data Analyses;Data Set;Diagnostic or Prognostic Factor;Disease;Endocrine;Estrogen Receptor alpha;Estrogen receptor positive;Fellowship;Foundations;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Glioblastoma;Goals;Human;Impairment;Invaded;Knowledge;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of lung;Mammary Neoplasms;Mass Spectrum Analysis;Modeling;Molecular;Motivation;Mutate;NF1 gene;Neoplasm Metastasis;Nuclear;Nuclear Protein;Outcome;Pathway interactions;Phase;Play;Post-Transcriptional Regulation;Postdoctoral Fellow;Process;Prognosis;Proliferating;Protein Isoforms;Proteins;RNA;RNA Binding;RNA Splicing;RNA-Binding Proteins;RNA-Protein Interaction;Rattus;Regulation;Research;Research Personnel;Resistance;Role;Selective Estrogen Receptor Modulators;Signal Transduction;Spliced Genes;Spliceosomes;Techniques;Tertiary Protein Structure;Therapeutic;Therapeutic Intervention;Training;Transcript;Transcription Process;Transcriptional Regulation;Tumor Suppressor Genes;biological adaptation to stress;breast cancer progression;career;crosslink;efficacy evaluation;environmental stressor;epigenomics;fitness;fluorescence imaging;genetic corepressor;in vivo;inhibitor;leukemia;loss of function;loss of function mutation;malignant breast neoplasm;mutant;next generation sequencing;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;overexpression;posttranscriptional;response;skills;therapy resistant;transcriptomics;tumor progression Impact of neurofibromin on ER-alpha and nuclear speck post-transcriptional gene regulation PROJECT NARRATIVEGermline and sporadic loss of function mutations in the tumor suppressor gene NF1 drives a subset of breastcancer with increased metastatic potential endocrine resistance and dismal outcomes in disease. Here Ipropose to study the mechanisms in which loss of neurofibromin-ER interaction contributes to this aggressivesubtype of breast cancers in order to identify tractable therapeutic options while receiving new training in nextgeneration sequencing and analysis along with comprehensive analysis of cancer datasets. In the next phaseof my career I will build upon this foundation of knowledge to expand my discoveries in identifying novelfunctions of NF1 and its role in cancer progression. NCI 10744501 8/15/23 0:00 RFA-CA-22-041 1F99CA284282-01 1 F99 CA 284282 1 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 77981935 "DISCHINGER, PATRICK " Not Applicable 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 48194 NCI 48194 0 PROJECT SUMMARY Alternative splicing (AS) of transcripts is an essential post-transcriptional process that is instrumentalfor numerous cell functions including proliferation differentiation and survival. The process of AS is regulatedby RNA binding proteins (RBPs) and their proper nuclear localization and interactions with spliceosomecomponents which form visibly dense compartments called nuclear specks (NS). The ability for cancer tohijack and utilize AS by targeting genes involved in EMT invasion cell cycle regulation and transcriptionalcontrol has been described to influence metastatic potential and therapeutic resistance. More recently it hasbeen shown that 50% of breast cancers contain overexpression or amplification of at least one RBP whichconsequently targets gene transcripts for AS to induce invasive characteristics. Furthermore a novel functionof estrogen receptor alpha (ER) recently revealed non-canonical RNA binding of ER to influence post-transcriptional regulation and promote cell fitness in response to environmental stressors. Our laboratoryalong with other recently established a critical link between NF1 and ER in regulation of ER signaling. NF1is a tumor suppressor gene encoding for the protein neurofibromin that when mutated drives of a subset ofbreast cancers with poor prognosis. These studies have sparked motivation to investigate mechanisms inwhich NF1-deficient breast cancers contribute to metastasis and endocrine resistance. The interaction between neurofibromin and ER describes neurofibromins ability to act as a co-repressor of ERs transcriptional activity. However it still remains unknown whether this neurofibromin-ERinteraction regulates ERs post-transcriptional regulation or the importance of neurofibromin localization forthis regulation. The overall goal of my F99 training phase (Aim 1) is to determine the role neurofibromin playsin ER post-transcriptional regulation. Specifically the Aims are 1.1) to define neurofibromins impact on ERdependent post-transcriptional regulation in NF1 mutant ER+ breast cancer models and 1.2) determine theefficacy of selective estrogen receptor modulators (SERMs) to impact ER post-transcriptional regulation inNF1-deficient cells. The training objectives in the F99 phase will expand my molecular techniques sequencingand data analysis in cancer biology. During my K00 phase (Aim 2) I will define the impact nuclearneurofibromin has on post-transcriptional regulation through nuclear speck formation and function. NF1-deficient breast cancer models will be used to determine nuclear speck formation composition and post-transcriptional and gene regulation. The training and data resulting from this fellowship award will establish thefoundation of scientific and professional skills for my career as an independent researcher. 48194 +No NIH Category available ABCG2 gene;Affect;Angiogenesis Inhibitors;Area;Ascites;Autocrine Communication;Award;Cancer Patient;Caring;Cells;Cellular Metabolic Process;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Complex;Conditioned Culture Media;Cytotoxic Chemotherapy;Databases;Defense Mechanisms;Development;Disease;Disease Resistance;Doxorubicin;Epithelium;FRAP1 gene;Family;Gene Expression;Genetic;Genomic approach;Grant;Human;Hypoxia;Hypoxia Inducible Factor;Hypoxia-Responsive Elements;Interleukin-6;Knowledge;LIF gene;LIFR gene;Link;MAP Kinase Gene;Maintenance Therapy;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mediating;Mesenchymal;Normal tissue morphology;Operative Surgical Procedures;Organoids;Ovarian;Pathway interactions;Patients;Phase;Proliferating;Proto-Oncogene Proteins c-akt;Publishing;Recurrence;Recurrent Malignant Neoplasm;Research;Research Personnel;Resistance;Resistance development;Role;STAT3 gene;Serous;Signal Pathway;Signal Transduction;Stress;Testing;Therapeutic;Training;Tumor Tissue;United States;Xenograft Model;autocrine;cancer cell;cancer recurrence;cancer stem cell;cancer therapy;career;cell growth;chemotherapy;clinically relevant;cytokine;experience;glycoprotein 130;inhibitor;member;mortality;mouse model;new therapeutic target;prevent;promoter;response;standard of care;stemness;targeted treatment;therapy resistant;treatment response;tumor;tumor hypoxia;tumor microenvironment;tumor progression;vasculogenesis Targeting chemotherapy resistant high grade serous ovarian cancer Project Narrative:The most lethal gynecologic malignancy in the US is ovarian cancer (OCa). Currently accepted standards ofcare for serous OCa patients include surgery and cytotoxic therapy. However about 90% experience recurrenceand eventually pass away from a disease that is chemo-resistant. This proposal aims to establish the significanceof LIF/LIFR signaling in hypoxia-driven OCa therapy resistance and identify the mechanisms through which LIFRautocrine signaling contribute to chemotherapy resistance of serous OCa. The study has clinical relevance sinceit will clarify the role of the LIFR axis in the resistance to antiangiogenic therapy and chemotherapy in OCa andidentify LIFR as a novel therapeutic target for the treatment of OCa. This F99/K00 award will also give me neededtraining for my academic career as a cancer researcher. NCI 10744479 8/16/23 0:00 RFA-CA-22-041 1F99CA284284-01 1 F99 CA 284284 1 "ELJANNE, MARIAM" 8/16/23 0:00 7/31/25 0:00 ZCA1-RPRB-7(M1) 78862533 "EBRAHIMI, BEHNAM " Not Applicable 20 OBSTETRICS & GYNECOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/16/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 36520 NCI 36520 0 Project SummaryOf all gynecologic cancers ovarian cancer (OCa) has the highest mortality rate in the US. Patients with serousOCa respond to current treatments including cytotoxic therapy and surgery. But about 90% of patients haverecurrence and they inevitably pass away from a disease that is chemoresistant. Leukemia inhibitory factor(LIF) a cytokine that belongs to the interleukin-6 family and it signals through the glycoprotein 130 (gp130) andLIFR complex. My preliminary research using tumor online data bases revealed that LIF is strongly expressedin OCa compared to normal tissues and expression levels of LIF and LIFR were significantly greater inchemotherapy non-responders as compared to responders. Further my analyses of conditioned medium andcell lysates collected form 18 different OCa cells confirmed existence of autocrine loops of LIF and LIFR inOCa. However the mechanisms and therapeutic utility of targeting LIFR axis to treat chemotherapy resistanceremain unknown representing a major knowledge gap and this premise will be tested in F99 phase. In F99phase I will test the hypothesis that disruption of LIF/LIFR signaling will sensitize resistant cells tochemotherapy and maintenance therapy with LIFR inhibitor will delay chemotherapy resistance.Specifically I will establish the significance and mechanisms of LIFR axis in promoting chemotherapyresistance in serous OCa cells using CRISPR KO and global genomic approaches. I will test the utility of LIFRinhibitor EC359 in treating/preventing development of chemotherapy resistance using patient derivedorganoid (PDO) and xenograft (PDX) models. The hypoxic circumstances that bigger tumors experiencedecrease chemotherapy response and are exacerbated by ascites. Hypoxia inducible factors (HIFs)are activated by cancer cells to stimulate vasculogenesis control cell metabolism and promote cellgrowth as a defense mechanism against hypoxic stress. Moreover hypoxia transactivates two functionalhypoxia responsive elements within LIF promoter and induces LIF expression. There is a relationship betweenOCa Stem Cells (CSCs) and tumor chemoresistance and recurrence. Antiangiogenic treatment resistance andchemoresistance of ovarian CSCs are both influenced by hypoxia. Together these recent findings implythat the hypoxic tumor microenvironment increases the expression of HIFs LIF and efflux transporters aswell as development of chemoresistance in CSCs. In the K00 phase I will expand my training into the area ofhypoxia mediated stemness epithelial mesenchymal transition (EMT) and therapy resistance. Specifically Iwill define the mechanisms by which hypoxia and LIF/LIFR axis induce EMT and stemness and establish thesignificance of hypoxia-LIF/LIFR axis in the development of OCa resistance to targeted therapy. The proposedresearch in F99/K00 is clinically important because it will define the significance of LIFR axis in OCaprogression chemotherapy and antiangiogenic therapy resistance and establish LIFR as a novel therapeutictarget for the treatment of OCa. 36520 +No NIH Category available Adoptive Transfer;Antigen Receptors;Antigen Targeting;Antigens;Antitumor Response;Autoimmune Diseases;CAR T cell therapy;CCR5 gene;CXCR6 gene;Cell Survival;Cells;Clinic;Colon;Colon Carcinoma;Cytokine Receptors;Drug or chemical Tissue Distribution;Effector Cell;Flow Cytometry;HIF1A gene;Image;Immune;Immunomodulators;Immunosuppression;Immunotherapy;Infiltration;Interferon Type II;Interleukin-12;Interleukin-2;Investigation;Kinetics;Leukocytes;Liquid substance;MC38;MHC Class I Genes;Macrophage;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Metastatic Melanoma;Methods;Modeling;Molecular;Myeloid Cells;Natural Killer Cells;Nature;Pathway Analysis;Peptide/MHC Complex;Peripheral;Population;Race;Regulatory T-Lymphocyte;Reporting;Role;Safety;Solid;Solid Neoplasm;Spatial Distribution;T-Lymphocyte;Testing;Tissues;Toxic effect;Tumor Immunity;Tumor-associated macrophages;anti-tumor immune response;cancer immunotherapy;cancer therapy;chemokine receptor;chimeric antigen receptor;chimeric antigen receptor T cells;clinical translation;cytokine;delivery vehicle;draining lymph node;effector T cell;immunogenic;improved;in vivo;luminescence;lung metastatic;mouse model;neoantigens;neoplastic cell;novel;perforin;recruit;trafficking;transcriptomics;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Activating Native Tumor Immunity with IL-33 Armored CARs NarrativeChimeric antigen receptor (CAR) T cell immunotherapies have little effect in the treatment of solid cancers dueto the tumors immunosuppressive microenvironment. We recently developed CAR T cells as delivery vehiclesfor immune modulators that neutralize immunosuppression and activate broad anti-tumor immune responses.Our strategy is effective with multiple CARs targeting different tumor types thereby supporting its potential as auniversal CAR T cell platform for solid cancer treatment. NCI 10744438 5/17/23 0:00 PA-20-185 1R01CA271553-01A1 1 R01 CA 271553 1 A1 "HU, ZHANG-ZHI" 6/1/23 0:00 5/31/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 9278084 "HUANG, YINA HSING" Not Applicable 2 MICROBIOLOGY/IMMUN/VIROLOGY 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 573520 NCI 350866 222654 ABSTRACTUnlike liquid cancers current CAR T cell immunotherapies have little effect against solid cancers largely due tothe immunosuppressive nature of the tumor microenvironment. The race between administered CAR T cells andtumor associated cells to kill off and/or neutralize the other is tipped heavily in favor of the tumor. Heterogeneoustumors or tumors able to shed or downregulate CAR-targeted antigens can also escape elimination by functionalCAR T cell effectors. We recently found that CAR T cells delivery of dual cytokines can enlist and activateendogenous T cells NK cells and myeloid cells to mount an effective anti-tumor immune response. Furtherinvestigation revealed that perforin and IFN are dispensable in CAR T cells supporting an accessory role forCAR T cells in mobilizing endogenous immune cells to ultimately control tumor growth. CAR T cell-mediateddual cytokine delivery was effective in controlling tumor growth with 3 different CAR T cell constructs and 4 invivo tumor models: primary and metastatic melanoma and primary colon cell carcinoma mouse models andimportantly was impervious to antigen loss. This suggests that the dual cytokine platform has potential foruniversal application against multiple solid tumor types. In this application we hypothesize that CAR T celldelivery of dual cytokines has broad application because it counteracts immunosuppressive innate and adaptiveimmune cells to elicit a broad endogenous anti-tumor response independent of CAR effector potential. We willtest this hypothesis by identifying CAR T cell survival and distribution dynamics (Aim 1) identify the commonand tumor-specific changes in immunosuppressive immunostimulatory and effector leukocyte populationsisolated from poorly and strongly immunogenic tumors pre- and post-CAR cytokine treatment (Aim 2) anddetermine their roles in activating endogenous tumor immunity (Aim 3). The cellular and mechanisms identifiedwill support further improvement and clinical translation of the Super2+IL-33 platform with various CAR targetingconstructs for CAR T cell therapies for solid tumors. 573520 +No NIH Category available 3-Dimensional;Antigens;Architecture;Bar Codes;Biological Assay;Biological Process;Cells;Cellular Immunity;Characteristics;Chromatin;Chromatin Loop;Chromosome Mapping;Complex;Cytotoxic T-Lymphocytes;Data;Dedications;Dependence;Development;Diagnosis;Disease Progression;Evolution;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Genetic;Genetically Engineered Mouse;Goals;Immune Evasion;Immune response;Immunophenotyping;KRAS oncogenesis;KRAS2 gene;Laboratories;Lung;Lung Neoplasms;Maintenance;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mediating;Mediator;Mentors;Methodology;Molecular;Molecular Conformation;Mus;Pancreatic Ductal Adenocarcinoma;Phase;Play;Positioning Attribute;Postdoctoral Fellow;Proteins;Regulation;Research;Research Project Grants;Role;Shapes;System;T cell response;T-Lymphocyte;Techniques;Time;Training;Tumor Immunity;Tumor Subtype;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Volume;Tumor stage;Work;anti-tumor immune response;cancer cell;cancer type;candidate identification;cell type;chemotherapy;cohesin;experience;experimental study;functional genomics;gene function;high throughput screening;immunoregulation;in vivo;innovation;insight;lung cancer cell;lung tumorigenesis;medical specialties;mouse model;multidisciplinary;multiple omics;neoplastic cell;novel;novel strategies;pancreatic ductal adenocarcinoma model;response;tumor;tumor growth;tumor heterogeneity;tumor immunology;tumor progression;tumorigenesis Chromatin and immune regulation of tumor growth and progression PROJECT NARRATIVEMolecular drivers and cellular interactions drive changes in cancer cell state that contribute to tumor growth andprogression but how these factors coordinatively drive tumorigenesis is not well defined. I propose to elucidatemechanisms of chromatin regulation and evasion of immune response by using innovative mouse models andfunctional genomics analyses. This work will provide novel insight into the principles of chromatin regulation andtumor heterogeneity that contribute to progression in lung and pancreas cancers which may also be applicableto other cancer types. NCI 10744436 8/10/23 0:00 RFA-CA-22-041 1F99CA284289-01 1 F99 CA 284289 1 "ELJANNE, MARIAM" 8/10/23 0:00 7/31/25 0:00 ZCA1-RPRB-7(M1) 16167689 "ASHKIN, EMILY LORIN" Not Applicable 16 GENETICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/10/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 PROJECT SUMMARYLung and pancreatic ductal adenocarcinomas are often diagnosed at very late stages of tumor progression whenthey are most aggressive and difficult to treat. Currently very little is known about the characteristics that makeup the complex tumor heterogeneity of late-stage tumors and what factors contribute to such changes in cancercell state and disease progression over time. Investigating how the mechanisms by which these contributingfactors impact tumorigenesis and tumor heterogeneity may uncover unappreciated biological processes thatcontrol tumor development. The goal of this work is to elucidate the molecular and cellular mechanisms thatdrive changes in chromatin state and immune response and how they shape tumor heterogeneity and tumorprogression. In the F99 phase I aim to elucidate how a novel tumor suppressor gene constrains lungtumorigenesis. My colleagues and I identified STAG2 as a tumor suppressor in a genetically engineered mousemodel of oncogenic KRAS-driven lung cancer. STAG2 is a subunit of one of the two major cohesin complexeswhich are implicated in regulating chromatin boundaries and gene expression. However the mechanism bywhich Stag2 inactivation drives lung tumor growth is unknown. I performed chromatin accessibility profiling andgene expression analyses on STAG2-proficient and STAG2-deficient mouse lung cancer cells and have unveiledpotential mediators of STAG2 function. Based on my analyses I hypothesize that STAG2 controls genesinvolved in early stages of tumorigenesis by directly impacting cohesin regulation of 3D chromatin organization.Using chromatin conformation assays I will assess how STAG2 regulates chromatin at different stages of tumorprogression and how Stag2 inactivation drives lung tumorigenesis. Additionally I will use Tuba-seq to identifykey epistatic and downstream mediators of STAG2 tumor suppression and chromatin conformation assays toascertain the STAG2-mediated mechanisms impacting lung tumor maintenance. In the K00 phase I aim toelucidate how cancer cell state shapes pancreatic ductal adenocarcinoma (PDAC) response to T-cell mediatedanti-tumor immunity. PDAC subpopulations with distinct transcriptional profiles stromal composition andresponse to chemotherapy have been previously established. However it remains unknown whether these tumorsubtypes harbor differential response to T-cell mediated immunity. To investigate how cancer cell state shapesPDAC progression by enabling evasion of cytotoxic T cell responses I will leverage PDAC mouse models thatenable the initiation of cytotoxic T cell responses at different stages of tumor progression using an induciblemouse model T cell antigen. Using longitudinal multi-omics immunophenotyping and tumor volume analyses Iwill investigate how aspects of tumor heterogeneity contribute to mechanisms of immune evasion at variousstages of tumor progression identify key mechanistic drivers and thus uncover novel strategies to enhance anti-tumor immune responses. Together this body of work will elucidate principles of chromatin regulation and tumorheterogeneity that contribute to progression and immune response in lung and pancreas cancers. 49194 +No NIH Category available Address;Adjuvant;Adjuvant Therapy;Adult;Age;Aging;Anxiety;Behavior;Binding;CDK4 gene;Cause of Death;Cell Communication;Cell Cycle Arrest;Cell Cycle Progression;Cell Proliferation;Cells;Chromatin;Clinical;Data;Development;Disease-Free Survival;Disseminated Malignant Neoplasm;Distant;Elderly;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;Fibroblasts;Frequencies;Glucocorticoid Receptor;Glucocorticoids;Goals;Growth;Hormones;Image;Immune;Immune response;Immune system;Immunization;Immunize;Immunohistochemistry;Immunologic Surveillance;In Vitro;Injections;Internet;Knowledge;Lead;Literature;Liver;Liver neoplasms;Malignant Neoplasms;Metastatic Neoplasm to the Liver;Modeling;Mus;Natural Killer Cells;Neoplasm Metastasis;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Patients;Phase;Postdoctoral Fellow;Primary Neoplasm;Proliferating;Protocols documentation;Relapse;Research;Research Personnel;Resected;Risk Factors;Role;Signal Induction;Signal Transduction;Site;Source;Stimulus;Stress;Stromal Cells;T-Cell Depletion;T-Lymphocyte;Therapeutic;Tissues;aged;cancer cell;cancer therapy;cancer type;clinically relevant;experience;extracellular;immune clearance;immunoregulation;improved;interest;mouse model;neutrophil;novel;pancreatic ductal adenocarcinoma cell;prevent;targeted treatment;therapy design;transcriptomics;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Immune Regulation of Dormancy at the Metastatic Site Project NarrativeWhile non-proliferating disseminated cancer cells in distant tissues have been observed in many types of cancermechanisms of how metastases originate from these dormant cancer cells are unclear. In this proposal we planto (1) interrogate how dormant cancer cells initiate proliferation and how immune cells regulate these dissemi-nated cancer cells in development to metastases upon stimuli such as glucocorticoids treatment and (2) deter-mine immune-stromal cell interactions and how they orchestrate to regulate cancer dormancy as we age. NCI 10744395 9/12/23 0:00 RFA-CA-22-041 1F99CA284292-01 1 F99 CA 284292 1 "ELJANNE, MARIAM" 9/12/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 77802163 "HAN, XIAO " Not Applicable 1 MICROBIOLOGY/IMMUN/VIROLOGY 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY SCHOOLS OF MEDICINE 117943362 UNITED STATES N 9/12/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 PROJECT SUMMARY/ABSTRACTPatients with pancreatic ductal adenocarcinoma (PDAC) and no clinically detectable metastases are treated bysurgery. However >70% of such patients later develop metastases most frequently in the liver. This is strongevidence that metastases can originate from disseminated cancer cells (DCCs). While most DCCs are eliminatedby the immune system a few DCCs escape immune surveillance by undergoing G0/G1 cell cycle arrest. Suchnon-proliferating DCCs can later proliferate and form lethal metastasis. What drives the dormant DCCs to prolif-erate escape immune surveillance and establish metastases are poorly understood largely due to a lack ofappropriate models. Here we have established a novel PDAC mouse model of dormant DCCs in the liver usingan immunization protocol followed by intrasplenic injection of PDAC cells we found that most DCCs were elim-inated in such immunized mice but a few survived as single non-proliferating DDCs and stayed dormant formonths. In the F99 phase we will use this dormant PDAC mouse model to examine what could drive DCCproliferation and how immune cells regulate metastasis. Patients with PDAC have 2-fold higher glucocorticoids(GCs) an immunomodulatory stress hormone than healthy adults. Mimicking this clinical phenomenon wetreated DCC-hosting mice with GCs achieving a 2-fold increase of GC in mice we found that DCCs began toproliferate. In addition the tumor microenvironment (TME) changed upon GCs treatment: numbers of neutrophilsincreased while T cells and natural killer (NK) cells decreased. GCs treatment did not cause metastasis and Tcell depletion caused only a few metastases in a small fraction of mice. However when GCs treatment wascombined with T cell depletion multiple metastases were observed in all mice examined. As proposed we willdefine and target the signals that trigger DCC proliferation and elucidate the mechanisms of GCs on T cells andNK cells suppression. In the K00 phase I plan to investigate immune-fibroblast crosstalk that regulate cancerdormancy in the context of aging. Advanced aging is the most important risk factor for cancer overall and forspecific metastatic cancer types including PDAC. Aging changes the TME significantly including immune cellsdistributions and effector functions fibroblasts activities ECM and secreted factors. However how thesechanges are relevant to the metastasis relapse from DCCs is unknown. My postdoctoral research interest is tostudy aging-induced changes in immune cells and fibroblasts with a focus on the immune-fibroblast crosstalkand their sequential influences on dormant DCCs. Eventually I plan to become an independent investigatorlead a research team to study cancer dormancy and TME and generate knowledge to facilitate development oftarget therapies that prevent metastasis and improve survival. 49194 +No NIH Category available ATAC-seq;Adhesions;Antineoplastic Agents;Antitumor Response;Architecture;Big Data;Binding;Biocompatible Materials;Bioinformatics;Biomedical Engineering;Blood Circulation;Bone Marrow;Bortezomib;Cancer Biology;Cell Adhesion;Cell Communication;Cells;Cessation of life;Chemistry;Clinic;Clinical;Complex;Custom;Cyclophilin A;Development;Disease;Drug Delivery Systems;Drug resistance;E-Selectin;Encapsulated;Endothelial Cells;Endothelium;Engineering;Formulation;Funding;Gene Silencing;Genetic Transcription;Goals;Hematologic Neoplasms;Histology;Homing;Hybrids;In Vitro;Knowledge;Laboratories;Laboratory Research;Libraries;Ligands;Lipids;Malignant Bone Marrow Neoplasm;Malignant Neoplasms;Mechanics;Membrane;Mentors;Messenger RNA;Methods;Microfluidics;Migration Assay;Modality;Modeling;Multiple Myeloma;Mus;Nanotechnology;Neoplasm Metastasis;Nucleic Acids;Patients;Pennsylvania;Phase;Plasma Cells;Polyethylene Glycols;Polymers;Postdoctoral Fellow;Property;Proteasome Inhibitor;RNA Interference Therapy;RNA Sequences;RNA delivery;Research;Research Project Grants;Resistance;Resistance development;Small Interfering RNA;Specificity;Surface;Technology;Testing;Therapeutic;Tissue Engineering;Training;Translating;Tumor Biology;Tumor Burden;United States;United States National Institutes of Health;Universities;Work;Xenograft Model;adhesion receptor;aptamer;cancer drug resistance;cancer therapy;clinical translation;design;dosage;effective therapy;high dimensionality;improved;in vitro Assay;in vivo;innovation;migration;nanoparticle;new therapeutic target;novel;nucleic acid delivery;post-doctoral training;pre-doctoral;programs;screening;skills;small molecule;targeted delivery;therapeutic RNA;therapeutic nanoparticles;therapeutic target;three-dimensional modeling;transcriptome sequencing;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;virtual;whole body imaging Engineering Biomaterials to Modulate the Bone Marrow Microenvironment in Multiple Myeloma PROJECT NARRATIVEMultiple myeloma is a cancer of bone marrow plasma cells that remains virtually incurable partly to interactionswith the bone marrow microenvironment which promote colonization progression and survival of myelomacells. During the F99 phase I will develop biomaterials-based strategies to deliver nucleic acids to the bonemarrow microenvironment as a novel form of multiple myeloma therapy to disrupt interactions betweenmyeloma cells and the bone marrow. For the K00 phase I propose to study cell-cell interactions in the tumorimmune microenvironment that promote myeloma progression and drug resistance employing high-dimensionalsingle-cell approaches and tissue-engineered models to ultimately uncover novel therapeutic targets. NCI 10744373 8/8/23 0:00 RFA-CA-22-041 1F99CA284294-01 1 F99 CA 284294 1 "ODEH, HANA M" 8/9/23 0:00 7/31/25 0:00 ZCA1-RPRB-7(M1) 78753420 "FIGUEROA-ESPADA, CHRISTIAN GABRIEL" Not Applicable 3 BIOMEDICAL ENGINEERING 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA BIOMED ENGR/COL ENGR/ENGR STA 191046205 UNITED STATES N 8/9/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 PROJECT SUMMARYMultiple myeloma (MM) accounts for ~23% of all hematologic malignancies with a 2.1% of cancer-related deathsin the United States in 2022. Despite tremendous efforts to develop effective therapies MM remains largelyincurable and virtually all patients develop resistance to current therapies. Thus there is an urgent clinical needfor innovative and improved MM therapeutics. It has been demonstrated that bone marrow endothelium is criticalto MM cell homing progression survival and drug resistance. Specifically cyclophilin A and E-selectin ahoming factor and adhesion receptor respectively expressed by bone marrow endothelial cells are critical toMM survival. Thus inhibition of cyclophilin A and E-selectin provides a potential therapeutic strategy to abolishMM dissemination and resistance. However direct- and specific-inhibition of cyclophilin A and E-selectin bysmall molecules has been elusive. Thus cyclophilin A and E-selectin are promising candidates for combinationRNA interference (RNAi) therapy which inhibits traditionally undruggable targets by directly reducing theirmessenger RNA (mRNA) expression. The challenge of utilizing small-interfering RNA (siRNA) is the need forsafe and effective delivery methods as siRNA degrades in the bloodstream and does not readily crossmembranes. During my predoctoral studies I have engineered a library of polymer-lipid hybrid biomaterials thatin combination with polyethylene glycol (PEG)-lipid conjugates and siRNA assembled into nanoparticles (NPs)via microfluidic mixing. Through high-throughput in vivo screening I identified a NP formulation with potent genesilencing in bone marrow endothelial cells in vivo. This formulation was used to encapsulate cyclophilin A siRNAand showed inhibition of MM progression in vivo and sensitized MM cells to the proteasome inhibitor bortezomiba current therapeutic modality to treat MM. During the F99 phase I will improve our NP design by incorporatingbone marrow endothelial-targeting ligands on the NPs surface to enhance their specificity to bone marrowendothelium minimizing off-target effects. I will use our targeted NP to co-encapsulate cyclophilin A and E-selectin siRNA sequences and evaluate their inhibition in vitro through adhesion and transendothelial migrationassays to determine the invasive abilities of MM cells. Further I will test our co-delivery siRNA nanotechnologythrough a survival study in a validated mouse xenograft model of MM and quantify its effects either alone or incombination with bortezomib. This technology is expected to provide with a broadly enabling platform to targetother bone marrow-homing cancers. For the K00 phase I will identify a renowned cancer biology laboratory tostudy cell-cell interactions in the bone marrow immune microenvironment utilizing high-dimensional single-cellapproaches and tissue-engineered models with the aim to determine mechanisms that drive cancer progressionand drug resistance. Completion of this project will successfully prepare me to launch an NIH-funded researchlaboratory that focuses on drug delivery targeting the tumor microenvironment as means of cancer therapy. 49194 +No NIH Category available African;African American;African American population;African ancestry;Alleles;Amino Acids;Apoptosis;Binding;Biochemical;Biological Assay;CRISPR/Cas technology;Cancer Etiology;Cancer Prognosis;Cell Death;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Colitis;Collaborations;Colon;Colorectal Cancer;DNA Binding Domain;Data;Development;Diet;Disparity;Engineering;Ethnic Origin;Ethnic Population;Etiology;Event;Faculty;Family;Fluorescence Polarization;Foundations;Fox Chase Cancer Center;Gatekeeping;Gene Targeting;Genes;Genetic;Genetic Polymorphism;Genetic Transcription;Genetic Variation;Genetically Engineered Mouse;Genotype;Glutathione;Goals;Impairment;Incidence;Individual;Induction of Apoptosis;Investigational Therapies;Iron;Iron Chelating Agents;Iron Chelation;KRAS2 gene;Knock-in Mouse;Knowledge;Learning;Li-Fraumeni Syndrome;Malignant Neoplasms;Mediating;Mentors;Modeling;Mus;Mutation;Pathway interactions;Persons;Phosphorylation;Population;Population Sciences;Positioning Attribute;Postdoctoral Fellow;Premenopause;Prognosis;Proteins;Publications;Reagent;Research;Research Personnel;Resources;Response Elements;Risk;Role;Single Nucleotide Polymorphism;Structure;Susceptibility Gene;TP53 gene;Techniques;Testing;The Wistar Institute;Tissues;Training;Transactivation;Transgenic Model;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States;Universities;Variant;Woman;adenoma;cancer health disparity;cancer risk;cancer therapy;career;career development;colon cancer cell line;colorectal cancer progression;colorectal cancer risk;dextran sulfate sodium induced colitis;genetic variant;interest;malignant breast neoplasm;minority health disparity;mortality;mouse model;novel;novel therapeutic intervention;pre-doctoral;skills;socioeconomics;targeted treatment;tool;tumor;tumor progression Genetics of Tumor Suppression by p53 PROJECT NARRATIVEWhile there are some indications that socio-economic forces play a role in minority health disparities therehave been over a dozen publications in the past three years that strongly indicate a genetic component to theincreased cancer risk and poorer prognosis for African Americans with many cancers including colorectalcancer. This proposal focuses on two coding region variants in the p53 tumor suppressor gene (Pro47Serand Tyr107His) that my research shows are hypomorphs; I will use genetically engineered mouse modelsto ascertain the impact of these variants on cancer risk and progression with a focus on colorectal cancer. NCI 10744250 11/14/23 0:00 PA-19-130 5R00CA241367-05 5 R00 CA 241367 5 "MAAS, STEFAN" 3/4/20 0:00 11/30/24 0:00 Transition to Independence Study Section (I)[NCI-I] 14449867 "BARNOUD, THIBAUT " Not Applicable 6 BIOCHEMISTRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Non-SBIR/STTR 2024 224101 NCI 159050 65051 PROJECT SUMMARYThe goals of this Pathway to Independence Career Development proposal are to gain expertise in colorectalcancer (CRC) population science and experimental therapeutics with a focus on the development of noveltherapeutic strategies for CRC dependent on the status of the p53 tumor suppressor gene TP53. Thetraining plan outlined in this proposal will take full advantage of the extensive resources and scientificexpertise at The Wistar Institute and incorporates training with experts at Wistar Columbia University andthe Fox Chase Cancer Center. My training will be guided by clinical and basic cancer researchers who havesuccessfully mentored predoctoral postdoctoral and clinical fellows in academic careers.African Americans have the highest incidence and mortality rates of CRC of any ethnic group in the UnitedStates. The most common genetic alterations in CRC include K-Ras Wnt and TP53. We have pioneeredthe analysis of naturally occurring coding region variants of p53 in different populations with emphasis on theimpact of these variants on cancer risk and the efficacy of cancer therapy. With this proposal I take aim attwo genetic variants in p53 that exist in African American populations and their impact on CRC progressionand therapy. The P47S variant alters p53 phosphorylation and transcriptional function; this variant is impairedfor ferroptotic cell death and knock-in mice containing the P47S variant are susceptible to a variety of tumortypes including CRC. The Y107H variant shows altered structure of the p53 DNA binding domain and mydata indicate that it too has poorer tumor suppressor function and transcriptional potential. I recently usedCRISPR engineering to create a mouse model for the Y107H variant.The P47S and Y107H variants together exist in over half a million African Americans in the United States.The goal of the proposed research is to use these naturally-occurring variants as biologically-relevant toolswith which to dissect p53 function. I will explore the following scientific aims: 1) to elucidate the mechanismswhereby the P47S variant promotes colorectal cancer development; and 2) to investigate the role of theAfrican-specific Y107H variant in tumor suppression. The completion of the scientific aims in this proposalwill develop my research skills and knowledge in both colorectal cancer and the impact of TP53 variants oncancer risk as well as gaining a more complete understanding of targeted therapies based upon TP53genotype. I expect this research to have a profound impact on the understanding and on the eventualsuccessful elimination of cancer disparities in African Americans. 224101 +No NIH Category available Address;Apoptosis;Cell Lineage;Cells;Complex;Cytoplasm;DNA Damage;Diagnosis;Gene Expression;Genes;Genetic Transcription;Goals;Human;Knowledge;Liver;Malignant Neoplasms;Mediating;Molecular;Mutation;Normal Cell;Oncogenic;Outcome;Radiation Tolerance;Research;Resistance;Role;Specificity;Spleen;TP53 gene;Therapeutic;Therapeutic Index;Thymus Gland;Tissue-Specific Gene Expression;Tissues;Transcriptional Regulation;Tumor Suppression;Tumor Suppressor Proteins;Tumor-Derived;base;design;functional restoration;gain of function;improved;in vivo;in vivo Model;insight;mouse model;mutant;neoplastic cell;new therapeutic target;response;targeted treatment;translational potential;tumor;tumorigenesis Cell lineage determinants of p53-driven fate outcomes in vivo PROJECT NARRATIVEThe proposed research is focused on understanding the molecular basis of the tumor suppressor activity ofwild-type p53 and the oncogenic functions of tumor-derived mutant p53. The long-term goal is to utilize thisknowledge to improve diagnosis and design novel targeted therapies for a wide variety of human cancers. NCI 10744218 11/8/23 0:00 PA-19-056 5R01CA257548-04 5 R01 CA 257548 4 "JOHNSON, RONALD L" 12/9/20 0:00 11/30/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 1898855 "MANFREDI, JAMES J" "PRIVES, CAROL " 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 529399 NCI 360642 168757 PROJECT SUMMARYMutation of the TP53 gene is frequent in human cancer with wild-type p53 clearly being implicated as a tumorsuppressor. A growing body of evidence now supports the notion that tumor-associated mutant p53 has not onlylost tumor suppressing activity but has also gained oncogenic roles. Thus a central and significant challenge isto elucidate the molecular bases both for the tumor suppressing functions of wild-type p53 and the oncogenicactivities of mutant p53 as well as deconvoluting the molecular relationship between these two. It is reasonableto expect that relevant detailed insights into wild-type-mediated tumor suppression will inform understanding ofmutant-driven oncogenesis and vice versa. It is further hypothesized that by studying wild-type and mutant p53in parallel insights will be gained that would have been otherwise elusive. Further confounding this complexquestion studies using mouse models in vivo indicate that p53-driven cell fate outcomes be they tumorsuppressing or oncogenic can be tissue-specific. Although p53 has been shown to have cytoplasmic functionsits role in controlling gene expression is certainly central to both its wild-type tumor suppressing role and itsmutant oncogenic function. The goal of the planned studies is to address this significant issue which carriesimportant translational potential. Specific aims are proposed to explore the tissue-specific transcriptional activityof either wild-type or mutant p53 in vivo and to identify lineage-specific determinants for p53-driven fate outcomesin a subset of tissues namely liver thymus and spleen. The first aim is focused on wild-type p53 in vivo andinvolves elucidating the molecular basis for cell lineage as a determinant for the wild-type p53-dependentresponse to DNA damage. The second aim deals with tumor-associated mutant p53 and is to explore themolecular basis for the tissue-specific oncogenic activity of mutant p53. Given the essential role of transcriptionalregulation in the activity of p53 it is postulated that downstream control of specific target genes are keydeterminants of cellular outcomes. Elucidating the molecular basis for the tumor suppressor activity of wild-typep53 is essential to be able to exploit such findings as a means to restore this function in tumor cells as atherapeutic approach. Likewise the existence of gained oncogenic activity by tumor-associated mutant p53provides the unexpected possibility for a targeted therapy involving a tumor suppressor. As a key differencebetween normal and tumor cells is their p53 status it is anticipated that such approaches are likely to have ahigh therapeutic index. Given the tissue-specificity of responses to p53 it is essential that studies of p53-drivenfate outcomes be addressed in a cell lineage-dependent manner providing a central tenet for the proposedresearch. 529399 +No NIH Category available Antineoplastic Agents;B-Lymphocytes;Biological Assay;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;CD47 gene;Cell Surface Receptors;Cell surface;Cells;Chemoresistance;Clinical Trials;Development;ERBB2 gene;Eating;Engraftment;Epidermal Growth Factor Receptor;Estrogen Receptors;Estrogens;Excision;FDA approved;Hematopoietic Neoplasms;Human;Immune;Immune Evasion;Immune system;Immunologic Surveillance;Immunotherapeutic agent;Immunotherapy;In Vitro;Journals;Macrophage;Malignant - descriptor;Malignant Neoplasms;Mediating;Molecular;Mus;Natural Killer Cells;PD-L1 blockade;Pathway interactions;Pattern recognition receptor;Phagocytes;Phagocytosis;Pre-Clinical Model;Primary Neoplasm;Progesterone;Progesterone Receptors;Prognosis;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;Site;Solid Neoplasm;Subgroup;T-Lymphocyte;Therapeutic;Tumor Escape;Tumor-associated macrophages;Up-Regulation;anti-PD-L1 antibodies;anti-cancer;cancer cell;cancer immunotherapy;cancer therapy;chemotherapeutic agent;cytotoxicity;effective therapy;efficacy evaluation;immune cell infiltrate;improved;in vivo;malignant breast neoplasm;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;pembrolizumab;pre-clinical;receptor;screening;small molecule;therapeutic target;therapeutically effective;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor-immune system interactions Targeting tumor-associated macrophages for triple-negative breast cancer treatment Project NarrativeInduction of tumoricidal functions of tumor-associated macrophages represents a new class of very promisingcancer immunotherapy. This study aims to dissect the molecular mechanism regulating antitumor functions oftumor-associated macrophages in triple-negative breast cancer. The understanding of these mechanisms shouldshed light on the basic principles of cancer immune evasion and inspire the development of novel and effectivecancer immunotherapy for triple-negative breast cancer treatment. NCI 10744194 11/16/23 0:00 PA-20-185 5R01CA258778-03 5 R01 CA 258778 3 "KUO, LILLIAN S" 12/1/21 0:00 11/30/26 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 12161561 "FENG, MINGYE " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 467633 NCI 281549 186084 Project Summary/AbstractTriple-negative breast cancer (TNBC) is characterized by the lack of estrogen receptor progesterone receptorand human epidermal growth factor receptor 2 all of which are important therapeutic targets. TNBC is the mostdifficult-to-treat subgroup of breast cancers and is resistant to many current cancer therapies. The presentsituation of poor prognosis with limited therapy options in TNBC emphasizes an urgent need for more effectivetherapeutics. The ability to escape from the surveillance by the immune system is regarded as one of theessential hallmarks of cancer cells. Recent exciting discoveries have identified many important signals andmechanisms mediating cancer cell immune evasion. Immunotherapies have been developed to target thesesignals revolutionizing the treatment of a variety of human cancers. Tumor-associated macrophages (TAMs)represent the major components of the tumor microenvironment in TNBC. Recent studies demonstrate that theblockade of a dont eat me signal CD47 leads to direct phagocytosis of living cancer cells by macrophagesand significantly inhibits the engraftment of various malignant hematopoietic and solid tumor cells in mice thatlack T B and NK cells indicating a critical role of macrophages in cancer immunosurveillance. Targeting TAMsin the tumor microenvironment represents a new class of promising cancer immunotherapy. While inducinganticancer functions of TAMs holds considerable promise for cancer treatment there are several barriers thatneed to be overcome to achieve desired efficacy for treating TNBC. In preliminary studies we found that TAMscan be reprogrammed by small molecule antineoplastic compounds to induce their phagocytic ability againstTNBC cells. However the underlying molecular mechanisms regulating the reprogramming of macrophagesremains unclear. The overall objective of the proposed study is to understand the underlying mechanisms ofmacrophage-mediated immunosurveillance in TNBC and to develop strategies to effectively treat TNBC byexploiting tumoricidal roles of TAMs with a combination of in vitro and in vivo preclinical TNBC models. In Aim1we will assess the efficacy of reprogramming macrophages in TNBC treatment by using metastatic TNBC modelsand chemotherapy-resistant patient-derived xenograft models. In Aim2 we will study the molecular mechanismsby which macrophages are reprogrammed by dissecting the functions and roles of Pattern Recognition Receptorsignaling pathways in macrophage reprogramming and characterizing TAM subgroups in TNBC tumors. In Aim3we will determine the effects of targeting macrophage cell surface molecular machinery on activating TAMs forTNBC treatment. Successful completion of the proposed studies should shed light on the basic principles ofcancer cell immune evasion and inspire the development of novel therapeutics for TNBC treatment. 467633 +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Address;Adult;Affect;Biology;CEBPE gene;Cell Differentiation Induction;Cell Differentiation process;Cell Line;Cells;Child;Chimeric Proteins;Chromosomal translocation;Data;Defect;Dependence;Development;Disease;Disease Outcome;Drug resistance;Enhancers;Failure;Family member;Fusion Oncogene Proteins;Gene Expression;Gene Expression Regulation;Gene Rearrangement;Gene Targeting;Genes;Genetic Predisposition to Disease;Genetic Transcription;Genome;Genomic approach;Goals;Growth;HOXA9 gene;Hematologic Neoplasms;Human;Invaded;Knowledge;Laboratories;Leukemic Cell;Lymphoid;MLL gene;MLL-rearranged leukemia;Maintenance;Malignant Neoplasms;Mediating;Menin;Modeling;Molecular;Mus;Muscle Development;Myelogenous;Myeloid Progenitor Cells;Neurons;Normal Cell;Oncogenic;Output;Pathogenesis;Pathway interactions;Patients;Play;Prognosis;Proliferating;Proteins;Recurrence;Regulation;Relapse;Repression;Research;Resistance;Role;Sampling;Signal Transduction;Testing;Therapeutic;Tissues;Transcriptional Regulation;Vertebrates;Work;acute myeloid leukemia cell;cell growth;cell killing;chemotherapy;comparative;gene repression;hematopoietic differentiation;improved;improved outcome;in vitro Model;in vivo;inhibitor;innovation;insight;leukemia;leukemia treatment;leukemogenesis;mouse model;muscle enhancer factor-2A;myocyte-specific enhancer-binding factor 2;myocyte-specific enhancer-binding-factor 2C;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;paralogous gene;preclinical efficacy;programs;protein complex;protein expression;protein function;self-renewal;targeted treatment;transcription factor;treatment response;tumor MEF2D-Mediated Transcriptional Control of Acute Myeloid Leukemia NARRATIVEDespite chemotherapy acute myeloid leukemia with MLL-rearrangement remains a therapeutic challenge withpoor prognosis and a major barrier to improved outcomes is a lack of mechanism-based targeted therapieswhich requires the discovery of key cancer drivers and gene targets. The proposed research will study a noveldependency of acute myeloid leukemia and dissect the underlying molecular pathways. Knowledge obtainedfrom the proposal will improve our understanding of the transcriptional regulation of MLL-rearranged AML andcan be useful for developing targeted therapeutics for this deadly disease. NCI 10744190 11/29/23 0:00 PA-20-185 5R01CA259480-03 5 R01 CA 259480 3 "KLAUZINSKA, MALGORZATA" 12/20/21 0:00 11/30/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 12084295 "LU, RUI " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 310541 NCI 222674 87867 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) with MLL (KMT2A) gene rearrangement (MLL-r) is an aggressive disease withuncontrolled proliferation of myeloid progenitor cells and a failure of proper cell differentiation. Despiteconventional chemotherapy the overall survival of MLL-r AML remains poor and therapeutic options are limitedhighlighting an unmet need to understand MLL-r AML pathogenesis and discover new genetic vulnerabilities.MEF2 transcriptional factors (MEF2A 2B 2C and 2D) play important functions in the development of muscleneuronal and lymphoid lineages. Despite the known role of MEF2C as a direct MLL-r target essential forleukemogenesis it remains unknown whether additional MEF2 family members are deregulated or involved inMLL-r leukemia. In this study we identified that MEF2D gains aberrant super-enhancers and is highlyupregulated in MLL-r AML. We demonstrate that MEF2D is selectively required for MLL-r AML and depletion ofMEF2D results in profound leukemia differentiation through transcriptional repression of CEBPE. We furthershow the MEF2D-CEBPE axis is critically involved in the anti-leukemia effects of DOT1L and Menin inhibitors.Furthermore we discovered a novel interdependency of MEF2 paralogs in MLL-r AML. These preliminary datahave provided us scientific rationale and enthusiasm for our central hypothesis that MEF2D a noveltranscriptional dependency highly expressed in MLL-r AML maintains leukemia through inhibition of a CEBPE-centered myeloid differentiation program. This hypothesis is supported by extensive preliminary data and will befurther tested by two specific aims: (1) establish the oncogenic function of MEF2D in MLL-r leukemogenesis andtherapeutic response and (2) investigate the mechanisms of MEF2D-mediated oncogenic regulation in MLL-rAML. In Specific Aim 1 we will determine the role of MEF2D in our pre-established genetically defined AMLmouse models in vitro and in vivo; we will also evaluate the role of MEF2D-CEBPE axis in Menin inhibitor-mediated anti-leukemia effects. In Specific Aim 2 we will determine the molecular mechanisms by which MEF2Drepresses CEBPE define MEF2D target genes using unbiased genome approaches and evaluate the role ofMEF2D-MEF2C interaction in MLL-r AML. The long-term goal of this project is to understand the MEF2 regulatorynetwork in MLL-r AML and to develop novel therapeutic approaches targeting oncogenic MEF2 factors forleukemia therapy. The main objective of this proposal is to establish the oncogenic function of MEF2D anddetermine how it regulates leukemia cell self-renewal and differentiation. Results from this proposal will providesignificant new knowledge on the critical role of MEF2D in AML reveal a new mechanism for suppression ofnormal hematopoietic differentiation in leukemia and serve as the basis for targeting MEF2-related pathways asa potential therapeutic strategy for AML patients. 310541 +No NIH Category available Affect;Benign;Bilateral;Biological;Biological Assay;Biological Markers;Calcium;Cancer Diagnostics;Cellular Morphology;Classification;Clinical;Clinical Management;Clinical Trials;Cytopathology;DNA Methylation;Data;Decision Making;Development;Diagnostic;Diagnostic Procedure;Diagnostic Specificity;Epigenetic Process;Evaluation;Excision;Failure;Fine needle aspiration biopsy;Gene Expression;Gene Fusion;Gene Mutation;Knowledge;Laboratories;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of thyroid;Medical center;Molecular;Morbidity - disease rate;Mutation;Nodule;Operative Surgical Procedures;Papillary thyroid carcinoma;Parathyroid gland;Pathologic;Patients;Performance;Physicians;Pilot Projects;Predictive Value;Prospective cohort;Publishing;Recurrent Laryngeal Nerve;Reproducibility;Sensitivity and Specificity;Specialist;Specimen;Surgeon;Testing;Thyroid Gland;Thyroid Hormones;Thyroid Nodule;Thyroidectomy;Tissues;Tracheostomy procedure;United States;Validation;Vocal Cord Paralysis;aspirate;cancer risk;clinical decision-making;diagnostic accuracy;diagnostic strategy;diagnostic value;epigenetic marker;epigenomics;genome-wide;improved;inter-institutional;internal control;methylation pattern;molecular diagnostics;pilot trial;prospective;ultrasound Validation of epigenomic biomarkers for thyroid cancer diagnostics PROJECT NARRATIVEAs many as 50000 unnecessary thyroidectomies are performed in the United States each year because thyroidnodules are deemed indeterminate preoperatively when they are indeed benign. We have developed a newmolecular test based on assessing DNA methylation in thyroid nodules that is accurate in preliminary tests andmust be tested in the proposed clinical trial. NCI 10744177 11/22/23 0:00 PAR-18-560 5R01CA241845-03 5 R01 CA 241845 3 "MCKEE, TAWNYA C" 6/15/21 0:00 11/30/26 0:00 Cancer Biomarkers Study Section[CBSS] 10420726 "HAHN, MARIA " "YIM, JOHN H" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 738387 NCI 537007 201380 PROJECT SUMMARY/ABSTRACTEach year up to 50000 patients in the United States receive unnecessary thyroidectomies. These unnecessarythyroidectomies are due to difficulties in preoperatively distinguishing benign thyroid nodules from thyroidcancers. In preliminary data we developed an epigenetic test that shows promise to distinguish benign versusmalignant thyroid nodules. Here we will rigorously test and validate the ability of our epigenetic biomarkers toevaluate the biologic aggressiveness of thyroid nodules and determine whether the new epigenetic testing willimprove thyroid nodule management towards the eradication of unnecessary thyroidectomies. Current moleculardiagnostics for indeterminate thyroid nodules while providing some improvement have not eliminated theunnecessary thyroidectomies. Current molecular diagnostics are based on molecular differences betweennormal thyroid tissue and thyroid cancer. However benign thyroid nodules can contain many molecularalterations including gene fusions and mutations. As a result over half of thyroid nodules with a significant cancerrisk according to the current molecular classifiers are found to be benign after thyroidectomy. In our publishedpreliminary data we performed a genome-wide DNA methylation analysis of 109 surgically excised thyroidnodules and adjacent benign tissue. We found that the DNA methylation pattern in benign nodules is differentfrom thyroid cancer and normal thyroid. Based on the DNA methylation pattern specific to benign nodules andthe DNA methylation pattern specific to thyroid cancer we developed the Diagnostic DNA Methylation Signature(DDMS) approach to distinguish between benign versus malignant nodules. In a retrospective pilot studyperformed under 1R21CA223367 we developed DDMS further (DDMS-2). We tested the ability of the DDMS-2assay to distinguish benign from malignant surgically excised thyroid nodules (n=121). In this Pilot study DDMS-2 had an estimated positive predictive value (PPV) of 96% and a negative predictive value (NPV) of 98%. Guidedby our preliminary data we hypothesize that DDMS (i) can be successfully used for molecular thyroid cancerdiagnostics of pre-operative thyroid nodule aspirations; (ii) will have superior performance in comparison tocurrent thyroid cancer molecular testing and (iii) can affect physician decision-making towards elimination ofunnecessary thyroidectomies. We will accomplish our overall objective by pursuing the following specific aims:Aim 1: To perform analytical validation of the DDMS-2 assay. Aim 2: To determine the DDMS-2 accuracy in aprospective cohort obtained from 7 medical centers and containing 1450 thyroid nodule aspirations including800 aspirations with indeterminate cytopathology. Aim 3: To compare the diagnostic accuracy between DDMS-2 and two current thyroid cancer molecular diagnostic approaches and to evaluate how the knowledge of theDDMS-2 results impacts clinical management of thyroid nodules. The development of a more accurate assay todistinguish benign and malignant thyroid nodules will address current clinical limitations and reduce the numberof needless thyroidectomies and associated morbidities. 738387 +No NIH Category available Acids;Acute;Adaptive Immune System;Affect;Animals;Antibodies;Biochemical;Bioinformatics;Biological Assay;Blood;Blood - brain barrier anatomy;Brain;Brain Neoplasms;CRISPR/Cas technology;Cancer Intervention;Cancer Patient;Cell membrane;Cells;Clinical;Clinical Data;Clinical Trials;Collaborations;Cytometry;DNA Sequence Alteration;Data;Development;Drug Delivery Systems;Endothelial Cells;Epidermal Growth Factor Receptor;Evaluation;Extracellular Matrix Proteins;Female;Gene Expression;Generations;Genes;Glioblastoma;Glioma;Growth;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Markers;Immunologic Surveillance;Immunotherapy;In Vitro;Innate Immune System;Intervention;Intravenous;Invaded;Laboratories;Laminin;Lead;Macaca fascicularis;Macrophage;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Maximum Tolerated Dose;Molecular Target;Mus;Nanotechnology;Neoplasm Metastasis;No-Observed-Adverse-Effect Level;Organ;Oryctolagus cuniculus;Pathologic;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Polymers;Population;Primary Brain Neoplasms;Primates;Production;Prognosis;Proliferating;Proteins;Protocols documentation;Radiation;Radiation therapy;Recurrence;Relapse;Sampling;System;TFAP2A gene;Technology;Testing;Therapeutic Uses;Therapeutic antibodies;Time;Toxic effect;Toxicology;Translational Research;Translations;Treatment Efficacy;Up-Regulation;Variant;anti-CTLA4;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;blood-brain barrier crossing;c-myc Genes;cancer cell;cancer therapy;clinically relevant;dosage;drug development;drug production;drug testing;effective therapy;endosome membrane;immune checkpoint;in vivo;male;molecular marker;mouse model;nano;nanodrug;nanomedicine;nanopolymer;nanotechnology platform;neoplastic cell;notch protein;novel;novel strategies;overexpression;pharmacologic;precision drugs;programmed cell death protein 1;scale up;single-cell RNA sequencing;small molecule;standard of care;temozolomide;therapeutic RNA;transcriptome sequencing;translational study;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Targeting tumor microenvironment by nanoimmunodrugs for glioma treatment Treatment of brain cancer and of its most common form glioblastoma multiforme(GBM) with a 15-month average survival still has limited treatment options. Theemergence of efficacious nanodrugs able to cross blood-brain barrier (BBB) gives hopefor new treatments of primary brain cancer. We will introduce new generation of nanoimmunopolymers that pass through BBB modulate tumor microenviroment and activatebrain tumor immune systems and block glioma specific molecular markers to achievetranslationally-related GBM treatment efficacy. NCI 10743942 9/19/23 0:00 PAR-22-071 1R01CA284247-01 1 R01 CA 284247 1 "CARDONE, MARCO" 9/19/23 0:00 7/31/27 0:00 Special Emphasis Panel[ZRG1-MCST-U(55)R] 1896755 "LJUBIMOV, ALEXANDER V" Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/19/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 577033 NCI 384604 192429 "Glioblastoma (GBM) is the most lethal form of brain cancer. Treatment options are limited in part because ofinefficient drug delivery across the blood-brain barrier (BBB). GBM microenvironment contributes to malignantgrowth invasion and escape from immune surveillance. We will develop a radically new strategy of GBMtreatment by simultaneous targeting of tumor microenvironment and activating brain cancer privileged immunesystem. This new combination approach aims to regulate tumor microenvironment components that are largelyindependent of heterogeneous genetic mutations in glioblastoma. It has potential advantage over conventionalGBM treatment with small molecule drugs radiation and targeted molecular marker(s) inhibition. In the frame ofthe FOA ""Toward Translation of Cancer Nanotechnology Interventions"" we will develop the translation of cancerinterventions using novel nanomedicines able to cross biobarriers such as BBB cell and endosomal membranesand modulate tumor microenvironment for effective therapy that may treat not only brain primary tumors (GBM)but other poorly treatable brain secondary/metastatic tumors.We plan to understand the interactions between extracellular matrix (ECM) protein laminin-411 (a4b1g1)expression and brain local immune system as parts of GBM-promoting immunosuppressive microenvironment.Our clinical data on 130 GBM patients showed that tumor laminin-411 correlated with tumor aggressivenesspoor patient survival and early recurrence. We developed nano drugs based on natural polymer poly(-L-malicacid) able to block the synthesis of trimer protein laminin-411 in vivo. We also used syngeneic mouse modelstreated with nano immuno drugs delivering to GBM checkpoint inhibitor antibodies anti-CTLA-4 or anti-PD-1 thatin free form do not cross BBB which increased animal survival. Nanodrugs were well characterized and non-toxic in mice and rabbits (collaboration with Nanotechnology Characterization Laboratory). Nano polymeric drugsproduction was scaled up to grams. Toxicity and PK studies were successfully performed on primatesmale/female Cynomolgus macaques using therapeutic 1X and acute 10X intravenous dosages.We also developed a nano immuno delivery system on the same platform bearing anti-CTLA-4 or anti-PD-1antibodies that traversed BBB activated local brain immune system and prolonged animal survival. Newpreliminary data demonstrate that laminin-411 regulates Notch pathway and activation of NK NKT IFNg+ NKTand macrophages whereas checkpoint inhibitors delivered to the brain on nanoplatform regulate both innateand adaptive immune system. Our translational research is geared towards developing clinically suitablecombinations of BBB-crossing nanomedicines for efficient glioma treatment.Aim 1. Synthesis of novel nano drug variants for combination brain cancer therapy. Aim 2. Lead nano drug testingfor glioma treatment efficacy. Aim 3. Pharmacological (PK PD) and toxicological examination of lead nanoimmunopolymers." 577033 +No NIH Category available Address;Affect;Binding;Biological Assay;Catalytic Domain;Cell Line;Chromosomal Breaks;Chromosome Pairing;Clinical Trials;Complex;DNA;DNA Binding;DNA Double Strand Break;DNA Repair;DNA-dependent protein kinase;Defect;Development;Distal;Double Effect;Double Strand Break Repair;Event;Excision;Frequencies;G22P1 gene;Ionizing radiation;Knock-out;Knowledge;Learning;Link;Liquid substance;Malignant Neoplasms;Measures;Mediating;Mission;Molecular Genetics;Mutation;Nonhomologous DNA End Joining;Outcome;Pathway interactions;Patient-Focused Outcomes;Phase;Phosphotransferases;Poison;Postdoctoral Fellow;Publications;Publishing;Radiation therapy;Regulation;Research;Research Personnel;Research Project Grants;Research Proposals;Role;Single-Stranded DNA;Site;Synapses;Techniques;Testing;Therapeutic;Topoisomerase;Training;Treatment outcome;United States National Institutes of Health;Work;XRCC4 gene;cancer cell;cancer clinical trial;cancer therapy;chromatin immunoprecipitation;clastogen;genetic approach;improved;inhibitor;insertion/deletion mutation;insight;mutant;nuclease;p53-binding protein 1;protein kinase inhibitor;repaired;response;skills;small molecule inhibitor;targeted cancer therapy;therapeutic target;treatment response Defining the role of chromosomal break end synapsis factors for DNA repair NARRATIVE. Clastogens (i.e. chromosomal-breaking agents) including ionizing radiation remain acornerstone of cancer therapy; however their efficacy could be improved by inhibiting chromosomal break repairin cancer cells. A central step of such repair is synapsis of chromosomal break ends and indeed inhibitors ofan end synapsis factor the DNA-dependent kinase catalytic subunit (DNA-PKcs) are being tested in clinicaltrials; but to identify the ideal contexts for using such inhibitors it is critical to understand the mechanism ofchromosomal break end synapsis. Thus our proposed studies to elucidate the mechanisms of chromosomalbreak end synapsis during DNA repair will support the mission of the NIH to improve cancer treatments andpatient outcomes. NCI 10743770 8/15/23 0:00 RFA-CA-22-041 1F99CA284248-01 1 F99 CA 284248 1 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 15491942 "CISNEROS, METZTLI " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 33194 NCI 33194 0 SUMMARY. Clastogenic cancer therapeutics i.e. agents that induce chromosomal DNA double-strand breaks(DSBs) such as radiotherapy remain a cornerstone of cancer treatment. A central aspect of DSB repair issynapsis of the two DSB ends to mediate repair such that DSB end synapsis is a potential therapeutic target.Indeed one factor important for DSB end synapsis DNA-dependent protein kinase (DNA-PKcs) is the target ofseveral inhibitors. This includes M3814/Peposertib (EMD Sereno) which is being tested in clinical trials.However at least two other factors XLF and 53BP1 have also been implicated in DNA end synapsis duringrepair. This suggests there may be some redundancy between these factors that could influence response toinhibitors of DNA-PKcs. In this research proposal I will investigate the role of end synapsis factors on end joining(EJ) repair and the regulation of DNA end resection. Aim 1: Define the role of end synapsis factors on EJ. Aim1a (Completed): EJ without insertions or deletions (No Indel EJ) is a repair outcome that represents high-fidelityEJ which requires factors involved in canonical non-homologous end joining (C-NHEJ) including KU70 andXRCC4. I sought to define the relative influence of two end synapsis factors (DNA-PKcs and XLF) on No IndelEJ. I found that DNA-PKcs and XLF promote No Indel EJ however loss of XLF caused a much greater decreasein No Indel EJ compared to DNA-PKcs. Importantly I found that disrupting DNA-PKcs (knockout or treatmentwith inhibitor) when combined with XLF mutations that weaken interaction interfaces caused a synergistic lossof No Indel EJ. Thus the conclusion of my published study is that the role of DNA-PKcs is magnified to promoteNo Indel EJ when XLF is weakened. Aim 1b (F99 Phase). Building on these findings I will investigate anotherend synapsis factor 53BP1. Specifically I will address the hypothesis that 53BP1 has a partially redundant rolewith DNA-PKcs and XLF to promote chromosomal EJ. In performing this research I will expand my skill set inseveral ways including learning to assess EJ outcomes using different computational approaches from thecompleted research. Aim 2 (K00 Phase). In the postdoctoral phase of the research proposal I will be assessingthe role of synapsis factors on cleaving of DNA ends bound to DNA-PKcs to initiate end resection. End resectionis the first step of homology-directed repair and is mediated by the MRN/CtIP nuclease complex. RecentlyMRN/CtIP was shown to cleave DNA ends bound to DNA-PKcs which may be the key initiating step of endresection. I propose to test the hypothesis that disruption of end synapsis causes an increase in this initiationstep of end resection which I will test with several techniques that will expand my research skill set. Altogetherthese studies will fill a major gap in our understanding of the role of end synapsis factors on the regulation ofDNA DSB repair mechanisms. Such research is significant for developing end synapsis as a target for cancertherapy including identifying the ideal circumstances to apply inhibitors of DNA-PKcs (e.g. M3814/Peposertib)during cancer treatment. 33194 +No NIH Category available Animal Model;Antioxidants;Binding;Biochemical;Biological Process;Biomass;Breast Cancer cell line;Breast cancer metastasis;CRISPR screen;Cancer Model;Cancerous;Cell Survival;Cells;Cytosol;Engineering;Ensure;Enzymes;Epitopes;Eukaryotic Cell;Feedback;Gene Expression;Glutathione;Glutathione Metabolism Pathway;Growth;Heterogeneity;Homeostasis;Immune system;Immunoprecipitation;Immunotherapy;Iron;Knock-out;Label;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Messenger RNA;Metabolic;Metabolic stress;Metabolism;Metastatic breast cancer;Mitochondria;Modeling;Mus;Neoplasm Metastasis;Nutrient;Organelles;Oxidation-Reduction;Paint;Pathologic;Pathway interactions;Peptide Hydrolases;Phase;Physiological;Play;Post-Translational Regulation;Process;Proteins;Proteolysis;Publishing;Radioactive;Reduced Glutathione;Refuse Disposal;Regulation;Reporter;Resolution;Role;Stress;Sulfur;Testing;Tumor stage;Work;activity-based protein profiling;cancer cell;cell type;detection of nutrient;insight;mutant;neoplastic cell;novel;novel therapeutic intervention;posttranscriptional;prevent;prototype;response;single cell sequencing;single-cell RNA sequencing;tool;tumor;tumor heterogeneity;tumor microenvironment;tumor progression;uptake Dissecting the role of mitochondrial glutathione homeostasis in cancer Project NarrativeEnhanced antioxidant capacity in cancer cells is an important contributor to the malignancy metastatic potentialand lethality of tumors. Antioxidants display heterogenous distribution among subcellular compartments throughits involvement in cancer progression and metastasis remains poorly understood. Using mitochondrialglutathione as a model this proposal seeks to determine its role in metastasis decipher its sensing mechanismand develop new tools to profile its distribution in the tumor microenvironment at the single-cell resolution. NCI 10743695 9/14/23 0:00 RFA-CA-22-041 1F99CA284249-01 1 F99 CA 284249 1 "ELJANNE, MARIAM" 9/14/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 78902720 "LIU, YUYANG " Not Applicable 12 NONE 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY UNIVERSITY-WIDE 100656399 UNITED STATES N 9/14/23 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 Project SummaryAll eukaryotic cells whether normal or cancerous require the ability to sense changes in nutrients levelsensuring their efficient use for survival and growth. Nutrient sensing mechanisms enable cells to rapidly adapt toenvironmental perturbation a feature particularly essential for cancer cells to overcome diverse metabolicstresses along the metastatic cascade. Although many nutrient sensing mechanisms have been described howmetabolites are sensed in subcellular compartments remains a major open question. This question is particularlyrelevant for redox-active molecules such as NAD and glutathione which display remarkably heterogenousdistribution across subcellular compartments and have been shown to play key roles in cancer metastasis.Recent breakthroughs in deorphanizing mitochondrial metabolite transporters provided unprecedentedopportunity to probe the dynamics and sensing mechanism of these metabolites at subcellular precision. In arecently published study SLC25A39 has been identified as a key transporter for mitochondrial glutathione amajor antioxidant molecule implicated in cancer progression and metastasis. Remarkably evidence suggeststhat SLC25A39 undergoes feedback regulation by mitochondrial glutathione and may be required for efficientmetastatic colonization implicating it in an adaptive mechanism for cancers to overcome metabolic stress duringmetastasis.This proposal seeks a deeper understanding of the implication of organellar glutathione metabolism in cancer.The Aim 1 of this proposal seeks to understand the role of mitochondrial glutathione homeostasis in tumorprogression and metastasis and decipher the mechanism of its regulation. The Aim 2 of this proposal seeks todevelop novel genetically encoded single-cell RNAseq-compatible reporters for profiling intercellularheterogeneity in mitochondrial glutathione in tumors. Using a combination of biochemical analysis unbiasedCRISPR screens and novel animal models this proposal aims to paint a multilayered picture of the dynamicsregulatory mechanisms and functional contribution of mitochondrial glutathione homeostasis in tumorprogression and metastasis. Completion of the proposed studies will deepen our understanding on the role ofcompartmentalized metabolite pools in metabolic rewiring of cancers and shed light on novel therapeuticstrategies to target metastasis. 49194 +No NIH Category available Address;Algorithms;Antibody Specificity;Architecture;Awareness;Back;Cells;Classification;Color;Complex;Computer software;Cryoultramicrotomy;Data;Data Set;Detection;Dimensions;Discrimination;Elasticity;Endometrial Carcinoma;Equilibrium;Freezing;Goals;Histologic;Histopathology;Image;Image Analysis;Immunohistochemistry;Individual;Ions;Laboratories;Learning;Lipids;Lung Adenocarcinoma;Machine Learning;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Medicine;Modality;Modeling;Molecular;Names;Neural Network Simulation;Optics;Pathologist;Pathology;Pattern;Peptides;Performance;Polysaccharides;Preparation;Publishing;Reporting;Research Personnel;Resolution;Sampling;Shapes;Stains;Structure;Techniques;Technology;Testing;Time;Tissue Stains;Tissues;Training;Vendor;Work;anticancer research;cancer diagnosis;cancer subtypes;convolutional neural network;data acquisition;data structure;deep learning;design;digital imaging;high dimensionality;human imaging;imaging detection;imaging modality;improved;informatics tool;interest;ion mobility;learning strategy;machine learning model;mass spectrometric imaging;molecular subtypes;multidimensional data;n-dimensional;neural network architecture;novel;optical imaging;people of color;protein biomarkers;tool;translational cancer research;two-dimensional Deep Learning of Mass Spectrometry Imaging PROJECT NARRATIVEMass spectrometry imaging (MSI) gives pathologists many new types of targets (metabolites and lipids) toresearch for cancer diagnosis but the data are even more complex than traditional images. The current proposalwill make MSI data accessible to machine learning approaches which will enable researchers and pathologiststo easily correlate known markers with novel metabolite and lipid ion images by addressing several of the currenthurdles. NCI 10743626 9/7/23 0:00 RFA-CA-22-021 1R21CA284233-01 1 R21 CA 284233 1 "OSSANDON, MIGUEL" 9/7/23 0:00 8/31/25 0:00 ZCA1-TCRB-9(M2) 11201459 "JONES, DREW R" Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/7/23 0:00 8/31/25 0:00 394 Non-SBIR/STTR 2023 435827 NCI 257125 178702 PROJECT SUMMARYMass spectrometry imaging (MSI) is a rapidly developing technology which gives pathologists many new typesof targets (e.g. metabolites and lipids) to assess for translational cancer research. However the resulting dataare even more complex than traditional images because they are highly-dimensional and large (~100GB pertissue section). Each pixel in the resulting data structure contains a 2-dimensional mass spectrum made ofboth measured ion mass and ion mobility (m/z 1/K0) and each spectrum typically contains hundreds tothousands of individual ions (metabolites and lipids). Deep-learning methods (machine learning) have beensuccessfully applied to histopathology data by several laboratories including Dr. David Fenyo Co-Investigator ofthe current proposal with such models being able to discriminate between different cancer subtypes and gradesfor example. However most machine learning models of image-data are designed around 3-data channels (RedGreen Blue) for analysis of digital images. Therefore the n-dimensional data structure of mass spectrometryimaging datasets is not easily amenable to these proven machine learning workflows. We will make MSI dataaccessible to these approaches by expanding to n-dimension color-channels with each unique metabolite orlipid image serving as an individual data input. For the deep learning component we will retain the same overallarchitecture and workflow of the Panoptes tool published by Fenyo et. al. (Cell Reports Medicine 2021) butwe will apply an n-dimensional approach and test the data structure on existing data which has parallel H&Estain information annotated by pathologists. These challenges are addressed in Aim1 of the current proposalwhile Aim 2 addresses a closely related challenge of detecting image correlations both within and between thesedata structures and other imaging modalities. Image correlations within such data are more trivial but theseanalyses are not well supported by existing academic or vendor software due to the amount of computationneeded for hundreds of data dimensions. We further propose and test an approach for converting these multi-dimensional data into centroided single ion images followed by linearization of the image to enable a simplePearson correlation metric thereby making a complete correlation matrix accessible by a scaling factor of n2 tothe number of detected ions. Secondly to deal with spatial correlations between MSI datasets and images fromother modalities or adjacent tissue sections which may be different in size and shape we propose to implementa spatially aware elastic transform of the centroided image data prior to correlation analysis and machinelearning. 435827 +No NIH Category available Adenocarcinoma;Affect;Age;Air Sacs;Alveolar;Architecture;Cancerous;Categories;Cell Differentiation process;Cell Line;Cell Nucleus;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Collection;DNA Methylation;Data;Development;Diagnosis;Disease;Disparate;Distal;Epidermal Growth Factor Receptor;Epithelial Cells;Epithelium;Ethnic Origin;Event;Exhibits;Gases;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Green Fluorescent Proteins;Heterogeneity;Histologic;Histology;Human;In Vitro;KRAS2 gene;KRASG12D;Label;Light;Lung;Lung Adenocarcinoma;MADH3 gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Molecular;Monoclonal Antibodies;Morphology;Mus;Mutation;Neoplasm Metastasis;Oncogenic;Outcome;Papillary;Pathologic;Patients;Phenotype;Population;Pre-Clinical Model;Prevention;Proteins;Pulmonary Surfactant-Associated Protein C;Research;Resistance;Role;Scanning;Solid;Surface;Therapy Evaluation;Transforming Growth Factor Beta 2;Transforming Growth Factor beta;Transgenic Mice;Translating;Transplantation;Tumor-Derived;United States;Variant;Vascular Endothelial Growth Factors;X-Ray Computed Tomography;alveolar epithelium;angiogenesis;cancer cell;cancer type;cell type;cohort;driver mutation;effectiveness evaluation;epithelial to mesenchymal transition;genome-wide;improved;in vivo;in vivo evaluation;inhibitor;microCT;mouse model;mutant;never smoker;novel therapeutic intervention;patient expectation;patient population;patient stratification;preclinical evaluation;promoter;response;sex;small molecule inhibitor;surfactant;therapy outcome;transcriptomic profiling;transcriptomics;treatment response;treatment strategy;tumor;tumor microenvironment Elucidating the Cellular Origins of lung adenocarcinoma PLung adenocarcinoma (LUAD) is the largest subtype of lung cancer and has significant heterogeneity in termsof what the cancer cells look like and how well patients survive. LUAD arises in the air sacs which consist ofsurfactant-producing AT2 cells with known roles in cancer and large flat gas-exchange facilitating AT1 cells thathad been thought to lack the ability to serve as a cell of origin for cancer. Here we investigate the role of AT1cells in LUAD development which shifts the current paradigm and establishes that AT1 cells can becomecancerous and give rise to one type of LUAD and may lead to better patient classification and new therapeuticstrategies. NCI 10743611 7/11/23 0:00 PA-20-185 1R01CA262258-01A1 1 R01 CA 262258 1 A1 "JOHNSON, RONALD L" 7/11/23 0:00 6/30/28 0:00 "Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]" 10445311 "MARCONETT, CRYSTAL NICOLE" Not Applicable 37 SURGERY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 7/11/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 494170 NCI 298592 195578 Lung cancer is responsible for the most cancer-related deaths in the United States and Lungadenocarcinoma (LUAD) is the major histologic subtype. LUAD presents clinically with four major histologicsubtypes (lepidic acinar papillary and solid) has variable presentation of EGFR and Kras mutationsdepending on ethnicity age and sex and can be subclassified into four separate categories based ongenome-wide DNA methylation profiles. To date there is little connection between these widely disparatemanifestations of LUAD besides their effects on overall patient survival. There is evidence in mouse modelsto suggest that the majority of LUAD arise from surfactant protein c (Sftpc)-positive alveolar epithelial type2 (AT2) cells and that Scgb1a1-positive club cells can also contribute a fraction of LUAD cases. Howeverit is unknown if LUAD can arise from AT1 cells the other major epithelial cell type in the distal lung thatcovers 95% of the alveolar surface. AT1 cells were historically thought to be terminally differentiated.However we have recently developed a Gramd2-driven CreERT2 mouse model that specifically activatedthe KrasG12D oncogenic driver in AT1 cells and found that AT1 cells can serve as a cell of origin for LUADwith predominantly papillary histology and distinct transcriptomic signatures including increasedtransforming growth factor beta (TGF-)-mediated epithelial to mesenchymal transition (EMT). This is incontrast to AT2 cell-specific Sftpc-driven KrasG12D which resulted exclusively in lepidic LUAD and wasenriched for VEGF-mediated angiogenesis. Therefore we hypothesize that LUAD as it is currently definedmay actually be a collection of at least 4 adenocarcinoma subtypes that arise in the distal alveolarcompartment from different cells of origin and that the great variation we see in LUAD presentation andclinical outcome can be explained in part by which cell type LUAD arises in. However; several questionsremain. We do not know if the oncogenic driver in AT1 cells influences histologic presentation. We willtherefore (Aim 1) characterize Gramd2-CreERT2 driven EGFR mutations the other major oncogenic driverin LUAD. It is also possible that induction of KrasG12D in AT1 cells results in disrupted tumormicroenvironments that stimulate AT2 cells; we will therefore (2) perform GFP+ lineage tracing to determinein vitro and in vivo cell contributions to tumor formation. We will also establish the translational implicationsof our prior research (Aim 3) and utilize inhibitors of TGF that have succeeded in preclinical models butfailed in clinical trials to determine if cell of origin influences response to therapy in both mouse models andunique human patient LUAD cohorts. Understanding the connection between cell of origin and clinicalpresentation will allow for enhanced patient stratification improved assessment of best therapeuticoutcomes and potential reclassification of LUAD into multiple cancer types. 494170 +No NIH Category available Acute Myelocytic Leukemia;Age;Aging;Alleles;Anti-Inflammatory Agents;Attenuated;Automobile Driving;Bone Marrow;CRISPR screen;Candidate Disease Gene;Cardiovascular Diseases;Cells;ChIP-seq;Chemicals;Chronic;Clinical;Clonal Expansion;Coculture Techniques;Complex;Credentialing;Custom;Dependence;Development;Development Plans;Doctor of Philosophy;Elderly;Endothelial Cells;Environment;Epigenetic Process;Feedback;Foundations;Gene Expression;Gene Targeting;Genes;Genetic;Genetic Transcription;Genotype;Goals;Hematologic Neoplasms;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;High Prevalence;Human;Immune response;Incidence;Inflammaging;Inflammation;Inflammation Mediators;Inflammatory;Institution;Interleukin-1;Interleukin-6;Knock-out;Knowledge;Laboratories;Libraries;Ligands;Link;Malignant - descriptor;Mediator;Memorial Sloan-Kettering Cancer Center;Mus;Mutation;Myeloid Cells;Non-Hematologic Malignancy;Pathology;Pathway interactions;Patients;Postdoctoral Fellow;Research;Resources;Risk;Role;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;Somatic Mutation;System;TNF gene;Testing;Training;Work;acute myeloid leukemia cell;adverse outcome;anticancer research;cancer therapy;career development;cell type;cohort;cytokine;design;epigenomics;fitness;graduate school;in vivo engraftment;inflammatory milieu;inhibitor;leukemia;leukemic transformation;mortality;mouse model;multiple omics;mutant;new therapeutic target;novel;novel therapeutics;pre-doctoral;precision medicine;pressure;prevent;rational design;research and development;self-renewal;small molecule;small molecule inhibitor;therapeutic target;therapeutically effective;transcriptomics Identifying Inflammatory Mediators of Clonal Hematopoiesis PROJECT NARRATIVEClonal hematopoiesis (CH) increases the risk of acute myeloid leukemia and mortality of cardiovascular diseaseand non-hematological cancers and is associated with increased inflammation which confers a selectiveadvantage to CH-mutant hematopoietic stem and progenitor cells (HSPCs). My predoctoral research will identifyinflammatory gene targets essential to CH-mutant HSPCs but not wild-type counterparts to restore oligoclonalhematopoiesis while avoiding disrupting global immune responses. In addition my postdoctoral direction willreveal the unique transcriptional and epigenetic circuitries that age-related inflammation exploits in CH-mutantHSPCs to promote their expansion critical knowledge to developing precision medicine therapies to prevent CHprogression to leukemia. NCI 10743540 8/16/23 0:00 RFA-CA-22-041 1F99CA284253-01 1 F99 CA 284253 1 "ODEH, HANA M" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 78905027 "FERNANDEZ MAESTRE, INES " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 PROJECT SUMMARY/ABSTRACTClonal hematopoiesis (CH) is a common phenomenon defined as the presence of somatic mutations inhematopoietic stem and progenitor cells (HSPCs) and their expansion in the absence of overt hematologicaldisease. CH-mutant mature myeloid cells are believed to generate an inflammatory microenvironmentpromoting the fitness advantage of mutant HSPCs. These in turn would expand at higher rates and differentiateinto more elevated numbers of myeloid cells thereby establishing a positive feedback loop between inflammatorysignaling and clonal expansion. Yet whether CH-mutant HSPCs can also trigger cell-autonomous inflammatorysignaling to provide a selective clonal advantage for themselves remains unknown. CH increases the risk ofhematological malignancy cardiovascular disease and mortality from solid tumors. Due to these adverseoutcomes and the high prevalence of CH in the elderly there is an unmet need to develop novel therapies.Targeting inflammation specifically in mutant HSPCs to avoid disruption of general immune responses maybe a potentially effective strategy. My predoctoral research (Aim 1) aims to identify inflammatory mediators ofCH-mutant HSPCs and evaluate their potential as therapeutic targets to restore oligoclonal hematopoiesis. Tofind novel cell-autonomous inflammatory pathways in CH I have designed an sgRNA library to targetinflammation-associated genes. Using this library for high-throughput CRISPR/Cas9 screening I have identifiedboth general and genotype-specific inflammatory dependencies of CH-mutant murine HSPCs. In this proposalSpecific Aim 1.1 seeks to validate the negative selection hits demonstrate that when present the hit genesconfer a selective advantage to CH-mutant HSPCs versus wild-type counterparts and delineate the specific roleof credential top hits in clonal expansion. In Specific Aim 1.2 I will use small molecule inhibitors targetingthe candidate genes both ex vivo and in mice to identify gene expression and cytokine profile changesspanning the hematopoietic cell subsets. I will then assess differences between genetic and chemical approachesconcerning their efficiency in achieving adequate target inhibition. My postdoctoral research (Aim 2) will focuson the role of inflammation at the nexus of aging and CH by uncovering the transcriptional and epigeneticmechanisms by which age-related inflammation promotes CH and potential malignant transformation toleukemia. Overall these two projects which will use human samples to validate the mouse findings will lead todeveloping new therapies targeting inflammation to halt or revert CH and mitigate its clinical sequelae. I theapplicant will conduct this proposal in the laboratory of Dr. Ross Levine at Memorial Sloan Kettering CancerCenter (MSK) one of the world's leading institutions in cancer treatment and research. MSK's rich environmentand abundant resources in conjunction with the support of the Gerstner Sloan Kettering Graduate Schoolguarantee the successful completion of the proposed research and career development plans. 49194 +No NIH Category available Adult;Allografting;Attenuated;Automobile Driving;Behavior;Bioinformatics;Biological Assay;Biological Models;Brain Neoplasms;Cell Survival;Cell model;Cell physiology;Cells;Characteristics;Clinical;Clonal Evolution;Coculture Techniques;Data;Dedications;Dependence;Development;Endowment;Environment;Event;Fatal Outcome;Gene Expression Profile;Genetic;Glioblastoma;Glioma;Goals;Grant;Growth;Heterogeneity;Hypoxia;Immune;Immune Evasion;Immune Targeting;Immune checkpoint inhibitor;Immune response;Immunocompetent;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Vitro;Interdisciplinary Study;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Mesenchymal;Metabolic;Methods;Modeling;Molecular;Mus;Nutrient;Oncogenic;Patients;Pharmaceutical Preparations;Phase;Phenotype;Population;Prognosis;Receptor Inhibition;Receptor Signaling;Regulatory T-Lymphocyte;Research;Resistance;Signal Induction;Signal Transduction;Specimen;T-Lymphocyte;TGFBR2 gene;Techniques;Technology;Therapeutic;Tissues;Training;Transgenic Organisms;Tumor Immunity;Tumor Promotion;Tumor-infiltrating immune cells;Vaccines;anti-tumor immune response;cancer stem cell;cell dedifferentiation;checkpoint therapy;chimeric antigen receptor T cells;clinical translation;effective therapy;immune cell infiltrate;improved;in vivo;inhibitor;interdisciplinary approach;knock-down;metabolic profile;metabolomics;molecular subtypes;neoplastic cell;novel;novel strategies;novel therapeutics;pharmacologic;pre-clinical;pressure;programs;response;self-renewal;single cell sequencing;single-cell RNA sequencing;small hairpin RNA;small molecule;small molecule inhibitor;stem;stem cell biology;stem cell function;stem cells;stem-like cell;targeted treatment;therapeutic target;therapy resistant;trait;transcription factor;transcriptional reprogramming;transcriptome sequencing;transcriptomics;translatable strategy;tumor;tumor growth;tumor heterogeneity;tumor microenvironment;tumor progression Dissecting the tumor cell-immune TME axis to identify therapeutically actionable vulnerabilities that potentiate immunotherapy in GBM Glioblastoma multiforme a common and highly aggressive form of brain cancer with a universally fatal outcomeis characterized by a vast degree of heterogeneity and an immune-suppressive tumor microenvironment drivenby cancer stem cells. Our preliminary results show that glioma cancer stem cells activate cell-intrinsicmechanisms to drive and maintain a unique immunosuppressive cell phenotype and suggest that targetingimmunosuppressive GBM cells will boost the anti-tumor immune response. Favorable results from this proposalwill provide a rationale for combining therapeutics directed at immunosuppressive GBM cells with otherimmunotherapies (e.g. checkpoint inhibitors CAR-T cells vaccines) to treat brain tumors. NCI 10743534 8/17/23 0:00 RFA-CA-22-041 1F99CA284254-01 1 F99 CA 284254 1 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 78409503 "JOHNSON, AMANDA " Not Applicable 7 OTHER BASIC SCIENCES 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 Glioblastoma multiforme (GBM) is a common and highly aggressive form of brain cancer in adults with a dismalprognosis and limited therapeutic options. A critical component of GBM malignancy derives from the distinctpopulation of glioma stem cells (GSCs) that function to promote and maintain malignancy through their capacityfor self-renewal cellular adaptation and multipotency. These stem-like cells engage in a synergistic relationshipwith the surrounding microenvironment to promote tumor progression and are key drivers of intratumoralheterogeneity immune-suppression and therapy resistance. Targeting GSCs and mechanisms that drive thestem-like phenotype presents a promising avenue for targeted therapeutics. The broad goal of this proposal is to understand the cell-intrinsic mechanisms driving maintenance of aunique immunosuppressive GSC subset identify cellular vulnerabilities associated with immunosuppressiveGBM cells and develop preclinical therapeutics to target these cells. We will achieve this goal by utilizing ourvalidated GSC cell models state-of-the art single-cell sequencing technology and cutting-edge spatiallyresolved omics platforms applied to clinical GBM specimens and advanced molecular in vitro techniques todefine immunosuppressive tumor cell populations and determine the transcriptomic and metabolic changesassociated with these cell populations that are amenable to therapeutic targeting. Our preliminary findings demonstrate that TGF-beta type II receptor (TGFBR2) signaling induces aTGFBR2high subset of GSCs that co-opt certain immunosuppressive mechanisms associated with and utilized byregulatory T cells (Tregs) to exert immunosuppressive behavior. In the F99 phase we will investigate thepotential for boosting the anti-tumor immune response by targeting this specific subset of TGFBR2-inducedimmunosuppressive GSCs endowed with Treg-like capabilities. To do so we will utilize inducible shRNAconstructs and a clinically translatable small-molecule drug to inhibit TGFBR2 in orthotopic tumor allografts inimmune-competent mice and analyze the effects on tumor growth immune cell infiltration and function andcooperativity with check point inhibitor therapy. In the K00 phase we will conduct spatially resolvedtranscriptomics and metabolomics on patient GBM tissue specimens to identify potential metabolic vulnerabilitiesin immunosuppressive GBM cells. Metabolic inhibitors will be utilized to exploit candidate vulnerabilities in anattempt to attenuate the transcriptomic and functional immune-suppressive characteristics of these cells.Subsequently validated metabolic vulnerabilities will be targeted in vivo to assess the effects on tumor growthand the anti-tumor immune response. Our proposed methods of pharmacological TGFBR2 inhibition andmetabolic exploitation will inform the development of novel strategies to reprogram the GBM microenvironmentand enhance anti-tumor immune responses when combined with current emerging immunotherapeutics (e.g.checkpoint inhibitors CAR-T cell technology vaccines). 49194 +No NIH Category available American;Antitumor Response;Apoptosis;Binding;CASP3 gene;CD8-Positive T-Lymphocytes;Cancer Patient;Cell Separation;Cell Survival;Cell secretion;Cells;Characteristics;Cutaneous Melanoma;Cytoplasmic Tail;Data;Diagnosis;Disease;Exhibits;FOXP3 gene;Fc Receptor;Fibrinogen;Flow Cytometry;Future;Gene set enrichment analysis;Goals;Grant;Hematopoietic;Homeostasis;Human;ITIM;Immune;Immune response;Immunity;Immunotherapeutic agent;Immunotherapy;Induction of Apoptosis;Infiltration;Inflammatory;Institution;Interferon Type II;Investigation;Knock-out;Label;Ligand Binding;Ligands;Malignant Neoplasms;Mediating;Memory;Modeling;Molecular;Mus;Pathway interactions;Patient-Focused Outcomes;Patients;Peptides;Phenotype;Population;Postdoctoral Fellow;Production;Prognostic Marker;Protein Secretion;Proteins;Proteomics;Publications;RNA;Regulation;Regulatory T-Lymphocyte;Research;Resistance;Role;Sampling;Signal Transduction;Skin;Skin Cancer;Source;Surface;T cell response;T-Cell Receptor;T-Lymphocyte;TNF gene;Transgenic Mice;Transgenic Organisms;Work;autocrine;cancer immunotherapy;cancer infiltrating T cells;cell type;cytokine;cytotoxic CD8 T cells;exhaust;fighting;improved;melanoma;mouse model;multiple omics;novel;patient response;programmed cell death protein 1;receptor;receptor binding;recruit;resistance mechanism;response;response biomarker;single-cell RNA sequencing;success;therapeutic target;transcriptomics;transmission process;tumor;tumor microenvironment Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells PROJECT NARRATIVECD8+ T cells are crucial immune cells in our bodys fight against cancer and the degree to which CD8+ T cellstraffic to and infiltrate the tumor greatly impacts cancer patient survival especially melanoma patient survival.The F99 section of this proposal focuses on a new pathway existing between CD8+ T cells and a protein presentat the tumor that negatively impacts CD8+ T-cell survival. Through mouse models we will illuminate thismechanism to be able to block this negative interaction between CD8+ T cells and this suppressive protein toincrease CD8+ T-cell survival and ultimately improve melanoma patient survival. NCI 10743485 8/16/23 0:00 RFA-CA-22-041 1F99CA284255-01 1 F99 CA 284255 1 "ELJANNE, MARIAM" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 16063615 "BENNION, KELSEY " Not Applicable 5 SURGERY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 PROJECT SUMMARYOne in fifty Americans will be diagnosed with melanoma in their lifetime and skin cutaneous melanoma is thedeadliest skin cancer. Cancer immunotherapy is a breakthrough approach to treat this disease and cytotoxicCD8+ T-cell tumor infiltration is a critical factor to immunotherapeutic success. As such identifying effectivestrategies to increase the magnitude and functionality of the patients tumor-specific CD8+ T-cell responseremains an important goal. Inhibitory molecules on CD8+ T cells are imperative to T-cell signaling and immunehomeostasis. However elevated expression of these molecules is correlated with dampened antitumor effectorresponse as well as poorer patient survival. FcRIIB is an inhibitory Fc receptor recently discovered on a subsetof CD8+ T cells. FcRIIB+ CD8+ T cells exhibit increased expression of activation markers higher proliferativeability and secrete more proinflammatory cytokines than their FcRIIB- counterparts in mice and humansmaking them imperative to the antitumor response. Recently we discovered that an immunosuppressivecytokine fibrinogen-like protein 2 (Fgl2) is a ligand that binds FcRIIB on CD8+ T cells and induces FcRIIB-mediated apoptosis of CD8+ T cells. The goal of this research is to interrogate the mechanism by which Fgl2regulates tumor-specific FcRIIB+ CD8+ T cells using syngeneic mouse models via the following aim. AIM 1(F99): Determine the cellular and molecular mechanism by which Fgl2 critically regulates tumor-specificCD8+ T cells. Our studies show that both Foxp3+ regulatory T cells and CD8+ T cells express Fgl2 at the tumorsof mice and humans. Thus we will determine if Fgl2 secreted by these cell types is necessary and/or sufficientfor FcRIIB-mediated CD8+ T-cell apoptosis findings which would provide the impetus for subsequenttherapeutic targeting of this cell type. Additionally as we have discovered that FcRIIB-Fgl2 binding inducesapoptosis the upstream requirements of apoptosis (e.g. T-cell receptor stimulation proteins recruited to theintracellular domain of FcRIIB) are proximal items of investigation in the latter part of Aim 1. Piecing togetherthe pathway by which FcRIIB induces apoptosis via Fgl2 could uncover a new CD8+ T cell pathway readilyharnessed for future immunotherapies. AIM 2 (K00): Identify novel mechanisms of T cell resistance tocancer immunotherapy. After the F99 stage I intend to transition to the K00 stage to begin postdoctoral studies.Numerous studies highlight the role of elevated checkpoint molecule expression (PD-1 TIM-3) as well asdecreased proinflammatory cytokine production (IFN TNF) in mediating resistance to ICB. The currentparadigm in cancer immunotherapy revolves around the suppressive impact of the tumor microenvironment onT cells but the existence and impact of immunosuppressive factors secreted by effector CD8+ T cells themselvesis incompletely understood. The impact of the proposed aims is considerable as they will identify novel targetsthat could rescue a population of memory CD8+ T cells that are crucial to the immune response to tumor. 49194 +No NIH Category available Address;Affinity;Alloys;Animal Model;Antibodies;Antibody Specificity;Binding;Biological Assay;Breast Cancer Model;Cancer Detection;Cell Culture Techniques;Clinical;Coupled;Deposition;Detection;Development;Diffuse;Disease;Engineering;Excision;G-substrate;Goals;Image;Image-Guided Surgery;Imaging technology;Immunoglobulin G;Individual;Label;Lanthanoid Series Elements;Lasers;Left;Lymph Node Involvement;Malignant Neoplasms;Malignant neoplasm of prostate;Microscope;Microscopic;Modeling;Modernization;Mus;Nanotechnology;Nature;Operative Surgical Procedures;Optics;Outcome;Patients;Photons;Protein Engineering;Proteins;Recombinants;Resectable;Residual Cancers;Residual Neoplasm;Sensitivity and Specificity;Silicon;Speed;Surface;Surgical Instruments;Surgical Models;Surgical margins;Technology;Testing;Thinness;Time;Tissue Sample;Tissue Stains;Tissue imaging;Tissues;Toxic effect;Visible Radiation;Visualization;Xenograft Model;absorption;antibody engineering;biomaterial compatibility;cancer care;cancer cell;cancer imaging;cancer risk;cancer subtypes;cancer surgery;crosslink;design;detector;diagnostic platform;fluorophore;imager;imaging modality;improved;improved outcome;instrument;instrumentation;integrated circuit;light emission;lymph nodes;malignant breast neoplasm;meter;microscopic imaging;molecular imaging;nano;nanocrystal;nanoparticle;nanoshell;neoplastic cell;new technology;novel;optical imaging;pre-clinical;sensor;theranostics;tool;tumor;two-photon Chip-Scale Intraoperative Optical Navigation with Immunotargeted Upconverting Nanoparticles Project NarrativeCurative cancer surgery requires removal of all cancer cells - however 20-40% of the timemicroscopic tumor cells are left behind significantly increasing the chance of cancer returning.The goal of this project is to solve this problem through development of an ultrasensitivetechnology to visualize individual cancers cells in tissue and during surgery. It integratesnanotechnology protein engineering and advanced microscope design with the goal ofintraoperative imaging of cancer cells with far greater sensitivity than available now. NCI 10743477 6/12/23 0:00 PAR-22-071 1R01CA278672-01A1 1 R01 CA 278672 1 A1 "SALVADOR MORALES, CAROLINA" 6/15/23 0:00 5/31/27 0:00 Special Emphasis Panel[ZRG1-MCST-U(55)R] 12633120 "ANWAR, MEKHAIL " "COHEN, BRUCE E" 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 6/15/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 655333 NCI 410586 244747 Project Summary/Abstract Residual cancer cells left behind following surgery increase the chance of cancer returningin almost every cancer subtype. The current inability to identify these tumor cells during surgeryhinders cancer care across the spectrum including breast and prostate cancers as 20-40% ofthese patients suffer from positive margins which doubles the risk of cancer returning. This proposal solves this problem through an original approach for ultrasensitive opticalimaging of cancer cells in live tissue and during surgery. Current intraoperative imaging methodsare unable to achieve high sensitivity both on the tissue surface and at depth due to inherentphysical limits of both current optical probes and their requisite imagers. They are also too bulkyto be integrated onto modern surgical tools which could guide precision surgery with far greateraccuracy than achievable today. Here we address these dual challenges by introducing a whollynew imaging strategy integrating nanotechnology protein engineering and advanced imagerdesign with the goal of real-time highly sensitive intraoperative imaging of cancer cells both onthe surface and at depth. We propose major advances in nanotechnology to redesignupconverting nanoparticles as optical probes that can be safely imaged in tissue proteinengineering to produce antibodies that selectively target the probes to tumor and detectorengineering to build an ultrathin imaging chip directly integrated into surgical instrumentation.The combination of these novel technologies transforms instruments themselves into imagers todramatically increase the sensitivity in identifying cancer cells with the ultimate goal of being ableto identify in real time all residual disease. 655333 +No NIH Category available Anabolism;Automobile Driving;Bioenergetics;CRISPR screen;Cancer Etiology;Cell Differentiation process;Cell Survival;Cells;Cessation of life;Coenzymes;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Colorectal Neoplasms;Common Neoplasm;Communication;Data;Development;Electron Microscopy;Electron Transport;Electron Transport Complex III;Electrons;Endoplasmic Reticulum;Enzymes;Epithelium;Fellowship;Foundations;Genetic;Genetic Screening;Genetically Engineered Mouse;Goals;Homeostasis;Hypoxia;Image;In Vitro;Intestines;Ions;Knowledge;Lipids;Maintenance;Malignant Neoplasms;Mentorship;Metabolic;Metabolic Pathway;Metabolism;Metaplasia;Methods;Mitochondria;Modeling;Molecular;Monitor;Mus;Organelles;Organoids;Oxidation-Reduction;Oxidative Phosphorylation;Pathway interactions;Patients;Phase;Postdoctoral Fellow;Pre-Clinical Model;Principal Investigator;Process;Proliferating;Pyrimidine;Reaction;Regulation;Reporter;Repression;Research;Research Personnel;Research Proposals;Respiration;Role;Sampling;Scanning Electron Microscopy;Science;Shapes;Site;Sterols;Stimulus;System;Therapeutic;Training;Ubiquinone;Work;cancer cell;career;career development;colon cancer cell line;colon cancer patients;colorectal cancer progression;complex IV;genome-wide;graduate school;improved outcome;in vivo;in vivo Model;inducible Cre;innovation;knowledge base;lipid biosynthesis;lipidomics;metabolic fitness;metabolomics;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;oxidation;pharmacologic;pressure;response;stem cell expansion;stem cells;stressor;treatment response;tumor;tumor growth;tumor hypoxia;tumor metabolism;tumor microenvironment;tumor progression Inter-organellar communication in metabolic reprogramming of colorectal cancer PROJECT NARRATIVEMetabolic reprogramming is required in colorectal cancer to maintain cellular plasticity and to thrive in theanoxic lumen. There is a strong body of research that coordinated inter-organellar interactions of endoplasmicreticulum-mitochondria are essential for compartmentalized metabolism. The proposed research will fill a majorgap in the fundamental understanding of the mechanisms in which endoplasmic reticulum-mitochondria drivecolon cancer metabolism and cell fate dynamics. NCI 10743454 8/25/23 0:00 RFA-CA-22-041 1F99CA284256-01 1 F99 CA 284256 1 "ODEH, HANA M" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-7(M1) 16562945 "CHEN, BRANDON " Not Applicable 6 PHYSIOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 42314 NCI 42314 0 PROJECT SUMMARYColorectal cancers (CRC) are characterized as having a hierarchical organization requiring proliferating andde-differentiated stem cells to maintain tumor growth and progression. Cellular plasticity underlying colorectalcancer is essential for a process which occurs following selective pressures of the tumor microenvironmentand chemotherapeutics. The colonic tumor microenvironment is characterized by extreme hypoxia due to theanoxic lumen. Hypoxia promotes metabolic rewiring and such processes are utilized by cancer cells to supportbiosynthesis cell survival and dynamic alteration in cell fates. A critical feature of cellular metabolism isorganellar interaction and coordination yet how these contribute to CRC plasticity survival progression andtreatment response are unclear. Endoplasmic reticulum-mitochondria contact sites (ERMCS) are the mostabundant inter-organellar interaction. I generated a panel of ERMCS reporter CRC cell lines and throughunbiased high content imaging and CRISPR screens I have identified essential mechanisms required for ER-mitochondrial interactions in CRC. Moreover I show a key role of tumor hypoxia in modulating ERMCS.Hypoxia inhibited mitochondrial complex III and IV to decrease ERMCS. Treating cells with the mitochondrialelectron carrier coenzyme (CoQ) rescued ERMCS suppression following hypoxia. I hypothesize that tumorhypoxia regulates ER-mitochondrial contacts (ERMCS) by altering mitochondrial respiration and CoQ redox formetabolic adaptation and survival. In aim 1 (F99 phase) I will focus on identifying the molecular mechanism ofhypoxia dependent ERMCS inhibition and expand into in vivo models with our novel ERMCS reporter mousemodel. During the K00 phase I will apply knowledge gained during graduate school in cancer metabolism andorganellar interaction to an independent postdoctoral project. The plasticity of colorectal tumor epitheliumdepends on integration of organellar functions to sustain metabolic demands. Therefore my goal as apostdoctoral fellow is to understand the dynamic changes and requirement for organellar interactions andmetabolic compartmentalization during cell fates alterations in CRC. I plan to use genetic murine and primarypatient organoid models of CRC volumetric electron microscopy in vivo organellar metabolomics andfunctional CRISPR screens to answer these questions. Lastly in addition to the proposed studies this trainingplan includes activities important for career development mentorship networking and scientificcommunication to prepare me for successful transition to a postdoctoral fellowship and my career as anindependent investigator studying cancer metabolism. 42314 +No NIH Category available 5'-Nucleotidase;Ablation;Abscopal effect;Adenocarcinoma;Adenosine;Adoption;Animal Model;Antitumor Response;CXCR4 gene;Cells;Chemotherapy and/or radiation;Clinical;Clinical Trials;Clinical Trials Design;Coagulative necrosis;Collaborations;Collagen;Combination immunotherapy;Combined Modality Therapy;Contralateral;Data;Deposition;Desmoplastic;Development;Diagnosis;Disease;Drug Delivery Systems;Endoscopic Ultrasonography;Evaluation;Excision;Failure;Fibroblasts;Funding;Future;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Granzyme;Health;Hypoxia;Image;Immune;Immune Targeting;Immune checkpoint inhibitor;Immunologic Stimulation;Immunosuppression;Immunotherapy;Incidence;Infrastructure;Institution;Knowledge;Life;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mediating;Mission;Modeling;Monitor;Mus;Outcome;Pancreatic Ductal Adenocarcinoma;Pancreatic duct;Patient-Focused Outcomes;Patients;Phase;Phase II Clinical Trials;Pre-Clinical Model;Publishing;Radiofrequency Interstitial Ablation;Research;Research Personnel;Resectable;Resected;Safety;Serum;Site;Stromal Cell-Derived Factor 1;Survival Rate;TNFRSF5 gene;Techniques;Testing;Therapeutic;Therapeutic Intervention;Tumor Immunity;Tumor Tissue;United States National Institutes of Health;Unresectable;Vascularization;anti-PD-L1;anti-tumor immune response;arm;bench to bedside;cancer clinical trial;cancer diagnosis;cancer infiltrating T cells;cancer therapy;chemotherapy;clinical care;clinically relevant;early phase clinical trial;immune activation;immune checkpoint blockade;immunomodulatory therapies;immunoregulation;improved;improved outcome;in vivo;inhibitor;innovation;minimally invasive;neovascularization;novel;novel therapeutic intervention;participant enrollment;phase 2 study;pre-clinical;primary outcome;programmed cell death ligand 1;programs;public health relevance;response;response biomarker;safety and feasibility;secondary outcome;single-cell RNA sequencing;standard of care;subcutaneous;success;survival outcome;targeted treatment;therapy resistant;transcriptomics;treatment response;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions A single-arm phase II study to evaluate the safety and efficacy of combination systematic chemotherapy and multiple rounds of endoscopic ultrasound-guided radiofrequency ablation in pancreatic cancer PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCEWe have created an innovative clinical and translational radiofrequency ablation (RFA) collaboration to studyRFA in pancreatic ductal adenocarcinoma (PDAC). This proposal is a phase II single-arm clinical trial to evaluateoutcomes using repeated Endoscopic ultrasound guided (EUS) RFA that leverages our strong clinical andpreclinical platform to explore immunotherapy strategies in combination with RFA to improve clinical trials andoverall survival for patients with PDAC. Thus the proposed research is relevant to part of the NIH's mission thatpertains to developing fundamental knowledge that will enhance health lengthen life and reduce illness. NCI 10743356 5/23/23 0:00 PAR-21-033 1R01CA277161-01A1 1 R01 CA 277161 1 A1 "VIKRAM, BHADRASAIN" 7/1/23 0:00 6/30/28 0:00 Clinical Oncology Study Section[CONC] 10459984 "LUNDBERG, JENNIFER BAILEY" "THOSANI, NIRAV " 18 ANESTHESIOLOGY 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF MEDICINE 770305400 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 676081 NCI 448134 227947 PROJECT SUMMARY/ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy and is often diagnosed ata late stage limiting treatment options. A contributing factor to therapeutic failure is profound desmoplasia anda well-documented hypoxic and immunosuppressive tumor microenvironment (TME). In PDAC severaltherapeutic approaches including chemotherapy and radiation alone or combined with immune checkpointinhibitors have shown minimal therapeutic success. Endoscopic ultrasound guided radiofrequency ablation(EUS-RFA) is a promising local ablative stromal and immunomodulator therapy for PDAC. We have establisheda comprehensive research program to evaluate therapeutic benefits of EUS-RFA in patients with resectablePDAC. In tandem we have published a preclinical model to test how RFA treatment alters the TME in the localablation site or systemically through evaluation of contralateral tumors (abscopal effect). Successfulamalgamation of our clinical and murine data will reveal mechanistic understanding of RFA-mediated immunestimulation immune inhibitory checkpoints and RFA-immunotherapy combination strategies to improve PDACsurvival outcomes. We recently established the safety and feasibility of a minimally invasive repeatabletechnique that can be used with systemic chemotherapy: EUS-RFA. Our phase II clinical trial (PANCARDINAL-1) with 12 enrolled patients demonstrates the tolerability safety and feasibility of repeated EUS-RFA withstandard chemotherapy for resectable PDAC. We further found CD40 in patient serum is elevated post EUS-RFA indicating immune activation and anti-tumor immunity. Using our preclinical model we have also shownCD73 or PD-L1 inhibition augments RFA-mediated tumor growth reduction. Given these findings wehypothesize that a multipronged approach that targets immune checkpoint blockade and immunosuppression incombination with RFA will improve future clinical trial design with EUS-RFA and improve PDAC survivaloutcomes. We propose the following Specific Aims: Aim 1: Evaluate effects of chemotherapy with repeatedEUS-RFA on tumor growth long-term outcomes and anti-tumor immunity mechanisms in resectable PDACpatients (PANCARDINAL-1 Trial) and Aim 2: Determine impact of repeated RFA treatment in sustaining anti-tumor immunity and improving drug delivery with and without novel combined immunotherapies. Impact andInnovation: This proposal is the first to execute a clinical trial examining EUS-RFA for improving chemotherapy-based treatment of PDAC. Through complementary incorporation of clinically relevant animal models we willidentify novel therapeutic strategies for future studies. This funding will solidify establishment of aPANCARDINAL Network to serve as a pipeline for ongoing bench-to-bedside approaches to establish a newstandard of care for the treatment of PDAC. 676081 +No NIH Category available 4T1;Autophagocytosis;Autophagosome;Biogenesis;Breast Cancer cell line;Cell Survival;Cells;Chloroquine;Culture Media;DNA Damage;Docking;Fluorescence;Goals;Harvest;Human;Hypoxia;Immune;Immunotherapy;In Vitro;Intercellular Fluid;Knock-out;Knowledge;Length;Link;Lysosomes;MDA MB 231;Malignant Neoplasms;Mammary Neoplasms;Measurement;Metabolic;Methods;Mitochondria;Mitochondrial DNA;Mitochondrial Proteins;Molecular;Molecular Analysis;Monitor;Morphology;Mus;Needles;Organelles;Outcome;Oxidative Stress;Oxidative Stress Induction;PINK1 gene;Pathway interactions;Peripheral;Phenotype;Population;Process;Protein Export Pathway;Proteins;Publishing;Radiation therapy;Role;Sampling;Sirolimus;Solid Neoplasm;Stress;System;Testing;Therapeutic;aspirate;bafilomycin A1;cancer cell;cancer therapy;chemotherapy;clinically relevant;extracellular;extracellular vesicles;improved;in vivo;in vivo monitoring;knock-down;neoplastic cell;new therapeutic target;particle;pressure;prevent;real time monitoring;recruit;sensor;therapeutic target;therapy resistant;tool;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor progression Secretory Mitophagy in Cancer Metabolic Reprogramming We have discovered a new mitochondrial metabolic adaptation process called secretory mitophagy that usedby cancer cells to survive under the stress of chemotherapy radiotherapy and molecular therapy. Under theAims we will explore the molecular controls of this process in vitro and in vivo because it constitutes a newtherapeutic target and a clinically-relevant means to monitor the ongoing efficacy of cancer therapy. NCI 10743163 7/11/23 0:00 PAR-21-061 1R21CA284201-01 1 R21 CA 284201 1 "RODRIGUEZ, LARITZA MARIA" 7/11/23 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-BTC-J(55)R] 15558313 "HOWARD, MARISSA ASHTON" Not Applicable 11 OTHER BASIC SCIENCES 77817450 EADLFP7Z72E5 77817450 EADLFP7Z72E5 US 38.834433 -77.310955 819801 GEORGE MASON UNIVERSITY FAIRFAX VA SCHOOLS OF ARTS AND SCIENCES 220304422 UNITED STATES N 7/11/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 204502 NCI 140250 64252 Tumor metabolic reprogramming is a hallmark of cancer progression survival and therapeutic resistance. Atargetable class of cancer metabolic adaptation exploits mitophagy a specialized autophagy pathway known tobe linked to the cancer phenotype. Mitophagy selectively eliminates dysfunctional mitochondria by targetingthem via autophagosome shuttling to the lysosome for degradation. Cancer cell mitophagy is triggered byelevated oxidative stress and mitochondria DNA damage caused by hypoxia radiotherapy molecular therapyand immunotherapy. A high mitophagy demand can overwhelm the lysosome capacity resulting in theaccumulation of damaged mitochondria that is harmful to the cell and can suppress biogenesis of healthymitochondria. We hypothesize that the newly discovered process of secretory mitophagy exports damagedmitochondrial fission-released segments to reduce the overload pressure on the lysosomal system and therebysustains cancer cell survival in the face of therapeutic mitochondrial stress. We have discovered a form ofsecretory mitophagy occurring in vivo in a growing solid tumor. Our molecular analysis of the full repertoire ofextracellular vesicles (EV) shed into the resident tumor interstitial fluid (IF) in vivo yielded a rich set of informationabout the functional state of mitochondria within the tumor cells and the host cells. Within tumor interstitial fluidand within the culture media of cancer cells undergoing oxidative stress we identified an EV-packaged full setof mitochondria molecules comprising the peripheral fission pinched-off segment of the mitochondrial organelle.It has recently been found that peripheral mitophagy fission regulated by mitochondrial fission 1 protein (FIS1)is a key essential regulator of mitophagy and is distinct from mid-zone mitochondria fission associated withmitochondria biogenesis. We also found that mitophagy inducer PTEN induced kinase 1 (PINK1) cleavage status(full length versus cleaved) is prominently reflected in the set of mitochondrial proteins exported within IF EVsand may constitute a new quantitative measurement tool to monitor the real-time state of tumor intracellularmitophagy. Our findings raise important mechanistic questions that we will explore in the Aims concerning theunknown intracellular steps of secretory mitophagy and how the content of the exported EVs reflects the internalmitophagy state. Under Aim 1 we will test the hypothesis that peripheral fission secretory mitophagy is inducedby high mitophagy demands that overwhelm lysosomal engulfment and explore if secretory mitophagy is distinctfrom secretory autophagy within the murine 4T1 and human MDA-MB-231 triple negative breast cancer celllines. Under Aim 2 we will test the hypothesis that the ratio of full length to cleaved PINK1 is elevated(mitochondria damage sensor) within the exported murine syngeneic breast tumor interstitial fluid EVs followingtreatment with mitophagy inducers Mito-CP and Rapamycin. The outcome is new understanding of theimportance of secretory mitophagy that can constitute an important therapeutic target and a new clinicallyrelevant means of monitoring the in vivo state of mitophagic flux within the tumor microenvironment. 204502 +No NIH Category available Acceleration;Address;Adolescent and Young Adult;Affect;Binding;Biochemical;Biochemistry;Biological Assay;Biological Models;Biological Process;CRISPR/Cas technology;Cancer Model;Catalytic Domain;Cell Cycle;Cell Line;Cell Proliferation;Cell Survival;Cell division;Cells;Centrosome;Chemoresistance;Childhood Liver Cancer;Chimera organism;Chimeric Proteins;Clinical;Clinical Trials;Co-Immunoprecipitations;Collaborations;Colorectal Cancer;Complex;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease;Disease Resistance;Event;Excision;Expression Profiling;Fibrolamellar Hepatocellular Carcinoma;Gene Fusion;Generations;Genetic;Goals;Gravin;Growth;Hepatocyte;Histology;Human;Immunofluorescence Immunologic;In Vitro;Knowledge;Life;Ligase;Liver;Machine Learning;Malignant Epithelial Cell;Malignant neoplasm of liver;Mitosis;Mitotic;Modeling;Molecular;Mus;N-terminal;Operative Surgical Procedures;Oral;PLK1 gene;Pathogenesis;Patients;Pharmacology;Pharmacotherapy;Phenotype;Phosphotransferases;Pre-Clinical Model;Property;Protein Array;Proteins;RNA Interference;Research Personnel;Resistance;Role;Signal Transduction;Slice;System;Systems Biology;Testing;Therapeutic;Tissues;Tumor Weights;Up-Regulation;Variant;Work;advanced disease;candidate validation;cell growth;chemotherapy;clinical application;clinical candidate;clinical efficacy;druggable target;efficacy evaluation;experimental study;follow-up;genetic signature;heat-shock proteins 40;inhibitor;insight;irinotecan;kinase inhibitor;knock-down;mortality;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;pharmacologic;polo-like kinase kinase 1;preclinical trial;research clinical testing;response;screening;stem;targeted treatment;trait;tumor;tumor growth;tumor progression Targeting PLK1 signaling for the treatment of fibrolamellar carcinoma PROJECT NARRATIVEFibrolamellar carcinoma a life-threatening variant of liver cancer affecting adolescents and young adults ischaracterized by a fusion event resulting in a novel chimeric protein that joins the N-terminal domain of DNAJwith the catalytic subunit of protein kinase A (PKAc). We aim to identify and validate druggable signaling networksthat regulate the growth of DNAJ-PKAc fusion-expressing FLC cells. The knowledge gained from this study willaccelerate the development of a novel therapeutic option for targeting childhood liver cancer. NCI 10742683 6/23/23 0:00 PA-20-185 1R01CA273081-01A1 1 R01 CA 273081 1 A1 "CHEN, WEIWEI" 8/1/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-MCTC-S(01)Q] 10914083 "GUJRAL, TARAN SINGH" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 492279 NCI 309516 182763 PROJECT SUMMARYFibrolamellar carcinoma (FLC) is a childhood liver cancer with a high case mortality rate. Patients with FLCtypically present with advanced disease as there are no early warning signs. Thus a cure by surgical resectionis rarely attainable. In addition FLCs are notoriously resistant to chemotherapies and other targeted therapiescurrently approved for liver cancer leading to a 5-year survival of just 30%. New therapeutic strategies thatcounteract the molecular signaling events that go awry in FLC are urgently needed. FLC is characterized by afusion event resulting in a novel chimeric protein that joins the N-terminal domain of DNAJ with the catalyticsubunit of protein kinase A (PKAc) in hepatocytes. However the underlying mechanism by which DNAJ-PKAcdrives FLC tumor growth remains unknown.This project's overall goal is to apply an unbiased systems-basedapproach to identify and validate druggable signaling networks that regulate the growth of DNAJ-PKAc-expressing FLC cells and uncover a mechanistic understanding of how DNAJ-PKAc chimeric protein drives FLC.The paucity of preclinical models such as immortalized primary human FLC cell lines has precluded manyinvestigators. Our lab has established three new model systems to address this significant gap: patient-derivedcell lines bearing the FLC gene fusion organotypic cultures and patient-derived xenograft (PDX) mice. Utilizingthese model systems we carried out a systems-pharmacology-based functional kinase inhibitor screening inFLC cells and normal hepatocytes. We identified and confirmed the role of PLK1 kinases as essential for thegrowth of FLC cells. Genetic depletion or pharmacological inhibition of PLK1 selectively reduces the growth ofmultiple patient-derived FLC cell lines and the viability of FLC organotypic tissue slices. Further treatment of theFLC tumor with PLK1 inhibitor significantly reduced the tumor growth in the PDX model. PLK kinases are keyregulators of centrosome maturation and mitosis. Follow-up experiments suggest that DNAJ-PKAc chimeralocalizes to the centrosomes where it physically interacts with PLK1.Thus we hypothesize that the heightenedsensitivity of the FLC cells to PLK inhibition stems from the localization of the DNAJ-PKAc fusion protein to thecentrosome its association with the PLK1 complex thereby enhancing the activation of PLK1 and promotingmitotic progression. We propose to 1. uncover molecular mechanisms of how DNAJ-PKAc fusion alters PLK1activation and function and 2. evaluate the efficacy of clinical-grade PLK1 inhibitors alone and in combinationwith chemotherapy in preclinical models.Functional analyses will highlight the mechanistic insights by whichDNAJ-PKAc drives FLC tumor progression and the role of the PLK1 signaling complex in FLC survival thusdeepening our understanding of disease pathogenesis. Our cross-disciplinary team consisting of Drs. GujralScott and Yeung represent a cohesive collaboration that brings systems biology PKA biochemistry and state-of-art human-derived FLC cancer models to address this deadly disease. Our findings have translationalsignificance as they will provide a rationale for targeting critical signaling nodes that sustain FLC tumors' survival. 492279 +No NIH Category available Address;Adjuvant;Adverse event;Affect;Animals;Architecture;Attenuated;Binding;Biological Markers;Bone Diseases;Bone Marrow;Bone Matrix;Bone Resorption;Bone Tissue;Bone remodeling;CD8-Positive T-Lymphocytes;Cadaver;Cells;Collagen Type I;Competence;Complication;Compression Fracture;Custom;Development;Extracellular Matrix;Extracellular Matrix Proteins;FLT3 ligand;Failure;Flow Cytometry;Fracture;Gelatinase B;Gene Expression;Heterogeneity;Human;Image;Immune;Immune checkpoint inhibitor;Immunoassay;Immunologic Markers;Immunotherapy;Interferon Type II;Interleukin-1;Interleukin-10;Interleukin-6;Knowledge;Lesion;Ligands;Linear Regressions;Logistic Regressions;Malignant Neoplasms;Malignant neoplasm of prostate;Mass Spectrum Analysis;Matrix Metalloproteinases;Measurement;Measures;Mechanics;Mediating;Metastasis Induction;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Modeling;Modification;Molecular;Mus;Myeloid-derived suppressor cells;NF-kappa B;Neoplasm Metastasis;Oncology;Osteoblasts;Osteocalcin;Osteoclasts;Osteolysis;Osteolytic;Pathogenesis;Pathological fracture;Patients;Peptides;Polymerase Chain Reaction;Population;Post-Translational Protein Processing;Primary Neoplasm;Production;Proteomics;Regulatory T-Lymphocyte;Reporting;Resistance;Risk;Risk Reduction;Role;Sampling;Signal Transduction;Solid;T-Cell Activation;T-Lymphocyte;TNF gene;Testing;Time;Training;Transforming Growth Factor beta;Validation;Vertebral Bone;anti-PD-1;anti-PD1 therapy;anti-cancer;bone;bone fragility;bone loss;bone preservation;bone sialoprotein;bone strength;cancer therapy;cathepsin K;checkpoint inhibition;clinical imaging;collagenase 3;crosslink;cytokine;efficacy evaluation;imaging modality;immune checkpoint;improved;in vivo;lumbar vertebra bone structure;male;mechanical properties;mineralization;mouse model;neoplastic cell;osteoclastogenesis;osteopontin;precision medicine;predictive marker;prevent;prognostic signature;programmed cell death ligand 1;programmed cell death protein 1;prostate cancer cell;prostate cancer model;receptor;response;skeletal;spine bone structure;substantia spongiosa;treatment response;tumor The role of extracellular matrix quality in the prediction of metastasis-induced skeletal fragility and response to immunotherapy Tumor metastasis to bone increases risk of pathologic fractures which is exacerbated by immune checkpointinhibition (ICI); however little is known about the effects of ICI on bone remodeling and structural integrity inmetastatic bone disease (MBD). This study will identify unique markers of bone extracellular matrix (ECM) qualitythat are associated with metastatic lesion heterogeneity mechanical properties and response to combined ICIand bone anti-resorptive agents which will be used to develop a prognostic signature of metastatic bone fragility.The results will extend our understanding of bone immune and tumor interactions in MBD which is critical fordeveloping precision medicine and mitigating MBD-induced bone fragility. NCI 10742484 9/18/23 0:00 PAR-21-061 1R21CA284159-01 1 R21 CA 284159 1 "RODRIGUEZ, LARITZA MARIA" 9/18/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-BTC-J(55)R] 15568601 "BAILEY, STACYANN R" Not Applicable 2 BIOMEDICAL ENGINEERING 153926712 VGJHK59NMPK9 153926712 VGJHK59NMPK9 US 42.386914 -72.521131 850904 UNIVERSITY OF MASSACHUSETTS AMHERST HADLEY MA BIOMED ENGR/COL ENGR/ENGR STA 10359450 UNITED STATES N 9/18/23 0:00 8/31/25 0:00 396 Non-SBIR/STTR 2023 392617 NCI 254858 137759 Metastatic bone disease (MBD) is a frequent and fatal complication in patients with advanced solid malignancies.Immune checkpoint inhibitors (ICIs) such as programmed cell death protein-1 (PD-1) have revolutionized cancertherapy over the past decade; however the positive impact of ICIs in MBD is attenuated due to some immune-related skeletal adverse events (irSAEs) including the formation of new bone lesions increased bone resorptionand vertebral compression fractures. The dynamic and multidirectional interactions between bone immune andtumor cells (osteoimmuno-oncology OIO) can alter bone extracellular matrix (ECM) quality influence bonemechanical integrity and affect response to therapy but OIO is currently underexamined in MBD. Receptoractivator of nuclear factor kappa- (RANK) and its ligand (RANKL) may be considered as key orchestrators ofOIO yet their role in the setting of ICIs remain unexplored. Metastatic prostate cancer (PCa) cells bone-formingosteoblasts and activated T-cells trigger osteolysis independently by producing RANKL which binds to RANKon bone-resorbing osteoclasts (OCs). We hypothesize that modulation of RANK/RANKL and PD-1 signaling inOIO may support T-cell activation while inhibiting osteoclastic activity thereby decreasing risk for worseningbone ECM quality and mechanical integrity and produce synergistic anticancer efficacy. Thus we will (1)Characterize the expression of OIO-related ECM biomarkers in metastatic human bone and develop a prognosticsignature of bone fragility; and (2) Evaluate the effects of combined RANKL and PD-1 blockade on bone ECMquality mechanical integrity and anti-cancer efficacy in mouse models of PCa bone metastases (BM). Cadaverichuman trabecular bone cores from the lumbar vertebrae containing osteolytic osteosclerotic and mixedmetastatic lesions will be compressed to failure for measurements of bone mechanical properties. Based on thedistribution of the failure loads of the lesions an appropriate threshold will be selected to create a binary measureof bone fragility. OIO-related bone ECM biomarkers and their posttranslational modifications will be extractedfrom each lesion. Using mixed effects multinomial logistic regression models a minimum set of biomarkers thatpredict bone fragility will be obtained. We will further validate these OIO-based biomarkers in distinct models ofosteolytic and osteosclerotic PCa BM and assess the efficacy of anti-RANKL in mitigating bone fragility in thesetting of anti-PD1 therapy. The results of this study will extend the current understanding of the effects ofmetastases and its treatment on bone matrix quality and mechanical integrity. OIO-related ECM markers thatregulate lesion heterogeneity and predict fragility will provide new molecular information of functional relevancethat can drive translational efforts. Moreover the mechanisms of immune-mediated bone remodeling andmitigation of bone fragility by combined blockade of RANKL and PD-1 can aid in risk-adapted selection forongoing and subsequent therapies. 392617 +No NIH Category available 3-Dimensional;4D Imaging;Address;Algorithms;Anatomy;Area;Biopsy;Cancer Center;Cancer Etiology;Cessation of life;Characteristics;Classification;Clinical;Colon;Colonoscopy;Colorectal Cancer;Colorectal Neoplasms;Computer Vision Systems;Confusion;Detection;Development;Devices;Diagnosis;Early Diagnosis;Elasticity;Endoscopes;Ensure;Evaluation;Excision;Feedback;Gastrointestinal Polyp;Geometry;Goals;Image;Incidence;Intelligence;Intuition;Machine Learning;Malignant neoplasm of gastrointestinal tract;Maps;Medical;Modulus;Morphology;Operative Surgical Procedures;Output;Performance;Polyps;Precancerous Polyp;Procedures;Qualitative Evaluations;Quantitative Evaluations;Radiation;Radiation therapy;Resected;Resolution;Review Literature;Robotics;Shapes;Surface;Surgeon;System;Tactile;Technology;Testing;Texture;Three-Dimensional Image;Time;Treatment outcome;Tumor stage;Vision;Visual;biomaterial compatibility;cancer type;chemotherapy;clinical diagnosis;colon cancer patients;design;diagnostic platform;experimental study;fabrication;improved;in vivo;innovation;intelligent algorithm;machine learning algorithm;microscopic imaging;mortality;novel;preclinical evaluation;response;screening;sensor technology;survival outcome;timeline;treatment stratification;tumor A Novel Framework for Sensitive and Reliable Early Diagnosis Topographic Mapping and Stiffness Classification of Colorectal Cancer Polyps PROJECT NARRATIVEThis project aims to improve early diagnosis of colorectal cancer polyps by development of anovel and soft tactile sensing device and complementary intelligent algorithms. The proposedtransformative diagnosis framework (1) readily integrates with the existing colonoscopic systemsand does not change the current clinical diagnosis workflow (2) provides high-resolution 4Dimaging (i.e. 3D texture mapping + stiffness classification) (3) dramatically decreases polypdiagnosis miss-rate and (4) enhances in vivo polyps type and stage classification. NCI 10742476 7/20/23 0:00 PAR-22-091 1R21CA280747-01A1 1 R21 CA 280747 1 A1 "YOUNG, MATTHEW R" 7/20/23 0:00 6/30/25 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 14428760 "ALAMBEIGI, FARSHID " Not Applicable 37 ENGINEERING (ALL TYPES) 170230239 V6AFQPN18437 170230239 V6AFQPN18437 US 30.291188 -97.737568 578403 UNIVERSITY OF TEXAS AT AUSTIN AUSTIN TX BIOMED ENGR/COL ENGR/ENGR STA 787121139 UNITED STATES N 7/20/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 178739 NCI 119546 59193 Summary/Abstract: Our long-term goal is to develop a novel soft robotic endoscope with intelligent tactile sensing balloons andcomplementary machine learning (ML) and computer vision (CV) algorithms to enhance early-stage detectionaccurate tumor localization and treatment stratification of various gastrointestinal (GI) cancers. This roboticframework provides clinicians with (i) a safe and intuitively-steerable soft robotic endoscope to perform precisediagnosis biopsy and surgical procedures; (ii) in vivo high-fidelity visual textural and stiffness information ofthe diagnosed anatomy; (iii) in vivo radiation-free quantified topographic mapping and morphologicalcharacterization (i.e. shape and texture) of GI polyps using CV algorithms; (iv) intelligent real-time in vivoclassification of type and stiffness of detected polyps using ML algorithms; and more importantly (v) quantitativeevaluations of tumor response during chemo- and radiation-therapy period via in vivo topographic/stiffnessmapping. Considering the 2-year timeline of this collaborative project in this proposal we will mainlyfocus on the design development and thorough evaluation of a novel and soft Vision-based TactileSensing Balloon (VTSB) with complementary Computer Vision (CV) and Machine Learning (ML)algorithms to perform high-resolution in vivo topographic mapping and stiffness classification ofColorectal Cancer (CRC) polyps. CRC is the leading cause of cancer incidence and mortality worldwide. In 2020 CRC accounted for 1.9 millionnew cases (i.e. #3 cancer type in ranking) and 935000 new deaths (i.e. #2 cancer type in ranking). Sincesurvival outcomes differ significantly based on the tumor stage at the time of detection early detection viacolonoscopy has a significant impact on treatment outcomes. Morphological characteristics (i.e. shape andtexture) and change in the modulus of elasticity of CRC polyps are well-known to be associated with tumor typeand stage. Colonoscopic procedures therefore are of paramount importance as they can help in early detectionand removal of pre-cancerous polyps. However state-of-the-art traditional colonoscopic procedures still solelyrely on visual 2D/3D images and cannot yet provide the clinicians with in vivo detailed textural and stiffnessfeedback. These limitations has caused high polyp miss rate (about 20%-30%) as well as heavily subjective andevaluator-dependent tumor identification and classifications. It is our central hypothesis that utilizing the proposed VTSB with complementary ML and CV algorithms cancollectively address the limitations of the state-of-the-art colonoscopic technologies by (1) readily integrating withthe existing colonoscopic systems and not changing the current clinical diagnosis workflow (2) providing high-resolution 4D imaging (3D texture mapping + stiffness classification) (3) decreasing polyp miss-rate and (4)enhancing in vivo polyps type and stage classification. The proposed contribution is significant high impact andinnovative and our goal is to demonstrate that it can significantly improve the current diagnosis procedures andshift the current clinical paradigm. 178739 +No NIH Category available 3-Dimensional;Acceleration;Acute Respiratory Distress Syndrome;Address;Appearance;Astronauts;Attention;Awareness;Benchmarking;Brain Neoplasms;Breast Cancer Detection;Breast Cancer Risk Factor;COVID-19 mortality;Cause of Death;Classification;Clinical;Code;Collaborations;Collection;Data;Data Analyses;Data Set;Decentralization;Development;Diagnosis;Diagnostic Procedure;Digital Breast Tomosynthesis;Digital Mammography;Disease;Early Diagnosis;Eligibility Determination;Environment;Evaluation;Feedback;Friends;Funding;Geography;Goals;Health Insurance Portability and Accountability Act;Health system;Healthcare;Histopathology;Image;Infrastructure;Institution;Learning;Legal;Libraries;Licensing;Life Cycle Stages;Lymphocyte;Magnetic Resonance Imaging;Malignant Neoplasms;Mammary Gland Parenchyma;Mammography;Measures;Medical Imaging;Modeling;New York;Ownership;Patients;Performance;Physiological;Population Characteristics;Population Heterogeneity;Privacy;Privatization;Probability;Procedures;Publishing;Radiation exposure;Radiation-Induced Cancer;Rare Diseases;Recommendation;Research;Resources;Risk Assessment;Risk Factors;Scanning;Secure;Sensitivity and Specificity;Site;Software Framework;Source Code;Tissues;Training;Training Activity;Tumor-Infiltrating Lymphocytes;Underserved Population;United States National Aeronautics and Space Administration;Woman;Work;Workload;X-Ray Medical Imaging;breast density;cancer diagnosis;cancer type;clinical translation;data sharing;deep learning model;digital;digital measure;diverse data;educational atmosphere;ethnic diversity;federated learning;frontier;generative adversarial network;health disparity;health disparity populations;health inequalities;imaging modality;improved;infrastructure development;laboratory development;malignant breast neoplasm;novel;open source tool;patient population;personalized screening;predictive modeling;privacy preservation;prototype;racial diversity;risk stratification;routine screening;screening;standard of care;trustworthiness;tumor Privacy-Aware Federated Learning for Breast Cancer Risk Assessment NARRATIVE:Successful completion of this proposal will lead to a trustworthy zero-code federated learning (FL) softwareframework lowering the barrier to leverage data from under-served populations in large-scale secure de-centralized multi-institutional collaborations without the need to share patient data thereby i) overcoming legalprivacy and data-ownership concerns and ii) paving the way to address health disparities and inequitiestowards accelerating discovery in healthcare. This framework will further support the clinical impact and lifecycleof FL studies by offering a) pre-trained breast cancer risk assessment models leveraging multi-site ethnicallydiverse data of women undergoing breast screening and functionality specific to b) improving these pre-trainedmodels by including additional geographically diverse sites c) data synthesis for data augmentation & privacypreservation based on realistic synthetic data matching each sites local patient population characteristics andd) an automated mechanism for quantitative & interpretable determination of optimal privacy preservation. NCI 10742425 9/20/23 0:00 RFA-CA-22-023 1U24CA279629-01A1 1 U24 CA 279629 1 A1 "KIM, BOKLYE" 9/20/23 0:00 8/31/28 0:00 ZCA1-TCRB-Q(M2) 12628303 "BAKAS, SPYRIDON " Not Applicable 7 PATHOLOGY 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 748154 NCI 573474 174680 ABSTRACT:Federated learning (FL) has gained a lot of attention recently as it enables analyses of data from numerouscollaborating sites without the need to share data i.e. each collaborators data are always retained within theirsite. FL is advantageous as it can: 1) overcome cultural/ownership privacy and regulatory concerns (since datanever leave the local site) 2) provide access to restricted data 3) allow the collection of meaningful amounts ofdata for analyses of rare diseases and 4) address health disparities and inequities. Thus FL can be noted as anovel paradigm for multi-site collaborations enabling access to ample and importantly diverse data essential todeveloping robust models generalizable in unseen data. To this end we have developed the Federated TumorSegmentation (FeTS) platform and the Open Federated Learning (OpenFL) library as open-source tools with acommercially friendly license that have facilitated a) the largest to-date real-world federation involving 3D braintumor MRI data from 71 sites across 6 continents and b) the very first computational challenge in FL formingthe first benchmarking environment and dataset in the field. This FeTS-OpenFL infrastructure has further beenused to c) identify tumor-infiltrating lymphocytes in histopathology images and d) segment dense tissue in 2Ddigital mammography (DM) highlighting its generalizability in different imaging and disease types. Building uponour successful FeTS-OpenFL infrastructure we propose to enhance its functionality with new developments onprivacy-aware FL towards classification workloads and evaluate it on a first-of-its-kind use case on breast cancer(BC) risk assessment. BC is the most diagnosed cancer in the US the 2nd leading cause of death from cancerin women and screening is performed routinely with 2D digital mammography (DM) for women in their 40s-50s.However DM yields a lot of false positives and unnecessary subsequent procedures. To alleviate these issues3D Digital Breast Tomosynthesis (DBT) has been developed and increasingly replacing DM. Our group hasdeveloped novel volumetric breast density (VBD) measures from DBT scans. Building upon our teams collectivepioneering work in FL and BC risk assessment in this proposal we focus on developing a trustworthy zero-codeprinciple FL framework for training AI-based classification models and built-in functionality to i) generate realisticsynthetic data matching local population characteristics for data augmentation & privacy preservation and ii)automatically determine quantitative & interpretable settings of optimal privacy preservation. We will use thisframework to perform the largest to-date evaluation of training deep-learning models for BC risk assessmentusing DBT VBD measures and other established risk factors while leveraging multi-site ethnically diverse dataof women undergoing BC screening. We will also disseminate resources via distribution of source codedeployment to collaborating sites and organization of training activities. Our overarching goal is an easy-to-usetranslatable trustworthy FL framework lowering the barrier for under-served populations to participate in large-scale FL studies and paving the way to address health disparities towards accelerating discovery healthcare. 748154 +No NIH Category available Biological Markers;Blood;Chemoresistance;Chemotherapy and/or radiation;Data;Disease;Disease Progression;Drug Delivery Systems;Early Diagnosis;Endoglin;Endothelium;Growth;Impairment;Malignant Neoplasms;Malignant neoplasm of pancreas;Methods;Neoplasm Metastasis;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Perfusion;Proteins;RNA Splicing;Reagent;Resistance;Role;Signal Transduction;Solid;Symptoms;Testing;Therapeutic;Transforming Growth Factor beta;Variant;Vascularization;angiogenesis;clinically relevant;improved;novel;pancreatic cancer cells;pancreatic neoplasm;paracrine;pharmacologic;receptor;screening;spatiotemporal;therapeutic target;tumor;tumor growth;tumor microenvironment Tumor-intrinsic and paracrine roles of endoglin in pancreatic cancer PROJECT NARRATIVEPancreatic cancer is one of the most lethal malignancies with poor long-term survival due to its delayed onsetof symptoms and notorious resistance to existing chemotherapy and radiation. Hence there is an unmeturgent need for better early diagnosis screening and treatment methods. Here our project investigates aprotein uniquely expressed in pancreatic tumors and released into patient blood which we will test as abiomarker and therapeutic target. NCI 10742322 7/28/23 0:00 PA-20-185 1R01CA275036-01A1 1 R01 CA 275036 1 A1 "WOODHOUSE, ELIZABETH" 8/1/23 0:00 7/31/28 0:00 Mechanisms of Cancer Therapeutics A Study Section[MCTA] 2047139 "LEE, NAM Y" Not Applicable 7 PHARMACOLOGY 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 376732 NCI 249000 127732 ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy featuring early metastasis late onset ofsymptoms and notorious resistance to existing therapies. A critically elusive aspect of this disease relates tothe tumors which are often hypovascularized relative to other solid cancers manifesting in poor perfusion andimpaired drug delivery. In preliminary studies we discovered that endoglin normally an endothelial-specificTGF-beta coreceptor required for angiogenesis is expressed as two variants in pancreatic cancer cells- thewildtype which supports tumor-intrinsic growth and chemoresistance; and a novel splice variant with distinctstructural features that gets secreted to inhibit tumor vascularization. To understand their interplay in thetumor microenvironment we have generated a variety of cellular and pharmacologic reagents to interrogatethe underlying mechanisms and their therapeutic potential. We propose to define novel paracrinemechanisms of TGF-beta signaling that suppress PDAC vascularization (Aim 1); and identify tumor-intrinsicendoglin pathways as critical therapeutic targets in PDAC (Aim 2); and determine the endoglin variants asdistinct spatiotemporal targets during disease progression (Aim 3). Results from these studies will define TGF-beta-based mechanisms critical for PDAC tumor growth and vascularization and deliver clinically relevantdata for improved patient-based therapeutics. 376732 +No NIH Category available Age;Aging;Area;Award;Cancer Patient;Communities;Data;Data Set;Development;Elderly;Environment;Future;Goals;Health;Health Benefit;Home;Home environment;Impairment;Injury;Knowledge;Link;Malignant Neoplasms;Measures;Medicare;Medicare claim;Mentors;Neighborhoods;Outcome;Patients;Phase;Physical Function;Physical environment;Population;Postdoctoral Fellow;Provider;Research;Research Personnel;Research Project Grants;Risk;Role;Sampling;Structure;System;Training;United States;Work;aging in place;beneficiary;cancer care;cancer diagnosis;cancer type;experience;falls;health care service utilization;improved;mortality;novel;pre-doctoral;prospective;response;skills;trend Aging in place for older adults with cancer: The role of physical function and home environment Project NarrativeWhile older adults prefer to remain in their own homes as they age (i.e. age in place) impairments inphysical function may limit their ability to do so. Meanwhile those who undergo residential relocation and thosewho live in less supportive neighborhood environments experience negative health outcomes including greaterhealthcare utilization mortality and falls with injury. Establishing: 1) whether older adults with cancer arevulnerable to residential relocation in response to impairments in mobility-related physical function and 2) howsuch relocation influences cancer-related health outcomes will inform development of patient- provider- andsystem-level strategies to assess and mitigate impairments in physical function and promote aging in place forthis growing population.1 NCI 10742252 8/10/23 0:00 RFA-CA-22-041 1F99CA284180-01 1 F99 CA 284180 1 "ELJANNE, MARIAM" 8/10/23 0:00 7/31/25 0:00 ZCA1-RPRB-7(M1) 16546122 "JENSEN-BATTAGLIA, MARIELLE " Not Applicable 25 INTERNAL MEDICINE/MEDICINE 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 8/10/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 49194 NCI 49194 0 Project Summary and AbstractThis award will support Dr. Jensen-Battaglias long-term goal of developing the expertise and skills needed tobecome an independent investigator exploring the overlapping roles of physical function and environment inhealth outcomes for older adults with cancer. By 2050 20% of new cancer diagnoses will be among those age80 or older comprising an estimated 6.9 million cases worldwide. The majority of older adults in the UnitedStates (U.S.) prefer to remain in their homes as they age (i.e. age in place) which is associated with healthbenefits. Conversely both unsupportive neighborhood environment and residential relocation are associatedwith increased healthcare utilization decreased survival and falls. Although impairments in physical functionare common and highly modifiable we do not yet know if older adults with cancer are at greater risk forresidential relocation as a result of these impairments compared to those without cancer. Whether negativehealth outcomes such as healthcare utilization mortality and falls associated with relocation are due torelocation itself or associated changes in the neighborhood environment remains unclear. Dr. Jensen-Battagliawill address these gaps in her proposed project by prospectively evaluating the association betweenimpairments in physical function and residential relocation among community dwelling older adults in the U.S.and examining how this association differs for those with cancer compared to those without cancer.Additionally she will assess how residential relocation modifies the effect of neighborhood environment onfuture health for those with cancer. For the F99 phase Dr. Jensen-Battaglia will leverage data from a nationallyrepresentative sample of U.S. Medicare beneficiaries [National Health and Aging Trends Study (NHATS)] torefine a novel measure of mobility-related physical function assess whether this is associated with increasedrisk of residential relocation and evaluate if cancer diagnosis positively modifies this relationship. She will alsoexplore how the relationship between mobility-related physical function and residential relocation differs acrosshome environments and cancer types. For the K00 phase she will create a dataset linking the NHATS withMedicare claims and area-based measures and evaluate if residential relocation positively modifies the effectof worsening (compared to stable or improving) neighborhood environment supports on cancer-related healthoutcomes. Dr. Jensen-Battaglia has worked closely with her sponsors to develop a training plan whichsupports successful completion of the predoctoral research project and smooth transition to a competitivecancer-focused postdoctoral placement. This includes training to improve knowledge of the patient cancer careexperience obtain expertise in analysis of residential relocation dynamics and identify a postdoctoral mentor.Together the proposed research and training plan provide optimal opportunities and structure for Dr. Jensen-Battaglia to develop new skills and progress toward becoming an independent cancer researcher. 49194 +No NIH Category available Address;Androgen Antagonists;Androgen Metabolism;Androgen Receptor;Androgens;Antiandrogen Therapy;Biological Availability;Biological Markers;Blood;Blood specimen;CYP17A1 gene;Cancer Etiology;Cancer Patient;Castration;Cell Line;Cessation of life;Chronic;Clinical;Clinical Trials;Combined Modality Therapy;Core Facility;Correlative Study;Data;Decision Making;Disease;Disease Outcome;Disease Progression;Disease Resistance;Drug Kinetics;Drug resistance;Enzymes;Ethics;Failure;Future;Genes;Goals;Growth;Human;In Vitro;Indomethacin;Intervention;Lead Poisoning;Liquid substance;Malignant neoplasm of prostate;Mediating;Messenger RNA;Modeling;Monitor;Names;Neoadjuvant Therapy;Oral;Organoids;Outcome Study;Participant;Pathway interactions;Patient Selection;Patients;Peripheral Blood Mononuclear Cell;Pharmacodynamics;Pharmacologic Substance;Plasma;Play;Primary Neoplasm;Process;Production;Prostate Cancer therapy;Proteins;Protocols documentation;RNA;Regulation;Relapse;Reporting;Research;Resistance;Role;Running;Sampling;Serum;Signal Transduction;Steroid biosynthesis;Steroids;Structure;System;Testing;Testosterone;Time;Translating;Translations;Ubiquitin;United States;Up-Regulation;Work;abiraterone;advanced disease;advanced prostate cancer;androgen biosynthesis;androgen deprivation therapy;cancer type;castration resistant prostate cancer;celecoxib;clinically relevant;cohort;comparison control;effective therapy;efficacy evaluation;efficacy testing;enzalutamide;experience;improved;improved outcome;in vivo;inhibitor;liquid chromatography mass spectrometry;men;multicatalytic endopeptidase complex;new therapeutic target;next generation;novel;novel marker;novel strategies;patient derived xenograft model;peripheral blood;precision medicine;programs;prostate cancer cell;prostate cancer cell line;prostate cancer model;prostate cancer progression;research clinical testing;side effect;small molecule;therapeutic target;therapy resistant;treatment comparison;treatment response;tumor xenograft Targeting intracrine steroidogenesis in anti-androgen resistant prostate cancer PROJECT NARRATIVEIntracrine steroidogenesis plays vital roles in resistance to abiraterone enzalutamide and apalutamide.Steroidogenesis genes such as AKR1C3 HSD3B and CYP17A1 not only play central roles in intracrineandrogen biosynthesis their presence is also closely correlated to disease stages. This proposal will be thefirst study that interrogates steroidogenesis genes and plasma steroid levels in next generation anti-androgen resistant prostate cancer patients and develop novel strategies using novel patient derivedxenograft models to overcome drug resistance. NCI 10742116 7/10/23 0:00 PAR-22-216 1R21CA277171-01A1 1 R21 CA 277171 1 A1 "COVELL, DAVID G" 7/10/23 0:00 6/30/25 0:00 ZCA1-RPRB-L(M2) 12621986 "LIU, CHENGFEI " Not Applicable 4 UROLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 7/10/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 224400 NCI 140250 84150 PROJECT ABSTRACTProstate cancer (PCa) is the second leading cause of cancer related death in men in the United States in 2022.A limit number of PCa cell lines and patient-derived xenograft (PDX) models hinders research to improvedisease outcome. To address this unmet need we have developed multiple PDX models conditionalreprogramed cultures (CRCs) and organoids from patients with advanced disease. AKR1C3 also namedHSD17B5 is one of the most important genes involved in androgen metabolism and elevated expression ofthis enzyme is associated with PCa progression and failure to androgen receptor pathway inhibitors (ARPIs)treatments. We have reported that upregulation of AKR1C3 concurrent with elevated testosterone and itsprecursors in prostate cancer cells and xenograft tumors that are resistant to anti-androgen treatments. Thisproposal will use blood AKR1C3 and plasma steroid levels as biomarkers to interrogate intracrinesteroidogenesis activation in ARPIs treated patients to signify drug resistance. We will also test a novelAKR1C3 inhibitor in the newly established PDX and CRC models. The inhibitor has great potential to increaseefficacy of ARPIs treatments in advanced PCa which might translate into the clinical trial directly. The goal ofthis program is to identify novel biomarkers and develop new pharmaceutical approaches to provide co-targeting neoadjuvant with ARPIs to treat CRPC patients. Manipulation of key enzymes contributing to theproduction of androgen potentially offers a novel targeted therapy for the advanced prostate cancer treatmentwhich will have a meaningful impact on patients lives. The data acquired from this project will establish aclinically relevant decision making for patient treatment and pave the way to future precision medicine inprostate cancer. 224400 +No NIH Category available Antigen Presentation;Antigens;B lymphoid malignancy;Cell Therapy;Cells;Complex;Cytotoxic T-Lymphocytes;Ecosystem;Endothelial Cells;Engineering;Epithelium;Fibroblasts;Goals;Growth;Immune;Immunotherapeutic agent;In Vitro;Individual;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Molecular;Normal tissue morphology;Organ;Play;Pre-Clinical Model;Role;Signal Transduction;Solid;Solid Neoplasm;Source;Specificity;Stromal Cells;Stromal Neoplasm;Supporting Cell;Surface Antigens;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Tumor Antigens;VTCN1 gene;Work;Xenograft Model;cancer cell;candidate identification;cell killing;cell type;chimeric antigen receptor;chimeric antigen receptor T cells;combinatorial;cross reactivity;design;efficacy evaluation;engineered T cells;improved;mesothelin;mouse model;neoplastic cell;pancreatic cancer model;receptor;spatial integration;success;tool;tumor;tumor microenvironment;tumor xenograft Recognizing the tumor ecosystem: Integrating stromal and cancer antigen signals to achieve precision recognition of solid tumors by CAR T cells Project NarrativeThe goal of this project is to engineer therapeutic immune cells that are substantially safer and more effectivein treating solid tumors. NCI 10741822 11/15/23 0:00 PA-19-056 5R01CA249018-04 5 R01 CA 249018 4 "ZAMISCH, MONICA" 12/1/20 0:00 11/30/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 1928388 "LIM, WENDELL A" Not Applicable 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 506913 NCI 317475 189438 Project Summary/AbstractDespite the remarkable success of engineered chimeric antigen receptor (CAR) T cells in the treatment of B cellmalignancies their application to solid cancers has been far less successful. One of the major challenges limitingtheir utility is the difficulty in identifying ideal surface antigens that can be used to discriminate between cancerand normal tissues many potential targets that are highly expressed in solid tumors are also found at lowerlevels in normal epithelial organs leading to off-tumor toxicity. Nonetheless we know that solid tumors comprisea complex and sophisticated tissue with a distinct ecosystem of malignant immune and stromal cells. Fromfirst principles one would predict that there should be ample discriminatory information in the tumor if one coulddesign therapeutic T cells that could integrate information from across different cells in the tumor ecosystem.We have recently developed new CAR T cell recognition circuits that can sense and respond to combinations ofantigens even if they are present on distinct cells within the same tissue microenvironment. These circuitsutilize a synNotch receptor to detect a priming antigen which in turn induces the expression of a CAR that killscells based on a killing antigen. In preliminary results we have shown that T cells with this kind of prime-and-killcircuit can recognize unique combinations of neighboring cells to induce killing. These types of engineered Tcells are one of the first known therapeutic agents that can integrate molecular information from across differentcells within the same tissue.In this proposal we hypothesize that this prime-and-kill T cell recognition circuit could be used to recognize solidtumors based on information distributed across the tumor ecosystem. Specifically we will target combinatorialintegration of signals that are present in cancer cells and cancer-associated stromal cells which play a centralsupportive role in a number of solid cancers. As a test case we propose to investigate whether antigens fromcancer associated fibroblasts can be used to locally prime CAR T cells to then kill based on a cancer associatedantigen. Even if this cancer associated antigen in not perfectly specific (i.e. it is expressed in other normaltissues) the combination of stromal and cancer cell signals should be far more specific for the tumor. Priorefforts have unsuccessfully explored using single antigen CARs to target stromal or cancer cells individually buthere we test whether using integrated combinatorial recognition of the cancer cell/stromal cell ecosystem canresult in significantly improved recognition specificity. If so then this kind of integrated tumor ecosystemrecognition could be applied to a large number of solid cancers. 506913 +No NIH Category available Address;Animal Model;Biochemistry;Biological Availability;Biological Models;Cancer Biology;Carbon;Cell physiology;Cellular Metabolic Process;Charge;Clinic;Data;Diet;Dietary Component;Effectiveness;Energy Metabolism;Engineering;Enzymes;Exclusion;Exhibits;Foundations;Fructose;Future;GLUT-2 protein;Gluconeogenesis;Glucose;Glucose Transporter;Glycolysis;Goals;Image;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;In Vitro;Insulin;Investigation;Isotopes;Ketohexokinase;Kidney;Liver;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Mediating;Metabolic;Metabolism;Methods;Modeling;Monosaccharides;Motivation;Mus;Nutrient;Oxygen;Pathway interactions;Patients;Production;Proliferating;Research;Serine;Small Intestines;Solid Neoplasm;System;T cell therapy;T-Cell Activation;T-Lymphocyte;Technology;Time;Tissues;Titrations;Translating;Translations;Warburg Effect;Work;cancer biomarkers;cancer cell;cancer immunotherapy;checkpoint inhibition;chimeric antigen receptor T cells;effector T cell;engineered T cells;exhaust;exhaustion;extracellular;fructose-1-phosphate;imaging approach;immune checkpoint blockade;in vivo;in vivo Model;innovation;liquid chromatography mass spectrometry;magnetic resonance spectroscopic imaging;melanoma;metabolic imaging;metabolomics;neoplastic cell;new technology;non-invasive imaging;novel;novel strategies;overexpression;response;sugar;tool;trafficking;tumor;tumor microenvironment Leveraging fructose transport to create a privileged substrate to selectively fuel T cells PROJECT NARRATIVEThe overarching goal of the proposed research is to explore the metabolism of T cells in order to developmetabolic imaging approaches with hyperpolarized (HP) MR. It has been shown that T-cell therapies arehindered by a dearth of metabolic precursors in the tumor microenvironment. In this work we aim to betterunderstand T-cell metabolism using novel tools and models and to develop strategies to overcome metaboliclimitations. We aim to enhance the glycolytic metabolism of T cells by giving them a unique endogenoussubstrate for their metabolism fructose which is present in our diet but not normally metabolized by a widerange of cancers. This work will advance the treatment of a range of solid tumors and develop non-invasivemetabolic biomarkers for cancer immunotherapy. NCI 10741821 11/1/23 0:00 PA-19-056 5R01CA248364-04 5 R01 CA 248364 4 "LIU, YIN" 12/11/20 0:00 11/30/25 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 10451505 "KESHARI, KAYVAN R" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 633044 NCI 357653 275391 PROJECT SUMMARY/ABSTRACTWhile checkpoint inhibitors and chimeric antigen receptor (CAR) T cells undergo widespread investigation asapproaches to unleash the immune systems tumor-targeting abilities the mechanisms by which these therapiesfail is the subject of great debate. In the setting of solid tumors it is believed that the microenvironment is hostileexcluding T cells and/or inhibiting their ability to proliferate or be activated. A dearth of metabolic precursorsmost notably glucose has been implicated as inhibiting T-cell function. There remains an unmet need forapproaches to better understand T-cell metabolism and its impact on tumors in vivo as well as a method to modulatethis metabolic limitation to overcome T-cell exhaustion.Given extensive preliminary data we have developed a model system to explore T-cell exhaustion using primary Tcells stimulated in vitro. We have also identified a metabolic mechanism that can overcome limited glycolytic flux byutilizing another biologically available substrate: fructose. Moreover we have optimized methods to tracemetabolism in vitro and in vivo using hyperpolarized magnetic resonance (HP MR) which can detect changes inmetabolism in real time. Taken together these approaches provide a platform for studying immunometabolism bothin vitro and in vivo in a syngeneic model of melanoma which has great potential for future immunotherapeutics.The objective of this innovative proposal is to utilize our in vitro and in vivo models to interrogate the metabolism ofT cells. In Aim 1 we will explore T-cell metabolism in vivo in order to reverse the reduced glycolytic flux in exhaustedT cells. In Aim 2 taking advantage of our newly developed HP fructose we will metabolically image fructosemetabolism in T cells using our newly developed HP microNMR and in vivo with HP magnetic resonancespectroscopic imaging (MRSI). We will then translate this approach to tumor-bearing mice in Aim 3 where wecombine T-cell therapy and HP MRI to treat a syngeneic model of melanoma.It is the overarching goal of this proposal to use these novel approaches in metabolism and metabolic imaging tofurther our understanding of immunometabolism and lay the foundation for future immunotherapy strategies inpatients. 633044 +No NIH Category available Bar Codes;Biological Models;Cancer Remission;Cells;Cessation of life;Clinical;Clinical Trials;Cytometry;DNA Sequence Alteration;Development;Disease remission;ERBB3 gene;Exhibits;FRAP1 gene;Future;Genetic;Genetic Engineering;Genomics;Grant;Head and Neck Squamous Cell Carcinoma;Human;Immune;Immune Evasion;Immune Targeting;Immune response;Immunooncology;Immunotherapy;In complete remission;Laboratories;Lesion;Ligands;Malignant Neoplasms;Modeling;Molecular;Monoclonal Antibodies;Morbidity - disease rate;Mus;Mutation;Nivolumab;Oncogenes;Oncogenic;PD-1 blockade;PIK3CA gene;PIK3CG gene;Pathway interactions;Patient Selection;Patients;Pharmacodynamics;Phase II Clinical Trials;Population;Precision therapeutics;Predictive Value;Prognosis;RNA interference screen;Resistance;Resolution;Signal Transduction;System;Therapeutic;Tobacco;Treatment Efficacy;Treatment Protocols;Tumor Suppressor Genes;Tyrosine Phosphorylation;United States;anti-PD1 therapy;anti-cancer;anti-tumor immune response;cancer cell;candidate validation;chromatin immunoprecipitation;genome editing;immune checkpoint;immune checkpoint blockade;improved;mTOR Signaling Pathway;mTOR inhibition;mortality;multimodality;novel;novel therapeutics;oncology trial;patient derived xenograft model;patient stratification;pembrolizumab;personalized immunotherapy;predictive signature;programmed cell death protein 1;response;restraint;single-cell RNA sequencing;targeted agent;targeted treatment;transcriptomics;tumor;tumor growth;tumor xenograft;tumor-immune system interactions Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC NARRATIVEThere is an urgent need to develop new therapeutic options to treat head and neck squamous cell carcinomas(HNSCC). Targeting the immune checkpoint PD-1 has revolutionized HNSCC treatment. However the overallresponse rate of anti-PD-1 therapies remains low (15-20%). Our overall objective is to increase the response toanti-PD-1 treatment by targeting oncogenic signaling circuitries and to exploit the emerging information of theHNSCC genomic mutational landscape and the single cell understanding of the anti-tumor immune response toinform the molecular stratification for patient selection in future precision immune oncology trials. NCI 10741816 11/30/23 0:00 PA-19-056 5R01CA247551-05 5 R01 CA 247551 5 "VENKATACHALAM, SUNDARESAN" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-OTC-H(02)M] 2028219 "GUTKIND, JORGE SILVIO " Not Applicable 50 PHARMACOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 449975 NCI 322963 127012 SummaryDespite recent advances in treatment the overall mortality for head and neck squamous cell carcinoma(HNSCC) remains high and current treatment regimens incur significant long-term morbidity. Targeting theimmune checkpoint PD-1 with pembrolizumab and nivolumab has revolutionized HNSCC treatment. Howeverthe overall response rate of these immunotherapies remains low around 15-20%. This highlights the urgentneed to identify novel therapeutic options for HNSCC to improve mortality reduce morbidity and enhance theactivity and response rate of immune oncology (IO) approaches for HNSCC. We hypothesize that targetingHNSCC oncogenic signaling networks and disabling their immune evasive mechanisms may increase theresponse to anti-PD-1 treatment as part of a novel rational therapeutic strategy. In this regard our laboratorycontributed to the discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the mostfrequent dysregulated signaling mechanism in HNSCC and that mTOR inhibition exerts potent antitumor activityin multiple experimental HNSCC model systems and in a Phase 2 clinical trial (NCT01195922). Remarkably~20% of HNSCC lesions harbor driver PIK3CA mutations encoding active PI3K subunits and yet ~90% ofHNSCC lesions exhibit aberrant PI3K/mTOR pathway signaling. In search for the underlying mechanisms weconducted a kinome wide RNAi screen which revealed that persistent HER3 tyrosine phosphorylation andassociation with PI3K sustain pathway activation in most of the HNSCC lesions. Indeed HER3 is highlyexpressed and persistently activated in most HNSCC lesions correlating with poor prognosis. The best-in-classanti-HER3 monoclonal antibody CDX-3379 inhibits the ligand-dependent and -independent activation of humanand murine HER3 by locking HER3 in its auto-inhibited configuration and has demonstrated pharmacodynamicand clinical activity in HNSCC patients. CDX-3379 exhibits potent antitumor activity in PIK3CA wild type HNSCCtumor xenografts and patient derived xenografts (PDXs). Furthermore we have obtained strong preliminaryresults supporting that CDX-3379 administration 1) abolishes PI3K-mTOR signaling 2) reverses the immuneevasive HNSCC microenvironment and 3) can result in complete remission when combined with anti-PD-1therapies in recently developed syngeneic mouse HNSCC models. Our premise is that co-targeting the HER3signaling circuitry combined with anti-PD-1 blockade may represent a novel multimodal precision therapeuticapproach for HNSCC aimed at achieving durable responses and cancer remission. We will now aim 1) toelucidate the contribution of genomic alterations in the PI3K-mTOR signaling network to anti-HER3 sensitivityand resistance and 2) to establish the impact of targeting and co-targeting the HER3-PI3K/mTOR signalingnetwork on the tumor immune microenvironment and response to PD-1 blockade aiming at achieving a singlecell level understanding of the anti-cancer immune response. These studies will inform the molecularstratification for patient selection in future multimodal precision immune oncology trials. 449975 +No NIH Category available Agonist;Cancer Model;Cellular Immunity;Chemotherapy and/or radiation;Clinic;Clinical;Clinical Trials;Combined Modality Therapy;Data;Disease;Disease Progression;Disease model;Exclusion;Functional disorder;Genetic;ITGAM gene;Immune;Immunity;Immunologic Memory;Immunotherapy;Impairment;Infiltration;Inflammation;Inflammatory;Integrins;Intelligence;Macrophage;Macrophage Colony-Stimulating Factor Receptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Molecular;Molecular Mechanisms of Action;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Pancreatic Ductal Adenocarcinoma;Pathology;Patients;Phase;Phenotype;Pre-Clinical Model;Radiation therapy;Research Personnel;Resistance;STING agonists;Sampling;Signal Transduction;Survival Rate;T cell infiltration;T cell response;T-Lymphocyte;TNFRSF5 gene;Testing;Therapeutic;Therapeutic Agents;Tissues;Translating;Treatment Efficacy;Tumor Immunity;Tumor-associated macrophages;anti-PD1 therapy;beta-Chemokines;cancer clinical trial;cancer type;checkpoint therapy;chemokine receptor;clinical development;combat;drug repurposing;granulocyte;improved;monocyte;novel strategies;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pharmacologic;pre-clinical;programs;recruit;response;small molecule;success;targeted agent;targeted treatment;tool;trafficking;translational approach;treatment response;tumor Exploiting Integrin Signaling to Overcome Resistance to Immunotherapy PROJECT NARRATIVEThese studies seek to understand if targeting integrins in myeloid cells can impact therapeutic responsivenessto immunotherapy in pancreas cancer. A better understanding of how integrins regulate innate immune controlof T lymphocytes and ultimately response to therapy can help us refine ongoing therapeutic approachestargeting this disease. NCI 10741812 11/27/23 0:00 PA-19-056 5R01CA244938-05 5 R01 CA 244938 5 "SINGH, ANJU" 12/1/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 8710339 "DENARDO, DAVID G" "GUPTA, VINEET " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 400191 NCI 286716 113475 PROJECT SUMMARY The potential of checkpoint immunotherapy to combat cancer has been established in several cancertypes. However in pancreatic ductal adenocarcinoma (PDAC) checkpoint immunotherapy has not led toclinical benefit. Although multiple factors likely contribute one significant factor is the extensive infiltration ofPDAC by multiple lineages of immunosuppressive myeloid cells. Therefore one promising therapeutic strategyis the targeting these myeloid cells to improve T cell-mediated immunity. These realizations have led to asignificant number of clinical trials combining myeloid targeted agent with checkpoint immunotherapy.However all current therapeutic strategies are subject to compensatory actions by untargeted subsets ofmonocytes granulocytes and/or tissue resident macrophages which may ultimately limit therapeutic efficacy.To overcome this limitation our team has developed a small molecule allosteric agonist of CD11b ADH-503.Our data will clearly demonstrate: 1) CD11b-agonism both rapidly repolarizes TAMs to support anti-tumorimmunity while simultaneously blunting the recruitment of multiple lineages of suppressive myeloid cellswithout the compensatory mechanisms seen with other myeloid-targeting agents. 2) CD11b-agonist-inducemyeloid reprograming reawakens T cell immunity that in-turn significantly limit disease progression. 3) Thecombination of CD11b-agonist with checkpoint immunotherapy leads to dramatic tumor regression and long-term survival in PDAC models that are otherwise completely resistant to PD-1 therapy. These stunning datadrive our hypothesis that CD11b agonism reprograms the TME to overcome resistance to checkpointimmunotherapy. To test this we will:Aim 1: Determine the molecular mechanisms by which CD11b-agonism directly impacts myeloid cells.Aim 2: Determine the cellular mechanism(s) by which CD11b-agonism enhances T cell immunity.Aim 3: Determine if chemotherapy or radiation therapy better maximize the anti-tumor immunity andthe efficacy generated by ADH-503 plus checkpoint immunotherapy.Impact: These studies investigate a new approach in current clinical development that can render PDACsresponsive to immunotherapy. 400191 +No NIH Category available 11q23;Acute Myelocytic Leukemia;Basic Science;Binding;Biology;Blast Cell;CD34 gene;Cell Line;Cells;Cyclic GMP;Cytogenetics;Data;Development;Disease Progression;Enzyme Inhibition;Exhibits;FLT3 gene;Genetic;Goals;Hematopoietic Neoplasms;Human;In Vitro;MLL-rearranged leukemia;Malignant Neoplasms;Malignant neoplasm of brain;Medical;Medicine;Messenger RNA;Modeling;Modification;Molecular;Mus;Mutate;Myelogenous;NPM1 gene;Obesity;Oncogenic;Overweight;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Play;Prognosis;Property;Protein Inhibition;Protein Overexpression;Proteins;Proteomics;RNA;RNA methylation;Refractory;Relapse;Renal carcinoma;Reporting;Research Design;Research Personnel;Risk;Role;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;Specificity;Structure;Talents;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Transcript;Translational Research;Treatment Efficacy;Treatment Failure;Validation;Variant;Xenograft procedure;acute myeloid leukemia cell;analog;anti-cancer;antitumor effect;cancer cell;cancer therapy;cancer type;clinical application;combinatorial;crosslinking and immunoprecipitation sequencing;design;druggable target;epidemiology study;epitranscriptome;experience;fat mass and obesity-associated protein;high risk;in vivo;inhibitor;innovation;leukemia;malignant breast neoplasm;manufacture;mutant;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;pharmacokinetics and pharmacodynamics;pharmacologic;relapse patients;response;self-renewal;side effect;small molecule;small molecule inhibitor;stem;success;therapeutically effective;transcriptome sequencing Targeting FTO to treat acute myeloid leukemia Project Narrative:Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancies with the majority (>70%) ofpatients that cannot be cured with contemporary therapies and thus effective novel therapeutics are urgentlyneeded. The major goal of this application is to develop highly effective selective and clinically applicable small-molecule inhibitors targeting FTO (the fat mass and obesity-associated protein which is a major eraser of acommon type of RNA methylation) and to assess the therapeutic efficacy/potential of FTO inhibitors alone orin combination with other therapeutic agents in treating unfavorable-risk AMLs with FTO overexpression; theunderlying cellular and molecular mechanisms will also be elucidated. Thus the success of this project may leadto the development of effective novel therapeutic strategies to treat unfavorable-risk AMLs (including refractoryor relapsed AMLs) with FTO overexpression. NCI 10741801 11/13/23 0:00 PA-19-056 5R01CA243386-05 5 R01 CA 243386 5 "CHEN, WEIWEI" 12/1/19 0:00 11/30/24 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8470188 "CHEN, JIANJUN " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 513526 NCI 291776 221750 PROJECT SUMMARY (ABSTRACT): Title: Targeting FTO to treat acute myeloid leukemia Background: Acute myeloid leukemia (AML) is a major form of leukemia with unfavorable prognosis. Withcurrently available therapies over 70% of patients with AML cannot survival over five years. Thus it is urgent todevelop more effective novel therapeutics. N6-methyladenosine (m6A) modification is the most abundant internalmodification in eukaryotic messenger RNAs and can be removed by m6A demethylases such as FTO. Recentlywe reported that as an m6A demethylase FTO plays a critical oncogenic role in AML pathogenesis and drugresponse (Li Z. et al. Cancer Cell. 2017). Moreover we showed that by suppression of the FTO/m6A signalingR-2-hydroxyglutarate (R-2HG) displays intrinsic and broad anti-leukemia effects (Su et al. Cell. 2018). Ourunpublished data suggests that FTO may also play a role in the self-renewal of leukemia stem/initiating cells(LSCs/LICs). Thus our results have shown the functional importance of FTO in AML pathogenesis and drugresponse and highlight the therapeutic potential of targeting FTO and the associated RNA epitranscriptome totreat FTO-high AMLs which account for >60% of total AML cases and are often associated with unfavorableprognosis. More recently we have identified a highly effective/selective small-molecule FTO inhibitor namelyCS-1 which shows the highest anti-leukemia efficacy amongst a panel of 213 FTO inhibitor hits with IC50 valuesaround 100 nM in suppression of viability of human AML cells (primary AML cells and cell line cells). Moreoverwe have also demonstrated that this compound binds directly to FTO protein and substantially prolongs survivalof AML mice in vivo. In addition we also showed that this FTO inhibitor can substantially sensitize FTO-highAML cells to other therapeutic agents. Objective/Hypothesis: Pharmacological inhibition of FTO with selective small molecule inhibitors alone orin combination with other anti-leukemia therapeutics is an effective novel treatment approach in AML. Specific Aims: (1) To optimize CS-1 and develop clinically applicable effective and selective FTO inhibitors;(2) To develop effective FTO inhibitor-based therapeutic strategies to treat unfavorable-risk FTO-high AMLs; and(3) To decipher the cellular and molecular mechanisms underlying the anti-AML efficacy of the FTO inhibitor(s). Study Design: 1) We will develop more effective CS-1 analogs and then assess and compare their FTO-inhibition efficacy selectivity drug-like properties and therapeutic efficacy and conduct PK/PD/toxicity studiesfor the top 2 compounds (Aim 1). 2) We will further use murine AML and patient-derived xeno-transplantation(PDX) AML models to assess the therapeutic efficacy of our top FTO inhibitor(s) alone or in combination withother therapeutic agents in treating unfavorable-risk FTO-high AMLs (Aim 2). 3) We will assess the effect ofgenetic depletion or pharmaceutical inhibition of FTO on LSC/LIC self-renewal and also decipher the molecularmechanism by which FTO inhibition or FTO depletion displays potent anti-leukemia effects (Aim 3). 513526 +No NIH Category available Antioxidants;Applications Grants;Aspartate;Biochemical;Biologic Characteristic;Biological Assay;Biological Markers;Biology;CRISPR screen;Cancer Model;Cancer Patient;Cancer cell line;Cell Proliferation;Cells;Chemicals;Companions;Complex;Cysteine;Dependence;Drug Metabolic Detoxication;Electron Transport;Environment;Enzymes;Equilibrium;Foundations;Functional disorder;Gene Deletion;Generations;Genes;Genetic;Genetic Transcription;Genomics;Goals;Growth;Homeostasis;Impairment;In Vitro;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methods;Mitochondria;Modeling;Modification;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenic;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Pharmacology;Play;Point Mutation;Production;Proliferating;Proteins;Proteomics;Reactive Oxygen Species;Regulation;Research;Respiration;Role;Series;Signal Transduction;Signal Transduction Pathway;Signaling Protein;Stress;Supplementation;Technology;Testing;Therapeutic;Tumor Suppressor Proteins;Work;anti-cancer therapeutic;biomarker identification;cancer cell;cancer therapy;cancer type;cell growth;cohort;efficacy evaluation;efficacy testing;experimental study;functional genomics;genome-wide;in vivo;insight;lung cancer cell;metabolomics;mitochondrial metabolism;mutant;next generation;novel;novel therapeutic intervention;pharmacologic;potential biomarker;protein function;reconstitution;response;small molecule inhibitor;synergism;therapeutic development;therapeutic evaluation;transcription factor;transcriptomics;translational therapeutics;tumor growth Deciphering the Role of Reductive Stress in Non Small Cell Lung Cancer Project narrativeThe NRF2 transcription factor orchestrates cellular anti-oxidant response promoting a reductive environmentthat is generally required for unchecked proliferation. Surprisingly in ~16% of non small cell lung cancer(NSCLC) cell lines NRF2 activation leads to a severe block in growth resulting from a decrease in mitochondrialmetabolism and electron transport chain dysfunction. The goal of this application is to use a suite of advancedmetabolomic chemical-proteomic and genomic technologies to understand how the NRF2 regulated cellularenvironment is detrimental to cell proliferation and to test the efficacy of activating NRF2 in vivo to block NSCLCgrowth. NCI 10741791 11/13/23 0:00 PA-20-185 5R37CA260062-03 5 R37 CA 260062 3 "SALNIKOW, KONSTANTIN" 12/13/21 0:00 11/30/26 0:00 Tumor Cell Biology Study Section[TCB] 14469963 "BAR-PELED, LIRON " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 345870 NCI 205875 139995 Project SummaryControl of the redox homeostasis is essential to cancer cell proliferation and requires the delicate maintenanceof oxidative and reductive metabolic pathways. This equilibrium is controlled by signal transduction pathwaysand imbalances lead to redox stress that potently blocks cancer growth. Much work has focused on the role ofoxidative stress in cancer proliferation however the converse reductive stress and its impact on malignantcells is poorly understood. We have studied the role of redox control in cancer in the context of modification ofproteinaceous cysteines by reactive oxygen species and the NRF2 transcription factor pathway. NRF2 functionsas the master regulator of the cellular antioxidant response and promotes the expression of key metabolic anddetoxification genes to generate a reductive environment and negate oxidative stress. NRF2 is activated in manycancers including ~30% of non small cell lung cancers (NSCLC) through mutation of its negative regulatorKEAP1. While NRF2 has been extensively studied in KEAP1-mutant NSCLCs we wondered what role thispathway plays in the proliferation of NSCLC cell lines which are wildtype (WT) for KEAP1. To this end wepharmacologically activated NRF2 in 50+ NSCLC cell lines (WT for KEAP1) and measured their proliferation.Unexpectedly we find that in ~16% of NSCLC cell lines NRF2 activation results in a severe block in proliferation.A genome wide CRISPR screen identifies that genes involved in mitochondrial metabolism mitochondrial fusionand the electron transport chain (ETC) are major sensitizers to NRF2 activation when lost and can function ascompanion biomarkers for NRF2-sensitivity. In line with the generation of reductive stress following NRF2activation key cysteines on enzymes involved in mitochondrial metabolism and mitochondrial fusion are reducedas determined by chemical proteomic platforms. To explain these surprising biological characteristics wepropose the following hypothesis: NRF2 activation in a subset of NSCLC cell lines promotes an overly reductiveenvironment that decreases the activity of key enzymes in mitochondrial metabolism and mitochondrialrespiration and fusion. The inactivation of these pathways synergize to block cell growth. In this grant applicationwe build on our research surrounding NRF2 sensitization and mechanistically characterize the role of reductivestress in NSCLC proliferation. In this grant application we will comprehensively define KEAP1-dependence byidentifying NRF2 regulation of mitochondrial metabolism/fusion at the protein cellular and organismal levels.The research proposed herein takes full advantage of a series of recently conceived methods: chemicalproteomics genome-wide CRISPR screens and untargeted metabolomics which have previously beendeployed in isolation to be used in an integrated manner to effectively dissect how protein reduction underliesprotein malfunction and KEAP1-dependence. These studies will not only provide a comprehensiveunderstanding of NRF2/KEAP1 biology but may also lay the foundation for developing translational therapeuticsto benefit lung cancer patients with deregulated NRF2 signaling. 345870 +No NIH Category available 2019-nCoV;Active Sites;Address;Algorithms;Amino Acid Sequence;Antibodies;Architecture;Base Sequence;Binding;Biological Assay;CRISPR/Cas technology;Cells;Chemistry;Chimera organism;Chimeric Proteins;Code;Complex;Consumption;DNA;Data Set;Databases;Development;Disease;Employment;Encapsulated;Engineering;Fibronectins;Fluorescence;Formulation;Foundations;Gene Delivery;Generations;Genetic;Goals;Human;In Vitro;Laboratories;Language;Learning;Length;Libraries;Malignant Neoplasms;Masks;Mediating;Messenger RNA;Methodology;Methods;Modality;Modeling;Molecular Conformation;Mutagenesis;Output;Pathogenicity;Peptides;Phosphoric Monoester Hydrolases;Phosphotransferases;Positioning Attribute;Post-Translational Protein Processing;Protac;Protein Engineering;Protein Isoforms;Proteins;Proteome;Protocols documentation;RNA;Rapid screening;Research;Specific qualifier value;Structure;Techniques;Technology;Testing;Therapeutic;Training;Translating;Translations;Ubiquitin-Proteasomal Pathway;Validation;Variant;Work;design;disease phenotype;experimental analysis;gene therapy;grasp;in silico;in vivo;in vivo evaluation;interest;iterative design;lipid nanoparticle;mutant;nanobodies;novel therapeutic intervention;novel therapeutics;pharmacologic;protein aminoacid sequence;protein complex;protein degradation;protein protein interaction;rapid testing;scaffold;screening;small molecule;small molecule inhibitor;tool;ubiquitin-protein ligase Programmable peptide-guided protein degradation Project NarrativeTargeted protein degradation represents a novel therapeutic strategy enabling proteasomal degradation ofpathogenic proteins. This project aims to integrate structure-based modeling language models fluorescentscreening and state-of-the-art gene delivery to develop a translatable peptide-guided protein degradationplatform. By integrating computational and experimental methodologies the proposed work will establish afoundational tool to design a peptide-guided degrader to any pathogenic protein of interest enablingprogrammable proteome editing for broad-ranging research and therapeutic applications. NCI 10741655 8/15/23 0:00 PAR-22-090 1R21CA278468-01A1 1 R21 CA 278468 1 A1 "AMIN, ANOWARUL" 9/1/23 0:00 8/31/25 0:00 Macromolecular Structure and Function A Study Section[MSFA] 78293495 "CHATTERJEE, PRANAM " Not Applicable 4 BIOMEDICAL ENGINEERING 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC BIOMED ENGR/COL ENGR/ENGR STA 277054673 UNITED STATES N 9/1/23 0:00 8/31/25 0:00 396 Non-SBIR/STTR 2023 387702 NCI 257125 130577 SummaryOver 600 human proteins have been recently prioritized as key cancer targets with nearly half beingconsidered intractable by standard small-molecule inhibition approaches due to target instability and activesite accessibility constraints. By redirecting the ubiquitin-proteasomal pathway (UPS) for targeted proteindegradation the proteolysis-targeting chimera (PROTAC) technology provides a potential solution enablingrapid and continuous target consumption as well as the stronger pharmacological effects than small moleculeinhibition. Nonetheless PROTACs suffer from similar developmental hurdles as small molecules and cannot beeasily designed for motif or post-translational modification-specific targeting. To address these hurdlesresearch efforts have shifted toward gene therapy approaches by introducing the concept of protein-mediatedprotein degradation. Here E3 ubiquitin ligases are redirected by replacing their natural substrate bindingdomains with off-the-shelf binding domains including nanobodies antibodies and DARPins to generatetarget-specific ubiquibodies. To augment this platform we recently exploited natural protein-protein interactioninformation to develop algorithmic pipelines that prioritize target-selective peptides which can be fused to theE3 ubiquitin ligase conjugation domains to induce target protein degradation. In this project we will augmentour current methods to enable the development of these ubiquibodies (uAbs) for any protein including thosedeemed intractable by small molecule-based means. To do this we will automate a bipartite algorithmicpipeline that leverages recent advancements in protein language modeling as well as existing co-complexdatabases to design peptide binders to diverse protein targets including those with solved co-crystals as wellas those with minimal structural information. Specifically our pipeline will take user-specified target proteins asinputs and generate prioritized lists of candidate peptide binders as outputs enabling subsequent generationof uAbs for target degradation. Through library-on-library fluorescence-based assays in human cells andsubsequent encapsulation of uAb mRNA in lipid nanoparticles (LNPs) we will develop a scalable method totest and translate our degraders for downstream in vivo validation. In total this work will generate a robustpeptide design tool that will enhance targeted protein degradation efforts and lay the foundation forprogrammable proteome editing. 387702 +No NIH Category available Academic Medical Centers;Address;Adoption;Advanced Malignant Neoplasm;Algorithms;Cancer Burden;Cancer Center;Cancer Research Project;Clinical;Clinical effectiveness;Collaborations;Colorectal Cancer;Complex;Computer software;Cost Analysis;Coupled;Data;Disparity;Education;Electronic Health Record;Eligibility Determination;Family;Fast Healthcare Interoperability Resources;Funding;Genetic;Genetic Counseling;Genetic Enhancement;Goals;Guidelines;Health;Health Expenditures;Health system;Healthcare Systems;Hereditary Malignant Neoplasm;Home;Hospitals;Implementation readiness;Individual;Informatics;Infrastructure;Intervention;Malignant Neoplasms;Malignant neoplasm of ovary;Marketing;Medical;Medical center;Medicine;Morbidity - disease rate;National Cancer Institute;National Comprehensive Cancer Network;New York;Patient Education;Patients;Phase;Population;Prevention Research;Primary Care;Process;Public Health;Randomized;Recording of previous events;Research;Research Personnel;Research Training;Resource-limited setting;Resources;Risk;Risk Assessment;Risk Factors;Risk Management;Scanning;Science;Screening for cancer;Services;Site;South Carolina;Technology;Test Result;Testing;Universities;Utah;Variant;Workload;anticancer research;budget impact;cancer genetics;cancer prevention;cancer risk;chatbot;clinical decision support;cloud based;detector;electronic health record system;evidence base;experience;genetic analysis;genetic testing;health disparity;health equity promotion;high risk;high risk population;implementation barriers;implementation evaluation;implementation framework;implementation strategy;implementation tool;informatics tool;interoperability;malignant breast neoplasm;marginalized population;meetings;mortality;novel;novel strategies;open source;patient outreach;patient population;personalized approach;population based;precision medicine;primary care clinic;primary care setting;programs;risk stratification;safety net;screening;support tools GARDE: Scalable Clinical Decision Support for Individualized Cancer Risk Management PROJECT NARRATIVE Evidence supports tailoring cancer screening to each individuals risk. We propose to enhance anddisseminate software that scans electronic health records of target patient populations to (i) automaticallyidentify those who may benefit from genetic testing for hereditary cancers according to national cancerguidelines; and (ii) use automated chatbots for patient outreach offering patient education and theopportunity to receive at-home genetic testing for hereditary cancers. Through wide dissemination our softwareplatform has the potential to reduce cancer burden by enabling evidence-based cancer screening tailored to theindividual. NCI 10741231 8/31/23 0:00 RFA-CA-22-023 1U24CA274582-01A1 1 U24 CA 274582 1 A1 "PATRIOTIS, CHRISTOS F" 9/1/23 0:00 8/31/28 0:00 ZCA1-TCRB-Q(M2) 9786619 "DEL FIOL, GUILHERME " "KAWAMOTO, KENSAKU " 1 MISCELLANEOUS 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 818820 NCI 607941 210879 PROJECT SUMMARY/ABSTRACT Evidence supports individualizing risk-stratified cancer screening with selective application of specificscreening interventions best suited to the individual. Yet individualizing cancer screening at a populationscale requires the implementation of personalized risk assessments which are quite challenging to achieve intodays overwhelmed primary care settings. A promising approach to address this challenge is to automate theidentification and management of eligible patients using electronic health record (EHR) technologies coupledwith advanced clinical decision support (CDS) tools and automated conversational agents (chatbots). Inprevious research funded by the National Cancer Institute (NCI) Informatics Technology for Cancer Research(ITCR) program we have enabled GARDE (Genetic Cancer Risk Detector) a standards-based CDS platformfor individualized cancer screening. GARDE (i) screens and identifies patients who meet NationalComprehensive Cancer Network (NCCN) criteria for genetic testing based on their family history and otherrisk factors in the EHR; and (ii) uses automated chatbots offering patient outreach and education offeringaccess to genetic testing and explanation of test results. GARDE has been integrated with two market-leadingEHR systems (Epic and Cerner) using the Fast Healthcare Interoperability Resources (FHIR) and CDS Hooksstandards. GARDE has been successfully deployed in clinical settings at two academic medical centers andtheir respective cancer centers (University of Utah/Huntsman Cancer Institute and New York University) insupport of the BRIDGE trial funded by the NCI Cancer Moonshot program (U01CA232826 Kaphingst PI).The overall objective of the present proposal is to enhance and disseminate GARDE across healthcare systemsincluding high resource medical centers and low resource safety net healthcare systems. Our approach will beguided by implementation science frameworks that help assess implementation readiness identify barriersand facilitators identify needs for adaptation and develop implementation strategies. Specifically we will (i)enhance GARDEs chatbots using open-source technologies; (ii) deploy GARDE at new collaborating sites(Cornell University Medical University of South Carolina [MUSC] Beaufort Memorial Hospital); (iii) conductrapid iterative pilot implementations at these new sites; (iv) iteratively develop and test an implementationtoolkit based on experience with the pilot sites; (v) conduct a cost analysis to catalyze further adoption; and(vi) disseminate GARDE beyond the collaborating sites through the implementation toolkit and directtechnical assistance. Through wide dissemination GARDE has the potential to enable evidence-basedindividualized cancer screening and reduce cancer burden through a scalable population-based andinteroperable approach. 818820 +No NIH Category available 2 arm randomized control trial;Abstinence;Address;Adherence;Argentina;Behavior;Behavioral Research;Birth;Clinical Research;Cotinine;Country;Disparity;Effectiveness;Epidemiology;Ferrous fumarate;Fright;Gender Identity;HIV;Health;Healthcare;Image;Income;Individual;Intervention;Interview;Latin American;Latino;Latino Population;Lesbian Gay Bisexual Transgender;Literature;Medical;Mentors;Mexico;Modality;Modification;Multimedia;Participant;Persons;Pharmacy facility;Pilot Projects;Population;Prevalence;Printing;Procedures;Puerto Rico;Randomized;Randomized Controlled Trials;Reporting;Research;Research Design;Research Personnel;Resources;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Social support;Suicide attempt;Testing;Text;Tobacco;Work;arm;career;community based participatory research;cost;efficacy evaluation;experience;follow up assessment;follow-up;gender affirmation;gender dysphoria;gender expression;health care service;health care settings;housing instability;mHealth;maltreatment;nicotine replacement;pilot test;programs;recruit;satisfaction;sex;smoking abstinence;smoking cessation;social;standard of care;stressor;systematic review;text messaging intervention;transgender;translational study;usability;virtual TRANSforma Tu Salud Dejando de Fumar: Advancing smoking cessation among transgender individuals PROJECT NARRATIVEMobile health (mHealth) interventions are a promising modality for overcoming barriers and providing culturallyappropriate treatment among transgender individuals. We propose to integrate our expertise in mHealthsmoking cessation transgender health care community-based participatory research and culturalaccommodation to develop pilot test (R21) and then formally evaluate (R33) TRANSform Tu Salud Dejandode Fumar (Spanish for TRANSform Your Health by Quitting Smoking) a culturally accommodated smokingcessation intervention for transgender individuals. TRANSform Tu Salud Dejando de Fumar will consist of 1) a12-week WhatsApp-based program that facilitates longitudinal and bidirectional multimedia-based (i.e. textimage video and audio) dialogue with participants and 2) integration with an e-Pharmacy to access nicotinereplacement therapy (NRT) at no cost. NCI 10741034 9/19/23 0:00 PAR-21-303 1R21CA284313-01 1 R21 CA 284313 1 "PEARLMAN, PAUL C" 9/22/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CCHI-X(57)R] 15929531 "CARTUJANO, FRANCISCO " "ARISTEGUI, INES ; MEJIA, RAUL MARIANO" 25 PUBLIC HEALTH & PREV MEDICINE 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 9/22/23 0:00 8/31/25 0:00 393 Non-SBIR/STTR 2023 325032 FIC 1478 522 PROJECT SUMMARYMobile health (mHealth) interventions are a promising modality for overcoming barriers and providing culturallyappropriate treatment among transgender individuals. mHealth interventions may be appropriate amongtransgender individuals as emergent evidence suggests that virtual spaces are used to access gender affirmingsupport and resources. Moreover mHealth interventions may enable authentic self-expression amongtransgender individuals which is not always possible offline. Over the past 7 years our team has developedDecdetexto a culturally accommodated smoking cessation text messaging intervention for U.S. Latino smokers.Decdetexto has been expanded to different Latin American countries/regions (e.g. Mexico and Puerto Rico)and has been adapted to different populations (e.g. U.S. Latino smokers living with HIV). A recently completedrandomized controlled trial (RCT) with U.S. Latino smokers (n=457) demonstrated that U.S. Latinos receivingthe Decdetexto intervention were significantly more likely than those receiving standard of care (smokingcessation printed materials) to be smoking abstinent at Month 6 (34.1% vs 20.6%; p<0.001). Despite the proveneffectiveness of Decdetexto among U.S. Latinos we have identified that this intervention does not adequatelyaddress unique barriers to smoking cessation encountered by transgender individuals (e.g. low social supportgender dysphoria as a stressor need for gender affirming medical procedures). We propose to integrate ourexpertise in mHealth smoking cessation transgender health care community-based participatory research andcultural accommodation to develop pilot test (R21) and then formally evaluate (R33) TRANSform Tu SaludDejando de Fumar (Spanish for TRANSform Your Health by Quitting Smoking) a culturally accommodatedsmoking cessation intervention for transgender individuals. TRANSform Tu Salud Dejando de Fumar willconsist of 1) a 12-week WhatsApp-based program that facilitates longitudinal and bidirectional multimedia-based(i.e. text image video and audio) dialogue with participants and 2) integration with an e-Pharmacy to accessnicotine replacement therapy (NRT) at no cost.R21 Aim 1: Develop TRANSform Tu Salud Dejando de Fumar a culturally accommodated smoking cessationintervention for transgender individuals. R21 Aim 2: Assess the feasibility acceptability and preliminary impactof TRANSform Tu Salud Dejando de Fumar among transgender individuals. R33 Aim 1: Assess the efficacy ofTRANSform Tu Salud Dejando de Fumar compared to standard of care on smoking abstinence at Month 6among transgender individuals. R21-R33 Capacity building. We will build capacity for mHealth behavioralresearch through the engagement of early career investigators in mentored activities and through academicpartnerships between the U.S. and Argentina. 2000 +No NIH Category available 2 arm randomized control trial;Abstinence;Address;Adherence;Argentina;Behavior;Behavioral Research;Birth;Clinical Research;Cotinine;Country;Disparity;Effectiveness;Epidemiology;Ferrous fumarate;Fright;Gender Identity;HIV;Health;Healthcare;Image;Income;Individual;Intervention;Interview;Latin American;Latino;Latino Population;Lesbian Gay Bisexual Transgender;Literature;Medical;Mentors;Mexico;Modality;Modification;Multimedia;Participant;Persons;Pharmacy facility;Pilot Projects;Population;Prevalence;Printing;Procedures;Puerto Rico;Randomized;Randomized Controlled Trials;Reporting;Research;Research Design;Research Personnel;Resources;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Social support;Suicide attempt;Testing;Text;Tobacco;Work;arm;career;community based participatory research;cost;efficacy evaluation;experience;follow up assessment;follow-up;gender affirmation;gender dysphoria;gender expression;health care service;health care settings;housing instability;mHealth;maltreatment;nicotine replacement;pilot test;programs;recruit;satisfaction;sex;smoking abstinence;smoking cessation;social;standard of care;stressor;systematic review;text messaging intervention;transgender;translational study;usability;virtual TRANSforma Tu Salud Dejando de Fumar: Advancing smoking cessation among transgender individuals PROJECT NARRATIVEMobile health (mHealth) interventions are a promising modality for overcoming barriers and providing culturallyappropriate treatment among transgender individuals. We propose to integrate our expertise in mHealthsmoking cessation transgender health care community-based participatory research and culturalaccommodation to develop pilot test (R21) and then formally evaluate (R33) TRANSform Tu Salud Dejandode Fumar (Spanish for TRANSform Your Health by Quitting Smoking) a culturally accommodated smokingcessation intervention for transgender individuals. TRANSform Tu Salud Dejando de Fumar will consist of 1) a12-week WhatsApp-based program that facilitates longitudinal and bidirectional multimedia-based (i.e. textimage video and audio) dialogue with participants and 2) integration with an e-Pharmacy to access nicotinereplacement therapy (NRT) at no cost. NCI 10741034 9/19/23 0:00 PAR-21-303 1R21CA284313-01 1 R21 CA 284313 1 "PEARLMAN, PAUL C" 9/22/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CCHI-X(57)R] 15929531 "CARTUJANO, FRANCISCO " "ARISTEGUI, INES ; MEJIA, RAUL MARIANO" 25 PUBLIC HEALTH & PREV MEDICINE 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 9/22/23 0:00 8/31/25 0:00 393 Non-SBIR/STTR 2023 325032 NCI 238674 84358 PROJECT SUMMARYMobile health (mHealth) interventions are a promising modality for overcoming barriers and providing culturallyappropriate treatment among transgender individuals. mHealth interventions may be appropriate amongtransgender individuals as emergent evidence suggests that virtual spaces are used to access gender affirmingsupport and resources. Moreover mHealth interventions may enable authentic self-expression amongtransgender individuals which is not always possible offline. Over the past 7 years our team has developedDecdetexto a culturally accommodated smoking cessation text messaging intervention for U.S. Latino smokers.Decdetexto has been expanded to different Latin American countries/regions (e.g. Mexico and Puerto Rico)and has been adapted to different populations (e.g. U.S. Latino smokers living with HIV). A recently completedrandomized controlled trial (RCT) with U.S. Latino smokers (n=457) demonstrated that U.S. Latinos receivingthe Decdetexto intervention were significantly more likely than those receiving standard of care (smokingcessation printed materials) to be smoking abstinent at Month 6 (34.1% vs 20.6%; p<0.001). Despite the proveneffectiveness of Decdetexto among U.S. Latinos we have identified that this intervention does not adequatelyaddress unique barriers to smoking cessation encountered by transgender individuals (e.g. low social supportgender dysphoria as a stressor need for gender affirming medical procedures). We propose to integrate ourexpertise in mHealth smoking cessation transgender health care community-based participatory research andcultural accommodation to develop pilot test (R21) and then formally evaluate (R33) TRANSform Tu SaludDejando de Fumar (Spanish for TRANSform Your Health by Quitting Smoking) a culturally accommodatedsmoking cessation intervention for transgender individuals. TRANSform Tu Salud Dejando de Fumar willconsist of 1) a 12-week WhatsApp-based program that facilitates longitudinal and bidirectional multimedia-based(i.e. text image video and audio) dialogue with participants and 2) integration with an e-Pharmacy to accessnicotine replacement therapy (NRT) at no cost.R21 Aim 1: Develop TRANSform Tu Salud Dejando de Fumar a culturally accommodated smoking cessationintervention for transgender individuals. R21 Aim 2: Assess the feasibility acceptability and preliminary impactof TRANSform Tu Salud Dejando de Fumar among transgender individuals. R33 Aim 1: Assess the efficacy ofTRANSform Tu Salud Dejando de Fumar compared to standard of care on smoking abstinence at Month 6among transgender individuals. R21-R33 Capacity building. We will build capacity for mHealth behavioralresearch through the engagement of early career investigators in mentored activities and through academicpartnerships between the U.S. and Argentina. 323032 +No NIH Category available Adoption;Anxiety;Argentina;Behavioral;Behavioral Model;Cancer Control;Cancer Etiology;Cancer Intervention;Cessation of life;Clinical;Cognitive;Communication;Confusion;Consolidated Framework for Implementation Research;Consultations;Counseling;Country;Data;Development;Diagnosis;Disease;Distress;Effectiveness;Evaluation;Face;Family;Fright;Health;Health Personnel;Health Resources;Health system;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human Resources;Intervention;Interview;Knowledge;Latin America;Latin American;Lesion;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Methods;Modeling;Outcome;Patients;Perception;Personal Communication;Phase;Prevention;Primary Health Care;Process;Proctor framework;Provider;Quality of life;Randomized Controlled Trials;Recommendation;Records;Regulation;Reporting;Sexually Transmitted Diseases;Shame;Solid;Structure;Surveys;Test Result;Testing;Time;Training;Vulnerable Populations;Woman;Work;burden of illness;cancer prevention;cervical cancer prevention;cost;design;effectiveness outcome;evidence base;follow-up;health training;implementation evaluation;implementation facilitators;implementation fidelity;implementation framework;implementation outcomes;implementation research;implementation science;implementation strategy;implementation study;improved;individual patient;innovation;mHealth;mobile application;mortality;premalignant;primary health center;psychosocial;screening;screening program;social vulnerability;sound;standard of care;theories;tool;usability;user centered design Developing and evaluating a mobile application-based intervention to support HPV-tested women and increase their retention to follow-up: a mixed-methods implementation study Project narrativeThis study will design and evaluate an app-based intervention targeted to HPV-tested women to increaseknowledge about HPV and cervical cancer prevention reduce the psycho-social impact of HPV positivity andincrease retention to follow-up. In addition it will evaluate implementation outcomes by potential users of theapp using the Consolidated Framework for Implementation Research (CFIR). The app will constitute a low-cost easy to use tool that will radically change how HPV-tested women access evidence-based information.In addition this innovative study will serve as a model of work and will contribute to the consolidation ofImplementation research applied to cancer control in Latin America which is still at its early stages ofdevelopment. NCI 10740962 9/21/23 0:00 PAR-21-303 1R21CA284314-01 1 R21 CA 284314 1 "PEARLMAN, PAUL C" 9/22/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CCHI-X(57)R] 12001586 "ARROSSI, SILVINA " Not Applicable n/a Unavailable 971835780 MR3DG3US89F4 971835780 MR3DG3US89F4 AR -34.61315 -58.37723 10029329 CENTER FOR THE STUDY OF STATE / SOCIETY BUENOS AIRES Unavailable c1173aaa ARGENTINA N 9/22/23 0:00 8/31/25 0:00 393 Non-SBIR/STTR 2023 246493 NCI 228234 18259 PROJECT SUMMARY/ABSTRACTCervical cancer (CC) is one of the leading causes of cancer death among women from Latin America. In theRegion screening programs face important problems to assure follow-up/treatment which is a majorobstacle for screening effectiveness. Human papillomavirus (HPV) testing has become the main strategy toreduce the burden of the disease. However HPV positivity can have an important negative impact on thepsychosocial health of tested women. In addition for many Latin-American women information provided byhealth providers about HPV is often confusing; women have difficulties in understanding HPV-test resultsand steps to follow. Both HPVs psychosocial impact of HPV-testing and lack of information regarding thefollow-up process might not only diminish women's quality of life but also reduce their retention to follow up.The specific aims of this project are the following:AIM 1. To develop and test usability of an app to increase women knowledge about HPV/ CC/FU reduce thepsycho-social impact of HPV-testing and increase retention to follow-up. (R21 phase)AIM 2. To evaluate the implementation strategy and preliminary effectiveness outcomes of the app-basedintervention and identify barriers and facilitators to the implementation. (R33 Phase)We will carry out a pilot implementation study of an app-based intervention aimed at providing HPV-testedwith evidence-based information about HPV reducing the psycho-social impact of HPV and increasingretention to follow-up. The app-based intervention will consist of an app to provide information and supportto HPV-tested women offered to women by trained health providers during the screening consultation.Wewill combine a user-centered design approach with behavioral models and Implementation Scienceframeworks to test and evaluate the implementation strategy of the app-based intervention in PHC centersin Argentina. We will use a mixed methods descriptive design composed of a quantitative Women study anda Quantitative -qualitative Study at Health provider level. Following Proctors taxonomy in the Women Studywe will evaluate acceptability appropriateness and adoption of the implementation strategy. To measurepreliminary effectiveness outcomes we will carry out three quantitative surveys at different moments of thescreening/follow-up process and we will analyze data from routine clinical records. In the Study of Healthproviders we will carry out semi-structured interviews to analyze CFIR selected constructs.This study will provide evidence about the implementation strategy of an app-based intervention that will beready for evaluation of its effectiveness in a randomized controlled trial. It will constitute a solid and soundexample of how Implementation Science can be used to produce rigorous evidence-based information aboutimplementation of mHealth interventions for cancer control. 246493 +No NIH Category available Acute-Phase Proteins;Address;Agonist;Amyloid Proteins;Biology;CD47 gene;Cancer Cell Growth;Cancer Model;Cell Proliferation;Cells;Clinical;Cytotoxic Chemotherapy;Deposition;Development;Disease;Elements;Environment;Equilibrium;Extracellular Matrix;Extracellular Matrix Proteins;Genetic;Goals;Growth;Hepatic Stellate Cell;Hepatocyte;Immunologics;Interleukin-6;KPC model;KRASG12D;Kupffer Cells;Liver;Macrophage;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mechanics;Metabolic;Metastatic Neoplasm to the Liver;Modeling;Molecular;Morbidity - disease rate;Mus;Myelogenous;Myeloid Cells;Nature;Neoplasm Circulating Cells;Neoplasm Metastasis;Neutrophil Infiltration;Non-Malignant;Outcome;Pancreas;Pliability;Primary Neoplasm;Process;Property;Risk Reduction;Role;STAT3 gene;Serum;Shapes;Signal Pathway;Signal Transduction;Soil;Stromal Cells;TNFRSF5 gene;Testing;Therapeutic;Treatment Efficacy;Tropism;Variant;Work;cancer cell;cancer site;carcinogenesis;chemotherapy;clinically relevant;design;human disease;improved;mortality;mouse model;neoplastic cell;novel;novel strategies;novel therapeutics;pancreatic ductal adenocarcinoma model;prevent;standard of care;therapeutic target;therapy design/development;tool;tumor Mechanisms and therapeutic targets of cancer metastasis Project NarrativeMetastatic disease remains the primary cause of morbidity and mortality in cancer with little improvement inoutcomes seen over the past decade. In this proposal we investigate (i) mechanisms regulating the formation(ii) the reversibility and (iii) therapeutic implications of a niche environment in the liver that is supportive ofcancer metastasis and growth. The proposed studies will incorporate clinically-relevant mouse models ofcancer to inform development of novel strategies to prevent and treat cancer metastasis. NCI 10740908 11/8/23 0:00 PA-19-056 5R01CA245323-05 5 R01 CA 245323 5 "SNYDERWINE, ELIZABETH G" 12/1/19 0:00 11/30/24 0:00 Tumor Microenvironment Study Section[TME] 9156575 "BEATTY, GREGORY L" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 334547 NCI 205875 128672 Project SummaryMetastasis is the primary cause of morbidity and mortality in cancer with little improvement in outcomes over thepast decade. This is particularly evident in gastrointestinal cancers where metastasis to the liver is the mostcommon site of cancer cell spread. We hypothesize that the spread and growth of cancer cells in the liver isdependent on formation of a reversible niche environment that is directed by hepatocytes the chief functionalcells of the liver. In support of this hypothesis we have found that primary tumors release soluble factors thatactivate hepatocytes in the liver. This process begins during the earliest stages of cancer development. Activatedhepatocytes respond by releasing acute phase reactants which orchestrate a niche environment in the liver thatis underpinned by the recruitment of neutrophils and myeloid cells and the deposition of extracellular matrixproteins. This environment supports cancer cell seeding and colonization. In the absence of this pro-metastaticniche disseminated cancer cells enter a state of cell dormancy in the liver. Although macrophages are a first-line of defense against metastasis to the liver their biology is also altered during formation of the nicheenvironment in the liver. Thus our findings identify an intercellular network within the liver underpinned byhepatocytes that responds to cancer development by preparing the soil that supports cancer cell seeding.Our ultimate goal is to devise novel therapies that will resolve the pro-metastatic niche and redirect the liverenvironment from pro- to anti-metastatic for treating and preventing cancer metastasis. However this will requirean understanding of the signals by which hepatocytes direct formation of the niche and identification of strategiescapable of reversing the pro-metastatic potential of the niche. Therefore in Aim 1 we will define the downstreamsignals by which hepatocytes coordinate formation of a pro-metastatic niche in the liver. In Aim 2 we will identifystrategies to shift the niche environment in the liver from pro- to anti-metastatic. In Aim 3 we will investigate theimpact of hepatocytes on cancer cell dormancy in the liver and the efficacy of cytotoxic chemotherapy. Togetherthese complementary aims will inform the development of therapies designed to condition the liver for anti-metastatic potential as a strategy to prevent and treat cancer metastasis. 334547 +No NIH Category available Adult;Aftercare;Amides;Angiogenesis Inhibitors;Biopsy;Biopsy Specimen;Brain Neoplasms;Caring;Chemicals;Clinical;Clinical Management;Clinical Pathways;Clinical Trials;Data;Diagnostic;Disease Progression;Early identification;Excision;FDA approved;Glioblastoma;Goals;Guidelines;Human;Image;Imaging Device;Investigational Therapies;Local Therapy;Localized Malignant Neoplasm;Magnetic Resonance Imaging;Malignant Glioma;Malignant Neoplasms;Maps;Methodology;Methods;Molecular;Operative Surgical Procedures;Output;Pathologic;Pathology;Patients;Positioning Attribute;Primary Brain Neoplasms;Proteins;Protocols documentation;Protons;Quality of life;Radiation therapy;Recurrence;Recurrent tumor;Repeat Surgery;Signal Transduction;Surrogate Markers;Techniques;Testing;Tissue Sample;Treatment Protocols;bevacizumab;chemotherapy;clinical practice;deep learning;deep learning algorithm;diagnosis standard;efficacy evaluation;imaging modality;improved;in vivo;neuro-oncology;neuroimaging;novel diagnostics;novel therapeutics;predicting response;radiomics;recruit;response;temozolomide;treatment effect;treatment planning;treatment response;tumor;tumor diagnosis;tumor heterogeneity Quantitative CEST MRI for GBM Early Response Prediction and Biopsy Guidance Distinguishing recurrent tumor from treatment effect following therapy remains a major clinical challenge inneuro-oncology. We will assess the potential of quantitative CEST imaging methodologies and develop anautomated deep-learning framework for post-treatment surveillance and biopsy guidance. If successful theimplications for the clinical management of patients with brain tumors and for the robust evaluation of theefficacy of experimental therapeutics are enormous. NCI 10740899 11/20/23 0:00 PA-19-056 5R37CA248077-04 5 R37 CA 248077 4 "ZHANG, HUIMING" 12/15/20 0:00 11/30/25 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 15227906 "JIANG, SHANSHAN " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 330670 NCI 219186 111484 ABSTRACT Despite advances in therapy the most aggressive form of brain tumor glioblastoma remains almostuniversally fatal. The first-line therapy for this devastating cancer is maximum feasible surgical resectionfollowed by radiotherapy with concurrent temozolomide chemotherapy (CRT). It is encouraging that there aremultiple second-line therapies in clinical trials that could improve life quality or prolong survival such as anti-angiogenic therapy (AAT). In this scenario the accurate determination of whether a patient is a responder or anon-responder at an early stage following CRT has become a significant factor in clinical practice. Howeverthe limitations in neuroimaging complicate the clinical management of patients and impede efficient testing ofnew therapeutics. Even with the improvements in advanced imaging modalities distinguishing true progressionvs. pseudoprogression (induced by CRT) or response vs. pseudoresponse (induced by AAT) remain two ofthe most formidable diagnostic dilemmas. Hence the current gold standard for diagnosis and local therapyplanning is still based on pathologic appraisal of tissue samples. However even this yields variable results dueto the intra-tumoral heterogeneity of treatment response. Therefore reliable imaging tools capable of earlyprediction of the tumor response to clinical therapies are urgently needed. Amide proton transfer-weighted(APTw) imaging is a chemical exchange saturation transfer (CEST)-based molecular MRI technique whichhas been demonstrated to add important value to the clinical MRI assessment in neuro-oncology. Howevermost currently used imaging protocols are essentially semi-quantitative and the images obtained are oftencalled APTw images because of other contributions. Notably it has been shown that quantitative CEST-MRI isable to achieve more pure and higher APT signals in patients with brain tumors. On the other hand deep-learning is a state-of-the-art imaging analysis technique that provides exciting solutions with minimum humaninput. In particular the saliency maps derived act as a localizer for class-discriminative regions and may havegreat potential to guide biopsies and local treatment regimens. The goals of this proposal are to demonstratethe potential of quantitative CEST-MRI to resolve two formidable diagnostic dilemmas for GBM patients and todevelop an automated deep-learning framework for post-treatment surveillance and biopsy guidance. Thisapplication has three specific aims: (1) Implement and optimize the quantitative CEST-MRI technique andquantify its accuracy in predicting early response to CRT and survival; (2) Determine the capability ofquantitative CEST-MRI to assess the response to bevacizumab; and (3) Develop a deep-learning pipeline thatincludes structural and CEST images for responsiveness differentiation and stereotactic biopsy guidance. Ifsuccessful our resultsand particularly the deep-learning platform establishedwill be readily available toaccurately identify early response and guide stereotactic biopsy thus changing the clinical pathway. 330670 +No NIH Category available Adaptive Immune System;Address;Adhesives;Affect;Affinity Chromatography;Behavior;Cells;Chronic;Development;Disease Progression;Effector Cell;Epithelial Cells;Exhibits;Fibrolamellar Hepatocellular Carcinoma;Gene Expression;Genes;Goals;Growth;Growth Factor;Health;Human;IL6 gene;Immune system;Infection;Inflammation;Inflammatory;Innate Immune Response;Innate Immune System;Knowledge;Leukocytes;Link;Macrophage;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Modeling;Myelogenous;Neutrophil Infiltration;Oncogenes;Pathway interactions;Phosphoric Monoester Hydrolases;Play;Population;Positioning Attribute;Public Health;Reactive Oxygen Species;Regulation;Research;Ribosomes;Role;STAT3 gene;Signal Pathway;Signal Transduction;TXN gene;Testing;Therapeutic;Time;Translating;Work;Zebrafish;cancer cell;cancer immunotherapy;cancer therapy;cell motility;cell transformation;design;early onset;fighting;human disease;improved;in situ imaging;interest;liver cancer model;melanoma;neutrophil;paracrine;real-time images;recruit;response;transcriptome sequencing;tumor;tumor microenvironment;tumor progression;tumorigenesis;wound healing Adhesive regulation during cell migration PUBLIC HEALTH STATEMENTThe proposed research contributes to human health by increasing our understanding of theinterplay between the immune system and cancer. Here we focus on the role of neutrophils whiteblood cells that fight infection but also contribute to chronic inflammation in the initiation andprogression of cancer. We are interested in tumor genes and neutrophil genes that regulatecancer progression and how these pathways can be targeted to facilitate the development of newtreatments for cancer. NCI 10740894 11/14/23 0:00 PA-20-185 5R01CA085862-23 5 R01 CA 85862 23 "WOODHOUSE, ELIZABETH" 6/10/00 0:00 11/30/26 0:00 Intercellular Interactions Study Section[ICI] 1881003 "HUTTENLOCHER, ANNA " Not Applicable 2 PEDIATRICS 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 326450 NCI 213750 112700 ABSTRACTCell migration is important in normal development wound healing and cancer. The long-termgoal of this work is to study cell migration in the context of cancer. The most motile andunderstudied population of cells in the tumor microenvironment (TME) are neutrophils which areprimary effector cells of the innate immune response. The presence of chronic neutrophil-mediated inflammation has been associated with the initiation and progression of cancer.However the role of neutrophils in the tumor microenvironment remains controversial in partbecause neutrophils can play both pro- and anti-tumor roles. We aim to address this gap byincreasing our understanding of how neutrophils are recruited and regulated by the tumormicroenvironment during tumor progression. We will test the overall hypotheses that specificsignaling pathways induced by transformed cells drive neutrophil recruitment and thatneutrophils educated in the tumor microenvironment alter tumor progression. Toaddress these hypotheses we have developed a robust toolbox using zebrafish to enable in situimaging of the dynamic behavior of neutrophils macrophages and cancer cells in real time inmelanoma and liver cancer models. We take advantage of a new zebrafish model of fibrolamellarcarcinoma (FLC) an aggressive early onset cancer that exhibits increased inflammation and earlyprogression similar to human disease. Here we propose to examine the role of neutrophils inliver cancer and melanoma inflammation and progression (Aim 1). We will harness TRAPseqfindings from neutrophils macrophages and epithelial cells to probe the role of oncogene-inducedgenes on neutrophils in the tumor microenvironment and tumorigenesis including the role ofneutrophil intrinsic genes p47phox and the phosphatase ptprja on neutrophil polarization andtumor progression (Aim 2). Finally we will examine neutrophil-macrophage cross talk in the tumormicroenvironment and the role of macrophage polarization on neutrophil inflammation and tumorprogression (Aim 3). While there has been substantial interest in manipulating the adaptiveimmune system to treat cancer the therapeutic possibilities of the innate immune system remainunder-studied. Understanding mechanisms that regulate neutrophils in the tumormicroenvironment will enhance basic mechanistic knowledge regarding intercellular interactionsfacilitate the design of new strategies to treat cancer and potentially improve the efficacy of cancerimmunotherapy. 326450 +No NIH Category available Affinity;CD8-Positive T-Lymphocytes;CXCL13 gene;Carcinoma;Cells;Chimera organism;Clinical;Colorectal Cancer;Colorectal Neoplasms;DNA;DNA Adduction;DNA Adducts;DNA Damage;Defect;Dependence;Disease;Epithelium;Fibroblasts;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genetically Engineered Mouse;Graft Enhancements;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunocompetent;Immunologic Deficiency Syndromes;Immunologic Surveillance;Immunologics;Immunotherapy;Implant;Infiltration;Inflammation;Inflammatory;Interferons;Intervention;Intestines;Killer Cells;LGR5 gene;Link;Macrophage;Malignant Neoplasms;Mammary Neoplasms;Metalloproteases;Methods;Microsatellite Instability;Microsatellite Repeats;Minority;Mismatch Repair;Mismatch Repair Deficiency;Modeling;Mus;Mutate;Mutation;Myeloid Cells;Neoplasm Metastasis;Neutrophil Infiltration;Operative Surgical Procedures;Organoids;Outcome;Pharmaceutical Preparations;Phenotype;Prognosis;Resistance;Small Interfering RNA;Somatic Mutation;Subcutaneous Injections;T-Lymphocyte;TACSTD1 gene;Testing;Therapeutic;Tissues;Tumor Antigens;Tumor Immunity;Tumor Tissue;Tumor-infiltrating immune cells;aggressive breast cancer;antitumor effect;aptamer;cancer cell;cancer diagnosis;cancer infiltrating T cells;cancer stem cell;checkpoint therapy;chemokine;chemotherapy;colon cancer cell line;colon cancer patients;design;immune checkpoint blockade;improved;knock-down;metastatic colorectal;monocyte;mortality;neoantigens;neutrophil;programs;promoter;recruit;repair enzyme;repaired;resistance mechanism;response;small molecule inhibitor;stem cells;subcutaneous;triple-negative invasive breast carcinoma;tumor;tumor growth;virtual Tumor-targeted disruption of mismatch repair in microsatellite stable colorectal cancer Most colorectal cancers are microsatellite stable (MSS) and do not respond to checkpoint inhibitor therapy; theyhave poor prognosis when they have spread locally or have metastasized. By contrast the minority of colorectaltumors with high microsatellite instability (MSI-high) which have defects in DNA mismatch repair respond tocheckpoint inhibitor therapy and have good prognosis. Here we will investigate a tumor-targeted geneknockdown strategy to convert immunologically cold MSS tumors to immunologically responsive MSI-hightumors which we hypothesize will dramatically improve clinical outcome when used on its own or when combinedwith chemotherapy or checkpoint inhibitors. NCI 10740874 11/13/23 0:00 PAR-20-292 5R21CA277460-02 5 R21 CA 277460 2 "CHEN, WEIWEI" 12/1/22 0:00 11/30/24 0:00 ZCA1-SRB-X(O1)S 1872898 "LIEBERMAN, JUDY " Not Applicable 7 Unavailable 76593722 Z1L9F1MM1RY3 76593722 Z1L9F1MM1RY3 US 42.337481 -71.104964 1504801 BOSTON CHILDREN'S HOSPITAL BOSTON MA Independent Hospitals 21155724 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 186183 NCI 105188 80995 Colorectal cancer (CRC) is the third most diagnosed cancer in the US with the second highest mortality rate.Locally advanced and metastatic disease have a poor prognosis. A small subset (5-15%) of metastatic CRCpatients who bear tumors deficient in DNA mismatch repair (MMR) that have high microsatellite instability (MSI-high) can respond to immunotherapy with checkpoint blockade (CPI) but most CRC do not. We hypothesizethat to induce immune responses in microsatellite stable (MSS) CRC new strategies that go beyond CPI areneeded. In MSI-high CRC tumors tumor-infiltrating myeloid cells fibroblasts and the tumors themselves all haveinflammatory gene expression signatures and are colocalized into inflammatory hubs with adjacent tumor-reactive CD8 T cells suggesting that MSI-high CRCs selectively provoke a robust inflammatory multicellularnetwork within the tumor that recruits anti-tumor killer cells. Disruption of MMR in CRC mouse tumor graftsenhances tumor neoantigen expression and recruitment of tumor-specific T cells to trigger immune surveillance.We hypothesize that interventions that convert MSS CRC to an MMR-deficient MSI phenotype could enhanceantitumor immunity and make resistant MSS CRC sensitive to CPI. This proposal will investigate whethertumor-targeted gene knockdown can convert MSS CRC to immune responsive MSI-high tumors. Thereare no known small molecule inhibitors of MMR. We will exploit a method of epithelial cancer-targeted geneknockdown that uses subcutaneous injection of aptamer-small interfering RNAs (AsiCs) which link a high affinityEpCAM aptamer for epithelial tumor targeting to small interfering RNAs for tumor-selective gene knockdown.EpCAM the first described tumor antigen is ~100-1000-fold more highly expressed in epithelial cancers(including virtually all CRC) than normal epithelia making it attractive for selective CRC tumor targeting. Wepreviously showed that EpCAM-AsiCs that knockdown tumor-dependency genes or genes whose knockdownpromotes immune recognition can strongly suppress aggressive breast cancer in orthotopic metastatic andgenetically engineered mouse tumor models and induce an effective immune response in immunologically coldtumors. In this proposal we will evaluate EpCAM-AsiCs to knockdown Mlh1 encoding a key MMR enzyme inMSS CRC subcutaneous and caecal tumor implants of 4 mouse CRC cell lines and 2 MMR-proficient MSSorganoid lines derived from an aggressive genetically engineered mouse model which conditionally expressmutations in intestinal stem cells of four key genes that are frequently mutated in human CRC Apc KrasTgfbr2 and Trp53. We will evaluate the effect of MMR disruption on tumor growth in immunodeficient andimmunocompetent mice and dissect in detail how microsatellite stability tumor mutational burden and geneexpression in the tumor and the immune response to the tumor are altered. We will also investigate whether CPIenhances the antitumor effect of tumor-targeted Mlh1 knockdown. 186183 +No NIH Category available Acceleration;Address;Algorithms;Biological Markers;Cancer Detection;Characteristics;Clinical;Cohort Analysis;Cohort Studies;Consumption;Cost efficiency;Data;Data Analyses;Development;Diabetes Mellitus;Diagnosis;Early Detection Research Network;Early Diagnosis;Eligibility Determination;Failure;Future;Guidelines;Hybrids;Laboratories;Lead;Malignant Neoplasms;Malignant neoplasm of pancreas;Medical Research;Methodology;Methods;Modality;Participant;Phase;Procedures;Process;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Research;Research Design;Research Personnel;Resources;Sampling;Scientific Advances and Accomplishments;Screening for cancer;Specimen;Statistical Methods;Target Populations;Testing;Time;Translating;Validation;Work;anticancer research;biomarker development;biomarker panel;biomarker performance;biomarker validation;cancer biomarkers;cancer site;cancer therapy;clinical application;clinical diagnosis;clinical practice;cohort;computed tomography screening;design;dissemination trial;efficacy evaluation;improved;innovation;low dose computed tomography;lung cancer screening;novel;phase 3 study;phase 4 study;phase IV trial;precision medicine;primary endpoint;programs;prospective;screening;screening guidelines;software development;tool;user-friendly;validation studies Accelerating biomarker development through novel statistical methods for analyzing phase III/IV studies Project NarrativeThis work aims to develop innovative statistical methods for analyzing phase III and IV biomarker studiesto accelerate biomarker development for cancer early detection. The proposed research is essential foranalyzing two high-impact collaborative studies for pancreatic cancer and lung cancer early detection; it willalso yield guidelines for addressing several critical issues in current practice including: 1) primary endpointselection and proper strategies to assess screening efcacy in phase IV trials 2) utilization of phase IVstudies in phase III biomarker panel development and 3) combination of studies with differential screeningmodalities and eligibility criteria when estimating design parameters for biomarker clinical utility trials. NCI 10740870 11/29/23 0:00 PA-20-185 5R01CA277133-02 5 R01 CA 277133 2 "ABRAMS, NATALIE" 12/1/22 0:00 11/30/27 0:00 Cancer Biomarkers Study Section[CBSS] 9297264 "HUANG, YING " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 361548 NCI 218755 142793 Project Summary/AbstractThe multitude of candidate cancer biomarkers being discovered across various laboratories hold greatpotential to enhance the practice of precision medicine. However it is a long and challenging process often culminating in failure to rigorously develop and validate these biomarkers before they can be usedin clinical practice. In particular phase III IV and V biomarker validation studies are expensive and time-consuming to conduct; it is essential to carefully design and analyze these studies and to make the mostefcient use of the specimens collected. Motivated by our collaborative work on biomarker developmentfor cancer early detection this proposal seeks to develop cutting-edge statistical tools for analyzing phaseIII and IV biomarker studies in order to accelerate the biomarker development process. The methodsproposed in Aim 1 target the selection of primary endpoints and inference procedures to accommodatepotential overdiagnosis when assessing screening efcacy in phase IV trials. The methods proposed in Aim2 enable the combination of phase IV samples with phase III samples in phase III biomarker development.The methods proposed in Aim 3 integrate information from heterogeneous study cohorts (which differ inscreening modalities and eligibility criteria) when estimating design parameters for biomarker clinical utilitytrials. Our statistical methods will have immediate applications to analysis of data from two cancer applica-tions: i) the New Onset Diabetes (NOD) Cohort study and the Early Detection Initiative (EDI) study forpancreatic cancer early detection and ii) ve low-dose CT (LDCT) screening cohorts and the ProstateLung Colorectal and Ovarian Cancer Screening (PLCO) trial for lung cancer screening. Moreover thedeveloped methodology will have broader application in other phase III and IV cancer biomarker studiesand will be valuable for advancing the NCI Early Detection Research Network (EDRN)'s current priority indesigning biomarker clinical utility trials. All statistical programs and algorithms developed in this proposalwill be made freely available to the public. 361548 +No NIH Category available Animals;Antibodies;Antigen Presentation;Antitumor Response;Autologous;Breast;Breast Cancer Cell;Breast Cancer Model;CAR T cell therapy;CD8B1 gene;Cell Therapy;Cells;Clinical;Complex;Consumption;Dose;Engineering;Epidermal Growth Factor Receptor;Exhibits;Face;Flow Cytometry;Gene Expression;Generations;Genes;Hematologic Neoplasms;Human;ITGAM gene;Immune;Immunocompetent;Immunofluorescence Immunologic;Immunologic Stimulation;In Vitro;Infusion procedures;Macrophage;Malignant Neoplasms;Maps;Mediating;Membrane;Messenger RNA;Metastatic breast cancer;Mus;Myeloid-derived suppressor cells;Nature;Pathway interactions;Phagocytes;Phagocytosis;Phenotype;Population;Pre-Clinical Model;Preparation;Production;Receptor Cell;Regimen;Research;Solid;Solid Neoplasm;Spatial Distribution;Specificity;T cell infiltration;T-Lymphocyte;Testing;Therapeutic;Time;Toxic effect;Viral Vector;antigen-specific T cells;antitumor effect;cancer immunotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;cytokine;design;draining lymph node;engineered exosomes;exosome;experimental study;extracellular;immune activation;in vivo;innovation;insight;interest;lymph nodes;mRNA delivery;malignant breast neoplasm;multiphoton microscopy;novel strategies;patient derived xenograft model;programs;protein expression;receptor;reconstitution;transcriptome sequencing;transcriptomics;tumor;tumor growth;tumor heterogeneity;tumor microenvironment Engineering In Vivo Chimeric Antigen Receptor Macrophages (CARMs) using mRNA-exosomes for Cancer Immunotherapy PROJECT NARRATIVEChimeric antigen receptor macrophage (ChARM) therapy offers great promises against solid tumors but theirex vivo production is complex and technically challenging. The proposed research aims to investigate aninnovative strategy of producing ChARMs in vivo using macrophage-targeting exosomes loaded with CAR-encoding mRNA. If successful the results generated from the proposal will pave the way for a new strategy toproduce CAR cells in vivo and greatly expand the utility of cell therapy against solid tumors. NCI 10740743 7/18/23 0:00 PAR-22-071 1R01CA284108-01 1 R01 CA 284108 1 "HU, ZHANG-ZHI" 8/1/23 0:00 7/31/27 0:00 Special Emphasis Panel[ZRG1-MCST-U(55)R] 14825632 "JIANG, WEN " "KIM, BETTY Y.S." 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 567816 NCI 350504 217312 PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologiccancers. However for solid tumors CAR T cells face challenges including intratumor heterogeneity dynamicexpression of target receptors and often the inability for T cells to traffic to tumors to mediate the desiredantitumor effect. In contrast to the lack of T cell infiltrates many solid tumors are abundant in immunesuppressive myeloid cells including macrophages. Therefore converting these immune suppressive cells intotumoricidal phenotype represents a promising strategy for cell-based therapy. There are now strong interest ingenerating CAR macrophages in which autologous macrophages are transduced with CAR delivered by viralvectors ex vivo to enhance their phagocytosis antigen presentation and cytokine producing capabilitiesfollowing re-infusion. However ex vivo preparation of CAR macrophages is complex time consuming and dueto the non-dividing nature of macrophages is often inefficient. With the recent advances in mRNA-basedtherapeutics it is now possible to reprogram specific immune cell populations in vivo thus eliminating thecomplex ex vivo production of autologous CAR cells. Our present proposal aims to propose an innovativestrategy of generating CAR macrophages in vivo using mRNA-loaded exosomes to treat HER2 receptorpositive breast cancer. This will be the first study to evaluate the feasibility of producing CAR macrophages invivo using mRNA delivery platforms and assessing the antitumor efficacy of CAR macrophages for cancerimmunotherapy. We hypothesize that our strategy represents a revolutionary way to produce CARmacrophages in vivo using CAR mRNA-loaded exosome and offers a promising new approach for cell therapyagainst solid tumors. Our previous study showed that we can efficiently produce mRNA-loaded exosomes torestore protein expression in solid tumors. Furthermore our preliminary experiments showed that theexosomes loaded with HER2 CAR mRNA can produce CAR macrophages in vivo with enhanced effectorfunctions. Our current study will test our overall hypothesis by using the following specific aims. In Aim 1 wewill evaluate the dynamics and toxicity of CAR macrophage production in vivo using CAR mRNA exosomes. InAim 2 we will evaluate transcriptomic and functional profiles of in vivo generated CAR macrophages Finallyin Aim 3 we will assess the antitumor effect of in vivo generated CAR macrophages against both murine andhuman HER2 expressing breast cancer. If successful our proposed research can overcome a major technicalhurdle that is currently facing cell therapy. The mRNA exosome platform could potentially be expanded to otherCAR constructs and greatly expand the potential utility of cell therapy for breast and other solid cancers. 567816 +No NIH Category available Biomedical Engineering;Biopsy;Cells;Code;Cytology;Education;Evaluation;Fine needle aspiration biopsy;Future;Goals;Grant;Growth;Image;Light;Lung;Mentors;Microscopy;Parents;Phase;Small Business Innovation Research Grant;career;experience;lung development;lung imaging;model development;parent grant;point of care Harnessing Coded Ptychography to Deliver AI-powered Evaluation of Unstained Lung Biopsies at the Point-Of-Care n/a NCI 10740674 3/13/23 0:00 PA-21-345 3R43CA278604-01S1 3 R43 CA 278604 1 S1 "GREVE, JOAN MARIE" 2/1/23 0:00 8/31/23 0:00 78592980 "LYON, TORSTEN " Not Applicable 7 Unavailable 54749447 NC5PBWCNX956 54749447 NC5PBWCNX956 US 47.618262 -122.357741 10056539 PATHWARE INC. Golden CO Domestic For-Profits 80401 UNITED STATES N 2/1/23 0:00 8/31/23 0:00 394 SBIR/STTR 2023 95567 NCI 74083 21484 The parent Phase I SBIR grant aims to analyze quantitative phase imaging of lung FNAsusing coded ptychography microscopy captured at different wavelengths of light(Specific Aim #1) and demonstrate that Al can correctly detect cells on unstained phaseimages (Specific Aim #2). Engaging the supplementee Arianna Pryor to directly supportspecific aim #2 is expected to allow us to pursue a more diverse solution space for Almodel development to detect cells on the unstained QPI imaging resulting in a morerobust solution and amplifying the results and impact of the parent grant. Ms. Pryer'sexperience in Al model development for lung cytology in conjunction with her educationin biomedical engineering makes her an ideal candidate for the project. Additionally thetechnical experience and mentoring direct clinician interactions and entrepreneurialexperience gained through working in a startup directly supports her growth and futurecareer goals. 95567 +No NIH Category available AIDS prevention;Acceleration;Active Learning;Address;Adherence;Adoption;Appointments and Schedules;Area;Award;Awareness;Behavior;Cancer Burden;Cancer Control;Cancer Control Research;Caring;Cervical Cancer Screening;Cities;Clinic;Clinical;Cluster randomized trial;Collaborations;Collection;Communities;Complex;Control Groups;Cues;Data;Detection;Early Diagnosis;Education;Educational Intervention;Eligibility Determination;Enhancement Technology;Enrollment;Extramural Activities;Faculty;Funding;Future;Goals;Government;Guidelines;HIV;HIV diagnosis;HPV-High Risk;Health;Health Personnel;Home;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human Resources;Human papilloma virus infection;Incidence;Infection;Institution;Instruction;Intention;Interdisciplinary Study;Intervention;Intervention Studies;Interview;Intraepithelial Neoplasia;K-Series Research Career Programs;Knowledge;Location;Malignant neoplasm of cervix uteri;Measures;Mentors;Mentorship;Methodology;Methods;Mission;Modality;Outcome;Patient Education;Patient-Centered Care;Patients;Persons;Pre-Post Tests;Preventive screening;Provider;Quasi-experiment;Randomized;Recommendation;Records;Reporting;Research;Research Activity;Research Methodology;Research Personnel;Research Project Grants;Research Support;Research Training;Risk;Sampling;Scientific Advances and Accomplishments;Screening for cancer;Security;Self Efficacy;Speculums;Surveys;System;Technology;Testing;Text Messaging;Training;Training Activity;Transportation;Triage;Visit;Vulnerable Populations;Wait Time;Woman;World Health Organization;acceptability and feasibility;behavioral health;biobehavior;cancer health disparity;cancer prevention;career;cervical cancer prevention;cervicovaginal;comparison control;cost;digital health;electronic medical record system;empowerment;evidence base;follow-up;health care availability;health care delivery;health disparity;health information technology;high risk;implementation science;improved;innovation;mHealth;marginalized population;meetings;participant enrollment;patient-clinician communication;pilot test;preference;primary care provider;primary care setting;primary health service;primary outcome;programs;recruit;remote delivery;screening;screening disparities;secondary outcome;self testing;shared decision making;skills;social;tool;uptake A Technology-enhanced and Multilevel Approach to Promote Cervical Cancer Prevention Among Women Living with HIV PROJECT NARRATIVEWomen living with HIV (WLH) have a greater risk of developing invasive cervical cancer due to greater incidence andlonger persistence of high-riskhuman papillomavirusinfection.The primary objectives of this NCI K01 proposal are to:(1) conduct formative research and pilot test the provider-level and patient-level components of the My Self-Sampling forHPV Awareness Results and Empowerment (MySHARE+) intervention to increase cervical cancer screening (HPV self-collection; Pap triage adherence) among under/never-screened WLH and (2) provide Dr. Le with didactic training directedmentorship and experiential learning opportunities to develop cancer prevention and control research methods skills andcontent expertise in quasi-experimental studies and cluster-RCTs using multilevel approaches digital health/technology-based interventions to promote patient-centered care and implementation science methodologies and frameworks. Thiscareer development award will undoubtedly enable the candidate to comprehensively and systematically expand hermultidisciplinary research training and effectively facilitate her successful progression towards independence as abehavioral health researcher with an extramurally-funded program in evidence-based bio-behavioral interventions to reducecancer health disparities. NCI 10740622 9/15/23 0:00 PAR-21-296 1K01CA276624-01A1 1 K01 CA 276624 1 A1 "VAHEDI, SHAHROOZ" 9/15/23 0:00 8/31/28 0:00 Career Development Study Section (J)[NCI-J] 11655807 "LE, DAISY " Not Applicable 98 NONE 43990498 ECR5E2LU5BL6 43990498 ECR5E2LU5BL6 US 38.898075 -77.043933 2863301 GEORGE WASHINGTON UNIVERSITY WASHINGTON DC SCHOOLS OF NURSING 200520042 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 172638 NCI 159850 12788 incidence and longer persistence of high-riskPROJECT SUMMARY/ABSTRACT (WLH) bear a disproportionate risk of invasive cervical cancer (CC) due to greaterhuman papillomavirus (HPV) infection. Despite the availability of effectiveWomen living with diagnosed HIVCC screening methods there is low CC screening uptake among WLH. Reasons for suboptimal CC screening uptakeamong WLH are complex and multifactorial. Multilevel interventions that simultaneously address modifiable barriers toscreening at different levels of influences are therefore needed to effectively reduce CC disparities among WLH. Toachieve the World Health Organizations recommended global target to eliminate CC by 2030 accelerated progress incomplex health problems may also likely come from the integration of social innovations and technological advances. The overall objective of this proposed K01 project is to conduct formative research and pilot test the provider-leveland patient-level components of the My Self-Sampling for HPV Awareness Results and Empowerment (MySHARE+)intervention. MySHARE+ aims to harness the power of technology and apply a multilevel approach to promote theadoption of CC screening (HPV self-sampling; Pap triage adherence) among under/never-screened WLH a vulnerablepopulation. The specific aims are to: 1) identify facilitators and barriers to implementing a healthcare provider prompt in aprimary care setting and 2) conduct a pilot RCT to examine the feasibility acceptability and preliminary efficacy of amHealth educational intervention in promoting CC awareness and HPV self-sampling among WLH. These aims alignwith the NCIs mission to advance scientific knowledge to reduce the unequal burden of cancer and purposely addressestheir areas of research emphasis in biobehavioral research and in improving health disparities by targeting multiple levelsof influences. Study findings will generate implementation feasibility and acceptability data from the provider and patientperspectives and inform a subsequent R01 that will test the impact of the MySHARE+ intervention in a large clusterrandomized trial where the independent and overlapping effects of the different components can be evaluated. Strongly supported by mentors and advisors who are leading experts in the methodological and content areas specificto her long-term goals Dr. Les proposed K01 includes a comprehensive training plan that will help her acquire newknowledge and advanced skills in: 1) quasi-experimental studies and cluster-RCTs using multilevel approaches 2) digitalhealth/technology-based interventions to promote patient-centered care and 3) implementation science methodologies andframeworks. Over the 5-year award period she will participate in mentored research one-on-one and advisory/teammeetings didactic instruction directed readings training seminars and scientific meetings. The aforesaid research andtraining activities will undoubtedly help Dr. Le achieve her overall academic career objective of leveraging academic-community-government partnerships to successfully execute and sustain community-driven and clinically-embeddedintervention research supported by health information technology and the remote delivery of primary health care servicesto enhance patient-centered care. GW is well poised to support Dr. Le in undertaking these research endeavors especiallydue to the expertise on faculty its location and reputation in the city and the institutions high quality research setting. 172638 +No NIH Category available Acute Myelocytic Leukemia;Allogenic;Antigen Targeting;Attention;B-Lymphocytes;Bioinformatics;Biology;Biometry;Bispecific Antibodies;C57BL/6 Mouse;CAR T cell therapy;CD19 gene;CRISPR/Cas technology;Cell Count;Cell Therapy;Cell physiology;Cells;Clinical;Complex;Data;Dendritic Cells;Development Plans;Disease;Disease Outcome;Effector Cell;Engineering;Environment;Environmental Risk Factor;Exposure to;Flow Cytometry;Foundations;Future;Gene Transfer;Goals;Harvest;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;Immune;Immune system;Immunocompetent;Immunology;Immunotherapy;Impairment;In Vitro;Individual;Infection;Investigation;Learning;Leukemic Cell;Macrophage;Mediator;Mentors;Methods;Modems;Mus;Myelogenous;Myeloid Cells;Myeloproliferative disease;Nature;Patients;Phenotype;Population;Research;Research Personnel;Resistance;T-Lymphocyte;TCR Activation;Time;Tissues;Toxic effect;Training;Universities;Viral Genes;Washington;Work;acute myeloid leukemia cell;antigen-specific T cells;antitumor effect;cancer immunotherapy;career;career development;cell behavior;cellular engineering;chimeric antigen receptor;chimeric antigen receptor T cells;disorder control;improved;improved outcome;in vivo;innovation;knockout gene;leukemia;mouse model;negative affect;novel;research and development;response;single-cell RNA sequencing;skills;stem cell genes;success;targeted treatment;therapy outcome;tumor Improving the activity of CAR T cells for acute myeloid leukemia Project NarrativeAcute myeloid leukemia (AML) has thus far proven resistant to recent advances in cancer immunotherapysuch as bispecific antibodies and chimeric antigen receptor (CAR) T cells. This proposal will investigate howtargeting normal myeloid cells can have detrimental effects on CAR T cell activity. These results will helpdetermine why CAR T cells have not been effective against AML and identify methods to overcome theselimitations and improve the success of this therapy. NCI 10740585 6/28/23 0:00 PA-20-203 1K08CA277000-01A1 1 K08 CA 277000 1 A1 "BIAN, YANSONG" 7/1/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 15032972 "KIM, MIRIAM Y" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 248962 NCI 230520 18442 Project SummaryAcute myeloid leukemia (AML) has thus far proven resistant to T cell redirecting therapies such as bispecificantibodies or chimeric antigen receptor (CAR) T cells which is unexpected given the proven success of thesein other hematologic malignancies. Preliminary studies show that the anti-tumor activity of CD19-targeting CART cells (CART19) is enhanced in the presence of myeloid cells and that targeting these myeloid cells withCD33-targeting CART cells (CART33) leads to diminished long-term anti-tumor effect. Furthermore removingCD33 from normal myeloid cells improves CART33 expansion and disease control. Based on these findingsthe central hypothesis of this proposal is that bystander myeloid cells enhance CART cell activity and directlytargeting myeloid cells compromises this effect. The objective of this proposal is to delineate how myeloid cellsinfluence CAR T cell behavior when they are targets of therapy as compared to when they are simplybystanders so that we can intervene within these interactions and improve CAR T cell therapy for AML. Thiswill be achieved through the following specific aims: 1) Determine how bystander myeloid cells modulate CART cell function; 2) Determine how targeting myeloid cells changes CAR T cell profile. To this endhematopoietic stem cells (HSCs) will be engineered through either viral gene transfer or CRISPR/Cas9 geneknockout to generate myeloid cells that are positive or negative for the antigen targeted by the CAR. Theeffects of wild-type or genetically modified myeloid cells on CAR T cells will be interrogated by in vitro cultureand in vivo mouse models using flow cytometry single-cell RNA-seq and functional studies. The innovationsof this project are that it draws attention to host environmental factors that influence CAR T cell activity andadvances the concept that the nature of the cell being targeted can influence CAR T cell behavior. Thisresearch is significant because it will contribute to a better understanding of how CAR T cells work with theimmune environment and illuminate methods to intervene within these interactions to improve the outcomes oftherapy. The long-term goal of this proposal is to establish the applicant Dr. Miriam Kim's career as anindependent researcher focused on developing novel cell therapies for AML. The proposed research andcareer development plan will provide Dr. Kim with training in HSC/myeloid biology immunology andbioinformatics. Her primary mentor Dr. John DiPersio and co-mentors Drs. Robert Schreiber Todd Fehnigerand Carl DeSelm offer complementary expertise in cell engineering and immunotherapy. Additionally Dr.Kim's collaborators Dr. Li Ding and Dr. Feng Gao will contribute to developing her skills in bioinforrnatics andbiostatistics. Furthermore Washington University provides an ideal environment for Dr. Kim to successfullyestablish herself as an independent investigator. 248962 +No NIH Category available Acute;Advisory Committees;Affect;Allosteric Regulation;Binding;Biochemical;Bone Tissue;Bone neoplasms;CRISPR screen;Cancer cell line;Cancerous;Cell Death;Cell Differentiation process;Cell Line;Cell physiology;Cells;Chemicals;Child;Chimeric Proteins;Chromosomal translocation;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;DNA Binding;DNA Binding Domain;Dedications;Dependence;Development;Differentiated Gene;Differentiation and Growth;Disease;Dominant-Negative Mutation;Drug Targeting;ETV6 gene;EWS-FLI1 fusion protein;Elements;Engineering;Environment;Ewings sarcoma;Exons;FLI1 gene;Faculty;Family;Family member;Funding Mechanisms;Future;Gene Expression;Generations;Genetic study;Genome;Goals;Growth;In Vitro;Knowledge;Maintenance;Malignant Bone Neoplasm;Malignant Neoplasms;Mediating;Mentors;Mesenchymal Differentiation;Metabolic Control;Methodology;Monitor;Mus;Mutagenesis;Mutation;Normal tissue morphology;Oncogenic;Patients;Pediatric Oncology;Penetration;Peptides;Phase;Phenotype;Phosphatidic Acid;Positioning Attribute;Postdoctoral Fellow;Proteins;Reporter;Research;SAM Domain;Site;Soft Tissue Neoplasms;Specific qualifier value;Specificity;Surface;Surveys;System;Testing;Therapeutic Index;Therapeutic Intervention;Tissues;Training;Transcription Repressor;Transcriptional Regulation;Variant;Work;Xenograft Model;anti-cancer;base editing;cancer cell;cancer type;drug development;effective therapy;fitness;functional genomics;in vivo;meetings;mortality;novel;programs;screening;small molecule;structural biology;symposium;targeted treatment;therapeutic target;therapy development;transcription factor;transcriptomics;transition mutation;tumor;tumorigenesis;young adult Function and Targeting of ETV6 in Ewing Sarcoma PROJECT NARRATIVEEwing sarcoma is a cancerous bone tumor affecting children and young adults which still lacks effective therapyand continues to be associated with high rates of mortality. Transcription factor ETV6 is a vulnerability in Ewingsarcoma cells while being largely dispensable in normal tissues indicating a wide therapeutic index for perturbingETV6 function in this disease. This proposal is dedicated to characterizing the cancer maintenance function ofETV6 and leveraging this new knowledge to develop beneficial therapies for Ewing sarcoma patients. NCI 10740562 6/22/23 0:00 PA-20-188 1K99CA273523-01A1 1 K99 CA 273523 1 A1 "SCHMIDT, MICHAEL K" 7/1/23 0:00 6/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 16440824 "GAO, YUAN " Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 135845 NCI 125782 10063 PROJECT SUMMARY/ABSTRACTEwing sarcoma is a highly aggressive bone and soft tissue tumor mainly affecting children and young adultswhich still lacks effective therapy. Due to its low mutational burden there are very few acquired vulnerabilities inEwing sarcoma cells. During my postdoctoral work I discovered that transcription factor ETV6 is among thevery few top Ewing sarcoma-biased dependencies. Remarkably although ubiquitously expressed ETV6 is notessential for cancer cells outside Ewing sarcoma based on CRISPR screening efforts from us and others.Genetic studies in mice also revealed that ETV6 is dispensable in the majority of tissues. Hence perturbingETV6 function in Ewing sarcoma will have a wide therapeutic index. In the proposed project I aim to furtherstudy the detailed mechanisms of how ETV6 maintains the cancer cell state and leverage this new knowledgeto develop therapies for Ewing sarcoma patients with exceptional potency and specificity. To do so I willcharacterize the mesenchymal differentiation phenotype of ETV6-deficient Ewing sarcoma cells using high-throughput functional genomics and single cell transcriptomics. Integration of these `-omic' approaches allow meto obtain a deep biochemical understanding of the cancer maintenance function of ETV6 (Aim 1). Moreover Ishowed that expression of the Sterile Alpha Motif (SAM) domain of ETV6 which is responsible for its self-oligomerization has a dominant-negative effect to endogenous ETV6 and inhibits sarcomagenesis in vivo.Therefore I propose to optimize this SAM peptide to increase its potency and further engineer it for exogenousdelivery (Aim 2). Successful generation of a potent and tumor penetrating ETV6 blocker will benefit therapydevelopment. Finally as transcription factors like ETV6 have proven to be challenging targets for drugdevelopment I profiled for endogenous metabolites that can bind ETV6 to unveil druggable pockets andidentified its association with phosphatidic acid. I will further explore the regulatory effects of phosphatidic acidbinding to ETV6 in Ewing sarcoma (Aim 3). Results from these studies will guide small molecule developmentand more importantly will also reflect a novel mechanism for metabolic control of gene expression through directallosteric regulation of transcription factors.During the mentored K99 phase I will work closely with my mentor Dr. Christopher Vakoc and co-mentor Dr.Carolyn Fein Levy and collaborators Drs. Stegmaier Kentsis Shi and Furukawa recognized experts in pediatriconcology peptide therapy screening methodology and structural biology respectively. I have also establishedan exceptional advisory committee at CSHL constituted by Drs. Joshua-Tor and Beyaz who will monitor andsupport my transition to independence. In addition CSHL will provide me an outstanding scientific environmentfor my research and training being a conference hub for world-renowned meetings and courses. My objectiveis to obtain a faculty position to develop an impactful research program where the K99/R00 funding mechanismwill serve as an essential step in my transition to independence. 135845 +No NIH Category available Address;Advisory Committees;Affect;Aggressive Clinical Course;Alleles;Antioxidants;Appointment;Award;Bioinformatics;Biological Models;Cancer Model;Cancer-Predisposing Gene;Cell Line;Clear cell renal cell carcinoma;Clinical;Collaborations;Core Facility;Cysteine;Development;Development Plans;Drug Targeting;Early identification;Ensure;Family;Fumarate Hydratase;Fumarate Hydratase Deficiency;Fumarates;Funding;Future;Gene Expression Profiling;Genes;Genetic;Genetic Predisposition to Disease;Genetic Services;Genitourinary system;Genomics;Germ-Line Mutation;Glutathione;Goals;Hereditary Renal Cell Carcinoma;Heritability;Histologic;Histology;Human Resources;Immunohistochemistry;In Vitro;Individual;Inherited;Institution;Laboratories;Lead;Loss of Heterozygosity;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Medical Genetics;Medicine;Memorial Sloan-Kettering Cancer Center;Mentors;Mentorship;Metabolic;Metabolic Pathway;Methodology;Molecular;Mutate;Mutation;Neurofibromin 2;Oncogenic;Oncology;Organoids;Pathologic;Pathway interactions;Patients;Phenotype;Positioning Attribute;Predisposition;Process;Prognosis;Renal Cell Carcinoma;Renal carcinoma;Research;Research Personnel;Resources;Risk;Risk Reduction;Role;Running;Scientist;Screening for cancer;Somatic Mutation;Susceptibility Gene;Syndrome;Techniques;Testing;Training;Translational Research;Tumor Suppressor Genes;United States;Up-Regulation;Variant;Work;cancer predisposition;cancer prevention;cancer therapy;career development;cell growth;cohort;experimental study;functional genomics;genetic epidemiology;genomic profiles;improved;in vivo;interest;loss of function;metabolomics;nephrogenesis;new therapeutic target;novel;patient derived xenograft model;patient subsets;predictive tools;response;screening;skills;targeted exome sequencing;targeted treatment;transcriptomics;translational model;tumor;tumorigenesis Investigating the Role of KEAP1 Germline and Somatic Mutations in Renal Cell Carcinoma PROJECT NARRATIVEKidney cancer can run in families; however in most families with multiple cases of kidney cancer a specificcausative gene cannot be identified. The goals of this project are to determine if inherited mutations in a genecalled KEAP1 increases the likelihood of developing kidney cancer and to determine whether kidney cancerswith mutations in KEAP1 may behave differently than other kidney cancers. A better understanding of the roleof KEAP1 and other genes in the development of kidney cancers may lead to earlier identification of kidneycancers through screening and to better therapies for patients with kidney cancer. NCI 10740481 6/24/23 0:00 PAR-21-300 1K08CA272960-01A1 1 K08 CA 272960 1 A1 "RODRIGUEZ, LARITZA MARIA" 7/1/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 14135003 "CARLO, MARIA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 258998 NCI 239813 19185 PROJECT SUMMARYCandidate: Maria I. Carlo MD is an Assistant Attending in Medicine at Memorial Sloan Kettering CancerCenter (MSK) with a dual appointment in the Genitourinary Oncology and Clinical Genetics services. Dr.Carlo's clinical and research interests are in hereditary RCC a cancer that has a poor prognosis whenidentified in advanced stages. Under the mentorship of Kenneth Offit MD MPH and Ari Hakimi MD she hasbegun work to elucidate the role of KEAP1 in the susceptibility to RCC and to define the phenotype of RCCswith KEAP1 mutations. Dr. Carlo's goal is to develop an independent laboratory to do translational work in thegenetic predisposition to RCC and its implication for cancer screening and targeted treatment.Career Development Plan: Drs. Carlo Offit and Hakimi have developed a plan to ensure that Dr. Carlo hasthe necessary training mentorship and support to effectively transition to an independent researcher who cansuccessfully lead genomic discovery studies in RCC. This plan entails formal courses in genetic epidemiologybioinformatics and cancer modeling informal collaborations with scientists from MSK laboratories and trainingwith personnel from MSK core facilities. Dr. Carlo has organized an Advisory Committee with expertiserelevant to her proposal and they will guide her in successfully completing the goals of her proposed research.Dr. Offit and the Advisory Committee will also guide Dr. Carlo to ensure progress in the promotion process andgarnering independent research funding towards the end of the K08 award period.Research Plan: Despite several known genetic RCC syndromes the majority of familial RCC remainsunexplained. The proposed project will use a large cohort of 928 patients with RCC who have undergoneparallel tumor and germline targeted exome sequencing. In a subgroup of patients with RCC of unclassifiedhistology germline and somatic predicted loss-of-function variants were identified in KEAP1 which encodes anegative regulator of NRF2 the key activator of the antioxidant response pathway. These tumors arehistologically similar to Fumarate Hydratase (FH)-deficient RCCs which arise from germline mutations in theFH gene. Loss of function of FH or KEAP1 can activate the NRF2 pathway. Dr. Carlo hypothesizes thatsimilar to FH KEAP1 loss-of-function germline variants increase risk of RCC and mutations in KEAP1contribute to the development of RCC in an NRF2-dependent manner. Dr. Carlo aims to (1) characterizeKEAP1-mutated RCC using genomic transcriptomic and metabolic techniques and (2) delineate theeffects of KEAP1 and FH mutations on malignant transformation in RCC model systems. The overarchinggoal is to elucidate the role and implications of germline and somatic KEAP1 mutations in RCC to direct cancerscreening and develop rational targeted therapies. 258998 +No NIH Category available AML1-ETO fusion protein;Acute;Acute Myelocytic Leukemia;Address;Binding;Binding Sites;Biochemical;Biological;Biological Markers;Cells;Chimeric Proteins;Clinical;DNA Methylation;DNA Sequence Alteration;DNMT3a;Disease;Disease Progression;Disease remission;Environment;Epigenetic Process;Genes;Genetic Transcription;Goals;Growth;HIF1A gene;Hormones;Hyperactivity;Hypoxia;Hypoxia Inducible Factor;In Vitro;Intervention;Investigation;Leukemic Cell;Link;Literature;Malignant Neoplasms;Mediating;Mediator;Medicine;Molecular;Nature;Oncogenic;Outcome;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Positioning Attribute;Prognosis;Prognostic Marker;Proteins;RUNX1 gene;Recurrence;Recurrent disease;Refractory;Relapse;Research;Role;Signal Transduction;Techniques;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Therapeutic Index;Time;Transcription Initiation;Transcriptional Regulation;Transgenic Mice;Transgenic Organisms;Treatment Protocols;Work;acute myeloid leukemia 1 protein;acute myeloid leukemia cell;cell growth;chemotherapy;clinical efficacy;cofactor;cytokine;driver mutation;drug testing;druggable target;improved;in vivo;inhibitor;innovation;insight;leukemia;leukemia treatment;leukemic stem cell;leukemogenesis;molecular pathology;mouse model;new therapeutic target;normoxia;novel;novel therapeutics;patient derived xenograft model;pharmacologic;predictive signature;promoter;relapse patients;response;t(8;21)(q22;q22);targeted treatment;therapeutic biomarker;therapeutic development;therapy outcome;transcription factor The Role of HIF1A-DNMT3A axis in AML1/ETO-Driven Acute MyelogenousLeukemia Leukemia patients harboring AML1/ETO fusion protein achieve complete remission initially but many of them relapse and die. This project aims to understand the ways in which AML/ETO contributes to leukemogenesis. Findings will inform intervention strategies for leukemia therapy. NCI 10740439 2/9/23 0:00 PA-21-268 7R01CA248019-03 7 R01 CA 248019 3 "KLAUZINSKA, MALGORZATA" 12/7/20 0:00 11/30/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 9226287 "LIU, SHUJUN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 396 Non-SBIR/STTR 2023 668694 NCI 490114 178580 "The fusion protein AML 1/ETO (AE) resulting from the t(8;21) translocation is a leukemia-initiating transcription factor that is frequently associated with acute myeloid leukemia (AML). Despite being defined as a ""favorable"" subtype of AML many AE positive (AE+) patients relapse and die with largely unknown causes. It is also unclear how AE mediates a disease-predictable DNA methylation signature. The long-term goals are to elucidate further the mechanisms of AE+ AML leukemogenesis discover new therapeutic targets and develop effective targeted therapies. The objective of this proposal is to explore the molecular basis of a disease-predictable DNA methylation signature underlying AE+ AML with a focus on the impact of hypoxia-independent HIF1alpha-DNMT3a signaling axis activation. The rationale underlying this proposal is that the hypoxia-independent HIF1alpha signaling activation is a new hallmark of cancer. In relation to this project the hyperactive HIF1alpha signaling may be a disease-promoting factor and an epigenetic mediator in AE+ AML. HIF1alpha forms a feedforward loop with AE and transactivates DNMT3a another prognostic marker in AE+ AML. HIF1alpha inhibition suppresses AML cell growth. However the detailed mechanistic and biochemical links between HIF1alpha signaling and AE AML pathogenesis and disease recurrence are poorly defined. The central hypothesis is that HIF1alpha promotes AE leukemogenicity through enhancing AE transcriptional activities and modulating the AE-governed DNA methylation landscape in AML cells; therefore HIF1alpha may be a vulnerable and druggable target in AE+ AML. This hypothesis will be tested by pursuing three specific aims: 1.) Dissect the mechanistic details of how HIF1alpha is critical for AE-driven leukemogenesis; 2) Determine the role of HIF1alpha in AE-dependent DNA methylation; 3) Test pharmacological targeting of HIF1alpha as a therapeutic option for AE+ AML. To pursue our aims we will use innovative combinations of biological techniques with unique transgenic and patient-derived xenograft (POX) mouse models as well as innovative integration of aberrant HIF1alpha signaling and epigenetics in understanding and treating AE+ AML. The proposed research is significant because it will disclose new genes/mechanistic pathways that are necessary for AE leukemogenicity identify the therapeutic biomarkers and discover new medicinal agents for AE+ AML. Further it will thoroughly investigate the epigenetic and oncogenic role of HIF1alpha in cancer. The proximate expected outcomes are to demonstrate HIF1alpha-epigenetics crosstalk in defining AE-initiated transcriptional regulation and leukemia pathogenesis and to establish the feasibility of using HIF1alpha inhibitors to enhance the therapeutic index of the existing treatment regimens. The results will have an important impact because they will advance our understanding of AE+ AML molecular pathology aberrant epigenetics in leukemia and the oncogenic functions of hypoxia-independent HIF1alpha signaling in cancers. The findings will also lay the groundwork to develop newer strategies to better target AE+ AML." 668694 +No NIH Category available Address;Administrator;Behavioral;Cancer Center;Clinical;Clinical Research;Communities;Computer software;Computerized Medical Record;Consensus;Country;Data;Development;Diagnosis;Diagnostic Neoplasm Staging;Disease Progression;Electronic Health Record;Exclusion;Family;Feedback;Funding;Future;Genomics;Goals;Grant;Hand;Human Resources;Information Retrieval;Information Retrieval Systems;Institution;Interview;Knowledge;Lead;Leadership;Link;Malignant Neoplasms;Maps;Measures;Michigan;Mothers;Multi-Institutional Clinical Trial;Names;Natural Language Processing;Ontology;Outcome;Pain;Pathology Report;Patients;Peer Review;Perception;Phenotype;Process;Recording of previous events;Recurrence;Research;Research Personnel;Review Literature;Running;Scanning;Secure;Security;Semantics;Services;Site;Social Network;Structure;Surveys;System;Targeted Research;Technology;Testing;Text;Toxic effect;Trust;Tumor Markers;Uncertainty;Unified Medical Language System;Universities;Work;anticancer research;application programming interface;base;cohort;data standards;data visualization;design;electronic health record system;empowerment;experience;health determinants;improved;indexing;individual patient;innovation;malignant breast neoplasm;meetings;novel;operation;optical character recognition;programs;rare cancer;search engine;social;social health determinants;software systems;systems research;text searching;timeline;tool;translational cancer research;treatment response;unstructured data Extending the Capabilities and Reach of EMERSE in Support of Cancer Research PROJECT NARRATIVEUnstructured (free-text) clinical notes in electronic health record (EHR) systems contain valuable phenotypicgenomic and other data needed to support cancer research ranging from identification of rare cancer cohorts todata abstraction. These notes remain underutilized in part because of the complexity of accessing andextracting details from the unstructured data. EMERSE (The Electronic Medical Record Search Engine) aneasy-to-use mature information retrieval software system that is being used or implemented at researchinstitutions across the nation simplifies this process. The aims of this proposal are to develop novel valuableuser-prioritized features to extend the power and reach of EMERSE including incorporating Natural LanguageProcessing (NLP) capabilities. NCI 10740137 9/12/23 0:00 RFA-CA-22-023 1U24CA269315-01A1 1 U24 CA 269315 1 A1 "DIVI, RAO L" 9/15/23 0:00 8/31/28 0:00 ZCA1-TCRB-Q(M2) 10456801 "HANAUER, DAVID ALAN" Not Applicable 6 OTHER BASIC SCIENCES 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 856489 NCI 571606 284883 PROJECT SUMMARYThe free text notes in electronic health records (EHRs) contain details vital to cancer research that often arefound nowhere else in the EHR. Such details include social and behavioral determinants of health familyhistories cancer staging tumor markers disease progression response to treatment overall outcomes andmore. Utilizing the free text (also called unstructured data) can be challenging and researchers need tools tohelp them leverage those data in a meaningful way. The electronic medical record search engine (EMERSE)has been in operation and under continuous development for 17 years and was designed to help cancerresearchers meaningfully use unstructured EHR data. EMERSE started as simple information retrieval systembut has since gained many features for supporting clinical research. It is distinguished from other text-processingresearch tools in part by its ease of use and other enterprise software features such as maintaining audit logsand providing administrator functions. With the support of an ITCR grant that is nearing completion EMERSEhas grown from a tool used at only one site (University of Michigan) to one that is running or being implementedat multiple cancer centers and other academic research institutions across the country. EMERSE also nowsupports the capability of searching across a network of instances to securely obtain obfuscated patient countsat other sites which can be valuable for identifying rare cancer cohorts. The innovations in this proposal include:(1) Building new functionality into EMERSE to expand its research capabilities such as timeline datavisualizations self-service data extraction workflows from templated notes support for optical characterrecognition (OCR) and integration with other ITCR tools such as DeepPhe through an application programminginterface (API); (2) Incorporating natural language processing (NLP) into EMERSE including named entityrecognition (mapped to the Unified Medical Language System UMLS) negation (e.g. patient denies pain)uncertainty (e.g. possibility of recurrence) and experiencer (e.g breast cancer in her mother); (3) Expandingthe EMERSE network in breadth capability security and trust by partnering with external sites to collectivelydevelop a consensus and a viable approach for broadly enabling this novel network technology; and (4)Continuing to evaluate EMERSE with a focus on networking security and scientific outcomes by conductingadditional user-centered studies to develop a deeper understanding of how EMERSE is being or could be usedwith a goal of continuous improvement. The EMERSE team routinely receives feedback from users and siteadministrators and the proposed work is highly responsive to our growing user base and will enable researchthat is currently impractical if not impossible for many researchers to accomplish. The enhancements andknowledge gained from this effort will make EMERSE even more powerful and capable of supporting a widerange of clinical and translational cancer research for a growing user base across the nation. 856489 +No NIH Category available 3-Dimensional;Acceleration;Address;Affect;Algorithms;Architecture;Back;Biodistribution;Cancer Research Project;Chelating Agents;Clinic;Clinical;Code;Collimator;Communities;Compton radiation;Computer Graphics;Computer software;Data;Detection;Development;Dimensions;Ensure;Gamma Cameras;Image;Informatics;Ionizing radiation;Ligands;Malignant Neoplasms;Maps;Methodology;Methods;Modeling;Monte Carlo Method;Normal Cell;Normal tissue morphology;Patients;Penetration;Photons;Physics;Play;Positioning Attribute;Probability;Process;Property;Radiation;Radioactive;Radioisotopes;Radiometry;Radionuclide therapy;Radiopharmaceuticals;Research;Resolution;Safety;Scanning;Scheme;Source;Speed;System;Techniques;Technology;Three-Dimensional Image;Three-Dimensional Imaging;Time;Translating;Update;Validation;absorption;attenuation;cancer cell;cancer type;cytotoxicity;detector;dosage;dosimetry;image reconstruction;improved;interest;neoplastic cell;novel;parallelization;photon-counting detector;physical model;physical process;quantitative imaging;reconstruction;response;simulation;single photon emission computed tomography;success;tool;tumor;uptake GPU-based SPECT Reconstruction Using Reverse Monte Carlo Simulations Project NarrativeAccurate quantitative SPECT imaging is an essential step toward personalized dosimetry in radiopharmaceuticaltherapy. Although iterative reconstruction methods of the 3D image from the acquired bidimensional projectionshave improved SPECT image some physical factors still contribute to degrading the image. Monte Carlomethods can correct them thus increasing the accuracy of the quantification and positioning of the therapeuticalradionuclides. This project explores a GPU-accelerated Monte Carlo method for SPECT reconstruction. NCI 10740079 9/8/23 0:00 RFA-CA-22-021 1R21CA279068-01A1 1 R21 CA 279068 1 A1 "TATA, DARAYASH B" 9/8/23 0:00 8/31/25 0:00 ZCA1-TCRB-9(M2) 78001348 "BERTOLET REINA, ALEJANDRO " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/8/23 0:00 8/31/25 0:00 394 Non-SBIR/STTR 2023 422508 NCI 257125 165383 Project Summary/AbstractInterest in applications of radiopharmaceutical conjugates has notably increased in the last few years for thetreatment of a variety of cancers. These conjugates are composed of chelators to target cancer cells andradionuclides to employ the cytotoxicity of ionizing radiation. Radiation dosimetry is required to determine thedosages efficacy and safety of these treatments and 3D quantitative imaging of the biodistribution of activityrepresents the best tool to perform dosimetry. For most radionuclides employed (non-positron-emitters) SPECTimaging is needed for patient-specific dosimetry. However multiple physical factors affect SPECT image qualitysuch as attenuation scattering or the response collimator-detector system in SPECT scans. To account forthem Monte Carlo techniques can be used due to their remarkable accuracy in representing physical processesrelevant to the transport of ionizing radiation. In particular 3D SPECT reconstruction from the acquiredbidimensional projections may be obtained by transporting backward the photons detected in the gamma cameraprojections although many photons to be reversely transported require specially optimized architecture andsimulations. This project will develop a new reverse Monte Carlo software for SPECT reconstruction built fromscratch in the GPU to speed up simulations. First only the relevant reverse physical processes will be selectedand modeled using inverse processes of the well-characterized TOPAS Monte Carlo code for radiation transport.Then specific properties of collimator-detector systems will be integrated into our code to determine the angulardistributions for the photons detected. Finally these developments will be integrated into a GPU-based platformand shared with the Informatics Technology for Cancer Research program at NCI for further results of specificcommercial SPECT scans from the research community. 422508 +No NIH Category available Activities of Daily Living;Age;Alaska Native;American Indians;Anti-Inflammatory Agents;Arizona;Biological Markers;Blood Pressure;CASP3 gene;Cancer Patient;Cancer Survivor;Carcinogenesis Mechanism;Clinical Oncology;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Comprehensive Cancer Center;Data;Development;Diagnosis;Diet;Dietary Intervention;Enrollment;Environment;Excision;Exercise;Fitness Centers;Food;Funding;Future;General Population;Goals;Habilitation;High Prevalence;Home;Hydrocortisone;Incidence;Inflammation;Inflammatory;Institution;Institutional Review Boards;Insulin;Insulin Receptor;Interleukin-6;Intervention;Intervention Studies;Intervention Trial;Interview;Juglans;Leptin;Life Style;Life Style Modification;Link;Literature;Malignant Neoplasms;Measurement;Measures;Mentorship;Metabolic dysfunction;Modeling;NOS2A gene;Native-Born;Obesity;Obesity associated cancer;Operative Surgical Procedures;Outcome;Outcome Measure;Outcome Study;Participant;Patients;Pattern;Phase;Physical activity;Population;Positioning Attribute;Postoperative Period;Poverty;Prealbumin;Process;Public Health;Publishing;Qualitative Research;Reporting;Research;Research Personnel;Resources;Risk;Sampling;Schedule;Serum;Serum Markers;Solid Neoplasm;Structure;Surgical Oncology;Surveys;Survival Rate;TNF gene;Testing;Time;Tissue Sample;Tissues;Training;Translations;Treatment-Related Cancer;Tribal Council;Tribes;Underrepresented Populations;United States;Universities;Walking;Weight;Work;Writing;adverse outcome;behavior change;behavior measurement;biomarker selection;cancer diagnosis;cancer health disparity;cancer risk;cancer subtypes;cancer surgery;cancer survival;carcinogenesis;career;clinical translation;diet and exercise;exercise intervention;experience;feasibility testing;functional improvement;health equity;improved;inflammatory marker;inflammatory milieu;inflammatory modulation;lifestyle intervention;mortality;novel;nutrition;obese patients;operation;peer;physical inactivity;post intervention;programs;psychologic;racial population;skills;smoking cessation;social health determinants;study population;therapy design;tissue biomarkers;tool;translational clinical trial;trial design;tribal Nation;tribal member;tumor;tumor microenvironment;waist circumference A Nutrition and Exercise Prehabilitation Intervention on Inflammatory Biomarkers in American Indian Cancer Patients PROJECT NARRATIVEAI/AN populations experience a disproportionate burden of obesity which contributes to inflammatorymechanisms of carcinogenesis that may add to AI/AN cancer disparities. The purpose of this study is to assessthe feasibility of a prehab intervention among AI patients diagnosed with obesity-related cancer and measureinflammatory biomarkers to evaluate the preliminary impact of the trial intervention. The results of this K08proposal will provide essential data and experience for the candidates development into a translational clinicaltrialist working on behalf of AI/AN cancer patients. NCI 10739958 6/22/23 0:00 PAR-21-299 1K08CA276137-01A1 1 K08 CA 276137 1 A1 "RODRIGUEZ, LARITZA MARIA" 7/1/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 10752421 "ERDRICH, JENNIFER A" Not Applicable 7 SURGERY 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 271631 NCI 251510 20121 PROJECT ABSTRACTThere are 13 cancer subtypes that are linked to obesity and these account for 40% of all cancers diagnosed inthe United States annually. American Indian/Alaska Native (AI/AN) populations are 1.6 times more likely to beobese than the general population. Many factors influence this elevated risk including poverty nontraditionalfoods related social determinants of health and physical inactivity. Furthermore AI/AN people have the worstcancer survival rates of any US racial group. Obesity-related inflammation likely drives cancer risk and adverseoutcomes and yet this is a reversible process. AI/AN are known to be underrepresented in clinical trials andresearch and even more importantly they have never been included in an intervention designed to modulateinflammation prior to cancer surgery. A small handful of studies in non-AI/AN featuring lifestyle interventionsfollowing diagnosis of obesity-related cancer and implemented during the short window of opportunity (WOO)before cancer surgery a strategy known as prehabilitation (prehab) have shown some significant findings.These include alterations in the expression levels of inflammatory markers in serum and the tumormicroenvironment (TME) factors that may influence carcinogenesis. Given the higher prevalence of obesityand worse cancer outcomes the AI/AN population may have the greatest gains from this line of research. Wehypothesize that a prehab intervention modeled after published literature then adapted with communitycollaboration for AI cancer patients will be feasible acceptable and successful at modulating inflammatorybiomarkers. The proposed project is to (1) complete the adaptation of a prehab intervention using thecandidates preliminary research (2) implement the prehab translational clinical trial for AI patients withobesity-related solid tumor cancer preparing for surgery and (3) measure inflammatory biomarkers pre andpost-intervention to assess responsiveness. Study outcomes include pre and post comparisons of serumbiomarkers (insulin leptin hsCRP IL-6 TNF cortisol AM prealbumin); tissue biomarkers (Ki67 insulinreceptor TNF NFB NOS2 cleaved caspase-3); anthropometric measurements (blood pressure weightwaist circumference); lifestyle behavioral measures (validated diet/exercise tools: REAPS IPAQ 6MWT STS).The proposed training plan builds on the applicants background in surgical oncology public health and AI/ANcancer disparities to include new training in (a) clinical trial design and implementation (b) biomarkermeasurement and (c) professional development. The rigorous research and training strategies will promote thecandidates goal of successfully transforming into an independent funded translational clinical trialist workingon behalf of AI/AN to narrow cancer disparities. This will be achieved with the support of a highly experiencedmentorship team and the well-resourced training environment of The University of Arizona an AI/AN-servinginstitution and home to the only NCI-designated Comprehensive Cancer Center in the state of Arizona. 271631 +No NIH Category available Acceleration;Adult;Agonist;Alleles;Biological;Biology;Bone Marrow Cells;Cancer Biology;Cancer Center;Cells;Characteristics;Coculture Techniques;Complex;Correlation Studies;Data;Developmental Biology;Diagnosis;Disease;Embryology;Endoderm;Epithelial Cells;Epithelium;Erinaceidae;FOXF1 gene;Fetal Development;Fibroblasts;Future;Gene Deletion;Gene Expression;Gene Expression Profile;Genetic;Genetically Engineered Mouse;Heterogeneity;Human;Immune;In Vitro;KRASG12D;Knowledge;Ligands;Light;Malignant Neoplasms;Malignant neoplasm of pancreas;Mesenchymal;Mesenchyme;Modeling;Molecular;Molecular Profiling;Mus;Oncology;Organ;Organoids;Pancreas;Pancreatic Ductal Adenocarcinoma;Paracrine Communication;Pathogenesis;Pathway interactions;Patients;Pattern;Phase;Physiology;Play;Postdoctoral Fellow;Regulation;Research;Role;Sampling;Testing;Therapeutic;Tissues;Training;Tumor Burden;Tumor-Derived;antagonist;anticancer research;cancer subtypes;cancer type;conditional knockout;design;effective therapy;experimental study;fetal;in vivo;insight;mouse model;neoplastic cell;novel;pancreatic tumorigenesis;progenitor;programs;restraint;skills;smoothened signaling pathway;stem;success;targeted treatment;therapeutically effective;transcription factor;treatment response;treatment strategy;tumor;tumor microenvironment;tumor progression Origin diversification and function of pancreatic cancer associated fibroblasts Project NarrativePancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is characterized by an expansionof fibroblasts which modulate the tumor microenvironment. This proposal aims to elucidate molecular signaturesand functions of cancer associated fibroblast subtypes in PDAC. This research will contribute to fundamentalknowledge of PDAC biology and may ultimately lead to design of more effective therapeutics for PDAC patients. NCI 10739919 7/6/23 0:00 PA-20-188 1K99CA263005-01A1 1 K99 CA 263005 1 A1 "SCHMIDT, MICHAEL K" 7/1/23 0:00 6/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 12157930 "HAN, LU " Not Applicable 6 BIOCHEMISTRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 131134 NCI 121420 9714 Project Summary/AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest cancers due to a lack of effectivetreatment options. One hallmark of PDAC is the expansion of cancer associated fibroblasts (CAFs). CAFs playcritical and complex roles in PDAC microenvironment to modulate tumor progression and therapeutic response.The long-term objective of my research program is to determine the cellular origin heterogeneity and function ofCAFs in pancreatic cancer. To identify the tissue origin of CAFs in PDAC I performed lineage tracingexperiments using genetically engineered mouse models. The splanchnic mesenchyme is a particular type ofmesenchyme adjacent to the pancreatic epithelium during fetal development. My studies demonstrated that thesplanchnic mesenchyme is the fetal origin of CAFs in PDAC (Han et al Nat Commun in press). In this currentproposal I aim to further investigate whether splanchnic-derived CAFs maintain certain molecular signatures oftheir fetal progenitors. The Hedgehog pathway is a critical paracrine signal between the epithelium andmesenchyme during fetal development and is reactivated during tumorigenesis of the pancreas. The Hedgehogsignal modulates PDAC progression but its downstream targets in CAFs have not been identified. My graduatestudy showed that transcription factors FOXF1 and GATA6 are downstream targets of the Hedgehog pathwayin the fetal splanchnic mesenchyme. My preliminary studies suggested that these factors are also expressed inPDAC CAFs in a regionally distinct pattern within the tumor microenvironment. In Aim 1 I will determine whetherFOXF1/GATA6 patterning in CAFs is regulated by the Hedgehog pathway activity. Hedgehog agonist orantagonist will be utilized in in vitro cell or organoid culture and in vivo mouse models. In Aim 2 I will determinethe function of FOXF1+ CAFs and GATA6+ CAFs in PDAC by deleting these genes specifically in CAFs both invitro and in vivo as well as in patient correlation studies. The completion of this study will provide critical insightsin PDAC CAF biology including novel cellular heterogeneity defined by selective persistence of fetal signaturesin coordination with the epithelium and certain fetal signatures playing tumor-suppressing roles in a non-cellautonomous manner. Ultimately such knowledge in tumor microenvironment may reveal critical targets andtherapeutic avenues to inhibit tumor progression and prolong PDAC patient survival. I received rigorous trainingin developmental biology during my graduate study. Four years ago I started my training in cancer biology as apostdoctoral fellow in the Hollings Cancer Center. During the K99 phase I aim to further enhance my expertisein pancreatic cancer research and to acquire several additional skills which are essential to launch myindependent research program during the R00 phase. I aspire to draw from paradigms in both embryology andoncology to develop novel perspectives and to tackle fundamental biological questions. 131134 +No NIH Category available Acute;Address;Automobile Driving;CRISPR library;CRISPR screen;CRISPR/Cas technology;Cancer Etiology;Cells;Cessation of life;Clinical;Combined Modality Therapy;Complex;Computer Analysis;Cytoplasm;Data;Development;Ectopic Expression;Engineering;Failure;Genetic;Goals;Growth;Growth Factor;In Vitro;KRAS2 gene;Knowledge;Libraries;Location;MAPK1 gene;MAPK3 gene;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Mentors;Mitogen-Activated Protein Kinase Inhibitor;Mitogen-Activated Protein Kinases;Mutate;Mutation;Normal tissue morphology;Nuclear;Nuclear Export;Oncogenes;Outcome;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phase;Phosphoproteins;Phosphorylation;Protein-Serine-Threonine Kinases;Proteins;Proteomics;Relapse;Research;Research Personnel;Resistance;Role;Serine;Signal Transduction;Site;System;Therapeutic;Toxic effect;Training;Transcript;United States;Variant;cancer cell;cancer therapy;cell growth;clinical efficacy;design;early phase clinical trial;effective therapy;experimental analysis;exportin 1 protein;genetic analysis;improved;in vivo;inhibitor;loss of function;mutant;new therapeutic target;novel therapeutic intervention;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pharmacologic;phosphoproteomics;post-doctoral training;preclinical development;programs;receptor;relapse patients;research clinical testing;resistance mechanism;response;spatiotemporal;standard of care;success;targeted treatment;therapeutic target;therapy development;transcriptome;tumor;tumorigenesis Mechanistic Basis for ERK in driving KRAS-dependent pancreatic cancer PROJECT NARRATIVEPancreatic cancer the third deadliest cancer in the US. The KRAS oncogene is mutated in 95% of pancreaticcancers and anti-KRAS therapies are anticipated to make a significant impact on improving patient survival. Ipropose to develop therapies that block key ERK regulated proteins which are critical for KRAS to drivemetastatic pancreatic cancer growth. NCI 10739653 6/23/23 0:00 PA-20-188 1K99CA276700-01A1 1 K99 CA 276700 1 A1 "SCHMIDT, MICHAEL K" 7/1/23 0:00 6/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11866566 "KLOMP, JENNIFER E" Not Applicable 4 PHARMACOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 111438 NCI 103183 8255 Project Summary/AbstractPancreatic ductal adenocarcinoma (PDAC) the third leading cause of cancer deaths in the United States ischaracterized by a 95% rate of mutational activation of the KRAS oncogene. After nearly four decades of failurethe recent clinical approval of a direct KRAS inhibitor targeting one KRAS mutation (G12C) for lung cancer marksa significant milestone in the development of therapies for KRAS-mutant cancers. KRASG12C-specific inhibitorshave demonstrated dramatic tumor shrinkage in a subset of KRASG12C-mutant patients but essentially all relapsedue to treatment-induced acquired resistance. Genetic analyses of relapsed patients have identified mechanismsof resistance with a majority involving mutational activation of signaling components that drive reactivation ofthe key KRAS effector pathway the three-tiered RAF-MEK-ERK mitogen-activated protein kinase cascade.Thus ERK reactivation will limit the long-term efficacy of direct KRAS inhibitors. Despite the highly successfuldevelopment of potent and selective inhibitors of each node of the ERK MAPK cascade when used asmonotherapy they have shown little to no clinical efficacy against RAS-mutant cancers. Two key issues havecontributed to this outcome toxicity for normal tissues and de novo or treatment-induced acquired resistance incancer cells. I propose that further delineation of the mechanisms by which ERK drives KRAS-dependent cancergrowth will guide the development of more effective anti-ERK therapies. However the mechanisms by whichERK drives PDAC growth remain poorly understood. One major unresolved issue is how ERK activity in differentsubcellular compartments supports cancer growth. Aim 1 studies comprise my K99 phase of training where I willtake two complementary approaches to gain a better understanding of the role of cytoplasmic and nuclear ERKactivity in supporting KRAS-dependent PDAC growth. First I will determine the capacity of cytoplasmic versusnuclear ERK activity in supporting the growth of KRAS-mutant PDAC. Second I will use a pharmacologicalinhibitor of the nuclear export protein exportin-1 (Selinexor) to determine whether it disrupts ERK cytoplasmic-nuclear dynamics and sensitizes PDAC models to KRAS inhibition. My Aim 2 studies comprise my R00-supported independent research and are based on our comprehensive ERK-dependent phosphoproteome/transcriptome studies in KRAS-mutant PDAC. Using these data I designed a CRISPR-Cas9 genetic loss-of-function screen library targeting ERK regulated phosphoproteins and/or transcripts. I will now perform a system-wide determination of how ERK contributes to PDAC tumorigenesis as well as identify new ERK dependenttargets to combine with KRAS inhibitors. To help me achieve these research goals and successfully transition tothe independent phase I have an exceptional mentoring committee comprised of leading researchers in the studyof KRAS signaling and therapeutics (Channing Der) in ERK spatiotemporal signaling (Jin Zhang) and ERKsubstrate utilization (John Blenis). With their guidance I am confident that I will successfully transition to establishan independent research program where I will advance our knowledge on ERK signaling and therapeutics. 111438 +No NIH Category available ATAC-seq;Acceleration;Affect;Apoptosis;Apoptotic;Biological;Biology;Bone Tissue;Bone neoplasms;Cardiovascular Diseases;Cell Survival;Cells;Cessation of life;Charge;Child;Chromatin;Chromatin Structure;Clinical;Clinical Trials;Cytotoxic Chemotherapy;Data;Disease;Drug Kinetics;Drug Targeting;EWSR1 gene;Enhancers;Ewings sarcoma;FDA approved;FLI1 gene;Family;Family member;Fusion Oncogene Proteins;Future;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Family;Genes;Genetic Transcription;Goals;Growth;Health;Histones;Impairment;In Vitro;Knockout Mice;Libraries;Link;Localized Disease;Lysine;Malignant Childhood Neoplasm;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Maximum Tolerated Dose;Microsomes;Mission;Modality;Modification;Mus;Normal Cell;Nuclear;Oncogenic;Operative Surgical Procedures;Pathway interactions;Patients;Pediatric Oncology;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phenotype;Post-Translational Protein Processing;Prognosis;Property;Proteins;Proteomics;Public Health;Publishing;Quality of life;Radiation;Reader;Recurrence;Relapse;Research;Research Support;Role;Second Primary Cancers;Sirtuins;Site;Specificity;Structure;Survival Rate;Survivors;Testing;Therapeutic;United States National Institutes of Health;Western Blotting;Work;analog;bone;cell type;druggable target;epigenomics;experimental study;fusion gene;genome-wide;histone modification;human disease;improved;in vivo;inhibitor;innovation;insight;long-term sequelae;loss of function;new therapeutic target;novel;novel therapeutic intervention;programs;side effect;small molecule;soft tissue;therapeutic target;tool;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;tumor;young adult SIRT5 inhibitors and degraders as novel treatments for Ewing sarcoma NarrativeThe proposed studies are relevant to public health because discovery of novel means to treat Ewing sarcomaexerting fewer deleterious sequelae in survivors represents a significant unmet need in pediatric oncology. Thiswork is thus relevant to NIHs mission in the context of supporting research to identify cures for human disease. NCI 10739630 2/1/23 0:00 PA-21-268 7R01CA253986-02 7 R01 CA 253986 2 "AGYIN, JOSEPH KOFI" 1/1/23 0:00 12/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 9675661 "LOMBARD, DAVID BENNER" "NEAMATI, NOURI " 27 PATHOLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 395 Non-SBIR/STTR 2023 518307 NCI 409622 108685 AbstractEwing sarcoma (EWS) is an aggressive tumor arising in soft tissue and bone of children and youngadults. EWS is treated with a combination of cytotoxic chemotherapy local radiation and/or surgery.Patients with localized disease show a favorable overall survival rate. However there is still a pressingneed for new therapeutic approaches for EWS. Patients with metastatic or recurrent EWS have a verypoor prognosis. Moreover current EWS treatments are associated with many short- and long-termsequelae e.g. accelerated cardiovascular disease and secondary cancers. EWS-FLI1 is the fusiononcoprotein present in most cases of EWS. It functions as a pioneer transcription factor to affectexpression of many target genes. The aberrant EWS transcriptome represents a potential therapeutictarget in EWS. This proposal focuses on the sirtuin SIRT5 as a novel therapeutic target in EWS. SIRT5is found throughout the cell and regulates protein targets in diverse pathways by removing negativelycharged modifications on lysine residues including succinylation. Although normal cell types and wholemice tolerate loss of SIRT5 with minimal phenotypes we have found that specific cancers notablyincluding EWS are exquisitely dependent on SIRT5 and rapidly undergo apoptosis following SIRT5depletion. We have linked this effect to a role for SIRT5 in desuccinylating nuclear histones therebymodulating gene expression in EWS. We and others have shown that SIRT5 is in principle amenable toselective inhibition or degradation with small molecules. Our long-term goal is to evaluate SIRT5 as apotential therapeutic target for EWS. The objective of this proposal is to generate new biological insightsinto SIRT5 function in EWS and characterize SIRT5 inhibitors and SIRT5 PROTAC-based degraders.The central hypotheses of this application are that: 1) SIRT5 is required for EWS cell survival via histonedesuccinylation and regulation of gene expression; and 2) SIRT5 inhibitors and degraders will representuseful tool compounds to interrogate SIRT5 biology and a starting point for potential future EWStherapeutics. The rationale for this application is that EWS cells show exquisite vulnerability to SIRT5loss-of-function while other cell types and whole mice show no major ill effects. Hence SIRT5 inhibitionwould likely be well tolerated clinically. The work will take place in the context of two Specific Aims. Firstwe will elucidate the impact of SIRT5 and Ksucc on histones and gene expression using massspectrometry along with transcriptomic and epigenomic approaches. Second we will optimize andvalidate SIRT5 inhibitors and degraders using medicinal chemistry approaches and based in part onSIRT5-inhibitor co-crystal structures. The application is innovative in that no published data currentlylink SIRT5 to EWS and no potent and selective SIRT5 inhibitors or PROTACs have as yet beendescribed. The work is significant since there is an unmet clinical need for improved therapies for EWS. 518307 +No NIH Category available Age;Antibiotics;Binding;Biological Markers;Cancer Detection;Cancer Intervention;Child;Chronic Obstructive Pulmonary Disease;Communities;Computer Models;Data;Databases;Development;Diabetes Mellitus;Diagnostic;Equilibrium;Etiology;Experimental Models;Future;Gene Expression;Genome;Health;Human;Immune response;Immunity;Individual;Inflammatory;Intervention;Link;Location;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Microbe;Military Personnel;Modeling;Nose;Obesity;Oncogenic;Outcome;Pathway interactions;Play;Prevention;Process;Publishing;Research;Role;Sampling;Severities;Smoking Status;System;Taxonomy;Testing;Transplantation;Validation;Work;anticancer research;asthmatic;cancer biomarkers;cancer immunotherapy;cancer prevention;cancer therapy;candidate marker;comorbidity;design;former smoker;genome-wide;host-microbe interactions;human disease;improved;interest;lung cancer prevention;lung cancer screening;lung tumorigenesis;machine learning algorithm;metatranscriptomics;microbial;microbial community;microbiome;microbiome composition;microbiome research;microbiota transplantation;microorganism interaction;nasal microbiome;nasal microbiota;novel strategies;pathogen;predictive marker;predictive modeling;receptor;screening;sex;targeted treatment;transcriptome sequencing;transcriptomics;tumor progression Microbiome-based biomarkers and models of lung cancer development and treatment Project NarrativeHere we propose to use metatranscriptomic sequencing of current and former smokers to develop effectivebiomarkers for lung cancer prediction and to explore the role of microbe-microbe and microbe-host interactionsin lung cancer development. Our hope is that this effort will pave the way for early diagnostics and interventionsto improve our early diagnostics and strategies for lung cancer prevention. NCI 10739531 11/21/22 0:00 PA-21-268 7R21CA260382-02 7 R21 CA 260382 2 "XI, DAN" 12/1/22 0:00 11/30/24 0:00 ZCA1-SRB-P(O1)S 7797183 "JOHNSON, WILLIAM EVAN" "SEGRE, DANIEL " 10 INTERNAL MEDICINE/MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 12/1/22 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2023 145579 NCI 105188 40391 Project Summary/AbstractThe microbiome has become an important focus of cancer research including its role in prevention diagnosticsand mechanistic causation. However there are still significant gaps in our understanding of the mechanisms andmolecular interactions (both microbe-microbe and microbe-host) that continue to hinder our abilities to developeffective microbiome-based biomarkers for cancer outcomes or for using the microbiome as a target for cancertreatment or prevention. For lung cancer there has been some recent progress studying the mechanistic role ofthe microbiome in lung tumorigenesis although lung cancer microbiome research has lagged behind progressin other cancers.Here we propose to use RNA-sequencing data from nasal samples of current and former smokers in combinationwith state-of-the art computational modeling to develop effective biomarkers and explore the role of microbe-microbe and microbe-host interactions in lung cancer. We will first develop and validate predictive biomarkersfor lung cancer using the microbiome and host gene expression. In the process we will also characterizemicrobe-microbe interactions associated with cancer status and evaluate microbiome interactions with humanoncogenic and inflammatory pathways. We will also develop predictive models for assessing the impact of hostand microbial targeted therapies as well as the impact of the transplantation of individual microbes or syntheticcommunities. 145579 +No NIH Category available Affect;Antibodies;Award;Biochemistry;Biological;Biology;Breast Cancer Detection;Breast Cancer gene;C-terminal;Cancer Biology;Cancer Diagnostics;Cancer Etiology;Cancer Patient;Cancer-Predisposing Gene;Cell Nucleus;Cell model;Cellular biology;Centrosome;Chromosome Mapping;Clinical Management;Cytoplasm;Cytosol;DNA;DNA Binding Domain;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Gene;DNA Repair Pathway;DNA replication fork;Defect;Development;Double Strand Break Repair;Ensure;Family member;Frameshift Mutation;Functional disorder;Gene Expression;Gene Mutation;Genome Stability;Genomic Instability;Goals;Hereditary Breast and Ovarian Cancer Syndrome;Human;Institution;Knowledge;Lead;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Missense Mutation;Molecular;Mutation;Nonsense Mutation;Normal Cell;Nuclear;Nuclear Import;Nuclear Localization Signal;Nuclear Protein;Oncogenes;Pancreas;Pathogenicity;Pathway interactions;Patients;Pharmaceutical Preparations;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Postdoctoral Fellow;Prevention;Principal Investigator;Process;Proteins;Proteomics;Reporting;Research;Risk Assessment;Testing;Therapeutic Intervention;Time;Tissue Microarray;Tissue Sample;Treatment outcome;Tumor Tissue;Uncertainty;Variant;cancer cell;cancer genetics;cancer risk;carcinogenesis;career;clinical application;diagnostic tool;driver mutation;genetic testing;genetic variant;genome integrity;hereditary risk;human tissue;malignant breast neoplasm;melanoma;neoplastic cell;novel;nucleocytoplasmic transport;patient stratification;prevent;prostate cancer risk;protein folding;protein misfolding;reconstitution;repair function;repaired;response;risk stratification;skill acquisition;success;targeted cancer therapy;targeted treatment;therapy resistant;tool;trafficking;tumor;variant of unknown significance;virulence gene DNA repair dysfunction in cancer induced by altered BRCA2 localization PROJECT NARRATIVEBRCA2 is an essential player in the DNA damage response pathway preventing genome instability and cancerthrough proper homologous directed repair (HDR) and protection of DNA replication forks. I recently identified anovel group of BRCA2 misssense mutations which affect nuclear localization and increase sensitivity to PARPinhibitors (PARPi) and platinum drugs but the mechanism by which this occurs is still not fully understood. Thegoal of my K22 proposal is to dissect the mechanisms of BRCA2 mislocalization the altered functions of cytosolicBRCA2 and detect BRCA2 expression in human tissues as a cancer diagnostic tool. NCI 10739521 9/12/23 0:00 PAR-21-301 1K22CA273681-01A1 1 K22 CA 273681 1 A1 "VAHEDI, SHAHROOZ" 9/12/23 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 15388694 "JIMENEZ SAINZ, JUDIT " Not Applicable 6 BIOCHEMISTRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 9/12/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 205848 NCI 190600 15248 PROJECT SUMMARY/ABSTRACTBRCA2 as part of the DNA repair pathway is a key regulator in homology-directed repair (HDR) and fork protectionmechanism which ensures genome instability. For full activity BRCA2 must be transported into the nucleus to repairDNA double-strand breaks (DSBs). In normal cells loss of nuclear BRCA2 can lead to genome instability and cancerbut in tumor cells BRCA2 cytosolic mislocalization can lead to sensitivity to targeted therapies.I identified a paradoxical relationship between BRCA2 nuclear import and treatment. Pathogenic missense mutationsin the DNA binding domain of BRCA2 direct the protein to the cytosol which increase sensitivity to PARP inhibitors(PARPi) and platinum drugs. Therefore although BRCA2 mislocalization might be a cause of cancer keeping itout of the nucleus allows for much better treatment outcomes. This has opened an avenue of research that I amperfectly aligned to study. In this K22 proposal I will address the nuclear transport of BRCA2 how cancer-drivermutations lead to cytosolic mislocalization and how BRCA2 localization can be used as a diagnostic tool. To test this Iwill define the molecular mechanism(s) regulating nuclear/cytoplasmic shuttling of BRCA2 pathogenic missensevariants (Aim 1) determine the impact of BRCA2 cellular localization on HDR fork protection and cytosolic processes(Aim 2) and exploit BRCA2 localization as a cancer diagnostic tool (Aim 3). My priority will be to focus on missensevariants identified during my postdoctoral career to decipher the underlying molecular mechanism of nuclear/cytosolicBRCA2 trafficking. At the successful completion of this K22 proposal I will reveal novel pathways and factors that ensureproper localization of BRCA2 and how pathogenic BRCA2 missense variants have altered localization and functionality.This knowledge will give us a better understanding of the pathogenicity of BRCA2 missense variants and how we canmodulate the functionality of BRCA2.My career goal is to obtain an independent position at a leading institution where I will dissect the functionality ofmissense variants in DNA repair proteins and how their cellular localization is important for genome stability as a tool topredict cancer risk and to treat cancer patients. My successful transition will be supported by advancing my expertise incell biology biochemistry mass spectrometry and human cellular models. I will use these acquired skills to define whyand how certain pathogenic BRCA2 missense variants are mislocalized to the cytosol. Importantly the protected timethat this award provides me will allow me to elucidate the factors and pathways by which BRCA2 is transported fromthe cytosol to the nucleus how this might be altered in BRCA2 missense variants and how this could be used fortargeted therapies. Furthermore the success of this project will be greatly enhanced by the outstanding advisors andcollaborators that advise me through the K22 period. The receipt of this award will allow me to expand my research planand establish myself as a principal investigator in the field of cancer biology. 205848 +No NIH Category available Adjuvant Therapy;Adolescent and Young Adult;Amputation;Automobile Driving;Biochemical;Biological;Biological Assay;Cells;Chimeric Proteins;Chromosomal translocation;Chronic Myeloid Leukemia;Clear Cell Sarcoma;Combined Modality Therapy;Complex;Cyclic AMP-Responsive DNA-Binding Protein;Development;Diagnostic;Disease;Ewings sarcoma;Excision;Exhibits;Genes;Genetic Transcription;Genomics;Goals;In Vitro;Lower Extremity;Mediating;Molecular;Oncogenes;Operative Surgical Procedures;Patients;Pharmaceutical Chemistry;Phosphorylation;Protein Family;Protein-Arginine N-Methyltransferase;RNA-Binding Protein EWS;Rare Diseases;Research;Role;Safety;Soft tissue sarcoma;Survival Rate;Tendon structure;Testing;Tissue Model;Tissue Survival;Transcription Coactivator;Transcriptional Activation;activating transcription factor 1;aponeurosis;bcr-abl Fusion Proteins;cancer cell;chemical genetics;chemotherapy;disorder control;genetic approach;in vitro activity;in vivo;inhibitor;innovation;member;new therapeutic target;novel drug combination;novel therapeutics;preclinical study;protein arginine methyltransferase 2;small molecule;small molecule inhibitor;targeted treatment;therapeutic target;transcription factor;treatment strategy;tumor Targeting EWS-ATF1 Fusion in Clear Cell Sarcoma of Soft Tissue PROJECT NARRATIVEThe proposed research is to develop a targeted therapy for clear cell sarcoma of soft tissue. NCI 10739324 12/1/23 0:00 PA-20-185 5R01CA245964-03 5 R01 CA 245964 3 "CHEN, WEIWEI" 12/1/21 0:00 11/30/26 0:00 Developmental Therapeutics Study Section[DT] 15706203 "LI, BINGBING " Not Applicable 1 PHYSIOLOGY 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 402551 NCI 261397 141154 PROJECT SUMMARY/ABSTRACTThe goals of this application are to develop novel targeted therapies for clear cell sarcoma of soft tissue(CCSST) and understand their mechanism of action. CCSST is a rare and aggressive soft tissue sarcoma thattypically develops in the lower extremity close to tendons and aponeuroses of adolescents and young adults. Itis an orphan disease presently with no cure. The 5-year survival rate is only 20% for metastatic cases. Thecurrent treatment option is to perform wide local surgical resection or amputation attempting to remove all thecancer cells. However in metastatic cases complete removal of cancer cells becomes impossible andsystemic adjuvant therapy is the key to control this disease. Unfortunately this disease is notorious for itsinsensitivity to existing chemotherapies underscoring an urgent need for developing novel targeted therapiesfor CCSST. The hallmark of CCSST is characterized by a balanced t(12;22) (q13;q12) chromosomaltranslocation which results in a fusion of the Ewing's sarcoma gene EWSR1 (EWS RNA-bind protein 1) withactivating transcription factor 1 (ATF1) to generate an oncogene EWS-ATF1. ATF1 is a member of the cAMP-responsive element binding protein (CREB) family transcription factor. EWS-ATF1 is constitutively active todrive the expression of target genes that are normally regulated by CREB/ATF1. In addition to ATF1 EWS-CREB fusion has also been detected in CCSST patients further supporting a critical role of CREB/ATF1'stranscription activity in driving the development of CCSST. In vitro and in vivo studies in various CCSSTmodels have convincingly shown that CCSST cells depend on the EWS-ATF1-mediated gene transcriptionactivity for continued survival. These results suggest that targeting EWS-ATF1 is a powerful and promisingapproach to develop novel targeted therapeutics for CCSST. As a transcription factor EWS-ATF1 has been achallenging target for developing small molecule inhibitors. In addition the mechanisms by which EWS-ATF1activates gene transcription are not well-understood. We recently developed a small molecule called 666-15 asthe first potent inhibitor of CREB/ATF1-mediated gene transcription. 666-15 is well-tolerated in vivo. In thisapplication we will investigate the activity of 666-15 in various CCSST models and its mechanism of action(Aim 1). We will further study how EWS-ATF1 activates gene transcription (Aim 2). In Aim 3 we will identifycombination treatment strategies for CCSST. 402551 +No NIH Category available 1-Phosphatidylinositol 4-Kinase;Acceleration;Address;Alleles;Behavior;Biogenesis;Biological;Blood Vessels;CD8-Positive T-Lymphocytes;CSF3 gene;CXCL1 gene;Cancer Model;Cause of Death;Cell Proliferation;Cell Survival;Cell physiology;Cell secretion;Cells;Chromosomes;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Coculture Techniques;Dedications;Development;Disease;Disseminated Malignant Neoplasm;Docking;Ectopic Expression;Endothelial Cells;Fibroblasts;Fluorescence;Foundations;GOLPH3 gene;Genetic Recombination;Golgi Apparatus;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;IL8 gene;Immunity;Induction of Apoptosis;Inflammation;Inflammatory;Interleukin-6;Invaded;KRAS2 gene;Lentivirus;Link;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Membrane;Modeling;Molecular;Mus;Myeloid Cells;Neoplasm Metastasis;Outcome;Phosphoric Monoester Hydrolases;Phosphotransferases;Play;Process;Property;Protein Secretion;Proteins;Regulation;Rest;Role;STC2 gene;Site;Structure;TIMP1 gene;Testing;Therapeutic;Tissues;Tumor Promotion;Tumor Volume;Vascular Endothelial Growth Factors;Vesicle;Work;aerosolized;angiogenesis;antagonist;behavior influence;cancer cell;clinical development;cytokine;effective therapy;improved;inhibitor;inorganic phosphate;insight;lung cancer cell;metastatic process;mutant;neoplastic cell;novel therapeutic intervention;novel therapeutics;phosphatidylinositol 4-phosphate;small hairpin RNA;small molecule;therapeutically effective;trafficking;trans-Golgi Network;tumor;tumor growth;tumor microenvironment;tumor progression;tumorigenic Regulation of lung cancer growth and metastasis by an actionable driver of vesicle biogenesis in the Golgi There are few effective therapeutic options for KRAS-mutant lung cancer (KMLC) and there is an urgent needto develop a better understanding of the biological basis of KMLC growth and metastasis. On the basis of thepreliminary results presented here we postulate that KMLC growth and metastasis is driven by a chromosome1q amplicon containing an actionable Golgi-dedicated kinase (PI4KIII) that promotes secretion of pro-tumorigenic effector proteins. If proven true these findings would advance our understanding of themechanisms of KMLC progression and would provide a rationale to advance PI4KIII antagonists into clinicaltrials for the treatment of KMLC and other chromosome 1q-amplified tumor types. NCI 10739321 11/21/23 0:00 PA-19-056 5R01CA236781-05 5 R01 CA 236781 5 "AULT, GRACE S" 12/1/19 0:00 11/30/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 1869259 "KURIE, JONATHAN M" Not Applicable 9 SURGERY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 398991 NCI 249837 149154 Few effective therapies are available for KRAS-mutant lung cancer(KMLC). To address this problem we seek to elucidate the biological basis for KMLC growth and metastasisand to develop novel therapies on the basis of that improved understanding. Cancer cells secrete factors thatpromote tumor growth matrix remodeling angiogenesis and inflammation a process hereafter termedmalignant secretion. Therapeutic strategies to block malignant secretion have not been developed. We have identified a chromosome 1q amplicon harboring and numerous regulators of vesicle biogenesisand trafficking including phosphatidylinositol 4-kinase III (PI4KIII) a Golgi-dedicated kinase that generatesphosphatidylinositol 4-phosphate (PI4P). We show that the viability and proliferative and invasive activities of1qamplified KMLC cells require PI4KIII. A selective PI4KIII antagonist preferentially induced apoptosis andinhibited the metastatic properties of 1qamplified KMLC cells. On the basis of these findings we hypothesizethat high PI4KIII levels promote KMLC growth and metastasis and confer vulnerability to PI4KIII antagonists.To test this hypothesis we propose in Aim 1 to an autochthonous PI4KIIIexpressing KMLC model anddetermine whether PI4KIII enhances KMLC metastatic propensity and confers vulnerability to PI4KIIIantagonists. Our findings will elucidate the way in which PI4KIII drives KMLC progression and may provide afoundation for new therapeutic approaches using PI4KIII antagonists. We show that high PI4KIII levels in 1qamplified KMLC cells enhanced anterograde vesicular traffickingand stimulated the secretion of pro-survival and pro-metastatic factors. PI4KIIIdriven metastatic propertiesrequired Golgi phosphoprotein 3 (GOLPH3) a PI4Ptethered Golgi protein that promotes vesicle budding fromthe trans-Golgi network. Therefore we postulate that PI4KIII-dependent secretion is required to activate pro-metastatic processes in the tumor microenvironment and maintain the viability of 1q-amplified KMLC cells. Totest this hypothesis we will inactivate Golph3 in PI4KIII-expressing autochthonous KMLCs and 1q-amplifiedorthotopic KMLCs. Resultant changes in tumor cell viability and inflammatory stromal and vascular cellfunctions in the tumor microenvironment will be measured. We will identify PI4KIII-dependent secretedproteins that mediate these changes and elucidate how they exert these functions. Our findings will provideinsight into how a secretory process activated by a chromosomal region that is frequently amplified in cancermaintains tumor cell viability and influences diverse processes in the tumor microenvironment. In summary the evidence presented here links malignant secretion to a chromosomal region that isfrequently amplified in KMLC and provides a basis for clinical studies to develop PI4KIII antagonists as first-in-class inhibitors of malignant secretion. Our findings elucidate the molecular underpinnings of malignantsecretion and show that chromosome 1q-amplified cancers are vulnerable to secretory blockade. 398991 +No NIH Category available Advertising;Affect;African American;African American population;Area;Attitude;Behavior;Behavioral;Belief;Biometry;Characteristics;Cigar;Cigarette;Collaborations;Color;Commercial Catalogs;Communications Media;Communities;Consumption;Data;Data Analyses;Data Set;Disparity;Economics;Education;Exposure to;Future;General Population;Geographic Locations;Goals;Health;High School Student;Imagery;Individual;Instagram;Knowledge;Latino Population;Link;Location;Longitudinal cohort;Marijuana;Marketing;Measures;Methodology;Misinformation;Modeling;Outcome;Outcome Measure;Patient Self-Report;Perception;Pharmaceutical Preparations;Policies;Population;Prevalence;Price;Public Opinion;Regulation;Research;Research Methodology;Risk Factors;Role;Sales;Scientific Advances and Accomplishments;Smoker;Smoking;Smoking Behavior;Source;Subgroup;Surveys;Time;Tobacco;Tobacco Industry;Tobacco use;Twitter;United States;Vulnerable Populations;Youth;analytical method;base;cigarette smoking;cigarillos;collaboratory;computer science;contextual factors;digital;experience;food marketing;hookah;innovation;insight;marijuana use;public policy on tobacco;social;social media;social networking website;tobacco advertising;tobacco control;tobacco prevention;tobacco products;tool Assessing the Effects of Cigar and Cigarillo Social Media Promotion on Tobacco and Marijuana Use PROJECT NARRATIVESocial media are a major marketing platform for reaching youth and vulnerable populations traditionallyexperiencing tobacco-related disparities with little cigar and cigarillo promotion. The goal of this project is toassess the intended and unintended effects of exposure to commercial and influencer social media content aboutcigar products on Twitter and Instagram with tobacco and marijuana product use and sales to inform futuretobacco use prevention education and marketing regulation efforts. NCI 10739300 11/20/23 0:00 PA-19-056 5R01CA248871-04 5 R01 CA 248871 4 "BLAKE, KELLY D" 12/2/20 0:00 11/30/25 0:00 Community Influences on Health Behavior Study Section[CIHB] 10371712 "KOSTYGINA, GANNA " Not Applicable 7 Unavailable 69512291 MPYFY5UMSDP4 69512291 MPYFY5UMSDP4 US 41.785875 -87.597545 5730401 NATIONAL OPINION RESEARCH CENTER CHICAGO IL Other Domestic Non-Profits 606035713 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 586749 NCI 398188 188561 PROJECT SUMMARYWhile digital marketing of tobacco products is becoming increasingly common the role of social media platformsin tobacco control is still understudied. There is a growing body of research suggesting that social mediapromotion of cigar products is rapidly increasing.1-3 With regulation lagging behind innovative digital marketingtactics social networking sites have become an important promotional vehicle for tobacco brands. Commercialsocial media messages often target youth and populations traditionally experiencing tobacco-related disparities.45 Thus disparities in the use of cigar and cigarillo products are persistent in the U.S. with nearly one in tenAfrican American high school students being cigar smokers in 2018.6 7 Youth African Americans and Latinosalso use social media at higher rates than the general population which potentially multiplies the effect of socialmedia marketing and contributes to disparities in tobacco marketing exposure. Understanding the impact ofexposure to messages about cigar little cigar and cigarillo products on social media can offer meaningful insightsfor tobacco control as social media data provide valuable measures of population norms targeted marketingand other previously unmeasured contextual factors associated with health outcomes. Unfortunately to date nostudies have examined the population level impact of social media marketing of cigar and cigarillo products. Thisproject will advance the scientific knowledge on cigar products by filling this critical research gap. Theoverarching goal of this project is to examine the direct effects and the unintended consequences of exposureto social media content related to cigars little cigars and cigarillos and provide timely scientific basis forregulatory actions on restricting marketing for cigar products including little cigars and cigarillos (LCCs). Thespecific aims of the proposed project are: 1) to examine the impact of exposure to little cigar and cigarillo socialmedia content on LCC use attitudes towards LCCs harm perceptions perceived prevalence of use initiationand intentions to use LCCs; 2) to assess the unintended consequences of LCC-related content exposure onsocial media examining its impact on attitudes beliefs and behaviors related to other combustible productssuch as cigarettes and hookah; as well as the impact of exposure on marijuana use and initiation; 3) to studywhether or to what extent state and local tobacco control policies and marijuana regulations modify the directeffects and unintended impact of potential exposure to social media content. These aims will be accomplishedby applying innovative research and analytic methods to a unique combination of data sets including socialmedia data from Twitter and Instagram Nielsen store scanner data on LCC and other tobacco product salesand survey data on tobacco-related outcomes. The findings from this project will provide highly policy-relevantscientific evidence on the population level impact of social media marketing of LCC products. This project willprovide unique insight into the direct effects and unintended influences of digital cigar promotion and build ascientific and methodological base for surveillance and regulation of social media marketing. 586749 +No NIH Category available Abdomen;Address;Animals;Benchmarking;Biodiversity;Biological Markers;Biology;Biopsy;Brain;Breast;Cancer Patient;Citric Acid Cycle;Clinic;Clinical;Clinical assessments;Collaborations;Computer software;Data;Development;Disease;Disseminated Malignant Neoplasm;Echo-Planar Imaging;Foundations;Future;Glycolysis;Goals;Heart;Histologic;Human;Human body;Image;Industrialization;Infrastructure;Infusion procedures;Label;Lesion;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolic;Metabolism;Metastatic Prostate Cancer;Methods;Monitor;Motivation;Mutation;Oncogenic;PSA level;Pathology;Patients;Perfusion;Pharmacotherapy;Phenotype;Physiologic pulse;Population;Prostate;Pyruvate;Pyruvate Metabolism Pathway;Radioactive Tracers;Research;Research Personnel;Role;Scientist;Sensitivity and Specificity;Site;Support System;Surface;System;Systems Biology;Techniques;Technology;Therapeutic Intervention;Time;Translating;Transrectal Ultrasound;Up-Regulation;Validation;Visualization;Work;androgen deprivation therapy;animal imaging;bone;cancer site;cancer therapy;castration resistant prostate cancer;cohort;design;first-in-human;follow-up;human study;image reconstruction;imaging biomarker;imaging capabilities;imaging modality;improved;in vivo;individualized medicine;industry partner;innovation;interest;men;metabolic abnormality assessment;metabolic imaging;molecular imaging;non-invasive imaging;non-invasive monitor;novel;novel therapeutic intervention;novel therapeutics;patient population;response;serum PSA;software development;tool;transmission process;treatment effect;treatment planning;treatment response;tumor;tumor metabolism;virtual Development of large-field-of-view hyperpolarized MRI PROJECT NARRATIVEThe over-arching goal of the proposed research is to translate a new MRI technology hyperpolarized (HP) MRto the clinic in the setting of large-field-of-view (FOV) MRI which utilizes both the agents HP [1-13C] pyruvateand [2-13C] pyruvate in metastatic prostate cancer patients. Prostate cancer demonstrates tremendous biologicdiversity and there is an urgent need to develop more sensitive and specific imaging biomarkers to characterizethe disease. We aim to develop a large-body transmit/receive system and pulse sequences for large FOV andapply them to a cohort of prostate cancer patients: this work will aid in future patient-specific treatment planningfacilitate earlier assessment of response to therapy and facilitate the development of novel experimentalstrategies for cancer treatment. NCI 10739293 11/7/23 0:00 PAR-18-009 5R01CA237466-05 5 R01 CA 237466 5 "ZHANG, HUIMING" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 10451505 "KESHARI, KAYVAN R" "CUNNINGHAM, CHARLES H.; HRICAK, HEDVIG " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 517861 NCI 356378 161483 PROJECT SUMMARY/ABSTRACTProstate cancers currently the most common cancer in men demonstrate a tremendous range of biologicdiversity. Clinical assessments of response to non-surgical therapy are often inadequate because as studieshave shown they lead to inaccuracies when they rely upon serum prostate specific antigen (PSA) levelsreaching a nadir or upon the histological confirmation of cancer using transrectal ultrasound guided biopsies.When progressing to metastatic cancer typically after androgen deprivation therapy castrate resistant prostatecancer (CRPC) results in bone lesions in more than 90% of cases. There remains a critical clinical need forgreater sensitivity and specificity in molecular imaging biomarkers of prostate cancer presence and of responseto novel therapeutics.An extraordinary new technique hyperpolarized magnetic resonance (HP MR) has the potential to change theway we interrogate metabolism in vivo. Through the utilization of 13C-labeled endogenous substrates we areable to non-invasively image a metabolic intermediate and its subsequent downstream products usingconventional MRI. In the setting of prostate cancer this provides a potentially invaluable tool for the study ofprostate cancer metabolism and its modulation as a function of tumor aggressiveness and response totherapeutic intervention. Unfortunately we are currently limited in our ability to visualize large volumes ofinterest whereas metastatic prostate cancer typically requires visualization of the abdomen and bone regionsvirtually inaccessible to current HP MRI approaches.The objective of this innovative academic industrial partnership is to address this problem by developing alarge-field-of-view HP MRI approach including both hardware and software. This proposal would establish arobust platform to enable the imaging of metastatic disease in prostate cancer patients. In the first aim of thisproposal we will develop a novel 13C body transmit coil and receive system capable of imaging the abdomen.In tandem we will also develop acquisition strategies to take advantage of this hardware for rapid HP MRI.Finally we will validate this approach in 2 cohorts of metastatic prostate cancer patients. The first will be imagedwith HP [1-13C] pyruvate to assess methods to visualize downstream glycolysis and the second with [2-13C]pyruvate to image the TCA cycle for a first-in-human study.It is the overarching goal of this proposal to build a novel large-field-of-view approach to HP MRI includingimportantly both hardware and software and apply it to the imaging of HP pyruvate metabolism in cancerpatients so as to provide benchmark for future studies using this technique and additionally to determine itsability to inform on prostate biology. 517861 +No NIH Category available Acceleration;Age;Age Years;Binding;Blood Vessels;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;CD8-Positive T-Lymphocytes;Cancer Etiology;Cell Death;Cell Survival;Cells;Cessation of life;Chemotactic Factors;Childbirth;Complex;Data;Diagnosis;Distant;Early Diagnosis;Early treatment;FRAP1 gene;Future;Genes;Genetic Transcription;Goals;Immune Evasion;Immune system;Immunosuppression;Integrins;Intercellular Junctions;Invaded;Link;Literature;Lymphangiogenesis;Lymphatic;Lymphatic Endothelial Cells;Macrophage;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Mediating;Meditation;Modeling;Monoclonal Antibodies;Neoplasm Metastasis;Nulliparity;PD-1 blockade;Pathway interactions;Patients;Phosphotransferases;Positive Lymph Node;Probability;Prognosis;Proliferating;Proteins;Proto-Oncogene Proteins c-akt;Recurrence;Resistance;Role;STAT3 gene;Semaphorins;Signal Transduction;Signaling Molecule;Site;T-Lymphocyte;Testing;Tissues;Tumor Cell Migration;Tumor Escape;Tumor Immunity;Tumor Promotion;Tumor-associated macrophages;Tumor-infiltrating immune cells;Up-Regulation;Woman;angiogenesis;anti-tumor immune response;breast cancer diagnosis;breast cancer progression;breast cancer survival;cancer cell;cell type;cytokine;density;immune cell infiltrate;improved;in vivo;insight;intercalation;knock-down;lymphatic Invasion;lymphatic vasculature;lymphatic vessel;malignant breast neoplasm;mammary;mouse model;neoplastic cell;novel;overexpression;podoplanin;postpartum breast cancer;pre-clinical;programmed cell death ligand 1;programmed cell death protein 1;recruit;reproductive;targeted treatment;therapy design;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenesis Discerning the role of semaphorin 7a in mammary tumor growth and anti-tumor immunity Project NarrativeWe have shown that SEMA7A promotes multiple aspects of breast cancer progression including proliferation survival invasion and immune evasion. This proposal aims to define the mechanisms by which SEMA7A induces pro-survival signaling in tumor-adjacent cells of the TME to suppress anti-tumor immunity while also promoting tumor cell dissemination via lymphatics. Understanding these mechanisms may reveal novel targets for the treatment of SEMA7A+ breast cancers and/or lymphatic-mediated metastases. NCI 10739289 7/11/23 0:00 PA-21-051 5F31CA268825-02 5 F31 CA 268825 2 "PURI, ANU" 7/1/22 0:00 8/31/23 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 12346407 "ELDER, ALAN MICHAEL" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 7/1/23 0:00 8/31/23 0:00 398 "Training, Individual" 2023 10839 NCI 10839 0 "Project Summary/AbstractEarly detection and treatment of breast cancer (BC) has reduced the number of BC-related deaths but remains the leading cause of cancer-related death in women ages 15-54. Over half of all BCs diagnosed in women <40 years of age fit the definition of postpartum breast cancer (PPBC) BCs diagnosed within 10 years of last childbirth which are 2-3 times more likely to metastasize compared to BCs diagnosed in nulliparous patients. These deaths are generally attributed to dissemination of tumor cells to distant tissues via blood and lymphatic vessels. Increased lymphatic vessel density (LVD) lymphovascular invasion and lymph node positivity (LN+) are frequently observed in PPBC and are associated with worse prognosis. We have identified that semaphorin 7a (SEMA7A)-a signaling molecule that activates integrin-131 signaling in cancer-is upregulated in PPBC and is associated with increased LVD TAMs and metastasis. Additionally SEMA7A+ tumors recapitulate the accelerated tumorigenesis and metastatic profiles observed in PPBC and high SEMA7A expression correlates with decreased overall survival. As such PPBCs likely only represent a subset of SEMA7A+ cancers; there are currently no therapies targeting SEMA7A. SEMA7A+ BCs exemplify four key hallmarks of cancer: 1) resistance to cell death 2) angiogenesis and lymphangiogenesis 3) immune evasion and 4) invasion and metastasis. Tumor-associated macrophages (TAMs) are implicated in each and in creating a pro-tumor microenvironment (TME). As TAMs and LVD are amplified in SEMA7A+ BC it is probable that they contribute to the worse prognosis of PPBC. SEMA7A can also polarize macrophages into a subset of TAMs (termed ""PoEMs"") that express lymphatic-associated proteins. These PoEMs intercalate into lymphatic vessels to form PoEM-LEC chimeric vessels and tumor cells associate with these vessels at PoEM-LEC junctions which may mediate tumor cell escape. Moreover SEMA7A can promote expression of PD-L 1-expression on BC cells LECs TAMs and PoEMs to suppress anti-tumor immunity; however additional effects of SEMA7A on immune cells of the TME have not been investigated. Altogether this led us to the hypothesis that SEMA7A activates pro-survival signaling in immunosuppressive PoEMs to promote tumor cell dissemination.The goals of this proposal are to: 1) determine the mechanisms by which SEMA7A induces cell survival and alters the immune TME to a pro-tumor state and 2) investigate the chemoattractants produced by PoEMs that recruit tumor cells to PoEM-LEC junctions and promote metastasis. In aim 1 we will define the mechanisms of SEMA7A-induced cell survival and effects on immune cells of the TME. We will also establish whether monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. In aim 2 we will define chemoattractants that recruit tumor cells to PoEM-LEC junctions. The results of these studies will identify how SEMA7A promotes tumor progression immunosuppression and lymphatic-meditated metastasis as well as offer insight for future therapies to target SEMA7A+ BCs thus improving survival for many BC patients." 10839 +No NIH Category available APC gene;APC mutation;Adenocarcinoma;Advisory Committees;Affect;Agonist;Award;Biological Assay;Biomedical Engineering;CRISPR interference;Caliber;Cancer Biology;Cancer Model;Carcinoma;Cell Nucleus;Cell Proliferation;Cell physiology;Cells;Clinical;Colon;Colon Adenocarcinoma;Colon Carcinoma;Colonic Adenoma;Colonic Neoplasms;Colorectal Cancer;Complex;Data;Dependence;Development Plans;Diet;Dose;Elements;Engineering;Ensure;Epithelium;Essential Genes;Exhibits;Foundations;Frequencies;General Hospitals;Genes;Genetic;Glycogen Synthase Kinase 3;Growth;Human;Institution;Intestines;KRAS2 gene;Knock-out;Lesion;Location;Loss of Heterozygosity;Maintenance;Malignant Neoplasms;Massachusetts;Medical;Mentors;Modeling;Moderna COVID-19 vaccine;Molecular;Mus;Mutate;Mutation;Normal Cell;Normal tissue morphology;Oncogenic;Organoids;Pathologist;Pathway interactions;Patients;Physicians;Polypectomy;Pre-Clinical Model;Protein Kinase;Proteins;Recording of previous events;Research;Resources;Rho-associated kinase;Scientist;Signal Transduction;Specimen;Stereotyping;TP53 gene;Technology;Therapeutic;Time;Toxic effect;Training;WNT Signaling Pathway;Wnt proteins;Work;adenoma;beta catenin;clinical care;colon cancer treatment;human model;improved;in vivo;inhibitor;knock-down;loss of function;loss of function mutation;mouse model;mutant;nanoparticle;nanoparticle delivery;neoplastic cell;novel;pharmacologic;progenitor;programs;small molecule inhibitor;stem cells;success;targeted treatment;transcriptome sequencing;transcriptomics;tumor;tumor growth Differential Wnt Dependencies in Colon Epithelium. Project NarrativeColonic neoplasia from adenoma to carcinoma exhibits niche independence where normal regulatorymechanisms involving Wnt signaling for cell proliferation are unchecked resulting in tumors. Strategies toinhibit such signaling have not worked therapeutically however increasing Wnt signaling even further intumors has a non-intuitive result where they end up ultimately inhibited. In contrast normal colonic epitheliumhas improved growth with increased Wnt signaling. This proposal seeks to leverage this phenomenon to inhibitcolon cancer but improve normal colon cell function which may unlock a new paradigm of colon cancertreatment. NCI 10739179 8/23/23 0:00 PA-20-203 1K08CA277011-01A1 1 K08 CA 277011 1 A1 "LIM, SUSAN E" 9/1/23 0:00 8/31/28 0:00 Career Development Study Section (J)[NCI-J] 9563525 "ENG, GEORGE " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 196204 NCI 181670 14534 Project Summary/AbstractThis proposal details a five-year training plan for the development of a research program focused onelucidating the therapeutic potential of superimposed additional Wnt signaling on colonic neoplasia.The molecular driver shared across the vast majority of colonic neoplasms is constitutive Wntsignaling most commonly caused by loss of function mutations in the APC gene. The loss of functionof APC permits beta catenin to constitutively translocate to the nucleus and induce the formation ofcolonic adenomas which can further mutate into colon cancer. To date strategies to inhibit Wntsignaling for therapeutic purposes have failed. However other elements of the beta catenindestruction complex that work with APC such as GSK3 alpha and beta can be pharmacologicallyinhibited. Therefore instead of inhibiting Wnt signaling and informed by the concept that a just rightamount of Wnt signaling may be selected for in tumor cells we hypothesized additional Wnt signalingwould be deleterious to tumor cells but would simultaneously enhance the function of normal cells.This project will elucidate fundamental dependencies of Wnt signaling in normal tissues as well astumors. Ultimately I believe this will engender a specific therapy for adenomas to which there is noexisting medical therapy other than polypectomy and additionally provide a broadly applicable andpotentially safe approach to treat colorectal cancer.I am clinically trained pathologist and physician scientist seeking K08 support for mentored research.This work will be mentored by Prof. Omer Yilmaz and Prof. Robert Langer. Prof. Yilmaz is apathologist and physician-scientist and studies the effects of diet on intestinal stem cells and state-of-the-art intestinal organoid models. Prof. Langer has fundamentally transformed and definedbiomedical engineering is the most cited engineer in history and most recently his expertise innanoparticle delivery provided the foundation for the Moderna COVID-19 vaccine. The work will beconducted at the Massachusetts Institute of Technology and Massachusetts General Hospital bothworld class institutions of the highest caliber. I have assembled a scientific advisory committeeconsisting of world class cancer biologists to help guide my scientific progress consisting of Prof.Tyler Jacks Prof. Michael Yaffe and Prof. William Kaelin. This K08 mentored research award willensure I have the time and resources to develop expertise in cancer biology and explore thispromising therapeutic and biologically intriguing concept of increased Wnt signaling to specificallytreat colonic neoplasia. This topic will provide ample substrate for me to grow as an independentphysician scientist. 196204 +No NIH Category available Address;Adjuvant;Age;Antibodies;Biological Markers;Blood;Brain;Brain Neoplasms;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Cessation of life;Chemotherapy and/or radiation;Clinical;Clinical Trials;Combined Modality Therapy;Data;Development;Diffuse;Disease remission;Dose;Epigenetic Process;Evaluation;Excision;Exclusion;Exhibits;Future;Gene Expression Profile;Genetic Transcription;Genotype;Glioma;Goals;Hematologic Neoplasms;Human;Immune;Immune checkpoint inhibitor;Immune system;Immunocompetent;Immunologic Markers;Immunologic Monitoring;Immunologic Surveillance;Immunologics;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Infiltration;Inflammatory;Institutional Review Boards;Interferon Type II;Interferons;Isocitrate Dehydrogenase;Knowledge;Lymphocyte;Lymphocyte Function;Lymphocytic Infiltrate;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Mediator;Modality;Modeling;Mus;Mutation;Myelogenous;Myeloid-derived suppressor cells;Natural Killer Cells;Neoadjuvant Therapy;Operative Surgical Procedures;Output;PD-1 inhibitors;Pathway interactions;Patients;Pennsylvania;Performance;Phase II Clinical Trials;Population;Prediction of Response to Therapy;Recurrence;Regimen;Regulatory T-Lymphocyte;Reporting;Resistance;Retinoids;Sampling;Series;Signal Pathway;Signal Transduction;Sleeping Beauty;Solid;Specificity;Specimen;T cell receptor repertoire sequencing;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte and Natural Killer Cell;Techniques;Testing;Therapeutic;Therapeutically Targetable;Tissues;Tretinoin;Tumor Biology;Tumor Immunity;Tumor Tissue;Tumor-Infiltrating Lymphocytes;Universities;Validation;XCL1 gene;cell type;checkpoint inhibition;clinical efficacy;cohort;design;epigenetic silencing;exhaustion;experimental study;gene network;genetic signature;human subject;immune checkpoint blockade;immunogenic;immunogenicity;mouse model;mutant;neoplastic cell;pre-clinical;predicting response;programmed cell death protein 1;response;restoration;small molecule;specific biomarkers;transcriptome sequencing;treatment response;tumor;tumor eradication;young adult Interrogating Mechanisms of Anti-tumor Immunity in Human Subjects and Murine Models of IDH-Mutant Glioma Treated with All-Trans Retinoic Acid and PD-1 Inhibition Project NarrativeRecurrent mutations in Isocitrate Dehydrogenase 1 and 2 (IDH1/IDH2) drive several epigenetically dysregulated solidand hematological malignancies most of which remain incurable. IDH mutant (IDHm) gliomas are a form of malignantbrain cancer. IDH gliomas are more common in younger adults are initially sensitive to chemotherapy and radiation yetuniversally result in lethal recurrence following variable periods of remission. These vexing clinical features of IDHmglioma are partially explained by multiple recently described mechanisms through which IDHm tumor cells escapesurveillance by the human immune system. Using mouse models and tumor samples derived from human patients ourgroup has discovered defective signaling in the Retinoic Acid pathway as a major driver of tumor-induced immuneescape. Remarkably clinical regimen containing All-Trans Retinoic Acid and Immune Checkpoint Inhibitors cureaggressive IDHm gliomas in an immunocompetent mouse model. This recent discovery led to a human clinical trialrecently opened at the University of Pennsylvania to investigating All-Trans Retinoic Acid and Retifanlimab (a PD-1inhibiting monocloncal antibody) in patients with recurrent IDHm glioma. Despite this promising development severalsubstantial questions regarding the mechanism of ATRA action remain unanswered. In this proposal we set out toanswer some of those questions by identifying the specific immune cells responsible for the therapeutic activity of All-Trans Retinoic Acid in IDHm gliomas. Equally importantly we propose a thoroughly designed set of experiments inmouse models to predict response to ATRA and ATRA+Immune Checkpoint blockade particularly in patients whoreceive ATRA or ATRA+Immune Checkpoint blockade prior to surgical resection as part of our trial. This proposalleverages recent advances in immune profiling of tumor tissue and circulating blood immune cells to carefully dissectimmune cell populations and genetic signatures that are required for response to therapy in IDHm glioma and provide areadout for immunotherapeutic efficacy of ATRA and potentially other immune-directed therapies in IDHm gliomas. Ifsuccessful our proposal will contribute several important data points to help advance the discovery of additionalimmunotherapeutic strategies to substantially extend the lives of patients with IDHm glioma. NCI 10739154 7/3/23 0:00 RFA-CA-22-050 1R37CA284132-01 1 R37 CA 284132 1 "LIU, YIN" 7/3/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M2)S 11921583 "AMANKULOR, NDUKA MGBECHINYERE" Not Applicable 3 NEUROSURGERY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 353 Non-SBIR/STTR 2023 683099 NCI 480948 202151 Project AbstractDiffuse gliomas are fatal brain tumors that respond poorly to current immunotherapies. Usingboth mice models and human clinical trial data we propose a series of experiments to identifyimmune biomarkers and key immune cell types that predict tumor responsiveness to therapy.These results will further our understanding of brain tumor biology and inform the futuredevelopment of new treatment modalities. 683099 +No NIH Category available Acceleration;Administrative Supplement;Adolescent;Adolescent and Young Adult;Adult;Brain;Breast;Canada;Cancer Biology;Cell Therapy;Child;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Clinical Trials Unit;Collaborations;Collection;Data Set;Development;Diagnosis;Ensure;Head and Neck Cancer;Hematology;Image;Information Technology;Infrastructure;International;Intervention;Leadership;Lung;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Molecular;National Clinical Trials Network;Operative Surgical Procedures;Outcome;Participant;Patients;Pharmacotherapy;Policies;Population;Public Health;Regulation;Research;Research Personnel;Resources;Role;Science;Scientific Advances and Accomplishments;Skin;Technology;Testing;Translating;Translational Research;Translations;cancer therapy;data sharing;digital health;examination questions;experience;improved;innovation;lifestyle intervention;method development;novel therapeutics;precision medicine;rare cancer;research clinical testing;technology development;urologic Canadian Cancer Trials Group - Canadian Collaborating Clinical Trials Network Canadian Cancer Trials Group PI = Dancey JanetUS National Clinical Trials Network Canadian Collaborating #CA180863Clinical Trials NetworkADMINISTRATIVE SUPPLEMENT 1 March 2022 28 February 2023NarrativeAs the Canadian Collaborating Clinical Trial Network the Canadian Cancer Trials Group(CCTG) enhances NCTNs capacity to conduct innovative and potentially practice-changing trials.CCTGs scientific and regulatory expertise and national network of Canadian researcherscontributes strategic and operational expertise leverages Canadian infrastructure andresources to develop new trial proposals increases the pool of potential trial participants forprecision medicine rare cancer and large definitive trials and ensures efficient and effectiveoversight of NCTN trial conduct in Canada. The single most important benefit to public healthrealized is the improvement in the quantity and quality of survival of patients with cancer. Byfacilitating the conduct of trials that examine questions developed and driven by clinicians andthat take advantage of emerging science and new cancer therapies patients will have earlieraccess to new treatments and results will be translated into practice policy and improvedcancer outcomes. NCI 10739132 1/13/23 0:00 PA-20-272 3U10CA180863-09S1 3 U10 CA 180863 9 S1 "MOONEY, MARGARET M" 5/6/14 0:00 2/28/23 0:00 10504321 "DANCEY, JANET ELLEN" Not Applicable n/a Unavailable 207884032 SU8CALPMK4C1 207884032 SU8CALPMK4C1 CA 44.22976 -76.48098 6817201 QUEEN'S UNIVERSITY AT KINGSTON KINGSTON ON Unavailable K7L 3N6 CANADA N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 25675 NCI 25675 0 C6;Reg-CV Canadian Cancer Trials Group PI = Dancey JanetUS National Clinical Trials Network Canadian Collaborating #CA180863Clinical Trials Network ADMINISTRATIVE SUPPLEMENT 1 March 2022 28 February 2023SummaryThe transformational advances in cancer biology and technologies to characterize cancers at amolecular level combined with the rapid expansion of novel drugs and cellular therapiesmandates a fundamental reevaluation of clinical trial design and delivery to ensure maximalpatient and societal benefits. The Canadian Cancer Trials Group (CCTG) has strong partnershipswith US investigators and groups within the NCTN which emphasize international collaborationto conduct definitive practice-changing trials trials in rare cancers settings and trials testingprecision-medicine strategies. As the Canadian Collaborating Clinical Trials Network (CCCTN) ofthe NCTN CCTG expands NCTNs scientific expertise by: 1) Involving the best and brightestwithin its network in NCTN leadership roles; 2) Increasing clinical trial capacity through itsnational network which includes all centres in Canada; and 3) Facilitates access to Canadianpatients which is particularly important for trials testing interventions in rare populations.CCTG contributes to scientific concept development accrual biospecimen collection andnetwork leadership and has expertise in instrumental components of trial conduct (includinginformation technology and regulations). CCTG develops and participates in NCTN adult cancertrial portfolios in breast lung urological and gastrointestinal malignancies in uncommon/raresettings of unmet need such as hematological skin brain and head and neck cancers andincludes adolescents and young adults on AYA trials. In addition CCTG capitalizes onopportunities to extend its scope of trial activity to include surgical and lifestyle interventionsand imaging and digital health endpoints. Research incorporates translational science and othercorrelative endpoints to enrich information derived from NCTN trials and methods andtechnology development to improve clinical trial designs endpoints and execution. FinallyCCTG contributes trial datasets from NCTN trials as part of its data sharing policy. As the CCCTNCCTG Canadas largest and most experienced clinical trials unit creates and delivers innovativestrategies that arise from the NCTN accelerating the translation of scientific advances intoimprovements in cancer treatments improving the lives of children adolescents and adultsdiagnosed with cancer. 25675 +No NIH Category available 3-Phosphoinositide Dependent Protein Kinase-1;Accounting;Acetates;Adhesions;Aftercare;Apoptosis;Arginine;Automobile Driving;Biopsy;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Catalytic Domain;Cell Communication;Cell Line;Cells;Chemoresistance;Clinical Trials;Combined Modality Therapy;Complement;Cytotoxic agent;Data;Data Analyses;Detection;Development;Disease;Drug resistance;Environment;Event;Exhibits;Funding;Genes;Growth;Health;Image;Immunocompetent;Immunofluorescence Immunologic;Invaded;Investigation;Lymphoid Cell;Macrophage;Malignant Neoplasms;Mediating;Metaplastic carcinoma of the breast;Metastatic Neoplasm to the Lung;Modeling;Molecular;Mus;Mutate;Mutation;Myeloid Cells;NOS2A gene;Neoplasm Metastasis;Nitric Oxide;Nitric Oxide Synthase;Nitric Oxide Synthetase Inhibitor;Oncogenic;PIK3CA gene;PTEN gene;Pathway interactions;Patient-derived xenograft models of breast cancer;Patients;Pharmaceutical Preparations;Phosphatidylinositols;Phosphotransferases;Population;Pre-Clinical Model;Primary Neoplasm;Production;Prognosis;Prognostic Factor;Property;Protein Isoforms;Proto-Oncogene Proteins c-akt;Publishing;RNA;RNA-Protein Interaction;Radiation therapy;Refractory;Regimen;Resistance;Resolution;Ribosomal Proteins;Ribosomes;Role;SUM-159 Breast Cancer Cell Line;Signal Pathway;Specimen;Stromal Cells;Surveys;Survival Rate;TP53 gene;Testing;Therapeutic;Translations;Treatment Efficacy;alpelisib;cancer subtypes;cell growth;cell motility;cell type;chemotherapy;clinical prognosis;combinatorial;druggable target;efficacy evaluation;gain of function;hormone therapy;imaging system;in vivo;inhibitor;intercellular communication;malignant breast neoplasm;mouse model;multimodal data;neoplastic cell;omega-N-Methylarginine;outcome prediction;participant enrollment;patient derived xenograft model;pre-clinical;response;ribosome profiling;stem cell self renewal;taxane;therapeutically effective;therapy resistant;transcriptome sequencing;transcriptomics;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumorigenesis Dual targeting of PI3K and NOS pathways in Metaplastic BreastCancer (MBC) Narrative:Metaplastic breast cancer (MpBC) is a rare aggressive highly lethal subtype of breast cancer and the maintherapeutic option for metastatic MpBC remains systemic chemotherapy despite known resistance to mostchemotherapy drugs. This proposal seeks to explore a targeted combinatorial approach consisting ofsimultaneous inhibition of two major pathways implicated in MpBC the nitric oxide synthase and thephosphoinositide 3-kinase pathways to eradicate primary tumor growth and metastasis. Our proposal willinvestigate the mechanisms by which these two pathways inhibit primary tumor growth and assess interactionsbetween various cells in the tumor and its environment using specimens derived from murine MpBC models. NCI 10739097 7/8/23 0:00 PA-20-185 1R01CA284315-01 1 R01 CA 284315 1 "GREENBERG, WILLIAM A" 7/8/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 6405059 "CHANG, JENNY C-N" Not Applicable 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 644191 NCI 398880 245311 ABSTRACTMetaplastic breast cancer (MpBC) is a rare subset accounting for <5% of all breast cancers. MpBC is a significanthealth challenge as it exhibits the most dismal prognosis of all breast cancer subtypes worse than non-MpBCtriple-negative breast cancer (TNBC) with median survival rate of 8 months or less in patients with metastaticdisease. Due to a lack of druggable targets the main therapeutic option for metastatic MpBC remains systemicchemotherapy despite known resistance to most cytotoxic drugs. One common molecular alteration in MpBC ishyperactivation of the phosphoinositide 3-kinase and protein kinase B (PI3K/AKT) pathway. Additionally wepublished that MpBC also displays a gain-of-function oncogenic mutation in ribosomal protein L39 (RPL39)which is responsible for treatment resistance stem cell self-renewal and lung metastasis. The mechanisticfunction of RPL39 is mediated through inducible nitric oxide synthase (iNOS)-mediated nitric oxide production.In a recently published clinical trial targeting this nitric oxide synthase (NOS) pathway with a pan-NOS inhibitorNG-methyl-L-arginine acetate (L-NMMA) high efficacy in chemorefractory TNBC patients was demonstrated.Furthermore in vivo studies performed showed a significant reduction in tumor growth associated with asignificant increase in apoptosis after the alpelisib/L-NMMA combinatorial regimen. Therefore we hypothesizethat the NOS and PI3K signaling pathways may exert their oncogenic responses synergistically topromote aggressive tumor growth. To test this hypothesis Specific Aim 1 seeks to demonstrate thetherapeutic efficacy of simultaneous inhibition of NOS and PI3K pathways with chemotherapy in MpBC pre-clinical models on primary tumor growth and metastasis. Specific Aim 2 will investigate the global and RPL39-specific ribosome translation landscape in response to NOS/PI3K inhibition in MpBC. In Specific Aim 3 the cell-cell interactions among tumor cells myeloid cells lymphoid cells and stromal cells within the tumormicroenvironment and their role in supporting cancer niche populations will be evaluated at the single-cell levelusing spatial transcriptomics immunofluorescence CyTOF imaging systems and a multi-modal data analysismodel. This study thus proposes a mechanistic investigation of a combinatorial targeted approach against thetwo key pathways in MpBC identifies cellcell interactions and develops unique crosstalk models that willeffectively predict outcome and treatment response and complement our recently funded U01 clinical trial onMpBC patients. 644191 +No NIH Category available 3-Dimensional;Adopted;Alginates;Allogenic;Architecture;Autologous;B lymphoid malignancy;Biocompatible Materials;Blood;CAR T cell therapy;CD28 gene;CD3 Antigens;CXCL10 gene;Cell Count;Cell Differentiation process;Cell Proliferation;Cell physiology;Cells;Cellular biology;Chemicals;Circulation;Clinical;Consumption;Data;Devices;Disease;Disease Progression;Dose;Dose Limiting;Drug Delivery Systems;Encapsulated;Engineering;Engraftment;Ensure;Generations;Goals;Hematopoietic Neoplasms;Immune;Implant;In Situ;In Vitro;Interleukin-2;Interleukins;Kinetics;Liquid substance;Longevity;Lymphocyte;Malignant Neoplasms;Measures;Mediating;Medical;Modeling;Patients;Phenotype;Procedures;Process;Production;Public Health;Publishing;Recurrent tumor;Resistance;Retroviral Vector;Signal Transduction;Solid;Solid Neoplasm;Specialist;Stream;Stress Tests;T-Cell Activation;T-Lymphocyte;Technology;Therapeutic;Time;Translating;Viral;Viral Vector;Work;biomaterial compatibility;bioscaffold;cellular transduction;chemokine;chimeric antigen receptor;chimeric antigen receptor T cells;clinically relevant;cost;engineered T cells;fighting;graft vs host disease;high reward;high risk;immunogenicity;improved;in vivo;innovation;leukemia/lymphoma;manufacture;manufacturing facility;manufacturing process;mechanical properties;mouse model;particle;patient population;prevent;procedure cost;programs;recruit;response;scaffold;success;tumor Biomaterial Scaffolds for In Vivo CAR T Cell Manufacture RELEVANCE TO PUBLIC HEALTHCAR-T cell therapy reprograms a patients own immune cells to identify and destroy tumors with precision trans-lating to revolutionary new treatment paradigm for certain blood cancers. Unfortunately CAR-T cell therapy isenormously expensive (~$500000 per dose) and has a slow manufacturing process and enormous regulatoryhurdles for facilities that manufacture CAR-T cells. We will develop a technology to manufacture CAR-T cellswithin a patient's own body to dramatically cut costs and increase patient access. NCI 10739094 6/14/23 0:00 PAR-22-091 1R21CA277018-01A1 1 R21 CA 277018 1 A1 "SALOMON, RACHELLE" 6/1/23 0:00 5/31/25 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 11876861 "BRUDNO, YEVGENY " Not Applicable 2 ENGINEERING (ALL TYPES) 42092122 U3NVH931QJJ3 42092122 U3NVH931QJJ3; XRPPWZ3TK937 US 35.784675 -78.677233 578204 NORTH CAROLINA STATE UNIVERSITY RALEIGH RALEIGH NC BIOMED ENGR/COL ENGR/ENGR STA 276957514 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 172076 NCI 116875 55201 PROJECT SUMMARYCAR-T cell therapy has revolutionized the treatment of liquid tumors including leukemia and lymphoma andhold enormous promise for treatment of solid cancers as well. However despite their unprecedented clinicalsuccess widespread utilization of this therapy is hampered by the lengthy and labor-intensive manufacturingprocedures. CAR-T cell manufacturing is both laborious and time-consuming results in very high costs of therapy(~$500000). The long manufacturing time creates delays of weeks or months to infuse CAR-T cells to patientswith rapidly progressing disease. Extensive ex vivo cell manipulation creates cell products with heterogeneouscomposition and terminal differentiation that limit CAR-T cell engraftment and persistence. Effort to overcomethese limitations have focused on closed and automatic manufacturing devices to contain the labor needed tomanufacture CAR-T cells ex vivo and allogeneic off-the-shelf CAR-T cells have been proposed to overcome theneed of CAR-T cell manufacturing for each single patient. These technologies are promising but reducing thetime costs and regulatory burden of manufacturing or eliminating ex vivo procedures entirely remains a criticalunmet need. In vivo generation of autologous CAR-T cells would eliminate the ex vivo procedures prevent theterminal differentiation of ex vivo expanded CAR-T cells and ensure the potency and longevity of autologous Tcells as compared to allogeneic CAR-T cell products that are extensively manipulated to prevent rejection andgraft-versus-host disease. This proposal outlines the first steps in a highly innovative high-risk/high-reward effortto develop bioinstructive biomaterials scaffolds that generate CAR-T cells entirely within the patient and produceCAR-T cells with improved efficacy and persistence. Our endeavor is built on significant published and prelimi-nary data demonstrating that our biomaterial scaffolds already efficiently activate and mediate CAR-T cell trans-duction in vitro and efficiently recruit and release CAR-T cells in vivo and reduce CAR-T manufacturing timesfrom weeks to a single day. We propose that biocompatible alginate biomaterial scaffolds can be modified toencapsulate T cell-attracting chemokines to recruit T cells to the scaffold. After recruitment the biomaterial scaf-folds will provide CD3/CD28 signaling to activate the T cells. After activation T cell-specific viral particles eitheralready present in the biomaterial or administered to the biomaterial as a separate step will transduce the T cellsgenerating tumor-specific CAR-T cells in situ in manner compatible with irradiative lymphodepletion. Finallyinterleukin signaling in the scaffold will expand and promote release of formed CAR-T cells for systemic efficacy.This approach could have enormous clinical impact by significantly reducing therapy costs and dramaticallyexpanding the patient population benefiting from CAR-T-cell therapy. We expect that these studies will providea foundational technology for CAR-T cells manufacturing and promote widespread patient access. In addition tothe clear application in cancer however this rational materials-based approach for cellular manufacturing couldbe adopted to program therapeutic lymphocytes in solid tumors and for other diseases. 172076 +No NIH Category available Achievement;Address;Adjuvant Chemotherapy;Affect;Aftercare;Award;Biological Assay;Bladder;Bladder Neoplasm;CD8-Positive T-Lymphocytes;CD8B1 gene;Chemical Engineering;Cisplatin;Clinical;Clinical Trials;Clinical Trials Design;Complement;Comprehensive Cancer Center;Cystectomy;Data;Data Analyses;Disease;Doctor of Philosophy;Ensure;Environment;Excision;FOXP3 gene;Future;Gene Expression Profile;Genes;Goals;Grant;Immune;Immune checkpoint inhibitor;In complete remission;Individual;Institution;Investigation;Investments;Knowledge;Leadership;Malignant Neoplasms;Measures;Medical Oncology;Mentors;Mentorship;Methods;Modernization;Molecular Analysis;Muscle;Neoadjuvant Therapy;Ohio;Outcome;Pathologic;Patient Selection;Patient-Focused Outcomes;Patients;Performance;Perioperative;Phase II Clinical Trials;Physicians;Preclinical Testing;Proteins;Proteomics;Radical Cystectomy;Regimen;Regulatory T-Lymphocyte;Research;Residual Neoplasm;Resources;Sampling;Scientist;Specimen;Stromal Cells;Systemic Therapy;T cell infiltration;Techniques;Time;Tissue Sample;Tissue-Specific Gene Expression;Tissues;Training;Transitional Cell Carcinoma;Treatment Protocols;Tumor-infiltrating immune cells;Universities;Urethra;Urogenital Cancer;Writing;biomarker development;biomarker driven;biomarker performance;biomarker validation;career development;chemotherapy;clinical training;cohort;design;differential expression;experience;gemcitabine;high dimensionality;immune cell infiltrate;improved;improved outcome;multiple omics;novel;overtreatment;phase II trial;preclinical study;predictive marker;prevent;prospective;protein expression;rational design;research and development;responders and non-responders;response;response biomarker;skills;standard of care;therapy resistant;transcriptomics;translational physician;translational scientist;treatment response;treatment stratification;tumor;tumor immunology;tumor microenvironment Characterizing the immune infiltrate in muscle-invasive urothelial carcinoma Project NarrativeUrothelial carcinoma is understudied despite being the 6th most common cancer in the US. Outcomes forlocalized muscle-invasive urothelial carcinoma are unsatisfactory with the current standard of care ofneoadjuvant chemotherapy followed by radical cystectomy. This project will characterize the immune infiltratebefore and after neoadjuvant therapy and will develop predictive biomarkers to ultimately design novel moreeffective personalized regimens to improve survival. NCI 10738992 7/3/23 0:00 PA-20-203 1K08CA277016-01A1 1 K08 CA 277016 1 A1 "BIAN, YANSONG" 7/4/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 16595515 "COLLIER, KATHARINE A." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 273561 NCI 253297 20264 Project SummaryUrothelial carcinoma is a common aggressive morbid and understudied disease. Many patients are not curedwith the current standard of care for localized muscle-invasive urothelial carcinoma which is neoadjuvantcombination cisplatin-based chemotherapy followed by radical cystectomy. But overall survival is significantlylonger in patients who obtain a pathologic complete response to neoadjuvant chemotherapy suggesting thatintensification of systemic therapy will improve survival. It is critical that we develop reliable predictive biomarkersthat can select patients that will or will not have a complete pathologic response to receive respectively eitherchemotherapy or an intensified peri-operative regimen. Preliminary evidence in urothelial carcinoma and othercancers suggests that infiltrating immune cells play a role in treatment response but this has not been rigorouslystudied in muscle-invasive urothelial carcinoma. In this study we will interrogate pre- and post-treatmentsamples from a completed pivotal phase II clinical trial harnessing our expertise in spatial transcriptomics andproteomics to interrogate differential gene and protein expression in tumor immune and stromal cells inannotated tissue specimens before and after neoadjuvant chemotherapy with or without a checkpoint inhibitor.Specifically we will evaluate baseline CD8:FOXP3 ratio and responses to therapy (Aim 1) determine the effectof neoadjuvant therapy on CD8:FOXP3 ratio (Aim 2) and leverage the full capacity of spatialtranscriptomic/proteomic assays to develop and evaluate the performance of novel predictive biomarkers ofresponse to neoadjuvant therapy (Aim 3). This study will result in predictive biomarkers while concurrentlyprofiling the immune infiltrate composition and how it is influenced by treatment. The ultimate goal is to designrational combination or sequential peri-operative regimens for biomarker-driven clinical trials to improve patientsurvival and cure rates. The project will provide the candidate Katharine Collier MD MSc MSE MS withtraining in rigorous quantitative methods cutting-edge spatial molecular analyses and high-dimensionalbiomarker development. The proposal capitalizes on Dr. Colliers quantitative background in ChemicalEngineering clinical training in Medical Oncology and formal training in clinical trial design while providing anopportunity to gain additional skills and knowledge in multi-omics techniques and data analyses preclinicalstudies leadership presentations and grant writing. Dr. Collier is committed long-term to improving outcomesfor patients with genitourinary cancers as a translational physician-scientist. Dr. Collier will be supported by anexperienced mentorship team (Amir Mortazavi MD Zihai Li MD PhD Daniel Stover MD Steven Clinton MDPhD) skilled collaborators the rich academic environment of the Ohio State University Comprehensive CancerCenter and an invested institution committed to providing protected time and resources for career developmentand research. This award will ensure Dr. Colliers successful transition to independence as a physician-scientistand translational researcher improving outcomes for patients with genitourinary cancers. 273561 +No NIH Category available Address;Adult;Age;American;Anxiety;Appearance;Award;Biopsy;Birth;Breast;Breast Cancer Detection;Breast Cancer Risk Factor;Callback;Caring;Chest Mass;Clinic;Cohort Studies;Collaborations;Communities;Complement;Consensus;Coupled;Data;Databases;Decision Making;Dedications;Detection;Development;Electronics;Equity;Estrogens;Exposure to;Face;Faculty;Focus Groups;Foundations;Funding;Future;Gender;Gender Identity;Goals;Health;Health Personnel;Healthcare Systems;Hormonal;Image;Incidence;Individual;Inferior;Institution;Interview;Knowledge;Lesbian Gay Bisexual Transgender Queer;Lesion;Literature;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Ultrasonography;Mammographic screening;Mammography;Mass in breast;Mediating;Medical;Mental Health;Mentors;Mentorship;Methods;Minority Groups;Modeling;Operative Surgical Procedures;Participant;Pathology;Perception;Persons;Population;Practice Guidelines;Process;Prospective cohort;Provider;Qualitative Methods;Radiology Specialty;Registries;Reporting;Research;Research Design;Research Proposals;Risk;Risk Factors;Role;Scientist;Screening for cancer;Sensitivity and Specificity;Stage at Diagnosis;Stigmatization;Suggestion;Surgeon;Surveys;Testosterone;Time;Tissues;Training;Training and Education;United States National Institutes of Health;Woman;Work;assigned female at birth;assigned male at birth;breast imaging;cancer care;cancer health disparity;career;cis-female;cis-male;cisgender;cohort;design;evidence base;experience;gender affirming hormone therapy;health belief;improved;innovation;insight;lifetime risk;malignant breast neoplasm;men;novel;participant interview;prevent;process improvement;programs;prospective;psychologic;psychosocial;recruit;routine screening;screening;screening guidelines;screening program;sex;sex assigned at birth;skills;social;system-level barriers;transgender;transgender men;transgender women Understanding Breast Cancer Risk and Screening in Transgender Persons through a Pilot Breast Cancer Screening Program PROJECT NARRATIVEThis application addresses a critical gap in the literature by providing critical foundational data to extend ourknowledge of breast cancer (BC) risk among transgender (TG) individuals and begin to inform TG BC screeningguidelines. This project will also extend the applicants knowledge skills and experience supporting a successfulcareer as a surgeonscientist. Next steps include an R01 application to develop a multi-institutional longitudinalTG breast cancer screening program to definitively establish lifetime risk and incidence of BC developmentprovide evidence-based BC screening guidelines for TG persons and address eliminating barriers to BCscreening access and delivery for TG persons. NCI 10738974 7/20/23 0:00 PA-20-203 1K08CA276706-01A1 1 K08 CA 276706 1 A1 "BIAN, YANSONG" 7/20/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 78429321 "CORTINA, CHANDLER SCOTT" Not Applicable 4 SURGERY 937639060 E8VWJXMMUQ67 937639060 E8VWJXMMUQ67 US 43.04575 -88.020374 46001 MEDICAL COLLEGE OF WISCONSIN MILWAUKEE WI SCHOOLS OF MEDICINE 532263548 UNITED STATES N 7/20/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 210324 NCI 196330 13994 PROJECT SUMMARY/ABSTRACTIn the U.S. an estimated 1.4 million people identify as transgender (TG) defined as a person whose gender isdifferent than their sex assigned at birth and are a designated minority population by the NIH (NOT-MD-19-001).Many TG persons take gender-affirming hormone therapy usually estrogen or testosterone based to alter theirphysical appearance and improve their psychological health. Lifetime exposure to estrogen is a well-establishedrisk factor for breast cancer (BC). Despite a growing TG population the risk of developing BC in TG persons isunclear and there is no consensus on how to ideally screen this undeserved population for BC. These knowledgegaps prevent informed decision-making among healthcare providers and TG persons likely contributing to thecancer disparities observed in the TG community. The overarching goal of my research agenda is to developevidence-based TG BC screening guidelines. The proposed K08 will begin to fill critical knowledge gaps. Incollaboration with our LGBTQ+ Inclusion Health Clinic we will establish a pilot BC screening program and utilizea mixed methods approach to explore BC risk and screening in this population. These data will provide thenecessary foundation to develop a multi-institutional longitudinal TG BC screening cohort study which will informthe development of BC screening guidelines and best practices for BC screening within the TG community. Thefoundational K08 work will be accomplished through three specific aims: 1) determine the callback and biopsyrates of TG persons after screening mammography and automated breast ultrasonography 2) assessperceptions towards BC risk screening and the screening experience of TG individuals through surveys andinterviews and 3) identify individual and systems-level barriers to BC screening for TG persons and methods tooptimize the screening process through interviews and focus groups. These findings will provide the first-everprospective scientific data on screening mammography and automated breast ultrasonography lesion detectionin TG persons. The qualitative data from Aims 2 and 3 will identify individual and systems-level barriers toscreening and opportunities to improve the screening process and experience. The research proposal iscomplemented by a comprehensive and distinctive training plan focused on mixed methods and survey researchgender studies database development and cohort recruitment and retention. In combination with my diverseand collaborative mentorship team this study and training plan is designed to optimize my seamless transitionto becoming an independently funded surgeonscientist and my efforts to mitigate BC disparities in TG personsthrough a 3-step process. The novel pilot BC screening study (Step 1) will provide the necessary preliminarydata and experience to submit an R01 application to develop a multi-institutional longitudinal TG BC screeningprogram (Step 2) which will definitively establish the lifetime risk and incidence of BC to inform the developmentof evidence-based BC screening guidelines for TG persons and best practice guidelines (Step 3). 210324 +No NIH Category available Address;Agonist;Apoptosis;Arachidonic Acids;Astrocytes;Binding;Biological Assay;Brain;Cancer Patient;Cells;Cephalic;Cessation of life;Clinic;Clinical;Coculture Techniques;Coin;Complex;Data;Disseminated Malignant Neoplasm;Distal;E-Cadherin;Epithelium;Experimental Models;Fatty Acids;Fatty acid glycerol esters;Gene Expression Profiling;Genes;Genetic;Goals;Growth;In Vitro;Incidence;Individual;Invaded;Kinetics;Location;Malignant Neoplasms;Malignant neoplasm of brain;Mass Spectrum Analysis;Mediator;Melanoma Cell;Mesenchymal;Metastatic Melanoma;Metastatic malignant neoplasm to brain;Modeling;Neoplasm Metastasis;Neuroglia;Neurons;Oleic Acids;Organ;PPAR gamma;Pathway interactions;Patients;Peroxisome Proliferator-Activated Receptors;Phenotype;Primary Neoplasm;Process;Production;Proliferating;Recurrent Malignant Neoplasm;Relapse;Reporter;Research;Response Elements;Role;Sampling;Signal Transduction;Site;Soil;Stains;Stromal Cells;Systemic Therapy;Techniques;Testing;Time;Unsaturated Fatty Acids;Xenograft procedure;aldehyde dehydrogenases;antagonist;astrogliosis;beta catenin;brain cell;cancer cell;cancer recurrence;cell motility;cell type;design;effective therapy;experimental study;in vitro Model;in vivo;insight;intravital microscopy;melanoma;metastatic process;migration;mouse model;novel;novel therapeutic intervention;pharmacologic;pre-clinical;promoter;receptor;small molecule inhibitor;spatiotemporal;therapeutic target;therapy resistant Understanding PPARgamma signaling in melanoma brain metastasis Project NarrativeMany individuals develop cancers. The brain is one of the common organs for cancer recurrence. Unfortunatelycancer brain metastasis is increasingly becoming a significant clinical problem due to its rising incidence andlimited efficacy of existing systemic therapies. Metastasis is the consequence of favorable interactions betweenthe invaded cancer cells and the microenvironment in the distal organ. To cancer cells the brain has the mostunique microenvironment since almost all the cells in the brain do not exist in any other organs. Thus thisproposal is designed to study crosstalks between cancer cells and brain stromal cells. If we can identify keychanges in this process we can better target brain metastatic cancer cells in order to eradicate them and providemore effective therapies for cancer patients. NCI 10738816 11/13/23 0:00 PA-19-056 5R01CA241490-05 5 R01 CA 241490 5 "SNYDERWINE, ELIZABETH G" 12/1/19 0:00 11/30/24 0:00 Tumor Microenvironment Study Section[TME] 10943112 "CHEN, QING " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 366709 NCI 209696 157013 Project SummaryMetastasis the spread of cancer from primary tumor site to distal organs is the cause of over 80% of deathsfrom cancer. The brain is one of the common metastasis locations. Brain metastasis which develops in the latecourse of illness has become a significant problem in clinic due to its rising incidence as a consequence ofprolonged survival and limited efficacy of existing systemic therapies. Metastasis is a multi-step process thatrequires the complex interplay between cancer cells and the stromal cells a process commonly referred to asseed and soil hypothesis coined over a century ago. The soil the microenvironment not only decides theoutgrowth of metastatic cancer cells but also contributes to therapy resistance. The seed the invaded cancercells directly modifies the surrounding brain stromal cells. Our long-term goal is to dissect the complexinteractions between cancer cells and brain stromal cells during metastasis.We have developed novel in vivo and in vitro models to address the gaps in our understanding of brainmicroenvironmental control of metastatic outgrowth. Our data implicate that astrocytes the unique and mostabundant brain cells activate PPAR signaling in brain metastatic melanoma cells. Through an integrativeapproach using in vitro co-culture assays and in vivo brain metastatic mouse models Aim 1 will delineate therole of PPAR pathway in melanoma cells during brain metastasis. We will track the dynamic changes and effectof PPAR signaling in melanoma cells throughout the whole brain metastatic process. Moreover PPARantagonist will be used in our pre-clinical mouse models to test its potential to treat melanoma brain metastasis.Aim 2 will address how astrocytes activate PPAR signaling in the invades melanoma cells. We hypothesizethat astrocytes serve as donor of unsaturated fatty acids natural agonist of PPAR to the invaded melanomacells. The gained insights may enable us to mechanistically deconstruct melanoma brain metastasis and developnew treatment strategies for patients with little clinical recourse. 366709 +No NIH Category available Advanced Malignant Neoplasm;Affect;Antibodies;Binding;Blocking Antibodies;Cancer Patient;Cell surface;Cells;Clinical;Cytotoxic Chemotherapy;DNA Repair;Data;Future;Human;Immune;Immune Targeting;Immune response;Immunotherapy;In Vitro;Interleukin-12;Knowledge;Ligation;Malignant Neoplasms;Mediating;Membrane;Metabolism;Mus;Myelogenous;Myeloid Cells;New Agents;Outcome;PD-1 blockade;Patients;Phase;Physicians;Production;Recycling;Research;Resistance;Signal Pathway;Signal Transduction;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic Agents;Therapeutic Effect;Translating;Up-Regulation;anti-tumor immune response;cancer cell;cancer survival;cancer therapy;chemotherapy;clinical application;cytokine;design;effector T cell;exhaustion;extracellular;immune checkpoint;immune checkpoint blockade;improved;in vivo;multicatalytic endopeptidase complex;neoplastic cell;novel therapeutic intervention;novel therapeutics;programmed cell death ligand 1;programmed cell death protein 1;receptor;response;synergism;targeted agent;targeted treatment;therapeutic evaluation;tool;tumor;tumor metabolism Targeting dual functions of PD-L1 for cancer therapy NarrativeLow responses rate to immune checkpoint blockade cancer therapy prompted us to find newstrategy to efficiently target therapeutic molecules on cancer cells and immune cells. We recentlydiscovered a new antibody H1A to PD-L1 that is expressed by both cancer cells and immunecells. We found H1A antibody induced PD-L1 depletion in cancer cells to make cancer cells moresensitive to chemotherapy and in immune cells to generate strong antitumor immune responses.Our proposed studies will address the synergistic effects of H1A with chemotherapy to overcomecancer resistance to chemotherapy and immunotherapy. The new knowledge and tools producedby our proposed studies will help physicians to treat cancer patients with appropriate combinationthat would not benefit patients clinical outcomes. NCI 10738807 11/21/23 0:00 PA-19-056 5R01CA256927-04 5 R01 CA 256927 4 "HU, ZHANG-ZHI" 12/1/20 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 8656827 "DONG, HAIDONG " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 327341 NCI 205875 121466 AbstractTargeting immune checkpoint signaling with blocking antibodies has reached a limitation in the treatment ofadvanced cancers. Although antibodies that bind programmed death ligand 1 (PD-L1) are effective in blockingPD-L1's extracellular interaction with PD-1 receptor on T cells the potential adaptive upregulation of PD-L1 andits recycling from intracellular compartment to the cell surface may compromise their efficacy. Importantly thediscovery of PD-L1's intracellular functions in cancer cells to promote thier survival and metabolismalso highlighta mechanism by which tumor cells can gain resistance to cytotoxic therapy andcall for a new strategy to targetPD-L1.There is therefore a critical need to design test and translate new agents that cansimultaneously inhibitPD-L1's extracellular and intracellular functions.This application will utilize a new PD-L1 antibody (clone H1A)that can reduce the expression of PD-L1 in tumor cells through disrupting the association of PD-L1 with CMTM6(a molecule that can stabilize PD-L1 recycling and expression) and subsequently directing PD-L1 for degradation.H1A-induced degradation of PD-L1 may not only disrupt PD-1/PD-L1 interactions due to the loss of PD-L1 thusremoving PD-1's suppressive signals in T cells but also disrupt PD-L1's cell-intrinsic functions within tumor cellsand myeloid cells thereby decreasing tumor resistance to chemotherapy and releasing the immune-stimulatoryfunction of myeloid cells. Thus H1A antibody may be a good candidate for targeting the dual functions of PD-L1for cancer therapy. Based on preliminary data the central hypothesis of this proposal is that intracellular signalingthrough PD-L1 results in tumor resistance to cytotoxic chemotherapy and limits the immune-stimulatory functionof myeloid cells. Thus targeted agents that result in degradation of PD-L1 and elimination of its intracellularsignaling ability represent a novel therapeutic strategy that will both synergize with chemotherapy and improvethe immune response. This hypothesis will be tested by pursuing two specific aims: (1) Determine how H1Aantibody synergizes with chemotherapy to overcome tumor resistance; (2) Determine how H1A antibodypromotes an enhanced T cell response to attack tumors. To further assess the future clinical use of H1A antibodya fully humanized version of H1A and humanized PD-1 and PD-L1 mice have been produced which will allowfor evaluation of the therapeutic effects of H1A either alone or in combination with chemotherapy and explorationof H1A's new mechanism of action in vivo. The overall impact of the proposed research is high because it willprovide a new therapeutic agent that is capable of targeting the dual functions of PD-L1 resulting in improvedefficacy of cytotoxic chemotherapy and an enhanced immune response. This strategy represents a significantparadigm shift within the field in terms of how to target immune checkpoint molecules like PD-L1 for future clinicalapplications. 327341 +No NIH Category available Antioxidants;Apoptosis;CRISPR screen;Cell Death;Communities;Complement;Data;Development;Genetic;Genetic Transcription;Goals;Heart Injuries;Human;Immune system;Iron;Link;Lipid Peroxidation;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Medical;Mutate;Mutation;Normal tissue morphology;Outcome;Pathway interactions;Publications;Radiation therapy;Radiobiology;Resistance;Role;Testing;Translating;Translations;Tumor Biology;Tumor Suppression;cancer therapy;comparative;effectiveness evaluation;inhibitor;innovation;lung cancer cell;mouse model;mutant;novel;novel therapeutic intervention;pre-clinical;radiation resistance;radiation-induced lung injury;radioresistant;refractory cancer;response;therapeutically effective;tumor;tumor growth Targeting ferroptosis in radioresistance in lung cancer: mechanisms and preclinical translation Project Narrative Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by excessive lipidperoxidation. The objectives of this application are to determine the mechanisms by which ferroptosis inactivationcontributes to radioresistance in KEAP1-mutant lung cancer cells and to assess the combination of radiotherapyand ferroptosis inducers in treating KEAP-mutant lung cancers. Our proposed studies will have a significantimpact on both our understanding of the fundamental mechanisms of ferroptosis and radiation biology and ourability to target ferroptosis-related radioresistance in cancer treatment. NCI 10738755 11/15/23 0:00 PA-19-056 5R01CA247992-04 5 R01 CA 247992 4 "PRASANNA, PAT G" 12/7/20 0:00 11/30/25 0:00 Radiation Therapeutics and Biology Study Section[RTB] 9939858 "GAN, BOYI " Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 353973 NCI 218502 135471 Project Summary Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by excessive lipidperoxidation. Previous studies by us and others identified ferroptosis as a natural tumor suppression mechanismand showed that ferroptosis inactivation like apoptosis inactivation contributes to tumor development. Recentlywe and others also showed that radiotherapy (RT) can potently induce ferroptosis and suggested that ferroptosisinducers (FINs) can be used in RT to overcome radioresistance. However the underlying mechanisms offerroptosis in radioresistance and the exact cancer or genetic contexts in which to target ferroptosis in RT stillremain largely unexplored. This application aims to determine the mechanisms by which ferroptosis inactivationcontributes to radioresistance in KEAP1-mutant lung cancer cells and to assess the combination of RT and FINsin treating KEAP1-mutant lung cancers. KEAP1 is commonly mutated in lung cancer and KEAP1-mutant lungcancers are resistant to RT. KEAP1 mutation or deficiency in lung cancer stabilizes NRF2 and promotes anNRF2-mediated antioxidant response. Our recent publication and new preliminary data support our centralhypotheses that (i) KEAP1 deficiency promotes radioresistance largely through inhibiting ferroptosis and KEAP1regulates ferroptosis through NRF2 transcriptional targets SLC7A11 and other unidentified downstream targets;and (ii) combining RT and FINs that inactivate SLC7A11 (or other potential ferroptosis inhibitors identified fromour studies) is an effective therapeutic strategy to overcome radioresistance in KEAP1-mutant lung cancerswithout causing significant damage in normal tissues. To test our hypotheses we will pursue the followingspecific aims: Specific Aim 1: To determine the mechanisms by which KEAP1 regulates ferroptosis andradioresistance in lung cancer cells. Specific Aim 2. To determine the effectiveness of combining FINs with RTfor treating KEAP1-mutant lung cancer. Our proposed studies are expected to identify novel mechanisms offerroptosis and radioresistance and to identify effective new therapeutic strategies to overcome radioresistancein lung cancer treatment. Our proposed studies will have a significant impact on both our understanding of thefundamental mechanisms of ferroptosis and radiation biology and our ability to target ferroptosis-relatedradioresistance in cancer treatment. 353973 +No NIH Category available Ablation;Acceleration;Affect;Alleles;Animals;Antibodies;Antigen Presentation;Antigen-Presenting Cells;Autoantigens;Biological Assay;Bone Marrow Transplantation;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Cancer Etiology;Cancer Model;Chimerism;Cloning;Code;Complex;Defect;Dendritic Cells;Detection;Embryo;Enrollment;Epithelium;Ethylnitrosourea;Failure;Frequencies;Generations;Genes;Genetic;Genome;Genome Stability;Genotype;Germ-Line Mutation;Histocompatibility;Histocompatibility Antigens Class I;Histocompatibility Antigens Class II;Homozygote;House mice;Human;Hyperplasia;Immune;Immune response;Immune system;Immunologics;Inbred Mouse;Inbred Strain;Individual;Induced Mutation;Knockout Mice;MHC Class I Genes;MHC Class II Genes;Malignant Neoplasms;Maps;Measures;Mediating;Meiosis;Melanoma Cell;Minor;Missense Mutation;Mus;Mutagenesis;Mutagens;Mutant Strains Mice;Mutate;Mutation;Myelogenous;Nitrosourea Compounds;Nuclear;Nutritional;Patients;Peptides;Phenotype;Point Mutation;Population;Productivity;Proteins;RNA Splicing;Reaction;Regulatory T-Lymphocyte;Resistance;Safety;Screening for cancer;Site;Skin graft;T cell therapy;T-Lymphocyte;Testing;Therapeutic;Thymus Gland;Transcript;Translating;Tumor Volume;Vascularization;Work;anti-PD1 antibodies;autosome;cancer genome;cancer therapy;cancer transplantation;causal variant;central tolerance;clinical application;functional mimics;genetic pedigree;humanized mouse;interest;male;melanoma;mutant;neoantigens;neoplastic cell;nonsynonymous mutation;novel;novel strategies;prevent;refractory cancer;repository;resistance allele;resistance mechanism;resistance mutation;screening;stem;subcutaneous;synergism;targeted cancer therapy;therapeutic development;translational applications;translational study;tumor;tumor growth Cancer Resistant Mice PROJECT NARRATIVEUsing random germline mutagenesis and tumor growth screening in mice we have identified several mutationsthat confer cancer resistance. We now focus on understanding mechanisms of resistance in mice with two ofthese mutations advancing our work to the point of translational application. We will also extend mutagenesisand screening to identify still more cancer resistance mutations and mechanistically analyze those that operateby effects on the immune system. NCI 10738747 11/14/23 0:00 PA-20-185 5R01CA258602-03 5 R01 CA 258602 3 "ZAMISCH, MONICA" 12/1/21 0:00 11/30/26 0:00 Cancer Genetics Study Section[CG] 1969455 "BEUTLER, BRUCE A" Not Applicable 30 GENETICS 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 612519 NCI 373487 239032 PROJECT SUMMARYCan germline mutations cause strong resistance to otherwise lethal cancers? Certain germline genotypes mightbe poorly supportive of tumor vascularization nutritional demands or resistance to immune attack yetcompatible with host survival. Of particular interest some mutations might abet the host response to neo-antigens or even to self-antigens highly expressed in syngeneic tumors. The identification of resistancemutations could provide new approaches and targets for cancer therapy. At least in human populationsresistance mutations would be very difficult to identify. Human germline genetic variability stem variability amongcancer genomes and the high frequency of humans who never develop cancer throughout their lives wouldmake mapping novel human resistance alleles all but impossible. In mice finding such mutations is much easier.Syngeneic tumor lines (with relatively stable genomes) exist for many inbred strains of Mus musculus. The inbredmice themselves have a defined germline reference sequence. Each individual is homozygous at nearly all lociand almost genetically identical to all others. Over the past several years we took advantage of this situation toidentify genes in which mutations confer cancer resistance. Using the random germline mutagen ENU wecreated third generation (G3) germline mutant mice (C57BL/6J strain). A total of 23751 third-generation (G3)mice from 561 pedigrees bearing a total of 32039 non-synonymous coding/splicing changes were enrolled intoa screen in which each mouse was injected subcutaneously with 2e5 B16F10 melanoma cells and anti-PD-1antibody was administered on days 5 8 and 11. Tumor volume was measured on days 13 and 20. The G1 malefounder of each pedigree was sequenced to identify all non-synonymous coding/splicing mutations induced bymutagenesis and all G3 descendants were genotyped at all induced mutation sites in advance of screening.Automated meiotic mapping allowed quick detection of even subtle phenotypes and assignment to causativemutations. This screen yielded several mutations causing resistance to transplantable cancers. 14.2% saturationof the autosomal genome was achieved in screening (fraction of autosomal genes with severely damaging ordestructive alleles tested in the homozygous state three times or more). Therefore much remains undiscovered.From what we know already there is a realistic chance of translating genetic discoveries from this screen tohuman cancer therapy. This proposal aims to extend screening for cancer resistance and to further advancemechanistic and translational studies of two resistance mutations each in a gene with a human orthologuetesting synergy between therapeutic approaches built around each protein target and laying groundwork forclinical applications. 612519 +No NIH Category available Antibodies;Binding;Biological Markers;Cell membrane;Cholesterol;Classification;Clinical;Clinical Data;Clinical Research;Clinical Trials;Combined Modality Therapy;Copy Number Polymorphism;Cytotoxic Chemotherapy;Data;Disease Progression;Dose;Drug Kinetics;Drug resistance;ERBB2 gene;Endocytosis;Exhibits;Fluorine;Foundations;Future;Goals;Heterogeneity;Human;Image;Incidence;Investigation;Label;Lovastatin;Lutetium;Malignant Neoplasms;Mediating;Medical Records;Membrane;Methods;Modeling;Molecular;Mus;Mutation;Organoids;Patient Selection;Patients;Pharmaceutical Preparations;Pharmacodynamics;Population;Positron-Emission Tomography;Protein Overexpression;Proteins;Radiation Dose Unit;Radiation therapy;Radiolabeled;Radionuclide therapy;Randomized;Resistance;Resistance development;Saline;Sampling;Site;Stains;Structure;Surface;Survival Analysis;Testing;Therapeutic;Therapeutic antibodies;Time;Tissues;Translations;Trastuzumab;Treatment Efficacy;Validation;Xenograft procedure;Zirconium;cancer cell;caveolin 1;clinical imaging;clinical translation;dosimetry;drug sensitivity;gastroesophageal cancer;humanized antibody;improved;molecular imaging;neoplastic cell;non-invasive imaging;novel;patient response;pharmacologic;pre-clinical;preclinical study;prevent;protein expression;radioligand;receptor;receptor internalization;resistance mechanism;response;targeted imaging;therapy resistant;treatment response;tumor;uptake;young man Improving radiolabeled imaging and targeting of HER2 positive EG cancers using lovastatin PROJECT NARRATIVEThis proposal seeks to validate caveolin-1 as a complementary biomarker of HER2 and to determine sensitivity orresistance of the tumor-targeting anti-HER2 antibody trastuzumab when administrated in combination with thecommon cholesterol-depleting drug lovastatin in the treatment of esophagogastric cancer. Retrospective clinicaland preclinical analyses will be performed using patient HER2+ tumor samples and patient-derived EG xenograftstreated with statin alone trastuzumab alone or the combination of the two. The long-term goal will be to informfuture therapeutic strategies that can prevent or delay the emergence of trastuzumab resistance. NCI 10738727 11/1/23 0:00 PA-19-056 5R01CA244233-04 5 R01 CA 244233 4 "WU, YICONG" 12/1/20 0:00 11/30/25 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 7614079 "LEWIS, JASON S." "JANJIGIAN, YELENA Y" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 626130 NCI 353746 272384 PROJECT SUMMARY/ABSTRACTThe incidence of esophagogastric (EG) cancer is increasing rapidly notably among young men. In patients clinicallyclassified as HER2-positive (ERBB2 amplification and/or 2+/3+ protein overexpression) the combination of thetherapeutic anti-HER2 antibody trastuzumab and standard cytotoxic therapy prolongs progression-free and overallsurvival. However intrinsic tumor resistance or mechanisms of resistance developed during treatment limit theclinical benefit in 32% of patients and other anti-HER2 therapeutic antibodies failed in clinical trials to treat EGcancer. Complementary biomarkers and methods are therefore needed to treat such patients. Guided by preclinicaldata suggesting that caveolin-1 (CAV1) the main protein of cholesterol-rich invaginations of the plasma membrane reduces trastuzumab binding to HER2-positive EG tumors we initiated retrospective clinical analyses to validateCAV1 as a complementary biomarker of HER2. Remarkably Kaplan-Meier survival analyses demonstrated thatHER2+ EG tumors expressing high CAV1 (IHC 2+/3+) had worse overall survival than those expressing low CAV1(IHC 0/+1) after trastuzumab therapy. These promising preliminary results prompted us to pharmacologicallydeplete CAV1 (which is present in cholesterol membrane domains) with lovastatin a cholesterol-depleting drug.Here we will perform retrospective analyses of patients with HER2-positive EG tumors to assess HER2 expressionand heterogeneity ERBB2 amplification CAV1 staining and the presence of genetic alterations (copy numbervariations) associated with trastuzumab resistance. We will analyze medical records to determine if concurrentstatin use is associated with enhanced response to trastuzumab. In addition to retrospective analyses we willperform randomized imaging and therapeutic preclinical studies using patient-derived EG xenografts (PDXs)representing HER2+/CAV1High and HER2+/CAV1Low tumor populations. We will determine the molecular imagingprofile (89Zr-Trastuzumab PET) and therapeutic efficacy in PDXs treated with (1) control saline (2) trastuzumabalone (3) lovastatin alone or (4) the combination of trastuzumab with lovastatin to identify molecular features thatconfer drug sensitivity and resistance to this promising investigational combination. Aim 1 will validate CAV1 as acomplementary biomarker to HER2 Aim 2 will determine the potential dosimetric impact of the statins on clinicalimaging and identify EG tumor populations that benefit from the trastuzumab/lovastatin combination and Aim 3 willvalidate the use of a statin as a new pharmacologic approach to HER2-targeted imaging and systemic radionuclidetherapy (endoradiotherapy) capable of reducing off-target radiation doses. All three aims will generate importantnew preclinical data on the use of statins to improve trastuzumab efficacy which should provide an excellentfoundation for many future investigations including clinical translation of trastuzumab/statin combination therapyand potential broader application to other HER2+ cancers. The long-term translational objectives are to establishthe foundation for a clinical trial combining statin with trastuzumab to prevent or delay the emergence of drugresistance in patients with HER2+ EG cancer. 626130 +No NIH Category available Address;Adoption;Adult;Age;Breast Cancer Detection;Cancer Control;Cancer Etiology;Caring;Cellular Phone;Cervical Cancer Screening;Colonoscopy;Colorectal Cancer;Country;Development;Diagnostic;Dissemination and Implementation;Early Diagnosis;Effectiveness;Electronic Health Record;Evidence based intervention;Family;Feedback;Funding;Gastroenterologist;Goals;Health Personnel;Health system;Healthcare;Healthcare Systems;Hybrids;Incidence;Institution;Integrated Health Care Systems;Interruption;Intervention;Interview;Knowledge;Link;Local Government;Malignant Neoplasms;Maps;Measures;Medical Care Team;Methods;Mexican;Mexico;Modeling;Morbidity - disease rate;Patient Education;Patients;Population;Process;Public Health;Records;Research;Research Project Grants;Resource-limited setting;Resources;Risk;Scientific Advances and Accomplishments;Screening for cancer;Series;Specialist;Standardization;Telephone;Testing;Texas;Text Messaging;Time;Training;Woman;arm;colorectal cancer screening;cost;cost effective;cost effectiveness;design;economic cost;economic evaluation;effectiveness evaluation;effectiveness outcome;effectiveness/implementation study;evidence base;implementation design;implementation facilitators;implementation outcomes;implementation research;implementation science;implementation strategy;improved;incremental cost;member;men;microcosting;mortality;organizational readiness;patient navigation;patient screening;primary care clinician;programs;prospective;relative cost;research study;retiree;screening;screening guidelines;screening program;testing uptake;virtual Research Project 1 n/a NCI 10738712 9/20/23 0:00 RFA-CA-22-019 1U54CA284109-01 1 U54 CA 284109 1 9/20/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8260 12335396 "LAJOUS, MARTIN " Not Applicable 18 Unavailable 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX Domestic Higher Education 770305400 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Research Centers 2023 399613 358007 41606 PROJECT SUMMARYColorectal cancer (CRC) is exerting a significant public health impact in Mexico despite the availability ofeffective screening strategies. Yet there are no national CRC screening (CRCS) guidelines or organized CRCSprograms in Mexico. We aim to implement a CRCS program in an integrated health system that is context-appropriate sustainable scalable and easily transferable to different health systems in Mexico. We willoptimize FIT uptake and CRCS completion by adapting and evaluating evidence-based interventions (EBIs)(patient education patient reminders patient navigation); designing implementation strategies (training withtechnical assistance practice champions audit and feedback) to deliver these EBIs; and evaluating theeffectiveness cost-effectiveness and implementation outcomes using a type 2 hybrid effectivenessimplementation study. Our proposed research is potentially groundbreaking and of substantial public healthsignificance in that it will be the first implementation research study in Mexico to address CRCS while applyingrigorous implementation science methods. It will advance scientific knowledge on the effectiveness of EBIs thathave been developed and tested in other countries and adapted for use in Mexico; it will also study the impactof implementation strategies to deliver them in a real-world setting. Our proposed study will incorporate aneconomic evaluation of the implementation of the EBIs to provide healthcare institutions with the necessaryinformation to plan for adoption and sustainability in settings with different resources. +No NIH Category available Active Learning;Address;Adoption;American;Cancer Burden;Cancer Control;Cancer Control Research Program;Caribbean region;Collaborations;Competence;Coupled;Development;Educational workshop;Fostering;Funding;Generations;Goals;Health Policy;Implementation readiness;Institution;Interview;Investments;Language;Latin America;Latin American;Latina;Leadership;Malignant Neoplasms;Measurement;Mentors;Mentorship;Methods;Mexican;Mexican Americans;Mexico;Modeling;Morbidity - disease rate;Output;Participant;Peer Review Grants;Public Health;Publishing;Readiness;Research;Research Design;Research Personnel;Resources;Scientist;Statistical Methods;Training;Training Activity;Training Programs;Training Support;Writing;cancer prevention;career;career development;certificate program;clinical practice;cohort;collaborative environment;evidence base;health care service organization;health inequalities;implementation research;implementation science;implementation strategy;improved;innovation;interest;leadership development;low and middle-income countries;meetings;member;mortality;multimodality;novel;oral communication;organizational readiness;programs;skills;symposium;systematic review;tool;training opportunity Research Capacity Building Core n/a NCI 10738711 9/20/23 0:00 RFA-CA-22-019 1U54CA284109-01 1 U54 CA 284109 1 9/20/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8259 2401885 "FERNANDEZ, MARIA EULALIA" Not Applicable 18 Unavailable 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX Domestic Higher Education 770305400 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Research Centers 2023 226113 184506 41607 The LISTOS Research Capacity Building Core (RCBC) will accomplish the followingaims: (1) develop a two-tiered training and mentoring program to build implementationresearch capacity for cancer control in Mexico and Latin America; (2) establish threeimplementation science (IS) capacity-building units (training & resources implementationstrategies and methods & measurement) to coordinate and support the training and mentoringprogram; and (3) create an implementation research pilot program for cancer control in Mexicoand Latin America. In accomplishing these aims the RCBC will address key gaps that have plagued capacitybuilding efforts for cancer control implementation research in LMIC settings. This core willtarget gaps in capacity building through enhanced mentoring coaching and technicalassistance; provide novel and innovative methods of developing the capacity of investigators inMexico and Latin America specific to their needs; conduct trainings and develop tools inSpanish to overcome language barriers; and establish a pilot program to expand the impact ofRCBC efforts. The three functional units of the RCBC will include investigators from all partnerinstitutions fostering a collaborative environment that allows for two-way dialogue betweenlocal practitioners and healthcare organization partners in Mexico and Latina American andbetween Mexican (INSP INCan) and US-based IS partners (UTHealth UCSF). Innovative capacity building strategies will be supported through the RCBC includingestablishing Project ECHO programs in Mexico and supporting participation by localinvestigators in D&I certificate programs. Key outputs of RCBC activities will include theadaptation of and training LISTOS partners on key implementation research tools.Implementation research tools and training will be made available to investigators in LISTOSnetworks in Mexico and Latin America as well as to members of the U54 Global CancerConsortium. RCBC efforts will build the capacity of a cadre of outstanding young investigatorsfrom Mexico and Latin America to conduct cancer IS research and address cancer related healthinequities in Latin America. +No NIH Category available Accountability;Address;Area;California;Cancer Control;Collaborations;Communication;Community Health;Complement;Complex;Decision Making;Disparity;Ensure;Equity;Goals;Health Sciences;Health system;Infrastructure;Institution;Intervention;Knowledge;Laboratories;Latin America;Latin American;Lead;Leadership;Learning;Malignant Neoplasms;Mentorship;Mexican;Mexican Americans;Mexico;Mission;National Cancer Institute;Pilot Projects;Policy Maker;Process;Public Health;Readiness;Research;Research Activity;Research Project Grants;Research Support;Resources;Role;San Francisco;Strategic Planning;Texas;United States;Universities;Vertebral column;Work;cancer care;cohesion;community engagement;experience;health organization;implementation science;insight;low and middle-income countries;operation;success Administrative and Engagement Core n/a NCI 10738710 9/20/23 0:00 RFA-CA-22-019 1U54CA284109-01 1 U54 CA 284109 1 9/20/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8258 2401885 "FERNANDEZ, MARIA EULALIA" Not Applicable 18 Unavailable 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX Domestic Higher Education 770305400 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Research Centers 2023 198208 156601 41607 ABSTRACT AECThe Administrative and Engagement Core (AEC) of LISTOSsupportfor Cancer Control seeks toadministrative communication and engagement activities across all Center functions.The AEC will function as a cross-functional matrixed organization that will include staff andcapabilities distributed across INCan INSP and UTHealth. Center cohesion relational andcollaborative capacity strong community engagement and effective project management are allimportant areas of focus for the AEC. The AEC will carry out its work through two functionalunits: the Administrative Unit and the Communications & Engagement Unit. Through theAdministrative Unit the AEC will provide coordination and project management support to allCenter activities. Through the Communications & Engagement Unit the AEC will provideeffective internal and external communications support and support a dynamic engagementstrategy that includes supporting a Center External Advisory Panel Implementation co-Laboratories and stakeholder engagement retreats. +No NIH Category available Acceleration;Address;Adoption;Cancer Burden;Cancer Control;Collaborations;Communication;Consolidated Framework for Implementation Research;Country;Development;Diagnosis;Disparity population;Dissemination and Implementation;Effectiveness;Ensure;Equity;Evidence based intervention;Funding;Generations;Goals;Health Services Accessibility;Health system;Healthcare Systems;Implementation readiness;Income;Infrastructure;Institution;Interactive Systems Framework;Intervention;Language;Latin America;Latin American;Lead;Leadership;Learning;Malignant Neoplasms;Maps;Measurement;Measures;Mentors;Mentorship;Methodology;Methods;Mexico;Modeling;Motivation;National Cancer Institute;Pathway interactions;Persons;Population;Population Heterogeneity;Primary Care;Problem-Based Learning;Public Health;Readiness;Research;Research Personnel;Research Project Grants;Research Support;Resources;Science;Scientist;Screening for cancer;System;Testing;Training;Training Activity;Uninsured;Work;base;breast cancer diagnosis;career;colorectal cancer screening;design;evidence base;experience;follow-up;health inequalities;implementation research;implementation science;implementation strategy;improved;innovation;integrated care;low and middle-income countries;malignant breast neoplasm;next generation;organizational readiness;personalized approach;programs;public health insurance;rapid diagnosis;research study;scale up;theories;tool;uptake LISTOS for Cancer Control - Leveraging Implementation Science To Optimize Strategies for Cancer Control LISTOS NarrativeOur proposed project LISTOSOcancerMexicofor Cancer Control - L everaging I mplementation S cience T optimize S trategies for Cancer Control will increase capacity for implementation science forcontrol in Mexico and Latin America. The project proposes to establish a new center inand carry out two cancer control implementation science research projects: 1)Implementing colorectal cancer screening in publicly funded health systems in Mexico and2) Implementation of integrated care for rapid diagnosis of breast cancer in Mexico. Theresearch projects and capacity building activities have the potential not only to advance thescience of cancer control implementation but most importantly to reduce the burden of cancerin Mexico and Latin America. NCI 10738709 9/20/23 0:00 RFA-CA-22-019 1U54CA284109-01 1 U54 CA 284109 1 "VEDHAM, VIDYA" 9/20/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 2401885 "FERNANDEZ, MARIA EULALIA" "LAJOUS, MARTIN ; UNGER, KARLA " 18 PSYCHOLOGY 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF PUBLIC HEALTH 770305400 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 397 Research Centers 2023 997335 NCI 830909 166426 ABSTRACT Populations in Mexico and Latin America experience substantial cancer-related healthinequities compared to those in high-income countries. Poor implementation of evidence-based cancercontrol interventions (EBIs) is in part to blame. We propose to establish a new Center: LeveragingImplementation Science To Optimize Strategies (LISTOS) for Cancer Control to advanceglobal implementation science (IS) in cancer control in Mexico and Latin America. Through tworesearch studies that address critical cancer control needs and two cores (Administrative and ResearchCapacity Building) the LISTOS Center will: 1) build organizational readiness for implementation ofcancer control EBIs in Mexico; and 2) build readiness for implementation research through capacitybuilding training and mentorship. The LISTOS Center has two content-related subthemescorresponding to the two primary ways that cancer control EBIs can be optimized: 1) adapting EBIsand implementation strategies to improve fit with the diverse populations and settings in Mexico; and2) developing implementation strategies to improve and accelerate EBI adoption integration scale-upand sustainment in Mexico. These subthemes are integrated across the research projects and cores. The Administrative and Engagement Core will provide leadership; offer administrativesupport coordination communication and engagement activities; and lead dissemination efforts.Leveraging substantial IS training experience existing programs and a strong and diverse team ofinvestigators mentors and partners the Research Capacity Building Core will support a range ofactivities to train the next generation of IS leaders throughout Latin America. The LISTOS center coreswill support two innovative research studies that will increase the reach effectiveness andsustainment of cancer early detection in health care systems that serve disadvantaged populations inMexico using innovative and scalable implementation strategies. These studies aim to: 1) increase theadoption implementation and sustainment of CRCS EBIs in a public insurance healthcare system; and2) integrate breast cancer rapid diagnosis pathways across health services available for the uninsured.The Center utilizes innovative and tailored approaches that will enable a new generation of LMIC-basedresearchers to conduct research that will accelerate and improve the use of effective and scalable cancercontrol EBIs. The aims will both advance the science of implementation in LMICs (measurementadaptation and strategy development) and create a sustainable infrastructure that will enablecontinued contributions to the field for years to come. 997335 +No NIH Category available Targeting NADPH Oxidase for Pancreatic Cancer Prevention and Therapy PROJECT NARRATIVEPancreatic cancer risk factors including pancreatitis and obesogenic high-fat diet conspire with mutant KRASto promote PDAC with high penetrance; however the underlying mechanism remains elusive. The objective ofthis proposal is to determine if NADPH oxidase is a critical mediator in this context. For this purpose we willemploy novel genetically engineered mouse models expressing pancreatic acinar cell-specific endogenouslevels of KRASG12D with or without a critical component of the NADPH oxidase docking subunit p22phhox in thecontext of these risk factors. Successful completion of this project will provide new insights into preventive andtherapeutic strategies against this extraordinarily lethal disease in humans. NCI 10738675 2/10/23 0:00 PA-21-268 7R01CA240818-04 7 R01 CA 240818 4 "SALNIKOW, KONSTANTIN" 8/1/20 0:00 8/31/25 0:00 Cancer Prevention Study Section[CPSS] 12288148 "LU, WEIQIN " Not Applicable 16 NONE 132051285 C1DEGMMKC7W7 132051285 C1DEGMMKC7W7 US 31.770518 -106.504149 578405 UNIVERSITY OF TEXAS EL PASO EL PASO TX SCHOOLS OF PHARMACY 799680001 UNITED STATES N 10/1/22 0:00 8/31/23 0:00 396 Non-SBIR/STTR 2022 344109 NCI 224175 119934 Pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming the second leading cause of cancer-relateddeaths in the U.S. The genetic landscape of PDAC shows prevalent mutations of KRAS; however expressionof mutant KRAS (KRASmt) alone at the adult stage is insufficient to drive PDAC suggesting that a second hit isrequired. KRASmt was previously regarded as an oncogene and thought to be fully active yet recent studieshave shown that an endogenous level of KRASmt is not fully active. Rather it can be hyperactivated by pancreaticcancer risk factors including pancreatitis and obesogenic high-fat diet challenge which act as the second hit topromote PDAC with high penetrance. However the molecular mediator linking these risk factors to KRASmthyperactivation remains elusive. NADPH oxidases (NOX) are major enzymes activated by KRASmt for thegeneration of reactive oxygen species and oxidative stress in cancer. Notably our preliminary data have shownthat inhibition of NOX suppresses KRASmt activation indicating that NOX is not only a downstream effector butalso a potential upstream regulator of KRASmt. Based on these observations we hypothesize that pancreaticcancer risk factors including pancreatitis and chronic high-fat diet consumption facilitate the formation of asustained NOX and KRASmt co-activation partnership which leads to full-blown PDAC. Targeted inhibition ofNOX breaks the partnership promoted by these risk factors thus hampering pancreatic tumorigenesis. To testthis hypothesis we will employ novel inducible genetically engineered mouse models expressing endogenouslevels of KRASG12D with ablation of NOX docking subunit p22phox in pancreatic acinar cells and expose the miceto inflammatory stimuli or obesogenic high-fat diet. Similarly mutant p53 also facilitates the NOX-KRASG12D co-activation partnership to promote aggressive PDAC. We will ablate p22phox in pancreatic acinar cells of themice expressing both KrasG12D/+ and p53R172H/+. The objective of this proposal is to determine if NOX is the bonafide critical molecular mediator linking these pancreatic cancer risk factors to KRASmt hyperactivation whichdrives pancreatic neoplastic progression a fundamental unanswered question in the pancreatic cancer field. Ifproven this study will delineate the molecular underpinnings and cellular events of the synergistic cooperationamong oncogenic KRAS NOX and pancreatic cancer risk factors and will provide insights into novel preventiveand therapeutic strategies against this devastating disease in humans. 344109 +No NIH Category available Age;Algorithms;Architecture;Automobile Driving;Behavior;Biological Assay;Biological Models;Birth Rate;Cancerous;Cause of Death;Cells;Cellular Morphology;Cessation of life;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Development;Developmental Gene;Disease;Distant;Ecosystem;Environment;Enzymes;Epithelium;Exhibits;Genes;Genetic Transcription;Genetically Engineered Mouse;Gland;Goals;Growth;Hybrids;Invaded;Keratin;Learning;Link;Literature;Longevity;Machine Learning;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Maps;Measurement;Modeling;Molecular;Morphogenesis;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Organ;Patient-Focused Outcomes;Patients;Periodicity;Pharmaceutical Preparations;Primary Neoplasm;Process;Proteins;Publishing;RNA;Regulator Genes;Resolution;Source;Structure;Systems Biology;Tail;Testing;Time;Tissues;United States;Veins;Vimentin;Weight;cancer cell;cancer site;candidate validation;cell type;computerized tools;differential expression;high dimensionality;high resolution imaging;in vivo;learning algorithm;malignant breast neoplasm;mammary epithelium;migration;neoplastic;new therapeutic target;patient derived xenograft model;prevent;programs;single cell sequencing;single-cell RNA sequencing;small hairpin RNA;small molecule;spatiotemporal;statistics;three dimensional cell culture;tool;transcriptome;transcriptomics;transfer learning;tumor;tumor progression Mapping the single cell state basis of metastasis in space and time Cancer is the second leading cause of death in the United States and 90% of deaths occur at metastatic stages.Metastasis requires the cancer cell to accomplish many distinct tasks as it moves through the body to form newtumors in distant organs. Our proposal seeks to identify systematically how a cancer cell's molecular toolkitchanges during metastasis with the goal of identifying new therapeutic targets to prevent metastasis and fortreating patients with metastatic disease. NCI 10738579 9/12/23 0:00 PAR-22-234 1U01CA284090-01 1 U01 CA 284090 1 "NADEAU, CHRISTINE FRANCES" 9/12/23 0:00 8/31/28 0:00 ZCA1-RTRB-4(M1) 9719315 "EWALD, ANDREW JOSEF" Not Applicable 7 ANATOMY/CELL BIOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/12/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 679564 NCI 415001 264563 We propose to leverage recent advances in machine learning and systems biology to enable highdimensional molecular assessment of the dynamic cell state transitions driving metastasis. We hypothesize thatthe interaction between a cancer cell's intrinsic reactivation of developmental programs with its spatiotemporalcontext determines its metastatic potential. We will exploit developmental changes in the mammary epitheliumto define their cell state basis and map the aberrant reuse of these transcriptional programs in metastatic disease. Both normal mammary epithelium and breast tumors undergo dramatic changes in differentiation andtissue architecture and loss of differentiation correlates with poor patient outcomes. We developed 3D cultureassays that recapitulate epithelial morphogenesis and cancer growth invasion and metastatic colony formation.The key concepts arising are that: (1) a conserved process of dedifferentiation and loss of polarity accompaniesboth normal and neoplastic morphogenesis and (2) the cancer cells in luminal and basal breast cancerrecapitulate basal epithelial and hybrid EMT programs. Recent advances in single cell sequencing spatialtranscriptomics and machine learning enable transcriptome-wide resolution of these states in tissue quantitativecomparison of normal and cancerous cell states and the identification of targetable cell state regulators.Aim 1: Map cell states in space and time during development tumor formation and metastasis. We willgenerate scRNA-seq data from normal glands ductal carcinoma in situ and invasive tumors collected at differentages and also longitudinally in 3D culture. We will use our CoGAPS algorithm to infer cell states and theirtemporal progression. We will then use our patternMarker2 statistic to identify cell state makers for MERSCOPEanalysis in tissue. We will map these states in normal glands primary tumors and metastases isolated fromgenetically engineered mouse models (GEMM) and patient derived xenografts (PDX).Aim 2: Model the dynamics of differentiation state during development and cancer progression. To definethe effect of cell state on metastatic progression we will construct an ecosystem-style multinomial diversitymodel. We will initialize the model with literature-based parameter values to predict the interactions between celltype and cell state. We will then extend the model to use the weights assigned by CoGAPS to each cell therebylinking gene regulatory programs to the cell state changes driving metastasis.Aim 3: Validate candidate regulators of metastatic cell state transitions in 3D culture and in vivo.To isolate the genes regulating metastasis we will use our transfer learning algorithm projectR to score eachcancer cell for its relative utilization of scRNA-seq-defined molecular programs. We will then use ourprojectionDriver statistic to identify differentially expressed (DE) genes at sites of cancer invasion relative to thetumor interior. DE genes will be tested genetically in 3D culture assays modeling invasion and colony formationand then in orthotopic and tail vein metastasis assays in vivo. 679564 +No NIH Category available Address;Animal Experiments;Animal Model;Animals;Antineoplastic Agents;Area;Behavior;Blood capillaries;Body Fluids;Brain;Brain Neoplasms;Camptothecin;Carmustine;Cells;Chemicals;Chemistry;Clinical;Clinical Trials;Combined Modality Therapy;Diagnosis;Diffuse;Diffusion;Disease;Distant;Drug Carriers;Drug Design;Drug Exposure;Drug Kinetics;Evaluation;Excision;Exhibits;Feedback;Foundations;Gel;Gliadel Wafers;Glioblastoma;Glioma;Goals;Histologic;Human;Hydrogels;Implant;In Vitro;Infiltration;Investigation;Laboratories;Location;Malignant - descriptor;Malignant Glioma;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Modeling;Molecular;Monitor;Morbidity - disease rate;Mus;Neoplasms;Newly Diagnosed;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Penetration;Pharmaceutical Preparations;Phase;Play;Primary Brain Neoplasms;Property;Radiation therapy;Recurrence;Recurrent disease;Recurrent tumor;Reproducibility of Results;Research Activity;Rodent;Rodent Model;Role;Safety;Series;Site;Surface;Surgically-Created Resection Cavity;Survival Rate;System;Technology;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Topotecan;Toxic effect;Translating;Translations;Tumor Tissue;Viscosity;Work;amphiphilicity;biomaterial compatibility;cancer cell;cancer type;chemotherapy;clinical development;clinical translation;combat;controlled release;critical period;cytotoxicity;design;drug release kinetics;drug release profile;effective therapy;experimental study;functional group;human disease;immunogenicity;implantation;improved;in vivo;irinotecan;millimeter;mortality;mouse model;nanofiber;novel;pre-clinical;rational design;residence;self assembly;side effect;technology platform;translational potential;treatment strategy;tumor Self-Assembling Camptothecin Nanofiber Hydrogels as Adjunct Therapy for Intraoperative Treatment of Malignant Glioma Project narrative (relevance)One of the greatest hurdles to prolonging survival in patients with malignant brain tumors is the inevitable tumorrecurrence in the vicinity of the original location or the resection cavities despite multimodal treatment includingsurgery radiotherapy and chemotherapy. We aim to develop a camptothecin drug amphiphile (DA)nanofiber hydrogel platform technology as adjunct therapy for intraoperative treatment of malignant braincancer that can eradicate infiltrated glioma cells by maintaining a therapeutic concentration within the brain whileminimizing systemic drug exposure. This goal will be achieved by evaluating and optimizing our current hydrogel-forming DA technology with in vitro ex vivo and in vivo brain tumor models well-established in our laboratoryand the results of our study will validate a new local treatment strategy to combat currently incurable braincancers with significant survival benefits and good tolerance. NCI 10738545 9/4/23 0:00 PAR-22-242 1R01CA284268-01 1 R01 CA 284268 1 "BEIER, HOPE THOMAS" 9/4/23 0:00 8/31/28 0:00 Drug and Biologic Therapeutic Delivery Study Section[DBTD] 10930335 "CUI, HONGGANG " "QUINONES-HINOJOSA, ALFREDO " 7 ENGINEERING (ALL TYPES) 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD BIOMED ENGR/COL ENGR/ENGR STA 212182680 UNITED STATES N 9/4/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 521070 NCI 400489 120581 Project summaryMalignant gliomas including the most common type glioblastoma (GBM) are histologically heterogeneous andinvasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodaltreatment including surgery radiotherapy and chemotherapy the disease inevitably recurs and proves fatal.Local application of carmustine implants (Gliadel wafers) as an adjunct to surgery and radiation therapy hasbeen clinically proven to extend the survival time for patients with malignant gliomas strongly suggesting thatlocal chemotherapy after tumor resection presents a feasible and effective strategy to treat brain tumorpatients. However the rapid depletion of carmustine and low tissue penetration greatly limit the clinical benefitsof Gliadel wafers which only extend the median survival of treated patients by six months compared to thoseuntreated. This proposal aims to develop a novel type of self-assembling nanofiber hydrogels that use theanticancer drug camptothecin (CPT) as the molecular building blocks and that can be locally administered to theresection cavities after tumor removal with the ultimate goal to achieve more effective treatments for patientsdiagnosed with malignant gliomas. We hypothesize that the proposed nanofiber hydrogels will spread acrosslarge tissue areas and sustainably release therapeutic agents for long-term cytotoxicity against glioma cells thusleading to significantly extended survival time in our rodent model. To test our hypothesis we outlined theproposed research activities in the three specific Aims seeking to address the three key challenges in localdelivery of therapeutic drugs into resection cavities: 1) the nanofiber gelation properties. The gel form enablesprolonged retention in the delivery sites and also minimizes capillary loss of free drugs that would otherwiseoccur; 2) the sustained release of free drugs over a long period of time. The release rate and period arecritical for effective elimination of glioma cells without causing devastating side effects; 3) diffusion across largetissue areas. In Aim 1 we will identify the key molecular parameters in the design of self-assembling CPT DAsto create CPT nanofibers of varying surface chemistries that would promote the formation of hydrogels uponcontact with body fluids. Aim 2 is focused on the evaluation and fine-tuning of the drug release rate andmechanism their ability to overcome the MDR mechanisms as well as diffusion distance within organotypictissues. In Aim 3 we will use an animal model to evaluate the nanofibers ability to diffuse across large tissueareas pharmacokinetics in vivo efficacy and toxicity of two already developed nanofiber hydrogels and alsothose to be developed in Aim 1 and Aim 2. Our ultimate goal is to develop a nanofiber hydrogel platformtechnology that will extend the survival time of rodents bearing human brain cancer and translate this platformto a pre-clinical approach. 521070 +No NIH Category available 1 year old;Acceleration;Acute;Acute Myelocytic Leukemia;Adolescent;Australia;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Complication;Country;Development;Diagnosis;Disease;Dose;Eligibility Determination;Enrollment;Ensure;Family;Foundations;Functional disorder;Generations;Goals;Hormonal;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Positioning Attribute;Productivity;Prognosis;Quality of life;Rare Diseases;Research;Research Personnel;Scientist;Second Primary Cancers;Site;Survival Rate;Survivors;Tissues;Translational Research;United States;Universities;Work;anticancer research;cancer diagnosis;cancer therapy;chemotherapy;childhood cancer survivor;clinical translation;design;experience;health related quality of life;high risk;improved;improved outcome;innovation;member;multidisciplinary;novel therapeutic intervention;operation;organizational structure;reproductive;small molecule;success;survivorship;translational study COG NCTN Network Group Operations Center - Year 9 Supplement: Additional Capitation to Support NCCAPS PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcomes for all children with cancer. NCI 10738458 1/12/23 0:00 PA-20-272 3U10CA180886-09S4 3 U10 CA 180886 9 S4 "MOONEY, MARGARET M" 3/1/01 0:00 2/28/23 0:00 10871228 "HAWKINS, DOUGLAS S." Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 314025 NCI 314025 0 C6;Reg-CV PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of the500000 survivors of childhood cancer (estimated as of 2020) experiencing a significant health related quality oflife complication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildrens Oncology Group (COG) the worlds largest organization devoted exclusively to childhood andadolescent cancer research was founded 20 years ago. The COGs multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading childrens hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institutes (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life for children with cancer and childhood cancer survivors. As more than90% of children diagnosed with cancer in the US are treated at COG member institutions COG has the abilityto offer a diverse population of children with cancer and their families the opportunity to participate in innovativeresearch. This research effort includes allowing for collection and annotation of biospecimens from all childrenwith cancer providing the foundation for discovery and accelerating the most promising research effortsconducted in laboratories around the world. The proposal is for support of the COG Network Operations Centerclinician-scientists who develop and conduct research and for member sites to participate through enrollment ofeligible subjects. 314025 +No NIH Category available Adult;Africa;African;Automobile Driving;Birth;Cancer Control;Caring;Cessation of life;Child;China;Chronic Hepatitis B;Clinic;Clinical;Communities;Community Developments;Community Health Aides;Consolidated Framework for Implementation Research;Country;Creativeness;Data;Decentralization;Dose;Elements;Engineering;Equity;Evaluation;Face;Guidelines;HBV Liver Cancer;Health Services;Hepatitis;Hepatitis B;Hepatitis B Infection;Hepatitis B Transmission;Hepatitis B Vaccines;Hepatitis B Virus;Home;Hospitals;Hour;Hybrids;Immunity;Immunization;Individual;Infant;Intervention;Liver diseases;Malignant neoplasm of liver;Measures;Medicine;Mothers;National Cancer Institute;Newborn Infant;Nigeria;Nigerian;Persons;Policies;Population;Pregnant Women;Prevention;Primary carcinoma of the liver cells;Printing;Protocols documentation;Randomized Controlled Trials;Recommendation;Records;Request for Applications;Research;Research Methodology;Research Project Grants;Risk;Services;Site;Time;Training;United States National Academy of Sciences;United States National Institutes of Health;Vaccination;Vaccines;Vertical Disease Transmission;chronic infection;cohort;community clinic;community engagement;concept mapping;crowdsourcing;effectiveness evaluation;effectiveness/implementation design;emerging adult;implementation outcomes;implementation process;implementation research;implementation science;implementation strategy;infant infection;innovation;low and middle-income countries;mathematical model;neonatal infection;post implementation;preference;primary outcome;secondary outcome;standard care;testing uptake;uptake;vaccine acceptance;vaccine delivery Research Project 2 n/a NCI 10738443 9/19/23 0:00 RFA-CA-22-019 1U54CA284110-01 1 U54 CA 284110 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8209 9545342 "IWELUNMOR, JULIET " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 Research Centers 2023 233768 168880 64888 Every hour over 150 people die of hepatitis-related liver diseases in African countries like Nigeria includinghepatocellular carcinoma (HCC) and other liver cancers. Much of this death is attributable to the hepatitis Bvirus (HBV). A hepatitis B birth dose (HepB-BD) vaccine initiated within 24 hours of birth followed by threeadditional pentavalent HBV vaccines (at six 10 and 14 weeks after birth) provide durable immunitysubstantially decreasing the risk of HBV and liver cancer. Nigerian national guidelines recommend HepB-BDvaccination for all newborns and provides them for free as part of the national immunization protocol yetuptake is suboptimal highlighting the need for implementation science research to develop locally relevantstrategies to increase HepB-BD vaccine uptake. We propose a crowdsourcing approach to enhance timelycoverage of HepB-BD vaccination in Nigeria. Crowdsourcing has a group of people solve all or part of aproblem then implement selected solutions. Our team used crowdsourcing to develop messages promotingHBV testing uptake inform global hepatitis guidelines and enhance hepatitis community engagement in lowand middle-income countries (LMICs). Our study will focus on developing and implementing strategies toincrease HepB-BD vaccination at community clinics home births and other sites outside of hospitals wheremost pregnant women receive care. The Consolidated Framework for Implementation Science Research(CFIR) and concept mapping will guide our evaluation of factors influencing uptake and sustainment.Our specific aims are: 1) To determine pregnant women's preferences on HepB-BD vaccination usingcommunity-engaged crowdsourcing research and finalize an implementation strategy to increase HepB-BDvaccination; 2) To determine the effectiveness of a finalized crowdsourced HepB-BD vaccination interventionamong a cohort of pregnant women using a community-based clinic-level cluster RCT. Trained communityhealth workers will implement the final intervention in a cluster randomized control trial of the crowdsourcedintervention versus standard care (i.e. printed guidelines) among a cohort of 720 dyads (pregnant women andnewborns) at 36 community-based clinics (n=1440); and 3) To use mixed methods research to determinemulti-level factors that influence uptake and sustainment of crowdsourced HepB-BD vaccination over time.Primary outcome is HepB-BD vaccination ascertained by clinic records. Secondary outcome is servicesustainment at the community-based clinic level defined here as the percent sustainment of core elements ofthe final campaign measured 12 months after the trial with sustained benefits and capacity for implementationat each community-based clinic. Our study is responsive to the U54 request for applications for globalimplementation science for equitable cancer control and and the strategic priorities of the National CancerInstitute. This study will provide a unique opportunity to expand HBV vaccine coverage driving equitableimplementation science research in settings traditionally under-represented in implementation science. +No NIH Category available 15 year old;Address;Affect;Africa;Area;Awareness;Behavior;Cancer Control;Characteristics;Charge;Climate;Clinical;Communities;Community Participation;Consolidated Framework for Implementation Research;Country;Data;Death Rate;Decentralization;Development;Dose;Effectiveness;Elements;Eligibility Determination;Equity;Evaluation;Evidence based intervention;Friends;Geography;Guidelines;HIV;Health;Health Services;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Hybrids;Improve Access;Incidence;Individual;Intervention;Leadership;Malignant Neoplasms;Medical Research;Mentorship;Methods;Modeling;Nigeria;Nigerian;Policies;Private Sector;Randomized Controlled Trials;Records;Research;Research Project Grants;Resources;Risk;Sampling;Services;Social support;Testing;Time;Training;Translations;Vaccination;Vaccines;Youth;aged;apprenticeship;cancer prevention;community based participatory research;community clinic;community setting;cost;crowdsourcing;effectiveness/implementation design;evidence base;experimental study;girls;implementation facilitators;implementation outcomes;implementation process;implementation science;implementation strategy;implementation/effectiveness;improved;innovation;policy recommendation;post implementation;preference;prevent;prevention service;primary outcome;programs;recruit;scale up;secondary outcome;self testing;skills;social;supportive environment;tool;treatment as usual;uptake;vaccine acceptance;vaccine access Research Project 1 n/a NCI 10738442 9/19/23 0:00 RFA-CA-22-019 1U54CA284110-01 1 U54 CA 284110 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8208 9545342 "IWELUNMOR, JULIET " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 Research Centers 2023 255473 183867 71606 1 Nigerians make up a significant proportion of individuals in Africa dying from human papillomavirus-(HPV) 2 associated cancers. However they do not access essential cancer prevention services such as evidence- 3 based HPV vaccination to prevent cancer. This is partly explained by barriers that are individual (low 4 awareness) social (insufficient social support) and structural (poor access to vaccines). Implementation of 5 HPV vaccine programs can mitigate some of these barriers by decentralizing vaccine access to reduce the 6 incidence and death rate of HPV-associated cancers. We propose to expand youth-friendly HPV vaccines 7 informed by a youth participatory action research framework (YPAR) the PEN-3 cultural model and the 8 Consolidated Framework for Implementation Science (CFIR). Unlike projects targeting youth as passive 9 recipients the YPAR considers youth to be partners in creating and leading solutions to problems that affect10 them. PEN-3 cultural model leverages local resources and partnerships from an equity mindset to improve11 health while CFIR enables an evaluation of the barriers and facilitators of implementation effectiveness. The12 proposed Innovative Tools to Expand youth-friendly Services and Translation of HPV services (I-TEST HPV)13 will draw on two participatory methods crowdsourcing (i.e. open calls and designathons) and apprenticeships14 to increase HPV vaccine uptake among girls aged 9-15 years old per national guidelines. We hypothesize that15 these two approaches (open challenges and apprenticeships) will increase the uptake of HPV vaccine16 campaigns in Nigeria. Using a hybrid type II effectiveness implementation design to simultaneously assess17 both clinical and implementation outcomes our aims are: 1) To use participatory approaches (crowdsourcing18 and apprenticeships) to develop new HPV vaccine campaigns; 2) To determine whether the final19 crowdsourced campaign increases HPV vaccination uptake among girls aged 9-15 years and evaluate20 intervention sustainment one-year post implementation. We will recruit 1120 girls from 32 communities to a21 stepped-wedge randomized control trial of the finalist campaign versus usual care. A total of sixty-four trained22 youth research facilitators from each setting (2 per setting) will implement the final HPV vaccination campaign.23 The primary outcome is the initial HPV dose vaccine uptake among girls ascertained by vaccination records at24 community clinics. The secondary outcomes include the second vaccine dose percent sustainment of core25 program elements with sustained benefits (uptake of HPV vaccines) and sustained capacity at participating26 communities at one year after the trial; and 3) To use mixed-methods to explore multilevel factors that27 influence the uptake of the HPV campaigns. This research aligns with the RFA-CA-11-019 request for research28 and the US Cancer Moonshot Initiative. The project builds on a strong relationship with the Nigerian Institute29 for Medical Research (NIMR) to implement a sustainable and scalable community-based model for equitable30 cancer control.31323334 . +No NIH Category available Adoption;Africa;Awareness;Cancer Burden;Cancer Control;Cancer Control Research;Cancer Science;Cancer Vaccines;Cervical;Cessation of life;Clinical;Collaborations;Communities;Country;Creativeness;E-learning;Equity;Evidence based intervention;Faculty;Fostering;Funding;Geography;Goals;Grant;Health;Healthcare;Hepatitis B Vaccines;Human Papilloma Virus Vaccine;Human Papillomavirus;Hybrids;Immunization;Individual;Institution;Institutionalization;Intervention;Lead;Malignant Neoplasms;Medical Research;Mentors;Mentorship;Methods;National Institute of Child Health and Human Development;Nigeria;Nigerian;Persons;Pilot Projects;Primary carcinoma of the liver cells;Research;Research Personnel;Research Support;Resources;Science;Series;Services;Site;Talents;Training;Travel;United States National Institutes of Health;Vaccines;Writing;Youth;anticancer research;apprenticeship;cancer type;cancer vaccination;career;cohort;community organizations;crowdsourcing;design;evidence base;experience;faculty mentor;implementation research;implementation science;improved;innovation;learning community;next generation;peer support;population health;prevent;programs;prototype;recruit;research to practice;skills;social;supportive environment;training opportunity;virtual Research and Capacity Building Core n/a NCI 10738441 9/19/23 0:00 RFA-CA-22-019 1U54CA284110-01 1 U54 CA 284110 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8207 9545342 "IWELUNMOR, JULIET " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 Research Centers 2023 358272 255845 102427 Nigeria Africas most populous country bears the second highest burden of cancer cases (11%) and deaths(12%) in Africa.1 Evidence-based cancer control interventions such as vaccines for cancer control exist but areunderutilized in Nigeria.23 To close this research-to-practice gap we propose a US-Nigerian Cancer ControlCenter for Research on Implementation Science and Equity (C3-RISE) capacity building core. The overallgoals are to increase the pipeline of early-career Nigerian-based investigators and practitioners who can leadIS research for equitable cancer control in Nigeria. We will use participatory implementation scienceapproaches10 (such as crowdsourcing11 and apprenticeships) to develop sustained capacity for implementationresearch at the Nigerian Institute of Medical Research. Crowdsourcing asks a group to solve a problem(through participatory activities such as open calls12 designathons13 or other activities) and then shares thesolutions with the public.14 Apprenticeships provide the practical skills direct mentorship and supportiveenvironment to increase the likelihood of launching successful IS interventions. In this capacity building corewe propose a series of in-person and online training opportunities in IS methods to spur innovative equitablecancer control research pilot studies. Each year open calls will be used to identify eight exceptional trainees(as part of two-person teams) from participating Nigerian-based institutions (including academic clinical andcommunity-based organizations). Each cohort will join a two-week residential training experience focused onIS for equitable cancer control. Trainees will also become part of a year-long virtual learning community andmentoring program designed to facilitate and sustain careers in the IS and cancer workforces. Trainee teamswill compete for small seed Pilot Partner grants to launch pilot plans of their final IS cancer pilots at communitysites. They will receive mentorship from established faculty mentors to carry out pilots focused on enhancingvaccines to prevent cancer (i.e. HPV and HBV vaccines). Our specific aims are: To identify and recruitNigerian trainees for the C3-RISE capacity building core ; 2) To develop IS research capacity building for equityin cancer control among trainees; and 3) To initiate sustain and evaluate a virtual participatory learningcommunity to facilitate access to curated resources and collaboration between geographically dispersedtrainees. Our strong focus on cultivating local Nigerian mentors and trainees will have an enduring impact oninstitutionalizing research mentorship and enhancing capacity for training at the organizational level. Our planaligns with Nigerian national NIH and strategic priorities related to building capacity for cancer research. +No NIH Category available Acceleration;Address;Adoption;Attention;Award;Cancer Control;Cancer Vaccines;Caring;Cervical cancer vaccine;Cessation of life;Clinical Services;Collaborations;Communication;Communities;Community Outreach;Country;Creativeness;Development;Educational workshop;Ensure;Environment;Equity;Ethics;Evaluation;Fostering;Foundations;Goals;Guidelines;Health;Health system;Hepatitis B Vaccines;Human Papilloma Virus Vaccine;Human Resources;Incidence;Individual;Infrastructure;Intervention;Logistics;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Medical Research;Methods;Modeling;Nigeria;Nigerian;North Carolina;Persons;Prevention;Process;Protocols documentation;Public Health;Research;Research Institute;Research Personnel;Resource-limited setting;Role;Societies;Surveys;Teleconferences;Testing;Training;Translational Research;Travel;United States National Institutes of Health;Universities;Vaccines;Visual impairment;World Health Organization;access disparities;community engagement;community involvement;community setting;cost;crowdsourcing;evidence base;health goals;implementation science;implementation strategy;improved;mortality;novel;operation;outreach;programs;response;success;symposium Administrative and Engagement Core n/a NCI 10738440 9/19/23 0:00 RFA-CA-22-019 1U54CA284110-01 1 U54 CA 284110 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8206 9545342 "IWELUNMOR, JULIET " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 198350 140048 58302 Nigeria is at a crossroads in its cancer control response. On the one hand the country remains an epicenter ofa growing cancer crisis. On the other hand there are existing guidelines (e.g. the National Cancer ControlPlan2 by the Nigerian Ministry of Health the Costing for Cervical Cancer Elimination in Nigeria by the WorldHealth Organization3 a Society-wide guideline for cervical cancer elimination4 and a recent National StrategicFramework on vaccines for cancer control).5 These have accelerated the tempo and created new opportunitiesto achieve the country's vision for reducing the incidence and mortality of cancer in Nigeria. As a result tosupport novel partnerships within and beyond traditional clinical services including in community settings andnon-health sector organizations we propose the US-Nigerian Cancer Control Center for Research onImplementation Science and Equity (C3-RISE) Administration and Engagement Core (AEC). Our overarchinggoal is to improve cancer control in Nigeria and exert a sustained impact on public health in partnership withkey stakeholders. Our proposed U54 Center brings together a transdisciplinary research team to meaningfullycollaborate with key stakeholders including individuals communities and local and state ministries of health.The U54 program will foster a Nigerian implementation science (IS) program to optimize the implementation ofvaccines for cancer control efforts in Nigeria. The AEC will be responsible for the overall administrationcoordination and management of the Center and communication with the NIH. It will foster collaborationbetween researchers and key stakeholders and provide critical infrastructure for equitable implementation ofevidence-based vaccines (i.e. human papillomavirus (HPV) vaccines for cervical cancer and hepatitis B (HepB)vaccines for liver cancer) for cancer control. We will also set a national and global standard for cutting-edgeparticipatory IS research approaches9 in a resource-constrained setting that accelerates the adoptionadaptation and sustainability of effective cancer control interventions in Nigeria. Our specific aims are: 1) Tocoordinate project management of the center wide-activities using agile methods; 2) To serve as a communityengagement hub for IS in Nigeria using crowdsourcing methods; and 3) To evaluate Center's milestones andoverall progress. By providing an infrastructure that facilitates Center-wide communications operationscommunity outreach and evaluation the AEC will serve as a central focal point to reinforce the overall vision ofreducing the incidence and mortality of cancer while advancing the role of IS for equitable cancer control inNigeria. +No NIH Category available Acceleration;Address;Adoption;Affect;Africa;Apical;Applications Grants;Attention;Award;Birth;Cancer Burden;Cancer Control;Cancer Vaccines;Cessation of life;Consolidated Framework for Implementation Research;Country;Coupled;Decentralization;Dose;Educational Activities;Environment;Equity;Evaluation;Evidence based intervention;Faculty;Goals;Grant;Guidelines;Health;Hepatitis B;Hepatitis B Vaccination;Hepatitis B Vaccines;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Incidence;Infrastructure;Institution;Intervention;Learning;Malignant Neoplasms;Malignant Vaginal Neoplasm;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of penis;Malignant neoplasm of vulva;Medical Research;Mentors;Mentorship;Mission;Modeling;Monitor;National Institute of Mental Health;Newborn Infant;Nigeria;Nigerian;North Carolina;Phase;Policies;Principal Investigator;Process;Productivity;Research;Research Personnel;Research Project Grants;Resource-limited setting;Resources;Science;Services;Students;System;Testing;Training;Training Programs;Translations;Travel;United States National Institutes of Health;Universities;Vaccination;Vaccines;Vision;aged;anticancer research;apprenticeship;cancer prevention;career;community based participatory research;community engagement;community setting;crowdsourcing;design;direct application;evidence base;girls;health equity;health inequalities;implementation evaluation;implementation facilitators;implementation outcomes;implementation science;implementation strategy;improved;innovation;low and middle-income countries;malignant mouth neoplasm;mortality;multidisciplinary;novel;outreach;prevent;public health relevance;research and development;research study;scale up;skills;success;symposium;tool;uptake;vaccine acceptance US-Nigerian Cancer Control Center for Research on Implementation Science and Equity (C3-RISE) PUBLIC HEALTH RELEVANCENigeria has a substantial burden of cancer that could be prevented through enhancing vaccination services.C3-RISE is a comprehensive implementation science partnership between the Nigerian Institute of MedicalResearch Saint Louis University and the University of North Carolina at Chapel Hill that open new horizons inequitable cancer control and builds sustainable capacity for high-quality implementation science to controlcancer using vaccines. This project will increase equity expand uptake and sustainment of evidence-basedvaccination services and develop a pipeline of Nigerian implementation science researchers for continuedsuccess. NCI 10738439 9/19/23 0:00 RFA-CA-22-019 1U54CA284110-01 1 U54 CA 284110 1 "VEDHAM, VIDYA" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 9545342 "IWELUNMOR, JULIET " "EZECHI, OLIVER CHUKWUJEKWU; TUCKER, JOSEPH DAVID" 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1045863 NCI 748640 297223 ABSTRACTNigeria has a substantial number of preventable cancer deaths each year. The human papillomavirus (HPV)vaccine and hepatitis B (HBV) vaccine are both evidence-based strategies to prevent cancer but they have notbeen widely scaled up in Nigeria. This suggests the need for innovative strategies that leverageimplementation science and tap the collective wisdom of Nigeria Africas most populous country. We proposethe US-Nigerian Cancer Control Center for Research on Implementation Science and Equity (C3-RISE). Ouroverall mission is two part: (a) use participatory implementation science strategies (i.e. crowdsourcing opencalls and apprenticeships) to expand uptake of HPV and HBV vaccines for cancer prevention; and (b) serve asa hub for equity and capacity building in implementation science to advance the understanding of interventionuptake and sustainment of evidence-based interventions to prevent cancer. This project brings together anexceptional group of multi-disciplinary researchers from the Nigerian Institute of Medical Research (the apexfederal health research organization similar to the US NIH) St. Louis University and the University of NorthCarolina at Chapel Hill. We propose the following aims: (1) To accelerate equitable cancer control bydeveloping testing and refining participatory implementation strategies to decentralize vaccines to preventcancer in community settings; (2) To enhance the scientific productivity of C3-RISE by providing overarchingoperational and scientific oversight; (3) To support innovative research and the development of scholarstrained to accelerate the uptake and sustainment of evidence-based cancer control interventions in Nigeria.These aims will be accomplished by a nurturing hub of two cores (Administrative Capacity Building) alongsidetwo research studies (Study 1 focused on HPV vaccination Study 2 on HBV vaccination). Our three partnerinstitutions launched a participatory implementation science project four years ago that directly informednational Nigerian health guidelines trained 231 students provided mentorship opportunities to 43 faculty andculminated in a WHO/TDR practical guide on crowdsourcing for health (UH3HD096929). This led to a recentlyawarded NCI R01 grant (R01-CA271033) that uses participatory implementation science to develop innovativestrategies to enhance HPV services in Nigeria. C3-RISE will leverage this momentum to catalyze cutting-edgecancer research training community engagement and policy translation. Our project will increase healthequity and it aligns with the Nigerian National Cancer Control Plan by focusing on participation capacitybuilding and sustainment. This U54 grant application directly responds to NIH NCI and NIMH strategicpriorities. 1045863 +No NIH Category available Address;Animal Model;Atlases;Biological Models;Biology;Bone Marrow;Cells;Clinical;Correlative Study;Cross Presentation;Data;Dendritic Cells;Development;Disease;Exclusion;Functional disorder;Genetic;Genomics;Goals;Human;Imaging Techniques;Immune;Immune checkpoint inhibitor;Immunity;Immunology;Immunotherapeutic agent;Immunotherapy;Impairment;Infiltration;Institution;Lead;Limes;Link;Location;Malignant Neoplasms;Malignant neoplasm of pancreas;Myeloid Cells;Myeloid-derived suppressor cells;Myelopoiesis;Nature;Neoplasm Metastasis;Organ;Pancreatic Ductal Adenocarcinoma;Patients;Phenotype;Primary Neoplasm;Prior Therapy;Process;Productivity;Prognosis;Publishing;Refractory;Reporting;Research;Sampling;Shapes;Site;Stromal Cells;T cell infiltration;T cell response;Testing;Tissue Banks;Tissue Model;Tissue Sample;Tumor Antigens;Tumor Biology;Tumor Immunity;checkpoint therapy;chemotherapy;conventional therapy;cytotoxic;density;human tissue;mouse model;multiple omics;programs;prospective;response;tumor;tumor microenvironment;tumor-immune system interactions The Impact of Metastatic Site On Dendritic Cell-Driven Tumor Immunity Project NarrativeWhile the majority of PDAC patients will develop metastatic disease the organ specific immunology and biologyof these metastatic lesions is poorly understood. These understandings are critical for the treatment of metastaticPDAC patients. This proposal will study the impact of metastatic disease on dendritic cells using human patientsamples and model systems. NCI 10738428 9/19/23 0:00 PAR-22-234 1U01CA284086-01 1 U01 CA 284086 1 "NADEAU, CHRISTINE FRANCES" 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-4(M1) 8710339 "DENARDO, DAVID G" "DING, LI ; FIELDS, RYAN C" 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 658369 NCI 437202 221167 Project Summary/AbstractThe prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately attempts atimmunotherapy for PDAC to date using single agents have not achieved significant clinical benefits. This is likelydue to the presence of a uniquely suppressive tumor microenvironment (TME). Our recent data suggest thatimmune priming by dendritic cells (cDCs) may ultimately a rate-liming barrier to productive anti-tumor immunity.While the focus of research in pancreatic cancer has been on the TME during primary disease we are onlynow realizing how significant the differences in the TME are between primary and metastatic disease and/ormetastatic lesions in different organs. These differences are critical as the majority of immunotherapeuticapproaches are being tested in refractory metastatic PDAC patients. We will address this shortcoming inunderstanding metastatic PDAC biology by determining the differential impact of metastatic disease site(s) onimmune priming by cDCs. cDCs are central for generating tumor antigen-specific T-cell responses. In animalmodels and human correlative studies cDCs are crucial for responsiveness to both cytotoxic and checkpointimmunotherapies. Our published data show that cDCs were severely dysfunctional in PDAC patients and thatthis dysfunction was driven by two distinct mechanisms. First we reported that PDAC patients had impaired cDCdevelopment in their bone marrow which led to a functional depletion of circulating pre-DCs impaired cross-presentationof tumor antigens and poor responses to checkpoint inhibitors. Even when DC development is notfully impaired we've shown cDCs are dysfunctional and excluded from the PDAC TME. Overall thesemechanisms impair the ability of conventional therapies to prime tumor antigen-specific T-cell responses andcheckpoint immunotherapy to drive efficacy. Together these data support our hypothesis that metastatic organsite-specific drivers lead to divergent effects on local and systemic tumor immunities. We will directlyaddress this hypothesis with the following aims:Aim 1. Determine the impacts of the site of metastatic disease on immune priming by cDCs.Aim 2. Determine the impacts of the site of metastatic disease on systemic immunity and cDCdevelopment.Aim 3. Determine how therapy differentially shapes the TME at different metastatic sites to impactimmune priming.Significance: These understandings are critical for the treatment of mPDAC patients. 658369 +No NIH Category available Adult;Alanine Transaminase;Alternative Splicing;Antineoplastic Agents;Astrocytoma;Automobile Driving;Binding;Binding Proteins;Bioinformatics;Biological Assay;Biology;Biophysics;Breast;Cancer Biology;Cell Line;Cell Proliferation;Cells;Cellular Stress;Chemistry;Childhood Glioma;Complex;Coupled;DNA Damage;Data;Disease;Dominant-Negative Mutation;Engineering;Event;Excision;Exons;Future;Generations;Genes;Genetically Engineered Mouse;Genome;Genotoxic Stress;Glioma;Goals;High-Throughput Nucleotide Sequencing;Human;In Vitro;Knowledge;Length;Lung;Lymphoma;MDM2 gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Mechanics;Mediating;Methodology;Methods;MicroRNAs;Modality;Modeling;Molecular;Mus;Mutation;Nuclear;Nuclear Protein;Nuclear RNA;Oligonucleotides;Oncogenic;Outcome;Ovary;Pathway interactions;Pharmacologic Substance;Phenotype;Play;Positioning Attribute;Primary Neoplasm;Property;Protein Isoforms;Proteins;Publishing;RNA;RNA Biochemistry;RNA Processing;RNA Sequences;RNA Splicing;RNA metabolism;RNA-Binding Proteins;Regulation;Regulatory Element;Repression;Research;Rhabdomyosarcoma;Role;Sampling;Stress;System;TP53 gene;Technology;Testing;Therapeutic;Therapeutic Intervention;Tumor Suppressor Proteins;Variant;Viral;Work;Xenograft procedure;cancer therapy;cancer type;cell growth;cell type;chemotherapeutic agent;combinatorial;design;drug discovery;exon skipping;genotoxicity;industry partner;liposarcoma;mRNA Precursor;mouse model;novel;novel therapeutic intervention;overexpression;prevent;response;therapy design;tumor;tumor progression;tumorigenesis;tumorigenic Mdm2 Alternative Splicing in DNA Damage and Cancer NARRATIVEMDM2 and its numerous isoforms are key regulators of the expression and function of the p53 gene a criticaltumor suppressor that prevents inappropriate cell growth and proliferation. The proposed research will study themolecular connection between DNA damage MDM2 isoform switching p53 and cancer. Unraveling thispathway could lead to the discovery of novel therapeutic intervention points and thus be a crucial stepping-stonefor cancer drug discovery. NCI 10738347 9/8/23 0:00 PA-20-185 3R01CA262873-03S1 3 R01 CA 262873 3 S1 "MAAS, STEFAN" 9/1/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7767900 "CHANDLER, DAWN S" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 65326 NCI 44866 20460 ABSTRACTTumor suppressor p53 is the quintessential guardian of the genome whose function is inhibited in greater than50% of all human cancers. Though mutation and deletion of p53 are major contributors to p53 inactivationoverexpression of the negative regulators MDM2 and MDM4 (MDMX) are also known to inactivate p53 thusleading to the cancer phenotype. Our lab has shown that specific types of cell stress initiate the generation ofan alternatively spliced isoform of MDM2. The predominant MDM2 alternative isoform MDM2-ALT1 alsoknown as MDM2-B functions to primarily activate the p53 pathway by inhibiting MDM2 and MDM4 in adominant negative fashion. Paradoxically this isoform is upregulated in several human cancers such aspediatric high-grade gliomas astrocytomas rhabdomyosarcomas (RMS) and liposarcomas as well as adultcancers such as lymphomas and those of the breast. Thus MDM2-ALT1 plays opposing roles in cancerprogression dependent upon the context of its expression. In the proposed research we will study theunderpinnings of the control of the p53 pathway by MDM2-ALT1 to better understand 1) the specificmechanism by which that MDM2-ALT1 is generated in cancer and 2) the ability of the resultant isoforms to betargeted using splice-switching oligonucleotides. We hypothesize that the expression of oncogenic MDM2-ALT1 is modulated by alterations in protein and RNA nuclear factors during the progression to tumorigenesisand can be targeted to induce splicing changes. We will use assays that identify and measure splice regulationin conjunction with gene editing approaches to identify RNA sequences and their respective nuclear factor-binding partners necessary for regulation of MDM2 splicing. Furthermore we will use novel geneticallyengineered mouse models as well as established mouse xenograft assays and novel splice switchingoligonucleotides (SSOs) to modulate MDM2 isoform levels. Our work will broaden our knowledge ofcombinatorial regulation of RNA processing in response to stress and in cancer and interrogate the utility ofMDM2 isoforms modulation for rational control of the p53 pathway. 65326 +No NIH Category available Acceleration;Alleles;BRAF gene;Biological;Biological Process;Cell Line;Cells;Cutaneous Melanoma;DNA;DNA Repair;DNA Sequence Alteration;DNA lesion;Data;Data Set;Development;Disease;Disease Progression;Dose;Etiology;Exposure to;Gene Mutation;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genome;Genomics;Genotoxic Stress;Growth;Human;Immunotherapeutic agent;Incidence;Individual;Intervention;Knowledge;Mediating;Melanins;Melanoma Cell;Metabolic;Modeling;Mus;Mutagenesis;Mutant Strains Mice;Mutation;Neonatal;Neoplasm Metastasis;Newborn Animals;Nucleotide Excision Repair;Oncogenes;Oxidation-Reduction;Pathology;Pathway interactions;Patient-Focused Outcomes;Pattern;Physiological;Physiological Processes;Pigmentation physiologic function;Pigments;Prevention strategy;Production;Prognosis;Recording of previous events;Relative Risks;Research;Residual state;Risk;Risk Factors;Role;Site;Skin;Skin Pigmentation;Sun Exposure;Sunburn;Sunlight;Sunscreening Agents;System;Testing;Transcription-Coupled Repair;UV Mutagenesis;UV Radiation Exposure;UV carcinogenesis;UV protection;UV response;Ultraviolet B Radiation;Ultraviolet Rays;Work;combat;exome sequencing;experimental study;human disease;immune cell infiltrate;improved;in vivo;irradiation;melanocyte;melanoma;mutant;mutant mouse model;pheomelanin;repaired;response;the sun;transcriptome sequencing;transcriptomics;tumor;tumor growth;tumor microenvironment;tumorigenesis;tumorigenic;ultraviolet;ultraviolet damage;ultraviolet lesions Mechanisms of UV-Mediated Melanoma Development NARRATIVEMajor risk factors for melanoma include fair skin and a history of sunburns yet incomplete understanding of howdifferent skin pigments and types of ultraviolet sunlight (UVA UVB) contribute to melanoma progression hashindered efforts to curb disease incidence. In this application we will use models genetically representative ofhuman melanoma to determine how different skin pigments and forms of UV light contribute to melanomaprogression. This work will identify deficiencies in the biological mechanisms that protect us from the sun whichcould be mitigated to improve melanoma prevention strategies and patient outcomes. NCI 10738341 5/22/23 0:00 PA-19-056 3R01CA237213-04S1 3 R01 CA 237213 4 S1 "JOHNSON, RONALD L" 9/4/20 0:00 5/31/25 0:00 Cancer Etiology Study Section[CE] 8481802 "BURD, CHRISTIN E" Not Applicable 3 GENETICS 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF ARTS AND SCIENCES 432101016 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 73383 NCI 52247 21136 ABSTRACTBiological processes that guard against melanoma are generally successful. Thus to understand melanomaetiology we must identify the flaws in these mechanisms that lead to tumorigenesis. This proposal will elucidatedeficiencies in the cellular mechanisms that combat UV damage and define the tumorigenic consequences ofmelanocyte pigment production. Our studies will improve mechanistic understanding of melanoma etiology byrevealing gaps in the physiological processes that block UV carcinogenesis.We hypothesize that melanoma progression is influenced by melanin production and accelerated by thepersistence of unresolved DNA lesions specific to the initiating UV wavelength. To test this hypothesis wewill define how full-spectrum (UVA/B) and partitioned solar irradiation (UVA or UVB) influence the onset andprogression of melanoma in genetically relevant Braf- and Nras-mutant mouse models. We will elucidatetranscriptional and mutational patterns enriched in tumors driven by each UV spectrum and oncogene and usethis information to define how UV lesions escape repair (Aim 1). Next we will cross our models to eumelanotic(black) amelanotic (albino) or pheomelanotic (red/yellow) alleles to determine how melanin impacts theformation progression and immunotherapeutic response of Braf- and Nras-mutant melanomas accelerated bydifferent UV spectra (Aim 2). Knowledge gained from these experiments will aid in the development of melanomapreventatives that progress beyond sunscreens including interventions that mitigate UV carcinogenesis after anexposure or reduce melanoma risk in individuals with more photosensitive skin types. 73383 +No NIH Category available ATP Citrate (pro-S)-Lyase;Acetyl Coenzyme A;Aftercare;Autophagocytosis;Benign;Binding;Bioinformatics;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Carrier Proteins;Cell model;Cells;Characteristics;Citrates;Citric Acid Cycle;Clinical;Clinical Data;Clinical Trials;Coenzyme A;Combined Modality Therapy;Communication;Cytoplasm;Dasatinib;Data;Dependence;Drug Combinations;Drug Targeting;Drug resistance;Enzymes;FDA approved;Fatty Acids;Generations;Glycine;Glycolysis;Goals;In Vitro;Invaded;Lipids;MEKs;Malignant Neoplasms;Mechanics;Mediating;Membrane;Messenger RNA;Mitochondria;Modeling;Modification;Myristates;Myristic Acylation Site;N-Myristoylation;N-myristoyltransferase;N-terminal;NMT2 gene;Neoplasm Metastasis;Nuclear;Oncogenic;Pathway interactions;Patient-derived xenograft models of breast cancer;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Phase Ib/II Trial;Phosphotransferases;Population;Primary Neoplasm;Prognosis;Property;Proteins;Publishing;Reactive Oxygen Species;Recurrence;Regulation;Reporting;Research;Resistance;Role;SRC gene;Severities;Signal Pathway;Signal Transduction;System;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;breast cancer progression;cancer subtypes;citrate carrier;clinical translation;drug resistance development;hormone receptor-negative;hormone receptor-positive;in vivo;inhibitor;inhibitor therapy;mRNA Expression;malignant breast neoplasm;metabolomics;multiple omics;myristoylation;novel;novel therapeutic intervention;oxidation;palmitoylation;patient derived xenograft model;preclinical study;resistance mechanism;response;src-Family Kinases;targeted treatment;translational approach;translational potential;treatment strategy;triple-negative invasive breast carcinoma;tumor Energy reprogramming-regulated oncopathways and drug resistance in triple negative breast cancer Triple negative breast cancer (TNBC) currently lacks reliable treatment options and we discovered criticalrole for mitochondrial reprogramming to fatty acid beta-oxidation (FAO) in the activation of Srconcopathway in TNBC. Using mechanical studies and translational approaches this project aims tounderstand the mechanism of FAO-mediated Src regulation and pathways that support the developmentof drug resistance to Src inhibitor therapy in TNBC. We will perform preclinical studies using multipleTNBC patient derived xenograft models to determine suitable drug combination strategy to overcomedrug resistance to Src inhibitor therapy to manage the currently non-targetable TNBC progression andmetastasis. NCI 10738335 2/10/23 0:00 PA-18-484 3R01CA234479-05S1 3 R01 CA 234479 5 S1 "CHEN, WEIWEI" 1/1/19 0:00 12/31/24 0:00 Basic Mechanisms of Cancer Therapeutics Study Section[BMCT] 10027528 "KAIPPARETTU, BENNY ABRAHAM" Not Applicable 9 GENETICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 1/1/23 0:00 12/31/24 0:00 395 Non-SBIR/STTR 2023 63342 NCI 39589 23753 Abstract: Compared to other subtypes of breast cancers (BC) basal or triple negative (TN) BC suffers a poorprognosis caused by limited understanding of the driver signaling pathways. Thus for TNBC clinical benefitfrom currently available targeted therapies is limited and new therapeutic strategies are urgently needed. PI'slab uses a research pipeline that utilizes transmitochondrial cybrid (cybrid) models. Cybrid system is anexcellent cell model that allows comparing mitochondria from different cells (example: benign and TNBC cellswith varying invasion/metastatic potential) in a common defined nuclear background. We apply multiple OMICsapproaches in cybrid models to discover mitochondria-nuclear communication and mitochondrial energyreprogramming regulated cancer pathways. Using this research pipeline we have recently published thatmetastatic TNBC has high energy-dependence to mitochondrial fatty acid -oxidation (FAO). We have alsodiscovered that FAO is a critical regulator of Src oncopathway in TNBC. We validated the findings from cybridmodels in parental BC cells PDX models and clinical data. Proto-oncogene c-Src is one of the mostcommonly upregulated cancer pathways in TNBC. However multiple clinical trials including our own trialshowed only limited clinical benefit with single drug approach of Src inhibitors in unselected TNBC patients.Thus it is important to understand the mechanism of activation and drug resistance of c-Src in TNBC todevelop reliable treatment strategies to inhibit TNBC progression. N-myristoylation is a lipid modification withthe attachment of a fatty acid myristate onto the N- terminal glycine residue of target proteins. Our preliminaryanalysis in cybrid models and parental cells suggest that FAO regulates myristoylation of c-Src by enhancingcytosolic availability of myristoyl CoA. In this project we will validate this interesting finding using systematicmodulation of FAO pathway. Since frequent drug resistance occurs after Src inhibitor therapy in TNBC wehave also analyzed the potential drug resistance mechanisms for FAO or Src inhibitor therapy in TNBC. Ourstrong preliminary data suggest that drug resistance to FAO or Src inhibition is due to autophagy-mediatedtumor survival that is regulated by the reactive oxygen species (ROS)-induced MEK/ERK pathway. Thus thisproject will also validate this exciting mechanism using multiple research approaches. Considering our strongin vitro and in vivo preliminary data we have proposed large-scale preclinical studies using multiple PDXTNBC models to determine benefit of combination drug strategy to overcome the resistance to FAO or Srcinhibition therapy in TNBC. Overall this proposal is highly significant as it is expected to 1) reveal thesignificance of mitochondrial crosstalk in the activation of Src signaling in TNBC and 2) develop strategies torepurpose the existing FDA approved Src targeting drugs with suitable combination therapy for rapid clinicaltranslation to manage currently non-targetable TNBC. 63342 +No NIH Category available Address;Aging;Antibodies;Binding;Biological Assay;Biological Models;Biology;Biophysics;Breast Cancer Cell;Cell physiology;Cells;Chemicals;Chromosomal Rearrangement;Clinical;Complex;Cytosine;Cytosine deaminase;DNA;DNA Double Strand Break;DNA Repair Enzymes;DNA Transposable Elements;Data;Deamination;Defect;Development;Diagnosis;Disease;Disease Progression;Disease Resistance;Drug resistance;Enzymes;Estrogen receptor positive;Family;Foundations;Genomics;Goals;Inherited;Knowledge;Lead;Leadership;Lesion;Malignant Neoplasms;Mammary Neoplasms;Metastatic breast cancer;Mission;Molecular;Monoclonal Antibodies;Mutagenesis;Mutation;Neoplasm Metastasis;Nucleic Acids;Nucleotides;Oncoproteins;Outcome;PIK3CA gene;Patients;Persons;Primary Lesion;Primary Neoplasm;Process;Proteins;Publishing;Reagent;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Regulation;Reporter;Reporting;Research;Research Project Grants;Residual state;Resistance;Scientific Advances and Accomplishments;Services;Single-Stranded DNA;Site;Source;System;Techniques;Testing;The Cancer Genome Atlas;Therapeutic;Time;Uracil;Virus Replication;Water;Woman;Work;antibody diagnostic;anticancer research;base;biophysical techniques;brca gene;cancer recurrence;clinical care;clinical translation;computational chemistry;computerized tools;diagnostic assay;experience;homologous recombination;improved;inhibitor;innovation;interdisciplinary approach;malignant breast neoplasm;member;molecular recognition;mouse model;multidisciplinary;new technology;novel;novel diagnostics;overexpression;preference;prevent;programs;repaired;small molecule;structural biology;technology development;therapy outcome;therapy resistant;tumor;tumor heterogeneity;tumor progression APOBEC MUTAGENESIS IN BREAST CANCER OVERALL APOBEC MUTAGENESIS IN BREAST CANCERNARRATIVE Mutations continue to accumulate in breast cancer cells even after the cancer is first diagnosed andtreated leading to treatment-resistant disease and metastasis. APOBEC contributes to this mutagenesis inmany cancers and thus provides an opportunity to therapeutically slow or prevent cancer recurrence andprogression after initial treatment. Our Program takes a multidisciplinary approach to better understand themechanism of APOBEC mutagenesis in breast cancer with the goal of diagnosing and improving treatmentsfor patients whose tumors are fueled by this process. NCI 10738334 8/11/23 0:00 PAR-18-290 3P01CA234228-05S1 3 P01 CA 234228 5 S1 "READ-CONNOLE, ELIZABETH LEE" 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L(M1) 8004071 "HARRIS, REUBEN S" "YEE, DOUGLAS " 20 BIOCHEMISTRY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 80536 NCI 80536 0 OVERALL APOBEC MUTAGENESIS IN BREAST CANCERABSTRACT APOBEC signature mutations make up 20% of base-substitution mutations in primary tumors whichincreases to over 50% in metastases. Additional enrichment is often observed in estrogen receptor (ER)-positive disease. APOBEC-catalyzed C-to-U lesions in single-stranded (ss)DNA lead to signature C-to-T andC-to-G mutations within 5-TCA and 5-TCT trinucleotide motifs. In addition APOBEC-derived C-to-U lesionscan be (mis)processed by cellular DNA repair enzymes resulting in single- and double-stranded DNA breaksand more complex chromosomal rearrangements. APOBEC expression levels and mutagenesis correspondwith poor clinical outcomes such as shorter disease-free and overall survival in women with operable ER-positive breast cancer. Elevated APOBEC levels also predict poor overall survival for patients diagnosed withrecurrent ER-positive metastases. These and other published data demonstrate that APOBEC mutagenesis isongoing in breast tumor cells and underpin our overarching Program hypothesis that inhibiting APOBEC willprevent a large proportion of additional mutations from happening in residual ER-positive disease and willthereby improve the durability of current treatments and result in better overall therapeutic outcomes. Threemultidisciplinary Projects will work together in an integrated and comprehensive manner to test this idea.Project 1 will develop reporter systems for quantifying APOBEC activity in living cells and determine themolecular mechanisms responsible for APOBEC regulation and for genomic uracil processing in breast cancercells. Project 2 will use chemical biology approaches to investigate the mechanism of APOBEC-catalyzedssDNA deamination and will develop nucleic acid and small molecule probes to inhibit APOBEC activity.Project 3 will leverage structural and biophysical approaches to investigate global mechanisms for APOBECbinding to ssDNA as well as the local structural features important for target sequence preferences andinhibition of APOBEC enzymes in breast cancer. These Projects will be supported by service Cores foradministration murine models computational chemistry and biophysics and enzymes and antibodies. OurProgram is poised to have both immediate and long-term impact for ER-positive breast cancer: immediateimpact by producing novel technologies and a comprehensive understanding of the mechanism of APOBECmutagenesis and long-term impact on clinical translation through the development of technologies fordiagnosing APOBEC-positive disease and the creation of novel chemical matter to inhibit this mutationalprocess for therapeutic benefit. 80536 +No NIH Category available Acetylation;Address;Automobile Driving;Binding;Binding Proteins;Biochemical;Blood;Blood Cells;Bromodomain;C-terminal;Cell Maintenance;Cells;ChIP-seq;Chimeric Proteins;Chromatin;Chromosomal translocation;Competitive Binding;Complex;Data;Development;Disease;Enhancers;Epigenetic Process;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Grant;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Histone Acetylation;Histones;Homologous Gene;In Vitro;Individual;K-18 conjugate;Knockout Mice;Laboratories;Link;Lysine;MLL gene;MLLT1 gene;MLLT2 gene;MLLT3 gene;Mixed-Lineage Leukemia;Multiprotein Complexes;Peptides;Phenotype;Point Mutation;Prognosis;Proteins;RNA;RNA Binding;RNA Recognition Motif;Reader;Regulator Genes;Role;SWP29;Site;Specificity;Structure;Work;drug development;epigenetic regulation;experimental study;gene repression;in vivo;leukemia;leukemogenesis;mutant;novel;programs;promoter;recruit;stem;stem cell function;stem cell homeostasis;stem cells;three dimensional structure;transcriptome sequencing AF9(MLLT3) Function in Leukemia and Normal Hematopoiesis AF9 is an important protein for the development of blood cells. In addition a portion of AF9 is fused to theprotein MLL in a type of leukemia that has a very poor prognosis. We will study the roles of functionalportions of AF9 in normal blood development and of the AF9 portion of the MLL-AF9 fusion protein in causingleukemia. Our efforts will increase understanding of the disease and may identify novel avenues for drugdevelopment. NCI 10738333 7/25/23 0:00 PA-18-484 3R01CA233749-05S1 3 R01 CA 233749 5 S1 "KLAUZINSKA, MALGORZATA" 7/1/19 0:00 6/30/24 0:00 Molecular and Cellular Hematology Study Section[MCH] 1885431 "BUSHWELLER, JOHN HACKETT" "FIGUEROA, MARIA EUGENIA; HEMENWAY, CHARLES S.; ZELEZNIK-LE, NANCY J" 5 PHYSIOLOGY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 65778 NCI 65778 0 MLLT3 (AF9) and its homolog MLLT1 (ENL) were initially identified as chromosome translocationpartners of the MLL (KMT2A) gene observed in Mixed Lineage Leukemia (MLL). The amino termini of MLLT3and MLLT1 proteins contain a nearly identical chromatin-binding YEATS domain which preferentially bindscrotonylated histone sites (Kcr). This distinguishes YEATS domains as crotonylation reader modules in contrastto other acetylation reader modules such as bromodomains. The MLLT3 YEATS domain directly links histoneKcr readout to active gene transcription but mechanisms underlying specific recruitment to direct target genesare not understood. Work from different laboratories including ours has revealed roles of MLLT3 and MLLT1 inat least four different complexes with critical gene regulatory functions based on direct binding to the C-terminalANC1 homology domain (AHD). The canonical functions of two of these complexes (AF4-containing SuperElongation Complex; DOT1L) are to activate gene transcription whereas the other two (CBX8 BCOR) most oftenfunction in gene repression. The factors that decide which of these four different complexes are recruited andwhether recruitment of one complex facilitates or inhibits recruitment of another are not understood. Aim 1: Functional effects of CBX8 and BCOR recruitment on MLL-MLLT3/1 (MLL-AF9/-ENL) function.We have determined 3D structures of MLLT3 AHD-CBX8 and AHD-BCOR complexes and used the structuralinformation to develop point mutations to selectively disrupt recruitment of CBX8 and BCOR. These will be usedto specifically delineate the role of direct recruitment of CBX8 and BCOR to MLL-MLLT3 and MLL-MLLT1 inaltering gene expression and driving leukemia as we have done previously for the AF4 and DOT1L interactions. Aim 2: MLLT3 (AF9) YEATS domain is a dual reader of H3K9 (and K18 K27) crotonylation and RNA.We have used a biochemical approach to show that the MLLT3 YEATS domain also binds to RNA in additionto specific binding to crotonylated H3 indicating this domain is a dual reader of both epigenetic marks and RNA.We are proposing to fully characterize the role of the RNA binding of this domain in MLLT3 function. This includesdelineation of the RNA binding specificity structural studies of a YEATS domain-H3K9cro-RNA ternary complexand development of point mutations which can selectively disrupt RNA binding and H3 peptide binding to probethe functional role of these interactions. Similar studies will be carried out with MLLT1. Aim 3: MLLT3 (AF9) and MLLT1 (ENL) have non-redundant roles in hematooietic stem and progenitorcell (HSPC) gene regulation which require their YEATS domain and C-terminal AHD functions. Using wildtypeand point mutant forms of MLLT3 and MLLT1 which can selectively disrupt either histone or RNA binding wewill probe the functional role of the H3Kcr and RNA interactions via ChIP-seq RNA-seq and effects on in vitroand in vivo HSPC functions. Wildtype and mutant MLLT3 and MLLT1 that specifically disrupt binding to AF4DOT1L BCOR and CBX8 will probe the roles of these interactions on gene expression and HSPC functions. 65778 +No NIH Category available Acceleration;Address;Adopted;Animal Model;Bioinformatics;Biometry;CD36 gene;Cancer Etiology;Carcinoma;Cessation of life;Clinical;Collaborations;Colon;Colon Carcinoma;Complement;Data;Dietary Intervention;Disparate;Doctor of Philosophy;Effectiveness;Endoglin;Engraftment;Ensure;Environment;Epithelium;Extracellular Matrix;Fatty Liver;Fatty acid glycerol esters;Glutamate-Ammonia Ligase;Glutamine;Goals;Growth;Health Personnel;Healthcare Systems;Hepatic;Hepatic Stellate Cell;Hepatocyte;High Fat Diet;Histone Deacetylase;Home;Human;Hyaluronic Acid;In Vitro;Institution;Investigation;Kupffer Cells;Liver;Los Angeles;Macrophage;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mediating;Medical center;Metabolic;Metastatic Neoplasm to the Liver;MicroRNAs;Modeling;Molecular;Morbidity - disease rate;Mus;Neoplasm Circulating Cells;Neoplasm Metastasis;Obesity;Oncogenic;Pancreas;Pathway interactions;Patients;Phenotype;Prevalence;Primary Neoplasm;Prostate;Proteins;Publishing;Regulation;Research;Research Personnel;Resistance;Resources;Role;Signal Pathway;Signal Transduction;Signaling Protein;Specimen;System;Terminal Disease;Testing;Tissues;Tumor Expansion;Tumor Promotion;Tumor-Derived;United States;Work;cancer cell;cancer type;endoplasmic reticulum stress;extracellular vesicles;falls;glycogen synthase kinase 3 beta;human tissue;innovation;innovative technologies;liver development;methionine adenosyltransferase;mortality;mouse model;non-alcoholic fatty liver disease;novel therapeutic intervention;permissiveness;pharmacologic;programs;prostate cancer metastasis;recruit;saturated fat;success;tool;tumor;tumor growth;tumor microenvironment Determinants of Liver Metastasis PROGRAM NARRATIVETumor metastasis to the liver is a leading cause of cancer death in the United States and it is known to beassociated with the increasing prevalence of obesity and non-alcoholic fatty liver disease. This Programrepresents the only coordinated multi-investigator effort nationwide to focus on the causes of and approachesto address liver metastasis from cancers of the prostate pancreas and colon. Successful completion of theProgram will lead to new targets for treatments for patients with liver metastasis. NCI 10738332 2/14/23 0:00 PAR-18-290 3P01CA233452-04S1 3 P01 CA 233452 4 S1 "WATSON, JOANNA M" 1/21/20 0:00 12/31/24 0:00 ZCA1-RPRB-F(O1) 1895258 "LU, SHELLY CHI-LOO" "BHOWMICK, NEIL A." 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2023 19749 NCI 31017 20781 PROGRAM TITLE: Determinants of Liver MetastasisPROGRAM ABSTRACTLiver metastasis indicates a terminal illness for many cancers and is a leading cause of cancer death in theUnited States. There is currently no integrated research program devoted to mechanisms of liver metastasis.While common in certain cancer types (such as pancreas and colon) metastasis is less common but highlymalignant in other cancer types (such as prostate cancer). The long-term goal of our Program is tounderstand and address the shared and unique drivers of liver metastasis in colon pancreas andprostate primary tumor types. Published work and preliminary data from the four integrated projects point tokey roles for four critical molecular signaling axes in mediating liver metastasis through mechanisms likelycommon across many primary tumor types. To complement this mechanistic expertise this Program assemblesclinical expertise across different tumor types and liver microenvironment models.Together this collaborative Program investigates the hypothesis that normal liver tissue is inherently suppressiveof metastatic tumor expansion unless alterations in the liver microenvironment result in the loss of metastaticsuppressors. Project 1 explores the acquisition of features that enable metastasis from circulating saturated fatand subsequent endoglin signaling in hepatocytes and cancer epithelia. The pro-metastatic impact of hepaticstellate cell (HSC)-derived hyaluronic acids in non-alcoholic fatty liver disease is examined in Project 2. Thoughtto activate pro-cancer phenotypes of HSCs and macrophages Project 3 investigates the regulation andcontribution of yes-associated protein (YAP) and downstream signaling pathways to create a pro-metastatic livermicroenvironment. Project 4 investigates the roles of methionine adenosyltransferase (MAT) proteins in livermetastasis from the loss of protective MAT1A to the pro-cancer elevated expression of MAT2A and MAT2B. Byexamining these four intersecting signaling pathways and comparing findings across models this Program willaugment current understanding of factors in the liver microenvironment and tumor that permit the developmentof liver metastases.This Program unites essential expertise in the fields of liver and cancer pathobiology to represent the first multi-investigator effort focused on common mechanisms involved in liver metastasis from disparate tumor models(prostate colon and pancreas). The Program adopts a unique approach investigating the role of the normalliver microenvironment and leveraging each project teams substantial expertise along with essential resourcesincluding pharmacologic means of addressing the signaling axes partnerships with healthcare providers tovalidate the findings in animal models through human tissue specimens and innovative technology to isolateand analyze metastatic factors including circulating tumor cells and extracellular vesicles. Successful completionof the Program will establish new paradigms in liver metastasis and test novel therapeutic strategies. 19749 +No NIH Category available Abdomen;Address;Adoptive Transfer;Adult;Advanced Malignant Neoplasm;Amino Acid Sequence;Antibiotics;Antigens;Antitumor Response;Bacteria;Body mass index;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Cellular Assay;Clinical;Data;Diet;Disease Progression;Disease remission;Education;Effectiveness;Environmental Risk Factor;Exposure to;Gender;Genetic;Germ-Free;Goals;Grant;Granzyme;Human;Human Microbiome;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunology;In Vitro;Integration Host Factors;Interferon Type II;Intestines;Malignant Neoplasms;Metastatic Melanoma;Microbiology;Modeling;Molecular;Mus;Oral Administration;Patients;Pre-Clinical Model;Probiotics;Production;Progressive Disease;Research;Role;Sequence Homologs;Testing;Treatment Efficacy;Weight;Yogurt;adaptive immune response;anticancer activity;cancer immunotherapy;cancer therapy;checkpoint therapy;draining lymph node;gut bacteria;gut microbiome;gut microbiota;human study;immune checkpoint;immunogenic;immunoregulation;in vivo;individual patient;innovation;insight;melanoma;mesenteric lymph node;microbial;microbiome;microbiota;microbiota profiles;microorganism;neoantigens;novel;novel strategies;pre-clinical;probiotic therapy;programmed cell death protein 1;recruit;response;translational oncology;translational study;treatment response;tumor Role of Gut Microbiota in Modulating Immune Checkpoint Inhibitory Therapy for Cancer The effectiveness of immune checkpoint inhibitor therapy a form of cancer immunotherapy is associated withthe presence of specific intestinal bacteria. In this grant we propose to explore the mechanisms by which gutbacteria the tumor and environmental factors modulate the efficacy of immune checkpoint inhibitor therapy. NCI 10738330 8/1/23 0:00 RFA-CA-18-019 3R01CA231303-05S1 3 R01 CA 231303 5 S1 "SOMMERS, CONNIE L" 9/1/19 0:00 8/31/24 0:00 ZCA1-SRB-5(M1)S 7935794 "KOH, ANDREW Y" "HOMSI, JADE ; PASARE, CHANDRASHEKHAR " 30 PEDIATRICS 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 73448 NCI 48987 24461 Immune checkpoint inhibitor therapy (ICT) unleashes the immune system resulting in durable remissions in upto 50% of patients with previously incurable cancers such as metastatic melanoma. But the host factors thatmodulate or dictate ICT response are poorly understood. Recent preclinical data suggests that specific gutmicrobiota are required for optimizing response to ICT. These commensal gut microbiota augment hostadaptive immune responses specifically host immune cells needed for anti-cancer activity. We recentlyshowed that adult melanoma patients who respond to ICT have a distinct gut microbiota signature compared topatients with progressive disease. In preliminary data we demonstrated that precision probiotic therapy (usingthe specific bacteria that we identified in our clinical/translational study) augmented the efficacy of ICT in micewith melanoma whereas a probiotic commonly found in yogurt did not. Microbiota dictated a reduction in PD-1expressing CD4 and CD8 T cells in mesenteric lymph nodes (MLNs) following ICT. Of note these specific gutmicrobiota had a greater number of protein sequences homologous to human melanoma neoantigens whencompared to the ineffective yogurt probiotic. Further these gut microbiota induced CD4 and CD8 T cellproduction of IFN-gamma and Granzyme B. Interestingly mice without draining lymph nodes in the gut did notrespond to ICT. ICT promoted gut microbiota translocation into MLNs. Finally oral administration of heat-killedgut microbiota did not augment ICT efficacy suggesting that live bacteria are required for augmenting ICT.Therefore our central hypothesis is that only gut microbiota that have both high immunogenic potential and theability to translocate into the abdominal draining lymph nodes will facilitate activation/education of immune cellsand thus augment ICT efficacy. To test this hypothesis we will pursue the following three specific aims. Firstwe will further define both gut microbiome and tumor genetic differences in melanoma patients who respond toICT compared to those with disease progression. Second we will identify environmental and microbial factorsthat dictate gut microbiota translocation into mesenteric lymph nodes. Third we will elucidate the mechanismsby which gut microbiota modulate host immune cell anti-tumor response by performing in vitro functionalimmune cell assays to determine if and how specific gut microbiota prime immune cells and in vivo studies toidentify the specific immune cells recruited by gut microbiota. These studies will lay the groundwork for thefollowing innovations: 1) a novel mechanism by which gut microbiota activate immune defenses against cancerand 2) a novel approach (precision probiotics) for optimizing ICT efficacy in advanced cancer patients. 73448 +No NIH Category available AMOT gene;Acetylation;Adipose tissue;Adult;Amputation;Binding;Binding Sites;CRISPR/Cas technology;Carcinoma;Cell Line;Cell Nucleus;Cell Proliferation;Cells;ChIP-seq;Complex;Consensus;DNA Binding;Data;Deacetylase;Development;Diagnosis;Distal;Epigenetic Process;Gene Chips;Gene Expression;Genetic;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth;Histology;Histones;Human;In Vitro;KRASG12D;Knowledge;Libraries;Lysine;Malignant Fibrous Histiocytoma;Malignant Neoplasms;Mediating;Mediator;Mesenchymal;Mesenchymal Cell Neoplasm;Methylation;Modeling;Modification;Molecular;Mus;Muscle;Muscle satellite cell;Mutate;Myomatous neoplasm;NF1 gene;Nucleic Acid Regulatory Sequences;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Peptide Hydrolases;Persons;Process;Proliferating;Promoter Regions;Protein Isoforms;Proteins;Radiation;Regulation;Role;Sampling;Signal Transduction;Skeletal Muscle;Skeletal Muscle Neoplasm;Soft tissue sarcoma;Testing;Therapeutic;Therapeutic Intervention;Tissues;Transferase;Ubiquitin;Work;cancer cell;clinically actionable;inhibitor;interest;mouse model;new therapeutic target;novel;p65;precursor cell;predictive marker;prevent;progenitor;programs;promoter;response;sarcoma;targeted treatment;therapeutic target;transcription factor;tumor;tumor initiation;tumorigenesis The role and regulation of Hippo pathway in sarcomagenesis Project NarrativeSoft tissue sarcomas are heterogeneous mesenchymal tumors for which there are no effective targetedtherapies. I am proposing to identify targetable gene expression changes in muscle-derived sarcomas. Ourgoal is to uncover novel therapeutic targets for the treatment of these tumors. NCI 10738329 2/17/23 0:00 PA-18-484 3R01CA229688-05S1 3 R01 CA 229688 5 S1 "XU, WANPING" 3/1/19 0:00 2/29/24 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 8065318 "EISINGER, TZIPORA SARAH KARIN" Not Applicable 3 PATHOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 78845 NCI 55570 23275 Project Summary/Abstract Soft tissue sarcomas are an aggressive group of mesenchymal malignancies diagnosed in 200000people per year worldwide. Unlike in epithelial cancers where novel targeted therapies have had a dramaticeffect on patient survival the treatment approach for mesenchymal tumors including sarcomas has notchanged significantly in 25 years. Our recent work revealed that deregulation of the Hippo pathway enhancessarcomagenesis in the aggressive muscle tumor Undifferentiated pleomorphic sarcoma (UPS). UPS is acommonly diagnosed and metastatic sarcoma subtype frequently found in adult muscle tissues. We haveobserved that loss of Angiomotin (AMOT) a crucial mediator of Hippo-associated growth restriction is requiredfor UPS sarcomagenesis. AMOT is highly expressed in differentiated human muscle tissue but is silenced inUPS and other sarcomas. Ectopic re-expression of the p130 isoform of AMOT significantly inhibits sarcomacell proliferation in vitro. This finding is consistent with the only known function of AMOT in cancer cells whichis to sequester the Hippo pathway effector YAP1 and facilitate its degradation. YAP1 is a pro-proliferationtranscriptional regulator whose deletion in an autochthonous mouse model of UPS significantly decreasedtumorigenesis. Together these data suggest that AMOT loss promotes YAP-mediated sarcomagenesis inmuscle-derived UPS. We next investigated the downstream effects of YAP1 expression in UPS by microarraygene expression studies of control and Yap1-deficient murine tumors. We found that Yap1 controls NF-Bsignaling in UPS by suppressing expression of Usp31 a negative regulator of NF-B activity. Furthermoreusing ChIP-seq of patient samples we found that NF-B signaling is substantially upregulated in human UPS.Consistent with these findings UPS cell proliferation is highly sensitive to NF-B inhibition. Based on thesefindings in Specific Aim1 we will determine how AMOT loss is controlled in UPS and if this process is requiredfor tumor initiation in soft tissue sarcomas. Next we will define the mechanism by which YAP1 suppressesUSP31 expression in Specific Aim 2. We will investigate whether YAP1 directly binds to the promoter regionof USP31 preventing its transcription. Loss of YAP1 restores expression of USP31 a peptidase that removesactivation specific ubiquitin modifications from lysine 63 in TRAF molecules upstream of p65 therebyinactivating NF-B. The role of NF-B in normal skeletal muscle progenitors the putative cell of origin of UPSis to promote proliferation and prevent differentiation. In Specific Aim3 we will determine which YAP1-dependent NF-B targets are necessary for regulating either or both of these processes. The goal of thisproposal is to test the hypothesis that deregulated Hippo signaling promotes sarcomagenesis via suppressionof AMOT resulting in YAP1/NF-B-associated proliferation and inhibition of differentiation. Ultimately thepurpose of these studies is to identify clinically actionable therapeutic targets to advance treatment for skeletalmuscle UPS patients. 78845 +No NIH Category available Acceleration;Biochemical;Biological;Biological Assay;Biology;C-terminal;Cancer Patient;Cells;Chimeric Proteins;Chromosomal translocation;Clinic;Clinical;Computer Models;DNA Sequence Alteration;Data;Development;Dimerization;Disease;Doctor of Philosophy;EGFR inhibition;ERBB2 gene;ERBB3 gene;Engineering;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;ErbB4 gene;Exons;FDA approved;Family;Family member;Future;Genomics;Genotype;Goals;Heterodimerization;Homodimerization;Human;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methods;Molecular;Mutate;Mutation;Mutation Detection;Nucleic Acid Regulatory Sequences;Oncogenic;Patient Care;Patients;Phenotype;Phosphorylation;Phosphotransferases;Physicians;Polymers;Principal Investigator;Proteins;Receptor Activation;Recurrence;Reporting;Research;Research Personnel;Role;Signal Transduction;Single Nucleotide Polymorphism;Somatic Mutation;Structural Models;Techniques;Test Result;Testing;Therapeutic Agents;Therapeutically Targetable;Translating;Transmembrane Domain;Variant;Work;actionable mutation;cancer therapy;cancer type;clinical diagnostics;clinical practice;clinically significant;diagnostic assay;diagnostic tool;dimer;drug development;drug sensitivity;experimental study;gene panel;genetic variant;in silico;in vivo;inhibitor;innovation;insight;multidisciplinary;next generation sequencing;novel;novel therapeutic intervention;polymerization;precision medicine;prospective;protein structure;receptor;screening;standard of care;structural biology;targeted agent;therapeutic target;tool;tumor;tumorigenesis;variant of unknown significance Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm PROJECT NARRATIVEPrincipal Investigators: Christine M. Lovly MD PhD and Jens Meiler PhDWith the advent of sophisticated tumor genotyping utilizing next generation sequencing (NGS) based assays inthe clinic the discovery of novel genetic variants is accelerating. However these NGS assays commonlyreveal novel somatic mutations that are of uncertain functional and clinical significance presenting a significantchallenge for physicians and their patients. The goal of this proposal is to develop a `personalized structuralbiology' approach encompassing both a computational and an experimental pipeline to systematically study`Variants of Uncertain Significance' (VUS) detected in patients with lung cancer and this strategy can betranslated to other forms of cancer with other VUS in the future as well. NCI 10738327 7/25/23 0:00 PA-18-484 3R01CA227833-05S1 3 R01 CA 227833 5 S1 "AMIN, ANOWARUL" 4/19/19 0:00 6/30/24 0:00 Cancer Genetics Study Section[CG] 10166448 "LOVLY, CHRISTINE M." "MEILER, JENS " 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 15047 NCI 15047 0 Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as aparadigmInvestigators: Christine M. Lovly MD PhD and Jens Meiler PhD The prospective identification and rational therapeutic targeting of tumor genomic alterations hasrevolutionized the care of patients with lung cancer and is now the accepted standard of care for patients withthis disease and with other tumor types. With the advent of sophisticated tumor genotyping the discovery ofnovel genetic variants is accelerating. In order to realize the promise of precision medicine there is an urgentneed to define the actionability of these variants to select targeted inhibitors. The objective of this proposalis to develop a novel data-driven paradigm for characterizing genomic Variants of UncertainSignificance (VUS) and generating actionable hypotheses about their functions. For this purpose wepropose an innovative `Personalized Structural Biology' approach. The central hypothesis of this paradigm isthat VUS can be best understood by placing the mutation into the context of protein structures and inferringfrom the structural consequences of the mutation on function phenotype and drug sensitivity. By analyzing the tumors of patients with lung cancer we have identified three EGFR genomicalterations that have not previously been reported: 1) EGFR exon 18-25 Kinase Domain Duplication 2) EGFR-RAD51 fusions and 3) EGFR transmembrane domain mutations. Importantly each of these EGFR variantswas reported as a VUS on clinical genotyping reports because there were no data regarding the sensitivity ofthe mutated proteins to EGFR inhibitors now used in clinical practice. We sought to study these EGFR VUS inan effort to understand on a fundamental mechanistic level how they activate the EGF receptor to promoteoncogenesis. We will integrate structural and computational modeling with various biochemical molecular cellbased and in vivo approaches to investigate the functional effects of these three distinct alterations. Throughthese studies we expect to define previously unrecognized mechanisms of oncogenesis in lung cancer definedby these novel and recurrently detected EGFR variants. Importantly understanding the structural andfunctional consequences of these EGFR variants is expected to provide novel insights into ErbB receptorbiology and reveal new uses for FDA approved agents in lung cancer and many other tumor types whichharbor ErbB (EGFR/HER2/HER3/HER4) alterations. Furthermore a key deliverable of the proposed studiesis the development of an innovative integrated in silico pipeline that is applicable to VUS in any type of cancerwhich we will make freely available via RosettaCommons (www.rosettacommons.org). Thereby the impact ofthe proposed research will go beyond that of the three EGFR variants discussed in this proposal. With therecent FDA approval of NGS-based tumor testing the problem of VUS will continue to grow as these large(>300) gene panel clinical diagnostic assays are reaching higher volumes of patients. Therefore it isimperative the field generate and systematically integrate such `personalized structural biology' methods tounderstand the functional significance of VUS in order to best serve all cancer patients. 15047 +No NIH Category available Acculturation;Adherence;Adoption;Affect;Aromatase Inhibitors;Atypical hyperplasia;Benign;Breast Cancer Risk Factor;Breast Diseases;Characteristics;Chemoprevention;Chemopreventive Agent;Clinic;Clinic Visits;Clinical Trials;Cluster randomized trial;Communication;Community Clinical Oncology Program;Community Networks;Conflict (Psychology);Counseling;Decision Aid;Educational Materials;Effectiveness;Electronic Health Record;Enrollment;Exposure to;Future;Health Personnel;High Risk Woman;Hybrids;Incidence;Infrastructure;Institution;Intervention;Interview;Knowledge;Maintenance;Malignant Neoplasms;Mammographic screening;Methods;Minority;Multicenter Trials;Online Systems;Patients;Phase;Primary Prevention;Provider;Questionnaires;Randomized;Randomized Controlled Trials;Reach Effectiveness Adoption Implementation and Maintenance;Relative Risks;Research;Risk Reduction;Sampling;Selective Estrogen Receptor Modulators;Site;Specialist;Structure;Surveys;Target Populations;Testing;Time;Woman;academic standard;breast lesion;cancer chemoprevention;design;effectiveness evaluation;follow-up;health literacy;high risk;high risk population;implementation evaluation;implementation framework;implementation outcomes;improved;informant;lobular breast carcinoma in situ;malignant breast neoplasm;mathematical ability;multi-ethnic;organizational readiness;patient oriented;patient portal;post implementation;practice setting;primary care provider;primary care setting;programs;risk perception;shared decision making;side effect;study population;support tools;theories;tool;treatment arm;uptake Multicenter trial of decision support for breast cancer chemoprevention PROJECT NARRATIVEBreast cancer chemoprevention with selective estrogen receptor modulators and aromatase inhibitors areunderutilized among high-risk women despite several randomized controlled trials demonstrating a 50-65%decrease in breast cancer incidence. Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)are an important high-risk population to target for chemoprevention. In this proposal we seek to evaluate theeffectiveness and implementation of web-based decision support tools for patients and providers integratedinto the electronic health record to increase chemoprevention informed choice among women with AH or LCIS. NCI 10738324 12/16/22 0:00 PAR-18-559 3R01CA226060-05S1 3 R01 CA 226060 5 S1 "HECKMAN-STODDARD, BRANDY" 12/1/18 0:00 11/30/24 0:00 ZCA1-RPRB-Z(O3) 8623141 "CREW, KATHERINE D" "KUKAFKA, RITA " 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 12/1/22 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2023 23902 NCI 14530 9372 Breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) and aromataseinhibitors (AIs) is underutilized despite several randomized controlled trials demonstrating a 50-65% decreasein breast cancer incidence among high-risk women. Women with atypical hyperplasia (AH) or lobular carcinomain situ (LCIS) have a 4- to 10-fold increased risk of breast cancer and derive up to a 70-80% relative risk reductionwith SERMs or AIs. Reasons for low chemoprevention uptake include inadequate time for counseling insufficientknowledge about SERMs and AIs and concerns about side effects. We hypothesize that standard educationalmaterials combined with decision support tools will increase chemoprevention informed choice compared tostandard educational materials alone among women with AH or LCIS. We have developed web-based decision support tools RealRisks for high-risk women and BNAV (Breastcancer risk NAVigation tool) for healthcare providers. Our patient-centered decision aid RealRisks is availablein English and Spanish and has been rigorously tested in multi-ethnic high-risk women of varying health literacynumeracy and acculturation. After exposure to these tools we have demonstrated an improvement in accuratebreast cancer risk perceptions chemoprevention knowledge and informed choice among multi-ethnic high-riskwomen. Our objective is to integrate these tools into clinic workflow via the electronic health record (EHR) andexpand their use in a multicenter trial targeting women with AH or LCIS. To evaluate effectiveness (Aim 1) andimplementation (Aim 2) we will conduct a hybrid cluster-randomized trial at 40 sites of standard educationalmaterials combined with RealRisks and BNAV or standard educational materials alone among 384 women withAH or LCIS. We will leverage the clinical trials infrastructure of the NCI Community Oncology Research Program(NCORP) including minority/underserved sites. Our primary effectiveness endpoint is chemopreventioninformed choice at 6 months after enrollment (Aim 1). Secondarily we will assess chemoprevention knowledgeperceived breast cancer risk/worry and decision conflict at baseline 6 and 12 months as well as shareddecision-making and chemoprevention uptake/adherence. For the implementation component of the trial (Aim2) we will evaluate the impact of portal integration of the decision support tools using surveys and key informantinterviews of healthcare providers including specialists and primary care providers and high-risk women withAH or LCIS to better understand barriers and facilitators to chemoprevention uptake. We will use the RE-AIM(Reach Effectiveness Adoption Implementation Maintenance) framework for the implementation evaluation. This proposal seeks to overcome important barriers to chemoprevention uptake among diverse women withAH or LCIS a population of high-risk women that is more likely to benefit from SERMs and AIs. Providing EHR-integrated decision support for patients and providers has the potential to improve informed shared decision-making about breast cancer chemoprevention which is sustainable and may be widely disseminated. 23902 +No NIH Category available Acute Myelocytic Leukemia;Acute T Cell Leukemia;Affinity;Allogenic;Area;Back;Basic Science;Bispecific Antibodies;Bone Marrow;CD7 gene;CXCR4 gene;Chemosensitization;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Complication;Effector Cell;Engraftment;Failure;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;IFNGR1 gene;IL3RA gene;IL8RB gene;Immune;Immunotherapeutic agent;Immunotherapy;Infusion procedures;Integrin alpha4beta1;JAK1 gene;JAK2 gene;Malignant Neoplasms;Marrow;Methods;Monoclonal Antibodies;Natural Killer Cells;Natural regeneration;Patients;Phase I Clinical Trials;Pre-Clinical Model;Progressive Disease;Reagent;Recurrent disease;Refractory;Relapse;Research;Signal Pathway;Stromal Cell-Derived Factor 1;System;T-Lymphocyte;Testing;Translating;Vascular Cell Adhesion Molecule-1;acute lymphoblastic leukemia cell;bench to bedside;cancer genomics;career;chemotherapy;chimeric antigen receptor T cells;curative treatments;design;early phase clinical trial;efficacy testing;first-in-human;graft vs host disease;graft vs leukemia effect;inhibitor;leukemia;leukemia relapse;novel;preclinical study;prevent;programs;success;targeted agent;targeted treatment;transplantation therapy Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies PROJECT NARRATIVEAllogeneic hematopoietic stem cell transplant (HSCT) is the only curative therapy for many patients withhematologic malignancies and marrow failure states. We will overcome many of the major limitations tosuccessful HSCT by designing and testing in clinical trials our basic science observations which have identifiedoptimal methods of mobilizing stem cells for HSCT and for sensitizing acute myelogenous leukemia (AML) tochemotherapy by developing and implementing novel methods to prevent graft-versus-host disease (GvHD)the major complication of allogeneic HSCT and by developing novel immunotherapies for AML and T-ALL. NCI 10738323 9/12/23 0:00 PAR-16-411 3R35CA210084-07S1 3 R35 CA 210084 7 S1 "SONG, MIN-KYUNG H" 9/7/17 0:00 8/31/24 0:00 ZCA1-GRB-I(M2) 1927565 "DIPERSIO, JOHN F." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 63892 NCI 41088 22804 PROJECT SUMMARY/ABSTRACTAllogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative therapy for many patientswith hematologic malignancies and marrow failure states. Key obstacles to the success of HSCT includecollecting optimal numbers of hematopoietic stem/progenitor cells (HSPCs) capable of multilineage anddurable engraftment control of graft-versus-host disease (GvHD) and treating disease recurrence both beforeand especially after HSCT. I have focused my career over the last 20 years on overcoming these threeobstacles to HSCT through the use of a bench-to-bedside and back again research approach. My researchprogram over the next seven years will use our strengths in preclinical modeling cancer genomics and thedesign and execution of early phase clinical trials to (1) develop novel methods to target the hematopoieticniche for optimal HSPC mobilization and chemosensitization of acute myeloid leukemia (AML) (2) target theinterferon gamma receptor (IFNR) and IL-6R signaling pathways via use of selective and balanced JAK1/2inhibitors to mitigate GvHD while maintaining graft vs. leukemia (GvL) after allo-HSCT and (3) design and testnovel AML and T cell acute lymphoblastic leukemia (T-ALL) immunotherapeutics. Successful HSCT requiresthe infusion of a sufficient number of HSPCs that are capable of homing to the bone marrow cavity andregenerating durable trilineage hematopoiesis in a timely fashion. In our first research area we will use newstrategies to enhance HSPC mobilization and leukemia chemosensitization via targeted modulation of theCXCR4/CXCL12 VLA-4/VCAM-1 and/or CXCR2/Gro- axes. Managing the threat of GvHD while maximizingthe beneficial GvL effect would broaden the scope and usefulness of allo-HSCT. In our second major researcharea we will perform preclinical and clinical studies to determine if targeting IFNR IL-6R and/or JAK1/JAK2can mitigate GvHD while maintaining GvL after T cell replete allo-HSCT. Finally since many patients with AMLdie from progressive disease after relapse our third research area will develop and translate into early phaseclinical trials novel bi- and tri-specific monoclonal antibody reagents for the treatment of AML relapse beforeand after HSCT. We will complete first-in-man phase I clinical trials of MGD006 a CD123xCD3 Dual AffinityRe-Targeting (DART) bispecific antibody-based molecule and AMV564 a CD33xCD3 Tandem Diabody inpatients with relapsed/refractory AML. While these trials are ongoing we are identifying novel targets forimmunotherapy in AML and testing the efficacy of new retargeting agents that engage either T cells NK cellsor other immune effector cells to kill AML blasts expressing CD123 CD33 or the novel targets. Finally sinceno targeted therapies currently exist for T-ALL we are developing allogeneic chimeric antigen receptor T cells(CAR-T) to CD7 a T and NK cell marker that is highly expressed in T cell malignancies and in up to 40% ofAML cases. To prevent normal T cell fratricide and alloreactivity we are using the CRISPR/Cas-9 system todelete CD7 and the TCR chain from donor T cells prior to transduction with the CD7 CAR. 63892 +No NIH Category available 6-phosphogluconate;A549;Acetylation;Acute;Acute Myelocytic Leukemia;Affect;Anabolism;Antioxidants;Binding;Cell Proliferation;Cells;Cellular Metabolic Process;Colorectal Cancer;Combined Modality Therapy;Complex;Enzymes;Focal Adhesion Kinase 1;Foundations;Gene Expression;Glucose-6-Phosphate;Glucosephosphate Dehydrogenase;Glycolysis;H1299;HCT116 Cells;HT29 Cells;Homeostasis;Human;Hydrolysis;In Vitro;K-562;Link;Lysine;Malignant neoplasm of lung;Metabolic;Metabolic Pathway;Mitochondria;Molecular;NADP;Nucleotide Biosynthesis;Oncogenic;Oxidation-Reduction;Pathway interactions;Patients;Pentosephosphate Pathway;Phosphogluconate Dehydrogenase;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Physiological;Play;Post-Translational Protein Processing;Probability;Proliferating;Property;Protein Phosphatase 2A Regulatory Subunit PR53;Proteins;Reactive Oxygen Species;Regulation;Reporting;Role;SOD2 gene;STK11 gene;Series;Signal Pathway;Signal Transduction;Signaling Molecule;Testing;acute myeloid leukemia cell;attenuation;cancer cell;in vivo;inhibitor;knock-down;leukemia;lipid biosynthesis;lung cancer cell;macromolecule;mouse model;novel;patient derived xenograft model;programs;recruit;response;ribulose 5-phosphate;tumor growth Oxidative pentose phosphate pathway regulates AMPK homeostasis by balancing opposing LKB1 and PP2A Project Narrative:The oxidative pentose phosphate pathway (oxiPPP) regulates cell metabolism by producing metabolicintermediates and reductive NADPH and inhibiting LKB1-AMPK signaling through ribulose-5-phosphate(Ru-5-P) the product of the third enzyme 6-phosphogluconate dehydrogenase (6PGD). We provide evidencesupporting that -6-phosphogluconolactone (-6PGL) a dead end byproduct of the oxiPPP with unknownphysiological function serves as a signaling molecule that contributes to AMPK activation by enhancinginhibition of AMPK upstream phosphatase PP2A by Src. Thus we hypothesize that oxiPPP regulates AMPKhomeostasis by balancing the opposing LKB1 and PP2A. NCI 10738318 2/28/23 0:00 PA-19-056 3R01CA174786-09S1 3 R01 CA 174786 9 S1 "WILLIS, KRISTINE AMALEE" 4/15/14 0:00 2/28/25 0:00 Tumor Cell Biology Study Section[TCB] 8238758 "CHEN, JING " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 15541 NCI 9476 6065 Project Summary/Abstract:The interplay between metabolic pathways and cell signaling networks that contribute to the metabolicreprogramming in cancer cells remains largely unknown. The oxidative pentose phosphate pathway (oxiPPP)plays a crucial role in the metabolic coordination of glycolysis biosynthesis and redox homeostasis in cells byproducing precursors for nucleotide and lipid biosynthesis as well as antioxidant NADPH that quenches thereactive oxygen species (ROS) produced during rapid proliferation of cancer cells. There are three key enzymesalong the oxiPPP. The first enzyme glucose-6-phosphate dehydrogenase (G6PD) converts glycolyticintermediate glucose-6-phosphate (G6P) to 6-phosphogluconolactone (6PGL) and produces NADPH. Thesecond enzyme 6-phosphogluconolactonase (PGLS) converts 6PGL to 6-phosphogluconate (6PG). The thirdenzyme 6-phosphogluconate dehydrogenase (6PGD) converts 6PG to ribulose-5-phosphate (Ru-5-P) and alsoproduces NADPH. We recently reported that 6PGD is commonly activated by lysine acetylation in cancer cellsand activates lipogenesis through controlling its product Ru-5-P which inhibits the LKB1-AMPK pathway bydisrupting the active LKB1 complex (Shan et al. 2014 Mol Cell; Lin et al. 2015 Nat Cell Biol.). Interestingly wefound that knockdown of G6PD did not alter AMPK activation despite decreased Ru-5-P and subsequent LKB1activation due to enhanced activity of PP2A the upstream phosphatase of AMPK. In contrast knockdown of6PGD or PGLS reduced PP2A activity. Mechanistically knockdown of G6PD or PGLS decreased or increased6PGL level respectively which enhanced the inhibitory phosphorylation of PP2A by Src. There are two forms of6PGL -6-phosphogluconolactone (-6PGL) is an oxiPPP byproduct with unknown function that is generatedthrough intramolecular rearrangement of -6-phosphogluconolactone (-6GL) while -6PGL is the onlysubstrate of PGLS and can undergo quick spontaneous hydrolysis. Thus -6PGL is relatively stable comparedto -6GL but does not participate in oxiPPP. Further studies revealed that -6PGL but not -6GL promotesSrc-PP2A association probably by binding to Src but not PP2A and enhancing PP2A recruitment. Thus we hypothesize that G6PD PGLS and 6PGD play differential roles in regulation of AMPKhomeostasis by balancing the opposing LKB1 and PP2A through the oxiPPP intermediate Ru-5-P and anoxiPPP byproduct -6PGL respectively; and -6PGL previously considered as a dead end byproduct of theoxiPPP with unknown physiological function functions as a signaling molecule that links the metabolic oxiPPPwith the Src-PP2A-AMPK signaling pathway. The specific aims are proposed: (1) To elucidate the molecular andsignaling basis underlying -6PGL-dependent contribution to AMPK activation through inhibition of PP2A by Src;(2) To determine the differential effects of G6PD and PGLS on AMPK activation redox homeostasis and tumorgrowth; and (3) To evaluate combined therapy with oxiPPP inhibitors and AMPK activator in the treatment ofhuman leukemia and lung cancer cells in vitro and in vivo. 15541 +No NIH Category available Address;Advanced Malignant Neoplasm;American;Antitumor Response;Apoptotic;Binding;CXCL10 gene;Cell Death;Cell Death Signaling Process;Cell Migration Inhibition function;Cell Survival;Cells;Cessation of life;Clinical;Clinical Data;Clinical Trials;Colorectal Cancer;Combination Drug Therapy;Cytotoxic T-Lymphocytes;DRD1 gene;DRD2 gene;DRD5 gene;Data;Dopamine D2 Receptor;Dopamine Receptor;Dose;Drug Synergism;Drug resistance;EIF-2alpha;Epigenetic Process;Exposure to;Fibroblasts;Fox Chase Cancer Center;Goals;Growth;Immune;Immune response;Immunologic Stimulation;Immunotherapy;Infiltration;Investments;Knock-out;Knockout Mice;Lymphoma;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Molecular Profiling;Mus;Mutation;NK Cell Activation;Natural Killer Cells;Neoplasm Metastasis;Operative Surgical Procedures;Pathway interactions;Patient Monitoring;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Publications;Publishing;Radiation therapy;Regulation;Research;Resistance;Role;Screening for cancer;Signal Pathway;Signal Transduction;Specimen;Stress;Subgroup;T-Cell Activation;T-Lymphocyte;TNFRSF10B gene;TNFSF10 gene;Therapeutic;Translating;Tumor Tissue;Uterine Cancer;analog;antagonist;anti-PD1 therapy;antitumor effect;biological adaptation to stress;cancer prevention;cancer stem cell;cancer therapy;cell type;combinatorial;cytokine;cytotoxic;first-in-human;host neoplasm interaction;human study;immune cell infiltrate;in vivo;insight;leukemia;neoplastic cell;novel;novel strategies;novel therapeutics;patient response;pharmacologic;pre-clinical;programs;receptor;receptor binding;recruit;resistance mechanism;small molecule;targeted treatment;tumor;tumor growth;tumor microenvironment;tumor progression;tumor specificity ONC201/TIC10 Anti-tumor Effect Through Regulation of the TRAIL pathway PROJECT NARRATIVEThis research program is directed towards the highly significant problem of drug resistance in advancedcancer that may be addressed by targeting anti-tumor cell death signaling pathways. The proposal buildson discovery in the El-Deiry Lab of a new drug ONC201 targeting the TRAIL death receptor pathway thathas been brought into multiple clinical trials and is showing promising activity in multiple tumor typesincluding prostate cancer GBM uterine cancer lymphoma leukemia and colorectal cancer. Theproposal provides unique and novel mechanistic insights regarding signaling within tumor cells includingimmune stimulation by ONC201 involvement of dopamine receptors and explores drug resistancemechanisms. NCI 10738317 6/20/23 0:00 PA-18-484 3R01CA173453-11S1 3 R01 CA 173453 11 S1 "KONDAPAKA, SUDHIR B" 9/30/13 0:00 4/30/24 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 1899817 "EL-DEIRY, WAFIK S" Not Applicable 1 PATHOLOGY 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF MEDICINE 29034202 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 93169 NCI 66421 26748 PROJECT SUMMARYThe project addresses the problem of drug resistance in cancer which is arguably the most importantproblem facing patients with advanced cancer. While advances have been made in targeted therapy andimmunotherapy over 600000 Americans will die in 2018 from cancer. Over the last two decades wediscovered TRAIL receptor DR5 and resistance mechanisms in cancer identified drug synergies anddiscovered small molecule ONC201 as a first-in-class TRAIL pathway inducer. Based on the novelty ofONC201 its emerging mechanism of action the specific impact my lab can have on the field and onpatients this proposal will focus in depth on ONC201 preclinical mechanistic directions. ONC201 hasprogressed as a monotherapy into multiple clinical trials with various tumor types. Our studies areproviding important basic information regarding the mechanism of action of ONC201 involving TRAILinduction after dual blockade of ERK and Akt converging on Foxo3a to activate TRAIL and an integratedstress response that involves eIF2-alpha dependent ATF4/CHOP-mediated induction of TRAIL deathreceptor 5. ONC201 depletes colorectal cancer stem cells and with dose intensification in mice weobserved anti-metastasis effects inhibition of cell migration and infiltration by NK and T cells into treatedtumors (recently published by Wagner et al. J. Clin. Invest. 2018). Our data has led to a change inclinical dosing in all open clinical trials including at Fox Chase Cancer Center (NCT02609230). Ourspecific aims include: Aim #1: Investigate ONC201 effects on the tumor microenvironment through NKand T cells leading to anti-tumor and anti-metastasis effects. Aim #2: Investigate the role of the immediatebinding target for ONC201 the sub-family of dopamine receptors DRD2/DRD3 in mediating its anti-tumor effects. We will explore novel connections between antagonism of the putative specific drugbinding target dopamine receptor D2 and D3 the TRAIL and integrated stress pathway mechanismtriggered by ONC201 their status in normal vs tumor cells and sensitive vs resistant cells or tumors frompatients exposed to ONC201. Our studies include in depth mechanism analysis of the immunestimulatory effects of ONC201 including analysis of immune infiltration by different immune cell subsetsvarious cytokines involved in attracting immune cells to tumors or those that may be potentially immune-suppressive and use of TRAIL and DR5 knockout as well as NCR1-GFP mice with GFP(+) NK cells toanalyze host tumor interactions of ONC201 (or ONC201 analogue) treated tumors. We explore ONC201resistance mechanisms through molecular profiling of tumor specimens from ONC201 trials and criticallyassess their role in preclinical models. 93169 +No NIH Category available Acceleration;Automobile Driving;Binding Proteins;Biological Models;Cancer cell line;Catalytic Domain;Cell Cycle Arrest;Cell Line;Cell physiology;Cells;Cervical;Chronology;Clinical;Collaborations;Complement;Cytoplasm;Data;Development;Differentiation and Growth;Disease;Etiology;Fostering;Future;Gene Targeting;Genetic Transcription;Genome;Goals;Growth;HPV-High Risk;Head and Neck Cancer;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Infection;Investigation;Knock-out;Knowledge;Laboratories;Life Cycle Stages;Link;Longevity;Longitudinal Studies;Maintenance;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Molecular;Oncogenic;Oncogenic Viruses;Oncoproteins;Papillomavirus Transforming Protein E6;Pathway interactions;Poly(A)-Binding Proteins;Preventive;Preventive vaccine;Proteins;Regulation;Research;Risk;Risk Factors;Signal Transduction;TERT gene;Target Populations;Telomerase;Therapeutic Intervention;Time;Viral;Viral Genes;Viral Markers;Viral Oncogene;Virus;Woman;Work;cancer initiation;cancer risk;cancer therapy;cancer type;cell growth;cellular longevity;cellular targeting;chronic infection;clinical risk;high risk;human papilloma virus oncogene;insight;keratinocyte;men;mutant;overexpression;posttranscriptional;prevent;protein function;protein protein interaction;senescence;therapeutic development;tumor progression;tumorigenesis;uptake High-risk HPV E6: dysregulation of immortalization growth and differentiation through protein partnerships in HPV-associated cancers PROJECT NARRATIVE High-risk human papillomaviruses (HPV) cause cervical anogenital and head and neck cancers.Despite the availability of preventive HPV vaccines their poor uptake leaves most men and women at risk forthese cancers many of which remain common globally and others which are increasing domestically. Throughdirect mechanistic studies of viral and host protein partnerships this project will uncover how cellular growth anddifferentiation are hijacked by HPV and how cellular immortalization is temporally and longitudinally activatedby HPV all of which must occur for HPV-associated cancer development and progression. NCI 10738316 5/1/23 0:00 PA-19-056 3R01CA172742-10S1 3 R01 CA 172742 10 S1 "READ-CONNOLE, ELIZABETH LEE" 6/4/14 0:00 5/31/25 0:00 Cancer Etiology Study Section[CE] 7682292 "KATZENELLENBOGEN, RACHEL ADRIA" Not Applicable 7 PEDIATRICS 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 70315 NCI 47980 22335 PROJECT SUMMARY/ABSTRACT High-risk human papillomaviruses (HR HPVs) cause 5% of all cancers. There are preventive vaccinesagainst HPV but less than 2% of the world's target population has received them. This leaves millions of womenand men at risk for HPV-associated cervical anogenital and head and neck cancers. We need to understandhow HR HPV establishes and maintains an active infection while also driving cancer development in order toguide focused therapeutic interventions to prevent arrest and reverse disease. The greatest clinical risk factor for cervical cancer is a persistent HR HPV infection. This persistenceoccurs through coordinated dysregulation of cellular pathways which both support the infection and foster cancerdevelopment. Underlying this dysregulation is the requirement that the HPV oncogenes E6 and E7 partner withcellular proteins. Our work has focused on the E6 oncogene from HPV type 16 (16E6) the most common HRHPV type in cancers. Previously we found that 16E6 required the cellular protein NFX1-123 and its proteinpartners cytoplasmic poly(A) binding proteins (PABPCs) to fully activate telomerase and the immortalizationpathway. Our current studies revealed that NFX1-123 is highly expressed in cervical cancers and together 16E6NFX1-123 and PABPCs amplify telomerase cellular growth and longevity over time. We also discovered thatNFX1-123 is increased during differentiation and together with 16E6 augments cellular differentiation cascadesand their host and viral gene targets while simultaneously protecting against concomitant cellular arrest andsenescence. These findings create a sightline for a new level of investigation that will uncover the connectivityand control of growth and differentiation and the temporal changes driving and accelerating immortalization byPABPCs NFX1-123 and 16E6. These results will also delineate targets for future treatments that specificallydisrupt universal pathways required for HPV and its cancers. Our specific aims are: (1) Determine how 16E6 NFX1-123 and PABPCs work together in co-regulatinggrowth and differentiation to better establish a persistent infection. We will mimic the initial steps of establishinga HR HPV infection to identify the way in which these proteins function to permit both differentiation and growthin concert during the initial foundational steps of a HR HPV infection. (2) Elucidate the mechanism of longitudinalsequential increases of hTERT and telomerase by 16E6 NFX1-123 and PABPCs. Telomerase activation leadsto cellular immortalization. We will leverage long-term cellular studies to determine the sequential changes tohTERT the catalytic subunit of telomerase due to 16E6 with NFX1-123 and PABPCs and to create a roadmapof molecular oncogenic progression that mirrors clinical chronology. Our proposed studies will elucidate thetemporal and interwoven dysregulation of oncogenic pathways by 16E6 and its host protein partners; they willalso provide foundational data on the oncogenic etiology and progression of increasingly common HPV-associated cancers. 70315 +No NIH Category available Antimetastatic Agent;Antineoplastic Agents;Bar Codes;Biochemical;Biological;Biological Assay;Breast Cancer Cell;Cell Line;Cells;Characteristics;Chemical Weapons;Chemicals;Collection;Colorectal Cancer;Coupled;Cyanobacterium;Cytotoxin;Data;Data Set;Development;Dimensions;Dolastatin 10;Drug resistance;Event;Florida;Funding;Future;G-Protein-Coupled Receptors;GSTP1 gene;Gene Cluster;Genes;Genetic;Growth;HCT116 Cells;Habitats;Hawaii;Histone Deacetylase Inhibitor;Investigation;Knowledge;Laboratories;Learning;Libraries;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Metagenomics;Microtubules;Modeling;Molecular;Molecular Analysis;Molecular Target;Morphology;Mus;Natural Product Drug;Natural Products;Neoplasm Metastasis;Nuclear;Organism;Pathway interactions;Pattern;Peptide Hydrolases;Pharmaceutical Chemistry;Phenotype;Phylogenetic Analysis;Planet Earth;Reporter Genes;Research;Ribosomal RNA;Sampling;Source;Structure;Synthesis Chemistry;Taxonomy;Translating;Validation;Vascular Endothelial Growth Factors;angiogenesis;apratoxin;cancer cell;cancer drug resistance;cancer prevention;cancer therapy;carcinogenesis;chemical synthesis;colon cancer cell line;cytotoxicity;drug discovery;efficacy study;experience;genetic information;hypoxia inducible factor 1;in vivo;inhibitor;innovation;malignant breast neoplasm;marine;milligram;novel;novel anticancer drug;novel therapeutics;preservation;programs;prostate cancer cell;rRNA Genes;screening;secondary metabolite;success;tool;transcription factor;tumor xenograft Novel Targeted Anticancer Agents from Marine Cyanobacteria PROJECT NARRATIVEMarine cyanobacteria produce selective anticancer agents with specific molecular targets. This research willlead to the discovery of new compounds that could become new drug leads for the treatment of cancer. NCI 10738315 9/13/23 0:00 PA-18-484 3R01CA172310-10S1 3 R01 CA 172310 10 S1 "FU, YALI" 3/6/13 0:00 8/31/24 0:00 Synthetic and Biological Chemistry B Study Section[SBCB] 7016782 "LUESCH, HENDRIK " Not Applicable 3 PHARMACOLOGY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF PHARMACY 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 44267 NCI 33421 10846 PROJECT SUMMARYCyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons fordefensive purposes which we are exploiting for anticancer drug discovery. Our past research has exemplifiedthat marine cyanobacteria produce compounds with exceptionally potent activity and/or possess unusual or first-in-class inhibitors with novel mechanisms of action. We apply a broad yet focused screening platform tomaximize discovery rate of new anticancer agents. We also integrate a synthetic chemistry component into ourprogram in order to perform rigorous biological studies to rapidly add value to our discoveries and to help solvethe supply problem. Specifically we will carry out field collections of marine cyanobacteria and prepare fractionlibraries for screening in a set of innovative pathway-focused cell-based assays utilizing various isogeniccolorectal cancer cell lines and reporter gene assays as well as newly developed unbiased phenotypic assays.We will perform dereplication identify cyanobacteria through molecular analysis and establish phylogeneticrelationships among benthic cyanobacteria. Samples will be prioritized based on bioactivity profiles and geneticuniqueness for further processing. Prioritized samples will be subjected to bioassay-guided isolation of the activecompounds. Structures will be determined using NMR and mass spectrometry. Basic validation of bioactivityand secondary assays will be performed before prioritizing targets for further investigation. Selected compoundswith intriguing structure and promising validated bioactivity will be targeted for total synthesis so that a rigorousbiological characterization can be performed to pinpoint the molecular changes induced in the cancer cell and todetermine potential direct targets. For novel noncytotoxic compounds that show potential antimetastatic activitywe will apply an orthogonal target-based screening platform. 44267 +No NIH Category available Antineoplastic Agents;Binding Proteins;Biological;Biological Assay;Biological Testing;Biometry;Biostatistics Core;Cancer cell line;Cells;Cessation of life;Chemicals;Chemistry;Chicago;Collection;Communication;Comprehensive Cancer Center;Consultations;Country;Coupled;Cyanobacterium;Databases;Decision Making;Developing Countries;Development;Disease;Doctor of Philosophy;Drug Industry;Drug Kinetics;Evaluation;Fiber;Formulation;Fractionation;Funding;Genomics;Goals;Human Resources;Illinois;In Vitro;Institution;Lead;Libraries;Lichen - organism;Malignant Neoplasms;Marketing;Metabolism;Methods;Modification;Molds;National Cancer Institute;National Center for Advancing Translational Sciences;Natural Compound;Natural Products;Neurofibromatosis 2;North Carolina;Ohio;Organism;Participant;Pediatric Hospitals;Pharmaceutical Chemistry;Plants;Play;Principal Investigator;Process;Provider;Regimen;Research;Research Personnel;Resistance;Resources;Role;Sampling;Solubility;Structure;Taxonomy;Testing;Therapeutic;Toxicology;United States;United States National Institutes of Health;Universities;Woman;Work;Xenograft procedure;analog;anticancer activity;antitumor drug;cancer therapy;chemotherapeutic agent;computerized;data management;drug development;drug discovery;experience;fungus;in vitro testing;in vivo;in vivo Bioassay;literature survey;meetings;men;novel;novel anticancer drug;programs;scale up;tumor;tumor growth Discovery of Anticancer Agents of Diverse Natural Origin OVERALL PROJECT NARRATIVECancer is responsible for about one in every four deaths in the United States and new treatments are urgentlyneeded. It is the overall goal of the integrated studies in this renewal application to discover novel chemicalsfrom selected tropical rainforest plants as well as lichens cyanobacteria and fungi for development as cancerchemotherapeutic agents particularly for tumors not cured by current treatment methods. NCI 10738313 7/25/23 0:00 PAR-18-290 3P01CA125066-14S1 3 P01 CA 125066 14 S1 "FU, YALI" 7/1/07 0:00 4/30/25 0:00 ZCA1-TCRB-Q(O1) 1877686 "KINGHORN, ALAN DOUGLAS" Not Applicable 3 NONE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF PHARMACY 432101016 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 50567 NCI 32415 18152 OVERALL PROJECT SUMMARYIn this Program Project renewal application the applicant group is representative of three primary institutionsThe Ohio State University (OSU) the University of Illinois at Chicago (UIC) and the University of North Carolinaat Greensboro (UNCG). The participants have combined their vast experience in the isolation structureelucidation and biological evaluation of natural products to the development of a consolidated integratedprogram for the discovery of novel anticancer agents of diverse origin for development as cancerchemotherapeutic agents. Plant materials to be studied in Project 1 (OSU) will be collected by establishedbotanists located in tropical countries with the assistance of the NAPRALERT database (Project 2; UIC) andlichens and their fungal associates (Project 1) cyanobacteria (Project 2) and filamentous fungi (Project 3;UNCG) will also be accessed. Organisms acquired will be extracted and evaluated in a diverse battery of relevantmechanism-based cell-based and tumor-growth related assays currently operational at OSU (Project 1) UIC(Core 1) Columbia University (through Project 3) and via other external collaborators (through Core A at OSU).Dereplication of known active compounds will be accomplished at OSU UIC and UNCG using computerizedliterature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed in Projects1-3 for the elucidation of the active principles. Lead development of active natural products via medicinalchemistry and pharmacokinetics-related studies will be conducted at OSU (Core 2) facilitated by the OSUBiostatistics group (Core A). Novel active compounds thus discovered will be further evaluated in our panel ofin vitro and in vivo bioassays (Projects 1 and 3 Core A and some external collaborators). Group decisions willbe made regarding the further development of agents for potential use as anticancer agents. The more advancedstages of biological and toxicological testing will be aided through consultation with the Drug Discovery Instituteof the OSU Comprehensive Cancer Center (through Core A). The Consortium will work with the involvement ofthe NCI Program Official in the discovery process and plans to hold regular meetings of key scientific personnel(inclusive of our External and OSU Internal Scientific Advisory Boards) to enhance communication and decision-making processes to be organized by Core A. Excellent facilities for the isolation structure determinationchemical modification synthesis and in vitro and in vivo biological evaluation and overall project datamanagement are available. The overarching goal of this P01 is to identify lead compounds that ultimately havetherapeutic value for the treatment of cancer. 50567 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;African;Alternative Splicing;Binding;Binding Proteins;Biogenesis;CRISPR/Cas technology;Cell physiology;Cells;Communities;Country;Data Set;Etiology;Funding;Genetic Transcription;Genome;Goals;HIV Seropositivity;Herpesviridae Infections;Highly Active Antiretroviral Therapy;Human;Human Herpesvirus 8;Immunity;Immunoprecipitation;Individual;Intervention;Kaposi Sarcoma;Knock-out;Life Cycle Stages;Malignant Neoplasms;Maps;Mediating;Messenger RNA;Methyltransferase;MicroRNAs;Modeling;Modification;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Nuclear Export;Nucleotides;Pathogenesis;Patients;Phase;Point Mutation;Poly(A)+ RNA;Population;Prevention;Prognostic Marker;Protein Overexpression;Proteins;RNA;RNA Degradation;RNA Splicing;RNA Viruses;RNA immunoprecipitation sequencing;Reader;Reagent;Regulation;Resolution;Role;Site-Directed Mutagenesis;Societies;Stains;System;Testing;Time;Transcript;Translations;Viral;Virus Diseases;Virus Latency;Virus Replication;Work;base;carcinogenesis;cell type;clinically relevant;crosslink;epitranscriptome;expectation;gain of function;innovation;insight;knock-down;loss of function;lytic replication;mRNA Translation;metaplastic cell transformation;mortality;neoplastic cell;new technology;novel;novel therapeutics;overexpression;primary effusion lymphoma;programs;reverse genetics;therapeutic target;transcriptome;tumor;tumorigenesis Regulation of KSHV replication by N6-methyladenosine (m6A) Project NarrativeKaposi's sarcoma-associated herpesvirus (KSHV) causes several human cancers including Kaposi'ssarcoma primary effusion lymphoma and multicentric Castleman's disease. These malignancies inflictmorbidity and mortality to the society in US and worldwide. This project will investigate the mechanismsregulating the replication of KSHV by RNA modifications and identify potential therapeutic targets fordeveloping novel prevention and treatment approaches. NCI 10738312 8/8/23 0:00 PA-19-056 3R01CA124332-15S1 3 R01 CA 124332 15 S1 "READ-CONNOLE, ELIZABETH LEE" 4/1/07 0:00 7/31/26 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 11026736 "GAO, SHOU-JIANG " Not Applicable 12 GENETICS 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 239052 NCI 239052 0 N6-methyladenosine (m6A) is the most abundant internal modification on poly(A) RNA. Dynamic regulation ofthe m6A epitranscriptome is involved in diverse cellular functions. m6A mediates these functions by affectingmRNA translation alternative splicing nuclear export and degradation and miRNA biogenesis and bindingthrough three groups of proteins: methyltransferases or writers demethylases or erasers and m6A-bindingproteins or readers. m6A is present in the genomes of RNA viruses and regulates the replication of theseviruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) andprimary effusion lymphoma (PEL) commonly found in AIDS patients. Understanding the mechanism regulatingKSHV latent and lytic replication can not only provide insights into the pathogenesis of KSHV-induced cancersbut also serve as the basis for developing novel therapy. In the current funding period we have madesignificant progresses toward this goal. For this renewal we have discovered that m6A is abundant on KSHVtranscripts and that m6A reader protein YTHDF2 acts as an antiviral factor during viral lytic replication. Wedemonstrate m6A dynamics during KSHV latent and lytic replications and in different cell types that supportdistinct viral replication programs. Despite these works the roles of m6A in KSHV infection have just started tobe revealed. The Objective of this application is to systematically map the dynamics of m6A modifications at asingle base resolution and bindings of m6A reader proteins in KSHV epitranscriptome and determine theirfunctions in different phases of KSHV life cycle and KSHV-induced tumorigenesis. The Central Hypothesis isthat KSHV m6A modifications are dynamically regulated and these modifications mediate different phases ofKSHV life cycle and hence KSHV-induced tumorigenesis. We will test this hypothesis by mapping m6A marksin KSHV transcriptome at a single base resolution and determine the roles of m6A writer and eraser proteins indifferent phases of KSHV life cycle and KSHV-induced tumorigenesis (Aim 1); determining the functions ofm6A reader proteins in different phases of KSHV life cycle by gain- and loss-of-function approaches and byexamining their bindings to KSHV transcripts (Aim 2); and examining the functions of KSHV m6A marks in thecontext of viral infection using Crispr-Cas9-guided m6A writer and eraser and by site-specific mutagenesis(Aim 3). It is our expectations that this project will provide comprehensive mapping and functional delineationof m6A marks and m6A writer eraser and reader proteins in different phases of KSHV life cycle and KSHV-induced tumorigenesis. This work is highly significant as it will for the first time systematically reveal thefunctions of these RNA modifications in KSHV infection thus providing insights into the mechanism regulatingKSHV life cycle and KSHV-induced pathogenesis. This study will also identify potential prognostic markers andtherapeutic targets. The proposed work is highly innovative as it will use new technologies to map m6A marksand bindings of m6A reader proteins as well as directly manipulate m6A marks on key viral transcripts byCrispr-Cas9-guided m6A writer and eraser KSHV reverse genetics and innovative tumor models.Furthermore the generated datasets information and reagents will be valuable to the scientific community. 239052 +No NIH Category available Acute-Phase Proteins;Address;Amyloid;Antigens;Applications Grants;Biology;CD8B1 gene;Cell physiology;Cellular biology;Clinical;Data;Dendritic Cells;Deposition;Development;Environment;Exposure to;Extracellular Matrix Proteins;Funding;Genetic;Grant;Hepatic Stellate Cell;Hepatocyte;Homeostasis;Immune Evasion;Immunobiology;Immunologic Surveillance;Immunologics;Immunosuppression;Immunotherapy;Impairment;Infiltration;Interleukin-6;KPC model;KRASG12D;Knowledge;Kupffer Cells;Liver;Macrophage;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Metastatic Neoplasm to the Liver;Modeling;Molecular;Mus;Myeloid Cells;Neutrophil Infiltration;Non-Malignant;Organ;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Play;Portal vein structure;Primary Neoplasm;Process;Productivity;Proteins;Reproducibility;Resistance;Retrospective Studies;Role;STAT3 gene;Serum;Shapes;Signal Pathway;Soil;Stromal Cells;T cell infiltration;T-Lymphocyte;Therapeutic;Tumor Escape;Variant;cancer cell;cancer immunotherapy;carcinogenesis;clinically relevant;design;effector T cell;human cancer mouse model;human disease;human tissue;immune checkpoint blockade;immunogenicity;immunoreaction;immunoregulation;improved outcome;liver inflammation;melanoma;mouse model;novel;novel strategies;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;peripheral tolerance;systemic inflammatory response;tool;trafficking;tumor;tumor microenvironment;tumor-immune system interactions Targeting the liver for immunotherapy in pancreatic cancer Project NarrativeT cell immunotherapy has yet to produce clinical benefit for most patients with pancreatic cancer. In thisproposal we investigate (i) mechanisms of primary resistance to immunotherapy with a focus on the liver as aknown immunoregulatory organ and (ii) therapeutic implications of the liver in shaping cancer immunogenicityand the efficacy of immunotherapy. The proposed studies will use clinically relevant mouse models of cancerand human tissues to inform the design of novel strategies to broaden the efficacy of cancer immunotherapy. NCI 10738295 11/21/23 0:00 PA-20-185 5R01CA197916-08 5 R01 CA 197916 8 "ZAMISCH, MONICA" 7/1/16 0:00 11/30/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 9156575 "BEATTY, GREGORY L" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 347344 NCI 213750 133594 Project SummaryImmunotherapy has shown the capacity to improve outcomes for some patients across a wide-range ofmalignancies. However many patients still do not achieve clinical benefit and in particular patients with livermetastases demonstrate poor responsiveness to immunotherapy. Emerging evidence suggest a role for the liverin determining outcomes with cancer immunotherapy. To this end the liver is a critical determinant of immuneregulation and plays a central role in T cell peripheral tolerance. Yet how the liver may regulate immunotherapyefficacy is unclear. This represents a significant gap in our knowledge that has strong translational implications.In gastrointestinal malignancies the liver may be continuously exposed to malignant cells as well as solublefactors and antigens released by primary tumors. We hypothesize that this connection between the gut and livermay have significant implications on T cell immunosurveillance in cancer. In support of this hypothesis we havefound that primary tumors release soluble factors that activate hepatocytes in the liver. This process can beginduring the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phasereactants which act to orchestrate an immunological niche environment in the liver that is underpinned by therecruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. In the setting ofhepatocyte activation primary tumor development occurring in the pancreas demonstrates poor T cellinfiltration. However genetic blockade of hepatocyte activation converts a T cell cold tumor into a hot tumor.This finding underscores the importance of the liver in regulating T cell immunosurveillance in cancer. Our priorityis to decipher mechanisms by which the liver regulates T cell immunosurveillance in cancer and to understandits implications in regulating the efficacy of cancer immunotherapy. Therefore in Aim 1 we will definemechanisms by which hepatocytes direct tumor immune evasion with a focus on signaling pathways regulatedby hepatocytes and their impact on T cell priming and trafficking. In Aim 2 we will investigate the impact ofhepatocyte activation on the immunobiology of PDAC and the efficacy of cancer immunotherapy. Together thesecomplementary aims will inform the development of novel treatment paradigms designed to curtail theimmunosuppressive effects of liver inflammation as a strategy to broaden the efficacy of cancer immunotherapy. 347344 +No NIH Category available ASCL1 gene;Acetylation;Automobile Driving;Biological Assay;Biological Process;Cancer Etiology;Carcinogens;Cell Lineage;Cells;Cessation of life;ChIP-seq;Chromatin;Chromatin Structure;Circadian Dysregulation;Circadian Rhythms;Complex;DNA Binding;Data;Disease;Drug resistance;Epigenetic Process;Gene Activation;Generations;Genes;Genetic Transcription;Genomic approach;Growth;In Vitro;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolism;Metastatic Prostate Cancer;Modeling;Molecular;Neoplasm Metastasis;Neuroendocrine Prostate Cancer;Neurosecretory Systems;Patients;Pharmaceutical Preparations;Proteins;Regulation;Regulator Genes;Resistance;Resistance development;Risk;Role;Safety;Series;Site;Squamous Cell Lung Carcinoma;Testing;Therapeutic;Time;advanced prostate cancer;antagonist;cancer stem cell;cancer subtypes;cancer type;castration resistant prostate cancer;chromatin modification;circadian;circadian pacemaker;effective therapy;efficacy evaluation;enzalutamide;in vivo;inhibitor;innovation;insight;knock-down;men;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;pancreatic cancer cells;patient derived xenograft model;programs;prostate cancer cell;prostate cancer model;recruit;small molecule;small molecule inhibitor;stem-like cell;success;therapeutic development;therapeutic target;therapeutically effective;therapy resistant;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor growth;tumorigenic Targeting aberrant circadian regulator in advanced prostate cancer Prostate cancer remains to be one of the leading causes of cancer-related death in U.S. men largelydue to resistance to current therapeutics. Therefore there is an urgent need of more effectivetherapeutics that can provide sustained benefits or cure to the patients. Our studies aim to achieve arelatively thorough understanding of the aberrant role of a circadian clock regulator in driving the lethalform of prostate cancer and offer a new therapy strategy for effective treatment of the lethal form ofprostate cancer. NCI 10738281 11/30/23 0:00 PA-20-185 5R01CA259081-03 5 R01 CA 259081 3 "KONDAPAKA, SUDHIR B" 12/15/21 0:00 11/30/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 1923149 "CHEN, HONGWU " Not Applicable 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 330258 NCI 205875 124383 ABSTRACTMetastatic prostate cancer (PCa) remains to be one of the leading causes of cancer-related death.Patients with metastatic castration-resistant PCa or mCRPC often develop resistance to the 2ndgeneration therapeutics including enzalutamide and the disease becomes deadly. Like many othercancer types PCa tumors display high cellular and epigenetic plasticity that are associated withtherapy resistance and progression to more lethal forms such as neuroendocrine PCs or NEPC.Circadian rhythm (CR) regulates daily oscillations of major biological processes. Circadian disruption(CD) is considered as a likely carcinogen. We found that PCa cells lost the normal CR regulation andthat one the CR regulators Rev-erb/NR1D1 acts as a strong candidate driver of growth and survivalof mCRPC cells. We also found that Rev-erb is overexpressed and amplified in metastatic CRPCtumors and that its small molecule antagonists displayed high efficacy in inhibition of growth of severalPCa models. Our preliminary mechanistic studies suggest that Rev-erb associates with severalepigenetic factors to activate multiple gene programs associated with advanced PCa. We hypothesizethat deregulated CR regulators such as Rev-erb drives tumor plasticity by establishing aberrantchromatin structures and that targeting the aberrant Rev-erb function is efficacious and safe fortreatment of the lethal forms of PCa. In Aim 1 and Aim 2 we will establish the driver role of aberrantRev-erb in tumor plasticity and therapy resistance and define the molecular mechanisms. In Aim 3we will use multiple models of therapy resistant CRPC to examine the efficacy of the Rev-erbinhibitors in sensitizing the treatment and the mechanism of action in blocking tumor plasticity. 330258 +No NIH Category available Address;Affect;BRCA1 Protein;BRCA1 gene;Biological Markers;Biological Models;Biology;Breast Cancer Cell;Breast Cancer Model;Breast Cancer cell line;CCNE1 gene;Cancer Patient;Cancer cell line;Cell Line;Cells;Chromatin;Chromosomal Rearrangement;Classification;Clinical;Clinical Data;Communities;Computer Analysis;DNA;DNA Structure;DNA biosynthesis;DNA replication fork;Data Set;Derivation procedure;Development;Endometrial Carcinoma;Engineering;Enterobacteria phage P1 Cre recombinase;Evolution;G-Quartets;Gene Mutation;Generations;Genes;Genetic;Genetic Anticipation;Genetically Engineered Mouse;Genome;Genomic Instability;Genomic Segment;Genomics;Goals;Growth;Harvest;Human;Hybrids;Immunooncology;In Vitro;Individual;Injections;Knockout Mice;Lead;Lentivirus;Link;Location;Malignant Neoplasms;Malignant neoplasm of ovary;Mammary Neoplasms;Mammary gland;Maps;Meta-Analysis;Modeling;Molecular;Monitor;Mus;Null Lymphocytes;Organoids;Pathway interactions;Pattern;Phenotype;Protein Deficiency;Proteins;RNA;Research;Resources;Role;Shapes;Site;Source;Structure;TP53 gene;Testing;Therapeutic;Tissues;anti-PD-1;anticancer research;breast tumorigenesis;cancer genome;cancer therapy;clinical development;conditional knockout;genetic element;genome sequencing;genome-wide;in vivo;in vivo Model;insight;longitudinal analysis;loss of function;malignant breast neoplasm;mammary;mouse model;neoantigens;p53-binding protein 1;pharmacologic;pre-clinical;precision oncology;premalignant;recombinase;repaired;replication stress;response;timeline;transcriptome;treatment response;triple-negative invasive breast carcinoma;tumor;tumorigenesis Genomic Biology of the Tandem Duplicator Phenotype in Mouse and Human Cancers PROJECT NARRATIVEUsing sequencing analyses of human cancer genomes we previously identified a form of extensivechromosomal rearrangement called the Tandem Duplicator Phenotype (TDP) which is found in ~50% of triple-negative breast cancers as well as ovarian and endometrial cancers. To understand how different types of TDPsare formed in mammary tissues and then evolve in established breast tumors our research will use genomesequencing analyses and exploit genetically engineered mouse models and cultured human breast cancer cells.The insights we gain into TDP formation and evolution will ultimately support clinical development of new TDP-targeting cancer treatments. NCI 10738275 11/20/23 0:00 PA-19-056 5R01CA255705-04 5 R01 CA 255705 4 "FINGERMAN, IAN M" 12/1/20 0:00 11/30/25 0:00 Cancer Genetics Study Section[CG] 8683998 "LIU, EDISON TAK-BUN" Not Applicable 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 633594 NCI 335235 298359 PROJECT SUMMARYWe have identified a group of genome instability configurations called the Tandem Duplicator Phenotypes(TDPs) that are found in ~50% of triple negative breast ovarian and endometrial cancers and are characterizedby the massive genome-wide distribution of somatic tandem duplications (TDs) of specific span sizes. We haveidentified the bona fide genetic drivers of these configurations demonstrated that loss of Trp53 and Brca1 in themouse mammary gland is sufficient to induce tumors with the short-span TDP configuration found in TP53- andBRCA1-deficient human cancers and shown that upon loss of Brca1 TDs are formed through the aberrantrepair of stalled replication forks. Here we propose to deploy a combination of computational analyses in vivomodelling and in vitro experimentation to achieve a deep mechanistic understanding of how the distinct TDPgenomic configurations emerge and impact the course of breast tumorigenesis. Specifically we will investigatethe molecular mechanisms leading to de novo TD formation across the different TDP groups by exploring howlocal DNA features associated with DNA replication and fork stalling contribute to the generation of new TDsacross a large pan-cancer dataset representing all TDP groups and all TDP genetic drivers (Aim 1A) and howloss of BRCA1 activity may modulate the spread and location of the de novo TDs formed in the context of theshort-span TDP (Aim 1B). We will establish new genetically engineered mouse models (GEMMs) of breastcancer to validate that activation of the Ccne1 pathway or loss of Cdk12 activity both in conjunction with Trp53loss of function induces medium- and long-span TDP configurations that mimic their human counterparts bothin terms of TD span size and distribution (Aim 2A) and of the genomic features and genetic elements that areassociated with and affected by TD formation (Aim 2B). We will also assess the tumor neo-antigen load of theTDP tumors emerging from the newly developed GEMMs and test whether immuno-oncology agents areeffective against mammary tumors with the TDP configuration as suggested by recently emerging clinicalobservations (Aim 2A). We will then use isogenic human cancer cell lines that are either proficient or deficientfor BRCA1 activity to determine the dynamics of de novo TD formation under different modes of cellularperturbation and as a function of BRCA1 status (Aim 3A). Finally we will use the newly developed GEMMs tounderstand the evolutionary path to genome-wide TD distribution in the mammary gland and to discern thedynamics of TDP emergence both in terms of the rate of de novo TD formation and with respect to the timelineof breast tumorigenesis (Aim 3B). If successful this proposal will uncover the root causes of a significant formof genomic instability in human cancer the TDP define the mutational dynamics leading to cancer formation inthis condition and generate model systems that can lead to the development of new and directed therapeuticsagainst cancer growth. 633594 +No NIH Category available Address;BRAF gene;Binding;Biochemical;Biological Assay;Biophysics;Cell Line;Cells;Clinical;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Computing Methodologies;Development;Dimerization;Drug Design;Drug Kinetics;Drug resistance;FDA approved;Feedback;Generations;Goals;Guanosine Triphosphate;Homo;Hybrids;In Vitro;Investigation;Knowledge;Lead;Light;MAP Kinase Gene;MAPK Signaling Pathway Pathway;MEKs;Malignant Neoplasms;Malignant neoplasm of thyroid;Mediating;Medical;Melanoma Cell;Modeling;Mus;Mutate;Mutation;Oncogenic;PTPN11 gene;Pathway interactions;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Play;Process;Prognosis;Progression-Free Survivals;Property;Quantitative Structure-Activity Relationship;RNA Splicing;Regulation;Resistance;Series;Signal Transduction;Solid;Specificity;Structure;Therapeutic;Therapeutic Index;Thyroid Gland;Toxic effect;Translating;Validation;Variant;Xenograft Model;cancer cell;clinically relevant;computational pipelines;design;dimer;drug development;drug discovery;experimental study;improved;in silico;in vivo;inhibitor;innovation;insight;lead optimization;melanoma;monomer;multidisciplinary;mutant;neoplastic cell;next generation;novel;pharmacologic;prototype;resistance mechanism;response;screening;thyroid neoplasm;tumor Allosteric inhibitors targeting oncogenic BRAF V600E dimers FDA-approved BRAF inhibitors that target effectively mutated monomeric BRAF elicit remarkable clinicalresponses in BRAFV600E mutant melanoma however activated BRAF dimers remain poorly targeted a factthat leads to limited progression free survival in melanoma and other tumors such as colorectal and thyroidwith oncogenic BRAF signaling. Our proposal addresses this significant unmet medical need. We propose touse our expertise in drug discovery and unique insights into BRAF structure and regulation to identify the next-generation BRAF inhibitors with high specificity for BRAFV600E dimers that will ultimately serve as prototypetherapeutics. NCI 10738270 11/10/23 0:00 PA-19-056 5R01CA238229-05 5 R01 CA 238229 5 "KONDAPAKA, SUDHIR B" 12/1/19 0:00 11/30/24 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 9508294 "GAVATHIOTIS, EVRIPIDIS " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 405904 NCI 277164 128740 Increased activation of the MAPK signaling pathway can induce malignancies. Oncogenic mutation V600E inBRAF is found in almost 50% of melanoma tumors. In addition substantial percentages of BRAFV600Emutants are found in colorectal and thyroid cancers about 10% and 40% respectively. FDA-approved RAFinhibitors for melanoma show remarkable responses in BRAFV600E patients however treatment leads almostinvariably to acquired resistance. Similarly colorectal and thyroid cancers with BRAFV600E are largelyresistant to RAF inhibitor treatment. Several studies have demonstrated that intrinsic or inhibitor-inducedBRAFV600E dimerization plays a key role in the resistance mechanism. In melanoma BRAFV600E usuallyacts as an active monomer however in a significant subset of tumors active spliced BRAFV600E dimersmediate primary resistance. Likewise in large portions of upstream RAS-activated cancers like colorectal andthyroid BRAFV600E dimers are promoted and the above drugs are ineffective. In light of the clinical relevanceof BRAFV600E dimers to drive resistance in several tumors we are currently in pressing need to developnovel inhibitors that target potently and specifically active BRAF dimers. We recently demonstrated thecorrelation of structural and biochemical effects of RAF inhibitors with their clinical manifestations. Using thisknowledge we initiated a systematic quest for novel inhibitors that specifically recognize BRAFV600E dimers.We discovered that Ponatinib an FDA-approved drug is such an inhibitor. In extensive preliminary studies wecharacterized the effect of Ponatinib in melanoma colorectal and other cancers and obtained its co-crystalstructure with BRAFV600E and BRAFWT. Remarkably the BRAF/Ponatinib structures demonstrated aperfectly symmetrical BRAF dimer and an allosteric inhibitor-binding mode unprecedented for any BRAFinhibitor to date. Our observations generate an exceptional opportunity for drug design towards next-generation allosteric BRAF inhibitors that specifically inhibit BRAF dimers. Based on these observations wecreated a ponatinib-hybrid compound determined its co-crystal structure and validated its biochemical andcellular activity. Our results demonstrate excellent potency and specificity for BRAFV600E dimers compared toBRAFV600E monomers and provide a solid basis for the development of such first-in-class allosteric BRAFinhibitors. In this proposal we will 1) design and synthesize ponatinib-hybrid compounds that bind to the novelallosteric pocket of BRAF and display improved binding and specificity to BRAFV600E dimers and desirableADME properties 2) robustly validate and optimize the potency and specificity of allosteric BRAF inhibitors inbiochemical biophysical and cellular experiments and 3) investigate the cellular mechanism of action ofimproved allosteric BRAFV600E inhibitors and their therapeutic potential in mouse tumor models. This projectwill investigate a broadly unmet therapeutic opportunity namely the pharmacological targeting of BRAFV600E-dimerization dependent tumors that are resistant to current treatments. 405904 +No NIH Category available Androgen Antagonists;Antiandrogen Therapy;Biological Availability;Biomedical Engineering;Cancer Patient;Cells;Chronic;Clinical Data;Clinical Research;Data;Development;Disease;Down-Regulation;Drug resistance;Future;Generations;Goals;Growth;In Vitro;Knowledge;LNCaP;Malignant neoplasm of prostate;Mediating;Metastatic Neoplasm to the Bone;Modeling;Patients;Pharmaceutical Preparations;Play;RNA;Resistance;Resistance development;Role;Signal Transduction;Small Interfering RNA;Specimen;System;Testing;Tissues;Toxic effect;Transfer RNA;Translating;Up-Regulation;Variant;WNT Signaling Pathway;abiraterone;advanced prostate cancer;carcinogenesis;castration resistant prostate cancer;cell growth;clinical development;effective therapy;efficacy evaluation;enzalutamide;experimental study;in vivo;inducible gene expression;inhibitor;knock-down;next generation;novel;novel strategies;novel therapeutic intervention;prostate cancer cell;prostate cancer progression;small molecule inhibitor;therapeutic target;therapy resistant;treatment strategy;tumor;tumor growth;tumor xenograft Therapeutic targeting Wnt5A signaling for advanced prostate cancer Resistance to next generation anti-androgen agents such as enzalutamide and abiraterone occurs frequentlyand the mechanisms are incompletely understood. This application is aimed to understand the roles and theunderlying mechanisms of Wnt5A signaling in resistant prostate cancer and develop novel treatmentstrategies by targeting Wnt5A to treat advanced prostate cancer and overcome resistance to anti-ARtherapies. NCI 10738266 11/13/23 0:00 PA-19-056 5R01CA250082-04 5 R01 CA 250082 4 "KONDAPAKA, SUDHIR B" 12/1/20 0:00 11/30/25 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 6615638 "GAO, ALLEN C" Not Applicable 4 UROLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 338175 NCI 229667 108508 Enzalutamide and abiraterone are initially effective for the treatment of castration-resistant prostate cancer(CRPC). However resistance to both drugs occurs frequently through mechanisms which are incompletelyunderstood. Evidence from both clinical and experimental studies demonstrate that Wnt signaling particularlythrough Wnt5A plays vital roles in promoting CRPC progression and induction of resistance to enzalutamideand abiraterone. Development of novel strategies targeting Wnt5A to overcome resistance is an urgent need.Preliminary and clinical data demonstrate that Wnt5A signaling is significantly activated in resistant CRPC cellsand specimens from CRPC patients. Down regulation of Wnt5A inhibits AR/AR variants expression suppressescell growth and resensitizes resistant cells to anti-androgen treatment. The objective of this proposal is to fullydelineate the role of Wnt5A signaling in drug resistance and determine the efficacy of targeting Wnt5A using twonovel strategies to overcome resistance. In Aim 1 we will determine the role of Wnt5A in the development ofresistance to enzalutamide and abiraterone. In aim 2 we will evaluate the efficacy of two novel strategiestargeting Wnt5A for inhibiting resistant CRPC tumor growth and re-sensitization to enzalutamide/abirateronetreatment. In aim 3 we will elucidate the mechanisms of action by Wnt5A inhibition in resistant CRPC. We hopethat by completion of this study we will provide a novel therapeutic approach to treat advanced CRPC throughtargeting Wnt5A. We also expect that targeting Wnt5A in conjunction with enzalutamide/abiraterone therapy willincrease the magnitude and duration of the benefits of second-generation antiandrogens. 338175 +No NIH Category available Abscopal effect;Adaptive Immune System;Address;Adjuvant;Anatomy;Antibodies;Antigen Presentation;Cancer Model;Cell physiology;Cells;Clinical;Clinical Treatment;Clinical Trials;Common Neoplasm;Data;Distant;Environment;Evaluation;Future;Goals;Human;Immune system;Immunity;Immunotherapeutic agent;Immunotherapy;Infection;Innate Immune System;Investigation;Malignant Neoplasms;Measurable;Modeling;Mus;Natural Killer Cells;Patients;Peptides;Phenotype;Preparation;Primary Neoplasm;Productivity;Recrudescences;Recurrence;Role;Site;Solid Neoplasm;Surveys;T cell response;T memory cell;T-Lymphocyte;Testing;Tissues;Tumor Biology;Viral;Virus;Virus Diseases;anti-PD-L1;anti-cancer;antiviral immunity;arm;cancer immunotherapy;cytokine;experience;fighting;immune checkpoint blockade;immunogenic;in vivo;melanoma;memory retention;neoantigens;neoplasm immunotherapy;novel strategies;prevent;programmed cell death ligand 1;recruit;response;sound;synergism;tissue resident memory T cell;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Repurposing TRM for tumor immunotherapy Project NarrativeThe goal of this proposal is to define the mechanism of a new strategy of immunotherapy: peptide alarmtherapy. Further investigations will test the potential for synergizing peptide alarm therapy with otherimmunotherapies and for testing abscopal effects in mouse cancer models followed by evaluation of peptidealarm therapy-induced sensing and alarm functions in human tumor explants. Successful execution shouldprovide the necessary information to proceed with a clinical trial for the treatment of human cancer. NCI 10738258 11/2/23 0:00 PA-19-056 5R01CA238439-05 5 R01 CA 238439 5 "SINGH, ANJU" 12/4/19 0:00 11/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 2541195 "MASOPUST, DAVID " Not Applicable 5 MICROBIOLOGY/IMMUN/VIROLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 395 Non-SBIR/STTR 2024 441143 NCI 288723 152420 Abstract: Repurposing TRM for tumor immunotherapyOvercoming the immunosuppressive tumor microenvironment and localizing adoptive cell and checkpointblockade therapies to solid tumors remain major impediments to successful cancer immunotherapy. Thisproposal addresses these issues. Preliminary data indicates that human tumors are populated with antiviral Tcells that remain competent to trigger immunostimulatory sensing and alarm function upon local recognition ofcognate peptide. In mice peptide alarm therapy synergizes with PD-L1 to clear tumors and mice are durablyprotected against tumor growth at alternative anatomic sites in the absence of further treatment. This proposalwill dissect the mechanisms by which peptide alarm therapy triggers tumor clearance and establishes systemictumor-specific immunity. It will test synergy with other immunotherapies. Further investigations will be made onthe ability to recapitulate peptide alarm therapy on human tumor explants in anticipation of informing a clinicaltrial. This proposal may have a sustained impact on the field by defining a new avenue of cancer immunotherapythat operates independently but synergizes with other therapies. 441143 +No NIH Category available Acceleration;Adoption;Advocate;Africa South of the Sahara;Awareness;Breast;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Treatment;Cancer Control;Cancer Etiology;Caring;Cervical Cancer Screening;Clinical;Communities;Complex;Consolidated Framework for Implementation Research;County;Data;Development;Diagnosis;Early Diagnosis;Early treatment;Effectiveness;Eligibility Determination;Equity;Evidence based intervention;Faculty;Focus Groups;Future;Government;HIV Seropositivity;Health Personnel;Health Resources;Health system;Healthcare Systems;Hospitals;Individual;Information Technology;Inservice Training;Institution;International;International Agency for Research on Cancer;Intervention;Interview;Kenya;Link;Malignant neoplasm of cervix uteri;Mammography;Maps;Mentors;Methods;Modeling;Morbidity - disease rate;Motivation;Nature;Oncology;Outcome;Patients;Phase;Policies;Primary Care;Primary Health Care;Process;Proctor framework;Randomized;Research;Research Personnel;Research Project Grants;Research Support;Resources;Screening for cancer;Services;Students;System;Technology;Testing;Training;Universities;Washington;Woman;base;breast exam;candidate identification;candidate selection;career;clinical research site;community engagement;cost;design;evidence base;feasibility testing;implementation evaluation;implementation intervention;implementation outcomes;implementation research;implementation science;implementation/effectiveness;improved;informant;intervention mapping;knowledge translation;mHealth;malignant breast neoplasm;mobile computing;mortality;multiphase optimization strategy;patient navigation;patient oriented;peer;pilot test;pilot trial;population based;primary care provider;programs;recruit;scale up;screening;screening program;synergism;systematic review;uptake;user-friendly Enhanced Cervical Cancer Screening Adoption and Treatment Linkage for HIV positive Women in Kenya (eCASCADE-Kenya) n/a NCI 10738135 9/19/23 0:00 RFA-CA-22-019 1U54CA284036-01 1 U54 CA 284036 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8146 8223125 "CHUNG, MICHAEL HOONBAE" Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 182112 163584 18528 CENTER OVERALL: PROGRAM SUMMARY / ABSTRACTWhile considerable evidence is available for screening and early treatment of breast and cervical cancershuge gaps remain in equitable and sustainable translation of this knowledge into practice and policy especiallyin sub-Saharan Africa. In Kenya gaps in screening and linkage to treatment result in late-stage presentation ofbreast and cervical cancers profound preventable morbidity and mortality and disproportionate hindrance towomens development. To close these gaps the Enhanced BReast and cErvical cAncer screening in KenyaTHROUGH implementation science research and training (BREAKTHROUGH) Center coalesces trans-disciplinary expertise at Kenyatta National Hospital (KNH) Emory University University of Washington andQueens University. BREAKTHROUGH will include an Administrative and Engagement Core that engagescommunity clinical and government stakeholders and scientific partners and seamlessly coordinates [OverallAim 1] our interrelated Research Capacity Building Core and two Research Projects. Our multi-institutionalcollaborative partners bring considerable breadth and depth of implementation science and oncology expertisea substantial research base matched resource commitments (>$125000 in contributions) internationalgravitas and >10 years of working together. To grow implementation science in womens cancer control andconduct impactful research BREAKTHROUGH has a training framework that engages investigators across thecareer spectrum (faculty fellows students) to sustainably strengthen capacity by supporting trainees tobecome mentors [Overall Aim 2]. We provide didactic training; engagement in Research Projects; and accessto stakeholders technologies networking and enrichment activities. BREAKTHROUGHs projects will mapand co-design (with stakeholders) strategies that overcome barriers to womens cancer control. We then testfeasibility implementation effectiveness and sustainment of context-specific theoretically-informed strategiesfor overcoming complex barriers to adoption and integration of breast and cervical cancer screening andreferral linkages in primary care [center theme; Overall Aim 3]. We also utilize these projects as trainingplatforms to strengthen local capacity and research administration for implementation science at KNH. Project1 is entitled accelerating aDoption of pAtient-centereD cervicAl cancer screening and treatment LINKage inKenya (DADA LINK) and Project 2 is entitled a Multi-level strATegy for InTegrating Information technologYand mobile health to strengthen linkAges to breast caNcer screeninG and early detection among womenUtilizing primary care in Kenya (MATITI YANGU). The Center Cores and Projects will produce actionablemixed methods user-friendly evidence and bidirectionally engage with key stakeholders as advisors anddisseminators maximizing reach uptake and sustainability. BREAKTHROUGH is well-integrated acrossCores and Projects and embodies an ethos of promoting equity in our institutions research and our impacts. +No NIH Category available Acceleration;Acetic Acids;Address;Adherence;Adopted;Adoption;Africa South of the Sahara;Age;Attitude;Awareness;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Treatment;Cancer Control;Cancer Etiology;Caring;Cervical;Cervical Cancer Screening;Cessation of life;Clinic;Clinical;Clinical Trials;Collaborations;Communities;Complex;Data;Development;Diagnosis;Early Diagnosis;Early treatment;Effectiveness;Ensure;Equity;Faculty;Female;Government;Guidelines;HIV Seropositivity;Health;Health Services Accessibility;Hospitals;Human;Human Papillomavirus;Human Resources;Hybrids;Incidence;Information Technology;Infrastructure;Institution;International;Intervention;Kenya;Knowledge;Lesion;Letters;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Measures;Mentors;Meta-Analysis;Methods;Morbidity - disease rate;Motivation;Oncology;Patients;Policies;Policy Making;Preparation;Primary Care;Procedures;Provider;Readiness;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Research Technics;Resources;Screening for cancer;Site;Structure;Students;System;Technology;Telephone;Testing;Text;Time;Training;Triage;Universities;Visual;Washington;Woman;base;behavior change wheel;care fragmentation;career;community engagement;cost;design;effectiveness outcome;effectiveness/implementation study;feasibility testing;follow-up;implementation evaluation;implementation outcomes;implementation research;implementation science;implementation strategy;improved;intervention cost;knowledge translation;low and middle-income countries;mHealth;malignant breast neoplasm;mobile application;mortality;patient oriented;patient screening;premalignant;primary care clinic;primary care setting;programs;response;screening;screening guidelines;self testing;treatment services;uptake;user-friendly Enhanced Cervical Cancer Screening Adoption and Treatment Linkage for HIV positive Women in Kenya (eCASCADE-Kenya) n/a NCI 10738134 9/19/23 0:00 RFA-CA-22-019 1U54CA284036-01 1 U54 CA 284036 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8145 8223125 "CHUNG, MICHAEL HOONBAE" Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 205759 194522 11237 CENTER OVERALL: PROGRAM SUMMARY / ABSTRACTWhile considerable evidence is available for screening and early treatment of breast and cervical cancershuge gaps remain in equitable and sustainable translation of this knowledge into practice and policy especiallyin sub-Saharan Africa. In Kenya gaps in screening and linkage to treatment result in late-stage presentation ofbreast and cervical cancers profound preventable morbidity and mortality and disproportionate hindrance towomens development. To close these gaps the Enhanced BReast and cErvical cAncer screening in KenyaTHROUGH implementation science research and training (BREAKTHROUGH) Center coalesces trans-disciplinary expertise at Kenyatta National Hospital (KNH) Emory University University of Washington andQueens University. BREAKTHROUGH will include an Administrative and Engagement Core that engagescommunity clinical and government stakeholders and scientific partners and seamlessly coordinates [OverallAim 1] our interrelated Research Capacity Building Core and two Research Projects. Our multi-institutionalcollaborative partners bring considerable breadth and depth of implementation science and oncology expertisea substantial research base matched resource commitments (>$125000 in contributions) internationalgravitas and >10 years of working together. To grow implementation science in womens cancer control andconduct impactful research BREAKTHROUGH has a training framework that engages investigators across thecareer spectrum (faculty fellows students) to sustainably strengthen capacity by supporting trainees tobecome mentors [Overall Aim 2]. We provide didactic training; engagement in Research Projects; and accessto stakeholders technologies networking and enrichment activities. BREAKTHROUGHs projects will mapand co-design (with stakeholders) strategies that overcome barriers to womens cancer control. We then testfeasibility implementation effectiveness and sustainment of context-specific theoretically-informed strategiesfor overcoming complex barriers to adoption and integration of breast and cervical cancer screening andreferral linkages in primary care [center theme; Overall Aim 3]. We also utilize these projects as trainingplatforms to strengthen local capacity and research administration for implementation science at KNH. Project1 is entitled accelerating aDoption of pAtient-centereD cervicAl cancer screening and treatment LINKage inKenya (DADA LINK) and Project 2 is entitled a Multi-level strATegy for InTegrating Information technologYand mobile health to strengthen linkAges to breast caNcer screeninG and early detection among womenUtilizing primary care in Kenya (MATITI YANGU). The Center Cores and Projects will produce actionablemixed methods user-friendly evidence and bidirectionally engage with key stakeholders as advisors anddisseminators maximizing reach uptake and sustainability. BREAKTHROUGH is well-integrated acrossCores and Projects and embodies an ethos of promoting equity in our institutions research and our impacts. +No NIH Category available Acceleration;Address;Adoption;Africa;Africa South of the Sahara;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Treatment;Cancer Control;Caring;Case Based Learning;Certification;Cervical Cancer Screening;Clinical;Clinical Skills;Competence;Complex;Data;Development;Early Diagnosis;Early treatment;Educational workshop;Effectiveness;Ensure;Epidemiology;Equity;Faculty;Fellowship;Fostering;Future;Government;Grant;HIV Seropositivity;Hospitals;Information Technology;Institution;International;Intervention;Journals;Kenya;Lead;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Medical Students;Mentors;Methods;Morbidity - disease rate;Nursing Students;Oncology;Paper;Persons;Policies;Positioning Attribute;Primary Care;Productivity;Public Health;Recording of previous events;Research;Research Infrastructure;Research Methodology;Research Personnel;Research Project Grants;Research Training;Resources;Scientist;Screening for cancer;Students;Teacher Professional Development;Technology;Training;Training Programs;Translating;Universities;Washington;Woman;Work;Writing;base;cancer therapy;career;community engagement;design;experience;feasibility testing;hands-on learning;health care disparity;implementation research;implementation science;interest;knowledge translation;low and middle-income countries;mHealth;malignant breast neoplasm;mortality;next generation;patient oriented;programs;science education;screening;secondary analysis;skills;tool;uptake;user-friendly;virtual Enhanced Cervical Cancer Screening Adoption and Treatment Linkage for HIV positive Women in Kenya (eCASCADE-Kenya) n/a NCI 10738133 9/19/23 0:00 RFA-CA-22-019 1U54CA284036-01 1 U54 CA 284036 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8144 8223125 "CHUNG, MICHAEL HOONBAE" Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 107425 97498 9927 CENTER OVERALL: PROGRAM SUMMARY / ABSTRACTWhile considerable evidence is available for screening and early treatment of breast and cervical cancershuge gaps remain in equitable and sustainable translation of this knowledge into practice and policy especiallyin sub-Saharan Africa. In Kenya gaps in screening and linkage to treatment result in late-stage presentation ofbreast and cervical cancers profound preventable morbidity and mortality and disproportionate hindrance towomens development. To close these gaps the Enhanced BReast and cErvical cAncer screening in KenyaTHROUGH implementation science research and training (BREAKTHROUGH) Center coalesces trans-disciplinary expertise at Kenyatta National Hospital (KNH) Emory University University of Washington andQueens University. BREAKTHROUGH will include an Administrative and Engagement Core that engagescommunity clinical and government stakeholders and scientific partners and seamlessly coordinates [OverallAim 1] our interrelated Research Capacity Building Core and two Research Projects. Our multi-institutionalcollaborative partners bring considerable breadth and depth of implementation science and oncology expertisea substantial research base matched resource commitments (>$125000 in contributions) internationalgravitas and >10 years of working together. To grow implementation science in womens cancer control andconduct impactful research BREAKTHROUGH has a training framework that engages investigators across thecareer spectrum (faculty fellows students) to sustainably strengthen capacity by supporting trainees tobecome mentors [Overall Aim 2]. We provide didactic training; engagement in Research Projects; and accessto stakeholders technologies networking and enrichment activities. BREAKTHROUGHs projects will mapand co-design (with stakeholders) strategies that overcome barriers to womens cancer control. We then testfeasibility implementation effectiveness and sustainment of context-specific theoretically-informed strategiesfor overcoming complex barriers to adoption and integration of breast and cervical cancer screening andreferral linkages in primary care [center theme; Overall Aim 3]. We also utilize these projects as trainingplatforms to strengthen local capacity and research administration for implementation science at KNH. Project1 is entitled accelerating aDoption of pAtient-centereD cervicAl cancer screening and treatment LINKage inKenya (DADA LINK) and Project 2 is entitled a Multi-level strATegy for InTegrating Information technologYand mobile health to strengthen linkAges to breast caNcer screeninG and early detection among womenUtilizing primary care in Kenya (MATITI YANGU). The Center Cores and Projects will produce actionablemixed methods user-friendly evidence and bidirectionally engage with key stakeholders as advisors anddisseminators maximizing reach uptake and sustainability. BREAKTHROUGH is well-integrated acrossCores and Projects and embodies an ethos of promoting equity in our institutions research and our impacts. +No NIH Category available Acceleration;Address;Adoption;Advocate;Africa South of the Sahara;Annual Reports;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Treatment;Cancer Control;Cervical Cancer Screening;Clinical;Collaborations;Communication;Communities;Complex;Country;Decision Making;Development;Discipline;Early Diagnosis;Early treatment;Education;Effectiveness;Electronic Mail;Electronics;Eligibility Determination;Ensure;Equity;Ethics;Faculty;Feedback;Government;HIV Seropositivity;Health;Hospitals;Human Resources;Information Dissemination;Information Technology;Infrastructure;Institution;International;Kenya;Knowledge;Leadership;Malignant neoplasm of cervix uteri;Maps;Mentors;Methods;Morbidity - disease rate;National Cancer Institute;Newsletter;Occupational activity of managing finances;Oncology;Patients;Personnel Management;Policies;Policy Maker;Primary Care;Professional Organizations;Publications;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resources;Screening for cancer;Services;Structure;Students;Teacher Professional Development;Technology;Training;Travel;United States National Institutes of Health;Universities;Voice;Washington;Woman;Women's Health;Work;base;career;community engagement;conflict resolution;design;experience;feasibility testing;global health;implementation science;knowledge translation;mHealth;malignant breast neoplasm;meetings;mortality;organizational structure;patient oriented;programs;screening;social media;synergism;uptake;user-friendly;web site;webinar;working group Enhanced Cervical Cancer Screening Adoption and Treatment Linkage for HIV positive Women in Kenya (eCASCADE-Kenya) n/a NCI 10738132 9/19/23 0:00 RFA-CA-22-019 1U54CA284036-01 1 U54 CA 284036 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8143 8223125 "CHUNG, MICHAEL HOONBAE" Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 466395 347095 119300 CENTER OVERALL: PROGRAM SUMMARY / ABSTRACTWhile considerable evidence is available for screening and early treatment of breast and cervical cancershuge gaps remain in equitable and sustainable translation of this knowledge into practice and policy especiallyin sub-Saharan Africa. In Kenya gaps in screening and linkage to treatment result in late-stage presentation ofbreast and cervical cancers profound preventable morbidity and mortality and disproportionate hindrance towomens development. To close these gaps the Enhanced BReast and cErvical cAncer screening in KenyaTHROUGH implementation science research and training (BREAKTHROUGH) Center coalesces trans-disciplinary expertise at Kenyatta National Hospital (KNH) Emory University University of Washington andQueens University. BREAKTHROUGH will include an Administrative and Engagement Core that engagescommunity clinical and government stakeholders and scientific partners and seamlessly coordinates [OverallAim 1] our interrelated Research Capacity Building Core and two Research Projects. Our multi-institutionalcollaborative partners bring considerable breadth and depth of implementation science and oncology expertisea substantial research base matched resource commitments (>$125000 in contributions) internationalgravitas and >10 years of working together. To grow implementation science in womens cancer control andconduct impactful research BREAKTHROUGH has a training framework that engages investigators across thecareer spectrum (faculty fellows students) to sustainably strengthen capacity by supporting trainees tobecome mentors [Overall Aim 2]. We provide didactic training; engagement in Research Projects; and accessto stakeholders technologies networking and enrichment activities. BREAKTHROUGHs projects will mapand co-design (with stakeholders) strategies that overcome barriers to womens cancer control. We then testfeasibility implementation effectiveness and sustainment of context-specific theoretically-informed strategiesfor overcoming complex barriers to adoption and integration of breast and cervical cancer screening andreferral linkages in primary care [center theme; Overall Aim 3]. We also utilize these projects as trainingplatforms to strengthen local capacity and research administration for implementation science at KNH. Project1 is entitled accelerating aDoption of pAtient-centereD cervicAl cancer screening and treatment LINKage inKenya (DADA LINK) and Project 2 is entitled a Multi-level strATegy for InTegrating Information technologYand mobile health to strengthen linkAges to breast caNcer screeninG and early detection among womenUtilizing primary care in Kenya (MATITI YANGU). The Center Cores and Projects will produce actionablemixed methods user-friendly evidence and bidirectionally engage with key stakeholders as advisors anddisseminators maximizing reach uptake and sustainability. BREAKTHROUGH is well-integrated acrossCores and Projects and embodies an ethos of promoting equity in our institutions research and our impacts. +No NIH Category available Acceleration;Address;Adoption;Advanced Malignant Neoplasm;Africa;Africa South of the Sahara;Awareness;Behavioral;Biometry;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Treatment;Canada;Cancer Burden;Cancer Control;Caring;Cervical Cancer Screening;Cessation of life;Clinic;Clinical;Communities;Complex;Country;Data;Development;Diagnosis;Disease;Early Diagnosis;Early identification;Early treatment;Economics;Effectiveness;Epidemiology;Equity;Faculty;Family;Future;Gender;Government;Guidelines;HIV;Health;Health Services Accessibility;Health system;Hospitals;Human Papillomavirus;Incidence;Individual;Inequity;Infection;Information Technology;Infrastructure;Institution;International;Intervention;Kenya;Knowledge;Leadership;Life Style;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Mentors;Mentorship;Methods;Morbidity - disease rate;Obesity;Oncology;Patients;Pattern;Personal Satisfaction;Policies;Policy Maker;Preventive screening;Primary Care;Process;Provider;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Rest;Scientist;Screening for cancer;Smoking;Students;System;Talents;Technology;Testing;Time;Training;Translations;Universities;Variant;Washington;Woman;Women's Health;Work;advanced disease;base;cancer diagnosis;cancer type;care coordination;career;community engagement;cost;design;disability;effectiveness testing;effectiveness trial;evidence base;experience;feasibility testing;implementation research;implementation science;implementation strategy;improved;knowledge translation;low and middle-income countries;mHealth;malignant breast neoplasm;mortality;next generation;patient oriented;premalignant;prevent;programs;screening;social;tumor progression;uptake;user-friendly Enhanced BReast and cErvical cAncer screening in Kenya THROUGH implementation science research and training (The BREAKTHROUGH Center) CENTER OVERALL: PROGRAM NARRATIVEBreast and cervical cancer kill many millions of women around the world particularly in Sub-Saharan Africadespite the fact that deaths and disability related to these cancers can be prevented by early detection andtreatment. There are major gaps in the screening for and coordination of care to prevent womens cancers incountries like Kenya; a profound inequity that threatens the health and well-being of women their families andcommunities. We propose to establish the Enhanced BReast and cErvical cAncer screening in KenyaTHROUGH implementation science research and training (BREAKTHROUGH) Center a partnership betweeninstitutions in Kenya the US and Canada to: 1/ promote research on how to improve womens cancer control;2/ to build the base of future researchers in Kenya that can continue and expand this work; and 3/ to informpolicy makers on the best ways to engage women in breast and cervical cancer screenings and link them withappropriate care. NCI 10738131 9/19/23 0:00 RFA-CA-22-019 1U54CA284036-01 1 U54 CA 284036 1 "VEDHAM, VIDYA" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8223125 "CHUNG, MICHAEL HOONBAE" "ALI, MOHAMMED KUMAIL; KINUTHIA, JOHN " 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 961691 NCI 802699 158992 CENTER OVERALL: PROGRAM SUMMARY / ABSTRACTWhile considerable evidence is available for screening and early treatment of breast and cervical cancershuge gaps remain in equitable and sustainable translation of this knowledge into practice and policy especiallyin sub-Saharan Africa. In Kenya gaps in screening and linkage to treatment result in late-stage presentation ofbreast and cervical cancers profound preventable morbidity and mortality and disproportionate hindrance towomens development. To close these gaps the Enhanced BReast and cErvical cAncer screening in KenyaTHROUGH implementation science research and training (BREAKTHROUGH) Center coalesces trans-disciplinary expertise at Kenyatta National Hospital (KNH) Emory University University of Washington andQueens University. BREAKTHROUGH will include an Administrative and Engagement Core that engagescommunity clinical and government stakeholders and scientific partners and seamlessly coordinates [OverallAim 1] our interrelated Research Capacity Building Core and two Research Projects. Our multi-institutionalcollaborative partners bring considerable breadth and depth of implementation science and oncology expertisea substantial research base matched resource commitments (>$125000 in contributions) internationalgravitas and >10 years of working together. To grow implementation science in womens cancer control andconduct impactful research BREAKTHROUGH has a training framework that engages investigators across thecareer spectrum (faculty fellows students) to sustainably strengthen capacity by supporting trainees tobecome mentors [Overall Aim 2]. We provide didactic training; engagement in Research Projects; and accessto stakeholders technologies networking and enrichment activities. BREAKTHROUGHs projects will mapand co-design (with stakeholders) strategies that overcome barriers to womens cancer control. We then testfeasibility implementation effectiveness and sustainment of context-specific theoretically-informed strategiesfor overcoming complex barriers to adoption and integration of breast and cervical cancer screening andreferral linkages in primary care [center theme; Overall Aim 3]. We also utilize these projects as trainingplatforms to strengthen local capacity and research administration for implementation science at KNH. Project1 is entitled accelerating aDoption of pAtient-centereD cervicAl cancer screening and treatment LINKage inKenya (DADA LINK) and Project 2 is entitled a Multi-level strATegy for InTegrating Information technologYand mobile health to strengthen linkAges to breast caNcer screeninG and early detection among womenUtilizing primary care in Kenya (MATITI YANGU). The Center Cores and Projects will produce actionablemixed methods user-friendly evidence and bidirectionally engage with key stakeholders as advisors anddisseminators maximizing reach uptake and sustainability. BREAKTHROUGH is well-integrated acrossCores and Projects and embodies an ethos of promoting equity in our institutions research and our impacts. 961691 +No NIH Category available Acceleration;Address;Adoption;Cancer Control;Cancer Control Research;Cervical Cancer Screening;Chronic Disease;Clinical Research;Collaborations;Community Health Aides;Competence;Country;Development;Education;Equity;Evaluation;Evidence based intervention;Foundations;Goals;Health;Health system;Healthcare Systems;Income;Inequity;Infrastructure;Knowledge;Lead;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;Mentorship;Methodology;Methods;Modeling;Politics;Population;Process;Program Development;Province;Reach Effectiveness Adoption Implementation and Maintenance;Research;Research Personnel;Research Project Grants;Research Training;Resources;South Africa;Testing;Trainers Training;Training;Universities;Women's Health;Work;World Health Organization;career development;economic evaluation;evidence base;experience;implementation framework;implementation research;implementation science;implementation strategy;innovation;interest;low and middle-income countries;prevent;programs;scale up;screening;social;theories;tool Research Capacity Building Core n/a NCI 10738105 9/19/23 0:00 RFA-CA-22-019 1U54CA284030-01 1 U54 CA 284030 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8132 14456149 "DENNY, LYNETTE " Not Applicable 13 Unavailable 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY Domestic Higher Education 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 248428 198856 49572 Project Summary/Abstract - Capacity Building CoreCapacity-building efforts in LMICs are critical to advancing the science of implementation and to have globalimpact on cancer inequities. Implementation science capacity strengthening is still in the nascent state for chronicdiseases focused on LMICs particularly in the context of cancer control efforts. The synergistic research andcores proposed in the U54 Center are well-poised to address these key gaps and aligned with the priorities ofregional stakeholders. The overarching goal of the Capacity Building Core within the Empilisweni Center forWomens Health is to increase implementation research opportunities and capacity in cancer control in theWestern Cape Province of South Africa through didactic and experiential implementation science training andmentorship for a range of interested researchers clinicians and implementation practitioners. The CapacityBuilding Core builds off of and extends our teams nearly three decades of partnership in cutting-edge clinicalresearch in cervical cancer screening and existing educational and research capacity and longstandingpartnerships. Aligned with our Centers theme on advancing equitable and integrated implementation for cancercontrol in South Africa our Specific Aims for building sustainable research capacity to conduct cancer control inIS include: 1) Deliver a sustainable implementation science training and career development program using thetrain-the-trainer model mentorship and innovative educational and capacity-building activities that will enhancelocal knowledge of core competencies in the field of implementation science (e.g. foundational theoriesframeworks strategies and methods; economic evaluation) supplemented with relevant cancer control andcareer development training and opportunities. Leveraging our teams experience in IS capacity-building andknowledge dissemination and utilization this program will be delivered among a range of trainees (researchersclinicians practitioners community health workers) in South Africa at UCT & MOH and will build sustainableimplementation research capacity regionally providing the foundation to equitably scale-up evidence-basedcervical cancer control innovations in the region. 2) In partnership with the Research Projects and StakeholderEngagement Core trainees and stakeholders will help inform and co-lead the development applicationevaluation and refinement of implementation science frameworks (e.g. Knowledge to Action CFIR RE-AIM)implementation strategies and training tools that reflect local context and stakeholder input with a focus on ourCenters theme. This Core has the expertise and infrastructure to successfully support and enhance theprofessional and career development of investigators and implementers in IS (including 2 lead IS Fellows) withthe ultimate goal of strengthening local capacity and building a sustainable cadre of scholars and practitionerswho are prepared to conduct and lead IS research for cancer control in this region. +No NIH Category available Acceleration;Address;Affect;Black race;Cancer Control;Cancer Etiology;Cervical;Cervical Cancer Screening;Cessation of life;Clinical;Clinical Trials;Collaborations;Communities;Coordination and Collaboration;Country;Decision Making;Disease;Eligibility Determination;Ensure;Equity;Evidence based intervention;Food;Fostering;Generations;Goals;Government;Guidelines;HIV/TB;Health;Health Services;Healthcare;Home;Human Papillomavirus;Incidence;Inequity;Infrastructure;Iron;Knowledge;Lead;Leadership;Malignant neoplasm of cervix uteri;Mission;Performance;Persons;Prevention strategy;Primary Prevention;Productivity;Province;Public Health;Recommendation;Research;Research Personnel;Research Project Grants;Resource Sharing;Resource-limited setting;Resources;Rest;Safety;Scientific Advances and Accomplishments;Secondary Prevention;Seminal;Shapes;Site;South Africa;Testing;Unemployment;Universities;Vaccinated;Woman;Women's Health;Wood material;World Health Organization;access disparities;aged;burden of illness;cancer health disparity;clinical care;community engagement;evidence base;experience;girls;global health;healing;health disparity;health inequalities;implementation research;implementation study;infection rate;low and middle-income countries;mortality;peri-urban;point of care;programs;response;scale up;screening;screening program;social;success;synergism;treatment duration;uptake Administrative and Engagement Core n/a NCI 10738104 9/19/23 0:00 RFA-CA-22-019 1U54CA284030-01 1 U54 CA 284030 1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 8131 7012821 "CASTOR, DELIVETTE " Not Applicable 13 Unavailable 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY Domestic Higher Education 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 188538 150222 38316 Our investigator team at Columbia University and the University of Cape Town through a nearly thirty-yearcollaboration under the Khayelitsha Cervical Cancer Screening Program (KCCSP) have conducted someseminal clinical trials demonstrating the safety and efficacy of HPV-based SAT both with treatment within 2-6days and with on-site same-day treatment.3-5 HPV-based SAT is included in South Africas national guidelines.6Like most countries South Africa is grappling with how to operationalize and promote equitable uptake andintegration of HPV-based screening in public health and clinical care settings. Aligned with RFA-CA-22-019 theKCCSP has been formalizing its longstanding partnership with the Western Cape Department of Health(WCDoH) with the mission to accelerate the integration and scale-up of evidence-based interventions forequitable cervical cancer elimination among women in resource-constrained settings. Under this formalpartnership we propose the Empilisweni (a place of healing) Center for Womens Health. The Center seeks tosupport the WHOs global strategy to accelerate the elimination of cervical cancer by the end of this millenniumby equitably integrating scalable affordable HPV-based point-of-care screen-and-treat (HPV-POC) strategiesby fostering effective collaboration coordination decision-making resource and knowledge sharing regionallyand building implementation capacity in local implementers researchers and stakeholder community. Successof the Centers goals rest on the principles that shape strong administration and best practices for stakeholderengagement. MPIs; Denny (UCT) and Kuhn (CUIMC) who founded KCCSP will be joined by MPI Castor(Contact: CUIMC) Mbatani (UCT) Saidu (UCT) and Arendse (UCT/WCDoH) in the daily management to ensurethat the Centers productivity performance meet its goals. MPIs Shelton (CUIMC) and Tehranifar (CUIMC) wholead the capacity building core and research project 1 respectively have experience in community engagementand will ensure that all aspects of the Center's responsibilities is met. The leadership team will be completedwith the addition of another WCDoH collaborator Dr. Cloete who will ensure equitable representation of healthservices implementation in collaboration and coordination with stakeholders. Through this administrative andstakeholder engagement core we propose to: 1) Strategically guide the Centers efficiency productivity andsuccess through administrative support infrastructure and program management that synergizes activitiesacross the Centers cores and projects; and 2) Foster effective collaboration coordination decision-makingknowledge and resource sharing across the Western Cape Province informed by best practices on communityengagement and ongoing theoretically grounded qualitative and quantitative research and engagement fromregional partners. By the end of five years the Empilisweni Center will contribute to the scale-up of HPV-basedSAT as part of the cervical cancer elimination goals through strategic management of the Centers core andproject activities for synergy generation and scientific advancement. +No NIH Category available Acceleration;Cancer Control;Cancer Etiology;Cervical;Cervical Cancer Screening;Cessation of life;Clinical;Clinical Trials;Collaborations;Communities;Complement;Cost Savings;Cytology;Detection;Development;Education;Effectiveness;Eligibility Determination;Equity;Evidence based intervention;Fostering;Goals;Guidelines;Health;Health Sciences;Healthcare;Human Papillomavirus;Intervention;Knowledge;Lead;Lesion;Malignant neoplasm of cervix uteri;Medical center;Mentorship;Mission;Outcome;Population Control;Prevention strategy;Primary Prevention;Province;Public Health;Public Sector;Recommendation;Research;Research Methodology;Research Personnel;Resource-limited setting;Safety;Secondary Prevention;Seminal;Site;South Africa;Testing;Training;Universities;Vaccinated;Vaccination;Woman;Women's Health;Work;World Health Organization;aged;clinical care;cost;evidence base;girls;global health;healing;health care settings;health inequalities;implementation barriers;implementation evaluation;implementation framework;implementation research;implementation science;implementation strategy;innovation;knowledgebase;low and middle-income countries;point of care;poor communities;premalignant;primary care setting;scale up;screening;screening program;treatment duration;treatment site;uptake The Empilisweni Center for Women's Health - Advancing Implementation of Equitable Cervical Cancer Control Project NarrativeAlthough human papillomavirus-based detection followed by same-day onsite treatment an approach calledHPV-based screen-and-treat (SAT) has been included in global and national guidelines the approach has notyet been widely implemented outside research settings. We hypothesize that an HPV-based point-of-carescreen-and-treat (POC-SAT) implementation strategy will increase the proportion of women who are screenedand treated will be complementary to centralized HPV testing and will be affordable. NCI 10738103 9/19/23 0:00 RFA-CA-22-019 1U54CA284030-01 1 U54 CA 284030 1 "VEDHAM, VIDYA" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M2) 7012821 "CASTOR, DELIVETTE " "ARENDSE, JUANITA OLIVIA; DENNY, LYNETTE ; KUHN, LOUISE ; MBATANI, NOMONDE HAZEL; SAIDU, RAKIYA ; SHELTON, RACHEL C; TEHRANIFAR, PARISA " 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 967556 NCI 789941 177615 Abstract (Overall). Cervical cancer is a leading cause of cancer-related deaths among women in low- andmiddle-income countries (LMICs) and it is almost entirely preventable.12-4 In 2020 the World HealthOrganization (WHO) announced a global strategy to accelerate the elimination of cervical by the end of thismillennium by vaccinating 90% of girls by aged 15 and screening 70% of women and treating 90% of treatmenteligible women by 2030.5 Based on strong empirical evidence of effectiveness and safety the WHO recommendsHuman Papillomavirus (HPV)-based testing followed by immediate treatment of pre-cancerous lesions anapproach called screen-and-treat (SAT) for achieving cervical cancer control in LMICs.6 Our investigator teamat Columbia University Irving Medical Center (CUIM) and the University of Cape Town (UCT) through a nearlythirty-year collaboration under the Khayelitsha Cervical Cancer Screening Program (KCCP) have conductedseminal clinical trials demonstrating the safety and effectiveness of HPV-based screening and treatment.7-9Although endorsed in global and national guidelines the SAT approach has not yet been widely implemented.Like most LMICs South Africa is grappling with how to operationalize and promote the widespread and equitableintegration and uptake of HPV screening in healthcare settings. Stakeholders cite a lack of context-specificimplementation costs and financing as important implementation barriers. Aligned with RFA-CA-22-019 and inpartnership between the KCCP and the Western Cape Department of Health (WCDoH) we propose theEmpilisweni (isiXhosa for a place of healing) Center for Womens Health with the overarching mission toaccelerate the integration and scale-up of evidence-based interventions for equitable cervical cancer eliminationamong women in resource-constrained settings. Led by MPIs; Denny (UCT) and Kuhn (CUIMC) who foundedKCCSP will be joined by MPI Castor (Contact: CUIMC) Mbatani (UCT) Saidu (UCT) Shelton (CUIMC)Tehranifar (CUIMC); and Arendse (UCT/WCDoH) and collaborator Cloete (WCDoH) Informed by implementationscience frameworks and stakeholder engagement approaches we propose to: Aim 1: Support the WHOs globalstrategy to accelerate the elimination of cervical cancer by the end of this millennium by equitably integratingscalable affordable HPV-based point-of-care screen-and-treat (POC-SAT) strategies to achieve the secondaryprevention cascade goal of 70% screening and 90% treatment of women who screen positive by 2030 in theWestern Cape Province of South Africa; and Aim 2. Catalyze equitable integration and sustainable scale-up ofPOC-SAT by fostering effective collaboration coordination capacity-building and knowledge sharing acrossmultiple key stakeholders. By the end of the five years POC SAT will increase the proportion of women who arescreened and treated regionally will complement centralized HPV testing and be economically feasible. We willhave a strengthened capacity for leading implementation research in the region and advanced work on strategiesto inform scalable delivery and innovative financing of cervical cancer control for population-level impact. 967556 +No NIH Category available Adolescent;Biological;Biological Assay;Biological Factors;Biological Markers;Biology;Bone Tissue;Cell Line;Cells;Child;Clinical Trials;Combined Modality Therapy;Complex;Computational Biology;DNA Damage;DNA Repair;Data Set;Development;Disease;EWSR1 gene;Evaluation;Ewings sarcoma;Fibroblasts;Foundations;Gene Fusion;Genetic;Genetic Complementation Test;Genetic Predisposition to Disease;Genomic Instability;Genomics;Genotoxic Stress;Germ-Line Mutation;Goals;Heterozygote;In Vitro;Inherited;Investigation;Knowledge;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Matched Case-Control Study;Mediator;Mentorship;Mesenchymal;Mesenchymal Stem Cells;Mitomycin C;Modeling;Molecular;Morbidity - disease rate;Mutation;Nonhomologous DNA End Joining;Parents;Pathogenesis;Pathogenicity;Patients;Pattern;Pharmacotherapy;Phenotype;Predisposition;Process;Recurrent disease;Relapse;Reporter;Research Proposals;Role;Therapeutic;Tissue-Specific Gene Expression;Variant;Work;cancer predisposition;childhood sarcoma;clinically relevant;cohort;gene repair;genomic signature;homologous recombination;improved;insight;loss of function;novel;novel strategies;predicting response;proband;prognostic;programs;response;risk prediction;risk stratification;risk variant;screening;skills;soft tissue;targeted agent;treatment response;tumor;tumorigenesis Dissecting the role of DNA damage repair deficiency in Ewing sarcoma pathogenesis for improved risk stratification and treatment PROJECT NARRATIVEEwing sarcoma is an aggressive bone and soft tissue cancer impacting children worldwide and a betterunderstanding of the underlying biology contributing to this disease is needed to enable more informed riskstratification treatment and screening approaches. I previously found that pathogenic germline variants inFANCC and other DNA damage repair genes are uniquely enriched among patients with Ewing sarcomarelative to other pediatric sarcoma subtypes. This proposal aims to comprehensively evaluate the role of DNAdamage repair deficiency in Ewing sarcoma pathogenesis through an integrated evaluation of germline andtumor genomics with the goals of informing clinical trial priorities for Ewing sarcoma and having high relevanceto the management of other pediatric cancers. NCI 10738078 9/19/23 0:00 PA-20-203 1K08CA276701-01A1 1 K08 CA 276701 1 A1 "LIM, SUSAN E" 9/19/23 0:00 8/31/28 0:00 Career Development Study Section (J)[NCI-J] 15579128 "GILLANI, RIAZ " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 208252 NCI 193270 14982 PROJECT SUMMARY Ewing sarcoma is the second most common bone and soft tissue cancer impacting children andadolescents worldwide. It is an aggressive malignancy requiring multimodal treatment that confers significantmorbidity and cure rates for metastatic and relapsed disease remain poor. While Ewing sarcoma ischaracterized and driven by EWSR1-ETS gene fusions the biological factors contributing to these simplerearrangements and complex rearrangements known as chromoplexy in a subset of cases are not well-characterized. I found that inherited pathogenic variants in FANCC and other DNA damage repair (DDR)genes are uniquely enriched among patients with Ewing sarcoma relative to other pediatric sarcoma subtypes(Gillani et al. AJHG 2022). Much work is still needed to understand how DNA damage repair deficiencycontributes to Ewing sarcoma pathogenesis. The guiding hypothesis of this research proposal is that DNAdamage repair deficiency promotes Ewing sarcoma pathogenesis manifesting as a unique pattern ofpredisposing germline variants and tumor genomic features that are integral to oncogenesis and canbe utilized for more informed risk stratification and treatment. We will apply computational and experimental approaches to sequencing datasets from patients withEwing sarcoma and cell line models to complete this research proposal. In Specific Aim 1 we will dissect theadditive contribution of larger germline structural variants impacting DDR genes in Ewing sarcoma byanalyzing a cohort of 301 parent-proband trios and evaluating the enrichment of germline structural variants in1180 cases relative to cancer-free controls. In Specific Aim 2 we will define the phenotype of FANCC variantsseen in the germline of Ewing sarcoma patients and knock these variants into mesenchymal stem cell lines tounderstand how they contribute to genomic instability in the presence of genotoxic stress. In Specific Aim 3we will derive genomic signatures to gain additional insight into the DNA damage processes that are operant inEwing sarcoma tumors and associate copy number signatures specifically with treatment response andrelapse. Finally we will conduct in-vitro drug treatment studies to demonstrate the utility of specific copynumber signatures as biomarkers of sensitivity to DNA damage response targeting agents. Through integrative investigations spanning the germline and tumor we intend to drive newunderstanding of how DNA damage operates in Ewing sarcoma pathogenesis knowledge that will be centralto improved risk stratification and treatment of this aggressive pediatric cancer. Moreover in extending ourbroader understanding about germline structural variants the role of heterozygous risk variants in cancerpredisposition and copy number signatures as clinically relevant biomarkers this work will also have highrelevance to other pediatric cancers. 208252 +No NIH Category available Address;Affect;Antisense Oligonucleotides;Asian Pacific Islander;Binding;Binding Sites;Biochemical;Biological;Biological Assay;Biophysics;Black Populations;Cancer Etiology;Cell Nucleus;Cell Proliferation;Cell model;Cessation of life;Chromatin;Chromatin Remodeling Factor;Clinical;Data;Death Rate;Diagnosis;E protein;Etiology;Event;Exclusion;Exons;Gene Amplification;Gene Expression;Genetic Models;Genetic Transcription;Genotype;Goals;Hepatocarcinogenesis;Hispanic Populations;In Vitro;Invaded;Knock-in;Liquid substance;MYC Gene Amplification;MYC gene;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Maps;Mediating;Membrane;Molecular;Negative Finding;Not Hispanic or Latino;Nucleosomes;Oncogenic;Organelles;Patients;Phase;Phenotype;Physical condensation;Primary carcinoma of the liver cells;Process;Prognosis;Protein Isoforms;Proteins;Proto-Oncogenes;RNA Recognition Motif;RNA Splicing;Recombinant Proteins;Recurrent tumor;Reporting;Resolution;Role;SMARCB1 gene;SWI/SNF Family Complex;Signal Transduction;Testing;Therapeutic;Time;Tumor Burden;biophysical analysis;gene regulatory network;genome editing;in vivo;migration;multiple omics;negative elongation factor;novel;overexpression;potential biomarker;promoter;protein protein interaction;therapy development;tool;transcriptome;tumor;tumor heterogeneity;tumorigenesis;tumorigenic Deciphering the role of NELFE in modulating MYC signaling in HCC PROJECT NARRATIVEHepatocellular carcinoma (HCC) is the second most common cause of cancer related deaths worldwide withlimited therapeutic options. This project addresses the important issues related to the clinical and biologicalimplications of how one deregulated protein can alter the transcriptome to promote HCC. Specifically the studyseeks to determine the impact of targeting this protein to decrease tumor burden. NCI 10738028 7/10/23 0:00 RFA-CA-22-050 1R01CA284017-01 1 R01 CA 284017 1 "JOHNSON, RONALD L" 7/10/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M2)S 10954087 "DANG, HIEN T." Not Applicable 2 SURGERY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 7/10/23 0:00 6/30/24 0:00 353 Non-SBIR/STTR 2023 368321 NCI 244161 124160 ABSTRACTHepatocellular carcinoma (HCC) is an aggressive tumor type with poor prognosis due to the diverse etiologytumor heterogeneity and the frequent late stage diagnosis. HCC is the fourth cause of cancer-related deaths inthe world and is seen at higher rates among Hispanics Blacks and Asian Pacific Islanders compared with non-Hispanic whites. In the U.S the rate of death from liver cancer has increased >40%. The proto-oncogene MYCis deregulated in ~80% of HCC. Yet MYC remains to be an undruggable target. Although the most commonalteration is gene amplification (~30%) a significant proportion of MYC-driven HCCs have deregulated MYCsignaling without concomitant MYC gene amplification. How MYC signaling is deregulated in HCC withoutconcomitant MYC gene amplification is not understood. Our long-term goal is to understand the molecular basisfor this phenotype to develop therapies to indirectly target MYC as a therapeutic strategy in HCC. The specificobjective of this proposal is to confirm Negative Elongation Factor E (NELFE) as a central regulator of MYCsignaling to promote HCC. The central hypothesis is deregulated NELFE modulates MYC signaling to promoteHCC regardless of MYC status. We recently discovered the NELFE is over-expressed in 48% of HCC and isrequired for MYC-induced hepatocarcinogenesis. Preliminary data indicate NELFE alters nucleosomeaccessibility to modulate MYC-signaling. Moreover we found NELFE localizes in the nucleus as biomolecularcondensates membraneless organelles that modulate transcription. Perturbation of NELFE condensates altersprotein-protein interactions important for MYC signaling suggesting NELFE condensation as a novel mechanismfor MYC-induced HCC. We discovered a novel truncated NELFE isoform with anti-tumorigenic effects inadvanced HCC. Isoform switching from FL NELFE to the truncated form via antisense oligonucleotidessignificantly reduced tumorigenic phenotypes and condensates. Here we will use biophysical biochemical invitro and in vivo assays to elucidate the role of NELFE on chromatin accessibility and biomolecular condensatesas promoters of HCC through MYC signaling. Furthermore we will use our established genetic models andantisense oligonucleotides to test the critical anti-tumorigenic function of the truncated NELFE isoform in HCC.Together our proposed studies will define the novel role NELFE as a regulator of MYC as an essential player inthe pathophysiological mechanisms of hepatocarcinogenesis and establish the function of the novel truncatedNELFE protein. 368321 +No NIH Category available Adenocarcinoma;Adenocarcinoma In Situ;Agreement;Antibodies;Archival Collection;Biology;Case Series;Catalogs;Cells;Chemoprevention;Classification;Clinical;Collection;Data;Detection;Development;Dimensions;Disease;Disease Progression;Disease-Free Survival;Event;Fluorescence Microscopy;Foundations;Frequencies;Fresh Tissue;Future;Gene Expression Profiling;Histologic;Histology;Human;Image;Immune;Immune Targeting;Immunofluorescence Immunologic;Immunoprevention;Indolent;Intercept;Invasive Lesion;Investigation;K-ras mouse model;Lesion;Longitudinal Studies;Lung;Lung Adenocarcinoma;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Metastatic Neoplasm to Lymph Nodes;Methods;Molecular;Molecular Profiling;Mutation;Natural History;Nodule;Non-Small-Cell Lung Carcinoma;Pathology;Pathway interactions;Patients;Phase;Phenotype;Prevention;Prevention trial;Resected;Resolution;Rest;Role;Sampling;Severities;Smoker;Testing;Therapeutic;Transcriptional Regulation;X-Ray Computed Tomography;cancer cell;cancer invasiveness;cancer subtypes;cell type;cohort;comparative;driver mutation;exome sequencing;experimental study;fluorescence imaging;global health;high risk;imaging modality;improved;insight;lung carcinogenesis;minimally invasive;mouse model;neoplastic cell;never smoker;novel;pre-clinical;preclinical study;prevent;progression risk;protein expression;radiological imaging;single cell analysis;transcriptome sequencing;treatment strategy;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Intercepting progression from pre-invasive to invasive lung adenocarcinoma Project NarrativeNon-small cell lung cancer (NSCLC) constitutes 85-90% of all lung cancers a major globalhealth concern with approximately 1.8 million new cases each year. An improved understandingof the biology of early lung cancer is needed to intercept the disease at a clinically-meaningfulearly point in its progression. Capturing the cellular and molecular events associated withprogression will provide the framework for future studies to develop strategies for earlyprevention including immunoprevention. NCI 10738024 8/21/23 0:00 RFA-CA-19-012 3UH3CA244697-05S1 3 UH3 CA 244697 5 S1 "MILLER, MARK S" 9/25/19 0:00 8/31/24 0:00 ZCA1-SRB-C(A1) 6771911 "ALTORKI, NASSER KHALED" "BORCZUK, ALAIN C; ELEMENTO, OLIVIER ; MCGRAW, TIMOTHY E; MITTAL, VIVEK " 12 SURGERY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 234178 NCI 138158 96020 AbstractDespite advances in therapeutic strategies non-small cell lung cancer remains a deadly disease. Animproved understanding of the biology of lung cancer is needed to intercept the disease at an early point inits progression. Our project which is inspired by that challenge focuses on events transpiring in the earliestradiographically-detected manifestation of lung cancer: the computerized tomography (CT)-detected non-solid nodule of which as many as 40% harbor frankly invasive adenocarcinoma. Thus despite conventionalwisdom that CT-detected non-solid nodules represent pre or minimally invasive malignancy clearly transitionto more invasive histologies occurs in a significant proportion of these nodules.Understanding the cellular and molecular changes within non-solid nodules that drive progression will provideunique and novel insights into the fundamental mechanisms of lung carcinogenesis. We hypothesize thatalterations in cells of the tumor microenvironment (TME) have a role in initiating and supporting thisprogression. In agreement with that proposal our preliminary multiplex immunofluorescence (IF) studiessuggest that progression to a more invasive phenotype is associated with the development of a strongimmunosuppressive TME. In this project we test our hypothesis using multidimensional methods to profile theTME and to determine the crosstalk between cancer cells and the TME in pre-invasive to invasive humanlung non-solid adenocarcinomas. Comparative analysis of the cellular and molecular events associated withthe distinct histological stages will lead to identification of the critical events triggering progression andthereby identify targets to intercept disease progression. We will use appropriate mouse models in pre-clinicalstudies to develop these targets as strategies to intercept progression of pre-invasive to invasive cancer.In the first phase of these studies (UG3 phase) we will define TME alterations associated with progression oflung nodules using RNAseq profiling and image-based methods (multiplex IF and imaging CyTOF) in studiesof our archival tumor samples. These studies will generate a comprehensive catalogue of the cellular andmolecular events that trigger progression of indolent lesions to frankly invasive cancers with a strong focuson immune mechanisms. These analyses will provide novel and detailed insights into how the compositionand activity of the TME changes with progression. In the second phase (UH3 phase) we will leverage mousemodels to explore interception strategies to target immune mechanisms and prevent progression.The proposed cohort satisfies the RFAs focus on High-Risk Cohorts for Cancer-Immunoprevention Studiessince lung nodules are premalignancies highly prevalent in smokers. 234178 +No NIH Category available 3-Dimensional;Ablation;Adenocarcinoma;Adoptive Transfer;Affect;Age;Age Years;American;Animal Model;Antibody Therapy;Atrophic Gastritis;Autoimmunity;Bone Marrow;CD4 Positive T Lymphocytes;CTLA4 blockade;CTLA4 gene;Cell Differentiation process;Cells;Chief Cell;Chimera organism;Chronic;Cytokine Receptors;DNA Sequence Alteration;Data;Development;Disease;Dysplasia;Environmental Risk Factor;Epithelial Cells;Epithelium;Etiology;Exhibits;Gastric Adenocarcinoma;Gastric Metaplasia;Gastritis;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genetic study;Goals;Growth Factor;Helicobacter pylori;Human;IL13 gene;IL4 gene;Immune;Immunophenotyping;Inflammation;Inflammatory;Integration Host Factors;Interleukin 4 Receptor;Interleukin-13;Knock-out;Knowledge;LGR5 gene;Link;Lymphoid Cell;Malignant - descriptor;Malignant Neoplasms;Mediating;Metaplasia;Modeling;Monoclonal Antibodies;Mucous Membrane;Mus;Neoplasms;Neoplastic Cell Transformation;Not Hispanic or Latino;Pathway interactions;Patients;Penetrance;Play;Population;Premalignant Cell;Proliferating;RNA Interference;Reporting;Role;Signal Transduction;Stomach;Surveys;T-Lymphocyte;Testing;Th2 Cells;Tissues;Transgenes;Transgenic Organisms;Tumor Immunity;Woman;anti-CTLA4;cancer cell;cancer initiation;cancer prevention;cancer therapy;connective tissue growth factor;cytokine;design;gastric organoids;germ free condition;heparin-binding EGF-like growth factor;human model;insight;interleukin-13 receptor;knock-down;malignant stomach neoplasm;neoplastic;novel;overexpression;potential biomarker;preneoplastic cell;preservation;small hairpin RNA;spasmolytic polypeptide;stem cells;transdifferentiation;trefoil factor;tumor;tumorigenesis The role of type 2 inflammation in the initiation and progression of metaplastic differentiation and neoplastic transformation of gastric epithelia This study investigates how chronic stimulation by cytokines leads to inflammation and cancer in thestomach. The knowledge generated from this study will help design strategies to break the link betweeninflammation and cancer development as well as to block pro-tumor inflammatory signal while preserving theanti-tumor effectors for cancer prevention and treatment. NCI 10737935 9/20/23 0:00 PA-19-056 3R01CA245673-04S1 3 R01 CA 245673 4 S1 "YASSIN, RIHAB R" 6/1/20 0:00 5/31/25 0:00 Special Emphasis Panel[ZRG1-DKUS-A(90)] 8842608 "CHEN, ZHIBIN " Not Applicable 27 MICROBIOLOGY/IMMUN/VIROLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 67844 NCI 44198 23646 Chronic inflammatory damage in the stomach can lead to metaplastic differentiation of epithelial lineagesand eventual development of gastric (stomach) cancer (GC). Gastric adenocarcinoma (GA) accounts for mostGC cases. The etiology of GA has been described as a histopathological progression from atrophic gastritismetaplasia dysplasia to adenocarcinoma. Gastric metaplasia includes Spasmolytic Polypeptide-ExpressingMetaplasia (SPEM) which is associated with human GA as a pre-neoplasia. Extensive studies have establishedH. pylori as a major environmental risk factor for GC and ~1% of infected cases are linked to GC. The role ofhost factors for GC are also indicated by accumulating evidence. As in other diseases rare cases of geneticmutations can offer novel insights that may be broadly relevant. Indeed gastritis and GC development inrecently-identified rare cases of human CTLA4 haplo-insufficiency highlight the potential of chronic inflammationin GC. A recent survey of 133 patients with CTLA4 haplo-insufficiency from ~2-50 years of age found atrophicgastritis in 9% of the patients and GC in 3% of the patients. The finding from these rare cases also consists withevidence for an association of human GA with a genetic predisposed CTLA4 insufficiency due to genepolymorphisms. We recently reported a transgenic CTLA4 RNAi knockdown (CTLA4KD) model for GC initiatedby CTLA4 insufficiency. On susceptible genetic backgrounds CTLA4KD mice exhibited spontaneousdevelopment of SPEM with 100% penetrance even in germ-free conditions. Corroborating the genetic evidenceCTLA4 blockade with monoclonal antibodies (mAb) also induced SPEM in mice. With age SPEM progressedto GA in all CTLA4KD mice. Thus CTLA4KD mice not only model human GC initiated by CTLA4 insufficiencybut also capture a shared feature of SPEM and GA progression with an entire cascade from gastritis metaplasiato invasive adenocarcinoma. Furthermore the CTLA4KD model illustrated a critical role of autoimmunity in GC.Autoimmunity has been suggested to be the cause of the recently identified rise of noncardia GC in Americanswho are less than 50 year old especially non-Hispanic white women. Overall our preliminary data suggest thatthe causality of CTLA4 insufficiency in GC was due to a type of inflammatory crosstalk between immune andepithelial cells. We hypothesize that type 2 inflammation initiates metaplastic differentiation of gastric epitheliaand drives malignant transformation of the pre-neoplastic lineage into invasive adenocarcinoma. Specifically wewill: 1) determine the subtypes of immune cells that cause aberrant epithelial-immune interaction in mucosaeleading to metaplastic differentiation and malignant transformation; 2) examine the origin and fate of pre-neoplastic cell differentiation mediated by epithelial-intrinsic signaling of type 2 cytokine receptors; 3) identify thegrowth factors in type 2 inflammatory niches that propel the proliferation and transformation of epithelial lineagesin the stomach. The study will reveal the origin and fate of pre-malignant cells and help a long-term goal toidentify potential biomarkers and targets to break the link between inflammation and tumorigenesis. 67844 +No NIH Category available APC gene;Amino Acids;Animals;Aryl Hydrocarbon Receptor;Automobile Driving;Binding;Biogenesis;Biomass;Cancer Cell Growth;Cell Nucleus;Cell Proliferation;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Colon;Colon Carcinoma;Development;Enzymes;Epithelial Cells;Gene Expression;Genes;Genetic;Genetic Transcription;Growth;Human;In Vitro;Knock-out;Kynurenine;Label;Ligands;MYC gene;Maintenance;Malignant Neoplasms;Manuscripts;Mediating;Metabolic;Metabolic Pathway;Modeling;Molecular;Monitor;Mus;Oncogenes;Oncogenic;Organoids;Pathway interactions;Physiological;Play;Preparation;Production;Proliferating;Protein Biosynthesis;Proteins;Proto-Oncogene Proteins c-myc;Regulation;Research;Ribosomes;Role;Seminal;T-Lymphocyte;Testing;Therapeutic Intervention;Translations;Tryptophan;cancer cell;cancer therapy;cell growth;colon growth;in vivo;inhibitor;knock-down;macromolecule;novel;novel strategies;nutrient absorption;prevent;transcription factor;tumor;tumor growth;tumor metabolism;uptake The kynurenine-AHR pathway in biomass production PROJECT NARRATIVE The continuous proliferation of cancer cells demands profound translational and metabolicreprograming. Nevertheless we still lack a clear picture of the unique adaptations that facilitateaberrant biomass accumulation specifically in cancer cells. This proposal seeks to understand the role ofthe transcription factor aryl hydrocarbon receptor (AHR) and its ligand kynurenine in protein synthesis andproliferation of colon cancer cells. NCI 10737934 5/2/23 0:00 PA-19-056 3R01CA245548-04S1 3 R01 CA 245548 4 S1 "WILLIS, KRISTINE AMALEE" 3/1/20 0:00 2/28/25 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10247449 "CONACCI-SORRELL, MARALICE " Not Applicable 30 ANATOMY/CELL BIOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 72971 NCI 48510 24461 PROJECT SUMMARY Increased uptake and synthesis of macromolecules is essential to sustain the demands of hyperproliferativecancer cells. Therefore developing approaches to limit biomass production specifically in tumors could haveprofound implications for cancer treatment. While seminal studies have shown that the universal oncogeneMYC promotes protein synthesis in cancer cells there is still a gap in our understanding of how MYC molecularlycontrols translation during oncogenic transformation. We found that the transcription factor aryl hydrocarbonreceptor (AHR) and its ligand kynurenine a byproduct of the amino acid tryptophan are induced by MYC incolon cancer cells. Our preliminary results indicate that AHR is necessary for the expression of genes involvedin ribosomal biogenesis and protein synthesis in proliferating cells. Our hypothesis is that AHR senses andresponds to tryptophan-derived kynurenine by translocating into the nucleus and inducing the transcription ofgenes that mediate ribosome biogenesis and translation in colon cancer cells. Aim 1 will directly test the role ofAHR in protein synthesis in colon cancer cells using genetic silencing in isogenic lines of human colonicepithelial cells and of mouse organoids progressed to colon cancer. Aim 2 will establish the contribution ofkynurenine to AHR-regulated protein synthesis and cell proliferation by examining the requirement forkynurenine for the expression of AHR target genes protein synthesis and growth. We will utilize AHR knockoutcells and animals and a competitive inhibitor that prevents the binding of kynurenine to AHR to define AHR-specific functions regulated by kynurenine. Aim 3 will directly test the importance of tryptophan-metabolizingenzymes in generating kynurenine and in regulating proliferation of colonic cells. We will determine the effectsof knocking down or knocking out enzymes in the kynurenine pathway to define their requirement for AHRactivity protein synthesis and proliferation of colon cancer cells and organoids. This study has the potential todefine a direct physiological role for the kynurenine-AHR pathway in driving increased biomass production andcell proliferation in colon cancer. Moreover this study will broaden the understanding of the role of kynurenineas an oncometabolite. Our findings could become the basis for the development of novel approaches to limitkynurenine production and AHR activity as a means to treat MYC-dependent tumors. 72971 +No NIH Category available Affect;Amino Acids;Architecture;Binding;Biological Assay;Blood;Blood Platelets;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Bypass;C-terminal;Cell secretion;Cells;Cessation of life;Circulation;Clinical;Collagen;Collagen Fiber;Collagen Type I;Confocal Microscopy;Cysteine;Data;Deposition;Disease;Event;Extracellular Matrix;Extracellular Matrix Proteins;Extravasation;Face;Fibroblasts;Fluorescence;Gene Expression;Generations;Human;Implant;In Vitro;Injections;Invaded;Knockout Mice;Malignant Neoplasms;Mammary Neoplasms;Mechanics;Mediating;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Microscopy;Modality;Modeling;Molecular;Mus;Neoplasm Metastasis;Pathogenicity;Play;Positioning Attribute;Primary Neoplasm;Process;Prognosis;Recombinants;Regulation;Role;Scanning Electron Microscopy;Signal Transduction;Site;Stream;Structure of parenchyma of lung;Tail;Tertiary Protein Structure;Testing;Therapeutic;Tumor Cell Invasion;Tumor Promotion;Veins;Visualization;WISP1 gene;aggressive breast cancer;breast cancer progression;cancer cell;clinical prognostic;in vivo;innovation;knock-down;knowledgebase;malignant breast neoplasm;mechanical force;migration;mouse model;multi-photon;mutant;neoplastic cell;novel;overexpression;patient derived xenograft model;prevent;prognostic value;second harmonic;therapeutic evaluation;time use;tumor;tumor microenvironment;tumor progression Regulation of collagen linearization during cancer progression and metastasis Collagen linearization in breast tumors is a key pathogenic event that leads to enhanced tumor cell invasionand metastasis and to poor prognosis. However despite its recognized clinical prognostic value little is knownabout the mechanisms responsible for collagen linearization. This project will determine the function of novelsecreted regulators of collagen linearization and test whether they could be exploited to normalize collagenarchitecture in tumors and as anti-metastasis therapy. NCI 10737930 3/1/23 0:00 PA-19-056 3R01CA245301-03S1 3 R01 CA 245301 3 S1 "AULT, GRACE S" 7/20/20 0:00 2/28/26 0:00 Tumor Progression and Metastasis Study Section[TPM] 10475174 "LABELLE, MYRIAM " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 126928 NCI 70712 56216 Metastasis accounts for the vast majority of cancer-related deaths but its underlying mechanisms areincompletely understood. During tumor progression extensive remodeling of the tumor microenvironmentoccurs and facilitates metastasis. In particular linearization of collagen one of the most abundant extracellularmatrix (ECM) proteins in tumors is recognized as a hallmark of aggressive breast cancers and is associatedwith poor prognosis. At the cellular level bundles of linearized collagen facilitate tumor cell invasion andmetastasis by providing tracks on which tumor cells can easily migrate. Cell-generated mechanical tension hasbeen proposed to contribute to collagen remodeling but it remained unknown whether this is the solemechanism by which collagen linearization is established or whether other mechanisms also play prominentroles in this process. Our recent studies revealed that cancer cells secrete factors that can linearize collagenindependently of cell-generated mechanical forces. Specifically we found that the tumor cell-secreted factorWISP1 (CCN4) promotes collagen linearization tumor cell invasion and metastasis. However the cellular andmolecular mechanisms by which WISP1 linearizes collagen and promote metastasis remain incompletelyunderstood. To uncover these mechanisms we will 1) define the specific steps of the metastatic cascade thatare impacted by WISP1 2) determine the molecular mechanisms by which WISP1 regulates collagenlinearization and promotes tumor cell invasion and 3) test therapeutic modalities to block WISP1s functionand prevent metastasis. This will be achieved by performing detailed analyses of breast cancer progressionand metastasis in mouse models and in vitro invasion assays. Central to our studies is also the use ofscanning electron microscopy and intravital multiphoton fluorescence and second harmonic generationmicroscopy to visualize alterations in ECM architecture in vitro and in vivo. Globally these studies will elucidatefundamental mechanisms of collagen fiber linearization and test innovative therapeutic approaches to limitmetastasis by normalizing collagen architecture. 126928 +No NIH Category available Acute Lymphocytic Leukemia;Address;Adolescent;Adverse event;Area;Biological;Canada;Cancer Patient;Cancer Relapse;Caring;Censuses;Central Nervous System Neoplasms;Cephalic;Cessation of life;Child;Clinical Trials Cooperative Group;Collection;Common Terminology Criteria for Adverse Events;Cytogenetics;Data;Diagnosis;Disparity;Enrollment;Ethnic Origin;Factor Analysis;Fever;Future;Goals;Hispanic;Hospitals;Infection;Institution;Insurance Coverage;International;Intervention;Location;Logistic Regressions;Lymphoma;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Mediating;Mediation;Methods;Minnesota;Molecular;Morbidity - disease rate;Necrosis;Neoadjuvant Therapy;Neuropathy;Neutropenia;Not Hispanic or Latino;Odds Ratio;Outcome;Outcome Study;Parents;Pathway interactions;Patients;Pediatric Oncology Group;Population;Primary Neoplasm;Protocols documentation;Race;Recommendation;Registries;Relapse;Research;Research Personnel;Residual Neoplasm;Resources;Risk;Risk Reduction;Serious Adverse Event;Socioeconomic Factors;Socioeconomic Status;Solid Neoplasm;Standardization;Survival Rate;Survivors;Therapeutic Trials;Time;Toxic effect;Treatment-related toxicity;United States;Work;adverse outcome;cancer diagnosis;cancer survival;cancer type;cohort;comorbidity;economic determinant;ethnic disparity;experience;follow-up;hazard;improved;indexing;leukemia;low socioeconomic status;mortality;outcome prediction;participant enrollment;patient population;racial disparity;relapse risk;risk stratification;sex;socioeconomic disparity;socioeconomics;survivorship;therapy outcome;tool;translational potential;tumor Socioeconomic determinants of childhood cancer outcomes in a large contemporary cohort Project NarrativeDespite improvements in childhood cancer survival over the last several decades marked racial ethnic andsocioeconomic disparities in outcomes persist. Thus understanding the socioeconomic factors contributing todisparities in relapse toxicities and survival may allow for intervention measures in the future. NCI 10737877 2/6/23 0:00 PA-20-185 3R01CA266105-02S1 3 R01 CA 266105 2 S1 "GALLICCHIO, LISA M" 2/1/22 0:00 1/31/26 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 10712104 "MARCOTTE, ERIN " Not Applicable 5 PEDIATRICS 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 393 Non-SBIR/STTR 2023 52153 NCI 34561 17592 ABSTRACTDespites improvements in childhood cancer survival in the last several decades marked racial ethnic andsocioeconomic disparities in outcomes persist. Compared with non-Hispanic white children non-Hispanic blackand Hispanic children experience lower survival from many cancers including leukemia the most commonlydiagnosed cancer in children. The underlying causes of these survival differences are poorly understood andmay vary by cancer type and both biological and socioeconomic pathways have been proposed. Recentevidence has suggested that lower socioeconomic status (SES) is associated with survival from some childhoodcancers. The Children's Oncology Group (COG) is an international clinical trial cooperative group of over 200hospitals which together treat more than 90% of all children and adolescents diagnosed with childhood cancerin the United States and Canada. In 2007 the COG opened the Childhood Cancer Registration Network (CCRN;COG protocol ACCRN07) to create a research registry. A total of over 56000 childhood cancer cases wereenrolled on ACCRN07 through the end of enrollment on December 8 2017. All children and parents enrolled onACCRN07 provided address information which was current at the time of diagnosis. We will work withinvestigators at the Minnesota Population Center to geocode all ACCRN07 patients with a valid U.S. addresscontextualize with socioeconomic status data and return small-area SES data to COG for dissemination. Wewill contextualize each geocoded address with Census data at the block level using seven variables from thesedata we will use factor analysis to derive a five-level SES indicator. We will then examine the influence of SESon risk of minimum residual disease at the end of induction therapy relapse other serious toxicities andadverse events and survival in >9500 acute lymphoblastic leukemia (ALL) patients. Over 9500 ALLpatients on ACCRN07 with a valid address will also have been treated on COG protocols. Ours will be the firststudy to evaluate SES as a predictor of childhood cancer outcomes on a large scale within the Children'sOncology Group and will include detailed cytogenetic and molecular characterization of each tumor. Additionallyto our knowledge this will be the first analysis of SES predictors of short-term treatment toxicities. We will createa highly useful resource on a large scale for a contemporary cohort of childhood cancer patients. Our findingswill have translational potential in that outcomes related to SES may indicate the need to develop tailoredinterventions for low-resource patient populations. Additionally this cohort's utility will extend beyond outcomesof therapy and into survivorship with linkages to the National Death Index (NDI) to obtain mortality data. Ourlong-term goal is to understand the factors that contribute to disparities in childhood cancer relapse survivaland the burden of morbidity in survivors. Thus this effort will inform targeted follow-up recommendations andrisk-reducing interventions. 52153 +No NIH Category available Abstinence;Address;Adult;Basic Science;Behavior;Carcinogens;Cigarette Smoker;Clinical Pathways;Cognitive;Cues;Data;Development;Ecological momentary assessment;Electronic cigarette;Exposure to;Follow-Up Studies;Goals;Health;Impulsive Behavior;Impulsivity;Intervention;Investigation;Maintenance;Malignant Neoplasms;Mediating;Methods;Modeling;Neurologic;Nicotine;Nicotine Dependence;Outcome;Participant;Pattern;Pharmaceutical Preparations;Prevalence;Process;Public Health;Randomized;Regulation;Relapse;Reporting;Research;Risk;Scientific Inquiry;Stimulus;System;Technology;Testing;Time;Tobacco;Toxin;Training;Translating;Work;addiction;alcohol use disorder;behavior change;brief intervention;cigarette smoking;cigarette user;combustible cigarette;computerized;craving;effective therapy;electronic cigarette use;electronic cigarette user;experience;follow-up;interest;intervention effect;nicotine cessation;nicotine use;nicotine user;post intervention;prolonged abstinence;randomized clinical trials;reduced substance use;substance use;substance user;theories;uptake Approach Bias Retraining for Nicotine Addiction among Dual Combustible and Electronic Cigarette Users PUBLIC HEALTH NARRATIVECurrent combustible cigarette (CC) smokers are more likely than other groups to use electronic cigarettes(ECIG) and engage in prolonged use of both products with 40.8% of ECIG using adults reporting dual ECIGand CC use. This co-use is concerning from a public health perspective because (1) dual CC/ECIG users areapt to experience cancers and tobacco-related health risks at rates comparable to exclusive CC users and (2)dual CC/ECIG use may prolong and sustain nicotine addiction and consequently inhibit CC cessation amongthose who might otherwise quit; yet little is understood about clinical pathways to support CC and ECIGcessation among dual users. The goal of the current R21 proposal is to evaluate CC and ECIG quit patternsfollowing a theoretically and empirically supported brief computerized intervention that targets approach biastoward drug-related stimuli (i.e. CC and ECIG stimuli) among dual users. NCI 10737867 1/27/23 0:00 PAR-19-309 3R21CA263765-02S1 3 R21 CA 263765 2 S1 "CICCOLO, JOSEPH THOMAS" 2/1/22 0:00 1/31/25 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 12160220 "GAREY, LORRA " Not Applicable 18 PSYCHOLOGY 36837920 QKWEF8XLMTT3 36837920 QKWEF8XLMTT3 US 29.718091 -95.336483 1449402 UNIVERSITY OF HOUSTON HOUSTON TX SCHOOLS OF ARTS AND SCIENCES 772042610 UNITED STATES N 2/1/23 0:00 1/31/25 0:00 393 Non-SBIR/STTR 2023 72008 NCI 50324 21684 ABSTRACT Electronic cigarette (ECIG) use has become a popular method for nicotine delivery. Combustible cigarette (CC)cessation or reduction are the primary reasons for ECIG uptake among adults.1-3 Yet most CC smokers who initiateECIG use do not fully transition from CC to ECIG despite intending to quit CC completely.4-9 Longitudinal work hasfound that 89% of dual usersusers of ECIG and CC concurrently--remain dual users a year after initialassessment.10 Continued dual use is alarming because it is associated with increased nicotine use anddependence.11 Consequently dual users are exposed to CC toxins and constituents including carcinogens atlevels comparable to exclusive CC smokers.12 Theory and empirical findings suggest that targeting automatedimpulsive implicit processes may hold promise for substance use reduction and cessation.13-18 Specificallyretraining approach bias or the approach action tendency toward stimuli related to the substance of interest hasbeen effective in alcohol use disorders (i.e. reduction in relapse rates by 10%-13%).18-20 When applied to CC-related stimuli approach bias retraining has been found to reduce approach bias which is subsequently related togreater number of days abstinent from CC following a self-guided quit attempt.21 This R21 application will evaluate the initial efficacy of approach bias retraining among dual CC/ECIG users. Toobtain initial effect size data for a larger R01 follow-up study we will randomly assign 90 dual CC/ECIG using adultsto one of three conditions: (1) CC+ECIG retraining; (2) CC only retraining; and (3) sham training (control).Participants will complete 4 sessions of approach bias retraining using the respective stimuli and then engage in aself-guided quit attempt to abstain from all nicotine products. Each session will consist of 15 minutes ofcomputerized approach bias retraining and a brief assessment. Participants will provide baseline data ecologicalmomentary assessment (EMA) data during the first two weeks post-intervention and complete follow-ups at 4- and6-week post-intervention. Abstinence will be assessed during the intervention (weeks 0-4) during the EMA periodand at both follow-ups. The proposed study represents a crucial and important next step in translating basic research to strategies fortreating nicotine dependence among dual CC/ECIG users. The investigation addresses an important public healthissue by testing a brief computerized intervention - informed by basic research - that may lead to a more effectivetreatment for at-risk nicotine users while simultaneously isolating explanatory mechanisms. The expected findingsshould: (1) guide advances in the theoretical conceptualization of nicotine addiction for dual users and mechanismsinvolved in maintaining and abstaining from CC and ECIG; and (2) provide initial effect size data for a briefintervention and thus provide the necessary data for a large-scale follow-up trial. 72008 +No NIH Category available Affect;Apoptosis;Biochemical;Biological Assay;Biological Models;Brain;Breast Cancer Treatment;Bypass;Cancer Patient;Cells;Chemicals;Cisplatin;Combined Modality Therapy;Cyclin-Dependent Kinases;Data;Development;Disease;Disseminated Malignant Neoplasm;Dose;Drug Kinetics;Drug Targeting;Drug Tolerance;Drug resistance;ERBB2 gene;Enhancers;Enzymes;Epigenetic Process;Epithelium;Evaluation;FRAP1 gene;Fatty acid glycerol esters;Future;Genes;Genetic Transcription;Goals;Growth Factor Receptors;Image;Immune system;Immunocompetent;Investigational Drugs;KRAS2 gene;Lead;Ligands;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mesenchymal;Metabolism;Microsomes;Mission;Modeling;Molecular;Molecular Probes;Mutation;Neoplasm Metastasis;New Agents;Non-Small-Cell Lung Carcinoma;Oncogenes;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Proliferating;Property;Proteomics;Receptor Signaling;Reporter;Reporting;Research;Resistance;Resistance development;Role;Signal Transduction;Solubility;Stress;Structure;Testing;Transcription Alteration;Transcription Process;Transcriptional Regulation;Trastuzumab;United States National Institutes of Health;Work;Xenograft Model;acquired drug resistance;analog;anti-cancer;anti-cancer therapeutic;anticancer activity;cancer cell;chemotherapy;clinical development;combat;design;disability;epigenetic regulation;first-in-human;fluorescence imaging;immune resistance;immunoregulation;improved;in vivo;ineffective therapies;inhibitor;innovation;insight;kinase inhibitor;lung cancer cell;malignant breast neoplasm;mammary;neoplastic cell;novel;novel strategies;novel therapeutics;overexpression;patient derived xenograft model;phosphoproteomics;posttranscriptional;pre-clinical;prevent;programs;research clinical testing;resistance mechanism;response;safety assessment;single-cell RNA sequencing;small molecule;stressor;success;targeted agent;targeted treatment;therapy resistant;three-dimensional modeling;transcriptome sequencing;translational approach;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers Project NarrativeAlthough targeted anti-cancer therapeutics have improved patient outcomes benefits can be short-lived andnew approaches are needed to prevent the emergence of drug resistance. We aim to determine if CDK12/13inhibition can prevent drug resistance in combination with targeted agents and use our new inhibitors to revealthe complexities of acquired drug resistance. Thus the proposed research is directly relevant to NIHs mission to fuel discovery reduce illness and disability. NCI 10737865 8/7/23 0:00 PA-20-185 3R01CA262530-03S1 3 R01 CA 262530 3 S1 "AGYIN, JOSEPH KOFI" 7/12/21 0:00 6/30/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 9621640 "DUCKETT, DEREK RONALD" "HAURA, ERIC B.; MONASTYRSKYI, ANDRII " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 72662 NCI 43123 29539 Project SummaryAlthough the development of targeted therapies has improved overall cancer patient survival adaptiveresponses by tumor cells can render these treatments ineffective. The development of agents that block adaptiveresponses thereby increasing treatment durability is desperately needed. We and others have demonstratedthat inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidatesto combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcometherapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overallobjective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiringand develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis isthat CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for thisproject posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticityas an adaptive stress resistance mechanism and (ii) elucidation of mechanisms underpinning compound actionwill offer a strong scientific framework that will facilitate future clinical development of these new agents forimproved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimizethe drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanismswhereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3)Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitorresistance in NSCLC. Accordingly using a battery of approaches we will: a) optimize key CDK12/13 inhibitorparameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translationalmechanisms whereby SR-4835 provokes resensitization to chemotherapy and c) validate cell-basedobservations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovativeas our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecularprobes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii)evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting moredurable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drivedrug resistance. The proposed research is highly significant and provides a strong scientific rationale for thecontinued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinningsof the master effectors of CDK12 and CDK13-driven signaling together with an optimized CDK12/13 inhibitorwill offer new opportunities for improved combination treatments for breast and lung cancer. 72662 +No NIH Category available CD8-Positive T-Lymphocytes;Clinic;Clinical;Data;Event;FDA approved;Funding;Germ-Line Mutation;Immune;Immunotherapy;Investigation;Malignant Neoplasms;Mediating;Molecular;Monoclonal Antibodies;Oncogenic;Patient-Focused Outcomes;Regulation;Research;Resistance;Sampling;Stream;T cell response;T-Lymphocyte;T-cell inflamed;Tumor Immunity;Work;anti-PD-1;cancer immunotherapy;commensal microbes;immune cell checkpoints;immune checkpoint blockade;immune resistance;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;patient subsets;predicting response;tumor;tumor microenvironment Overcoming resistance to anti-PD1 immunotherapy PROJECT NARRATIVEThe overall purpose of this proposal is to continue to identify new strategies for cancerimmunotherapy based on understanding the molecular features of the T cell-inflamed and non-Tcell-inflamed tumor microenvironment. Our overall approach centers on a bi-directional work flowbetween patient outcomes and clinical samples and mouse models for mechanisticunderstanding. Our 5-pronged research stream investigates novel T cell immune checkpointsinnate immune strategies to promote de novo T cell responses in the tumor microenvironmenttumor cell-intrinsic oncogenic events mediating immune resistance regulation of anti-tumorimmunity by the commensal microbiota and germline variants influencing host anti-tumor T cellresponses. NCI 10737852 9/22/23 0:00 RFA-CA-22-045 2R35CA210098-08 2 R35 CA 210098 8 "SONG, MIN-KYUNG H" 12/7/16 0:00 8/31/30 0:00 ZCA1-SRB-E(M1) 1902936 "GAJEWSKI, THOMAS F" Not Applicable 1 PATHOLOGY 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 970168 NCI 600000 375296 ABSTRACTNovel immunotherapies for cancer are having a major clinical impact in particular anti-PD-1 mAbswhich have been FDA-approved for 20 cancer entities. However the mechanisms that explainwhy a subset of patients fails to respond to these therapies is incompletely understood.Understanding these mechanisms should lead to new therapeutic strategies for expandingefficacy further. Our prior data indicated that a baseline T cell-inflamed tumor microenvironmentwas predictive of response to anti-PD-1 which augments the functionality of CD8+ T cells alreadypresent within the tumor microenvironment. During the previous funding period we made multiplenovel discoveries that have been paradigm-shifting for the field which have coalesced to motivatecontinued investigation into 5 research directions: investigation of novel T cell immunecheckpoints innate immune strategies to promote de novo T cell responses in the tumormicroenvironment tumor cell-intrinsic oncogenic events mediating immune resistance regulationof anti-tumor immunity by the commensal microbiota and germline variants influencing host anti-tumor T cell responses. Each of these directions is identifying novel therapeutic opportunitiesthat are expected to expand the circle of efficacy for checkpoint blockade immunotherapy in theclinic. 970168 +No NIH Category available Address;Aftercare;Back;Biological Assay;Biological Markers;Blood specimen;Bromodomains and extra-terminal domain inhibitor;CCNE1 gene;Cancer Model;Cell Line;ChIP-seq;Chemicals;Clinic;Clinical;Clinical Trials;Combined Modality Therapy;Complement;DNA Methyltransferase Inhibitor;Data;Drug Combinations;Epigenetic Process;Future;Gene Expression;Genes;Genetic Transcription;Histone Deacetylase Inhibitor;In Vitro;Knowledge;Malignant neoplasm of ovary;Measures;Methods;Molecular;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase I/II Trial;Phenotype;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Pre-Clinical Model;Publishing;Regimen;Repression;Resistance;Surrogate Markers;Testing;Therapeutic;Toxic effect;Translational Research;Validation;antitumor effect;cancer cell;carcinogenesis;cell type;chemotherapy;clinical development;clinically relevant;companion diagnostics;design;effective therapy;epigenetic drug;epigenetic therapy;gene function;gene repression;genome-wide;homologous recombination;in vivo;inhibitor;inhibitor therapy;innovation;insight;mutant;patient derived xenograft model;pre-clinical;preclinical development;prognostic;response;response biomarker;transcriptome sequencing;translational approach;tumor Epigenetic Drug Regimens for Homologous Recombination Proficient Ovarian Cancer Poly ADP ribose polymerase inhibitor (PARPi) have changed treatment paradigms with greatest clinical benefitsin BRCA mutant homologous recombination (HR) deficient ovarian cancer. A critical clinical problem ischemotherapy drugs including PARPi are far less effective in BRCA wild-type HR proficient ovarian cancer (e.g.CCNE1 amplification/gain). This proposal will apply an innovative translational research approach to determinethe potential benefits of PARPi-epigenetic drug combinations for the treatment of poor prognostic ovarian cancer. NCI 10737850 2/25/23 0:00 PA-19-056 3R01CA243511-05S1 3 R01 CA 243511 5 S1 "KONDAPAKA, SUDHIR B" 7/1/20 0:00 2/28/25 0:00 Developmental Therapeutics Study Section[DT] 7605639 "KHABELE, DINEO " Not Applicable 1 OBSTETRICS & GYNECOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 109193 NCI 69920 39273 Poly ADP ribose polymerase inhibitors (PARPi) have shown extraordinary clinical benefits in the treatment ofBRCA mutant homologous recombination (HR) deficient ovarian cancer. A critical clinical problem ischemotherapy drugs including PARPi are far less effective in BRCA wild-type HR proficient poor prognosticovarian cancer (e.g. CCNE1 amplification/gain). Combining PARPi with other drugs is an emerging strategy toovercome this problem. The PI has shown epigenetic drugs histone deacetylase inhibitors (HDACi)bromodomain extra-terminal inhibitors (BETi) and DNA methyltransferase inhibitors (DNMTi) enhance PARPiefficacy in preclinical models of HR proficient ovarian cancer. Epigenetic drugs primarily activate or repress genetranscription in a cell type- and context-dependent manner. In the context of CCNE1 amplified/gain HR proficientovarian cancer the PI has demonstrated chemically diverse epigenetic drugs induce a BRCA mutant-likecontextual synthetic lethal phenotype characterized by repressed HR gene expression and function. The overallobjective of this proposal is to determine if the extraordinary benefits of PARPi therapy can be extended throughrational PARPi-epigenetic drug combinations for a new indication in BRCA wild-type HR proficient poorprognostic ovarian cancer. Even with extensive published and preliminary results from the PI's group and othersgaps in knowledge remain regarding optimal PARPi-epigenetic regimens for clinical use appropriate biomarkersof response and precise underlying mechanisms of action. To address these gaps we will apply a translationalresearch approach that takes full advantage of our collective expertise including: unique primary cell lines andpatient-derived xenograft (PDX) preclinical models clinical patient biosamples associated with an approvedphase 1/2 trial and state-of-the-art genome-wide strategies. As a result we are perfectly positioned to test thecentral hypothesis that epigenetic drugs enhance PARPi efficacy in BRCA wild-type HR proficient ovarian cancerby inducing a BRCA mutant-like phenotype through repression of common HR transcriptional targets andcontextual synthetic lethality. The Specific Aims are designed to determine the therapeutic potential of newPARPi-epigenetic drug regimens in preclinical models of ovarian cancer to investigate HR deficient status as asurrogate biomarker of a new PARPi-epigenetic drug regimen in clinical development and to elucidatemechanisms of response to PARPi-epigenetic drug regimens in HR proficient ovarian cancer cells usinggenome-wide strategies. This innovative translational approach has high potential for advancing new preclinicalPARPi-epigenetic drug regimens to the clinic along with new biomarkers as companion diagnostics and newmechanistic insights for both PARPi and epigenetic drugs. As a result the proposed studies will have broadimplications beyond ovarian cancer. Because a critical clinical problem is the lack of effective treatment optionsfor BRCA wild-type HR proficient tumors establishing benefits of PARPi-epigenetic therapy for this typically poorprognostic ovarian cancer has the potential for high impact. 109193 +No NIH Category available Accounting;Address;Adherence;African American;Age;Annual Reports;Area;Asian;Asian population;Attenuated;Biological;Biological Factors;Body mass index;California;Cancer Etiology;Caring;Cells;Cessation of life;Characteristics;Classification;Clinical;Clinical Data;Clinical Management;Clinical Pathology;Cohort Studies;Complex;Comprehensive Health Care;Crime;Data;Diagnosis;Diagnostic;Disease;Disparity;Dose;Electronics;Epithelial ovarian cancer;Ethnic Origin;Ethnic Population;Evaluation;Exclusion;Gene Expression;Genetic;Geographic Factor;Geography;Goals;Guidelines;Health Insurance;Health Services Accessibility;Healthcare;Healthcare Systems;Hispanic;Hispanic Populations;Inequity;Insurance Coverage;Integrated Health Care Systems;Malignant Neoplasms;Malignant neoplasm of ovary;Managed Care;Medical;Medical Geography;Minority Groups;Molecular;Morphology;Nature;Neighborhoods;Not Hispanic or Latino;Outcome;Pacific Islander;Participant;Pathology;Patient Self-Report;Patients;Physicians;Policies;Population Heterogeneity;Prospective cohort study;Race;Recommendation;Recurrence;Reporting;Research;Residual Neoplasm;Resources;Sample Size;Serous;Social support;Societies;Socioeconomic Status;Specimen;Stress;Structural Racism;Time;Toxic effect;Treatment outcome;Underserved Population;United States;Woman;Work;World Health Organization;cancer diagnosis;cancer subtypes;cancer survival;cancer therapy;chemotherapy;clinical database;cohort;comorbidity;contextual factors;disparity reduction;ethnic difference;ethnic disparity;experience;health care availability;health care service;improved;insight;member;molecular subtypes;mortality;mortality disparity;mortality risk;multi-ethnic;novel;prognostic;protein expression;racial determinant;racial difference;racial disparity;residence;segregation;social;social factors;social stressor;sociodemographics;standard of care;survival disparity;survival outcome;treatment guidelines;treatment response;tumor Racial/Ethnic Disparities in Ovarian Cancer Treatment and Survival: An Integrative Approach PROJECT NARRATIVEOvarian cancer is a deadly disease but survival varies widely by race/ethnicity. We propose to examinewhether differences in neighborhood characteristics patient and clinical factors including receipt ofrecommended treatments or molecular features of the tumors can account for these disparities at least inpart. Ovarian cancer is understudied in diverse populations and the proposed work is one of the largest tosearch for potentially modifiable factors that can reduce disparities in survival. NCI 10737847 6/5/23 0:00 PA-19-056 3R01CA243188-04S1 3 R01 CA 243188 4 S1 "GALLICCHIO, LISA M" 7/1/20 0:00 6/30/25 0:00 Health Disparities and Equity Promotion Study Section[HDEP] 9733280 "DOHERTY, JENNIFER A." "BANDERA, ELISA V; GOMEZ, SCARLETT L; KUSHI, LAWRENCE H" 1 PUBLIC HEALTH & PREV MEDICINE 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 7/1/23 0:00 1/8/24 0:00 393 Non-SBIR/STTR 2023 100833 NCI 100833 0 ABSTRACT Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths in women. Compared to non-Hispanic white (NHW) women African American (AA) women have much poorer survival after an EOCdiagnosis which as we have found may be in part due to AA women being less likely to receive standard-of-care therapy and more likely to have chemotherapy dose reduction even within an equal-access healthcaresystem. However these factors do not completely explain survival disparities among AAs and furthermorelittle is known about other groups (e.g. Hispanics and Asians/Pacific Islanders (API)) although there is someevidence that Hispanic women also experience worse survival. Moreover emerging evidence suggests racialdifferences in molecular subtype distribution. We propose to conduct the first integrative cells-to-societyevaluation of the interplay among multilevel factors on disparities in EOC treatment and survival outcomes. We will assemble a cohort of ~4600 EOC cases including ~280 AA ~520 Hispanic ~730 API and~2980 NHW women diagnosed at Kaiser Permanente Northern California (KPNC) between 2000 and 2023.KPNC has longstanding electronic clinical databases complete pathology specimen storage long-termretention of members and substantial variability in sociodemographic clinical and neighborhoodcharacteristics among races/ethnicities. We will perform centralized pathology review to classify histotypes bythe recent gold standard WHO criteria and will conduct chart review to capture data that are not availableelectronically. We will examine determinants of racial/ethnic differences in treatment received recurrence andsurvival (overall and EOC-specific) including neighborhood social stressors through linkage to data onsegregation structural racism ethnic enclaves and geographic medical accessibility health care system andpatient-level factors. In 800 women (200 each of NHW AA Hispanic and API) with high grade serous EOCwe will also characterize gene expression subtypes (to date studied almost exclusively in NHW women) toidentify whether the relative distribution of aggressive subtypes contributes to the observed survival disparities.We will examine these factors in the context of both self-reported race/ethnicity and genetic ancestry. Our comprehensive integrative approach to examine the interplay among patient health care socialcontextual and biological factors will provide unique insights into the persistent racial disparities in EOCsurvival. The KPNC setting provides the opportunity to examine these factors while minimizing confounding bythe known contribution of insurance status leveraging rich clinical databases to investigate and control fordetailed prognostic variables and avoiding survival bias. For EOC this proposed study is unprecedented in itstransdisciplinary nature sample size and multi-ethnic population and will serve as a unique resource forfuture research related to multilevel factors to reduce EOC survival disparities. 100833 +No NIH Category available Ablation;Address;Adrenergic Agents;Afferent Neurons;Attention;Axon;Biological Models;Biometry;Blood Vessels;Breast;Cancer Biology;Cell Communication;Cells;Cellular Structures;Cellular biology;Clinical;Complement;Complex;Cues;Data;Development;Epithelium;Event;Genes;Genetic Engineering;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth;Head and Neck Cancer;Human;Infiltration;Inflammation;Knowledge;Light;Malignant Neoplasms;Mediating;Mediator;MicroRNAs;Molecular;Neoplasms;Nerve;Nerve Fibers;Neurobiology;Neuroepithelial Perineurial and Schwann Cell Neoplasm;Neurogenic Inflammation;Neurons;Oncology;Oral;Outcome;Pancreas;Pathologic;Pathology;Patients;Peripheral Nervous System;Persons;Phenotype;Play;Positioning Attribute;Pre-Clinical Model;Process;Prostate;Quality of life;RNA;Research;Resistance;Role;Shapes;Signal Induction;Signal Repression;Signal Transduction;Small RNA;Solid Neoplasm;Stomach;Supporting Cell;TP53 gene;Testing;Therapeutic;Time;Transcriptional Activation;Tumor Biology;Tumor Cell Invasion;Tumor Promotion;Tumor-Derived;Work;afferent nerve;angiogenesis;axonal sprouting;cancer cell;cancer genetics;cancer therapy;cancer type;candidate identification;cell type;exosome;genetic approach;improved;innovation;insight;malignant mouth neoplasm;mouse model;mouth squamous cell carcinoma;neoplastic cell;nerve supply;neural;neurodevelopment;neuronal tumor;neurotransmission;new therapeutic target;novel strategies;novel therapeutic intervention;oral cavity epithelium;perineural;pharmacologic;pre-clinical;prevent;programs;recruit;release factor;response;success;targeted cancer therapy;therapy development;therapy resistant;treatment response;tumor;tumor behavior;tumor growth;tumor microenvironment;tumor progression;tumorigenesis Defining the Role of Tumor-Neural Crosstalk in head and Neck Cancer Progression and Treatment Resistance PROJECT NARRATIVEThe solid tumor microenvironment includes nerve fibers arising from the peripheral nervous system. The formation of newnerve fibers within and around solid tumors plays an active role in cancer development progression and resistance totreatment. This proposal will explore the exact mechanisms that drive nerves to infiltrate tumors and support their growthand progression. NCI 10737845 6/1/23 0:00 PAR-16-245 3R37CA242006-04S1 3 R37 CA 242006 4 S1 "JHAPPAN, CHAMELLI" 6/1/20 0:00 5/31/25 0:00 Special Emphasis Panel[ZRG1-OBT-H(55)R] 15297738 "AMIT, MORAN " Not Applicable 9 SURGERY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 67758 NCI 41826 25932 PROJECT SUMMARYSolid tumors can shape their microenvironments to maximize their growth and metastatic potential. The formation of newnerve fibers within and around tumors can alter tumor behavior and higher densities of nerve fibers in the tumormicroenvironment are associated with poor clinical outcomes in patients with oral prostate breast gastric pancreatic andother types of cancer. Preclinical and pathological studies have described neoneurogenesis the process by which cancercells induce the growth of nerves into tumors as analogous to neoangiogenesis in which cancer cells release factors thatelicit the growth of blood vessels into the tumor. However the exact mechanisms that drive nerves to infiltrate tumors andsupport their growth and progression is unknown. Preliminary research shows that cancer cells `communicate' with neuronsthrough shuttling of p53-dependent RNA species that further induce tumor innervation.The hypothesis of this study is thataxonal sprouting and autonomic reprogramming of existing nerves occur as a result of orchestrated miRNA shuttling fromcancer cells to neurons and via activation of the transcriptional programs that establish neuronal identity and that infiltrationof tumors by autonomic neonerves enables tumor progression. The neonerve's phenotype includestransformation into asprouting cell able to infiltrate and interact with other cell types the release of adrenergic neuroactive molecules and thedevelopment of neurogenic inflammation. Each of these acquired capabilities may promote tumor progression and resistanceto therapy.The proposed research is innovative because it will capitalize on new concepts in cancer biology and advancedmodel systems to yield insights into the mechanisms of tumor progression and identify new targets for cancer therapy.Thiscross-disciplinary proposal will combine expertise from oncology neurodevelopment cell biology neurobiology cancergenetics pathology and biostatistics to pursue three specific aims: (1) Delineate the signaling events that occur betweencancer cells and neurons during tumorigenesis using pharmacologic and genetic approaches to understand how cancer cellscause normally quiescent neurons to reprogram and continually sprout to sustain neoplastic growth. (2) Elucidate the driversof tumor-associated neuronal reprogramming. By using human-derived sensory neurons we will determine how the normalnerve response to signals from cancer cells supports cancer progression. (3) Characterize sensory nerve reprogramming and itsrole in oral cancer progression. Using a genetically engineered syngeneic mouse model we will elucidate the neural-tumorinteractions that lead to neurogenic inflammation and promote oral cancer progression. Our long-term goal is to elucidatethe reciprocal nerve-cancer signals that drive cancer progression to identify novel targets for therapy. Once the signals thatinduce tumor innervation are known therapeutic approaches to target this critical component of tumor biology can bedeveloped to improve survival treatment responses and patients' quality of life. 67758 +No NIH Category available Acute;Alternative Splicing;BRCA1 Protein;Binding;Biological Assay;Biology;Cell Cycle;Cell Cycle Progression;Cell physiology;Cells;ChIP-seq;Chemicals;Childhood;Chimeric Proteins;DNA Damage;DNA Repair;Data;Data Analyses;Defect;EWSR1 gene;Ewings sarcoma;FLI1 gene;Genes;Genetic;Genetic Transcription;Genome;Genome Stability;Genomic Instability;Genomics;Goals;Growth;Impairment;Intervention;Lesion;Link;Location;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Modeling;Molecular;Monitor;Nature;Oncogenes;Paper;Pathologic;Pathway interactions;Pharmacologic Substance;Phenotype;Physiological;Process;Proteins;Publishing;RNA;RNA Interference;RNA Polymerase II;RNA Processing;RNA Splicing;RNA helicase A;RNA metabolism;Reporter;Reporting;Resolution;Role;SETX gene;Site;Small Interfering RNA;Techniques;Testing;Text;Therapeutic;Time;Toxic effect;Transcription Process;Uridine;Work;cDNA Expression;cell type;comparison control;efficacy testing;fitness;genome-wide;global run on sequencing;helicase;in vivo;inhibitor;insight;interest;prevent;programs;protein function;replication stress;response;single cell sequencing;stem cells;targeted treatment;transcriptome sequencing;tumor;tumor growth;tumor xenograft;young adult Dysregulated transcription processes in Ewing sarcoma NarrativeIt is well established that Ewing sarcoma is driven by a fusion oncogene EWSR1-FLI1 however the biology ofthis oncogene is poorly understood. In our prior work we identified that EWSR1-FLI1 dysregulates afundamental process transcription causing an increase in R-loops. While R-loops serve normal functions highlevels of R-loops are considered deleterious and are often associated with genome instability and a loss ofcellular fitness. The mechanism of how Ewing sarcoma is able to maintain high levels of R-loops withoutgenomic instability is not known. If we can determine this mechanism then we should be able to specificallytarget it as an alternate therapy for the treatment of Ewing sarcoma. NCI 10737841 6/15/23 0:00 PA-19-056 3R01CA241554-04S1 3 R01 CA 241554 4 S1 "WITKIN, KEREN L" 5/1/20 0:00 4/30/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 2088993 "BISHOP, ALEXANDER JAMES" Not Applicable 20 ANATOMY/CELL BIOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 64850 NCI 44500 20350 AbstractEwing sarcoma (EwS) is a pediatric and young adult cancer that is driven by the EWSR1-FLI1 translocation.Despite decades of work this cancer is still an enigma with poorly understood biology and no targetedtreatments. Our recent work published in Nature demonstrated a previously overlooked consequence ofEWSR1-FLI1 that this fusion causes hyperphosphorylated RNA polymerase II (pRNAPII) due to loss ofEWSR1 inhibition of CDK7 and CDK9. We observed high levels of transcription with high levels of R-loopspresent in locations that R-loops normally (physiologically) occur. Based upon these findings we began toreconsider cellular phenotypes of EwS to identify the molecular basis of these phenotypes and ask whetherthese changes provide a fundamental defect in all EwS. One phenotype that was previously identified in EwSis that these cells display altered splicing profiles. In recent years there were several reports linking R-loops tosplicing with splicing defects causing R-loop accumulation and R-loops being associated with sites ofalternative splicing. Further it was reported that the splicing machinery inhibits DHX9 (aka RNA helicase A;RHA) from causing accumulation of toxic R-loops. Also of interest is that EWSR1-FLI1 interacts with andimpairs DHX9 activity. By performing a genomic RNAi viability screen we determined that EwS is acutelysensitive to a loss of RNA processing capability. These collective observations led us to the hypothesis thatEwing sarcoma is dependent upon RNA processing machinery to prevent accumulation of toxic R-loops. If our hypothesis is correct then it suggests that there may be a therapeutic opportunity to targetsplicing components converting the high levels of physiological R-loops in EwS into pathological R-loops todrive toxic genomic instability. We propose to test our hypothesis with two Aims. In Aim 1 we will investigatethe mechanistic relationship between transcription levels R-loops and splicing in EwS. For this we willmodulate splicing components by siRNA depletions cDNA expression or use of pharmaceutical inhibitorsexamining transcription activity (Gro-Seq and uridine incorporation) splicing (reporters and RNA-Seq analysis)and R-loops (DRIP-Seq). In Aim 2 we will examine whether EwS is particularly reliant on splicing componentsor RNA:DNA helicases to block toxic conversion of R-loops and how targeting these processes impacts EwSviability DNA damage response and/or cell cycle progression. We will ask if these modulations effect EwScells at a particular time during cell cycle or stem cell state using single cell sequencing techniques. We willalso assess how these various components of R-loop biology interact with one another with pRNAPII and withR-loops in EwS. Finally based upon these results we will extend our findings to test efficacy of removing theR-loop metabolizing program that EwS is most reliant upon as a means to inhibit EwS tumor growth. Overallthis work should provide critical insight into the biology of Ewing sarcoma and provide new avenues fortreatment beyond the standard chemotherapeutics currently used. 64850 +No NIH Category available Address;Antigens;Antioxidants;Blood;Blood Pressure;Blood Vessels;Cancer Model;Cancer Patient;Cell Line;Cell Respiration;Cell Transplantation;Cells;Chemoresistance;Chemotherapy and/or radiation;Chronic;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Complex;DNA sequencing;Data;Data Set;Databases;Dependence;Dose;Drops;Effectiveness;Electron Transport;Engineering;Enrollment;Equilibrium;Erectile dysfunction;FDA approved;Future;Gastrointestinal tract structure;Gene Expression;Genes;Genetic;Genetic Transcription;Human;Hypoxia;Image;Immune;Immunocompetent;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Intervention;Intravenous infusion procedures;Lead;Lung;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of lung;Maximum Tolerated Dose;Metabolic;Metabolism;Mitochondria;Modality;Modeling;Mus;Muscle relaxants;Mutation;Neoplasm Transplantation;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Oncogenic;Outcome;Oxidative Phosphorylation;Oxygen;Oxygen Consumption;PD-1 blockade;Papaverine;Parents;Pathway interactions;Patient-Focused Outcomes;Patients;Perfusion;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase I Clinical Trials;Phenotype;Physiology;Population;Pre-Clinical Model;Process;Radiation;Radiation therapy;Radio;Radioimmunotherapy;Radiosensitization;Refractory;Reporter;Research Personnel;Resistance;Safety;Side;Smooth Muscle;System;T cell infiltration;T-Cell Activation;T-Lymphocyte;Testing;The Cancer Genome Atlas;Theft;Therapeutic;Tumor Oxygenation;Up-Regulation;Vascular resistance;Vasospasm;anti-PD-1;anti-PD1 therapy;cancer therapy;chemoradiation;chemotherapy;design;driver mutation;exhaust;exhaustion;imaging study;immune cell infiltrate;immune checkpoint blockade;improved;in vitro testing;inhibitor;innovation;mRNA sequencing;migration;mitochondrial metabolism;mutant;neoplastic cell;novel;novel strategies;pharmacologic;phase I trial;phosphoric diester hydrolase;progenitor;prognostic indicator;programs;radiation resistance;radiation response;response;standard of care;theories;treatment response;tumor;tumor DNA;tumor hypoxia;tumor microenvironment;vascular bed Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism PROJECT NARRATIVESome lung cancer patients respond well to therapy while others do not. We are investigating the repurposing ofan FDA-approved drug to enhance the effectiveness of established radiation and immunotherapy for lung cancer. NCI 10737837 9/13/23 0:00 PAR-18-560 3R01CA262388-03S1 3 R01 CA 262388 3 S1 "VIKRAM, BHADRASAIN" 9/22/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OTC-L(02)M] 1933683 "DENKO, NICHOLAS C." "LI, ZIHAI ; WILLIAMS, TERENCE MARQUES" 3 RADIATION-DIAGNOSTIC/ONCOLOGY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 212016 NCI 134613 77403 PROJECT SUMMARYMany groups are investigating why some lung cancer patients respond well to radio- and immuno-therapies andsome do not. One variable is tumor hypoxia and many groups have shown it can significantly inhibit theeffectiveness to these therapeutic modalities. Clinical studies have identified hypoxia as an independentprognostic indicator of poor patient outcomes but even though this connection has been known for decades noFDA-approved intervention exists to clinically overcome hypoxia. Some investigators have tried to deliver moreoxygen to the tumor but this approach remains constrained due to the poorly formed tumor vasculature. Wehave taken an innovative approach and asked if we can reduce demand for rather than increase supply ofoxygen to reduce hypoxia. We have found that the FDA-approved vasorelaxant papaverine (PPV) has an off-target ability to inhibit mitochondrial complex 1 and reduce oxygen consumption rapidly in low micromolarconcentrations in every cell line tested in vitro. We have also shown that PPV can enhance the effectiveness ofradiation and immune checkpoint blockade (ICB) in preclinical models of lung and other cancers withoutsensitizing well-oxygenated normal tissue. Reducing hypoxia reverses immune privilege decreases terminally-exhausted T cells and increases progenitors that are responsive to PD-1 blockade. We have more recentlydeveloped new derivatives of PPV that have lost their vasorelaxant capability and increased their duration ofaction so that they can be improved immuno-sensitizers. We now propose to test the hypothesis that PPV caneffectively enhance the radio- and immuno-therapeutic treatment of preclinical models of lung cancer and thatit is feasible to add PPV to standard of care therapy for advanced non-small cell lung cancer (NSCLC). We haveexamined TCGA databases and found that lung cancer driver mutations in the KEAP1/NRF2 pathway lead tohigh levels of mitochondrial gene expression that can cause elevated oxygen metabolism contributing to hypoxia.In Aim 1 we will investigate the effects of oncogenic NRF2 activation human and murine cells and model tumorsto determine the dependence of these cells on mitochondrial function how increased oxygen metabolismcontributes to tumor hypoxia and if therapy-refractory tumors are sensitized by PPV or its derivatives. In Aim 2we will examine the effect of tumor hypoxia on the migration and activation of T-cells in model tumors and howthe immune infiltrate changes after reduction of hypoxia with PPV or its derivatives. Finally in Aim 3 we willperform a phase 1 clinical trial to determine if the addition of PPV is feasible for patients receiving standard ofcare chemoradiation followed by immunotherapy for advanced NSCLC. We will look for effectiveness in changingtumor oxygenation using paired blood level oxygen determination (BOLD) MRIs and for changes in immunepopulations of peripheral blood mononuclear cells. These studies will let us know if and how to use PPV or itsnovel derivatives in future clinical trials for the treatment of NSCLC. 212016 +No NIH Category available Anus;Bilateral;Biological Markers;Biological Models;Blood;Blood Cells;Blood Volume;Body mass index;Cancer Control;Cancer Patient;Chronic Kidney Failure;Clinical;Collection;DNA;DNA analysis;DNA sequencing;Data;Detection;Diagnosis;Disease;Eligibility Determination;Excretory function;Filtration;Future;Gender;Gene Frequency;Genital;Genitalia;Genome;Goals;HPV analysis;HPV oropharyngeal cancer;Head Cancer;Home;Hour;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Iatrogenesis;Imaging Techniques;Incidence;Kidney;Kidney Diseases;Kinetics;Knowledge;Lead;Longitudinal Studies;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Methodology;Modeling;Molecular;Monitor;Mutation;Mutation Detection;Nature;Neck Cancer;Nephrectomy;Newly Diagnosed;Nonmetastatic;Oncogenic;Organ;Outcome;Patients;Performance;Persons;Pharmaceutical Preparations;Pharyngeal structure;Physiological Processes;Pilot Projects;Plasma;Radiation Dose Unit;Radiation therapy;Rattus;Recurrence;Research;Screening for cancer;Sensitivity and Specificity;Source;Stream;Swab;Testing;Time;Tissues;Tube;Urine;Validation;biomarker performance;blood fractionation;cell free DNA;cohort;detection sensitivity;improved;in vivo Model;in vivo fluorescence imaging;interest;liquid biopsy;malignant oropharynx neoplasm;men;novel;performance tests;pharyngeal swab;routine care;single molecule;targeted treatment;tumor DNA Urine based circulating tumor DNA analysis NARRATIVEWe developed a novel urine-based HPV test with test performances comparing favorably to blood-based HPVtesting. Using this test we obtained preliminary data suggesting first details of the physiological processesunderlying blood cell free DNA excretion into urine. This proposal will expand on these findings and explore thepotential of our test as a biomarker in oropharyngeal cancer patients undergoing curative intent radiationtherapy. NCI 10737836 8/15/23 0:00 PA-20-185 3R37CA262238-03S1 3 R37 CA 262238 3 S1 "OSSANDON, MIGUEL" 7/1/21 0:00 6/30/26 0:00 Cancer Biomarkers Study Section[CBSS] 9848398 "LAUTENSCHLAEGER, TIM " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 72064 NCI 45466 26598 ABSTRACTUrine is an underappreciated source for systemic circulating tumor DNA in patients with non-genitourinarycancers. Based on recent data suggesting that blood-based HPV DNA testing is useful for disease monitoringin HPV positive oropharynx cancer patients we identified non-metastatic HPV positive oropharyngeal cancerpatients as an excellent model system to examine the potential of urine-based transrenal DNA analysis. Ourpreliminary data suggests that our newly developed urine-based HPV test could have biomarker performancescomparing favorably to blood-based HPV testing.The specific objectives of this application are to establish that urine is a suitable source for HPV DNA in non-metastatic HPV positive oropharynx cancer patients and that at-home urine based molecular testing is feasiblefor these patients. Specifically we will compare sensitivity and specificity of pre-therapy urine-based HPVtesting to tissue gold standard testing in a cohort of newly diagnosed non-metastatic oropharyngeal cancerpatients. Recurrence detection lead time of urine-based HPV testing will be compared to clinical routine care inthe same cohort after curative intent treatment. Controls will include blood-based HPV testing pharyngealswab-based HPV testing and blood based personalized ctDNA sequencing panel testing. Additional controlcohorts will include cervical and anal cancer patients as well as cancer-free patients with recently diagnosedoncogenic HPV infections. Using in vivo fluorescence imaging techniques we will generate fundamentalknowledge on renal handling of cell free DNA and determine the impact of chronic kidney disease and otherpatient disease and iatrogenic factors on cell free DNA excretion. 72064 +No NIH Category available ATAC-seq;Address;Affect;Afferent Neurons;Cancer Patient;Cells;Chemotherapy-Oncologic Procedure;Chemotherapy-induced peripheral neuropathy;Chromatin;Clinical;Clinical Trials;Coupled;Critical Pathways;Cytoskeleton;Data;Development;Dose Limiting;Drug usage;Event;GTP-Binding Proteins;Gene Expression;Gene Expression Regulation;Genes;Genetic Polymorphism;Genetic Transcription;Genomic approach;Goals;HDAC4 gene;High Prevalence;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;Knowledge;Lead;Link;Malignant Neoplasms;Measures;Mediating;Metabolism;Microtubules;Modeling;Molecular;Molecular Conformation;Morphology;Neurites;Neurons;Paclitaxel;Pathway interactions;Patients;Peripheral;Peripheral Nervous System Diseases;Pharmacogenetics;Pharmacotherapy;Play;Prevention;Quality of life;Receptor Signaling;Regulation;Research;Risk;Rodent;Rodent Model;Role;Serious Adverse Event;Signal Pathway;Signal Transduction;Sphingolipids;Sphingosine-1-Phosphate Receptor;Structure;Testing;Therapeutic;Time;Toxic effect;Toxicity due to chemotherapy;Traction;Translating;Validation;Work;axonal degeneration;cancer therapy;chemotherapy;chromatin modification;experimental study;genetic approach;genetic association;improved;induced pluripotent stem cell;inorganic phosphate;mortality;multiple sclerosis treatment;neuroprotection;neurotoxic;neurotoxicity;novel;patient safety;pharmacologic;prevent;receptor-mediated signaling;response;rho GTP-Binding Proteins;single-cell RNA sequencing;sphingosine 1-phosphate;survival outcome;targeted agent;targeted treatment;therapeutic effectiveness;translational study Sphingolipid Signaling and Chemotherapy-Induced Peripheral Neurotoxicity PROJECT NARRATIVEChemotherapy-induced peripheral neuropathy is a dose-limiting toxicity of many drugs used in cancertreatment and can adversely affect patient quality of life for years after therapy. The studies proposed in thisapplication will examine the significance of sphingolipid signaling in this neurotoxicity. A detailed understandingof the mechanisms for chemotherapy-induced peripheral neuropathy will support strategies for its preventionand treatment. NCI 10737832 4/5/23 0:00 PA-20-185 3R01CA261068-03S1 3 R01 CA 261068 3 S1 "ALTSHULER, RACHEL DINA" 4/1/21 0:00 8/31/23 0:00 Xenobiotic and Nutrient Disposition and Action Study Section[XNDA] 1882790 "KROETZ, DEANNA L" Not Applicable 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 4/1/23 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2023 72055 NCI 44616 27439 PROJECT SUMMARY/ABSTRACTChemotherapy induced peripheral neuropathy is a common dose-limiting toxicity that can reduce therapeuticeffectiveness and impact quality of life for cancer patients. The overarching goal of this research is todetermine the molecular basis of chemotherapy-induced peripheral neuropathy to support the development oftargeted therapies to prevent and treat this toxicity. The proposed studies are based on a reverse translationalpharmacogenetic approach that uses genetic association findings to implicate critical pathways in peripheralneuropathy. Recent genetic association and functional validation findings support a role for sphingosine-1-phosphate (S1P) signaling in chemotherapy-induced neurotoxicity which are consistent with previous studiesin rodent models. The studies proposed in this application will extend these findings and address a significantgap in our knowledge of S1P signaling in target cells for toxicity peripheral sensory neurons. The centralhypothesis that will be tested is that modulation of S1P signaling in peripheral sensory neurons by microtubuletargeting agents plays a critical role in their neurotoxicity. A human induced pluripotent stem cell derivedsensory neuron model of chemotherapy neurotoxicity (iPS-SNs) will be employed for all studies.Pharmacological and genetic approaches will be used to modulate S1P signaling and interrogatechemotherapy toxicity linked to this signaling pathway. The three aims are complementary and addressdiscrete functions of S1P. The first aim will investigate whether microtubule targeting agents alter sphingolipidmetabolism in sensory neurons and will link specific S1P receptors to cytoskeletal changes. The studiesproposed in the second aim will focus on Rho GTPase signaling downstream of S1P receptors and willestablish the S1P signaling axis that is critical for chemotherapy-induced changes in neurite structure and thedevelopment of retraction bulbs. The third aim will use scRNA-seq and sc-ATACseq to elucidate whetherpaclitaxel-induced changes in gene expression in iPS-SNs involve S1P effects on chromatin accessibility. Theability of fingolimod a multiple sclerosis therapy that targets S1P receptor signaling and is currently beingtested for prevention and treatment of paclitaxel-induced peripheral neuropathy to protect againstchemotherapy-induced neurotoxicity will be examined. Collectively these studies will reveal molecularmechanisms underlying the axon degeneration that occurs in sensory neurons in response to microtubuletargeting agents and elucidate novel mechanisms for neuroprotection with fingolimod. 72055 +No NIH Category available Abraxane;Address;Albumins;Allografting;Apoptosis;Apoptotic;Automobile Driving;BRCA1 gene;Basic Science;Benchmarking;Binding;Biodistribution;Biological;Biomedical Engineering;Breast Cancer Model;Breast Cancer Patient;Breast Cancer therapy;Cell membrane;Cells;Chemicals;Chemistry;Cholesterol;Clinical;Clinical Oncology;Consultations;Development;Dose;Doxorubicin Hydrochloride Liposome;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Endosomes;Extrahepatic;FDA approved;Face;Formulation;Gene Silencing;Genes;Genome;Goals;Hepatic;Hepatocyte;Human;Immunocompetent;In Situ;In Vitro;Injections;Investigation;Investigational Therapies;Lipid Binding;Lipids;Liver;Liver neoplasms;Luciferases;MCL1 gene;Malignant Neoplasms;Measures;Medical Oncologist;Modeling;Modification;Molecular Target;Mus;Nanotechnology;Oligonucleotides;Oncogenes;Organ;Pathway interactions;Penetrance;Penetration;Permeability;Pharmaceutical Preparations;Pharmacologic Substance;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Pre-Clinical Model;Property;Publishing;RNA Interference;RNA Interference Therapy;RNA Transport;Renal clearance function;Safety;Serum;Serum Albumin;Serum Proteins;Site;Small Interfering RNA;Technology;Testing;Therapeutic;Toxic effect;Toxicology;Transgenic Organisms;Treatment Efficacy;Tropism;Tumor Tissue;Untranslated RNA;Work;Xenograft procedure;c-myc Genes;cancer clinical trial;cancer subtypes;chemical synthesis;chemotherapy;clinical translation;cooking;design;endosome membrane;ethylene glycol;improved;in vitro activity;in vivo;inhibitor;interest;intravenous injection;knock-down;lead candidate;lipid nanoparticle;malignant breast neoplasm;molecular targeted therapies;mutant;nano;nanocomplexes;nanoformulation;nanomedicine;nanopolymer;nanotherapeutic;nuclease;orthotopic breast cancer;patient derived xenograft model;pre-clinical;response;screening;siRNA delivery;small molecule;small molecule inhibitor;success;taxane;theories;therapeutic siRNA;triple-negative invasive breast carcinoma;tumor;tumor xenograft In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy Project NarrativeRNAi molecules can be designed against conventionally-undruggable tumor-driving genes but siRNA use inclinical oncology faces delivery barriers such as nuclease degradation rapid renal clearance poor distributioninto tumor tissues and poor cell membrane penetration. The overarching goal of this project is to developsiRNA chemical modifications that provide potent safe tumor-penetrating and molecularly-targeted nano-therapeutics against currently undruggable tumor drivers. This approach will specifically yield siRNAs that formnano-complexes with albumin in situ following intravenous injection and will be developed to target the anti-apoptotic tumor driver Mcl-1 to treat triple negative breast cancer. NCI 10737831 9/14/23 0:00 PA-20-185 3R01CA260958-03S1 3 R01 CA 260958 3 S1 "FU, YALI" 7/5/21 0:00 6/30/26 0:00 Nanotechnology Study Section[NANO] 9163585 "DUVALL, CRAIG LEWIS" "COOK, REBECCA SARA; UDDIN, MD JASHIM; VICKERS, KASEY C" 5 BIOMEDICAL ENGINEERING 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN BIOMED ENGR/COL ENGR/ENGR STA 372032408 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 117567 NCI 74175 43392 Cancer nano-formulations for delivery of small molecule drugs are limited by the ability to target only ~10%of the genome. RNAi molecules can in theory be designed against any gene of interest but siRNA use in clinicaloncology faces delivery barriers such as nuclease degradation rapid renal clearance poor distribution into tumortissues and poor cell membrane penetration. To overcome these challenges most RNAi therapies focus onsynthetic lipo- and poly-plex nano-formulations. Unfortunately while these technologies typically achieve veryhigh delivery into the liver high-penetrance siRNA tumor delivery remains elusive. The overarching goal of this project is to develop siRNA chemical modifications that provide potent safetumor-penetrating and molecularly targeted nano-therapeutics against currently undruggable tumor drivers. Theapproach builds upon our recently published proof of principle siRNA molecules end-modified through a PEG45linker with a diacyl lipid (siRNA-EG451 year off treatment). Using a rigorous matched control design we willassess peer interactions and friendships in the elementary classrooms (i.e. grades 3-5) of 200 survivors.Individual and family functioning will be assessed during home visits with families of survivors and 200matched classmates. We will identify deficits in social cognition and peer interactions as well as environmentalresources (e.g. parenting school climate) that predict long-term psychosocial adjustment (i.e. friendshipsdistress). The rationale is that deficits in social cognition and peer interactions contribute to psychosocial riskwhich could be mitigated by resources in the school and family environments. Aim 1. Compare the long-termpsychosocial adjustment of young survivors to matched peers and identify group differences in social cognitionand peer interactions that may predict poor adjustment. Aim 2. Identify specific social cognitive and peerinteraction factors that account for psychosocial adjustment in young survivors. Aim 3. Identify environmentalresources that protect psychosocial adjustment in young survivors. This research is significant as it willdelineate early risk and protective factors that predict long-term adaptation for young survivors and leave us ina prime position to develop interventions that will improve survivorship care and prevent long-term morbidity. 29006 +No NIH Category available Abdomen;Address;Animals;Benchmarking;Biodiversity;Biological Markers;Biology;Biopsy;Brain;Breast;Cancer Patient;Citric Acid Cycle;Clinic;Clinical;Clinical assessments;Collaborations;Computer software;Data;Development;Disease;Disseminated Malignant Neoplasm;Echo-Planar Imaging;Foundations;Future;Glycolysis;Goals;Heart;Histologic;Human;Human body;Image;Industrialization;Infrastructure;Infusion procedures;Label;Lesion;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolic;Metabolism;Metastatic Prostate Cancer;Methods;Monitor;Motivation;Mutation;Oncogenic;PSA level;Pathology;Patients;Perfusion;Pharmacotherapy;Phenotype;Physiologic pulse;Population;Prostate;Pyruvate;Pyruvate Metabolism Pathway;Radioactive Tracers;Research;Research Personnel;Role;Scientist;Sensitivity and Specificity;Site;Support System;Surface;System;Systems Biology;Techniques;Technology;Therapeutic Intervention;Time;Translating;Transrectal Ultrasound;Up-Regulation;Validation;Visualization;Work;androgen deprivation therapy;animal imaging;bone;cancer site;cancer therapy;castration resistant prostate cancer;cohort;design;first-in-human;follow-up;human study;image reconstruction;imaging biomarker;imaging capabilities;imaging modality;improved;in vivo;individualized medicine;industry partner;innovation;interest;men;metabolic abnormality assessment;metabolic imaging;molecular imaging;non-invasive imaging;non-invasive monitor;novel;novel therapeutic intervention;novel therapeutics;patient population;response;serum PSA;software development;tool;transmission process;treatment effect;treatment planning;treatment response;tumor;tumor metabolism;virtual Development of large-field-of-view hyperpolarized MRI PROJECT NARRATIVEThe over-arching goal of the proposed research is to translate a new MRI technology hyperpolarized (HP) MRto the clinic in the setting of large-field-of-view (FOV) MRI which utilizes both the agents HP [1-13C] pyruvateand [2-13C] pyruvate in metastatic prostate cancer patients. Prostate cancer demonstrates tremendous biologicdiversity and there is an urgent need to develop more sensitive and specific imaging biomarkers to characterizethe disease. We aim to develop a large-body transmit/receive system and pulse sequences for large FOV andapply them to a cohort of prostate cancer patients: this work will aid in future patient-specific treatment planningfacilitate earlier assessment of response to therapy and facilitate the development of novel experimentalstrategies for cancer treatment. NCI 10737742 11/15/22 0:00 PAR-18-009 3R01CA237466-04S1 3 R01 CA 237466 4 S1 "ZHANG, HUIMING" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 10451505 "KESHARI, KAYVAN R" "CUNNINGHAM, CHARLES H.; HRICAK, HEDVIG " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 394 Non-SBIR/STTR 2023 29063 NCI 16420 12643 PROJECT SUMMARY/ABSTRACTProstate cancers currently the most common cancer in men demonstrate a tremendous range of biologicdiversity. Clinical assessments of response to non-surgical therapy are often inadequate because as studieshave shown they lead to inaccuracies when they rely upon serum prostate specific antigen (PSA) levelsreaching a nadir or upon the histological confirmation of cancer using transrectal ultrasound guided biopsies.When progressing to metastatic cancer typically after androgen deprivation therapy castrate resistant prostatecancer (CRPC) results in bone lesions in more than 90% of cases. There remains a critical clinical need forgreater sensitivity and specificity in molecular imaging biomarkers of prostate cancer presence and of responseto novel therapeutics.An extraordinary new technique hyperpolarized magnetic resonance (HP MR) has the potential to change theway we interrogate metabolism in vivo. Through the utilization of 13C-labeled endogenous substrates we areable to non-invasively image a metabolic intermediate and its subsequent downstream products usingconventional MRI. In the setting of prostate cancer this provides a potentially invaluable tool for the study ofprostate cancer metabolism and its modulation as a function of tumor aggressiveness and response totherapeutic intervention. Unfortunately we are currently limited in our ability to visualize large volumes ofinterest whereas metastatic prostate cancer typically requires visualization of the abdomen and bone regionsvirtually inaccessible to current HP MRI approaches.The objective of this innovative academic industrial partnership is to address this problem by developing alarge-field-of-view HP MRI approach including both hardware and software. This proposal would establish arobust platform to enable the imaging of metastatic disease in prostate cancer patients. In the first aim of thisproposal we will develop a novel 13C body transmit coil and receive system capable of imaging the abdomen.In tandem we will also develop acquisition strategies to take advantage of this hardware for rapid HP MRI.Finally we will validate this approach in 2 cohorts of metastatic prostate cancer patients. The first will be imagedwith HP [1-13C] pyruvate to assess methods to visualize downstream glycolysis and the second with [2-13C]pyruvate to image the TCA cycle for a first-in-human study.It is the overarching goal of this proposal to build a novel large-field-of-view approach to HP MRI includingimportantly both hardware and software and apply it to the imaging of HP pyruvate metabolism in cancerpatients so as to provide benchmark for future studies using this technique and additionally to determine itsability to inform on prostate biology. 29063 +No NIH Category available 4T1;Abscopal effect;Biodistribution;Blood Tests;Body Weight decreased;Breast Cancer Model;Breast Cancer cell line;Cell Death;Cells;Colorectal Cancer;Derivation procedure;Development;Dimerization;Disease remission;Dose;Epidermal Growth Factor Receptor;Esters;Future;Galectin 1;Hispanic;Homing;Human;Imiquimod;Immune;Immune response;Immunocompetent;Immunologic Adjuvants;Immunologic Stimulation;Immunotherapeutic agent;Implant;In Situ;Integrin alpha4beta1;Integrins;Ligand Binding;Ligands;Light;Lighting;Macrophage;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of urinary bladder;Mediating;Memory;Micelles;Modeling;Monoclonal Antibodies;Mouse Mammary Tumor Virus;Mus;Nanodelivery;Pathway interactions;Patient-derived xenograft models of breast cancer;Patients;Peptides;Permeability;Pertuzumab;Phototherapy;Porphyrins;Positron-Emission Tomography;Proliferating;Regimen;Reporting;Signal Transduction;Site;T-Lymphocyte;Therapeutic Studies;Time;Transgenic Mice;Trastuzumab;Treatment Efficacy;Xenograft Model;Xenograft procedure;anti-PD1 antibodies;anti-cancer;anti-tumor immune response;aqueous;cancer type;chelation;chemotherapy;design;esterase;hormone therapy;imaging modality;imaging system;immune stimulatory agent;improved;in vivo monitoring;inhibitor;innovation;intravital imaging;malignant breast neoplasm;malignant phenotype;malignant stomach neoplasm;nano;nanofibrillar;nanotechnology platform;nanotherapeutic;nanotherapy;neoplastic cell;novel;optical imaging;overexpression;patient derived xenograft model;receptor;resiquimod;response;self assembly;side effect;targeted treatment;translational potential;tumor HER2-targeting transformable nanotherapeutic platform against HER2+ cancers Narrative Human epidermal growth factor receptor 2 (HER2) is overexpressed in over 20% breast cancers andto a lesser degree in gastric cancers colorectal cancer ovarian cancers and bladder cancers. Here wewill develop a novel HER2-targeting transformable cancer targeting nanoplatform (TCTN) that not onlycan directly suppress HER2 dimerization and signaling leading to tumor cell death but can also greatlyaugment systemic anti-tumor immune response. NCI 10737741 3/22/23 0:00 PAR-17-240 3R01CA247685-04S1 3 R01 CA 247685 4 S1 "GRODZINSKI, PIOTR" 2/11/20 0:00 1/31/25 0:00 Special Emphasis Panel[ZRG1-IMST-K(55)R] 1899553 "LAM, KIT S" Not Applicable 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 394 Non-SBIR/STTR 2023 113453 NCI 72263 41190 Abstract Human epidermal growth factor receptor 2 (HER2) is overexpressed in over 20% breast cancers andto a lesser degree in gastric cancers colorectal cancer ovarian cancers and bladder cancers. In HER2+tumors HER2s are massively overexpressed and constitutively dimerized leading to unrelentingactivation of down-stream proliferation and survival pathways and malignant phenotype. Because of thehigh expression level of HER2 trastuzumab and pertuzumab the two anti-HER2 monoclonal antibodiesare ineffective as monotherapy against these tumors. They need to be given in combinations with otherHER2-targeted therapy chemotherapy or hormonal therapy. Here we will optimize and further improvea novel HER2-mediated peptide-based and non-toxic transformable nano-agent that has been provento be highly efficacious as a monotherapy against HER2+ breast cancer xenograft models. This receptor-mediated transformable nanotherapy is comprised of a peptide with unique domains that allow self-assembly forming micelles under aqueous conditions and transformation into nanofibrils at the tumor sitewhere HER2 is encountered. The resulting nanofibrillar network effectively suppresses HER2dimerization and downstream signaling leading to increased tumor cell death and complete remission ofthe HER2+ tumors in xenograft models. We recently reported the development of an ICG-derivatized nanoplatform that can deliver potentimmuno-stimulant imiquimod to the tumor sites in a 4T1 syngeneic breast cancer model and we wereable to demonstrate that upon local light illumination (800nm) of the tumor the photo-active micellarnanoplatform was able to elicit a strong systemic anti-tumor immune response particularly when givenin conjunction with anti-PD1 antibody. In addition to potent abscopal effects this nano-photo-immuno-therapeutic regimen was able to elicit strong immuno-memory against future tumor implants. For this R01-IRCN proposal we will apply some of the promising features of the two above mentionednanoplatforms to generate a novel HER2-targeting transformable cancer targeting nanoplatform (TCTN)that not only can directly suppress HER2 dimerization and signaling leading to tumor cell death but canalso greatly augment systemic anti-tumor immune response. To achieve this we will modularlyincorporate to the transformable nanoplatform HER2 binding ligands T-cell and macrophage capturingagents (e.g. LLP2A targets activated 41 integrin of immune cells) galectin-1 inhibitor (e.g. LLS30) andimmunostimulant (e.g. resiquimod).Specific Aims:Aim 1. To design synthesize & characterize the novel transformable HER2-targeting TCTNnanoplatform.Aim 2. To use optical and MR imaging methods to determine the biodistribution of the TCTN constructsin xenograft PDX and syngeneic tumor models. To use the novel in-house developed EyePod intravitalimaging system to longitudinally evaluate in real time the intra-tumoral distribution and in situtransformation of TCTN cellular immune response and tumor response of sub-retinal tumor implant.Aim 3. To evaluate the therapeutic efficacy of TCTN in HER2+ PDX models of breast and gastric cancers.Aim 4. To evaluate the immunotherapeutic efficacy of TCTN in an immunocompetent murine syngeneicbreast cancer model comprised of HuHER2-L2-Luc+ murine breast cancer cell lines implantedorthotopically in MMTV.f.HuHER2 transgenic mice. 113453 +No NIH Category available Address;Adjuvant Therapy;Aftercare;Animal Model;Animals;Autopsy;Brain;Brain Neoplasms;Canis familiaris;Cell Death;Chemotherapy and/or radiation;Clinical;Clinical Research;Clinical Trials;Computer Models;DNA Double Strand Break;Data;Deposition;Dose;Effectiveness;European;Excision;Exposure to;External Beam Radiation Therapy;Finite Element Analysis;Formulation;Foundations;Generations;Glioblastoma;Glioma;Heat shock proteins;Heating;Histopathology;Human;Hyperthermia;Image;Infiltration;Injections;Iron;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Methodology;Modeling;Mus;Nanotechnology;Normal Cell;Normal tissue morphology;Oral Administration;Oryctolagus cuniculus;Patients;Penetration;Pilot Projects;Prognosis;Radiation therapy;Recurrence;Rodent;Safety;Solid;Study of magnetics;Technology;Temperature;Tissues;Toxic effect;Treatment Efficacy;Tumor Debulking;Work;antitumor effect;bioluminescence imaging;brain tissue;cancer cell;chemoradiation;chemotherapy;clinical translation;clinically relevant;design;effective therapy;fractionated radiation;hyperthermia treatment;hyperthermia tumor treatment;image guided;imaging modality;improved;innovation;iron oxide nanoparticle;magnetic dipole;magnetic field;nanoparticle delivery;neoplastic cell;radiation effect;safety and feasibility;temozolomide;therapy resistant;tissue injury;tool;translation to humans;translational applications;translational potential;treatment planning;treatment response;tumor;tumor microenvironment Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma Project NarrativeGlioblastoma (GBM) is one of the most devastating human cancers that almost always recurs due to thepresence of invasive therapy-resistant infiltrating cancer cells at the tumor margin. Magnetic hyperthermiatherapy (MHT) is a powerful nanotechnology-based treatment that may enhance the effects of radiation therapy(RT) and chemotherapy against infiltrating GBM tumors. NCI 10737738 2/27/23 0:00 PA-21-268 3R01CA247290-04S1 3 R01 CA 247290 4 S1 "BUCHSBAUM, JEFFREY" 12/1/19 0:00 11/30/23 0:00 Special Emphasis Panel[ZRG1-OTC-E(02)M] 7078345 "HADJIPANAYIS, CONSTANTINOS GEORGE" "IVKOV, ROBERT " 12 NEUROSURGERY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/22 0:00 7/31/23 0:00 395 Non-SBIR/STTR 2023 72417 NCI 45545 26872 Project Summary/AbstractGlioblastoma (GBM) remains a fatal brain cancer for which there is no cure. Maximal safe tumor resectioncombined with adjuvant therapies such as fractionated external beam radiation therapy (RT) and temozolomide(TMZ) chemotherapy known as chemoradiation (CRT) has provided the greatest benefit to GBM patients.However local recurrence occurs in most patients due to invasive therapy-resistant infiltrating cancer cells atthe tumor margin. Magnetic hyperthermia therapy (MHT) is a powerful nanotechnology-based treatment thatmay enhance the effects of CRT. MHT consists of local heat generation in the tumor region through directdelivery of magnetic iron-oxide nanoparticles (MIONPs) that are activated by exposure to an external alternatingmagnetic field (AMF) that is safe to normal cells. The AMF interacts with the magnetic dipoles of the MIONPs togenerate local heat and hyperthermia. Human clinical trials have demonstrated overall survival benefits of MHTwith fractionated RT in recurrent GBM resulting in European approval. Current MHT strategies howeverrequire high concentrations of nontargeted MIONPs (>100 mg/ml; 50-100mg Fe/g of tumor) delivered byinjection with leakback and without image-guided control of energy deposition. As a result normal tissueinjury limits MHT effectiveness and treatment of the infiltrative tumor margins is poorly defined whichcompromises MHT efficacy. Our proposal is designed to address these challenges and optimize the translationalpotential for enhanced MHT of GBM in combination with CRT using both small and large animal models withclinical proof-of-concept demonstration in spontaneous canine gliomas. We have recently completed a pilot studyin spontaneous canine gliomas demonstrating feasibility and safety of image-guided MIONP delivery alone. Wehypothesize that image-guided MHT will enhance CRT of GBM. Key innovations of our proposal are to: 1)evaluate the enhancement of CRT by MHT in mouse GBM models with an innovative proprietary MIONPformulation that requires 20-fold lower Fe concentration in tumors for more effective treatment than currentapproved MIONPs; 2) optimize image-guided MIONP delivery and MHT treatment planning with computationalmodelling in a rabbit brain tumor model; 3) enhance thermal treatment at the infiltrative tumor margins bycontrolling power deposition with innovative AMF power application that will also limit off target heating; and 4)complete a clinically relevant proof-of-concept study of our MHT approach in a spontaneous canine gliomamodel. We have Preliminary Data that demonstrate intracranial hyperthermia with a 3-fold increase in TMZconcentration within GBM tumors leading to a robust antitumor effect with increased survival after MHT + CRTin a therapy-resistant rodent glioma model. Overall this interdisciplinary work will provide a solid foundation formeaningful clinical translation of MHT with CRT for treatment of GBM. Imaging methods that correlate tumorheat distribution after MHT will be developed for translation to human patients. 72417 +No NIH Category available Ablation;Address;Affect;American;Animal Model;Animals;Anti-Inflammatory Agents;Apoptosis;Area;Autoimmune Diseases;Biological Assay;Biomedical Engineering;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Coculture Techniques;Colitis;Colon;Colon Carcinoma;Combined Modality Therapy;Complementary and alternative medicine;Crohn's disease;DNA;DNA Damage;Dangerousness;Disease;Dose;Drug Kinetics;Economic Burden;Effectiveness;Europe;Exposure to;FDA approved;Fractionation;Functional disorder;Genetically Engineered Mouse;Genome;Ginseng Preparation;Goals;Immune;Induction of Apoptosis;Infiltration;Inflammatory;Inflammatory Bowel Diseases;Intestines;Knowledge;Lead;Life Style;LoxP-flanked allele;Macrophage;Malignant Neoplasms;Mediating;Modeling;Molecular;Mus;Myeloid Cells;Natural Compound;Natural Source;Nature;North America;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Plants;Prevalence;Property;Research;Resveratrol;SIRT1 gene;Sepsis;Signal Pathway;Signal Transduction;Standardization;TNF gene;TP53 gene;Testing;Toxic effect;Treatment outcome;Ulcerative Colitis;anti-cancer;anticancer activity;cancer chemoprevention;cell type;cellular targeting;colon cancer prevention;colon cancer risk;conditional knockout;conventional therapy;cost;dextran sulfate sodium induced colitis;efficacy testing;experimental study;improved;in vivo;innovation;microbiota;murine colitis;novel;p53 Signaling Pathway;pharmacologic;replication stress;response;sex;side effect;single molecule;small molecule;sound;treatment strategy Harnessing the power of p53 with Panaxynol from American Ginseng to suppress colitis and prevent colon cancer NARRATIVE The purpose of this project is to address the issue of alternative and impactful options for patients withInflammatory Bowel Disease (IBD) to both treat their disease and prevent colon cancer that can result from long-standing and uncontrolled IBD. In comparing innovative treatment strategies panaxynol (PA; isolated fromAmerican Ginseng) stands out as our most potent molecule tested; and we are exploring a unique mechanismthat might not only elucidate colitis mechanisms and cures but branch into other diseases driven by dysregulatedm function. The results of this project will lead to clinical trials and the standardization of PA as a stand-aloneproduct or as part of a synergistic combination therapy for patients with IBD. NCI 10737737 1/6/23 0:00 PA-19-056 3R01CA246809-04S1 3 R01 CA 246809 4 S1 "PERLOFF, MARJORIE" 1/1/20 0:00 12/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-T(02)M] 7955996 "HOFSETH, LORNE J" "MURPHY, ELIZABETH ANGELA" 6 PHARMACOLOGY 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF PHARMACY 292080001 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 393 Non-SBIR/STTR 2023 157894 NCI 105969 51925 PROJECT SUMMARY Affecting upwards of 4 million people in North America and Europe with an economic burden of $30 -$45 billion Inflammatory Bowel Diseases (IBDs) are debilitating significantly affect life-style and carry a highcolon cancer risk. Because conventional treatment outcomes are modest with dangerous side effects about halfof IBD patients turn to complementary and alternative medicines (CAMs). Although CAMs have been used forthousands of years there is a gap in our knowledge of the mechanisms supporting their effectiveness.Understanding these mechanisms will lead to standardized treatment for IBD outside of toxic FDA-approveddrugs. This will lower their colon cancer risk. Over the past decade we have shown that American Ginseng (AG)suppresses colitis and prevents colon cancer in mice. Using scientifically rigorous Bioassay-GuidedFractionation we have isolated a polyacetylene called panaxynol (PA) that has anti-inflammatory and anti-cancerproperties. PA (compared to the100's of other CAMs being tested) comes from a natural source and is a singleingredient allowing it to be standardized on its own or in a cocktail. What makes this molecule particularlyinteresting and innovative is the mechanism - it is a single molecule extracted from AG with a unique capacityto target macrophages (m) for apoptosis. Our long-term goal is to identify the primary component(s) of AGresponsible for the robust anti-inflammatory and chemopreventive properties of AG we have observed over thepast decade; and to determine their mechanism of action. The overall objective of this application is to gain adeeper understanding of both: (a) the broad treatment potential of PA (i.e. multiple pharmacologic andbioengineered animal models of colitis and colon cancer); and (b) the underlying mechanism(s) behind theobservation that PA targets m for apoptosis. We focus here on a DNA-damage independent p53 signalingpathway as a mechanism toward m apoptosis. The scientific premise underlying the proposed research isrobust. Comparing nine FDA-approved drugs small molecules and CAMs PA is the most efficacious atsuppressing colitis in a DSS mouse model. Our central hypothesis is that PA isolated after a decade of rigorousbioassay-guided fractionation has anti-inflammatory and anti-cancer activity in the colon because it activatesp53- mediated apoptosis in infiltrating m; mitigating colitis; and preventing colon cancer associated with colitis.Furthermore PA acts as an anti-inflammatory in these models because it induces p53 through a DNA damage-like signaling response in m that is independent of detectable DNA damage. To address this hypothesis wewill test the efficacy of PA in three mouse models of colitis and in genetically engineered mice. Because itappears that PA is taking advantage of a unique p53 mechanism in m we will test PA in mice with p53conditionally knocked out in colonic m. A DNA damage-independent mechanism is explored. Resultsconsistent with our hypothesis would identify an innovative low cost safe specific and natural compound withanti-inflammatory and cancer chemopreventive properties that could quickly be implemented clinically. 157894 +No NIH Category available Attenuated;Cell Compartmentation;Cells;Clinical;Clonal Evolution;Clonal Expansion;Dependence;Development;Epigenetic Process;Evolution;Genomic approach;Hematopoiesis;Homeostasis;Intercept;Malignant - descriptor;Malignant Neoplasms;Modeling;Mutation;Patients;Pre-Clinical Model;Role;Sampling;Signal Transduction;Somatic Mutation;Therapeutic;Tissues;Work;cancer initiation;cancer therapy;cell type;functional genomics;gene network;in vivo;innovation;insight;leukemic transformation;new therapeutic target;novel;novel therapeutics;prevent;response;therapeutic gene;tool;treatment response;tumor progression Synergistic role of signaling and epigenetics in leukemic transformation PROJECT NARRATIVEWe will use studies in patient samples and in innovative preclinical models to delineate how clonal evolutioncontributes to malignancy and to the response to cancer therapies. We will model clonal evolution using novelin vivo preclinical models and perform functional studies to delineate the key networks and targets which governmalignancy. This work will delineate how mutational evolution contributes to cancer initiation and progressionand use these insights to identify novel therapeutic targets which can intercept/prevent or attenuate malignancy. NCI 10737736 7/17/23 0:00 RFA-CA-22-045 2R35CA197594-08 2 R35 CA 197594 8 "KLAUZINSKA, MALGORZATA" 1/17/17 0:00 7/31/30 0:00 ZCA1-SRB-E(M1) 7776127 "LEVINE, ROSS L" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 1062000 NCI 600000 462000 PROJECT ABSTRACTWe propose to use single cell studies of clinical isolates to explicate how mutations and differentiation statuscoordinately regulate cell state clonal expansion and malignant transformation. We will model sequentialactivation/inactivation of somatic mutations in defined cell compartments and perform functional studies touncover critical gene networks and therapeutic dependencies. This will include single cell studies in primarypatient samples use of innovative models which allow for sequential mutational activation/inactivation andfunctional genomic approaches to delineate mechanisms of transformation and novel therapeutic dependencies.Moreover we will delineate crosstalk between different cell types in normal and malignant hematopoiesis andhow these interactions impact therapeutic response. These tools will be distributed widely to enable studies oftissue development/homeostasis cell state changes transformation and therapeutic dependencies. 1062000 +No NIH Category available Binding;Biochemical;Biological Assay;CDK4 gene;Cachexia;Cancer Etiology;Cell Line;Cells;Chemicals;Clear cell renal cell carcinoma;Clustered Regularly Interspaced Short Palindromic Repeats;Compensation;Cyclin D1;DHODH gene;DNA;Development;Dioxygenases;Drosophila genus;Drug Targeting;Endogenous Retroviruses;Event;Failure;Genetic Screening;Genomics;Glioma;Human;Hydroxylation;Hypercalcemia;KRAS2 gene;Link;Malignant Neoplasms;Multiple Myeloma;Mutation;Oncoproteins;Oxygen;Patients;Peptides;Procollagen-Proline Dioxygenase;Protein Secretion;Proteins;Renal carcinoma;Resistance;Retinoblastoma Protein;Site;Source;Thalidomide;Translating;VHL Gene Inactivation;VHL gene;Validation;Vegf Inhibitor;Von Hippel-Lindau Tumor Suppressor Protein;Work;alpha ketoglutarate;beta catenin;c-myc Genes;cancer therapy;histone demethylase;hypoxia inducible factor 1;immunogenic;inhibitor;insight;interest;knockout gene;leukemia;mouse model;mutant;paralogous gene;programs;prototype;recruit;small molecule;somatic cell gene editing;transcription factor;tumor;ubiquitin ligase The von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer: Insights into Oxygen Sensing and Treating Cancers Caused by Undruggable Mutations We've used kidney cancer one of the 10 most common cancers in the U.S. as a prototype for treating cancersthat are caused by undruggable mutations (in this case inactivation of the VHL tumor suppressor gene). Weaim to identify new kidney cancer treatments and to establish paradigms that can be applied to other cancers. NCI 10737695 9/22/23 0:00 RFA-CA-22-045 2R35CA210068-08 2 R35 CA 210068 8 "FORRY, SUZANNE L" 9/1/16 0:00 8/31/30 0:00 ZCA1-SRB-E(M1) 1886242 "KAELIN, WILLIAM G." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 997800 NCI 600000 397800 VHL tumor suppressor protein (pVHL) inactivation is the usual initiating (truncal) event in the most commonform of kidney cancer clear cell renal cell carcinoma (ccRCC). pVHL forms a ubiquitin ligase that targets theHIF transcription factor for degradation. HIF2 but not HIF1 promotes ccRCC. Binding to pVHL requires thatthe HIFalpha subunit be prolyl hydroxylated by one of the 3 oxygen-sensitive EglN prolyl hydroxylases whichare 2-oxoglutarate (2-OG)-dependent dioxygenases (as are the TET DNA demethylases and KDM histonedemethylases). IDH mutant cancers accumulate the 2-OG competitor 2-hydroxyglutarate (2-HG). Our workcontributed to the development of VEGF inhibitors/HIF2 inhibitors for ccRCC and 2-HG inhibitors for IDHmutant leukemia. Our discovery that thalidomide reprograms cereblon to destroy the IKZF1/3 myelomaoncoproteins has also galvanized interest in small molecule degraders. Not all ccRCCs respond to VEGF inhibitors/HIF2 inhibitors and 2-HG inhibitors are fairly inactive againstIDH mutant gliomas. Synthetic lethality (SL) should be a source of alternative drug targets for such tumors andmore generally for cancers linked to undruggable mutations. We have identified new potential SL interactorsfor VHL (CDK4/6 and ITGAV) and mutant IDH (DHODH and GSK3b) and now propose further validation andmechanistic studies. Intriguingly Cyclin D1 the partner for CDK4/6 is a HIF2 target in ccRCC but the SLbetween VHL and CDK4/6 is not HIF2-dependent. We also embarked on SL screens in Drosophila cellsbecause paralog compensation likely causes many false-negatives in genetic screens with human cells. We created an up screen for chemicals and gene knockouts that can degrade a protein of interest. Weused it to discover that Spautin-1 is a cereblon-independent IKZF1 degrader and are pursuing the underlyingmechanism. We are also applying it to various undruggable oncoproteins (e.g. c-Myc K-Ras b-Catenin). Failure to downregulate Cyclin D1 causes resistance of VHL-/- ccRCC to HIF2 inhibitors in a pRB-independent manner. We are using biochemical approaches to identify the relevant Cyclin D1 substrate(s). We unexpectedly found that HIF1 and HIF2 bind to approximately the same genomic sites yet recruitdifferent proteins. We are validating these associated proteins in biochemical and functional assays. We arealso using substrate-trapping conditions to recover non-HIF EglN substrates and non-histone KDM substrates. We are continuing our efforts to use somatic gene editing with CRISPR to make a murine model of HIF2-dependent VHL-/- ccRCC. We have also identified new pVHL-dependent secreted proteins including PTH-LHwhich might cause the cachexia and hypercalcemia seen in some ccRCC patients. ccRCC is highly immunogenic but the reason is unknown. We found that HIF2 drives the expression ofmany endogenous retroviruses some of which can be translated and presented as HLA-bound peptides. Weare examining additional ccRCC cell lines and tumors for such peptides and whether they are immunogenic. 997800 +No NIH Category available Acceleration;Address;Advisory Committees;Area;Award;Basic Science;Black Populations;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Catchment Area;Cervix Uteri;Clinic;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communities;County;Data Science;Detection;Development;Doctor of Philosophy;Ecosystem;Education;Elderly;Evaluation;Evolution;Exclusion;Faculty;Florida;Fostering;Foundations;Funding;Future;Grant;Growth;HIV;Health;Health Services Accessibility;Health behavior and outcomes;High School Student;Hispanic Populations;Human Papilloma Virus-Related Malignant Neoplasm;Immunooncology;Immunotherapy;Incidence;Informatics;Infrastructure;Institution;Intervention Trial;Investments;Journals;Leadership;Legal;Legal patent;Lung;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Minority;Mission;Molecular Medicine;National Health Policy;Oropharyngeal;Ovarian;Patients;Peer Review;Peer Review Grants;Persons;Policies;Population;Population Sciences;Prevention;Protocols documentation;Publications;Publishing;Puerto Rican;Research;Research Infrastructure;Research Personnel;Research Training;Resource Sharing;Science;Scientist;Series;Strategic Planning;Structure;Students;Training;Training and Education;Translations;Underrepresented Minority;Vulnerable Populations;Woman;anticancer research;cancer care;cancer epidemiology;cancer prevention;care delivery;career development;clinical practice;community engagement;design;education research;health disparity;implementation science;improved;inter-institutional;mathematical learning;melanoma;member;next generation;oncology program;prevent;programs;recruit;research and development;rural dwellers;screening;sociodemographic group;standard of care;treatment trial Moffitt Cancer Center Support Grant PROJECT NARRATIVEMOFFITT CANCER CENTER SUPPORT GRANTMoffitt Cancer Center (Moffitt) is a free-standing 501(c)3 not-for profit institution that was founded by legal statuteto address cancer needs in the area the State of Florida and beyond with the singular mission to contribute tothe prevention and cure of cancer. Fully informed by the cancer burden in our community and catchment areaguided by highly effective driven and synergistic senior leadership and a rigorous research strategic plansupported by outstanding institutional funding and cultivated by its five research Programs that span the basicpopulation data and clinical sciences Moffitt fosters exceptional cancer research that spans discovery totranslation to the clinic and that has the momentum to accelerate its scientific impact for decades to come. Morespecifically Moffitts research has provided paradigm shifts in our understanding of the cancer ecosystem hasdiscovered and advanced new means to prevent treat and cure some forms of cancer that have led to changesin clinical practice and national health policy and which over the next award period will be further acceleratedby investments in research focused on: 1) our catchment area; 2) health disparities; 3) immuno-oncology; 4)metabolism; 5) data science; and 6) cancer care delivery and implementation science. NCI 10737674 2/14/23 0:00 PAR-20-043 3P30CA076292-25S2 3 P30 CA 76292 25 S2 "PTAK, KRZYSZTOF" 2/18/98 0:00 1/31/27 0:00 Cancer Centers Study Section (A)[NCI-A] 1877243 "CLEVELAND, JOHN L." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 397 Research Centers 2023 169651 NCI 100683 68968 PROJECT SUMMARYOVERALLUnder leadership of its fourth Center Director John L. Cleveland PhD the singular mission of Moffitt CancerCenter (Moffitt) established in state statute only 30 years ago is to contribute to the prevention and cure ofcancer. Fully informed by cancer needs in our community and catchment area; guided by highly effective drivenand synergistic senior leadership and a rigorous research strategic plan; supported by tremendous institutionalfunding; and cultivated by its five research Programs that span the basic population data and clinical sciences;Moffitt fosters exceptional cancer research that spans discovery to translation to the clinic and to the community.Moffitt serves a 15-county catchment area of West Central Florida comprised of diverse sociodemographicgroups and vulnerable populations including Blacks Hispanics (particularly of Puerto Rican descent) ruralresidents persons living with HIV and the elderly. Key catchment area cancers at higher incidence than thestate and nation include lung melanoma ovarian and HPV-related cancers (oropharynx cervix). Community-driven priorities are cancer prevention and screening access to care clinical trials and vulnerable populations.Moffitts 183 Members are organized into five highly collaborative research Programs Cancer Biology &Evolution; Cancer Epidemiology; Health Outcomes & Behavior; Immuno-Oncology; and Molecular Medicine whose research is supported by four Centers of Excellence focused on catchment area needs. Members haveproduced exceptional science supported by 14 Shared Resources (2 developmental) more than $2M in annualinstitutional pilot funds and exceptional central administration. Peer-reviewed grants have increased 32% andfunding has risen to $36.0M including $18.1M from NCI (excluding CCSG and $2.4M training grants). Membersnow hold 68 MPI awards (53 peer-reviewed). 3279 articles were published including 543 in journals with animpact factor > 10. Publication rates are 24.2% 18.7% and 91.2% for intra-programmatic inter-programmaticand inter-Center collaborations respectively. 123 INDs and 184 patents were filed and 15309 patients (16321including affiliates) were accrued to interventional trials; 5471 to treatment trials (5716 including affiliates).Guided by a new Research & Education Training Office Moffitt educated more than 5700 students traineesand faculty over the award period impacting all five Programs and clinical activities. Moffitt has 15 peer-reviewtraining grants (T32 R25 F and K) and two NCI-funded minority-focused inter-institutional partnerships.Importantly Moffitts research has provided paradigm shifts in our understanding of the cancer ecosystem hasdiscovered and advanced new means to prevent treat and even cure some forms of cancer and has led tochanges in clinical practice and national health policy. Over the next cycle Moffitt research and clinical impactwill be accelerated by investments focused on: 1) our catchment area; 2) health disparities; 3) immuno-oncology;4) metabolism; 5) data science; and 6) cancer care delivery and implementation science. These efforts willsupport Moffitts remarkable growth trajectory for decades to come and its mission to reduce the cancer burden. 169651 +No NIH Category available Acceleration;Address;Advisory Committees;Area;Award;Basic Science;Black Populations;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Catchment Area;Cervix Uteri;Clinic;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communities;County;Data Science;Detection;Development;Doctor of Philosophy;Ecosystem;Education;Elderly;Evaluation;Evolution;Exclusion;Faculty;Florida;Fostering;Foundations;Funding;Future;Grant;Growth;HIV;Health;Health Services Accessibility;Health behavior and outcomes;High School Student;Hispanic Populations;Human Papilloma Virus-Related Malignant Neoplasm;Immunooncology;Immunotherapy;Incidence;Informatics;Infrastructure;Institution;Intervention Trial;Investments;Journals;Leadership;Legal;Legal patent;Lung;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Minority;Mission;Molecular Medicine;National Health Policy;Oropharyngeal;Ovarian;Patients;Peer Review;Peer Review Grants;Persons;Policies;Population;Population Sciences;Prevention;Protocols documentation;Publications;Publishing;Puerto Rican;Research;Research Infrastructure;Research Personnel;Research Training;Resource Sharing;Science;Scientist;Series;Strategic Planning;Structure;Students;Training;Training and Education;Translations;Underrepresented Minority;Vulnerable Populations;Woman;anticancer research;cancer care;cancer epidemiology;cancer prevention;care delivery;career development;clinical practice;community engagement;design;education research;health disparity;implementation science;improved;inter-institutional;mathematical learning;melanoma;member;next generation;oncology program;prevent;programs;recruit;research and development;rural dwellers;screening;sociodemographic group;standard of care;treatment trial Moffitt Cancer Center Support Grant PROJECT NARRATIVEMOFFITT CANCER CENTER SUPPORT GRANTMoffitt Cancer Center (Moffitt) is a free-standing 501(c)3 not-for profit institution that was founded by legal statuteto address cancer needs in the area the State of Florida and beyond with the singular mission to contribute tothe prevention and cure of cancer. Fully informed by the cancer burden in our community and catchment areaguided by highly effective driven and synergistic senior leadership and a rigorous research strategic plansupported by outstanding institutional funding and cultivated by its five research Programs that span the basicpopulation data and clinical sciences Moffitt fosters exceptional cancer research that spans discovery totranslation to the clinic and that has the momentum to accelerate its scientific impact for decades to come. Morespecifically Moffitts research has provided paradigm shifts in our understanding of the cancer ecosystem hasdiscovered and advanced new means to prevent treat and cure some forms of cancer that have led to changesin clinical practice and national health policy and which over the next award period will be further acceleratedby investments in research focused on: 1) our catchment area; 2) health disparities; 3) immuno-oncology; 4)metabolism; 5) data science; and 6) cancer care delivery and implementation science. NCI 10737673 2/13/23 0:00 PAR-20-043 3P30CA076292-25S1 3 P30 CA 76292 25 S1 "PTAK, KRZYSZTOF" 2/18/98 0:00 1/31/27 0:00 Cancer Centers Study Section (A)[NCI-A] 1877243 "CLEVELAND, JOHN L." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 397 Research Centers 2023 236988 NCI 152344 84644 PROJECT SUMMARYOVERALLUnder leadership of its fourth Center Director John L. Cleveland PhD the singular mission of Moffitt CancerCenter (Moffitt) established in state statute only 30 years ago is to contribute to the prevention and cure ofcancer. Fully informed by cancer needs in our community and catchment area; guided by highly effective drivenand synergistic senior leadership and a rigorous research strategic plan; supported by tremendous institutionalfunding; and cultivated by its five research Programs that span the basic population data and clinical sciences;Moffitt fosters exceptional cancer research that spans discovery to translation to the clinic and to the community.Moffitt serves a 15-county catchment area of West Central Florida comprised of diverse sociodemographicgroups and vulnerable populations including Blacks Hispanics (particularly of Puerto Rican descent) ruralresidents persons living with HIV and the elderly. Key catchment area cancers at higher incidence than thestate and nation include lung melanoma ovarian and HPV-related cancers (oropharynx cervix). Community-driven priorities are cancer prevention and screening access to care clinical trials and vulnerable populations.Moffitts 183 Members are organized into five highly collaborative research Programs Cancer Biology &Evolution; Cancer Epidemiology; Health Outcomes & Behavior; Immuno-Oncology; and Molecular Medicine whose research is supported by four Centers of Excellence focused on catchment area needs. Members haveproduced exceptional science supported by 14 Shared Resources (2 developmental) more than $2M in annualinstitutional pilot funds and exceptional central administration. Peer-reviewed grants have increased 32% andfunding has risen to $36.0M including $18.1M from NCI (excluding CCSG and $2.4M training grants). Membersnow hold 68 MPI awards (53 peer-reviewed). 3279 articles were published including 543 in journals with animpact factor > 10. Publication rates are 24.2% 18.7% and 91.2% for intra-programmatic inter-programmaticand inter-Center collaborations respectively. 123 INDs and 184 patents were filed and 15309 patients (16321including affiliates) were accrued to interventional trials; 5471 to treatment trials (5716 including affiliates).Guided by a new Research & Education Training Office Moffitt educated more than 5700 students traineesand faculty over the award period impacting all five Programs and clinical activities. Moffitt has 15 peer-reviewtraining grants (T32 R25 F and K) and two NCI-funded minority-focused inter-institutional partnerships.Importantly Moffitts research has provided paradigm shifts in our understanding of the cancer ecosystem hasdiscovered and advanced new means to prevent treat and even cure some forms of cancer and has led tochanges in clinical practice and national health policy. Over the next cycle Moffitt research and clinical impactwill be accelerated by investments focused on: 1) our catchment area; 2) health disparities; 3) immuno-oncology;4) metabolism; 5) data science; and 6) cancer care delivery and implementation science. These efforts willsupport Moffitts remarkable growth trajectory for decades to come and its mission to reduce the cancer burden. 236988 +No NIH Category available Address;Advanced Malignant Neoplasm;Authorization documentation;Basic Science;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Institute of New Jersey;Cancer Patient;Cancer Survivor;Catchment Area;Cell Separation;Cessation of life;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Creativeness;Education;Family member;Flow Cytometry;Genomic Instability;Genomics;Growth;Health Sciences;Health system;Histopathology;Immunologic Monitoring;Incidence;Individual;Infrastructure;Institution;Malignant Neoplasms;Mission;Names;National Cancer Institute;New Jersey;Oncology;Pathogenesis;Patients;Peer Review;Persons;Pharmacy facility;Population;Population Heterogeneity;Population Research;Population Sciences;Positioning Attribute;Precision therapeutics;Prevention;Process;Public Health;Publications;Publishing;Quality of life;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Risk;SEER Program;Science;Services;Statutes and Laws;Strategic Planning;Structure;Talents;Therapeutic Intervention;Training and Education;Translating;Translational Research;Translations;Universities;Vision;anticancer research;authority;biobank;biomedical informatics;cancer care;cancer genetics;cancer pharmacology;cancer prevention;cancer risk;care delivery;clinical care;clinical investigation;genome editing;innovation;inter-institutional;interdisciplinary collaboration;member;metabolomics;mortality;multidisciplinary;neoplasm registry;next generation;oncology service;programs;public health relevance;screening;small molecule;tumor metabolism Cancer Center Support Grant RUTGERS CANCER INSTITUTE OF NEW JERSEYPUBLIC HEALTH RELEVANCE STATEMENTNew Jersey has a population of approximately 8.9 million with a yearly cancer incidence of 50000 new casesand a yearly mortality of 16500 deaths. Rutgers Cancer Institute of New Jersey (CINJ) is the State of NewJersey's only National Cancer Institute (NCI)-designated Comprehensive Cancer Center. The mission of CINJis to reduce the burden of cancer by advancing cancer research prevention screening and education for one ofthe nations most diverse and densely populated states as well as for the broader nation. NCI 10737672 5/4/23 0:00 PAR-17-095 3P30CA072720-24S1 3 P30 CA 72720 24 S1 "HE, MIN" 3/1/97 0:00 2/29/24 0:00 Cancer Centers Study Section (A)[NCI-A] 9845089 "LIBUTTI, STEVEN K." Not Applicable 10 SURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 353 Research Centers 2023 1507000 NCI 959873 547127 RESEARCH PLAN RUTGERS CANCER INSTITUTE OF NEW JERSEY OVERALLPROJECT SUMMARY/ABSTRACTThe Rutgers Cancer Institute of New Jersey (CINJ) is a matrix/consortium (with Princeton University) and NewJerseys only NCI-designated Comprehensive Cancer Center serving a diverse population of 8.9 million people.CINJ focused the strengths and resources of the major research institutions in NJ on addressing the cancerburden in its catchment area (NJ). The rapid trajectory of CINJs growth validated the initial vision that one of theNations largest public universities of the health sciences would rapidly bring forth an NCI-designated CancerCenter. CINJ has 227 members (206 Rutgers 19 Princeton and 2 collaborating). The State Cancer Registryand Surveillance Epidemiology and End Results (SEER) Program was moved to CINJ in 2011 and as a resultof state legislation in 2013 CINJ became an independent institute of Rutgers University optimizing CINJspotential for growth transdisciplinary collaboration and impact across the catchment area. In FY2018 CINJreceived over $68 million in support from Rutgers and Princeton the State the Health System and philanthropy.Direct peer-reviewed support increased ~16%. Members published 3664 cancer focused publications since2011 (20% inter- and 24% intra-programmatic 55% inter-institutional). In January 2017 Steven K. Libutti wasappointed Director of CINJ and Vice Chancellor for Cancer Programs for Rutgers Biomedical and HealthSciences (RBHS). In a strategic partnership with the RWJBarnabas Health System Libutti was named SeniorVice President for Oncology Services. CINJ is now positioned to coordinate both cancer research and carethroughout its catchment area. An iterative strategic planning process resulted in reorganization of researchPrograms to increase collaborations cancer focus translation and investigator-initiated clinical trials. These fivePrograms are: 1) Cancer Metabolism and Growth (CMG) 2) Genomic Instability and Cancer Genetics (GICG)3) Cancer Pharmacology (CP) 4) Clinical Investigations and Precision Therapeutics (CIPT) and 5) CancerPrevention and Control (CPC). These Programs are supported by eight shared resources (BiomedicalInformatics Biometrics Biorepository and Histopathology Services Comprehensive Genomics FlowCytometry/Cell Sorting Genome Editing Metabolomics and Research Pharmacy) with two developing sharedresources (Immune Monitoring Small Molecule Screening). The Statewide authority of CINJ derives from itsstatus as the only NCI-designated Cancer Center; extensive and direct support by the State of New Jersey toserve as the States oncology resource; opportunities to conduct translational and population research within themost diverse and densely populated State in the nation; and the synergistic opportunities for collaboration acrossoutstanding research institutions. This supports CINJs mission to reduce the burden of cancer in its catchmentby advancing cancer research prevention screening and education. 1507000 +No NIH Category available Acceleration;Achievement;Advanced Malignant Neoplasm;Advisory Committees;Area;Atlases;Automobile Driving;Behavior;Blood Tests;Breast;Breast Cancer Detection;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Survivor;Catchment Area;Characteristics;Climate;Clinical;Clinical Cancer Center;Clinical Trials;Collaborations;Colonoscopy;Colorectal;Communities;Community Outreach;Comprehensive Cancer Center;County;Dedications;Detection;Development;Doctor of Medicine;Drug resistance;Early Diagnosis;Education;Employee;Enrollment;Ensure;Equity;Evaluation;Event;Exercise;Extramural Activities;Funding;Genetic;Genetic Screening;Goals;Grant;Guidelines;Health;Hereditary Nonpolyposis Colorectal Neoplasms;Human;Human Papilloma Virus Vaccination;Immunotherapeutic agent;Individual;Infrastructure;Institution;International;Intervention;Investments;Knowledge;Lead;Leadership;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Mission;Molecular Target;NCI-Designated Cancer Center;National Cancer Institute;Oncology;Oregon;Pancreas;Patient-Focused Outcomes;Patients;Peer Review;Performance;Persons;Pilot Projects;Prevention;Prevention strategy;Process;Proteomics;Publications;Publishing;Reporting;Research;Research Personnel;Resource Sharing;Science;Screening for cancer;Solid Neoplasm;Strategic Planning;Systems Biology;Testing;The Cancer Genome Atlas;Tobacco use;Training;Training Programs;Training and Education;Treatment Side Effects;Treatment-Related Cancer;Trust;Tumor Biology;Tumor-infiltrating immune cells;Universities;Work;anti-racism;anticancer research;cancer genetics;cancer genome;cancer prevention;clinical care;cohort;colon cancer screening;combat;community engagement;community organizations;community partnership;design and construction;diversity and inclusion;drug sensitivity;improved;improved outcome;innovation;investigator-initiated trial;leukemia;leukemia/lymphoma;lung cancer screening;meetings;melanoma;member;molecular targeted therapies;next generation;pandemic disease;population based;precision medicine;precision oncology;professional atmosphere;programs;recruit;screening guidelines;symposium;targeted cancer therapy;targeted treatment;translational oncology;translational progress;treatment trial;tumor;tumor-immune system interactions OHSU Knight Cancer Institute PROJECT NARRATIVE: Directors Overview and Essential CharacteristicsBrian Druker M.D. Center DirectorThe OHSU Knight Cancer Institute has made numerous impactful contributions since its designation as one ofthe nations National Cancer Institute Cancer Centers in 1997. Accomplishments include establishing theparadigm of targeted cancer therapy now referred to as precision medicine. Through the work supported by ourCancer Center Support Grant we conduct cancer research that spans basic clinical and prevention and controland aims to improve outcomes for individuals in our catchment area and throughout the nation. NCI 10737671 7/21/23 0:00 PAR-20-043 3P30CA069533-25S1 3 P30 CA 69533 25 S1 "ROBERSON, SONYA" 8/1/97 0:00 6/30/27 0:00 Cancer Centers Study Section (A)[NCI-A] 1894087 "DRUKER, BRIAN J" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 191618 NCI 125000 66618 PROJECT SUMMARY: Directors Overview and Essential CharacteristicsBrian Druker M.D. Center DirectorThe Knight Cancer Institute (KCI) at Oregon Health & Science University (OHSU) in Portland Oregon is theonly NCI-designated comprehensive cancer center in our catchment area the state of Oregon. Our goal is toleverage our unique strengths into treatment early detection and prevention strategies to improve patientoutcomes. The KCI has 191 members belonging to four scientific programs (Cancer Biology TranslationalOncology Quantitative Oncology and Cancer Prevention and Control) and using six Shared Resources.In the past reporting period we developed and are implementing a comprehensive strategic plan which definesthree focus areas for our center: Culture of Inclusion and Innovation Precision Oncology and Precision EarlyDetection. We have defined a comprehensive Diversity Action Plan to align with OHSU's efforts to be an anti-racist institution and drive our efforts to ensure a Culture of Inclusion and Innovation within the KCI. Using ourstrategic plan as a compass we recruited 56 investigators including 12 senior leaders. We completed the designand construction of three new buildings which allowed for the consolidation of our research and clinical care.We restructured our administration and advisory committees to ensure our members' engagement in the effectiveimplementation of the strategic plan. These efforts have led to substantial increases in CCSG metrics includingNCI funding intra- and inter-programmatic interactions collaborative grants and investigator-initiated trials.Thus our current 191 KCI members are supported by $61.6 million in extramural funding $26.9 million from theNCI. In the current funding period members published 2265 cancer-focused peer-reviewed publications ofwhich 26% were intra-programmatic 20% inter-programmatic and 63% externally collaborative. In 2019 thelast full year before the pandemic 556 patients were enrolled on interventional treatment trials representing11% of our 5065 new analytic cases.We continue our leadership in precision oncology (implementing sophisticated clinical trials based oncomprehensive tumor analytics) and in advancing understanding of tumor biology the immunemicroenvironment and immunotherapeutics. We have provided leadership in numerous collaborative NCIprojects and were selected to lead a Biden Cancer Moonshot grant Evaluation of Population Based Testing forHBOC and Lynch Syndromes. We have refined and improved screening guidelines for multiple cancerscontributed to exercise guidelines for cancer survivors made substantial investments in Community Outreachand Engagement and invested in the education and training of the next-generation cancer workforce. Togetherthese achievements have accelerated progress towards driving scientific discoveries in precision oncology andprecision early detection through our culture of inclusion and innovation. 191618 +No NIH Category available Affect;Asian population;Award;Baltimore;Basic Science;Behavior;Biology;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Catchment Area;Cigarette;Cities;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Comprehensive Cancer Center;County;Dentistry;Detection;Discipline of Nursing;Doctor of Medicine;Education;Ethnic Origin;Faculty;First Independent Research Support and Transition Awards;Flow Cytometry;Funding;Future;Genomics;Grant;Head Cancer;Human;Image;Investigational Therapies;Investments;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maryland;Medical;Medical center;Middle School Student;Minority;Minority Groups;Mission;Molecular;Molecular Biology;Names;National Cancer Institute;Neck;Participant;Pathology;Patient Care;Patient Participation;Patients;Pharmacy Schools;Pharmacy facility;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention Research;Prevention strategy;Public Health Schools;Reporting;Research;Research Activity;Research Design;Research Personnel;School Dentistry;School Nursing;Schools;Screening for cancer;Services;Structure;Students;System;Talents;Therapeutic;Therapeutic Trials;Training;Translational Research;Translations;Underrepresented Minority;Universities;Work;acronyms;anticancer research;biobank;cancer care;cancer health disparity;cancer therapy;clinical care;clinical phenotype;clinical training;clinically relevant;college;community based research;design;fundamental research;health disparity;hormone related cancer;innovation;medical schools;member;minority communities;mortality;multidisciplinary;neoplasm immunotherapy;news;prevent;programs;racial diversity;science education;standard of care;structural biology;tumor immunology;tumor registry;virology UNIVERSITY OF MARYLAND GREENEBAUM CANCER CENTERSUPPORT GRANT 1.1 Project Narrative: OverallThe mission of the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center(UMGCCC) is to undertake innovative basic and clinical and population research that will impact theunderstanding and treatment of cancer around the world and to provide state-of-the-art clinical care to cancerpatients in Maryland and beyond. NCI 10737665 8/31/23 0:00 PAR-20-043 3P30CA134274-16S1 3 P30 CA 134274 16 S1 "BELIN, PRECILLA L" 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 1967833 "CULLEN, KEVIN J." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 248849 NCI 215786 33063 1.0 Abstract: OverallOur strategy at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center(UMGCCC) is to take advantage of discoveries in basic cancer biology in conjunction with clinical populationand prevention research to (a) develop and apply innovative therapeutic and preventive strategies to cancerpatients (b) describe the molecular mechanisms involving specific clinical phenotypes and behaviors (c) applydiscoveries and strategies to the Maryland community with a specific focus on cancer disparities and (d) providetraining in cancer biology and cancer care for students fellows clinicians and staff. These strategies collectivelywill serve the clinical and research missions of the Cancer Center for the Maryland community well into thefuture. In this application UMGCCC seeks the second competitive renewal of the Cancer Center Support Grant(CCSG) which was first awarded to UMGCCC in August 2008; Comprehensive designation was awarded in2016. For this application UMGCCC is represented by 137 full and 88 associate members working in 5 researchprograms unchanged since our 2015 application. The application describes seven shared services. UMGCCCprovides an effective structure to support the multidisciplinary cancer research activities of this talented group ofinvestigators. Total direct cancer funding is $79.1 million with $14.2 million from the National Cancer Institute.Direct cancer funding has increased 70 percent in the last cycle. In 2019 UMGCCC served 3095 new cancerpatients. In the last funding cycle a total of 9702 patients participated in clinical trials. Fifty-six percent of allparticipants in clinical trials were minorities reflecting UMGCCC's unique position and mission to involve theminority community in state-of-the-art clinical and translational research. This includes 48.2 percentunderrepresented minorities as well as 7.8 percent Asians the latter reflecting clinical trials examining healthdisparities in that group. Underrepresented minority accrual to therapeutic trials is 34.7 percent. UMGCCCcontinues to make outstanding contributions to understanding cancer biology and important recent work fromUMGCCC labs and clinics is now the standard of care or in advanced clinical trials. The U.S. News & WorldReport ranking of U.S. cancer programs has named UMGCCC in the top 50 for 13 consecutive years. Reflectingremarkable and continued progress UMGCCC seeks to renew its CCSG to enhance and expand its efforts andsupport high-quality and clinically relevant cancer research. 248849 +No NIH Category available Address;Area;Award;Basic Science;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Caring;Catchment Area;Cellular biology;Cities;Clinic;Clinical;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;Correlative Study;County;Development;Disparity;Education;Epidemiology;Faculty;Faculty Recruitment;Funding;Genetic;Geography;Gifts;Goals;Health Policy;Health system;High School Student;Hospitals;House Staffs;Individual;Institution;Investigation;Laboratory Scientists;Leadership;Long Island;Malignant Neoplasms;Medical Students;Medicine;Mentorship;Mission;NCI-Designated Cancer Center;New York;New York City;Nursing Students;Patient Care;Patients;Peer Review;Phase;Population;Population Research;Population Sciences;Provider;Public Health;Research;Research Personnel;Resource Sharing;Schools;Science;Scientist;Strategic Planning;Strategic vision;System;Thinking;Time;Training;Translating;Translational Research;Translations;Universities;Weather;anticancer research;cancer care;cancer cell;cancer epidemiology;cancer genome;cancer prevention;cancer therapy;cancer type;college;community engagement;disorder control;frontier;graduate student;health disparity;improved;innovation;insight;medical schools;melanoma;member;next generation;outcome disparities;outreach program;patient oriented;patient population;population health;precision medicine;prevent;programs;recruit;research facility;senior faculty;tumor immunology;undergraduate student Cancer Center Support Grant Project NarrativeThe Laura and Isaac Perlmutter Cancer Center (PCC) is a university-based matrix cancer center thatoversees and directs all cancer research and care in the NYU Langone Health system (NYULH) and affiliatedunits within New York University/NYU. Our 180 Members and 56 Associate Members belong to 17 NYULangone School of Medicine (NYUSoM) departments (including scientists in the Skirball Institute and theInstitutes of Computational Medicine and Systems Genetics) or to 7 NYU colleges and schools. Membersactively engage in basic translational clinical and/or population science research have peer-reviewed cancerresearch funding and/or conduct clinical trials that meet the needs of our unique New York City catchmentarea. Although PCC is located in a city with four other NCI-designated cancer centers our catchment areadiffers substantially from the others: we are the major provider to lower Manhattan and have expanded intoBrooklyn the largest and fastest growing borough in New York City as well as to Queens and Long Island. NCI 10737664 4/10/23 0:00 PAR-17-095 3P30CA016087-42S1 3 P30 CA 16087 42 S1 "BELIN, PRECILLA L" 12/1/97 0:00 2/29/24 0:00 Cancer Centers Study Section (A)[NCI-A] 8586116 "KIMMELMAN, ALEC " Not Applicable 12 PEDIATRICS 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 397 Research Centers 2023 211875 NCI 125000 86875 Project SummarySince the last competitive review of this Cancer Center Support Grant (CCSG) in 2012 the NCI-designatedPerlmutter Cancer Center (PCC) previously NYU Cancer Institute has weathered the devastation ofSuperstorm Sandy and emerged into a period of profound transformation and expansion. Propelled by atransformative gift from Laurie and Isaac Perlmutter renewed and enhanced institutional support from the NYULangone Health system (NYULH) and a new Director we have overhauled our leadership team expanded ourclinical and research facilities and developed a new strategic vision and began implementing a new StrategicPlan. Guided by this plan our Scientific Programs and Shared Resources have been restructured and weembarked on a major recruitment campaign that has yielded 12 additional new leadership and/or senior facultyrecruits 15 other new cancer center faculty recruits and 68 new members overall. Under revised morestringent criteria membership has been streamlined to 180 full members and 56 associate members. Memberscarry out research as part of 5 Scientific Programs Cancer Genome Dynamics Cancer Cell Biology TumorImmunology Melanoma or Epidemiology and Cancer Control assisted by 10 Shared Resources and 2Developing Shared Resources. Our clinical trials office has been reorganized and substantially expandedunder new leadership and a new Phase I unit has opened. Subsequently trial availability quality and accrualhave increased while the time to trial opening has been markedly reduced. In line with our increasedgeographic scope and patient population we have redefined and enlarged our catchment area. Aided by thecreation of a new Department of Population Health at NYU Langone School of Medicine and the College ofGlobal Public Health at the NYU main campus our Population Sciences research has increased in breadthand quality. Most importantly our laboratory scientists have made paradigm-shifting discoveries our clinicianshave led multiple practice-changing trials and our population scientists have yielded new insights into thecauses of cancer and how to control the disease contributed to major public health policy changes andinitiatives and established new community outreach programs that address the specific cancer burdens andhealth disparities in our catchment area. Although PCC is located in a city with four other NCI-designatedcancer centers our catchment area differs substantially from the others: we are the major provider to lowerManhattan and have expanded into Brooklyn the largest and fastest growing borough in New York City aswell as to Queens and Long Island. 211875 +No NIH Category available Appointment;Arts;Authorization documentation;Award;Basic Cancer Research;Basic Science;Behavioral;Bioinformatics;Biology;Budgets;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Caregivers;Caring;Catchment Area;Chemicals;Clinic;Clinical Data;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Data;Development;Direct Costs;Discipline of Nursing;Disease;Disparity;Early Diagnosis;Education and Outreach;Epidemiology;Epigenetic Process;Evaluation Research;Facility Construction;Faculty;Fostering;Funding;Future;Genetic Research;Genomic approach;Government;Grant;Health;Health Resources;Health Services;Healthcare;Human;Incidence;Information Systems;Infrastructure;Institution;Insurance Carriers;Intervention;Intervention Trial;Investments;Leadership;Malignant Neoplasms;Measures;Medicaid;Medicare;Minority Groups;Mission;Molecular Epidemiology;Monitor;Morbidity - disease rate;Names;North Carolina;Oncology;Outcome;Patient Care;Patients;Performance;Pharmacologic Substance;Pharmacy facility;Policies;Population;Population Heterogeneity;Population Sciences;Prevention;Privatization;Productivity;Protocols documentation;Public Health;Publications;Publishing;Research;Research Personnel;Resource Sharing;Resources;Role;Rural Population;Schools;Science;Scientist;Services;Stretching;System;Talents;Technology;The Cancer Genome Atlas;Therapeutic;Training;Training and Education;Translating;Translations;United States;Universities;Urban Population;anticancer research;authority;cancer care;cancer epidemiology;cancer genetics;cancer research center director;cancer therapy;career;chimeric antigen receptor T cells;college;community based participatory research;community college;community engagement;data management;drug discovery;epidemiology study;imaging detection;innovation;malignant breast neoplasm;medical schools;member;minority disparity;mortality;multidisciplinary;neoplasm registry;operation;outreach;population based;population health;programs;public policy on tobacco;recruit;safety net;screening services;senior faculty;survivorship;undergraduate student Cancer Center Support Grant PROJECT NARRATIVEThe Lineberger Comprehensive Cancer Center (LCCC) forms the nexus for researchers focused onunderstanding and identifying the mechanisms leading to the prevention of and treatments for cancer. LCCCis an integral component of the research mission at The University of North Carolina (UNC) at Chapel Hillcoalescing the cancer research capabilities of the Schools of Medicine Public Health Pharmacy and Nursingand the College of Arts and Sciences. The LCCC strives to reduce cancer incidence morbidity and mortality inNorth Carolina the United States and across the globe through innovative research cutting-edge treatmentsmulti-disciplinary training education and outreach. NCI 10737663 1/30/23 0:00 PAR-20-043 3P30CA016086-47S1 3 P30 CA 16086 47 S1 "SHAFIK, HASNAA" 6/1/97 0:00 11/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6477317 "EARP, HENRY SHELTON" Not Applicable 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 397 Research Centers 2023 219205 NCI 159431 59774 ABSTRACTOver the past 5 years the Center sustained its upward trajectory in cancer research excellence and service toits catchment area the State of North Carolina. With Dr Sharplesss appointment to NCI Director inconsultation with University leadership and the Centers Scientific Advisors Dr Earp was re-appointed UNCLineberger Comprehensive Cancer Center (LCCC) Director for an additional term. The LCCC continued itsexceptional performance of the past decade with respect to all important metrics including state service. Directcost cancer research funding in 2019 increased to $161M of which over $54M comes from NCI; Centerresearch space under the Directors authority increased by ~10000nsf; participation in interventional trials wasover 11000 accruals for the 5 year period; 36% of the more than 6000 cancer related publication werecollaborative; construction of a GMP facility was begun and a CAR T program was initiated with multiple INDsand 8 trials opened; and the Office of Community Outreach Engagement expanded LCCCs traditional strengthin community-based participatory research and implementation .The Centers 324 members span the basic clinical and population sciences organized into 9 programs withsubstantial inter- and intra-programmatic productivity. Faculty additions in the physical and pharmaceuticalsciences created new opportunities in drug discovery delivery imaging and early detection. Substantialinvestment in faculty technology and bioinformatics dramatically expanded cancer genetics research includingleadership in the TCGA and expanded use of sequencing in clinical trials. LCCC population scientists initiatedsignificant new efforts in cancer outcomes with recruitment and infrastructure for analyzing all cancer cases inour catchment area as well as new endeavors in cancer communication health access survivorship andmolecular epidemiology. Groundbreaking observations in breast cancer minority disparity research emergedfrom Center programs. Our basic programs continue to publish high-impact observations that are beingtranslated into human therapeutics. A trans-Center Global Oncology effort received grants in each of the NCIsnew competitions. The Centers continued expansion is driven by remarkable institutional support includingdirect support for cancer research from the state legislature. The UNC Lineberger requests continued fundingfor: 9 scientific programs; 13 shared resources; Clinical Protocol and Data Management; Protocol Review andMonitoring System Developmental Funds Planning Leadership and Evaluation and Cancer Research andCareer Enhancement The CCSG budget supports technological and operational expansion for a talentedfaculty integrated through cancer center mechanisms towards making advancements in the prevention earlydetection and treatment of cancer in North Carolina and the nation. 219205 +No NIH Category available Alaska;Area;Biology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Detection;Cancer Etiology;Carcinogenesis Mechanism;Caregivers;Catchment Area;Cause of Death;Cessation of life;Child;Childhood;Clinical;Clinical Research;Collaborations;Communities;Comprehensive Cancer Center;Computational Biology;County;Development;Diagnosis;Diagnostic;Discipline;Disease;Educational process of instructing;Enrollment;Ensure;Equation;Equity;Exposure to;Faculty;Faculty Recruitment;Fostering;Funding;Genomics;Goals;Grant;Health;Health Sciences;Hematopoietic Stem Cell Transplantation;Idaho;Immunology;Immunotherapeutic agent;Individual;Institution;Intervention;Investments;Knowledge;Laboratories;Laboratory Research;Leadership;Malignant Neoplasms;Measures;Mentors;Mission;Molecular;Montana;Outcome;Patients;Peer Review;Population Research;Postdoctoral Fellow;Prevention;Prevention strategy;Primary Prevention;Public Health;Quality of Care;Research;Research Infrastructure;Research Personnel;Resources;Risk Factors;Risk Marker;Science;Secondary Prevention;Students;Therapeutic;Training;Training and Education;Translating;Translational Research;Translations;Transplantation;Underrepresented Populations;United States;Universities;Washington;Work;Wyoming;anticancer research;base;cancer care;cancer diagnosis;cancer therapy;carcinogenesis;clinical care;clinical practice;computer studies;epigenomics;graduate student;host neoplasm interaction;improved;insight;inter-institutional;interdisciplinary collaboration;interest;member;mortality;multidisciplinary;next generation;outreach;pathogen;profiles in patients;programs;synthetic biology;targeted treatment;therapy development;treatment center;treatment trial;tumor;tumor metabolism;tumor progression Cancer Center Support Grant PROJECT NARRATIVE: OVERALLThere were an estimated 1.7 million new cases of cancer in the United States in 2018 and an estimated609000 deaths from the disease. Cancer is the second leading cause of the death in the U.S. The goal of theFred Hutchinson/University of Washington Cancer Consortium is the elimination of cancer as a cause ofsuffering and death through more effective prevention diagnosis and treatment deriving from fundamentalinsights into the biology of the disease. NCI 10737660 12/29/22 0:00 PAR-17-095 3P30CA015704-48S1 3 P30 CA 15704 48 S1 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 8549026 "LYNCH, THOMAS JAMES" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 397 Research Centers 2023 194375 NCI 194375 0 PROJECT SUMMARY: OVERALLThe Fred Hutchinson/University of Washington Cancer Consortium (the Consortium) brings together morethan 600 members with research interests in basic clinical and public health sciences related to cancer. Thegoal of the Consortium is the elimination of cancer as a cause of suffering and death through more effectiveprevention diagnostics and treatment deriving from fundamental insights into the biology of the disease. Theextensive interdisciplinary collaboration among the partner institutions in the cancer research disciplines ofbasic clinical and public health sciences affords new opportunities to reduce suffering and mortality fromcancer.The Consortium was established in 2002 to build upon the complementary strengths and resources of threepartner institutions: the Fred Hutch which has been an NCI-designated Comprehensive Cancer Center since1976; the University of Washington which has significant strength in cancer research clinical care andteaching; and Seattle Childrens the major pediatric academic center in the region. In 2008 the Seattle CancerCare Alliance the cancer treatment center founded and equally co-owned by the three founding institutionswas formally added to the cancer center designation.The Consortiums total funding base (direct dollars) is $242M of which $117M is peer-reviewed including$50M from the NCI. During the last grant period over 170 new faculty members joined the Consortium addingbreadth and depth to our research and clinical capabilities. In the most recent year we enrolled 1338 patientsonto interventional treatment trials of which more than 50% were investigator-initiated. The ratio of accruals tonewly registered patients was 28%.The Consortium serves a catchment area of 13 counties in western Washington. This equates to the region inwhich 83 percent of our patients reside. As the only NCI-designated comprehensive cancer center in a five-state region (Washington Wyoming Alaska Montana and Idaho) we not only seek to serve the health needsof the catchment area through research training and outreach but also to ensure high impact throughout thelarger region.The Consortium continues to build upon historic strengths in basic cancer biology immunology andtransplantation pathogen associated malignancies tumor specific translational research computationalbiology and studies of cancer etiology prevention and outcomes. The Consortium is well poised to continue itsexceptional level of research in these areas. The CCSG continues to have a high impact on the Consortiumfostering new inter-institutional collaborations strengthening the translational research platform andintensifying research efforts on problems of the catchment area. Partner institutions contributed nearly $1.2billion in institutional support during the last project period including investments in our laboratory and clinicalresearch infrastructure as well as in faculty recruitment and trainee support. 194375 +No NIH Category available Achievement;Arts;Authorization documentation;Award;Basic Science;Businesses;Cancer Burden;Cancer Center Support Grant;Cancer Patient;Cancer Science;Caring;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Health;Community Outreach;Complex;Development;Direct Costs;Discipline of Nursing;Duke Comprehensive Cancer Center;Education;Engineering;Enrollment;Environment;Faculty;Faculty Recruitment;Fellowship;Funding;Future;Goals;Grant;Health;Health system;Infrastructure;Interdisciplinary Study;Intervention;Investigation;Investments;Laboratories;Leadership;Link;Malignant Neoplasms;Medicine;Mission;Oncology;Paper;Patient Care;Patients;Peer Review;Pilot Projects;Population;Population Research;Population Sciences;Process;Public Policy;Publishing;Recommendation;Research Activity;Research Infrastructure;Research Personnel;Research Technics;Resource Allocation;Resource Sharing;Schools;Science;Scientist;Series;Signal Transduction;Strategic Planning;Structure;Testing;Therapeutic;Time;Training;Training and Education;Translational Research;Translations;Universities;University Hospitals;Work;anticancer research;authority;cancer care;cancer genomics;career development;clinical care;community based participatory research;community engagement;cost;design;health disparity;innovation;medical schools;member;multidisciplinary;new technology;next generation;novel;outpatient facility;population based;programs;recruit;therapeutic development;therapeutic evaluation;training opportunity;translational study Cancer Center Support Grant PROJECT NARRATIVE (RELEVANCE STATEMENT) OVERALLThe Duke Cancer Institute which has authority and responsibility for all cancer-related activities at DukeUniversity and in the Duke University Health System provides support and promotes collaborations betweenfaculty and staff involved in cancer research education and patient care. This Cancer Center Support Grantfacilitates oversight and integration of all cancer-related research activities from basic research to translationalstudies to clinical and population investigation to community outreach to global cancer. Building upon anextensive strategic planning process priority activities to maximize local regional and national impact havebeen identified. NCI 10737659 7/25/23 0:00 PAR-17-095 3P30CA014236-49S1 3 P30 CA 14236 49 S1 "HE, MIN" 1/1/97 0:00 12/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 1865395 "KASTAN, MICHAEL B" Not Applicable 4 PHARMACOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 397 Research Centers 2023 250000 NCI 155280 94720 PROJECT SUMMARY/ABSTRACT OVERALLThe Duke Comprehensive Cancer Center was founded as a matrix center within the Duke University School ofMedicine in 1972 and the Duke Cancer Institute (DCI) was created as a new administrative entity within DukeHealth in October 2010 with authority and responsibility for all cancer-related activities at Duke University andin the Duke University Health System. The DCI was started with significant investments from Duke Healthincluding a new $243M clinical care outpatient facility over $60 million of new funds available to support newinitiatives and a commitment for ongoing annual investment by the Duke Health System. DCI faculty includewell-established and funded experts spanning the full spectrum of cancer research fields from intracellularsignaling to cancer genomics to therapeutic development and testing to population science. DCI programmaticactivities support the career development of the next generation of cancer experts and provide platforms formulti-disciplinary scientific teams to develop and test new hypotheses. During the most recent funding periodthe DCI structure has continued to evolve and mature currently consisting of 304 members from 34 departmentswithin 7 schools at Duke University (Medicine Nursing Arts and Sciences Engineering Public PolicyEnvironment and Business) and organized as 8 multi-disciplinary research programs (2 basic discovery 1population science and 5 translational/clinical) whose work is supported by 14 Shared Resources (8 lab-basedand 6 supporting translational/clinical/population research activities). In addition to Program and SharedResource leaders DCI senior leadership which includes an Executive Director Deputy Director 7 AssociateDirectors and 8 other key leaders provides oversight and direction of DCI initiatives. DCI members are currentlysupported by over $111M of external cancer-related grant support (direct costs) over $63M of which is peer-reviewed including 32 peer-reviewed multi-investigator grants (involving 81 subprojects/cores) and 61 trainingand fellowship awards. DCI members published over 5750 cancer-focused papers during the past fundingperiod ~40% of which represent collaborative efforts between DCI investigators. On average ~7000 newcancer patients are seen each year at the Duke University Hospital. In 2018 DCI Programs enrolled over 4000patients on clinical trials including nearly 2000 interventional accruals and 770 therapeutic accruals. DCI isheavily engaged in both community outreach/engagement and educating the next generation of cancer cliniciansand scientists. Duke Health support of the DCI included a total of over $65M of additional investment in the mostrecent funding period including support for recruitment retention and protected academic time for DCI faculty.The DCI completed an extensive 5-year Strategic Planning process identifying strategic goals and priorities thatenable the DCI mission to Discover Develop and Deliver the future of cancer carenow resulting in a seriesof discrete recommendations that are serving as a guide for determining current and future resource allocationrecruiting priorities and infrastructure changes required to achieve DCI goals. 250000 +No NIH Category available Achievement;Agreement;Area;Award;Basic Cancer Research;Basic Science;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Research Project;Cancer Vaccines;Chromatin;Clinic;Collaborations;Communities;Community Clinical Oncology Program;Competence;Credentialing;DNA Vaccines;Dedications;Development;Direct Costs;Disease;Disease model;Drug resistance;Early Diagnosis;Education;Educational Activities;Ensure;Epigenetic Process;Faculty Recruitment;Family;Foundations;Funding;Future;Goals;Grant;Immunology;Immunosuppression;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;Investments;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mission;Neoplasm Metastasis;Oncogenic;Pathway interactions;Patients;Peer Review;Pilot Projects;Productivity;Program Research Project Grants;Publications;Research;Research Personnel;Resource Sharing;Running;Science;Scientist;Site;Specialized Program of Research Excellence;Technology;Therapeutic;Therapeutic Intervention;Time;Training;Tumor Immunity;Untranslated RNA;Vaccines;Virus Inhibitors;Vision;Workforce Development;anticancer research;cancer research center director;checkpoint inhibition;collaborative approach;commercialization;design;drug discovery;early detection biomarkers;innovation;inter-institutional;melanoma;member;multidisciplinary;next generation;novel;novel therapeutics;patient oriented;programs;recruit;response;synergism;tool;translational cancer research;translational immunology;translational model;tumor;tumor immunology;tumor metabolism;tumorigenesis;vaccine immunotherapy Consolidated Basic Cancer Research Program PROJECT NARRATIVE OVERALLMembers of the Wistar Cancer Center elucidate the mechanistic underpinning of malignancy pursueinnovative disease models and identify novel tumor vulnerabilities suitable for therapeutic intervention. Drivenby collaboration and partnership the Wistar Cancer Center delivers on innovative basic and translationalcancer research brings cutting-edge science to the community trains the next generation of research leadersand strives to advance its discoveries to the clinic for the benefit of cancer patients and their families. NCI 10737658 3/2/23 0:00 PAR-17-095 3P30CA010815-54S1 3 P30 CA 10815 54 S1 "ROBERSON, SONYA" 4/1/97 0:00 2/29/24 0:00 Cancer Centers Study Section (A)[NCI-A] 1882783 "ALTIERI, DARIO C" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 397 Research Centers 2023 249893 NCI 137078 112815 PROJECT SUMMARY OVERALLThe vision of the Wistar Cancer Center is to conquer cancer through outstanding research education andpartnership and its mission is to merge basic translational and patient-oriented cancer research in asingle scientific continuum. Rated Exceptional (Impact score 19) at the 2013 renewal of the Cancer CenterSupport Grant (CCSG) the Cancer Center has continued on a path of scientific excellence impactfulcontributions in basic and translational cancer research and productive partnerships with neighboringacademic Institutions. Leveraging the 2014 opening of the Fox Research Tower the largest building built onWistar campus a science-focused leadership where the Cancer Center Director (Dr. Altieri) is also InstitutePresident and Chief Executive Officer (CEO) and a nimble opportunity-driven administration the CancerCenter has recruited 10 new members during the last CCSG budget cycle expanded technological capabilitiesin all Shared Resources and realigned Programs for optimal scientific impact and collaboration. Its basicresearch contributions have elucidated fundamental underpinnings of tumorigenesis in chromatin organizationnon-coding RNA local immunosuppression and metastatic competence whereas disease site-specific themesin melanoma and ovarian cancer have run the gamut from defining new oncogenic pathways to unravelingmechanisms of drug resistance to bringing novel therapeutics to the clinic. Against this backdrop the CancerCenter currently receives $12.4 million in peer-reviewed cancer-related funding with $8.9 million from the NCIfor an exceptional cancer focus of 76%. The three Programs in the Cancer Center have succeeded in auniquely collaborative approach to cancer research: 76% of all peer-reviewed funding and over 40% ofdiscovery publications in the Programs are currently the product of multi-investigator collaborations. For aCancer Center with only 27 members Wistar now contributes to three Specialized Programs of ResearchExcellence (SPOREs) five Program Project grants six multi-PI awards and four U-type grants. Theoverarching goal of the Cancer Center to move its basic discoveries to the clinic has been met with a landmarkagreement with the Helen F. Graham Cancer Center (HFGCC) the first partnership in the nation to bringtogether two NCI-sponsored programs: an NCI-designated basic Cancer Center (Wistar) and a member ofthe NCI Community Oncology Research Program (HFGCC). This has enabled impactful collaborationsbetween Wistar scientists and HFGCC clinicians bringing cutting-edge cancer research to the community. TheCancer Center will continue on this successful trajectory of accomplishments during the next CCSG budgetcycle creating new multidisciplinary research themes in basic and translational tumor immunology early-stage academic drug discovery and exploitation of tumor metabolism for novel cancer therapeutics. As anorganization solely dedicated to biomedical discovery Wistar is uniquely poised to continue makingtransformative advances in basic translational and patient-focused cancer research. 249893 +No NIH Category available ATAC-seq;Biological Markers;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast cancer metastasis;Cancer Patient;Cells;ChIP-seq;Chicago;Chromatin;Collaborations;Combined Modality Therapy;Complex;Cytometry;Cytoplasm;Data;Diagnosis;Disease;Disease Resistance;Disease-Free Survival;Endocrine;Ensure;Epigenetic Process;Estrogen Receptors;Estrogens;Event;Follow-Up Studies;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;Health;Hypoxia;Intervention;Knowledge;Link;Longevity;Lung;Mammary Neoplasms;Mass Spectrum Analysis;Mediating;Mediator;Metabolic;Metabolism;Metastatic breast cancer;Modeling;Mouse Mammary Tumor Virus;NCOA3 gene;Neoplasm Metastasis;Nuclear;Oncogenes;Oncogenic;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Population;Positive Lymph Node;Process;Progesterone;Progesterone Receptors;Proliferating;Protein Kinase;Receptor Signaling;Recurrence;Recurrent Malignant Neoplasm;Resistance;Resistance development;Resolution;Risk;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Specific qualifier value;Steroid Receptors;Stress;Tamoxifen;Target Populations;Testing;Time;Transcription Coactivator;Transgenic Mice;Woman;Work;breast cancer progression;cancer recurrence;cancer stem cell;chromatin remodeling;epigenetic regulation;hormone therapy;in vitro Model;in vivo;innovation;knock-down;malignant breast neoplasm;mortality;mouse model;neoplastic cell;new therapeutic target;novel;overexpression;prevent;programs;promoter;protein complex;recruit;scaffold;stem;stem cells;stem-like cell;steroid hormone receptor;targeted treatment;therapy duration;therapy resistant;transcriptome;transcriptome sequencing;tumor;tumor metabolism;tumorigenesis SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer Project NarrativeBreast cancer recurrence remains a significant health burden for women undergoing long-term endocrinetherapy following diagnosis with luminal (ER+) breast cancer. The goal of these studies is to reveal how steroidhormone receptors become dysregulated during metabolic and cell fate transitions that contribute to breastcancer progression escape from ER-targeted therapies and dissemination as long-lived cancer stem or stem-like cells capable of successful metastatic spread. Non-ER mediators of these reversible epigenetic eventsare highly targetable as part of future combination therapies. NCI 10737629 11/8/23 0:00 PA-19-056 5R01CA236948-05 5 R01 CA 236948 5 "JOHNSON, RONALD L" 12/1/19 0:00 11/30/24 0:00 Molecular Oncogenesis Study Section[MONC] 1868359 "LANGE, CAROL A" "OSTRANDER, JULIE H" 5 INTERNAL MEDICINE/MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 440941 NCI 296901 144040 AbstractBreast cancer recurrence remains a significant risk among node-positive patients. Breast cancer stem or stem-like cells (BCSCs herein) disseminate and evade first-line therapies and account for high mortality amongpatients with advanced endocrine-resistant disease. The objective of this proposal is to define the signalingpathways that drive the emergence and expansion of endocrine-resistant BCSCs with the goal of blockingepigenetic events to specifically target this population of tumor cells. Filling this knowledge gap will pave the wayfor intervention that blocks BCSCs and ensures long-term disease-free survival. We identified the chromatin-associated steroid receptor (SR) transcriptional coregulator PELP1 as a mediator of BCSC expansion. Utilizingmass spectrometry we identified the steroid receptor coactivator-3 SRC-3 (also known as AIB1) as a noveland preferential interactor with cytoplasmic relative to nuclear PELP1. Notably PELP1 increased activation ofSRC-3 in BC cells while SRC-3 knockdown blocked PELP1-induced BCSC expansion suggesting an essentialrole for active PELP1/SRC3 complexes in BCSC outgrowth. In follow-up studies we found that cytoplasmicPELP1 promotes the phosphorylation of SRC-3 on Thr24 and Ser857. Work of others has implicated SRC-3pSer857 in breast cancer metastasis as a key substrate of the bifunctional kinase/phosphatase known asPFKFB4. In related work we showed that PELP1 forms constitutive transcriptional complexes with both estrogen(ER) and progesterone (PR) receptors in breast cancer models and patient tumors; a scaffolding action of PR-B but not progesterone was required for ER phosphorylation and regulation of genes by ER/PR/PELP1complexes including gene sets important for tamoxifen resistance. Herein we hypothesize thatER/PR/PELP1/SRC-3 complexes recruit and amplify key cytoplasmic signaling pathways that mediateepigenetic events required for chromatin remodeling and reprogramming of steroid receptor (SR)-regulatedtranscriptomes required for expansion of therapy resistant BCSC populations. We will test this hypothesis inbreast cancer models and in the following Specific Aims: Identify PELP1/SRC-3-activated signaling pathways essential for BCSC expansion and therapy resistance. Determine how PELP1/SRC-3 complexes reprogram SR transcriptomes. Determine if PELP1/SRC-3/SR cooperation promotes tumorigenesis in vivo.Current therapies primarily inhibit BC proliferation but fail to adequately target BCSCs. Understanding themechanisms of PELP1/SRC-3/SR signaling and reversible epigenetic regulation of BCSCs will reveal noveltherapies that target the required components of this complex (i.e. other than ER) or downstream signalingmolecules and prevent or reverse this process thus significantly impacting on the longevity of patients withmetastatic breast cancer. 440941 +No NIH Category available Acceleration;Agonist;Animal Model;Antibodies;Biopsy;Chemotherapy and/or radiation;Clinical;Clinical Trials;Clinical assessments;Colorectal Cancer;Combination immunotherapy;Complex;Coupled;Data Set;Dendritic Cells;Development;Disease Management;Evaluation;Event;Experimental Models;Future;Histologic;Human;Immune;Immune Targeting;Immune response;Immune signaling;Immunofluorescence Immunologic;Immunotherapy;In complete remission;Incidence;Individual;Innate Immune Response;Knowledge;Learning;Local Therapy;Malignant Neoplasms;Maps;Mismatch Repair Deficiency;Modeling;Molecular;Neighborhoods;Neoadjuvant Therapy;Operative Surgical Procedures;Pathway interactions;Patient Selection;Patients;Pharmacodynamics;Phase;Population;Proteomics;Radiation;Radiation therapy;Rectal Cancer;Risk Reduction;Signal Transduction;Systemic Therapy;TNFRSF5 gene;Technology;Therapeutic;Therapeutic Effect;Tissues;Tumor Tissue;Validation;adaptive immune response;anti-tumor immune response;cancer immunotherapy;chemotherapy;curative treatments;deep learning;efficacy testing;enhancing factor;evidence base;high risk;immunogenic;immunotherapy trials;improved;improved outcome;innovation;insight;novel;participant enrollment;patient population;patient response;permissiveness;personalized medicine;phase II trial;precision oncology;radiation response;randomized trial;randomized clinical trials;receptor;responders and non-responders;response;single-cell RNA sequencing;success;synergism;therapy development;treatment response;trial design;tumor;tumor microenvironment Early response to radiotherapy and immunotherapy in rectal cancer: an integrated molecular cellular and spatial approach Project NarrativeDeveloping optimal radiation and immunotherapy combinations is hindered by the limited ability to deeplyunderstand therapeutic responses and there is a critical need to innovate with rectal cancer when cure withradiation and systemic therapy could save a morbid surgery. We have developed an integrated approach toassess early biopsy tissue after short course radiation therapy to assess molecular cellular and spatialdynamics that could improve our ability to nominate promising therapies. With pre- and post- therapy biopsiesfrom our CD40 trial we will perform single cell RNA sequencing multiplexed immunofluorescence deeplearning from histopathologic tissue to identify therapeutic opportunities and study mechanisms of response toCD40. NCI 10737592 7/26/23 0:00 RFA-CA-22-050 1R01CA283953-01 1 R01 CA 283953 1 "SOMMERS, CONNIE L" 8/1/23 0:00 7/31/28 0:00 ZCA1-RPRB-6(M2)S 7799057 "AGUILERA, TODD A" Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 353 Non-SBIR/STTR 2023 656670 NCI 413086 243584 Project AbstractWith increased incidence in young populations and ~65% three-year survival of high-risk locally advanced rec-tal cancer innovative approaches to improve outcomes is imperative. Neoadjuvant therapy with radiation (RT)and chemotherapy (CT) is now the standard curative treatment but there is demand for non-operative man-agement (NOM) if the disease can be cured with local and systemic therapy. Thus innovations could be trans-formative with the aim to improve durable complete responses by personalizing therapy which includes how todeliver RT CT and the incorporation of novel agents such as immunotherapy. Cancer Immunotherapy hashad little impact on colorectal cancer outside of mismatch repair deficient tumors. The CD40 agonist antibodyis an emerging class of immunotherapy and sotigalimab has shown promise in phase I and multiple ongoingphase II trials. The CD40 receptor is important in both innate and adaptive immune responses and a greatertherapeutic effect can be achieved combining CD40 with RT in animal models. We hypothesize that shortcourse RT (SCRT) and CT when combined with CD40 in human tumors can result in a greater antitumor im-mune response reduce risk of metastatic progression and extend survival in a poorly immunogenic malig-nancy like rectal cancer. We developed the INNATE trial a phase II randomized trial of neoadjuvant SCRT fol-lowed by CT with or without the addition of sotigalimab for locally advanced rectal cancer. This trial design hasallowed us to collect fresh pre- and post-SCRT biopsy tissue which we have obtained from 21 of 30 patientsenrolled to date. In this proposal we focus on the central hypothesis that an integrated molecular cellular andspatial assessment of treatment response dynamics in the tumor microenvironment early after SCRT can re-veal insights into the immunobiological responses which can inform mechanisms of efficacy and therapeuticselection. We will perform 1) molecular and cellular single cell (sc) RNAseq with proteomic and immune reper-toire analysis 2) molecular cellular and spatial multiplex immunofluorescence and 3) cellular and spatialquantitative deep learning based histopathologic analysis to achieve our aims. These three technologies willenable us to investigate early changes across RT and CD40 treated groups. Then we will aim to identify ther-apeutic opportunities for the combination of SCRT with immune active agents though an integrated RT re-sponse assessment. Lastly we will establish innate and adaptive immunologic signaling events triggered bySCRT in combination with CD40 immunotherapy and factors that enhance or hinder efficacy. We will usemodels to start validating key findings and aim to propose future therapeutic directions to build off these effortsand ultimately improve outcomes. Specifically regarding our patient population we expect this proposal willlead to evidenced based trials for most patients with locally advanced rectal cancer who strive to achieve curewithout a morbid surgery. 656670 +No NIH Category available Affect;Antibodies;Breast Cancer Cell;Cell Communication;Cell Culture Techniques;Cells;Clinical;Cytosol;DNA;DNA Repair;DNA Sequence Alteration;Data;Dependence;Diagnosis;Dimerization;ERBB2 gene;ErbB4 gene;Estrogen receptor positive;Experimental Models;FDA approved;Family member;Genome Stability;Goals;Growth;Heterodimerization;Impairment;In Situ;In Vitro;Inflammatory;Ligand Binding;Ligand Binding Domain;Ligands;Link;MLH1 gene;Malignant Neoplasms;Mammary Neoplasms;Mediating;Metastatic breast cancer;Mismatch Repair;Mutagenesis;Mutate;Mutation;Neuregulin 1;Pathway interactions;Patients;Pattern;Phenotype;Predictive Value;Predisposition;Proteins;Publishing;RNA Interference;Receptor Protein-Tyrosine Kinases;Regulation;Research;Resistance;Role;Seminal;Signal Transduction;Stimulator of Interferon Genes;Testing;Therapeutic;Tumor Suppressor Proteins;Woman;Work;behavior influence;betacellulin;cancer cell;cancer diagnosis;carcinogenesis;cytokine;digital;heparin-binding EGF-like growth factor;hormone therapy;in vivo;inhibitor;insight;interest;malignant breast neoplasm;neoplastic cell;novel;novel therapeutic intervention;overexpression;predicting response;prognostic value;resistance mechanism;therapy resistant;treatment response;tumor;tumor behavior;tumor growth;tumor microenvironment Regulation of the tumor microenvironment by DNA damage repair proteins PROJECT NARRATIVEThe results of this project will generate new insight into the role of mismatch repair proteins in regulating tumorbehavior beyond their impact on maintaining genome stability. It will also provide first understanding of thefunctional impact of heterogeneous loss of mismatch repair proteins on tumor growth and treatment response. NCI 10737565 7/14/23 0:00 PA-20-185 1R37CA270362-01A1 1 R37 CA 270362 1 A1 "BERA, TAPAN K" 7/14/23 0:00 6/30/28 0:00 Cancer Cell Biology Study Section[CCB] 11834576 "HARICHARAN, SVASTI " Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 7/14/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 498188 NCI 255481 242707 PROJECT SUMMARYBackground ER+ breast cancer accounts for 2/3 of invasive breast cancer cases diagnosed in the world today. Inpatients ~12% of ER+ tumors have complete loss of MLH1 a tumor suppressor and mismatch repair protein.We previously showed that MLH1 loss in ER+ breast cancer cells activates HER2 to induce resistance to standardendocrine therapy. However the underlying mechanism remains unknown. Preliminary data support a role forMLH1 loss in altering secretion of HER ligands to mediate HER2 activation. This is of particular interest becausean additional 14% of ER+ patient tumors have heterogeneous loss of MLH1. Although the functional consequenceof heterogeneous MLH1 loss is as yet unknown a role for MLH1 loss in altering the cancer secretome suggestsa potentially significant impact on bulk tumor phenotypes.Hypothesis Based on our published work and preliminary data the proposed study will test the hypothesis thatMLH1 loss in ER+ breast cancer induces secretion of HER ligands by co-opting cGAS-STING signaling topromote HER2-dependent growth of both MLH1 and MLH1+ cells in heterogeneously MLH1 tumors.Specific Aims Aim 1 will test whether the secretion of HER ligands induced by MLH1 loss mediates HER2activation to promote endocrine therapy resistance. Here we will use both in vitro and in vivo approaches todetermine whether the ligands secreted by MLH1- ER+ breast cancer cells promote HER2 heterodimerizationand consequent activation and thereby endocrine therapy resistant growth. Aim 2 will investigate the mechanismlinking MLH1 loss to HER ligand secretion. Specifically we will test whether inefficient DNA damage repair inthe absence of MLH1 triggers the cGAS-STING secretory pathway. We will also determine how cGAS-STINGactivation promotes HER ligand secretion. Aim 3 will examine the therapeutic impact of heterogeneous MLH1loss. Using in vitro and in vivo experimental models established in my lab we will test whether HER2 activationin both MLH1+ and MLH1- cells in tumors with heterogeneous MLH1 loss renders these tumors globallysusceptible to HER2 inhibitors. We will also use digital spatial profiling to assess the contribution of the secretometo signaling patterns and therapeutic response in heterogeneously MLH1- tumors.Impact The results of this study will present new therapeutic strategies to help >25000 women diagnosed eachyear with ER+ breast cancer characterized by heterogeneous MLH1 loss. Our work will also provide novel insightinto how MLH1 loss modulates the cGAS-STING pathway to promote a pro-growth tumor secretome. Overallresults from this study will shed new insight into the how MLH1 loss promotes cancer phenotypes. 498188 +No NIH Category available ATAC-seq;Adoptive Transfer;Affect;Antibodies;Antigens;Antitumor Response;Automobile Driving;CD8-Positive T-Lymphocytes;CTLA4 gene;Cells;Cellular immunotherapy;Colitis;Colon;Combined Modality Therapy;DNA Binding;Data;Development;Dose;Enhancers;Epithelial Cells;Evaluation;Exhibits;Frequencies;Gene Expression Profile;Generations;Genes;Genetic Engineering;Genetic Transcription;Half-Life;Human;Immune;Immunology;Immunosuppression;Immunotherapy;Impairment;Infiltration;Link;Maintenance;Malignant Neoplasms;Modeling;Molecular;Mus;Nature;Neoadjuvant Therapy;Non-Malignant;Organ;Pathogenicity;Pathway interactions;Patients;Phosphatidylinositols;Phosphotransferases;Placebo Control;Primary Neoplasm;Property;Randomized;Regimen;Regulatory T-Lymphocyte;Role;Skin;Solid;Solid Neoplasm;T cell response;T-Lymphocyte Subsets;Testing;Therapeutic;Tissues;Toxic effect;Translating;Treatment Efficacy;Tumor Immunity;Tumor Tissue;anti-CTLA4;anti-PD1 therapy;antitumor effect;cancer immunotherapy;cancer type;cell type;cellular targeting;chromatin immunoprecipitation;cohort;draining lymph node;gastrointestinal epithelium;genetic approach;immune checkpoint blockade;immune-related adverse events;immunoregulation;improved;in vivo;inhibitor;insight;keratinocyte;melanoma;mouse model;neoantigens;novel;pharmacologic;phase II trial;precursor cell;programmed cell death protein 1;programs;protein expression;response;secondary lymphoid organ;selective expression;single-cell RNA sequencing;standard care;stem;survival outcome;targeted treatment;tertiary lymphoid organ;therapy development;transcription factor;transcriptomics;tumor;tumor growth;tumor microenvironment Evaluation of T follicular regulatory cells as novel cellular targets of cancer immunotherapy Project NarrativeImmunotherapies have become crucial treatment options for a variety of cancer types and several novel targetsare currently being explored to evaluate their anti-tumor capacity. Crucially however most of these targets sufferfrom on-target off-cell effects as other immune cell types can express high levels of these molecules or inducewidespread toxicity in non-malignant organs severely limiting viable treatment options. The proposed study willelucidate the anti-tumor effects of TFR cells a novel cellular immunotherapy target and test ways to target themmore specifically to induce long-lasting anti-tumor responses without causing irAEs. NCI 10737557 6/23/23 0:00 PA-20-185 1R37CA276779-01A1 1 R37 CA 276779 1 A1 "SOMMERS, CONNIE L" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 15359671 "ESCHWEILER, SIMON " Not Applicable 50 Unavailable 603880287 ZPAUY3FQMM26 603880287 ZPAUY3FQMM26 US 32.838775 -117.253243 2465301 LA JOLLA INSTITUTE FOR IMMUNOLOGY LA JOLLA CA Research Institutes 920371387 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 418613 NCI 228750 189863 Project SummaryImmune checkpoint blockade (ICB) targeting CTLA-4 or PD-1 rapidly assumed its role as a standard treatmentfor solid tumors and can lead to dramatic long-lasting responses; nonetheless fewer than 30% of patientsrespond to monotherapy with either agent. Combination therapy results in better long-term survival outcomesbut also causes more frequent and severe immune-related adverse events (irAEs). Several novelimmunotherapies are currently being explored to evaluate their anti-tumor capacity. Crucially however most ofthese targets suffer from on-target off-cell effects as other immune cell types can express high levels of thesemolecules. Hence as low overall response rates off-cell effects and widespread immune related toxicity severelylimit both treatment efficacy and monotherapy and combination therapy options there is urgent need to developnovel immunotherapy targets that exhibit a more restricted expression profile. We have recently demonstratedthat PD-1+ follicular regulatory T (TFR) cells were prevalent in tumor tissues of several cancer types in humansand mice and that they were critical cellular determinants of anti-PD-1 treatment efficacy. TFR cells were primarilylocated within tertiary lymphoid structures (TLS) and exhibited superior suppressive capacity and in vivopersistence when compared to regulatory T (TREG) cells suggesting a key role for TFR cells in impairing patientsurvival and impeding immunotherapy treatment efficacy. While we have shown that intratumoral TFR cells derivefrom TREG precursor cells the mechanisms and transcription factors (TFs) that are driving this differentiation stepare largely unknown. In Aim1 we propose to employ single-cell RNA-seq single-cell ATAC-seq and micro-scaled ChIP assays to fully characterize the transcriptomic signatures of tumor-infiltrating TREG cells transitioning(4-1BB+) TREG cells and TFR cells. Elucidating the enhancer profiles in different developmental stages of TREG toTFR differentiation is likely to provide crucial insights into the TFs that instruct this differentiation step. Theseanalyses will define genes and TFs that are pivotal for the heightened suppressive capacity of TFR cells as wellas for their maintenance or differentiation. Strategies to deplete TREG cells or to curb their functionality with theaim of enhancing anti-tumor immunity are being intensively investigated. Crucially however most of theseapproaches are based on antibodies (i.e. ADCC-optimized for TREG cell depletion; i.e. anti-CTLA-4) which havean inherently long half-life in vivo thus increasing the likelihood of causing irAEs. Conversely our data imply thatalternative dosing regimens of Phosphoinositide 3-kinase (PI3K) inhibitors might offer a pathway to target TFRcells more specifically. We propose that PI3K represents a novel and appealing immunotherapy target in solidtumors. In Aim 2 and Aim 3 we will assess whether alternative dosing regimens of PI3Kd inhibitors can beutilized to effectively and safely exploit the immunomodulatory impact of PI3K inhibitors in solid cancers andwhether a transient depletion or inhibition of TFR cells might suffice to restrict the immunosuppressive milieu inthe tumor and thus drive anti-tumor immunity without causing toxicity. 418613 +No NIH Category available Age;Antibodies;Biological;Biological Assay;Biological Markers;Cancer Detection;Categories;Cell Line;Cells;Circulation;Complex;Control Groups;Detection;Diagnosis;Disease;Early Diagnosis;Elasticity;Enrollment;Enzyme-Linked Immunosorbent Assay;Field Flow Fractionation;Future;Image;Imaging technology;Individual;Integrins;Label;Linear Models;Lipids;Location;MLLT2 gene;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Measures;Mediating;Medicine;Memorial Sloan-Kettering Cancer Center;Methods;Modeling;Molecular Profiling;Monitor;Newly Diagnosed;Normal Cell;Nucleic Acids;Pancreatic Adenocarcinoma;Pancreaticoduodenectomy;Pathology;Patients;Performance;Peripheral;Physicians;Physiology;Plasma;Procedures;Protein-Protein Interaction Map;Proteins;Proteome;Proteomics;Race;Reaction;Reproducibility;Research Personnel;Resolution;Resources;S100A12 gene;Sampling;Screening for cancer;Serum;Specimen;Spectrometry;Speed;System;Technology;Tenascin;Time;Tumor Tissue;Ultracentrifugation;Western Blotting;Work;analytical tool;bench-to-bedside translation;biomarker development;biomarker discovery;biomarker validation;cancer biomarkers;candidate identification;candidate marker;cohort;differential expression;early detection biomarkers;exosome;extracellular vesicles;flotillin;follow-up;improved;ineffective therapies;intercellular communication;ion mobility;liquid biopsy;mass spectrometer;nanoparticle;neoplastic cell;novel;novel marker;particle;patient response;potential biomarker;protein biomarkers;protein protein interaction;random forest;sex;signature molecule;single molecule;specific biomarkers;superresolution imaging;superresolution microscopy;targeted treatment;therapy development;tool;translational applications;ultra high resolution Application of 4D proteomics and super-resolution microscopy in extracellular vesicle and particle-borne biomarker discovery for early pancreatic cancer detection Project NarrativeMounting evidence suggests that circulating extracellular vesicles and particles (EVPs) carry a variety ofbiological molecules and can serve as a reservoir of biomarkers for early cancer detection. In combination withour recently improved EVP isolation procedure and asymmetric-flow field-flow fractionation (AF4) we willfurther develop and validate the application of novel analytic technologies including timsTOF 4D proteomicmass spectrometry super-resolution dSTORM imaging analysis of single EVPs and photocatalytic proximitylabeling (Map) technology for mapping protein-protein interactions to discover and validate novel circulatingEVP-borne biomarkers for early detection of pancreatic cancer. NCI 10737386 8/31/23 0:00 PAR-20-053 2R01CA218513-06A1 2 R01 CA 218513 6 A1 "YOUNG, MATTHEW R" 7/15/17 0:00 8/31/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 6484128 "LYDEN, DAVID CHARLES" "GERI, JACOB ; ZHANG, HAIYING " 12 PEDIATRICS 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 488306 NCI 288086 200220 Project Summary/AbstractPancreatic adenocarcinoma (PDAC) ranks among the most lethal cancers due to a late diagnosis andineffective treatments. Extracellular vesicles and particles (EVPs) are secreted by most cells including tumorcells and package selective molecules including proteins lipids nucleic acids and metabolites. EVPs areactively released into the circulation and mounting evidence suggests that circulating EVPs can serve asbiomarkers for early cancer detection. Mass spectrometry (MS) has been extensively utilized for biomarkerdiscovery in liquid biopsies including EVP protein characterization. However the scope and depth of theinformation obtained is limited by (i) the sensitivity and resolution of the analytic technologies and (ii) theproteomic complexity resulting from highly abundant serum-derived contaminants. The objective of this studyis to apply an optimized reproducible EVP isolation method in conjunction with asymmetric-flow field-flowfractionation (AF4) technology to isolate EVP subsets with significantly improved purity and to employ threenovel analytic technologies including extremely sensitive timsTOF 4D proteomic MS super-resolutiondSTORM imaging analysis of single EVPs and photocatalytic proximity labeling-proteomics (Map) technologyto discover and validate novel circulating EVP protein biomarkers for early detection of PDAC. In Aim 1 byemploying the label-free timsTOF MS and using samples (blood plasma and tumor tissues) collected frompatients with newly diagnosed PDAC we will identify novel circulating EVP protein biomarkers that correlatewith early stage disease. Top-ranked candidates will be further validated by robust absolute quantitation assaysemploying targeted parallel reaction monitoring (PRM) MS. In Aim 2 we will determine the percentrepresentation and structural location of specific EVP biomarker proteins identified in Aim 1 at the single EVPlevel by utilizing the super-resolution dSTORM imaging analysis. The performance of single EVP analysis willbe compared to the bulk analysis of individual protein targets via western blotting and/or ELISA analysis. Wewill further explore the potential to apply this analytic tool directly to plasma samples without prior EVP isolation.Lastly in Aim 3 we will define protein-protein interactions (PPIs) of individual biomarkers by employing ourrecently developed photocatalytic proximity labeling-proteomics (Map) technology. Three potential biomarkercandidates identified in our previous study and novel candidates discovered in this study Aim 1 and Aim 2 willbe subjected to the PPI analysis. These interactions will be further validated by super-resolution imaginganalysis at the single-EVP single-molecule level. We will establish if the presence or absence of theseinteractions provides a more robust approach for early cancer detection. We predict that combined applicationof these technologies will greatly facilitate novel biomarker discovery for early detection of pancreatic cancer. Italso explores EVP PPIs as a new category of biomarkers and provide a rationale for developing therapiestargeting these interactive networks in the future. 488306 +No NIH Category available Ablation;Academic Medical Centers;Adjuvant;Adoption;Behavior;Bioinformatics;Biological;Biological Markers;Biometry;Biopsy;Boston;Bronchoscopy;Cancer Detection;Cancer Etiology;Cessation of life;Chest;Clinical;Data;Detection;Diagnosis;Disease;Enrollment;Excision;Gene Combinations;Gene Expression;Genomics;Goals;Health Care Costs;Histologic;Histology;Histopathologic Grade;Hospitals;Image;Indolent;Interventional radiology;Lesion;Lung;Lung Adenocarcinoma;Malignant neoplasm of lung;Measures;Medical center;Modeling;Molecular Analysis;Molecular Biology;Morbidity - disease rate;Morphologic artifacts;Neoadjuvant Therapy;Operative Surgical Procedures;Outcome;Participant;Pathologic;Pathology;Patient observation;Patient-Focused Outcomes;Patients;Performance;Prognosis;Prospective cohort;Radiology Specialty;Recurrence;Research;Resected;Risk;Sampling;Specimen;Systemic Therapy;Testing;Texture;Time;Tissues;Training;Tumor Tissue;Universities;Validation;biomarker performance;cancer subtypes;cancer survival;cancer therapy;chest computed tomography;clinical care;clinical predictors;cohort;cost;deep learning;disorder risk;high risk;high risk population;improved;individual patient;individualized medicine;lung cancer screening;molecular marker;mortality;novel;overtreatment;patient subsets;personalized management;personalized screening;predictive marker;predictive modeling;primary endpoint;prospective;radiomics;secondary endpoint;survivorship;transcriptome sequencing;treatment strategy;tumor;tumor heterogeneity Integrating imaging and biopsy-derived molecular markers for the pre-surgical detection of indolent and aggressive early stage lung adenocarcinoma PROJECT NARRATIVEThere is currently no clinically accepted way to predict a lung cancer's likely aggressiveness prior toremoving the tumor via surgery resulting in imprecise treatment. We propose to characterize theaggressiveness of early-stage lung adenocarcinoma (the most common lung cancer subtype) beforetreatment based on detailed and quantitative analysis of chest CT and molecular analysis of a smallbiopsy of the tumor obtained before surgery. The ability to determine the aggressiveness of lung cancercould facilitate treatment tailored to individual patients: improving lung cancer survival in patients withthe most aggressive tumors and decreasing complications from lung cancer treatment in patients withthe least aggressive tumors. NCI 10737330 7/10/23 0:00 PAR-22-131 1R01CA275015-01A1 1 R01 CA 275015 1 A1 "OSSANDON, MIGUEL" 7/10/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-ISB-L(59)R] 9462381 "LENBURG, MARC ELLIOTT" "MALDONADO, FABIEN " 7 INTERNAL MEDICINE/MEDICINE 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 7/10/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 704857 NCI 549573 155284 ABSTRACTLung adenocarcinoma (LUAD) is the most common lung cancer subtype diagnosed in the US; characterized bya broad spectrum of biological behaviors and clinical trajectories. Yet LUAD is managed uniformly based onclinical stage with the potential for under- and over-treatment of aggressive and indolent lesions respectively.This contributes both to suboptimal lung cancer outcomes and unnecessary morbidity mortality and healthcarecosts. While histologic grade of resected tumors correlates with patient outcome it is only available after surgicaltreatment and cannot be used to inform pre-surgery management or surgical planning. We have developed andvalidated CANARY a radiomic biomarker that predicts LUAD aggressiveness. We have further developed twogene expression biomarkers from resected FFPE Stage I LUAD for predicting indolent or aggressive tumorhistology. These gene expression biomarkers are insensitive to intratumoral heterogeneity suggesting that theymight retain good performance when measured in limited tissue available from small presurgical biopsies. Thisis potentially transformative as histologic assessment of these small biopsies is frequently insufficient forpredicting tumor aggressiveness. Our goal is to refine and validate these radiomic and gene expressionbiomarkers and then integrate them into a single model for detecting indolent and aggressive Stage I LUADwhich is supported by our preliminary data. To accomplish these goals we will prospectively enroll a cohort ofpatients undergoing transthoracic or transbronchial biopsy for suspected lung cancer and collect additionalspecimens for research. In the subset of tumors who are later resected for Stage I LUAD we will perform acentral pathologic assessment of tumor grade. Predicting tumor histologic grade at resection will be the primaryendpoint for assessing the performance of the integrated presurgical prediction model. Refinement of theradiomic biomarker will involve testing whether the addition of features extracted from the peri-nodular lung usingdeep learning can improve the prediction of the Stage I LUAD histologic grade. Refinement of the geneexpression biomarker will involve determining their performance in biopsy tumor tissue relative to resected tumortissue and optimizing the biomarkers for assessment in biopsies. Finally we will develop and assess anintegrated model combining both radiomics and gene expression. As a secondary endpoint we will comparethe association between recurrence free survival and predicted tumor grade vs. actual tumor grade at resection.An improved ability to predict tumor aggressiveness prior to treatment has the potential to transform themanagement of Stage I LUAD as it could allow clinicians and patients to confidently choose precisely tailoredtreatment. The team from Boston University Boston Medical Center Vanderbilt University Medical Center andLahey Hospital & Medical Center has the diverse expertise in lung cancer clinical care advanced bronchoscopyinterventional radiology histology pathology radiology radiomics molecular biology genomics bioinformaticsdeep learning and biostatistics required to complete this project. 704857 +No NIH Category available Adjuvant Therapy;Adult;Animals;Antibodies;Antigens;Architecture;Cephalic;Characteristics;Childhood;Clinical;Clinical Trials;Complement;Complication;Data;Detection;Development;Discrimination;Disease;Drug Kinetics;Epidermal Growth Factor Receptor;Excision;Exposure to;Eye Surgeon;FDA approved;Face;Family suidae;Fluorescence;Fluorescent Antibody Technique;Goals;Hand;Head and Neck Cancer;Heterogeneity;Human Resources;Image;Imaging Device;Indocyanine Green;Label;Lesion;Location;Malignant Childhood Neoplasm;Manuals;Metastatic Neoplasm to Lymph Nodes;Modality;Modeling;Molecular;Molecular Target;Near-infrared optical imaging;Neoadjuvant Therapy;Nerve;Neuroblastoma;Non-Malignant;Operative Surgical Procedures;Organ;Palpation;Patient-Focused Outcomes;Patients;Pediatric Neoplasm;Pentetic Acid;Performance;Perfusion;Perioperative;Primary Neoplasm;Public Health;Radiation exposure;Radio;Radioisotopes;Rattus;Regional Disease;Research;Rodent;Safety;Sentinel Lymph Node Biopsy;Site;Solid Neoplasm;Structure;Surgeon;Surgical Oncology;Systemic Therapy;Testing;Time;Tissue Model;Tissues;Tracer;Transgenic Mice;Tumor Antigens;Tumor Biology;Tumor Promotion;Visual;Visualization;Work;Xenograft procedure;cancer surgery;high risk;image guided;imaging agent;imaging system;improved;improved outcome;innovation;molecular imaging;mortality;mouse model;near infrared dye;novel;operation;pre-clinical;preservation;radiotracer;success;targeted agent;tool;tumor;tumor specificity;uptake Intraoperative dual-labeled molecular tracer to improve surgery on neuroblastoma Project Narrative. The proposed research is relevant to public health because it develops a noveland innovative approach to cancer surgery. The main goal is to improve tumor and marginidentification thereby increasing the safety and completeness of surgery for neuroblastoma toultimately improve outcomes for the most common extracranial solid tumor in children.Importantly successful completion of this work should invigorate further research in intraoperativemolecular tracer development for other adult and pediatric cancers. NCI 10737309 6/23/23 0:00 PA-20-185 1R01CA277664-01A1 1 R01 CA 277664 1 A1 "PEREZ, J MANUEL" 7/1/23 0:00 6/30/28 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 9886376 "MALEK, MARCUS M." "KOHANBASH, GARY " 12 SURGERY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 596251 NCI 424938 171313 Abstract. With a mortality rate of over 50% high-risk neuroblastoma (NB) requires improved therapy includingsafer and more complete resection of aggressive poorly circumscribed tumors and their often remote difficultto locate lymph node metastases. Thus there is a critical need for new intraoperative molecular imaging (IMI)agents that will allow identification of NB and aid in preservation of adjacent vital structures. The long-termgoal of our research is to develop an IMI tracer for use in NB (and other tumors) to improve the outcomes andsafety of surgical resection. The objective of this study is to evaluate a novel dual-labeled IMI tracer to guide NBidentification and safe resection. We therefore hypothesize that a dual-labeled IMI tracer can be optimized forintraoperative detection and safe removal of NB. The first aim will focus on optimizing a dual-labeled IMItracer specifically for intraoperative use. In the second aim tumor and tissue heterogeneity will be studied todetermine their effects on IMI tracer performance. In the final aim we will evaluate the impact of the IMI traceron extent of resection and survival in a transgenic mouse model and a rat model of NB with or withoutneoadjuvant and adjuvant therapies. If successful with the proposed studies our IMI tracer should allowsurgeons to perform safer and more complete resection of NB leading to improved patient outcomes. NB surgeryis among the most challenging operations to confront the pediatric surgeon due to extensive spread of diseaseand the intimate relationship between the tumor and normal vital structures. The surgeon faces these challengestoday with the same tools they have used for over a century visualization and manual palpation. We propose anew solution to this problem with a novel dual-labeled molecular tracer for specific detection of NB. This novelsubstantively different approach to intraoperative identification and detection of NB will enable more efficacioussurgery thereby opening new horizons in the application of IMI agents for pediatric cancer surgery. 596251 +No NIH Category available 2019-nCoV;Affinity;Albumins;Antineoplastic Agents;Antitumor Response;Binding;Biodistribution;Carcinoma;Cells;Circulation;Clinic;Clinical;Colon Carcinoma;Coupling;Data;Diagnostic;Disease;Dose;Drug Kinetics;Drug Targeting;FDA approved;FOLH1 gene;Folic Acid;Funding;Gene Targeting;Generations;Goals;Half-Life;Hour;Implant;Kinetics;Lead;Life;Ligands;Liver;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mediating;Methods;MicroRNAs;Mission;Mus;Non-Small-Cell Lung Carcinoma;Oncology;Phase;Property;Public Health;RNA;RNA Interference;RNA vaccine;Renal carcinoma;Renal clearance function;Safety;Serum;Serum Albumin;Small RNA;Specificity;Testing;Therapeutic Agents;Therapeutic antibodies;Time;Treatment Protocols;United States National Institutes of Health;Work;Xenograft procedure;cancer cell;cancer therapy;delivery vehicle;folate-binding protein;improved;in vivo;in vivo Model;malignant breast neoplasm;microRNA delivery;nuclease;overexpression;prevent;prostate cancer cell;risk mitigation;safety study;success;therapeutic RNA;therapeutic miRNA;tumor;uptake Ligand-mediated vehicle-free delivery of small RNAs PROJECT NARRATIVEThe project is relevant to the NIHs mission and to public health because successful completion of this work willfinally unveil the decade-long promise of using small RNAs as anti-cancer agents. Here we will generate smallRNA delivery vehicles with exceptional specificity and improved pharmacokinetics along with a fully modifiedversion of the notorious tumor suppressive microRNA miR-34a. Coupling these second-generation ligands thathave enhanced circulation kinetics with a stabilized version of miR-34a will finally allow for transitioningmicroRNAs successfully into the clinic in this case for treating the top two most deadliest cancers lung andprostate cancers. NCI 10737260 9/8/23 0:00 PA-20-185 2R01CA226259-06 2 R01 CA 226259 6 "FU, YALI" 4/1/18 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-BBBT-J(83)S] 10328000 "KASINSKI, ANDREA L" Not Applicable 4 BIOLOGY 72051394 YRXVL4JYCEF5 72051394 YRXVL4JYCEF5 US 40.41872 -86.910361 1481402 PURDUE UNIVERSITY WEST LAFAYETTE IN SCHOOLS OF ARTS AND SCIENCES 47906 UNITED STATES N 9/8/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 386276 NCI 250000 136276 PROJECT SUMMARYLike the challenges and skepticism that faced the antibody therapeutics field over a decade ago RNAtherapeutics is facing the same. And like the antibody therapeutics field we are beginning to realize the clinicalimpact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval oftwo mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted tothe liver. Unfortunately RNA-based drugs targeted to cancer cells is lagging behind even with countless yearsof work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in thisspace is attributed to inability to deliver RNAi safely and effectively. We previously developed a method that cansafely deliver therapeutic microRNAs (miRNAs) to tumors that overexpress the folate receptor. However theanti-tumor response was short-lived due to instability of the miRNA and poor pharmacokinetics necessitatingfrequent dosing. To overcome these insufficiencies requires a stabilized miRNA that retains targeting activity.Recently we screened a panel of fully modified versions of miR-34a (FM-miR-34a) and identified one with >400-fold increased stability and outstanding in vivo efficacy when conjugated to folate. Treatment of mice implantedwith breast cancer xenografts with folate-FM-miR-34a resulted in complete cures in two out of six mice andsignificant tumor regression in the remaining four. Based on this exciting data here we propose to advance FM-miR-34 forward in two ways. In Aim 1 we will evaluate the activity efficacy and safety profile of FM-miR-34a inin vivo models of lung and prostate cancer. FM-miR-34a will be conjugated to: i) folate for delivery to lung cancerand ii) PSMA-617 a ligand that targets prostate specific membrane antigen (PSMA) for delivery to prostatecancer. In Aim 2 we propose to capitalize on the stability afforded by FM-miR-34 to increase the circulation time of folate-FM-miR-34 and PSMA-617-FM-miR-34a though incorporating an albumin binding moiety (ABM)into the ligands. Using these ligands we will evaluate serum albumin binding and stability of the new ligands. Wewill also verify that conjugation to ABM does not alter the activity of miR-34a nor cell binding and internalizationkinetics. Finally we will assess in vivo distribution of ligand-ABM-miR-34a conjugates. At the completion of this work we expect to have an all-encompassing miRNA delivery vehicle that cantarget a stabilized tumor suppressive RNAs specifically to NSCLC and prostate cancer. We will also have newligands with increased circulation life. The data obtained will ultimately have a significant impact in cancertreatment by providing new opportunities to advance the next phase of miRNA-based therapeutics. Whileproposed for NSCLC and prostate cancer based on the utility of miR-34a for treating other cancers andoverexpression of the folate receptor alone on many epithelial cancers including ovary kidney and coloncancers successful completion of this study could have far-reaching positive consequences. 386276 +No NIH Category available B-Cell NonHodgkins Lymphoma;B-Lymphocytes;BCL2 gene;BCL6 gene;Binding;CAR T cell therapy;CRISPR correction;CRISPR/Cas technology;CXCR4 gene;Cells;Cellular biology;Classification;Clinical;Code;Disease;Down-Regulation;Enhancers;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genome;Glucocorticoid Receptor;Goals;Impairment;Link;Lymphomagenesis;Mutate;Mutation;NR3C1 gene;Nature;Oncogenes;Oncogenic;PRDM1 gene;Pathogenesis;Pathway interactions;Patients;Phenotype;Proto-Oncogenes;Recurrence;Research;Role;Site;Steroid Receptors;Taxonomy;Transcription Repressor;Untranslated RNA;cell growth;genome sequencing;large cell Diffuse non-Hodgkin's lymphoma;new therapeutic target;novel;prevent;programs;therapeutic target;tumor heterogeneity From pathogenesis to new therapeutic targets in diffuse large B cell lymphoma NARRATIVE Diffuse-Large-B-cell-lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma and remainsincurable in ~30% of patients. Coding-genome sequencing efforts identified several genes/pathways altered inthis disease including new potential therapeutic targets; however the non-coding genome of DLBCL remainslargely unexplored. This proposal builds on our recent discovery of a highly pervasive pathogenetically relevantmutational mechanism targeting super-enhancers in DLBCL that is likely to significantly influence the currentunderstanding of the somatic genetic landscape of this disease by identifying novel mechanisms ofdysregulation for known oncogenes as well as new dysregulated genes and pathways with implications forprecision classification and therapeutic targeting of DLBCL. NCI 10737214 9/12/23 0:00 RFA-CA-22-045 2R35CA210105-08 2 R35 CA 210105 8 "JHAPPAN, CHAMELLI" 9/12/23 0:00 7/31/30 0:00 ZCA1-SRB-E(M1) 1863955 "DALLA-FAVERA, RICCARDO " Not Applicable 13 PATHOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/12/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 987000 NCI 600000 387000 PROJECT SUMMARYDiffuse Large B cell Lymphoma (DLBCL) is incurable in ~30% of patients and despite recent advances in CAR-T cell therapies remains a significant clinical challenge. One barrier to rationally targeted new therapies is theremarkable heterogeneity of these tumors which leaves as many as 20-50% of cases unclassified based oncell-of-origin or more recent genetic-based classifications. This may be due in part to the fact that currenttaxonomies are limited to the analysis of coding regions representing only 3% of the genome while furthergenetic complexity of pathogenetic relevance may reside in the non-coding regulatory portion of the genome. Tothis end we recently investigated whether critical regulatory domains such as enhancers and super-enhancers(SEs) could be the site of functionally relevant mutations in DLBCL. We found that regions corresponding toactive SEs are highly and specifically hypermutated in 97% of DLBCL cases as compared to the same loci whennot active as SE. Such aberrant SE hypermutation displays signatures of AID activity and is linked to genesencoding B cell regulators and well-established oncogenes. As evidence of oncogenic relevance we showedthat the hypermutated SEs linked to the BCL6 BCL2 and CXCR4 proto-oncogenes prevent the binding andtranscriptional downregulation of the corresponding target gene by transcriptional repressors including BLIMP1(BCL6) and the steroid-receptor NR3C1 (BCL2 and CXCR4). Of note CRISPR/Cas9-mediated correction of theSE hotspot mutation restored target gene regulation and impaired cell growth indicating a key role for the SEmutation in maintaining the transformed phenotype (Bal et al. Nature 2022). Overall these findings identify ahighly pervasive pathogenetically relevant mutational mechanism that is likely to significantly influence thecurrent understanding of the somatic genetic landscape of DLBCL. The overall goal of this research program willbe to: i) identify and mechanistically dissect the top recurrently mutated/functionally relevant SEs and associatedtarget genes; ii) understand the role of the glucocorticoid receptor pathway which appears to be commonlytargeted by the SE hypermutation mechanism as well as by direct coding mutations in normal B cell biology andlymphomagenesis. We anticipate that this new layer of genetic alterations will identify novel mechanisms ofdysregulation for known oncogenes as well as new dysregulated genes and pathways with implications forprecision classification and therapeutic targeting of DLBCL. 987000 +No NIH Category available Abate;Address;Androgen Receptor;Animals;Architecture;Automobile Driving;Back;Binding;Biological Assay;Biology;Cancer Burden;Cells;ChIP-seq;Chromatin;Clinic;Clinical;Clinical Management;Combined Modality Therapy;DNA;Data;Disease;ELF3 gene;Enhancers;Exposure to;Gene Expression;Genetic Transcription;Goals;Knowledge;Malignant neoplasm of prostate;Mediating;Modeling;Molecular;Neighborhoods;Organoids;Pathway interactions;Patients;Pattern;Phase I Clinical Trials;Phase II Clinical Trials;Phenotype;Physicians;Play;Population;Pre-Clinical Model;Proteins;Proteomics;RARA gene;Reporting;Resistance;Resistance development;Resolution;Role;Scientist;Signal Transduction;Systemic Therapy;Testing;Therapeutic;Toxicology;Translating;abiraterone;addiction;advanced disease;advanced prostate cancer;antagonist;cancer cell;castration resistant prostate cancer;drug discovery;effective therapy;enzalutamide;high risk;improved;improved outcome;interest;men;multimodality;multiple omics;neoplastic cell;novel;optimal treatments;patient derived xenograft model;patient subsets;pharmacologic;pre-clinical;preclinical trial;promoter;protein expression;receptor expression;recruit;relapse patients;targeted treatment;therapeutic target;therapy resistant;transcription factor;transcriptome sequencing;transcriptomics;treatment strategy;tumor;tumor heterogeneity Therapeutic targeting of master regulators in non-canonical AR driven advanced lethal prostate cancers PROJECT NARRATIVEThe androgen receptor (AR) plays a critical role in lethal prostate cancer and despite initial clinical benefit withAR targeted therapy both intrinsic and more often acquired resistance represents a major challenge. Anemerging mechanism of acquired resistance is adaptation to non-canonical AR activity. Thus in this proposalwe will test the role of identified master regulatory TFs in modulating non-canonical AR activity that aidsenzalutamide resistance and determine optimal therapeutic options to overcome resistance using preclinicalmodels. NCI 10737204 8/10/23 0:00 PA-20-185 1R37CA272726-01A1 1 R37 CA 272726 1 A1 "GREENBERG, WILLIAM A" 8/10/23 0:00 7/31/28 0:00 "Advancing Therapeutics A Study Section +[ATA]" 77926996 "ADELAIYE-OGALA, REMI " Not Applicable 26 INTERNAL MEDICINE/MEDICINE 38633251 LMCJKRFW5R81 38633251 LMCJKRFW5R81 US 43.003074 -78.785924 5992614 STATE UNIVERSITY OF NEW YORK AT BUFFALO AMHERST NY SCHOOLS OF MEDICINE 142282567 UNITED STATES N 8/10/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 589183 NCI 393859 195324 PROJECT SUMMARY (ABSTRACT)Androgen receptor (AR) targeted therapies such as abiraterone enzalutamide apalutamide and darolutamide are effectivetreatments for patients with advanced castrate-resistant prostate cancer (CRPC). However resistance to these therapiesrepresents a significant hurdle in the clinical management of advanced CRPC. Despite initial clinical benefit most patientsrelapse with acquired resistance within a year. An emerging mechanism of acquired resistance to AR-targeted therapy is theability of tumor cells to adapt a non-canonical AR activity for survival. Preliminary suggests that increased expression of amaster regulatory transcription factor (TF) cluster (ELF3 JDP2 PBX1 RARA) is associated with the non-canonical ARactivity observed with acquired enzalutamide resistance. Interestingly expression levels of known AR partners FOXA1and HOXB13 were either unaffected or slightly decreased following exposure to enzalutamide in resistant models. ARchromatin profiling showed a unique binding pattern of AR to novel master regulatory TFs at promoter and enhancer regionsthat were absent in the presence of DHT. Preliminary data also suggests a decrease in these master TFs suppresses non-canonical AR activity and reverses acquired resistance to enzalutamide in preclinical models. The overall objective of thisapplication is to determine the role of identified master regulatory TFs on non-canonical AR activity associated withacquired enzalutamide resistance in CRPC and develop optimal therapeutic options that shift cells back to a phenotype thatis clinically manageable and re-sensitized to enzalutamide. Our central hypothesis is that non-canonical AR cistromeassociated with resistance is driven by the recruitment of novel master regulatory transcription factors. Targeting theirvulnerability can re-sensitize resistant cells to enzalutamide. The rationale is that through multimodal molecularcharacterization we can explore therapeutic options that can push back these cancer cells to a canonical AR state sensitiveto enzalutamide. We will test our central hypothesis and accomplish the objective of this application by pursuing thefollowing specific aims: (i) Multimodal characterization of non-canonical AR activity in patient-derived xenograft modelsof advanced disease. (ii) Assess the functional role of identified master regulatory TF on non-canonical AR activity. (iii)Assess the antitumor activity of candidate combination therapies in multiple PDX models and gather pharmacological andToxicology information. Impact: Results from this project will significantly expand our knowledge of the biology of lethalprostate cancer (PCa) and provide optimal treatment strategies that improve outcomes for men with lethal PCa reducingthe unequal burden of cancer. Our immediate goal is to leverage information from molecular studies to recognize the subsetof patients where resistance is driven by non-canonical AR activity using multi-omic-based markers. Furthermore our studywill provide the mechanisms and vulnerabilities of the altered AR cistrome drivers and the implications for drug discoveryand developing optimal therapeutic options for this subset of patients. Our long-term goal is to translate our preclinicalfindings into the clinic in the setting of phase I & II clinical trials. 589183 +No NIH Category available Address;Adherence;Affect;Behavioral;Behavioral Risk Factor Surveillance System;Breast Cancer Detection;Characteristics;Clinical Trials;Communication;Data;Data Set;Data Sources;Decision Aid;Decision Making;Development;Diagnostic Procedure;Early Diagnosis;Effectiveness;Eligibility Determination;Equilibrium;Female;General Population;Individual;Intervention;Left;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Medicare claim;Methodology;Methods;National Cancer Institute;National Health Interview Survey;North Carolina;Observational Study;Outcome;Outcome Assessment;Patients;Pattern;Policy Maker;Population;Population Characteristics;Procedures;Provider;Randomized;Randomized Controlled Trials;Recommendation;Registries;Research;Research Personnel;Risk Factors;Sampling;Screening for cancer;Selection Bias;Selection for Treatments;Smoking;Subgroup;Surveys;Time;United States Preventative Services Task Force;Update;Work;cancer therapy;clinical practice;colon cancer screening;cost;design;evidence base;follow-up;human old age (65+);improved;intervention effect;low dose computed tomography;lung cancer screening;mortality;novel;practice setting;randomized trial;routine screening;screening;screening guidelines;screening program;shared decision making;tool;trial enrollment;uptake Applying causal inference methods to improve estimation of the real-world benefits and harms of lung cancer screening NARRATIVERandomized controlled trials demonstrated a reduction in lung cancer mortality with annual lung cancerscreening with low dose computed tomography yet real-world populations eligible for and undergoing lungcancer screening differ substantially from trial populations. By leveraging data from a randomized controlledtrial and multiple real-world data sources the proposed study will evaluate the benefits and harms of lungcancer screening in clinical practice settings with a focus on optimizing internal and external validity byapplying novel causal inference methodologies. The proposed research is consistent with the CancerMoonshot Initiative of the National Cancer Institute which issued a call to action on cancer screening and earlydetection in February 2022. NCI 10737187 6/30/23 0:00 PAR-21-190 1R01CA277756-01A1 1 R01 CA 277756 1 A1 "SARMA, ELIZABETH ANNE" 7/1/23 0:00 6/30/28 0:00 Cancer and Hematologic Disorders Study Section[CHD] 11028143 "LUND, JENNIFER " "HENDERSON, LOUISE " 4 PUBLIC HEALTH & PREV MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PUBLIC HEALTH 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 348648 NCI 228750 119898 ABSTRACTRandomized controlled trials have demonstrated that low-dose computed tomography can substantially reducelung cancer mortality albeit at the cost of relatively high rates of false positives and complications fromdownstream procedures. However systematic differences between trial and general populations eligible forlung cancer screening raise concerns about the relevance of trial findings for guiding the development anddissemination of lung cancer screening programs in clinical practice. Despite clear recommendations from theUnited States Preventative Services Task Force lung cancer screening uptake and adherence remain low.Several studies have documented dramatic and selective attrition across the screening continuum whereabout 10-20% of eligible individuals undergo lung cancer screening and of those only about 40-60% are up-to-date with their annual screening at 15 months. When the benefits and harms of an intervention vary acrosssubgroups and there is selective attrition the balance of population-level benefits and harms is expected tochange. As such there is an urgent need to better characterize the effectiveness of lung cancer screening withlow-dose computed tomography when applied to individuals outside of clinical trial settings. The primaryobjective of this proposal is to generate real-world evidence of the benefits and harms of lung cancer screeningwith low-dose computed tomography that explicitly considers the characteristics of populations at each step ofthe screening continuum from the screening-eligible to the screened to the adherent. To address thisobjective we will use cutting-edge causal inference methods including trial transport and target trial emulationusing real-world data which can avoid the potential for time-related biases. To carry-out our proposedanalyses we will draw upon individual-level data from the randomized National Lung Screening Trial as wellas four real-world datasets including the National Health and Interview Survey the Behavioral Risk FactorsSurveillance Survey (Lung Cancer Screening Module) a 20% nationwide sample of Medicare claims and theNorth Carolina Lung Screening Registry. Findings from this study will generate information about theeffectiveness of lung cancer screening in real-world settings that can be used by patients providers andpolicymakers. This work will enhance the evidence base used by policymakers to update screeningrecommendations and refine decision aids to support communication with patients about screening net-benefits during shared decision-making. Ultimately this work will support efforts to improve the delivery of lungcancer screening at the population level. 348648 +No NIH Category available Address;Adipocytes;Adipose tissue;Affect;Biochemical;Bioinformatics;Biology;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Breast cancer metastasis;Calibration;Cancer Burden;Cancer Prognosis;Cause of Death;Cell Culture Techniques;Cells;Coculture Techniques;Computer Models;Computer Simulation;Computing Methodologies;Coupled;Couples;Coupling;Data;Data Set;Deposition;Disparity;Elements;Engineering;Extracellular Matrix;Frequencies;Gene Expression;Gene Expression Profile;Genetic;Histologic;Histology;Human;Inflammatory;Invaded;Ligands;Link;Lipids;Malignant Neoplasms;Mammary gland;Mechanics;Methods;Modeling;Molecular;Myofibroblast;Neoplasm Metastasis;Obesity;Obesity Epidemic;Pathogenesis;Pathologic;Patients;Phenotype;Play;Prevalence;Process;Prognosis;Property;RNA;Role;Sampling;Shapes;Specimen;Technology;Testing;Thinness;Time;Tissues;Transgenic Mice;Tumor Cell Invasion;Tumor Promotion;Visualization;Work;adipokines;advanced breast cancer;biological systems;biophysical properties;cell motility;clinically relevant;computer studies;effective therapy;experimental study;genetic signature;improved;in vivo;insight;interstitial;malignant breast neoplasm;mechanical properties;mouse model;neoplastic cell;novel;obese patients;obese person;particle;patient prognosis;physical property;receptor;risk prediction;simulation;transcriptome sequencing;transcriptomics;transdifferentiation;tumor;tumor metabolism Mechanical properties of adipose tissue and its effect on breast cancer PROJECT NARRATIVEMetastasis is the leading cause of death in patients with advanced breast cancer and increases in frequencywith obesity; however the underlying mechanisms that cause breast cancer metastasis remain unclear. Byiteratively coupling computer simulations experiments and advanced omics approaches the proposed studieswill improve understanding of how obesity-dependent changes in breast adipose tissue mechanical propertiesregulate breast cancer invasion and metastasis and link these changes to targetable cellular mechanisms. Thegenerated new insights have the potential to decrease breast cancer burden associated with the obesityepidemic in the U.S. NCI 10737165 9/12/23 0:00 PA-20-185 1R01CA276392-01A1 1 R01 CA 276392 1 A1 "JOHNSON, ERIC MICHAEL" 9/12/23 0:00 8/31/28 0:00 Modeling and Analysis of Biological Systems Study Section[MABS] 9205867 "FISCHBACH, CLAUDIA " "HORSLEY, VALERIE ; O'HERN, COREY " 19 ENGINEERING (ALL TYPES) 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY BIOMED ENGR/COL ENGR/ENGR STA 148502820 UNITED STATES N 9/12/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 530974 NCI 430001 100973 PROJECT SUMMARYWe recently discovered an unexpected and intriguing role for white adipose tissue (WAT) in breast cancer. Ourpast studies identified that the mechanical properties of WAT extracellular matrix (ECM) regulate tumor cellinvasion a key rate-limiting step of metastasis and that these properties are altered in obesity contributing tothe increased prevalence and worse prognosis of breast cancer in obese patients. Now recent preliminary datafrom our labs additionally suggest that adipocyte mechanical properties may be similarly important. Howeverhow adipocyte mechanics change with obesity and which effect these changes have on ECM remodeling andtumor invasion remains largely unclear. Understanding these connections is important for several reasons: Firstwhile the biochemical functions of WAT are widely known to contribute to the pathogenesis of breast cancer theinfluence of WAT mechanical properties on breast cancer invasion is largely unexplored. Second our preliminarydata suggest that aberrant remodeling of WAT in obese individuals promotes breast cancer invasion due toadipocyte lipid loss transdifferentiation into myofibroblasts and consequential changes in ECM deposition all ofwhich affect WAT mechanics. Last our preliminary results also indicate that tumor-induced lipid loss maysynergistically promote invasion by changing WAT mechanical properties and tumor cell metabolism. Elucidatinghow these parameters are interconnected will be critical to decrease breast cancer burden and requirescomputational methods to uncover how single-cell properties of adipocytes and tumor cells affect WATmechanics and tumor cell invasion. Through three focused and complementary Specific Aims the proposedwork iteratively couples computational models of tumor cell invasion into WAT materials characterization ofadipocytes and ECM engineered cell culture models and transgenic mouse models that allow visualization andmanipulation of WAT in the mammary gland. Furthermore single cell and spatial RNA transcriptomics coupledwith advanced bioinformatics approaches and human specimens will determine the associated molecularmechanisms and potential value to patient prognosis. In particular we will (1) define WAT physical properties inthe breast as a function of obesity and determine their effect on tumor invasion (2) determine the synergisticeffect of tumor-induced lipid loss on WAT physical properties and tumor cell metabolism and (3) establish themolecular basis of tumor-induced lipid loss in lean versus obese adipocytes and determine their effect on WATphysical properties and tumor invasion. These studies will identify specific obesity-dependent changes in WATmechanical properties and their associated molecular mechanisms that will help predict the risk of breast cancerinvasion for a given patient based on histological analysis. 530974 +No NIH Category available 3-Dimensional;Animals;Antitumor Response;Autoimmune Diseases;Biological;Biological Assay;Blood;Breast;Cancer Detection;Cancer Model;Cations;Cells;Cellular Assay;Clinical Trials;Complex;Data;Detection;Diagnostic;Diagnostic Imaging;Disease;Disease Progression;Dissociation;Dose;Effectiveness;Encapsulated;Exclusion;Flow Cytometry;Fluorocarbons;Formulation;Future;Growth;Half-Life;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Hydrophobicity;Image;Immune checkpoint inhibitor;Immunooncology;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Vitro;Incidence Study;Inflammation;Inflammatory;Intervention;Intravenous;Label;Laboratories;Lipids;Macrophage;Malignant Neoplasms;Measurement;Metals;Methods;Modeling;Molecular Probes;Mus;Nature;Neoplasm Metastasis;Non-Invasive Detection;Oils;Phagocytes;Phase;Phenotype;Play;Positron-Emission Tomography;Prediction of Response to Therapy;Prognosis;Proteins;Radiochemistry;Radiopharmaceuticals;Reproducibility;Residual state;Reticuloendothelial System;Rodent;Rodent Model;Role;Signal Transduction;Site;Solid Neoplasm;Surface;Suspensions;Technology;Therapeutic;Toxic effect;Treatment Efficacy;Tumor Markers;Tumor-associated macrophages;Vesicle;Water;Zirconium;acute infection;angiogenesis;anti-cancer therapeutic;bioluminescence imaging;cancer clinical trial;cancer imaging;chelation;clinical translation;detection sensitivity;diagnostic biomarker;dosimetry;imaging biomarker;imaging probe;imaging study;improved;in vivo;intravenous injection;mouse model;nanoemulsion;non-invasive imaging;novel;novel diagnostics;patient stratification;personalized medicine;pre-clinical;preclinical study;predicting response;predictive marker;response;scale up;targeted treatment;therapy resistant;translational potential;treatment response;tumor;tumor microenvironment Metallo-fluorocarbon nanoemulsion for PET detection of cancer inflammation In cancer tumor inflammation plays a multifaceted role in disease progression and response to therapies. Theability to non-invasively image tumor inflammation would greatly enhance our ability to stratify patients fortreatments. This project will develop and characterize novel diagnostic imaging radiopharmaceutical agents thatenable sensitive and precise quantification of tumor inflammation in vivo. NCI 10737153 5/31/23 0:00 PA-20-185 1R01CA279271-01A1 1 R01 CA 279271 1 A1 "TANDON, PUSHPA" 6/1/23 0:00 5/31/27 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 1970914 "AHRENS, ERIC T." Not Applicable 50 RADIATION-DIAGNOSTIC/ONCOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 655698 NCI 414999 240699 In cancer macrophages play a multifaceted role in disease progression and response to therapies. Tumor-associated macrophages (TAMs) serve several pro-tumoral functions including the expression of factorspromoting growth immune suppression and angiogenesis. A high TAM burden in the tumor microenvironmentis often associated with poor prognosis and therapeutic resistance to certain immunotherapies. Moreover TAMsare emerging as a target for anti-cancer therapeutics. Overall an imaging probe that can non-invasively detectTAM burden could help stratify patients and personalize treatments to improve response rates. Recently ourlaboratory has developed novel molecular probes enabling sensitive and precise imaging of inflammatory foci invivo. We synthesized functionalized fluorocarbon nanoemulsions incorporating a fluorous-encapsulatedradiometal chelate (FERM). Pre-formed FERM nanoemulsion rapidly captures zirconium-89 into the fluorousphase. The highly hydrophobic nature of fluorocarbons helps exclude competition from water cations lipids andproteins that contribute to the dissociation of 89Zr from the carrier. By encapsulating the radiometal inside thevolume of nanoemulsion droplet one can achieve a high payload and cell detection sensitivity with lowbackground. Following an intravenous injection of FERM nanoemulsion droplets are scavenged by phagocyticmacrophages. The labeled cells accumulate at inflammatory sites resulting in sensitive and quantifiable positronemission tomography (PET) signals reflecting predominantly macrophage burden. Preliminary PET results fromour lab demonstrate excellent sensitivity and versatility of the FERM probe in a diversity of inflammation rodentmodels including solid tumor acute infection and autoimmune disease. Building on these results our projecthas three Aims: Aim 1. 89Zr FERM formulation. We will perform FERM nanoemulsion formulation optimizationand scale-up. We will also develop optimal radiopharmacy methods to maximize labeling efficiency of FERMand product yield. Aim 2. Biological characterizations. Cell-based assays will be performed to evaluatepotential toxicity of 89Zr FERM. Moreover we will characterize the in vivo blood half-life probe stability andpreliminary dosimetry. Aim 3. In vivo immuno-oncology studies. We will characterize the effectiveness ofFERM for TAM detection and quantification responsiveness to treatments that deplete TAM burden and theprobes potential for predicting response to immunotherapeutic interventions in multiple murine solid tumormodels. Parallel phenotypic profiling of FERM-labeled cells in the tumor will be performed. The proposed studieswill generate essential data needed to drive potential clinical translation of the FERM imaging biomarker for usein future immuno-oncology clinical trials. 655698 +No NIH Category available Acoustics;Address;Affect;Algorithms;Anxiety;Area;Benign;Biopsy;Classification;Clinical;Collaborations;Cytology;Data;Detection;Discriminant Analysis;Disease;Disease Management;Disseminated Malignant Neoplasm;Evaluation;Excision;Fine needle aspiration biopsy;Foundations;Image;Lead;Light Microscope;Lymph Node Tissue;Lymphoma;Magnetic Resonance;Medical;Medicine;Metastatic Neoplasm to Lymph Nodes;Methods;Micrometastasis;Microscopic;Modeling;Neoplasm Metastasis;New York;Nonmetastatic;Operating Rooms;Operative Surgical Procedures;Outcome;Pathologist;Patient Recruitments;Patients;Performance;Procedures;Process;Property;Prostate;ROC Curve;Research;Research Personnel;Research Project Grants;Risk;Signal Transduction;Slice;Slide;Specimen;Staging;Surgical Pathology;System;Testing;Thyroid Gland;Time;Tissues;Ultrasonics;Universities;Validation;artificial neural network;attenuation;cost;data acquisition;electric impedance;improved;in vivo;in vivo evaluation;instrument;instrumentation;laptop;lymph node biopsy;lymph nodes;patient population;personalized care;quantitative ultrasound;side effect;standard of care;statistics;support vector machine;synergism;time use;tool;treatment planning;ultrasound;virtual In vivo Evaluation of Lymph Nodes Using Quantitative Ultrasound NarrativeReliable evaluation of lymph nodes (LNs) is essential for proper disease management. However current non-invasive methods cannot reliably distinguish metastatic LNs from non-metastatic LNs. The proposed study willdevelop low-cost in-vivo ultrasonic instrumentation for more-reliable metastasis detection and hence forimproved staging and treatment of disease. NCI 10737152 8/2/23 0:00 PA-20-185 1R01CA277038-01A1 1 R01 CA 277038 1 A1 "SALVADOR MORALES, CAROLINA" 8/2/23 0:00 7/31/28 0:00 Imaging Technology Development Study Section[ITD] 8467008 "MAMOU, JONATHAN " Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 8/2/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 735941 NCI 521766 214175 Project SummaryThis application proposes a collaborative study to be performed by Weill Cornell Medicine (WCM) in NewYork NY as the lead organization in collaboration with GE Research (GER) in Niskayuna NY and StonyBrook Medicine (SBM) affiliated with the State University of New York in Stony Brook NY. The proposedproject addresses the need for reliable highly sensitive means of detecting metastases to lymph nodes(LNs) and distinguishing them from primary lymphomas and LNs affected by benign conditions. Thiscapability will allow improved staging and treatment of disease. Accordingly we seek to validate existingencouraging results obtained in prior studies by WCM and SBM using quantitative-ultrasound (QUS)methods to detect metastases in LNs by applying and evaluating these promising methods using amodified clinical scanner to acquire ultrasonic echo-signal data from patients undergoing medicallyrequired ultrasonically guided fine-needle aspirations (FNAs) of suspicious LNs. The study will include afar broader range of disease types from a larger and more-diverse patient population than has beenpossible in studies to date. Validation efforts will develop deploy and validate an application for QUS-based detection and characterization of LNs implemented in a clinical scanner. Successful validation willestablish a foundation for incorporation of QUS-based methods for LN evaluation into clinical ultrasonicscanners. Such instruments will be able to evaluate suspicious LNs intra-operatively in the operating roomor pre-operatively in the examination room. The collaborating researchers will synergize capabilities in thefollowing general ways: WCM will provide project oversight and coordination and will apply refine and testQUS and classification methods; GER will provide ultrasound instrumentation and will develop andvalidate the QUS application for the scanner; SBM will recruit patients and acquire ultrasonic andcytopathological data from patients undergoing FNAs of their LNs. 735941 +No NIH Category available Affect;Amino Acids;Anatomy;Animals;Antibiotics;Aspartic Acid;BCG Live;BCG Vaccine;Bacillus Calmette-Guerin Therapy;Behavior;Biodistribution;Biological Assay;Biological Markers;Bladder;Bladder Neoplasm;Bypass;Cancer Patient;Catheterization;Catheters;Charge;Chemicals;Combined Modality Therapy;Data;Deposition;Diagnosis;Disease;Disease Management;Doxorubicin;Drug Carriers;Drug Delivery Systems;Drug Kinetics;Excision;Excretory function;Goals;Hospital Costs;Human;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunotherapy;Implant;Infection;Infective cystitis;Infusion procedures;Intravenous;Kidney;Length;Liver;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Microtubules;Mitomycins;Morbidity - disease rate;Mus;Operative Surgical Procedures;Optics;Organ;Outcome;Output;Pain;Patients;Peptides;Pharmaceutical Preparations;Pharmacotherapy;Procedures;Property;Quality of life;Radical Cystectomy;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Renal clearance function;Residual Cancers;Reticuloendothelial System;Serine;Spleen;Surface;Survival Rate;Symptoms;System;Techniques;Therapeutic Studies;Time;Toxic effect;Transitional Cell Carcinoma;Treatment Efficacy;Treatment outcome;Treatment-related toxicity;United States Food and Drug Administration;Urinary system;Urinary tract;Urine;Urothelium;X-Ray Computed Tomography;absorption;analog;cancer cell;cancer recurrence;cancer therapy;chemotherapy;clinical translation;combinatorial;comparative;compliance behavior;cost;design;digital;flexibility;functional group;high risk;immune cell infiltrate;improved;improved outcome;in vivo;inhibitor;interest;intravesical;minimally invasive;mortality;muscle invasive bladder cancer;non-muscle invasive bladder cancer;novel;novel strategies;pembrolizumab;peptide analog;precision drugs;preclinical study;preservation;protein aminoacid sequence;standard care;survival outcome;translational study;treatment duration;treatment response;tumor;tumor microenvironment;uptake;urinary An urinary drug disposing approach for treatment of bladder Cancer Project Narrative Intravesical chemotherapy for bladder cancer is unreliable and limited by incomplete drug delivery andinvasiveness. The goal of this project is to develop an urgently needed new approach that will improve outcomeswith a novel combinatorial treatment that covers the entire urinary system prolonging exposure of tumors todrugs while using low-morbidity administration techniques. NCI 10737090 7/13/23 0:00 PA-20-185 1R01CA276506-01A1 1 R01 CA 276506 1 A1 "FU, YALI" 7/13/23 0:00 6/30/28 0:00 Drug and Biologic Therapeutic Delivery Study Section[DBTD] 9199113 "LAW, BENEDICT SHEK HANG" Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 7/13/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 665916 NCI 414999 250917 Project Summary Most bladder cancer (BC) patients are diagnosed at an early stage. More than 80% of cases are non-muscleinvasive BC (NMIBC). The standard treatment involves removing the tumors surgically followed by intravesicalimmunotherapy bacillus Calmette-Gurin (BCG) or intravesical chemotherapy (ITC) to eradicate residualcancer cells. This involves direct instillation of the BCG or drug solution into the bladder via a catheter. Howeverthe cancer recurrence rate is still unacceptably high (50-80%). On the other hand there is a growing interest inpreserving the bladders of muscle invasive BC (MIBC) patients who are ineligible for radical cystectomy withITC. BCG and ITC have limitations. The treatments are local. The drug solution is unable to reach tumors locatedin the upper urinary tract. Patients often need to void shortly after drug administration. The catheterizationprocedure is invasive which can potentially cause infection and urinary symptoms resulting in poor patientcompliance. Currently there is also a shortage of BCG. The goal of this project is to develop an approach tocounter the significant drug delivery obstacles of BC therapy to improve treatment and survival outcomes. Apeptides rapid renal clearance can be advantageous for directing treatments to the urinary system (URS). Wepropose a bio-inert peptide (Bdd) to overcome the drug-delivery barriers. Bdd can be given intravenously ratherthan intravesically. The use of Bdd as a carrier was shown to promote drugs such as mertansine (DM1) anddoxorubicin (DOX) to be eliminated exclusively via renal clearance with minimalif not undetectabledeposition in major organs. We hypothesize that this platform used as an alternative to ITC will offer an urgentlyneeded treatment that is more complete and effective. The advantages of such a urinary drug disposing (UDD)system include: (1) continuous drug flow throughout the entire URS (2) prolongation of bladder-dwelling time(treatment duration) and (3) minimally invasive application. If successful this approach will also avoidcatheterization improve patient quality of life and reduce hospitalization costs. Our Specific Aims will focus onpreclinical and translational studies to: (Aim 1) investigate the desired physicochemical properties (includingfunctional group length and surface charges) and administration parameters (infusion rate and volume) of anewly developed Bdd analogue Bds with an improved UDD property for precision drug delivery to the URS;and (Aim 2) evaluate the therapeutic efficacy and anatomic flexibility of a DM1-Bds conjugate for BC treatment.We will assess DM1-Bds alone or in combination with pembrolizumab an immune checkpoint inhibitor approvedby the Food and Drug Administration for treating both NMIBC and MIBC. Immune profiling will address the anti-tumor activities. This information will be crucial for significantly improving treatment outcomes. With additionaladvancements we also foresee our UDD approach will be unusually transposable and useful for treating otherdiseases (e.g. bladder infections) simply by replacing the drugs attached to the peptide sequence withantibiotics. 665916 +No NIH Category available Age;Antineoplastic Agents;Automobile Driving;Biochemical;Biology;Categories;Cell Culture Techniques;Cell Death;Cell Line;Child;Chromatin Remodeling Factor;Clinic;Clinical;Clinical Trials;Code;Combination Drug Therapy;Complex;DNA Damage;Data;Databases;Deposition;Development;Diagnosis;Disease;Employment;Event;Funding;Gene Fusion;Genes;Genetic;Grant;Immunotherapy;Light;Malignant Neoplasms;Mediating;Modeling;Mus;Mutation;Neoplasm Metastasis;Oncogenic;Organoids;Pathway interactions;Patients;Pharmacologic Substance;Phosphotransferases;Post-Translational Protein Processing;Prognosis;Proteins;Proteome;Proteomics;Recurrence;Refractory;Research Design;Research Personnel;Role;SMARCE1 gene;Safety;Series;Small Interfering RNA;Soft tissue sarcoma;Sumoylation Pathway;Survival Rate;Systemic Therapy;Teenagers;Testing;Therapeutic;Toxic effect;Translating;Translations;addiction;chemotherapy;clinically actionable;combat;efficacy testing;expectation;experimental study;in vivo;inhibitor;innovation;insight;kinase inhibitor;knock-down;member;mortality;mouse model;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;pharmacologic;pre-clinical;preclinical study;restoration;sarcoma;standard of care;stem;success;synovial sarcoma;targeted treatment;transcriptome;tumor;tumor growth;whole genome;young adult SUMOylation disruption is toxic for SS18-SSX-driven synovial sarcoma Project NarrativeSynovial sarcoma (SS) is an aggressive malignancy driven by the SS18-SSX oncofusion that is refractory tochemotherapy leading to a high mortality rate. Here we identify a remarkable therapeutic vulnerability to bothgenetic and pharmaceutical disruption of the SUMOylation pathway including with the in-clinic SUMOylationinhibitor TAK-981 that is dependent on SS18-SSX. We provide data the mechanistic basis is throughdeSUMOylation-mediated re-distribution of BAF complexes leading to DNA damage cell death and franktumor regressions in mouse models of SS. NCI 10736999 8/2/23 0:00 PA-20-185 1R01CA272710-01A1 1 R01 CA 272710 1 A1 "GREENBERG, WILLIAM A" 8/2/23 0:00 7/31/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 10310162 "FABER, ANTHONY CHARLES" Not Applicable 4 DENTISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF DENTISTRY/ORAL HYGN 232980568 UNITED STATES N 8/2/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 571084 NCI 426819 144265 Project Summary:Synovial Sarcoma (SS) is driven by the SS18-SSX oncofusion and SS18-SSX is the only reoccurring mutationin SS. SS normally metastasizes resulting in a 15-year overall survival rate of less than 50%. This presents aparticular problem as 1/3 of the patients that are diagnosed are under the age of 30. Polychemotherapy has amodest and variable effect on patients immunotherapy activity is unremarkable and there are currently notargeted therapy options to combat SS. SS18-SSX remains undruggable despite clearly being the driving eventin these cancers. Thus SS requires entirely new therapeutic approaches. In light of this we tried to identifypotential novel therapies by assessment of full genome short-interfering (si)-RNA screen data deposited into theDepMap database and subsequent cell culture experiments with SS cell lines and patient-derived xenograft cellcultures. Through these efforts we have identified a clinically actionable synthetic lethality with SSX-SS18 in SSnamely disruption of the post-translational modification SUMOylation. We find SS18-SSX activates theSUMOylation and disruption of this pathway with the in-clinic SUMOylation inhibitor TAK-981 disrupts SS18-SSX function induces DNA damage and shrinks SS tumors in mice.Specific AimsSpecific Aim 1: Test a diverse set of synovial sarcoma mouse models for efficacy and safety of SUMOylationinhibitionSpecific Aim 2: Investigate the relationship between SS18-SSX and the SUMOylated proteome in synovialsarcomaStudy Design: We will further characterize the sensitivity of TAK-981 (alone and with chemotherapy and BRD9degrader) in SS cell culture models including patient-derived organoids and in vivo in orthotopic patient-derivedxenograft (PDX) models and genetic mouse models of SS. Through a series of proteomic and biochemicalexperiments we will further categorize the mechanism of SS18-SSX-dependent toxicity stemming fromdisruption of the SUMOylation pathway. We will further examine the role of SS18-SSX in activating theSUMOylation pathway and the mechanism of action of TAK-981 in SS which involves disrupting the SS18-SSX-ncBAF transcriptome. In all we will attempt to gather the preclinical evidence supporting the translation ofSUMOylation inhibitors to treat SS. 571084 +No NIH Category available Address;Alpha Particles;Beta Particle;Biological Markers;Biopsy Specimen;Blood specimen;Cancer Patient;Cells;Circulation;Clinical;Clinical Research;Clinical Trials;Clone Cells;Combination immunotherapy;Combined Modality Therapy;Development;Dose;External Beam Radiation Therapy;FOLH1 gene;Future;Granzyme;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunologics;Immunosuppression;Immunotherapy;In Vitro;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Modality;Molecular Target;Multiplexed Ion Beam Imaging;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Outcome;Patient Selection;Patients;Phase;Phase II Clinical Trials;Phase III Clinical Trials;Phase Ib Trial;Population;Positron-Emission Tomography;Pre-Clinical Model;Progression-Free Survivals;Proteomics;Radiation;Radiation therapy;Radioimmunotherapy;Reporting;Research Personnel;Role;Schedule;Spatial Distribution;T cell receptor repertoire sequencing;T cell response;T-Lymphocyte;Techniques;Testing;Time;Translating;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Visualization;advanced prostate cancer;anti-PD-1;castration resistant prostate cancer;checkpoint inhibition;clinical effect;clinical efficacy;exhaustion;immunogenic;immunogenic cell death;immunogenicity;immunoregulation;improved;improved outcome;in vivo;men;microscopic imaging;mouse model;multiple omics;new therapeutic target;novel;novel strategies;particle;patient biomarkers;pembrolizumab;pre-clinical;preclinical study;prospective;pyrrolidin-3-yl-methanesulfonic acid;radioligand;radiotracer;randomized trial;response;single cell analysis;single-cell RNA sequencing;targeted treatment;translational study;treatment strategy;tumor;tumor microenvironment;tumor-immune system interactions Combining immunotherapy with molecularly targeted radiation therapy PROJECT NARRATIVERadiation therapy is being studied as an approach to enhance immunotherapy; however the optimal approachto combine these modalities is unknown. The successful outcome of this proposal will result in dissecting theimmunogenic impact of various forms of systemic radioligand therapy as a means to enhance response toimmune checkpoint inhibition. While this project focuses on advanced prostate cancer this novel combinationtreatment strategy could ultimately translate into improved outcomes with immunotherapy in other cancers. NCI 10736873 6/28/23 0:00 PAR-21-033 1R01CA276785-01A1 1 R01 CA 276785 1 A1 "VIKRAM, BHADRASAIN" 8/1/23 0:00 7/31/28 0:00 Clinical Oncology Study Section[CONC] 1953991 "FONG, LAWRENCE " "AGGARWAL, RAHUL ; EVANS, MICHAEL JOHN" 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 663343 NCI 410739 252604 PROJECT SUMMARY/ABSTRACTImmune checkpoint inhibitors (ICI) have limited single agent activity in metastatic castration resistant prostatecancer (mCRPC) in part related to the low number of tumor-infiltrating lymphocytes (TILs) relative to moreresponsive tumor types. Radiation therapy (RT) may enhance immunotherapy by either enhancing priming of animmune response and/or resetting the immunosuppressive tumor microenvironment to enhance effectorfunction. Understanding the mechanisms by which RT can enhance immunotherapy in mCRPC is a significantunmet need. Using single cell RNA sequencing (scRNAseq) we have found that external beam RT induces thewholesale replacement of preexisting T cell clones with novel clonotypes in the prostate cancer tumormicroenvironment consistent immunologic priming. This treatment however also induces novel myeloid stateswithin the tumor microenvironment that may mediate immunosuppression and dampen the newly primed T cells.We hypothesize that molecularly-targeted radioligand therapy may induce immunologic priming withoutinducing the concomitant immunosuppression seen with external beam radiation. In prostate cancer the beta-particle emitting 177Lu-PSMA-617 which targets prostate specific membrane antigen (PSMA) represents anemerging treatment of mCRPC. However the optimal schedule and form of radioligand therapy to achieve anoptimal immunogenicity remains to be elucidated. In Aim 1 we will use multi-omic single cell analyses(scRNAseq T cell receptor sequencing and single cell proteomics) to dissect the treatment induced changesin immune effectors and regulatory cell states both within the TME and circulation of mCRPC patients treatedon our phase 1b trial with pembrolizumab and one dose of 177Lu-PSMA-617. In Aim 2 we will perform aprospective investigator-initiated phase 2 clinical trial combining pembrolizumab with repeated dosing of 177Lu-PSMA-617 where subsequent doses of 177Lu-PSMA-617 are triggered at the time of PSA progression to rescueanti-tumor immunity. In Aim 3 we define the immunogenic impact of beta- (177Lu) vs. alpha- (225Ac) particleemitting therapy and external beam radiation therapy to help guide future trials of radioimmunotherapy. With this proposal we seek to advance the field of immunotherapy in prostate cancer in several importantways by: 1) determining the optimal schedule and form of radiation to prime anti-tumor immunity 2) developinga novel approach to functionally and quantitatively visualize immune response through granzyme B PET 3)understanding the role of treatment-induced myeloid cells in modifying T cell states 4) developing biomarkersthat will enable patient selection in future trials and 5) identifying novel therapeutic targets on myeloid and/or Tcells to enhance the efficacy of radioimmunotherapy. 663343 +No NIH Category available 2-tyrosine;Acute;Acute leukemia;Adult;Affect;Antineoplastic Agents;Binding;Biological Markers;Cell Line;Childhood Leukemia;Chronic;Circulation;Clinical;Combined Modality Therapy;Data;Dependence;Disease;Dose;Dose Limiting;Drug Kinetics;Drug Prescriptions;Etiology;Event;Experimental Models;FDA approved;Future;Genetic;Goals;Human;Image;In Vitro;Incidence;Intervention;Investigation;Kyocristine;LYN gene;Lead;Leukemic Cell;Libraries;Link;Malignant - descriptor;Measures;Mediating;Microtubules;Modeling;Mus;Neurons;OATP Transporters;Oncology;Outcome;Pathway interactions;Peripheral;Peripheral Nerves;Peripheral Nervous System Diseases;Phosphotransferases;Phylogenetic Analysis;Plasma;Prevention strategy;Preventive treatment;Process;Property;Proteomics;Quality of life;Regimen;Rifampin;Safety;Sampling;Schedule;Severities;Solid Neoplasm;Specificity;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spinal Ganglia;Testing;Therapeutic;Time;Toxicokinetics;Treatment Protocols;Tyrosine Kinase Inhibitor;Tyrosine Phosphorylation;Validation;Vinca Alkaloids;Vincristine;Vitamin E;Wild Type Mouse;Work;Xenobiotics;access restrictions;acute leukemia cell;alpha Tocopherol;anti-cancer;biomarker driven;biomarker performance;clinical implementation;combinatorial;companion diagnostics;cytotoxic;efficacy evaluation;future implementation;improved;in vivo;in vivo evaluation;inhibitor;insight;leukemia;metabolomics;mouse model;negative affect;neuronal transport;neuroprotection;neurotoxicity;novel;overexpression;pharmacologic;preservation;prevent;side effect;specific biomarkers;uptake;validation studies Targeting neuronal transport to ameliorate vincristine neurotoxicity Project NarrativeThe microtubule-binding agent vincristine is among the most effective and widely prescribed anticancer agentsbut its clinical use is associated with dose-limiting damage to peripheral neurons (neurotoxicity). Using uniquegenetic mouse models we found that acute and chronic forms of neurotoxicity caused by vincristine aredependent on an uptake process in neurons that is mediated by the transporter OATP1B2 (in humansOATP1B3). The proposed studies are a logical continuation of our mechanistic studies and will directly test thehypothesis that targeted interference of OATP1B2 and OATP1B3 with pharmacological inhibitors can mitigatethe incidence and severity of this debilitating side effect without affecting the agents anticancer properties. NCI 10736789 7/11/23 0:00 PAR-21-329 1R01CA272254-01A1 1 R01 CA 272254 1 A1 "ALTSHULER, RACHEL DINA" 7/11/23 0:00 6/30/28 0:00 Drug Discovery and Molecular Pharmacology B Study Section[DMPB] 14307048 "HU, SHUIYING " "BAKER, SHARYN D; PETERSON, BLAKE " 3 PHARMACOLOGY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF PHARMACY 432101016 UNITED STATES N 7/11/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 645896 NCI 410093 235803 AbstractMicrotubule-binding chemotherapeutics such as vincristine are among the most widely used anticancer agentsin oncology for the treatment of multiple solid tumors and leukemias in children and adults. The clinical use ofvincristine is associated with a debilitating dose-limiting peripheral neurotoxicity for which no effectivepreventative treatments are presently available. In addition the mechanism by which vincristine accumulatesinto dorsal root ganglion (DRG) neurons remains unclear to this day. Using a transporter screen of xenobioticuptake carriers in heterologous overexpressed models we recently found that the organic anion transportingpolypeptide OATP1B3 (in mice OATP1B2; collective referred to as OATP1B2/3) is an efficient transporter ofvincristine that is expressed in human and mouse DRG neurons. Functional validation studies in OATP1B2-deficient mice and secondary screens confirmed that vincristine is transported into DRG neurons by OATP1B2.Furthermore deficiency of OATP1B2 protected mice from vincristine-related changes in various hallmarks ofperipheral neurotoxicity without altering the plasma levels of vincristine. To provide proof-of-principle anddemonstrate translational relevance of this transport mechanism we found that several knownpharmacological inhibitors of OATP1B including rifampin and the tyrosine kinase inhibitor nilotinib canpreserve DRG neuronal function following treatment with vincristine without affecting its plasma levels or itscytotoxic potential against multiple acute leukemia cell lines. Finally we identified -tocopherol (vintamin E) asa previously unrecognized biomarker of neuronal OATP1B2/3 function that can be measured in the systemiccirculation and we validated the translational utility of this biomarker in a mouse model receiving treatmentwith OATP1B inhibitors. Based on these preliminary findings we now outline three sets of related studies thatwill further test and refine the validity of our central hypothesis that targeted modulation of OATP1B2/3 functionwith optimized doses and schedules of novel OATP1B2/3 inhibitors can specifically affect accumulation ofvincristine in DRG neurons and affect downstream toxic events without negatively influencing its plasmapharmacokinetic profile or anti-leukemic properties: (i) mechanistic characterization of nilotinib as the proof-of -principle OATP1B inhibitor and identification and validation of additional modulators derived from a libraryscreen that includes FDA-approved agents; (ii) biomarker-driven optimization using -tocopherol as acompanion diagnostic to guide dose selection of OATP1B modulators for in vivo testing; and (iii) safety andefficacy analyses of optimized combinatorial regimens of OATP1B inhibitors with vincristine includingsimultaneous assessment of neuroprotection and anti-leukemic properties in established experimental modelsof acute leukemia. It is expected that these collective studies will not only shed light on the etiology ofvincristine-induced peripheral neurotoxicity but will be of translational relevance and provide a rationale for thefuture implementation of novel targeted intervention strategies to prevent this debilitating side effect. 645896 +No NIH Category available Adoption;Algorithmic Software;Algorithms;Anus;Area;Artificial Intelligence;Biopsy;Brazil;Cancer Etiology;Cancer Hospital;Carcinoma;Cell Nucleus;China;Chinese;Classification;Clinical;Clinical Research;Colon;Computer Assisted;Computer software;Computers;Data;Data Set;Detection;Devices;Diagnosis;Diagnostic;Dissemination and Implementation;Early Diagnosis;Eastern Africa;Effectiveness;Endoscopy;Environment;Epithelium;Esophagus;Ethnic Origin;Evaluation;Geographic Locations;Goals;Health Status;Hospitals;Image;Incidence;Inflammatory;International;Iran;Language;Malignant Neoplasms;Malignant neoplasm of esophagus;Microscopic;Modeling;Neoplasms;Nuclear;Optical Biopsy;Oral;Participant;Patients;Performance;Pilot Projects;Population Heterogeneity;Prevention strategy;Randomized Controlled Clinical Trials;Randomized Controlled Trials;Resolution;Risk;Screening for cancer;Sensitivity and Specificity;Site;Skin;South America;Specificity;Speed;Stomach;Technology;Testing;Texas;Time;Training;Validation;Veterans Hospitals;Visual;Work;arm;automated algorithm;cancer prevention;chromoscopy;clinically relevant;contextual factors;coronavirus disease;cost;deep learning;deep learning algorithm;digital;esophageal squamous cell neoplasia;experience;handheld mobile device;health literacy;high risk;implementation facilitation;improved;innovation;microendoscope;microendoscopy;microscopic imaging;mortality;neoplastic;patient population;pilot trial;portability;screening;simulation;socioeconomics;standard of care AI-Assisted Microendoscopy for the Early Detection of Esophageal Cancer Narrative: Esophageal cancer is the 6th leading cause of cancer mortality worldwide. In this renewal we willbuild on our prior work developing a low cost mobile high resolution microendoscope with artificial intelligenceto evaluate its performance acceptability feasibility and clinical impact in diverse settings in the US and Brazil. NCI 10736719 9/19/23 0:00 PAR-21-033 2R01CA181275-07 2 R01 CA 181275 7 "GRODZINSKI, PIOTR" 9/17/14 0:00 8/31/28 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 9038472 "ANANDASABAPATHY, SHARMILA " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 612665 NCI 423675 188990 Abstract: Esophageal cancer is the 6th most common cause of cancer-related mortality worldwide. Whileesophageal squamous cell neoplasia (ESCN) carries a significant global burden those in certain underservedgeographic regions (South America eastern Africa eastern Iran northern China) have particularly highincidence and mortality rates due to lack of endoscopic screening capacity. While endoscopy with Lugolschromoendoscopy or digital chromoendoscopy has shown high sensitivity (>95%) for screening specificity ispoor (<60%) and false-positive results abound due to confounding inflammatory areas. As a result standard ofcare endoscopy produces many unnecessary biopsies increasing risk and cost of endoscopic screening andsurveillance. In our ongoing R01 project we developed and validated a mobile high-resolution microendoscope (mHRME)for screening and surveillance of ESCN. Despite 2 years of COVID delays which especially impacted theChinese sites we completed: (1) a randomized controlled clinical trial (USA and China; n=918) of mHRME withvisual interpretation in patients undergoing screening or surveillance for esophageal squamous cell neoplasia(2) deep-learning software algorithms for automated detection of neoplastic images and (3) a pilot trial (n=41)of the software-assisted mHRME in Brazil. The trial revealed higher specificity for qualitative (visual)interpretation by experts but not novices in surveillance arm (100% vs. 19% p<0.05). In the screening armdiagnostic yield (neoplastic biopsies/total biopsies) increased 3.6 times (8 to 29%); 16% of patients werecorrectly spared any biopsy; and 18% had a change in clinical plan. In a single-arm pilot study we also evaluatedan artificial intelligence-based mobile HRME (AI-mHRME) in 41 Brazilian subjects. This study (January 2022)confirmed that quantitative interpretation (AI-mHRME) doubled diagnostic yield improved endoscopistsconfidence and had significant clinical impact (change of clinical plan in 64%). Our initial deep-learning algorithmhad a sensitivity/specificity of 100%/85%. Participating clinicians uniformly said they favored an AI-guidedapproach but expressed concerns about its implementation. In this competing renewal we will build on this valuable global data to optimize an AI-mHRME and evaluateits clinical impact and implementation potential in ethnically and socioeconomically diverse populations in theUSA and Brazil. A stakeholder-engaged approach will be used to evaluate barriers acceptabilityappropriateness and feasibility of using AI-mHRME in ESCN management and to determine contextual factorsinfluencing adoption. Data obtained will facilitate implementation and dissemination of innovative AI-assistedcancer screening strategies in diverse populations and other cancers. 612665 +No NIH Category available Affect;BRCA1 gene;Birth;CRISPR interference;Cancer cell line;Cell Survival;Cells;Clinic;Complex;DNA;DNA Primase;DNA Repair;Diagnosis;Dicentric chromosome;Excision;Funding;Future;Genes;Genetic;Genome;Genomic Instability;Goals;Length;Malignant Neoplasms;Mentors;Molds;Mutation;Oncologist;Pathway interactions;Poly(ADP-ribose) Polymerase Inhibitor;Prevention;Research;Research Personnel;Resected;Role;TERF1 gene;Telomerase;Telomere Shortening;Testing;Tissues;Tumor Suppressor Proteins;Work;cancer genome;chromothripsis;design;experimental study;fitness;in vitro Model;innovation;insight;p53-binding protein 1;prevent;recruit;repaired;telomere;telomere loss;tumorigenesis Genome instability in cancer: telomeres and DNA repair Project NarrativeThis project is focused on understanding how genome rearrangements occur in cancer with a particularemphasis on understanding how telomere shortening prevents tumorigenesis and how loss of telomerefunction in developing cancers changes the cancer genome. The proposed experiments will illuminate newaspects of genome instability in cancer and are designed to deliver insights that will ultimately inform and guidedecisions in the cancer clinic. NCI 10736646 8/29/23 0:00 RFA-CA-22-045 2R35CA210036-08 2 R35 CA 210036 8 "WITKIN, KEREN L" 9/2/16 0:00 8/31/30 0:00 ZCA1-SRB-E(M1) 1888482 "DE LANGE, TITIA " Not Applicable 12 ANATOMY/CELL BIOLOGY 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY GRADUATE SCHOOLS 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1007774 NCI 600000 407774 Project SummaryThis project focuses on the role of telomeres and DSB repair in genome instability in cancer. Numerous recentWGS studies have revealed that most cancer genomes carry a remarkable level of structural changesaffirming the need to understand how this genome instability arises. In this context our work asks howtelomeres affect tumorigenesis with emphasis on the two major contributions of telomeres in cancer: thetelomere tumor suppressor pathway and telomere-driven genome instability. During the current funding periodwe have provided genetic evidence for the telomere tumor suppressor pathway and showed that the correcttelomere length setting at birth prevents cancer in a wide range of tissues. We have dissected the mechanismby which telomere crisis a stage at which telomere shortening drives genome instability in checkpoint-deficientcancer clones instigates breakage-fusion-bridge (BFB) cycles chromothripsis and kataegis. We haveprovided the first evidence that telomerase can create new telomeres (neotelomeres) at DSBs and proposethat neotelomere formation can mold the cancer genome by increasing the fitness of cells struggling withongoing BFB cycles. Finally our lab continued its work on the role of 53BP1 in DSB repair and PARPitreatment of BRCA1-deficient cells showing that unlike what was generally believed 53BP1 does not blockresection but recruits the CST-Pola/primase complex to fill-in resected DNA ends. These findings set the stagefor our future work in which we aim to continue our path-breaking research and the mentoring of future cancerresearchers. Examples of projects we will pursue are: 1. Using an innovative approach we will use CRISPRi screens for repressors of neotelomere formation and query hits for gene loss/mutation in cancer. 2. Our proposal that neotelomere formation can terminate BFB cycles and enhance the viability of cells with dicentric chromosomes will be tested in an in vitro model for induction of BFB cycles. 3. To gain deeper insights into the telomere tumor suppressor pathway we will determine how telomere length is regulated. 4. Following a recent demonstration that cancer cell lines with short telomeres are exceptionally sensitive to loss of the telomeric factors CST and TRF1 we will determine the mechanistic basis of these vulnerabilities in hopes that our insights may point to new treatments.Our aim is to derive deep insights into how cancer genomes are altered with the overarching goal of providingoncologists with information that can inform their decisions on diagnosis treatment and prevention.1 1007774 +No NIH Category available Acute;Affect;Alleles;Animal Model;Animals;Biochemical;Biological Assay;Biology;Bypass;CDC2 gene;Cancer Biology;Cell Aging;Cell Cycle;Cell Cycle Inhibition;Cell Cycle Regulation;Cell Death;Cell Fraction;Cell Proliferation;Cell division;Cell physiology;Cells;Cessation of life;Chemicals;Chromosome Segregation;Clinical Trials;Compensation;Coupled;Cyclin B;Cyclin-Dependent Kinase Inhibitor;Cyclin-Dependent Kinases;DNA Damage;DNA biosynthesis;Development;Disseminated Malignant Neoplasm;Engineering;Epidermal Growth Factor Receptor;Eukaryotic Cell;Event;Genetic Models;Growth;Homeostasis;Human;Immunotherapy;Lead;Life;M cell;MAP Kinase Gene;Malignant Neoplasms;Mammalian Cell;Maps;Mitosis;Mitotic;Modeling;Mole the mammal;Morbidity - disease rate;Mus;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Oncogenes;Oncogenic;Outcome;Pathway interactions;Patients;Phase;Phosphotransferases;Play;Precision therapeutics;Primary Neoplasm;Proliferating;Protein Biosynthesis;Protein Family;Protein Kinase;Proteins;Publishing;Regulation;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Therapeutic;Time;Toxic effect;Transgenic Mice;Transgenic Organisms;Tumor Tissue;analog;cancer cell;cancer therapy;cell transformation;chemical genetics;clinical translation;early phase clinical trial;epigenetic regulation;genetic approach;in vivo;in vivo evaluation;inhibitor;innovation;interest;kinase inhibitor;model organism;mortality;mouse model;neoplastic cell;novel;overexpression;programs;receptor;response;senescence;small molecule inhibitor;synthetic lethal interaction;targeted cancer therapy;targeted treatment;therapeutic target;triple-negative invasive breast carcinoma;tumor;tumor growth Understanding CDK1 Function and Cancer Vulnerabilities Project NarrativeNormal cellular proliferation requires an orderly progression through the cell cycle but cancer cells proliferateinappropriately and without end causing morbidity and mortality. Since tumor cells proliferate inappropriatelyprecise inhibition of the cell cycle may lead to the death of tumor cells while normal cells may be spared.Herein we investigate CDK1 as a therapeutic target for cancer with broad utility in tumors and metastasis. NCI 10736617 6/13/23 0:00 PA-20-185 1R01CA266756-01A1 1 R01 CA 266756 1 A1 "GHOSH-JANJIGIAN, SHARMISTHA" 6/13/23 0:00 5/31/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 1865459 "GOGA, ANDREI " Not Applicable 11 ANATOMY/CELL BIOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF DENTISTRY/ORAL HYGN 941432510 UNITED STATES N 6/13/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 483857 NCI 299602 184255 "Project Summary/Abstract Precision therapies for aggressive or metastatic cancers while offering the promise of greater efficacyand less toxicity rarely achieve durable responses and only modestly extend a patient's life. The majorlimitation to these approaches is that cancer cells evolve and alternate signaling pathways can compensate forpathways blocked with targeted therapies i.e. multiple alternative mechanisms to activate theEGFR/RAS/MAPK pathway lead to a ""whack-a-mole"" approach with serial treatment with different kinaseinhibitors. Cyclin-dependent kinases (CDKs) are a conserved family of protein kinases that play a central rolein regulating the eukaryotic cell cycle. CDK1 in conjunction with its activating subunit Cyclin B plays a criticalrole in permitting cells to enter mitosis coordinates the events required for faithful mitotic progression andchromosome segregation. To our knowledge CDK1/B activity is essential for all cells to proliferate and thereare no alternative pathways to bypass the requirement for CDK1. We hypothesize that CDK1 is an idealtherapeutic target in the context of specific oncogenic signaling pathways which result in an abortive cell cycleprogram such as cell death or senescence while non-tumor cells are only transiently arrested. Until nowspecific inhibitors of CDK1 have not existed limiting our ability to discover the underlying mechanisms of CDK1inhibition as a cancer therapy. Our lab developed a novel engineered mouse using a chemical-geneticapproach that allows us to inhibit CDK1 selectively and reversibly in normal and oncogene transformed cellsor in the context of transgenic tumor models. Our aims will define the mechanisms through which CDK1 elicitsgrowth arrest and senescence (Aim 1) regulates the unfolded protein response (Aim 2) and how CDK1inhibition and other therapeutics can be best combined to block tumor growth (Aim 3). We bring together ateam with a track record of innovative research in oncogene signaling and cell cycle regulation (Andrei Goga);expertise in chemical biology and analog-sensitive kinases (Kevan Shokat); in vivo studies of senescence (AnilBhushan) and expertise in mechanisms of regulation of the unfolded protein response (UPR). We hypothesizethat CDK1 controls previously unexplored cellular processes which can be exploited for tumor-specificvulnerabilities. Such discoveries will hasten the clinical translation of CDK1 inhibitors for a broad variety ofhuman cancers." 483857 +No NIH Category available Address;Antibodies;Antigens;Antitumor Response;Biological Markers;Biopsy;Blood;Blood specimen;CD8-Positive T-Lymphocytes;Cells;Clinical;Clinical Data;Clinical Oncology;Clinical Trials;Data Set;Development;Effectiveness;Eligibility Determination;FDA approved;Flow Cytometry;Foundations;Goals;Immune;Immune system;Immunologic Markers;Inferior;Leadership;Link;Malignant Neoplasms;Microsatellite Instability;Mission;Monoclonal Antibodies;Morbidity - disease rate;Mutation;Nivolumab;Outcome;PD-1 blockade;Patient Selection;Patient-Focused Outcomes;Patients;Phenotype;Population;Progression-Free Survivals;Refractory;Resistance;Risk;Sampling;T-Lymphocyte;Testing;Therapeutic;Toxic effect;United States;Urothelium;Work;anti-CTLA4;biobank;biomarker discovery;cancer biomarkers;cancer therapy;cancer type;clinical biomarkers;clinical development;cost;disorder control;exhaust;experience;immune checkpoint blockade;immune checkpoint blockers;improved;melanoma;multidisciplinary;novel;novel marker;peripheral blood;personalized medicine;pharmacodynamic biomarker;predictive marker;programmed cell death ligand 1;programmed cell death protein 1;prospective;prospective test;refractory cancer;resistance mechanism;response;tool;tumor;tumor microenvironment Understanding Immunotype a Novel Biomarker for Checkpoint Blockade Resistance NARRATIVEProspective identification of patients with cancers resistant to immune checkpoint blockade (ICB) would reduceunnecessary risk and cost and give patients opportunities to seek more appropriate treatment options. We haverecently described an immune profilewhich we called Immunotype-1 (IT-1)as a promising biomarker of ICBresistance which can be detected in patients' peripheral blood prior to ICB treatment. In this proposal we aim totest the hypothesis that IT-1 is a pan-cancer biomarker for ICB reflecting an exhausted tumor-specific LAG-3+CD8+ T cell population whose function can be recovered for therapeutic benefit using -LAG-3 blockade. NCI 10736515 7/10/23 0:00 PA-20-185 1R01CA276286-01A1 1 R01 CA 276286 1 A1 "SINGH, ANJU" 7/10/23 0:00 6/30/28 0:00 Clinical Oncology Study Section[CONC] 11086089 "CALLAHAN, MARGARET KATHLEEN" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/10/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 566873 NCI 320267 246606 ABSTRACTAn estimated 44% of patients with cancer in the United States are eligible to receive immune checkpoint blockade(ICB). FDA-approved ICB agents include -PD-1 and -CTLA-4 antibodies but the majority of patients do notbenefit because their tumors are resistant to these agents. ICB treatment is expensive and may lead to serioustoxicity. Prospective identification of patients with ICB-resistant cancers would reduce unnecessary risk and costand give patients opportunities to seek more appropriate treatment options. To address the unmet need for aperipheral blood biomarker for ICB effectiveness we performed immune profiling of ICB-treated patients withmelanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood.Our analyses revealed a new peripheral blood immune profilewhich we called Immunotype-1 (IT-1) definedin part by the presence LAG-3+CD8+ T cellsas a promising biomarker of ICB resistance. This finding wasvalidated in an independent dataset of metastatic urothelial cancer. Patients with IT-1 have inferior overallsurvival progression-free survival and response rates to -PD-1 blockade. Leveraging our leadership in theclinical development of ICBs we have assembled one of the largest biobanks of peripheral blood samples from>600 ICB-treated patients across cancer types. In this proposal we aim to test the hypothesis that IT-1 is a pan-cancer biomarker for ICB reflecting an exhausted tumor-specific LAG-3+CD8+ T cell population whose functioncan be recovered for therapeutic benefit using -LAG-3 blockade. The Specific Aims are to: 1) Phenotypicallyand functionally characterize the peripheral blood LAG-3+CD8+ T cell population and determine if this populationis represented in the tumor microenvironment in patients with the IT-1 phenotype; 2) Determine the associationbetween IT-1 and clinical outcome in ICB-treated patients across cancer types; and 3) Assess whether IT-1identifies patients who will respond to relatlimab (-LAG-3) + nivolumab (-PD-1). Our project is rooted in strongclinical data and thus likely to identify a biomarker that is mechanism-based clinically implementable and mostimportantly therapeutically actionable. 566873 +No NIH Category available Address;Adverse effects;Aftercare;Age;Behavior Therapy;Behavioral;Biological Factors;Biological Markers;Biological Sciences;California;Cancer Patient;Cancer Survivor;Chronic Disease;Clinic;Cohort Studies;Comprehensive Cancer Center;Confusion;County;DNA Methylation;Disease;Distress;Economics;Education;Emotional;Emotions;Epigenetic Process;Family;General Population;Genes;Glucocorticoid Receptor;Goals;Hormones;Hydrocortisone;Impairment;Individual;Inflammation;Informal Social Control;Interleukin-6;Interruption;Intervention;Late Effects;Life;Longevity;Malignant Neoplasms;Malignant neoplasm of testis;Measures;Mediation;Medical;Memorial Sloan-Kettering Cancer Center;Mental Depression;Morbidity - disease rate;NR3C1 gene;Oncology;Oranges;Outcome;Participant;Pattern;Pediatric Hospitals;Population;Positioning Attribute;Prevalence;Production;Psychological Factors;Race;Random Allocation;Randomized;Receptor Gene;Reproductive Health;Research;Resolution;Risk;Salivary;Second Primary Cancers;Sexuality;Stress;Survivors;Testing;Time;Treatment Side Effects;Urologic Oncology;Value of Life;Videoconferencing;Work;adverse outcome;anakinra;anxiety symptoms;biobehavior;cancer diagnosis;cancer therapy;career;comparative;depressive symptoms;design;effective intervention;efficacy evaluation;emerging adulthood;emotion regulation;experience;follow-up;improved;mood regulation;neoplasm registry;novel;pilot test;post intervention;primary outcome;psychologic;psychological distress;psychosocial;psychosocial adjustment;recruit;response;secondary outcome;serotonin transporter;side effect;skills;stress reactivity;success;survivorship;systemic inflammatory response;therapy design;video chat;young adult A Biobehavioral Intervention to Reduce Adverse Outcomes in Young Adult Testicular Cancer Survivors Project NarrativeThe majority of young adult cancer survivors experience impairing distressing and modifiable physicalbehavioral and psychosocial adverse outcomes that persist long after the completion of primary medicaltreatment including psychological distress and poor psychosocial adjustment impairment in the navigation andpursuit of life goals persistent treatment side effects elevated risk of secondary malignancies and chronicillness and biobehavioral burden (e.g. enhanced inflammation dysregulated diurnal stress hormones). Yetfew targeted effective interventions exist to assist young survivors in re-negotiating life goals and regulatingcancer-related emotions and none focus on reducing the burden of morbidity via biobehavioral mechanisms.Responsive to the need for feasible effective and scalable interventions this study will utilize a randomizedcontrolled repeated measures design to investigate the efficacy of a novel intervention (Goal-FocusedEmotion Regulation Therapy or GET) vs. Individual Supportive Listening (ISL) to improving depressivesymptoms (primary outcomes) as well as emotion regulation goal attainment skills and career confusion(secondary outcomes) in young adult testicular cancer patients whether GET is associated with reductions inbiological markers of stress and inflammation and evaluate whether gains in emotion regulation and goalattainment skills reflect mechanisms of underlying change at baseline post-treatment 3-month follow-up and6-months follow-up. NCI 10736501 7/5/23 0:00 PAR-21-035 1R01CA276143-01A1 1 R01 CA 276143 1 A1 "MOLLICA, MICHELLE A" 7/8/23 0:00 6/30/28 0:00 Biobehavioral Medicine and Health Outcomes Study Section[BMHO] 10221191 "HOYT, MICHAEL A" Not Applicable 47 PUBLIC HEALTH & PREV MEDICINE 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF PUBLIC HEALTH 926970001 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 672977 NCI 478726 194251 Project Abstract Testicular cancer diagnosis and treatment especially given its threat to sexuality and reproductive healthcan be distressing in the formative period of young adulthood. Cohort studies reveal the prevalence ofdepressive symptoms in testicular cancer exceeds the general population. In fact the majority of young adultcancer survivors will experience impairing distressing and modifiable physical behavioral and psychosocialadverse outcomes that persist long after the completion of primary medical treatment. These includepsychological distress impairment in the navigation and pursuit of life goals persistent side effects elevatedrisk of secondary malignancies and chronic illness and biobehavioral burden (e.g. enhanced inflammationdysregulated stress hormones) which influence morbidity and disease-related vulnerabilities. However fewtargeted effective interventions exist to assist young survivors in re-negotiating life goals and regulatingcancer-related emotions and none focus on reducing the burden of morbidity via biobehavioral mechanisms. Young or emerging adulthood is a period marked by goal attainment. Chronic illness experienced as offtime in the lifespan interrupts goal pursuits and threatens valued life directions. As young adults return to goalpursuits re-entry to post-cancer life can be a critical point in the survivorship trajectory. Behavioral interventionat this time is well positioned to confer longer-term impact. Emergent from our groups preliminary research wedeveloped and pilot-tested Goal-focused Emotion-Regulation Therapy (GET) as a novel behavioralintervention to enhance self-regulation through improved goal navigation skills improved sense of purposeand better ability to regulate emotional responses in young adults with testicular cancer. GET is a promisingcandidate intervention to address the mechanisms likely complicating the resolution of cancer-related burden. Responsive the need for feasible effective and scalable interventions we will randomly allocate 300young adult (ages 18-39) testicular cancer patients to 6 sessions of GET or ISL (individual supportivelistening) and evaluate primary and secondary outcomes at baseline post-treatment 3-month follow-up and6-months follow-up. We predict that GET will be associated with superior distress outcomes and comparativelygreater reductions in adverse biobehavioral indicators (dysregulated diurnal stress hormones elevatedinflammation) and these advantages will be maintained at three- and six-months following intervention. Theintervention will be delivered via video conferencing to enhance access. An exploratory aim focuses onpotential epigenetic vulnerabilities to understand how environmental influences (via DNA methylation) ongenes implicated in stress and mood regulation are related to cancer adjustment and intervention response. This study capitalizes on the study teams unique expertise in biobehavioral oncology and salivarybioscience to test a novel behavioral intervention for young adult survivors. It has potential to understand howto alter proximal behavioral biological and psychological factors that underscore long term adverse effects. 672977 +No NIH Category available Adjuvant;Adjuvant Therapy;Aftercare;Aggressive behavior;Aneuploidy;Angiopoietins;Animal Model;Antineoplastic Agents;Benefits and Risks;Biological Availability;Biological Models;Blood;Blood Vessels;Blood flow;Blood specimen;Breast Cancer Cell;Breast Cancer Detection;Breast Cancer Patient;Breast Cancer therapy;Breast cancer metastasis;Cell Death;Cells;Cessation of life;Chemoresistance;Clinical;Complex;DNA analysis;Data;Development;Diagnosis;Disease;Dissection;Distant;Drug Delivery Systems;Drug resistance;Ecosystem;Epidemiologist;Evolution;Family;Generations;Genes;Genome;Genomics;Hand;Heterogeneity;Histologic;Human;Hypoxia;Impairment;Individual;Malignant Neoplasms;Mammary Neoplasms;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Modeling;Molecular;Mus;Mutate;Mutation;Necrosis;Necrosis Induction;Neoadjuvant Therapy;Neoplasm Metastasis;Nutrient;Organ;Outcome;Oxygen;Patients;Penetration;Perfusion;Pharmaceutical Preparations;Phenotype;Population Study;Prevention;Primary Neoplasm;Prognostic Marker;Protein Secretion;Rattus;Recurrence;Recurrent Malignant Neoplasm;Residual Cancers;Resistance;Risk;Risk Factors;Risk Reduction;Role;Sampling;Source;Testing;Therapeutic;Tissue Sample;Tissues;Toxic effect;Tumor-Derived;Woman;Work;aggressive therapy;barrier to testing;cancer recurrence;cancer subtypes;cancer therapy;chemotherapy;clinical prognostic;cohort;driving force;drug development;genomic signature;improved;innovation;knock-down;liquid biopsy;malignant breast neoplasm;member;molecular marker;mouse model;neoplastic cell;patient derived xenograft model;population based;prevent;prognostic;prognostication;programs;response;risk prediction;synergism;therapeutic development;therapy development;therapy resistant;trait;tumor;tumor DNA;tumor growth;tumor heterogeneity Role of necrosis in the evolution of highly metastatic and chemo-resistant breast cancers Over 40000 women die every year from aggressive therapy-resistant metastatic breast cancer. In this application we will use animal models and patient samples to define how necrosis helps breast tumor cells mutate and spread to distant organs and spread to distant organs and determine whether preventing necrosis can block development of therapy resistance and tumor evolution. NCI 10736486 8/23/23 0:00 PA-20-185 1R01CA277045-01A1 1 R01 CA 277045 1 A1 "GREENBERG, WILLIAM A" 8/23/23 0:00 7/31/28 0:00 "Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]" 10214765 "CHEUNG, KEVIN JON" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/23/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 641961 NCI 368044 273917 High-grade fast-growing breast cancers often display necrosis usually within the tumor interior where perfusion nutrients and oxygen are limited. Recent studies indicate that necrosis is not just an indicator of aggressive disease but also a regulator of the aggressive phenotype by impairing cancer drug delivery promoting genomic evolution and instigating metastasis to distant organs. However we currently lack an understanding of the molecular mechanisms regulating necrosis development and consequently there are no therapies to prevent the development of necrosis and its downstream effects on tumor aggression. For this application we have developed animal models that enable the robust dissection of the tumor-host ecosystem in the necrotic interior. Our studies reveal that a secreted protein angiopoietin-like 7 (Angptl7) is produced by tumor cells adjacent to the necrotic core and is a regulator of tumor core vasculature development. Importantly when Angptl7 is suppressed genetically tumor necrosis tumor growth and metastatic dissemination are each drastically reduced. Thus necrosis development is not inevitable but rather is preventable by Angptl7 suppression. In the proposed work we will combine studies using innovative animal models and breast cancer patient blood and tissue samples to test the hypothesis that the development of necrosis is a driving force for the evolution of highly metastatic and drug-resistant breast tumor cells. In Aim 1 we will use mouse models to test the hypothesis that Angptl7-induced necrosis limits delivery of chemotherapeutics to the tumor core and that Angptl7 suppression synergizes with neoadjuvant chemotherapeutics to improve drug delivery and improve tumor killing. In Aim 2 we will use tissue from a large population-based cohort of early-stage breast cancer patients to determine how dilated blood vessels an indicator of Angptl7-induced necrosis influences risk of local and distant metastatic dissemination to predict benefit from adjuvant therapy. In Aim 3 we will apply genomic sequencing and circulating tumor DNA analysis in an innovative rat model for liquid biopsy studies to define the genomic signatures associated with Angptl7-induced necrosis. We will then determine the prognostic impact of a circulating tumor DNA signature of necrosis in human clinical samples. This work will define necrosis development as an engine for tumor diversification and aggression and the clinical contexts both in early stage and metastatic settings where necrosis prevention could benetits patients with breast cancer and tumor types. 641961 +No NIH Category available Anabolism;Antioxidants;Apoptosis;Apoptotic;Applications Grants;BCL1 Oncogene;BCL2 gene;Biological;Cell Culture Techniques;Cell Death;Cell Line;Cells;Chemicals;Child;Clinic;Clinical;Clinical Investigator;Coenzyme A;Combination Drug Therapy;Combined Modality Therapy;Complex;Cysteine;Dependence;Disease;Drug Metabolic Detoxication;Drug Targeting;FDA approved;Genetic;Genetic Screening;Genomics;Glutathione;Goals;Grant;Growth;Immunotherapy;Iron;MYCN gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Modeling;Mus;Nature;Neuroblastoma;Oncogenes;Oncogenic;Oxygen;Pantothenate kinase;Pantothenic Acid;Pathway interactions;Patients;Pediatric Neoplasm;Peroxidases;Pharmacologic Substance;Phenotype;Phosphotransferases;Production;Proliferating;Reaction;Reactive Oxygen Species;Refractory;Relapse;Research Design;Resistance;Selenocysteine;Stress;Testing;Therapeutic;Time;Translating;Translational Research;Work;aged;cancer cell;cancer therapy;combat;disorder risk;experimental study;glutathione peroxidase;high risk;improved;in vivo Model;inhibitor;iron metabolism;kinase inhibitor;mouse model;neuroblastoma cell;new combination therapies;novel;novel therapeutics;patient derived xenograft model;pre-clinical;programs;resistance mechanism;response;screening;selenoprotein;transcription factor;translational medicine;treatment response;tumor MYCN drives a ferroptotic vulnerability in neuroblastoma Project NarrativeThe oncogenic transcription factor MYCN drives a subset of neuroblastoma tumors which is deadly in half thecases despite protracted and intense therapy including polychemotherapy and immunotherapy (anti-GD2therapy). As MYCN remains undruggable finding synthetic lethal relationships that may result in newtreatments is one of the holy grails of pediatric cancer therapy. In this grant proposal we provide evidencethat amplified MYCN orchestrates a complex and intricate re-wiring of the neuroblastoma cell to 1) increaseiron metabolism 2) increase cysteine and selenocysteine biosynthesis to counteract reactive oxygen speciescreated from iron metabolism-related Fenton reactions and 3) increase synthesis of pantothenate kinase 3(PANK3) to subsequently increase coA levels; the result of which is the creation of a synthetic lethality andtherapeutic vulnerability to ferroptosis induction which we aim to explore clarify and translate to newtherapeutic options for this recalcitrant pediatric tumor. NCI 10736479 8/30/23 0:00 PA-20-185 1R01CA276207-01A1 1 R01 CA 276207 1 A1 "FORRY, SUZANNE L" 9/1/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-MCTC-S(01)Q] 10310162 "FABER, ANTHONY CHARLES" "OLZMANN, JAMES A" 4 DENTISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF DENTISTRY/ORAL HYGN 232980568 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 696725 NCI 541440 155285 Project Summary: Apoptosis is a type of programmed cell death and has for a long time been appreciated tobe a hallmark of cancer cells. In recent years drugs targeting the apoptotic pathway such as the FDA-approved BCL-2 inhibitor venetoclax have revolutionized therapy in cancers which have a particularvulnerability to targeting this pathway. A different programmed cell death pathway ferroptosis has recentlybeen discovered. Understanding which cancers may be vulnerable to the induction of ferroptosis and whichtargetable molecules are involved could lead to a new wave of successful cancer therapy. MYCN-amplifiedneuroblastoma (NB) is one of the deadliest subtypes of pediatric cancer. Here in we demonstrate thatamplified MYCN drives an aberrant iron capture program in NB and increases intracellular cysteinebiosynthesis and selenocysteine dependence through multiple mechanisms to detoxify reactive oxygenspecies (ROS) accumulation as a result of high cellular iron. The consequence of these MYCN-directedchanges is a synthetic lethality to genetic or pharmaceutical targeting of the glutathione/glutathione peroxidase4 (GPX4) pathway resulting in ferroptotic cell death. This grant aims to expand our understanding of howMYCN alters cysteine and selenocysteine production and ferroptotic inducing pathways to sustain anantioxidant defense and how these pathways may be exploited pharmaceutically to improve therapeuticresponses in this recalcitrant tumor type.Specific Aims:Aim 1: Characterize the ability of MYCN to suppress ferroptosis in neuroblastomaAim 2: Identification of synthetic lethal ferroptosis resistance mechanisms in MYCN-amplified neuroblastomaAim 3: In MYCN-amplified neuroblastoma mouse models evaluate novel ferroptotic combination therapiesStudy Design: Using well characterized isogenic cell lines and patient-derived xenograft cell cultures we willmobilize expertise in selenocysteine biosynthesis (Copeland) pantothenate kinase inhibitors (Rock) andgenomic screening of ferroptotic pathway modifiers (Olzmann) to better define the ferroptotic vulnerability inMYCN-amplified NB and to uncover novel sensitizers to ferroptotic inducers in MYCN-amplified NB. The goalof these experiments is to not only better understand how the MYCN oncogene hijacks cysteine forselenocysteine production to mount a defense against an oxidized phenotype but to create new therapeuticsto create better anti-ferroptotic approaches in MYCN-amplified NB. To this end we will work with our preclinicalmouse model expert (Koblinski) and a NB clinical investigator (Glod) to build the preclinical evidence ofsynthetic lethal new therapies into the clinic for refractory NB patients. 696725 +No NIH Category available Bar Codes;Brain;Brain Neoplasms;Cell Proliferation;Cells;Childhood Malignant Brain Tumor;Chromatin;Chromatin Remodeling Factor;Clinical;Collection;Coupled;Data;Development;Disparate;Electroencephalography;Electroporation;Embryo;Ependymoma;Epigenetic Process;Event;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Fusion;Genetic;Genetic Transcription;Genome;Goals;Growth;Histones;Human;Hyperactivity;Knowledge;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Mediator;Metabolic;Modeling;Mus;Neuroglia;Neurons;Neuropeptides;Neurotransmitters;Oncogenic;Pathway interactions;Patients;Proteins;RELA gene;Radial;Regulation;Repression;Role;SMARCA4 gene;Seizures;Shapes;Site;Synapses;Testing;Tissue-Specific Gene Expression;Transcriptional Regulation;Tumor stage;epigenomics;gene repression;gliogenesis;human model;in utero;lead candidate;loss of function;member;mouse model;neuronal tumor;neuropeptide Y;novel;overexpression;programs;protein protein interaction;screening;transcription factor;tumor;tumor initiation;tumor progression;tumorigenesis Transcriptional Regulation in ZFTA-RELA Ependymoma NARRATIVEThe overall goal of this proposal is to dissect the regulation and function of developmental transcription factorson brain tumor development and understand how these factors shape the microenvironment. Our studies areimportant for a more complete understanding of the regulation of gene expression programs in brain cancer. NCI 10736436 7/24/23 0:00 PA-20-185 1R01CA284455-01A1 1 R01 CA 284455 1 A1 "WITKIN, KEREN L" 8/1/23 0:00 7/31/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 15299181 "MACK, STEPHEN C" "DENEEN, BENJAMIN " 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 663500 NCI 513603 149897 SUMMARYTranscriptional networks in cancer are a collection of inputs from developmental and cell identity programsoncogenic proteins metabolic circuits and micro-environmental interactions. Together these culminate to drivedisparate stages of tumor initiation maintenance and progression. Ependymoma (EPN) is an aggressive formof pediatric brain cancer driven by a single genetic event a gene fusion between ZFTA and RELA. ZFTA-RELA(denoted ZRFUS) is a potent driver of transformation and its expression is sufficient to induce EPN whenexpressed in the developing mouse brain. Despite evidence that ZRFUS functions as an aberrant transcriptionalregulator the downstream mechanisms it utilizes to drive tumorigenesis remain poorly defined. This knowledgegap has hindered the identification of clinically tractable approaches for EPN which have remained stagnant forover 30 years. Therefore the overarching goal of this proposal is to dissect how ZRFUS impacts andintersects with the diverse transcriptional programs that drive EPN tumorigenesis. To dissect how ZRFUSdrives EPN tumorigenesis we established the first autochthonous mouse model of ZRFUS EPN using in uteroelectroporation (IUE) of the developing mouse brain. Using this model we demonstrated that transcription factor(TFs) essential for developmental gliogenesis such as SOX9 are required for the initiation of ZRFUS EPNdevelopment. Barcode screening of these developmental TFs in our model identified ETV5 as a lead candidatethat is both necessary and sufficient for ZRFUS progression. Further examination of ETV5 function in EPNrevealed that it suppresses gene expression by promoting repressive chromatin states. Among the key targetgenes repressed by ETV5 is Neuropeptide Y (NPY) a potent neurotransmitter which we found functions tosuppress ZRFUS progression and remodel neuronal synapses in the peritumoral margins towards decreasedactivity. Based on these compelling preliminary studies we hypothesize that developmentally encoded TFsgovern tumor initiation and manipulate chromatin accessibility that regulate tumor-neuron interactionsin the brain microenvironment to drive EPN growth. This hypothesis will be tested in the following aims: 1)Determine how SOX9 impacts ZRFUS EPN initiation through modifying chromatin accessibility 2) Decipher therole of ETV5 in ZRFUS EPN progression and 3) Define the role of NPY in remodeling the ependymoma neuronalmicroenvironment. 663500 +No NIH Category available Advanced Malignant Neoplasm;American College of Radiology Imaging Network;Ancillary Study;Area;Cancer Intervention;Chicago;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Eastern Cooperative Oncology Group;Faculty;Goals;Home;Infrastructure;Institution;International;Lead;Leadership;Malignant Neoplasms;Patient Recruitments;Patients;Persons;Productivity;Recording of previous events;Research Infrastructure;Resources;Role;Science;Scientific Advances and Accomplishments;Site;Southwest Oncology Group;Universities;improved;inter-institutional;metropolitan;recruit;senior faculty Northwestern University Lead Academic Participating Site GY4 Supplemental Request NarrativeHome for exceptional science and of internationally renowned cancer experts and supported by acomprehensive clinical research infrastructure the Robert H. Lurie Comprehensive Cancer Center ofNorthwestern University (LCC) is will continue leadership of and participation in NCTN trials as a high performingLAPS recruiting patients in the Chicago metropolitan area to trials aiming to improve the lives of people withcancer. NCI 10736415 1/10/23 0:00 PA-20-272 3UG1CA233320-04S1 3 UG1 CA 233320 4 S1 "MOONEY, MARGARET M" 11/11/22 0:00 2/28/23 0:00 1894210 "BENSON, AL B" "MATEI, DANIELA E" 5 INTERNAL MEDICINE/MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 11/11/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 299998 NCI 187499 112499 Summary/Abstract:The Robert H. Lurie Comprehensive Cancer Center of Northwestern University (LCC) has a long history of NCTNparticipation with ECOG membership since 1973. Currently the LCC infrastructure supports participation inclinical trials and ancillary studies through the ECOG-ACRIN SWOG Alliance NRG and COG. LCC has anestablished history of accruing to and participating in NCTN trials including selection as a high performing site in2015 2016 and 2017.In 2019 Northwestern University was designated as a Lead Academic Performing site (LAPS) and in this newrole continues to significantly accrue patients to NCTN trials exceeding planned accrual goals in both years asa LAPS institution.Through continued demonstration of significant scientific accomplishments and new initiatives recruitment ofaccomplished senior faculty and productive junior faculty comprehensive and integrated infrastructure foroversight of cancer-related clinical trials LCC will continue to expand participation in NCTN trials providescientific leadership of key network activities and increase inter-institutional collaborations and access to uniquescientific resources to advance cancer interventions. 299998 +No NIH Category available Barrett Esophagus;Bioinformatics;Biological;Burn injury;Cells;Cellular biology;Chromosomal Instability;Chromosomes;Clonal Expansion;Colon Carcinoma;Complement;Complementary DNA;Computer Analysis;DNA;DNA Damage;DNA Repair;DNA Sequence Rearrangement;DNA Transposable Elements;DNA copy number;DNA sequencing;Data;Data Set;Dependence;Detection;Development;Dicentric chromosome;Elements;Esophageal Adenocarcinoma;Event;Evolution;Experimental Models;Gene Rearrangement;Genes;Genetic Screening;Genetic Transcription;Genetic Variation;Genetic study;Genome;Genomic Instability;Genomics;High Prevalence;Human;Human Genetics;In Vitro;Insertion Mutation;Joints;Knowledge;Laboratories;Lesion;Long Interspersed Elements;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mediating;Methods;Methylation;Modeling;Molecular;Molecular Biology;Monitor;Mutation;Open Reading Frames;Outcome;Pathology;Population;Prevalence;Process;Proteins;RNA;RNA-Binding Proteins;RNA-Directed DNA Polymerase;Research Personnel;Resolution;Retrotransposition;Retrotransposon;Reverse Transcription;Role;S phase;Shotguns;Somatic Mutation;Source;System;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;Work;analytical method;cancer cell;cancer genome;cancer prevention;cancer type;endonuclease;experimental study;genome analysis;genome integrity;genome sequencing;genomic data;human disease;human tissue;in vitro Model;insight;live cell imaging;malignant stomach neoplasm;metaplastic cell transformation;novel strategies;overexpression;premalignant;promoter;replication stress;tumor;tumorigenesis;whole genome Consequences of retrotransposition on genome integrity NarrativeThis project will investigate the roles of DNA-damaging transposons during tumorigenesis including theircontributions to the progression of Barrett's esophagus to esophageal cancer. Using in vitro experimentalsystems and new approaches to genomic analyses in human tissues we will determine the full scope of DNArearrangements attributable to transposon activity. NCI 10736406 7/28/23 0:00 PA-20-185 1R01CA276112-01A1 1 R01 CA 276112 1 A1 "FINGERMAN, IAN M" 8/1/23 0:00 7/31/28 0:00 Cancer Genetics Study Section[CG] 2137442 "BURNS, KATHLEEN H" "LEE, EUNJUNG ALICE; ZHANG, CHENG-ZHONG " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 770690 NCI 505706 264984 Project SummaryTransposable elements are a major source of human genetic variation and also contribute to human diseases by causing somatic mutations. The activity of transposition in human cancers is well established. Both expression of the RNA binding protein ORF1p encoded by the L1 element and insertions of L1 and other transposons are commonplace in cancer cells and cancer genomes. However whether and how retrotransposition contributes to cancer genome evolution and promotes tumorigenesis remain unclear. Here we hypothesize that retrotransposition may promote cancer evolution by causing long-range genomic rearrangements in addition to insertions. This hypothesis is formulated based on both genomic observations in primary cancer genomes and molecular and genomic data from our in vitro experiments. To test this hypothesis we will combine experimental approaches in in vitro models (Aim 1) with computational analyses (Aim 2) of retrotransposition and retrotransposition-associated rearrangements in primary cancers and precancer cells (Aim 2). Specifically we propose that non-canonical resolution of LINE-1 insertions can cause DNA breaks and long-range DNA rearrangements and a subset of these rearrangements further destabilizes genomes by generating acentric or dicentric chromosomes that undergo waves of rearrangements. To test this we first assess DNA damage and its dependence on the endonuclease (EN) and reverse transcriptase (RT) activities of L1 ORF2p (Aim 1a). We then determine both immediate and downstream genomic consequences of ORF2p-induced DNA damage using state-of-the-art Look-Seq approaches that combine cell biology and whole-genome sequencing (Aim 1b and 1c). Complementing these in vitro analyses of retrotransposition we propose to analyze bulk cancer genomes (Aim 2b) and single pre-cancer cell genomes (Aim 2c) to definitively assess the prevalence of insertions and long-range rearrangements that bear the hallmarks of retrotransposition. We focus on esophageal cancers with an extremely high prevalence of retrotransposition (in >90% of cancers) and the precancer condition known as Barrett's Esophagus (BE) where LINE-1 retrotransposition has also been observed previously. The proposed work includes development of new bioinformatic packages for joint rearrangement and transposition detection in shotgun cancer sequencing data that will benefit researchers studying genetic variation genome instability and somatic genome evolution (Aim 2a). Together the proposed studies will thoroughly characterize the relationships between LINE-1 retrotransposition and genome instability writ large and the roles of retrotransposition in cancer evolution. This knowledge may lead to new avenues of cancer prevention and therapeutics. 770690 +No NIH Category available Acceleration;Advocate;Aging;Animals;Area;Automobile Driving;Award;Black race;Cancer Survivor;Cancer Survivorship;Caring;Cell Aging;Cohort Studies;Collaborations;Complex;Data;Discipline;Disease;Disparity;Environment;Epigenetic Process;Ethnic Origin;Exposure to;Funding;Gene Expression;Geroscience;Goals;Hispanic;Human;Inflammatory;Infrastructure;Institution;Intervention;Knowledge;Laboratories;Lead;Machine Learning;Malignant Neoplasms;Mediation;Methods;Minority;Modeling;Mutation;Oncology;Outcome;Pathway interactions;Policies;Population;Population Sciences;Pre-Clinical Model;Process;Public Health;Quality of life;Race;Research;Research Personnel;Risk;Role;Scientist;Signal Transduction;Stress;Survivors;Testing;Transducers;Translating;United States National Institutes of Health;Vision;cancer care;cancer health disparity;career;clinical care;clinically relevant;cohort;demographics;ethnic minority;health determinants;health disparity;health inequalities;insight;intersectionality;novel;pre-clinical;programs;racial minority;simulation;social health determinants;success;survivorship;transcriptomics;virtual Social Determinants of Health as Transducers of Cellular Aging: A New Multi-level Paradigm to Reduce Survivorship Disparities at the Intersection of Cancer and Aging We lack sufficient data about the complex relationships at the intersectionality of disparities aging and cancerperpetuating health inequities and leaving older survivors and their oncology teams with insufficient evidence toguide care especially older racial/ethnic survivors for whom data is virtually lacking. My population sciencelaboratory will lead teams of transdisciplinary researchers and advocates to fill this gap by providing amechanistic understanding of the role of cellular aging in the relationships between social determinants of healthand quality of life of diverse older cancer survivors. We will use this paradigm to conduct human and animalstudies to Identify and test aging mechanistically-based interventions that can support efforts to tailor clinicalcare for the growing older minority survivor population and transform how we approach cancer disparities in thecontext of aging. NCI 10736380 8/8/23 0:00 RFA-CA-22-045 1R35CA283926-01 1 R35 CA 283926 1 "HOROWITZ, TODD S" 9/1/23 0:00 8/31/30 0:00 ZCA1-SRB-E(M1) 1868936 "MANDELBLATT, JEANNE " Not Applicable 98 INTERNAL MEDICINE/MEDICINE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 980446 NCI 682022 298424 By 2030 three-quarters of the 22 million US cancer survivors will be 65 and older and the number of olderHispanic and Black survivors will have grown three times faster than Whites. These shifting demographics aredriving a crisis in cancer care due to a paucity of evidence to guide care for older survivors especially olderracial/ethnic survivors for whom data is virtually lacking. Filling these gaps will require an understanding ofseveral complex multidirectional relationships at the intersection of health disparities aging and cancer.Compared to older White survivors older racial/ethnic minority survivors have had more lifetime exposures toadverse social determinants of health. These exposures accelerate aging processes. Aging increases the riskof developing cancer through accumulated damage and mutations. Cancer and its therapies in turn are diseasedrivers of aging. Together these intersecting forces are likely to exacerbate current racial/ethnic cancerdisparities in the health and quality of life of older survivors. The vision for this Outstanding Investigator Awardis to fundamentally shift how we approach cancer disparities by providing a mechanistic understanding of therole of cellular aging in the relationships between social determinants of health and survivorship outcomes. I willuse a conceptual model that integrates a multi-level disparities framework with oncology and geroscienceperspectives to conduct research using transcriptomic and other -omics analyses epigenetics machine learningmediation models meta-synthesis and population simulation methods. The broad goals of my transdisciplinaryresearch program are to: 1) discover cellular aging processes in large cohorts of older Black Hispanic andWhite survivors that explain relationships between health determinants and quality of life (e.g. via stresssignaling and downstream effects on cellular aging via inflammatory gene expression) 2) define mechanisticpathways suggested by cohort results and test the impact of interventions targeting those pathways in apreclinical model of cancer survivorship and 3) translate results to practice and policy. During my continuouslyNIH-funded research career I have made transformative contributions that support my proposed researchprogram. There are few population scientists with the unique background and proven track record to successfullyconduct this in-depth research program spanning the full translational continuum from preclinical to cohortstudies and practice and policy. Collaboration with scientists from outside my discipline will support my successand generate novel insights. The newly established Georgetown Lombardi Institute on Cancer and Aging that Ilead and exceptional institutional commitment and infrastructure provide an exceptional environment. ThisOutstanding Investigator Award will provide me with the stability needed to accelerate knowledge in anunderstudied research area with high public health significance and clinical relevance. Identification and testingof aging mechanistically-based interventions will support efforts to tailor clinical care for the burgeoning olderminority survivor population and could to transform how we approach cancer disparities in the context of aging. 980446 +No NIH Category available AFP gene;Abdomen;African American population;Algorithms;Applications Grants;Artificial Intelligence;Behavioral;Biological;Biological Markers;Biological Specimen Banks;Blinded;Blood;Cancer Detection;Center for Translational Science Activities;Cirrhosis;Clinical;Clinical Data;Clinical/Radiologic;Collaborations;Costs and Benefits;DNA;Data;Decision Analysis;Development;Dimensions;Disease;Early Detection Research Network;Early Diagnosis;Enrollment;Ensure;Equilibrium;Evaluation;Fatty acid glycerol esters;Fibrosis;Funding;Future;Genetic Markers;Goals;Guidelines;Healthcare Systems;Hepatitis C;Hepatitis C virus;Hispanic Populations;Image;Infrastructure;Institution;Liver;Liver Fibrosis;Liver diseases;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Maps;Metabolic Marker;Methods;Modality;Modeling;Morbidity - disease rate;Nodule;Patients;Pattern;Performance;Phase;Portal Hypertension;Primary carcinoma of the liver cells;Productivity;Prospective cohort;Reporting;Research;Research Personnel;Resources;Risk;Risk Assessment;Risk Factors;Sampling;Science;Screening for Hepatocellular Cancer;Screening for cancer;Serum;Severities;Site;Societies;Source;Spleen;Subgroup;Surveys;Testing;Texas;Underrepresented Populations;Visceral fat;Visit;Work;biobank;biomarker panel;biomarker validation;blood-based biomarker;cancer biomarkers;clinical decision-making;clinical practice;cohort;comparative;cost;cost effectiveness;design;detection sensitivity;early detection biomarkers;ethnic diversity;follow-up;high risk;image archival system;imaging biomarker;improved;innovation;liver function;liver imaging;machine learning pipeline;mathematical model;mortality;multidisciplinary;muscle form;neoplasm registry;non-alcoholic fatty liver disease;novel;phase 3 study;programs;prospective;racial diversity;radiomics;recruit;risk stratification;sample collection;screening;subcutaneous;surveillance strategy;tool;translational approach;translational scientist;ultrasound;virtual Risk Stratification for and Early Detection of Liver Cancer The Translational Research Center includes a multidisciplinary team of clinical and translational researcherswho will leverage a unique active prospective (in-liver cancer surveillance) cohort of patients with cirrhosis todevelop and validate methods for risk stratification and early detection of liver cancer. NCI 10736168 9/19/23 0:00 RFA-CA-22-031 2U01CA230997-06 2 U01 CA 230997 6 "YOUNG, MATTHEW R" 9/13/18 0:00 8/31/28 0:00 ZCA1-TCRB-Q(M1) 9113992 "KANWAL, FASIHA " "CHHATWAL, JAGPREET ; EL-SERAG, HASHEM B; KOAY, EUGENE J" 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 963046 NCI 735089 227957 The Translational Research Center (TRC) includes a diverse team of clinical and translational researchers witha strong track record of working together to reduce hepatocellular cancer (HCC). The TRC uses data from aunique group of patients with cirrhosis who are being recruited from eight different sites throughout Texas (theTRC cohort). Our TRC cohort currently includes > 3700 patients with cirrhosis (>10000 follow up surveillancevisits and >190 HCC cases) who have diverse risk factors including cured HCV and non-alcoholic fatty liverdisease. These patients are under routine HCC surveillance and their biological samples and clinical andradiological data for each visit is stored; it is a valuable resource for our research and other Consortium projects.We also launched a separate prospective cohort of patients with indeterminate liver nodules which is a high riskand high priority group for HCC risk stratification and early detection. We are collecting surveys clinical dataimages and biospecimens from this cohort. The catalytic effects of our TRC are seen in the productivity of ourjunior investigators who started innovative new initiatives and programs. Our work had a broad impact includinghelping develop various society guidelines on HCC surveillance. Using data and the strong network ofinvestigators and institutions collaborating with our TRC we have already generated important data on riskfactors and risk stratification for HCC. We also developed and demonstrated the framework for adding patient-and liver disease-related factors to new blood-biomarker profiles to improve early HCC detection. Here wepropose to build a novel imaging repository including MRI images from our cohort. We will annotate andincorporate data from abdominal ultrasound reports for our TRC cohort using novel scalable machine learningpipelines. We will also strengthen our data by appending information from the State cancer registries. Using datafrom different sources available to us we will develop and test new personalized methods to stratify risk thatblends information from clinical factors blood-based biomarkers and imaging (radiomics) to predict futuredevelopment of HCC in patients with cirrhosis across diverse risk factors (Aim 1). We showed that the HCCEarly Detection Screening (HES) algorithm when combined with HCC blood-based biomarkers (AFPL3 DCP)in HES version 2.0 (HES v2.0) substantially improved early detection. We will validate and compare HES v2.0with GALAD another early detection algorithm and evaluate their performance versus the current standardultrasound-based surveillance (Aim 2). In Aim 3 we will develop a new mathematical model to look at howuseful current and emerging biomarkers are for detecting HCC. We will also assess the risks costs and benefitsof HCC surveillance using different cutoffs of existing and novel blood and imaging biomarkers. We will developand disseminate an online Simulator so that other investigators can evaluate the potential clinical utility of HCCearly detection biomarkers as potential surveillance tools. Our translational approach will have both an immediateand long-lasting impact on HCC-related morbidity and mortality. 963046 +No NIH Category available Advanced Malignant Neoplasm;Biochemical Pathway;Biopsy;Cancer Model;Cancer Patient;Cells;Cessation of life;Citric Acid Cycle;Clear cell renal cell carcinoma;Clinical;Data;Defect;Dependence;Electron Transport;Excision;Glucose;Human;Inborn Errors of Metabolism;Infusion procedures;Isotope Labeling;Isotopes;Kidney;Label;Malignant - descriptor;Malignant Neoplasms;Measures;Metabolic;Methodology;Methods;Mus;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nutrient;Oxidative Phosphorylation;Pathway interactions;Patient-Focused Outcomes;Patients;Physiological;Procedures;Productivity;Property;Sampling;Series;Site;Source;Stable Isotope Labeling;Techniques;Time;Tracer;Variant;Work;cancer initiation;cohort;experimental study;imaging modality;insight;metabolic abnormality assessment;mitochondrial metabolism;mouse model;novel therapeutics;rare genetic disorder;success;therapeutic target;therapy resistant;tumor;tumor metabolism;tumor progression Human metabolic variation as a window into cancer initiation and progression PROJECT NARRATIVEMost cancer patients die when their tumors progress by metastasizing or becoming resistant to therapy. Wedeveloped techniques to study tumor metabolism directly in patients and as a result discovered metabolicproperties that promote cancer progression and early death. We will now 1) block these pathways to prolongsurvival in mouse models of cancer; 2) develop methods to discover more metabolic properties that drive cancerprogression in patients and could be blocked with new therapies; and 3) use a unique orthogonal approachbased on rare genetic diseases to discover how some metabolic defects prime cells to become malignant. NCI 10736053 8/8/23 0:00 RFA-CA-22-045 2R35CA220449-07 2 R35 CA 220449 7 "WILLIS, KRISTINE AMALEE" 9/4/17 0:00 8/31/30 0:00 ZCA1-SRB-E(M1) 1900629 "DEBERARDINIS, RALPH J" Not Applicable 30 PEDIATRICS 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 967027 NCI 600000 367277 PROJECT SUMMARY/ABSTRACTMetabolic reprogramming is a hallmark of malignancy and potential source of therapeutic targets. Recent workindicates that metabolic liabilities change as cancer progresses meaning that the pathways most relevant toadvanced cancers may not be apparent in locally-invasive treatment-nave tumors at the site of origin.Recognizing the dearth of direct information about human cancer metabolism we developed an approach toprobe the metabolic network of intact human tumors by infusing patients with stable isotope-labeled nutrients(e.g. 13C-glucose) during tumor resection or biopsy. By measuring isotope labeling in metabolites extracted fromtumor samples and following the outcomes of patients who underwent this procedure we identified metabolicproperties associated with poor survival. Of hundreds of metabolic features 13C labeling in tricarboxylic acid(TCA) cycle metabolites was the most predictive of cancer progression and early death. In non-small cell lungcancer (NSCLC) patients whose tumors have high labeling of these metabolites succumb much earlier thanpatients with low labeling and blocking this pathway in mouse models of NSCLC suppresses metastasis. Inclear cell renal cell carcinoma (ccRCC) TCA cycle labeling is low when tumors are localized to the kidney butmuch higher in metastatic tumors and activating the TCA cycle promotes metastasis in mice. Therefore in bothkinds of cancer data from patients lead us to conclude that oxidative mitochondrial metabolism particularly theTCA cycle electron transport chain (ETC) and oxidative phosphorylation (OxPhos) promote cancer progression.The success of these experiments prompts us to further study the metabolic basis of human cancer progressionin the hopes of developing new insights and therapies. We propose three general directions. First using acombination of approaches in humans and mice we will thoroughly examine how mitochondrial metabolismstimulates metastasis to identify discrete metabolic dependencies that could be safely targeted in patients.Second we will develop approaches to discover new metabolic liabilities in human tumors. Strategies include apipeline to probe viable tumor explants with a series of isotope-labeled nutrients under physiological conditionsto choose the most informative tracers for isotope infusions in patients; and dynamic imaging methods to observeand quantify informative aspects of metabolic flux in tumors in real time. Third we will use the orthogonalapproach of studying human inborn errors of metabolism (IEMs) to discover why some metabolic anomaliesprime cells to become malignant. This approach capitalizes on a clinical cohort of over 1000 subjects includingpatients with IEMs associated with highly penetrant cancers and will provide unique insights into cancer initiationand progression. Altogether these efforts will build on our long-standing productivity in human cancer metabolismby uncovering new mechanisms governing the metabolic basis of cancer progression and producing newmethodologies to understand and treat lethal malignancies. 967027 +No NIH Category available Acidosis;Amyloid;Animal Model;Applications Grants;Balbiani Body;Biochemical;Biological;Biological Assay;Catalytic Domain;Cell Cycle Regulation;Cells;Clinical;DNA biosynthesis;DNA-Directed DNA Polymerase;Data;Dedications;Depressed mood;Detection;Dinucleotide Repeats;Elements;Environment;Enzyme Activation;Enzymes;Evolution;Genetic Transcription;Germ Cells;Growth;Human;Human Genome;Hypoxia;Immobilization;Junk DNA;Liquid substance;Malignant - descriptor;Malignant Neoplasms;Mediating;Membrane;Metabolic;Metabolism;Names;Nature;Normal tissue morphology;Nuclear Envelope;Nucleic Acids;Oncogenic;Organelles;Participant;Pathway interactions;Phase Transition;Phenotype;Physical condensation;Physiological;Play;Process;Proliferating;Protein Array;Proteins;Proteome;Proteomics;Publishing;RNA;Reporting;Reproduction spores;Ribosomal RNA;Ribosomes;Role;Sampling;Signal Transduction;Solid;Stimulus;Stress;System;Tail;Testing;Untranslated RNA;Xenopus;Yeasts;amyloid formation;amyloidogenesis;biophysical properties;cancer cell;cell assembly;extracellular;fascinate;granule cell;in vivo;malignant phenotype;metabolic depression;neoplastic cell;programs;response;solid state;stress granule;stressor;tumor;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Amyloid-bodies and the Evolution of Malignancies Amyloid-bodies and the Evolution of MalignanciesNarrativeCancer cells encounter various adverse environmental conditions during tumorigenesis. Our group has recentlydiscovered that cancer cells solidify their proteins to enter spore-like state like how yeast undergo sporulation.By this process of protein solidification cancer cells can resist the harsh conditions of the tumormicroenvironment. NCI 10736039 8/7/23 0:00 PA-20-185 1R01CA275828-01A1 1 R01 CA 275828 1 A1 "FINGERMAN, IAN M" 8/7/23 0:00 7/30/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 11232879 "LEE, STEPHEN " Not Applicable 27 BIOCHEMISTRY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 8/7/23 0:00 7/30/24 0:00 393 Non-SBIR/STTR 2023 388191 NCI 252893 135298 Amyloid-bodies and the Evolution of Malignancies Project SummaryThe ability of cancer cells to adapt to a wide variety of stress conditions plays a critical role in variousphysiological facets of tumorigenesis. We recently reported the discovery of stress-induced low complexitynoncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmaticregion of the human genome historically dismissed as junk DNA. We showed that low complexity rIGSRNAactivate a physiological amyloidogenic program that converts nucleoli into Amyloid-bodies: reversible nuclearmembrane-less compartments composed of immobilized proteins in an amyloid-like state. While many cellularbodies have been described as liquid-like (e.g. stress granules P-bodies germ cell granules) the discovery ofAmyloid-bodies provided evidence of an amyloidogenic program that can physiologically transition biologicalmatter to a solid state. Amyloid-bodies are found in sub-populations of cells in normal tissues the core of low-grade human tumors and cells responding to various stimuli highlighting their ubiquitous nature. Proteomicanalysis revealed that Amyloid-bodies immobilize participants of the DNA synthesis machinery and cell cyclecontrol amongst many other metabolic regulators. Intriguingly Amyloid-bodies share many biophysicalproperties with the amyloidogenic solid-like Balbiani-bodies involved in metabolic suppression in Xenopus.Likewise yeast solidify elements of their proteome to sporulate and arrest growth in non-permissive conditions.This raises the fascinating possibility that stressed cancer cells assemble Amyloid-bodies to enter a spore-likestate of extreme metabolic depression. In this grant proposal we will show preliminary data that low complexityrIGSRNA coordinate unusual RNA tailing programs to drive system-wide amyloidogenic phase transition. Thispost-translational pathway enables cancer cells to immobilize elements of the DNA synthesis machinery and haltoncogenic signaling in an adaptive response to severe environmental insults. Based on these preliminary andpublished results we hypothesize that Nucleolar phase transition programs temporarily suspend oncogenicity.We plan to test this hypothesis by: 1- Uncovering mechanisms of physiological phase transition; 2- Examininghow low complexity rIGSRNA activate RNA tailing programs; 3- Demonstrating a role for RNA tailing-mediatedphase transition in tumorigenesis. The discovery of dedicated enzymatic programs that drive physiologicalamyloidogenesis provides a unique opportunity to study the role of liquid-to-solid phase transition in humanclinical samples and in vivo tumor assays. By studying clinical samples in culture and orthotopic animal modelswe will test if phase transition induces a unique and yet uncharacterized cancer cell state of extreme metabolicdepression while highlighting biochemical functions for low complexity RNA typically discarded as uselessnucleic acids. 388191 +No NIH Category available AR gene;Androgen Metabolism;Androgen Receptor;Antibody-drug conjugates;Automobile Driving;Biological;Biological Markers;Biopsy;Blood;Bypass;Cancer Patient;Castration;Cell surface;Chromatin;Clinical;Clinical Trials;Combined Modality Therapy;Consensus;Disease;Disease Resistance;Enhancers;Epigenetic Process;Epithelial Cells;FDA approved;Future;Gene Amplification;Gene Expression Profiling;Gene Rearrangement;Generations;Genetic Transcription;Genomics;Goals;Human;In Vitro;Life;Malignant Neoplasms;Malignant neoplasm of prostate;Medical;Metastatic Prostate Cancer;Molecular;Molecular Analysis;Mutation;Mutation Analysis;Neoplasm Circulating Cells;Neuroendocrine Cell;New Agents;Pathway interactions;Patient Selection;Patients;Phase II Clinical Trials;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Progression-Free Survivals;Receptor Signaling;Regimen;Regulation;Resistance;Sampling;Solid Neoplasm;Specimen;Surface Antigens;TACSTD2 gene;Testing;Therapeutic;Tissues;Transcription Alteration;Translational Research;Treatment Efficacy;Trophoblastic Cell;Variant;abiraterone;advanced prostate cancer;castration resistant prostate cancer;chemotherapy;clinical efficacy;constitutive expression;docetaxel;effective therapy;enzalutamide;epigenomics;hormone therapy;improved;in vivo;inhibitor;liquid biopsy;men;novel;novel therapeutics;pharmacodynamic biomarker;phase II trial;pre-clinical;preclinical study;predictive marker;programs;prospective;radioligand;radiological imaging;research study;resistance mechanism;response;single cell proteins;targeted treatment;taxane;therapeutic target;therapy resistant;treatment strategy;tumor Molecular regulation and expression of Trop-2 in advanced prostate cancer: Identifying optimal therapeutic niches Project NarrativeAs highly effective though non-curative therapies for metastatic prostate cancer are now being used in earlierstages of disease there is a critical need for new treatments in castrate resistant prostate cancer (mCRPC).We have identified Trop-2 as a high value target that can be expressed in treatment resistant prostate cancer.We will study biomarkers of Trop-2 in a clinical trial for men with mCRPC with an antibody drug conjugate thattargets Trop-2. Integrated blood and tumor biopsies will be analyzed to identify novel predictive biomarkers. NCI 10735996 6/22/23 0:00 PA-20-185 1R01CA276269-01A1 1 R01 CA 276269 1 A1 "MCKEE, TAWNYA C" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 10134900 "LANG, JOSHUA MICHAEL" "DEHM, SCOTT M." 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 695050 NCI 544769 150281 PROJECT SUMMARY/ABSTRACTThe last decade has seen a significant increase in the number of FDA approved treatments for menwith metastatic castrate resistant prostate cancer (mCRPC). Even greater improvements in survivalwere observed for men with metastatic castration sensitive PC (mCSPC) treated with chemotherapy orandrogen receptor signaling inhibitors compared to hormone therapy alone (Despite these advancesin mCSPC median OS for men with mCRPC remains less than two years and cross-resistance totherapies within the same class (e.g. Enzalutamide and Abiraterone) occurs in >90% of patients limitingeffective treatments in mCRPC to agents with OS improvements ranging from only 2-4 months. Thereis a critical need to identify new agents that can eliminate resistant disease5. Understanding themolecular associations driving resistance may identify new therapeutic sensitivities in these aggressivecancers to improve quality and quantity of life for men with mCRPC. Translational research studiesfocused on understanding the underlying mechanisms driving treatment resistance in CRPC haveidentified a wide range of genomic epigenomic and transcriptional alterations. Approximately 15-20%of patients with mCRPC develop lineage plasticity with small cell neuroendocrine CRPC (SCNPC)representing the most aggressive subtype. However the field lacks consensus definitions for thediverse lineage plasticity phenotypes observed in mCRPC and few therapeutic targets have beendeveloped to date. In this study we propose Trop-2 (Trophoblastic cell-surface antigen) as a high valuetarget for therapy of mCRPC with an antibody-drug conjugate Sacituzumab Govitecan (SG). Wehypothesize that ARSI-resistant phenotypes in mCRPC can be identified through integrated solidtumor and liquid biopsy analysis and targeted therapeutically with SG. To test this hypothesis wepropose to study Trop-2 regulation in pre-clinical and clinical specimens and test this agent in aprospective Phase II clinical trial for ARSI-resistant mCRPC. In Aim 1 we will conduct molecular-spatialanalysis of Trop-2 expression in mCRPC PDX tissues as well as solid tumor and liquid biopsies frompatients with CSPC CRPC and SCNPC In Aim 2 we will evaluate solid tumor and liquid biopsiescollected longitudinally from patients with mCRPC treated with SG in a prospective Phase II trial. Aim2 will characterize chromatin enhancer profiles in the TACSTD2 gene encoding Trop-2 to identifyfactors regulating Trop-2 levels in prostate cancer. We will test if Trop-2 levels determine sensitivity toSG therapy and identify SG-based combination regimens that enhance therapeutic efficacy in vitroand in vivo. 695050 +No NIH Category available Animal Model;Architecture;Atlases;BAY 54-9085;Biopsy;CCL15 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;CTNNB1 gene;Cancer Etiology;Cells;Cellular Structures;Clinic;Clinical;Clinical Trials;Coupled;Cultured Tumor Cells;Data;Diabetes Mellitus;Etiology;Exclusion;Fresh Tissue;Generations;Genes;Genomics;Goals;Hepatocarcinogenesis;Heterogeneity;Histologic;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immunologic Surveillance;Immunology;Immunooncology;Immunotherapeutic agent;Immunotherapy;Impairment;Incidence;Knowledge;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of liver;Maps;Mitogen-Activated Protein Kinase Inhibitor;Molecular;Mus;Mutation;Obesity;Organoids;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Population;Positioning Attribute;Prevalence;Primary carcinoma of the liver cells;Probability;Public Health;Refractory;Regulatory T-Lymphocyte;Reproducibility;Resistance;Resolution;Sampling;Subgroup;Systemic Therapy;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic Uses;Tissues;Tumor-Infiltrating Lymphocytes;VEGFA gene;Viral;WNT Signaling Pathway;anti-PD-1;anti-PD-L1;anti-PD1 therapy;antitumor effect;bevacizumab;biomarker driven;biomarker identification;candidate marker;cohort;combinatorial;drug testing;experience;gain of function mutation;genetic signature;immune resistance;individualized medicine;inhibitor;insight;matrigel;molecular marker;mortality;mouse model;neoplastic cell;neutrophil;nonalcoholic steatohepatitis;objective response rate;patient stratification;predicting response;preservation;programmed cell death protein 1;prospective;reconstitution;resistance mechanism;response;response biomarker;single cell technology;single-cell RNA sequencing;standard of care;synergism;three dimensional cell culture;tool;transcriptomics;treatment strategy;tumor;tumor microenvironment Determinants of immunotherapy response in NASH-Hepatocellular carcinoma PROJECT NARRATIVEHepatocellular carcinoma (HCC) the most common type of liver cancer is a global public health problem. Thegoal of our proposal is to explore determinants of immunotherapy response in a subgroup of HCCs associatedwith non-alcoholic steatohepatitis (NASH) that are prone to immune evasion. NCI 10735947 8/4/23 0:00 PA-20-185 1R01CA273932-01A1 1 R01 CA 273932 1 A1 "SINGH, ANJU" 8/4/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 7926229 "LLOVET, JOSEP M" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 8/4/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 473881 NCI 280403 193478 PROJECT SUMMARY / ABSTRACTHepatocellular carcinoma (HCC) incidence and mortality is increasing in the US and worldwide. Around ~50-60% of HCC patients will receive systemic therapies. After a decade of primacy of sorafenib the combinationregime of immune checkpoint inhibitor (ICI) atezolizumab (anti-PDL1) with bevacizumab (anti-VEGFA)demonstrated superior clinical benefits (median survival of ~19 months) and has become the standard of care.However the rate of objective response remains at ~30%. In parallel our group demonstrated that 1) HCCetiology differentially impacts outcome with patients with HCC deriving from non-alcoholic steatohepatitis (NASH)benefitting significantly less from immunotherapy; 2) Dysfunctional CD8 cells are implicated in the underlyingmechanism of resistance in NASH-HCC; 3) Newly generated gene signatures predict response to ICI; and 4)The immune excluded class is driven by Wnt signaling/CTNNB1 mutations in HCC and thus discoveredKIT/MAPK/Wnt inhibitors combined with ICI are adequate strategies to rescue this mechanism of immune-evasion. Our central hypothesis is that such decreased response to ICIs in patients with NASH-HCC can bereverted therapeutically using combinations of ICI and KIT/MAPK/Wnt signaling blockers; and candidatebiomarkers of response can be identified and validated. Thus the overarching goal of this proposal is to gainfurther insight into mechanisms of both NASH-HCC immune response and resistance via state-of-the-art singlecell technologies so as to identify biomarkers and overcome resistance through the rational testing ofcombinatorial immunotherapeutic strategies which could eventually increase the number of HCC patientsderiving clinical benefit from immunotherapy. To accomplish this goal we seek to achieve the following specificaims: 1) To map the immune cell microenvironment in human NASH-HCC by using single cell-based approachesand high-resolution spatial transcriptomics; 2) To identify biomarkers predicting response and resistance to thecombination of atezolizumab plus bevacizumab in human NASH-HCC by testing identified gene signatures andmolecular markers of response (using transcriptomics and mutational profiling) as well as spatialtranscriptomics; 3) To develop therapeutic strategies to overcome ICI resistance in NASH-HCC using specificpatient-derived organoids with immune component and mouse models that recapitulate the human NASH-HCCmicroenvironment. These hypothesis-driven strategies include testing drugs blocking key pathways of immuneevasion (Wnt) in combination with ICI. The pursuit of these aims will be coupled with our expertise in NASH-related hepatocarcinogenesis genomics and transcriptomics single-cell based technologies immuno-oncologygeneration of organoids reconstituted with TILs and mouse modeling. We expect that our proposal will bringprecision immune-oncology closer to the clinics will promote clinical trials including KIT/MAPK/WNT inhibitorswith promise of significant benefit to the outcomes of HCC patients. Overall our discoveries will create aparadigm shift in the field of NASH-HCC. 473881 +No NIH Category available Adoptive Immunotherapy;Affect;Aftercare;Autologous;B-Cell Activation;B-Cell Lymphomas;B-Lymphocytes;Biochemical;Biology;Blood;CD4 Positive T Lymphocytes;Cancer Cell Growth;Cell Count;Cell Differentiation process;Cell Maturation;Cell Survival;Cell model;Cell secretion;Cells;Chronic Lymphocytic Leukemia;Clinical;Communication;Cues;Data;Development;Disease;Disease Progression;Elements;Engraftment;Experimental Models;FDA approved;Functional disorder;Future;Generations;Glean;Goals;Growth;Helper-Inducer T-Lymphocyte;IL17 gene;Immune;In Vitro;Individual;Knowledge;Laboratories;Learning;Link;Lymphoid Tissue;Mediating;Membrane;MicroRNAs;Modality;Molecular;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphorylation;Process;Proliferating;Publishing;Regimen;Regulation;Research;Role;STAT3 gene;Shapes;Signal Transduction;Stromal Cells;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Therapeutic;Treatment Efficacy;Work;Xenograft procedure;adult leukemia;antitumor effect;cell growth;chronic T-cell leukemia;chronic lymphocytic leukemia cell;cohort;curative treatments;cytokine;effective therapy;genetic approach;genome-wide analysis;immune modulating agents;improved;improved outcome;in vivo;inhibitor;innovation;leukemia;molecular modeling;receptor;response;targeted treatment;therapeutic effectiveness;trafficking;translational study;tumor microenvironment Th17 generation action and therapeutic relevance in chronic lymphocytic leukemia PROJECT NARRATIVE:B-cell chronic lymphocytic leukemia (CLL) the most common adult leukemia in the US remains incurable andtherefore there is an urgent need to develop new effective therapies based on a more precise understanding ofdisease pathophysiology. The objective of this proposal is to build upon our recent discovery of a previouslyunrecognized role for the Th17/IL-17 axis in improving the clinical course of CLL patients. Using a combinationof molecular cellular and experimental model approaches we will identify the pathways that induce and aremediated by the Th17/IL-17 axis in patients with CLL and that might be manipulated by the drug idelalisib toimprove the outcome of patients with this still fatal disease. NCI 10735876 11/10/23 0:00 PA-19-056 5R01CA238523-05 5 R01 CA 238523 5 "LIU, YIN" 12/1/19 0:00 11/30/24 0:00 Clinical Oncology Study Section[CONC] 8936361 "CHIORAZZI, NICHOLAS " "SHERRY, BARBARA A" 3 Unavailable 110565913 C5LHMPRJ9J19 110565913 C5LHMPRJ9J19 US 40.775574 -73.703024 4155008 FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH MANHASSET NY Research Institutes 110303816 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 396 Non-SBIR/STTR 2024 495764 NCI 315228 180536 PROJECT SUMMARY/ABSTRACTSurvival and growth of cancer cells depend on environmental cues delivered by cell contact and soluble factors.These shape disease biology and aggressiveness reflected by the effectiveness of therapeutic regimens inblocking trophic inputs. This principle is exemplified in the relatively common and still incurable chroniclymphocytic leukemia (CLL) a disease of clonal CD5+ B cells requiring ongoing signaling from membranereceptors and cells within the tumor microenvironment. While considerable information has been gleaned aboutthe bi-directional dialogue between CLL B cells and autologous T cells little information is available aboutindividual T-cell subsets particularly Th17 cells a unique subset of T helper cells. The scientific premise ofthis proposal comes from our findings that in CLL: [1] higher levels of Th17-related cytokines and numbers ofcirculating Th17 cells associate with better clinical outcomes; [2] leukemic B cells promote Th17 generation fromautologous CD4 T cells in vitro; [3] expression of miR155 which promotes Th17 cell differentiation is significantlyhigher in Th17 cells from CLL patients than in healthy subjects; [4] Th17 cells modulate CLL B-cell survival andgrowth in vitro and in vivo; and [5] treatment of nave CLL T cells from CLL patients with the PI3K inhibitoridelalisib significantly enhances Th17-cell generation. These findings underlie our central hypothesis that CLLB cells promote the generation of Th17 cells which exert anti-tumor effects within the leukemic compartment.We expect that enhancing idelalisib's ability to positively affect Th17 generation and function will significantlyimprove its clinical value. Our long-range goal is to define this cellular bi-directional communication more clearlyat the molecular level so as to manipulate these interactions to therapeutic advantage. To advance ourhypotheses and goal we propose studies to: elucidate cellular and molecular mechanism(s) whereby leukemicB cells regulate Th17 cell generation in CLL focusing on the STAT3/miR155 pathway (Aim 1); determine theinfluence of Th17 cells on leukemic B-cell survival growth and maturation in vitro and in vivo (Aim 2) andinvestigate the effects of idelalisib on Th17-cell generation and function in CLL (Aim 3). The proposed work isinnovative as it is the first to explore underlying mechanisms by which leukemic B cells regulate the generationand function of Th17 cells and the impact this regulation has on clinical outcome; it is also the first study ofgenome-wide miR expression in T cells from CLL patients. Also these innovative studies will have considerableimpact on CLL since we will identify mechanisms generating Th17s in CLL and the impact this T-cell subset hason leukemic B cell growth proliferation and maturation. Finally we will determine if lower Th17-cell numbers inCLL patients with poor outcomes results from inherent differences in the CLL T or B cells. This will serve to betterinform future studies on how to enhance Th17 responses in CLL as a therapeutic modality achieved by targeteddrug therapy or adoptive immunotherapy. 495764 +No NIH Category available Academy;American;Area;CAR T cell therapy;Cancer Hospital;Cancer Patient;Capital;Caring;Clinical Data;Collaborations;Complex;Comprehensive Health Care;Country;Data;Data Set;Data Sources;Databases;Development;Diffusion;Disparity population;Enrollment;Expenditure;Fee-for-Service Plans;Foundations;Genomics;Growth Factor;Guidelines;Health system;Healthcare Systems;Hospitals;Immunotherapy;Improve Access;Incentives;Individual;Infrastructure;Investments;Knowledge;Link;Malignant Neoplasms;Marketing;Measurement;Measures;Medicaid;Medicare;Medicine;Modeling;Neutropenia;Oncology;Organizational Change;Outcome;Ownership;Palliative Care;Patient Care;Patient Outcomes Assessments;Patients;Performance;Pharmaceutical Preparations;Physicians;Policies;Policy Maker;Population;Poverty;Price;Provider;Quality of Care;Recommendation;Records;Regimen;Reporting;Risk;Rural;Source;System;Systems Integration;Taxes;Test Result;Testing;Time;Underserved Population;United States Agency for Healthcare Research and Quality;United States Centers for Medicare and Medicaid Services;Variant;Vulnerable Populations;acute care;bundled payment;cancer care;care coordination;care delivery;care providers;design;ethnic minority;evidence base;experience;genetic testing;health care delivery;health care service utilization;health information technology;hospice environment;hospital care;improved;innovation;multiple chronic conditions;novel;novel therapeutics;participant enrollment;patient population;payment;programs;racial minority;rural area;survivorship;targeted treatment;trend;tumor The Impact of a Changing Health Care Delivery System on the Quality of Oncology Care Project Narrative/RelevanceThis study will examine changes in the organization of oncology care providers over time and the impact ofthese changes on the quality of care diffusion of new therapies health care utilization and outcomes forcancer patients overall and for vulnerable/disadvantaged subgroups. The findings will provide oncologypractitioners payers and policy makers valuable information to improve access quality and outcomes ofcancer care. Our results also will inform policies and practices related to the value of integration of oncologycare quality measurement design of alternative payment models and development of innovative deliverymodels to care for vulnerable/disadvantaged populations. NCI 10735870 11/2/23 0:00 PA-19-056 5R01CA255035-04 5 R01 CA 255035 4 "WEAVER, SALLIE JAYNE" 12/15/20 0:00 11/30/25 0:00 Health Services Organization and Delivery Study Section[HSOD] 2087176 "KEATING, NANCY L" "LANDRUM, MARY BETH" 7 ADMINISTRATION 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 630209 NCI 403720 226489 Project Summary The cancer care delivery system frequently provides care that is not patient-centered evidence-basedor accessible to vulnerable and underserved populations. Cancer care and outcomes are particularly poor forpatients living in rural areas areas with high poverty racial/ethnic minorities and patients with multimorbidity.Recent advances such as genomic testing targeted therapy immunotherapy and CAR T cell therapy havemade oncology care more complex. Concurrently there has been substantial integration and consolidation ofthe delivery of cancer care and little is known about how consolidation impacts cancer care and outcomes. As part of an Agency for Health Care Research and Quality initiative on Health Systems Organizationand Performance our team created a novel national database (Enhanced DataBase [EDB]). The EDBcombines a wide variety of governmental and non-governmental proprietary sources to identify health systemsas groups of commonly owned providers and contains microdata on physicians physician practices hospitalsand health systems. We propose to leverage longitudinal data from the EDB to characterize the integration of cancer careover time using these changes to understand effects on care delivery including quality diffusion of newtherapies utilization and outcomes. We will study care for patients enrolled in fee-for-service Medicare andthose enrolled in Medicaid. In addition to studying claims-based measures of quality and utilization we will linkwith clinical data about genetic testing and test results from Foundation Medicine one of the country's largestproviders of somatic genomic testing. Specifically we will:1. Describe changes in integration and ownership of oncology care providers since 2010 and assess differences in these trends for providers serving large numbers of vulnerable or disadvantaged populations including rural and urban poor patients racial/ethnic minorities and individuals with multimorbidity.2. Leverage changes in the organization of care to assess the impact of integration and health system affiliation on quality of care outcomes utilization and spending for patients with cancer. We will examine quality across multiple domains including care coordination guideline recommended care avoidance of low-value care and patient experiences.3. Understand the extent to which quality and value of cancer care delivered within vs. outside of integrated systems differs for various disadvantaged populations including individuals living in rural and urban poor areas racial/ethnic minorities and individuals with multi-morbidity. Our study will provide oncology practitioners payers and policy makers valuable information toimprove access quality and outcomes of oncology care. Our results will inform policies and practices related tothe value of integration of oncology care quality measurement and design of alternative payment models. 630209 +No NIH Category available Acute;Address;Adult;Anatomy;Biological;Biological Assay;Biology;Blood Vessels;Brain;Brain Neoplasms;Cancer Patient;Carbon ion;Central Nervous System;Central Nervous System Neoplasms;Cessation of life;Charge;Childhood;Childhood Brain Neoplasm;Childhood Central Nervous System Neoplasm;Childhood Glioma;Chronic;Clinical;Cognitive;Complex;Control Groups;Cranial Irradiation;DNA Damage;Data;Development;Dose;Electrons;Exposure to;Foundations;Fright;Genetic Diseases;Glioma;Heterozygote;High-LET Radiation;Immune response;Immunocompetent;Immunohistochemistry;Impaired cognition;In Vitro;Induced Mutation;Knowledge;Laboratories;Late Effects;Linear Energy Transfer;Link;Longevity;Low Dose Radiation;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of central nervous system;Mediating;Methods;Modality;Modeling;Monitor;Mus;Neurologic;Neurosciences;Normal tissue morphology;Outcome;Outcome Assessment;PDGFRA gene;Pathologic;Patients;Pediatric Neoplasm;Physics;Pre-Clinical Model;Property;Protons;Radiation;Radiation Dose Unit;Radiation Oncology;Radiation therapy;Relative Biological Effectiveness;Research;Risk;Rodent Model;Roentgen Rays;Second Primary Cancers;Solid Neoplasm;TP53 gene;Testing;Therapeutic;Tissues;Toxic effect;Treatment outcome;Tumor Tissue;Uncertainty;United States National Aeronautics and Space Administration;Variant;Work;X-Ray Therapy;behavior test;biophysical properties;cancer risk;carbon ion therapy;clinical practice;clinically relevant;density;disorder control;efficacy evaluation;experience;high-LET heavy ion therapy;human disease;improved;in vivo;in vivo imaging;insight;interdisciplinary approach;ionization;millimeter;mosaic analysis;neurogenesis;neuroinflammation;neurotoxic;novel therapeutics;particle;particle therapy;pediatric patients;physical property;pre-clinical;radiation carcinogenesis;radiation risk;radioresistant;recombinase-mediated cassette exchange;response;side effect;sound;treatment risk;tumor;tumor growth;white matter damage Optimizing Carbon Ion Therapy for Pediatric CNS Tumors NARRATIVECarbon-ion radiation therapy (CIRT) has the potential to improve survival of adult patients with radioresistantbrain tumors due to its physical dose distributions and its high linear-energy transfer making it possible to treatbrain cancer using less radiation dose than x rays or protons. However for younger pediatric patientsundergoing critical stages of brain development the question shifts: what are the risks of functional neurotoxicand other late side effects? This critical and unanswered question is addressed by systematically quantifyingthe 1) RBE for CIRT-mediated normal-tissue toxicity in a rodent model of pediatric brain and 2) efficacy forCIRT in a preclinical rodent model of pediatric glioma. NCI 10735860 9/18/23 0:00 PA-20-185 1R37CA276936-01A1 1 R37 CA 276936 1 A1 "BUCHSBAUM, JEFFREY" 9/18/23 0:00 8/31/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 1984490 "ELEY, JOHN G." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/18/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 603073 NCI 361118 241955 SUMMARYPrimary central nervous system (CNS) tumors are the most common solid tumors in children and the leadingcause of childhood-cancer-related deaths. Thus there is an urgent need to identify novel therapeutic treatments.One such advancement is carbon-ion radiation therapy (CIRT). Yet despite treating 20000 patients over 2decades there is a significant reluctance to use this modality to treat pediatric brain tumors because of a fearthat normal tissue would be irreparably harmed. This fear is a consequence of the many questions that areunanswered regarding the ability to quantify the relative biologic effectiveness (RBE) of CIRT. An importantattribute of the physical dose delivered by charged particles is ionization density which varies with particle chargeand velocity. Ionization density is frequently described in terms of linear energy transfer (LET) defined as themean energy lost / by a charged particle per unit distance traversed due to interactions with electronsin matter. For charged particles the dose and LET increase dramatically over the terminal few millimeters of thepristine Bragg peak as the particle halts. A major uncertainty is the scaling from dose and LET to biological effectwhich varies within tumors and normal tissues in a complex manner. The computational dose and RBE modelssimulate on a millimeter-scale the variation of dose energy and LET spectra and particle fragment spectra withinthe patient anatomy and link these physical properties to biologic data often determined from in vitro clonogenicsurvival assays. A critical gap in knowledge is the true in vivo tissue response to high-LET radiation in clinicallyrelevant biological assays. The uncertainty is enormous and the impact of incorrect assignment of an RBE valueto a given voxel can be catastrophic in clinical practice. Therefore RBE values need to be determined with thegreatest possible accuracy. Our central hypothesis is that optimization of carbon-ion radiation therapy willallow for improved curative outcomes for pediatric brain tumors with equivalent or lower neurologictoxicity compared to x-ray therapy. Two specific aims will be used to test the hypothesis. Aim 1 willsystematically quantify the RBE of CIRT normal-tissue toxicity in a rodent model of pediatric brain for variousfunctional and pathologic endpoints at variable dose and LET compared to x-ray therapy. Aim 2 will test theworking hypothesis that high-LET carbon ions are more effective in controlling pediatric high-grade glioma thanconventional radiation. Thus the overall objective of this work is to investigate the normal brain toxicity cognitiveside effects second cancer risks and anti-tumor efficacy in preclinical models relevant for pediatric patientsproviding a sound foundation for advancing this modality into clinical practice. We will answer the question as towhether carbon-ion therapy which shows immense potential for historically radioresistant cancers can beexpected to improve the therapeutic window for pediatric high-grade glioma patients. Furthermore we willcontribute fundamental new knowledge regarding treatment risks and neurotoxic side effects relevant for allpediatric CNS tumors treated with radiation. 603073 +No NIH Category available Acceleration;Agonist;Binding;Bioinformatics;Biology;Cell Culture System;Cell Differentiation process;Cells;ChIP-seq;Clinical;Clinical Data;Clinical Research;Correlation Studies;Data;Data Correlations;Diagnosis;Disease;Disease Progression;Estrogen Receptor beta;Estrogen decline;Estrogens;Exhibits;Experimental Models;Exposure to;Genes;Genetic;Genetic Transcription;Goals;Gonadal Steroid Hormones;Hormones;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologics;Immunotherapy;In Vitro;Infiltration;Inflammatory;Knock-out;Knockout Mice;Lead;Link;Lymphocyte;Malignant Neoplasms;Mediating;Menopause;Metastatic Melanoma;Modeling;Molecular;Mus;Oncogenes;Outcome;Pathway interactions;Play;Population;Production;Proliferating;Regulation;Repression;Risk;Role;Signal Transduction;Skin Cancer;T cell infiltration;T-Cell Activation;Testing;Tumor Suppressor Proteins;Woman;Work;cell motility;checkpoint therapy;cytokine;epidemiology study;hormonal signals;hormone therapy;immune cell infiltrate;improved;melanocyte;melanoma;melanomagenesis;men;migration;mouse model;pharmacologic;receptor;response;transcription factor;transcriptome;treatment response;tumor;tumor initiation;ultraviolet;ultraviolet damage Estrogen receptor beta is a targetable melanoma tumor suppressor NARRATIVEEpidemiological studies and clinical data correlate decreased estrogen signaling and loss of estrogen receptorbeta (ER) expression to increased melanoma risk and disease progression. This proposal will determine howestrogen signaling through ER regulates melanocyte biology impacts immune recognition of the tumor andprotects against melanoma. As an integral part of these studies we propose to evaluate the potential of ER-specific agonists in enhancing current melanoma therapies. NCI 10735798 11/3/23 0:00 PA-20-185 5R01CA255158-03 5 R01 CA 255158 3 "JOHNSON, RONALD L" 12/1/21 0:00 11/30/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10454730 "BURD, CRAIG J" Not Applicable 3 BIOCHEMISTRY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 316320 NCI 205875 110445 PROJECT SUMMARY/ABSTRACTMelanoma is more prevalent in men than women suggesting sex hormones may influence this disease. Clinicalstudies correlate decreased estrogen receptor beta (ER) expression with disease progression. However themechanisms by which the receptor protects against melanoma formation and progression remain unknown.Our preliminary data show that ER loss accelerates tumor formation in a murine melanoma model therebyconfirming the tumor suppressor activity implicated in the clinical data. The melanocyte ER cistrome overlapswith key melanocyte transcription factors that act as master regulators of differentiation proliferation andmigration. Estrogen-regulated genes in melanocytes are associated with differentiation and migration pathwayssupporting a co-regulatory link between ER and these master regulators.In addition to the tumor suppressor function of ER in melanocytes ER has a melanocyte-nonautonomousfunction that results in reduced immune infiltrates within the tumor. Furthermore an ER-specific agonist canactivate T cells reduce immune checkpoint inhibitor expression and increase T cell activation.These data lead to the overarching hypothesis that ER activity represses melanoma initiation andprogression by modulating melanocyte-intrinsic master regulator activity and enhancing immuneresponses to the tumor. In this proposal the hypothesis will be tested by 1) Defining the melanocyte-intrinsicER activities that repress melanoma onset and progression; 2) Determining the influence of ER-regulatedimmune activities on melanoma initiation and therapeutic response. 316320 +No NIH Category available Acyltransferase;Aggressive Fibromatosis;Animal Cancer Model;Animal Model;Antineoplastic Agents;Apoptosis;Apoptotic;Biochemical;Cancer Model;Caspase;Cell Death;Cell Death Induction;Cell Line;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Coenzyme A;Connective Tissue;Elements;Enzymes;Fatty Acids;Future;Genes;Genetic Screening;Genetically Engineered Mouse;Goals;Human;Image;Investigation;Lecithin;Link;Lipids;Lysophospholipids;Malignant Neoplasms;Mesenchymal Cell Neoplasm;Metabolic;Metabolism;Modeling;NF-kappa B;Names;Oxidoreductase;Palmitates;Palmitoyl Coenzyme A;Pathway interactions;Patients;Post-Translational Protein Processing;Proteins;Regulation;Research;Resistance;Role;Soft tissue sarcoma;Testing;Therapeutic;Therapeutic Effect;Toxic effect;Tumor Suppressor Proteins;analog;cancer cell;cancer therapy;cell type;conventional therapy;design;drug candidate;genome-wide;improved outcome;in vivo;innovation;interest;lipid metabolism;lipidomics;molecular marker;novel;novel strategies;novel therapeutic intervention;novel therapeutics;palmitoylation;protein transport;sarcoma;small molecule;targeted cancer therapy;therapeutic target;tool Triggering a New Cancer Cell Death Mechanism in Sarcoma Project NarrativeWe find that disruption of lipid metabolism triggers a novel form of cell death in sarcoma andother cancer cells. These studies will investigate the biochemical regulation of this cell deathmechanism and its potential application to the treatment of cancer. NCI 10735740 6/1/23 0:00 PA-20-185 1R01CA272485-01A1 1 R01 CA 272485 1 A1 "SALNIKOW, KONSTANTIN" 6/1/23 0:00 5/31/28 0:00 Cancer Cell Biology Study Section[CCB] 9662037 "DIXON, SCOTT " Not Applicable 16 BIOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF ARTS AND SCIENCES 943052004 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 458362 NCI 295990 162372 Project AbstractLethal small molecules are powerful tools to discover and characterize new cell deathmechanisms that may be useful for cancer treatment. Using small molecules we have identifiedan unconventional form of non-apoptotic cell death that is distinct from apoptosis ferroptosisand other known forms of cell death. This lethal mechanism requires protein palmitoylation andinvolves the disruption of protein trafficking. In this research we propose to test the role of lipidmetabolic enzymes that may positively or negatively regulate palmoptosis. One Aim of thisresearch will focus on the lipid metabolic enzyme TECR (trans-23-enoyl-CoA reductase). Wewill test the hypothesis that TECR synthesizes palmitate that is used by protein palmitoylationenzymes to drive cell death via altered protein trafficking. A second Aim of this research will testthe hypothesis that cell death is triggered by the disruption of phosphatidylcholine metabolismwhich alters protein trafficking. A third Aim of this research will test the hypothesis that this newcell death mechanism can be activated in genetically engineered mouse models of cancer by aclinical drug candidate. While this cell death mechanism can be activated in diverse cancers amajor focus of the proposed studies is on sarcoma which is highly sensitive to this lethalmechanism and for which new treatments are urgently needed. Together these studies willdefine a new form of cell death and associated biochemical mechanisms that may be exploitedfor the treatment of sarcoma and other cancers. 458362 +No NIH Category available Address;Adoption;Age;Archives;Black race;California;Cancer Diagnostics;Cancer Etiology;Categories;Cessation of life;Clinical;Cohort Studies;Data;Detection;Diagnosis;Economics;Electronic Health Record;Erectile dysfunction;European;Exposure to;Frequencies;Future;Goals;Health;Health Care Costs;Human Glandular Kallikrein 2;Integrated Health Care Systems;Investigation;Kininogenase;Length;Literature;Malignant Neoplasms;Malignant neoplasm of prostate;Morbidity - disease rate;PSA level;PSA screening;Phase;Population;Preventive care;Prostate;Prostate Cancer therapy;Prostate-Specific Antigen;Psyche structure;Race;Recommendation;Relative Risks;Research Priority;Risk;Running;Sample Size;Sampling;Screening for Prostate Cancer;Serum;Specimen;Testing;Treatment Side Effects;Uncertainty;United States Preventative Services Task Force;Variant;base;black men;checkup examination;clinical predictors;clinically relevant;cohort;comorbidity;cost;design;early screening;empowerment;evidence base;follow-up;high risk men;high standard;improved;indexing;member;men;mortality;novel;novel strategies;older men;overtreatment;preservation;prevent;prostate cancer prevention;prostate cancer risk;racial diversity;risk prediction;risk stratification;screening;screening guidelines;study population;validation studies;young man Tailored prostate cancer screening: addressing USPSTF priority research gaps in a racially-diverse study population NARRATIVECurrently the best way in which to screen men for prostate cancer (PCa) is unknown resulting in a large burdenof invasive expensive and unnecessary PCa diagnostic investigations and therapies. Our proposed R01 willaddress this problem by optimizing screening and identifying who when and how often men should bescreened for PCa to prevent the high morbidity and mortality of this cancer while also reducing the physicalmental and economic harms of screening. NCI 10735739 7/24/23 0:00 RFA-CA-22-050 1R01CA283896-01 1 R01 CA 283896 1 "MARCUS, PAMELA M" 8/1/23 0:00 7/31/28 0:00 ZCA1-RPRB-6(M2)S 11600168 "LANGSTON, MARVIN EPOLIAN" "SUTCLIFFE, SIOBHAN " 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 353 Non-SBIR/STTR 2023 680237 NCI 537308 142929 ABSTRACTScreening for prostate cancer (PCa) is highly controversial as accumulated evidence indicates that widespreadroutine prostate-specific antigen (PSA)-based screening reduces PCa mortality but at the cost of significant over-diagnosis and over-treatment. PSA-based risk-stratified screening could capture much of the benefit of screeningwhile greatly reducing over-diagnosis. This promising approach uses mens baseline PSA values to inform theirrisk of future aggressive and/or fatal PCa and determine their frequency of further screening. Under thisapproach men with high baseline age-specific total PSA levels receive more frequent screening and men withlower levels receive less frequent screening. This efficient approach is currently supported by at least three USadvisory agencies but not by several others including most notably the US Preventive Services Task Force.This agency recommends additional validation studies with longer-term follow-up before considering PSA-based risk-stratified screening. Additional data are also needed to optimize each of the components of PSA-based risk-stratified screening including the: (1) age at which baseline PSA values should be obtained (2) lengthof tailored re-screening intervals (3) tailored age at screening cessation (4) tailored strategies for Black menas these men are at higher risk of aggressive and fatal PCa yet remarkably under-represented in the screeningliterature and (5) prostate-specific kallikreins used for screening as kallikreins beyond total PSA have also beenfound to predict PCa risk and mortality and thus might help to optimize PSA-based risk-stratified screening.Therefore to address each of these gaps we propose to leverage data and serum specimens collected in thelarge racially-diverse Kaiser Permanente Northern California integrated health system along with its long-running (over 5 decades) embedded Multiphasic Health Checkups cohort and nested case-cohort to: (1)evaluate the utility of initiating baseline PSA screening before age 50 (2) determine the optimal re-screeninginterval after a baseline PSA test (3) identify populations of men at age 60 who might consider stoppingscreening (4) explore whether Black men should initiate screening earlier and be screened more frequently thanWhite men and (5) evaluate whether adding other prostate-specific kallikreins to total PSA enhances predictionof clinically-relevant PCa. Our overall goal is to provide evidence for smarter or more nuanced PSA screeningstrategies to preserve or enhance the mortality benefits of PSA screening while greatly minimizing its harmsand costs. 680237 +No NIH Category available 3-Dimensional;Ablation;Acute;Address;Adhesions;Affect;Aftercare;Animal Model;Antibodies;Basic Science;Behavior;Behavioral;Biology;Biomedical Engineering;Blood Vessels;Blood capillaries;Brain;Brain Death;Brain Edema;CAR T cell therapy;CD19 gene;Capillary Endothelial Cell;Cell Adhesion Molecules;Cell-Cell Adhesion;Cells;Cellular immunotherapy;Central Nervous System;Cerebral Edema;Child;Childhood;Clinical;Clinical Trials;Collaborations;Collagen;Coma;Delirium;Development;Dose;Endothelium;Engineering;Epitopes;Equilibrium;Flow Cytometry;Gene Expression Profiling;Genetic;Hematologic Neoplasms;Hemorrhage;Human;Human Engineering;Hydrogels;Hypoxia;Image;Immune system;Immunocompetent;Immunoprecipitation;Impaired cognition;Impairment;In Vitro;Inflammatory;Infusion procedures;Injury;Integrin Binding;Integrins;Interdisciplinary Study;International;Investigation;Leukocytes;Link;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Medical;Modality;Modeling;Molecular;Motor;Mus;Neurologic;Neuronal Dysfunction;Neurosciences;Oncology;Pathway Analysis;Patients;Perfusion;Pericytes;Phenotype;Plasma;Positioning Attribute;Property;Proteins;Protocols documentation;Receptor Activation;Risk;Risk Factors;Safety;Sampling;Seizures;Signal Induction;Signal Transduction;Small Interfering RNA;Stimulus;T-Cell Proliferation;T-Lymphocyte;Techniques;Testing;Therapeutic Intervention;Toxic effect;Transgenic Organisms;Translating;Work;brain dysfunction;brain endothelial cell;cancer cell;cancer immunotherapy;cell type;cerebral capillary;cerebral microvasculature;chimeric antigen receptor;chimeric antigen receptor T cells;cohort;cytokine;cytokine release syndrome;experience;experimental study;genetically modified cells;high risk;human model;immunological synapse;in vitro Model;in vivo;in vivo imaging;in vivo two-photon imaging;innovation;knock-down;leukemia/lymphoma;manufacture;mouse model;natalizumab;neurotoxicity;neurovascular unit;novel;peripheral blood;preclinical safety;prevent;preventive intervention;protein protein interaction;receptor binding;side effect;systemic inflammatory response;tumor Endothelial-Leukocyte Adhesion in CAR T Cell Treatment Associated Neurotoxicity PROJECT NARRATIVEThis project investigates the mechanism of neurologic toxicity in chimeric antigen receptor (CAR) T cell therapya novel and highly effective cancer immunotherapy that unfortunately has frequent side effects of cognitivedisturbances seizures or even fatal brain swelling. We have found in a mouse model that white blood cellsobstruct capillaries in the brain during neurotoxicity. We will now determine whether dislodging these cells fromthe vessels can prevent neurotoxicity whether this mechanism can be recapitulated in a human in vitro brainmicrovessel model and how the signaling properties of CAR T cells contribute to toxicity and cell-cell adhesion. NCI 10735681 9/20/23 0:00 PA-20-185 1R37CA275954-01A1 1 R37 CA 275954 1 A1 "CARDONE, MARCO" 9/22/23 0:00 8/31/28 0:00 Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] 8856715 "GUST, JULIANE " Not Applicable 7 Unavailable 48682157 SZ32VTCXM799 48682157 SZ32VTCXM799 US 47.66243 -122.282291 1531401 SEATTLE CHILDREN'S HOSPITAL SEATTLE WA Independent Hospitals 981053901 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 602466 NCI 326286 276180 PROJECT SUMMARY This project studies the mechanism of neurologic toxicity in chimeric antigen receptor (CAR) T celltherapy. CAR T cells are genetically modified patient derived T cells that use the CAR to recognize and destroymalignant target cells. Although CAR T therapy has shown impressive results against leukemia and lymphomaapproximately 30-40% of patients experience neurologic side effects in the first month after receiving CD19-targeted CAR T cells. This includes cognitive disturbances seizures and in rare cases fatal cerebral edema.Systemic cytokine release syndrome after CAR T cell infusion is a well-established risk factor for neurotoxicitybut the connection between systemic inflammation and brain dysfunction is poorly understood. To study the mechanisms of neurotoxicity we have developed an immunocompetent mouse model. Aftertreatment with high dose CD19-directed murine CAR T cells mice develop motor and balance difficulties aswell as brain microhemorrhages. Surprisingly we found that >10% of cortical capillaries are obstructed by whiteblood cells during neurotoxicity. This was accompanied by capillary remodeling and decreased vessel coverageby pericytes. Based on these findings we now propose the following experiments:Aim 1: What molecular mechanisms cause white blood cells to plug capillaries during neurotoxicity? Wewill use in vivo two-photon imaging in mice to determine which cell types cause the capillary plugging themouses own or the transferred CAR T cells? We will then measure how CAR T cell treatment changes theexpression of adhesion molecules in brain capillary endothelial cells and in leukocytes and test whetherblockade of these adhesion interactions can prevent capillary plugging and neurotoxicity. Aim 2: Is neuroendothelial-leukocyte adhesion increase in human microvessels during neurotoxicity? Inparallel to our work in mice we will use a 3D in vitro model of human brain capillaries to measure how solublefactors in patient plasma affect adhesion molecule expression in the endothelium. We will then test whetherwhite blood cells from CAR T cell patients with neurotoxicity have increased predilection for plugging syntheticmicrovessels that mimic capillaries and whether we can prevent this plugging by blocking adhesion molecules. Aim 3: Can the strength of cell-cell adhesion signaling separate CAR T cell efficacy from toxicity? We willuse quantitative multiplex immunoprecipitation to probe protein-protein interaction networks in CAR T cells thatcause high or low neurotoxicity in mice to understand what activation states are conducive to neurotoxicity. Wewill then test whether knock down of adhesion molecule expression can direct CAR T cells away from a toxicityphenotype by impairing their ability to signal to other cells and to adhere to the brain microvasculature. This work is innovative because it combines advanced imaging in vitro modeling techniques and proteinnetwork analysis in a unique collaboration between neuroscience vascular biology and oncology. The work issignificant because it addresses key safety issues in emerging cancer immunotherapy modalities. 602466 +No NIH Category available 3' Untranslated Regions;Acceleration;Address;Affect;Affinity;African American;African American population;Automobile Driving;Binding;Biological Factors;Biological Markers;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Epithelial Cells;Caucasians;Cell Death;Cell Death Induction;Cell Line;Cell Survival;Cells;Clinic;Clinical;DNA;Data;Dependence;Development;Disease;Disease Progression;Enzymes;Eukaryotic Initiation Factors;Frequencies;Genetic Polymorphism;Genome;Immunocompetent;In Vitro;Incidence;Inositol;Knockout Mice;Mammary Neoplasms;Mammary Tumorigenesis;Measures;Messenger RNA;Modeling;Mutation;Oncogenic;Outcome;Oxidoreductase;Pathway interactions;Patient-Focused Outcomes;Patients;Phenocopy;Phenotype;Phosphotransferases;Pre-Clinical Model;Predisposition;Proliferating;Proteins;RNA;Race;Regulation;Reporter;Repression;Ribonucleases;Risk;SNP genotyping;Sampling;Selenocysteine;Single Nucleotide Polymorphism;Stains;Testing;Therapeutic;Therapeutic Intervention;Translational Repression;Translations;Treatment Efficacy;Tumor Suppressor Proteins;Variant;Woman;Work;XBP1 gene;Xenograft Model;Xenograft procedure;aggressive breast cancer;breast tumorigenesis;cancer genome;candidate marker;cell growth;dimethylbenzanthracene;disparity gap;effective therapy;in vitro Assay;in vivo;in vivo Model;inhibitor;mRNA Expression;malignant breast neoplasm;metaplastic cell transformation;mortality;mouse model;novel;novel therapeutic intervention;overexpression;personalized medicine;pharmacologic;preclinical study;racial disparity;response;selenoprotein;therapeutic target;three dimensional cell culture;transcription factor;treatment response;tumor;tumor DNA;tumor growth;tumor progression;tumorigenesis SELENOF is a Novel Tumor Suppressor and a New Target to Overcome Racial Disparity in Breast Cancer. Project NarrativeThis work will establish that reduction in SELENOF levels is an underlying biological factor contributing to racialdisparity in breast cancer and thus supports the development of SELENOF-based therapeutics. Successfulcompletion of pre-clinical studies on two different therapeutic strategies investigated here may result inpersonalized and more effective therapy options for African American patients affected by low SELENOF.SELENOF polymorphisms and protein levels can be developed into biomarkers to identify African Americanpatients at risk of lethal breast cancer disease. NCI 10735662 9/11/23 0:00 PAR-21-322 1R01CA276482-01A1 1 R01 CA 276482 1 A1 "MAAS, STEFAN" 9/11/23 0:00 8/31/28 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 10906031 "KASTRATI, IRIDA " Not Applicable 7 NONE 791277940 RFRPFMNR8LA5 791277940 RFRPFMNR8LA5 US 41.865155 -87.833381 4689203 LOYOLA UNIVERSITY CHICAGO MAYWOOD IL UNIVERSITY-WIDE 601533328 UNITED STATES N 9/11/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 465767 NCI 340217 125550 Project Summary / AbstractThis proposal addresses the challenge of closing the racial disparity gap in breast cancer mortality by identifyinga contributing biological factor and developing therapeutic strategies to overcome its impact. The selenoproteinSELENOF was recently identified as a new tumor suppressor in breast cancer. The broad hypothesis is thatlower SELENOF levels in African American patients contribute to the racial disparity in breast cancer mortalityby driving tumor progression and poor patient outcome. Therefore therapeutic strategies to mitigate its loss areneeded to help close the disparity gap. The scientific premise for the hypothesis is based on the following: 1) thegenomes of breast tumors from African Americans have a 5-10 fold higher frequency of SELENOF singlenucleotide polymorphisms (SNPs) which account for lower SELENOF protein levels 2) SELENOF mRNAexpression is significantly lower in breast tumors from African American patients compared to Caucasians andlower SELENOF levels predict shorter survival in these patients 3) loss of SELENOF in normal breast epithelialcells resulted in increased proliferation and abrogated cell death features of cellular transformation and 4)overexpression of SELENOF in breast cancer cells induced cell death blocked proliferation and survivalenhanced response to therapies and inhibited tumor growth in vivo. The eukaryotic initiation factor 4a3 (eIF4a3)was identified as a translational repressor of SELENOF. The SELENOF locus SNPs are predicted to enhanceeIF4a3s binding affinity resulting in stronger repression of SELENOF translation. Preliminary data showed thatpharmacologic inhibition of eIF4a3 results in increased SELENOF protein levels and reduced breast cancer cellviability in a SELENOF-dependent manner. Loss of SELENOF also resulted in hyperactivation of thekinase/RNase inositol-requiring enzyme 1 (IRE1) a master regulator of the unfolded protein response. Thisrendered cells highly susceptible to IRE1 inhibition thus identifying a new vulnerability in these cells. Four aimsare proposed: 1) Determine the mechanisms underlying SELENOF-induced cell fate in breast cancer 2)Determine whether loss of SELENOF drives tumorigenesis by using African American derived xenografts and amurine model of breast cancer 3) Determine the impact of SNPs on the regulation of SELENOF translation byeIF4a3 and 4) Determine whether eIF4a3 overexpression and the SNPs contribute to reduced SELENOF tumorlevels and poor outcome in African American breast cancer patients. Our work will establish SELENOF as a newtarget to reduce racial disparity in breast cancer and thus support the development of SELENOF-basedtherapies. In the clinic SELENOFs SNPs and levels can also serve as candidate biomarkers to identify AfricanAmerican patients at risk of aggressive disease. The distinct therapeutic strategies investigated here are likelyto result in novel and more effective personalized medicine and may help close the disparity gap. 465767 +No NIH Category available Aftercare;Amides;Aneuploidy;Attention;Bioinformatics;Biological Assay;Biological Markers;Biopsy;Cells;Cerebrospinal Fluid;Characteristics;Clinical;Complex;Correlation Studies;DNA;DNA analysis;Data;Diagnostic;Disease;FDA approved;Genetic Markers;Genetic Status;Genomics;Genotype;Glioblastoma;Glioma;Goals;Heterogeneity;Human;Image;Individual;Investigation;Longitudinal Studies;MGMT gene;MRI Scans;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Methods;Modality;Modeling;Molecular;Monitor;Mutation;Names;Neurosurgical Procedures;Newly Diagnosed;Operative Surgical Procedures;Outcome;Patient Care;Patients;Pattern;Phenotype;Plasma;Primary Brain Neoplasms;Prognosis;Progression-Free Survivals;Proteins;Protocols documentation;Protons;Recurrence;Recurrent disease;Recurrent tumor;Reporting;Risk;Sampling;Signal Transduction;Somatic Mutation;Techniques;Text;Time;Tissue Sample;Tissues;Tumor Burden;Tumor Tissue;Tumor-Derived;burden of illness;chemoradiation;deep learning;deep learning model;diagnostic strategy;improved;indexing;liquid biopsy;minimally invasive;molecular imaging;multimodality;neurosurgery;novel;predictive modeling;prognostic;radiomics;recruit;response;standard care;success;temozolomide;tool;treatment effect;treatment response;tumor;tumor DNA;tumor progression Integrating circulating tumor DNA assay and protein-based MRI to accurately monitor glioma therapy This study will perform novel released tumor DNA (rtDNA) and protein-based APT-weighted MRI assays onnewly diagnosed glioblastoma patients. We will determine the accuracy of combined rtDNA/APT indices inidentifying disease recurrence following the therapy. If our rtDNA/APT investigation is successful it will allowclinicians to monitor response more accurately (as a result potentially obviating the need for invasiveneurosurgical procedures) and alter therapies more timely. NCI 10735404 6/30/23 0:00 PAR-21-290 1R01CA276221-01A1 1 R01 CA 276221 1 A1 "LIN, CHARLES" 7/1/23 0:00 6/30/28 0:00 Clinical Translational Imaging Science Study Section[CTIS] 15227906 "JIANG, SHANSHAN " "BETTEGOWDA, CHETAN " 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 691360 NCI 441578 249782 SUMMARY Glioblastoma is the most common primary brain tumor with substantial genomic molecular and phenotypicheterogeneity but uniformly dismal outcomes despite the current standard treatment of concurrenttemozolomide chemo-radiotherapy (CRT). Given the pace of disease recurrence and the challengesassociated with obtaining tumor tissue there is an unmet clinical need for the real-time noninvasiveassessment of GBM responsiveness to CRT. As demonstrated previously most cancers shed tumor-derivedfragmented DNA into biofluids including plasma and cerebrospinal fluid (CSF) and these cell-free moleculescan be quantified as a measure of disease burden. The approach named liquid biopsy has recentlyemerged as a breakthrough diagnostic and monitoring tool for diseases such as cancer with the added benefitof being minimally invasive. Through the sampling and analysis of biofluids a number of promising gliomabiomarkers derived from tumor-derived DNA in plasma (ctDNA) and CSF (CSF-tDNA) (together called rtDNA)have been reported as diagnostic strategies for gliomas. Meanwhile numerous previous studies havedemonstrated that protein-based amide proton transfer (APT) MRI can accurately identify tumor burden andgenetic markers (such as IDH MGMT status) in gliomas. The goals of this proposal are to combine ctDNA andCSF-tDNA with APT MRI to resolve the diagnostic challenges associated with discriminating treatment effectfrom tumor progression and to develop an efficient and reliable deep-learning framework for post-treatmentmonitoring. We propose the following specific aims to be performed: (1) correlate ctDNA and CSF-tDNA levelswith protein-based APT MRI characteristics when monitoring GBM treated with CRT; (2) determine theaccuracy of combined rtDNA/APT indices in identifying GBM recurrence; and (3) develop a transformerpipeline using rtDNA and mpMRI to assess GBM prognosis. The success of this aim will help to understandthe dynamic patterns of rtDNA/APT throughout the treatment course for individuals with GBM. If ourrtDNA/APT investigation is successful the results would dramatically improve the care of patients treated withCRT and spare many patients from undergoing surgery for diagnostic purposes. 691360 +No NIH Category available Funding;Southwest Oncology Group;operation NCTN Supplement Request for Additional Restricted Capitation SWOG NCTN OPERATIONS SUPPLEMENT REQUEST GY09SWOG is requesting additional funding for restricted capitation. NCI 10735369 1/30/23 0:00 PA-20-272 3U10CA180888-09S2 3 U10 CA 180888 9 S2 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 6765159 "BLANKE, CHARLES D." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 697175 NCI 697175 0 C6;Reg-CV SWOG NCTN OPERATIONS SUPPLEMENT REQUEST GY09SWOG is requesting additional funding for restricted capitation. 697175 +No NIH Category available Antigen Presentation;Antigen Presentation Pathway;Binding;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer cell line;Carboplatin;Characteristics;Chemoresistance;Complex;DNA;DNA Adduction;DNA Adducts;DNA Damage;DNA Repair;Data;Development;Effectiveness;Fatality rate;Frequencies;Gamma-H2AX;Genomic Instability;Human;Immune checkpoint inhibitor;Immune response;Immuno-Chemotherapy;Immunocompetent;Immunotherapy;In Vitro;Individual;Inflammatory;Knock-out;Knowledge;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Natural Killer Cells;Organoids;Phenotype;Phosphoric Monoester Hydrolases;Platinum;Play;Process;Protein Deficiency;Protein Dephosphorylation;Protein Inhibition;Protein phosphatase;Proteins;Reaction;Research;Resolution;Role;STAT1 gene;Serous;Signal Pathway;Signal Transduction;T cell infiltration;T-Lymphocyte;Testing;Therapeutic;Translating;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Woman;anti-tumor immune response;cancer cell;cancer therapy;cancer type;cancer/testis antigen;cell motility;checkpoint therapy;chemotherapy;crosslink;cytotoxicity;drug resistance development;experimental study;immune checkpoint blockade;immunogenic cell death;immunogenicity;improved;improved outcome;in vivo;innovation;knock-down;micronucleus;mortality;mouse model;new therapeutic target;novel therapeutic intervention;novel therapeutics;ovarian neoplasm;overexpression;p53-binding protein 1;phosphoproteomics;programmed cell death protein 1;protein function;protein phosphatase inhibitor-4;recruit;repaired;response;synergism;tumor;tumor growth;tumor microenvironment Targeting PP4 to improve ovarian cancer response to immunotherapy PROJECT NARRATIVEThe immune response is highly active in ovarian cancer but ovarian tumors do not respond well to immunecheckpoint blockade (ICB). We propose to investigate whether inhibition of DNA damage repair by blocking thefunction of the protein phosphatase 4 complex during chemotherapy will increase immunogenicity in ovariancancer and enhance response to ICB. Ultimately such knowledge has the potential to inform the developmentof new therapies benefiting many types of cancer. NCI 10735367 8/3/23 0:00 PA-20-185 1R37CA276047-01A1 1 R37 CA 276047 1 A1 "LIU, YIN" 8/3/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 15768750 "CURTIS, MARION " Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 8/3/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 510892 NCI 306842 204050 PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer has the highest mortality rate of all gynecologic cancers. There is acritical unmet need to identify new therapeutic targets and therapeutic approaches that will improve outcomesfor women with chemo-resistant ovarian cancer. Deficiencies in the DNA damage response (DDR) can driveincreased tumor immunogenicity which leads to enhanced responses to immune checkpoint inhibitor therapy.PP4 is a multi-subunit phosphatase complex that plays a central role in the response to DNA damage throughthe dephosphorylation of many proteins that play crucial roles in the DDR. However the role of PP4 in cancerdevelopment chemoresistance and anti-tumor immunity is currently unknown. The central hypothesis is thatPP4 inhibition will sensitize OC cells to chemotherapy-mediated immunogenicity leading to enhanced anti-tumor immunity and increased response to immune checkpoint blockade. The rationale for the proposedresearch is that understanding of the how the immune response is activated in reaction to deficiencies in PP4-mediated DNA damage repair has the potential to translate into new therapeutic strategies that will benefitthose with ovarian cancer. This hypothesis will be tested by pursuing the following two specific aims: 1)Determine the role of the PP4 complex in the immunogenicity of OC; and 2) Determine the role of PP4 intumor-infiltrating lymphocyte recruitment function and response to immunotherapy. In Aim 1 the effect of PP4knockout on chemotherapy-induced immunogenicity will be assessed using mechanistic studies of genomicinstability antigen presentation and immunogenic cell death. Under the second Aim the effect of PP4deficiency combined with PD-1 inhibition and chemotherapy will be evaluated in organoid cultures of primaryhuman ovarian cancer and in two immunocompetent mouse models of ovarian cancer. Mechanisms ofinflammatory signaling will be investigated. The research proposed in this application is innovative because itrepresents a new theoretical concept by shifting the focus on PP4 function to its role in anti-tumor immunity.The proposed research is significant because it is predicted to advance and expand our understanding of theimportance of how DNA damage repair resolution contributes to anti-tumor immunity and response toimmunotherapy. Ultimately such knowledge has the potential to inform the development of new therapiesbenefiting many types of cancer. 510892 +No NIH Category available Activities of Daily Living;Acute Myelocytic Leukemia;Adult;Aftercare;Age;Aging;Attention;Auditory;BCL-2 Protein;Brain;Cognition;Cognitive;Cognitive aging;Data;Decision Making;Diagnosis;Disease;Disease remission;Dorsal;Education;Elderly;Electroencephalography;Enrollment;European Organization for Research and Treatment of Cancer;Event;Exercise;Goals;Hematologic Neoplasms;Impaired cognition;Impairment;Interdisciplinary Study;Knowledge;Longitudinal cohort study;Measures;Methods;Neuropsychological Tests;Neurosciences;Newly Diagnosed;Oncologist;Outcome;Participant;Patients;Physical Function;Quality of life;Questionnaires;Recommendation;Research;Risk;Risk Factors;Scientist;Short-Term Memory;Time;Visual;attentional control;cancer therapy;chemotherapy;cognitive function;cognitive process;cognitive reserve;comorbidity;comparison control;distraction;executive function;frailty;functional decline;functional improvement;functional independence;health related quality of life;improved;insight;instrumental activity of daily living;leukemia;leukemia treatment;multiple chronic conditions;neuroprotection;novel;novel strategies;novel therapeutic intervention;sex;shared decision making;success Aging trajectories and outcomes of older adults with acute myeloid leukemia PROJECT NARRATIVEOur study aims to determine changes in cognition functional independence and health-related quality of life inolder adults with acute myeloid leukemia following new venetoclax-based treatment. This knowledge can informcritical decision-making of older adults considering chemotherapy for this fatal disease. NCI 10735257 7/12/23 0:00 PA-20-185 1R37CA276928-01A1 1 R37 CA 276928 1 A1 "STRECK, BRENNAN PARMELEE" 7/12/23 0:00 6/30/28 0:00 Aging Systems and Geriatrics Study Section[ASG] 14587852 "BHATT, VIJAYA RAJ" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 7/12/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 610707 NCI 431955 178752 PROJECT SUMMARYIn the US over one-third of older adults 60 years with acute myeloid leukemia (AML) die without receiving anychemotherapy primarily due to concerns of cognitive decline and loss of functional independence if they choseto undergo intensive chemotherapy. A combination of venetoclax and low-intensity chemotherapy offers aneffective new treatment for AML. However several knowledge gaps exist about this new approach. Venetoclaxtargets neuroprotective B-cell lymphoma 2 (Bcl-2) proteins but the actual risk of cognitive decline and loss offunctional independence following its use and the factors that increase such risks are still unclear. Ourpreliminary data demonstrated that many older adults with AML had stable or improved cognitive and physicalfunction functional independence and health-related quality of life (HRQOL) from the time of diagnosis to threemonths following newer treatments. These novel findings highlight the success of newer treatments in improvingcognitive function functional independence and HRQOL. Despite this frailty and multimorbidity were identifiedas risk factors for functional decline. We also utilized the NCI-recommended neuroscience approach andconducted electroencephalography (EEG)/event-related brain potential (ERP) studies. In our study adults withhematological cancers versus healthy adults demonstrated altered activity in the dorsal attention and centralexecutive brain networks prior to treatment. Confirmation of these findings will identify the risk of a decline inattention and executive function functional independence and HRQOL and will provide novel mechanisticinsights into the activity of brain networks in older adults with AML. In the proposed longitudinal cohort study wewill enroll older adults with a new diagnosis of AML who will receive venetoclax-based treatments and age-sex- and education-matched non-cancer controls. We will compare the two groups on the following outcomes:attention and executive function (Trail Making and other neuropsychological tests) functional independenceHRQOL and EEG/ERP measures (ERP studies during auditory-visual distraction tasks to measure brain activity)at enrollment and over 12 months. The study aims are: Aim 1. Determine the longitudinal attention and executivefunction of older adults with AML before and after venetoclax-based treatment as compared to age- sex- andeducation-matched non-cancer controls. Aim 2. Determine longitudinal changes in functional independence andHRQOL in older adults with AML versus controls and examine their associations with longitudinal changes inattention and executive function. Aim 3. Measure longitudinal changes in the activity of brain networks of olderadults with AML before and after venetoclax-based treatment as compared to controls. This is the first study toapply rigorous methods to overcome key limitations of prior studies and to advance the current limited cognitiveaging research in patients with AML. Understanding factors associated with stable/improved functional trajectoryfollowing new treatment can change treatment paradigms and is essential to inform critical decision-making ofolder adults with AML considering chemotherapy for this fatal disease. The goals align with the NCI/NIA priorities. 610707 +No NIH Category available Acceleration;Affect;Alcohols;Apoptosis;Blood specimen;Carbon Nanotubes;Cell Death;Cell Differentiation process;Cells;Cessation of life;Clinical;Complementary therapies;Complex;Data;Development;Disabled Persons;Engineering;Genetic;Genetic Models;Glutathione;Goals;Human;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immunosuppression;Immunotherapy;In Vitro;Infiltration;Ions;Iron;Lipid Peroxidation;Lipid Peroxides;Lipids;MEKs;Macrophage;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mediating;Melanins;Melanogenesis;Melanoma Cell;Metastatic Skin Cancer;Methods;Modeling;Modernization;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Nanodelivery;Neoplasm Transplantation;Outcome;Oxidation-Reduction;Pathway interactions;Patients;Population;Predisposition;Process;Publishing;Refractory;Regulation;Resistance;Sampling;Signal Transduction;System;T-Lymphocyte;Testing;Therapeutic;Tissue Sample;Tumor Immunity;Tumor Tissue;Tumor-infiltrating immune cells;alternative treatment;analytical tool;anti-tumor immune response;cancer cell;cancer therapy;cell type;checkpoint therapy;clinically relevant;cytotoxic;cytotoxicity;graphene;imaging modality;immune checkpoint;immunogenic;immunomodulatory strategy;immunoregulation;improved;in vivo;inhibitor;lipidomics;melanoma;monocyte;mortality;nanodot;nanomaterials;neoplastic cell;neutrophil;novel;novel strategies;novel therapeutics;oxidation;pharmacologic;phospholipid-hydroperoxide glutathione peroxidase;prevent;quantum;repaired;standard of care;tumor;tumor growth;tumor microenvironment;tumor progression Re-engineering differential regulation of ferroptosis in melanoma microenvironment Project NarrativeMelanoma is an aggressive cancer with high mortality rate and multiple modes of resistance tocurrent standard-of-care therapies. We have determined that ferroptosis a recently discoveredmechanism of programmed cell death is a promising method of killing melanoma cells which areresistant to other therapies and that the tumor-infiltrating myeloid cells should be concurrentlyprotected from ferroptosis to overcome immune tolerance to melanoma. We propose to developnovel therapy based on the differential regulation of ferroptosis in cancer and immune cells of themelanoma tumor microenvironment. NCI 10735217 7/12/23 0:00 PA-20-185 1R01CA272946-01A1 1 R01 CA 272946 1 A1 "CHEN, WEIWEI" 7/12/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 10569986 "BUNIMOVICH, YURI " "KAGAN, VALERIAN E; NEFEDOVA, YULIA " 12 DERMATOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 7/12/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 690908 NCI 508518 182390 Project SummaryMelanoma is an aggressive and highly metastatic skin cancer. Although modern combination checkpointinhibitors revolutionized clinical outcomes in advanced cases over half of all patients are refractory toimmunotherapy and require alternative or complementary treatment options. The discovery of ferroptosisprovided a novel way to treat cancer. Recently described vulnerability of melanoma cells to ferroptosis offersa new therapeutic opportunity particularly against the malignant cells which are resistant to current therapies.However how to exploit such vulnerability is still unclear due to the lack of mechanistic understanding offerroptosis regulation in melanoma and the tumor-infiltrating immune cells. We discovered that anindiscriminate induction of ferroptosis of the entire tumor tissue has a deleterious impact on protective anti-tumor immune responses which promotes melanoma progression. Specifically we found that ferroptoticdeath of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in tumors is a major mechanismof immune suppression. Therefore a shift in the current approach to harness ferroptosis for cancer therapyis required. Only by understanding the regulatory mechanisms of ferroptosis in different cellular compartmentsof the tumor microenvironment (TME) will we be able to engineer effective melanoma therapy based on thedifferential modulation of ferroptosis. Utilizing cutting-edge redox lipidomics mass spectrometry and single-cell lipidomics imaging methods this project will uncover critical mechanisms of ferroptosis regulation in theintratumoral PMN-MDSC and melanoma cells. In addition we will optimize our recently developed therapeuticapproach which will promote ferroptosis of the malignant cells while protecting and enhancing anti-tumorimmunity. To achieve these goals we will pursue three specific aims. In Aim 1 we will decipher how theprocesses of melanogenesis and cell differentiation regulate melanoma cell susceptibility to ferroptosis. Theresults will provide a strategic approach to maximizing the efficacy of pro-ferroptotic therapy againstmelanoma cells. Aim 2 will focus on identifying mechanisms of ferroptosis-mediated immune regulation byPMN-MDSC in melanoma TME. The results will reveal how to protect anti-tumor immune responses viatargeted ferroptosis inhibition in the myeloid cells of the TME and prevent immune tolerance to cancer. Finallyin Aim 3 we will expand on our preliminary data to investigate therapeutic potential of differentially regulatingferroptosis in the malignant and the myeloid cells of the melanoma TME. This will be accomplished using ourpreviously developed nano-delivery systems based on graphene quantum nanodots and carbon nanotubes.Such approach is highly clinically relevant as it employs both cytotoxic and immunomodulatory strategiesagainst melanoma aimed at reducing immune tolerance to cancer and overcoming modes of cancerresistance to the standard-of-care combination immune checkpoint and Braf/MEK inhibitors currentlyrepresenting a significant clinical challenge. 690908 +No NIH Category available Advance Care Planning;Advanced Malignant Neoplasm;Caregivers;Caring;Categories;Cessation of life;Collaborations;Communication;Consensus;Correlation Studies;Development;Diagnosis;Distant Metastasis;Emergency department visit;Ensure;Exclusion;Family;Fostering;Goals;Grief reaction;Health;Health Personnel;Healthcare;Hospice Care;Hospitalization;Individual;Intervention;Investigation;Knowledge;Length of Stay;Malignant Neoplasms;Mediating;Methods;Modeling;Outcome;Palliative Care;Patient Care;Patient Preferences;Patients;Play;Process;Proxy;Quality of Care;Quality of life;Research;Resources;Risk;Role;Science;Severities;Symptoms;Theoretical model;Time;Value of Life;aggressive therapy;care outcomes;contextual factors;end of life;end of life care;end-of-life decision making;experience;health care service;improved;informal caregiver;insight;loved ones;member;preference;provider factors;research study;satisfaction;social;theories Improving Understanding of Quality End of Life Care Using a Dyadic Approach Project NarrativeThe proposed research study explores patient and caregiver dyadic factors that can influence the quality ofend of life (EOL) care for patients with advanced cancer and their informal caregivers. This is a very uniquestudy because it is looking at how close (or far apart) patients and their informal caregivers are in theirassessments of the severity of patient symptoms their understanding of the patients EOL values and theirunderstanding of the patients EOL preferences for treatment. The study is highly relevant as it will provideinformation that has not been obtained before that can help guide methods of providing information andsupport at EOL for patients with advanced cancer and their informal caregivers. NCI 10735211 7/13/23 0:00 PA-20-185 1R01CA276712-01A1 1 R01 CA 276712 1 A1 "FERRER, REBECCA" 7/13/23 0:00 6/30/28 0:00 Clinical Management in General Care Settings Study Section[CMGC] 8579261 "DOUGLAS, SARA L." Not Applicable 11 NONE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF NURSING 441061712 UNITED STATES N 7/13/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 692474 NCI 433708 258766 Project Summary/AbstractThere is strong national consensus about the need to deliver high-quality care at the end of life (EOL) forpatients with advanced (distant metastasis) cancer. Yet despite the efforts of healthcare providers manypatients receive care that they do not want at EOL and leave their informal caregivers struggling withcomplicated grief months after their death. Research to date has tended to define quality EOL care usingunidimensional factors that do not encompass key aspects of EOL care such as patient and family-centeredEOL care that holds individual preferences for EOL care at its core. Specifically quality EOL care has beendefined in terms of either: (a) amount of aggressive health care services received or (b) whether it was goalconcordant care---care that aligned with the patients preferences and goals for EOL care. These approacheshave provided limited perspectives of what constitutes quality EOL care. Aggressiveness metrics (e.g. days ofhospitalization number of emergency department visits) for example ignore the fact that some patients wantaggressive care at EOL and goal concordant care metrics ignore the post-death QOL of caregivers. It isusually the patient-caregiver dyad who experience the trajectory of care and who need support throughout.With patients continuing to receive EOL care that they do not want and caregivers struggling with poor post-death outcomes such as complicated grief we need a new paradigm for conceptualizing quality EOL care.This project will be the first to apply the principles of a dyadic theory of illness to examine the relationshipsbetween patient-caregiver dyadic factors (e.g. dyadic incongruence for patient symptom severity) and dyadicquality EOL care. We have reconceptualized quality EOL care to be care that benefits both members of thedyad and is present when the patient identifies the receipt of goal concordant care at EOL and the caregiverdoes not demonstrate complicated grief 3 months post-death. This longitudinal descriptive correlational studywill address the following aims: Aim 1: Examine the influence of dyadic appraisal of illness factors upon dyadicquality EOL care (present or absent); Aim 2: Examine the influence of risk-protective contextual factors(individual dyadic family/social) on dyadic appraisal of illness factors (symptoms EOL treatment preferencesEOL values) over time; and Aim 3: Assess the extent to which dyadic appraisal of illness factors mediate therelationship between risk-protective contextual factors and dyadic quality EOL care. Identifying specific dyadicvariables (such as symptom severity incongruence) that relate to dyadic outcomes can facilitate thedevelopment of dyadic interventions aimed at enhancing communication or knowledge for example for bothmembers of the dyad over time. By enhancing dyadic outcomes we will have better stewardship of healthcareresources for patients at EOL and ensure improved quality EOL care for patients and improved post-deathoutcomes for caregivers---those who must carry on after the patients death. 692474 +No NIH Category available Amendment;Animal Model;Animals;Antisense Oligonucleotide Therapy;Antisense Oligonucleotides;Apoptosis;Biogenesis;Bioinformatics;Biological;Biological Models;Biological Process;Cell Proliferation;Cells;Complement;Data;Defect;Disease;Dose;Effectiveness;Excision;Gene Expression Regulation;Gene Transfer;Goals;Health;Homeostasis;Human;Induction of Apoptosis;Journals;Learning;Left;Leucine;Liver;Liver Regeneration;Liver neoplasms;Malignant Neoplasms;Malignant neoplasm of liver;Medicine;Messenger RNA;Modeling;Molecular;Mus;Nature;New England;Nomenclature;Oligonucleotides;Paper;Pathologic;Patients;Phenotype;Porifera;Primary carcinoma of the liver cells;Production;Property;Protein Biosynthesis;Proteins;RNA;RNA Ribosomal 18S;Recombinant adeno-associated virus (rAAV);Ribosomal Proteins;Ribosomal RNA;Ribosomes;Role;Small RNA;Technology;Therapeutic;Time;Tissues;Transfer RNA;Translations;Tumor-Derived;Untranslated RNA;Work;Xenograft procedure;antitumor effect;gene therapy;guided inquiry;human disease;improved;insight;molecular sequence database;mouse model;pre-clinical;regenerative;screening;tissue regeneration;tumor;vector 3' tsRNAs: biologic function and pre-clinical targeting for treating human disease NARRATIVEOur general goal is to identify specific 3tsRNAs that have therapeutic potential for treating humandisease. We will do this using gene transfer and oligonucleotide delivery strategies in various modelsystems. NCI 10735190 7/8/23 0:00 PA-20-185 1R01CA277059-01A1 1 R01 CA 277059 1 A1 "FU, YALI" 7/8/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-BBBT-V(81)S] 1876509 "KAY, MARK A" Not Applicable 16 PEDIATRICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 545950 NCI 352958 192992 ABSTRACTOver the last decade we characterized and studied the properties of various tRNA derivedsmall RNAs (tsRNAs). In recent years we have focused on one class commonly referredto as 3tsRNAs (derived from the 3end of mature tRNAs) because they are the least wellstudied but appear to play a role in tissue regeneration (e.g. liver regeneration) andhyperproliferative states including cancer. Here we plan to establish the potential of targetingthe 3tsRNAs for therapeutic purposes. Recently we established that one specific RNA the22nt CAG-Leucine 3tsRNA which when down regulated by the addition of antisenseoligonucleotides in rapidly dividing but not quiescent cells inhibit ribosome biogenesis. Lossof this specific tsRNA limits the translation (at the elongation step) of at least one ribosomalprotein mRNA. This results in a block in rRNA processing and rapid cellular apoptosis. Incontrast the addition of a 3tsRNA mimic increases cellular proliferation and can complementthe ribosome biogenesis defect in cells. We propose to further identify other 3tsRNA-mRNAinteractions and establish their biologic and molecular function and develop gene therapyand oligonucleotide antisense delivery technologies to pursue the therapeutic potential ofmanipulating 3tsRNAs in animals. Although the tsRNAs are expressed in many tissues wewill focus these studies on the liver including liver cancer. This work will provide newinformation related to 3tsRNA function in gene regulation and cellular homeostasis in healthand disease states as well as establish their potential therapeutic value by the proposedpreclinical human xenotransplant murine animal models. In the amended application weremoved all the studies related to screening for improved LNPs outlined in previous specificaim 3 as suggested by the reviewers. 545950 +No NIH Category available Address;Adult;African American;Age;Algorithms;Area;Biological;Biometry;Black race;Breast;Cancer Cluster;Chronic Disease;Cohort Studies;Collaborations;Colorectal;Communities;Data;Dimensions;Disadvantaged;Disparity;Enrollment;Environment;Environmental Exposure;Environmental Pollutants;Epidemiology;Etiology;Exposure disparity;Exposure to;Fostering;Goals;Health;High-Risk Cancer;Home;Income;Individual;Individual Adjustment;Knowledge;Length;Life Cycle Stages;Link;Location;Low income;Lung;Malignant Neoplasms;Measurement;Measures;Methods;Modeling;Movement;Neighborhood Health Center;Neighborhoods;Outcome;Ownership;Participant;Pathway interactions;Patient Recruitments;Patient Self-Report;Pattern;Physical environment;Population;Population Group;Population Heterogeneity;Poverty;Poverty Areas;Predictive Factor;Prospective cohort;Prostate;Questionnaires;Race;Recording of previous events;Research;Residential Mobility;Resources;Risk;Risk Factors;Rural;Sampling;Social Environment;Socioeconomic Status;Space-Time Clustering;Subgroup;Surveys;Telephone;Testing;Time;Translations;Underrepresented Populations;Underserved Population;Vendor;anticancer research;cancer diagnosis;cancer epidemiology;cancer health disparity;cancer risk;cancer subtypes;clinical care;cohort;conflict resolution;data registry;deprivation;design;experience;follow-up;health disparity;high risk;improved;improved mobility;innovation;interdisciplinary approach;marginalized community;marginalized population;medically underserved;multidisciplinary;neoplasm registry;novel;poor communities;prospective;racial disparity;racial diversity;recruit;research study;residence;sex;social;social adversity;social health determinants;socioeconomics;spatiotemporal;structural determinants Incorporating residential histories into assessment of cancer risk in a predominantly low-income and racially diverse population PROJECT NARRATIVEResidential histories provide a historical record of the social and physical environment that can have a lasting impact on health; however few cancer research studies have incorporated life-course residential histories for underrepresented populations. To remedy this we will develop methods to reconstruct life-course residential histories for a racially diverse and low socioeconomic population and link to area-level environmental exposures to identify cancer disparities. NCI 10735164 9/21/23 0:00 PA-20-185 1R01CA276266-01A1 1 R01 CA 276266 1 A1 "DELLAVALLE, CURT TAVIS" 9/21/23 0:00 8/31/27 0:00 Cancer and Hematologic Disorders Study Section[CHD] 9385468 "ALDRICH, MELINDA " "RAO, J SUNIL; SHRUBSOLE, MARTHA J." 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 601879 NCI 407297 194582 PROJECT SUMMARY/ABSTRACTThere is growing recognition that area-level biological and physical exposures associated with residential location across the life-course must be considered for more precise cancer risk and outcomes. Yet many cohort studies lack comprehensive residential history information or limit analyses to the residence at enrollment or cancer diagnosis a critical limitation in assessment of exposure causation potentially leading to misclassification or biased associations. Residential histories derived from commercial vendors offer an exciting opportunity to integrate the neighborhood environment into cancer research. Little research has been conducted incorporating life-course residential history information into cohort studies particularly among historically marginalized populations living in persistent poverty regions such as in the Southeast. Populations living in the Southeast have the highest cancer risk and some of the poorest health outcomes among all U.S. populations. To address gaps in knowledge of how best to integrate geospatial data via life-course residential histories into cancer research cohort studies we propose to evaluate residential histories in a well-resourced and large-scale observational prospective cohort of underrepresented adults with the following specific aims: 1) collect and describe self-reported adult life-course residential histories from a historically marginalized population 2) develop algorithms to reconstruct temporal residential histories for historically marginalized individuals and 3) evaluate residential mobility and spatiotemporal changes in area-level life-course exposures and cancer disparities. We hypothesize concordance of residential history between vendor and self-report varies by population group and incorporating residential mobility improves exposure assessment and reduces bias in cancer research. We propose to construct residential histories link residential histories to geospatial exposures and test associations between geospatial exposures across the life-course and cancer disparities. We will focus on the four most common cancers (breast lung colorectal prostate) in over 84000 participants recruited across 12 Southern states. Our design focuses on robust methods to identify factors predictive of residential history patterns among historically marginalized populations including those living in persistent poverty regions and novel translation of residential history information into an interpretable context. Our project then examines neighborhoods which can influence cancer risk over space and time. Our project fosters innovative collaborations among a multidisciplinary team with scientific expertise in cancer disparities cancer epidemiology survey design geospatial analyses small area estimation and biostatistics. Findings from our multidisciplinary approach will have sustained impact since it will reveal pathways for improved precision to incorporate area-level exposures across the life-course and motivate strategies to address disparities. 601879 +No NIH Category available Amygdaloid structure;Architecture;Blood;Brain;Brain Injuries;Brain-Derived Neurotrophic Factor;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer survivor;Cancer Patient;Cancer Survivor;Cell Culture Techniques;Cell Maintenance;Chemotherapy-Oncologic Procedure;Chronic;Clinical;Clinical Data;Clinical Research;Cognition;Cognitive;Cognitive deficits;Cyclophosphamide;Data;Dendrites;Disease;Distress;Doxorubicin;Drug Kinetics;Electrophysiology (science);Ensure;Exposure to;Future;Genetic;Glutamates;Hippocampus;Human;Impaired cognition;Impairment;Link;Long-Term Potentiation;Measurement;Mediating;Modeling;Mus;Nerve Degeneration;Neurobiology;Neurons;Oral;Pathologic;Patients;Performance;Pharmaceutical Preparations;Plasma;Play;Pre-Clinical Model;Prefrontal Cortex;Quality of life;Riluzole;Risk;Rodent;Rodent Model;Role;Safety;Series;Severities;Slice;Survivors;Synapses;Testing;Therapeutic;Toxic effect;Vertebral column;axon growth;behavior measurement;cancer therapy;cancer-related cognitive impairment;chemobrain;chemotherapy;cognitive function;cognitive task;enhancing factor;high risk;improved;in vivo;malignant breast neoplasm;mouse model;nerve stem cell;neural circuit;neurogenesis;neuroinflammation;neuroprotection;pharmacologic;phase 1 study;pre-clinical;preclinical study;prevent;regenerative approach;repaired;response;side effect;stem cell proliferation Neurotrophic strategy to mitigate chemotherapy-related brain injury PROJECT NARRATIVECancer-related cognitive impairment (CRCI) or chemobrain is one of the major quality of life issuefor cancer survivors thereby mechanism-based mitigating strategies are clearly needed. Thisproposal (in response to a chemobrain RFA PAR-21-329) will evaluate the augmentation of brainderived neurotrophic factor (BDNF) as a viable strategy for improving CRCI through genetic andpharmacological strategies using in vivo pre-clinical models to ascertain the neuroprotective roleof enhancing BDNF to ameliorate CRCI. NCI 10735146 9/6/23 0:00 PAR-21-329 1R01CA276212-01A1 1 R01 CA 276212 1 A1 "SCHWEPPE, CATHERINE ANN" 9/6/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-CN-K(55)R] 77802225 "CHAN, ALEXANDRE " "ACHARYA, MUNJAL M" 47 MISCELLANEOUS 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA ORGANIZED RESEARCH UNITS 926970001 UNITED STATES N 9/6/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 471019 NCI 315079 155940 ABSTRACTCancer-related cognitive impairment (CRCI) often referred as chemobrain is prevalent up to75% of all breast cancer survivors. These impairments cause significant distress and reduce thequality for life for survivors. Despite growing realization of the long-term clinical problem of CRCIin millions of cancer survivors there is a conspicuous absence of clinical recourse available.Therefore regenerative strategies to restore cognition and normal brain function in the cancerpatients and survivors are clearly needed. Our past clinical and pre-clinical studies haveestablished that doxorubicin which is commonly used in breast cancer can lead to a significantdecline in the blood (human) and brain (rodent) levels of brain derived neurotrophic factor (BDNF).BDNF is abundantly expressed in the prefrontal cortex and hippocampus and plays importantroles in neuronal repair and survival dendritic and axonal growth long-term potentiation andneural stem cell maintenance. In our human studies pathological reductions of BDNF were linkedto higher risk of cognitive toxicity. Similarly we have shown that chronic chemotherapysignificantly impaired performance on the hippocampus and cortex-dependent cognitive tasks inthe rodents. These deficits were linked with reduced neurogenesis elevated neuroinflammationand significant damage to the newly born and mature neuronal architecture dendrites spinesand synaptic integrity. To mitigate these deficits our preliminary rodent studies involving micereceiving doxorubicin with riluzole an orally active glutamate-modulating medication hasprevented the reduction of hippocampus BDNF levels. Thus we hypothesize that: i)chemotherapy-induced reduction of BDNF leads to the long-term neurodegenerativeconsequences culminating into cognitive impairments and ii) augmentation of BDNF in vivo willrestore cognitive function in brains exposed to chemotherapy and will provide neuroprotectionagainst CRCI. We will test our hypothesis with three specific aims. In Aim 1 we will systematicallyexamine brain and plasma BDNF levels to link its trajectory with CRCI and neurobiologicalunderpinnings in a mouse model of breast cancer chemotherapy. In Aim 2 we will determine theneuroprotective impact of enhancing BDNF in vivo to reverse CRCI. In Aim 3 we will evaluatethe neuroprotective effect of BDNF-enhancing riluzole to ameliorate CRCI. This study will link theneurobiological underpinnings of chemotherapy and neuroprotective effects of BDNF againstCRCI. If demonstrated to be successful our translationally feasible pharmacologicalapproach will provide basis for future studies to repurpose riluzole as a therapeutic optionfor mitigating CRCI. 471019 +No NIH Category available Abstinence;Address;Affect;Age;Behavioral;Biochemical;Biological Markers;Cannabis;Cigarette;Clinical;Collaborations;Collection;Complement;Data;Evaluation;Goals;Health;Individual;Individual Differences;Intervention;Liquid substance;Literature;Measures;Medical;Methods;Nicotine;Oral;Outcome;Participant;Patient Self-Report;Pattern;Pharmaceutical Preparations;Positioning Attribute;Prevalence;Prospective Studies;Public Health;Publishing;Recommendation;Research;Role;Sampling;Smoking;South Carolina;Time;Tobacco;Tobacco Use Cessation;Treatment outcome;United States;Universities;Withdrawal;Youth;adverse outcome;age group;behavioral economics;clinical care;contingency management;diaries;experience;individualized medicine;innovation;marijuana use;nicotine cessation;nicotine treatment;nicotine use;prolonged abstinence;prospective;recruit;remote administration;secondary analysis;substance use;success;tobacco products;vaping;vaping nicotine;virtual therapy;young adult The impact of cannabis and tobacco/nicotine product co-use in young adults: Prospective cessation evaluation and substitution PROJECT NARRATIVE The co-use of nicotine/tobacco products and cannabis among young adults is prevalent and may adverselyaffect treatment and other clinical outcomes yet little is known regarding the treatment implications of co-useand the underlying relationship between substances. The overall goal of this project is to characterize andevaluate the underlying relationship between nicotine and cannabis and its impact on nicotine/tobacco cessationthrough a behavioral economics framework to determine how impactful cannabis co-use may be on nicotinecessation and which individuals who co-use experience greater difficulty achieving cessation. Findings from thisproposed R01 will be positioned to have substantial impact on treatment recommendations for young adults whoare using nicotine/tobacco products and co-using cannabis to provide them with the best chances of successfuland sustained abstinence. NCI 10735046 9/1/23 0:00 PAR-21-035 1R01CA276066-01A1 1 R01 CA 276066 1 A1 "REYES-GUZMAN, CAROLYN" 9/1/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-BP-P(02)M] 8409004 "MCCLURE, ERIN A" Not Applicable 6 PSYCHIATRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 689656 NCI 434618 255038 PROJECT SUMMARY/ABSTRACT The co-use of nicotine/tobacco products and cannabis among young adults is prevalent and varies widely interms of patterns and products of use. Nicotine-cannabis co-use among this age group may adversely affecttreatment and other clinical outcomes yet little is known regarding the underlying relationship between nicotineand cannabis and the resulting treatment implications particularly during an attempt to quit or reduce use of oneor both substances. Prior literature on the treatment implications of co-use including results from our groupsuggest that cannabis serves as an obstacle to nicotine cessation for a sub-set who use both products thoughthe literature is mixed. Past studies also suffer from important limitations resulting in critical gaps in ourunderstanding with only 2 secondary analyses published from youth tobacco trials on the impact of co-use. Todate there are no prospective studies that have examined the treatment implications of nicotine-cannabis co-use or the underlying relationship between substances among young adults when engaged in a quit attempt.[[[Therefore the overall goal of this project is to characterize and evaluate the underlying relationship betweennicotine/tobacco and cannabis and its impact on nicotine cessation through a behavioral economics framework.This study will determine how impactful cannabis co-use may be on nicotine cessation and which individualswho co-use experience greater difficulty achieving cessation. To accomplish this goal we propose a completelyremote prospective 12-week nicotine cessation trial among young adults (ages 18-25; N=350) from across theUnited States who use nicotine (vaping cigarettes or both) and cannabis products regularly. We will leverageour ongoing collaboration with DynamiCare Health to administer remote contingency management (CM) as thenicotine/tobacco treatment intervention while cannabis use will not be addressed. Biochemical verification(through oral fluid samples) and self-reports (mobile daily diaries) of substance use will be collected. The aimsof this proposed study are to: 1) evaluate the impact of behavioral economically derived measures of substancesubstitutability on end of treatment nicotine abstinence (Aim 1); 2) determine if treatment-induced nicotineabstinence reduction and/or withdrawal (a) is associated with co-occurring changes in cannabis demand anduse and (b) if substance substitutability modifies this relationship (Aim 2); and 3) assess the reciprocalprospective relationship between patterns of nicotine and cannabis use during nicotine treatment (Aim 3).Evaluating nicotine-cannabis co-use as part of a prospective treatment study through a behavioral economicsframework has never been conducted and will be important to informing the literature regarding individual co-use pattern differences compensatory cannabis use and treatment success.]]] Nicotine cessation treatment inyoung adults is a growing body of work and the role of cannabis co-use and results from the proposed studywill inform clinical care and guide tailored treatment recommendations to promote successful and sustainedabstinence. 689656 +No NIH Category available Address;Adverse effects;Affect;Age;Agonist;Air Pollution;Allografting;American Indians;Antibiotics;Bacteria;Biological;Biological Sciences;Birth;Black race;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Risk Factor;C57BL/6 Mouse;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Cell physiology;Cells;Child;Clinical;Clostridiaceae;Cognitive;Communities;Consumption;Crime;Daughter;Diabetes Mellitus;Dietary Fiber;Dietary Intervention;Discipline of Nursing;Emotional;Endocrinology;Etiology;Exposure to;FFAR2 gene;FFAR3 gene;Female;Female of child bearing age;Fetal Tissues;Fiber;Functional disorder;Generations;Goals;Growth;Human;Immune;Immunity;Impairment;Incidence;Individual;Inflammation;Inflammatory;Intervention;Intervention Studies;Inulin;Knock-out;Knockout Mice;Life;Link;Long-Term Effects;Mammary Neoplasms;Mammary Tumorigenesis;Mass Spectrum Analysis;Measures;Mediating;Metabolism;Microbe;Minnesota;Mouse Mammary Tumor Virus;Mus;Not Hispanic or Latino;Obesity;Obesity Epidemic;Organ;Outcome;Play;Predisposition;Pregnancy;Pregnant Women;Prevention strategy;Prevotella;Probiotics;Production;Public Health;Reporting;Risk;Role;Shotguns;Signal Transduction;Testing;Tissues;Transplantation;Tumor-infiltrating immune cells;Volatile Fatty Acids;Whole Blood;Woman;anti-tumor immune response;cell type;clinical translation;diet-induced obesity;dietary;dietary control;drinking water;effective intervention;fecal microbiota;fecal transplantation;gut bacteria;gut dysbiosis;gut microbes;gut microbiota;health disparity;immune cell infiltrate;immune function;inflammatory marker;low socioeconomic status;malignant breast neoplasm;mammary;maternal obesity;metagenomic sequencing;mitochondrial metabolism;mortality;obese mothers;obesity in pregnancy;offspring;polyoma middle tumor antigen;pregnant;prevent;programs;receptor;stem cell differentiation;western diet Effect of maternal obesity on breast cancer among offspring: role of the gut microbiota We will investigate if gut dysbiosis characterized by significantly reduced fecal levels of short-chain fatty acids (SCFAs) and the expression of SCFA receptors GPR43/Ffar2 and GPR41/Ffar3are causally linked to increased mammary tumorigenesis in the offspring of obese dams. We alsowill investigate if supplementing obese pregnant dams with SCFA producing probiotics and fiberwill prevent the increase in mammary tumorigenesis in their offspring. NCI 10734892 7/11/23 0:00 PA-20-185 1R01CA276775-01A1 1 R01 CA 276775 1 A1 "KUMAR, AMIT" 7/15/23 0:00 6/30/28 0:00 Cancer Prevention Study Section[CPSS] 1894992 "HILAKIVI-CLARKE, LEENA A." Not Applicable 5 INTERNAL MEDICINE/MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 7/15/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 354579 NCI 228750 125829 In Minnesota American Indian (34.1%) and non-Hispanic Black (33.4%) women are over twice as likely to beobese during pregnancy than non-Hispanic White women of whom 16.6% are obese during pregnancy. Thishigh incidence reflects the causes of maternal obesity such as low socioeconomic status high crime rate andexcess exposure to air pollution. Maternal obesity has widespread adverse effects on the offspring includingincreasing their risk of dying from breast cancer. Maternal obesity also permanently disrupts the mutuallybeneficial interaction between the offspring and offsprings gut microbiota causing gut dysbiosis. Gut dysbiosisin the offspring is characterized by a reduction in the gut bacteria that produce fecal short-chain fatty acids(SCFA). SCFAs play pivotal roles in maintaining healthy immune functions cellular metabolism and other criticalfunctions. These compounds act mostly through their receptors GPR43 and GPR41 which are expressed inimmune cells and multiple other cell types. Here we will test the central hypothesis that the composition ofcommensal gut microbes in the offspring of obese dams is causally responsible for an offsprings increasedsusceptibility to mammary tumorigenesis an effect that likely also reflects altered immunity. We will test thiscausal link by performing fecal microbiota transfers (FMTs). The role of GPR43 and GPR41 in mediating theimpact of maternal obesity on offspring will be tested using CRISPR/Cas9 knockout mice. The potential forclinical translation of our findings will be established by supplementing obese pregnant dams with a commerciallyavailable probiotic mix of SCFA-producing gut bacteria and dietary fiber that increases SCFA production. Sucha combination has been earlier found to be most effective in reversing loss of critical microbes of healthy gutmicrobiota from individuals who have consumed an unhealthy Western diet for multiple generations. We will useallografted E0771 and Py230 mammary tumor models and MMTV-PyMT mice developing mammary tumors atabout age 3 months. Shotgun metagenome sequencing and mass spectrometry will be applied to study gutmicrobiota and their metabolites respectively. Changes in immune cell infiltration and activity will be measuredin multiple tissues and compared with the expression of GPR43 and GPR41 in immune cells. Our studies couldlead to effective and safe prevention strategies against breast cancer and its growth in the daughters of obesemothers and be particularly beneficial for communities suffering from health disparities. 354579 +No NIH Category available Adipocytes;American;Automobile Driving;Binding;Biological Assay;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer therapy;Breast cancer metastasis;CCL2 gene;Cancer Cell Growth;Cancer Patient;Cells;Cessation of life;Cytokine Gene;Data;Disease;Drug resistance;ESR1 gene;Endocrine;Endothelial Cells;Environment;Estrogen Antagonists;Estrogen Receptor alpha;Estrogen receptor positive;Estrogens;Estrone;Fatty acid glycerol esters;Fulvestrant;Future;Gene Activation;Gene Expression;Genes;Goals;Growth;Human;IL6 gene;Immune;Immune Evasion;Immunologic Stimulation;Impairment;In Vitro;Infiltration;Inflammation;Inflammatory;Life Style;Ligands;MCF7 cell;Malignant Neoplasms;Mediating;Mediator;Modeling;Mus;Mutation;Myeloid-derived suppressor cells;Neoplasm Metastasis;Obese Mice;Obesity;Oncogenic;Organoids;Outcome;Pharmacotherapy;Postmenopause;Premenopause;Preventable cancer cause;Repression;Resistance;Response Elements;Risk;S100A8 gene;Signal Transduction;TLR4 gene;Testing;Therapeutic;Thinness;Tumor Immunity;Work;acquired drug resistance;cancer stem cell;cancer subtypes;cell type;chemokine;clinical investigation;comorbidity;cytokine;diet-induced obesity;effective therapy;gene induction;hormone therapy;immunoregulation;in vivo;inhibitor;inhibitor therapy;malignant breast neoplasm;mammary;mortality;mouse model;mutant;neoplastic cell;novel strategies;obese patients;obesity treatment;patient derived xenograft model;preclinical study;programs;receptor for advanced glycation endproducts;recruit;response;single-cell RNA sequencing;stem cell expansion;synergism;therapy resistant;transcription factor;transcriptome;transcriptomics;treatment response;tumor;tumor microenvironment;tumor progression;weight loss intervention Targeting RAGE in tumor and TME to oppose inflammation and drug resistance in obesity associated ER+ breast cancer Project NarrativeObesity is associated with increased estrogen receptor-positive (ER+) breast cancer (BC) risk and a 2-4 foldincrease in mortality across all BC subtypes but mechanisms of increased acquired resistance to therapy andensuing fatal BC metastasis in obesity remain unclear. This project studies how the estrogen estrone (E1)which dominates after menopause and is much higher in obese local mammary fat co-operates with ER/ NFBand the Receptor for Advanced Glycation End-products (RAGE) in BC cells adipocytes and the tumormicroenvironment to impair drug treatment responses. Preclinical studies in organoids and PDX models test theability of new RAGE inhibitor drugs to reverse acquired endocrine therapy resistance. NCI 10734834 7/7/23 0:00 PA-20-185 1R01CA276587-01A1 1 R01 CA 276587 1 A1 "BERA, TAPAN K" 7/7/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 8824775 "HUDSON, BARRY IAN" "SLINGERLAND, JOYCE MARIE" 98 NONE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC UNIVERSITY-WIDE 200570001 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 516548 NCI 332759 183789 PROJECT SUMMARY/ABSTRACT Obesity is associated with increased postmenopausal estrogen receptor-positive (ER+) breast cancer (BC)risk and a 2-4 fold increase in mortality from all BC subtypes. Mechanisms of increased resistance to therapyand ensuing fatal BC metastasis in obesity remain unclear. Here we study how the inflammatory state of obesitydrives ER+ BC. We study how postmenopausal estrogen estrone (E1) which is 3-fold higher in obesity co-operates with NFB and the Receptor for Advanced Glycation End-products (RAGE) to upregulate metastasis. Our data indicate that BC cell:adipocyte contact activates NFB and E1:ER to induce pro-inflammatorycytokine genes in both cell types stimulating greater cancer stem cell expansion and rapid ER+ BC growth andmetastasis. Preliminary data show NFB and E1:ER co-stimulate genes encoding RAGE-ligands (S100A8/A9).RAGE is a major NFB activator in other cell types (including immune and endothelial cells) but little is knownof RAGE/NFB signaling in BC. We showed that RAGE acts in both tumor cells and the host microenvironment(stroma and fat) to upregulate cytokines that recruit myeloid-derived suppressor cells (MDSC) to promotemetastasis. In obese mice E1 increases BC growth in part by stimulating immune evasion. New data showantiestrogen-resistant ER+BC lines including those bearing ESR1 mutations show increased NFB activity andRAGE levels. Moreover the investigational RAGE inhibitor TTP488 cooperates with the ER-blocker fulvestrantto arrest antiestrogen-resistant ER+ BC cell growth in multiple resistant lines. Here we test if E1-bound ERNFB and RAGE interact in ER+ BC adipocytes and immune cells to drive gene programs of endocrine therapyresistance and if RAGE inhibitors reverse this. We hypothesize that E1:ER and NFB cooperate to induce RAGE and RAGE activates NFB in ER+ BCtumor cells and peritumoral fat to drive pro-inflammatory pro-metastatic gene expression programs of tumorprogression and acquired drug resistance. Aim 1 will identify tumor cell-intrinsic feed-forward mechanismsmediating RAGE/ NFB activation in an E1-rich breast cancer environment testing if E1 and NFB induce RAGEto activate Rac1 and TLR4 driving feed-forward oncogenic NFB activation in ER+ BC. Aim 2 will test if RAGEmediates pro-oncogenic pro-inflammatory target gene activation by E1/ER and NFB in breast cancer cells. Wewill identify E1/ER and NFB cistromes and transcriptomes and test if these require RAGE. The relevance ofRAGE-dependent ER/B co-target genes activation in obesity will be validated by comparing ScRNAseq inhuman ER+ breast cancers from obese and lean donors. Aim 3 will identify tumor cell-extrinsic mechanismswhereby peritumoral fat in obese hosts promotes acquired antiestrogen resistance and immune evasion in ER+cancers. Aim 4 will test if RAGE inhibitors restore endocrine therapy responses in organoid and PDX modelsderived from ER+ breast cancers. This work could identify new approaches to treating acquired endocrineresistance in metastatic ER+BC particularly in obese patients. 516548 +No NIH Category available APEXL2 Gene;Address;Attention;Base Excision Repairs;Biochemical;Biological Assay;CRISPR screen;Cells;Chemicals;Comprehension;DNA Binding;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;Data;Defect;Development;Double Strand Break Repair;Drug resistance;Exonuclease;Future;Genome Stability;Genomic Instability;Human;Immunofluorescence Immunologic;Impairment;In Vitro;Knowledge;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mediating;Methods;Modeling;Molecular;Mutate;Mutation;Nonhomologous DNA End Joining;Normal Cell;Ovarian Carcinoma;Pathway interactions;Peptides;Phosphodiesterase I;Play;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Progression-Free Survivals;Proteins;Proteomics;Relapse;Reporter;Research;Resistance;Role;Testing;Therapeutic;Up-Regulation;Zinc Fingers;cancer cell;cell growth;chromatin immunoprecipitation;cost;design;endonuclease;experimental study;genetic approach;genome-wide;homologous recombination;improved;inhibitor;innovation;interest;malignant breast neoplasm;new therapeutic target;novel;novel strategies;novel therapeutic intervention;nuclease;phosphoric diester hydrolase;prevent;recruit;repair function;repaired;sensor;synergism;synthetic lethal interaction;telomere;therapeutic evaluation;therapeutic target;tool;tumor Deciphering the function of the APE2 nuclease during repair by alternative end-joining and its role in HR-deficient cells PROJECT NARRATIVECancer cells that are deficient in homologous recombination (HR) rely on an alternative pathwayAlt-EJ to repair DNA breaks induced by replication. As a consequence inhibition of Alt-EJ islethal in these cancers and could be used as a therapeutic approach to eliminate HR-deficientcancers. We have identified the nuclease APE2 as an uncharacterized central player of Alt-EJand we will determine its molecular function and its potential as a novel therapeutic target. NCI 10734772 11/20/23 0:00 PA-20-185 5R01CA266100-03 5 R01 CA 266100 3 "WITKIN, KEREN L" 12/1/21 0:00 11/30/26 0:00 Cancer Etiology Study Section[CE] 12160938 "ARNOULT, NAUSICA C." Not Applicable 2 BIOCHEMISTRY 7431505 SPVKK1RC2MZ3 7431505 SPVKK1RC2MZ3 US 40.013296 -105.251932 1199902 UNIVERSITY OF COLORADO Boulder CO SCHOOLS OF ARTS AND SCIENCES 803031058 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 393 Non-SBIR/STTR 2024 316200 NCI 209246 106954 PROJECT SUMMARY Homologous recombination (HR) a pathway that repairs DNA double strand breaks (DSB) is frequentlymutated in cancers. HR-deficient cancers are prone to genomic instability and are critically dependent on otherDNA repair mechanisms for survival. Among them is the DNA damage sensor PARP and PARP inhibitors havetherefore proved an efficient therapy to eliminate HR-deficient cancers. However some HR-deficient tumors donot respond to PARP inhibitors and most tumors eventually relapse and become resistant to the drug. Newtherapeutic strategies are therefore urgently needed to treat HR-deficient cancers and overcome PARPinhibitor resistance. Among the potential strategies growing attention has focused on alternative end-joining (Alt-EJ) a back-up DSB repair pathway that is dispensable in normal cells but critical to cellular survival when HR iscompromised. While mounting evidence suggests that inhibition of Alt-EJ could be a powerful strategy toovercome the problem of resistance to PARP inhibitors the Alt-EJ pathway remains poorly characterized limitingthe potential number of therapeutic targets that could be developed. To address this gap in knowledge my lab has designed a novel approach to identify Alt-EJ factors usinggenome-wide CRISPR/Cas9 screens. Using this method as well as Alt-EJ assays based on repair reporters orAlt-EJ-mediated fusion of telomeres we have identified the nuclease APE2 as a critical protein in Alt-EJ. Thiscompelling discovery raises the exciting possibility that APE2 inhibition could be used to specifically target HR-deficient cancer cells and thereby prevent or overcome resistance to PARP inhibitors. Several questionshowever need to be addressed first as the exact function of APE2 in Alt-EJ and its role in HR-deficient cellsremain elusive. First we will characterize at the molecular level the function and mechanism of action of APE2 in Alt-EJ.We will determine: (1) the role of APE2 in Alt-EJ (2) the domains and biochemical activities involved and (3)the mechanism of its recruitment to DSBs. The interest here is both to significantly improve our fundamentalunderstanding of the Alt-EJ repair pathway and to gain sufficient knowledge on APE2 to enable the futuredevelopment of an inhibitor. Second we will uncover the therapeutic potential of APE2 inhibition in HR-deficient cancer cells. (1) Wewill identify the repair function of APE2 that drives its synthetic lethality with HR and (2) we will determine thepotential of APE2 inhibition to synergize with PARP inhibitors and to prevent or overcome resistance to PARPinhibitors. Our novel discovery that APE2 plays a critical function in alternative end-joining and the innovative toolsthat we have created to study APE2s role in Alt-EJ places my lab in a unique position to successfully carry outthis proposed research. 316200 +No NIH Category available Address;Artificial Intelligence;Bioinformatics;Biological Markers;Biological Specimen Banks;Biological Specimen database;Biometry;Cancer Burden;Cancer Center;Cancer Detection;Center for Translational Science Activities;Cirrhosis;Clinical;Clinical Data;Cohort Studies;Collaborations;Collection;Common Data Element;Communication;Computer Analysis;Consultations;Country;Dana-Farber Cancer Institute;Data;Data Collection;Data Coordinating Center;Data Management Resources;Data Science;Data Set;Databases;Discipline;Early Detection Research Network;Early Diagnosis;Ensure;Evaluation;Evaluation Studies;Image;Information Technology;Infrastructure;Lead;Leadership;Liver;Malignant Neoplasms;Malignant neoplasm of liver;Manuals;Mission;Modeling;Monitor;Nodule;Output;Patients;Procedures;Prospective Studies;Prospective cohort study;Protocols documentation;Public Health;Qualifying;Randomized;Research;Research Design;Research Personnel;Research Support;Retrospective Studies;Risk;Sampling;Science;Scientist;Screening for Hepatocellular Cancer;Secure;Services;Specimen;Statistical Data Interpretation;Statistical Methods;System;Testing;Time;Translational Research;United States;University of Texas M D Anderson Cancer Center;Work;anticancer research;artificial intelligence method;biomarker evaluation;cancer biomarkers;computational intelligence;computerized data processing;data management;data repository;data sharing;experience;improved;informatics tool;innovation;instrument;meetings;operation;programs;protocol development;research study;risk stratification;success;symposium;validation studies;web site Consortium on Translational Research in Early Detection of Liver Cancer:Data Management and Coordinating Center (DMCC) PROJECT NARRATIVEThe proposed study is highly relevant to public health because early detection has great potential to reduce livercancer burden in United States and worldwide. Rigorous evaluation of biomarker tests for their potential clinicalutility is imperative for public health. NCI 10734730 9/11/23 0:00 RFA-CA-22-032 2U24CA230144-07 2 U24 CA 230144 7 "MARQUEZ, GUILLERMO" 9/17/18 0:00 8/31/28 0:00 ZCA1-TCRB-Q(M1) 2110020 "FENG, ZIDING " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 738030 NCI 467958 270431 PROJECT SUMMARY ABSTRACTThe key to success of the Consortium on Translational Research in Early Detection of Liver Cancer (Consortium)lies in good communication among scientists in multiple disciplines efficient evaluation and prioritization ofpromising biomarkers and rigorous validation studies to demonstrate their potential clinical utilities in improvingthe surveillance and early detection of liver cancer and stratifying the risk of liver cancer in patients with cirrhosis.The overall aims of the proposed Data Management and Coordinating Center (DMCC) are to (i) enhancecommunication and collaboration among Consortium investigators; (ii) coordinate Consortium collaborativeresearch and provide statistical support; (iii) develop and maintain integrated research and biorepositorydatabases for Consortium studies; and (iv) support and facilitate trans-Consortium collaborative research.Under the direction of the Consortium Steering Committee the DMCC will 1) perform network coordination andpromote collaborations among scientific investigators by providing support for Consortium meetings andconference calls developing and maintaining all Consortium documents including the Manual of Operations andProcedures (MOP) and by maintaining and enhancing the Consortiums secure website; 2) support Consortiumcollaborative studies by working with Consortium investigators on study design protocol development dataforms and study manuals; coordinating and monitoring studies; tracking specimen sharing blinding andrandomization; and performing QA/QC and study evaluation; 3) maintain and enhance the COMPASS DataManagement System (CDMS) used to facilitate Consortium collaborative activities. CDMS provides online end-to-end data management solutions including investigator and study coordinator communications regulatorycompliance remote subject registration clinical data capture biospecimen sample management imaging datarepository and document management. CDMS can provide online visibility of analytical datasets for allparticipating researchers and statistical and informatic tools relevant to Consortium research; 4) support andfacilitate trans-Consortium collaborative studies by promoting team science monitoring study procedures andusing cutting edge statistical computational and Artificial Intelligence methods to ensure efficient yet rigorousstudy design and maximize research outputs.Our research strategy is built from this guiding principle: provide the highest quality service to the Consortiumwhile remaining innovative and providing scientific leadership to help the Consortium achieve its mission. Ourqualifications include being the DMCC for the Early Detection Research Network since its inception serving aslead statisticians for the two largest ongoing cirrhosis cohort studies in this country and being responsible fortwo FDA-cleared Imaging AI products and many statistical innovations in early detection research. 738030 +No NIH Category available African;African ancestry;Alleles;Allelic Imbalance;Asian;Asian ancestry;BRCA2 gene;Biological;Biology;CHEK2 gene;Cancer Patient;Candidate Disease Gene;Clinical;Code;DNA Repair Pathway;Data;Development;Diagnosis;Disease;Disease susceptibility;European;European ancestry;Family history of;Frequencies;Gene Expression Profile;Gene Frequency;Genes;Genetic Predisposition to Disease;Genetic Risk;Genetic Variation;Genome;Germ-Line Mutation;Gleason Grade for Prostate Cancer;Heritability;Heterogeneity;Hispanic;Latino;Malignant neoplasm of prostate;Metastatic Prostate Cancer;Minor;Modeling;Modification;Mutate;Mutation;PALB2 gene;Pathogenicity;Pathway interactions;Phenotype;Population;Protein Truncation;Proteins;Reporting;Resources;Risk;Sample Size;Somatic Mutation;Surveys;Susceptibility Gene;Testing;Time;Trans-Omics for Precision Medicine;Variant;biobank;clinical translation;cohort;cost;density;disease phenotype;disorder risk;diverse data;driver mutation;exome;genome wide association study;genome-wide;high risk;man;men;novel;personalized risk prediction;polygenic risk score;prevent;prospective;prostate cancer prevention;prostate cancer risk;rare variant;risk variant;screening;transcriptomics;tumor;whole genome Leveraging whole-exome sequence data from diverse biobanks and cohorts to study rare coding variation in prostate cancer Project NarrativeIn this project we will conduct exome-wide discovery efforts to identify rare variants and genes that contributeto risk of prostate cancer and aggressive disease in men of European African Asian and Latino ancestry. Weexpect findings from this study will make a major contribution to our understanding of genetic susceptibility toprostate cancer and will have widespread applicability and significance leading to better risk models to moreaccurately predict a man's risk of developing prostate cancer and aggressive disease. NCI 10734712 9/20/23 0:00 PA-20-185 1R01CA276826-01A1 1 R01 CA 276826 1 A1 "DAEE, DANIELLE L" 9/20/23 0:00 8/31/28 0:00 Cancer and Hematologic Disorders Study Section[CHD] 8474689 "HAIMAN, CHRISTOPHER ALAN" "BOUTROS, PAUL CHRISTOPHER" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 765904 NCI 598915 166989 AbstractThere is strong evidence that prostate cancer (PCa) is a heritable phenotype. In addition to greater risk observedin men with a family history of PCa genome-wide association studies (GWAS) have identified over 400 commonindependent risk variants which explain ~40% of the familial risk. It is increasingly recognized that much of theunknown heritability for PCa may also be due to variants of low minor allele frequency (<1%). While large multi-ancestry genome-wide reference panels (e.g. TOPMed) have been developed to facilitate studies of lesscommon alleles (down to 0.1%) they cannot be used to enumerate and accurately study very rare alleles thatcan only be characterized via sequencing. Pathogenic variants in DNA repair pathway genes (e.g. BRCA2ATM NBN CHEK2 PALB2) identified through candidate gene studies provide strong support for exceedinglyrare (<0.1%) protein coding variation contributing to overall PCa and aggressive disease susceptibility.Unfortunately we remain limited in our ability to comprehensively survey and study very rare variation genome-or exome-wide due to high sequencing costs limiting current sample sizes. Here we propose to combine existingwhole-exome (WES) and whole-genome (WGS) sequence data from multi-ancestry biobanks and cohorts toconduct the first large-scale study of rare coding variation in PCa and to integrate tumor somatic and germlinemutation data to elucidate the biology of gene-risk associations. In Aim 1 we will leverage existing WES data for>90000 PCa cases (58000 European ancestry 20000 African ancestry 4000 Asian ancestry and 6700Latino/Hispanic) and >500000 controls within biobanks and cohorts in the US and UK and conduct exome-wideanalyses of overall PCa and aggressive disease phenotypes. In Aim 2 we will examine the combined effect ofrare coding variants and a polygenic risk score (PRS) on risk of overall PCa and aggressive disease and estimateabsolute risks for the combined effects of rare coding variants and PRS in prospective biobanks and cohortsacross populations. In Aim 3 we will integrate somatic tumor and germline variation data to inform genes andbiological pathways involved in PCa and aggressive disease. For this Aim we have assembled a somaticresource of >7000 PCa patients with germline exome/PRS data and somatic mutation profiling from WES andWGS studies including >2000 with transcriptomic data. We expect this study to provide the most comprehensiveand well-powered examination of rare coding variation in PCa across populations to date. Findings from thisstudy will have immediate clinical translation by informing personalized risk prediction and the development ofnovel risk-based screening strategies for overall and aggressive PCa. Integrating germline and somatic data willalso define biological mechanisms that may be clinically important for understanding how to treat and preventPCa and lethal disease across populations. 765904 +No NIH Category available Acinar Cell;Address;Adenovirus Vector;Adenoviruses;Anatomy;Animal Model;Binding;Biodistribution;Body Size;Bystander Effect;CD46 Antigen;Cancer Biology;Cancer Etiology;Cancer Model;Cells;Cessation of life;Clinical;Clinical Trials;Data;Development;Diagnosis;Diagnostic;Diagnostic Imaging;Disadvantaged;Disease;Disseminated Malignant Neoplasm;Drug Kinetics;Duct (organ) structure;Ductal Epithelial Cell;Engineering;Enterobacteria phage P1 Cre recombinase;Evaluation;Excision;Family suidae;Fostering;Generations;Genes;Genetic;Goals;Human;Image;Imaging technology;Immunity;Immunocompetent;Industrialization;Intravenous;KRAS2 gene;KRASG12D;Lesion;Malignant neoplasm of pancreas;Mediating;Metabolism;Methods;Modeling;Monitor;Mus;Mutation;Neoplasm Metastasis;Oncogenes;Oncolytic;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Pathologist;Patient Selection;Patient imaging;Patients;Pattern;Phase I Clinical Trials;Physiology;Preclinical Testing;Radiation therapy;Radioactive Iodine;Radioisotopes;Recording of previous events;Reporting;Rodent;Rodent Model;SLC5A5 gene;Safety;Serotyping;Survival Rate;System;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translating;Translations;Treatment Protocols;Unresectable;Virus;Work;X-Ray Computed Tomography;Xenograft Model;anticancer treatment;cancer cell;cancer therapy;canine model;carcinogenesis;clinical development;clinical translation;clinically relevant;collaborative environment;curative treatments;design;desmoglein 2;detection sensitivity;effective therapy;experience;gene function;immunogenicity;improved;mouse model;neoplastic;neoplastic cell;novel;novel diagnostics;novel therapeutic intervention;oncolysis;oncolytic adenovirus;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;permissiveness;porcine model;pre-clinical;preclinical study;prevent;radioiodine imaging;radioiodine therapy;radiologist;receptor;safety study;screening;single photon emission computed tomography;success;surgical service;theranostics;tool;tumor;tumor progression;tumorigenesis;uptake;vector Advancing Systematic Delivery of Oncolytic Adenovirus for Pancreatic Cancer Project Narrative: The goal of this proposal is to develop a new swine model of pancreatic cancer to enable preclinical testingof systemically delivered oncolytic adenoviruses to detect and treat pancreatic cancer. Successful products fromthis proposal can be promptly translated to the clinical arena bringing novel therapeutic approaches to thepatients with pancreatic cancer including those with unresectable metastatic disease.1 NCI 10734709 6/23/23 0:00 PA-20-185 1R01CA276179-01A1 1 R01 CA 276179 1 A1 "AHMED, MANSOOR M" 7/1/23 0:00 6/30/28 0:00 Drug and Biologic Therapeutic Delivery Study Section[DBTD] 8916123 "DAVYDOVA, JULIA " Not Applicable 5 SURGERY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 480793 NCI 310189 170604 ABSTRACT The goal of this project is to enable the clinical translation of systemically delivered Oncolytic Adenoviruses(OAds) for combined diagnostic imaging and curative therapy of Pancreatic Ductal Adenocarcinoma (PDAC) adevastating disease without effective therapies. PDAC has no effective screening methods and its spread andmetastases are difficult to assess. This new generation of OAds expressing Sodium-Iodide Symporter (OAd5/3-NIS vectors) developed in the Davydova lab induces uptake of radioactive iodine by pancreatic cancer cellsthus facilitating both SPECT/CT imaging and radiotherapy with 131I. We have demonstrated remarkable pre-clinical data to support the applicability of the OAd5/3-NIS platform to facilitate radioiodine-based imaging andtreatment of PDAC. However the clinical translation of intravenously administrated OAds has been stalled bythe lack of an animal model that allows OAd replication. Murine tissues do not support replication of humanadenovirus preventing the use of mice to study biodistribution and off target effects of systemically deliveredOAds. Moreover all rodent systems lack Adenovirus type 3 (Ad3) receptors necessary to bind to Ad3-basedvectors (including our OAd5/3-NIS). The need for reliable animal models is critical. Less than 5% of anti-cancertreatments that are promising in murine models are successful in human clinical trials. Therefore to address thisurgent need we are developing a novel translational swine model of PDAC. Pigs have been attractive as analternative platform for cancer modeling because of their similarity with humans in terms of anatomy metabolismtumorigenesis genetics immunity and body size. Furthermore as we have recently reported unlike rodent andcanine models pigs permit replication of both Adenovirus type 5 and Adenovirus type 3 vectors on the levelsimilar to that in humans. Validating systemic administration of OAd5/3-NIS in our swine model of pancreaticcancer is the next step before clinical trials. In this work we will 1) Produce a novel transgenicKrasG12D/+/TP53R167H/+ swine model of PDAC; 2) Monitor and characterize PDAC tumor development; and 3)Conduct the preclinical studies to evaluate the potential of intravenously administrated OAd5/3-NIS to facilitateboth radioiodine-based imaging and radiotherapy with 131I in swine PDAC models. Completion of this proposalwill enable clinical translation of systemically injected OAd5/3-NIS vectors for treatment and diagnostic imagingof patients with PDAC including patients with metastatic cancer. Importantly these studies will generateessential information on biodistribution clearance off target effects and overall therapeutic potential of otherOAds in a clinically relevant adenovirus replication permissive immunocompetent model. In addition our novelpig model will overcome many of the disadvantages inherent in rodents particularly with respect to size geneticscancer biology metabolism and immunity leading to translation of safer more effective cancer treatments forpatients with PDAC a dismal disease with no effective treatments available.1 480793 +No NIH Category available Acute;Address;Adhesions;Apoptosis;Basic Science;Biochemical;Biological Assay;Cell Adhesion;Cell Death;Cell membrane;Cell physiology;Cells;Ceramidase;Ceramides;Cessation of life;Development;Elements;Enzymes;Event;Family;Generations;Goals;Grant;Growth;Human;Hydroxylation;In Vitro;Length;Lipids;Measures;Mediating;Membrane;Membrane Microdomains;Metabolism;Molecular;Pathway interactions;Phorbol Esters;Phosphoric Monoester Hydrolases;Production;Productivity;Protein Dephosphorylation;Protein Phosphatase 2A Regulatory Subunit PR53;Protein phosphatase;Protein translocation;Proteins;Publishing;Quantitative Evaluations;Regulation;Role;Scheme;Signal Pathway;Signal Transduction;Sphingolipids;Sphingomyelinase;Sphingosine;Stimulus;TNF gene;Time;acid sphingomyelinase;biological adaptation to stress;cancer cell;cell fixing;cell growth;cell motility;combinatorial;experimental study;ezrin;liquid chromatography mass spectrometry;migration;novel;programs;response;senescence;stem;targeted cancer therapy;tumor progression Ceramide Activated Protein Phosphatases Bioactive sphingolipids are a class of lipids (fatty molecules) which are emerging asimportant regulators of cell functions including effects on cell growth cell death and cellmigration and the bioactive sphingolipid ceramide is a key molecule in sphingolipidmetabolism and function. Our studies have implicated this lipid in regulating cell growthand death and in this proposal we focus on a novel pathway mediated by this lipidwhich is located in the plasma membrane and we also focus on the mechanisms bywhich this pathway regulates cancer cell migration and adhesion key events in cancerprogression. By dissecting out the molecular mechanisms of this pathway we stand tonot only advance our basic science understanding of how these molecules operate butwe anticipate to advance novel targets for cancer therapy. NCI 10734669 7/12/23 0:00 PA-20-185 2R01CA218678-06 2 R01 CA 218678 6 "XU, WANPING" 7/12/18 0:00 6/30/28 0:00 Biochemistry and Biophysics of Membranes Study Section[BBM] 1869058 "HANNUN, YUSUF AWNI" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY SCHOOLS OF MEDICINE 117943362 UNITED STATES N 7/12/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 395387 NCI 250000 145387 Ceramide constitutes a family of closely related molecules that function as bioeffectorlipids with roles in the regulation of stress responses and growth/death of various humancancer cells. Critical missing elements in our understanding of ceramide stem from thelack of defining compartment-specific functions of ceramides and from lack of molecularly-defined targets of action. Studies in our lab supported by this project have identifiedceramide-activated SerThr phosphatases (CAPPs) specifically PP1 and PP2A as directtargets activated by ceramide in vitro. Recent results have provided us a breakthrough indefining a specific pathway of ceramide generation at the plasma membrane (PM). Herewe will investigate the hypothesis that ceramide generated at the PM acutely activatesPP1 that leads to the dephosphorylation of distinct proteins launching a distinct programof regulation of cell adhesion and migration. We are also developing a novel assay toquantitate PM ceramide specifically. With this breakthrough we will address these aims:Aim 1. Develop a quantitative assay to measure ceramide generation at the PM anddefine key enzymes of ceramide metabolism in this compartment (steady state). Aim 2.Define stimulus-induced formation of PM ceramide and the mechanisms involved. Aim 3.Define biochemical mechanisms of regulation of PP1a by PM ceramide. Taken togetherthese approaches should result for the first time in clearly defining a specific direct andrelevant target for ceramide action (PP1) with a specific function in mediating the effectsof PM ceramide on cell adhesion and migration. 395387 +No NIH Category available Acceleration;Animal Model;Antineoplastic Agents;Biological;Cancer Patient;Cancer cell line;Cell Culture Techniques;Cell Line;Cessation of life;Chimeric Proteins;Clinical;Clinical Trials;Collection;Complex;Defect;Development;Drug Kinetics;Drug Targeting;Epidermal Growth Factor Receptor;Gleevec;Human;Imatinib;Immune system;Licensing;Malignant Neoplasms;Methods;Molecular;Mutate;Mutation;Normal Cell;Oncology;Output;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Toxicology;Translations;Vision;Work;anti-cancer;anticancer activity;cancer cell;cancer subtypes;cancer therapy;cancer type;cell type;drug discovery;efficacy evaluation;efficacy study;experience;experimental study;neoplastic cell;novel;novel anticancer drug;novel strategies;overexpression;personalized medicine;precision drugs;success;targeted treatment;tumor Developing a Suite of Targeted Anticancer Drugs Project NarrativePersonalized drugs for cancer exploit specific alterations in the cancer cell for example a mutatedoverexpressed or fused protein that is present in tumor cells but not normal cells but only a handful ofsuch drugs are available and the pace of development is slow. We have implemented a strategy thatenables discovery of novel compounds that are selective for certain cancer subtypes leading to 4 of ouranticancer drugs moving toward clinical trials in the last 15 years. As described herein we will nowaccelerate this discovery platform utilizing a novel compound collection biased for selective anticanceractivity; this strategy will allow us and others to discover and develop scores of new cancer drugs thatare matched to specific molecular defects in a patients tumor. NCI 10734624 9/19/23 0:00 RFA-CA-22-045 1R35CA283859-01 1 R35 CA 283859 1 "AGYIN, JOSEPH KOFI" 9/20/23 0:00 8/31/30 0:00 ZCA1-SRB-E(M1) 8062717 "HERGENROTHER, PAUL " Not Applicable 13 CHEMISTRY 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL SCHOOLS OF ARTS AND SCIENCES 618207473 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 515200 NCI 334257 180943 AbstractThe stunning clinical success of Gleevec (imatinib) two decades ago appeared to usher in a new era forcancer treatment whereby a molecular defect in a patients tumor was known and could be exploited witha selective drug. A suite of such selective drugs were envisioned 100s of different drugs that could beprescribed to appropriate patients based on tumor profiling of 100s of different potential defects.Unfortunately this vision has not come to pass and with only a handful of approved drug-target pairs thefull potential of personalized medicine in oncology has not been realized. While drugs such as imatinib (andvemurafenib osimertinib and a few others) have been game-changers for those cancer subtypes (e.g.certain cancer types with Bcr-Abl translocation BRAFV600E mutation and EGFRT790M mutation respectively)there remain 100s of cancer subtypes and hundreds of exploitable molecular defects that are not matchedwith drugs. The plodding progress of traditional drug discovery in this realm suggests new approaches areneeded to fully realize the potential of targeted therapy for oncology. My lab has developed a discoveryplatform from compound synthesis to cell culture to target identification to sophisticated animal modelsto translation that has resulted in 4 novel cancer drugs licensed and moving to cancer patients in 15 years.Building off the observation that truly selective drugs that are successful in human cancer patients also showexquisite selectivity in cell culture we have identified compounds that have wide activity differential for killingsensitive cell lines versus non-sensitive cell lines; through this method we have identified compounds with>100-fold selectivity and that have advanced (or are advancing) to human cancer patients. In work for theOIA we will create an unprecedented collection of complex-and-diverse compounds with the novel twistthat these compounds will be biased for anticancer activity through incorporation of an electrophile.Compounds able to induce selective death in a panel of >100 cancer cell lines and normal cell types will beadvanced through medicinal chemistry optimization. Top compounds will then progress through two paralleltracks 1) discovery of the biological target (basis for the anticancer selectivity) with our experience showingthat in most cases this work will reveal novel exploitable defects in cancer and 2) translational advancementthrough the pharmacokinetic/toxicology/efficacy studies and assessment of the ability to engage the immunesystem experiments needed to move the very best compounds to clinical trials in cancer patients. We havedemonstrated the ability to accomplish all parts of this workflow at a high level enlisting key collaboratorsas needed. Through this OIA we will increase our output 2-5-fold meaning the discovery and developmentof 4-10 novel cancer drug/target pairs during the 7 year OIA. As importantly this work will provide a blueprintfor success that others can mimic which will ultimately enable full realization of the potential of personalizedmedicine with hundreds of drugs for the hundreds of different cancer subtypes. 515200 +No NIH Category available Address;Advanced Malignant Neoplasm;American College of Radiology Imaging Network;Back;Basic Science;Cancer Patient;Cancer and Leukemia Group B;Caring;Catchment Area;Clinical Cancer Center;Clinical Oncology;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Comprehensive Cancer Center;Consent;Development;Disease;Eastern Cooperative Oncology Group;Eligibility Determination;Enrollment;Geographic Locations;Geography;Health;Image;Immunologics;Industry;Institution;Intervention;Lead;Leadership;Malignant Neoplasms;Mission;Molecular;Multi-Institutional Clinical Trial;NCI Center for Cancer Research;National Cancer Institute;National Clinical Trials Network;New England;New Hampshire;Norris Cotton Cancer Center;Nursing Research;Oncology;Oncology Group;Patient Selection;Patients;Performance;Phase;Process;Recording of previous events;Reporting;Research Personnel;Science;Services;Site;System;Target Populations;Translating;Vermont;cancer imaging;cancer therapy;clinical application;college;community based practice;design;innovation;medical schools;medical specialties;member;multimodality;operation;patient population;programs;rare cancer;screening;symposium;treatment trial NCI National Clinical Trials Network - Network Lead Academic Participating Sites Project NarrativeDartmouth-Hitchcock Health is the leading specialty care network for a vast geographic regioncovering New Hampshire and Vermont statewide. The Norris Cotton Cancer Center (NCCC) isthe academic hub for services for rare and advanced cancer cases across the region. As aLead Academic Participating Site in the National Cancer Institutes National Clinical TrialsNetwork our overarching mission is to advance the NCTN collaborative clinical researchprogram of definitive clinical trials including multi-modality umbrella/basket and rare tumortrials and to translate basic science studies into meaningful advancements in the care ofNorthern New England cancer patients. NCI 10734623 1/10/23 0:00 PA-20-272 3UG1CA233323-04S1 3 UG1 CA 233323 4 S1 "MOONEY, MARGARET M" 11/4/22 0:00 2/28/23 0:00 10458229 "DRAGNEV, KONSTANTIN H." Not Applicable 2 Unavailable 150883460 LLLYTJ6LYD21 150883460 LLLYTJ6LYD21 US 43.637006 -72.252383 10051750 DARTMOUTH-HITCHCOCK CLINIC LEBANON NH Independent Hospitals 37560001 UNITED STATES N 11/4/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 199936 NCI 130677 69259 AbstractNorris Cotton Cancer Center (NCCC) the keystone of the cancer-related activities of both Dartmouth Collegeincluding its Geisel School of Medicine and Dartmouth-Hitchcock Health will participate in the NCI's NationalClinical Trials Network as a Lead Academic Participating Site. NCCC has a long history of leadership innational cooperative group clinical trials dating back to serving as an operating center for CALGB and morerecently as a main member of the Alliance for Clinical Trial in Oncology NRG COG and ECOG/ACRIN. Asthe only NCI designated Comprehensive Cancer Center in northern New England NCCC currently servesannually over 5000 new patients and 30000 returning cancer patients. NCCC is the specialty academic centerfor Vermont and New Hampshire anchoring a network of 17 community-based practice sites across the regionand receiving referrals of rare and advanced cancers the target population for enrollment on innovative clinicaltrials from a large geographic catchment area. Within Dartmouth NCCC has a central Office of ClinicalResearch (OCR) which coordinates full participation in the entire range of available clinical trials. NCCCintends to participate fully in all NCTN activities expanding its prior focus on participation in the Alliance.NCCC investigators are active in many NCTN Operations Center committees facilitating a bi-directionalintegration of NCCC concepts into the NCTN while NCTN studies will be seamless incorporated into theNCCC trial portfolio. We anticipate accrual of 55 consented subjects on high performance intervention fortreatment trials and 20 subjects on screening only accruals for treatment or imaging trials. Care at DH isorganized into 17 designated interdisciplinary disease-based teams which bring together all relevantspecialties 14 on a weekly basis for new patient conferences at which eligibility for enrollment on clinical trialsis assessed routinely. NCCC research nurses assigned to these Clinical Oncology Groups (COGs) areresponsible for keeping the teams informed of available trials and the NCCC clinical trials managementsystem (Velos eResearch) provides the teams reports tracking current enrollment. While highest priority isgiven to translating NCCC science into clinical application Dartmouth's size precludes most single-institutionstudies and national cooperative group trials are prioritized ahead of industry-initiated studies for fulfillment ofNCCC's clinical research mission. 199936 +No NIH Category available Address;Affect;Age;Algorithms;Benign;Biopsy;California;Cancer Control;Cancer Intervention;Characteristics;Clinical;Collaborations;Communities;Community Practice;Complex;Confusion;Data;Data Analyses;Data Collection;Data Set;Databases;Decision Making;Detection;Development;Diagnosis;Disease Progression;Expert Opinion;Face;Feedback;Future;Gender;Geography;Goals;Health;Health Care Costs;Health system;Healthcare;Heating;Histology;Hospitals;Image;Impairment;Individual;Institution;Internet;Kidney;Learning;Left;Life;Malignant - descriptor;Malignant Neoplasms;Medical;Medical center;Modality;Modeling;Needles;Nephrectomy;Online Systems;Operative Surgical Procedures;Outcome;Pathologic;Pathway interactions;Patient Preferences;Patient-Focused Outcomes;Patients;Persons;Process;Provider;Quality of life;Recommendation;Renal Cell Carcinoma;Renal Mass;Renal function;Resources;Rest;Risk;San Francisco;Secure;Surveys;System;Thermal Ablation Therapy;Translations;Triage;Uncertainty;Universities;Urologist;Validation;Variant;Virginia;Wisconsin;Work;cancer cell;cohort;community partnership;comorbidity;cost;cost comparison;expectation;functional decline;geographic difference;health care service utilization;individual patient;intervention cost;kidney cell;markov model;multidisciplinary;novel therapeutics;patient oriented;patient variability;personalized care;personalized management;preservation;prospective;prototype;shared database;shared decision making;side effect;tool;treatment effect;treatment optimization;treatment planning;tumor;usability;web based interface;web-based tool;willingness Optimizing Treatment Decision Making for Patients with Localized Renal Mass Project Narrative When a person is found to have a mass that is localized to their kidney (LRM) they facemany choices on what to do about it but their doctors can offer little advice since there is littleguidance from prior studies. To address this we will first create a database between threedifferent academic hospital systems that gathers all known information about the health of thepatient and the LRM. This information can then be used to create specific treatment pathwaysthat can help the doctor and patient decide what is best for the patient particularly in terms oftreating the cancer while trying to save the function of their kidney and minimize side effects. NCI 10734606 5/31/23 0:00 PAR-21-190 1R01CA284057-01 1 R01 CA 284057 1 "GALLICCHIO, LISA M" 7/1/23 0:00 6/30/27 0:00 Biodata Management and Analysis Study Section[BDMA] 10802111 "LOBO, JENNIFER MASON" "CULP, STEPHEN HEMBREE" 5 PUBLIC HEALTH & PREV MEDICINE 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 396067 NCI 256690 139377 Project Summary Kidney cancer or renal cell carcinoma (RCC) is one of the 10 most common cancers inthe US. In 2022 over 79000 people will be diagnosed with RCC. Localized renal masses (LRMtumors confined to the kidney) make up two-thirds of all RCC. Patients found to have a LRM facemany choices on what to do especially since it is not uncommon for these LRM to be benign.There are currently four ways to manage LRM active surveillance (watching the mass but nottreating it) thermal ablation (heating the mass by putting a needle in it from the outside) partialnephrectomy (surgery to cut the mass out but leave the rest of the kidney in place) and radicalnephrectomy (surgery to remove the entire kidney). Patients and doctors are often confused asto which option to pursue since there have been few previous studies to guide them. It is currentlyrecommended that the kidney be preserved in patients who may have future problems with theirkidney function. However it is hard to identify these patients especially when they have otherhealth issues. Current recommendations are based on expert opinion and it is typically left upto the doctor to decide what is best for the patient in terms of risk to the kidney and whether thecancer threatens the life of the patient over other medical conditions the patient may have. The primary goal of our study is to identify specific management plans that can beindividualized for a patient with a LRM. This will make it easier for the doctor and patient to decideon the best way to manage the mass. By using a tool built with real-world information the trade-off with each option (like kidney function) will be clearer to the patient thereby helping them makethe best decision. We will create an internet-based database shared between three different majoracademic hospitals. We will collect information about the health of the patient how good theirkidney function is and the details of the LRM. We will assess how often biopsies are done priorto treatment of the LRM and what treatments patients tend to pursue. We will develop a set ofrules for management of a LRM using a Markov decision process model and real-world patientinformation. We will then use this model to identify treatment decisions that are in line with patient-driven goals including what is best for their quality of life and approaches that minimize healthcare cost. Our work will enable patients and their doctors to participate in a shared-decisionmaking process. We will create a web-based tool and assess the feasibility of communityurologists helping with gathering patient information and collaboration to optimize patientmanagement (i.e. community versus academic setting). 396067 +No NIH Category available Yale Cancer Center Yale Cancer Center NCTN LAPS Not required by RFA. NCI 10734497 1/10/23 0:00 PA-20-272 3UG1CA233337-04S1 3 UG1 CA 233337 4 S1 "MOONEY, MARGARET M" 3/8/19 0:00 2/28/23 0:00 1925253 "HERBST, ROY S" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 120000 NCI 71642 48358 Not required by RFA. 120000 +No NIH Category available Address;Alkylating Agents;Alkylation;Apoptosis;Biological Availability;Cells;Central Nervous System Agents;Chemicals;Clinic;Colon Carcinoma;Cyclization;Cytosine;DNA;DNA Alkylation;DNA Damage;DNA Interstrand Crosslinking;DNA Repair;DNA Repair Disorder;DNA Repair Gene;Data;Dealkylation;Development;Drug resistance;Excision;Futile Cycling;Genes;Genetic;Genome;Genomics;Glioblastoma;Glioma;Goals;Grant;Guanosine;Human;Hypermethylation;Ions;Kinetics;Lesion;MGMT gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methyltransferase;Mismatch Repair;Modeling;Modification;Mutagens;Non-Small-Cell Lung Carcinoma;Oligonucleotides;Oral;Pathway interactions;Patients;Penetration;Pharmaceutical Preparations;Phenotype;Polymerase;Prodrugs;Proliferating;Radiation therapy;Reaction;Research;Resected;Resistance;Structure;Testing;Therapeutic;Therapeutic Index;Thymine;Time;Tissues;Toxic effect;Transferase;Translating;Translations;Work;adduct;bench to bedside;chemotherapy;clinically significant;crosslink;cytotoxicity;design;efficacy evaluation;experience;functional loss;improved;in vivo;ineffective therapies;inhibitor;mouse model;new therapeutic target;novel;novel strategies;promoter;repaired;response;small cell lung carcinoma;standard of care;synergism;systemic toxicity;targeted agent;temozolomide;tissue culture;treatment strategy;trial design;tumor;tumor specificity Novel therapeutics for the targeted eradication of DDR-defective tumors PROJECT NARRATIVE.O6-Methylguanine methyltransferase (MGMT) is a DNA repair protein that converts O6-alkylguanosine residuesarising from endogenous and exogenous genotoxins to guanosine. MGMT is ubiquitously expressed in healthytissue but silenced in a broad range of cancers by promoter hypermethylation. This grant seeks to exploit MGMTsilencing to develop targeted agents for the eradication of nave and drug-resistant tumors. NCI 10734414 7/25/23 0:00 PA-20-185 1R01CA276186-01A1 1 R01 CA 276186 1 A1 "AGYIN, JOSEPH KOFI" 7/25/23 0:00 6/30/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 8604318 "HERZON, SETH B." "BINDRA, RANJIT " 3 CHEMISTRY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF ARTS AND SCIENCES 65208327 UNITED STATES N 7/25/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 654163 NCI 390545 263618 PROJECT SUMMARY/ABSTRACT.O6-Methylguanine methyltransferase (MGMT) reverts O6-alkylguanosine residues to guanosine via dealkylationby SN2 displacement. MGMT is ubiquitously expressed in healthy tissue but is silenced (referred to as MGMT) in ~50% of glioblastomas (GBMs) most gliomas and in up to 40% of colon cancers 35% of small cell lungcancers and 25% of non-small cell lung cancers. MGMT tumors are sensitized to DNA alkylation agents suchas temozolomide (TMZ). This sensitization creates a therapeutic index (TI). TMZ prolongs survival of patientswith MGMT GBM by ~8 mo. The cytotoxicity of TMZ relies on an intact DNA mismatch repair (MMR) pathway.MMR silencing (referred to as MMR) is the primary mechanism of acquired TMZ resistance and second-linetherapies are ineffective. Despite >20 y of research efforts to overcome MMR silencing-based resistance havenot been successful. Herein we present 2-fluoroethylating agents (FEtAs) as novel orally bioavailable com-pounds that selectively eradicate MGMT/MMR GBM in vivo without systemic toxicity. Our data indicate FEtAsinduce DNA interstrand cross-links (ICLs) only in MGMT tumors by formation of O6-(2-fluoroethyl)guanosine(O6FEtG) slow cyclization to an N1O6-ethanoguanine (EG) intermediate and ring-opening by the adjacentcytosine. The slow rates of EG formation provide time for MGMT to reverse the initial alkylation in healthy (e.g.MGMT+) cells leading to a high TI. In contrast chloroethylation agents such as mitozolomide generate O6-(2-chloroethyl)guanosine (O6ClEtG) which cyclizes to EG competitively with MGMT reversal. This leads to theformation of ICLs or toxic DNAMGMT cross-links via opening of EG by MGMT in healthy cells. Additionallythe chloroethylsulfide formed on MGMT reversal of O6ClEtG converts to a reactive episulfonium ion which alsocross-links MGMT to DNA while MGMT reversal of O6FEtG creates a stable fluoroethylsulfide. Together thesedifferences lend a higher MGMT TI to FEtAs suggesting they are likely to display improved tolerability in humans.Since ICL toxicity is MMR-independent FEtAs retain activity in TMZ-resistant MMR tumors. Here we will studythe amount of O6FEtG formed from FEtAs and the rate of its reversal by MGMT. We will characterize the structureand reaction kinetics of the ICLs using oligonucleotides containing a single O6FEtG. We will conduct studies toimprove FEtA CNS penetration. We will probe for synergy between FEtAs and DDR inhibitors other DNA repairdeficiencies and radiotherapy. Completion of this research will lead to the identification of novel chemotherapieswith high CNS penetration that operate by a novel MMR-independent mechanism thereby addressing acquiredTMZ resistance. As FEtAs are structurally-related to TMZ we expect rapid translation to the clinic. MGMT issilenced in a range of tumor types; this work will set the stage to evaluate FEtAs as treatments for other MGMTtumors alone or in combination regimes. Finally to the best of our knowledge the relative rates of DNA chemicalmodification and repair have not previously been exploited to obtain tumor specificity; we believe this kineticlethal strategy may constitute the first iteration of a new approach to targeted chemotherapeutic design. 654163 +No NIH Category available Address;Adoption;Advanced Development;Age;Attitude;Benefits and Risks;Cancer Detection;Cancer Etiology;Caring;Categories;Cessation of life;Characteristics;Clinical;Clinical Data;Collaborations;Colon;Colonoscopy;Colorectal Cancer;Communities;Cost Analysis;Coupled;Data;Diagnosis;Early identification;Eligibility Determination;Evaluation;Excision;Family;Future;Genetic;Genetic Databases;Genetic Risk;Genetic Services;Genomics;Genotype;Goals;Guidelines;Health Services Research;Incidence;Individual;International;Knowledge;Link;Lung;Managed Care;Methods;Neoplasms;Outcome;Pathologic;Patients;Performance;Play;Policies;Polypectomy;Polyps;Precancerous Polyp;Productivity;Prostate;Randomized Controlled Trials;Recommendation;Recording of previous events;Research;Resources;Risk;Risk Estimate;Risk Factors;Risk Reduction;Role;Scheme;Screening for Ovarian Cancer;Screening for cancer;Sensitivity and Specificity;Techniques;Technology;Testing;United States;United States Preventative Services Task Force;Unnecessary Procedures;Validation;Work;clinical risk;cohort;colorectal cancer prevention;colorectal cancer risk;colorectal cancer screening;comorbidity;cost;cost effective;cost-effectiveness evaluation;ethnic diversity;experience;follow-up;genetic risk factor;genome-wide;high risk;high risk population;implementation barriers;implementation facilitators;improved;indexing;interest;life time cost;models and simulation;mortality;novel;patient oriented;personalized approach;polygenic risk score;population based;pragmatic trial;predictive modeling;predictive tools;racial diversity;risk prediction;risk prediction model;risk stratification;risk variant;screening;screening guidelines;service providers;sex;surveillance strategy;time interval Personalizing Post-Polypectomy Surveillance for Colorectal Cancer Prevention PROJECT NARRATIVERandomized controlled trials have shown that screening reduces the incidence of and mortality from colorectalcancer (CRC) the second leading cause of cancer deaths in the United States. However screening hasresulted in a growing cohort of patients with precancerous polyps and little is known about effectively managingtheir post-polypectomy surveillance. Thus in this proposal we will develop and validate a comprehensive riskprediction model using polyp characteristics and clinical and genetic risk factors to tailor surveillance; anddetermine the optimal strategy for CRC surveillance given an individuals risk. NCI 10734405 9/19/23 0:00 PA-20-185 1R37CA276306-01A1 1 R37 CA 276306 1 A1 "FEUER, ERIC J" 9/19/23 0:00 8/31/28 0:00 Health Services: Quality and Effectiveness Study Section[HSQE] 11528568 "LEE, JEFFREY KUANG ZOU" Not Applicable 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 690753 NCI 536776 153977 PROJECT SUMMARY AND ABSTRACTScreening is an established method for decreasing colorectal cancer (CRC) incidence and mortality. Howeverdespite guidance supporting CRC screening initiation (i.e. 45 years) relatively little is known about what to doafter a precancerous polyp is detected and removed. This is particularly concerning given that over 40% ofindividuals who undergo CRC screening are found to have a precancerous polyp and then instructed toundergo frequent colonoscopies (termed surveillance) every 3-10 years for CRC risk reduction. Currentguidelines utilize a risk-stratification scheme that categorizes patients as high or low risk based only on polypcharacteristics from their initial colonoscopy. However polyp-based risk stratification methods are imprecisewith a sensitivity and specificity of 59-81% and 43-58% respectively for predicting subsequent advancedneoplasia after polyp removal. Thus our current guideline-based risk stratification methods both miss high-riskindividuals who may benefit from early surveillance and subject many low-risk individuals to unnecessarycolonoscopies and its associated harms. Recent studies from our group and others have identified severalclinical and genetic (i.e. polygenic risk score) risk factors associated with CRC; these may further optimize riskstratification following CRC screening and polyp removal but remain understudied. For this R01 proposal wewill first develop and validate a practical clinically useful risk prediction tool that incorporates both detailedpolyp characteristics and other important predictors known to play an important role in CRC risk such asclinical and genetic (i.e. polygenic risk score) risk factors (Aims 1 and 2). Second we will identify optimalstrategies for CRC surveillance given individual risk estimates defined in Aims 1-2 and evaluate the cost-effectiveness of different risk-stratified surveillance strategies compared to current guideline recommendedpolyp-based surveillance strategies (Aim 3). This Aim will leverage our ongoing collaboration with anestablished internationally recognized micro-simulation model (MISCAN-Colon) that informs U.S. PreventativeTask Force recommendations. Lastly we will gain patient clinician and service providers perspectives onthese novel comprehensive risk prediction methods to optimize potential adoption and assess potentialimplementation barriers and facilitators (Aim 4). This aim will incorporate group experiences with mixedmethods techniques to identify attitudes and barriers of implementation. The overall aims will leveragecomprehensive data from an extremely large contemporary community-based cohort and an independentcohort for validation. These cohorts detailed data include genome-wide genotype arrays coupled with priorscreening pathologic and clinical data and surveillance outcomes. This study can substantially transform howwe manage care for over 7 million patients diagnosed annually with precancerous polyps personalize post-polypectomy surveillance using a new novel comprehensive patient-centered risk prediction model andoptimize post-polypectomy surveillance to reduce CRC incidence and mortality. 690753 +No NIH Category available Address;Adjuvant;Adoptive Cell Transfers;Adult;Affect;Antibody Specificity;Biochemical;Brain Neoplasms;Cell Survival;Cell physiology;Cells;Cessation of life;Chimeric Proteins;Clinical;Clinical Trials;Cytolysis;Data;Disease;Doctor of Philosophy;Dominant-Negative Mutation;Drug Utilization;Drug toxicity;Drug vehicle;Epidermal Growth Factor Receptor;Esters;Evaluation;Excision;FDA approved;Gingiva;Glioblastoma;Goals;Growth Factor Inhibition;Growth Factor Receptors;Half-Life;Hematologic Neoplasms;Hemorrhage;Histiocytosis;Immune;In Vitro;Intracranial Hemorrhages;Kansas;Label;Laboratories;Life;Macrophage;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of prostate;Mediating;Modeling;Mus;Nanotechnology;Oncogenic;Patients;Penetration;Peptides;Pharmaceutical Preparations;Phosphotransferases;Polymers;Pre-Clinical Model;Principal Investigator;Production;Recurrence;Reporting;Research;Resistance;Route;Solid Neoplasm;T cell therapy;T-Lymphocyte;Technology;Testing;Therapeutic;Toxic effect;Transforming Growth Factors;Universities;Up-Regulation;cell killing;chemoradiation;chimeric antigen receptor;chimeric antigen receptor T cells;comparative efficacy;cytokine;design;dosage;drug candidate;experience;immunotoxicity;improved;in vivo;inhibitor;interest;invention;kinase inhibitor;manufacture;nanocarrier;nanotechnology platform;new therapeutic target;novel;novel therapeutics;overexpression;pre-clinical;programmed cell death ligand 1;receptor;research clinical testing;response;small molecule;small molecule inhibitor;success;systemic toxicity;targeted treatment;technology platform;therapeutic target;tumor;tumor eradication;tumor microenvironment;tumor specificity;uptake Design of a Novel Nanocarrier Technology to Drug-Load CAR T cells Project NarrativeWe propose to develop a platform technology to drug-load CAR T cells with nanocarriers thus enhancing thetherapeutic window of CAR T cells and addressing one of the major obstacles to CAR T cells in brain tumors. NCI 10734365 6/28/23 0:00 PAR-20-284 1R01CA284065-01 1 R01 CA 284065 1 "SALOMON, RACHELLE" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-MCST-U(55)R] 8425838 "AKHAVAN, DAVID " "BOSSMANN, STEFAN H" 3 RADIATION-DIAGNOSTIC/ONCOLOGY 16060860 YXJGGNC5J269 16060860 YXJGGNC5J269 US 39.026584 -94.636347 1484303 UNIVERSITY OF KANSAS MEDICAL CENTER KANSAS CITY KS SCHOOLS OF MEDICINE 661608500 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 574360 NCI 373500 200860 Project summary:Current treatment for Glioblastoma Multiforme (GBM) the most common malignant brain tumor in adultsinvolves maximal safe resection followed by adjuvant chemoradiation. Although this treatment is life prolongingit is never curative. Five year survival is less than 7 %1 and improved therapies are urgently needed. In thisproposal we aim to develop a new targeted therapy with reduced toxicity and increased efficacy for GBM patientsby leveraging nanotechnology discoveries in our laboratory to improve adoptive cell therapy. Chimeric AntigenReceptor (CAR) T cells combine the cytolytic potency of a T cell with the tumor specificity of an antibody. Recentclinical trial experiences of CAR T cells in solid tumors have identified the immune-suppressive tumormicroenvironment (TME) as a major barrier to clinical success2-4. One immune-suppressive endogenousnegative regulator in GBM TME is TGF which has been identified as barrier to CAR T tumor eradication. Smallmolecule inhibitors of the TGF receptor as well as TGF resistant CAR T cells have been developed and testedclinically however they are limited due to systemic toxicity. Herein we propose developing a platform technologyto drug-load CAR T cells with nanocarriers thus enhancing the therapeutic window of CAR T cells andaddressing one of the major obstacles to CAR T cells in brain tumors. 574360 +No NIH Category available Benign;Cancer Biology;Cancer Patient;Clinical Data;Clinical Research;Clinical Trials;Enrollment;Grant;Institution;Lead;Malignant - descriptor;Molecular;Operative Surgical Procedures;Patient advocacy;Patients;Populations at Risk;Process;Quality of life;Radiation;Radiology Specialty;Research;Research Personnel;Resources;Roswell Park Cancer Institute;Site;Specimen;Techniques;Therapeutic;cancer prevention;cancer therapy;data submission;experience;improved;inter-institutional;novel therapeutics;premalignant;prognostic Network Lead Academic Participating Site Grant from the Roswell Park Cancer Institute PROJECT NARRATIVEThe aim of inter-Institutional cooperative clinical research is to advance our understanding of cancer prevention pre-cancers and both benign and malignant processes and thereby to improve our ability to treat people at risk orafflicted with them. These aims are accomplished by resolving scientific questions of importance regarding cancerbiology and therapy through the cooperation of selected Institutions that can pool their intellectual technical andpatient resources. The rapid accumulation of clinical data and experience through cooperative group researchexpedites progress in cancer therapy. NCI 10734330 1/10/23 0:00 PA-20-272 3UG1CA233191-04S1 3 UG1 CA 233191 4 S1 "MOONEY, MARGARET M" 3/6/19 0:00 2/28/25 0:00 1869475 "LEVINE, ELLIS G" "LELE, SHASHIKANT ; PUZANOV, IGOR ; SINGH, ANURAG KISHOR" 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 25000 NCI 14409 10591 PROJECT SUMMARYThe Roswell Park Cancer Institute has had a long tradition of contributing to the national cooperative groupsover many decades. Those contributions have been scientific administrative and participatory (enrollment onclinical trials). Contributions have been consistent and numerous over the years. This application summarizesthe intent of its 4 Co-PIs (Levine/Ernstoff/Lele/Singh) and the membership of RPCI to sustain its commitmentto the many strengths inherent to cooperative group research: therapeutic advances; a better understanding ofthe biology of cancer; cancer prevention; means to improve the quality of life of cancer patients; piloting of newdrugs and radiologic and radiation and surgical techniques; establishing the relevance of new cellular andmolecular advances to the predictive prognostic and therapeutic approaches to patients; and theadvancement of patient advocacy. Investigators at RPCI and its supporting staff fully recognize the essentialimportance of the timely and accurate submission of data and specimens to achieve these aims. 25000 +No NIH Category available ALK gene;Accounting;Address;Adoptive Cell Transfers;Alleles;Automobile Driving;Biopsy;Bypass;Cancer Etiology;Cancer Patient;Cell Line;Cessation of life;Chimeric Proteins;Chromosomal Rearrangement;Clinic;Clinical;Clinical Trials;Collection;Combined Modality Therapy;Data;Development;Diagnosis;Disease;Drug resistance;EP300 gene;Engineering;Epigenetic Process;Epitopes;Foundations;Future;Gene Fusion;Gene Rearrangement;Generations;Genetic Transcription;Genomics;Goals;IL2-Inducible T-Cell Kinase;Immune;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Institution;Institutional Review Boards;MHC Class I Genes;Malignant neoplasm of lung;Maps;Mediating;Methods;Mutation;Neurons;New Agents;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Oncogenic;Outcome;Patients;Pattern;Phosphotransferases;Pre-Clinical Model;Protocols documentation;Receptor Activation;Receptor Protein-Tyrosine Kinases;Recurrence;Recurrent disease;Research;Research Personnel;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;T-Cell Receptor;T-Lymphocyte;Therapeutic;Tissues;Transcription Coactivator;Tumor Cell Line;Tyrosine Kinase Inhibitor;United States;acquired drug resistance;anaplastic lymphoma kinase;cohort;crizotinib;immunogenic;improved;in vivo;inhibitor;kinase inhibitor;molecular subtypes;mortality;neoantigens;next generation;non-genomic;novel;novel strategies;novel therapeutic intervention;pharmacologic;programs;rational design;resistance mechanism;resistance mutation;standard care;standard of care;therapeutic target;therapy development;tumor Overcoming Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors Project NarrativeLung cancer is the leading global cause of cancer-related mortality. For patients with advanced lung cancerharboring ALK gene fusions (ALK+ lung cancer) highly effective ALK inhibitors have improved their outcomesand yet acquired resistance to these drugs remains a major problem resulting in disease relapse and ultimatelydeath. The goal of this research is to identify therapeutic strategies to overcome resistance to the currentstandard-of-care ALK inhibitors in hopes to extend and improve lives of patients living with this disease. NCI 10734260 6/15/23 0:00 PA-20-185 2R01CA164273-11A1 2 R01 CA 164273 11 A1 "FORRY, SUZANNE L" 2/20/12 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 6831353 "HATA, AARON N" "LIN, JESSICA JIYEONG" 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 417500 NCI 250000 167500 Project SummaryNon-small cell lung cancers (NSCLC) harboring oncogenic anaplastic lymphoma kinase (ALK) generearrangements (i.e. ALK+) comprise a distinct molecular subset of lung cancer with marked sensitivity to ALKtyrosine kinase inhibitors (TKIs). While ALK TKIs are initially highly effective acquired drug resistance remainsa fundamental challenge that limits clinical benefit and causes disease relapse in most patients. We and othershave characterized mechanisms of resistance in particular so-called on-target resistance mediated bysecondary acquired ALK kinase domain mutations that can be overcome with more potent next-generation (2nd-or 3rd-generation) inhibitors. In recent years the standard treatment paradigm for patients diagnosed withadvanced ALK+ lung cancers has shifted from sequential therapy using the 1st-generation ALK TKI crizotinibfollowed by next-generation TKIs to initial therapy using a next-generation ALK TKI upfront. Our preliminary dataindicate that off-target (i.e. ALK-independent) resistance mechanisms are prevalent following next-generationALK TKIs. Yet the spectrum of off-target resistance mechanisms and strategies to overcome these remainpoorly understood presenting a barrier to the development of treatment options for these patients. Theoverarching objective of the proposed research is to identify and develop complementary mechanism-informedand mechanism-agnostic approaches for overcoming off-target resistance to next-generation ALK TKIs. We willuse comprehensive genomic and non-genomic assessment of an expanded cohort of patient tumor specimensto determine the clinical spectrum of off-target resistance mechanisms after first-line use of next-generation ALKTKIs and we will develop new methods for identifying patients with bypass-mediated resistance most likely tobenefit from rationally designed combination therapies. Using ALK TKI-resistant tumor cell lines derived frompatient biopsies we will screen for epigenetic mechanisms that drive resistance independent of canonical bypasssignaling pathways with initial studies focused on defining the role of the transcriptional co-activator p300/CBPas a novel driver of off-target ALK TKI resistance and therapeutic target. These efforts will enable patient-specificmechanism-informed therapeutic strategies. In parallel we will develop a mechanism-agnostic approach thatleverages ALK as a tumor-specific neoantigen whose expression is maintained in resistant tumors. Using Tcell-based functional screens we will identify ALK-reactive T cell receptors (TCRs) that are capable ofrecognizing resistant ALK+ NSCLCs. This will provide the foundation for engineering ALK TCR adoptive cellulartherapy as a TKI-orthogonal immune-based approach for overcoming resistance. Collectively the proposedstudies will provide a comprehensive understanding of resistance to next-generation ALK TKIs and pave the wayfor the development of new therapeutic strategies that can effectively overcome most of off-target resistance inthe clinic ultimately improving and prolonging the lives of patients with advanced ALK+ lung cancers. 417500 +No NIH Category available Affect;Apoptotic;Attention;BCL2 gene;Biological Assay;Biopsy;Breast Cancer Cell;Breast Cancer Patient;CD8-Positive T-Lymphocytes;Cancer Etiology;Cell Membrane Permeability;Cells;Cessation of life;Chemotherapy and/or radiation;Chronic Lymphocytic Leukemia;Clinical;Clinical Management;Clinical Trials;Clinical Trials Design;Competence;Coupled;Cytosol;Data;Diagnosis;Diagnostic;Disease;Disease model;Dose;Enzyme-Linked Immunosorbent Assay;Exhibits;FDA approved;FOXP3 gene;Flow Cytometry;Genetic;Goals;Hormone Receptor;Human;Immune;Immune Targeting;Immune response;Immunocompetent;Immunologic Deficiency Syndromes;Immunologics;Immunotherapy;In Vitro;Infiltration;Interferon Type I;Knock-out;Link;MHC Class I Genes;Methods;Microscopy;Mitochondria;Mitochondrial DNA;Modeling;Mus;Patients;Process;Proteins;Radiation Tolerance;Radiation therapy;Regimen;Regulation;Regulatory T-Lymphocyte;Resistance;Role;Signal Transduction;Testing;Therapeutic;Translating;Translations;Treatment Efficacy;Tumor Immunity;Woman;XCR1 gene;anti-cancer;cancer cell;cancer survival;clinically relevant;combinatorial;ds-DNA;human disease;immune cell infiltrate;immune checkpoint;immune checkpoint blockers;immunogenicity;in vivo;inhibitor;innovation;malignant breast neoplasm;mitochondrial membrane;mouse model;novel strategies;overexpression;pharmacologic;pre-clinical;preservation;prevent;programmed cell death ligand 1;programmed cell death protein 1;radiation effect;radiation response;research clinical testing;resistance mechanism;single-cell RNA sequencing;standard care;therapy resistant;tool;transcriptomics;tumor;tumor microenvironment;tumor-immune system interactions;virtual Targeting the BCL2 immune checkpoint to enhance the immunostimulatory effects of radiation in breast cancer NARRATIVEThe studies proposed herein will determine the impact of BCL2 a protein that supports the survival of cancercells responding to treatment on the immunological configuration of hormone receptor (HR)+ breast cancer(BC) as well as the therapeutic value of combining radiation therapy (RT) with BCL2 inhibitors inimmunocompetent mouse models of HR+ BC. These findings will provide preclinical ground to the initiation ofclinical trials testing RT plus venetoclax (a BCL2 inhibitor currently approved by regulatory agencies for use inpatients with chronic lymphocytic leukemia) in women with HR+ BC a type of BC that still affects >200000 andkills >25000 new women every year in the US. NCI 10734237 8/1/23 0:00 PA-20-185 1R01CA271915-01A1 1 R01 CA 271915 1 A1 "SOMMERS, CONNIE L" 8/1/23 0:00 7/31/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 14655329 "GALLUZZI, LORENZO " Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 703149 NCI 414837 288312 SUMMARYHormone receptor (HR)+ breast cancer (BC) causes the majority of BC-related deaths in the US reflecting anunmet need for innovative therapeutic approaches. Indeed resistance to standard treatments and metastaticspread remain major challenges and novel approaches such as immune checkpoint blockers (ICBs) have shownlimited efficacy so far. The long-term objective of this proposal is to mechanistically dissect the impact of BCL2an antiapoptotic protein that favors the resistance of cancer cells to death imposed by chemotherapy andradiation therapy (RT) on the immunological configuration of treatment nave and irradiated HR+ BCs.Specifically this project will test the highly innovative hypothesis that BCL2 may represent a therapeuticallyactionable immune checkpoint because of its ability to preserve mitochondrial integrity based on thesespecific aims: 1) determining the influence of BCL2 levels on the immune microenvironment of treatment-navehuman and mouse HR+ BCs; 2) defining the impact of BCL2 on the immune microenvironment of HR+ BCsresponding to RT in vitro and in vivo; and 3) elucidating the value of BCL2 as a target to boost theimmunostimulatory effects of RT in mouse models of HR+ BCs including an innovative model that mimics keyfeatures of human HR+ BC. BCL2 is a particularly significant target because ~80% of HR+ BC casesoverexpress BCL2 and the BCL2 inhibitor venetoclax is approved for clinical use. To achieve our goalsdiagnostic biopsies from women with HR+ BC will be evaluated by CODEX for BCL2 expression tumor infiltrationby key immune cells that regulate anticancer immunity and expression of immunosuppressive proteins like MHCClass I and PD-L1. The impact of BCL2 on the immunological response of HR+ BC cells to RT will be interrogatedin vitro by genetic (deletion overexpression) and pharmacological (e.g. venetoclax administration) methodscoupled to flow cytometry IF microscopy and ELISA for the assessment of key regulators of anticancer immunity.Similar genetic and pharmacological approaches will be harnessed to alter BCL2 competence and delineate theinfluence of BCL2 on the immunological TME of treatment-nave and irradiated mouse HR+ BCs established inimmunocompetent hosts based on IHC flow cytometry and single-cell RNA sequencing. In vitro studies by flowcytometry and clonogenic assays as well as in vivo studies based on mouse HR+ BC cells growing inimmunodeficient vs immunocompetent mice will be employed to dissect the impact of BCL2 on intrinsicradiosensitivity vs immune-dependent tumor control. Finally different combinatorial regimens involving RT andvenetoclax will be investigated for efficacy (in both treatment-nave and treatment resistance settings) andpotential mechanisms of resistance in an endogenous mouse model of HR+ BCs that mimics key features ofhuman HR+ BC. Our findings will elucidate the impact of BCL2 on the immune TME of HR+ BC and identifythe best approach to inform the initiation of clinical trials testing RT plus venetoclax in women with HR+BC a devastating disease that still affects >200000 and kills >25000 new women every year in the US. 703149 +No NIH Category available ACK1 Gene;AR gene;Ablation;Antitumor Response;Back;CD8-Positive T-Lymphocytes;Cancer Etiology;Cancer Patient;Cell Separation;Cessation of life;Chemotactic Factors;Clinical Trials;Data;Deposition;Enhancers;Epigenetic Process;Exhibits;Failure;Genetic;Growth;Immune;Immune response;Immune system;Immunologic Surveillance;Interleukin-2;Knock-in;Knockout Mice;Ligand Binding;Lymphocyte Activation;Lymphocyte-Specific p56LCK Tyrosine Protein Kinase;Malignant neoplasm of prostate;Mediating;Modality;Mus;Oral;Organoids;PTEN gene;PTPN11 gene;Patients;Peripheral Blood Mononuclear Cell;Phosphorylation;Phosphotransferases;Process;Production;Property;Prostate;Prostatic Neoplasms;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Receptor Activation;Receptor Signaling;Recurrent disease;Refractory;Resistance;Resistance development;Role;Series;Signal Transduction;Site;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;TP53 gene;Therapeutic;Treatment Efficacy;Ubiquitination;abiraterone;adaptive immune response;androgen deprivation therapy;antagonist;anti-tumor immune response;cancer immunotherapy;castration resistant prostate cancer;chemokine;enzalutamide;immune cell infiltrate;immune checkpoint blockade;inhibitor;insight;men;mouse model;neoplastic cell;novel;paracrine;pharmacologic;prostate cancer model;protein-tyrosine kinase c-src;restraint;small molecule inhibitor;src-Family Kinases;suicidal;trafficking;transcriptome sequencing;tumor;tumor growth;tumor-immune system interactions;ubiquitin-protein ligase;virtual Targeting a Novel Signaling Nexus pACK/pCSK/pLCK in Immune Checkpoint Blockade (ICB)-Resistant Prostate Cancer Project NarrativeOur study uncovered that tumor-insensitive T cells could be reinvigorated by overcoming ACK1-CSK kinasesignaling cascade by genetic as well as pharmacological inhibition of ACK1. This distinct mode of enhancingimmune surveillance by ACK1 inhibitor could be a new cancer immunotherapy for castration resistant prostatecancer. NCI 10734202 6/27/23 0:00 PA-20-185 1R01CA276502-01A1 1 R01 CA 276502 1 A1 "ZAMISCH, MONICA" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 8554632 "MAHAJAN, NUPAM P" Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 484364 NCI 311488 172876 Project AbstractProstate cancer (PC) patient although initially respond to androgen deprivation therapy most patients developthe resistance developing a stage referred to as the Castration Resistant Prostate Cancer (CRPC). Prostatecancer is a non-inflamed or Immune desert tumor where no immune infiltrate is observed suggesting thatfailure has occurred somewhere in the process of T-cell priming or T-cell trafficking back to the tumor. Notsurprisingly prostate cancer is highly refractory to immune checkpoint blockade (ICB) therapies exhibitingmarginal efficacy in clinical trials both as a single agent or in combination with other agents. Precisely howprostate cancer enforce evasion of anti-tumor immune response is not fully understood.Previously we uncovered that a non-receptor tyrosine kinase ACK1 deposited novel pY88-H4 epigenetic marksin AR gene enhancer regulating AR/AR-V7 expression. Building on this discovery we developed a new ACK1small molecule inhibitor (R)-9b which suppressed enzalutamide-resistant tumor growth. To examine ACk1signaling further we generated a viable conditional ACK1 knockout (KO) mice and noticed a significant increasein activated CD4+ and CD8+ T cells in KO mice causing loss of syngeneic prostate tumor growth.The subsequent studies have revealed a crucial role for ACK1 kinase in the initiation of T cell antigenreceptor (TCR) signaling by phosphorylation of CSK at a previously unknown site Tyr18. CSK phosphorylatedLCK at Tyr505 promoting auto-inhibition inhibiting an adaptive immune response. Thus ACK1 KO mice or the(R)-9b injected mice exhibited increased CD4+ and CD8+ T cells activation and inhibition of tumor growth. Inaddition (R)-9b functionally reinvigorated peripheral blood mononuclear cells (PBMCs) of the CRPC patients tomount robust immune response against CRPC organoids. Together these data indicate that (R)-9b fulfills aunique niche wherein it not only suppresses AR/AR-V7 within the tumor cells but also activates host immunesystem to mount a robust `dual anti-tumor response. The specific aims of this project are:Aim 1: Examine roles of ACK1-mediated CSK Tyr18-phosphorylation in T cell quiescenceAim 2: Interrogate role of renewed pACK1/pY18-CSK/pY505-LCK signaling in silencing of anti-tumor immuneresponseAim 3: Evaluate therapeutic efficacy of (R)-9b in models of prostate cancer 484364 +No NIH Category available Adjuvant;Bile fluid;Biodistribution;Cancer Model;Chemistry;Chemotherapy-Oncologic Procedure;Collaborations;Colon;Colon Carcinoma;Colorectal;Colorectal Cancer;Combination Drug Therapy;DNA;Deoxyuridine;Dose;Drug Kinetics;Extrahepatic;Fluorouracil;Formulation;Generations;Genetically Engineered Mouse;Goals;Half-Life;Hepatic;Immune response;In Vitro;Injections;Integrins;Link;Liver;Lung;Malignant - descriptor;Metabolism;Metastatic Neoplasm to the Liver;Methodology;Methods;Modeling;Molecular Target;Mus;Nanodelivery;Nucleic Acids;Peptides;Periodicity;Pharmaceutical Preparations;Phase;Plasma;Plasma Enhancement;Polyethylene Glycols;Polymers;Prevention;Property;RGD (sequence);Rattus;Recurrence;Recurrent disease;Regimen;Relapse;Resistance;Ribonucleotides;Risk;Risk Reduction;Single-Stranded DNA;Specificity;System;Testing;Therapeutic;Thymidine;Thymidylate Synthase;Time;Tissues;Toxic effect;Toxicity Tests;Toxicology;Treatment Failure;Tumor Tissue;Vertebral column;analog;anticancer activity;cancer cell;clinical candidate;clinical development;clinical translation;colon cancer patients;copolymer;cytotoxic;cytotoxicity;design;fluoropyrimidine;improved;improved outcome;in vivo evaluation;lipid nanoparticle;liquid chromatography mass spectrometry;metastatic colorectal;monomer;mouse model;nanoformulation;nanomaterials;nanopolymer;nanoscale;novel;novel strategies;nucleotide analog;overexpression;pharmacologic;potency testing;pre-clinical;preclinical study;pyrimidine metabolism;scaffold;standard of care;systemic toxicity;tumor;tumor specificity Nanodelivery of FP polymers to improve treatment of metastatic colorectal cancer PROJECT NARRATIVEThis R01 proposal will develop novel nanoformulations of CF10 the first DNA-based fluoropyrimidine (FP)polymer. CF10 displays improved anti-cancer activity relative to standard of care 5-FU in pre-clinical colon cancermodels and an improved toxicity profile. Lipid nanoparticle (LNP) formulation and conjugation with polyethyleneglycol (PEG) polymers will be implemented to improve CF10s pharmacological properties. Further ournanomaterials will be targeted specifically to tumor tissue using a tripeptide motif RGD recognized only bymalignant cells. We prepare for the first time FP polymers including EdU a nucleotide analog withcomplementary cytotoxicity to CF10 and implement the most effective nanoformulation to deliver the most potentFP polymer. Our project will produce a novel nanomaterial with exceptional antitumor activity for clinicaldevelopment. NCI 10734188 6/16/23 0:00 PAR-20-284 1R01CA284083-01 1 R01 CA 284083 1 "AVULA, LEELA RANI" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-MCST-U(55)R] 1862406 "GMEINER, WILLIAM H" Not Applicable 5 BIOLOGY 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 592748 NCI 418923 173825 PROJECT SUMMARYMetastatic colorectal cancer (mCRC) remains highly lethal despite decades of optimizing 5-fluorouracil (5-FU)-based combination chemotherapy regimens that are central to treatment. The causes of treatment failure with5-FU-based regimens include decreased metabolism to FdUMP the primary active metabolite andoverexpression of thymidylate synthase (TS) the molecular target of FdUMP. To improve outcomes andovercome resistance we have developed a nanoscale FP polymer CF10 that is comprised of FdUMP monomerslinked in a single-stranded DNA backbone that releases FdUMP in a single step. CF10 displays markedlyimproved anti-tumor activity with low systemic toxicity relative to 5-FU and is a candidate for clinical translation.We hypothesize that nanoformulation of CF10 to increase plasma retention and actively target malignant tissuewill improve anti-tumor activity and specificity. Lipid nanoparticle (LNP) formulation has proven to be a robustdelivery strategy for multiple nucleic acid drugs and in collaboration with NanoVation Therapeutics (NTx) in Aim1 we will test two CF10:LNP formulations designed to differentially target CF10 to liver and more broadly to targetmetastatic tissue while protecting CF10 from degradation in plasma. In Aim 2 we will investigate PEGylation ofCF10 together with active targeting to tumor tissue through conjugation with a cyclic RGD peptide that targetsintegrin V3 expressed specifically in malignant tissue. We will test our novel nanomaterials for improved anti-metastatic activity using: (i) a novel genetically engineered mouse model iKAP that forms tumors specifically inthe colon with metastatic progression to the liver and lung; and (ii) a rat model of established colorectal livermetastases (CRLMs). Pharmacokinetic profiling (PK) will be evaluated using LC/MS/MS. In Aim 3 we willdevelop a 3rd generation FP polymer that includes 5-ethynyl-2-deoxyuridine (EdU) a thymidine analog that iscytotoxic through complementary mechanisms to FdU. We will use the optimal LNP formulation and PEGylationstrategies determined for CF10 in Aims 1 and 2 to develop a highly novel nanomaterial with exceptional potentialfor improved treatment of mCRC. 592748 +No NIH Category available Acute;Affect;Age;BRCA1 gene;Biochemical;Birth;Breast;Breast Adenocarcinoma;Breast Cancer Risk Factor;Breast Epithelial Cells;Cancer Model;Cells;Cellular biology;Chromatin;DNA Methylation;Data;Development;EZH2 gene;Enhancers;Epigenetic Process;Event;Exposure to;Female;Future;Gene Expression;Genetic Transcription;Goals;Hormones;Human;Hyperplasia;Incidence;Knowledge;Lesion;Life;Link;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Methods;Modeling;Molecular;Morphogenesis;Mus;Nulliparity;Oncogenes;Oncogenic;Organoids;Outcome;Output;Pathway interactions;Phenotype;Physiology;Pregnancy;Preventive treatment;Property;Regulatory Element;Reproduction;Research;Risk;Rodent;Rodent Model;Role;System;Testing;Therapeutic Intervention;Tissues;Transcriptional Activation;Transcriptional Regulation;Transgenic Animals;Transgenic Mice;Wild Type Mouse;Woman;Work;c-myc Genes;cancer subtypes;cell type;chromatin remodeling;cofactor;epidemiology study;epigenome;epigenomics;genetic approach;in vivo;insight;malignant breast neoplasm;mammary;mouse model;novel;overexpression;parous;post pregnancy;pregnant;prepregnancy;prevent;protective effect;response;small molecule inhibitor;tumor;tumorigenesis Blockade of cMYC oncogenic function by pregnancy-induced alterations and remodeling of the mammary gland Project NarrativePregnancy has a profound impact on the physiology of a woman's body in addition to its central role inreproduction including a significant effect on the risk of developing breast cancer. In this proposal we will usemouse models to elucidate novel mechanisms cell types and pathways that are altered by pregnancy and theirinvolvement in cMYC oncogene function with the long-term objective of exploiting this knowledge for the futuredevelopment of strategies that decrease breast cancer risk in humans. NCI 10734182 8/29/23 0:00 PA-20-185 1R01CA284630-01 1 R01 CA 284630 1 "FINGERMAN, IAN M" 9/1/23 0:00 8/31/28 0:00 Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] 11852640 "DOS SANTOS, CAMILA " Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 509988 NCI 265619 244369 Abstract/Project SummaryThe goal of this proposal is to understand how transitions through pregnancy influence the molecular and cellularstate of mammary epithelial cells and oncogenesis. Numerous epidemiological studies have found thatpregnancy alters the risk of breast cancer. These studies have shown consistently that a full-term pregnancyprior to the age of 25 is associated with a one-third decrease in the life-time incidence of breast cancer. While aprotective effect of pregnancy has been validated in rodent models of cancer the underlying molecular basis forthis effect remains unclear.We have found that pregnancy leads to persistent changes in the epigenome and enhancer landscape of MECs.Using an inducible c-MYC mouse model we also find that oncogenesis and the transcriptional outputdownstream of this oncogene are reduced in post-pregnancy MECs. In this proposal we will investigate themolecular basis underlying these robust phenotypes. We will use epigenomics ex vivo in vivo and biochemicalmethods to define how the transcriptional function of c-MYC is modulated by pregnancy. We hypothesize that c-MYC interactions with cofactors and with specific cis-regulatory elements are altered in this system.We will also study how specific chromatin regulators contribute to pregnancy-mediated epigenomic rewiring.These efforts will build upon our recent data suggesting that EZH2 supports the post-pregnancy epigenome inwild-type mice. Collectively this research will provide fundamental insights into the cell biology of the mammarygland and carry the potential for discoveries that could be harnessed to develop preventative treatments thatmodulate breast cancer risk in humans. 509988 +No NIH Category available Agonist;Androgens;Binding;Biological Markers;CYP17A1 gene;Cancer Etiology;Carboplatin;Cessation of life;Clinical;Clinical Trials;Complex;DNA Damage;Data;Defect;Family;Feedback;GNRH1 gene;Generations;Growth;Ligand Binding;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator;Molecular;Neuroendocrine Prostate Cancer;Neurofibromin 2;Nuclear;Pathway interactions;Patients;Pharmaceutical Preparations;Physiological;Poly(ADP-ribose) Polymerase Inhibitor;Prognosis;Prostate;Prostate Cancer therapy;Proteins;ROR1 gene;Reporting;Resistance;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;Testing;Therapeutic;Tumor Promotion;WNT Signaling Pathway;abiraterone;androgen deprivation therapy;antagonist;beta catenin;biomarker identification;castration resistant prostate cancer;deprivation;effective therapy;efficacy evaluation;enzalutamide;inhibitor;link protein;men;mimetics;novel;patient derived xenograft model;planar cell polarity;predict responsiveness;receptor;resistance mechanism;response;restraint;standard of care;taxane;transcription factor;tumor WNT5a/ROR2-Mediated Hippo Pathway Activation in Prostate Cancer We have found that the growth suppressive effects of noncanonical Wnt signaling by Wnt5a in prostate cancerare mediated through ROR2 and that this Wnt5a/ROR2 signaling is activating the Hippo pathway to suppressYAP1/TAZ activity. We hypothesize this reflects a novel function of ROR2 that is context dependent and thatbiomarkers can be identified that will identify the subset of tumors that will be responsive to Wnt5a-mimetic drugssuch as Foxy5. The objectives are to determine the precise molecular basis for Wnt5a-mediated activation ofthe Hippo pathway (Aim 1) and to assess the therapeutic potential of stimulating this pathway includingidentification of biomarkers that can predict which tumors may respond to Wnt5a-mimetic drugs (Aim 2). NCI 10734173 5/18/23 0:00 PA-20-185 1R01CA272934-01A1 1 R01 CA 272934 1 A1 "KONDAPAKA, SUDHIR B" 6/1/23 0:00 5/31/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 1863884 "BALK, STEVEN P." "YUAN, XIN " 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 395509 NCI 228750 166759 Androgen deprivation remains the standard systemic treatment for prostate cancer (PCa) that has spreadbeyond the prostate but most patients progress to metastatic castration-resistant prostate cancer (mCRPC).Many of these tumors will respond to abiraterone or to second generation AR antagonists but resistanceinevitably develops. Some patients at this stage may respond to taxanes or to PARP inhibitors but options forthe majority of patients are limited. Increased Wnt signaling is one of the mechanisms that has been implicatedin the progression to ASI resistance. The canonical Wnt/-catenin pathway is initiated when a Wnt ligand bindsto a Frizzled family receptor which results in increased -catenin and coactivation of TCF family transcriptionfactors. A subset of Wnts can preferentially activate noncanonical Wnt pathways through receptors includingROR1 and ROR2. The downstream signaling pathways are less well-defined and are context dependent butinclude the planar cell polarity and Wnt-Ca++ pathways. Notably noncanonical Wnt signaling has also beenreported to inhibit the tumor suppressive Hippo pathway thereby enhancing the nuclear expression of YAP1 andTAZ with subsequent stimulation of the TEAD-family transcription factors. Wnt5a is the predominantnoncanonical Wnt whose expression is often dysregulated in cancer and it has been implicated in both tumor-suppressive and tumor-promoting activities. In PCa increased Wnt5a expression has been associated withmCRPC and with neuroendocrine PCa but has also been associated with better prognosis in localized PCaand with growth suppression and dormancy. While these studies indicate that noncanonical Wnt signaling canhave growth suppressive as well as stimulatory effects the downstream signals mediating these effects remainto be established. We have found that the growth suppressive effects of Wnt5a in PCa are mediated throughROR2 and that this Wnt5a/ROR2 signaling is activating the Hippo pathway to suppress YAP1/TAZ activity.While Wnt signaling has been linked to suppression of the Hippo pathway our studies are the first to show it canactivate Hippo and provide a mechanism for the growth suppressing effects of Wnt5a. We hypothesize thisreflects a novel function of ROR2 that is context dependent and that biomarkers can be identified that will identifythe subset of tumors that will be responsive to Wnt5a-mimetic drugs such as Foxy5 which is currently in clinicaltrials. The central hypotheses of this proposal are that Wnt5a-mimetic drugs that drive noncanonical Wntsignaling can be an effective treatment for a subset of mCRPC (and other solid tumors) that their growthsuppressive effects are through Hippo pathway activation and that this reflects a physiological negativefeedback loop to restrain YAP1/TAZ activity. The objectives are to determine the molecular basis for Wnt5a-mediated activation of the Hippo pathway (Aim 1) and to assess the therapeutic potential of stimulating thispathway including the identification of biomarkers that can predict which tumors may respond to availableWnt5a-mimetic drugs (Aim 2). 395509 +No NIH Category available Address;Age;Basic Science;Behavior Therapy;Behavioral;Cellular Phone;Communication;Cues;Data;Data Analyses;Effectiveness of Interventions;Emotional;Emotions;Evidence based intervention;Goals;Health;Heavy Drinking;Human;Image;Imagery;Individual;Intervention;Interview;Knowledge;Life;Malignant Neoplasms;Measures;Mediator;Mental Health;Meta-Analysis;Motivation;Obesity;Oncology;Outcome;Participant;Personal Satisfaction;Persons;Placebo Control;Population;Protocols documentation;Psychology;Quality of life;Randomized;Randomized Controlled Trials;Reporting;Reproducibility;Research;Risk Factors;Sampling;Science;Social Environment;Social Psychology;Social isolation;Statistical Models;Symptoms;Testing;Text;Tobacco use;Translations;Underserved Population;United States;Visual;Vulnerable Populations;Well in self;Work;behavioral adherence;cancer diagnosis;cost;demographics;design;digital;digital delivery;digital intervention;effective intervention;emerging adult;evidence base;experience;experimental study;health communication;improved;intervention effect;mortality;multidisciplinary;novel;peer;pilot test;positive emotional state;post intervention;primary outcome;programs;promote resilience;psychologic;psychological distress;psychosocial;secondary outcome;sedentary;social;social interventions;social media;theories;therapy design;young adult Optimizing a Social Connectedness Intervention for Young Adults with Cancer PROJECT NARRATIVESocial isolation is common among young adults with cancer which can compromise their psychosocial health.We propose to optimize an evidence-based social connectedness intervention for young adults with cancerand conduct a randomized controlled trial to test its efficacy to improve psychosocial health in this population.This research leverages a highly scalable behavioral intervention to address the unmet psychosocial needs ofyoung adults with cancer. NCI 10734095 7/21/23 0:00 PAR-21-035 1R01CA276176-01A1 1 R01 CA 276176 1 A1 "EVERSON, NICOLE MARIE" 8/1/23 0:00 7/31/28 0:00 "Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]" 12470275 "LAZARD, ALLISON JOAN" "FREDRICKSON, BARBARA LEE" 4 PUBLIC HEALTH & PREV MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PUBLIC HEALTH 275995023 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 680456 NCI 410964 269492 PROJECT SUMMARY/ABSTRACTYoung adults with cancer need tailored behavioral interventions to improve their psychosocial health. Anycancer diagnosis in early adulthood can create debilitating life disruptions that increase social isolation that inturn can compromise psychosocial health. Social isolation also predicts mortality comparably to other well-established risk factors including tobacco use excessive alcohol consumption obesity and sedentary status.This conclusiondescribed as unequivocalwas established by a large-scale meta-analysis and now fuelsthe call for low-cost and scalable behavioral interventions optimized for vulnerable populations to increasesocial connectedness. The demand for such interventions is especially pressing for young adults with cancerwhose unique needs have long gone unmet. The broad overarching objective of this work is to optimize anevidence-based social connectedness intervention for young adults with cancer and test whether it improvestheir psychosocial health. This intervention delivered digitally and effective among young adults (noncancersamples) prompts individuals to increase the emotional quality of their in-person social encounters. Our multi-disciplinary team will carry out a rigorous randomized controlled trialthe Keep Social RCTusing oursimulated social media platform to deliver intervention messages optimized for young adults with cancer whilecollecting repeated measures of day-to-day experiences and psychosocial health outcomes. This program ofresearch is designed to meet three specific aims. SPECIFIC AIM 1 is to optimize our social connectednessintervention for young adults with cancer. This aim will be met using a human-centered communication scienceapproach to enhance the positive reception of health messages with social context cues (human imagery peerstories) and conduct an online experiment with 400 young adults with cancer to identify the most effectiveintervention messages for use in the Keep Social RCT. SPECIFIC AIM 2 is to pilot conduct and analyze theKeep Social RCT to test whether our social connectedness intervention delivered via social media improvespsychosocial health in young adults with cancer. After thorough pilot testing this aim will be met by conductingour placebo controlled Keep Social RCT with repeated assessments over six weeks. These data will allow usto test whether our intervention raises social and emotional well-being (primary outcomes) and improvesresilience and negative mental health symptoms (secondary outcomes). SPECIFIC AIM 3 is to extend dataanalyses of the AIM 2 Keep Social RCT to test theory-based mechanisms and explore moderators ofintervention effectiveness to pave the way for further optimization. This aim will be met with statistical modelingto identify how and for whom our social connectedness intervention improves psychosocial health amongyoung adults with cancer. Our multi-disciplinary team brings together expertise in social psychology emotionscience communication science and oncology to pursue these aims to produce translation-ready pragmaticknowledge to improve the quality of life among young adults with cancer in the United States. 680456 +No NIH Category available Address;Affinity;Alleles;Amino Acids;Antigen Presentation;Antigen Targeting;Antigens;Binding;Biological Assay;Biophysics;Cancer Burden;Cancer Patient;Cancer Vaccines;Cells;Characteristics;Clinical;Codon Nucleotides;Complex;Computer Models;Computer software;Data;Data Set;Development;Epitopes;Excision;Generations;HLA Antigens;Histocompatibility Antigens Class I;Human;Immune system;Immunotherapy;KRAS2 gene;KRASG12D;Libraries;Ligands;Malignant Neoplasms;Measurement;Mechanics;Modeling;Modification;Mutate;Mutation;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Peptide Vaccines;Peptides;Peripheral Blood Mononuclear Cell;Population;Privatization;Prognosis;Proteins;Resistance;Somatic Mutation;Structural Models;Structure;Survival Rate;T cell response;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Treatment outcome;Tumor Antigens;Vaccines;antigen binding;antigen-specific T cells;biophysical properties;cancer cell;cancer immunotherapy;cancer subtypes;cancer type;cancer vaccination;chemotherapy;clinical application;clinical translation;cohort;computational pipelines;computational platform;cytotoxic;design;exome sequencing;immunogenic;immunogenicity;improved;neoantigen vaccine;neoantigens;novel;protein aminoacid sequence;rational design;refractory cancer;response;therapeutic vaccine;tumor;vaccine candidate Structural modeling of neoantigen presentation for rational design of heteroclitic neoepitope vaccines Project narrativeImmunotherapy activates a patient's immune system to detect and kill cancer cells by recognizing the mutatedproteins they express called neoantigens. In this proposal we investigate what these neoantigen look like toour immune system and how this information can be used to improve neoantigen-targeted cancer vaccines. NCI 10734037 12/11/23 0:00 PA-21-048 5F32CA271470-02 5 F32 CA 271470 2 "JAKOWLEW, SONIA B" 12/1/22 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 15766467 "HUFF, AMANDA L" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 321 "Training, Individual" 2024 74000 NCI 74000 0 Project SummaryPancreatic ductal adenocarcinoma cancer (PDAC) is highly resistant to frontline surgical resection andchemotherapy treatments. Many treatment-resistant cancer types have benefited from immunotherapies thatactivate cytotoxic anti-tumor T cells against the somatic mutations or neoantigens expressed in cancer cells.One major challenge to the development of neoantigen-targeted immunotherapy for PDAC has been the lownumber and weakly immunogenic profile of identified neoantigens. Efficient activation of neoantigen-specific Tcells is dependent on the recognition of 8- to 11-mer neoepitopes displayed on human leukocyte antigen (HLA)class I molecules. This recognition is the culmination of the biophysical and stereochemical contacts betweenthe peptide HLA and T cell receptor (TCR) molecules. One mechanism to improve neoepitopeimmunogenicity is by modifying the peptide amino acid residues to enhance HLA binding or TCR recognitionthereby enhancing cognate T cell activation while conserving reactivity to the parental epitope. These modifiedepitopes are termed heteroclitic epitopes. However the stereochemical features of heteroclitic epitopes thatenhance HLA binding or TCR recognition are understudied. Additionally heteroclitic epitopes have beenexplored in the context of a limited number of HLA subtypes restricting their development and applicationacross patients. We hypothesize that rational design of heteroclitic neoepitope vaccines through structuralmodelling will improve T cell responses against PDAC neoantigens. To address this hypothesis we will definethe structural binding and spatial display dynamics of both shared and private PDAC heteroclitic neoepitopes indiverse HLAs. Among shared neoantigens expressed in PDAC activating mutations in KRAS at codon 12 arepresent in up to 80% of PDAC tumors. In Specific Aim 1 we will interrogate the structural mechanics andimmunogenic profile of heteroclitic KRAS G12D/V/C epitopes in a panel of 18 globally representative HLAsubtypes. In Specific Aim 2 we will develop a computational pipeline to identify prioritize and optimize patient-specific heteroclitic neoantigen vaccine candidates based on structural epitope features. We will use HLAbinding measurements and T cell reactivity assays to validate immunogenic features of our computationallymodelled heteroclitic epitopes. Together these aims will define the structural features of immunogenicneoantigens in diverse HLAs generate heteroclitic epitope vaccine candidates for shared and private PDACantigens and improve the therapeutic potential of cancer vaccines for hard-to-treat cancers such as PDAC. 74000 +No NIH Category available Acute T Cell Leukemia;Adult;Affect;Binding;Cell Proliferation;Cells;Child;Childhood;Chromatin;Chromatin Remodeling Factor;Clinical Trials;Collaborations;Complex;DNA Repair;DNA amplification;Data;Development;Dose Limiting;Drosophila genus;ETS1 gene;Elements;Enhancers;Gene Expression;Genetic Enhancer Element;Genetic Transcription;Goals;Health;Impairment;Intestines;Knowledge;Label;Learning;Link;Maintenance;Malignant Neoplasms;Methods;Modeling;NOTCH1 gene;Names;Oncogenes;Oncogenic;Oxidative Phosphorylation;Pathway interactions;Patients;Polymerase;Proliferating;Public Health;Regulatory Element;Repression;Research;Response Elements;Role;Signal Transduction;Site;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Tissues;Toxic effect;Trans-Activators;Transcription Coactivator;Transcriptional Regulation;Withdrawal;Work;acute T-cell lymphoblastic leukemia cell;cell type;chemotherapy;cofactor;combat;combinatorial;deprivation;early phase clinical trial;genome-wide;human model;inhibitor;innovation;intestinal homeostasis;leukemia;leukemogenesis;mouse model;notch protein;programs;promoter;recruit;scaffold;stem;stem cells;targeted agent;targeted treatment;therapeutic target;therapy development;time use;transcription factor ETS1-dependent combinatorial control of oncogenic transcription in Notch-activated T-ALL PROJECT NARRATIVEThe proposed research is relevant to public health because it could reveal strategies to target thecombinatorial control of Notch-dependent promoter and enhancer elements in T-cell acute lymphoblasticleukemia a cancer affecting both children and adults and in which Notch inhibitors have been proven to be tootoxic in early clinical trials. We discovered that ETS1 promotes enucleation of many oncogenic transcriptionfactor players at Notch-responsive elements. In this proposal we will learn how these players cooperativelyinteract and find ways to disrupt these interactions to target oncogenic Notch transcriptional programs andcircumvent the toxicity of pan-Notch inhibitors. NCI 10733945 5/22/23 0:00 PA-20-185 1R01CA276117-01A1 1 R01 CA 276117 1 A1 "READ-CONNOLE, ELIZABETH LEE" 6/1/23 0:00 5/31/28 0:00 Gene Regulation in Cancer Study Section[GRIC] 1873480 "CHIANG, MARK Y" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 441405 NCI 284008 157397 The discovery of NOTCH1 as the most prevalent oncogene in T-cell acute lymphoblastic leukemia (T-ALL)patients raised hopes for targeted therapy in this cancer. Unfortunately in clinical trials the pan-Notch inhibitorGSI caused dose-limiting toxicities particularly intestinal due to abrogation of Notch functions. Our idea to meetthis challenge stems from Drosophila studies showing that Notch requires co-binding transcriptional factorpartners at its response elements to generate cell-type specific gene expression programs. If these Notch-collaborating transcription factors are hijacked to help drive Notch-induced T-ALL then inhibiting them mightoppose Notch signals and circumvent GSI toxicities. Thus our long-term goal is to identify Notch-collaboratingtranscription factors and determine their potential as safe therapeutic targets. In our preliminary data we showthat ETS1 is the top-ranked Notch-associated transcription factor in the context of T cells but not intestinal cells.Compared to GSI the effects of Ets1 inactivation were just as deleterious to T-ALL cells but were much milderon intestinal homeostasis and overall health in mouse models. Mechanistically we show that CDC73 thescaffold component of the polymerase-associated factor complex (PAF1C) binds ETS1 and is recruited toactivate ETS1 response elements. One of these elements is a previously unrecognized but highly conservedsuperenhancer which we have tentatively labeled E-Me for ETS1-dependent MYB enhancer. Our objectiveis to determine the effects of Ets1-dependent trans-factors and cis-elements on the control of oncogenictranscriptional programs in Notch-activated T-ALL. We hypothesize that disrupting the ETS1-dependentcombinatorial control of transcriptional elements by targeting CDC73 or the E-Me will safely repress Notch-induced T-ALL. To test this we will determine the effects of inhibiting Ets1-dependent factors like Cdc73 onleukemia maintenance in mouse and human models of T-ALL. We will also determine the effects of inhibitingEts1-dependent factors on oncogenic transcriptional programs and cis-element activation. Finally we willdetermine the role of the E-Me element where trans-acting factors are recruited by ETS1 to collectively drive theoncogenic MYB effector pathway. Our work raises the possibility of targeting co-binding Notch-collaboratingtranscriptional regulators like Ets1 that create the chromatin context that directs Notch functions. Here we willestablish Cdc73 as the bridge that connects Ets1 to transcriptional machinery and chromatin modifiers thatactivate promoters and enhancer elements and highlight E-Me as an important example. Therefore if successfulour project is significant because we target the #1 ranked Notch-associated cofactor in a cancer to disable Notch-driven oncogenic signals without the toxicities of pan-Notch inhibitors seen in clinical trials. This project isinnovative because to our knowledge no other Notch cofactor besides ETS1 has been shown to physicallyrecruit Notch to chromatin genome-wide with strong statistical and orthogonal rigor and with a strikingly highconvergence of Notch cofactor and Notch binding motifs that was validated by chromatin profiling. 441405 +No NIH Category available ATP phosphohydrolase;Affect;Antibodies;Antineoplastic Agents;Biochemical;Biological Assay;Cancer Etiology;Cancer Patient;Cancer cell line;Cells;Cessation of life;Chromatin;Clinical;Combined Modality Therapy;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;DNA-PKcs;DNA-dependent protein kinase;Development;Disease;External Beam Radiation Therapy;Genes;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Stimulation;Immunotherapy;In Vitro;In complete remission;Ionizing radiation;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Microscopy;Minority;Modality;Modeling;Natural Immunity;Non-Small-Cell Lung Carcinoma;Nonhomologous DNA End Joining;Normal Cell;Normal tissue morphology;Operative Surgical Procedures;Oral;Outcome;PI-3-kinase-related kinase;Pathway interactions;Patients;Pharmaceutical Preparations;Platinum;Proteins;Pulmonary Fibrosis;Radiation;Radiation Toxicity;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Recurrence;Research;Research Personnel;Resistance;Resources;Role;Signal Transduction;Site;Specificity;Structure of parenchyma of lung;Systemic Therapy;Testing;Therapeutic;Therapeutic Studies;Toxic effect;Treatment Efficacy;Treatment-related toxicity;Tumor Burden;United States;Woman;Work;acute toxicity;anti-PD-1;anti-PD1 antibodies;anti-cancer;antitumor effect;ataxia telangiectasia mutated protein;cancer immunotherapy;cancer therapy;checkpoint inhibition;chemotherapy;cytotoxic;drug development;efficacy evaluation;efficacy testing;genetic variant;immune cell infiltrate;improved;in vivo;inhibitor;lung cancer cell;mRNA Expression;men;molecular targeted therapies;mouse model;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;precision medicine;response;synergism;taxane;timeline;tumor Development of a RUVBL1/2 Inhibitor as a Radiosensitizer and Immune Stimulator for NSCLC PROJECT NARRATIVENon-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in both men and women in the UnitedStates. This proposal aims to study an orally available inhibitor of the ATPases RUVBL1 and RUVBL2 as aradiosensitizer and immune stimulator for cancer therapy.If successful this work may provide the framework for developing a combination therapy that enhances theefficacy of both radiotherapy and immune checkpoint inhibitors which are currently used for treatment of patientswith NSCLC. NCI 10733863 5/19/23 0:00 PA-20-185 1R01CA276058-01A1 1 R01 CA 276058 1 A1 "AHMED, MANSOOR M" 6/1/23 0:00 5/31/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 10449039 "KITTLER, RALF " "AKBAY, ESRA ; DAVIS, ANTHONY J" 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 551399 NCI 336219 215180 Lung cancer is the second most common malignancy and the leading cause of cancer-related death in both menand women in the United States and non-small cell lung cancer (NSCLC) accounts for ~85% of all cases.Localized and regional NSCLC are frequently treated with external beam radiation therapy alone or incombination with surgery and chemotherapy using platinum-based drugs and taxanes. Metastatic NSCLC istypically treated with systemic therapies such as chemotherapy targeted molecular therapies immunecheckpoint inhibitors alone or in combination. Chemotherapy and targeted molecular therapies do not offerdurable complete responses for metastatic disease which can be achieved only in the minority of patients withimmune checkpoint inhibitors. Also recurrence is common for localized and regional NSCLC treated withradiation therapy (RT). RT has cytotoxic activity by causing DNA damage in NSCLC cells but is limited by intrinsiccellular mechanisms that repair DNA damage and confer resistance to RT. Thus there is a need for novel agentsto overcome DNA repair mechanisms and enhance the therapeutic efficacy of RT in NSCLC and increase theresponse rates for immune checkpoint inhibitors. We propose that the inhibition of the ATPases RUVBL1 andRUVBL2 with an orally available inhibitor is an effective and cancer-selective strategy for radiosensitization thatefficiently blocks DNA repair pathways by reducing protein levels of three key DNA damage repair factors DNA-PKcs and ATM/AR in NSCLC cells but not in normal cells. Because of that unique activity we expect that theRUVBL1/2 inhibitor will be more effectively enhance the antitumor effects of IR than specific DNA-PKcs/ATM/ARin vitro and in vivo and elicit less radiotoxicity. Also we propose that the RUVBL1/2 inhibition elicits immunestimulation and therefore will therapeutically synergize with IR and immune checkpoint inhibitors. This projectwill (1) determine the efficacy specificity and determinants of radiosensitization by RUVBL1/2 inhibition (2)characterize immune stimulatory effects of RUVBL1/2 inhibition alone and in combination with radiation and (3)study the therapeutic potential of RUVBL1/2 inhibition in combination with IR and immune checkpoint inhibition.If our project is successfully completed it may provide the framework for a new therapeutic strategy for NSCLCpatients which could improve clinical outcomes for this hard-to-treat disease. 551399 +No NIH Category available ACK1 Gene;Address;Advanced Development;Affinity;Applications Grants;Automobile Driving;Award;Biology;Cancer Center;Cancer Center Support Grant;Center Core Grants;Chemicals;Collaborations;Communities;Comprehensive Cancer Center;Development;Disease;Drug resistance;Evaluation;Excipients;Formulation;Goals;Human;Immune Evasion;Leadership;Libraries;Malignant Neoplasms;Medicine;Mission;Molecular;Molecular Immunology;Molecular Medicine;Multiple Myeloma;Mutation;Oncogenic;PTPN11 gene;Peer Review;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phosphotransferases;Positioning Attribute;Prodrugs;Protein-Serine-Threonine Kinases;Proteins;Proteomics;Public Health;Publications;Research;Research Project Grants;Resource Allocation;Serine;Signal Pathway;Signal Transduction;Sodium Chloride;Solvents;Specialist;Structure;Synthesis Chemistry;Tumor Promotion;United States National Institutes of Health;Validation;anticancer research;chemical synthesis;clinical development;design;drug candidate;drug discovery;drug synthesis;drug-like compound;experience;in vivo;inhibitor;lead optimization;leukemia;malignant breast neoplasm;member;mutant;novel;novel strategies;novel therapeutics;patient population;precision medicine;preclinical study;programs;scale up;small molecule;targeted treatment;treatment strategy;tumor growth Developing chemical probes for oncogenic signaling pathways The proposed research in this application is relevant to public health and supports the NIHsmission because the results from the studies will make a major contribution to our understandingof the mechanisms of proteins involved in oncogenic cell signaling pathways. It will also revealpreviously unrecognized opportunities for the clinical development of advanced drug candidates.Identifying novel approaches and chemical probes/compounds as novel drugs is likely to producepersonalized targeted therapies/precision medicine and significant survival benefits for a greatlyunderserved patient population. NCI 10733845 9/19/23 0:00 PAR-22-188 2R50CA211447-06A1 2 R50 CA 211447 6 A1 "FORRY, SUZANNE L" 9/19/17 0:00 8/31/28 0:00 ZCA1-SRB-1(M1) 10222002 "LAWRENCE, HARSHANI R" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 293933 NCI 174441 119492 Abstract: The goal of the NCI Research Specialist Award prepared by Dr. Harshani Lawrence Developingchemical probes for oncogenic signaling pathways will promote identification of small molecules/chemicalprobes for cancer targets to elucidate underlying molecular mechanisms driving cancer and drug discoveryresearch at the Moffitt Cancer Center (Moffitt). Dr. Lawrence a synthetic/medicinal chemist with over 20years of cancer research experience is the Scientific and Managing Director of the Chemical Biology Core(CBC) at Moffitt. Dr. John Cleveland Center Director of the Moffitt NCI-designated Comprehensive CancerCenter and PI/PD of the Cancer Center Support Grant (CCSG) P30 CA076292 will serve as the Unit Directorfor this R50 NCI Research Specialist Award and provide leadership guidance and be responsible for executiveoversight and resource allocation to the CBC. The 4 projects described in this proposal will involve synthesisof drug-like compounds that are inhibitors of the 1. ACK1 and 2. ULK3 serine/threonine kinases 3.Development of bifunctional gilteritinib degraders and 4. Validation of novel inhibitors of PERK. The syntheticchemistry strategies/approaches described in this proposal will generate novel compounds to addresssignificant challenges in several types of human cancers. Evaluation of novel potent and selective inhibitorsof ACK1 to target PTPN11-mutant cancers that harbor SHP2 (PTPN11) mutations and breast cancer willgenerate novel compounds for advanced pre-clinical studies. Potent and selective ULK3 inhibitors will lead toour understanding of drug resistance in Multiple myeloma and novel strategies for treatment of the disease.The synthesis and validation of bifunctional molecules as PROTACs for gilteritinib is expected to advancethe field/help to define tractable targets for leukemia. Synthesis/validation of novel potent inhibitors of proteinER kinase (PKR)-like ER kinase (PERK) to reduce tumor promoted immune evasion and thereby reduce tumorgrowth. As part of this award Dr. Lawrence will continue to provide the Moffitt research community with criticalenabling chemical biology support. This will include structure based design and synthesis of focused libraries(hit-to-lead-optimization) to identify new compounds/chemical probes to explore the molecular mechanisms ofproteins involved in cancer; scale-up synthesis/formulation of potent compounds (e.g. prodrug/salt formationsolvent/excipient optimization) for in-vivo studies; design/synthesis of chemical probes for affinity-basedproteomics. In addition to the projects described here she is involved in several other medicinal chemistrycollaborations with Cancer Center members and she is in a unique position to integrate projects from theMolecular Medicine and Immunology programs. Dr. Lawrences contribution via synthesis of compounds isessential for peer reviewed publications and grant applications. The research projects/strategies described inthis application will facilitate new directions approaches chemical probes /drugs to study and target cancer. 293933 +No NIH Category available Address;Award;Basic Science;Biometry;Biostatistical Methods;Cancer Control;Cancer Detection;Cancer Diagnostics;Cancer Model;Cancer Research Project;Cancer Surveillance Research Program;Clinical;Clinical Trials;Collaborations;Communication;Computer Models;Data Analyses;Data Analytics;Diagnostic tests;Early Diagnosis;Early treatment;Evaluation;Fostering;Generations;Lead;Leadership;Malignant neoplasm of prostate;Methods;Modeling;Natural History;Outcome;Pathway interactions;Patients;Peer Review;Phase;Policies;Policy Developments;Population;Precision therapeutics;Principal Investigator;Productivity;Program Research Project Grants;Protocols documentation;Reduce health disparities;Research;Research Support;Scientific Inquiry;Screening for cancer;Services;Specialist;Statistical Data Interpretation;Statistical Models;Study models;Technology;Uncertainty;biomathematics;care delivery;computer program;data modeling;detection test;diagnostic technologies;experimental study;health disparity;improved;novel;programs;research study;screening;skills;sound;translational cancer research;treatment strategy Statistical modeling to support population and translational cancer research PROJECT NARRATIVERevolutionary advances in cancer detection technologies promise to improve patients' lives but timelyevaluation is challenging. This project will support rigorous statistical modeling and analyses to close gapsin evidence for new and established cancer diagnostic tests including developing sound screening andconfirmation protocols investigating precision treatments and identifying pathways to narrow healthdisparities. NCI 10733838 8/17/23 0:00 PAR-22-188 2R50CA221836-07A1 2 R50 CA 221836 7 A1 "ZHU, LI" 9/20/17 0:00 8/31/28 0:00 ZCA1-SRB-1(M1) 14859702 "GULATI, ROMAN " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 245182 NCI 139308 105874 PROJECT SUMMARY/ABSTRACTDeveloping effective strategies for cancer control requires rigorous analysis of empirical evidence andsimilarly rigorous analysis to address inevitable gaps in empirical evidence. During the previous projectperiod the Principal Investigator provided critical statistical support for a broad spectrum of research studiesfocused on prostate cancer ranging from basic science experiments through clinical trials and populationmodeling studies. In this renewal application he will continue to provide biostatistical analysis services for amulti-project translational prostate cancer research program and computer modeling expertise for a cancersurveillance research program that uses biomathematical models to address evidence gaps and informpopulation prostate cancer policies. He will also serve as lead modeler in the Data Modeling and AnalyticsCore of a new multi-project research program that will investigate clinical utility of novel cancer diagnostictechnologies and multi-cancer early detection tests. Successfully supporting these research programsrequires broad expertise in biostatistical methods computer programming and data analysis to identify andimplement appropriate methods interrogate model assumptions and bracket uncertainty in results.Outstanding scientific collaboration and communication skills are essential to explain strengths andlimitations of selected approaches and to bring projects from the scientific inquiry phase through peerreview so that their results can impact the delivery of care. During the previous project period the PrincipalInvestigator consistently demonstrated all these skills and has been instrumental in establishing hisresearch group's leadership in cancer modeling for evidence generation and policy development. Plannedstudies for the renewal period include modeling of natural history and outcomes for new multi-cancer earlydetection tests investigating outcomes of strategies for precision early detection and treatment andidentifying targeted screening and treatment strategies to reduce health disparities. Renewal of the PrincipalInvestigator's Research Specialist award will facilitate his research group's continued stellar level ofproductivity and foster his continued dissemination of high-impact research characterized by statistical andmodeling approaches that are transparent rigorous and reliable. 245182 +No NIH Category available ATAC-seq;Adult;Advanced Development;Award;Bioinformatics;Biology;Cancer Biology;Cell Line;Childhood;Childhood Solid Neoplasm;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Computer software;Data Sources;Development;Drug Targeting;Drug resistance;Engineering;Enhancers;Ewings sarcoma;Funding;Genetic Transcription;Goals;Grant;Immune checkpoint inhibitor;In Vitro;Laboratories;Malignant neoplasm of lung;Manuscripts;Mediating;Mentors;Molecular;Outcome;Pathogenesis;Patients;Pre-Clinical Model;Proteins;Publishing;Repression;Research;Role;Site;Solid Neoplasm;Specialist;Technology;Testing;Therapeutic;Tissues;Untranslated RNA;anticancer research;career;chromatin isolation by RNA purification sequencing;chromatin remodeling;clinically relevant;computational pipelines;computerized tools;high throughput analysis;in vivo Model;insight;member;multiple omics;novel;patient derived xenograft model;programmed cell death ligand 1;receptor;sarcoma;single-cell RNA sequencing;software development;tumor progression Utilizing Multi-omics to Facilitate Cancer Biology Research Project NarrativeThis R50 NCI Research Specialist Award will support my ongoing and new bioinformatic developments andutilization within the context of the following three NCI-funded projects. (1) Development of AdvancedPreclinical Models for Pediatric Solid Tumors (R01CA243555) (2) Development of Novel Protein-basedTherapeutics for Lung Cancer (R01CA225103) (3) Role of Long Non-coding RNAs in Sarcoma Pathogenesis(R01CA211657). Software/data sources generated from these projects will be published and integrated intoother computational workflows and released to the wider public. NCI 10733768 8/1/23 0:00 PAR-22-187 1R50CA274213-01A1 1 R50 CA 274213 1 A1 "GRIL, BRUNILDE M" 8/1/23 0:00 7/31/28 0:00 ZCA1-SRB-1(M1) 10395927 "LEE, ALEX " Not Applicable 11 PEDIATRICS 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 233631 NCI 144663 88968 Project SummaryAs a member of the E. Alejandro Sweet-Cordero laboratory my efforts are directed at executing thecomputational aspects of the grants manuscripts and the general goals of the lab as well as mentoring otherlab members. The goals of our projects are to study the mechanism of cancer progression and obtain clinicallyrelevant insights for pediatric and adult solid tumors. The R50 NCI Research Specialist Award would provideme with the necessary funds to continue to further develop my computational tools and ongoing support forthe following NCI-funded projects: (1) Development of Advanced Preclinical Models for Pediatric Solid Tumors(R01CA243555). There are three main goals to this project: a) verify that matched patient tissue and patient-derived xenografts (PDX) or PDX-derived cell lines are transcriptionally and molecularly similar; b) utilize high-throughput analyses to nominate drug targets for testing and c) study drug resistance using single-cellRNAseq technologies. (2) Development of Novel Protein-based Therapeutics for Lung Cancer(R01CA225103). The main goals of this grant are to understand the biology of CLCF1-CNTFR as it relates toadult lung cancer and evaluate the synergistic outcomes of the engineered decoy CNTFR receptor(eCNTFR) with other compounds (e.g. eCNTFR+ PDL1 checkpoint inhibitor). (3) Investigate the Role of LongNon-coding RNAs (lncRNA) in Sarcoma Pathogenesis (R01CA211657). The goals of this grant are toelucidate the role of lncRNA EWSAT1/2 in chromatin remodeling at EWS-FLI repressed enhancer sitesutilizing ChIRP-Seq and ATACseq. Other lncRNAs revealed from a prior lncRNA CRISPR-mediatedinterference screen will also be investigated for their role in Ewing Sarcoma using both in vitro and in vivomodels. My ongoing efforts to develop software and computational pipelines will not only go toward the goalsof these NCI grants but also align with my long-term career goals and benefit the broader cancer researchcommunity. 233631 +No NIH Category available Academic Medical Centers;Adult;African American;Area;Award;Basic Science;Bioinformatics;Cancer Center;Categories;Clinic;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Network;Comprehensive Cancer Center;Conduct Clinical Trials;Country;Disease;Eligibility Determination;Enrollment;Faculty;Funding;Grant;Growth;Hispanic;Hospitals;Image;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Mentors;National Clinical Trials Network;Outcomes Research;Parents;Patient-Focused Outcomes;Patients;Population;Population Heterogeneity;Positioning Attribute;Publications;Race;Recording of previous events;Renal carcinoma;Research;Role;Site;Texas;Therapeutic;Time;Translating;Universities;base;career development;clinical trial enrollment;cost;design;drug discovery;ethnic diversity;ethnic minority;innovation;medical schools;member;metropolitan;participant enrollment;pressure;programs;racial minority;screening;timeline UT Southwestern NCI National Clinical Trials Network (NCTN) LAPS - Supplemental Funds YR4 PROJECT NARRATIVE (from UG1CA233302 parent award)UT Southwestern proposes to maintain a Network Lead Academic Participating Site (LAPS) for the NCINational Clinical Trials Network (NCTN). As an NCTN Network LAPS UT Southwestern will provide scientificleadership by helping to develop and conduct clinical trials in association with adult Network Groups and willcontribute substantial accrual to clinical trials conducted across the entire NCTN. Key strengths of our siterelevant to this effort include a history of leadership in multiple cooperative groups and excellent accrual tocooperative group trials (including ethnic and racial minorities) innovative basic research and drug discovery(which can be translated to clinic trials) an Advanced Imaging Research Center and our unique position as theonly NCI designated Comprehensive Cancer Center and academic medical center in the fourth largestmetropolitan area in the country. NCI 10733732 1/10/23 0:00 PA-20-272 3UG1CA233302-04S1 3 UG1 CA 233302 4 S1 "MOONEY, MARGARET M" 5/22/19 0:00 2/28/23 0:00 9606632 "GERBER, DAVID ERIC" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 45278 NCI 31746 13532 PROJECT SUMMARY/ABSTRACT (from UG1CA233302 parent award)For years the University of Texas Southwestern Medical Center (UTSW) has provided key leadership withinthe National Clinical Trials Network (NCTN). The leaders of this UG1 application and other faculty membershold major NCTN roles including chairing clinical trials and committees. From March 2014 through August2017 UTSW enrolled 520 patients on adult NCTN trials across 13 disease categories. During that time UTSWfaculty authored or co-authored 27 publications directly related to NCTN trials and have chaired co-chaired orserved as cooperative group committee chairs on 13 cooperative group trials. Substantial recent growthpositions UTSW to expand accrual and scientific contributions. After receiving initial NCI designation in 2010the Harold C. Simmons Cancer Center received comprehensive designation in 2015. Since 2015 two newhospitals affiliated with UTSW have been constructed. We have a vibrant drug discovery program; SPOREgrants in lung cancer and kidney cancer; an Advanced Imaging Research Center; and a Patient CenteredOutcomes Research (PCOR) Center. As the only academic medical center and medical school in theDallas/Ft. Worth (DFW) Metroplex (population 7.2 million) and the only NCI-designated Comprehensive CancerCenter in North Texas UTSW reaches a large and diverse population that otherwise would not have access toNCTN trials. In recent years up to 29% of our patients enrolled on NCTN clinical studies were Hispanic andup to 21% were African American. The specific aims of the UTSW UG1 are the following: Aim 1. Contributeto NCTN trial accrual. We will continue to enroll patients with diverse ethnic and racial backgrounds ontherapeutic and non-therapeutic trials. Aim 2. Contribute to NCTN scientific direction. We will bring UTSWbasic translational and imaging research into hypothesis-driven clinical trials. Aim 3. Provide NCTNleadership. UTSW faculty will continue to chair and co-chair clinical trials and committees in the variousNCTN groups and by participate in NCI activities and initiatives. Aim 4. Promote career development ofjunior faculty and trainees. UTSW faculty will provide mentoring and guidance in the NCTN. Aim 5. SupportNCTN administrative efforts. UTSW faculty will continue to serve on NCTN and NCI regulatory and auditingcommittees. At multiple steps the design and conduct of cancer clinical research has become morechallenging. Financial pressures have limited the protected time of clinical investigators nationwide. Increasingcost and complexity of clinical trials has prolonged activation timelines and restricted eligibility. UTSW is poisedto meet and overcome these challenges. With designated funding and mentoring programs we continue todevelop clinical investigators and disease experts. We have capitalized on a large and diverse patient base aswell as growing bioinformatics capabilities to optimize the identification screening and enrollment of clinicaltrial subjects. Together these approaches position UTSW to continue to help lead and expand NCTN efforts. 45278 +No NIH Category available Basic Science;Bioinformatics;Biometry;Clinical Data;Clinical Medicine;Communities;Complex;Data;Development;Dimensions;Disease;Environmental Exposure;Genetic;Genomics;Heritability;Human;Immunologics;Laboratories;Malignant Neoplasms;Modeling;Outcome;Prevention;Productivity;Reproducibility;Research;Research Personnel;Scientist;Specialist;Testing;Therapeutic;cancer genome;cancer genomics;clinical care;computerized tools;design;epigenomics;genome-wide;genomic data;improved;in vivo;insight;novel strategies;precision medicine;programs;response;skills;translational scientist;tumor Research Specialist in Cancer Genomics to Integrate Basic Research and Clinical Data PROJECT NARRATIVEThe analyses of cancer genomes have provided remarkable insights into the origin of cancer and exposedfeatures that have been leveraged for prevention and treatment. This proposal will provide support for a scientistskilled in laboratory and computational genomics to engage a range of translational researchers developingapproaches to improve cancer outcomes. NCI 10733649 8/4/23 0:00 PAR-22-188 1R50CA274336-01A1 1 R50 CA 274336 1 A1 "SCROGGINS, BRADLEY TODD" 8/15/23 0:00 7/31/28 0:00 ZCA1-SRB-1(M1) 15710183 "COLEMAN, ILSA " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/15/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 112973 NCI 64189 48784 ABSTRACTHuman cancers are complex diseases with pathobiology driven by heritable genetics environmental exposuressomatic genomic and epigenomic alterations and contributions for immunological and other responses in thehost micro- and macroenvironment. Cancer therapeutics overlay another dimension with respect to particularvulnerabilities that underly concepts of precision medicine. Currently integrating genome-scale data frommechanistic cause-effect laboratory-based studies to the pathobiology of in vivo tumors in the context of clinicalcare remains challenging. This proposal is designed to provide support for a highly skilled and productivescientist with expertise across laboratory bioinformatics and clinical medicine. The objectives are (i) to providebiostatistical and bioinformatics skills for a range of program investigators that seek to bi-directional integrationfor the development and testing of hypotheses involving cancer genomics; (ii) to develop new approaches(modeling and computational tools) for the analyses and integration of genome-scale data; and (iii) apply rigorand reproducibility in data annotation for submission/sharing of program genomics data to the researchcommunity. 112973 +No NIH Category available Adjuvant Chemotherapy;Antibiotics;Anticoagulation;Antioxidants;Biochemical;Biological Markers;Blood;Blood Platelets;Blood coagulation;Blood specimen;Cancer Patient;Cells;Clinical;Data;Early Intervention;Fibrinolytic Agents;Gene Expression;Gene Expression Profile;General Population;Generations;Genes;Genetic Markers;Goals;Haplogroup;Hemorrhage;Hemostatic Agents;Injections;Institution;Laboratories;Ligation;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of ovary;Methionine;Mitochondria;Mitochondrial DNA;Mitochondrial Proteins;Modeling;Moon;Morbidity - disease rate;Mus;Mutation;Neoadjuvant Therapy;Nuclear;Patients;Peptides;Plasma;Reactive Oxygen Species;Reagent;Risk;Risk Factors;Role;Sampling;Somatic Mutation;Specimen;Thrombophilia;Thrombosis;Thrombus;Tumor-Derived;University of Texas M D Anderson Cancer Center;Venous;Venous Thrombosis;biomarker identification;cancer cell;cancer diagnosis;cancer genome;carcinogenesis;chemotherapy;clinical database;cohort;extracellular;extracellular vesicles;genetic makeup;genetic risk factor;genetic variant;high risk;improved;inhibitor;microvesicles;mortality;mouse model;neutrophil;novel;novel marker;ovarian neoplasm;podoplanin;predictive marker;prevent;programs;prophylactic;small molecule;thrombotic;tumor;tumor DNA;venous thromboembolism;vesicular release Novel Biomarkers Predicting Blood Clots in Ovarian Cancer NARRATIVEMany patients with ovarian cancer suffer and even die from blood clots. Our goal is to determine the riskfactors for blood clots in ovarian cancer. We will use tumor specimens blood samples from patients andextensive clinical and laboratory data available in our institution to achieve our goals. NCI 10733645 9/19/23 0:00 PA-20-185 1R01CA275762-01A1 1 R01 CA 275762 1 A1 "ALTSHULER, RACHEL DINA" 9/19/23 0:00 7/31/28 0:00 "Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT]" 7918598 "AFSHAR-KHARGHAN, VAHID " "SHETH, RAHUL ANIL; SOOD, ANIL K" 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/19/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 634124 NCI 407279 226845 Project Summary/AbstractVenous thromboembolism (VTE) develops in about one-fourth of patients with ovarian cancer and is associatedwith significant morbidity and mortality. Chemotherapy increases VTE risk but administration of prophylacticanticoagulation to all patients on chemotherapy is associated with a substantial risk of bleeding. Therefore it iscrucial to identify patients with a higher risk of VTE. In the University of Texas MD Anderson Cancer Center(MDACC) Ovarian Cancer Moon Shot program we have assembled a cohort of 354 patients who have receivedneoadjuvant chemotherapy. The availability of tumor specimens blood samples and an extensive clinicaldatabase from these patients provides us a unique opportunity to investigate the novel predictive biomarkers forVTE in ovarian cancer. Most previous studies on cancer thrombosis analyzed clinical demographic orhemostatic factors already known to be risk factors for VTE in cancer patients instead of identifying tumor-specificprothrombotic factors. We will explore cancer cell products that increase VTE risk and particularly investigatethe impact of cancer cell-derived podoplanin and mitochondria on VTE. We found mitochondria in plasmasamples of cancer patients and showed that ovarian cancer cells release mitochondria (both free andmicrovesicle-embedded). Injection of mitochondria caused venous thrombi in mice rich in neutrophils andneutrophil extracellular trap (NETs). We speculate that mitochondria-targeted antioxidants and antibioticsblocking the synthesis of chemotactic formylmethionine(fMet)-tagged peptides reduce cancer VTE. We foundthat podoplanin is expressed on ovarian cancer cells and tumor-derived extracellular vesicles (EVs) and itsexpression is increased by chemotherapy. Podoplanin-expressing EVs activate platelets and their injection intomice causes platelet-rich venous thrombi. We propose that a small molecule blocking podoplanin interaction withplatelets reduces cancer thrombosis. We will examine whether the number of mitochondria and concentration ofpodoplanin in plasma predict VTE risk in ovarian cancer patients receiving chemotherapy. We will investigatethe effect of a mitochondria-targeted antioxidant an antibiotic blocking synthesis of fMet peptides and apodoplanin inhibitor on venous thrombosis in a murine model of IVC ligation. Finally we will compare themutation profile and mutation burden of mitochondria and nuclear genes in tumors of ovarian cancer patientswith and without VTE to identify the genetic changes in cancer cells associated with an increased VTE risk. 634124 +No NIH Category available Breast;Breast Oncology;Budgets;Cancer Center;Clinical Trials;Comprehensive Cancer Center;Faculty;Funding;Goals;Lead;Medical Oncology;Protocols documentation;Site;Time;Travel;Wages;member;participant enrollment;programs;symposium NCI NCTN-Network Lead Academic Participating Site at UPMC Hillman Cancer Center Narrative:The main goal of this supplement is to increase accrual to LAPS trials at UPMC. With the addition of Dr.Julia Foldi to the Hillman Comprehensive Cancer Centers' (HCCC) medical oncology breast program weanticipate a significant uptick in clinical trial accruals to breast protocols. The two components beingsupported by this supplement include faculty salary support for continued and expanded patientenrollment to LAPS trials as well as travel budget support. NCI 10733571 1/10/23 0:00 PA-20-272 3UG1CA233184-04S1 3 UG1 CA 233184 4 S1 "MOONEY, MARGARET M" 11/4/22 0:00 2/28/23 0:00 1888578 "BRUFSKY, ADAM M" "KIRKWOOD, JOHN MUNN" 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 11/4/22 0:00 2/28/23 0:00 395 Other Research-Related 2023 40000 NCI 25157 14843 Abstract:This supplement will be used to support additional faculty time to devote to increasing patientenrollment to LAPS studies. A new faculty member has joined the medical oncology breast program (Dr.Julia Foldi). A portion of her salary will be supported by this supplement. In addition two additionalfaculty (Dr. Haider Mahdi and Dr. Melissa Burgess) will obtain additional salary support from thissupplement. In addition due to travel constraints over the past couple years some funding from thissupplement will be used to support travel for UPMC faculty and study team members to attend nationalconferences such as NRG and Alliance conferences. 40000 +No NIH Category available Actins;Adenocarcinoma Cell;Affect;Animals;Benzo(a)pyrene;Biology;Biosensor;CRISPR/Cas technology;Cancer Etiology;Cancer Model;Carcinogens;Carcinoma;Cell Separation;Cells;Cellular biology;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Competence;Cytoskeletal Modeling;Data;Defect;Development;Dimensions;Disease;Environmental Carcinogens;Epithelial Cells;Epithelium;Event;Exposure to;Extracellular Matrix;Family;Fluorescence;Fluorescence Resonance Energy Transfer;Gene Expression;Genetic;Genetically Engineered Mouse;Goals;Grant;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate;Hematopoietic;Human;In Vitro;Invaded;Joints;KRAS oncogenesis;KRAS2 gene;KRASG12D;Knock-out;Link;Lipids;LoxP-flanked allele;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mass Spectrum Analysis;Mediating;Membrane;Mesenchyme;Modeling;Molecular;Monomeric GTP-Binding Proteins;Mus;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nude Mice;Oncogenic;Outcome;Patients;Peptide Hydrolases;Phenotype;Phorbol Esters;Phosphorylation;Phosphotransferases;Play;Positioning Attribute;Production;Protein Analysis;Protein Deficiency;Protein Kinase C;Publishing;RAS driven cancer;Rationalization;Receptor Protein-Tyrosine Kinases;Recurrence;Role;Second Messenger Systems;Series;Signal Pathway;Signal Transduction;Stromal Cells;Techniques;Testing;Tumor Promoters;Work;adenoma;cancer cell;cancer initiation;candidate identification;cell motility;cell type;experience;in vivo;innovation;insight;lung cancer cell;lung carcinogenesis;lung metastatic;lung tumorigenesis;malignant breast neoplasm;member;mouse model;mutant;neoplastic cell;novel;permissiveness;protein activation;protein kinase C epsilon;protein kinase C kinase;rac1 GTP-Binding Protein;receptor;screening;targeted treatment;tumor;tumor initiation;tumor microenvironment;tumorigenesis Protein kinase C and lung carcinogenesis NARRATIVE KRAS mutations represent one of the most frequently recurrent initiating events in lung cancer. We identifiedprotein kinase C epsilon (PKCe) as an essential player in KRAS- and carcinogen-mediated lung tumor initiationand as an important regulator of signaling that promotes lung cancer cell motility and invasion. In this applicationwe will investigate the molecular basis of the permissive role for PKCe in oncogenic KRAS-mediated lung tumordevelopment and identify downstream effectors responsible for PKCe-driven lung tumorigenesis and metastaticphenotypes. NCI 10733467 6/6/23 0:00 PA-20-185 1R01CA276350-01A1 1 R01 CA 276350 1 A1 "XU, WANPING" 6/6/23 0:00 5/31/28 0:00 Tumor Host Interactions Study Section[THI] 1878620 "KAZANIETZ, MARCELO G." "FELDSER, DAVID " 3 PHARMACOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 6/6/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 674373 NCI 414999 259374 ABSTRACT Lung cancer is the leading cause of cancer-related deaths in the U.S. with ~236700 new cases and ~130200deaths estimated for 2022. A joint effort by both PIs in this grant led to the identification of the oncogenic kinaseprotein kinase C epsilon (PKCe) as a key player in lung carcinogenesis. PKCe is aberrantly up-regulated in lungadenocarcinoma and is associated with poor outcome in patients specifically harboring KRAS mutations. Usinggenetically engineered mouse (GEM) models we demonstrated that PKCe is required for both carcinogen- andKras-driven lung tumorigenesis. In addition to this role in cancer initiation our work established novel roles forPKCe in cellular events associated with late cancer stages. Indeed PKCe is a major player in lung cancer cellmotility and invasion via activation of the small G-protein Rac1 linking this kinase to metastatic dissemination. ThatPKCe plays critical permissive roles first during adenoma initiation and then again later during the acquisition ofmetastatic competency highlights the functional complexities of the PKCe signaling events in lung cancer.Interestingly CRISPR-mediated inactivation of PKCe in the initiating cell-of-origin does not significantly affect Kras-G12D-induced tumor development leading us to hypothesize that PKCe does not strictly act in a tumor cellautonomous manner to permit oncogenic KRAS-mediated tumorigenesis. To test this hypothesis in Aim 1 we willgenerate and characterize a series of GEM models to restrict genetic deletion of PKCe to either oncogenic Kras-expressing cancer cells or to diverse stromal cell types present in the tumor microenvironment including non-cancerous epithelial mesenchyme and hematopoietic cells. Gene expression studies on isolated cells usingfluorescence-based lineage tracing techniques will provide significant mechanistic insights. In Aim 2 we willthoroughly dissect the mechanistic basis of motility/invasive signaling activation by PKCe. Our hypothesis is thatPKCe activates Rac1-mediated formation of cell ruffles and motility in KRAS mutant lung cancer cells via RacGuanine nucleotide Exchange Factors (Rac-GEFs). We will identify and characterize candidate Rac-GEFs asPKCe effectors responsible for this phenotype. In Aim 3 we will establish the involvement of PKCe and its effectorRac-GEFs for the development of metastatic lung cancer. We will use combined in vitro and in vivo approaches topin down mechanistic defects in the metastatic cascade upon CRISPR-mediated deletion of PKCe and Rac-GEFsin lung adenocarcinoma cells. We will establish GEM models and use lentiviral CRISPR-based approaches todetermine the permissive contribution of PKCe and its GEF effectors to lung adenocarcinoma metastasis andidentify relevant gene expression and signaling signatures contributing to this phenotype. Thus by usinginnovative state-of-the-art genetic and molecular approaches our studies should reveal the vast multidimensionalcomplexity of PKCe signaling in lung cancer development as well as underscore unappreciated mechanisms ofcarcinogen- and KRAS-mediated lung oncogenesis. 674373 +No NIH Category available Achievement;Administrator;Affect;African American;Asian Americans;Basic Cancer Research;California;Cancer Model;Cancer Patient;Cells;Collaborations;Collection;Comprehensive Cancer Center;Conduct Clinical Trials;Data Commons;Decision Making;Development;Discipline;Disparity;Doctor of Philosophy;Drug Combinations;Ensure;Evaluation;Fostering;Funding;Goals;Grant;Health Disparities Research;Human Resources;International;Latino;Latino Population;Lead;Los Angeles;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Minority Groups;Monitor;Moon;Native Hawaiian;Pacific Islander;Pathology;Pharmaceutical Preparations;Phase;Pilot Projects;Preclinical Testing;Procedures;Reproducibility;Research;Research Personnel;San Francisco;Site;Stomach Neoplasms;System;Technology;Testing;Texas;Universities;Validation;Woman;Xenograft procedure;cancer health disparity;chemotherapy;community engagement;design;drug testing;efficacy validation;ethnic minority;ethnic minority population;experience;innovative technologies;malignant stomach neoplasm;meetings;minority patient;novel;novel therapeutics;patient derived xenograft model;people of color;pre-clinical;precision oncology;preclinical study;programs;racial minority;racial minority population;repository;symposium;targeted treatment;treatment response;tumor Pilot Projects and Trans-Network Activities PILOT PROJECTS AND TRANS-NETWORK ACTIVITIES CORE NARRATIVEThe University of California and University of Texas Southwestern Diversity Patient-Derived Xenograft (PDX)Development and Trial Center leverages the collective strengths of six NCI- Comprehensive Cancer Centers tocreate minority patient cancer models and characterize targeted treatment responses to stomach and lungtumors. The Pilot Projects and Trans-Network Activities Core will administer NCI-funded pilot projectopportunities to facilitate interactions among UCaTS the PDXNet Consortium and non-PDXNet investigators.Additionally this Core will coordinate the development of standard operating procedures and develop methodsof experimental validation and reproducibility that will be shared within the Trans-Network and in collaborationwith non-Network projects. Through UCaTS activities we expect to extend our large repository to facilitate thediscover of new therapies that could impact vulnerable racial and ethnic minority cancer patients. NCI 10733397 7/31/23 0:00 RFA-CA-22-012 1U54CA283766-01 1 U54 CA 283766 1 8/1/23 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7855 1884703 "CHEN, MOON SHAO-CHUANG" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 3366 2102 1264 PILOT PROJECTS AND TRANS-NETWORK ACTIVITIES COREUniversity of California and UT Southwestern Diversity Patient-Derived Xenograft (PDX) Developmentand Trial Center (UCaTS) to Reduce Cancer Health DisparitiesPROJECT SUMMARY/ABSTRACTThe goal of the Pilot Projects and Trans-Network Activities Core (PPTNAC) is to contribute to the achievementof the University of Californiaand UT Southwestern Diversity Patient-Derived Xenograft (PDX) Development andTrial Center (UCaTS) overall objectives of developing PDX trial strategies for preclinical testing of single agentsand drug combinations. This D-PDTC focuses on the predominant racial/ethnic minority populations residing inCalifornia and Texas namely Latinos African American [AAs] and Asian American/Native Hawaiian/PacificIslander [AANHPIs]. The focus will be on gastric cancer which disproportionately affect Latinos and allpopulations of color and lung cancer which has a high burden in Latino and AANHPI women. Key personnelfor this Core include the PPTNAC Lead Moon S. Chen Jr. who has successfully led PPTNAC in our ongoingUCaMP PDX Development and Trial Center (PDTC) all Site PIs Contact PI and Administrative Core Lead LuisCarvajal-Carmona and UCaTS Grant Administrator. As such PPTNAC investigators reflect multiple relevantdisciplines that foster the evaluation of pilot studies and trans-network activities including cancer healthdisparities pre-clinical studies pathology and basic cancer research. PPTNAC will also facilitate the interactionof UCaTS with NCI PDXNet Data Commons and Coordinating Centers (PDCCC) other PDTCs and non-PDXNet investigators through funded projects. Specifically the PPTNAC Aims are to: (1) Facilitate Internal PilotProjects; (2) Facilitate Cross-PDXNet Activities (Pilot Studies Development and Evaluation); and (3) EngageNon-Network Investigators; and (4) Share Innovative Technologies using PDXs (Collaboration with non-PDXNetinvestigators). +No NIH Category available Address;African American;Biological Assay;California;Cancer Burden;Cancer Etiology;Cancer Model;Cancer Patient;Cancer Therapy Evaluation Program;Cell Cycle;Chemotherapy-Oncologic Procedure;Clinical Research;Clinical Trials;Collection;Complex;Comprehensive Cancer Center;Data;Development;Diagnosis;Disparity;Drug Combinations;Drug Modelings;Ethnic Origin;Ethnic Population;European;FDA approved;FRAP1 gene;Frequencies;Funding;Generations;Genes;Genetic;Genome;Genomics;Goals;High Prevalence;In Vitro;Incidence;Indigenous American;Infrastructure;Knowledge;Latina Population;Latino;Latino Population;Lung Neoplasms;Malignant Neoplasms;Medicine;Minority;Minority Groups;Modeling;Molecular Target;Mutate;Mutation;Organoids;PI3K/AKT;PIK3CA gene;PIK3CG gene;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phosphotransferases;Population;Race;Receptor Protein-Tyrosine Kinases;Research;Research Personnel;Resistance;Signal Pathway;Somatic Mutation;Stomach Neoplasms;Testing;Texas;The Cancer Genome Atlas;Translating;Translational Research;Universities;Woman;Work;cancer genome;cancer genomics;cancer health disparity;cancer therapy;cancer type;candidate identification;candidate marker;chemotherapy;ethnic minority;exome sequencing;genomic data;high risk;in vivo;inhibitor;kinase inhibitor;male;malignant stomach neoplasm;men;minority patient;molecular subtypes;mortality;mortality disparity;mutant;novel drug combination;novel therapeutics;patient derived xenograft model;pre-clinical;precision medicine;precision oncology;racial minority;racial population;repository;response;survival disparity;targeted cancer therapy;targeted therapy trials;targeted treatment;treatment response;tumor;tumor growth Advancing gastric cancer precision medicine in Latinos through patient-derived modeling PROJECT 1 NARRATIVEThe University of California and University of Texas Southwestern Diversity Patient-Derived Xenograft (PDX)Development and Trial Center leverages the collective strengths of six NCI- Comprehensive Cancer Centers tocreate minority patient cancer models and characterize targeted treatment responses to stomach and lungtumors.Thisprojectaddressesagastriccancer disparity-focusedresearchproblemusingPDXmodels. ThroughUCaTS activities we expect to extend our large repository to facilitate the discover of new therapies that couldimpact vulnerable racial and ethnic minority cancer patients. NCI 10733395 7/31/23 0:00 RFA-CA-22-012 1U54CA283766-01 1 U54 CA 283766 1 8/1/23 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7853 11805960 "CARVAJAL CARMONA, LUIS GUILLERMO" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 317920 198532 119388 PROJECT SUMMARY/ASTRACTGastric cancer (GC) is a leading cause of cancer incidence mortality and survival disparities in Latinos thelargest and youngest U.S. minority and the largest racial/ethnic group in the UCaTS states of California andTexas. When compared to non-Latino whites (NLW) GC incidence and mortality is ~>2-fold higher in Latinos.Indeed among all cancer types GC is the malignancy with the highest disparity ratio among Latinos. Latinashave a 2.6-fold higher GC mortality compared to NLW women while Latino men are at a 2.1.-fold higher risk ofdying when diagnosed with GC relative to NLW men. Despite this high GC burden and the fact that most gastrictumors carry druggable mutations only three targeted therapies have been approved for GC. As part of ourongoing UCaMP (University of California Minority Patient-Derived Xenograft Development and Trial) minority-focused PDTC we have shown that most GC molecular subtypes in Latinos carry druggable mutations and thatthey are particularly enriched in tumors carrying multiple and complex genome alterations in PI3K/AKT/mTORCDK WNT and RTK/RAS pathway genes. Over half of Latino tumors have mutations in multiple genes in theseand other pathways. Because ~35% of Latino GCs have dual/concurrent PI3K and CDK pathway alterations wewill initially focus our studies using these two pathways but will aim to expand to other type of tumors with co-mutated pathways. This project aims to develop a body of pre-clinical and mechanistic data that will help addressLatino GC disparities and that will be necessary for the establishment of minority-focused clinical trials oftargeted therapies. As part of our NCI-funded UCaMP PDTC our UCaTS research team has already successfullycreated 55 patient-derived GC models with ~60% of the models from Latinos. We have also shown that LatinoPDXs are responsive to dual treatments with PI3K inhibitors (PI3Ki) and CDK inhibitors (CDKi) and haveidentified a model with PIK3CA hotspot mutations with an exquisite response to the PIK3i taselisib. Using ourUCaTS infrastructure of six comprehensive cancer centers in California and Texas our goal in the next cycle ofour U54 study is to establish an additional 60 GC models all from minorities and to work on the following aims:i) To evaluate GC patient-derived models for identifying efficacious drug combination in tumors with multiplepathway alterations; ii) To understand the mechanisms of response to taselisib in PIK3CA mutant tumors and;iii) To evaluate the effect of genetic ancestry in response to chemotherapies and targeted therapies in Latinos.Through these studies we will develop effective drug combinations that can be rapidly translated into minority-focused clinical trials for gastric cancer patients. +No NIH Category available Alaska Native;American Indians;Animals;Antineoplastic Agents;Asian Americans;Asian population;Bioinformatics;Biology;Budgets;California;Cancer Model;Cancer Patient;Catchment Area;Charge;Clinical;Clinical Trials;Collection;Color;Communities;Comprehensive Cancer Center;Country;Cryopreservation;Data;Dedications;Deposition;Development;Diagnosis;Disparity;Drug Combinations;Early Diagnosis;Ensure;Environment;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Ethnic Origin;Evaluation;Failure;Goals;Grant;Guidelines;Harvest;Healthcare;Human;Human Resources;Immune;Implant;Implantation procedure;Incidence;Individual;Infrastructure;Institution;Intervention;Laboratories;Latino;Latino Population;Lead;Light;Los Angeles;Lung Neoplasms;Lymphoma;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Minority;Modeling;Molecular;Morphology;Mus;Mutation;Native Hawaiian;Oncogenes;Operative Surgical Procedures;Organoids;Pacific Islander;Patient Isolation;Patients;Pharmaceutical Preparations;Pharmacotherapy;Preclinical Testing;Prevention;Procedures;Qualifying;Quality Control;Race;Research;Research Personnel;Research Project Grants;Research Support;Resistance;Resource Sharing;Resources;San Francisco;Service delivery model;Site;Smoking History;Standardization;Stomach Neoplasms;System;Testing;Texas;Universities;Validation;Work;animal care;animal colony;anticancer research;biobank;cancer health disparity;cancer therapy;clinical development;cohort;cost;drug efficacy;drug testing;ethnic minority;experience;genomic data;human pathogen;implantation;improved;malignant stomach neoplasm;member;minority patient;mortality;mutant;novel therapeutics;operation;pathogen;patient derived xenograft model;personalized medicine;precision oncology;programs;racial minority;repository;response;rituximab;success;targeted treatment;treatment response;tumor;tumor xenograft PDX Core PDX CORE NARRATIVEThe University of California and University of Texas Southwestern Diversity Patient-Derived Xenograft (PDX)Development and Trial Center leverages the collective strengths of six NCI- Comprehensive Cancer Centers tocreate minority patient cancer models and characterize targeted treatment responses to stomach and lungtumors. The PDX Core will establish maintain characterize store and distribute lung and stomach cancerminority PDX models adhering to applicable guidelines standards quality control procedures and ongoingsurveillance procedures for animal and human pathogens. Through UCaTS activities we expect to extend ourlarge repository to facilitate the discover of new therapies that could impact vulnerable racial and ethnic minoritycancer patients. NCI 10733393 7/31/23 0:00 RFA-CA-22-012 1U54CA283766-01 1 U54 CA 283766 1 8/1/23 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7851 1866581 "LLOYD, KC KENT" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 184796 115399 69397 PROJECT SUMMARY/ABSTRACTThe primary objectives of the Patient Derived Xenograft (PDX) Core will be to establish and characterize PDXsand to support the research aims of the two integrated research projects of UCaTS a disparity-relevant studiesPDX Development and Trials Center (D-PDTC). The PDX Core will be responsible for the creation andcharacterization of 120 PDX models in immune-deficient mice (NSG) from tumors of patients with either gastricor lung cancers and diagnosed at any of the six sites: The five NCI designated comprehensive cancer centers(CCC) of the University of California (UC) system (Davis Los Angeles San Francisco Irvine and San Diego)and the University of Texas Southwestern CCC. All of the newly established PDX lines will be from tumorsharvested frompatients representing racial/ethnic minorities based on the combined catchment areas we expectto enrich for Latino and Asian American Native Hawaiians/Pacific Islanders (AANHPI) patients. These PDXmodels will be used to generate cohorts of specific individual tumor-bearing (PDX) mice for drug efficacy anddisparities studies. The PDX Core will consist of the expertise and infrastructure of experienced and capableshared resources at the UCDCCC (The Mouse Biology Shared Resource [MBSR] and the Biorepository SharedResource [BSR]. Over the last five years the MBSR and BSR have been involved in establishing maintainingcharacterizing storing and distributing numerous PDX models from human patients and PetDX models fromveterinary patients in dedicated highly-contained and infectious pathogen-free environments. Specificallyduring UCaMP the core implanted 383 distinct tumors which were passaged to successfully establish 101models in which the majority of models were derived from racially/ethnically communities of color. Further byengaging qualified and experienced personnel and fully functioning and readily available infrastructure in twopreexisting shared resources the only costs charged to the grant budget are limited solely to PDX modelingservices for this project. In this way the PDX Core will be integral to the successful development of PDX trialstrategies for preclinical testing of single agents and drug combinations that can feasibly lead to clinicalvalidation. The PDX Core will also contribute to the PDX Network (PDXNet) by facilitating the deposition of PDXmodels tumors and data into the NCI Patient-Derived Models Repository at the Frederick National Laboratoryfor Cancer Research so that our models can be shared with the wider research community in addition sharingof the PDXs among UCaTS members. In addition the PDX Core will also work with the PDXNet to develop andvalidate SOPs for development and characterization of PDX models for pre-clinical testing. +No NIH Category available Academic Medical Centers;Accountability;Administrator;Animals;Benchmarking;Bioinformatics;Budgets;California;Cancer Center;Cancer Model;Cancer Patient;Cancer health equity;Catchment Area;Certification;Clinical Research;Collaborations;Collection;Communication;Complex;Comprehensive Cancer Center;Data Commons;Decision Making;Deposition;Development;Doctor of Philosophy;Documentation;Ensure;Family;Funding;Generations;Genetic;Genomics;Goals;Grant;Health;Health Disparities Research;Infrastructure;Institution;International;Interruption;Laboratories;Leadership;Los Angeles;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Minority;Modeling;Monitor;Pathway interactions;Patients;Pre-Clinical Model;Procedures;Productivity;Quality Control;Recommendation;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Role;San Francisco;Site;Specimen;Stomach;Stomach Neoplasms;Texas;Universities;Work;Xenograft Model;Xenograft procedure;anticancer research;cancer health disparity;cancer type;data exchange;data sharing;ethnic diversity;ethnic minority;ethnic minority population;expectation;experimental study;human subject;malignant stomach neoplasm;meetings;member;minority patient;novel therapeutics;patient derived xenograft model;pre-clinical research;precision oncology;programs;quality assurance;racial diversity;racial minority;racial minority population;repository;sample collection;success;targeted treatment;timeline;treatment response Admin Core ADMINISTRATIVE CORE NARRATIVEThe University of California and University of Texas Southwestern Diversity Patient-Derived XenograftDevelopment and Trial Center leverages the collective strengths of six NCI- Comprehensive Cancer Centers tocreate minority patient cancer models and characterize targeted treatment responses to stomach and lungtumors. The responsibility of the Administrative Core is to create an efficient infrastructure to a) coordinatespecimen collection and data exchange b) manage scientific progress and fiscal responsibilities c) sustainquality assurance and quality control procedures d) maintain communication with key stakeholders and e)centralize standard operating procedures. Through UCaTS activities we expect to extend our large repositoryto facilitate the discover of new therapies that could impact vulnerable racial and ethnic minority cancer patients. NCI 10733392 7/31/23 0:00 RFA-CA-22-012 1U54CA283766-01 1 U54 CA 283766 1 8/1/23 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7850 11805960 "CARVAJAL CARMONA, LUIS GUILLERMO" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 226466 185735 40731 PROJECT SUMMARY/ABSTRACTThe overall goal of this application is to establish and characterize a large collection of minority patient-derivedcancer xenografts (PDXs) from two cancer types (gastric and lung) and utilize these PDXs to guide cancerprecision medicine decision making focusing on racial/ethnic minority populations. We established the Universityof California and UT Southwestern Diversity-PDX and Trial Development Center (UCaTS) that is built on anexisting cancer health disparity research network and includes six NCI-designated Comprehensive CancerCenters: UC Davis UC Irvine Health Chao Family Comprehensive Cancer Center (UC Irvine) UC Los AngelesJonsson Comprehensive Cancer Center (UCLA) UC San Diego Moores Cancer Center UC San FranciscoHelen Diller Family Comprehensive Cancer Center (UCSF) and University of Texas Southwestern Harold C.Simmons Cancer Center (UTSW). The role of the Administrative Core is to coordinate the research effort amongdifferent campuses and to maximize the use of the funding and resources. The Administrative core membersinclude UCaTS contact PI who has conducted extensive research in PDXs and has national/internationalleadership expertise in cancer health disparities. The contact PI Dr. Carvajal-Carmona will be responsible forthe overall program administration. Working closely with the contact PI this Core will have support from aBiostatistician five Site PIs and a UCD CRC to help coordinate patient specimen collection the two ResearchProject leads and a grant administrator to operationalize UCaTS goals. The Administrative Core will maintainconstant contact with the NCI staff the PDXNet Data Commons and Coordinating Center (PDCCC) Patient-Derived Models Repository at Frederick National Laboratory for Cancer Research (PDMR-FNLCR) and otherPDX Development and Trials Centers (PDTCs) to develop standard operating procedures (SOPs) coordinateresearch activities cross-validate PDX research and deposit PDX models into PDXNet. The Admin Core will beresponsible for establishing and maintaining Center communication and fiscal management to ensure UCaTSwill deliver its objectives in a timely manner. +No NIH Category available Advanced Malignant Neoplasm;Affect;Asian;Asian ancestry;Asian population;Bioinformatics;Biological;Biological Process;California;Cancer Biology;Cancer Center;Cancer Model;Cancer Therapy Evaluation Program;Catchment Area;Cause of Death;Cell Cycle;Cells;Clinical;Clinical Trials;Collection;Combination Drug Therapy;Combined Modality Therapy;Complex;Comprehensive Cancer Center;Data;Decision Making;Development;Digit structure;Disease;Disparity;Drug Combinations;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;FDA approved;FRAP1 gene;Family;Female;Frequencies;Genetic;Genome;Genomics;Goals;Grant;Health Disparities Research;Implant;Indigenous American;Infrastructure;Latina Population;Latino;Latino Population;Light;Los Angeles;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Minority;Minority Groups;Modeling;Molecular;Molecular Abnormality;Mutate;Mutation;Oncogenes;PI3K/AKT;Pathway interactions;Patient Isolation;Patients;Pharmaceutical Preparations;Phosphotransferases;Pilot Projects;Population;Population Heterogeneity;Pre-Clinical Model;Precision Health;Precision therapeutics;Preclinical Drug Development;Preclinical Testing;Process;Productivity;Publishing;Regimen;Research;Research Personnel;Research Project Grants;Resistance;Resources;Risk Factors;Role;San Francisco;Signal Transduction;Site;Smoking;Smoking History;Solid;Stomach;Stomach Neoplasms;Testing;Texas;Time;Translating;Underrepresented Minority;Universities;Woman;Work;cancer diagnosis;cancer health disparity;cancer subtypes;comparative;effective therapy;ethnic diversity;ethnic minority;expectation;health equity;malignant stomach neoplasm;member;minority patient;molecular subtypes;mortality;mortality disparity;multidisciplinary;mutant;never smoker;new therapeutic target;novel;patient derived xenograft model;people of color;precision oncology;racial diversity;racial minority;resistance mechanism;response;response biomarker;targeted cancer therapy;targeted treatment;therapeutically effective;treatment response;tumor;tumor diagnosis;tumorigenesis University of California and UT Southwestern D-PDTC OVERALL NARRATIVEThe University of California and University of Texas Southwestern Diversity Patient-Derived XenograftDevelopment and Trial Center takes advantage of the collective strengths of six NCI-Comprehensive CancerCenters to create minority patient cancer models and characterize targeted treatment responses to stomach andlung tumors. The impact of this collaborative is to understand the biological processes involved in cancer healthdisparities and to develop new effective treatments in patient-derived models to translate into clinical trials. NCI 10733391 7/31/23 0:00 RFA-CA-22-012 1U54CA283766-01 1 U54 CA 283766 1 "WALLACE, TIFFANY A" 8/1/23 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 11805960 "CARVAJAL CARMONA, LUIS GUILLERMO" "RIESS, JONATHAN W" 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 1061087 NCI 706932 354155 PROJECT SUMMARY/ABSTRACTThe University of California and the University of Texas Southwestern (UCaTS) Diversity Patient-DerivedXenograft (PDX) Development and Trial Centers is a diversity-focused grant with a goal of establishing andcharacterizing at least 120 new PDXs from racially and ethnically diverse populations and use these PDXs aspreclinical models to better understand the mechanisms of oncogenesis to test FDA-approved and NCI-CTEPsingle agent and drug combination therapies and to advance cancer health disparities research. Expanding theexisting PDX infrastructure from our ongoing University of California Patient Derived and Trial Center (UCaMPU54CA233306) UCaTS is comprised of six NCI-designated Comprehensive Cancer Centers (CCC): UC DavisComprehensive Cancer Center (UCD) [lead institution] UC Irvine Chao Family Comprehensive Cancer Center(UCI) UC Los Angeles Jonsson Comprehensive Cancer Center (UCLA) UC San Diego Moores Cancer Center(UCSD) UC San Francisco Helen Diller Family Comprehensive Cancer Center (UCSF) and the University ofTexas Southwestern Harold C. Simmons Cancer Center (UTSW). Collectively UCaTS includes a team oftransdisciplinary investigators with strengths in PDX development preclinical drug testing cancer healthdisparities clinical trial development bioinformatics and large multicenter administration. UCaTS will achieveits goal through two Research Projects. Project 1 Advancing gastric cancer precision medicine in Latinosthrough patient-derived modeling focuses on developing novel effective therapeutic regimens for mostcommonly druggable and genomically complex Latino GC subtype which involves co-mutations in multiplepathway (such as cell cycle kinase PI3K/AKT/mTOR WNT and RTK-RAS) and to study resistance mechanismsto targeted therapies identify response biomarkers and assess how ancestry influences response. Project 2 Precision targeting of disparity-associated EGFR mutant lung tumors to circumvent early resistance to EGFRinhibitors focuses on one of the most common lung cancer (LC) subtypes in minority populations EGFR-mutated lung tumors. This molecular subtype represents a high proportion of lung cancer diagnosed in femalepatients of Latino and Asian ancestry. The project will utilize PDXNet and our UCaTS lung cancer PDX expertiseand resources to develop effective targeted therapy combinations with FDA-approved and NCI-CTEP agentsseeking to overcome early resistance to EGFR-TKIs. 1061087 +No NIH Category available Acute Myelocytic Leukemia;Alpha Particles;Antibodies;Antibody-drug conjugates;Astatine;Binding;Biological Assay;Blood Cells;Cell Line;Cell physiology;Cells;Clinical;Development;Disease;Distal;Doctor of Philosophy;Drug Targeting;Effector Cell;Foundations;Gemtuzumab Ozogamicin;Generations;Genes;Goals;Hematopoietic Neoplasms;Hematopoietic stem cells;Human;Immunotherapy;In Vitro;Infrastructure;Institution;Joints;Laboratories;Lead;Membrane;Methodology;Monoclonal Antibodies;Myelosuppression;Patients;Peer Review;Pharmaceutical Preparations;Process;Production;Publications;Radiation Tolerance;Radioimmunotherapy;Radioisotopes;Reagent;Recombinants;Research;Research Project Grants;Research Support;SET Domain;Safety;Specialist;Supervision;Therapeutic;Therapeutic Monoclonal Antibodies;Toxic effect;Training;United States National Institutes of Health;Validation;Variant;Work;acute myeloid leukemia cell;bench to bedside;drug efficacy;drug testing;genetically modified cells;human monoclonal antibodies;improved outcome;in vivo;interest;member;novel;novel therapeutics;patient subsets;programs;skills;targeted treatment;therapeutic target;tool Optimizing the Efficacy and Safety of CD33-Targeted Immunotherapy for Acute Myeloid Leukemia and Other CD33+ Disorders PROJECT NARRATIVEWidely expressed on acute myeloid leukemia (AML) cells CD33 is of great interest as a therapeutic target forthis highly aggressive blood cancer but current CD33-directed drugs are often ineffective. Using newly raisedCD33-binding antibodies the Walter Lab plans to optimize the efficacy and safety of CD33-targeted therapyfocusing efforts on the delivery of highly potent radioisotopes a treatment approach called radioimmunotherapy.Dr. George S. Laszlo PhD the Research Specialist in the Walter Lab since 2010 has developed all experimentalmethodologies approaches assays and tools/reagents that build the foundation for this research and will leadstudies over the next 5 years that have the explicit goal of bringing new therapy options to patients with AML. NCI 10733379 8/11/23 0:00 PAR-22-187 1R50CA274319-01A1 1 R50 CA 274319 1 A1 "BOURCIER, KATARZYNA" 8/15/23 0:00 7/31/28 0:00 ZCA1-SRB-1(M1) 8411238 "LASZLO, GEORGE S" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/15/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 161878 NCI 91976 69902 ABSTRACTTherapies targeting CD33 have long been pursued to improve outcomes in acute myeloid leukemia (AML).Longer survival with the CD33 monoclonal antibody (mAb)-drug conjugate gemtuzumab ozogamicin (GO)validates this approach. However CD33 is a challenging target: several drugs have failed clinically and benefitwith GO is restricted to AML patient subsets. As one possible shortcoming almost all CD33-directed drugsincluding GO recognize the membrane-distal V-set domain of CD33. As a basis for new therapies the laboratoryof the Unit Director (Roland B. Walter MD PhD MS) has raised new fully human mAbs not only against the V-set domain but also the membrane-proximal C2-set domain of CD33; the latter show enhanced effector cellfunctions and target all naturally occurring CD33 variants (i.e. are CD33PAN mAbs). With these mAbs nowavailable the Walter Lab will conduct well-controlled mechanistic in vitro and in vivo studies to optimize theefficacy and safety of CD33-targeted therapy with the explicit goal of patient application. We will primarily focusour efforts on radioimmunotherapy (RIT) with the alpha particle emitting radioisotope astatine-211 (211At)leveraging the exquisite radiosensitivity of AML cells the high potency and target cell selectivity of 211At and ourinstitutional infrastructure and expertise in bringing 211At-based RIT from the bench to the clinic. Because CD33is also displayed on normal blood cells CD33-targeted drugs cause significant on-target off-AML cell toxicitymost notably prolonged profound myelosuppression. Therefore in parallel to our work on maximizing theefficacy of CD33-targeted therapy we are also developing novel gene editing approaches to protect normalhematopoietic stem and progenitor cells from these drugs to widen their therapeutic window and make their usesafer. The Research Specialist George S. Laszlo PhD has been a member of the Walter Lab since its inceptionin 2010. He has been responsible for the training guidance and supervision of all technicians as well as thedevelopment and validation of all experimental methodologies approaches assays and generation of alltools/reagents that together built the foundation for the NCI-supported research program on optimizing CD33-directed therapy as well as several other NIH-supported research projects that the Walter Lab is involved in. Atotal of 22 peer-reviewed joint publications between Drs. Laszlo and Walter (9 with Dr. Laszlo as first author)document their fruitful work relationship. Over the next 5 years Dr. Laszlo will be essential for the conduct of ourstudies described in this application with key roles in the generation production purification andcharacterization of recombinant mAbs and derived therapeutics the development of genetically engineered cellline-based tools for drug testing and the in vivo assessment of drug efficacies against human AML cells. Withhis skills and expertise Dr. Laszlo will be indispensable for our efforts to develop new efficacious CD33-targeteddrugs in a stream-lined process for the benefit of patients with AML and other CD33+ disorders for whom currenttherapies are often ineffective. 161878 +No NIH Category available Affect;Affinity;Binding;Binding Sites;Biological Assay;Cancer Etiology;Cancer cell line;Cells;Cisplatin;Clinic;DNA;DNA Damage;DNA Repair;Data;Defect;Development;ERCC1 gene;ERCC2 gene;Evaluation;Foundations;Functional disorder;Generations;Genomics;Goals;Human;Knowledge;Lead;Libraries;Link;Location;Malignant Neoplasms;Missense Mutation;Modeling;Molecular;Mutate;Mutation;Nucleotide Excision Repair;Nucleotide Excision Repair Inhibition;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Platinum;Platinum Compounds;Process;Proteins;Publications;Radiation;Reporter;Research;Resistance;Scaffolding Protein;Testing;Therapeutic;Therapeutic Intervention;Toxin;Work;X-Ray Crystallography;Xenograft Model;Xeroderma Pigmentosum Complementation Group A;anticancer treatment;antitumor drug;cancer cell;cancer genome;cancer therapy;cancer type;chemotherapy;combinatorial;design;drug sensitivity;gene repair;genome database;improved;inhibitor;insight;loss of function mutation;mutant;neoplastic cell;precision medicine;repaired;replication factor A;scaffold;small molecule inhibitor;therapeutic evaluation;tool;tool development;translational potential;tumor The XPA scaffold protein in Nucleotide Excision Repair NARRATIVEThe human nucleotide excision repair (NER) pathway processes damage to DNA caused by radiation andvarious environmental and endogenous toxins but also contributes to resistance to chemotherapies that damageDNA. This research will test the hypothesis that defects in NER sensitize cancer cells to DNA damaging drugssuch as platinum agents by investigating the effect of mutations in and developing inhibitors of the criticalscaffolding NER protein XPA. These studies will provide important new insights into the etiology of cancertherapy resistance and lay the foundation to explore the potential of inhibiting NER as a means to enhanceanticancer therapies and contribute to the implementation of precision medicine in treating cancers. NCI 10733350 9/19/23 0:00 PA-20-185 2R01CA218315-06A1 2 R01 CA 218315 6 A1 "GREENBERG, WILLIAM A" 2/9/18 0:00 8/31/28 0:00 Cancer Etiology Study Section[CE] 1879138 "CHAZIN, WALTER J." Not Applicable 5 BIOCHEMISTRY 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN SCHOOLS OF MEDICINE 372032408 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 471156 NCI 307459 163697 SUMMARYNucleotide excision repair (NER) protects human cells by removing harmful DNA damage but repair ofdamaged DNA by NER can reduce the efficacy of some antitumor drugs such as cisplatin. NER genes arefrequently missense mutated in cancers and decreased expression or loss of function mutation of NER genesERCC1 and ERCC2 respectively has been shown to correlate with improved patient outcomes after cisplatintreatment. This proposal investigates the hypothesis that reduced NER capacity arising from tumor mutationscorrelates with greater sensitivity to platinum (Pt) agents. It focuses on the NER scaffolding protein XPA whichis required for proper assembly and organization of the NER machinery. XPA is an Achilles Heel of NERbecause it interacts with the DNA substrate and nearly all core NER proteins. Our recent publications (i) showNER is suppressed by XPA mutations that inhibit interaction with its partner scaffold RPA and (ii) identify XPAmutations from tumor genomes that disrupt NER including some that our current work suggests are highlylikely to disrupt the interaction of XPA with RPA. Thus XPA represents the ideal factor to investigate thehypothesis that reduced NER capacity correlates with sensitivity to DNA damaging agents. Aim 1 will test thehypothesis that missense mutations in XPA can lead to NER defects that reduce repair capacity and sensitizetumor cells to Pt agents. XPA mutations will be screened for reduced NER capacity using a high throughputreporter assay to select those for which NER deficiency will be further characterized in cells expressing XPAmutants. We will then determine the mechanism of their dysfunction and test their sensitivity to Pt agents. Aim2 will use a fragment-based discovery approach to develop small molecule inhibitors that disrupt the XPA-RPAinteraction to enable further tests of the correlation between NER capacity and sensitivity to Pt agents. A highlycurated library of small molecular fragments will be screened by NMR and the binding location and orientationof hits will be defined by X-ray crystallography. After cycles of optimization involving structural analysis designand evaluation linked fragment compounds will be validated for physically inhibiting XPA-RPA interactionsuppressing NER and eliciting sensitivity to Pt agents in cancer cell lines. Together these aims will not onlytest the correlation between NER deficiency and sensitivity to Pt agents but also generate tool compoundsthat lay the foundation for testing the therapeutic value of inhibiting NER. They will also provide valuable insightsto move closer to the use of Pt sensitivity predictors in the clinic and explore how NER inhibition affectssensitivity to other DNA damaging agents. Ultimately we seek to understand how the tumor genomic landscapepredisposes cancer cells to drug sensitivity to enable identification of patient tumors that will be sensitive toDNA damaging agents alone or require combinatorial treatment with NER inhibitors. 471156 +No NIH Category available Affect;Bioinformatics;Brain;Breast Cancer Patient;Cell Line;Cells;Chemoresistance;Clinical Trials;Collection;Coupling;Cytotoxic agent;DNA;Data;Data Set;Development;Diagnosis;Disease;Disparity;Drug Combinations;Drug Compounding;Drug Targeting;ERBB2 gene;Endocrine;Environment;Estrogen Receptors;European ancestry;Excision;Exhibits;Fostering;Future;Genetic;Genomics;Goals;Growth;Hi-C;Human;In Vitro;Injections;Investigational Drugs;Lentivirus;Liver;Luciferases;Lung;Malignant Neoplasms;Mammary Neoplasms;Mass Spectrum Analysis;Metastatic breast cancer;Modeling;Neoplasm Metastasis;Nuclear Export;Oncogenes;Organ;Organoids;Patient-Focused Outcomes;Patient-derived xenograft models of breast cancer;Patients;Persons;Pharmaceutical Preparations;Physiology;Pilot Projects;Property;Proteomics;Research Personnel;Research Project Grants;Resistance;Resistance development;Sampling;Suspensions;Testing;Therapeutic;Woman;anticancer research;antitumor agent;black patient;bone;cancer cell;cancer diagnosis;cancer type;chemotherapy;chromosome conformation capture;clinically actionable;cytotoxic;cytotoxicity;data integration;drug candidate;efficacy evaluation;exhaust;exome sequencing;experience;experimental study;genome sequencing;health equity;hormone therapy;in vivo;inhibitor;insight;interest;malignant breast neoplasm;novel therapeutics;patient derived xenograft model;phosphoproteomics;preclinical study;programs;prospective;proteogenomics;receptor;response;single-cell RNA sequencing;standard of care;therapeutic evaluation;therapeutic target;therapy outcome;transcriptome sequencing;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor growth;whole genome Research Project 2 Proteogenomic-guided therapeutic targeting of breast cancer patient-derived xenograft metastases n/a NCI 10733315 7/19/23 0:00 RFA-CA-22-012 1U54CA283762-01 1 U54 CA 283762 1 7/19/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7836 10934899 "HARRELL, JOSHUA (CHUCK) " Not Applicable 4 Unavailable 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA Domestic Higher Education 232980568 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 Research Centers 2023 285795 184087 101708 Project Summary/AbstractBreast cancer is diagnosed in 1-of-8 women and is the most common type of cancer diagnosed at VCU. Thereare several genetically distinct subtypes of human breast cancers defined largely based on proliferative statusand expression of targetable receptors such as estrogen receptors and the HER2 oncogene. The majority ofthe cell lines and PDX models used for breast cancer research arise from White patients of EuropeanAncestry however all ancestral groups are affected by breast cancers. Over the past twenty years there hasbeen a clear disparity identified in the subtype of breast tumors found based on genetic ancestry with Blackpatients being diagnosed more frequently with Basal-like Triple-Negative Breast Cancers which are highlymetastatic. Therefore in these studies we are (1) focused on developing PDX models from breast cancerpatients. With these models we will (2) quantitatively determine their genetic ancestry and then (3) selectmodels that are genetically Basal-like and obtained from Black patients so that we can (4) use these models todetermine the organs that the colonize (5) determine the genomic and proteomic profile of the tumors andmetastases (6) define efficacy of NCI-INDs of interest with a focus on selinexor based drug combinations oncells obtained from the PDXs and (7) identifying new therapeutic drug combinations that are effective in themetastatic setting. At the conclusion of these studies we may have identified a new effective two-drugapproach that could be useful for Basal-like patients that have exhausted the current standard-of-careapproaches for treatment of metastatic breast cancer. +No NIH Category available Address;African ancestry;Awareness;Basic Science;Benchmarking;Bioinformatics;Bioinformatics Shared Resource;Biological Markers;Biometry;Black race;Breast Cancer Patient;Cancer Center;Cancer Research Project;Cells;Clinical Medicine;DNA;DNA sequencing;Data;Data Commons;Data Storage and Retrieval;Databases;Dedications;Development;Discipline;Disparity;Drug Combinations;Ensure;European ancestry;Experimental Designs;Future;Gene Expression;Genome;Genomics;Goals;Health Insurance Portability and Accountability Act;Length;Malignant Neoplasms;Methodology;Minority;Molecular;Pancreatic Adenocarcinoma;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Procedures;Protein Isoforms;Proteomics;Protocols documentation;Quality Control;Randomized;Reproducibility;Research;Research Design;Research Project Grants;Resources;Sample Size;Sampling;Secure;Specific qualifier value;Statistical Data Interpretation;Structure;System;Variant;Wages;bioinformatics pipeline;bioinformatics tool;central database;computerized data processing;data analysis pipeline;data management;data sharing;data standards;design;genetic variant;good laboratory practice;health equity;human reference genome;improved;informatics shared resource;malignant breast neoplasm;member;operation;pancreatic cancer patients;parallelization;patient derived xenograft model;programs;reference genome;response;single-cell RNA sequencing;statistics;transcriptome sequencing Bioinformatics Core n/a NCI 10733313 7/19/23 0:00 RFA-CA-22-012 1U54CA283762-01 1 U54 CA 283762 1 7/19/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7834 9275058 "LIU, JINZE " Not Applicable 4 Unavailable 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA Domestic Higher Education 232980568 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 Research Centers 2023 110536 71199 39337 Project Summary/AbstractThe primary goal of the Bioinformatics Core of VCUs U4HELPP is to provide data management quality controlreproducible analyses data storage and data sharing with the PDXNet network for all information generated byour project. In addition it will provide centralized bioinformatics statistical and methodological support for thetwo research projects Pilot Project and future projects that will build upon them. The Core will serve as the focalpoint governing the experimental design data management and statistical analyses for the two researchprojects. We will reach these goals through three aims. The first aim establishes the protocol to develop andmaintain a central data resource and sample management system that enables an interface between multipledisciplines including genomics basic science and clinical medicine. This aim will ensure that all data andanalyses are of high quality conform to good laboratory practices specifications and are disseminated to allPDXNet members in a timely fashion. The second aim will be to provide bioinformatics statistics andmethodological support from project initiation through completion and beyond. The third aim will improve qualityof analysis of sequencing data from minorities by constructing and applying the ancestry appropriate referencegenome. The Core includes members from the Department of Biostatistics at VCU the Bioinformatics SharedResource and Cancer Informatics Shared Resource at Massey Cancer Center (MCC). +No NIH Category available Advanced Malignant Neoplasm;Archives;Bioinformatics;Biological Specimen database;Black Populations;Black race;Breast;Cancer Center;Carcinomatosis;Characteristics;Clinical;Collaborations;Collection;Communication;Communities;Data;Data Commons;Development;Diagnosis;Educational workshop;Equity;Genitourinary system;Genomics;Gynecologic;Health Disparities Research;Histologic;Investigation;Latinx;Libraries;Link;Lung;Malignant Neoplasms;Massey Cancer Center at the Virginia Commonwealth University;Minority Groups;Modeling;Molecular;Organoids;Pancreas;Pancreatic Adenocarcinoma;Patients;Peritoneal;Pilot Projects;Population;Preclinical Testing;Primary Neoplasm;Program Research Project Grants;Quality of Care;RNA;Research;Research Project Grants;Research Support;Sampling;Site;Specimen;System;Tissue Expansion;Tissue Harvesting;Tumor Tissue;Underrepresented Minority;Underrepresented Populations;Universities;Virginia;advanced system;cancer subtypes;cancer type;central database;ethnic diversity;ethnic minority population;gastrointestinal;health equity;immunohistochemical markers;improved;malignant breast neoplasm;meetings;multiple omics;operation;patient derived xenograft model;patient population;personalized approach;programs;racial diversity;racial minority population;relational database;repository;safety net;therapeutic development;tumor PDX Core n/a NCI 10733312 7/19/23 0:00 RFA-CA-22-012 1U54CA283762-01 1 U54 CA 283762 1 7/19/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7833 2044665 "KOBLINSKI, JENNIFER E" Not Applicable 4 Unavailable 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA Domestic Higher Education 232980568 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 Research Centers 2023 301027 193898 107129 PROJECT SUMMARY / ABSTRACTU4HELPP PDX COREA profound limitation to personalized approaches for therapeutic development in cancer is the lack of relevantpatient derived models in all cancer types especially those from underrepresented minority groups with moreaggressive recalcitrant and/or advanced clinical stages. The overall objectives of United for Health Equity inLiving PDX Program (U4HELPP) will be to increase diverse representation and study of racial/ethnic minoritypopulations through development and investigations on more racial/ethnically diverse patient-derived xenograftmodels (PDX) to advance cancer health disparity research. The U4HELPP PDX Core will serve as a central pointfor patient-derived viable tumor tissue harvest and expansion to fully support Research Projects 1 & 2 and PilotProject and Trans-network Activities Core. The U4HELPP PDX Core will also serve as a central database ofthese specimens with clinical and molecular characteristics including ancestry of each cancer subtype linkedto molecular genomics. +No NIH Category available Acute Myelocytic Leukemia;Address;Biology;Chimeric Proteins;Classification;Clinical;Collection;Combined Modality Therapy;Communities;Complex;DNMT3a;Data;Development;Disease;Documentation;Drug Combinations;Engraftment;Epigenetic Process;FLT3 gene;FLT3 inhibitor;Failure;Genetic;Human;MLL gene;Malignant Neoplasms;Menin;Mixed-Lineage Leukemia;Modeling;Molecular;Mouse Strains;Mus;Mutate;Mutation;Oncogenes;Pathogenesis;Pennsylvania;Performance;Pharmaceutical Preparations;Phase;Phenotype;Pre-Clinical Model;Proteins;Relapse;Research Project Grants;Sampling;Subgroup;Survival Rate;TP53 gene;Therapeutic;Tissue Transplantation;Transplant-Related Disorder;Transplantation;United States National Institutes of Health;Universities;Xenograft procedure;advanced disease;cohort;disorder subtype;drug development;drug testing;in vivo;inhibitor;leukemia;leukemic stem cell;molecular modeling;molecular targeted therapies;mutant;new therapeutic target;next generation sequencing;novel;novel therapeutics;nucleophosmin;patient derived xenograft model;phase II trial;response;targeted treatment;therapy development;transcriptome sequencing;treatment response Acute myeloid leukemia (AML) Research Project n/a NCI 10733236 7/5/23 0:00 RFA-CA-22-012 1U54CA283759-01 1 U54 CA 283759 1 7/5/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7811 1949919 "CARROLL, MARTIN " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 230344 141750 88594 Summary Acute myeloid leukemia (AML) is one of the most intensely studied of human malignancies. In recent yearsthere have been major advances in defining the molecular pathogenesis of AML and introduction of newtherapies. But the three-year survival rate remains below 50% indicating failures to make therapeutic advancesfor the disease. In part we believe that this reflects a failure to adequately use genetically defined PDX modelsto develop new therapies targeted at molecularly defined subsets of the disease. As discussed below althoughthe overall genetics of AML is complex we and others have found that there are dominant oncogenes in AMLand that targeting of these oncogenes can induce therapeutic responses although not cures. Examples of thisapproach include the use of FLT3 inhibitors for de novo and relapsed FLT3 ITD mutant AML and developmentof IDH1 and IDH2 inhibitors. In each of these cases current therapy includes a choice of targeted therapieswhich are active but not curative. This likely reflects the multi-variate molecular pathogenesis. To advance thefield we have collected thousands of independent AML collections and characterized dozens of PDX models ofAML. These models have been widely used for studies of basic biology but here we propose to advance theuse of AML PDX modeling for therapy development. There are several obstacles to progress. First there arenot widely available and well characterized AML PDX models defined by genetic alterations. To address thisconcern we have chosen to separate AML into 7 subsets defined by dominant oncogenes as recently done bythe NIH MyeloMatch study. Leukemias will be sub-classified based on mutations in FLT3 DNMT3A NPM1cIDH1 IDH2 TP53 or KMT2A fusion protein (FP). Here we will characterize xenotransplantation of three AMLmodels for each of these seven sub-groups and specifically characterize the biology of serial transplant of AMLin the NSG mouse strain. Initial documentation of engraftment has already been completed for 33 of the 35samples. In SA2 we will focus on performance of an XP2 study to direct ongoing clinical efforts. Two of thesesub-groups are defined by the presence of fusion proteins involving KMT2A (previously mixed lineage leukemiaor MLL) or Nucleophosmin (NPM) mutations (that cause cytosolic re-localization of the protein) (NPMc). Both ofthese sub-types of AML require menin an epigenetic co-regulator for pathogenesis and AMLs with either classof mutations responding in pre-clinical models to Menin inhibition. Menin inhibitors are currently in Phase 1 andPhase 2 human studies and early results suggest that these drugs like other targeted therapies in AML areactive but not curative. Recent results have suggested that enhanced differentiation of AML samples containingKMT2A fusion proteins (FP) can be achieved by combining a Menin inhibitor with a KAT6A inhibitor. Here wewill use our characterized KMT2A FP and NPMc mutant AML PDX models to study the effect in vivo of targetingboth proteins in genetically defined subsets of AML. +No NIH Category available Address;Artificial Intelligence;Bioinformatics;Biological Markers;Biometry;Cancer Center;Clinical;Clinical Trials;Collaborations;Consensus;Consultations;Data;Data Analyses;Data Storage and Retrieval;Development;Ensure;Epidemiology;Evolution;Faculty;Genomics;Home;Human;Human Resources;Informatics;Leukemic Cell;Measurement;Mentors;Methodology;Patients;Pennsylvania;Phenotype;Pilot Projects;Productivity;Proteomics;Reporting;Research;Research Design;Research Personnel;Role;Students;Techniques;Time;Transplantation;Tumor Volume;Universities;Variant;Work;Xenograft procedure;arm;biomedical informatics;clinically relevant;data management;design;experience;high standard;in vivo;medical schools;multiple omics;next generation sequence data;next generation sequencing;novel;novel strategies;patient derived xenograft model;phase II trial;potential biomarker;preclinical study;professor;response;transcriptome sequencing;tumor;tumor growth Bioinformatics Core n/a NCI 10733235 7/5/23 0:00 RFA-CA-22-012 1U54CA283759-01 1 U54 CA 283759 1 7/5/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7810 8892698 "LONG, QI " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 111881 68850 43031 Summary:The Bioinformatics Core is the primary data management and analysis arm of the UP-PDTC. Of note theBioinformatics Core will include biostatistics bioinformatic and data management. The Bioinformatics Coreenhances the productivity of the proposed project investigators PDX Core and eventually the PDXNet byproviding them access to a statistical/bioinformatics/data management team who possess expertise in studydesign and conduct and data analysis in patient derived xenotransplantation studies including the analysis ofgenomic proteomic and RNA sequencing data. Timely and in-depth collaboration ensures that the proposedstudies are designed managed analyzed and reported to the highest standard and provide valid and robustanswers to the scientific questions that the U54 project seeks to address. Importantly Bioinformatics Corepersonnel will work with other experts in PDXNet to ensure a consensus of tumor and response measurementwhich can be widely used across the network. The Core is located within the Department of BiostatisticsEpidemiology and Informatics and the Institute for Biomedical Informatics (IBI) at Penn Perelman School ofMedicine. The DBEI and IBI are interdisciplinary homes for faculty staff and students specialized in biostatisticsepidemiology and clinical/bioinformatics research on campus. Furthermore Dr. Long is a Professor of Biostatisticsand Director of the Biostatistics and Informatics Core for the Abramson Cancer Center. Through his roles Dr. Longhas substantial experience addressing clinically relevant endpoints for pre-clinical studies which will be necessaryfor development of XP2 trials using biomarkers to guide development of expected human Phase 2 trials. Dr. E. PaulWileyto is an experienced biostatistician with expertise in pre-clinical study design including tumor measurementsand appropriate study design. Dr. Taehyong Kim is Interim Director of Bioinformatics Core at the Penn Institutefor Biomedical Informatics with extensive experience in analysis of NGS data RNA sequencing and other omicdata. This team has already contributed to definitions of tumor volume and growth in PDX models as well as toplanned XP2 studies in Projects 1 and 2. Importantly a major role of the Bioinformatics Core will be studies oftumor changes during serial transplantation. These studies will involve multi-omics analysis for Project Two and thedevelopment of novel potential biomarkers using artificial intelligence. Project One will work closely withBioinformatics personnel to apply recently developed techniques to study leukemia cell phenotypic evolution usingdeconvolution of RNA seq data using CIBERSORTx. This novel approach will help define leukemic cellevolution in vivo to a degree never previously done. +No NIH Category available Acceleration;Advocate;Award;Awareness;Biostatistics Core;Cancer Patient;Clinic;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Data Commons;Development;Disabled Persons;Ensure;Goals;Human Resources;Individual;Institution;Leadership;Malignant Neoplasms;Manuscripts;Minority Groups;Outcomes Research;Patients;Pennsylvania;Pilot Projects;Progress Reports;Publications;Research;Research Personnel;Resources;Schedule;Services;Tissue Banks;Tissues;Translational Research;Underrepresented Minority;Universities;Update;Visit;Work;Writing;community engagement;equity diversity and inclusion;innovation;lecturer;meetings;patient derived xenograft model;preclinical development;programs;recruit;success;training opportunity;women with disabilities University of Pennsylvania Patient-derived Xenograft Development and Trials Center n/a NCI 10733232 7/5/23 0:00 RFA-CA-22-012 1U54CA283759-01 1 U54 CA 283759 1 7/5/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7808 1949919 "CARROLL, MARTIN " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 68446 42121 26325 Summary:The goal of the Administrative Core of the University of Pennsylvania PDX Development and Trials Center isprimarily to facilitate innovative translational science that will accelerate the application of new discoveries tothe clinic for cancer patients. This will be achieved through a combination of enhancing both the developmentof unique PDX models at UPENN and through facilitating interaction with the PDXNet. The AdministrativeCore will be responsible to make sure that the UP-PDTC acts effectively as a research unit of PDXNet. Theprimary responsibilities of the Administrative Core are to provide scientific leadership administrative servicesand financial oversight as well as to function as a communication hub for all UP-PDTC-related activities. TheAdministrative Core will support investigators and personnel in Projects 1-2 the PDX Core the Pilot Projectsand Trans-Network Core and the Biostatistical Core. The Administrative Core will arrange at least annualmeetings of the SAB of the UP-PDTC. Of note the Administrative Core coordinates all efforts in support ofdiversity equity and inclusion including ensuring and facilitating wide representation of all minority groups inthe tissue banks and PDX models developed by the UP-PDTC. The Administrative Core provides each ofthese groups with centralized organization and support for their activities and helps each group stay informedabout activities meetings opportunities and other information pertinent to the UP-PDTC. The AdministrativeCore will be responsible for communication with PDXNet personnel (PDXNet Steering Committee) as well asNCI personnel and will provide support for all collaborations. In particular the Administrative Core will facilitateinteractions between UP-PDTC personnel and the PDXNet Data Commons and Administrative Center.Continuity of support provided by the staff will result in efficient and effective administration for the UP-PDTC. +No NIH Category available 15 year old;Acute Myelocytic Leukemia;Bioinformatics;Biology;Cancer cell line;Characteristics;Clear cell renal cell carcinoma;Clinical;Clinical Trials;Collection;Combined Modality Therapy;Communities;Core Facility;Dedications;Development;Disease;Glioblastoma;Goals;Human;Human Resources;Infection;Infection Control;Link;MDM2 gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Menin;Modeling;Molecular;Multiple Myeloma;Mus;NCI Center for Cancer Research;Non-Malignant;Ovarian;Ovarian Clear Cell Tumor;Ovarian Serous Adenocarcinoma;Patients;Pennsylvania;Phase;Phase I Clinical Trials;Phase I/II Clinical Trial;Pilot Projects;Primary carcinoma of the liver cells;Recording of previous events;Renal Cell Carcinoma;Reproducibility;Research;Research Personnel;Sampling;TP53 gene;Testing;Therapeutic;Tissue Banks;Universities;University resources;Work;Xenograft Model;Xenograft procedure;animal facility;bioinformatics infrastructure;burden of illness;cancer type;clinical implementation;experience;malignant breast neoplasm;member;mortality;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;phase 2 study;pre-clinical;precision oncology;rare cancer;response;skills;stem cells;targeted treatment;translational potential;treatment response;tumor University of Pennsylvania Patient-derived Xenograft Development and Trials Center University of Pennsylvania PDX Development and Trial Centers Project Narrative Human malignancies particularly AML and ovarian continue to have a high mortality. We will optimize humanpatient derived xenotransplantation models for AML ovarian cancer and other malignancies and use thesemodels to test new therapies for these diseases. NCI 10733231 7/5/23 0:00 RFA-CA-22-012 1U54CA283759-01 1 U54 CA 283759 1 "HENDERSON, LORI A" 7/5/23 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 1949919 "CARROLL, MARTIN " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 7/5/23 0:00 6/30/24 0:00 397 Research Centers 2023 930590 NCI 572671 357919 Project Summary/Abstract:The overall goal of the University of Pennsylvania PDX Development and Therapeutics Center (UP-PDTC) isto (i) exploit the translational potential of PDX models for evaluating the response of various treatments inmodels with specific molecular characteristics and to (ii) work with PDXNet to enhance and extend use of PDXmodels to the research community with the goal to guide development of human Phase 1/2 clinical trials forhuman malignancies. As PDX models more faithfully reproduce human cancer than cell lines they cancontribute to the ultimate clinical implementation of cancer precision medicine. The UP-PDTC is uniquelypoised to contribute to such research due to the long history of PDX research at UPENN. The UP-PDTC willcomprise 4 Cores and 2 projects. The four Cores are: Administrative PDX Pilot Projects and Trans-Networkand a Bioinformatics Core. The Administrative Core will coordinate all UP-PDTC activities. The PDX Corebuilds on 15 years of experience within the Stem Cell and Xenograft Core facility of UPENN. The PDX Corecurrently provides over 900 mice per month to investigators at UPENN using PDX modeling for malignant andnon-malignant disease. The animal facility of the PDX Core is a dedicated 6 room suite controlled by highlyskilled PDX Core personnel with comprehensive infection control measures. Using these measures the PDXCore has not had a significant infection in the colony in seven years. The Pilot Projects Core will takeadvantage of a growing group of collaborators to build tissue banks for hepatocellular carcinoma (HCC) clearcell renal cell carcinoma (ccRCC) breast cancer glioblastoma and myeloma. A major goal of the UP-PDTC isto develop and characterize new models across common and rare cancer types that can be linked with theoriginating patient clinical response profile and shared with PDXNet. The Bioinformatics Core takes advantageof the extensive Bioinformatics infrastructure at UPENN and will work with the Projects to more rigorouslydescribe PDX modeling for acute myeloid leukemia (AML) and ovarian cancer. There are two projects. ProjectOne is directed by Dr. Martin Carroll and will focus on acute myeloid leukemia. Project 1 takes advantage ofone of the largest tissue banks of viable fully annotated AML samples in the world. This tissue bank currentlyhas over 3300 collections from over 1700 patients collected over 20 years including over 40 PDX primograftmodels currently available of over 100 that have been described. Dr. Carroll working with members of thePDX Core has a long history of developing and using the AML PDX model to define AML biology andresponses to therapy. Project 2 is directed by Dr. Fiona Simpkins and takes advantage of the Ovarian CancerResearch Center Tumor BioTrust Collection. This collection is fifteen years old also fully annotated andincludes 140 well characterized PDX models. Drs. Carroll and Simpkins have extensive experience inxenotransplantation models and in the use of xenotransplantation models to both understand disease biologyand develop new therapeutic approaches for implementation in clinical trials. In their projects they proposetwo discrete xenotransplantation Phase 2 studies. Dr. Carroll will test the effects of a combined therapy withMenin inhibition and KAT6A inhibition on AML differentiation and disease burden. Dr. Simpkins will studyTP53 wild type clear cell ovarian carcinoma (CCOC) and low-grade serous ovarian carcinoma (LGSOC) andtheir response in PDX models to a p53 stabilizer combination (MDM2 and XPO1 inhibition). Both Dr. Carrolland Dr. Simpkins have significant experience moving pre-clinical work into human early-stage clinical trials andwe anticipate that these xenotransplant phase 2 (XP2) studies will lead to molecular defined Phase 1/2 humanstudies. Overall the unique resources of the UP-PDTC should enhance the use of PDX models for robust andreproducible studies that will lead to precision targeted therapeutics in humans. 930590 +No NIH Category available Development;Fostering;Foundations;Funding;Goals;Measures;Monitor;Peer Review;Pilot Projects;Process;Progress Reports;Publications;Research;Research Personnel;Resources;Technology;Underrepresented Minority;Woman;Writing;expectation;high standard;melanoma;programs;success Pilot-Trans Network Core n/a NCI 10733198 8/21/23 0:00 RFA-CA-22-012 2U54CA224070-05 2 U54 CA 224070 5 9/1/17 0:00 8/31/28 0:00 ZCA1-RTRB-U(M1) 7795 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 12027 11035 9060 Project Summary - Pilot Projects and Trans-Network Activities Core DThe overall goals of the Pilot Core are to advance high-quality research foster new ideas for the PDXDevelopment and Trial Center and the PDXNet in order to strengthen the foundation of ongoing studies in theprojects and to interact with investigators inside and outside of the PDTC. To accomplish these goals twospecific aims are proposed:Aim 1: To attract select and fund the most outstanding proposals with significant potential to benefit thePDTC and the PDXNet.Aim 2: To support and integrate the selected pilot projects into the PDTC program with established processesto review and monitor progress.Women and underrepresented minorities will be strongly encouraged to participate. The Pilot Core has atransparent peer-reviewed selection process that incorporates defined criteria for funding decisions.We will require that Pilot Project awardees be active in PDTC functions use the PDTC and core resourcesand provide formal written progress reports. Within the context of the core we have established high standardsand expectations of the investigators and have established a formal process to review and monitor progress offunded pilot projects. The program measures success by resulting publications resulting funding stimulatingnew aims in existing PDTC projects and strengthening the resources technologies and approaches within thePDTC and PDXNet. +No NIH Category available Acral Lentiginous Malignant Melanoma;Address;Aftercare;Apoptosis;Apoptotic;Automobile Driving;BCL2 gene;BRAF gene;Cancer Therapy Evaluation Program;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;Collection;Combined Modality Therapy;Cutaneous Melanoma;DNA Damage;DNA Repair;Data;Dose Limiting;Drug resistance;Exhibits;Future;Gene Mutation;Genes;Genotoxic Stress;Goals;High Prevalence;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Induction of Apoptosis;Lead;MAP Kinase Gene;MCL1 gene;MEKs;Malignant Neoplasms;Mediating;Metastatic Melanoma;Mitogen-Activated Protein Kinase Inhibitor;Molecular;Molecular Analysis;Mutation;Non-Cutaneous Melanoma;Pathway interactions;Patients;Proteins;Refractory;Research Personnel;Resistance;Resistance development;Resources;Skin Cancer;Somatic Mutation;Testing;Therapeutic;Toxic effect;Translating;Treatment Efficacy;Treatment outcome;Tumor Promotion;biological adaptation to stress;biomarker driven;biomarker identification;clinically relevant;design;early phase clinical trial;effective therapy;efficacy evaluation;gene repair;in vivo;inhibitor;melanoma;mutant;neoplastic cell;novel;novel strategies;overexpression;personalized medicine;personalized therapeutic;prevent;responders and non-responders;response;response biomarker;targeted agent;targeted sequencing;targeted treatment;therapeutically effective;therapy resistant;treatment strategy;tumor;tumor growth;years of life lost Personalized targeting of anti-apoptosis pathways to overcome therapeutic resistance in melanoma n/a NCI 10733197 8/21/23 0:00 RFA-CA-22-012 2U54CA224070-05 2 U54 CA 224070 5 9/1/17 0:00 8/31/28 0:00 ZCA1-RTRB-U(M1) 7794 9439732 "DAVIES, MICHAEL " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 130262 408240 20525 Project Summary Project 2 Melanoma is an aggressive skin cancer and is only second in the number of life-years lost per cancer-related death in the US. Although targeted therapies with combinations of BRAF and MEK inhibitors(BRAFi+MEKi) achieve very high clinical response rates in BRAFV600-mutant melanoma ultimately ~80% ofpatients develop resistance. Notably there are no approved targeted therapies for BRAFWT melanoma patients.Further only ~40% of metastatic melanomas achieve durable responses to immune checkpoint inhibitors. Thusthere is a significant unmet clinical need to identify novel strategies to prevent/counteract resistance to clinicallyapproved targeted therapies in BRAFV600-mutant melanoma patients and to develop effective therapeuticapproaches for BRAFWT cutaneous and non-cutaneous melanomas like acral melanomas which are under-represented in clinical studies. Therapeutic resistance in melanoma is mostly mediated by proteins that preventapoptosis of the tumor cells and promote their survival. Therefore to address the unmet needs for melanomatherapy we will develop personalized therapeutic approaches targeting aberrant anti-apoptotic pathways drivingdrug resistance. We hypothesize that inhibiting survival mechanisms in targeted therapy-resistantmelanoma will sensitize them to undergo apoptosis leading to tumor regression. We will test thishypothesis with two aims. Aim 1 is based on our preliminary results showing that BRAFV600-mutant melanomaPDXs with high MCL1 are resistant to BRAFi+MEKi. Our preliminary studies also show that MCL1Hi tumors aresensitive to MCL1 inhibition. We will optimize MCL1 inhibition in combination with MAPKi to overcome drugresistance. In Aim 2 we will exploit the presence of somatic mutations in DNA damage repair (DDR) genes inBRAFWT melanomas and will determine the efficacy of DDR inhibitors in PDXs selected based on alterations inDDR genes. Importantly as a large percentage of acral melanomas are BRAFWT and are resistant to currenttherapies we will include acral melanoma PDXs in this study and determine the therapeutic value of DDRinhibitors. For both aims we will use a novel in vitro MicroOrganoSphere platform (Xilis Inc.) and in vivo tumorgrowth inhibition studies in our large collection of molecularly characterized PDXs to identify the most effectivetreatments that can be translated into future clinical trials. We will then perform whole tumor/spatial/single cellmolecular analyses on responders and non-responders to identify biomarkers of response and resistance. Toachieve these goals we have assembled an outstanding team of investigators with diverse and complementaryexpertise. Together our expertise and resources will facilitate optimization and prioritization of the bestcombination treatments to effectively address the two urgent unmet needs for melanoma patients. +No NIH Category available Address;Bioinformatics;Characteristics;Consultations;Data;Data Analyses;Data Security;Development;Ensure;Environment;Experimental Designs;Generations;Goals;Manuscripts;Molecular;Mutation;Pharmacotherapy;Preclinical Testing;Preparation;Process;Progress Reports;Protocols documentation;Quality Control;Research;Research Design;Research Personnel;Research Project Grants;Research Proposals;Sample Size;Statistical Data Interpretation;Writing;data management;experimental study;mRNA Expression;melanoma;member;preclinical study;programs;protein expression;treatment response Bioinformatics Core n/a NCI 10733195 8/21/23 0:00 RFA-CA-22-012 2U54CA224070-05 2 U54 CA 224070 5 9/1/17 0:00 8/31/28 0:00 ZCA1-RTRB-U(M1) 7792 10441510 "KOSSENKOV, ANDREW V" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 46170 42366 34782 Project Summary Bioinformatics Core CThe Bioinformatics Core will conduct bioinformatics and statistical analyses of data generated by the projectsand cores to address research hypotheses defined in the project-specific proposals. The core will also performintegrative analyses to combine data from all experiments. The PDX Core will provide central storage datamanagement and information security for generated raw and processed high throughput data within the PDXDevelopment and Trial Center (PDTC). The core will assist with preparation and writing of progress reportsabstracts manuscripts and future research proposals. During the span of the Research Program theBioinformatics Core will ensure timely progress tracking of PDX trials and sharing of generated results betweenmembers of the PTDC. +No NIH Category available 3-Dimensional;Biological;Biological Assay;Biological Models;Cell Aggregation;Cell Line;Cells;Cellular biology;Clinical;Collaborations;Collagen;DNA;DNA sequencing;Data;Data Storage and Retrieval;Databases;Development;Dimensions;Disease;Ensure;Freezing;Future;Genetic;Genetic Fingerprintings;Growth;Guidelines;Human;Immunodeficient Mouse;In Vitro;Laboratories;Lesion;Melanoma Cell;Methodology;Methods;Modeling;Molecular;Molecular Abnormality;Molecular Profiling;Monitor;Mus;Neoplasm Metastasis;Organoids;Patients;Pilot Projects;Pre-Clinical Model;Quality Control;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Scientist;Services;Skin;Specimen;Testing;Training;Work;cell bank;data sharing;exome;experimental study;in vitro Model;in vivo Model;investigator training;melanoma;member;neoplastic cell;novel therapeutics;pathogen;patient derived xenograft model;pre-clinical;preclinical study;programs;protein expression;screening;subcutaneous;success;three-dimensional modeling;tool;transcriptome sequencing;tumor;tumor growth PDX Core n/a NCI 10733194 8/21/23 0:00 RFA-CA-22-012 2U54CA224070-05 2 U54 CA 224070 5 9/1/17 0:00 8/31/28 0:00 ZCA1-RTRB-U(M1) 7791 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 112092 128093 77661 Project Summary PDX Core BThe PDX Core provides major resources to the program investigators including melanoma PDX melanomacell lines and 3D models such as organoids spheres and spheroids to explore new therapies. Our melanomaPDX pre-clinical platform encompasses >500 different tumors representing all clinical biologic and geneticgroups of the disease. The primary focus of the PDX Core is to establish bank and distribuite new PDX andPDX-derived models. The PDX Core also coordinates the characterization the pre-clinical melanoma models atat the biological (e.g. growth and metastasis) and molecular (e.g. DNA- and RNA-sequencing and proteinexpression) levels. The core maintains a master cell bank conducts quality control of specimens and derivedmodels and monitors for mouse pathogens. The core is also the central facilitator for exchanging PDX withinthe PDXNet and coordinates collaborations with other investigators within the program the overall PDXNetand outside scientists. The core coordinates data storage data sharing and distribution to other investigatorswithin the program.The PDX Core is available to train investigators of the program in all biological assays and models. Overallthis core will provide efficient and high-quality service to all investigators within this PDTC. The PDX Core isalso available to assist investigators withinPDXNet and collaborators as requested.1 +No NIH Category available Biological Assay;Carcinoma;Characteristics;Chemoprevention;Clinical;Colloids;Cyst;Cyst Fluid;Cystic Neoplasm;Data;Development;Diagnostic;Disease;Double-Blind Method;Duct (organ) structure;Dysplasia;Emotional;Epithelium;Evaluation;Excision;Financial cost;Gene Expression;Genes;Goals;High grade dysplasia;Histologic;Imaging technology;Inflammation;Intervention;Intestines;Laboratories;Lesion;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Minority;Modeling;Moderate Dysplasia;Molecular;Morbidity - disease rate;Mucinous Neoplasm;Nomograms;Pancreatic Adenocarcinoma;Pancreatic Cyst;Pancreatic cystic neoplasia;Papillary;Pathway interactions;Patient risk;Patients;Persons;Pilot Projects;Placebos;Population;Prevention;Prevention trial;Prospective Studies;Proteins;Proteomics;Publishing;Randomized;Resected;Resources;Risk;Sampling;Technology;Testing;Time;Tissues;Validation;Work;arm;aspirate;assay development;biomarker development;biomarker panel;biomarker validation;cancer invasiveness;curative treatments;design;diagnostic accuracy;diagnostic value;differential expression;digital;disorder risk;follow-up;high risk;improved;mortality;new technology;novel;operation;pancreatic neoplasm;predictive modeling;protein biomarkers;protein expression;radiological imaging;repository;transcriptome;transcriptomics Biomarker validation for intraductal papillary mucinous neoplasms of the pancreas Project Narrative:Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are radiographically identifiablecystic precursor lesions of pancreatic cancer that evolve from low-grade dysplasia to high-gradedysplasia to carcinoma. Through the use of spatial transcriptomics we have identified sub-typespecific (intestinal vs. pancreaticobiliary) epithelial markers of high-grade dysplasia. In thisproposal we utilize this novel technology to precisely identify sub-type specific markers of high-grade dysplasia; to incorporate these cyst fluid markers into a recently developed preoperativeprediction model; and to validate this improved prediction model on two large clinical and cystfluid repositories that have been created by our group. NCI 10733187 7/25/23 0:00 PA-20-185 2R01CA182076-06A1 2 R01 CA 182076 6 A1 "YOUNG, MATTHEW R" 9/1/14 0:00 6/30/28 0:00 Clinical Oncology Study Section[CONC] 8876021 "ALLEN, PETER J" Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/25/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 422074 NCI 298280 123794 PROJECT SUMMARY/ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) of thepancreas are cystic tumors that represent a radiographically identifiable precursor lesion ofpancreatic cancer. Currently IPMN represent our best opportunity for intervention - andinterception - prior to the development of an incurable cancer. The challenge however is currentlaboratory endoscopic and imaging technologies are unable to distinguish between IPMN that isat low-risk (low-grade dysplasia) or at high-risk (high-grade dysplasia) of becoming an invasivecancer. In addition our ability to improve diagnostic accuracy - particularly through biomarkerdevelopment - has been difficult as IPMN is very heterogeneous with multiple histologic sub-types and grades of dysplasia existing within the same lesion. Over the past 18 months we havedesigned and performed pilot studies utilizing a novel spatial transcriptomics platform as a meansto spatially identify precise sub-type specific epithelial markers of high-grade dysplasia in thetissue from patients resected for IPMN. These studies have found significant differences in geneexpression between both low-grade and high-grade dysplasia - and for the first time - have clearlydefined gene expression differences between intestinal and pancreaticobiliary sub-type IPMN.The importance of this latter finding cannot be overemphasized as intestinal sub-type IPMN willtypically progress to invasive colloid cancer which is a much less aggressive malignancy.Furthermore we have identified differences in cyst fluid protein abundances between intestinaland pancreaticobiliary sub-type IPMN that mirror these gene expression differences. In thisproject we will utilize this spatial platform to expand our work and identify sub-type specificepithelial markers of high-grade dysplasia. We will then assess cyst fluid for these proteins usinga novel proteomics platform (Olink Focus) and further develop a prediction model for high-riskdisease (validated during the previous project period AUC approximately 0.8). Finally we willattempt to rapidly validate this model(s) by applying the model(s) to two separate cyst fluidrepositories developed by our group that contain cyst fluid from hundreds of patients who havebeen managed for pancreatic cysts - and have mature follow-up. We believe this approach willallow us to identify very specific cyst fluid protein markers to both epithelial sub-type and grade ofdysplasia and develop a very accurate test for high-risk IPMN. Patients with IPMN represent apopulation in which the identification of accurate markers of high-grade dysplasia will allow forcurative intervention (resection) prior to the development of an incurable disease while sparingthose with low-grade lesions the morbidity and even mortality of operation. 422074 +No NIH Category available 3-Dimensional;Academia;Autophagocytosis;Benchmarking;Bioinformatics;Biological Markers;Biology;Blood;Cancer Model;Clinical;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Collaborations;Colon;Colon Carcinoma;Cytotoxic Chemotherapy;Data;Development;Disease Progression;ERBB2 gene;Ensure;Exposure to;Funding;Future;Genes;Genomics;Immunohistochemistry;In Vitro;Industry;Inflammatory;Institution;Investigational Therapies;KRAS2 gene;KRASG12D;Letters;Lung;MAPKAPK2 gene;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mitogen-Activated Protein Kinase Inhibitor;Mitogen-Activated Protein Kinases;Modeling;Mus;Mutation;NF-kappa B;Oncogenes;Oncoproteins;Organ;PIK3CG gene;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phosphotransferases;Prediction of Response to Therapy;Proteomics;Proto-Oncogene Proteins c-akt;Research Project Grants;Resistance;Signal Pathway;Signal Transduction;Stress;Surface;TNF gene;Testing;Therapeutic;Therapeutic Agents;Tissues;Topoisomerase-I Inhibitor;Translating;Trastuzumab;Universities;Washington;Work;Xenograft procedure;antibody conjugate;autocrine;biomarker driven;biomarker identification;cancer type;chemotherapy;combinatorial;efficacy evaluation;efficacy testing;improved;in vivo;inhibitor;innovation;malignant breast neoplasm;member;multiple omics;mutant;novel;novel strategies;novel therapeutics;objective response rate;pancreatic ductal adenocarcinoma cell;patient derived xenograft model;pharmacologic;pre-clinical;preclinical efficacy;predictive marker;protein kinase inhibitor;receptor;resistance mechanism;response;success;systemic toxicity;transcriptomics;treatment response;tumor;tumor growth Research Project 2 n/a NCI 10732991 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7742 12479630 "LIM, KIAN H" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 Research Centers 2023 230918 148500 82418 PROJECT 2 SUMMARYAfter several decades of intensive efforts from academia and industry targeting KRAS using KRAS-specificinhibitors (KRASi) such as sotorasib and adagrasib has finally become a clinical reality. However clinicalreponses to KRASi vary widely across different cancer types (higher in lung cancer but much lower in colon andpanceraic cancers) and are typically not durable. Importantly cancers that eventually became resistant to KRASiwere found to have acquired secondary mutations that restore KRAS signaling. For these patients there is stilla strong need for therapeutic combinations that can abrogate KRAS signaling pathways such as the RAF-MEK-ERK (MAPK) or PI3K-AKT cascades. To meet these clinical needs Project 2 of the WU-PDTC aims at testingthree novel therapeutic combinations to deepen the therapeutic response of KRASi in different KRAS-mutantcancer PDXs. Because these combinatorial strategies were developed from panceratic cancer models we willalso preform start-of-the-art proteo-transcriptomic analyses to determine the shared and distinct primary andsecondary resistance mechanisms of pancreatic lung and colon cancer PDXs to KRAS and MAPK pathwyainhibtiors. Our project capitalizes on the large repertoire of genetically-defined PDX models from different cancertypes is based on novel exciting biology supported by state-of-the-art technqiues including innovative 3D-heterotypic culture model spatio-transcriptomics snRNAseq multiplex immunohistochemistry and anoutstanding bioinformatic team. We have strong institutional commitment to provide additional fund to ensurethis Project is smoothly executed. Our novel therapeutic concepts are based on therapeutic agents that arealready in clincial trials. If successful results from our Project can be immediately translated into biomarker-driven clinical trials under the NCI Experimental Therapeutics Clinical Trials Network in which WU is an activeparticipating member. +No NIH Category available Address;Aftercare;Antibody-drug conjugates;Apoptosis;Area;Biological Assay;Biological Markers;Biopsy;Cell Death;Clinic;Clinical;Clinical Trials;Colorectal Cancer;DNA;DNA Damage;DNA Markers;Data;Development;Drug Design;ERBB2 gene;Future;Immunohistochemistry;In Vitro;Investigation;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Modeling;Mutation;Non-Small-Cell Lung Carcinoma;Organoids;Pancreatic Adenocarcinoma;Pathway interactions;Patient Selection;Patient-derived xenograft models of breast cancer;Pharmaceutical Preparations;Poly(ADP-ribose) Polymerase Inhibitor;Proteins;Proteome;Proteomics;Research Project Grants;Sampling;Small Nuclear RNA;Spatial Distribution;Surface;Testing;Topoisomerase-I Inhibitor;Trastuzumab;Tumor-Derived;Type I DNA Topoisomerases;Universities;Validation;Washington;antitumor effect;cancer cell;cancer type;cell killing;chemotherapy;cytotoxic;design;drug testing;exome sequencing;gastroesophageal cancer;homologous recombination;improved;in vitro Model;in vivo;inhibitor;malignant breast neoplasm;malignant stomach neoplasm;multiple reaction monitoring;next generation;patient derived xenograft model;patient subsets;phosphoproteomics;predicting response;proteogenomics;repaired;response;response biomarker;synergism;transcriptome;transcriptome sequencing;transcriptomics;treatment effect;treatment response;tumor;tumor heterogeneity;uptake Research Project 1 n/a NCI 10732990 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7741 8579729 "MA, CYNTHIA X" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 Research Centers 2023 230918 148500 82418 RESEARCH PROJECT 1 - SUMMARYAntibody-drug conjugates (ADCs) are a rapidly growing class of chemotherapy drugs designed to deliver cancercell specific cytotoxic payloads. Trastuzumab-deruxtecan (DS-8201a) is a pioneer next generation ADCcomprised of trastuzumab attached to a topoisomerase I (TOP1) inhibitor payload via a unique cleavable linker.DS-8201a is under active investigation for the treatment of multiple cancer types and has received FDA approvalfor several indications including advanced HER2-positive (IHC 3+ or ISH+) and more recently the HER2-low(IHC 1+ 2+/ISH-) breast cancer (BC). However a subset of patients with HER2 IHC 0 BC also responded toDS-8201a in clinical trials. The immunohistochemistry (IHC) assay routinely used in the clinic is inadequate indistinguishing the lower ranges of HER2 expression. Development of a more quantitative HER2 assay is anunmet need. Using multiple-reaction monitoring mass spectrometry (MRM-MS) proteomic approach ourcollaborator Dr. Amanda Paulovich has developed a CLIA assay which is capable of detecting a large range ofHER2 expression in BCs that are HER2-low or HER2 0 by conventional IHC. In this proposal we will examinethe utility of this assay in predicting DS-8201a efficacy in HER2 low BC defined by HER2 IHC 0-2+/ISH-. Wehypothesize that HER2 expression quantified by the MRM-MS could predict DS-8201a activity. Another area ofunmet clinical need that this project addresses is to develop mechanism-based strategies to improve the efficacyof DS-8201a for HER2 low tumors since they often derive less benefit from DS-8201a monotherapy. Based onour preliminary data we hypothesize that inhibitors against components of the DNA damage response and repairpathway (DDRi) could enhance the anti-tumor effect of DS-8201a. In Aim 1 we will examine whether the HER2expression by MRM-MS and DDR pathway alterations predict response to single agent DS-8201a using 100HER2 low BC PDX derived organoid models. Drug response in organoids will be validated in selected PDXmodels in vitro. In Aim 2 we will determine whether DDRi including the PARPi (olaparib) ATRi (AZD6738)ATMi (AZ1930) BERi (TRC-102) and DNA-PKi (M3814) enhances the anti-tumor effect of DS-8201a in HER2low BC in vitro and in vivo. We will investigate treatment effects of DDRi and DS-8201a alone or in combinationon HER2 level markers of DNA damage apoptosis and on the transcriptome and proteome/phosphoproteome.We will also perform spatial transcriptomics and snRNA sequencing of selected PDX models to analyze intra-tumor heterogeneity in treatment response. In Aim 3 we will examine whether DDRi enhances the anti-tumoractivity of DS-8201a in HER2 low colorectal cancer lung cancer and pancreatic adenocarcinoma. By assessingthe utility of a quantitative HER2 assay and proteogenomic analyses of DDR pathway we aim to improve theselection of patients likely to respond to DS-8201a in future trials. Results from the PDX and organoid testing ofDDRi in combination with DS-8201a will likely lead to the design of biomarker directed clinical trials. +No NIH Category available ATAC-seq;Address;Anatomy;Atlases;Bioinformatics;Biological Assay;Biological Markers;Cells;Characteristics;Clinical;Complex;DNA;Data;Development;Drug resistance;Effectiveness;Ensure;Future;Genitourinary system;Genomics;Goals;Heterogeneity;Human;Image;Immunofluorescence Immunologic;Individual;Infrastructure;Maps;Mission;Modeling;Molecular;Molecular Profiling;Monitor;Oncogenes;Predictive Value;Procedures;Productivity;Proteins;Proteomics;RNA;Research;Research Design;Research Project Grants;Resistance;Resolution;Resource Sharing;Resources;Sampling;Services;Speed;Stains;Standardization;Stromal Cells;Structure;Supervision;Surveys;Technology;Testing;Tissues;Treatment outcome;United States National Institutes of Health;Universities;Validation;Visualization;Washington;Work;biomarker identification;cancer genome;clinical imaging;cost;exome sequencing;genome sequencing;improved;in vivo;individual response;molecular imaging;multiple omics;neoplastic cell;new technology;patient derived xenograft model;patient engagement;phosphoproteomics;potential biomarker;pre-clinical;programs;radiological imaging;senescence;single nucleus RNA-sequencing;stress reduction;targeted imaging;therapy resistant;tool;trait;transcriptome;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor growth Shared Resources Core n/a NCI 10732989 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7740 7352481 "CHEN, FENG " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 Research Centers 2023 139952 90001 49951 SHARED RESOURCES CORE: SUMMARYThe Shared Resources Core (SRC) is structured as a physical shared resource that will support both ResearchProjects the PDX Core as well as pilot and trans-Network projects. The most critical goal of the SRC is toprovide services and resources that are either unavailable to individual research teams within PDXNet or thatare unable to meet the cost technical and speed requirements of the Projects and other components at WU-PDTC. Other important missions for the SRC include optimization of the procedures for project/sample-specificrequirements standardization of the assays to ensure data consistency and incorporation of the latesttechnologies. This centralized arrangement takes full advantage of the expertise and infrastructure existing atour institute developed through participation in several large-scale NIH consortia including HTAN (Human TumorAtlas Network) SenNet (Senescence Network) GUDMAP (GenitoUrinary Development Molecular AnatomyProject) CPTAC (Clinical Proteomic Tumor Analysis Consortium) PE-CGS (Participant Engagement andCancer Genome Sequencing) CRIP (Co-Clinical Imaging Research Program) and PDXNet in order to increaseeffectiveness and efficiency avoid duplicated effort and reduce stress on individual projects. SRC will be tightlyintegrated with the Research Projects Pilot and Trans-Network Projects the PDX Core and the BioinformaticsCore under the supervision of the Administrative Core. Detailed characterization of the PDX tumors at the DNARNA and protein levels will be important for validation model selection revelation of molecular changes inresponse to treatment illustration of mechanisms of treatment resistance as well as the identification ofbiomarkers and targets for future treatment testing. To accomplish these goals the SRC will work with theResearch Projects and other Cores to perform two main types of assays: Omics and imaging. For omics theSRC will cover bulk and single cell omics including whole exome sequencing (WES) bulk RNA-seq singlenucleus RNA-seq and ATAC-seq (snRNA-seq and snATAC-seq) spatial transcriptomics (Visium) as well asglobal proteomics and phospho-proteomics. For imaging the SRC covers multiplex target imaging(CODEX/Phenocycler) in vivo preclinical molecular and radiologic imaging and standard immunofluorescence(IF) staining. The SRC is also tasked with adjusting to the changing needs of the projects as well as introducingnew technologies and tools to assist the Projects and to accomplish the mission of the center. +No NIH Category available Algorithms;Bioinformatics;Biometry;Breast;Categories;Characteristics;Clinical Data;Clinical Trials;Colon;Communities;Complex;Computational Biology;Data;Databases;Development;Drug Combinations;Drug Targeting;Fostering;Funding;Future;Genes;Genome;Genomics;Goals;Human;Human Genome Project;Human Resources;Informatics;Information Management;Information Systems;Infrastructure;Lung;Metadata;Methods;Modeling;Molecular;Mus;Mutation;Pancreas;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Pilot Projects;Preclinical Testing;Procedures;Public Domains;Recommendation;Research;Research Project Grants;Research Support;Residual Neoplasm;Resistance;Resources;Series;Signal Transduction;Specificity;Statistical Data Interpretation;The Cancer Genome Atlas;Therapeutic;Time;Translating;Universities;Washington;analysis pipeline;anticancer research;cancer type;clinical imaging;clinically relevant;computational pipelines;computational platform;computerized tools;drug repurposing;evidence base;experimental study;falls;improved;in vivo;multiple omics;neoplasm resource;neoplastic cell;novel;patient derived xenograft model;phosphoproteomics;pre-clinical;preclinical study;preclinical trial;programs;proteogenomics;resistance mechanism;response;software development;software systems;tool;treatment response;trial design;tumor Bioinformatics Core n/a NCI 10732988 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7739 9766169 "DING, LI " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 Research Centers 2023 230919 148501 82418 BIOINFORMATICS CORE: SUMMARYThe Bioinformatics Core will support the WU-PDTC Research Projects and Cores over the spectrum of theircomputational biology needs. The research program we propose involves many facets of algorithmscomputation and information management which require formalized bioinformatics support to effectivelytranslate results into recommendations for human clinical trials. The Bioinformatics Core will provide both theinfrastructure to house the experimental data and the interpretive tools and personnel to analyze these data.These responsibilities fall into 3 basic categories. This will enable scaling the PDX-based approach into asignificant resource for the cancer research community in three important ways: (1) provide uniform high-qualityproteogenomic characterization for all WU-PDTC PDX tumor models for curation into the public domain (2)provide therapeutic response data on PDX models (e.g. breast colon pancreatic and lung) including correlationwith molecular characterization and phenotypic response that may be applied to other cancer types with similarcharacteristics and (3) provide informatic and biostatistical tools to support evidence-based selection ofpromising agents for subsequent clinical trials based on known molecular and clinical data. We will organize allof this information as well as all PDX-associated metadata (e.g. molecular and histopathologic data for both thepatient and PDX tumors passages and therapeutic experimental data etc.) time series metrics representingtreatment responses etc. in an extension of our WU-PDXdb relational tracking database developed in the priorfunding period. This will support both our local analysis and submission obligations and the informationintegration with other PDTCs and PTCCCs. These informatic and statistical tools will be integrated across thePDXNet to provide a valuable and lasting resource for future clinical and pre-clinical trial designs and possiblerepurposing of drugs across cancer types. +No NIH Category available Address;Antineoplastic Agents;Authorization documentation;Bioinformatics;Biological Markers;Biological Models;Breast;Cancer Biology;Cancer Model;Catchment Area;Characteristics;Clinical;Clinical Data;Clinical Oncology;Clinical Research;Clinical Trials;Collaborations;Collection;Colorectal;Communities;Comprehensive Cancer Center;Coupled;Data;Databases;Development;Drug Modelings;ERBB2 gene;Early Therapeutic-Clinical Trials Network;Ensure;Evaluation;Feedback;Funding;Genome;Genomics;Goals;Heterogeneity;Human;Infrastructure;Institution;KRAS2 gene;Link;Lung;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Merkel cell carcinoma;Minority Groups;Modeling;Molecular;Molecular Profiling;Monitor;Mus;Mutation;Oncology;Organoids;Pancreatic Adenocarcinoma;Patients;Procedures;Proteomics;Quality Control;Research;Research Personnel;Research Project Grants;Resistance;Resources;Safety;Sampling;Short Tandem Repeat;Solid Neoplasm;Specimen;Structure;Therapeutic;Tissue Banks;Tissues;Underrepresented Minority;Universities;Washington;authority;cancer subtypes;cancer type;clinically relevant;cohort;drug testing;exome sequencing;genomic profiles;improved;inhibitor;malignant breast neoplasm;medical schools;member;metabolomics;model development;mutant;oncology program;pathogen;patient derived xenograft model;patient oriented;programs;proteogenomics;rare cancer;refractory cancer;repository;sarcoma;screening;success;synergism;tissue registry;tool;transcriptome sequencing;transcriptomics;translational study;triple-negative invasive breast carcinoma;tumor PDX Core n/a NCI 10732987 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7738 8182718 "FIELDS, RYAN C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 Research Centers 2023 195930 126000 69930 PDX CORE SUMMARYThe Patient Derived Xenograft (PDX) Core is the epicenter of the Washington University PDX Development andTrial Center (WU-PDTC). It will be responsible for the development organization characterization storage anddissemination of high quality pathogen free PDX models for research projects investigating anticancer agentswithin and outside of WU-PDTC. Leveraging prior success and streamlined and efficient infrastructure the PDXCore will continue PDX development with a focus on creation of high-value specimens from biologicallyprioritized specimens (e.g. treatment resistant cases). The Human and Mouse Linked Evaluation of Tumors(HAMLET) PDX Core at the Institute of Clinical and Translational Study (ICTS) and the Solid Tumor Tissue Bankand Registry (STTBR) led by Drs. Li and Fields respectively have a proven record of success in generatingPDX models from a wide variety of cancers and in utilizing these models for drug testing. These synergisticprograms have generated >1000 models from >15 solid tumors including large cohorts of recalcitrant cases(e.g. treatment resistant pancrcreatic and triple-negative breast cancer) and genomically similar (e.g. HER-2amplified) solid tumors that have led to multiple clinical trials in the ETCTN. These existing models will becomepart of the renewal WU-PDTC where ~400 new PDX models will be developed and added to this collection. Thenew PDX models will further enhance our capability to support ongoing projects and open new opportunities forresearch in clinically prioritized cancer themes. Taking advantage of the strong proteogenomic capability withinthe proposed WU-PDTC and WUSM we will expand the characterization of these PDX models to include cutting-edge genomics transcriptomics proteomics and metabolomics. This will provide investigators with a morecomprehensive picture of the mutational profiles the molecular signatures clonal structures and heterogeneitiesof the models to help with cancer sub-typing and target selection. Besides research projects at WU-PDTC PDXmodels in the PDX Core collection will also be shared with other PDTCs and made broadly available toauthorized non-network investigators. Existing infrastructure copuled with the large clinical oncology program atWU and exceptionally strong institutional support including matching funds will ensure that the goals of the WU-PDTC PDX Core goals are achievable. +No NIH Category available Bioinformatics;Biometry;Budgets;Collaborations;Communication;Contracts;Development;Documentation;Electronics;Funding;Goals;Grant;Group Meetings;Infrastructure;Leadership;Maintenance;Newsletter;Participant;Pilot Projects;Preparation;Process;Progress Reports;Publications;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Universities;Washington;clinical translation;medical schools;meetings;outreach;patient derived xenograft model;programs;web site;working group Admin Core n/a NCI 10732986 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 7737 9766169 "DING, LI " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/4/23 0:00 6/30/24 0:00 Research Centers 2023 76043 48903 27140 Administrative Core SummaryThe Administrative Core will provide executive oversight biostatistical support and administrative support for allof the Research Projects PDX Core Bioinformatics Core Shared Resources Core and Pilot Project and Trans-Network Activities Core that comprise the Washington University PDX Development and Trial Center (WU-PDTC). The Administrative Core is responsible for fiscal and regulatory oversight for the WU-PDTC. TheAdministrative Core will provide the communication infrastructure for the Projects and Cores of the WU-PDTCand also with the PDXNet consortium and the NCI. To this end the Administrative Core will coordinate meetingsworking groups and perform other logistical tasks to support the WU-PDTC. The Administrative Core will alsosupport the Pilot and Trans-Network Activities Core with the solicitation for proposals for the WU-PDTC. Scientificoutreach to support the PDXNet and sharing of PDX models for clinical translation will be a primary goal of theAdministrative Core. +No NIH Category available Area;Biodiversity;Bioinformatics;Breast;Cancer Center;Cancer Therapy Evaluation Program;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Colorectal Cancer;Combined Modality Therapy;Complex;DNA Repair;Data;Development;Disease;Drug usage;Early Therapeutic-Clinical Trials Network;Engraftment;Ensure;Evaluation;Event;Fostering;Funding;Future;Genes;Genome;Genomics;Germ-Line Mutation;Goals;Grant;Human;Image;Inflammatory;Institution;Investigation;KRAS2 gene;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Metadata;Methods;Modeling;Molecular Target;Participant;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Physicians;Pilot Projects;Pre-Clinical Model;Preclinical Testing;Protocols documentation;Recording of previous events;Regimen;Relapse;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Resources;Somatic Mutation;Standardization;Technology;Testing;Therapeutic;Tissues;Translational Research;Treatment Protocols;Underrepresented Populations;Universities;Validation;Variant;Washington;Work;bioinformatics pipeline;cancer therapy;cancer type;candidate identification;capsule;chemotherapy;clinical predictors;combinatorial;drug testing;exome sequencing;experience;follow-up;improved;improved outcome;inhibitor;innovation;malignant breast neoplasm;medical schools;novel anticancer drug;patient derived xenograft model;personalized medicine;predictive marker;programs;prospective;proteogenomics;rare cancer;refractory cancer;resistance mechanism;response;success;targeted agent;transcriptome sequencing;translational impact;treatment response;tumor Washington University PDX Development and Trial Center OVERALL PROJECT NARRATIVECancer is a complex and heterogenous disease that can arise from somatic and/or germline predispositionalevents in driver genes/pathways. Because of complex resistance and relapse mechanisms combinationtherapies are generally viewed as necessary to improve the outcomes of patients with advanced malignancies.PDX models provide a platform for large-scale testing of combinations allowing both identification of promisingtherapeutic regimens for future clinical trials and deeper investigation of the mechanisms governing therapyresponse and resistance. NCI 10732985 7/4/23 0:00 RFA-CA-22-012 2U54CA224083-05 2 U54 CA 224083 5 "HENDERSON, LORI A" 9/30/17 0:00 7/31/28 0:00 ZCA1-RTRB-U(M1) 9766169 "DING, LI " "FIELDS, RYAN C; GOVINDAN, RAMASWAMY " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 1133597 NCI 729001 404596 OVERALL PROJECT SUMMARY/ABSTRACTThe myriad of both newly-available molecular targets and novel anti-cancer agents has underscored the crucialneed to develop preclinical models in order to optimize clinical trial design. Several technical benefits makepatient-derived xenograft (PDXs) models particularly attractive for drug testing and personalized medicine.Biologists and physicians at Washington University School of Medicine (WUSM) and the Siteman Cancer Center(SCC) developed and operated the Washington University PDX Development and Trial Center (WU-PDTC) aspart of the PDXNet program during a prior funding period (CA224083) from 2017-2022. Based on the successof this program we propose to renew WU-PDTC funding as a T-PDTC with the goal of continuing our efforts inpreclinical testing and prioritizing and studying unmet needs in cancer in this collaborative nation-wide effort.The PDX Core within WU-PDTC will develop and characterize 400 new PDX models across major tumor types.These models will be characterized using the latest omics technologies and analyzed using the most currentbioinformatics pipelines that have been deployed for PDXNet and other large scale NCI programs. Tumorsrepresenting unmet needs and priority areas for collection will be emphasized (e.g. treatment resistant cancers).The Bioinformatics Core will integrate these analyses with clinical annotation from the originating patient toinclude treatment history and tumor response (Aim 1). Our two Research Projects will conduct PDX clinical trialsof single and combination agents using drugs in the NCI CTEP portfolio (Aim 2). Project 1 will investigatepredictive biomarkers and resistance mechanisms for DS-8201a alone and in combination with DDRi in breastcancer (expanding to GI and lung cancers) while Project 2 will study targeting the onco-inflammatory circuitry incombination with anti-KRAS and chemotherapies in GI and lung cancer (this will expand to breast cancer).Proteogenomic imaging and clinical response data will be collected for these models as part of a broader effortof characterizing PDX models and conducting clinical correlation and treatment response analyses by theBioinformatics Core (Aim 3). Proteogenomic features of PDX models and treatment/response histories will betracked using our well-established WU-PDXdb that will be accessible to PDXNet and PDMR-FNLCR. In Aim 4the WU-PDTC will leverage existing expertise and programs from Siteman Cancer Center (SCC) Institute ofClinical and Translational Research (ITCS) McDonnell Genome Institute (MGI) Mallinkrodt Imaging ResearchCenter (MIRC) and Early Therapeutic Clinical Trials Network (ETCTN) to support the goals of developing andutilizing PDX models to test and improve cancer treatment in collaboration with other components of PDXNet.Finally WU-PDTC through coordination by the Administration Core will support Pilot Projects utilizing thesePDX resources to foster collaboration across PDTCs PDMR-FNLCR and other NCI programs (Aim 5). Insummary the goals are to increase the spectrum of agents tested in PDX clinical trials and to improve thereliability validation utility and standardization of PDX models through innovative cross-PDXNet research. 1133597 +No NIH Category available Adjuvant;Adjuvant Chemotherapy;African American;African American population;American Indians;Asian population;Breast Cancer Patient;Breast Cancer Prevention;Breast Cancer therapy;Carboplatin;Caucasians;Cause of Death;Cisplatin;Clinical;Clinical Trials;Collection;Combination Drug Therapy;Combined Modality Therapy;Computing Methodologies;Coupled;Cytotoxic Chemotherapy;Data;Data Set;Disease;Disease Outcome;Distant;Dose;Epidermal Growth Factor Receptor;Ethnic Origin;Generations;Goals;Grant;Hand;Hispanic;Hispanic Populations;Human;Immune checkpoint inhibitor;In complete remission;Measurable;Metastatic/Recurrent;Modeling;Molecular Computations;Molecular Target;Monitoring for Recurrence;Neoadjuvant Therapy;Newly Diagnosed;Oncogenic;Operative Surgical Procedures;Organoids;Paclitaxel;Pathway interactions;Patient Selection;Patient-derived xenograft models of breast cancer;Patients;Platinum Compounds;Poly(ADP-ribose) Polymerase Inhibitor;Proteins;Publishing;Random Allocation;Recurrence;Recurrent Malignant Neoplasm;Refugees;Research Project Grants;Residual Neoplasm;Resistance;Salvage Therapy;Slice;Survival Rate;System;Testing;Time;Toxic effect;Woman;biomarker identification;cancer recurrence;chemotherapy;co-clinical trial;cohort;cytotoxic;docetaxel;drug candidate;drug response prediction;follow-up;hormone receptor-positive;improved;in vivo;malignant breast neoplasm;molecular targeted therapies;overexpression;patient derived xenograft model;pre-clinical;predicting response;predictive marker;predictive signature;prevent;prospective;racial population;responders and non-responders;response;response biomarker;screening;targeted agent;taxane;treatment response;triple-negative invasive breast carcinoma;tumor Research Project 1: Enhancing neoadjuvant therapy to prevent breast cancer recurrence n/a NCI 10732951 8/17/23 0:00 RFA-CA-22-012 2U54CA224076-05 2 U54 CA 224076 5 9/25/17 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7728 1972445 "LEWIS, MICHAEL T." Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 197856 156075 41839 RESEARCH PROJECT 1: Enhancing Neoadjuvant Therapy To Prevent Breast Cancer RecurrencePROJECT SUMMARYBased on our strong preliminary and published data our overarching hypothesis guiding the project is that agentsthat enhance response to neoadjuvant combination chemotherapy will decrease recurrence rates by reductionor elimination of minimal residual disease. These targeted agents may also function in combination with oneanother which may allow elimination of cytotoxic systemic chemotherapy. We further hypothesize that responsedata can be used to refine computational methods for drug response prediction.Aside from study of frank resistance to chemotherapies which is also possible using our combined PDX platformstudy of minimal residual disease as well as both local and distant recurrence is also important particularly inPDX derived from racial groups whose disease outcomes are worse than those in Caucasian women (i.e. AfricanAmerican and Hispanic women). Under our current PDTC we have already identified seven PDX as recurrentafter apparent complete response (CR) to combination carboplatin/docetaxel. We will apply a refined set ofcomputationally determined predictive signatures of differential response to carboplatin and taxanes (paclitaxelgoing forward to match an upcoming clinical trial) to the remainder of TNBC in our combined PDX collectionas well as to TNBC PDX to be created in both PDTC projects to identify PDX most likely to show completeresponse to the combination. Importantly response to either carboplatin or docetaxel correlates with response totheir combination 86% of the time. Existing and new PDX will be evaluated for CR and recurrence in responseto combination chemotherapy in Aim 1 with the ultimate goal of identifying a total of at least 20 but optimally30 recurrent PDX models for testing of the ability of targeted agents computationally predicted to augmentchemotherapy response in Aim 2 to reduce or prevent recurrence in Aim 3. +No NIH Category available Animals;Bioinformatics;Biostatistics Core;Breast Cancer therapy;Budgets;Collaborations;Complex;Computer software;Core Facility;Data;Data Analyses;Data Commons;Databases;Development;Experimental Designs;Funding;Goals;Human Resources;Institution;Malignant Neoplasms;Manuscripts;Medicine;Modeling;Molecular;Organoids;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Procedures;Recording of previous events;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Site;Standardization;Statistical Models;Work;Writing;college;cost effective;data repository;design;experimental analysis;novel strategies;operation;preclinical trial;response;success;tumor Bioinformatics Core n/a NCI 10732950 8/17/23 0:00 RFA-CA-22-012 2U54CA224076-05 2 U54 CA 224076 5 9/25/17 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7727 7387185 "MARTH, GABOR T" Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 197857 156075 41840 Project SummaryThe PDTC Bioinformatics Core is a key integration point of the PDTC and will provide the expertise to notonly interpret complex omics data that is already associated with each of our PDX and organoid models but alsothe expertise to identify molecular features of tumors that positively or negatively correlate with drug responses.The goals of the PDTC Bioinformatics Core are: 1. Provide a major point of integration between Research Projects since the Bioinformatics Core will be applying complementary analyses to data from both Research Projects for cross-comparison. 2. To provide statistical modeling for experimental design particularly with respect to animal preclinical trials and their analyses for both Research Projects and Pilot Projects in conjunction with the two existing institutional cores at HCI and BCM. 3. To import data from institutional core facilities (e.g. standard omics data/pipelines) and directly from Research Projects and the PDTC PDX Core (e.g. drug response data) as well as from public data repositories in order to perform analysis of omics and drug response data. 4. To maximize use of support from the two existing institutional cores at HCI and BCM in support of work with patient-derived models including software and database development. 5. To continue to develop novel approaches for experimental design and analytics that can be implemented at HCI and BCM and across the PDXNet. 6. To facilitate data organization and exchange between HCI and BCM and across the PDXNet via the PDX Data Commons and Coordinating Center. 7. To collaborate in research projects data analysis interpretation of results and the writing of final study reports and manuscripts. +No NIH Category available Animals;Bioinformatics;Breast;Breast Cancer therapy;Characteristics;Collaborations;Collection;Communities;Core Facility;Data;Data Analyses;Data Commons;Data Display;Development;Drug resistance;Goals;Grant;Growth and Development function;Human;Infrastructure;Institution;Joints;Logistics;Maintenance;Malignant Neoplasms;Medicine;Modeling;Modification;Molecular;Mus;Organ;Patients;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Population Heterogeneity;Procedures;Quality Control;Reproducibility;Research;Research Institute;Research Project Grants;Resources;Sampling;Site;Testing;Texas;Therapeutic;Tissue Sample;anticancer research;cancer prevention;cancer subtypes;college;cost effective;data exchange;ethnic diversity;in vivo Model;individual patient;malignant breast neoplasm;pathogen;patient derived xenograft model;preclinical trial;programs;racial diversity;refractory cancer;repository;response;standard of care;success;technology development;treatment response;tumor PDX Core n/a NCI 10732949 8/17/23 0:00 RFA-CA-22-012 2U54CA224076-05 2 U54 CA 224076 5 9/25/17 0:00 6/30/28 0:00 ZCA1-RTRB-U(M1) 7726 1972445 "LEWIS, MICHAEL T." Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 197857 156076 41840 PDX CORE PROJECT SUMMARYThe goals of the PDTC PDX Core are to establish and maintain PDX lines for the purpose of conducting animalpreclinical trials using experimental and standard-of-care therapeutics; to promote quality control reproducibilityand collaboration by developing and maintaining shared Standard Operating Procedures (SOPs) for PDXdevelopment maintenance experimentation and pathogen testing; to provide infrastructure to manage large PDXcollections and to generate store and manage PDX-based experimental data generated by the projects; tofacilitate exchange of PDX models between the PDXNet program; and to facilitate transfer of experimental datato the PDTC Bioinformatics Core and the PDTC PDXNet Data Commons and Coordinating Center to relatetreatment responses to the molecular characteristics of individual patients tumors. Our PDTC PDX Core currentcomprises 262 breast PDX lines available for projects within our PDTC Center and across the PDXNet program. +No NIH Category available 3-Dimensional;Accounting;Atlases;Behavior;Breast;Classification;Collaborations;Communication;Complement;Comprehensive Cancer Center;Data;Data Analyses;Ensure;Ethics;Evaluation;Expenditure;Extramural Activities;FAIR principles;Feedback;Funding;Human;Human Resources;Infrastructure;Institution;Leadership;Life;Longitudinal cohort;Malignant Neoplasms;Manuscripts;Modeling;Molecular;Monitor;Natural History;Noninfiltrating Intraductal Carcinoma;Office of Administrative Management;Parents;Patients;Policies;Preparation;Quality Control;Reporting;Reproducibility;Research;Research Personnel;Resource Development;Resources;Retrospective cohort;Teleconferences;Testing;Tissues;United States National Institutes of Health;Work;computerized data processing;conflict resolution;data integrity;data sharing;expectation;innovation;meetings;member;multimodality;novel;operation;premalignant;programs;skills;success;synergism;tumor Administrative Core n/a NCI 10732797 11/10/22 0:00 RFA-CA-17-035 3U2CCA233254-01S2 3 U2C CA 233254 1 S2 "GHOSH-JANJIGIAN, SHARMISTHA" 9/21/18 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-W] 7707 6985255 "HWANG, E.SHELLEY " Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/18 0:00 8/31/19 0:00 Other Research-Related 2023 160662 99790 60872 ABSTRACT Administrative Core The Administrative Core will support the general objectives of the Breast Pre-Cancer Atlas which are to 1) develop a findable accessible interoperable and reusable platform for organizing and sharing three- dimensional multi-modal breast pre-cancer data derived that facilitates the discovery of both the natural history of the pre-cancer and predictors of progression to life-threatening cancers and 2) populate that platform with data from both retrospective and longitudinal cohorts of patients with DCIS and demonstrate its use to construct an atlas to test novel predictors of progression. To do this the Administrative Core will facilitate administrative management of the Breast Pre-Cancer Atlas cultivate collaboration and communication within the Atlas as well as with other HTAN Pre-Cancer Centers ensure fiscal and regulatory compliance and provide consistent evaluation and monitoring to ensure effective progress of the program. The Specific Aims of this Core will be: 1) To provide organizational administrative and scientific leadership by having mPIs with complementing skill sets to provide credible examples of research success demonstrate respect and concern for all team members build team identity culture and coherence cultivate expectations of innovation and excellence leverage institutional as well as extramural resources provide constructive feedback and conflict resolution and model ethical behavior; 2) To provide administrative management by overseeing distribution of funds to and accounting for all expenditures in the Center including Research Units and provide clerical support. It will also coordinate with other PCA and HTA Research Centers to implement compliance with NIH policies oversee quality control and product release and ensure fiscal and regulatory compliance; 3) To promote integration within the Breast Pre- Cancer Atlas Center and across the Institutional PCA and HTA Research Centers by leveraging institutional support and working closely with the infrastructure of the affiliated NCI-designated Comprehensive Cancer Centers to ensure that resources and infrastructure are optimally utilized economies of scale are realized and overlaps eliminated. The Administrative Core also will help to plan and coordinate HTAN meetings and teleconferences; 4) To develop capabilities and oversee data operations by confirming data sharing and defining and developing best practices for data operations in collaboration with the Data Analysis Unit to ensure that reliable and valid data are generated managed and analyzed in a way that ensures data integrity and reproducibility of research findings; 5) To evaluate and report research progress and to ensure bidirectional exchange of research findings between the Breast Pre-Cancer Atlas Center and other PCA and HTAN Centers. +No NIH Category available 3-Dimensional;Address;Anxiety;Atlases;Bilateral;Biological Assay;Breast;Cells;Characteristics;Chemotherapy and/or radiation;Clinical;Clinical Trials;Communities;Confusion;Consensus;Data;Data Storage and Retrieval;Detection;Development;Diagnosis;Dimensions;Disease;Disease Management;Distress;Duct (organ) structure;Ecology;Elements;Evolution;FAIR principles;Future;Gene Expression;Histologic;Image;Inflammatory;Informatics;Intervention;Investigation;Life;Longitudinal Studies;Malignant Neoplasms;Mammography;Mastectomy;Measures;Methodology;Methylation;Modeling;Molecular;Morbidity - disease rate;Mutation;Natural History;Noninfiltrating Intraductal Carcinoma;Operative Surgical Procedures;Outcome;Pathologic;Pathway interactions;Patient Care;Patient observation;Patients;Phase;Premalignant Cell;Provider;Quality of life;Radiology Specialty;Research Personnel;Resources;Risk;Sampling;Solid Neoplasm;Sum;Testing;Tissues;Toxic effect;United States;Woman;Work;breast lumpectomy;calcification;cancer invasiveness;clinical diagnosis;cohort;data visualization;design;disease natural history;evidence base;experience;flexibility;improved;knowledge of results;malignant breast neoplasm;member;multimodal data;multimodality;next generation;novel;premalignant;prevent;progression risk;prospective;risk stratification;screening;statistics;tool;tumor Breast Pre-Cancer Atlas Center PROJECT NARRATIVE OverallOver 60000 women in the United States will be presented with a diagnosis of breast ductal carcinoma in situ(DCIS) each year with relatively weak evidence-based guidance for disease management which ranges fromactive surveillance to bilateral mastectomy. We propose to compile multi-dimensional and multi-scaleinformation on DCIS to construct a Pre-Cancer Atlas that can be used to better understand the disease butalso to better stratify risk of progression a useful translational endpoint. NCI 10732796 11/10/22 0:00 RFA-CA-17-035 3U2CCA233254-01S2 3 U2C CA 233254 1 S2 "MAZURCHUK, RICHARD V" 9/21/18 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-W(55)R] 6985255 "HWANG, E.SHELLEY " "MALEY, CARLO ; WEST, ROBERT B" 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/21/18 0:00 8/31/24 0:00 353 Other Research-Related 2023 160662 NCI 99790 60872 ABSTRACT OverallDevelopment of invasive breast cancer may frequently progress through a preinvasive precursor called ductalcarcinoma in situ (DCIS). DCIS is an extremely common clinical diagnosis that is essentially a disease ofscreening triggered by the detection of abnormal breast calcifications on mammography. Before the advent ofmammography DCIS was an incidental and relatively uncommon finding. Over 60000 women in the UnitedStates will be presented with this diagnosis each year with relatively weak evidence-based guidance fordisease management which ranges from active surveillance to bilateral mastectomy. We propose to compilemulti-dimensional and multi-scale information on DCIS to construct a Pre-Cancer Atlas that can be used tobetter understand the disease but also to better stratify risk of progression a useful translational endpoint. Todo this we have assembled a team of investigators with deep and complementary clinical experimental andquantitative expertise and experience with DCIS and breast cancer in general. Further we conduct thesestudies with full consideration of tumor evolution and ecology as it pertains to precancer development andprogression. Specific aspects of the proposed Atlas construction include: 1) Several types of DCIS cohorts thatwill capture spatial and longitudinal information including a prospective clinical trial cohort undergoing activesurveillance 2) Analyses designed to maintain relevant spatial organization of the disease for evolutionary andAtlas building considerations based on 3) Radiologic-histologic-cellular-molecular registration approaches 4)Characterization at multiple scales including whole tumor single duct and single cell levels 5) Characterizationof relevant parameters including mutations copy number changes methylation gene expression andmicroenvironmental elements including inflammatory cell profiles. 6) Incorporation of the breast cancer intrinsicsubtype paradigm into the analytic phase and 7) Layered spatial and longitudinal data visualization. Overallthis work will provide a comprehensive platform to guide the next generation of studies on DCIS and otherprecancers. 160662 +No NIH Category available Adoptive Transfer;Adult;Adverse effects;American;Antigen Targeting;Antigens;Biological;Brain Neoplasms;CAR T cell therapy;CBLB gene;CD276 gene;CD28 gene;CRISPR screen;CRISPR/Cas technology;Cell Cycle;Cell surface;Cells;Cellular immunotherapy;Chemotherapy and/or radiation;Childhood;Childhood Brain Neoplasm;Clinical;Clinical Research;Core Facility;Disease;Down-Regulation;Engineering;Generations;Genes;Genetic;Glioma;Goals;Hematologic Neoplasms;Heterogeneity;Homing;IL3RA gene;Image;Immune;Immune response;Immunocompetent;Immunology;Immunotherapy;Impaired cognition;Impairment;In Vitro;Inflammatory;Intervention;Life;Macrophage;Mediating;Mediator;Memory;Modeling;Modification;Molecular;Mus;Mutate;Operative Surgical Procedures;Outcome;Patients;Penetration;Performance;Persons;Phase;Phenotype;Play;Positioning Attribute;Pre-Clinical Model;Primary Brain Neoplasms;Proliferating;Receptor Signaling;Research;Research Personnel;Resistance;Role;Safety;Saint Jude Children's Research Hospital;Shapes;Subgroup;T-Cell Activation;T-Cell Homing Receptors;T-Cell Receptor;T-Lymphocyte;TCR Activation;Techniques;Testing;Training;Transmembrane Domain;Tumor Antigens;Tumor-associated macrophages;Xenograft Model;antigen-specific T cells;antitumor effect;career;chimeric antigen receptor;chimeric antigen receptor T cells;cytokine;cytotoxicity;design;engineered T cells;exhaustion;extracellular;genome wide screen;human disease;immune cell infiltrate;improved;improved outcome;in vitro activity;in vivo;innovative technologies;interest;motor impairment;mouse model;neoplastic cell;novel;prototype;receptor;research clinical testing;success;targeted treatment;tool;trafficking;transcriptomics;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions Improving CAR T cell therapy for brain tumors using immune competent models PROJECT NARRATIVEAccording to the American Brain Tumor Association over 16000 people are estimated to die from brain tumorsthis year while the currently available therapies cause motor and cognitive impairments and only extend life by2 years. CAR T cell immunotherapy has the potential to improve outcomes in adult and pediatric brain tumorpatients; however optimized CAR design must be evaluated in models that closely mimic human disease andbarriers for therapy. In this study I propose using immune competent brain tumor models to enhance CAR T cellefficacy for brain tumors by optimizing CAR costimulatory domains silencing negative T cell regulators andtargeting suppressive effectors of the brain tumor microenvironment including tumor associated macrophages. NCI 10732795 12/23/22 0:00 RFA-CA-20-014 4R00CA256262-03 4 R00 CA 256262 3 "HU, ZHANG-ZHI" 1/1/21 0:00 12/31/25 0:00 ZCA1-RTRB-U(O1) 12419173 "HAYDAR, DALIA " Not Applicable 98 Unavailable 143983562 M3KHEEYRM1S6 143983562 M3KHEEYRM1S6 US 38.927274 -77.014396 1518602 CHILDREN'S RESEARCH INSTITUTE WASHINGTON DC Research Institutes 200102916 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 395 Non-SBIR/STTR 2023 249001 NCI 141319 107682 PROJECT SUMMARY/ABSTRACTThe overall objective of this study is to engineer a potent CAR T cell therapy for high grade glioma (HGG)a subgroup of brain tumors for which outcomes remain poor. CAR T cell therapy is an innovative technologybased on adoptive transfer of antigen-specific T cells engineered to elicit a clinically effective and specificimmune response against tumor cells. Early clinical studies in HGG patients demonstrated safety of CAR T celltherapy for brain tumors; yet only limited benefits were observed. Lack of efficacy is most likely multifactorialand include heterogenous antigen expression limited homing to and penetration of tumors T cell exhaustionand limited persistence as well as the immunosuppressive tumor microenvironment (TME). Therefore thecentral hypothesis of this proposal is that optimized design and additional genetic modifications of CART cells will improve their antitumor effects and that these interventions will be evaluated in immunecompetent mouse models that closely mimic human disease. Three interrelated research aims are proposedto test this hypothesis and the rationale of each is outlined below. First CAR design has to be optimized andevaluated in immune competent glioma models. In Aim 1 I will generate CAR T cells containing different co-stimulatory domains (CD28. 41BB. CD28.mut and 41BB.mut) and compare their activity in vitro and invivo. Second a genome wide screen in primary T cells has identified key regulators of T cell activation post T-cell receptor (TCR) stimulation. Identified genes belong to molecules that regulate cell cycle proliferation anddownstream TCR signaling including SOCS1 RASA2 or CBLB. In Aim 2 I will therefore explore if CRISPR-Cas9 mediated silencing of Socs1 Rasa2 and/or Cblb enhances the effector functions of CAR T cells. Theindependent Aim 3 will then explore a dual CAR targeting approach in which I will not only target glioma cellsbut also immunosuppressive cells within the glioma microenvironment. These studies are focused on tumorassociated macrophages (TAMs) since they are abundantly present in gliomas and play a critical role in shapingthe TME. To support the feasibility of this project I have adapted the well-established immune competent GL261glioma model to study CAR T cell therapies targeting the relevant tumor antigen B7-H3 which is not onlyexpressed by GL261 cells but also in a broad range of pediatric and adult brain tumors. In addition mypreliminary studies indicate that `prototype' B7- H3 CAR T-cells readily recognize and kill GL261 cells in vitroand have antitumor activity in vivo highlighting that the developed model is well suited for the proposed aims ofthis project. State of the art technique will be used in all three Aims to not only study the function and in vivo fateof CAR T-cells but also their antitumor activity and how CAR T-cells interact with glioma- infiltrating immunecells. Completion of this study will define the most optimal CAR design that best controls HGG tumors andpersists longer in the context of inflammatory brain tumors. Additionally results will illustrate if targeting TAMswill overcome the suppressive effects of TME on B7-H3 CAR T cells. 249001 +No NIH Category available Address;Adhesions;Antibody-drug conjugates;Antigen Presentation;CD4 Positive T Lymphocytes;Cells;Clinical;Cues;Data;Disease;Drug Delivery Systems;Embryo;Epithelial Cells;Exclusion;Extracellular Matrix;Fibroblasts;Fibrosis;Genes;Immune Evasion;Immunosuppression;Immunotherapy;Impairment;In Vitro;Inflammatory;Interleukin-1;Invaded;Malignant Neoplasms;Membrane;Mesenchymal;Mesoderm;Mesothelial Cell;Mesothelium;Monoclonal Antibodies;Myocardial Infarction;Operative Surgical Procedures;Organ;Outcome;Pancreatic Ductal Adenocarcinoma;Pathologic;Peripheral;Peritoneal;Phase;Phenotype;Physiological;Population;Preclinical Testing;Process;Reporting;Resistance;Signal Pathway;Solid Neoplasm;Source;Surface;Survival Rate;System;T cell infiltration;T cell regulation;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Training;Transforming Growth Factor beta;Tumor Volume;Vaccines;anti-cancer;cancer cell;chemotherapy;chimeric antigen receptor T cells;combat;immune checkpoint blockade;immune resistance;in vivo Model;lipid biosynthesis;mesothelin;mouse genetics;neglect;novel;novel strategies;prevent;single-cell RNA sequencing;targeted cancer therapy;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;wound healing Function of mesothelial cells in the tumor microenvironment of pancreatic ductal adenocarcinoma Project NarrativePancreatic ductal adenocarcinoma (PDA) is characterized by extensive desmoplasia caused by differentcancer-associated fibroblast (CAF) populations. As a major source of fibroblasts in other pathologicalconditions such as wound healing peritoneal fibrosis and surgical adhesions mesothelial cells have beenhistorically neglected as a potential functional constituent of the PDA microenvironment. This project aims toinvestigate the contribution of mesothelial cells to CAF formation and the function of mesothelial-fibroblastictransition in PDA which will elucidate a novel mesothelial cell-CAF system and has the potential to result in theidentification of novel strategies to target CAFs in PDA. NCI 10732793 12/1/22 0:00 PA-20-188 4R00CA252009-03 4 R00 CA 252009 3 "LIU, YIN" 12/1/22 0:00 11/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 15233515 "HUANG, HUOCONG " Not Applicable 30 SURGERY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 398 Non-SBIR/STTR 2023 249000 NCI 151829 97171 Project Summary/AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by extensive desmoplasia causedby the rapid expansion of cancer-associated fibroblasts (CAFs) resulting in the formation of dense stroma.CAFs stimulate cancer progression by secreting a variety of factors that support cancer cells and facilitateimmunosuppression. In addition they also secrete extracellular matrix (ECM) that provides survival andinvasion cues to cancer cells and impairs drug delivery. Recently several populations of CAFs with distinctfunctions have been characterized in PDA by our group and others using single cell RNA sequencing (scRNAseq). One population is characterized as myofibroblastic CAFs (myCAFs) another population is characterizedas inflammatory CAFs (iCAFs) the third population was first identified as antigen-presenting CAFs (apCAFs)which express MHC II molecules and can effectively present antigen to T cells. My preliminary datademonstrated that apCAFs are mesothelial cells. Mesothelial cells form a continuous layer of epithelial cellsknown as mesothelium. The mesothelium is traditionally thought to be a membrane providing a non-adhesivesurface covering organs and tissues. However until the description of apCAF population mesothelial cellshave been neglected as a potential functional constituent of the tumor microenvironment. My preliminary datasuggest that during PDA progression mesothelial cells go through a mesothelial-fibroblastic transition (MFT)in which they down-regulate MHC II molecules that are required for CD4+ T cells activation and up-regulatefibroblast genes that have been known to prevent T cell infiltration and activation. Peripheral T cell exclusion isa major immune evasion phenotype in PDA and my preliminary data show that this exclusion occurs at theregion where mesothelial cells are transitioning to CAFs. Therefore MFT might be an important mechanism ofimmune evasion and understanding this process is critical. In this proposal I will test the hypothesis that thefibroblastic transition of mesothelial cells promotes immune evasion in PDA and identify potentialstrategies to inhibit this process. I propose the following two aims: Aim 1. Determine the fate of mesothelialcells during PDA progression. Aim 2. Determine the functions of MFT on immune evasion. The outcomeof the proposed study has the potential to shift the paradigm of tumor microenvironment studies identify novelstrategies to target CAFs and overcome resistance of immune therapies in PDA and other tumor types. 249000 +No NIH Category available Ablation;Antineoplastic Agents;Automobile Driving;Binding;Biochemical;Biological Assay;CRISPR/Cas technology;Cell Fractionation;Clinical;Cultured Cells;Data;Data Set;Dependence;Disease;Drug Targeting;Enhancers;Future;Genes;Genetic;Genetically Engineered Mouse;Genotype;Goals;Grant;Homeostasis;Human;Immunotherapy;K-ras mouse model;KRAS oncogenesis;KRAS2 gene;Label;Libraries;Lipids;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator;Membrane;Mining;Mutate;Mutation;Nature;Oncogenes;Oncogenic;Oncoproteins;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pancreas;Pathway interactions;Pentosephosphate Pathway;Pharmaceutical Preparations;Phase;Phosphatidylinositol Phosphates;Phosphatidylinositols;Phosphotransferases;Prevalence;Process;Protein Isoforms;Proteins;RAS driven cancer;RAS genes;RAS inhibition;Ras Inhibitor;Research;Research Personnel;Role;Signal Transduction;Signaling Protein;Stress;Systems Biology;Techniques;Testing;Therapeutic;Training;Validation;Xenograft procedure;cancer cell;cell growth;cell transformation;experimental study;inhibitor;inorganic phosphate;mouse model;mutant;new therapeutic target;novel;novel therapeutics;pancreatic cancer model;pharmacologic;phosphoproteomics;ras Oncogene;ras Proteins;response;small molecule inhibitor;therapeutic target;tumor growth;tumor xenograft;tumorigenesis;tumorigenic Interrogating the RAS interactome for therapeutic vulnerabilities Project Narrative The RAS genes are mutated in a third of human cancers in the USA including in some of the most intractable cancers like pancreatic. Despite this prominence the encoded oncoproteins are extremely difficult to pharmacologically target. I therefore propose to identify the proteins RAS oncoproteins interact with to drive tumorigenesis as a way to unveil potential new drug targets to treat a huge proportion of human cancers. NCI 10732791 12/13/22 0:00 PA-19-130 4R00CA248495-03 4 R00 CA 248495 3 "XU, WANPING" 3/10/20 0:00 12/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 14158826 "ADHIKARI, HEMA " Not Applicable 1 BIOCHEMISTRY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2023 248224 NCI 158610 89614 PROJECT SUMMARY AND ABSTRACT The RAS genes KRAS NRAS or HRAS are commonly mutated in human cancers. Clinically inhibiting RAS has proven challenging and RAS-mutant cancers remain some of the most intractable diseases even to immunotherapies. It is thus critical to elucidate oncogenic RAS signaling not only to better understand the tumorigenic process but also to identify new potential therapeutic targets. To this end I exploited the novel technique of BirA-mediated proximity labeling to identify proteins within the immediate vicinity (interactome) of each RAS isoform. I then screened an sgRNA library targeting interactome components for genes promoting RAS transformed cell growth identifying the druggable phosphatidylinositol phosphate lipid kinase PIP5K1A as specifically driving KRAS oncogenesis. PIP5K1A represents an entirely new therapeutic target in KRAS-mutant cancers and suggests that other proteins in the RAS interactome may similarly mediate RAS oncogenesis. I will capitalized on these discoveries in three aims. As PIP5K1A is a druggable kinase it provides a way to specifically inhibit KRAS oncogenesis which could be exploited to enhance the antineoplastic activity of drugs targeting RAS effector pathways. Thus in aim 1 I will elucidate the role and therapeutic potential of targeting PIP5K1A in KRAS-mutant cancers. The identification of PIP5K1A promoting KRAS oncogenesis suggests that other interactome proteins may similarly mediate RAS function. Thus in aim 2 I will mine the RAS interactome for novel modifiers of RAS oncogenesis focusing on the interactome protein EFR3A as a potential general mediator of oncogenic RAS-driven tumorigenesis. Finally the RAS interactome is most certainly dynamic varying under different conditions. Determining the content of the RAS interactome under distinct settings may thus identify new vulnerabilities specific to diverse cellular conditions. Thus in aim 3 I will probe the RAS interactome in response to cellular perturbations. In sum I will expand upon my discovery that PIP5K1A promotes KRAS oncogenesis to explore this kinase as a new therapeutic target and identify other novel therapeutic vulnerabilities that exists within the RAS interactome. The K99 segment of this grant will complete my training in RAS signal transduction extend my training into phosphoproteomics xenograft and genetically engineered mouse models of tumorigenesis. The R00 segment will capitalize on the use of proximity labeling to study the dynamic nature of oncogenic RAS signaling. My long-term goal is to transition into an independent investigator and apply systems biology approaches to uncover the signaling circuitry of oncogene drivers with the objective of identifying novel therapeutic vulnerabilities in RAS-mutant cancers. 248224 +No NIH Category available 3-Dimensional;Apoptosis;Architecture;Atomic Force Microscopy;Biomimetics;Breast Cancer Cell;Breathing;Cancer Biology;Cancer Cell Growth;Cell Death;Cell model;Cell secretion;Cells;Cessation of life;Clinical;Communication;Complex;Coupled;Desmoplastic;Development;Disease;Doctor of Philosophy;Educational process of instructing;Endocrine;Engineering;Epithelium;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Flow Cytometry;Foundations;Glycoproteins;Goals;Growth;Lead;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mechanics;Mentors;Mesenchymal;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Methods;Modeling;Morbidity - disease rate;Neoplasm Metastasis;Nonmetastatic;Output;Pathway interactions;Patients;Periodicity;Phenotype;Positioning Attribute;Postdoctoral Fellow;Primary Neoplasm;Production;Proliferating;Proteins;Proteomics;Research;Research Personnel;Role;Signal Transduction;Site;Stretching;Stromal Cells;Structure of parenchyma of lung;Survival Rate;Testing;Tissue Engineering;Tissues;Training;Tumor Cell Migration;Universities;Vesicle;Western Blotting;Woman;Work;cancer cell;cancer diagnosis;cancer subtypes;cell type;conditioning;defined contribution;effective therapy;experimental study;extracellular;extracellular vesicles;improved;in vivo;insight;interest;lung volume;malignant breast neoplasm;mechanical force;mechanical load;mechanical properties;mechanotransduction;metabolic rate;migration;mortality;neoplastic;neoplastic cell;novel;paracrine;phenotypic biomarker;prevent;single-cell RNA sequencing;skills;targeted treatment;therapy development;three dimensional cell culture;three-dimensional modeling;transmission process;tumor microenvironment Matrix Accumulation in the Metastatic Niche Project NarrativeAfter metastasis to the lungs breast cancer cells are exposed to unique forces and matrix proteins that are notpresent at the primary tumor. My previous findings indicate that cyclic stretching mimicking breathing dynamicswithin a 3D model of the early metastatic niche can drive tumor cells into a state of growth arrest withoutwidespread cell death. Because stromal cells are the key contributor of matrix composition and architecture mygoal is to evaluate the unique fibroblast subtypes conditioned by breast cancer cells at different stages of themetastatic cascade and characterize how the tissue changes they produce alter the metastatic progression ofdisseminated breast cancer cells. NCI 10732790 12/1/22 0:00 RFA-CA-20-048 4K00CA264734-03 4 K00 CA 264734 3 "ELJANNE, MARIAM" 9/1/21 0:00 11/30/26 0:00 ZCA1-SRB-H(M1) 15315991 "LIBRING, SARAH " Not Applicable 5 BIOMEDICAL ENGINEERING 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN BIOMED ENGR/COL ENGR/ENGR STA 372032408 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 398 Other Research-Related 2023 85860 NCI 79500 6360 Project SummaryBreast cancer (BC) is the most frequently diagnosed cancer in women. In addition metastatic BC has a 5-yearsurvival rate of only 27% and metastases are associated with the vast majority of cancer-related deaths. Recentresearch has highlighted a complex dynamic between cancer cells and the tumor microenvironment as essentialfor the formation of macrometastases. Within this field tissue stiffening through matrix accumulation and alteredmatrix organization were recently linked with sustained proliferation and increased migration of tumor cells.Elevated levels of the glycoprotein fibronectin (FN) have been correlated to poor patient survival in BC and arelinked to enhanced seeding of disseminated tumor cells at metastatic sites. My previous work has indicatedseveral mechanisms through which accumulated FN impacts the metastatic potential of BC cells. Foremost Ihelped identify a transient increase in extracellular FN in the lungs which peaked before overt metastasiscoupled with a non-transient increase in total lung volume. I further found that cyclic mechanical force acted asa suppressor of cancer cell growth in a biomimetic lung model implicating the accumulation of extracellularmatrix (ECM) as an attempt by the cancer cells to alter the mechanical properties of the lung tissue and resistentering dormancy. However my results showed that BC cells could not organize FN into ECM independently.Instead BC cells altered the accumulation and architecture of FN by conditioning resident fibroblasts throughsoluble factors and extracellular vesicles. I observed that the FN produced by conditioned fibroblasts varied notonly based on the phenotype of the BC cell but also from the method of conditioning which tested paracrine andendocrine signaling. These preliminary results indicate that unique subtypes of cancer associated fibroblasts(CAFs) may develop based on the BC cell conditioning mechanism where unique subtypes may be associatedwith the specific needs of the various stages of the metastatic cascade. Therefore Aim 1 of the proposed studiesduring my Ph.D. research will define the contribution of cyclic strain on BC cell phenotype and dormancy usingour novel actuating platform. Aim 2 which I will undertake during my postdoctoral research will seek to betterdefine the varied roles of CAFs in metastatic progression through the development of a foundation of subtypesafter conditioning with media isolated extracellular vesicles and contact from BC cancer cells includingmetastatic and non-metastatic BC cells with epithelial and mesenchymal phenotypes. These findings will enableadvanced interaction studies and promote the development of novel targets for fibroblasts which may be a moreconsistent target than genetically unstable cancer cells and lead to more effective treatment. In addition theproposed studies and training plan will expand my current tissue engineering skillset to include advancedunderstanding of mechanotransduction pathways and CAF formation as well as improve my communicationmentoring and teaching. Together these skills will place me as a competitive candidate for an independentprinciple investigator position in a research university at the intersection of cancer biology and engineering. 85860 +No NIH Category available Accounting;American;Antibodies;Antigens;Autoantibodies;Autoantigens;Biological Assay;Breast;Cancer Center;Cancer Etiology;Cancer Patient;Central Nervous System;Cessation of life;Clinic;Clinical;Colon Carcinoma;Complex;Data Set;Detection;Development;Diagnosis;Diagnostic;Disease;Early Diagnosis;Extensive Stage;Generations;Goals;Human;Hybrids;Image;Length;Lesion;Limited Stage;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Methodology;Minority;Modality;Modeling;Molecular;Nodule;Non-Small-Cell Lung Carcinoma;Outcome;Ovarian;Pancreas;Paraneoplastic Syndromes;Patients;Plasma;Prevention;Process;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Proteins;Proteomics;Reproducibility;Sampling;Screening for cancer;Specimen;Survival Rate;Testing;Time;Translating;Validation;Variant;Women's Health;X-Ray Computed Tomography;biomarker panel;candidate marker;cardiovascular health;case control;chemotherapy;clinical diagnosis;clinical practice;cohort;computed tomography screening;detection method;detection platform;early detection biomarkers;high dimensionality;implementation strategy;improved;lung cancer screening;novel;screening;small cell lung carcinoma;statistics;tumor Tumor-specific autoantibodies for SCLC early detection PROJECT NARRATIVESmall cell lung cancer (SCLC) accounts for >30000 American lives each year and portends five-year survivalrates of just ~7%. Detection of SCLC at early stage drastically improves these survival metrics. We propose toleverage molecular features unique to SCLC such as the development of autoantibody-antigen complexes tovalidate a plasma biomarker panel capable of SCLC early detection to allow for early initiation of potentiallycurative chemotherapy. NCI 10732773 11/15/23 0:00 PA-19-056 5R01CA243328-06 5 R01 CA 243328 6 "MARQUEZ, GUILLERMO" 12/17/19 0:00 11/30/24 0:00 Cancer Biomarkers Study Section[CBSS] 6786529 "HOUGHTON, A MCGARRY" "LAMPE, PAUL D." 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2024 384742 NCI 224599 160143 ABSTRACT/SUMMARYSmall cell lung cancer (SCLC) is one of the few malignancies with such poor outcomes that it meets the definitionof a recalcitrant cancer accounting for 30000 American lives each year with five-year survival rates of just~7%. Somewhat lost in these dismal statistics is the fact that patients diagnosed early (limited stage) displayvastly superior survival metrics when compared to those diagnosed late (extensive stage). Unfortunately only aminority of cases are identified at limited stage and the computed tomography (CT) screening approachescapable of early detection for non-small cell lung cancer (NSCLC) have not proven effective for SCLC. We willemploy a novel two-mode array based hybrid plasma marker methodology capable of detecting autoantibody-autoantigen complex and unbound autoantibody markers for SCLC early detection. One of the major problemswith studying SCLC is there are few studies and cohorts that have appropriate plasma samples. We haveaccumulated robust biomarker candidates centered around autoantibody-antigen complexes using theCardiovascular Health Study (prediagnostic) Fred Hutch Lung Cancer Early Detection and Prevention Clinicand Vanderbilt SCLC sample sets and will comprehensively define free autoantibodies levels in these samecohorts. We propose to test a fixed combination rule combining both autoantibody approaches using all of theprediagnostic SCLC samples from the Women's Health Initiative (WHI) the Prostate Lung Colorectal OvarianCancer Screening Trial (PLCO) and the National Lung Screening Trial (NLST) cohorts and diagnostic samplesfrom Moffitt Cancer Center. Using prediagnostic samples allows us to effectively model early detection muchmore accurately than after diagnosis occurs and this is particularly important for SCLC as diagnosis at theextensive stage is nearly almost always fatal. Part of our analysis will determine how early our autoantibodymarker panel can predict the presence of SCLC and whether a tumor can be observed via CT at that time inorder to evaluate the timing and implementation of our early-detection procedure. 384742 +No NIH Category available Acceleration;Address;Antineoplastic Agents;Bioinformatics;Biological;Biological Models;Cancer Biology;Cancer Model;Cancer Patient;Cancer Therapy Evaluation Program;Clinical;Clinical Trials;Cloud Computing;Collaborations;Collection;Communication;Communities;Complement;Coordination and Collaboration;Data;Data Analyses;Data Collection;Data Commons;Data Set;Data Storage and Retrieval;Databases;Development;Drug resistance;Engineering;Environment;Feedback;Generations;Genetic;Genomics;Goals;Grant;Human Resources;Image;Incentives;Information Resources;Institution;Journals;Leadership;Letters;Malignant Neoplasms;Metadata;Methods;Modeling;Molecular;National Cancer Institute;Nature;Outcome;Patients;Performance;Pharmaceutical Preparations;Phase;Precision therapeutics;Process;Publications;Publishing;Recording of previous events;Research;Resources;Review Committee;Science;Scientist;Services;Software Engineering;Specimen;Speed;Standardization;The Jackson Laboratory;Therapeutic;Translations;United States National Institutes of Health;Validation;Vision;Work;Xenograft procedure;anticancer research;cancer clinical trial;cancer genomics;cancer therapy;cancer type;candidate identification;candidate marker;clinical predictors;cloud based;computer infrastructure;data modeling;data resource;data sharing;data standards;data submission;database of Genotypes and Phenotypes;diverse data;efficacy evaluation;experience;flexibility;fundamental research;genomics cloud;improved;innovation;insight;large datasets;multiple omics;network models;patient derived xenograft model;pre-clinical;precision oncology;preclinical study;repository;research clinical testing;response;success;tool;treatment comparison;treatment response PDXNet Data Commons and Coordinating Center PROJECT NARRATIVETo realize the full promise of patient-derived xenografts (PDXs) to advance precision therapies for cancerstandardized PDX procedures and coordinated sharing of PDX specimens are needed to validate results acrossresearch groups and determine which results may be robust for cancer patients. To address these needs ourPDX Data Commons and Coordination Center unifies the activities of NIH-supported PDX Development andTrial Centers and the National Cancer Institute's Patient-Derived Models Repository. Our Data Commons andCoordination Center uses innovative administrative cloud computing and bioinformatic approaches to enablePDX method standardization model sharing data sharing and massive-scale data analysis to acceleratetranslation of PDX studies into cancer clinical trials. NCI 10732421 7/24/23 0:00 RFA-CA-22-013 2U24CA224067-05 2 U24 CA 224067 5 "HENDERSON, LORI A" 9/25/17 0:00 8/31/28 0:00 ZCA1-RTRB-U(M1) 8556573 "CHUANG, JEFFREY HSU-MIN" "DEAN, DENNIS A" 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Other Research-Related 2023 930436 NCI 592331 338105 PROJECT SUMMARYPatient-derived xenografts (PDXs) are a powerful model system to assess efficacy of anti-cancer agents andunderstand molecular mechanisms of drug resistance. By applying agent combinations against patient-derivedmodels it is possible to obtain evidence to determine the most promising combinations for advancement toclinical testing in defined sub-populations of cancer patients. However integration of PDX drug response withmolecular characterization data across diverse PDX collections is needed to enable this vision. A key aspect isthe need for well-managed resources for community sharing and large-scale analysis of standardized datasetsfrom PDXs and other patient-derived models. The Jackson Laboratory-Seven Bridges (JAX-SB) PDX DataCommons and Coordination Center (PDCCC) has addressed this challenge for the last 5 years uniting theefforts of the data-generating (PDX Development and Trial Centers/PDTCs) and PDX model sharing (NCIsPatient-Derived Model Repository/PDMR) components of the PDX Development and Trials Centers ResearchNetwork (PDXNet) into a cohesive trans-Network whole. Using innovative cloud computing and bioinformaticapproaches our PDCCC provides administrative and computational infrastructure for PDXNet to enable PDXmethod standardization model sharing data sharing and massive-scale data analysis. To date we have builtthe PDXNet Portal which currently contains PDXNet model information and data resources from 334 newmodels across 33 cancer types. Our PDCCC team has both facilitated and actively guided consortiumcollaborative projects leading to several major publications and 10 Cancer Therapy Evaluation Program Lettersof Intent. Here we propose to enhance the PDXNet Portal and refine our organizational activities to addressneeds clarified by the NCI and PDX communities including: faster translation of PDX studies to clinical trials;precise organization and sharing of multi-omic and treatment response data; and development of predictors ofclinical treatment response. Our Specific Aims are: 1) To provide robust PDCCC support for PDXNetstakeholders through regular committees personnel expertise and project tools; 2) To enhance PDXNet Portalcontent functionality and data sharing; and 3) To develop and implement strategies that accelerate PDXtranslation to clinical trials. Through these Aims we will coordinate the activities of the PDXNet to increase thevalue of patient-derived cancer model treatment studies and speed the generation of clinical trials. 930436 +No NIH Category available Address;Adjuvant;Adjuvant Therapy;Adult;Adverse event;Affect;Apoptosis;Biological;Biological Markers;Biopsy;Brain;Brain Neoplasms;Cancer Patient;Cell Death;Cell Proliferation;Cells;Chemotherapy and/or radiation;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Combined Modality Therapy;DNA Damage;Data;Data Set;Development;Devices;Diffuse;Disease;Dose;Drug Catalogs;Drug Combinations;Drug Delivery Systems;Drug Exposure;Excision;Exposure to;Future;Genetic;Glioblastoma;Glioma;Goals;Head;Histologic;Immune;Immunologic Markers;Implant;In Situ;Intraoperative Complications;Knowledge;Length;MGMT gene;Malignant - descriptor;Malignant neoplasm of brain;Mass Spectrum Analysis;Measurable;Measurement;Measures;Metabolic;Methylation;Modeling;Molecular;Needle biopsy procedure;Newly Diagnosed;Oncogenic;Operative Surgical Procedures;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phenotype;Physiological;Pilot Projects;Predictive Value;Procedures;Process;Prognosis;Progression-Free Survivals;Proteomics;Regimen;Resected;Resistance;Retrieval;Safety;Schedule;Selection for Treatments;Severities;Signal Pathway;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stromal Cells;System;Techniques;Technology;Testing;Tissues;Treatment Protocols;Tumor Markers;Work;biomarker identification;brain tumor resection;cancer type;chemotherapy;clinical decision-making;cohort;comparative;drug efficacy;drug response prediction;drug sensitivity;early detection biomarkers;effective therapy;functional status;implantation;improved;improved outcome;in vivo;individual patient;interest;metabolomics;microdevice;miniaturize;minimally invasive;multiple omics;novel therapeutics;optimal treatments;patient response;precision drugs;precision medicine;predicting response;predictive marker;promoter;response;response biomarker;safety and feasibility;specific biomarkers;standard of care;survival outcome;systemic toxicity;temozolomide;tissue biomarkers;tool;tool development;transcriptome;transcriptomics;treatment response;treatment strategy;tumor;tumor microenvironment Using implantable microdevices for deep phenotyping of multiple drug responses in brain tumor patients Narrative:This project utilizes an implantable microdevice to measure multiple drug responses directly withinthe native tumor of glioblastoma cancer patients. We will determine whether these localmicrodose drug responses are predictive of systemic drug sensitivity for these patients and willidentify biomarkers of drug response that may be used to guide more effective therapy for patientsin the future. NCI 10732396 7/20/23 0:00 PAR-22-243 1R01CA283905-01 1 R01 CA 283905 1 "SORG, BRIAN S" 8/1/23 0:00 7/31/28 0:00 "Bioengineering, Technology and Surgical Sciences Study Section[BTSS]" 12560800 "JONAS, OLIVER " "PERUZZI, PIER PAOLO " 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 746821 NCI 428392 318429 Gliomas are a particularly aggressive type of brain cancer with poor prognosis that affect about 20000 newly diagnosedpatients in the US annually. There is high interest in identifying predictive biomarkers of response to establishedtreatments such as Temozolomide and to identify response and resistance biomarkers for new single and combinationstreatments for gliomas as there is evidence that an effective adjuvant treatment strategy can improve survivaloutcomes for patients. Few tools exist currently to identify such biomarkers and prioritize which agent(s) to administerto individual patients in order to maximize the impact of drug treatment.We will conduct a clinical study in which we measure the tumor responses to 20 distinct therapies across a cohort of32 patients. Using only intrasurgical procedures implantable microdevices (IMD) are placed into tumors placed intotumors during already scheduled tumor resections remain in the patient for the duration of surgery and are extractedalong with the resected tumor specimen. IMDs enable readouts for each treatment that include immunohistochemicaltranscriptomic immune and tissue biomarkers thereby effectively performing 20 biomarker trials at minute drugexposure levels in each patient with three-fold replicates.Several key advances will be achieved in this project. First safety feasibility and clinical integration of the technicalworkflow will be demonstrated in a statistically significant manner. This is key towards establishing broader clinical usefor this technology in the intrasurgical setting. Secondly we will examine in a retrospective analysis whether the IMDreadout at Temozolomide (TMZ) reservoirs can serve as a predictive marker for standard systemic TMZ treatmentresponse and progression-free survival at 6 months for each patient. This would constitute a major advance for gliomapatients as TMZ is the most frequently administered adjuvant treatment in this disease and the MGMT promotermethylation status is only a limited predictor of TMZ efficacy for a subset of glioma patients. Third we will usemultiplexed state-of-the-art deep tissue phenotyping to characterize the biological response of each patients tumorexposed to each of 20 drugs on the microdevice. This will result in a comprehensive catalogue of drug phenotypes for20 distinct therapies in GBM patients and we will use this data to systematically identify resistance pathways toavailable therapies. In addition by examining the tumor for genetic and physiologic changes we can in vivo correlateexisting omic biomarkers of tumor response to multiple drugs. This addresses a major knowledge gap in the field assuch a dataset is not feasible to obtain with traditional systemic clinical trials. The drug phenotyping includes spatialtranscriptomics and metabolomics to identify specific biomarkers in the tumor microenvironment that correlate withhigh and low phenotypic response to each therapy. This study will lay the ground work to prove that local intratumorresponse to microdoses of multiple agents can be used to effectively screen for and tailor optimal treatment for gliomapatients. Assessing the predictive value of the IMD for therapy selection opens the door to broader use as a precisionmedicine and drug development tool to improve outcomes in glioma. 746821 +No NIH Category available Accounting;Adoptive Immunotherapy;Adult;Adverse event;Affect;Antibiotics;Antibodies;B lymphoid malignancy;Bacterial Infections;Benefits and Risks;Blood;CAR T cell therapy;CD19 gene;Caring;Cell Cycle Kinetics;Cell Surface Proteins;Cell physiology;Cells;Cessation of life;Clinical;Communicable Diseases;Controlled Study;Cox Models;Cytometry;Data;Disease remission;Double-Blind Method;Dropout;Emergency department visit;Ensure;Equity;Future;Health Resources;Healthcare;High Prevalence;Hospitalization;Humoral Immunities;Image;Immune;Immunoglobulin G;Immunoglobulins;Immunooncology;Incidence;Infection;Infection prevention;Infusion procedures;Intention;Kinetics;Life;Lymphoma;Malignant Neoplasms;Measures;Medical;Medical Records;Outcome;Outcomes Research;Outpatients;Participant;Patients;Persons;Pharmaceutical Preparations;Physicians;Placebos;Population;Prevention strategy;Progression-Free Survivals;Randomized;Randomized Controlled Trials;Recovery;Replacement Therapy;Resolution;Resources;Risk;Scientist;Serum;Severities;Signal Transduction;Site;Streptococcus pneumoniae;Subgroup;Toxic effect;Visit;arm;cancer therapy;chimeric antigen receptor T cells;clinical efficacy;clinical risk;cost;cytokine release syndrome;design;dimensional analysis;evidence base;follow-up;hypogammaglobulinemia;immune reconstitution;infection rate;infection risk;insight;neurotoxicity;pathogen;patient population;placebo controlled study;prophylactic;radiological imaging;randomized placebo controlled trial;randomized trial;randomized controlled study;side effect;tumor Immunoglobulin Replacement Therapy and Infectious Complications After CD19-Targeted CAR-T-Cell Therapy PROJECT NARRATIVEPeople receiving chimeric antigen receptor T cell therapy (CARTx) for cancer treatment are often givenimmunoglobulin G (IgG) replacement therapy (IGRT) to prevent infections; however no data support thispractice in this patient population and IGRT requires careful stewardship given national shortages potentialside effects and high expense. To establish the risks and benefits of this frequently used infection-preventionstrategy we will conduct a randomized placebo-controlled trial of IGRT in CARTx patients. We will compareinfection rates antibody levels health resource utilization and CAR-T cell kinetics and function amongparticipants who do and do not receive IGRT to establish evidence-based data to guide the use of IGRT in therapidly growing population of CARTx recipients. NCI 10732195 8/28/23 0:00 PAR-21-035 1R01CA276040-01A1 1 R01 CA 276040 1 A1 "ROSS, SHARON A" 9/1/23 0:00 8/31/28 0:00 Clinical Oncology Study Section[CONC] 11706357 "HILL, JOSHUA AIDEN" "PERALES, MIGUEL-ANGEL " 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 930383 NCI 630863 299520 PROJECT SUMMARY/ABSTRACTChimeric antigen receptor T cell therapy (CARTx) has transformed treatment for B cell malignancies. Howeverthe effects of CARTx on humoral immunity and infection risk are incompletely understood. The high prevalenceof hypogammaglobulinemia in CARTx recipients has driven frequent use of prophylactic immunoglobulin G (IgG)replacement therapy (IGRT) to prevent infections in this patient population. However limited data exist to supportthis practice and shortages side effects and cost necessitate careful stewardship of IGRT. Emerging dataindicate that pathogen-specific antibodies often persist after CD19-CARTx potentially contesting the need forIGRT. Well controlled studies are needed to ascertain the clinical utility of IGRT in CARTx recipients. Within thisclinical context other important and connected questions remain about how IGRT affects CAR-T cell functionin addition to the possible costs versus benefits of the effect of IGRT on healthcare resource utilization.This timely and unique proposal will be the first randomized controlled trial of IGRT use in CARTx recipients andprovide critical insights into the potential risks and benefits of IGRT in this patient population. The key objectivesof this study are to evaluate whether IGRT in CARTx recipients reduces infection rates compared to placeboand to understand the impact of IGRT on previously unexplored outcomes such as CAR-T cell expansion CAR-T cell persistence CAR-T cell function and healthcare resource utilization. For the proposed study we haveassembled an interdisciplinary group of physicians and scientists from high-volume CARTx centers who willleverage our expertise in immuno-oncology infectious diseases and cancer outcomes research.We propose a randomized trial of IGRT versus placebo in 150 adults with serum total IgG 400 mg/dL prior toCD19-CARTx. Participants will be randomized 1:1 to receive IGRT or placebo within 14 days prior to CARTxand at 28-day intervals after CARTx for 4 months. Aim 1 will compare between study arms the incidence rate ofinfections through 6 months after CD19-CARTx; we will also longitudinally characterize and compare total andpathogen-specific IgG levels and their association with infections. Aim 2 will explore the association of IGRT withhealthcare resource utilization cytokine release syndrome and CARTx-associated neurotoxicity. Aim 3 willcharacterize the impact of IGRT on CAR-T cell expansion persistence and function.This will be the first randomized controlled study of IGRT after CARTx and will provide foundational data toestablish evidence-based estimates of the clinical efficacy and risk-benefit of IGRT in CD19-CARTx recipients.In parallel this study will explore other potential effects of IGRT on CAR-T cell dynamics and healthcare resourceutilization. The data generated by this proposal will provide the groundwork for future studies to refine infectionprevention strategies in the growing population of CARTx recipients. 930383 +No NIH Category available Address;Age;Binding;Biochemical;Biological;Blood Cells;Body Size;Brain;Cancer Model;Cell Differentiation process;Cell division;Cells;Chemicals;Chromatin;Chromatin Structure;Cryoelectron Microscopy;DNA;DNA Methylation;DNA Modification Methylases;DNMT3B gene;DNMT3a;Development;Embryonic Development;Enzymes;Etiology;Funding Mechanisms;Genes;Genetic;Hematopoiesis;Human;Knock-out;Malignant Neoplasms;Methylation;Mus;Mutation;Normal Cell;Nucleosomes;Prevalence;Process;Protein Isoforms;Proteins;Regulation;Role;Signal Transduction;Solid;Solid Neoplasm;Structure;Testing;Work;cancer cell;cancer initiation;carcinogenesis;cell transformation;flexibility;follow-up;insight;leukemia;methyl group;mouse model;novel;overexpression;postnatal development;transcription factor;virtual Establishing and Interpreting Abnormal DNA Methylation in Cancer Project NarrativeThe DNA methyltransferase DNMT3A applies methyl groups to DNA and has been found to be necessary fordevelopment of the human brain regulation of body size control of blood cell differentiation and for leukemiadevelopment. A particular form of the enzyme DNMT3A2 is overexpressed in human cancers and maycontribute to the widespread methylation changes found in every cancer. We will test whether thisoverexpression can initiate cancer use cryo-EM to determine how it works on chromatin and determine howcells read methylation signals in DNA. NCI 10732031 9/6/23 0:00 RFA-CA-22-045 2R35CA209859-08 2 R35 CA 209859 8 "OKANO, PAUL" 1/1/17 0:00 6/30/30 0:00 ZCA1-SRB-E(M1) 1862413 "JONES, PETER A" Not Applicable 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 1146514 NCI 642938 503576 Project Summary/AbstractThe mammalian de novo DNA methyltransferase DNMT3A is essential for postnatal development of the braincontrol of body size and for the regulation of hematopoiesis. Mutations in the gene are commonly found in age-associated clonal hematopoiesis of indeterminant potential and are drivers for certain leukemias making itimportant that we understand how the enzyme functions in living cells. All human cancers contain DNAmethylation anomalies however mutations in DNMT3A are relatively rare in solid tumors suggesting that alteredenzyme regulation might be responsible for these changes. Although we know in exquisite detail how DNMT3Amethylates naked DNA we know virtually nothing about how this occurs in the context of nucleosomes thefundamental building blocks of chromatin. The focus of this application is to address this issue using new insightsrecently developed in the lab. We will concentrate on the role of a truncated isoform DNMT3A2 normallyexpressed during embryonic development but overexpressed in most solid cancers. Our novel cryo-EM structureshows how this enzyme partners with an accessory protein DNMT3B3 to bind to nucleosomes through the acidicpatch a totally unexpected discovery. We will follow up on this work using biochemical cryo-EM cellular andmouse studies to gain a more precise understanding of how DNA methylation works in the context of chromatin.A mouse model in which Dnmt3a2 but not the more widely studied longer isoform Dnmt3a1 has been knockedout will be used to test for causality in the process of immortalization and carcinogenesis in genetic and chemicalmouse models of cancer. This comprehensive approach will help in our understanding of how this fundamentalprocess works in normal and transformed cells.Studies on how DNA methylation marks are interpreted in cells has long been confined to comparison betweenfully and completely unmethylated CpG dyad states. Because of the flexibility in the R35 funding mechanismwe serendipitously discovered that CpG hemimethylation can either stimulate or inhibit binding by CTCFdepending on which duplex strand is methylated. We will investigate the prevalence of hemimethylation in cancercells and investigate its effects on binding of other transcription factors and chromatin structure. Differentialbinding may play a role in asymmetric cell divisions in cancer cells. We hope to answer three critical questions:1) Does DNMT3A2 overexpression contribute to carcinogenesis? 2) How does de novo methylation occur in anucleosomal context? 3) What are the potential biological roles for hemimethylation? 1146514 +No NIH Category available Address;Adopted;Age;Awareness;BRCA mutations;Black race;Breast Cancer Risk Factor;Caring;Clinic;Clinic Visits;Communication;Consultations;Disparity;Education;Effectiveness;Eligibility Determination;Ethnic Population;Evaluation Research;Exploration Preparation Implementation and Sustainment;Family;Family history of;Genetic;Genetic Risk;Genetic Screening;Genetic Services;Genomics;Goals;Guidelines;Health Services Research;Infrastructure;Left;Life;Malignant Neoplasms;Measures;Minority Groups;Oncology;Phase;Population;Population Heterogeneity;Poverty;Preparation;Prevention;Process;Program Sustainability;Public Health;Randomized Controlled Trials;Reach Effectiveness Adoption Implementation and Maintenance;Recording of previous events;Research;Risk;Rural;Rural Community;Screening Result;Screening for cancer;Services;Site;Testing;Time;Uninsured;United States Preventative Services Task Force;Visit;Woman;aggressive breast cancer;black women;breast imaging;cancer genetics;cancer genomics;cancer prevention;cost;effectiveness evaluation;ethnic minority population;evidence base;federal poverty level;follow-up;genetic testing;health disparity;health organization;high risk;implementation framework;implementation research;improved;insight;mutation carrier;population based;program dissemination;programs;psychosocial;racial diversity;racial population;risk stratification;rural area;rural dwellers;screening;screening program;secondary outcome;service uptake;success;underserved community;uptake Evaluating an evidence-based family history screening program adapted to increase reach and uptake of screening for BRCA-associated cancers in rural public health clinics PROJECT NARRATIVEWe propose to adapt Gegorias existing statewide family history screening program for BRCA-associated cancerswith the goal to increase the number and diversity of women who receive family history assessment and theopportunity to access risk-stratified cancer prevention in rural public health clinics. Study findings will furtherinform program dissemination and sustainability across all 187 Georgia public health clinics and yield insightsenabling improved implementation of other genomic applications at the population level and among other ruralunderserved communities. NCI 10731993 7/6/23 0:00 PAR-21-035 1R37CA276317-01A1 1 R37 CA 276317 1 A1 "SARMA, ELIZABETH ANNE" 7/6/23 0:00 6/30/28 0:00 Health Services: Quality and Effectiveness Study Section[HSQE] 14432989 "GUAN, YUE " Not Applicable 5 PUBLIC HEALTH & PREV MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF PUBLIC HEALTH 303221007 UNITED STATES N 7/6/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 615683 NCI 428762 186921 PROJECT SUMMARYBrief and low-cost family history-based screening assessments to identify families at high risk for BRCA-associated cancers have been endorsed by national guidelines (e.g. USPSTF) and public health organizations(e.g. CDC). Public health departments offer an infrastructure for systematically reaching women historically leftout of cancer genomic advances (e.g. uninsured Black women rural residents). Georgia is among the few statesto have implemented statewide family history screening for BRCA-associated cancers. Despite its potentialcurrent clinic-based approaches that identify at risk women are not sustainable and show limited reach.Additionally uptake of follow-up cancer screening is suboptimal and solely focuses on women screened as highgenetic risk. Therefore we propose a two-phase study to adapt Georgias existing statewide family historyscreening program and evaluate its effectiveness to increase the number and diversity of women who receivefamily history assessment and the opportunity to access risk-stratified follow-up services. Guided by theExploration Preparation Implementation and Sustainment (EPIS) framework the aims of this two-phase studyare: Phase I (Exploration & Preparation stages) Aim 1: Conduct a multilevel adaptation of GA COREs existingstatewide family history screening program for BRCA-associated cancers to maximize sustainable program reachand improve communication suitability and effectiveness. Phase II (Implementation stage) Aim 2: Use a multi-site parallel group cluster randomized controlled trial to evaluate effectiveness of the adapted program relativeto the current screening program in promoting uptake of family history screening and correct screening resultinterpretation among women ages 25 and older who are receiving care in up to 6 of 14 Public Health Clinics inSouthwest Georgia. Secondary outcomes include the uptake of appropriate risk-stratified screening (e.g. highrisk: genetic consultation and testing; low risk: appropriate breast imaging screening). Aim 3: Use the RE-AIM(Reach Effectiveness Adoption Implementation and Maintenance) framework to conduct an implementationresearch evaluation to measure program process indicators (e.g. reach fidelity barriers/facilitators) that mayinfluence program implementation and sustainability. Our application will be among the first to evaluate asustainable multi-level population-based approach to implement evidence-based cancer genetic screening andto increase the likelihood for fair distribution of genomic advances among diverse populations in rural areas. 615683 +No NIH Category available Ablation;Agreement;Androgen Receptor;Androgens;Apoptosis;Binding;Biochemical;Biometry;Cancer Patient;Castration;Cell Cycle;Cells;Chemoresistance;Clinical Research;Clinical Trials;Complex;Creativeness;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Drug resistance;Event;FRAP1 gene;Fostering;Genetically Engineered Mouse;Goals;Growth;Health;Human;Investigation;Knock-out;Laboratories;Malignant Neoplasms;Malignant neoplasm of prostate;Mission;Operative Surgical Procedures;Outcome;PLK1 gene;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Peptides;Pharmaceutical Preparations;Phosphorylation;Play;Prostate Cancer therapy;Proteins;Public Health;Receptor Signaling;Regulation;Reporting;Repression;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Tertiary Protein Structure;Testing;Therapeutic;Tumor Suppression;Tumor Suppressor Proteins;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;castration resistant prostate cancer;clinically significant;design;docetaxel;effective therapy;enzalutamide;genetic approach;improved;in vivo;inhibitor;innovation;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;programmed cell death protein 1;prostate cancer cell;prostate cancer progression;protein degradation;receptor expression;success;tumor growth;tumor initiation;tumor progression Targeting the Plk1/Pdcd4/mTORC2 Signaling to Treat Castration-Resistant Prostate Cancer NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NIH's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer. NCI 10731943 6/5/23 0:00 PA-20-185 1R01CA272483-01A1 1 R01 CA 272483 1 A1 "GREENBERG, WILLIAM A" 7/1/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 8042648 "LIU, XIAOQI " "YANG, HSIN-SHENG " 6 PHARMACOLOGY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 634489 NCI 414699 219790 Title: Targeting the Plk1/Pdcd4/mTORC2 signaling to treat castration-resistant prostate cancerAbstractAndrogen receptor (AR) signaling is essential for development of prostate cancer (PCa) including castration-resistant prostate cancer (CRPC). Consequently androgen signaling inhibitors (ASIs) such as abiraterone andenzalutamide are becoming the first line treatment for CRPC. However the limited success of ASIs makes iturgent to develop approaches to treat CRPC patients who are no longer responsive to ASIs. Programmed celldeath 4 (Pdcd4) is a tumor suppressor which has been demonstrated to inhibit tumor progression andchemoresistance. Furthermore Pdcd4 is an androgen-repressed protein that regulates PCa growth andcastration resistance. As such it will be of clinical significance to understand the regulation mechanism of Pdcd4as it will reveal novel approaches to overcome ASI resistance. Polo-like kinase 1 (Plk1) a critical regulator ofcell cycle-related events is a documented target for PCa treatment. Of note we previously demonstrated thatinhibition of Plk1 enhances the efficacy of ASIs. The long-term goals of this study are to identify druggablesignaling pathways that offer effective treatment options for patients with CPRC who are no longer responsiveto ASIs. The objective is to define the role of Plk1 in regulating Pdcd4 and to exploit these pathways as a noveltherapeutic target for CRPC. Our data show that 1) Pdcd4 enhances the sensitivity to enzalutamide due toinhibition of mTORC2 (the mammalian target of rapamycin complex 2) and AR expression; 2) Plk1phosphorylation of Pdcd4 results in its protein degradation; and 3) the dominant negative Pdcd4 peptide (TAT-RBD) overcomes ASI resistance in PCa. Based on these observations we aim to test the central hypothesis thatPlk1-associated phosphorylation of Pdcd4 results its degradation which causes subsequent activation of themTORC2 eventually contributing to activation of AR signaling and ASI resistance. Our hypothesis will be testedby pursuing three Specific Aims - (1) to demonstrate that loss of Pdcd4 to activate mTORC2 contributes to ASIresistance; (2) to dissect how Plk1 phosphorylation of Pdcd4 regulates its function as a tumor suppressor; and(3) to analyze clinical significance of Plk1 phosphorylation of Pdcd4. These complementary aims will beaccomplished using biochemical analyses of signaling intermediates and employing genetic strategies withculture systems inducible PCa mouse models patient-derived xenograft (PDX) and human PCa samples. Therationale for the research is that it will probe the importance of Plk1-associated activity to Pdcd4 and to examinewhether TAT-RBD peptide is a novel approach to treat ASI-resistant CRPC. This contribution is significantbecause if positive the results of the proposed study will support an immediate clinical trial for TAT-RBD peptideto treat CRPC that not respond to ASIs. The multiple-PI team consisted of complementary expertise on Plk1 (X.Liu) and Pdcd4 (Yang) as well as prostate cancer pathology (Allison) and biostatistics (Chen) will be able tofinish the proposed research in a timely manner. 634489 +No NIH Category available Ablation;Address;Adoptive Cell Transfers;Adult;Aftercare;Alleles;Biotechnology;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CRISPR/Cas technology;Cancer Patient;Case Study;Cell Proliferation;Cell Therapy;Cells;Cellular immunotherapy;Clinic;Clinical;Clinical Trials;Codon Nucleotides;Collaborations;Correlative Study;DNA Sequence Alteration;Data;Development;Dose;Drug Combinations;Effector Cell;Eligibility Determination;Engineering;Ensure;Epitopes;Genes;Genetic Transcription;Genomics;Goals;HLA-A gene;HLA-C Antigens;Human;Immune;Immune Targeting;Immune system;Immunology;Immunooncology;In Vitro;KRAS2 gene;Laboratories;Lesion;Leukocytes;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Missense Mutation;Mutate;Myelogenous;Myeloid Cells;Neoplasm Circulating Cells;Oncoproteins;Patients;Pennsylvania;Pharmacologic Substance;Phenotype;Population;Productivity;Proteomics;Publishing;Rattus;Reagent;Recurrence;Research;Research Personnel;Resistance;Resources;Safety;Site;Solid Neoplasm;T cell infiltration;T cell therapy;T-Cell Receptor;T-Lymphocyte;T-cell receptor repertoire;Technology Transfer;Testing;Translations;Tumor Antigens;Universities;Variant;Vertebral column;Virus;Work;base editing;biomarker development;biomarker discovery;cancer clinical trial;cell growth;clinical translation;cost;design;engineered T cells;exhaustion;improved;in vivo;insight;lead candidate;manufacture;molecular marker;molecular pathology;multi-site trial;mutant;neoantigens;next generation;novel;pediatric patients;peripheral blood;personalized medicine;phase 1 study;premalignant;receptor;research clinical testing;resistance mechanism;response;safety engineering;sarcoma;single cell technology;small molecule inhibitor;success;targeted treatment;technological innovation;tumor;tumor microenvironment Next generation T cell therapies for mutant KRAS solid tumors Project NarrativeOur goal is to develop the next generation of T cell therapies for adult solid tumors. Recent advances in CRISPR-Cas9 technology allow investigators to design better and safer T cell products for adoptive cell therapy. Anoutstanding team of investigators has been assembled to develop a new TCR-T cell therapy directed to mutantKRAS that overcomes the critical challenges posed by the tumor microenvironment and T cell exhaustion.Laboratory correlatives using state-of-the art single cell technologies will be employed to investigate mechanismsof response and resistance after treatment. In this personalized medicine-based strategy we estimate that 5000new adult cancer patients in the US per year will be eligible for this cell therapy. NCI 10731929 9/1/23 0:00 RFA-CA-22-028 1UG3CA283652-01 1 UG3 CA 283652 1 "HU, ZHANG-ZHI" 9/1/23 0:00 8/31/25 0:00 ZCA1-RTRB-Y(M1) 10217795 "CARRENO, BEATRIZ M." "JUNE, CARL H.; LINETTE, GERALD P" 3 PATHOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 1305260 NCI 875160 430100 Project SummaryThis proposal Next generation T cell therapies for KRAS mutated solid tumors was developed in response toRFA-CA-22-028 and to fulfill the Cancer Adoptive Cellular Therapy Network (Can-ACT) objectives. The focus ofour proposal is targeting mutant KRAS a clonal driver oncoprotein by the early-stage clinical testing ofTCR1020 a T cell receptor specific for mKRAS G12V restricted to HLA-A*11:01. If successful this novel-state-of-the-art Adoptive Cell Therapy (ACT) could be available to ~5000 new solid tumor patients per year in the US.Advances in gene editing together with new insights related to mechanisms of T cell exhaustion provide thescientific basis for development of the next generation T cell therapies in solid tumors. Our central hypothesisis that targeting mutant KRAS through the action of TCR1020-T cells engineered to overcome cell intrinsicmechanisms of exhaustion and counteract a cell extrinsic myeloid checkpoint to overcome TME resistance willpromote durable tumor regression in solid tumors. There are three hypothesis-driven specific Aims in thisproposal. In Aim 1 we will develop genetically modified T cells expressing TCR1020 targeting mKRASG12V/HLA-A*11:01 to overcome extrinsic and intrinsic mechanisms of resistance. In Aim 2 we plan to evaluateTCR1020-T CD4+ cells to improve the persistence and potency of mKRAS specific CD8+ effector cells. In Aim3 the safety and clinical activity of engineered TCR1020-T cell products will be determined in a dose escalationmulti-site phase 1 study. We have assembled an exceptional group of investigators with an extensive trackrecord of collaboration and productivity with expertise in human immunology immuno-oncology cell therapy Tcell engineering and gene editing. Additionally experts in molecular pathology and biomarker discovery willcontribute to cutting-edge correlative studies to aid in biomarker development and TME characterization todelineate potential mechanisms of response and resistance. The Center for Cellular Immunotherapies (CCI) atthe University of Pennsylvania has extensive expertise in the development of ACT therapies producing morethan 2500 cell products for administration to adult and pediatric patients. CCI has a long track record oftechnology transfer related to cell therapies to both large pharmaceutical companies (Novartis Kymriah) andbiotechnology companies over the past decade. As a multi-site trial application an important programmaticcomponent of our proposal is to leverage NCI resources thru utilization of the Immune Cell Network (ICN) Coreat FNLCR to manufacture test release and distribute the engineered TCR1020-T cell products. In summaryour proposal incorporates multiple scientific and technological innovations that targets a recurrent clonal driveroncoprotein with engineered T cells modified to resist T cell exhaustion and overcome the immunosuppressiveTME. 1305260 +No NIH Category available Achievement;Address;Antibodies;Antigen Targeting;Antigens;Binding;Biological Assay;Biology;Bispecific Antibodies;Blood;Bone Marrow;CAR T cell therapy;CD3 Antigens;Cell Therapy;Cell physiology;Cells;Clinical Trials;Correlative Study;Data;Dose;Drug Combinations;Drug Targeting;Effectiveness;Engineering;Engraftment;Extracellular Matrix;Fibroblasts;Genetic Markers;Hematologic Neoplasms;Immune;Immune response;Immune system;In Vitro;Infiltration;Infusion procedures;Injections;Intravenous;Intravenous infusion procedures;Knowledge;Lentivirus Vector;Malignant Neoplasms;Malignant neoplasm of pancreas;Methods;Modeling;Monitor;Neoplasm Metastasis;Normal Cell;PD-1 inhibitors;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patient Monitoring;Patient-Focused Outcomes;Patients;Peripheral;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phenotype;Plasmids;Pre-Clinical Model;Preclinical Testing;Protocols documentation;Recommendation;Resistance;Role;Route;Safety;Solid;Solid Neoplasm;Supporting Cell;T cell infiltration;T-Lymphocyte;Testing;Time;Tissues;Toxic effect;Tumor Antigens;Tumor Promotion;Tumor Suppression;Work;advanced disease;advanced pancreatic cancer;adverse event monitoring;antigen binding;antitumor effect;cancer cell;cell killing;cell type;chimeric antigen receptor;chimeric antigen receptor T cells;combinatorial;cytokine;density;design;detection assay;disease prognosis;fibroblast-activating factor;improved;in vivo;inhibitor;manufacture;mesothelin;mouse model;neoplastic cell;neurotoxicity;novel;pancreatic cancer cells;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;pembrolizumab;peripheral blood;phase I trial;pre-clinical;prevent;programmed cell death protein 1;programs;protein expression;response;synergism;treatment optimization;trial design;tumor;tumor growth;tumor microenvironment CAR T cells targeting mesothelin and secreting bispecific antibodies targeting fibroblasts in pancreatic cancer PROJECT NARRATIVESolid tumors are a mixture of cell types that support tumor growth and prevent the immune system fromkilling cancer cells. Weve designed a method to reprogram immune cells to target not only cancer cellsbut also eliminate support cells. We will optimize this therapy through rigorous preclinical testing andthen test it in a clinical trial in patients with pancreatic cancer. NCI 10731635 8/9/23 0:00 RFA-CA-22-028 1UG3CA283619-01 1 UG3 CA 283619 1 "BOURCIER, KATARZYNA" 8/9/23 0:00 7/31/25 0:00 ZCA1-RTRB-Y(M1) 10066497 "MAUS, MARCELA VALDERRAMA" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 8/9/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 1413547 NCI 892490 521057 PROJECT SUMMARYCAR T cell therapy for solid tumors is hindered by a lack of tumor-specific antigens that are safe to target andhomogenously expressed throughout the tumor difficulty infiltrating the tumor due to dense tumor stroma andsuppression of CAR T cell function by the tumor microenvironment (TME). We plan to address these issuesusing novel meso-FAP CAR-TEAM cells that simultaneously target mesothelin a solid tumor antigen that hasalready been proven safe to target in patients and cancer-associated fibroblasts (CAFs) which inhibit T cellinfiltration and suppress T cell function in the TME. The CAFs are targeted with T cell-engaging antibodymolecules (TEAMs) secreted from the CAR T cells that bind to CD3 and fibroblast activation protein (FAP) whichis highly expressed on CAFs. The TEAM allows for CAF elimination by CAR and non-CAR T cells in the tumor.We have already demonstrated that meso-FAP CAR-TEAM cells kill pancreatic cancer cells and CAFs in vitroin vivo and in patient-derived ex vivo models and have superior anti-tumor function compared to meso-CAR Tcells alone. For the UG3 phase of this project we will further optimize meso-FAP CAR-TEAM cells bydetermining the best mesothelin binder to use (SS1 vs. a novel binder developed by our lab) optimal route ofinjection (IV vs. IP) for targeting pancreatic tumors and rationale drug combinations that address CAR T celllimitations in solid tumors. We will improve antigen density using an ADAM17 inhibitor (INCB7839) to preventmesothelin cleavage from pancreatic cancer cells optimize CAR T cell killing and persistence using ibrutinib topolarize meso-FAP CAR T cells to a Th1/Th17 phenotype and further prevent suppression by the tumormicroenvironment using a PD1 inhibitor (pembrolizumab). These drugs will be singly combined with meso-FAPCAR-TEAM cells to determine which best promotes efficacy in our preclinical models. Collectively these resultswill inform the design of a phase I clinical trial for pancreatic cancer patients with advanced disease. During theUH3 phase we will determine the safety and tolerability of meso-FAP CAR-TEAM cells. We have chosenpancreatic cancer as our first solid tumor target due to the dismal prognosis of the disease the high percentageof patients with mesothelin-expressing tumors and the known role of CAFs in promoting tumor growth. Whileour primary objective will be to determine safety we will also monitor patient outcomes (progression and survival)while performing correlative studies to determine CAR T cell phenotype and function. We will also monitor thetumor and tumor microenvironment for mechanisms of response or resistance such as changes in antigenexpression and immunosuppressive cells. Overall this project will develop a novel CAR-TEAM design to targeta solid tumor and its microenvironment while optimizing the trial design through rigorous preclinical testing. Ifsuccessful the meso-FAP CAR T cell product could be directly applied to other mesothelin-expressing solidtumors and the knowledge gained from the UG3 phase will inform on the critical aspects of CAR T cell functionto optimize prior to initiating a clinical trial. 1413547 +No NIH Category available Acquired Immunodeficiency Syndrome;Area;Award;Base Sequence;Big Data;Bioinformatics;Biological Assay;Biology;Cancer Center;Cancer Patient;Cancer Research Project;Cell Culture Techniques;Cell physiology;Center Core Grants;Chromatin;Comprehensive Cancer Center;Computer Analysis;Data;Data Science Core;Data Set;Defect;Development;Epigenetic Process;Functional disorder;Funding;Gene Activation;Genetic Transcription;Goals;Grant;Human;Human Herpesvirus 8;Investigation;Kaposi Sarcoma;Malignant Neoplasms;Mutation;Patients;Pharmacologic Substance;Regulation;Reproducibility;Research;Research Personnel;Role;Toxic effect;Transcription Elongation;Universities;Work;cancer cell;high standard;improved outcome;insight;member;molecular dynamics;next generation sequencing;programs Bioinformatics Analysis of Next Generation Sequencing Data from Cancer Cells Project NarrativeSequence-based assays provide a powerful toolset for gaining insight into the function and disfunction ofcancer cells. Unfortunately the resulting data sets are a classic example of big data and experimentalbiologists are traditionally not trained to handle or analyze them. The goal of this R50 proposal is toprovide Dr. Bartoms expertise in both computation and biology to the cancer research programs of theRobert H. Lurie Comprehensive Cancer Center and more specifically to the Quantitative Data SciencesCore (QDSC). NCI 10731590 9/14/23 0:00 PAR-22-188 2R50CA221848-06A1 2 R50 CA 221848 6 A1 "JOHNSON, ERIC MICHAEL" 9/19/17 0:00 8/31/28 0:00 ZCA1-SRB-1(M1) 12620113 "BARTOM, ELIZABETH THOMAS" Not Applicable 5 BIOCHEMISTRY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/14/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 229792 NCI 143620 86172 Project SummaryThis proposal is a renewal of a prior R50 grant that supported the bioinformatics needs of cancerresearchers at Northwestern University. The initial award primarily supported two NCI fundedOutstanding Investigators Dr. Marcus Peter and Dr. Ali Shilatifard with a small fraction of support for theRobert H. Lurie Comprehensive Cancer Center. Now Dr. Bartom has become the Scientific AssociateDirector for Bioinformatics for the Cancer Center and she will support a broader array of researchprograms for different cancer center members. The Unit Director for this proposal is Dr. Leon PlataniasPI of the Cancer Center. A specific area of note will continue to be Dr. Marcus Peters investigations intothe role of 6mer seed toxicity in the bodys natural defenses against cancer and how this mechanismcan be activated in order to improve outcomes for cancer patients. She will also continue to work withcolleagues within the Simpson Querrey Center for Epigenetics including Dr. Ali Shilatifard to understandhow genetic changes in the machinery of chromatin regulation can lead to epigenetic mutations anddefects in gene activation and transcriptional elongation. Research into the molecular dynamics inprimary human cell cultures infected with Kaposis Sarcoma-associated Herpesvirus will continue withDr. Eva Gottwein giving insight into how Kaposis Sarcomas arise in AIDS patients. All three of theseinvestigators are cancer center members whose research is supported by the Cancer Center P30 grant.The common thread in all of these projects is the need for careful biologically motivated computationalanalysis to make sense of next generation sequencing data that is essential in examining the function ofcells both before and after cancer development and before and after pharmaceutical perturbation. Dr.Bartom will provide this analysis and her expertise in both biology and computation will allow cancerbiologists to extract more insight from their data and to maintain a high standard of scientific rigor andreproducibility. 229792 +No NIH Category available Address;Antibodies;Apoptosis;Binding;Cells;Chimeric Proteins;Clinical;Data;Development;Disease;Enzymes;FDA approved;Failure;Follow-Up Studies;Genetic;Goals;Human;Immune;Inflammation;Interferons;Interleukin-12;Knowledge;Mediating;Membrane;Methods;Modeling;Molecular;Myxoma virus;Nature;Oncolytic;Oncolytic viruses;Outcome;PD-1 inhibitors;PD-1/PD-L1;Pathway interactions;Patients;Play;Pre-Clinical Model;Property;Receptors Tumor Necrosis Factor Type II;Regulatory Pathway;Role;Solid Neoplasm;Specificity;T-Lymphocyte;TNF gene;TNFRSF1B gene;Testing;Therapeutic antibodies;Toxic effect;Translating;Translations;Treatment Efficacy;Tumor Immunity;Viral;Virus;Virus Replication;Work;anti-tumor immune response;cancer infiltrating T cells;clinical application;clinical effect;clinical translation;design;immune clearance;immune-related adverse events;improved;in vivo;inhibitor;novel;oncolytic virotherapy;prevent;success;synergism;tumor;tumor microenvironment Impact of TNF on Oncolytic Virotherapy Project Narrative:The anti-tumor immunity induced by oncolytic virotherapy is blunted by numerous poorly characterized cellularpathways. For example our preliminary data demonstrates the presence of TNF within the tumormicroenvironment prevents effective oncolytic therapy by directly killing anti-tumor T cells. The currentproposal will more fully examine the impact of TNF on oncolytic therapy by understanding the molecularmechanisms involved and identifying how to best translate these findings into human patients. NCI 10731525 8/24/23 0:00 PA-20-185 1R01CA276134-01A1 1 R01 CA 276134 1 A1 "SALOMON, RACHELLE" 9/1/23 0:00 8/31/28 0:00 "Advancing Therapeutics A Study Section +[ATA]" 10501140 "BARTEE, ERIC CARTER" Not Applicable 1 GENETICS 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM SCHOOLS OF MEDICINE 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 438164 NCI 289892 148272 Project Summary: Oncolytic virotherapy (OV) represents a novel method to treat a variety of solid tumors byinducing anti-tumor immune responses. While this therapy has been extremely efficacious in a wide variety ofpreclinical models translating these successes into human patients has proven challenging. It has recentlybecome clear that one of the major reasons for these failures is the existence of immune-regulatorymechanisms which dampen the efficacy of virally induced anti-tumor immunity. However the exact nature ofthese regulatory pathways remains unclear. Our lab has previously developed a novel oncolytic MYXV which expresses a soluble PD1 inhibitor and anIL12 fusion protein (vPD1/IL12). This construct is highly effective at treating disseminated disease however~50% of tumor models remain at least partially non-responsive and viral treatment is associated with thedevelopment of immune-related adverse events. In our follow-up studies into the mechanisms mediating theefficacy of vPD1/IL12 we have observed that the virus induces high levels of TNF during therapy. Strikinglyboth genetic elimination or antibody-based blockade of this TNF results in a significant INCREASE intherapeutic efficacy as well as a significant REDUCTION in toxicity. To our knowledge no other studies havedemonstrated a positive impact of TNF blockade on OV and therefore both the mechanism(s) involved as wellas how to leverage this finding into improved clinical outcomes remains unclear. We therefore put forth thecurrent proposal which contains three specific aims designed to build off of our exciting preliminary data by:identifying the mechanism through which TNF restricts OV efficacy understanding how TNF mediates OV-induced toxicities and determining clinically applicable methods to apply TNF-blockade during OV. This workwill advance not only the clinical use of our existing vPD1/IL12 virus but also improve our understanding of thebasic mechanisms involved in successful OV. 438164 +No NIH Category available Animal Model;Award;Biochemical;Biological Assay;Bioluminescence;Bone Marrow;Cancer Biology;Cancer Model;Cells;Code;Complement;Complex;Custom;Data;Disparate;Disseminated Malignant Neoplasm;Engineering;Environment;Event;Exhibits;Firefly Luciferases;Funding;Goals;Heterogeneity;Image;Interdisciplinary Study;Investigational Therapies;Malignant Neoplasms;Metabolism;Methods;Michigan;Myelofibrosis;Myeloproliferative disease;Neoplasm Metastasis;Oncology;Organism;Pharmacodynamics;Physiological;Process;Productivity;Qualifying;Reporter;Research;Research Personnel;Resources;Scientist;Signal Pathway;Signal Transduction;Specialist;Standardization;Stress;Systems Biology;Technology;Time;Universities;Visualization;Writing;automated segmentation;bioluminescence imaging;cancer cell;cancer imaging;clinical imaging;co-clinical trial;disease heterogeneity;environmental change;environmental stressor;experience;fluorescence imaging;fluorescence lifetime imaging;image processing;imaging modality;in vivo;in vivo bioluminescence imaging;invention;molecular imaging;molecular scale;multidisciplinary;multiphoton microscopy;novel;precision medicine;prevent;programs;quantitative imaging;response;treatment response;tumor;tumor heterogeneity;tumor progression Specialist in Multi-Scale Molecular Imaging of Tumor Environments Cancer cells reprogram signaling metabolism and other functions in response to changingenvironmental conditions. Understanding how malignant cells adapt to environmental stressesrequires the ability to analyze cancer cells in real time in physiologic settings. I develop newimaging methods to visualize and quantify functions of cancer cells in tumor environmentsproviding information and technologies needed to better prevent and treat primary and metastaticcancer. NCI 10731131 9/19/23 0:00 PAR-22-187 2R50CA221807-06 2 R50 CA 221807 6 "JOHNSON, ERIC MICHAEL" 9/20/18 0:00 6/30/28 0:00 ZCA1-SRB-1(M1) 8314730 "LUKER, KATHRYN " Not Applicable 6 RADIATION-DIAGNOSTIC/ONCOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 217491 NCI 139417 78074 Cancer cells exhibit remarkable heterogeneity in cell signaling metabolism and other functionalstates. Changing environmental conditions impose additional stresses on cancer cells furtherincreasing tumor heterogeneity as subsets of cells reprogram key functions to survivedisseminate and ultimately produce metastases. Tumor heterogeneity and adaptations of cancercells emerge dynamically over the course of tumor progression and treatment underscoring thecritical need to analyze cancer cells over space and time. As an expert in molecular imagingcancer model systems and cancer biology I develop approaches to quantify key processes incancer biology including signaling metabolism and pharmacodynamics of therapy in complexliving systems from cell-based assays to animal models. My expertise in fluorescence andbioluminescence imaging makes me uniquely qualified to accomplish these goals. I am a pioneerof in vivo bioluminescence imaging of biochemical events having invented firefly luciferasecomplementation. I remain at the forefront of developing new bioluminescence methods fordiscovery in cancer. I have a strong record of engineering new reporters and implementingmethods to extend capabilities of in vivo multiphoton microscopy both with multiplexedfluorescence imaging reporters and fluorescence lifetime imaging. To capture tumorheterogeneity from imaging data I write custom image processing code to automatically segmentand quantify multiple imaging reporter signals from thousands of cells. My effort is fully funded by3 NCI research programs. 1) Integrators of Metastatic Potential: Discover how GIV a signalinghub for multiple signaling pathways drives programs necessary for metastasis-initiating cells; 2)Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis: Develop novelimaging methods to analyze the bone marrow environment and pharmacodynamics of therapy inmyelofibrosis and other myeloproliferative neoplasms; and 3) University of Michigan QuantitativeCo-Clinical Imaging Research Resource: Establish and standardize quantitative imaging methodsfor co-clinical trials using established and investigational therapies for myelofibrosis. Theseprojects are dynamic productive multidisciplinary collaborations involving me the ResearchDirector (Dr. Gary Luker MD) and a network of exceptional investigators in oncology cancerbiology cell signaling and imaging. My multidisciplinary expertise and experience allow me toeffectively bridge the gap that may exist among scientists and trainees from disparate scientificfields. This award will enable me to continue interdisciplinary molecular imaging research focusedon understanding and overcoming tumor heterogeneity to advance precision medicine in cancer. 217491 +No NIH Category available Adolescent;Alveolar;Alveolar Cell;Anchorage-Independent Growth;Automobile Driving;Binding;Biological;Biology;Bypass;CDKN2A gene;Categories;Cell Differentiation process;Cell Line;Cell Proliferation;Cells;Child;Chimeric Proteins;Complex;Data;Development;Differentiation Inhibitor;Disease;Event;FOXO1A gene;Failure;Family member;Fibroblast Growth Factor;Fibroblast Growth Factor Receptors;Gene Family;Gene Silencing;Gene Targeting;Genes;Genetic Transcription;Genome;Goals;Growth;HDAC1 gene;Histologic;Histone Deacetylase;Histone Deacetylase Inhibitor;In Vitro;Knowledge;Malignant Childhood Neoplasm;Mediating;Mediator;Melanoma Cell;Molecular;Morphogenesis;Muscle Fibers;Muscle satellite cell;Mutation;Myoblasts;Myogenic Regulatory Factors;Oncogenes;Oncogenic;Oncology;PAX3 gene;PIK3CG gene;PTEN gene;Pathology;Pathway interactions;Patients;Pediatric Neoplasm;Play;Polycomb;Proliferating;Receptor Protein-Tyrosine Kinases;Regulation;Regulator Genes;Regulatory Pathway;Repression;Rhabdomyosarcoma;Role;Signal Induction;Signal Pathway;Signal Transduction;Skeletal Muscle;Soft Tissue Neoplasms;System;TP53 gene;Therapeutic;Transactivation;Transcription Repressor;Tumor Promotion;Tumor Suppressor Genes;Tumor Suppressor Proteins;Work;cancer cell;cell growth;cell type;design;forkhead protein;gene repression;improved;in vivo;insight;member;migration;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;oncoprotein p21;overexpression;programs;recruit;response;skeletal muscle differentiation;therapeutically effective;transcription factor;tumor;tumor growth;tumor progression Characterization of the Regulation and Gene Targets of TBX2 in Rhabdomyosarcoma NarrativeIn this proposal we will examine the regulation and target genes of a transcription factor that drives cell growthand proliferation in rhabdomyosarcoma. The knowledge gained from this work will enhance the understandingof this disease which may enable new therapeutic options for children suffering from this pediatric cancer. NCI 10731025 7/5/23 0:00 PAR-22-060 1R15CA274384-01A1 1 R15 CA 274384 1 A1 "LUO, RUIBAI" 7/8/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-MGG-X(81)A] 9347701 "DAVIE, JUDITH KIMBERLY" Not Applicable 12 BIOCHEMISTRY 939007555 Y28BEBJ4MNU7 939007555 Y28BEBJ4MNU7 US 37.728408 -89.222946 1194502 SOUTHERN ILLINOIS UNIVERSITY CARBONDALE CARBONDALE IL SCHOOLS OF MEDICINE 629014709 UNITED STATES N 7/8/23 0:00 6/30/26 0:00 396 Non-SBIR/STTR 2023 445500 NCI 300000 145500 My lab is focused on understanding the molecular events that result in the transition of a skeletalmuscle precursor cell to a rhabdomyosarcoma (RMS) tumor cell in hopes to suggest therapeutic strategies toreduce the oncogenic potential of this childhood cancer. We have discovered that TBX2 a T-box familymember is a novel oncogene in RMS tumor cells. TBX2 is often over expressed in cancer cells and is thoughtto function in bypassing cell growth control by the repression of p14ARF and p21. The cell cycle regulator p21 isrequired for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have foundthat TBX2 represses p21 p14ARF and the tumor suppressor PTEN in RMS cells and inhibits the activity of themyogenic regulatory factors through binding to MYOG and MYOD1. Thus TBX2 both promotes proliferationand represses terminal differentiation. Given the crucial importance of TBX2 in driving tumor cell proliferation inRMS it is important to understand the regulation of TBX2. In other cells TBX2 is regulated by PAX3 a paired-box transcription factor essential in skeletal muscle progenitor cells. RMS cells are characterized by expressionof PAX3 and the more aggressive subtype of RMS contains a translocation that fuses PAX3 with thetransactivation domain of a forkhead transcription factor producing a PAX3-FOXO1 fusion protein. FGFsignaling has been shown to activate both PAX3 and TBX2 in other systems suggesting that this may occur inskeletal muscle as well. We have also found that the highly related T-Box factor TBX3 represses TBX2 innormal skeletal muscle and RMS but TBX3 is itself silenced by the polycomb repressive complex (PRC2) inRMS. Our data suggest that TBX2 is part of the normal regulatory program expressed in proliferatingmyoblasts which is silenced in differentiated cells during development. The goal of this proposal is toinvestigate the regulation and additional gene targets of TBX2 in RMS cells which will provide the neededmolecular insight to potentially harness the expression or function of TBX2 therapeutically. In our first aim wewill identify mechanisms regulating TBX2 expression by determining if PAX3/PAX-FOXO1 and the FGFsignaling pathway activate TBX2. In the second aim we will characterize novel tumor suppressor genesregulated by TBX2 including TP53 and TCEAL7. P53 is a well known tumor suppressor that has beenextensively studied in RMS but our data are the first to implicate TBX2 in the silencing of TP53 in any systemand suggest that TP53 is transcriptionally silenced in ARMS. The function of TCEAL7 is unexplored in RMSand may represent a novel therapeutic target. Finally we will profile TBX2 binding on the genome to identify allgenes bound by TBX2 in RMS. Taken together this work will provide essential insight into the role andregulation of the novel oncogene TBX2 in RMS cells thus providing a novel therapeutic target for RMS.Understanding abnormalities in gene regulatory pathways is crucial for understanding the pathology of cancercells and for designing effective therapeutic strategies to improve treatment of rhabdomyosarcoma. 445500 +No NIH Category available Address;Administrator;Adolescent;Age;Anogenital cancer;Area;Cancer Control;Cancer Etiology;Caring;Charge;Child;Clinical Trials;Communication;Communities;Consult;Decision Making;Dose;Drops;Educational Curriculum;Effectiveness;Eligibility Determination;Enrollment;Ensure;Epidemic;Evaluation;Exposure to;Female;Focus Groups;Gender;Goals;Government;Grant;HIV;Health;Health behavior;Healthcare;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human Resources;Hybrids;Immunization;Immunization Programs;Income;Individual;Influentials;Institution;Interruption;Intervention;Interview;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Medical;Methods;Misinformation;Nurses;Ownership;Parents;Participant;Phase;Population Heterogeneity;Preparation;Prevention;Questionnaires;Randomized;Randomized Controlled Trials;Research;Research Personnel;Resource-limited setting;Sampling;School-Age Population;Schools;Sexually Transmitted Diseases;South Africa;South African;Structure;Students;System;Testing;United States;Vaccinated;Vaccines;Voice;Vulnerable Populations;Woman;acceptability and feasibility;boys;cancer prevention;civil society;community engagement;coronavirus disease;design;effectiveness evaluation;elementary school;feasibility trial;fifth grade;girls;health communication;health equity;hybrid type 2 trial;improved;learning materials;malignant oropharynx neoplasm;mortality;programs;recruit;school health;sexual debut;social media;study population;teacher;trial planning;uptake;urban setting;vaccination strategy;vaccine acceptance;vaccine hesitancy;working group;young woman Multi-level school-based intervention to improve HPV vaccine uptake and completion in South Africa PROJECT NARRATIVEThe proposed study will refine and evaluate components of a school-based multi-level communicationsstrategy that addresses intrapersonal interpersonal and institutional factors associated with HPVvaccination uptake and completion. Participatory methods and community engagement are foundational tothe approach. Achieving the goals of this project has the potential to inform the South African IntegratedSchool Health Programme regarding effective strategies to promote uptake and completion of HPVvaccine amongst girls and boys and provide an approach that is replicable in other low- and middle-incomesettings where the burden of HPV-associated cancers is high. NCI 10730916 8/7/23 0:00 PAR-22-173 1R34CA283483-01 1 R34 CA 283483 1 "CHOLLETTE, VERONICA" 8/7/23 0:00 7/31/26 0:00 ZCA1-TCRB-V(M2) 10005639 "KATZ, INGRID T." "BUTLER, LISA MICHELLE" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 8/7/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 339735 NCI 212824 126911 PROJECT SUMMARY Human Papillomavirus (HPV) is the most common sexually transmitted infection globally and is causallylinked to cervical anogenital and oropharyngeal cancers. HPV-associated cancers have a disproportionateimpact in low-resource settings and nowhere is this evident than in South Africa which has a uniquelyvulnerable population due to the convergence of the largest HIV epidemic globally with HPV rates of up to85% in young women under the age of 25. Cervical cancer is the leading cause of cancer-related mortalityamong women in South Africa. In 2014 the South African National Department of Health implemented anational school-based HPV immunization program. Despite a promising start vaccine coverage and dosecompletion rates dropped precipitously after 2014 with only 37% of girls receiving their first dose in 2021.Recent declines have been attributed to COVID-related program interruptions increased medical mistrust andvaccine hesitancy related to misinformation spread on social media. There are additional critical gaps in care specifically boys who are ineligible for this program as well as adolescents outside the public school system.There is an urgent need to identify effective replicable and scalable strategies to optimize HPV vaccineuptake and completion in school-age children. The overall objective of the proposed R34 is to refine andevaluate a school-based multi-level communications strategy that addresses intrapersonal interpersonal andinstitutional factors associated with HPV vaccine uptake and completion amongst fifth graders as part of a pilotfeasibility trial. The proposed study is led by investigators from the United States and South Africa inpartnership with the Department of Health and elementary schools in an urban setting with high burden of HPVvaccine preventable cancers in KwaZulu Natal South African. The project builds upon our teams expertise inHPV prevention vaccine decision making health communications participatory design and communityengagement to pursue the following Specific Aims. (1) To refine components of a school-based multi-levelcommunication strategy to improve HPV vaccine uptake and completion among girls and boys and (2)To evaluate preliminary effects of the communications strategy and key criteria to advance to a full-scale hybrid type 2 trial. Our systems-focused approach leverages established partnerships with areaschools serving diverse populations who are not always effectively served by traditional healthcare channels.We will ensure health equity is at the core of our research integrating the voices of individuals living in low-resource settings to understand and reduce the barriers to HPV vaccine initiation and completion. Thisproposal is responsive to NCIs call for cancer prevention and control clinical trials planning grants (PAR-22-173) both in its active stakeholder engagement and its focus on engaging a diverse scientifically appropriatestudy population. 339735 +No NIH Category available Adaptive Immune System;Adenovirus Vector;Adult;Adverse effects;Affect;Antigen Presentation;Binding;Biological Assay;Bystander Effect;CAR T cell therapy;CAV2 gene;CD276 gene;Canis familiaris;Cell Death;Cell Line;Cells;Child;Childhood Osteosarcoma;Combined Modality Therapy;Cytolysis;Development;Disease;Disease-Free Survival;Distant;Down-Regulation;Environment;Generations;Goals;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologic Stimulation;Immunotherapy;Individual;Infiltration;Inflammatory Response;Laboratories;Malignant Bone Neoplasm;Malignant Neoplasms;Measurement;Mediating;Membrane Proteins;Modality;Modeling;Molecular;Monoclonal Antibodies;Oncolytic viruses;Operative Surgical Procedures;PD-1 inhibitors;PD-1/PD-L1;PDL1 inhibitors;Patients;Pattern;Production;Proteins;Recombinants;Site;Surface Antigens;Survival Rate;T-Lymphocyte;Testing;Transgenes;Translations;Tumor Antigens;Tumor Immunity;United States;Virotherapy;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;bone;cancer cell;cancer genetics;cancer immunotherapeutics;cancer immunotherapy;cancer therapy;cell killing;chemokine;chemotherapy;chimeric antigen receptor T cells;combat;conditionally replicative adenovirus;cytokine;cytotoxic;design;effector T cell;immune checkpoint;interdisciplinary treatment approach;long bone;multimodality;nanobodies;neoantigens;neoplastic cell;novel;novel strategies;oncolytic adenovirus;oncolytic virotherapy;osteosarcoma;programmed cell death ligand 1;programmed cell death protein 1;receptor;response;skills;synergism;targeted treatment;three dimensional cell culture;transmission process;tumor;tumor eradication;tumor initiation;tumor microenvironment;tumor-immune system interactions;vector Exploration of different immunotherapy modalities in osteosarcoma Project NarrativeA combination cancer immunotherapy utilizing CAR T cells and an oncolytic virus armed with immune checkpointinhibitors will be used to target osteosarcoma cells. Each treatment will be assessed individually and incombination for their ability to stimulate the immune system and kill osteosarcoma cells in 2D and 3D cell culture.These activities will be assessed by measurement of cell responses including cytokines and chemokinessecreted to induce immune responses in the tumor microenvironment. NCI 10730833 7/6/23 0:00 PAR-22-060 1R15CA283777-01 1 R15 CA 283777 1 "SOMMERS, CONNIE L" 7/5/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-CDPT-J(80)A] 14293817 "AGARWAL, PAYAL " Not Applicable 3 VETERINARY SCIENCES 66470972 DMQNDJDHTDG4 66470972 DMQNDJDHTDG4 US 32.602139 -85.508496 1470402 AUBURN UNIVERSITY AT AUBURN Auburn AL SCHOOLS OF VETERINARY MEDICINE 368325888 UNITED STATES N 7/5/23 0:00 6/30/26 0:00 395 Non-SBIR/STTR 2023 440640 NCI 300000 140640 Project Summary/AbstractOsteosarcoma (OS) is the most common primary bone malignancy affecting long bones in children and the thirdmost frequent in adults in the United States. The survival rates over the last 20 years are unchanged. OS is alsothe most common malignant bone tumor (80%) in dogs. Treatment options for OS are limited. Immunotherapyis a promising new approach that has yet to be fully explored in OS. Chimeric antigen receptor (CAR) T cells aredesigned to express recombinant receptors to target specific tumor cell surface antigens and promote T cell-mediated cancer cell death. However one of the biggest challenges in CAR T cell therapy is theimmunosuppressive tumor micro-environment (TME). Another immunotherapy strategy is the use of immunecheckpoint inhibitors such as monoclonal antibodies (mAb) against PD-1. Anti-PD-1 mAbs have shownsignificant efficiency in treating multiple tumors but cause adverse effects due to systemic delivery of the mAb.To avoid systemic delivery oncolytic viruses can be designed to produce immune checkpoint inhibitors directlyin TME to boost the immune system and enable T cells to kill tumor cells. Conditionally replicative adenoviruses(CRAds) replicate only in tumor cells lyse them and stimulate anti-tumor immunity in TME and at distant sitesof disease causing a bystander effect. However the limited number of effector T cells against cancer antigenslimits the efficacy of this approach. Therefore we propose a combination therapy to synergize these strategiesto combat tumor cells. We will combine CAR T cell therapy oncolytic virus and PD-1/PD-L1 inhibitor to targetosteosarcoma tumor cells. We have developed an armed oncolytic adenovirus to produce anti-PD-1 Ab in theTME. We will create two more armed oncolytic viruses that will produce secreted single domain antibodies (sdAb)to PD1 and PDL1. We will evaluate CRAd and CAR T cell (against B7-H3) induced tumor cells lysis. Theconditionally replicated oncolytic viruses will produce anti-PD1 and anti-PDL1 sdAb in TME reducing the adverseeffects of systemic administration and enhancing anti-tumor immunity. CAR T cells against B7-H3 will initiatetumor cell killing in an activated TME. Ultimately beyond the scope of this proposal this approach will be testedin spontaneous OS in canine patients before translation to pediatric OS patients. 440640 +No NIH Category available Administrative Coordination;Administrative Supplement;Adoptive Cell Transfers;Adult;Animal Model;Area;Bioinformatics;Biological;Biological Specimen Banks;Biometry;Cancer Center;Cell Therapy;Cells;Childhood;Clinic;Clinical;Clinical Research;Clinical Trials;Collaborations;Collection;Communication;Communities;Data;Data Collection;Data Management Resources;Data Science;Data Security;Development;Elements;Foundations;Funding;Human;Individual;Industry;Infrastructure;Institution;Leadership;Learning;Malignant Neoplasms;Multicenter Trials;Oncology;Patients;Policies;Positioning Attribute;Process;Reagent;Research;Research Personnel;Resources;Solid Neoplasm;Specimen;Standardization;Structure;Testing;Therapeutic;Therapeutic Agents;Translational Research;Work;anticancer research;biobank;clinical translation;data harmonization;data management;data sharing;data submission;design;early phase clinical trial;electronic data;experience;innovation;interest;manufacture;meetings;member;novel therapeutics;operation;pre-clinical;pre-clinical research;preclinical development;preclinical study;programs;research study;synergism;treatment response;web site;working group Cancer Adoptive Cell Therapy (Can-ACT) Network Coordinating Center at Mayo Clinic PROJECT NARRATIVE NETWORK COORDINATING CENTERThe Network Coordinating Center at Mayo Clinic (NCC-MC) will facilitate and be responsible for network-widecoordination and harmonization of scientific and administrative needs of the funded UG3/UH3 centers as partof the Cancer Adoptive Cellular Therapy (Can-ACT) Network. The NCC-MC will serve as the administrativehub and coordinating center for all network-related trials and projects including but not limited to: (1)administrative coordination of the Can-ACT Network (2) oversight and management of biological specimensand associated policies and (3) provision of analytic and data management support for the Can-ACT Networkincluding biostatistical and bioinformatics and data science collaboration and clinical and correlative datamanagement. The infrastructure expertise and experience of the individuals at Mayo Clinic is extensive forthe national coordination of translational and clinical cellular product-based research making this group well-positioned to effectively function as an outstanding coordinating center for the Can-ACT Network. NCI 10730805 8/29/23 0:00 RFA-CA-22-030 1U24CA283479-01 1 U24 CA 283479 1 "BOURCIER, KATARZYNA" 9/1/23 0:00 8/31/28 0:00 ZCA1-RTRB-Y(M1) 6854103 "GEYER, SUSAN MICHELLE" "ASMANN, YAN W." 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Other Research-Related 2023 480332 NCI 355564 124768 PROJECT SUMMARY/ABSTRACT NETWORK COORDINATING CENTERThe Network Coordinating Center (NCC) will facilitate and be responsible for network-wide coordination andharmonization of scientific and clinical needs of the funded UG3/UH3 centers comprising the Cancer AdoptiveCellular Therapeutics (Can-ACT) Network. The Network Coordinating Center at Mayo Clinic (NCC-MC) willserve as the administrative hub and coordinating center for all network-related trials and projects. This willinclude multiple aspects of the functioning of this network including the administrative and scientificcoordination of the Can-ACT Network. The administrative coordination will include (a) providing leadership andfacilitating interactions across the network (b) providing administrative infrastructure to support the activities ofthe Can-ACT Network and (c) the coordination of the restricted collaborative funds and administrativesupplements for the network. Scientific coordination of this network will include several different criticalcomponents including (a) identifying and establishing strategies for facilitating reagent and specimen sharing(b) identification and harmonization of process development and manufacturing steps for cell productmanagement and utilization for the functioning of the network between centers and the ICN Core (c)biostatistical support and collaboration for preclinical and clinical research studies and centralized datamanagement and shared data governance and (d) bioinformatics and data science support and collaboration.The infrastructure expertise and experience of the individuals at Mayo Clinic with national coordination oftranslational and clinical research is extensive making this group well-positioned to function as an outstandingcoordinating center for the Can-ACT Network. The leadership of this proposed coordinating center brings withthem complementary and deep experience and background across these key aims and they have workedextensively with multi-institutional trials consortia and networks as well as cooperative groups in researchleadership trial coordination and implementation data structures and importantly development of SOPs andguidance for newly formed collaborative research networks across multiple institutions. Beyond the experienceand expertise the NCC-MC also leverages institutional infrastructure and resources to adapt and evolve as theCan-ACT Network develops and grows through the expected and necessary collaborations across allUG3/UH3 centers and project leaders. 480332 +No NIH Category available Area;Automobile Driving;Award;Bioinformatics;Cancer Biology;Cell Reprogramming;Dedications;Developmental Process;Epigenetic Process;Funding;Grant;Inflammation;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of prostate;Medicine;Mesenchymal;Metabolism;Molecular;Molecular Biology;Neurosecretory Systems;Pathology;Process;Prostatic Neoplasms;Research;Resistance;Scientist;Seminal;Signal Transduction;Solid;Specialist;Technical Expertise;Therapeutic;Time;Training;Variant;Wages;bioinformatics tool;cancer cell;cancer cell differentiation;castration resistant prostate cancer;design;effective therapy;human disease;in vivo;mouse model;novel;pressure;programs;prostate cancer cell;success;tumor metabolism Molecular mechanisms driving therapy-induced lineage plasticity PROJECT NARRATIVELineage plasticity is a developmental process of cell reprogramming employed by cancer cells as a mechanismof therapy resistance. Dr. Linaress application for the R50 Research Specialist Award will support Dr.Diaz-Mecos research program focused on elucidating the molecular mechanisms that regulate lineage plasticityin prostate tumors. Unveiling the mechanisms that control this process is crucial to find new targets forcastration-resistant prostate cancer. NCI 10730635 9/19/23 0:00 PAR-22-187 1R50CA283476-01 1 R50 CA 283476 1 "KAI, MIHOKO" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-1(M1) 10454918 "LINARES RODRIGUEZ, JUAN FRANCISCO " Not Applicable 12 PATHOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 160725 NCI 94823 65902 SUMMARYThis proposal seeks Dr. Juan Francisco Linaress salary as a Research Specialist to support Dr. Maria T.Diaz-Mecos research program at the Weill Cornell Medicine Department of Pathology and Laboratory Medicineto study the molecular and cellular mechanisms that regulate lineage plasticity in prostate cancer. Theelucidation of the molecular mechanisms that castration-resistant prostate cancer cells (CRPC) use to evadetherapeutic pressures requires scientists with an in-depth understanding of the molecular biology of this processbut also with the required technical expertise in in vivo mouse models that faithfully recapitulate human diseaseas well as the necessary bioinformatics tools to perform rigorously epigenetic analysis. Therefore with thisResearch Specialist Award we intend to provide stable research opportunities for the exceptional scientist JuanFrancisco Linares to develop impactful research in this area of expertise. He has made seminal contributions insignaling inflammation metabolism and cancer and has solid interdisciplinary training that will be critical for theprojects success. He will contribute to the research program focused on defining the molecular and cellularmechanisms that drive the differentiation of CRPC to more aggressive prostate cancer variants such asNeuroendocrine and Mesenchymal prostate cancer. With his expertise in cancer biology and cancer metabolismand his capacity to apply novel mouse models and bioinformatics approaches he is filling a unique niche withinthe Diaz-Meco lab that will provide continuity stability and detailed scientific knowledge to achieve the aims ofthe NCI-funded grants. Dr. Linaress long-time expertise and dedication will advance our understanding of thelineage plasticity in CRPC to help design more effective therapies to overcome the acquired resistance inprostate cancer. 160725 +No NIH Category available Apoptotic;Benign;Bioinformatics;Biologic Characteristic;Biological;Biological Assay;Biological Markers;Biological Process;Blood;Cancer Detection;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Chest;Clinical;DNA;DNA Library;DNA sequencing;Data;Development;Diagnosis;Disease;Drug resistance;Early Diagnosis;Early Intervention;Elements;Epidermal Growth Factor Receptor;Face;Frequencies;Generations;Hematopoiesis;Individual;Libraries;Lung Neoplasms;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Methods;Modeling;Molecular Profiling;Monitor;Morbidity - disease rate;Mutation;Names;Necrosis;Nodule;Non-Invasive Detection;Non-Small-Cell Lung Carcinoma;Nucleic Acids;Patients;Pattern;Performance;Plasma;Population;Preparation;Procedures;Publications;Research;Sensitivity and Specificity;Single-Stranded DNA;Solid Neoplasm;Somatic Mutation;Source;Statistical Data Interpretation;Testing;Therapeutic;Thoracic Radiography;Validation;Variant;Work;X-Ray Computed Tomography;actionable mutation;cell free DNA;clinical application;cohort;computed tomography screening;diagnostic strategy;direct application;early detection biomarkers;effective therapy;genome-wide;high risk population;improved;liquid biopsy;low dose computed tomography;lung basal segment;lung cancer screening;molecular diagnostics;molecular marker;mortality;neoplastic cell;new technology;novel;novel marker;predictive modeling;response;screening program;tumor;tumor DNA Novel ultra-short cell free DNA biomarkers for early detection of non-small cell lung cancer. PROJECT NARRATIVELung cancer is the leading cause of cancer death in the U.S. and worldwide. This application seeks to developnovel blood-based lung cancer-associated molecular markers to distinguish between patients with benign ormalignant nodules detected on computed tomography. It can provide a ground-breaking improvement insensitivity and specificity as required to reliably detect lung cancer at an early stage. NCI 10730508 7/5/23 0:00 PAR-22-216 1R21CA283665-01 1 R21 CA 283665 1 "MARQUEZ, GUILLERMO" 7/15/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 14097927 "LI, FENG " "WONG, DAVID T" 36 DENTISTRY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF DENTISTRY/ORAL HYGN 900952000 UNITED STATES N 7/15/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 183494 NCI 116875 66619 PROJECT SUMMARY/ABSTRACT Lung cancer remains the leading cause of cancer-related deaths in the U.S. and worldwide. Nonsmall celllung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Early detection of indeterminatepulmonary nodules (IPNs) with chest low dose computed tomography (LDCT) screening followed by effectivetreatments can reduce mortality by 20% relative to chest radiography. However the high false positive ratefinding as >95% limits the application. The unmet clinical need for early diagnosis is the lack of a noninvasivetest that can be applied to individuals with CT-detected lung nodules and reliably discriminates betweenmalignant or benign nodules. Liquid biopsy focused on the characterization of tumor-associated geneticalterations in cell free circulating tumor DNA can non-invasively profile the molecular landscape of solid tumors.However the low biological concentrations of ctDNA low frequency of somatic mutations and the confoundingimpact of clonal hematopoiesis-related variants in early-stage lung cancer limit the sensitivity of ctDNA-basedliquid biopsy assays. It would be essential if additional cell free DNA biomarkers could be included to allow thedevelopment of more sensitive molecular diagnostics approaches for the early assessment of lung cancer. We have discovered a distinct population of ultra-short single-stranded cell-free DNA (uscf/ctDNA) with asize of 40-70nt in healthy and NSCLC plasma. Our preliminary data showed that the fragmentomic featuresincluding functional element profile fragmentation patterns and end motifs of uscfDNA molecules candistinguish NSCLC patients from healthy donors. This R21 application is to explore and test our hypothesis thatthe fragmentomic features of uscfDNA molecules can serve as novel biomarkers to differentiate NSCLC patientsfrom non-cancer subjects with IPNs and allow more sensitive liquid biopsy molecular diagnostics for earlyNSCLC detection. Two specific aims are in place for hypothesis testing. Aim 1 is to develop a predictive modelusing uscfDNA-seq assay on uscfDNA fragmentomic analysis for liquid biopsy of NSCLC. Aim 2 is to pre-validateuscfDNA-Seq test for the early detection of NSCLC. Together the translational and pre-validation targetinguscfDNA for early detection of NSCLC can break new ground and extend previous discoveries towards impactfulnew directions and clinical applications. 183494 +No NIH Category available 16S ribosomal RNA sequencing;Acceleration;Achievement;Administrator;Adverse event;Agreement;Antigens;Architecture;Biological Assay;Biological Markers;Biometry;Blood;Cancer Center;Cell Therapy;Cells;Characteristics;Clinical;Clinical Trials;Collaborations;Communities;Complex;Correlative Study;Dana-Farber Cancer Institute;Data;Data Commons;Data Scientist;Data Set;Dedications;Ensure;FDA approved;Fruit;Funding;Genetic;Goals;Heart;Hematologic Neoplasms;Human;Human Resources;Immune;Immunologic Monitoring;Immunologics;Immunologist;Immunooncology;Immunotherapy;Institution;Joints;Knowledge;Laboratories;Leadership;Malignant Neoplasms;Manuscripts;Methodology;Mission;Modality;Modeling;Molecular;Molecular Profiling;Mutation;Outcome;Output;Pathologist;Pathology;Pathway interactions;Patients;Phenotype;Play;Postdoctoral Fellow;Practice Guidelines;Procedures;Process;Prognostic Marker;Proteomics;Protocols documentation;Recommendation;Reproducibility;Research;Resistance;Resources;Sampling;Scientist;Serum;Solid Neoplasm;Specialist;Specimen;Standardization;T cell receptor repertoire sequencing;Technology;Thinking;Time;Tissues;Tumor Tissue;Universities;Viral;Work;biomarker discovery;cancer clinical trial;cancer immunotherapy;cancer therapy;candidate marker;clinically actionable;complex data;cost;data integration;data repository;data sharing;demographics;design;early phase clinical trial;empowerment;exceptional responders;expectation;fitness;high dimensionality;immune checkpoint;immune checkpoint blockade;immunotherapy clinical trials;immunotherapy trials;improved;innovation;interest;machine learning method;medical schools;microbiome;multidimensional data;multiple omics;new therapeutic target;next generation;novel;novel marker;pharmacodynamic biomarker;predictive marker;programmed cell death ligand 1;programs;repository;response;response biomarker;sample collection;technology platform;transcriptome sequencing;transcriptomics;tumor;tumor-immune system interactions High-Dimensional Immune Monitoring of NCI-Supported Immunotherapy Trials NARRATIVEThrough rigorous implementation of state-of-the-art cross-compared technological platforms we aim toaccelerate identification of clinically actionable biomarkers of response resistance and adverse events anddefine mechanisms at play to guide and improve novel NCI-supported cancer immunotherapy clinical trials. NCI 10730469 7/21/23 0:00 RFA-CA-22-038 2U24CA224319-02 2 U24 CA 224319 2 "SONG, MIN-KYUNG H" 9/30/17 0:00 6/30/28 0:00 ZCA1-SRB-K(M1) 9612909 "GNJATIC, SACHA " "KIM-SCHULZE, SEUNGHEE " 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 7/21/23 0:00 6/30/24 0:00 353 Other Research-Related 2023 1983570 NCI 1698738 1147979 SUMMARYDefining who is likely to respond to cancer immunotherapy and who may not benefit due to primary/secondaryresistance or adverse events is of critical interest for improving immuno-oncology (IO) treatments. Most clinicaltrials of novel combinations either fail to include any support for complex correlative biomarker discovery oftendue to costs of specimen collection and assays or are performed in an idiosyncratic manner making non-standardized data difficult to integrate as part of a larger repository. There is a need to go beyond just PD-L1tissue expression and tumor mutation burden as FDA-approved yet imperfect predictors of immune checkpointblockade by generating high-dimensional datasets that characterize the tumor immune microenvironmentsystemic circulating immune and proteomic markers from blood and host-level immune fitness information(microbiome). The Cancer Immune Monitoring and Analysis Centers Cancer Immunologic Data Commons andPartnership for Accelerating Cancer Therapies (CIMAC-CIDC-PACT) is a Cancer Moonshot-funded network thatbrings together laboratory clinical and computational scientists administrators and regulatory specialists fromfour institutions Icahn School of Medicine at Mount Sinai (ISMMS) MD Anderson Cancer Center (MDACC)Dana-Farber Cancer Institute (DFCI) and Stanford University. Our unprecedented coordinated effort to conductIO clinical trial correlative studies and define new candidate biomarkers to improve immunotherapy had resultedin 37 clinical trials selected in the first funding period with ongoing datasets resulted for 17 of them. This wasachieved using rigorously assessed SOPs and processes from trial selection to data sharing. We propose tocontinue and expand these efforts as follows: A set of well-established harmonized high-dimensional tumor andblood-based assays will be applied to all newly selected trials with the aim of evaluating and validating novelbiomarker of treatment clinical response and/or adverse events (Aim 1). To spur innovation and increasegranularity of our understanding of mechanism of action high-tech yet validated single cell and spatialtranscriptomic technologies as well as other omics will be proposed in exceptional patients for unbiasedphenotyping tissue composition architectural organization and immune profiling (Aim 2). The resulting unifieddata repository will be mined to define multi-omic and cross-trial markers through biostatistical andcomputational innovative design to integrate datasets from various assays into higher analytical archetypesacross studies (Aim 3). Together our network is at the forefront of immune monitoring standards by balancinginnovation with reproducibility to comprehensively assess biomarkers and strive for precision cancer treatment.We are poised to create an unparalleled resource of harmonized clinically annotated datasets shared with thepublic that will establish best practice guidelines with the research community. Through rigorous implementationof state-of-the-art cross-compared platforms the CIMAC-CIDC initiative aims to accelerate identification ofclinically actionable biomarkers of response resistance and adverse events and define mechanisms at play. 1983570 +No NIH Category available ATAC-seq;Biological Assay;Biological Markers;Biometry;Cancer Center;Cancer Control;Cells;Clinical;Clinical Data;Clinical Trials;Collaborations;Correlative Study;Data;Data Commons;Databases;Elasticity;Ensure;Genomics;Grant;Guidelines;Image;Immune;Immunologic Monitoring;Immunology procedure;Immunotherapy;Lead;Machine Learning;Malignant Neoplasms;Measures;Mining;Mission;Outcome;Phenotype;Polysaccharides;Proteomics;Publishing;Quality Control;Regimen;Research;Sampling;Specific qualifier value;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Standardization;T cell receptor repertoire sequencing;Techniques;Technology;Testing;Work;cancer clinical trial;data submission;innovation;meetings;nano-string;novel;predictive marker;regression algorithm;transcriptome sequencing;transcriptomics;treatment response;working group Stanford Cancer Immune Monitoring and Analysis Center (CIMAC) Project NarrativeThe Stanford CIMAC center will provide access to a suite of state-of-the-art immune assaysmany of them developed or refined at Stanford and work collaboratively with the other CIMACcenters as well as the CIDC clinical trial teams NCI PACT/FNIH and pharma collaborators.Our unmatched set of technologies will facilitate the discovery of new biomarkers for predictingcancer outcome or therapeutic response as well as defining potential new mechanisms ofimmune control of cancer. NCI 10730465 7/12/23 0:00 RFA-CA-22-038 2U24CA224309-02 2 U24 CA 224309 2 "SONG, MIN-KYUNG H" 9/30/17 0:00 6/30/28 0:00 ZCA1-SRB-K(M1) 1968457 "MAECKER, HOLDEN T." "BENDALL, SEAN CURTIS" 16 MICROBIOLOGY/IMMUN/VIROLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 7/12/23 0:00 6/30/24 0:00 353 Other Research-Related 2023 1836054 NCI 1188000 648054 AbstractFor this CIMAC renewal the Stanford Cancer Immune Monitoring and Analysis Center(CIMAC) will continue to collaborate with NCI and the CIMAC/CIDC network to identify andwhere appropriate lead correlative studies for trials testing novel immunotherapy regimens. Wewill participate in working group calls network meetings and coordination with clinical teams.The Stanford CIMAC performs highly comprehensive assays of immune phenotype andfunction for NCI-identified clinical trials. These will include already validated and harmonizedTier 1 assays validated Tier 2 assays and newly proposed exploratory Tier 3 assays. For Tier 1assays we propose CyTOF singleplex IHC Olink TCRseq and RNAseq. For Tier 2 wepropose single-cell TCRseq MIBI ATACseq and CyTOF proteomics. For Tier 3 we proposesingle-cell glycan imaging (by MALDI-ToF) spatial transcriptomics (Nanostring DSP platform)and single-cell genomics/proteomics (Mission Bio Tapestri and BD Rhapsody platforms). We willuse longitudinal reference materials for tracking inter-batch and inter-project consistency. Wewill assess quality control measures on all assays before uploading data to the Cancer ImmuneData Commons (CIDC) according to their specifications.We will also perform biostatistical analysis of results for all assays performed in relation toclinical outcome data. For those trials where Stanford is the lead CIMAC we will performintegrative analysis across assays using appropriate machine learning techniques andmultivariate regression algorithms such as LASSO or Elastic Net. We will work closely with theclinical teams to obtain standardized clinical data and to disseminate and publish results inaccordance with NCI guidelines. 1836054 +No NIH Category available 3-Dimensional;Behavior;Biological Markers;Calibration;Cataloging;Cells;Clinical;Complex;Computer software;Data;Development;Dimensions;Ecological Change;Ecology;Ecosystem;Environment;Feedback;Generations;Genotype;Heterogeneity;Histology;Image;Immune;Immunofluorescence Immunologic;Investigation;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Modeling;Non-Small-Cell Lung Carcinoma;Pattern;Recording of previous events;Resolution;Sampling;Shelter facility;Slice;Speed;Stains;Techniques;Testing;Thinking;Time;Tissues;Visualization;cancer therapy;computational pipelines;data pipeline;high dimensionality;histological specimens;image registration;imaging modality;improved;insight;interest;mathematical model;multimodality;multiplexed imaging;novel therapeutic intervention;spatiotemporal;three dimensional structure;tissue reconstruction;tool;treatment response;tumor;tumor behavior;tumor heterogeneity;tumor microenvironment;tumor progression;tumor-immune system interactions;whole slide imaging Core 2: Ecological Core n/a NCI 10730409 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7470 12573241 "BROWN, JOEL " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 337871 205578 132293 Summary Ecological CoreRecent advances in spatial omics have led to an increased interest in studying and predicting emergentaggregate behavior and interactions between the tumor and its microenvironment. Tumors are dynamicrapidly evolving and undergoing ecological shifts; therefore the understanding of tumor progression andresponse to therapy will benefit from studying eco-evolutionary interactions over time. Investigation of thespatial and spatiotemporal interactions within the tumor immune microenvironment requires computationalapproaches to identify and investigate the diverse ecological patterns that emerge by virtue of these complexdynamics. The Ecological Analysis Core will cater to the generation investigation and application of the spatialecological models and techniques to support the two non-small cell lung cancer (NSCLC)-focused Projects ofthe proposal. Given that ecological change over space and/or time (the -Ecology) is a central theme sharedby both Projects the Core is poised to support and tailor the tools to the requirements of each Project. TheCore will have the capability to the ability to manage visualize store share and perform quantitative analysesof the high-dimensional and high-resolution clinical and experimental histology images. We will also buildimportant computational approaches and developmental frameworks to improve our understanding andprediction of emergent tumor behavior using the images. In summary the Core will develop and apply spatialecological models in concert with mathematical models from the Mathematical Modeling Core to understandthe evolutionary ecology underlying the diversity and maintenance of tumor heterogeneity and how this can beleveraged to guide new therapeutic strategies for lung cancer. +No NIH Category available Animals;Basic Science;Blood;Blood Vessels;Bone Tissue;Breast;Calibration;Cancer Center;Clinical;Clinical Data;Clinical Trials;Complex;Computer Models;Connective Tissue;Data;Data Collection;Development;Differential Equation;Disease;Ecology;Evolution;Faculty;Goals;Heterogeneity;Histology;Human;Hybrids;Immune;In Vitro;Link;Logic;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mathematics;Metabolism;Methods;Modeling;Mus;Non-Small-Cell Lung Carcinoma;Oncology;Pathway interactions;Patients;Phenotype;Play;Preclinical Testing;Process;Prostate;Regimen;Resolution;Science;Services;Skin;Stromal Neoplasm;Testing;Tissues;Tumor Burden;Uncertainty;Work;body system;brain tissue;cancer cell;cancer therapy;cancer type;cell type;clinical investigation;cohort;data integration;dynamic system;flexibility;in vivo;innovation;insight;mathematical model;member;molecular dynamics;molecular scale;multidisciplinary;novel;phase I trial;pre-clinical;programs;sarcoma;theories;tool;treatment optimization;treatment response;treatment strategy;tumor;tumor growth;tumor initiation;tumor microenvironment;virtual;virtual patient Core 1: Mathematical Core n/a NCI 10730408 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7469 9790902 "ANDERSON, ALEXANDER ROBERTSON ALLAN" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 406144 241035 165109 Summary Mathematical Modeling CoreUnderstanding the changes in tumor ecology (-Ecology) that occur during tumor initiation progression andtherapy requires careful study of a complex dynamical system involving multiple scales from molecular tocellular to tissue to systemic. An important tool in this study is the use of mathematical models which canbridge temporal gaps in clinical and experimental data. Ecological histology data from patients is difficult andrare to obtain and experimental work while crucial for teasing apart mechanism and testing hypothesescannot fully reproduce the human setting of disease. Mathematical modeling serves as a link between theseapproaches allowing ecological principles arising from mechanisms studied in vitro and in vivo to play out inthe patient setting calibrated to available patient data. The Mathematical Modeling Core will develop thesemodels using a variety of approaches. Key is the use of spatial agent-based models which can handle therich diversity of cell types and molecules as well as the multiple scales involved in tumor ecology andevolution. We have built a platform for developing these models that is fast and flexible including numerousadd-ons that will serve the science in the two projects of this proposal. In addition our expertise in non-spatialmodels will be applied in parallel as these approaches can capture the broad dynamics of tumor growth andthe response to treatment in ways that have significant translatable potential as evidenced by ongoing trials inEvolutionary Therapy at Moffitt. In addition to constructing these models we will develop tools for initializingcalibrating and analyzing models based on clinical and pre-clinical data collected in each project. This willinvolve the use of virtual Phase i trials where virtual patients/mice are generated from a model takingparameter uncertainty into account. In summary the Core models will provide insight into the ecologicalprocesses that occur during tumor growth and treatment. +No NIH Category available Acceleration;Advocate;Applications Grants;Archives;Area;Award;Biological;Biological Models;Biological Sciences;Cancer Center;Cancer Patient;Clinic;Clinical;Clinical Data;Clinical Oncology;Collaborations;Communities;Complex;Data;Dedications;Development;Dryness;Ecology;Education;Education and Outreach;Educational process of instructing;Educational workshop;Elements;Experimental Models;Faculty;Festival;Fostering;Funding;Future;Gene Expression;General Population;Generations;Goals;High School Student;Home;Image;Incubators;Individual;Institution;Internships;Joints;Journals;Life;Literature;Malignant Neoplasms;Manuscripts;Mathematics;Minority;Modality;Modeling;Molecular;Non-Small-Cell Lung Carcinoma;Oncologist;Oncology;Organ;Paper;Participant;Patients;Pilot Projects;Postdoctoral Fellow;Preparation;Process;Publications;Recruitment Activity;Research;Research Design;Research Personnel;Science;Scientist;Senior Scientist;Series;Students;System;Systems Biology;Taste Perception;Techniques;Tissues;Training;Training Activity;Translating;Translations;Update;anticancer research;career;college;data sharing;design;experience;experimental study;graduate student;high school program;histological stains;innovation;interdisciplinary collaboration;interest;learning materials;lectures;mathematical model;member;minority investigator;minority patient;next generation;novel;novel therapeutic intervention;outreach;predicting response;programs;symposium;tool;training opportunity;treatment strategy;tumor initiation;undergraduate student;university student;web site;working group Outreach Core n/a NCI 10730407 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7468 10062275 "ENDERLING, HEIKO " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 142691 84683 58008 SummaryCentral to the Moffitt-CSBC Education core is an annual innovative unique and intense one-weekinterdisciplinary hands-on workshop to accelerate the training of the next generation of integrated cancerresearchers. Future leaders in cancer research must be well-versed at the interface of quantitative and lifesciences. The workshop uses current Center projects to teach integration of ecology biological experimentsand mathematical modeling to decipher tumor initiation promotion and progression and predict response to avariety of treatment modalities. Each team led by CSBC investigators will be comprised of students postdocspatients and faculty members with different expertise. During the intense 5 day workshop each team willdevelop quantitative models for the specific projects develop a set of specific aims for a pilot grant proposaland give a short presentation that will be critically evaluated by a panel of senior scientists and patientadvocates. Moffitt Cancer Center has committed to funding the best grant applications with a $50K pilot projectaward for the next 5 years in order to facilitate project continuation. Participation from Consortium centers isencouraged to foster close collaborations between CSBC network investigators. Center students andpostdoctoral fellows will participate in young investigator exchange programs and career enhancing educationworkshops. To spark interest in the application of ecology and systems biology in oncology early in life we willimplement a variety of new internship programs ranging from high-school student research experiences tocollege undergraduate and graduate student internships all with a dedicated focus in integrating minorityresearchers and patient perspectives. The Moffitt Outreach core introduces novel programs to present cancersystems biology to the general public. CSBC public evening lectures as well as participation in and support ofthe annual Festival of Science festival in the Tampa Bay area will introduce cancer systems biology research inlayman terms and offers opportunities for the patient community and general public to engage in a directdialogue with eminent researchers. Outreach and training lectures as well as developed course materials andscience projects will be made available and archived on our professionally designed Center-dedicated website. +No NIH Category available Allografting;Birth;CRISPR library;Calibration;Cell Proliferation;Cells;Cessation of life;Combined Modality Therapy;DNA Sequence Alteration;Data Analyses;Development;Disease remission;Ecology;Ecosystem;Epidermal Growth Factor Receptor;Epigenetic Process;Evolution;Experimental Models;Failure;Genetic Programming;Guide RNA;Interdisciplinary Study;KRAS2 gene;Lentivirus Vector;Modeling;Molecular;Mus;Mutation;Non-Small-Cell Lung Carcinoma;Oncogenic;Outcome;Patients;Phenotype;Population;Probability;Proliferating;Property;Receptor Protein-Tyrosine Kinases;Relapse;Residual Neoplasm;Residual state;Resistance;Shapes;Shelter facility;Signal Transduction;Speed;System;Therapeutic;Therapeutic Intervention;Time;Vertebral column;Xenograft Model;Xenograft procedure;analysis pipeline;cancer therapy;digital pathology;experimental study;functional genomics;in silico;in vivo;inhibitor;insight;knowledge base;model development;mouse model;mutant;neoplastic;neoplastic cell;novel;novel strategies;paracrine;pharmacologic;resistance mechanism;resistance mutation;response;spatiotemporal;targeted treatment;tool;transcriptomics;translational approach;treatment optimization;tumor;tumor growth Project 2: Delta Stromal Ecology of NSCLC n/a NCI 10730406 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7467 10202847 "MARUSYK, ANDRIY " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 481470 285739 195731 Project 2 abstractProject 2 will investigate the changes in neoplastic and stromal compartments during the acquisition ofresistance to ALK and KRAS targeting therapies with specific emphasis on the therapy-sheltering impact ofthe stromal niche observed in multiple experimental models. Despite the growing appreciation of the potentialcontribution of stromal on the sensitivity of tumor cells to targeted therapies there are no establishedconceptual frameworks and experimental pipelines to account for this effect on evolving resistance.Confounding the challenge acquired resistance cannot be understood just with before-after snapshotanalyses as the sensitivity of tumor cells to therapies stroma-tumor ratio and stromal composition and effectare dynamically changing over the course of treatment. To understand the Decology of acquired resistance wewill perform system-level characterization of temporal and spatial phenotypic changes within the tumor andstromal compartments including changes in proliferation/death and clonal dynamics. These changes will becaptured in the formalism of in silico models through careful integration of experimental and modeling tools.The quality and utility of the models will be assessed by making experimentally testable predictions. Followingcalibration the models will be used to find novel strategies for combination therapies that optimize long-termremission. Initial model development and calibration will be performed in a xenograft model of ALK+ NSCLCthat has been the focus of our recent interdisciplinary studies. Subsequently we will use the pipelines to gainan understanding of the eco-evolutionary dynamics of other xenograft and syngeneic models of ALK+ andKRASG12C NSCLC. These studies will help develop the robust knowledge base required for the developmentof novel and impactful translational strategies. +No NIH Category available Affect;Antitumor Response;Autopsy;Biological Markers;Biopsy;Blood;CT26;Calibration;Cancer Patient;Cells;Clinical;Clinical Data;Clinical Research;Clinical Trials;Colon Carcinoma;Combined Modality Therapy;Data;Development;Disease;Ecological Change;Ecology;Evolution;Future;Goals;Human;Immune;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotherapy;KRAS2 gene;Lung Neoplasms;MEKs;Machine Learning;Malignant Neoplasms;Modeling;Mus;Nature;Non-Small-Cell Lung Carcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I/II Trial;RAS inhibition;Randomized;Resistance;Resistance development;Sampling;Signal Pathway;Specimen;Stains;Study models;System;T cell response;T cell therapy;Testing;Thoracic Oncology;Tissue Donations;Treatment Protocols;Tumor-Infiltrating Lymphocytes;Work;analysis pipeline;anti-PD-1;arm;cancer cell;cancer therapy;clinical efficacy;computer infrastructure;deep learning;design;experimental study;improved;improved outcome;in vivo;inhibitor;inhibitor therapy;mathematical model;multiplexed imaging;mutant;neoplastic cell;novel;patient response;pembrolizumab;phase I trial;pre-clinical;predicting response;predictive modeling;prevent;programs;resistance mechanism;response;spatiotemporal;statistics;synergism;targeted agent;targeted treatment;tool;treatment response;treatment strategy;tumor;tumor progression;whole slide imaging Project 1: Delta immune Ecology of NSCLC n/a NCI 10730405 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7466 9790902 "ANDERSON, ALEXANDER ROBERTSON ALLAN" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 500733 297171 203562 Summary Project 1Project 1 will study the -Ecology of tumor-immune interactions in NSCLC with a focus on KRAS-mutantcancers. Immunotherapy has demonstrated response rates of 30 to 45%. Most responses are followed byevolution of resistance and progression. Recently we have quantified the immune ecology of these cancersfrom pre-treatment biopsies and found unique ecological interactions that predetermine therapy response. Afocus of this proposal will be to use both pre- and on-treatment biopsies from a clinical trial to quantify theimmune -Ecology during therapy. We will use a computational multiplexed-image analysis pipeline that takeswhole-slide images and segments the data into cells and quadrats to analyze the spatial and spatiotemporalfeatures representing ecological changes that drive tumor progression. We will then harness this analysis as aspatiotemporal biomarker to alter treatment strategies via mathematical modeling. The computationalinfrastructure will be grounded in mechanistic models spatial statistics machine learning and deep learning.Targeted therapies are also a key component in the treatment of this disease. In an exciting discoveryinhibitors that target KRAS-G12C mutant cancers have been developed and have demonstrated clinicalefficacy. Furthermore preclinical work has demonstrated that these inhibitors alter the immune ecology oftumors offering promise that combination targeted therapy and immunotherapy can significantly improveresponses. We will perform in vivo work with murine tumors and deep ecological analysis of human tumors todetermine the mechanisms of immune -Ecology fomented by KRAS inhibitors and probe combinationtherapies that synergize the anti-tumor response. Our ultimate goal is the development of a predictive model of-Ecology that delivers novel treatment strategies and improves outcomes for use in future clinical trials. +No NIH Category available Adherence;Award;Budgets;Cancer Center;Collaborations;Communication;Development;Ecology;Education;Education and Outreach;Educational workshop;Ensure;Evaluation;Fostering;Funding;Funding Opportunities;Information Distribution;Institution;Internships;Investigation;Letters;Malignant Neoplasms;Mission;Non-Small-Cell Lung Carcinoma;Organization and Administration;Pilot Projects;Play;Preparation;Process;Progress Reports;Reporting;Research;Research Personnel;Resources;Role;Systems Biology;Travel;dashboard;equity diversity and inclusion;high school;innovation;interest;meetings;member;outreach;programs;social media;symposium;web site Administrative Core n/a NCI 10730404 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7465 9790902 "ANDERSON, ALEXANDER ROBERTSON ALLAN" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 220388 130794 89594 ADMINISTRATIVE CORE SUMMARYThe Administrative Core remains a central component of the Moffitt CSBC. It has oversight of the disbursal offunds to the Projects and Cores. It is the clearinghouse for communication between the Moffitt CSBC and theNCI and other members of the network. The core prepares the yearly reports to the NCI and will host theExternal Scientific Advisory Board as well as the annual Integration Symposium. The Administrative Core willprovide travel support for the Moffitt CSBC team invited guest speakers and external advisors. To fosterscientific collaborations with researchers interested in related research with particular focus on CancerSystems Biology the admin Core will be responsible for the distribution of information materialscommunication with other institutions and collaborations with other relevant research programs. The admincore plays a particularly critical role in the CSBC pilot projects. The administrative core will advertise pilotfunding opportunities collect applications organize the review panel and oversee the conduct of the fundedresearch. These funds will be used to support exploratory research that aligns with the evolutionary andecological theme of our CSBC as well as unexpected avenues of investigation that arise through developmentsin the CSBC projects and core. Applications will be prioritized according to their (a) scientific merit i.e.significance and feasibility; (b) centrality to the mission of the Moffitt CSBC i.e. an eco-evolutionary view ofcancer and (c) innovation i.e. a new paradigm. These projects will be supported by the $50000 annualinstitutional funding for pilot awards (see intuitional letter of support). In addition in years 1-5 the Moffitt CSBCbudget includes another $50K for pilot awards. The Moffitt Cancer Center currently funds $50K per year to thewinner of the annual IMO transdisciplinary workshop (also guaranteed for the next 5 years). Finally our CSBCbudget also provides an annual budget of $75000 for trans-network projects (a requirement of the RFA) thatwill enrich for center-center collaborations ensuring the CSBC network flourishes. +No NIH Category available Aftercare;Anatomy;Automobile Driving;Biological Models;Calibration;Cells;Clinical;Clinical Data;Collaborations;Collection;Complex;Computing Methodologies;Data;Development;Disease;Disease Progression;Ecological Change;Ecology;Ecosystem;Encapsulated;Engineering;Environment;Epidermal Growth Factor Receptor;Evolution;Extinction;Failure;Fibroblasts;Genes;Goals;Grant;Growth;Heart;Homeostasis;Human;Immune;Immune response;Immunity;Immunologics;Immunologist;Immunotherapy;In Vitro;Individual;Infiltration;Invaded;KRAS2 gene;Knowledge;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mathematics;Microanatomy;Modeling;Molecular;Mutate;Mutation;Neoplasms;Non-Small-Cell Lung Carcinoma;Normal Cell;Nutrient;Oncologist;Oncology;Organ;Outcome;Oxygen;Pathologist;Patients;Philosophy;Population;Process;Production;Proliferating;Property;Relapse;Resistance;Resistance development;Resource Sharing;Resources;Sampling;Shapes;Shelter facility;Testing;Therapeutic;Therapy Clinical Trials;Thoracic Oncology;Time;Tissues;Treatment Protocols;Work;cancer cell;cancer therapy;cell transformation;cell type;clinical decision-making;cytokine;cytotoxic;data repository;driver mutation;fitness;host neoplasm interaction;in silico;in vivo;inhibitor therapy;mathematical analysis;mathematical methods;mathematical model;multidisciplinary;neoplastic;neoplastic cell;novel therapeutic intervention;outcome prediction;predictive modeling;pressure;response;success;targeted agent;targeted treatment;tool;treatment response;treatment strategy;tumor;tumor behavior;tumor growth;tumor progression The Delta Ecology of NSCLC Treatment NARRATIVETumors are not simply collections of mutated cells that grow in isolation; rather they respond to and modify boththe physical microenvironment and a variety of host cells in the organ they are invading. These changes inecology (-Ecology) are key to understanding tumor progression and the response to therapy particularly thedevelopment of resistance. We focus on NSCLC the most common and among the most lethal of human cancersand will define the ecological and evolutionary dynamics that govern disease progression and treatment withthe goal of driving novel therapeutic strategies that exploit this -Ecology. NCI 10730403 9/15/23 0:00 RFA-CA-21-048 1U54CA274507-01A1 1 U54 CA 274507 1 A1 "ZAMISCH, MONICA" 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 9790902 "ANDERSON, ALEXANDER ROBERTSON ALLAN" "GATENBY, ROBERT A" 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 397 Research Centers 2023 2089297 NCI 1245000 844297 Summary Moffitt CSBC Proposal Overview The Moffitt CSBC proposal is focused on the essential and highly dynamical interplay between cancer cellevolution and the constantly changing ecology of the lung microenvironment. Tumors are not simply collectionsof mutated cells that grow in isolation. Rather they respond to and modify both the physical microenvironmentand a variety of host cells and these changes in ecology (-Ecology) are key to understanding tumorprogression and the response to therapy particularly the development of resistance. Central to this proposalis quantifying understanding and actioning the change that occurs during treatment to both the tumor andnon-tumor ecology in non-small cell lung cancer (NSCLC) which is the most common and among the mostlethal of human cancers. We will define the ecological and evolutionary dynamics that govern NSCLCprogression and treatment success or failure through 2 projects and 2 shared resource cores. Each project willfocus on different D-Ecology dynamics in the presence of different driver mutations (RAS EGFR ALK) forwhich targeted therapy is available. Each project demonstrates our unifying theme of tightempirical/mathematical integration through the sequence of develop predict calibrate test optimize andvalidate. Thus each project begins with available clinical data followed by in silico (predict and optimize) invitro (calibrate and test) and in vivo (validate) model systems leading to readily translatable treatment options.The mathematical and ecological Cores incorporate the mathematical and computational methods needed forbridging the projects. The Math Core will serve as the mechanistic model engine of the center facilitating bothspatial and non-spatial models of eco-evolutionary processes to generate and test hypotheses regarding -Ecology. The Ecology Core serves as data repository and ecological analysis engine working in lockstep withthe three Projects focused on different aspects of NSCLC -Ecology (Immune and Stromal) to develop andapply spatial ecological models. These cores will serve our two projects:Project 1: Delta immune Ecology of NSCLC 1.1 Quantify the -Ecology of patient samples pre- and on-treatment to predict outcomes; 1.2 Impact of KRAS inhibitor therapy with immunotherapy on lung tumorecology; 1.3 Use predictive modeling to generate evolutionary inspired multi-agent treatment strategies.Project 2: Delta stromal Ecology of NSCLC 2.1 Decipher in vivo the -Ecology of acquired resistance totargeted therapies in NSCLC; 2.2 Define the impact of stromal sheltering on the emergence of resistance andtumor growth relapse; 2.3 Discover optimal therapeutic strategies to suppress resistance. 2089297 +No NIH Category available Address;Adjuvant Therapy;Aftercare;Animal Model;Animals;Autopsy;Brain;Brain Neoplasms;Canis familiaris;Cell Death;Chemotherapy and/or radiation;Clinical;Clinical Research;Clinical Trials;Computer Models;DNA Double Strand Break;Data;Deposition;Dose;Effectiveness;European;Excision;Exposure to;External Beam Radiation Therapy;Finite Element Analysis;Formulation;Foundations;Generations;Glioblastoma;Glioma;Heat shock proteins;Heating;Histopathology;Human;Hyperthermia;Image;Infiltration;Injections;Iron;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Methodology;Modeling;Mus;Nanotechnology;Normal Cell;Normal tissue morphology;Oral Administration;Oryctolagus cuniculus;Patients;Penetration;Pilot Projects;Prognosis;Radiation therapy;Recurrence;Rodent;Safety;Solid;Study of magnetics;Technology;Temperature;Tissues;Toxic effect;Treatment Efficacy;Tumor Debulking;Work;antitumor effect;bioluminescence imaging;brain tissue;cancer cell;chemoradiation;chemotherapy;clinical translation;clinically relevant;design;effective therapy;fractionated radiation;hyperthermia treatment;hyperthermia tumor treatment;image guided;imaging modality;improved;innovation;iron oxide nanoparticle;magnetic dipole;magnetic field;nanoparticle delivery;neoplastic cell;radiation effect;safety and feasibility;temozolomide;therapy resistant;tissue injury;tool;translation to humans;translational applications;translational potential;treatment planning;treatment response;tumor;tumor microenvironment Translational Application of Magnetic Hyperthermia Therapy with Adjuvant Therapies for Glioblastoma Project NarrativeGlioblastoma (GBM) is one of the most devastating human cancers that almost always recurs due to thepresence of invasive therapy-resistant infiltrating cancer cells at the tumor margin. Magnetic hyperthermiatherapy (MHT) is a powerful nanotechnology-based treatment that may enhance the effects of radiation therapy(RT) and chemotherapy against infiltrating GBM tumors. NCI 10730272 2/7/23 0:00 PA-21-268 7R01CA247290-04 7 R01 CA 247290 4 "BUCHSBAUM, JEFFREY" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-OTC-E(02)M] 7078345 "HADJIPANAYIS, CONSTANTINOS GEORGE" "IVKOV, ROBERT " 12 NEUROSURGERY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 395 Non-SBIR/STTR 2023 675474 NCI 562642 112832 Project Summary/AbstractGlioblastoma (GBM) remains a fatal brain cancer for which there is no cure. Maximal safe tumor resectioncombined with adjuvant therapies such as fractionated external beam radiation therapy (RT) and temozolomide(TMZ) chemotherapy known as chemoradiation (CRT) has provided the greatest benefit to GBM patients.However local recurrence occurs in most patients due to invasive therapy-resistant infiltrating cancer cells atthe tumor margin. Magnetic hyperthermia therapy (MHT) is a powerful nanotechnology-based treatment thatmay enhance the effects of CRT. MHT consists of local heat generation in the tumor region through directdelivery of magnetic iron-oxide nanoparticles (MIONPs) that are activated by exposure to an external alternatingmagnetic field (AMF) that is safe to normal cells. The AMF interacts with the magnetic dipoles of the MIONPs togenerate local heat and hyperthermia. Human clinical trials have demonstrated overall survival benefits of MHTwith fractionated RT in recurrent GBM resulting in European approval. Current MHT strategies howeverrequire high concentrations of nontargeted MIONPs (>100 mg/ml; 50-100mg Fe/g of tumor) delivered byinjection with leakback and without image-guided control of energy deposition. As a result normal tissueinjury limits MHT effectiveness and treatment of the infiltrative tumor margins is poorly defined whichcompromises MHT efficacy. Our proposal is designed to address these challenges and optimize the translationalpotential for enhanced MHT of GBM in combination with CRT using both small and large animal models withclinical proof-of-concept demonstration in spontaneous canine gliomas. We have recently completed a pilot studyin spontaneous canine gliomas demonstrating feasibility and safety of image-guided MIONP delivery alone. Wehypothesize that image-guided MHT will enhance CRT of GBM. Key innovations of our proposal are to: 1)evaluate the enhancement of CRT by MHT in mouse GBM models with an innovative proprietary MIONPformulation that requires 20-fold lower Fe concentration in tumors for more effective treatment than currentapproved MIONPs; 2) optimize image-guided MIONP delivery and MHT treatment planning with computationalmodelling in a rabbit brain tumor model; 3) enhance thermal treatment at the infiltrative tumor margins bycontrolling power deposition with innovative AMF power application that will also limit off target heating; and 4)complete a clinically relevant proof-of-concept study of our MHT approach in a spontaneous canine gliomamodel. We have Preliminary Data that demonstrate intracranial hyperthermia with a 3-fold increase in TMZconcentration within GBM tumors leading to a robust antitumor effect with increased survival after MHT + CRTin a therapy-resistant rodent glioma model. Overall this interdisciplinary work will provide a solid foundation formeaningful clinical translation of MHT with CRT for treatment of GBM. Imaging methods that correlate tumorheat distribution after MHT will be developed for translation to human patients. 675474 +No NIH Category available Address;Affect;Cancer Control;Cancer Control Research;Cancer Patient;Caregivers;Chronic stress;Clinic;Clinical Trials;Code;Collaborations;Communication;Communities;Community Outreach;Consultations;Diagnosis;Disparity;Effectiveness;Emotional;Face;Family;Feedback;Focus Groups;Friends;Future;Goals;Grant;Health;Healthcare Systems;Heterosexuals;Improve Access;Intervention;Lesbian Gay Bisexual Transgender;Lesbian Gay Bisexual Transgender Queer;Link;Malignant Neoplasms;Manuals;Minority Health Research;Modeling;Monitor;Names;Outcome;Outcome Measure;Patients;Persons;Population;Problem Solving;Psychosocial Assessment and Care;Quality of life;Randomized;Recurrent Malignant Neoplasm;Resources;Sampling;Self Efficacy;Services;Sexual and Gender Minorities;Stigmatization;System;Testing;Transcript;Treatment Efficacy;Uncertainty;Waiting Lists;acceptability and feasibility;arm;cancer care;cancer recurrence;caregiving;cisgender;community engaged research;coping;design;evidence base;experience;follow up assessment;follow-up;gender minority community;gender minority group;improved;informal caregiver;member;minority patient;minority stress;mortality;phenomenological models;pilot trial;post intervention;programs;psychoeducation;psychoeducational;psychoeducational intervention;psychological distress;psychosocial;randomized trial;recruit;response;sexual relationship;symptom management;theories;trial planning Adapting the FOCUS Program for Sexual and Gender Minority (SGM) Cancer Patients and Caregivers PROJECT NARRATIVESexual and gender minority (SGM) patients with cancer have asked for programs that can 1) improve their qualityof life and 2) help their caregivers as well. However very few programs that serve cancer patients and theircaregivers together have included the perspectives of SGM community members. Our project will address thisgap by adapting an intervention called FOCUS with feedback from the SGM community and then test theadapted intervention FOCUS-SGM to see if it is acceptable for SGM cancer patients and their caregivers. NCI 10730265 7/3/23 0:00 PAR-22-173 1R34CA283408-01 1 R34 CA 283408 1 "DEAN, DAVID WORTH" 7/3/23 0:00 6/30/26 0:00 ZCA1-TCRB-V(M2) 10552100 "KAMEN, CHARLES STEWART" "HASTERT, THERESA ANN" 25 SURGERY 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 294171 NCI 183000 111171 PROJECT ABSTRACTThe goal of this project is to adapt the empirically-validated FOCUS intervention and test its feasibility andacceptability among sexual and gender minority (SGM) cancer patients and their caregivers. SGM cancerpatients face unaddressed challenges that adversely impact their quality of life (QOL) including minority stressor the chronic stress engendered by living with a stigmatized SGM identity. Furthermore caregivers of SGMpatients are often not acknowledged in healthcare systems primarily designed to serve heterosexual/cisgender(H/C) patients; resources for caregivers of H/C patients often do not address their needs; SGM patients may bemore likely to rely on SGM friends or ex-partners as caregivers; and these diverse SGM caregivers may beaffected by minority stress in cancer care settings. Psychoeducational interventions are needed to address thesedisparities and improve the QOL of SGM cancer patients and their caregivers together. The FOCUS interventionuses both psychoeducation and problem solving to improve QOL coping and self-efficacy in cancer patientsand their caregivers and has been shown to be efficacious in three prior clinical trials. However as noted by ourSGM community partners the LGBT Cancer Action Council (CAC) its content has not been tailored to SGMrelationships. Consequently we propose to adapt the evidence-based FOCUS Program for SGM cancerpatients and their caregivers (Aim 1). In collaboration with the LGBT CAC and guided by the transtheoreticalSGM-affirmative adaptation model and ADAPT-ITT framework we will conduct 6 focus groups with 24 SGMcancer patients and their 24 caregivers to theater test FOCUS and elicit qualitative feedback about adaptation.We will also elicit feedback from our panel of 5 topic experts in SGM research and create a manualized adaptedintervention called FOCUS-SGM. We will then assess the feasibility and acceptability and explore potentialoutcomes of the adapted FOCUS-SGM intervention in a two-arm pilot trial (Aim 2). We will randomize 80SGM cancer patients and their caregivers (total N160) to either FOCUS-SGM or a waitlist control. Assessmentof patients and caregivers will occur at baseline post-intervention and at a 3-month follow-up (~6 monthsafter baseline). We hypothesize that it will be feasible to recruit a sample of SGM cancer patients and caregiversthrough clinic community and online approaches; at least 80% of SGM patients and caregivers will be highlysatisfied with the content and delivery of FOCUS-SGM; 75% will complete 3 or more FOCUS-SGM sessions;and 75% will complete post-intervention and 3-month follow-up assessments. We will also explore whetherpotential outcome measures (QOL coping self-efficacy to manage cancer relationship communication andminority stress) are responsive to the effect of FOCUS-SGM versus control. This grant represents a critical stepin preparing our team to conduct a definitive trial of FOCUS-SGM responds to community and NCI prioritiesand has potential to address QOL disparities in SGM populations. 294171 +No NIH Category available 3-Dimensional;Address;Adult;Age;Anthracycline;Architecture;Artificial Intelligence;Biomedical Engineering;Calibration;Cancer Patient;Cancer Survivor;Cardiac;Cardiology;Cardiomyopathies;Cardiotoxicity;Chemotherapy and/or radiation;Chest;Child;Clinical;Community Clinical Oncology Program;Computers;Consensus;Data;Data Set;Dependence;Detection;Development;Diagnosis;Disease Outcome;Early Diagnosis;Early Intervention;Echocardiography;Equilibrium;Exposure to;Functional disorder;General Population;Geometry;Guidelines;Heart;Heart Diseases;Heart failure;Image;Individual;Interdisciplinary Study;International;Interobserver Variability;Ionizing radiation;Left;Left Ventricular Dysfunction;Left Ventricular Ejection Fraction;Long-Term Survivors;Machine Learning;Malignant Childhood Neoplasm;Measurement;Measures;Medical Imaging;Medicine;Methods;Monitor;Morbidity - disease rate;National Clinical Trials Network;Network-based;Oncology;Onset of illness;Patients;Pattern;Pediatric Oncology Group;Process;Radiation therapy;Recommendation;Research;Risk;Sedation procedure;Shortening Fraction;Standardization;Survivors;Testing;Therapeutic;Time;Training;Treatment-Related Cancer;Ventricular;cancer imaging;cardiac magnetic resonance imaging;childhood cancer survivor;cohort;convolutional neural network;cost;deep learning;disease diagnosis;efficacy evaluation;heart function;high risk;high risk population;image archival system;imaging biomarker;imaging modality;improved;improved outcome;insight;interest;outcome prediction;premature;programs;screening;standard of care;two-dimensional;ultrasound;unstructured data Machine Learning-Based Identification of Cardiomyopathy Risk in Childhood Cancer Survivors PROJECT NARRATIVEChildhood cancer patients have an increased risk of developing heart failure because of chemotherapy andradiation treatments. As a result many survivors of childhood cancer receive lifetime screening withechocardiograms (ultrasound of the heart) to monitor their long-term heart function. The proposed project wouldapply new computer artificial intelligence-based methods to improve the ability of echocardiograms to detectearlier heart disease in these high-risk survivors. NCI 10730177 6/30/23 0:00 PAR-22-216 1R21CA277746-01A1 1 R21 CA 277746 1 A1 "SHELBURNE, NONNIEKAYE F" 7/1/23 0:00 6/30/25 0:00 ZCA1-RTRB-B(M1)S 8441297 "CHOW, ERIC JESSEN" "BOYLE, PATRICK M; EDWARDS, LINDSAY ATHERTON" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 227486 NCI 165980 61506 PROJECT SUMMARY / ABSTRACTTreatment-related cardiomyopathy/heart failure (CHF) is a leading cause of premature morbidity in childhoodcancer survivors. Given the widespread use of anthracycline and related cardiotoxic chemotherapeutics and incombination with radiotherapy exposure to the chest over half of long-term survivors of childhood cancer are atsignificantly increased risk of early CHF compared with an age-matched general population. Currently nationaland international consensus guidelines recommend the routine use of 2-dimensional (2D) echocardiography toscreen this high-risk population for early signs of CHF in particular left ventricular (LV) systolic dysfunction andchanges in LV geometry. At present 2D echocardiography represents the standard of care across the US givenits widespread availability relatively lower cost and avoidance of ionizing radiation or sedation. Neverthelesslimitations of 2D echocardiography include greater intra-patient and inter-observer variability. As a result currentechocardiography-based surveillance continues to have limited sensitivity and often requires serial studiesbefore a patient is identified as having a potential abnormality. Although there is insufficient evidence to guideCHF management specific to pediatric cancer survivors the evidence for non-cancer-related cardiomyopathy inboth children and adults suggests that earlier intervention can mitigate or delay CHF progression. Thereforemethods that improve the detection of early CHF in childhood cancer survivors may have important clinicalimplications. Deep learning (DL) a subfield of machine learning can automatically extract patterns from largeunstructured datasets such as medical images and is increasingly being utilized in medicine for diseasediagnosis as well as disease onset and outcome prediction. We propose to leverage a unique imaging datasetwe have assembled from the Childrens Oncology Group (COG) a part of the NCI-sponsored National ClinicalTrials Network and Community Oncology Research Program to explore the potential of DL for enhanceddetection of CHF. We have longitudinal echocardiographic data on over 100 survivors of childhood cancer whodeveloped CHF and over 350 who did not all defined using standardized criteria representing an imagingrepository of >3000 individual echocardiograms (and growing). Using this extant and clinically annotated datasetwe propose to: 1) Using a deep convolutional neural network (DCNN) identify the optimal process for a DL-based assessment of CHF in pediatric cancer survivors; and 2) Assess the feasibility and preliminary efficacy ofDCNN-based prediction of cardiomyopathy onset from pre-CHF diagnosis echocardiograms. Expected resultsinclude the development of a DCNN that will differentiate between abnormal and normal echocardiograms frompediatric cancer survivors with and without CHF respectively. After optimization we will conduct a preliminaryefficacy analysis to determine how many years in advance a survivor's transition to CHF can be predicted usingan optimized DCNN. 227486 +No NIH Category available Address;Binding;Biology;Breathing;Catalogs;Cell Line;Cell Nucleus;Cells;Characteristics;Chemicals;Chimera organism;Clinical;Cyclization;Cytidine Deaminase;Cytoplasm;Cytosine;DNA;DNA Damage;DNA biosynthesis;Deaminase;Deamination;Dinucleoside Phosphates;Disease;Distant;Engineering;Enzymes;Exonuclease;Family;Family member;Frequencies;Future;Genome;Genomics;Goals;HIV;Host Defense;Immune;In Vitro;Knowledge;Ligands;Link;Malignant - descriptor;Malignant Neoplasms;Mediating;Molecular;Molecular Probes;Mutagenesis;Mutate;Mutation;Nature;Outcome;Pathogenesis;Pathologic;Pathologic Mutagenesis;Physiological;Play;Positioning Attribute;Process;Proteins;Proteolysis;Resistance;Retroelements;Retroviridae;Risk;Role;Route;Shapes;Single-Stranded DNA;Somatic Mutation;Specificity;Structural Models;Structure;Structure-Activity Relationship;Technology;Testing;Therapeutic;Time;Ubiquitination;Uracil;Viral;Virus;Work;Zebularine;amino group;antagonist;base;cancer cell;cancer genome;cancer initiation;cancer type;cellular engineering;cytosine analog;density;design;genetic approach;improved;inhibitor;insight;interest;member;meter;mimicry;multicatalytic endopeptidase complex;nanomolar;novel;novel strategies;nucleic acid delivery;nucleic acid inhibitor;preference;protein degradation;recruit;response;small molecule;stem;therapeutic target;tool;tumor;tumor initiation;tumor progression;ubiquitin-protein ligase;whole genome Inhibition and Catalytic Degradation of Promutagenic DNA Deaminases PROJECT NARRATIVEDNA deaminase enzymes of the AID/APOBEC3 family are critical for immune defense but can also mistargetthe host genome and contribute to cancer mutagenesis. This proposal aims to leverage knowledge ofmechanism and specificity of these enzymes to develop potent antagonists to counteract their pro-mutagenicactivities. The outcome of this work will be the first specific and cell-active inhibitors developed using a newparadigm whereby functionalized DNA can be used to probe or therapeutically inhibit DNA-altering processes. NCI 10729968 7/6/23 0:00 PAR-22-216 1R21CA277463-01A1 1 R21 CA 277463 1 A1 "GREENBERG, WILLIAM A" 7/6/23 0:00 6/30/25 0:00 ZCA1-RPRB-H(M2)S 9628674 "KOHLI, RAHUL MANU" Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 7/6/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 189922 NCI 116875 73047 PROJECT SUMMARYThis proposal aims to develop the first potent and specific antagonists of the pro-mutagenic effects of APOBECDNA deaminase enzymes in cells. Access to whole genome sequences has helped reveal common mutationalsignatures across various cancers. One such prominent mutational signature termed SBS2 includeshypermutated clusters containing a high density of C to T/G substitutions on the same strand a phenomenonknown as kataegis. These features in addition to the enrichment of the mutations in 5-TC motifs point to acausative role for APOBEC3 (A3) family enzymes. While these enzymes normally mutate and restrictretroviruses or retroelements studies have confirmed that two family members APOBEC3A (A3A) andAPOBEC3B (A3B) have a prominent role in pathological mutagenesis targeting the host genome. The relativecontributions of each enzyme remain a matter of vigorous debate as genetic approaches specifically targetingA3A or A3B are limited by their high homology to one another and juxtaposition on the genome. Furthermoreno molecular tools currently exist that can disrupt A3 function. There is therefore a pressing need for molecularprobes that can either inhibit or deplete A3 enzymes from cells. This proposal builds on the hypothesis thatinsights into the mechanism and substrate selectivity of A3 enzymes can be leveraged to design potent andspecific antagonists. Specifically we have demonstrated that mechanism-based inhibitor moieties can bepresented in preferred secondary structures and engineered into exonuclease-resistant DNA molecules to yieldpotent nanomolar inhibitors of A3A. These molecules present the opportunity for facile functionalization whichcan be utilized to convert classical inhibitors into molecules capable of inducing the catalytic degradation of thetarget APOBEC enzymes in cells via an unprecedented combination of nucleic acid inhibitors and proteasometargeting (PROTAC) technology. Taken together this proposal aims to fill a critical gap in the field by introducingtools to perturb APOBEC function in cells in order to reveal their underlying biology and offer a roadmap forpotential therapeutics. 189922 +No NIH Category available Evolution and targeting of the functional states of glioblastoma Project NarrativeAlthough advances have been made in the understanding of the pathogenesis of glioblastoma multiforme thisknowledge has not been translated into encouraging outcomes. We have introduced a new classification ofglioblastoma that highlights the fundamental functional states of glioblastoma cells and delivers prognostic andtherapeutic information. This grant proposes to study evolution of glioma cellular states investigate thechanges of cell states under therapy pressure and test points of interventions for targeted therapeuticsidentified by integrating genomics and proteomics. NCI 10729932 3/22/23 0:00 PA-21-268 7R01CA268592-02 7 R01 CA 268592 2 "WILLIS, KRISTINE AMALEE" 7/1/22 0:00 6/30/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 7147873 "LASORELLA, ANNA " "IAVARONE, ANTONIO " 27 BIOCHEMISTRY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 11/1/22 0:00 6/30/23 0:00 396 Non-SBIR/STTR 2022 162282 NCI 105721 56561 Project SummaryThe application is focused on glioblastoma multiforme (GBM) one of the most lethal forms of human cancer forwhich the massive knowledge generated by genomic data has provided little therapeutic improvement. One keyelement in the success of clinical studies for cancer patients is the selection of homogeneous groups of patientsharboring tumors that share identifiable functional vulnerabilities rather than general biomarkers. In GBM thelack of a functional classifier has hindered the targeting of fundamental cancer-driving mechanisms in well-defined patient subgroups leading to discouraging results. The proposal is founded on a novel classification ofGBM that we have recently proposed. Different from previously established marker-based classification the newclassifier is centered on functional activities of cancer cells that we identified by single cell transcriptomicanalysis. The classifier was validated in several cohorts of bulk primary GBM and includes four subtypes twolinked to neurodevelopmental programs neuronal and proliferative-progenitor and two characterized bydivergent metabolic activities mitochondrial and glycolytic-plurimetabolic. Notably the mitochondrial subtype isendowed with a distinct sensitivity to oxidative phosphorylation inhibition and is associated with a better survivalwhile the glycolytic-plurimetabolic subtype is characterized by redundant metabolic activities. Our preliminaryanalysis revealed that each functional GBM subtype is association with biologically coherent proteomic andphosphoproteomic features. In this application we will combine innovative computational tools and state-of-the-art experimental models in vitro and in vivo to study the impact of functional cell states of GBM in therapyresistance. We built the research plan with the following aims: i) examine and target the plasticity of theneurodevelopmental glioma states under therapy pressure and the cross-talk with signals from themicroenvironment; ii) determine how mitochondrial cells adjust to therapy pressure when treated withmitochondrial inhibitors and the mechanism of induced resistance; iii) retrieve therapeutic intervention pointsfrom proteomic data focusing on DNA-PK and PKCd two protein kinases active selectively in theproliferative/progenitor and glycolytic/plurimetabolic subtypes of GBM respectively. Experimental validations willbe applied to these nodal factors and will be performed by our laboratories which in the course of many yearshave generated and perfected the array of experimental tools including sequence-annotated patient-derivedmodels to pursue each question. By integrating novel computational and experimental platforms to study theevolution of distinct GBM subtypes the proposal is conceptually and technically innovative. The successfuloutcome of this proposal will be the delivery of key information to decipher evolving tumor dependencies undertreatment and accurate therapeutic strategies specifically tailored to distinct subgroups of GBM patients. 162282 +No NIH Category available Mechanisms of ID2 regulation in glioma Project NarrativeMechanisms that maintain cancer stem cells are crucial to tumor progression. Both ID proteins and HIFtranscription factors are essential to preserve neural stem cell properties and inhibit differentiation of normalcells and support stemness tissue invasion and angiogenesis in malignant glioma and other tumor types. Wewill use protein biochemistry mouse genetics and glioma models to characterize the molecular elements thatactivate ID2 and drive HIF2 accumulation in cancer stem cells. NCI 10729929 5/12/23 0:00 PA-21-268 7R01CA239721-05 7 R01 CA 239721 5 "YASSIN, RIHAB R" 4/1/19 0:00 8/31/24 0:00 Molecular Oncogenesis Study Section[MONC] 7147873 "LASORELLA, ANNA " Not Applicable 27 BIOCHEMISTRY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 4/1/23 0:00 8/31/23 0:00 396 Non-SBIR/STTR 2022 50640 NCI 32990 17650 AbstractMechanisms that maintain cancer stem cells are crucial to tumor progression. ID proteins are essential to supportstemness tissue invasion and angiogenesis in malignant glioma and other tumor types. Among ID proteins ID2contributes to cancer hallmarks promotes chemoresistance of neural tumors and is part of a gene signature thatpredicts poor outcome in patients with high-grade glioma. HypoxiaInducible Factors (HIFs) most notablyHIF2 are expressed in and required for maintenance of cancer stem cells. However the pathways that areengaged by ID2 or drive HIF2 accumulation during tumor progression have remained unclear. In this proposalwe will follow on our most recent work that has reconstructed the molecular events linking activation of ID2 andelevation of HIF2 in cancer. Our work indicates that disruption of the VHL-Elongin C-Elongin B (VCB)-Cul2complex by un-phosphorylated ID2-Thr-27 is an important mechanism of HIF2 stabilization in stem cells andglioma stem cells (GSCs) and that ID2 activity is restrained by prolyl hydroxylase 1 (PHD1)-induced DYRK1kinase activation and ID2-Thr-27 phosphorylation under normoxic conditions. Interestingly an ID2-T27A mutantconstitutively inactivates VCB-Cul2 elevates HIF and maintains cancer stem cells. In the proposal we willcharacterize biochemically and functionally PHD-DYRK1 activity a new tumor suppressor pathway that operatesby restraining the interfering effect of active ID2 on VCB-Cul2 ubiquitin ligase. In Aim 1 we will identify the ID2-pT27 phosphatase a potential oncoprotein and elucidate the broad significance of Thr-27 phosphorylation forthe ID2 interactome. The biological implication of the PHD1-DYRK1-ID2-HIF2 pathway for glioma progressionwill be explored in Aim 2. Using PHD1Flox mice we will mechanistically dissect the function of constitutive ID2activation in the absence of PHD1 in vivo. We will also model VHL inactivation HIF stabilization andgliomagenesis by ID2-T27A mutation in an inducible mouse model harboring a knock-in allele of the mutant ID2.We will use this mouse to validate the biochemical and biological effects of ID2-T27A that converge on VHL andHIF in vivo. The mouse model will also be used to determine whether ID2-T27A promotes glioma progressionin cooperation with other tumor-specific mutations that are known to cooperate with ID2 in human cancer. Studieswill address fundamental questions in cancer biology and greatly enhance the understanding of how hallmarksof glioma progression are effected by ID2. Finally the significance of the ID2-VHL-HIF-axis for the humandisease will be tested in patient-derived GSCs and primary GBM. 50640 +No NIH Category available Oncogenic mechanisms molecular stratification and therapeutic targets of brain tumors Project narrativeThe genomic and phenotypic complexity of malignant glioma has been implicated as the root causes of mosttreatment failure. Long-term goal of our research program is to develop strategies to model predict and targettherapeutic sensitivity and resistance of glioblastoma. This research plan is articulated around the developmentof a novel and integrated computational-experimental framework for the dissection of biologically homogeneoussubgroups of glioblastoma the study of cancer heterogeneity at the single cell level that will inform on theirreplaceable tumor cell-specific core pathways and the therapeutic exploitation of synthetically lethal drivermodules. NCI 10729917 2/17/23 0:00 PA-21-268 7R35CA253183-03 7 R35 CA 253183 3 "LI, JERRY" 9/24/21 0:00 8/31/28 0:00 ZCA1-GRB-S(M1) 6189067 "IAVARONE, ANTONIO " Not Applicable 27 NEUROSURGERY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 2/20/23 0:00 8/31/23 0:00 396 Non-SBIR/STTR 2022 827365 NCI 539000 288365 AbstractThe work to be pursued in this application will continue and expand the program pioneered by Dr. Iavarone tocombine innovative computational tools and state-of-the-art experimental cancer models in vitro and in vivo toidentify homogeneous subgroups of cancer patients in order to dissect the pathogenesis of cancer and designtailored and fully validated personalized therapeutic approaches. The application is focused on glioblastomamultiforme one of the most lethal forms of human cancer. The investigation of glioblastoma has represented along-standing effort of Dr. Iavarones laboratory which in recent work has produced novel targeted therapeuticopportunities currently being tested in clinical studies. The proposal will also benefit from the organizationalcontexts recently set in motion by the large network operations coordinated by the PI. The research plan isarticulated around the development of a novel and integrated computational-experimental framework for: i) theidentification of homogeneous groups of tumors sharing activation of the same biological pathways; ii) the studyof cancer heterogeneity at the single cell level to accurately inform tumor classifications; iii) the therapeuticprediction emerging from the identification of driver modules and synthetic lethal relationships of malignantglioma. We will develop and apply novel technologies for high-throughput transcriptomic and proteomic analysisof individual cells within malignant glioma tissues. These approaches which we have pioneered in our laboratoryat Columbia University during the last few years will serve as the basis for the multifaceted computationalanalysis that will extract genes and proteins responsible for the phenotypic state of individual cells. Experimentalvalidations will be selectively applied to the novel and most exciting molecular pathways and will be performedby our laboratory that has an array of experimental tools and sequence-annotated patient-derived models topursue each individual question. As for the selection of oncogene-dependent and independent vulnerabilitiesidentified by our previous work the ability of our studies to identify novel driver phenotypes and master regulatorsof individual tumor cells will be geared towards routing the new mechanisms into pathway-based syntheticlethality that will inform specific drug sensitivities. The successful outcome of this proposal is an integratedcomputational-experimental pipeline that will be able to mechanistically identify the determinants of tumorgenomes and phenotypes of solid tumors. This information will be of invaluable significance to decipher evolvingtumor dependencies and provide the most accurate therapeutic predictions. 827365 +No NIH Category available AIDS related cancer;Acquired Immunodeficiency Syndrome;Affect;Africa South of the Sahara;Antiviral Response;Apoptosis;Apoptotic;Autoimmune Diseases;Biology;CASP8 gene;Caspase;Cell Death;Cells;Cessation of life;Communicable Diseases;Complex;Cytoplasm;DNA;Data;Development;Disease;Enzymes;Genetic Transcription;Herpesviridae;Herpesviridae Infections;Human Herpesvirus 8;Immune Evasion;Immune response;Infection;Innate Immune Response;Interferon Type I;Interferons;Kaposi Sarcoma;Lytic Phase;Maintenance;Mediating;Mediator;Molecular;Nature;Oncogenic Viruses;Pathway interactions;Peptide Hydrolases;Production;Proteins;Receptor Signaling;Regulation;Regulatory Pathway;Reporting;Role;Signal Transduction;Stimulus;TLR3 gene;Testing;Toll-Like Receptor Pathway;Toll-like receptors;Tumor Immunity;Up-Regulation;Viral;Virus;Virus Replication;Work;cancer type;druggable target;experience;inhibitor;insight;mutant;new therapeutic target;overexpression;pathogen;prevent;reactivation from latency;receptor;response;targeted treatment;tumor;virus host interaction Determining how Kaposis sarcoma-associated herpesvirus hijacks caspase function to inhibit anti-viral responses PROJECT NARRATIVEDuring replication the AIDS-associated tumor virus Kaposis sarcoma-associated herpesvirus (KSHV)strongly blocks cellular responses to replicate efficiently. Since replication is needed for developmentand maintenance of Kaposis sarcoma and other KSHV-induced tumors KSHV immune evasion couldbe exploited to treat these diseases. In this project we will investigate the role of a cellular enzymecaspase-8 in KSHV inhibition of cellular response to understand immune evasion by this virus andpotentially identify new druggable targets against KSHV infection. NCI 10729751 12/8/22 0:00 PA-21-268 7R01CA268976-02 7 R01 CA 268976 2 "READ-CONNOLE, ELIZABETH LEE" 12/1/21 0:00 11/30/26 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 10791399 "GAGLIA, MARTA MARIA" Not Applicable 2 MICROBIOLOGY/IMMUN/VIROLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI GRADUATE SCHOOLS 537151218 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 396 Non-SBIR/STTR 2023 349096 NCI 228782 120314 Project summary. During lytic infection the AIDS-associated tumor virus Kaposis sarcoma-associatedherpesvirus (KSHV) blocks cells from activating the anti-viral type I interferon (IFN) responses. This block ofthe innate immune response facilitates efficient viral replication which in turn contributes to development ofKaposis sarcoma. Thus elucidating the mechanisms by which KSHV evades the host innate immuneresponse may provide insights on how to target this and other KSHV-induced tumors. However because ofthe complex and redundant nature of the type I IFN induction pathway how KSHV blocks this early antiviralresponse is still incompletely understood. In a previous study we found that the host protease caspase-8 is amajor mediator of type I IFN inhibition by KSHV. KSHV reactivation from latency only triggers minimal type IIFN induction but there is a much stronger transcriptional induction and secretion of type I IFNs whencaspase-8 is also inhibited. This stronger IFN induction in turn reduces KSHV reactivation. These resultsindicate that caspase-8 activity is necessary to inhibit IFN induction and thus promotes KSHV replication.This finding was surprising because caspase-8 activation is generally considered antiviral as it inducesapoptotic cell death. However we do not detect wide-spread cell death during reactivation from latencydespite caspase-8 activation suggesting that caspase-8 is hijacked and repurposed by KSHV to inhibit type IIFN responses. At present the molecular mechanisms that lead to caspase-8 activity and the pathways thatare targeted by caspase-8 to control type I IFN during KSHV infection remain unclear. We have newpreliminary data suggesting that caspase-8 is activated by a pathogen sensing pathway the Toll-like receptor(TLR) pathway as a cellular response to infection. Caspase-8 then proceeds to inhibit a different pathogensensing pathway cGAS-mediated DNA sensing. Therefore we hypothesize that KSHV is taking advantageof a TLR-mediated cellular response to infection that activates caspase-8. KSHV is then able to redirect thisactivity to inhibit DNA sensing instead of activating apoptosis. We will test this hypothesis and determine howcaspase-8 is activated by TLR signaling in KSHV-infected cells without triggering cell death (Aim 1) andwhich host protein(s) are cleaved by caspase-8 to block cGAS-induced type I IFN responses (Aim 2).Moreover we will also investigate whether and how caspase activity is connected to other previouslydescribed mechanisms of immune evasion by KSHV (Aim 3). As caspase-8 is a druggable targetunderstanding how caspase-8 is used by KSHV to regulate type I IFNs and promote its replication will revealwhether and how this enzyme could be exploited for KSHV therapy. This is important as there are no targettherapies for this virus and Kaposis sarcoma remains one of the leading types of cancers in sub-SaharanAfrica and the second most common AIDS-associated malignancy in the US. This project will also uncoverfundamental aspects of caspase signaling that may play a role in other diseases connected to IFN. 349096 +No NIH Category available 3-Dimensional;Adipose tissue;Adoptive Cell Transfers;Affect;Affinity;Antibodies;Antigens;Antitumor Response;Autologous;Binding;Cancer Biology;Cancer cell line;Cell Count;Cell Death;Cell Degranulation;Cell Therapy;Cells;Cellular Immunology;Clinic;Clinical Trials;Complement;Complex;Correlative Study;Cryopreservation;Dimensions;ERBB2 gene;Engraftment;Epitopes;Equus caballus;FDA approved;Fluorescence;Folic Acid Antagonists;Foundations;Future;Genetic;Goals;Good Manufacturing Process;Hematologic Neoplasms;Histamine;Human;Human Activities;IgE;Immune;Immune response;Immunocompetent;Immunocompromised Host;Immunotherapy;In Vitro;In complete remission;Incubated;Infiltration;Infusion procedures;Intravenous;Investigational New Drug Application;Knock-out;Learning;Lentivirus Vector;Lymphoma;MS4A1 gene;Malignant Neoplasms;Mediating;Mediator;Medicine;Modeling;Monitor;Mus;Pathology;Patient-Focused Outcomes;Patients;Production;Proteins;Protocols documentation;Role;Signal Transduction;Solid;Solid Neoplasm;Survival Rate;Techniques;Testing;Therapeutic;Time;Tissues;Toxic effect;Toxicology;Tumor Volume;Work;adaptive immune response;adipose derived stem cell;antitumor effect;cancer cell;cancer immunotherapy;cancer therapy;cancer type;chimeric antigen receptor T cells;comparison control;efficacy study;efficacy testing;engineered T cells;folate-binding protein;good laboratory practice;graduate student;human tissue;in vivo;intravenous administration;loss of function;mRNA Expression;malignant breast neoplasm;mast cell;mouse model;neoplastic cell;novel;novel strategies;peripheral blood;progenitor;safety study;translational study;treatment planning;tumor;tumor microenvironment;tumor progression;tumor xenograft;undergraduate student Human mast cells as a platform for new cancer immunotherapy strategies PROJECT NARRATIVEThe goal of this project is to use for the first time autologous mast cells armed with tumor targeting IgEantibodies as a novel Trojan horse therapy against diverse cancer types including lymphoma and breastcancer. Based on evidence already obtained demonstrating in vitro and in vivo efficacy this translational studywill ultimately lead to further safety and efficacy studies required to move this novel approach into the clinic. NCI 10729728 7/19/23 0:00 PAR-22-060 1R15CA283490-01 1 R15 CA 283490 1 "BOURCIER, KATARZYNA" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-CDPT-J(80)A] 1971817 "KEPLEY, CHRIS L" Not Applicable 5 NONE 66001074 CK9CNLPNKLK5 66001074 CK9CNLPNKLK5 US 37.356108 -79.172242 4378001 "LIBERTY UNIVERSITY, INC." LYNCHBURG VA UNIVERSITY-WIDE 245150002 UNITED STATES N 9/1/23 0:00 8/31/26 0:00 395 Non-SBIR/STTR 2023 372846 NCI 299999 72847 ABSTRACTThe role of human tissue mast cells (MC) in the pathology of many cancers is not known. Correlative studies inhumans have found high MC numbers in the tumor microenvironment have pro- and anti-tumor effects andcontrasting patient outcomes depending on the cancer types. We discovered that human MC are activated byand promote killing of cancer cells in vitro and in vivo infiltrate solid cell tumor masses bind to tumors in vivocan be obtained in quantities necessary for patient infusion cryopreserved without loss of function and displayno overt toxic effects when injected intravenously into mice with engrafted human tumors. To develop this novelcell-based cancer immunotherapy we will utilize FDA approved humanized IgE (which bind MC FcRI withextremely high affinity) to target MC to cancer cells. This new approach is premised on efficient autologousproduction of MC tumor targeting and effective tumor specific killing. This strategy has not been feasibleheretofore as these cells reside in tissue and cannot be obtained for autologous use. Our overall hypothesis istumor targeted MC will bind to cancer cells in vitro and in vivo after intratumoral or intravenous administrationand elicit significant anti-tumor activity. Here we will determine the in vitro and in vivo activity of human MCagainst several cancer types. These studies could lead to new adoptive cell therapies for diverse cancers rangingfrom lymphoma to breast cancer. 372846 +No NIH Category available Affect;Animal Model;BARD1 gene;BRCA mutations;BRCA1 gene;Binding;Biochemical;Biological Assay;Cell Aging;Cell Cycle;Cell Cycle Progression;Cell Cycle Proteins;Cell Cycle Regulation;Cell Line;Cell Proliferation;Cell physiology;Cells;Clinic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Critical Pathways;DNA Damage;DNA Repair;DNA Repair Gene;DNA biosynthesis;Data;Defect;Development;Diagnosis;Disease;Drug Combinations;Future;Genetic;Genetic Heterogeneity;Goals;Growth;In Vitro;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Mitosis;Molecular;Oncogenic;PALB2 gene;PLK1 gene;Pancreatic Ductal Adenocarcinoma;Patients;Pharmaceutical Preparations;Phenotype;Phosphorylation;Platinum;Play;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Predisposition;Prognosis;Property;Protein-Serine-Threonine Kinases;Proteins;Publishing;Regulation;Role;Survival Rate;System;Testing;Therapeutic Effect;Therapeutic Intervention;Toxic effect;Treatment Efficacy;Treatment-related toxicity;Up-Regulation;acquired drug resistance;brca gene;cancer therapy;cancer type;cdc Genes;clinically relevant;conventional therapy;design;drug development;effective therapy;experimental study;homologous recombination;in vivo;inhibitor;inhibitor therapy;knock-down;mouse model;new therapeutic target;novel therapeutic intervention;novel therapeutics;overexpression;oxaliplatin;pancreatic ductal adenocarcinoma cell;patient population;personalized medicine;pleiotropism;recombinational repair;response;success;synergism;targeted treatment;therapy resistant;transcriptomic profiling;treatment response;tumor;tumor growth;tumor heterogeneity;tumorigenesis Elucidating the relevance of BARD1-PLK1 interaction in PDAC and response to therapy PROJECT NARRATIVETumor heterogeneity and limited chemotherapeutic efficacy in pancreatic ductal adenocarcinoma underscoresthe need to find new targets and molecular interactions for PDAC diagnosis and therapy. In this proposal wewill determine the molecular interaction between a DNA repair protein BARD1 and a cell cycle regulator PLK-1 using biochemical assays and determine if this interaction plays a role in regulating therapeutic efficacy ofPARP inhibitors and platinums. Completion of this project would advance our understanding of pancreatic ductaladenocarcinoma and provide new possibilities for targeted therapeutic interventions. NCI 10729693 7/14/23 0:00 PAR-20-052 1R03CA283232-01 1 R03 CA 283232 1 "SHARMAN, ANU" 7/14/23 0:00 6/30/25 0:00 ZCA1-RPRB-T(M1) 78231695 "JAIN, ADITI " Not Applicable 2 SURGERY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 7/14/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 78000 NCI 50000 28000 ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. The overall5-year survival rate is only 11% and there is an unmet need for better therapies. For patients with homologousrecombination repair (HRR) deficient tumors (BRCA1/2 PALB2) poly (ADP-ribose) polymerase (PARP) inhibitor(PARPi)/platinum-based therapies offer the best-personalized treatment approach. However the efficacy ofthese treatments is often limited due to inherent (HRR proficient tumors) or acquired drug resistance. Thisunderscores a dire need to identify new targets to enhance the sensitivity of these promising agents and expandthe PDAC patient population that could benefit from them. We recently discovered that BARD1 (BRCA1-Associated- Ring- Domain- 1) an obligate binding partner of BRCA1 and a key factor in HR is upregulated inPDAC cells under DNA damage conditions (Jain et al Cancers (Basel) 6;14(7):1848 2022). We found thatdeletion of BARD1 rendered PDAC cells (HRR proficient) extremely sensitive to PARPi/platinums and enhancedDNA damage. Although these effects may be attributed to BARD1s canonical role in HRR transcriptomeprofiling of BARD1 silenced cells suggests BARD1 has pleiotropic effects on cellular functions linked to cell cyclecellular senescence and DNA replication. In line with these predictions we noted that BARD1 silencing stronglyreduced cell proliferation decreased clonogenic capacity in vitro slowed tumor growth in vivo of PDAC cells andreduced expression of several cell cycle proteins notably Polo-Like-Kinase-1 (PLK-1). PLK-1 is a serinethreonine kinase that strongly promotes the progression of cells through mitosis. PLK-1 is overexpressed inPDAC and deregulation of PLK-1 activity contributes to genetic instability which in turn leads to oncogenictransformation. We hypothesize that PLK-1 interacts with BARD1 and this interaction is necessary for PDAC cellresponse to DNA damage agents. We will test our hypothesis through two specific aims. In aim 1 we willdetermine the molecular interaction of BARD1 and PLK-1 in PDAC cells using biochemical assays and in aim2 we will determine if BARD1s regulation of PLK-1 in PDAC cells is a driver of response to DNA damage agentsusing overexpression systems in a murine model. The overarching goal of this project is to elucidate the role andsignificance of BARD1-PLK-1 interaction in PDAC and therapy response to DNA damage agents. Thecompletion of this project will lay the groundwork for development of novel targeted therapeutic strategies againstPDAC and in the future could be applied to other cancer types as well.Keywords: Pancreatic ductal adenocarcinoma DNA damage cell cycle BARD1 78000 +No NIH Category available Address;Animal Model;Biological Assay;Biological Models;Cancer Etiology;Carcinoma;Cell Cycle Checkpoint;Cell Proliferation;Cessation of life;Characteristics;Clinical;Clinical Data;Data Set;Development;Diethylnitrosamine;Disease;Genes;Genetic;Hepatocarcinogenesis;Hepatocyte;Heterogeneity;Human;Incidence;Invaded;Investigation;Knowledge;Liver;Liver diseases;Location;Lymphoma;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of liver;Meta-Analysis;Mitotic;Molecular;Monitor;Mus;Mutation;Neoplasms;Oncogenic;Outcome;PLK1 gene;Pathogenesis;Patients;Play;Pre-Clinical Model;Primary carcinoma of the liver cells;Property;Proto-Oncogenes;Research;Role;Testing;Therapeutic;Transgenes;Transgenic Mice;Transgenic Model;Transgenic Organisms;Tumor Biology;cancer therapy;cancer type;druggable target;in vivo;insight;mortality;mouse model;novel;sarcoma;senescence;targeted treatment;tool;tumor;tumorigenesis Define the oncogenic role of Plk1 during hepatocellular carcinoma development using a genetically modified mouse model Hepatocellular carcinoma (HCC) represents one of the most common malignancies in humansand the leading cause of cancer-related death worldwide with a steadily increasing incidence andmortality rate. The proposed studies aim to define the oncogenic role of Plk1 during HCCdevelopment using a genetically modified mouse model. Successful completion of the proposedstudies will allow us to establish the first liver-specific Plk1 transgenic murine model which wewill use to unambiguously dissect the oncogenic function of Plk1 during hepatocarcinogenesisand determine whether Plk1 is a driver gene of this invariably fatal disease. NCI 10729603 8/16/23 0:00 PAR-20-052 1R03CA283221-01 1 R03 CA 283221 1 "LUO, RUIBAI" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-T(M1) 8199442 "FU, ZHENG " Not Applicable 4 GENETICS 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 9/1/23 0:00 8/31/25 0:00 396 Non-SBIR/STTR 2023 155250 NCI 100000 55250 Hepatocellular carcinoma (HCC) represents one of the most common malignancies in humansand the leading cause of cancer-related death worldwide with a steadily increasing incidence and . A major hallmark of HCC is its high heterogeneity in clinical presentation andunderlying tumor biology. Therefore there is an urgent need to understand the molecularpathogenesis of the disease and to explore novel targets and strategies for the management ofHCC. Mammalian polo-like kinase 1 (Plk1) is a key mitotic regulator that has been implicated inthe initiation and progression of various types of cancer including liver cancers and hassubsequently been highlighted as a promising target for anticancer therapy. We generated Plk1transgenic mice with globally elevated expression of Plk1 which showed marked increases intumor incidence when compared to wild-type littermates with HCC being the second mostpredominant neoplasm observed. Furthermore our meta-analysis of the publicly available clinicaldatasets demonstrates that Plk1 is frequently upregulated in HCC and is significantly correlatedwith poorer patient survival. The strong clinical evidence and the striking abnormality present inthe livers of Plk1 transgenic mice strongly suggests a role of Plk1 in the pathogenesis of HCCdevelopment and thereby prompted us to investigate whether elevated levels of Plk1 drives livercarcinogenesis. In this study we propose to define the oncogenic role of Plk1 during HCCdevelopment using a genetically modified mouse model. The central hypothesis is that Plk1functions as a prominent proto-oncogene in HCC. We propose the following specific aims: 1)Generate liver-specific Plk1 transgenic mice; and 2) Determine hepatocarcinogenesis in liver-specific Plk1 transgenic mice. This study will allow us to establish the first liver-specific Plk1transgenic murine model with which we will use to unambiguously dissect the oncogenic functionof Plk1 during hepatocarcinognesis and determine whether Plk1 is a driver gene of this invariablyfatal disease. The knowledge gained from this study will not only enhance our understanding ofthe pathogenesis of HCC also provide important insights into the management of HCC and ourliver-specific Plk1 transgenic model will serve as the ideal pre-clinical model to test mechanism-based therapeutic approaches that target PLK1 in advanced and metastatic HCC. Furthermorethis animal model provides an important research tool for exploring interactions of some of thegenetic alterations observed in HCC patients. Plk1s function may go beyondhepatocarcinogenesis; our liver-specific Plk1 transgenic mouse model will also shed light on itspossible role in other liver diseases.mortality rate 155250 +No NIH Category available Acute;Address;Aftercare;Anxiety;Assessment tool;Behavioral Research;Body Image;Cancer Center;Cancer Survivor;Cardiovascular Diseases;Choking;Clinic;Clinic Visits;Clinical;Data;Deglutition;Demographic Survey;Development;Disease;Distress;Evaluation;Face;Factor Analysis;Feedback;Gagging;Generations;Goals;Guidelines;Head and Neck Cancer;Health;Impairment;Individual;Interview;Larynx;Loneliness;Longitudinal Studies;Malignant Neoplasms;Measurement;Measures;Mental Depression;Mental Health;Methods;Modeling;Nose;Oral cavity;Oropharyngeal;Outcome;Persons;Pharyngeal structure;Population;Populations at Risk;Prevention strategy;Property;Psyche structure;Psychometrics;Quality of life;Review Literature;Risk;Risk Factors;Screening procedure;Sinus;Social Desirability;Social Development;Social isolation;Societies;Speech;Stroke;Suggestion;Survival Rate;Survivors;Symptoms;Taste Perception;Testing;Time;Treatment Side Effects;United States;Visit;brief screening;evidence base;experience;facial disfigurement;improved;innovation;member;physical conditioning;physical symptom;prevent;recruit;social;survivorship The Development and Psychometric Evaluation of the SIRS: A Social Isolation Risk Scale for Survivors of Head and Neck Cancer Head and neck cancer (HNC) survivors due to their unique illness- and treatment-related effects andsymptoms are at risk for social isolation (the objective lack of contact with other people) a demonstratedprecursor to poor physical and mental health outcomes. The goal of this study is to develop (through itemgeneration and refinement) and conduct a preliminary psychometric evaluation of the SIRS (Social IsolationRisk Scale) a brief screening tool that will allow clinicians to routinely identify HNC survivors at risk for socialisolation and simultaneously capture the specific risk factors unique to HNC (e.g. facial disfigurement troublespeaking) that potentiate social isolation. Identifying HNC survivors at risk for social isolation using the SIRSand administering targeted evidence-based prevention strategies is critical to preventing the development ofsocial isolation in the short-term and negative health outcomes in the long-term. NCI 10729500 8/24/23 0:00 PAR-20-052 1R03CA273478-01A1 1 R03 CA 273478 1 A1 "JENSEN, ROXANNE ELAINE" 8/24/23 0:00 7/31/25 0:00 ZCA1-RTRB-C(M1)S 14814108 "MARZILIANO, ALLISON " Not Applicable 3 Unavailable 110565913 C5LHMPRJ9J19 110565913 C5LHMPRJ9J19 US 40.775574 -73.703024 4155008 FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH MANHASSET NY Research Institutes 110303816 UNITED STATES N 8/24/23 0:00 7/31/25 0:00 393 Non-SBIR/STTR 2023 156616 NCI 93502 63114 Head and neck cancer (HNC) survivors have unique survivorship challenges (e.g. facial disfigurement) whichoften lead to social isolation. To address social isolation and prevent associated negative health outcomes it iscritical to identify HNC survivors at risk for social isolation. Currently these efforts are hampered by a lack ofscreening tools that are both sufficiently brief to be used routinely in a fast-paced clinic and capture the riskfactors unique to HNC that potentiate social isolation. Hence the overall purpose of this proposal is todevelop and conduct a preliminary psychometric evaluation of the Social Isolation Risk Scale (SIRS) abrief screening tool to identify HNC survivors at risk for social isolation. Aim 1: Develop the SIRS: Item poolgeneration (1a): Our team will use inductive and deductive methods to generate a pool of potential scaleitems (i.e. reasons why HNC survivors socially isolate general social isolation risk factors) throughdiscussions among HNC survivor members of our advisory board and experts in HNC social isolation andmeasurement as well as a literature review. Item pool refinement (1b): We will refine the item pool through1-on-1 interviews with N = 30 socially isolated HNC survivors. We will solicit feedback on item relevance(quantitative scale 1 to 5 higher values indicate more relevance) addition/deletion of items (items will beadded/deleted if 70% of those asked endorse addition/deletion) and suggestions for alternative wording viaqualitative feedback. At the conclusion of 1b we will have a ~16-item SIRS (~8 items related to non-physicalsocial isolation risk factors and ~8 items related to physical social isolation risk factors) to undergo preliminarypsychometric evaluation during Aim 2b. Aim 2: Administer (2a) and conduct preliminary psychometricevaluation (2b) of the SIRS. 2a. We will conduct a 3-month longitudinal study in which we will administer theSIRS a demographic survey and a battery of validated assessments of social isolation general distressloneliness social connectedness social desirability and HNC-related quality of life to N=130 HNC survivors attheir 6-month (T1) and 9-month (T2) post-treatment completion visits. 2b. We will perform preliminarypsychometric analyses of the SIRS evaluating both items properties and SIRS properties as well as performa factor analysis. Based on a priori established guidelines we will select a final set of items to retain for theSIRS with the goal of ~10 items in total (~5 items related to physical risk factors and ~5 items related to non-physical risk factors). This project is (a) significant as it will improve the long-term health of a substantial (atleast 36%) subset of HNC survivors and will serve as a model for identifying and preventing social isolation inother at-risk groups; and (b) innovative as it approaches the problem from a different perspective- focusing onthe root cause (i.e. social isolation) of negative outcomes rather than the negative outcomes themselves. 156616 +No NIH Category available Area;Cancer Biology;Collaborations;Communities;Data;Documentation;Education;Educational workshop;Environment;Evaluation;Event;Feedback;Fostering;Immune;Institution;Link;Malignant Neoplasms;Mentorship;Methodology;Modeling;Pilot Projects;Process;Publications;Research;Research Personnel;Research Project Grants;Resources;Series;Surveys;Systems Biology;Techniques;Training;Tumor Biology;Underrepresented Populations;United States National Institutes of Health;Work;anticancer research;career;effectiveness evaluation;experience;high school;member;novel;outreach;posters;programs;recruit;response;symposium;tool;tumor;web site Outreach Core n/a NCI 10729468 9/19/23 0:00 RFA-CA-21-048 1U54CA274511-01A1 1 U54 CA 274511 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7285 9261375 "GENTLES, ANDREW J." Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 146338 94351 51987 ABSTRACT Outreach CoreThe Stanford CCSB is committed to advancing and promoting systems biology approaches to cancer research.The Outreach Core will coordinate scientific outreach activities to disseminate to the cancer research andbroader communities our Centers scientific and methodological advances in applying the principles of cancersystems biology to the study of tumor-immune-stromal interactions in metastatic progression. We will work torecruit involvement of diverse investigators cancer biologists and clinicians. We will also develop and implementan evaluation process to assess the effectiveness of our proposed outreach activities. The specific aims of ourOutreach Core are: (1) disseminate advances in cancer systems biology to the cancer research and broadercommunities (2) promote the involvement of diverse and underrepresented cancer systems biologyinvestigators cancer biologists and clinicians enriching our environment with opportunities for exposure andtraining and (3) develop and implement an evaluation strategy to assess our outreach activities. We willdisseminate our work through avenues including scientific publications conferences annual symposia monthlyseminar series workshops think tank program and an up-to-date website. We will continue to foster a fertileenvironment for investigators from diverse and underrepresented groups. Opportunities will include monthlyseminars enabling cross-training at participating consortia institutions and encouraging attendance and abstractsubmission to national conferences. We will partner with local and national efforts to promote diversity inmentorship and participation in our outreach activities. We will expand our efforts to involve trainees at all pointswithin their career progression from high school onwards. Our pilot projects will also seek to advanceopportunities for less represented groups. Furthermore we will develop and implement an evaluation strategyto assess our outreach activities by soliciting responses from CCSB members and non-members and thebroader community attending our events. The research experience will be evaluated through online surveys aswell as documentation of publications abstracts and presentations. +No NIH Category available Adaptive Immune System;Algorithms;Anatomy;Architecture;Atypical lymphocyte;Automobile Driving;Back;Biological Markers;Blocking Antibodies;Cell Communication;Cells;Chronology;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Computing Methodologies;Cytometry;Data;Development;Diagnosis;Disease;Disease Progression;Distal;Distant;Distant Metastasis;Education;Flow Cytometry;Gene Expression Profile;Genes;Genetic Transcription;Head and Neck Cancer;Human;Image;Immune;Immune Evasion;Immune Tolerance;Kinetics;Knockout Mice;Label;Leukocyte Trafficking;Leukocytes;Lymph Node Involvement;Lymphatic;Malignant Neoplasms;Mediating;Metastatic Neoplasm to Lymph Nodes;Modeling;Mus;Nature;Neighborhoods;Neoplasm Metastasis;Nodal;Non-Small-Cell Lung Carcinoma;Patients;Population;Predisposition;Prevention;Primary Neoplasm;Process;Property;Regulatory T-Lymphocyte;Role;Site;Solid;Stromal Cells;Study models;Systems Biology;Tissues;Tumor Biology;Tumor Promotion;Tumor-infiltrating immune cells;cancer cell;conditioning;cytokine;data integration;high dimensionality;imaging platform;implantation;lymph nodes;markov model;migration;mouse model;neoplastic cell;new therapeutic target;novel;prevent;programs;single-cell RNA sequencing;therapy design;trafficking;transcriptomics;tumor Project 1 Mouse Models Analysis n/a NCI 10729466 9/19/23 0:00 RFA-CA-21-048 1U54CA274511-01A1 1 U54 CA 274511 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7283 1862821 "ENGLEMAN, EDGAR G. " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 563617 363390 200227 SUMMARY/ABSTRACT: PROJECT 1Lymph node (LN) metastasis precedes further dissemination for most solid malignancies and confers a stage IIIdiagnosis. Nonetheless the mechanistic role of LN metastasis in further disease progression is poorlyunderstood. We discovered in mice that in colonizing LNs tumor cells activate transcriptional programs thatenable their induction of tumor-specific immune tolerance through interactions with LN leukocytes. Theseleukocytes subsequently recirculate throughout the host resulting in systemic immune tolerance facilitatingmetastatic seeding of distant sites. Importantly we found the same conserved transcriptional signature in LNmetastases in humans suggesting that the mechanisms driving LN metastasis and immune tolerance in ourmouse model are pertinent to human cancers. We hypothesize that local interactions between tumor cellsleukocytes and stroma within LNs before during and following LN colonization alter distant tissues to promotedisease progression. We expect these interactions to involve homotypic and heterotypic cell-cell interactionsorchestration of architectural changes within LNs tumors and distant sites and trafficking of various populationsthroughout the host. We will use syngeneic mouse models to identify the mechanisms by which these interactionsfacilitate disease progression through the following approaches. 1: Determine the kinetics by which tumorsgenerate systemic immune tolerance. Using a high-dimensional imaging platform (CODEX) we will uncoverlongitudinal changes in local microenvironments across the host. 2: Interrogate the nature of heterotypic cell-cellinteractions within LNs and the mechanisms by which these interactions facilitate immune evasion and inductionof immune tolerance. We will use scRNA-seq to identify transcriptional changes in immune and stromalpopulations interacting with malignant cells within LNs. Using spatial transcriptomics we will determine how thegene expression patterns of cells interacting with malignant cells differ from those at a distance. To confirm thefunctional significance of these targets identified and those identified in Project 2 we will combine CRISPR-mediated gene editing of LN metastatic tumors along with cell depletion studies and knockout mice or induciblemouse models. 3: Determine how trafficking of immune cells from tumor-involved LNs establish a pro-metastaticmicroenvironment at distant sites. We will employ a novel cell labeling platform to evaluate trafficking ofleukocytes and stromal cells from tumor-involved LNs to distant sites and back to the primary tumor. Thesestudies will reveal the mechanisms whereby LN metastases promote tumor spread to distant sites and identifynovel targets for the prevention and treatment of metastatic disease. +Biotechnology; Cancer; Childhood Leukemia; Clinical Research; Genetics; Hematology; Immunization; Immunotherapy; Neuroblastoma; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Bench to Beside and Back translational immuno-onocology-Cures n/a NCI 10729449 1ZIABC012128-01 1 ZIA BC 12128 1 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 70148 NCI Four CCR projects are currently supported by this Cancer Moonshot Bench to Beside and Back award: 1. TME informed NK cell therapy for pediatric sarcomas led by Rosandra Kaplan (CCR) and Timothy Cripe (Nationwide Children's Hospital). The overall goal of this project is to develop natural killer (NK) cell therapy with TGF-beta imprinting that can be augmented through manipulation of the immune suppres sive tumor microenvironment (TME) leading to improved NK cell-mediated anti-tumor immunity and serves as a potential effective therapy for patients with relapsed pediatric sarcoma. Bone and soft tissue sarcomas are one of the most common solid tumors in pediatric adolescent/young adult (AYA) patients. Despite improved outcomes due to advances in surgical local control and multi-agent chemotherapy prog nosis for patients who develop recurrent metastatic or refractory disease remains poor. For these patients new therapeutic approaches are urgently needed. The team at Nationwide Children's Hospital (NCH) has developed a genetically modified feeder cell line that enables extensive ex vivo propagation of highly-active human NK cells from various sources and this methodology has been evaluated in early- phase clinical trials for hematologic malignancies and brain tumors. 2. Targeting neuroendocrine tumors with DLK1 directed immunother apy led by Nitin Roper (CCR) and John Maris (CHOP). A central goal of this project is to discover and prioritize immunotherapeutic targets in childhood cancers. Surface receptor Delta Like Non-Canonical Notch Ligand 1 (DLK1) has been prioritized as a target due to the pro tein's high expression in many pediatric and adult neuroendocrine (NE) tumors but with restricted normal expression. Based on pre-clinical data demonstrating efficacy of a novel DLK1-directed antibody-drug conjugate (ADCT-701) in neuroblastoma the investigator team pro poses to study adult and pediatric patients with NE tumors to further develop DLK1-directed immunotherapy. The discovery that DLK1 is hiqhly expressed in many pediatric and adult NE tumors is of high significance since neuroendocrine tumors are difficult to treat and novel therapeutics are needed. DLK1 is a key mediator of the undifferentiated state in neuroblastoma and neuroblastomas terminally differenti ate upon genetic depletion of DLK1. The proposed work has the potential to result in enhanced understanding of an important disease process and lead to a new therapeutic intervention. 3. B2B and Back: CD22 and CD19/22 CAR immunotherapies for childhood leukemia led by Naomi Taylor (CCR) and Crystal Mackall (Stanford). The Taylor and Mackall teams are carrying out clinical trials with identical CD22 and CD19/CD22-bivalent CAR vectors but the two sites are using different manufacturing procedures to generate the CAR-transduced T cells that are being infused into patients. The current proposal is to test the hypothesis that variability in CAR-T cell immunotherapeutic po tential is affected by variations in manufacturing platforms and can be predicted through evaluation of antigen-dependent CAR-T cell activ ity. High throughput analyses of these parameters will be leveraged to optimize CAR manufacturing evaluate divergent patient outcomes and enhance durable responses in pediatric leukemia patients. 4. Alternative splicing of CD22 following Inotuzumab led by Nirali Shah (CCR) and Andrei Thomas-Tikhonenko (CHOP). This project is designed to explore the mechanism(s) by which altered splicing of CD22 mRNA to delete Exon 2 leads to loss of CD22 protein expression in B-ALL tumor cells and thus leads to the acquired resistance of those tumor cells to CD22-specific immunotherapies. The project is an attractive blend of characterization of clinical samples from CD22-based clinical trials and in vitro plus in vivo studies of the regulation of CD22 splicing; together these studies could identify new therapeutic strategies to force CD22 protein expression in B-ALL cells and improve anti-CD22-immunotherapy. 70148 +No NIH Category available Address;Architecture;Benign;Biological Markers;Biological Sciences;Biology;CDK2 gene;Cells;Cellularity;Characteristics;Chromosome Mapping;Complex;Coupled;Cutaneous Melanoma;Cytokeratin;Data;Dermis;Development;Diagnosis;Diagnostic Errors;Early Diagnosis;Endothelial Cells;Epidermis;Epithelial Cells;Fibroblasts;Gene Combinations;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Goals;Immune;Immunohistochemistry;Knowledge;MART-1 Tumor Antigen;Malignant - descriptor;Malignant Neoplasms;Maps;Melanocytic Neoplasm;Melanocytic nevus;Metastatic Melanoma;Methodology;Mole the mammal;Morphology;Neoplasm Metastasis;Neoplasms;Nevi and Melanomas;Nevus;PTPRC gene;Patient-Focused Outcomes;Pattern;Peripheral;Population;Regulation;Research;Resolution;Role;Skin Cancer;Space Perception;Structure;Survival Rate;Testing;Tissues;Transcript;Tumor Biology;Tumor Markers;Tumor Tissue;biomarker development;biomarker identification;cell type;cellular imaging;diagnostic accuracy;diagnostic biomarker;diagnostic criteria;diagnostic value;differential expression;digital;gene panel;imaging platform;improved;innovation;keratinocyte;melanocyte;melanoma;melanoma biomarkers;neoplastic cell;novel diagnostics;novel marker;preservation;prevent;single cell sequencing;single-cell RNA sequencing;success;transcriptome;tumor;tumor heterogeneity;tumor microenvironment;tumor progression;tumor-immune system interactions Spatial Profiling of Melanocytic Tumors and Their Microenvironment NARRATIVE DESCRIPTIONMelanocytic nevi (moles) are mimics and precursors of melanoma the deadliest of the common forms of skincancer. Early diagnosis improves survival rates of melanoma but diagnosing moles and melanoma is not alwaysclear-cut and markers that would improve accuracy of diagnosis are inadequate. This research builds detailedmaps of moles and melanoma that combine gene expression and tissue architecture of the tumors and theirsurrounding tissues to understand how the tumors develop and to identify markers for a more reliable diagnosisultimately leading to improved patient outcomes. NCI 10729434 6/27/23 0:00 PAR-20-052 1R03CA277645-01A1 1 R03 CA 277645 1 A1 "LI, JERRY" 7/1/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 14244787 "KIURU, MAIJA HELENA TUULIA" Not Applicable 4 DERMATOLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 80000 NCI 50000 30000 Spatial profiling of melanocytic tumors and their microenvironmentUnderstanding tissue structure is fundamental for biological sciences and for distinguishing benign versusmalignant neoplasms but histopathological assessment alone is inaccurate for the diagnosis of certain tumorsincluding a subset of melanocytic neoplasms (melanocytic nevi and melanomas) resulting in diagnostic errorsand worsened patient outcomes. Therefore novel biomarkers for the diagnosis of melanoma are needed. Toidentify such markers it is imperative to better understand the interaction between melanocytes and neighboringkeratinocytes immune cells and other components of the complex tumor microenvironment in nevi andmelanoma.Nevi and early primary melanoma display intratumoral heterogeneity often coupled with low cellularity and purity.Therefore the tumor-microenvironment interactions could be missed by bulk approaches or single-cellsequencing of advanced/metastatic tumors only which has been the focus of most prior studies. The goal of thisresearch is to build high-resolution spatial maps of gene expression of the tumor and its microenvironment inmorphologically preserved nevi and melanomas to identify novel diagnostic biomarkers.The hypothesis is that melanocytic tumors and their microenvironments contain subpopulations of cells withcharacteristic gene expression patterns that differ between nevi and melanoma. We hypothesize that some ofthese differentially expressed genes are spatially confined and cell-type specific and could be used as potentialdiagnostic markers. Our prior data demonstrated differences in CDK2 gene expression between melanocyte-rich regions of nevi and melanoma. In Aim 1 we will assess spatial expression of CDK2 byimmunohistochemistry in a tumor panel of over 200 nevi versus melanoma comparing it to proliferative markersas well as established melanoma biomarkers including PRAME. In Aim 2 to identify novel biomarkers we willestablish high-resolution spatial maps of gene expression of tumor and microenvironment subpopulations in neviversus melanoma by performing a spatial whole transcriptome analysis and a high-plex single-cell imaging. Topdifferentially expressed genes in these subpopulations will be validated via immunohistochemistry in the tumorpanel described above.This study improves current theoretical concepts by investigating tumor and microenvironment populations innevi and early primary melanoma the common yet previously understudied tumor types. Furthermore thisstudy utilizes improved state-of-the-art approaches including high-plex single-cell spatial gene expressionprofiling. This research will improve the understanding of tumor-microenvironment subpopulations in theirspatially correct context relevant for tumor biology and biomarker development ultimately leading to improveddiagnostic accuracy of melanoma and improved patient outcomes. 80000 +No NIH Category available Acceleration;Address;Adjuvant Therapy;Adult;Adverse effects;Affect;Aftercare;Age;Aging;Anthracycline;Biological;Biological Aging;Biological Assay;Biology of Aging;Blood specimen;Breast Cancer Patient;Breast Cancer survivor;Cancer Survivor;Caring;Characteristics;Childhood Cancer Survivor Study;Chronology;Clinical;DNA Methylation;Data;Diagnosis;Epigenetic Process;Ethnic Origin;Follow-Up Studies;Future;Goals;Health;Impairment;Intervention;Life Style;Long-Term Survivors;Longevity;Longterm Follow-up;Malignant Neoplasms;Measures;Modality;Molecular;Morbidity - disease rate;National Cancer Institute;Nutritional;Operative Surgical Procedures;Patient Care;Patient Self-Report;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Physical Function;Physical Performance;Physiological;Population;Postmenopause;Pre-Clinical Model;Race;Radiation;Recording of previous events;Rejuvenation;Research;Risk;Severities;Survival Rate;Survivors;Testing;Time;Toxic effect;United States;Variant;Woman;Women's Health;Work;age related;anticancer research;biomarker validation;breast cancer diagnosis;cancer diagnosis;cancer therapy;chemoradiation;clinical diagnosis;cohort;comparison control;design;experience;frailty;functional decline;functional status;hazard;healthspan;human old age (65+);indexing;malignant breast neoplasm;mortality;multidisciplinary;optimal treatments;performance tests;personalized intervention;premature;survivorship;treatment duration Long-Term Trajectories of Accelerated Biological Aging and Functional Decline Associated with Breast Cancer and its Treatment PROJECT NARRATIVEBy understanding how cancer treatments alter the course of biological and functional aging in cancer survivorsour study can help to guide patient care. Specifically our study will help identify patients at risk for long-termphysical function impairment as a result of cancer treatment provide clues as to the biological mechanismsthrough which these adverse effects occur and inform future strategies to mitigate these effects. NCI 10729432 8/16/23 0:00 PA-20-185 1R01CA283839-01 1 R01 CA 283839 1 "GALLICCHIO, LISA M" 9/1/23 0:00 8/31/28 0:00 "Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study +Section[AIMR]" 12179280 "FELICIANO, ELIZABETH MARJORIE CESPEDES" "BINDER, ALEXANDRA MARGARET LYNN" 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 656996 NCI 610820 46176 PROJECT SUMMARY/ABSTRACTMore than 3.8 million women living in the United States have a history of invasive breast cancer a majority ofwhom are over age 65. With 15-year survival rates exceeding 80% older breast cancer survivors are agrowing population with distinct health considerations relative to patterns of usual aging. Cancer survivors areat an increased risk of age-related conditions but little is known about the trajectories of aging that underliethis elevated risk or factors affecting the severity of decline. Evidence from preclinical models suggest cancertreatment contributes to molecular and cellular changes consistent with aging that may underlie the lateremergence of functional decline. Frailty is highly prevalent in breast cancer patients and is associated with agreater hazard of long-term morbidity and mortality. Epigenetic age acceleration is an indicator of biologicaging that is influenced by cancer and its treatment and also a strong predictor of healthspan and lifespan. Wehypothesize that cancer and its treatment will contribute to accelerated trajectories of functional and epigeneticaging relative to women without a history of cancer that these changes will be sustained long-term and varyby treatment type and intensity. To test these hypotheses we will combine three decades of pre- and post-diagnosis clinical self-reported and physiological data from post-menopausal women in the Womens HealthInitiative (WHI) including annual assessments of functional status in over 9000 breast cancer survivorsmatched by age to cancer-free controls. We will estimate epigenetic age from blood samples collected atmultiple pre- and post-treatment time points in a subset of breast cancer survivors and usual aging controls.With this unique data and multidisciplinary team of relevant experts we will conduct the first large study withlong-term longitudinal measures of epigenetic and functional aging before and after breast cancer diagnosisand treatment addressing the following specific aims: 1) Characterize long-term trajectories of physicalfunction in breast cancer survivors (v. usual aging in controls) and test whether they are modified by the typeand intensity of cancer treatments; 2) Examine whether breast cancer and its treatment increase the rate ofepigenetic aging and whether this aging continues to accelerate after treatment; and 3) Test the relationshipbetween the rate of epigenetic aging and functional decline and how it may differ between breast cancersurvivors and usual aging controls. This work is a critical first step to characterize predictors of agingtrajectories among cancer survivors and identify those who could benefit from supportive interventions tomaximize healthspan in this rapidly growing population. 656996 +No NIH Category available Authorization documentation;Bioinformatics;Biological;Biopsy;Calibration;Cancer Patient;Clinical;Clinical Data;Clinical Research;Code;Collection;Computer Models;Data;Data Management Resources;Data Sources;Disease;Ensure;Generations;Glioma;Histology;Home;Hybrids;Image;Infrastructure;Institution;Institutional Review Boards;Location;Machine Learning;Magnetic Resonance Imaging;Malignant neoplasm of brain;Mathematics;Measurement;Mission;Modeling;Molecular;Oncology;Online Systems;Outcome;Pathology;Patients;Process;Reporting;Reproducibility;Resources;Scanning;Secure;Services;Site;Source;Specimen;Statistical Data Interpretation;Statistical Models;Structure;Systems Analysis;Techniques;Texture;Tissues;Work;authority;clinical imaging;data access;data infrastructure;data integration;data sharing;demographics;digital;diverse data;genomic data;imaging Segmentation;imaging facilities;in vivo;innovation;large datasets;machine learning model;model development;predictive modeling;repository;response;sex;single-cell RNA sequencing;success;support tools;systems research;tool;tumor MOSAIC: Data Integration and Computation Core NARRATIVE: DATA INTEGRATION AND COMPUTATION COREThe Data Integration and Computation Core will be central to our Mayo/Columbia CSBC MathematicalOncology Systems Analysis Imaging Center (MOSAIC) collecting the diverse data types and sources andproviding infrastructure for data resource management of the large datasets relied upon and generated throughthe center including those provided by the Biospecimen Core. The Data Integration and Computation Corewill support both projects with its three aims: Aim 1) collect and store data across all sites Aim 2) providereproducible bioinformatics workflows and Aim 3) provide computational modeling tools and techniques. NCI 10729426 9/18/23 0:00 RFA-CA-21-048 1U54CA274504-01A1 1 U54 CA 274504 1 A1 9/18/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7270 12330142 "HAWKINS-DAARUD, ANDREA JEANINE" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 651065 453679 197386 SUMMARY: DATA INTEGRATION AND COMPUTATION COREA major challenge to any integrated collaborative multi-institutional effort is the centralized management andsynthesis of shared data. The Data Integration and Computation Core will be central to every part of ourMayo/Columbia CSBC Mathematical Oncology Systems Analysis Imaging Center (MOSAIC) assimilatingdiverse data types and sources. The primary mission of this Core is to provide infrastructure for data resourcemanagement including modeling tools and support.The Data Integration Core will house and integrate the digital data generated by the Biospecimen Core whileproviding a central resource for modeling tools to support our CSBC and interacting with the AdministrationCore for ensuring IRB compliance. We will achieve the mission of our Data Integration and Computation Corethrough three specific aims. In Aim 1 we collect and process and store data across all CSBC sites. In Aim 2 weprovide and integrate reproducible bioinformatics workflows. And in Aim 3 we provide computational modelingtools and techniques.The Data Integration Core will provide support for both projects. Project 1: Targeting Glioma Tissue States will utilize the image-localized biopsy locations. They will further utilize the stored molecular data accessed through this core making use of the provided bioinformatics. Project 2: Imaging the Dynamic Tissue State in Patients In Vivo will utilize the stored molecular and imaging data along with all segmentations and generated image features. Project 2 will also make extensive use of the mechanistic modeling and calibration support along with the bioinformatics support. +No NIH Category available Advocacy;Arizona;Awareness;Biological;Biological Sciences;Biology;Brain Neoplasms;Cancer Biology;Cell physiology;Clinic;Clinical;Clinical Oncology;Collaborations;Communities;Complex;Computational Science;Consent;Discipline;Disease;Education and Outreach;Educational workshop;Engineering;Ensure;Exposure to;Facebook;Family;Future;General Population;Genetic;Glioblastoma;Goals;Image;Institution;Internships;Journals;Knowledge;Language Development;Malignant Neoplasms;Mathematics;Methodology;Methods;Modeling;Oncology;Outcome;Outcome Assessment;Output;Patient Care;Patients;Postdoctoral Fellow;Research;Research Project Grants;Scientist;Social Network;Solid;Students;System;Systems Analysis;Systems Biology;Techniques;Tissues;Training;Twitter;Universities;Update;Work;cancer education;clinical imaging;clinical translation;design;experience;graduate student;imaging facilities;improved;individual patient;innovation;large datasets;mathematical learning;mathematical methods;mathematical model;neuro-oncology;next generation;novel strategies;outreach;outreach program;patient advocacy group;personalized medicine;programs;recruit;skills;social media;success;summer research;symposium;tool;undergraduate student;web site Outreach Core NARRATIVE: OUTREACH COREGetting computational results into the clinic requires a broader understanding of the methods and generalprinciples by scientists clinicians and patients alike. Thus the primary goal of the Outreach Core is todisseminate knowledge of the iterative dialogue between mathematical oncology cancer systems biology andexperimental and clinical oncology to students colleagues and the general public. To accomplish our goal wewill train new cross-disciplinary scientists inform the research community engage with the general public andassess our outcomes. NCI 10729424 9/18/23 0:00 RFA-CA-21-048 1U54CA274504-01A1 1 U54 CA 274504 1 A1 9/18/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7268 11790051 "JACKSON, PAMELA ROSE" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 141951 85256 56695 SUMMARY: OUTREACH COREThe goals of the scientific portion of this proposal are directed towards bringing personalized medicine to theclinic for glioblastoma patients through integrative mathematical methods. Effectively bringing computationalresults into the clinic requires a broader understanding of the methods and general principles by scientistsclinicians and patients alike. More scientists need to be aware of these non-traditional techniques in order tobuild additional models and enhance methodology for the clinic. Interpretation of model output for use in therapywill require clinicians to have a solid understanding of a given models strengths and limitations. Also for patientsto choose and feel confident in therapies directed by these techniques they will require a broader awareness ofthe existence potential benefit and value of these therapies. The primary goal of the Outreach Core is todisseminate knowledge of mathematical oncology and cancer systems biology to students colleagues and thegeneral public. To accomplish our goal we will strive to appeal to each target group through the following:Training new cross-disciplinary scientists. We will recruit undergraduate and graduate students along withpostdoctoral trainees at our various institutions providing them with opportunities for research and improvingcross-disciplinary understanding. For undergraduates this will take the form of internships senior thesis projectsand summer research experiences. For graduate students and postdoctoral trainees this will take the form oflonger-term research projects possibly culminating in masters thesis and/or doctoral dissertation projects.Inform the research community. Beyond presenting our work at conferences targeting many differentaudiences we will design conferences and workshops to attract clinicians and research scientists from multipledisciplines to inspire and update them about emerging research at the interface of oncology mathematicalmodeling and imaging.Engage with the general public. We will develop an online easily accessible presence by creating a websiteand using social networking platforms including Twitter YouTube and Facebook. We will work with Mayo Clinicpatient advocacy groups to engage brain tumor patients and their families by hosting informational workshopsfor brain tumor advocacy groups in our PNT lab at Mayo Clinic. In addition we will partner with the Mayo ClinicCancer Education Center to host the general public through evening and weekend workshops designed for a layaudience.Outcome assessment We will assess the success of our outreach efforts across each sphere of influence. +No NIH Category available Abate;Address;Algorithms;Behavior;Cancer Center;Cancer Patient;Cell Line;Cell model;Cells;Clinical;Complement 1q;Complex;Data;Dependence;Disease-Free Survival;Drug Targeting;Drug resistance;Duct (organ) structure;Excision;Fibroblasts;Fostering;Funding;Genetically Engineered Mouse;Goals;Health;Heterogeneity;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunotherapy;In Vitro;Individual;Infiltration;Inter-tumoral heterogeneity;Intervention;Isogenic transplantation;KPC model;Logic;MAP Kinase Gene;Macrophage;Malignant - descriptor;Malignant Neoplasms;Mediating;Metaplasia;Methodology;Modeling;Molecular;Network-based;Neurosecretory Systems;Olives - dietary;Organoids;Outcome;Pancreatic Ductal Adenocarcinoma;Paracrine Communication;Pathway interactions;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Prediction of Response to Therapy;Printing;Proteins;Proteome;Publications;Reagent;Regulatory T-Lymphocyte;Relapse;Sampling;System;TREM2 gene;Therapeutic;Validation;Xenograft Model;actionable mutation;cancer cell;castration resistant prostate cancer;cell behavior;clinically relevant;design;drug mechanism;drug sensitivity;drug-sensitive;genome database;genome-wide;human model;immune checkpoint blockade;improved;in vivo Model;neoplastic cell;novel;panacea;patient derived xenograft model;patient responsibilities;pharmacologic;programs;recruit;relapse patients;response;single cell analysis;small molecule inhibitor;targeted treatment;tumor;tumor heterogeneity;tumor microenvironment;tumor-immune system interactions;virtual Drug Mechanism of Action-based targeting of tumor subpopulations n/a NCI 10729387 9/19/23 0:00 RFA-CA-21-048 1U54CA274506-01A1 1 U54 CA 274506 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7252 7827402 "CALIFANO, ANDREA " Not Applicable 13 Unavailable 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY Domestic Higher Education 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 479435 322234 157201 Patients with aggressive cancers often present with no pharmacologically actionable mutations and fail torespond to immune checkpoint blockade thus deriving only modest improvement in disease-free survival fromtargeted therapy and immunotherapy. Tumor heterogeneity further complicates these challenges by fosteringparacrine signal-mediated reprogramming adaptation selection and expansion of drug-resistant cell states aswell as emergence of an immunosuppressive tumor microenvironment (TME) which are ultimately responsiblefor patient relapse and poor outcome . We propose that addressing these challengesi.e. identifying moreuniversal mechanistic targets for pharmacological intervention and assessing their potential value in highlyheterogeneous tumorsis critically dependent on the availability of accurate and comprehensive cellularnetworks which underlie both the cell-autonomous behavior of cancer cells and their interaction with other TMEsubpopulations. In Project 3 we propose to match the proteome-wide Mechanism of Action (MoA) of clinicallyrelevant compoundsas dissected from in our PanACEA database of genome-wide molecular perturbations inhigh-fidelity models of human malignanciesto the non-oncogene dependencies of molecularly distinct yetcoexisting subpopulations representing either transformed malignant cells or healthy cells recruited to the TMEto create a pro-malignant immunosuppressive milieu as dissected by single cell analyses. Targeting individualsubpopulations is becoming increasingly critical because the heterogeneity and plasticity of both transformedand non-transformed TME subpopulations have emerged as perhaps the most fundamental obstacles toachieving durable responses in cancer patients and distinct subpopulations appear to either have potentiallyorthogonal drug sensitivities or to represent healthy immunosuppressive cells that will require an entirelydifferent approach to targeting their recruitment to the TME rather than causing their demise. To accomplishthese goals Project 3 will leverage data models and reagents generated during the prior CSBC funding cyclefor the study of metastatic castration resistant prostate cancer (mCRPC) and pancreatic ductal adenocarcinoma(PDAC) two aggressive highly heterogeneous malignancies with 20% 5-year survival. We will focus onmCRPC and on its aggressive neuroendocrine subtype (NEPC) to explore a novel molecular triangulationmethodology (OncoLoop) designed to identify high-fidelity modelsi.e. cell lines organoids geneticallyengineered mouse models (GEMMs) and patient derived xenografts (PDXs)to generate patient-relevant drugperturbation profiles in vitro and to validate drugs predicted from patient-derived sample analysis in preclinicalmodels in vivo. We will then focus on 6 molecularly distinct malignant PDAC subpopulationscomprisingLineage Morphogenic and Acinar to Ductal Metaplasia-like cells each detected in either a MAPK pathwayactive or inactive stateexploring multiple pro-malignant TME subpopulations (including tumor infiltrating Tregulatory cells macrophages and fibroblasts) to identify small molecule inhibitors that effectively deplete them. +No NIH Category available Address;Behavior;Binding;Biological;Biology;Brain;Brain Neoplasms;Cancer Center;Cancer Patient;Cell Communication;Cells;Cephalic;Chronology;Clinical;Complex;Coupled;Cues;Cutaneous Melanoma;Data;Dedications;Dependence;Disease;Disease Progression;Dissection;Drug Screening;Drug resistance;Ecosystem;Event;Fostering;Future;Gene Expression Profiling;Genetic Transcription;Genome;Genomics;Goals;Heterogeneity;Human;Immune checkpoint inhibitor;Immunosuppression;Immunotherapy;In Situ;Label;Ligands;Link;Logic;Malignant - descriptor;Malignant Neoplasms;Mediating;Metastatic malignant neoplasm to brain;Methods;Minority;Modeling;Molecular;Neoplasm Metastasis;Network-based;Non-Small-Cell Lung Carcinoma;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Primary Neoplasm;Printing;Process;Proteins;Publications;Research Personnel;Resistance;Resolution;Series;Signal Transduction;Site;Slice;Somatic Mutation;Stratification;System;Testing;Therapeutic;Time;Tissues;Validation;actionable mutation;analytical tool;cancer cell;cancer heterogeneity;cell behavior;checkpoint therapy;clinically relevant;computerized tools;design;genome editing;genome sequencing;human model;immune checkpoint blockade;improved;in vivo;innovation;insight;machine learning framework;malignant state;multimodality;multiple omics;novel;paracrine;pharmacologic;programs;receptor;recruit;response;spatiotemporal;targeted treatment;therapeutic development;tool;transcriptomics;treatment response;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenic;whole genome Single-Cell Spatial and Functional Dissection of Cancer Cell States Co-Evolving Ecosystems and Vulnerabilities During Tumor Progression and Metastasis n/a NCI 10729386 9/19/23 0:00 RFA-CA-21-048 1U54CA274506-01A1 1 U54 CA 274506 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7250 14551452 "IZAR, BENJAMIN " Not Applicable 13 Unavailable 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY Domestic Higher Education 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 384868 233962 150906 Aggressive cancers often lack pharmacologically actionable mutations and do not respond to immune checkpointblockade thus deriving only modest clinical benefit from targeted and immune therapy. The heterogeneity ofboth transformed and healthy cells in the Tumor Microenvironment (TME) represents a critical obstacle toachieving more durable response in cancer patients. Recent insights using multi-omics approaches have shownthat cancer cells can exist in a variety of transcriptionally distinct yet co-existing states some of which arealready primed for metastatic progression or drug resistance. The plasticity of these statesi.e. the ability ofcancer cells to reprogram across multiple states either spontaneously or because of drug perturbationsandtheir homeostatic coexistence with other TME subpopulation via paracrine molecular interactions creates aconstant challenge to therapeutic approaches by fostering the emergence of drug-resistance tumor progressionand the creation of a pro-malignant immunosuppressive milieu. Malignant states and transitions are only partiallyexplained by sequential acquisition of somatic mutations suggesting that they result from integration of a varietyof cell-intrinsic and -extrinsic molecular cues that determine their lineage attribution establishment andinterconversion. To date several technical clinical and analytical challenges have hampered a comprehensiveunderstanding of the natural biology of these processes in patients. Project 2 is dedicated to resolving thevariability and plasticity of malignant cells and of the healthy cells that define the TME by developing and applyinga battery of technical and analytical tools for the dissection of cancer heterogeneity at the single-cell level andfor the nomination validation and testing of novel drivers of tumor-progression and therapy response andresistance. We will delineate these concepts in a defined biological context that is the progression from a primarytumor towards brain-metastatic disease. To this end we will leverage a series of innovations from CaSTinvestigators including (a) multi-modal single-cell profiling from archival tissues (b) simultaneous low-passwhole-genome sequencing (lpWGS) of the same cell pool (c) integrated single-cell and spatial single-celltranscriptomics (d) analytical approaches to integrate and model multi-modal single-cell data in space time andcontext of interactions among cells (e) tools to elucidate cell state stability and transitions (f) combinations ofgenome-editing perturbations with single-cell read outs that can be linked to drug screens via gene expressionprofiling and (g) network-based Master Regulator analyses to elucidate mechanistic determinants oftranscriptional cell state. This will be extended by experimental innovations that (h) accurately model tumorprogression in vivo and recapitulate entire human ecosystems (i) enable labeling of metastatic niches coupledwith single-cell genomics and (j) provide a platform to test pharmacological modulation of cancer cell intrinsicand tumor-microenvironmental features predicted from human studies and modeling. The presented innovativeframework will be broadly application to other cancer contexts. +No NIH Category available 3-Dimensional;Address;Algorithms;Automobile Driving;Behavior;Binding;Biological Assay;Biomedical Engineering;Cancer Center;Cell Line;Cells;Colon Adenocarcinoma;Colonic Neoplasms;Communities;Complex;Coupled;Data;Dependence;Development;Dissection;Drug resistance;Environment;Foundations;Funding;Gene Expression Profile;Generations;Genetic Transcription;Goals;Human;Individual;Investigation;Knowledge;Language;Ligands;Malignant - descriptor;Malignant Neoplasms;Maps;Mediating;Methodology;Modeling;Molecular;Natural Language Processing;Nature;Network-based;Normal Cell;Oncoproteins;Organ;Pancreatic Ductal Adenocarcinoma;Paracrine Communication;Peptides;Pharmaceutical Preparations;Phenotype;Phosphoproteins;Physiology;Printing;Process;Proteins;Proteome;Publications;Reagent;Research;Research Personnel;Reverse engineering;Scientist;Signal Transduction;Stromal Cells;Structure;System;Techniques;Technology;Therapeutic;Time;Tissues;Validation;Work;analytical tool;cancer cell;clinically relevant;deep learning;deep learning algorithm;drug sensitivity;extracellular;improved;in vivo;individual variation;innovation;intercellular communication;multiple omics;neoplastic cell;network models;novel;organ on a chip;paracrine;pharmacologic;phosphoproteomics;protein protein interaction;protein structure;receptor;recruit;response;small molecule;small molecule inhibitor;technology validation;therapeutic target;three dimensional structure;tumor;tumor microenvironment;tumorigenic Structure-informed dissection of cancer-specific intracellular and paracrine networks n/a NCI 10729385 9/19/23 0:00 RFA-CA-21-048 1U54CA274506-01A1 1 U54 CA 274506 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7248 1863346 "HONIG, BARRY H" Not Applicable 13 Unavailable 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY Domestic Higher Education 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 580864 353109 227755 Understanding cancer cell-autonomous behavior and recruitment of pro-malignant subpopulations to the tumormicroenvironment (TME) is critically dependent on the generation of accurate and comprehensive cellular andintercellular networks. The goal of Project 1 is to develop a novel integrated and extensively validatedframework to model manipulate and dissect cell-cell signaling in the tumor microenvironment involvingextracellular ligand-receptor interactions coupled to intracellular signaling networks. Project 1 will build on themethodologies and results generated during the previous CSBC funding period to address multiple challengesby (a) expanding structure-informed prediction of protein-protein interactions (PPI) networks by leveraging noveldeep learning approaches (b) improving signal transduction networks based on the analysis of time-dependentdrug perturbation assays and (c) elucidating ligand/receptor-mediated paracrine interaction networks thatmediate recruitmentand possibly reprogrammingof healthy cells to the TME to create a pro-malignantenvironment. To accomplish these goals the focus will be on two highly aggressive tumorscolonadenocarcinoma (COAD) and pancreatic ductal adenocarcinoma (PDAC)for which data models reagentsand analytical tools were generated during the prior funding cycle.Project 1 is based on three specific aims. Through the integration of deep learning approaches to protein-proteininteractions and the creation of structure-based networks for the Hallmarks of Cancer Aim 1 will provide a 3D-structural context for the proposed work throughout Project 1. Aim 2 will define phosphoproteomics-basedintracellular signaling networks and describe their response to drug perturbations. Aim 3 will define paracrine-based cell-cell signaling networks and validate them with a novel organs-on-a-chip platform.The impact of Project 1 will derive largely from its innovative approaches which include the use of structure-based analyses to model protein interaction networks; the integration of structure-based modeling with deeplearning algorithms including Protein Language Models to provide models for essentially all interactions thatwill be predicted and observed in the proposal; the inference of phosphoproteomics-based phosphoproteinactivity to provide critical time-dependent and perturbation-sensitive components of cellular signaling; theincorporation of paracrine signaling; and novel experimental validation technologies including matchedphosphoproteomic and transcriptional profiles and the bioengineering of tumors and normal cells withininterconnected micro-chambers to better recapitulate tissue physiology in vivo.The major deliverable for Project 1 is an interrogable and holistic model for coupled intra- and inter-cellularsignaling which will serve as the foundation for the entire center by enabling the dissection of the mechanismscontributing to the stability of tumor-related cell states their ligand/receptor-mediated interaction with othersubpopulations in the TME and their pharmacologically actionable molecular dependencies. +No NIH Category available Address;Administrator;Advisory Committees;Award;Biomedical Research;Budgets;Calibration;Cancer Center;Cities;Collaborations;Collection;Committee Members;Communication;Communities;Complex;Computer software;Consultations;Data;Data Set;Decision Making;Education;Educational workshop;Elements;Ensure;Environment;Evaluation;Feedback;Fostering;Funding;Funding Opportunities;Future;Grant;Guidelines;High Performance Computing;Human Resources;Individual;Knowledge;Leadership;Learning;Logistics;Maintenance;Malignant Neoplasms;Minority-Serving Institution;Monitor;New York City;Organization administrative structures;Persons;Pilot Projects;Policies;Preparation;Procedures;Process;Progress Reports;Qualifying;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Resources;Services;Shapes;Site Visit;Structure;System;Systems Biology;Technology;Teleconferences;Therapeutic;United States National Institutes of Health;Work;analytical tool;data harmonization;data sharing;data submission;diversity and inclusion;high school;meetings;member;operation;outreach;programs;recruit;repository;success;synergism;university student;web site;working group Administrative Core n/a NCI 10729384 9/19/23 0:00 RFA-CA-21-048 1U54CA274506-01A1 1 U54 CA 274506 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7247 7827402 "CALIFANO, ANDREA " Not Applicable 13 Unavailable 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY Domestic Higher Education 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 54039 32850 21189 PROJECT SUMMARYThe Administrative Core will provide coordination and oversight across all Center activities. It will help maximizeinteractions and synergies and will enable optimal use of available research infrastructure including Coreresources and services and a state-of-the-art high-performance computing environment. It will also facilitateparticipation of CaST members to CSBC activities ensure that programmatic feedback from the CSBC isintegrated into the Centers operations and administer the one-year intra-Center pilot research projects. Aneffective management structure will be put in place to ensure that the Centers complex objectives are achievedin timely fashion including an Executive Steering Committee (ESC) comprising the Centers Directors CenterAdministrator Project/Core Leads and NCI program officerswhich will oversee the Centers operations andprovide overall guidance to the investigators; a Center Administrator who will meet frequently with Project andCore leads to track progress on project activities facilitate interactions and integration between Projects andensure that the decisions made at the ESC meetings are properly communicated; and a Data Manager who willensure that resources and data generated by the Center are consistently annotated and prepared for submissionto NIH repositories in a timely and effective manner. The ESC will meet quarterly to candidly assess Projectprogress address operational and research issues that require corrective action prioritize use of Centerresources make decision about Pilot Project awards and ensure coordination with related NCI and NIHactivities. The Administrative Core will provide logistical support for the annual NCI site visit coordinatepreparation of progress reports monitor compliance with regulatory requirements and provide timely fiscalreviews and budget analysis. In support of these efforts the Core will define and track a broad collection ofquantitative metrics to assess the quality and utility of Center deliverables. The Core will be responsible forassembling a world class scientific External Advisory Committee (EAB) to advise the Centers co-Directors andto provide an impartial assessment of the Centers research program. In addition to ad hoc communications theEAB members will meet in person once a year at the Centers NCI site visit where they will attend scientificpresentations from Project and Core investigators and will offer feedback on research progress and futuredirections as well as advice on program management and the administration of the Pilot Project program. TheAdministrative Core will coordinate the participation of Center personnel to all Consortium activities includingattending meetings and workshops contributing to working groups and technical committees and interfacingwith other NIH initiatives. Finally it will support a broad educational program implemented through the Outreachcore aiming to expand inclusivity and diversity in Cancer Systems Biology by offering education and learningopportunities to underprivileged high school and college students from minority-serving institutions in New YorkCity and other big cities. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;Behavior;Binding;Biological;Biological Markers;Buffers;Cancer Center;Cells;Clinical;Collaborations;Combined Modality Therapy;Dependence;Development;Disease-Free Survival;Dissection;Drug resistance;Education;Endocrine;Epigenetic Process;Event;Fostering;Genetic;Genetic Transcription;Goals;Immunotherapy;Individual;Intervention;Intervention Trial;Ligands;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mediating;Metastatic malignant neoplasm to brain;Methodology;Molecular;Mutation;Network-based;Non-Malignant;Non-Small-Cell Lung Carcinoma;Outcome;Patients;Pharmaceutical Preparations;Pharmacology;Phenotype;Printing;Productivity;Prognosis;Proteome;Proteomics;Publications;Research;Research Personnel;Reverse engineering;Science;Scientist;Signal Transduction;Structure;System;Systems Biology;Systems Integration;Technology;Therapeutic;Therapy trial;Tissues;Validation;actionable mutation;cancer cell;cancer therapy;cell type;clinical translation;clinically relevant;design;drug mechanism;evidence base;forging;immune checkpoint blockade;improved;innovation;interest;melanoma;multiple data sources;multiple omics;next generation;novel;outreach;paracrine;patient responsibilities;pharmacologic;programs;receptor;receptor-mediated signaling;recruit;relapse patients;single cell technology;targeted treatment;three dimensional structure;tumor;tumor heterogeneity;tumor initiation;tumor microenvironment;tumor progression;tumor-immune system interactions;virtual Center for Cancer Systems Therapeutics (CaST) PROJECT NARRATIVEThe proposed Center for Cancer Systems Therapeutics (CaST) will seek to perform systematic single-cell-level elucidation of stable cell states and state transitions in tumor-related cells and in their tumormicroenvironment (TME) to identify and target complementary dependencies leading to mechanism-basedcombination therapy trials. This will provide a more holistic understanding of the fundamental steps underlyingtumor initiation and progression and of the critical mechanisms that can be targeted pharmacologically totransform cancer treatment. Critically we have shown that the Systems Biology framework developed by CaSTCenter investigators can effectively generalize to virtually any tumor of interest leading to highly innovativebiomarker-based interventional trials thus accelerating progression from biological analysis to cures. NCI 10729383 9/19/23 0:00 RFA-CA-21-048 1U54CA274506-01A1 1 U54 CA 274506 1 A1 "ZAMISCH, MONICA" 9/19/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7827402 "CALIFANO, ANDREA " "HONIG, BARRY H" 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1754138 NCI 1097129 657009 PROJECT SUMMARYPatients with aggressive cancers often present with no pharmacologically actionable mutations and poor or nosensitivity to immune checkpoint blockade thus deriving only modest improvement in disease-free survival fromtargeted therapy and immunotherapy. Tumor heterogeneity adds further complexity by fostering reprogrammingadaptation selection and ultimately expansion of drug-resistant cells as well as emergence of animmunosuppressive tumor microenvironment (TME) both of which are ultimately responsible for patient relapseand poor outcome. Addressing these challengesi.e. identifying more universal mechanism-based targets forpharmacological intervention and assessing their potential value in highly heterogeneous tumorsis criticallydependent on the availability of accurate comprehensive and cell type-specific molecular interaction networks(cellular networks hereafter) which underlie both the cell-autonomous behavior of cancer cells and theirinteraction with other TME subpopulations. The proposed Cancer Systems Therapeutics (CaST) Center willcontinue its highly productive collaboration within the U54 Cancer Systems Biology Center (CSBC) network byextending its successful network-based methodologieswhich integrate cutting edge computational advancesand novel experimental technologies including use of 3D structure and multi-omics-based evidence. This willsupport studying cancer as a fully integrated system of co-evolving interacting subpopulations comprising bothmolecularly distinct coexisting malignant cell states as well as non-malignant cell states recruited to the tumormicroenvironment and potentially reprogrammed to implement a pro-malignant immunosuppressive milieu. Theultimate goal of this proposal is to leverage recent advances by CaST center investigators to elucidate theMechanism of Action of clinically relevant drugs and late-stage experimental compounds to target individualsubpopulation to either drive combination therapy or to rescue immunotherapy in drug resistant tumors. 1754138 +No NIH Category available Alcohol consumption;Big Data;Bioinformatics;Biological Models;Cancer Etiology;Cell model;Cells;Cessation of life;Cirrhosis;Complement;Complex;Data;Databases;Development;Disease;Ethnic Origin;Ethnic Population;Exhibits;Functional disorder;Gender;Gene Expression;Generations;Genetic;Genetic Polymorphism;Genotype;Haplogroup;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;High Prevalence;Hispanic;Hispanic Populations;Human;Incidence;Inpatients;Investigation;Liver;Mediating;Metabolic Diseases;Metabolic syndrome;Mitochondria;Mitochondrial DNA;Molecular;Mutation;NADH dehydrogenase (ubiquinone);Neoplasm Metastasis;Not Hispanic or Latino;Nuclear;Obesity;Oxidative Stress;Pathologic;Pathway interactions;Patients;Physiological;Play;Population;Positioning Attribute;Prevention;Primary carcinoma of the liver cells;Procedures;Proteins;Regulation;Reporting;Research;Rest;Risk Factors;Role;Sampling;South Texas;System;Technology;Testing;Time;Tissue Sample;Tissues;United States;Viral Proteins;Virus Diseases;biobank;burden of illness;cancer type;dosage;epidemiology study;genetic risk factor;health disparity;hepatocellular carcinoma cell line;high risk;inducible gene expression;mitochondrial DNA alteration;mitochondrial dysfunction;mortality;non-alcoholic fatty liver disease;novel;protein expression;public database;success;transplant centers;tumorigenesis The mitochondrial aspects of health disparity of hepatocellular carcinoma in Hispanic population In the United States HCC is one of the fastest growing causes of cancer related death with a 5-year survival of less than 12%. Notably this disease burden is disproportionately expressedamong different demographic ethnic groups as the incidence and mortality rates in the US areabout three times as high in Hispanics as in non-Hispanic whites in both genders. Our researchis expected to generate a mechanistic linkage among the mitochondrial genotype HCV infectionmitochondrial function and tumorigenesis in HCC a disease that is over-represented in theHispanic population. NCI 10729283 6/26/23 0:00 PA-20-185 1R01CA283840-01 1 R01 CA 283840 1 "WILLIS, KRISTINE AMALEE" 7/1/23 0:00 6/30/28 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 7607969 "BAI, YIDONG " Not Applicable 20 ANATOMY/CELL BIOLOGY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 484566 NCI 316894 167672 Hepatocellular carcinoma (HCC) is one of the fastest-rising causes of cancer-related mortality in the UnitedStates. The biggest risk factor for developing HCC is viral infection (HBV and HCV). Other factors include non-alcoholic fatty liver disease (NAFLD) alcohol use and obesity/metabolic syndromes. Genetics also plays animportant role in the development and progression of HCC. Notably HCC burden is disproportionatelyexpressed among different ethnic groups; the incidence and mortality rates are much higher in Hispanics thanin non-Hispanic whites (NHW) for both genders particularly in South Texas where Hispanics are the fastest-growing population. Moreover Hispanics with Hepatitis C Virus (HCV) infection are at a signicantly higher riskof developing cirrhosis and HCC compared to NHW with HCV. One major target of HCV proteins is themitochondria. Mitochondrial DNA (mtDNA) alterations and mitochondrial dysfunction are implicated in varioustypes of cancer including HCC. A human mtDNA haplogroup is defined by unique sets of mtDNApolymorphisms reflecting mutations accumulated by a discrete lineage. The distribution of mitochondrialhaplogroups in the Hispanic population differs greatly from that of the NHW population which may have someinflucence on the higher incidence of HCC in Hispanics. Based on these facts and our previous studies weseek to determine whether and how distinct mitochondrial haplogroups mitochondrial dysfunction and HCVinfection (as well as the interactions between these factors) impact HCC tumorigenesis and progresion. Thehypothesis tested here is that (1) Hispanic-specific mitochondrial haplogroup(s) and possible associatedreduced OXPHOS provide a mitochondrial background that favors HCC progresion and (2) that theinteractions between HCV proteins and mitochondrial machinery compromise OXPHOS and critical aspects ofmitochondrial pathways leading to HCC tumorigenesis. Our recent breakthroughs include the following: (1) theestablishment of Hispanic HCC cell lines and (2) the generation of an inducible dosage-dependent non-mitochondrial-conflicting expression system which will enable us to test the overarching hypothesis. We willgenerate cybrids with a Hispanic HCC nuclear background but different mitochondrial haplogroups andinvestigate mitochondrial function and tumorigenesis in these cybrids. We will also test the hypotheses that (1)reduced mitochondrial function increases HCC tumorigenesis while enhanced OXPHOS activity will decreaseHCC tumorigenesis and (2) a Hispanic-specific background will sensitize the cells to HCV-mediated HCCtumorigenesis. Finally taking advantage of big data about HCC patients in public databases and our uniqueaccess to our institutes large liver Biobank with Hispanic HCC patient samples we will complement thesemolecular investigations with bioinformatics and human epidemiology studies to verify associations betweenmitochondrial genetics mitochondrial function and HCV infection in the development and progression of HCCin the Hispanic population. 484566 +No NIH Category available ATAC-seq;Acute Myelocytic Leukemia;Acute leukemia;Adult;Animal Model;Anti-Inflammatory Agents;Antibodies;Atlases;B-Lymphocytes;B-cell receptor repertoire sequencing;Blast Cell;Bone Marrow;Bone remodeling;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Censuses;Chromatin;Clinical;Clonality;Collection;Coupled;Cytarabine;Data;Daunorubicin;Development;Disease;Disease Progression;Epitopes;Event;Exhibits;Gene Expression;Generations;Genes;Genetic;Genomics;Genotype;Goals;Hematopoietic stem cells;Human;IL1R1 gene;IRAK1 gene;Immune;Immune response;Immune system;Immunocompetent;Inferior;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interleukin-1;Leukemic Cell;Malignant - descriptor;Malignant Neoplasms;Mediating;Mediator;Membrane Proteins;Modeling;Molecular;Mus;Mutate;Mutation;Myeloid Cells;Myeloproliferative disease;Other Genetics;Outcome;Patients;Phenotype;Play;Population;Predisposition;Regimen;Resolution;Risk;Role;Sampling;Signal Transduction;Specificity;Structure;Subgroup;Supporting Cell;T-Lymphocyte;Testing;Therapeutic;Time;Tissues;Treatment Protocols;cancer cell;cell transformation;cohort;design;effectiveness testing;exome sequencing;immunoregulation;improved;indexing;inhibitor;insight;leukemia;leukemogenesis;monocyte;mouse model;multiple omics;negative affect;new therapeutic target;novel;prevent;protein expression;response;single cell technology;single-cell RNA sequencing;standard of care;survival outcome;targeted agent;transcriptome;transcriptome sequencing;treatment effect;treatment response;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions The role of inflammation in the regulation of immune response in acute myeloid leukemia Project NarrativeWe recently showed that patients with acute myeloid leukemia (AML) that have high inflammation have pooroutcomes and demonstrate that a distinct immune response cooperates with mutational background to promoteleukemogenesis including remodeling of the bone marrow niche expansion of dysfunctional B and T cellpopulations. We hypothesize that targeting this aberrant immune response will modulate disease progressionand therapeutic response. Our proposal is designed to deepen our understanding of the different contributors toinflammation in AML and to delineate the inflammatory response of AML patients of specific molecular subgroupsof AML that generally confer high inflammation during different frontline therapies to improve treatment responseand survival of these poor-risk patients. NCI 10729281 7/6/23 0:00 PA-20-185 1R01CA283574-01 1 R01 CA 283574 1 "KLAUZINSKA, MALGORZATA" 7/6/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-BTC-Q(80)S] 7647769 "AIFANTIS, IANNIS " "EISFELD, ANN-KATHRIN " 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 7/6/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 570317 NCI 382115 188202 Project Summary/AbstractSurvival outcomes of acute myeloid leukemia (AML) patients are negatively affected by high inflammation in thebone marrow compared to low inflammation patients within the same molecular subgroup. The overarching goalof our study is to delineate functionally relevant contributors to aberrant inflammation characterize changes tothe inflammatory state longitudinally during different standard-of-care treatment approaches and determinewhether targeting inflammation via inhibitors that target the crucial mediators of inflammation can improvetreatment response and survival. The proposal was prompted by our recent characterization of inflammation-mediated progression to AML in animal models and the notable cooperation with select mutational backgroundsto promote leukemogenesis; and our notion of distinct cellular remodeling of both leukemic cells and themicroenvironment to promote inflammation. We believe that the observed strong negative treatment responseand survival association that was independent from other genetic contributors provides an exciting rationale totarget aberrant inflammation in AML patients in order to improve treatment response and disease progression.This goal will be achieved by two independent but complementary Specific Aims. (1) Utilizing our large cohortof 1600 AML patients who were molecularly and clinically characterized and have a defined inflammatory statewe will characterize those patients with the highest and the lowest inflammation and compare cell state cell fateand immune response at the single cell level via a comprehensive multi-omic approach. (2) We will trackdynamics of inflammatory immune-regulatory and associated clonal structures during different treatments viathe same multi-omic profiling with an integrated approach that first profiles longitudinally collected patientsamples with select genotypes during different treatments followed by patient derived xengraft models of thesame patients that will undergo 2 different therapeutic approaches followed by serial profiling thereby allowingfor direct comparison and definitive characterization of the observed changes. Lastly we will test theeffectiveness of anti-inflammatory agents (IL-1 inhibitors) to lower inflammation and prevent the inflammation-associated bone marrow remodeling and inferior treatment response. Together our results will for the first timeprovide critically needed information to provide a basis for targeting aberrant inflammation in AML patients. 570317 +No NIH Category available Affect;Agar;Animal Model;Biological;Biology;Brain Neoplasms;Cell Communication;Cell Culture Techniques;Cell Nucleus;Cells;Clinical;Clinical Research;Complex;Core Biopsy;Cryoultramicrotomy;Data;Dimensions;Ensure;Equipment;Experimental Models;Expression Profiling;Gene Expression;Gene Expression Profiling;Geography;Glioblastoma;Glioma;Goals;Human;Human Resources;Image;Immune;Immunologics;In Vitro;Knowledge;MHC Class I Genes;Malignant - descriptor;Maps;Measurement;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metadata;Methodology;Methods;Modeling;Molecular;Molecular Profiling;Multiomic Data;Neuroglia;Neurons;Patients;Peptides;Performance;Pharmaceutical Preparations;Phosphorylation;Population;Pre-Clinical Model;Proteomics;Protocols documentation;Quality Control;Reagent;Reproducibility;Resolution;Resources;Sampling;Services;Signal Transduction;Specimen;Study models;System;Systems Biology;Technology;Therapeutic;Thick;Time;Tissues;accurate diagnosis;brain tissue;cell type;clinically relevant;data management;data sharing;drug distribution;dynamical evolution;forest;human tissue;image guided;imaging biomarker;information gathering;mass spectrometric imaging;mathematical model;metabolomics;neoplastic cell;phosphoproteomics;pre-clinical;programs;protein expression;single nucleus RNA-sequencing;spatial integration;tissue culture;tool;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor microenvironment Core 2: Analytical Core n/a NCI 10729279 9/15/23 0:00 RFA-CA-21-048 1U54CA283114-01 1 U54 CA 283114 1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7197 9384989 "AGAR, NATHALIE YR" Not Applicable 7 Unavailable 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA Domestic Higher Education 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 351745 310003 41742 ABSTRACT ANALYTICAL CORE The Analytical Core will serve as a central resource for the deep systems-level molecular characterization ofbiological samples generated by the Projects and from the Biospecimens Core. The primary objective of thisCore is to integrate diverse single cell bulk and spatial analytical platforms to define the complex interactionsbetween brain tumor cells and the associated brain tumor microenvironment (TME). To this end we havedeveloped an analytical platform encompassing transcriptional profiling at the single cell single nuclei and bulktissue scale; protein expression profiling phosphoproteomics and immunopeptidomics with cell type-specificresolution; and quantitative metabolomics and drug distribution profiling with high spatial resolution by massspectrometry imaging (MSI). These complementary analytical approaches have the requisite sensitivity togenerate ultra-deep systems-level molecular profiling of 10-20 micron thick tissues from single core biopsies;performance of our platform has already been demonstrated on multiple image-guided core biopsies fromgeographically distinct regions of a GBM tumor. Multi-omics data acquired in our Analytical Core will be managedusing a FAIR compliant metadata management tool that prioritizes connections between samples and definesdiscrete sample types that can be freely connected as described in the Overall Section of our proposal. TheAnalytical Core will provide expert personnel facilitate the sharing of knowledge within the program and maintainthe sophisticated equipment necessary to generate data for both Projects. By acting as a common resource theAnalytical Core provides expertise for each Project. +No NIH Category available AMPA Receptors;Affect;Aftercare;Animals;Antiepileptic Agents;Biological Process;Blood Vessels;Brain;Brain Neoplasms;Cell Communication;Cells;Classification;Clinical Trials;Clone Cells;Communication;Communities;Competence;Computer Models;Data;Dedications;Development;Electrophysiology (science);Excision;Exhibits;Extracellular Matrix;Favorable Clinical Outcome;Glioblastoma;Glioma;Glutamates;Heterogeneity;High Frequency Oscillation;Immunologics;Individual;Invaded;Levetiracetam;Location;Logistic Regressions;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Glioma;Maps;Measurement;Measures;Metabolic;Metabolic Pathway;Microscopic;Mitochondria;Modeling;Molecular;Multiomic Data;Nature;Neuroepithelial Perineurial and Schwann Cell Neoplasm;Neurons;Operative Surgical Procedures;Oxidative Phosphorylation;Pathway interactions;Patients;Phenotype;Proliferating;Radiation therapy;Recurrence;Resected;Resistance;Resolution;Resources;Route;Sampling;Signal Pathway;Signal Transduction;Slice;Specimen;Synapses;System;Systems Biology;Testing;Therapeutic;Time;Tissues;Treatment Efficacy;Tumor Markers;Tumor Promotion;Work;cancer proteomics;cell growth;cell motility;cell type;chemotherapy;clinically relevant;cohort;data integration;deep learning;design;dynamical evolution;experimental study;in vivo;inhibitor;innovation;multiple omics;neoplastic cell;neuronal tumor;novel;patient derived xenograft model;pharmacologic;pre-clinical;progenitor;random forest;response;single-cell RNA sequencing;standard of care;therapeutic development;therapy resistant;tumor;tumor metabolism;tumor progression;tumorigenesis;white matter Project 1: Deciphering the Dynamic Evolution of the Tumor-Neural Interface n/a NCI 10729275 9/15/23 0:00 RFA-CA-21-048 1U54CA283114-01 1 U54 CA 283114 1 9/15/23 0:00 8/31/28 0:00 ZCA1-RTRB-F(M2) 7193 9384989 "AGAR, NATHALIE YR" Not Applicable 7 Unavailable 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA Domestic Higher Education 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 473047 428797 44250 ABSTRACT PROJECT 1The central premise of our CSBC MIT/DFCI Center for Systems Biology in Glioblastoma is that high-contentsystems-level measurements at molecular microscopic and macroscopic scales with spatial resolution willenable the development of computational models to map and predict tumor dynamics leveraging data integrationand deconvolution for computational modeling of the glioblastoma-microenvironment. The establishment of thisnovel GBM model will support the identification of critical signaling and metabolic pathways and networksregulating tumor progression and therapeutic resistance while providing biomarkers of tumor state and efficacyfor therapeutic developement. Project 1 will focus on elucidating networks coordinating the tumor-neuronalinterface. Recent results uncovered the ability of subpopulations of glioblastoma cells to organize in brain tumorcell networks that include the formation of glutamatergic synapses formed between individual glioblastoma cellsand neural cells from the normal brain. The establishment of synaptic connectivity was proposed to promotetumor cell movement along white matter therefore implying that the mutually connected glioma cells may driveinvasion of the normal brain which is the primary mechanism of progression and aggressiveness of malignantglioma that ultimately renders these tumors incurable. We will now leverage key preclinical resources establishedby our labs including an integrated computational-experimental framework annotated GBM patient-derivedxenografts (PDXs) for ex vivo and in vivo mechanistic experiments to derive a model of glioma-neuroninteractions that drive the malignant nature of glioblastoma and how perturbation of this signaling network affectstumor proliferation invasion and therapeutic resistance. In Aim 1 we will use our innovative multi-omics platformwith ex vivo slice culture models to investigate the ability of neurons to support tumor cell growth and invasionand affect cell state and develop and implement computational modeling strategies to model the dynamicevolution of different cell types and tumor cell clones over time and in response to stimulation. Aim 2 will allowfurther parametrization of the computational model with data acquired from in vivo orthotopic models testedfor the effect of anti-epileptic drugs on tumor proliferation and invasion in the context of standard of care treatmentwith radiotherapy and recurrence. In Aim 3 we will analyze the impact of anti-epileptic therapeutics on theglioma-brain network in clinical trial tissue specimens with our multi-omics platform allowing to test andoptimize the model accuracy with clinically relevant data. +No NIH Category available Acute Myelocytic Leukemia;Address;Anabolism;Automobile Driving;Biological Markers;Carbohydrates;Carbon;Cell Compartmentation;Cell Line;Cells;Cellular Metabolic Process;Clinical;Collaborations;Companions;Complex;Data;Dependence;Development;Diet;Disease;Environment;Enzyme Inhibition;Enzymes;FLT3 gene;Future;Genetic;Genetic Variation;Glucose;Glutamine;Glycolysis;Goals;Hematopoietic;Heterogeneity;Human;Image;Isocitrate Dehydrogenase;Isotopes;Knowledge;Link;Lipids;MLL-AF9;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Motivation;Mus;Mutation;Myeloid Leukemia;Nutrient;Organism;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoglycerate dehydrogenase;Publishing;Pyruvate;Relapse;Research;Resistance;Role;Sampling;Science;Serine;Sorting;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Therapeutic;Translating;Visualization;Work;acute myeloid leukemia cell;cancer therapy;cell growth;chemotherapy;dehydroascorbate;design;human cord blood CD34+ cell;imaging approach;imaging biomarker;in vivo;individualized medicine;innovation;insight;leukemia;leukemic stem cell;mass spectrometric imaging;metabolic abnormality assessment;metabolic imaging;new therapeutic target;novel;novel marker;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;pharmacologic;programs;response;stem cell biology;stem cells;stemness;stress state;therapeutic development;therapy resistant;tool;treatment planning;treatment response;tumor metabolism Interrogation of the oxidative-stress-induced leukemia program in vivo using metabolic imaging PROJECT NARRATIVELeukemia remains difficult to treat indicating an urgent need to develop new therapeutic strategies; thus theoverarching goal of the proposed research is to explore leukemia metabolism and develop novel biomarkers andtherapeutic strategies. Our preliminary data demonstrates that specific metabolic pathways driving serinebiosynthesis are increased in leukemia; these reflect vulnerabilities that we can develop imaging biomarkers totarget. Our proposed work will facilitate future patient-specific treatment planning and novel experimentalstrategies for cancer treatment. NCI 10729140 6/27/23 0:00 PA-20-185 1R01CA283578-01 1 R01 CA 283578 1 "TANDON, PUSHPA" 7/1/23 0:00 6/30/28 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 10451505 "KESHARI, KAYVAN R" "KHARAS, MICHAEL " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 728079 NCI 411344 316735 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) is a genetically complex and heterogeneous set of diseases characterized by adiverse set of mutations. Although many patients initially respond to treatment many end up relapsing. Over thelast decade an appreciation of the genetic diversity and clonal hierarchy in AML has opened the door to noveltherapeutic targets and therapeutic approaches to specific AML subtypes. Moreover AML has been found tobear unique metabolic features with therapeutic implications. Most importantly mutations in the enzymesisocitrate dehydrogenase (IDH1/2) have led to clinically approved drugs. However many patients becomeresistant to this therapy as well further underscoring the need for new strategies to target dysregulatedmetabolism in leukemia. Through the development of novel microcoil platforms to explore leukemia metabolismwith HP MR (Jeong et al. Science Advances 2017) we have identified a new metabolic vulnerability in theglycolytic metabolism of leukemia (Jeong et al. Cell Metabolism 2021). This reliance on glycolytic metabolismalters not only glucose flux to lactate but also one-carbon flux through the serine pathway which facilitates themetabolism of glutamine. Moreover we found that genetically targeting or pharmacologically inhibiting theenzyme that mediates flux through this pathway (PHGDH) capitalizes on a new vulnerability in these cells.Importantly this targeting does not affect normal hematopoietic cell growth. Thus building upon extensivecollaboration between our labs and ample preliminary data we aim to employ innovative approaches to studymetabolism (Keshari Lab) including by developing non-invasive probes to measure changes in glycolysis andoxidative stress with hyperpolarized magnetic resonance imaging. This metabolism will be characterized in well-defined models of AML (Kharas Lab) with both genetic and pharmacological modulation in order to develop astrategy to assess leukemia-stem-cell-driven AML metabolism and the inhibition of serine metabolism.Altogether these studies will result in new mechanistic insights and novel cancer therapies. 728079 +No NIH Category available ARNTL gene;Acceleration;Address;Affect;Area;Biological Markers;Biological Models;Biological Process;Biological Rhythm;Biology;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Cell Line;Cells;Circadian Dysregulation;Circadian Rhythms;Coupled;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Diurnal Rhythm;Dominant-Negative Mutation;Doxycycline;Drosophila genus;Ectopic Expression;Engineering;Exclusion;Fasting;Gene Expression;Genes;Growth;Heterogeneity;Hour;Human;Human Engineering;Immune;Immune signaling;Immunity;Immunocompetent;Immunologics;Immunotherapy;Infiltration;Inflammation;Inflammatory;Interferons;Intermittent fasting;Knock-out;Link;Malignant Neoplasms;Melanoma Cell;Metabolic;Metabolism;Modeling;Molecular;Mus;Mutation;Null Lymphocytes;Oncogenic;Patients;Phenocopy;Polycomb;Prognosis;Proteins;Proteome;Reagent;Research;Resistance;Role;Series;Signal Transduction;Sleep;System;T cell infiltration;Testing;The Cancer Genome Atlas;Therapeutic;Tumor Biology;Tumor Immunity;anti-PD-1;anti-PD1 therapy;cancer cell;cancer risk;chemokine;circadian;circadian pacemaker;comparison control;cytokine;cytotoxic CD8 T cells;exhaustion;feeding;humanized mouse;immune reconstitution;immune resistance;immunoregulation;in vivo;melanoma;metabolome;monocyte;mouse model;novel;programmed cell death ligand 1;reconstitution;response;shift work;targeted treatment;therapy resistant;transcription factor;transcriptome;transcriptome sequencing;treatment response;tumor;tumor heterogeneity;tumor progression;tumorigenesis;vector;virtual Defining the Role of the Cancer Circadian Clock in Tumor Immunity and Tumorigenesis Project NarrativeDisruption of circadian rhythm which are biological processes that oscillate with a period of 24 hours has beenlinked to increased cancer risk in night-shift workers. Cancer cells can have disrupted cellular circadian clocksthat could make them more or less aggressive or resistant to therapy. This unexplored research area whichis likely to contribute to a better understanding of resistance to standard and immunotherapy will be the focusof this application which is expected to provide concepts for better therapeutic strategies. NCI 10729129 2/16/23 0:00 PA-21-268 7R01CA051497-31 7 R01 CA 51497 31 "ZAMISCH, MONICA" 1/1/90 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 1870828 "DANG, CHI V." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 396 Non-SBIR/STTR 2023 331594 NCI 202500 129094 Project SummaryCircadian rhythms are biological processes a period of 24 hours driven by the circadian CLOCK-BMAL1transcription factor that regulates diurnal variations of cellular metabolism and inflammation signaling.Disruption of the circadian clock has been linked to cancer but mechanisms of how the clock affects cancerprogression are not well understood. We previously shown that oncogenic MYC could disrupt the circadianclock in cancer cells and in vivo in Drosophila and note that analysis of TCGA data indicates widespreadmutations in the circadian clock circuitry genes. To address the role of the clock heterogeneity in tumor biologywe chose to study melanomas which respond to immunotherapy and targeted therapy with varying degrees oftherapeutic resistance. In preliminary studies of a panel of 14 patient-derived melanoma cell lines we foundheterogeneity in clock function and increased interferon response genes when the clock is molecularlydisrupted in engineered cells. Further we found in a mouse model of melanoma that clock disruption wasassociated with accelerated tumorigenesis in immunocompetent but not immunocompromised mice. Increasedor decreased BMAL1 the central clock component induced dedifferentiation rendering mouse melanomacells immune privileged with altered chemokine expression and resistance to immunotherapy in vivo. Basedon our preliminary studies we hypothesize that functional clock heterogeneity alters cancer cell immunity andcontribute variable therapeutic responses. We propose to alter clock function through loss and gain of BMAL1function in engineered human and mouse melanoma cell lines and determine the molecular mechanismsunderlying resistance of melanoma to anti-PD1 treatment. We will use a humanize mouse (Hu-mice) system tostudy the clock-engineered human melanoma cells in vivo. These findings are expected to contribute novelconcepts of therapeutic resistance biomarkers based on clock biology and eventual better therapeuticstrategies. 331594 +No NIH Category available Adjuvant;Animals;Breast Cancer Cell;Breast Cancer Model;Breast Cancer therapy;Cell Survival;Cells;Chemicals;Clinical;Combination Drug Therapy;Combination immunotherapy;DNA Damage;Data;Drug Carriers;Drug Delivery Systems;Dyes;Enhancers;Environment;Enzyme-Linked Immunosorbent Assay;Exhibits;Future;Goals;Growth;Immune;Immune system;Immunologic Stimulation;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Vitro;Incubated;Intervention;Malignant Neoplasms;Measures;Microscopy;Molecular;Mouse Cell Line;Mus;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Optics;Outcome;Pathway interactions;Patients;Pattern;Phenotype;Primary Neoplasm;Production;Prognosis;Property;Public Health;Publishing;Quantitative Reverse Transcriptase PCR;RNA chemical synthesis;RNA delivery;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Research;Role;Small Interfering RNA;Survival Rate;Testing;Therapeutic;Therapeutic Effect;Therapeutic immunosuppression;Transforming Growth Factor beta;Transmission Electron Microscopy;Treatment Efficacy;Tumor Immunity;Tumor Tissue;Tumor-infiltrating immune cells;Work;Xenograft Model;anti-cancer;anti-tumor immune response;antitumor effect;cancer cell;cancer immunotherapy;cancer radiation therapy;cancer type;cyanine dye 5;cytokine;design;immune checkpoint blockers;immunogenic cell death;immunogenicity;immunomodulatory therapies;immunoregulation;improved;in vivo;in vivo optical imaging;innovation;interest;malignant breast neoplasm;mouse model;multimodality;nanoGold;novel strategies;prospective;radiation effect;recruit;response;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;uptake;zeta potential siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy Project NarrativeThe proposed research aims to explore new approaches to stimulate antitumor immune response in triplenegative breast cancer. Our study will show that the use of targeted gold nanoparticle together with radiationtreatment can change the immune profile of tumor tissue into an environment promoting antitumor immuneresponse. This work is directly relevant to public health as the findings of this study will help the design ofimmunotherapeutic interventions that will improve clinical outcome and survival in patients with triple negativebreast cancer as well as the other cancer types. NCI 10729127 7/10/23 0:00 PAR-20-052 1R03CA277216-01A1 1 R03 CA 277216 1 A1 "PRASANNA, PAT G" 7/10/23 0:00 6/30/25 0:00 ZCA1-SRB-K(M2)S 8624419 "JANIC, BRANISLAVA " Not Applicable 13 Unavailable 73134603 R9NXPE2GTCN9 73134603 R9NXPE2GTCN9 US 42.371987 -83.076406 218602 HENRY FORD HEALTH SYSTEM DETROIT MI Independent Hospitals 482023450 UNITED STATES N 7/10/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 76225 NCI 52822 23403 ABSTRACTRadiation therapy (RT) modulates immunological properties of tumor microenvironment (TME) to stimulateantitumor immune response. However RT initiates immunosuppressive mechanisms as well and thereforediminishing the effects of RT immuno-stimulation. One of the main RT immunosuppressive modes is exerted byan increase in TGF production that in breast cancers (BC) has an additive effect on already high TGF levelsproduced by cancer cells themselves. Triple negative breast cancer (TNBC) in particular was demonstrated tohave higher TGF levels compared to other BCs and this finding correlated with increased tumor grade andinvasiveness and a diminished patient survival. Consequently RT induced increase in TGF within the TMEmay further potentiate invasiveness and metastatic potential of TNBC. Due to stimulatory aspects of RTimmunomodulation RT has gained interest as a prospective therapeutic enhancer in cancer immunotherapysuch as immune checkpoint blockers that has shown great potential in improving local control and overallsurvival in select cancers. Unfortunately in most forms of BC including TNBC response to immunotherapyremains modest. Our long-term goal is to use RT to enhance TNBC response to immunotherapy by takingadvantage of RT immunomodulatory potential. Antitumor RT effects including TME immunomodulation can beimproved by using radiosensitizers such as gold nanoparticles (AuNP). Furthermore AuNPs can also serve asa drug delivery system by conjugation of small interfering RNAs (siRNAs). In this project we propose to useAuNPs functionally modified by TGF siRNA to simultaneously enhance RT immunomodulation and counteractthe immunosuppressive effects related to the increased TGF production. This approach will enhance RTantitumor effects and create a favorable TME environment for better response to future immunotherapies. Thiswill be tested by the following specific aims: Aim 1: To synthesize and characterize AuNP-siRNATGF1; Aim2: To investigate the therapeutic effect of combination of RT and AuNP-siRNATGF1 in in vitro and in vivomouse TNBC model. The proposed studies in determining the potential of AuNPs simultaneously targetantitumor and immunomodulatory RT effects will provide critical information for improving TNBC response toimmune checkpoint blockers and for designing future RT/ immune checkpoint blockers multimodal TNBCtherapies. 76225 +No NIH Category available Address;Adopted;Adult;Affect;Age;Age Years;Alcohols;Behavior;Belief;Black American;Cancer Control;Categories;Code;Colorectal Cancer;Communication;Communication Research;Data;Data Collection;Death Rate;Diagnosis;Disease;Disparity;Disparity population;Early Diagnosis;Environment;Evaluation;Exposure to;Future;Goals;Guidelines;Health;Health Policy;Health Promotion;Human;Incidence;Individual;Inequality;Information and Media;Knowledge;Light;Malignant Neoplasms;Methods;Misinformation;Monitor;Natural Language Processing;Not Hispanic or Latino;Perception;Persons;Persuasive Communication;Population;Population Heterogeneity;Populations at Risk;Prevention;Procedures;Public Health;Public Opinion;Race;Randomized;Randomized Controlled Trials;Recommendation;Research;Research Personnel;Respondent;Risk;Sampling;Scanning;Social Network;Source;Survey Methodology;Surveys;Techniques;Technology;Testing;Tobacco;United States;Woman;caucasian American;colon cancer screening;colorectal cancer prevention;colorectal cancer risk;colorectal cancer screening;crowdsourcing;design;digital media;efficacy trial;evidence base;experimental study;formative assessment;health communication;high risk;improved;innovation;men;novel;novel strategies;preference;racial population;recruit;screening;screening guidelines;social media;wiki Using Natural Language Processing and Crowdsourcing to Monitor and Evaluate Public Information and Communication Disparities about Colon Cancer Screening PROJECT NARRATIVEEfforts to improve public health communication about colorectal cancer (CRC) and CRC screening (CRCS)require understanding what information is commonly seen by target audiences and consideration of existinginformation and behavior disparities for populations at higher risk for CRC (e.g. Black Americans). The currentproject uses novel computational approaches to monitor the public communication environment about CRCScrowdsourcing to engage in formative evaluation of possible message content and a randomized controlledtrial to validate these computational and crowdsourcing approaches. The project tests novel approaches tomonitor and evaluate public health information to inform health communication research and practice. NCI 10729069 3/2/23 0:00 PA-21-268 7R37CA259156-03 7 R37 CA 259156 3 "CHOU, WEN-YING" 4/15/21 0:00 2/28/25 0:00 Biomedical Computing and Health Informatics Study Section[BCHI] 12046556 "KING, ANDY J" Not Applicable 1 MISCELLANEOUS 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF ARTS AND SCIENCES 841129049 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 393 Non-SBIR/STTR 2023 474710 NCI 308587 166123 PROJECT SUMMARYColorectal cancer (CRC) incidence and death rates are higher among Black Americans than non-HispanicWhite Americans. While some CRC-related disparities have decreased (e.g. incidence and stage ofpresentation) disparities persist in the context of CRC screening (CRCS). Studies suggest that supportive andinformation-rich social networks both online and offline could improve CRCS among Black Americans. Agrowing body of evidence indicates the importance of online sources of health information seeking andscanning about CRC and CRCS but little is known about the impact of the messages that individuals areencountering on these platforms. Research on the content and volume of messages White and BlackAmericans encounter from online health information sources is still unclearparticularly regarding anydisparities that exist about what specific information is sought scanned or shared by Black Americans. Thereis a critical need to understand which messages resonate among populations at-risk for specific diseases (e.g.CRC) and who may have concerns about engaging in early detection behaviors (e.g. CRCS) and may facedisparities in exposure to public information online. The proposed project utilizes and applies novel cancercommunication surveillance approaches (e.g. natural language processing and crowdsourcing) to examinepublic health communication about CRC prevention and control. Aim 1 will use computational naturallanguage processing approaches to capture and analyze digital and social media information about CRC andCRCS to identify prominent messages sources and types of misinformation and information inequalities. Thisapproach offers an efficient effective and responsive method to monitor (mis)information and emergingmessages about CRCS. Aim 2 will use a crowdsourcing approach (wiki surveys) to assess populationperceptions of public information and messages about CRCS. Recruiting nationally representative samples ofWhite (N = 1000) and Black American (N = 1000) adults ages 45-74 we will use an innovative data collectionprocedure known as wiki surveys to rank candidate messages as potential message targets in strategic effortsto promote CRCS. For Aim 3 we will conduct a randomized controlled message trial (N = 1600) to determinethe validity of the wiki survey approach to selecting messages for targeted audience segments. We will usedata collected from Study 2 to identify four sets of messages with strong arguments respective to each targetaudiences rankings: highest rated messages for both audiences highest rated messages for target in-grouphighest rated messages for target out-group and middle-/median-rated messages. We will cross thosemessage categories with target audience (White/Black American) to test if messages selected via the wikisurvey are associated with intentions to adhere to screening recommendations in the future and share CRCSmessages. The project will offer evidence to help determine the validity and scalability of these novel methodswhich is essential to innovate formative research and evaluation approaches in the future. 474710 +No NIH Category available 13q;Alleles;Atlases;Automobile Driving;Basic Science;Biological Assay;Biology;Career Choice;Cell Line;Cell model;Cells;Chronic Lymphocytic Leukemia;Clonal Evolution;DNA Repair;DNA Sequence Rearrangement;DNA replication fork;Data;Disease Progression;Doctor of Philosophy;Enzymes;Excision;Excision Repair;Exhibits;Future;Genes;Genetic;Genetic Materials;Genome;Genome Stability;Genomic Instability;Genomics;Goals;Hematologist;Human;Human Cell Line;Hydrolysis;In Vitro;Institution;Laboratories;Light;Loss of Heterozygosity;Maintenance;Malignant Neoplasms;Measures;Mediating;Mentorship;Methods;Molecular;Mutagenesis;Mutate;Mutation;Oncologist;Pathogenicity;Pathway interactions;Patients;Pattern;Peptides;Physicians;Poly(ADP-ribose) Polymerase Inhibitor;Prediction of Response to Therapy;Predisposition;Process;Proteins;RNA;RNase 2;Recombinants;Recurrence;Regulation;Relapse;Research;Ribonuclease H;Ribonucleases;Ribonucleotides;Role;Running;Sampling;Scientist;Stimulator of Interferon Genes;Stress;Tertiary Protein Structure;Testing;Therapeutic Intervention;Topoisomerase;Tumor Suppressor Proteins;Universities;University Hospitals;Variant;Work;chromothripsis;chronic lymphocytic leukemia cell;doctoral student;exome;in vivo;insight;micronucleus;mutant;novel;prevent;programs;protein purification;recruit;repaired;replication stress;response;termination factor;tumor initiation;tumor progression;whole genome Mechanisms of genomic instability tumor initiation and progression following the disruption of the RTF2-RNase H2 axis Project NarrativeThe repair of DNA is vital to maintain the stability of our genetic material as well as prevent the formation ofmutations that can lead to the initiation and progression of malignancy. This proposal seeks to 1) gain insightinto how the removal of ribonucleotides from the genome is regulated and 2) propose a novel method allowingthe quantitative study of ribonucleotide incorporation in human cells. Completion of this work will shed light intohow the enzyme RNase H2 and enzyme exhibiting frequent copy number loss in a Chronic LymphocyticLeukemia maintains genomic stability and prevents transformation to malignancy. NCI 10728877 6/30/23 0:00 PA-21-049 5F30CA268717-02 5 F30 CA 268717 2 "DAMICO, MARK W" 7/1/22 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15119650 "BLOBEL, NICOLAS JOHANNES" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 Project Summary/AbstractThe aberrant incorporation or retention of ribonucleic acids (RNAs) in the genome is a common cause of genomicinstability rendering it susceptible to hydrolysis and downstream mutagenesis. The enzyme RNase H2 is one ofthe primary mechanisms protecting against this destabilization of the genome by removing these genome-embedded RNAs.Our lab recently uncovered a novel mechanism of regulation of RNase H2 by uncovering that replicationtermination factor 2 (RTF2) is involved in localizing and regulating the levels of RNase H2 at the replication fork.Further elucidation of this interaction is required to understand the basic biology behind the regulation andfunction of how RNase H2 prevents genome instability. Interestingly copy number loss of RNase H2 is commonlyfound in Chronic Lymphocytic Leukemia (CLL) in over 30% of cases. In my preliminary work I have developedvarious cellular models in which RNase H2 and RTF2 can be depleted and I have expressed and purifiedrecombinant RNase H2 and RTF2 allowing for both in vivo studies of which RNase H2 activities are regulatedby RTF2 and in vitro studies of their interaction. Furthermore I have developed a novel assay allowing aquantitative analysis of ribonucleotide incorporation in the genomes of human cells. This assay will be used tostudy the regulation of RNase H2 by RTF2 and will be assessed in its applicability to predict CLL responses toPARP-inhibitors. The direct mechanism behind tumor progression in the loss of RNase H2 has not been studied.In this proposal building on my above preliminary work I will test the hypothesis that RTF2 interacts directly withand regulates the activities of RNase H2 at the replication fork and examine the mechanism behind how loss ofRNase H2 compromises genomic stability and leads to tumor progression.I am an MD/PhD student at the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional Program where I amin the laboratory of Dr. Agata Smogorzewska at The Rockefeller University. My long-term goal is to become aphysician scientist practicing as a hematologist-oncologist as well as running an independent basic science labas an academic university hospital. The plan outlined in this proposal along with the support and mentorship ofDr. Agata Smogorzewska my thesis research committee and the Tri-Institutional MD-PhD program will help meachieve these career aspirations. 52694 +No NIH Category available Agonist;Allografting;Apoptosis;Area;BCL1 Oncogene;Biomedical Research;Cancer Cell Growth;Cancer Patient;Cell Survival;ChIP-seq;Clinical;Colon Carcinoma;Colonic Neoplasms;Data;Development;Disease;Distal;Drug Kinetics;Exhibits;Gastrointestinal tract structure;Gene Expression Profile;Gene Expression Regulation;Genetic Models;Growth;Human;In Vitro;Induction of Apoptosis;Inhibition of Cell Proliferation;Invaded;MEKs;Mediating;Medical;Modeling;Molecular;Morphology;Mus;Neoplasm Metastasis;Normal Cell;Oncogenic;Organ;Organoids;Parkinson Disease;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Probability;Process;Protein Family;Psychoses;Regulation;Research Priority;Role;Safety;Serotonin;Serotonin Receptor 5-HT2A;Signal Pathway;Signal Transduction;Solid Neoplasm;Source;Structure;Therapeutic;Therapeutic Agents;Tissue-Specific Gene Expression;Toxic effect;Transforming Growth Factor beta;Treatment Failure;Tumor Suppressor Proteins;Tumor-Derived;anti-cancer;anticancer activity;cancer cell;cancer therapy;cell growth;chemotherapeutic agent;chemotherapy;colon cancer cell line;colon cancer treatment;cost;drug development;drug repurposing;experimental study;humanized mouse;in vivo;interest;migration;mouse model;novel;pharmacokinetics and pharmacodynamics;pharmacologic;pre-clinical;receptor;receptor expression;response;serotonin receptor;side effect;therapeutically effective;transcriptome sequencing;translational potential;tumor;tumor growth;tumor initiation;tumor progression Anticancer Effects of a Repurposed Drug in Colon Cancer PROJECT NARRATIVEThe repurposing of existing non-cancer drugs is a potential source of new treatment options forcancer patients with high unmet medical needs. While reducing costs in the long and difficult processof drug development repurposing presents a number of other crucial advantages regarding readilyavailable pharmacological data. This first attempt of investigating the novel anticancer functions ofPimavanserin (a drug for Parkinson's disease) will provide strong translational potential to develop pre-therapeutic leads with low toxicity and will have broad impact on the development of anti-colon cancertherapies. NCI 10728673 8/23/23 0:00 PAR-22-216 1R21CA277249-01A1 1 R21 CA 277249 1 A1 "CHEN, WEIWEI" 9/1/23 0:00 8/31/25 0:00 ZCA1-RPRB-T(M1) 6875894 "DATTA, PRAN K" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/1/23 0:00 8/31/25 0:00 395 Non-SBIR/STTR 2023 381834 NCI 257127 124707 PROJECT SUMMARY/ABSTRACT About 2530% of confirmed colon cancers (CC) without detectable local or distal invasion willeventually develop metastases and there is currently no cure for metastatic disease. The response ratesof current chemotherapy are low around 20%. Therefore this study related to repurposing a drugPimavanserin (PIMA) for CC therapy is crucial. The strategy of using existing drugs originally developedfor another disease promises to have high impacts on cancer patients. While reducing costs in the longand difficult process of drug development repurposing presents a number of other pivotal advantagesregarding known PK/PD posology toxicity and safety. Elevated serotonin (5-HT 5-hydroxytryptamine) andits receptor levels in CC and their signaling may be involved in promoting oncogenic activities. However littleis known regarding the mechanism of action. 5-HT2A receptor's (5-HT2AR) selective inverse agonist PIMA iswidely used in the clinical setting for treatment of Parkinson's disease psychosis. As serotonin and itsreceptor 5-HT2AR have been suggested to be involved in cell growth promotion and the receptor expression ishigh in gastrointestinal tract we inquired about the role of PIMA in anticancer activities. We have observedthat PIMA inhibits CC cell growth and induces apoptosis by activating TGF- tumor suppressor functions andantagonizing the effects of serotonin/5-HT2AR on the regulation of BCL-2 family proteins and MEK/ERKsignaling. Interestingly our initial RNA-seq results from CC cells treated with PIMA reveal the regulation ofgenes related to cell growth and apoptosis and to TGF-/Smad and MEK/ERK signaling. Our initialexperiments indicate that PIMA inhibits tumor growth in an in vivo allograft model (syngeneic) with no toxiceffects. Therefore these studies provide a strong proof-of-principle that PIMA is an effective therapeutic agentwith low toxicity for CC. We hypothesize that Pimavanserin proffers its potent anti-cancer activities in coloncancer by inhibiting cell proliferation and inducing apoptosis through abrogating the activity of 5-HT2AR and itscrosstalk with TGF- and MEK/ERK signaling. Here we propose to (1) determine the functional mechanismsof action of PIMA in suppressing tumor growth and (2) determine the anti-cancer efficacy and mechanism ofaction of PIMA in CC using a humanized mouse model with organoids and a spontaneous genetic model.Impact: Although several chemotherapeutic agents have been introduced for the treatment of CC they are stillfraught with side effects limited scope and long-term treatment failure. Repurposing non-cancer drugs withpotent anti-cancer activities is crucial to facilitate patient access to new treatment options. PIMA issuccessfully used for Parkinson's disease but it has never been explored in the treatment of solid tumors.Therefore this first attempt of investigating the novel anticancer functions of PIMA in CC will have a broadimpact on the development of anti-colon cancer therapies. This exploratory and preclinical biomedicalresearch perfectly matches with two priority research areas of specific interest of NCI (PAR-22-216). 381834 +No NIH Category available DATA MANAGEMENT FOR CANCER DIAGNOSIS PROGRAM ACTIVITIES n/a NCI 10728478 75N91021D00017-0-759102200003-1 N02 8/1/22 0:00 7/31/23 0:00 78792328 "ANNETTE, DAVE " Not Applicable 4 Unavailable 83656892 LGGFBF8YVA71 83656892 LGGFBF8YVA71 US 39.047465 -77.125049 1069201 "INFORMATION MANAGEMENT SERVICES, INC." CALVERTON MD Domestic For-Profits 207053407 UNITED STATES N R and D Contracts 2022 810247 NCI C6 DATA MANAGEMENT FOR CANCER DIAGNOSIS PROGRAM ACTIVITIES 810247 +Cancer CHARACTERIZATION OF SMALL-MOLECULE DRUG CANDIDATES USING STANDARDI n/a NCI 10728466 75N91022P00919-0-0-1 N02 9/16/22 0:00 9/15/23 0:00 78868036 "GEIBEN LYNN, RALF " Not Applicable Unavailable YNGLSAF57T14 YNGLSAF57T14 US -521234 WATERTOWN MA Other Domestic Non-Profits 24722418 UNITED STATES N R and D Contracts 2022 157158 NCI CHARACTERIZATION OF ABSORPTION DISTRIBUTION METABOLISM EXCRETION AND TOXICITY (ADMET) PROPERTIES OF SMALL-MOLECULE DRUG CANDIDATES 157158 +No NIH Category available "Defining metabolic adaptations within the PDAC ""arid"" tumor microenvironment" PROJECT NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human cancers (currently the 3rdleading cause of cancer death in the US) and existing therapies confer unsatisfactory clinical responses. Thetumor microenvironment (TME) of PDAC is among the most inhospitable of any cancer type and the ability ofpancreatic tumor cells to survive and grow under these conditions likely contributes to their recalcitrantbehavior. The main goals of our proposal are to define the molecular mechanisms by which PDAC cells adaptto these nutrient- and oxygen-deprived (arid) environments determine how such environments affectinteractions between tumor cells and other cells making up the TME and to identify drug vulnerabilities thatcan be exploited for therapy. NCI 10728412 3/29/23 0:00 PA-21-268 7R01CA252225-03 7 R01 CA 252225 3 "WILLIS, KRISTINE AMALEE" 5/1/21 0:00 4/30/26 0:00 Tumor Cell Biology Study Section[TCB] 1870828 "DANG, CHI V." "STANGER, BEN Z" 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 10/22/22 0:00 4/30/23 0:00 396 Non-SBIR/STTR 2022 462168 NCI 393318 68850 PROJECT SUMMARYThe goal of our proposal is to identify therapeutic vulnerabilities associated with nutrient-poor conditions intumors. Pancreatic ductal adenocarcinoma (PDAC) remains a major clinical challenge and is characterized bya dense stroma and paucity of blood vessels. The resulting hypoxia and scarcity of nutrients forces cancercells to seek alternative sources of nutrients for growth. Paradoxically cells residing in these nutrient-deprived microenvironments are among the most resistant to therapy as a result of poor drug diffusionand reduced cell proliferation (rendering DNA-damaging agents less effective). To target these cells thereforea better understanding of the adaptive mechanisms by which they cope with nutrient deprivation is urgentlyneeded.In preliminary studies we developed a culture protocol limiting for oxygen glucose amino acids and serum to model the arid conditions of pancreatic tumors. Under such conditions tumor cells slow downproliferation and metabolic activity. Using this system we performed a whole genome CRISPR screen toidentify genes required under arid conditions but dispensable under nutrient-replete (fertile) conditions. Thisrevealed a strong dependency on the TCA cycle and oxidative phosphorylation for survival but also suggestedthat genes involved in many biosynthetic activities (e.g. translation and cell division) are detrimental under aridconditions. Based on these results we hypothesize that cells survive severe nutrient and oxygen deprivationby maximizing energy generation from limited fuel supplies while minimizing the use of such resources formacromolecule production. We further hypothesize that nutrient and oxygen deprivation alters the dynamiccrosstalk between cancer cells and other cells comprising the tumor microenvironment (TME). Importantlyindividual tumors may respond to these metabolic changes in different ways contributing to inter-tumoralheterogeneity. Our proposal will explore these ideas to develop strategies that target therapy-resistantcancer cells residing in these nutrient-deprived niches.Aim 1. Characterize the heterogeneity in metabolic adaptations to arid conditions.Aim 2. Determine how arid conditions influence cellular crosstalk in the TME.Aim 3. Test the activity of metabolic inhibitors against cells in arid conditions in vitro and in vivo. 462168 +No NIH Category available Advanced Malignant Neoplasm;Aftercare;Archives;Attention;Biological Markers;Bioluminescence;Biopsy;Body Fluids;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cells;Cessation of life;Clinical;Detection;Diagnosis;Disease;Disease Progression;Early identification;Engineering;FDA approved;Future;Genetic Engineering;Goals;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Investigation;Label;Lipids;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Modality;Molecular Analysis;Molecular Profiling;Monitor;Mutation;Non-Small-Cell Lung Carcinoma;Nucleic Acids;Patient Monitoring;Patients;Peripheral;Physicians;Population;Prediction of Response to Therapy;Proteins;Recurrence;Research;Resistance;Sampling;Serum;Source;Surface;Survival Rate;Technology;Testing;Therapeutic;Time;Tissues;Transcript;Treatment Efficacy;Treatment outcome;Tumor Burden;Tumor Markers;Tumor-Derived;Untranslated RNA;Woman;anti-PD-1/PD-L1;anti-PD-L1 therapy;anti-cancer;cancer diagnosis;cancer therapy;data integration;design;diagnostic tool;druggable target;exosome;experience;immune checkpoint blockade;immune-related adverse events;innovation;intercellular communication;men;mortality;nanoparticle;next generation sequencing;non-invasive monitor;novel;predictive marker;programmed cell death ligand 1;real time monitoring;responders and non-responders;response;screening;success;therapy outcome;tool;treatment response;tumor;tumor progression Noninvasive monitoring of therapeutic response to immune checkpoint inhibitors using circulating exosomes in non-small cell lung cancer PROJECT NARRATIVEImmune checkpoint blockade therapy has changed the treatment paradigm of lung cancer a very aggressivecancer with leading cause of cancer-related deaths; however most patients fail to respond to it and many ofpatients who initially respond to treatment eventually experience recurrence. The research strategy proposedherein seeks to develop an innovative method to specifically access circulating exosomes from lung cancerpatients via characterizing these disease-associated exosomes to explore molecular signatures associated withtherapeutic outcome. The technology developed will help physicians to accurately predict and identify patientswho are the responders and non-responders during a course of treatment as well as identify resistant biomarkersand druggable targets for future therapeutic modalities. NCI 10727974 7/19/23 0:00 PAR-22-090 1R21CA283881-01 1 R21 CA 283881 1 "OSSANDON, MIGUEL" 7/19/23 0:00 6/30/25 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 1964876 "DAUNERT, SYLVIA " Not Applicable 27 BIOCHEMISTRY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 7/19/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 179403 NCI 116875 62528 Summary/ Abstract: The emergence of immune checkpoint blockade (ICB) therapy has revolutionized thetreatment for advanced cancers including lung cancer. Particularly anti-PD-1/PD-L1 therapy shows promisingtherapeutic outcomes and some of these therapies are employed as the first line treatment of patients withmetastatic NSCLC. However not all patients benefit from ICB and some of patients who initially respond to ICBdevelop acquired resistance and sometimes. multisystem immune-related adverse events. Thus it is criticallyimportant to accurately identify and predict lung cancer patients who will respond to ICB before and during acourse of treatment. Here we propose an innovative screening strategy aiming at early prediction and real-timemonitoring of responders and non-responders to ICB for lung cancer patients. This approach is based on theisolation detection and characterization of circulating exosomes specifically associated with anticancer immuneresponse rather than analyzing total pool of exosomes. Exosomes are secreted nano-sized particles containingnucleic acid protein and lipid cargo specific to the cell of origin which are considered as a mirror of the parentalcells. Besides they can be easily extracted from biofluids as a source of biomarkers of disease status andtreatment response. Herein we seek to specifically analyze two population of circulating exosomes includingtumor-derived exosomes (TEXs) and PD-L1+ exosomes that serve as the invaluable determinants of the statusof tumor burden and anticancer-immune activity respectively. We have formulated two Specific Aims that hingeon developing technologies to achieve our goals: Aim1 will develop a highly sensitive and selective sensingplatform for quantitative analysis of TEXs and PD-L1+ exosomes followed by molecular analysis of TEXs toexplore the molecular signatures associated with treatment outcome. For that we will genetically engineer novelbioluminescence-based probes by fusing bioluminescence proteins with tumor-specific and PD-L1-specifictargeting molecules respectively. Aim 2 will evaluate circulating exosomes from serum of NSCLC patientstreated with ICB therapy. The platform developed in Aim 1 will be used for the quantitative analysis of TEXs andPD-L1+ exosomes during the treatment and whether the observed changes can be utilized as a predictivemarker for early identification and monitoring of responders and non-responders to ICB. The circulating TEXswill be subsequently isolated; their exosomal transcripts and long non-coding RNAs will be characterized byusing next-generation sequencing to explore the molecular signatures associated with therapeutic outcome. Wewill apply computational approaches for data integration analysis and interpretation based on the number ofTEXs expression level of exosomal PD-L1 molecular signatures of TEXs and patients clinical features. In sumour project is highly translational and could have a significant impact on lung cancer patients. If successful thisresearch will help physicians to accurately predict and identify patients who will benefit from ICB therapy anddevelop potential novel treatments for patients who are non-responders to ICB therapy. 179403 +No NIH Category available Abnormal Cell;Animal Model;Apoptosis;Bioinformatics;Cancer Cell Growth;Cause of Death;Cell Culture Techniques;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemicals;Data;Defect;Detection;Development;Drug Targeting;Enzymes;Failure;Foundations;Future;Genetic;Genetic Transcription;Health;Heat-Shock Proteins 70;Human;Immunofluorescence Immunologic;In Vitro;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Medicine;Messenger RNA;Modeling;Modification;Molecular;Molecular Chaperones;Neoplasm Metastasis;Normal Cell;Pathway interactions;Persons;Pharmaceutical Preparations;Pharmacological Treatment;Pilot Projects;Play;Positioning Attribute;Production;Prognosis;Property;Protein Biosynthesis;Proteins;Quality Control;RNA Interference;Recording of previous events;Regulation;Ribosomes;Role;Set protein;Signaling Protein;Site;Small Interfering RNA;Societies;Stat3 protein;System;Techniques;Technology;Testing;Time;Toxic effect;Transfer RNA;Translational Regulation;Translations;United States;Western Blotting;anti-cancer;anticancer treatment;cancer care;cancer cell;cancer diagnosis;cancer therapy;cancer type;cell growth;cell transformation;chaperonin;clinical application;cost;design;experimental study;inhibitor;knock-down;mRNA Expression;mRNA Transcript Degradation;novel;novel therapeutic intervention;overexpression;pharmacologic;polypeptide;prefoldin;protein expression;success;targeted treatment;tool;tumor;tumor growth;tumor progression;uncontrolled cell growth Development of an Anti-Cancer Approach Through a Novel Pathway of Translational Regulation PROJECT NARRATIVEAbnormal STAT3 protein expression leads to uncontrolled cell growth cancer progression and it is associatedwith about 70% of all human tumors. Here we propose a pilot study to test modulation of a novel pathway oftranslational regulation recently discovered by us to decrease STAT3 synthesis and thus stop cancerdevelopment. Potentially the project will lead to development of new types of anti-cancer treatments in thefuture. NCI 10727837 9/19/23 0:00 PAR-20-052 1R03CA277115-01A1 1 R03 CA 277115 1 A1 "LUO, RUIBAI" 9/19/23 0:00 8/31/25 0:00 ZCA1-RPRB-H(M2)S 10381031 "KARAMYSHEV, ANDREY L" Not Applicable 19 BIOCHEMISTRY 609980727 E4Z2NUYUMHF9 609980727 E4Z2NUYUMHF9 US 33.592746 -101.898787 8285902 TEXAS TECH UNIVERSITY HEALTH SCIS CENTER LUBBOCK TX SCHOOLS OF MEDICINE 794306271 UNITED STATES N 9/19/23 0:00 8/31/25 0:00 396 Non-SBIR/STTR 2023 153000 NCI 100000 53000 ABSTRACTSTAT3 (Signal Transducer and Activator of Transcription 3) is a transcriptional regulator that plays crucial rolein malignant transformation of the cells tumor growth and metastasis. STAT3 activity or expression isupregulated in 70% of human tumors contributing to a rapid cancer progression and therefore it is a potentialpharmacological target in cancer treatments. It was demonstrated that STAT3 knockdown reduced abnormalcell growth. However direct and indirect inhibitors of STAT3 activity did not provide expected efficacydemanding search for alternative strategies for STAT3 inhibition. The presence of STAT3 aberrant expressionin different types of tumors and potential ability to treat cancer through decrease of STAT3 expressiondetermines high significance of the study. The central idea of the current project is based on control of STAT3expression during its synthesis on the ribosome through modulation of components of the novel pathwayrecently discovered by us. The RAPP (Regulation of Aberrant Protein Production) pathway specificallyregulates protein synthesis degrading mRNAs of the proteins that do not properly interact during theirsynthesis on the ribosome. Our hypothesis is that the RAPP translational regulators may be used tocontrol STAT3 expression and therefore restrict cell proliferation and tumor growth. The concept of thistype of STAT3 regulation was never explored before little is known about STAT3 translational partners andabout their modulation to control STAT3 expression thus demonstrating novelty of the project. Our preliminarydata demonstrate that the RAPP pathway is involved in regulation of STAT3. The following specific aims aredesigned for this project: (1) identify novel STAT3 translational partners during its synthesis on the ribosomeand (2) test the hypothesis that RAPP translational regulators can be modulated to decrease STAT3expression and cancer cell proliferation. The study is based on unique technologies for detection andidentification of proteins during translation by site-specific photo-crosslinking and iPINCH approaches. We willuse candidate and unbiased approaches to test RAPP regulators in STAT3 control. The experiments will alsoinvolve cell culture models and RNA interference techniques or overproduction to verify involvement of theRAPP components in STAT3 regulation. In this project we will determine potential anti-cancer properties of theRAPP modulation by measuring cancer cell proliferation and apoptosis. The success of the proposal will builda foundation for the future studies with animal models and use of chemical regulators (potential drugs) todevelop new anti-cancer medicine. Potentially this proposal will lead to development of conceptually newdirections in pharmacological treatments of cancer. 153000 +No NIH Category available Anatomy;Automobile Driving;Biochemical Reaction;Bioenergetics;Biological Assay;Biological Markers;Cancer Etiology;Cancerous;Cell Survival;Cessation of life;Characteristics;Chronic;Clinical;Development;Diagnosis;Diagnostic;Diethylnitrosamine;Disease;Disease Progression;Early Diagnosis;Emerging Technologies;Energy Metabolism;Enzymes;Epidemic;Fibrosis;Functional disorder;Generations;Glycolysis;Goals;Guidelines;HepG2;Hepatic;Hepatitis Viruses;Hepatocarcinogenesis;Hepatocyte;Histology;Image;In Vitro;Incidence;Inflammation;Interdisciplinary Study;Intravenous;Investigation;Isotope Labeling;Kinetics;Label;Libraries;Liver;Liver diseases;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Measurement;Measures;Medical Imaging;Metabolic;Metabolic Pathway;Metabolism;Methods;Mitochondria;Modeling;Monitor;Morphology;Obesity;Onset of illness;Oxidation-Reduction;Oxidative Stress;Pathogenicity;Pathologic;Pathology;Pathway interactions;Patients;Pattern;Phosphoenolpyruvate;Physical assessment;Play;Prevalence;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Prognosis;Property;Pyruvate;Pyruvate Kinase;Rattus;Reaction;Relaxation;Reporting;Research;Risk;Role;Sampling Errors;Series;Signal Transduction;Staging;Survival Rate;Technology;Testing;Time;Tissues;Toxic effect;cancer diagnosis;chemical property;chemotherapy;clinical translation;clinically significant;cytotoxicity;design;experimental study;high risk population;imaging biomarker;imaging modality;improved;in vivo;in vivo evaluation;in vivo imaging;innovation;interest;liver biopsy;liver metabolism;metabolic imaging;metabolic phenotype;non-invasive monitor;noninvasive diagnosis;novel;novel therapeutics;physical property;prevent;real-time images;scaffold;tool;tumor;tumor microenvironment;tumorigenesis Hyperpolarized 13C Metabolic Imaging of Tumorigenesis in the Liver Narrative.The pathophysiology of hepatocellular carcinoma (HCC) relies on aberrant metabolic pathways but accuratemeasurement of hepatic metabolism in vivo remains challenging due to the lack of effective methods. Theproposed study will develop a novel in vivo imaging method that directly assesses glycolysis a critical metabolicpathway for HCC onset and progression. This project will then investigate a stepwise progression from normalliver to HCC potentially providing a noninvasive means to assess disease development in at-risk patients. NCI 10727760 9/19/23 0:00 PAR-21-155 1R15CA277814-01A1 1 R15 CA 277814 1 A1 "AMIN, ANOWARUL" 9/19/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-BBBT-M(80)A] 11904301 "BILLINGSLEY, KELVIN L" Not Applicable 9 CHEMISTRY 74368911 CVNBL4GDUKF3 74368911 CVNBL4GDUKF3 US 41.897385 -87.624242 4689201 LOYOLA UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF ARTS AND SCIENCES 606601537 UNITED STATES N 9/19/23 0:00 8/31/26 0:00 396 Non-SBIR/STTR 2023 461844 NCI 355572 106272 Project Summary.Aberrant glycolysis and mitochondrial function are features of most liver diseases including hepatocellularcarcinoma (HCC). Despite these metabolic signatures the absence of methods to noninvasively assessmetabolic fluxes in vivo limits the accurate characterization of liver diseases and in turn impedes the developmentof new therapies. In the proposed study we will employ novel hyperpolarized (HP) 13C probes to imageglycolysis a pathway that plays a critical role in HCC onset and progression. Importantly our cross-disciplinaryresearch team has made significant advancements in the design and application of HP 13C-glycerate probes.We have demonstrated that HP [1-13C]glycerate is a non-toxic substrate with a long T1 relaxation time (60 sec)and this HP probe is sensitive to alterations in liver metabolism in vivo offering inroads for clinical translation. Inaddition our recent studies in HCC (diethylnitrosamine [DEN]-induced rat model) demonstrated that HP [1-13C]glycerate can successfully distinguish HCC from healthy liver based upon the unique metabolic fluxesdetected in the cancerous tissue. Given these advancements we now propose that the HP 13C-glyceratescaffold can be systematically optimized to yield 2nd generation HP probes which provide highly sensitiveanalyses of enzymatic reactions in the liver and diagnostic assessments of abnormal fluxes in HCC. Theoverarching goal of the proposed project is to use the HP 13C-glycerate technology to establish in vivo imagingbiomarkers for assessing altered metabolism during HCC development. To this end in Aim 1 we will synthesizea focused library of 2nd generation 13C-glycerate probes that are specifically designed to increase the metabolicinformation obtained from HP experiments. In Aim 2 we will analyze the physicochemical properties of theseprobes in order to determine top agents to advance towards in vivo HP studies. In Aim 3 we will initially establishimaging biomarkers for HP 13C-glycerates in the DEN rat model and identify specific probes that provide clearmetrics for distinguishing HCC. These 13C-glycerate probes will then be used to evaluate a stepwise progressionfrom normal liver to HCC in the DEN model. Four pathological states will be examined: baseline chronicinflammation fibrosis and HCC. In vivo metrics for glycolysis will be compared among the states and theseresults will be validated with tissue analyses. Overall the proposed studies offer an innovative strategy fortackling a challenge of clinical significance. State-of-the-art HP probes will be used to assess altered glycolysisin hepatocarcinogenesis. This technology will in turn provide specific in vivo biomarkers that represent themetabolic pathways of interest in HCC providing a noninvasive method for assessing disease progression in at-risk patients. 461844 +No NIH Category available Address;Adenine;Adult;Androgen Receptor;Androgens;Bacterial DNA;Binding Proteins;Biological;Biological Assay;Bladder;Bladder Neoplasm;Cancer Model;Carcinogens;Cell Proliferation;Chemicals;Chimeric Proteins;Complex;DNA;DNA-Binding Proteins;Development;EP300 gene;Embryo;Enzymes;Epithelium;Gene Expression;Genes;Genetic Transcription;Genital;Genitalia;Genitourinary system;Gonadal Steroid Hormones;Incidence;Knowledge;Laboratories;Lower urinary tract;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Maps;Masculine;Methylation;Modeling;Molecular;Organoids;Pathway interactions;Physiological;Play;Predisposition;Proteins;Protocols documentation;Publications;Publishing;Recording of previous events;Reporting;Research;Rodent;Role;Sex Bias;Sex Chromosomes;Sex Differences;Signal Transduction;Site-Specific DNA-Methyltransferase (Adenine-Specific);Small Interfering RNA;Smoking;Technology;Testing;Transgenic Mice;Transgenic Model;Transgenic Organisms;Urothelium;WNT Signaling Pathway;Woman;beta catenin;cancer initiation;carcinogenesis;clinically relevant;improved;in vivo;male;men;protein complex;reconstitution;sex;tool;transcription factor;transcriptome sequencing Androgen and Wnt signaling in bladder cancer PROJECT NARRATIVEThis project proposes to identify in vivo direct targets of androgen and WNT signaling duringbladder carcinogenesis. Bladder cancer incidence is three times higher in men than in women butthe underlying cause remains largely unknown. Using split DamID this project will reveal crucialdrivers of bladder carcinogenesis in males. NCI 10727745 5/30/23 0:00 PAR-22-219 1R21CA283677-01 1 R21 CA 283677 1 "JOHNSON, RONALD L" 6/1/23 0:00 5/31/25 0:00 Cancer Genetics Study Section[CG] 1974052 "MA, LIANG " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 213653 NCI 137250 76403 ABSTRACTBladder cancer is the 4th most common cancer in men and 11th in women. Despite that bladderdevelopment and function are not sex hormone-dependent men are three times more likely to developbladder cancer than women. Smoking has been shown not to be a contributor for this gender bias. Insteadintrinsic sex-differences likely underpin the molecular mechanism for male susceptibility to bladder cancer.Sex hormones and sex chromosomes are obvious suspects to account for this male predilection forbladder cancer. In fact experimental evidence in rodents strongly support a crucial role for androgenreceptor in promoting cancer development in a chemical-induced bladder cancer model. In addition toandrogen signaling the other undeniably powerful regulator of lower urinary tract development andcarcinogenesis is the WNT signaling pathway. -catenin is the signal integrator of canonical WNT signalingand AR and -catenin physically interact to synergistically activate transcription. This interaction is crucialfor downstream target expression during genital masculinization bladder cancer development andprogression. Despite the crucial roles these two pathways play in bladder carcinogenesis their directtranscriptional targets which are likely drivers of bladder cancer initiation remain elusive. In thisapplication we propose to use a recently developed powerful technology Split DamID to reveal in vivotranscriptional targets downstream of AR p300 and -catenin during bladder cancer development. In Aim1 we will use our newly generated transgenic model to reveal direct AR and p300 transcriptional targets ina carcinogen-induced bladder cancer model. Next in Aim 2 we will use SpDamID on bladder organoids toreveal AR and -catenin direct targets followed by siRNA functional screen for their roles in promotingorganoid formation. Together these studies should greatly improve our understanding of bladder cancerinitiation especially those controlled by AR and Wnt signaling. 213653 +No NIH Category available Address;Affect;American Cancer Society;Animals;Apoptotic;Biological;Biological Assay;Breast;Cancer Model;Carboplatin;Castration;Cell Culture Techniques;Cells;Cellular Assay;Chemicals;Clinic;Clinical;Colon;Color;Combination Drug Therapy;Complex;Data;Development;Diagnosis;Diet;Disease;Environment;Estrogens;FDA approved;Female;Flow Cytometry;Future;Genetic;Genetic Predisposition to Disease;Gonadal Steroid Hormones;Growth;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Stimulation;Immunotherapy;Incidence;Incubated;Innate Immune System;Kidney;Knowledge;Lewis Lung Carcinoma;Life Style;Literature;Lung Neoplasms;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Monoclonal Antibodies;Mus;Natural Killer Cells;Nature;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;Ovariectomy;Ovary;Pemetrexed;Pharmaceutical Preparations;Phenotype;Progesterone;Prognosis;Serum;Sex Differences;Smoking;TNFSF10 gene;Testing;Therapeutic;Time;United States;Woman;anti-PD-1;anti-PD-L1;anti-cancer;anti-tumor immune response;cancer diagnosis;cancer therapy;cell killing;chemotherapy;design;gain of function;human disease;improved;improved outcome;in vivo;inhibitor;innovation;lifetime risk;loss of function;lung cancer cell;male;melanoma;men;mortality;mouse development;neoplastic cell;novel;novel therapeutic intervention;patient derived xenograft model;receptor;response;sex;sex disparity;standard of care;therapy outcome;treatment response;tumor;tumor growth;tumor progression;tumor xenograft Development of Mouse and Humanized Models to Study Sex Disparities in Tumor Progression and Treatment of NSCLC Contact PD/PI: Landry Joseph WNarrative StatementThis project is designed to address the problem of sex disparaties in NSCLC progression and treatment. Studiesin both cell culture and tumor bearing animals will identify the contribution(s) of bioactive molecules anddifferences in the immune system between males and females that can affect NSCLC growth and their responseto therapies.Project Narrative Page 7 NCI 10727735 7/17/23 0:00 PAR-21-323 1R21CA283631-01 1 R21 CA 283631 1 "WALLACE, TIFFANY A" 9/1/23 0:00 8/31/25 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 8903361 "LANDRY, JOSEPH WILLIAM" "LI, HOWARD " 4 GENETICS 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 217738 NCI 140250 77488 Project SummaryAccording to the American Cancer Society lung cancer is the second most commonly diagnosed cancer in menand women. Outside of the sex-specific cancers lung cancer and melanoma have the greatest sex disparitythough the exact mechanisms behind these differences are not well understood. In the United States men havea higher lifetime risk of developing lung cancer and are more likely to develop severe disease than women.Additionally there are sex disparities in responses to treatment such as men having better responses toimmunotherapies over women. There are multiple factors contributing to this sex disparity including lifestylechoices sex hormones and differences in immune response. Our preliminary data shows that two mouse tumorsmodels of lung cancer CMT-167 and Lewis Lung Carcinoma (LLC) two models of non-small cell lung cancer(NSCLC) grow slower in female than in male mice. This sex difference is dependent on the ovary as tumors inovariectomized female mice grow equivalent to those in male mice. Innate immune cells (macrophages and NKcells) and more specifically NKG2D receptor activity are required for reduced tumor growth in females. Multi-parameter flow cytometry analysis shows significant sex differences in NSCLC tumor resident innate immunecells. We show that these sex-disparities extend to several chemotherapy and anti-PDL1 immunotherapytreatments. In preliminary in vivo data we show that the sex-disparity in NSCLC tumor growth and the responseto chemotherapy requires NK cells. Ex vivo NK cell killing assays show that preincubation of NSCLC cells withfemale serum but not male serum or serum from ovariectomized females stimulates enhanced NK cell activityutilizing the secreted pro-apoptotic factor TRAIL. This ex vivo NK cell assay provides a means to identify bioactivemolecules. Based upon this preliminary data we propose two Aims for our future studies. Aim 1 we willfractionate serum from female mice to identify a biological molecule from female serum required for LLC andCMT-167 sensitization to NK cell killing via TRAIL. The sensitization of LLC and CMT-167 tumor cells in femalemice to the effects of TRAIL are proposed to contribute to the observed sexdifferences in tumor growth andsensitivity to therapies (both chemotherapy and immunotherapy). For Aim 2 we will determine if the responseto standard of care chemotherapies or anti-PD1 immunotherapy using orthotopic CMT-167 and LLC tumormodels is dependent on sex. If a sex difference in response is observed we will characterize the immuneresponses of male and female mice to lung tumors in the context of these drugs. In summary this project aimsto gain an understanding of the biological mechanisms behind the sex disparities in NSCLC progression andresponse to treatment with the hopes of gaining knowledge to inform clinic decisions and treatment of the humandisease. 217738 +No NIH Category available Adverse event;Affect;Anatomy;Animal Model;Animals;Antineoplastic Agents;Biological Markers;Biopsy;Breast;Cancer Patient;Cause of Death;Cell Death;Clinical;Clinical Trials;Complication;Custom;Data;Device Designs;Device Removal;Devices;Dose;Drug Combinations;Drug Evaluation;Drug Exposure;Drug toxicity;Effectiveness;Enrollment;Environment;Evaluation;Excision;Feasibility Studies;Future;Goals;Hemorrhage;Hindlimb;Human;Implant;In Situ;Injury;Intervention;Interventional radiology;Liquid substance;Methods;Modeling;Morbidity - disease rate;Needle biopsy procedure;Oncology;Operative Surgical Procedures;Oryctolagus cuniculus;Outcome;Outpatients;Patients;Pharmaceutical Preparations;Pharmacotherapy;Procedures;Radiology Specialty;Regional Anatomy;Reproducibility;Research;Retrieval;Risk;Safety;Serum Markers;Skin;Soft tissue sarcoma;Solid Neoplasm;Specimen;Structure;Surgical incisions;Techniques;Technology;Testing;Tissues;Tumor Debulking;Tumor Tissue;Work;cancer imaging;cancer therapy;clinical translation;cohort;effective therapy;first-in-human;image guided;implantation;improved;innovation;method development;microdevice;miniaturized device;minimally invasive;mouse model;multiple omics;next generation;novel;personalized cancer therapy;personalized medicine;personalized strategies;precision drugs;preclinical study;predicting response;prototype;response;safety and feasibility;tool;treatment optimization;treatment strategy;tumor Interventional method development for multiplexed personalized drug evaluation using implantable microdevices NarrativeThis project seeks to validate an interventional radiology approach to non-surgically deliver andretrieve implantable microdevices (IMDs) designed to rapidly test multiple drug responses directlywithin a live tumor in its native environment. This approach is less invasive and more practicalcompared to current surgical methods of IMD delivery and provides a more comprehensive anddirect assessment of drug response compared to current biomarker-based personalizationstrategies. If successful it could enable clinicians to screen and optimize personalized cancertreatments in nearly all patients with solid tumors. NCI 10727646 7/25/23 0:00 PAR-20-052 1R03CA270772-01A1 1 R03 CA 270772 1 A1 "OSSANDON, MIGUEL" 7/25/23 0:00 6/30/25 0:00 ZCA1-RPRB-H(M2)S 15566390 "BHAGAVATULA, SHARATH " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/25/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 76860 NCI 50000 26860 Abstract: Novel implantable miniaturized devices (IMDs) placed directly in patient tumors can rapidly evaluatemulti-drug responses in-situ. They can be used in any solid tumor to provide direct comprehensive spatial multi-omic readouts of >20 drugs simultaneously with potential to eclipse liquid and tissue biopsy biomarkercapabilities. However placing and retrieving IMDs in tumors currently requires highly invasive surgery withexcessively high patient morbidity and complication risks. For most cancer patients these risks are prohibitiveand as a result ongoing first-in-human IMD trials have had limited enrollment. We have developed a fully interventional (minimally invasive) non-surgical method to place and retrieveIMDs. We use custom needle biopsy devices and image guidance to deliver and precisely remove only the IMDand adjacent drug-exposed tissue. This is a simple outpatient procedure similar to routine percutaneous tumorbiopsies using a single tiny (<2mm) skin incision. It reduces the morbidity and risks of IMD use and wouldgreatly increase enrollment in current and future clinical IMD trials. However a preclinical study in an animalmodel is needed to demonstrate technical feasibility and safety of this interventional method prior to first-in-human use. This proposal describes a preclinical study in a rabbit hindlimb tumor model that closely simulates atypical soft tissue sarcoma setting with the following specific aims: 1) determine the technical feasibility of ourinterventional (non-surgical) approach for IMD-placement and retrieval; and 2) determine the overall safety andadverse event rate of this same interventional method. Interventional IMD placement and retrieval procedureswill be performed in a statistically-powered cohort of 15 rabbits. Technical feasibility and safety endpoints will beassessed and used to inform further method refinement and ultimately first-in-human trials. The proposed study is innovative as it will develop and validate new interventional tools for personalizedcancer treatment that could serve as the next generation of tumor biopsy. It is significant as it will directly enablea first-in-human trial to evaluate IMD-based drug optimization in patients with advanced soft tissue sarcomas. Itwill also enable greater enrollment in ongoing IMD clinical trials in other similar or lower risk anatomic regions(e.g. breast). Ultimately if the overall long-term goal of clinically validating IMD-based personalized treatmentoptimization is achieved the interventional methods developed here could be applicable to every oncologypatient with a percutaneously accessible tumor (similar to routine percutaneous tissue biopsies). 76860 +No NIH Category available Address;Administrative Supplement;Adoption;Cancer Control;Cancer health equity;Caring;Clinic;Clinical;Collaborations;Data;Documentation;Electronic Health Record;Equity;Financial Hardship;Goals;Health;Housing;Incidence;Individual;Inequity;Interview;Malignant Neoplasms;Measurement;Measures;Morbidity - disease rate;Oncology;Outcome;Patient-Focused Outcomes;Patients;Phase;Pilot Projects;Population;Provider;Randomized Controlled Trials;Risk;Risk Factors;Screening procedure;Shapes;Structure;Testing;Transportation;cancer care;cancer therapy;evidence base;experience;food insecurity;forest;health equity;health inequalities;implementation science;implementation strategy;implementation study;improved;informant;mortality;screening;social;social health determinants Administrative Supplements for the Implementation Science Centers in Cancer Control (ISC3): Advancing Health Equity through Implementation Science Project NarrativeSocial determinants of health (SDOH) social risk factors and unmet social needs have critical implications forshaping and exacerbating health and health inequities for cancer incidence morbidity and mortality. Reliablewidespread and available measurement of individual-level SDOH for all patients is a critical first step inidentifying those patients at greater risk for experiencing inequities and that have unmet social needs. In thisstudy we propose to increase previously identified low rates of SDOH screening by developing and evaluatingtailored implementation strategies for increasing SDOH screening reach equity and adoption. NCI 10727614 5/2/23 0:00 PA-20-272 3P50CA244693-04S1 3 P50 CA 244693 4 S1 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 7892228 "FOLEY, KRISTIE L" "CUTRONA, SARAH LELEIKO; HOUSTON, THOMAS K" 5 PUBLIC HEALTH & PREV MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 5/1/23 0:00 8/31/23 0:00 353 Research Centers 2023 124953 NCI 80615 44338 Project SummarySocial determinants of health (SDOH) social risk factors and unmet social needs have critical implications forshaping and exacerbating health and health inequities for cancer incidence morbidity and mortality. There is acritical need for accurate and comprehensive approaches to understanding how SDOH impact theimplementation of evidence-based cancer care equitable cancer outcomes and health equity. Reliablewidespread and available measurement of individual-level SDOH for all patients is a critical first step inidentifying those patients at greater risk for experiencing inequities and that have unmet social needs. In ourPhase I ISC3 Administrative Supplement for Advancing Health Equity through Implementation Science WakeForest iDAPT ISC3 and Penn ISC3 collaborated to evaluate the recent deployment of an electronic health record(EHR) module called the Epic SDOH Wheel (herein the Wheel). The Wheel includes 16 items (e.g. foodinsecurity transportation needs housing financial strain) that address social risk factors and unmet socialneeds. Phase I was a pre-implementation study to document current rates of SDOH screening and identify gapsin delivery to inform strategies for increasing equitable reach of SDOH screening. We found markedly low ratesof adoption of SDOH screening by oncology care teams and limited reach to oncology patients. Nonethelessour key informant interviews revealed a commitment to measuring and addressing SDOH by the oncology careteams and clinical leaders as well as context-specific SDOH screening tools that oncology care teams usedinstead of the Wheel. Findings from Phase 1 inform our proposed Phase 2 implementation pilot study to increaseSDOH screening in patients undergoing cancer treatment at our Centers. Specifically in Aim 1 we will developtailored implementation strategies for increasing reach equity and adoption of SDOH screening in patients withcancer across a diverse range of cancer care settings and populations through rigorous rapid assessment ofoncology care teams setting in the proposed clinics); adaptation of existing SDOH screening tools andidentification of implementation strategies to increase timely and widespread assessment and documentation ofSDOH screening in patients with cancer. In Aim 2 we will assess the impact of tailored implementation strategieson reach equity and adoption of SDOH screening in patients with cancer using electronic health record data.We will use semi-structured interviews to understand factors influencing reach equity and adoption of SDOHscreening from the perspective of patients providers and staff. We will use findings from the proposed study todevelop an R01 application for a randomized controlled trial to test the effect of CD2 on SDOH screening reachequity and adoption and subsequent efforts to address persistent or emergent social needs with the overarchinggoal of optimizing patient outcomes and improving cancer health equity. 124953 +Cancer; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD) "SBIR TOPIC 411 ""IMAGEDEPHI: IMAGE DE-IDENTIFICATION FOR THE ACCELERATION OF CANCER RESEARCH""" n/a NCI 10726855 75N91022C00033-0-9999-1 N44 9/16/22 0:00 9/15/24 0:00 78868018 "MANTHEY, DAVID " Not Applicable 20 Unavailable 10926207 DK6LPWMS5LP5 10926207 DK6LPWMS5LP5 US 42.849889 -73.759124 4014501 "KITWARE, INC." CLIFTON PARK NY Domestic For-Profits 120653104 UNITED STATES N R and D Contracts 2022 2000000 NCI The objective of this project is to produce software that can de-identify and anonymize WSI and CT data in a reliableefficient manner. The end result will be a software product that can be used by the pathology and medical researchcommunity to share data while minimizing the risk of exposing PHI/PII. 2000000 +No NIH Category available Accounting;Actins;Affect;African American;American;Annexins;Biological Models;Biology;Body Fluids;Brain;Breast Cancer Patient;Breast cancer metastasis;CD8-Positive T-Lymphocytes;Cell Adhesion;Cell Line;Communication;Cytoskeleton;Data;Depressed mood;Detection;Disease;Disease-Free Survival;Disparity;Distant;Distant Metastasis;Endocytosis;Exocytosis;Extracellular Matrix;Frequencies;Goals;Growth Factor;IL6 gene;Immune system;In Vitro;Literature;Liver;Location;Lung;Macrophage;Malignant Neoplasms;Mammary Gland Parenchyma;Measures;Mediating;Mediator;Membrane;Molecular;Natural Killer Cells;Neoplasm Metastasis;Non-Malignant;Nucleic Acids;Organ;Pathway interactions;Patients;Peptides;Plasminogen;Play;Population;Prevention;Process;Prognosis;Proteins;Publishing;Race;Regulatory T-Lymphocyte;Research;Role;STAT3 gene;Sampling;Serum;Site;Stromal Cells;T-Lymphocyte;TNF gene;Therapeutic;Tissues;Transforming Growth Factor beta;Tumor Necrosis Factor Ligand Superfamily Member 6;Tumor Tissue;Tumor-Derived;Woman;angiogenesis;bone;breast cancer diagnosis;cancer health disparity;cancer subtypes;caucasian American;clinical translation;comorbidity;cytokine;cytotoxic CD8 T cells;exosome;extracellular;extracellular vesicles;health care availability;health care disparity;humanized mouse;immunoregulation;improved;in vivo;intercellular communication;malignant breast neoplasm;migration;mortality;mouse model;neoplastic cell;novel;novel therapeutic intervention;p38 Mitogen Activated Protein Kinase;peripheral blood;prognostic;small hairpin RNA;socioeconomics;stem;therapeutic target;therapeutically effective;triple-negative invasive breast carcinoma;tumor;tumorigenesis Emerging role of tumor-derived exosomes in immune modulation and breast cancer health disparity. Project NarrativeTumor-derived exosomes are mediators of aggressive distant metastasis by contributing to the establishmentof a pre-metastatic niche. Therefore it is critical to investigate the molecular mechanism(s) that drive tumor-derived exosome-mediated immune modulation and pre-metastatic niche formation for aggressive metastasisin TNBC. Furthermore determining the mechanisms that drive the aggressive metastasis in TNBC will lead todeveloping novel therapeutic strategies. NCI 10726647 7/28/23 0:00 PAR-21-323 1R21CA283524-01 1 R21 CA 283524 1 "WALLACE, TIFFANY A" 8/1/23 0:00 7/31/25 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 10560594 "CHAUDHARY, PANKAJ " Not Applicable 12 MICROBIOLOGY/IMMUN/VIROLOGY 110091808 JE8AKPCR2KA4 110091808 JE8AKPCR2KA4 US 32.749542 -97.36903 6108502 UNIVERSITY OF NORTH TEXAS HLTH SCI CTR FORT WORTH TX GRADUATE SCHOOLS 761072699 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 172975 NCI 116875 56100 Project AbstractTriple-negative breast cancer (TNBC) is an aggressive and invasive breast cancer subtype accounting for10-15% of breast cancer diagnoses. TNBC affects African-American (AA) women three times more thanCaucasian-American (CA) women. Metastasis to distant vital organs such as bone liver lung and brain is themost devastating feature of TNBC in AA women. Tumor-derived exosomes are mediators of aggressive distantmetastasis by contributing to the establishment of a pre-metastatic niche. Therefore it is critical to investigatethe molecular mechanism(s) that drive tumor-derived exosome-mediated immune modulation and pre-metastatic niche formation for aggressive metastasis in TNBC. Annexin A2 (AnxA2) is an often identifiedexosomal protein with elevated levels in TNBC patient sera and cell lines. The higher expression of exosomalAnxA2 (exo-AnxA2) in serum samples is associated with poor overall survival and poor disease-free survivalin breast cancer patients. In addition the expression of serum exo-AnxA2 is significantly high in AA womenwith TNBC and promotes angiogenesis. Our data suggest a role for Exo-AnxA2 in establishing a pre-metastatic niche by immune modulation which subsequently promotes TNBC metastasis. The goal of ourresearch is to develop improved therapeutic options for TNBC. We hypothesize that high expression of Exo-AnxA2 plays a vital role in immune modulation at the pre-metastatic niche thereby promoting TNBCmetastasis. We will address this hypothesis by the following two specific aims: Aim 1: Determine themechanism(s) that drive exo-AnxA2-mediated immune modulation and metastatic niche formation foraggressive metastasis in breast cancer. Aim 2: Determine the role of patient-derived exo-AnxA2 withmeasures of disease aggressiveness among racially distinct populations of TNBC patients using humanizedmouse model system. We predict that high concentrations of exo-AnxA2 in the sera of TNBC patients will beshown to contribute to the aggressive biology of this disease especially in AA women by immune modulationat the pre-metastatic niche site. 172975 +No NIH Category available Affect;Anemia;Autophagocytosis;Biological;Biological Assay;Blood Transfusion;Bone Marrow;CD34 gene;CRISPR/Cas technology;Cancer Center;Cancer Science;Cell Culture System;Cell Line;Cells;Cellular Assay;Clinic;Deposition;Development;Dysmyelopoietic Syndromes;Engineering;Enzymes;Erythroblasts;Erythrocytes;Erythroid;Erythroid Cells;Erythropoiesis;Eukaryotic Initiation Factors;Event;Future;Gene Expression;Genetic Transcription;Hematology;Hematopoietic;Hematopoietic stem cells;Heme;Hemoglobin;Impairment;In Vitro;Iron;Iron Overload;K-562;Malignant Neoplasms;Mitochondria;Molecular;Morphology;Mutation;Pathway interactions;Patients;Permeability;Phenotype;Phosphotransferases;Prokaryotic Initiation Factor-2;Protein Family;Protein Kinase;RNA Splicing;Recurrence;Risk;Sampling;Sickle Cell Anemia;Sideroblast;Signal Pathway;Signal Transduction;Spliced Genes;Testing;Therapeutic;Transforming Growth Factor beta;Transfusion;Translating;Validation;Vision;Work;adverse outcome;alternative treatment;cancer cell;candidate validation;cell type;clinical candidate;clinical development;clinical phenotype;cohort;effective therapy;engineered stem cells;erythroid differentiation;expectation;falls;genetically modified cells;heme biosynthesis;improved;improved outcome;induced pluripotent stem cell;inhibitor;insight;leukemic transformation;member;multidisciplinary;mutant;nanomolar;novel therapeutic intervention;novel therapeutics;peripheral blood;pharmacologic;progenitor;programs;response;side effect;single cell technology;small molecule;small molecule inhibitor;targeted treatment;therapeutic target;therapy development Developing an inhibitor of EIF2AK1 to overcome ineffective erythropoiesis in myelodysplastic syndromes with ringed sideroblasts PROJECT NARRATIVEMyelodysplastic syndromes with ringed sideroblasts (MDS-RS) are characterized by significant anemia.Patients with MDS-RS are transfusion-dependent and die from a shortage of red blood cells and the sideeffects of iron overload due to their constant need for these transfusions. Our study aimed to develop a newcompound targeting the EIF2AK1 pathway to heme deficiency has implications for the development of a newtherapy able to achieve long-lasting hematological responses in this cohort of patients. NCI 10726479 9/19/23 0:00 PAR-22-216 1R21CA283679-01 1 R21 CA 283679 1 "O'HAYRE, MORGAN" 9/19/23 0:00 8/31/25 0:00 ZCA1-RPRB-J(M2)S 10333419 "COLLA, SIMONA " Not Applicable 9 MISCELLANEOUS 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/19/23 0:00 8/31/25 0:00 395 Non-SBIR/STTR 2023 378674 NCI 233749 144925 ABSTRACT Mutations in the splicing factor SF3B1 (SF3B1MT) which occur in 20% of patients with myelodysplasticsyndromes (MDS) are the hallmarks of MDS-RS an MDS subtype characterized by the accumulation ofringed sideroblasts (RS) in the bone marrow. SF3B1MT are found in different hematopoietic cell types butpreferentially deregulate erythroid progenitors. Although MDS-RS has a low propensity for leukemictransformation most patients with MDS-RS have severe anemia and depend on regular blood transfusionsdespite the increased risk of iron overload and other adverse outcomes. The only agent approved for the treatment of transfusion-dependent MDS-RS patients who are ineligiblefor or have no response to erythropoiesis-stimulating agents is luspatercept an inhibitor of TGF signaling.However luspatercept has a response rate of less than 40% which underscores the need for alternativetreatment options that can alleviate impaired erythroid differentiation in these patients. In our previous study we identified the EIF2AK1 response to heme deficiency as a potential driver of theSF3B1MT-induced arrest of erythroid differentiation. We therefore hypothesize that pharmacologically inhibitingEIF2AK1 activation overcomes ineffective erythropoiesis in patients with SF3B1-mutant MDS-RS. To test thishypothesis we will pursue the specific aim of developing a small-molecule inhibitor of EIF2AK1 activity forproof-of-concept studies in SF3B1-mutant MDS samples. The findings of this aim will provide a direct lineof sight to future compounds suitable for clinical development. We have partnered with the Institute of Applied Cancer Science at MD Anderson Cancer Center to developsmall molecules targeting the EIF2AK1 pathway in MDS-RS. Our multidisciplinary team has already identifiedseveral EIF2AK1 inhibitors that have low nanomolar potency are highly permeable and free of efflux and havegood selectivity relative to other members of the EIF2AK family of protein kinases. In the proposed work wewill functionally validate these candidates using cellular assays (employing primary cells induced pluripotentstem cells and genetically engineered cell lines) that we have developed over the last 3 years. If successfulthis study will enable the development of the first inhibitor of EIF2AK1 activity. The proposed work has implications for the development of therapies to achieve long-lasting hematologicalresponses in transfusion-dependent MDS-RS patients. Given that EIF2AK1 inhibition is one of the mostpromising therapeutic approaches for sickle cell anemia to date the results of our work may have a broadspectrum of application. 378674 +No NIH Category available Aberrant DNA Methylation;Acceleration;African American population;Age;Aging;American;Anatomy;Biological;Biology;Biopsy;Chronology;Clinical;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal;Colorectal Cancer;Colorectal Neoplasms;DNA Methylation;Data;Deceleration;Development;Diagnosis;Disease;Environmental Exposure;Epidemiology;Epigenetic Process;Ethnic Origin;Etiology;European;Exhibits;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genome;Heterogeneity;Human;Hypermethylation;Incidence;Individual;Left;Lesion;Link;Location;Methylation;Molecular;Multiple Anatomic Sites;Normal tissue morphology;Obesity;Organoids;Pathway interactions;Patients;Positioning Attribute;Prevention strategy;Race;Rectum;Residual state;Risk;Risk Assessment;Risk Factors;Sampling;Side;Site;Smoking;Tissues;Triplet Multiple Birth;age related;carcinogenesis;cohort;colon carcinogenesis;colon tumorigenesis;colorectal cancer risk;comparative;follow-up;genome-wide;insight;methylome;mortality;novel;racial difference;racial disparity;racial diversity;rectal;response;transcriptome;transcriptome sequencing;transcriptomics;tumor Racial Disparities and Colorectal DNA Methylation- Driven Gene Expression Project NarrativeThis project aims to identify racial differences in DNA methylation-driven gene expression profiles between theright vs. left colon and vs. the rectum. NCI 10726172 9/14/23 0:00 PAR-21-323 1R21CA283132-01 1 R21 CA 283132 1 "WALLACE, TIFFANY A" 9/15/23 0:00 8/31/25 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 8268042 "LI, LI " Not Applicable 5 FAMILY MEDICINE 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 9/15/23 0:00 8/31/25 0:00 393 Non-SBIR/STTR 2023 415257 NCI 257125 158132 ABSTRACT Racial disparities in colorectal cancer (CRC) are widening. There are well-documented racialdifferences in anatomical location distribution of CRC. African Americans (AAs) are more likely to develop rightside CRC and diagnosed at younger age than European Americans (EAs). The mechanisms underlying theseobserved racial disparities and the relationship to sidedness remain poorly understood. DNA methylation is akey epigenetic regulator of transcription. Epigenetic alterations result in accelerated aging and changes in geneexpression which are believed to drive colon tumorigenesis. In a recent study of colorectal biopsies from 128patients we discovered that human colon exhibits remarkable racial and side differences in DNA methylationand epigenetic aging. The right colon of AAs shows enrichment of hypermethylated differentially-methylatedpositions (DMPs) and accelerated epigenetic aging whereas the right colon of EAs shows decelerated aging ascompared to left colon. Our analysis of rectal DNA methylation shows similar racial differences. We furthershow that in patient-derived normal colon organoids response to environmental exposures is colon sidespecific and impacts global gene expression further implying differing biology between right vs left colon andvs rectum. These novel observations led to our central hypothesis that there are distinct epigenetic andtranscriptomic perturbations underlying racial disparities in the development of site-specific colorectalneoplasia. We here propose to perform RNA-sequencing of 384 individual-matched triplet colorectal biopsies(right vs. left colon vs. rectum) from the 128 patients in our hands. In combination with DNA methylation dataalready generated on these patients we will use a supervised approach to integrate omics data on thetranscriptome and methylome and to identify DNA methylation-driven gene expression signatures that mayprovide biological insight of the racial disparities and colorectal site differences observed. In Aim 1 we willidentify within-individual site-specific DNA methylation-associated gene expression signatures acrosscolorectum locations (right vs left colon vs rectum). In Aim 2 we will identify cross-individual racial differencesin site-specific DNA methylation-associated gene expression signatures. In Aim 3 we will identify geneexpression signatures associated with site- and race-specific epigenetic age acceleration. Our study willprovide novel insight of the epigenetic and transcriptomic underpinnings of racial disparities in risk of sitespecific CRC and guide the development of prevention strategies to reduce racial disparities by targetingcritical epigenetic/transcriptomic pathways linked to colon carcinogenesis. 415257 +No NIH Category available Adjuvant;Adjuvant Chemotherapy;Adjuvant Therapy;Adoption;Adult;Age;American Cancer Society;American Joint Committee on Cancer;Architecture;Biological Assay;Cancer Center;Categories;Cells;Cessation of life;Classification;Clinic;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Clinical stratification;Cloud Computing;Collaborations;Computer Assisted;Computer Vision Systems;Diagnosis;Disease;Eligibility Determination;European Organization for Research and Treatment of Cancer;Excision;Foundations;Head and neck structure;Hematoxylin and Eosin Staining Method;Histologic;Image;India;Institution;Invaded;Left;Malignant Neoplasms;Measurement;Measures;Modeling;Molecular;Morphology;Nuclear;Operative Surgical Procedures;Oral cavity;Outcome;Patient Selection;Patient risk;Patient-Focused Outcomes;Patients;Pattern;Pattern Recognition;Platinum;Postoperative Period;Prognostic Marker;Radiation;Radiation Therapy Oncology Group;Radiation therapy;Recurrence;Regimen;Relapse;Resources;Risk;Risk Marker;San Francisco;Shapes;Slide;Smoking;Staging;Stains;Standardization;Surgical Oncology;Surgical Pathology;System;Systemic Therapy;Testing;Texture;Therapeutic;Tissue Microarray;Tissue Stains;Tissues;Training;Tumor Cell Invasion;Tumor stage;Tumor-Infiltrating Lymphocytes;United States;United States National Institutes of Health;Universities;Validation;Visual;Woman;Work;advanced disease;behavioral outcome;chemoradiation;chemotherapy;cohort;collaborative trial;companion diagnostics;computerized;cost;density;diagnostic tool;digital;digital imaging;high risk;high risk population;improved;innovation;lymphatic Invasion;malignant mouth neoplasm;men;mouth squamous cell carcinoma;neoplastic cell;outcome prediction;patient prognosis;patient stratification;perineural;precision medicine;predict clinical outcome;predictive marker;predictive test;prognostic;prognostic assays;prognostic of survival;prognostication;progression risk;prospective;risk stratification;success;targeted treatment;tool;treatment choice;tumor;tumor behavior Oral Cavity Quantitative Histomorphometric Risk Classifier (OHbIC) in Oral Cavity Squamous Cell Carcinoma (OC-SCC) Project Relevance: In this project we seek to improve the predictive accuracy of a computerizedhistomorphometric predictor (OHbIC) for risk stratification outcome prediction and added benefit of adjuvantchemotherapy for patients with oral cavity squamous cell carcinoma (OC-SCC) from routine H&E tissue slideimages. The success of this project will pave the way for its adoption as a tissue non-destructive AffordablePrecision Medicine (APM) companion diagnostic tool allowing for the identification of OC-SCC patients for whomtherapies could be either left as standard or require escalation depending on the OHbIC risk score. NCI 10726124 3/10/23 0:00 PA-21-268 7R01CA249992-03 7 R01 CA 249992 3 "OSSANDON, MIGUEL" 12/30/20 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-SBIB-S(59)R] 8352708 "MADABHUSHI, ANANT " "LEWIS, JAMES " 5 BIOMEDICAL ENGINEERING 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 394 Non-SBIR/STTR 2023 654803 NCI 442529 212274 SUMMARY: In 2018 nearly 34000 adults in the US and over 275000 worldwide were diagnosed with oral cavitysquamous cell carcinoma (OC-SCC). In the US alone >6600 died from the disease in 2018. In addition to stageperineural invasion lymphovascular invasion depth of invasion and close or frankly positive resection marginsare used to help stratify patients into low- intermediate- or high risk categories. Currently all OC-SCC patientsare treated primarily by surgical resection. Post-operative treatment depends on patient risk category. Low-riskpatients receive surgery alone and studies have shown the benefit of PORT (Post-operative radiation therapy)in selected patients. A retrospective analysis of 1467 patients with low-risk OC-SCC where 740 (50.4%) receivedPORT had improved overall survival compared to 727 patients treated with surgery alone. Identifying thesepatients and better stratifying their risk of progression is critical. Meanwhile patients with loco-regionallyadvanced (i.e. intermediate and high risk) disease are treated with PORT as standard. Select high risk patientsmay be treated with concomitant chemoradiation or subsequent chemotherapy. There is thus an urgent need todevelop companion diagnostic tools to better define which patients will benefit from PORT or if intermediate orhigh risk who will benefit from systemic therapy intensification. Recently our group has developed a OC-SCC histomorphometric based image risk classifier (OHbIC)that uses computerized measurements of nuclear orientation texture shape architecture from digital images ofH&E-stained tumor sections to identify patients who are likely to recur versus those who are not. OHbIC wastrained and validated on N=115 OC-SCC patients and it had a 2 and 7-fold higher-correlation with diseasespecific survival compared to the 7th edition AJCC N- and T-stage (clinical variables used in patient prognosis).In this NIH R01 we seek to further improve the prognostic and predictive accuracy of OHbIC by incorporatingnew classes of image features relating to stromal morphology pattern of invasion at the tumor leading edgedensity and patterns of tumor infiltrating lymphocytes and tumor cell multi-nucleation features now recognizedas potential histopathological markers of prognostic relevance in OC-SCC. Additionally we seek to 1) validateOHbIC as prognostic of survival in clinically defined low-risk patients and identify those low-risk patients whowould benefit from PORT and 2) validate OHbIC as not only prognostic of survival but also predictive of benefitfrom chemotherapeutic intensification for patients with loco-regionally advanced disease. This partnership will leverage long-standing collaborations in (1) digital pathomics from the Madabhushigroup at Case Western Reserve (2) surgical pathology and oncology expertise in oral cancer from VanderbiltUniversity Cleveland Clinic San Francisco VA and Tata Memorial Centre Mumbai to establish OHbIC as atissue non-destructive and Affordable Precision Medicine (APM) solution for OC-SCC patients. 654803 +American Indian or Alaska Native; Arctic; Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Genetics; Immunization; Immunotherapy; Minority Health; Prevention; Rare Diseases; Vaccine Related Blood;Cancer Prevention Trial;DNA;Development;Family member;Frameshift Mutation;Hereditary Nonpolyposis Colorectal Neoplasms;Immunoprevention;Individual;Inuits;Malignant Neoplasms;Mucous Membrane;Mutation;PMS2 gene;Preventive;RNA;Reagent;Recurrence;Sampling;Syndrome;Testing;Tumor Tissue;Vaccines;base;cancer prevention;cohort;high risk;high risk population;mouse model;neoantigen vaccine;neoantigens;next generation sequencing;tumor;vaccine strategy Development of Cancer Immunoprevention in a High-Risk Population of Canadian Inuits: Characterization of Frame-Shift Neoantigen Expression in Homozygous Individuals and Carriers of PMS2 Mutations n/a NCI 10725425 75N91019D00024-P00018-759102000003-56 N01 8/31/20 0:00 8/30/22 0:00 78754791 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 24717 NCI Project hypothesizes that the recurrent frame-shift mutations observed in Lynch Syndrome will also occur in CMMRD Syndrome and that the neoantigen vaccine strategy and reagents will be directly relevant to cancer prevention in CMMRD Syndrome. 24717 +No NIH Category available Address;Architecture;Cancer Prognosis;Cardiovascular Diseases;Case Study;Clinical;Colonoscopy;Colorectal Cancer;Complement;Complex;Computer software;Computerized Medical Record;Data;Data Analyses;Databases;Development;Devices;Disease;Elderly;Ensure;Erlotinib;Excision;Fluorouracil;Future;Infrastructure;Literature;Lobectomy;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medical Records;Medicare;Methodology;Methods;Modeling;Network-based;Non-Small-Cell Lung Carcinoma;Observational Study;Operative Surgical Procedures;Outcome;Paclitaxel;Performance;Pharmaceutical Preparations;Policy Research;Population;Procedures;Public Policy;Publishing;Pythons;Radical Prostatectomy;Reproducibility;Research Design;Resources;Survival Analysis;Techniques;Testing;United States Department of Veterans Affairs;advanced pancreatic cancer;cancer diagnosis;cancer survival;clinical practice;clinical trial analysis;clinically significant;comparative effectiveness;cooperative study;cost effective;data access;data warehouse;deep learning;deep neural network;design;effectiveness research;experience;flexibility;gemcitabine;insurance claims;neglect;programs;prototype;randomized clinical trials;relative effectiveness;screening;simulation;software development;success;treatment effect;user friendly software Cancer Emulation Analysis with Deep Neural Network Project NarrativeEmulation analysis of large medical record/insurance claims databases provides a viable way of drawing causalconclusions on treatment effects and complements randomized clinical trials. This study will methodologicallysignificantly expand the scope of emulation analysis by developing deep neural network-based approaches thathave more interpretable and more stable architectures provide valid statistical inference and can accommodatesequential trials. With the SEER-Medicare and VA's Cooperate Data Warehouse data we will conduct clinicallyhighly significant case studies on lung and prostate cancer. NCI 10725293 9/19/23 0:00 PAR-20-052 1R03CA276790-01A1 1 R03 CA 276790 1 A1 "OSSANDON, MIGUEL" 9/19/23 0:00 8/31/25 0:00 ZCA1-RTRB-C(M1)S 8798938 "MA, SHUANGGE " Not Applicable 3 PUBLIC HEALTH & PREV MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/19/23 0:00 8/31/25 0:00 394 Non-SBIR/STTR 2023 167500 NCI 100000 67500 Project SummaryTo objectively quantify the relative effectiveness of drugs devices and treatment procedures on cancerprognosis rigorously designed and executed randomized clinical trials (RCTs) remain the gold standard.However as exemplified in this application and many published studies RCTs are not always feasible.Fortunately the fast development of electronic medical records and insurance claims databases has made itpossible to mine a large amount of observational data and efficiently complement RCTs. This strategy has beenenthusiastically endorsed by multiple national organizations. Among the available observational data analysistechniques that aim to draw RCT-type conclusions emulation has emerged as especially appealing with its trial-like architecture interpretability and scalability. It has been applied to multiple cancers and other complexdiseases and led to clinically significant findings. This study has two equally important aims. The first aim is to develop deep neural network (DNN)-basedemulation analysis methods and software. Most of the existing emulation analyses are based on classicregression techniques. Compared to regression DNN excels with superior model fitting and higher flexibility.Recently our group was the first to develop a DNN-based emulation analysis approach and applied it tocardiovascular diseases. Advancing from this recent success we will develop more interpretable and morestable DNNs tailored to RCT analysis. We will then further expand the analysis scope and conduct DNN-basedanalysis of a sequence of emulated trials. For both a single emulated trial and a sequence of trials we willdevelop valid inference which is essential for RCT analysis but has been neglected in most DNN studies. User-friendly software will be developed. This methodological development will substantially expand the scope ofemulation analysis deep learning causal inference observation data analysis and medical record/insuranceclaims data analysis. The second aim is to develop and analyze two emulated trials. We will address thecomparative effectiveness of (a) lobectomy and limited resection on lung cancer survival for the SEER-Medicareelderly population and (b) radical prostatectomy and observation on localized prostate cancer survival for theVA population. The findings will be comprehensively and rigorously evaluated. To provide a more comprehensivepicture we will also analyze using multiple alternative methods and compare against existing RCTs andobservational studies. With the significant methodological advancements and powerful data our analysis willlead to more definitive findings directly inform clinical practice and serve as the prototype for future applications. 167500 +Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome Academia;Cancer Center;Cancer Model;Catalogs;Clinical;Communities;Data;Data Sources;Foundations;Genomic Data Commons;Genomics;Goals;Human;In Vitro;Institutes;Institution;Intellectual Property;International;Libraries;Malignant Neoplasms;Methods;Modeling;Molecular;National Cancer Institute;Office of Cancer Genomics;Online Systems;Organoids;Research Personnel;Resources;Source;System;Technology;Tissue Donors;Trust;anticancer research;biopharmaceutical industry;cancer genomics;clinical diagnostics;data modeling;interest;member;model development;next generation;novel;query tools;response HCMI Searchable Catalog n/a NCI 10725212 75N91019D00024-P00018-759102000003-55 N01 8/31/20 0:00 8/30/22 0:00 78754791 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 200000 NCI Systematic application of novel culture methods now presents an opportunity to develop a large library of cancer models that can be made available as a community resource to investigators in academia and the biopharmaceutical industry. In response to the opportunity the National Cancer Institutes (NCI) Office of Cancer Genomics (OCG) in the Center for Cancer Genomics (CCG) together with international institutions has established a consortium the Human Cancer Models Initiative (HCMI). HCMIs goal is to make available to the scientific community large numbers of next generation in vitro cancer models that are not encumbered with excessive intellectual property (IP) constraints. To support the US contribution to HCMI OCG established four Cancer Model Development Centers (CMDCs). The other founding HCMI collaborators are Cancer Research UK (CRUK) Wellcome Trust Sanger Institute (WTSI) and the Hubrecht Organoid Technology foundation (HUB). 200000 +No NIH Category available Acetates;Address;Anthracenes;California;Cancer Biology;Candidate Disease Gene;Carcinoma;Cell Cycle;Cell physiology;Cell surface;Cells;Chemical Models;Chronic;Comprehensive Cancer Center;Computational Biology;Data;Data Analyses;Dermal;Development;Dorsal;Early Diagnosis;Environment;Environmental Exposure;Epithelial Cells;Exhibits;Family;Gene Expression;Gene set enrichment analysis;Genes;Genetic;Goals;Growth;Histologic;Hour;Human;Infiltration;Inflammation;Inflammatory;Institution;Investigation;KRAS oncogenesis;Knowledge;Ligands;Link;Macrophage;Malignant Neoplasms;Measures;Mediating;Mediator;Mentors;Modeling;Molecular;Mus;Mutagens;Mutate;Mutation;Neoplasms;Oncogenic;Pathway Analysis;Play;Population;Prevention;Prevention strategy;Process;Proliferating;Regimen;Research;Resolution;Resources;Role;San Francisco;Science;Signal Transduction;Skin;Skin Cancer;Students;Tetradecanoylphorbol Acetate;Therapeutic;Time;Tissues;Training;Tumor Promotion;Universities;Work;cancer genetics;candidate identification;carcinogenesis;carcinogenicity;career;cell type;chemical carcinogenesis;dimethylbenzanthracene;experience;extracellular;graduate student;human tissue;immune cell infiltrate;immunoregulation;inflammatory milieu;innovation;insight;mouse model;mutant;novel;novel strategies;permissiveness;population based;pressure;programs;promoter;receptor;response;single-cell RNA sequencing;skin squamous cell carcinoma;theories;tool;transcriptome;tumor;tumor growth;tumorigenesis;tumorigenic;wound healing Selection of oncogenic Ras mutations through tumor promotion mechanisms Project NarrativeHealthy cells with mutations associated to tumor growth do not all become tumors. In the proposed researchthe mechanisms connecting oncogenic Ras to microenvironmental selection pressures which promoteneoplastic growth will be identified. Understanding promotion or non-mutagenic processes that are involved inthe evolutionary selection of mutant cells to become tumorigenic will inform novel strategies for early detectionand therapeutic prevention of deadly Ras-dependent cancers. NCI 10725112 12/8/23 0:00 PA-21-052 5F31CA271737-02 5 F31 CA 271737 2 "DIBELLO, ANTHONY THOMAS" 12/1/22 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16130549 "BOLLAM, SAUMYA REDDY" Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 "Training, Individual" 2024 39670 NCI 39670 0 Project SummaryRecent investigations have revealed that oncogenic mutations are not sufficient for initial stages of tumorigenesisand that the microenvironment plays a significant role in promoting neoplastic growth of a tumor. Thismicroenvironment surrounding a mutated cell can be influenced by many promotion processes includingenvironmental exposures tissue damage and chronic inflammation. This proposal aims to investigate themechanisms by which promotion or non-mutagenic processes can influence the selection of mutant cloneswhich eventually populate a tumor. This project will rely on theories from cancer genetics tumor promotion andevolutionary cancer biology in order to provide insight into the coordination between promotion and oncogenicmutations present in a cell. Through the use of a well-established model of chemical carcinogenesis this projectwill address a fundamental question regarding the molecular consequences of tumor promotion. Thiscarcinogenic regimen can produce both Hras mutant tumors and Kras mutant tumors merely by adjusting thegenetic background of the mouse. This provides the ideal tool for us to ask the question what are the differentpromotion mechanisms which select for tumors with different mutations? To address this question the proposedproject aims to characterize promotion mechanisms on the backgrounds of the mice which are known to producetumors with different mutations. The first aim will investigate how macrophage infiltration during promotioncoordinates with oncogenic Hras signaling. This will be addressed by computationally identifying signaling axesbetween macrophages and epithelial cells from skin collected at different time points after application of apromoter. The second aim will define the active functional modules in the Kras-tumor-permissive skin inresponse to a promoter. This will be achieved by constructing gene co-expression networks from single cell RNAsequencing of skin collected subsequent to promoter treatment in the skin. The proposed research will becompleted by a graduate student with significant experience in both cancer biology and computational biology.It will be supervised by and conducted in the lab of Allan Balmain an expert in the field of skin cancer geneticsand tumor promotion. This training plan takes advantage of the highly collaborative and innovative researchenvironment in the Helen Diller Family Comprehensive Cancer Center which facilitates access to renownedscientific mentors and guidance in the proposed work. At the University of California San Francisco (UCSF) thegraduate program in Biomedical Sciences is regarded as one of the best due to its inclusion of professionaldevelopment and training resources offered which will support this highly motivated student to develop anindependent research career. Completion of the proposed work will thus expand knowledge on a critical questionin cancer biology and is enabled by an excellent institutional environment. Understanding how oncogenicmutations can coordinate with tumor promotion mechanisms in the mutant cells microenvironment will providenovel insights towards early detection and prevention strategies for cancer. 39670 +Cancer; Dissemination and Implementation Research; Prevention Achievement;Area;Cancer Control;Cancer Survivorship;Communication;Division of Cancer Control and Population Sciences;Effectiveness;Funding;Goals;Health;Health Professional;Intervention;Population;Population Sciences;Progress Reports;Research;Resources;Science;Services;health disparity;high standard;implementation science;population based;programs STRATEGIC COMMUNICATIONS AND ANALYTIC SUPPORT FOR DCCPS n/a NCI 10724962 26117003B91022F00002-0-0-2 N02 9/30/22 0:00 9/29/23 0:00 78868225 "GEAGHAN, TAYLOR " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2022 250000 NCI Moonshot funded support: The goal for this project is to maximize the NCIs ability to facilitate significant achievements in cancer control and population sciences through strategic communication. Communication activities cut across all our programs with a goal of greater integration and enhancement of cross-cutting scientific areas including implementation science cancer survivorship and health disparities. Part of what contributes to DCCPSs effectiveness is the breadth of activities undertaken. These include dissemination of research results and resources reports of progress on major initiatives and the provision of health information to health professionals practitioners and the public. It is important to maintain the high standard set for the type of services that are provided as well as meet the need to communicate about science and initiatives to new and expanding audiences. NCI must continue to promote and communicate cancer control and population-based interventions in a way that meets the needs of and is accessed by a variety of constituent populations. 250000 +Cancer; Clinical Research Funding;Medical Genetics;Services CLINICAL GENETICS BRANCH SUPPORT SERVICES n/a NCI 10724960 261201800004C-P00012-9999-1 N02 9/1/18 0:00 8/31/23 0:00 78832451 "GLASHOFER, SARA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2022 200000 NCI CLINICAL GENETICS BRANCH SUPPORT SERVICES 200000 +Cancer; Patient Safety Adherence;Biological Assay;Biological Products;Cancer Center;Clinical Trials;Clinical Trials Network;Community Clinical Oncology Program;Conduct Clinical Trials;Contract Services;Data;Division of Cancer Treatment and Diagnosis;Ensure;Funding;Funding Agency;Good Clinical Practice;Guidelines;Institution;International;Investigational Therapies;Laboratories;Medidata;Monitor;Monitoring Clinical Trials;Patients;Phase;Phase II Clinical Trials;Policies;Procedures;Process;Protocols documentation;Quality Control;Randomized;Regulation;Research;Resources;Services;Site;Site Visit;Support Contracts;System;United States Dept. of Health and Human Services;United States Food and Drug Administration;Visit;data integrity;data management;early phase clinical trial;good laboratory practice;manufacturing facility;patient registry;quality assurance;research and development;symposium CLINICAL TRIALS MONITORING SERVICE_ Moonshot support n/a NCI 10724946 75N91022C00013-0-9999-2 N01 5/1/22 0:00 4/30/23 0:00 78653629 "ANDERSON, BARRY " Not Applicable 12 Unavailable 61814323 HFYTJGWFPMR7 61814323 HFYTJGWFPMR7 US 40.362811 -74.600076 1721601 "THERADEX SYSTEMS, INC." PRINCETON NJ Domestic For-Profits 85405748 UNITED STATES N R and D Contracts 2022 360000 NCI This is a Research and Development Support contract. The purpose of this acquisition is to assist the NCI in fulfilling its responsibilities to the Food and Drug Administration (FDA) and Department of Health and Human Services (DHHS) regulations as IND sponsor and funding agency. The scope of the Clinical Trials Monitoring Service (CTMS) contract is to provide data management quality assurance clinical trial monitoring and auditing capability for NCI sponsored clinical trials conducted by the NCI's Experimental Therapeutics Clinical Trials Network (ETCTN) at participating sites both domestically and internationally. Additionally the CTMS contract provides a mechanism for the auditing of biopharmaceutical manufacturing facilities to ensure compliance with current Good Manufacturing Practices (GMP) and compliance with Good Laboratory Practices (GLP) for laboratories performing integral assays. 360000 +Biomedical Imaging; Cancer Contracts;Funding;Goals;Pathology;Process;Radiology Specialty;Recommendation;Registries;Reporting;SEER Program;Standardization;Technology;Time;United States;Work;cost;improved;insight;program costs SEER PROGRAM PATHOLOGY AND RADIOLOGY REPORTS ACQUISITION ENHANCEMENTS_ Moonshot funded n/a NCI 10724936 75N98019D00018-P00005-759101900129-2 N02 5/13/19 0:00 5/12/23 0:00 78667343 "FERNANDEZ, ANNA " Not Applicable 11 Unavailable 6928857 JCBMLGPE6Z71 6928857 JCBMLGPE6Z71 US 38.922512 -77.231057 682902 BOOZ ALLEN HAMILTON MC LEAN VA Domestic For-Profits 221023830 UNITED STATES N R and D Contracts 2022 450000 NCI This contract is to support the Surveillance Epidemiology and End Results (SEER) Program in assessing and developing efficient mechanisms for processing Pathology and Radiology reports at the state registry levels. This work will drastically improve quality and efficiency in processing vital documents for the SEER program and reduce costs in the current workflows. The goal of the contract is to provide key insights into 1) developing efficient and more standardized pathology and radiology processing workflows across multiple states in the United States and 2) current technologies which would improve processing and reduce cost for program. Additionally through nationwide assessments this contract will produce recommendations that will highlight new standardized processes to help reduce time and improve quality of processing of pathology and radiology reports. 450000 +No NIH Category available Address;Administrative Supplement;Adopted;Adoption;Appointment;Caring;Clinic;Clinical;Collaborations;Colonoscopy;Communication;Communities;Community Health;Data;Databases;Decision Making;Documentation;Electronic Health Record;Ensure;Evaluation;Federally Qualified Health Center;Funding;Healthcare;Informatics;Intervention Studies;Laboratories;Learning;Medicaid;Methods;Missouri;Modeling;Patients;Persons;Phase;Population;Positioning Attribute;Preparation;Prevention;Primary Care;Process;Recommendation;Reporting;Research;Resources;Risk;Role;Rural;Screening for cancer;Series;Services;Site;Social Work;Social Workers;Testing;Transportation;Universities;Variant;Washington;Work;design;evidence base;guidebooks;health disparity;health inequalities;implementation barriers;implementation strategy;improved;member;parent grant;patient navigation;patient screening;pilot test;preventive intervention;primary care clinic;primary care practice;rapid test;referral services;response;rural area;social;social interventions;tool;urban area;waiver PULSE DeveloPing a pragmatic gUide to impLementing social riSk assistancE PROJECT NARRATIVEThis supplement is a collaborative effort across four ISC3 Centers: BRIDGE-C2 Harvard ISCCCE Universityof Washington OPTICC and Washington University (WU)-ISC3. We propose to: (1) develop a pragmaticapplied guidebook (the Guide) for clinics seeking to implement or expand efforts to address patient-reportedsocial risks using Assistance strategies; (2) use rapid-cycle testing to identify best practices for implementingthe Guide; and (3) iterate and disseminate the refined Guide. This supplement will allow our team to collect thedata needed to inform and align the research of our WU-ISC3 Center Parent grant as social risks are keyinfluencers of health inequality and contribute to health disparities between populations and communities. NCI 10724918 4/28/23 0:00 PA-20-272 3P50CA244431-04S1 3 P50 CA 244431 4 S1 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 1885266 "BROWNSON, ROSS C" "COLDITZ, GRAHAM A." 1 PUBLIC HEALTH & PREV MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF SOCIAL WELFARE/WORK 631304862 UNITED STATES N 1/2/23 0:00 8/31/23 0:00 353 Research Centers 2023 124983 NCI 79869 45114 PROJECT SUMMARYThis supplement is a collaborative effort across four ISC3 Centers: BRIDGE-C2 Harvard ISCCCE Universityof Washington OPTICC and Washington University (WU)-ISC3. Addressing patients social needs is a criticalpart of enabling patients to access evidence-based cancer screening and prevention interventions a focus ofthe WU-ISC3 Center. Well-documented challenges in addressing social needs include determining how best tomaintain up-to-date information about available service agencies to which persons with social needs may bereferred and developing and adopting optimal workflows for doing so. Social service resource locators(SSRLs) that identify currently available resources take varying forms ranging from a social worker maintaininga hard-copy binder of resources to an informatics platform integrated into the electronic health record anddesigned to enable bidirectional communication with local organizations about referred patients receipt ofservices (also called community resource referral platforms). Building on the findings from the Phase Isupplement we propose to: (1) develop a pragmatic applied guidebook (the Guide) for clinics seeking toimplement or expand efforts to address patient-reported social risks using Assistance strategies; (2) use rapid-cycle testing to identify best practices for implementing the Guide; and (3) iterate and disseminate the refinedGuide. WU-ISC3 will test the guide in Missouri Highlands Health Care a Federally Qualified Health Center inrural southern Missouri who face some of the most difficult implementation challenges as they primarily servepatients with high social needs and are located in an outer context with fewer resources than urban areas. 124983 +No NIH Category available American;Awareness;BARD1 gene;BRCA mutations;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Benefits and Risks;Biological;Biological Assay;Biological Markers;Blinded;Blood;Blood Tests;CHEK2 gene;Case/Control Studies;Cessation of life;Classification;Clinical Trials;Collection;Colon Carcinoma;Colorectal;DNA Repair;DNA Repair Gene;DNA Sequence Alteration;DNA Sequence Rearrangement;Data Set;Defect;Detection;Diagnosis;Endometrial Carcinoma;Enrollment;Epigenetic Process;Epithelial ovarian cancer;Event;Family Cancer History;Family history of;Future;General Population;Genes;Genetic Predisposition to Disease;Genetic Risk;Germ-Line Mutation;Guidelines;Hereditary Breast and Ovarian Cancer Syndrome;Individual;Institution;Lung;Malignant neoplasm of ovary;Measures;Methylation;MicroRNAs;Modeling;Mutate;Mutation;Operative Surgical Procedures;Ovarian;PALB2 gene;PTEN gene;Pathway interactions;Population;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;RAD51C gene;Recording of previous events;Risk;Risk Assessment;Risk Factors;Risk Reduction;Salpingo-Oophorectomy;Sampling;Screening for Ovarian Cancer;Serum;Testing;Transvaginal Ultrasound;Triage;Woman;brca gene;cancer prevention;cancer risk;case control;circulating microRNA;comparison control;cost;design;early phase clinical trial;feasibility testing;gene repair;genetic information;genetic testing;high risk;high risk population;lifetime risk;malignant breast neoplasm;mutation carrier;mutational status;next generation sequencing;prevent;promoter;prospective;repaired;risk stratification;risk variant;sample collection;screening;study population;surveillance strategy;tool Ovarian cancer risk stratification using circulating miRNAs to assess BRCAness Project NarrativeOvarian cancer risk stratification using circulating miRNAs to assess BRCAnessRisk-reducing surgery is the most effective means to prevent ovarian cancer. Currently there is no blood test toscreen for high-risk individuals who would benefit from this approach. In this proposal we test the feasibility of amicroRNA-based blood test to identify women among the general population with an increased likelihood ofdeveloping ovarian cancer. NCI 10724815 9/21/23 0:00 PAR-20-052 1R03CA283252-01 1 R03 CA 283252 1 "PATRIOTIS, CHRISTOS F" 9/12/23 0:00 8/31/25 0:00 ZCA1-SRB-K(M2) 14265369 "ELIAS, KEVIN " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/12/23 0:00 8/31/25 0:00 394 Non-SBIR/STTR 2023 178989 NCI 99994 78995 AbstractCurrent strategies to prevent ovarian cancer deaths remain limited. Unlike breast and colon cancer clinical trialsfor early detection of ovarian cancer have not been effective at reducing ovarian cancer deaths. In contrast risk-reducing salpingo-oophorectomy for women with germline mutations in BRCA1/2 reduces the risk of ovariancancer death by more than 95%. However since current guidelines limit genetic testing to individuals with apersonal or close family history of breast or ovarian cancer only 10% of the estimated 1 million Americans withBRCA1/2 mutations are aware of their mutation status. We have shown that BRCA1/2 mutation carriers have adistinct serum microRNA (miRNA) profile which can be used to rapidly identify likely mutation carriers. In thisproposal we will use previously collected sample and datasets to discover the generalizability of this miRNAprofile to other potentially high-risk groups. We will examine the serum miRNA profiles of both BRCA1/2 mutationcarriers as well as carriers of mutations in other DNA repair genes and women with no discernible germlinemutation but a strong family history of breast or ovarian cancer. Samples will be classified in terms of BRCAnessi.e. how closely they resemble BRCA1/2 mutation carriers versus healthy controls with average cancer risk. Wewill determine whether the BRCA1/2 miRNA profile is restricted to alterations in these specific genes or reflectsa more general deficiency in DNA repair which could increase the risk of ovarian cancer. Independently we willtest whether the BRCAness miRNA profile is sufficient as an ovarian cancer risk triage tool even in the absenceof known genetic information. Using a case-control format we will compare baseline miRNA profiles among astudy population of average risk women who were enrolled in an ovarian cancer screening trial. We will calculatewhether cases were more likely to have a BRCAness miRNA profile at study entry compared to controls. Thefinal result of these studies will be to test whether serum miRNAs can serve as a biomarker to identify morewomen at risk for ovarian cancer who could benefit from risk-reduction strategies. This group can then beprioritized for future biologic studies and clinical trials. 178989 +No NIH Category available Address;Administrative Supplement;Adopted;Adoption;Appointment;Caring;Clinic;Clinical;Collaborations;Colonoscopy;Communication;Communities;Community Health;Community Health Networks;Databases;Decision Making;Documentation;Electronic Health Record;Ensure;Evaluation;Face;Federally Qualified Health Center;Funding;Guidelines;Informatics;Intervention;Intervention Studies;Laboratories;Learning;Medicaid;Methods;Modeling;Neighborhood Health Center;Patients;Persons;Phase;Physiologic pulse;Population;Positioning Attribute;Preparation;Prevention;Primary Care;Process;Recommendation;Reporting;Research;Resources;Risk;Role;Rural;Screening for cancer;Series;Services;Site;Social Work;Social Workers;Testing;Transportation;Universities;Variant;Washington;Work;cancer prevention;design;evidence base;guidebooks;health disparity;health inequalities;implementation barriers;implementation strategy;improved;member;patient screening;pilot test;preventive intervention;primary care clinic;primary care practice;rapid test;referral services;response;rural area;screening;social;social health determinants;social interventions;socioeconomics;tool;waiver PULSE - BRIDGE-C2: DeveloPing a Pragmatic GUide to ImpLementing Social RiSk AssistancE PROJECT NARRATIVEThis supplement is a collaborative effort across four ISC3 Centers: BRIDGE-C2 Harvard ISCCCE Universityof Washington OPTICC and Washington University-ISC3. We propose to: (1) develop a pragmatic appliedguidebook (the Guide) for clinics seeking to implement or expand efforts to address patient-reported socialrisks using Assistance strategies; (2) use rapid-cycle testing to identify best practices for implementing theGuide; and (3) iterate and disseminate the refined Guide. This supplement will support and enhance theresearch conducted by the BRIDGE-C2 Center as social risks (adverse social determinants of health) drivehealth inequality and health disparities in receipt of guideline-concordant cancer prevention. NCI 10724461 7/3/23 0:00 PA-20-272 3P50CA244289-04S2 3 P50 CA 244289 4 S2 "CZAJKOWSKI, SUSAN" 9/19/19 0:00 8/31/24 0:00 11703978 "HUGUET, NATHALIE " "HUGUET, NATHALIE " 1 FAMILY MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 1/2/23 0:00 8/31/23 0:00 353 Research Centers 2023 124999 NCI 110631 14368 PROJECT SUMMARYThis supplement is a collaborative effort across four ISC3 Centers: BRIDGE-C2 Harvard ISCCCE Universityof Washington OPTICC and Washington University-ISC3. The BRIDGE-C2 Center Implementation Laboratoryis a network of community health centers (CHCs) which face particularly difficult implementation challenges asthey primarily serve socioeconomically vulnerable patients with high rates of social needs (adverse socialdeterminants of health). Addressing social needs through `Assistance' interventions can be critical to ensuringpatients' ability to access evidence-based cancer screening and prevention interventions. Well-documentedchallenges in addressing social needs include determining how best to maintain up-to-date information aboutavailable service agencies to which persons with social needs may be referred and developing and adoptingoptimal workflows for doing so. Methods for doing so range from having a clinic social worker maintain a hard-copy binder of resources to using social service resource locators (informatics platforms integrated into theelectronic health record) to identify available resources and enable bidirectional communication with localorganizations about patients' receipt of services (also called community resource referral platforms). Buildingon findings from the Phase I supplement we propose to: (1) develop a pragmatic applied guidebook (theGuide) for clinics seeking to implement or expand efforts to address patient-reported social risks usingAssistance strategies; (2) use rapid-cycle testing to identify best practices for implementing the Guide; and (3)iterate and disseminate the refined Guide. 124999 +No NIH Category available ARHGEF5 gene;Acute;Adolescent;Adult;Affect;Aftercare;Age;Aging;Animals;Antineoplastic Agents;Apoptosis;Apoptotic;Atherosclerosis;Automobile Driving;BAX gene;BCL1 Oncogene;Bax protein;Biological Models;Birth;Blood Vessels;Blood capillaries;Cancer Patient;Cancer Survivor;Cell Death;Cell physiology;Cells;Cellular Morphology;Cellular Stress;Chemotherapy and/or radiation;Cisplatin;Clinic;Clinical;Complement;Cytochrome P450;Cytotoxic agent;DNA;Databases;Detection;Development;Disease model;Doxorubicin;Elderly;Endothelial Cells;Exposure to;External Beam Radiation Therapy;FDA approved;Future;Gene Expression;Gene Family;Genes;Health;Heart failure;Human;Hypertension;Impairment;In Vitro;Induction of Apoptosis;International;Ionizing radiation;Irreversible Toxicity;Ischemia;Knockout Mice;Knowledge;Laboratories;Life;Link;Longevity;Malignant Neoplasms;Measurement;Measures;Migration Assay;Mitochondria;Molecular;Morphology;Mus;Normal tissue morphology;Outcome;Patients;Peripheral;Pharmaceutical Preparations;Predisposition;Prevention;Proliferating;Protein Family;Proteins;Quality of life;Radiation therapy;Regimen;Regulation;Role;Signal Pathway;Smooth Muscle Myocytes;Testing;Therapeutic;Thrombosis;Tissues;Toxic effect;Tube;Tyrosine Kinase Inhibitor;VDAC1 gene;Vascular Diseases;Vascular Endothelial Cell;Vascular Endothelium;Vascular Smooth Muscle;Vegf Inhibitor;Work;cancer cell;cancer therapy;carcinogenesis;cell injury;cell type;chemotherapy;curative treatments;cytotoxic;differentiation protocol;effective therapy;endothelial stem cell;experience;experimental study;high risk;human model;improved;in vivo;induced pluripotent stem cell;innovation;mimetics;neonate;neoplastic cell;pharmacovigilance;prevent;pro-apoptotic protein;response;screening;targeted agent;therapy development;transcriptomics;tumor;tumor xenograft;vascular stress;venous thromboembolism Investigating the role of apoptosis regulation in cancer therapy-induced vascular toxicities PROJECT NARRATIVELife-threatening vascular toxicities reduce long-term quality of life in cancer patients after treatment andalthough this phenomenon has long been observed in the clinic the mechanisms that cause this to occurremain unclear. We propose to investigate the mechanisms behind vascular toxicities by modulating theapoptotic machinery in cells within the vasculature and identify the contributions of each vascular cell type inresponse to various chemotherapies and radiation therapy. Our studies will ultimately lead to improvedtherapeutic strategies that will reduce vascular toxicity and improve health outcomes in cancer patients. NCI 10724247 12/11/23 0:00 PA-21-052 5F31CA275321-02 5 F31 CA 275321 2 "DIBELLO, ANTHONY THOMAS" 12/1/22 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-F10C-C(20)L] 16033408 "FLORIDO, MARY HEATHER CELINE " Not Applicable 7 PUBLIC HEALTH & PREV MEDICINE 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 "Training, Individual" 2024 40122 NCI 40122 0 PROJECT SUMMARYCancer treatments have evolved extensively over the past few decades leading to vast improvements inoverall survival and cure rates. However the collateral damage inflicted upon healthy tissues by both targetedand cytotoxic agents frequently causes life-threatening irreversible toxicities. Some of the most commontoxicities include therapy-induced vascular impairments such as atherosclerosis heart failure ischemia acutethrombosis and venous thromboembolism. Despite their widespread use it is poorly understood howchemotherapies and ionizing radiation cause vascular toxicities. Most cancer therapies typically induceapoptosis (programmed cell death) by damaging common cellular components such as DNA or by blockingcritical signaling pathways. Since vascular cells are also exposed to these agents at high concentrations theycould be vulnerable to therapy-induced apoptosis. However the vasculature is comprised of several cell typesincluding vascular endothelial and smooth muscle cells; it is unknown which cells are sensitive to anti-canceragents and how they may contribute to long-term vascular dysfunction in patients. Using human inducedpluripotent stem cells (hiPSCs) for in vitro disease modeling we will investigate vascular toxicities in hiPSC-derived vascular endothelial cells and vascular smooth muscle cells. Utilizing robust differentiation protocolsalready established in our laboratory we will rigorously test how the survival and function of these cells areaffected by cancer treatments. We will also characterize the regulation of apoptosis in both vascular cell typesby measuring apoptotic priming and expression of BCL-2 family proteins. Additionally we will look at thefunctional and morphological changes that these cells undergo in response to cancer treatments that maycontribute to vascular toxicities. We hypothesize that each vascular cell type possesses differential levels ofapoptotic priming and unique vulnerabilities to our panel of FDA-approved cancer therapies that drive therapy-induced vascular toxicities. Our studies will elucidate potential mechanisms and determine contributions ofeach cell type to vascular toxicities observed in cancer patients. Further since aging is known to play a role inboth vascular toxicity and regulation of apoptosis we will investigate how age affects apoptotic priming andtherapy sensitivity of vascular cells. We will replicate key experiments in mice at various life stages (neonatejuvenile adult and advanced age) to validate our in vitro findings and elucidate how age affects thedevelopment of vascular toxicities. We will also utilize endothelial cell-specific BAX/BAK double knockout miceto determine the extent to which apoptosis blockade can ameliorate vascular toxicity induced by cancertreatment. Altogether our work will test how apoptosis regulation affects the sensitivity of vascular cells tochemotherapy and radiation and how this is altered by aging. These results will lay the groundwork forimproved therapy regimens in the clinic that may decrease long-term vascular toxicities in cancer patients. 40122 +No NIH Category available Acetylation;Acute Myelocytic Leukemia;Adult;Adult Acute Myeloblastic Leukemia;Animals;Binding;Biogenesis;Biological Assay;Bone Marrow;Cell Line;ChIP-seq;Chromatin;Chromatin Structure;Complex;DNA;DNA Modification Methylases;DNMT3a;DNMT3a mutation;Data;Development;Diagnosis;Epigenetic Process;Feedback;Fluorescent in Situ Hybridization;Gene Expression;Gene Expression Regulation;Gene Silencing;Genes;Global Change;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic stem cells;Heterochromatin;Histones;Homeobox Genes;Immunofluorescence Immunologic;In Vitro;Individual;Knock-out;Leukemic Cell;Ligation;Maintenance;Malignant Neoplasms;Mediating;Methylation;Molecular;Mus;Mutate;Mutation;Myelogenous;Nuclear;Outcome;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Preleukemia;Prognosis;Proteins;Publishing;Regulation;Reporting;Ribosomes;Role;Somatic Mutation;Testing;Transposase;Undifferentiated;United States;Update;Variant;Work;acute myeloid leukemia cell;chromatin immunoprecipitation;epigenetic regulation;experimental study;genomic locus;high risk;histone modification;improved;in vivo;insight;leukemia;leukemogenesis;mouse model;mutant;novel therapeutics;nucleophosmin;prevent;protein protein interaction;relapse risk;response;synergism;targeted treatment Defining the Synergistic Role of NPM1 and DNMT3A Mutations on HOX Gene Regulation in the Pathogenesis of Acute Myeloid Leukemia Project NarrativeNPM1 and DNMT3A are the most frequently mutated genes in adult acute myeloid leukemias (AML) where theirco-occurrence is associated with higher risk of relapse and poor outcome. Individually mutant NPM1 andDNMT3A are implicated in the epigenetic regulation of HOX genes critical for maintaining the undifferentiatedleukemic state however their synergistic relationship in HOX regulation has not been well characterized. Thegoal of this proposal is to determine how mutations in NPM1 and DNMT3A cooperatively regulate HOXexpression at the chromatin level with the long-term goal of identifying novel therapeutic vulnerabilities in AML. NCI 10724246 8/22/23 0:00 PA-21-049 5F30CA268725-02 5 F30 CA 268725 2 "ODEH, HANA M" 9/1/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F08-M(20)L] 14342533 "DATAR, GANDHAR KIRAN" Not Applicable 9 ANATOMY/CELL BIOLOGY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 51112 NCI 51112 0 Project Summary/AbstractThe overarching goal of this proposal is to determine how mutations in Nucleophosmin 1 (NPM1) and DNAMethyltransferase 3A (DNMT3A) cooperatively regulate HOX gene expression in the development of acutemyeloid leukemia (AML). AML is a hematological malignancy arising from somatic mutations in hematopoieticprogenitor cells that lead to their expansion in the bone marrow niche. Approximately 20000 cases of AML arediagnosed annually in the United States with a 5-year survival of less than 30%. NPM1 and DNMT3A are themost frequently mutated genes in AML occurring in 30% and 20% of all cases respectively. These mutationsfrequently co-occur with nearly 70% of NPM1-mutant AML harboring a concomitant DNMT3A mutation.Together these mutations confer a worse overall prognosis. Despite their established association thesynergistic mechanisms that drive robust malignancy in the presence of both NPM1/DNMT3A mutations arepoorly understood thus preventing the development of effective targeted therapies.Our group and others have shown that these mutations converge on HOX regulation where high HOXexpression maintains leukemic cells in an undifferentiated state. Our group has shown that mutant NPM1 isrequired for HOX expression in AML. Moreover DNMT3A mutations have been associated with global changesin methylation particularly at HOX loci. To better define the mechanism of mutant NPM1 I performed a proteininteraction screen that revealed mutant NPM1 interacts with the rixosome a conserved ribosomal biogenesiscomplex with additional roles in HOX gene silencing. We hypothesize that during AML pathogenesisDNMT3A mutations enhance chromatin accessibility at HOX gene loci which robustly increases theability of mutant NPM1 to interfere with rixosome-mediated HOX gene silencing. To test this hypothesiswe will first determine the mechanism of increased HOX expression by mutant NPM1 with specific focus on therixosomes role in HOX gene silencing. We will also characterize HOX chromatin organization in NPM1/DNMT3Amutant AML in vitro and in vivo. This proposed work will reveal key molecular mechanisms underlying the mostcommon co-mutations found in AML. As a result these studies will identify new therapeutic vulnerabilities inNPM1/DNMT3A mutant AML and clear a path for the development of targeted therapies to improve patientoutcomes. 51112 +Bioengineering; Cancer Antigen-Antibody Complex;Cells;Clinical;DNA sequencing;Development;Devices;Dysplasia;Fibroblasts;Genomics;Genotype;Immune response;Individual;Lymphocyte;Malignant Neoplasms;Measures;Metaplasia;Molecular;Molecular Profiling;Morphology;Patients;Performance;Protocols documentation;Research;Research Personnel;Technology;Therapeutic Intervention;cell type;flexibility;genomic platform;histological slides;neoplastic cell;new technology;novel diagnostics;prognostic;prototype;tumor;tumor initiation;tumor microenvironment;tumor progression TOPIC 403: DEVELOPMENT OF SPATIAL MICROPURIFICATION TECHNOLOGY n/a NCI 10724142 75N91022C00040-0-9999-1 N44 9/19/22 0:00 9/18/24 0:00 78868021 "EMMERT-BUCK, MICHAEL " Not Applicable 1 Unavailable 79401249 HS4UNLJDUYJ6 79401249 HS4UNLJDUYJ6 US 38.720944 -76.091009 10036482 "AVONEAUX MEDICAL INSTITUTE, LLC" EASTON MD Domestic For-Profits 216018575 UNITED STATES N R and D Contracts 2022 1999386 NCI The tumor microenvironment (TME) comprises a mixture of cell types including tumor cells cancer sub-clones metaplasia dysplasia desmoplasia reactive fibroblasts and a complex immune response. Measuring the molecular status of each cellular component within the TME is important to understanding tumor initiation and progression as well as in determining the interplay between cancer and normal host cells.The proposal describes a new DNA sequencing and genomic analysis technology for histological slides called spatial micropurification which can be developed into a commercial device that permits localized cell-specific interrogation of the TME. SMP devices can analyze individual target cells called single cell spatial micropurification (Single-Cell SMP) or can procure groups of target cells of the same lineage such as tumor cells or lymphocytes called multiple cell spatial micropurification (Multi-Cell SMP). Together the two versions of SMP provide a flexible platform for genomic analyses of the cancer tumor microenvironment (TME) that investigators can employ to meet their research and clinical needs.Development and deployment of this novel technology for spatial molecular profiling of tumors will provide a deeper understanding of the relationship between cell genotype and morphology providing valuable information towarddevelopment of new diagnostic prognostic or therapeutic interventions in patients with cancer. 1999386 +Bioengineering; Biotechnology; Cancer; Immunotherapy Address;Biosensing Techniques;Biosensor;Clinical;Contracts;Dose;Foundations;Future;Glioblastoma;Goals;Immunotherapy;Magnetism;Measures;Metastatic malignant neoplasm to brain;Modeling;Monitor;Patient Selection;Patients;Performance;Phase;Preparation;Quality Control;Reaction Time;Reader;Resistance;Safety;Solid Neoplasm;Survival Rate;System;Testing;Therapeutic;Therapeutic Agents;Work;cancer survival;clinical translation;design;drug candidate;high throughput screening;high throughput technology;in vivo;individualized medicine;melanoma;overtreatment;performance tests;preclinical safety;product development;response;safety testing;treatment optimization;treatment response;tumor;wireless TOPIC 405: INTRATUMORAL BIOSENSING FOR IN VIVO PHARMACOTYPING n/a NCI 10724131 75N91022C00043-0-9999-1 N44 9/19/22 0:00 9/18/24 0:00 78868024 "KNOPKE, CHRISTIAN " Not Applicable 2 Unavailable 79599845 KSGGUNHRF8D5 79599845 KSGGUNHRF8D5 US 43.745001 -72.218704 10037753 "LODESTONE BIOMEDICAL, LLC" LEBANON NH Domestic For-Profits 37661630 UNITED STATES N R and D Contracts 2022 2050000 NCI This project addresses the problem that several rounds of varied immunotherapy treatments over an extended period are often needed to find one that is effective in treating tumors in a particular patient. The proposed solution is an Immunotherapy Response Indication System (IRIS) to monitor treatment response directly in a patients own tumor while testing sub therapeutic doses of multiple candidate drugs to determine the best therapeutic option rapidly and safely. The intratumoral monitoring capabilities of the proposed IRIS implantable biosensor and wireless magnetic reader are key to enabling this pharmacotyping strategy. The work plan in this Phase II contract focuses on preclinical safety and performance testing that is foundational to future clinical translation. This pharmacotyping capability enabled by IRIS will allow clinicians to optimize treatment decisions in the early stages of treatment and during the later stages of treatment in cases of acquired resistance. Our initial clinical product development goal is to track real-time responses within the tumor to immunotherapy in glioblastomas and melanoma brain metastases. Enabling faster selection ofpatient-specific treatments could increase cancer survival rates in the future 2050000 +Bioengineering; Cancer Address;Agreement;Biological Assay;Boston;Calibration;Cells;Clinical Chemistry;Clinical Trials;Concentration measurement;Discipline;Fluorescence;Goals;Immunohistochemistry;Laboratories;Manufacturer Name;Measurement;Medical Device;Methods;Phase;Problem Solving;Protocols documentation;Reference Standards;Standardization;Surgical Pathology;System;Testing;Time;Tissues;base;immunoreactivity;improved;research clinical testing;tissue biomarkers;tool;tool development TOPIC 442: QUANTITATIVE TRACEABLE REFERENCE MATERIALS AS MDDTS FOR TISSUE BIOMARKERS n/a NCI 10724128 75N91022C00032-0-9999-1 N43 9/16/22 0:00 6/15/23 0:00 78858767 "BOGEN, STEVE " Not Applicable 7 Unavailable 126775860 HA17F32KXEV8 126775860 HA17F32KXEV8 US 42.132465 -71.168022 10001083 BOSTON CELL STANDARDS INC BOSTON MA Domestic For-Profits 21111552 UNITED STATES N R and D Contracts 2022 385889 NCI This goal of this project is to qualify the first system of reference standards and measurement traceability in immunohistochemistry (IHC) testing as a Medical Device Development Tool (MDDT) topic 442. In all other types of laboratory testing such as clinical chemistry these metrologic tools are a standard of laboratory practice. FDA requires test manufacturers to identify methods of assay calibration. IHC is the exception. Instead there are poorly standardized improvised systems of calibration based on immunoreactivity with various tissues. This deficiency has led to IHC error rates that are ten times those in other laboratory testing disciplines. Boston Cell Standards developed tools to solve this problem and validated them in 3 large clinical trials.Our proposed MDDT a system of IHC assay calibration traceable to NIST SRM 1934 is applicable to any manufacturers IHC assay. This Phase I proposal addresses 4 improvements that were identified during clinical testing: (1) commutability of reference materials (2) calculating the difference between ERF and molar concentrations (3) improving traceability to NIST SRM 1934 and (4) developing a better method for calibrator value assignment. These small steps will make a large impact in the field of surgical pathology and IHC. 385889 +No NIH Category available Affect;Algorithms;Applied Research;Award;Biological Markers;Biopsy;Biopsy Specimen;Cancer Patient;Cancer Prognosis;Career Transition Award;Cellular Structures;Cessation of life;Clinical;Data;Data Science;Derivation procedure;Diagnosis;Diffusion;Disease;Ecosystem;Extracellular Matrix;Extracellular Matrix Proteins;Gleason Grade for Prostate Cancer;Goals;Image;Imaging Techniques;Immune system;Inflammatory;Link;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Molecular;Monitor;Morbidity - disease rate;Neoplasm Metastasis;Patient Selection;Patients;Pattern;Performance;Polysaccharides;Population Surveillance;Positioning Attribute;Prediction of Response to Therapy;Prognosis;Prognostic Marker;Prostate;Prostate-Specific Antigen;Prostatectomy;Proteins;Recommendation;Research;Research Personnel;Resources;Retrospective cohort;Risk;Screening for Prostate Cancer;Specificity;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Staging System;Students;Symptoms;System;Talents;Technology;Testing;Time;Training;Visualization;Work;anticancer research;cancer cell;cancer diagnosis;candidate selection;career;cell type;clinical decision-making;clinical imaging;clinical investigation;curative treatments;diagnostic biomarker;early detection biomarkers;genomic signature;histological slides;improved;innovation;male;mass spectrometric imaging;men;molecular imaging;mortality;novel diagnostics;overtreatment;patient stratification;predictive marker;predictive signature;prognostic;prognostic assays;prospective;prostate cancer progression;radiological imaging;radiomics;randomized trial;recruit;spectrograph;synergism;therapeutic biomarker;translational medicine;tumor;tumor progression Prognostic Radiomic Signatures in Prostate Cancer Patients on Active Surveillance PROJECT NARRATIVEProstate cancer is the second most common cancer diagnosed in males worldwide and a significant cause ofmorbidity and mortality. At this time there is a significant unmet need for identifying men at initial diagnosis whowill develop more aggressive disease possibly leading to symptoms metastases or death. This project proposesthe combination of clinically established prognostic biomarkers and radiomic signatures extracted from magneticresonance imaging of the prostate gland co-registered with diffusion basis spectrum imaging (DBSI) and matrix-assisted laser desorption ionization (MALDI) imaging to optimally select candidates for active surveillance frommales being assessed at initial diagnosis. NCI 10724101 9/11/23 0:00 PAR-21-301 1K22CA282357-01 1 K22 CA 282357 1 "VAHEDI, SHAHROOZ" 9/11/23 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 15253154 "LUNA CASTANEDA, JOSE MARCIO" Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/11/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 161100 NCI 150000 11100 PROJECT SUMMARY/ABSTRACTWith prostate cancer (PCa) being among the most common cancers in men worldwide (estimated 1600000cases 366000 deaths annually) the need for new biomarkers for early detection diagnosis monitoring andprognosis remains urgent. Among the available management alternatives for PCa active surveillance (AS) isrecommended as an initial treatment for males with very low- low- and favorable intermediate-risk. AS relies onserial monitoring over time to identify progression so that the patient receives timely curative treatment whilereducing morbidities related to definite treatment delivered at time of diagnosis. However identifying idealcandidates for AS is challenging. Despite its limited specificity the prostate-specific antigen (PSA) is the mostused test for early detection of PCa. Other factors based on biopsies such as the Gleason Group (GG) areaffected by limited biopsy sampling while the non-invasive magnetic resonance imaging (MRI) has beenconnected to false positives and false negatives. Finally the implementation of molecular prognostic tests suchas Decipher in AS populations has been limited due to the lack of randomized trials using actual AS patients.Previous work suggests that PCa progression can be dependent on the interactions between extracellular matrix(ECM) proteins in the stroma with various cell types including the immune system and cancer cells. On thisregard my team of collaborators has developed clinical imaging techniques such as diffusion basis spectrumimaging (DBSI) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry that visualizeinflammatory stromal/ECM and cancer cell components of the tumor that could be associated with cancerprogression. Therefore I propose to leverage radiomics a method based on data-characterization algorithms toextract imaging features to detect patterns in pre-op MRI with the guidance of DBSI and MALDI toward optimallyselecting AS candidates. My central hypothesis is that the spatial analysis of structural components in the ECMextracted from the co-registration of molecular and radiological imaging accurately predicts tumor upgradingand upstaging in PCa. In Aim 1 I will identify a baseline radiomic signature derived from pre-op MRI to accuratelypredict tumor upgrading (i.e. from GG1 to GG2 or higher) by augmenting well-established biomarkers (i.e. PSAGG Decipher) with an exploratory SubAim co-registering DBSI and MRI to improve the prediction. In Aim 2 Iwill use MALDI co-registered with pre-op MRI to guide the derivation of the radiomic signature to accuratelypredict tumor upstaging (i.e. from T1/T2 stage to T3 or higher). This research is innovative because to date nodistinct spatial signatures linked with the ECM and derived from co-registered molecular and radiological imaginghave been associated with prediction of tumor progression in PCa. Furthermore this K22 career transition awardwill provide me with the training and resources needed to advance my career as an independent researcher inthe field of data sciences applied to cancer research and also to support my goal of recruiting the nations mosttalented students from backgrounds nationally underrepresented in cancer research. 161100 +Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Health Services; Lung; Lung Cancer; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Prevention Data;Image;low dose computed tomography LOW-DOSE COMPUTED TOMOGRAPHY IMAGES AND CORRESPONDING DATA n/a NCI 10724040 91022A00691022F00001-0-0-1 N02 9/16/22 0:00 9/15/25 0:00 78868303 "FERNANDEZ, ANNA " Not Applicable 11 Unavailable 6928857 JCBMLGPE6Z71 6928857 JCBMLGPE6Z71 US 38.922512 -77.231057 682902 BOOZ ALLEN HAMILTON MC LEAN VA Domestic For-Profits 221023830 UNITED STATES N R and D Contracts 2022 6707503 NCI The National Lung Screening Trial (NLST) demonstrated a substantial reduction in lung cancer mortality in subjects screened with low-dose computerized tomography (LDCT) as compared to chest radiographs; however there was also a very high false positive rate (FPR) with the LDCT screens. The FPR was around 25% for the first two screening rounds and 16% in the final round. In addition to the high FPR there is a need for improvement in predicting risk among those with positive LDCT screens. In the NLST of those with positive LDCT screens who went on to lung biopsy about 40% did not have cancer. Conversely there is also the problem of diagnostic uncertainty leading to delay in proceeding to biopsy among those who do have lung cancer. Among 21% of the NLST subjects who were retrospectively determined to have had lung cancer present at the baseline LDCT scan it took over 18 months to diagnose the cancer. Therefore the assessment of whom among those with positive screens needs to proceed to biopsy and when has room for major improvement.The high FPR of LDCT lung cancer screening along with the limited ability in predicting risk levels has three major detrimental effects as follows: 1) it constitutes a significant harm to patients undergoing screening in terms of short-term anxiety increased radiation from follow-up CTs and the potential for complications from invasive diagnostic procedures 2) it contributes to increased health care costs and increased utilization of scarce health-care resources and 3) it serves to lower the uptake of LDCT screening due to the perceived and real burden of false positives on patients and health care providers. Therefore decreasing the FPR should serve to ameliorate these detrimental effects. Artificial intelligence (AI) is poised to transform medical imaging. In the past decade significant progress has been made in computer aided detection (CAD) to assist with cancer detection and diagnosis leading to a number of FDA-approved software tools. More recently efforts are focused on deep learning to develop more accurate and integrated tools that can replicate or out-perform medical professionals. It is anticipated that AI can substantially reduce the FPR of LDCT screening while minimally affecting test sensitivity thereby reducing diagnostic uncertainty. 6707503 +Cancer; Prevention; Tobacco; Tobacco Smoke and Health Contractor;Development;Literature;Monograph;Printing;Production;Research;Services;base;dissemination strategy;technical writing;tobacco control DEVELOPMENT PRODUCTION AND DISSEMINATION OF NCI TOBACCO CONTROL MONOGRAPHS n/a NCI 10724019 75N91022D00010-0-759102200002-1 N02 8/1/22 0:00 1/31/26 0:00 78832468 "KLEIN, AMANDA " Not Applicable Unavailable JP6YLTEYJLT5 JP6YLTEYJLT5 US -519575 WASHINGTON DC Other Domestic Non-Profits 200371542 UNITED STATES N R and D Contracts 2022 900000 NCI The overall objective of this Task Order is to provide services to support the development production and dissemination of up to 2 NCI Tobacco Control Monographs.The services to be provided by the Contractor involve a range of activities and include administrative support literature research technical writing and intellectual contribution to the production of the Monograph volumes. 900000 +Cancer; Prevention; Tobacco; Tobacco Smoke and Health Behavioral Research;Contractor;Division of Cancer Control and Population Sciences;Grant;Logistics;Persons;Preparation;Services;Tobacco Control Research;Writing;editorial;meetings;programs;symposium;tobacco regulatory science;virtual Tobacco Control Research Branch Scientific and Logistic Support Core Services n/a NCI 10724008 75N91022D00010-0-759102200001-1 N02 8/1/22 0:00 7/31/27 0:00 78832466 "KLEIN, AMANDA " Not Applicable Unavailable JP6YLTEYJLT5 JP6YLTEYJLT5 US -519575 WASHINGTON DC Other Domestic Non-Profits 200371542 UNITED STATES N R and D Contracts 2022 1000000 NCI The Contractor shall provide scientific and logistical support services to the Tobacco Control Research Branch (TCRB) and the Division of Cancer Control and Population Sciences (DCCPS) in the conduct of:1) scientific writing editorial and graphic services 2) project management to support completion of scientific projects 3) coordination of scientific conferences and meetings4) programmatic support for Tobacco Regulatory Science Program (TRSP) tasks and 5) programmatic support for behavioral research tasks. 1000000 +No NIH Category available American Cancer Society;Antiestrogen Therapy;Artificial Intelligence;Biological Assay;Biological Markers;Biopsy;Cancer Etiology;Cancer Prognosis;Cell Density;Cells;Cessation of life;Chicago;Clinical;Clinical Data;Clinical Research;Data;Databases;Diagnosis;Disease;Disparity;ERBB2 gene;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Goals;Guidelines;Hematoxylin and Eosin Staining Method;Histology;Hormone Receptor;Image;Image Analysis;Immune;Immunofluorescence Immunologic;Immunological Models;Immunology;Institution;Malignant Neoplasms;Modeling;Pathologic;Pathologist;Pathology;Patient Care;Patient Selection;Patients;Performance;Positioning Attribute;Prognosis;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Research Personnel;Resource-limited setting;Retrospective cohort;Risk;Sampling;Selection for Treatments;Stains;Techniques;Test Result;Testing;Time;Training;Tumor-Infiltrating Lymphocytes;United States;Universities;Validation;Woman;Work;biobank;biomarker validation;breast cancer diagnosis;cancer diagnosis;cancer prevention;cancer recurrence;cancer survival;career;chemotherapy;clinical implementation;clinical practice;clinical predictors;clinically relevant;cohort;combat;cost effective;cost effective treatment;data streams;deep learning;deep learning model;design;digital;digital pathology;experience;genomic biomarker;health care disparity;hormone receptor-positive;hormone therapy;implementation science;improved;individualized medicine;malignant breast neoplasm;model development;mortality;novel;participant enrollment;patient subsets;personalized medicine;predictive marker;prognostic;prognostic model;quantitative imaging;receptor expression;treatment response Integrating Clinical Pathologic and Immune Features to Predict Breast Cancer Recurrence and Chemotherapy Benefit Project NarrativeNearly one in eight women will develop a diagnosis of breast cancer over the course of their lifetime andselection of treatment is often based off a gene expression assay such as OncotypeDX. Deep learning canintegrate readily available clinical pathologic and immune features to predict recurrence and chemotherapybenefit resulting in more accurate faster and cost-effective treatment decisions. NCI 10723924 7/5/23 0:00 PA-20-203 1K08CA283261-01 1 K08 CA 283261 1 "BOULANGER-ESPEUT, CORINNE A" 7/7/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 16436053 "HOWARD, FREDERICK MATTHEW" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 201055 NCI 187588 13467 Abstract Breast cancer is the leading cause of cancer death for women globally with over 2.3 million casesdiagnosed each year. Most cases are hormone receptor positive and effectively treated with anti-estrogentherapy but some patients have aggressive disease and are at risk for recurrence and death withoutchemotherapy. Gene expression based recurrence assays such as OncotypeDX were designed to predictrecurrence on hormonal therapy and are used to select patients for chemotherapy. However these assays areexpensive (> $3000 per test) take considerable time to perform leading to treatment delays and testing isunderutilized or frankly unavailable in low resource settings in the US and globally. Conversely every patientwith breast cancer has a biopsy to confirm the diagnosis which is routinely analyzed by pathologist to determinesubtype of breast cancer and grade. Deep learning is an emerging technique for quantitative image analysisand can identify non-intuitive features from pathology including gene expression patterns. In preliminary work Ihave demonstrated that deep learning on pathology samples can provide rapid and cost-effective prediction ofOncotypeDX score using readily available data and can identify patients at low risk of recurrence on hormonaltherapy. However OncotypeDX remains an imperfect predictor of chemotherapy benefit as it was developed topredict recurrence on hormonal therapy. By refining my deep learning biomarker to incorporate clinical andimmune features of breast cancer I can improve accuracy in prediction of chemotherapy benefit and thus theability to personalize treatment. First I will capitalize on the recent expansion of clinical data in the NationalCancer Data Base to develop a more accurate clinical models of prognosis and chemotherapy benefit. Next Iwill use multiplex immunofluorescence to better characterize spatial and cell density features associated withchemotherapy benefit and use deep learning models to infer these features from standard hematoxylin andeosin stained digital pathology. Finally I will integrate these clinical and immune models with my existing deeplearning pathologic model and validate the integrated model in a multi-institutional cohort. The result of this workwill result in a prognostic and predictive deep learning biomarker that makes accurate predictions from readilyavailable clinical pathologic and inferred immune features. This approach has the potential to reducechemotherapy delays due to rapid turnaround time combat healthcare disparities through improved availabilityof testing and improve personalization of treatment by tailoring a biomarker for prediction of chemotherapybenefit. 201055 +Cancer; Pediatric; Pediatric Cancer; Rare Diseases NATIONAL CHILDHOOD CANCER REGISTRY (NCCR) n/a NCI 10723797 75N91021D00018-0-759102200001-1 N02 7/1/22 0:00 6/30/23 0:00 78754532 "KOHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2022 976000 NCI NATIONAL CHILDHOOD CANCER REGISTRY (NCCR) 976000 +Cancer Collaborations;Collection;Contractor;Ensure;Goals;Individual;Institution;Malignant Neoplasms;Medical;National Cancer Institute;Participant;Population;Research;Resources;Services;United States;biobank;data management;improved;recruit Biospecimen Core Resource (BCR) services n/a NCI 10723529 75N91022D00008-0-759102200001-1 N02 6/28/22 0:00 6/27/27 0:00 78751577 "JEWELL, SCOTT " Not Applicable 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N R and D Contracts 2022 7912119 NCI The contractor is responsible for establishing and maintaining a Biospecimen Core Resource (BCR) with biospecimen and data management services for the Cancer Moonshot Biobank (CMB) to facilitate research through collection and distribution of biospecimens from a diverse participant population recruited at multiple medical institutions throughout the United States. The services shall be provided in close collaboration with the National Cancer Institute (NCI) and other CMB stakeholders to manage this unique biospecimen resource so that longitudinal biospecimens from the same individual are appropriately collected tracked prioritized analyzed stored and distributed. Key goals include ensuring that standards are developed implemented continually improved and maintained for all aspects of cancer-related annotated biospecimen management and processing. 7912119 +No NIH Category available Adherence;Agreement;Anxiety;Award;Awareness;Benefits and Risks;Cancer Control;Cancer Etiology;Cardiopulmonary;Cessation of life;Characteristics;Clinic Visits;Clinical;Clinical Informatics;Comparison arm;Consumption;Critical Care;Data;Data Collection;Development;Education;Electronic Health Record;Electronics;Eligibility Determination;Enrollment;Ensure;Equity;Evaluation;Evidence based practice;Feedback;Fostering;Foundations;Funding;Future;Goals;Grant;Health Professional;Individual;Internet;Interview;Knowledge;Language;Lung;Malignant neoplasm of lung;Massachusetts;Measures;Medicare;Mentored Clinical Scientist Development Program;Mentors;Mentorship;Mission;Motivation;Patient Care;Patients;Physicians;Pilot Projects;Population;Practical Robust Implementation and Sustainability Model;Provider;Public Health Informatics;Quasi-experiment;Radiation exposure;Randomized;Recommendation;Research;Research Design;Rural Community;Sampling;Scientist;Smoking History;Statistical Data Interpretation;Structure;Surveys;System;Technology;Testing;Text Messaging;Time;Training;United States;United States National Institutes of Health;United States Preventative Services Task Force;Visit;Work;arm;automated text message;cancer prevention;clinical investigation;cognitive interview;design;experience;follow-up;health communication;health literacy;high risk population;implementation barriers;implementation science;implementation strategy;implementation study;improved;informant;innovation;low socioeconomic status;lung cancer prevention;lung cancer screening;mHealth;medical schools;mortality;pilot test;pragmatic trial;preference;primary care clinic;primary care provider;primary care setting;primary care visit;programs;shared decision making;skills;tool;treatment as usual;uptake;usability;user centered design Facilitation of Information Exchange for Shared Decision Making for Lung Cancer Screening PROJECT NARRATIVEShared decision making prior to lung cancer screening is recommended since lung cancer screening has bothbenefits and risks. However shared decision making rarely happens in primary care settings due to difficulty inidentifying lung cancer screening eligible patients lack of patient awareness lack of provider knowledge andlimited visit time. This pilot study will compare a multi-strategy technology-assisted implementation program tousual care on lung cancer screening uptake and will provide a foundation for a future large-scale pragmatictrial to improve the uptake of and longitudinal adherence to annual lung cancer screening by supporting shareddecision making. NCI 10723285 7/24/23 0:00 PA-20-202 1K08CA283304-01 1 K08 CA 283304 1 "RADAEV, SERGEY" 7/24/23 0:00 6/30/28 0:00 Career Development Study Section (J)[NCI-J] 15722369 "ITO FUKUNAGA, MAYUKO " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 7/24/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 229994 NCI 212957 17037 ABSTRACTI am a pulmonary critical care physician at the UMass Chan Medical School and a former scholar of theMassachusetts Consortium for Cardiopulmonary Implementation Science program funded by an NIH K12 award.My long-term goal is to be an implementation scientist with expertise in applying health informatics to promoteevidence-based practice in lung cancer prevention and control. During my K12 I completed a Masters in ClinicalInvestigation and received training in implementation science. However I still have gaps in my training and seekthis K08 award to obtain additional training and mentoring to become a successful independent clinician-scientist. Building upon the single patient strategy that I developed during my K12 project I propose to developand pilot test a multi-strategy implementation program called Facilitation of Information eXchange for SharedDecision Making (FIX-SDM) for Lung Cancer Screening for this K08. Although lung cancer screening isrecommended for high-risk individuals it is underutilized. The known barriers to lung cancer screening aredifficulty identifying lung cancer screening eligible patients lack of patient awareness lack of providerknowledge and need for shared decision making. Because lung cancer screening has both benefits and risksshared decision making is recommended. However shared decision making rarely happens in primary carevisits since patients and providers often lack the necessary information to conduct shared decision making duringthe time-constrained visit. FIX-SDM is a multi-strategy technology-assisted implementation program that isdesigned to support shared decision making and uptake of lung cancer screening by facilitating informationexchange in advance of patient visits. Using texting FIX-SDM will help patients prepare for shared decisionmaking by delivering the information collecting patient-generated data and providing feedback based on patient-generated data. Leveraging patient-generated data via texting FIX-SDM will provide the information and toolsthat primary care providers (PCPs) need for shared decision making in the EHR. During this K08 I will developthe new patient strategies in Aim 1 and the PCP strategies in Aim 2. In Aim 3 I will integrate both patient andPCP strategies of FIX-SDM into the workflow of primary care clinics and conduct a pilot implementation studycomparing FIX-SDM and usual care of lung cancer screening uptake. Under the experienced mentorship of Drs.Mazor Houston Wiener Sadasivam and Crawford I will carry out the proposed research plan in consort witha structured training plan focusing on mHealth clinical informatics patient-generated data user-centered designhealth communication study design and statistical and qualitative analysis. At the end of the K08 award I willbe poised to successfully compete for a R01 to conduct a large-scale pragmatic trial of FIX-SDM for LCS toimprove the uptake of and longitudinal adherence to annual lung cancer screening. My overall research goalsalign with NCIs mission to foster rapid integration of evidenced based practices in cancer prevention and control. 229994 +No NIH Category available Ablation;Acceleration;Active Learning;Advisory Committees;Antibiotics;Area;Bacteria;Basic Science;Biological Assay;Biological Models;Cancer Biology;Cell Communication;Cell Proliferation;Cell physiology;Cells;Coculture Techniques;Combined Modality Therapy;Culture Techniques;Cytometry;Data;Development;Development Plans;Diagnosis;Disease;Doctor of Philosophy;Environment;Epithelial Cells;Epithelium;Event;Fibroblasts;Gastrointestinal tract structure;Gnotobiotic;Goals;Human;Hypoxia;Image;Immune;Immunity;Immunofluorescence Immunologic;Immunohistochemistry;Immunosuppression;Immunotherapy;In Vitro;Inflammatory;Inflammatory Response;Knock-out;Knowledge;Label;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mediating;Mentors;Metabolic;Microbe;Microbiology;Modeling;Mus;Organoids;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pathogenicity;Pathologic;Patients;Phenotype;Production;Proliferating;Proteobacteria;Research;Research Personnel;Signal Transduction;Stromal Cells;System;TLR4 gene;Testing;Therapeutic;Time;Training;Transgenic Organisms;Tumor Promotion;Tumor-infiltrating immune cells;Up-Regulation;Work;advanced disease;cancer cell;cancer initiation;carcinogenesis;career development;cytokine;dysbiosis;experience;experimental study;gut bacteria;gut microbiome;immune cell infiltrate;improved;in vitro Model;in vivo;insight;interest;melanoma;member;microbial;microbiome;microbiome composition;mouse model;neoplastic cell;novel;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;pathogenic bacteria;recruit;screening;single-cell RNA sequencing;survival outcome;transcriptome sequencing;tumor;tumor growth;tumor microbiome;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Microbial Dysbiosis in Pancreatic Cancer Initiation and Progression Project NarrativeThe tumor-associated microbiome regulates pancreatic cancer progression but the exactmechanisms via which bacteria regulate tumorigenesis is still unknown. The proposed work will(1) determine the influence of tumor-associated bacteria on pancreatic cancer cells (2) determinetheir ability to activate and differentiate pancreatic stromal cells and (3) characterize themechanisms of pathogenicity unique to pancreatic cancer-associated bacteria. Knowledgegained from our proposed experiments will provide insight into therapeutic strategies for gutmicrobial modulation in treating pancreatic cancer. NCI 10723251 7/25/23 0:00 PAR-21-300 1K08CA282374-01 1 K08 CA 282374 1 "RODRIGUEZ, LARITZA MARIA" 8/1/23 0:00 7/31/28 0:00 Career Development Study Section (J)[NCI-J] 16491248 "DALEY, DONNELE " Not Applicable 6 SURGERY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 280670 NCI 259880 20790 Project SummaryPancreatic adenocarcinoma is a devastating disease with a five-year survival of only 10%. The rise ofimmunotherapy has led to breakthrough treatments in many cancers like melanoma drastically improvingsurvival outcomes. However unlike malignant melanoma we have seen minimal changes in survival forpancreatic cancer because we still do not completely understand the regulators of immunity in this disease.Bacterial dysbiosis is emerging as an accomplice to carcinogenesis and is associated with pancreaticcancer progression and poorer survival. We found that gut bacteria can directly access the pancreas andpancreatic tumors harbor a unique microbiome. The tumor-associated microbiome regulates pancreaticcancer progression by skewing tumor-infiltrating immune cells towards an immunosuppressive phenotype.However the exact mechanisms via which bacteria regulate immune cell function is still unknown.Inflammatory signaling in cancer cells and stromal cells in the tumor microenvironment has been shown togreatly regulate the immune cell infiltrate in pancreatic cancer. Our preliminary data suggests thatpathogenic bacteria can directly interact with pancreatic epithelial cells inducing proliferation and aninflammatory response. Furthermore we found that the presence of bacteria in tumors skews fibroblastdifferentiation towards an inflammatory tumor-promoting phenotype. In this proposal we seek todetermine how tumor-associated bacteria modulate the epithelial and stromal compartments in thepancreatic tumor microenvironment thereby aiding their ability to promote pancreatic cancer progression.The overall goal of this application is to support my continued training and development to become anindependent investigator in microbiology and pancreas cancer biology. The career development plan isbased on formal didactic coursework experiential learning and mentored basic science training. I havereceived generous support and protected time from my department and will work closely with my mentorDr. Marina Pasca di Magliano PhD a respected and experienced pancreatic cancer biologist. I have alsoconstructed an advisory committee with expertise in microbiology and bacteria-host interaction to furthermy microbiology training while completing this project. The major themes of my research interests arereflected in the Specific Aims of this proposal: (1) to determine the influence of tumor-associated bacteriaon pancreatic cancer cells (2) to determine their ability to activate and differentiate pancreatic stromal cellsand (3) to further characterize the mechanisms of pathogenicity unique to pancreatic cancer-associatedbacteria. Successful completion of these proposed experiments will delineate the mechanisms via whichmicrobes interface with non-immune cells in the tumor microenvironment and provide insight intotherapeutic strategies for gut microbial modulation in treating pancreatic cancer. 280670 +Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome Attention;Automation;Biological;Buffers;Cell Count;Cell Line;Cell Separation;Cell Size;Cells;Centrifugation;Clinical;Collaborations;Data;Development;Digestion;Dissociation;Enzymes;Erythrocytes;Expression Library;Filtration;Freezing;Gel;Gene Expression;Genomics;Goals;Hour;Human;Image;Individual;Intervention;Libraries;Liquid substance;Liver;Manuals;Modification;Monitor;Mus;Organ;Pancreas;Pathology;Performance;Phase;Preparation;Procedures;Process;Protocols documentation;Reagent;Recovery;Residual state;Resort;Retrieval;Running;Sampling;Selection Criteria;Small Business Innovation Research Grant;Solid;Source;Technology;Testing;Time;Tissues;Tube;Tumor Tissue;Validation;Variant;base;cell fixing;digital;experimental study;gene expression variation;gene panel;human tissue;image guided;improved;multiple omics;operation;protocol development;transcriptome;transcriptome sequencing;tumor SBIR TOPIC 439 - ADVANCED SAMPLE PROCESSING PLATFORMS FOR DOWNSTREAM SINGLE-CELL MULTI-OMIC ANALYSIS n/a NCI 10723179 75N91022C00062-0-9999-1 N43 9/19/22 0:00 9/18/23 0:00 78873878 "BISOGNI, ADAM " Not Applicable 19 Unavailable 81267157 VBDURZTP43R3 81267157 VBDURZTP43R3 US 35.22494 -111.603636 10051810 INSO BIOSCIENCES INC Ithaca NY Domestic For-Profits 148537202 UNITED STATES N R and D Contracts 2022 399674 NCI Single cell purifications are usually needed for most single cell multiomics platforms. Unwanted cells such as dead cells doublet or residual red blood cells will greatly reduce the effective data. Sample preparation of solid tissues into viable non-red blood cells consists of three major steps: tissue dissociation clump/debris filtration and single cells purification.Improvements been made to individual steps to enhance efficiency and reduce time. Though each step can be individually optimized to high completeness and efficiency extensive pipetting and centrifugation operations are still required to bridge most if not all three steps. Therefore the multistep loosely monitored attention-intensive process normally takes much longer in practice and the material loss during the whole process can be rather high (from 10^8 to 10^4 -10^6 or99%- 99.99%). Using Enrich TroVo technology we believe eliminating intermediate steps while keeping all material in one place is a more effective strategy than improving the efficiency of individual steps. And we found the key of eliminating intermediate steps is to enhance the overall debris tolerance of the cell sorting process and to combine multiple purification goals into one single isolation step. Using image guided digital filter multiple selection criteria such as viability singularity cell size can be combined into one composite filter and directly applied to a complicated mixtureof tissue digests. The purpose of this proposed project is to further specialize such image-based technology into a highthroughput application ready product. With the newly forged collaboration with Yale pathology Enrich will be able to validate this platform using multiple clinical samples. 399674 +No NIH Category available Ablation;Adult;Aggressive Clinical Course;BRCA1 gene;Biology;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Candidate Disease Gene;Cell Transplantation;Cells;Chromatin;Complement 3a;DNA Binding;Data;Data Analyses;Development;Embryo;Embryonic Development;Enhancers;Environment;Epithelial Cells;Epithelium;Future;Gene Expression;Genes;Genetic;Genetic Engineering;Genetic Transcription;Gland;Goals;Heterogeneity;Homeostasis;Human;Hyperplasia;Lesion;Literature;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Maps;Medicine;Mentorship;Modeling;Molecular;Multipotent Stem Cells;Mus;Mutation;Oncogenic;Paper;Pathway interactions;Physicians;Population;Precancerous Conditions;Predisposition;Prevalence;Process;Prognosis;Proliferating;RNA;Research;Resolution;Role;Scientist;TP53 gene;Testing;Therapeutic;Training;Transcription Factor AP-1;Transitional Cell;Transplantation;Tumor Promotion;Tumor Suppressor Proteins;Undifferentiated;Up-Regulation;Women's Health;Work;cancer subtypes;college;effective therapy;experimental study;follow-up;gene regulatory network;improved;in vivo;malignant breast neoplasm;mammary;mortality;mouse model;novel;premalignant;progenitor;single-cell RNA sequencing;skills;stem cell biology;stem cells;synergism;targeted treatment;therapy resistant;triple-negative invasive breast carcinoma;tumor;tumor heterogeneity;tumor progression;tumorigenesis The Role of Dedifferentiation in Basal like Breast Cancer PROJECT NARRATIVEGiven the prevalence and disproportionate mortality associated with Basal-like Breast Cancer(BLBC) compared to other breast cancer subtypes investigating its biology is of paramountimportance to womens health. This proposal investigates the BLBC founder cell and theaberrant dedifferentiation that promotes cellular plasticity and treatment resistance. Findingsfrom these studies will enhance our understanding of gene regulatory networks responsible formultipotency reactivation in the adult mammary gland and could lead to advancements in thetreatment of highly plastic malignancies. NCI 10723094 9/8/23 0:00 PA-21-052 5F31CA271757-02 5 F31 CA 271757 2 "DIBELLO, ANTHONY THOMAS" 9/28/22 0:00 9/27/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15581405 "LARIOS-VALENCIA, JESSIE " Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 9/28/23 0:00 9/27/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 ABSTRACTThe adult mammary gland is maintained by unipotent progenitor populations which are derivedfrom multipotent stem cells exclusive to embryonic development. The emergence of multipotencycaused by oncogenic mutations in adult glands is a common process in malignant breast cancertransformation that enables cellular plasticity and promotes tumor heterogeneity. Although theseprocesses pose immense therapeutic challenges for aggressive undifferentiated breast cancerssuch as Basal-like Breast Cancer (BLBC) the most common Triple Negative Breast Cancer(TNBC) the mechanisms underlying cellular plasticity in the adult mammary gland remain poorlyunderstood. The BLBC founder cell (BFC) is likely of the ER- luminal lineage as suggested bymultiple groups however concrete evidence to prove this notion is lacking. In this proposal weseek to identify and characterize the BFC and to uncover mechanisms responsible formultipotency reactivation in these cells. We hypothesize that a transformation competentunipotent luminal progenitor acquires multipotency through a conserved pathway or gives rise tomultipotent progeny that undergo stepwise reprogramming essential for BLBC tumor progression.To test this hypothesis I have performed single cell RNA sequencing of hyperplastic mammaryglands in the C3/Tag BLBC mouse tumor model to (1) establish candidate BFC populations byintegrating epithelial clustering data with RNA velocity and pseudotemporal analysis of cellpopulations (2) determine the role of suspected BFC clusters in mammary gland and tumordevelopment and finally (3) identify the molecular determinants of dedifferentiation in the BFC.Findings from the analysis of this data and from follow up lineage tracing experiments will revealthe BFC in the highest resolution to date as well as pathways involved in its transformation andsubsequent dedifferentiation. A detailed understanding of aberrant dedifferentiation in BLBC maybe useful for improving the state of current and future BLBC treatments and for treatment of otheraggressive cancers that employ cellular plasticity for treatment resistance and evasion. Under theproven mentorship and expertise of Dr. Wenjun Guo I will execute the research and training planoutlined in this proposal. This combined with the training environment provided by the AlbertEinstein College of Medicine will allow me to contribute to the fields of breast cancer and stemcell biology and to develop the research and professional skills necessary to become anindependent physician-scientist. 52694 +No NIH Category available ARID Domain;ATAC-seq;Affect;American;Androgen Antagonists;Androgen Receptor;Area;Cancer Etiology;Cells;Cessation of life;ChIP-seq;Chromatin;Chromatin Remodeling Factor;Cytokine Gene;Cytokine Signaling;DNA Binding Domain;Data;Down-Regulation;Epigenetic Process;Epithelium;Exhibits;Flow Cytometry;Gene Expression;Genes;Genetically Engineered Mouse;Human;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunofluorescence Immunologic;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Induced Mutation;Infiltration;Inflammation;Inflammatory;Interleukin-8;Investigation;Knock-out;Ligands;Longevity;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maps;Mediating;Mesenchymal;Metastatic Prostate Cancer;Molecular;Mutate;Mutation;Myeloid-derived suppressor cells;Nature;Neoplasm Metastasis;Neuroendocrine Prostate Cancer;Neurosecretory Systems;Operative Surgical Procedures;Pathway interactions;Patient Care;Patients;Point Mutation;Primary Neoplasm;Prostate;Proteins;Quantitative Reverse Transcriptase PCR;Radiation;Regulation;Reporting;Repression;Resistance;Role;Sampling;Shapes;Signal Induction;Signal Transduction;Site;Testing;Tissues;Transforming Growth Factor Beta 2;Tumor Promotion;Tumor-associated macrophages;advanced prostate cancer;androgen deprivation therapy;anti-tumor immune response;cancer diagnosis;castration resistant prostate cancer;cell motility;chemokine;cytokine;design;forkhead protein;gene repression;genetic corepressor;histone modification;immune cell infiltrate;improved;inhibitor;interest;knock-down;loss of function;male;mouse model;mutant;next generation;overexpression;programs;prostate cancer cell;prostate cancer progression;recruit;replication factor C;response;single-cell RNA sequencing;transcription factor;transcriptome sequencing;transforming growth factor beta3;tumor;tumor-immune system interactions FOXA1 loss-of-function induces inflammatory cytokine signaling and immune suppression in prostate cancer PROJECT NARRATIVEEpithelial pioneer transcription factor FOXA1 (Forkhead Box A1) is frequently mutated or downregulated inadvanced prostate cancer. While previous studies have established FOXA1 functions in repressing epithelial-mesenchymal transition metastasis and neuroendocrine de-differentiation the role of FOXA1 in regulating thetumor immune microenvironment is poorly understood. The objectives of this project are to study the roles ofFOXA1 loss or mutations in inducing tumor infiltration by immunosuppressive cells and elucidate the underlyingmolecular mechanisms in order to identify vulnerabilities that can be targeted to improve prostate cancer patientcare. NCI 10723093 8/17/23 0:00 PA-21-052 5F31CA271826-02 5 F31 CA 271826 2 "DIBELLO, ANTHONY THOMAS" 9/9/22 0:00 9/8/24 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 77837437 "BREA, LOURDES " Not Applicable 5 RADIATION-DIAGNOSTIC/ONCOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/9/23 0:00 9/8/24 0:00 398 "Training, Individual" 2023 42907 NCI 42907 0 PROJECT SUMMARY/ABSTRACT Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancerdeath in American males. Androgen deprivation therapies extend patient lifespan but can result in progressionto castration resistant prostate cancer (CRPC). Moreover treatment with next generation antiandrogens oftenresults in further resistance and differentiation to neuroendocrine prostate cancer. Recently immunotherapiessuch as immune checkpoint inhibitors have become an area of much interest. However CRPC has shown apoor response to immune checkpoint inhibitors due to its immunosuppressive nature. Thus we need a betterunderstanding of how genetic alterations commonly seen in advanced PCa shape the tumor immunemicroenvironment (TIME) in order to inform the design of better-targeted immunotherapeutic approaches. Wehere propose to investigate the role of epithelial transcription factor Forkhead Box A1 (FOXA1) in regulating theTIME in PCa. FOXA1 is found to be downregulated in CRPC and is among the most highly mutated genes inPCa. In accordance we have previously shown that FOXA1 loss or mutation induces epithelial-mesenchymaltransition and metastasis. However whether FOXA1 loss-of-function induces an immunosuppressive TIMEin PCa remains poorly understood. In preliminary studies we noticed that inflammatory cytokines such asCCL2 TGFB3 and IL8 which are associated with recruitment of immunosuppressive myeloid derivedsuppressor cells and tumor-associated macrophages were among the most highly upregulated genes uponFOXA1 depletion or mutation. In our investigation of the mechanism by which FOXA1 represses the expressionof inflammatory cytokines we identified ARID1A as a FOXA1 co-repressor. Notably we found FOXA1 andARID1A proteins interacted and exhibited extensive co-occupancy on the chromatin in PCa cells. MoreoverARID1A repressed genes were also enriched for inflammatory pathways. Thus we hypothesize that FOXA1loss or mutation in PCa unleashes ARID1A and induces epigenetic reprogramming and inflammatorycytokine signaling thereby promoting an immunosuppressive tumor microenvironment and PCaprogression. We here propose to: (1) decipher the molecular mechanisms by which wild type and mutantFOXA1 regulate inflammatory cytokine signaling and (2) determine the extent to which FOXA1 loss or mutationinduces an immunosuppressive tumor microenvironment in PCa. 42907 +No NIH Category available Acinar Cell;Address;Adult;B cell differentiation;B-Lymphocytes;Beta Cell;Binding;Cancer Biology;Cancer Etiology;Cells;Cessation of life;Cholecystokinin;Clustered Regularly Interspaced Short Palindromic Repeats;Computer software;Data;Dependovirus;Development;Developmental Biology;Disease;Duct (organ) structure;Educational workshop;Endocrine;Endocrinology;Environment;Exhibits;Exocrine pancreas;Gene Expression;Generations;Genetic;Genetic Models;Genetic Transcription;Goals;High Fat Diet;Hormones;Human;Immunofluorescence Immunologic;In Vitro;Insulin;Intercept;Islet Cell;Islets of Langerhans;KRAS oncogenesis;Label;Lead;Malignant neoplasm of pancreas;Mentors;Mentorship;Methods;Modeling;Molecular;Mus;Nerve Growth Factors;Neuropeptides;Non obese;Obese Mice;Obesity;Pancreatic Ductal Adenocarcinoma;Pancreatic Injury;Physiological;Play;Preparation;Prevalence;Proliferation Marker;Quantitative Reverse Transcriptase PCR;RNA Interference;Regulator Genes;Research;Resources;Risk;Risk Factors;Role;Scientist;Signal Transduction;Source;Specific qualifier value;Survival Rate;Tamoxifen;Technical Expertise;Testing;Training;Transcription Repressor;Tumor Burden;United States;Up-Regulation;Viral;Work;cDNA Expression;cDNA delivery;career;chromatin immunoprecipitation;computerized tools;congenic;epidemiology study;experimental study;gain of function;gene repression;genetic manipulation;hormonal signals;in silico;in vivo;insulinoma;islet;islet amyloid polypeptide;knock-down;loss of function;mouse model;multidisciplinary;novel;overexpression;pancreatic cancer model;pancreatic ductal adenocarcinoma model;pancreatic tumorigenesis;prevent;promoter;receptor;response;single-cell RNA sequencing;skills;small hairpin RNA;symposium;transcription factor;transcriptome sequencing;transdifferentiation;tumor initiation;tumor progression;tumorigenesis;tumorigenic Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer PROJECT NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the UnitedStates with a 5-year survival rate of 10%. Despite the rapid rise in the nationwide prevalence of obesity amajor risk factor for PDAC how obesity drives PDAC progression is not known. In this project we seek todefine the mechanisms by which obesity promotes pro-tumorigenic hormone expression in the endocrinepancreas to elucidate targets for the development of novel PDAC therapies. NCI 10723092 9/1/23 0:00 PA-21-052 5F31CA268845-02 5 F31 CA 268845 2 "DIBELLO, ANTHONY THOMAS" 9/30/22 0:00 9/29/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16134066 "GARCIA, CATHY " Not Applicable 3 GENETICS 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/30/23 0:00 9/29/24 0:00 398 "Training, Individual" 2023 32612 NCI 32612 0 PROJECT SUMMARY/ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death and soon tobecome the second in the next few years. Numerous epidemiologic studies have shown that obesity increasesthe risk of developing and dying of PDAC. Given the rise in worldwide obesity rates a better understanding ofthe mechanisms by which obesity promotes PDAC progression is necessary. To study how obesity drives PDACour lab recently combined a well-established genetic model of obesity with an oncogenic Kras-driven pancreaticcancer model and showed increased tumor burden and decreased survival compared to non-obese controls.Obese mice exhibited aberrant expression of the neuropeptide hormone cholecystokinin (CCK) in pancreaticislet beta (b) cells the latter of which was sufficient to enhance Kras-driven pancreatic tumorigenesis. Theseresults uncovered a novel mechanism of obesity-driven PDAC by local hormonal signaling between endocrineislets and exocrine acinar cells. Therefore my overall goal is to elucidate the cellular and molecularmechanisms by which islets adapt in response to obesity and in turn promote PDAC progressionthrough endocrine-exocrine hormonal signaling. In Aim I I will perform lineage tracing studies in vivo and insilico to identify the cell-of-origin that gives rise to b cells mis-expressing hormones such as CCK. In Aim II Iwill determine whether loss of transcription factors required for b cell identify lead to aberrant hormone expressionin mouse insulinoma (insulin-producing) cells and primary human b cells using genetic knockdown experimentsand chromatin immunoprecipitation. Lastly in Aim III I will perform in vivo gain-of-function and loss-of-functionexperiments using islet specific gene manipulation by adeno-associated viruses to evaluate the pro-tumorigenicpotential of hormones beyond CCK that are overexpressed in b cells in obesity. Together these studies willreveal novel endocrine adaptations that could be targeted to halt obesity-driven pancreatic exocrinetumorigenesis. In addition through the acquisition of new technical skills in this project extensive mentorship(from her sponsor co-sponsor and collaborators) interactions within an outstanding scientific environmentparticipating in advanced classes and workshops and attendance and presentation at conferences andseminars the comprehensive training plan will markedly broaden the applicants skillset in preparation to be asuccessful independent research scientist. 32612 +No NIH Category available Adoptive Transfer;Adult;Animals;Bioenergetics;Brain Neoplasms;CAR T cell therapy;Cell Line;Cells;Cellular Metabolic Process;Central Nervous System;Characteristics;Child;Clinical;Clinical Trials;Consumption;Disease;Engineering;Environment;Evaluation;GLUT-3 protein;Glioblastoma;Glioma;Glucose;Glucose Transporter;Glycolysis;Goals;Human;Immune;Immune Evasion;Immune System Diseases;Immune response;Immune system;Immunotherapeutic agent;Immunotherapy;Infiltration;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of brain;Metabolic;Metabolic Pathway;Metabolism;Methods;Modeling;Mutant Strains Mice;NF1 gene;Nature;Nutrient;Nutrient availability;Pathway interactions;Patients;Phenotype;Proliferating;Protein Isoforms;Regulation;Reporting;Resistance;Role;SLC2A1 gene;Safety;Solid Neoplasm;Surveys;Survival Rate;T cell therapy;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Tumor Immunity;Tumor-infiltrating immune cells;aerobic glycolysis;cancer cell;cancer immunotherapy;cancer therapy;cancer type;chimeric antigen receptor;chimeric antigen receptor T cells;clinical application;design;effector T cell;engineered T cells;experience;flexibility;glucose metabolism;improved;in vivo;innovation;interest;metabolic engineering;metabolic fitness;mouse model;neoplastic cell;overexpression;pressure;prognostic;programs;restraint;success;therapy resistant;thymocyte;tumor;tumor microenvironment;uptake Optimizing CAR T therapy via metabolic engineering for thetreatment of GBM NARRATIVEThe metabolic switch observed in GBM leads to increased glycolysis in tumor cells and impacts the tumormicroenvironment which in turn acts as a major barrier for successful targeting of cancer by anti-tumor immunecells like T cells. The tremendous increase in tumor glucose consumption imposes a great metabolic pressureon T cells which experience glucose restriction. The overarching goal of this project is to manipulate themetabolic fitness of chimeric antigen receptor (CAR) modified T cells to ameliorate their tumoricidal activity inthe context of immunotherapy to treat GBM NCI 10722922 7/5/23 0:00 PAR-22-216 1R21CA282979-01 1 R21 CA 282979 1 "SINGH, ANJU" 7/5/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 10520176 "DELEYROLLE, LOIC PIERRE" Not Applicable 3 NEUROSURGERY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 7/5/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 178234 NCI 116875 61359 PROJECT SUMMARY AND ABSTRACTSignificance: Glioblastoma (GBM) is an extremely devastating disease with reported median survivals rangingfrom 13 to 73 months and 5-year survivals of less than 20% in children and about 15 months with less than 5%5-year survival rate for adult patients. Cancer immunotherapy using chimeric antigen receptor (CAR) modified Tcells is a promising treatment however its efficacy in GBM has been limited.Hypothesis: We hypothesize that the fierce competition for nutrients within the tumor microenvironmentespecially glucose between tumor cells and the immune system imposes an abundant metabolic pressure toCAR T cells dampening their effector function and intratumoral infiltration expansion and persistence.Objective: The goal of this study is to validate a new strategy to overcome this metabolic imbalance and providea competitive advantage to CAR T cells over tumor cells. We propose to improve CAR T cell therapy byenhancing metabolic fitness to outcompete GBM cells for nutrients like glucose.Methods: Our approach will be to directly target the first step of glucose metabolism (i.e. uptake) by permanentoverexpression of GLUT1 or GLUT3 and generating the following CAR T cells: CD70CAR.G1 and CD70CAR.G3.The murine model of glioma KR158B derived from Nf1;Trp53 mutant mouse that we engineered to expressCD70 as well as CD70 expressing human GBM patient-derived cell lines will be used for the following aims:Specific Aims 1. Investigate the phenotypic and functional characteristics of metabolically modified CD70CAR T cells 2. Evaluate in vivo the metabolic TME of animals treated with CD70CAR.G1 or CD70CAR.G3 3. Examine the safety and anti-tumor efficacy of CD70CAR.G1 or CD70CAR.G3. 178234 +No NIH Category available Antidiabetic Drugs;Blood Glucose;Body Weight;Body Weight Changes;Body Weight decreased;Body mass index;Cachexia;Cancer Etiology;Cessation of life;Clinical;Comparative Effectiveness Research;Continuous Glucose Monitor;Dangerousness;Data;Desire for food;Diabetes Mellitus;Diagnosis;Disadvantaged;Drug Exposure;Drug usage;Effectiveness;Electronic Health Record;Enrollment;Equilibrium;Genetic;Glipizide;Glucose;Histology;Hyperglycemia;Hypoglycemia;Inflammation;Insulin;Intervention;Knowledge;Laboratories;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Malnutrition;Measurement;Measures;Metabolic;Metformin;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Phase III Clinical Trials;Placebos;Population;Probability;Production;Property;Publishing;Quality of life;Randomized;Recording of previous events;Research;Research Proposals;Resistance;Retrospective cohort study;Sample Size;Subgroup;Sulfonylurea Compounds;Supportive care;Survival Rate;Systemic Therapy;Testing;Time;Translating;United States;Weight Gain;anticancer treatment;arm;blood glucose regulation;clinical practice;comparative effectiveness;effectiveness outcome;electronic structure;experience;gastrointestinal;healthy weight;improved;improved outcome;mortality;neglect;prevent;randomized trial;repaired;safety assessment;safety outcomes;secondary analysis;side effect;tool;tumor progression;weight maintenance Managing metabolic disruption in pancreatic cancer to prevent weight loss and improve quality of life NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer death in the United States with60 000 cases diagnosed annually and five-year survival rate of only 10%; patients with PDAC very commonlydevelop diabetes (high blood sugar) and rapid weight loss. Some drugs that can be used to treat diabetes inPDAC notably sulfonylureas may be particularly effective in controlling blood sugar and preventing weight loss;however sulfonylureas can also cause dangerously low blood sugar. We will compare sulfonylureas to the mostcommonly used drug for diabetesmetforminto assess whether sulfonylureas can safely be used to controlblood sugar levels and prevent weight loss in patients with PDAC. NCI 10722888 7/21/23 0:00 PAR-22-216 1R21CA277464-01A1 1 R21 CA 277464 1 A1 "ROSS, SHARON A" 8/1/23 0:00 6/30/25 0:00 ZCA1-RPRB-T(M1) 10081258 "FLORY, JAMES H" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 248243 NCI 140250 107993 PROJECT SUMMARYPancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer death in the United States with60 000 cases diagnosed annually and five-year survival rate of only 10%. It is projected to become the second-leading cause of cancer-related mortality by 2030. PDAC is also associated with poor quality of life (QOL)including cachexia in approximately 80% of patients. Cachexia is a contributing cause to 30% of deaths in PDACand has no approved pharmacologic treatment. PDAC is also strongly associated with hyperglycemia. Half ofpatients have diabetes at the time of diagnosis and 80% experience hyperglycemia during treatment; theassociation is likely bi-directional meaning that there is both evidence that diabetes causes PDAC and thatPDAC causes diabetes. As a result many patients with PDAC must use antidiabetic drugs such as metforminsulfonylureas or insulin. Hyperglycemia management during PDAC is an important aspect of supportive carewith direct implications for QOL. Comparative effectiveness research on hyperglycemia management in PDACis almost certain to improve supportive care by identifying which drugs best balance glucose control side effectsand maintenance of healthy weight. This need for evidence in this specific population is especially pressingbecause the usual hierarchy of diabetes drugs may be inverted in PDAC patients. For example prescribersdeprecate sulfonylureas in routine diabetes practice in part because they promote weight gain but that propertycould make them especially useful in patients with PDAC. Very little research has been done comparingsulfonylureas to metformin (the most widely used antidiabetic drug) or other alternatives as a supportive careintervention in PDAC. This proposal aims to close this evidence gap by in Aim 1 conducting a retrospectivecohort study testing the hypothesis that compared to metformin sulfonylureas are associated with better weightmaintenance in patients with PDAC and in Aim 2 enrolling 40 patients with hyperglycemia undergoing systemictreatment for PDAC in a trial assessing the safety of glipizide a sulfonylurea with respect to the key safetyoutcome of rate of hypoglycemia and the key effectiveness outcome of reducing blood glucose levels. Thisproject will lay the groundwork for phase 3 clinical trials to determine whether choice of antidiabetic drug canimprove QOL and even overall survival in patients with PDAC. 248243 +No NIH Category available Automobile Driving;Binding;Biological;Biopsy;Blood specimen;Bypass;Cell Nucleus;Cells;Clinical;Clinical Oncology;Clinical Trials;Combination immunotherapy;Coupled;Data;Double-Stranded RNA;Fibroblasts;Human;Immune response;Immunity;Immunofluorescence Immunologic;Immunologic Adjuvants;Immunologics;Immunosuppression;Immunotherapy;In Situ;Inflammatory;Inflammatory Response;Influenza;Informatics;Innate Immune Response;Interferon Type I;Left;Malignant - descriptor;Malignant Neoplasms;Metastatic Melanoma;Metastatic/Recurrent;Mind;Myeloid-derived suppressor cells;Natural Killer Cells;Neoadjuvant Therapy;Nivolumab;Nuclear;Nuclear Protein;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Pre-Clinical Model;Proteins;RIPK3 gene;RNA;RNA Binding;Refractory;Resistance;Safety;Signal Transduction;Solid Neoplasm;T cell infiltration;Testing;Tissue Sample;Tumor Antigens;Validation;Viral;Virus;Virus Diseases;Virus Replication;Work;Z-Form DNA;anti-cancer;anti-tumor immune response;cancer clinical trial;cancer immunotherapy;cell type;experience;feasibility trial;immune checkpoint blockade;immunogenic;immunogenicity;influenza infection;influenzavirus;insight;intravenous administration;ipilimumab;melanoma;mimetics;mouse model;novel;response;sensor;small molecule;synergism;transcriptomics;translational oncology;tumor;tumor microenvironment;tumor-immune system interactions;viral detection A Phase I Proof-of-Concept Study of CBL0137 Combined with Ipilimumab and Nivolumab Therapy in Locally Advanced or Metastatic Melanoma PROJECT NARRATIVEThis proposal will test the ability of CBL0137 to induce Z-DNA formation in advanced and metastatic melanoma.This effect of CBL0137 as of a virus mimetic is predicted to activate nuclear necroptosis via the ZBP1-RIPK3-MLKL signaling cascade in melanoma TME and synergize with immunotherapy. We will therefore clinicallyvalidate an entirely new concept for making immunologically cold tumors hot with a broader reach toimmunotherapy-refractory human cancers. NCI 10722873 6/14/23 0:00 PAR-22-216 1R21CA277402-01A1 1 R21 CA 277402 1 A1 "SONG, MIN-KYUNG H" 7/1/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 10639342 "ASTSATUROV, IGOR " "OLSZANSKI, ANTHONY J." 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 263670 NCI 140250 123420 PROJECT SUMMARY/ABSTRACTThis proposal will investigate a novel small-molecule strategy as a means to activate necroptosis overcome theimmunosuppressive tumor microenvironment (TME) and rekindle immune checkpoint blockade (ICB)responsiveness of human solid tumors. Our recent work with influenza virus (IAV) has outlined a new pathwayof nuclear necroptosis. Nuclear necroptosis during IAV infections is initiated when the host sensor protein ZBP1detects viral Z-RNA (left-handed dsRNA) and triggers RIPK3-dependent necroptosis from the nucleus releasingnuclear danger signals (DAMPs and alarmins) and driving a potent inflammatory response. But what isdeleterious in severe influenza may be beneficial for cancer immunotherapy because triggering inflammatorynuclear necroptosis in the TME is an attractive way to make a cold tumor hot. We have discovered a compound(CBL0137) which activates ZBP1 and potently reverses ICB unresponsiveness in mouse models of melanoma.CBL0137 activates ZBP1 by inducing Z-DNA formation in cells bypassing need for active virus replication.Here we propose to test the combination of CBL0137+nivolumab/ipilimumab in a small feasibility trial in patientswith locally advanced and metastatic melanoma a tumor type in which ICB has shown great promise but whereunresponsiveness remains a significant problem. We hypothesize that that induction of necroptosis withCBL0137 in combination with immunotherapy will not only invigorate the anti-melanoma immune response toICB but will also overcome the resistance conferred by CAFs and MDSCs in the melanoma TME. We proposetwo Aims to test this hypothesis:Aim 1. Conduct a proof-of-concept clinical trial to examine the feasibility of CBL0137+ICB (nivolumaband ipilimumab) in melanoma. This Aim will establish whether intravenous administration of CBL0137 is safeand tolerated in the setting of the frontline immunotherapy by combining CBL0137+nivolumab/ipilimumab inlocally advanced and metastatic melanoma.Aim 2. Elucidate the biological effects of neoadjuvant CBL0137+ICB in melanoma patients. We willsystematically analyze on-treatment biopsies: (1) to evaluate Z-DNA formation and necroptosis activation in themelanoma TME; and (2) to characterize treatment-induced changes in both malignant and reactive cell types(e.g. CAFs and MDSCs) in the melanoma TME using in situ spatial transcriptomics and immunofluorescenceapproaches each coupled with cutting edge informatics. These studies will provide unprecedented mechanisticinsight into the effects of CBL0137 on the tumor stroma during ICB therapy.A team of experts in clinical and translational oncology (Olszanski Astsaturov) and necroptosis and immunity(Balachandran) will lead the proposed studies. This concept will establish CBL0137 synergy with ICB and willopen an entirely new range of opportunities for using this necroptosis-activating virus mimetic as a means tomake immunologically cold tumors hot. 263670 +No NIH Category available 3' Splice Site;Acute Myelocytic Leukemia;Address;Affect;Alleles;Anatomy;Biomedical Engineering;Biotechnology;Breast Cancer Cell;Cancer Biology;Cancer Patient;Cells;Chronic Myelomonocytic Leukemia;Clinical;Disease;Dissection;Drug Delivery Systems;Dysmyelopoietic Syndromes;Elements;Engineering;Event;Exons;FDA approved;Frequencies;Ganciclovir;Gene Expression;Growth;Health;Hematologic Neoplasms;Hematological Disease;Hematopoietic;Hematopoietic Neoplasms;In Vitro;Individual;Interleukin-15;Introns;Left;Lesion;Leukemic Cell;Malignant Neoplasms;Mediating;Melanoma Cell;Messenger RNA;Methods;Molecular;Mutate;Mutation;Myeloid Leukemia;Myeloproliferative disease;Nature;Patient Care;Patients;Pattern;Pharmaceutical Preparations;Physicians;Precision therapeutics;Production;Proteins;RNA Splicing;Recurrence;Refractory;SRSF2 gene;Safety;Scientist;Simplexvirus;Solid Neoplasm;Spliceosomes;System;Technology;Testing;Therapeutic;Thymidine Kinase;Tissues;Work;Xenograft procedure;cancer cell;cancer type;cell killing;cell type;clinical phenotype;conventional therapy;efficacy evaluation;experimental study;functional genomics;immunostimulatory therapy;in vivo;insight;leukemia;lipid nanoparticle;loss of function;malignant breast neoplasm;melanoma;mutant;neoplasm relapse;new technology;novel therapeutics;protein expression;selective expression;side effect;suicide gene;therapeutic protein;therapeutic target;tumor;tumorigenic Synthetic introns for selective targeting of RNA splicing factor-mutant leukemia NARRATIVEMutations affecting RNA splicing factors are common across many cancers with particularly high frequenciesin disease types with few effective FDA-approved treatments. New therapies to treat these diseases areurgently needed. Here we will create new precision therapeutics that selectively target and eliminate cellscarrying cancer-causing mutations affecting RNA splicing factors. NCI 10722782 7/20/23 0:00 PA-20-185 1R01CA283364-01 1 R01 CA 283364 1 "SALOMON, RACHELLE" 8/1/23 0:00 7/31/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 11105415 "BRADLEY, ROBERT K" "ABDEL-WAHAB, OMAR " 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 748641 NCI 574200 174441 SUMMARYMany cancers carry recurrent change-of-function mutations affecting RNA splicing factors resulting insequence-specific changes in RNA splicing that promote disease initiation and progression. Thesespliceosomal mutations are the most common class of mutations in myelodysplastic syndromes (MDS) andrelated hematologic disorders which have few effective FDA-approved treatments. Despite the high frequencyof spliceosomal mutations and corresponding need for new therapeutics there currently exist no therapies thatspecifically and selectively target these lesions.Here we propose to address this clinical need by creating new precision therapeutics that selectivelykill cells with spliceosomal mutations. Our interdisciplinary team consists of a physician-scientist with expertisein cancer biology and patient care (Abdel-Wahab) a basic scientist with expertise in RNA splicing andfunctional genomics (Bradley) and a bioengineer with expertise in drug delivery (Heller). In preliminaryexperiments we developed the synthetic intron technology to harness altered RNA splicing activitycaused by spliceosomal mutations to drive cancer-specific gene expression showed that syntheticintrons permit highly selective expression of therapeutic payloads in cancer cells while leaving healthycells unharmed and used this system to suppress the growth of diverse cancer types in vivo (North etal Nature Biotechnology 2022). We additionally demonstrated that synthetic introns enable simultaneous andselective delivery of multiple therapeutic payloads and allow for detailed mechanistic dissection of the cis- andtrans-acting sequence elements and splicing factors that govern pro-tumorigenic mis-splicing caused byrecurrent spliceosomal mutations.We will now build on these preliminary studies to develop synthetic intron-based therapeutics formyeloid neoplasms including MDS acute myeloid leukemia (AML) and chronic myelomonocytic leukemia(CMML) and additionally utilize synthetic introns to understand the mechanistic basis for aberrant splicing inthese diseases as follows: Aim 1 Dissect and exploit the molecular mechanisms underlying common as wellas allele-specific splicing changes induced by different SF3B1 mutations; Aim 2 Develop synthetic introns thatenable selective therapeutic protein expression for each of the commonly mutated RNA splicing factors inleukemia; Aim 3 Optimize in vivo delivery and rigorously test an immunostimulatory therapy for treatingSF3B1-mutant hematopoietic malignancies.The significance of these studies is that they will develop a newtechnology that enables mechanistic studies of cancer-associated spliceosomal mutations and also provides aspecific means for therapeutically targeting these mutations. The health relatedness is that the proposed workwill create specific therapeutic products for treating cancer types that currently have few effective FDA-approved treatments. 748641 +No NIH Category available Address;Area Under Curve;Bioinformatics;Biological Assay;Biological Markers;Blood;CA-19-9 Antigen;Cancer Etiology;Cells;Cessation of life;Clinical;Development;Diagnosis;Diagnostic;Diagnostic Sensitivity;Diagnostic Specificity;Disease;Early Diagnosis;Enrollment;Excretory function;Funding;Genes;High grade dysplasia;Human;Imaging Device;Individual;Institution;Intellectual Property;Intraepithelial Neoplasia;Lead;Legal patent;Lesion;Life;Malignant Neoplasms;Malignant neoplasm of pancreas;Measurement;Messenger RNA;MicroRNAs;Monitor;Neoplasms;Non-Invasive Detection;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic cystic neoplasia;Participant;Patients;Performance;Plasma;Prospective cohort;Resectable;Risk;Screening for cancer;Serology;Serum;Specificity;Specimen;Survival Rate;Time;Tumor Markers;Tumor-Derived;Untranslated RNA;Validation;advanced disease;biobank;biomarker discovery;biomarker panel;biomarker validation;cancer biomarkers;cancer cell;cancer diagnosis;cancer invasiveness;clinical diagnosis;clinical implementation;clinical translation;clinically significant;cohort;diagnostic strategy;ethnic diversity;ethnic minority population;exosome;extracellular vesicles;genome-wide;high risk;improved;machine learning algorithm;miRNA expression profiling;microRNA biomarkers;molecular marker;pancreatic cancer patients;participant enrollment;premalignant;prognostic;prospective;racial diversity;racial minority population;response;sample collection;success;transcriptomics;tumor Exosome-based microRNA biomarkers for Non-invasive and Early Detection of Pancreatic Cancer NARRATIVE:We will perform systematic validation of cell-free and exosomal microRNA biomarkers that we have alreadydiscovered for the early-detection of cancer in large multi-institutional multi-national and ethnically diverseprospective cohorts of patients with pancreatic cancers and precancerous lesions. Successful validation of thesebiomarkers will exert a substantial diagnostic and prognostic impact on the management of this fatal disease. NCI 10722729 9/15/23 0:00 PAR-21-334 2U01CA214254-06 2 U01 CA 214254 6 "YOUNG, MATTHEW R" 9/1/17 0:00 7/31/28 0:00 ZCA1-RPRB-8(M2)R 8552045 "GOEL, AJAY " "VON HOFF, DANIEL D" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/15/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 923881 NCI 585613 338268 PROJECT SUMMARY: Pancreatic cancer is a highly aggressive malignancy that is estimated to become thesecond leading cause of cancer-related deaths by 2026. Pancreatic ductal adenocarcinoma (PDAC) accountsfor >90% of all pancreatic cancer cases and has an overall five-year survival rate of ~8% the lowest among themajor cancers. In PDAC only 1520% of patients present with localized resectable potentially curable tumorsat initial diagnosis. However currently there is an unmet clinical need for the lack of availability of highly robustdiagnostic strategies for the early detection of PDAC. MicroRNAs (miRNAs) are small non-coding RNAs thatregulate genes implicated in every human cancer including PDAC and may thus be ideal biomarkers. Indeedcirculating cell-free miRNAs (cf-miRNAs) have been shown to have diagnostic potential. Furthermore the recentdiscovery that cancer cells actively excrete miRNAs in small extracellular vesicles called exosomes(exo-miRNAs) has revolutionized the field as tumor-derived exosomal cargo enables the identification of cancer-specific molecular markers. During the previous cycle of funding we performed unbiased and genome-widesequencing-based miRNA profiling approaches together with rigorous bioinformatics and machine-learningalgorithms and 1) identified panels of 5 cf-miRNAs and 8 exo-miRNAs that could robustly identify patients withearly-stage PDAC; 2) combined the cf- and exo-miRNAs into a transcriptomic signature that was superior toindividual biomarker panels including patients with early-stage (stage I/II) disease; 3) showed that combiningour transcriptomic signature with CA19-9 further improved diagnostic performance; and 4) most importantlyshowed that our transcriptomic signature accurately identified patients with PDAC who were CA19-9-negative.In this competing renewal application we will build upon our previous success by undertaking 4 specific aims.In Aim 1 we will expand our biorepository via continued prospective enrollment of patients with PDAC andprecancerous neoplasms (PNs) including those with pancreatic cystic neoplasms (PCNs) and familial risk withan additional focus on enrollment of and specimen collection from patients of racial/ethnic minority populations.In Aim 2 we will further validate the transcriptomic signature and establish its performance in prospective cohortsof patients with early-stage PDAC. In Aim 3 we will determine the clinical significance of our transcriptomicsignature to detect the presence of high-grade dysplasia and invasive cancer in pre-operative plasma collectedfrom patients clinically diagnosed as PCNs. In Aim 4 we will evaluate the ability of our transcriptomic signatureto detect PDAC at its earliest stages in pre-diagnosis plasma specimens and to determine lead time beforedisease presentation. Our proposed project will be the first to establish a clinically feasible sensitive specificand robust blood-based assay for identifying patients with PDAC at the earliest possible stages. If successfulthis project will advance a simple facile and inexpensive non-invasive assay for routine clinical implementationthat will profoundly transform the early detection of PDAC with relevance for other cancers. 923881 +Clinical Research; Women's Health Biliary;Chile;Longitudinal Studies;Services;epidemiology study SUPPORT SERVICES FOR INTEGRATIVE EPIDEMIOLOGICAL STUDIES n/a NCI 10722685 261201800043C-P00009-9999-1 N02 9/21/22 0:00 9/22/23 0:00 78875686 "GLASSHOFER, SARA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2022 250000 OD Chile Biliary Longitudinal Study 250000 +Acquired Cognitive Impairment; Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Brain Cancer; Brain Disorders; Cancer; Dietary Supplements; Neurosciences; Orphan Drug; Prevention; Radiation Oncology; Rare Diseases Adolescent;Adult;Affect;Age;Biological Assay;Blood - brain barrier anatomy;Brain;Brain Neoplasms;CDKN1A gene;CDKN2A gene;Cancer Survivor;Cells;Chemoprevention;Chemotherapy and/or radiation;Chemotherapy-Oncologic Procedure;Chronic;Cisplatin;Cognitive aging;Cranial Irradiation;Disease;Dose;Exposure to;Gamma-H2AX;Gene Expression Profiling;Goals;Hour;Impaired cognition;Individual;Inflammasome;Inflammation;Inflammatory;Lead;Link;Methotrexate;Modeling;Morbidity - disease rate;Mus;Myeloid Cells;Neoplasm Metastasis;Neuraxis;Neurons;Oral;Oral Administration;Phase;Phenotype;Production;Quality of life;Radiation;Radiation therapy;Reporter;Risk;Rodent;Rodent Model;Role;Target Populations;Therapeutic;Time;Tissues;Toxic effect;age related;aging brain;behavior test;cancer therapy;chemobrain;chemotherapy;childhood cancer survivor;cognitive function;cognitive testing;design;dietary supplements;improved;irradiation;neuroinflammation;neuroprotection;normal aging;novel;oleanane;pre-clinical;preservation;prevent;programs;recruit;senescence;small molecule TOPIC 430: A NEW SMALL MOLECULE SENOTHERAPEUTIC FOR THE CHEMOPREVENTION OF THERAPY-RELATED COGNITIVE AGING n/a NCI 10722549 75N91022C00030-0-9999-1 N43 9/16/22 0:00 3/15/24 0:00 78867729 "CHOI, JIN-KYU " Not Applicable 8 Unavailable 81353247 JA25GYTMYJP3 081353247; 081324657 JA25GYTMYJP3 US 42.226334 -71.027115 10053142 "TRITERPENOID THERAPEUTICS, INC." BRAINTREE MA Domestic For-Profits 2184 UNITED STATES N R and D Contracts 2022 400000 NCI Cognitive impairment is a cause of significant morbidity and diminished quality of life for cancer survivors and particularly for survivors of childhood cancer. There is now substantial evidence supporting the role of the pro-inflammatory senescence-associated secretory phenotype (SASP) as a major contributor to cognitive aging and other age-related diseases. Microglial senescence has profound consequences for neuronal activity and cognitive function in the normal aging brain and is known to be induced by exposure to radiation and to cancer chemotherapy. These studies have demonstrated the potential of senolytic agents to reduce chemotherapy induced microglial activation reduce expression of SASP factors and to thereby improve age-associated and cancer therapy-related cognitive impairment. The goal of this project is to develop the novel synthetic oleanane triterpenoid (SOT) CDDO-2P-Im (2P-Im) as an effective senotherapeutic for use in neuroprotection against therapeutic radiation (RT)-induced central nervous system (CNS) toxicity. The goal of this project is to develop the novel orally bioavailable synthetic oleanane triterpenoid (SOT) CDDO-2P-Im (2P-Im) as senotherapeutic for use in neuroprotection against cancer therapy-induced cognitive aging. The proposed preclinical effort is designed to validate the oral administration 2P-Im will mitigate risk for therapy-related toxicity in target populations that include individuals undergoing either systemic chemotherapy or therapeutic irradiation (IR) of brain tumors and metastatic tumors affecting the central nervous system (CNS). The goals of this Phase I program are to clearly define the capacity of oral administration of CDDO-2P-Im to: 1). suppress therapy-induced production of SASP factors 2). limit accumulation of senescent cells and 3). prevent chronic microglial activation thereby preserving cognitive function following administration of either chemotherapy (Aim 1) or radiation therapy (Aim 2) in mice. 400000 +No NIH Category available Abscopal effect;Antigen Targeting;Benchmarking;Cancer Model;Cancer Patient;Catalytic Domain;Cells;Clinical;Combined Modality Therapy;Complex;DNA;DNA sequencing;DRADA2b protein;Data;Dependovirus;Development;Disease remission;Distant;Engineering;Enzymes;Epitope spreading;Epitopes;Evaluation;Event;Flow Cytometry;Goals;Growth;Human;Hyperactivity;Immune;Immune checkpoint inhibitor;Immune system;Immunologics;Immunotherapy;Infiltration;Injection of therapeutic agent;Injections;Malignant Neoplasms;Malignant neoplasm of pancreas;Mammary Neoplasms;Mass Spectrum Analysis;Measures;Mus;Mutation;Organoids;Outcome;Patients;Point Mutation;Primary Neoplasm;Process;Production;Proteins;Proteomics;RNA Editing;Radiation therapy;Research;Research Project Grants;Safety;Site;Solid Neoplasm;T cell infiltration;T cell response;T-Lymphocyte;Technology;Testing;Translating;Tumor Antigens;Tumor Suppression;Tumor-infiltrating immune cells;Vaccinated;Validation;Viral;Work;anti-PD-1;cancer immunotherapy;cancer infiltrating T cells;cancer type;cellular transduction;comparative efficacy;dsRNA adenosine deaminase;immune cell infiltrate;immunogenicity;improved;innovation;innovative technologies;malignant breast neoplasm;melanoma;mouse model;neoantigens;neoplastic cell;new technology;novel;patient subsets;pre-clinical;preclinical efficacy;preclinical study;response;standard of care;technology validation;therapeutic RNA;transcriptome;transcriptome sequencing;transcriptomic profiling;translation to humans;translational approach;translational potential;treatment strategy;tumor;tumor growth;tumor microenvironment Inducing Tumor Neoantigens Through RNA Editing for Cancer Immunotherapy PROJECT NARRATIVECancer immunotherapies have provided significant benefit for many cancer patients but the treatment oftumors with low mutational burden that lack immune cell infiltration remains a major roadblock. To furtherexpand immunotherapies to many more cancer types the proposed project aims to validate a novel technologythat improves tumor immunogenicity by enhancing the visibility of tumors to immune cells through RNA editingapproaches. NCI 10722488 7/25/23 0:00 PAR-22-216 1R21CA277414-01A1 1 R21 CA 277414 1 A1 "SINGH, ANJU" 8/1/23 0:00 7/31/25 0:00 ZCA1-SRB-A(M2)S 2291359 "HUBBELL, JEFFREY A." "ROSENTHAL, JOSHUA J.C." 1 BIOCHEMISTRY 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 246711 NCI 162251 84460 PROJECT SUMMARY/ABSTRACTImmune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy but remain effective in only asubset of patients and tumor types. The successful treatment of tumors that lack T cell infiltration known asimmunologically cold tumors remains a major roadblock in cancer immunotherapy. Tumor mutational burdenhas been correlated with ICI efficacy due to the abundance of neoantigens that are recognizable by theimmune system after ICI. This proposal aims to enhance the visibility of multiple tumor types with lowmutational burden by inducing the expression of neoantigens through RNA editing approaches. Ourpreliminary data in a highly aggressive immunologically cold model of murine melanoma show that thecombination of RNA editing and anti-PD-1 ICI results in a significant survival benefit over anti-PD-1 alone. Wehypothesize that the induction of neoantigens enhances T cell infiltration into the tumor and promotes epitopespreading such that the immune system recognizes endogenous tumor antigens in addition to inducedneoantigens. We will test this hypothesis with two specific aims. Aim 1 will elucidate the mechanism of actionof this novel cancer immunotherapy through transcriptomic profiling of isolated tumor cells analysis of tumor-infiltrating immune cells and evaluation of the abscopal effect whereby growth of a distant tumor is suppressedfollowing localized treatment of the primary tumor. Aim 2 will determine the generalizability of this approach toadditional immunologically cold murine cancer models as well as its translation to human cancers throughevaluation in multiple patient-derived tumor organoids. The successful completion of these aims would providepreclinical validation and further support the advancement of this innovative approach. This strategy has thepotential to diversify the neoantigen repertoire and expand ICIs as frontline therapies in many tumor typesimproving clinical outcomes for cancer patients. 246711 +No NIH Category available Ablation;Affect;Afferent Neurons;Antigen Presentation;CD8-Positive T-Lymphocytes;Calcitonin Gene-Related Peptide;Calcitonin-Gene Related Peptide Receptor;Cells;Clinical;Colon Adenocarcinoma;Colorectal Cancer;Communication;Cross Presentation;Data;Dendritic Cells;Disease;Experimental Models;Fostering;Functional disorder;Funding;Gene Expression;Genetic Transcription;Growth;Health;Immune;Immune response;Immune system;Immunotherapy;Inflammation;Infrastructure;Interdisciplinary Study;Knowledge;Lung Neoplasms;Malignant Neoplasms;Modeling;Neoplasm Metastasis;Nerve;Nervous System;Neurogenic Inflammation;Neuroimmune;Neuroimmunomodulation;Neuromodulator;Neurons;Neuropeptide Receptor;Neuropeptides;Neurosciences;Neurosciences Research;Nociceptors;Normal tissue morphology;Organ;Pancreas;Pathogenesis;Pathway interactions;Patients;Peripheral;Physiological;Physiology;Play;Population;Pre-Clinical Model;Prevention;Process;Prostate;Reporter;Reporting;Research;Role;Sampling;Sensory;Sensory Receptors;Shapes;Skin Neoplasms;Stimulus;T-Lymphocyte;TRPV1 gene;Testing;Therapeutic;Tissues;Translating;Tumor Antigens;Tumor Burden;Tumor Immunity;Tumor Markers;Tumor Promotion;Tumor Tissue;Tumor-infiltrating immune cells;Work;anti-tumor immune response;anticancer research;cancer cell;cancer therapy;cytokine;density;design;draining lymph node;immunoregulation;malignant stomach neoplasm;multiplexed imaging;nerve supply;novel;novel therapeutic intervention;receptor;recruit;response;systemic inflammatory response;tool;treatment response;tumor;tumor immunology;tumor initiation;tumor microenvironment;tumor progression Dissecting Neuro-Immune Interactions in Cancer PROJECT NARRATIVE: It is expected that novel pathways and neuro-immune mechanisms uncovered by thisresearch will have far reaching consequences in terms of how neurons regulate immune responses ininflammation and cancer thus enhancing our understanding of the immune system in health and disease. NCI 10722350 7/28/23 0:00 PAR-22-216 1R21CA282866-01 1 R21 CA 282866 1 "SINGH, ANJU" 8/1/23 0:00 7/31/25 0:00 ZCA1-SRB-A(M2)S 14783692 "DIXON, KAREN OLIVIA" Not Applicable n/a Unavailable 484650064 GCXQV9JENLH1 484650064 GCXQV9JENLH1 SZ 47.55839 7.57327 676401 UNIVERSITY OF BASEL BASEL Unavailable CH - 4001 SWITZERLAND N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 143231 NCI 132621 10610 PROJECT SUMMARY/ABSTRACT: Cancer is highly adept at exploiting normal physiological functions tosupport its growth. One important component of tissue physiology is neurons which weave through ourorgans releasing neuropeptides into nearby tissue. Importantly the role innervation plays in malignancy andanti-tumor immunity remains largely unknown and understudied. Our preliminary analysis shows that tumorinfiltrating immune cells express high levels of receptors for sensory neuropeptides which further positivelycorrelates with expression of genes associated with immune cell dysfunction. These data suggest thatinnervation may play an important role in regulating anti-tumor immunity. To test this hypothesis we proposestrategies to investigate the role of innervation in cancer and to determine how neuropeptide sensing onimmune cells impacts anti-tumor immunity in the following objectives:Objectives of Unnerving Cancer: (1) Investigate the degree of sensory neuron innervation in cancer (2)Determine how neuropeptide sensing on DCs impacts anti- tumor immune responses.Using reporter tools and multiplexed imaging we will determine innervation of tumor tissues in pre-clinicalmodels and patient samples. Building on our results we will investigate the functional and transcriptionaleffects of neuropeptide sensing on immune populations using endogenous and syngeneic models.Results from this project have the potential to significantly advance our current understanding of the nervoussystem's contribution to cancer. Therapeutically exploiting the neuronal vulnerability of cancer using existingclinically approved neuromodulators has the potential to rapidly translate clinically for the prevention andtreatment of cancer. The legacy of this NCI funded interdisciplinary research will be to understand the neuro-immune communication in cancer opening doors for novel therapeutic strategies.Keywords: Tumor Immunology Immunotherapy Cancer Neuroscience Dendritic cells Neuro-ImmuneInteractionsGraphical Abstract: Tumor innervation correlates with poor survival in several tumours. I propose to studyneuronal density in Skin and Lung tumour and query correlation of neuronal density to therapeutic responses.I hypothesise that Sensory Neurons release neuropeptides including CGRP which acts on receptorexpressing dendritic cells (DCs). Together this leads to blunted DC responses perpetuating CD8+ T celldysfunction and tumor progression.Objective 1Objective 2 143231 +No NIH Category available Acids;Active Sites;Apoptosis;Area;Binding;Biological Assay;Cancer Biology;Catalytic Domain;Cell Proliferation;Cell Survival;Cell physiology;Chimera organism;Chromatin;Clinical;Complex;Coupled;Cues;Cytosine;Development;Diagnosis;Disease;Epigenetic Process;Evaluation;Family;Foundations;Future;Gene Expression Regulation;Genes;Genetic Transcription;Goals;High Prevalence;Histones;Intervention;Ions;Iron;Left;Length;Libraries;Ligand Binding;Ligands;Lysine;Malignant Neoplasms;Malignant neoplasm of prostate;Metalloproteins;Metals;Methodology;Methylation;Modality;Modification;Molecular Target;National Cancer Institute;Normal Cell;Oncogenic;Oncoproteins;Oxygenases;Peripheral;Persons;Phosphorylation;Post-Translational Protein Processing;Process;Protac;Protein Isoforms;Proteins;Proteome;Regulation;Reporting;Role;Sequence Homology;Signal Pathway;Surface;Technology;Therapeutic Intervention;Ubiquitination;United States;Water;cancer type;cofactor;design;drug discovery;efficacy evaluation;epigenetic regulation;high reward;high risk;histone methylation;histone modification;inhibitor;innovation;interest;lens;malignant breast neoplasm;metalloenzyme;neoplastic cell;novel;novel anticancer drug;pharmacophore;preclinical development;programs;protein degradation;protein protein interaction;rapid technique;recruit;response;small molecule;success;targeted agent;therapeutic development;therapeutic protein;therapeutic target;tumor;tumor progression;tumorigenesis;ubiquitin-protein ligase Targeting Metal-Dependent Epigenetic Modulators via MetalloPROTACs Project Narrative. The National Cancer Institute estimates that in 2018 approximately 1.7 million people willbe diagnosed with cancer in the United States alone and of those approximately 600000 will succumb to theirdisease. One of the key drivers of cancer is the aberrant expression of cancer-causing proteins. This programwill develop a platform to evaluate the efficacy of heterobifunctional small molecules for targeted degradationof currently undruggable metalloproteins activated during tumorigenesis or tumor progression. NCI 10722294 6/14/23 0:00 PAR-22-216 1R21CA273632-01A1 1 R21 CA 273632 1 A1 "FU, YALI" 7/1/23 0:00 6/30/25 0:00 ZCA1-RPRB-H(M2)S 6272585 "BURKART, MICHAEL D." "COHEN, SETH M" 50 CHEMISTRY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF ARTS AND SCIENCES 920930621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 205385 NCI 140250 65135 Project Summary. While recent efforts have identified the need for methodologies capable of inactivatingoncoproteins current intervention strategies have left much of the proteome undruggable. In response theNCI has recognized this challenge as outlined in PAR-22-216 by incentivizing the development of newmolecular targeting agents based on specific signaling pathways activated during the process of tumorigenesisor tumor progression. This program proposes an important next step in reaching these goals by providing aplatform for the rapid development and characterization of heterobifunctional molecules capable of inducingdegradation of cancer related metalloenzymes with new molecular targeting agents. In this program our teamwill develop proteolysis targeting chimeras (PROTACs) containing state-of-the-art metal-bindingpharmacophores (MBPs) with the ultimate goal of achieving isoform-selective degradation of jumonji C-domaincontaining lysine demethylases. Current strategies to inhibit conserved catalytic domain Jumonjis (JMJCs)involve targeting the -ketoglutaric acid (2OG) substrate-accepting active site of JMJCs with inhibitors that cancoordinate to the iron ion in the active site. Targeting the histone-binding helper domain of JMJCs generatesadditional isoform selectivity. However no inhibitor has been shown to be selective for only one isoform ofJMJCs. We have chosen to take a targeted degradation approach in order to increase the surface area of theperipheral interaction by recruiting an E3 ligase. This program will demonstrate how the potential protein-protein interaction induced by these chimeras can be leveraged to induce selective degradation ofmetalloproteins (`MetalloPROTACs') through rational MBP and linker design and will serve as a platform for thestudy of cancer biology as well as laying the foundation for future development of therapeutic agents. 205385 +No NIH Category available Ablation;Animals;Antibodies;Cancer Etiology;Cell Line;Cells;Cellular Metabolic Process;Cessation of life;Clinical;Clinical Trials;Data;Disease;Environment;Exhibits;Exposure to;FDA approved;Flow Cytometry;Gene Deletion;Genes;Genetic;Goals;Growth;Harvest;Histocompatibility Antigens Class I;Human;Hyperlipidemia;Hypoxia;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunocompetent;Immunohistochemistry;Immunologics;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Implant;Infiltration;KPC model;KRAS oncogenesis;KRAS2 gene;KRASG12D;Laboratories;Leucocytic infiltrate;MHC Class I Genes;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mediating;Metabolic;Mus;Mutation;Names;Oncogenic;Operative Surgical Procedures;PIK3CA gene;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Pilot Projects;Play;Proteins;RNA;Reporting;Resistance;Role;SCID Mice;Signal Transduction;T cell infiltration;T cell therapy;T-Cell Receptor;T-Lymphocyte;Target Populations;Testing;Therapeutic;Therapeutic Studies;Treatment Protocols;Up-Regulation;Work;alpelisib;anti-PD-1;anti-PD1 antibodies;cancer cell;cancer infiltrating T cells;carboxylate;carboxylation;cell type;effective therapy;efficacy testing;exhaustion;experimental study;genome-wide;immune checkpoint;immune clearance;implantation;improved;in vivo imaging system;in vivo monitoring;inhibitor;instrument;metabolic profile;methylmalonyl-coenzyme A;mouse model;neoplastic cell;neutralizing antibody;pancreatic cancer cells;pancreatic neoplasm;pharmacologic;programmed cell death ligand 1;programmed cell death protein 1;propionyl-coenzyme A;side effect;single cell sequencing;therapeutic target;tumor;tumor growth;tumor progression;tumor-immune system interactions PIK3CA signaling and pancreatic cancer Pancreatic cancer causes approximately 40000 deaths every year in the U.S.A. and currently there is noeffective treatment for tumors that cannot be surgically removed. More than 90% of human pancreatic cancersare caused by mutations in a protein named KRAS that works together with another protein called PIK3CA topromote cancer growth. The goals of this proposal are to clarify how PIK3CA causes pancreatic cancerprogression and to test whether a drug that blocks PIK3CA can be used to treat this deadly disease. NCI 10722155 7/8/23 0:00 PAR-22-216 1R21CA274425-01A1 1 R21 CA 274425 1 A1 "SOMMERS, CONNIE L" 7/8/23 0:00 6/30/25 0:00 ZCA1-SRB-A(M2)S 1932469 "LIN, RICHARD Z" Not Applicable 1 PHYSIOLOGY 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY SCHOOLS OF MEDICINE 117943362 UNITED STATES N 7/8/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 220554 NCI 140250 80304 The goal of this proposal is to explore how to target PIK3CA signaling for treatment of pancreatic ductaladenocarcinoma (PDAC). This deadly cancer is highly resistant to current treatment regimens includingimmunotherapy with checkpoint inhibitors. More than 90% of PDAC have oncogenic mutations in KRAS andPIK3CA is a direct effector of KRAS. Our group first reported that genetic ablation of PIK3CA in the pancreascompletely protected mice against oncogenic KRAS-induced tumor formation and subsequently reported thatPIK3CA plays a critical role in sustaining pancreatic tumors by shielding them from the immune system.Orthotopic implantation of KrasG12D;Trp53R172H;Pdx1-Cre (KPC) pancreatic tumor cells in immunocompetentmice caused 100% lethality whereas mice implanted with Pik3ca-/- KPC (PIK3CA-KO) KPC cells exhibitedtumor regression with 100% animal survival. A genome-wide gene deletion screen to search for molecules thatcan reverse the elimination of PIK3CA-KO cells by the immune system identified PCCB which catalyzes thecarboxylation of propionyl-CoA to produce methylmalonyl-CoA. PCCB-null PIK3CA-KO KPC cells weregenerated and when implanted in mice these tumors were not cleared by the host immune system. Twohypotheses will be tested: 1) Oncogenic KRAS activation of PIK3CA modulates a PCCB-regulated metabolicenvironment that favors evasion of pancreatic cancer from immune elimination; and 2) Alpelisib inhibition ofPIK3CA enhances the activity of anti-PD1 plus anti-PCSK9 therapy against pancreatic tumors. Aim 1investigates mechanisms by which KRAS activation of PIK3CA modulates a PCCB-regulated metabolicenvironment that favors immune evasion of pancreatic cancer including upregulation of immune checkpointsand T cell exhaustion. Tumor infiltrating T cells will be isolated and analyzed by single-cell RNA and T cellreceptor (TCR) V(D)J sequencing flow cytometry and IHC. Adoptive T cell transfer experiments will beperformed to determine if T cells previously exposed to PCCB-null PIK3CA-KO tumors will eliminate PIK3CA-KO tumors implanted in SCID mice. Cell metabolism and immunological profile of PCCB-null PIK3CA-KO vs.PIK3CA-KO and parental KPC cell lines will be measured to better understand the metabolic alterationscontrolled by PIK3CA and PCCB and how these changes may lead to immune suppression. Aim 2 is atherapeutic study that tests the efficacy of alpelisib a PIK3CA inhibitor in combination with neutralizingantibodies against PD-1 and PCSK9 for treatment of pancreatic cancer using the orthotopically implanted KPCmouse model. Tumor infiltrating T cells will also be isolated and analyzed by single-cell sequencing. Insummary this proposal will investigate how PIK3CA signaling regulates the metabolic and immunologicalprofile of pancreatic cancer. Alpelisib anti-PD1 antibodies and anti-PCSK9 antibodies are all FDA-approved forclinical use. Successful completion of our studies may lead to clinical trials with these approved drugs fortreatment of pancreatic cancer. 220554 +No NIH Category available Address;Adenocarcinoma;Affinity;Alkynes;Azides;Binding;Binding Sites;Biochemical;Biological;Biological Assay;Biology;Cancer Model;Cancer Patient;Cancer cell line;Cell Line;Cell Survival;Cell model;Cells;Chemicals;Chemistry;Clustered Regularly Interspaced Short Palindromic Repeats;Colon;Copper;DNA Sequence Alteration;Data;Databases;Dedications;Development;Diazomethane;Disease Progression;Dose;Drug resistance;Engineering;Epigenetic Process;Epithelial Cells;Epithelium;Future;Genetic;Genetic Transcription;Genomics;Histologic;Histology;Induction of Apoptosis;Informatics;KRAS2 gene;Lead;Libraries;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Mesenchymal;Mining;Modeling;Mutation;Outcome;Parents;Pathway interactions;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phenotype;Proteomics;RNA Interference;Reporting;Research;Resistance;Signal Transduction;Structure;Testing;Time;Translations;Validation;Western Blotting;Work;analog;cancer therapy;cell type;chemoproteomics;cycloaddition;cytotoxic;drug discovery;drug-like compound;drug-sensitive;functional group;in vivo;inhibitor;lung cancer cell;mutant;non-genomic;novel;novel strategies;novel therapeutics;rare cancer;resistance mechanism;response;scaffold;screening;small molecule;tool;transcriptional reprogramming;tumor;tumor progression Overcoming resistance to KRAS inhibitors through a fragment-based chemoproteomics approach NarrativeThis project will use a fragment based chemoproteomics approach to discover new targets that mediateresistance to KRAS inhibitors and at the same time deliver new lead compounds. NCI 10722113 9/19/23 0:00 PAR-22-216 1R21CA282568-01 1 R21 CA 282568 1 "COVELL, DAVID G" 9/19/23 0:00 8/31/25 0:00 ZCA1-SRB-P(M2)S 3047481 "HAURA, ERIC B." "RIX, UWE " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/19/23 0:00 8/31/25 0:00 395 Non-SBIR/STTR 2023 433256 NCI 257125 176131 AbstractA major breakthrough in recent years has been the development of selective inhibitors that target KRASG12Cmutations found in lung colon and other rare cancer typ. Both sotorasib and adagrasib have response rates ofnearly 40% in KRASG12C mutant lung cancer. Despite this advance there remains two major problems toaddress. First a substantial group of patients fail to have tumor regressions. Second the responses aretransient with the emergence of resistance leading to tumor progression. While genomic mechanisms havebeen identified that drive acquired resistance a sizeable group of tumors lack obvious genomic mechanismsand appear to rely on transcriptional reprogramming or epigenetic mechanisms. We have generated cell linemodels that recapitulate non-genomic mechanisms of resistance to (i) identify such targets associated withresistance and (ii) develop lead compounds to serve in future drug discovery efforts. To identify both new targetsand lead compounds we will leverage a new fragment based chemoproteomics approach. Fragment-like probeshave the distinct advantage over larger more decorated drug-like molecules because of their (i) smaller size and(ii) simpler structures that can engage target binding sites that are inaccessible to more developed and complicatedmolecules.Thus fragment-like molecules are unique tools to identify novel targets and probe uncharted biologicaltarget space. Our preliminary data in Sotorasib resistant cell models indicates the ability of this screen to identifyfragments with enhanced activity in the resistant cells compared to drug sensitive parent. In addition using agroup of functionalized 20 fragments we demonstrate in the KRASG12C mutant H1792 cell the ability to identifytargets of these fragments using chemical proteomics. Aim 1 will test the hypothesis that we can identifyfragments that have enhanced activity in the Sotorasib resistant cells compared to untreated drug sensitive cells.We will leverage additional cell line models of Sotorasib resistance and use non-KRASG12C mutant lung cancermodels and non-tumor lung epithelial cells to enhance selectivity. Aim 2 we will test the hypothesis that targetsthat drive the resistant phenotype can be identified by chemoproteomics. We will assess targets in our 20functionalized fragment library as well as assess targets identified in our larger fragment screening. By usingthis approach that enables probing a significantly larger biological target space we expect to identify uniquetargets for KRASG12C inhibitor resistant cells. At the same time our approach will identify chemical leads engagingthese targets for future dedicated drug discovery projects. 433256 +No NIH Category available Address;Adopted;Adoption;Alabama;Attention;Award;Cancer Patient;Caring;Characteristics;Clinical;Complement;Complex;Consultations;Cutaneous Melanoma;Data;Data Science;Decentralization;Deimplementation;Dissemination and Implementation;Ensure;Equity;Evidence based practice;Future;Goals;Health Services;Health care facility;Health system;Hospitals;Improve Access;Integrated Health Care Systems;Intervention;Interview;Investments;Joints;Knowledge;Level of Evidence;Link;Location;Logic;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Malignant neoplasm of thyroid;Medicare;Mission;Modeling;Needs Assessment;Operative Surgical Procedures;Ownership;Patient-Focused Outcomes;Patients;Penetration;Performance;Population;Process;Provider;Quality of Care;Research;Research Methodology;Research Personnel;Resources;Rural;Rural Population;Science;Site;Solid Neoplasm;Structure;System;Theoretical model;Training;United States;United States National Institutes of Health;Universities;Variant;Vulnerable Populations;Work;advanced analytics;analytical method;biomedical referral center;cancer care;cancer health disparity;cancer risk;cancer surgery;cancer therapy;care coordination;care delivery;care outcomes;common treatment;cost;design;effective therapy;evidence base;health care availability;health care delivery;health care disparity;health care service organization;implementation science;implementation strategy;improved;ineffective therapies;intervention mapping;malignant breast neoplasm;medical specialties;multilevel analysis;novel;outcome disparities;programs;remote location;secondary analysis;surgical risk;therapy design;treatment effect Leveraging Health Systems to Increase Implementation of Evidence-based Surgical Cancer Care PROJECT NARRATIVEMost patients with common cancers in the United States receive surgical care within health systems butquality is inconsistent across system hub and spoke sites. This project will evaluate the effect of treatment in ahealth system hub or spoke on receipt of evidence-based surgical cancer care and will identify health systemcharacteristics and strategies that are associated with system performance and consistency across sites. Theproduct an intervention map for system-level implementation of oncologic evidence can be used by healthsystems to provide consistent high-quality care across sites increasing equity in cancer care delivery. NCI 10722091 8/1/23 0:00 PA-20-203 1K08CA283001-01 1 K08 CA 283001 1 "RADAEV, SERGEY" 8/1/23 0:00 7/31/28 0:00 Career Development Study Section (J)[NCI-J] 12238878 "BROMAN, KRISTY KUMMEROW" Not Applicable 7 SURGERY 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 197173 NCI 182568 14605 PROJECT SUMMARYHospitals are increasingly consolidating into health systems with shared ownership and management. Care in ahealth system has potential benefits for surgical cancer patients including improved access care coordinationand strategies to disseminate and implement a rapidly evolving evidence-base into practice across system huband spoke sites. Prior research has demonstrated that these potential benefits remain elusive. The impact ofconsolidation on quality varies widely and there are disparate outcomes for surgical cancer patients treated atdifferent facilities in the same systems. We have shown that location of surgical cancer care determines whethereffective treatments are adopted (implementation) or ineffective treatments discontinued (de-implementation). We hypothesize that health system characteristics and strategies are associated with variabilityin implementation of oncologic evidence among hub and spoke hospitals and that through exploration ofobserved differences we will identify levers for targeted multi-level interventions.This work addresses the NIH Blueprint objective to enhance research investments by ensuring adoption intopractice and targets rural individuals a population with disparate healthcare access and outcomes who areoften treated at spoke hospitals. We will examine the influence of treatment for common cancers in health systemhubs and spokes on patient access and receipt of evidence-based care by linking SEER-Medicare data withhealth system data. Then we will identify health system characteristics associated with evidenceimplementation both quantitatively using multilevel modeling and qualitatively through structured interviews withhealth system stakeholders. Finally we will use the resources within our Health System at the University ofAlabama at Birmingham (UAB) to develop a system-level intervention for dissemination and implementation ofoncologic evidence across hub and spoke sites.My long-term goal is to become an independent investigator who improves the quality of cancer care delivery bydesigning implementing and studying health system-level interventions to increase clinical adoption of oncologicevidence. Through this training award I will complement my health services and quality improvement scienceexpertise with advanced training in the organization of healthcare delivery multilevel analysis of secondary dataand implementation science to develop a system-level intervention to improve evidence-based surgical cancercare. 197173 +No NIH Category available Affinity;Agreement;Alleles;Amino Acid Substitution;Amino Acids;Antigen Presentation;Antigen-Presenting Cells;Antigens;Autologous Dendritic Cells;Automobile Driving;Binding;Biological Assay;Biopsy;Blood;Cancer Etiology;Cancer Patient;Cell Maturation;Cessation of life;Charge;Clinical;Clinical Research;Clinical Trials;Clone Cells;Coculture Techniques;Computational algorithm;Data;Dendritic Cell Vaccine;Dendritic Cells;Dissociation;Dose;Electrostatics;Evaluation;Exposure to;Foundations;Frequencies;Future;Gene Modified;HLA Antigens;Immune response;Immunotherapeutic agent;Immunotherapy;In Situ;In Vitro;Incubated;Injections;Institution;Lead;Malignant neoplasm of lung;Methods;Minority;Monitor;Mutation;Non-Small-Cell Lung Carcinoma;Outcome;Patients;Peptides;Physiologic pulse;Positioning Attribute;Research;Role;Specimen;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Time;Toxic effect;Tumor Antigens;Tumor Immunity;United States;Vaccination;Vaccine Therapy;anti-tumor immune response;antigen binding;antigen-specific T cells;bak protein;cancer therapy;clinical investigation;clinically relevant;comparison control;dendritic cell vaccination;experimental study;immune checkpoint blockade;in situ vaccination;in vivo;innovation;interest;neoantigens;novel;novel therapeutic intervention;patient population;pembrolizumab;phase I trial;prediction algorithm;programmed cell death protein 1;recruit;response;therapeutically effective;treatment strategy;tumor;tumor microenvironment;vaccination strategy;vaccine platform Evaluation of a therapeutic vaccination strategy with motif neoepitope peptide-pulsed autologous dendritic cells for non-small cell lung cancer patients harboring a charged HLA-B binding pocket. PROJECT NARRATIVEAmong the approximately 50% of non-small cell lung cancer patients who have a charged HLA-B supertypeallele greater clinical activity of programmed cell death 1 (PD-1) inhibitors is seen when mutations generatepeptides in which a wild type amino acid is substituted with an amino acid that has a charge opposite from theHLA-B binding pocket presumably based on favorable binding. Utilizing specimens from our ongoing study ofgene modified dendritic cells plus pembrolizumab we propose to assess the ablity of these peptides to induceanti-tumor T cell responses in co-culture assays. We will also evaluate whether we would be able to pulseautologous dendritic cells with these peptides as a potential personalized immunotherapeutic approach. NCI 10721983 7/25/23 0:00 PAR-22-216 1R21CA277172-01A1 1 R21 CA 277172 1 A1 "HU, ZHANG-ZHI" 7/25/23 0:00 6/30/25 0:00 ZCA1-SRB-A(M2)S 2055300 "GARON, EDWARD B" "LIU, BIN " 36 INTERNAL MEDICINE/MEDICINE 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 7/25/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 183494 NCI 116875 66619 PROJECT SUMMARYLung cancer is the leading cause of cancer related deaths in the United States and the World. Inefficientprediction of functional tumor neoantigens and insufficient understanding of host anti-tumor immune responseslimit optimization of immunotherapeutic approaches. We recently demonstrated that programmed cell death 1(PD-1) inhibitors which lead to durable responses in a minority of non-small cell lung cancer (NSCLC) patientshave greater efficacy in patients with charged human leukocyte antigen (HLA)-B binding pockets whose tumorsharbor mutation(s) leading to what we have designated as motif neoepitopes. Motif neoepitopes lead to anamino acid substitution in the second position of a nonamer (anchor for HLA-binding) generating a change incharge from the wild type peptide in which the resultant amino acid has a charge opposite to the HLA-B bindingpocket. This substitution leads to enhanced binding affinity to the corresponding HLA-B supertype demonstratedby in vitro competition assays. These data suggest that optimal presentation of motif neoepitopes bycorresponding charged HLA supertypes results in effective host anti-tumor immune responses in vivo.Dendritic cell (DC)-based vaccination has emerged as a potential component for immunotherapy due to both itsfavorable toxicity profile and its essential role in antigen-specific T cell priming and activation. We have expertisein clinical studies evaluating a DC in situ vaccination strategy in NSCLC. In this proposal we intend to combineDCs as functional antigen presenting cells (APCs) with putative motif neoepitopes as an innovative vaccinationapproach to enhance host systemic tumor-specific T cell responses and potentiate clinical benefits of currentimmunotherapies.We hypothesize that 1) peptides derived from motif neoepitopes are functional neoantigens in vivo that arecapable of inducing host tumor-specific immune responses and 2) autologous DCs pulsed with motifneoepitope-derived peptides particularly at optimal conditions will induce systemic activation of motifneoepitope-specific T cells. As part of this proposal we are analyzing multiple biospecimens collected from ourongoing phase I trial of intratumoral injection of autologous DCs combined with PD-1 inhibition in advancedNSCLC. Collected specimens include serial blood and tumor biopsies as well as autologous DCs. We willevaluate whether exposing DCs to peptides derived from motif neoepitopes can induce tumor-specific T cellactivation in co-culture experiments. We will assess the binding affinity of these peptides and the correspondingwild type peptides to their respective HLA-B supertype. We will further optimize conditions including addition ofPD-1 blockade to achieve optimal T cell activation by autologous DCs pulsed with motif neoepitope-derivedpeptides. These studies will greatly enhance our understanding of the potential function of motif neoepitopes ininducing host anti-tumor immune responses and lay the foundation for future clinical investigations of motifneoepitope-pulsed autologous DCs as a novel treatment strategy for NSCLC. 183494 +No NIH Category available Advanced Malignant Neoplasm;Apoptosis;BRAF gene;Cancer cell line;Cell Death;Cells;Cessation of life;Clinic;Combined Modality Therapy;Data;Development;Diagnosis;Future;Gatekeeping;Goals;Growth;Human;In Vitro;Incidence;Iron;Knowledge;Lipids;MAP Kinase Gene;MAPK Signaling Pathway Pathway;Malignant Neoplasms;Malignant neoplasm of thyroid;Mesenchymal;Mission;Mitogen-Activated Protein Kinase Inhibitor;Mitogen-Activated Protein Kinases;Mutate;Mutation;Oncoproteins;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Peroxidases;Persons;Public Health;Refractory;Research;Resistance;Safety;Science;Signal Induction;Signal Pathway;Testing;Therapeutic;Time;Toxic effect;Translations;Treatment Efficacy;Treatment Protocols;United States National Institutes of Health;acquired treatment resistance;anaplastic thyroid cancer;anticancer activity;cancer cell;cancer therapy;cell type;combinatorial;disability;efficacy evaluation;evidence base;improved;in vivo;inhibitor;innovation;melanoma;mortality;mutant;novel;novel therapeutic intervention;pre-clinical;preclinical safety;response;standard care;therapeutic effectiveness;translational framework;treatment strategy Targeting Ferroptosis in BRAF (V600E) Mutant Anaplastic Thyroid Cancer PROJECT NARRATIVEThe proposed research is relevant to public health because it focuses on developing a new andalternative strategy to treat cancer that simultaneously inhibits a common mutated oncoprotein (BRAF)and induces a mechanism of cell death (ferroptosis) that are involved in the growth and spread ofvariety of human cancers. Once such a strategy has been developed there is a potential for asignificant advance in anti-cancer therapy for advanced cancers that fail standard treatmentapproaches. Thus the proposed research is relevant to the part of the NIHs mission that pertains toreducing illness and disability. NCI 10721967 6/29/23 0:00 PAR-22-216 1R21CA273495-01A1 1 R21 CA 273495 1 A1 "COVELL, DAVID G" 7/1/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 2226044 "KEBEBEW, ELECTRON " Not Applicable 16 SURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 223693 NCI 140250 83443 PROJECT SUMMARY/ABSTRACTBRAFV600E mutations are common in anaplastic thyroid cancer (ATC 50-75% positive) which is refractory tostandard treatment and has high mortality rates. Monotherapy with BRAF inhibitors is ineffective in patientswith BRAFV600E-mutant ATC. Although combination therapy using a BRAF inhibitor and a mitogen-activatedprotein kinase (MEK) inhibitor is more effective than BRAF inhibitor monotherapy acquired resistance iscommon because BRAF and MEK act on the same downstream target and largely the same pathway. Afeature of resistance to BRAF inhibition or combined BRAF and MEK inhibition is increased sensitivity toagents that induce ferroptosis (a distinct mechanism of programmed cell death dependent on iron). Moreoverit has been shown that treatment-resistant (including BRAF inhibitor-resistant) cancer cells (persister cells) areassociated with a mesenchymal state that is dependent on GPX4 (a gatekeeper and suppressor of ferroptosis)and show increased sensitivity to ferroptosis induction. Our unpublished preliminary data show that ferroptosisinduction is more pronounced in BRAFV600E-mutant than wild type ATC cells and that combination BRAFinhibition and ferroptosis induction has synergistic activity in causing cell death in BRAFV600E-mutant ATC cells.The long-term goal is the development of novel science-based treatment strategies for ATC that improvepatient outcomes. The overall objective in this application is to determine the safety and preclinical therapeuticefficacy of combined BRAF inhibitor and ferroptosis induction treatment in BRAFV600E-mutant ATC. The centralhypothesis in this proposal is that combination therapy with BRAF inhibitor and ferroptosis induction will havesynergistic/additive anti-cancer activity in BRAFV600E-mutant ATC. The rationale for this project is thatdetermination of the safety and preclinical therapeutic efficacy of ferroptosis induction with BRAF inhibition islikely to offer a strong scientific basis for translation of this novel combinatorial treatment strategy to the clinic.The central hypothesis will be tested by pursuing two specific aims: 1) Evaluate the safety and anticanceractivity of targeting ferroptosis in combination with BRAF inhibition in BRAFV600E-mutant ATC in vitro and invivo; and 2) Evaluate the efficacy of combined ferroptosis induction and BRAF inhibition compared tocombination BRAF and MEK inhibition. The research proposed in this application is innovative in theapplicants opinion as it represents a significant departure from the current strategy of targeting BRAF only ora single signaling pathway in BRAFV600E-mutant ATC to the concept that combined treatment with a BRAFinhibitor and ferroptosis induction will result in more robust and synergistic/additive anticancer activity. Theproposed research is significant because it is expected to provide a strong scientific justification for futurestudies that could provide a new mechanism-based treatment regimen for BRAFV600E-mutant ATCs that couldresult in durable response. Ultimately such knowledge has the potential of offering new opportunities for thedevelopment of novel therapeutic strategy for BRAFV600E-mutant ATC. 223693 +No NIH Category available Algorithms;Antigens;Autoantibodies;Biological Markers;Blood Tests;Breast Cancer Detection;Breast Cancer Prevention;Breast Cancer Risk Assessment Tool;Characteristics;Clinical;Colorectal;Data;Development;Diagnosis;Diagnostic;Disease;Early Detection Research Network;Early Diagnosis;Exhibits;Female;Immunoassay;Individual;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Modeling;Ovarian;Participant;Patients;Pattern;Performance;Phase;Plasma;Predictive Value;Principal Investigator;Probability;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Proteins;Random Allocation;Resources;Risk;Risk Assessment;Sampling;Series;Specificity;Specimen;Standardization;TP53 gene;Technology;Testing;Time;Tumor Antigens;Validation;biomarker discovery;biomarker panel;biomarker validation;blood-based biomarker;cancer risk;candidate marker;cohort;follow-up;improved;long short term memory;malignant breast neoplasm;multidisciplinary;novel;pre-clinical;recurrent neural network;risk prediction;risk prediction model;screening;screening program;success;tool;tumor;validation studies Blood-Based Biomarkers for Personalized Risk Assessment of Breast and Ovarian Cancer Project NarrativeThe applicant group led by the Principal Investigator (PI) has conducted a series of Early Detection ResearchNetwork (EDRN) defined Phase 1-3 biomarker studies that have led to the identification and development of apanel of circulating proteins as well as autoantibodies directed against tumor proteins (including TP53 and novelcitrullinated antigens) for detection of breast and ovarian cancers. The primary translational objective of thisproject is to advance candidate biomarkers for detection of breast and ovarian cancers via testing in pre-diagnostic plasmas from the Prostate Lung Colorectal and Ovarian (PLCO) cohort and to develop a multi-analyteblood-based biomarker panel based on protein and autoantibody biomarkers for risk assessment of breast andovarian cancers. The resulting biomarker test would then be integrated with other risk models based on individualsubject characteristics such as the Gail Model for breast cancer to deliver personalized cancer risk assessmentand inform on a need for further pertinent tests that enable earlier diagnosis. NCI 10721949 9/19/23 0:00 PAR-21-330 1U01CA282216-01 1 U01 CA 282216 1 "ZHU, CLAIRE" 9/1/23 0:00 8/31/28 0:00 ZCA1-TCRB-9(M1) 14158591 "FAHRMANN, JOHANNES F" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 672298 NCI 414999 257299 Project Summary There remains a need to develop biomarker tests for personalized risk assessment of breast and ovariancancers. Such tests would not replace screening programs but would instead be a basic tool that can beintegrated with other risk models based on a subjects characteristics to personalize the risk of harboring cancerand inform on the need for screening and surveillance for earlier detection. The primary translational objective of this proposal is to develop a multi-analyte blood-basedbiomarker panel based on circulating proteins and autoantibodies against tumor antigens that inform about asubjects probability of harboring a breast or ovarian cancer. Studies by the applicant team have led to theidentification of a panel of cancer-relevant circulating proteins as well as autoantibodies against tumor proteinsincluding TP53 and novel citrullinated antigens for detection of breast and ovarian cancers. The PLCO cohortis an excellent resource to further advance testing of candidate biomarkers and to also establish combinationrules together with subject characteristics for individualized risk assessment of breast and ovarian cancers tooptimized screening and surveillance for earlier detection of these diseases.In Specific Aim 1 leveraging pre-diagnostic plasmas from 969 breast cancer cases and 106 ovarian cancercases as well as four times the number of non-case plasmas from female PLCO participants that did not developcancer during study follow-up we will assess the time-dependent (e.g. 0-1 year 1-2 years etc) predictiveperformance (AUC sensitivity specificity positive predictive value (PPV) and negative predictive value (NPV))of candidate biomarkers for detection of breast and ovarian cancers. Priority biomarker candidates will beadvanced to establish models together with pertinent patient characteristics (e.g. Gail Model for breast cancer)for 1-year risk prediction of BrCa and OvCa. For modeling we will adhere to the Predictability Computability andStability framework. The entire PLCO specimen set will be divided into a Development Set and a Set-Aside TestSet. Modeling and tuning of hyperparameters as well as initial validation will be performed in the DevelopmentSet. The model with the best predictive performance (AUC) in the Development Set will be selected forsubsequent testing in the Set-Aside Test Set. In Specific Aim 2 we will leverage serial samples procured fromcases preceding a diagnosis of a BrCa or OvCa and serial samples for non-cases and we will testwhether longitudinal trajectories of biomarker panel scores improve risk prediction. The proposed studyrepresents a validation of cancer-associated protein and autoantibody biomarkers and has high probability todevelop a blood test that can be implemented in the clinical setting for individualized risk assessment of breastand ovarian cancers. 672298 +No NIH Category available Affect;Antibodies;Antibody-drug conjugates;Binding;Biological Markers;Biological Process;Biology;CRISPR/Cas technology;Cancer Center;Cancer Vaccines;Cancer cell line;Cell Line;Cell Surface Proteins;Cell Survival;Cell Therapy;Cell physiology;Cell surface;Cells;ChIP-seq;Chickens;Child;Chimeric Proteins;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Coupled;Data;Data Set;Dependence;Development;Disease;Disease Progression;Drug Targeting;EWS-FLI1 fusion protein;EWSR1 gene;Enhancers;Ensure;Ewings sarcoma;FLI1 gene;Foundations;Gene Expression;Genes;Genetic Transcription;Genotype;Germany;Growth;Human;Hydrolase;Immune system;Immunohistochemistry;Immunotherapeutic agent;Immunotherapy;In Vitro;Invaded;Knock-out;Laboratories;Lipase;Lipids;Malignant Neoplasms;Maps;Mediating;Membrane;Metastatic Ewing's Sarcoma;Microsatellite Repeats;Modeling;Monoclonal Antibodies;Mus;Natural Killer Cells;Neoplasm Metastasis;Normal tissue morphology;Oncogenes;Oncogenic;Oncoproteins;Outcome;Pathology;Patients;Pattern;Pennsylvania;Phenotype;Phospholipase;Physicians;Physiology;Prognostic Marker;Proliferating;Proteins;Proteomics;Reagent;Recurrence;Regulation;Research;Role;Scientist;Signal Pathway;Signal Transduction;Specimen;Surface;Surface Antigens;Survival Rate;T-Lymphocyte;The Cancer Genome Atlas;Therapeutic;Tissue Microarray;Tissues;Transcriptional Regulation;Transmembrane Domain;Tumor Antigens;University Hospitals;Upstream Enhancer;Work;Xenograft Model;Zebrafish;cancer type;chimeric antigen receptor T cells;clinically relevant;clinically significant;design;drug discovery;epigenetic silencing;extracellular;genetic signature;in vivo;lysophosphatidic acid;member;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;overexpression;prion-like;professor;programs;receptor;sarcoma;success;transcription factor;transcriptome;transcriptomics;tumor growth;vaccine-induced antibodies;young adult Discovery and characterization of exceptionally specific surface oncoprotein LIPI in Ewing Sarcoma Project NarrativePatients with metastatic Ewing sarcoma have a less than 10% survival rate at five years; thereforeidentification of novel therapeutic targets and strategies are urgently needed to treat this type of cancer. Thisproposal focuses on the functional characterization of LIPI as a cell surface protein with oncogenic functionand a potential immunotherapy target due to its highly specific expression pattern in Ewing sarcoma.Ultimately the results obtained from this proposal will offer significant mechanistic understanding of theplayers involved in Ewing sarcoma growth and metastasis as well as making a clinical impact by identifyingpotential targets for treating this disease through cellular therapy. NCI 10721942 7/6/23 0:00 PAR-22-216 1R21CA274009-01A1 1 R21 CA 274009 1 A1 "COVELL, DAVID G" 7/6/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 12001657 "ASANGANI, IRFAN AHMED" Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 7/6/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 189922 NCI 116875 73047 Project SummaryChildren and young adults with metastatic Ewing sarcoma driven by oncogenic fusion transcription factor EWS-FLI1 continue to have poor outcomes. Immunotherapies using T cells NK cells cancer vaccines andmonoclonal antibodies are being considered for Ewing sarcoma especially for recurrent patients. Theidentification of human tumor-associated antigens (TAAs) recognized by the immune system is crucial forimmunotherapy. Through integration of Ewing sarcoma cell line gene expression ChIP-seq and normal andcancer tissue gene expression from the Genotype-Tissue Expression (GTEx) and the TCGA project we haveidentified LIPI as a highly specific tumor antigen and a potential oncogene that relies on the transcriptional activityof EWS-FLI1 in Ewing sarcoma. LIPI (Lipase member I (EC:3.1.1.-) is an evolutionarily conserved proteinpredicted to poses a transmembrane domain and extracellular lipid hydrolase domain. The biological function ofLIPI is not known but the enzymatic activity of LIPI is expected to produce lysophosphatidic acid (LPA) thatpotently affects several biological functions including proliferation cell survival and metastasis of tumor cells.We hypothesize that the LIPI is a unique biomarker and an oncogene that is expressed exclusively in Ewingsarcoma and is a potential target for cell based therapy. To our knowledge this proposal represents the firststudy evaluating the role of LIPI in cellular physiology and in particular Ewing sarcoma progression andmetastasis. The two specific aims of the projects are:Specific Aim 1: To elucidate the regulation and role of cell surface LIPI in Ewing sarcomaSpecific Aim 2: To investigate the role of LIPI in Ewing sarcoma growth/metastasis.Following the successful completion of the proposed aims in this application we will have evaluated the potentialof LIPI as a Ewing sarcoma specific surface oncoprotein and will have a long-term impact by establishing thestrong foundation for the development of LIPI-directed immunotherapeutics against Ewing sarcoma. 189922 +No NIH Category available AGR2 gene;Active Sites;Advanced Malignant Neoplasm;Adverse effects;Affect;African American;Agonist;American;Animal Model;Animals;Antineoplastic Agents;Apoptosis;Apoptotic;Autopsy;Binding;Biological Markers;Blood Cell Count;Breast;Breast Cancer Cell;Breast Cancer Patient;CASP8 gene;Cell Death;Cell surface;Cessation of life;Chemicals;Client;Clinical;Clinical Trials;Dependence;Disseminated Malignant Neoplasm;Disulfides;Dose;Down-Regulation;Drug Kinetics;Drug resistance;ERBB2 gene;ERBB3 gene;Epidermal Growth Factor Receptor;Ethnic Population;Exhibits;Family;Formulation;Future;Health;Heterodimerization;Histologic;Human;IGF1R gene;Induction of Apoptosis;Kidney;Knock-out;Ligands;Link;Liver;Malignant Neoplasms;Mediating;Medicine;Metabolism;Modeling;Monitor;Mus;Muscle;Needle biopsy procedure;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Oncogenic;Oncoproteins;Pathway interactions;Patients;Pharmaceutical Preparations;Plasma;Preparation;Primary Neoplasm;Property;Protein Disulfide Isomerase;Protein Inhibition;Proteins;Publishing;Receptor Protein-Tyrosine Kinases;Refractory;Resistance;Role;Route;Safety;Sampling;Signal Transduction;Structure;TNFRSF10A gene;TNFRSF10B gene;Therapeutic;Toxic effect;Tumor Escape;Tumor Necrosis Factor Receptor;Tumor Necrosis Factors;Up-Regulation;Woman;Work;advanced breast cancer;anti-cancer;biomarker validation;breast cancer survival;cancer cell;cancer subtypes;cancer survival;carcinogenesis;clinically relevant;disulfide bond;dosage;improved;in vivo;inhibitor;malignant breast neoplasm;mortality;overexpression;patient stratification;pharmacokinetics and pharmacodynamics;pharmacologic;preclinical efficacy;preclinical study;predictive marker;prevent;protein folding;receptor;refractory cancer;response;targeted agent;therapeutically effective;therapy resistant;treatment effect;triple-negative invasive breast carcinoma;tumor HER1-3 and Death Receptor protein folding as therapeutic vulnerabilities Therapeutics effective against metastatic and drug resistant breast cancers are desperately neededto improve patient survival. The objective of the present project is to characterize the pharmacokineticand pharmacodynamic properties and evaluate the safety of a new class of anticancer drugs termedDisulfide bond Disrupting Agents (DDAs) and select an optimal candidate for future IND-enablingstudies. DDAs are the first identified active site inhibitors of the protein disulfide isomerases ERp44AGR2 and act through a unique mechanism involving downregulation of EGFR HER2 and HER3and activation of Death Receptors 4 and 5 resulting in selective killing of EGFR+ or HER2+ breastcancer cells. NCI 10721930 7/7/23 0:00 PAR-22-216 1R21CA277485-01A1 1 R21 CA 277485 1 A1 "COVELL, DAVID G" 7/7/23 0:00 6/30/25 0:00 ZCA1-SRB-K(M2)S 2044683 "LAW, BRIAN K." Not Applicable 3 PHARMACOLOGY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 209624 NCI 140250 69374 Breast cancer remains a major killer of women due to the ineffectiveness of current drugs againstmetastatic and drug-resistant cancers. Additionally African American (AA) women sufferdisproportionately from breast cancer mortality in part because they develop the aggressive Triple-Negative Breast Cancer (TNBC) subtype more frequently than other ethnic groups. Thus agentseffective against drug-resistant and metastatic cancers and TNBCs may improve the survival ofbreast cancer patients. These aggressive cancers evade cell death through a variety of mechanismsincluding overactivation of the pro-survival HER-family of Receptor Tyrosine Kinases (RTKs)including EGFR/HER1 HER2 and HER3 (HER1-3) and inactivation of pro-apoptotic signaling.Tumors expressing HER1-3 are difficult to treat due to the partial redundancy among these receptorstheir oncogenic signaling as heterodimers and their ability to aberrantly heterodimerize with non-HERRTKs such as MET and IGF1R. Thus resistance to current HER-targeted agents is a significantclinical problem. Defective cancer cell apoptosis can result from inactivation of the TNF ReceptorApoptosis Inducing Ligand (TRAIL)/Death Receptor 4/5 (DR4/5) pathway which selectively killscancer cells while not affecting normal cells. Tumor resistance to TRAIL and other DR4/5 agonistsresults primarily from poor pharmacological properties of the agonists and the ability of cancer cells todownregulate DR4/5. Consequently agents that could inactivate the EGFR/HER2/HER3 signalingaxis and upregulate and activate DR4/5 independently of the TRAIL ligand may be efficacious againstbreast cancers unresponsive to current medicines. Disulfide bond Disrupting Agents (DDAs) are anew class of anti-cancer agents that induce regression of primary tumors and metastatic lesions ofdrug-resistant patient-derived tumors in animal models. In addition to the structural uniqueness ofDDAs recent studies indicate that DDAs are the first identified active site inhibitors of the ProteinDisulfide Isomerases (PDIs) ERp44 and AGR2. Further DDA inhibition of the PDIs ERp44 AGR2and PDIA1 alters the disulfide bonding of HER1-3 and DR4/5 resulting in HER1-3 downregulationDR5 upregulation and disulfide bond-mediated oligomerization and activation of DR4/5. Theobjective of the current project is to move DDAs toward clinical trials. The two Specific Aims proposedto achieve this objective are to 1) optimize DDA pharmacological properties and dosing for futureIND-enabling studies and 2) validate biomarkers to predict tumor sensitivity to DDAs and to monitortarget engagement and thoroughly evaluate any adverse effects of DDAs on normal tissues oranimal health. Based on their unique mechanisms of action and preclinical efficacy we expect DDAsto benefit breast cancer patients with treatment-refractory breast cancers. 209624 +No NIH Category available Amiloride;Apoptosis;Apoptotic;Autophagocytosis;Biochemical;Biological;Breast Cancer Cell;Caspase;Cathepsins;Cell Cycle;Cell Death;Cell Death Induction;Cell Death Process;Cell Differentiation process;Cell Membrane Permeability;Cell Survival;Cell membrane;Cell model;Cells;Ceramides;Cessation of life;Clinical;Communication;Complement;Cytosol;DNA Sequence Alteration;Development;Disease;Disease Management;Diuretics;Drug Modelings;Drug resistance;ERBB2 gene;Enzymes;Event;Failure;Future;Genes;Genetic;Goals;Induction of Apoptosis;Lactosylceramides;Lead;Lipids;Lysophosphatidylcholines;Lysosomal Storage Diseases;Lysosomes;Malignant - descriptor;Mammalian Cell;Mammary Neoplasms;Mediating;Membrane;Membrane Lipids;Metabolism;Mitochondria;Modeling;Molecular;Molecular Target;Morphology;Necrosis;Normal Cell;Organelles;Pathway interactions;Patient-Focused Outcomes;Peptide Hydrolases;Permeability;Pharmaceutical Preparations;Phenotype;Potassium;Production;Publishing;Reactive Oxygen Species;Recurrent Malignant Neoplasm;Recurrent tumor;Reporting;Resistance;Rupture;Second Messenger Systems;Secondary to;Signal Transduction;Sphingolipidoses;Sphingomyelins;Supplementation;Testing;Therapeutic;Therapeutic Agents;Tissues;Tumor Subtype;amphiphilicity;bis(monoacylglyceryl)phosphate;blood pressure control;cancer cell;cancer recurrence;cancer stem cell;cell transformation;cell type;cytotoxic;cytotoxicity;improved;insight;knock-down;lipid metabolism;lipidomics;metabolomics;metaplastic cell transformation;molecular modeling;neoplastic cell;novel;novel anticancer drug;novel strategies;novel therapeutics;overexpression;oxidation;parent grant;parent project;peroxidation;response;stem cell population;stem cells;targeted treatment;therapy resistant;tool;tumor Lysosomal-mitochondrial signaling in non-apoptotic cancer cell death PROJECT NARRATIVE Parent GrantThe proposed studies are aimed at understanding inter-organelle communication between lysosomes andmitochondria in mammalian cells and how this communication contributes to cell viability and disease state.The successful completion of the studies could shed light on the cellular and molecular mechanisms underlyingsome of the genetic lysosomal storage diseases and could provide an avenue for the development of novelanti-cancer drugs. NCI 10721789 5/11/23 0:00 PA-21-071 3R01CA250211-03S2 3 R01 CA 250211 3 S2 "SALNIKOW, KONSTANTIN" 7/1/20 0:00 6/30/25 0:00 1880465 "CARRAWAY, KERMIT L" Not Applicable 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 396 Non-SBIR/STTR 2023 45419 NCI 34078 11341 PROJECT SUMMARY Parent GrantThe overwhelming majority of conventional and targeted chemotherapeutics in clinical use or underdevelopment rely on engaging apoptotic pathways to elicit tumor cell death. However resistance to apoptosis-inducing agents is a particularly thorny clinical problem. A novel approach to targeting therapy-resistant cells isto engage cell death mechanisms other than apoptosis to eradicate these malignant subpopulations. Theoverall goal of the proposed studies is to define the lysosomal-mitochondrial inter-organelle signalingmechanisms underlying tumor cell-specific and programmed necrotic lysosomal cell death (LCD) processinduced by a number of drugs. Our lead compound hexamethylene amiloride (HMA) a derivative of a drug thathas been employed clinically in the management of blood pressure for over forty-five years kills differentiatedand stem cancer cells independent of tumor type subtype or species but does not efficiently kill normaldifferentiated cells or stem cells. Moreover HMA kills cancer cells independent of cell cycle autophagyengagement and caspase-dependent apoptosis; indeed cell death appears to result from drug-inducedpermeabilization of the lysosomal limiting membrane and subsequent cathepsin-mediated plasma membranerupture. Our observations indicate that efficient HMA-induced cell death requires the production and action ofmitochondrially-produced reactive oxygen species (ROS). Our observations also indicate that HMA induceshallmarks of some of the sphingolipidosis lysosomal storage diseases including the accumulation of a varietyof lipid species that are normally broken down by the lysosome. Notably lipids such as lactosylceramide andlysophosphatidylcholine that have been demonstrated to act as signaling second messengers in the productionof mitochondrial ROS accumulate specifically in tumor cells but not normal cells upon HMA treatment. Ourobservations point to a model where drug-induced aberrant lipid accumulation and ROS-mediated lysosomalmembrane lipid oxidation disrupt lysosomal membrane integrity allowing cathepsin release and induction ofnecrotic cell death. To test this model we will use biochemical cell biological and metabolomics approaches.In Aim 1 we will assess the contribution of bis(monoacylglycerol)phosphate (BMP) a lysosome resident lipidthat is suppressed in tumor relative normal cells and is further suppressed with HMA treatment in regulatinglysosomal membrane stability and cell viability via its ability to activate lysosomal enzymes of thesphingomyelin breakdown pathway. Complementing these studies will be an in-depth analysis of lipidomic andmetabolomic changes associated with cellular transformation and LCD-inducing agents. In Aim 2 we willexamine lysosomal-mitochondrial signaling events that couple mitochondrial ROS production to dysregulatedlysosomal lipid metabolism. These studies will uncover lysosomal targets that will allow future development ofnovel therapeutic agents that more effectively elicit cancer cell-specific programmed necrotic cell death. 45419 +No NIH Category available Advocacy;Advocate;Age;Behavior;Complex;Data;Decision Making;Documentation;Electronic Health Record;Face;Gender;Goals;Happiness;Health;Health Policy;Individual;Knowledge;Life;Life Style;Link;Medical;Medicare;Methods;Mission;National Cancer Institute;Nature;Outcome;Patient-Centered Care;Patient-Focused Outcomes;Patients;Predictive Factor;Preventive care;Process;Professional Organizations;Public Health;Readiness;Recording of previous events;Research;Risk;Screening for cancer;Smoker;Surveys;Testing;Trust;Uncertainty;United States National Institutes of Health;Visit;Vulnerable Populations;Work;alternative communication;anticancer research;behavioral outcome;cigarette smoking;design;disability;effective intervention;experience;health communication;high risk;improved;innovation;lung cancer screening;next generation;patient population;provider factors;public health relevance;satisfaction;screening;screening guidelines;shared decision making;smoking cessation;social stigma;support tools Using a Mixed Methods Approach to Understand Shared Decision-Making in Lung Cancer Screening PUBLIC HEALTH RELEVANCEThe proposed research is relevant to public health because understanding shared decision-making more fullyfrom the patient and clinician perspectives can support high quality decision-making and improved healthoutcomes in high-risk smokers. Thus the proposed research is relevant to the cancer research mission of theNational Cancer Institute and more broadly the National Institutes of Health's mission to seek fundamentalknowledge about the nature and behavior of individuals and the application of that knowledge to enhancehealth lengthen life and reduce illness and disability. NCI 10721731 3/1/23 0:00 PA-21-268 7R01CA222090-06 7 R01 CA 222090 6 "KOBRIN, SARAH" 10/8/22 0:00 8/31/24 0:00 Psychosocial Risk and Disease Prevention Study Section[PRDP] 11849887 "CARTER-BAWA, LISA " Not Applicable 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 10/8/22 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2022 219125 NCI 197619 21506 PROJECT SUMMARY/ABSTRACTEfforts to enhance patient-centered care have resulted in increasing advocacy for shared decision-making(SDM). Yet the active ingredients of SDM that positively impact decision quality and patient outcomes remainelusive. Lung cancer screening discussions and decisions are challenging for both patients and clinicians wherebenefits are present but risk and uncertainty exist and vary by individual. There is a critical need to determinehow patients and clinicians are approaching SDM in lung cancer screening and the impact on decision qualityand important behavioral outcomes. Without this knowledge effective interventions that support both the patientand clinician cannot be developed. Our long term goal is to develop the next generation of decision support toolsand alternative communication strategies to support clinicians and patients as they face increasingly complexcancer screening decisions. Our overall objective in this application is to identify the components of patient-clinician discussions that contribute to high quality lung cancer screening decisions and subsequent importantbehavioral outcomes. Our central hypothesis is that patients who perceive lung cancer screening discussionswith their clinician as shared will have positive decisional and behavioral outcomes. Guided by strong preliminarydata this hypothesis will be tested by pursuing three specific aims: 1) determine the key components of the SDMprocess that predict patient-perceived lung cancer screening decision quality screening completion amongpatients who decide to screen and stage of readiness for smoking cessation among current smokers; 2) identifyclinician factors that predict patient-perceived lung cancer screening decision quality screening completionamong patients deciding to screen and stage of readiness for smoking cessation among current smokers; and3) identify patient factors that predict patient-perceived lung cancer screening decision quality screeningcompletion among patients deciding to screen and stage of readiness for smoking cessation among currentsmokers. We will use a convergent mixed methods design to examine clinician (N=75) and patient (N=550)factors simultaneously by linking patient and clinician survey data with electronic health record data. We willexamine further the decision process through content analysis of audio-recordings of preventive care visits inwhich lung cancer screening is discussed (N=30). This proposal is innovative in that results will exponentiallyadvance our ability to create the next generation of decision support tools including alternative communicationstrategies to support patients and clinicians in lung cancer screening. This contribution is significant becauseidentifying the active ingredients in the SDM process will open new research horizons particularly in healthcommunication between clinicians and patients who are navigating complex health-related decisions such aslung cancer screening. Because of this work we will also open new paths toward improving healthcommunication among high-risk long-term smokers and their clinicians about their health. 219125 +No NIH Category available Affect;Alcohols;Animal Model;Asian;Asian population;Authorization documentation;Biological Markers;Biology;Black Populations;Black Indigenous People of Color;Cancer Etiology;Characteristics;Chemicals;Chinese;Cirrhosis;Clinic;Clinical;Clinical Data;Clinical Management;Communication;Consent;Data;Development;Drug Screening;Drug toxicity;Drug usage;E-learning;Educational Intervention;Epigenetic Process;Equity;Ethnic Origin;Ethnic Population;Etiology;Evaluation;FDA approved;Feedback;Feeds;Focus Groups;Funding;Future;Genetic;Genomics;Goals;Grant;HBV HCC;Health;Hepatitis B Virus;Hepatitis C virus;Hispanic;Hispanic Populations;Intervention;Latinx;Lead;Link;Liver diseases;Malignant neoplasm of liver;Modeling;Organoids;Parents;Participant;Patient Education;Patients;Pre-Clinical Model;Precision therapeutics;Prevalence;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Race;Reporting;Research;Risk Factors;Testing;Therapeutic;Tissue Donations;Tissues;Toxic effect;Translations;Treatment Efficacy;chronic liver disease;clinical material;community based participatory research;digital intervention;drug discovery;drug efficacy;drug use screening;efficacy trial;ethnic disparity;ethnic diversity;feasibility trial;field study;improved;insight;kinase inhibitor;liver cancer model;mortality;multidisciplinary;nonalcoholic steatohepatitis;novel;patient stratification;patient subsets;patient-level barriers;personalized therapeutic;pre-clinical;pre-clinical research;preclinical study;preference;racial disparity;racial diversity;racial minority;racial population;response;satisfaction;screening;tumor;usability;willingness AN INTEGRATED PLATFORM FOR NOVEL PERSONALIZED LIVER CANCER THERAPEUTICS NARRATIVEDespite increasing racial/ethnic disparities in HCC mortality rates there is a lack of diverse preclinical modelsthat capture the distinct racial/ethnic groups and that can be used for drug screening studies. In this project wewill investigate the upstream barriers and facilitators for Black Indigenous and People of Color (BIPOC)-HCCpatients to donate tissues for preclinical research and develop a culturally-tailored educational intervention fordiverse racial/ethnic groups to encourage such donations. We will finally generate establish preclinical models(i.e. patient derived organoids/PDOs) that take into account such differences in etiology and racial-ethnicbackground to advance new class of lead compounds for precision-based therapeutics in HCC. NCI 10721585 8/31/23 0:00 PAR-22-114 3R01CA256480-03S1 3 R01 CA 256480 3 S1 "VENKATACHALAM, SUNDARESAN" 7/1/21 0:00 6/30/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 14078747 "GUCCIONE, ERNESTO " "DAR, ARVIN ; LUJAMBIO, AMAIA " 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 8/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 253500 NCI 150000 103500 SUMMARY Hepatocellular carcinoma (HCC) is a major health problem with increasing mortality rates. In the US HCCmortality is strongly affected by race/ethnicity and the highest mortality is found among racial minorities such asBlack Indigenous and People of Color (BIPOC). This is partly due to (a) limited efficacy of current FDA-approvedtherapies and (b) a lack of personalized (biomarker-guided) therapeutic options which is compounded by a lackof HCC preclinical models from diverse race-ethnic backgrounds. Thus there is an urgent need to identify novel personalized therapeutic options that are validated inpreclinical HCC models that represent the racial/ethnic diversity observed in HCC patients. In this proposal for a supplement to our parental RO1 we expand our original team to integrate new expertisein equity research qualitative analytics communications research community-based participatory researchimplementation and organizational research (Mohamed Bickell) to the existing one in clinical management ofliver disease (Villanueva) chemical biology (Dar) HCC animal models (Lujambio) and patient derived-organoidsand 2D lines (Guccione). The major hypothesis that we seek to test is that BIPOC patients will report significant barriers to tissuedonation and that by facilitating the creation of such preclinical models (i.e. PDO) from diverse etiology and abroad spectrum of ethnic/racial backgrounds we will identify differences in drug efficacy and toxicity in relationto specific tumor genetic and epigenetic backgrounds. We propose to (a) Elucidate BIPOC HCC patients barriers and facilitators to donate tissue; (b) Develop andtest a culturally tailored educational intervention for diverse racial-ethnic groups to encourage tissue donationfrom HCC patients; and to (c) Establish better preclinical models (i.e. patient derived organoids PDOs) that takeinto account differences in etiology and racial-ethnic background. The latter models will then feed into our originalpipeline for drug screening with the aim to identify new precision therapeutic leads. The proposed research will increase our understanding of the barriers that limit or enable tissue donationfrom BIPOC HCC patients and to tailored intervention strategies to improve availability of preclinical models fromBIPOC patients ultimately resulting in improved preclinical studies and translation into the clinics. Key deliverables include new preclinical models and leads for drug discovery derived from well-validatedchemical starting points and mechanistic insights into patient stratification and therapeutics for HCC. 253500 +No NIH Category available Acclimatization;Address;Adoptive Immunotherapy;Antitumor Response;Apoptotic;Back;Cell Differentiation process;Cell Reprogramming;Cell Therapy;Cells;Clinical;Clinical Trials;Cytolysis;Data;Dose;Electroporation;Environment;Fishes;Fluorescent in Situ Hybridization;Frequencies;Future;Generations;Genes;Goals;Harvest;Image;Immune checkpoint inhibitor;Immune system;Immunologic Factors;Immunotherapy;In Vitro;In complete remission;Individual;Infrastructure;Infusion procedures;Insertional Mutagenesis;Interleukin-2;Knowledge;Laboratories;Lesion;Ligands;Longevity;Lymphocyte;Lymphocyte Activation;Malignant - descriptor;Malignant Neoplasms;Mediating;Memory;Messenger RNA;Metastatic Melanoma;Methods;OX40;Outcome;Pathway interactions;Patients;Phenotype;Population;Population Heterogeneity;Positioning Attribute;Production;Property;Proteins;Protocols documentation;RNA;Rejuvenation;Research;Safety;Sampling;System;T cell receptor repertoire sequencing;T cell therapy;T-Cell Receptor;T-Lymphocyte;TNFSF4 gene;Therapy Clinical Trials;Time;Transfection;Treatment Efficacy;Tumor Antigens;Tumor Expansion;Tumor-Infiltrating Lymphocytes;Variant;Work;advanced disease;cell mediated immune response;cytokine;design;effector T cell;efficacy evaluation;experimental study;fighting;gene therapy;humanized mouse;improved;instrument;long term memory;lymphocyte product;mRNA Expression;manufacture;melanoma;mouse model;multidisciplinary;neoplastic cell;novel;objective response rate;patient derived xenograft model;patient population;pre-clinical;programs;response;single cell analysis;single-cell RNA sequencing;success;transcriptomics;tumor;tumor growth;tumor microenvironment Enhancing Melanoma TIL Efficacy with Multifactor mRNA-Mediated T Cell Reprogramming PROJECT NARRATIVEHarnessing a patients immune system to attack melanoma is remarkably successful. In one promising approachT cells are harvested directly from the patients tumor expanded to very high numbers in the laboratory wherethey can be rejuvenated and returned to the patient to fight their cancer. As this is only effective in approximatelyhalf of patients with advanced disease here we develop a novel safe and efficient method to further boost thesetumor-reactive T cells by mRNA reprogramming. NCI 10721549 5/30/23 0:00 PAR-22-216 1R21CA282629-01 1 R21 CA 282629 1 "HU, ZHANG-ZHI" 7/1/23 0:00 6/30/25 0:00 ZCA1-SRB-P(M2)S 10234038 "KATZ, SAMUEL G" "HURWITZ, MICHAEL E" 3 PATHOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 234919 NCI 140250 94669 PROJECT SUMMARYAlthough T cell mediated immune responses are critical for the success of immunotherapy those T cellsassociated with malignant lesions are typically dysfunctional and fail to control tumor growth. Treatment withtumor infiltrating lymphocytes (TIL) that are isolated activated and expanded ex vivo has proven very effectivein some patient populations of melanoma. However a substantial number of patients do not respondpresumably due to one of a number of host immune factors. Current understanding of TIL mechanism of actionsuggests that both an early robust expansion of tumor-specific effector T cells and transfer of less differentiatedcells with long-term survival capacity are key to a successful therapy. Evidence for the former includes the needfor high dose exogenous IL-2 at the time of TIL infusion the correlation of response with a high frequency ofeffector T cells and the majority of tumor killing occurring very early after the initiation of therapy. Evidence forthe latter is found in many pre-clinical experiments as well as clinical observations where the presence of TILsfrom the central memory subset in the infusion product correlates with tumor regression. Our overall goal is toimprove TIL therapeutic efficacy through the generation of TIL products with both the transient ability to effectivelyimmediately kill tumor cells as well as the long-term ability to persist and maintain durable anti-tumor responses.To address these challenges we have developed robust methods to reprogram TILs with mRNA-mediated genetherapy. The use of our mRNA approach has the advantages of increased safety high efficiency rapidproduction tightly controlled expression levels and simultaneous multi-factor reprogramming. In preliminarywork we have developed a system that increases mRNA lifespan by an order of magnitude. Our single cellanalysis of patient TILs pre- and post-expansion has identified two specific pathways deficient in the expandedTIL product that likely contribute to their poor immediate efficacy and absence of memory fate. Both of thesewill be augmented by TIL mRNA reprogramming. In Aim 1 we will develop a method to enhance post-expansionTIL survival while in Aim 2 we will improve the production of central memory TILs. We will evaluate the effectof these improvements in TIL production using paired tumor/TIL sets derived from the melanomas from multiplepatients by studying tumor-mediated TIL activation and tumor lysis in vitro and in pre-clinical humanized mousemodels using single cell analysis and advanced spatial transcriptomics. This application addresses the need toimprove response rates to adoptive cell immunotherapies for melanoma and is designed to be translatable toclinical trials in the near future. 234919 +No NIH Category available Achievement;Adherence;Adoption;Agreement;Benchmarking;Cancer Survivor;Cardiopulmonary;Cardiovascular system;Caregiver Burden;Caregivers;Caring;Categories;Clinic;Communication;Communities;Couples;Data;Devices;Dimensions;Disease;Distress;Elements;Eligibility Determination;Emotional;Exercise;Family Caregiver;Family member;Fatigue;Frequencies;Goals;Health Promotion;Health behavior;Health behavior change;Hematologic Neoplasms;Hematological Disease;Heterogeneity;Home;Hour;Immune;Individual;Infection;Infusion procedures;Intervention;Joints;Light;Link;Lung;Maintenance;Medical;Moderate Exercise;Monitor;Motion;Muscle;Outcome;Outcome Measure;Pain;Participant;Partner in relationship;Patient Care;Patient Self-Report;Patients;Pattern;Personal Satisfaction;Physical Endurance;Physical Function;Physical Performance;Physical activity;Pilot Projects;Problem Solving;Procedures;Protocols documentation;Provider;Quality of life;Radiation;Randomized;Reporting;Role;Self Care;Self Direction;Services;Shortness of Breath;Site;Spouses;Supportive care;Techniques;Testing;Therapeutic;Training;Transplant Recipients;Transplantation;Treatment Efficacy;Walking;Whole-Body Irradiation;acceptability and feasibility;actigraphy;behavior change;behavioral outcome;cancer care;cancer therapy;cardiorespiratory fitness;caregiving;chemotherapy;commune;coping;cytopenia;design;efficacy testing;exercise intensity;exercise intervention;feasibility testing;fitbit;fitness;follow up assessment;follow-up;graft vs host disease;hematopoietic cell transplantation;improved;informal caregiver;malignant breast neoplasm;member;mortality;neglect;physical conditioning;physical symptom;pilot test;poor sleep;post-transplant;programs;prostate cancer survivors;recruit;satisfaction;sedentary;skills;sleep quality;social cognitive theory;stem cells;treatment as usual;treatment effect;treatment response Mates in Motion: Feasibility and Acceptability of a Couple-Based Physical Activity Intervention PROJECT NARRATIVEPhysical functioning and physical activity are reduced following hematopoietic cell transplantation (HCT) ademanding treatment for hematologic malignancies. Family caregivers are burdened in ways that interfere withtheir own health promotion. This study will test feasibility and acceptability of Mates in Motion a couple-basedphysical activity intervention for HCT recipients and their caregiving spouses/partners; the program prescribesweekly step (walking) goals and trains couples in problem-solving skills to support one another in theachievement of these goals. NCI 10721446 9/20/23 0:00 PAR-21-341 1R21CA275085-01A1 1 R21 CA 275085 1 A1 "MITCHELL, SANDRA A" 9/20/23 0:00 8/31/25 0:00 Lifestyle Change and Behavioral Health Study Section[LCBH] 8185975 "LANGER, SHELBY " Not Applicable 4 NONE 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ SCHOOLS OF NURSING 852876011 UNITED STATES N 9/20/23 0:00 8/31/25 0:00 393 Non-SBIR/STTR 2023 419253 NCI 333488 85765 PROJECT SUMMARYLevels of physical activity (PA) among cancer survivors are low yet PA may ameliorate difficult effects oftreatment. We focus here on PA following the most intensive form of cancer treatment hematopoietic celltransplantation (HCT). While potentially curative the procedure is highly demanding with multiple sequelaeincluding chemotherapy- and radiation-induced cytopenia and cardiovascular and pulmonary complications.PA is diminished post-transplant and this decrease is associated with poorer physical functioning. Moderateexercise has been deemed safe for HCT patients and PA interventions feasible. Findings regarding efficacyhowever are mixed in part due to heterogeneity of intervention components and outcomes. The largest trial todate reported null findings but the exercise intervention was self-directed (arguably light) and PA was assessedvia self-report. Findings from other studies suggest that PA may improve cardiorespiratory fitness physicalperformance and fatigue among HCT patients. All PA interventions in the HCT setting have focused entirelyon patients ignoring an opportunity to engage and benefit the family caregiver a 24/7 role requiring theprovision of medical and logistical support. Distress is common among HCT caregivers and their own healthpromotion is neglected. We aim to leverage the patient-caregiver relationship to improve PA among bothpatients and their caregiving spouses/partners. To do so we will test feasibility and acceptability of a couple-based PA intervention developed for general cancer survivors and caregivers but translatable to HCT. Guidedby social cognitive theory and interdependence/ communal coping perspectives this intervention providestraining in communication skills and joint problem-solving in the service of helping partners support oneanother in PA. We have adapted this protocol for the early post-HCT setting and will use Actigraph devices tomonitor PA and inform weekly individualized step prescription. Specific aims are to: (1) Determine feasibility ofrecruitment [% of eligible couples agreeing to participate] adherence [% of intervention sessions attended #valid Actigraph wear days % therapeutic elements covered by therapist] and retention [% follow-upassessments completed] in a single-site pilot RCT. (2) Determine acceptability of the intervention amongpatients and caregivers (multiple dimensions of treatment satisfaction). (3) Describe patterns of change in PAand communal coping (intervention targets) for those in the intervention relative to usual care. Findings willinform the design of a full-scale RCT to test efficacy of the intervention to improve physical well-being testmechanisms of action and identify potential moderators of treatment response. Findings will also inform effortsto optimize the intervention for integration into standard transplant care expanding providers' repertoire ofsupportive care options. More broadly the intervention could be adapted for different types of patient-caregiverdyads and illness contexts. 419253 +No NIH Category available Acceleration;Address;American Association of Cancer Research;American Society of Clinical Oncology;Area;Basic Science;Cancer Patient;Career Choice;Caring;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Conduct Clinical Trials;Consent Forms;Contracts;Data;Data Reporting;Development;Discipline;Educational workshop;Effectiveness;Ensure;Ethnic Origin;Evaluation;Faculty;Feedback;Fostering;Funding;Future;Gender;Geography;Goals;Grant;Home;Immunologics;Individual;Institution;Institutional Review Boards;International;Knowledge;Malignant Neoplasms;Mentors;Mentorship;Methodology;Methods;National Cancer Institute;New Agents;Oncology;Participant;Patient Recruitments;Patient Self-Report;Patients;Phase;Positioning Attribute;Prevention;Preventive;Procedures;Process;Program Effectiveness;Protocols documentation;Public Health;Publications;Published Comment;Research Personnel;Review Literature;Site;Speed;Student Selections;Students;Surveys;Teaching Method;Technology;Testing;Training;Translational Research;Work;anticancer research;cancer clinical trial;cancer therapy;career;career development;career networking;clinical practice;clinical trial readiness;data mining;design;effectiveness evaluation;evaluation/testing;experience;falls;flexibility;follow-up;improved;lectures;member;novel therapeutics;patient oriented research;peer;phase 2 designs;phase II trial;pre-clinical;prevent;programs;protocol development;recruit;sound;student participation;success;targeted treatment;tool;trial design Methods in Clinical Cancer Research Workshop Project NarrativeThe Workshop trains early-career investigators how to design and conduct cancer clinical trialsthat produce definitive results. Its primary goal is to assure that new therapeutic and preventiveagents are tested in the clinic in as sound and as efficient a manner as possible. Trainingmentoring and retaining clinical cancer trialists benefits public health by increasing the speedand number of agents that can be tested and made available to prevent cancer and improve thecare and treatment of cancer patients. NCI 10721362 7/21/23 0:00 PA-20-272 3R25CA068647-23S1 3 R25 CA 68647 23 S1 "ELJANNE, MARIAM" 1/1/23 0:00 12/31/23 0:00 6842110 "HIDALGO, MANUEL " Not Applicable 2 Unavailable 139203590 K4LZTWHBSGN6 139203590 K4LZTWHBSGN6 US 39.949341 -75.150986 210901 AMERICAN ASSOCIATION FOR CANCER RESEARCH PHILADELPHIA PA Other Domestic Non-Profits 191064404 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 398 Other Research-Related 2023 70000 NCI 64815 5185 Project Summary/AbstractThe Methods in Clinical Cancer Research Workshop is a week-long program designed toeducate and train early-career investigators in the best practices of clinical trial design provideaccess to experienced clinical investigators from different institutions with expertise across allareas of clinical research and develop and foster both peer-to-peer and mentoring relationshipsto enhance career development beyond the dates of the Workshop. Students are selected usinga competitive application process that consists of a protocol concept personal statement andsupport from an existing mentor. Those accepted to the Workshop will have access to dozens offaculty members who through the course of the Workshop will help students develop conceptsheets into IRB-ready clinical trials including informed consent documents ready forsubmission at their home institutions.Students participate in pre- and post-tests to determine the effectiveness of the program whichfeatures a mix of didactic lectures small group discussions one-on-one mentoring sessionsand daily protocol development group sessions. The protocol development group sessions aremade up of 3-4 faculty members and 8-10 students that work collaboratively as a group for theweek. This makes up the core of the Workshop as the groups meet daily to review progressmade each day and provide feedback and guidance for next steps in their individual trialdesigns. Daily progressive assignments are submitted each evening with reviews andcomments from the faculty provided the following morning.The Workshop is offered to early-career investigators in all oncology disciplines who are nearingcompletion of their training or have recently begun their initial faculty positions. A review of theliterature comments from Workshop attendees and the number of similar programs beingdeveloped in the U.S. and internationally shows that despite advances in basic science andnew preclinical agent development there is a serious shortage of clinical investigators who havethe pre-requisite knowledge to actually design and conduct effective clinical trials to match theattributes of these new agents. With the ever-increasing pace of technology and its implicationsin clinical trial design the knowledge and number of tools that a clinical investigator needs to beable to utilize effectively continue to grow at a rapid rate. The Workshop is designed to addressthe needs today while maintaining flexibility to implement changes to train early-careerinvestigators on how to conduct effective clinical trials in the future. The Workshop is organizedby the American Association for Cancer Research and the American Society of ClinicalOncology and has provided training to over 1800 investigators since its inception in 1996.The Workshop is evaluated through the use of pre- and post-tests given to the students; dailyand week-long evaluations completed onsite; a 1-year 3-year 5-year and 10-year followupsurvey each fall. The Workshop also contracted with an independent data-mining and analysisfirm in 2013-2014 to provide a long-term historical comparison of students and non-students(applicants that were not accepted) that quantified their effectiveness pre- and post-Workshop inthe areas of successful clinical trials publications grants and collaborations. 70000 +No NIH Category available Acceleration;Adjuvant Chemotherapy;Affect;Anatomy;Area;Biliary Tract Cancer;Biological Assay;Biological Markers;Biology;Cancer Biology;Cancer Etiology;Cancer Patient;Cells;Chemicals;Clinic;Clinical;Clinical Laboratory Improvement Amendments;Clinical Oncology;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Computational Biology;Computing Methodologies;Credentialing;Data;Data Set;Dependence;Derivation procedure;Development;Drug Combinations;Drug Screening;Drug Targeting;Drug resistance;Drug usage;Environment;Epigenetic Process;Evolution;Future;Gene Expression;Genetic;Genetic Markers;Genomics;Goals;In Situ;Lethal Genes;Letters;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Methodology;Methods;Modeling;Molecular Genetics;Molecular Profiling;Multiomic Data;Mutation;Neoadjuvant Therapy;Oncogenic;Oncologist;Oncology;Organoids;Outcome;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Proteomics;Public Domains;Recording of previous events;Research;Resistance;Resistance development;Resource Sharing;Resources;Role;Sampling;Serous;Site;Stable Disease;Surgical Oncology;System;Technology;Testing;Translating;Translations;Treatment Failure;Validation;Work;cancer genetics;cancer type;chemotherapeutic agent;chemotherapy;clinically relevant;computerized tools;computing resources;drug development;drug resistance development;drug sensitivity;effective therapy;epigenetic profiling;epigenomic profiling;functional genomics;gemcitabine;genetic analysis;improved;individual patient;innovation;insight;mortality;neoplastic cell;new therapeutic target;novel;pancreatic cancer patients;patient response;pre-clinical;precision medicine;precision oncology;predictive modeling;pressure;prospective;protein degradation;refractory cancer;small molecule;small molecule inhibitor;standard of care;targeted agent;targeted treatment;therapeutically effective;tool;tumor;tumor heterogeneity A Patient-Centric Approach to Advance Functional Precision Oncology PROJECT NARRATIVEBecause each patients tumor is unique treatments should be tailored to individual patients.We will develop a patient-centric approach that integrates novel experimental and computationalmethods using patient derived tumor cells to identify novel drug targets and potentially effectivedrugs and drug combinations. Identifying targets and effective drugs directly in patient derivedsamples with known clinical history will significantly enhance translation of our findings leadingto improved clinical outcomes. NCI 10721205 9/22/23 0:00 PAR-21-274 1U01CA282109-01 1 U01 CA 282109 1 "ZENKLUSEN, JEAN C" 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-P(M1) 1894034 "KEMP, CHRISTOPHER J" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1098796 NCI 728833 369963 PROJECT SUMMARY/ABSTRACTThe development of drug resistance is a major cause of cancer treatment failure and mortality. Althoughmuch is known about the mechanisms by which tumor cells can become resistant to a given drug translatingthis into effective therapeutic solutions remains an unmet clinical need. Here we propose to pioneer the useof patient derived tumor organoids (PDTOs) as a platform to identify and validate novel targets and effectivedrugs to overcome drug resistance in ovarian cancer pancreatic cancer and other tumor types. In ourpreliminary studies we show that PDTOs genetically and phenotypically match the tumor from which theywere derived and can be used to study the phenotypic consequences of tumor heterogeneity tumorevolution and drug resistance. Using a Clinical Laboratory Improvement Amendments (CLIA) approvedhigh complexity assay we show that PDTO drug sensitivities are highly concordant with known geneticbiomarkers retrospective treatment history and prospective patient responses. Tumor organoids derivedfrom patients who developed in situ drug resistance demonstrate ex vivo resistance to those same drugs butalso demonstrate sensitivity to other alternative oncology drugs. Additional preliminary studies show stabledisease or tumor regression in patients treated with drugs identified from organoid drug screens. Here wepropose to combine drug screening and molecular profiling of PDTOs derived from a given patient fromdifferent anatomic tumor sites and before and after therapy to elucidate the mechanistic basis for drugsensitivity or resistance and to identify novel targets and effective drugs to treat metastatic drug resistantcancers. Accompanying computational prediction models that integrate large public datasets as well asinnovative methods of mechanistic target validation including CRISPR targeted protein degradationtechnologies and epigenetic profiling will be used to prioritize and advance targets and associatedbiomarkers with greatest clinical potential. The rationale behind our approach is that identifying targets andeffective drugs directly in patient derived samples with known clinical history and outcomes will significantlyenhance translation of our findings. This proposal is significant because it will demonstrate the utility ofPDTOs as both a research tool for target discovery and validation but also as a clinically useful platform toguide functional precision medicine. The findings and methods developed can be readily applied to othercancer types and clinical challenges will accelerate preclinical drug and drug target development and willtranslate to clinical studies. The models approaches and expected outcomes of this proposal are highlyresponsive to the requirements of PAR-21-274. 1098796 +No NIH Category available Area;Award;Board Certification;California;Cancer Center;Cervix Uteri;Clinical;Clinical Trials;Committee Members;Community Outreach;Development;Developmental Therapeutics Program;Early Therapeutic-Clinical Trials Network;Ensure;Equity;Female;Female Genital Diseases;Funding;Goals;Grant;Gynecologic;Gynecologic Oncology Group;Immune;Information Dissemination;Institution;K-Series Research Career Programs;Leadership;Malignant neoplasm of cervix uteri;Medicine;Mentors;Mentorship;Molecular;Oncology;Oncology Group;Outcome;Patients;Phase;Positive Lymph Node;Principal Investigator;Qualifying;Radiation;Radiation Oncologist;Radiation Oncology;Rebecca and John Moores UCSD Cancer Center;Research;Research Personnel;Role;Sampling;Services;Testing;Therapeutic;Therapeutics Committee;Translational Research;Underrepresented Minority;Underserved Population;Universities;Writing;anti-PD-L1;biomarker driven;cancer clinical trial;chemoradiation;clinical trial enrollment;community engagement;early phase clinical trial;health care disparity;high risk;improved;ipilimumab;member;novel;phase I trial;professor;programs;translational clinical trial;treatment trial NCI Clinical Trial Research Strategy Harnessing of Equity and Implementation PROJECT NARRATIVEThis proposal describes my 13 yr. long-standing qualifications and contributions for NCI funded clinical trialsthough my leadership within the NRG Oncology network as former co-chair of the GYN developmentaltherapeutics phase I committee current co-chair of the cervix committee service as a core and executivecommittee member principal investigator status on two early phase clinical trials in cervical cancer with noveltranslational outcomes and my development of new clinical trials through strategy. I am a clinical trials leaderas GYN co-chair at my institution UCSD Moores Cancer Center (MCC) which has a strong well-establishedNational Cancer Clinical Trials program with over 265 therapeutic treatment trials open. My clinical trialresearch focuses on health care disparities and increasing underrepresented minority accrual andrepresentation as a PI on national clinical trials through extensive mentorship within the NRG Oncology forjunior investigators. NCI 10721134 9/4/23 0:00 PAR-21-306 1R50CA282102-01 1 R50 CA 282102 1 "LINDWASSER, ONN WOLF" 9/4/23 0:00 8/31/28 0:00 ZCA1-SRB-1(M2) 10480605 "MAYADEV, JYOTI " Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/4/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 173920 NCI 110076 63844 PROJECT SUMMARY/ABSTRACTI am a female board-certified radiation oncologist and Professor at the University of California (UC) San Diegoin the Department of Radiation Medicine. My research and clinical efforts involve every phase of gynecologic(GYN) clinical trials with a focus on translational science and I am a leader in the NRG Oncology NCI network.My national leadership within NRG Oncology spans over 13 years: I served as a core Member of the RadiationOncology GOG committee (20092015) the Phase I Developmental Therapeutics Committee and theCervical Cancer Committee which lead to service as Co-Chair of the GYN Developmental TherapeuticsCommittee 20152018 and receipt of a National Service Award from NRG Oncology as the Co-Chair of thePhase I Committee in 2018. I then transitioned to the NRG cervical cancer co-chair from 2018-present. Inthese roles I develop the strategic outline of advancing NCI clinical trials though writing development of newtrials accrual and public dissemination of the results in a timely fashion. I am also keenly involved with thementorship of junior investigators at the NRG to increase underrepresented diversity as investigators onnational clinical trials and serve as the principal investigator primary mentor or study team on 13 proposals inthe GYN portfolio at NRG since 2018. At UCSD I am heavily involved with the clinical trials office and havegrants through the UCSD community outreach and engagement to increase equity among NCI clinical trialenrollment. I serve as the Co-Leader of the GYN Disease Team at the Moores Cancer Center (MCC) theUCSD Co-PI for the ECTCN trial network on MCCs UM1 ETCTN grant (VICKtOrY Early Clinical TrialsConsortium; UM1CA186689) with the goal of bringing lab discoveries to the treatment of patients andimproving accrual of underserved populations. I developed a pipeline of early phase clinical trials in nodepositive high risk cervical cancer with NCI funding as principal investigator from 2009 for GOG 9292 Phase Itrial using sequential ipilimumab in locally advanced cervical cancer. and received a NCI career developmentaward for the clinical trial in 2018 as principal investigator on GYN NRG 017 Anti PD-L1 (Atezolizumab) as animmune primer and concurrently with extended field chemoradiotherapy for node positive locally advancedcervical cancer. My goal is to expand our current efforts to offer NCI-funded clinical trials throughout theregion and ensure equity access to them through clinical trial development expansion of our clinical trialsoffice in strategic areas of underrepresented minority accrual. With the R50 Award I would (1) expand mycurrent efforts as a PI and mentor PI for novel clinical trial submissions in the NCI funded NRG Oncologynetwork for GYN patients nationally and locally; (2) ensure equity leadership as investigator status within NRGOncology clinical trials and explore biomarker-driven clinical trial translational samples with equity in moleculartesting; (3) take on new and higher leadership roles within the NRG oncology group. 173920 +No NIH Category available Address;American College of Radiology Imaging Network;Award;Cancer Center;Clinic;Clinical;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Conduct Clinical Trials;Country;Data;Development;Disease;Early Therapeutic-Clinical Trials Network;Eastern Cooperative Oncology Group;Enrollment;Ensure;Funding;Future;Growth;Home;Improve Access;Institution;Lead;Leadership;Lymphoma;Malignant Neoplasms;Modality;Monitor;National Clinical Trials Network;Oncologist;Patient-Focused Outcomes;Patients;Persons;Positioning Attribute;Research;Research Personnel;Resources;Role;Safety;Series;Site;Specialist;Therapeutic Studies;Tumor Expansion;Universities;career;cohort;community engagement;experience;improved;improved outcome;innovation;interest;metropolitan;next generation;participant enrollment;programs;skills;standard of care;success;virtual;working group Increasing Participation in NCI-Funded Clinical Trials at Winship Cancer Institute PROJECT NARRATIVEI am committed to the successful implementation of NCI-funded clinical trials and have devoted a large portionof my career to ensuring such studies are available to patients nationwide. I will utilize the support provided bythis award to improve accrual to studies throughout the state of Georgia and access to leadership roles fortrainees and junior colleagues. I will leverage leadership in real world evidence cohorts to develop the nextgeneration of impactful trials. NCI 10721093 9/22/23 0:00 PAR-21-306 1R50CA276010-01A1 1 R50 CA 276010 1 A1 "TAWAB-AMIRI, ABDUL" 9/22/23 0:00 8/31/28 0:00 ZCA1-SRB-1(M2) 14758459 "COHEN, JONATHON B." Not Applicable 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 156603 NCI 100066 56537 PROJECT SUMMARY/ABSTRACTI have devoted my career to the improvement of outcomes for patients with lymphoma and have utilized myexpertise to improve clinical trial conduct at my home institution and nationally. I have developed a sincerecommitment to the success of NCI-funded clinical trials which often address the most critical clinical questionsand which consistently challenge the standard of care in order to improve patient outcomes nationwide. WinshipCancer Institute of Emory University is a National Clinical Trial Network Lead Academic Participating Site andboasts a robust clinical trial portfolio enrolling roughly 1000 patients per year to therapeutic studies at multiplesites throughout metropolitan Atlanta. I am the co-director of the lymphoma disease program leader of thelymphoma treatment modality working group and chair of the Data Safety Monitoring Committee. In these rolesI can impact clinical trials in my clinic and throughout the Cancer Center. I have also assumed leadership of trialsthrough the ECOG-ACRIN lymphoma committee (PrE0404 A051201) have recently been appointed torepresent ECOG-ACRINs lymphoma committee on a Real World Evidence Working Group and am the co-chairof the lymphoma disease specific working group for Winships ETCTN consortium. As a result I am well-positioned to significantly impact of the success of NCI-funded studies. I will utilize the resources of the R50Research Specialist Award to improve NCI-funded clinical trials through improved access and accrual to NCTNand ETCTN trials in Atlanta and the state of Georgia by strengthening existing collaborations with oncologiststhroughout the state in association with Winships Office of Community Outreach and Engagement. This willinclude expansion of tumor boards and national programming 1:1 in person and virtual communication withcolleagues and facilitation of opportunities to enroll patients in NCTN studies closer to their home communities.I will continue to develop a pipeline of junior investigators and trainees nationwide who are interested in clinicaltrials and will ensure they have access to NCTN and ETCTN support to support development of their ownconcepts. I will develop the next series of trials by utilizing my experience as a leader in Real World Evidencecohorts both within ECOG-ACRIN and with colleagues throughout the country. I will continue growth of theNCTN and ETCTN at Winship and will ensure that colleagues continue to have innovative studies to which toenroll patients and have the skills needed to develop their own projects based on current and future clinicalneeds. 156603 +No NIH Category available Affect;Antibodies;Architecture;CD8-Positive T-Lymphocytes;CRISPR screen;Cancer Biology;Candidate Disease Gene;Categories;Cell Communication;Cell Cycle;Cell Death;Cell Fraction;Cell membrane;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Collection;Complementary DNA;Computer Analysis;Data;Development;Drug Targeting;Environment;Fibroblasts;Gene Expression;Genes;Genomics;Goals;Growth;Head Cancer;Immune;Immunity;Immunocompetent;Immunologic Surveillance;Immunotherapy;In Situ;Infiltration;Invaded;Knock-out;Knowledge;Ligands;Machine Learning;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Maps;Measures;Mediating;Modeling;Morphology;Mutate;Mutation;Neck Cancer;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Outcome Study;Ovarian Serous Adenocarcinoma;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Patients;Pharmaceutical Preparations;Phenotype;Positioning Attribute;Process;Publishing;Resistance;Resolution;Role;Selection for Treatments;Serous;Solid Neoplasm;T cell therapy;Testing;The Cancer Genome Atlas;Tumor Biology;Tumor Immunity;Tumor-Associated Process;antiangiogenesis therapy;cancer cell;cancer imaging;cancer therapy;candidate identification;cell stroma;chemokine;cohort;cytokine;extracellular;fitness;functional genomics;gene function;genomic platform;immune checkpoint blockade;immunosuppressed;improved;in vivo;innovation;insight;malignant breast neoplasm;mouse model;mouth squamous cell carcinoma;multiplexed imaging;novel therapeutic intervention;overexpression;personalized medicine;predicting response;preservation;recruit;refractory cancer;response;therapy resistant;transcriptomics;treatment response;tumor;tumor behavior;tumor growth;tumor microenvironment Spatial functional genomics to identify regulators of the tumor microenvironment and cancer immunity PROJECT NARRATIVEThe objective of this project is to determine the genes regulating tumor composition and facilitating tumor growthand resistance to immunity & immunotherapy with the goal of identifying factors that can be targeted to enhancetumor immunity and improve cancer treatment. We will focus on four highly prevalent and deadly cancers - nonsmall cell lung cancer (NSCLC) pancreatic ductal adenocarcinoma (PDAC) high grade serous ovarian cancer(HGSOC) and oral squamous cell carcinomas (OSCC) and utilize large-scale genomic and transcriptomic datafrom patient tumors spatial functional genomics and computational analysis to reach our goal. NCI 10720979 9/19/23 0:00 PAR-21-274 1U01CA282114-01 1 U01 CA 282114 1 "ZENKLUSEN, JEAN C" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-P(M1) 9353594 "BROWN, BRIAN D" "MERAD, MIRIAM ; SAMSTEIN, ROBERT M" 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1032278 NCI 616338 415940 PROJECT SUMMARY Tumor growth and response to therapy particularly immunotherapy are all highly dependent on the tumormicroenvironment (TME): the collection of cells and extracellular factors (cytokines chemokines collagens etc.)that form around cancer cells. This is evident from the major impact drugs targeting TME components can haveon cancers including immune checkpoint blockade (ICB). Though there is a relatively good understanding ofkey genes regulating cancer cell intrinsic processes such as cell cycle there is less known about genescontrolling the extrinsic environment that protects cancer cells from immunity and aids growth. The objective of this project is to determine the genes controlling tumor composition and facilitating tumorgrowth and resistance to immunity & immunotherapy with the goal of identifying vulnerability factors that canbe targeted to enhance tumor immunity and improve cancer treatment. The overarching hypothesis whichforms the rationale for this U01 is that malignant cells turn on or off genes including intrinsically operating genesthrough mutations and selective gene expression that act extrinsically to recruit position & polarize immune &stroma cells into a state that subverts immunity & facilitates tumor growth1 2. To reach our objective we willemploy a first-of-its-kind spatial functional genomics platform called Perturb-map which permits extensivephenotypic analysis of dozens of single or multiple gene perturbations in a tumor at single cell resolution andwith spatial architecture preserved. With Perturb-map CRISPR knockout (KO) or cDNA overexpression (OE)screens are resolved by multiplex imaging & spatial transcriptomics (ST) and this allows study of entire classesof genes (e.g. secreted factors) and phenotypes (e.g. TME composition) not feasible with existing screens. We will use Perturb-map to determine the role of 100s of genes in controlling many critical tumor processesincluding tumor: (i) growth (ii) morphology (iii) metastasis (iv) cell-cell interactions (v) subclonal interactions(vi) immune/stroma recruitment & polarization (vii) resistance to immunotherapy & other treatments. The breadth& depth of analysis of each gene will be achieved at a scale and efficiency not previously feasible. We will focuson 3 broad categories of genes identified through analysis of TCGA ICB-treated cohorts single cell-omics andother patient data including: commonly mutated cancer genes in solid tumors (Aim 1) genes correlating withresistance or response to ICB immunotherapy (Aim 2) and cancer cell-derived ligands and secreted molecules(Aim 3). Studies will be carried out in immunocompetent orthotopic models of non-small cell lung carcinomahigh grade serous ovarian carcinoma pancreatic adenocarcinoma and oral squamous cell carcinoma. The study outcome will determine the roles of 100s of genes in many processes critical to unimpeded cancergrowth including identifying genes shielding cancers from immunity. In doing so they will generate insights intomechanisms of aggressive tumor behavior and treatment resistance that will help to improve and personalizetreatment selection and drive the immediate next steps towards the development of novel therapeutic strategies. 1032278 +No NIH Category available Advanced Development;Advertising;Advocacy;Advocate;Antismoking;Attention;Attitude;Behavior;Brain;COVID-19 pandemic;Cigarette;Clutterings;Communication;Community Health;Confusion;Consensus;Consumption;Development;Devices;Diffuse Pattern;Diffusion;Effectiveness;Electronic Nicotine Delivery Systems;Electronic cigarette;Environment;Exposure to;Foundations;Freedom;Frequencies;Future;Gatekeeping;Harm Reduction;Health;Health behavior;Individual;Intervention;Linguistics;Machine Learning;Marketing;Measures;Media Campaign;Media Intervention;Misinformation;Nonprofit Organizations;Pattern;Policies;Prevalence;Prevention;Probability;Process;Public Health;Published Comment;Reporting;Research;Risk;Sales;Science;Semantics;Smoking;Social Network;Social isolation;Source;Technology;Teenagers;TikTok;Time;Tobacco;Tobacco Dependence;Tobacco use;Twitter;Youth;cigarette smoking;combat;combustible cigarette;community organizations;comparative;design;digital media;effectiveness evaluation;electronic cigarette use;health organization;improved;innovation;insight;non-cigarette tobacco product;peer;prevent;prevention effectiveness;programs;promoter;respiratory health;response;smoking cessation;social media;social structure;theories;tobacco control;tobacco products;tool development;vaping;young adult Using Innovative Machine Learning to Detect Organized Support and Opposition to E-cigarette Use Prevention Campaign Messaging on Twitter and TikTok PROJECT NARRATIVE Social media have been increasingly used to disseminate e-cigarette use prevention messages howeververy limited research has comprehensively examined the amount themes and sources of these campaignsand the social networks embedded in the campaign conversations. This project will fill this gap by measuringreach and engagement of such campaigns and analyzing comparative themes major strategies counteringthese interventions and the social networks upon which campaign effectiveness depends. These insights willthen be used to develop concepts and technologies to help create effective social media campaigns preventinge-cigarette use among youth and young adults. NCI 10720700 6/26/23 0:00 PAR-22-164 1R01CA283038-01 1 R01 CA 283038 1 "D'ANGELO, HEATHER" 7/1/23 0:00 6/30/28 0:00 Lifestyle and Health Behaviors Study Section[LHB] 14100793 "FENG, MIAO " Not Applicable 7 Unavailable 69512291 MPYFY5UMSDP4 69512291 MPYFY5UMSDP4 US 41.785875 -87.597545 5730401 NATIONAL OPINION RESEARCH CENTER CHICAGO IL Other Domestic Non-Profits 606035713 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 691116 NCI 414097 277019 Using Innovative Machine Learning to Detect Organized Support and Opposition to E-cigarette UsePrevention Campaign Messaging on Twitter and TikTok In recent years sharp increases in the consumption of non-cigarette tobacco products including vapingproducts or electronic nicotine delivery systems (ENDS) have largely offset the significant decline in cigarettesmoking rates in the US over the past five decades. In response several state local and federal tobaccocontrol programs have developed prevention campaign messages for youth vaping and e-cigarette use. Someof these campaigns have also provoked significant opposition on social media from tobacco harm reductionadvocates. Strong evidence supports the effectiveness of anti-smoking media campaigns in preventing youth cigarettesmoking but little research has examined the effects of campaigns that aim to prevent other types of tobaccouse such as anti-vaping campaigns. Further previous evidence about prevention campaign effects did nottake into account the current cluttered media environment where campaign messages compete for audienceattention with tobacco product promotion messages and both supportive and oppositional messaging about thecampaigns themselves. Thus social media interventions to prevent e-cigarette use are necessary but have unknown potentialeffects in a competitive communication environment characterized by an influx of ENDS product marketing andadvocacy potentially resulting in audience confusion and misinformation. Therefore measuring engagement with e-cigarette use prevention campaigns on social media andunderstanding the patterns of such engagement and information flow represent important advancements in thescience of prevention and lend evidential support for tobacco regulatory policy. The proposed project willassess the e-cigarette use prevention-related content amount reach and engagement on social media (Aim1); identify sources and major themes associated with both supportive and oppositional messages usingmachine learning (Aim 2); and apply social network theories and approaches to examine patterns of socialmedia users information seeking exposure dissemination and gatekeeping in the campaign periods overtime (Aim 3). 691116 +No NIH Category available Cellular biology;Training Programs;cancer cell Cancer Cell Biology Training Program 8. Project NarrativeThe need for well-trained cancer biologists is more acute than ever with the growing impact of cancer on life andhealth. In this renewal application for our long-standing interdisciplinary Cancer Cell Biology Training Programfor predoctoral students at the University of North Carolina at Chapel Hill we propose our vision for the trainingof cancer biologists who will be well prepared to contribute rigorously and effectively to the changing landscapeof cancer biology whether their future paths are in academic or non-academic careers. NCI 10720341 6/23/23 0:00 PA-20-142 2T32CA071341-26 2 T32 CA 71341 26 "LIM, SUSAN E" 9/30/96 0:00 6/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1860326 "DER, CHANNING J." "COX, ADRIENNE D" 4 PHARMACOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 314720 NCI 305964 15597 AbstractThis application seeks the continuation of the University of North Carolina at Chapel Hill (UNC)'s longstandingand highly successful Cancer Cell Biology Training Program (CCBTP) the flagship and sole predoctoral-onlycancer-focused T32 of UNC's Lineberger Comprehensive Cancer Center. CCBTP is now in its 25th year. As wealways have more highly qualified applicants than we can accommodate we request renewed support for all sixpredoctoral training slots. The premise of CCTBP is that the biology of cancer cells is an interdisciplinarybiomedical science encompassing experimental approaches and didactic knowledge from diverse fields. TheCCBTP mission is to train the next generation of basic and translational cancer biologists preparing them tocontribute in both academic and non-academic careers. As a non degree-granting program CCBTP providestrainees with unique opportunities beyond their departmental requirements and offerings. In this renewalapplication CCBTP seeks to build on past success while also recognizing that the landscape of cancer researchand training has entered a new era of very dynamic change. Precision medicine and the genomic era of big datain cancer research continue to evolve at warp speed. Dramatic improvements in technology have enabledincreased understanding of the contributions of single cells to specific populations and to the interactions ofcancer cells with their tumor microenvironment of stromal and immune cells. To keep the CCBTP program freshand to best address the needs of future cancer biology trainees we have critically evaluated the program andremodeled some aspects to keep abreast of this changing landscape. Our refreshed program thus includes arevised core course on cancer pathobiology and signaling a new core course developed specifically for CCBTPon cancer immunology and the tumor microenvironment and our unique experiential course on targeted cancertherapeutics. In the past cycle CCBTP added novel interactions with faculty mentors improved the diversitypipeline and obtained enhanced institutional support. We continue to build on all of these improvements. Goingforward in addition to continued emphasis on both basic and translational cancer biology trainees have newopportunities to develop and utilize their knowledge of state-of-the-art methodologies to profile and dissect thecancer genome kinome and proteome; to become familiar with bioinformatics and computational biology; toengage with the rapidly emerging areas of immunotherapy and the tumor microenvironment; to understand andapply the most appropriate and useful model systems to study cancer biology; to enhance the rigor andreproducibility of their research; and to engage thoughtfully with the larger world outside their own labs andinstitution. CCBTP trainees describe their community as one of the most important and valuable aspects of theirpredoctoral training. The CCBTP serves a vital role in our mission of training to support the pipeline of futurecancer biologists preparing them to accelerate progress in the understanding and treatment of cancer. 314720 +No NIH Category available Address;Affect;Aftercare;Antigens;B-Cell Activation;B-Cell Lymphomas;B-Lymphocytes;Biological Assay;Cancerous;Cell Reprogramming;Cell Survival;Cells;Chromatin;Dependence;Development;Diagnostic;Disease;Disease Progression;Down-Regulation;Endowment;Enhancers;Epigenetic Process;Gene Expression Profile;Genetic;Genetic Transcription;Genomics;Goals;Hematopoietic Neoplasms;Histone H1;Image;Immuno-Chemotherapy;Immunobiology;Incidence;Lymphoma;Lymphoma cell;Lymphomagenesis;Maintenance;Mature B-Lymphocyte;Mature Lymphocyte;Molecular;Mutation;Nature;Patients;Population;Property;Publishing;Reaction;Regimen;Relapse;Research;Residual state;Resistance;Role;Sampling;Signal Transduction;Solid Neoplasm;Structure of germinal center of lymph node;T-Lymphocyte;TNFSF5 gene;Technology;Testing;Therapeutic;Work;chromatin remodeling;derepression;experience;gain of function;in vivo;induced pluripotent stem cell;induced pluripotent stem cell technology;innovation;large cell Diffuse non-Hodgkin's lymphoma;leukemia;loss of function;mouse model;multiple omics;novel;pathogen;prevent;progenitor;programs;relapse patients;relapse risk;response;self-renewal;single cell technology;stem;stem cell genes;stem cells;stem-like cell;stemness;synergism;targeted treatment;transcriptional reprogramming;tumor;tumorigenesis;tumorigenic Characterizing stem cell-like B cell subpopulations and dissecting their role in tumorigenesis NarrativeIdentifying and targeting the subset of lymphoma cells that maintain and repopulate the diseaseis a critical unmet need. Building on our strong foundational work and interdisciplinary expertisewe have devised a bold strategy to provide definitive answers on how stem-like populations arisefrom mature lymphocytes and how are they hijacked by specific mutations to promote diseaseprogression and relapse. Our studies promise to transform the way we understand and treatlymphoma. NCI 10720153 6/22/23 0:00 PA-20-185 1R01CA283327-01 1 R01 CA 283327 1 "JHAPPAN, CHAMELLI" 7/1/23 0:00 6/30/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 12411671 "APOSTOLOU, EFFIE " Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 405817 NCI 239420 166397 One third of B-cell lymphoma patients relapse and remain incurable despite effective targetedtherapies. Although the serially relapsing nature of these tumors support the presence of stem-like lymphoma repopulating cells this notion remains controversial and underexplored.Resistance to this concept arise from the fact that -in contrast to leukemia or other solid tumorsthat originate from stem-like cells- most lymphomas arise from fully differentiated mature B cells.However our preliminary studies provide strong evidence for the existence of rare subpopulationsof B-cells undergoing antigen-activation (in response to pathogens) with stem-like molecularfeatures and functional properties in a T-cell dependent manner. Moreover we found that specificlymphoma-associated mutations further enhance the preexisting stemness program andpotential. We therefore hypothesize that a subset of mature B cells is transiently endowedwith stem-like epigenetic features which are hijacked by specific lymphoma drivers andconstitute the molecular basis of their increased tumorigenic potential and tumorrepopulating capacity. To address this hypothesis we have built an interdisciplinary team ofcollaborators with expertise in stem cell reprogramming epigenetics immunobiology single-celltechnologies and lymphoma research. We have devised an innovative and bold approachemploying multiple cutting-edge single-cell and chromatin technologies as well as ex vivo and invivo functional assays that will allow us to (i) determine the key regulators that promote or preventincreased GC B-cell plasticity in normal and cancerous contexts (ii) decipher the signal and inter-cellular dependencies that enable emergence of a GC stem-like state and key vulnerabilities and(iii) dissect the synergies between common lymphoma drivers with GC stem-like propertiescontributing to aggressive disease and relapse. The discovery of B-cell stem-like features andsubpopulations will be paradigm-shifting and have a tremendous impact on the way weunderstand and treat lymphomas opening new avenues for the development of superiordiagnostic and therapeutic strategies. 405817 +No NIH Category available Advisory Committees;Award;Cancer Center;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Network;Colon;Colorectal Cancer;Committee Members;Communication;Community Clinical Oncology Program;Conduct Clinical Trials;Development;Disease;Enrollment;Florida;Future;Goals;Health;Hepatobiliary;Institution;Investigational Therapies;Leadership;Malignant neoplasm of anus;Mentorship;National Clinical Trials Network;Neurosecretory Systems;Oncology;Pancreas;Patient Participation;Patients;Pediatric Oncology Group;Peer Review;Positioning Attribute;Process;Productivity;Rectum;Research;Research Personnel;Scientist;Services;Specialist;Voting;Wages;career;cost;data centers;expectation;experience;faculty support;gastrointestinal;improved;meetings;member;next generation;oncology program;oncology trial;programs;rectal;statistical center;success NCI-sponsored Clinical Trial Research Specialist PROJECT NARRATIVENCI-sponsored clinical trials represent some of the highest priority clinical trials conducted by the UF HealthCancer Center. These trials include patients seen at our center as well as those at our affiliate programs acrossthe state. Through this Clinician Scientist Award we will enhance the engagement of clinician scientists withprerequisite expertise in NCI-sponsored clinical trials and institutional oversight to expand the reach of thesetrials and opportunities for more patients to access them. NCI 10720142 8/29/23 0:00 PAR-21-306 1R50CA281930-01 1 R50 CA 281930 1 "LINDWASSER, ONN WOLF" 9/1/23 0:00 8/31/28 0:00 ZCA1-SRB-1(M2) 9795894 "GEORGE, THOMAS J." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 115272 NCI 75588 39684 ABSTRACTNCI-sponsored clinical trials represent some of the highest priority clinical trials conducted by the UF HealthCancer Center (UFHCC). These trials include participation by patients seen at our center as well as thosethrough our academic research consortium across the entire state of Florida to deliver trial access to wherepatients are. The UFHCC is committed to the success of NCI-sponsored clinical trials through robust partnershipswith the National Clinical Trials Network (NCTN) through the Children's Oncology Group (COG) NRG Oncologyas well as the Experimental Therapeutics Clinical Trial Network (ETCTN). This commitment is demonstrated atmultiple levels including but not limited to prioritizing investigator participation in NCI-sponsored clinical trialsfacilitating rapid and efficient activation financially subsidizing the costs of trial conduct supporting faculty toattend meetings serving as content experts/committee members hosting the COG Statistical and Data Centerembedding expectations for participation into salary support and providing a mechanism to allow regionalcommunity oncology practices to access trials. My involvement and effort at each of these institutional levels hasresulted in improved productivity efficiency and impact. These include my leadership as the inaugural UFHCCAssociate Director for Clinical Research (ADCR) Director of the Experimental Therapeutics Group and Directorof the GI Oncology Program. Portfolio priority oversight and enrollments to the NCI-sponsored clinical trials area demonstrated institutional priority. Within the NCI-sponsored clinical trial networks I am also active and provideimpact through administrative leadership. I serve as the NRG Oncology Co-Chair of the GI Committee Chair ofthe Colorectal Cancer Subcommittee and member of the Communications Committee. I also serve as theUFHCC institutional PI to the ETCTN and Yale LAO member. I am personally involved in the NCI peer-reviewprocess by which concepts are evaluated for scientific merit impact and feasibility prior to being approved astrials. These reviews occur in the NCI disease-specific Task Forces specifically the EsophagogastricHepatobiliary Pancreatic Neuroendocrine Colon and Rectal-Anal Cancer NCI Task Forces as well as trial finalapproval as a voting member of the NCI Gastrointestinal Steering Committee. Through these positions and withadditional contributions I have actively and positively influenced the current and future landscape of the NCTNand ETCTN programs particularly the GI Oncology trial portfolio. My career goals include continued service tothe NCI-sponsored clinical trial networks through leadership new member engagement and trialdevelopment/completion while simultaneously increasing my institutional engagement through expanded trialconduct and expanding the next generation of capable and diverse NCI clinical investigators leveraging myleadership experience mentorship and sponsorship. 115272 +No NIH Category available Acceleration;Address;Apoptosis;Back;Benign;Biological;Cell Proliferation;Cell Survival;Cell physiology;Cells;Computer Analysis;Consensus;DNA Damage;DNA Methylation;Data;Development;Disease;Disease Progression;Event;Gene Expression;Genetic;Genetic Transcription;Genome Stability;Genomic Instability;High Prevalence;Human;Injury;Intercept;KRAS oncogenesis;KRAS2 gene;Knowledge;Lesion;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Metabolism;Modeling;Mus;Mutate;Mutation;Mutation Detection;Neoplasms;Neoplastic Cell Transformation;Null Lymphocytes;Oncogene Activation;Oncogenes;Oncogenic;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Ductal Carcinoma;Polyploidy;Precancerous Conditions;Premalignant Cell;Process;Prognosis;Research;Role;Signal Transduction;TP53 gene;Testing;Tumor Promotion;Tumor Suppressor Proteins;Work;cancer initiation;cancer prevention;cancer therapy;cancer type;cell transformation;computerized tools;in vivo;insight;mouse model;mutant;neoplastic cell;novel;premalignant;prevent;programs;restoration;senescence;single cell analysis;tool;transcription factor;tumor;tumor heterogeneity;tumorigenesis Mechanisms of p53 Engagement and Action at the Benign-to-Malignant Transition in Sporadic Tumorigenesis PROJECT NARRATIVEGenetic inactivation of the tumor suppressor p53 drives progression to malignancy during the initiation ofpancreatic cancer. This proposal aims to investigate the mechanisms of p53 engagement and action duringsporadic pancreatic cancer initiation as well as the immediate consequences of p53 loss using novel toolsthat allow us to examine the critical transition from benign to malignant disease. This work will provide insightsinto early events in the formation of pancreatic cancer and the many other p53-mutant cancers and theseinsights may lead to new strategies for cancer prevention and treatment. NCI 10720034 7/3/23 0:00 PA-20-185 1R01CA283378-01 1 R01 CA 283378 1 "MAAS, STEFAN" 7/3/23 0:00 6/30/28 0:00 Biochemical and Cellular Oncogenesis Study Section[BCO] 1928317 "LOWE, SCOTT W." "PE'ER, DANA " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 726881 NCI 415000 311881 PROJECT SUMMARYThe transcription factor p53 is one of the most critical barriers to tumorigenesis. p53 is mutated in over half ofall human tumors and p53-mutant tumors typically carry a worse prognosis. As a tumor suppressor p53appears to act at the transition from benign to malignant disease preventing transformation of cells that havealready acquired some pro-tumor features such as oncogene activation or DNA damage. Decades of researchhave sought to identify what makes p53 a potent tumor suppressor as such knowledge could inform effectivestrategies for cancer prevention and treatment. This research has shown that p53 can be activated by a varietyof signals and in turn activated p53 can regulate a wide variety of cellular processes including cell survivalsenescence genomic stability and plasticity. However the inducers and actions of p53 vary with context andthere is still no consensus on what signals engage p53 during early neoplasia and what biological programsare most important for its tumor-suppressive functions. Furthermore we still do not know the key eventsfollowing p53 loss that enable transition to malignancy. Attempts to gain this knowledge have been hamperedby a lack of tools to directly study p53 in the specific cells undergoing transformation within endogenouscontexts. To address these gaps in knowledge we will study the events surrounding p53 activation and lossduring the initiation of pancreatic ductal carcinoma (PDAC) an aggressive cancer in which p53 losswhichoccurs in 70% of PDACsenables progression from benign precursor lesions to full-blown cancer. Werecently developed new mouse models of PDAC that allow us to see p53 in action as cells progress throughthe benign-to-malignant transition. Among the premalignant pancreas cells we discovered a subpopulationthat shares many transcriptional features with established tumor cells and thus these cells appear to betransitioning from premalignant to malignant. These transitioning cells are also the cells with the strongest p53activation and so they provide a unique opportunity to study p53 engagement and tumor-suppressive functionat the benign-to-malignant transition. Using single-cell transcriptional and spatial analyses new computationalapproaches to infer cell state transitions and our well-established platform for rapid genetic perturbations invivo we will define the cell-intrinsic and cell-extrinsic events that lead to this p53-active transitioning cell state.Furthermore we will investigate the mechanisms by which activated p53 suppresses neoplastic transformationin the transitioning cells as well as the events that influence cancer initiation immediately following p53 loss.This project will provide novel insight into the mechanisms that drive PDAC initiation and provide a direct anddetailed characterization of p53 in action in endogenous contexts. Given the high prevalence of TP53mutations in human cancers we expect the insights into tumorigenesis to be applicable to many cancer types. 726881 +No NIH Category available Acceleration;Affect;Aftercare;Age;Aging;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease related dementia;Alzheimer's disease risk;Amyloid beta-Protein;Animal Model;Autologous;Autopsy;Behavioral;Biological;Biological Markers;Blood Banks;Blood specimen;Brain;CAR T cell therapy;Cancer Patient;Cancer Survivor;Cell Aging;Cellular Phone;Chronology;Clinical;Cognition;Cognitive;Cognitive aging;DNA Damage;Data;Delirium;Dementia;Disease;Ecological momentary assessment;Effector Cell;Elderly;Encephalitis;Epigenetic Process;Exhibits;Funding;Future;Goals;Granulocyte Colony-Stimulating Factor;Granulocyte-Macrophage Colony-Stimulating Factor;Hematologic Neoplasms;Human;Immune;Impaired cognition;Individual;Inflammation;Inflammatory;Investigation;Knowledge;Lewy Bodies;Malignant Neoplasms;Metabolism;Molecular;Nerve Degeneration;Neurocognition;Neurocognitive;Neurotoxicity Syndromes;Neutropenia;Observational Study;Oxidative Stress;Pathogenesis;Pathogenicity;Pathologic;Pathology;Patients;Persons;Phenotype;Physical activity;Plasma;Play;Population;Process;Psychological Stress;Quality of life;Questionnaires;Recovery;Refractory;Relapse;Research;Resources;Risk;Risk Factors;Role;Sampling;Sleep;Stress;T-Lymphocyte;Telomere Shortening;Time;Toxic effect;Treatment Side Effects;United States;Vascular Dementia;Work;actigraphy;biological sex;cancer type;chimeric antigen receptor T cells;circulating biomarkers;cognitive change;cognitive process;cognitive reserve;comorbidity;cytokine;cytokine release syndrome;dementia risk;depressive symptoms;experience;follow-up;hematopoietic cell transplantation;high risk;improved;in vivo;innovation;insight;mental state;mild cognitive impairment;misfolded protein;modifiable risk;neuroinflammation;neuropathology;novel;parent grant;patient population;phase II trial;physical inactivity;poor sleep;predictive marker;protein aggregation;psychosocial;response;sedentary lifestyle;senescence;socioeconomics;symptomatology;systemic inflammatory response;tau Proteins;theories;ubiquitin C-terminal hydrolase Accelerated aging after chimeric antigen receptor T-cell therapy (CART): Leveraging a novel population of cancer survivors to elucidate mechanisms of dementia PROJECT NARRATIVEA central question in Alzheimers disease (AD) is why cognitive pathology manifests in some individuals but notothers. In this supplement we will leverage a newly-funded study (R01CA244328) of patients treated withchimeric antigen receptor T-cell therapy (CAR-T) to explore the roles of accelerated cellular aging andneurodegeneration on cognitive variability an early indicator of AD. These patients may be at high risk ofaccelerated cellular and cognitive aging and neurodegeneration due to the high levels of systemic andneuroinflammation they experience after treatment. NCI 10719874 5/18/23 0:00 PA-20-272 3R01CA244328-01A1S1 3 R01 CA 244328 1 A1S1 "JENSEN, ROXANNE ELAINE" 12/1/22 0:00 6/30/27 0:00 8664421 "JIM, HEATHER S.L." "LOCKE, FREDERICK ; SMALL, BRENT JOHN" 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 12/1/22 0:00 6/30/23 0:00 393 Non-SBIR/STTR 2023 470597 NIA 352139 118458 PROJECT SUMMARY/ABSTRACTAggregations of misfolded proteins (e.g. tau amyloid-b) are known to play a causal role in Alzheimers disease(AD) and related dementias (i.e. frontotemporal Lewy body vascular dementias) (ADRD) but can also be foundin the postmortem brains of older adults without ADRD. Thus a central question in AD is why cognitive pathologymanifests in some individuals but not others. Animal models can provide insight into molecular mechanisms ofpathogenic protein aggregation and clearance but generalizability to humans is less clear. This supplement willbuild on the teams previous collaborative research demonstrating that observational studies of cancer patientscan be used to gain insights into ADRD pathobiology. Specifically the supplement will focus on the associationof accelerated cellular aging (i.e. DNA damage response telomere shortening cellular senescence epigeneticaging inflammatory senescence-associated secretory phenotype oxidative stress cellular metabolism) andplasma markers of neurodegeneration (e.g. amyloid-b tau ) with cognitive variability (i.e. an early indicator ofADRD). We will leverage data from a newly-funded study (R01CA244328) of longitudinal change in PROs andneurocognition in a novel cancer patient population recipients of chimeric antigen receptor T-cell therapy (CAR-T) for relapsed/refractory hematologic malignancies. Over 90% of CAR-T recipients experience excessiverelease of pro-inflammatory cytokines (i.e. cytokine release syndrome or CRS) and/or neuroinflammation (i.e.immune effector cell neurotoxicity syndrome or ICANS) as side effects of treatment. We know of no otherdisease paradigm by which such extreme phenotypes of accelerated cellular aging inflammation andneuroinflammation can be observed in humans. As such this supplement will provide a window into how thesephenotypes are associated with human cognitive processes in vivo. Parent grant data to be leveraged bysupplement includes smartphone-based real-time ecological momentary assessment (EMA) to asses cognitivevariability; validated PRO questionnaires; actigraphy data regarding sleep physical activity and sedentarybehavior; clinical information; and banked blood. New work in the supplement includes analysis of banked bloodat the same time points (i.e. pre-CAR-T baseline 3 and 12 months later) the addition of a blood sample at 7days post-CAR-T (i.e. when systemic inflammation and neuroinflammation are expected to be greatest) andisolation and storage of T-cells at each time point to use as a resource for future scientific investigation. Goalsof the supplement are as follows: 1) to examine accelerated cellular aging neurodegeneration and cognitivevariability (i.e. an early indicator of ADRD) in the year after CAR-T therapy 2) to determine psychosocial andbehavioral ADRD risk factors associated with accelerated cellular aging neurodegeneration and cognitivevariability in the year after CAR-T therapy and 3) to explore the association of accelerated cellular aging withrecovery and response to CAR-T. Results will provide new insights into putative mechanisms of ADRD whichwill be evaluated further in ADRD patients in future studies. 470597 +No NIH Category available Adverse event;Affect;Aftercare;Age;Antineoplastic Agents;Biological;Biological Availability;Biological Markers;Biopsy;Cell Communication;Cell Cycle Arrest;Cell Maintenance;Cell Proliferation;Cell Survival;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;DNA Binding;Data;Disease;Dose;Dose Limiting;Drug Kinetics;Ecosystem;Enrollment;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Lymphoma;Epstein-Barr Virus-Related Malignant Neoplasm;Exhibits;Funding;Gene Expression;Genes;Grant;Human;Human Herpesvirus 4;Image;Immune Evasion;Immune response;Immunity;Immunofluorescence Immunologic;Immunosuppression;In Vitro;Industry;Infection;Inferior;Infrastructure;Investigation;Kimmel Cancer Center at the Thomas Jefferson University;Lead;Link;Lymphoid Cell;Lymphoma;Maintenance;Malignant Neoplasms;Measures;Medical;Metabolic;Metabolic Pathway;Modality;Modeling;Mus;Myeloid Cells;Nasopharynx Carcinoma;Oncogenic Viruses;Oral Administration;Orthologous Gene;Pathway Analysis;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Phase Ib Clinical Trial;Plasma;Process;Prognosis;Property;Proteins;RNA;Recommendation;Research Personnel;Role;Safety;Serious Adverse Event;Signal Pathway;Signal Transduction;Specimen;Stable Disease;Stromal Cells;Testing;The Wistar Institute;Therapeutic;Therapeutic Agents;Toxic effect;Toxicology;Universities;Viral;Viral Genes;Viral Genome;Viral Load result;Viral Oncogene;cancer stem cell;carcinogenesis;cell growth;chemotherapy;clinical candidate;first-in-human;genetic regulatory protein;human study;immune function;in vivo;inhibitor;large cell Diffuse non-Hodgkin's lymphoma;lead optimization;medication safety;neoplastic cell;novel;novel therapeutic intervention;open label;patient population;pharmacologic;phase 1 study;pre-clinical;preclinical study;prevent;response;small molecule inhibitor;specific biomarkers;stem cell population;stem cells;transcriptomic profiling;transcriptomics;translational scientist;treatment effect;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;tumorigenesis EBNA1 Inhibitor for Treatment of EBV-positive DLBCL PROJECT NARRATIVENew targeted anticancer agents are urgently needed for the treatment of Epstein-Barr Virus (EBV)-positivelymphomas chief among them Diffuse Large B Cell Lymphoma (DLBCL) the most common lymphomaworldwide. VK-2019 a potent EBNA1 inhibitor is selectively toxic to EBV-infected tumor cells but not to EBV-negative cells in vitro and in vivo. A phase I clinical study with patients with advanced EBV-positivenasopharyngeal carcinoma demonstrated that VK-2019 exhibits a favorable pharmacokinetics and safety profile.In this Phase Ib study we propose to confirm the safety and tolerability of the drug obtain a preliminary signalof anti-tumor efficacy study the effects of VK-2019 treatment on EBV and cellular gene expression and on thetumor microenvironment in EBV-positive DLBCL patients. NCI 10719866 7/7/23 0:00 PAR-21-033 1R01CA282411-01 1 R01 CA 282411 1 "SONG, MIN-KYUNG H" 7/7/23 0:00 6/30/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 1869983 "LIEBERMAN, PAUL M" "MESSICK, TROY E; PORCU, PIERLUIGI " 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 745842 NCI 453107 292735 PROJECT SUMMARYThe Epstein-Barr Virus (EBV) is responsible for approximately 200000 new cancer cases each year worldwide.Among these EBV+ Diffuse Large B-Cell Lymphoma (DLBCL) is an emergent global cancer threat in patientswithout overt immunosuppression irrespective of age and represents a growing unmet medical need. Newtherapeutic approaches are needed to treat EBV+ DLBCL. Only one viral-encoded protein EBNA1 isconsistently expressed in all known EBV-associated malignancies and is a validated target for inhibition of EBV-dependent transformation and carcinogenesis.Investigators at the Wistar Institute have developed VK-2019 a first-in-class EBNA1 inhibitor as a therapeuticagent selecting it from over 2500 candidate inhibitor compounds during the hit-to-lead and lead optimizationphases. VK-2019 meets or exceeds industry-accepted criteria for potency selectivity metabolic stability drugsuitability drug safety toxicology and bioavailability. We anticipated that VK-2019 would have a favorable safetyprofile because there are no human orthologs of EBNA1. Based on preclinical evidence and a first-in-humanPhase I clinical study in patients with advanced nasopharyngeal carcinoma (NPC) VK-2019 met all safetytolerability and pharmacokinetic endpoints with few documented adverse events (AEs) or Severe AdverseEvents (SAEs). In this early study we observed stable disease in more than a third and a significant decreasein EBV plasma levels a known biomarker of NPC progression in more than half of the patients that correlatedwith pharmacokinetic exposure. We believe that data from this Phase I study are encouraging in terms of bothon target effect and clinical benefit and supports a follow-on proof-of-concept study in patients with EBV-positiveDLBCL.The purpose of this grant is to fund a phase Ib clinical trial of daily oral administration of VK-2019 to (1) furtherconfirm the safety profile and determine any dose-limiting toxicities (DLT) in advanced EBV+ DLBCL patientpopulations; (2) understand the effects of treatment on EBV-specific biomarkers including EBV and cellular geneexpression and (3) study the effects of treatment on the tumor microenvironment and immune response.The clinical trial infrastructure necessary for the conduct of this study is already in place at the Sidney KimmelCancer Center at Thomas Jefferson University. This clinical trial will provide critical information on the safetytolerability and preliminary efficacy of VK-2019 in a EBV+ DLBCL patient population. This application bringstogether basic and translational investigators to understand whether EBNA1 inhibitors can be a therapeuticoption for latent EBV infection and cancer and examines the mechanism of action. 745842 +No NIH Category available Academia;Affect;Alleles;Amino Acids;Animal Model;Apoptosis;Binding;Bioinformatics;Biological;Biology;Biophysics;Biotechnology;Cancer Patient;Cell Cycle Arrest;Cell Proliferation;Cells;Chemicals;Clinic;Clinical Trials;Collection;Crystallography;DNA;DNA Binding;DNA Binding Domain;Development;Diagnosis;Exposure to;Future;Gene Expression;Genes;Genetic;Genetic Induction;Genetic study;Goals;Human;In Vitro;Knowledge;Length;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Missense Mutation;Molecular;Molecular Conformation;Mutate;Mutation;Oxidation-Reduction;Pathway interactions;Pharmaceutical Preparations;Pharmacologic Substance;Positioning Attribute;Process;Property;Proteins;Reporting;Series;Site;Structure;Structure-Activity Relationship;System;TP53 gene;Testing;Therapeutic;Tumor Suppression;Tumor Suppressor Proteins;United States;cancer cell;cancer therapy;crosslink;drug development;drug-like compound;experience;experimental study;gain of function;in vivo;inhibitor;mutant;novel therapeutic intervention;pharmacologic;prevent;programs;reconstitution;small molecule;success;targeted cancer therapy;therapeutic protein;therapeutic target;tool;translational therapeutics;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression Mechanisms of mutant p53 reactivation Project NarrativeThe gene encoding the tumor suppressor protein p53 is the most frequently mutatedgene in cancer. Therapeutics that restore p53 activity in cancer could havetransformative impact on treatment of cancer patients. This proposal aims to understandrequirements and mechanisms for restoring tumor suppressor activity to mutant p53proteins in cancer. NCI 10719196 7/10/23 0:00 PA-20-185 1R01CA283462-01 1 R01 CA 283462 1 "AGYIN, JOSEPH KOFI" 7/10/23 0:00 6/30/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 6981288 "KAISER, PETER " "RYCHNOVSKY, SCOTT D." 47 BIOCHEMISTRY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 7/10/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 498061 NCI 323151 174910 PROJECT SUMMARYThe tumor suppressor protein p53 is the most frequently mutated protein in human cancers. About 600000new cancer patients in the United States are diagnosed each year with tumors expressing mutated p53. Mostof the mutations are missense mutations that affect one of six hotspot sites in the p53 DNA binding domain.These cancers express full length p53 that has lost tumor suppressor activity but has acquired gain-of-functiononcomorphic properties that provide selective advantage to cancer cells.The large number of affected cancers make p53 an exquisite target for cancer therapy. However therapeuticapproaches require reactivation of mutated p53. Developing reactivation or corrector drugs is challenging initself but further complicated by very limited experience in pharma biotech and academia in this domain.These challenges in exploring novel therapeutic approaches by developing p53 corrector drugs have led tovery slow and limited success in clinical trials with proposed p53 reactivator compounds. It recently emergedthat several of the reported compounds are likely not acting on mutant p53 in vivo but rather exploit redox-sensitivity of cells expressing p53 mutants. Development of bona fide p53 mutant corrector drugs that bind p53and restore a wild-type like conformation/activity in p53 cancer mutants thus remains a central goal withpotentially very high impact. To achieve this goal mechanistic understanding of the p53 cancer mutantreactivation process is essential but currently mostly lacking due to the lack of genuine p53 correctormolecules with the exception of compounds developed specifically for the relatively rare p53-Y220C allele.We have extensively studied genetic and pharmacological p53 reactivation. We found that Intragenic rescuemutations and small molecules we are developing induce a similar conformational change and stabilize anactive conformation of p53 hotspot mutants. Although reactivation mutations have no direct therapeuticpotential they help in our understanding of p53 mutant reactivation mechanisms and can guide corrector drugdevelopment. Using information obtained from reactivating second-site mutations we have developed toolcompounds that bind mutant p53 and thereby restore DNA binding activity of mutant p53 in a reconstitutedpurified in vitro system. p53 target genes are induced when cells harboring p53 hotspot mutants are exposedto these compounds. Furthermore cell proliferation is halted and apoptosis is induced in a p53 mutantdependent manner. Importantly growth of tumors carrying p53 mutants is blocked by this compound series inanimal models. Tumors lacking p53 or expressing wild-type p53 are not affected by such treatment. Thesecompounds provide strong support for feasibility to develop drug-like molecules that act as genuine p53 mutantcorrectors. We now propose to use these tool compounds as well as well-characterized rescue mutations todevelop detailed molecular understanding of the reactivation process for p53 hotspot mutants. Findings fromthese studies will be essential to jump start the development of chemically diverse p53 corrector drugs. 498061 +No NIH Category available Address;Adopted;Antibodies;Automobile Driving;Biology;Brain Glioblastoma;Brain Neoplasms;CD8B1 gene;Cell Line;Cells;Clinical;Clinical Research;Clinical Trials;Combined Modality Therapy;Complex;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Development;Development Plans;Educational workshop;Engineering;Environment;Exposure to;Faculty;Flow Cytometry;Foundations;Glioblastoma;Glioma;Goals;Immune;Immunity;Immunochemistry;Immunooncology;Immunotherapeutic agent;Immunotherapy;Infiltration;Integral Membrane Protein;Interferon Type II;Interleukin-12;Interleukin-12 therapy;K22 Award;Label;Leadership;Lentivirus Vector;Life Expectancy;Lymphocyte Function;MHC antigen;Macrophage;Malignant neoplasm of brain;Mediating;Membrane Proteins;Mentors;Microglia;Modality;Modeling;Monitor;Mus;Myelogenous;Myeloid Cells;Newly Diagnosed;Oncogenic;Paper;Patients;Phase;Positioning Attribute;Production;Recombinants;Recurrence;Relapse;Research;Resistance;Resolution;Signal Transduction;Site;Source;System;T-Lymphocyte;Techniques;Technology;Testing;Therapeutic;Time;Training;Transforming Growth Factors;Transgenic Mice;Transgenic Model;Translating;Tumor Immunity;Work;Writing;antitumor effect;attenuation;brain cell;career;career development;clinically relevant;cytokine;design;experimental study;extracellular;extracellular vesicles;fitness;immuno-gene therapy;immunoregulation;improved;monocyte;mouse model;nanocarrier;neoantigens;neoplastic cell;next generation;programmed cell death ligand 1;programs;release factor;resistance mechanism;response;single-cell RNA sequencing;small molecule;symposium;tumor;tumor microenvironment;tumor-immune system interactions;tumorigenic;vector Boosting IL-12-induced anti-glioblastoma activity via immunotherapeutic extracellular vesicles. PROJECT NARRATIVERecurrent glioblastoma is associated with poor response to immunotherapy due in part to the immune-suppressive tumor microenvironment. Localized interleukin 12 (IL12) is making progress in therapy formalignant brain tumors by triggering anti-tumor immunity in patients. Our proposal will study IL12-induced anti-and pro-tumoral signaling in GB mouse models and develop a next-generation treatment whereby multi-factorialnanocarriers (extracellular vesicles) sustain IL12-triggered immunomodulating effects. NCI 10719099 11/30/23 0:00 PAR-21-128 1K22CA282019-01 1 K22 CA 282019 1 "JAKOWLEW, SONIA B" 12/1/23 0:00 11/30/26 0:00 ZCA1-RTRB-R(M1) 15316490 "BREYNE, KOEN " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 160537 NCI 149000 11537 PROJECT SUMMARYThe objective of this application is to develop the career of Dr. Breyne facilitating his transition to a stableindependent phase and establishing his research program. He will pursue a rigorous career development planto further his training in (i) extracellular vesicle (EV) biology (ii) immune-oncology and (iii) professionaldevelopment. Progress in these domains will be accomplished through coursework attendance and speaking atconferences and workshops writing last author papers mentoring others and leading team efforts. The trainingenvironment is exceptional and the collaborators are world-class. The K22 Award will give the PI protected timeto generate data for an R01 proposal while launching his independent faculty position.Once glioblastoma (GB) progresses after first-line therapy treatment options are limited and managing recurrentGB remains challenging. While newly diagnosed GB patients have a life expectancy of ~15 months it is reducedto 6 to 9 months after relapse. Recently localized delivery of interleukin-12 (IL12) has had promising anti-tumoraleffects in patients with high-grade recurrent GB extending the survival to ~17 months. Our preliminary data showthat intratumoral IL12 together with local expression of a costimulatory factor for cytotoxic T lymphocytes (CTLs)- 4-1BBL can induce sustained anti-glioma responses. The objective of our studies is to develop a clinicallyrelevant strategy combining these factors while expanding our understanding of immune-suppressive resistanceagainst IL12-induced anti-glioma activity. In Aim 1 we will establish disruptive technology presentingcombinations of immuno-modulatory factors on a single nanocarrier. In essence dendritic cell (DC)-derived EVswill be designed to display IL12 4-1BBL and a neoantigen:MHC complex. In line with our findings of GB-treatedmice with IL12/4-1BBL combo- compared to IL12 monotherapy we anticipate that immunotherapeutic EVs willtranslate to ~68% improvement in the survival of GB-bearing mice. In Aim 2 the resistance mechanisms inducedby GB against IL12 treatment will be explored. We have observed that myeloid cell subsets sense antitumorimmunity activated by IL12. By combining single-cell RNA sequencing analysis with multiparametric flowcytometry in IL12-treated GB mouse models we will uncover the pro-oncogenic signaling resulting in a PD-L1increase and 4-1BBL decrease. In turn these targets will be monitored in response to intratumoral EV treatmentanticipating the attenuation of GB resistance. Aim 3 will investigate CTL:DC crosstalk driving IL12 treatment.CTLs are responsible for IL12-induced anti-glioma activity as shown by our CD8 depletion experiments.However little is known about DCs in an IL12-stimulated GB brain. Transgenic mouse models will aid us bymarking or depleting relevant DCs in the tumor and studying the anti-tumor activity of our engineered EVs.This unique proposal addresses a crucial and timely unmet need in the field. We plan to engage the therapeuticpotential of EVs to arrest GB progression. This work will undoubtedly provide a strong foundation for thecandidate's independent leadership in brain tumor research. 160537 +No NIH Category available Absence of pain sensation;Acute;Acute Pain;Affect;Affinity;Aftercare;Analgesics;Antidepressive Agents;Antineoplastic Agents;Anxiety;Behavior;Behavior Control;Behavioral;Biological Assay;Brain;CARTPT gene;Cancer Patient;Cells;Chemicals;Chemotherapy-induced peripheral neuropathy;Clinical;DNQX;Data;Dose;Evaluation;Excitatory Amino Acid Antagonists;Exhibits;Face;Female;Genetic;Glutamates;Hyperalgesia;Hypersensitivity;Impairment;Knockout Mice;Lysophosphatidic Acid Receptors;Mass Spectrum Analysis;Measures;Mediating;Mental Depression;Microdialysis;Molecular;Mood Disorders;Mus;Neuropeptides;Neurotransmitters;Nociception;Norepinephrine;Nucleus Accumbens;Opioid;Opioid Peptide;Output;Paclitaxel;Pain;Pain management;Patients;Peptides;Pharmacologic Actions;Pharmacology;Pilot Projects;Quality of life;Risk;Role;Safety;Serotonin;Sex Differences;Signal Pathway;Signal Transduction;Site;System;Tactile;Testing;Therapeutic;Work;allodynia;antagonist;antinociception;chronic pain;drug candidate;duloxetine;experimental study;extracellular;in vivo;inhibitor;male;midbrain central gray substance;neurochemistry;neurotransmission;non-opioid analgesic;novel;novel therapeutic intervention;novel therapeutics;pain relief;painful neuropathy;positive allosteric modulator;prevent;receptor;response;sex;tool;treatment response;uptake Anti-nociceptive actions of CART II in chemotherapy-induced peripheral neuropathy Chemotherapy-induced peripheral neuropathy (CIPN) affects ~70% of cancer patients in the firstmonth and may persist indefinitely. Pain hypersensitivity and affective disorders impair patientquality of life underscoring the need for new treatments. This proposal evaluates the anti-nociceptive effects of cocaine and amphetamine-regulated transcript peptide II (CART II) as apotential non-opioid alterative approach for treating CIPN. NCI 10719026 6/9/23 0:00 PA-20-185 1R01CA284075-01 1 R01 CA 284075 1 "ALTSHULER, RACHEL DINA" 6/9/23 0:00 5/31/28 0:00 Neurobiology of Pain and Itch Study Section [NPI] 10122404 "BUCZYNSKI, MATTHEW WALLACE" Not Applicable 9 NEUROSCIENCES 3137015 QDE5UHE5XD16 3137015 QDE5UHE5XD16 US 37.233061 -80.421005 8968001 VIRGINIA POLYTECHNIC INST AND ST UNIV BLACKSBURG VA SCHOOLS OF ARTS AND SCIENCES 240616100 UNITED STATES N 6/9/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 357684 NCI 228750 128934 PROJECT SUMMARYChemotherapy-induced peripheral neuropathy (CIPN) manifests in nearly 70% of patients treated with anti-neoplastic drugs and persists after treatment discontinuation thereby impacting patient quality of life. The anti-depressant duloxetine (selective inhibitor of serotonin and norepinephrine uptake) offers limited pain relief whilelong-term use of opioids for chronic pain carries safety risks. Thus novel non-opioid analgesics are needed forpain management in cancer patients. Our findings show that supraspinal (in the brain) delivery of cocaine andamphetamine-regulated transcript peptide II (CART II) reverses pain-like behaviors (tactile) in male and femalemice with CIPN. Multiple behavioral outputs would provide clinical face validity and bolster translatability of agiven target thus a comprehensive dose-evaluation of CART II anti-hyperalgesic effects during chronic painstates of CART II in both sexes at multiple endpoints of chronic pain in both sexes is warranted. Previous studieshave uncovered broader pharmacological actions of CART II and systemic administration of a neuropeptidelikely will impose a challenge so it is critical to determine the neurochemical signaling mechanisms of CART IIin CIPN. While the lack of a known receptor for CART II has prevented such mechanistic studies we discoveredthat Lysophosphatidic Acid Receptor 2 (LPAR2) is a high affinity receptor for CART II in the brain. We used cell-based assays and in vivo pharmacology tools to show that supraspinal LPAR2 is necessary CART II-inducedacute analgesia. However the role of LPAR2 in chronic pain states has not been evaluated. Our findings alsodemonstrate that therapeutic doses of supraspinal CART II increase glutamate release in ventrolateralperiaqueductal gray (vlPAG) and nucleus accumbens (NAcc) in nave mice and previous work shows excitatoryinputs into these brain sites can relieve neuropathic pain states. However neurotransmission during CIPN in thevlPAG and NAcc has not been fully established. The central hypothesis in this proposal is that CART II producesits anti-hyperalgesic effects via activation of LPAR2 and increased glutamate release. Thus we propose to fullyexamine anti-hyperalgesic actions of this signaling pathway in vlPAG and NAcc in males and females via twoindependent yet interconnected aims. Aim 1 will comprehensively evaluate dose-dependent anti-hyperalgesiceffects of supraspinal CART II in 4 different behavioral output measures (tactile cold anxiety depression) tointerrogate any sex differences in therapeutic potential for CIPN. Incorporation of a positive allosteric modulatorand knockout mice will reveal if LPAR2 is necessary and sufficient for the anti-hyperalgesic actions of CART II.Aim 2 will examine CART II-mediated neurotransmission as a mechanism of action for its anti-hyperalgesiceffects in CIPN. Collectively the expected results will address significant gaps in understanding of thesupraspinal mechanisms underlying neuropathic pain states and interrogate the CART II/LPAR2 axis as a noveltherapeutic strategy in reversing already established CIPN. 357684 +No NIH Category available Affect;Age;Aqueous Humor;Award;Behavior;Biological Assay;Biological Markers;Biopsy;Blindness;Child;Childhood;Clinical;Clinical Trials;Collaborations;Communication;DNA Methylation;DNA Sequence Alteration;DNA methylation profiling;Detection;Diagnosis;Disease;Early Diagnosis;Epigenetic Process;Evaluation;Excision;Eye;Eye Enucleation;Future;Genetic;Genomics;Goals;Grouping;Injections;Knowledge;Laboratories;Logistic Regressions;MYCN gene;Malignant Neoplasms;Measures;Methylation;Modality;Modeling;Modification;Molecular;Monitor;Mutation;Nature;North America;Operative Surgical Procedures;Outcome;Pathogenicity;Patients;Positioning Attribute;Prediction of Response to Therapy;Prognosis;Prognostic Factor;Prognostic Marker;Prospective Studies;RB1 gene;Recurrence;Relapse;Research;Residual state;Retina;Retinoblastoma;Risk;Risk Marker;Sampling;Source;Specimen;Testing;Time;Treatment Failure;Treatment outcome;Tumor Markers;Tumor Subtype;Tumor Suppressor Genes;Tumor Tissue;Tumor-Derived;Validation;Variant;biomarker identification;biomarker validation;cancer biomarkers;cancer risk;candidate marker;cell free DNA;chemotherapy;chromosome 6p gain;clinical examination;clinically relevant;design;disease diagnosis;disease prognosis;epigenomics;genome sequencing;genome-wide;genomic biomarker;high risk;in vivo;liquid biopsy;malignant neoplasm of eye;molecular diagnostics;molecular subtypes;multimodality;multiple omics;novel;participant enrollment;personalized medicine;precision medicine;precision medicine clinical trials;prognostic;prognostication;prospective;relapse risk;targeted sequencing;therapeutic target;treatment response;treatment risk;tumor;tumor DNA;tumor behavior;tumorigenesis;whole genome Validation of an aqueous humor liquid biopsy for molecular prognostication and monitoring of children with retinoblastoma. Project NarrativeRetinoblastoma is an eye cancer that forms in the developing retina of young children; it is unique in that it cannotbe directly biopsied making tumor tissue unavailable. As a result there is a lack of understanding of theassociation between the clinical behavior of this cancer and the mechanisms that drive its behavior. Thus wepropose to use a liquid biopsy of the eye aqueous humor for molecular characterization and prognostic biomarkervalidation of this cancer to help the design of future clinical trials. NCI 10718932 7/17/23 0:00 PA-20-185 1R01CA282759-01 1 R01 CA 282759 1 "OSSANDON, MIGUEL" 8/1/23 0:00 7/31/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 15094708 "BERRY, JESSE L" Not Applicable 30 Unavailable 52277936 DVL1CMRMWRN9 52277936 DVL1CMRMWRN9 US 34.098065 -118.29069 1520001 CHILDREN'S HOSPITAL OF LOS ANGELES LOS ANGELES CA Independent Hospitals 900276062 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 581965 NCI 386263 195702 Project SummaryThere is a significant body of research into the genetic genomic and epigenomic alterations of retinoblastoma(RB) a primary eye cancer that forms in the developing retina in young children. However these studies weredone on tumor tissues from surgically removed (enucleated) eyes with advanced RB as tumor biopsy is notpossible due to the real risk of tumor extraocular dissemination. As a result RB tumor DNA was never previouslyaccessible aside from these enucleated specimens and there is limited understanding of the molecularalterations that may drive tumor behavior. Furthermore any application of molecular diagnostic or use ofprognostic biomarkers for personalized medicine in vivo is limited by the lack of tumor tissue at diagnosis orduring therapy. Thus a liquid biopsy approach which overcomes this critical lack of tumor tissue was neededfor this disease. With support of an NCI K08 we demonstrated that the aqueous humor (AH) an intraocular fluidis an enriched source of tumor-derived cell-free DNA (cfDNA). We developed a liquid biopsy assay to detectsomatic copy number alterations (SCNAs) and pathogenic variants in the RB1 tumor suppressor gene from asingle 100 l sample of AH. We identified that the genomic alterations from the AH are highly concordant (>94%)with those found in the tumor of enucleated eyes. We identified potential candidate biomarkers chromosome 6pgain and/or focal MYCNa in the AH cfDNA that are associated with a 16.5-fold increased risk of treatment failurerequiring surgical removal of the eye. We demonstrated that changes in AH cfDNA tumor fraction (TFx) correlatewith treatment response with increases in TFx indicative of recurrence or minimal residual intraocular disease.This suggests that TFx alone may serve as a reliable real-time biomarker for treatment response. We alsodemonstrated the feasibility of evaluating tumor methylation profiles using the AH thereby facilitating a betterunderstanding of tumor biomarkers that may predict tumor behavior and potentially treatment response. Basedin these results we hypothesize that AH cfDNA can be used for molecular characterization of in vivo RB tumorsto inform diagnosis and prognosis for eye salvage based on validated genomic and epigenomic biomarkers. Totest this hypothesis we now propose a multi-center multi-omics prospective study to characterize prognosticAH biomarkers prospectively and longitudinally to determine treatment outcomes.Benefits from this study will include advancing knowledge about the course of the disease at any stage providingbiomarkers to guide treatment and forming the basis for future molecular-based precision medicine clinical trialsfor RB. 581965 +No NIH Category available Ablation;Address;Adjuvant;Adjuvant Chemotherapy;Advanced Malignant Neoplasm;Biological Markers;Bladder;Bladder Neoplasm;CD44 gene;Cancer Model;Chemoresistance;Chemotherapy-Oncologic Procedure;Chondroitin Sulfate Proteoglycan;Chondroitin Sulfates;Chondroitinases;Cisplatin;Clinic;Clinical;Clip;Combined Modality Therapy;Cystectomy;Cytidine Deaminase;Development;Dose;Drug Kinetics;Enzymes;Evaluation;Evidence based treatment;Excision;FDA approved;Failure;Goals;Human;Immunocompetent;Immunotherapy;Interstitial Cystitis;Intravesical Instillation;JAK2 gene;Malignant neoplasm of urinary bladder;Mediating;Micrometastasis;Modeling;Molecular;Morbidity - disease rate;Multicenter Studies;Mus;Muscle;Myelofibrosis;Neoadjuvant Therapy;Neoplasm Metastasis;Operative Surgical Procedures;Oral;Outcome;Pathway interactions;Patients;Pentosan Polysulfate;Pharmaceutical Preparations;Prediction of Response to Therapy;Prognosis;Radical Cystectomy;Recurrence;Recurrent Malignant Neoplasm;Resistance;STAT3 gene;Serum;Signal Pathway;Signal Transduction;Specificity;Specimen;Testing;Tissues;Toxic effect;Transgenic Model;Translating;Treatment Failure;Tumor Cell Invasion;Up-Regulation;Urologic Cancer;Xenograft procedure;cancer cell;cancer recurrence;chemotherapy;clinical translation;comparative efficacy;design;docetaxel;drug repurposing;evidence base;gemcitabine;high risk;improved;improved outcome;inhibitor;intravesical;mortality;mouse model;muscle invasive bladder cancer;mutant;novel;patient derived xenograft model;pre-clinical;predicting response;prevent;public health relevance;response;response biomarker;standard care;tumor;tumor growth;tumorigenesis Biomarker guided combinations for treating high-risk bladder cancer PUBLIC HEALTH RELEVANCE STATEMENT:This study addresses the unsolved problem of chemotherapy resistance in advanced cancers through evidence-based treatment combinations that target Chase an enzyme first of its kind. Chase renders the commonchemotherapy drug Gemcitabine ineffective. Development of the combinations concurrently with the evaluationof Chase and related molecules as predictors of treatment response could enable the clinical translation of thesecombinations for the treatment of high-risk advanced bladder cancers. NCI 10718874 7/6/23 0:00 PA-20-185 1R01CA283699-01 1 R01 CA 283699 1 "GREENBERG, WILLIAM A" 7/5/23 0:00 6/30/28 0:00 Mechanisms of Cancer Therapeutics A Study Section[MCTA] 1917879 "LOKESHWAR, VINATA B" Not Applicable 12 BIOCHEMISTRY 966668691 N4WWJC8T2593 966668691; 809593387 JJJNQAJY5RN6; N4WWJC8T2593 US 33.470962 -81.991405 676605 AUGUSTA UNIVERSITY AUGUSTA GA SCHOOLS OF MEDICINE 309120004 UNITED STATES N 7/5/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 557016 NCI 361699 195317 Bladder cancer (BC) is a common cancer of the urinary tract. While low-grade tumors have a goodprognosis two-thirds of patients with high-grade BC have tumors invading the bladder wall muscle and beyond(MIBC). Patients with MIBC are at high-risk for metastasis significant morbidity and mortality. Cystectomy(bladder removal) is the primary treatment for MIBC. Many patients with MIBC receive treatment before surgery(neoadjuvant) to downstage the tumor and to treat micrometastases. However half of these patients developmetastasis within two years. Although immunotherapy is approved for treatment the response rate is ~ 25%leaving chemotherapy as the main treatment. Gemcitabine (Gem)-based combination treatments are used in theneoadjuvant and adjuvant/salvage settings for better tolerability. Sequential Gem-based bladder instillations areincreasingly being used to delay/prevent recurrence in patients with high-grade non-MIBC (NMIBC). HoweverGem combinations are empirical not without toxicity and few consider Gem-resistance. The goal of this study isto evaluate two evidence-based Gem combinations to improve outcome in patients with NMIBC and MIBC. Chase is the first of its kind in humans that cleaves chondroitin sulfate from proteoglycans. Chase wasdiscovered to drive bladder tumorigenesis tumor growth metastasis and Gem resistance. Chase and itsmolecular signaling pathway that induces Gem resistance are expressed in bladder tumor specimens. We foundtwo well-characterized compounds with potential to overcome Chase-induced Gem resistance. While onecompound inhibited the Chase activity another inhibited its downstream signaling pathway. Combination of Gemwith either compound re-sensitized Gem-resistant pre-clinical BC models to Gem. The project is designed to testthe hypothesis that inhibition of Chase or its signaling abolishes Gem resistance. Furthermore the developmentof Gem combinations with one or both compounds together with the evaluation of Chase and Chase-signalingfor predicting response to Gem-based treatments will enable the clinical translation of these combinations forthe treatment of advanced BC. In BC models we will investigate the molecular mechanism of ablating Chase-induced Gem resistance by either of the two compounds (inhibitor of Chase or of Chase-signaling) (Aim 1). Wewill evaluate Chase-related molecules to predict treatment response optimize the dose of the combinations andvalidate their favorable tolerability and target specificity (Aim 2). We will use advanced BC and patient-derivedxenograft models to compare the efficacy of Gem combination with each compound and with the current Gem-based treatments (Aim 3).Impact: Few studies have evaluated Gem resistance and how to overcome it. Evaluation of evidenced-basednovel combinations that target Chase-induced Gem resistance and of Chase-related molecules as predictors ofresponse to Gem-based treatments should reveal which combination is superior and who could receive it. 557016 +No NIH Category available Binding;Biological Assay;Biology;Cell Nucleolus;Cell Nucleus;Cell Proliferation;Cell Survival;Cells;Chimeric Proteins;Chromatin;Chromatin Structure;Clinic;Clinical;Clinical Data;Clinical Trials;Combined Modality Therapy;Cytoprotection;DNA;DNA Binding;DNA Binding Agent;DNA Damage;DNA Minor Groove Binding;Data;Dependence;Development;Disease;Dose;Doxorubicin;Drug resistance;EWS-FLI1 fusion protein;EWSR1 gene;Enhancers;Epigenetic Process;Etoposide;Ewings sarcoma;FLI1 Transcription Factor;Genes;Genetic Transcription;Genome;Goals;Heat-Shock Proteins 70;Impairment;Malignant Neoplasms;Microsatellite Repeats;Modeling;Mutation;Normal Cell;Nucleotides;Oncogenes;Oncogenic;Output;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase Transition;Poison;Proteins;Proteomics;Recovery;Recurrence;Relapse;Reporting;Response Elements;Site;Testing;Therapeutic;Toxic effect;Translating;Treatment Efficacy;Ultraviolet Rays;actinomycin;cell type;driver mutation;effective therapy;epigenetic silencing;global run on sequencing;improved;improved outcome;in vivo;inhibitor;insight;irinotecan;novel;novel strategies;patient derived xenograft model;pre-clinical;recruit;research clinical testing;resistance mechanism;response;success;targeted agent;targeted treatment;transcription factor;tumor;tumor growth The interface of transcription DNA damage and epigenetics: A therapeutic vulnerability of the EWS-FLI1 transcription factor We have developed and clinically translated the combination of trabectedin and irinotecan as an EWS-FLI1targeted therapy for Ewing sarcoma. While the clinical evaluation of this combination is promising andmultiple tumor regressions have been observed the activity has been limited by what appears to be intrinsicmechanisms of resistance. The goal of the current study is to exploit these mechanisms to develop novelEWS-FLI1 directed combination therapies with improved activity and less toxicity. NCI 10718793 5/18/23 0:00 PA-20-185 1R01CA283058-01 1 R01 CA 283058 1 "GREENBERG, WILLIAM A" 6/1/23 0:00 5/31/28 0:00 Mechanisms of Cancer Therapeutics B Study Section[MCTB] 10824831 "GROHAR, PATRICK J" Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 505743 NCI 284125 221618 There is an urgent need to develop novel approaches to target oncogenic transcription factors. Ewingsarcoma (ES) is emblematic of this need. It has been known for more than 25 years that ES is absolutelydependent on the EWS-FLI1 transcription factor for cell survival. EWS-FLI1 is the only recurrent mutation ofES (>20% of tumors) and the dependence of the cells on this protein has been established by multipleindependent studies. Our overarching goal is to identify and clinically translate compounds that inhibit EWS-FLI1 to improve outcomes for patients with Ewing sarcoma. Consistent with this goal we have identified theminor groove DNA binding compound trabectedin as an inhibitor of EWS-FLI1. We have moved thiscompound into the clinic in combination with low dose irinotecan and have seen striking clinical responses.However some patients progress while on therapy. Other patients have required dose reductions due totoxicity that limits the efficacy of the therapy. Therefore in this study we propose that a deeper understandingof the mechanisms of activity and drug resistance will improve the therapy. We hypothesize that while thesecompounds poison EWS-FLI1 by mechanisms that we have defined they also alter chromatin structure andcellular state in such a way that poises the cell for recovery. More precisely we have shown that trabectedinredistributes EWS-FLI1 in the nucleus to the nucleolus to trigger an epigenetic switch to alter chromatinaccessibility at the EWS-FLI1 driven GGAA microsatellite enhancer. However here we propose that additionalepigenetic DNA damage response mechanisms identified by unbiased approaches leaves the chromatinpoised for recovery. Additionally we have shown that redistribution of EWS-FLI1 to the nucleolus stabilizes thefusion protein thus providing a reserve pool that facilitates transcriptional recovery. Therefore the goal of thisstudy is to directly target these poised states to improve the activity of the compound limit toxicity and restrictmechanisms of resistance. Importantly these approaches should improve the toxicity profile because theyfocus on EWS-FLI1 which is only found in Ewing sarcoma cells and its downstream GGAA microsatelliteenhancer which has no known function in normal cells. If successful the study will yield a novelmechanistically focused combination therapy for relapsed Ewing sarcoma patients that will build on thepreliminary success of trabectedin/irinotecan. In addition the study will provide important insight into the use ofDNA binding compounds as inhibitors of oncogenic transcription factors. Finally it will yield a novel trappingapproach to target phase transitioned transcription factors. 505743 +Clinical Research; Coronaviruses; Emerging Infectious Diseases; HIV/AIDS; Infectious Diseases Acquired Immunodeficiency Syndrome;Address;Area;Budgets;COVID-19;Computers;Contract Services;Contractor;Contracts;Development;Diagnosis;Environmental Health;Funding;HIV Infections;Human Herpesvirus 8;In Vitro;International;Laboratory Animal Science;Libraries;Maintenance;Malignant Neoplasms;Modeling;Molecular Virology;Office of Administrative Management;Prevention;Public Health;Research;Satellite Viruses;Services;Technology;Translational Research;Viral Epidemiology;Virus;Work;data management;improved;in vivo;multidisciplinary;nonhuman primate;novel coronavirus;operation;pandemic coronavirus;programs;repaired;repository;research and development;statistical service;tumor THE COVID 19 SERVICES CATALYZE TRANSLATIONAL RESEARCH FINDINGS INTO PUBLIC HEALTH CHANGES TO ADDRESS THE NOVEL CORONAVIRUS PANDEMIC THROUGH IMPLEMENTA n/a NCI 10718773 75N91019D00024-P00018-759102000003-53 N01 8/31/20 0:00 8/30/22 0:00 78754791 "FREEDMAN, LEONARD " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 648604 OD AbstractThese funds are used to provide support for the NCI AIDS & Cancer Virus Program (ACVP) and overhead/management support for all the AIDSresearch within the $425M FY2013 NCI budget at the NCI-Frederick. This overhead/management support includes appropriate allocations of thefollowing areas: facility maintenance; building support; utilities; scientific library; computer and statistical services; environmental health and safetyprograms; subcontract staff; repository services; advanced technology and laboratory animal science program support; and general FederallyFunded Research and Development Center (FFRDC) Contract administration. The ACVP headed by Dr. Jeff Lifson is an integratedmultidisciplinary program that pursues basic and applied studies aimed at improving our understanding of AIDS-associated viruses including studiesintended to facilitate the improved diagnosis prevention and treatment of HIV infection and AIDS and AIDS related tumors particularly thoseassociated with other viruses such as KSHV. The Program consists of six independent but highly interactive research Sections headed by PrincipalInvestigators whose work spans from fundamental molecular virology through in vitro studies to in vivo studies in non-human primate (NHP)models to international viral epidemiology. 648604 +Cancer Cancer Surveillance Research Program;Development;Modeling;Risk;Time DEVELOPMENT OF COMPETING RISKS SURVIVAL PARAMETRIC MODELS FOR CONTINUOUS TIME IN TWO-TIME SCALES. n/a NCI 10718594 75N91022P00862-0-0-1 N01 9/15/22 0:00 9/14/23 0:00 1900687 "FINE, JASON " Not Applicable Unavailable 622781578 E5HLKXD77F77 622781578 E5HLKXD77F77 US 43.087927 -89.504593 -440508 MIDDLETON WI Other Domestic Non-Profits 535623748 UNITED STATES N R and D Contracts 2022 24750 NCI PURCHASE ORDER: DEVELOPMENT OF COMPETING RISKS SURVIVAL PARAMETRIC MODELS FOR CONTINUOUS TIME IN TWO-TIME SCALES. In support of THE SURVEILLANCE RESEARCH PROGRAM. 24750 +Cancer; Clinical Research; Health Services Academy;Address;Affect;Assessment tool;Characteristics;Climate;Communities;Data;Data Collection;Diagnosis;Extramural Activities;Funding;Future;Health Services Accessibility;Health system;Healthcare;Intervention;Justice;Measurement;Measures;Medicine;National Cancer Institute;Nature;Organizational Culture;Outcome;Patients;Performance;Policies;Process;Process Measure;Provider;Reporting;Research;Safety;Screening for cancer;Standardization;Structure;System;Time;cancer care;care delivery;care outcomes;comparative;health care delivery;health care service organization;method development;neoplasm resource;online resource;organizational climate;organizational readiness;organizational structure;technical report;webinar Measuring Healthcare Organization Characteristics in Cancer Care Delivery Research n/a NCI 10718593 APC22006001-1-0-1 Y01 78893968 "BRESLAU, ERICA " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 225750 NCI The characteristics of healthcare organizationsdefined as the structures processes and organizational level policiesaffect cancer care delivery and outcomes at the patient provider and system levels. The National Academy of Medicine noted that additional research is needed to understand how healthcare organizational characteristics and processes of care delivery in organizations influence cancer care access quality outcomes and disparities. Several organizational construct frameworks exist to advance such research. However applying these frameworks and measuring organizational variables in practice can be challenging due to the multilevel and dynamic nature of healthcare and multifaceted nature of organizational variables.The Compendium of U.S. Health Systems created as part of the Comparative Health System Performance (CHSP) initiative was an important step in collating available administrative data on several structural aspects of health systems and their component care delivery organizations. However several healthcare organizational frameworks point to important organizational structure and process variables that are not available in administrative or claims data and are therefore more challenging to measure. For example the healthcare organizational culture and climate domain from Pina et al.3 includes subdimensions such as organizational safety climate justice climate and organizational readiness for change. These constructs show promise as indicators of organizational performance yet they may vary substantially over time while also requiring intensive primary data collection via distinct validated assessment tools.Federal care delivery research funders are encouraging multilevel research that includes measurement and intervention on healthcare organizational characteristics; however there is no compendium of relevant valid measures for assessing these constructs. One difficulty is that some measures of organizational constructs have only been applied to organizations outside of healthcare. Their relevance to healthcare and cancer care specifically is not known.To address the gaps identified above the technical brief will:Identify and describe existing healthcare organization structure and process measures relevant to research on the delivery of cancer screening diagnosis and treatment;review the consistency of existing measures (i.e. standardization);review the usefulness of existing measures that have been developed or validated in healthcare delivery contexts and their use (if any) in cancer care delivery research;identify gaps where future measure or method development may be needed to advance multilevel cancer care delivery research; andidentify measures that will be collated into a technical report and an online compendium resource for the cancer care delivery research community.The report will ultimately inform a National Cancer Institute (NCI) funding announcement(s) and supplements that encourage the extramural community to study healthcare organizations and use identified measures. It will also inform NCI-hosted webinars that will educate the research community as well as an online compendium resource for the cancer care delivery research community. 225750 +No NIH Category available Amplifiers;Antineoplastic Agents;BRAF gene;Biological Markers;Blood;Cancer Model;Cell Death;Cells;Chromatin;Chromatin Structure;Clinical;Clinical Data;Clinical Trials;Colorectal Adenocarcinoma;Colorectal Cancer;Combined Modality Therapy;DNA;DNA Damage;DNA Repair;DNA Repair Disorder;DNA biosynthesis;DNA damage checkpoint;Data;Deoxyuridine;Development;Dose;Elements;Evaluation;FDA approved;Future;G2 Phase;Genes;Genetic Transcription;Genomics;Human;Malignant Neoplasms;Metabolism;Modeling;Molecular Abnormality;Mutation;Neoplasm Metastasis;Oncogenic;Patient Selection;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phase I Clinical Trials;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Predictive Value;Prognosis;Randomized;Refractory;Regimen;Research;Resistance;Sampling;Scientist;Solid Neoplasm;Stress;TP53 gene;Testing;Therapeutic;Thymidine;Time;Tissues;Trifluridine;Validation;Work;analog;biomarker driven;biomarker identification;biomarker selection;cancer cell;clinical application;clinical biomarkers;clinical efficacy;clinical implementation;cohort;design;first-in-human;follow-up;gene repair;genome integrity;genome-wide;improved;inhibitor therapy;insight;mutant;next generation sequencing;novel;novel drug combination;novel strategies;novel therapeutic intervention;patient population;phase 3 study;pre-clinical;pre-clinical research;predict clinical outcome;predictive marker;prospective;repaired;replication stress;response;response biomarker;side effect;therapeutically effective;transcriptome;treatment planning;treatment strategy;tumor;tumor progression;uptake Novel synthetic lethality strategy for TP53 mutant colorectal cancer PROJECT NARRATIVEThe proposal investigates a novel therapeutic strategy for management of aggressive p53-deficient colorectalcancer. This novel therapeutic strategy is based on our inducer-amplifier concept for selective damaging ofdeadly cancer carrying a genetic abnormality commonly found in most solid tumors. Our work provides a noveland immediately feasible plan for treatment of patients with p53-deficient CRC using a combination of FDA-approved clinical drugs that have never been combined before. NCI 10718572 8/10/23 0:00 PAR-21-033 1R37CA282430-01 1 R37 CA 282430 1 "UNDALE, ANITA H" 8/10/23 0:00 7/31/27 0:00 Mechanisms of Cancer Therapeutics A Study Section[MCTA] 15628897 "FOUNTZILAS, CHRISTOS " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 8/10/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 585984 NCI 341158 244826 PROJECT SUMMARY/ABSTRACTGenetic alterations in the tumor suppressor p53 gene (TP53) are found in most colorectal adenocarcinomas(CRC) and contributes to poor prognosis. The p53 protein encoded by TP53 is a key element of DNA damagecheckpoints that are activated by DNA damage response and control genome integrity. Although decades ofresearch generated immense information on the functional consequences of p53 mutations therapeutic effortstargeted to mutant p53 have proven largely unfruitful. Existing therapeutic options for p53-deficient CRC areineffective and cause toxic side effects stressing the need for better therapeutics. We developed aconceptually novel treatment strategy for selectively targeting p53-deficient cancer cells that takes advantageof their unique DNA repair deficiencies. Our preclinical research revealed that p53-deficient tumors accumulateDNA damage upon incorporation into DNA of a thymidine analogue (i.e. trifluorothymidine a component ofFDA-approved drug called TAS102). The thymidine analogue does not interrupt DNA replication but ratherprompts DNA repair that requires p53-dependent checkpoint. We found that p53-deficient cells lacking thep53-dependent checkpoint selectively accumulate DNA breaks. Importantly this DNA damage is stronglyenhanced by inhibitors of poly (ADP) ribose polymerase (PARP) leading to cell death. This novel inducer-amplifier strategy was extensively validated in multiple preclinical models. Our preclinical data demonstrated asuperior anti-tumor activity of TAS102 in combination with PARP inhibitor (PARPi) compared to either drugalone in p53-deficient cancer models. Based on our preclinical data we developed a first-in-human Phase Iclinical trial for advanced CRC with two FDA-approved drugs TAS102 and PARPi talazoparib. Thus wehypothesize that the combination of TAS102 with PARPi talazoparib is an effective biomarker-driven treatmentfor patients with p53-deficient CRC. The current proposal is aimed to define the efficacy of our combinationtherapy strategy for the first time in humans with advanced CRC in a collaborative effort of basic translationaland clinical scientists. The study will generate the biomarkers to guide clinical implementation and furtherdevelopment of our inducer-amplifier strategy by using patient-derived material from our ongoing clinical trial.The study will employ state-of-the art next-generation sequencing approaches to define genome-wide changesin response to the TAS102-PARPi combination in CRC models. Importantly we will examine the antitumorefficacy of our novel two-drug therapy in p53-deficient CRC patients. Together this work will providemechanistic insights in the action of our two-drug therapy and will serve as a platform for development of bettertreatments. Our study matters for thousands of patients with aggressive p53-deficient CRC. 585984 +Cancer; Prevention Agreement;Censuses;Centers for Disease Control and Prevention (U.S.);Chronic Disease;Computer Security;Consultations;Data;Data Collection;Data Files;Data Security;Ensure;Grant;Health Promotion;Institutional Review Boards;Interviewer;Maintenance;Malignant Neoplasms;National Cancer Institute;National Health Interview Survey;Preparation;Publications;Questionnaire Designs;Research;Sampling;Security;Surveys;Testing;Training;Travel;United States National Center for Health Statistics;Weight;authority;cohesion;data centers;data exchange;data integrity;data quality;data sharing;design;disorder prevention;instrument;operation;quality assurance;web site Cancer Questions on the 2023 National Health Interview Survey n/a NCI 10718567 APC22004001-1-0-1 Y01 78893916 "CROSWELL, JENNIFER " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 2000000 NCI Pertaining to the National Health Interview Survey (NHIS) in general and cancer questions specifically this agreement supports the implementation of the NHIS including questions on cancer. These functions include but are not limited to:Sample design and maintenanceSample selection and listingQuestionnaire design and testingExpert consultationProgramming and testing of the CAPI instrumentInterviewer training and data collectionPost data collection editing and processingOversight and management of the operationsData weighting and estimation Preparation and submission of all OMB and IRB clearances packagesPreparation of Public Use Data FilesData publications presentations and analysisTravel related to any of the above mentioned itemsMany of these functions are provided in whole or in part by the Census Bureau. In addition to the above mentioned tasks the National Center for Health Statistics (NCHS) collaborated with the National Cancer Institute (NCI) and National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) to develop the cancer questions. NCHS retains the right to final approval of the content of the sponsored questions with the objective of maintaining quality appropriateness and cohesiveness of the entire survey. NCHS will collaborate with NCI in the editing of the data if it is determined that it is necessary for data quality assurances. Should sharing of data be required for the purpose of editing NCI agrees to comply with all NCHS and other federal requirements to ensure data integrity security and confidentiality. NCHS may share data for the purposes of editing through pre-tabulated tables provided by NCHS through the use of the Research Data Center (RDC) or by the transfer of selected data. Transfer of data would require NCI to complete the requirements and sign a separate Designated Agent Agreement and depending on the type of data transferred demonstration of an accepted System Security Plan including an Authority to Operate granted or acknowledged by the Centers for Disease Control and Prevention (CDC) Office of the Chief Information Security Officer. Supplement sponsors shall not use the opportunity to edit data for the purpose of working on or disseminating results of their own separate analyses before the supplement microdata are publicly released.NCHS anticipates the release of the public use data file approximately 6-9 months after the end of the data collection year and will post the public use data file on our website http://www.cdc.gov/nchs/nhis.htm. 2000000 +No NIH Category available 90Y;Aftercare;Antibodies;Area;Autoimmune;Binding;Cancer Etiology;Catheters;Cell Death;Cell Maturation;Cessation of life;Clinical;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Complement;Cytotoxic T-Lymphocytes;Dendritic Cells;Dose;Excision;Flow Cytometry;Gold;Immune;Immune response;Immune system;Immunohistochemistry;Immunologic Stimulation;Immunologics;Immunotherapy;In Vitro;Individual;Infusion procedures;Intervention;Intra-Arterial Infusions;Lead;Lesion;Ligands;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Measurement;Microspheres;Monitor;Nanoimmunotherapy;Nanostructures;Normal tissue morphology;Oncology;PD-L1 blockade;Patients;Primary carcinoma of the liver cells;Procedures;Protocols documentation;Radiation;Radiation Dose Unit;Radiation therapy;Radio;Radioembolization;Radiology Specialty;Reactive Oxygen Species;Research;Resistance;Risk;Rodent Model;Safety;Surface;Therapeutic;Therapeutic Effect;Tissues;Transplantation;Treatment Efficacy;Treatment Protocols;Treatment outcome;Tumor Tissue;Tumor-infiltrating immune cells;Up-Regulation;X-Ray Computed Tomography;anti-PD-L1;anti-PD-L1 therapy;anti-cancer;anti-cancer therapeutic;attenuation;cancer cell;curative treatments;dosage;follow-up;image guided;imaging properties;immune activation;immune checkpoint;immune checkpoint blockade;immunogenic cell death;improved;liver cancer model;novel strategies;programmed cell death protein 1;response;side effect;targeted delivery;therapy outcome;tumor Local Tumoral Delivered Immune Checkpoint Blockades Immunotherapy and Radioembolization Combination Therapy NARRATIVE We propose transcatheter tumoral intra-arterial delivery of immune checkpoint blockades (ICB) loadedmultifunctional carriers permitting combinational local ICB immunotherapy and 90Y-radioembolization (90Y-RE) ofliver cancer. Selective transcatheter tumoral intra-arterial delivery of ICB loaded Au (gold) supra-nanostructures(AuSN) will permit efficient local delivery of immunostimulatory ICB molecules allowing an increase in thedosage and improve their safety profile. Local tumoral delivered ICB loaded AuSN will offer the potential tosignificantly increase the radio-immune-stimulating efficacy of 90Y-RE. This salient combination of local ICBimmunotherapy and 90Y-RE using the multifunctional carriers offers the potential to significantly improvelongitudinal treatment outcomes in liver cancer. NCI 10718531 8/29/23 0:00 PA-20-185 1R01CA282664-01 1 R01 CA 282664 1 "CARDONE, MARCO" 9/1/23 0:00 8/31/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11280383 "KIM, DONG-HYUN " Not Applicable 5 RADIATION-DIAGNOSTIC/ONCOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 357212 NCI 228750 128462 PROJECT SUMMARYSystemic mono- or combination- immune checkpoint blockade (ICB) immunotherapy has been an establishedtherapeutic paradigm. However a risk of serious autoimmune side effect has been evidenced with non-specificcytotoxic T cell expansion. Substantial research has investigated into how best to harness the antitumorpotential of combination immunotherapies and how to direct immunotherapies at the tumor. Hepatocellularcarcinoma (HCC) is the 5th most common malignancy in the world and the 4th leading cause of cancer death inthe US. Resection and transplantation are the sole potentially curative treatments for HCC but only 10-15% ofpatients are candidates. Recent clinical trials demonstrate the potential of ICB antibodies against programmedcell death 1 (PD-1) or its ligand PD-L1 for the treatment of HCC. However the strong immune suppressivemicroenvironment and low expression of immune checkpoint molecules within the HCC tumor lead to aresistance to immunotherapy in HCC; thus the efficacy of ICB immunotherapy may not be sufficient to elicitdurable clinical benefits. 90Y-radioembolization (90Y-RE) can precisely deliver high doses of radiation to HCCprotecting healthy tissues and avoiding side effects. 90Y-RE should be an ideal complement to ICBimmunotherapy given that 90Y-RE induces immunogenic cell death. Recently clinical trials have been initiatedto evaluate systemic ICB immunotherapy in combination with 90Y-RE in the hope of enhancing overalltherapeutic effects. However one limitation that accounts for the compromised efficacy of combined ICBimmunotherapy is off-target binding of the ICBs to normal tissues upon systemic administration. Ideally theseICBs should be delivered selectively to the tumor lesion to avoid systemic non-specific activation of theimmune system. We propose catheter-directed intra-arterial (IA) infusion of anti-PD-L1 (aPD-L1) loaded Ausupra-nanostructures (AuSN) in a combination with 90Y-RE. Catheter directed local infusion of aPD-L1 withhigh surface area and reactive oxygen species responsive degradable AuSN will augment the localization ofimmunotherapy to the targeted HCC permitting radiation-enhanced activation of the immune system forsuperior therapeutic outcomes. Our proposed tumoral IA infused anti-PD-L1 loaded AuSN will permit efficientand targeted delivery of immunostimulatory aPD-L1 to allow an increase in the dosage and improved safetyprofile. The local ICB delivery of AuSN carriers will offer the potential to significantly increase the local immune-stimulating efficacy of 90Y-RE. Our CT visible AuSN and cross-sectional CT and MR image guidance shouldalso permit us to monitor/track/quantify the delivery of aPD-L1-AuSN to the targeted tumor tissues. It shouldallow early prediction of elicited responses to prompt timely adjustments to individual treatment regimens.Through a collaborative project we seek to develop a powerful new approach for tumor directed localcombinational aPD-L1 immunotherapy and 90Y-RE for the treatment of HCC. 357212 +No NIH Category available 3D Print;Acceleration;Affect;American;Artificial Intelligence;Benign;Biochemical;Biological Assay;Biological Markers;Biopsy;Blood Banks;Cancer Etiology;Cessation of life;Clinical;Collagen;Data;Diagnosis;Diet;Diffusion;Disease;Enrollment;Extracellular Matrix;Fucose;Genomic approach;Genomics;Goals;Histologic;Histology;Image;Imaging Device;Imaging technology;Inflammation;Inflammatory;Information Systems;Institution;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metabolic;Metabolism;Methods;Modeling;Molds;Molecular;Morbidity - disease rate;Neoplasm Metastasis;Nomograms;Organ;Outcome;Pathology;Patient-Focused Outcomes;Patients;Polysaccharides;Prognosis;Prospective cohort;Prostate;Prostate Adenocarcinoma;Prostatectomy;Prostatic Neoplasms;Provider;Race;Radiation therapy;Radical Prostatectomy;Recurrence;Recurrent disease;Reporting;Sensitivity and Specificity;Serum;Severities;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stromal Cells;Stromal Hyperplasia;Testing;Time;Tissues;Training;Variant;Visualization;artificial intelligence algorithm;biobank;clinic ready;clinical risk;clinical translation;cohort;curative treatments;effective therapy;experience;experimental study;extracellular;genomic platform;genomic signature;genomic tools;histological image;histological specimens;imaging biomarker;imaging modality;in vivo;in vivo imaging;insight;liquid biopsy;mass spectrometric imaging;men;molecular imaging;molecular marker;mortality;multidisciplinary;non-invasive imaging;novel;outcome prediction;patient stratification;patient subsets;prognostic;prognostic model;prospective;racial disparity;radiomics;risk prediction model;risk stratification;spectrograph;structural imaging;survival outcome;tool;tumor;tumor microenvironment;water diffusion Identifying lethal prostate cancer at diagnosis with advanced proteoglycomic radiomic and genomic approaches PROJECT NARRATIVEProstate cancer (PCa) is a significant cause of morbidity and mortality in men. Currently there is a significantunmet need for identifying men at initial diagnosis who will ultimately progress to metastatic lethal disease. Thisproject investigates the combination of clinically translatable imaging technologies: diffusion basis spectralimaging (DBSI) MRI and matrix assisted laser desorption ionization (MALDI) histologic molecular imaging toidentify imageable biomarkers associated with poor outcomes in men being evaluated for prostate cancer atinitial diagnosis.OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page NCI 10718530 7/7/23 0:00 PAR-22-131 1R01CA282022-01 1 R01 CA 282022 1 "WANG, YISONG" 7/7/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-ISB-L(59)R] 11661535 "IPPOLITO, JOSEPH EDWARD" "KIM, ERIC HWAN" 1 RADIATION-DIAGNOSTIC/ONCOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 637936 NCI 476756 161180 PROJECT SUMMARYConventional prostate adenocarcinoma (PCa) is the second leading cause of cancer death in American men.Patients with organ-confined disease are candidates for potentially curative treatment by either radicalprostatectomy or radiation therapy. However 20-40% of patients undergoing radical prostatectomy and 30-50%of patients undergoing radiation therapy can experience biochemical recurrence within 10 years. These findingsindicate that there is suboptimal identification of lethal PCa at the time of diagnosis. Therefore identification ofaggressive disease at the time of diagnosis could stratify patients develop more effective therapy options andextend survival. In the clinical setting noninvasive imaging biomarkers are routinely measured withmultiparametric magnetic resonance imaging (mpMRI). However mpMRI has multiple limitations that result inreduced sensitivity and specificity for PCa in part from obscuration from inflammatory or stromal cells in theprostate. This proposal advances the use of a clinical magnetic resonance imaging (MRI) sequence diffusionbasis spectral imaging (DBSI) that has the ability to detect structural and cellular changes in the PCamicroenvironment (e.g. stroma inflammation tumor) that cannot otherwise be determined with conventionalmpMRI a significant advancement. In parallel our team has discovered a panel of extracellular proteoglycomicbiomarkers in lethal forms of PCa (i.e. fucosylated glycans and modified collagensFuCol biomarkers) withMatrix Assisted Laser Desorption Ionization (MALDI) mass spectrometry imaging of histologic specimens. Thesemolecular markers provide insight into the structural derangements of lethal PCa and because structural changesaffect water diffusion it suggests that these structural changes may actually be detectable with DBSI. Wehypothesize that MALDI-detected proteoglycomic markers expressed as the FuCol score are associated withstructural and metabolic changes in lethal PCa that can be visualized with DBSI to better identify aggressivepotentially lethal PCa at the time of diagnosis. In the first Aim we will continue to validate our FuCol score as apredictor of disease recurrence and metastasis in a large institutional biorepository. In this Aim we willinvestigate the effects of race and diet on the FuCol score and its ability to predict poor outcomes. We will alsoestablish the ability to measure a FuCol score as part of a noninvasive liquid biopsy to predict outcomes. InAim 2 we will enroll a prospective cohort of prostatectomy patients to develop Diffusion Molecular Imaging(DMI); an AI-driven tool that generates in vivo FuCol scores using in vivo DBSI as its input prior to prostatectomyhence a non-invasive imaging readout of lethal disease. In Aim 3 we will develop an augmented risk predictionmodel that incorporates novel DBSI imaging the clinical Decipher genomics platform and conventional clinicalmetrics (grade stage PSA) to better predict lethal disease at prostatectomy. In summary these experimentswill result in rapid acceleration of a clinically-ready workflow to detect molecular biomarkers associated with pooroutcomes. This will dovetail with parallel strategies that our group is developing to treat these cohorts of patientswith lethal prostate cancer variants. 637936 +Basic Behavioral and Social Science; Behavioral and Social Science; Cancer; Prevention Area;Behavior;Behavioral Risk Factor Surveillance System;Centers for Disease Control and Prevention (U.S.);Contractor;County;Data;Information Management;Modeling;National Cancer Institute;National Health Interview Survey;Outcome;Research;Risk Factors;Running;Science;United States National Center for Health Statistics;cancer risk;data centers;programs;screening Small Area Estimation for Cancer Risk Factors and Screening Behaviors by Combining NHIS and BRFSS for years 2017 to 2019 n/a NCI 10718527 APC22005001-1-0-1 Y01 78893852 "LIU, BENMEI " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 15750 NCI Collaborating with staff at the National Center for Health Statistics (NCHS) and the Centers for Disease Control and Prevention (CDC) the National Cancer Institute (NCI) has been continuing leading the efforts on producing up-to-date small area estimates for outcomes on cancer risk factors and screening behaviors using data from the National Health Interview Survey (NHIS) and the Behavioral Risk Factor Surveillance System (BRFSS) through small area modeling approach. In the past NCHS staff has been providing programming support. For the 2017-2019 data cycle NCI and Information Management Sciences contractor staff will run all the necessary programs through the NCHS Research Data Center (RDC) to access to the confidential county identifier information. 15750 +Cancer Cancer Surveillance Research Program;County;Data;Division of Cancer Control and Population Sciences;Race NCI SURVEILLANCE RESEARCH PROGRAM (SRP) SUPPORT n/a NCI 10718474 75N91022P00936-0-0-1 N02 9/23/22 0:00 9/22/23 0:00 78877318 "LIEBLER, CAROLYN " Not Applicable Unavailable MDH9JYXPEAK1 MDH9JYXPEAK1 US -521335 CROOKSTON MN Other Domestic Non-Profits 56716 UNITED STATES N R and D Contracts 2022 34953 NCI THE DIVISION OF CANCER CONTROL AND POPULATION SCIENCES (DCCPS) SURVEILLANCE RESEARCH PROGRAM (SRP) REQUIRES 1) AGGREGATED COUNTY LEVEL MULTIPLE-RACE DATA 34953 +Cancer; Nutrition Computer software;Dietary History;Licensing;Minnesota;Questionnaires;Universities;nutrition ANNUAL LICENSE FOR ACCESS TO NDSR SOFTWARE n/a NCI 10718425 75N91022P00534-0-0-1 N02 7/1/22 0:00 6/30/23 0:00 78737976 "HARNACK, LISA " Not Applicable 5 Unavailable 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN Domestic Higher Education 554552070 UNITED STATES N R and D Contracts 2022 20000 NCI ANNUAL LICENSE FOR ACCESS TO NDSR SOFTWARE FROM UNIVERSITY OF MINNESOTA NUTRITION COORDINATING CENTER IN SUPPORT OF THE NCI DIET HISTORY QUESTIONNAIRE 20000 +Burden of Illness; Cancer; Dental/Oral and Craniofacial Disease; Digestive Diseases; Prevention; Rare Diseases Address;Affect;Agreement;Algorithms;Area;Cancer Burden;Cancer Patient;Cause of Death;Characteristics;Clinical;Communities;Complex;Data;Databases;Development;Disease;Dissemination and Implementation;Ensure;Face;Family;General Population;Head and Neck Cancer;Head and neck structure;Health Professional;Incidence;Individual;Language;Life Expectancy;Link;Literature;Malignant Neoplasms;Malignant neoplasm of prostate;Medical;Medicare;Modeling;Nomograms;Outcome;Paper;Patients;Periodicity;Persons;Physicians;Population;Probability;Radiation therapy;Radical Prostatectomy;Reporting;Research;Risk;Risk Estimate;SEER Program;Structure;Surveillance Program;System;United States Department of Veterans Affairs;Veterans;Visual Aid;Work;cancer care;cancer site;cancer statistics;cancer survival;cancer therapy;clinical implementation;clinical risk;clinically relevant;comorbidity;demographics;experience;follow-up;improved;individual patient;malignant mouth neoplasm;mortality;mortality risk;neoplasm registry;patient advocacy group;personalized decision;population based;predictive modeling;prognostic signature;prognostic tool;programs;rare cancer;response;statistics;tool;web site Clinical Prediction Tools for Head and Neck Cancers n/a NCI 10718396 APC18006001-1-0-1 Y01 78893635 "FEUER, ERIC " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 20000 NCI "A growing number of clinical prediction models (CPMs) have been developed to provide individualized estimates of the risk of various clinical outcomes including mortality (or survival) for cancer patients. By utilizing patient disease and treatment characteristics to estimate these outcomes at the individualrather than aggregatelevel these CPMs produce the critical evidence that patients and clinicians need to make rational personalized decisions about cancer treatment. The individualized risk information produced by CPMs thus holds great promise for improving the quality of cancer care.The clinical implementation and dissemination of CPMs in cancer care however faces a critical challenge. Existing CPMs are each limited in their focus. Some CPMs estimate mortality risk conditional on cancer patients comorbidities without adjusting for the treatments they undergo while numerous other CPMs focus on mortality risk conditional on patients particular treatments but irrespective of comorbidities. For example separate CPMs have been developed to estimate mortality risk of clinically localized prostate cancer following radical prostatectomy and conservative treatment; however these models do not account for comorbidities and no CPMs estimate mortality risk following radiation therapy. Hence there is no single CPM that can support most clinical decisions related to cancer management even for a single cancer site.The Surveillance Epidemiology and End Results (SEER) Program is one of the premiercancer surveillance programs in the world currently composed of population-based cancerregistries covering 30% of the total US population. The information collected on each and every cancer patient in SEER coverage areas includes demographics a description oftheir cancer treatment and patient follow-up including cause of death for deceasedpatients. Periodic reports on various aspects of the cancer burden on the populationincluding incidence survival treatment and mortality using the SEER database are madeavailable to the general research community and the public and are routinely cited in themedical literature and the media. In most statistical reports on cancer provided by SEERin the past information on survival has been net survival i.e. survival which reflects thelikelihood of dying of causes related to a patient's cancer in the absence of competingcauses of death and is of limited value to clinicians and patients because it does notreflect a patient's actual survival experience. An initiative of the SEER Program has beento utilize the high-quality patient follow-up data (that SEER has collected since its inceptionin 1973) for the purpose of creating statistical tools that provide survival information that ismore clinically relevant to physicians and individual patients. The approach taken was todevelop the SEER*Cancer Survival Calculator (SEER CSC) which will include algorithmsor nomograms for various cancers that will provide survival statistics that account forcompeting causes of death including the crude probabilities of dying from cancer and fromother causes along with the probability of survival. These probabilities are provided inresponse to inputting a profile of prognostic variables for a patient. One unique aspect ofthe SEER CSC is the ""life expectancy in the absence of cancer which is derived fromMedicare data linked to SEER and quantifies how much longer someone is expected to live if they did not have their cancer.The purpose of this agreement is to work with the Veterans Administration to further revise and refine the SEER*CSC module for oral cancer the language and structure of which we now also plan to use as a model for the other cancers the CSC is addressing. SEER*CSC was originally developed with the idea that it would just be released for health care professionals but after substantial discussion over the past several years it was determined that it will be released on a public website for use by patients and their families. This has required new revisions to make the language and overall format more accessible to a general audience and making appropriate disclaimers so that people will not use the calculator for inappropriate purposes. Work involves discussions with head and neck patient advocacy groups which will lead to refinements to the user interface for the entire SEER*CSC program (to include visual aids for example) to accurately place it in the landscape of other prognostic tools ensuring the information links to correct deeper level information about cancer statistics and interpretation more broadly and revising the academic paper summarizing the development of the oral cancer module and its use in a general public setting. This work is of great import to the VA because Veterans are disproportionately affected by head and neck cancer compared to other populations in the U.S. In addition as a relatively rare cancer the power of case capture by the NCI makes them an ideal partner for this kind of work which could not be carried out by the Department of Veterans Affairs alone - there are not enough cases or a record keeping system in the VA to easily create the models that are needed to make these sorts of complex calculations." 20000 +No NIH Category available Abscopal effect;Acceleration;Active Sites;Address;Adverse effects;Affect;Affinity;Aneuploidy;Antibiotics;Apoptosis;Biological Assay;Cancer Patient;Caring;Cell Aging;Cell Death;Cell Line;Cell Proliferation;Cell Survival;Cell division;Cells;Characteristics;Chemicals;Clinic;Clinical;Combined Modality Therapy;Cysteine;Cytotoxic T-Lymphocytes;DNA;DNA Damage;Data;Dendritic Cells;Dendritic cell activation;Distant;Dose;Double Strand Break Repair;Drug Modelings;Drug Targeting;Enzymes;Excision;Experimental Neoplasms;Failure;Gene Expression;Genotoxic Stress;Growth;Hand;Immune Evasion;Immunologic Cytotoxicity;In Vitro;Inbred BALB C Mice;Infiltration;Inflammation;Inflammatory Infiltrate;Ionizing radiation;Malignant Neoplasms;Measures;Mediating;Modeling;Modernization;Modification;Molecular Target;Mus;Natural Products;Neoplasm Metastasis;Nonhomologous DNA End Joining;Normal Cell;Normal tissue morphology;Outcome;Oxidative Stress;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Property;Publishing;RNA-Directed DNA Polymerase;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Reaction;Recurrence;Resistance;Reverse Transcriptase Inhibitors;Role;Safety;Series;Signal Transduction;Solid Neoplasm;Structure;Supporting Cell;T-Cell Proliferation;TERT gene;Telomerase;Telomerase Inhibitor;Telomerase inhibition;Therapeutic;Therapeutic Index;Tissues;Toxic effect;Translating;Treatment Efficacy;Tumor Immunity;Validation;Work;analog;anti-tumor immune response;cancer cell;cell immortalization;cell injury;clinically significant;drug development;homologous recombination;image guided;immune checkpoint blockade;immunogenic;immunogenicity;improved;in silico;in vivo;inhibitor;irradiation;lead optimization;natural product inspired;neoplastic cell;novel;oxidative damage;pre-clinical;programmed cell death ligand 1;radiation resistance;radiation response;repaired;response;senescence;success;targeted agent;telomere;tumor;tumor progression PAIRS: Validating telomerase reverse transcriptase (TERT) as an intrinsic vulnerability toward sensitizing cancer to radiation Narrative Best known for a role in maintaining cancer cell immortality the telomerase enzyme TERT also protectscancer cells from radiation therapy. Here we will study new TERT blocking agents as model drugs to sensitizecancer to radiation in cell lines and in experimental tumors. Success may lead to highly cancer-specific agentsthat will improve patient outcomes. NCI 10718390 5/23/23 0:00 PAR-22-198 1R01CA282781-01 1 R01 CA 282781 1 "PRASANNA, PAT G" 7/1/23 0:00 6/30/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 1927504 "KRON, STEPHEN J." "SCHEIDT, KARL A" 1 GENETICS 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 472393 NCI 343069 129324 Summary A favorable target for radiation synthetic combinations would be a feature of cancer cells criticallyinvolved in growth signaling repair or survival that can be blocked with an otherwise non-toxic drug leavingtumors vulnerable to radiation without adverse effects on normal tissue. This project is directed at validatinginhibition of telomerase reverse transcriptase (TERT) as a means to enhance the therapeutic index of radiationand achieving key progress toward translating this strategy to the clinic. While TERT is not expressed in mostnormal cells approximately 90% of cancers display reactivation of TERT expression supporting the catalyticactivity of telomerase to maintain telomere integrity despite deregulated growth. While drugs targeting TERThave displayed sufficient safety in patients to evaluate effects of blocking telomere repeat synthesis this hasfailed in solid tumors as telomere erosion is too slow to affect tumor progression. Beyond its essential role incancer cell immortality TERT also contributes to pathways that support multiple cancer hallmarks. By limitingoxidative stress accelerating double strand break repair and supporting cell survival TERT expression incancer cells may confer clinically significant resistance to radiation. This raises the question whether transientlytargeting TERT during radiotherapy to enhance the toxicity of the resulting DNA damage to the cancer cellsmight significantly improve the therapeutic index of radiation. In recently published work our groups described a novel class of TERT inhibitors inspired by theantibiotic chrolactomycin. Like the natural product our streamlined natural product analogs react with an activesite cysteine in the TERT reverse transcriptase active site. The optimized inhibitor NU-1 is otherwise nontoxicin vitro or in vivo but inhibits telomerase activity at low micromolar concentrations. NU-1 confers sensitivity toradiation to TERT-expressing cancer cells. Our data suggest that TERT may promote non-homologous end-joining repair thereby affecting repair pathway choice. Finally using a syngeneic tumor model in BALB/c micewe have demonstrated marked sensitization to radiation in vivo apparently mediated by persistent DNAdamage and increased anti-tumor immune response. With these preliminary studies in hand we propose to 1)Dissect the roles of TERT in double strand break repair and immune evasion and 2) Improve the drug-likeproperties of NU-1 and use these novel compounds to understand how best to obtain radiation sensitizationand an effective anti-tumor immune response. 472393 +No NIH Category available ARID1A gene;Algorithms;Biological Assay;Biological Process;Biology;Bladder;Cancer Etiology;Cancer Patient;Carcinogens;Cells;Cessation of life;Computational algorithm;Data;Disease;Disease Outcome;Dose;Drug Targeting;Epigenetic Process;Evolution;Foundations;Genetically Engineered Mouse;Goals;Health;Human;Incidence;Investigation;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Metastatic to;Modeling;Molecular;Molecular Analysis;Mus;Neoplasm Metastasis;Nitrosamines;Organ;Organoids;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Reporter;Research;Site;System;Systems Biology;TP53 gene;United States;actionable mutation;biobank;candidate identification;driver mutation;drug candidate;improved;in vitro Model;in vivo;in vivo Model;longitudinal analysis;loss of function;muscle invasive bladder cancer;new therapeutic target;non-muscle invasive bladder cancer;novel;novel strategies;novel therapeutics;pre-clinical;single-cell RNA sequencing;translational goal;tumor;tumor microenvironment;tumorigenesis Investigating mechanisms of bladder cancer metastasis Despite significant improvements in cancer outcomes over the past several decades metastasiscontinues to be the primary cause of cancer-related death as exemplified for bladder cancer. Indeed mostpatients with non-muscle invasive bladder cancer and at least half of those with muscle-invasive bladder cancercan expect to be cured (5-year survival ~90% and ~50% respectively) whereas most patients with metastaticbladder cancer will succumb to the disease within a few years (5-year survival ~15%). My research utilizes novelin vivo models to elucidate the biological processes and molecular mechanisms underlying metastatic bladdercancer with the translational goal of identifying new therapeutic targets that may improve patient outcomes. NCI 10718278 9/19/23 0:00 PAR-22-218 1R01CA283068-01 1 R01 CA 283068 1 "AULT, GRACE S" 9/19/23 0:00 8/31/28 0:00 "Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]" 7751746 "ABATE-SHEN, CORY " Not Applicable 13 PHARMACOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 516846 NCI 314192 202654 The major cause of bladder cancer deaths is due to metastasis yet to date metastatic bladder cancer(mMIBC) has not been extensively studied and many salient issues remain unresolved. One of the majorchallenges that has hampered progress in studying mMIBC is the lack of suitable models to investigatemetastatic progression in vivo. We have now generated novel genetically-engineered mouse models (GEMMs)that develop highly penetrant mMIBC. These new are based on our established GEMM in which bladder-specificco-inactivation of the Pten and p53 tumor suppressors leads to invasive disease with a low incidence ofmetastasis. Crossing these Pten; p53 mice with mice harboring loss-of-function of Arid1a an epigenetic regulatorthat is dysregulated in a high percentage of human bladder cancers results in lethal bladder cancer with >80%incidence of metastasis. In addition treatment of the Pten; p53 mice with a low dose of the carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) leads to mMIBC with >60% incidence. In parallel we have implementedstate-of-the-art systems biology approaches to identify mechanistic determinantsmaster regulators (MRs)ofmetastatic progression in the GEMMs. MRs enriched in metastatic tumors in the GEMMs are conserved withhuman bladder cancer and are enriched for those associated with lineage plasticity. To identify drugs that targetthese conserved MRs we implemented OncoTreat a computational algorithm that prioritizes drugs based ontheir ability to invert the activities of biologically-relevant MR. To validate these drugs we have generated anextensive biobank of human patient derived organoid models. Leveraging these GEMMs human patient derivedorganoids and systems approaches we are ideally poised to investigate the hypothesis that the transition frompre-invasive to metastatic disease is driven by the sequential activities of master regulators including for lineageplasticity which can be elucidated and targeted by studying metastatic progression in these GEMMs. We willpursue three Specific Aims: In Aim 1 we will leverage our GEMMs of mMIBC to systematically investigate thebiological processes and molecular mechanisms underlying metastatic progression in vivo. In Aim 2 we willelucidate master regulators of metastatic progression focusing on those associated with the transition from pre-metastatic to metastatic MIBC and/or that distinguish tumors from their corresponding metastases metastasesto different organ sites and as feasible pre-metastatic clusters from overt metastases. We will prioritize MRsthat are conserved with human bladder cancer as well as those associated with lineage plasticity. In Aim 3 wewill seek to identify new drugs for mMIBC using the OncoTreat algorithm to identify compounds that invert theactivity of MRs of metastasis. We will prioritize candidate drugs that (1) target lineage plasticity mechanismsand/or (2) are inferred for patients that do not have evident actionable driver mutations. Altogether our studieswill provide a comprehensive analysis of the biology mechanisms and treatments for mMIBC with thetranslational goal of identifying new therapeutic targets that may improve patient outcomes. 516846 +No NIH Category available Address;Artificial Intelligence;Asian;Behavioral;Biometry;California;Cancer Etiology;Cancer Patient;Cancer Survivor;Cessation of life;Clinical;Clinical Informatics;Clinical Trials;Communities;Consensus;Cost Savings;Data;Data Sources;Databases;Diagnosis;Electronic Health Record;Eligibility Determination;Epidemiology;Ethnic Origin;General Population;Goals;Guidelines;Health;Healthcare;Healthcare Systems;Immunologic Markers;Incidence;Individual;Link;Longterm Follow-up;Lung;Malignant neoplasm of lung;Measures;Methods;Modeling;Morbidity - disease rate;Oncology;Outcome;Patients;Pattern;Population;Population Heterogeneity;Public Health;Race;Radiology Specialty;Recording of previous events;Records;Registries;Research;Research Personnel;Risk;Risk Factors;Smoke;Smoker;Smoking;Smoking Status;Statistical Methods;Survivors;Thoracic Surgical Procedures;Time;Translational Research;United States Preventative Services Task Force;Universities;cancer diagnosis;cancer risk;cancer survival;computed tomography screening;electronic health record system;epidemiologic data;ethnic diversity;high risk;improved;interest;lung cancer screening;mortality;neoplasm registry;neutrophil;never smoker;never smoking;novel;population based;predictive modeling;randomized trial;risk prediction;screening;screening guidelines;sex;shared database;smoking cessation;standard of care;targeted treatment;tool;translational impact Integrating Multiple Electronic Health Records Systems to Improve Lung Cancer Outcomes Lung cancer (LC) causes significant mortality and morbidity in the U.S. How to guide screenings for LCsurvivors is a critical and timely public health concern as CT screening becomes the standard of care withincreased LC survivors in the US population. From a public health perspective our study has high impactbecause the completion of this study will provide a valuable decision tool for evaluating an individuals risk ofdeveloping second primary lung cancer (SPLC) and a set of efficient screening strategies for SPLC among LCsurvivors which will ultimately result in a substantial reduction of the LC mortality and in turn a substantialcost-savings for the healthcare system. NCI 10718073 7/12/23 0:00 PA-20-185 1R01CA282793-01 1 R01 CA 282793 1 "MARCUS, PAMELA M" 7/12/23 0:00 6/30/28 0:00 Clinical Data Management and Analysis Study Section[CDMA] 11974186 "HAN, SUMMER S" Not Applicable 16 NEUROSURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 7/12/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 658892 NCI 449748 209144 Recent advances in screening and treatment have increased the number of lung cancer (LC) survivors (~571340LC survivors as of 2019). However studies have shown that these survivors have a high risk for developingsecond primary lung cancer (SPLC) with the median 10-year SPLC risk of 8.36% after surviving 5 years fromthe initial diagnosis. Further survivors with SPLC have significantly higher mortality vs. those who remain withsingle primary LC. Many unaddressed challenges exist: (1) While prior studies identified several risk factors forSPLC these are mostly measured and fixed at the time of initial diagnosis with findings focused on survivorswho have ever smoked. However SPLC risk is likely to be influenced by dynamic changes of various factors(e.g. smoking cessation) and our preliminary data show that SPLC risk remains just as high among survivorswho never smoked. (2) Nevertheless current epidemiologic data mainly used for SPLC do not offer detailed datameasured after initial diagnosis (3) nor have risk factors or predictions been evaluated for never-smokingsurvivors. (4) Further limited trial evidence exists to address the important clinical question of whether and howto continue CT screening after IPLC diagnosis among LC survivors which requires a long-term follow-up that isoften not feasible in clinical trials. (5) Importantly data on detailed screening for LC survivors are typically lackingin most population-based data. We plan to address these multiple challenges by leveraging electronic healthrecords (EHRs) and novel analytical approaches to generate evidence to inform clinical decisions. Our long-termgoal is to improve LC outcomes by focusing on SPLC utilizing large EHR data combined with novel statisticalmethods that integrate patient data measured after initial diagnosis. Our Specific Aims are: (AIM 1) to use anovel 3-way linkage to establish an integrated shared database for LC (i.e. Oncoshare-Lung) using EHRs fromcommunity-based and academic healthcare systems (with an ethnically diverse population with a high proportionof Asian never smokers) linked to the California Cancer Registry (CCR) ; (AIM 2) to provide a set of clinicaldecision tools for efficiently managing LC survivors by developing a novel statistical framework for predictingdynamic SPLC risks by capturing data measured after IPLC diagnosis; and (AIM 3) to evaluate the feasibilityand utility of a novel causal inference method to assess efficient screening strategies for SPLC in LC survivorsusing EHRs. We will apply a new causal inference method that explicitly emulates the target trials (hypotheticalrandomized trials to answer the question of interest) in estimating the effects of continuing CT screening in long-term LC survivors under varying eligibility criteria. We expect that the completion of this research will fill thecritical gaps in SPLC by providing: (1) clinical decision tools to assess individuals dynamic SPLC risks to identifyhigh-risk survivors for tailored surveillance (2) new analytic pipelines to evaluate efficient screening criteria forSPLC and (3) a well-curated database for high-impact translational research for LC outcomes and surveillancein an ethnically diverse population that provides a unique opportunity to examine critical questions in SPLC. 658892 +No NIH Category available Acetylation;Acetyltransferase;Affect;Algorithmic Analysis;Autoimmunity;Biochemical Pathway;CD8-Positive T-Lymphocytes;Cell physiology;Cells;Cellular Metabolic Process;Computing Methodologies;Data;Data Set;Disabled Persons;Ecosystem;Enzymes;Equilibrium;Genes;Goals;Immune;Immune Targeting;Immune Tolerance;Immune system;Immunity;In Situ;Individual;Knowledge;Malignant Neoplasms;Maps;Mediating;Melanoma Cell;Metabolic;Metabolism;Methods;Modeling;Morbidity - disease rate;Mus;Mutant Strains Mice;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Network-based;Outcome;Oxidative Phosphorylation;Pathway interactions;Phenotype;Polyamines;Population;Production;Productivity;Proliferating;Recycling;Regulatory T-Lymphocyte;Resolution;Role;S100A9 gene;Shapes;Spermidine;Spermine;Symbiosis;System;Therapeutic Intervention;Time;Tissue Harvesting;Tissues;Tumor Immunity;cancer cell;cancer therapy;cell type;conditional mutant;design;effector T cell;exhaust;fighting;immune cell infiltrate;in silico;in vivo;longitudinal analysis;melanoma;metabolic profile;metabolomics;mortality;mouse model;neoplastic cell;novel;nutrient deprivation;pre-clinical;response;single-cell RNA sequencing;stemness;targeted treatment;tool;transcriptomics;tumor;tumor microenvironment;tumor progression;wasting Role of metabolic crosstalk in determining immunity during tumor progression NARRATIVE STATEMENTCancer is a significant cause of morbidity and mortality worldwide. The immune system has the capacity to fightcancer but it becomes disabled as cancer progresses. The proposed studies will advance our knowledge of howtumor cells and immune cells influence each others metabolism over the course of tumor progression with thegoal of devising new anti-cancer therapies. NCI 10718070 7/14/23 0:00 PA-20-185 1R01CA282794-01 1 R01 CA 282794 1 "LIU, YIN" 7/14/23 0:00 6/30/28 0:00 Cancer Cell Biology Study Section[CCB] 1941445 "ANDERSON, ANA C" "KUCHROO, VIJAY K." 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/14/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 513916 NCI 341961 171955 PROJECT SUMMARYTumor cells and infiltrating immune cells co-evolve during the course of tumor progression with the immunesystem progressively losing its efficacy as tumors advance. Immune cells are highly dependent on cellularmetabolism to manifest their effector functions but in the tumor microenvironment (TME) metabolic competitionwith rapidly proliferating cancer cells leads to nutrient deprivation alongside increased metabolic waste both ofwhich negatively impact immune cell function. Moreover metabolic symbiosis between cancer and immunecells can promote the acquisition of suppressive immune cell phenotypes ultimately disfavoring anti-tumorimmunity. These dynamic metabolic interactions are shaped by the niches occupied by cells within the TME.Thus the metabolic cross talk between tumor and immune cells over the course of tumor progression can be amajor determinant of immune cell function and consequently response to immune-targeted therapies.Unfortunately the study of immune cell metabolism and crosstalk in the TME has been very challenging due toreliance on methods that analyze metabolism in bulk cell populations which obscures individual cellular diversitydifficulties in predicting downstream outcomes of metabolic perturbations because of the complexity of themetabolic network and the lack of tools to map metabolic alterations in situ. To overcome these challenges wedeveloped Compass a flux balance analysis (FBA) algorithm that applies a network-based analytical approachto single-cell RNA-sequencing (scRNA-seq) data to predict metabolic states of individual cells in tissue1. Wehave applied Compass as well as standard computational methods to the analysis of longitudinal scRNA-seqdata from a pre-clinical murine model of melanoma with the goal of determining the temporal- and tumor-size-based metabolic alterations in both tumor and infiltrating immune cells during tumor progression.Our preliminary data indicate that polyamine metabolism is a key hub of metabolic crosstalk between tumor andimmune cells that are either static or dynamic over the course of melanoma tumor progression and that mayoccupy distinct tissue niches. We find that CD4+ regulatory T cells (Treg) exhausted CD8+ T cells andsuppressive myeloid cells upregulate spermine/spermidine acetyltransferase (Sat1) which catalyzes acetylationof polyamines with tumor progression. Conversely a subset of c-Met+ melanoma cells that has features ofstemness is high for polyamine recycling genes. Based on these observations we hypothesize that thatsystems-based analysis of the alterations and crosstalk involving polyamine metabolism in tumor andimmune cells during tumor progression will uncover novel means for therapeutic intervention. Wepropose to: 1) Dissect the functional role of polyamine metabolism in immune cells and tumor cells during tumorprogression; 2) Construct a high resolution spatial map of tumor:immune metabolic crosstalk via the polyaminepathway. 513916 +No NIH Category available Acute Myelocytic Leukemia;Adjuvant;Adjuvant Therapy;Adult;Adult Acute Myeloblastic Leukemia;Adverse effects;Age Years;Aggressive behavior;Alleles;Animal Model;Antineoplastic Agents;Antioxidants;Ascorbic Acid;Biological Assay;Biological Availability;Bone Marrow Transplantation;Cell Line;Cell model;Chemicals;Chemistry;Combined Modality Therapy;DNA;Data;Dedications;Dependence;Diagnosis;Disease;Dose;Drug Combinations;Drug Kinetics;Elderly;Elderly Acute Myeloblastic Leukemia;Enzymes;Foundations;Gene Expression;Gene Silencing;Genetic;Genetic Screening;Goals;Growth;Hematologic Neoplasms;Hematopoietic;Heterozygote;Human;Hypermethylation;Impairment;Infusion procedures;Lesion;Leukemic Cell;Libraries;Liposomes;Measures;Mediating;Micronutrients;Modeling;Molecular;Mus;Mutation;Myeloid Cells;Oncogenic;Patients;Physiological;Prognosis;Property;Proteins;Research;Residual state;Role;Sodium;Surface;Testing;Tetanus Helper Peptide;Therapeutic;Therapeutic Agents;Treatment Efficacy;Treatment outcome;Tumor Suppressor Proteins;Water;Xenograft procedure;acute myeloid leukemia cell;alternative treatment;analog;aqueous;ascorbate;cancer cell;chemotherapy;clinical translation;cofactor;combinatorial;demethylation;epigenome;functional restoration;improved;in vivo;leukemia;leukemia treatment;lipophilicity;loss of function;loss of function mutation;mouse model;mutant;novel;novel strategies;oxidation;patient subsets;pharmacologic;preclinical efficacy;programs;rational design;screening;self-renewal;synergism;targeted treatment;therapeutically effective;treatment response;treatment strategy;tumor;uptake Enhancing TET activity for the treatment of hematological malignancy PROJECT NARRATIVEAggressive chemotherapy cannot be tolerated in the majority of adult AML patients due to advanced age. Novelnon-toxic therapeutic strategies are highly sought after to improve AML survival. We have shown that ascorbatetreatment can block AML progression by enhancing the activity of TET enzymes without adverse effects. Ourgoal is to elucidate the mechanistic role of TET proteins in ascorbate-mediated AML sensitivity identify rationaldrug combination treatment strategies using ascorbate as an adjuvant and optimize the bioavailability ofascorbate to increase its efficacy as a TET cofactor for AML therapy. NCI 10717715 7/28/23 0:00 PA-20-185 1R01CA282453-01 1 R01 CA 282453 1 "XI, DAN" 8/1/23 0:00 7/31/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 12051333 "CIMMINO, LUISA " Not Applicable 27 BIOCHEMISTRY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 351131 NCI 228750 122381 PROJECT SUMMARYAdvanced age in the majority of acute myeloid leukemia (AML) patients limits the use of aggressivechemotherapy leading to poor overall survival. Alternative treatment strategies for AML are highly sought after.Our research has revealed vitamin C (ascorbate) to be a potential non-toxic therapeutic adjuvant for thetreatment of AML. Ascorbate is an essential micronutrient in humans that in addition to its role as a cellularantioxidant participates as a direct cofactor of Ten-eleven (TET) enzymes. Mammalian TET proteins (TET1-3)are tumor suppressors of the hematopoietic lineage that catalyze the oxidation of 5-methylcytosine (5mC)leading to DNA demethylation and the reversal of gene silencing. TET2 loss-of-function mutations are frequentlyobserved in AML patients and are associated with a worse overall prognosis. Importantly TET2 mutations arealmost always heterozygous suggesting that enhancing residual TET2 activity (encoded by the remaining wild-type TET2 allele) could be a viable therapeutic strategy for the treatment of TET2-mutant AML. We have shownin cellular and animal models that ascorbate in a TET-dependent manner reprograms the AML epigenome byincreasing DNA hydroxymethylation leading to DNA demethylation a block in aberrant self-renewal increaseddifferentiation and slowing of leukemia progression. We hypothesize that ascorbate will be an effectivetherapeutic agent in the treatment of TET2 mutant AML by enhancing residual TET tumor suppressive function.There are currently no other therapeutic agents that target TET proteins for functional restoration. We proposeto understand the mechanistic basis of how physiological or pharmacological doses of ascorbate influence TETactivity and whether uptake capacity through sodium-dependent vitamin C transporters or total residual TETactivity influences ascorbate treatment efficacy (Aim1). AML progression in the context of TET2 mutation anddiverse oncogenic drivers will be tested for sensitivity to ascorbate in combination with standard AMLchemotherapy and data already obtained from our loss of function genetic screens in AML cells will be used todesign rational combinatorial treatment strategies that maximize the efficacy of ascorbate as a therapeuticadjuvant (Aim2). Finally we will explore approaches to enhance the bioavailability of ascorbate as a TET2cofactor using lipophilic ascorbyl analogs and genetic or pharmacological modulation of vitamin C transporterson AML cells (Aim3). The goal of this proposal is to understand the dose and AML context in which ascorbatetreatment will be most efficacious how to combine ascorbate with existing therapies to improve treatmentoutcome and identify novel approaches to enhance ascorbate bioavailability for increased TET-activatingpotential. We believe these studies will provide a strong foundation for clinical translation of ascorbate as a non-toxic adjuvant in combination therapies for the treatment of AML. 351131 +American Indian or Alaska Native; Arctic; Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Genetics; Immunization; Immunotherapy; Minority Health; Orphan Drug; Prevention; Rare Diseases; Vaccine Related Blood;Cancer Prevention Trial;Collection;Constitutional;DNA;Data Reporting;Development;Frameshift Mutation;Funding;Generations;Hereditary Nonpolyposis Colorectal Neoplasms;Human;Inuits;Libraries;Malignant Neoplasms;Mismatch Repair Deficiency;Mucous Membrane;Mutation;PMS2 gene;Preventive;RNA;Reagent;Recurrence;Sampling;Syndrome;Testing;Tumor Tissue;Vaccines;Work;base;cancer prevention;cohort;high risk;high risk population;mouse model;mutant mouse model;neoantigen vaccine;next generation sequencing;sample collection;vaccine strategy PMS2 MUTATIONS PROJECT: BIOSPECIMENS PROCUREMENT FOR CHARACTERIZATION FROM HIGH-RISK POPULATION OF CANADIAN INUIT n/a NCI 10717504 75N91019D00024-0-759102200022-1 N01 9/1/22 0:00 8/31/24 0:00 78846869 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 412586 NCI DCP hypothesizes that recurrent frame-shift mutations as observed in Lynch Syndrome will also occur in Constitutional Mismatch Repair Deficiency (CMMRD) and that the neoantigen vaccine strategy and reagents already under development by DCP will be relevant to cancer prevention in CMMRD Syndrome.To test this hypothesis DCP is conducting targeted next generation sequencing using a panel of ~30 mononucleotide repeat loci in samples of normal mucosa tumor tissue blood (cfDNA and RNA) and fecal DNA from the Pms2 mutant mouse model (GEMM). This will establish the relevance of the mouse model to the available Lynch Syndrome vaccines. If the current vaccines are relevant they will be tested for cancer preventive efficacy in the GEMM.A biospecimen collection of human samples is needed for the next stage. Specimens from the collection will be sequenced using an expanded panel of ~120 mononucleotide repeat loci. Based on the results consideration will be given to creation of a new frame-shift vaccine or expanding planned Lynch Syndrome cancer prevention trials to include CMMRD and particularly the high-risk Inuit cohort.The downstream work for generation of sequencing libraries analysis and data reporting for human samples obtained for this biospecimen collection will be performed under the DCP-funded severable Unit of Work for the CIPL lab (currently part of NCI Operational Task Order 75N91020F00003). 412586 +Cancer; Clinical Research Laboratories FY22 - APA BUILDINGS - BUILDING 1 n/a NCI 10717479 75N91019D00024-0-759102200027-1 N01 9/20/22 0:00 12/12/25 0:00 78875717 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 5449223 NCI This project will refurbish one of four existing APA Buildings (1026 1033 1034 or 1045). These buildings are currently vacant. The NCI is currently expanding the capabilities of the DCTD laboratories at the FNLCR and requires additional laboratory space to accommodate the new requirements. These buildings will require a full refurbishment 5449223 +Cancer; Clinical Research Laboratories FY22 - APA BUILDINGS - BUILDING 2 n/a NCI 10717471 75N91019D00024-0-759102200028-1 N01 9/20/22 0:00 12/12/25 0:00 78875720 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 5708113 NCI This project will refurbish one of four existing APA Buildings (1026 1033 1034 or 1045). These buildings are currently vacant. The NCI is currently expanding the capabilities of the DCTD laboratories at the FNLCR and requires additional laboratory space to accommodate the new requirements. These buildings will require a full refurbishment 5708113 +Cancer; Clinical Research Air;Animals;Automation;Complex;Computer software;Failure;Fees;Health;Heating;Monitor;Research;Risk;System;Technology;computer network;cost;exhaust THIS COST PLUS FIXED FEE TASK ORDER IS FOR COORDINATED FACILITIES REQUIREMENTS FOR FY22 FACILITIES BAS UPGRADE n/a NCI 10717452 75N91019D00024-0-759102200029-1 N01 9/26/22 0:00 7/20/26 0:00 78877452 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 3596890 NCI The NCI Frederick Building Automation System (BAS) is a complex network of computers which control and monitor nearly all the NCI Frederick building systems including air handlers exhaust systems chillers and heating systems. Failure of a component of the BAS can result in the failure of one of these critical building systems with subsequent impact to scientific research or animal health. Many of the BAS controllers are the original version Micro-Smart Controllers (MSC) from the late 1990s and early 2000s. Advancements in technology have made the MSC system obsolete and antiquated. Replacement parts for the MSC system are no longer available nor is the software supported. Hardware is unavailable creating risks to the BAS and the building systems it controls. 3596890 +Cancer; Clinical Research Accreditation;Agreement;Certification;Contractor;Elements;Engineering;Ensure;Exhibits;Government;Guidelines;Hour;Maintenance;Regulation;Specific qualifier value;Work THIS IS A CPFF TO TO REFURBISH APA BUILDINGS (1033). n/a NCI 10717450 75N91019D00024-0-759102200030-1 N01 9/26/22 0:00 12/18/25 0:00 78877455 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 5719596 NCI In accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick.The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs.The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines. 5719596 +No NIH Category available Accounting;Activated Lymphocyte;Antibody Therapy;Beds;Biological Assay;Bone Marrow;CD8-Positive T-Lymphocytes;CD8B1 gene;CXC chemokine receptor 3;CXCL10 gene;CXCL9 gene;CXCR3 gene;Cancer Etiology;Cancer Patient;Cathepsin G;Cell surface;Cells;Cessation of life;Chemotaxis;Clinical;Clinical Trials;Cytoplasmic Granules;Data;Dendritic Cells;Event;Failure;Feedback;Fluorescent in Situ Hybridization;Genes;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunohistochemistry;Immunotherapy;In Vitro;Infiltration;Interferon Type II;Leukocyte Elastase;Link;Lung Neoplasms;Lymphocyte;Lymphocyte Function;MMP8 gene;MMP9 gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Modeling;Mus;Myelogenous;Myeloid-derived suppressor cells;Neutrophil Collagenase;Neutrophil Infiltration;Non-Small-Cell Lung Carcinoma;Outcome;PD-1/PD-L1;Peptide Hydrolases;Predictive Factor;Process;Production;Property;Protease Inhibitor;Proteinase 3;Proteins;Reporting;Signal Transduction;Site;Source;Surface;System;T cell infiltration;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Thinking;Treatment outcome;Tumor-associated macrophages;Work;anti-PD-1;anti-PD-L1;anti-PD-L1 therapy;cell type;checkpoint therapy;chemokine;chemokine receptor;cohort;cytokine;exhaust;immune checkpoint;improved;in vivo;inhibitor;mouse model;mutant;neoplastic cell;neutrophil;novel;proteinase In;recruit;response;success;treatment response;tumor;tumor microenvironment Neutrophil derived proteinases abolish the IFNG signature in NSCLC PROJECT NARRATIVELung cancer is the leading cause of cancer deaths worldwide accounting for ~130000 lives annually in the USalone. We have generated data from a large cohort of lung cancer patients showing that neutrophils inverselycorrelate with CD4+ and CD8+ lymphocyte content within lung tumors. The purpose of this project is todemonstrate that tumor-associated neutrophils limit the ability of T cells to infiltrate into the malignant portionsof tumors. Successful completion of the proposed studies should identify a therapeutic strategy with which toimprove T cell infiltration into cancers that would improve response rates to immune based therapies. NCI 10717448 7/7/23 0:00 PA-20-185 1R01CA282465-01 1 R01 CA 282465 1 "KUO, LILLIAN S" 7/7/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-BTC-Q(80)S] 6786529 "HOUGHTON, A MCGARRY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/7/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 573105 NCI 325628 247477 ABSTRACTAlthough immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success just ~20% of non-small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. The two major factors predictive offavorable treatment response to ICI therapy are the presence of the IFNG signature and evidence of CD8+ T cellinfiltration into malignant tumor. Work from our group has shown that neutrophil infiltrated non-small cell lungcancers do not display the IFNG signature do not display CD8+ infiltration into malignant tumor and do notrespond to ICI treatment. Our hypothesis to explain these observations is that tumor-associated neutrophilsrelease proteinases that degrade key cytokines (IFNG) chemokines (CXCL-9 -10 -11) and a chemokinereceptor (CXCR3) that destroys the IFNG mediated chemotactic gradient that facilitates T cell infiltration intotumors. The proposed studies will demonstrate that a number of key neutrophil-derived proteinases are capableof degrading T cell recruiting chemokines and CXCR3 and identify the novel cleavage products resulting fromthese events. The functional consequences of these proteolytic events will be demonstrated in novel multicellulartumor-in-chip systems and in state-of-the art mouse models of lung cancer. Lastly we will employ a combinedfluorescent in-situ hybridization (FISH) and multiplexed immunohistochemistry (M-IHC) panel to study therelationship between CXCL9 expressing tumor cells infiltrating CD8+CXCR3+ T cells and TAN and determinethe impact that these measures have on ICI treatment outcomes in NSCLC patients. 573105 +Cancer; Clinical Research Accreditation;Agreement;Certification;Contractor;Elements;Engineering;Ensure;Exhibits;Government;Guidelines;Hour;Infrastructure;Maintenance;Regulation;Specific qualifier value;Work THIS CPFF TO IS FOR REFURBISHMENT AND INFRASTRUCTURE PROJECTS FOCUSED ON FACILITY IMPROVEMENTS WITHIN THE NCI AT FREDERICK CAMPUSMOD001 n/a NCI 10717434 75N91019D00024-0-759102200026-1 N01 9/23/22 0:00 8/1/25 0:00 78877449 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 6109119 NCI In accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick.The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs.The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines 6109119 +Cancer; Clinical Research Accreditation;Agreement;Certification;Contractor;Elements;Engineering;Ensure;Exhibits;Government;Guidelines;Hour;Maintenance;Regulation;Specific qualifier value;Work THIS IS A CPFF TO TO REFURBISH APA BUILDINGS 1034 n/a NCI 10717424 75N91019D00024-0-759102200031-1 N01 9/26/22 0:00 12/18/25 0:00 78877458 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 5685147 NCI In accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick.The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs.The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines. 5685147 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Health Services; Rural Health Address;COVID-19 pandemic;Cancer Center;Cancer Patient;Caring;Clinic;Clinical Research;Clinical Trials;Communities;Community Participation;Community Physician;Community Practice;Data;Distant;Division of Cancer Treatment and Diagnosis;Documentation;Enrollment;Human Resources;Location;Minority;Minority Groups;Nursing Research;Oncologist;Oncology;Patient Care;Patient Participation;Patient Selection;Patients;Policies;Private Practice;Privatization;Procedures;Provider;Research Personnel;Research Support;Research Training;Site;System;Training;Underserved Population;United States;Work;Workplace;cancer clinical trial;clinical research site;compliance behavior;flexibility;improved;minority patient;participant enrollment;programs;rural area;screening;telehealth;underserved area;virtual VIRTUAL RESEARCH SUPPORT PILOT n/a NCI 10717397 75N91019D00024-0-759102200023-1 N01 9/15/22 0:00 9/14/27 0:00 78868012 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 9216983 NCI The Division of Cancer Treatment and Diagnosis NCI is requesting support for establishment of a Virtual Research Support Pilot to Enhance minority and underserved population accrual to NCI clinical trials 9216983 +Cancer; Clinical Research Aftercare;Age;Biopsy;Blood;Canis familiaris;Clinical Trials;Data;Division of Cancer Treatment and Diagnosis;Feces;Human;Individual;Investigation;Longevity;Longitudinal Studies;Malignant Neoplasms;Modeling;Molecular;Natural History;Oncology;Patients;Recurrence;Specimen;Therapeutic;Time;Treatment Protocols;Work;cancer diagnosis;comparative;effectiveness evaluation;response LONGITUDINAL STUDIES OF DOGS WITH CANCER AS A COMPARATIVE ONCOLOGY MODEL n/a NCI 10717329 75N91019D00024-0-759102200020-1 N01 9/9/22 0:00 9/8/26 0:00 78859064 "HECHT, TOBY " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 3323184 NCI The Division of Cancer Treatment and Diagnosis NCI is requesting establishment ofrelationships with ongoing projects/organizations involving the tracking of canines asthey age and develop cancer. The purpose is to obtain specimens that can be analyzed toinform our understanding of the molecular basis of canine cancer and determine if thedog is a good model for evaluating the effectiveness of human investigationaltherapeutics and treatment regimens. 3323184 +No NIH Category available 3-Dimensional;Adult;Bioinformatics;Cell Line;Cell Proliferation;Cells;Characteristics;Citric Acid Cycle;Clinical;Clinical Trials;Coculture Techniques;Combined Modality Therapy;Critical Pathways;Data;Development;Disease;Dose;Drug Combinations;Drug resistance;Enzymes;Evaluation;Future;Gene Expression;Generations;Genes;Genetic Transcription;Growth;Hypoxia;In Vitro;Individual;Investigational Drugs;Lead;Malignant neoplasm of pancreas;Metabolic;Metabolic Pathway;Metabolic stress;Metabolism;Methods;Mitochondria;Molecular Target;Mus;Neoplasm Metastasis;Organoids;Outcome;Oxidation-Reduction;Pancreatic Ductal Adenocarcinoma;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I Clinical Trials;Play;Proliferating;Reaction;Resistance;Role;Signal Transduction;Signaling Protein;Solid Neoplasm;Testing;Therapeutic;Time;Tissues;Toxic effect;Treatment Efficacy;Triage;United States National Institutes of Health;Xenograft procedure;advanced disease;analog;cancer cell;candidate selection;carbonate dehydratase;clinical development;combinatorial;design;disorder control;improved;in vivo;in vivo Model;inhibitor;knock-down;lead candidate;lead optimization;metabolic abnormality assessment;next generation;novel;novel therapeutics;nutrient deprivation;pancreatic cancer cells;pancreatic cancer patients;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;patient derived xenograft model;patient screening;personalized approach;phase I trial;pre-clinical;preclinical development;programs;resistance mechanism;response;synergism;targeted agent;targeted treatment;therapeutic target;therapy resistant;transcription factor;trial design;tumor;tumor growth;tumor metabolism Metabolic flux analysis and PDX models to understand therapeutic vulnerabilities following inhibition of Ref-1 redox signaling in pancreatic cancer Project NarrativeWhile some patients with pancreatic cancer are living longer additional approaches including combinatorialtherapies against new targets are needed. Therefore we propose to investigate a validated therapeutic targetRedox factor-1 (Ref-1) alone and in combinations that selectively kill the tumor by impinging on criticalpathways the tumor is using to survive. After advancing the first-generation Ref-1 inhibitor (APX3330) to aphase I clinical trial in adult patients we have identified next generation Ref-1 inhibitors a strategy to screenfor patients that have sensitivity to Ref-1 inhibition and molecular targets that are likely to synergize with Ref-1inhibition. NCI 10717281 7/28/23 0:00 PA-20-185 1R01CA282478-01 1 R01 CA 282478 1 "CHEN, WEIWEI" 8/1/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-MCTC-S(01)Q] 1899304 "KELLEY, MARK R." "FISHEL, MELISSA L" 7 PEDIATRICS 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 466315 NCI 294205 172110 ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is particularly resistant to therapy and typically presents asmetastatic disease. Characterized by hypoxia dense stroma and metabolic rewiring original approaches andcombination strategies are desperately needed. We propose to investigate inhibition of a redox signaling proteinand drug combinations that selectively kill the tumor by impinging on critical pathways the tumor is using tosurvive. Redox factor-1 (Ref-1) regulates the activity of various transcription factors that drive pancreatic cancercell proliferation and drug resistance as well as genes involved in cellular metabolism. Under hypoxia inhibitionof Ref-1 significantly perturbed metabolic pathways (TCA cycle and OXPHOS) and HIF-regulated genes andthus slowed the growth of pancreatic cancer co-culture spheroids and xenografts. The first-generation Ref-1inhibitor (APX3330) completed phase I trial and demonstrated 32% response predicted PK and targetengagement with no significant toxicities. There was disease stabilization in six patients with four on treatmentfor an extended time (>250 days). Based on encouraging phase I data and a detailed structural-activityrelationship (SAR) program we have also identified next generation Ref-1 inhibitors that are at lead optimizationstage a strategy to screen for patients that have sensitivity to Ref-1 inhibition and molecular targets that arelikely to synergize with Ref-1 inhibition. However adaptive mechanisms of resistance eventually emerge withtargeted therapy therefore we will also focus on the development of novel combinations. Our hypothesis is thattargeting the redox function of Ref-1 alone and in mechanistically designed combination therapies will inducemetabolic lethality and inhibit pancreatic cancer growth and metastasis. In Aim 1 identification of metaboliccharacteristics of cancer cells/tissues that associate with the outcome of Ref-1 inhibition and prediction of newmetabolic targets to improve the efficacy of Ref-1 inhibition. Our recently developed computational predictor ofcell-wise metabolic flux will be used to study the metabolic changes due to Ref-1 inhibition in PDAC cells at thesingle cell level. In Aim 2 NMR to establish direct interactions of Ref-1 and the new analogues efficacy toxicityand metabolic stability studies will allow us to advance the top lead candidate(s) for in vivo studies for CandidateSelection (NIH Milestone 4) and IND (Investigational New Drug) submission leading to eventual Phase I trial.Lastly in Aim 3 evaluation of Ref-1 in preclinical combination therapy will be used to overcome adaptiveresistance. To further predict metabolic nodes that could be perturbed to synergize with Ref-1 inhibition creatinga metabolic lethality computational predictor of cell-wise metabolic flux described in Aim1 will be used. Theefficacy of Ref-1 alone and in new combinations will be investigated using organoids in vitro and the mouse trialdesign in vivo. In summary for a precision approach to kill PDAC we will deliver a potent and selective Ref-1inhibitor and combine novel metabolic bioinformatics and drug combinations for enhanced efficacy to have asignificant impact on the field and clinical therapeutics. 466315 +No NIH Category available A549;Address;Affect;Antibodies;Apoptosis;Binding;Biodistribution;Biological Markers;C57BL/6 Mouse;CD8-Positive T-Lymphocytes;Cancer Model;Cancer cell line;Cell surface;Cells;Chimeric Proteins;Collaborations;Cytometry;Data;Detection;Development;Diagnosis;Diagnostic;Drug Kinetics;Drug Targeting;E-Cadherin;Endoplasmic Reticulum;Flow Cytometry;Glycocalyx;Glycoconjugates;Goals;Histopathology;Human;IgG1;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunodeficient Mouse;Immunohistochemistry;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;In Vitro;Infiltration;Investigational Drugs;Lectin;Link;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mannose;Melanoma Cell;Modeling;Monitor;Mus;Mutate;Mutation;Myeloid Cells;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Normal Cell;Oligosaccharides;Pharmaceutical Preparations;Phase I Clinical Trials;Polysaccharides;Population;Prognosis;Proteins;Radiolabeled;Recombinant Antibody;Recombinant Fusion Proteins;Research;Resistance;SCID Mice;Safety;Structure of parenchyma of lung;Surface;TP53 gene;Therapeutic;Therapeutic Effect;Time;Treatment Efficacy;Tumor Markers;Variant;Vascularization;Visualization;X-Ray Computed Tomography;Xenograft procedure;advanced disease;anti-PD-1;anti-PD1 antibodies;anti-tumor immune response;antibody mimetics;antibody-dependent cell cytotoxicity;antitumor effect;cancer cell;cancer diagnosis;cancer immunotherapeutics;cancer immunotherapy;cancer therapy;clinically relevant;design;detection sensitivity;efficacy evaluation;immune cell infiltrate;immune checkpoint;immune checkpoint blockers;improved outcome;lung cancer cell;melanoma;microPET/CT;monocyte;mouse model;mutant;new therapeutic target;novel;novel therapeutics;preclinical development;response;targeted agent;targeted treatment;therapy outcome;tool;tumor;tumor growth;tumor progression;tumor xenograft Antitumor potential of AvFc lectibody in non-small cell lung cancer NARRATIVEThis project will evaluate the immunotherapeutic and tumor-targeting effects of Avaren-Fc in a Kras/p53mutation-driven non-small cell lung cancer mouse model. Avaren-Fc is a lectin-Fc fusion protein targeting tumor-associated high-mannose glycans. Successful completion of the proposed studies will establish an importantproof-of-concept data package justifying further preclinical development of the glycobiomarker-specificimmunotherapeutic and diagnostic candidate. NCI 10717195 9/19/23 0:00 PAR-22-216 1R21CA282484-01 1 R21 CA 282484 1 "HARRIS, RAYMOND D" 9/19/23 0:00 8/31/25 0:00 ZCA1-SRB-P(M2)S 8640855 "MATOBA, NOBUYUKI " "GUO, HAIXUN ; TELANG, SUCHETA " 3 PHARMACOLOGY 57588857 E1KJM4T54MK6 57588857 E1KJM4T54MK6 US 38.215024 -85.760145 4679701 UNIVERSITY OF LOUISVILLE LOUISVILLE KY SCHOOLS OF MEDICINE 402920001 UNITED STATES N 9/19/23 0:00 8/31/25 0:00 395 Non-SBIR/STTR 2023 402402 NCI 257126 145276 PROJECT SUMMARY / ABSTRACTThe goal of this project is to develop a novel tumor glycobiomarker-targeting agent against non-small cell lungcancer (NSCLC). NSCLC accounts for the majority of all lung tumors and is frequently diagnosed at an advancedstage with poor prognosis. Current therapies including novel targeted drugs and immunotherapies have led toimproved outcomes but have had less efficacy in advanced disease and several of these agents result inresistance. Given that a combination of multiple therapeutic strategies may be necessary to produce an optimaltherapeutic outcome development of novel therapeutic agents targeting a unique biomarker of NSCLC iswarranted. Particularly tumor-targeted immunotherapy that can boost an antitumor immune response mightenhance the efficacy of immune checkpoint inhibitors. There is growing evidence for an aberrant increase ofhigh-mannose glycans in the glycome of cancer cells including those of NSCLC. To target this glycobiomarkerthe applicants lab has developed Avaren-Fc (AvFc) a recombinant antibody-like molecule lectibody efficientlyrecognizing high-mannose glycans on the surface of malignant cells. The antitumor potential and safety of AvFchas been demonstrated in human A549 and H460 NSCLC xenograft challenge models using immunodeficientmice as well as in syngeneic B16F10 melanoma challenge models using immunocompetent C57bl/6 mice. Inthe latter model AvFc treatment increased the infiltration of non-classical monocytes and other myeloid cells aswell as CD4/CD8 T lymphocytes. Furthermore immunohistochemical analysis revealed that AvFc can selectivelyrecognize primary human NSCLC tumors over adjacent non-tumor lung tissues. Based on these findings wehypothesize that AvFc may serve as a novel immunotherapeutic agent targeting tumor-associated high-mannoseglycans in NSCLC. To substantiate the possibility in a more clinically relevant NSCLC model the goal of thisR21 project is to reveal the immunotherapeutic efficacy and tumor-targeting profile of AvFc in a conditionalKras/p53 mutation-driven NSCLC mouse model. In Specific Aim 1 we will determine and characterize thetherapeutic effects of AvFc based on overall survival immunohistochemistry of lung tumors andimmunophenotyping of lung-infiltrated immune cells. Additionally we will assess the efficacy of AvFc incombination with the immune checkpoint blocker anti-PD-1 antibody. In Specific Aim 2 we will analyzebiodistribution and tumor detection profiles of AvFc in the NSCLC mice using a radiolabeled AvFc derivative ina microPET/CT imaging analysis. Building on our preliminary data we will design and optimize radiolabeledAvFc derivatives to have an optimal pharmacokinetic profile and tumor-detection sensitivity. In particular we willassess the capability of radiolabeled AvFc to detect tumor progression and metastasis. Collectively theproposed research will provide critical information addressing the question of whether AvFc could be a viableimmunotherapeutic and/or diagnostic agent against NSCLC. Should the answer be positive the results willsignificantly facilitate further preclinical development of AvFc towards a Phase I clinical trial. 402402 +No NIH Category available Adoptive Cell Transfers;Adverse effects;Alternative Splicing;Asthma;Autoimmune Diseases;Autoimmunity;Bioinformatics;Birth;Breast Cancer Model;Breast Cancer Treatment;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cancer Biology;Cell physiology;Cells;Clinical;Data;Development;Disease;Duchenne muscular dystrophy;Elements;Exhibits;Exons;FDA approved;FOXP3 gene;Gene Expression;Homeostasis;Human;Hypersensitivity;IL2 gene;Immune;Immune checkpoint inhibitor;Immune system;Immunity;Immunology;Immunosuppression;In Vitro;Infiltration;Inflammation;Injections;Interferon Type II;Knock-in;Knock-out;Length;Mammary Neoplasms;Mediating;Messenger RNA;Modeling;Mus;Mutant Strains Mice;Organoids;Outcome;Patients;Pharmaceutical Preparations;Play;Protein Isoforms;Public Health;Publications;RNA Splicing;Regulatory Element;Regulatory T-Lymphocyte;Research;Research Personnel;Resistance;Role;Science;Severities;Systemic Lupus Erythematosus;T cell therapy;T-Cell Development;T-Lymphocyte;Testing;The Cancer Genome Atlas;Toxic effect;Transgenic Organisms;Tumor Immunity;Tumor Promotion;Wild Type Mouse;anti-tumor immune response;cancer genomics;cancer immunotherapy;cancer therapy;cancer type;clinical development;directed differentiation;efficacy evaluation;efficacy testing;human disease;in vivo;mRNA Expression;malignant breast neoplasm;mouse model;neoantigens;neoplastic cell;novel;novel therapeutic intervention;patient derived xenograft model;patient subsets;precision medicine;programs;success;targeted treatment;transcriptomics;tumor;tumor growth Targeting FOXP3 mRNA splicing for breast cancer immunotherapy Project Narrative-Relevance to Public HealthTumor-infiltrating regulatory T cells (Tregs) suppress effective immunity against breast tumors. We propose todevelop a novel morpholino-based drug to direct FOXP3S isoform expression in Tregs and test its efficacy inbreast cancer immunotherapy. This research will integrate Treg functions into precision medicine to fuel excitingtranslational development in breast cancer immunotherapy. NCI 10717185 7/27/23 0:00 PA-20-185 1R01CA282917-01 1 R01 CA 282917 1 "BOURCIER, KATARZYNA" 7/27/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 8135679 "LU, XIONGBIN " "OPYRCHAL, MATEUSZ ; ZHOU, BAOHUA " 7 GENETICS 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 7/27/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 585212 NCI 369219 215993 Project Abstract The development of cancer immunotherapy including immune checkpoint inhibitors and adoptive cell transfer(ACT)-based therapies revolutionized cancer treatment. The success however is limited to a relatively smallsubset of patients and cancer types. Regulatory T cells (Tregs) play a central role in maintaining immune systemhomeostasis and negatively regulate immune-mediated inflammation such as autoimmune diseases asthmaand allergy. However tumor infiltrating Tregs also suppress effective anti-tumor immunity. FOXP3 is a masterregulator of Treg development and function. Human FOXP3 gene encodes two major isoforms through mRNAalternative splicing a long full-length isoform (FOXP3L) and a shorter isoform lacking exon 2 region (FOXP3S).To study the function of FOXP3S in Tregs we generated a Foxp3S mouse line expressing only the Foxp3Sisoform. Our preliminary studies with orthotopic mouse breast tumor models demonstrate that the Foxp3S miceare completely resistant to tumor development while the littermate wildtype mice expressing Foxp3L exhibitsignificant tumor growth. Intratumoral injection of Foxp3S-promoting morpholino drug (MO) into the breasttumors in wildtype mice markedly increases IFN-+ CD4 and CD8 T cells in the tumors and thus suppressestumor growth. Interestingly bioinformatics analysis of transcriptomic data from The Cancer Genome Atlas(TCGA) reveals that FOXP3S mRNA expression in human breast cancer is positively correlated with clinicaloutcomes. Given that over 60% of tumor-infiltrating CD4 T cells are Tregs and the most dominant TCRs fromintratumoral Tregs were tumor-reactive and recognize specific tumor neoantigens we hypothesize thatpromoting FOXP3S isoform expression will reprogram tumor-reactive Tregs and convert these immunesuppressive Tregs to tumor-specific T helpers thus promoting antitumor immunity. We propose to use uniquemouse lines FOXP3S-promoting morpholinos and patient-derived organoids to test our hypothesis. We willdetermine the mechanisms for FOXP3S-mediated antitumor immunity and further define the efficacy of FOXP3S-promoting morpholinos in breast cancer treatment. Successful completion of this study will identify a noveltherapeutic strategy for breast cancer immunotherapy. 585212 +No NIH Category available Affect;Age;Attenuated;BRCA1 Mutation;BRCA1 gene;Breast Epithelial Cells;CD8-Positive T-Lymphocytes;Cancer Biology;Cancer Etiology;Cells;Cellular biology;Clinical;Complement;Coupled;DNA Double Strand Break;DNA Repair;Data;Defect;Development;Dimensions;Double Strand Break Repair;Epithelium;Foundations;Genetic;Genomic Instability;Germ-Line Mutation;Heterozygote;Human;Immune;Immune Evasion;Immune system;Immunotherapy;Impairment;Incidence;Knock-out;Knowledge;Label;Laboratory Finding;Malignant Neoplasms;Mass Spectrum Analysis;Mature T-Lymphocyte;Molecular;Mus;Neoplasms;Oncogenes;Operative Surgical Procedures;Positioning Attribute;Research;Risk;Risk Reduction;Role;Sampling;Somatic Cell;T-Lymphocyte;Technology;Testing;Time;Transcriptional Regulation;Tumor Immunity;Tumor Suppressor Proteins;Woman;Work;breast tumorigenesis;cancer immunotherapy;cancer prevention;cancer risk;cohort;driving force;epithelial repair;experimental study;genomic tools;lifetime risk;malignant breast neoplasm;mammary epithelium;mouse genetics;multidisciplinary;mutant;mutant mouse model;mutation carrier;mutational status;neoplasm immunotherapy;neoplastic cell;novel;preclinical study;prophylactic;repaired;response;tool;translational impact;tumor;tumor immunology;tumorigenesis;virtual T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy NARRATIVE By combining the awesome power of mouse genetics precious clinical samples and cutting-edgetechnologies this multidisciplinary team is poised to illuminate a novel function of T cell-specific BRCA1 inantitumor immunity immunotherapy and transcriptional regulation. The proposed work promises to have a far-reaching conceptual and translational impact on the current understanding of BRCA1 tumor suppressor functionand development of new cancer prevention options for BRCA1 mutation carriers. NCI 10716957 7/3/23 0:00 PA-20-185 1R01CA282303-01 1 R01 CA 282303 1 "ZAMISCH, MONICA" 7/15/23 0:00 6/30/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 2093296 "LI, RONG " "HU, YANFEN " 98 BIOCHEMISTRY 43990498 ECR5E2LU5BL6 43990498 ECR5E2LU5BL6 US 38.898075 -77.043933 2863301 GEORGE WASHINGTON UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200520042 UNITED STATES N 7/15/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 614606 NCI 380561 234045 ABSTRACT Women with germline mutations of BRCA1 have about an 80% lifetime risk of developing breast cancer. Allsomatic cells in a germline BRCA1 mutation carrier harbor the same mutant copy of the BRCA1 gene yet BRCA1research is almost exclusively focused on BRCA1s role in repair of double-strand DNA breaks in the breastepithelium. This is due to the cardinal tenet of the current BRCA1 paradigm increased genetic instability ofthe breast epithelium solely drives development of BRCA1 mutation-related breast cancer. In addition currentprophylactic risk-reducing surgeries are aimed at curtailing tumorigenesis of breast epithelial cells of BRCA1mutation carriers. In contrast virtually nothing is known about whether BRCA1 heterozygosity in cells beyondthe breast epithelium could also contribute to BRCA1-related tumorigenesis. Neoplasia is antagonized by the ability of the immune system to detect and eliminate neoplastic cells. Clearlyimpaired antitumor immunity enables immune evasion and tumor outgrowth. We recently found that women withBRCA1 germline mutations have less abundant circulating CD8+ T cells versus age-matched donors with wild-type BRCA1 genes. In support of this clinical finding heterozygous knockout of Brca1 specifically in CD8+ T cellsof mice is sufficient to attenuate antitumor immunity. Based on our preliminary data we hypothesize that T cell-intrinsic function of BRCA1 in enhancing antitumor immunity contributes to the overall tumorsuppressor activity of BRCA1. We further propose that in BRCA1 mutation carriers increased genomicinstability in the breast epithelium and attenuated antitumor immunity in CD8+ T cells act together to elevatecancer incidence. To validate this novel hypothesis we will combine our established teams tools and expertisein cancer biology tumor immunology and transcriptional regulation through the following three Specific Aims:(1) Discern the impact of T cell-intrinsic BRCA1 on antitumor immunity and immunotherapy (2) Elucidate themolecular basis for BRCA1s function in antitumor immunity and (3) Examine BRCA1 mutation-related T celldeficiency in human samples. Our proposed work represents a new direction in elucidating a previously unappreciated tumor-suppressingfunction of BRCA1 in immune cells. The concept to be validated clearly departs from the prevailing paradigmregarding BRCA1-related cancer etiology which is focused on the breast epithelium and DNA repair. From atranslational perspective our proposed study focusing on BRCA1 in immune cells will likely inform developmentof novel immune-boosting strategies for women with BRCA1 germline mutations. Thus this line of work haspotential for far-reaching and sustained impact on breast cancer cancer risk reduction. 614606 +No NIH Category available Administrative Supplement;Adult;African;African American;African American population;Age;Alzheimer disease screening;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimer's disease risk;Applications Grants;Archives;Asian Americans;Biological Aging;Biological Markers;Blood;Blood Vessels;California;Cause of Death;Cerebrospinal Fluid;Characteristics;Chronic Disease;Clinic;Clinical assessments;Cohort Analysis;Cohort Studies;Data;Data Linkages;Death Certificates;Dementia;Diagnosis;Diagnostic;Diet;Dietary Practices;Disease Outcome;Disparity;Education;Environmental Risk Factor;Epigenetic Process;Ethnic Origin;Ethnic Population;Evaluation;FDA approved;Foundations;Frequencies;Genetic;Genetic Predisposition to Disease;Grant;Hawaii;Household Air Pollution;Individual;Infrastructure;Investigation;Island;Japanese;Japanese American;Latino;Life Style;Light;Malignant Neoplasms;Manuscripts;Mediation;Medical Records;Medicare;Medicare claim;Metabolic;Metabolic Diseases;Modality;Modeling;Native Hawaiian;Neighborhoods;Nested Case-Control Study;Participant;Patients;Peer Review;Physical activity;Plasma;Population;Population Attributable Risks;Primary Care Physician;Private Practice;Prospective cohort;Race;Recording of previous events;Recurrence;Reporting;Research;Risk;Risk Adjustment;Risk Factors;Role;Sampling;Sleep;Socioeconomic Status;Specialist;Testing;Time;United States National Institutes of Health;Validation;Variant;Woman;Work;accurate diagnostics;apolipoprotein E-4;blood-based biomarker;burden of illness;clinical diagnosis;cohort;comparison control;cost;dementia risk;ethnic difference;ethnic disparity;ethnic minority;ethnic minority population;follow-up;genetic risk factor;genome wide methylation;human old age (65+);men;metabolomics;modifiable risk;mortality;multi-ethnic;neuroimaging;novel;polygenic risk score;population based;practice setting;prospective;racial disparity;racial minority;racial minority population;racial population;response;rural residence;sex;sex disparity;tau-1 Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study PROEJCT NARRATIVEWe propose to analyze a recently FDA-approved highly accurate blood-based maker (BBM) of Alzheimer'sdisease (AD) in the archived blood of the Multiethnic Cohort for AD cases and healthy controls. We will confirmthe BBM is elevated among AD cases compared to controls which would validate the Medicare claims-basedcases. We will also compare the BBM levels and the relationship between the BBM and AD by sex race/ethnicity(across African American Japanese American Latino Native Hawaiian and White groups) and individualgenetic susceptibility. NCI 10716739 6/6/23 0:00 PA-20-272 3U01CA164973-11S2 3 U01 CA 164973 11 S2 "MAHABIR, SOMDAT" 9/1/12 0:00 8/31/23 0:00 1898900 "LE MARCHAND, LOIC " "HAIMAN, CHRISTOPHER ALAN; WILKENS, LYNNE R" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 9/16/22 0:00 8/31/23 0:00 866 Non-SBIR/STTR 2023 410244 NIA 287108 123136 PROJECT SUMMARY / ABSTRACTIn Alzheimer's disease (AD) research to mitigate the disease burden there is a critical need to better utilizeprospective cohorts. The need is especially great for population-based cohorts that include significant numbersof racial/ethnic minority individuals. In light of this we initiated AD and related dementias (ADRD) research inthe Multiethnic Cohort Study (MEC; 1993-current) the largest and most diverse cancer cohort in the UScomposed at baseline of >215000 adults of five ancestries (African Japanese Latino Native Hawaiian White)sampled in Hawaii and Southern California. We observed that the AD rates and the known risk factorassociations in the MEC-Medicare linkage data are highly comparable to those reported in clinic-based studieswhich assures the quality and generalizability of the MEC data for AD/ADRD research. We also foundsubstantially higher AD risks and APOE e4 frequencies among Native Hawaiians as well as African Americanscompared to Whites. This and other important findings speak to the unique values of the MEC for AD/ADRDdisparities research. However one recurrent concern is that the AD/ADRD definitions in MEC are solely basedon Medicare claims and thus may include misclassifications. Medicare claims-based disease outcomes arevalidated against clinical diagnosis. This approach is however less reliable for AD/ADRD because the currentdiagnostic gold standard neuroimaging or cerebrospinal fluid biomarkers is often inaccessible or intolerableparticularly to individuals of racial/ethnic minorities rural residences and older ages while clinical assessmentwithout these biomarkers has known low accuracy. In this context the blood-based maker (BBM) newlyapproved by FDA for initial screening of AD phosphorylated tau-181 (pTau-181) provides a vital opportunity torobustly validate AD cases in MEC while at the same time producing timely evaluation of the BBM byrace/ethnicity. Thus we propose to (Aim 1) replicate the association between plasma pTau-181 and ~570incident AD cases using archived blood collected within 5 years of the first Medicare claim in a nested case-control study. We will evaluate the association overall and by sex race/ethnicity and APOE e4. We will also (Aim2) identify the determinants of plasma pTau-181 in AD cases among the case-related demographic (sexrace/ethnicity age cohort education neighborhood socioeconomic status) genetic (APOE polygenic risk score)and modifiable risk factor (vascular-metabolic disease history physical activity diet quality sleep duration)characteristics available from the long-term prospective follow-up in order to understand the biomarker variation.The proposed work is within the scope of the active MEC grant (U01 CA164973; 2022-2027) as it will enhancethe cohort infrastructure for investigations of genetic lifestyle and environmental risk factors for an importantchronic disease in US adults across multiple racial/ethnic groups. Given the breadth and depth of the cancer andother chronic disease research that has been supported by the MEC this proposed BBM-based validation andinvestigation of AD is likely to stimulate an array of additional activities leading to progress on AD/ADRD research. 410244 +No NIH Category available Academic Medical Centers;Acceleration;Advisory Committees;African American population;Area;Authorization documentation;Basic Science;Biological Markers;Cancer Etiology;Cancer Patient;Communication;Communities;Consultations;Data;Databases;Development;Discipline;Dissemination and Implementation;Documentation;Ensure;Environmental Risk Factor;Epidemiology;Evaluation;Focus Groups;Foundations;Genetic;Genetic Variation;Genetic study;Genomics;Goals;Guidelines;Individual;International;Leadership;Maintenance;Malignant neoplasm of lung;Minority Groups;Nicotine Dependence;Occupational activity of managing finances;Play;Population Heterogeneity;Predisposition;Procedures;Process;Qualitative Research;Regulation;Research;Research Personnel;Resources;Risk;Risk Assessment;Risk Factors;Role;Science;Series;Site;Smoking;Smoking Behavior;Teleconferences;Time Management;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Washington;authority;cancer risk;cohort;data exchange;data harmonization;database of Genotypes and Phenotypes;epidemiology study;financial relationship;future implementation;genome wide association study;implementation science;improved;interdisciplinary approach;lung carcinogenesis;meetings;multidisciplinary;novel;novel strategies;programs;protocol development;screening;screening program;tobacco carcinogenesis;web site;webinar Administrative Core Project NarrativeThe administrative core ensures that data and processes needed to support all needs for the IntegrativeAnalysis of Lung Cancer Risk and Etiology Application and Translation program project are met. Theadministrative core also supports early stages of implementation science to translate findings from discoveryscience to communities at risk for lung cancer development. NCI 10716720 9/25/23 0:00 PAR-20-077 2U19CA203654-07 2 U19 CA 203654 7 8/1/17 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 6539 1881790 "AMOS, CHRISTOPHER I." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 365637 262887 102750 Project Summary/AbstractThe Administrative Core is responsible for managing all project and core resources and ensuring compliancewith all governmental and specific NIH regulations and requirements including timely communication andconsultation with project offices and other NCI staff. The core will convene all necessary meetings includingmonthly meetings of the internal oversteering committee and annual meeting of the external scientific advisorycommittee. The specific aims are: Specific Aim 1. Maintain and further develop a database forepidemiological genetic and biomarker data. The Mt. Sinai group in Toronto has harmonized data from 80studies comprising 125000 lung cancer patients and more than 1 million cohort individuals. The availability ofthis resource for Program Project leaders allows the proposed projects to be launched rapidly efficiently andeffectively. Specific Aim 2. Provide Integrative Support for Program Project Activities. A primary functionof this core is to ensure the efficient functioning of Program Project relationships and communication.Communication is supported by development of clear guidelines of communication and authority procedures forproposing new projects regular teleconference calls and maintenance of a website that collects and managesresults from all meetings. Specific Aim 3. Develop and evaluate the translation of findings in diversepopulations. A new component focusing on implementation science will be led by Washington University in St.Louis. This component leverages their implementation science core to support projects that assess the impactsof personalized evaluation and of messaging of smokings impact upon lung cancer risks and its mitigation withan emphasis on minority populations. The core component also uses the Qualitative Research Core available atthe Vanderbilt University Medical Center to advice in conducting focus groups targeting different communitiesincluding minority populations that are typically underserved in evaluating genomic risk and in the LDCTscreening program.Specific Aim 4. Ensure compliance of the Program Project with all RegulatoryRequirements. The administrative core supports the development of protocols that support studies. Itcoordinates relationships with dbGAP and other entities for whom data transfers are required. It will also manageall communications with NCI programmatic technical and administrative staff. The administrative core alsooversees financial management and ensures timely management of financial relationships among the Projectsand Cores. The administrative core plays a central role in supporting investigator interactions and ensuringcompletion of aims. Administration for the P01 builds from successfully completed studies led by our teams ofinvestigators across a distributed network that is managed by clear communications and extensivedocumentation. +No NIH Category available Academic Medical Centers;Accounting;Address;Adherence;African American population;Asia;Asian;Asian population;Benign;Biological Assay;Biological Markers;Calibration;Canada;Cancer Etiology;Cessation of life;Classification;Clinical Data;Collaborations;Communities;Data;Data Element;Diagnosis;Diagnostic;Early Diagnosis;Epidemiology;Europe;Focus Groups;Frequencies;Genetic;Genomics;Goals;Image;Individual;International;Lead;Lung;Lung nodule;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Methods;Minority Groups;Modeling;Molecular;Nodule;North America;Ontario;Participant;Pathway interactions;Patients;Population Heterogeneity;Positioning Attribute;Probability;Proteins;Race;Research;Research Personnel;Resources;Risk;Risk Management;Risk Reduction Behavior;Role;Sampling;Site;Smoking Status;Spirometry;Taiwan;Translating;Translations;Underrepresented Populations;United Kingdom;United States Preventative Services Task Force;Universities;Validation;Visit;Washington;Work;biomarker panel;biomarker validation;cancer diagnosis;cancer risk;case control;circulating biomarkers;cohort;community engagement;computed tomography screening;data resource;design;epidemiologic data;ethnic diversity;feature selection;high risk;improved;low dose computed tomography;lung cancer screening;model building;mortality;multiple omics;never smoker;predictive marker;prognostic value;programs;prospective;protein biomarkers;public health priorities;racial disparity;radiomics;screening;screening program;sex;smoking exposure;uptake Translating Molecular and Clinical Data to Biomarker-Informed Screening Pathway Project NarrativeLung cancer continues to be the most common cancer and the leading cause of cancer deathworldwide and the reduction of lung cancer death remains to be a global priority. While low-dose computed tomography (LDCT) can reduce lung cancer mortality by 20-30% there areemerging challenges including how to optimize screening intervals address issues of racialdisparity and possible overdiagnosis. To maximize the benefit-harm ratio our project aims tooptimize biomarker-informed screening pathway while focusing on under-representedpopulations such as African Americans and Asian never smokers. NCI 10716719 9/25/23 0:00 PAR-20-077 2U19CA203654-07 2 U19 CA 203654 7 8/1/17 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 6538 8948631 "HUNG, RAYJEAN J." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 662868 647868 15000 Project SummaryLung cancer remains to be a global public health priority. While low-dose computed tomography (LDCT)screening was shown to reduce lung cancer mortality by 20-30% there remain to be unresolvedchallenges issues such as optimizing intervals for LDCT screening and how best to increase LDCTscreening uptake and adherence. In addition it has been shown previously that lung cancer risks forAfrican Americans are higher than for Whites when having the same level of smoking exposure whileuptake of LDCT screening among African Americans has been one of the lowest. Moreover theproportion of lung cancer among never smokers continues to rise across the world particularly amongAsians where over 50% of lung cancers are diagnosed among never smokers. None of these emergingissues are addressed under the recently expanded US Preventative Service Task Force criteria.The overall objective of this project is to establish a biomarker-informed LDCT screening pathway tomaximize screening efficiency and benefit-harm ratio while accounting for racial disparity. Our researchteam is in the unique position to conduct this much-needed work as we have already establishedextensive resources for the data elements needed being the lead investigators of the major CTscreening programs in the US Canada Europe and Asia along with international lung cancer consortia.Specifically we will (i) Establish a biomarker-informed LDCT screening pathway accounting forracial disparity using data and samples from 3 ongoing LDCT screening programs in North Americawith a total of 3500 participants and oversampling African Americans; (ii) Identify circulatingbiomarkers that predict lung cancer risk and differentiate nodule malignancy in Asian neversmokers using data and samples from the Taiwan Lung Cancer Screening for Never Smoker Trial(TALENT) with 12011 high-risk Asian never smokers and 311 lung cancer cases detected by LDCTscreening; (iii) Assess the prognostic values of biomarkers for lung cancer mortality based onmulti-omics approaches using data and samples from 6 LDCT screening studies from US CanadaEurope and Asia with a total of 1267 lung cancer cases.The results from this Project will shift the paradigm of what is considered an optimal CT screeningpathway and address the need of under-represented populations and potential over-diagnosis byinvestigating mortality. It will provide necessary information toward the implementation of individual risk-profile based screening strategies that will increase efficiency improve patient management and reducelung cancer mortality in an ethnically diverse population. +No NIH Category available Address;Age;Bioinformatics;Biological Markers;Biometry;Blood specimen;Cancer Detection;Cancer Etiology;Cessation of life;Communities;Complement;Data;Diagnosis;Diagnostic;Early Diagnosis;Eligibility Determination;Etiology;Exclusion;Family history of;General Population;Genotype;Harm Reduction;Healthcare Systems;Individual;Kentucky;Lung;Malignant neoplasm of lung;Measurement;Measures;Modality;Modeling;Occupational Exposure;Participant;Patients;Performance;Persons;Prospective cohort;Proteins;Proteomics;Public Health;Recording of previous events;Research;Risk;Risk Assessment;Risk Factors;Risk Marker;Sampling;Smoke;Smoking;Smoking History;Smoking Status;Symptoms;Technology;Test Result;Testing;Time;Training;Translating;Translational Research;United States Preventative Services Task Force;Update;Validation;Work;biomarker panel;biomarker performance;blood-based biomarker;cancer biomarkers;cancer genetics;cancer risk;case control;clinical implementation;cohort;computed tomography screening;curative treatments;early detection biomarkers;high risk;improved;innovation;low dose computed tomography;lung basal segment;lung cancer screening;mortality;never smoker;never smoking;novel;novel marker;polygenic risk score;predictive modeling;predictive tools;prevent;programs;protein biomarkers;psychosocial;recruit;risk prediction model;screening;screening program;smoking exposure Integrating Biomarkers into Lung Cancer Risk Profiling Project 2: Integrating Biomarkers into Lung Cancer Risk ProfilingNarrativeMany lung cancers occur in individuals who are not eligible for screening with low-dose computedtomography (LDCT). The INTEGRAL-AT Project 2 will improve LDCT screening eligibility criteria byincorporating biomarkers in risk assessment and evaluating the user acceptability in a community-basedscreening program. We will also identify novel biomarkers for lung cancer in never smokers. NCI 10716718 9/25/23 0:00 PAR-20-077 2U19CA203654-07 2 U19 CA 203654 7 8/1/17 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 6537 10811291 "JOHANSSON, MATTIAS ALEXANDER" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 697735 682735 15000 Project 2: Integrating Biomarkers into Lung Cancer Risk ProfilingSummaryScreening by low-dose computed tomography (LDCT) has revolutionized early detection of lung cancer theleading cause of cancer death. However current eligibility criteria require participants to have a history ofheavy smoking exposure. People with many years of cessation are excluded as are those who neversmoked. Currently 30-50% of lung cancers occur in individuals who are not eligible for screening and withdecreasing smoking rates these numbers will increase. The overarching aim of Project 2 is to address thischallenge by leveraging complementary information from blood-based biomarkers to identify individualswho have high lung cancer risk despite not meeting screening eligibility criteria.Our project is a natural extension of the initial INTEGRAL program where we developed the novelINTEGRAL protein biomarker panel which measures absolute concentrations of key risk biomarkers. InINTEGRAL-AT Project 2 we aim to move the INTEGRAL panel towards clinical implementation and alsoupdate the panel with risk markers of lung cancer in never smokers. We will first establish a biomarker-informed risk prediction model for smoking-related lung cancer. This will involve using the INTEGRAL panelprotein measurements on 1700 lung cancer cases and 2900 cohort representatives from the Lung CancerCohort Consortium (LC3) to develop and independently validate a model that estimates the 3-year absoluterisk of lung cancer. Second we will evaluate the acceptability of applying such a biomarker-based eligibilitycriterion to screening participants. This will involve recruiting 1000 individuals who are nearly eligible byUS Preventive Services Task Force criteria within the St Elizabeth community based LDCT screeningprogram. Finally we will carry out a de-novo proteomics discovery analysis on 616 never-smoking casesand 616 matched controls from LC3 to identify novel protein markers for lung cancer in never smokers andupdate the INTEGRAL panel to include these markers.Our long-term vision is that by using personalized information from a risk-informative and readilyimplementable multiplex protein-panel lung cancer screening can be more precisely targeted to people athigh risk of lung cancer. This would allow a higher fraction of lung cancer cases to be detected early withoutsubjecting more individuals to LDCT screening thus optimizing the benefit-to-harm ratio. We also envisagethat this panel will be highly useful outside the screening context to work up never-smoking patients with afamily history of lung cancer with occupational exposures or who present with symptoms. +No NIH Category available Adopted;African ancestry;Asian ancestry;Behavior Therapy;Behavioral;Bioinformatics;Biological Markers;Biology;Biometry;Cancer Etiology;Cancer Patient;Cessation of life;Characteristics;Child;Clinical;Collection;Communities;Data;Data Sources;Development;Disease;Ensure;Environment;Environmental Exposure;Environmental Risk Factor;Ethnic Origin;Etiology;European;Feedback;Foundations;Genes;Genetic;Genetic Polymorphism;Genetic Risk;Genetic Variation;Genetic study;Genomics;Genotype;Goals;Health Personnel;Hispanic ancestry;Human;Individual;Joints;Malignant neoplasm of lung;Mendelian randomization;Methodology;Methods;Minority Groups;Modeling;Molecular;National Heart Lung and Blood Institute;National Human Genome Research Institute;Patients;Play;Polygenic Traits;Population;Population Heterogeneity;Predisposition;Research;Resources;Risk;Risk Estimate;Risk Management;Risk Reduction;Role;Scoring Method;Serum Proteins;Smoking;Smoking Behavior;Susceptibility Gene;Testing;Time;Trans-Omics for Precision Medicine;Translating;Translations;behavior change;cancer prevention;cancer risk;causal variant;cohort;computed tomography screening;ethnic minority;evidence base;genetic analysis;genetic approach;genetic architecture;genetic risk factor;genetic variant;genome sequencing;genome wide association study;genomic locus;high risk;improved;innovation;instrument;interest;low-dose spiral CT;lung cancer screening;member;minority communities;motivated behavior;multi-ethnic;never smoker;novel;polygenic risk score;posters;programs;protein biomarkers;racial minority;recruit;risk prediction;screening;screening program;social culture;therapy development;tool;translational applications;uptake;whole genome Project 1: Smoking environmental and genomic factors in lung cancer and managing risk Project NarrativeLung cancer is the leading cause of cancer death and results from interplay of environmental and genetic riskfactors. This project seeks to use very large data sources to interrogate joint effects of environment andgenetics that increase cancer risks for individuals to inform risk reduction and recruitment to and managementof low dose spiral CT screening. NCI 10716717 9/25/23 0:00 PAR-20-077 2U19CA203654-07 2 U19 CA 203654 7 8/1/17 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 6536 1881790 "AMOS, CHRISTOPHER I." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 872066 611318 260748 Project Summary/AbstractLung cancer (LC) is a poster child for a disease resulting from interactions between genetic and environmental riskfactors. Ongoing LC genome wide association studies (GWAS) conducted by us have identified over 40 loci involvedin LC susceptibility that have dramatically improved the understanding of the genetic architecture of LC risk. Howeverthere is a significant bias in the conducted GWASs: most studies have involved populations of European descent.Ancestry plays an important role in LC risk through contribution of ancestry- specific germline polymorphisms as wellas socio-cultural differences including environmental exposures. We hypothesize that a one size (ancestry) fitsall model is not applicable to LC and that exploring risk of LC and its translation across ancestries mannerwill improve the understanding of LC risk and prevention in diverse human populations. Our specific aimsinclude the following. Aim 1. To precisely characterize the contribution of genetic variation to lung canceretiology. The genetic approach will include genotyping arrays and low pass whole genome sequencing (WGS) andimputation into the large multi-ethnic reference panels to generate the world largest resource for the discovery of lungcancer susceptibility variants influencing lung cancer risk across a range of ethnicities. Aim 2. To perform post-GWAS analysis to identify environmental and host-specific factors influencing lung cancer development.Mendelian randomization will enable the identification of causal molecular factors such as biomarkersinfluencing lung cancer which facilitates developing screening programs for lung cancer (Projects 2 and 3. Inaddition we will also use forward and reverse Mendelian randomization to partition the causal effects ofbiomarkers on lung cancer risk according to cis-acting genetic components trans-acting components related tobroader host-exposures and external factors. We will develop and use novel annotation methods to identify mostlikely causal variants to improve polygenic risk score development. Aim 3. To develop population-specific aswell as multi-ancestry polygenic risk scores (PRSs) to refine risk estimation of LC for minoritypopulations. In this aim we will first build and characterize PRSs from genomic analyses to identify subsets ofindividuals at high risk for lung cancer development1. Second to date studies have focused on analysis inEuropean-descent populations. Aim 4. To evaluate the impact of returning genetic risk factors informationto motivate behavior change in diverse populations and to scrutinize direct translational implications ofthe genomic findings from our ancestry-specific and cross-ancestry studies. In this translational aim wewill engage both patients and healthcare providers by adopting a rapid cycle research approach to reduce thetime lag from discovery to practice while accommodating evolving genomic evidence base. This project providesdata to the other projects and plays a key role in developing translational applications to evaluate interest incommunities for biomarker-informed recruitment for screening and risk reduction. +No NIH Category available Adopted;Adoption;Advisory Committees;Basic Science;Behavior;Behavior assessment;Biological Markers;Cancer Burden;Cancer Control;Cancer Detection;Cancer Etiology;Cessation of life;Clinical;Communities;Data Analyses;Development;Diagnosis;Dose;Early Diagnosis;Environmental Risk Factor;Funding Agency;Goals;Health;Individual;Life Cycle Stages;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Minority Groups;Names;National Institute of Drug Abuse;National Institute of Environmental Health Sciences;National Institute of General Medical Sciences;Output;Paper;Population;Population Heterogeneity;Population Research;Population Study;Populations at Risk;Primary Prevention;Prognosis;Publishing;Research;Risk;Risk Assessment;Risk Factors;Risk Management;Risk Reduction;Smoking Behavior;Spiral Computed Tomography;Stage at Diagnosis;Suggestion;Translating;Translations;behavior influence;biomarker identification;cancer prevention;cancer risk;clinical practice;computed tomography screening;environmental tobacco smoke exposure;genetic risk factor;genomic predictors;high risk;implementation research;improved;insight;interest;low dose computed tomography;low-dose spiral CT;lung cancer screening;lung development;malignant breast neoplasm;mortality;never smoker;non-smoker;novel;novel marker;novel strategies;programs;radiological imaging;risk prediction;screening;screening guidelines;success;translational approach;tumor progression;uptake Integrative Analysis of Lung Cancer Etiology and Risk Project NarrativeWorldwide and in the U.S. lung cancer is the leading cause of cancer mortality. Our proposal identifies riskfactors at each step of lung cancer development to understand the mechanisms controlling and influencing itsprogression and to identify biomarkers that can be used clinically for early detection. We have also includeddiverse communities in our research program in order to identify approaches to engage them in risk reductionstrategies. NCI 10716716 9/25/23 0:00 PAR-20-077 2U19CA203654-07 2 U19 CA 203654 7 "CARRICK, DANIELLE M" 8/1/17 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 1881790 "AMOS, CHRISTOPHER I." "HUNG, RAYJEAN J.; JOHANSSON, MATTIAS ALEXANDER; LIN, XIHONG " 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2910518 NCI 2474957 435561 Project Summary/AbstractLung cancer is the leading cause of cancer worldwide. The mortality rate represents over 25% of all cancersdeaths four times the number of breast cancer deaths in the U.S. Despite substantial improvements in thetreatment of lung cancer its prognosis remains dismal with a current 5-year mortality of approximately 85%in large part because it is usually diagnosed at stage III or IV. This high lung cancer burden reflects howubiquitous are exposures to tobacco smoke and other behaviorally influenced factors. These exposures along withpoor adoption of screening and cancer control approaches impedes improvements in survival. Management of lungcancer risk can be accomplished at all steps of the cancer prevention continuum starting with primary preventionprimarily by modifying smoking behavior. After the development of lung cancer early detection dramatically reducesmortality but compliance with existing guidelines for screening is poor. Furthermore the majority of lung cancers thatwill develop occur among the population that is ineligible for screening. Finally even among those who are screeneda large number of positive findings are detected and improved approaches to resolving high versus low-risk findingsare needed to reduce the burden of excess management and overdiagnosis. Our program project entitledIntegrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)-Applications and Translation is broadening ourstudies to identify predictive risk factors in minority populations and among never smokers. Our aims are thefollowing. Aim 1: To use genomic predictors to identify individuals who are at higher risk for lung cancerdevelopment. This aim focuses on developing and applying methods for risk assessment in diverse populationsAim 2: To develop and implement novel biomarkers that identify individuals who are at elevated lungcancer risk and will benefit from low dose spiral CT screening. This aim extends our prior research toidentify risks for nonsmokers and evaluate the translation of biomarker studies for population-based research.Aim 3: To evaluate predictors of lung cancer detection and progression based on an integrative analysisof data from screening populations. This aim evaluates new approaches to integrative analysis of biomarkerand radiographic marker studies in screening populations. Aim 4: To implement novel frameworks to managerisk reduction at all stages of lung cancer development and management. This aim cuts across projectsand evaluates the barriers and interests of populations who will benefit from the research being conducted bythis P01. This proposal builds upon a highly successful prior program project to broaden the populations we arestudying and engage and translate the findings to diverse populations. 2910518 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities ATP phosphohydrolase;Animals;Biological;Biological Assay;Biological Products;Budgets;Clinical Trials;Contractor;Development;Dose;Goals;In Vitro;Knowledge;MCL1 gene;MLL gene;Malignant Neoplasms;Mind;Mission;Nature;Outcome;Patients;Performance;Pharmaceutical Chemistry;Pharmacologic Substance;Phase I Clinical Trials;Process;Research Project Grants;Running;Schedule;Series;Specificity;Stream;Synthesis Chemistry;Therapeutic;Time;TimeLine;Validation;anti-cancer therapeutic;clinical candidate;commercialization;drug discovery;experience;flexibility;high throughput screening;in vivo;inhibitor;novel therapeutics;programs;scale up DISCOVERY AND DEVELOPMENT OF CANCER THERAPEUTICS FOR NEXT PROGRAM n/a NCI 10716676 75N91019D00024-0-759102200019-1 N01 9/9/22 0:00 9/8/27 0:00 78859061 "DIFILIPPANTONIO, MICHAEL " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 22364766 NCI The mission of NExT is to develop agents that eventually become approved anticancer therapeutics. Numerous interconnected activities need to be successfully completed before an IND can be filed with the FDA to move into clinical trials. As is the case with scientific research projects drug discovery is often fraught with unforeseen technical difficulties biological dead ends and the need to retrace ones steps along the way.Successfully navigating the drug discovery process requires the ability to quickly take advantage of new knowledge the flexibility to change technical approach mid-stream and an understanding that project timelines and budgets can and will deviate at many times along the way. Therefore although the drug discovery process is often depicted as a linear series of stage gates in reality projects seldom follow a predictable linear path but rather entail the performance of numerous not always sequential and often iterative activities the exact timing of which can rarely be predicted a priori. This has been one of the main and in fact the hardest lesson learned from more than a decade of drug discovery in DCTD.DCTDs mission to advance new therapies into patients requires that promising compounds navigate numerous technical activities in order to qualify for IND directed studies. This process includes the development of a high throughput screening assay running the high throughput screen (often with >200000 compounds) validation of hit compounds development and use of secondary assays assessing the specificity and selectivity of the hit compounds against the target medicinal and synthetic chemistry in vitro and in vivo (e.g. animal) dose and schedule efficacy PK and PD studies in order to consider a compound sufficiently validated to have the intended biological outcome. The experience of DCTDs drug discovery efforts over the past decade has demonstrated that 6 - 10 years is required to go from conducting a high-throughput screen to having a clinical candidate and conducting IND-enabling studies and that many projects fail at different stages along the way to reaching that goal.Under a previous NS TO (#34) the contractor successfully demonstrated the ability to deliver to NCI at least 1 Clinical Candidate (p97 AAA ATPase inhibitor) were close to nominating a Clinical Candidate for a second project (Mcl-1 inhibitor) when it was terminated by the applicant so they could pursue commercialization with a Pharmaceutical company and were close to nominating a Clinical Candidate for a thirdproject (WDR5-MLL1 inhibitor) within a 5-year POP. At the conclusion of TO-34 we therefore initiated another NS-TO (20-019) with the same goal in mind to deliver at least 1 Clinical Candidate. Due to the nature of the deliverable only projects which were further along in the pipeline were considered under the NS TO. For this reason NCI is submitting this new NS TO to allow for projects at earlier stages in the pipeline that if successful would feed into TO20-019. Additionally this new Task Order would also allow for activities required subsequent to the identification of a Clinical Candidate such as scale-up and manufacturing to support IND-enabling studies and Phase 1 Clinical Trials particularly in the case of Biologics. 22364766 +No NIH Category available Abdomen;Address;Anatomy;Bone Marrow;Bone Marrow Transplantation;Bone marrow biopsy;Chest;Clinical;Clinical Trials;Detection;Development;Diagnosis;Diagnostic;Diffusion;Diffusion Magnetic Resonance Imaging;Disease;Fatty acid glycerol esters;Generations;Goals;Image;Image Enhancement;Imaging Techniques;Imaging technology;Industry Standard;Lesion;Limb structure;Liquid substance;Localized Lesion;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Maps;Marrow;Measurement;Measures;Metastatic Neoplasm to the Bone;Methods;Morphologic artifacts;Motion;Multiple Myeloma;Musculoskeletal;Neoadjuvant Therapy;Non-Malignant;Outcome;PET/CT scan;Pain;Paralysed;Pathological fracture;Pathology;Patient Care;Patients;Pelvis;Performance;Perfusion;Prognosis;Prognostic Marker;Progression-Free Survivals;Protocols documentation;Quality of life;Recommendation;Reference Standards;Renal carcinoma;Resolution;Roentgen Rays;Scanning;Signal Transduction;Skeleton;Solid Neoplasm;Testing;Time;Vertebral column;Visualization;bone;bone imaging;bone loss;clinical practice;clinical translation;clinically relevant;contrast enhanced;cost;cost effective;experience;fluorodeoxyglucose positron emission tomography;imaging biomarker;imaging detection;imaging modality;improved;in vivo;innovation;malignant breast neoplasm;neoplastic cell;next generation;novel;pediatric patients;spinal cord compression;standard of care;treatment response;tumor Next-Generation Whole-Body MRI for Detection and Assessment of Therapy Response in Bone Lesions Project Narrative Bone lesions from a variety of pathologies including multiple myeloma can occur anywhere in theskeleton cause pain and spinal cord compressions leading to pathologic fractures and paralysis therebydiminishing the patient's quality of life. We propose to develop and evaluate an efficient whole-body magneticresonance imaging (WBMRI) technology that can accurately identify these lesions and measure their responseto treatment. This will provide relevant clinical information for treatment decisions to positively impact patients'quality of life and overall survival. NCI 10716642 6/30/23 0:00 PA-20-185 1R01CA283663-01 1 R01 CA 283663 1 "BEIER, HOPE THOMAS" 7/1/23 0:00 6/30/28 0:00 Clinical Translational Imaging Science Study Section[CTIS] 11324178 "MADHURANTHAKAM, ANANTH JAYASEELAN" Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 548249 NCI 318593 229656 Project Summary Bone lesions from solid tumors such as breast prostate or kidney cancers tumors originating in the bonemarrow such as multiple myeloma (MM) or other non-malignant musculoskeletal pathologies can occuranywhere in the skeleton. These bone lesions cause pain and spinal cord compressions leading to pathologicfractures and paralysis thereby diminishing the patient's quality of life. Current therapies rely on diagnosingthese bone lesions by whole-body X-ray or bone scans which only identify them at advanced stages. Whilewhole-body magnetic resonance imaging (WBMRI) is recommended for pretreatment assessment (e.g. inMM) MRI is often limited to spine and pelvic regions in practice to minimize patient discomfort compromisedimage quality from geometric distortion and high costs due to prolonged acquisition times. To address thisunmet clinical need we developed a novel WBMRI technique: `Dual-Echo T2-weighted acquisition forEnhanced Conspicuity of Tumors' (DETECT) for improved lesion visualization by simultaneously separatingthe confounding signals of fat and fluid. Compared to WBMRI with diffusion-weighted imaging (DWI) single-shot DETECT increased lesion detection (>40%) in considerably shorter scan times (<10 min) and withoutimage distortions. This method also improved robustness to motion in the thoracic and abdomen regionshowever it suffers from image blurring due to T2-decay particularly in spine and extremities limiting thediagnostic performance. In the current proposal we will address these limitations by developing the next-generation WBMRI-DETECT using an efficient combination of single-shot and multi-shot acquisitions. DETECTalso generates fat signal for quantitative fat fraction (FF) maps that can be used as a prognostic biomarker inMM since tumor cells replace fat a major constituent of bone marrow. This method also led us to develop aDETECT-based DWI technique for accurate measurement of apparent diffusion coefficient (ADC). The specificaims are: 1) To develop an integrated WBMRI using single-shot and multi-shot DETECT along withquantitative FF maps; 2) To develop a DETECT-based DWI with accurate ADC measurements; and 3) Toevaluate the integrated WBMRI including DETECT-DWI and contrast-enhanced perfusion for efficient bonelesion detection and therapy response assessment. We will use bone lesions in MM as the proof-of-conceptdisease to achieve these project goals. The successful outcome of this project will be an efficient WBMRIprotocol with accurate FF and ADC measures as imaging biomarkers validated in detection and measuringtherapy response in MM patients. This WBMRI in combination with contrast-enhanced MRI including perfusionwill be an excellent cost-effective and practical approach (<45 minutes of table time) for widespread use inclinical practices across the world. This will benefit MM patients and patients suffering from other bone lesionsincluding pediatric patients during long follow-ups without the drawbacks of PET/CT. This will provide relevantclinical information for treatment decisions to positively impact patients' quality of life and overall survival. 548249 +No NIH Category available Accounting;Adult;Biological Markers;Biological Models;Biology;CD8-Positive T-Lymphocytes;Cell Death;Cell physiology;Cells;Cessation of life;Clinical;Data;Databases;Development;Diagnosis;Experimental Models;Functional disorder;Genes;Genetic;Genetic Screening;Goals;Immune;Immune Evasion;Immunotherapy;In Vitro;Inflammatory;Inflammatory Response;Knockout Mice;Laboratories;Lymphoid Cell;Macrophage;Malignant Neoplasms;Mediating;Melanoma Cell;Metastatic Melanoma;Modeling;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Nature;PD-1 blockade;PD-1/PD-L1;PDL1 pathway;Patients;Population;Production;Protein Kinase;Publishing;RIPK1 gene;Regulation;Resistance;Role;Signal Transduction;Skin Cancer;T-Lymphocyte;TANK-binding kinase 1;TNF gene;Testing;Therapeutic;Tumor Immunity;Tumor-infiltrating immune cells;United States;Woman;anti-tumor immune response;cancer cell;cancer immunotherapy;cell type;conditional knockout;cytokine;cytotoxicity;effective therapy;effector T cell;exhaust;exhaustion;immune checkpoint blockade;in vivo;insight;loss of function;melanoma;men;molecular targeted therapies;mouse model;neoplastic cell;novel;novel therapeutic intervention;pharmacodynamic biomarker;pharmacologic;progenitor;response;restraint;single-cell RNA sequencing;success;tool;treatment strategy;tumor;tumor microenvironment Dissecting the tumor-intrinsic and -extrinsic roles of TBK1 in tumor immunity PROJECT NARRATIVEMelanoma is the fifth most common form of cancer in adults (men and women) and is thedeadliest form of skin cancer (NCI-SEER-Database 2019) and has been rising in theUnited States and worldwide (Karimkhani et al. 2017; Schadendorf et al. 2018) with anestimated 96480 adults (57220 men and 39260 women) diagnosed with melanoma inthe United States in 2019 accounting for 5.5% of all new cancer cases and resulting in7230 deaths (1.2% of all cancer deaths). While the treatment of metastatic melanomahas undergone a dramatic transformation over the past decade with the advent ofmolecular targeted therapy and immunotherapy additional therapeutic approaches areneeded for patients resistant to available targeted and immune treatments. We haveidentified TANK-binding kinase 1 (TBK1) is an emerging target to overcome resistance tocancer immunotherapy and aim to define the cell type specific roles of TBK1 in tumorimmunity. NCI 10716636 7/3/23 0:00 PA-20-185 1R37CA283560-01 1 R37 CA 283560 1 "HU, ZHANG-ZHI" 8/1/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 14183311 "JENKINS, RUSSELL WILLIAM" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 631104 NCI 377337 253767 Project SummaryImmune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway has induced dramatic and durable clinicalresponses in melanoma and other cancers. Despite the success of ICB effective treatment strategies toovercome resistance to cancer immunotherapy are lacking. TANK-binding kinase 1 (TBK1) is a versatile innateimmune protein kinase nominated as a candidate immune evasion gene in a number of pooled genetic screens.Using genetic and pharmacologic tools across multiple experimental model systems we have confirmed a rolefor TANK-binding kinase 1 (TBK1) as an immune evasion gene. Targeting TBK1 enhances response to ICB bylowering the cytotoxicity threshold to effector cytokines (TNFa/IFNg) secreted by immune cells. Tumor cellslacking TBK1 are primed to undergo RIPK1-dependent cell death in response to TNFa/IFNg. Beyond its effecton cancer cells targeting TBK1 in immune cells appears to augment this effect as TBK1 inhibition +/- PD-1blockade not only promoted accumulation of effector/progenitor exhausted CD8 T cells and M1-likemacrophages but was sufficient to enhance production of inflammatory cytokines (e.g. IFNg TNFa) from thesecells. Taken together our results demonstrate that targeting TBK1 is a novel and effective strategy to overcomeresistance to cancer immunotherapy and raise important questions about the function of TBK1 in cancer cellsversus immune cells in tumor immunity. In this proposal we aim to confirm and extend these initial observationsand resolve the cell type specific roles of TBK1 in tumor immunity.In Aim 1 we will determine the cancer cell-specific roles and regulation of TBK1 in resistance to cancerimmunotherapy by defining the downstream substrates of TBK1 in the setting of ICB resistance and definingupstream the mechanism(s) of TBK1 regulation promoting immune evasion.In Aim 2 we define the T cell-specific role of TBK1 in anti-tumor immunity by examining the effect of conditionaldeletion of TBK1 in CD8+ T cells. We will use CD8+ T cell specific TBK1 conditional knockout mouse models todefine the effect of TBK1 deletion in T cells on the efficacy of ICB and profile of tumor-infiltrating immune cellsand CD8+ T cell effector function/dysfunction.In Aim 3 we will dissect the role of TBK1 in regulating intratumoral myeloid cells. Using myeloid-specific TBK1conditional knockout mouse models we will define the effect of myeloid-specific TBK1 deletion on the efficacyof ICB and the landscape of tumor infiltrating immune cells as well as the effector function of macrophages andother myeloid cell populations. 631104 +Biotechnology; Clinical Research; Gene Therapy; Genetics Bioreactors;Chemistry;Clinical;Clinical Research;Cyclic GMP;Development;Equipment and supply inventories;Generations;Genes;Investigational New Drug Application;National Center for Advancing Translational Sciences;Pharmaceutical Preparations;Preparation;Process;Serotyping;Shipping;Testing;adeno-associated viral vector;analytical method;cell bank;gene therapy;interest;manufacturing process;open source NCATS-DPI-22-0101 - CREATION OF AN OPEN-SOURCE PROCESS TO MANUFACTURE AAV VECTOR-BASED GENE THERAPY CANDIDATES FOR NON-COMMERCIAL CLINICAL STUDIES n/a NCI 10716633 75N91019D00024-0-759102200016-1 N01 9/12/22 0:00 9/11/27 0:00 78864285 "MANGALAMPALLI, VENKATA " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 9308321 NCATS Project Objectives: Develop an open- access process for the generation of at least two of the AAV serotypes broadly in current use. All AAV serotypes will use a GFP gene and a gene of interest (GOI) identified by NCATS to validate the lab scale process. Demonstrate the scalability of that process by manufacturing the NCATS GOI for all AAV serotypes (non-GMP) at 50 L pilot scale and subsequently at a 200 L bioreactor scale. Develop all the required analytical methods for in-process testing and quality attributes of the material generated throughout the development stages to support regulatory filings. Provide comprehensive project management support Provide quality audit support during the process development and final process definition stage Provide regulatory support for preparation of the Chemistry Manufacturing and Controls (CMC) section of an Investigational New Drug (IND) application Manufacture AAV-GOI material at cGMP for clinical use and validate relevant analytical methods for release and stability analysis. Perform stability studies on the drug substance and drug product for up to 48 months Provide inventory support for storage and shipping of cell banks drug substance and drug product 9308321 +Cancer Accreditation;Agreement;Certification;Contractor;Elements;Engineering;Ensure;Exhibits;Government;Guidelines;Hour;Infrastructure;Maintenance;Regulation;Specific qualifier value;Work FY22 Facilities Task Order B Refurbishment and Infrastructure Projects focused on Facility Improvements within the NCI at Frederick Campus n/a NCI 10716602 75N91019D00024-0-759102200011-1 N01 5/23/22 0:00 7/3/23 0:00 78685098 "BRISCOE, LYNN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 439550 NCI In accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick. The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs. The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines. 439550 +Cancer Area;Contractor;Fire - disasters;Laboratories;Process;Site;System CONSOLIDATED FACILITIES REQUIREMENTS FOR FY22 TASK ORDER-A. n/a NCI 10716600 75N91019D00024-0-759102200003-1 N01 2/11/22 0:00 3/24/25 0:00 78539263 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 2273479 NCI PURPOSE OF THE PROJECT / TASK1.1 This project is intended to upgrade the existing fire alarm systems in 30+Frederick National Laboratory Buildings at Ft. Detrick.2.0 PROGRAM OF REQUIREMENTS2.1 General Requirements2.1.1 Required Site Interfaces. This will be a subcontracted constructionproject performed throughout Ft. Detrick.2.1.2 Parking. There is minimal parking in the area for the craft workers. AParking / Laydown Area will be determined and presented to theContractor as part of the procurement process. 2273479 +No NIH Category available Aging;Bypass;Cell Aging;Cell division;Cells;Chemicals;Cockayne Syndrome;Critical Pathways;Cytoprotection;DNA Damage;DNA Repair Pathway;DNA biosynthesis;DNA lesion;DNA replication fork;Dependence;Future;Genomic Instability;Human;Investigation;Lesion;Link;Longevity;Malignant Neoplasms;Mediating;Molecular;Mus;Pathway interactions;Patients;Phenotype;Premature aging syndrome;Process;Proteins;RAD52 gene;Radiation;Reactive Oxygen Species;Role;Source;Stress;Telomerase;Telomere Pathway;Telomere Shortening;Testing;Untranslated RNA;anticancer research;cancer cell;cancer type;cell age;clinical investigation;coping;novel;oxidative DNA damage;oxidative damage;pre-clinical;protective pathway;repaired;response;senescence;sensor;targeted cancer therapy;telomere;telomere loss;tumorigenesis Understanding and Targeting the R-Loop-Mediated DNA Damage Response at Telomeres Project NarrativeOxidative DNA damage at telomeres induced by radiation or other stresses is a source of genomicinstability which fuels both aging and tumorigenesis. We have discovered a new DNA repair pathway thatprotects cells against telomeric oxidative damage and found it remarkably similar to the alternativelengthening of telomere (ALT) pathway used by cancer cells to maintain telomeres. We will molecularlydelineate this repair pathway understand its relationship to ALT and develop strategies to selectively killcancer cells reliant on these pathways bringing a new front to the interface of aging and cancer research. NCI 10716512 8/10/23 0:00 PA-20-185 1R01CA282939-01 1 R01 CA 282939 1 "WITKIN, KEREN L" 8/10/23 0:00 7/31/28 0:00 Radiation Therapeutics and Biology Study Section[RTB] 10334726 "LAN, LI " Not Applicable 4 GENETICS 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 8/10/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 368288 NCI 228750 139538 Project SummaryOxidative DNA damage is frequently generated by radiation chemicals and endogenous oxygen radicalscontributing to genomic instability during both aging and tumorigenesis. Oxidative damage at telomeres canlead to telomere loss or attrition which triggers cellular senescence and limits the lifespan of dividing cells.While it is clear that oxygen radicals can inflict multiple types of DNA lesions how these lesions are repaired attelomeres is still largely unknown. By inducibly and locally generating reactive oxygen species (ROS) attelomeres we discovered a novel DNA repair pathway critical for the protection of cells against telomericoxidative damage. This pathway is activated by ROS-induced R-loops and is mediated by break-inducedreplication (BIR) a process that jumpstarts DNA synthesis at collapsed replication forks. In parallel with ourstudies on the oxidative damage response at telomeres we also investigated how cancer cells maintaintelomeres to bypass senescence. In particular we have molecularly dissected the alternative lengthening oftelomere (ALT) pathway which is used by ~10-15% of human cancers to extend telomeres. Interestingly wefound that ALT is also an R-loop-triggered and BIR-mediated repair pathway. The unexpected similaritiesbetween the repair pathway dealing with telomeric oxidative damage and the ALT pathway lead us tohypothesize that these telomere repair pathways are mechanistically linked. Furthermore cancer cells hijackthe R-loop and BIR-mediated repair pathway to extend telomeres and bypass senescence. In Aim 1 we willsystematically delineate the R-loop and BIR-mediated pathway that repairs telomeric oxidative damage andinvestigate if this pathway contributes to ALT activation in cancer cells. In Aim 2 we will develop strategies toexploit the cellular dependency on the R-loop and BIR-mediated ALT pathway which may allow us toselectively kill ALT+ cancer cells and aged cells harboring high telomeric oxidative damage. Our studies mayestablish a new link between cellular aging and tumorigenesis and provide new opportunities to eliminatecancer cells by targeting a hijacked DNA repair pathway. These studies may have transformative impacts atthe interface between aging and cancer research opening a new avenue to future preclinical and clinicalinvestigations. 368288 +Cancer Infrastructure;Laboratory Animals;Plants;Production;Pump;Steam;Water;Work;operation BUILDING 436 - BACKUP POWER (WO#126555) AS RELATES TO REFURBISHMENT AND INFRASTRUCTURE IMPROVEMENTS WITHIN THE NCI AT FREDERICK CAMPUS n/a NCI 10716501 75N91019D00024-0-759102200009-1 N02 5/5/22 0:00 4/15/24 0:00 78662070 "BRISCOE, LYNN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 282340 NCI The objective of this work order is to put B436 on backup power. B436 houses the main steam condensate return for thesouth boiler plant. During extended power outages the condensate pumps do not operate. Without condensate return tothe boiler plant there is insufficient treated water to operate the boilers. During a recent outage the boiler plant had tooperate on untreated water in order to keep the boilers operating. Operating with untreated water can damage the boilerhowever loss of steam production is immediately detrimental to laboratory and animal building operations 282340 +Cancer Acceleration;Accreditation;Agreement;American;Area;Award;Budgets;Businesses;Certification;Code;Computer software;Contingency Fund;Contractor;Contracts;Cost Control;Critical Pathways;Data;Development;Documentation;Effectiveness;Elements;Engineering;Ensure;Event;Exhibits;Expenditure;Feedback;Funding;Government;Growth;Guidelines;Hour;Infrastructure;Maintenance;Manuals;Methodology;Monitor;Notification;Parents;Performance;Policies;Procedures;Process;Professional Organizations;Quality Control;Reaction Time;Recovery;Regulation;Reporting;Schedule;Services;Site;Specific qualifier value;Strategic Planning;System;Techniques;Time;United States National Institutes of Health;Work;authority;cost;cost estimate;design;improved;indexing;meetings;operation;professional atmosphere;programs;quality assurance;risk mitigation FY22 Facilities Task Order B Refurbishment and Infrastructure Projects focused on Facility Improvements within the NCI at Frederick Campus n/a NCI 10716465 75N91019D00024-0-759102200008-1 N02 4/26/22 0:00 10/24/25 0:00 78650929 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 6128216 NCI Statement of Work Appendix: General Requirements FY22 Facilities Task Order B Refurbishment and Infrastructure Projects focused on Facility Improvements within the NCI at Frederick Campus1. General RequirementsIn accordance with FFRDC SOW Maintenance plans shall be compatible with elements of the current Interagency Agreement including any revisions thereto between the U.S. Army Garrison (USAG) Fort Detrick and the NCI at Frederick with the Contractor performing those functions designated as the responsibility of the NCI at Frederick. The Contractors work and responsibility shall include all planning programming engineering maintenance administration and management necessary to provide work as specified. The Contractor shall ensure that staffing hours and levels are sufficient to meet the Governments needs. The work shall be conducted in accordance with the FFRDC SOW Exhibit 1 Regulations/Certifications/Accreditations/Guidelines. 2. Facility Operations & Management of Planned WorkThe Contractor shall work closely with the Government to determine needs and priorities associated with customer requirements. The Contractor shall coordinate with EHS during project concept design and closeout to ensure project milestones submitted in project schedules are reflective of both FME and EHS requirements. a) Planned Work ManagementThe Contractor shall have the authority to manage all aspects of work orders to include but not limited to the use of approved project budget schedule and project quality. The Contractor shall estimate the project contingency needs using qualitative and quantitative metrics approval must be obtained in accordance with the task order terms and conditions prior to any release of contingency funds. The Contractor shall keep the customer and FME COR informed of project progress. All project changes must follow Facility Change Management process. During task order performance when an impact to scope cost schedule or performance is identified the Contractor shall notify the Government by inclusion in the monthly progress notification. If the critical path is changed the notification shall include an explanation of the cumulative events that resulted in the change Fragnet and risk mitigation strategy including schedule recovery and/or acceleration. Contractor shall coordinate across all directorates to ensure each project has an integrated Master Schedule. b) Planned Work CloseoutThe Contractor shall work collaboratively with the FME COR to establish standard practices for project closeout. The Contractor shall consistently apply closeout practices. Contractor shall ensure project09/26/20192close-out consideration in scope/cost/schedule account for processes across all Contractor business directorates.3.Facility Strategic PlanningAs a component of the development and ongoing growth and refinement of the Facilities Operations Manual required per the parent IDIQ the Contractor shall continually assess and analyze all aspects of Facility Maintenance and Engineering activities. The Contractor shall seek to consider procedures to improve efficiency in facilities maintenance engineering and renovation/ alteration/ maintenance/ refurbishment/ improvement projects. The Contractor shall to seek to identify improvements in all aspects of performance that will increase the effectiveness or efficiency of contract performance. Identified improvements shall align with Government requirements customer feedback and stakeholder input.4.Quality Assurance/Quality Control (QA/QC)Contractor shall develop and maintain a baseline program of quality assurance (QA) and quality control (QC) that will document performance and quality standards and management controls and assessment techniques to ensure components services and products meet HHS/NIH/NCIs design criteria and other governing and applicable specifications. The Contractor shall identify policies and procedures to improve performance and efficiencies in all project areas. The Contractor shall establish and maintain an effective quality control (QC) system. QC consist of plans procedures and organization necessary to produce a product which complies with the Contract requirements.Contractor shall provide Construction Quality Management (CQM) plan to ensure that work is performed according to plans and specifications on time within a defined budget and a safe work environment. Contractor shall provide a detailed Quality Control Plan (QCP) for all projects > $50000.00 contractor shall identify certified Quality Control Manager for all projects >$1m. The contractor has primary responsibility for compliance with plans and specifications.5.Cost control (EstimatingThe Contractor shall use historical data market analysis and RS Means software to develop cost estimates of any change requests and/ or impact analysis reports. The Contractor must adhere to the requirements established in the DRM (Section 1.6.3). The Contractor shall also follow American Society of Professional Estimators (ASPE) methodology.6.MeetingsThe following meetings between the Contractor and NCI designated representatives are held non-severable projects awarded on task orders shall be included in content and discussions as applicable:1)FME Operations Meeting (Weekly)This meeting to include FME MOSB and FME COR shall be held weekly to review and discussprogram operational priorities and performance.2)Plan of the Week (POW) Meeting (Weekly)09/26/20193This meeting to include FME EHS Program Representatives MOSB OSO and FME and EHS CORs shall be held weekly to review status of all new work orders work orders in development and approved work orders.7.Tracking and Monitoring of MetricsUnder the requirements of the NCI FFRDC Operational Task Order the Contractor and the FME COR shall identify Key Performance Indicators that have designated targets. Once identified the Contractor shall track and monitor metrics to the identified KPIs. For planned work awarded under non-severable task orders the Contractor shall track and monitor at a minimum the following metrics:Percentage of Work orders (WO) rescheduled from the initial approved schedule.Work order expenditure by type:oGeneral Work OrderoInspectionoEmergencyoCorrective MaintenancePercentage of Planned WOs verses all other WOsBacklog (Funding threshold)oSpecial AssistsWork order backlog including 30+ days total and per shopWork order completion response time per shopShop support to FME Planned Work Orders hours and percent of total8.ContingencyContingency notifications shall include:1-Narrative explanation of need for contingency use2-Contingency log tracking each instance of contingency use amount subtotal and remainingbalance3-Contingency Index CalculationContingency Index = Physical % Complete / % Contingency Expended.4-Supporting documentation as applicable including but not limited to:PCORFIsBulletinsSubmittalsChange order code:oAE error omissionsoUnforeseen site conditionsoUser directed change requestsInspectionsSchedule change -Fragnet09/26/20194Additional contingency requirements:1.If LBRs Best & Final subcontractor award is lower than LBR subcontractor estimateper NCI award amt then all excess funds must be returned to NCI controlled reservewithin 15 business days.2.LBR Direct labor cannot use project contingency unless approved by NCI FME CORand CO.3.NCI Reserves the right to request additional information 6128216 +Behavioral and Social Science; Cancer; Clinical Research; Health Services; Tobacco; Tobacco Smoke and Health Adoption;Awareness;Communication;Communities;Community Health;Contractor;Development;Division of Cancer Control and Population Sciences;Equipment;Future;Government;Health Services;Human Resources;Intervention;Measures;National Cancer Institute;Population Group;Public Health;Research;Research Institute;Research Support;Services;Work;behavioral health;improved;insight;mHealth;outreach;smoking cessation;tool INTERNAL AND EXTERNAL COMMUNICATIONS AND DISSEMINATION SUPPORT FOR DCCPS n/a NCI 10716342 91021A00291022F00001-0-0-1 N02 9/15/22 0:00 9/14/23 0:00 78859097 "KILGORE, ELIZABETH " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2022 2908308 NCI The National Cancer Institute (NCI) has created smoking cessation and other behavioral health services for multiple population groups and diverse audiences. NCI needs to provide support for the ongoing development and maturation of these services adoption within the public health community and among target audiences and engagement with research communities to continue to evolve and advance mobile health interventions and the awareness of them. Independently and not as an agent of the Government the Contractor shall furnish all the necessary services qualified personnel material equipment and facilities not otherwise provided by the Government as needed to perform the Statement of Work.The primary objectives of this task are to provide engagement and outreach support to internal and external audiences to help set and refine research agendas improve awareness of NCI research and availability of NCI-developed tools to support research efforts by grantees and other partners; reach target audiences through partnerships as well as earned paid and other outreach efforts; measure the impact of these efforts and provide analysis and insights that may be used in similar future efforts. 2908308 +Cancer; Dissemination and Implementation Research; Prevention Achievement;Area;Cancer Control;Cancer Survivorship;Communication;Division of Cancer Control and Population Sciences;Effectiveness;Goals;Health;Health Professional;Intervention;Population;Population Sciences;Progress Reports;Research;Resources;Science;Services;health disparity;high standard;implementation science;population based;programs STRATEGIC COMMUNICATIONS AND ANALYTIC SUPPORT FOR DCCPS n/a NCI 10716324 26117003B91022F00002-0-0-1 N02 9/30/22 0:00 9/29/23 0:00 78868225 "GEAGHAN, TAYLOR " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2022 5890000 OD The goal for this project is to maximize the NCIs ability to facilitate significant achievements in cancer control and population sciences through strategic communication. Communication activities cut across all our programs with a goal of greater integration and enhancement of cross-cutting scientific areas including implementation science cancer survivorship and health disparities. Part of what contributes to DCCPSs effectiveness is the breadth of activities undertaken. These include dissemination of research results and resources reports of progress on major initiatives and the provision of health information to health professionals practitioners and the public. It is important to maintain the high standard set for the type of services that are provided as well as meet the need to communicate about science and initiatives to new and expanding audiences. NCI must continue to promote and communicate cancer control and population-based interventions in a way that meets the needs of and is accessed by a variety of constituent populations. 30000 +Cancer; Dissemination and Implementation Research; Prevention Achievement;Area;Cancer Control;Cancer Survivorship;Communication;Division of Cancer Control and Population Sciences;Effectiveness;Goals;Health;Health Professional;Intervention;Population;Population Sciences;Progress Reports;Research;Resources;Science;Services;health disparity;high standard;implementation science;population based;programs STRATEGIC COMMUNICATIONS AND ANALYTIC SUPPORT FOR DCCPS n/a NCI 10716324 26117003B91022F00002-0-0-1 N02 9/30/22 0:00 9/29/23 0:00 78868225 "GEAGHAN, TAYLOR " Not Applicable 11 Unavailable 72648579 QHBLBNKKV4U3 72648579 QHBLBNKKV4U3 US 38.872349 -77.265823 1644201 "ICF, INC., LLC" FAIRFAX VA Domestic For-Profits 220316050 UNITED STATES N R and D Contracts 2022 5890000 NCI The goal for this project is to maximize the NCIs ability to facilitate significant achievements in cancer control and population sciences through strategic communication. Communication activities cut across all our programs with a goal of greater integration and enhancement of cross-cutting scientific areas including implementation science cancer survivorship and health disparities. Part of what contributes to DCCPSs effectiveness is the breadth of activities undertaken. These include dissemination of research results and resources reports of progress on major initiatives and the provision of health information to health professionals practitioners and the public. It is important to maintain the high standard set for the type of services that are provided as well as meet the need to communicate about science and initiatives to new and expanding audiences. NCI must continue to promote and communicate cancer control and population-based interventions in a way that meets the needs of and is accessed by a variety of constituent populations. 5860000 +Bioengineering; Cancer Clinical;Dose;Dose-Rate;Electrons;Frequencies;Goals;Individual;Ions;Measurement;Measures;Modality;Monitor;Performance;Phase;Physiologic pulse;Protocols documentation;Protons;Signal Transduction;Small Business Innovation Research Grant;Structure;System;Testing;Time;beamline;design;design and construction;dosimetry;instrument;ionization;irradiation;novel;pre-clinical;prototype;radiation detector;response FY22 SBIR TOPIC 434 PHASE I - NOVEL NIST TRACEABLE IONIZATION CHAMBER FOR FLASH DOSIMETRY. n/a NCI 10716299 75N91022C00039-0-9999-1 N43 9/23/22 0:00 9/22/23 0:00 78877025 "HOLMES, SHANNON " Not Applicable 2 Unavailable 788084705 EQENAAXF6AV1 788084705 EQENAAXF6AV1 US 43.11528 -89.52492 3443701 "STANDARD IMAGING, INC." MIDDLETON WI Domestic For-Profits 535621461 UNITED STATES N R and D Contracts 2022 399504 NCI One of the major factors limiting pre-clinical and clinical use of FLASH RT is the difficulty in measuring the FLASH irradiation parameters such as dose dose per pulse pulse repetition frequencies and time structure with the available conventional radiation detectors electrometers and dosimetry protocols. The goal of this project is to design and construct a novel NIST-traceable ionization chamber for FLASH dosimetry. We will also develop a standards-level electrometer to achieve high frequency monitoring of the measured signal providing both integrated dose measurements for the entire irradiation and time-resolved information about individual pulses delivered during FLASH irradiations. Both instruments will be NIST traceable. To reach this goal we aim to determine the optimal ionization chamber design for FLASH RT to use one of our existing electrometers as a springboard for creating a new electrometer that responds rapidly to FLASH irradiation and to fully characterize a working prototype system in FLASH beamlines. Although we plan to verify performance in both proton and electron FLASH beams the ultimate test of an ion chamber developed for absolute dosimetry in FLASH beams will be in electron FLASH beamlines because these have the highest instantaneous dose rates and dose per pulse of the available modalities. 399504 +No NIH Category available Achievement;Affinity;Area;Asian Americans;Award;Cancer Center;Clinical Trials;Collaborations;Communities;Development;Disabled Persons;Discipline;Disparity;Ensure;Ethnic Origin;Ethnic Population;Faculty;Focus Groups;Fostering;Funding;Goals;Grant;Hawaii;Incidence;Individual;Institution;Intervention;Journals;Leadership;Malignant Neoplasms;Mentors;Mentorship;Minority;Minority Health Research;Monitor;Native Hawaiian or Other Pacific Islander;Outcome;Outcome Measure;Pacific Islands;Policies;Population;Procedures;Process;Program Effectiveness;Progress Reports;Publications;Race;Research;Research Personnel;Research Support;Resources;Scientist;Services;Sexual and Gender Minorities;Standardization;System;Talents;Training;Translational Research;Underrepresented Populations;Universities;Veterans;Woman;Work;Writing;cancer health disparity;cancer prevention;cancer risk;cancer therapy;candidate selection;career;career development;design;effectiveness evaluation;ethnic disparity;faculty mentor;health care quality;improved;innovation;member;minority disparity;minority health;minority health disparity;multi-ethnic;multidisciplinary;programs;racial disparity;racial population;senior faculty;success Career Enhancement Program n/a NCI 10716161 9/19/23 0:00 PAR-20-305 1P20CA275734-01A1 1 P20 CA 275734 1 A1 9/19/23 0:00 7/31/26 0:00 ZCA1-RPRB-H(M1)S 6497 1903184 "MASKARINEC, GERTRAUD " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 84123 53753 30370 SUMMARYThe University of Hawai`i Cancer Center (UHCC) SPORE Career Enhancement Program (CEP) will identify andmentor investigators who show promise for independent research careers in translational research in minorityhealth and correcting ethnic/racial disparities in cancer. We understand that creating a sustained high-impactminority health program is dependent upon attracting the most promising investigators from a diverse talentedpool inclusive of underrepresented groups including racial/ethnic and sexual/gender minorities women veteransand individuals with disabilities to help these faculty members excel through quality mentorship and researchsupport. UH Cancer Center members have access to unique opportunities in Hawai`i and the Pacific to doinnovative research in minority health and disparities research in cancer due to the multiple racial and ethnicpopulations living here and their varying cancer incidence and outcomes. Further Hawai`i's high-quality healthcare and cancer registration systems offers access to needed resources for these studies. UHCC has anextensive record of successfully working with Hawaii's multiethnic population around minority health issues andto identify and understand disparities in various cancers. We also have a long track record of mentoring ourpromising junior faculty to independent research careers with particular success among researchers fromAANHPI background. The UHCC has also been successful engaging established researchers in developing newprojects in minority health and disparities research by providing forums to disseminate and discuss ideas thatare important to cancer prevention and treatment in our catchment. The goal of the CEP is to provide funding andmentoring to junior faculty to develop independent research programs and to provide support to establishedinvestigators to greatly enhance or refocus their careers on minority health research. In service of this goal wepropose the following Specific Aims: 1) Coordinate identification of promising new research in disparitiesresearch from junior faculty and established investigators looking to refocus their research in this area; 2) Providetraining career development and mentoring to awardees in minority health research; 3) Monitor the progress ofCEP awardees as they develop independent careers and/or new research programs in minority health andassess effectiveness of the CEP approach. Through these activities we will foster development of new diversefaculty who conducts highly collaborative translational research in minority health focusing on Asian AmericansNative Hawaiians and Pacific Islanders aimed at understanding differences in cancer risk and outcomes andcorrecting ethnic/racial disparities in Hawai`i the Pacific Islands and more broadly on the US and global stages. +No NIH Category available Address;Area;Award;Behavioral;Biological;Cancer Burden;Cancer Center;Catchment Area;Characteristics;Clinical Trials;Collaborations;Community Outreach;Creativeness;Data;Development;Education;Educational workshop;Elements;Ensure;Equity;Ethnic Origin;Ethnic Population;Evaluation;Faculty;Fostering;Funding;Future;Goals;Hawaii;Human;Institution;Intervention;Investigation;Leadership;Malignant Neoplasms;Mentors;Minority Health Research;Mission;Monitor;National Cancer Institute;Outcome;Patient Care;Pilot Projects;Population Heterogeneity;Process;Request for Applications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Review Committee;Seminal;Standardization;Strategic Planning;Talents;Therapeutic;Translating;Translational Research;Underrepresented Minority;Universities;Work;cancer health disparity;cancer risk;clinical diagnostics;ethnic difference;improved;innovation;inter-institutional;minority disparity;minority health;minority health disparity;programs;racial difference;racial population;success;translational impact Developmental Research Program n/a NCI 10716160 9/19/23 0:00 PAR-20-305 1P20CA275734-01A1 1 P20 CA 275734 1 A1 9/19/23 0:00 7/31/26 0:00 ZCA1-RPRB-H(M1)S 6496 1903184 "MASKARINEC, GERTRAUD " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 120510 77003 43507 SUMMARYThe University of Hawai`i Cancer Center (UHCC) is the only National Cancer Institute-designated cancercenter in Hawai`i and the Pacific. The Center's mission is to reduce the burden of cancer through researchcommunity outreach education and patient care with an emphasis on the unique ethnic cultural andenvironmental characteristics of Hawai`i and the Pacific. In alignment with this mission the DevelopmentalResearch Program (DRP) will draw upon areas of unique opportunity at UHCC to foster minority healthresearch that will improve our biological understanding of ethnic/racial differences in cancer risk and outcomesin our catchment area and translate our findings into therapeutic behavioral and diagnostic clinical trials andinterventions that address these challenges. The DRP is a central element of the P50 for developing newtranslational research projects in minority health that will nurture new lines of investigation researchinnovation and collaboration. The funded pilot projects will provide important preliminary data for future largeresearch project applications and support their feasibility and impact. Also DRP studies with translationalresearch potential may become full SPORE projects if the DRP study incorporates a human endpoint withinone of the project aims. Therefore the DRP will be an engine for innovation in translational minority healthresearch at UHCC. As such we have integrated its activities closely with the leadership of the P50 and that ofthe UHCC. Here we describe the process by which pilot projects will be solicited reviewed awarded andmonitored. The goal of the DRP is to identify and fund 10 new research projects and collaborations over fiveyears that address minority health issues in UHCC's catchment area. In support of this goal the DRPcoordinate pilot funding requests reviews and award activities and identify areas of unique opportunity andpotential collaborations. UHCC is poised to make seminal contributions to understanding and alleviating theburden of cancer in our diverse catchment area through strategic minority health and disparities research. TheDRP will proactively take advantage of these advantages to foster creative work that will translate intotherapeutic behavioral and diagnostic clinical trials and interventions that directly impact minority health.These projects will form the basis for the continued success of this minority health SPORE and expand itsimpact by fostering the development of new research topics. +No NIH Category available Address;Affect;Asian Americans;Asian population;Biological Specimen Banks;Blood;Blood specimen;Breast;Cancer Burden;Cancer Center;Cancer Patient;Cancer Research Project;Cells;Choline Kinase;Clinical;Cohort Studies;Collection;Colorectal;Colorectal Cancer;Communities;Community Hospitals;Community Participation;Consent;Cultural Sensitivity;Development;Diagnosis;Disparate;Endometrial Carcinoma;Endometrium;Ensure;Equity;Ethnic Population;Etiology;Excess Mortality;Feces;Filipino;Formalin;Foundations;Freezing;Future;Goals;Hawaii;Hexokinase 2;Human;Image;Individual;Infrastructure;Investigation;Japanese;Japanese American;Length;Liver;Lung;MDM2 gene;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mammary Gland Parenchyma;Medical;Methylation;Minority Groups;Minority Health Research;Multiple Myeloma;Native Hawaiian;Native Hawaiian or Other Pacific Islander;Not Hispanic or Latino;Oral;Oral cavity;Organoids;Oropharyngeal;Outcome;Pacific Islander;Paraffin Embedding;Pathogenesis;Pathology;Pathway interactions;Population;Primary carcinoma of the liver cells;Procedures;Program Research Project Grants;Protein Kinase;Reliability of Results;Reporting;Research;Research Personnel;Resources;SPHK1 enzyme;Samoan;Sampling;Slide;Somatomedins;Specimen;Standardization;Stomach;TP53 gene;Testing;Tissues;Translational Research;Tumor Tissue;Universities;Urine;Viral hepatitis;anticancer research;biobank;cancer health disparity;cancer risk;career;diagnosis standard;epidemiology study;ethnic difference;ethnic disparity;ethnic diversity;ethnic minority;ethnic minority population;experience;human subject;malignant breast neoplasm;malignant stomach neoplasm;melanoma;minimally invasive;minority communities;minority health disparity;mortality;multi-ethnic;nonalcoholic steatohepatitis;programs;prospective;racial difference;racial disparity;racial minority;racial minority population;repository;sample collection;telomere;translational cancer research;translational potential;tumor;tumor registry Core 3: Pathology & Biospecimens Core n/a NCI 10716159 9/19/23 0:00 PAR-20-305 1P20CA275734-01A1 1 P20 CA 275734 1 A1 9/19/23 0:00 7/31/26 0:00 ZCA1-RPRB-H(M1)S 6495 1890717 "HERNANDEZ, BRENDA Y" Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 152008 97130 54878 SUMMARY /ABSTRACT Access to relevant biospecimens is critical to translational research on minority populations. The lack ofresearch specimens from racial and ethnic minority populations in the U.S. remains a barrier to understandingracial/ethnic differences in cancer development progression and outcomes. In particular the paucity of clinicalbiospecimens from understudied populations including Native Hawaiians other Pacific Islanders and AsianAmericans has limited the ability to address critical disparities in cancer risk and outcomes affecting these U.S.communities. Hawaii the most ethnically diverse state in the nation has experienced a higher burden ofcommon cancers-- including liver breast lung colorectum endometrium and stomach compared to the U.Soverall. Moreover wide racial and ethnic disparities are observed within Hawaii's uniquely diverse multiethnicpopulation including Native Hawaiians who have the highest mortality for breast liver lung and other commonmalignancies. The value of the biospecimens collected at the University of Hawaii Cancer Center (UHCC) isevident in the breadth and scope of its translational research. Despite this progress biorepository efforts at theUHCC to date have been fragmented and limited for certain types of specimens especially fresh frozen tumortissue. Current UHCC biospecimen resources include a statewide repository of clinically-annotated de-identifiedarchival formalin-fixed paraffin-embedded (FFPE) tumor tissue and prospectively and retrospectively collectedblood urine oral rinses and stool from consented individuals. In contrast the collection of fresh frozen tissuehas been largely limited to small scale collections for disparate investigator-initiated studies. There is a crucialneed at UHCC to standardize and centralize the collection of fresh frozen tumor and blood from cancer patientsin our participating community hospitals and to integrate these collections with existing resources in order tooptimize their utility for cancer research. We propose to develop a Pathology and Biospecimen Core that willintegrate and augment existing and new biospecimen resources with respect to their acquisitionprocessing tracking storage and distribution and will support Project 1 (NASH/liver cancer) Project 2 (lungcancer) Project 3 (breast cancer) Career Enhancement Program (CEP) and Developmental Research Program(DRP) projects as well as other UHCC investigations with the goal of developing a robust infrastructure toaddress differences in cancer risk and outcomes in Asian American Native Hawaiian and Pacific Islander(AANHPI) ethnic minority populations. Aim 1 will focus on the development of a repository of paired fresh frozentumor tissue and blood specimens from multiethnic cancer cases diagnosed in the state of Hawaii with cancersof the lung liver breast colorectum endometrium pancreas and stomach. Potential cases will be identified viarapid reporting from medical facilities statewide through the NCI SEER Hawaii Tumor Registry. For Aim 2 wewill provide biospecimens from new and existing resources in support of Projects 1 2 and 3 CEP and DRPprojects and future cancer research projects. +No NIH Category available Address;Advocate;Asian Americans;Awareness;Biological Markers;Breast Cancer Risk Factor;California;Cancer Center;Catchment Area;Clinical Cancer Center;Clinical Trials;Collaborations;Communities;Community Outreach;Complex;Data;Data Collection;Development;Diagnosis;Education;Eligibility Determination;Ethnic Origin;Ethnic Population;Evaluation;Focus Groups;Foundations;Funding;Future;Geography;Goals;Hawaii;Health;Health Personnel;Infrastructure;Institution;Interview;Knowledge;Los Angeles;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Mammography;Minority Groups;Minority Health Research;NCI-Designated Cancer Center;Native Hawaiian;Native Hawaiian or Other Pacific Islander;Obesity;Observational Study;Oncology;Outcome;Overweight;Pacific Islands;Participant;Patients;Perception;Phenotype;Physicians;Play;Primary Care;Process;Protocols documentation;Provider;Race;Randomized;Recruitment Activity;Reproduction spores;Research;Research Personnel;Research Project Grants;Risk Assessment;Role;Smoker;Testing;Translational Research;Universities;Work;cancer health disparity;cancer risk;career;cohort;community engagement;community organizations;comorbidity;complex data;dietary;disease disparity;ethnic difference;ethnic disparity;exercise intervention;experience;health care service organization;high risk;informant;lifestyle intervention;lung cancer screening;malignant breast neoplasm;minority health disparity;multi-ethnic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;outreach;pilot test;programs;racial difference;racial population;radiomics;recruit;smoking cessation;success;translational impact Core 2: Outreach & Recruitment Core n/a NCI 10716158 9/19/23 0:00 PAR-20-305 1P20CA275734-01A1 1 P20 CA 275734 1 A1 9/19/23 0:00 7/31/26 0:00 ZCA1-RPRB-H(M1)S 6494 9561608 "LIM, UNHEE " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 232124 148322 83802 SUMMARY / ABSTRACTThe Outreach and Recruitment Core (ORC) of this P50 application will play an integral role in the proposedresearch to achieve the overarching goal of maximizing the translational impact of our ethnic disparities researchin our catchment area [Hawai`i and the US-Affiliated Pacific Islands (USAPIs)]. We will perform communityoutreach and recruitment activities specifically in support of the three projects and in the process engage ourminority populations broadly to increase their awareness of newly identified cancer disparities and obtain theirinput on our research and dissemination. The ORC team is highly experienced in community outreach especiallyin engaging local physicians and high-risk minority populations including Asian Americans Native Hawaiiansand Pacific Islanders (AANHPI) in Hawai`i and USAPI. Also the P50 and ORC team collectively has a strongtrack record of recruiting research participants and administering complex study protocols over the past 30 years.In Aim 1a we will establish the P50 SPORE's Community Advisory Board (CAB) to increase public andhealthcare provider awareness of racial/ethnic and geographic cancer disparities among AANHPI in Hawai'i andelicit community input participation and knowledge related to P50 research projects addressing liver lung andbreast cancers. In Aim 1b increase awareness of P50 SPORE's newly identified cancer disparities amonghealthcare providers and patient community organizations and engage their input and participation in P50projects. In Aim 2 to a) conduct the recruitment and data collection for the randomized lifestyle intervention inProject 1; b) conduct provider and community key-informant interviews and pilot message testing for Project 2;c) disseminate the risk assessment research and study findings to stakeholders for Project 3; and d) support thepilot work funded by the Developmental Research Program (DRP) and Career Enhancement Program (CEP).Bidirectional engagement with the community throughout the research process is essential for translationalresearch in minorities to be successful. The ORC in collaboration with the P50 CAB will assist current andfuture P50-affiliated investigators in obtaining stakeholder and community inputs into their research. The ORCwill build on the extensive experience in community outreach and engagement activities of our Cancer Centerthe only NCI-designated cancer center in the Pacific region and will establish the foundation for importanttranslational research addressing cancer disparities in our catchment area and beyond as part of a P50 SPORE. +No NIH Category available Address;Administrative Coordination;Advisory Committees;Advocate;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Survivorship;Catchment Area;Center Core Grants;Characteristics;Clinical;Clinical Research;Collaborations;Communication;Communities;Community Clinical Oncology Program;Community Outreach;Consultations;Core Facility;Data;Development;Disparity;Education;Educational workshop;Ensure;Ethnic Origin;Evaluation;Fostering;Foundations;Future;Goals;Grant;Hawaii;Health Disparities Research;Infrastructure;Institution;Intervention Trial;Joints;Leadership;Mission;Monitor;National Cancer Institute;Office of Administrative Management;Outcome;Patient Care;Patients;Pilot Projects;Play;Productivity;Program Evaluation;Protocols documentation;Race;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Site Visit;Strategic Planning;Translational Research;Universities;anticancer research;cancer health disparity;cancer risk;career;career development;clinical center;community engagement;data sharing;ethnic difference;ethnic diversity;expectation;experience;meetings;minority communities;minority health disparity;multidisciplinary;oncology program;patient population;programs;racial difference;skills;symposium;timeline;translational research program;underserved minority Administrative Core n/a NCI 10716153 9/19/23 0:00 PAR-20-305 1P20CA275734-01A1 1 P20 CA 275734 1 A1 9/19/23 0:00 7/31/26 0:00 ZCA1-RPRB-H(M1)S 6489 1898900 "LE MARCHAND, LOIC " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 249648 159519 90129 AbstractThe purpose of the Administrative Core is to provide the leadership and administrative management for theproposed multidisciplinary P50 SPORE aimed at capitalizing on the infrastructure at the University of Hawai`iCancer Center (UHCC) and the racial/ethnic diversity of its catchment area to conduct translational researchaddressing the racial/ethnic differences in cancer risks and outcomes that exist in Hawai`i and the Pacific. TheAdministrative Core will build upon a number of UHCC resources both administrative and scientific to foster theimplementation and coordination of the research in this P50. This Core will also closely coordinate the P50resource-building and career-development activities with those implemented by UHCC so greater efficiency isachieved at the institutional level. Thus this Core serves major administrative and integrative functions for thegrant. The P50 will rely on an Internal Advisory Committee (IAC) consisting of key senior basic and clinicalresearchers on cancer disparities to receive input on research opportunities and to facilitate coordination withpotentially synergistic local initiatives. The program will also benefit from the input of a Community AdvisoryBoard (CAB) composed of community leaders and patient advocates with experience in cancer disparities and/orsurvivorship and who will advise on the responsiveness of our activities to community needs and expectations.Program evaluation will heavily rely on the input of an External Advisory Board (EAB) composed of outsideinvestigators who are leaders in SPOREs and/or cancer health disparities research and a nationally-recognizedpatient advocate. Specific Aim 1 will be to provide the overall scientific and administrative coordination and jointleadership for the P50 grant. Specific Aim 2 will be to coordinate and integrate the P50 activities with those ofUHCC. Specific Aim 3 will be to plan and evaluate current and future translational cancer disparities researchas part of the P50 SPORE program. The Administrative Core will play an essential role in supporting the researchprogram proposed in the P50. We believe that the skills and experience of each Core Co-Leader and the provenapproaches described in this section will provide both the foundation and the building blocks to achieve ourgoals. +No NIH Category available Address;Adenocarcinoma;Adherence;Asian Americans;Behavioral;Bioinformatics;Biological;Biological Markers;Biometry;Blood specimen;Breast;Breast Cancer Risk Factor;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Prognosis;Catchment Area;Cells;Center for Translational Science Activities;Central obesity;Characteristics;Clinical;Clinical Management;Collaborations;Communities;Community Clinical Oncology Program;DNA Methylation;Data Analyses;Data Science;Development;Dietary Practices;Disease;Economics;Environment;Ethnic Population;Etiology;Evaluation;Fatty acid glycerol esters;Freezing;Funding;Future;Goals;Grant;Hawaii;Image;Individual;Infrastructure;Institution;Intervention;Intervention Studies;Leukocytes;Liver;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Mammary Neoplasms;Measures;Methylation;Minority;Minority Groups;Minority Health Research;Molecular;Mutation;Native Hawaiian;Native Hawaiian or Other Pacific Islander;Not Hispanic or Latino;Obesity;Outcome;Pacific Islands;Pathology;Patients;Performance;Phase;Pilot Projects;Population;Population Group;Population Heterogeneity;Prevention;Primary carcinoma of the liver cells;Randomized;Research;Research Infrastructure;Research Personnel;Rest;Risk;Small Cell Carcinoma;Smoker;Specialized Program of Research Excellence;Squamous Cell;Strategic Planning;Testing;Therapeutic;Translating;Translational Research;Translations;Tumor Biology;Universities;Visceral;Vulnerable Populations;biobank;cancer health disparity;cancer risk;career;chronic liver disease;community based participatory research;community center;data management;efficacy testing;elastography;ethnic difference;ethnic disparity;experience;follow-up;health care quality;health disparity;health equity;improved;innovation;lifestyle intervention;lung cancer screening;malignant breast neoplasm;minority health disparity;multi-ethnic;multidisciplinary;non-alcoholic fatty liver;non-alcoholic fatty liver disease;outreach;phase III trial;pilot trial;prediction algorithm;prognostic significance;programs;racial difference;racial disparity;radiomics;randomized trial;recruit;risk prediction model;screening;screening guidelines;secondary endpoint;social culture;tool;transcriptomics;translational study;tumor;tumor microenvironment;underserved minority;uptake Hawaii Minority Health and Cancer Disparities SPORE Project NarrativeWe propose to establish a SPORE program leveraging Hawai`i's multiethnic population and the University ofHawaii Cancer Center's community-facing translational research infrastructure to conduct minority healthresearch among Asian Americans Native Hawaiians and Pacific Islanders (AANHPI). We will test innovativeapproaches to address ethnic/racial disparities in non-alcoholic fatty liver disease (NAFLD) (a liver condition thatmay lead to chronic liver disease and liver cancer) lung cancer and breast cancer and develop additionalinnovative translational research that will benefit Hawai`i the Pacific region and the rest of the US. NCI 10716152 9/19/23 0:00 PAR-20-305 1P20CA275734-01A1 1 P20 CA 275734 1 A1 "HUBBARD, LEAH" 9/19/23 0:00 7/31/26 0:00 ZCA1-RPRB-H(M1)S 1898900 "LE MARCHAND, LOIC " "BERENBERG, JEFFREY LEE" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 9/19/23 0:00 7/31/24 0:00 397 Research Centers 2023 1673168 NCI 1070376 602792 Project Summary/AbstractAt the root of health disparities is the diversity that exists in the biological behavioral sociocultural andenvironmental characteristics of individuals and populations. Hawai`i offers exceptional opportunities for minorityhealth research due to its uniquely diverse population with varying cancer burdens and its high-quality healthcare and cancer registration. The University of Hawai`i Cancer Center has a successful track record of leveragingHawai`i's multiethnic population to study racial/ethnic differences in cancer risk and outcomes. It has built acommunity-facing infrastructure to translate these findings into major biological discoveries and clinicalinnovations that would help to alleviate cancer disparities in the US. We propose in this P50 (PAR-20-305) toestablish a SPORE program to conduct translational research focusing on Asians Americans Native Hawaiiansand Pacific Islanders (AANHPI) the fastest growing US minority to initially address three cancers of particularlyhigh relevance. Project 1 will address the high rates of hepatocellular carcinoma (HCC) in this population byimplementing a randomized lifestyle intervention among AANHPI patients with non-alcoholic fatty liver (NAFLD)and by investigating mechanistic biomarkers (cell-free and leukocyte DNA methylation) that may also providemuch needed clinical management tools. We will test the efficacy of intermittent vs. continuous energy restrictionto reverse the progression of NAFLD in AANHPI the most common etiology of chronic liver disease and livercancer in this population. Project 2 will address the excess lung cancer burden experienced by Native Hawaiiansby developing a risk-based and culturally-informed lung cancer screening strategy and investigate the mutationmethylation and transcriptomic profiles of lung squamous cell and small cell carcinomas and adenocarcinomasthat contribute to the unexplained poor survival in this vulnerable population. Project 3 will address the very highbreast cancer burden of Native Hawaiians and the rising rates in Asian Americans by testing the adequacy ofcurrent radiomic risk prediction algorithms for predicting breast cancer in these populations and by investigatingrelated molecular and histopathologic features of breast tumor environment which may be related to visceraladiposity and have prognostic significance. We will also establish: 1) an Administrative Core with strategicplanning advisory and evaluation components; 2) an Outreach and Recruitment Core (ORC) facilitatingstudies among minorities; 3) a centralized biorepository of paired fresh-frozen tumor and blood samples as wellas archival tumor blocks (Pathology & Biospecimen Core); 4) a Biostatistics & Bioinformatics Core; 5) aDevelopmental Research Program to fund innovative pilot studies and a Career Enhancement Program tosupport promising investigators new to translational research; and 6) new collaborations with other institutionsfor the further translation of our findings. The successful completion of this grant will significantly advance ourability to reduce the high burden of liver lung and breast cancers in AANHPI and to conduct other innovativetranslational minority health research that will benefit Hawai`i the Pacific region and the rest of the US. 1673168 +No NIH Category available Acute Myelocytic Leukemia;Automobile Driving;Binding;Cell Cycle;Cell Death;Cell Line;Characteristics;Chromatin;Clinical;Clinical Treatment;Clinical Trials;Complex;Correlative Study;Data;Development;Disease;Drug Combinations;Drug Synergism;Drug Targeting;Enhancers;Epigenetic Process;Evaluation;FLT3 gene;FLT3 inhibitor;Gene Expression;Genes;Granulocyte Colony-Stimulating Factor Receptors;Investigation;JAK2 gene;KDM1A gene;Link;MEKs;MYC Family Protein;MYC gene;Mediating;Minority;Molecular;Mutation;Oncogenic;Outcome;Patients;Pharmaceutical Preparations;Phase Ib Trial;Phosphotransferases;Play;Refractory;Regulation;Relapse;Repression;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Stat5 protein;Testing;Therapeutic;Translating;Tyrosine Kinase Inhibitor;Work;acute myeloid leukemia cell;antileukemic activity;cancer cell;clinical translation;effective therapy;efficacy evaluation;epigenetic profiling;improved;inhibitor;inhibitor therapy;kinase inhibitor;member;molecular subtypes;mouse model;mutant;novel therapeutic intervention;participant enrollment;patient derived xenograft model;pre-clinical;preclinical efficacy;programs;promoter;response;synergism;transcription factor;treatment response Dual Kinase and LSD1 Inhibition in Acute Myeloid Leukemia PROJECT NARRATIVEKinase plus LSD1 inhibition is a new treatment approach for patients with AML in whom kinase inhibitormonotherapy has not historically provided a large clinical benefit. In this proposal we will investigate themechanism of action of FLT3 plus LSD1 and MEK plus LSD1 inhibition in FLT3- and NRAS-mutant AMLrespectively. These studies will provide a pre-clinical framework for the clinical translation of kinase plus LSD1inhibitor therapy for patients with AML. NCI 10716085 7/13/23 0:00 PA-20-185 1R01CA282133-01 1 R01 CA 282133 1 "O'HAYRE, MORGAN" 7/13/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-MCTC-S(01)Q] 8832014 "BRAUN, THEODORE PAUL" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 7/13/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 485097 NCI 314998 170099 PROJECT SUMMARY/ABSTRACTKinase inhibitor therapy has made a minimal impact on the clinical treatment of patients with Acute MyeloidLeukemia (AML). We have shown that inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1)augments the efficacy of kinase inhibition in AML including drugs targeting FLT3 cKIT and JAK2. This occursvia the repression of the MYC super enhancer (MYC-SE) leading to a loss of MYC gene expression andconsequently decreased expression of a pro-proliferative gene expression program. However we lack acomplete mechanistic understating of how kinase plus LSD1 inhibition produces this effect or whether the drugcombination has important effects that are independent from the MYC-SE. Our long-term objective is to establishthe efficacy of kinase plus LSD1 inhibition in AML translating this concept into new effective treatment forpatients with AML. The overall objective of this proposal is to: 1) define the mechanistic basis for drug responsesto FLT3 plus LSD1 inhibition in FLT3-mutant AML and 2) evaluate the potential of dual MEK and LSD1 inhibitionin NRAS-mutant AML. Our central hypothesis is that the suppression of MYC-target genes is an essentialmechanism of kinase plus LSD1 inhibition-mediated cell death. In Aim 1 we will investigate three possiblemechanisms for FLT3 plus LSD1 inhibition-induced suppression of MYC target genes: 1) Via inactivation of theMYC-SE leading to decreased MYC gene expression resulting in a loss of MYC-target gene expression 2) Viainhibition of LSD1-dependent activation of MYC-target genes and 3) through inhibition of signaling pathwaysdown-stream of activated FLT3 resulting in a loss of MYC binding to the promoters of target genes. We will alsoperform correlative studies investigating these mechanisms in AML patients enrolled in the FRIDA trial receivingFLT3 plus LSD1-inhbitor therapy. In Aim 2 we will evaluate the efficacy and mechanism of action of MEK plusLSD1 inhibitor therapy in NRAS-mutant AML using an integrated evaluation of chromatin and signaling pathwaydynamics. We will also employ multiple mouse models of NRAS-mutant AML including a patient-derivedxenograft model. At the completion of these studies our expected outcomes are to 1) have identified how FLT3plus LSD1 inhibition drives cell death in FLT3-mutant AML and 2) establish the preclinical efficacy of dual MEKplus LSD1 inhibition in NRAS-mutant AML. These studies will provide key pre-clinical rationale for expandingthe indications for kinase plus LSD1 inhibitor to a larger proportion of patients with AML. 485097 +No NIH Category available Training Programs;cancer imaging Stanford Cancer Imaging Training (SCIT) Program The American Cancer Society estimates that in 2022 there will be over 1.9 million new cancer cases diagnosedand over 600000 cancer deaths. The Stanford Cancer Imaging Training (SCIT) Program trains new generationsof researchers and physician scientists to become cutting-edge investigators working at the intersection ofmedical imaging and disciplines such as engineering artificial intelligence chemistry cancer biologyphysiology and informatics. Through the SCIT program we promote advancing clinical applications of image-based techniques for better cancer detection and treatment which will in turn drive down cancer mortality andmorbidity. NCI 10716073 6/28/23 0:00 PA-20-142 2T32CA009695-31 2 T32 CA 9695 31 "DAMICO, MARK W" 2/1/93 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9060443 "DAHL, JEREMY " "DANIEL, BRUCE L" 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 413296 NCI 385148 29812 This proposal is a competing renewal for our longstanding T32 the Stanford Cancer Imaging Training (SCIT)Program. Drs. Jeremy Dahl PhD and Bruce Daniel MD will lead this program which features 25 mentors withindependent funding and 10 (7 internal/3 external) distinguished program advisors. This is a 2-year programthat trains 5 fellows (a mix of PhD and radiology-trained MDs) per year over a 5-year funding cycle. Our requiredcoursework includes 2 courses in the clinical/cancer sciences 2 in imaging science 1 in biostatistics 1 inmedical ethics (Responsible Conduct of Research) 2 workshops in grant writing an attendance at a minimumof 4 multidisciplinary tumor boards and regular attendance during a continuing education workshop that coverstopics in responsible conduct of research and rigor and reproducibility. In addition trainees can select from amultitude of electives offered by various Stanford University faculty across numerous clinical science andengineering departments. Each trainees primary focus is a mentored cancer-imaging research project aimedat publications in peer-reviewed journals and presentations at National meetings. We pair each trainee with botha basic science and physician mentor to provide guidance in course and research-topic selection and to developa translational mindset. Through the SCIT program we will continue our longstanding mission of training thenext generation of researchers in the development and clinical application of advanced techniques for cancerimaging. In addition we will recruit trainees from a nationwide pool that includes women candidates fromunderrepresented minorities and/or with disabilities and from disadvantaged backgrounds so as to increasediversity in the U.S. research workforce. The need for the SCIT Program is even greater now than when it began in 1993. Radiology plays a key rolein the diagnosis and treatment of cancer patients. Our Department is one of the very few that has been able togrow in response to this role and embrace what is now a multidisciplinary vision towards image-based cancerresearch. The SCIT Program leverages the Stanford Cancer Institute (an NIH-designated ComprehensiveCancer Center) and the Stanford Canary Center for Cancer Early Detection as well as many other Stanfordresources and programs. All of our SCIT trainees were productive while in the program with nearly 90% whocontinue research activity in cancer imaging today. Current trainees are pursuing research in radiology-pathology fusion to predict treatment response of breast cancer improving accuracy of prostate cancerdetection on MRI with deep learning methods optical coherence tomography histology to decrease the positivemargin rate in lumpectomy for breast cancer developing a partial ring time-of-flight positron emissiontomography scanner with 3D event positioning to visualize and quantify cancer lesions AI-based detectionmodels to distinguish ductal carcinoma in situ from invasive breast cancer on pre-operative breast MRI andoptimizing MR lymphangiography to maximize clinically relevant data and drive therapeutic innovation. 413296 +Cancer; Clinical Research; Health Services NCI Scholars Program;Research;health care delivery;visiting scholar HEALTHCARE DELIVERY RESEARCH VISITING SCHOLARS PROGRAM n/a NCI 10715922 75N91022P00839-0-0-1 N02 9/1/22 0:00 8/31/23 0:00 78844050 "KING, TAMIKA " Not Applicable 98 Unavailable 804535342 ERAEDE6KENE6 804535342 ERAEDE6KENE6 US 38.905341 -77.038765 1638101 ACADEMYHEALTH WASHINGTON DC Other Domestic Non-Profits 200364647 UNITED STATES N R and D Contracts 2022 58343 NCI NCI support for HEALTHCARE DELIVERY RESEARCH VISITING SCHOLARS PROGRAM 58343 +No NIH Category available Cancer Control Research;Program Development;Research Training;cancer prevention;career development Cancer Prevention and Control Research Training and Career Development Program PROJECT NARRATIVEThe sixth renewal of the University of Texas Health Science Center at Houston (UTHealth) School of PublicHealth training program builds on a 29-year track-record preparing fellows (many from underrepresentedminority groups) to become independent skilled and principled cancer control scientists. The trainingprogram is designed to prepare cancer prevention and control researchers to fill evidence gaps about multi-level causes of cancer-related inequities; to develop and evaluate cancer control multilevel interventions(MLIs); and develop and test strategies to increase the adoption implementation sustainment and scale up ofeffective interventions in community and health care settings. Ultimately the long-term goal of the proposedtraining program is to reduce cancer morbidity and mortality and decrease cancer-related health inequities. NCI 10715827 8/31/23 0:00 PA-20-142 2T32CA057712-31 2 T32 CA 57712 31 "BOULANGER-ESPEUT, CORINNE A" 9/18/92 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 2401885 "FERNANDEZ, MARIA EULALIA" "BALASUBRAMANIAN, BIJAL A." 18 MISCELLANEOUS 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF PUBLIC HEALTH 770305400 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 300085 NCI 464832 32760 PROJECT SUMMARY-ABSTRACTThe University of Texas Health Science Center at Houston (UTHealth) School of Public Health seeks itssixth renewal of our highly successful Cancer Control Research Training and Career Development Pro-gram for doctoral students and postdoctoral trainees. The long-term goal of the proposed training pro-gram is to reduce cancer morbidity and mortality and decrease cancer-related health inequities. Thetraining program objective is to increase the number of outstanding cancer control scientists - with anemphasis on training scientists from underrepresented minority groups - in cutting edge research andanalytic skills. The training program is designed to prepare cancer prevention and control researchers tofill evidence gaps about multi-level causes of cancer-related inequities; to develop and evaluate cancercontrol multilevel interventions (MLIs); and develop and test strategies to increase the adoption imple-mentation sustainment and scale up of effective interventions in community and health care settings.The proposed program renewal builds on a 29-year track-record preparing fellows (many from un-derrepresented minority groups 44% currently) to become independent skilled and principled cancercontrol scientists. Using exceptional innovative instruction mentored learning experiences professionaldevelopment skills participatory research processes and hands-on experience in diverse settings theproposed training program prepares fellows to conduct pragmatic actionable research that addressescancer-related health inequities. Outstanding cancer control researchers participating as mentors and co-mentors have created long-standing community and healthcare research partnerships across the statenationally and globally and a wide variety of cancer-related funding from diverse federal and non-federalsources providing unparalleled opportunities for trainees. Key areas of the program include: (1) trainingon the use of large databases such as healthcare claims EHRs surveys and cancer registry data to iden-tify multi-level cancer-related determinants; 2) training on innovative research design and analytic skillssuch as geo-spatial analysis systems science Bayesian approaches ecological momentary assessmentand pragmatic trial designs to tackle the multilevel multidimensional factors influencing cancer; 3) thedevelopment and evaluation of MLIs using community based participatory research and systematic plan-ning; and 4) training on adaptation of cancer control interventions and the design and testing of imple-mentation strategies. By the end of the current cycle our program will have graduated 68 fellows and 5fellows will continue their training in the next cycle. In this renewal the training program will appoint 15new trainees supporting approximately 4 predoctoral and 4 postdoctoral positions annually. Building ona strong track record the program will continue to recruit retain and train minority pre- and postdoc-toral fellows with a strong commitment to research for the elimination of cancer-related health inequities. 300085 +No NIH Category available Address;American;Antibodies;Antigens;Autoantibodies;Autoantigens;Autoimmune Responses;Autoimmunity;B-Lymphocytes;Benefits and Risks;Binding;Biodistribution;Biological Assay;Biological Markers;Blood;Blood Tests;Cancer Patient;Cell Line;Cell membrane;Cell surface;Cessation of life;Chelating Agents;Clinic;Clinical;Complex;Data;Detection;Development;Diagnosis;Disease;Early Diagnosis;Early Intervention;Eligibility Determination;Ensure;Epitopes;Excision;Future;Guidelines;Human;Image;Immunoconjugates;Label;Limited Stage;Location;Lung;Malignant Neoplasms;Mediastinal;Mediating;Monoclonal Antibodies;Nerve Tissue;Neuroendocrine Cell;Neurologic;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Performance;Persons;Plasma;Population;Positron-Emission Tomography;Post-Translational Protein Processing;Pre-Clinical Model;Primary Neoplasm;Production;Proteins;Protocols documentation;Radioimmunoconjugate;Radioisotopes;Recombinant Antibody;Recommendation;Reproducibility;Resected;Risk Factors;Role;SPINK1 gene;Sensitivity and Specificity;Site;Smoker;Smoking;Survival Rate;Syndrome;TFRC gene;TIMP2 gene;Testing;Therapeutic Intervention;Translating;Translations;Tumor stage;Tumor-Derived;United States Preventative Services Task Force;Woman;Xenograft Model;cell immortalization;circulating biomarkers;cohort;computed tomography screening;density;diagnostic biomarker;diagnostic platform;early detection biomarkers;early screening;experimental study;expression vector;first-in-human;fluorodeoxyglucose;fluorophore;high risk;high risk population;human monoclonal antibodies;human tissue;humanized monoclonal antibodies;imaging agent;imaging modality;immune imaging;improved;in vivo;low dose computed tomography;lung cancer screening;men;mortality;mouse model;neoantigens;non-invasive imaging;novel;patient derived xenograft model;preclinical study;protein expression;risk stratification;small cell lung carcinoma;standard of care;subcutaneous;targeted imaging;therapy resistant;tumor Autoantibodies to tumor-derived neoepitopes as biomarkers and immunoPET agents for the early detection of small cell lung cancer Project Narrative Small cell lung cancer (SCLC) is a highly aggressive recalcitrant and deadly cancer that can only beeffectively treated if fortuitously detected early; however no early detection protocol exists. We have discoveredthat the presence of tumor-specific autoantibodies can accurately predict SCLC earlier. Radioimmunoconjugatesbased on these autoantibodies could also be used to image SCLC tumors creating a paradigm in which theearly detection of SCLC biomarkers circulating in blood triggers targeted PET imaging and treatment. NCI 10715807 7/31/23 0:00 PAR-22-131 1R01CA281801-01 1 R01 CA 281801 1 "MAZURCHUK, RICHARD V" 8/1/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-ISB-L(59)R] 3168785 "LAMPE, PAUL D." "CHEN, DELPHINE L; ZEGLIS, BRIAN MATTHEW" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 582047 NCI 405549 176498 Project Summary/Abstract Small-cell lung cancer (SCLC) kills over 30000 Americans every year and has a dismal 5-year overallsurvival rate of less than 7%. However SCLC outcomes are greatly improved by early detection and interventionwith a nearly 50% 5-year survival rate for patients diagnosed at an early stage. These discrepant outcomesindicate that by far the majority of SCLC cases are diagnosed at later stages at which tumors rapidly becomeresistant to therapy with death quickly following. Thus an effective early detection strategy is necessary thatboth identifies cancer in people at high risk and facilitates non-invasive imaging that can confirm and delineatesmall tumors to guide surgical resection and treatment. We have found that autoantibodies (AAb) are present inthe plasma of essentially all SCLC patients (much more common than in other major cancers) and have validatedat least 7 AAb-identified neoantigens expressed by SCLC tumors that can be exploited as highly cancer-specificearly detection biomarkers and/or imaging targets. We envision an early detection/diagnosis platform performedduring the recommended annual low-dose computed tomography (LD-CT) lung cancer screenings for heavysmokers. However LD-CT and all current imaging modalities are not suitable for SCLC early detection even insmoking enriched populations due to lower than required sensitivity/specificity and risk/benefit analyses. Herewe propose a two-tiered approach with a blood test that detects the presence of AAb specific for SCLC thatwould trigger immuno-positron emission tomography (immunoPET) imaging utilizing a radioimmunoconjugatethat specifically targets the autoantigenic proteins expressed only on SCLC tumors. The blood test ensures thatonly high-risk individuals are screened and the immunoPET confirms and localizes the tumor for future treatment.Thus in Aim 1 we propose to define the role of SCLC-specific autoantigens (AAg) isolate human B cells specificto the AAg test the AAg as highly sensitive and specific early detection biomarkers and sequence the AAbvariable regions and clone them into expression vectors to produce human monoclonal recombinant antibodiesfor imaging purposes. In Aim 2 we propose to perform immunoimaging of SCLC tumors using fluorophore- andradionuclide-labeled AAb immunoconjugates specific for these cancer targeted neoantigens/epitopes.Preliminary data for the 2 antibodies that we have tested so far show that they specifically bind to SCLC tumorsin preclinical models underscoring the feasibility of the entire pipeline. In summary we will combine AAb-AAgearly detection for risk stratification with immunoPET imaging to confirm and localize tumors thereby establishingan early detection pathway capable of reducing the mortality of this highly aggressive cancer. 582047 +No NIH Category available Address;Administrative Personnel;Advanced Development;Basic Science;Bioinformatics;Biological;Biometry;Biostatistics Core;Cells;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communication;Communities;Computing Methodologies;Data;Data Analyses;Data Collection;Data Scientist;Data Set;Development;Elements;Ensure;Environment;Epidemiologist;Equity;Experimental Designs;Formulation;Genetic;Genomics;Genotype;Goals;Grant;Housing;Image;Infrastructure;Institution;Intervention;Laboratory Study;Maintenance;Methods;Mission;Molecular;Observational Study;Output;Pathway interactions;Patient Monitoring;Phenotype;Play;Policies;Positioning Attribute;Procedures;Program Research Project Grants;Publications;Randomized;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Sample Size;Science;Secure;Services;Specialist;Statistical Data Interpretation;Statistical Methods;Structure;Supervision;Talents;Technology;Translational Research;United States National Institutes of Health;Universities;biomedical data science;biomedical informatics;cancer genomics;cellular imaging;data harmonization;data management;data repository;data standards;design;experience;experimental study;follow-up;genomic data;human data;human subject;human tissue;innovation;interdisciplinary approach;malignant stomach neoplasm;medical schools;meetings;member;mid-career faculty;next generation sequencing;novel;open source;pre-clinical;prevent;risk stratification;single cell analysis;web-based tool Core C: Biostatistics NARRATIVE BIOSTATISTICS CORE CThe large scale of genomic and clinical data that will be generated by the Program Project Grant (PPG) offersinnumerable opportunities. The Biostatistics Core is advantageously positioned to develop study designs andnovel computational methods which will ensure completion of the research projects within the PPG and serveas lasting scientific resources for the broader biomedical community. NCI 10715767 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 6402 11974186 "HAN, SUMMER S" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 132415 85664 46751 ABSTRACT BIOSTATISTICS CORE CThe goal of the Biostatistics Core is to provide support for the statistical analysis generated from three projects.These supportive functions include the implementation of the study design and data analysis the developmentand applications of innovative statistical methods for single cell genomics and the timely dissemination of findingsas related to publications and research meetings. In summary this support consists of the following: (1) Provide expert and timely consultative services to Project investigators throughout the course ofresearch. (2) Organize clinical data generated from the PPG. (3) Develop statistical methods suitable for single cell analysis. (4) Aid in reporting results with the Project teams.The core team consists of biostatisticians data management specialists data scientists epidemiologists andadministrative personnel. The Biostatistics Core team will communicate regularly and in a structured format withproject investigators to ensure the appropriate design analysis and interpretation of preclinical and clinicalexperiments of the PPG. The Biostatistics Core has experience and expertise across the breadth of biostatisticsincluding within the domains of computational genetic data set analysis analysis of biological pathways clinicaltrial design and analysis and observational study design and analysis. This support will include the planning ofnew studies with regards to experimental design estimation of sample size and power calculations and methodsfor randomization when appropriate. The Biostatistics Core will collaborate with the PPG investigators in allstages of research from the formulation of the research questions through study design data management anddata analyses for laboratory studies (Projects 1-2) studies involving human tissues observational and clinicaltrial studies (Project 3) and principal interpretation for dissemination. The Biostatistics Core will closelycoordinate with the Administrative Core A and the Cellular Genomics and Imaging Core B to ensure timelycompletion of research objectives efficient use of shared resources effective dissemination of research findingsand compliance with regulatory policy and reporting requirements. +No NIH Category available 16S ribosomal RNA sequencing;Achievement;Antibodies;Biological Assay;Biology;Biometry;Biopsy;Cancer Detection;Cell physiology;Cells;Cellular Assay;Chromatin;Clinical Trials;Confocal Microscopy;DNA sequencing;Data;Data Analyses;Data Set;Detection;Ensure;Epigenetic Process;Experimental Models;Future;Gastric Tissue;Generations;Genetic;Genomic Library;Genomics;Goals;Helicobacter pylori;Image;Imaging Techniques;Immunohistochemistry;Individual;Laboratories;Leadership;Learning;Libraries;Malignant Neoplasms;Management Information Systems;Metadata;Methods;Molecular;Molecular Analysis;Molecular Genetics;Multiomic Data;Organoids;Pathologic;Precancerous Conditions;Preparation;Process;Production;Program Research Project Grants;Protocols documentation;Quality Control;Recording of previous events;Reproducibility;Research;Research Personnel;Resources;Sampling;Sampling Studies;Sequence Read Archive;Services;Stains;Standardization;Stomach;Structure;System;Techniques;Technology;Tissue Sample;Tissues;Transposase;United States National Institutes of Health;Work;automated analysis;cellular imaging;cohort;data management;data repository;database of Genotypes and Phenotypes;experience;experimental analysis;follow-up;gastric organoids;genetic profiling;genomic data;high risk;human tissue;image archival system;imaging study;malignant stomach neoplasm;microscopic imaging;next generation sequencing;pathology imaging;premalignant;programs;risk stratification;single-cell RNA sequencing;tissue culture;tissue processing;transcriptome sequencing;transcriptomics;translational study;wasting Core B: Translational Cellular and Molecular Analysis PROJECT NARRATIVE CELLULAR IMAGING AND GENOMICS CORE BCore B's experimental processing services will determine the cellular and genomic features defining high riskgastric precursors. The core will support experimental models to define the underlying biology. By providing arange of sophisticated imaging molecular and sequencing assays the core will streamline the progress of theProgram Project Grant and its goal of advancing precision cancer detection. NCI 10715766 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 6401 1927468 "AMIEVA, MANUEL R" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 434885 285738 149147 ABSTRACT CELLULAR IMAGING AND GENOMICS CORE BCore B the Cellular Genomics and Imaging Core (CGI) will provide centralized experimental processingservices and primary data analysis for the Program Project Grant (PPG). The interactions between Projects 1 2and 3 primarily involve shared biospecimens and data; therefore the PPG relies on the CGI to coordinate: (1) Experimental and translational sample management. (2) Cellular genomics that includes RNA-seq single cell genomics and spatial transcriptomics. (3) Imaging studies for cellular characterization of primary tissue cultures. (4) Sample molecular and genomic data management. The CGI core enables the PPG to leverage the combined expertise of molecular technologists cellularbiologists imaging experts and informaticians to streamline data production. Biospecimens of human tissuebiopsies and organoids will be tracked in a laboratory information management system (LIMS). These sampleswill be processed using standard operating protocols optimized by the CGI to facilitate reproducibility andconsistency across all projects. These protocols will cover confocal microscopy imaging RNA-seq targetedDNA sequencing spatial transcriptomics and single cell RNA sequencing. The CGI will produce acomprehensive landscape of the gastric microenvironment across a range of precancerous conditions and workin tandem with Core C for data analysis to further the PPG overall aims. The molecular genomic and epigeneticcharacterization will allow investigators to conduct numerous studies on the drivers of gastric cancer andhypothesize methods for precision cancer interception. +No NIH Category available Budgets;Clinical;Clinical Trials;Collaborations;Communication;Communities;Conflict of Interest;Consent Forms;Data;Development;Ensure;Expenditure;Fostering;Funding;Goals;Grant Review;Guidelines;Human Resources;Institution;Institutional Review Boards;Intercept;Manuscripts;Mission;Molecular;Monitor;Occupational activity of managing finances;Office of Administrative Management;Patients;Productivity;Program Research Project Grants;Protocols documentation;Quality Control;Reporting;Research;Resource Sharing;Resources;Sampling;Services;Supervision;Support System;United States National Institutes of Health;Universities;Work;cost effectiveness;data dissemination;data resource;data sharing;database of Genotypes and Phenotypes;gastric cancer prevention;improved;interdisciplinary collaboration;malignant stomach neoplasm;meetings;member;multidisciplinary;online resource;precision cancer prevention;precision medicine;programs;recruit;risk stratification Core A: Administrative NARRATIVE ADMINISTRATIVE CORE AThe objective of the Project Program Grant (PPG) is to improve precision cancer prevention for patients with ahigh likelihood of developing gastric malignancies. To achieve this goal the PPG will rely on a centralizedoperational fiscal and regulatory support system. Core A will streamline managing the administrativecomponents of the research program and enables the PPG to be successful in achieving its goal of improvingprevention of stomach cancer. NCI 10715765 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 6400 8471415 "JI, HANLEE P" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 154726 100098 54628 ABSTRACT ADMINISTRATIVE CORE AThe overarching goal of the Administrative Core is to provide the operational support necessary to meet thegoals of each Project and the overall Program Project Grant (PPG) Precision Interception of Gastric CancerPrecursors Through Molecular and Cellular Risk Stratification. This core will support the ultimate missionof the PPG which is to develop precision medicine strategies for preventing gastric cancer. The Core will functionas the organizational hub for the PPG centralizing resources to maximize efficiency for the three Projects. Thefive major objectives of the Core are: (1) Managing the finances of the PPG and allocating specific funds to each Project. (2) Communicating with all appropriate regulatory entities. (3) Coordinating translational activities and clinical trial efforts. (4) Monitoring progress and facilitating interactions across Projects Cores and Advisory Boards. (5) Ensuring timely data and resource sharing.The Core will contribute fiscal management and oversight to the PPG through the efforts of multidisciplinarypersonnel with expertise in these distinct responsibilities. It will provide coordinated and consistentcommunication with all regulatory entities to ensure proper research conduct. Frequent PPG review meetingswill also be facilitated by the Core. The Core Leads will serve as liaisons with Divisional and Departmentalpersonnel to enhance interprofessional collaboration and advance discoveries. All Projects and SharedResource Cores will utilize the functions of this Administrative Core. As a result the Core's work will contributeto the overarching theme of intercepting and developing precision cancer prevention of gastric cancer. +No NIH Category available 16S ribosomal RNA sequencing;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Back;Biological Assay;Biological Specimen Banks;Biology;Biopsy;Blinded;Carcinoma;Chile;Chromosome Mapping;Clinical;Clinical Management;Cohort Studies;DNA Sequence Alteration;Detection;Development;Diagnosis;Dysplasia;Endoscopy;Enrollment;Epithelial Cells;Epithelium;Evaluation;Gastric Adenocarcinoma;Gastric Glands;Gastric Tissue;Gene Expression;Gene Expression Profile;Genetic;Genomics;Gland;Goals;Helicobacter Infections;Helicobacter pylori;Histologic;Histology;Histopathology;Immunohistochemistry;Individual;Intervention;Label;Lesion;Link;Machine Learning;Malignant Neoplasms;Methods;Molecular;Mucous Membrane;Network-based;Organism;Outcome;Pathologist;Patients;Pattern;Placebos;Precancerous Conditions;Prevalence;Prognostic Marker;Program Research Project Grants;Randomized;Recrudescences;Research;Research Personnel;Risk;Risk Factors;Risk Reduction;Sampling;Severities;Slide;Specimen;Stains;Stomach;Surrogate Endpoint;Techniques;Technology;Testing;Training;Translating;Universities;Work;adjudication;antimicrobial;arm;biomarker panel;cancer risk;cell type;clinical data repository;cohort;design;experience;expression vector;gastric intestinal metaplasia;gastrointestinal;high risk;histological specimens;human subject;improved;malignant stomach neoplasm;neural network;novel;patient subsets;premalignant;prevent;progression risk;randomized placebo controlled trial;recruit;risk stratification;transcriptome sequencing;tumor;tumor progression Project 3: Molecular Risk Stratification of Gastric Precancerous Lesions NARRATIVE PROJECT 3This project is geared towards developing better ways of detecting stomach cancer in its earliest stages whenthere is a high chance of cure. This research will lead to ways of reducing the risk of developing stomach cancer. NCI 10715764 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 6399 1951134 "HWANG, JOO HA" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 389450 251949 137501 ABSTRACT PROJECT 3Project 3 proposes a concerted effort to decrease the 10-15% rate of Helicobacter pylori (Hp) recrudescencethat is currently experienced by patients. Previous work by the investigators in this Program Project Grant hasshown that a small number of Hp colonies persist deep within the gastric glands after eradication therapy. Thesecolonies may not be detected using conventional clinical tests as the colonies reside in recrudescence nichesthat are consequently resistant to antibiotic treatment. Highly sensitive molecular technology can reveal thepresence of Hp in conventionally negative gastric histology samples. The central hypothesis of Project 3 is thatuse of highly sensitive sequencing-based technology to identify persistent Hp organisms and guide eradicationmay both prevent Hp recrudescence and arrest neoplastic progression. The specific aims of Project 3 are: (1) Leverage gene expression profiles of gastric epithelial cells as a predictor of gastric intestinal metaplasia (GIM) progression in Hp negative individuals. (2) Develop molecular risk-stratification strategies in Hp histology negative subjects.In Aim 1 300 Hp negative subjects will undergo RNA sequencing and concordance with the high-risk patternswill be assessed through a gene expression vector. We will then translate the high-risk expression signatureinto a clinically useful multiplex IHC test. In Aim 2 samples from patients with GIM who are histology negativefor Hp on biopsies will be sequenced for molecular detection of Hp. A subset of patients will participate in arandomized placebo-controlled trial evaluating the effect of antibiotic therapy on molecular Hp titers. This trialwill demonstrate whether a sequencing-based eradication strategy can reduce Hp burden to molecularlyundetectable levels in human subjects. +No NIH Category available 3-Dimensional;Address;Anatomy;Antibiotics;Apical;Atrophic;Bacterial Genes;Basic Science;Behavior;Biological;Biology;Biopsy;Cancer Etiology;Carcinoma;Categories;Cell Communication;Cell Polarity;Cell model;Cells;Cellular biology;Cessation of life;Characteristics;Chronic;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Confocal Microscopy;Correa cascade;DNA Sequence Alteration;Data;Development;Disease Progression;Dysplasia;Endoscopic Biopsy;Epithelial Cells;Epithelium;Experimental Models;Exposure to;Gastric Glands;Gastric Tissue;Gastritis;Gene Expression;Gene Expression Profile;Genes;Genomics;Genotype;Gland;Growth;Helicobacter Infections;Helicobacter pylori;Human;Immune response;In Situ;In Vitro;Infection;Inflammation;Inflammatory;Intestines;Laboratory Research;Lesion;Libraries;Location;Malignant Neoplasms;Measures;Methods;Microscopy;Modeling;Molecular;Monitor;Mutation;Organoids;Pathogenesis;Patients;Peptide Initiation Factors;Persons;Phenotype;Precancerous Conditions;Process;Property;Quantitative Microscopy;Recrudescences;Research;Research Personnel;Resolution;Resources;Risk;Risk Factors;Risk Marker;Role;Sampling;Site;Stomach;Stomach Carcinoma;Surface;System;Techniques;Testing;Time;Tissue Model;Tissues;Tumor Stem Cells;Virulence Factors;Visualization;carcinogenesis;chronic infection;epithelial stem cell;experimental study;fitness;gastric intestinal metaplasia;gastric organoids;genetic selection;high risk;human tissue;improved;insight;malignant stomach neoplasm;mortality;neoplastic;next generation sequencing;novel;premalignant;programs;response;risk stratification;single-cell RNA sequencing;stem;stem cell niche;stem cell population;stem cells;tissue culture;tumor progression Project 2: Ex Vivo Modeling and Analysis of Gastric Precancerous Lesions NARRATIVE PROJECT 2Project 2 will develop a renewable human gastric tissue culture model that represents stages of pre-neoplasticprogression. Investigators will be able to study and induce changes in gastric stem cells with the hopes ofunderstanding the mechanisms behind cancer development. NCI 10715763 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 6398 1927468 "AMIEVA, MANUEL R" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 322612 208709 113903 ABSTRACT PROJECT 2The central purpose of Project 2 is to utilize a primary human tissue model to investigate the features of gastricstem cells and how the cells interact with Helicobacter pylori (Hp). Hp commonly triggers an inflammatoryprocess that leads to gastric intestinal metaplasia (GIM) a condition that can evolve into invasive carcinoma.However not all people with GIM develop gastric cancer. This project proposes an experimental platform toinvestigate the features of high-risk GIM. Its hypothesis is that high-risk GIM lesions possess epithelial stem cellswith unique properties predisposed to neoplastic progression especially in the setting of Hp infection. Project 2has three aims to investigate this hypothesis: (1) Characterizing the epithelial progenitor cells of high-risk GIM. (2) Modeling genomic alterations from high-risk GIM. (3) Elucidating interactions between Hp and gastric organoids from high-risk GIM.For Aim 1 Dr. Amievas group will develop a library of stem-cell rich apical-out gastric organoids representingthe gastric neoplastic spectrum across various topographical locations in the stomach. The characteristics ofthese stem cell organoids will be identifying using next generation sequencing and advanced microscopy. InAim 2 the organoids will be perturbed with select genetic alterations (identified in Project 1) through CRISPRgene editing. Subsequent changes to gene expression may provide insight into the biology of high-risk versuslow-risk GIM tissues. Lastly in Aim 3 the investigators will infect apical-out gastric organoids (from Aim 1) withhuman-derived Hp strains of known genotypes and phenotypes. Single-cell genomics will allow investigators todistinguish the unique transcriptional profiles of organoids at different time points states of infection andinflammation and enable studies into bacterial genes that are crucial for colonization and host perturbations.While Project 2 will be conducted in a basic research laboratory its aims and results are directly related toimproving overall understanding of Hp behavior in the human stomach and molecular changes that prime tissuefor carcinogenesis. +No NIH Category available 20q;Age;Anatomy;Atrophic;Bacteria;Biology;Cancer Detection;Cancer Etiology;Categories;Cells;Cellular biology;Cessation of life;Chromosome Arm;Chromosome Mapping;Chromosome abnormality;Chronic;Classification;Clinical;Correa cascade;DNA Sequence Alteration;Diagnosis;Dysplasia;Early Diagnosis;Epigenetic Process;Epithelial Cells;Epithelium;Event;Gastric Tissue;Gastritis;Gene Expression Profile;Gene Expression Profiling;Genes;Genetic;Genomics;Goals;Health;Helicobacter Infections;Helicobacter pylori;Helicobacter pylori induced gastric cancer;Histologic;Human;Immunohistochemistry;Individual;Infection;Inflammation;Intestinal Metaplasia;Intestines;Lesion;Lesion by Stage;Link;Location;Methods;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Outcome;Patients;Pattern;Population;Precancerous Conditions;Prevention;Prevention strategy;Process;Property;Proteins;Risk;Risk Assessment;Risk Factors;Sampling;Somatic Mutation;Specimen;Staging;Staging System;Stomach;Stomach Carcinoma;Therapeutic;Tissues;Translating;United States;Work;candidate marker;clinical biomarkers;clinical risk;cohort;detection method;gastric intestinal metaplasia;gastric organoids;genomic aberrations;high risk;high risk population;improved;insight;malignant stomach neoplasm;mortality;multi-ethnic;multiple omics;novel;premalignant;progression risk;risk stratification;sex;stem cells;transcriptome sequencing;transcriptomics;tumor progression Project 1 - Molecular and Cellular Determinants of High Risk Gastric Precancerous Lesions NARRATIVE PROJECT 1Gastric cancer is a leading cause of cancer morbidity and mortality worldwide and is associated with poor clinicaloutcomes and limited therapeutic options. Early detection of precancerous lesions particularly gastric intestinalmetaplasia has the potential to identify patients at highest risk for neoplastic progression enable novelprevention strategies and ultimately enhance health outcomes and reduce mortality for individuals with gastriccancer. Project 1 aims to characterize the precise molecular and cellular landscape of high-risk gastric intestinalmetaplasia and leverage this information to improve gastric cancer detection prevention and treatment. NCI 10715762 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 6397 8471415 "JI, HANLEE P" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 368913 238663 130250 ABSTRACT PROJECT 1The main objective of Project 1 is to deconvolute the molecular features of high-risk gastric cancer precursorlesions. Dr. Hanlee Ji Project Leader previously found that the epithelium of early gastric cancer is characterizedby distinct genomic transcriptomic and cellular properties. In addition the Ji Group has identified a distinct geneexpression profile associated with high-risk precancerous gastric lesions compared to low-risk lesions andnormal controls. Project 1 represents a continuation of this work with a specific focus on characterizing thegenetic and molecular profile of precancerous gastric tissue. There are two specific aims to this project: (1) Identify the specific gene expression signatures associated with high-risk gastric intestinal metaplasia(GIM). (2) Characterize aberrant epithelial cells and their subtypes in high-risk gastric cancer precursors.In Aim 1 Dr. Ji will employ bulk RNA sequencing and spatial transcriptomics to study GIM lesions that rangeacross the spectrum of neoplastic progression. Hp infection status will be used as a stratifying risk factor. Theseresults will identify the molecular profile associated with the highest risk of progression to gastric cancer and Hp-associated alterations in stomach cells. Aim 2 will use single cell multi-omics to identify the subset of GIMepithelial cells with somatic mutations copy number alterations and epigenetic patterns that are associate withgastric cancer. The results will determine the genetic and genomic features of epithelial cells that comprise high-risk precancerous lesions in the stomach. Ultimately this project will elucidate the precise molecular and cellularfeatures associated with high-risk GIM to gain novel insight into the molecular cellular and genomic factors thatcontribute to a high-risk premalignant state. +No NIH Category available Address;Administrative Coordination;Affect;American;Attenuated;Bacteria;Basic Science;Biological Markers;Biological Specimen Banks;Biology;Biometry;Cancer Biology;Cancer Diagnostics;Cancer Etiology;Chile;Clinical;Clinical Data;Clinical Research;Clinical Trials;Communicable Diseases;Communication;Data;Data Analyses;Detection;Development;Diagnosis;Early Diagnosis;Ensure;Epithelial Cells;Epithelium;Experimental Models;Foundations;Gastric Adenocarcinoma;Gastroenterology;Genome;Genomics;Goals;Health Expenditures;Helicobacter Infections;Helicobacter pylori;Image;Individual;Infection;Inflammatory;Intercept;Interdisciplinary Study;Lesion;Longterm Follow-up;Malignant Neoplasms;Methods;Modeling;Molecular;Molecular Analysis;Morbidity - disease rate;Occupational activity of managing finances;Oncology;Outcome;Patients;Persons;Precancerous Conditions;Preneoplastic Change;Prevention;Prevention strategy;Program Research Project Grants;Public Health;Research;Resources;Risk;Risk Factors;Sampling;Screening for Gastric Cancer;Screening for cancer;Stomach;Translational Research;United States;Universities;antimicrobial;attenuation;biomarker discovery;biomarker identification;cancer diagnosis;cancer prevention;cancer risk;carcinogenesis;clinical care;clinical practice;clinically relevant;cohort;data management;epidemiology study;gastric cancer prevention;gastric carcinogenesis;gastric intestinal metaplasia;gastrointestinal;genetic analysis;genomic data;high risk;improved;insight;interdisciplinary approach;malignant stomach neoplasm;medical specialties;mortality;neoplasm registry;novel;novel strategies;patient subsets;precision cancer prevention;precision medicine;premalignant;programs;risk stratification;single cell sequencing;stem cell niche;synergism;tumor progression Precision Interception of Gastric Cancer Precursors Through Molecular and Cellular Risk Stratification NARRATIVE OVERALLThis Program Project Grant (PPG) was developed to improve precision cancer diagnostics develop newmethods to prevent of stomach cancer and address important questions surrounding Helicobacter pyloris (Hp)effect on cancer development. The research team will develop new ways of intercepting stomach cancer in itsearliest stage such that it can be eliminated from patients. NCI 10715761 9/20/23 0:00 PAR-20-077 1P01CA265772-01A1 1 P01 CA 265772 1 A1 "UMAR, ASAD" 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 8471415 "JI, HANLEE P" "HWANG, JOO HA" 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1803001 NCI 1170821 632180 ABSTRACT OVERALLGastric cancer is a leading cause of cancer morbidity and mortality worldwide. The bacterium Helicobacter pylori(Hp) is the single greatest risk factor for gastric cancer its infection triggering an inflammatory cascade withinthe gastric microenvironment. Many people infected with Hp develop a precancerous lesion called gastricintestinal metaplasia (GIM) and while some are minimally affected by the condition others go on to developinvasive gastric cancer. There remain many unanswered questions about how Hp interacts with the gastricmicroenvironment and promotes gastric cancer and why GIM poses variable risk to patients. The focus of thisProgram Project Grant (PPG) is characterizing the molecular and genomic features of gastric epithelial cells inhigh-risk versus low-risk gastric precancerous lesions with Hp as a stratifying risk factor. The PPG involves threedistinct yet synergistic projects: (1) Molecular and Cellular Determinant of High-Risk Gastric Precancerous Lesions. (2) Ex Vivo Modeling of Gastric Precancerous Lesions. (3) Molecular Risk Stratification of Gastric Precancerous Lesions.The leaders of the PPGs multidisciplinary research teams have backgrounds in the relevant clinical specialtiesof infectious disease gastroenterology and gastrointestinal oncology. The PPG leverages broad and deepresearch expertise in single-cell sequencing Hp biology epidemiology and clinical research for gastric cancerprevention. There are several robust and synergistic clinical cohorts and biospecimen repositories that make upthe foundation of the PPG. These include two cohorts of gastric precancerous lesions the Gastric PrecancerousConditions Study (GAPS Stanford University) and the NCI-supported Gastric Cancer Precursor Lesions Study(GPCL Pontificia Universidad Catlica de Chile) the Gastric Cancer Registry (GCR Stanford University) andthe NCI-supported Hp Genome Project (HpGP Vanderbilt University). The translational and clinical projects inthe PPG offer a novel strategy of high-impact precision interception and cancer prevention to reduce gastriccancer risk. The interdisciplinary approach in this PPG is essential for improving clinical prevention strategiesand risk attenuation of gastric cancer. 1803001 +No NIH Category available 27-hydroxycholesterol;Address;Antineoplastic Agents;Attenuated;Blood Cells;Cancer Model;Cancer Patient;Cell physiology;Cells;Cholesterol;Cholesterol Homeostasis;Clinical;Clinical Trials;Cytotoxic Chemotherapy;Data;Development;Disease;Doxorubicin;Drug Carriers;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug toxicity;Encapsulated;Enzymes;FDA approved;Failure;Functional disorder;Health;Human;Hydroxycholesterols;Immune;Immune System Diseases;Immune response;Immune system;Immunologic Tests;Immunologics;Immunosuppression;Immunotherapy;In Vitro;Inflammatory;Interferon Type II;Knockout Mice;Knowledge;Liposomal Doxorubicin;Liposomes;Macrophage;Malignant Neoplasms;Mediator;Membrane;Meta-Analysis;Metabolic;Metabolic Pathway;Metabolism;Mixed Function Oxygenases;Modeling;Molecular;Mus;Normal tissue morphology;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phospholipids;Phytosterols;Production;Progression-Free Survivals;Property;Reporting;Role;STAT3 gene;STAT6 gene;Safety;Signal Pathway;Signal Transduction;Sitosterols;Solid Neoplasm;Sterols;Testing;Therapeutic;Therapeutic Effect;Time;Translating;Tumor Antigens;Tumor Immunity;Wild Type Mouse;Work;analog;anti-cancer;anti-cancer therapeutic;antigen-specific T cells;biophysical properties;cancer infiltrating T cells;cancer therapy;chemotherapy;cholesterol analog;design;immune function;immunoregulation;improved;in vivo;inhibitor;lipid metabolism;lipid nanoparticle;liposomal delivery;liposomal formulation;mouse model;nanoparticle drug;new therapeutic target;novel;novel anticancer drug;objective response rate;pharmacologic;randomized clinical trials;response;screening;smoothened signaling pathway;theories;tumor;tumor growth;tumorigenic CHOLESTEROL METABOLISM IN THE PHARMACOLOGY OF LIPOSOMAL THERAPEUTICS Project NarrativeThis proposal will identify novel mechanisms by which liposomes are metabolized within the body and willdetermine metabolites that alter immune function and tumor growth. The new knowledge generated isexpected to lead to the development of new cancer drug formulations that are both safer and more effective.This proposal will also test new formulations of liposomal doxorubicin containing cholesterol analogs for thetreatment of cancer. Our results have the potential to have an immediate clinical impact by swiftly translatinginto clinical trials. Since dysfunction in lipid metabolism is implicated in other health conditions the applicationof this knowledge extends beyond cancer therapy. NCI 10715758 9/19/23 0:00 PA-20-185 1R01CA282339-01 1 R01 CA 282339 1 "BOURCIER, KATARZYNA" 9/19/23 0:00 8/31/28 0:00 Innovations in Nanosystems and Nanotechnology Study Section [INN] 11070716 "LA-BECK, NINH " "ZHANG, QISHENG " 19 PHARMACOLOGY 609980727 E4Z2NUYUMHF9 609980727 E4Z2NUYUMHF9 US 33.592746 -101.898787 8285902 TEXAS TECH UNIVERSITY HEALTH SCIS CENTER LUBBOCK TX SCHOOLS OF PHARMACY 794306271 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 497111 NCI 384193 112918 ABSTRACTDrug delivery using liposomes increases tumor drug accumulation while sparing normal tissue. Several liposomalchemotherapies are approved to treat cancer. Unfortunately lipid nanoparticles such as liposomes interact withthe immune system and their impact on the tumor immunologic milieu is largely unknown. We have reported thatliposomes composed of phospholipids and cholesterol similar to those used in patients doubled tumor size inmice by suppressing the immune response against tumors. We recently identified macrophages as the cells thatare responsible for these detrimental effects. In this proposal we seek to identify the precise molecularmechanisms. Our preliminary data show that liposomal cholesterol is metabolized into oxysterols that are knownto alter the function of macrophages. Based on this we theorize that liposomal oxysterols cause macrophagesto suppress antitumor immunity and enhance tumor growth. Notably oxidized metabolites of beta-sitosterol (aplant sterol) lack the protumoral inflammatory activity of oxysterols suggesting that more efficacious liposomaldrug formulations can be developed using analogs of cholesterol. The objectives of this proposal are tounderstand the metabolism of liposomal cholesterol and to develop cholesterol analogs without tumorigeniceffects for liposomal drug formulation. We will dissect the metabolism pathways by conducting time-dependentstudies in immune cells and in mouse models. To identify the metabolic and cell signaling pathways that areinvolved we will conduct mechanistic studies in wildtype and knockout mice and donor human immune cells.Finally we will design and test the immunological and anticancer effects of cholesterol analogs in immune cellsand in mouse models of cancer. Our team has unique combined expertise necessary for successful completionof this project. This proposal is expected to have a positive impact by addressing critical gaps in currentunderstanding of the role of the immune system in liposomal drug pharmacology and the role of oxidized sterolsin cancer. This is likely to lead to new therapeutic targets and drug formulation strategies with potential tosignificantly advance both cancer drug delivery and immunotherapy. 497111 +No NIH Category available Animal Model;Biological Models;Brain Neoplasms;CAR T cell therapy;Cell Therapy;Cell physiology;Cells;Chemicals;Childhood Brain Neoplasm;Clinical Research;DNA;DNA Methylation;DNA Methylation Inhibition;DNA Modification Process;Data;Development;Disease;Elements;Environment;Epigenetic Process;Evaluation;Frequencies;Future;Genetic;Genetic Transcription;Goals;H3 K27M mutation;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunocompetent;Immunologic Stimulation;Immunotherapy;In Vitro;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Molecular;Patients;Phenotype;Population;Pre-Clinical Model;Process;Recurrent tumor;Resistance;Solid Neoplasm;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Transferase;Translating;Translational Research;Work;Xenograft procedure;cancer cell;chimeric antigen receptor;chimeric antigen receptor T cells;combinatorial;demethylation;diffuse midline glioma;effective therapy;effector T cell;epigenome;exhaustion;genetic selection;human disease;immune cell infiltrate;improved;in vivo;inhibitor;innate immune pathways;innovation;insight;methylome;mouse model;multidisciplinary;neoplastic cell;novel;pharmacologic;prevent;programs;recruit;response;translational medicine;tumor;tumor DNA;tumor microenvironment Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma NARRATIVEThe overall goal of this proposal is to evaluate the impact of DNA methylation inhibition of tumor cells CAR Tcells and combined towards more effective treatments against diffuse midline glioma. Our secondary goal is tounderstand the treatment nave microenvironment in DMG and how this environment changes in response toDNA methylation inhibition and CAR T cell administration. Our studies may pave the way for more effectivetreatments against DMG a universally fatal disease with limited treatment options. NCI 10715739 9/7/23 0:00 RFA-CA-22-016 1U01CA281823-01 1 U01 CA 281823 1 "LIU, YIN" 9/7/23 0:00 8/31/28 0:00 ZCA1-SRB-A(M1) 15299181 "MACK, STEPHEN C" "KRENCIUTE, GIEDRE ; PHOENIX, TIMOTHY N" 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/7/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 807680 NCI 542000 265680 SUMMARY/ABSTRACTWhile improvements in immune therapies have revolutionized treatments in some cancers pediatric brain tumorsare especially resistant to current immunotherapy treatments including immune check point inhibitors. This maybe because many pediatric brain tumors have been characterized as immune cold with little to no immune cellinfiltration. Chimeric antigen receptor (CAR) T cell therapies have shown promise against fatal brain tumors suchas diffuse midline glioma (DMG) in early clinical studies. However in early studies patients inevitably succumbto this fatal disease. This raises important questions about mechanisms of CAR T cell resistance and devisingstrategies to improve and prolong CAR T cell function. Targeting epigenetic programs has been identified as onestrategy to overcome deficient immune responses in solid tumors through both tumor cell intrinsic and tumormicroenvironment mechanisms. We have shown in DMG that inhibition of DNA methylation activates innateimmune pathways that may stimulate immune cell recruitment and activity (Krug et al. Cancer Cell 2019). Ourdata in CAR T cells deficient for a DNA methyl transferase (DNMT3A) displays reduced exhaustion andenhanced anti-tumor activity against multiple tumor models including brain tumors (Prinzing et al. ScienceTranslational Medicine 2021). We hypothesize that combinatorial approaches that target distinct DMG andCAR T cell DNA methylomes represents a rational strategy to enhance CAR T cell therapy. We propose to testthis in two specific aims: AIM1: Determine how tumor DNA demethylation in DMG impacts CAR T cell recruitmentand function. We will test the hypothesis that inhibition of DNA methylation induced endogenous retroviralactivation will enhance CART cell activation and persistence. AIM2: Determine if CAR T cell effector function isimproved by DNA methylation inhibition in DMG. We will test the hypothesis that inhibition of DNA methylationin CAR T cells is a phenotype that translates to DMG by preventing T cell exhaustion and improving long-termeffector function. 807680 +No NIH Category available Accountability;Address;Adherence;Adolescent and Young Adult;Adult;Age;Appointment;Behavior;Cancer Center;Cardiovascular Diseases;Caring;Childhood;Chronic Disease;Disparity;Education;Emotions;Enrollment;Failure;Feedback;Financial Hardship;Future;Goals;Guidelines;Health;Health Services Accessibility;Health behavior;Healthcare;Hispanic;Informal Social Control;Insurance;Intervention;Knowledge;Late Effects;Latino;Learning Module;Link;Longterm Follow-up;Malignant Childhood Neoplasm;Malignant Neoplasms;Managed Care;Mediating;Mediator;Medical Records;Mental Health;Monitor;Neurocognitive;Online Systems;Outcome;Outcome Measure;Parents;Participant;Pediatric Oncology Group;Quality of life;Randomized;Recommendation;Recording of previous events;Reporting;Research;Risk;Sampling;Screening for cancer;Self Care;Self Efficacy;Self Management;Social support;Socioeconomic Status;Subgroup;Surveillance Program;Survivors;Testing;Translating;Translations;Treatment Efficacy;Vulnerable Populations;aged;arm;barrier to care;cancer therapy;childhood cancer survivor;clinical practice;critical developmental period;critical period;digital;digital platform;efficacious intervention;efficacy evaluation;efficacy trial;ethnic health disparity;experience;feasibility trial;follow-up;health management;health record;health related quality of life;improved;innovation;interest;low health literacy;medical appointment;mobile application;neoplasm registry;novel;peer coaching;poor health outcome;racial disparity;randomized trial;scale up;screening guidelines;skills;social;social health determinants;survivorship;theories;therapy design;treatment as usual;treatment center;treatment effect;usability;virtual;young adult Digital Self-Management and Peer Mentoring Intervention to Improve the Transition from Pediatric to Adult Health Care for Childhood Cancer Survivors Project NarrativeChildhood cancer survivors are at risk for adverse late health effects from their treatment but many disengagefrom follow-up care during the transition from pediatric to adult-oriented health care. The proposed randomizedtrial will evaluate a novel digital self-management and peer mentoring intervention designed to improve self-management behaviors enhance health-related quality of life and increase adherence to guideline-concordantcare among adolescent and young adult survivors. Results will advance clinical practice to reduce the long-termburden among this vulnerable group. NCI 10715644 6/30/23 0:00 PAR-21-035 1R01CA282147-01 1 R01 CA 282147 1 "ADAMS, LYNN S" 7/1/23 0:00 6/30/28 0:00 Clinical Management in General Care Settings Study Section[CMGC] 10171639 "DEVINE, KATIE A" Not Applicable 10 PEDIATRICS 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 690045 NCI 485922 204123 Project Summary/Abstract Childhood cancers require lifelong risk-based follow-up care tailored to their treatment exposuresincluding routine medical appointments monitoring for late effects and regular cancer screenings. Unfortunatelyless than 1 in 5 adult survivors of childhood cancer obtain such risk-based follow-up care. The transition frompediatric to adult follow-up care for adolescent and young adult (AYA) survivors is a critical period when manysurvivors are lost to follow-up particularly AYA survivors who identify as Hispanic or have low self-efficacy tomanage their care. While the barriers to care are well-characterized there are no efficacious interventions tohelp improve this transition for AYA survivors of childhood cancer. To address this gap we developed Managing Your Health a digital self-management and peer mentoringintervention to improve survivorship care self-management. It consists of six 1:1 virtual sessions with a peermentor another young adult survivor who independently manages their own care. Each session involvesdiscussion of a complementary web-based self-management educational module. Peer mentors act assupportive accountability agents providing specialized support based on shared experience and facilitatingengagement with the modules. Our preliminary two-arm randomized feasibility trial showed that survivors foundthe intervention useful were highly engaged and reported significant improvements in self-management. Perparticipant feedback we translated the web-based modules into a mobile app for easier accessibility. The goalof this project is to evaluate the efficacy of Managing Your Health (app + peer mentoring) compared witheducational control in a two-arm randomized trial with 300 young adult survivors of childhood cancer currentlyaged 18-25 years. We will oversample for AYA survivors who identify as Hispanic given evidence of low self-efficacy and follow-up care in this group. Participants will complete outcome measures at baseline 3 monthsand 12 months post-randomization with medical record abstraction for guideline-concordant care at 12 months.Specific aims will evaluate the efficacy of the intervention on self-management behaviors quality of life andadherence to guideline-concordant follow-up care as well as mediators and moderators of treatment effects.The proposed research aligns with priorities detailed in the notice of special interest Navigating Pediatric toAdult Health Care: Lost in Translation and seeks to address gaps in the long-term health care of childhoodcancer survivors by evaluating an innovative theory-based intervention to facilitate the transition from pediatricto adult self-management of care. 690045 +No NIH Category available Acetylation;Apoptotic;Automobile Driving;Biological;Blood capillaries;Body Fluids;Cell Death;Cell Line;Cell model;Cells;Computer software;Defect;Development;Dose;Drosophila genus;Drug Targeting;Elements;Event;FRAP1 gene;Genes;Glucose;Glutamine;Hamartoma;Human;Human Cell Line;Hybrids;Immunoprecipitation;Ions;Isotopes;Joints;Kidney;Label;Lipids;Liquid substance;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Metabolic;Metabolic Control;Metabolic Pathway;Metabolism;Modeling;Molecular;Monitor;Mus;Mutation;Nonesterified Fatty Acids;PTEN gene;Pathogenesis;Pathway interactions;Peptides;Pharmacotherapy;Phase;Phospholipids;Phosphorylation;Phosphorylation Site;Post Translational Modification Analysis;Post-Translational Modification Site;Post-Translational Protein Processing;Preparation;Protein Kinase;Proteins;Proteomics;Publications;Pyrimidine;Reaction;Regulation;Resolution;Resources;Role;Running;STK11 gene;Sampling;Services;Signal Transduction;Sirolimus;Source;Stable Isotope Labeling;Stimulus;Syndrome;TERT gene;TSC1 gene;TSC1/2 gene;TSC2 gene;Technology;Tissues;Triglycerides;Tuberous Sclerosis;Tumor Tissue;Ubiquitination;Xenograft procedure;cancer cell;experimental study;fly;gain of function;genetic manipulation;improved;in vitro Model;in vivo;induced pluripotent stem cell;inhibitor;instrument;instrumentation;jun Oncogene;lipidomics;mTOR Inhibitor;metabolomics;mouse model;multiple omics;multiple reaction monitoring;mutant;novel;novel therapeutics;phosphoproteomics;potential biomarker;programs;protein complex;response;scaffold;stem;success;tandem mass spectrometry;targeted biomarker;targeted treatment;transcription factor;tumor;tumor growth Core B: Mass Spectrometry proteomics metabolmics and lipidomics Core B: NarrativeThe mass spectrometry core will provide proteomics/phosphoproteomics metabolomics and lipidomics servicesfor the three major projects from cancer cells tumor tissue and biological fluids using tandem mass spectrometry(LC-MS/MS). These services will support the discovery of novel pathways and drug targets for Hamartomasyndromes and related cancers stemming from defects in the tuberous sclerosis complex (TCS1-TSC2) genes. NCI 10715603 9/19/23 0:00 PAR-20-077 2P01CA120964-16 2 P01 CA 120964 16 4/24/07 0:00 7/31/28 0:00 ZCA1-SRB-F(M1)S 6354 1898020 "KWIATKOWSKI, DAVID J." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 169663 149913 19750 Core B: Project Summary/AbstractThe mass spectrometry core has expertise in proteomics/phosphoproteomics metabolomics and lipidomicsresources to enable the three major P01 projects achieve success in uncovering the molecular mechanisms ofHamartoma syndromes and related cancers in the TSC1-TSC2 pathways for new drug targets and noveltherapies using tandem mass spectrometry (LC-MS/MS). The core utilizes both high resolution hybrid Orbitrap(Exploris 480 QExactive HF) mass spectrometry and hybrid triple quadrupole (QTRAP 6500/5500) massspectrometry. For proteomics microcapillary tandem mass spectrometry (LC-MS/MS) services will includeprotein complex identification global post-translational modification (PTM) site mapping such asphosphorylation ubiquitination acetylation etc. and the relative and absolute quantification of peptides/proteinsusing both stable isotope labeling (SILAC and TMT) and label-free quantification [spectral counting total ioncurrent (TIC) multiple reaction monitoring (MRM)]. These studies will be performed from cell lines xenografts inaddition to in vivo tissue sources from mouse/human tumors and drosophila models. We have developedexpertise in metabolomics profiling and services will include polar metabolite profiling using selected reactionmonitoring (SRM) with polarity switching to target more than 300 molecules in 15 min. We will profile cells tumortissues and biological fluids using both steady-state profiling and 13C and 15N stable isotope labeled fluxexperiments to determine which metabolic pathways are altered in cells harboring defects in the TSC1/2 relatedpathways. Non-targeted metabolomic profiling by HR-LC-MS/MS will also be performed to discover novelmetabolic targets. Core B will use non-targeted lipidomics based on high resolution mass spectrometry withpolarity switching with novel software to identify more than 1500 lipid ions (phospholipids triglycerides free fattyacids etc.) in less than 30 min. using reversed-phase LC-MS/MS. We will also use recently developed stable13C/15N/18O isotope flux for lipidomics. In addition to running samples for Projects 1-3 Core B has developeda serial-omics technology that utilizes the preparation of a single tisue cell or bodily fluid sample for performingthree different omics (global phosphoproteomics/proteomics metabolomics and lipidomics) via partitioningliquid-liquid extraction layers. We will also continue to develop -omics strategies to overlap model species(drosophila) to cancer cells and tumor tissue to uncover conserved biological interactions for potential biomarkertargets in TSC1/2 and related pathways. +No NIH Category available Accounting;Administrator;Area;Boston;Budgets;Collaborations;Core Facility;Counseling;Effectiveness;Electronic Mail;Facilities and Administrative Costs;Funding;Genes;Goals;Hamartoma;Human Resources;Individual;Institution;Laboratories;Location;Malignant Neoplasms;Medical;Molecular;Monitor;PTEN gene;Pathogenesis;Preparation;Productivity;Progress Reports;Reporting;Research;Research Personnel;STK11 gene;Syndrome;System;TSC1 gene;TSC2 gene;Visit;Work;meetings;member;programs;symposium Core A: Administration Core A: NarrativeThe overall goal of this program project application is to find treatments for the hamartoma syndromes and thecommon cancers in which these same genes (TSC1 TSC2 LKB1 PTEN) are involved. This administrativecore serves a critical function in the administration and facilitation of this overall research program. NCI 10715602 9/19/23 0:00 PAR-20-077 2P01CA120964-16 2 P01 CA 120964 16 4/24/07 0:00 7/31/28 0:00 ZCA1-SRB-F(M1)S 6353 1898020 "KWIATKOWSKI, DAVID J." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 84006 46931 37075 Core A: AbstractAdministrative Core. This administrative Core will have both scientific and organizational responsibilities. Thescientific aspects will be carried out by Dr. Kwiatkowski. He will advise investigators on strategic and technicalissues promote collaboration and contact among projects monitor the functions and effectiveness of the corefacilities and assess the scientific quality and progress of the work. This will require active interactions with allinvestigators on a regular basis. Any scientific problems or organizational issues that arise will be discussedwith the co-PI Dr. Henske. There will be regular meetings with presentations by each PI and an annual all-daymeeting at which Project and Core Investigators will present research progress at a symposium organizedjointly with the DFHCC. Organizational aspects of the PPG will be handled by Dr. Kwiatkowski and theAdministrative Coordinator Mrs. Karen Forti. She will organize all interactions among the projects and thecores including arranging the annual meeting and deal with all other administrative aspects includingpreparations of all progress reports and applications related to this PPG. +No NIH Category available Ablation;Adult;Anabolism;Angiomyolipoma;Apoptotic;Automobile Driving;Brain;Cell Death;Cell Death Induction;Cell Line;Cells;Chromatin;Collaborations;Data;Dependence;Development;Drosophila genus;Epigenetic Process;Event;Family member;Frequencies;Gene Expression;Genes;Genetic Transcription;Genotype;Glutathione;Growth;Hamartoma;Health;Heart;Human;JUN gene;Kidney;Kidney Neoplasms;Knock-out;Libraries;Lung;Lymphangioleiomyomatosis;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Methods;Modeling;Molecular;Mus;Mutate;Mutation;Neoplasm with Perivascular Epithelioid Cell Differentiation;Nuclear;Null Lymphocytes;Organoids;Outcome;Pathogenesis;Pathology;Pathway interactions;Patients;Phenotype;Phosphorylation;Phosphotransferases;Post-Translational Protein Processing;Proteins;Publishing;Renal Angiomyolipoma;Renal Cell Carcinoma;Research;Research Personnel;Resolution;Role;Running;Signal Transduction;Sirolimus;Specificity;Syndrome;System;TFE3 gene;TSC1 gene;TSC1/2 gene;TSC2 gene;Therapeutic;Translating;Tuberous Sclerosis;Tumor Cell Line;Xenograft Model;Xenograft procedure;cancer cell;data sharing;in vivo;inhibitor;jun Oncogene;kinase inhibitor;metabolomics;novel;phosphoproteomics;programs;single-cell RNA sequencing;stem cells;transcription factor;transcriptome sequencing;tumor;tumor growth Project 3: Identifying transcriptional driver genes and targeting transcription in TSC Project 3: NarrativeIn this project we will examine the JUN-AXL pathway in TSC2/TSC1 deficient tumors clarify how MITF/TFEtranscription factors are regulated in TSC null cells and tumors and study how renal organoids derived fromTSC2 null induced pleuripotent stem cells (iPSC) are dependent on transcription factors. This research hasrelevance for all of the tumors that occur in TSC including renal angiomyolipomas andlymphangioleiomyomatosis. In addition this research has potential value for any cancer with TSC gene losswhich is about 2% of all adult cancers. NCI 10715601 9/19/23 0:00 PAR-20-077 2P01CA120964-16 2 P01 CA 120964 16 4/24/07 0:00 7/31/28 0:00 ZCA1-SRB-F(M1)S 6352 1898020 "KWIATKOWSKI, DAVID J." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 792435 456815 335620 Project 3: AbstractIn this project we will examine the transcription factors and expression pathways that drive tumor developmentin tuberous sclerosis complex (TSC). We have published already that transcription is a key dependence forTSC tumors and that MITF is a driver transcription factor for angiomyolipoma (AMLK) development. In additionwe have recently generated a new model of TSC renal AML by inducing renal differentiation in TSC2-/- humaninduced pleuripotent stem cells (hIPSCs) to generate renal organoids. A major cell subset of TSC2-/- renalorganoids have an AML expression phenotype in contrast to control renal-differentiated hIPSCs. In separatestudies we have used single cell RNA sequencing (scRNA-Seq) to characterize the composition of AML athigh resolution and have confirmed the importance of MITF-driven transcription in AML cells. In the currentproposal we will examine the JUN-AXL pathway in TSC tumor development which leads to a novel kinaseinhibitor sensitivity. Using a Drosophila model we will dissect in further detail how mTORC1 regulates Mitfactivity and then translate key findings to mammalian cells. Last we will use the TSC2-/- hiPSC renalorganoid model to identify the transcriptional circuitry required for AML development using scRNA-SeqscATAC-Seq and scChIP-Seq for H3K27ac and MITF. We will also determine the entire panel of transcriptionfactors required for AML cell development using Perturb-Seq applied to the TSC2-/- hiPSC renal organoidmodel. Expected health-related outcomes include identification of multiple potential therapeutic approachesfor both TSC patients and cancers with TSC2/TSC1 mutations. +No NIH Category available Alanine;Algorithms;Back;Binding;Biochemical;Biological;Biophysics;CRISPR/Cas technology;Cell Line;Cells;Cellular Metabolic Process;Clinical Trials;Collaborations;Computer software;Data;Dietary Intervention;Disease;Drosophila genus;Drug usage;Engineering;Enzymes;Event;FRAP1 gene;Family;Folliculin;Funding;Genes;Genetic;Genetic Crosses;Germ-Line Mutation;Glycerol;Growth;Hamartoma;Human;Human Cell Line;Impairment;Knock-in;Knock-out;Lung Neoplasms;Malignant Neoplasms;Metabolic;Metabolic Control;Metabolism;Methods;Molecular;Mus;Mutation;Normal Cell;Nuclear Translocation;Nutrient;Oncogenes;PIK3CG gene;PTEN gene;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Protein Kinase;Proteins;Proteomics;Regulation;Research;Role;STK11 gene;Sampling;Serine;Signal Transduction;Site;Substrate Interaction;Substrate Specificity;Syndrome;TFE3 gene;TSC1 gene;TSC2 gene;Therapeutic;Tissues;Triose-Phosphate Isomerase;Tumor Suppressor Proteins;Work;biomarker development;biomarker driven;cancer cell;cell growth;drug development;fly;gene network;glucose metabolism;lipid metabolism;loss of function mutation;mTOR Signaling Pathway;metabolomics;mosaic variant;mutant;new technology;new therapeutic target;novel;novel therapeutics;phosphoproteomics;pre-clinical;rapid growth;response;transcription factor;tumor Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes Project 2: NarrativeOver the past ten years it has become clear that many tumors rewire their metabolism to support rapid growthbut that the molecular details of how each tumor rewires its metabolism depends on the unique oncogenes andtumor suppressors that dominantly control metabolism which include all of the hamartoma syndrome genesas the PI3K/ mTOR/ LKB1 pathways play a major role in metabolic control in normal and cancer cells.The focus of this project is to better understand metabolic vulnerabilities and to more comprehensively definetherapeutic metabolic targets that would support the development of biomarker driven clinical trials to evaluatesuch drugs in patients with germline or the many tumors containing sporadic mutations in hamartomasyndrome genes (PTEN LKB1 TSC1 TSC2). NCI 10715600 9/19/23 0:00 PAR-20-077 2P01CA120964-16 2 P01 CA 120964 16 4/24/07 0:00 7/31/28 0:00 ZCA1-SRB-F(M1)S 6351 1898020 "KWIATKOWSKI, DAVID J." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 591500 552000 39500 Project 2: AbstractThe hypothesis guiding this proposal is that mutations in hamartoma syndrome genes (PTEN LKB1 TSC1TSC2) dominantly rewire metabolism exposing unique vulnerabilities. The focus of this project is to betterunderstand the molecular and biochemical basis for the metabolic vulnerabilities and provide preclinical datathat would support the development of biomarker driven clinical trials to evaluate such drugs in patients withgermline or the many tumors containing sporadic mutations in hamartoma syndrome genes. We havedecoded the optimal substrate motif for every single mammalian protein kinase in the last funding period andmade an algorithm that allows us to decode which kinases are active or inactive in a given biological samplesbased on unbiased phospho-proteomics. Here we will focus on use of this new method to identify newmetabolic enzymes targeted by LKB1-dependent kinases. The specific aims are: 1) Defining critical kinase-substrate interactions deregulated in hamartoma genes in cell lines and tissues; 2) Defining metabolicvulnerabilities deregulated in hamartoma genes in cell lines and tissues; and 3) Defining how AMPK control ofTFEB contributes to the survival of hamartoma cells and how to target tumors based on new understanding ofthis pathway. +No NIH Category available Adult;Antitumor Response;Atlases;Biochemical Pathway;Cell Culture Techniques;Cell model;Cells;Clinical;Cytostatics;Data;Development;Drosophila genus;Elements;Event;FRAP1 gene;Genetic;Genetic Transcription;Goals;Growth;Growth Factor;Hamartoma;Heart;Human;Inherited;Insulin;Intestines;Kidney;Malignant Neoplasms;Mammalian Cell;Metabolic;Metabolism;Modeling;Molecular;Mus;Nature;Nutrient;PTEN gene;Pathogenesis;Physiological;Proliferating;Property;Protein Kinase;Proteomics;Pyrimidine;Research;Resistance;Role;Signal Transduction;Sirolimus;Substrate Specificity;Syndrome;TSC2 gene;Testing;Therapeutic;Tissue Model;Tissues;Tuberous Sclerosis;Tumor Suppressor Proteins;Validation;analog;antitumor agent;experimental study;fly;improved;in vivo;inhibitor;lipidomics;mTOR Inhibitor;melanoma;metabolomics;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;nucleotide metabolism;pharmacologic;phosphoproteomics;programs;response;stem cells;success;synergism;transcription factor;tumor;tumor growth;tumor metabolism;tumor microenvironment Project 1: Identifying new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation Project 1 NarrativeIn this project we seek to identify novel therapeutic approaches to selectively and safely eliminate tumor cellswith aberrant activation of a common cancer-causing biochemical pathway that contributes to the developmentand progression of both inherited tumor syndromes and the most common forms of cancer. This project lies atthe heart of a larger research program to identify and test new therapies for a broad array of human cancers. NCI 10715599 9/19/23 0:00 PAR-20-077 2P01CA120964-16 2 P01 CA 120964 16 4/24/07 0:00 7/31/28 0:00 ZCA1-SRB-F(M1)S 6350 1898020 "KWIATKOWSKI, DAVID J." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 530842 491341 39501 Project 1 AbstractWhile mTORC1 is activated in a growth factor-independent manner in most human cancers and is believed tocontribute to the uncontrolled anabolic growth of tumors mTOR inhibitors such as rapamycin and its analogs(rapalogs) have had limited clinical success as anti-tumor agents. Furthermore even in settings in whichtumors respond favorably to rapalogs such as with the genetic tumor syndrome tuberous sclerosis complex(TSC) the effects are reversible with rapid tumor regrowth upon halting treatment. This limited response isdue at least in part to the strictly cytostatic nature of rapalogs. In order to identify therapeutic strategies toimprove on mTOR inhibitors in both tumor syndromes and sporadic cancers we must systematically define themolecular response to mTOR inhibitors inherent to cells and tumors. Thus in this project we use bothhypothesis-driven and unbiased omics approaches to reveal the nature and consequences of network-widechanges in transcription (Aim 1) tumor metabolism (Aim 2) and protein kinase signaling (Aim 3) uponmTORC1 activation and inhibition. Our approaches combine reductionist cell and tissue models in Drosophilawhere the mTOR signaling network is very well conserved with syngeneic mouse tumor models driven in partby uncontrolled mTORC1 signaling. Within the broader context of this P01 this project is discovery-based andfoundational to the overarching goal of the program to define and target the signaling network that connectsthe hamartoma syndrome tumor suppressors and mTORC1 impacting both genetic tumor syndromes and themajority of sporadic cancers. The novel candidate targets and mechanisms revealed through our project serveas a key point of integration for all 3 projects. +No NIH Category available Adult;Alleles;Automobile Driving;Bannayan Syndrome;Cell Line;Cell division;Cells;Critical Pathways;Dependence;Development;Drosophila genus;Event;Frequencies;Genes;Genetic;Genetic Transcription;Germ-Line Mutation;Goals;Growth;Hamartoma;Human;Individual;Kidney;Malignant Neoplasms;Metabolic;Modeling;Molecular;Multiple Hamartoma Syndrome;Mutation;Oncogenic;Organoids;PTEN gene;Pathogenesis;Pathway interactions;Peutz-Jeghers Syndrome;Phosphotransferases;Program Research Project Grants;Regulation;Renal Angiomyolipoma;Ruvalcaba syndrome;STK11 gene;Secondary to;Signal Pathway;Signal Transduction;Substrate Interaction;Syndrome;TFE3 gene;TSC1 gene;TSC2 gene;Technology;The Cancer Genome Atlas;Tissues;Tuberous Sclerosis;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States National Institutes of Health;cell preparation;clinical care;gene function;inhibitor;jun Oncogene;loss of function mutation;mTOR Inhibitor;mTOR Signaling Pathway;novel;novel therapeutic intervention;novel therapeutics;programs;response;stem cells;transcription factor;tumor Molecular Pathogenesis of the Hamartoma Syndromes Overall: NarrativeThe overall goal of this program project application is to find treatments for the hamartoma syndromes and thecommon cancers in which these same genes (TSC1 TSC2 LKB1 PTEN) are involved. Please see individualProjects and the Core for each Project Narrative. NCI 10715598 9/19/23 0:00 PAR-20-077 2P01CA120964-16 2 P01 CA 120964 16 "MAAS, STEFAN" 4/24/07 0:00 7/31/28 0:00 ZCA1-SRB-F(M1)S 1898020 "KWIATKOWSKI, DAVID J." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/19/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 2168446 NCI 1697000 471446 Overall - Project Summary/AbstractPlease see each project/core for individual Project Summary/Abstract 2168446 +No NIH Category available Address;Adoption;Aftercare;Age;Area;Assisted Reproductive Technology;Behavior;Behavioral Mechanisms;Behavioral Model;Belief;Cancer Survivor;Cancer Survivorship;Caring;Categories;Child;Clinic;Clinical;Communication;Computer software;Conflict (Psychology);Continuance of life;Control Groups;Counseling;Data;Decision Aid;Decision Making;Distress;Emotional;Emotions;Ensure;Family;Female;Fertility;Fertilization in Vitro;Future;Generations;Goals;Gynecology;High-Risk Cancer;Infertility;Intervention;Intervention Trial;Interview;Knowledge;Legal;Malignant Neoplasms;Mediating;Mediator;Medical;Mission;Modeling;Motivation;Oncology;Online Systems;Pamphlets;Patients;Pilot Projects;Pregnancy;Premature Menopause;Primary Care;Provider;Quality of life;Randomized;Randomized Controlled Trials;Recommendation;Recording of previous events;Reporting;Reproductive Health;Reproductive Medicine;Research;Resources;Risk;Self Efficacy;Surveys;Survivors;Testing;Time;Trauma;Treatment Efficacy;United States National Institutes of Health;Woman;Work;acceptability and feasibility;assigned female at birth;attentional control;cancer therapy;comparison control;cost;efficacy testing;efficacy trial;expectation;experience;family building;fertility preservation;follow-up;future implementation;group intervention;implementation facilitators;implementation intervention;improved;intervention effect;medical specialties;novel;oncofertility;patient-clinician communication;pilot test;preference;pregnant;primary outcome;provider communication;psychosocial;reproductive;secondary outcome;skills;success;surrogacy;survivorship;therapy development;tool;web based decision aid;young adult Testing the efficacy of a decision aid and planning tool for family building after cancer PROJECT NARRATIVEYoung adult female cancer survivors who complete gonadotoxic treatment often need to use assistedreproductive technology or adoption to have a child which have physical/medical emotional financial legaland logistical challenges. Roadmap to Parenthood is a web-based decision aid and planning tool for familybuilding after cancer and across two pilot studies demonstrated positive effects on decisional conflictknowledge self-efficacy and patient-provider communication. The proposed study will test the efficacy of theRoadmap tool to support fertility and family-building decisions and planning behaviors and explore its futureimplementation potential thereby ensuring women are prepared and able to have a child if and when theywant to after cancer. NCI 10715548 9/11/23 0:00 PAR-21-035 1R37CA282148-01 1 R37 CA 282148 1 "ADAMS, LYNN S" 9/8/23 0:00 8/31/28 0:00 Clinical Management in General Care Settings Study Section[CMGC] 11819581 "BENEDICT, CATHERINE " Not Applicable 16 PSYCHIATRY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/8/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 632887 NCI 417918 214969 Project Summary/AbstractUp to 93% of young adult female (YA-F) cancer survivors report fertility distress; 30-46% meet criteria formoderate-severe fertility-related trauma. Gonadotoxic cancer treatments can cause infertility earlymenopause or problems getting pregnant and carrying a pregnancy to term. Family building after cancer oftenrequires in vitro fertilization surrogacy or adoption which have medical/physical psychosocial financial legaland logistical barriers. Prior work shows that YA-Fs are unprepared for the challenges of family building aftercancer have unrealistic expectations (such as overestimating the likelihood of success) and risk missing theirnarrowed reproductive window and experiencing greater difficulty distress and higher costs than expected.The long-term goal of the proposed research is to improve oncofertility care in post-treatment survivorship. Wepropose to test the efficacy of the Roadmap to Parenthood software an interactive web-based decision aidand planning tool for family building after cancer for YA-F survivors (18-45 years old; assigned female at birth)and explore its implementation potential. First we will conduct a rigorous 12-month randomized controlled trial(Aim 1). YA-F cancer survivors (N=256) will be randomized into the (a) Roadmap intervention condition or (b)time and attention control condition that includes a web-based young adult cancer survivorship informationalbooklet. Surveys will be administered at baseline (pre-intervention) and 1- 6- and 12-month follow uptimepoints. We hypothesize the intervention group compared to the control group will report lower decisionalconflict about family building (primary outcome) more planning behaviors aligned with family-building goals(e.g. fertility testing financial planning) and improved quality of life (secondary outcomes). Then we will testmediators and moderators of intervention efficacy (Aim 2). We hypothesize age partnership status fertilitypreservation history and engagement with the decision aid will moderate the relationship between theintervention and decisional conflict and increased levels of knowledge and self-efficacy and improvedcommunication with providers will mediate the intervention effect on decisional conflict. Finally we will evaluatefuture implementation potential of the Roadmap tool in clinical settings (Aim 3). Guided by the Capability-Opportunity-Motivation Behavior (COM-B) implementation model we will conduct qualitative interviews withproviders representing four specialties (N=32; 8 from each) to understand barriers and facilitators to theimplementation of the Roadmap tool across clinics. Providers working in diverse settings in oncology primarycare gynecology and reproductive medicine all of whom address reproductive health clinically will beincluded. Themes related to barriers/facilitators within the categories of capability (e.g. skills knowledge)opportunity (e.g. resources) and motivation (e.g. emotion beliefs) will be identified. This research willcomprehensively respond to the identified needs of YA-F survivors that hope to have a child after cancerthrough a novel intervention that provides information and support for decision making and early planning. 632887 +No NIH Category available Address;Administrative Supplement;Adult;Affect;African American;African ancestry;Asian ancestry;Asian population;B-Cell Lymphomas;B-Lymphocytes;Behavior;Biological;Biological Process;Biology;Breast Cancer Patient;Categories;Caucasians;Cells;Characteristics;Classification;Clinical;Cohort Studies;DNA Sequence Alteration;Databases;Demographic Factors;Development;Diagnosis;Disease;Disease Progression;Disparity;Epigenetic Process;European;Exhibits;Extracellular Matrix;Fibroblasts;Flowers;Gene Expression;Genetic;Genomics;Goals;Immune;Immune response;Immunity;Immuno-Chemotherapy;Incidence;Inflammation;Inflammatory;Insurance Coverage;Knowledge;Link;Lymphoma;Lymphoma cell;Malignant Neoplasms;Malignant lymphoid neoplasm;Modernization;Molecular;Mutation;Outcome;Parents;Patients;Phenotype;Population;Prognosis;Race;Research;Research Personnel;Research Project Grants;Role;Rural;Sampling;Socioeconomic Status;Structure of germinal center of lymph node;Subgroup;Therapeutic;Time;Tumor Biology;Western World;Work;activated B cell like;biobank;cancer cell;cancer subtypes;clinically significant;cohort;epigenome;immune cell infiltrate;interest;large cell Diffuse non-Hodgkin's lymphoma;multi-ethnic;novel;novel therapeutic intervention;outcome disparities;parent grant;prognostic;prognostic value;trait;transcriptomics;treatment response;tumor Role of the stromal microenvironment in B-cell lymphoma progression and immune escape Project NarrativeThe purpose of our studies is to understand the impact of African ancestry in the biology of a common type ofaggressive lymphoma (diffuse large B-cell lymphoma). We will specifically determine how African ancestryaffects the lymphoma immunity by analyzing non-cancer cells that constitute the lymphoma microenvironment.We expect these studies to help explain some potentially modifiable biological aspects related to worseoutcomes in African American patients. NCI 10715434 7/27/23 0:00 PAR-22-114 3R01CA242069-04S1 3 R01 CA 242069 4 S1 "JHAPPAN, CHAMELLI" 12/1/19 0:00 11/30/24 0:00 Special Emphasis Panel[ZRG1(01)-S] 9987337 "CERCHIETTI, LEANDRO C" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 12/1/22 0:00 11/30/23 0:00 396 Non-SBIR/STTR 2023 254250 NCI 150000 104250 PROJECT SUMMARY/ABSTRACTThis project focus in the biology of diffuse large B-cell lymphoma (DLBCL) that are common aggressivemalignancies with a curability rate of 65% despite intensive chemoimmunotherapy. DLBCL represents asignificant clinical problem for disparities research in that it is a potentially curable cancer but one that isuniversally fatal if untreated or improperly treated. Untreated DLBCL patients have an expected survival of <1year whereas with modern standard chemoimmunotherapy >58% of patients are alive and cured at 5 years.The collective work of investigators involved in this administrative supplement demonstrated that despite thehigh cure rates for DLBCL outcomes remain heterogeneous. In fact for DLBCL patients who are of Africanancestry outcomes are significantly worse: in the US African American (AA) patients were diagnosed on average10 years younger more commonly presented with advance stage disease and had worse overall survival thantheir white counterparts. These disparities in lymphoid malignancies sparked interest in elucidating the role ofgenetic ancestry in influencing differences among populations. As proposed in the parent R01 usingtranscriptomic analysis of the lymphoma microenvironment for 4655 DLBCLs we defined four major lymphomamicroenvironment (LME) categories that associate with distinct biological aberrations and clinical behaviorindependently to previously described genomic DLBCL subgroups. All these studies genomic andtranscriptomics have been focused primarily on populations of European descent with no or minimalrepresentation of AA patients. However there remains a gap in knowledge regarding the relationships betweenthe LME and clinical and demographic factors associated with worse survival including AA ancestry rural statusinsurance status and socio-economic status. In this supplement we will close this gap by exploring theserelationships in an AA cohort study characterizing LME subtypes in relation to genomic alterations in cancercells. Thus we propose the following Specific Aims: Specific Aim 1: Elucidate the characteristics of the LME inAA DLBCL patients and the relationship with the epigenome; and Specific Aim 2: Characterize CAF and ECMphenotypes in genetically defined LME DLBCL categories across multiethnic cohort. Our proposal will addressfor the first time the role of the microenvironment in the biology and clinical outcomes in AA DLBCL patients. Wewill determine the influence of race and ancestry in tumor biology and tumor immune responses associated withAfrican ancestry and their potential therapeutic and prognostic implications. 254250 +No NIH Category available Abstinence;Acceleration;Address;Adult;Affect;Barrier Contraception;Behavior Therapy;Behavioral;Black Populations;Cigarette;Clinical Practice Guideline;Collaborations;Control Groups;Data Collection;Effectiveness;Enrollment;Exercise;Failure;Goals;Health;Health behavior;Intervention;Latinx population;Mental Health;Methods;Modeling;Motivation;National Cancer Institute;Outcome;Outcome Measure;Participant;Pattern;Persons;Pharmacological Treatment;Prevalence;Process;Psychology;Public Health;Race;Readiness;Reporting;Research;Self Efficacy;Series;Single-Blind Study;Smiling;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Surveys;Testing;Therapeutic;United States;Withdrawal;Work;behavior test;comparison control;craving;effectiveness testing;efficacious treatment;efficacy testing;health disparity;improved;meetings;novel;pharmacologic;preference;primary endpoint;primary outcome;public health priorities;randomized trial;randomized clinical trials;smartphone application;smoking abstinence;smoking cessation;theories;therapy resistant;treatment duration;treatment guidelines;trial comparing Randomized clinical trial to test the efficacy of a smartphone app for smoking cessation for nondaily smokers Project NarrativeThe goal of this project is to test the effectiveness of a novel behavioral treatment for nondaily smokers;namely a smartphone app that engages app users in positive psychology exercises to bolster their positiveaffect as they undergo the process of quitting smoking. This app has been rigorously and iteratively developedwith and for nondaily smokers. If found effective it would be the first treatment for nondaily smokers found tobe effective. NCI 10715401 8/3/23 0:00 PAR-21-035 1R01CA282223-01 1 R01 CA 282223 1 "REYES-GUZMAN, CAROLYN" 8/3/23 0:00 7/31/28 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 7978890 "HOEPPNER, BETTINA B" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 8/3/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 706777 NCI 452996 253781 Project SummaryNondaily smoking is an increasingly prevalent pattern of smoking with substantial health detriments. Currently25% of all U.S. adult smokers are nondaily smokers and this prevalence has increased by 27% in the lastdecade. Formerly believed to be a transient pattern of smoking research has established that nondailysmoking is often a persistent pattern. Nondaily smoking is more prevalent among Black and Latinx persons inthe United States and is increasingly prevalent among people with serious mental health issues. Despitesubstantial harms associated with nondaily smoking the U.S. Clinical Practice Guidelines for smokingcessation offer no guidance on how to support nondaily smokers in smoking cessation due to a lack ofevidence for efficacious approaches. A continued failure to address nondaily smoking widens existing healthdisparities at an increasingly accelerated rate. Empirically supported interventions are critically needed. Onlytwo trials to date have targeted nondaily smoking cessation. Both focused on pharmacological options andboth failed to show efficacy in achieving smoking abstinence. Our team has developed a behavioral treatmentfor nondaily smokers: the Smiling Instead of Smoking (SiS) smartphone app. This app utilizes positivepsychology exercises to enhance engagement of nondaily smokers and to maintain positive affect while theyundergo a quit attempt. This approach is based on nondaily smokers' preference to focus on positive self-identity and wellness and evidence that shows that greater positive affect is associated with increased self-efficacy to quit smoking decreased desire to smoke and greater readiness to process self-relevant healthinformation all of which are constructs highlighted in dominant health behavior theories as causal agents insuccessful behavioral change. In collaboration with nondaily smokers we have rigorously and iterativelydeveloped and tested this app in a series of small-scale studies. This work has demonstrated the app's abilityto engage nondaily smokers and has shown proof-of-concept efficacy in a small randomized trial whereparticipants using the SiS app had significantly higher self-efficacy lower craving and higher positive affect atthe end of treatment compared to controls. We now propose to test the efficacy of this app to improve 6-monthabstinence in a large-scale single-blind remote parallel randomized clinical trial comparing the SiS app to theNCI's app QuitGuide. All participants will be asked to set a quit date and to use the provided app for 7 weeks1 week prior to and 6 weeks after their quit date. Online surveys will be conducted at enrollment and 2 6 1224 and 52 weeks after the initially chosen quit date. The primary outcome measure will be 30-day pointprevalence abstinence 6 months post quit. If found to be efficacious this study would provide the first evidenceof an efficacious treatment for nondaily smokers for whom currently no treatment guidelines exist. 706777 +No NIH Category available Address;Androgens;Antibodies;Antitumor Response;Arginine;Arginine deiminase;Biological Markers;Biopsy;CD8-Positive T-Lymphocytes;Cancer Biology;Carboplatin;Cell model;Cell physiology;Cells;Citrulline;Clinical Data;Clinical Research;Clinical Trials;Combination Drug Therapy;Combined Modality Therapy;Cytotoxic Chemotherapy;Data;Development;Disease;Dose;Elements;Enzymes;Epithelium;Evaluation;Goals;Human;Immune;Immune system;Immunohistochemistry;Immunology;Ions;Maintenance;Malignant Neoplasms;Malignant neoplasm of prostate;Mass Chromatography;Mass Spectrum Analysis;Measures;Mediating;Metabolic Pathway;Metabolism;Mus;Neoplasm Metastasis;Nitric Oxide;Outcome;Participant;Pathway interactions;Patients;Phagocytosis;Phase;Phase I/II Trial;Phenotype;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Polyamines;Population;Positioning Attribute;Pre-Clinical Model;Prognosis;Proteins;Reporting;Role;Safety;Sampling;Series;Serum;Signal Pathway;Signal Transduction;Signaling Molecule;Subjects Selections;T cell infiltration;Technology;Time;Tissues;Tumor-associated macrophages;Variant;Vertebral column;Virulence;advanced prostate cancer;anti-PD-1;argininosuccinate synthase;biomarker identification;chemotherapy;digital;effective therapy;effector T cell;experimental study;extracellular;immunoregulation;improved;inhibitor;men;mouse model;peripheral blood;pre-clinical;preclinical study;prospective;prostate cancer cell;prostate cancer cell line;response;single-cell RNA sequencing;synergism;targeted treatment;taxane;treatment effect;trial design;tumor;tumor metabolism;tumor microenvironment;tumor-immune system interactions Effects of Arginine Depletion Combined with Platinum-Taxane Chemotherapy in Aggressive Variant Prostate Cancers (AVPC) PROJECT NARRATVEAggressive variant prostate cancers (AVPC) respond to carboplatin+cabazitaxel but remain with a poorprognosis. We propose a tissue-rich clinical trial and co-clinical studies in mice combining ADI-PEG20 (whichdepletes serum arginine levels) with carboplatin+cabazitaxel to evaluate the safety efficacy and effects of thiscombination on intratumoral metabolites signaling pathways and immune profiles of the AVPC tumormicroenvironment. The results of these studies will serve to inform further rational combinations for the treatmentof the AVPC. NCI 10715329 9/20/23 0:00 PAR-21-033 1R01CA283402-01 1 R01 CA 283402 1 "SONG, MIN-KYUNG H" 9/21/23 0:00 8/31/28 0:00 Clinical Oncology Study Section[CONC] 9011566 "APARICIO, ANA " "FRIGO, DANIEL EDWARD; SHARMA, PADMANEE " 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 636578 NCI 414999 221579 PROJECT SUMMARY/ABSTRACT Androgen indifferent prostate cancers account for a large proportion of the disease lethality and havelimited therapy options partly due to the lack of identifying biomarkers. To address the unmet need ofdeveloping effective therapies for this subset we defined the aggressive variant prostate cancers (AVPC)criteria. Through a series of prospective trials and studies in mice we showed that the AVPC criteria can enrichfor prostate cancers that respond poorly to androgen inhibition and benefit from adding carboplatin tocabazitaxel. In recent trials we examined the contribution of PARP inhibitor maintenance and of anti-PD1inhibition to the chemotherapy backbone in men with AVPC. Early data show meaningful improvements inoutcomes with these additions but many men with AVPC are still progressing rapidly. Our overall goal is toarrive at rational biologically-based combination therapies that effectively treat the AVPC. The analysis of samples from our trial participants and preclinical studies converge on altered argininemetabolism as a key metabolic pathway in androgen-indifferent prostate cancer biology. We also foundevidence of argininosuccinate synthase 1 (ASS1) silencing with platinum chemotherapy in AVPC cell linesand patient samples. ASS1 deficiency renders cells dependent on extracellular arginine and thus sensitive toarginine depletion with agents such as PEGylated arginine deiminase (ADI-PEG20). ADI-PEG20 depletesserum arginine levels has activity in several malignancies (alone and in combination with chemotherapy) andhas immunomodulatory effects. However the effects of serum arginine depletion on intratumoral metabolitelevels in patients are unknown and its effects on the human immune tumor microenvironment (TME) remainpoorly understood. We hypothesize that the addition of ADI-PEG20 will improve the efficacy ofcarboplatin+cabazitaxel by modifying intratumoral arginine metabolism and immune profiles in theAVPC TME. In AIM 1 we will conduct a phase I/II dose escalation trial to identify the optimal dose (in terms of safety andefficacy) of ADI-PEG20 to combine with carboplatin+cabazitaxel in men with AVPC. In AIM 2 peripheral bloodand metastatic tumor biopsies obtained from trial participants at baseline after 1 and after 6 cycles of treatmentand at parallel time-points in PDX and syngeneic mouse models will be used to measure associations between:(a) serum levels of arginine and citrulline (b) intratumoral levels of arginine (c) ASS1 expression and (d) theexpression of other arginine metabolism enzymes and (e) outcomes. In AIM 3 we will examine the effects oftreatment on immune profiles and immune cell distribution within the TME. Our studies will provide a comprehensive evaluation of the effects of serum arginine depletion on the immuneand non-immune AVPC TME shed light on the mechanisms of synergy between ADI-PEG20 and cytotoxicchemotherapy and ultimately serve to prioritize rational combinations for the treatment of the AVPC. 636578 +No NIH Category available Address;Adult;Behavior Therapy;Caregivers;Characteristics;Child;Child health care;Childhood;Clinic;Clinic Visits;Clinical;Clinical Decision Support Systems;Clinical Informatics;Communities;Control Groups;Cotinine;Data;Decision Support Systems;Effectiveness;Electronic Health Record;Enrollment;Evidence based treatment;Exposure to;Family;Funding;Healthcare;Home;Household;Individual;Interdisciplinary Study;Intervention;Low income;Measures;Medicaid;Methods;Office Visits;Outcome;Parents;Patients;Persons;Positioning Attribute;Pragmatic clinical trial;Primary Care;Public Health Informatics;Randomized Controlled Trials;Recommendation;Reporting;Research Proposals;Respondent;Smoke;Smoking;Source;Surgeon;Surveys;System;Testing;Tobacco;Tobacco use;Underserved Population;United States Dept. of Health and Human Services;United States Preventative Services Task Force;Visit;Work;arm;compare effectiveness;effectiveness/implementation design;environmental tobacco smoke;environmental tobacco smoke exposure;ethnic minority population;evidence base;health care settings;health equity;implementation intervention;implementation strategy;informatics tool;innovation;medically underserved;member;nicotine replacement;novel;pediatric patients;pediatrician;population based;population health;pragmatic trial;quitline;racial minority;socioeconomics;tobacco advertising;treatment as usual;underserved community Refer 2 Quit: Proactive Promotion of Tobacco Use Treatment for Underserved Household Members Who Smoke through Pediatric Primary Care Project NarrativeRacial and ethnic minority groups and those from low socioeconomic groups suffer disproportionately from theeffects of tobacco marketing have less access to evidence-based treatments for tobacco use and reportneeding more support for cessation efforts. Pediatricians are uniquely positioned to help medicallyunderserved families to address smoking and protect children from secondhand smoke (SHS) exposure but amajor barrier to protecting children from SHS exposure and extending tobacco use treatment to underservedadults who smoke is identifying an effective and scalable method to engage all household members whosmoke not just parents who present to the pediatric clinic with the child. To address this barrier we willconduct a pragmatic trial through a large urban pediatric network to evaluate a novel proactive interventionthat uses population health and clinical informatics implementation strategies to increase the reacheffectiveness and health equity of tobacco use treatments for underserved families. NCI 10715232 7/31/23 0:00 PAR-21-035 1R37CA282153-01 1 R37 CA 282153 1 "RODITIS, MARIA LEIA" 9/1/23 0:00 8/31/28 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 9359702 "JENSSEN, BRIAN P." Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 779874 NCI 442640 337234 Project Summary/AbstractRacial and ethnic minority groups and those from low socioeconomic groups suffer disproportionately from theeffects of tobacco marketing have less access to evidence-based treatments for tobacco use and reportneeding more support for cessation efforts. Pediatricians are uniquely positioned to help medicallyunderserved families to address smoking and protect children from secondhand smoke (SHS) exposure butappropriate treatments are rarely delivered to parents who smoke. Emerging clinical decision support (CDS)systems within electronic health records (EHRs) including those developed by this team help pediatriciansscreen for SHS exposure motivate parent treatment engagement and prescribe and/or connect caregivers totobacco interventions. Office-based approaches however focus only on caregivers attending clinic visits withtheir children failing to reach additional household members who smoke leaving many adults without accessto evidence-based treatments and children continually exposed to detrimental effects of SHS. Thus a majorbarrier to protecting children from SHS exposure and extending tobacco use treatment to underserved adultswho smoke is identifying an efficient and scalable method to engage all household members who smoke notjust parents who present to the pediatric clinic with the child. This proposal uses an innovative multi-disciplinary research approach incorporating both population health and clinical informatics implementationstrategies to overcome this barrier and systematically expand the reach of tobacco use treatment throughpediatric healthcare settings. EHR-based informatics tools can efficiently identify additional householdmembers who smoke and proactively offer tobacco treatment. Using a rigorous 2-arm pragmatic randomizedcontrol trial within a large pediatric network comprising practices with high rates of Medicaid-insured childrenwe will compare a novel intervention using population health and clinical informatics implementationstrategies vs. usual care to increase the reach effectiveness and health equity of tobacco use treatments.We will use a Type 2 hybrid effectiveness-implementation design measuring the clinical intervention's impacton priority outcomes and testing an implementation strategy. The specific aims are: Aim 1) To compare thereach of Refer2Quit - a proactive population health and clinical informatics implementation intervention ontobacco use treatment engagement for household members who smoke vs. usual care; Aim 2) To compare theeffectiveness of the Refer2Quit intervention for increasing quit rates among household members who smokevs. usual care; and Aim 3) To study household member and pediatric patient characteristics that areassociated with reach and effectiveness of Refer2Quit. This addresses a significant practice gap in theutilization of evidence-based treatments for tobacco particularly for underserved populations. Leveraging thepediatric setting can increase access and use of evidence-based tobacco treatments. This proposal will yield ascalable strategy to address the impacts of tobacco use within under-served communities. 779874 +No NIH Category available 3-Dimensional;Acoustics;Address;Algorithms;Anatomy;Anxiety;Arteries;Biopsy;Blood Vessels;Brain;Brain imaging;Breast;Breast Cancer Detection;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer therapy;Breast conservation;Calibration;Cancer Burden;Cities;Clinical;Contrast Media;Data;Detection;Diagnostic;Dimensions;Discrimination;Elasticity;Emerging Technologies;Engineering;Evaluation;Feasibility Studies;Frequencies;Functional Imaging;Heavy Metals;Hemoglobin;Human;Image;Imaging Techniques;Imaging problem;Imaging technology;Intravenous;Ionizing radiation;Light;Lilium;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Metabolic;Methods;Modeling;Morphologic artifacts;Morphology;Motion;Neoadjuvant Therapy;Operative Surgical Procedures;Optics;Outcome;Oxygen;Pathology;Patients;Performance;Physicians;Prognosis;Resected;Resolution;Resources;Sampling;Scientist;Side;Signal Transduction;Specimen;Speed;Surgical Pathology;System;Technology;Testing;Three-Dimensional Imaging;Time;Tissues;Training;Tumor Volume;Ultrasonography;X-Ray Computed Tomography;anatomic imaging;breast imaging;contrast enhanced;cost;cost effective;density;design;diffuse optical spectroscopy and imaging;exceptional responders;experience;imaging modality;imaging system;improved;improved outcome;innovation;malignant breast neoplasm;model building;new technology;non-invasive imaging;optoacoustic tomography;patient oriented;performance tests;personalized cancer therapy;photoacoustic imaging;precision medicine;predicting response;prognostic;prospective;prototype;research clinical testing;respiratory;response;standard of care;success;tomography;treatment planning;treatment response;tumor Advancing Photoacoustic Tomography in breast imaging to predict response in breast cancers treated with neoadjuvant therapy PROJECT NARRATIVEOftode-escalatinginvasivetomography neoadjuvant therapy (NAT). These outcomes result in a decrease in cancer burden by improving prognosissurgery and enabling response-driven precision medicine. To address the need for reliable non-imaging method to identify responseprototypes into one system.critical importance to improving outcomes for breast cancer patients is identifying who respondswe propose to integrate two photoacoustic computed NCI 10715163 7/3/23 0:00 PA-20-185 1R01CA282505-01 1 R01 CA 282505 1 "WU, YICONG" 7/3/23 0:00 6/30/28 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 8449556 "LAI, LILY LAU" Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 7/3/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 643569 NCI 589490 54079 PROJECT SUMMARY/ABSTRACTObjective: We will develop an advanced photoacoustic computed tomography (PACT) breast imaging systemcapable of detecting anatomical and functional changes in breast cancer treated with neoadjuvant therapy(NAT).Significance: NAT improves outcomes in breast cancer patients by increasing the likelihood of breastconservation providing important prognostic information and enabling adaptive therapy such as change insystemic treatment and de-escalation of surgery in exceptional responders. As such identification ofresponders enables personalized cancer treatment.Challenges: Current breast imaging does not sufficiently detect breast cancer treatment response. Standardof care (SOC) breast imaging technology either assesses anatomical details or metabolic function not both. Inaddition ionizing radiation exogenous contrast agents and patient perceived discomfort and inconvenienceusually restrict imaging frequency required for timely evaluation of response. For example although dynamiccontrast-enhanced magnetic resonance imaging (DCE-MRI) is considered the SOC in breast imaging this testis limited by the need for intravenous heavy metal contrast duration of study patient discomfort and highresource costs while delivering only moderate accuracy in detection of NAT response. As such thereisnoreliablenon-invasive cost-effective imaging method to identify treatment response.PACT is an emergingtechnology with great potential to address these problems by imaging both function and anatomy withoutexogenous contrast.Solutions: Capitalizing on our experience and success in building two PACT breast imaging systems wepropose the construction and clinical testing of an innovative PACT imaging system that integrates the twoprevious systems to enable both anatomical and functional imaging. The Dual Mode PACT (DM-PACT) willcombine dual-sided light delivery large-view detection aperture and dense acoustic sampling for rapidfunctional and high-resolution anatomical imaging to assess treatment-related responses in breast cancer. Theimaging features generated by the DM-PACT will be first characterized and correlated with thehistopathological results of the resected breast cancer specimens from patients treated with NAT. A diagnosticmodel using the imaging features will be trained and tested in a larger group of breast cancer patients treatedwith NAT. We will compare the performance of DM-PACT with the performance of SOC DCE-MRI in treatmentresponse discrimination. The success of this project will result in imaging technology that directs response-driven personalized breast cancer treatment plans. 643569 +No NIH Category available Adolescent;Adult;Antibodies;Antigens;Biological;Bone neoplasms;Brain Neoplasms;Caring;Cell Therapy;Cells;Child;Childhood Leukemia;Childhood Solid Neoplasm;Chromatin;Clinical;Clinical Trials;Combination Drug Therapy;Common Neoplasm;Credentialing;Data;Development;Diagnosis;Diffuse intrinsic pontine glioma;Disease;Drug Targeting;Engineering;Enzymes;Epigenetic Process;Ewings sarcoma;Failure;G(M2) Ganglioside;Ganglioside GD2;Gangliosides;Genetic Engineering;Genetic Transcription;Glycolipids;Goals;Heterogeneity;Immune checkpoint inhibitor;Immune response;Immunotherapeutic agent;Immunotherapy;In Vitro;Late Effects;Left;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Metastatic Ewing's Sarcoma;Methods;Modeling;Molecular;Mutation;Neuroblastoma;Operative Surgical Procedures;Pathway interactions;Patients;Radiation therapy;Receptor Signaling;Recurrence;Recurrent disease;Regulation;Relapse;Repression;Safety;Sampling;Signal Transduction;Solid Neoplasm;Surface;Survival Rate;T cell response;T-Lymphocyte;Testing;Tissues;Toxic effect;Translating;ZAP-70 Gene;advanced disease;bone;cancer cell;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;combinatorial;exhaustion;gene translocation;improved;in vivo;inhibitor;insight;leukemia relapse;leukemia/lymphoma;mouse model;neoplastic cell;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;postnatal;primary bone cancer;relapse prevention;resistance mechanism;response;sialogangliosides;sugar;tumor;young adult Immunotherapeutic targeting of gangliosides in Ewing Sarcoma Project Narrative:Ewing sarcoma is the second most common bone tumor occurring in children but there have been no improvements in treatments or survival rates for more than a decade for patients with advanced disease. While immunotherapy with chimeric antigen receptor (CAR) T cells has mediated major advances in pediatric leukemia it has not yet proven effective in Ewing sarcoma. We will explore approaches to apply CAR T cells targeting the validated target GD2 and other ganglioside targets to treat this highly recalcitrant pediatric cancer. NCI 10715119 9/19/23 0:00 RFA-CA-22-016 1U01CA281840-01 1 U01 CA 281840 1 "SINGH, ANJU" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-A(M1) 14980986 "MAJZNER, ROBBIE G." "STEGMAIER, KIMBERLY " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 795150 NCI 450000 345150 Project SummaryEwing sarcoma (EWS) is the second most common tumor involving bone in children and young adults and isfatal in most patients with metastatic or relapsed disease. Patients who survive are left with a lifetime of lateeffects from the toxic therapy they receive. There have been no new successful targeted drugs developed totreat EWS for nearly forty years and we have reached the limit on how much we can intensify chemotherapytreatments. New therapeutic approaches are necessary to prevent relapse and cure more patients.Immunotherapy has altered the treatment landscape for many adult solid tumors but has not yet mediatedsubstantial benefit for children with EWS. Chimeric antigen receptor (CAR) T cells have revolutionized thetreatment of children with relapsed leukemia and lymphoma. Recently we found that CAR T cells targeting GD2a sugar expressed on the surface of many pediatric cancers are active in children with incurable brain tumors.This proposal focuses on applying GD2 CAR T cells to EWS. Because GD2 is heterogeneously expressed onEWS we will explore multiple mechanisms to effectively apply CAR T cells in this disease: 1) targeting a closelyrelated ganglioside that is highly expressed when GD2 is low and 2) utilizing epigenetic inhibitors to significantlyincrease GD2 making CAR T cells better able to recognize tumor cells. In Aim 1 we will define the expressionof gangliosides and their related synthase enzymes on patient tissues and test CARs against an alternativeganglioside. In Aim 2 we will utilize epigenetic inhibitors to increase GD2 on EWS tumors in vitro and in vivo. InAim 3 we will test combinatorial approaches of CAR T cells and epigenetic inhibitors. Successful completion ofthese studies will result in new therapeutic options for children with Ewing sarcoma. 795150 +No NIH Category available Acceleration;Accreditation;Area;Biological Markers;Biology;Cancer Biology;Clinical;Clinical Medicine;Clinical Trials Design;Collaborations;Combined Modality Therapy;Communication;Competence;Complex;Data;Data Science;Development;Discipline;Doctor of Philosophy;Ensure;Environment;Face;Faculty;Fellowship Program;Fostering;Foundations;Funding;Future;Goals;Image;Individual;Informatics;Interdisciplinary Study;International;Language;Leadership;Learning;Machine Learning;Malignant Neoplasms;Medical;Mentors;Methodology;Methods;Modeling;Modernization;Molecular Biology;Molecular Immunology;Oncology;Pathway interactions;Persons;Physicians;Physics;Process;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Radiobiology;Relapse;Research;Research Design;Research Personnel;Resource Development;Resources;Role;Science;Scientific Advances and Accomplishments;Series;Societies;Students;Technology;Time;Training;Training Programs;Tumor Biology;Tumor-Derived;United States National Institutes of Health;Universities;Visualization;Washington;Work;biomedical informatics;cancer imaging;career development;certificate program;clinical translation;cohesion;data management;data visualization;design;digital;interdisciplinary collaboration;learning materials;meetings;multidisciplinary;programs;radiation resistance;scientific organization;skills;success;symposium;theories;tool;treatment planning;tumor;tumor microenvironment;tumor-immune system interactions;virtual METEOR-Integrated Training Environment (METEORITE) n/a NCI 10715026 8/23/23 0:00 RFA-CA-22-046 1U54CA274318-01A1 1 U54 CA 274318 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 6173 6379463 "HUGO, GEOFFREY D" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 79419 51073 28346 Project SummaryThrough existing advances in the field of radiation oncology it has become clear that success is bestachieved when experts in biology physics and clinical medicine collaborate. However as technologyand treatment paradigms grow more complex it has become increasingly difficult for experts tomaintain cutting-edge specialization in their own specific discipline and at the same time converge tofacilitate multi-disciplinary collaboration. While current graduate training does expose trainees to fieldsoutside their own this exposure is insufficient to develop meaningful research collaborations acrossthe modern oncology workforce. A formal training program that can provide both breadth and depth inthe theme areas of tumor biology tumor immune microenvironment advanced imaging and treatmenttechnologies and informatics is needed to allow trainees to develop a set of common cross-disciplinaryfundamentals that can then be used to accelerate multidisciplinary research in radiation oncology.Given the amount of data generated in the fields of cancer biology medical physics and clinicalradiation oncology we envision that our ROBIN program cross training core METEORITE (METEORIntegrated Training Environment) will use data science and informatics as the common language tofacilitate communication and promote interdisciplinary collaboration with the ultimate goal of leveragingthis model across the ROBIN network to increase collaboration among the larger oncology workforce.In Aim 1 we will first develop an interdisciplinary training program within our own METEOR ROBINCenter by integrating pre-existing courses and established training programs to support METEOR andrelated science. Trainees will develop an individualized training pathway that will allow them to partakein common coursework while also customizing their learning. In Aim 2 we will develop new digitalcontent resources for key high need topics such as clinical trial design and the fundamentals of TMEfor non-specialists to be used within METEORITE but also disseminated across the wider ROBINnetwork. Finally in Aim 3 we will develop and host both in-person and virtual seminar series andsymposia to promote trainee cohesion within METEOR and across the ROBIN network. The goal ofthese seminar series and symposia is to develop leadership skills among ROBIN network trainees andalso to ensure our developed content can be disseminated and used to promote interdisciplinarycollaboration in the future workforce. Through funding of METEORITE we will generate resources andcareer development expertise that will facilitate a future NIH T32 application focused on trainingdisseminating and advancing multidisciplinary informatic partnerships radiation oncology. +No NIH Category available Address;Adopted;Algorithmic Analysis;Atlases;Biological;Cells;Clinical Data;Collaborations;Collection;Data;Data Analyses;Data Sources;Databases;Digital Imaging and Communications in Medicine;Dose;Ecosystem;Ensure;FAIR principles;Genomic Data Commons;Genomics;Health;Health Insurance Portability and Accountability Act;Human;Image;Informatics;Institution;Link;Manuals;Measures;Metadata;Multiomic Data;Online Systems;Outcome;Patients;Phenotype;Process;Productivity;Proteomics;Radiation Oncology;Radiation therapy;Reproducibility;Research;Resource Sharing;Sampling;Secure;Specimen;Structure;System;TRUST principles;Tissues;Universities;Visualization;Washington;data ecosystem;data format;data ingestion;data integration;data management;data repository;data sharing;design;educational atmosphere;experimental study;genomic data;image archival system;innovation;metabolomics;multiple data sources;multiscale data;open data;tool;transcriptomics;tumor;user-friendly;web based software METEOR-Data Synthesis and Transfer (METEOR-DST) n/a NCI 10715025 8/23/23 0:00 RFA-CA-22-046 1U54CA274318-01A1 1 U54 CA 274318 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 6172 9758086 "LAI, ALBERT M" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 148471 95480 52991 METEOR-DST SUMMARYThe METEOR Data Synthesis and Transfer (DST) shared resource provides expertise and systems forsynthesizing data from across all data sources in METEOR and enabling the ability to transfer the synthesizeddata into the larger NCI Data ecosystem and repositories. DST addresses the critical issue of aggregating multi-omics data imaging radiotherapy and clinical data as well as enabling these data to be shared in a user-friendlymanner. With the successful completion of the aims outlined we will ensure that the collection and managementof patient-derived data is performed in a manner consistent with FAIR and TRUST principles.We will augment CIELO a HIPAA-secure open science platform for health research to support the workflowsand data types needed for ROBIN. CIELO allows diverse end-users to share discover and adapt/adoptbundles of health information such as multi-scale longitudinally defined phenotypes. This will serve as acomprehensive and end-to-end solution for enabling Trans-ROBIN data-centric research collaborationsinvolving multiple ROBIN Centers and beyond. We will add: (1) the capability to ingest the data from multiplesources and then harmonize and integrate the data by creating consistent identifiers for patients tissues andsample; (2) API-based interfaces with a number of internal platforms and systems such as REDCap XNATOpenSpecimen and institutional EHR warehouse; (3) addition of support for external data export to other datarepositories in the NCI data ecosystem.We will deploy and enhance XNAT to support imaging and radiation therapy data in ROBIN and integrate withCIELO. XNAT is a web-based software platform designed to facilitate common management and productivitytasks for imaging and associated data. It consists of an image repository to store raw and post-processedimages a database to store metadata and non-imaging measures and user interface tools for accessingquerying visualizing and exploring data. We will enhance XNAT to store radiation therapy DICOM formats (RTStructure Set RT Dose Segmentation Objects) and to visualize radiation therapy annotations in XNATs web-based imaging viewer. We will fully integrate XNAT with CIELO via XNATs extensive REST API.We will ensure that the collection and management of patient-derived data is performed in a manner consistentwith FAIR and TRUST principles. All METEOR data (eCRFs biospecimen availability & characterization) will beaggregated into CIELO and XNAT using REST interfaces and automated data extraction from our ResearchData Core as well as manual upload capabilities. Processed results of the METEOR-BLST teams genomicstranscriptomics proteomics and metabolomics analyses including bulk single-cell and spatial experimentswill be uploaded into CIELO. +No NIH Category available Adherence;Aftercare;Atlases;Bioinformatics;Biological;Biological Assay;Biological Response Modifier Therapy;Blood specimen;Cataloging;Cervix Neoplasms;Clinical;Collaborations;Comprehensive Cancer Center;Computer Analysis;Core Facility;Custom;Data;Data Analyses;Data Reporting;Development;Disease;Educational process of instructing;Ensure;Extramural Activities;Faculty;Feedback;Foundations;Funding;Human;Image;Institution;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mentorship;Mission;Modeling;Molecular;Nuclear;Patients;Pre-Clinical Model;Procedures;Process;Proteins;Proteomics;Quality Control;Radiation therapy;Radiobiology;Reproducibility;Resource Sharing;Sampling;Scientist;Signal Pathway;Specimen;Statistical Data Interpretation;Technology;Testing;Time;Training;Translations;United States National Institutes of Health;Universities;Washington;cancer genomics;chemoradiation;data management;data quality;design;empowerment;exome sequencing;experience;innovation;insight;instrumentation;medical schools;metabolomics;mid-career faculty;multimodality;multiple omics;neoplastic cell;operation;pancreatic neoplasm;patient derived xenograft model;personalized medicine;protein function;radiomics;radioresistant;sample collection;standard of care;transcriptome sequencing;tumor;tumor microenvironment;tumor-immune system interactions METEOR-BioLogical Specimen Translation (METEOR-BLST) n/a NCI 10715024 8/23/23 0:00 RFA-CA-22-046 1U54CA274318-01A1 1 U54 CA 274318 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 6171 10230204 "MAJOR, MICHAEL BENJAMIN" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 422630 271788 150842 The BioLogical Specimen Translation (BLST) Shared Resource of the METEOR ROBIN Center was designedin concert with the leaders of both Projects the METEORITE cross straining core and the CRATR MolecularCharacterization Trial. The BLST shared resource provides expertise instrumentation and computationalanalyses for the full multimodal molecular characterization of cervical and pancreas tumor specimens beforetreatment in-treatment and after treatment with radiation therapy. In doing so the BLST will empower theprojects and CRATR to test the global hypothesis that standard of care chemo-radiation therapy (CRT) remodelsthe tumor microenvironment to support the survival and expansion of radiation resistant tumor cells. We willprovide instrumentation and proven experience for the following characterizations: 1) RNAseq and whole exomesequencing 2) single nuclear snRNAseq and single nuclear snATACseq 3) targeted SureQuant protein massspectrometry 4) NIMS-based spatial metabolomics and 5) spatial proteomics by CODEX. The BLST is not astand-alone core facility but rather functions integratively and synergistically across METEOR. Tumor and bloodsamples originate within the CRATR molecular characterization trial and from pre-clinical models within theProjects. The BLST will ensure sample quantity quality storage and tracking before analysis. Through a suiteof pipelined commercial and custom computation raw data produced in the BLST will be searched statisticallyscored integrated and bioinformatically analyzed. Raw and processed data will be transferred to the DataManagement DST shared resource for further integration with clinical annotation and radiomics as well as forstorage and dissemination across the ROBIN consortium. Reciprocally the DST shared resource will providereal-time feedback to the BLST for on-the-fly prioritization and pipeline adjustments. A direct line between theBLST and Projects enables real-time integration in guiding biological insight. Finally the BLST will directlyempower the Cross Training Core through associated faculty teaching and mentorship as well as by providingvarious datatypes for trainee processing integration and interpretation. To accomplish these objectives wethematically organized the BLST across two Specific Aims. In Specific Aim #1 we will leverage optimizedworkflows to extract and comprehensively detect and quantify biomolecules from the METEOR CRATR clinicalsamples. As planned the BLST will process: 15 samples for combined scRNAseq and scATACseq 155 samplesfor scRNAseq 70 samples for SureQuant targeted MS 115 samples for NIMS metabomic imaging and 85 forCODEX spatial proteomics. In Specific Aim #2 we will ensure adherence to principles of rigor and reproducibilityand transparency. Data points will be integrated across platforms space and time. Bioinformatic enrichmentanalyses will be used to annotate the resulting maps including responding signaling pathways protein functionsdruggability and disease associations. Finally the BLST will collaborate across ROBIN centers to share itsexpertise and for continued optimization data reporting and discovering of radiation biology. +No NIH Category available Address;Animal Model;Antigens;Biology;Bone Marrow;Cell Count;Cell Differentiation process;Cell Survival;Cell physiology;Cells;Cellular Immunity;Cellular Metabolic Process;Clinical;Correlative Study;Cross Presentation;Data;Dendritic Cells;Development;Exclusion;Foundations;Functional disorder;Genetically Engineered Mouse;Heterogeneity;Human;Hypoxia;Immune;Immune checkpoint inhibitor;Immunity;Immunotherapy;Impairment;Infiltration;Institution;Lead;Limes;Malignant Neoplasms;Malignant neoplasm of pancreas;Metabolic;Metabolism;Myeloid Cells;Myeloid-derived suppressor cells;Myelopoiesis;Natural Immunity;Nature;Pancreatic Ductal Adenocarcinoma;Patients;Phenotype;Pre-Clinical Model;Primary Neoplasm;Productivity;Prognosis;Prospective cohort;Proteins;Publishing;Radiation Oncology;Radiation therapy;Regulation;Reporting;Research Project Grants;Role;Shapes;Signal Transduction;Stimulant;Stromal Cells;T cell infiltration;T cell response;T-Lymphocyte;Testing;Tissue Banks;Tissue Engineering;Tissue Model;Tissues;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Tumor-Derived;Universities;Washington;cancer cell;cancer type;checkpoint therapy;chemotherapy;density;human imaging;human tissue;immune cell infiltrate;improved;metabolic imaging;metabolic profile;metabolomics;mouse model;neoplastic cell;radiation effect;radiation response;response;targeted treatment;transcriptome sequencing;tumor;tumor microenvironment Research Project Pancreatic Cancer n/a NCI 10715023 8/23/23 0:00 RFA-CA-22-046 1U54CA274318-01A1 1 U54 CA 274318 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 6170 8710339 "DENARDO, DAVID G" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 312270 200817 111453 PROJECT 2 (PANCREAS) SUMMARYThe prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately attempts atimmunotherapy for PDAC to date have not achieved significant clinical benefits. It is widely accepted thatradiation therapy (RT) can prime anti-tumor immunity by releasing tumor-derived antigens and danger signalsand this immune priming effect has a crucial role in RT efficacy in multiple cancer types. In contrast combiningRT with checkpoint immunotherapy has been generally underwhelming in PDAC. It is unclear if this reflects aninability of RT to prime tumor-specific T cells or a need for additional stimulants that are supportive of T-cellpriming. Dendritic cells (cDCs) are central for generating tumor antigen-specific T-cell responses. In animalmodels and human correlative studies cDCs are crucial for responsiveness to checkpoint immunotherapy andRT-induced tumor immunity. Our hypothesis is that RT drives divergent effects on local and systemic tumorimmunities through regulation of cDCs. We will directly address this hypothesis focusing on how DCs andT-cell responses are co-shaped during SOC RT. We will use a combination of scRNAseq spatially resolvedprotein metabolomic profiling in human PDAC tissues and mouse models to test the following. In Aim 1 we willdetermine the local and systemic impacts of RT on local immune priming by cDCs. These studies will use acombination of longitudinally collected human tissues from patients undergoing SBRT and geneticallyengineered mouse models (GEMMs) to assess the impact of RT on DC phenotype and function. Leveraging ourinstitutional strengths we will conduct these studies in three cohorts of prospective and retrospective tissuecollections from human PDAC patients receiving SBRT and conduct mechanistic studies using PDAC GEMMs.These studies will assess the local impact of SBRT on cDC function. In Aim 2 we will determine the impact ofRT on cDC differentiation and systemic immunity in PDAC patients. Our data in both human PDAC patients andmouse models demonstrated that key differences in myelopoiesis and cDC development in PDAC can impairtumor immunity. Furthermore our preliminary data indicated that SBRT could alter cDC development andphenotype. In this aim we will use a combination of human tissues and GEMMs to specifically study how RTsimpact systemic DC development phenotype and function and the net impact this has on tumor immunity andT-cell priming in response to RT. In Aim 3 we will determine the impact of RT on interactions between regionalmetabolism and cDC-directed T-cell immunity. RT can have a dramatic impact on tumor and stromal cellmetabolism. In parallel these metabolic changes can regulate cDC and T-cell survival and function. Howeverthese interactions have not been well studied in the context of intact PDAC tissues where regional heterogeneityin immune infiltrate hypoxia and stromal density are dominant players. We will therefore use multiple orthogonalapproaches including CODEX NIMS and advanced imaging of human PDAC tissues to spatially resolve theimpact of SBRT on subregional heterogeneities in cellular immunity stromal composition and metabolic profiles. +No NIH Category available Apoptosis;Apoptotic;Biological;Breast Cancer Cell;Bypass;Cancer Patient;Carboplatin;Cells;Cellular Stress;Cessation of life;Characteristics;Chemoresistance;Clinic;Clinical;Combined Modality Therapy;Data Set;Development;Disease;Disease Management;Drug Combinations;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Estrogens;FDA approved;Genes;Genetic;Genomics;Goals;Growth;Health;Human;In Vitro;Individual;Interferometry;Knowledge;Mammary Neoplasms;Mediating;Mediator;Metastatic breast cancer;Mission;Modeling;Neoplasm Metastasis;Operative Surgical Procedures;Organ;Organism;Outcome;Pathway interactions;Patient-derived xenograft models of breast cancer;Patients;Pharmaceutical Preparations;Prognosis;Proliferating;Proteomics;Receptor Inhibition;Research;Research Proposals;Resistance;Sampling;Signal Pathway;Signal Transduction;Speed;Testing;Therapeutic;Translating;Translations;United States;United States National Institutes of Health;Unresectable;Work;advanced disease;cancer cell;compare effectiveness;cytotoxic;cytotoxicity;efficacy evaluation;in vivo Model;inhibitor;innovation;malignant breast neoplasm;molecular drug target;new therapeutic target;novel strategies;novel therapeutic intervention;patient derived xenograft model;pharmacologic;response;safety testing;targeted treatment;transcriptome sequencing;treatment response;triple-negative invasive breast carcinoma;tumor Circumventing acquired carboplatin resistance in triple-negative breast cancers Project NarrativeThe proposed research is relevant to human health because it can directly benefit a group of cancer patientsthat currently have extremely poor prognosis by providing them with targeted treatment options that overcomechemotherapy resistance. Through development and testing of innovative research strategies with in vitro andin vivo models these studies are directly in line with the mission of the National Institutes of Health; seekfundamental knowledge about living systems and apply that knowledge to enhance human health. NCI 10714928 6/20/23 0:00 PA-21-071 3R01CA246182-03S1 3 R01 CA 246182 3 S1 "KONDAPAKA, SUDHIR B" 7/1/20 0:00 6/30/25 0:00 10934899 "HARRELL, JOSHUA (CHUCK) " Not Applicable 4 PATHOLOGY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 395 Non-SBIR/STTR 2023 34436 NCI 27875 6561 Project Summary/AbstractThe uncontrolled growth of breast cancer cells in vital organs is attributable to nearly all the ~40000 deaths thathappen each year in the United States. The long-term goal of this project is to identify new therapeutic strategiesto overcome chemotherapy resistance in triple-negative breast cancers (TNBC). The objective of this proposalis to identify biological pathways that can be targeted in addition to the epidermal growth factor receptor (EGFR)to promote apoptosis of disseminated cancer cells. The central hypothesis is that EGFR inhibition leads toactivation of cellular stress responses that can be targeted with pro-apoptotic agents. The goal at the completionof this project is for the results to immediately translate to the clinical setting and provide options for currentpatients with metastatic disease. The proposed work will also develop a unique dataset that can be used forfurther research towards identifying and developing targeted inhibitors that bypass carboplatin-resistance. Thecentral hypothesis will be tested by pursuing two specific aims: 1) Delineate targetable pathways that aresynergistic with Afatinib for cytotoxicity of carboplatin-resistant TNBCs; 2) Determine the efficacy of Afatinib-synergsitic combinations in multiple diverse in vivo models of TNBC. These aims will be pursued using aninnovative set of patient-derived xenograft models (PDX) which consist of isogenic pairs that are carboplatin-sensitive or those that have been generated to be carboplatin-resistant. This research proposal issignificant because it will identify new therapeutic targets that can be used to treat patients with advanceddisease and then compare the effectiveness of various targeted combinations on surgically unresectablemetastases. The expected outcome of these efforts is that we will identify subsets of TNBC PDXs that willfavorably respond to Afatinib-based combination therapies and subsequently that we will identify genomic and/or proteomic predictors of anti-EGFR response that will make a positive impact on disease management byidentifying patients that may benefit from this treatment approach. 34436 +No NIH Category available Agonist;Anabolism;Androgen Antagonists;Androgen Receptor;Androgens;Animal Model;Antiandrogen Therapy;Autophagocytosis;Autophagosome;Biochemical Pathway;Biogenesis;Biology;Cell Line;Cell model;Cells;Chimera organism;Clinical Research;Complex;Cytoplasm;DNA Binding Domain;DNA Sequence Alteration;Data;Development;Disease;Disease Progression;Excision;Gene Expression Profile;Goals;Histopathology;Human;In Vitro;Knock-out;Knockout Mice;Length;Ligand Binding;Ligand Binding Domain;Ligands;Link;Literature;Lysosomes;Malignant neoplasm of prostate;Mediating;Membrane;Modeling;Molecular;Nuclear;Oncogenic;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Production;Prostate;Protac;Proteins;RNA Splicing;Receptor Inhibition;Receptor Signaling;Resistance;Role;Stanolone;Technology;Testing;Testosterone;Therapeutic;Therapeutic Agents;Tissues;Treatment Efficacy;Ubiquitination;Variant;androgen deprivation therapy;androgen sensitive;antagonist;cancer cell;castration resistant prostate cancer;clinically relevant;deprivation;dimer;enzalutamide;gain of function;high risk;in vivo;inhibitor;innovation;malignant phenotype;men;mortality risk;mouse model;mutant;neoplastic cell;novel;novel therapeutics;patient derived xenograft model;programs;prostate cancer cell;prostate cancer model;prostate cancer progression;protein complex;protein degradation;receptor;receptor binding;receptor function;response;single-cell RNA sequencing;small molecule;standard of care;therapeutic evaluation;therapeutic target;therapeutically effective;therapy resistant;transcription factor;transcriptome;treatment response;tumor;tumor heterogeneity;tumor microenvironment A novel AR degrader in castrate-resistant prostate cancer The goal of this application is to test the therapeutic efficacy of novel therapeutic agents for ARprotein degradation using autophagy-targeting chimera (AUTOTAC) in castrate-resistantprostate cancer. NCI 10714811 8/15/23 0:00 PA-20-185 1R01CA282040-01 1 R01 CA 282040 1 "GREENBERG, WILLIAM A" 8/15/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-MCTC-S(01)Q] 1888624 "KIM, HYEONG-REH CHOI" Not Applicable 13 PATHOLOGY 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 8/15/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 594227 NCI 392009 202218 Androgen receptor (AR) plays a critical role in prostate cancer (PCa) in all stages. While a majority of patientswith PCa initially respond to androgen deprivation and/or anti-androgen therapies a significant portion ofpatients develop castrate-resistant prostate cancer (CRPC). Clinical studies showed that CRPC is oftenenriched with AR splice variants lacking the ligand binding domain (LBD) thereby being constitutively active inan androgen-independent manner and escaping from the antiandrogen enzalutamide-mediated AR inhibition.The goal of this RO1 application is to develop and characterize novel therapeutics that effectively degrade(remove) AR proteins in PCa. Technical innovations include the development of a novel therapeutic platformfor AR protein degradation using autophagy-targeting chimera (AUTOTAC). We successfully generated AR-targeted AUTOTACs which are bifunctional molecules composed of enzalutamide (an AR ligand bindingdomain inhibitor) or VPC-14449 (an AR DNA binding domain inhibitor) as a target binding ligand linked toYTK-6-2 as a ligand of the autophagic cargo receptor p62/Sequestosome-1/SQSTM1. AR-targeted AUTOTACbrings the target protein AR to p62 forming a ternary complex. YTK-6-2 induces p62 self-oligomerizationresulting in AR-p62 oligomeric complexes. YTK-6-2-activated p62 facilitates AR-p62-LC3 interaction onautophagic membranes and promotes autophagosome biogenesis and degradation of AR proteins. Usingclinically relevant animal models that reflect the relevant tumor microenvironment and tumor heterogeneity wewill test our novel hypothesis that AUTOTAC-mediated degradation (removal) of AR and its variants is a moreeffective approach than the currently available therapeutics including anti-androgen therapy. We alsohypothesize that unlike anti-androgens which result in therapy-resistant PCa cells involving activation ofnoncanonical AR signaling programs the AR-targeted AUTOTAC platform is unlikely to result in noncanonicalAR signaling-associated malignant phenotypes. Aim 1 will characterize the molecular actions of AR LBD-targeted AUTOTAC (Enz-AUTOTAC) and AR DBD-targeted AUTOTAC (VPC-AUTOTAC) and evaluate theirtherapeutic efficacies in prostate cancer cell models. Aim 2 will evaluate the therapeutic efficacies of Enz-AUTOTAC and VPC-AUTOTAC in vivo using PTEN knockout and patient-derived xenograft (PDX) mousemodels of prostate cancer. Activation of potential oncogenic pathways in therapy-resistant tumors will beexamined in relation to the expression levels of AR and the status of AR variants. In addition to thetranscriptome analysis of tumor cells tumor heterogeneity cancer cell plasticity and tumor microenvironmentswill also be assessed by single cell RNA-seq analysis before and after drug treatments. These data may leadto the identification of additional therapeutic target(s) in castrate-resistant PCa.Successful completion of the proposed study will develop a revolutionary drug platform of ARdegraders for patients with CRPC. 594227 +No NIH Category available Cancer Biology;Training Programs Integrative Training Program in Cancer Biology PROJECT NARRATIVEThe Massey Cancer Center (MCC) Integrative Training in Cancer Biology program aims to provide breakthroughopportunities to empower predoctoral and postdoctoral scientists from traditionally underrepresented groups totackle the most difficult scientific challenges in addressing the nations cancer burden. Trainees will be orientedto the importance of integrating bidirectional community engagement in all research efforts and the consciousrole scientists have in addressing cancer disparities. These predoctoral and postdoctoral scientists will alsobenefit from research training in the most contemporary approaches in cancer biology as well as professionalcareer development mentoring with a highly select group of successful MCC scholars. NCI 10714789 6/27/23 0:00 PA-20-142 1T32CA272382-01A1 1 T32 CA 272382 1 A1 "BOULANGER-ESPEUT, CORINNE A" 7/1/23 0:00 6/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9977356 "ATFI, AZEDDINE " Not Applicable 4 BIOCHEMISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 249318 NCI 233724 15594 PROJECT SUMMARYThis proposal seeks support for launching a new Integrative Training in Cancer Biology (ITCB) program whichwill be supervised by a select group of cancer scientists affiliated with the Massey Cancer Center (MCC) at theVirginia Commonwealth University (VCU) a 47-year National Cancer Institute-designated cancer center. Theprogram will provide contemporary training in cancer biology to both predoctoral and postdoctoral participantswith priority opportunities given to traditionally underrepresented individuals in cancer biology including womenracial/ethnic minorities individuals from disadvantaged backgrounds and those whose families have likelyexperienced deep-rooted generational health inequalities. Known national inequality in advanced trainingopportunities and health care are interrelated and intrinsically shape each other. It is within this context that theITCB program which will not only provide the most contemporary training in cancer biology but also an intentionalfocus on developing scientific approaches designed to address cancer disparities and the important role ofcommunity engagement in research will ultimately succeed in offsetting the significant cancer disparities facednot only by MCCs immediate catchment area but throughout the nation. The ITCB program aims to provide atwo-year training experience to three new predoctoral trainees and one postdoctoral trainee each year 20 totaltrainees over the five-year project period. The main programmatic objectives of the ITCB program are to 1) matchtrainees with a mentorship team who will develop a tailored cancer biology-training experience and careerdevelopment plan; 2) demonstrate best practices for incorporating community engagement into the designimplementation and dissemination of research; 3) provide workshops and hands-on training with experts incutting-edge biotechnologies; 4) offer interactive engagement through a unique cancer biology curriculuminfused with the principles of community engagement and cancer disparities; a cancer biology journal club; andan ITCB program monthly meeting to discuss research in progress the latest advances in cancer science andbest practices for laboratory management and career development; 5) promote interdisciplinary engagementthrough MCC-sponsored program meetings seminars and retreats; 6) afford opportunities to network nationallythrough attendance at professional cancer research conferences; and 7) support trainees in developingextramural peer-reviewed grant applications and submitting manuscripts based on their research. The ITCBprogram will be under the leadership of a Program Director and two Associate Directors who have substantialbackgrounds in cancer biology and notable leadership experiences. The program will receive evaluative inputfrom an external and an internal advisory committee and the program faculty includes prominent MCC scientistswho reside in an outstanding interdisciplinary research environment that offers remarkable opportunities forintellectual collaborative interactions supported by extensive center-supported resources. 249318 +No NIH Category available Address;Advisory Committees;Alaska Native;American Indians;Awareness;Career Choice;Censuses;Chronic Disease;Classification;Clinical;Communities;Comprehensive Cancer Center;Coupled;Coupling;Creativeness;Degree program;Economics;Education;Educational Curriculum;Educational workshop;Enrollment;Ensure;Evaluation;Future;Goals;Health;Health Occupations;Health education;High Prevalence;Hispanic;Hispanic Americans;Hispanic Populations;Incidence;Inflammation;Interdisciplinary Study;Internships;Knowledge;Lead;Learning;Malignant Neoplasms;Mentors;Middle School Student;Minority-Serving Institution;Morbidity - disease rate;Native Americans;New Mexico;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Pathway interactions;Personal Satisfaction;Persons;Population;Poverty;Productivity;Professional Competence;Race;Research;Research Activity;Research Training;Resources;Rural;Schools;Science;Self Efficacy;Student Persistence;Students;Talents;Training;Training Programs;Translating;Tribes;Underrepresented Minority;Underrepresented Populations;Underrepresented Students;Universities;Work;Youth;anticancer research;career;career development;cohort;college;community engagement;cultural values;design;ethnic diversity;ethnic minority population;experience;health disparity;high school;high school program;higher education;hispanic community;improved;innovation;interest;junior high school;mortality;outreach;pedagogy;peer;peer coaching;peer learning;peer networks;programs;racial diversity;recruit;response;role model;rural dwellers;science education;skills;socioeconomics;student participation;success;summer research;symposium;synergism;tribal community;undergraduate student;underserved community University of New Mexico's CURE for Cancer PROJECT NARRATIVEThe proposed CURE for Cancer program will develop and implement a multifaceted culturally relevant cancer-focused research experience for American Indian and Hispanic high school and undergraduate students. Bycultivating student interests in college to graduate and professional schools boosting their self-efficacy inscience and helping them attain skills needed to apply and ultimately succeed in higher education programswe expect CURE for Cancer trainees will productively contribute to tackling the significant education and healthneeds of underserved communities locally and nationally. Moreover the emphasis on American Indian andHispanic students from under-resourced communities will address national priorities for their recruitment andretention in STEM-H careers especially biomedical science and cancer-related health careers that address thehealth disparities experienced by these populations. NCI 10714649 9/20/23 0:00 RFA-CA-21-020 1R25CA247794-01A1 1 R25 CA 247794 1 A1 "LOPEZ, BELEM G" 9/20/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9203925 "GILLETTE, JENNIFER " "WANDINGER-NESS, ANGELA " 1 PATHOLOGY 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM SCHOOLS OF MEDICINE 871310001 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 273246 NCI 253006 20240 ABSTRACT / SUMMARYResponding to community concerns related to higher cancer incidences and worse outcomes among NewMexicos ethnically and racially diverse communities the University of New Mexico (UNM) Continuing Umbrellaof Research Experiences (CURE) for Cancer program was inaugurated in 2015. Since then the program hastrained 45 high school (85% AI any race) and 47 undergraduate students (51% AI 32% Hispanic any race)who have continued/completed their education through pursuit of college and advanced degree programs andare entering the scientific and health professions workforce. Cancer and inflammation associated chronicdiseases (type 2 diabetes and obesity) represent disproportionate causes of morbidity and mortality among NewMexicos populations; including people with limited economic resources and rural residents. In response to theNCI R25 Youth Enjoy Science program call for developing a diverse biomedical workforce the CURE for Cancerprogram builds on well-established experiential cancer-focused summer research internships and curricula thatadvance knowledge of current and emerging cancer innovations and career paths. Relevant role models andpeer-networks that value cultural identity while building science identity is shown to promote persistence. TheCURE for Cancer program has established networks to allow statewide and national recruitment and training ofAmerican Indian Hispanic and other underrepresented students. Thus the CURE for Cancer program isuniquely poised to increase the representation of American Indians and Hispanics in the sciences and addressa pressing national challenge to reduce the higher prevalence of cancer among these populations. The CUREfor Cancer Program Specific Aims synergize with the overarching goals of the University of New MexicoComprehensive Cancer Center and will: 1) Increase participation and persistence of students underrepresentedin cancer research from the high school to the undergraduate levels through targeted recruitment inter-programmatic connectivity tracking and formal evaluation 2) Encourage cancer career pursuit throughspecialized curricula clinical exposure and immersive research programs for high school and undergraduatestudents and 3) Engage New Mexico's rural and underserved Hispanic and tribal communities in science andhealth education through a Cancer-STEM Pathways Conference for middle school students and engaged youthambassadors. Annual evaluation student tracking and regular review by an Advisory Committee will assessstudent benefit and program impact. The successful completion of these aims is expected to increase thelikelihood that underrepresented populations will proceed to and graduate from college attendgraduate/professional school or work in cancer related professions. Moreover what makes UNM CURE uniqueis its coupling of culturally relevant pedagogy with cutting edge cancer research training that is integrated withHispanic and Native American community needs. 273246 +Cancer; Clinical Research; Health Services; Patient Safety; Social Determinants of Health Address;Adherence;Area;Bluetooth;Cancer Center;Cancer Patient;Caring;Clinical;Communication;Contracts;Data;Development;Distress;Enrollment;Evaluation;Feedback;Funding;Goals;Health;Health Insurance Portability and Accountability Act;Health system;Institutes;Interview;Malignant Neoplasms;Methodology;Monitor;Patient Education;Patient Schedules;Patient-Focused Outcomes;Patients;Phase;Privacy;Provider;Reporting;Research Training;Resources;Risk;Schedule;Secure;Security;Site;Social support;Testing;Thermometers;University of Virginia Cancer Center;Update;base;cancer diagnosis;care coordination;commercialization;dashboard;data visualization;design;handheld mobile device;improved;insight;interoperability;meetings;member;patient engagement;phase 1 testing;programs;prototype;recruit;social health determinants;tool;usability Cancer Navigation Platform (Cancer Moonshot) n/a NCI 10714603 75N91022C00038-0-9999-2 N44 9/19/22 0:00 9/18/24 0:00 78867732 "ARCHER, ANDREW " Not Applicable Unavailable 71785162 CPEBAW8M5TN1 71785162 CPEBAW8M5TN1 US -499974 CHARLOTTESVILLE VA Other Domestic Non-Profits 22902 UNITED STATES N R and D Contracts 2022 1988212 NCI Locus Health in this Phase II effort will further develop and demonstrate the utility and commercial viability of itsscalable HIPAA-compliant Cancer Navigation Platform. The long-term goals of this Platform are to improve cancerpatient outcomes and the efficiency and quality of patient navigation. Building on Phase I results the project team willfurther develop the Platforms patient engagement and navigation capabilities that promote targeted patient educationcommunication with patients and among the care team care coordination including effective two-way integration withthe EMR patient scheduling and resource access and referrals with particular emphasis placed on support for SocialDeterminants of Health. The project will test patient engagement adherence navigator efficiency and key patientoutcomes by initiating pilot implementations at two sites Inova Schar Cancer Institute and the University of VirginiaCancer Center. At the end of these pilots parallel usability studies will be conducted at both sites to test key aspects ofthe patient navigator and integration capabilities to provide specific feedback for a further development cycle. Inaddition to commercializing the Platform at the two sites the team expects to also secure 2-3 additional commercialcommitments at leading Cancer Centers/Health Systems. (Funded by Cancer Moonshot) 1988212 +Bioengineering; Cancer; Radiation Oncology Animals;Clinical;Dependence;Development;Dose;Dose-Rate;Engineering;Environment;Feedback;Future;Goals;Investigation;Normal tissue morphology;Pattern;Phase;Polychlorinated Biphenyls;Protons;Radiation therapy;Reporting;Research;Safety;Scanning;Structure;Suggestion;System;Technology;Test Result;Testing;Time;To specify;Toxic effect;base;density;design;detector;dosimetry;interest;ionization;novel;proton beam;radiation detector Ultra-Fast Dose Rate (FLASH) Radiation Detector and Safety System n/a NCI 10714550 75N91022C00056-0-9999-1 N01 9/16/22 0:00 6/15/23 0:00 78868030 "BOISSEAU, RAYMOND " Not Applicable 5 Unavailable 933575748 CK4RUCAF1GC6 933575748 CK4RUCAF1GC6 US 42.414634 -71.232085 2668201 "PYRAMID TECHNICAL CONSULTANTS, INC." Waltham MA Domestic For-Profits 2452 UNITED STATES N R and D Contracts 2022 397893 NCI Animal studies show that external-beam radiotherapy reduces normal tissue toxicities when delivered at ultra-high dose rates (>40 Gy/s) a condition referred to as FLASH. The dependence of the FLASH effect on peak dose rate and beam time structure is under intense investigation. An enormous range of peak dose rates has been proposed leading to research interest in a range of novel detector technologies that are not generally used in clinical dosimetry. We will concentrate ona specific feasible configuration while still accommodating the full range of detectors under consideration. 397893 +No NIH Category available Address;Adjuvant Radiotherapy;Adjuvant Therapy;Administrator;Affect;Behavior;Breast;Cancer Center;Caring;Cessation of life;Clinical;Cluster randomized trial;Colon;Communication;Data;Disease;Disparity;Effectiveness;Equity;Guidelines;Head and Neck Cancer;Head and Neck Surgery;Health behavior;Hybrids;Immunotherapy;Intervention;Interview;Knowledge;Lung;Malignant Neoplasms;Methods;Multicenter Trials;National Comprehensive Cancer Network;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Performance;Population;Postoperative Period;Process;Provider;Publishing;Radiation;Radiation therapy;Randomized;Recommendation;Referral and Consultation;Site;Social support;Structure;Surgeon;System;Translating;Work;arm;black patient;cancer care;cancer therapy;cancer type;care coordination;care delivery;chemotherapy;clinical care;clinical practice;effective therapy;effectiveness evaluation;effectiveness testing;effectiveness/implementation study;effectiveness/implementation trial;evidence base;implementation outcomes;improved;mortality disparity;mortality risk;multidisciplinary;racial disparity;racial minority;randomized trial;standard of care;survival disparity;treatment as usual A Type I Hybrid Effectiveness-Implementation Trial to Evaluate a Navigation-Based Multilevel Intervention to Decrease Delays Starting Adjuvant Therapy Among Patients with Head and Neck Cancer PROJECT NARRATIVEFor patients with head and neck cancer delays starting adjuvant radiation therapy are commondisproportionately burden racial minorities and contribute to poor survival and racial disparities in mortality.However effective therapies to improve the delivery of timely equitable guideline-adherent adjuvant radiationtherapy are lacking. We have developed a navigation-based multilevel intervention to enhance care coordinationcommunication and key cancer care delivery processes that could provide the first effective treatment in thispopulation thereby improving survival decreasing racial disparities in outcomes and developing new standardsof clinical care. NCI 10714537 6/14/23 0:00 PAR-21-035 1R01CA282165-01 1 R01 CA 282165 1 "WEAVER, SALLIE JAYNE" 8/1/23 0:00 7/31/28 0:00 Health Services: Quality and Effectiveness Study Section[HSQE] 14865589 "GRABOYES, EVAN MICHAEL" Not Applicable 6 OTOLARYNGOLOGY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 751693 NCI 589953 161740 PROJECT SUMMARY/ABSTRACTThis R01 proposal aims to test the effectiveness mechanism and implementation of a navigation-basedmultilevel intervention to improve the delivery of timely equitable guideline-adherent adjuvant therapy amongpatients with head and neck cancer (HNC). HNC is a disease with poor survival and profound racial disparitiesin mortality. For locally advanced HNC guidelines recommend initiating postoperative radiation therapy (PORT)within 6-weeks of surgery to optimize survival. However delays starting guideline-adherent PORT (i.e. > 6weeks after surgery) affect ~50% of patients with HNC and nearly 70% of Black patients with HNC and are thusa key driver of poor survival and racial disparities in mortality. To date interventions that improve the delivery oftimely equitable guideline-adherent PORT among patients with HNC are lacking. To address this gap wedeveloped ENDURE (Enhanced Navigation for Disparities and Untimely Radiation thErapy) as a navigation-based multilevel intervention that modifies the structure care delivery pathways and behaviors of the cancercare multiteam system to address patient- team- and organization-level barriers and thus improve the deliveryof timely equitable PORT following surgery for HNC. Data from our single-arm and pilot randomized trial provideevidence of NDUREs feasibility acceptability and preliminary effectiveness at improving timely guideline-adherent PORT and decreasing racial disparities in delays. To build on these promising data and characterizeENDUREs implementation across diverse settings we propose a hybrid type 1 effectiveness-implementationstudy. We will conduct a stepped wedge cluster randomized trial with n = 4 cancer centers (N = 484 patients)randomized to sequentially deliver treatment as usual (TAU) then ENDURE to patients with HNC undergoingsurgery and PORT. Concurrently we will conduct a mixed-methods study with quantitative assessmentssupplemented by semi-structured interviews of patients providers and administrators to characterize theimplementation of ENDURE. Specific Aim 1 will evaluate the effectiveness of ENDURE at decreasing delaysstarting guideline-adherent PORT relative to TAU. Specific Aim 2 will identify the mechanisms through whichENDURE reduces treatment delays. Specific Aim 3 will characterize the implementation of ENDURE acrossdiverse clinical settings. Findings from our proposal have potential to address three important gaps. First resultsmay support ENDURE as the first evidence-based strategy to decrease delays starting adjuvant therapy forpatients with HNC. Such a result may help change the current standard of care improve survival and decreaseracial disparities in mortality for these patients. Second findings address an understudied but critical aspect ofcancer care delivery and could be translated to other types of cancer (e.g. breast colon lung) for which delaysinitiating adjuvant therapy are common. Third mechanism data may provide actionable knowledge to improvethe delivery of effective interprofessional team-based cancer care. 751693 +No NIH Category available Active Learning;Address;Advanced Malignant Neoplasm;Advertising;American;Area;Behavioral;Big Data;Biometry;Cancer Patient;Characteristics;Clinical;Communication;Communities;Competence;Comprehensive Cancer Center;Data;Data Collection;Dedications;Development;Dimensions;Doctor of Philosophy;Education;Educational Curriculum;Educational workshop;Environmental Exposure;Epidemiology;Ethics;Etiology;Event;Face;Faculty;Family;Feedback;Funding;Goals;Guidelines;Health;Health Sciences;High School Student;Historically Black Colleges and Universities;Individual;Inherited;Internships;Knowledge;Malignant Neoplasms;Memorial Sloan-Kettering Cancer Center;Mentors;Methodology;Modeling;Molecular;Morbidity - disease rate;New York City;Nigerian;Oncology;Online Systems;Oral;Outcome;Patients;Peer Review;Persons;Population;Publications;Published Comment;Publishing;Reporting;Research;Research Training;Role;Science;Scientist;Series;Students;Surveys;System;Technology;Training;Underrepresented Students;United States;Work;Writing;anticancer research;career;cohort;curriculum enhancement;design;epidemiologic data;equity diversity and inclusion;experience;faculty mentor;global health;hands on research;improved;innovation;insight;mobile computing;mortality;next generation;novel;outreach;patient oriented;peer;professional students;programs;real world application;recruit;resilience;responsible research conduct;satisfaction;skills;success;symposium;tribal college;tumor progression;undergraduate research experience;undergraduate student;underserved community Quantitative Sciences Summer Undergraduate Research Experience (QSURE) PROJECT NARRATIVEData the building blocks of knowledge are becoming ubiquitous in all areas of health sciences particularlycancer research. The Quantitative Sciences Undergraduate Research Experience at Memorial Sloan KetteringCancer Center uses a multi-pronged approach integrating research education and career/professionaldevelopment to help reinforce students professional goals and prepare them to become strong quantitativescientists dedicated to advancing cancer research. NCI 10714502 12/6/23 0:00 PAR-21-279 2R25CA214255-07 2 R25 CA 214255 7 "RADAEV, SERGEY" 12/1/17 0:00 11/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1888536 "BEGG, COLIN B" "DU, MENGMENG ; TAN, KAY SEE " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 12/6/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 174571 NCI 161640 12931 ABSTRACT: The rapid accumulation of big data has initiated a new model for conducting cancer researchand has resulted in a pressing need for a workforce with quantitative skills. To meet this need we used our firstNCI R25 funding period to establish the Quantitative Sciences Undergraduate Research Experience (QSURE)at Memorial Sloan Kettering Cancer Center (MSK) in Summer 2018. QSURE provides experiential learningover a 10-week period for up to 10 students in quantitative fields powered by the application of real-world dataincluding biostatistics epidemiology health outcomes and computational oncology. In only 5 years QSUREhas demonstrated substantial demand for quantitative training and expanded the volume of students whosuccessfully engage in hands-on research in our department by nearly 4-fold. We have achieved the aims ofthe first funding period and reported high post-program student and mentor satisfaction as well as improvedstudent competencies in all years. Most QSURE alumni (71%) have gone on to pursue a PhD or Masters in aquantitative field. We will build on these successes and use the next funding period to continue to cultivate acadre of responsible rigorous quantitative scientists through an intensive multidimensional curriculum thatreinforces successful programmatic components including hands-on research carried out under the guidanceof a faculty mentor discussion series in the ethical and responsible conduct of research educational seminarsillustrating wide applications of data training workshops in quantitative methodology training and opportunitiesfor written/oral scientific communication and career and professional development. We will integrate newcomponents that address contemporary viewpoints in cancer research and prompt students to consider equitydiversity and inclusion in their own research. These will include patient led fireside chats that highlight therole of research in the patient experience panel discussions that provide global health perspectives throughexchanges with an NCI-funded program for Nigerian trainees and student-led discussions of works thatreinforce themes in equity diversity and inclusion. We will recruit diverse cohorts of motivated undergraduateinterns with a passion for applying quantitative science to reduce cancer morbidity and mortality and evaluateshort- and long-term program success and use these outcomes to inform and disseminate best practices.Since initial funding QSURE has demonstrated success and resilience in preparing and facilitating the nextgeneration of research scientists for graduate studies and careers in quantitative fields. During the next fundingperiod we will reinforce the successes of our first funding period by designing an enhanced curriculum to helpstudents contextualize and broaden their understanding of the potential of quantitative science to advance andsupport the health of all communities. QSURE will continue to prepare and facilitate interns for graduatestudies and careers in quantitative fields. This is vital to fulfilling our long-term vision of training strongquantitative scientists dedicated to advancing cancer research. 174571 +Bioengineering; Cancer; Radiation Oncology Algorithmic Software;Characteristics;Charge;Collection;Computer software;Cyclotrons;Development;Devices;Dose;Dose-Rate;Genetic Recombination;Human body;Ions;Measurement;Measures;Modality;Normal tissue morphology;Positioning Attribute;Protons;Radiation Dose Unit;Radiation therapy;Spottings;Synchrocyclotron;Systems Development;Systems Integration;Toxic effect;Validation;cell killing;design;improved;neoplastic cell;proton beam;quality assurance;research study;tool Development of Multilayer Strip Ion Chamber Device for the Measurement of Proton FLASH-Radiotherapy n/a NCI 10714482 75N91022C00055-0-9999-1 N43 9/16/22 0:00 9/15/23 0:00 78868027 "JIANG, HAO " Not Applicable 1 Unavailable 80194879 HFW2MYZMLMP6 80194879 HFW2MYZMLMP6 US 38.636981 -90.252702 10041506 "TETRAIMAGING, LLC" SAINT LOUIS MO Domestic For-Profits 631082979 UNITED STATES N R and D Contracts 2022 396190 NCI Ultra-high dose rate radiotherapy or FLASH-RT has shown the potential to drastically reduce the normal tissue toxicity without compromising tumor cell killing. Proton is the only treatment modality that can treat deep seated target in human body with FLASH-RT. With radiation dose delivered in less than a second an ultra-fast quality assurance (QA) device is needed to verify the delivery of FLASH-RT. We will develop a multilayer strip ion chamber (MLSIC) device can measure the characteristics of a proton flash beam spot-by-spot including spot position and profile energy and absolute dose. The MLSIC device can be used for development commissioning and QA of proton flash-beams. To develop the MLSIC and achieve the unmet need of QA device for flash-RT we will perform the research studies to achieve following objectives: 1) Design optimization and characterization of a MLSIC device for proton FLASH-RT QA in a synchrocyclotron and an isochronous cyclotron; and 2) Development of proton beam QA algorithm and software for the MLSIC. 396190 +No NIH Category available Address;Advanced Malignant Neoplasm;Adverse effects;Anxiety;Aromatase Inhibitors;Attenuated;Biological Markers;Body Composition;C-reactive protein;CDK4 gene;Carbohydrates;Chemotherapy and/or radiation;Circadian Rhythms;Cyclin-Dependent Kinase Inhibitor;Data;Development;Diet;Dietary Intervention;Dose;Eating;Effectiveness;Enrollment;Evaluation;Exercise;Fasting;Fatigue;Fulvestrant;Goals;Hormone Receptor;Hour;Individual;Inflammation;Inflammatory;Interleukin-6;Intermittent fasting;Intervention;Life;Mediating;Menopausal Symptom;Mental Depression;Metastatic breast cancer;Minority Groups;Mood Disorders;Neutropenia;Outcome;Outcome Study;Participant;Patient Outcomes Assessments;Patients;Pharmaceutical Preparations;Phase;Physical Function;Physical activity;Physical assessment;Pilot Projects;Population;Quality of life;Randomized;Randomized Controlled Trials;Reporting;Research;Risk;Sampling;Sleep;Sleep disturbances;TNF gene;Testing;Toxic effect;Treatment Side Effects;Treatment-related toxicity;Underrepresented Minority;Well in self;Woman;acceptability and feasibility;advanced breast cancer;advanced disease;adverse outcome;attentional control;cancer initiation;cancer therapy;chemotherapy;circadian;diet and exercise;ethnic diversity;exercise intensity;exercise intervention;exercise training;experience;feasibility testing;gastrointestinal;hormone receptor-positive;hormone therapy;improved;improved outcome;improvement on sleep;inflammatory marker;inhibitor;inhibitor therapy;intervention effect;lifestyle intervention;malignant breast neoplasm;novel;patient population;phase II trial;post intervention;preservation;primary outcome;psychologic;secondary outcome;side effect;targeted treatment;tumor Randomized Phase II Trial of Prolonged Overnight Fasting and/or Exercise on Fatigue and Other Patient Reported Outcomes in Women with Hormone Receptor Positive Advanced Breast Cancer (FastER) Project NarrativeWomen with advanced hormone receptor (HR)+ breast cancer being treated with endocrine therapy incombination with an inhibitor of cyclin dependent kinase 4/6 (CDK4/6) inhibitor are at risk for debilitating fatiguewhich can lead to poor quality of life and reductions or even discontinuation of the medication. Lifestyleinterventions particularly exercise and intermittent fasting are well-tolerated and favorably impact fatiguebiomarkers of inflammation physical function patient reported outcomes and body composition in women withearly-stage breast cancer however there have been few studies in women with advanced breast cancer. Toaddress this gap we propose a 2 x 2 trial in 260 women with advanced HR+ breast cancer initiating treatmentwith hormonal therapy in combination with a CDK4/6 inhibitor to evaluate the impact of either prolongedovernight fasting intervention alone moderate-intensity exercise alone or in combination on fatigue andassociated inflammatory biomarkers. NCI 10714371 9/20/23 0:00 RFA-CA-22-027 1R01CA281861-01 1 R01 CA 281861 1 "MOLLICA, MICHELLE A" 9/20/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M1) 11968300 "CRANE, TRACY E" "DIELI-CONWRIGHT, CHRISTINA ; LIGIBEL, JENNIFER A." 27 INTERNAL MEDICINE/MEDICINE 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 810559 NCI 669871 140688 AbstractMore than 40000 women die each year of metastatic breast cancer. The majority of these tumors are hormonereceptor positive (HR+) that are treated with a cyclin dependent kinase 4/6 (CDK4/6) inhibitor in combinationwith an aromatase inhibitor or fulvestrant. With these treatments women with advanced breast cancer areliving longer but treatment related toxicities inevitably occur and quality of life is limited by side effects ofcancer treatment which may result in dose reductions and delays. Fatigue is the most commonly cited adverseside effect reported for women taking CDK4/6 inhibitors and mechanistically may be associated withinflammation. When unmanaged fatigue is debilitating directly impacting both psychological and physicalquality of life and a key driver in discontinuation of therapy. Lifestyle interventions targeting diet and exercisehave evidence for improving fatigue in early stage breast cancer however whether these strategies areefficacious for improving outcomes in women with advanced breast cancer remains unknown with even lessinformation for women from underrepresented backgrounds who suffer disproportionately from breast cancerand its treatment. Research regarding the impact of these strategies on high grade fatigue induced by CDK4/6inhibitors in advanced disease from a diverse patient population are needed. The prolonged overnight Fasting and/or Exercise on fatigue and other patient reportedoutcomes in women with hormone Receptor positive advanced breast cancer (FastER) study willevaluate a phase II 2 x 2 randomized controlled trial testing the effects of a prolonged overnight fasting (POF)intervention alone moderate-intensity exercise alone or in combination on fatigue in 260 women withadvanced breast cancer initiating treatment with hormonal therapy in combination with a CDK4/6 inhibitor.Participants would undergo assessment of fatigue and associated inflammatory biomarkers as well asassessment of physical activity diet physical function body composition and patient reported outcomes atbaseline (prior to the initiation of CDK4/6 inhibitor) and 12 weeks (post-intervention) 6 and 12 months afterstudy enrollment. The primary outcome of the study is to evaluate the impact of the interventions (vs control)on fatigue in women at 12 weeks. Secondary outcomes include inflammatory biomarkers patient-reportedoutcomes physical function and body composition. The FastER study will also explore the impact of theintervention on circadian rhythms fatigue sleep depression anxiety quality of life physical function and bodycomposition.The overarching goal of the FastER study is to determine whether prolonged overnight fasting or moderate-intensity exercise alone or in combination can mitigate the adverse consequences of treatment and improvefatigue and other outcomes in women with advanced breast cancer treated with CDK4/6 inhibitors to ultimatelyimprove both quantity and quality of life for this growing population of women. 810559 +Bioengineering; Cancer; Radiation Oncology Calibration;Charge;Clinic;Collimator;Data;Dose;Electrons;Ensure;Feedback;Film;Height;Individual;Interruption;Ions;Linear Accelerator Radiotherapy Systems;Measurement;Monitor;Output;Physiologic pulse;Reproducibility;Signal Transduction;Solid;Speed;Structure;System;Testing;Time;Vacuum;Validation;Water;Width;base;beamline;design;irradiation;millisecond;nanosecond;prototype;real time monitoring Ultra-Rapid RF-Based Beam Monitor for Real-Time FLASH Beam Control n/a NCI 10714368 75N91022C00054-0-9999-1 N43 9/16/22 0:00 9/15/23 0:00 78868258 "GANGULY, ARUNDHUTI " Not Applicable 17 Unavailable 79645501 YMJ7WMKNYDJ5 79645501 YMJ7WMKNYDJ5 US 37.416032 -122.161743 10038849 "TIBARAY, INC." Santa Clara CA Domestic For-Profits 950511301 UNITED STATES N R and D Contracts 2022 399617 NCI TibaRay has developed a beam monitor that is capable of resolving the nanosecond-scale bunch structure within individual linear accelerator pulses. This speed makes inter-pulse beam control (on the millisecond time scale) readily achievable and even creates the possibility of intra-pulse beam control i.e. measurement and interruption of partial pulses on the microsecond time scale. We have now designed and prototyped the next stage of integration of this concept by building a beam monitoring RF cavity directly within a 6 MeV FLASH electron linear accelerator structure. The aims of this proposal are to validate the calibration of our integrated RF beam monitor for absolute charge and absolute dose under FLASH irradiation conditions and to demonstrate a basic closed loop feedback system capable of interrupting the beam between pulses based on the detected signal. With this validation our approach would represent a general platform for ensuring safe and robust delivery of FLASH RT in the clinic. 399617 +No NIH Category available Malignant Neoplasms;Neurosciences;Training Programs Cancer Neuroscience Training Program Project NarrativeAn emerging new discipline termed Cancer Neuroscience addresses functional interactions between tumorsand the nervous system. We propose a training program that will enable doctorate level basic scientists towork within this new field. Our trainees will address therapeutic challenges and develop new medicines forcancers and for a variety of neurologic disease states. NCI 10714321 6/30/23 0:00 PA-20-142 1T32CA272386-01A1 1 T32 CA 272386 1 A1 "LIM, SUSAN E" 7/1/23 0:00 6/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 6257805 "BATCHELOR, TRACY T" "GREENBERG, MICHAEL ELDON" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 496170 NCI 462528 33642 AbstractContemporary new technologies such as optogenetics and single cell genomics show that electrically activeneurons stimulate growth of adult and pediatric gliomas. Conversely cancers and cancer therapies alternervous system form and function (e.g. cancer therapy-related cognitive impairment colloquially known aschemobrain or chemofog). The two-way dialogue between tumors and the nervous system defines anemerging new scientific discipline termed Cancer Neuroscience. The Department of Neurology at Brighamand Womens Hospital (BWH) together with the Department of Neurobiology at Harvard Medical School(HMS) propose an integrative first-in-kind postdoctoral training program in this new field. The Program will beco-led by a clinician scientist Tracy Batchelor M.D. (Chair of Neurology at BWH) and a basic scientist MichaelGreenberg Ph.D. (co-director Harvard Brain Science Initiative). A faculty of 29 mentors will be drawn from theDana-Farber/Harvard Cancer Center and from the Harvard Brain Science Initiative. This will be a basic scienceprogram. Candidates with Ph.D. and/or M.D. degrees will be eligible but there will be no clinical training. We request support for 6 postdoctoral fellows per year to serve 2-year appointments. The Program willfoster both scientific development and professional development of these trainees. For ScientificDevelopment the Program will bring doctorate level basic scientists with skill sets in neural developmentelectrophysiology neural circuitry optogenetics brain metabolism and neurochemistry into the laboratories ofclinical/translational investigators working on primary and also metastatic cancers of the brain. For laboratoryresearch fellows will be taught to identify important questions and approaches that will move the field forwardand provide translational opportunities to impact cancer treatment. For professional development we willprovide trainees with (i) opportunities to refine and enhance their grantsmanship and scientific communicationskills; (ii) individual Development Plans; (iii) individual postdoctoral mentoring committees and (iv) customizedopportunities for trainees to acquire experience in mentoring and teaching depending on their career goals. The program Director and co-Director will work closely with a Training Oversight Committee and anExternal Advisory Board. Collaborative relationships with Morehouse School of Medicine and with theUniversity of Massachusetts-Boston (the largest center of higher education for minority students in NewEngland) will help identify ways to recruit underrepresented minorities into the program and to maintain awelcoming environment for these trainees. Additional strategies to measure trainee satisfaction quantifyoutcomes and evaluate the effectiveness of the program will include annual surveys from trainees andmentors as well as exit and alumni interviews. Institutional support in the form of state-of-art core facilitiestechnology platforms and funds to support T32-specific training activities and yearly EAB meetings willsignificantly enhance the training program. 496170 +No NIH Category available Address;Adoptive Cell Transfers;Adoptive Transfer;Adult;Affinity;Antigens;Autoantigens;Binding;Binding Proteins;Bone neoplasms;CRISPR/Cas technology;Cancer Burden;Cancer Etiology;Chemoresistance;Child;Childhood Solid Neoplasm;Data;Dendritic Cells;Development;Disease;Dose;Engineering;Ewings sarcoma;HLA-A2 Antigen;IGF2 gene;Immune Targeting;Immune Tolerance;Immune response;Immune system;Immunotherapeutic agent;Immunotherapy;Incidence;Individual;Knock-out;Knowledge;Late Effects;Lead;Lipase;Longevity;Malignant Neoplasms;Mediating;Metastatic/Recurrent;Mission;Mutation;Nature;Nonmetastatic;Normal tissue morphology;Oncogenes;Outcome;Patients;Pediatric Neoplasm;Pediatric Oncology;Peptides;Process;Proteins;Public Health;Quality of life;Recurrence;Regimen;Research;Resistance;Risk;Safety;Science;Severities;Signal Transduction;Solid;Solid Neoplasm;Survival Rate;Survivors;T cell therapy;T-Cell Receptor;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Tissues;Toxic effect;Translating;Tumor Antigens;Tumor Cell Derivative Vaccine;United States National Institutes of Health;Variant;Work;antigen-specific T cells;autologous lymphocytes;bench to bedside;cancer cell;candidate identification;checkpoint inhibition;chemotherapy;childhood cancer mortality;chimeric antigen receptor T cells;comparison control;cross reactivity;effector T cell;engineered T cells;exhaustion;experience;fitness;high risk;immunotherapy trials;improved outcome;interest;lead candidate;neoantigens;next generation;novel;novel strategies;novel therapeutics;overexpression;postnatal;prevent;prototype;research clinical testing;screening;targeted treatment;therapeutic candidate;therapeutic evaluation;tumor Attacking the Immunopeptidome of Ewing Sarcoma PROJECT NARRATIVEThis proposal is relevant to public health since Ewing sarcoma (EWS) is the second most common bone tumorof children and treatment remains suboptimal with survival rates for patients who present without metastaticdisease plateaued at 70% and less than 30% for patients who present with metastatic disease. Due to the doseintensity of current standard therapies patients who survive EWS experience an unacceptable incidence andseverity of late effects. The proposed research is highly relevant to the NIH mission as it seeks to discover newapproaches to harness the immune system for the treatment of EWS which will deliver novel therapeutics fortesting in this disease and will also provide generalizable knowledge regarding optimal approaches to developimmunotherapies for low mutational burden cancers. NCI 10714230 9/11/23 0:00 RFA-CA-22-016 1U01CA281865-01 1 U01 CA 281865 1 "SINGH, ANJU" 9/11/23 0:00 7/31/28 0:00 ZCA1-SRB-A(M1) 14354500 "MACKALL, CRYSTAL " Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/11/23 0:00 7/31/24 0:00 353 Non-SBIR/STTR 2023 467370 NCI 300868 166502 PROJECT SUMMARYSolid cancers are a leading cause of cancer related death in children and there is great interest in harnessingrecent progress in immunotherapy for the treatment of pediatric solid tumors. Immune checkpoint inhibition (ICI)is the most active form of immunotherapy for adult solid cancers but ICI is not effective in pediatric solid tumors.This discrepancy is explained by the low mutational burden of pediatric solid tumors since neoantigens arisingfrom tumor specific mutations are the target of the most potent ICI induced immune responses. Overexpressednon-mutated self-antigens that are not expressed on normal vital tissues can serve as the basis for effectiveimmune therapies but immune tolerance must be overcome to induce potent immune responses to this class ofmolecules. This project focuses on Ewing Sarcoma (EWS) a prototype low mutation burden solid tumor forwhich progress has stalled. Standard therapies for EWS rely on dose intensive regimens largely developed inthe 1970s and 80s which leave survivors with severe lifelong late effects. No targeted therapeutics have beendemonstrated to be effective. Few patients with metastatic or recurrent EWS survive. Using immunopeptidomeprofiling we discovered novel peptides from lipase-1 (LIPI) and IGF2 binding protein 1 (IGF2BP1) that arepresented by HLA-A2+ on EWS. These non-mutant proteins are overexpressed at high levels in the vast majorityof EWS and are essentially absent from vital normal tissues thereby demonstrating a very favorable profile forimmune targeting. To translate this discovery into a therapeutic application for EWS this project applies aworkflow we developed to discover characterize and engineer T cells receptors (TCRs) targeting thesepeptides. The major overarching challenge that the project addresses is determining the optimal approach toidentify and/or engineer high potency TCRs capable of targeting self-antigens without incurring cross-reactivitythat would result in unacceptable toxicity. In Aim 1 we test the hypothesis that TCRs targeting LIPI- andIGF2BP1-derived peptides will be identified in HLA-A2+ hosts but will manifest low potency due to immunetolerance. We will simultaneously discover and compare antigen reactive TCRs present in HLA-A2 hosts whichwe predict will be more potent but may be unsafe due to cross-reactivity. In Aim 2 we use next generationapproaches to engineer natural TCRs identified in HLA-A2+ hosts into more potent but safe antigen-specificTCRs through affinity maturation or catch bond engineering. Given the known risks for cross reactivity of highpotency TCRs next generation engineered TCRs developed here will be closely vetted across several platformsfor cross-reactivity. In Aim 3 we use fitness enhancements developed in the Mackall lab to enhance the potencyof CAR T cells to enhance the potency of T cells expressing our lead candidate LIPI- and IGF2BP1-reactiveTCRs. The work conducted in this project will deliver state-of-the-art therapeutics ready for clinical testing inEWS and provide general understanding regarding the optimal approach to engineer TCRs targeting self-antigens which will provide value in pediatric oncology and low mutation burden cancers beyond EWS. 467370 +No NIH Category available 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine;Affect;Automobile Driving;B lymphocyte immortalization;Binding;Burkitt Lymphoma;Carcinoma;Cell Line;Cell Survival;Cells;CpG Island Methylator Phenotype;DNA Methylation;DNA Tumor Viruses;Data;EBNA2 protein;Environment;Enzymes;Epigenetic Process;Episome;Epithelium;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Malignant Neoplasm;Genes;Genetic Transcription;Human;Human Herpesvirus 4;Hypoxia;Immune response;Knowledge;Lymphoid;Maintenance;Malignant Neoplasms;Maps;Metabolism;Nuclear;Nutrient Depletion;Oncogenic;Oncogenic Viruses;Oxidative Stress;Oxygen;Pathway interactions;Play;Primary Infection;Process;Procollagen-Proline Dioxygenase;Proteins;Regulation;Role;Signal Pathway;Site;Testing;Therapeutic Intervention;Tumor Suppressor Genes;Viral;Virus;Virus Latency;epigenome;gammaherpesvirus;genomic locus;histone modification;hypoxia inducible factor 1;insight;latent infection;member;normoxia;programs;response;small molecule inhibitor;tumorigenesis;virus episome maintenance;virus related cancer Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia Narrative: Epstein-Barr virus (EBV) is responsible for 200000 new cancers each year. Like other DNA tumorviruses EBV utilizes cellular oxygen-dependent metabolism and signaling pathways to drive oncogenictransformation. This proposal focuses on understanding how EBV responds to hypoxia and oxidative stress todrive epigenetic changes associated with viral latency and cellular oncogenesis. This study is highly aligned withother projects of this Program Project and will enhance our knowledge and strategies for therapeutic interventionin viral associated cancers. NCI 10714176 8/28/23 0:00 PAR-20-077 1P01CA281867-01 1 P01 CA 281867 1 9/1/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 5958 1869983 "LIEBERMAN, PAUL M" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 474921 459296 15625 Abstract:Epstein-Barr Virus (EBV) a human gammaherpesvirus that is associated with diverse lymphoid and epithelialmalignancies. Like all cancers EBV-associated cancers must compete and survive in nutrient depletedenvironments. Adaptation to oxygen fluctuation is a hallmark of most cancers. In this proposal we investigatehow oxygen metabolism plays a central role in EBV latency and tumorigenesis. For aim 1 we will investigatehow EBV modulates the host hypoxic response during primary infection. Our preliminary data indicates EBNA1and EBNA2 can bind and regulate cellular genes controlling the hypoxic response including hypoxia induciblefactor 1 alpha (HIF1A). We will test the hypothesis that EBV infection modulates the host response to hypoxiato promote infected cell survival and promote tumorigenesis. For aim 2 we will investigate how the viralepigenome is regulated by oxygen sensing enzymes. EBV associated Burkitt lymphoma (BL) and epithelialmalignancies are known to acquire high DNA methylation commonly referred to as the CpG island methylatorphenotype (CIMP). We will investigate how DNA methylation is regulated through the oxygen-sensitive controlof TET2 enzymes and explore how hypoxia contributes to CIMP and silencing of tumor suppressor genes. Foraim 3 we will test how oxygen sensing enzymes regulate EBNA1 and EBV episome maintenance during latency.We have found that proline and lysine hydroxylases regulate EBNA1 and EBNA2 protein stability and function.We have mapped interaction sites on EBNA1 that bind the lysine hydroxylase PLOD1 and found this interactionessential for EBNA1 protein stability under normoxia. We now propose to investigate how hypoxia regulates theinteraction of PLOD1 with EBNA1 to control EBV episome maintenance and persistence during latent infection.These aims are highly integrated with other members of the program project exploring hypoxia effects on relatedtumor viruses. Together these aims will provide a framework to understand how viruses respond to hypoxia topromote host cell survival and drive the oncogenic process. +No NIH Category available Address;Adoptive Cell Transfers;Atlases;Biology;Brain Neoplasms;CAR T cell therapy;CD8-Positive T-Lymphocytes;CRISPR screen;Cancer Etiology;Cell Communication;Cell Therapy;Cell physiology;Cells;Cellular biology;Child;Childhood Malignant Brain Tumor;Classification;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Development;Disease;Exclusion;Exhibits;Genetic;Genetically Engineered Mouse;Genomics;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunology;Immunotherapeutic agent;Immunotherapy;Joints;Macrophage;Maps;Mediating;Modeling;Molecular;Multiomic Data;Mus;Network-based;PTPRC gene;Patients;Phenotype;Pre-Clinical Model;Proteomics;Refractory;Resistance;Reverse engineering;Saint Jude Children's Research Hospital;Sampling;Signal Transduction;Sorting;Subgroup;System;Systems Biology;T cell response;T cell therapy;T-Lymphocyte;TCF Transcription Factor;Technology;Testing;Tumor Immunity;Tumor stage;Tumor-infiltrating immune cells;Visualization;cancer type;childhood cancer mortality;chimeric antigen receptor T cells;clinically relevant;cloud based;data visualization;disorder risk;experimental study;functional genomics;high risk;high risk population;improved;in vivo;insight;medulloblastoma;mouse model;multiple omics;neoplastic cell;nerve stem cell;notch protein;novel;overexpression;screening;single cell analysis;single-cell RNA sequencing;spatiotemporal;stem-like cell;tool;transcriptomic profiling;transcriptomics;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology PROJECT NARRATIVEMedulloblastoma is the most common malignant pediatric brain tumor and Group 3 medulloblastoma is themost aggressive form of this disease which is mostly refractory to immunotherapies. This project will dissectthe crosstalks between tumor and tumor microenviorment and the mechansims of immune evasion in Group 3medulloblsatoma. We will also investigate cellular therapy strategies that will circumvent tumor-mediatedimmunosuppressive mechanisms and reinvigorate anti-tumor immunity in this devastating disease. NCI 10714138 9/7/23 0:00 RFA-CA-22-016 1U01CA281868-01 1 U01 CA 281868 1 "LIU, YIN" 9/7/23 0:00 8/31/28 0:00 ZCA1-SRB-A(M1) 8338849 "CHI, HONGBO " "YU, JIYANG " 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/7/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 819000 NCI 450000 369000 PROJECT SUMMARY / ABSTRACTThe goal of this project is to dissect the immune evasion mechanisms and enable immunotherapy for childrenwith high-risk Group 3 medulloblastoma (G3MB) via systems immunology approaches. Brain tumors are theleading cause of cancer-related deaths in children. Medulloblastoma is the most prevalent malignant pediatricbrain tumor and is characterized by four major molecular subgroups among which G3MB is the most aggressiveform and features MYC overexpression. The immunosuppressive tumor microenvironment (TME) is poorlyunderstood in G3MB and no immunotherapy is available for children with this high-risk disease. Systemsimmunology approachesespecially single-cell and spatial multi-omics profiling and in vivo CRISPR-basedfunctional screeninghave proven powerful in dissecting tumorTME interactions and identifying novelimmunotherapy targets in various cancer types but very few studies have integrated these approaches. In ourpreliminary studies we applied two unique immunocompetent genetically-engineered mouse models (GEMMs)of MYC-driven G3MB and performed scRNA-seq scATAC-seq and spatial transcriptomics profiling. We enrichedimmune cells from the TME by sorting CD45 positive cells for single-cell studies. Our preliminary analysis ofsingle-cell and spatial omics data revealed striking interactions of neural stem cell-like tumor cells withmacrophages and other immune cells that potentially create a suppressive TME and drive immune evasion inmouse G3MB. We also performed in vivo CRISPR screening in tumor cells using the GEMMs to identifymodulators of tumor development which demonstrated the feasibility of in vivo functional genomics screeningin our preclinical models. In this project first we propose to utilize cutting-edge single-cell and spatial omicstechnologies to characterize the two G3MB GEMMs at different stages of tumor progression. We will use ournetwork-based tools to integrate these multi-omics data to dissect the dynamic tumorimmune interactions andunderlying hidden drivers that drive the immune exclusion and suppression during G3MB progression. We willalso validate discoveries of G3MB from mouse studies in patient samples. We will develop a cloud-based portalto visualize and explore our single-cell and spatial data and tumorTME interactomes of G3MB. Second we willestablish the mechanistic basis of tumorT cell interactions and strategies to enable adoptive T cell therapy forG3MB by discovering functional drivers and putative targets in both tumor cells and T cells. To this end we willapply both candidate approach and in vivo CRISPR screening in immunocompetent GEMMs to identify tumor-intrinsic modulators that will remodel the suppressive TME and sensitize G3MB tumors to adoptive T cell andCAR-T cell therapies. We will also test if targeting inhibitory factors for T cell function will enable and optimizeeffective adoptive T cell therapies against such tumors. Our studies promise to provide new insights intomechanisms of tumorTME interactions in G3MB and manifest legitimate immunotherapeutic opportunities. 819000 +No NIH Category available Accident and Emergency department;Acute;Address;Admission activity;Adult;Agreement;Ambulatory Care;Applications Grants;Automobile Driving;Black race;Cancer Patient;Caring;Categories;Classification;Clinic;Clinical;Code;Community Hospitals;Computerized Medical Record;Cost aspects;Data;Data Set;Diagnosis;Diarrhea;Disease;Emergency Situation;Emergency department visit;Environment;Feedback;Future;Goals;Health;Health system;Hispanic;Hospitals;Immunotherapy;Inpatients;Insurance;Interview;Learning;Link;Malignant Neoplasms;Managed Care;Measurement;Measures;Medical Records;Medicare;Modeling;National Comprehensive Cancer Network;Nausea;Nausea and Vomiting;Oncology;Organization and Administration;Outpatients;Pain;Paracentesis;Participant;Patients;Performance;Procedures;Provider;Radial;Reporting;Sampling;Sensitivity and Specificity;Services;Specific qualifier value;Surveys;Triage;Uninsured;Visit;Vomiting;Work;acute care;cancer care;cancer diagnosis;care delivery;care providers;chemotherapy;clinically actionable;cost;data exchange;data integration;electronic structure;hospital care;improved;payment;programs;prospective;safety net;success;theories;treatment effect;tumor registry;urgent care Actionable categories of avoidable hospital care among adults with cancer PROJECT NARRATIVEWe will examine existing quality measures that define avoidable hospital care among adults with cancer andcompare their performance to in-depth clinician reviews of medical records. We will recategorize hospital visitsinto actionable clinical scenarios to help cancer providers identify avoidable hospital visits and create a newquality measure to identify conditions that could be treated in oncology urgent care clinics. We will validatefindings with patients and emergency clinicians then survey cancer care providers nationwide to ensure thatthese categories and quality measure are accurate and useful. NCI 10714125 9/20/23 0:00 PA-20-185 1R01CA282242-01 1 R01 CA 282242 1 "DAVIDOFF, AMY" 9/20/23 0:00 8/31/28 0:00 Organization and Delivery of Health Services Study Section[ODHS] 14316018 "HONG, ARTHUR SEOKJAE" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 611294 NCI 372740 238554 PROJECT SUMMARY/ABSTRACTNearly all provider groups in Medicares five-year Oncology Care Model alternative payment programexpressed a goal to reduce hospital use by cancer patients but very few achieved this. Identifying potentiallyavoidable hospital care for cancer patients using diagnosis codes is difficult: depending on the definition used20-60% of hospital visits may be avoidable. The leading diagnosis code-based definition is the chemotherapyoutpatient quality measure (OP-35) which collects emergency department (ED) and inpatient admissions with~300 discharge diagnosis codes into 10 avoidable conditions. Unlike similar measures of avoidable hospitalcare for general patients OP-35 has not yet been clinically validated. While OP-35 allows payers to comparegroups of providers two issues limit its usefulness to cancer providers: First clinicians might agree that someOP-35 conditions (e.g. nausea/vomiting) are treatable in an outpatient or urgent care setting but that otherssuch as hematemesis (bloody vomiting) would be difficult to evaluate outside of a hospital. Second OP-35reports only a percentage of hospital visits to each provider group obscuring what exactly is driving avoidablehospital use. Based on preliminary work we propose to develop a classification of actionable scenarios leadingto hospital care (e.g. patient required non-emergent procedure; patient did not call for triage help beforehand)so that cancer providers can better understand how to reduce this frequent disruptive and costly aspect oftreatment. We will assemble an integrated dataset from tumor registry electronic medical record (EMR) andregional health information exchange data for a diverse sample representing a range of cancers across allinsurance types including the uninsured. This dataset will identifiably link >75% of all hospital visits in a 100-mile radius of Dallas TX to the EMR of three large health systems in the region. Our aims are: Aim 1:Clinically validate diagnosis code-based measures of avoidable hospital care (including OP-35) with clinicianEMR review; re-categorize hospital visits into actionable scenarios; and specify a new measure for oncologyurgent care-treatable conditions. H1: Most OP-35 defined avoidable will not be avoidable based on clinicianreview. H2: Actionable categories of clinical scenarios will be identifiable in the EMR and can be furtherspecified by a measure that identifies conditions treatable in an urgent care setting. Aim 2: Prospectivelyvalidate our actionable categories and new oncology urgent care-treatable conditions measure with patientsand ED clinicians using post-discharge interviews. H1: Patients and ED clinicians will largely agree with ourcategorizations with some refinements. Aim 3: Conduct a national survey of cancer provider groups to assessthe feasibility and applicability of our new definitions for avoidable hospital care in the context of their acutecare management capabilities. H1: A broad range of cancer providers will find our definitions feasible anduseful. Findings from our study will advance quality measurement and data-driven care improvement and willbe especially useful to participants in Medicares upcoming Enhancing Oncology Model payment program. 611294 +No NIH Category available Affinity;Animals;Antibodies;Antibody Specificity;Antigens;Area;Artificial Membranes;Bacteria;Bacteriophages;Bar Codes;Binding;Biological Assay;Biology;CRISPR/Cas technology;Cancer Biology;Cancer Detection;Cancer cell line;Cell Surface Proteins;Cell surface;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Communities;Complex;Consumption;Cytometry;DNA Library;DNA Sequence;Dependence;Detection;Development;Diagnostic;Engineering;Ensure;Epitopes;Family;G-Protein-Coupled Receptors;Generations;Genotype;High-Throughput Nucleotide Sequencing;Human;In Vitro;Individual;Integral Membrane Protein;Knock-out;Libraries;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measurement;Measures;Medicine;Membrane Proteins;Methodology;Methods;Molecular Target;Nanotechnology;Nucleic Acid Hybridization;Open Reading Frames;Phenotype;Production;Proteins;Proteome;Proteomics;RNA Sequences;Rapid screening;Reagent;Research Personnel;Resources;Ribosomal RNA;Ribosomes;SARS-CoV-2 spike protein;Slide;Solubility;Specificity;Surface;System;Targeted Research;Technology;Testing;Therapeutic;Time;Tissues;Validation;Virus;antibody detection;antibody engineering;antibody libraries;anticancer research;cancer cell;cell dimension;cell growth;cost effective;cost efficient;design;detection method;empowerment;flexibility;high dimensionality;in situ sequencing;indexing;interest;method development;nanobodies;nanoscale;new technology;novel;novel strategies;nucleic acid detection;protein profiling;receptor binding;screening;single cell sequencing;tool Development of methods for highly multiplexed quantification of cancer proteomes using large-scale nanobody libraries Antibodies represent some of the most important tools in biology and medicine which are used to detect andperturb molecular targets for research diagnostics and therapeutics. Here we propose a new method toengineer and use nanobodies a small form of antibody in a massively parallel method against proteinsrelevant to cancer thus making affordable antibody development accessible to any investigator. NCI 10714023 8/9/23 0:00 RFA-CA-22-001 1R61CA281807-01 1 R61 CA 281807 1 "AMIN, ANOWARUL" 8/9/23 0:00 6/30/26 0:00 ZCA1-TCRB-5(M1) 1925825 "HACOHEN, NIR " Not Applicable 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 8/9/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 221595 NCI 140250 81345 The development of scalable cost-effective antibody libraries for detecting proteins (or other molecules) hasgreatly lagged the development of methods for detecting (e.g. by hybridization or sequencing) specific RNA orDNA sequences. If we were able to engineer antibodies against diverse targets and create large-scale librariesof barcoded antibodies that could be detected by nucleic acid hybridization or sequencing many applicationswould be enabled to empower the cancer research community including high-dimensional cell cytometry (similarto CITE-seq) spatially-indexed sequencing (e.g. using Slide-seq MERFISH etc) in situ sequencing to detectantibodies bound to targets (similar to CODEX) and targeted proteomics (such as the Olink proximity extensionassay). These applications currently rely on laborious and expensive barcoding of individual (commercial)antibodies followed by pooling for parallel detection. Here we propose to develop a novel strategy to discoverengineer and apply synthetic VHH-domain nanobodies against hundreds to thousands of human protein targetssimultaneously thus enabling creation of sequence-defined antibodies and enabling rapid production of pools ofbarcoded-antibodies at large scale by any investigator. Our proposal builds novel methods that leverage ourrecently developed cell-free platform for producing large libraries of distinct nanobodies (with an input library of1011-1012 complexity) that are barcoded with their encoding RNA by ribosome display. We will develop methodsto use these libraries for parallel selection of nanobodies that bind each of hundreds (to thousands) of cell surfaceproteins (i.e. a many-to-many screen) in cancer cells. Our approach combines cell-free nanobody engineeringectopic ORF expression or CRISPR/Cas9 knockout with single cell sequencing to achieve generation ofnanobodies against a large number of targets in parallel. Importantly by analyzing many targets at once ourapproach for the first time validates nanobody specificity at scale by measuring off-target binding systematicallyfor each nanobody to ensure binding specificity. We envision that the resulting methods for discovering andusing nanobodies against cancer cell surface molecules would enable highly multiplexed single cell and spatialtissue proteomics. Building on the proposed proof of principle one can envision the platform enabling any lab todevelop sequence-defined novel detection reagents and highly multiplexed libraries of detection reagentsagainst conventional and unconventional targets across many projects of high value to cancer research. 221595 +No NIH Category available Barrett Esophagus;Barrett's carcinogenesis;Cells;Clinical;Collaborations;Communication;Complex;Comprehensive Cancer Center;Computer Analysis;Data;Data Analyses;Data Set;Database Management Systems;Databases;Development;Diagnosis;Disease;Duke Comprehensive Cancer Center;Dysplasia;Early Diagnosis;Ensure;Environmental Risk Factor;Esophageal injury;Etiology;Experimental Designs;Faculty;Formulation;Foundations;Genes;Goals;Grant;Human Resources;Information Dissemination;Infrastructure;Inherited;Injury;Institution;Investments;Leadership;Malignant neoplasm of esophagus;Manuscripts;Metaplasia;Methods;Molecular;Molecular Profiling;Multiomic Data;Pathway interactions;Physiology;Positioning Attribute;Pre-Clinical Model;Predisposition;Prevention;Program Research Project Grants;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resources;Secure;Specialized Program of Research Excellence;Systems Biology;Testing;Tissue Model;Tissues;Training Programs;Universities;Writing;analytical method;cancer epidemiology;cancer prevention;carcinogenesis;computer infrastructure;data management;data sharing;design;experimental study;gastrointestinal;genetic epidemiology;genome-wide;injury and repair;innovation;large scale data;medical schools;meetings;multiple omics;novel;programs;repaired;skills;wound healing Integrative Systems Biology Core PROJECT NARRATIVEThe Integrative Systems Biology Core will interact with all investigators to develop and apply appropriate analysismethods to ensure that the experimental data is analyzed appropriately to test the hypotheses relevant to eachproject. NCI 10713944 9/20/23 0:00 PAR-20-077 1P01CA269019-01A1 1 P01 CA 269019 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 5913 8877980 "LAFRAMBOISE, THOMAS LOUIS" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 326898 255353 71545 PROJECT SUMMARY/ABSTRACTThe Integrative Systems Biology Core will interact with all investigators to develop and apply appropriate analysismethods and designs to most efficiently achieve project goals. We will ensure that the experimental data isanalyzed appropriately to test the hypotheses relevant to each project. In addition the Integrative SystemsBiology Core will provide infrastructure and oversight for secure management of all study data working closelywith the Bioreagents & Resource Core to facilitate accuracy and completeness of datasets for all projects andinvestigators. Our specific aims are: (1) To integrate cutting-edge analytic approaches in the design analysisand interpretation of experimental studies across projects in our program; and (2) To provide secure andaccessible database systems and computational infrastructure to facilitate reliable and reproducible analysesconducted by all program investigators. The Integrative Systems Biology Core leverages faculty and resourcesin the Case Comprehensive Cancer Center Case Western Reserve University School of Medicine and theDuke Molecular Physiology Institute. Dr. Thomas LaFramboise will direct the Core with Dr. Simon Gregoryas co-director. The Integrative Systems Biology Core will serve as a centralized resource for all personnelincluding the leaders of the three research projects and the Bioreagents & Resource Core. The Core will assistinvestigators with all facets of design computational analysis and interpretation. Established as well as noveltailored analytic methods are available to promote scientific discovery for investigators within the Core. Corepersonnel will interact with investigators in all stages of research from data management data analysisinterpretation writing scientific manuscripts and grants to dissemination of results. The Core will alsofacilitate access to secure and accessible database systems facilitating analysis discovery andcollaboration. The Core will assist all investigators with development management and reliability of their projectdata and will also integrate information across databases such as incorporating clinical and experimental datawith biospecimen data as provided by the Bioreagents & Resource Core. The Integrative Systems Biology Corewill provide a natural foundation for cross-pollination among the projects and Cores the Core personnelcollaborating with all project investigators and Core directors. +No NIH Category available Address;Administrator;Barrett Esophagus;Barrett's carcinogenesis;Biological Markers;Biology;Budgets;Chemopreventive Agent;Clinical;Communication;Complex;Development;Disease;Duke Comprehensive Cancer Center;Dysplasia;Ensure;Esophageal Adenocarcinoma;Esophageal injury;Esophagus;Financial Activity;Generations;Genetic;Goals;Growth and Development function;Human Resources;Individual;Inherited;Institution;Internet;Leadership;Malignant - descriptor;Malignant Neoplasms;Metaplasia;Mission;Modeling;Molecular;Molecular Target;Monitor;Morbidity - disease rate;Pathway interactions;Patients;Predisposition;Prevention;Principal Investigator;Program Development;Program Evaluation;Progress Reports;Reporting;Research;Research Project Grants;Resources;Risk;Schedule;Scientific Evaluation;Services;Structure;Systems Biology;Therapeutic;Time;Translating;Translational Research;United States;United States National Institutes of Health;Universities;c-myc Genes;cancer prevention;carcinogenesis;design;evidence base;experience;injury and repair;medical schools;meetings;member;molecular marker;mortality;programs;screening;success;symposium;synergism;timeline;transcriptomics;wasting;wound healing Administrative Core PROJECT NARRATIVEBarrett's esophagus is a complex disorder and patients with Barrett's esophagus are at an increased risk ofdeveloping esophageal adenocarcinoma a lethal and most common esophageal malignancy in the UnitedStates. To date the mechanisms contributing to the onset and malignant progression of Barrett's esophagusremain poorly understood. Our proposed studies are accordingly designed to unravel the molecularunderpinnings of Barrett's esophagus and associated esophageal malignancy with an overarching goal ofdeveloping evidence-based biomarkers and rational chemopreventive/therapeutic strategies for this increasinglyprevalent and complex disease. NCI 10713942 9/20/23 0:00 PAR-20-077 1P01CA269019-01A1 1 P01 CA 269019 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 5911 2067894 "CHAK, AMITABH " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 134100 101830 32270 PROJECT SUMMARYThe Administrative Core provides strong centralized scientific and administrative leadership to the PPG whichfacilitates synergistic interactions between the four projects and two scientific cores and maintains the overallfocus of the program project. The Core will coordinate the research mission monitor timelines for achievingresearch milestones coordinate and integrate PPG activities and implement a plan for regular evaluation ofscientific progress. Drs. Chak Guda and Garman will be assisted by the Executive Steering Committee (projectand core leaders) as well as the Advisory Board which includes internal and external members. TheAdministrative Core will oversee annual budgets monitor expenses and provide monthly statements of financialactivities to the projects and scientific cores. In addition all program-related meetings will be scheduled throughthe core. These include the weekly meeting of the Executive Steering Committee monthly Cross-ProgramProgress Seminars and the Annual Program Retreat. In addition generation of materials to be reviewed bythe Advisory Board will be handled through the Administrative Core. Finally the Administrative Core will preparegenerate and assemble materials required for the annual progress reports and will ensure that all additional NIHand institutional reporting requirements concerning PPG activities are fulfilled in a timely manner. +No NIH Category available 3-Dimensional;Acceleration;Animal Model;Barrett Esophagus;Barrett's carcinogenesis;Barrett's neoplasia;Bile Acids;Binding;Binding Proteins;Biological;Biological Markers;Biopsy;Cell Line;Cell Lineage;Cells;Chemopreventive Agent;Complex;Coupled;Development;Disease;Disease Progression;Distal;Dysplasia;EPHB2 gene;Ephrin-B2;Epithelium;Esophageal Adenocarcinoma;Esophageal Squamous Cell;Esophageal injury;Esophageal mucous membrane;Esophagus;Etiology;Exposure to;Family suidae;Gastroenterology;Genetic Transcription;Gland;Goals;Human;In Situ;In Vitro;Inflammation;Inflammatory;Inherited;Injury;Interleukin-1 beta;Intestines;Lesion;Link;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Metaplasia;Modeling;Molecular;Mucous Membrane;Mus;NF-kappa B;Neoplasms;Organoids;Pathogenesis;Pathologic;Pathway Analysis;Pathway interactions;Patients;Phenotype;Phosphorylation;Phosphotransferases;Predisposition;Receptor Protein-Tyrosine Kinases;Reflux;Regulation;Risk;Risk Factors;Rodent Model;Role;Signal Transduction;Source;Submucosa;Testing;Therapeutic;Time;Tissues;Transcriptional Regulation;Transitional Cell;United States;c-myc Genes;cancer prevention;carcinogenesis;clinical implementation;design;evidence base;genome-wide;in vivo;injury and repair;molecular shape;mouse model;novel;phosphoproteomics;preclinical study;precursor cell;progenitor;programs;promoter;single-cell RNA sequencing;stem cells;synergism;transcription factor;transcriptome sequencing;transcriptomics;tumor growth;ubiquitin-protein ligase;wound healing EPHB2-Dependent Signaling: A New Molecular Paradigm in Barrett's Neoplasia PROJECT NARRATIVEBarrett's esophagus is a complex disorder and patients with Barrett's esophagus are at an increased risk ofdeveloping esophageal adenocarcinoma a lethal and most common esophageal malignancy in the UnitedStates. To date the mechanisms contributing to the onset and malignant progression of Barrett's esophagusremain poorly understood. Our proposed studies are accordingly designed to unravel the molecularunderpinnings of Barrett's esophagus and associated esophageal malignancy with an overarching goal ofdeveloping evidence-based biomarkers and rational chemopreventive/therapeutic strategies for this increasinglyprevalent and complex disease. NCI 10713941 9/20/23 0:00 PAR-20-077 1P01CA269019-01A1 1 P01 CA 269019 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 5910 10531371 "BLUM, ANDREW EDWARD" Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 408114 259721 148393 PROJECT SUMMARY/ABSTRACTThe etiology of Barrett's esophagus (BE) a molecularly complex disorder of the distal esophagus remainselusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC) a lethalincreasingly prevalent and the most common esophageal malignancy in the U.S. Our long-term objective is toidentify the causative mechanisms underlying the onset and malignant progression of BE and to developevidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical implementation.Project 3 of this program is based on our recent discovery of EphB2 Receptor Tyrosine Kinase as a novelpromoter of Barrett's neoplasia. RNA sequencing coupled with pathway modeling in treatment-nave patientbiopsies showed significant hyperactivation of EphB2 signaling in the vast majority (>90%) of BE and EAClesions. Phenotypic assessments in vitro and in vivo demonstrated EphB2 signaling to be essential for theviability of EAC and dysplastic/BE cells. Subsequent mechanistic studies identified c-MYC as a novel target ofEphB2 signaling while single-cell RNA sequencing of esophageal progenitor cells further confirmed a strongassociation of EphB2 activation with columnar/BE-like cell lineage. Collectively our study implicates EphB2signaling for the first time in BE-EAC pathogenesis and further reveals a novel link between EphB2 and MYC inany disease context. Expanding on these provocative findings we now propose to fully characterize the biologicrole of EphB2 in Barrett's neoplasia as follows: In Aim 1 we will determine whether EphB2 activation is aconsequence of or a pre-requisite for columnar/BE metaplasia development. We will test whether activation ofEphB2 signaling in putative BE-progenitor cells promote columnar/BE-like transformative state. In Aim 2 we willdetermine the pathologic consequences of EphB2 activation in vivo in the esophagus using a constitutively-active EphB2 kinase (Ephb2F613D) mouse model that we recently developed. We will specifically test if EphB2activation induces BE-like metaplasia and dysplasia/cancer in the esophagus; either spontaneously or uponexposure to reflux injury and/or in the setting of esophageal inflammation. We will further characterize the keymolecular programs disrupted by EphB2 activation in the esophagus. In Aim 3 we will determine the downstreamand upstream regulatory cascades of EphB2 signaling. Collectively our proposed studies will delineate the roleof EphB2 signaling for the first time uncovering novel driver mechanisms of BE-EAC pathogenesis. +No NIH Category available Acids;Acinus organ component;Acute;Address;Adenocarcinoma Cell;Aftercare;Area;Barrett Esophagus;Barrett's carcinogenesis;Biological Markers;Cells;Chemoprevention;Chemopreventive Agent;Chronic;Clinical;Coculture Techniques;Complex;Databases;Development;Disease;Distal;Duct (organ) structure;Dysplasia;Epithelium;Esophageal Adenocarcinoma;Esophageal injury;Esophagectomy;Esophagogastric Junction;Esophagus;Etiology;Excision;Family suidae;Gastroesophageal reflux disease;Gene Expression;Genes;Gland;Goals;High grade dysplasia;Histologic;Human;IL8 gene;Immune;Individual;Inflammation;Inflammatory;Inherited;Injury;Intervention;Knowledge;Lesion;Ligands;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of esophagus;Mediating;Metaplasia;Modeling;Molecular;Molecular Profiling;Mucinous;Mucous Membrane;Names;Non-Steroidal Anti-Inflammatory Agents;Organ;Organoids;Outcome;Pancreas;Pathogenesis;Pathway interactions;Patients;Pattern;Phenotype;Population;Predisposition;Prevention;Prevention strategy;Preventive;Process;Program Research Project Grants;Proliferating;Radiofrequency Interstitial Ablation;Recurrence;Reflux;Refractory;Reporting;Research;Residual state;Risk;Role;Sampling;Signal Pathway;Signal Transduction;Source;Specimen;Squamous Cell;Submucosa;Testing;Therapeutic;Transitional Cell;Treatment Failure;biomarker identification;cancer prevention;cancer risk;carcinogenesis;chemokine;cohort;cytokine;evidence base;experimental study;gastroesophageal junction adenocarcinoma;healing;immune cell infiltrate;immunoregulation;improved;improved outcome;in vivo;injury and repair;insight;mortality;pre-clinical;prevent;progenitor;programs;recruit;repaired;response to injury;screening;spatiotemporal;stem cells;stomach cardia;synergism;tumor;tumor-immune system interactions;wound healing Inflammation And Submucosal Glands During Esophageal Injury And Repair PROJECT NARRATIVEEsophageal and gastroesophageal junction adenocarcinomas remain cancers associated with poor survival andcurrent preventive strategies have been limited in reducing this high mortality. Improvements in screening andpreventive approaches may emerge from more complete understanding of how esophageal adenocarcinomasarise in the context of chronic injury and abnormal wound healing. We focus on esophageal submucosal glandsas a potential source of progenitor cells in the esophagus where we have observed inflammation and we nowpropose experiments to understand this microenvironment and how it may influence wound healing with the goalof identifying more effective preventive strategies to reduce cancer risk and improving current strategies foresophageal cancer interception. NCI 10713940 9/20/23 0:00 PAR-20-077 1P01CA269019-01A1 1 P01 CA 269019 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 5909 10596122 "GARMAN, KATHERINE " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 664035 630856 33179 PROJECT SUMMARYThe etiology of Barrett's esophagus (BE) a complex metaplastic disorder of the distal esophagus remainselusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC) a lethaland increasingly prevalent disease and the most common esophageal malignancy in the U.S. Our long-termobjective is to identify the causative mechanisms underlying the onset and malignant progression of BE and todevelop evidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinicalintervention. Project 2 of this program addresses a controversial area in the field that has been understudied.Esophageal submucosal glands (ESMGs) represent a progenitor cell source in the esophagus and our grouphas previously demonstrated increased proliferation and acinar ductal metaplasia (ADM) in ESMGs in thecontext of injury and EAC. We have observed immune cell infiltrates in ESMGs associated with ADM butimportant knowledge gaps persist about the types of immune cells found in areas of ADM and the effect of thismicroenvironment on ADM wound healing and the molecular programs associated with BE/EAC. Project 2 willthus investigate the relationship between injury-induced cytokines such as C-X-C motif chemokine ligand 8(CXCL8 or IL8)) esophageal wound healing and ADM. Ongoing inflammation and abnormal signaling in ESMGsand at the GEJ may provide a persistent source of abnormal progenitor cells after radiofrequency ablationcontributing to treatment failures including refractory and recurrent dysplasia and progression to EAC. Theproposed project will address preclinical questions about how to improve outcomes after radiofrequency ablationor endoscopic resection of early lesions including high grade dysplasia and very early cancers. To addressthese research questions we will use our 1) large human esophagectomy database that includes failed-radiofrequency ablation cases that resulted in esophagectomy and 2) our porcine radiofrequency ablation modeland porcine and patient-derived organoids. Our project has strong synergy with both projects 1 and 3 expandingthe scope our program project grant to include models with ESMGs and allowing comparison to wound healingat the gastroesophageal junction. We will investigate how targeting the inflammation in ESMGs and at thegastroesophageal junction may provide a potential cancer interception and preventive strategies.. +No NIH Category available 3-Dimensional;Ablation;Acceleration;Address;Affect;Age Months;Barrett Esophagus;Barrett's carcinogenesis;Barrett's neoplasia;Biological Assay;Biological Markers;Biopsy;Cell-Cell Adhesion;Cells;Chemopreventive Agent;Complement 3d;Complex;Desmosomes;Development;Disease;Distal;Duct (organ) structure;Dysplasia;Electron Microscopy;Ephrin-B2;Epithelium;Esophageal Adenocarcinoma;Esophageal injury;Esophageal mucous membrane;Esophagus;Etiology;Exhibits;Exposure to;Family;Functional disorder;Genes;Genetic;Genotype;Germ-Line Mutation;Gland;Goals;Homeostasis;Human;Impairment;Inflammation;Inherited;Injury;Intercellular Junctions;Interleukin-1 beta;Knock-in;Knock-in Mouse;Knock-out;Knockout Mice;Lead;Lesion;Malignant - descriptor;Malignant Neoplasms;Metaplasia;Methods;Modeling;Molecular;Molecular Genetics;Morphology;Mucous Membrane;Mus;Mutant Strains Mice;Mutation;Organoids;Orthologous Gene;Oxidative Stress;Pathogenesis;Pathology;Pathway interactions;Patients;Phenotype;Phosphotransferases;Pilot Projects;Predisposition;Recurrence;Reflux;Risk;Role;Signal Transduction;Squamous Cell;Squamous Differentiation;Squamous Epithelium;Submucosa;Testing;Therapeutic;Tissues;United States;Variant;cancer prevention;carcinogenesis;clinical implementation;comparison control;deoxycholate;design;evidence base;exome sequencing;experimental study;follow-up;genotoxicity;healing;human subject;indexing;induced pluripotent stem cell;injury and repair;interstitial;microscopic imaging;mouse model;mutant;novel;prevent;programs;prospective;segregation;synergism;transcriptomic profiling;transdifferentiation;translational goal;wound healing Deciphering the Molecular Genetics of VSIG10L in Barrett's Neoplasia PROJECT NARRATIVEBarrett's esophagus is a complex disorder and patients with Barrett's esophagus are at an increased risk ofdeveloping esophageal adenocarcinoma a lethal and most common esophageal malignancy in the UnitedStates. To date the mechanisms contributing to the onset and malignant progression of Barrett's esophagusremain poorly understood. Our proposed studies are accordingly designed to unravel the molecularunderpinnings of Barrett's esophagus and associated esophageal malignancy with an overarching goal ofdeveloping evidence-based biomarkers and rational chemopreventive/therapeutic strategies for this increasinglyprevalent and complex disease. NCI 10713939 9/20/23 0:00 PAR-20-077 1P01CA269019-01A1 1 P01 CA 269019 1 A1 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 5908 2067894 "CHAK, AMITABH " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 549691 362325 187366 PROJECT SUMMARY/ABSTRACTThe etiology of Barrett's esophagus (BE) a molecularly complex disorder of the distal esophagus remainselusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC) a lethalincreasingly prevalent and the most common esophageal malignancy in the U.S. Our long-term objective is toidentify the causative mechanisms underlying the onset and malignant progression of BE and to developevidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical implementation.Project 1 of this program is based on our prior discovery of a novel germline susceptibility mutation in VSIG10L(S631G) that modulates the epithelial integrity of squamous epithelium. VSIG10L is expressed in suprabasalcells as squamous epithelium matures. Furthermore we have generated mice that are either null for Vsig10l orcarry the mouse ortholog of the human S631G variant. Homozygous Vsig10l knockout (KO) and homozygousS631G knockin (KI) mice are both viable. Electron microscopy imaging demonstrates decreased desmosomalcell to cell junctions in the suprabasal squamous cells of mice with altered VSIG10L. Further both mousegenotypes initially develop multilayered epithelium at 12 months of age and BE like metaplasia by 24 months atthe squamo-columnar junction (SCj) upon exposure to genotoxic/oxidative stress (Deoxycholate). The threeAims of Project 1 strategically address how mutations in VSIG10L lead to a susceptibility to BE. Aim 1 will definephenotypic and molecular alterations affected by VSIG10L mutations in three dimensional organotypic cultures.Aim 2 will define phenotype of our mouse models and identify molecular alterations that lead to BE likemetaplasia and dysplasia. Aim 3 studies how VSIG10L expression is associated with a susceptibility to developBE in human subjects. Collectively our proposed studies will delineate the role of VSIG10L in esophagealhomeostasis uncovering novel mechanisms of BE-EAC pathogenesis. +No NIH Category available Address;Affect;Barrett Esophagus;Barrett's carcinogenesis;Basic Science;Bibliometrics;Bioinformatics;Biological Markers;Biology;Cell Adhesion Molecules;Cell Communication;Cell Differentiation process;Cells;Clinical;Collaborations;Complex;Detection;Development;Devices;Disease;Duct (organ) structure;Dysplasia;EPHB2 gene;Epithelial Cell Junction;Epithelium;Esophageal Adenocarcinoma;Esophageal injury;Esophagus;Genes;Genetic;Genetic Predisposition to Disease;Gland;Goals;Grant;HNF4A gene;Hyperactivity;IL8 gene;Individual;Inflammatory;Inflammatory Infiltrate;Inherited;Injury;Institution;Interdisciplinary Study;Laboratories;Laboratory Research;Laboratory Scientists;Lead;Legal patent;MAPK8 gene;Manuscripts;Mediating;Mediator;Metaplasia;Molecular;Molecular Target;Morbidity - disease rate;Mutate;Pathway interactions;Pattern;Phenotype;Population;Predisposition;Prevention;Prognosis;Public Health;Publishing;Reflux;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Services;Signal Pathway;Signal Transduction;Signaling Molecule;Specialized Program of Research Excellence;Squamous Epithelium;Submucosa;Susceptibility Gene;System;TGFB1 gene;Therapeutic;Tissues;Translating;Translational Research;Universities;biobank;c-myc Genes;cancer prevention;carcinogenesis;carcinogenicity;cell growth;cell motility;clinical application;detection method;esophageal carcinogenesis;fusion gene;genetic approach;healing;improved;injury and repair;instructor;molecular marker;mortality;mouse model;notch protein;novel;precursor cell;prevent;professor;programs;repaired;response to injury;risk stratification;screening;support network;synergism;transcription factor;transcriptomics;wound healing;wound response Pathways of Injury and Repair in Barrett's Carcinogenesis PROGRAM NARRATIVEEsophageal adenocarcinoma (EAC) is a rapidly rising public health problem and its prognosis remains poor.Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma but it often goes undetected. TheProgram Project focuses on genetic and molecular studies that will develop better understanding of how refluxinjury and repair result in development of BE and its progression to EAC in susceptible individuals. The ultimategoal is to develop improved methods for detecting BE predicting its progression to EAC and preventing BE fromprogressing to EAC. NCI 10713938 9/20/23 0:00 PAR-20-077 1P01CA269019-01A1 1 P01 CA 269019 1 A1 "RICHMOND, ELLEN S" 9/20/23 0:00 8/31/28 0:00 ZCA1-RPRB-L(M1)S 2067894 "CHAK, AMITABH " "GUDA, KISHORE " 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2268872 NCI 1756207 512665 PROGRAM SUMMARYThe central hypothesis of this program project is that Altered squamous epithelial integrity (Prj 1) andinflammatory injury (Prj 2) activate signaling pathways including EPHB2 (Prj 3) that affect precursor cellsat the squamocolumnar junction (SCj) transition esophageal submucosal gland (ESMG) and basalsquamous niches resulting in the alteration of regulatory factors that include Notch Myc p63 andSOX9 leading to acinar ductal metaplasia (ADM) multi-layered epithelium (MLE) Barrett's esophagus(BE) and ultimately esophageal adenocarcinoma (EAC). The Specific Aims of our program are:1) To elucidate signaling pathways by which mutated VSIG10L alters epithelial integrity leading to MLE and BElike metaplasia on novel mouse models.2) To define the spatial and temporal pattern of CXCL8 (IL-8) in ESMG following esophageal injury andphenotype the inflammatory infiltrate that leads to the development of acinar ductal metaplasia (ADM) in ESMGassociated with BE/EAC.3)To identify mediators of EPHB2 signaling that lead to c-MYC activation and metaplastic cellular differentiationafter injury in the development of BE and its progression to EAC.4) To define how altered epithelial integrity inflammatory cells and alteration of signaling molecules that controldifferentiation (EPHB2) lead to metaplasia by altering transcription factors.5) Integrate projects by providing investigators effective support through Core resources with state-of-the-artBiorepository Bioinformatics and Administrative Services.These objectives build and synergize on the considerable clinical basic science and translational expertiseavailable at our institutions 1) to focus laboratory research on understanding the genetic susceptibility andmolecular changes that influence the development of BE and EAC; and 2) to then translate laboratory discoveriesinto clinical applications for effective detection molecular risk stratification and prevention of progression fromBE to EAC. 2268872 +No NIH Category available 2019-nCoV;Agreement;Antibodies;Antibody Response;Antigens;Autoimmune Diseases;Automation;Bacteria;Bar Codes;Benchmarking;Binding;Binding Proteins;Biological Assay;COVID-19 assay;COVID-19 diagnosis;COVID-19 pandemic;COVID-19 patient;Cancer Biology;Cancer Burden;Cancer Diagnostics;Cancer Patient;Cervical Squamous Cell Carcinoma;Characteristics;Clinic;Clinical;Communicable Diseases;Competence;Consumption;DNA;DNA Sequence;DNA sequencing;Data;Detection;Development;Diagnosis;Diagnostic tests;Disease;Disease Progression;Educational process of instructing;Enzyme-Linked Immunosorbent Assay;Epidemiology;Epitopes;Etiology;FDA Emergency Use Authorization;Fluorescence;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Hepatitis C;Heterogeneity;Human;Human Herpesvirus 4;Human Papillomavirus;Immune response;Immunoassay;Individual;Informatics;Kinetics;Laboratories;Legal patent;Length;Libraries;Liquid substance;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measurement;Measures;Methods;Monitor;Noise;Oropharyngeal;Oropharyngeal Squamous Cell Carcinoma;Patients;Peptides;Performance;Phase;Play;Preparation;Procedures;Production;Protein Array;Protein Array Analysis;Protein Microchips;Proteins;Proteome;Protocols documentation;Quality Control;Reagent;Reproducibility;Research;Risk Assessment;Running;SARS-CoV-2 antibody;Sampling;Screening for cancer;Serology test;Serum;Signal Transduction;Surface;Technology;Testing;Tumor Antigens;Variant;Viral Antigens;Virus;antibody test;anticancer research;carcinogenesis;co-infection;comparison control;cost;data pipeline;detection limit;detection method;early screening;experience;fungus;improved;indexing;innovation;large scale production;malignant oropharynx neoplasm;microbial;microorganism;microorganism antigen;multiplex assay;next generation;next generation sequencing;pathogen;process optimization;programs;protein folding;respiratory pathogen;response;screening;seasonal coronavirus;tool Multiplex In-Solution Protein Array (MISPA) for high throughput quantitative early profiling of pathogen-induced head and neck Project Narrative/RelevanceMeasuring the strength of patient antibody responses in clinical samples is important in cancer biology anddiagnostics. We propose to develop an innovative high-throughput platform in which we will marry thepowerful DNA sequencing technology and immunoassay to assess antibody response to many hundreds ofcancer related pathogens in many thousands of individuals simultaneously. This will create a fast sensitivelow cost robust research tool for early screening of pathogen induced cancers. NCI 10713928 8/28/23 0:00 RFA-CA-22-002 1R33CA281802-01 1 R33 CA 281802 1 "WANG, WENDY" 9/1/23 0:00 8/31/26 0:00 ZCA1-TCRB-5(M1) 6770746 "LABAER, JOSHUA " Not Applicable 4 MISCELLANEOUS 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ ORGANIZED RESEARCH UNITS 852876011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 390906 NCI 248985 141921 AbstractProfiling antibody response to disease-associated antigens is important to cancer research. In contrast to thehistorical approach of testing responses to individual proteins screening and diagnosis increasingly rely onmultiplexed assays to elucidate disease and patient heterogeneity. Protein microarrays allow proteome-scalescreening with low sample consumption but are constrained by binding kinetics of surface-bound proteinsnon-specific binding limited dynamic range of fluorescence detection and not readily available in clinics.Peptide-based approaches limit the assay to linear epitopes. With support from IMAT R21 we havedeveloped a next-generation liquid-phase protein microarray platform Multiplex In Solution Protein Array(MISPA) which exploits the extraordinary dynamic range of next generation sequencing (NGS) with wideapplicability in both research and clinical labs. We quantitatively profiled the immune responses oforopharyngeal (OPSCC) patient and control samples using a barcoded human papillomavirus (HPV)antigen library for 12 HPV subtypes NGS. The assay successfully detected the positive responses in theOPSCC samples and demonstrated greater signal-to-background ratio reproducibility and dynamic range.Subsequently we have advanced MISPA to assay antibody response against SARS-CoV-2 seasonalcoronaviruses and other respiratory pathogens in more than 1000 samples simultaneously as part of theNCI SeroNet with over 90% overall percent agreement with a clinical COVID-19 diagnosis and commercialEUA serological assays. In the R33 phase we propose to further develop the MISPA platform to a fullyautomated research platform that is quantitative robust highly reproducible high-throughput andinexpensive for early cancer screening. We will establish SOPs for robust protein production stable proteinlibrary storage and minimal reagent lot-to-lot variations. We will demonstrate the versality of MISPA byincreasing the barcoded protein library size to 192 by including antigens from different subtype of HPV otherviruses bacteria fungi and tumor antigens. We will improve reproducibility and throughput with end-to endautomation for the MISPA platform to support large-scale projects requiring assaying tens of thousandssamples. We will determine the limit of blank limit of detection linear dynamic range precision and otherperformance measures for quantitative assays. We will profile the 192 cancer related antibodies in hundredsof patients with OPSCC and cervical cancer and more than 1000 cancer free controls and benchmark theperformance with the current gold standard ELISA platform. Our experience with developing innovative high-throughput immunoproteomics platforms using laboratory automation and the quality of our preliminary dataspeak for our competency in implementing our proposed development. A quantitatively reproducible assay tomeasure hundreds of antibodies against full length properly folded proteins in thousands of individualssimultaneously will greatly benefit cancer sero-epidemiology risk assessment and screening. 390906 +No NIH Category available Activities of Daily Living;Alginates;Antibodies;Area;B lymphoid malignancy;Back;Biocompatible Materials;CAR T cell therapy;CD28 gene;CD3 Antigens;Cancer Patient;Cell Count;Cell Differentiation process;Cell Therapy;Cell physiology;Cells;Clinic;Clinical;Clinical Protocols;Communities;Data;Development;Disease Progression;Disseminated Malignant Neoplasm;Drug Delivery Systems;Dryness;Encapsulated;Engineering;Engraftment;Generations;Goals;Implant;In Vitro;Interleukins;Liquid substance;Lung Neoplasms;Lymphoma;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Measures;Mediating;Medical;Methods;Modeling;Names;Oncology;Pancreatic Adenocarcinoma;Patient Isolation;Patients;Performance;Peripheral Blood Mononuclear Cell;Phenotype;Prevention;Procedures;Process;Production;Proliferating;Proteins;Public Health;Receptor Cell;Research;Research Personnel;Retroviral Vector;Signal Transduction;Solid;Solid Neoplasm;Specialist;Speed;System;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Translations;Treatment Efficacy;Viral;Viral Vector;Virus;Visual impairment;Work;barrier to testing;bioscaffold;cancer care;cancer therapy;cellular transduction;chimeric antigen receptor;chimeric antigen receptor T cells;cost;design;engineered T cells;improved;in vivo;innovation;manufacture;manufacturing cost;manufacturing process;mouse model;multidisciplinary;new technology;novel;ovarian neoplasm;pre-clinical;prevent;procedure cost;prototype;response;retroviral transduction;scaffold;success;therapeutic candidate;tool;transcriptome sequencing;transduction efficiency;tumor;tumor growth MASTER Scaffolds for Rapid Single-Step Manufacture and Prototyping of CAR-T cells RELEVANCE TO PUBLIC HEALTHChimeric Antigen Receptor T (CAR-T) cell therapy is revolutionizing treatment for cancer. However there is adesperate need to speed up and reduce the costs of producing CAR-T cells both for treatment and in theresearch setting. This proposal will develop a novel material-based technology to improve CAR-T cell efficacywhile reducing CAR-T manufacturing from 2-4 weeks to a single day. NCI 10713795 8/17/23 0:00 RFA-CA-22-004 1R33CA281875-01 1 R33 CA 281875 1 "GUAN, PING" 8/17/23 0:00 7/31/26 0:00 ZCA1-TCRB-J(M1) 11876861 "BRUDNO, YEVGENY " Not Applicable 2 ENGINEERING (ALL TYPES) 42092122 U3NVH931QJJ3 42092122 U3NVH931QJJ3; XRPPWZ3TK937 US 35.784675 -78.677233 578204 NORTH CAROLINA STATE UNIVERSITY RALEIGH RALEIGH NC BIOMED ENGR/COL ENGR/ENGR STA 276957514 UNITED STATES N 8/17/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 379446 NCI 258794 120652 PROJECT SUMMARYDespite the unprecedented clinical success of chimeric antigen receptor (CAR) T cell therapy its widespreadapplication is limited by lengthy and labor-intensive ex vivo manufacturing procedures that result in: (i) high cost;(ii) delays to infuse CAR cells to patients with rapidly progressing disease; and (iii) CAR cells with heterogeneouscomposition and terminal differentiation which limit their engraftment and persistence. There is a clear scientificand medical need for approaches to improve CAR T cell production including methods to reduce cell processingtimes reduce manufacturing costs and reduce CAR cell differentiation. Recently our labs collaborativelydeveloped a new technology for CAR cell production called MASTER (Multifunctional Alginate Scaffolds for Tcell Engineering and Release). MASTER consists of dry macroporous alginate materials conjugated to CD3and CD28 antibodies and encapsulating interleukin signaling. CAR generation with MASTER technologyinvolves seeding freshly isolated non-activated patient PBMCs together with CAR-encoding retroviral vectorsand implanting scaffolds back into patients. Once implanted MASTER mediates every step of the CARproduction process thereby eliminating the current standard procedural steps of CD3/CD28 pre-activationviral transduction with spinoculation and interleukin-mediated CAR expansion. In vitro MASTER-generated CARcells demonstrate reduced cellular differentiation as compared to CAR cells generated with gold-standardconventional clinical protocols. In vivo MASTER-generated CAR cells demonstrate far superior in vivo cellpersistence enhanced anti-tumor efficacy and far superior prevention of tumor growth after rechallenge. Theutility of this system is two-fold: 1) as a transformative therapeutic technology creating enhanced and affordableCAR therapy for cancer care and 2) as a research tool enabling rapid development prototyping and testing ofCAR therapeutic candidates. We have assembled a focused multidisciplinary team comprised of an expert inbiomaterials and drug delivery (Brudno) an expert in viral engineering and protein production (Birnbaum) twospecialists in clinical CAR cell production (Chen Roy) and a clinician focused on CAR cell therapies (Grover). Inthis proposal we seek to further develop and validate MASTER scaffolds and the associated methods to makethem ready for widescale utilization by the research and clinical communities including researchers in relatedareas eager to work in the CAR field but deterred by the barriers to test CAR construct in vivo. Leveragingtransformative preliminary data that show that the shelf-stable MASTER scaffolds outperform conventional CARcells in preclinical mouse models of lymphoma orthotopic pancreatic cancer and metastatic lung and ovariantumors this proposal will validate MASTER scaffolds with a wide range of donors and at different scales withmultiple viral vectors and CAR constructs and delineate the phenotype and function resulting from MASTERproduction of CAR cells. The successful completion of these aims will propel our ultimate vision of low-cost andtunable generation of CAR cells for both liquid and solid tumors and potentially beyond the oncology space. 379446 +No NIH Category available Acoustics;Adverse event;Biological Markers;Cause of Death;Chemoprevention;Chemopreventive Agent;Cirrhosis;Clinical;Clinical Chemoprevention;Clinical Trials;Conduct Clinical Trials;Consent;Controlled Clinical Trials;Development;Double-Blind Method;Epigallocatechin Gallate;Future;Goals;Green tea;Hepatic;Histologic;Immunohistochemistry;Incidence;Individual;Liver;Lung;Malignant Neoplasms;Measurement;Measures;Mediating;Medical;Molecular;Molecular Target;Monitor;Myofibroblast;Oral Administration;Participant;Patient Selection;Patient-Focused Outcomes;Patients;Phase;Phase III Clinical Trials;Placebo Control;Placebos;Plasma;Prevention;Primary carcinoma of the liver cells;Quality of life;Randomized;Research Design;Risk;Rodent Model;Safety;Sample Size;Sampling;Serum;Slice;Stromal Cells;Surrogate Endpoint;Testing;Therapeutic;Time;Tissues;cell type;clinical translation;clinically relevant;design;dietary supplements;elastography;experimental study;follow-up;high risk;improved;indexing;insight;liver biopsy;liver stiffness;mortality;novel;patient prognosis;patient subsets;permissiveness;phase I trial;phase III trial;prevent;prevention clinical trial;primary endpoint;prognostic;response;secondary endpoint;senescence;translational approach;translational therapeutics;tumor Epigallocatechin gallate for prevention of lethal cirrhosis complications NarrativePrevention of hepatocellular carcinoma (HCC) in cirrhosis is an urgent unmet medical need given the limitedefficacy of existing therapies and resulting poor HCC mortality. We will test epigallocatechin gallate (EGCG) agreen tea catechin as a biomarker-guided dietary-supplement-based HCC chemoprevention in a phase IIplacebo-controlled clinical trial for its safety and efficacy in patients with cirrhosis. We will also explore clinicaland molecular correlates with the response to inform design of subsequent phase III trial toward clinicaltranslation of the therapy. NCI 10713745 9/6/23 0:00 PAR-21-035 1R01CA282178-01 1 R01 CA 282178 1 "UMAR, ASAD" 9/6/23 0:00 8/31/28 0:00 Hepatobiliary Pathophysiology Study Section[HBPP] 9925976 "HOSHIDA, YUJIN " "SINGAL, AMIT " 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/6/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 684526 NCI 417394 267132 SummaryHepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis and the fastest risingcancer mortality in the U.S. Due to the limited efficacy of existing therapies for established HCC tumorsprognosis for patients remains poor with five-year survival under 15%. Thus HCC chemoprevention in cirrhosisis likely the most impactful strategy to improve survival. However despite the candidate chemopreventive agentssuggested in experimental studies it remains an unmet need due to logistical difficulty in conducting clinical trialsthat require large sample size and long follow-up time. To overcome the challenge we identified Prognostic LiverSecretome signature (PLSec) to quantitatively monitor therapeutic modulation of HCC risk level in cirrhosispatients and predict reduction of future incident HCC. PLSec has been used as a surrogate endpoint in ourongoing and planned HCC chemoprevention clinical trials. Experimental studies in rodent models by us andothers suggested that epigallocatechin gallate (EGCG) a green tea catechin prevents HCC developmentwithout any adverse events. Our ex vivo organotypic culture of precision-cut liver slice (PCLS) from cirrhosispatients revealed suppression of high-risk signature by EGCG supporting its clinical relevance. Based on thesepromising findings the goal of our proposal is to test our hypothesis that EGCG treatment safely suppressesPLSec in patients with cirrhosis. Aim 1. Evaluate safety and efficacy of EGCG in cirrhosis patients (phase IIdouble-blinded placebo-controlled clinical trial). We will evaluate 24-week EGCG treatment or placebo in 60patients (1:1 randomization) with early-stage cirrhosis enriched for elevated HCC risk by a clinical variable-basedscore (FIB-4 index) and PLSec. Participants will be monitored monthly for adverse events. Serum samples willbe obtained before during and at the end of treatment. Primary endpoint: reduction of risk level as measuredby PLSec (delta-PLSec). Secondary endpoints: safety profile change in quality of life. Exploratory endpoints:change in on-treatment PLSec immunohistochemistry of HCC-risk-related markers for participants consentedfor liver biopsy and incident HCC. Aim 2. Identify factors associated with response to EGCG in cirrhosis patients.We will evaluate pre-treatment PLSec and clinico-histological variables; on-treatment PLSec modulation andplasma concentration of EGCG and its metabolites for their association with the primary endpoint. We will alsoassess modulation of the FIB-4 index and liver stiffness measurement by acoustic elastography as potentialalternative clinical endpoints to monitor effect of EGCG We expect to establish novel HCC chemopreventionwith a dietary supplement for subsequent pivotal phase III clinical trial toward clinical translation of this approachwhich will contribute to a transformative improvement in the outcome of patients with HCC by enabling individual-risk-based molecular-targeted and safe chemoprevention of this deadly cancer. 684526 +No NIH Category available Adherence;Adoption;Agreement;Alpha Particle Emitter;Clinical Data;Clinical Research;Collaborations;Data;Data Collection;Databases;Dose;Drug Kinetics;ERBB2 gene;Ethics;FOLH1 gene;Future;Goals;Image;Industry;J591 Monoclonal Antibody;Patient imaging;Patients;Positron-Emission Tomography;Privacy;Protocols documentation;Radiobiology;Radiopharmaceuticals;Research;Research Personnel;Scientific Inquiry;Standardization;Toxic effect;Work;absorption;data acquisition;data sharing;dosimetry;flexibility;programs;response;single photon emission computed tomography;standard of care;treatment optimization;tumor Core 3: Patient Data Project NarrativeThe Patient Data Core will provide oversight of patient data collection and use required to complete the scientificobjectives of the program project assuring that Investigators have access to the required data with adherenceto all standards of privacy and ethics. This core will also work towards increasing collaboration and data sharingamong academic and industry researchers in the field of radiopharmaceuticals as well as encouraging datacollection as part of standard of care radiopharmaceutical therapy to strengthen future scientific inquiry in thisexciting and growing field. NCI 10713717 9/19/23 0:00 PAR-20-077 1P01CA272222-01A1 1 P01 CA 272222 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 5881 11809168 "KIESS, ANA PONCE" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 200198 122258 77940 Project SummaryOverall the primary effort of this Core will be to conduct a master imaging trial for patients undergoing RPTtreatment at Johns Hopkins as well as to establish deep research collaborations among investigatorscollaborators and industry sponsors. For Aim 1 the Core Investigators will conduct a master imaging trial(SeeToTreat) to acquire data for the P01 projects with flexibility to include patients receiving standard of care orresearch RPT on other protocols. For Aim 2 Dr. Sgouros Dr. Kiess and the research staff have establisheddeep research collaborations with Bayer (227Th-HER2-TTC and 227Th-PSMA-TTC) Rayzebio (225Ac-DOTATATE) and Cornell (225Ac-J591) to support the P01 Projects as well as future collaborative work. Theseresearch collaborations will include sharing of images and data from completed and ongoing clinical studiesincluding SPECT dosimetry PET surrogate images and response data. The industry research agreements arenow fully executed. For Aims 3 and 4 the Core will establish a de-identified RPT database of images absorbeddose tumor response and toxicity data. This will include collection of data from SEEtoTREAT RAVENS andfrom industry and academic collaborators. +No NIH Category available Address;Alpha Particle Emitter;Alpha Particles;Anatomy;Animal Experiments;Animal Model;Animals;Area;Autopsy;Biodistribution;Biological;Biological Assay;Biological Markers;Cancer Patient;Cell Line;Clinical;Clinical Trials;Collaborations;Collection;Communities;Consultations;DNA Damage;DNA Repair;DNA Repair Pathway;Data;Data Analyses;Data Storage and Retrieval;Disseminated Malignant Neoplasm;Dose;Drug Kinetics;Experimental Designs;Goals;Guidelines;Healthcare;Histopathology;Human;Human Experimentation;Image;In Situ;Institution;Knock-out;Knowledge;Malignant Neoplasms;Measurement;Methodology;Modality;Molecular;Monitor;Neoplasm Metastasis;Normal tissue morphology;Organ;Pathologic;Pathologist;Pathology;Patient Care;Patients;Peripheral;Pharmaceutical Preparations;Pharmacodynamics;Phase I Clinical Trials;Photons;Predisposition;Procedures;Process;Protocols documentation;Public Health;Radiation;Radiobiology;Radioisotopes;Radiopharmaceuticals;Reproducibility;Research;Research Personnel;Resources;Retrieval;Role;Services;Specimen;Techniques;Testing;Therapeutic;Therapeutic Agents;Therapeutic Research;Therapeutic procedure;Tissue Sample;Tissues;Toxic effect;Translating;Tumor Tissue;Universities;Work;absorption;animal tissue;cancer therapy;cost;data management;design;digital imaging;dosimetry;experience;experimental study;human tissue;improved;inhibitor;member;model design;non-invasive imaging;programs;prospective;resistance mechanism;sample collection;sex;side effect;single photon emission computed tomography;success;timeline;treatment planning Core 1: Animal Models Pathology and Tissue Project NarrativeThe Animal Models Pathology and Tissue Core B will collect process and provide centralized gross andhistopathologic and in situ biomarker analysis for all biospecimens in the 4 Program Projects. These projects allrely on core B for expertise and methodologies to test hypotheses on optimization of RPT dose adjustmentswithout causing toxicity a current unmet need in RPT cancer therapeutics and public health. To address thisunmet need in experiments outlined in the application facilitated by Core B dosimetry-driven treatmentplanning in combination with a radiobiologic understanding of how absorbed dose translates to biologic effectwill reduce the scope of human experimentation (costs and timeline) needed to clinically optimize RPT forcancer patients. NCI 10713715 9/19/23 0:00 PAR-20-077 1P01CA272222-01A1 1 P01 CA 272222 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 5879 1900899 "GABRIELSON, KATHLEEN LOUISE" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 227403 138872 88531 Project SummaryAlpha-particle -emitter radiopharmaceutical therapy (RPT) is a new and rapidly evolving therapeutic modalitythat can deliver highly potent alpha-particles to disseminated cancer metastases with 100 micron preciseradiation trajectory and less toxicity in patients. Since almost all of the radionuclides used in RPT emit photonsthat can be imaged non-invasively valuable pharmacokinetic and anatomical data is provided. Preciselytargeting the cancer without side effects to normal tissues would be a breakthrough for patient care. All patientsare different though and each patient may need RPT dose adjustments but current implemented RPTprotocols dont achieve this goal. To address this unmet need in experiments outlined in the applicationfacilitated by Core B dosimetry-driven treatment planning in combination with a radiobiologic understanding ofhow absorbed dose translates to biologic effect will reduce the scope of human experimentation (costs andtimeline) needed to clinically optimize RPT. To achieve these goals and test project hypotheses Projects 1-4address multiple steps to improve RPT and rely on the Animal Models Pathology and Tissue Core to facilitateall projects using animal models or human tissue-based analyses. Core B molecular tissue techniques willaddress the role of DNA damage by RPT and DNA repair pathway inhibitors in project 4. The overall hypothesisof this PPG is that RPT is a systemic cancer therapy modality that is particularly applicable to targetingmetastatic cancer; and far less susceptible to conventional resistance mechanisms; yet it is amenable todosimetry-driven treatment planning. In the experiments proposed S values measurements can be perfecteddown to a microscale to focus the alpha-particle delivered dose on cancer and eliminate peripheral collateralorgan damage. The Animal models Pathology and Tissue Core are led by an experienced veterinarypathologist/toxicologist and a MD pathologist at Johns Hopkins University who have long contributed to cancertherapeutic research at this institution. The emphasis of the Core is to assist PIs of the four projects in threedifferent areas (1) animal models (2) necropsy tissue sampling processing and histopathology with RPTimage correlation and (3) in situ assays on human and animal tissues to assess DNA damage and repair.Standard operating procedures of the Core for biospecimens incorporate the guidelines as outlined by the 2011Revised NCI Best Practices for Biospecimen Resources. Rigor and reproducibility as well as sex as a biologicalvariable and appropriate animal numbers will be addressed in experimental design. The PIs of this Core havethe necessary expertise and methodologies to provide pathology consultation for use of the human specimensand animal tissues for the proposed studies with a combined 30 years of collaboration with members of thisprogram project and JHU research community. This valued knowledge and experience is applied to improvingpatient cancer RPT therapeutics reducing toxicity resulting in a high impact on public health and patient care. +No NIH Category available Alpha Particle Emitter;Alpha Particles;Anatomy;Animals;Antibodies;Bone Marrow;Clinical;Clinical Trials;Combined Modality Therapy;Data;Dose;Dose Limiting;Drug Kinetics;ERBB2 gene;FDA approved;FOLH1 gene;Family suidae;Fractionation;Goals;Human;Image;Kidney;Lacrimal gland structure;Link;Literature;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Measures;Medicine;Metastatic Neoplasm to the Bone;Methodology;Methods;Microscopic;Miniature Swine;Modality;Modeling;Mus;Organ;Organ Model;Patients;Peptides;Pre-Clinical Model;Process;Publishing;Radiobiology;Radioisotopes;Radiopharmaceuticals;Reporting;Risk;Salivary Glands;Small Intestines;Standardization;Testing;Therapeutic;Therapeutic Uses;Time;Toxic effect;Translating;Translations;Uncertainty;United States National Institutes of Health;Work;absorption;cancer therapy;clinical practice;clinically relevant;design;dosimetry;interest;mouse model;particle;particle therapy;porcine model;pre-clinical;predicting response;programs;response;single photon emission computed tomography;small molecule;spatiotemporal;targeted delivery;targeted treatment;translation to humans;treatment planning Macro-to-micro (M2) Activity Apportionment for RPT PROJECT NARRATIVEWe propose a cellular and functional sub-unit-based dosimetry model for organs at risk for a more accurateassessment and prediction of response and toxicity in -particle radiopharmaceutical therapy of cancer.Radiopharmaceutical/Organ combination-specific pharmacokinetic data will be acquired for translatingmacroscopic activity measurements to relevant sub-organ (standardized) absorbed dose. NCI 10713712 9/19/23 0:00 PAR-20-077 1P01CA272222-01A1 1 P01 CA 272222 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 5876 10425968 "HOBBS, ROBERT FRANCOIS" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 498900 304672 194228 Recent advances in the targeted delivery of radionuclides and the increased availability of -emitters appropriatefor clinical use have led to patient trials of multiple -emitter radiopharmaceutical therapeutics (RPTs). One ofthese Xofigo (223RaCl2) was FDA-approved and is in routine clinical practice with many others likely to follow.One of the stated goals (pillars) of the NIH is a greater level of personalization in medicine. In the realm ofradiopharmaceutical therapy (RPT) this translates directly as a need for more accurate personalized dosimetryin order to enable fractionation and administered activity tailored to each patient. However current dosimetryparadigms are poorly suited to RPT. This reality is reflected by the discrepancies between clinical (orexperimental) toxicity and expected toxicity calculated using standard organ-level (or voxel-level) dosimetryincluding most notably: (a) hematotoxicity in 223Ra therapy of bone metastases (b) renal and salivary glandtoxicity in pre-clinical models and patients. The objective of this work is to create a dosimetric methodology moresuited to RPT namely the Macro to micro (M2) methodology which requires sub-organ activity apportionmentfactors for organs at risk. This will be accomplished via the following Aims: 1. In murine models measure RPTactivity concentration in selected whole organs and in relevant organ sub-regions; generate apportionment factorhistograms. The translation to human assumes that the link between macroscopic and microscopicspatiotemporal relationship for a given agent measured in a pre-clinical model will apply to the human as thedistribution of the agent to the different microscopic compartments should remain the same. We will test andquantify the validity of this assumption and refine the human apportionment factors by introducing a third speciesthe mini-pig In Aim 2. We will assess apportionment factor transferability by obtaining correspondingapportionment factor histograms for a porcine model. In Aim 3. We will demonstrate that M2 predicts toxicity inthe porcine model. 4. Apply the M2 methodology to clinical trial data to quantify the potential benefit ofpersonalized M2 dosimetry and/or derive doseresponse relationships. Successful completion of the proposalwill reconcile experimental and clinical results not currently understood and provide a robust standardizeddosimetry for personalized dosimetry-based treatment planning of RPT. Such standardization will enable thedosimetry to be normalized to EQD2 thus enabling rational combinations with other RPTs or external beamtherapy as well as relevant absorbed dose reporting. Here we plan to expand this approach to encompass thewide range of RPT/organ combinations that have either been shown to be or are potentially dose-limiting andthat require the Macro to micro (M2) methodology to properly correlate dosimetry with toxicity thresholds andprovide a deliverable that will allow end-users to convert macroscopically-measured activity to standardizeddosimetry at the organ and (clinically relevant) sub-organ-level for a wide range of RPTs and correspondinglyrelevant organs. +No NIH Category available 3-Dimensional;Address;Alpha Particle Emitter;Alpha Particles;Anatomic Models;Anatomy;Beta Particle;Blood;Blood capillaries;Bone Marrow;Cells;Chemoresistance;Clinical;Clinical Trials;Development;Disease;Disseminated Malignant Neoplasm;Dose;Family suidae;Freezing;Future;Generations;Geometry;Goals;Harvest;Hemorrhage;Histology;Human;Image;Individual;Kidney;Kupffer Cells;Label;Laboratory mice;Lacrimal gland structure;Libraries;Linear Energy Transfer;Liver;Lobe;Lobule;Lung;Marrow;Methodology;Methods;Microanatomy;Miniature Swine;Modeling;Mus;Nephrons;Normal tissue morphology;Organ;Organ Model;Pathology;Patients;Photons;Population;Pre-Clinical Model;Predisposition;Publishing;Radiation Dose Unit;Radiobiology;Radioisotopes;Radiopharmaceuticals;Risk;Risk Assessment;Salivary Glands;Series;Sinus;Site;Small Intestines;Source;Specimen;Structure;Systemic Therapy;Testing;Time;Tissue Model;Tissues;Toxic effect;Uncertainty;Work;absorption;cancer radiation therapy;cancer therapy;digital imaging;dosimetry;effective therapy;human imaging;in vivo;individual patient;individualized medicine;interest;interpatient variability;kidney cortex;microCT;neoplastic cell;novel;particle;porcine model;preservation;programs;radiation resistance;skeletal;soft tissue;targeted treatment;three-dimensional modeling;tissue preparation;tool;treatment planning;tumor;validation studies Microscale Radionuclide S-values for RPT Project Narrative Project 2Radiopharmaceutical therapy with alpha-particle emitters (RPT) provides a unique and effective treatment forcancer in its advanced stages. In the development of patient-specific treatment planning for RPT one objectiveis to ensure that the radiation dose to normal tissues and organs approaches but remains below thresholds fortoxicity. The primary objective of this project is to develop microscale radionuclide S-values which will permitclinically feasible methods for assessing tissue-level dosimetry of alpha-particles in individual patients. NCI 10713711 9/19/23 0:00 PAR-20-077 1P01CA272222-01A1 1 P01 CA 272222 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 5875 2106046 "BOLCH, WESLEY E" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 477048 444247 32801 Abstract / Summary Project 2Radiopharmaceuticals labeled with alpha-particle emitters (RPT) uniquely satisfy various conditions for therapyof cancer in its advanced stages. Alpha particles have high linear-energy transfer (~100 keV / m) and thus shorttissue ranges (~50-80 m). Resultantly they can sterilize tumor cells with as few as 1-3 particle traversals incontrast to the requirement of 1000s of beta-particle traversals. Furthermore they are not susceptible tochemoresistance and are minimally susceptible to radioresistance. In the development of patient-specifictreatment planning for RPT one primary objective is to ensure that the radiation dose to normal tissues andorgans approaches but remains below thresholds for toxicity. Assessment of alpha-particle dosimetry of organsat potential toxicity risk can be performed via the MIRD schema but it ideally must be applied at a spatial scalethat is pertinent to the specific cell populations which drive toxicity and that is relevant to the ranges of theemitted alpha particles. The MIRD schema states that the absorbed dose to a target region may be computedas the product of the time-integrated activity in a source region (i.e. total number of radionuclide decays) andthe radionuclide S-value (absorbed dose to the target region per decay in the source region). Traditionally theMIRD defines source and target regions as whole organs (liver or kidney) or perhaps organ subregions (e.g.liver lobe or renal cortex). Given the ranges of alpha particles however source and target regions would ideallybe defined at a more microscale level. The main goal of Project 2 is thus to develop a comprehensive library ofmicroscale S-values which will support RPT in the following organs: bone marrow kidneys liver lungs salivaryglands lacrimal glands and small intestine. Aim 1 will develop geometric-based models of these tissues in boththe human and mouse; we have previously published such models for both bone marrow and kidneys. In Aim2 we will develop a new generation of 3D tissue models for microscale S-value computation based upon anextensive library of high-quality serial histology images of these same tissues. These models (both mouse andhuman) will be constructed across multi-ROIs (quantifying intra-organ variability) and multiple individuals(quantifying inter-patient variability). Prior studies have indicated that the laboratory mouse is not a robust pre-clinical model for RPT induced marrow toxicity. Consequently in Aim 3 studies will focus on microscale bonemarrow S-values in the higher-species model of the mini-pig. Also a microscale model of the porcine kidney willbe developed to allow for inter-species extrapolation. Aim 4 studies will focus on validating our Aim 2 and 3models with respect to tissue volume changes and potential loss of blood in the tissue capillaries. Understandingthese changes will allow more accurate modeling of their in-vivo state. +No NIH Category available 3-Dimensional;Address;Adopted;Alpha Particle Emitter;Alpha Particles;Area;Biological Response Modifier Therapy;Characteristics;Clinical;Clinical Trials;Collaborations;Complex;Data;Data Collection;Daughter;Development;Diagnostic Imaging;Diagnostic Procedure;Discipline of Nuclear Medicine;Disseminated Malignant Neoplasm;Distributional Activity;Dose;Drug Kinetics;Gamma Rays;Goals;Histologic;Image;Knowledge;Linear Energy Transfer;Maximum Tolerated Dose;Measures;Methodology;Methods;Modality;Modeling;Monitor;Organ;Outcome;PET/CT scan;Patient Selection;Patient-Focused Outcomes;Patients;Phase;Photons;Physics;Procedures;Program Research Project Grants;Property;Protocols documentation;Radiobiology;Radioisotopes;Radiopharmaceuticals;Resistance;Surface;System;Techniques;Testing;Time;Tissues;Toxic effect;Treatment Efficacy;Treatment Protocols;Uncertainty;Validation;Work;X-Ray Computed Tomography;absorption;animal data;animal-assisted therapy;cancer cell;cancer therapy;chemotherapy;clinical practice;cost;design;dosimetry;image reconstruction;imaging modality;improved;improved outcome;in vivo;individualized medicine;member;optical spectra;patient population;patient response;patient screening;quantitative imaging;reconstruction;response;screening;single photon emission computed tomography;therapy outcome;treatment optimization;treatment planning;tumor Alpha-emitter Imaging for Dosimetry and Treatment Planning NarrativeQuantitative imaging of -particle emitters is important for dosimetry needed to optimize patient therapy. Wellvalidated methods for such imaging do not currently exist. We will develop and validate such methods while alsoconsidering different approaches to reduce the number of imaging sessions required for accurate dosimetry ofRPT NCI 10713710 9/19/23 0:00 PAR-20-077 1P01CA272222-01A1 1 P01 CA 272222 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-F(M1)S 5874 8655324 "DU, YONG " Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 450405 327974 122431 Radiopharmaceutical therapy with -particle emitters (RPT) is a highly effective cancer therapy modality; itdelivers potent alpha-particle radiation to cancer cells and is therefore not susceptible to resistance seen withmost other cancer therapies. It is also unique in that alpha-emitters also emit photons that can be imaged bynuclear medicine modalities. This allows for patient-specific treatment planning and optimization of patienttherapy. These unique features of RPT have not been used however because RPT is so effective that theactivity used to treat patient is too low to be imaged with conventional nuclear medicine imaging methods. In thisproject we will develop and implement accurate single photon emission computed tomography (SPECT) imagingmethods that overcome this limitation. Our hypothesis is that enabling quantitative RPT imaging and making itconvenient so that it is widely adopted will improve the outcome of patients treated with RPT. The distributionof the radionuclide in vivo is a prerequisite for estimating the absorbed dose distributions needed to plan andoptimize RPTs. There are several significant challenges to imaging the distribution of -emitters in patients.Due to their high linear energy transfer (LET) and resulting lethality low administered activities are used. Typicaldecay chains include multiple daughter radionuclides that emit photons and it is important to also determinetheir activity distribution. Also the photon emission spectrum for -emitters typically has many low-abundancegamma rays spread over a wide energy range. These properties have made imaging-based dosimetry difficult;the imaging that has been performed has not been quantitatively rigorous. We propose to develop imagingreconstruction methods applicable to clinical SPECT systems that will account for the complex imaging physicsand allow for validated quantitative SPECT imaging of RPT for accurate dosimetry calculations. The overallgoal is to incorporate such quantitative SPECT imaging into a clinically implementable imaging workflow that canprovide accurate dosimetry for treatment planning and efficacy monitoring. Our group in collaboration withmembers of a Hopkins startup company Radiopharmaceutical Imaging and Dosimetry LLC (Rapid) havealready made considerable progress on SPECT imaging of RPT agents. In Aim1 we will extend this work todevelop quantitative reconstruction methods for SPECT imaging of alpha emitters that produce accuratemeasures of activity distribution for dosimetry which will also be useful for SPECT diagnostic imaging in general.Another challenge for imaging RPT is the requirement that patients return for several imaging sessions to obtainthe needed pharmacokinetics in normal organs and tumors. Thus in Aim 2 we will investigate the trade-offbetween number of imaging time-points and the accuracy of dosimetry. In Aim 3 we will apply the developedimaging method and statistically analyze the relationships between quantitative image measures dosimetrydose-response and therapy outcome. In Aim 4 we consider several potential surrogate radionuclides andassess their utility for pre-therapy dosimetry. +No NIH Category available Address;Biological;Biological Phenomena;Biology;Chemicals;Collection;Complex;Coupled;Coupling;Cryoelectron Microscopy;Dendrimers;Deposition;Development;Devices;Gases;Goals;Heterogeneity;Image;Imaging Techniques;Ions;Mass Spectrum Analysis;Measurement;Methods;Molecular;Morphology;Property;Proteins;Resolution;Retrieval;Route;Shapes;Spectrometry;Structure;System;Techniques;Technology;Translating;Travel;aspirate;biological research;biological systems;biomacromolecule;dalton;electric field;ion mobility;macromolecule;nanoparticle;novel;particle;preservation;pressure;protein complex;simulation;small molecule;ultra high resolution HIGHLY SELECTIVE MACROBIOMOLECULAR ISOLATION SOFT-LANDING AND CHARACTERIZATION USING STRUCTURES FOR LOSSLESS ION MANIPULATIONS PROJECT NARRATIVEStructures for Lossless Ion Manipulations (SLIM) will be developed to enable biomacromoleculeseparations and coupled to a TOF-MS to perform high resolution IMS/MS of macrobiomoleculesselective rerouting of a portion of the ion mobility spectrum for soft-landing (to deposition substrates)and characterize the soft-landed species using orthogonal characterization techniques (e.g. cryoEM). NCI 10713577 7/28/23 0:00 PAR-21-038 1R01CA283818-01 1 R01 CA 283818 1 "AMIN, ANOWARUL" 8/1/23 0:00 7/31/28 0:00 Instrumentation and Systems Development Study Section[ISD] 12270400 "GARIMELLA, SANDILYA " Not Applicable 4 Unavailable 32987476 CWKJEXDG79A7 32987476 CWKJEXDG79A7 US 46.280405 -119.290503 685903 BATTELLE PACIFIC NORTHWEST LABORATORIES RICHLAND WA Research Institutes 993520999 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 406640 NCI 216745 189895 PROJECT SUMMARY/ABSTRACT (30 lines)This project aims to address the current gap in technology for rapid and comprehensive (massstructure) profiling of biomacromolecules. While high resolution ion mobility and mass spectrometryseparations techniques have been extensively developed their application has been largely limited tosmall molecules (m/z < 2000). The ability to access structure and mass information in a high-throughputfashion for macrobiomolecules is an aspirational goal in mass spectrometry. In pursuance of this goalwe will develop a high-resolution ion mobility chemical analysis device based on Structures for LosslessIon Manipulations and in conjunction with mass spectrometry obtain high-throughput high-resolutionIMS/MS of biomacromolecules. The study of the significant heterogeneity in large biomolecularsystems i.e. macrobiomolecules critical to biological research will be enabled by the development ofa new high resolution high throughput analytical system. The SLIM platform currently enabled forultra-high resolution ion mobility profiling (up to the point of separating isotopomers and isotopologues)and manipulations of small molecular ions (<3000 Daltons) will be optimized to efficiently confinetransport and separate macrobiomolecules. Initial optimization of the SLIM will be done by couplingwith a TOF-MS system. SLIM-TOF will be used to perform high resolution IMS/MS of ensembles ofmacrobiomolecular species (with an upper mass limit of about 20000 Da dictated by the TOF). We willuse SLIM-based IMS separations and other manipulations to reveal the extensive structuralheterogeneity of macrobiomolecules. Further we will perform size and mass selective soft-landing ofmacrobiomolecules using the dynamic switching and rerouting (to deposition substrates) of a selectiveion mobility distribution in the SLIM. The soft-landed species will be characterized using cryo-EM andcomplimentary imaging techniques to elucidate the morphologies of macrobiomolecules with selectedmobilities or collision-cross-sections. The combination of ion mobility information and imaging willprovide a detailed structural characterization of macrobiomolecules. 406640 +No NIH Category available Activities of Daily Living;Adaptive Immune System;Affinity;Allografting;Antigen Receptors;Antigens;Biological Models;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Burden;Cancer Vaccines;Cell membrane;Childhood;Childhood Malignant Brain Tumor;Childhood Solid Neoplasm;Clinical Trials;Combined Modality Therapy;Credentialing;Data;Dendritic Cells;Development;Disease;Disease remission;Engineering;Epigenetic Process;Epitopes;Evaluable Disease;Exhibits;FDA approved;Generations;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;HLA Antigens;Health;Human;Immune response;Immunize;Immunotherapeutic agent;Immunotherapy;In Vitro;Incidence;Individual;Infiltration;Infrastructure;Lipids;MYCN gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Monoclonal Antibodies;Morbidity - disease rate;Motivation;Mus;Mutation;Neoplasm Metastasis;Neuroblastoma;Oncogenic;Oncoproteins;Outcome;Patient-Focused Outcomes;Patients;Peptide Vaccines;Peptides;Phenotype;Polymers;Prevention;Prevention strategy;Principal Investigator;Proliferating;Proteins;Public Health;Publishing;Relapse;Research;Residual Neoplasm;Resistance;Sampling;Specificity;Specimen;Survival Rate;Sympathetic Nervous System;System;T cell response;T-Cell Receptor;Testing;Therapeutic;Toxic effect;Transgenic Mice;Treatment Efficacy;Tumor Specific Peptide;Tumor-infiltrating immune cells;United States National Institutes of Health;Vaccines;Validation;adaptive immune response;adaptive immunity;chimeric antigen receptor;clinically relevant;density;design;disorder risk;evidence base;exome sequencing;experience;high risk;immunogenic;immunogenicity;improved;improved outcome;innovation;mouse model;nanoparticle;neoantigens;novel;novel therapeutic intervention;overexpression;pre-clinical;preclinical evaluation;predictive tools;proteogenomics;relapse prediction;relapse prevention;response;self assembly;sialogangliosides;standard of care;transcriptome sequencing;tumor;vaccination strategy;vaccine development;vaccine evaluation;vaccine formulation;vaccine platform;vaccine strategy;vaccine trial Personalized neuroblastoma vaccines PROJECT NARRATIVEThis proposal is relevant to public health because it seeks to develop personalized anti-tumor vaccines focusinghere on the childhood malignancy neuroblastoma. The research is highly relevant to the NIH mission and theurgent unmet need of developing rational evidence-based therapeutic and relapse preventative strategies toreduce the health burden of cancer. This integrated multiple principal investigator project is designed to catalyzeimproved cure rates with decreased morbidity for patients with high-risk neuroblastoma and many advances willbe applicable to the field of cancer in general. NCI 10713548 7/18/23 0:00 RFA-CA-22-016 1U01CA281881-01 1 U01 CA 281881 1 "KUO, LILLIAN S" 8/1/23 0:00 7/31/28 0:00 ZCA1-SRB-A(M1) 1938303 "MARIS, JOHN M" "SCHOENBERGER, STEPHEN PHILIP" 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 353 Non-SBIR/STTR 2023 839128 NCI 620847 218281 PROJECT SUMMARYThis Multiple Principal Investigator (MPI) Project proposal for the Pediatric Immunotherapy Network is focusedon high-risk neuroblastoma a diverse and enigmatic malignancy arising from the developing sympatheticnervous system that remains lethal in 50% of patients despite intensive multi-modal therapy. There is an urgentunmet need for developing novel therapeutic interventions to decrease the incidence of relapse increase overallsurvival and reduce devastating toxicities associated with standard therapy. The primary goal of this Project isto achieve improved outcomes for patients with high-risk neuroblastoma through the development of apersonalized vaccination strategy targeting individualized neoantigens. The central hypothesis is that high-riskneuroblastomas despite a low tumor mutation burden (TMB) harbor a sufficient number of neoepitopes throughcanonical and non-canonical mutations to identify predict and validate optimal neoantigen peptides to engineereffective multivalent personalized neuroblastoma vaccines. The motivation for the proposed research is theurgent need to improve survival and to decrease treatment-related morbidities for patients with high-riskneuroblastoma. Indeed the majority of high-risk neuroblastoma patients achieve a remission with standardtherapy and here we seek to engage the adaptive immune system to eradicate residual disease and preventrelapse. We will test our hypothesis through the two Specific Aims: 1) define the neoantigen landscape of high-risk neuroblastoma patient and genetically engineered mouse model (GEMM) tumors; 2) develop and test areadily translatable personalized vaccination strategy. In Aim 1 we will both provide the proof-of-concept that amultivalent vaccine consisting of both CD4+ and CD8+ epitopes is feasible for each high-risk patient and alsocredential our GEMM system for preclinical vaccination trials in Aim 2. We will use an integrative proteogenomicapproach to identify up to eight immunogenic peptides for each personalized vaccine. In Aim 2 we will test bothpreventative and therapeutic efficacy of self-assembling nanoparticle multivalent peptide vaccines using ourGEMM system on the CB57BL/6 background and then compare this vaccine platform to a new lipid-peptidepolymer vaccine system optimized to deliver peptides to dendritic cells. This Project proposes an innovativeexperimental strategy to identify prioritize and validate neoantigens in high-risk neuroblastoma and a clinicallyrelevant neuroblastoma GEMM system for preclinical evaluation of neuroblastoma vaccines. The significance ofthe proposed Project is the creation and validation of a novel immunotherapeutic approach that has the potentialto revolutionize high-risk neuroblastoma standard of care by providing durable cures and decreased therapy-related morbidity. The expected outcome of this collaborative MPI Project is to establish the preclinical proof-of-concept for a personalized neuroblastoma clinical trial that we would seek to launch in the out years of this grantgiven the infrastructure we have in place. The successful completion of this Project will also enable personalizedneoantigen-based vaccine development for other pediatric malignancies. 839128 +No NIH Category available Biomedical Research;Clinical;Training Programs Clinical Scholars Biomedical Research Training Program NARRATIVEPhysician-scientists functioning at the interface between laboratory research and clinical practice play a criticalrole in the translation of scientific discoveries into new diagnostics and therapeutics. The Clinical ScholarsBiomedical Research Training Program (CSTP) is designed to prepare board eligible/certified physician-scientists to carry out independent laboratory-based research aimed towards clinical translation. Theseindividuals will increase our understanding of the pathogenesis of cancer and lead the development of newcancer treatments. NCI 10713494 8/29/23 0:00 PA-20-142 2T32CA009512-34A1 2 T32 CA 9512 34 A1 "LIM, SUSAN E" 2/1/85 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 8725605 "CHI, PING " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 362617 NCI 348016 26177 ABSTRACTThe Clinical Scholars Biomedical Research Training Program (CSTP) at Memorial Sloan Kettering CancerCenter (MSK) provides a mentored laboratory training experience in cancer research for outstanding MD andMD/PhD residents/fellows who are emerging clinician-scientists. The CSTP is unique among training programsat MSK since it prepares clinically active investigators from a range of research disciplines to pursue researchacross the translational research spectrum. The goal of the program is to prepare highly qualified physician-scientists for an independent research career at the interface of cancer biology and clinical research. TheClinical Scholars in CSTP are trained by principal investigators with an exceptionally broad range of scientificinterests spanning most areas of modern cancer research. Out of 42 preceptors 27 (67%) are physician-scientists who excel at laboratory research clinical research and academic clinical practice and representstrong role models for young investigators pursusing careers in oncology research. The CSTP consists of astructured and cohesive two-year curriculum that combines laboratory research didactic course work in cancerbiology bioinformatics and computational training and career development workshops. Trainees have accessto all resources of MSK an instituion where basic translational and clinical research activites take place inclose proximity in a highly collaborative research environment. The research areas of principal emphasisinclude: 1) human cancer biology mouse models of cancer genetics epigenetics and molecular pathology; 2)drug development and mechanism-based therapeutics; 3) signaling pathways involved in control of cellproliferation; 4) regulatory pathways involved in developmental biology and cell differentiation; 5) cell-cellinteractions adhesion and protein targeting; 6) tumor immunology immunotherapy and transplantation biology.The CSTP has had a long and successful training history with nearly all of its graduates continuing in highlyproductive biomedical research careers. Thus the CSTP has had signficant impact in meeting the nationalneed for physician-scientists who can play leading roles in translating basic discoveries in cancer biology intoclinical practice. 362617 +No NIH Category available Address;African American;Alzheimer's disease diagnosis;Alzheimer's disease related dementia;Alzheimer's disease risk;Area;Award;Benefits and Risks;Cancer Patient;Cancer Survivor;Cancer Survivorship;Clinical;Cognitive;Complement;Data;Data Set;Decision Making;Dementia;Disparity;Distress;Education;Educational Status;Employment Status;Ensure;Equity;Ethnic Origin;Hispanic;Household;Impaired cognition;Income;Individual;Knowledge;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Meta-Analysis;Methodology;Not Hispanic or Latino;Outcome;Paper;Parents;Participant;Patient Education;Patient Self-Report;Patients;Persons;Prevention;Prostate Cancer therapy;Psychosocial Assessment and Care;Public Health;Race;Reporting;Research;Risk;Risk Factors;Risk Reduction;Sampling;Scoring Method;Statistical Methods;Surveys;Symptoms;androgen deprivation therapy;cognitive function;cohort;deprivation;ethnic diversity;ethnic minority;genetic risk factor;health disparity;high risk;improved;indexing;large datasets;men;mild cognitive impairment;neighborhood disadvantage;prostate cancer survivors;psychosocial;racial diversity;racial minority;recruit;social health determinants Identifying Disparities in Mild Cognitive Impairment and Alzheimer's Disease and Related Dementias in Diverse Prostate Cancer Survivors PROJECT NARRATIVEMild cognitive impairment is often a precursor to Alzheimers and related dementias and it is common amongpeople with prostate cancer. This study will identify social determinants of health as risk factors for mild cognitiveimpairment and Alzheimers and related dementias among prostate cancer survivors. This knowledge gap is asignificant public health issue because prostate cancer is the most common malignancy in US men and androgendeprivation therapy is prescribed for most prostate cancer patients. NCI 10713284 4/7/23 0:00 PA-20-272 3R01CA242742-03S1 3 R01 CA 242742 3 S1 "GALLICCHIO, LISA M" 7/23/20 0:00 6/30/25 0:00 11903870 "GONZALEZ, BRIAN D" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 4/7/23 0:00 6/30/23 0:00 393 Non-SBIR/STTR 2023 327239 NIA 194207 133032 PROJECT SUMMARY/ABSTRACTMild cognitive impairment is common among people with cancer and is often a precursor to Alzheimers andrelated dementias. Recent research has focused on risk of mild cognitive impairment in prostate cancersurvivors including among patients receiving androgen deprivation therapy. For example a recent meta-analysisfound androgen deprivation therapy recipients had higher odds of dementia than controls. However previousstudies have not examined social determinants of health disparities as risk factors for mild cognitive impairmentor dementia in prostate cancer. This is a significant public health issue because prostate cancer is the mostcommon malignancy in US men and most prostate cancer patients are prescribed androgen deprivation therapy.To address this gap this study will leverage the parent award study recruiting a diverse cohort of 250 AfricanAmerican 250 Hispanic and 250 non-Hispanic White prostate cancer survivors. This cohort overcomeslimitations in the rigor of prior research that had relatively small samples of racial/ethnic minority prostate cancersurvivors. All participants in the cohort will be asked to complete a validated survey of cognitive function. Weconservatively estimate 200 participants in each group will join the supplement study. This will enable us toidentify social determinants of health risk factors for mild cognitive impairment in prostate cancer survivorship.These risk factors will include race/ethnicity neighborhood disadvantage measured using the Area DeprivationIndex household income education level and employment status. This supplement will also enable us toexamine social determinants of health disparities in risk of mild cognitive impairment after receiving androgendeprivation therapy for prostate cancer. Because mild cognitive impairment is often a precursor to Alzheimersdisease and related dementias we will also aim to replicate these findings in a large dataset with over 1000000racially and ethnically diverse prostate cancer survivors. This will enable us to identify disparities in risk ofdiagnosis of Alzheimers disease or related dementia in prostate cancer survivors including after receivingandrogen deprivation therapy.The parent award study does not currently examine any cognitive outcomes. Instead the parent award studyexamines disparities and risk factors for symptom burden among PC survivors. This study complements theparent award by examining disparities in mild cognitive impairment and Alzheimers disease and relateddementias. This studys specific aims are to identify among prostate cancer survivors social determinants ofhealth disparities in risk of 1) mild cognitive impairment 2) mild cognitive impairment after receiving androgendeprivation therapy and 3) Alzheimers disease or related dementia. This study will contribute to reducing riskof mild cognitive impairment and Alzheimers disease and related dementias and will improve informed decision-making and education on risks/benefits of androgen deprivation therapy for prostate cancer survivors. 327239 +No NIH Category available ATF6 gene;Ascites;Bioenergetics;Biological Assay;CD8-Positive T-Lymphocytes;Cancer Control;Cancer Patient;Cell physiology;Cells;Cellular Metabolic Process;Cellular immunotherapy;Chromatin;Cytoskeletal Proteins;Cytoskeleton;Defect;Development;Effectiveness;Elements;Endocrine;Endoplasmic Reticulum;Epithelium;Event;Exhibits;Exposure to;Follicle Stimulating Hormone Receptor;Generations;Goals;Homeostasis;Human;Immune;Immune Evasion;Immune system;Immunosuppression;Immunotherapy;Intervention;Knowledge;Lipids;Luciferases;Maintenance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Maps;Memory;Metabolic;Mitochondria;Modification;Molecular;Organelles;Pathologic;Pathway interactions;Process;Program Sustainability;Protein Biosynthesis;Recurrent Malignant Neoplasm;Refractory;Replacement Therapy;Reporter;Repression;Research;Respiration;Role;SM 22 muscle protein;Safety;Signal Transduction;Site;Solid;Solid Neoplasm;Stress;T cell infiltration;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Tissues;Transcription Repressor;Transgenic Mice;Tumor Immunity;Tumor-infiltrating immune cells;XBP1 gene;anti-cancer;anti-tumor immune response;anticancer activity;arm;biological adaptation to stress;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cancer recurrence;carcinogenesis;chimeric antigen receptor T cells;cytotoxic;effector T cell;endoplasmic reticulum stress;fatty acid oxidation;fatty acid-binding proteins;immune cell infiltrate;immunoregulation;improved;inhibitor;metabolic fitness;misfolded protein;novel;novel strategies;ovarian neoplasm;overexpression;pharmacologic;preservation;programs;protein folding;sensor;trafficking;tumor;tumor growth;tumor microenvironment;tumor progression;uptake Immunometabolic Programs Controlled by ER Stress in Cancer Project NarrativeThe proposed project will uncover new approaches to enhance the anti-cancer activity of immune cellsespecially in the setting of aggressive malignancies that are refractory to current immune-based treatments.Upon completion our project will provide new mechanistic understanding of how stress signals generated anddelivered by tumors inhibit the protective function of our immune system. This knowledge should pave the wayfor developing novel forms of immunotherapy that more effectively control cancer progression and recurrence. NCI 10713279 6/22/23 0:00 PA-20-185 1R01CA282072-01 1 R01 CA 282072 1 "ZAMISCH, MONICA" 7/1/23 0:00 6/30/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 12607891 "CUBILLOS-RUIZ, JUAN R" Not Applicable 12 OBSTETRICS & GYNECOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 589582 NCI 351920 237662 Project Summary Immunometabolic Programs Controlled by ER Stress in CancerTumors create hostile microenvironments that impede the development and maintenance of effective anti-cancerimmunity. Yet how intratumoral immune cells integrate and interpret persistent stress signals in this harsh milieuremains incompletely defined. We have uncovered that adverse conditions within malignant masses disrupt theprotein-folding capacity of the endoplasmic reticulum (ER) in infiltrating immune cells triggering dysregulatedER stress responses that promote immunosuppression and malignant progression. Therefore we postulatethat understanding and targeting detrimental ER stress responses in the tumor microenvironmentrepresents a major opportunity to develop new and more effective forms of cancer immunotherapy. In akey recent advance we determined that the IRE1a-XBP1s arm of the ER stress response inhibits the expressionof Tagln2 an understudied cytoskeletal protein implicated in T cell activation and effector function. We foundthat XBP1s-deficient T cells demonstrate enhanced Tagln2 expression that supports their protective function attumor sites. Moreover we established that Tagln2 coordinates major metabolic programs that sustain robust Tcell mitochondrial respiration and effector capacity. These new findings have prompted us to dissect themechanisms by which the novel IRE1a-XBP1s-Tagln2 axis controls T cell metabolism and function in cancer.Hence the goals of this project are to i) understand how ER stress inhibits Tagln2 expression ii) establish thatTagln2 equips T cells with robust metabolic fitness that supports their anti-tumor activity and iii) determine thatTagln2 replacement therapy enhances the activity of chimeric antigen receptor (CAR)-T cells in solid tumors.We hypothesize that dysregulated ER stress responses hinder intratumoral T cell function by disabling Tagln2-driven bioenergetic programs and that sustaining this cytoskeletal-mitochondrial axis could be used to improvethe efficacy of adoptive T cell immunotherapy in solid tumors. We will test this novel hypothesis in the setting ofimmunotherapy-refractory ovarian cancer (OvCa) through the following Specific Aims:Aim 1. Define the mechanisms by which ER stress responses inhibit Tagln2 in OvCa-infiltrating T cells.Aim 2. Establish the role of Tagln2 as a metabolic driver of competent anti-tumor T cell function.Aim 3. Test the hypothesis that preserving Tagln2 activity enhances CAR-T cell immunotherapy in OvCa.Collectively the proposed project will expand our mechanistic understanding of immune regulation in the tumormicroenvironment and promises to pave the way for novel interventions that augment the efficacy of cellularimmunotherapy against solid malignancies. 589582 +No NIH Category available Affect;Alzheimer's Disease;Astrocytes;Astrocytosis;Brain;Cancer Patient;Carboplatin;Cells;Chemotherapy-Oncologic Procedure;Cisplatin;Cognitive;Communication;Complex;Data;Dementia;Dendritic Cells;Development;Disease Progression;Exhibits;Fatty Acids;Functional disorder;Genes;Glutamine;Homeostasis;Immune;In Vitro;Infiltration;Inflammatory;Knowledge;Link;Lipids;Malignant Neoplasms;Mediating;Metabolism;Microglia;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Pathogenesis;Pathologic;Pathology;Phenotype;Platinum;Platinum Compounds;Play;Production;Proteins;Regulation;Role;Severities;Severity of illness;Signal Transduction;Structural defect;TREM2 gene;Tauopathies;Testing;Toxic effect;Tumor-Derived;anti-cancer;cancer cell;chemotherapy;exosome;genetic variant;genome wide association study;in vivo;in vivo Model;lipid metabolism;long chain fatty acid;neuroinflammation;neurotoxicity;non-genetic;prevent;programs;response;risk variant;tau Proteins;tau aggregation;tau mutation;therapeutically effective;tumor;tumor microenvironment;uptake The role of platinum-regulated lipid metabolism in tau-related dementia PROJECT NARRATIVEAlzheimer's disease (AD) and tauopathies are characterized with widely distributed neurofibrillary tangles (NFTs)which is composed of abnormal tau aggregates and plays an important role in the pathogenesis of AD. Pathologictau can activate the proinflammatory signaling in microglia and induce neuroinflammation further promotingdisease progression and severity of AD. This proposal seeks to uncover how a widely used anti-cancerchemotherapy agent platinum promotes dysregulation of lipid metabolism in microglia neuroinflammation andtau pathology. NCI 10713249 6/22/23 0:00 PA-20-272 3R01CA269782-02S1 3 R01 CA 269782 2 S1 "SINGH, ANJU" 7/1/22 0:00 6/30/27 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 12404395 "JIN, LINGTAO " Not Applicable 20 GENETICS 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 866 Non-SBIR/STTR 2023 412188 NIA 329688 82500 "PROJECT SUMMARYAlzheimer's disease (AD) is characterized by widely distributed neurofibrillary tangles (NFTs) which plays animportant role in AD pathogenesis. NFTs are composed of abnormal tau aggregates filling the neurons.Pathologic tau can activate the proinflammatory signaling in microglia and induce neuroinflammation whichforms a vicious cycle and significantly contributes to the disease progression and severity of AD. Moreoveractivated microglia can subsequently cause a pronounced transformation of astrocytes called ""reactiveastrocytosis"" leading to substantial neurotoxicity in AD. Increasing evidence demonstrate a critical role ofaberrant microglial lipid metabolism in AD. Microglia exhibit a lacy phenotype featuring highly enriched lipiddroplets and lipid-laden microglia represent a dysfunctional and proinflammatory state. These observations allpoint to an important functional link between aberrant lipid metabolism microglial dysfunction andneuroinflammation. However there are still significant knowledge gaps in understanding the complex networkincluding both genetic variants and non-genetic insults that induces lipid-mediated microglial dysfunction. We previously uncovered that tumor-derived long-chain fatty acids critically contribute to lipid accumulationand consequently dysfunction of tumor-infiltrating dendritic cells. Our preliminary data also discovered thatplatinum agent (e.g. cisplatin and carboplatin) one of the most widely used chemotherapy agents for a varietyof cancers further exacerbates lipid accumulation and dysfunction of dendritic cells through reprograming of lipidmetabolism in cancer cells. While studying how platinum treatment affects lipid metabolism in cancer cells aswell as surrounding immune cells we unexpectedly discovered that platinum also induces aberrant lipidaccumulation in the brain particularly in microglia. Importantly this platinum-induced reprograming of lipidmetabolism is associated with tau pathology in vivo. Therefore the recently discovered neuron-microglia lipidcommunication may be impacted by platinum treatment which may contribute to neuroinflammation pathologictau spreading and AD disease progression. We hypothesize that platinum treatment through reprograming lipidmetabolism in neurons promotes production of neuron-derived fatty acids-enriched exosomes which leads tolipid accumulation in surrounding microglia. This platinum-induced lipid accumulation consequently inducesproinflammatory state of microglia and drives neuroinflammation which further promotes pathological tauspreading and severity of AD. We will test our hypothesis through the following aims: Aim 1: To investigate themechanism by which platinum drives microglial lipid accumulation. Aim 2: To elucidate how platinum-inducedneuron/microglial lipid reprogramming promotes neuroinflammation and AD progression." 412188 +No NIH Category available Achievement;Area;Award;Biochemistry;Bioinformatics;Biological;Biological Sciences;Biomedical Engineering;Biomedical Research;Blood;Cancer Biology;Cancer Diagnostics;Career Choice;Communication;Communities;Complement;Country;Data Analyses;Dedications;Development;Device or Instrument Development;Early Diagnosis;Education;Educational workshop;Engineering;Ensure;Ethics;Ethnic Origin;Evaluation;Faculty;Feedback;Fostering;Future;Generations;Goals;Individual;Institution;Instruction;Interdisciplinary Study;Internships;Laboratory Research;Malignant Neoplasms;Medicine;Mentors;Minority Groups;Mission;Participant;Population;Productivity;Publications;Race;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Science;Scientist;Screening for cancer;Series;Serinus;Shapes;Structure;Students;Talents;Testing;Training;Training Programs;Translational Research;Travel;Underrepresented Minority;Work;Writing;anticancer research;biomarker discovery;biomarker validation;cancer biomarkers;cancer imaging;career;career development;clinical imaging;clinical translation;design;diversity and inclusion;education research;effectiveness evaluation;effectiveness research;experience;faculty mentor;hands on research;imaging approach;in vivo;in-vitro diagnostics;innovation;liquid biopsy;mathematical sciences;meetings;minimally invasive;molecular imaging;multidisciplinary;physical science;posters;programs;recruit;research facility;skills;socioeconomics;success;summer internship;summer program;summer research;symposium;undergraduate research experience;undergraduate student CANARY CANCER RESEARCH EDUCATION SUMMER TRAINING (CANARY CREST) PROGRAM NARRATIVE: The Canary CREST Program fulfills the mission of the Canary Center at Stanford by educatingand training a new generation of scientists as they explore new research experiences in the biologicalsciences. The importance of this training offered at the undergraduate level with a focus on cancer earlydetection provides a new understanding of career opportunities in biomedical research including clinicaltranslational science. NCI 10713237 8/23/23 0:00 PAR-21-279 2R25CA217729-06 2 R25 CA 217729 6 "RADAEV, SERGEY" 9/1/17 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 8631559 "DEMIRCI, UTKAN " "PITTERI, SHARON " 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 418613 NCI 387605 31008 PROJECT SUMMARY/ABSTRACT: The Canary Center at Stanford for Cancer Early Detection (CanaryCenter) is a world-class facility with the mission to foster interdisciplinary research leading to the developmentof blood (and other minimally invasive) tests and molecular imaging approaches to detect localize and stratifyearly cancers by integrating research in in vivo and in vitro diagnostics. Embedded within this mission is the needto formally present new and innovative approaches to scientific communities at all levels. This competitiverenewal application is for continued support of the Canary Cancer Research Education Summer Training(Canary CREST) Program which fulfills an educational mission by introducing students to research educationand new career paths. The overall goal of the program is to train a new generation of interdisciplinary scientistsin early cancer detection by offering an integrative hands-on research experience at an early stage of theirscientific education. The Canary CREST Program is a 10-week instructional summer program for 30undergraduate students in the biological engineering mathematical and/or physical sciences and offers astructured research experience with a focus on early cancer detection. The program will be administered by theCanary Center and brings together a multidisciplinary group of 26 faculty whose research groups are dedicatedto the field of early cancer detection using experimental and computational approaches in biochemistrybioengineering bioinformatics molecular imaging and cancer biology. Proposed Canary CREST Programactivities include: (1) Mentor-directed research in one of six investigative areas namely development of devicesfor cancer diagnostics cancer biomarker discovery and validation cancer biology molecular imaging of cancerclinical imaging of cancer and cancer bioinformatics; (2) Specially-designed classroom sessions to provide aconceptual framework of the field of early cancer detection; (3) Seminars in scientific research; (4) Acomprehensive professional development component that includes career talks student presentationsworkshops on communication skills career opportunities and diversity. The key aspect of this program is to offerparticipants the opportunity to conduct mentor-directed research while developing an understanding ofhypothesis-driven studies with critical interpretation of results and analysis of data. The long-term objective ofthis educational research program is to support the growing need of specialized researchers who will have asignificant impact in the rapidly-expanding area of cancer early detection. 418613 +No NIH Category available Acute Myelocytic Leukemia;Applications Grants;Award;Biological Assay;CAR T cell therapy;CD19 gene;CD34 gene;CRISPR/Cas technology;Cell Therapy;Cells;Cellular immunotherapy;Characteristics;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Color;Correlative Study;Cryopreservation;Data;Data Collection;Development;Disease;Engraftment;Flow Cytometry;Future;Gene Expression Profile;Gene Modified;Genes;Genetic Transcription;Goals;Grant;Hematologic Neoplasms;Human Genome;In Vitro;Individual;Informed Consent;Infusion procedures;Knock-out;Laboratories;Laboratory Study;Lentivirus;Leukapheresis;Malignant lymphoid neoplasm;Methods;Molecular;Multiple Myeloma;Mycoplasma;PTPRC gene;Patient-Focused Outcomes;Patients;Phase I Clinical Trials;Phenotype;Population;Procedures;Process;Protocols documentation;Refractory;Regulation;Relapse;Research;Research Personnel;Resources;Safety;Sampling;Science;Services;System;T cell differentiation;T cell therapy;T-Lymphocyte;Technical Expertise;Techniques;Technology;Technology Transfer;Testing;Therapeutic;Translating;Validation;Work;base editing;biobank;cellular transduction;chimeric antigen receptor T cells;clinical development;cytotoxicity;digital;exhaustion;first-in-human;gene therapy;genome editing;improved;in vitro Assay;in vivo;manufacture;manufacturing facility;manufacturing process;next generation;novel;pre-clinical;process optimization;product development;programs;response;scale up;self-renewal;technology validation;tissue culture;transcriptome;transduction efficiency;translational study;tumor CORE C Technology Implementation/Development and Correlative Sciences CORE C PROJECT NARRATIVECore C will support the goals of the three proposed projects in three ways; 1. Developing improved methods tomanufacture gene-edited CAR T and HSPC products and transferring these processes to the manufacturingCore B to ultimately translate research bench concepts to bedside therapies; 2. Supporting the three proposedclinical trials by performing specialized assays on product and patient samples to describe productcharacteristics and safety aspects and to identify the fate of infused CAR T or CD34+ cells to predict and evaluatetheir impact on disease; 3. Refining and developing new sophisticated analysis platforms for characterizingproducts and clinical trial samples on a molecular and clonal level. NCI 10713205 9/19/23 0:00 PAR-20-077 2P01CA214278-06A1 2 P01 CA 214278 6 A1 8/15/17 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5767 78849522 "HERBST-NOWROUZI, FRIEDERIKE " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 644007 396312 247695 CORE C: Summary AbstractCore C is comprised of two groups: the Human Genome Editing Laboratory (HGEL) led by Dr. Friederike Herbstand the Translational and Correlative Studies Laboratory (TCSL) led by Dr. Joseph A. Fraietta. Core C worksclosely with Cores A and B to actively support the proposed P01 grant renewal with the following three Aims:In Specific Aim 1: Process Optimization Development and Product Characterization Core C will provideknowhow and consulting support to Core B to manufacture CRISPR-edited CAR T cells in a shortenedmanufacturing process (Project 1: CD5 knockout anti-CD19 CAR T cells). Core C will conduct scale-up studiesto optimize base editing of T cells and matching HSPC cell populations for further lockdown of manufacturingprocesses to tech transfer to Core B (Project 2). Core C will develop a pipeline for subsequent characterizationof the gene edited cell products (T cells and HSPC) including assay developmental procedures important forproduct safety and release testing in line with FDA regulations for future IND applications. In Specific Aim 2:Support of Clinical Trials Proposed by the 3 Projects Core C will support all three clinical trials within thisgrant proposal. Project 1: CD5 knockout anti-CD19 CAR T cells in patients with relapsed or refractory lymphoidmalignancies. Project 2: CD45-edited CART45 in tandem with CD45-edited matching HSPCs in patients withacute myeloid leukemia; and Project 3: combination of MIL- and PBL-derived anti-BCMA CAR T cells in patientswith relapsed/refractory multiple myeloma. In addition to supporting the manufacturing Core B with product safetyanalysis and product release assays testing for on-/off target editing transduction efficiency replication-competent lentivirus and mycoplasma Core C will perform a range of sample processing biobanking andcorrelative assays and data collection that will be tailored to the individual needs of each of the clinical trials. InSpecific Aim 3: Analytical Platform Development Core C will strengthen three assay platforms identified asbeing key correlative assay technologies needed to support the projects and clinical trials in this grant proposal.Overall all platforms - once established - will allow the identification as well as the molecular and phenotypiccharacterization of rare subpopulations of therapeutic cells. Moreover the generated data package will beevaluated and utilized to predict and improve patient outcome. 1. Single cell transcriptome analysis to expandcorrelative analysis by extending established protocols and existing data to optimize single-cell methods onsamples drawn from internally biobanked accessions. 2. Digital PCR using a new QIAcuity One plate-basedsystem to perform sensitive standard-independent quantification of rare sequences and support the trials withassessment of gene editing and gene marking. 3. Flow cytometry Developing new 28+ color panels on aspectral cytometer to be used for retrospective batch analysis of leukapheresis material transduced cellularproducts and post-infusion samples to investigate T cell differentiation activation exhaustion and antitumoractivity as well as CD34+ cell engraftment multi-lineage differentiation and function. +No NIH Category available Achievement;Address;Annual Reports;Authorization documentation;Basic Science;Biometry;Budgets;CAR T cell therapy;Cancer Center;Cellular immunotherapy;Clinical;Clinical Data;Clinical Protocols;Clinical Trials;Collaborations;Communication;Data;Disease;Doctor of Philosophy;Ensure;Genes;Genetic Engineering;Goals;Grant;Hematologic Neoplasms;Human Resources;Infrastructure;Institution;Leadership;Learning;Letters;Maintenance;Monitor;Pennsylvania;Physician Executives;Progress Reports;Publishing;Registered nurse;Reporting;Research;Research Personnel;Role;Safety;Schedule;Scientist;Services;Structure;T cell therapy;Technology;Testing;Translational Research;Universities;Update;authority;cancer immunotherapy;chimeric antigen receptor T cells;clinical development;clinical research site;clinical translation;clinical trial implementation;data management;data sharing;design;innovation;medical schools;meetings;novel;operation;organizational structure;pharmacovigilance;preclinical development;preservation;programs;protocol development;response;success;synergism;timeline Core A: Administrative and Clinical Translational Core NARRATIVE CORE A: ADMINISTRATIVE AND CLINICAL TRANSLATIONAL COREThe Administrative and Clinical Translational core of this Program Project renewal grant is designed toprovide scientific and clinical oversight IND-enabling regulatory and clinical development expertise andbiostatistical and budgetary structure to support effective operations for each P01 project and core and topromote project integration and synergies. The essential services provided by Core A include: biostatisticalsupport; fiscal management; all clinical protocol development; IND submissions and maintenance; clinicaldata management and facilitation of communication between projects cores internal and external advisoryboards and the NCI to ensure effective execution and integration of all Program projects and coreobjectives. NCI 10713203 9/19/23 0:00 PAR-20-077 2P01CA214278-06A1 2 P01 CA 214278 6 A1 8/15/17 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5764 1970082 "JUNE, CARL H." Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 248019 152627 95392 SUMMARY CORE A: ADMINISTRATIVE AND CLINICAL TRANSLATIONAL COREThe Administrative and Clinical Translational Core of this renewal Program Project will provide: (1) scientificand clinical operational oversight; (2) IND-enabling regulatory and clinical development expertise andbiostatistical and budgetary structure to support effective operations for each P01 Project and Scientific Core;and (3) promote project integration and synergy. This renewal proposal seeks to build upon our proven trackrecord in genetically engineered T cell therapy by enhancing the chimeric antigen receptor T cell platform tospecifically address systemic vulnerabilities that we have observed in our clinical trials to date. Ouroverarching hypothesis is that novel gene editing approaches can remove the remaining obstacles in the pathof universally-available and universally-active CAR T cell therapy for hematologic malignancy. We havebrought together a cadre of exceptional investigators who have collaborated and published together for manyyears. Each disease-focused project will be led by a recognized authority in the field. The three cores thatsupport this proposal have been critical to the success of our clinical CAR T cell program to date and theirexpertise will underpin the success of this proposal. The centerpiece of each project is an innovative clinicaltrial that seeks to test our major hypotheses.We are leveraging the proven translational infrastructure administrative staff and the centralized researchorganizations at the Center for Cellular Immunotherapies at the Perelman School of Medicine to achieve ourobjectives. Strong institutional commitment from the Abramson Cancer Center Perelman School of Medicinethe Parker Institute for Cancer Immunotherapy and the University of Pennsylvania have facilitated ourscientific and translational achievements. The essential services provided by Core A include administrativesupport for all investigators in each project and core; fiscal management and oversight for all components ofthe Program Project; clinical protocol development IND submissions and maintenance and clinical datamanagement; and organization and communication of all Program Project meetings and activities. The overallgoal of this Core is effective and efficient leadership of the P01. The roles of the Director Co-investigatorsand administrative staff are to facilitate communication and organizational structure while stimulating scientificand technological interactions. In order to achieve this goal the Core has established four objectives: (1) Tooversee the safety and monitoring activities for Penn and CHOP clinical sites; (2) To provide regulatorypreclinical development and statistical support for clinical trials projects and cores and implement datasharing plans.; (3) To coordinate the interactions among clinicians and scientists in projects and cores internaland external advisory boards and NCI personnel regarding effective implementation of proposed objective;(4) To provide budgetary services such as tracking expenses and providing investigators monthly reports. +No NIH Category available Acceleration;Address;Adoptive Immunotherapy;Alanine;Allogenic;Antibody-drug conjugates;Antigens;B lymphoid malignancy;Biotechnology;Bone Marrow Purging;CAR T cell therapy;CD19 gene;CD34 gene;CD45 Antigens;CRISPR/Cas technology;Cell Therapy;Cells;Cessation of life;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Credentialing;Disease;Engineering;Engraftment;Epitopes;Extracellular Domain;Functional disorder;Genes;Genetic Engineering;Goals;HLA Antigens;Hematologic Neoplasms;Hematology;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;Immunodeficient Mouse;Immunotherapy;In Vitro;Individual;Infusion procedures;Knock-out;Lead;Malignant Neoplasms;Medical;Mission;Multiple Myeloma;Mutagenesis;Mutation;PTPRC gene;Patients;Pharmaceutical Preparations;Physicians;Protein Tyrosine Phosphatase;Public Health;Reporting;Research;Resistance;Scientist;Site;Stem cell transplant;Surface;T cell therapy;T-Lymphocyte;Technology;Testing;Translating;Work;base editing;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;conditioning;design;donor stem cell;drug development;engineered T cells;immunological synapse;in vivo;leukemia;next generation;novel therapeutics;prevent;receptor;screening;self-renewal;stem cells;stemness;tool Next-generation genetic engineering of the pan-leukocyte antigen CD45 to facilitate CAR-T cell therapy against hematologic malignancies NARRATIVE (PROJECT 2)This proposal seeks to bring the power of genetically-modified T cell therapy to the treatment of patients withAML using cutting edge genetic engineering approaches. The proposed research is relevant to public healthbecause it addresses the challenges facing physician-scientists in the quest to find and use cancer-specificantigens for immunotherapy and is relevant to those parts of the NCIs mission that pertain to eliminatingsuffering and death due to cancer. This work is expected to open new therapeutic horizons in the field ofadoptive immunotherapy for AML and new research horizons that could be translated to other malignancies bycombining CART cell therapy with gene editing. NCI 10713201 9/19/23 0:00 PAR-20-077 2P01CA214278-06A1 2 P01 CA 214278 6 A1 8/15/17 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5760 10917511 "GILL, SAAR " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 472594 290827 181767 SUMMARY/ABSTRACT (PROJECT 2): Next-generation genetic engineering of the pan-leukocyteantigen CD45 to facilitate CAR-T cell therapy against hematologic malignanciesCurrently chimeric antigen receptor (CAR)-T cells must be individually designed for each disease targetinglineage-associated antigens such as CD19 for B-cell malignancies or BCMA for myeloma. While this approachhas led to the successful treatment of hundreds of patients on clinical trials or with commercial CAR-T celltherapies from a drug development standpoint this approach is inefficient. By targeting a pan-hematologicantigen a single drug could be used for all indications thereby accelerating clinical research. CD45 is areceptor tyrosine phosphatase that is expressed on the surface of most hematopoietic cells from immature stemcells to differentiated progeny. As expected antibody-drug conjugates targeting CD45 cause profoundmyeloablation and are in clinical development as conditioning agents prior to stem cell transplantation. A uniquehurdle limiting the use of anti-CD45 CAR T cells (CART-45) is that T cells themselves express CD45 and CART-45 are therefore vulnerable to fratricide. Furthermore CD45 is crucial for proper function of the T cell immunesynapse. The overarching goal of this project is to render CD45 targetable using genetic engineering ofT cells and of hematopoietic stem cells (HSC). To achieve this goal we will test the central hypothesis thatsite-specific mutation of CD45 in hematopoietic cells (including T cells) can abrogate recognition by CART-45while retaining all other domains required for the function of this molecule. We expect that this approach willprevent T cell dysfunction and myeloablation. This will be accomplished in three specific aims. In Aim 1 we willgenerate fratricide-resistant CD45-targeting CAR-T cells. We have identified a candidate CAR construct basedon unbiased functional screening and shown that CART-45 are indeed subject to fratricide. While this fratricidecould be rescued by CRISPR-based knock out of CD45 CD45-deficient CART cells were dysfunctional. Usingalanine mutagenesis we then identified the target epitope on CD45 that is recognized by our lead CAR candidateand we have now successfully edited this epitope to abrogate fratricide resulting in CAR-T cells that recognizenative CD45 in trans without themselves being the target of anti-CD45 CAR. In this aim we will test the hypothesisthat the function of CD45-edited T cells is equivalent to unmodified control T cells and superior to that of CD45-deleted T cells. In Aim 2 we will genetically engineer hematopoietic stem cells to generate a CART-resistanthematopoietic system. To demonstrate that engineered CD34+ HSCs are resistant to CD45 targeted CAR-Tcell therapy engineered HSPCs will be engrafted into immunodeficient mice followed by treatment with CD45CAR-T cells. Finally to target CD45 in human AML we will disrupt CD45 expression in primary human AML andtest leukemogenicity in vitro and in vivo. In Aim 3 up to 6 patients will undergo allogeneic stem cell transplantationusing donor stem cells where CD45 expression has been edited using CRISPR/Cas9 followed by infusion ofdonor-derived CART-45. Successful completion of this Aim will provide proof-of-concept for our overall strategyto create a leukemia-specific antigen using gene editing tools. +No NIH Category available Ablation;Acute Lymphocytic Leukemia;Address;Adopted;Adoptive Immunotherapy;Antigen Receptors;Antigens;Autoimmune Diseases;Automobile Driving;Award;B lymphoid malignancy;B-Cell Acute Lymphoblastic Leukemia;B-Cell Leukemia;B-Cell NonHodgkins Lymphoma;Biological Assay;Biological Markers;Biology;Blood;CAR T cell therapy;CBL gene;CD19 Antigens;CD19 gene;CRISPR/Cas technology;CTLA4 gene;Cell Culture Techniques;Cell physiology;Cells;Characteristics;Chemoresistance;Chronic Lymphocytic Leukemia;Clinic;Clinical;Clinical Trials;Collaborations;Critical Pathways;Data;Development;Disease remission;Dose;Engineering;Exhibits;Flow Cytometry;Future;Gene Targeting;Genes;Genetic;Genetic Transcription;Goals;Hematological Disease;Heterogeneity;Human;Immune;Immunologics;Immunotherapy;Infiltration;Infusion procedures;Investigation;Knock-out;Laboratories;Lead;Libraries;Link;Lupus;Lymphocyte;Malignant Lymph Node Neoplasm;Malignant Neoplasms;Malignant lymphoid neoplasm;Mediator;Modeling;Outcome;PRDM1 gene;PTPN6 gene;Pathway interactions;Patients;Population;Proliferating;Property;Proteins;Public Health;Publishing;Reagent;Receptor Signaling;Recurrent disease;Refractory;Relapse;Research;Resistance;Resolution;Safety;Sampling;Science;Series;Serum;Specific qualifier value;Structure;T cell therapy;T-Cell Development;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;Technology;Testing;Therapeutic;Therapeutic Index;Time;Toxic effect;Translating;Treatment Failure;Tumor Tissue;Veins;Work;Xenograft Model;biobank;cancer immunotherapy;cellular engineering;chimeric antigen receptor;chimeric antigen receptor T cells;clinically actionable;cohort;cytokine;design;exhaust;experience;experimental study;first-in-human;follow-up;genome editing;head-to-head comparison;immune checkpoint;improved;improved outcome;in vivo;inhibitor;innovation;leukemia;manufacture;manufacturing process;mouse model;multiple omics;neoplastic cell;new technology;next generation;novel;pre-clinical;prevent;programmed cell death protein 1;refractory cancer;resistance mechanism;response;safety assessment;success;synthetic biology;tool;trafficking;treatment optimization;tumor;vector From the Past to the Future: Chimeric Antigen Receptor T cells for Lymphoid Malignancies Narrative (PROJECT 1)The goal of this project is to address major challenges and unmet needs of chimeric antigen receptor or CART cells that currently limit treatment success in patients with blood and lymph node cancers. We propose toidentify critical characteristics of effective CAR T cell products to obtain information useful in optimizing therapyand then engineer around resistance mechanisms using cutting-edge gene editing tools with the goal of creatingCAR T cells more effective at inducing long-lasting remissions. The proposed research is relevant to public healthbecause it will help increase the potency of CAR T cells used to treat chemotherapy-resistant cancers whichmay make this strategy viable and efficacious for many more patients. NCI 10713200 9/19/23 0:00 PAR-20-077 2P01CA214278-06A1 2 P01 CA 214278 6 A1 8/15/17 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5758 12666868 "FRAIETTA, JOSEPH ANTHONY" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 442180 284664 157516 Summary/Abstract (PROJECT 1)Chimeric antigen receptor (CAR) T cells directed to the CD19 protein (CART19) have revolutionized thetreatment of a variety of B cell malignancies with complete remission rates as high as 97% in certain types ofadvanced leukemia. Many of these responses are sustained but poor CAR T cell expansion and persistencefollowing infusion and antigen-negative escape are common mechanisms of treatment failure. It is critical toinvestigate factors driving successful CAR T cell function in responding patients. Previous studies have indicatedthat in lymphoid malignancies durable remission is associated with activation of specific T cell pathways andonly some patients experience therapeutic levels of CAR T cell expansion and antitumor activity. During theprevious award period we successfully developed a comprehensive understanding of the T cell-intrinsic and -extrinsic mechanisms of resistance as well as tumor cell-intrinsic mechanisms that lead to relapse. Here wepropose extensive next-generation analyses to understand properties of optimal CAR T cell therapy elucidatemechanisms of resistance and develop strategies to overcome resistance and enhance CAR T cell activity tocure more patients with hematologic diseases. We will take advantage of already established successfulcollaborations with core laboratories possessing expertise in cell manufacturing gene editing and state-of-the-art correlative science platforms to explore a number of innovative aims. In Aim 1 we will carry out an extensiveanalysis of T cell receptor (TCR) rearrangements vector copy number T cell subsets analyzed by flowcytometry serum cytokines and biomarkers (~7000) and transcriptional landscapes of CAR T cells in blood aswell as tumor tissues and formulate multi-omics models linking correlative data and outcome. In Aim 2 we havedesigned a high-impact clinical trial to knockout CD5 an unconventional negative immune checkpoint moleculeand inhibitor of antigen-receptor signaling with the goal of increasing the therapeutic index of 3-daymanufactured CART19 cells for relapsed/refractory B-cell malignancies. Finally in Aim 3 we will carry outfunctional analyses of genes implicated in potentiating CAR T cell proliferation persistence and antitumorfunction to develop `best-in-class' products for ALL CLL and NHL. Using a structured multi-pronged strategywe hope to ameliorate resistance to CAR T cell-based therapies for B-cell malignancies and clinically advanceseveral next-generation synthetic biology tools. This work is expected to open therapeutic horizons in the fieldof adoptive immunotherapy for cancer and offer new research prospects that could be translated to improvingthe treatment of other cancers and autoimmune disorders. +No NIH Category available Acute Myelocytic Leukemia;Acute T Cell Leukemia;Acute leukemia;Address;Adoptive Transfer;Authorization documentation;Autoimmune Diseases;B lymphoid malignancy;B-Cell Acute Lymphoblastic Leukemia;Back;Biological;Biometry;Blood;CAR T cell therapy;CD19 gene;CRISPR/Cas technology;CTLA4 gene;Cell Therapy;Cells;Chronic Lymphocytic Leukemia;Clinic;Clinical;Clinical Trials;Collaborations;Development;Discipline;Disease;Engineering;FDA approved;Funding;Future;Generations;Genes;Genetic;Genetic Engineering;Gills;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic Neoplasms;Hematopoietic System;Human Genome;Immune;Immunologics;Immunotherapy;In complete remission;Individual;Interleukin-2;International;Joints;Journals;Laboratories;Licensing;Lymphoblastic Leukemia;Lymphoma;Malignant Neoplasms;Marrow;Mediating;Medical;Medicine;Messenger RNA;Modification;Monitor;Multiple Myeloma;Mutate;Myeloid Leukemia;New England;PTPRC gene;Paper;Patients;Persons;Publications;Publishing;Refractory;Relapse;Research;Research Personnel;Resistance;Resource Sharing;Safety;Sampling;Services;Small-Cell Lymphoma;Solid;Source;Surface Antigens;T-Lymphocyte;Technology;Testing;Therapeutic;Toxic effect;Translating;United States;Vaccines;antitumor effect;authority;base editing;bench to bedside;cancer cell;cancer immunobiology;cancer immunotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical investigation;efficacy testing;engineered T cells;gene therapy;genome editing;improved;indexing;innovation;leukemia;leukemia/lymphoma;lipid nanoparticle;manufacturing facility;multidimensional data;next generation;novel;novel therapeutics;overexpression;preclinical study;programs;rational design;standard of care;synthetic biology;tool;tumor Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: Beyond CART 19 Overall NarrativeOur goal is to develop practice changing next-generation immunotherapies for hematologic malignancies whichstrike more than 200000 people every year in the United States. Our approach involves the development ofnext-generation therapies with chimeric antigen receptor (CAR) T cells involving innovative combinations ofCAR T cells and genetic editing with CRISPR/Cas9 technology and base editing to be tested in several clinicaltrials. Our team has provided paradigm-shifting impact in B cell malignancies and these projects have thepotential to transform therapies for numerous cancers beyond acute leukemia. NCI 10713199 9/19/23 0:00 PAR-20-077 2P01CA214278-06A1 2 P01 CA 214278 6 A1 "HENDERSON, LORI A" 8/15/17 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 1970082 "JUNE, CARL H." Not Applicable 3 PATHOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 2782255 NCI 1724710 1057545 OVERALL PROJECT SUMMARY / ABSTRACTThe long-term goals of this renewal P01 are to develop next generation immunotherapy with chimeric antigenreceptor (CAR) T cells and to translate this research into new therapies with curative potential for patients withblood cancer. The CAR developed at our center was the first cell and gene therapy to ever receive approval fromthe FDA initially for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL) in 2017 and lymphoma in2018. However multiple myeloma (MM) acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL)remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies withcombination of CAR T cells and advanced forms of human genome editing will enable this powerful therapy toreach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptionalinvestigators from multiple disciplines who have collaborated and published together for many years. Eachdisease-focused project will be led by recognized authorities in the field. To achieve our goals we have threeProjects that build on progress during the previous funding period and will continue to coordinate closely withessential shared resource cores. In Project 1 we will determine the clinical and immunological impact of treatingpatients on two clinical trials: (i) CAR T cells targeting CD19 will be tested with genetic disruption of CD5 CTLA-4 and TET2 to address CLL and lymphoma which is lack of sustained effector CAR T function in these patients.In AML the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AMLbut lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window for AML bygenetically-modifying normal marrow to make it resistant to killing by anti-AML CAR T cells and delivering potentanti-leukemic CAR T cells specific for CD45. Engineered HSC that are genetically edited to install ahematopoietic system facilitating non-toxic therapy with these potent CAR T cells will be developed. In Project3 the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) testing the efficacy of marrow-derived CAR T compared to current standard of care blood-derived CAR T (ii) improving persistence of BCMACAR T with orthogonally mutated IL-2/IL-2R technology and mRNA/lipid-nanoparticle vaccine technology toovercome suboptimal persistence and efficacy of current BCMA T cells.The Scientific and Administrative Cores for this P01 are essential for our progress including provision of projectmanagement for collaboration and biostatistics clinical safety and monitoring and fiscal support (Core A) aGMP facility for manufacture of cells and identification of new binders for CAR targets (Core B) and a state-of-the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (CoreC). Our renewal application has the potential for paradigm-shifting impact to transform the lessons of CAR T forALL into meaningful efficacy against all hematologic malignancies solid cancers and provides direction forextending beyond cancer to autoimmune disorders. 2782255 +No NIH Category available 3-Dimensional;Acceleration;Adjuvant Chemotherapy;Adoption;Antibodies;Biological;Brain Mapping;Breast;Cancer Etiology;Cessation of life;Characteristics;Clinical;Computers;Consumption;Data;Development;Dictionary;Diffusion;Diffusion Magnetic Resonance Imaging;ERBB2 gene;Early Diagnosis;Eligibility Determination;Exhibits;Female;Fingerprint;Genetic;Goals;Heterogeneity;Image;In complete remission;Lesion;Magnetic Resonance;Magnetic Resonance Imaging;Mammary Gland Parenchyma;Mammary Neoplasms;Maps;Measurement;Measures;Methods;Monitor;Morphology;Multiparametric Analysis;Neoadjuvant Therapy;Operative Surgical Procedures;Pathologic;Patient Care;Patients;Phenotype;Physicians;Physics;Physiological;Prediction of Response to Therapy;Preparation;Prone Position;Relaxation;Reproducibility;Resolution;Sampling;Scanning;Standardization;Techniques;Therapeutic;Time;Treatment outcome;Variant;Visualization;Woman;algorithm training;breast exam;breast imaging;breast lesion;breast surgery;cancer diagnosis;chemotherapy;clinical translation;cloud based;cohort;convolutional neural network;cost;deep learning;diagnostic accuracy;early detection biomarkers;experimental study;healthy volunteer;hormone therapy;imaging biomarker;improved;individualized medicine;ineffective therapies;invention;learning strategy;magnetic field;magnetic resonance imaging biomarker;malignant breast neoplasm;novel;partial response;patient response;quantitative imaging;reconstruction;research clinical testing;research study;response;side effect;targeted treatment;therapy outcome;tissue mapping;tool development;treatment planning;treatment response;trend;triple-negative invasive breast carcinoma;tumor;volunteer Development of Magnetic Resonance Fingerprinting (MRF) to Assess Response to Neoadjuvant Chemotherapy in Breast Cancer Project NarrativeNeoadjuvant chemotherapy is commonly applied to women with breast cancer and monitoring tumor responseto chemotherapy is currently based on tumor size measured by physical exam which is subjective difficult toquantify and most importantly temporally delayed compared to underlying biological changes. Quantitativereproducible and objective methods that could provide an early detection of tumor physiological changesbefore size changes could significantly improve treatment outcome and the quality of patient care. Here wepropose to leverage Magnetic Resonance Fingerprinting (MRF) a new platform for quantitative MR imagingthat was developed by our team to develop new imaging biomarkers for early assessment of treatmentresponse in women with breast cancer with the ultimate goal to reduce ineffective treatment in eligiblesubjects and tailor the treatment methods for optimum therapeutic outcomes. NCI 10713097 7/26/23 0:00 PA-20-185 1R01CA282516-01 1 R01 CA 282516 1 "DARDZINSKI, BERNARD JOSEPH" 9/1/23 0:00 8/31/28 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 12144227 "CHEN, YONG " "MA, DAN ; MARSHALL, HOLLY " 11 RADIATION-DIAGNOSTIC/ONCOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 563925 NCI 355689 208236 AbstractIn women breast cancer is the most commonly diagnosed cancer and leading cause of cancer related deathsworldwide with approximately 2.3 million new cases and 685000 deaths in 2020. Neoadjuvant chemotherapy(NAC) is commonly applied to reduce the tumor size before surgery for breast neoplasms. Unfortunately dueto the genetic and phenotypic heterogeneity of breast tumors not all patients respond to conventional NAC.Currently only about 22% of patients show pathologic complete response (pCR) while the remaining non-pCRpatients show either partial response (54% of all patients) or no response to chemotherapy. Early prediction oftumor response to chemotherapy to identify non-responders could 1) reduce unnecessary side effects andcosts related to ineffective therapy and 2) help physicians tailor the treatment plan earlier to achieve bettertherapeutic outcomes and improve survival. Monitoring tumor response to chemotherapy is currently based ontumor size measured by physical exam which is subjective difficult to quantify and most importantlytemporally delayed compared to underlying biological changes. Quantitative repeatable and objective methodsthat could provide an early detection of tumor physiological changes before size changes could significantlyimprove treatment outcome and the quality of patient care. However quantitative imaging poses significanttechnical challenges which is rarely performed in the clinical setting. Here we propose to leverage MagneticResonance Fingerprinting (MRF) a revolutionary new platform for quantitative MR that was invented by ourteam to develop new imaging biomarkers for early assessment of treatment response in women with breastcancer. Our team has developed a breast MRF method to simultaneously generate quantitative 3D T1 and T2maps in ~6 minutes with excellent reproducibility. We have also expanded our MRF method to simultaneousquantify T1 T2 and ADC maps of the brain with no image distortion. Here we plan on optimizing this newrelaxometry / diffusion MRF method specifically for women with breast cancer (Aim 1). Novel deep learningmethods will be developed to provide a fast (<5 minute) and high resolution (1.2 mm isotropic) acquisition forwhole-breast coverage along with an efficient post-processing pipeline based on cloud computation (Aim 2).Finally we will evaluate the developed method for early prediction of treatment response in two patient cohortswith either HER2-positive or triple negative breast cancers (Aim 3). Upon successful completion of this projectthe developed MRF technique will provide a practical quantitative breast exam for early prediction of treatmentresponse to NAC and other treatment methods (hormone therapy antibody-based target therapy etc.) forwomen with breast cancer with the ultimate goal to reduce ineffective treatment in eligible subjects and tailorthe treatment methods for optimum therapeutic outcomes. 563925 +No NIH Category available Binding;Biological Response Modifiers;Biopsy;Blood;CD8-Positive T-Lymphocytes;CXCL9 gene;Cancer Patient;Carcinoma;Cells;Clinical Trials;Correlative Study;Data;Dose;Effector Cell;Erinaceidae;Event;Exclusion;Fibroblasts;Fostering;Human;Immune;Immune checkpoint inhibitor;Immunosuppression;Immunotherapeutic agent;In Vitro;Infiltration;Lead;Link;Macrophage;Malignant neoplasm of ovary;Measures;Mediating;Mediator;Mesenchymal Stem Cells;Modeling;Mus;Myeloid Cells;Natural Killer Cells;Ovarian Carcinoma;Patient-Focused Outcomes;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phase;Phase II Clinical Trials;Phenotype;Physiologic pulse;Plasma;Platinum;Prediction of Response to Therapy;Progression-Free Survivals;Proteins;Recurrence;Reporting;Resistance;Role;Safety;T cell receptor repertoire sequencing;T cell regulation;T-Cell Activation;T-Lymphocyte;TGFBI gene;Testing;Tissues;Transforming Growth Factor beta;Tumor Immunity;Tumor Tissue;Tumor-associated macrophages;Tumor-infiltrating immune cells;anti-PD-L1;arm;cancer cell;cell motility;checkpoint therapy;chemokine;cytokine;design;genetic approach;humanized mouse;immune cell infiltrate;improved outcome;in vivo;inhibitor;inhibitor therapy;islet;migration;monocyte;mouse model;nano-string;neutralizing antibody;new therapeutic target;patient prognosis;patient response;preclinical study;predicting response;predictive marker;primary endpoint;recruit;response;restoration;secondary endpoint;single-cell RNA sequencing;smoothened signaling pathway;therapeutic target;therapy outcome;translational study;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Project 3: Hedgehog Inhibition to Enhance Response to ICI Therapy NARRATIVE PROJECT 3We will perform a Ph1b/II clinical trial to evaluate the ability of hedgehog inhibitors to increase immunecheckpoint inhibitor response in patients with ovarian cancer. We will determine if changes in bloodchemokine levels and immune cell localization predicts response. Finally we will assess the role of BIGH3(TGF-1induced protein) as a regulator of tumor immune cell infiltration and as a therapeutic target. NCI 10713054 9/8/23 0:00 PAR-20-305 1P50CA272218-01A1 1 P50 CA 272218 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(M1)S 5733 9076039 "BUCKANOVICH, RONALD J" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 372036 233985 138051 SUMMARY/ABSTRACT PROJECT 3When effective immune checkpoint inhibitor (ICI) therapy can significantly improve the outcome of patients withovarian cancer (OvCa). However only 10-20% of OvCa patients respond to ICI therapy. One reason for the lowICI response rate of OvCa may be OvCas unique immunosuppressive tumor microenvironment (TME) which istypified by a dense stroma infiltrated by immunosuppressive M2 tumor associated macrophages (TAMs). Werecently found that ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) orchestrate animmunosuppressive OvCa TME; differentiating into BIGH3 expressing fibroblast/tumor stroma recruitingmonocytes to the stroma and promoting the differentiation of immunosuppressive BIGH3 expressing M2 TAMs.The combined effect is that CA-MSC drive tumor immune exclusion and a resultant resistance to ICItherapy. Importantly we find that hedgehog inhibitors (HHi) reverse CA-MSC-driven immune exclusionpromote M2 to M1 TAM conversion and restore response to ICI therapy. HHi therapy down-regulatesBIGH3 in CA-MSC and TAMs and promotes the conversion of TAMs from an M2 to and M1 phenotype. Ourstudies are consistent with numerous recent reports that HHi promote M1 macrophage polarization and promoteanti-tumor immunity. Based on these results we hypothesize that CA-MSC create an immunosuppressive OvCaTME and that HHi will reverse CA-MSC mediated immune-suppression and enhance patient response to ICItherapy. To test our hypothesis we propose the following specific aims: SA1. Conduct a single arm Phase-IIclinical trial evaluating Atezolizumab (aPD-L1) combined with Vismodegib (HHi) in patients with platinumresistant recurrent ovarian cancer. Primary endpoints will be efficacy and safety. Secondary endpoints will beduration of response PFS OS and translational correlatives. SA2: Evaluate the impact of HHi on patientstumor immune infiltrates and peripheral chemokines and determine if changes predict response to therapy.SA3: To assess BIGH3 as a driver of tumor immune exclusion and immunotherapeutic target. Usingmurine models of OvCa we will assess the impact of BIGH3 on immune effector migration and function anddetermine if anti-BIGH3 therapy can enhance ICI response in murine tumor models.IMPACT: This will be the first clinical trial in OvCa to determine (i) the impact of HHi on ICI therapy in patientswith epithelial cancer and (ii) the role of targeting CA-MSCs to overcome the immunosuppressive OvCa TME.Correlative translational studies will reveal potential predictive biomarkers of response to therapy. Finally wewill evaluate BIGH3 as an immune regulator and novel therapeutic target. Ultimately we believe these studieswill impact OvCa patients response to ICI therapy and will improve outcomes. +No NIH Category available 19p13;ATAC-seq;Address;BRCA1 gene;Biopsy;Bromodomains and extra-terminal domain inhibitor;Cancer Patient;Cell Cycle;ChIP-seq;Clinical;Combination Drug Therapy;DNA Damage;Data;Disease Resistance;Dose Limiting;Epithelial ovarian cancer;G2/M Checkpoint Pathway;Gene Expression;Genes;Impairment;M cell;Malignant Neoplasms;Malignant neoplasm of ovary;Maximum Tolerated Dose;Measures;Mitosis;Mitotic;Modeling;Mutation;Organoids;PARP inhibition;Pathway interactions;Patients;Pharmaceutical Preparations;Phase Ib Clinical Trial;Platinum;Play;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Prediction of Response to Therapy;Prognosis;Rationalization;Recurrence;Regimen;Resistance;Role;Safety;Sampling;Serous;TOPBP1 Gene;Testing;Time;Tissues;Toxic effect;Up-Regulation;biomarker driven;cancer cell;clinical application;clinical predictors;efficacy evaluation;epigenetic therapy;genome-wide;genomic locus;homologous recombination;improved outcome;inhibitor therapy;innovation;novel;novel therapeutics;objective response rate;overexpression;participant enrollment;patient derived xenograft model;predicting response;predictive marker;response;response biomarker;restoration;safety assessment;standard of care;synergism;therapy development;treatment response;tumor;tumor DNA Project 2: Combination PARPi-BETi to Overcome PARPi Resistance NARRATIVE PROJECT 2PARP inhibitors (PARPi) are widely used in ovarian cancer and now are approved in first- and second-linesettings but they are limited by emergence of resistance. We propose to address this unmet need and reversePARPi resistance by targeting BRD4 with the clinically applicable BET inhibitor (BETi) ZEN3694. We proposethat BET-PARP inhibition combination will lead to functional deficiency in homologous recombination andimpairment of G2-M cell cycle by suppressing WEE1 expression. NCI 10713053 9/8/23 0:00 PAR-20-305 1P50CA272218-01A1 1 P50 CA 272218 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(M1)S 5732 15234951 "MAHDI, HAIDER " Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 451827 408489 43338 ABSTRACT PROJECT 2PARP inhibitors have emerged as an established standard of care option in epithelial ovarian cancer (OvCa).Approximately half of OvCa patients harbor inactivating genetic alterations in the homologous recombination(HR) pathway which results in synthetic lethality with PARP inhibition (PARPi). PARPi have promising activityin HR-deficient OvCa. Even though less effective compared to HR-deficient OvCa PARPis have also beenshown to be active in HR-proficient OvCa. Unfortunately the activity of PARPi is limited by the emergence ofPARPi resistance. Therefore there is an urgent need to identify potential strategies to reverse PARPi resistancein OvCa. Our preliminary studies suggest that inhibition of BRD4 activity by bromodomain extraterminal inhibitors(BETi) is an attractive approach to reverse PARPi resistance. Notably the BRD4 genomic locus 19p13.12 isoften amplified in high-grade serous OvCa (~20%). Indeed BRD4 amplification/overexpression correlates witha poor prognosis in these patients.We and others have shown that BETis play a major role in suppressing the HR pathway and impairing the G2/Mcheckpoint which reverses resistance to PARPi caused by restoration of the HR pathway. Therefore ourcentral hypothesis is that targeting BRD4 activity using clinically applicable BET inhibitor is sufficientto overcome resistance to PARPi developed in recurrent OvCa. We also hypothesize that targeting BRD4will sensitize tumor to PARPi by simultaneously downregulating HR activity specifically BRCA1 RAD51 andTOPBP1 expression and impairing the G2/M phase of the cell cycle by suppressing WEE1 activity leading toDNA damage accumulation and mitotic catastrophe. Accordingly the objective of the present study is toevaluate the safety and efficacy of a combination of PARPi and BETi in recurrent PARPi-resistantplatinum-sensitive OvCa. We also plan to assess the impact of PARPi-BETi combination on functional HRactivity and percent reduction compared to baseline and correlate with objective response to therapy. Furtherwe plan to investigate the mechanistic basis of these findings in patient-derived models obtained from thepatients enrolled in the trial. To achieve that we propose the following specific aims (SA): SA1. To determinethe safety and efficacy of PARPi combined with BETi in patients with recurrent PARPi-resistant OvCa in a phaseIb clinical trial. SA2. To investigate the impact of the combined regimen on modulating HR and DNA damageresponse (DDR) pathways as well as G2-M cell cycle checkpoint using tissue and circulating tumor DNA samplesboth at baseline on treatment and at time of progression. SA3: To investigate the mechanisms of response andresistance to the combination regimen in preclinical models. The potential impact is significant as there is anurgent need to overcome resistance to PARPi in OvCa. This project investigates a novel new therapeuticdirection combining PARPi with epigenetic therapy by BETi. PARPi resistance is a major challenge given thatPARPi are now approved in first line and recurrent settings. Further this study will investigate predictivebiomarkers which will help identify patients who benefit from this regimen. Successful execution of this studywill provide a rationale to advance this regimen into scientifically rationalized trials focused on improving theoutcome of this most lethal cancer with limited treatment options. +No NIH Category available Adipocytes;BMP2 gene;BMP4;Binding;Biopsy;Cancer Patient;Carboplatin;Carcinoma;Cell Reprogramming;Cell Survival;Cells;Chemoresistance;Chemotherapy-Oncologic Procedure;Complex;Data;Deposition;Development;Dose;Enhancers;Epigenetic Process;Event;Extracellular Matrix;Fibroblasts;Fostering;Future;Generations;Genomics;Goals;Growth Factor;Histones;Homologous Gene;Immune;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Mass Spectrum Analysis;Maximum Tolerated Dose;Mediating;Mediator;Mesenchymal;Mesenchymal Stem Cells;Modeling;Myofibroblast;Neoplasm Metastasis;Ovarian;Patients;Pattern;Phase;Phenotype;Platinum;Play;Prevalence;Production;Progression-Free Survivals;Property;Recurrence;Recurrent disease;Reporting;Role;Safety;Sampling;Site;Stromal Cells;Stromal Neoplasm;Time;Transcriptional Regulation;Treatment Efficacy;WT1 gene;Work;cancer stem cell;cancer therapy;chemotherapy;directed differentiation;high risk;histone methyltransferase;improved;improved outcome;inhibitor;mortality;mortality risk;neoplastic cell;novel strategies;overexpression;pharmacologic;prevent;primary endpoint;protein crosslink;recruit;response;secondary endpoint;stem;stem cells;stem-like cell;stromal progenitor;therapy resistant;transcription factor;treatment response;tumor microenvironment;tumor progression;tumorigenic Project 1: EZH2 Inhibition to Prevent/Overcome Chemoresistance NARRATIVE PROJECT 1The development of chemotherapy resistance is one of the deadliest steps in ovarian cancer progression.Carcinoma-associated mesenchymal stem cells (CA-MSCs) are stromal progenitor cells within the ovariancancer tumor microenvironment which drive chemotherapy resistance. Our goal is to target CA-MSCs toprevent the development of chemotherapy resistance. NCI 10713052 9/8/23 0:00 PAR-20-305 1P50CA272218-01A1 1 P50 CA 272218 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(M1)S 5731 8784701 "EDWARDS, ROBERT PAGE" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 361391 227290 134101 ABSTRACT PROJECT 1The ability to overcome the development of chemotherapy resistance and maintain sensitivity to the mosteffective chemotherapy in ovarian cancer platinum is critical to improving outcomes in ovarian cancer. Theovarian cancer tumor microenvironment (TME) is an important though understudied mediator of treatmentresistance. Specifically the stromal composition of this TME dramatically influences how cancer responds tochemotherapy yet no strategies exist to target the cancer-supportive properties of the stromal TME.Carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs) are stromal progenitor cells that dictatethe composition and function of the stromal TME. CA-MSCs strongly promote the development ofchemotherapy resistance through the secretion of growth factors such as BMP2 and BMP4 and alteration ofthe extracellular matrix (ECM). CA-MSCs arise from cancer mediated epigenetic reprogramming of normalMSCs through altered genomic localization of the histone methyltransferase EZH2. WT1 a transcription factorhighly upregulated in CA-MSCs appears to drive this altered genomic localization of EZH2 necessary for CA-MSC formation. Importantly the CA-MSC phenotype appears to be reversible and CA-MSC reversion ornormalization correlates with improved sensitivity to platinum and patient survival. Our preliminary dataindicate pharmacologic inhibition of EZH2 blocks the reprograming of MSC into CA-MSC and increases CA-MSC normalization to prevent chemotherapy resistance. We thus hypothesize that inhibiting EZH2 will disruptstromal support of ovarian cancer leading to improved treatment response reduction in metastasis anddelayed disease recurrence with maintenance of platinum sensitivity. We propose to:Aim 1: Conduct a phase 1 dose-escalation study of the second generation EZH2 inhibitor CPI-0209 incombination with Carboplatin in platinum sensitive recurrent ovarian cancer.Aim 2: Determine the impact of EZH2 inhibition on the ovarian stromal TME.Aim 3: Determine the role of WT1 in mediating EZH2-driven CA-MSC reprogramming andchemotherapy resistance.Upon completion of this work we will have determined the potential for using CPI-0209 in combination withplatinum chemotherapy in recurrent ovarian cancer to prevent stromal-mediated chemotherapy resistance. Wewill also define the ability of CPI-0209 to induce CA-MSC normalization in patients. Further we will haveidentified the mechanism of WT1 mediated EZH2 genomic localization during CA-MSC reprogrammingenabling future more focused targeting of the CA-MSC phenotype. Collectively this work represents a novelapproach to enhancing ovarian cancer chemotherapy sensitivity by targeting the cancer stromal TME. +No NIH Category available Administrator;Advocacy;Advocate;Agreement;Biotechnology;Budgets;Cancer Center;Clinical Trials Cooperative Group;Clinical Trials Network;Code;Collaborations;Communication;Communities;Community Outreach;Computer software;Data;Development;Doctor of Philosophy;Educational workshop;Ensure;Evaluation;Funding;Future;Goals;Guidelines;Individual;Institution;Intellectual Property;Leadership;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Manuscripts;Monitor;Patients;Periodicals;Policies;Preparation;Productivity;Program Research Project Grants;Progress Reports;Publications;Qualifying;Regulation;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resource Sharing;Resources;Safety;Schedule;Science;Scientist;Services;United States National Institutes of Health;Universities;Update;Work;advocacy organizations;career;experience;material transfer agreement;meetings;outreach;patient health information;patient oriented;programs;sharing platform;success;tool;translational goal;translational research program Administrative Core n/a NCI 10713051 9/8/23 0:00 PAR-20-305 1P50CA272218-01A1 1 P50 CA 272218 1 A1 9/1/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(M1)S 5730 9076039 "BUCKANOVICH, RONALD J" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 234893 147731 87162 PROJECT SUMMARY/ABSTRACT CORE AThe HCC OvCa SPORE Administrative Core (Core A) is co-directed by SPORE PIs Ronald Buckanovich MDPhD and Robert Edwards MD. Core A will (i) provide scientific fiscal and general administrative oversight toall SPORE components (ii) work to facilitate the research productivity of the three SPORE Projects (iii)expand the utility and efficiency of the SPOREs two Shared Resource Cores and (iv) ensure the success ofthe Career Enhancement Program (CEP) and Developmental Research Program (DRP) to generate a pipelineof new OvCa investigators and projects. To ensure the success of the SPORE Core A will coordinate sharingof SPORE data as well as internal and external communications and interactions. This includes coordinatingagreements with collaborating institutions and community outreach with patient advocates. Core A will convenemonthly meetings attended by all SPORE Investigators coordinate periodic administrative and scientificreviews release and publicize RFAs and arrange for the review of received CEP and DRP applications andwork closely with the NCI Translational Research Program Office. It will provide the administrative frameworkthrough which the SPORE Executive Committee Internal Advisory Board (IAB) and External Advisory Board(EAB) can evaluate program activities and will redirect resources as appropriate to maximize progress towardthe SPOREs translational goals. Core A will monitor the budgets of the individual SPORE CEP and DRPProjects and Cores to ensure that no duplication of effort occurs between the SPORE and institutional sharedresources national consortia or cooperative groups or other funded research grants. The Core will alsoensure that the SPOREs research activities are conducted in compliance with all local and federal regulationsand guidelines including those for protecting the safety and personal health information of patients. Core A willbenefit from the effort of a qualified SPORE Administrator who assists in scheduling and in preparing reportsand manuscripts.Impact: Through Core A functions the SPORE as a whole will benefit from the centralization of essentialservices and each SPORE component will be afforded the opportunity to maximize the effort devoted toresearch and patient-oriented advances in ovarian cancer. +No NIH Category available Address;Advocate;American;Archives;BRCA1 gene;Bioinformatics;Biometry;Bromodomains and extra-terminal domain inhibitor;Cancer Center;Cancer Etiology;Cancer Patient;Carboplatin;Cell Cycle Checkpoint;Cell Cycle Checkpoint Genes;Cells;Cessation of life;Chemoresistance;Clinical;Clinical Data;Clinical Trials;Collaborations;Cost Sharing;DNA Repair;Development;Diagnosis;Disease;Disease Progression;Disease Resistance;Doctor of Philosophy;Dose;EZH2 gene;Ensure;Epigenetic Process;Erinaceidae;Exclusion;Experimental Models;Funding;Future;Generations;Goals;Human;Immune;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Incidence;Individual;Institution;Investments;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Mesenchymal Stem Cells;Minority Groups;Mitotic;Modeling;Molecular;Myeloid-derived suppressor cells;New Agents;Newly Diagnosed;Operative Surgical Procedures;Pathology;Patient Care;Patient-Focused Outcomes;Patients;Pennsylvania;Phase;Phase Ib Trial;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Prediction of Response to Therapy;Principal Investigator;Prognosis;Program Research Project Grants;Proteins;Recurrence;Relapse;Research;Research Infrastructure;Research Personnel;Resistance;Resource Sharing;Science;Scientist;Signal Transduction;TOPBP1 Gene;Technology;Testing;Time;Translational Research;Underrepresented Minority;Woman;anticancer research;cancer care;career;career development;checkpoint therapy;chemotherapy;data resource;design;experience;homologous recombination;improved;improved outcome;in vivo;inhibitor;inhibitor therapy;innovation;mortality;multidisciplinary;multipotent stromal progenitor;notch protein;novel diagnostics;novel therapeutic intervention;novel therapeutics;patient response;personalized medicine;phase II trial;potential biomarker;pre-clinical;prevent;programs;recruit;response;smoothened signaling pathway;stem cells;stromal progenitor;success;synergism;therapeutic development;therapy resistant;tissue resource;treatment strategy;tumor;tumor microenvironment HCC Ovarian Cancer SPORE NARRATIVE OVERALLThe goal of the UPMC HCC Ovarian Cancer SPORE is to improve the outcomes of patients with ovariancancer. We propose (i) three clinical trials each with critical translational aims to identify patients most likely tobenefit from therapy; and (ii) a Career Enhancement Program (CEP) and Developmental Research Program(DRP) to ensure a pipeline of ovarian cancer researchers as well as novel diagnostic and therapeuticstrategies. The three projects CEP and DRP will be supported by three cores to increase success. NCI 10713050 9/8/23 0:00 PAR-20-305 1P50CA272218-01A1 1 P50 CA 272218 1 A1 "BASA JANAKIRAM, NAVEENA" 9/1/23 0:00 8/31/28 0:00 ZCA1-RPRB-H(M1)S 9076039 "BUCKANOVICH, RONALD J" "EDWARDS, ROBERT PAGE" 12 RADIATION-DIAGNOSTIC/ONCOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2163827 NCI 1485218 678609 PROJECT SUMMARY/ABSTRACT OVERALLOvarian cancer (OvCa) has the third highest mortality to incidence ratio and is the fifth leading cause of cancerdeath in American women. The typical disease course of a patient with OvCa spans four and a half years fromthe time of diagnosis to death. During the course of patient care acquired and innate resistance to our mosteffective and promising therapies such as chemotherapy PARP inhibitor therapy and immunotherapy drivesdisease progression. The overall goal of the UPMC Hillman Cancer Center (HCC) OvCa SPORE is to preventand/or overcome therapeutic resistance to improve patient survival. Each of the SPOREs three Projectsevolved from the innovative concepts and findings of SPORE investigators. Each project involves a clinical trialwith a new agent. In addition each project through complementary investigator expertise incorporates criticaltranslational aims to identify patients most likely to respond to therapy. Project 1 will assess the ability ofinhibitors of the epigenetic regulator EZH2 to prevent/overcome OvCa stromal progenitor cell-driven resistanceto platinum-based chemotherapy. Project 2 will determine whether BET inhibitors which downregulate criticalDNA repair and cell cycle checkpoint proteins can reverse resistance to PARP inhibitors. Project 3 will testwhether inhibitors of the hedgehog signaling pathway which drives tumor immune exclusion can improveOvCa patient response to immune checkpoint inhibitor therapy. The HCC OvCa SPORE will include a CareerEnhancement Program (CEP) and Developmental Research Program (DRP) in order to both encourage earlycareer investigators to enter the field of translational OvCa research and engage more establishedinvestigators in OvCa research. The CEP and the DRP which are cost-shared and proactive at providingresearch funding to investigators from under-represented minority groups will provide a pipeline of potentialfuture SPORE Projects. All SPORE CEP and DRP Projects will be receive fiscal and scientific oversight froman Administrative Core and support from two shared resource cores. The Translational Pathology Core willcollect annotate archive and distribute biospecimens and clinical data derived from the more than 300 HCCOvCa patients seen each year. It will also develop new preclinical experimental models that behave more likehuman OvCa. The Biostatistics and Bioinformatics Core will aid in design and analysis of all studies includingomic technologies that can provide molecular and spatial characterization of individual cells within a tumor.The SPORE Projects will also be supported by established and new collaborators who are internal andexternal to HCC. Combined the SPORE projects CEP DRP and cores are positioned together with ourvertical collaborators to improve the outcomes of patients with ovarian cancer. The findings generated by theSPORE will be advanced through further collaboration and future non-SPORE funding. 2163827 +No NIH Category available Grant;Oncology;Research Training Oncology Research Training Grant NarrativeThe goal of the Oncology Research Training Program is to teach MD cancer specialists-in-training the skillsnecessary to pursue careers in cancer research so that they can contribute to the development of advances inthe prevention diagnosis and treatment of cancer. NCI 10712973 6/30/23 0:00 PA-20-142 2T32CA009357-41 2 T32 CA 9357 41 "LIM, SUSAN E" 7/1/80 0:00 6/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9217503 "LI, QING " Not Applicable 6 INTERNAL MEDICINE/MEDICINE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 361107 NCI 400740 30456 AbstractThe Oncology Research Training Program (ORTP) has been in existence for 40 years and was developed withthe primary goal of preparing physician-trainees (fellows in Adult Medical Oncology) for careers in academicmedicine. The rationale for training in oncology research is four fold: (a) Cancer remains one of the leading causeof morbidity and mortality; (b) there is a need to maintain momentum that has been achieved in our fundamentalunderstanding of carcinogenesis genomics and immunology (c) there is a need to translate progress gained inthe laboratory to the development of novel and better strategies for the diagnosis therapies and prevention ofcancer and (d) in the rapidly chaniging health care advances and economics landscape a critical need fordevelopment of tools and policy to determine the most effective and efficient ways to deliver care and measureoutcomes in the society. The five Research training themes of the Program are carefully developed to build onthe past successes of training academic leaders. It melds emerging aspects of cancer biology care and policyis aligned with the investigative interest and expertise of 44 established extramurally-funded program facultymembers leverages the outstanding resources of the Division of Hematology/Oncology the ComprehensiveCancer Center (UMCCC) the medical school and other units of the University of Michigan. The research trainingthemes are: (1) Molecular-genetic mechanisms of neoplastic transformation aberrant signaling and metastasis(2) Biomarkers in cancer prevention and therapy; (3) Molecular targets of drug discovery and experimentaltherapuetics of cancer; (4) Immunological approaches to cancer therapy and (5) Health services researchfocused on delivery outcomes reform and value. The trainees selected for this program will first experiencewell-defined curriculum and training to the important concepts in the chosen research theme and then spend 2-3 years in the relevant laboratory and/ or clinical or health services research environment under the directsupervision of a training program faculty mentor. The trainees will develop skills in: (a) to identify importantquestions in oncology research (b) develop testable hypotheses that will address the pertinent questions (c)aquire the necessary technical expertise to rigorously test the hypotheses identified; (d) critically evaluate thedata generated; (e) develop the necessary skills of written and oral communication to promulgate the conclusionsmade and (f) develop and compete of peer-reviewed grants. The trainees will have an MD or MD-PhD degreecompleted residency training in Internal Medicine and a year of clinical subspecialty training in ADULT medicaloncology/hematology. The ultimate goal of the program is to prepare trainees for careers in academic oncologyas independent faculty members in schools of medicine at research universities. 361107 +No NIH Category available Acute Myelocytic Leukemia;Acute leukemia;Affinity;Animal Model;BMI1 gene;Binding;Biology;Blood Cells;Bone Marrow Cells;Cell Line;Cells;Chemicals;Chromatin;Complex;Deposition;Development;Disease;Drug Kinetics;Epigenetic Process;Generations;Goals;HOXA9 gene;Hematopoiesis;Histone H2A;Hydrolysis;Leukemic Cell;Maintenance;Modeling;Molecular Abnormality;Monoubiquitination;Mus;Names;Nucleosomes;Oncogenes;Outcome;PRC1 Protein;Patients;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Prodrugs;Property;Proteins;Recurrence;Research;Resistance;Sampling;Solubility;Stem Cell Research;Structure;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Ubiquitination;Undifferentiated;Work;Xenograft Model;acute leukemia cell;acute myeloid leukemia cell;analog;anti-cancer therapeutic;antileukemic agent;cell growth;chemotherapy;clinical application;design;efficacy study;improved;in vivo;inhibitor;innovation;interdisciplinary approach;leukemia;leukemic stem cell;leukemogenesis;mouse model;novel;novel anticancer drug;novel strategies;novel therapeutic intervention;overexpression;paralogous gene;patient derived xenograft model;pharmacologic;screening;self-renewal;small molecule;small molecule inhibitor;stem cells;structural biology;targeted treatment;ubiquitin-protein ligase Targeting PRC1 in leukemia Project NarrativeWe propose to develop small molecule inhibitors blocking activity of PRC1 E3 ubiquitin ligase in leukemia.PRC1 blocks differentiation of leukemic cells and this research may yield valuable chemical probes for stemcell research and new anti-cancer agents. NCI 10712963 8/24/23 0:00 PA-20-185 1R01CA282082-01 1 R01 CA 282082 1 "AGYIN, JOSEPH KOFI" 9/1/23 0:00 8/31/28 0:00 Drug Discovery and Molecular Pharmacology C Study Section[DMPC] 9339278 "CIERPICKI, TOMASZ " Not Applicable 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 624980 NCI 403132 221848 AbstractAcute leukemia is an aggressive disease resulting from various genetic abnormalities and is characterized bythe presence of undifferentiated blood cells. Emerging evidence shows that recurrence of acute leukemiaresults from the activity of leukemic stem cells (LSCs) which are resistant to chemotherapy supporting theneed for new pharmacological agents inducing differentiation of LSCs. The self-renewal and differentiationcapacity of stem cells including LSCs are dependent on the activity of the Polycomb repressive complex 1(PRC1). The core of all PRC1 complexes comprises heterodimeric complexes involving RING1B or RING1Aand one of the PCGF1-6 paralogs which catalyze monubiquitination of histone H2A (H2Aub) constituting astrong repressive mark. Simultaneous depletion of core PRC1 components RING1A/B results in a loss ofH2Aub deposition cell growth arrest and differentiation of acute leukemia cells driven by the oncogenesassociated with expression of HOXA9. Therefore blocking PRC1 activity with small molecules could lead toeradication of LSCs and differentiation of leukemic blasts.The major goal of this project is to develop potent small molecule inhibitors blocking the activity of PRC1 by adirect inhibition of the RING1B-BMI1 E3 ubiquitin ligase to induce differentiation of leukemic cells. To this endwe employed fragment-based screening followed by extensive medicinal chemistry to develop the first-in-classsmall molecules that directly bind to the RING1A/B proteins and inhibit PRC1 activity through blocking theinteraction of the PRC1 complex with nucleosomes. Our first-generation inhibitor RB-3 decreases global levelof H2Aub and induces differentiation in leukemia cells and primary AML samples. The goal of this proposal isto optimize this class of compounds and develop potent PRC1 inhibitors with optimized drug-like propertiesand pronounced in vivo efficacy in animal models of acute leukemia. We will employ extensive medicinalchemistry and structure-based design approach to optimize PRC1 inhibitors. All inhibitors will be characterizedto determine binding affinity inhibitory activity and cellular activity to inhibit H2Aub. Best compounds will beextensively evaluated in a panel of leukemia cell lines. We will assess the mechanism of action of the PRC1inhibitors and test their activity in the models of LSCs and in the primary AML patient samples. The optimizedcompounds will be assessed in vivo for their potential to block development of leukemia in mouse models ofAML. Our studies will explore a new approach to induce differentiation of leukemia cells and LSCs and maylead to the development of highly valuable chemical probe compounds or novel pharmacologic agents foracute leukemia patients. 624980 +No NIH Category available ART protein;Animals;Automation;Biological Markers;Biological Process;Cancer Center Support Grant;Cells;Cryoelectron Microscopy;Data;Data Analyses;Data Collection;Disease;Disease model;Dissection;Experimental Designs;Generations;Infrastructure;Insecta;Label;Laboratories;Lead;Leadership;Light;Mammalian Cell;Mass Spectrum Analysis;Molecular;Movement;New York;Nucleic Acids;Pathologic Processes;Pathway interactions;Pharmaceutical Chemistry;Photons;Post-Translational Protein Processing;Preparation;Principal Investigator;Production;Protein Biosynthesis;Protein Engineering;Proteins;Proteomics;Research Personnel;Research Project Grants;Resolution;Resource Sharing;Resources;Sampling;Science;Services;Source;Strategic Planning;Structure;Synchrotrons;Technology;Therapeutic;Treatment Protocols;Validation;X-Ray Crystallography;computerized data processing;data acquisition;design and construction;experience;flexibility;insight;member;programs;protein expression;response;structural biology;tool Structural Biology Shared Resource Program Director/Principal Investigator (Last First Middle): Chu EdwardSTRUCTURAL BIOLOGY SHARED RESOURCE - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712896 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5701 1864522 "ALMO, STEVEN C." Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 112532 66984 45548 Program Director/Principal Investigator (Last First Middle): Chu EdwardSTRUCTURAL BIOLOGY SHARED RESOURCE - PROJECT SUMMARY/ABSTRACTThe Structural Biology Shared Resource (SBSR) supports a wide range of technologies for identifying newtargets defining molecular mechanisms and generating tool compounds and therapeutic leads. Servicesinclude: 1) state-of-the-art protein production; 2) high resolution structure determination by X-ray crystallographyNMR and cryo-EM; 3) mass spectrometry-based proteomics analyses; and 4) additional advanced technologies.SBSR provides access to state-of-the-art infrastructure located in-house and at regional centers and nationallaboratories to support the scientific priorities outlined in the MECC Strategic Plan. Protein-based tools facilitatethe mechanistic dissection of fundamental biological and pathological processes and the validation of potentialtherapeutic strategies in cell- and animal-based disease models. Mass spectrometry and proteomics enablesthe discovery of new targets and biomarkers and provides deep mechanistic insight into responses associatedwith disease states and treatment regimens. Structural data provide atomic-resolution insight for protein designand medicinal chemistry essential for enhancing initial hits and lead therapeutics. The SBSR Specific Aims are:Aim 1: Provide state-of-the-art technologies for protein expression purification and characterization andvalidation. These resources include bacterial insect cell and mammalian cell expression platforms supportedby considerable automation to facilitate these efforts. SBSR staff provide the full range of support servicesincluding construct design and downstream characterization.Aim 2: Enable high resolution structural characterization. Available resources include in-house capabilities inNMR X-ray crystallography and cryo-EM as well as extensive access to state-of-the art national facilities forNMR and cryo-EM (New York Structural Biology Center) and X-ray crystallography (Brookhaven NationalLaboratory and Argonne National Laboratory). SBSR staff provide the full range of support services includingdata collection and processing structure determination validation and structure interpretation.Aim 3: Provide state-of-the-art mass spectrometry capabilities for proteomics analyses including proteinabundance determination of regulated protein pathways and other networks identification and quantification ofprotein post-translational modifications and protein synthesis rates. SBSR staff provide the full range of supportservices spanning experimental design sample preparation data acquisition and data interpretation.The breadth of core services supports the entire spectrum of investigators and the extensive coordination amongthe SBSR leaders allows for the seamless movement among core-supported technologies. As such projectscan enter the pipeline at any stage. For example inexperienced investigators can enter the pipeline at the proteinexpression stage and receive support all the way through structure determination and interpretation.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Back;Biological Assay;Biological Sciences;Biometry;Cancer Center Support Grant;Cancer Patient;Cell Separation;Cell surface;Cells;Cellular Assay;Chromatin;Chromium;Clinical;Complement;Consultations;Core Facility;Cost Savings;Data;Data Analyses;Data Analytics;Data Storage and Retrieval;Drops;Equipment;Event;Experimental Designs;Fostering;Foundations;Funding;Genomics;Genomics Shared Resource;Goals;Hematopoiesis;Human Resources;Individual;Institution;Institutional Review Boards;Investments;Malignant Neoplasms;Mission;Modeling;Molecular Cytogenetics;Outcome;Outsourcing;Patients;Pattern;Population;Principal Investigator;Process;Protocols documentation;Provider;Reagent;Research;Research Design;Research Personnel;Resource Sharing;Resources;Sampling;Services;Somatic Mutation;Techniques;Technology;Tissues;Work;cancer genomics;cancer health disparity;clinical sequencing;computing resources;cost;cost efficient;data management;epigenomics;exome sequencing;experimental study;genomic data;health disparity;health equity;improved;innovation;insight;laboratory experience;migration;minority patient;neighborhood disadvantage;patient population;precision medicine;programs;response;single cell sequencing;single-cell RNA sequencing;skills;socioeconomic disadvantage;transcriptome sequencing;transcriptomics;tumor;underserved community;underserved minority Genomics Shared Resource Program Director/Principal Investigator (Last First Middle): Chu EdwardGENOMICS SHARED RESOURCE - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712895 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5700 1863727 "GREALLY, JOHN " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 232267 138254 94013 Program Director/Principal Investigator (Last First Middle): Chu EdwardGENOMICS SHARED RESOURCE - PROJECT SUMMARY/ABSTRACTThe Genomics Shared Resource (GSR) integrates our legacy Genomics Epigenomics ComputationalGenomics and Molecular Cytogenetics core facilities. As a result of this integration we have combined theactivities and expertise of individuals in core facilities performing closely related work into a unified entity thatenhances efficiency and quality of services so that cancer researchers can hand off samples to core personneland receive analyzed data providing a complete workflow housed in a single facility. The GSR is now implementing long-read sequencing services in addition to short-read services. Whenappropriate we facilitate outsourcing of short-read sequencing to low-cost commercial providers. However wehave recently purchased the Illumina NextSeq 2000 platform that upgrades our short read sequencingcapabilities. This investment anticipates a substantial drop in reagent costs in the next 1-2 years and migrationof some of the currently outsourced sequencing back into the GSR. The GSR has also been proactive in optimizing new single cell assays for researchers with a current focus onsingle cell RNA-sequencing and chromatin assays as well as spatial transcriptomics of tissue sections. Costsavings through multiplexing for single cell experiments on the 10X Chromium platform has been used to makethese assays substantially more cost-efficient while reducing batch effects. Single cell sequencing combinedwith cell surface marker studies are being provided using the Mission Bio Tapestri platform which is a foundationfor ongoing clonal hematopoiesis research. We have increased our focus on collecting genomics data as aresource within the GSR. Our new institutional arrangement with Caris Life Sciences to perform exome andtranscriptome sequencing on our Bronx cancer patients is accompanied by a research protocol to allow theprimary sequence data to be returned to our FISMA-compliant data storage and computing resource. These dataare made available under defined IRB protocols for researchers to gain insights into the genomic eventsoccurring in the ancestrally diverse socioeconomically disadvantaged communities of the Bronx. Our goals for the next funding period will be to continue to support MECC researchers in their genomic assaysand data analyses. We are continuing to develop and support new assays to invest in new equipment and tohelp analyze data generated in the GSR. Investigators are encouraged to contact the leaders of the GSR andBiostatistics colleagues to discuss study design before initiating a project. For data analytical services we willcontinue to train lab personnel to process data independently and can troubleshoot problems with researchers.Finally a new goal is to tailor our services so that they allow insights into cancer genomics in the ancestrally-diverse Bronx population with the goal that GSR can help foster health equity and precision medicine for all.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Ablation;Accreditation;Alleles;Amino Acids;Animal Husbandry;Animal Model;Biological Sciences;Board Certification;Breeding;CRISPR interference;CRISPR-mediated transcriptional activation;CRISPR/Cas technology;Cancer Center Support Grant;Cancer Model;Cancer cell line;Caring;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Constitution;Constitutional;Cryopreservation;Derivation procedure;Development;Down-Regulation;Embryo;Ensure;Enterobacteria phage P1 Cre recombinase;Evaluation;Fertilization in Vitro;Gene Expression;Gene Modified;Gene Targeting;Generations;Genes;Genotype;Goals;Hematologic Neoplasms;Heterozygote;Histologic;Housing;Human;Injections;Knock-in Mouse;Knock-out;Knockout Mice;Label;Maintenance;Malignant Neoplasms;Mammalian Cell;Methodology;Methods;Microinjections;Modification;Mus;Oocytes;Pathologist;Patients;Principal Investigator;Proteins;RNA;Reporter Genes;Research;Research Personnel;Resource Sharing;Rodent;Services;Solid Neoplasm;Specificity;Study models;System;Tamoxifen;Techniques;Technology;Tissue Model;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Transplantation;Xenograft procedure;animal facility;animal imaging;base;base editing;conditional knockout;cost;cost efficient;embryo cryopreservation;embryonic stem cell;genomic locus;germ free condition;human cancer mouse model;human model;imaging system;implantation;improved;in vivo;in vivo imaging;in vivo imaging system;inducible Cre;innovation;knock-down;mouse genome;mouse model;neoplastic cell;novel;novel anticancer drug;novel imaging technology;offspring;overexpression;patient derived xenograft model;preclinical study;preservation;programs;red fluorescent protein;reproductive;sperm cryopreservation;stem;tumor;tumor growth;tumor xenograft Animal Model Shared Resource Program Director/Principal Investigator (Last First Middle): Chu EdwardANIMAL MODEL SHARED RESOURCE - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712890 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5695 7272825 "EDELMANN, WINFRIED " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 346226 206087 140139 Program Director/Principal Investigator (Last First Middle): Chu EdwardANIMAL MODEL SHARED RESOURCE - PROJECT SUMMARY/ABSTRACTThe objective of the Animal Model Shared Resource (AMSR) is to provide a comprehensive a service for thegeneration housing and analysis of mouse models of human cancer. The AMSR provides services for themodification of the mouse genome through CRISPR/Cas9 gene targeting technology as well as conventionalgene targeting in embryonic stem (ES) cells. The AMSR generates conventional knockout mouse lines knock-in mouse lines and mouse lines with conditional alleles for the temporal and spatial ablation of genes. The AMSRalso provides services for the generation of transgenic mouse lines either by conventional random transgeneintegration or by targeted insertion of transgenes into safe harbor genomic loci to ensure stable gene expression.An AAALAC-accredited AMSR animal facility provides specific pathogen-free (SPF) rodent housing and a broadspectrum of animal husbandry services as well as the services of a board-certified veterinary pathologist.Comprehensive mouse reproductive services for embryo and sperm cryopreservation and re-derivation oftransgenic and gene-targeted mouse lines as well as IVF services are offered. The AMSR established a GeneModification Service to provide a complete service for the rapid and cost-efficient generation of geneticallymodified mouse lines to MECC investigators. Furthermore the AMSR provides a robust array of xenograftmethodologies for cell implantation and propagation of tumor grafts by serial transplantations and supports pre-clinical studies on novel anticancer agents in murine tumors as well as in human patient-derived tumor xenografts(PDX). Finally the AMSR provides in vivo IVIS imaging of animals bearing tumors that express bioluminescentor fluorescent proteins allowing non-invasive quantitation of tumor growth in mice. The AMSR has three SpecificAims to accomplish these goals: 1) To provide comprehensive services required for the generation of geneticallymodified mouse models of human cancer and the generation of xenotransplantation mouse models for studyinghematologic malignancies and patient-derived solid tumor xenografts; 2) To provide services for husbandry andpreservation of genetically modified mouse lines including sperm and embryo freezing for cryopreservation re-derivation of transgenic and gene-targeted mouse lines and in vitro fertilization (IVF) services; and 3) To provideinnovative methods and technologies to support MECC research including novel CRISPR technologies such asbase edit technology CRISPR interference (CRISPRi) CRISPR activation (CRISPRa) and CRISPR RNAtechnology for knockdown of gene expression as well as novel imaging technologies to increase the range ofdetectable fluorescent labels in tumor cells.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page diff --git a/tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub2.txt b/tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub2.txt new file mode 100644 index 0000000..6c64010 --- /dev/null +++ b/tutorials/notebooks/Azure_AI_Studio/search_documents/grant_data_sub2.txt @@ -0,0 +1,2499 @@ +No NIH Category available Binding;Budgets;Businesses;COVID-19;COVID-19 pandemic;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Cancer Center;Clinical Data;Clinical Investigator;Clinical Protocols;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Community Outreach;Conduct Clinical Trials;Data;Dedications;Development;Disease;Eligibility Determination;Employee;Enrollment;Ensure;Equity;Ethics;Ethnic Origin;Faculty;Funding;Good Clinical Practice;Grant;Growth;Hematology;Infrastructure;Institution;Intervention;Investigational Therapies;Investments;Journals;Leadership;Malignant Neoplasms;Medical center;Modality;Monitor;National Clinical Trials Network;Operations Research;Outcome Study;Patient advocacy;Peer Review;Phase;Physician Executives;Principal Investigator;Procedures;Protocols documentation;Publications;Race;Reporting;Research;Research Personnel;Resources;Risk;Safety;Science;Structure;Time;Training;Training and Education;Underrepresented Populations;Underserved Population;cancer clinical trial;community engagement;data management;investigator-initiated trial;marginalized population;multidisciplinary;neuro-oncology;operation;patient engagement;process improvement;programs;protocol development;quality assurance;recruit;success;underserved minority Clinical Protocol and Data Management Program Director/Principal Investigator (Last First Middle): Chu EdwardCLINICAL PROTOCOL AND DATA MANAGEMENT - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712887 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5692 8683247 "HALMOS, BALAZS " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 356338 212106 144232 Program Director/Principal Investigator (Last First Middle): Chu EdwardCLINICAL PROTOCOL AND DATA MANAGEMENT - PROJECT SUMMARY/ABSTRACTThe Montefiore Einstein Cancer Center (MECC) Clinical Protocol and Data Management (CPDM) which isoperationalized through the recently established business unit called the Cancer Clinical Trials Office (CCTO).The CCTO has been created to unify all cancer clinical research operations under one unit with distinct standardoperating procedures and workflows to ensure consistency and high-quality research across all departmentsconducting cancer clinical research at the Montefiore Medical Center. The CCTO provides the centralizedadministrative and operational structure for cancer related research at MECC. The CCTO also administrativelysupports the Data and Safety Monitoring Committee Protocol Review and Monitoring Committee and the QualityAssurance Program. The CCTO has an annual operating budget of $6.5M in 2022 and has expanded our full-time employees to 75+ including existing and planned recruits who support nine Disease and Modality Teamsand over 80 investigators. Since the prior review the CPDM has undergone a leadership restructuring. BalazsHalmos MD was appointed Associate Director for Clinical Science and interim Medical Director of the CCTO in2021 and Nicholas Shuman MSN was recruited in June 2022 to serve as the Senior Director Cancer ClinicalResearch Administration and oversee the daily operations of the CCTO. During the last funding periodinterventional accruals remained strong in 2019 (559) but due to the COVID-19 pandemic and staff shortageshad a precipitous decline in 2020 (281). In 2021 Interventional accruals rebounded to 447. The CCTO continuesto prioritize MECC science and investigator-initiated clinical trials. In 2021 23.5% of treatment accruals and 36%of interventional enrollments were to institutional trials. The CCTO also supports participation in multiple NationalClinical Trials Network studies (38% of treatment accruals in 2021) under the Minority Underserved NCORPgrant and our involvement in the NCI Experimental Therapeutics Clinical Trials Network (ET-CTN). Newinitiatives beyond the creation of the CCTO as a separate business unit include: (1) the development of aFeasibility Committee to increase operational efficiencies and decrease time to activation (2) through ourcollaborative efforts with Community Outreach and Engagement we demonstrated continued success in theenrollment of underrepresented groups (URG) (>80% of accruals identify as URG) (3) a restructuring of theData and Safety Monitoring Committee to conduct monitoring of MECC investigator-initiated trials on a risk-based approach to align with the NCI CCSG PAR (4) expansion of the Quality Assurance Program withdedicated staff - Assistant Director of Quality Assurance and (5) key faculty clinician investigator recruitmentsin hematology neuro-oncology and Phase I.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Accountability;Advocacy;Affect;Appointment;Area;Authorization documentation;Awareness;Basic Science;COVID-19 pandemic;Cancer Center;Cancer Center Support Grant;Cancer health equity;Caring;Catchment Area;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communities;Comprehensive Cancer Center;Discipline;Disease;Education;Elements;Ensure;Environment;Evaluation;Faculty;Feedback;Fostering;Funding;Goals;Institution;Investments;Laboratory Research;Lead;Leadership;Malignant Neoplasms;Measures;Medicine;Mission;Modality;NCI Center for Cancer Research;Names;Patient Participation;Patients;Population Sciences;Positioning Attribute;Principal Investigator;Process;Program Evaluation;Research;Resource Allocation;Role;Schedule;Science;Strategic Planning;Structure;Training and Education;Translating;Translational Research;Trust;Vision;Work;anticancer research;authority;cancer clinical trial;cancer health disparity;cancer research center director;clinical care;college;community engagement;design;equity diversity and inclusion;experience;high school program;interdisciplinary collaboration;meetings;member;programs;reconstitution;recruit;response;social health determinants;success;working group Leadership Planning and Evaluation Program Director/Principal Investigator (Last First Middle): Chu EdwardLEADERSHIP PLANNING AND EVALUATION - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712886 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5691 2087647 "CHU, EDWARD " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 776891 462435 314456 Program Director/Principal Investigator (Last First Middle): Chu EdwardLEADERSHIP PLANNING AND EVALUATION - PROJECT SUMMARY/ABSTRACTEdward Chu MD was named the 4th Director and first Vice President of Cancer Medicine at the MontefioreEinstein Cancer Center (MECC) in October 2020. With this appointment Dr. Chu was given expanded executiveleadership authorities and is responsible to set mission vision and strategy and position the MECC as acomprehensive integrated cancer enterprise between the Albert Einstein College of Medicine (Einstein) andMontefiore Medicine (Montefiore). Since his arrival Dr. Chu has transformed the MECC and expanded theCCSG Senior Leadership Team (SLT) with two deputy directors and eight associate directors all experts andexperienced leaders in their respective fields. Each leader has well-defined roles and responsibilities thatincludes accountability and responsibility for planning and evaluation efforts at the MECC. The SLT has diverserepresentation across all strategic scientific areas and cancer disciplines to catalyze transdisciplinarycollaborations and translational research while engaging the community and nurturing an environment ofinclusion and belonging. MECC leaders are highly engaged as a mission-driven team and work collaborativelyto serve lead govern and execute on all strategic initiatives. Leaders participate and collaborate via 10 internalcommittees 2 external advisory boards and 8 Strategic Working Groups to enhance planning and evaluationefforts. The SLT has developed and implemented an operational structure and schedule designed and alignedto meet and exceed the milestones and tactics defined in the new 2021-2026 MECC Strategic Plan to dateover 60% of the goals have been realized. Since the previous CCSG review in 2019 the SLT has facilitated andled several transformative processes which include: (1) integrated four scientific cross-cutting themes across allareas of the cancer center; (2) appointed 8 new Program Leaders; (3) restructured Research Programs to moretightly align and focus cancer research and effectively foster transdisciplinary collaboration and translationalresearch; (4) tightened MECC membership criteria to enhance cancer focus; (5) appointed a new AssociateDirector for Diversity Inclusion and Equity (DEI) and launched a new DEI Committee; (6) re-established theCommunity Advisory Board; (7) expanded Cancer Research Training and Education and launched new BronxHigh School Program BEYOND Albert; (8) strategic shared investment in COE CRTEC and CPDM DiseaseModality Teams to increase awareness and access to clinical trials. (9) convened 2 external ad hoc EABmeetings focused on COE strategies and catchment area research and the second on reviewing progress todate on strategies to enhance CPDM DSM clinical accrual and PRMS. To date the Center Director and hisSLT have affected change that has resulted in renewed cancer focus over ~1000 patients participated in clinicaltrials in 2021 20% increase in cancer relevant funding and $33M in philanthropy.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Achievement;Address;Advisory Committees;Basic Science;Behavioral;Biology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communities;Data;Department chair;Development;Disparity;Education and Outreach;Ensure;Epidemiology;Etiology;Evaluation;Faculty;Feedback;Future;Genetic;Goals;Human Resources;Infrastructure;Institution;Instruction;Investments;Leadership;Malignant Neoplasms;Medicine;Methodology;Molecular;Monitor;Patients;Performance;Pharmacology;Population;Population Research;Population Sciences;Principal Investigator;Reporting;Research;Research Support;Resource Sharing;Sampling;Series;Service provision;Services;Shapes;Signal Transduction;Source;Strategic Planning;Surveys;Therapeutic;Thinking;Time;Training;Training and Education;Translational Research;Work;anticancer research;cancer care;career;college;community center;cost effective;cost effectiveness;early-career faculty;expectation;innovation;instrumentation;meetings;member;new technology;novel;patient population;programs;social health determinants;success;tool Shared Resource Management Program Director/Principal Investigator (Last First Middle): Chu EdwardSHARED RESOURCE MANAGEMENT - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712885 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5690 1935153 "BACKER, JONATHAN M." Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 41345 24610 16735 Program Director/Principal Investigator (Last First Middle): Chu EdwardSHARED RESOURCE MANAGEMENT - PROJECT SUMMARY/ABSTRACTThe Montefiore Einstein Cancer Center (MECC) Shared Resources (SRs) support the entire range of cancer-focused basic clinical translational and population sciences and provide access to MECC members to state-of-the-art methodology and instrumentation high-level expertise and instruction and cost-effective sources ofresearch support. MECC SRs are closely aligned with the scientific strategic priorities of the MECC. They greatlyfacilitate research investigating cancer biology at the molecular cellular and organismic level including thebiology and signaling that are directly relevant to the unique Bronx patient population served by MECC;development and evaluation of new cancer therapeutics; and identification of genetic epidemiologicalbehavioral and social determinants of health causality in our diverse catchment area population. Additional SRspromote the acquisition storage and analysis of patient sample and the management and coordination of clinicaltrials within the MECC catchment area for ongoing cancer-focused research. MECC SRs are managed atmultiple levels to ensure a high quality of services responsiveness to MECC members and alignment with theMECC Strategic Plan. Management tools and strategies include input to the SR directors from expert UserAdvisory Committees and survey data from MECC membership; monitoring of SR performance by the SharedResource Oversight Committee (SROC) which is chaired by the Associate Director for SR; monthly ResearchLeadership Council (RLC) meetings with all MECC SR Directors and Program Leaders; meetings with theExcellence in Career Enrichment Leadership (ExCEL) Committee composed of junior and mid-level facultymembers; and direct reporting by the Associate Director for SR to the Senior Leadership Team of the MECC.MECC SRs are managed in partnership with the Albert Einstein College of Medicine (Einstein) such that MECCcontributions are used to leverage substantial institutional support. As such oversight of SR finances isconducted on a quarterly basis by the Associate Director for SR and the Deputy Director for Administration incollaboration with senior administrative officials from the Deans office. Leveraging Einstein support has greatlyfacilitated the expansion of SR services and acquisition of innovative new instrumentation in multiple SRs.Moreover these quarterly meetings with the Deans office ensure that MECC priorities are recognized. Our activeengagement with MECC membership through user surveys User Advisory Committees Research LeadershipCouncil and ExCEL Committee provide critical guidance in shaping new initiatives within our MECC SRprogram. Future initiatives focus on developing and implementing innovative new technologies services andexpansion of critical SR personnel; enhancing coordination between MECC SRs; expanding education andtraining initiatives; and expanding administrative infrastructure and support.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Address;Affect;Aging;Air Pollution;Applications Grants;Articulation;Award;Behavioral;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Capital;Cataloging;Catchment Area;Cell Therapy;Chemoprevention;Clinical Trials;Communities;Community Outreach;Data;Development;Diagnosis;Disclosure;Doctor of Philosophy;Environmental Exposure;Evaluation;Expenditure;Faculty Recruitment;Fostering;Funding;Funding Agency;Funding Mechanisms;Future;Genomic medicine;Goals;Grant;Health;Health Services;Health Services Accessibility;Immunotherapy;Institution;Investments;Leadership;Legal patent;Licensing;Link;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Modeling;Neoplasm Metastasis;Outcome;Patients;Peer Review;Phase;Philanthropic Fund;Pilot Projects;Principal Investigator;Prize;Process;Publications;Reporting;Request for Proposals;Research;Research Personnel;Science;Signal Transduction;Source;Strategic Planning;Therapeutic;Translational Research;Underrepresented Populations;Underserved Population;United States National Institutes of Health;cancer epidemiology;cancer health disparity;colon cancer prevention;community engagement;drug development;effective intervention;equity diversity and inclusion;health disparity;implementation science;improved;innovation;interdisciplinary collaboration;invention;investigator-initiated translational research;member;oncofertility;patient population;pilot trial;precision medicine;programs;research study;small molecule;social health determinants;targeted agent;tumor;tumor immunology;tumor microenvironment Developmental Funds Program Director/Principal Investigator (Last First Middle): Chu EdwardDEVELOPMENTAL FUNDS - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712884 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5689 2087647 "CHU, EDWARD " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 420175 250104 170071 Program Director/Principal Investigator (Last First Middle): Chu EdwardDEVELOPMENTAL FUNDS PROJECT SUMMARY/ABSTRACTDevelopmental Funds (DF) at the Montefiore Einstein Cancer Center are used to invest in new scientificinitiatives to catalyze transdisciplinary translational research team science and research relevant to the MECCCatchment Area (CA). Funds are aligned to the 10 strategic scientific priorities as detailed in the MECC StrategicPlan 2021-2026: (1) to be a national model for community outreach and engagement and research focused onCA; (2) cancer therapeutics/drug development with specific focus on small molecules and targeted agents; (3)cancer immunology and new immunotherapies/cell therapies; (4) cancer biology and signaling; (5) cancerdormancy tumor microenvironment and metastasis; (6) cancer and aging; (7) cancer epidemiology focused onthe Bronx CA patient population; (8) tumor genomics and precision medicine in underserved andunderrepresented groups (URGs); (9) environmental and behavioral factors affecting common cancers in BronxCA; and (10) heath disparities health services and health implementation science. Four distinct Pilot ProjectPrograms were developed during the current project period: (1) MECC Team Science Awards; (2) MECCTranslational Research and Investigator-Initiated Clinical Trials Pilot Program; (3) MECC Catchment AreaResearch Pilot Program; (4) MECC Research Program Pilot Projects. Use of DF is based upon a rigorousassessment of MECC strategic needs as articulated in the Centers strategic planning process and coordinatedby the MECCs Senior Leadership Team. A substantial proportion of DF was allocated to support 9 pilot projectsfocused on research relevant to the CA. MECC Administration has refined processes for the solicitation andreview of pilot project applications and the allocation of funds. Strategic scientific priorities funded with DFrelevant to the CA and that directly impact our Bronx patients include chemoprevention of colon cancer onco-fertility and strategies to increase access to services environmental exposures from air pollution and links tolung cancer and understanding barriers to effective diagnosis and treatment of liver cancer for effectiveintervention. Future plans for the expenditure of DF in the next project period will continue to reflect prioritiesdesignated in the Strategic Plan. A program under development will focus on new MECC investigators whoidentify with an Underrepresented Group (URG) conducting research to address the disproportionate cancerburden among URGs. The goal of this funding mechanism is to facilitate research that will generate pilot datafor future competitive NCI grant applications.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Address;Advanced Malignant Neoplasm;Affect;Articulation;Back;Behavioral;Biological;Biological Models;Black race;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cancer Patient;Catchment Area;Cervical Cancer Screening;Clinical;Clinical Data;Collaborations;Communities;Community Outreach;County;Detection;Development;Disparity;Early Diagnosis;Effectiveness;Ensure;Epigenetic Process;Etiology;Evolution;Genetic;Goals;Guidelines;HIV;Health;Health Personnel;Health Services Accessibility;Health system;Home;Human;Human Papillomavirus;Incidence;Individual;Inequity;Institution;International;Intervention;Laboratories;Language;Latinx;Leadership;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mentors;Minority;Mission;Modeling;Molecular;NCI Center for Cancer Research;Nature;New York;Obesity associated cancer;Organ;Outcome;Participant;Patients;Peer Review;Personal Satisfaction;Persons;Play;Policies;Population;Population Heterogeneity;Population Research;Population Study;Poverty;Predisposition;Prevention;Principal Investigator;Productivity;Public Health;Public Health Practice;Quality of life;Research;Research Design;Research Personnel;Risk Factors;Role;Shapes;Statistical Methods;Strategic Planning;Supportive care;Testing;Tobacco smoking behavior;Training;Translating;Translations;Variant;Vulnerable Populations;Western Africa;Work;anticancer research;cancer care;cancer education;cancer epidemiology;cancer health disparity;cancer prevention;care delivery;care outcomes;clinical practice;community engagement;community involvement;community setting;design;effectiveness testing;electronic medical record system;equity diversity and inclusion;fire fighter;health inequalities;high risk;high risk population;improved;infection related cancer;innovation;malignant breast neoplasm;member;mortality;multiple chronic conditions;non-smoker;novel;novel therapeutic intervention;outreach;patient retention;prevent;programs;psychosocial;screening;smoking intervention;social;social determinants;social health determinants;trend;tumor;virtual Cancer Epidemiology Prevention and Control Program Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER EPIDEMIOLOGY PREVENTION AND CONTROL PROGRAM - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712882 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5687 11595078 "HOSGOOD, H DEAN " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 56146 33420 22726 Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER EPIDEMIOLOGY PREVENTION AND CONTROL PROGRAM PROJECT SUMMARY/ABSTRACTThe Cancer Epidemiology Prevention and Control (CEPC) Program plays a central role in the scientific clinicaland public health mission of MECC. The Programs overarching goal is to better understand and address driversof cancer burden and cancer disparities in our Bronx catchment area and other vulnerable populations. Programinvestigators focus on studies in human populations to determine the behavioral environmental and molecularrisk factors that underlie cancer etiology and outcomes leading to studies that devise implement and test theeffectiveness of novel interventions to promote cancer prevention screening treatment and supportive care.Program members collaborate extensively with one another and with the other three MECC research programs.Given the inter- and trans-disciplinary nature of this program CEPC is the focal point for translating laboratory-based research into population level studies and for bridging findings from clinical and community settings backto the lab. CEPC has three specific aims: (1) to characterize the risk factors that drive cancer health disparitiesin our catchment area most notably breast lung prostate and cervical cancer; (2) to improve cancer preventionand screening among vulnerable and high-risk groups in our catchment area and beyond; and (3) to developand implement innovative strategies to enhance cancer care outcomes. CEPC research has contributed toimproved health of the largely poor and minoritized Bronx population as well as populations worldwide.Completed and ongoing research in CEPC has substantively influenced clinical guidelines and public healthpractice with new studies poised to continue this trend. CEPC research: (i) has identified novel susceptibilitymarkers for breast cancer prostate cancer CRC and lung cancer in non-smokers -- the major causes of cancermortality in the Bronx demonstrating efforts to understand the mechanisms of cancer in an environmental andbehavioral context; (ii) contributed to major policy decisions regarding cancer care of firefighters who worked atthe 9/11 WTC; (iii) developed innovative in-reach and outreach strategies that overcome social determinants toincrease early detection and timely access to care; (iv) developed effective tobacco smoking interventions thathave been integrated in to standard clinical practice as well as in clinical guidelines for persons living with HIV;(v) implemented comprehensive cervical cancer screening and treatment in Western Africa; and (vi) introduceda novel appraisal paradigm that emphasizes patients own personal criteria for quality of life.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Antineoplastic Agents;Bioinformatics;Biological Products;Cancer Center;Cancer Center Support Grant;Cancer Therapy Evaluation Program;Catchment Area;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Conduct Clinical Trials;Credentialing;Development;Developmental Therapeutics Program;Disease;Disparity;Doctor of Philosophy;Early Diagnosis;Equity;Goals;Human;Interdisciplinary Study;Laboratories;Malignant Neoplasms;Mentors;Mission;Molecular;NCI Center for Cancer Research;Organ;Outcome;Pharmacologic Substance;Phase;Prevention;Principal Investigator;Research;Research Personnel;Resistance;Resource Sharing;Science;Scientist;Therapeutic;Translating;Translational Research;Translations;Treatment Protocols;Variant;anticancer research;cancer pharmacology;cancer therapy;clinical development;design;drug development;improved;innovation;interest;member;novel;novel anticancer drug;novel therapeutics;pre-clinical;preclinical development;programs;recruit;small molecule;translational scientist;tumor Cancer Therapeutics Program Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER THERAPEUTICS PROGRAM - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712881 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5686 1864522 "ALMO, STEVEN C." Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 56090 33387 22703 Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER THERAPEUTICS PROGRAM - PROJECT SUMMARY/ABSTRACT Significant advances have been made in the development of novel agents and combination regimens for thetreatment of human cancers. Despite this progress major research efforts are still needed to develop new drugsto improve anticancer therapy and overcome resistance to current therapies. To achieve this goal a closeinteraction between basic scientists translational scientists and clinical investigators is essential to translatenovel preclinical laboratory observations into the clinical setting for the treatment of human cancers. Theresearch objectives of our MECC Cancer Therapeutics (CT) Program have been greatly facilitated by organizinginter- and trans-disciplinary teams of chemists cancer biologists cancer pharmacologists biostatisticians andbioinformatics experts computational biologists and clinical investigators. The Cancer Therapeutics Program is a long-standing interdisciplinary research program. The three newProgram Co-Leaders are leaders in the field of cancer therapeutics with scientific expertise that spans the entirespectrum of preclinical and clinical cancer drug development. A high priority is placed on the recruitment andmentoring of members who are deeply committed to the goals set forth by the Program and who focus ondeveloping intra-programmatic interactions as well as strong inter-programmatic interactions/collaborations withother MECC research programs. Significant emphasis is placed on the preclinical and clinical development ofnovel anticancer agents and new combination regimens for the treatment of human cancers. The overarching mission of the Program is to develop innovative approaches to discover design and developnovel anticancer agents and/or therapeutic regimens for the treatment of human cancers. To achieve thismission the Program focuses on the following Specific Aims:1) preclinical discovery and development of small molecules2) preclinical discovery and development of biologics3) conduct clinical trials that span early Phase I/II to late Phase III with a focus on translation of MECC discoveries/science into investigator-initiated clinical trials and the clinical development of novel agents in partnership with NCI-CTEP NCI cancer centers NCI cooperative groups and pharmaceutical companies Notably these specific aims align with all four of MECCs cross-cutting themes: 1) Catchment Area Disparitiesand Equity; 2) Tumor and Organ Microenvironments; 3) Prevention Early Detection and Interception of Primaryand Secondary Disease; and 4) Molecular Variations as Determinants of Outcome.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Animal Model;Basic Science;Biostatistics Shared Resource;Cancer Biology;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell model;Cells;Clinic;Clinical;Clinical Investigator;Collaborations;Credentialing;Disease model;Doctor of Philosophy;Epigenetic Process;Evolution;Flow Cytometry Shared Resource;Funding;Genetic Transcription;Genomics Shared Resource;Goals;Hematologic Neoplasms;Industry;Investigation;KRAS2 gene;Malignant - descriptor;Malignant Neoplasms;Medicine;Mission;Molecular;Myeloproliferative disease;NCI Center for Cancer Research;Physicians;Physiological;Post-Translational Regulation;Preleukemia;Principal Investigator;Research;Resistance;Resource Sharing;Science;Scientist;Specific qualifier value;Therapeutic;Therapeutic Studies;Translational Research;Translations;Work;anti-cancer;biobank;cancer cell;cancer stem cell;cancer therapy;clinical translation;college;experience;imaging facilities;insight;interest;leukemia;leukemic stem cell;member;model organism;mouse model;new therapeutic target;novel;pre-clinical;preclinical study;programs;recruit;stem;stem cell biology;stem cell function;translational applications;translational research program;translational scientist;tumor progression Stem Cell and Cancer Biology Program Program Director/Principal Investigator (Last First Middle): Chu EdwardSTEM CELL AND CANCER BIOLOGY PROGRAM - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712880 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5685 9871820 "GRITSMAN, KIRA " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 56146 33420 22726 Program Director/Principal Investigator (Last First Middle): Chu EdwardSTEM CELL AND CANCER BIOLOGY PROGRAM - PROJECT SUMMARY/ABSTRACTThe overarching goal of the Stem Cell and Cancer Biology (SCCB) Program is to provide fundamental insightsinto the basic cell and molecular mechanisms facilitating cancer evolution progression and therapy resistancewhich enable the identification of novel anti-cancer strategies. To achieve this mission the Program has threespecific aims which are to: (1) discover mechanisms underlying the evolution of malignant cancer (stem) cells;(2) delineate drivers of cancer progression and therapy resistance; and (3) characterize the principalmechanisms establishing and governing cellular differentiation and identity. The strategy for successfullycarrying out this mission requires the involvement of basic preclinical and clinical/translational research. TheSCCB Program critically relies on a diverse and broad spectrum of scientific expertise encompassing highlyfocused molecular and cell physiological mechanisms and is substantiated through various model organismsand platforms. It also relies upon collaborations with other MECC research programs including the CancerTherapeutics Program for clinical translation of new discoveries by SCCB members that have translationalapplications. Centralized MECC support particularly Shared Resources such as (but not limited to) the AnimalModel Shared Resource Biostatistics Shared Resource Genomics Shared Resource Analytical ImagingFacility Flow Cytometry Shared Resource and Cancer Biorepository Shared Resource greatly facilitatesstreamlines and enhances SCCB research.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Acceleration;Address;Aging;Antineoplastic Agents;Basic Science;Biochemical;Biological Markers;Biological Models;Biology;Breast;Breast Cancer Risk Factor;Cancer Biology;Cancer Center Support Grant;Cancer Patient;Catchment Area;Cell Survival;Cells;Clinical;Clinical Markers;Collaborations;Communities;Development;Diabetes Mellitus;Disease;Disseminated Malignant Neoplasm;Education;Epigenetic Process;Extravasation;Fostering;Genetic;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Human;Imaging technology;Immune;Immunofluorescence Immunologic;Immunotherapy;Individual;Institution;Knowledge;Life Style;Lung;Magnetic Resonance Imaging;Malignant Neoplasms;Metastatic breast cancer;Metastatic/Recurrent;Multiple Myeloma;Mus;Neoplasm Metastasis;New York;Oncology Group;Organ;Organoids;Output;Pathology;Pathway interactions;Patient Care;Positioning Attribute;Predisposition;Prevention;Principal Investigator;Prostate;Recurrence;Relapse;Research;Research Personnel;Residual Neoplasm;Resistance;Resolution;Science;Signal Transduction;Site;Systemic Therapy;Technology;Therapeutic;Tissues;Translating;Vision;Zebrafish;cancer cell;cancer epidemiology;chemotherapy;clinically relevant;epidemiologic data;hormone therapy;imaging modality;in vivo;innovation;insight;intravital imaging;melanoma;multi-photon;neoplastic cell;new therapeutic target;novel;personalized medicine;programs;relapse prevention;stem;stem cell biology;targeted agent;therapeutic biomarker;translational potential;tumor microenvironment Tumor Microenvironment and Metastasis Program Program Director/Principal Investigator (Last First Middle): Chu EdwardTUMOR MICROENVIRONMENT AND METASTASES PROGRAM - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712879 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5684 7852195 "AGUIRRE-GHISO, JULIO A." Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 56146 33420 22726 Program Director/Principal Investigator (Last First Middle): Chu EdwardTUMOR MICROENVIRONMENT AND METASTASIS PROGRAM - PROJECT SUMMARY/ABSTRACTThe Tumor Microenvironment and Metastasis (TMM) Program is focused on investigating the geneticepigenetic biochemical microenvironmental and developmental pathways that drive dissemination dormancyand recurrence. These studies will identify novel therapeutic targets and biomarkers to address each of thesestages of metastatic progression. The overall goal of TMM is to catalyze basic research on the mechanisms bywhich cancer cell intrinsic and microenvironmental signals conspire to fuel cancer cell systemic disseminationpersistence during dormancy and metastatic outgrowth in target organs. The overarching hypothesis is thatdetailed mechanistic studies of both the tumor cell and the microenvironment during dissemination from primarysites re-dissemination from metastatic foci dormancy and stem programs in collaboration with the Stem Celland Cancer Biology Program and metastatic recurrence will lead to the identification and characterization ofnovel therapeutic targets in collaboration with Cancer Therapeutics Program and biomarkers that may be usefulfor personalizing the treatment of metastatic disease. Importantly understanding target organ biology and howit relates to individuals predispositions to disease lifestyle and aging (in collaboration with Cancer EpidemiologyPrevention and Control Program) will provide insights into management of metastatic cancer. TMM investigatorsutilize the power of basic science and an array of model systems (e.g. zebrafish mice organoids) imagingmodalities (e.g. intravital imaging multiplex immunofluorescence) and human studies (e.g. tissue analysesepidemiological data) to characterize key aspects of how cancer cells together with the immune and non-immune microenvironment control mechanisms of: (i) early and late dissemination (ii) re-dissemination frommetastatic foci (iii) extravasation and residual disease dormancy and (iv) metastatic cell sensitivity/resistanceto systemic therapies (e.g. chemotherapy targeted agents immunotherapy) and effect of therapies on the TME.Each of these approaches is explored in multiple cancers relevant to the catchment area (prostate breastHNSCC melanoma multiple myeloma). These objectives will be achieved through two specific aims bothfostering intra- and inter-programmatic activities as well as community programs to accelerate TMMstranslational clinical and educational output to ultimately impact cancer patients represented within ourcatchment area. TMMs specific aims are to: (1) Identify tumor microenvironments and signaling networks thatfuel dissemination and (2) Discover the target organ-driven mechanisms for cancer cell survival and dormancyand how niche alterations drive metastasis.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Behavior;Cancer Center;Cancer Center Support Grant;Catchment Area;Chronic Disease;Clinical;Clinical Services;Clinical Trials;Collaborations;Communicable Diseases;Communities;Community Outreach;Data;Disparity;Education;Ensure;Environment;Equity;Ethnic Origin;Evaluation;Extramural Activities;Faculty;Fostering;Gender;Goals;Grant;Health;Health Sciences;Heart;Incidence;Individual;Individual Differences;Infrastructure;Institution;Intervention;Investments;Knowledge;Leadership;Longevity;Malignant Neoplasms;Mentorship;Methods;Mission;Modeling;Monitor;NCI Center for Cancer Research;NCI-Designated Cancer Center;Outcome;Population;Poverty;Prevention;Principal Investigator;Process;Race;Religion;Research;Resources;Scientific Advances and Accomplishments;Scientist;Service setting;Sex Orientation;Training;Training and Education;Underrepresented Populations;United States National Institutes of Health;Vision;Woman;Work;Workplace;access disparities;anticancer research;cancer epidemiology;care delivery;career life balance;clinical care;community engagement;demographics;equity diversity and inclusion;ethnic discrimination;ethnic minority;experience;improved;member;programs;racial minority;role model Plan to Enhance Diversity Program Director/Principal Investigator (Last First Middle): Chu EdwardPLAN TO ENHANCE DIVERSITY - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712878 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5683 10485528 "ADEDIMEJI, ADEBOLA " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 210087 125052 85035 Program Director/Principal Investigator (Last First Middle): Chu EdwardPLAN TO ENHANCE DIVERSITY - PROJECT SUMMARY/ABSTRACTThe Montefiore Einstein Cancer Centers overarching mission is to become a national model for reducing cancerincidence and disparities in the most diverse and impoverished catchment area of all NCI-designated cancercenters in the U.S. Our Plan to Enhance Diversity will ensure that all groups that are underrepresented in thecancer workforce including individuals from very different demographic racial ethnic religious gender andsexual orientation backgrounds etc. currently not represented in visible numbers in cancer research educationand clinical care delivery given the population of our catchment area in the Bronx have the opportunity and aresupported to participate and be included in all aspects of our Cancer Center activities. We plan to achieve thisgoal by establishing sustaining and continuously monitoring our investments in institutional infrastructure andimplementing programs to establish promote and sustain a culture of diversity equity and inclusivity increaseparticipation of women racial/ethnic minorities and other underrepresented groups in the cancer workforce andin leadership through pipeline program with key stakeholders in the Bronx and building by strengthening andevaluating the capacity of the workforce to integrate a culture of diversity equity and inclusivity excellence inresearch clinical care delivery and community engagement. It is essential that an effective plan to enhancediversity must be cross-cutting and for this reason we will synergistically coordinate all activities among othercomponents of the Cancer Center such as Community Outreach and Engagement (COE) and Cancer ResearchTraining and Education Coordination (CRTEC) components Cancer Epidemiology Prevention and ControlProgram and the clinical services and clinical trials in support of our core mission and vision.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Advisory Committees;Award;Cancer Center Support Grant;Career Exploration;Catchment Area;Communication;Community Health Education;Community Outreach;Community Physician;Databases;Detection;Development;Disease;Education;Educational Activities;Educational workshop;Effectiveness;Ensure;Extramural Activities;Faculty;Female;Fostering;Funding;Grant;Guidelines;Health Personnel;High School Student;Hispanic;Institution;Leadership;Logistics;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Mission;Outcome;Postdoctoral Fellow;Prevention;Principal Investigator;Process;Research;Research Activity;Research Personnel;Research Support;Students;Training;Training Activity;Training and Education;Travel;Underrepresented Populations;Woman;anticancer research;cancer education;career;career development;college;community engagement;equity diversity and inclusion;gender equality;graduate student;high school;innovation;interest;meetings;member;next generation;pre-doctoral;programs;recruit;skill acquisition;undergraduate student Cancer Research Training and Education Coordination Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER RESEARCH TRAINING AND EDUCATION COORDINATION - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712877 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5682 1939127 "BRESNICK, ANNE R" Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 155034 92282 62752 Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER RESEARCH TRAINING AND EDUCATION COORDINATION - PROJECT SUMMARY/ABSTRACTTo fulfill the MECCs mission to train a diverse biomedical workforce CRTEC is committed to education trainingand career development activities that promote a better understanding of the origins of cancer and the effectivedetection prevention and treatment of these diseases. CRTEC fosters education and training across the entireeducational spectrum including high school students undergraduates medical and graduate studentspostgraduate trainees junior faculty community physicians and other healthcare providers. CRTEC activitiesare organized into three Specific Aims that provide career enhancement opportunities across the biomedicaltraining pipeline and develop the next generation of cancer researchers. Aim 1 will coordinate MECC andinstitutional programming to educate and inspire high school students undergraduates predoctoral andpostdoctoral trainees and junior faculty to pursue careers in cancer research. Key activities include implementingand expanding MECC high school and undergraduate pipeline programs which focus on historicallyunderrepresented populations expanding MECCs extramurally funded training grant portfolio and ensuring thatthe training pipeline is diverse and inclusive. Aim 2 will support career and professional development activitiesacross the educational continuum. Key activities include enhancing the mentorship program for junior facultythrough an iterative process of review and refinement providing mentor (faculty) and mentee (postdoctoralfellows and graduate students) training offering career exploration workshops with a focus on alternative careersin cancer research and providing training and opportunities for trainees in the communication of cancer researchinnovations to audiences in the Bronx catchment area. Aim 3 will track and assess the impact of MECCs cancertraining and education activities. Key activities will include providing travel awards for trainees to present atcancer meetings or workshops for skills development incorporating trainees into the annual MECC retreat andmaintaining a trainee database to follow career progression and outcomes.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Administrative Efficiency;Award;Awareness;Basic Science;Budgets;Cancer Burden;Cancer Center;Cancer Center Support Grant;Caregivers;Caring;Catchment Area;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Data;Data Analytics;Data Reporting;Decision Making;Early Therapeutic-Clinical Trials Network;Education;Education and Outreach;Ensure;Equipment;Evaluation;Event;Face;Faculty Recruitment;Fostering;Goals;Grant;Human Resources;Inequity;Informatics;Infrastructure;Institution;Institutional Policy;Investments;Lead;Leadership;Malignant Neoplasms;Marketing;Medicine;Mentors;Mission;Operations Research;Patient advocacy;Patients;Phase;Pilot Projects;Policies;Population Research;Principal Investigator;Process;Recommendation;Reporting;Research;Research Personnel;Resource Sharing;Resources;Science;Strategic Planning;Structure;Time;Training and Education;Translational Research;Work;analytical tool;anticancer research;college;community engagement;dashboard;equity diversity and inclusion;health data;innovation;meetings;operation;outreach;programs;recruit;social health determinants;stem;success;tool;translational research program;underserved community;web site;working group Administration Program Director/Principal Investigator (Last First Middle): Chu EdwardCANCER CENTER ADMINISTRATION - PROJECT NARRATIVEPer PAR-21-321 a Project Narrative is not required for this Component.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712876 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5681 8664912 "HACKETT, LAUREN E" Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 143986 85706 58280 Program Director/Principal Investigator (Last First Middle): Chu EdwardADMINISTRATION - PROJECT SUMMARY/ABSTRACTMontefiore Einstein Cancer Center (MECC) Administration provides efficient and innovative centralizedadministration analytics and programmatic infrastructure that enables exceptional basic translational clinicaland population-based research at MECC. Administration partners with and serves MECC senior leadership tofoster scientific collaboration implement strategic planning and evaluation efforts create and disseminatemembership tools and metrics staff leadership meetings and retreats coordinate and manage pilot projectcompetitions recruit and onboard new investigators and manage and report on investments and all MECCaccounts ensuring compliance with all institutional policies and federal requirements. Administration facilitatesrigorous cancer-related research operations and administration community outreach and engagementcatchment area research cancer research training and education and plans to enhance diversity to carry outMECCs mission to reduce the burden of cancer in the Bronx and the nation through our cancer-focusedresearch education and training and community outreach and engagement with delivery of compassionate carefor all including historically underserved communities that face heightened inequities in cancer and socialdeterminants of health. MECC Administration staffs all internal and external planning and evaluation effortsdevelops policies and processes to manage membership and all corresponding metrics and tracking has sharedoversight of shared resources with the Deans Office at the Albert Einstein College of Medicine (Einstein)supports the Director in all faculty recruitment administers and tracks pilot projects and other internal researchawards has shared oversight of space and facilities oversees communications marketing and the MECCwebsite and is staff to Senior Leadership Team and Research Leadership Council meetings and all MECCscientific retreats. Administration has direct oversight for all MECC budgets and finance space facilities andequipment human resources philanthropy and clinical trials and clinical research operations.Administrations success is demonstrated through the extensive work with Senior Leadership to develop andimplement a rigorous planning and evaluation process to support the MECC Strategic Plan 2021-2026 inclusiveof staffing eight Strategic Working Groups with tools to track progress; manage the exceptional institutionalinvestment to realize goals support analytics and strategic decision making for the new research programstructure align and implement new shared resource collaborations launch a new integrated website for theMECC and create a new Membership Dashboard and online administrative tools to manage membership pilotprojects and CCSG metrics.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page +No NIH Category available Address;Advisory Committees;Affect;Albert Einstein Cancer Center;Basic Science;Biological Products;Biology;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Caring;Catchment Area;Characteristics;Chromatin;Clinical;Clinical Informatics;Clinical Research;Clinical Trials;Communities;Community Outreach;Detection;Diagnostic;Early Diagnosis;Education;Effectiveness;Electronics;Epigenetic Process;Equilibrium;Face;Faculty;Fostering;Funding;Gender;Genetic;Genetic Transcription;Health Professional;Hematologic Neoplasms;Home;Hormonal;Human;Imaging technology;Immunotherapy;Inequity;Malignant Neoplasms;Metabolic;Minority;Mission;Modeling;NCI Center for Cancer Research;NCI-Designated Cancer Center;Neoplasm Metastasis;Normal Cell;Obesity;Oncology;Pathogenesis;Phase;Play;Population Heterogeneity;Population Research;Prevention;Prevention program;Principal Investigator;Process;Provider;Research;Research Personnel;Resource Sharing;Resources;Role;Science;Scientist;Services;Strategic Planning;Therapeutic;Therapeutic Studies;Training;Training and Education;Translating;Translational Research;Translations;Underrepresented Populations;Woman;anticancer research;cancer care;cancer cell;cancer epidemiology;cancer health disparity;cancer therapy;career development;college;community engagement;education research;epidemiology study;equity diversity and inclusion;ethnic diversity;graduate school;health care delivery;high school;human stem cells;innovation;interdisciplinary collaboration;marginalized community;medical schools;member;mouse model;next generation;novel;outreach;postdoctoral investigator;preclinical study;programs;racial diversity;recruit;screening;small molecule;social health determinants;socioeconomics;stem;stem cell biology;tumor microenvironment;tumor progression;underserved community Cancer Center Support Grant Program Director/Principal Investigator (Last First Middle): Chu EdwardOVERALL - PROJECT NARRATIVEThe Montefiore Einstein Cancer Center (MECC) seeks to reduce the burden of cancer through its basic clinicaland population-based research and the translation of preclinical and epidemiological studies into clinicalinitiatives for the prevention detection and treatment of cancer. This is accomplished through MECCs fourestablished research programs and eight shared resources. MECC seeks to understand the basis for andameliorate cancer disparities that affect the 1.5M largely minority under-represented population of the Bronxthe Centers main catchment area.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page NCI 10712875 9/7/23 0:00 PAR-21-321 2P30CA013330-51 2 P30 CA 13330 51 "ROBERSON, SONYA" 6/1/97 0:00 6/30/28 0:00 Cancer Centers Study Section (A)[NCI-A] 2087647 "CHU, EDWARD " Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 8/25/23 0:00 6/30/24 0:00 397 Research Centers 2023 4087971 NCI 2433316 1654655 Program Director/Principal Investigator (Last First Middle): Chu EdwardOVERALL - PROJECT SUMMARY/ABSTRACTThe Montefiore Einstein Cancer Center (MECC) formerly known as the Albert Einstein Cancer Center is thefourth oldest NCI-designated cancer center in the U.S. having received NCI designation in 1972 and is nowcelebrating its 50th year as an NCI designated cancer center. The overarching mission of MECC is to reduce theburden of cancer in the Bronx and the nation through exceptional cancer research education & trainingcommunity outreach and engagement and provide compassionate care for all including historically marginalizedcommunities that face heightened inequities in cancer and social determinants of health. Our Bronx catchmentarea is home to 1.5M residents and we serve one of the most racially and ethnically diverse populations andone of the poorest communities in the U.S. To achieve our mission MECC has 132 members organized into 4Research Programs (RPs): Tumor Microenvironment and Metastasis (TMM) Stem Cell and Cancer Biology(SCCB) Cancer Therapeutics (CT) and Cancer Epidemiology Prevention and Control (CEPC). The science ofthese RPs is facilitated by 8 Shared Resources (SRs). All MECC RPs conduct cancer-focused research that isrelevant to the Bronx catchment area and this science is greatly facilitated by the Office of Community Outreachand Engagement (COE). The MECC COE is the main vehicle by which our Center understands engages withand serves the needs of the underserved communities in our catchment area and it plays a critical role infacilitating the Centers research that is relevant to the catchment area. Our Cancer Research Training andEducation Coordination (CRTEC) programs are well integrated with the four RPs and with our COE initiatives.Moreover the MECC is focused on creating a diverse pipeline for the next generation of cancer scientists andclinicians. With the arrival of the new Director in October 2020 MECC has engaged in several transformativeprocesses which include the following: (1) created a new MECC Strategic Plan; (2) appointed 9 new SeniorLeaders and 8 Program Leaders; (3) restructured the RPs to more tightly align and focus cancer research andto more effectively foster transdisciplinary collaboration and translational research; (4) tightened MECCmembership criteria to enhance cancer focus; (5) formed 7 new internal MECC committees and 2 new MECCexternal committees to enhance organizational capabilities; (6) created Offices for COE and CRTEC; (7)appointed a new Associate Director for Diversity Inclusion and Equity (DEI); (8) created a new Department ofOncology that is more tightly aligned with MECC; (9) formed a Cancer Service Line Executive Committee and anew funds flow model to MECC; (10) recruited 42 new faculty that span the entire spectrum of cancer-focusedscience; and (11) established a Womens Task Force to enhance gender balance and diversity.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page 4087971 +No NIH Category available Address;Area;Back;Baltimore;Career Exploration;Caregivers;Communities;Community Outreach;Comprehensive Cancer Center;Data;Development;Development Plans;Disadvantaged;Disparity;Diverse Workforce;Education;Educational Activities;Educational Curriculum;Educational Intervention;Ensure;Faculty;Family;Fostering;Foundations;Funding;Goals;Health Care Research;Health Professional;Health Sciences;Healthcare;Incidence;Individual;Infrastructure;Institution;Journals;Learning;Longterm Follow-up;Malignant Neoplasms;Maryland;Medical;Mentors;Middle School Faculty;Middle School Student;Outcome;Participant;Peer Review;Population;Positioning Attribute;Production;Productivity;Publishing;Research;Research Methodology;Research Personnel;Research Project Grants;Research Training;Resources;Schools;Science;Science Technology Engineering and Mathematics Education;Secondary Schools;Social Network;Structure;System;Teacher Professional Development;Trust;Underrepresented Minority;United States National Institutes of Health;Universities;Vision;Visualization;Washington;anticancer research;cancer education;cancer health disparity;career;community engagement;curriculum development;disadvantaged student;education pathway;experience;fighting;high school;holistic approach;improved;innovation;interest;junior high school;minority children;minority communities;next generation;novel;outcome disparities;outreach;peer;program dissemination;programs;recruit;science education;social determinants;social health determinants;social learning;success;successful intervention;teacher;underrepresented minority student;urban underrepresented Catalyzing Cancer Research among Urban Underrepresented Minority Youths and Teachers (CATALYST) NARRATIVE.The Catalyzing Cancer Research among Urban Underrepresented Minority Youths and Teachers (CATALYST)program expands upon seven years of a successful intervention pilot to excite middle school (MS) students fromdisadvantaged West Baltimore communities about cancer-related STEM subjects and careers. CATALYST willincorporate cancer research experiences for teachers that are used to develop MS curriculum and communityoutreach components. Integral to the success of this program is a holistic approach to address scholar familyand community needs that are essential for academic success. CATALYST scholars are part of a cancer-focusedSTEM education pipeline that will produce the next generation of researchers and healthcare professionals. Thisdiverse workforce will stimulate innovation enhance productivity and foster consideration of disparities issues inthe fight against cancer. NCI 10712869 9/6/23 0:00 RFA-CA-21-020 1R25CA274166-01A1 1 R25 CA 274166 1 A1 "LOPEZ, BELEM G" 9/6/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9180528 "ADEBAMOWO, CLEMENT ADEBAYO" "ADEBAMOWO, SALLY NNEOMA; HASSEL, BRET A" 7 PUBLIC HEALTH & PREV MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/6/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 388800 NCI 360000 28800 Project SummaryWest Baltimore is comprised of majority minority communities that are among the most economically andacademically disadvantaged in the US and are disproprotionately impacted by cancer. A healthcare and cancerresearch workforce that understands the challenges facing West Baltimore residents and similar communitiesacross the US is essential to addressing cancer incidence and outcome disparities. To excite and sustainunderrepresented minorities (URM) scholars interest in cancer-related science subjects healthcare researchand careers early educational intervention that takes account of the social determinants of educational successis critical. In this Catalyzing Cancer Research among Urban Underrepresented Minority Youths and Teachers(CATALYST) program we will implement an innovative and immersive program for Middle School scholars theirfamilies teachers and communities in West Baltimore.The aims of the program are to: 1) Excite scholars their families and communities about cancer research usingcancer-focused research experiences and mentoring programs from an early stage in their education. 2) Developnovel curricula and individually mentored hands-on cancer research training and experiences for Baltimore Mid-dle School teachers that are aligned with scholars curriculum and lead to improved science learning. 3) Developand implement novel scholars curricula integrated with research experiences to improve science learning inMiddle Schools. And 4) Expand the rich tapestry of outreach and community engagement activities to includecancer-related research trainings in West Baltimores Middle Schools. Scholars and teachers projects will pro-vide cancer-focused material for use in community outreach and engagement activities to be implemented bythe scholars and teachers in their schools and communities. The outcomes of scholars and teachers educa-tional activities curriculum development and research projects will be published in peer-reviewed journals andpresented at local regional and national forums as well as during collaborative exchanges with peer NCI YESprograms across the US.CATALYST is built on the highly successful University of Maryland Baltimore Continuing Umbrella of ResearchExperiences (UMB CURE) Middle Schools Pilot Program the first NCI CURE Middle School program whichwas implemented by the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC) inWest Baltimore for seven years. The UMB CURE pilot developed a robust cancer-focused program that lever-aged strong UMB and UMGCCC resources in a holistic approach to scholars education and community's needsand is the framework for the proposed CATALYST program. The impact of CATALYST on all program stake-holders will be rigorously evaluated and outcomes will be longitudinally tracked. This data will inform best prac-tices and identify areas for improvement which is fed back to develop a sustainable and scalable program thatproduces the next generation of URM cancer researchers and caregivers and ultimately increase diversity in thebiomedical workforce. 388800 +No NIH Category available Address;Biometry;Cancer Burden;Cancer Center Support Grant;Catchment Area;Clinical Research;Clinical Trials;Discipline;Disease;Ensure;Feasibility Studies;Goals;Investigator-Initiated Research;Malignant Neoplasms;Monitor;Process;Protocols documentation;Research;Research Design;Research Priority;Resources;Review Committee;Site;Strategic Planning;System;Time;marginalized community;research study;underserved community Protocol Review and Monitoring System n/a NCI 10712684 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5638 10157976 "CLARKE, JENNIFER " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 289148 179039 110109 Protocol Review and Monitoring System: Summary/AbstractThe goal of the HDFCCC Protocol Review and Monitoring System (PRMS) is to ensure rigorous scientificreview and monitoring of all clinical research undertaken in the HDFCCC. This is accomplished through a two-stage process first by disease-focused and discipline-focused site committees that undertake initial scientificreview of protocols assessment of feasibility and projected accrual rates and study prioritization; and then bythe Protocol Review and Monitoring Committee (PRMC) that reviews scientific rationale study designexpected accrual rates adequacy of biostatistical input feasibility of study completion within an appropriatetime period and ongoing review of scientific progress including scientific relevance and accrual rates. As partof its review process the PRMC undertakes prioritization of all clinical research studies across the HDFCCC.This provides a touchpoint to assess alignment of clinical trials with the Center-wide strategic plan andpriorities and an opportunity to prioritize research related to the cancer burden in the catchment area highpriority cancers and underserved or marginalized communities. +No NIH Category available Address;Affect;Age;Area;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Community Outreach;Conduct Clinical Trials;Data;Data Aggregation;Development;Disease;Disparity;Equity;Ethnic Origin;Gender;Goals;Individual;Infrastructure;Institutional Review Boards;Life Cycle Stages;Longevity;Maintenance;Malignant Neoplasms;Minority;Monitor;Patients;Population Heterogeneity;Race;Reporting;Research;Research Activity;Research Personnel;Research Priority;Research Support;Research Training;Safety;Site;Woman;Work;anticancer research;clinical training;clinical trial enrollment;community engagement;data management;demographics;improved;investigator training;patient population;protocol development;research study;success Clinical Protocol and Data Management n/a NCI 10712683 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5637 11986239 "ANDREADIS, CHARALAMBOS " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 1064552 659165 405387 Clinical Protocol and Data Management: Summary/AbstractThe goal of HDFCCC Clinical Protocol and Data Management (CPDM) is to support and facilitate clinical trialconduct in the HDFCCC across the entire life cycle of a clinical trial including protocol development activationaccrual and conduct monitoring closure and reporting. Clinical protocol development and data managementfunctions in the HDFCCC are provided by the Clinical Research Support Office (CRSO) which provides theinfrastructure to support the efficient development implementation conduct and reporting of clinical researchstudies including the management of clinical research personnel across the HDFCCC. The CRSO alsointegrates and coordinates clinical cancer research activities with campus-wide entities affecting clinical trialconduct such as the UCSF IRB and the campus-wide UCSF Office of Research. Data and safety monitoring(DSM) functions as detailed in the NCI-approved Data and Safety Monitoring Plan (DSMP) of the HDFCCCare carried out by the DSM staff and overseen by the Data and Safety Monitoring Committee (DSMC). Inaddition to conducting data and safety review DSM activities include the development maintenance andmanagement of clinical research training for investigators and clinical research training for clinical researchpersonnel undertaken in collaboration with the CRSO. CPDM also facilitates the HDFCCCs commitment toaccrue diverse populations of patients on clinical studies including women minorities and individuals acrossthe lifespan. The HDFCCC strives to ensure that the diverse population of its catchment area has equitableaccess to representation in and benefit of clinical research. HDFCCC analyzes demographic data relating torace/ethnicity gender and age to identify areas to improve inclusion of minorities women and individualsacross the lifespan in clinical research. Specifically the CPDM (1) aggregates data regarding catchment areaHDFCCC and clinical trial enrollment demographics at a disease-specific level; (2) analyzes these data tounderstand potential reasons for disparities that are encountered; (3) based on these data works withinvestigators site committees and Community Outreach and Engagement (COE) to develop focused actionplans; and (4) defines and analyzes metrics of success to evaluate progress in addressing these disparities. +No NIH Category available Address;Advisory Committees;Authorization documentation;Breast Oncology;Cancer Center;Cancer Center Support Grant;Cancer Control;Clinical Sciences;Communities;Data;Doctor of Philosophy;Education;Evaluation;Goals;Health;Individual;Institution;Intervention;Joints;Laboratory Research;Leadership;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Medical;Medicine;Mission;Neurologic Oncology;Output;Participant;Performance;Physicians;Population Sciences;Research;Resource Sharing;Resources;Role;Services;Site;Strategic Planning;Structure;Translational Research;anticancer research;authority;cancer immunotherapy;clinical translation;community engagement;design;disparity reduction;equity diversity and inclusion;improved;meetings;member;molecular oncology;operation;outcome disparities;programs;success;tumor immunology Leadership Planning and Evaluation n/a NCI 10712682 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5636 10746885 "ASHWORTH, ALAN " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 997892 617890 380002 Leadership Planning and Evaluation: Summary/AbstractThe HDFCCC is driven by its tight network of leaders planning and tracking activities and regular evaluationinternal and external groups. These leadership planning and evaluation resources allow the HDFCCC to beimmediately responsive to member needs and address issues as they arise as well as engage incomprehensive strategic planning. The HDFCCC has been strategic and intentional in designing leadershipgroups advisory groups and roles and in aligning them with the Cancer Research in 2030 strategic plan.HDFCCC Administration is integrated within each group with members serving as active participants andexperts as well as serving as support staff for conducting meetings tracking action items and operationalizingideas. The HDFCCC accomplishes its leadership planning and evaluation activities across the Center by (1)establishing a leadership structure that supports and is responsive to member needs and the HDFCCCmission; (2) conducting strategic planning and implementing appropriate outputs; and (3) defining and trackingmetrics of success and convening appropriate advisory groups. +No NIH Category available Businesses;Cancer Center Support Grant;Ensure;Feedback;Funding;Funding Agency;Goals;Grant;Home;Leadership;Monitor;Policies;Productivity;Research;Resource Sharing;Services;Source;Structure;Technology;Tissues;adjudication;cost effective;member;metabolomics;operation;programs Shared Resource Management n/a NCI 10712681 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5635 1865461 "BRAUN, BENJAMIN " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 2711670 1679053 1032617 Shared Resource Management: Summary/AbstractThe HDFCCC supports shared resources to ensure HDFCCC members have access to the technologies andexpertise necessary for their research. This is accomplished by providing centralized management andoversight of shared resource operations; monitoring service quality and user feedback; and providingmechanisms for members to easily access any service within the HDFCCC shared resources or elsewhere oncampus. The ability of HDFCCC shared resources to provide access to specialized technologies services andexpertise that enhance scientific interaction and productivity is evident in the high number of users of sharedresources across all seven CCSG programs. +No NIH Category available Brain Neoplasms;Comprehensive Cancer Center;Family;Funding;Funding Mechanisms;Goals;Grant;Individual;Mentors;Neurosurgical Procedures;Process;Recording of previous events;Research;Research Personnel;Research Support;Source;Underrepresented Minority;United States National Institutes of Health;Woman;Work;career;minority investigator;programs Career Enhancement Program (CEP) Project NarrativeThe Career Enhancement Program is required component of all SPOREs and must be maintained for theentire funding period. The UCSF Brain Tumor SPORE commits $100000 per year to the CEP in support ofresearch that facilitates the goals of the program. Another $50000 per year is provided by funds from theUCSF Department of Neurological Surgery through the Helen Diller Family Comprehensive Cancer Center(HDFCCC) allowing the SPORE to fund up to three CEP projects per year NCI 10712678 9/5/23 0:00 PAR-20-305 2P50CA097257-21 2 P50 CA 97257 21 9/20/02 0:00 8/31/28 0:00 ZCA1-RPRB-6(M1)S 5614 6867892 "COSTELLO, JOSEPH F" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 163883 101645 62512 Project Summary/AbstractThe Career Enhancement Program (CEP) exists to identify support and mentor candidates with promisingindependent careers in translational brain tumor research. The CEP also represents an opportunity toencourage new and established non-translational investigators including women and under-representedminorities (URM) to consider careers in translational brain tumor research. In this manner the programultimately serves to expand translational brain tumor research as well as a source of translational projects andinvestigators for the SPORE Program itself. The Specific Aims of the UCSF Brain Tumor SPORE CEP are: 1.To identify support and mentor individuals with promising careers in translational brain tumor research 2. Toencourage new and established investigators to develop careers in translational brain tumor research. 3. Toencourage women and URM candidates to develop independent careers in translational brain tumor research. +No NIH Category available Academy;Award;Brain Neoplasms;CRISPR/Cas technology;Cells;Collaborations;Comprehensive Cancer Center;Development;Direct Costs;Family;Funding;Genetic;Glioma;Goals;Grant;Institution;Journals;Medicine;Monitor;Nature;Neurosciences;Neurosurgical Procedures;Peer Review;Pilot Projects;Program Research Project Grants;Publications;Research;Research Project Grants;Research Support;Resources;Science;Scientist;Translational Research;United States National Institutes of Health;Work;high risk;new technology;programs;translational medicine Developmental Research Program (DRP) Project NarrativeThe Developmental Research Program is required component of all SPOREs and must be maintained for theentire funding period. The UCSF Brain Tumor SPORE commits $100000 per year to the DRP in support ofresearch that facilitates the goals of the program. Another $50000 per year is provided by funds from theUCSF Department of Neurological Surgery through the Helen Diller Family Comprehensive Cancer Center(HDFCCC) allow the SPORE to provide $50000 direct costs for up to three DRP projects per year. NCI 10712676 9/5/23 0:00 PAR-20-305 2P50CA097257-21 2 P50 CA 97257 21 9/20/02 0:00 8/31/28 0:00 ZCA1-RPRB-6(M1)S 5613 6867892 "COSTELLO, JOSEPH F" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 201368 124895 76810 Project Summary/AbstractThe Developmental Research Program (DRP) is an integral part of the UCSF Brain Tumor SPORE andrepresents the best opportunity to explore new ideas as pilot projects to develop new resources to apply newtechnologies to translational brain tumor research and to promote collaborations among scientists at UCSFand outside institutions. In this manner the DRP ultimately serves as a means to build and support newtechnologies to support the early-stage development of projects that can compete successfully for peer-reviewed funding and in the best-case scenario for inclusion as full projects in the SPORE Program.The Specific Aims of the UCSF Brain Tumor SPORE DRP are to:1. Support research projects that can generate a strong publication record2. Support high-risk/high-impact projects3. Help develop collaborations among scientists within UCSF and at different institutions4. Develop new ideas as pilot projects to replace SPORE projects or generate outside funding +No NIH Category available Affect;Back;Biological Markers;Biology;Brain;Brain Neoplasms;Cancer Center Support Grant;Caring;Characteristics;Clinical;Clinical Trials;Collaborations;Databases;Development;Developmental Biology;Disease;Dissemination and Implementation;Drug Delivery Systems;Ensure;Epidemiology;Evaluation;Evolution;Genetic;Genomics;Glioblastoma;Glioma;Goals;Government Agencies;Growth;Image;Immunotherapy;Industry;Infrastructure;Institution;Interdisciplinary Study;International;Leadership;Malignant Neoplasms;Malignant neoplasm of brain;Molecular;Neurologic Oncology;Neurons;Neurosciences;Outcome;Patients;Phase;Positioning Attribute;Prediction of Response to Therapy;Predictive Factor;Prognostic Factor;Progression-Free Survivals;Quality of life;Research;Research Personnel;Resources;Risk Assessment;Role;Science;Scientist;Signal Transduction;Therapeutic;Training and Education;Translating;Translational Research;Translations;Tumor Biology;Tumor Markers;Work;blood-brain barrier disruption;clinical application;collaborative environment;community engagement;effective therapy;health determinants;imaging probe;improved;innovation;insight;interest;member;meningioma;metabolic imaging;neuroimaging;neuroimmunology;novel therapeutics;oncology program;personalized approach;precision medicine;programs;response;therapeutic target;therapeutically effective;therapy resistant;tumor;tumor microenvironment;ultrasound Neurologic Oncology Program n/a NCI 10712673 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5630 7690446 "CHANG, SUSAN M" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 183249 113467 69782 Neurologic Oncology Program: Summary/AbstractThe overarching scientific goal of the HDFCCC Neurologic Oncology (NE) Program is to use a team approachto advance the understanding of brain tumor biology and drive translation toward more effective and targetedtreatments. This is achieved through the close collaboration of multidisciplinary clinicians and scientistsdevoted to studying brain tumors and combine expertise in genomics cell signaling developmental biologyimmunotherapy neuroimaging epidemiology and molecular therapeutics. A major goal of the NE Program isto more effectively move promising discoveries from the lab into clinical trials by strengthening relationshipswith clinical trials consortia government agencies and industry. All activities of the NE Program reflect theHDFCCCs cross-cutting Themes of Impactful Discovery (Theme 1); Effective Translation (Theme 2); andImplementation and Dissemination (Theme 3) (see Directors Overview) and are bolstered by the resourcesand collaborative environment provided by the HDFCCC. Specifically NE member research focuses on (1)improving the understanding of the underlying biology of brain tumors; predicting patient disease responseand survival in brain cancers; and (3) improving therapy for brain tumors. +No NIH Category available Address;Adoptive Cell Transfers;Attention;Back;Biological Models;Biology;Blood;Brain Neoplasms;Cancer Center Support Grant;Catchment Area;Cell Therapy;Cells;Clinic;Clinical;Clinical Investigator;Complement;Data;Development;Disparity;Environment;Genetic Engineering;Goals;Immune;Immune response;Immune system;Immunologic Surveillance;Immunology;Immunotherapeutic agent;Immunotherapy;Laboratories;Lymphoma;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Multiple Myeloma;Myelogenous;Myeloid Cells;Myeloproliferative disease;Non-Hodgkin's Lymphoma;Patients;Population;Population Heterogeneity;Positioning Attribute;Regulatory T-Lymphocyte;Research;Resistance;Role;Sampling;Science;Scientist;T-Lymphocyte;Techniques;Technology;Therapeutic;Therapeutic Intervention;Training and Education;Translating;Translational Research;Tumor Immunity;Work;cancer immunotherapy;cell type;checkpoint therapy;clinical application;clinical investigation;community engagement;cytokine;engineered T cells;high dimensionality;improved;improved outcome;interest;leukemia;melanoma;member;mouse model;next generation;novel;novel therapeutics;pre-clinical;programs;resistance mechanism;response;therapy resistant;translational study;tumor;tumor immunology;tumor microenvironment;tumor progression Cancer Immunology and Immunotherapy Program n/a NCI 10712669 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5628 1953991 "FONG, LAWRENCE " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 183249 113467 69782 Cancer Immunology and Immunotherapy Program: Summary/AbstractThe overarching scientific goal of the Cancer Immunology and Immunotherapy Program (CII) is to advance theunderstanding of the interplay between the immune system and cancer to discover new strategies for immune-based immunotherapies and to mitigate therapeutic resistance. Overall CII Program research has led toadvances in the understanding of the molecular basis for immune cell recognition of tumors evasivemechanisms evolved by tumors to escape immune surveillance how the microenvironment influences theimmune response to cancer and technological advances in genetic engineering of T cells for adoptive celltherapies. The CII Program is a new program since the prior competing renewal. The HDFCCC-widerealignment of research programs enhances opportunities for direct interaction between discovery scientistsand clinical investigators within the CII Program and between programs. Research strengths of membersinclude expertise in immunology immunotherapy the tumor microenvironment cellular therapy and immunetherapeutic resistance. The CII Program provides a unique opportunity to address issues related to disparitiesin the catchment area in leukemia multiple myeloma lymphoma melanoma and lung cancer with specialattention placed on understanding differences in the overall clinical responses as well as access to novelimmunotherapies in this diverse population. CII members are therefore positioned to translate HDFCCCdiscovery science into the clinic and to bring clinical observations back to HDFCCC laboratories. SpecificallyCII members conduct research to (1) define the mechanistic interplay between cancer and the immune system(2) advance therapeutic interventions to improve outcomes with cancer immunotherapy and (3) identifymechanisms of resistance to cancer immunotherapy. +No NIH Category available Adult;Adult Glioma;Aftercare;Biological;Biological Markers;Biology;Biostatistics Core;Brain;Brain Neoplasms;Characteristics;Classification;Clinical;Clinical Research;Clinical Trials;Collaborations;Development;Diagnosis;Diagnostic;Early treatment;Edema;Evaluation;Excision;Genetic Engineering;Glioblastoma;Glioma;Gliosis;Glutamates;Grant;Growth;Image;Infrastructure;International;Isocitrate Dehydrogenase;Leadership;Lesion;Location;Magnetic Resonance Imaging;Malignant - descriptor;Measures;Metabolic;Metabolic Marker;Metabolism;Modeling;Monitor;Multimodal Imaging;Mutation;Newly Diagnosed;Normal tissue morphology;Operative Surgical Procedures;Pathologic;Pathology;Patient Schedules;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Population;Positioning Attribute;Production;Prognosis;Property;Pyruvate;Rattus;Recurrence;Reporting;Research Personnel;Resources;Scanning;Specificity;Surgical Management;Technology;Testing;Time;Tissue Sample;Tissues;Translating;Translations;Tumor Burden;activity marker;alpha ketoglutarate;anatomic imaging;clinical implementation;cohort;design;drug development;early detection biomarkers;experience;high risk;image guided;imaging approach;imaging biomarker;imaging capabilities;imaging probe;improved;industry partner;innovation;metabolic imaging;mutant;non-invasive imaging;novel;novel therapeutic intervention;novel therapeutics;pharmacodynamic biomarker;pre-clinical;recruit;response;response biomarker;therapeutic development;treatment response;tumor;tumor metabolism;volunteer Project 2: Novel hyperpolarized C-13 imaging as metabolic markers of response in IDH mutant glioma Project NarrativeThe discovery of isocitrate dehydrogenase (IDH) mutation has had a significant impact on the diagnosis andprognosis of adult infiltrative glioma and provides an opportunity for the development of novel treatments. Theproposed study will utilize novel hyperpolarized probes selected because of the specificity of IDHm tumormetabolism to better delineate tumor burden and elucidate early biomarkers of treatment response. Thetranslation of dynamic non-invasive metabolic imaging biomarkers will enhance the evaluation of novel therapiesand assist in the optimal management of IDHm patients. NCI 10712668 9/5/23 0:00 PAR-20-305 2P50CA097257-21 2 P50 CA 97257 21 9/20/02 0:00 8/31/28 0:00 ZCA1-RPRB-6(M1)S 5609 7690446 "CHANG, SUSAN M" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 405940 251777 154843 Project Summary/AbstractIsocitrate dehydrogenase (IDH) mutant glioma are mostly non-enhancing which makes it difficult to distinguishthe boundaries of infiltrative lesions from normal tissue and edema in both newly diagnosed and post-treatmentsettings. The standard efficacy endpoints of response rate or overall survival are also challenging for such slowgrowing tumors. These limitations have led to the consideration of innovative imaging approaches to improvethe characterization of tumor burden and early assessment of treatment response. Expanding imagingcapabilities to include robust metrics to describe the biological properties of lesions could be important to assessthe population of IDH mutant glioma that are associated with specific metabolic reprogramming slow growthrate and high risk of malignant transformation.The proposed project will leverage our experience in the clinical implementation of hyperpolarized [1-13C]pyruvate imaging for glioblastoma in the previous cycle to assess dynamic metabolism in IDH mutant glioma.Metabolic reprogramming in IDHm tumors specifically results in the conversion of alpha-ketoglutarate (-KG) toa novel oncometabolite 2-hydroxyglutarate (2HG) with a concomitant decrease in conversion of -KG toglutamate. Dynamic metabolic conversions in IDHm glioma can therefore be measured using novel imagingprobes HP [2-13C]pyruvate and [1-13C] (-KG). We will first establish the preclinical utility of using [2-13C]pyruvateand [1-13C] -KG as a non-invasive imaging biomarker of treatment response and tumor burden in Aim 1. In Aim2 we will take advantage of ongoing clinical trials at UCSF that specifically target the metabolism of IDH mutantglioma to assess the impact of using dynamic hyperpolarized [2-13C]pyruvate imaging to assess early metabolicchanges in patients undergoing treatment. Aim 3 will improve the characterization of tumor burden in newly-diagnosed and recurrent IDH mutant glioma patients using hyperpolarized [1-13C] -KG metabolic imaging withcorrelation to tissue characteristics. Ultimately we plan to translate dynamic non-invasive metabolic imagingbiomarkers to enhance the evaluation of novel therapies and assist in the optimal management of IDHm patients. +No NIH Category available Address;African American;Attention;Behavioral;Biological;Cancer Biology;Cancer Burden;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer health equity;Caring;Catchment Area;Cells;Cigar;Cigarette;Clinical;Clinical Practice Guideline;Communities;Data;Electronic cigarette;Equity;Etiology;Evidence based intervention;Geography;Goals;Health;Health Disparities Research;Health Policy;Incidence;Individual;Industrialization;Intervention;Knowledge;Malignant Neoplasms;Malignant neoplasm of prostate;Menthol;Outcome;Physical activity;Policies;Policy Research;Population;Population Heterogeneity;Positioning Attribute;Prevention;Regulation;Research;Resources;Risk;Risk Factors;Sales;San Francisco;Science;Screening for cancer;Societies;Source;Structural Racism;System;Testing;Tobacco use;Training and Education;Translating;cancer prevention;cancer risk;community based participatory research;community engagement;health equity;health inequalities;improved;meetings;member;men;multidisciplinary;neoplasm registry;novel;population based;programs;public policy on tobacco;screening;social;social determinants;structural determinants;survivorship;tobacco flavor;tobacco products;tool Cancer Control Program n/a NCI 10712667 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5627 7849117 "GOMEZ, SCARLETT L" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 185194 114671 70523 Cancer Control Program: Summary/AbstractThe goal of the HDFCCC Cancer Control (CC) Program is to use a multi-disciplinary team approach tounderstand and intervene on the structural and social determinants of cancer leading to improved cancerhealth outcomes and equity. This goal will be achieved by using intra- and inter-programmatic team science toadvance understanding of these multilevel determinants and to develop translate and implement effectivebehavioral clinical and policy interventions that will reduce the burden of cancer in the catchment area andachieve equity in cancer health outcomes.The CC Program follows a cells-to-society approach interrogate the biological mechanisms underlyingstructural and social determinants of cancer and translate these into interventions. The CC Program has thecapacity to integrate discovery intervention and delivery research. To do so the program (1) identifies thecauses of outcomes across the cancer continuum with attention to diverse populations including structuralsocial policy industrial and environmental influences on tobacco use physical activity other risk factorscancer screening and care; (2) develops implements and evaluates evidence-based interventions to reducethe cancer burden and improve cancer health equity in the HDFCCC catchment area; and (3) translatesknowledge into effective policies and programs to achieve equity in outcomes across the cancer continuum. +No NIH Category available Adoptive Transfer;Autologous;Award;Basic Science;Biological Markers;Brain Neoplasms;Clinical;Communication;Communities;Complex;Decision Making;Development;Diagnosis;Doctor of Philosophy;Ensure;Funding;Glioma;Grant;Immunotherapy;Individual;Institution;Manuscripts;Patients;Play;Preparation;Reporting;Research;Research Personnel;Research Project Grants;Role;Schedule;Science;Series;T-Lymphocyte;Time;Translational Research;United States National Institutes of Health;Vision;career;cost;experience;imaging modality;meetings;mutant;non-invasive imaging;novel;operation;programs;treatment response Administrative Core n/a NCI 10712664 9/5/23 0:00 PAR-20-305 2P50CA097257-21 2 P50 CA 97257 21 9/20/02 0:00 8/31/28 0:00 ZCA1-RPRB-6(M1)S 5607 1898964 "BERGER, MITCHEL S." Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 185711 115183 70839 Project Summary/AbstractThe UCSF Brain Tumor SPORE has three overall specific objectives: 1) to identify novel immunomethylomics-based biomarkers that contribute to the survival diagnosis and therapy response in glioma patients; 2) todevelop noninvasive imaging modalities that can define response to therapy in patients with IDH-mutant glioma;and 3) to develop novel adoptive transfer therapy using autologous T lymphocytes that allow us to overcome thecurrent challenges for immunotherapy. The Administrative Core of the UCSF Brain Tumor SPORE has beenestablished to supervise the activities of the UCSF Brain Tumor SPORE and to provide fiscal managementadministrative support and the framework by which researchers can communicate and interact. The specificaims of the SPORE Administrative Core are: 1) To evaluate research progress. The Administrative Core throughthe SPORE Executive Committee the SPORE Steering Committee and the SPORE External Advisory Boardwill be responsible for evaluating the progress of projects and making decisions regarding the continuation orreplacement of projects. 2) To provide fiscal management. The Administrative Core will distribute funds from theSPORE Award the Career Enhancement and Developmental Research Programs SPORE Supplement Awardsand discretionary funds provided by the institution. The Administrative Core will also be responsible for timelyfinancial reporting to Project Leaders and the SPORE PI/co-PIs. 3) To provide administrative support. TheAdministrative Core will be responsible for the daily operations of the SPORE the preparation of SPORE-relatedmanuscripts and communications with the NIH. 4) To facilitate communication between SPORE investigatorsand between the SPORE and outside entities. The Administrative Core will be responsible for scheduling allmeetings seminar series and retreats and distributing notices inviting participation in the Career EnhancementProgram and the Developmental Research Program. The Administrative Core also facilitates communicationwith NIH and NIH-funded entities and the brain tumor patient community. 5) To assist in compliance. TheAdministrative Core will be responsible for ensuring compliance and scientific integrity of all components of theSPORE. The Administrative Core will be used by all Projects Programs and Cores in the SPORE. +No NIH Category available APBA1 gene;American Society of Clinical Oncology;Area;Biomedical Research;Body mass index;Breast;Cancer Center Support Grant;Caring;Clinical Oncology;Collaborations;Communities;Community Outreach;Complement;Data;Development;Dissemination and Implementation;Diverse Workforce;Education;Educational workshop;Ensure;Faculty;Fostering;Future;Goals;Grant;Health Professional;Health education;Healthcare;Individual;Interest Group;Internships;K-Series Research Career Programs;Leadership;Malignant Neoplasms;Mentored Clinical Scientist Development Program;Mentors;Mission;Oncology;Oncology Group;Play;Program Development;Research;Research Personnel;Research Training;Resource Sharing;Resources;Role;Science;Series;Site Visit;Strategic Planning;Training;Training Programs;Training and Education;Translations;Travel;Underrepresented Populations;United States National Institutes of Health;Work;Writing;anticancer research;career development;college;community engagement;design;educational atmosphere;equity diversity and inclusion;experience;girls;high school;interest;member;neurosurgery;patient oriented;programs;science education;skills;skills training;success;summer internship Cancer Research Training and Education Coordination n/a NCI 10712663 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 5625 1917311 "BERGSLAND, EMILY K" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 361541 223864 137677 Cancer Research Training and Education Coordination: Summary/AbstractThe mission of HDFCCC Cancer Research Training and Education Coordination (CRTEC) is to provideexceptional cancer research training and education across the learner continuum in alignment with theHDFCCC mission. CRTEC activities are intended to foster the development of a robust diverse network oftransdisciplinary researchers and healthcare professionals and represents a foundational principle of theCenter that is integrated throughout the HDFCCC. CRTEC ensures that current and future learners are trainedto contribute to the Centers cross-cutting themes of Impactful Discovery (Theme 1); Effective Translation(Theme 2); and Implementation and Dissemination (Theme 3). To accomplish these goals CRTEC (1) delivershigh-quality cancer-related education and mentoring activities across the training continuum; (2) promotes andsupports diversity equity inclusion and accessibility in cancer research training and education; and (3)integrates training and education across the HDFCCC. +No NIH Category available Acceleration;Achievement;Address;Adopted;Adoptive Transfer;Age;Antigens;Autologous;Biological;Biological Markers;Biometry;Blood;Brain;Brain Neoplasms;CAR T cell therapy;Cells;Cellular immunotherapy;Central Nervous System;Central Nervous System Neoplasms;Clinic;Clinical;Comprehensive Cancer Center;DNA Methylation;Data;Development;Dexamethasone;Diagnosis;Diagnostic;Early treatment;Evaluation;Exhibits;Faculty;Family;Funding;Genes;Genetic Engineering;Glioblastoma;Glioma;Glutamates;Grant;Heart;Heterogeneity;Homing;Human;Image;Immune;Immunotherapy;Incidence;Individual;Intravenous infusion procedures;Isocitrate Dehydrogenase;Laboratory Finding;Magnetic Resonance Imaging;Malignant neoplasm of brain;Measures;Metabolic Marker;Methods;Modality;Modeling;Myeloid-derived suppressor cells;Neurosurgeon;Pathology;Patient Care;Patients;Persons;Phenotype;Pre-Clinical Model;Production;Pyruvate;Research;Research Personnel;Research Project Grants;Resected;Role;Safety;Sampling;Scientist;Stratification;System;T cell therapy;T-Lymphocyte;Techniques;Testing;Therapeutic;Tissues;Toxic effect;Translating;Translational Research;Tumor Burden;Work;Xenograft procedure;alpha ketoglutarate;blood-based biomarker;career;chimeric antigen receptor;chimeric antigen receptor T cells;early detection biomarkers;efficacy evaluation;exhaustion;first-in-human;imaging approach;imaging biomarker;imaging probe;immunoregulation;improved;innovation;member;methylation biomarker;mortality;mutant;neuro-oncology;non-invasive imaging;notch protein;novel;novel therapeutic intervention;peripheral blood;phase 1 study;phase I trial;pre-clinical;preclinical study;prognostic model;prognostic tool;programs;prospective;radiation response;radiological imaging;receptor;response;response biomarker;tool;treatment response;tumor Brain Tumor SPORE Grant Project NarrativeDespite the best efforts of neurosurgeons and neuro-oncologists the incidence and mortality rates of braincancer have remained stable over the past 20 years. Unfortunately in 2021 alone more than 18000 peopledied of brain and other CNS tumors. Through the work proposed in this SPORE application we will developnoninvasive measures to improve our diagnosis and response-assessment and novel cellular immunotherapy toimprove the lives of individuals with brain cancer. NCI 10712661 9/5/23 0:00 PAR-20-305 2P50CA097257-21 2 P50 CA 97257 21 "HUBBARD, LEAH" 9/20/02 0:00 8/31/28 0:00 ZCA1-RPRB-6(M1)S 1898964 "BERGER, MITCHEL S." Not Applicable 11 NEUROSURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2316634 NCI 1436850 883663 Project Summary/AbstractThis SPORE renewal application represents the efforts of interdisciplinary teams of investigators from the Neuro-Oncology Program of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) to build on ouraccomplishments to continue to translate our findings to improve care for patients with brain cancer. We havethree specific objectives: (1) to develop novel peripheral blood-based biomarkers for glioma patients (2) toidentify novel metabolic markers for noninvasive imaging to evaluate tumor burden and treatment response and(3) to develop a novel immunotherapy strategy to overcome the current significant challenges. At the heart ofthe proposal are three translational research projectseach intended to evaluate paradigm-changing novel toolsfor prognostic diagnostic and therapeutic modalities with defined human endpoints. Project 1 will build on theteams pioneering work during the current funding cycle that they established as immunomethylomics. The teamidentified GBM survival to be independently predicted by an interactive model of age and peripheral bloodimmune profiles a methylation biomarker of myeloid-derived suppressor cells or a methylation biomarker ofdexamethasone response. Using prospectively collected >1800 samples from the current cycle and additionalsamples from the new cycle the team plans to create blood DNA methylation-based biomarkers for integratedGBM prognosis models stratification of isocitrate dehydrogenase (IDH)-wild type vs. mutant gliomas andassessments of treatment response. Project 2 team will also build on their achievements during the currentfunding cycle related to the development of hyperpolarized C-13 imaging as novel imaging markers of response.In the current proposal the team will evaluate their central hypothesis that the use of hyperpolarized C-13 (HP)imaging probes (HP [2-13C]pyruvate or [1-13C]-ketoglutarate [-KG]) in magnetic resonance (MR) imaging willserve as metabolic markers of treatment response and tumor burden in patients with IDH-mutant glioma. Theteam will first evaluate their hypothesis in preclinical models and the roles of HP [2-13C ] pyruvate and HP [1-13C]-KG probes in the treatment response and tumor burden respectively in patients. Project 3 will developthe first-in-human phase I trial of adoptive transfer therapy using autologous T lymphocytes that are geneticallyengineered with a novel prime and kill gene circuit. Based on preclinical data this approach will allow us toovercome significant challenges for developing effective immunotherapy for GBM such as antigen-heterogeneity on-target off-tumor toxicities exhaustion and the lack of effective GBM-homing of the therapeuticT lymphocytes. This SPORE proposal also requests continued support for the Career Enhancement andDevelopmental Research Programs and for three Cores (Administrative Biospecimen/Pathology andBiostatistics and Clinical) that will support the efforts of the three projects. The research proposed here hassignificant potential to change how we detect diagnose and treat brain cancer. 2316634 +No NIH Category available Area;Automobile Driving;Awareness;Basic Science;Biological;California;Cancer Center Support Grant;Caring;Catchment Area;Characteristics;Clinical;Clinical Research;Communities;Comprehensive Cancer Center;Data;Dedications;Development;Diagnosis;Disease;Dissemination and Implementation;Early Diagnosis;Ensure;Environment;Family;Funding;Health;Individual;Inequity;Infrastructure;Intervention;Location;Malignant Neoplasms;Mission;Outcome;Patient-Focused Outcomes;Population;Population Heterogeneity;Population Research;Population Sciences;Prevention;Process;Research;Research Support;Resource Sharing;Risk;San Francisco;Science;Strategic Planning;Training and Education;Translating;Translations;Treatment outcome;Universities;anticancer research;community engagement;equity diversity and inclusion;improved;improved outcome;innovation;insight;member;programs;screening;treatment center Cancer Center Support Grant UCSF Helen Diller Family Comprehensive Cancer Center: NarrativeThe UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) seeks to drive scientific discoveryand develop tailored interventions to improve cancer outcomes in the catchment area and beyond. Thismission established through a unique strategic planning process encompasses three Center-wide themesthat are integrated throughout the HDFCCC and will drive research into the next decade and thereafter:Impactful Discovery Effective Translation and Implementation and Dissemination. NCI 10712659 9/20/23 0:00 PAR-21-321 2P30CA082103-24 2 P30 CA 82103 24 "SHAFIK, HASNAA" 8/5/99 0:00 5/31/28 0:00 Cancer Centers Study Section (A)[NCI-A] 10746885 "ASHWORTH, ALAN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/20/23 0:00 5/31/24 0:00 397 Research Centers 2023 8129891 NCI 5033988 3095903 UCSF Helen Diller Family Comprehensive Cancer Center: Summary/AbstractThe UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) seeks to drive scientific discoveryand develop tailored interventions to improve cancer outcomes in the catchment area and beyond. Thismission established through a unique strategic planning process encompasses three Center-wide themesthat are integrated throughout the HDFCCC and will drive research into the next decade and thereafter. Theme 1 (Impactful Discovery): Advance innovative basic clinical and population research focused on unique characteristics of the individual disease population and community. Theme 2 (Effective Translation): Translate research to define risk emphasize prevention optimize diagnosis tailor screening and treatment and improve outcomes. Theme 3 (Implementation and Dissemination): Reduce inequities in cancer awareness prevention early detection and diagnosis care treatment and patient-centered outcomes through data-driven science and community engagement.The environment of the HDFCCC allows transdisciplinary connections between each theme thus ensuringcontinuity of support for research across the cancer continuum from basic discovery science to populationscience. This is accomplished through seven research programs supported by seven shared resourcesdevelopmental funds and robust clinical and administrative infrastructure. The HDFCCC defines threeFoundational Principles that are integrated throughout the Center and inform every aspect of cancer research:Community Engagement; Education and Training; and Diversity Equity Inclusion and Accessibility.The HDFCCC builds on the richness of the basic biological insights and the extensive and exceptional clinicalresearch and facilities at UCSF a university dedicated to health research. Moreover its location in the SanFrancisco Bay Area of Northern California allows the HDFCCC to leverage one of the most culturally diversepopulations and highly innovative and intellectually vibrant environments in the world. This environment helpssupport the translational transdisciplinary research of HDFCCC members in alignment with the Centersresearch mission of driving scientific discovery and developing tailored interventions to improve canceroutcomes. 8129891 +No NIH Category available Address;Adherence;Adopted;Advanced Malignant Neoplasm;Androgens;Attenuated;Cancer Survivorship;Caring;Castrate sensitive prostate cancer;Clinical;Colorectal Cancer;Complement;Creatine;Disease;Double-Blind Method;Dual-Energy X-Ray Absorptiometry;Educational Intervention;Effectiveness;Elasticity;Elderly;Energy Metabolism;Exercise;Exhibits;Fatigue;Fatty acid glycerol esters;Head and Neck Cancer;Health;Home;Incidence;Individual;Institution;Intervention;Intervention Studies;Knowledge;Life Style;Link;Literature;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metastatic Prostate Cancer;Modeling;Nonmetastatic;Outcome;Phosphocreatine;Physical Function;Physical Performance;Placebos;Play;Population;Pre-Clinical Model;Proliferating;Protocols documentation;Quality of Care;Quality of life;Randomized;Randomized Controlled Trials;Reporting;Research;Resistance;Role;Safety;Signal Transduction;Skeletal Muscle;Supplementation;Survival Rate;Survivors;System;Telemedicine;Testing;Thinness;Training Programs;Translating;Vertebral column;Work;analog;androgen deprivation therapy;anti-cancer;cancer biomarkers;cancer survival;cancer therapy;cell free DNA;chemotherapy;double-blind placebo controlled trial;efficacy testing;exercise capacity;exercise training;improved;inhibitor;insulin sensitivity;intervention effect;men;muscle form;patient oriented;preservation;primary outcome;prostate cancer survivors;resistance exercise;survivorship;telehealth;tumor growth;tumor progression;week trial Creatine supplementation and resistance training to preserve muscle mass and attenuate cancer progression: A double-blind randomized controlled trial PROJECT NARRATIVEAndrogen deprivation therapy (ADT) with an androgen signaling inhibitor is the backbone of treatment formen with metastatic castration sensitive prostate cancer (mCSPC) but diminished muscle mass due toandrogen blockade is linked with poor overall survival and adverse changes in health outcomes important tomCSPC survivors (e.g. fatigue physical function independence insulin sensitivity and quality of life).Resistance training (RT) is an effective approach to preserve muscle mass and improve these healthoutcomes in non-metastatic CSPC survivors receiving ADT; however there is a gap in our understanding ofhow RT impacts outcomes in mCSPC survivors and the impact of 52-weeks of RT in a home-based setting asetting that is more practical for sustained adherence and the reported preferred setting for exercise in mCSPCsurvivors receiving ADT. Furthermore the addition of creatine monohydrate supplementation to an RTprogram (Cr+RT) enhances the effects of RT in cancer-free older adults and individuals with advanced headand neck cancer and creatine supplementation has demonstrated anti-cancer effects in preclinical modelsincluding prostate cancer; as such this 52-week randomized double-blind placebo-controlled trial willcompare our established effective home-based telehealth RT program with creatine or placebo (PLA; Cr+RTvs. PLA+RT) in order to identify the superior strategy to preserve muscle mass improve health outcomes andattenuate cancer progression in mCSPC survivors receiving ADT. NCI 10712432 8/24/23 0:00 RFA-CA-22-027 1R01CA281759-01 1 R01 CA 281759 1 "PERNA, FRANK" 9/1/23 0:00 8/31/28 0:00 ZCA1-SRB-2(M1) 14657323 "COLETTA, ADRIANA " "AGARWAL, NEERAJ " 1 MISCELLANEOUS 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCH ALLIED HEALTH PROFESSIONS 841129049 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 692568 NCI 453189 239379 ABSTRACTThe incidence of metastatic prostate cancer has increased 3% per year since 2012 and the survival rate isonly 29%. Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). Androgendeprivation therapy (ADT) with an androgen signaling inhibitor is the backbone of treatment for men withmetastatic castration sensitive prostate cancer (mCSPC). But the androgen blockade diminishes muscle massand contributes to adverse health outcomes critical to mCSPC survivors such as fatigue and declines inphysical function independence insulin sensitivity and QoL. Resistance training (RT) can preserve musclemass and improve health outcomes in non-metastatic CSPC survivors receiving ADT. The addition of creatinemonohydrate supplementation to an RT program amplifies the effects of RT in cancer-free older adults andother clinical populations. Evidence also suggests that creatine supplementation can complement cancertreatment. Thus creatine monohydrate supplementation with RT (Cr+RT) is a strategy that addresses animportant knowledge gap pertaining to survivorship needs of mCSPC survivors. We hypothesize that Cr+RTwill preserve muscle mass and improve health outcomes greater than RT alone and that creatine use will leadto favorable changes in markers of cancer progression in mCSPC survivors receiving ADT. Here we propose aparallel double-blind randomized controlled trial to test the effects of 52-weeks of Cr+RT compared withplacebo (PLA) and RT (PLA+RT) with our team's established effective home-based telehealth RT programin 200 mCSPC survivors receiving ADT. We will evaluate muscle mass (primary outcome) health outcomes(fatigue physical function independence insulin sensitivity QoL) and markers or cancer progression (PSAcfDNA) at baseline 24- and 52-weeks. RT will be carried out twice weekly with elastic resistance bands andwe will utilize an established creatine supplementation protocol for creatine and PLA delivery. Our trial buildson work done by our investigative team and addresses an evidence gap listed in this RFA (CA-22-027:Research to Understand and Address Survivorship Needs of Individuals Living with Advanced Cancer) re:Interventional research to determine the best ways to improve the quality of care and QoL for individuals livingwith likely incurable cancer identified gaps in the literature and unmet needs of mCSPC survivors. Ourapproach addresses a major facilitator to RT in mCSPC survivors a home-based RT program while utilizing asupervised model for safety. Our approach can be translated on a large-scale as it can be adopted byinstitutions who use an established telemedicine system and creatine monohydrate supplementation andelastic resistance bands are inexpensive and widely available. These findings will improve delivery ofcomprehensive survivorship care by providing a multicomponent patient-centered lifestyle strategy to preservemuscle mass improve health outcomes and QoL and complement cancer treatment. 692568 +No NIH Category available Acute Myelocytic Leukemia;Administrative Supplement;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Behavior;Binding;Brain;Calcium Channel;Calcium Channel Blockers;Cancer Patient;Cells;Complex;Dementia;Development;Disease;Enzymes;FDA approved;Future;Gene Expression Regulation;Genetic;Genetic Transcription;Grant;Human;Hypertension;Impaired cognition;In Vitro;Lead;Libraries;MLL gene;MLL-rearranged leukemia;Malignant Neoplasms;Mediating;Memory;Mus;Neurodegenerative Disorders;Nimodipine;Pancreatic Ductal Adenocarcinoma;Pathologic Processes;Penetration;Pharmaceutical Preparations;Plasma;Play;Preclinical Drug Development;Prefrontal Cortex;Prognosis;Proliferating;Property;Proteins;Reporting;Role;SYNJ1 gene;Senile Plaques;Solid Neoplasm;Structure-Activity Relationship;Synapses;Tertiary Protein Structure;Therapeutic;Transcriptional Regulation;United States National Institutes of Health;aging population;analog;anti-cancer therapeutic;blood-brain barrier penetration;c-myc Genes;cancer cell;cognitive function;design;efficacy study;histone methyltransferase;improved;in vivo;inhibitor;interest;lead optimization;malignant breast neoplasm;mouse model;novel;novel therapeutic intervention;overexpression;parent project;protein degradation;protein protein interaction;response;scaffold;screening;small molecule;synaptic function;therapeutically effective;tumorigenesis Discovery of First-in-class WDR5 PROTACs as a Novel Therapeutic Strategy for MLL-rearranged Leukemias PROJECT NARRATIVEIn this administrative supplement we propose to optimize synj1-lowering compounds for the treatment ofAlzheimers Disease (AD). These agents will also benefit cancer patients who suffer from AD. They could alsobe useful anticancer therapeutics. NCI 10712396 4/27/23 0:00 PA-20-272 3R01CA268384-02S2 3 R01 CA 268384 2 S2 "O'HAYRE, MORGAN" 5/1/22 0:00 4/30/27 0:00 Developmental Therapeutics Study Section[DT] 9738898 "JIN, JIAN " "WANG, G GREG " 13 PHARMACOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 422496 NIA 249997 172499 PROJECT SUMMARYThe main objective of the parent project is to develop WDR5 small-molecule degraders as anticancertherapeutics. WD40 repeat domain protein 5 (WDR5) which functions an essential subunit of the MLL histonemethyltransferase complex is critical for gene transcription regulations and essential for sustaining oncogenesisin human cancers. WDR5 is also implicated in Alzheimers Disease (AD) and WDR5 inhibitors are efficaciousin improving prefrontal cortex synaptic function and memory-related behaviors in AD mice. The parent projectdoes not focus on AD. This administrative supplement is in response to the Notice of Special Interest NOT-AG-22-025 Alzheimers-Focused Administrative Supplements for NIH Grants that are Not Focused on AlzheimersDisease. Some cancer patients also suffer from AD a devastating neurodegenerative disorder which currentlyhas no effective disease-modifying therapeutics. Synaptojanin 1 (synj1) the main phosphoinositol bisphosphatedegrading enzyme in the brain and synapses plays a critical role in AD pathology. Increased synj1 expressionand activities have been associated with cognitive decline and pathological processes of AD. Synj1 is alsoimplicated in cancer. It is overexpressed in various cancers and high expression of synj1 correlates with poorprognosis in cancer patients. In our preliminary studies compounds that lower the synj1 protein level have beendiscovered. The lead synj1-lowering compounds were efficaciousin several AD mouse models. In thisadministrative supplement we propose to conduct a lead optimization campaign to generate optimized synj1-lowering compounds withimproved potency selectivity and brain penetration. The synj1-lowering compoundsgenerated in this administrative supplement could ultimately be developed into effective therapeutics for thetreatment of AD which will also benefit cancer patients who suffer from AD. These synj1-lowering compoundscould also be useful anticancer therapeutics. 422496 +No NIH Category available Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Amyloid;Apoptotic;Biology;Brain;CRISPR/Cas technology;Cancer Patient;Cell Death;Chaperonin 60;Collaborations;Defect;Dementia;Deposition;Development;Disease;Disease Progression;Genes;Goals;Human;Impaired cognition;Knock-in Mouse;Malignant neoplasm of prostate;Mediating;Memory Loss;Memory impairment;Mitochondria;Mitochondrial Proteins;Molecular;Molecular Chaperones;Mus;Mutation;Neurodegenerative Disorders;Neurofibrillary Tangles;Phenotype;Play;Point Mutation;Positioning Attribute;Prognosis;Proteins;Research;Resources;Role;Senile Plaques;Signal Transduction;Testing;Wild Type Mouse;amyloid peptide;androgen deprivation therapy;brain tissue;cofactor;cognitive function;disease phenotype;disease prognosis;experience;extracellular;hyperphosphorylated tau;insight;misfolded protein;mitochondrial dysfunction;mouse model;novel;proteostasis;response;tau Proteins;tau aggregation;tau-1 The Role of HSP60 in Alzheimer's Disease The primary goal of this application is to understand the importance of mitochondria in Alzheimersdisease biology. We will use mouse models of Alzheimers disease and a unique mouse model ofmitochondrial dysfunction to understand the underlying mechanism of Alzheimers diseaseprogression. The proposal has relevance to understand Alzheimers disease biology and prognosisas well as the findings will be relevant to understand the occurrence of Alzheimers disease inprostate cancer patients undergoing androgen deprivation therapy. NCI 10712368 9/1/23 0:00 PA-20-272 3R01CA246437-03S1 3 R01 CA 246437 3 S1 "SALNIKOW, KONSTANTIN" 9/1/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7767901 "CHANDRA, DHYAN " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 296191 NIA 170715 125476 Alzheimers disease (AD) the most common type of dementia is characterized by progressive memory loss andimpaired cognitive function. The development of these phenotypes associates with extracellular deposition of b-amyloid peptide accumulation of hyperphosphorylated tau (phospho-tau) protein in brain and alteration inmitochondrial biology and function. Whether and how mitochondria play role in the formation of b-amyloid plaqueswhich consist of b-amyloid peptide and neurofibrillary tangles (NFTs) containing phosphor-tau protein are not clearlyunderstood. Mitochondrial protein homeostasis (mitochondrial proteostasis) is mediated by mitochondrial unfoldedprotein response (UPRmt). UPRmt is regulated by chaperones such as heat shock protein 60 (HSP60). Oligomerizationof HSP60 and association with its cofactor HSP10 maintain mitochondrial proteostasis via folding of nave proteinsand refolding of misfolded proteins. We have generated a unique mouse model by introducing a point mutation atposition 3 (D3G) of the mature mitochondrial HSP60 protein (HSP60D3G knock-in mice) via CRISPR-Cas9 approach.HSP60D3G destabilizes the oligomerization of HSP60 leading to the accumulation of unfolded/misfolded proteins inmitochondria. Importantly a point mutation at position 3 (D3G) of the mature mitochondrial HSP60 protein (HSP60D3G orD29G mutation in HSPD1 gene) also associates with neurodegenerative disorder. Therefore the utilization of this uniquemouse model will address a critical unmet need to characterize the levels and functional significance of b-amyloid andphospho-tau accumulation upon disrupting the mitochondrial proteostasis. Using HSP60D3G knock-in mouse model wewill study molecular insights of AD biology and functional significance of defects in mitochondrial proteostasis. Wewill dissect the underlying mechanism on whether/how destabilizing mitochondrial proteostasis leads to enhancedlevels of b-amyloid and phospho-tau accumulation causing decline of cognitive function in HSP60D3G mouse. We willtest our hypothesis that destabilization of mitochondrial proteostasis enhances the accumulation of b-amyloidand phospho-tau in brain causing AD phenotypes in HSP60D3G mice. Two Specific Aims are proposed to test thishypothesis. Aim 1. Determine the significance of defective HSP60 oligomerization on cellular signaling that regulates b-amyloid and phospho-tau in mouse brain. Aim 2. Functional characterization of defective HSP60 oligomerization oncognitive function in HSP60D3G mice.Impact: Androgen deprivation therapy (ADT) associates with increased risk of AD in prostate cancer (PCa) patients.HSP60 is highly upregulated and required for PCa development and progression. Therefore understanding the impactof defective HSP60 oligomerization will provide deeper understanding on the causes and consequences of developingAD in PCa patients undergoing ADT therapy. The findings may provide the impact of mitochondrial proteostasis inAD biology and prognosis including in PCa patients as well as identify HSP60 as a novel target for the treatment andmanagement of AD in humans. 296191 +No NIH Category available Academia;Address;Admission activity;African American;Alaskan;Award;Cancer Biology;Cancer Patient;Clinical Trials;Community Outreach;Development;Disabled Persons;Doctor of Philosophy;Education;Educational Curriculum;Employment;Enrollment;Exposure to;Faculty;Foundations;Funding;Future;Generations;Goals;Government;High School Student;Hispanic;Hispanic-serving Institution;Historically Black Colleges and Universities;Home;Immersion;Individual;Industry;Institution;Iowa;Latino;Leadership;Learning;Literature;Malignant Neoplasms;Mentors;Minority;Native Americans;Pacific Islander;Performance;Play;Policies;Population;Postbaccalaureate;Principal Investigator;Privatization;Publishing;Research;Research Methodology;Research Project Grants;Research Training;Rural;Schools;Science;Scientist;Students;Training;Training Programs;Underrepresented Populations;Underrepresented Students;Universities;Vocational Guidance;Youth;anticancer research;cancer survival;career;college;community college;community involvement;course development;design;disadvantaged student;experience;follow-up;high school;medical schools;meetings;posters;programs;recruit;research study;socioeconomic disadvantage;success;summer program;summer research;teacher;undergraduate student R25 YES: Cancer Research Opportunities at Iowa "Houtman/LubaroffNarrativeThe proposed summer research training program ""Cancer Research Opportunities at Iowa"" atthe University of Iowa will include a research methods training immersion in an outstandingresearch project a course in cancer biology career counseling and follow-up after thestudents complete the summer research training program and community involvement. Ourplan is to train underrepresented students both undergraduate and high school. We will alsohost faculty from these institutions to expose them to research projects and to learn aboutdevelopment and enhancement of the science curricula at their home institution." NCI 10712349 9/11/23 0:00 RFA-CA-21-020 1R25CA273964-01A1 1 R25 CA 273964 1 A1 "LOPEZ, BELEM G" 9/11/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1899715 "HOUTMAN, JON C.D." "LUBAROFF, DAVID M." 1 MICROBIOLOGY/IMMUN/VIROLOGY 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF MEDICINE 522421320 UNITED STATES N 9/11/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 275153 NCI 254771 20382 Houtman/LubaroffSummary/AbstractUnderrepresented (UR) populations are less likely to obtain advanced degrees in the field ofcancer research. In an attempt to address this problem the Principal Investigators (Co-Pis) andtheir colleagues at the University of Iowa (UI) have previously enrolled 123 undergraduate (UR)students during previous 16 summer programs. In order to continue our successful summerprograms we are submitting this application for an NCI-funded summer training program incancer research for Underrepresented High School and Undergraduate Student ResearchExperiences (R25 YES). The proposed program will include a research methods trainingemersion in an outstanding research project courses in cancer biology career counselingfollow-up after the students complete the summer research training program and communityoutreach programming. Our plan is to train both undergraduate and high school students toencourage their future participation in cancer research. We will also host faculty from theseinstitutions to expose them to research projects and to learn about development andenhancement of the science curricula at their home institution. We will utilize of the Ul'sDepartment of Educational Policy and Leadership Studies in the College of Education in thedevelopment of the course. The goals or objectives of the proposed program include: (a) torecruit UR students who would not routinely have access to a program that will be designed toprovide opportunities to learn about and perform cancer research; (b) to design a trainingprogram for these students that will expose them to a cancer research career; (c) to providecareer counseling about the variety of employment options such as academia industry andgovernment or private research centers; (d) to provide one-on-one conversations with heads ofdepartments directors of interdisciplinary graduate programs directors of PREP at Iowa apost-baccalaureate program medical school admissions and directors of the MD-PhD program;(e) to continue training and career counseling between the two years of the training program aswell as after completion of the University of Iowa's R25 YES program; and (f) communityoutreach and extended mentoring. Exposing underrepresented students and teachers toscience and research will support our goal and the goal of the NCI to support cancer researchand ultimately long-term survival for cancer patients or their cure by increasing the number anddiversity of new scientists engaged in research studies including clinical trials. The proposedprogram has a strong likelihood of success based both on our design of the program and ourpast successes with previous summer research training programs. 275153 +No NIH Category available Affect;African;African American;African American population;Age;Applications Grants;BRAF gene;Biopsy;Black race;Blood;Blood specimen;Cancer Detection;Cancer Patient;Caucasians;Clinical;Coin;Colon;Colonoscopy;Colorectal;Colorectal Cancer;Communities;CpG Island Methylator Phenotype;CpG Islands;DNA;DNA Markers;DNA Methylation;Data;Development;Diagnosis;Diagnostic;Diet;Early identification;Endoscopy;Environmental Risk Factor;Epigenetic Process;Fecal occult blood;Frequencies;Future;Gastroenterology;Gene Expression;Genes;Genetic;Genotype;Goals;Health;Incidence;Individual;KRAS2 gene;Location;MLH1 gene;Malignant Neoplasms;Methylation;Mucous Membrane;Mutation;Normal tissue morphology;Outcome;Patients;Phenotype;Polyps;Prevention;Procedures;Questionnaires;Race;Recording of previous events;Research;Risk;Sampling;Screening for cancer;Screening procedure;Single Nucleotide Polymorphism;Subgroup;Surrogate Markers;Testing;The Cancer Genome Atlas;Tissues;Treatment Protocols;Tumor Tissue;University Hospitals;Variant;Whole Blood;adenoma;anticancer research;cancer health disparity;cancer type;caucasian American;colon cancer family registry;colon cancer patients;colorectal cancer prevention;colorectal cancer risk;colorectal cancer screening;comparative;dietary;early detection biomarkers;epigenome;follow-up;genetic variant;high risk population;methylation biomarker;methylation pattern;methylome;molecular marker;molecular subtypes;mortality;patient population;patient subsets;peripheral blood;prognostic;prognostic tool;racial disparity;recruit;research study;response;risk prediction;screening;sex;social health determinants;tool;treatment response;tumor Development of blood-based methylation biomarkers for CRC risk prediction NarrativeWe have identified a subgroup of colorectal cancer (CRC) patients as having Outlier Methylation Phenotype(OMP) using normal tissue methylome and OMPs are significantly associated with CRC patients over healthycontrols and African American CRC patients are more than twice as likely to have OMP than Caucasians. Inour current grant application we propose to develop OMP as a less- invasive CRC screening and prognostictool by evaluating the consistency of OMP status in a less-invasive (whole blood) tissue with an invasive tissue(normal colorectal mucosa). We will test whether OMPs identified in colorectal tissues can also be identified inwhole blood samples using epigenome-wide data from >850K CpGs and analyze the association of OMP inCRC patients with known CRC molecular subtypes and with future clinical outcomes in controls; and study theassociation of genetic (single nucleotide polymorphisms including ancestry informative markers) andenvironmental (diet and social determinants of health) factors with OMPs. NCI 10712300 9/20/23 0:00 PAR-21-322 1R01CA281948-01 1 R01 CA 281948 1 "YOUNG, MATTHEW R" 9/20/23 0:00 8/31/28 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 12102563 "GHOSH, JAYASHRI " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA SCHOOLS OF MEDICINE 191226003 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 390661 NCI 246474 144187 Development of blood-based methylation biomarkers for CRC risk predictionColorectal cancer (CRC) incidence and mortality rates are disproportionately higher in African Americans (AA)compared to Caucasian Americans (CA). Current non-invasive screening tools like fecal occult blood test(FOBT) or Cologuard detect cancer after it occurs and more effective tools for prevention and treatment ofhigher risk individuals such as colonoscopy or endoscopy are invasive less popular and subjective.Therefore identification of early biomarkers that distinguish normal colon mucosa of cancer patients fromnormal colon mucosa of patients without cancer might decrease racial disparities in CRC. We have identified asubgroup of patients as having Outlier Methylation Phenotype (OMP) using normal tissue methylome. OMPsare highly epigenetically disrupted and display abnormal DNA methylation patterns throughout theirepigenome. We have been able to significantly associate this phenotype with CRC patients over healthycontrols. Furthermore AA CRC patients appear more than twice as likely to have OMP than CA. In our currentgrant application we propose to develop OMP as a less- invasive CRC screening and prognostic tool byevaluating the consistency of OMP status in a less-invasive (whole blood) tissue with an invasive tissue(normal colorectal mucosa). In Specific Aim 1A we will test whether OMPs identified in colorectal tissues canalso be identified in whole blood samples in 200 CRC patients (100 AA 100CA) and age sex racial ancestryand location (for colorectal tissues) matched 400 healthy controls (200 with history of adenomas and 200without history of adenomas) using epigenome-wide data from >850K CpGs. In Specific Aim 1B we willanalyze the association of OMP in CRC patients with known CRC molecular subtypes or mutations like CpGisland methylation phenotype (CIMP) KRAS BRAF MLH1 to estimate whether or not OMP is a surrogatemarker of any known CRC molecular subtype. In Specific Aim 1C we will follow-up the controls (especiallyOMPs) after 3-4years of screening colonoscopy and compare the clinical outcomes to evaluate the relevanceof this phenotype in screening or CRC prevention. We will also study the association of genetic (Specific Aim2) and environmental (Specific Aim 3) factors with OMPs. In Specific Aim 2 we will genotype the blood DNA toconfirm the self-identified racial ancestry of our samples and to study the association of genetic variants withabnormal methylation in OMPs. In Specific Aim 3 we will evaluate the effect of diet and social determinants ofhealth on OMP. Overall the proposed study aims to identify and characterize molecular markers (OMP) in aless- invasive tissue (whole blood) that can be used both as a diagnostic and a prognostic tool especially inthe underprivileged AA population who have the lowest CRC screening rates highest CRC incidence andhighest CRC mortality rates. 390661 +No NIH Category available Area;Artificial Intelligence;Attention;Cancer Biology;Categories;Cells;Cementation;Clinical;Collection;Communities;Competence;Complement;Couples;Data Science;Dedications;Development;Development Plans;Discipline;Education;Educational Status;Educational process of instructing;Environment;Faculty;Family;Fostering;Funding;Future;Generations;Goals;Grant;Individual;Interdisciplinary Education;Knowledge;Learning;Libraries;Link;Malignant Childhood Neoplasm;Medicine;Mentors;Mentorship;Methods;Mission;Modeling;Modernization;Participant;Pediatric Oncology;Radiation;Radiation Oncology;Radiation Physics;Radiobiology;Research;Research Personnel;Research Project Grants;Resources;Schools;Science;Scientist;Series;Site;Structure;Training;Training and Education;Transcend;Travel;Underrepresented Minority;Underserved Population;United States National Institutes of Health;cancer care;data hub;didactic education;education resources;equity diversity and inclusion;hands-on learning;health care disparity;imaging science;innovation;interdisciplinary approach;interdisciplinary collaboration;knowledge integration;lectures;member;minority trainee;multidisciplinary;next generation;novel;outreach;patient population;posters;programs;prospective;radiation during childhood;radiation resistance;radiation response;skill acquisition;skills;social;underrepresented minority student;web site Cross-Training Core (ROBIN-NEST) n/a NCI 10712297 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 5515 9344387 "BERBECO, ROSS I." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 123103 74194 48909 PROJECT SUMMARYEducation and training in the radiation medicine sciences are frequently compartmentalized along specific well-worn paths with only superficial attention given to complementary disciplines. The mission of theHarvard/UCSF ROBIN-Next generation Education and Scientific Training (NEST) is to organize andsupport integrated educational research and professional development initiatives that operate acrossdisciplines and training stages and serve as a model environment for the future radiation sciences workforce.The ROBIN-NEST will disrupt the traditional training paradigm by creating and supporting a novel educationaland knowledge-sharing network that drives training individual engagement and networking. TheHarvard/UCSF ROBIN-NEST will advance the following aims: 1) develop didactic materials with a newlearning platform for inter-disciplinary learning 2) integrate knowledge-sharing across disciplines in the ROBINNetwork and 3) advance professional development of the next generation of leaders in radiation medicine.Through multidisciplinary educational partnerships the ROBIN-NEST will engage a wide and diverse networkof learners and educators including outreach to local schools through established highly subscribed NIH-funded programs. In all educational training and professional development activities attention will be givenexplicitly and implicitly to principles of diversity equity and inclusion. The long-term objective of the ROBIN-NEST is to establish and grow a new and unique cross-training paradigm. The ROBIN-NEST will cultivate anew generation of scientists ready to break down traditional barriers. We anticipate that this model will inspirean enduring legacy of inter-disciplinary innovation beyond the ROBIN Network to bring impactful ideas to theaid of the increasing population of patients and families seeking hope. +No NIH Category available Academic Training;Acceleration;Address;Adoption;Algorithmic Analysis;Apache;Artificial Intelligence;Artificial Intelligence platform;Biological Assay;Cancer Biology;Cancer Research Project;Characteristics;Clinic;Clinical;Clinical Data;Communities;Community Clinical Oncology Program;Complex;Computer software;Computerized Medical Record;Data;Data Analyses;Data Commons;Data Science;Data Science Core;Data Set;Ensure;Goals;Heterogeneity;Image;Industry;Informatics;Infrastructure;Intelligence;Investigation;Investments;Knowledge;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Medical;Medical Imaging;Medicine;Methods;Modeling;Molecular;Multiomic Data;Natural Language Processing;Neuroblastoma;Patients;Pattern;Phenotype;Prediction of Radiation Response;Preparation;Radiation;Radiation Oncology;Radiation therapy;Reproducibility;Research;Research Project Grants;Research Support;Resource Sharing;Resources;Scientific Advances and Accomplishments;Semantics;Standardization;Technology;Text;The Cancer Imaging Archive;Toxic effect;Training;anticancer research;artificial intelligence algorithm;artificial intelligence method;cancer therapy;clinical phenotype;clinical translation;data streams;electronic data;experience;imaging biomarker;imaging probe;improved;multiple omics;open source;programs;quantitative imaging;radiation during childhood;radiation resistance;radiation response;radiological imaging;radiomics;response;synergism;tool;treatment response;tumor;tumor heterogeneity;usability Shared Resource Core 2: Clinical Artificial Intelligence Core n/a NCI 10712296 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 5514 11813048 "AERTS, HUGO " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 141876 106546 35330 PROJECT SUMMARYArtificial intelligence (AI) algorithms have the potential to fundamentally change medicine through their ability torecognize complex patterns in medical data. The Clinical Artificial Intelligence and Imaging Core (AI Core)is an essential shared resource that will support the Aims of the Harvard/UCSF ROBIN Research Projects toenable large-scale analysis of granular clinical data allowing non-invasive characterization of tumoral andpatient heterogeneity and a path towards clinical translation. This will be achieved through the followingSpecific Aims: i) retrieve curate and annotate digitized clinical data to support quantitative analyses andAI/informatics pipelines for the ROBIN Molecular Characterization Trial and Research Projects which willproduce one of the most comprehensive datasets for DMG and neuroblastoma patients in existence for AI-based data analysis ii) develop and evaluate task-specific AI pipelines using our well-established datapreprocessing AI-derived imaging biomarkers and natural language processing (NLP) platforms for tumorheterogeneity radiation resistance/response and toxicity characterization in accordance with the ResearchProjects and Data Science Core and iii) standardize and release AI/informatics methods across data typesand applications in ways that ensure transparency reproducibility and access to advance scientific knowledgewithin the wider research field as well as accelerate clinical translation to the pediatric radiation oncologyclinic. Achieving these aims will be possible through synergy with the molecular mechanistic analyses in theData Science Core as well as with the ROBIN-NEST Cross-Training Core and Administrative Core todisseminate our methods and provide training to the greater ROBIN Network and the scientific community.This Core is led by pioneers in the field of AI analysis of medical imaging (PI: Aerts) and clinical text (PI:Savova) with significant experience building open access platforms for medical AI applications. For imaginganalysis we developed and maintain PyRadiomics one of the worlds most widely used and highly citedradiomics pipelines developed with support of NCIs investments in infrastructure and data including theInformatics Technology for Cancer Research (ITCR) Imaging Data Commons (IDC) and Quantitative ImagingNetwork (QIN) programs. For clinical text we have developed Apache cTakes() a leading open accessnatural language processing platform for extracting medical grammatical and semantic information fromclinical texts and DeepPhe an open-source software for cancer clinical phenotyping also supported by theNCIs ITCR program (PI: Savova). We will use and build on our open access methods and state-of-the art AI-based phenotyping methods developed in these NCI projects to support the Harvard/UCSF ROBINinvestigators to incorporate fundamental clinical -omics data into their investigation of intratumoralheterogeneity and predictors of radiation response and late effects. +No NIH Category available Acute;Address;Artificial Intelligence;Biological;Biological Markers;Biological Models;Biology;Blood specimen;Cancer Biology;Carrier Proteins;Catalogs;Cells;Child;Childhood;Classification;Clinical;Clinical Trials;Cohort Studies;Collaborations;Combined Modality Therapy;Computer Models;Coupled;DNA;DNA Repair;Data;Data Science;Development;Diagnosis;Disease;Disease-Free Survival;Education;Endothelial Cells;Evaluation;Exposure to;Failure;Functional disorder;Funding;Gene Expression Profile;Genetic Transcription;Genomics;Goals;Growth;Heterogeneity;Image;Immune;Late Effects;Long-Term Survivors;Malignant Childhood Neoplasm;Measures;Mediating;Medical;MicroRNAs;Modality;Molecular;Neuroblastoma;Nodal;Normal tissue morphology;Oncology;Outcome;Patients;Pediatric Oncologist;Pediatric Oncology Group;Play;Point Mutation;Population;Populations at Risk;Radiation;Radiation Dose Unit;Radiation Oncology;Radiation Tolerance;Radiation therapy;Radiobiology;Radiopharmaceuticals;Randomized;Relapse;Research Project Grants;Resected;Resistance;Resources;Role;Sampling;Scientist;Second Primary Neoplasms;Series;Specimen;Stromal Cells;Survivors;Systemic disease;Targeted Radiotherapy;Testing;Thyroid Gland;Time;Toxic effect;Treatment Failure;Tumor Markers;Work;adverse outcome;case control;cohort;design;dosimetry;genetic variant;high risk;improved;improved outcome;innovation;insight;irradiation;large datasets;metaiodobenzylguanidine;molecular marker;neoplastic cell;novel;peripheral blood;phase III trial;predicting response;predictive marker;prognostic;prophylactic;protein expression;psychologic;radiation response;radiomics;randomized trial;response;serial imaging;skills;theranostics;transcriptomics;treatment strategy;tumor;tumor DNA;tumor heterogeneity;tumor microenvironment Research Project 2: Neuroblastoma n/a NCI 10712294 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 5512 9389403 "CHOWDHURY, DIPANJAN " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 377436 212560 164876 Project Summary Radiopharmaceuticals have shown tremendous clinical promise resulting in regulatory approvals ofseveral agents. Such targeted radiotherapy exposes tumor cells to continuous exponentially decayingradiation resulting in biological effects distinct from those of external beam radiotherapy. Despite thisfundamental difference there is limited understanding of the impact of radiopharmaceuticals on tumor cellpopulations and other components of the tumor microenvironment such as stromal cells immunecompartments and endothelial cells. The proposed work will provide novel insights into tumor cell-intrinsic and-extrinsic mechanisms of radiation response that can inform the study of radiopharmaceuticals acrossoncology. Against this backdrop Project 2 will deeply characterize samples imaging and data from a cohort ofchildren with high-risk neuroblastoma treated with the targeted radiopharmaceutical 131I-MIBG. In Aim 1 wewill evaluate pre-treatment tumor cell-intrinsic and tumor cell-extrinsic factors including somatic and hostgenomic variants single cell and bulk transcriptomics and DNA damage repair profiling. In Aim 2 we willassess dynamic changes in these factors in response to 131I-MIBG therapy including evaluation of tumormaterials resected after 131I-MIBG as well as serial circulating tumor DNA samples. In Aim 3 we will leveragetwo large national studies to assess the late effects of 131I-MIBG in this vulnerable pediatric population. By theconclusion of Project 2 we will understand predictors of response and toxicity following 131I-MIBG therapy andmore fundamentally will understand the changes in a comprehensive set of molecular markers reflective ofradiation biology following treatment with this radiopharmaceutical. We have embedded our work within the only randomized phase 3 trial of 131I-MIBG ever conductedCOG ANBL1531 (NCT03126916). However beyond our utilization of goal-oriented clinical trials to enable aquestion-oriented hypothesis-driven study plan in close collaboration with our Data Science and AI CoresProject 2 advances several transformative innovations. A major barrier limiting our understanding of thebiological effects of radiopharmaceuticals is a lack of paired tumor samples obtained before and after exposureto radiation. Our work overcomes this barrier by exploiting our unique access to detailed cross-sectional dataon long-term medical psychological and educational outcomes coupled with paired longitudinal biologicspecimens dosimetry serial images data science mechanistic computational modeling and radiomics toidentify the critical changes in our markers of tumor heterogeneity that are associated with 131I-MIBG responseand late effects. Importantly biospecimens are available from patients treated with or without 131I-MIBGtherapy on this trial enabling us to validate specific markers as truly predictive rather than simply prognostic.Finally our proposal leverages a series of other federally-funded efforts in order to establish an enduringcollaborative initiative with broad impacts at the intersection of radiation oncology and cancer biology. +No NIH Category available Adult;Artificial Intelligence;Attention;Autopsy;Biological Markers;Biology;Biopsy;Cancer Biology;Cells;Cessation of life;Child;Childhood;Chromatin;Clinical;Clinical Trials;Collection;Complement;Complex;Computer Models;DNA;DNA Repair Pathway;Daphne plant;Data;Data Analyses;Data Science;Data Science Core;Data Set;Development;Diagnosis;Doctor of Medicine;Doctor of Philosophy;Elements;Enzymatic Biochemistry;Epigenetic Process;Equilibrium;Evaluation;Evolution;Fostering;Funding;Genetic;Genomics;Gifts;Goals;Heterogeneity;Histopathology;Image;Laboratory Research;Leadership;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Matched-Pair Analysis;Methodology;Methods;MicroRNAs;Modality;Molecular;Mutation;Neurocognitive;Normal Cell;Normal tissue morphology;Oncologist;Operative Surgical Procedures;Outcome Assessment;Parents;Pathway interactions;Patient Outcomes Assessments;Patients;Pediatric Neoplasm;Population;Positioning Attribute;Proteomics;Quality of life;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Radiogenomics;Regimen;Relapse;Research Project Grants;Resistance;Sampling;Specific qualifier value;Testing;Time;Tissues;Toxic effect;Transcend;Tumor Tissue;Variant;anti-cancer;cancer cell;cancer genomics;cell type;cohort;demographics;differential expression;diffuse midline glioma;dosimetry;epigenomics;health related quality of life;insight;longitudinal dataset;macroglia;neoplastic cell;neural;oligodendrocyte progenitor;patient population;precision medicine;programs;prospective;radiation during childhood;radiation resistance;radiation response;radioresistant;response;stem;treatment response;tumor;tumor heterogeneity;tumor microenvironment Research Project 1: Diffuse Midline Glioma n/a NCI 10712293 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 5511 1940535 "HAAS-KOGAN, DAPHNE A." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 372253 209641 162612 Project SummaryConventional wisdom holds that radiation therapy is a physically targeted anti-cancer modality and that itscancer targets are genetically and biologically uniform. However the stromal composition of tumors is complexand variable giving rise to extrinsic variability of the cancer target. Moreover recent studies using single cellgenomics show intrinsic heterogeneity even within the tumor cells per se. The broad goal of ourHarvard/UCSF ROBIN initiative is to test the hypothesis that intra-tumoral variability underlies resistance to -and relapse from radiotherapy. Towards this goal our Center has chosen to focus on pediatric cancers ofneuro-ectodermal origin. Pediatric tumors have a low mutational burden relative to common adult cancers andthus a cleaner genetic surround for the low N/high content Molecular Characterization Trials specified bythe ROBIN RFA. Against this backdrop this project focuses upon diffuse midline glioma (DMG) of children. The majority of DMGs initially respond to radiation but all progress and none are cured. In preliminarystudies we have used single cell genomics to show that the malignant cells within DMG are developmentallyheterogeneous. Our testable hypothesis is that DMG intratumoral heterogeneity transcends developmentalmarkers to include differential expression/utilization of common DNA repair pathways. This hypothesis makespredictions that will be assessed by drawing upon paired samples of pre-and post-radiotherapy tumor tissuefrom children treated prospectively with a uniform radiotherapy regimen and profiled in our MolecularCharacterization Trial (MCT). We have three specific aims: Aim 1 is to test the prediction that intratumoralheterogeneity is reflected at levels above and beyond tumor cell-specific developmental markers noted ourpreliminary studies; Aim 2 is to test the prediction that radiotherapy reduces DMG intratumoral heterogeneityvia selection of replication-competent radio-resistant stem-like cancer cells; Aim 3 is to test the prediction thatheterogeneous radiation responses within tumor cells underlie patient heterogeneity in radiation-associatedtoxicities neurocognitive effects and quality of life. The study plan incorporates contemporary methods in cancer genomics epigenomics chromatinbiology and DNA enzymology. We will draw upon our Clinical Artificial Intelligence and Imaging Core todevelop non-invasive methods to track intra-tumoral heterogeneity in these (surgically challenging) pediatrictumors. With our Molecular Data Science and Advanced Dosimetry Core we will develop computationalmodeling of tumor cell evolution and treatment response that will be critical to understanding selection forradioresistant subclones. The co-leaders of this Project have complementary expertise to enable the studyplan. Daphne Haas-Kogan M.D. is a pediatric radiation oncologist who treats patients with DMG and holdsleadership positions in two key consortia (COG and PNOC) for pediatric clinical trials. Mariella FilbinM.D./Ph.D. is a pediatric neuro-oncologist with expertise in single cell genomics and DMG biology. +No NIH Category available Acceleration;Adult;Aftercare;Amendment;Appearance;Artificial Intelligence;Autopsy;Biological Assay;Biopsy;Blood;Blood specimen;California;Cancer Biology;Cancer Center;Caregivers;Characteristics;Child;Childhood;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Collection;Communities;Consent;Data;Data Collection;Data Element;Data Science;Data Storage and Retrieval;Ensure;Goals;Hand;Health protection;Heterogeneity;Image;Institution;Investigation;Knowledge;Late Effects;Lead;Long-Term Survivors;Malignant Childhood Neoplasm;Malignant Neoplasms;Molecular;Mutation;National Clinical Trials Network;Neuroblastoma;Oncology;Operative Surgical Procedures;Parents;Patients;Pediatric Oncology Group;Performance;Pilot Projects;Procedures;Protocols documentation;Radiation;Radiation Oncology;Radiation exposure;Radiation therapy;Radiopharmaceuticals;Recurrence;Reproducibility;Research;Research Project Grants;Resource Sharing;Resources;Sampling;San Francisco;Signal Transduction;Site;Solid Neoplasm;Source;Standardization;Testing;The Cancer Genome Atlas;Therapeutic Trials;Tissues;Universities;Work;age group;biobank;clinical trial protocol;cohort;data resource;design;diffuse midline glioma;dosimetry;embryo tissue;high risk;immune-related adverse events;innovation;metaiodobenzylguanidine;multidimensional data;multimodality;neoplastic cell;neuro-oncology;novel;pediatric patients;programs;radiation response;risk minimization;sample collection;standard of care;structured data;success;tumor;validation studies Molecular Characterization Trial n/a NCI 10712292 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 5510 10357531 "KOZONO, DAVID " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 325058 286274 38784 PROJECT SUMMARYThe Molecular Characterization Trial (MCT) is the source of biospecimen and data resources for the ROBINCenter. As such its success is paramount to the success of the entire initiative and strategies that expeditethe acquisition of these essential resources will accelerate the timeframe in which they are made available forall the innovative work performed in the Research Projects and Cores. The Harvard/UCSF ROBIN has chosenfor its theme the study of pediatric malignancies as the optimal setting for in depth investigation into the impactof heterogeneity in both its tumor cell intrinsic and extrinsic manifestations on radiation responses. The MCTwill achieve these goals via the following Aims: Aim 1: Coordinate the collection of biospecimens andclinical data from cooperative group studies for use in ROBIN studies. The MCT will leverage two ongoingtrials: Pacific Pediatric Neuro-Oncology Consortium PNOC023 for diffuse midline glioma (DMG) andChildrens Oncology Group (COG) ANBL1531 for neuroblastoma (NBL). The study chairs for each trial are co-leads of the MCT and Project 2 respectively. As a novel feature of the MCT matched pairs of tumor sampleswill be available from subjects who underwent pre-treatment biopsies and subsequently had post-treatmentsurgical (NBL) or post-mortem (DMG) tissues obtained via established protocols. The ROBIN investigators willalso leverage additional resources that are uniquely available to them including a collection of thirty DMGtumor samples that are distinct from those obtained on the PNOC023 study and already in hand. The MCT willalso bolster an aim on late effects by obtaining blood samples and clinical data from the COG Late Effects afterHigh-Risk Neuroblastoma (LEAHRN) study which includes 24 long-term survivors previously treated with theradiopharmaceutical 131I-MIBG. Aim 2: Manage the regulatory aspects of the MCT including site protocolsfor collection of protected health information (PHI) and biospecimens in institutional biorepositories. Clinicalresearch and data coordinators will work with site leads at both Dana-Farber/Harvard Cancer Center andUCSF to ensure rigorous and timely submission of study protocols amendments and continuing reviews sothat the work can steadfastly proceed. Also because all PHI will flow through the MCT which provides de-identified resources to other ROBIN components this will minimize risks to subject confidentiality. Aim 3:Maintain standard operating procedures for processing and analyzing tumor blood and CSF samples andstoring incoming and resultant high-dimensional data. Given the vast amounts of data involved and theintricate assays being performed it is essential that the work is performed in a harmonized way to maintainrigor and reproducibility. The MCT will rely on the combined expertise within the Clinical Artificial Intelligenceand Imaging Core and the Molecular Data Science and Advanced Dosimetry Core to ensure compliancewith de-identification and data storage standards so that the rich resources generated by the ROBIN can beused effectively by the broader research community in pilot projects and beyond. +No NIH Category available Accounting;Achievement;Address;Adult;Advisory Committees;Advocate;Archives;Artificial Intelligence;Award;Biometry;Boston;Cancer Biology;Cells;Client;Clinical;Clinical Research;Clinical Trials;Code;Communication;Communication Methods;Communities;Community Services;Computer Models;Dana-Farber Cancer Institute;Daphne plant;Data;Data Science;Data Science Core;Data Set;Databases;Department chair;Doctor of Medicine;Doctor of Philosophy;Education and Outreach;Electronic Mail;Electronics;Evaluation;Face;General Population;Genome;Goals;Grant;Hospitals;Image;Institution;Leadership;Logistics;Machine Learning;Malignant Childhood Neoplasm;Medical;Mission;Molecular;Nature;Occupational activity of managing finances;Oncology;Patient advocacy;Patients;Pediatric Hospitals;Pediatric Oncology;Performance;Persons;Pharmacology;Physics;Pilot Projects;Protocols documentation;Quality of life;Radiation;Radiation Oncology;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Services;Site;Source;Talents;Technology;Text;Training;Videoconferencing;Vision;Woman;Work;cloud based;design;dosimetry;experience;mathematical model;meetings;multidisciplinary;neoplastic cell;outreach program;participant enrollment;pediatric patients;physical science;programs;radiation resistance;radiation response;radioligand;recruit;repository;resistance mechanism;sharing platform;skills;theranostics;tool;web site Administrative Core n/a NCI 10712291 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 5509 1940535 "HAAS-KOGAN, DAPHNE A." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 51672 29100 22572 The Harvard/UCSF ROBIN Center will address molecular mechanisms of radiation response and resistancein childhood cancers using the quieter genome of pediatric malignancies to identify radiation resistancemechanisms that are broadly applicable to adult and pediatric patients. The Center consists of a MolecularCharacterization Trial two Research Projects two supporting Cores [one focused on Data Science andAdvanced Dosimetry and the second on Imaging and Artificial Intelligence (AI)] as well as the critical Cross-Training Core (ROBIN-NEST). Collectively these ROBIN Center components can be conceptualized aseither Scientific or Programmatic in nature. Against this backdrop this Administrative Core has two broad goals. Firstly as the ROBIN Centersinward looking face the Administrative Core will support the Scientific and Programmatic missions. Secondlythe Administrative Core will serve as the outward face of the Harvard/UCSF Center and as point of contactwith NCI other ROBIN Centers diverse learners the radiation sciences workforce and the lay public. TheAdministrative Core has three Specific Aims. Aim 1 (Scientific Support): The Administrative Core will implement electronic communicationmethods to facilitate transfer of accounting information access to Research and Technology Managementforms access to clinical research databases and access to cloud-based data and code sharing platforms. Aim 2 (Programmatic Support): The Core will integrate the Harvard/UCSF sites and unify the Centervia videoconferencing in-person meetings and online communication. Together with the ROBIN-NEST theCore will host an Annual Retreat to share and harmonize vision and logistics across the ROBIN Center. Finallythe Core will request applications for evaluate award and administer pilot and trans-Network Projects. Aim 3 (NCI and Community Service): The Administrative Core will create the Harvard/UCSFROBIN Centers website as a public-facing source of data and resources. Critically the Core will also work tostrengthen the Harvard/UCSF Center with proactive strategies to enhance diversity of our research groupsthe radiation sciences workforce communities served by our Center and patients enrolled in our clinical trials. Daphne Haas-Kogan M.D. and Franziska Michor Ph.D. will serve as co-leaders of the AdministrativeCore and also as co-PIs of the Harvard/UCSF ROBIN itself. Each of the co-leads has extensive experience inleading multi-investigator multi-institutional research initiatives. Dr. Haas-Kogan is the Chair of the Departmentof Radiation Oncology at Dana-Farber Cancer Institute (DFCI) Brigham and Womens Hospital and BostonChildrens Hospital and Dr. Michor has led two iterations of NCIs Physical Sciences Oncology Networks(PSON) U54 initiative and also leads the DFCI Physical Sciences Oncology Center (DFCI PSOC). Drs. Haas-Kogan and Michor will be assisted by Simon Maisel MS who will report directly to the co-PIs. +No NIH Category available Accounting;Address;Adult;Advisory Committees;Advocate;Anatomy;Artificial Intelligence;Award;Biological;Biological Markers;Biology;Boston;California;Cancer Biology;Cancer Center;Cells;Child;Childhood;Childhood Glioma;Childhood Solid Neoplasm;Clinical;Clinical Investigator;Clinical Trials;Clinical Trials Network;Collection;Communities;Comprehensive Cancer Center;Computational Biology;Core Facility;Credentialing;Daphne plant;Data;Data Science;Data Set;Development;Discipline;Doctor of Medicine;Doctor of Philosophy;Education;Elements;Evolution;External Beam Radiation Therapy;Extramural Activities;Face;Family;Funding;Future;General Population;Genetic;Heterogeneity;Image;Infrastructure;Infrequent Neoplasm;Institution;International;Investigational Therapies;Late Effects;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical;Methodology;Mission;Modality;Molecular;Mutation;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;Oncology;Outcome;Patient advocacy;Patients;Pediatric Neoplasm;Persons;Physics;Pilot Projects;Population;Positioning Attribute;Process;Productivity;Quality of life;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Radiobiology;Radiogenomics;Radiopharmaceuticals;Records;Regimen;Research;Research Personnel;Research Project Grants;Resistance;Resources;Robin bird;Sampling;San Francisco;Scientist;Solid Neoplasm;Specific qualifier value;Specimen;Students;Sum;Technology;Testing;Toxic effect;Training;Training Programs;Tumor Tissue;Universities;Variant;Work;cancer cell;cancer genetics;cancer research center director;clinical material;cohort;data integration;data modeling;design;diffuse midline glioma;dosimetry;experience;genomic data;high risk;improved;insight;mathematical model;metaiodobenzylguanidine;multimodality;multiscale data;neoplastic cell;novel;outreach program;physical science;professor;programs;prospective;radiation during childhood;radiation resistance;radiation response;radioresistant;response;skills;spatiotemporal;standard of care;treatment response;tumor;tumor heterogeneity;tumor-immune system interactions Radiation Oncology at the Interface of Pediatric Cancer Biology and Data Science Research NarrativeRadiation therapy is efficacious for many cancers but only partially effective or totally ineffective for manyothers. The National Cancer Institute has issued a request for multi-institutional teams to improve the potencyof radiation and expand its repertoire of responsive tumors through formation of a Radiation Oncology Biology-Integration Network (ROBIN). In response scientists and clinicians from the Dana-Farber/Harvard CancerCenter in Boston have joined forces with their counterparts at the University of California San Francisco topropose a Harvard/UCSF Robin Center. NCI 10712290 9/19/23 0:00 RFA-CA-22-046 1U54CA274516-01A1 1 U54 CA 274516 1 A1 "VIKRAM, BHADRASAIN" 9/19/23 0:00 8/31/28 0:00 ZCA1-SRB-X(M1) 1940535 "HAAS-KOGAN, DAPHNE A." "MICHOR, FRANZISKA " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1645000 NCI 1089405 555595 Project SummaryBasic scientists and clinical investigators from Dana-Farber/Harvard Cancer Center (DF/HCC) join forces withtheir counterparts at University of California San Franciscos (UCSF) Helen Diller Family ComprehensiveCancer Center to propose a Harvard/UCSF ROBIN Center. Our Objective is to improve potency andselectivity of two key radiation modalities--external beam radiation and radiopharmaceuticals. A distinctivefeature of our ROBIN Center is its selection of two clinically aggressive pediatric tumors--diffuse midline glioma(DMG) and high-risk neuroblastoma (NBL) as scientific vehicles for the study plan. The genetic drivers ofthese two pediatric cancers are found also in more common adult solid tumors. Moreover the low mutationalburden of these pediatric cancers provides a clean genetic background for the low N/high content MolecularCharacterization Trials (MCTs) specified by the ROBIN RFA. The malignant cells within DMG and NBL areheterogenous with respect to developmental stage. The central hypothesis of our study plan is that thisdevelopmental heterogeneity is echoed at the level of radiation-response mechanisms and enables radiationresistance. Our study plan features two research projects configured to test predictions of this hypothesis. Project 1 draws upon paired samples of pre-and post-radiotherapy tumor tissue from children treatedprospectively with a uniform radiotherapy regimen to test the prediction that radiation selects for radioresistantintra-tumoral variants. Project 2 tests the prediction that 131I-MIBG therapy of aggressive neuroblastomaselects for intra-tumoral subtypes with unfavorable responses to treatment. Our ROBIN MCT providesresources needed to complete the objectives and specific aims of the two Projects. Multimodal analysis andmathematical modeling of data from the Projects and the MCT will be performed in a Clinical ArtificialIntelligence and Imaging Core and a Molecular Data Science and Advanced Dosimetry Core. A Cross-Training Core and an Administrative Core will support scientific activities and serve also as the Centersoutward face to the broader scientific community and lay public. The Center will serve as a value-added component of the NCIs extramural support mission byleveraging (i) P30 core facilities of DF/HCC and UCSF (ii) a U54-funded DFCI Physical Sciences OncologyCenter and (iii) the NCI's Experimental Therapeutics Clinical Trials Network and National Clinical TrialsNetworks. Conversely an NCI ROBIN award to the Harvard/UCSF Center would be value-added to the fieldof radiation oncology by catalyzing productive interactions between radiation biology artificial intelligence anddata science disciplines that are well-established in Boston and San Francisco but have never been appliedcoordinately to the problem of radioresistance. Center co-leads Professors Daphne Haas-Kogan M.D. andFranziska Michor Ph.D. have much experience in management of multi-investigator multi-institutionalresearch programs together with complementary skillsets in radiation oncology and advanced data science. 1645000 +No NIH Category available 3-Dimensional;Autopsy;Biology;CD8B1 gene;CTLA4 gene;Cd68;Cell Line;Cells;Clinical;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Collection;Combined Modality Therapy;Consent;DNA sequencing;Data;Dedications;Development;Effectiveness;Ensure;Epidermal Growth Factor Receptor;Evaluation;Fingerprint;Funding Mechanisms;Future;Genomics;Giant Cells;Glioblastoma;Glioma;Goals;Grant;Human;Human Cell Line;Immune;Immunofluorescence Immunologic;Immunohistochemistry;Immunology;Immunooncology;Immunotherapy;In Vitro;Individual;Infection;Institution;Institutional Review Boards;Investigation;Maintenance;Malignant Glioma;Malignant Neoplasms;Methods;Modeling;Modification;Molecular;Molecular Analysis;Mouse Cell Line;Mus;Myelogenous;Neurosphere;Oncolytic viruses;Operative Surgical Procedures;PTEN gene;Pathologic;Pathology;Patients;Pattern;Phenotype;Protocols documentation;Research Personnel;Research Project Grants;Resistance;Resources;Sampling;Services;Site;Stains;Study models;Therapeutic;Tissues;Transgenic Model;Tumor-Derived;Tumorigenicity;United States National Institutes of Health;Validation;Viral;Virus;Xenograft procedure;biobank;cBioPortal;cell preparation;deep learning algorithm;digital pathology;epigenomics;fluorescence imaging;high dimensionality;human model;humanized mouse;immunopathology;improved;in vitro Model;in vivo;liquid crystal polymer;member;mouse model;mutant;neoplastic cell;neuropathology;novel;oncolytic herpes simplex virus;oncolytic virotherapy;patient derived xenograft model;programmed cell death ligand 1;programmed cell death protein 1;programs;prospective;receptor;repository;response;single nucleus RNA-sequencing;targeted treatment;transcriptome sequencing;tumor Core 2: Glioblastoma Biorepository Core PROJECT NARRATIVE CORE 2Glioblastoma (GBM) is amongst the most lethal forms of cancer. The Core 2 Glioblastoma Biorepositoryproposes to provide services of neuropathology review digital pathology tissue and cell line banking andcreation of patient derived xenografts for use by the Projects to develop methods to improve effectiveness ofoHSV in GBM. In addition we will provide expert immuno-oncology approaches to the P01 such as novelmultiplex fluorescent imaging genomics and model modifications to understand resistance to oHSV therapy. NCI 10712286 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5507 6885500 "LIGON, KEITH LLOYD" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 152772 121545 31227 PROJECT SUMMARY CORE 2The goals of the Glioblastoma Biorepository Core (Core 2) are to provide all P01 members with centralizedaccess to professional banking of samples patient derived models (PDX/cell lines) neuropathology servicesand expertise. This includes access to human tumors derived from rQNestin clinical trial patients as well asnewly created human and mouse cell lines and xenografts critical to all experimental Project aims. The presenceof the Core ensures that all resources are clinically and molecularly annotated with respect to relevantparameters with the goal to aid study and development of oncolytic virus and study of immunotherapyapproaches. These resources will specifically aid the projects in their studies of oncolytic virus biologyimmunology and therapeutics in a manner not possible though individual project (e.g. R01) funding mechanismsor through existing cores at each of the P01 institutions. Moreover by interacting with multiple projects andinvestigators the Core will continue to act as a resource that drives collaboration and sharing of the pathologicalresults and findings across the P01. Core 2 has 3 Specific Aims to accomplish its goals. Aim 1: To generateand maintain a repository of consented glioblastoma samples and data. (all Projects) which includes criticalsamples and pre- post-rQNestin trial patient samples and models for study. Aim 2: To create and distributeglioblastoma patient derived cell lines (PDCL) and xenografts (PDX) (all Projects) which will be used to studypatterns of infection and effects of novel oHSV derivatives. Aim 3: To provide expert neuropathologyimmunopathology and molecular analysis of glioblastoma tissues and models (all Projects) including noveldigital pathology deep-learning algorithms and multiplex immunofluorescence. In summary the Core serviceswill be essential to all Projects and will promote and prioritize collaboration to develop more effective oncolyticviral therapies for GBM and other cancers. +No NIH Category available Adopted;American Cancer Society;Animals;Bacterial Artificial Chromosomes;Biodistribution;Biological Assay;CRISPR interference;CRISPR-mediated transcriptional activation;Cell Line;Cells;Cessation of life;Cities;Clinical Trials;Contracts;Cyclic GMP;DNA;Data;Development;Dexamethasone;Dextran Sulfate;Engineering;Ensure;Excision;Freeze Drying;Gene Expression;Genes;Genome;Glioblastoma;Glycerol;Goals;HSV vector;Herpesvirus 1;Human;IgG1;Immune response;Immunity;Individual;Infection;Interferons;Laboratories;Lentivirus;Libraries;Malignant Glioma;Malignant neoplasm of brain;Methodology;Modeling;Monoclonal Antibodies;Nervous System Neoplasms;Normal Cell;Oncolytic;Oncolytic viruses;Pathway interactions;Phase;Phase I Clinical Trials;Phase I/II Clinical Trial;Positioning Attribute;Procedures;Process;Production;Proteins;Protocols documentation;RANTES;Reagent;Research;Research Personnel;Safety;Simplexvirus;Site;Standardization;Sterility;Stress;System;Technology;Temperature;Test Result;Testing;Time;Toxic effect;Translations;Variant;Vendor;Viral;Virus;Virus Replication;Work;cost;efficacy study;efficacy testing;exosome;experimental study;improved;in vivo;inhibitor;interest;manufacture;manufacturing capabilities;manufacturing facility;neoplastic cell;novel;oncolytic herpes simplex virus;oncolytic virotherapy;particle;phase I trial;pre-clinical;preclinical efficacy;response;safety testing;scale up;success;transcriptome sequencing;tumor;vector Core 1: oHSV Production Core PROJECT NARRATIVE CORE 1The American Cancer Society predicts there will be >12000 deaths/yr from brain cancer. The recent Phase-1clinical trial with oncolytic Herpes Simplex Virus (oHSV) rQNestin34.5V2 has shown considerable promise. Thegoal of the P01 renewal is to improve upon this process. Doing so requires high-titer purified stocks grown andpurified by one Core 1 otherwise considerable variation in purity stability sterility and identity occurs. Core 1will provide the projects with highly purified oHSV stocks based on the detailed protocols we have developed foroHSV production purification and quality assessment. NCI 10712285 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5506 2413377 "GOINS, WILLIAM F." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 145641 125891 19750 PROJECT SUMMARY CORE 1Nervous system tumors such as glioblastoma (GBM) remain amongst the most difficult to tumors treat. We havebeen interested in using oncolytic viruses based on herpes simplex virus type 1 (HSV-1) as a selective nervoussystem tumor-killing virus. Considerable effort in the development of HSV-1 vectors has resulted in theengineering of oncolytic HSV vectors (oHSV) such as rQNestin34.51 that are non-toxic for normal cells yetcapable of selective replication in GBM tumor cells. To effectively use oHSV in animal tumor models it isnecessary to propagate and purify oHSV to high titers. Our efforts in process development have resulted inscalable systems capable of manufacturing rQNestin34.5 and other oHSVs and our protocols have beenmodified by Project 4 (Yu/Caligiuri) and the City of Hope Contract Manufacturing Facility to produce cGMP-grade oHSV-CCL5 for the upcoming Phase-I trial as part of the P01 Renewal.The primary goal of the oHSV Production Core will be to provide large quantities of research-grade concentratedand purified oHSV vectors for Project 1 (Glorioso; armed and unarmed rQNestin34.5v1 non-SYN and SYN)Project 2 (Chiocca; rQNestin34.5v1 and rQNestin34.5v2) Project 3 (Kaur; oHSV-rQ1 and oHSV-P10-aCD73mAb) and Project 4 (Caligiuri; oHSV-CCL5 and oHSV-CD47-IgG1). Since the P01 started in 2012we have produced purified and distributed over 60 oHSV stocks to the 4 projects while producing 23 MVBswith 36 oHSV stocks produced from 2017-2022. The oHSV Production Core will continue to work with theProjects to provide optimal vector quantity and purity while providing the support necessary to successfullyexploit the available technology. We have shown that inclusion of dextran sulfate in production increased oHSVyield 15x and that our stocks are devoid of contaminating exosomes. We have also engineered a cell line forefficient BAC removal cloned a non-adherent cell line determined that HEK293 cells are superior to Vero-basedcells for optimal oHSV yield and developed a novel assay to assess DNA genome containing oHSV particles.Should any of the engineered oHSV vectors tested in the Projects prove efficacious the oHSV Production Corewould provide support in transfer of SOPs and QA/QC assays to cGMP facilities for the production/purificationtechnology for large-scale oHSV manufacture for possible Phase-I human clinical trials as seen withrQNestin34.5 and more recently with oHSV-CCL5 that underwent cGMP manufacturing by an outside vendor. +No NIH Category available Accounting;Achievement;Affect;Antibody Therapy;Authorship;Budgets;Clinical;Collaborations;Communication;Coordination and Collaboration;Data;Development;Diagnosis;Effectiveness;Ensure;Evaluation;Evaluation Research;Expenditure;Funding;Grant;Individual;Institution;Investigation;Journals;Knowledge;Laboratories;Malignant Glioma;Monitor;Oncolytic;Online Systems;Outcome;Program Research Project Grants;Publications;Reagent;Recommendation;Reporting;Research;Research Personnel;Resolution;Resources;Services;Solid Neoplasm;Telephone;Time;computerized data processing;data sharing;design;improved outcome;meetings;member;novel;oncolytic virotherapy;operation;programs;shared database;success;symposium;theranostics;tool;verbal Core A - Administrative Core PROJECT NARRATIVE ADMINISTRATIVE CORE (CORE A)The primary objectives of the Administrative Core are to provide overall administrative and fiscal support to allof the Projects and Cores of this Program Project focused on the discovery and development of novel antibodytherapies and theranostics for the treatment and diagnosis of solid tumors. This Core will serve as the communicationhub for the Program Project and is essential to the success of the investigations proposed in this P01. NCI 10712284 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5505 2785736 "CHIOCCA, E. ANTONIO" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 83459 51588 31871 PROJECT SUMMARY ADMINISTRATIVE CORE (CORE A)In this competing renewal P01 application the Administrative Core (Core A) will continue to provide criticalcentralized grant administration data processing communication and budget management for all the projectsand cores. This Core will also serve to amalgamate the investigators their experimental findings and theirideas evaluation of research efforts and critically direct the summary efforts toward maintaining a highlyintegrated program outcome. The Specific Aims of Core A are to: 1). Provide administrative services to theinvestigators. This includes the management of project supplies filing development of memos meetingminutes and communications covering all operations including publications; 2). Organize Program-relatedmeetings. Organize monthly or bi-monthly meetings/conferences of all P01 investigators; quarterly meetingsof the Program Steering Committee; annual meetings of the Scientific Advisory Board 3). Maintain programintegration activities. These include data sharing rapid publication efforts and identify and institute othernovel activities critical to maintaining and strengthening the integration of the program. 4). Provide overallfiscal review accounting and real time budgets analyses. This includes reports verbal communicationsreviews and forward-looking projections on expenditures. This Core is essential for maintaining a highlyintegrated program and effective communication of the P01 program. +No NIH Category available Adenosine;Adoptive Cell Transfers;Anti-CD47;Antibodies;Binding;Biodistribution;Biological Markers;Brain;CCR1 gene;CD47 gene;Cells;Cetuximab;Circulation;Cities;Clinical;Clinical Trials;Combined Modality Therapy;Data;Development;Dose;Eating;Engineering;Epidermal Growth Factor Receptor;Fc Receptor;Future;Glioblastoma;Goals;Good Manufacturing Process;Growth Factor;Herpes Simplex Infections;Herpesvirus 1;Human;IgG1;Immune;Immune response;Immunity;Immunocompetent;Immunologic Stimulation;Immunosuppression;Immunotherapy;In Vitro;Inflammatory;Investigational Drugs;Investments;Length;Link;Macrophage;Malignant - descriptor;Malignant Glioma;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Modeling;Monitor;Monoclonal Antibodies;Mus;NK Cell Activation;Natural Killer Cells;Normal tissue morphology;Oncolytic;Oncolytic viruses;Outcome;PD-1/PD-L1;PTPNS1 gene;Patients;Production;Publications;Publishing;RANTES;Research;Safety;Sampling;Schedule;Signal Transduction;Solid Neoplasm;Surface;System;T-Lymphocyte;Testing;Tissues;Toxic effect;Tumor-infiltrating immune cells;Viral;Virus;Virus Replication;anti-PD-1;anti-tumor immune response;antibody-dependent cell cytotoxicity;antibody-dependent cellular phagocytosis;arm;chemokine;chimeric antigen receptor T cells;cytokine;design;efficacy study;immune cell infiltrate;immune checkpoint blockade;immunoregulation;improved;in vivo;innovation;manufacture;migration;mouse model;neoplastic cell;novel;oncolysis;oncolytic virotherapy;patient prognosis;peripheral blood;pharmacokinetics and pharmacodynamics;pre-clinical research;preclinical efficacy;preclinical safety;preclinical study;prevent;receptor;recruit;response;scaffold;synergism;trafficking;treatment optimization;tumor;tumor microenvironment;tumor progression Project 4: Awakening immune responses to GBM by enhancing immune cell trafficking and activation with oHSV armed with Cetuximab-CCL5 and anti-CD47 antibody payloads. PROJECT NARRATIVE PROJECT 4Despite decades of research prognosis for patients suffering from malignant glioblastoma (GBM) remains poor.We engineered two innovative clinical-grade oncolytic viruses with multiple mechanisms of action and willevaluate their safety and efficacy against GBM. The proposed preclinical research arms oncolytic virus withpowerful payloads to maximize immune responses in the tumor microenvironment to enhance oncolyticvirotherapy efficacy for malignant GBM. NCI 10712283 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5504 6487056 "CALIGIURI, MICHAEL A" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 354954 335204 19750 PROJECT SUMMARY PROJECT 4The ultimate goal of this proposal is to develop a novel effective and safe oncolytic herpes simplex viral (oHSV)-based immunotherapy for the treatment of glioblastoma (GBM) a highly fatal and the most common malignantbrain tumor. oHSV treatment of GBM relies on cancer-specific replication of the virus leading to tumor destructionwith minimal toxicity to adjacent non-neoplastic tissue. Its safety in patients has been proven yet efficacy remainsto be improved. Project 4 will focus on enhancing anti-tumor immune responses by arming oHSVs with powerfulimmune-modulation payloads by testing two newly generated novel oHSVs termed OV-Cmab-CCL5 and OV-CD47-IgG1 designed to induce immune infiltration and block a checkpoint respectively as monotherapies inaddition to their combination. The two oHSVs are expected to synergize with each other to maximize immuneresponses in the GBM microenvironment by targeting both immune stimulation and immune suppression tocreate an overall pro-inflammatory tumor microenvironment which has been demonstrated to positively correlatewith patient survival in the rQNestin34.5 clinical trial of Project 2. We generated OV-Cmab-CCL5 an oHSVexpressing a secretable single-chain variable fragment of the epidermal growth factor receptor (anti-EGFR) IgG1antibody cetuximab linked to CCL5 by an Fc knob-into-hole system that produces heterodimers and preventshomodimers. To target a checkpoint on innate immune cells we also engineered oHSV to express a full-lengthsoluble anti-CD47 antibody with a human IgG1 scaffold (so-called OV-CD47-G1) for locoregional control ofGBM. The antibody CD47-IgG1 secreted by virus-infected GBM cells blocks the CD47 don't eat me signaland exerts additional functions of Fc receptor-mediated antibody-dependent cellular phagocytosis bymacrophages and antibody-dependent cellular cytotoxicity by NK cells. Our data show that in GBM mousemodels both oHSVs reduced tumor size and prolonged survival owing to enhanced anti-tumor immuneresponses. We hypothesize that OV-Cmab-CCL5 is a safe and effective agent that can improve GBM therapywith multiple mechanisms of action and the combination therapy of OV-Cmab-CCL5 and OV-CD47-IgG1 willhave better efficacy than the respective monotherapies. We have manufactured Good Manufacturing Practice(GMP)-grade viruses at our in-house GMP facility and now propose to conduct Investigational New Drug (IND)enabling studies so that our innovative oHSVs will be ready for testing in future clinical trials. Project 4 has threeSpecific Aims: (1) dissect systemic and regional immune responses identify a marker(s) in the peripheral bloodof mouse models or clinical samples from Project 2 that correlates with anti-tumor activity and improve theefficacy of rQnestin34.5.v2 in GBM mouse models after OV-Cmab-CCL5 treatment; (2) perform IND-enabling invivo efficacy and toxicity studies using GMP-grade OV-Cmab-CCL5; and (3) determine the preclinical efficacyand safety of OV-Cmab-CCL5 combined with OV-CD47-IgG1. We are confident that our approaches willprovide a novel effective and safe oncolytic virotherapy against GBM. +No NIH Category available Adenosine;Affect;Alternative Therapies;Antibodies;Antigen Presentation;Avastin;Biological;Brain Neoplasms;Cells;Clinic;Collaborations;Decision Making;Development;Diagnosis;Educational process of instructing;Equilibrium;Extracellular Matrix;Fab Immunoglobulins;G207;Generations;Glioblastoma;Glioma;Goals;Grant;Human;IgG1;Immune;Immune response;Immune system;Immunoglobulin Fragments;Individual;Infection;Inflammatory;Intracranial Neoplasms;Investigation;Japan;Knockout Mice;Length;Licensing;Malignant - descriptor;Malignant Glioma;Marketing;Mediating;Metabolic;Metastatic Melanoma;Modality;Mus;Neoplasm Metastasis;Oncolytic;Patients;Primary Brain Neoplasms;Primary Neoplasm;Process;Production;Program Research Project Grants;RANTES;Recurrence;Research;Research Personnel;Role;Safety;Signal Transduction;Solid Neoplasm;Stromal Cells;Testing;Therapeutic;Translating;Treatment Efficacy;Tumor Immunity;Viral;Virotherapy;Virus;Work;adenosine deaminase;anti-PD1 therapy;anti-cancer;bevacizumab;exosome;extracellular;immune system function;improved;melanoma;neoplastic cell;novel;oncolytic herpes simplex virus;oncolytic virotherapy;overexpression;patient prognosis;phase 1 study;programs;research clinical testing;synergism;tumor;tumor eradication;tumor microenvironment;vector Project 3: Circumventing extracellular Adenosine barrier to oncolytic virotherapy PROJECT NARRATIVE PROJECT 3Despite decades of research prognosis for patients suffering from malignant glioblastoma (GBM) remains poor.Oncolytic viral (OV) therapy is an exciting therapeutic modality that has been approved for non resectablemelanoma in USA and for brain tumors in japan. The proposed research in this project will investigate impact ofthis therapy on tumor and stromal cells and with a goal to improve virotherapy. NCI 10712282 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5503 8464810 "KAUR, BALVEEN " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 306607 267107 39500 PROJECT SUMMARY PROJECT 3Oncolytic viral (OV) therapy is a promising biological approach for treating solid tumors with oncolytic herpessimplex virus-1 (oHSV) being the most advanced. Indeed the FDA has approved the use of the oHSV Imlygicfor metastatic melanoma and more recently G47 marketed by Daiichi Sankyo gained conditional approval forGBM treatment in Japan. As a result of the close collaborations developed between the PIs on this programproject grant we have recently made an oHSV that encodes for PTEN (oHSV-P10). This virus shows significantantitumor efficacy against intracranial glioma in mice and has recently been licensed by Mesoblast for GMPproduction and IND enabling studies for Phase 1 clinical testing.Recent investigations into metabolic changes upon oHSV-P10 treatment led to the discovery of increased ATPproduction and release into the tumor microenvironment. While the extracellular ATP (eATP) can act as astimulator of the immune system its breakdown (via the ectoenzymes CD39 and CD73) produces adenosine(eAd) which eventually dampens anti-tumor immunity. CD73 activity represents a significant rate limiting step inthis process by converting ATP to adenosine. The overall goal of this application is to evaluate how oHSVantitumor activity may be improved by suppressing the conversion of extracellular ATP (immune stimulatory) toeAd (immune suppressive) through CD73 blockade.In preliminary results we have identified a novel human antibody that can recognize and functionally block humanCD73 activity. While we are pursuing the translational development of this antibody outside of this grant herewe propose to evaluate the impact of CD73 blockade using this antibody on oHSV anti-tumor efficacy. In thisproject proposal we hypothesize that CD73 inhibition will synergistically combine with oHSV therapy byenhancing anti-tumor efficacy. This research will elucidate the role of the ATP/adenosine balance in the tumormicroenvironment. In Aim 1 we will identify the human antibody fragment that efficiently inhibits CD73 functionin combination with oHSV-P10. In Aim 2: we will evaluate the impact of newly generated oHSV-P10-CD73 onanti tumor efficacy. In Aim 3 we will evaluate the impact of oHSV-P10-CD73 alone and in combination withAvastin (anti-VEGF frequently given to recurrent GBM patients) on efficacy and anti-tumor immunity. +No NIH Category available Adenosine;Antigen Presentation;Antitumor Response;B-Cell Antigen Receptor;B-Lymphocytes;Biological;Biological Markers;Biopsy Specimen;Blood;CD4 Positive T Lymphocytes;CD8B1 gene;Cells;Clinical;Clinical Trials;Data;Development;Down-Regulation;FDA approved;Failure;Funding;Future;Glioblastoma;Glioma;Growth;HLA Antigens;Herpes Simplex Infections;Human;Image;Immune;Immune response;Immunologics;Immunosuppression;Immunotherapy;In Situ;Infection;Infiltration;Japan;Magnetic Resonance Imaging;Malignant Glioma;Malignant Neoplasms;Measures;Mediating;Medical;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Oncolytic;Oncolytic viruses;Patient-Focused Outcomes;Patients;Phase I Clinical Trials;Plasma;Population;Pre-Clinical Model;Proteome;Publishing;Recurrence;Serum;Simplexvirus;Specimen;Stimulus;T cell response;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Therapeutic;Transcript;Tumor Antigens;Tumor Virus Infections;Tumor-Infiltrating Lymphocytes;Viral Antigens;Virus Diseases;Work;Xenograft procedure;antigen binding;cancer infiltrating T cells;chemokine;cytokine;cytotoxic;human subject;imaging biomarker;immune cell infiltrate;immune checkpoint blockade;immunotherapy trials;improved;melanoma;novel;oncolytic herpes simplex virus;oncolytic virotherapy;patient response;peripheral blood;phase I trial;potential biomarker;pre-clinical;programs;rate of change;response;success;tumor;tumor microenvironment;tumor-immune system interactions Project 2: Analyses of the human GBM microenvironment form clinical trial specimens treated with the oncolytic HSV rQNestin34v.2 PROJECT NARRATIVE PROJECT 2We are pursuing detailed immunologic biologic and imaging analyses on human GBMs that were treated in aphase 1 clinical trial with a novel oncolytic virus (OV). We find that this form of immunotherapy induces a rapidT cell response characterized by infiltration of treated GBMs with CD8+ CD4+ T cells and B cells. Both theabundance of transcripts related to T cell and B cell infiltrates and the imaging changes observed correlate withpatient responses. Proposed further analyses of tumors and peripheral blood will characterize changesassociated with a response as well as characterize the tumor and viral antigens that these immune cells respondto. These studies are needed to fully understand the results of this completed trial in order to inform avenues toimprove GBM immunotherapy. NCI 10712281 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5502 2785736 "CHIOCCA, E. ANTONIO" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 400081 243322 156759 PROJECT SUMMARY PROJECT 2Glioblastoma (GBM) arguably the deadliest of all cancers has remained impervious to treatments includingimmunotherapies that have seen evidence of success in other cancers. The profound immunosuppressivemicroenvironment in GBM thwarts immune activating stimuli like immune checkpoint blockade and significantlylimits activated T cell tumor infiltration. In fact GBM has been described as an immune-desert. As part of thisProgram Project we plan to analyze the immune infiltration in clinical specimens from human GBMs injectedwith a novel oncolytic virus (NCT03152318 clinicaltrial.gov). Oncolytic viruses (OV) are a form ofimmunotherapy being investigated clinically against multiple cancers with one oncolytic Herpes Simplex Virus(oHSV) approved in the USA against melanoma and a different oHSV approved against GBM in Japan. In theprevious funding period we started and finished a phase 1 clinical trial of the novel oHSV rQNestin34.5v.2 thataccrued 50 human subjects with recurrent high-grade gliomas. Preliminary data from tumors after in situadministration of this oHSV shows increased TILs. In addition we show that elevated T cell and/or B cell receptor(TCR/BCR) transcripts are associated with improved subject survival. Volumetric analyses of MRIs from subjectsalso show that growth rate changes correlate with increased response in treated patients. These published andpreliminary data thus provide a conceptual framework justifying in situ administration of OVs to revert theimmunosuppressive microenvironment of GBM into one whose cellular and molecular components becomeimmuno-activating. Based on the above we hypothesize that in situ oHSV administration profoundlychanges the human GBM microenvironment into one that is more favorable for immunotherapy. We planto utilize clinical GBM specimens obtained from the current clinical trial to validate the hypothesis via thefollowing Specific Aims: Aim 1. Validate the immune-activating changes in the human GBMmicroenvironment perturbed by oHSV in situ administration; Aim 2. Investigate subjects plasmaproteome serum cytokine/chemokine and MRI volumetrics as potential biomarkers of oHSV responseand correlate with TCR/BCR transcript abundance; and Aim 3. Utilize human GBM patient derived cellsand xenografts obtained from current clinical trial patients to characterize HLA-immunopeptidomes afteroHSV infection. These aims if successful will support the development of oHSV-elicited tumor antigens toboost the immune response to oHSV infection and thereby improve patient outcomes. In addition we will workwith Project 4 to develop the studies needed to bring the novel oHSVs to future clinical trials and with Project 1to add our discovered oHSV-tumor antigens to the preclinical therapeutic models with armed oHSV. With Project3 we will measure immunosuppressive metabolites in biopsy specimens. +No NIH Category available Adenosine;Affect;Aggressive behavior;American;Animals;Antigen-Presenting Cells;Antitumor Response;Area;Biological Assay;CD8-Positive T-Lymphocytes;Cell Death;Cell Line;Cell Separation;Cells;Characteristics;Clinic;Clinical Trials;Clonal Expansion;Collaborations;Data;Development;Dissociation;Engineering;Evaluation;Exhibits;Genes;Glioblastoma;Glycoproteins;Goals;Growth;HSV vector;Heterogeneity;Human;Immune;Immune checkpoint inhibitor;Immunosuppression;In Vitro;Infiltration;Inflammatory;Interleukin-12;Ligands;Macrophage;Malignant Glioma;Malignant neoplasm of brain;Mediating;Metabolic;Modeling;Modification;Monitor;Mus;Mutation;Myeloid Cells;Myeloid-derived suppressor cells;Nature;Oncolytic;Oncolytic viruses;Outcome;PD-1 inhibitors;PTEN gene;PVRL1;Pathway interactions;Patients;Performance;Phenotype;Population;Production;Proteins;Receptor Cell;Recruitment Activity;Recurrence;Resistance;Safety;Simplexvirus;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Time;Transgenes;Translating;Treatment Efficacy;Tumor Antigens;Tumor Cell Line;Tumor Immunity;Variant;Vertebral column;Viral;Viral Antigens;Viral Genes;Viral Load result;Virus;Virus Replication;adaptive immune response;adenosine deaminase;anti-cancer;arm;cell killing;clinical development;combinatorial;design;effective therapy;effector T cell;efficacy evaluation;efficacy study;exhaust;immunogenic;improved;in vitro activity;in vivo;in vivo evaluation;insight;mouse model;mutant;neoplastic cell;novel;oncolysis;oncolytic herpes simplex virus;oncolytic virotherapy;patient derived xenograft model;patient response;pre-clinical;prevent;programmed cell death protein 1;recruit;response;single-cell RNA sequencing;tumor;tumor microenvironment;vector Project 1: Treatment of GBM using an oncolytic HSV engineered to improve immunogenic tumor destruction PROJECT NARRATIVE PROJECT 1Glioblastoma (GBM) is a lethal form of brain cancer that affects approximately 10000 Americans annually.Oncolytic viruses (OV) are a promising therapeutic option for GBM patients; however durable treatment willrequire both vigorous viral oncolytic activity and awakening of anti-tumor immunity. We propose to enhance theanti-cancer efficacy of an existing oHSV platform (Project 2) through vector modifications intended to improveviral oncolysis and by arming the virus with genes that support the induction of anti-tumor immunity. NCI 10712280 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 5501 1860763 "GLORIOSO, JOSEPH C" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 343160 303660 39500 PROJECT SUMMARY PROJECT 1The effective treatment of glioblastoma (GBM) using oncolytic Herpes Simplex Virus (oHSV) will almost certainlyrequire both broad intratumoral virus spread and tumor destruction and virus-induced anti-tumor immunity. Thetumor microenvironment (TME) must be supportive of adaptive immune responses through the recruitment ofactive tumor antigen presenting cells and responsive CD8+ T cells. However GBM tumors are notoriously coldtumors that are metabolically adept at preventing the development of a pro-inflammatory TME. This immune-suppressive GBM TME exhibits upregulated expression of (1) the checkpoint proteins TIGIT and PD-1 and theirrespective inhibitory ligands and (2) the ectoenzymes CD39 and CD73 that increase local production ofadenosine (ADO); both pathways confer immunosuppression and tumor aggression. Here we propose toimprove the anti-tumor activity of rQNestin34.5v.1 an F strain oHSV-1. This virus has been engineered to allowtumor-specific expression of natural viral genes that thwart innate anti-viral cellular responses (e.g. ICP34.5).rQNestin34.5v.2 a modified version of rQNestin34.5v.1 with GFP removed was shown to be safe in a patienttrial with evidence of intratumoral viral antigen expression for extended time periods (NCT03152318). Threeaims are designed to evaluate rQNestin34.5v.1 enhancement in patient derived xenograft (PDX) models and insyngeneic GBM mouse models. We propose in Aim 1 to test the hypothesis that syncytial mutant variants ofrQNestin34.5v.1 will exhibit enhanced oncolytic activity augmenting viral spread and persistence within thetumor. In Aim 2 we propose to test the hypothesis that the therapeutic efficacy of rQNestin34.5v.1 can beimproved by arming the vector with a combination of IL-12 the checkpoint inhibitors (CPI) anti-PD-1 and anti-TIGIT (Aim 2A) or with the adenosine deaminase (ADA) gene (Aim 2B). The efficacy of ADA-armed oHSV willbe tested in combination with oHSV expressing PTEN and anti-CD73 (oHSV-P10-CD73; Project 3) anddepending on the outcome both arming genes will be introduced into a single vector for treatment efficacystudies. Analysis of human clinical trial data has allowed Project 2 to define a TME profile characteristic ofrQNestin34.5v2 responders demonstrating a correlation between patient response and increased TCR diversity.In Aim 3 we will test the hypothesis that rQNestin34.5v.1 and armed derivatives will increase the accumulationof effector T cell populations and induce clonal expansion of T cells that recognize viral- and tumor-specificantigens. Aim 3 analyses will compare the armed vectors generated in Aim 2 to those generated by Projects 3and 4 and will allow us to establish correlations across multiple oHSV variants with respect to clonal T cellexpansion and animal survival. The proposed vector modifications may substantially improve rQNestin34.5v.1performance and effectively increase the number of tumors responsive to oHSV treatment thereby potentiallyproviding a novel vector suitable for clinical development. +No NIH Category available Adenosine;Antibodies;Back;Bioinformatics;Biological;Biometry;CD47 gene;Cities;Clinic;Clinical;Clinical Data;Clinical Trials;Dana-Farber Cancer Institute;Data;Eating;Effectiveness;Engineering;Funding;Genes;Glioblastoma;Herpesvirus 1;Hospitals;Human;Immune;Immune system;Immunologic Stimulation;Immunologics;Immunosuppression;Immunotherapy;In Situ;Learning;Macrophage;Malignant Glioma;Malignant Neoplasms;Malignant neoplasm of brain;Medical;Medical center;Molecular;Myeloid Cells;Ohio;Oncolytic Immunotherapy;Oncolytic viruses;Pathway interactions;Patients;Phase I Clinical Trials;Pre-Clinical Model;Preclinical Testing;Prediction of Response to Therapy;Principal Investigator;Production;RANTES;Recurrence;Research;Resistance;Signal Transduction;Solid Neoplasm;Testing;Therapeutic;Translating;Universities;Vertebral column;Woman;arm;bench to bedside;biobank;checkpoint inhibition;chemokine;clinical translation;design;efficacious treatment;experience;first-in-human;human subject;improved;insight;medical schools;neoplastic cell;next generation;notch protein;novel;oncolytic herpes simplex virus;oncolytic virotherapy;palliative;peripheral blood;phase I trial;proteomic signature;response;service utilization;standard of care;success;survival outcome;timeline;transcriptomics;tumor;tumor microenvironment Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas OVERALL PROJECT NARRATIVEGlioblastoma (GBM) remains a fatal brain cancer with little progress in therapy. We aim to improveimmunotherapy against this cancer by exploiting the capacity of oncolytic viruses (OVs) to rapidly change themicroenvironment of the tumor from one that is profoundly immunosuppressive to one that is more immune-activated. We have generated novel OVs and have tested one in a first in human clinical trial over the lastfunding cycle. Data from this trial is now informing the next steps in improving OV immunotherapy: we proposeclinical trial scientific correlate analyses that will lead to improved versions of OVs for clinical trials subscribingto the concept from the lab bench to the clinic and back to the lab bench. The ultimate impact from our findingswill result in improved patient survival outcomes. NCI 10712279 9/19/23 0:00 PAR-20-077 2P01CA163205-11 2 P01 CA 163205 11 "UNDALE, ANITA H" 2/7/13 0:00 8/31/28 0:00 ZCA1-RPRB-J(M)S 2785736 "CHIOCCA, E. ANTONIO" "CALIGIURI, MICHAEL A" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 1883308 NCI 1504567 378741 OVERALL PROJECT SUMMARYGlioblastoma (GBM) and recurrent GBM (rGBM) is arguably one of the most fatal of cancers: it remainsimpervious to treatment with the current standard of care (SOC) therapies and numerous clinical trials (includingimmunotherapy) have failed to meet end points for FDA approval. This makes GBM/rGBM an unmet medicalneed. The unresolved problem we are trying to solve is that the rGBM tumor microenvironment (TME) ishighly immunosuppressive. To revert this immunosuppression we and others have been utilizing direct intra-tumoral administration of oncolytic viruses (OVs) based on herpes simplex virus type 1 (HSV1). During thecurrent funding cycle (2018-2023) the Principal Investigators of this P01 have contributed several discoveriesboth in preclinical models of GBM and in a 50 subject phase 1 clinical trial of recurrent GBM (rGBM). Majorfindings relate to how human subject rGBMs change in response to oHSV (Project 2/ Chiocca) how Notchsignaling of myeloid cells in the GBM TME impedes oHSV function (Project 3/Kaur) and how to further immune-stimulate oHSVs by arming with immune-stimulatory genes (Project 1/Glorioso and Project 4/Caligiuri).Lessons learned informs the overall hypothesis for this P01: oHSVs induce a rapid and persistently inflamedrGBM microenvironment correlating with efficacy in human subjects and informing further therapeuticexploitation by arming oHSVs with additional immunostimulatory genes. To test this overall hypothesisthe four Projects will address the following overall aims: Overall Aim 1 Validate the findings that improvedsurvival for human subjects treated with oHSV correlates with rGBM and peripheral blood biologictranscriptomic and proteomic signatures (Projects 2 3 and 4); and Overall Aim 2- Engineer andpreclinically test the next-generation oHSVs armed with selected immune-activating genes focusingon clinical translation for a new phase 1 trial (Projects 1 3 and 4) To support the efforts of these 4Projects we will continue to utilize the services of the oHSV Production Core (Core 1/ Goins) of the GBMBiorepository Core (Core 2/Ligon) and of the Biostatistics and Bioinformatics Core (Core 3/Mo & Zhang). Theproposed timeline for the successful completion of the overall aims is 5 years. The principal investigators of thisP01 espouse the principle of from the lab to the clinic and back to the lab where the lessons from our treatedpatients can be applied to build more efficacious therapies for this fatal cancer. The potential impact of thisresearch is that we are proposing to not only test preclinically and clinically potentially impactful oncolyticimmunotherapies for an incurable cancer but we have shown commitment to analyze the biologic andimmunologic effects in treated human subjects so that we can iteratively learn possible pitfalls and devisesolutions for patients with GBM. 1883308 +No NIH Category available Leveraging Social Media to Increase Lung Cancer Screening Awareness Knowledge and Uptake in High-Risk Populations PROJECT NARRATIVEThe proposed research is relevant to public health because leveraging a social media platform to increaseawareness among individuals eligible for lung cancer screening is a novel untapped platform to reachvulnerable high-risk individuals. Thus the proposed research is relevant to the cancer research mission of theNational Cancer Institute and more broadly the National Institutes of Healths mission to seek fundamentalknowledge about the nature and behavior of individuals and the application of that knowledge to enhancehealth lengthen life and reduce illness and disability through early detection of lung cancer. NCI 10712275 12/16/22 0:00 PA-21-268 7R01CA263662-02 7 R01 CA 263662 2 "BLAKE, KELLY D" 10/1/22 0:00 8/31/27 0:00 Health Promotion in Communities Study Section[HPC] 11849887 "CARTER-BAWA, LISA " Not Applicable 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 10/1/22 0:00 8/31/23 0:00 393 Non-SBIR/STTR 2022 731657 NCI 426312 305345 PROJECT SUMMARY/ABSTRACTLung cancer screening is recommended by the U.S. Preventive Services Task Force (USPSTF) has thepotential to detect lung cancer at earlier more treatable stages. However population uptake of lung cancerscreening has been abysmal. It has been 7 years since the USPSTF released its official recommendation yetless than 5% of screening-eligible Americans have been screened. Screening-eligible individuals are generallyunaware about the option of finding lung cancer early through screening and our teams prior work revealedthat in addition to lack of awareness screening-eligible individuals in the U.S. do not screen when they areaware because of perceived barriers to screening. If high-risk patient populations are not aware that lungcancer screening exists then formative work is needed to increase awareness about screening. It is essentialto employ novel community-focused strategies to increase awareness about lung cancer screening to reachdiverse screening-eligible individuals who might not otherwise learn about the option to screen. Our long termgoal is to increase screening uptake among appropriate high-risk individuals nationwide. Our overall objectivein this application is to test the effectiveness of: 1) leveraging a social media-based platform to reachscreening-eligible individuals in the community upstream before they engage with the healthcare system and2) a novel tailored health communication and decision support intervention related to lung cancer screening(LungTalk). Our central hypothesis is two-fold: 1) Facebook targeted advertisement will be a successfulplatform to reach high-risk individuals unaware of lung cancer screening; and 2) tailored compared to non-tailored lung cancer screening information will increase knowledge and improve health beliefs about screeningand subsequent screening uptake. Our study is informed by our prior studies which led us to consider theimportance of increasing awareness and knowledge on a population level from the screening-eligibleindividuals perspective as a precursor to health behavior change. Successful use of Facebook to recruitscreening-eligible individuals in our prior studies also led us to consider how social media might be used toincrease awareness of lung cancer screening and as a platform to link the screening-eligible individual with atailored health communication and decision support intervention that has the potential to influence screeningbehavior and uptake. Using a randomized controlled trial design we will randomize 500 screening-eligibleindividuals recruited through Facebook nationwide to receive either a tailored intervention (LungTalk) or non-tailored ACS Lung Screening Informational Video. Specific aims are to (1) examine the use of a social mediaplatform to reach high-risk individuals eligible for lung screening; (2) compare the effectiveness of a computer-tailored health communication tool to a web-based ACS Lung Screening Informational Video to improve lungcancer screening: a) knowledge; b) health beliefs; and c) screening uptake and completion in a high-riskpopulation; and (3) Explore the sustainability of a social media-based approach among key stakeholders. 731657 +No NIH Category available Acceleration;Address;Adherence;Adverse event;Affect;Aftercare;Aging;Biology;Body Composition;Body fat;Bone Mineral Contents;Cancer Survivor;Characteristics;Clinical;Colorectal Cancer;Creatine;Data;Diagnosis;Dietary Intervention;Economic Burden;Effectiveness;Elderly;Etiology;Exercise;Future;Goals;Health;Healthcare Systems;Hospital Costs;Individual;Inflammation;Intervention;Investigation;Malignant Neoplasms;Malnutrition;Measures;Mitochondria;Molecular;Morbidity - disease rate;Muscle;Muscle Cells;Muscle function;Natural Compound;Nutritional Study;Outcome;Outcome Measure;Physical Function;Placebos;Play;Population;Prognosis;Quality of life;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research Priority;Role;Safety;Sampling;Signal Transduction;Supplementation;Testing;Therapeutic;Thinness;Treatment-related toxicity;Tumor Burden;Woman;acceptability and feasibility;arm;cancer care;cancer diagnosis;cancer therapy;chemotherapy;colon cancer patients;colorectal cancer treatment;cost estimate;density;design;dietary supplements;disability;exercise intervention;exercise training;experience;health related quality of life;innovation;insight;intervention effect;lifestyle intervention;men;mitochondrial dysfunction;mortality;multimodality;muscle form;muscle strength;novel;physical inactivity;pilot trial;prognostic;protein degradation;recruit;reduced muscle mass;resistance exercise;response;sarcopenia;secondary outcome;side effect;skeletal muscle wasting;success;trial comparing The Feasibility and Acceptability of Resistance Training and Creatine Supplementation to Promote Physical Function in Sarcopenic Colorectal Cancer Survivors Sarcopenia defined as low muscle mass and function affects up to 60% of individuals diagnosed withcolorectal cancer and is associated with treatment complications poor prognosis and reduced overall andcancer-related survival. Currently there have been no investigations into therapeutic strategies to amelioratethe burden of sarcopenia in cancer. The goal of this proposed study is to examine the feasibility andacceptability of creatine supplementation and resistance training in individuals who are sarcopenic aftertreatment for colorectal cancer and to measure outcomes related to body composition physical function andquality of life. NCI 10712237 6/14/23 0:00 PAR-21-341 1R21CA281951-01 1 R21 CA 281951 1 "PERNA, FRANK" 7/1/23 0:00 6/30/25 0:00 Biobehavioral Medicine and Health Outcomes Study Section[BMHO] 14924572 "FAIRMAN, CIARAN " Not Applicable 6 OTHER HEALTH PROFESSIONS 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF PUBLIC HEALTH 292080001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 202696 NCI 140250 62446 Colorectal cancer is the third most commonly diagnosed cancer in the world. Sarcopenia defined as a loss ofskeletal muscle mass and function is highly prevalent in colorectal cancer with rates of up to 60% reported.Sarcopenia etiology in cancer is multifactorial with aging and inactivity compounded by treatment toxicitiesmalnutrition tumor burden and high-grade inflammation. Consequently its unlikely that unimodalinterventions will be sufficient to overcome the burden of sarcopenia in this population. Creatine monohydrateis a naturally occurring compound in the body that plays a critical role in energy provision during exercise.4Creatine is the most widely studied nutritional supplement to date with well over 1000 studies establishing itssafety and effectiveness in men women and older adults in addition to other clinical populations. There isstrong and consistent evidence that creatine supplementation can enhance the positive adaptations toresistance training in older adults and clinical populations. Therefore there is strong potential for theapplication of creatine and resistance training to offset the decline in muscle mass and function after cancertreatment. The purpose of the proposed study is to examine the feasibility and acceptability of creatinesupplementation combined with resistance exercise compared to resistance exercise alone in individualstreated for colorectal cancer who are sarcopenic. We propose a randomized controlled pilot trial examining theeffects of 10-week multimodal resistance exercise and creatine supplementation (EXSUPP) (n=20) relative toresistance exercise alone (EXPLA) (n=20) in individuals treated for colorectal cancer who have sarcopenia.The specific aims of this project are to 1) determine the feasibility and acceptability of the intervention incolorectal cancer patients? diagnosed with sarcopenia after cancer treatment 2) compare the effects of anexercise and creatine supplementation intervention (EXSUPP) to exercise alone (EXPLA) on bodycomposition muscle strength physical function and quality of life and 3) explore muscle molecular-leveladaptations i.e. mitochondrial health and protein turnover in response to the interventions. This project will beone of the first to combine exercise with creatine specifically targeting sarcopenia in individuals previouslytreated for colorectal cancer. This project is directly in line with the priority research initiative from the NCICancer MoonshotSM to minimize Cancer Treatments Debilitating Side Effects. Our trial is innovative inaddressing one of the most important health problems for individuals treated for colorectal cancer in that it willbe the first to 1) examine the feasibility and acceptability of a multimodal exercise and nutritional interventionrelative to exercise alone in individuals treated for colorectal cancer who are sarcopenic and 2) explore themolecular mechanisms underpinning the response to exercise and nutritional interventions. 202696 +No NIH Category available Area;Authorization documentation;Basic Science;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Catchment Area;Charge;Clinical Cancer Center;Clinical Oncology;Clinical Protocols;Clinical Research;Clinical Trials;Committee Members;Communication;Conduct Clinical Trials;Data;Discipline;Disease;Education;Electronics;Ensure;Evaluation;Faculty;Funding;Goals;Guidelines;Individual;Industry;Institution;Institutional Review Boards;Intervention;Intervention Studies;Kentucky;Laboratory Research;Malignant Neoplasms;Mission;Modification;Monitor;Observational Study;Outcome;Pathology;Patients;Peer Review;Performance;Pharmacology;Policies;Population Heterogeneity;Prevention;Process;Protocols documentation;Radiology Specialty;Recommendation;Reporting;Research;Research Personnel;Resources;Review Committee;Safety;Scientific Advances and Accomplishments;Structure;System;Time;Underserved Population;Universities;Vulnerable Populations;authority;cancer clinical trial;cancer prevention;cancer research center director;clinical care;clinical translation;clinically relevant;community engagement;expectation;human subject;innovation;interest;member;mid-career faculty;patient population;professor;success;trial enrollment Protocol Review and Monitoring System Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements. NCI 10712125 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 5471 1926108 "ANTHONY, LOWELL B" Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 224973 147041 77932 PROJECT SUMMARY/ABSTRACT In accordance with CCSG guidelines the Markey Cancer Center (MCC) has established appropriatemechanisms for ensuring rigorous scientific oversight of cancer clinical trials through the Protocol Review andMonitoring System (PRMS). Protocols undergo initial scientific review by Clinical Care and Research Teams(CCARTs) including assessment of relevance to the patient population fit within the portfolio and interest ofinvestigators. In 2019 the MCC formalized first-stage review by CCARTs expanding structure and functionand enhancing communication with the Protocol Review and Monitoring Committee (PRMC). FollowingCCART approval review for operational feasibility is completed by the Feasibility Review Committee. The goalof these reviews is to ensure that only the highest quality trials are submitted to the PRMC. The MCC PRMC isresponsible for independent peer-review of scientific merit feasibility and prioritization of new protocols.Following activation PRMC monitors protocols for ongoing scientific progress and has ultimate authority tosuspend or close protocols that do not meet MCC scientific standards. The Specific Aims of the PRMS are: 1)Optimize the PRMS structure and process for sufficient size and breadth of expertise to conduct a criticalrigorous and fair scientific review of all institutional cancer-related research protocols involving human subjects;2) Ensure that clinical trials conducted at MCC support and enable the scientific mission of the center arerelevant to patients in the catchment area including those from underserved groups and enhance theinclusion of diverse populations; 3) Safeguard the scientific integrity feasibility and prioritization of all cancer-related interventional clinical research of the MCC and apply rigorous scientific review criteria in a consistentand objective manner; 4) Oversee the progress and performance of all interventional cancer clinical trials toensure their continued scientific merit and accomplishment of the scientific goals of the protocol and the MCC.Highlights during the funding period include incorporation of first-stage reviews into PRMS frameworkenhanced member education expanded representation in key scientific areas and strengthened quorumexpectations. From 2019 to 2021 the CCARTs reviewed 409 clinical trials for potential opening approved 294(72%) and declined 115 (28%); the Feasibility Review Committee declined 20 (4%) due to lack of feasibility.From 2019 to 2021 the PRMC reviewed and/or prioritized 239 new protocols of which 230 were approved and9 were disapproved. In the past three years the PRMC reviewed 552 active protocols for scientific progressclosing 29 protocols due to low accrual or a change in scientific merit. The PRMC continuously assesses itsown performance. In 2021 median time from PRMC submission to approval was 8 days overall (7 national 8industry 24 institutional). As the MCC has matured the PRMS has continued to optimize the first- and second-stage review and to increase scientific rigor objectivity and scrutiny of each trials relevance to our diversepopulation in order to ensure MCC brings the highest quality clinical research to Kentuckians. +No NIH Category available Acceleration;Address;Advocacy;Advocate;Appalachian Region;Award;Back;Black Populations;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cervical;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Colorectal;Communities;Community Health Education;Community Outreach;Consultations;Data;Data Sources;Development;Disparity;Dissemination and Implementation;Education;Education and Outreach;Electronics;Environmental Exposure;Equity;Evidence based practice;Feedback;Fostering;Funding;Geography;Goals;Grant;Head and neck structure;Health Services Accessibility;Hepatitis C virus;Hispanic Populations;Hospitals;Human Papilloma Virus Vaccination;Human Papillomavirus;Incidence;Individual;Investments;Kentucky;Leadership;Lung;Malignant Neoplasms;Monitor;NCI Center for Cancer Research;Needs Assessment;Obesity;Outcome;Patient Education;Patients;Persons;Policies;Population;Poverty;Preventive service;Printing;Process;Professional Practice;Quality Indicator;Race;Recording of previous events;Reporting;Research;Research Personnel;Research Priority;Risk Factors;Rural;Screening for cancer;Shapes;Smoking;Therapeutic Trials;Tobacco;Training;Training Activity;Underrepresented Minority;Universities;Virus;Visit;cancer care;cancer health disparity;cancer site;colon cancer screening;community engagement;ethnic disparity;evidence based guidelines;geographic disparity;health equity;improved;innovation;lung cancer screening;meetings;melanoma;member;mortality;outreach program;programs;racial disparity;screening program;social media;socioeconomics;volunteer Community Outreach and Engagement Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements. NCI 10712124 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 5470 8310976 "HULL, PAMELA CARMEN" Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 224973 147041 77932 PROJECT SUMMARY/ABSTRACT The University of Kentucky (UK) Markey Cancer Center (MCC) embraces the entire Commonwealth ofKentucky as its catchment area. Despite notable recent advances Kentucky has the highest all-site cancerincidence and mortality in the U.S. driven largely by socioeconomic geographic and racial/ethnic inequities.With a 47-year history the goal of MCC Community Outreach and Engagement (COE) is to engagecommunities practitioners and researchers in mutually beneficial collaborations to accelerate health equity andreduce the burden of cancer. MCCs long-standing COE programs include regionally-based communityoutreach management of the states cancer coalition and policy efforts and the MCC Affiliate Network(MCCAN) MCCs innovative clinical outreach program with 19 community-based (non-UK) hospitals acrossthe state. Since 2018 MCC made strategic investments to enhance COE strengths and further integrateresearch and cancer control. COEs previous needs assessment shaped the FY19-23 MCC ResearchPriorities. Key accomplishments include conducting the 2021 Kentucky Cancer Needs Assessment (KY CNA)launching new research engagement initiatives (e.g. Community Impact Ambassadors as Research Programliaisons Research Advocacy Program Clinical Trial Referral Ambassadors internal COE funding) and cancercontrol activities with extensive reach (e.g. training/technical assistance policy changes individual educationfacilitating access to services). Building on existing efforts and FY24-28 MCC Research Priorities COESpecific Aims are to: 1) Monitor cancer burden and disparities in Kentucky and identify community-drivenpriorities. In addition to monitoring cancer burden and disparities and conducting the next KY CNA in 2026each year COE will carry out a focused needs assessment on a specific population to address data gaps anddisparities identified in the 2021 KY CNA. 2) Foster impactful research that responds to community needs andpromotes equity. COE will expand the Research Advocacy Program with a training module for basic andclinical researchers and Rapid Feedback Sessions. COE will add two new strategies to facilitate clinical trialparticipation: providing culturally appropriate patient and community education including testimonial videosand assisting studies prioritized for underrepresented minority accruals through consultations and diverseresearch advocate feedback. 3) Disseminate and implement sustainable evidence-based guidelines practicesand policies. COE is currently using the 2021 KY CNA to guide development of the states new five-yearCancer Action Plan. Next COE will assess its portfolio of community cancer control programs to strategicallyrealign them with the new state plan to address gaps leverage partnership opportunities and maximize impact.IMPACT: COE has made important advances in synergizing MCC research and cancer control efforts withstatewide partners and significant contributions to population-level improvements in colon and lung cancerscreening and outcomes smoking and HPV vaccination. COE is poised to further accelerate MCC impact. +No NIH Category available Adherence;Adult;Age;Appalachian Region;Awareness;Biometry;COVID-19 pandemic;Cancer Center;Cancer Center Support Grant;Catchment Area;Child Care;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Research Associate;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Community Outreach;County;Data;Data Collection;Data Management Resources;Dedications;Development;Devices;Disease;Education;Electronics;Ensure;Ethnic Origin;Faculty;Female;Gender;Goals;Improve Access;Individual;Industry;Infrastructure;Institution;Institutional Review Boards;Intervention;Investigational Drugs;Investigational Therapies;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Minority;Mission;Molecular;Monitor;NCI Center for Cancer Research;National Cancer Institute;National Clinical Trials Network;Needs Assessment;Nurses;Office Management;Patients;Pediatric Oncology;Performance;Policies;Population;Procedures;Process;Protocol Compliance;Protocols documentation;Race;Reporting;Research;Research Activity;Research Design;Research Personnel;Research Priority;Research Support;Resource Allocation;Resource Sharing;Risk;Safety;Services;Site;Special Population;Specialist;System;Testing;Therapeutic Trials;Time;Toxic effect;Training;Training and Education;Translational Research;Underserved Population;United States National Institutes of Health;Universities;Vision;Woman;anticancer research;cancer care;cancer health disparity;clinical care;community engagement;data management;design;experience;improved;industry partner;investigator-initiated trial;oncology program;operation;patient engagement;patient oriented;patient population;patient safety;programs;protocol development;quality assurance;response;success;tool;tumor Clinical Protocol and Data Management Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements. NCI 10712123 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 5469 6772940 "ARNOLD, SUSANNE M" Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 224973 147041 77932 PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) Clinical Protocol and Data Management (CPDM) facilitates all clinicalcancer research at the University of Kentucky. CPDMs Specific Aims are: 1) To provide comprehensivecentralized support for MCC clinical research activities; 2) To ensure the safety compliance and quality of allclinical cancer research performed at the center and MCCs Research Network (MCCRN) in accordance withthe Data Safety and Monitoring Plan and NCI requirements; 3) To integrate all efforts of the Cancer Center toprovide clinical trial access to MCCs patients including women minorities underserved populations andindividuals across the lifespan; and 4) To provide ongoing education and training services for CPDM andMCCRN staff and faculty that enhance quality diversity consistency and efficiency of teams and lead toincreased engagement with MCCs catchment population. The CPDM facilitates clinical research through theClinical Research Offices four units (72 FTEs) Protocol Development Teams (10 FTE) a Quality AssuranceProgram (5 FTE) and MCCRN (11 FTE) which provide centralized expertise for development coordinationand execution of trials. In 2022 the Clinical Research Office managed 369 active trials211 cooperativegroup 113 industry sponsored and 45 investigator-initiated (12 investigational new drug-enabling). MCCsstatewide infrastructure supports research referral and accrual within the catchment area. As the CPDM hasmatured the center increased clinical research engagement to 98 of Kentuckys 120 counties with 18753 totalaccruals (8857 interventional; 9896 non-interventional 2018-2022). The Quality Assurance Program andAudit Committee function independently from other CPDM components to support education safety andquality of trial conduct. All cancer trials are guided by MCCs Data and Safety Monitoring Plan which providesoversight in accordance with NCI CCSG requirements. The Data and Safety Monitoring Committee ensurespatient safety and protocol compliance by staff and investigators. MCC leaders investigators and staff promotethe inclusion of women minorities and Kentuckys special population of Appalachia in clinical cancer researchwith impactful engagement of females (77% of all interventional accrual 2018-2022) and AppalachianKentuckians (61%). Enhanced efforts have increased minority trial participation to reflect this patientpopulation focusing on important cancer disparities such as lung and prostate cancers. In support of NIHpolicies MCC strives for inclusion of individuals across the lifespan in clinical research. In 2021 40% oftherapeutic trial accruals were adults 65 or older surpassing national averages. Cancer care for children isprovided by one of two comprehensive pediatric oncology programs in the state. MCC is the first center in theregion to offer germline testing to all pediatric oncology patients supported by the Molecular Tumor Boardinterpretation of results. +No NIH Category available Address;Area;Award;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Community Participation;Comprehensive Cancer Center;Data;Dedications;Development;Ecosystem;Education;Electronics;Ensure;Evaluation;Extramural Activities;Fostering;Funding;Funding Agency;Future;Goals;Grant;Guidelines;Institution;Investments;Kentucky;Leadership;Link;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Obesity;Participant;Philanthropic Fund;Pilot Projects;Population;Population Sciences;Prevention;Process;Program Description;Program Research Project Grants;Racial Equity;Recurrence;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Secure;Strategic Planning;Translational Research;Universities;Vision;Vulnerable Populations;Work;anticancer research;cancer genomics;cancer prevention;cancer research center director;cellular oncology;clinical center;clinically relevant;community engagement;design;evidence base;flexibility;health disparity;innovation;interest;member;molecular oncology;novel;patient oriented;programs;recruit;screening;translational cancer research;translational oncology Developmental Funds Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements. NCI 10712122 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 5468 1901765 "EVERS, BERNARD MARK" Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 224973 147041 77932 PROJECT SUMMARY/ABSTRACT CCSG Developmental Funds are a vital mechanism for furthering the strategic mission and vision of theMarkey Cancer Center (MCC) through pilot funding to MCC members and support of emerging SharedResource Facilities. During the current funding period Developmental Funds helped support 17 basic clinicalpopulation and translational cancer research pilot projects from MCCs Molecular and Cellular OncologyCancer Prevention and Control and Translational Oncology Research Programs stimulating a high return oninvestment of $15.16 per CCSG dollar. These projects have fostered five new extramurally funded grants andhave opened clinical trials that accrued 241 new participants. In close alignment with MCCs scientific direction14 of the 17 projects are on topics that correspond to the centers FY19-23 Research Priorities for the currentfunding period including those involving clinical and health disparity issues within the MCC catchment area.Outside of the routine CCSG pilot award process MCC also elected to use Developmental Funds to supporttwo interdisciplinary teams of researchers who ultimately successfully applied for a CCSG Supplementdesigned to foster the development of multiproject research programs. Developmental Funds were alsoinvested in two developing Shared Resource Facilities (Oncogenomics and Patient-Oriented and PopulationSciences) which have supported research projects from all three MCC programs and after careful annualevaluation have been approved by the MCC Directors Council as fully functioning resources presented assuch in this CCSG application. Leveraged with philanthropic investment and institutional supportDevelopmental Funds will also be strategically allocated during the upcoming funding period to address twoSpecific Aims: 1) Cultivate innovative and collaborative science through the use of pilot grants in areas thatalign with MCCs FY24-28 Strategic Plan and Research Priorities and reflect the scientific aims of MCCs threeResearch Programs; and 2) Foster deeper collaboration across the UK campus through strategic partnershipsto fund innovative pilot awards and ensuring the continuation of community input through the CCSG pilotreview process. To achieve these aims MCC requests $150000 per year in Developmental Funds allowingthe center to achieve several key objectives outlined in the Strategic Plan including fostering research thataligns with its research priorities expanding transdisciplinary opportunities for research teams and increasingclinical studies that are informed by MCC basic research. MCC will also continue partnerships with other majorresearch centers across campus allowing cancer research to have an impact far beyond what MCC alone canachieve and will foster the maturity of a new process by which Community Advisory Board members directlycontribute to the CCSG pilot reviews allowing community input to inform and influence funding decisions. +No NIH Category available Address;Area;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Clinical;Clinical Research;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Development;Education;Effectiveness;Electronics;Ensure;Epidemiologist;Equity;Evaluation;Fostering;Funding;Future;Goals;Growth;Healthcare;Infrastructure;Institution;Intervention Trial;Investments;Kentucky;Lead;Leadership;Legal patent;Malignant Neoplasms;Mentors;Mission;Molecular;NCI Center for Cancer Research;Names;Needs Assessment;Patients;Population Sciences;Positioning Attribute;Preparation;Prevention;Process;Recording of previous events;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Secure;Source;Strategic Planning;Time;Training;Training and Education;Universities;University resources;Vision;Vulnerable Populations;Work;anticancer research;cancer education;cancer genomics;cancer prevention;cancer research center director;clinical care;clinical translation;community engagement;community organizations;diversity and inclusion;equity diversity and inclusion;experience;functional status;improved;meetings;novel therapeutics;outreach;patient oriented;programs;recruit;success;translational pipeline;translational scientist;tumor metabolism Leadership Planning and Evaluation Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements. NCI 10712121 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 5467 1901765 "EVERS, BERNARD MARK" Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 224974 147042 77932 PROJECT SUMMARY/ABSTRACT B. Mark Evers MD (TO) Director of the Markey Cancer Center (MCC) is assisted by eight Senior Leaderswho support activities in cancer research outreach education and training diversity and inclusion clinical careand administration. With the exception of some notable additions during this reporting period that haveexpanded the effectiveness and expertise of the Senior Leadership team this highly experienced group ofleaders has worked together since 2009 overseeing MCCs initial NCI designation in 2013 a successfulrenewal application in 2018 the preparations for this renewal and quest for Comprehensive Cancer Centerstatus as well as a future five-year outlook in the form of MCCs FY24-28 Strategic Plan. MCCs SeniorLeaders leverage all available resources at the University of Kentucky state and national levels to further theircohesive plan to fulfill MCCs mission to reduce the cancer burden with a focus on Kentucky and its mostvulnerable populations through research prevention treatment education and community engagement. Tothat end MCCs Leadership Planning and Evaluation efforts are centered around the following Specific Aims:1) Implement and execute MCCs FY24-28 Strategic Plan and lead MCC based on the opportunities andneeds of the statewide catchment area and in tandem with institutional and NCI priorities; 2) Lead the ongoingplanning and evaluation of the center coordinating and responding to internal and external reviews; and 3)Ensure the appropriate resources and infrastructure to foster success across all areas of MCCs StrategicPlan including the success of MCCs Research Programs Shared Resources clinical and translationalscientific endeavors and outreach mentoring and diversity-focused initiatives. MCCs planning and evaluationefforts sustaining its substantial growth since 2018 are accomplished through External and Internal AdvisoryBoards that meet regularly the Directors Council and committees that provide both the Director and SeniorLeadership ongoing guidance and support. Future directions for the center are guided by plans outlined inMCCs FY24-28 Strategic Plan which was constructed through an extensive review and vetting process withinput from key internal and external stakeholders. The plan is a living document and roadmap to guide the nextfive years of excellence in key pillars of activity across the center: 1) basic research 2) clinical translation 3)cancer prevention and control 4) cancer education and mentoring 5) community outreach and engagement6) diversity equity and inclusion and 7) clinical care. These pillars are reinforced by strong institutionalsupport philanthropy Shared Resource Facilities and administration all of which work in tandem to support acancer center poised to continue its trajectory of increasing contributions to cancer research trainingeducation equity and outreach. +No NIH Category available Address;Antineoplastic Agents;Appalachian Region;Area;Award;Basic Science;Biological Markers;Biological Models;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Clinic;Clinical;Clinical Oncology;Clinical Trials;Clinical Trials Network;Collaborations;Colorectal Cancer;Communities;Community Outreach;Data;Development;Devices;Diet;Direct Costs;Disparity;EIF4EBP1 gene;Early Therapeutic-Clinical Trials Network;Early identification;Electronics;Enrollment;FASN gene;Fostering;Funding;Future;Genomics;Goals;Gold Compounds;Hydroxychloroquine;Incidence;Individual;Infrastructure;Institution;Interdisciplinary Study;International;Intestinal Hormones;Investigational Drugs;Investigational Therapies;Kentucky;Lead;Leadership;Malignant Neoplasms;Manuscripts;Mediator;Mission;Molecular;Molecular Target;Multi-Institutional Clinical Trial;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Nursing Faculty;Obesity;Oncology;Participant;Patient-Focused Outcomes;Patients;Peer Review;Pharmaceutical Preparations;Phase;Phenotype;Population;Prostate;Public Policy;Publications;Publishing;Radiopharmaceuticals;Research;Research Personnel;Research Priority;Resources;Role;Ruthenium Compounds;Science;Strategic Planning;Structure;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Translating;Translations;Tumor Suppressor Proteins;United States National Institutes of Health;Universities;Up-Regulation;Validation;anticancer treatment;cancer care;cancer prevention;cancer therapy;cellular oncology;clinical development;clinical translation;clinical trial enrollment;clinically relevant;college;community engagement;cross disciplinary program;design;drug repurposing;early phase clinical trial;ethnic disparity;genome resource;inhibitor;insight;inter-institutional;intervention program;investigator-initiated trial;member;molecular oncology;mortality;next generation sequencing;novel;novel anticancer drug;novel therapeutic intervention;novel therapeutics;oncology program;phase 1 study;pre-clinical;precision medicine;preclinical development;programs;racial disparity;recruit;repository;translational goal;translational oncology;translational pipeline;translational study;treatment trial;tumor;working group Translational Oncology Research Program Project NarrativeNot applicable. This document is attached to satisfy electronic submission requirements. NCI 10712120 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 5466 2020455 "KOLESAR, JILL MARIE" Not Applicable 6 Unavailable 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY Domestic Higher Education 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 224974 147042 77932 PROJECT SUMMARY/ABSTRACT The Markey Cancer Centers (MCC) Translational Oncology (TO) Research Program is scientificallyfocused on identifying novel targets discovering new anticancer agents and devices and leading catchment-relevant clinical trials to decrease cancer burden in Kentucky and the nation. The overarching theme of the TOProgram is to use precision medicine to enhance patient outcomes through three Specific Aims: 1) Identify andvalidate mechanistic targets of cancer 2) Discover re-design and develop new anticancer agents and devicesand 3) Develop and lead biomarker directed catchment-relevant clinical trials. Currently 33 ongoingtranslational studies are evaluating molecular targets and mediators of cancer. Since 2018 38 new drugsnovel combinations and repurposed anticancer agents and devices have been developed with a focus onidentified mutations and phenotypes as informed by COE catchment area data. TO is a cross-disciplinaryprogram with 67 investigators from four colleges and 16 departments producing research awards ofapproximately $10M in annual direct costs a 68% increase from 2017 including $1.8M from the NCI and$3.4M from other NIH agencies. Members have published 613 manuscripts (2018 to 2022) of which 148(24%) are inter-programmatic 169 (28%) are intra-programmatic 344 (56%) are inter-institutional and 13% ofwhich have an impact factor >10. TO members lead 26 new therapeutic interventional investigator-initiatedtrials (IITs) a 53% increase since the previous funding period (17 IITs 2013-2017). These IITs have enrolled870 patients (2018-2022) a 111% increase in IIT accruals (413 patients 2013-2017) with 52% of participantsfrom Appalachia. In addition TO investigators enrolled 12689 individuals to the programs interventional andnon-interventional trials compared to 8571 from 2013-2017 a 48% increase. TO Program members areinternational leaders in target discovery and validation have national and international collaborations and holdleadership roles in the National Cancer Institutes Experimental Therapeutics Clinical Trials Network theOncology Research Information Exchange Network and Onco-Array Networks and the MCC-led GlobalCancer Consortium. The TO Program fosters continuous collaboration among MCC program members toinform and advance MCC basic science into the clinic. Examples include translating early identification of thebiomarker FASN to an ongoing colorectal cancer trial and demonstrating the upregulation of tumor suppressorPAR-4 by hydroxychloroquine in three trials. The TO Program has a cohesive and collaborative team focusedon translating MCC scientific discoveries into safe and effective anticancer treatments with a demonstrateddepth and breadth of impact in MCCs catchment area nationally and internationally. +No NIH Category available Acceleration;Achievement;Address;Appalachian Region;Award;Basic Science;Behavioral;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Centers of Research Excellence;Climate;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Community Outreach;Comprehensive Cancer Center;Development;Devices;Education;Education and Outreach;Epigenetic Process;Faculty Recruitment;Flow Cytometry;Foundations;Funding;Genetic;Geography;Goals;Grant;Immunologic Monitoring;Incidence;Informatics;Infrastructure;Institution;International;Intervention;Intervention Studies;Intervention Trial;Investigational Therapies;Investments;Kentucky;Leadership;Legal patent;Link;Malignant Neoplasms;Mediator;Mentors;Metabolic;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Needs Assessment;Oncology;Outcome;Oxidation-Reduction;Paper;Participant;Pathology;Patients;Peer Review;Phase;Policies;Population;Population Sciences;Positioning Attribute;Preclinical Testing;Prevalence;Prevention;Program Development;Publications;Publishing;Quality of life;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Rural;Rural Appalachia;SEER Program;Science;Scientist;Series;Services;Shapes;Signal Transduction;Strategic Planning;Students;Textiles;Therapeutic Clinical Trial;Therapeutic Trials;Training;Training Programs;Training and Education;Translating;Translational Research;Underserved Population;Universities;Validation;Vision;Vulnerable Populations;Work;Workforce Development;Youth;acronyms;anticancer research;burden of illness;cancer care;cancer education;cancer genomics;cancer health disparity;cancer prevention;cancer risk;cancer site;cancer survival;career;cellular oncology;clinical practice;clinical translation;community engagement;community organizations;equity diversity and inclusion;expectation;health disparity;health equity;improved;in vivo;innovation;instrumentation;interdisciplinary collaboration;investigator-initiated trial;member;molecular oncology;mortality;neoplasm registry;next generation;novel therapeutics;patient oriented;personalized diagnostics;personalized therapeutic;precision medicine;programs;recruit;social;translational impact;translational oncology;translational pipeline;treatment response;tumor University of Kentucky Markey Cancer Center Cancer Center Support Grant PROJECT NARRATIVE As the only NCI-designated Cancer Center in Kentucky the University of Kentucky Markey Cancer Centerserves a statewide catchment area with a population of 4.4 million residents and extraordinary cancerprevalence. In its mission to reduce the cancer burden with a focus on Kentucky and its most vulnerablepopulations through research prevention treatment education and community engagement the center hasmade and will continue to make significant strides in advancing access to quality cancer care; implementingbold transformational research spanning basic translational and population science including clinical trials toaddress Kentuckys unique cancer burden; and introducing innovative population-level interventions toaccelerate translational impact in reducing challenging health disparities and significantly impact patients in thestate and the nation. NCI 10712114 9/5/23 0:00 PAR-21-321 2P30CA177558-11 2 P30 CA 177558 11 "ROBERSON, SONYA" 7/8/13 0:00 6/30/28 0:00 ZCA1-RTRB-F(M1) 1901765 "EVERS, BERNARD MARK" Not Applicable 6 SURGERY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 9/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 2699683 NCI 1764499 935184 PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) is a university-based matrix cancer center at the University of Kentucky(UK) with a mission to reduce the cancer burden with a focus on Kentucky and its most vulnerable populationsthrough research prevention treatment education and community engagement. As the only National CancerInstitute (NCI)-designated Cancer Center in the state the MCC is vital to Kentucky the U.S. leader for highestall-site cancer incidence and mortality. Notably recognition of the extraordinary disease burden in Kentuckysvulnerable populations as a significant underpinning of that national ranking shapes the MCC vision and goalsand drives its unique focus on prevalent cancers and cancer risk factors in the catchment population. Over$569M in state institutional and philanthropic investment since 2009 has supported significant research andresource expansion propelling new faculty recruitment program development clinical and shared resourcespace renovations new state-of-the art instrumentation and statewide education and community outreach.MCCs 159 members align with one of three MCC Research Programs: Cancer Prevention and ControlMolecular and Cellular Oncology and Translational Oncology and are supported by seven Shared ResourceFacilities that facilitate cutting-edge research via robust infrastructure specialized expertise and advancedmethods: Biospecimen Procurement and Translational Pathology Biostatistics and Bioinformatics CancerResearch Informatics Flow Cytometry and Immune Monitoring Oncogenomics Patient-Oriented andPopulation Sciences and Redox Metabolism. Significant achievements in this funding period include anincreased research depth and breadth as indicated by increased total cancer-relevant funding (41%) peer-reviewed funding (35%) and NCI funding (55%). Expanded transdisciplinary collaborations driven in partthrough a strategic focus on precision medicine and a more streamlined translational pipeline resulted in 26new therapeutic trials 8 concepts or devices in Phase I or II clinical trials 10 agents or devices undergoing invivo validation 43 patent applications and 17 patents during the current funding periodall based on MCCscience. In collaboration with other U.S. and international cancer centers the number of U- and P-series grantsawarded to the MCC increased by 80%. The number of member publications increased by 28% (total of 1093)with 62% of the publications with cancer investigators at other institutions. Expanded education and traininginitiatives include a new NCI T32 focused on rural cancer health disparities a new NCI R25 Youth EnjoyScience award to engage Appalachian students in cancer research and two new training programsemphasizing diversity equity and inclusion. With unique research strengths and integrated statewidecommunity outreach and engagement MCCs programs provide robust capacity to deliver transformativeinterventional research to Kentuckys underserved populations thereby contributing to national efforts toconquer cancer through discovery and clinical translation cancer prevention and community outreach. 2699683 +No NIH Category available Accounting;Affect;Aftercare;Age;Anxiety;Benefits and Risks;Biological;Cancer Etiology;Cessation of life;Characteristics;Clinical;Clinical Management;Clinical effectiveness;Complex;Data;Databases;Decision Making;Decision Modeling;Diagnostic;Diagnostic Neoplasm Staging;Dimensions;Disease;Disease Management;Disease Outcome;Disease Progression;Disseminated Malignant Neoplasm;Early Diagnosis;Effectiveness;Electronic Health Record;Evaluation;Funding;Goals;Harm Reduction;Health Care Costs;Hormones;Image;Individual;Institution;Interview;Knowledge;Lead;Life Expectancy;Long-Term Effects;Malignant neoplasm of prostate;Measures;Modeling;Motion;Outcome;Outcome Measure;Output;PSA level;Pathway interactions;Patient Outcomes Assessments;Patient Preferences;Patients;Performance;Physicians;Positron-Emission Tomography;Provider;Radiation;Refractory Disease;Risk;Risk Assessment;Role;Screening for Prostate Cancer;Source;Staging;Surrogate Endpoint;Systemic Therapy;Test Result;Testing;Time;Tracer;Treatment-related toxicity;Uncertainty;United States;United States Food and Drug Administration;Vacuum;Work;X-Ray Computed Tomography;androgen deprivation therapy;bone imaging;cancer care;cancer site;cancer type;castration resistant prostate cancer;clinical care;clinical efficacy;clinical risk;cost;cost effectiveness;data integration;diagnostic accuracy;effectiveness evaluation;experience;health related quality of life;holistic approach;imaging agent;imaging modality;improved;innovation;insight;men;models and simulation;molecular imaging;patient subsets;preference;psychologic;reduce symptoms;treatment duration Optimizing prostate cancer care: integrating risks benefits and patient experiences in the new era of molecular imaging PROJECT NARRATIVENew molecular imaging tests offering improved detection of prostate cancer are changing the management ofthe disease in ways that are not understood but have the potential for both positive and negative effects onpatients and their disease. In this proposal we aim to understand the effectiveness of molecular imaging testswith the goal of helping patients and prostate cancer stakeholders make more informed clinical decisions thataccount for the cascade of effects that can be set into motion. To accomplish this we will generate newevidence relating to the effects of PET imaging in the real-world setting ultimately integrating this data in adecision model that will generate a clearer picture about the tradeoffs of imaging including practical scenariosthat are most or least likely to benefit patients. NCI 10712074 9/13/23 0:00 PA-20-185 1R01CA281959-01 1 R01 CA 281959 1 "KOBRIN, SARAH" 9/13/23 0:00 8/31/28 0:00 Health Services: Quality and Effectiveness Study Section[HSQE] 15194447 "LEAPMAN, MICHAEL STUART" Not Applicable 3 UROLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/13/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 660392 NCI 394264 266128 PROJECT SUMMARY/ABSTRACTA molecular imaging revolution is underway in prostate cancer. To overcome longstanding limitations inprostate cancer staging several positron-emission tomography (PET) scans have recently been approved andrapidly integrated into clinical care based on evidence of improved diagnostic accuracy. However theconsequences of widespread PET imaging are unknown. This is because the approvals of these tests arebased on improved diagnostic accuracy a surrogate endpoint rather than direct evidence of patient benefit. Byfinding small sites of cancer earlier PET imaging could introduce a cascade of effectsboth positive andnegativethat could vary from patient to patient. PET imaging could lead to improved survival and fewersymptoms from metastatic cancer in a subset but could also increase treatment toxicity psychologicalburdens and costs in others. Currently no information is available to help guide patients or stakeholders whenconsidering these tradeoffs. To reduce these uncertainties our goal is to develop a decision model thatconsiders the effects of PET imaging across multiple dimensions. To inform this model we will generate real-world evidence from a diversity of sources. In aim one we will conduct complementary analyses of largenationally representative databases to evaluate the effectiveness of PET imaging focusing on the associationsbetween imaging initiation of systemic therapy progression to hormone-refractory disease and costs. In aimtwo we will measure the longitudinal impact of PET imaging on patient-reported outcome measures relating topsychological effects (anxiety and uncertainty) and health-related quality of life. To gain a deeper perspectiveabout patient experiences with testing we will also conduct longitudinal qualitative interviews among a smallersubset of patients and integrate the findings from quantitative and qualitative sources. In the third study aim wewill incorporate inputs from Aims 1 and 2 to construct individual-based state-transition microsimulation modelsexamining common scenarios for PET imaging use. The outputs from these models will include estimates ofeffectiveness as well as patient characteristics that may be associated with greater or lesser degrees ofbenefit or harm. The results of this study will equip patients providers and other prostate cancer stakeholderswith practical new information about the potential short and long-term effects of PET imaging. If successfulthis approach for evaluating effectiveness will be applicable to other similar molecular imaging modalities thatwill soon enter clinical care on the basis of surrogate endpoints of improved diagnostic accuracy but withoutevidence of long-term clinical efficacy. 660392 +No NIH Category available Address;Adipose tissue;Administrative Supplement;Biological Markers;Black race;Body Composition;Body fat;Body mass index;Breast;Breast Cancer Patient;CD8-Positive T-Lymphocytes;Cancer Prognosis;Cell Proliferation;Collaborations;Data;Disease;Disparity;Drug or chemical Tissue Distribution;Eligibility Determination;Epidemiology;Ethnic Origin;FRAP1 gene;Gene Expression;Genes;Goals;High Prevalence;Hormonal;Hormone Receptor;Immune;Impairment;Infrastructure;Integrated Health Care Systems;Intervention;Link;Malignant Neoplasms;Mammary Neoplasms;Measures;Medical;Medical Oncology;Metabolic;Metabolic Pathway;Metabolic dysfunction;Molecular;Neighborhoods;Not Hispanic or Latino;Obesity;Outcome;PIK3CG gene;Pathology;Pathway interactions;Patient Care;Patients;Physiological;Pre-Clinical Model;Race;Research;Research Personnel;Retrieval;Risk;Risk Factors;Role;Sampling;Series;Socioeconomic Status;Specimen;T-Lymphocyte;Tumor Biology;Tumor Immunity;Visceral;Waist-Hip Ratio;Woman;Work;analysis pipeline;black women;breast cancer survival;cancer care;cancer health disparity;cancer therapy;cohort;comorbidity;disparity reduction;ethnic disparity;ethnic diversity;exhaust;exhaustion;experience;follow-up;hormone receptor-negative;human data;lifestyle intervention;malignant breast neoplasm;modifiable risk;molecular subtypes;mortality;parent grant;racial difference;racial disparity;racial diversity;study population;subcutaneous;survival prediction;therapy resistant;tumor;tumor microenvironment;tumor progression Body composition and breast cancer survival: immune and metabolic biomarkers in breast tumors - Disparities Supplement NARRATIVENon-Hispanic black women experience a disproportionate burden of breast cancer mortality. Thisadministrative supplement will focus on understanding whether the amount and distribution of body fatcontributes to this increased mortality through differences in tumor biology. NCI 10712034 9/19/23 0:00 PAR-22-114 3R01CA251589-04S1 3 R01 CA 251589 4 S1 "MERCER, NATALIA" 7/1/20 0:00 6/30/25 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 12179280 "FELICIANO, ELIZABETH MARJORIE CESPEDES" Not Applicable 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 230018 NCI 202246 27772 ABSTRACTThis Supplement to R01CA251589 Body composition and breast cancer survival: immune and metabolicbiomarkers in breast tumors responds to the PAR-22-114 Administrative Supplements to Support CancerDisparity Collaborative Research. The long-term goal is to reduce the disproportionate burden of breastcancer mortality experienced by non-Hispanic black (NHB) women by understanding the role of a keymodifiable risk factor: excess adiposity.Preclinical models indicate that excess adiposity impairs anti-tumor immunity and alters metabolic and cellproliferation pathways to promote cancer progression. Given the markedly higher prevalence of obesity (bodymass index [BMI] >30-kg/m2) in NHB vs. vs. non-Hispanic white (NHW) women obesity is assumed tocontribute to disparities in survival. Yet BMI does not consistently predict survival after breast cancer in NHBwomen or in women hormone receptor negative breast tumors which are more common in NHB women.Preliminary studies suggest that more specific measures of adipose tissue distribution outperform BMI topredict breast cancer survival. Given racial differences in adipose tissue distribution at a given BMI there is aneed to study body composition to elucidate the role of adiposity in generating racial disparities.This administrative supplement establishes a new collaboration between a cancer disparities expert and astudy team with expertise in epidemiology tumor biology and breast medical oncology. The parent grant seeksto understand how systemic factors such as patient body composition impact the local breast tumormicroenvironment and therefore breast cancer survival. With this administrative supplement we expand thoseaims to include a disparities focus by comparing NHB vs. NHW women. We will expand representation oftumors from NHB women in our study and conduct a series of analyses focused on racial disparities.Specifically we will examine: racial differences in the distribution of visceral v. subcutaneous adiposity and inassociations of these adipose tissue depots with survival (Aim 1); racial differences in the associations of eachadipose tissue depot with expression of immune and metabolic genes in the breast tumor microenvironment(Aim 2); and racial differences in the associations of immune and metabolic genes in the breast TME withsurvival (Aim 3). Potential harms of excess adiposity may be mitigated through both medical and lifestyleinterventions; thus understanding the role of adiposity in generating racial disparities in breast cancer is a highpriority not only for research but patient care. 230018 +No NIH Category available Accounting;Archives;Autoantibodies;Biological Markers;Blinded;Blood;Blood Vessels;Blood specimen;CA-19-9 Antigen;Cancer Etiology;Case/Control Studies;Cessation of life;Clinical;Consensus;Cyst;Cyst Fluid;Cystic Lesion;Development;Diabetes Mellitus;Diagnosis;Disease;Distant;Dysplasia;Early Diagnosis;Epitopes;Evaluation;Excision;Familial pancreatic cancer;Family;Family history of;Funding;General Population;Genetic;Germ-Line Mutation;Goals;Guidelines;Individual;Inherited;Laboratories;Lesion;Localized Disease;MUC5AC gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Medical center;Minority;Morbidity - disease rate;Mucinous;Mucins;Mutation;Nature;Neoplasms;Newly Diagnosed;Operative Surgical Procedures;Organ;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Cyst;Pancreatic Diseases;Pancreatic cystic neoplasia;Pathogenicity;Patients;Performance;Persons;Phase;Population;Predisposition;Prospective Studies;Recording of previous events;Reporting;Resectable;Resected;Retrospective Studies;Risk;Sampling;Serum;Specificity;Survival Rate;TIMP2 gene;United States;Validation;Variant;biomarker panel;biomarker performance;biomarker validation;blood-based biomarker;candidate marker;candidate validation;case control;chronic pancreatitis;cohort;diagnostic biomarker;draining lymph node;early detection biomarkers;high risk;high risk population;improved;inflammatory marker;mortality risk;novel;patient subsets;prospective;risk prediction;risk stratification;sample collection;screening;surveillance imaging;surveillance strategy;tumor;validation studies Validation of biomarkers for risk prediction and early diagnosis of Pancreatic Adenocarcinoma Project NarrativeEarly diagnosis of pancreatic cancer (PDAC) remains challenging due to its asymptomatic nature lack of earlydetection biomarkers and limited availability of samples. This Clinical Validation Center (CVC) proposal aimsto validate a previously optimized panel of biomarkers in blood and cyst fluid for risk stratification and earlydetection of PDAC in high-risk surveillance (pancreatic cystic lesions and subjects with a family history ofmalignancy due to germline mutation) and sporadic cohorts that are an increased risk for having anundiagnosed PDAC (patients with new-onset diabetes and chronic pancreatitis). A combination of retrospectiveand prospective studies will establish the clinical utility of biomarker panels for detecting interval malignancy insurveillance cohorts and early detection of sporadic malignancy. NCI 10711703 4/24/23 0:00 RFA-CA-22-054 2U01CA200466-06A1 2 U01 CA 200466 6 A1 "YOUNG, MATTHEW R" 5/17/16 0:00 3/31/28 0:00 ZCA1-SRB-P(J2) 8645623 "BRAND, RANDALL " "BATRA, SURINDER K." 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 4/24/23 0:00 3/31/24 0:00 394 Non-SBIR/STTR 2023 915566 NCI 725475 194700 Abstract Pancreatic adenocarcinoma (PDAC) with an overall 5-year survival of 11% is the 3rd most commoncause of cancer deaths in the United States despite accounting for only 2% of all malignancies. Only a minorityof patients (~11%) are diagnosed with localized disease (I or IIA) which has a 5-year survival rate of about40% in setting of a node-negative margin negative pancreatic resection. An obvious strategy for improving thedismal survival would be to detect PDAC when localized and thus at a more curable stage. Since screening thegeneral population for PDAC is not feasible current efforts have focused on identifying a subset of the people atan increased risk for PDAC development. Currently only up to 25% of individuals who develop PDAC arecandidates for pancreatic cancer surveillance. About 10% are individuals with a strong family history or acombination of family history and germline mutations associated with the risk of PDAC development. The other~15% are individuals with cystic neoplasms of the pancreas including IPMNs and MCNs. The inability to predictthe malignant transformation of mucinous cysts and thus identify the cysts that should be surgically removedrequires appropriate surveillance. Despite developing multiple consensus guidelines on managing cystic lesionsit is still challenging to determine which mucinous cysts will undergo malignant transformation. During theprevious funding cycle we identified and evaluated novel serum biomarker panels comprising mucins (MUC4MUC5AC) mucin-associated glycoepitopes (STRA) TGM2 THSP2 TIMP2 and autoantibodies that werevalidated in a blinded case-control cohort aimed at detecting resectable PDAC. Preliminary mutational profilingof pancreatic cyst fluid (phase I and II) identified a unique panel (PancreaSeq) that helped define the malignantrisk of pancreatic cysts. The goal of the current Clinical Validation Center (CVC) is to validate further thesepanel(s) in a prospective-specimen-collection retrospective-blinded-evaluation (PRoBE) compliant manner incohorts of high-risk individuals who are current or potential candidates for early detection or diagnosis of PDAC.Aim 1 will validate cyst fluid and blood-based biomarkers in patients with cystic lesions to identify advancedprecursor lesions and differentiate low-grade dysplasia and no lethal potential. In this aim we will validatecandidate biomarkers including PancreaSeq mutational panel (Phase 3) inflammatory markers (Phase 2) andmucins (MUC4 MUC5AC STRA) (Phase 3) in the cyst fluid (high specificity) and serum samples (highsensitivity) to identify interval malignancy during surveillance imaging. Aim 2 will evaluate the performance ofoptimized biomarker panel(s) for early detection of malignant disease in patients with a hereditary predispositionundergoing surveillance for PDAC development and in patients with new-onset diabetes and chronic pancreatitisdefined as within two years of initial diagnosis who are at a significantly increased risk compared to the generalpopulation for having an undiagnosed PDAC. Impact: The proposed studies will validate the clinical utility ofpromising biomarker panels for early detection of PDAC and risk stratification of pancreatic cystic lesions whichcan be used in phase IV clinical utility studies. 915566 +No NIH Category available Advocate;Applied Research;Basic Science;Black race;Cancer Control Research;Clinical;Data;Dedications;Development;Discipline of obstetrics;Endometrial;Endometrial Carcinoma;Ensure;Epidemiology;Faculty;Funding;Future;Goals;Grant Review;Gynecologist;Gynecology;Institution;Knowledge;Life;Malignant Neoplasms;Minority;Monitor;New Mexico;Oklahoma;Oncologist;Outcome Assessment;Patients;Pilot Projects;Prevention strategy;Program Research Project Grants;Recommendation;Request for Applications;Research;Research Personnel;Research Project Grants;Review Committee;Route;Science;Scientist;Secure;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Universities;Washington;Woman;Work;anticancer research;cancer prevention;career;disability;innovation;member;novel therapeutic intervention;programs;recruit;success Developmental Research Program n/a NCI 10711641 8/23/23 0:00 PAR-20-305 1P50CA265793-01A1 1 P50 CA 265793 1 A1 8/23/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 5356 1884469 "LESLIE, KIMBERLY K." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 160387 103143 57244 PROJECT SUMMARY/ ABSTRACTThe overall goals of the Route 66 Endometrial Cancer SPORE Developmental Research Program (DRP) areto support innovative early-stage research in endometrial cancer to develop pilot projects to the point ofinclusion as full SPORE projects to increase the number of investigators committed to endometrial cancerand to diversify the workforce. This last goal is important because less than 3% of oncologists and less than4% of academic obstetricians and gynecologist identify as Black. Moreover although over 80% of thoseworking in obstetrics and gynecology are women fewer than 30% of tenured faculty members in Departmentsof Obstetrics and Gynecology are women. To achieve these goals the Route 66 Endometrial Cancer SPOREDRP will provide one- to two-year pilot funding for projects in basic translational clinical epidemiologic andcancer prevention and control research. The DRP will be open to all three participating institutions in theSPORE (Washington University in St. Louis University of New Mexico and University of Oklahoma). We willencourage investigators to submit collaborative proposals with investigators from other SPOREs. We will useboth NCI and institutional funding to support up to three DRP projects each year throughout the life of theSPORE. Requests for applications for DRP projects in endometrial cancer research will be released once peryear. All applications will be reviewed by a Grant Review Committee consisting of scientists (representingbasic and applied science) with expertise in endometrial or related cancers or relevant science abiostatistician a patient advocate and ad hoc members as necessary. Once a DRP project is funded we willprovide dedicated support to ensure success of the project evaluate progress regularly assess outcomes anddecide whether DRP projects should be recommended for funding as a full SPORE project in this or a futurefunding cycle. As a result of the DRP bold new ideas in endometrial cancer research will be funded at the pilotstage and developed to lead to new treatment or prevention strategies. We fully anticipate that one or moreDRP projects will be elevated to full SPORE projects in the next funding period. Additionally new investigatorswill leverage DRP support to develop their projects obtain preliminary data and secure external funding andthus establish their careers in endometrial cancer research. Finally established investigators who are new tothe field will apply their knowledge and expertise to the field of endometrial cancer. +No NIH Category available Award;Biostatistics Core;Blood;Cancer Center;Cancer Model;Cancer Patient;Catalogs;Cells;Characteristics;Clinical;Clinical Data;Collaborations;Collection;Communities;Consent;Correlative Study;Credentialing;Data;Databases;Development;Diagnosis;Disease;Eligibility Determination;Endometrial Carcinoma;Ensure;Equipment and supply inventories;Equity;Evaluation;Experimental Designs;Freezing;Future;Goals;Grant;Infrastructure;Institution;Institutional Review Boards;Isotopes;Leadership;Link;Liquid substance;Manuscripts;Metabolic;Methods;New Mexico;Newly Diagnosed;Nucleic Acids;Oklahoma;Organoids;Outcome;Pathology;Patients;Peer Review;Plasma;Preparation;Process;Prognostic Factor;Protocols documentation;Publications;Qualifying;Recurrence;Research;Research Design;Research Personnel;Research Project Grants;Resources;Route;Sampling;Serum;Services;Specimen;Standardization;Structure;Time;Tissues;Translational Research;Universities;Validation;Washington;Work;anticancer research;biobank;career;clinical database;data interoperability;data sharing;experience;genome sequencing;metabolomics;model development;operation;patient derived xenograft model;preservation;prevent;programs;prospective;sample collection;secondary analysis;success;tool;whole genome Core 2: Biospecimen Metabolomics and Pathology Core n/a NCI 10711640 8/23/23 0:00 PAR-20-305 1P50CA265793-01A1 1 P50 CA 265793 1 A1 8/23/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 5355 12156231 "HAGEMANN, IAN S." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 130426 83875 46551 PROJECT SUMMARY/ABSTRACTThe goal of the Biospecimen Metabolomics and Pathology Core (BMP Core) is to create a federated multi-institutional resource to provide high-quality clinically annotated biospecimens metabolomic analyses andexpert pathology review to all research projects in this SPORE application as well as future SPORE-sponsoredDRP and CEP projects while serving as an unparalleled biospecimen resource to the broader endometrialcancer research community. The Core will provide specific tissue and biosample-related services for eachSPORE project. In addition the BMP Core will prospectively build a biospecimen resource bank at WUSTLOUHSC and UNM by identifying cases of new and recurrent endometrial cancer at the participating institutionsand facilitating the consent and procurement process. Tissue and fluid biospecimens from these patients willbe collected processed and stored by leveraging the extensive infrastructure of existing biorepositories at theparticipating institutions. Clinical data will be collected prospectively by integrating with and extending existingclinical databases. Interactions with the Biostatistics Core will ensure interoperability of data tables maintainedat each institution. The BMP Core will provide access to the world-class Center for Metabolomics and IsotopeTracing at WUSTL. Validated methods for sample processing and preservation focused on optimizingmetabolic analyses will be provided to increase the scientific utility of all biospecimens collected. Atransparent and equitable mechanism to publicize existing biospecimen resources and evaluate any requestfor their use will be implemented. As such the BMP Core will supplement existing cancer center resourceswith focused expertise and effort to comprehensively collect annotate quality review and distributebiospecimens specifically for translational endometrial cancer research. +No NIH Category available Adverse event;Bioinformatics;Biological Markers;Biometry;Cancer Center;Clinical Research;Clinical Trials;Collaborations;Computer Analysis;Consult;Core Facility;Data;Data Analyses;Data Collection;Databases;Development;Endometrial Carcinoma;Ensure;Faculty;Genomics;Health Sciences;Immunotherapy;Minority;Monitor;New Mexico;Oklahoma;Output;Quality Control;Reporting;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resources;Route;Statistical Methods;System;Tissue Sample;Training;Universities;Visualization;Washington;Work;career;data integration;data management;data sharing;design;experience;genomic data;medical schools;meetings;member;next generation sequencing;personalized medicine;programs;targeted therapy trials;trial design Core 1: Biostatistics and Bioinformatics Core n/a NCI 10711639 8/23/23 0:00 PAR-20-305 1P50CA265793-01A1 1 P50 CA 265793 1 A1 8/23/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 5354 10507678 "LU, ESTHER " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 150421 96734 53687 PROJECT SUMMARYThe Biostatistics and Bioinformatics Core facility provides state-of-the-art statistical support for all Route 66Endometrial Cancer SPORE investigators and projects. The Core will provide statistical support on all aspectsof study design study execution and monitoring database development and quality control and data analysisand interpretation. Biostatistics and Bioinformatics Core members have diverse expertise a combined 57years as faculty biostatisticians and bioinformaticians and established long-term collaborations with SPOREmembers at Washington University School of Medicine University of Oklahoma Health Sciences Center andUniversity of New Mexico. Their statistical expertise will support newly developing research themes of theSPORE projects such as Bayesian adaptive trial design immunotherapy and target therapy trial designbiomarker-guided personalized medicine study next-generation sequencing and high-throughput omics dataanalysis. The Biostatistics and Bioinformatics Core team also has extensive expertise collaborating acrosscenters and in monitoring minority accrual OnCore REDCap and data management/analysis for clinicalstudies. In Aim 1 the Core will provide biostatistics and bioinformatics collaborations for SPORE projects andDevelopmental Research Program studies. Core members have and will continue to regularly participate inSPORE project investigator meetings and provide statistical support for designing studies and analyzing data.Additionally they will help Developmental Research Program awardees design studies and analyze data. InAim 2 the Core will provide biostatistics and bioinformatics support and training to early-career investigatorsthrough the Career Enhancement Program. In their activities the Core will draw on Clinical Trials Offices intheir respective Cancer Centers for multiple purposes: creating forms for data collection uniform adverse eventreports and tissue sample storage and management; and collating/integrating outputs from high-throughputgenomics to streamline data analysis and interpretation. In achieving its aims the Biostatistics andBioinformatics Core will ensure that robust statistical methods and reproducible omics analyses are availableto support all Route 66 Endometrial Cancer SPORE investigators. +No NIH Category available Address;Aftercare;Agonist;Atypia;Atypical Endometrial Hyperplasias;Behavior Therapy;Behavioral;Biopsy;Body Weight decreased;Combined Modality Therapy;Development;Diagnosis;Early Diagnosis;Endometrial;Endometrial Carcinoma;Endometrial Hyperplasia;Enrollment;Ensure;Equity;Estrogen Receptors;Estrogens;FDA approved;Fertility;Funding;Future;GLP-I receptor;Genetic Transcription;Hyperplasia;Hysterectomy;Impairment;Injections;Institution;Insulin Resistance;Intrauterine Devices;Levonorgestrel;Live Birth;Malignant Neoplasms;Measures;Metabolism;Obesity;Overweight;Pathology;Patients;Persons;Pharmaceutical Preparations;Placebos;Plasma;Population Sciences;Pregnancy Rate;Premenopause;Prevention;Primary Prevention;Progesterone;Progesterone Receptors;Progestin Therapy;Progestins;Proliferation Marker;Psychologist;Randomized;Randomized Controlled Trials;Relapse;Route;Serum;Standardization;Telemedicine;Testing;Therapeutic;Time;Tissues;Universities;Uterus;Washington;Weight;Weight Gain;Woman;Work;bariatric surgery;biomarker identification;cancer prevention;efficacy evaluation;experience;improved outcome;insulin secretion;metabolomics;predicting response;premalignant;preservation;prevent;randomized clinical trials;recruit;response;secondary endpoint;treatment as usual;weight loss intervention Project 3: Primary Prevention and Uterine Preservation in Premenopausal Women with Obesity and Endometrial Hyperplasia/Cancer PROJECT NARRATIVEThis project tests two strategies to help premenopausal patients with endometrial precancer and obesity loseweight preserve their uterus for fertility and avoid developing cancer. NCI 10711638 8/23/23 0:00 PAR-20-305 1P50CA265793-01A1 1 P50 CA 265793 1 A1 8/23/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 5353 11263519 "HAGEMANN, ANDREA " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 596971 468795 128176 PROJECT SUMMARY/ ABSTRACTUp to 90% of the ~65000 women diagnosed with endometrial cancer each year in the U.S. are overweight orobese and up to 60% of endometrial cancer cases are attributed to obesity. This is in large part becauseobesity promotes development of atypical endometrial hyperplasia (AEH) a precursor of grade 1 endometrialcancer. If diagnosed at one of these stages a patient can be treated with hysterectomy which is 100%effective in preventing/curing endometrial cancer. However hysterectomy is often unacceptable topremenopausal women who would like to retain fertility. Instead such patients are commonly treated withprogestin most commonly via a levonorgestrel-releasing intrauterine device (IUD). However up to 41% ofwomen on progestin eventually experience relapse and require a hysterectomy. Moreover fewer than 12% ofwomen who choose this option go on to have a live birth likely because obesity and the commonly co-occurring insulin resistance impair fertility. As weight loss alone can also reverse AEH and grade 1 endometrialcancer an ideal treatment for premenopausal women desiring future fertility would be to simultaneouslyprovide a progestin IUD along with an effective weight loss strategy. This Early detection Prevention andPopulation Science project includes two randomized controlled trials testing the overall hypothesis thatcombined treatment with progestin and either therapeutic or behavioral weight loss interventions leads togreater uterine preservation than progestin use alone. Aim 1 is to determine the efficacy of progestin plus abehavioral weight loss intervention to allow uterine preservation and cancer prevention in premenopausalwomen with AEH or grade 1 endometrial cancer. Aim 2 is to determine the efficacy of a glucagon-like peptide 1receptor agonist plus progestin plus a behavioral weight loss intervention to allow uterine preservation andcancer prevention in premenopausal women with AEH. The therapeutic drug in this trial is approved by theFDA for treating obesity. Exploratory Aim 3 is to identify biomarkers that reflect response to progestin plusweight loss. If this project identifies effective strategies they can be widely implemented to allowpremenopausal women with AEH or grade 1 endometrial cancer to both avoid cancer and preserve their uterusfor future fertility. +No NIH Category available Address;Advanced Malignant Neoplasm;Aneuploid Cells;Animal Model;Apoptosis;Autophagocytosis;Binding;CDK4 gene;Cancer Patient;Cancer cell line;Carcinoma;Categories;Cell Cycle Arrest;Cell Cycle Progression;Cell Death;Cell Line;Cell Nucleus;Cell Survival;Cells;Centrosome;Cessation of life;Chromosomes;Classification;Client;Clinical Trials;Complement;Complex;Cyclin D1;Cyclin-Dependent Kinases;DNA Sequence Alteration;Data;Defect;Development;Disease;Dose;Drug Combinations;Drug Kinetics;Endometrial;Endometrial Carcinoma;Endoplasmic Reticulum;Epigenetic Process;Epithelial Cells;Future;G1 Arrest;GRP78 gene;Gene Mutation;Genes;Genetic;Genetic Induction;Grant;Growth;Growth and Development function;Heat shock proteins;Homeostasis;Incidence;Induction of Apoptosis;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Measures;Mediating;Metabolism;Mitochondria;Molecular;Molecular Chaperones;Molecular Profiling;Mutation;Oncoproteins;Organelles;Organoids;Outcome;Outcomes Research;PTEN gene;Paclitaxel;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I Clinical Trials;Phase Ib/II Clinical Trial;Phosphorylation;Phosphotransferases;Preparation;Progression-Free Survivals;Proliferating;Proteins;Randomized;Recurrence;Recurrent disease;Refractory;Regulation;Route;SHetA2;Schedule;Serous;Specimen;Stress;Systems Biology;TP53 gene;Testing;The Cancer Genome Atlas;Therapeutic;Toxic effect;Treatment Efficacy;Tumor Burden;Uterus;Woman;Xenograft procedure;advanced disease;biomarker identification;cancer cell;cancer survival;cancer therapy;carcinogenesis;drug testing;endoplasmic reticulum stress;first-in-human;improved;in vivo;inhibitor;mortalin;mortality;novel therapeutics;overexpression;patient prognosis;phase III trial;preclinical study;predictive marker;prevent;protein complex;response;side effect;standard of care;synergism;tumor;tumor growth Project 1: Targeting HSPA Proteins in Advanced and Recurrent Endometrial Cancer Therapy PROJECT NARRATIVEThe rate of endometrial cancer deaths is increasing and current treatments cause serious side effects. Thisproject will study a new drug called SHetA2 that has shown no significant toxicities to date and is targeted atspecific molecular defects that occur in endometrial cancers. The outcome of this research has the potential tooptimize SHetA2-based treatments for endometrial cancer patients and identify those patients who will mostlikely benefit from this therapy. NCI 10711636 8/23/23 0:00 PAR-20-305 1P50CA265793-01A1 1 P50 CA 265793 1 A1 8/23/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 5351 1865399 "BENBROOK, DORIS MANGIARACINA" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 403383 375633 27750 PROJECT SUMMARYThe incidence and mortality of endometrial cancer has increased over the past few decades and is predicted tocontinue rising. There is significant need for improved therapies with reduced toxicity for women with endometrialcancers that are advanced recurrent or refractory to standard of care. Endometrial cancer is a heterogeneousdisease that has been classified into molecular profile categories with different degrees of patient prognosis.Across these categories endometrial cancer has the highest rates of mutations in heat shock protein A(HSPA)5 8 and 9 genes compared to other The Cancer Genome Atlas-studied cancers. The HSPA5 HSPA8 andHSPA9 genes encode chaperone proteins Grp78 hsc70 and mortalin respectively which become elevatedduring carcinogenesis to bind and modulate oncoproteins in a way that assures cancer cell survival. Thus thesechaperone/oncoprotein complexes represent differential targets present at higher levels in cancer cellscompared to healthy cells. We developed a drug SHetA2 (NSC 726189) which disrupts these complexes.SHetA2 induces growth arrest altered metabolism mitophagy and cell death in endometrial cancer cells whilethe effects on healthy cells is limited to G1 cell cycle arrest. Preclinical studies found lack of SHetA2 toxicity andthis drug is now in a Phase 1 clinical trial in advanced recurrent or persistent gynecologic cancers(NCT04928508). In vivo studies revealed that SHetA2 has complementary activities and efficacies with paclitaxeland cyclin dependent kinase (CDK4/6) inhibitors. In this project we hypothesize that SHetA2 will safely reduceendometrial cancer tumor burden and complement the efficacies of paclitaxel and CDK4/6 inhibitors withoutincreasing toxicity; the mechanism will be mediated through SHetA2 disruption of HSPA/client proteincomplexes; and the treatment efficacies will be modulated by mutations in PTEN and TP53 genes. To test thisand optimize SHetA2-based therapies we propose to study the mechanism of SHetA2 in healthy endometrialcells endometrial cancer cell lines and patient derived organoids and xenografts with a range of natural orinduced genetic mutations in PTEN and TP53 genes. We will conduct a Phase 1 clinical trial of SHetA2 incombination with paclitaxel in advanced recurrent or persistent endometrial cancer patients; a Phase 2expansion will evaluate response. Using specimens from this and other trials we will test the hypothesis thatmortalin co-localization with the Mps1 kinase or p53 at the centrosome correlates with poor or improvedresponse respectively of paclitaxel-treated endometrial cancer patients. In preparation for a future clinical trialwe will use a quantitative systems biology approach that integrates pharmacokinetic pharmacodynamic andtoxicity data to optimize dose and schedule for testing SHetA2 in combination with CDK4/6 inhibitors. Theoutcome is anticipated to identify biomarkers predictive of which patients will most likely benefit from SHetA2-based therapies and provide justification and data for development of a randomized Phase 3 trial of a SHetA2combination anticipated to have an improved therapeutic window over current therapy. +No NIH Category available Accounting;Alcohol abuse;Biliary;CD8-Positive T-Lymphocytes;Cell Communication;Cell Nucleus;Cell Surface Receptors;Cells;Characteristics;Cholestasis;Clinical;Clinical Management;Complement;Complication;Data;Desmoplastic;Diagnosis;Differential Diagnosis;Early Diagnosis;Epigenetic Process;Evaluation;Evolution;Exclusion;Exhibits;Failure;Fibroblasts;Goals;Hepatobiliary;Hepatocyte;High Fat Diet;Human;Immune;Immune checkpoint inhibitor;Immunobiology;Immunocompetent;Immunophenotyping;Immunosuppression;Immunotherapy;Incidence;Inflammatory Bowel Diseases;Intraepithelial Neoplasia;Intrahepatic Cholangiocarcinoma;KDR gene;Lesion;Malignant - descriptor;Malignant Neoplasms;Maps;Mediating;Modeling;Molecular;Mus;Mutation;Myeloid-derived suppressor cells;Nodule;Non-Insulin-Dependent Diabetes Mellitus;Oncogenic;Pathogenesis;Pathologic;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Radiology Specialty;Reaction;Risk Factors;Signal Transduction;Study models;Survival Rate;T cell receptor repertoire sequencing;T-Lymphocyte;T-cell receptor repertoire;Techniques;Therapeutic;Transcriptional Activation;Translating;Tumor-Infiltrating Lymphocytes;Variant;Vegf Inhibitor;biliary tract;cancer cell;cancer type;checkpoint inhibition;cholangiocyte;endoplasmic reticulum stress;experimental study;immunogenic;improved;information gathering;inhibitor;mouse model;neoplastic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;overexpression;pressure;prevent;progenitor;regenerative;response;tobacco abuse;transcription factor;transcriptomics;tumor;tumor microenvironment;tumor-immune system interactions A new mouse model for studying the pathogenesis and immunobiology of intrahepatic cholangiocarcinoma and improving its immunotherapy Project NarrativeIntrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with a poor response to immunecheckpoint inhibitors (ICI) which has not been improved due to poor understanding of the immunosuppressivemechanisms associated with ICC progression. We have developed a novel mouse model of ICC that showshuman-like stepwise progression accompanied by desmoplasia and CD8+ T cell exclusion. This model is ideallysuited for studying the immunobiology of ICC and finding new ways to improve the efficacy of existing ICI-basedtherapies for this malignancy. NCI 10711615 9/19/23 0:00 PAR-20-131 1R01CA281784-01 1 R01 CA 281784 1 "SNYDERWINE, ELIZABETH G" 9/19/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-CTH-E(55)R] 1861927 "KARIN, MICHAEL " Not Applicable 50 PHARMACOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 563902 NCI 356900 207002 ABSTRACTIntrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer (PLC) that is particularly hard totreat having an overall 5-year survival rate of 8%. Like the major PLC hepatocellular carcinoma (HCC) ICCincidence is on the rise due to the ongoing increase in cholestatic liver diseases non-alcoholic fatty liver diseasestype 2 diabetes and alcohol and tobacco abuse. Unlike HCC ICC is often detected at an advanced stage whensurvival prospects are poor a complication of its imprecise differentiation from early HCC by current radiologicaltechniques. Early differential diagnosis of two PLCs is critical due to their distinct management and the absenceof targetable oncogenic drivers shared by ICC and HCC. This problem could be solved by identification of a PLC-type agnostic therapeutic approach such as immune checkpoint inhibition (ICI) that is applicable to both ICCand HCC. However while ICI based therapies were approved for HCC and their efficacy has been improved bycombination with VEGF inhibitors they have performed poorly in ICC. This failure can be attributed in part topoor mechanistic understanding of the ICC-specific immunosuppressive tumor microenvironment (TME) andlack of suitable mouse models that allow the evaluation of ICI in combination with therapeutics capable ofdismantling immunosuppression. We have solved this problem by developing a new ICC model that unlikeprevious mouse models does not depend on forced overexpression of potent oncogenic drivers that rapidlyinduce ICC in the absence of selective pressure for acquisition of additional mutations. Our MUP-uPA/NRF2Actmodel depends on combination of ER stress with activation of transcription factor NRF2 in bipotentialhepatobiliary progenitors and mature hepatocytes and shows robust highly penetrant human-like stepwiseprogression towards ICC that is accompanied by the buildup of an immunosuppressive TME exhibiting CD8+ Tcell exclusion. We plan to establish the MUP-uPA/NRF2Act mouse as the leading model for studying the evolutionof ICC and its immunosuppressive TME and for finding treatments that will dismantle immunosuppression andboost the response to existing PD-(L)1 inhibitors. To accomplish this goal we will fully characterize the MUP-uPA/NRF2Act mouse defining the transcriptomic epigenetic and genetic alterations at each stage of ICCprogression including ductular reactions biliary intraepithelial neoplasia and established desmoplastic cancer.We will also define the T cell receptor (TCR) repertoire of tumor infiltrating lymphocytes at each stage ofmalignant progression and mine the transcriptomic data for cancer cell produced factors that mediatedesmoplasia immunosuppression and CD8+ T cell exclusion. These studies will be complemented byimmunophenotyping and immunodepletion experiments whose goal is the identification of targetable molecularswitches responsible for establishment of the ICC-specific immunosuppressive TME. We will use this informationto identify clinically approved treatments that can overcome immunosuppression and vastly improve the efficacyof ICI therapy based on PD-(L)1 inhibitors. 563902 +No NIH Category available Address;Area;Basic Science;Biometry;British Columbia;Cancer Center;Clinical;Clinical Management;Clinical Sciences;Collaborations;Development;Disease Management;Early Diagnosis;Endowment;Etiology;Faculty;Feedback;Foundations;Funding;General Hospitals;Goals;Government;Grant;Guidelines;Health;Health Promotion;Infrastructure;Institution;Investments;Malignant neoplasm of prostate;Manuscripts;Minority Groups;Monitor;Morbidity - disease rate;Oregon;Outcome;Pacific Northwest;Patients;Phase;Pilot Projects;Population;Population Study;Prevention;Prevention strategy;Prognosis;Program Research Project Grants;Prostate;Quality of life;Reporting;Research;Research Personnel;Research Project Grants;Research Proposals;Resources;Science;Scientist;Site;Source;Therapeutic;Translational Research;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Washington;Work;anticancer research;cancer health disparity;cancer therapy;design;feasibility testing;improved;innovation;interest;meetings;member;mortality;multidisciplinary;programs;research study;survivorship;translational goal;treatment strategy Developmental Research Program n/a NCI 10711595 9/4/23 0:00 PAR-20-305 2P50CA097186-22 2 P50 CA 97186 22 9/19/02 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5348 2046172 "LIN, DANIEL W." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 122369 69750 53010 PROJECT SUMMARY/ABSTRACTThe Developmental Research Program (DRP) of the Pacific Northwest (PNW) Prostate Cancer SPORE is de-signed to solicit evaluate and support innovative pilot projects in translational prostate cancer research. Projectsfunded under the DRP are intended to rapidly advance a new idea or concept that has the potential to substan-tially impact our understanding of prostate cancer and ultimately influence the clinical management of this dis-ease through improved prevention and treatment strategies. Since the inception of the PNW Prostate CancerSPORE the infrastructure of the DRP has established mechanisms to quickly respond to translational researchopportunities within the PNW SPORE institutions that require support to advance hypotheses or confirm feasi-bility in order to justify larger resource investments. Developmental projects include research in basic scienceclinical science and population-based studies and will continue to build collaborations between PNW SPOREsites and other institutions with SPOREs in prostate cancer.The Specific Aims for the Developmental Research Program are to:1. Stimulate the development of innovative impactful early-phase research studies that include multi-discipli- nary interactions with basic clinical and population scientists across the PNW Prostate SPORE institutions and including inter-SPORE collaborative studies;2. Provide funding (1-2 years) and infrastructure (e.g. biospecimens biostatistical support) to rapidly test the feasibility of original investigator-initiated projects in all areas of PC research;3. Prioritize funding to rapidly exploit new opportunities or support specific areas of strategic importance for advancing the translational research goals of the PNW Prostate SPORE;4. Advance early stage scientific research that addresses prostate cancer health disparities and promote re- search directed by scientists from underrepresented minority groups; and5. Monitor (and facilitate) the progress of each DRP project and consider their advancement to a full SPOREproject. +No NIH Category available Address;Bioinformatics;Biological;Biometry;British Columbia;Cancer Center;Cancer Research Project;Collaborations;Collection;Communication;Communities;Complex;Data;Data Analyses;Data Collection;Data Set;Detection;Development;Ensure;Funding;Head;Health;Human Resources;Individual;Investigation;Leadership;Link;Malignant neoplasm of prostate;Measurement;Metastatic Prostate Cancer;Methodological Studies;Methods;Molecular;Oregon;Outcome;Pacific Northwest;Play;Productivity;Program Research Project Grants;Publications;Publishing;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Role;Sample Size;Sampling Studies;Science;Services;Source;Specific qualifier value;Statistical Data Interpretation;Statistical Methods;Systematic Bias;Target Populations;Translational Research;Uncertainty;Universities;Validation;Work;anticancer research;bioinformatics tool;design;experience;innovation;interest;invention;novel;prevent;translational research program Core C: Biostatistics and Bioinformatics n/a NCI 10711594 9/4/23 0:00 PAR-20-305 2P50CA097186-22 2 P50 CA 97186 22 9/19/02 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5347 1883893 "ETZIONI, RUTH D" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 179560 102245 77706 PROJECT SUMMARY/ABSTRACTThe Biostatistics and Bioinformatics Core will provide essential data and analytics support to investigators onthe Pacific Northwest Prostate Cancer SPORE. This Core will link study design data collection measurementand analysis to validly address critical hypotheses and questions of SPORE investigators through the followingSpecific Aims.Aim 1: Study design. Define study hypotheses target populations and outcomes to efficiently interrogate theresearch questions of interest reduce the chance of systematic bias and ensure a high likelihood of detectionof biologically meaningful effects.Aim 2: Statistical analysis. Implement quantitative methods tailored to study design and data features toestimate effects of interest quantify uncertainty and provide valid inferences about the evidence supporting thestudy hypotheses.Aim 3: Bioinformatics support. Source appropriate bioinformatics tools and routines to explore biological ormechanistic explanations for study findings and generate hypotheses for further investigation based onmolecular information from study samples.The Biostatistics and Bioinformatics Core is integral to the collection validation and analysis of data for SPOREprojects. Further where appropriate statistical methods are inadequate or lacking Core personnel devise andimplement novel analytic approaches. The Core will provide: (1) prompt responsiveness with respect tobiostatistical and bioinformatics analyses; (2) appropriate expertise to select and implement an optimal approachto study design and analysis; (3) customized dataset creation and analysis; and (4) clear communication of studyfindings conclusions and limitations to investigators and the broader community. +No NIH Category available Adoptive Cell Transfers;Adoptive Transfer;Affect;Androgen Receptor;Androgens;Antigen Presentation;Antigens;Biological;Biological Markers;Biopsy;CAR T cell therapy;Cancer Etiology;Cancer Patient;Cancer Vaccines;Cell physiology;Cells;Cessation of life;Clinical;Clinical Data;Clinical Research;Clinical Trials;Combined Modality Therapy;Cytotoxic T-Lymphocytes;DNA;Dendritic Cell Vaccine;Disease;Evolution;FOLH1 gene;Future;Genetic;Goals;Granzyme;Hematologic Neoplasms;Heterogeneity;Human;Immune system;Immunologics;Immunotherapy;Inflammation;Inflammatory;Infusion procedures;Interferon Type II;Investigational Therapies;Malignant Neoplasms;Malignant neoplasm of prostate;Medical Oncology;Membrane;Memory;Metastatic Prostate Cancer;Molecular Analysis;Mus;Normal tissue morphology;Pacific Northwest;Patients;Phase;Phase I Clinical Trials;Phenotype;Process;Prostate;Prostatic Neoplasms;Proteins;Radioisotopes;Receptor Inhibition;Receptor Signaling;Resistance;Role;Safety;Solid Neoplasm;Specificity;Surface Antigens;T-Lymphocyte;Testing;Therapeutic;Time;Tissues;Toxic effect;Translating;Treatment-related toxicity;Tumor Antigens;Tumor Immunity;Tumor Tissue;United States;advanced prostate cancer;antigen-specific T cells;cancer immunotherapy;castration resistant prostate cancer;checkpoint inhibition;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical translation;comparative;cytokine release syndrome;density;effector T cell;enzalutamide;exhaust;exhaustion;fighting;first-in-human;human study;improved;inhibitor;insight;men;mortality;novel;novel therapeutic intervention;palliative;pharmacologic;pre-clinical;preclinical efficacy;preclinical safety;preclinical study;prevent;programs;prostate cancer model;radioligand;response;sex;six transmembrane epithelial antigen of the prostate 1;success;targeted treatment;therapy outcome;treatment response;tumor;tumor microenvironment Project 3: Modulating Androgen Receptor Signaling to Enhance the Efficacy of CAR T Cell Therapy for Advanced Prostate Cancer PROJECT NARRATIVEWe have discovered a prostate-specific protein that is highly expressed in advanced prostate cancer developeda chimeric antigen receptor T cell therapy product to target this protein and discovered that androgen receptorblockade improves T cell function. Therefore the goal of this proposal is to perform preclinical studies to revealfeasibility and toxicity of this therapy and then open a novel phase I clinical trial. NCI 10711591 9/4/23 0:00 PAR-20-305 2P50CA097186-22 2 P50 CA 97186 22 9/19/02 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5344 10992109 "LEE, JOHN KYUNG" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 326549 243398 83543 PROJECT SUMMARYAdoptive cell transfer in the form of chimeric antigen receptor T cell (CART) therapy has revolutionized thetreatment of hematologic malignancies and is slowly making inroads into solid tumors. Challenges to the efficacyand safety of CARTs in prostate cancer include antigen heterogeneity an immunologically cold tumormicroenvironment poor persistence and exhaustion. We have developed a novel CART therapy targeting sixtransmembrane epithelial antigen of the prostate 1 (STEAP1) which we found to be expressed more broadlythan prostate-specific membrane antigen (PSMA) in over 87% of lethal metastatic prostate cancers. In preclinicalhuman-in-mouse and mouse-in-mouse studies STEAP1 CART demonstrated 1) specificity and antitumoractivity in multiple prostate cancer models with varying levels of STEAP1 antigen density and 2) preliminaryevidence of safety. The STEAP1 CART program has been accepted into the NCI Experimental Therapeutics(NExT) Program to support clinical translation to a first-in-human study in men with metastatic castration-resistant prostate cancer (mCRPC). Furthermore androgens are well known to be immunosuppressive yetCART therapy is used without consideration of local androgen concentrations or the sex of the patient. Wepresent evidence that targeting the androgen receptor is necessary for effective T cell-specific immunotherapyand enhances the function of adoptive cell therapy products. In addition we demonstrate that androgen receptorsignaling inhibitors (ARSI) improve antigen presentation and promote T cell function within the prostate tumormicroenvironment. Together our observations suggest that combining CART therapy with ARSI could improvetherapeutic outcomes in advanced prostate cancer patients. To the best of our knowledge this is the firstcombination of preclinical studies and a CART clinical trial to target STEAP1 in advanced prostate cancerpatients.The goal of this proposal is to understand if we can improve CART function by perturbing androgen receptorsignaling with an ARSI. We hypothesize that we can improve STEAP1 CART cell persistence and functionby combining it with ARSI treatment. We will test this hypothesis in the following Aims: 1) Evaluate the effectof AR modulation on STEAP1 CART phenotype and function; 2) Investigate whether inflammation and ARSIimpacts safety and toxicity of STEAP1 CART therapy; and 3) Conduct a phase I clinical trial to assess thefeasibility safety and efficacy of STEAP1 CART therapy alone and in combination with enzalutamide in menwith STEAP1+ mCRPC.These studies provide the preclinical framework for understanding how ARSI and/or AR deletion impacts thefunction of a novel prostate CART product. Importantly these studies will provide critical insight into the safetyand toxicity of STEAP1 CART therapy alone or with ARSI and reveal potential therapeutic toxicity. +No NIH Category available ASCL1 gene;Ablation;Acute;Address;Aftercare;Androgen Receptor;Androgens;Back;Biological Markers;Castration;Cell Lineage;Cells;Clinical;Clinical Management;Combined Modality Therapy;DNA;DNA Sequence Alteration;Development;EZH2 gene;Enrollment;Epigenetic Process;Epithelium;Evolution;Future;Genetic;Genetic Transcription;Genomic Segment;Genomics;Goals;In complete remission;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metastatic Prostate Cancer;Molecular;Molecular Analysis;Names;Neoadjuvant Study;Neoadjuvant Therapy;Neurons;Neurosecretory Systems;PTEN gene;Pacific Northwest;Pathologic;Pathway interactions;Patient Selection;Patients;Pharmacodynamics;Phenotype;Population;Population Dynamics;Pre-Clinical Model;Predisposition;Process;Prognosis;Prostatectomy;Proto-Oncogene Proteins c-akt;Protocols documentation;RB1 gene;RNA;Receptor Signaling;Regimen;Residual Neoplasm;Resistance;Shapes;Stains;Systemic Therapy;TP53 gene;Testing;Therapeutic;Tissues;Triplet Multiple Birth;Up-Regulation;Work;abiraterone;biomarker development;cancer subtypes;cancer therapy;clinical heterogeneity;comparative;enzalutamide;epigenome;high risk;improved;inhibitor;inhibitor therapy;insight;men;multi-arm trial;multiple omics;neoplastic cell;neuroendocrine phenotype;novel;novel therapeutic intervention;patient derived xenograft model;pharmacologic;programs;prostate cancer cell;prostate cancer progression;rational design;resistance mechanism;response;standard care;standard of care;stem cells;targeted treatment;therapy development;therapy resistant;trial design;tumor Project 2: Understanding and Targeting the Lineage plasticity in the Genomic Umbrella Neoadjuvant Study (GUNS) PROJECT NARRATIVEThe proposed work will evaluate combinations of systemic therapies approved in metastatic PC earlier in menwith localized PC enrolled in GUNS to understand mechanisms of action and resistance as well as theheterogeneity of clinical response. Insights into therapy-induced cellular plasticity will help guide biomarkerdevelopment and expose new vulnerabilities to guide future combination strategies. These studies will definethe ideal context for epigenetic targeting to reverse plasticity and increase vulnerability to standard caretherapies. NCI 10711590 9/4/23 0:00 PAR-20-305 2P50CA097186-22 2 P50 CA 97186 22 9/19/02 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5343 10319536 "GLEAVE, MARTIN EDWIN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 214466 195858 19000 PROJECT SUMMARY/ABSTRACTThe androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression which hasled to a concerted effort to develop pharmacological agents to ablate AR activity and extend survival in men withmetastatic prostate cancer. However paradoxically increasingly potent AR pathway inhibitors (ARPI) therapieshave shaped the emergence of highly aggressive lineage plastic tumours with markedly distinct epigeneticprofiles low canonical AR signaling and activation of neuronal and developmental/stem cell-associatedtranscriptional programs. Recent clinical observations support that ~20% of advanced PCa patients with distinctgenomic alteration including loss of TP53 RB1 and PTEN and upregulation of EZH2 are more primed to developlineage plasticity and neuroendocrine phenotype. Notably prognosis remains poor due to a lack of ourunderstanding of the molecular and functional cell states underlying lineage reprogramming. Hence it is crucialto improve our understanding of these emergent resistance mechanisms in genomically segmented populationsin order to better inform future development of novel therapeutic strategies. We developed a novel clinical andtranslational neoadjuvant platform as a framework to understand the molecular basis for responses to intensiveARPI therapy. This adaptive multi-stage multi-arm trial named the Genomic Umbrella Neoadjuvant Study(GUNS NCT04812366) will evaluate ARPI-based therapeutic combinations in biomarker pre-selected patientswith high-risk localized PC. We hypothesize that genomic alterations determine depth of response to ARPI andthat co-targeting the AR with other contextually relevant targets defined by specific genomic subtype will increaserates of pCR and minimal residual disease in high-risk localized PCa. Certain PC subtypes with loss (isolated orcombined) of TP53 RB PTEN BRCA or gain in MYC and upregulation of EZH2 are better primed to surviveadapt develop linage plasticity and progress after ARPI.We will test our hypothesis in the following aims:Aim 1: Define the genomic predisposition of response to potent neoadjuvant ARPI in the GUNS trial.Aim 2: Assess fidelity of response and pathways activation to ARPI with targeted therapies in PDX models with analogous genomic alterations matched with subprotocols in GUNS.Aim 3: Conduct sub-protocol 5 in GUNS to evaluate combined ARPI with EZH2 inhibitor tazemetostat in PCs with defined genetic subtypes. +No NIH Category available Address;Adherence;African ancestry;Age;BRCA2 gene;Biological;Biological Assay;Cancer Biology;Cancer Etiology;Cancer Patient;Cessation of life;Characteristics;Clinical;Clinical Data;Clinical Management;Clinical Trials;DNA Repair Gene;Data;Disease;Disease Progression;Early Diagnosis;Early Intervention;Enrollment;Equity;Evaluation;Familial prostate cancer;Family;Family history of;First Degree Relative;Gene Mutation;Genetic;Germ-Line Mutation;Goals;Health behavior;Incidence;Individual;Inherited;Intervention;Life;Malignant neoplasm of prostate;Medical History;Metastatic Prostate Cancer;Methods;Molecular;Molecular Profiling;Morbidity - disease rate;Pacific Northwest;Patients;Pattern;Population;Population Heterogeneity;Prognosis;Proprotein Convertase 2;Relative Risks;Reporting;Risk;Risk Factors;Sampling;Screening for Prostate Cancer;Socioeconomic Status;Tumor Biology;Variant;cancer diagnosis;cancer genetics;clinical implementation;clinical practice;clinical translation;cohort;genetic information;genetic risk factor;genetic testing;genetic variant;health care availability;health care disparity;health disparity;high risk;high risk men;human old age (65+);improved;interest;male;men;mortality;novel;polygenic risk score;population based;prospective;prostate cancer progression;prostate cancer risk;rare variant;recruit;research clinical testing;risk prediction;synergism;translational impact;tumor Project 1: Molecular Predictors of Prostate Cancer Progression and Mortality PROJECT NARRATIVEThe goals of this proposal are to use population methods to recruit a diverse cohort of men with incident prostatecancer perform combined evaluation of rare variant germline DNA repair genes (e.g. BRCA2) and a novel multi-ancestry polygenic risk score to develop a clinical-grade paired tumor-germline assay and determine thebiological significance of high PRSm and specific PRSm variants using tumor molecular profiles. We will alsoconduct a tailored prostate cancer screening clinical trial including at-risk first-degree relatives of men recruitedthrough population methods and determine patterns of interest enrollment and adherence to prostate cancerscreening. Overall we seek to investigate the synergy of germline genetic information with relevance to a diversepopulation with the goal of improving risk prediction and tailored PC screening for men across multi-ancestrypopulations. NCI 10711589 9/4/23 0:00 PAR-20-305 2P50CA097186-22 2 P50 CA 97186 22 9/19/02 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5342 6259707 "CHENG, HEATHER " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 523852 397508 126736 PROJECT SUMMARYProstate cancer (PC) remains a leading cause of cancer-related morbidity and mortality and represents one ofthe largest health disparities in the US with men of African ancestry having the highest incidence and mortalityrates. Additional risk factors for PC include older age family history of PC and germline genetics. We previouslyreported that rare germline variants in DNA repair genes (gDRG) are enriched in men with lethal/metastatic PC.We have also developed a novel multi-ancestry polygenic risk score (PRSm) that is highly predictive of PC riskacross diverse populations and associated with a younger age at PC diagnosis and conversion from activesurveillance to treatment. The combined impact of gDRG and PRS on PC progression is not well understoodparticularly in multi-ancestry patients. In this Project we will use a population-based approach to identify andrecruit diverse non-European multi-ancestry PC patients examine the interplay between rare variants in gDRG(e.g. BRCA2) with PRSm and the association with PC clinical features. To accomplish this we will also developa clinical-grade paired tumor-germline assay which will additionally enable large-scale examination of gDRG incombination with high PRSm using tumor molecular profiles. We will also parse out specific individual variantsthat contribute the greatest effect on a high PRSm Finally we will conduct a tailored PC screening clinical trialfor individuals at highest risk of PC due to gDRG and determine patterns of interest enrollment and adherenceto PC screening. Together we seek to address and mitigate health care disparities related to prostate cancergenetics and the factors influencing clinical implementation. Ultimately we seek a better understanding of theinterplay between rare gDRG variants and PRSm for a combined analysis of germline genetic information toimprove risk prediction and tailored PC screening for men across a broader populations. +No NIH Category available Achievement;Address;Applications Grants;Award;Bioinformatics;Biometry;Cells;Characteristics;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Complex;Comprehensive Cancer Center;Computational Biology;Data;Data Analyses;Data Collection;Deposition;Development;Doctor of Philosophy;Ensure;Faculty;Fostering;Funding;Goals;Guidelines;Head and neck structure;Individual;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Methods;Monitor;Multiomic Data;Network-based;Pathway interactions;Play;Policies;Postdoctoral Fellow;Preparation;Publications;Publishing;Regulation;Reporting;Research;Research Design;Research Personnel;Role;Science;Services;Skin Cancer;System;The Cancer Genome Atlas;Training;Training and Education;United States National Institutes of Health;Visit;biomedical data science;career;cost effective;data management;database of Genotypes and Phenotypes;design;early phase clinical trial;experience;graduate student;innovation;meetings;melanoma;next generation;posters;programs;repository;student training;success Core C: Biostatistics and Bioinformatics Core CORE C: PROJECT NARRATIVEWith a stellar team of bioinformaticians and biostatisticians the Core will provide the whole spectrum of analyticsupport to all SPORE projects and investigators. The Core will ensure that all studies are properly designed andexecuted and that data are properly managed analyzed reported and published. NCI 10711515 9/19/23 0:00 PAR-20-305 2P50CA121974-16 2 P50 CA 121974 16 6/1/06 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5326 8798938 "MA, SHUANGGE " Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 206456 130200 87885 CORE C: PROJECT SUMMARYThe goals of the Biostatistics and Bioinformatics Core are to address the study design and analysis needs of theYale SPORE in Skin Cancer projects the Developmental Research Program (DRP) and the CareerEnhancement Program (CEP) and to address the analytical and data management needs of the BiospecimenCore. Drs. Kluger and Ma will continue to serve as Co-Directors of this Core and will be assisted by statisticiansand bioinformaticians with unique expertise and extensive experience. The Specific Aims of the Biostatistics andBioinformatics Core are as follows. Aim 1: Provide strong biostatistical and bioinformatics support to all SPOREprojects and investigators. The Core will provide timely and comprehensive support to address analytic questionsarising from the SPORE projects. Our service will cover the whole spectrum of the studies including studydesign data management and analysis result interpretation and preparation of manuscripts abstracts postersand applications. The Core will have regular research meetings with the SPORE investigators and maintain anopen-door policy for all analytic needs. Aim 2: Provide effective data management for all the SPORE projects.The Core will offer data management services to all projects and investigators and ensure that all NIH data-sharing regulations are properly followed. This includes deposit of properly curated data to repositories such asGEO SRA dbGaP and others. Aim 3: Develop innovative biostatistics and bioinformatics methods. Data withmore complex characteristics are and will continue being generated by the SPORE and other studies. The Corewill develop new analysis methods which will facilitate more effective utilization of data and foster melanomaanalytic research. Aim 4: Promote program-specific research opportunities involving biostatistics andbioinformatics trainees and faculty. The Core will promote opportunities within existing Yale programs andcenters including the Yale Graduate Program for Computational Biology and Bioinformatics (CBB) Yale Centerfor Biomedical Data Science (CBDS) Yale Center for Analytic Sciences (YCAS) and others. During the pastand ongoing funding period the Core has made significant contributions to research and training which is partlyreflected in our strong publication record and successes in training postdoc associates and graduate students.We will continue to do so in the proposed funding period. The Core will borrow strength while not overlap withthat of other SPOREs and Yale Comprehensive Cancer Center (YCC). The Core will also be a key partner inthe SPORE with representation on the Senior Leadership Team and participation in all key meetings. +No NIH Category available Address;Adult;Antibodies;Archives;Area;Basic Science;Bioinformatics;Biological;Biological Specimen Banks;Biometry;Biostatistics Core;Biotechnology;Cancer-Predisposing Gene;Cell Culture Techniques;Cell Extracts;Cells;Clinical;Clinical Data;Clinical Services;Clinical Trials;Collaborations;Collection;Consent;Core Facility;Cytometry;DNA;Data;Data Storage and Retrieval;Dermatopathology;Development;Dimethyl Sulfoxide;Ensure;Epidemiology;Evaluation;Family;Freezing;Future;Gene Expression Profiling;Genetic;Genomics;Goals;Health Insurance Portability and Accountability Act;Health protection;Hospitals;Human;Image;Immune response;Infrastructure;Institution;Laboratories;Lesion;Link;Liquid substance;Lymphocyte;Measures;Melanoma Cell;Methods;Methylation;Molecular;Molecular Analysis;Mutation;Mutation Analysis;Necrosis;Nevus;Newborn Infant;Nitrogen;Oligonucleotides;Paraffin;Pathologic;Pathology;Patients;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Plasma;Plasmids;Policies;Procedures;Process;Proteomics;Quality Control;RNA;Reagent;Recording of previous events;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Resources;Review Committee;Sampling;Scientist;Secure;Security;Serum;Services;Skin;Skin Cancer;Slide;Specimen;Sun Exposure;Surgical Pathology;System;Testing;The Cancer Genome Atlas;Tissue Banks;Tissues;Translational Research;Tumor Tissue;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Yale Cancer Center;bench to bedside;biomarker discovery;career;central database;chromatin modification;clinically relevant;cost effective;data warehouse;exome;follow-up;genome analysis;genomic data;innovation;liquid crystal polymer;melanocyte;melanoma;nano-string;neoplastic cell;new therapeutic target;operation;patient health information;peripheral blood;preclinical study;programs;promoter;quality assurance;transcriptome sequencing;translational study;tumor;tumor microenvironment;tumor registry;tumor-immune system interactions Core B: Biospecimen Core CORE B BIOSPECIMEN CORE: PROJECT NARRATIVEBiospecimen Core (Core B) provides a variety of clinically annotated samples (tumor normal skin plasmaperipheral blood lymphocytes tumor infiltrating lymphocytes serum short term cultures DNA and RNA) toSPORE investigators and other collaborators at Yale and outside of Yale. Integration with Core C for storage ofdata is key to maximizing utilization of specimens and distribution of samples is governed by a Tissue Committee.The Core is central to all the activities of YSPORE and well integrated with pathology and clinical services atYale Cancer Center. NCI 10711514 9/19/23 0:00 PAR-20-305 2P50CA121974-16 2 P50 CA 121974 16 6/1/06 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5325 1861045 "HALABAN, RUTH " Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 193550 122061 82391 CORE B BIOSPECIMEN CORE: PROJECT SUMMARYThe Biospecimen Core (Core B) is the cornerstone of all Yale SPORE in Skin Cancer (YSPORE) activities. Itaddresses the broad melanoma patient specimen needs of all the projects that are not met by current sharedfacilities at Yale. In addition to collecting storing and distributing a wide range of specimens and reagents thecore performs quality assurance testing and a wide range of molecular analyses of specimens. More specificallythe core: a) collects a large repertoire of specimens for translational and preclinical studies in melanomaincluding melanocytic lesions melanoma tumors and cells normal skin serum and circulating lymphocytes;b) ensures high quality control proper long-term storage detailed annotation and timely distribution ofspecimens to YSPORE investigators; c) establishes and maintains a central database of essential pathologicalclinical epidemiological and follow-up information and basic research data generated by the YSPORE projectsthat is integrated with the Biostatistics and Bioinformatics Core; d) provides special services such as the analysisof specimens from clinical trials mutations chromatin modification and collection of TIL (tumor infiltratinglymphocytes); e) maintains and distributes validated reagents (antibodies oligonucleotides for PCR DNA RNAplasmids cell extracts) needed for molecular analyses of tumors by different YSPORE investigators;f) establishes links with shared facilities at Yale and similar resources in other institutions including otherSPOREs; g) distributes samples to collaborating investigators outside of Yale; and h) provides specimens forlarger NCI objectives such as melanoma specimens peripheral blood lymphocytes and annotated clinical datafor The Cancer Genome Atlas (TCGA). The core interacts extensively with investigators in each project theBioinformatics and Biostatistics Core the Clinical Trial Office and Yale Cancer Center shared resource coressuch as Yale Pathology Tissue Services and Yale Center for Genome Analysis. The services of the BiospecimenResource Core enhance the efficient operation of the translational studies by YSPORE investigators in a cost-effective manner and expedite the application of discoveries from the bench to clinical practice and clinicalresults to basic research. +No NIH Category available Address;Administrator;Advocacy;Bioinformatics;Biometry;Cancer Hospital;Clinical;Collaborations;Communication;Community Outreach;Consultations;Dermatology;Development;Educational workshop;Ensure;Funding;Goals;Grant;Head and neck structure;Institution;Joints;Leadership;Malignant neoplasm of lung;Monitor;National Cancer Institute;Patients;Pharmaceutical Preparations;Program Evaluation;Progress Reports;Publications;Regulation;Research;Research Personnel;Research Priority;Resource Sharing;Resources;Series;Services;Site;Skin Cancer;Technology;Translational Research;United States National Institutes of Health;Universities;Update;Work;Yale Cancer Center;career;clinical infrastructure;data integration;data sharing;medical schools;meetings;melanoma;neoplasm resource;operation;outreach;patient outreach;programs;scientific organization;success;synergism;wasting;website development Core A: Administrative Core n/a NCI 10711510 9/19/23 0:00 PAR-20-305 2P50CA121974-16 2 P50 CA 121974 16 6/1/06 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 5321 6483185 "BOSENBERG, MARCUS W" Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 179822 113404 76548 CORE A: PROJECT SUMMARYThe Administrative Core (Core A) is critical to the success of the Yale SPORE in Skin Cancer (YSPORE). Theprimary purpose of the Core is to support and facilitate transdisciplinary research efforts in skin cancer and identifynew challenges and opportunities as they emerge. The Administrative Core serves as the central coordinationpoint for YSPORE investigators with responsibility for monitoring the progress of all projects and cores towarda translational/clinical endpoint. These services include provision of (a) fiscal management (b) clerical andorganizational support (c) mechanisms for internal and external review (d) support for enhancement of scientificinteractions and collaborations among the Project/Core leaders (e) mechanisms to monitor projects and coresfor scientific progress (f) coordination of outreach efforts and (g) mechanisms to expand research in skin cancerbeyond the activities of the SPORE both within Yale and outside of Yale. Core A will also be responsible forensuring full integration of activities of the Yale SPORE in Skin Cancer with those of Yale Cancer Center andthe other Yale SPOREs with the goal of avoiding overlap and duplication of efforts while maximizing synergyand use of resources. Any conflicts that might arise between SPORE investigators will be addressed by the CoreA Directors with input from the Executive Committee and the External and Internal Advisory Boards and EricWiner MD if needed. Core A will work closely with the Biostatistics and Bioinformatics Core (Core C) to ensurethe integration of data generated by the SPORE program into that of Yale Cancer Center and vice versa and tooversee sharing of data with other skin cancer/melanoma SPORE sites and when appropriate with the YaleSPORE in Lung Cancer and the Yale Head and Neck SPORE. Core A will organize joint scientific research inprogress meetings held with the SPORE researchers to ensure bi-directional flow of ideas and sharing ofresources. Investigators involved in this program will also participate in the annual inter-SPORE workshopsorganized by Core A in collaboration with Administrative Cores at other sites. The Core will be directed by Drs.Marcus Bosenberg and Harriet Kluger and the Co-Director is Dr. Mario Sznol. Program oversight by Core A willbe done with input from the Executive Committee and input for scientific and administrative functions will besought from the Internal and External Advisory Boards. Annual meetings with the Internal and External AdvisoryBoards will be organized by Core A. The Core will also organize research in progress seminars talks by outsideinvestigators and patient and community outreach. +No NIH Category available Adaptive Immune System;Address;Agonist;Animal Model;Antibodies;Antitumor Response;Award;Back;Bioinformatics;Biological Assay;Biological Markers;Biology;Biometry;Cell Culture Techniques;Cells;Clinic;Clinical;Clinical Trials;Collaborations;Data;Development;Disease;Effector Cell;Environment;Epigenetic Process;Eye;Fostering;Funding;Future;Genetic;Goals;Histone-Lysine N-Methyltransferase;Human;IL18 gene;Immune Evasion;Immune checkpoint inhibitor;Immunobiology;Immunocompetent;Immunooncology;Immunotherapy;Incidence;Innate Immune System;Institution;Interdisciplinary Study;Interferon Type II;KDM5B gene;Macrophage;Malignant Neoplasms;Melanoma Cell;Messenger RNA;Metastatic Melanoma;Methods;Modeling;Morbidity - disease rate;Mus;Natural Immunity;Natural Killer Cells;Neoplasm Metastasis;Outcome;PD-1 inhibitors;PD-1/PD-L1;PD-L1 blockade;Pathway interactions;Patient Selection;Patient-Focused Outcomes;Patients;Phase I Clinical Trials;Pre-Clinical Model;Productivity;Program Development;Proteins;Regimen;Research;Research Personnel;Resistance;Resources;Retroelements;SETDB1 gene;Sampling;Science;Series;Signal Repression;Site;Skin Cancer;Systemic Therapy;T cell infiltration;T-Lymphocyte;TNFRSF5 gene;Technology;Thinness;Tissues;Toxic effect;Translating;Treatment Protocols;Variant;Work;Yale Cancer Center;advanced disease;anti-CTLA4;anti-PD-1;bench to bedside;biomarker development;career;clinical application;cohort;cytokine;cytokine therapy;derepression;design;digital pathology;effector T cell;histone demethylase;immunomodulatory therapies;improved;improved outcome;inhibitor;innovation;interleukin-18 receptor;medical schools;melanoma;mortality;mouse model;neoantigens;neoplastic cell;new technology;new therapeutic target;next generation;novel;novel strategies;novel therapeutics;optimal treatments;predicting response;predictive marker;preservation;prevent;programs;resistance mechanism;response;stem;therapy resistant;translational cancer research;translational scientist;tumor Yale SPORE in Skin Cancer OVERALL: PROJECT NARRATIVEThe goal of the Yale SPORE in Skin Cancer is to decrease morbidity and mortality from melanoma. We haveassembled a group of interdisciplinary investigators to conduct a series of bench-to-bedside studies aimed atpreventing melanoma and improving outcomes for patients in whom melanoma has metastasized. These studieswill capitalize on advances made in the last funding period and build on the extensive resources such as tumorsamples animal models and novel drugs and technologies developed in the past decade by YSPOREinvestigators. NCI 10711509 9/19/23 0:00 PAR-20-305 2P50CA121974-16 2 P50 CA 121974 16 "KUZMIN, IGOR A" 6/1/06 0:00 8/31/28 0:00 ZCA1-RPRB-N(M1)S 6483185 "BOSENBERG, MARCUS W" "KLUGER, HARRIET M." 3 DERMATOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 397 Research Centers 2023 1533274 NCI 966950 652691 OVERALL: PROJECT SUMMARYThe Yale SPORE in Skin Cancer (YSPORE) now in its third funding cycle involves a broad range of projectsand investigators with diverse expertise whose goal is to decrease mortality from melanoma by developing noveldrugs and regimens to treat patients once it metastasizes and develop predictive biomarkers to select patientsfor the optimal treatment regimen. YSPORE leans on the immense scientific and clinical strengths at Yale Schoolof Medicine and Yale Cancer Center including immunobiology genetics epigenetics quantitative sciencesimmuno-oncology animal models and digital pathology. YSPORE investigators have made major contributionsin recent years to developing improved immune therapy approaches for melanoma patients with advanceddisease and novel single cell tumor profiling platforms. Advances in systemic therapies for advanced melanomaparticularly immune checkpoint inhibitors that prolong survival pose a new set of challenges for clinicians whichwill be addressed by the proposed research program as we strive to increase the long term survival for allmelanoma patients. The YSPORE translational research team proposes to accomplish the objective ofdecreasing morbidity and mortality from skin cancer through four specific aims: Specific Aim 1: Develop newapproaches to enhancing activity of PD-1 inhibitors by co-targeting the innate and adaptive immune systems inimmune checkpoint inhibitor nave patients; Specific Aim 2: Study novel drugs that target the epigenetic modifierKDM5B to upregulate endogenous retroelements and enhance T cell infiltration in tumors that are unresponsiveor poorly responsive to immune checkpoint inhibitors; Specific Aim 3: Study novel cytokines to overcomeresistance to immune checkpoint inhibitors in patients whose melanoma has progressed on anti-PD-1; andSpecific Aim 4: Develop new research directions to decrease mortality from melanoma and nurture the nextgeneration of translational investigators focusing on skin cancer through a Developmental Research Programand a Career Enhancement Program. We propose three cores (Administrative Core Biospecimen Core andBiostatistics and Bioinformatics Core) to support the projects their clinical aims mechanistic studies andbiomarker development for clinical application. The Projects and Cores are designed to be highly coordinatedwith the goal of maximizing resources and potential impact. New collaborations will be established during thefunding period through the Developmental Research Program with the support of the Administrative Core.Collaborations with other institutions and skin cancer SPORE sites will be fostered by the Administrative Core.These coordinated efforts will enhance analysis of patient samples use of cell cultures and animal models anddevelopment of predictive biomarker assays. Our purpose is to translate the innovative approaches proposedhere to clinical therapies for treatment of advanced skin cancer. 1533274 +No NIH Category available 4T1;Affinity;Agonist;Animal Model;Antibody-drug conjugates;Apoptosis;Binding;Biodistribution;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;CD276 gene;CTLA4 gene;Cell Death;Cells;Circulation;Clinic;Clinical Trials;Combined Modality Therapy;Cytotoxic Chemotherapy;Data;Development;Distant;Drug Kinetics;Drug resistance;Engineering;Evaluation;Event;Excision;Extracellular Domain;Flow Cytometry;Future;Goals;Heterogeneity;Histopathology;Human;Immune;Immune Tolerance;Immuno-Chemotherapy;Immunocompetent;Immunohistochemistry;Immunotherapy;In Vitro;Infiltration;Interferon Type II;Invaded;Investigation;Laboratories;MDA MB 231;Macrophage;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Medical;Membrane;Membrane Glycoproteins;Microtubules;Modeling;Monoclonal Antibodies;Names;Neoplasm Metastasis;Operative Surgical Procedures;Organ;Pathology;Patients;Pharmaceutical Preparations;Pharmacotherapy;Prognosis;Proliferating;Proteomics;Quality of life;Radiation therapy;Receptor Activation;Recurrence;Refractory;Relapse;Resistance;Specificity;Surface;Survival Rate;T-Lymphocyte;TLR1 gene;TLR7 gene;TNF gene;Technology;Testing;Therapeutic;Therapeutic Monoclonal Antibodies;Tissue Microarray;Tissues;Toll-like receptors;Toxic effect;Toxicology;Transcript;Translations;Treatment Efficacy;Treatment Protocols;Tumor Burden;Tumor Immunity;Tumor Promotion;Xenograft Model;Xenograft procedure;angiogenesis;anti-PD-1;anti-PD1 antibodies;anti-cancer;cancer cell;cancer subtypes;cancer therapy;cell killing;chemotherapy;clinically relevant;confocal imaging;cytokine;cytotoxic;cytotoxicity;dosage;effective therapy;effectiveness evaluation;efficacy study;glycosylation;high dimensionality;humanized mouse;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;immune checkpoint blockers;immune function;immunoregulation;improved;in vivo;innovation;mouse model;neoplastic cell;novel;novel therapeutic intervention;optimal treatments;patient derived xenograft model;pembrolizumab;phase III trial;pre-IND studies;pre-clinical;programmed cell death ligand 1;programmed cell death protein 1;response;restoration;standard of care;synergism;systemic toxicity;targeted treatment;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor-immune system interactions Dual-payload antibody-drug conjugate for chemo-immunotherapy of triple-negative breast cancers PROJECT NARRATIVEThe triple-negative breast cancers (TNBCs) are highly aggressive and recurrent. Targeted therapy and combinedchemo-immunotherapy have great potential to treat metastatic and heterogenous TNBCs. This project willdevelop and fully evaluate a humanized anti-CD276 antibody-drugs conjugate (Hu276-DualADC) which carriesboth highly potent payload to kill cancer cells and toll-like receptor agonist to activate effector immune cells intumor microenvironment and in combination with PD-1-targeted ADC for TNBCs treatment. NCI 10711488 7/25/23 0:00 PA-20-185 1R01CA281980-01 1 R01 CA 281980 1 "CARDONE, MARCO" 7/25/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 11598177 "LIU, XIAOGUANG MARGARET" "CARSON, WILLIAM E." 3 ENGINEERING (ALL TYPES) 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH BIOMED ENGR/COL ENGR/ENGR STA 432101016 UNITED STATES N 7/25/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 587169 NCI 372806 214363 SUMMARYTriple-negative breast cancers (TNBCs) are highly aggressive and often relapse post standard cytotoxicchemotherapies. The immunotherapies such as immune checkpoint blockers (ICBs) that target PD-1 PD-L1 orCTLA-4 represent a major breakthrough in cancer treatment but 75-90% of TNBC patients failed to respond dueto primary and acquired resistance. The Sacituzumab-SN38 and Pembrolizumab-chemotherapy have beendeveloped and applied to treat refractory metastatic TNBC showing the great potential of combined and targetedtherapies but novel effective treatment strategies for TNBC are urgently needed. We recently detectedtransmembrane CD276 (B7-H3) associated with angiogenesis metastasis and immune tolerance in most TNBCpatients and developed a humanized anti-CD276 monoclonal antibody (mAb) capable of targeting CD276+TNBC and upregulating tumoral immunity. Furthermore we established innovative platforms for concurrentconjugation of highly cytotoxic emtansine and immunoregulating toll-like receptor (TLR) agonist in one antibody-drug conjugate (ADC). Our preliminary evaluations showed that the CD276-targeted dual-payload ADC (276-DualADC) effectively killed multiple TNBC subtypes significantly enhanced immune functions and overcameICB resistance to PD-1 mAb and reduced tumor burden by 90-100% and metastasis in three animal models.These results indicate 276-DualADC is a promising therapeutic to treat TNBCs. Our goal is to develop andexamine the effectiveness of combining humanized CD276 mAb-directed Hu276-DualADC which targetingdelivers a potent chemotherapy and immunotherapy TLR 7/8 agonist and PD-1-targeting ADC to eliminateheterogenous and metastatic TNBC cells in vivo. It is hypothesized that this novel combinatory strategy namedas Hu276/PD-1-DualADC synergizes multiple chemo- and immuno-mediated anti-cancer mechanisms i.e.direct cancer cell killing tumoral immunity tumoral cytokine and immune checkpoint blockade to enhanceTNBC treatment efficacy. Three aims were proposed to test the hypothesis. Aim 1 will produce large-scaleHu276-DualADC carrying mertansine and imidazoquinoline and characterize its affinity TNBC-specificitybiodistribution and toxicity. Optimal treatment strategy will be determined in maximal tolerated dose andpharmacokinetics studies. Finally anti-TNBC efficacy will be evaluated in primary xenograft models and distantmetastatic models. Aim 2 will assess the synergistic effects of HuCD276/PD-1-DualADC in threeimmunocompetent models. The underlying mechanisms (proliferation apoptosis immune cell infiltration andactivation tumoral cytokine and ICB restoration) will also be delineated. Aim 3 will fully evaluate the long-termtherapeutic efficacy in metastatic syngeneic TNBC xenograft models post surgical resection and patient-derivedxenograft (PDX) models. Pre-IND toxicology will also be investigated to collect preclinical data for future clinicaltrial launching. Successful completion of this project will provide a new strategy to treat aggressive TNBCs. 587169 +No NIH Category available Academic Training;Address;Age;Aging;American Indians;Arizona;Awareness;Behavior;Cancer Center;Cancer Control;Cancer Control Research;Career Exploration;Caring;Catchment Area;Communities;Comprehensive Cancer Center;Continuing Education;Discipline;Education;Educational Activities;Enrollment;Ensure;Environmental Hazards;Ethnic Origin;Evaluation;Faculty;Feedback;Fostering;Funding;Future;Goals;Grant;Habits;Health Promotion Sciences;Health Sciences;Healthcare;Hispanic;Immersion;Institution;Instruction;Interdisciplinary Study;International;Investments;Knowledge;Laboratory Research;Leadership;Learning;Life Style;Location;Malignant Neoplasms;Mentors;Mentorship;Methodology;Methods;NCI Center for Cancer Research;Native Americans;Obesity;Pathway interactions;Perception;Populations at Risk;Prevention Research;Program Development;Race;Research;Research Peer Review;Research Personnel;Research Project Grants;Research Training;Resources;Retirement;Risk;Risk Factors;Science;Scientist;Self Efficacy;Silver;Students;Time;Training;Training Programs;Training Support;Training and Education;Tsunami;Universities;anticancer research;cancer health disparity;cancer prevention;cancer risk;cancer survival;care providers;career;career development;career networking;community engagement;design;dissemination research;early-career faculty;empowerment;experience;faculty community;faculty mentor;graduate student;hands on research;health disparity;improved;improved outcome;innovation;interest;intrinsic motivation;member;multidisciplinary;next generation;pedagogy;peer;peer coaching;post-doctoral training;programs;recruit;senescence;senior faculty;skills;student participation;student retention;summer research;undergraduate student Student Transformative Experiences to Progress Undergraduate/Graduate Professionals (STEP-UP) for cancer prevention PROJECT NARRATIVEThere continues to be a need to engage students in cancer prevention and control research early in theiracademic training to inspire cancer prevention and control careers and renew the pool of scientists andclinicians in the field. The overall goal of this program entitled Student Transformative Experiences toProgress Undergraduate and Graduate Professionals (STEP-UP) for cancer prevention is to provideundergraduate and Masters' degree seeking students with an intensive hands-on summer researchexperience in cancer prevention and control. This research training experience includes the conduct of amentored research project didactic instruction and career development guided by highly experiencedmultidisciplinary leadership and mentoring teams with peer reviewed research funding to assure a qualityprogram that will build and sustain the cancer prevention and control workforce of the future. NCI 10711389 6/23/23 0:00 PAR-21-279 1R25CA275753-01A1 1 R25 CA 275753 1 A1 "ELJANNE, MARIAM" 7/1/23 0:00 6/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 10162095 "BEA, JENNIFER WRIGHT" "THOMSON, CYNTHIA A." 7 PUBLIC HEALTH & PREV MEDICINE 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF PUBLIC HEALTH 857210158 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 286654 NCI 265420 21234 PROJECT SUMMARY / ABSTRACTThis application entitled Student Transformative Experiences to Progress Undergraduate and GraduateProfessionals (STEP-UP) for cancer prevention is a multidisciplinary research training initiative led by theHealth Promotion Sciences faculty and the University of Arizona (UA) Comprehensive Cancer Center CancerPrevention and Control (CPC) Program. It is uniquely designed to provide 75 upper division undergraduate and25 Masters' degree seeking students with an intensive summer research experience in CPC over the grantperiod. The research training includes immersion in mentor research laboratories and programs full-time for 10weeks to experience CPC science across the entire continuum of basic to applied and even disseminationresearch. Faculty mentor matching is carefully tailored to trainee interests gaps in prior training and careergoals from 39 faculty members from diverse disciplines committed to this program who are funded in CPCresearch. Trainees will also engage in weekly complimentary educational activities including learning aboutcommunity engagement and career exploration and development. Educational pedagogy will inform on ourmethodology in order to assure students receive a quality educational experience that not only will increaseunderstanding but also will motivate students toward a continued educational commitment to advance in CPCsciences. An embedded mentor development program will enhance faculty mentor training and engageMasters' students and high-performing STEP-UP trainees from past years to serve as peer-to-peer mentors.The STEP-UP program fills early gaps in our research training pathway programs builds on purpose-drivenefforts at the UA Cancer Center to attract and retain a diverse student body in CPC research leverages ourinternational reputation in CPC supports continuous renewal of CPC mentors in academics and care throughthe mentor training program and has garnered significant institutional support. Our specific aims are: 1.Recruit and retain undergraduate and Master's level graduate students into the STEP-UP research trainingprogram; 2. Provide a multidisciplinary research training experience in CPC that strengthens self-efficacy andintrinsic motivation to become a CPC scientist; 3. Support mentor training across academic stages frommentee to peer-to-peer up through senior faculty mentors and cultivate professional relationships withscientists research programs and community partners; 4. Conduct formative and summative evaluations toimprove the program over time. The training program is centralized in Southern Arizona and offers hands-onresearch training within our unique catchment area which is rich in diversity relative to ethnicity (31.7%Hispanic) race (5.3% Native Americans) and age (18.0% 65 years). This distinctive location strongcommunity ties university facilities and resources for research as well as committed and experienced facultymentors and leaders assures a quality program that will build and sustain the CPC workforce of the future. 286654 +No NIH Category available AIDS related cancer;Acceleration;Basic Science;Cancer Control;Career Choice;Clinical;Clinical Research;Communities;Complement;Development;Education;Educational Curriculum;Ensure;Environment;Evaluation;Exposure to;Fostering;Foundations;Funding;Future;Gastrointestinal Neoplasms;Goals;Health Disparities Research;Institution;Investigation;Knowledge;Leadership;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Mammary Neoplasms;Measures;Medical;Medical Education;Medical Students;Mentors;Multiple Myeloma;Myeloproliferative disease;Outcome;Participant;Physicians;Population Research;Process;Research;Research Project Grants;Resources;Scholars Program;Scientist;Seasons;Structure;Students;Time;Training;Translational Research;United States National Institutes of Health;anticancer research;cancer prevention;career;clinical investigation;design;educational atmosphere;experience;fundamental research;health disparity;health equity;improved;innovation;interest;medical schools;member;next generation;novel;pedagogical content;pedagogy;pre-doctoral;programs;recruit;response;skills;student participation;success;summer student;tool;tumor immunology TCI Mentored Medical Student Summer Scholars (TCI-MMSSS) Program The overarching goal of the proposed Tisch Cancer Institute (TCI)-Mentored Medical Student SummerScholar (TCI-MMSSS) Program is to inspire medical students to pursue careers in cancer research throughengagement in an innovative highly structured program of strongly mentored research projects and interactivecurricular activities. Our program leverages institutional strengths in novel pedagogy and curricular innovationas well as the seasoned mentoring capacity and research expertise of the TCI Scientific Programs in CancerImmunology Cancer Mechanisms Cancer Clinical Investigation Cancer Prevention and Control and HealthEquity and Health Disparities. Our outstanding cadre of exceptional mentors enthusiastic pool of diverse andcompelling students and academically rigorous and innovative training environment will accelerate thedevelopment of the next generation of MD physician scientists committed to meaningful and clinically impactfulcancer investigation. NCI 10711268 7/17/23 0:00 PAR-21-279 1R25CA281789-01 1 R25 CA 281789 1 "RADAEV, SERGEY" 7/17/23 0:00 6/30/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1901145 "GABRILOVE, JANICE L" "FERRARA, JAMES L. M.; LIN, JENNY J." 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 7/17/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 103291 NCI 95640 7651 The goal of our Tisch Cancer Institute (TCI) Mentored Medical Student Summer Scholars (TCI-MMSSS)Program is to inspire medical students to pursue careers in cancer research through engagement in aninnovative highly structured program of strongly mentored research and interactive curricular activities. Ourprogram builds upon the foundation of a successful 10 week pilot initiative of a summer mentored researchexperience for medical students in which 69% of participants (rising second year medical students) have eitheralready completed or have committed to pursuing an additional year of research with their mentors. Ourproposed 15 week rigorously mentored research experience is designed to recruit exceptional and highlymotivated students interested in cancer research and enriched by novel pedagogical approaches to foster aninnovative and nurturing learning environment using a strategically crafted Cancer Research Fundamental 101(CRF 101) curriculum to advance research knowledge mindset and skills. Our program leverages theseasoned mentoring capacity and scientific strengths of the TCI scientific programs including CancerImmunology (CI) Cancer Mechanisms (CM) Cancer Clinical Investigations (CCI) and Cancer Prevention andControl (CPC) as well as our acknowledged expertise in health equity and health disparities research. Ourprogram is also informed by excellence in basic translational clinical and population research in community-recognized catchment-relevant cancers including Liver Lung Multiple Myeloma HIV-related malignancies andProstate Cancer as well as Breast Gastrointestinal and Myeloproliferative Neoplasms. Our program Multi-PILeadership team reflects complementary expertise in pre-doctoral education and medical student research toensure the realization of potential for cancer research by each student participating in the TCI-MMSSSProgram. We propose a holistic valuation process that incorporates validated tools to evaluate studentsmentors and the overall program to achieve continuous quality improvement and propose to follow programalumni over several years to obtain longitudinal outcomes to assess integration of cancer research into medicalcareers. 103291 +No NIH Category available Administrator;Age;Alaska Native;American Indians;Arizona;Awareness;Basic Cancer Research;Biology;Cancer Center;Cancer Control;Collaborations;Communication;Communities;Consultations;Development;Education;Education and Outreach;Educational Curriculum;Educational Status;Educational workshop;Electronics;Elements;Ensure;Evaluation;Event;Exposure to;Faculty Workshop;Feedback;Fostering;Frequencies;Goals;Grant;Health;Health Occupations;Health Sciences;High School Student;Humanities;Indigenous;Infrastructure;Instruction;Internships;Knowledge;Laboratories;Learning;Malignant Neoplasms;Measures;Medical;Medical center;Medicine;Mentors;Modeling;Native Americans;Native-Born;Nebraska;Next Generation Science Standards;Online Systems;Outcome;Ownership;Participant;Pathway interactions;Patient Recruitments;Peer Review;Persons;Population;Program Development;Program Evaluation;Publications;Readiness;Relationship-Building;Research;Resources;Rural;STEM research;Schools;Science;Science Technology Engineering and Mathematics Education;Services;Site;South Dakota;Strategic Planning;Students;Surveys;System;Technology;Testing;Training;Tribal School;Tribes;Trust;Universities;Work;Youth;anticancer research;cancer education;cancer prevention;career;career development;college;community building;community engagement;community partnership;curriculum development;education resources;evidence base;experience;implementation facilitation;improved;innovation;interest;junior high school;learning materials;literate;meetings;member;novel;outreach;process evaluation;program dissemination;programs;recruit;scale up;science education;sixth grade;stakeholder perspectives;student mentoring;success;summer research;symposium;teacher;tool;translational cancer research;tribal community;undergraduate student;urban Native American;virtual Ignite-Engage-Sustain: A Comprehensive Approach to Motivate Involve Educate and Mentor Native American Students and Their Communities in Cancer Prevention Treatment and Research PROJECT NARRATIVEPrograms that engage and sustain interest in science health professions and cancer research amongAmerican Indian and Alaska Native (AI/AN) students and their teachers from middle school through college aredesperately needed. With an experienced team cutting-edge campus resources and strong partnershipsupport the Youth Enjoy Science program will continue to build community trust and recruit participantsthrough outreach train participants through research experiences and develop and implement Indigenousscience and cancer education curriculum and career development activities. Our aim is to not only increaseAI/AN representation in cancer-related health professions and research but also advance the health of AI/ANsthrough improvements in cancer prevention treatment and research in AI/AN communities. NCI 10711114 9/21/23 0:00 RFA-CA-21-020 2R25CA221777-06A1 2 R25 CA 221777 6 A1 "LOPEZ, BELEM G" 9/20/17 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 14877070 "IDOATE, REGINA EMILY" "GODFREY, MAURICE ; SOLHEIM, JOYCE C" 2 MISCELLANEOUS 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF PUBLIC HEALTH 681987835 UNITED STATES N 9/21/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 388800 NCI 360000 28800 PROJECT SUMMARYThe University of Nebraska Medical Center (UNMC)College of Medicine and the University of Nebraska Omaha's Biology Department and its programs in NativeAmerican Studies and in Medical Humanities will leverage the trust and cooperative spirit that has beengarnered working with tribal schools and communities in Nebraska South Dakota and Arizona to developimplement and evaluate cancer-related science curricula and research experiences aimed to support NativeAmerican students. The UNMC in community-based cancer preventioncombined with the Munroe- excellence in educational outreach and the first-rate basic andtranslational cancer research in state-of-the-art laboratories at the Eppley Institute in the NCI-designated Fred& Pamela Buffett Cancer Center are consolidated in the UNMC Youth Enjoy Science program (UNMC-YES)for the benefit of Native American students' education in all aspects of cancer research. The long-term goalsof this project are to promote student interest in the sciences foster a more science-literate publicand increase the number of Native Americans entering health and science careers with a particularemphasis in cancer research. UNMC-YES aims to: 1) Cultivate and sustain trusting community partnershipsto expand outreach initiated in the original grant cycle to rural and urban Native American students 2)Develop disseminate and implement culturally relevant technology-based cancer education curricula withNative American populations and 3) Expand Native American student horizons through hands-on culture-and standards-based science activities research experiences and exposure to health science careers. Theseaims will be accomplished through innovative and evidence-based 1) outreach and engagement 2) curriculumdevelopment and dissemination and 3) provision of research experiences. UNMC-YES will generate anddeliver cancer-related activities lessons and research experiences to Native American students in grades 6through undergraduate. UNMC-YES will also provide teachers with research experiences workshopsmentoring and in-service education to facilitate implementation of project curriculum with Native Americanstudents. Student participants will experience a range of highly intensive activities such as summer researchcamps to higher frequency activities such as school-based science clubs mentored cancer researchinternships and ongoing research talking circles. Professional evaluations will be made at all stages withmajor emphasis on the educational professional and community impact of the project. Pre- and post-testmeasures will analyze participant outcomes. Stakeholder perspectives and community systems for reducingcancer will be assessed to inform continuous improvement. Our objective is not only to increase NativeAmerican representation in cancer-related health professions and research but also to advance the health ofNative Peoples through improvements in cancer prevention treatment and research. 388800 +No NIH Category available Address;Area;Behavioral Risk Factor Surveillance System;Black Populations;Black race;Budgets;Cancer Patient;Caring;Censuses;Characteristics;Clinical Trials;Code;Commuting;Complex;County;Data;Data Set;Databases;Diagnosis;Disparity;Emergency department visit;Evaluation;Excess Mortality;Future;Geographic Factor;Geographic Locations;Geography;Health;Health Information National Trends Survey;Health Insurance;Health Services Accessibility;Health behavior;Healthcare;Hospitalization;Individual;Inferior;Insurance;Intervention;Link;Malignant Neoplasms;Mediating;Mediation;Methodology;Modeling;Nature;Office Management;Outcome;Participant;Play;Policies;Policy Developments;Policy Maker;Population;Poverty;Poverty Areas;Quality of Care;Race;Reasons for Geographic And Racial Differences in Stroke;Reporting;Research Personnel;Role;Rural;Rural Population;SEER Program;Sampling;Social support;Socioeconomic Status;Specialist;Stroke Belt;System;Transportation;Work;cancer health disparity;cohort;comorbidity;contextual factors;data registry;deprivation;evidence base;experience;health literacy;indexing;malignant breast neoplasm;mortality;mortality disparity;multilevel analysis;neoplasm registry;primary outcome;rural area;rural disparities;rural patients;rural poverty;rural residence;rurality;screening;social vulnerability;sociodemographics;statistics;therapy development;urban area;urban disparity;urban residence;virtual Understanding rural mortality disparities in cancer: a multi-level approach Relevance narrativeApproximately 19% of the US population resides in rural areas; for over three decades this population hasexperienced increasingly inferior health outcomes when compared with their urban counterparts. The underlyingcause(s) of the widening rural/urban gap in cancer outcomes is hypothesized to be multifactorial and this studywill provide a comprehensive multi-level evaluation of rural/urban mortality disparities. Findings will provide thecritical evidence needed to inform policy as well as to inform intervention development to address the systemicdisparities in mortality experienced by rural patients with cancer. NCI 10711063 11/16/22 0:00 PA-21-268 7R37CA266193-02 7 R37 CA 266193 2 "DELLAVALLE, CURT TAVIS" 1/1/22 0:00 12/31/26 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 11262899 "KENZIK, KELLY " Not Applicable 7 SURGERY 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 1/1/23 0:00 12/31/23 0:00 393 Non-SBIR/STTR 2023 303219 NCI 205625 97594 AbstractCancer mortality rates in the US declined by 26% between 1991 and 2015 but the decline has not been equalacross all populations. Approximately 19% of the US population resides in rural areas; for over three decadesthis population has experienced increasingly inferior outcomes when compared with their urban counterparts.The underlying cause(s) of the widening rural/urban gap in cancer outcomes is hypothesized to be multifactorialwith socioeconomic status (SES) both at the individual-level and geographic area-level likely playing a significantrole. Gaps in evidence include the use of multiple rural definitions a lack of evidence on associated geographicfactors and limited evidence based on multi-level approaches to understand the complex nature of ruraldisparities. Therefore the overall objective of this study is to conduct a comprehensive examination of theunderlying causes of rural/urban disparities in mortality among individuals diagnosed with cancer. In the first aimthe Surveillance Epidemiology and End Results (SEER) population-level data will be used to examine mortalityamong individuals diagnosed with cancer across three definitions of rurality providing researchers and policymakers with the magnitude of differences by each definition. In the second aim SEER will be linked via county-indicators to 16 databases (US Census Bureau Area Deprivation Index Bureau of Labor Statistics CountyHealth Rankings and Roadmaps AMA Healthcare Workforce Mapper BRFSS Social Vulnerability Index HealthInformation National Trends Survey etc.). These linkages will allow us to estimate the contribution of specific area-level factors (e.g. area-level SES access to high-quality care) on rural/urban mortality differences using effectdecomposition methodology. In the third aim the Reasons for Geographic and Racial Differences in Stroke(REGARDS) cohort (U01 NS041588) will be linked to state level cancer registry data using the Virtual PooledRegistry Cancer Linkage System (VPR-CLS). REGARDS includes longitudinally collected data for 30239participants (44% blacks) oversampled from stroke belt/buckle states (56% of participants from NC SC GATN AL MS AK LA) with large rural populations experiencing the highest mortality. REGARDS collectsinformation at the individual level on sociodemographics health literacy and distance to healthcaretransportation and risky health behaviors. Multi-level modeling and mediation modeling approaches will allow forthe examination of the contribution of individual-level characteristics and the area-level characteristics simultaneously.Results will provide estimates of how much of the mortality disparity is explained by differences in urban andrural geographic characteristics overall as well estimates that describe the potential impact of hypotheticalinterventions on specific mediating factors. Findings will provide the critical evidence needed to inform policy andintervention development aimed at addressing the systemic disparities in mortality experienced by rural patientswith cancer. 303219 +No NIH Category available Address;Adjuvant Therapy;Adverse effects;Antigens;Ascites;Biological Assay;Biology;CD147 antigen;CD47 gene;Cancer Etiology;Cancer Model;Cell Culture Techniques;Cell Therapy;Cells;Cessation of life;Chemicals;Clinical Trials;Collaborations;Colon Carcinoma;Combined Modality Therapy;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Engineering;Enhancers;Ensure;Gene Expression;Genes;Genetic;Genetic Engineering;Genetic Transcription;Goals;Growth;Hematopoietic stem cells;Homing;Homologous Transplantation;Human;Hypoxia;Immune;Immune response;Immunity;Immunologist;Immunophenotyping;Impairment;In Vitro;Inflammatory;Intravenous;KRAS2 gene;Knowledge;Liver;Lung;MSLN gene;Macrophage;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mediating;Methods;Mus;Neoplasm Metastasis;Oncogenic;Organ;Outcome;Oxygen;PTPNS1 gene;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phagocytosis;Physiological;Pre-Clinical Model;Primary Neoplasm;Proliferating;RXR;Receptor Activation;Recurrence;Recurrent tumor;Research;Resistance;Risk;Role;SIRT1 gene;Safety;Signal Transduction;Solid Neoplasm;Spleen;System;Tertiary Protein Structure;Therapeutic;Tissues;Toxic effect;Transplantation;Tumor-associated macrophages;United States;allotransplant;anti-tumor immune response;cellular engineering;chimeric antigen receptor;clinical application;clinical risk;cytokine;cytokine therapy;cytotoxic;cytotoxicity;design;disorder control;experience;human disease;in vivo;inhibitor;mouse model;mutant;neoantigens;novel;pancreatic ductal adenocarcinoma model;pancreatic tumorigenesis;permissiveness;pre-clinical;programs;promoter;screening;self-renewal;single cell sequencing;single-cell RNA sequencing;suicide gene;synergism;systemic toxicity;targeted treatment;therapeutically effective;transgene expression;tumor;tumor growth;tumor microenvironment Develop Conditionally Armored CAR Macrophage Therapy for Pancreatic Cancer NARRATIVEPatients with advanced pancreatic ductal adenocarcinoma desperately need novel and effective therapeutics.Macrophage allotransplantation seems permissive making them a safe choice as a third-party off-the-shelfcell therapy option. The proposed research will not only provide a proof-of-concept regarding the combinationtherapy of KRAS inhibitors and macrophages genetically engineered with chimeric antigen receptors and pro-inflammatory cytokines but will also enhance the understanding of macrophage self-renewal plasticity signalingtransduction and function execution. NCI 10710883 9/5/23 0:00 PAR-21-038 1R01CA275761-01A1 1 R01 CA 275761 1 A1 "SINGH, ANJU" 9/5/23 0:00 7/31/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 12480666 "HOU, PINGPING " Not Applicable 10 MICROBIOLOGY/IMMUN/VIROLOGY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 9/5/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 602518 NCI 389010 213508 SUMMARY/ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with limited therapeutic options. About95% PDAC patients harbor oncogenic mutant KRAS (KRAS*) that promotes pancreatic carcinogenesis and isrequired for PDAC maintenance. Given that KRAS* can be druggable now therapy resistance occurs in severalpre-clinical models and clinical trials suggesting that therapy combination is required to achieve durable diseasecontrol. Targeting KRAS* results in enrichment of tumor associated macrophages (TAMs) in pancreatic colonand lung cancer models offering opportunities for chimeric antigen receptor (CAR) macrophage (M) therapyand for M-mediated cancer-specific delivery of pro-inflammatory cytokines. However transplanted Ms wereprone to accumulate in liver lung and spleen despite that most of the remaining Ms were localized in tumorsrising safety concerns that might be addressed by conditional gene expression systems. The hypothesis is thattumor-conditionally expressed cytokine armored CAR Ms (ca-CAR-Ms) may synergize with KRAS* inhibitors(KRASi) to effectively suppress primary tumor growth metastasis and tumor recurrence and to prolong survivalin PDAC spontaneous metastasis mouse models. A successful outcome of proposed study will generate the firstca-CAR-M therapy for PDAC treatment pave the way for clinical trials in KRAS* PDAC patients and provideapplicable methods to develop ca-CAR-Ms for other M-enriched cancers. Aim 1. Optimize cell culture andengineering platforms for adoptive macrophage therapy. Primary Ms are non-proliferative in vitro andaccumulation of donor Ms in healthy organs is a latent safety risk. Aim 1a will enable in vitro expansion of Msby genetic or chemical screening of M self-renewal regulators. Aim 1b will limit off-tumor activity of donor Msby employing dual oxygen-sensing switch and identifying TAM-specific genes versus tissue-resident Ms whosepromoter/enhancers will be used for tumor-specific gene expression. Aim 2. Design CAR Ms to target PDAC.The comprehensive CAR optimization for effective antigen-specific activation of phagocytosis and cytotoxicity inMs is lacking. Aim 2a will design and optimize constituent protein domains of CAR to direct M activities againstPDAC. Aim 2b will determine the tumoricidal effect of CAR-Ms as an adjuvant therapy of KRASi in PDAC models.Aim 2c will dissect mechanisms how CAR activation reprograms M transcription secretion and pathwaytransduction to elicit tumoricidal effect. Aim 3. Engineer conditionally armored Ms to trigger tumoricidalimmunity. Ms are tumor-homing so delivery of pro-inflammatory cytokines by Ms may reduce systemictoxicity while elicit strong anti-tumor immune response. Aim 3a will develop safe and effective cytokine armoredM therapy by cytokine screening and employing conditional transgene expression system. Aim 3b will assesstumoricidal activity of Ms engineered by the optimal CAR construct the top cytokine candidate or both as anadjuvant therapy of KRASi in various PDAC models. Aim 3c will delineate the role of cytokine armored Ms inthe tumor microenvironment remodeling by single cell RNA sequencing and immunophenotyping. 602518 +No NIH Category available Cancer Biology;Therapeutic;Training Programs Training Program in Cancer Biology and Therapeutics NARRATIVEAt this exceptional time in oncology fundamental discoveries in our understanding of cancer biology are leadingto dramatic changes in cancer therapies ranging from genotype-directed targeted therapies to antibody andcell-based immunotherapies and the application of liquid biopsies to enable the earlier detection of cancer.There is a critical need for physician scientists who are expert in both sophisticated molecular approaches toscience and the clinical challenges of caring for patients with cancer and who can lead innovation in basictranslational and clinical cancer research and bridge between rapidly evolving fields. The MGH T32 physicianscientist Training Program in Cancer Biology and Therapeutics selects trainees from the most competitive clinicalprograms at our institution offering them advanced training in either laboratory or clinical cancer research withhighly accomplished mentors drawn from a multidisciplinary faculty at MGH as well as our partnering institutionsat Harvard and MIT. Over the past 25 years graduates of the MGH T32 grant have made and will continue tomake major contributions to the field of cancer research and as members of the faculty at our own institutionand others in the US they are poised to emerge as the next generation of physician leaders in oncologycontributing to the critical integration of scientific and clinical innovation in cancer. NCI 10710776 6/29/23 0:00 PA-20-142 2T32CA071345-26 2 T32 CA 71345 26 "LIM, SUSAN E" 8/1/97 0:00 6/30/28 0:00 ZCA1-RTRB-R(M1) 1882057 "HABER, DANIEL A." "SEQUIST, LECIA V." 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 523031 NCI 655808 49329 PROJECT SUMMARYThe Massachusetts General Hospital (MGH) Cancer Center proposes to renew its T32 Training Program inCancer Biology and Therapeutics supporting mentorship of physician scientists (MDs and MD/PhDs) forcareers in cancer research. With a 25-year history the program enrols trainees who have completed clinicalfellowships in any cancer-related discipline and supports their training in laboratory-based or clinical cancerresearch. The program is poised at the intersection of basic translational and clinical cancer research and aimsto prepare the next generation of physician scientists for academic careers in oncology tuned to the latestadvances in basic cancer research and the rapid evolution of novel cancer therapies. Program Directors (PD)are Dr. Daniel Haber an accomplished laboratory-based cancer genetics investigator and Dr. Lecia Sequist aleading clinical researcher in thoracic oncology. Together they oversee all administrative aspects of the programwith Dr. Haber overseeing the mentoring of lab-based trainees and Dr. Sequist overseeing the mentoring ofclinical research trainees. An Internal Advisory Committee (IAC) participates in the competitive selection oftrainees and the selection of faculty mentors; an External Advisory Board (EAB) convenes annually to evaluatethe strategic direction of the program. Mentors are drawn from multiple disciplines and departments primarilyfrom MGH but also from neighboring MIT and other Harvard institutions. Laboratory mentors span disciplinesincluding molecular cancer biology cancer immunology computational biology and single cell systems biologywhile clinical research mentors have expertise in first-in-human/phase 1 clinical trials and molecularpathology/diagnostics. Trainees are selected from highly competitive clinical programs including the combinedDana Farber/Mass General Brigham medical oncology fellowship program. The PDs and IAC have a strongcommitment to enhancing diversity among the pool of applicants and the roster of mentors. In addition tofacilitating the selection of an appropriate research mentor the T32 program provides both mandatory andoptional courses as well as a broad range of educational experiences. Mandatory didactic courses includebiostatistics/computational biology and the ethical conduct of research. In addition to regular meetings with theirmentors and with the PDs trainees present their work at an annual retreat providing for ongoing feedback atsuccessive stages of their research training. Success is measured by trainees academic productivity during andafter their T32 support as well as by their self-reported learning experience. In summary through its emphasison multi-disciplinary integration of laboratory and clinical investigation this T32 training grant has a long trackrecord of success in providing a rigorous and comprehensive scientific foundation to outstanding physicianinvestigator trainees. Based on its track record the program respectfully requests an increase from six to eighttraining positions (total program) so that it can adequately meet the needs of an exceptional applicant pool andprovide necessary support for physician scientists training in academic oncology. 523031 +No NIH Category available Architecture;Area;Biochemical;Biochemistry;Biological;Biomimetics;Breast;Cancer Biology;Cancer Etiology;Carcinoma;Chemicals;Classification;Collagen;Collagen Fiber;Coupling;Cytoskeleton;DNA Sequence Alteration;Data;Diagnostic;Dimensions;Disease;Disease Progression;Etiology;Extracellular Matrix;Fiber;Fibronectins;Gel;Generations;Heterogeneity;Human;Image;In Vitro;Knowledge;Label;Laminin;Libraries;Malignant Neoplasms;Malignant neoplasm of ovary;Methods;Microscopy;Modality;Modeling;Modification;Molecular;Molecular Profiling;Morphology;Multimodal Imaging;Neoplasm Metastasis;Normal tissue morphology;Optics;Ovary;Pancreas;Phosphorylation;Post-Translational Protein Processing;Prognosis;Protein Isoforms;Resolution;Role;Serous;Shapes;Specimen;Spectrum Analysis;Speed;Structure;Surface;Tissue Sample;Tissue imaging;Tissues;Tumor Promotion;carcinogenesis;computerized data processing;crosslink;glycosylation;image reconstruction;imaging approach;imaging modality;imaging platform;insight;migration;multimodality;nanophotonic;novel;ovarian neoplasm;performance based measurement;prognostic;second harmonic;second harmonic generation imaging;self assembly;spectrograph;treatment response;tumor;tumor microenvironment A novel multimodal ECM analysis platform for tumor characterization combining morphological and spectrochemical tissue imaging approaches. Project NarrativeThe combination of Second Harmonic Generation microscopy and Surface Enhanced Mid InfraRed SpectralImaging will provide a comprehensive characterization of extracellular matrix changes in human carcinomas.This knowledge will provide new insight into cancer etiology and may form the basis for enhanceddiagnostic/prognostic approaches. The method will be applicable to numerous carcinomas. NCI 10710735 7/26/23 0:00 RFA-CA-22-001 1R61CA281795-01 1 R61 CA 281795 1 "BECKER, STEVEN" 8/1/23 0:00 7/31/26 0:00 ZCA1-TCRB-5(M1) 2232872 "CAMPAGNOLA, PAUL J" "YESILKOY, FILIZ " 2 BIOMEDICAL ENGINEERING 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI BIOMED ENGR/COL ENGR/ENGR STA 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 208402 NCI 140250 68152 PROJECT SUMMARYThe tumor microenvironment (TME) in essentially all epithelial cancers is associated with significant biochemicaland structural changes in the extracellular matrix (ECM). Many tumors including those of the breast pancreasand ovary are characterized by profound changes in the collagen architecture. ECM changes (~micron scale)are below the resolution of conventional imaging modalities but analysis of this structure is critical forunderstanding carcinogenesis and metastasis. We have used the collagen-specific modality of Second HarmonicGeneration (SHG) optical microscopy to discriminate cancer specimens from normal tissues based on changesin supramolecular structure fibril structure and fiber morphology where we have focused on high grade serousovarian cancer (HGSOC). However SHG cannot identify the specific molecular alterations which could providecritical information on disease etiology prognosis and response to therapy. Now we will develop a novel methodthat combines spatially registered SHG and surface enhanced mid-infrared spectral imaging (SE-MIRSI)correlating morphometric and chemometric information to elucidate tumor-promoting ECM alterations. The latterspatially probes specific molecular signatures from vibrational spectroscopy and provides increased sensitivityusing nanophotonic substrates allowing rapid and large-area chemical imaging of whole tissue sections.Specifically SE-MIRSI can quantitatively identify specific changes in isoform distribution posttranslationalmodifications and altered crosslinking of the collagen fibers. Spatial registration of SHG and SE-MIRSI then willprovide a comprehensive ultrasensitive label free non-destructive high-resolution structural and biochemicalimaging platform to investigate the role of ECM alterations in promoting tumor carcinogenesis and metastasis.Here we will develop a multivariate data processing workflow that identifies the specific signatures of collagenand other ECM components from the two modalities establishing the basis of an accurate classifier. We willvalidate the multimodal characterizations on HSGOC tissue samples. At the end of this project we will havedeveloped a multimodal imaging platform that will uniquely identify collagen and other ECM biochemicalalterations in the TME. We will establish performance measures based on imaging speed and throughputsensitivity and classification accuracy. These structural and biochemical analyses will provide new insight intocarcinogenesis and disease progression in several carcinomas. We propose these Aims:Aim 1. Identify specific structural and biochemical signatures of in vitro ECM models through the combined useof SHG and SE-MIRSI.Aim 2. Validate spatially registered SHG/SE-MIRSI method on high grade serous ovarian cancer and identifyspecific associated structural morphology and biochemical signatures. 208402 +Biotechnology; Cancer; Cervical Cancer; HPV and/or Cervical Cancer Vaccines; Immunization; Infectious Diseases; Prevention; Sexually Transmitted Infections; Vaccine Related; Women's Health Bioinformatics;Cervarix;Contractor;Costa Rica;Data;Data Analyses;Disease;Dose;Epidemiology;Follow-Up Studies;Gardasil;Goals;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Immunology;Infection prevention;Longterm Follow-up;Malignant Neoplasms;Natural History;Preparation;Prevention;Scientific Evaluation;Services;Vaccines;Woman;data infrastructure;data management;girls;prophylactic;vaccine trial;young adult THE CONTRACTOR SHALL MAINTAIN AND SUPPORT STUDY DATA INFRASTRUCTURE DATA MANAGEMENT AND DATA PREPARATION AND ADVANCED STATISTICAL AND BIOINFORMATICS n/a NCI 10710597 75N91020D00007-0-759102200001-1 N02 9/23/22 0:00 9/22/23 0:00 78877315 "GIFFEN, CAROL " Not Applicable 4 Unavailable 83656892 LGGFBF8YVA71 83656892 LGGFBF8YVA71 US 39.047465 -77.125049 1069201 "INFORMATION MANAGEMENT SERVICES, INC." CALVERTON MD Domestic For-Profits 207053407 UNITED STATES N R and D Contracts 2022 550000 OD Goals: 1.To maintain and support study data infrastructure data management and data preparation and advanced statistical and bioinformatics data analysis services specifically for the one dose HPV Vaccine trials (i.e. Costa Rica HPV Vaccine Trial [CVT ClinicalTrials.gov NCT00128661] and its extended long-term follow-up studies Scientific Evaluation of One or Two Doses of the Bivalent or Nonavalent Prophylactic HPV Vaccines [ESCUDDO NCT03180034] Single Dose of Cervarix Vaccine in Girls or Three Doses of Gardasil Vaccine in Women for the Prevention of Human Papillomavirus Infection [PRIMAVERA NCT03728881] and Single-dose HPV Vaccination among young adult women in Costa Rica [PRISMA NCT05237947]. 2.To provide data management and advanced statistical and bioinformatics data analysis support for projects related to HPV natural history HPV immunology HPV vaccination and HPV-driven cancers and other activities associated with the epidemiology and prevention of infections and related diseases. 550000 +Cancer Contracts;Oral;dosage NEXT DTP-22-018 GMP PRODUCTION OF 40 MG Z-ENDOXIFEN (NSC 774768) CAPSULES n/a NCI 10710317 75N98019D00058-0-759102200004-1 N02 6/27/22 0:00 6/26/26 0:00 78742042 "GIANNINI, ROBERT " Not Applicable 51 Unavailable 79682716 YRPTVKHDL7Z5 79682716 YRPTVKHDL7Z5 US 32.882508 -117.171157 3452401 "IRISYS, INC." SAN DIEGO CA Domestic For-Profits 921212285 UNITED STATES N R and D Contracts 2022 189535 NCI NEXT DTP-22-018 GMP PRODUCTION OF 40 MG Z-ENDOXIFEN (NSC 774768) CAPSULES CONTRACT/TO#DCTD-2022-1007 DEVELOPMENT & MANUFACTURE OF ORAL & TOPICAL DOSAGE 189535 +Cancer Clinical;Contracts;Life NEXT DTP-22-013 PRODUCTION OF TAK-243 INJECTABLE FOR CLINICAL USE n/a NCI 10710314 75N98019D00058-0-759102200003-1 N02 4/11/22 0:00 4/10/26 0:00 78634347 "GIANNINI, ROBERT " Not Applicable 51 Unavailable 79682716 YRPTVKHDL7Z5 79682716 YRPTVKHDL7Z5 US 32.882508 -117.171157 3452401 "IRISYS, INC." SAN DIEGO CA Domestic For-Profits 921212285 UNITED STATES N R and D Contracts 2022 639151 NCI NEXT DTP-22-013 PRODUCTION OF TAK-243 INJECTABLE FOR CLINICAL USE AND STUDY THE SHELF-LIFE. 639151 +Cancer Clinical Trials;Pharmaceutical Preparations;cancer therapy;capsule AZA-TDC CAPSULES FOR USE IN CLINICAL TRIAL n/a NCI 10710313 75N98019D00058-0-759102200001-1 N01 11/19/21 0:00 11/18/25 0:00 78508303 "GIANNINI, ROBERT " Not Applicable 51 Unavailable 79682716 YRPTVKHDL7Z5 79682716 YRPTVKHDL7Z5 US 32.882508 -117.171157 3452401 "IRISYS, INC." SAN DIEGO CA Domestic For-Profits 921212285 UNITED STATES N R and D Contracts 2022 177135 NCI AZA-TDC CAPSULES FOR USE IN CLINICAL TRIAL FOR POSSIBLE CANCER TREATMENT. THE DRUG PRODUCT (DP) WILL BE A 4 MG STRENGTH CAPSULE WHICH IS NOT AVAILABLE 177135 +Cancer Ammonium;Clinical Trials;Cyclic GMP;Engineering;Life;Production;capsule PRODUCTION OF AMMONIUM TETRATHIOMOLIBDATE (ATTM) CAPSULES FOR USE IN CLINICAL TRIALS n/a NCI 10710311 75N98019D00058-0-759102200002-1 N01 3/8/22 0:00 3/7/26 0:00 78587934 "GIANNINI, ROBERT " Not Applicable 51 Unavailable 79682716 YRPTVKHDL7Z5 79682716 YRPTVKHDL7Z5 US 32.882508 -117.171157 3452401 "IRISYS, INC." SAN DIEGO CA Domestic For-Profits 921212285 UNITED STATES N R and D Contracts 2022 413130 NCI PRODUCTION OF AN ENGINEERING BATCH CGMP BATCH DELIVERY AND SHELF-LIFE STUDY OF AMMONIUM TETRATHIOMOLIBDATE (ATTM) CAPSULES FOR USE IN CLINICAL TRIALS 413130 +No NIH Category available 2019-nCoV;Address;Affect;Aging;Albert Einstein Cancer Center;Antibodies;Biological Assay;Biology;COVID-19;COVID-19 booster;COVID-19 vaccine;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Catchment Area;Chromatin;Clinical;Clinical Informatics;Colon Carcinoma;Colorectal Cancer;Community Outreach;Data;Development;Diagnosis;Diagnostic;Dose;Education and Outreach;Effectiveness;Enrollment;Epigenetic Process;Ethnic Origin;Evolution;Funding;General Population;Genetic;Genetic Transcription;Health system;Hematologic Neoplasms;Hematology;Home;Hormonal;Human;Humoral Immunities;Imaging technology;Immune;Immunity;Immunoglobulin G;Immunotherapeutic agent;Intestines;Investigation;Investigational Therapies;Malignant - descriptor;Malignant Neoplasms;Medicine;Metabolic;Minority;Minority Groups;Morbidity - disease rate;NCI Center for Cancer Research;Neoplasm Metastasis;Normal Cell;Obesity;Pathogenesis;Patients;Pfizer-BioNTech COVID-19 vaccine;Population Research;Prevention;Prevention program;Prevention strategy;Provider;RNA vaccine;Randomized;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Role;Safety;Scheme;Science;Secondary Immunization;Services;T-Lymphocyte;Technology;Therapeutic Studies;Therapeutic Trials;Translating;Translations;Vaccination;Vaccines;Villus;Virus;anti-CD20;cancer care;cancer cell;cancer diagnosis;cancer epidemiology;cancer health disparity;cancer prevention;cancer therapy;cohort;combat;community engagement;dietary;epidemiology study;follow-up;human cancer mouse model;human stem cells;immunogenicity;innovation;microbiome;mortality;mouse model;novel;patient population;pre-clinical;preclinical study;programs;response;seroconversion;small molecule inhibitor;socioeconomics;stem cell differentiation;stem cells;study characteristics;tumor microenvironment;tumor progression;vaccination strategy Core Support for Cancer Center PROJECT NARRATIVE OVERALLThe Albert Einstein Cancer Center (AECC) seeks to reduce the burden of cancer through its basic clinical andpopulation based research and the translation of preclinical and epidemiological studies into clinical initiativesfor the prevention and treatment of cancer. This is accomplished through AECC's five established researchprograms and twelve shared resources. With its clinical partner the Montefiore Health System and itscommunity outreach and engagement capabilities AECC seeks to understand the basis for and amelioratecancer disparities that affect the 1.4M largely minority population of the Bronx the Center's catchment area. NCI 10710267 9/27/22 0:00 PAR-17-095 3P30CA013330-50S5 3 P30 CA 13330 50 S5 "ROBERSON, SONYA" 6/1/97 0:00 6/30/23 0:00 Cancer Centers Study Section (A)[NCI-A] 2087647 "CHU, EDWARD " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 394 Research Centers 2022 334913 NCI 199353 135560 C6;Reg-CV Abstract It is now well-established that COVID-19 in patients with cancer carries a higher morbidity and mortality especially in amongst patients with hematologic malignancies1 2. Effective vaccines have been developed and authorized by the FDA to combat this pandemic3-5. However emerging data suggests that despite these vaccines inducing high levels of immunity in the general population patients with hematologic malignancies have lower rates of seroconversion for the SARS-CoV-2 Spike antibody6-9. Indeed our prior data had suggested excellent immunogenicity of the currently FDA authorized Covid-19 vaccines for most patients with a malignant diagnosis with exception of unique cohorts- patients with hematological malignancies and following highly immune suppressive therapies (SCT CAR-T anti-CD20). Our current study plans to address the efficacy of Covid-19 booster vaccinations amongst patients with a cancer diagnosis with a special focus on patients with undetectable or low anti-Spike IgG antibody levels. 250 patients with a diverse range of ethnicities cancer diagnosis and prior cancer therapies will be enrolled in this study and the response to booster vaccinations will be assessed using standard anti-Spike IgG as well as investigational T cell and Virus Neutralization assays. In addition in a second cohort we will define if a mix and match vaccination strategy might be more successful at achieving detectable immunity in patients with persistently negative/low antibody levels despite booster vaccinations. In this cohort 100 patients will be accrued who by anti-spike IgG assays have not developed detectable or have low levels of humoral immunity. These patients will be randomized to receive an additional dose of an mRNA based vaccine (BNT162b2) versus an adenoviral vaccine (AdCov2.S). Both studies will assess safety and efficacy of these vaccination schemes and will provide long-term data with 24 months of follow up planned. These studies should provide critical information to best address proper protective strategies for uniquely vulnerable patient populations with a cancer diagnosis. 334913 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Genetics; HIV/AIDS; Health Services; Human Genome; Immunotherapy; Infectious Diseases; Prevention; Sexually Transmitted Infections; Stem Cell Research; Stem Cell Research - Nonembryonic - Human 2019-nCoV;AIDS related cancer;Address;Affect;Aging;Agonist;Albert Einstein Cancer Center;Antigens;Biological;Biological Products;Biology;CD28 gene;CD8-Positive T-Lymphocytes;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Cancer Patient;Catchment Area;Cells;Chromatin;Clinical;Clinical Informatics;Clinical Trials;Clone Cells;Cohort Studies;Colon Carcinoma;Colorectal Cancer;Community Outreach;Conduct Clinical Trials;Development;Diagnostic;Disease;Education and Outreach;Effectiveness;Elements;Enrollment;Epigenetic Process;Epitopes;Ethnic Origin;Evaluation;Evolution;Fc domain;Funding;Future;Gender;Gene Expression;Genetic;Genetic Transcription;HIV;HIV Seronegativity;HIV Seropositivity;HPV E7;Harvest;Health system;Hematologic Neoplasms;Home;Hormonal;Human;Human Papillomavirus;Human papilloma virus infection;Imaging technology;Immune;Immunotherapeutic agent;Immunotherapy;In Vitro;Individual;Industry;Infection;Infrastructure;Interleukin-2;Intestines;Investigational Therapies;Link;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Medical;Medicine;Metabolic;Minority;Minority Groups;NCI Center for Cancer Research;Names;Neoplasm Metastasis;New York City;Normal Cell;Obesity;Participant;Pathogenesis;Patients;Peptide/MHC Complex;Perception;Peripheral Blood Mononuclear Cell;Persons;Phenotype;Population;Population Research;Prevention;Prevention program;Prevention strategy;Provider;Race;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Role;Science;Services;Signal Transduction;Site;T cell response;T-Cell Activation;T-Lymphocyte;T-cell receptor repertoire;Technology;Testing;Therapeutic Studies;Therapeutic Trials;Translating;Translations;Vaccination;Villus;Viral;Viral Load result;Women's Interagency HIV Study;arm;cancer care;cancer cell;cancer diagnosis;cancer epidemiology;cancer health disparity;cancer prevention;cancer therapy;community engagement;comorbidity;dietary;efficacy evaluation;epidemiology study;ethnic diversity;experience;human cancer mouse model;human stem cells;immunological synapse;immunoregulation;in vivo;innovation;microbiome;mouse model;novel;oral HPV-positive head and neck cancers;patient population;pre-clinical;preclinical study;programs;response biomarker;scaffold;side effect;single-cell RNA sequencing;small molecule inhibitor;socioeconomics;stem cell differentiation;stem cells;study characteristics;treatment strategy;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Antigen specific strategies for treatment of HIV+ cancer patients in the Montefiore/Einstein Cancer Center Catchment Area (Immuno/microenvironment) PROJECT NARRATIVE OVERALLThe Albert Einstein Cancer Center (AECC) seeks to reduce the burden of cancer through its basic clinical andpopulation based research and the translation of preclinical and epidemiological studies into clinical initiativesfor the prevention and treatment of cancer. This is accomplished through AECC's five established researchprograms and twelve shared resources. With its clinical partner the Montefiore Health System and itscommunity outreach and engagement capabilities AECC seeks to understand the basis for and amelioratecancer disparities that affect the 1.4M largely minority population of the Bronx the Center's catchment area. NCI 10710266 9/27/22 0:00 PAR-17-095 3P30CA013330-50S4 3 P30 CA 13330 50 S4 "ROBERSON, SONYA" 6/1/97 0:00 6/30/23 0:00 Cancer Centers Study Section (A)[NCI-A] 2087647 "CHU, EDWARD " Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 397 Research Centers 2022 249999 NCI 148809 101190 ABSTRACT. This supplement will evaluate the efficacy of our highly selective immunotherapeutic platform in HIV-positive cancer patients. This novel biologics platform termed synTac for artificial immunological synapse for T-cell activation recapitulates elements of the antigen-specific and costimulatory signals experienced at the immunological synapse. Composed of covalently tethered peptide-MHC modules (c-pMHC) and costimulatory molecules linked to an Fc domain scaffold synTac directs epitope-specific delivery of a wide range of costimulatory signals to targeted T cell populations. The sc-pMHC domain acts as an address to target specific T cell clones for delivery of a range of comodulatory domains (e.g. IL-2 4-1BBL CD28 agonists) resulting in antigen-selective modulation of disease relevant T cells in vitro and in vivo thus eliminating the side effects of current immunotherapeutics which elicit global immune modulation. Initial efforts will leverage the infrastructure of the Bronx site of the MACS/WIHS Combined Cohort Study (MWCCS) previously named the Women's Interagency HIV Study (WIHS) at Einstein/Montefiore. These studies will define the ability of the synTac platform to expand and activate SARS-CoV-2 specific T cells that are broadly represented across HIV-positive patients and healthy individuals as the consequence of natural infection and vaccination. Next we will examine the ability of our platform to modulate cancer specific CD8 T cells in HIV-positive cancer patients using synTacs that selectively target HPV E7-specific CD8 T cells. One such synTac is the subject of a multi-arm clinical trial for HPV-positive head and neck cancer. Importantly HPV is implicated in a number of HIV-associated cancers (e.g. anal cancer cervical cancer) found within the Montefiore Einstein Cancer Center catchment area in the Bronx in New York City; additional future opportunities may be provided by the MWCCS which has collected PBMCs and has performed serial testing for HPV infection at multiple timepoints for all participants. T cell responses will be evaluated for polyfunctionality TCR repertoire diversity and by single cell-RNAseq. The impact of synTacs delivering different costimulatory signals will be correlated with clinical parameters including viral load gender stage of disease and race and ethnicity. The ability of synTacs to activate HPV E7-specific T cells will also be correlated with features of the tumor immune micro-environment including quantification and analysis of E7- specific T cells from fresh harvested tumors evaluation of viral and immune gene expression as well as quantification and phenotyping of tumor infiltrating T cells. Together these studies will define the responsiveness of HIV-associated malignancies to the antigen-specific synTacs identify the mechanistic differences between HIV-positive cancer patients HIV-negative cancer patients and healthy individuals and define biomarkers of response to synTacs in ethnically diverse HIV+ patient populations. These results will directly impact our understanding of the relationship between HIV-status and responsiveness to a cutting-edge immunotherapy and set the stage for future translational and clinical opportunities.NARRATIVE. People with HIV are excluded from most clinical trials conducted by industry due to the perception that they would not respond to immunotherapies and a general reluctance to enroll patients with serious co-morbid medical problems onto therapeutic trials for cancer diagnosis. In an effort to move beyond this practice we will examine the effectiveness of a novel biologic developed in our lab for modulating protective immune cells from HIV+ patients and HIV+ cancer patients. 249999 +Cancer Project-008 n/a NCI 10710260 9/27/22 10:07 PA-21-071 3P50CA165962-09S2 3 P50 CA 165962 9 S2 "HUBBARD, LEAH" 9/1/22 0:00 8/31/24 0:00 ZCA1(M1) 5150 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 252388 140999 111389 No abstract available +Cancer Project-007 n/a NCI 10710259 9/27/22 10:01 PAR-18-313 3P50CA165962-09S1 3 P50 CA 165962 9 S1 "HUBBARD, LEAH" 9/1/22 0:00 8/31/24 0:00 ZCA1-RPRB-J(M1) 5149 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 240300 240300 No abstract available +No NIH Category available Area;Award;Bioinformatics;Cancer Biology;Cancer Science;Comprehensive Cancer Center;Data;Data Analyses;Educational Activities;Educational workshop;Future;Genetic Diseases;Genomics;Goals;Inherited;Journals;Laboratories;Malignant Neoplasms;Medicine;Mentors;Mutation;NCI Center for Cancer Research;Organism;Protocols documentation;Publications;Research;Research Activity;Research Personnel;Resource Sharing;Screening for cancer;Services;Standardization;Students;Techniques;Technology;Training;Training and Education;Work;Yale Cancer Center;anticancer research;bioinformatics tool;cancer diagnosis;cancer therapy;cancer type;data analysis pipeline;design;genome analysis;innovation;insight;method development;next generation sequencing;prevent;programs;skills;tool Cancer Bioinformatics: Data analysis and method development for the Yale Cancer Center OVERALL PROJECT NARRATIVECancer is a genetic disease driven by somatic or inherited mutations and thus genomictechnologies particularly next-generation sequencing and bioinformatic analysis have madesignificant impact on cancer diagnosis management and treatment. However unlikelaboratory protocols and benchwork researchers find it difficult to bring the necessary expertisein bioinformatic data analysis into their labs. The support of this R50 award will allow Dr. Lopez-Giraldez to provide broader bioinformatics analysis access and training to Yale Cancer Centerresearchers and to expedite the progress enable innovative NGS technologies and enrich thescope of their research. NCI 10710188 8/4/23 0:00 PAR-21-286 5R50CA265359-02 5 R50 CA 265359 2 "JOHNSON, ERIC MICHAEL" 9/27/22 0:00 7/31/27 0:00 ZCA1-SRB-1(M1) 10379862 "LOPEZ GIRALDEZ, JUAN FRANCISCO" Not Applicable 3 GENETICS 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 139849 NCI 83492 56357 ABSTRACTBioinformatics skills and tools are critical for the analyses of vast amount of data generated byNext-Generation Sequencing (NGS) and have become an integral field for gaining insight intocancer biology. While laboratory protocols to generate NGS data have become morestandardized researchers find it difficult to bring expertise in bioinformatic data analysis into theirpractice. The Yale Cancer Center (YCC) one of the 51 NCI-Designated Comprehensive CancerCenters in the nation aims to understand and prevent cancer detect cancer early and managecancer treatments more accurately and effectively. YCC is committed to fulfilling these goals bysupporting collaborative research and education activities aimed at achieving breakthroughdiscoveries and training future leaders in cancer science and medicine. The YCC supports andmanages Shared Resources that provide unique expertise and enabling technologies that enrichthe scope and expedite progress for each of the YCC research programs. As Associate Directorof Bioinformatics at the Yale Center for Genome Analysis (YCGA) one of the YCC SharedResources I established the bioinformatics analysis services for the YCC with the goal of bringingbioinformatics and NGS expertise closer to the cancer investigators. My bioinformatics work withthem for the last 9 years has focused on three areas: 1) providing full design-to-publicationbioinformatics support; 2) facilitating access to new genomic technologies and develop/build newanalytical pipelines to enable cutting edge genomics; and 3) providing training and education incancer bioinformatics through mentoring seminars and workshops. I have brought suchexpertise to over 300 projects for 78 laboratories have developed new data analysis pipelinesand enabled new NGS applications and have trained many students and researchers to becomeproficient in their own bioinformatics analyses. During my work for the YCC I have co-authoredover 28 publications in leading scientific journals with YCC investigators involving a diverse setof analysis for different techniques cancer types and organisms. The support of the R50 awardwill allow me to continue to develop and use bioinformatics tools to increase the progress andscope of cancer research and provide broader access and training to YCC researchers. 139849 +Cancer; Genetics; Health Disparities; Lung; Lung Cancer; Minority Health Animal Model;Antioxidants;Auranofin;Biology;Cancer Biology;Cancer Patient;Cell Death;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Detection;Doctor of Philosophy;Drug resistance;Glutathione Reductase;Growth;Immune;Immune response;Immunocompetence;Impairment;In Vitro;Knock-in Mouse;Knowledge;Lewis Lung Carcinoma;Lewis lung carcinoma cell;Malignant - descriptor;Malignant Neoplasms;Melanoma Cell;Modeling;Mouse Strains;Mus;Mutant Strains Mice;NADP;NADPH Oxidase;NF-kappa B;Neoplasm Metastasis;Organism;Oxidases;Oxidation-Reduction;Patients;Phenotype;Plasmids;Production;Proteins;Reactive Oxygen Species;Reporter;Research Project Grants;Resistance;Signal Transduction;Small Interfering RNA;System;Testing;Therapeutic;Work;analog;anti-cancer therapeutic;cancer cell;cancer therapy;carcinogenesis;cell transformation;improved;in vivo;in vivo Model;inhibitor;insight;macrophage;melanoma;mouse model;neoplastic cell;premalignant;public health relevance;response;therapy resistant;thioredoxin reductase;transcription factor;tumor;tumor growth;tumor progression Redox modulation - Impact on Tumor Growth and Therapeutic Anticancer Efficacy PUBLIC HEALTH RELEVANCE STATEMENT (PROJECT NARRATIVE)The findings from this project would contribute to the fundamental understanding of oxidative-reductive (Redox)biology in living systems and when these systems are challenged with cancer. The findings have a potential toyield ground breaking insights into changes in Redox biology within living systems as 1) their cells transformfrom pre-malignant growths to malignant growths and 2) when these cells and hosts are challenged by anti-cancer therapies. Most importantly the knowledge gained from this research project may be used to developimproved therapies for cancer patients. NCI 10710094 9/26/22 0:00 PA-16-308 3F31CA224806-04X1S1 3 F31 CA 224806 4 X1S1 "DIBELLO, ANTHONY THOMAS" 3/1/18 0:00 2/28/23 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)] 14881788 "BONNER, MICHAEL YI" Not Applicable n/a Unavailable 350582235 ND1DSMJ54BD3 350582235 ND1DSMJ54BD3 SW 59.33258 18.0649 4216101 KAROLINSKA INSTITUTE SOLNA Unavailable 171 65 SWEDEN N 3/1/21 0:00 2/28/23 0:00 398 "Training, Individual" 2022 4400 NCI 4400 0 PROJECT SUMMARYDespite advances in cancer biology drug resistance is a major obstacle to patients and clinicians. Many currentcancer therapeutics work in part by elevating reactive oxygen species (ROS) production often leading to tumorregression followed by tumor reoccurrence and therapeutic resistance. Previously Kelkka and coworkers lookedat tumor progression in mice with macrophages deficient in ROS from the protein NOX2 (Kelkka et al. 2013).They concluded that immune cells are more efficacious against metastasis and tumor progression when ROSproduction in macrophages is inhibited. On the other hand others have demonstrated the relationship betweencarcinogenesis and our innate antioxidant systems such as the thioredoxin reductase (TrxR) system and theglutathione reductase system (Gorrini et al. 2013). As carcinogenesis progress cells produce increasing levelsof ROS. Tumor cells cope with high levels ROS via an adaptive antioxidant response such as the thioredoxinreductase system. However when this system is impaired within tumor cells in vivo tumor progression andmetastasis may be significantly inhibited (Yoo et al. 2006).Given these findings we believe that tumor cells become resistant to current therapies in part by the systemicincrease of ROS production which 1) is insufficient to promote cell death in tumor cells because of their adaptiveantioxidant response and 2) elevated levels of ROS impairs immune cells from effectively combating tumor cells.Therefore we propose that a combined approach is required for effective anticancer therapy. We hypothesizethat tumor cells with dysfunctional antioxidant systems will significantly regress and that the hosts immuneresponse under low ROS conditions will be primed to eradicate the remaining malignancy.The focus of this proposed PhD project is to investigate this hypothesis and characterize the optimal Redoxconditions for tumor regression. We plan to accomplish this using two well-established murine tumor models: 1)the metastatic B16F10 melanoma and 2) the metastatic Lewis Lung Carcinoma LLC1. We will characterize invitro the baseline Redox systems in these tumor models make alterations using siRNA or CRISPR. We will alsolook at tumor progression in living hosts. We will use six mouse strains to help us understand the significance ofhost Redox biology in both the immune cells and systemically in response to cancer. Specifically we will usemouse models with key phenotypes: B6.129P2-Txnrd1tm1Marc B6.129P2-Txnrd1Cond BQ.Ncf1m1J (Ncf1 mutantmice) BQ.Ncf4 (Ncf4 mutant mice) BQMN (expressing Ncf1 in macrophages only) and BQ.TN3conditional knock-in mice. Finally we will study tumor redox systems challenged with Auranofin and otherTrxR1 inhibitors. 4400 +No NIH Category available 2019-nCoV;ACE2;Adult;Advocate;Age;Aggressive course;Antibodies;Antibody Response;Bioinformatics;Biology;Biometry;Budgets;COVID-19;COVID-19 mortality;COVID-19 patient;COVID-19 susceptibility;COVID-19 vaccination;COVID-19 vaccine;Cancer Patient;Cardiopulmonary;Cells;Characteristics;Clinical;Clinical Sciences;Clinical Trials;Complement;Contracts;Control Groups;Cytoprotection;Data Science;Data Science Core;Demographic Factors;Development;Disease;Doctor of Philosophy;Epithelial Cells;Ethnic Origin;Fatality rate;Gender;Histology;Immune;Immune response;Incidence;Individual;Infection;Informatics;Kinetics;Knowledge;Longevity;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Morbidity - disease rate;Normal tissue morphology;Patient Recruitments;Patients;Persons;Play;Population Control;Predisposition;Race;Recording of previous events;Research;Risk Factors;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Science;Serology;Seroprevalences;Smoking;Smoking History;Tobacco;Vaccination;Vaccines;Viral;Viral Load result;Virus;Virus Diseases;Virus Replication;base;cancer therapy;cigarette smoking;comorbidity;data dissemination;human subject;inter-individual variation;lung cancer cell;member;multidisciplinary;neoplastic cell;neutralizing antibody;patient population;programs;protective efficacy;public database;response;sample collection;tumor;vaccine trial Admin-Core-001 OVERALL: Vulnerability of SARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody AnalysesProgram Director: Fred R. Hirsch MD PhD; Co-PI: Adolfo Garcia-Sastre PhD. PROJECT NARRATIVEThe overarching research theme for the Serological Center of Excellence at Mount Sinai NY is to understandfactors contributing to the vulnerability of SARS-CoV-2 infection in patients with lung cancer through serologicalanalysis of antibody response and to characterize and compare the antibody response to SARS-CoV-2 infectionor SARS-CoV-2 vaccines in patients with lung cancer compared to a matched healthy control group. NCI 10710092 9/26/22 10:41 RFA-CA-20-038 3U54CA260560-02S1 3 U54 CA 260560 2 S1 "KRUEGER, KARL E" 9/1/22 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 5111 7822511 "HIRSCH, FRED R" "GARCIA-SASTRE, ADOLFO " 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 120079 94061 26018 OVERALL ABSTRACTThe overarching research theme for the Mount Sinai U54 Serological Center of Excellence Vulnerability ofSARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses is to fill the vital knowledgegap in factors contributing to the great vulnerability of lung cancer patients to morbidity and mortality from SARS-CoV-2 infection through serological analysis of antibody responses and studies of inter-individual variation inpatient-derived lung tumor and epithelial cells to SARS-CoV-2 infection. We will characterize and compare lungcancer patients antibody responses to SARS-CoV-2 infection or SARS-CoV-2 vaccines with a matched non-lung cancer control group; quantitate differences in SARS-CoV-2 viral replication in lung cancer and normal lungepithelial cells from different lung cancer patients; and quantitate differences in neutralizing antibody responsesin lung cancer patients. This information is urgently needed to enact vaccine and other strategies for protectinglung cancer patients against development of COVID-19. While antibodies induced by infection or vaccines areprotective against many viruses it has not yet been established if antibodies to SARS-CoV-2 are protective howmuch and what types of antibody are needed for protection and how long protection will last are unknown.Likewise we do not know if lung cancer patients can mount an effective immune response and if different aspectsof lung cancer or its treatment influences this immune response. Our overall hypothesis is that lung cancerpatients have a different (e. g. weaker) antibody response to SARS-CoV-2 infection compared to persons withoutlung cancer and that their lung cancer or lung epithelial cells play a role in viral replication of host responseswhich together could explain the aggressive course and high fatality rate demonstrated in lung cancer patientswith COVID-19. Our U54 will determine whether natural infection or SARS-CoV-2 vaccines (forecast fordeployment) will give comparable serological antibody responses longitudinally in 1000 lung cancer patientsand a matched non-lung cancer control group (1000 individuals); and determine if there are differences inantibody responses related to age gender tobacco history and race/ethnicity. The U54 proposal has twoProjects and three Cores (Administrative Clinical and Data Sciences). Project 1: Characterization of theAntibody Response to SARS-CoV-2 in Lung Cancer Patients quantitatively characterizes anti-SARs-CoV-2antibody responses and their functionality longitudinally in lung cancer patients compared to a control populationafter natural infection and vaccination and relates the serological response characteristics to key clinicaldemographic information. Project 2: Susceptibility of Lung Cancer Cells to SARS-CoV-2 Infection and Antibody-Mediated Neutralization determines the inter-individual variation in lung cancers and lung epithelial cells tosupport SARS-CoV-2 viral replication the inter-individual variation of antibodies to neutralize viral infection andhow these host viral responses relate to host cell characteristics and important clinical demographic information. +No NIH Category available 2019-nCoV;Address;Affect;Age;Antibodies;Antibody Response;Antigens;Basic Science;Biometry;COVID-19;COVID-19 patient;COVID-19 severity;Cell surface;Cells;Cessation of life;Clinical;Clinical Sciences;Collaborations;Communicable Diseases;Complement;Complex;Coupled;Data Analyses;Development;Diabetes Mellitus;Disease;Ensure;Enzyme-Linked Immunosorbent Assay;Epidemiologic Monitoring;Epidemiology;Ethnic Origin;Evaluation;Flow Cytometry;Foundations;Gender;Goals;HIV;Health;Healthcare Systems;Heart Diseases;Human;Immune;Immune response;Immunity;Immunoglobulin Class Switching;Immunology;Immunomodulators;Infant;Infection;Inflammasome;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Leadership;Mediating;Metabolic;Methods;Mission;Modeling;Monoclonal Antibody Therapy;Myeloid-derived suppressor cells;Organ Transplantation;Outcome;Pathogenesis;Pathologic;Pathology;Patients;Peripheral Blood Mononuclear Cell;Persons;Population;Prospective cohort;Proteins;Protocols documentation;Public Health;Race;Reagent;Regimen;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Respiratory Tract Infections;Risk;SARS-CoV-2 antibody;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sampling;Science;Serology;Serology test;Severity of illness;Sex Differences;Solid;Stains;Statistical Data Interpretation;Statistical Models;Surrogate Markers;Symptoms;T-Lymphocyte;Testing;Therapeutic;Training;Translational Research;Ursidae Family;Vaccine Design;Viral;Viral Pathogenesis;Virus;age difference;antibody-dependent cell cytotoxicity;base;biosafety level 3 facility;comorbidity;experimental study;gender difference;innate immune sensing;insight;intersectionality;male;neutralizing antibody;new therapeutic target;novel;novel marker;pandemic disease;racial difference;rational design;response;sample fixation;severe COVID-19;sex;single cell analysis;therapeutic evaluation;therapy development;vaccine candidate;vaccine development;vaccine evaluation;virology Admin-Core-001 Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)Overall NarrativeThe goal of the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)is to define the immune responses that can either protect or harm during infection. The JH-EPICS team willevaluate the immune responses required to detect the presence of SARS-CoV-2 initiate inflammatoryresponses eliminate infected cells and engage the antibody responses against the virus in COVID-19patients. Using statistical analyses and modeling JH-EPICS will identify the variables such as demographic(e.g. age sex gender race and ethnicity) and clinical (e.g. severity of COVID-19 and comorbidities) factorsthat predict COVID-19 immune responses and outcomes. NCI 10710090 9/26/22 10:37 RFA-CA-20-038 3U54CA260492-02S1 3 U54 CA 260492 2 S1 "KUO, LILLIAN S" 9/1/22 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 5110 3088131 "KLEIN, SABRA L." "COX, ANDREA L" 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 119719 73111 46608 Johns Hopkins has broad expertise in the science of human health with viral immunity pathogenesisepidemiology biostatistics and surveillance emerging as integral components of the multidisciplinary researchmounted at Johns Hopkins during the current pandemic. We propose development of a Serological SciencesCenter of Excellence: the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2(JH-EPICS). The overarching goal of JH-EPICS is to distinguish immune responses that protect from thosethat cause pathology during infection. Under the Multiple PI leadership of Drs. Klein and Cox the JH-EPICSAdministrative Core will ensure resources and samples are available to systematically evaluate innate T celland antibody responses to SARS-CoV-2 in peripheral blood mononuclear cells and serological samples fromCOVID-19 patients sampled longitudinally. JH-EPICS contains three interconnecting Research Projects (RPs).RP1 focuses on innate immune sensing and activation of the human inflammasome by SARS-CoV-2 withevaluation of how anti-SARS-CoV-2 antibodies modulate innate sensing. RP2 uses a novel flow-cytometrybased platform that enables single cell analysis of traditional cell surface markers combined with intracellularstaining for proteins involved in metabolic programming. Using this platform we have identified distinct myeloidderived suppressor cells (MDSCs) and T cells abundant in COVID-19. RP1 will characterize these MDSCswhile RP2 will explore novel populations of T cells identified in COVID-19 patients. RP2 will also define novelbiomarkers in order to predict severity of disease track the course of disease and define novel surrogatemarkers for testing therapeutic regimens. Together RP1 and RP2 will identify novel therapeutic targets. InRP3 the magnitude duration and class switching of SARS-CoV-2-specific antibody isotypes as well as virus-specific neutralizing antibody responses will be analyzed and compared with non-neutralizing antibodyfunctions e.g. complement fixation and antibody-dependent cellular cytotoxicity using a novel core set ofserological assays. A centralized Virology Reagent Core will provide antigen for ELISAs reagents to identifyvirus-specific immune cell populations inactivated SARS-CoV-2 viruses methods for quantifying SARS-CoV-2 and access to biosafety level 3 facilities and training needed to perform any experiments involving liveSARS-CoV-2. The Analysis Resource Core will provide statistical modeling and analysis to frame and testhypotheses about the mechanisms mediating the severity of COVID-19 as well as the intersectionality of sexgender age and racial differences in immune mechanisms of COVID-19. In concert with the trans-networkcollaborations this research will provide significant insights into pathologic immune responses to SARS-CoV-2identification of novel therapeutic targets and definition of immunity against SARS-CoV-2 infection. Byuncovering the correlates of protective immunity JH-EPICS research will further enhance vaccine design andevaluation of vaccine candidates. +Cancer; Health Disparities; Minority Health; Prostate Cancer; Urologic Diseases Admin-Core-001 n/a NCI 10710089 9/26/22 10:31 PA-20-272 3U54CA233465-05S1 3 U54 CA 233465 5 S1 "BARFIELD-STEWARD, WHITNEY" 9/1/22 0:00 8/31/23 0:00 ZCA1(A1) 5109 6367572 "CARPTEN, JOHN D." "REAMS, ROMONIA RENEE; REDDA, KINFE KEN; STERN, MARIANA C; WILKIE, DIANA J; XING, CHENGGUO " 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 124539 94978 29561 This supplement award application focuses on strengthening the capacity of an African early stage investigator (ESI) to conduct high-quality research in sub-Saharan Africa and to generate context-appropriate evidence to address the burden of CaP in that region. This is with the aim of providing high-quality mentored translational cancer research to an African ESI and support the training of the ESI in developing professional competencies needed to establish a successful research career. To achieve this we have worked with Dr Benson Nyambega (the ESI) to research project on investigating the Biological Determinants of Quality of Life Among Prostate Cancer Survivors in Kenya and Nigeria. +No NIH Category available ATAC-seq;Address;Adoptive Cell Transfers;Adoptive Transfer;Antigens;Automobile Driving;Binding;Biology;CTAG1 gene;Cells;Characteristics;Chimera organism;Chromatin;Chronic;Cytokine Receptors;Data;Endowment;Epigenetic Process;Extracellular Domain;Face;Functional disorder;Gene Expression Profile;Genetic Transcription;Goals;Hematologic Neoplasms;Homing;Human;IL2 gene;IL4R gene;IL7R gene;IL9 gene;Immunotherapy;In Vitro;Infiltration;Interleukin 2 Receptor;Interleukin 2 Receptor Gamma;Interleukin-2;Maps;Memory;Modeling;Mus;Patients;Peripheral;Phenotype;Phosphorylation;Positioning Attribute;Receptor Signaling;Research Personnel;Resistance;Role;Series;Signal Transduction;Solid Neoplasm;T cell therapy;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Toxic effect;Translating;antitumor effect;cancer therapy;chemotherapy;chimeric antigen receptor;conditioning;cytokine;draining lymph node;effector T cell;engineered T cells;exhaustion;genetically modified cells;improved;in vivo;interleukin-21 receptor;lymph nodes;mouse model;next generation;novel strategies;prevent;programs;rational design;receptor;safety and feasibility;stem cells;success;synthetic biology;transcriptomics;translational therapeutics;transmission process;tumor Synthetic IL9R signaling to rewire T cells for adoptive cell therapy of cancer PROJECT NARRATIVEAdoptive T cell therapy though promising faces significant hurdles for the treatment of patients with solid tumorsincluding the need for conditioning chemotherapy. In mouse models the investigators observed that T cellsendowed with synthetic IL9 receptor signaling have great promise in the treatment of solid tumors even in theabsence of conditioning chemotherapy. In this proposal they will study how synthetic IL9R signaling rewires Tcells for better anti-tumor effects overcoming the need for conditioning chemotherapy. NCI 10710036 8/29/23 0:00 PA-20-185 5R37CA273074-02 5 R37 CA 273074 2 "HU, ZHANG-ZHI" 9/30/22 0:00 8/31/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 14677764 "KALBASI, ANUSHA " Not Applicable 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 353100 NCI 230969 122131 PROJECT SUMMARYAdoptive cell therapy (ACT) using engineered T cells such as chimeric antigen receptor (CAR) or T cell receptor(TCR) modified T cells is an effective immunotherapy for hematologic malignancies. Success with ACT hasbeen elusive for solid tumors which present unique challenges to T cells. ACT also requires conditioningchemotherapy to deplete a patients endogenous T cells which results in significant toxicity. Our goal is toengineer T cells with synthetic functions to overcome hurdles of ACT for solid tumors including the need forconditioning chemotherapy which would dramatically improve the feasibility and safety of this therapy.In this proposal we use the orthogonal IL2 cytokine-receptor pair developed by our collaborator Dr. Garcia atStanford. Orthogonal IL2R (o2R) is only activated by the orthogonal IL2 (oIL2) cytokine and not by wildtypeIL2. When activated o2R signals through the intracellular domain (ICD) of IL2R which involves cooperationwith the native common gamma chain (c). Leveraging this cooperation we studied chimeric orthogonalreceptors in which the IL2R ICD of o2R is replaced with ICDs of receptors for other c cytokines such that oIL2elicits the corresponding c signal. Of these chimeras signaling through the IL9R ICD (o9R) generated a uniqueSTAT phosphorylation profile and differentiation trajectory prompting further exploration in vivo. Despite aweaker proliferative signal than o2R signaling o9R signaling resulted in T cells with superior anti-tumor efficacyan effect pronounced in the absence of lymphodepletion.To translate this finding into a viable treatment for patients with advanced solid tumors will require anunderstanding of the functional features of o9R signaling T cells that permit their anti-tumor efficacy especiallyin the absence of conditioning chemotherapy. Our preliminary data led us to focus on two of these featureswhich we tackle in Aims 1 and 2. In Aim 1 we focus on the peripheral in vivo effects of o9R signaling that relyon interaction with the host especially lymph node homing and priming. We hypothesize that the o9R signalingreprograms T cells in the periphery for efficient lymph node homing and spatial positioning that promotes primingthat is critical for their anti-tumor effects in vivo. Aim 1 will use both TCR- and CAR- based syngeneic mousesolid tumor models of ACT. In Aim 2 we turn to the cell-intrinsic effects of o9R signaling on effector capacity inthe face of chronic antigen stimulation. We hypothesize that o9R signaling interferes with the epigenetic changesthat drive T cell dysfunction in the context of chronic antigen stimulation resulting in superior effector capacity.Aim 2 will primarily use human T cells engineered with a TCR specific for the NY-ESO-1 antigen along with thepmel model.Our complementary aims outline an approach to define the effects of IL9R signaling in T cells that underlie theiranti-tumor functions in solid tumors without conditioning chemotherapy. Our findings will set the stage for thetherapeutic translation of T cells endowed with IL9R signaling. 353100 +No NIH Category available AR gene;Address;Age;Androgen Receptor;Androgen Suppression;Androgens;BRAF gene;Biochemical;Cell Aging;Cells;Collection;Cytoplasm;Cytotoxic T-Lymphocytes;DNA;DNA Damage;DNA Repair;Data;Development;Epigenetic Process;Estrogens;Extravasation;Female;Gene Expression Profile;Gene Silencing;Genes;Genetic;Genetic Transcription;Genome Stability;Gonadal Steroid Hormones;Immunocompetent;Incidence;Infiltration;Inflammatory;Lamin Type A;Lamins;Ligands;Link;Macrophage;Maintenance;Malignant Neoplasms;Melanoma Cell;Modeling;Mutation;Nuclear Envelope;Nuclear Lamin;Nuclear Receptor Coactivator 4;Organ;Pathway interactions;Patients;Phosphorylation;Play;Population;Predisposition;Process;Proliferating;Protein phosphatase;Proteins;RNA Helicase;Receptor Inhibition;Receptor Signaling;Resistance;Resources;Role;Sex Differences;Signal Transduction;T-Cell Activation;Testing;Up-Regulation;Validation;Work;cancer type;clinically significant;ds-DNA;genome integrity;hormonal signals;in vivo;inhibitor;male;melanoma;mouse model;overexpression;patient derived xenograft model;patient response;pharmacologic;prevent;prognostic significance;receptor expression;receptor function;response;self-renewal;sex;sexual dimorphism;transcriptomics;treatment response;tumor;tumorigenesis Androgen receptor function in melanoma NarrativeMalignant melanoma is an example of primary clinical significance for investigating sex hormonesdependent differences in cancer in organs with non-reproductive functions. We will be exploringthe interplay between androgen receptor and associated proteins in control of melanomadevelopment and response to treatment. NCI 10709864 8/24/23 0:00 PA-20-185 5R01CA269356-02 5 R01 CA 269356 2 "XU, WANPING" 9/23/22 0:00 8/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 1880455 "DOTTO, GIAN-PAOLO " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 448034 NCI 267096 180938 AbstractMalignant melanoma is an example of primary clinical significance for investigating sex-relateddifferences in cancer arising in organs with non-reproductive functions. Differences in sexhormone levels and in downstream pathways are likely to play a key role which is however stillpoorly understood. Our main working hypothesis is that androgen receptor (AR) and associatedproteins converge on control of melanoma development and response to treatment. In recentwork we have found that genetic and pharmacological suppression of AR activity in a large panelof melanoma cells reduces self-renewal potential and tumorigenesis inducing double strand DNAdamage and cytoplasmic leakage a STING-dependent pro-inflammatory cascade and a geneexpression signature associated with better patients' survival. Based on further preliminary datawe will test two specific hypotheses: 1) AR signaling plays a key role in melanoma cells at theintersection between gene transcription and DNA repair / genomic stability with nuclear lamins asco-determinants. We will probe into the biochemical and functional significance of endogenousAR-lamin interactions and AR-dependent lamin A/C association with the PPP1 proteinphosphatase impinging on lamin phosphorylation at critical residues and with the DDX3X andDDX3Y RNA helicases encoded by X- and Y-linked genes and with expression of prognosticsignificance for female and male patients respectively. 2) Targeting AR is of translationalsignificance for preventing / counteracting resistance of melanomas with BRAFv600 mutations toBRAF inhibitors (BRAFi). In preliminary work we found striking up-regulation of AR expression inresponse to BRAFi proliferation and tumorigenesis of BRAFi resistant melanoma cells aresuppressed by AR inhibition AR overexpression is by itself sufficient to confer BRAFi resistance.In further studies we will assess to what extent suppression of AR expression and activity has animpact on melanoma cell subpopulations with intrinsic BRAFi resistance and/or BRAFi-inducedepigenetic reprogramming. We will analyze a collection of freshly derived cells from Patient-Derived Xenografts (PDX) of BRAFi sensitive and resistant melanomas and assess to what extentthe beneficial effects of suppression of AR signalling occur in vivo restoring one or more aspectsof the BRAFi response of the corresponding PDXs. 448034 +Biotechnology; Cancer; Genetics; Lung; Lung Cancer; Radiation Oncology; Rare Diseases BCL2 gene;Bioinformatics;Cancer Model;Cancer Therapy Evaluation Program;Candidate Disease Gene;Cell Line;Cells;Chemicals;Chemoresistance;Chest;Cisplatin;Clinical;Collaborations;Complex;Data;Development;Drug Combinations;Epigenetic Process;Etiology;Etoposide;Experimental Models;Follow-Up Studies;Funding;Gene Expression;Gene Expression Profiling;Gene Targeting;Genetic;Genetic Transcription;Genetically Engineered Mouse;Human;In Vitro;Limited Stage;Malignant Neoplasms;Mediating;Medical;Medical Oncologist;Modeling;Molecular;Molecular Target;Natural History;Organoids;Outcome;Pathway interactions;Patients;Pattern;Pharmacology;Phenotype;Population;Positioning Attribute;Radiation Oncologist;Radiation therapy;Recurrence;Recurrent disease;Refractory;Regulator Genes;Research;Research Design;Resistance;Signaling Protein;Techniques;Testing;Transgenic Mice;Treatment Protocols;Variant;Veterinarians;Work;Xenograft procedure;animal imaging;base;candidate validation;chemoradiation;chemotherapy;combat;gene regulatory network;genetic approach;improved;in vivo;inhibitor;innovation;insight;irradiation;lung small cell carcinoma;mouse model;neoplastic cell;novel;patient derived xenograft model;pre-clinical;programs;resistance gene;resistance mechanism;response;therapy resistant;tool;transcription factor;transcriptome sequencing;treatment response;tumor Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC PROJECT NARRATIVEThe work we have proposed has a direct impact on the etiology and possibly treatment of chemoradiationresistance in small cell lung cancer. As chemoradiation resistance mechanisms are not being intensely studiedusing relevant preclinical small cell lung cancer models our findings can have an immediate and large impacton the field. Lastly the study of chemoradiation resistance mechanisms in small cell lung cancer may allow abroader understanding of chemoradiation resistance mechanisms in other cancers and expose new pathwaysto target treatment resistance. NCI 10709676 9/23/22 0:00 PAR-16-049 3U01CA231776-05S1 3 U01 CA 231776 5 S1 "FORRY, SUZANNE L" 9/3/18 0:00 8/31/24 0:00 ZCA1-RTRB-U(M3) 10893334 "HANN, CHRISTINE L." "MARCHIONNI, LUIGI ; TRAN, PHUOC T." 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/22 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2022 368438 NCI 225000 143438 PROJECT ABSTRACTLimited stage small cell lung cancer (LS SCLC) the only curable form of SCLC is remarkably sensitive toetoposide plus cisplatin combined with thoracic radiotherapy with response rates > 70%; however therapy-refractory recurrence is common. LS SCLC has less than a 25% 5-year overall survival (OS) and ultimately astrategy for improving long-term SCLC outcomes needs to successfully target tumor cell populations thatsurvive standard therapy and give rise to recurrent disease. There is however a considerable gap inunderstanding the specific mechanisms responsible for chemoradiotherapy resistance in SCLC. Our project isunique among the current portfolio of SCLC funded programs in that we have focused onchemoradioresistance to increase cure rates in LS SCLC. Recently our work has suggested using patient-derived xenograft (PDX) models of SCLC may be an important tool to elucidate mechanisms of therapyresistance. This approach was remarkably successful identifying a tolerable and strongly synergistic anti-SCLC interaction that led to a CTEP-approved trial based on our preclinical data - (NCI #10070; Study Chair:Hann). In this research program we will test key hypotheses via three specific aims that will provide moremechanistic insights into the rapidly emergent chemoradiation resistance observed in LS SCLC.One central hypothesis of this proposal is that adaptive gene expression changes mediate rapid emergence ofthe chemoradiation resistance phenotype in LS SCLC. We have developed a novel chemoradiation treatmentregimen with SCLC PDX models to facilitate these studies. Development and characterization of this novelmodel involves a unique collaboration between medical oncologists radiation oncologists bioinformaticiansmedical physicists veterinarians and molecular/cell biologists that is extremely well suited to develop anintegrated program dedicated to resolving questions of SCLC chemoradioresistance. Finally we have alreadyidentified novel gene targets that are correlated with SCLC chemoradioresistance.Our research program is organized as follows: Aim #1: Characterize natural history of response ofexperimental models of SCLC to chemoradiation in vivo. We will determine response rates and recurrencepatterns of a panel of SCLC PDXs and transgenic mouse models. Aim #2: Characterization of molecularunderpinnings of SCLC chemoradiation resistance. We will reconstruct gene regulatory networks and geneexpression profiles associated with chemoradiation resistance and develop small-scale predictive classifiers fortherapy response to be validated in follow-up studies. Aim #3: Pharmacologic and genetic validation ofcandidate genes for SCLC chemoradiation resistance in vitro and in vivo. We will validate our novel genecandidates for conferring chemoradiation resistance using pharmacologic and genetic approach with SCLCPDX-derived organoids and SCLC transgenic mouse models. 368438 +No NIH Category available Address;Adult;African American;American;American Association of Cancer Research;Animal Feed;Asian Americans;Baseline Surveys;Behavior;Black race;Body Size;Body Weight;Body mass index;California;Cancer Survivor;Caregivers;Centers for Disease Control and Prevention (U.S.);Cessation of life;Chinese;Clinical;Coffee;Cohort Studies;Cox Proportional Hazards Models;Dairying;Data;Diabetes Mellitus;Diagnosis;Diagnostic;Diet;Dietary Component;Dietary Factors;Dietary Fiber;Edible Plants;Enrollment;Ensure;Ethnic Origin;Ethnic Population;Fabaceae;Family;Food;Food Selections;Frequencies;Funding;Hawaii;Health behavior;Heart Diseases;Hispanic;Incidence;Intake;Intervention;Japanese;Knowledge;Latino;Latinx;Latinx population;Malignant neoplasm of prostate;Measures;Meat;Mediating;Medical;Native Hawaiian;Nonmetastatic;Nuts;Outcome;Pacific Islander;Participant;Patients;Persons;Pharmaceutical Preparations;Physical activity;Physicians;Plants;Population;Population Heterogeneity;Processed Meats;Progress Reports;Prospective Studies;Prostate;Public Health;Questionnaires;Race;Recommendation;Recording of previous events;Reporting;Research;Risk;Risk Factors;Risk Reduction;Self Administration;Smoking;Smoking History;Surveys;Tea;United States;Update;Vascular Plant;Vegetable Oils;Vegetables;Weight;Work;advanced disease;anticancer research;cancer diagnosis;cancer health disparity;cancer risk;cohort;demographics;dietary;egg;ethnic disparity;ethnic diversity;follow-up;fruits and vegetables;healthy lifestyle;high risk;improved;indexing;interest;men;modifiable risk;mortality;mortality risk;multi-ethnic;population based;primary outcome;prostate cancer risk;prostate cancer survivors;racial disparity;racial diversity;racial population;research study;saturated fat;secondary outcome;tumor progression Health Behaviors and Mortality in Prostate Cancer Survivors in the Multiethnic Cohort Study PROJECT NARRATIVE:Prostate cancer the most diagnosed cancer among men in the United States has large racial/ethnicdisparities in incidence and mortality. Data from non-Latinx White populations suggest that health behaviorsare associated with prostate cancer incidence and mortality but data are lacking from racially/ethnicallydiverse cohorts. Thus we aim to determine whether a post-diagnostic Healthful Plant-based Diet Index and aProstate Health Behavior Score are associated with lower risk of all-cause mortality and prostate cancer-specific mortality among men with prostate cancer from the population-based Multiethnic Cohort Study (MEC)including 19% who identify as African American 25% who identify as non-Latino White 23% who identify asLatino 28% who identify as Asian American and 5% who identify as Native Hawaiian. NCI 10709584 8/11/23 0:00 PAR-20-052 5R03CA273486-02 5 R03 CA 273486 2 "GALLICCHIO, LISA M" 9/23/22 0:00 8/31/24 0:00 ZCA1-RTRB-B(M1)S 9522143 "KENFIELD, STACEY " Not Applicable 11 UROLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 80750 NCI 50000 30750 PROJECT ABSTRACT:Large racial/ethnic disparities exist for prostate cancer (PC) incidence and mortality. Between 2001-2017 the5-year relative survival for Black Asian American/Pacific Islander and Latinx groups was lower compared tonon-Latinx White men. Progressing to advanced disease is a pivotal concern among patients with non-metastatic PC their family caregivers and physicians. A major gap in current knowledge is the lack ofresearch studies focused on post-diagnostic modifiable factors from racially/ethnically diverse populations.Preliminary data suggest that a Healthful Plant-based Diet Index may be associated with a ~60% lower risk ofincident fatal PC among healthy men. In addition our team recently developed a post-diagnostic ProstateHealth Behavior Score (focused on physical activity weight and diet) with higher scores associated with a~55% lower risk of PC-specific mortality among men with PC. Even so 92% of participants in these twoanalyses identified as non-Latinx White; thus the findings may not be generalizable to the racially/ethnicallydiverse populations of people living with PC. In this R03 we propose to examine whether a Healthful Plant-based Diet Index or composite Prostate Health Behavior Score is associated with survival among men with PCin the population-based Multiethnic Cohort Study (MEC). The MEC is a diverse cohort of over 215000 adultsliving predominately in southern California and Hawaii when enrolled between 1993-1996. For these analyseswe will use data from 2652 men with PC who have measures of health behaviors before and after diagnosis;19% identified as African American 25% identified as non-Latino White 23% identified as Latino 28%identified as Asian American and 5% identified as Native Hawaiian. A comprehensive self-administeredquestionnaire captured demographics body size medical and family histories medication use smokinghistory and physical activity at enrollment; and a quantitative food frequency questionnaire (FFQ) was alsoadministered. Follow-up surveys have been administered every 4-6 years. Data from the baseline survey willbe used to adjust for pre-diagnosis health behaviors and body weight. Using these data we aim to 1) examinewhether the Healthful Plant-based Diet Index a Prostate Health Behavior Score and their componentsmeasured after PC diagnosis are associated with lower risk of all-cause and PC-specific mortality; and 2)explore whether associations between these modifiable risk factors and mortality vary across racial/ethnicgroups and the degree to which health behaviors contribute to observed racial/ethnic disparities in PCmortality. This work will be completed in the largest prospective study of racially/ethnically diverse men with PCin the U.S. ensuring the generalizability of our results and directly informing clinical and public healthrecommendations. In addition this proposal will strengthen the evidence on the impact of health behaviors onoutcomes in cancer survivors and could help reduce racial/ethnic disparities in PC outcomes and guideinterventions to ultimately help people with PC lower their risk of cancer progression and death. 80750 +No NIH Category available Acute;Address;Adult;Biological Assay;Biological Markers;Breast Adenocarcinoma;CLIA certified;Cancer Patient;Categories;Cells;Clinical;Clinical Trials;Collaborations;Combined Modality Therapy;Data Set;Dependence;Desmoplastic Small Round Cell Tumor;Development;Dissection;Drug Controls;Drug Targeting;Drug resistance;Genetic;Genetic Transcription;Glioblastoma;Goals;Health;Immunotherapy;Individual;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Molecular;Mutate;Mutation;Network-based;Neuroblastoma;Neuroendocrine Tumors;Oncogenes;Oncoproteins;Pathway interactions;Patients;Pediatric Neoplasm;Pharmaceutical Preparations;Population;Progression-Free Survivals;Prostate;Prostate Adenocarcinoma;Proteins;Relapse;Reporter Genes;Research Personnel;Reverse engineering;Role;Signal Transduction;Slice;Testing;The Cancer Genome Atlas;Tissues;Tumor Subtype;Validation;biomarker development;cancer cell;cancer genetics;cohort;design;drug sensitivity;falls;follow-up;improved;neoplastic cell;novel;patient derived xenograft model;pharmacologic;resistance mechanism;response;sarcoma;single-cell RNA sequencing;success;targeted treatment;therapeutic target;therapeutically effective;transcription factor;tumor;tumorigenesis Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level NarrativeClonal selection and inherent cancer cell plasticityas well as the ability of cancer cells to undergo adaptationand reprogramming to drug resistant states following treatment are currently challenging the concept ofindividual proteins as effective therapeutic targets for an entire tumor massespecially if identified frombulk tissue analyses. To address these challenges we have identified a more universal class of mutation-agnostic non-oncogene dependencies implemented by Tumor Checkpoint (TC) modules comprising smallsets of Master Regulator (MR) proteins working in concert to implement and maintain tumor cell state bycanalizing the effect of mutations and signals in their upstream pathways. Our proposal will thus focus on theelucidation and pharmacological targeting of MRs and TC-modules at the single cell level withinmolecularly distinct yet co-existing tumor subpopulations leading to design of successful combinationtherapy approaches and discovery of mechanisms of drug resistance and cell adaptation. NCI 10709574 9/7/23 0:00 PAR-21-274 5U01CA272610-02 5 U01 CA 272610 2 "ZENKLUSEN, JEAN C" 9/21/22 0:00 8/31/27 0:00 ZCA1-RPRB-N(M2)R 7827402 "CALIFANO, ANDREA " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 956166 NCI 625423 330743 Cancer targets fall into two major categories: oncoproteins that elicit tumor essentiality due to their direct role intumorigenesis or tumor maintenance (oncogene dependencies) and proteins that elicit synthetic lethality withoncogene mutations but are not themselves mutated (non-oncogene dependencies). Unfortunately clonalselection and inherent cancer cell plasticityas well as the ability of cancer cells to undergo adaptation andreprogramming to drug resistant states following treatmentare currently challenging the concept ofindividual proteins as effective therapeutic targets for an entire tumor massespecially if identified frombulk tissue analyses. Indeed despite several successes only 5% 11% of cancer patients benefit fromtargeted therapy based on progression free survival often with no substantial overall survival differences; whilepromising immune therapy is also subject to selective response and relapse. To address these challenges ourproposal will study a more universal class of mutation-agnostic non-oncogene dependencies implementedby tightly-autoregulated sets of Master Regulator (MR) proteins that we have called Tumor Checkpoint (TC)modules. We have shown that MR proteins mechanistically implement a tumor cells transcriptional state bycanalizing the effect of mutations and aberrant signals in their upstream pathways. As such within the contextof a transcriptionally-distinct tumor subtype they represent largely mutation-agnostic dependencies. Ourproposal will thus focus on the elucidation and pharmacological targeting of MRs and TC-modules at thesingle cell level within molecularly distinct yet co-existing tumor subpopulations. This will lead to designof successful combination therapy approaches and will help elucidate and pharmacologically target mechanismsof drug resistance and cell adaptation. To accomplish these goals we will extend a highly successful network-based framework developed by our CTD2 Center for the elucidation validation and pharmacological targetingof MR proteins and TC-modules. Indeed we have shown that genetic or pharmacological targeting of this newclass of tumor dependencies can induce collapse of TC-module activity and induce loss of tumor viability in awide range of malignancies ranging from glioblastoma neuroblastoma and neuroendocrine tumors to prostateand breast adenocarcinoma among many others. In particular analysis of 25 TCGA cohorts has identified 112transcriptionally distinct tumor subtypes each one regulated by a distinct subtype-specific TC-module whichwas independent of patient-specific mutations. These methodologies are especially relevant in rare aggressivetumorsincluding several pediatric malignancieswhere cohort size may be too small to support correlativeanalyses. Critically these studies have led to the development of two NY/CA Dpt. of Health approved CLIA-compliant tests OncoTarget and OncoTreat whose predictions have spurred several clinical trials. Theseapproaches will be extended to elucidate TC-module dependencies and to develop drug sensitivity biomarkersat the single cell level. 956166 +No NIH Category available ADP-ribosylation factor 6;Actins;Address;Affect;Allografting;Alveolar Rhabdomyosarcoma;Animal Model;Animals;Binding;Biochemical;Biology;Cancer Biology;Cancer Model;Cell Culture Techniques;Cell Line;Cell Lineage;Cells;Child;Childhood;Chromatin;Classification;Clinical;Complex;Data;Development;Developmental Biology;Developmental Gene;Disease;Embryonal Rhabdomyosarcoma;Endocytic Vesicle;Event;FOXO1A gene;Gene Expression Profile;Gene Fusion;Genetic;Genetic Diseases;Genetic Transcription;Genomics;Goals;Human;Knock-out;Knowledge;Malignant Childhood Neoplasm;Malignant Neoplasms;Maps;Mediating;Modeling;Molecular;Monomeric GTP-Binding Proteins;Mus;Muscle;Muscle Development;Mutation;Myoblasts;NCOA2 gene;Nuclear Receptors;Oncogenes;Oncogenic;Oncology;Operative Surgical Procedures;PAX3 gene;Pathway interactions;Patients;Predisposition;Property;Radiation;Research;Rhabdomyosarcoma;Role;Sampling;Series;Skeletal Muscle;Structure;System;Tertiary Protein Structure;Testing;Therapeutic;Transcription Coactivator;Transgenic Organisms;Validation;Zebrafish;chemotherapy;clinical care;clinical sequencing;comparative;disease-causing mutation;druggable target;human disease;infancy;innovation;malignant muscle neoplasm;mutant;myogenesis;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;progenitor;programs;side effect;small molecule;spatiotemporal;targeted treatment;therapeutic target;transcription factor;tumor;tumor initiation;tumorigenesis;tumorigenic;zebrafish development Understanding Infantile Rhabdomyosarcoma Biology and Therapeutic Targets PROJECT NARRATIVEInfantile rhabdomyosarcoma (RMS) is a newly identified and poorly understood aggressive pediatric musclecancer that affects young children. There is one single mutation that causes the disease but we do not havespecialized treatments targeting this genetic event and patients are treated with general strategies that are oftenineffective or have harsh life-long side effects. We will leverage novel zebrafish and mouse cancer models tohelp young children with cancer by understanding the biology of how infantile RMS develops and implementingthese models to identify clinically tractable therapeutic targets. NCI 10709542 9/11/23 0:00 PA-20-185 5R01CA272872-02 5 R01 CA 272872 2 "WITKIN, KEREN L" 9/23/22 0:00 8/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 12075462 "KENDALL, GENEVIEVE CLAIRE" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 375214 NCI 243645 131569 PROJECT SUMMARY/ABSTRACTInfantile rhabdomyosarcoma (RMS) is a newly identified and poorly understood aggressive cancer with immatureskeletal muscle properties that affects young children. Recent clinical sequencing efforts have identified aspectrum of likely biologically related gene fusions that genetically define infantile RMS: the most common beinga fusion between two transcriptional co-activators with roles in normal muscle development termed VGLL2-NCOA2. Although we know the defining oncogenic event there are no therapies targeting the genetics of thedisease. Thus patients are treated with general chemotherapy surgery and radiation often ineffectively or withharsh long-term side effects. There is a pressing need to understand the biology of infantile RMS contextualizeinfantile RMS biology with other RMS sub-types and leverage this information to delineate therapeutic targets.Progress is limited by a lack of animal models cell lines and PDXs to study the disease dynamics. My long-termgoal is to integrate vertebrate zebrafish mouse cell culture models and patient samples to identify conservedgenetic programs for RMS tumorigenesis and novel therapeutic strategies. Toward that end this projects mainobjective is to elucidate the underlying biology and therapeutic targets in fusion-oncogene driven infantile RMS.Our central hypothesis is that VGLL2-NCOA2 leverages normal developmental programs including ARF6 tomediate infantile RMS tumorigenesis and that targeting these pathways is a therapeutic opportunity. Our specificaims will address this hypothesis by: (Aim 1) Delineating VGLL2-NCOA2 structure-function requirements fortumorigenesis (Aim 2) Establishing mechanisms of VGLL2-NCOA2 and ARF6 cooperation inrhabdomyosarcoma and (Aim 3) Determining VGLL2-NCOA2 muscle lineage context and temporalprerequisites for tumorigenesis. Completing these studies at the interface of developmental and cancer biologywill generate significant new knowledge regarding fusion-oncogene leveraging of developmental programs andwill identify potential therapeutic targets. The proposed research is conceptually innovative because it leveragesa cross-species comparative oncology approach to pinpoint the most important molecular drivers in a newdisease and it is experimentally innovative because it utilizes multiple new vertebrate (zebrafish and mouse)infantile RMS models developed by our group. Successful execution of this project will generate exciting datafocused on delineating the basic biology of infantile rhabdomyosarcoma to directly impact and guide clinical care. 375214 +No NIH Category available Address;Area;Biological;Biological Markers;Black American;Black Populations;Black race;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer gene;Cancer Etiology;Cancer Prognosis;Cessation of life;Chronic;Clinical;Cohort Studies;Communities;Crows;DNA Methylation;Data;Diagnostic;Disparate;Disparity;Dyslipidemias;Environment;Epigenetic Process;Estrogen receptor negative;Ethnic Population;Evaluation;Exposure to;Fibrinogen;Future;Genes;Genetic;Health;Hyperinsulinism;IL8 gene;Immune;Incidence;Inequity;Inflammation;Inflammatory;Institution;Institutional Racism;Interleukin-10;Interleukin-6;Investigation;Knowledge;Laws;Legal;Life Cycle Stages;Link;Literature;Measures;Mediating;Metabolic;Metabolic Pathway;Modeling;Outcome;Parents;Participant;Pathogenesis;Pathway interactions;Patient Self-Report;Patients;Prevention strategy;Primary Prevention;Process;Prognosis;Prognostic Marker;Prospective Studies;Prospective cohort;Psychosocial Stress;Public Health;Race;Reasons for Geographic And Racial Differences in Stroke;Recording of previous events;Research;Resources;Risk;Risk Factors;Sampling;Socioeconomic Status;Support Groups;Testing;Time;United States;Woman;adverse outcome;allostatic load;biological adaptation to stress;black women;breast cancer survival;cancer health disparity;clinically relevant;cohort;comorbidity;data infrastructure;epigenome;experience;follow-up;hypothalamic-pituitary-adrenal axis;improved;indexing;malignant breast neoplasm;mortality;mortality disparity;mortality risk;multi-ethnic;neoplasm registry;novel;people of color;perceived discrimination;poor health outcome;prognostic model;prospective;pyrosequencing;racial discrimination;racial disparity;racial population;residential segregation;tumor Systemic Racism and Biological Embodiment of Risk in Breast Cancer Mortality Black women in the US continue to experience much higher breast cancer mortality rates than any otherrace/ethnic group in the US and current knowledge regarding this mortality gap does not adequately explainits magnitude; thus effective strategies to address the problem remain elusive. We propose to investigate ahighly understudied factor i.e. exposure to an overarching environment of systemic racism which wehypothesize is biologically embodied in a stress response that alters key immune metabolic and epigeneticpathways important in breast cancer etiology. Our study will determine whether and to what extent exposureto systemic racism alters key biological pathways and helps explain the increased breast cancer mortality riskamong Black vs. White women helping to inform clinical and public health mitigation strategies. NCI 10709512 8/21/23 0:00 PA-20-185 5R01CA263770-02 5 R01 CA 263770 2 "MOMIN, BEHNOOSH RAMJI" 9/23/22 0:00 8/31/27 0:00 Social Sciences and Population Studies A Study Section[SSPA] 9235849 "AKINYEMIJU, TOMI F" Not Applicable 4 PUBLIC HEALTH & PREV MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 788797 NCI 625951 162846 Black women experience much higher breast cancer mortality than any other race/ethnic group in the US.Despite extensive investigation the known causes to date do not adequately explain this mortality gap. Largelymissing in the disparities literature is a rigorous examination of systemic racism i.e. how exposure to anoverarching environment of systemic racism (SR) might impact breast cancer outcomes in Black women.Multiple lines of evidence when considered together indicate this exposure merits investigation. SR (e.g.perceived discrimination residential segregation) is associated with a range of adverse health effects inBlacks and chronic psychosocial stress due to SR can become embodied via hyperactivation of thehypothalamic pituitary adrenal (HPA) axis leading to inflammatory metabolic and epigenetic dysregulation.Thus we hypothesize that exposure to SR leads to alterations in key biological pathways which in turncontribute to excess breast cancer mortality in Black women. No empirical study has directly tested thishypothesis in a single cohort. To address this gap we will generate a new prospective cohort with 2498incident breast cancer and 2678 sub-cohort random sample from two parent cohorts -- the REasons forGeographic and Racial Differences in Stroke (REGARDS) and Southern Community Cohort Study (SCCS)cohorts. Both parent cohorts over sampled Blacks and include participants from southern states with a historyof SR and obtained extensive baseline and biomarker data enabling us to measure biomarkers ofinflammation and metabolic dysregulation. We will newly assess measures of SR at the structural andinterpersonal levels and characterize epigenome-wide DNA methylation profiles. Our study will conduct the firstthorough prospective evaluation of the distinct influence of SR above and beyond other racially pattered riskfactors on breast cancer disparities in a large diverse cohort. By quantifying the distinct impact of SR onbreast cancer mortality and identifying pathways and biomarkers that mediate this association our study willhelp improve the poor accuracy of breast cancer prognostic models in Black women and inform primaryprevention strategies focused on mitigating SR to reduce racial disparities in breast cancer mortality 788797 +No NIH Category available Address;Age;Algorithms;Artificial Intelligence;CD3 Antigens;CD8-Positive T-Lymphocytes;California;Cancer Prognosis;Characteristics;Clinical;Clinical Data;Colorectal Cancer;Colorectal Neoplasms;Computers;Computing Methodologies;Crohn's disease;Data;Detection;Diagnosis;Ensure;Epidemiology;Expression Profiling;Failure;Florida;Genetic;Goals;Histology;Image;Image Analysis;Immune;Immune response;Immune system;Immunologics;Immunology;Immunotherapy;Israel;Location;Lymphocyte;Lymphoid;Machine Learning;Maps;Measures;Methods;Microsatellite Instability;Microscopic;Modeling;Molecular;New York;Other Genetics;Outcome;Pathologic;Pathologist;Pathology;Patients;Pattern;Performance;Persons;Physicians;Population;Population Heterogeneity;Predictive Value;Process;Prognosis;Proteins;Puerto Rico;Reaction;Recording of previous events;Reproducibility;Research;Sampling;Slide;Solid Neoplasm;Spain;Spatial Distribution;Specimen;Statistical Methods;System;TNM;Technology;Testing;Training;Tumor-Infiltrating Lymphocytes;Validation;Visual;accurate diagnosis;cancer diagnosis;cancer survival;clinical predictors;clinically relevant;colon cancer patients;colorectal cancer treatment;deep learning;design;digital;digital imaging;driver mutation;effective therapy;epidemiologic data;ethnic diversity;immunoreaction;immunoregulation;improved;improved outcome;insight;learning strategy;low income country;machine learning algorithm;machine learning prediction algorithm;medical specialties;novel;prediction algorithm;predictive modeling;prognostic;prognostic model;prognostic value;protein expression;racial diversity;response;sex;survival prediction;task analysis;tool;treatment response;tumor;whole slide imaging Integration of epidemiology pathology immunology and outcomes in colorectal cancer NARRATIVEPathologists are experts in making a diagnosis of cancer and describing the microscopic features that helpguide treatment decisions. Computers are rapidly catching up to pathologists and this study compares hownew computer methods that recognize how the body's immune system reacts to colorectal cancer performagainst expert pathologists. It is also possible to directly measure immune reactions and map these to specificlocations inside the tumor; together with information about age sex and a person's genetics and history thegoal of this study is to improve predictions of survival and to automate the diagnosis colorectal cancer. NCI 10709493 8/23/23 0:00 PA-20-185 5R01CA263318-02 5 R01 CA 263318 2 "OSSANDON, MIGUEL" 9/22/22 0:00 8/31/27 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 1902433 "GRUBER, STEPHEN B" Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 650087 NCI 432086 218001 ABSTRACTMachine learning has the potential to transform pathologic diagnosis and to address very limited accessibility ofexpert pathology in low-income countries. Routine histology images of solid tumors contain an immense numberof visual features that can be extracted and processed by artificial intelligence tools like machine learning whichexcels at basic image analysis tasks such as tumor detection. In addition machine learning can also predictclinically relevant features directly from histology images including microsatellite instability and immune featuresthat independently predict prognosis response to therapy. This large multicultural racially and ethnically diversestudy uses images of whole slides from routinely collected clinical specimens and applies computationalpathology methods and digital spatial expression profiling to quantifiably improve CRC diagnosis prognosis andpredictive models together with clinical epidemiologic and genetic data. The study goals will be accomplishedthrough three specific aims. In Aim 1 we will apply novel machine learning algorithms from whole slide imagesto reproducibly identify MSI histopathologic and immune features of colorectal cancer in racially/ethnicallydiverse populations. We will study H&E slides from 6751 CRC cases digitizing existing slides from 5551 CRCcases and 1200 new cases of CRC with contemporaneous clinical and epidemiologic data. Then we will applydeep learning methods to accurately identify histopathologic features and immune characteristics of CRC. Wewill use a robust training validation and testing design (70%/15%/15%) to ensure the rigor and reproducibility ofour findings. In Aim 2 we will test whether machine learning algorithms that predict MSI and immune featuresrelated to CRC prognosis improve with the addition of clinical epidemiologic and germline genetic data. We willuse machine learning statistical methods to test whether algorithms developed in Aim 1 improve prediction ofoverall survival and response to therapy with the addition of supplemental information beyond whole slide digitalimages. Finally in Aim 3 we will compare the information derived from digital spatial profiling of expressedproteins in colorectal tumors with the information derived from Immunoscore quantification of lymphocytepopulations at the tumor center (CT) and the invasive margin (IM) and explore whether these measures improvethe models developed in Aims 1 and 2 in a subset of samples. We will perform GeoMx digital spatial profiling of56 proteins expressed in 150 Stage I-III TNM colorectal cancers to compare the performance of digital spatialprofiling to Immunoscore a scoring system relying exclusively on expression patterns of CD3+ and CD8+ T cells.This study takes advantage of pathologic epidemiologic clinical immunologic and germline genetic data fromracially/ethnically diverse CRC patients from California Detroit New York Florida Puerto Rico Israel and Spain.Our overarching goal is to improve the efficient diagnosis of colorectal cancer with clinically impactful immuneprofiles. 650087 +No NIH Category available ATAC-seq;Acute;Architecture;Biology;Carboplatin;Carcinoma;Cell Reprogramming;Cells;Cessation of life;Chemoresistance;Chromatin;Cisplatin;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;DNA Damage;DNA Repair;DNA Sequence Alteration;Data;Dose;Enhancers;Epigenetic Process;Gatekeeping;Gene Expression;Genes;Genetic;Genetic Transcription;Genome;Genomics;Goals;Growth;Immunocompetent;In Vitro;Malignant - descriptor;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Maps;Measures;Mediating;Modeling;Molecular;Non-Malignant;Operative Surgical Procedures;Ovarian Serous Adenocarcinoma;Pathway interactions;Patients;Platinum;Play;Population;Primary Neoplasm;Prognosis;Publishing;Recurrence;Relapse;Repression;Research;Resistance;Role;Sampling;Serous;Technology;Testing;Therapeutic;Tumor Debulking;Tumor Immunity;Tumor Tissue;Up-Regulation;Work;arginine methyltransferase;cancer cell;cancer subtypes;cancer therapy;chemotherapy;clinically relevant;cohort;combinatorial;comparative;epigenome;epigenomics;genome editing;genome-wide;improved;in vivo;insight;mortality;non-genetic;novel;novel therapeutic intervention;programmed cell death ligand 1;programs;response;screening;single-cell RNA sequencing;stem-like cell;therapeutic target;therapeutically effective;tool;transcription factor;transcriptional reprogramming;transcriptome;transcriptomic profiling;transcriptomics;tumor Chemo-mediated transcriptional reprogramming in ovarian cancer Narrative Platinum-resistance is the ultimate cause of mortality in OC. Here we test a hypothesis thatchemoresistance emerges due to therapy-induced population-level transcriptional reprogramming. We haveidentified specific sets of drivers that reprogram nave cells into the Pt-resistant one. This proposal tests thehypothesis and investigates the molecular drivers of chemoresistance using cutting edge genome editing andsingle-cell level genome profiling tools in vitro and in vivo using clinical samples. Furthermore we are testing aclinically relevant promising therapeutic target to overcome chemoresistance and boost anti-tumor immunity. NCI 10709477 9/1/23 0:00 PA-20-185 5R01CA267544-02 5 R01 CA 267544 2 "O'HAYRE, MORGAN" 9/23/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-OTC1-B(60)C] 11132085 "ADLI, MAZHAR " Not Applicable 5 OBSTETRICS & GYNECOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 452366 NCI 283467 168899 AbstractHigh-grade serous carcinoma (HGSC) is the most aggressive OC subtype that accounts for 80% of OC-relateddeaths. Rapid emergence of platinum (Pt)-resistance is the main reason for this mortality. Despite initialresponse to surgery plus chemotherapy tumors relapse and rapidly become chemoresistant in 80% of patients.Although few genetic mutations have been associated with chemoresistance in a large fraction of tumors driversof the chemoresistance's rapid emergence are unknown. Here we propose that non-genetic mechanisms playan important part in regulating cellular transition to a resistant state in high grade serous ovarian cancer. Wewill tackle the emergence of Pt resistance from a global transcriptional reprogramming point of view. Ourpublished and preliminary findings support the hypothesis that Pt resistance emerges from therapy-inducedpopulation-level epigenomic and transcriptional reprogramming. Through integrative analysis of epigenomesand transcriptomes of multiple nave and cisplatin-resistant isogenic cells we identified resistant-state specificsuper-enhancers and their target transcription factor networks (TFN). The first aim employs cutting edgegenomic mapping and manipulation technologies including single cell-level CRISPR-perturbations followed bytranscriptome profiling to identify which TFs and TF-combinations are necessary to reprogram nave cells intothe resistant state. The second aim investigates a novel combinatorial target to achieve synthetic lethality withcarboplatin in HGSOC. The findings from this proposal will provide new mechanistic insight into the role of keytranscription factor network that govern platinum resistance in ovarian cancer. 452366 +No NIH Category available Adhesions;Affect;Behavior assessment;Behavioral;Biological Markers;Body Composition;California;Cancer Survivor;Cells;Central obesity;Clinical;Clinical Data;Colorectal Cancer;Data;Data Set;Development;Diabetes Mellitus;Diagnosis;Disease;Distant Metastasis;Dose;Dyslipidemias;Etiology;Excision;Fatty acid glycerol esters;Foundations;Future;Goals;Guidelines;Hepatic;Image;Individual;Infiltration;Inflammatory;Intervention;Link;Liver;Liver Cirrhosis;Liver diseases;Machine Learning;Manuals;Measurement;Measures;Mediating;Metabolic;Metabolic syndrome;Metastatic Neoplasm to the Liver;Methods;MicroRNAs;Micrometastasis;Morbidity - disease rate;Neoplasm Circulating Cells;Neoplasm Metastasis;Operative Surgical Procedures;Pathway interactions;Patients;Pattern;Pharmacologic Substance;Plasma;Population;Predisposition;Prevalence;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Prognosis;Prognostic Factor;Prognostic Marker;Recurrence;Recurrent Malignant Neoplasm;Relapse;Risk;Risk Factors;Role;Scanning;Signal Pathway;Site;Skeletal Muscle;Soil;Spleen;Standardization;Subgroup;Testing;Thinness;Time;Visceral fat;X-Ray Computed Tomography;aged;attenuation;cancer diagnosis;cancer recurrence;cohort;colon cancer patients;colorectal cancer metastasis;colorectal cancer progression;comorbidity;cost;cost efficient;design;future implementation;high risk;improved;inclusion criteria;innovation;liver development;mortality;neoplasm registry;non-alcoholic fatty liver disease;non-diabetic;novel;pharmacologic;physical inactivity;radiologist;response;risk stratification;sarcopenia;sociodemographics;subcutaneous;tool;tumor-immune system interactions Association between pre-diagnosis hepatic fat infiltration and risk of liver metastasis and mortality in a large cohort of stage I-III colorectal cancer survivors PROJECT NARRATIVEWe propose to conduct a comprehensive study on the relationship between hepatic fat infiltration and riskof liver metastases. This study will help to establish a safe and cost-efficient prognostic biomarker for stageI-III CRC patients and provide the scientific foundation for future exploration into behavioral andpharmacological interventions specifically targeting high hepatic fat infiltration. Considering the alarmingrise in prevalence of non-alcoholic fatty liver disease in the U.S. and globally these interventions may helpto reduce morbidity and mortality in a substantial number of stage I-III CRC patients. NCI 10709469 8/17/23 0:00 PA-20-185 5R01CA255184-02 5 R01 CA 255184 2 "TANDON, PUSHPA" 9/23/22 0:00 8/31/26 0:00 Cancer Prevention Study Section[CPSS] 1881447 "GIOVANNUCCI, EDWARD " Not Applicable 7 NUTRITION 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 674019 NCI 598916 75103 PROJECT SUMMARY/ABSTRACTDevelopment of liver metastases among stage I-III colorectal cancer (CRC) patients following resectionsuggests the presence of clinically undetectable liver micro-metastases prior to CRC diagnosis. Non-alcoholic fatty liver disease (NAFLD) is quickly emerging as the most common liver disease worldwide withan estimated prevalence of 20-30% in the U.S. population. To date various lines of evidence support ourhypothesis of the potential role of liver fat in enhancing CRC liver metastasis; the next step is todemonstrate the utility of quantitative assessment of hepatic fat as a prognostic biomarker for stage I-IIICRC patients in clinical settings. Almost all CRC patients in the U.S. get a computerized tomography (CT)scan at diagnosis and NAFLD is a highly prevalent and treatable disease thus if our hypothesis isconfirmed we hope to establish a safe and cost-efficient prognostic biomarker which is currently lacking.The recently expanded C-SCANS (CRC-Sarcopenia and Near-term Survival) cohort was derived from theKaiser Permanente Northern California cancer registry with ascertainment of patients with stage I-III CRCdiagnosed between 2006 and 2018 aged 1880 years who underwent surgical resection. Inclusion criteriainclude that patients had baseline CT images within 4 months of diagnosis and prior to treatment.In Aim 1hepatic fat (quantitative assessment) will be measured in CT scans performed at time of CRC diagnosisand prior to treatment. First measurements will be performed manually and then using a novel machinelearning-based tool for liver segmentation and measurement of liver and spleen attenuation. In Aims 2 and3 we will examine (a) whether increased hepatic fat infiltration is associated with higher risk of livermetastases recurrence and CRC mortality and (b) whether associations are modified by comorbiditiesand risk factors related to the metabolic syndrome. In Aim 4 we will examine whether hepatic fat affectsliver metastases through a direct and/or indirect effect (e.g. mediated through the metabolic syndrome).Specifically we hypothesize that the direct effect of hepatic fat is more important in explaining therelationship between hepatic fat and liver metastases than the indirect effect. Data on body compositionincludingskeletal muscle and total subcutaneous and visceral fat and hepatic fat for each patient aremeasured on the same CT scans which combined with assessment of behavioral risk factors clinical dataand metabolic plasma markers around the same time provide an unprecedented opportunity to rigorouslystudy these effects. Thus this cost-efficient and innovative application will address the urgent need formore accurate prognostic biomarkers and relatively safe interventions to improve prognosis in stage I to IIICRC patients. Considering the alarming rise in prevalence of NAFLD this application has the potential toreduce morbidity and mortality in a substantial number of stage I-III CRC patients. 674019 +No NIH Category available Acute Myelocytic Leukemia;Acute T Cell Leukemia;Adjuvant;Adult;Adult Acute Myeloblastic Leukemia;Adult T-Cell Leukemia/Lymphoma;Agonist;Antigen-Presenting Cells;Antitumor Response;Apoptotic;Autoimmunity;Autologous;Autologous Tumor Cell;Bacteria;Barbering;Biological;Biotechnology;Blood;CAR T cell therapy;CD8B1 gene;Cell Death;Cell Lineage;Cell Nucleus;Cell division;Cells;Cellular immunotherapy;Clinic;Clinical;Clinical Data;Clinical Trials;Collaborations;Communicable Diseases;Cross Presentation;Cyclic GMP;Cytosol;Cytotoxic T-Lymphocytes;DNA;DNA Damage;Data;Dendritic Cells;Deoxyribonucleases;Development;Dinucleoside Phosphates;Disease;Embryo;Event;Exodeoxyribonuclease III;FDA approved;Future;Generations;Hematologic Neoplasms;Host Defense;Human;Human T-lymphotropic virus 1;Immune;Immune checkpoint inhibitor;Immune signaling;Immune system;Immunologics;Immunooncology;Immunotherapeutic agent;In Vitro;Infection;Inflammation;Infusion procedures;Interferon Type I;Invaded;Laboratories;Length;Letters;Leukemic Cell;Lymphoblastic Leukemia;Lymphoid Cell;Macrophage;Malignant - descriptor;Malignant Neoplasms;Modeling;Mus;Myeloid Cells;Myeloid Leukemia;Normal Cell;Nucleic Acids;Nucleotides;Participant;Patients;Periodicity;Phagocytes;Phagocytosis;Phase I Clinical Trials;Play;Process;Production;Property;Proteins;Refractory;Relapse;Research;Research Personnel;Resistance;Role;Safety;Signal Pathway;Signal Transduction;Stimulator of Interferon Genes;T-Cell Leukemia;T-Lymphocyte;Techniques;Technology;Testing;Therapeutic;Therapeutic Trials;Three Prime Repair Exonuclease 1;Toxic effect;Tumor Antigens;Tumor Burden;Tumor Immunity;Universities;Work;adult acute myeloid leukemia cell;animal data;anti-cancer;anti-tumor immune response;antigen-specific T cells;cancer cell;cancer therapy;conventional therapy;cytokine;defense response;ds-DNA;fighting;immunogenic;in vivo;leukemia;microbial;mouse model;neoplastic cell;novel;novel strategies;personalized approach;phase I trial;pilot trial;pre-clinical;prevent;sensor;tumor;ultraviolet irradiation STING Activators as Therapy for Cancer PROJECT NARRATIVETumor cells are notoriously non-immunogenic through their ability to mimic the properties of normal cells whichhave naturally evolved to avoid activating the immune system following cell death and phagocytosis. We havethus developed a new approach to overcome this obstacle and make previously immuno-evasive inert tumorcells highly immunogenic. This has been achieved through developing activators of the STING-dependent innateimmune signaling pathway a strategy which holds considerable promise for the therapeutic treatment of cancer. NCI 10709468 8/23/23 0:00 PA-21-261 5R42CA250629-03 5 R42 CA 250629 3 "LOU, XING-JIAN" 9/17/20 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-S(12)B] 15943806 "BARBER, GLEN N" "AHN, JEONGHYUN ; RAMOS, JUAN CARLOS " 26 Unavailable 2058614 PJV5A55KF6T5 2058614 PJV5A55KF6T5 US 25.79466 -80.206795 10055061 "STINGINN, LLC" MIAMI FL Domestic For-Profits 331361128 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 993879 NCI 798741 130118 PROJECT SUMMARYThe Immuno-oncology (IO) arena affords a new and exciting approach to stimulate the bodys own immunesystem to fight cancer. The generation of anti-cancer T cells is predominantly triggered by phagocytosed cancercells stimulating innate immune signaling pathways in professional antigen presenting cells (APCs). Thissignaling process is largely governed by STING (stimulator of interferon genes) a cellular protein discovered bythe laboratory of Dr. Glen N. Barber that plays an essential role in host defense against infectious disease andcancer. Activation of STING triggers cytokine production and facilitates tumor antigen cross-presentation.Indeed considerable effort is now underway in the biotech arena to discover techniques to augment STINGactivity with the objective of invigorating the generation of anti-tumor cytotoxic T cells. Along with check-pointinhibitors and CAR-T cell therapy the plausible utilization of STING agonists affords a new complementaryimmunotherapeutic strategy to treat malignant disease.Here STINGINN LLC (STINGINN) in collaboration with the University of Miami proposes to perform an FDAapproved investigator sponsored small Phase I clinical trial for patients suffering from highly aggressiveleukemias specifically relapsed/refractory acute myeloid leukemia (AML) and adult lymphocytic leukemia (ALL)focusing on HTLV-1 associated adult T cell lymphocytic leukemia (ATLL). Our strategy involves reinfusingautologous tumor cells loaded with STING-dependent adjuvants (STAVs) into patients to stimulate APCs in vivoand thus anti-tumor CTLs. Our pre-clinical data indicates that STAV loaded cells are highly immunogenic potentactivators of APCs. We have already submitted an IND FDA application based on this work and have assembledan appropriate team to carry out the proposed trial. Our proposal is also applicable to a variety of cancers notjust leukemia providing the opportunity to initiate a number of alternate cancer therapeutic trials in the future. 993879 +No NIH Category available Acceleration;Affect;Alleles;Alternative Splicing;Antigen Presentation;Bar Codes;Basic Science;Brain;Brain Neoplasms;Cancer Patient;Childhood Glioblastoma;Chromatin;Clinical;Cytotoxic T-Lymphocytes;Engineering;Epidermal Growth Factor Receptor;Epigenetic Process;Evolution;Genetic;Glioblastoma;Glioma;Goals;Heterogeneity;Human;Immune Evasion;Immunocompetent;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Laboratories;MHC Class I Genes;Malignant neoplasm of brain;Modeling;Morbidity - disease rate;Mus;Mutation;Oncogenic;PDGFRA gene;Pathology;Patients;Plasmids;Pre-Clinical Model;Preclinical Testing;Proteins;Radiation;Recurrence;Research;Research Project Grants;Scientist;Series;Site;Structure;System;T cell therapy;T-Cell Receptor;TP53 gene;Technology;Testing;Therapeutic;Transgenes;Translating;Translational Research;Tyrosine Kinase Receptor Inhibition;Vaccines;Work;Yeasts;antigen binding;antigen-specific T cells;chemotherapy;clinical care;driver mutation;efficacy testing;epidermal growth factor receptor VIII;experimental study;fascinate;genome editing;immune checkpoint blockade;improved;in vivo;life history;mosaic analysis;mouse model;mutant;neoantigens;novel;novel strategies;novel therapeutic intervention;recombinase;response;small molecule inhibitor;standard of care;targeted treatment;transcriptome;treatment response;tumor;tumor microenvironment;tumorigenesis Novel mouse models using MADR-GESTALT technology to accelerate glioma research n/a NCI 10709379 8/15/23 0:00 RFA-CA-22-009 3P50CA211015-07S1 3 P50 CA 211015 7 S1 8/11/17 0:00 7/31/24 0:00 ZCA1-TCRB-J(M1) 5036 3143458 "LIAU, LINDA M" Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 235632 176485 59147 ABSTRACT (Project)The proposed experiments leverage novel mouse models created using MADR-GESTALT technology. Thesemodels will enhance information derived from in vivo experiments and are being applied in the following aims.Aim 1: Evaluate rational combinations of brain penetrant receptor tyrosine kinase inhibition and immunotherapyfor study in new mouse models of oncogenically similar glioblastoma. This project will investigate mechanismsof immune evasion following treatment with immune-based therapy and develop rational combinations ofimmunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor micro-environment.Immunocompetent models that accurately recapitulate the known dominant oncogenic drivers in human GBMare crucial to this work. We propose to use the MADR-GESTALT system to create models of EGFRvIII-drivenGBM in order to test how small molecule inhibitors can be effectively paired with active vaccines and checkpointblockade immunotherapy.Aim 2: Evaluate the therapeutic potential of TCR-engineered cytotoxic T cells in H3G34R/V HGG. Previousresearch has identified a small number of tumor-associated neoantigens that are presented on class I MHC andare bound by antigen-specific T cell receptors in H3F3A mutant glioblastoma. H3F3A mutant and wild-typemodels will be used to further delve into the mechanisms by which these particular mutations affect oncogenesisin H3G34R glioblastoma and will be used for pre-clinical testing of the efficacy of TCR-engineered adoptive Tcell transfer as targeted therapy for H3F3A mutant glioblastoma. +No NIH Category available Acceleration;Address;Adult;Affect;Alternative Splicing;Animal Model;Antigen Targeting;Apoptosis;Apoptotic;Applications Grants;Area;Award;BCL2L1 gene;Bar Codes;Brain Neoplasms;Brain Stem;CRISPR/Cas technology;CSF1R gene;Cancer Biology;Cancer Patient;Childhood Brain Neoplasm;Childhood Glioblastoma;Clinic;Clinical;Communities;Cytotoxic T-Lymphocytes;DNA Damage;Data;Development;Diagnosis;Disease;Electroporation;Emerging Technologies;Enhancement Technology;Evolution;Funding;Gene Transfer Techniques;Genes;Genetic;Genetic Heterogeneity;Genetic Variation;Glioblastoma;Glioma;Goals;Heterogeneity;Histones;Human;Immune response;Immunocompetent;Immunotherapeutic agent;Immunotherapy;International;Lymphocyte Activation;Malignant Glioma;Malignant Neoplasms;Malignant neoplasm of brain;Mediating;Methodology;Modeling;Mus;Mutation;Myeloid-derived suppressor cells;Nature;Newly Diagnosed;Oncogenes;Parents;Patients;Perinatal;Pharmaceutical Preparations;Primary Brain Neoplasms;Prognosis;Recurrence;Research;Research Project Grants;Resistance;Safety;Somatic Mutation;System;T-Cell Receptor;Techniques;Technology;Testing;Transgenes;Translational Research;Translations;Tumor Subtype;Tumor-infiltrating immune cells;Vaccination;Validation;Variant;anti-tumor immune response;anticancer research;combinatorial;disease heterogeneity;drug candidate;effective therapy;flexibility;genome editing;genomic locus;improved;in vivo;innovation;insight;loss of function mutation;mosaic analysis;mouse model;mutant;neoantigens;neoplasm immunotherapy;novel;novel strategies;novel therapeutics;pre-clinical;pressure;programmed cell death protein 1;programs;receptor binding;recombinase;recombinase-mediated cassette exchange;resistance mechanism;small molecule inhibitor;stem cells;targeted treatment;therapy resistant;tool;translational goal;translational research program;tumor;tumorigenesis Incorporation of Novel MADR-GESTALT Technology into UCLA SPORE in Brain Cancer NARRATIVE (Overall)Malignant gliomas are heterogeneous and evolve under selective pressure making treatment resistance afundamental barrier to effective therapy and in order to understand the genetic diversity and heterogeneity ofthe disease pre-clinical animal models that better recapitulate human glioma heterogeneity are required. A state-of-the-art methodologymosaic analysis with dual recombinases (MADR) and genome editing of synthetictarget arrays for lineage tracing (GESTALT)addresses this by providing a flexible means for single-copysomatic transgenesis (or mutation with CRISPR/Cas9) with genetic barcodes. This novel MADR-GESTALTtechnology will be employed in translational research projects of the UCLA Brain Cancer SPORE in order toaccelerate the development of more effective therapies for glioblastoma. NCI 10709378 8/15/23 0:00 RFA-CA-22-009 3P50CA211015-07S1 3 P50 CA 211015 7 S1 "HUBBARD, LEAH" 8/11/17 0:00 7/31/24 0:00 ZCA1-TCRB-J(M1) 3143458 "LIAU, LINDA M" Not Applicable 36 NEUROSURGERY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 235632 NCI 176485 59147 ABSTRACT (Overall)Glioblastoma the most common primary brain tumor in adults is one of the most lethal of all human cancers.This disease requires innovative approaches and more effective treatments. Treatment resistance presents afundamental barrier and given the heterogeneous nature of malignant gliomas a combination of diverseapproaches will likely be needed to overcome it. To achieve this we need a better understanding of the geneticdiversity and heterogeneity of the disease as well as better pre-clinical animal models that recapitulate humanglioma heterogeneity. A state-of-the-art methodologymosaic analysis with dual recombinase-mediatedcassette exchange (MADR) and genome editing of synthetic target arrays for lineage tracing (GESTALT)addresses this need. MADR provides a flexible means for single-copy somatic transgenesis (or mutation withCRISPR/Cas9). MADR-GESTALT provides a suite of tools to study the emergent heterogeneity in cancerformation and recurrence by providing a consistent single-copy genetic framework for the expression of multiplepersonalized patient driver genes. Perinatal electroporation is used to deliver genes to brain stem andprogenitor cells and to avoid multiple copy insertion a new technique for single-copy transgene insertion in vivowas developed. Mosaic Analysis with Dual Recombinases (MADR) employs dual recombinase-mediatedcassette exchange for high efficiency insertion of transgenes to a single genetic locus. To model loss-of-functionmutations CRISPR/Cas9-mediated gene editing is also incorporated into the MADR-GESTALT system. Severalareas of MADR can be expanded and leveraged to enhance specific projects within the UCLA Brain CancerSPORE which in addition will independently validate the utility of MADR-GESTALT for the wider cancerresearch community. This proposal utilizes an IMAT-funded technology that enhances three ongoing projectswithin our SPORE program: 1) Targeting immunotherapy-resistance with DC vaccination and PD-1/CSF-1Rinhibition. 2) Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma. MADR will be used todevelop syngeneic immunocompetent mice with gliomas and GESTALT will be used to evaluate barcodediversity with and without treatment to further understand tumor evolution under immunotherapeutic and smallmolecule inhibitor pressure. 3) Adaptive immunotherapy to target the H3.3G34 mutation in pediatricglioblastoma. MADR-GESTALT models will be used to examine mechanisms by which particular histonemutations affect oncogenesis and immunotherapy for G34R mutant glioblastoma. 235632 +No NIH Category available Acute Lymphocytic Leukemia;Admission activity;Adolescent;Adult;Auxins;B lymphoid malignancy;B-Lymphocytes;B-cell precursor acute lymphoblastic leukemia cell;Beauty;Brain Edema;CAR T cell therapy;CD19 gene;Cell Compartmentation;Central Nervous System Diseases;Characteristics;Chemotherapy and/or radiation;Child;Chronic;Clinic;Clinical;Clinical Data;Clinical Trials;Confusion;Development;Diagnosis;Dose;Effector Cell;Face;Fever;Future;Goals;Heart Rate;Hematopoietic Stem Cell Transplantation;High Dose Chemotherapy;Hispanic;Human;Hypotension;Immune;Immunoglobulins;In Vitro;Incidence;Infusion procedures;Length of Stay;Life;Long-Term Survivors;Malignant Neoplasms;Medical;Medication Management;Medicine;Modeling;Morbidity - disease rate;Mus;Neurologic;Neurotoxicity Syndromes;PTPN6 gene;Patients;Pharmaceutical Preparations;Plant Growth Regulators;Plants;Prevention;Property;Protein Tyrosine Phosphatase;Proteins;Refractory;Refractory Disease;Regulation;Relapse;Resolution;Risk;Safety;Savings;Seizures;Signal Transduction;Solid Neoplasm;Specificity;System;T-Cell Activation;T-Lymphocyte;Technology;Testing;Tissues;Toxic effect;Translating;Work;Xenograft procedure;attenuation;base;cancer diagnosis;cancer immunotherapy;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;cytokine release syndrome;cytotoxicity;efficacy evaluation;experience;in vivo;leukemia;mortality risk;mouse model;neoplastic cell;neurotoxicity;novel;novel strategies;overexpression;pediatric patients;pre-clinical;prevent;protein degradation;public health relevance;side effect;tool;young adult A New Approach to Modulating CAR T Cell Activity Public Health Relevance StatementA recent new anti-cancer immunotherapy chimeric antigen receptor (CAR) T cell therapy that specificallytargets and kills tumor cells has been highly successful in treating children and adults with leukemia who donot respond to any other treatment saving many lives. However these patients experience significant andsometimes life-threatening systemic (very high fever very fast heart rate very low blood pressure etc.) andneurologic side effects (confusion difficulty speaking seizures brain swelling etc.) which can be fatal evenunder optimal drug management of these toxicities. Here we aim to develop a new safer CAR T cells that isonly active when the patient takes a plant-based medicine called Auxin which would create a controllable CART cell therapy that is significantly safer in both the short and long term thereby potentially preventing many ICUadmissions and long hospital stays that are currently associated with CAR T cell therapies for leukemia. NCI 10709301 4/15/23 0:00 PA-21-268 7R21CA267955-02 7 R21 CA 267955 2 "CARDONE, MARCO" 9/23/22 0:00 5/31/25 0:00 ZCA1-SRB-A(O2) 7651037 "LORENZ, ULRIKE " Not Applicable 1 PATHOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/23/22 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2022 186104 NCI 118412 67692 AbstractChimeric antigen receptor (CAR) T cells targeting CD19 are highly effective in children withrefractory/relapsed acute lymphoblastic leukemia (ALL) including those with primaryrefractory or CNS disease. Current CAR T cell therapies infuse patients with T cellsconstitutively expressing CARs which are not susceptible to any controllable regulation.Cytokine release syndrome (CRS) and CAR-associated neurotoxicity (CAN) both of whichcan be fatal arise from uncontrolled CAR T cell activation and expansion. While a fewpharmacological management approaches have been attempted to overcome this issue theyare often suboptimal. In addition chronic B-cell aplasia from persistent CD19 CAR T cellsrequires monthly infusions of immunoglobulin which is burdensome and expensive especiallyfor pediatric patients facing potentially a lifetime need. Here we propose to develop a systemfor controllable CAR T cells that can be turned on and off as needed. We have previouslydemonstrated that exogenous expression of the tyrosine phosphatase SHP-1 acts as anegative regulator to dampen T cell activation. Recently we have developed an inducible andreversible protein degradation system for SHP-1 by adapting the plant Auxin-induced degron(AID) system for T cells. Combining these two tools in Aim 1 we propose to develop CD19CAR T cells that will be kept basally dormant through overexpression of SHP-1. Howeverupon administration of Auxin the CAR T cells can be temporarily and reversibly activatedthrough the degradation of SHP-1. As the doses of Auxin sufficient to activate the AID systemhad no significant toxicities in humans we do not foresee a problem translating this systeminto the clinic. In Aim 2 we will examine the efficacy of this novel CAR T cell system in a murinemodel of ALL. In Aim 3 we will expand the studies to test whether this regulatable CAR T cellssystem can control and/or limit CAR T cell-associated toxicities using a muring model of ALLCRS and neurotoxicity. Such an exogenously regulatable CAR T cell system may provideclinicians a tool to avoid/limit severe CRS and CAN and allow repopulation of the B-cellcompartment after a sufficient treatment course. This approach will greatly enhance the safetyof CD19 CAR T cells and is likely applicable to CARs for other malignancies including solidtumors where on-target off-tissue cytotoxicity is more problematic. 186104 +No NIH Category available American Association of Cancer Research;American Society of Clinical Oncology;Area;Award;Basic Science;Budgets;Cancer Biology;Cancer Research Project;Clinical;Clinical Research;Collaborations;Dedications;Development;Development Plans;Diagnosis;Disease;Early Diagnosis;Early treatment;Education;Ensure;Faculty;Fostering;Foundations;Funding;Goals;Grant;Healthcare;Institution;International;Intervention;Investigation;Laboratories;Leadership;Malignant neoplasm of ovary;Mentors;Mentorship;Minority;Morbidity - disease rate;National Center for Advancing Translational Sciences;Ovarian;Paper;Patients;Peer Review;Postdoctoral Fellow;Prevention;Publishing;Research;Research Personnel;Resources;Scientist;Training;Translating;Translational Research;United States National Institutes of Health;University of Texas M D Anderson Cancer Center;Woman;Work;Writing;anticancer research;bench to bedside;cancer diagnosis;career;career development;clinical care;design;experience;improved;innovation;meetings;member;mortality;next generation;novel;programs;recruit;supportive environment;symposium;translational approach Career Enhancement Program n/a NCI 10709236 9/19/23 0:00 PAR-20-305 1P50CA281701-01 1 P50 CA 281701 1 9/19/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 9985 2717823 "BAST, ROBERT C" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 85150 52562 32588 Career Enhancement Program SUMMARY/ABSTRACTThe central goal of the Career Enhancement Program (CEP) is to use the resources at MD Anderson to trainexceptional young investigators who will reduce the morbidity and mortality from ovarian cancer by makingadvances in the early detection prevention and treatment of this disease. To achieve this goal the SPORECEP will provide two awards each of $50000 annually for up to two years funded from the SPORE andmatching funds from MD Anderson. The intent of each CEP award is to prepare the selected scientists to becomeinternational leaders in academic research relevant to ovarian cancer. We will achieve this through focusedrecruitment of a diverse cadre of promising young investigators. We will work in partnership with awardees togenerate individualized development plan and provide them with outstanding clinical and a laboratory mentorsand a mentoring committee formal course work coaching in grant and paper writing leadership trainingattendance at national meetings networking with ovarian cancer scholars and completing and publishing atranslational ovarian cancer research program. Over the past two decades the Ovarian Cancer SPORE CEPhas developed the careers of 27 young investigators. In the first year of the original grant three postdoctoraltrainees received CEP awards and of the 24 faculty members supported since 2000 all but two have remainedin academic research and 13 are engaged predominantly in ovarian cancer research. Seventeen have achievedfederal peer-reviewed funding and five additional awardees have received competitive foundation grants. Threeawardees from our 2017-2021 funded cycle have received two Ovarian Cancer Research Alliance (OCRA)Awards one CPRIT award one R01 one R21 and one U01. Since the inception of the program in 1999 ourCEP awardees have published over 1100 peer-reviewed papers regarding ovarian cancer. +No NIH Category available Address;Ally;Area;Award;Basic Science;Budgets;Cancer Center;Clinical;Clinical Investigator;Clinical Research;Collaborations;Data;Dedications;Department of Defense;Development;Discipline;Disease;Early Diagnosis;Early treatment;Financial Support;Foundations;Funding;Funding Mechanisms;Future;Goals;Human;Incidence;Institution;Malignant Neoplasms;Malignant neoplasm of ovary;Manuscripts;Medical center;Ovarian;Peer Review;Population Research;Prevention;Productivity;Program Research Project Grants;Publishing;Quality of life;Research;Research Personnel;Research Project Grants;Resources;Rest;Scientist;Specimen;Texas;Translational Research;University of Texas M D Anderson Cancer Center;Woman;Work;anticancer research;candidate identification;design;improved;innovation;mortality;novel;ovarian cancer prevention;patient population;peer;programs;supportive environment;translational potential;translational study Developmental Research Program n/a NCI 10709235 9/19/23 0:00 PAR-20-305 1P50CA281701-01 1 P50 CA 281701 1 9/19/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 9984 2717823 "BAST, ROBERT C" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 85150 52562 32588 Developmental Research Program SUMMARY/ABSTRACTThe purpose of the Developmental Research Program (DRP) is to fund promising projects by investigatorswhose current work may not focus exclusively on ovarian cancer but who propose highly innovativetranslational studies of ovarian cancer that could become full SPORE projects or compete successfully forfunding outside of the SPORE. The DRP provides a unique opportunity for making available significant financialsupport and for demonstrating active institutional support through a program that is rapidly responsiveto newideas or initiatives. Moreover this program is rooted in a spirit of collaboration promoted by the SPOREinvestigators who have an extensive track record of bringing investigators from other disciplines into ovariancancer research. The strength of the DRP rests in its ability to make available financial support needed toaccess all the critical expertise and resources within the entire SPORE. This will allow us to developcollaborative multi-investigator multi-institutional research projects with the support of innovative investigator-initiated projects that have the potential to flourish into reliable and productive translational research projectsthat make a path from basic and/or population research projects into research focused on human clinicalspecimens/patient populations. Over the course of the past decade the MD Anderson OvarianSPORE hassupported DRP projects from 22 investigators. Collectively these investigators have published 470 peer-reviewed manuscripts related to ovarian cancer. Thirteen of the recipients have received peer-reviewedfundingin ovarian cancer as either PI Co-PI or Co-Investigator. The investigators have received funding from threeR01s three R21s three CPRIT awards two Department of Defense Awards and four OCRA awards. Oneawardee in the most recently funded cycle just received support from both the Ovarian Cancer Research Alliance andFoundation for Womens Cancer. Additionally three former awardees have participated in full SPORE projectsafter completing a DRP project. +No NIH Category available Archives;Ascites;Award;Benign;Biopsy Specimen;Cancer Center;Clinical;Clinical Data;Code;Colon;Confidentiality of Patient Information;Consult;Cyst;Databases;Development;Diagnosis;Drug resistance;Endometrium;Evaluation;Experimental Designs;Feasibility Studies;Female Genital Neoplasms;Formalin;Freezing;Frozen Sections;Funding;Generations;Goals;Gynecologic;Human;Immunohistochemistry;In Situ Hybridization;Individual;Institution;Internet;Intranet;Laboratories;Laboratory Research;Link;Malignant neoplasm of ovary;Mammalian Oviducts;Microscopic;Modeling;Mucous Membrane;Mus;Normal tissue morphology;Organoids;Ovarian;Ovarian Diseases;Ovary;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patients;Population Research;Process;Research;Research Personnel;Research Project Grants;Research Proposals;Resources;Sampling;Security;Services;Slide;Solid Neoplasm;Source;Specimen;Technology;Testing;Tissue Banks;Tissue Embedding;Tissue Microarray;Tissues;Tumor Bank;Tumor Tissue;University of Texas M D Anderson Cancer Center;biomarker identification;career;data access;endometriosis;experience;experimental study;novel therapeutics;patient derived xenograft model;quality assurance;tumor;virtual Pathology Core n/a NCI 10709234 9/19/23 0:00 PAR-20-305 1P50CA281701-01 1 P50 CA 281701 1 9/19/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 9983 1943645 "LIU, JINSONG " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 225990 139500 86490 Core C: Pathology SUMMARY/ ABSTRACTThe individual research projects comprising this Ovarian Cancer SPORE application require the procurementprocessing and analysis of histopathological material from patients with ovarian cancer and benign ovariandiseases. The research projects have needs for frozen and formalin-fixed paraffin-embedded samples oftumor and normal tissue. The research projects also need patient-derived xenograft models and organoids totest the effects of novel drugs and define the mechanisms of drug resistance. The proposed Pathology Coreaugments the already established MD Anderson Cancer Center Gynecological Tumor Bank and the P30-sponsored MD Anderson Cancer Center Centralized Tissue Repository with supporting database and intranetaccess. The Core provides for tissue acquisition by experienced gynecological pathologists to assure high-quality tissues for the investigators participating in this SPORE as well as investigators of other SPOREs.The goal of the Pathology Core is to provide frozen tissue paraffin-embedded tissue histopathologicalexpertise tissue arrays patient-derived xenografts and organoids related to the specific needs of the researchprojects comprising this SPORE proposal. To meet this goal the following Specific Aims are proposed for thisCore. Aim 1 is to maintain a frozen and paraffin-embedded tissue repository of ovarian cancers normalovaries and benign ovarian processes (such as cysts and endometriosis). Aim 2 is to provide pathologicalreview for all clinical specimens utilized in the SPORE projects and to provide histopathological andimmunohistochemical technical services as necessary. Aim 3 is to create tissue microarrays patient-derivedxenografts (PDXs) and organoid models and maintain a relational SPORE Database. This SPORE Databasewill provide for a virtual tissue repository that can be shared electronically with all SPORE investigators. +No NIH Category available Affect;BRCA mutations;Binding;Biopsy;Blood;CD8-Positive T-Lymphocytes;Cancer Model;Cancer cell line;Carboplatin;Cell physiology;Cells;Chromatin;Clinical;Cytotoxic T-Lymphocytes;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Gene;DNA Repair Inhibition;DNA Repair Pathway;DNA Sequence Alteration;DNA replication fork;Data;Diagnosis;Dose;Double Strand Break Repair;EXO1 gene;Enhancers;Excision;Exhibits;FANCD2 protein;FOXP3 gene;Frequencies;Gene Expression;Genetic Transcription;Goals;HDAC4 gene;Human;IL2RA gene;IL6 gene;IRF3 gene;ITGAM gene;Immunotherapy;Impairment;Infiltration;Malignant Neoplasms;Malignant neoplasm of ovary;Marrow;Maximum Tolerated Dose;Mediating;Messenger RNA;Modeling;Morbidity - disease rate;Mus;Muscle Cells;Myeloid-derived suppressor cells;Myelosuppression;Names;Nuclear;Nucleic Acid Regulatory Sequences;Organoids;Outcome;Ovarian;Paclitaxel;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Phase;Phase I Clinical Trials;Phase Ib Trial;Phosphorylation;Phosphotransferases;Platinum;Play;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Primary Neoplasm;Progression-Free Survivals;Regulatory T-Lymphocyte;Relapse;Repression;Resistance;Resistance development;Sampling;Second Look Surgery;Site;Sodium Chloride;Stimulator of Interferon Genes;T cell infiltration;T-Lymphocyte;TBK1 gene;TGFB1 gene;Testing;Toxic effect;University of Texas M D Anderson Cancer Center;Woman;Xenograft procedure;brca gene;cancer cell;cancer immunotherapy;cancer type;checkpoint therapy;conventional therapy;cytotoxicity;experience;first-in-human;homologous recombination;immune checkpoint blockade;inhibiting antibody;inhibitor;mRNA Expression;mortality;mouse model;novel;patient derived xenograft model;phase I trial;preclinical study;prevent;programmed cell death ligand 1;recombinational repair;refractory cancer;response;restoration;targeted agent;transcriptome sequencing;tumor The SIK2 Inhibitor GRN-300 Enhances PARP Inhibitor Sensitivity and Cytotoxic T-Cell Function in Ovarian Cancer Project 1 NARRATIVEOvarian cancer is a significant cause of morbidity and mortality that affects nearly 300000 women worldwideeach year and its poor outcomes are related to delayed diagnosis and development of resistance to conventionaltherapy with carboplatin paclitaxel and PARP inhibitors. Inhibition of salt induced kinase 2 (SIK2) has enhancedsensitivity to all three agents. Our proposal will explore the ability of GRN-300 a SIK-2 inhibitor to enhanceresponse to the PARP inhibitor olaparib and to immune checkpoint blockade enhancing their antitumor activity. NCI 10709229 9/19/23 0:00 PAR-20-305 1P50CA281701-01 1 P50 CA 281701 1 9/19/23 0:00 7/31/28 0:00 ZCA1-RPRB-H(M1)S 9978 2717823 "BAST, ROBERT C" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 306593 189255 117338 Ovarian cancer is a significant cause of morbidity and mortality that affects nearly 300000 women worldwideeach year. Its poor outcomes relate to delayed diagnosis and development of resistance to conventional therapywith carboplatin and paclitaxel. In the last SPORE cycle we evaluated a novel inhibitor of salt-induced kinase 2(SIK2) GRN-300 that enhances sensitivity to both carboplatin and paclitaxel. With the support of the SPOREwe carried out a first-in-human phase IA/B trial to define the maximum tolerated dose of GRN-300 alone and incombination with weekly paclitaxel. We also conducted preclinical studies to demonstrate that GRN-300enhanced olaparib sensitivity in homologous recombination (HR)-proficient and deficient ovarian cancer cell linesand xenografts. We have demonstrated that GRN-300 enhances olaparib sensitivity by 1) abolishing the classIIa histone deacetylase 4/5/7-associated transcriptional activity of myocyte enhancer factor 2D (MEF2D) 2)decreasing MEF2D binding to regulatory regions with high chromatin accessibility in DNA repair genes and 3)repressing critical gene expression in the DNA repair pathway. Whereas poly(ADP-ribose) polymerase inhibitors(PARPi) have played a large part in maintaining progression-free survival in patients with HR-deficient ovariancancers the majority of patients will have resistance to PARPi and experience relapse. Moreover combiningconventional or other targeted agents with PARPi has been limited by additive myelosuppression. To date GRN-300 has had no significant marrow toxicity in our phase I clinical trial. GRN-300 enhanced olaparib activity inboth olaparib-sensitive and acquired olaparib-resistant ovarian cancer cells. Cancer immunotherapy includingimmune checkpoint blockade (ICB) has shown great promise for cancers at multiple sites but the frequencyand duration of response of ovarian cancer has been limited. Recent studies suggest that a deficiency in DNArepair is associated with increased response of cancer cells to immunotherapy. We have found that GRN-300increases phosphorylation of TBK1 and nuclear localization of IRF3 in murine ovarian cancer cells. Both TBK1and IRF3 are downstream targets of the cGAS/STING pathway. GRN-300 or GRN-300 combined with olaparibincreases the expression of programmed death-ligand 1 (PD-L1) in human and murine ovarian cancer cells.GRN-300 combined with anti-PD-L1 enhances CD8+ T-cell infiltration and antitumor activity in a syngeneicovarian cancer model. The goal of our project is to determine whether GRN-300 overcomes resistance to PARPiand enhances PARPi sensitivity and whether GRN-300 promotes adaptive T-cell function and enhances immunecheckpoint therapy. We will pursue three aims: 1) to perform a phase IB trial of GRN-300 in combination with aPARPi 2) To determine the underlying mechanisms of olaparib resistance that can be overcome with the SIK2inhibitor GRN-300 in combination with olaparib in ovarian cancer cell lines xenografts and PDXs and 3) Toidentify the mechanism(s) by which the SIK2 inhibitor GRN-300 sensitizes ovarian cancer cells to ICB andenhances T-cell cytotoxicity. +No NIH Category available Address;Aftercare;Base Sequence;Biological;Biological Assay;Biological Markers;Biosensing Techniques;Biosensor;Blood;Blood Plasma Volume;Calibration;Cancer Detection;Cell physiology;Clinical;Clonal Evolution;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Complement;DNA;DNA Sequence;DNA Sequence Alteration;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Discrimination;Disease;Disease remission;Effectiveness;Elements;FDA approved;Fluorescence;Gene Frequency;Genes;Genomics;Guide RNA;Hour;Human;KRAS2 gene;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Measurement;Measures;Methods;Microscopy;Molecular;Molecular Abnormality;Monitor;Mutation;Mutation Detection;Nucleic Acid Probes;Nucleic Acids;Office Visits;Performance;Pharmaceutical Preparations;Plasma;Process;Protocols documentation;RNA Probes;Rapid diagnostics;Recommendation;Recurrence;Reference Standards;Residual Neoplasm;Resolution;Sampling;Screening for cancer;Selection for Treatments;Single-Stranded DNA;Slide;Specificity;Specimen;Surface;System;Technology;Testing;Time;Tissues;Tube;Tumor Biology;Validation;Variant;assay development;cancer biomarkers;clinical efficacy;clinical practice;clinically relevant;comparative;cost;design;designbuildtest;detection limit;detection sensitivity;digital;follow-up;genetic variant;genomic biomarker;improved;innovation;insight;instrument;liquid biopsy;multiplex detection;mutant;nanoGold;next generation sequencing;novel;nucleic acid detection;photonics;point of care;point-of-care detection;point-of-care diagnostics;portability;pressure;screening;sensor technology;targeted treatment;technology platform;tool;treatment effect;tumor;tumor DNA Rapid simple and ultrasensitive quantitation of KRAS ctDNA at the point of care using CRISPR/Cas amplification and digital resolution biosensor microscopy NarrativeRapid and quantitative detection of KRAS circulating tumor DNA (ctDNA) from blood with a simple workflowand inexpensive instrument will open opportunities for point of care therapy selection and remission monitoring.To address limitations of sensitivity sequence specificity cost and complexity of existing technologies thisproject will develop and rigorously characterize a digital-resolution biomolecular sensing technology combinedwith an isothermal CRISPR/Cas-based amplification process to achieve multiplexed detection of mutant geneswith <0.001% mutant allele frequency. The approach is applicable to broad classes of ctDNA for many formsof cancer with FDA-approved targeted therapies and even more cancers for minimal residual diseasemonitoring. NCI 10709211 7/31/23 0:00 RFA-CA-22-002 1R33CA272271-01A1 1 R33 CA 272271 1 A1 "SORG, BRIAN S" 8/1/23 0:00 7/31/26 0:00 ZCA1-TCRB-5(M1) 8604953 "CUNNINGHAM, BRIAN T." "MANSFIELD, AARON SCOTT; WANG, XING " 13 GENETICS 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL ORGANIZED RESEARCH UNITS 618207473 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 391467 NCI 270715 120752 AbstractWhile a growing arsenal of drugs is available to treat specific molecular abnormalities across cancers therapyeffectiveness can now be predicted by detecting specific genomic circulating tumor DNA (ctDNA) in plasma.While next-generation sequencing (NGS) can provide a comprehensive readout of genomic tumor variants thatmay provide biological and clinical efficacy insights its cost complexity and sample-to-answer timeframe arenot compatible with frequent routine point of care diagnostics. Meanwhile currently available laboratory-basedmethods for quantifying strategically-selected ctDNA biomarkers in plasma for liquid biopsy lack sensitivitymultiplexing and workflow simplicity required for clinical needs. A genomic liquid biopsy that can be rapidlyperformed in a clinical setting in the timeframe of an office visit offers a compelling alternative for identifying thepresence absence and concentration changes in circulating nucleic acid molecules whose specific basesequences represent mutations that drive cancer-associated cellular processes. Such an approach wouldenable therapy selection to be performed at the earliest time while facilitating more frequent remissionmonitoring. To address the gaps in current technology we seek to develop and rigorously validate a novel assaymethod called Activate Cleave Capture and Count (AC3) that combines two innovative elements. First weapply a recently-demonstrated photonic crystal (PC) biosensor microscopy technology with digital resolutioncapability for quantifying surface-captured gold nanoparticle (AuNP) tags. Second we utilize the CRISPR/Cassystem with target-specific guide RNA probes that selectively activate cleavage of ssDNA tethers linking AuNPsto a surface generating many released AuNPs for each ctDNA molecule. The released AuNPs are subsequentlycaptured on a PC biosensor where they are digitally counted. Our amplify-then-digitize strategy offers acompelling alternative to digital PCR-based technologies while also circumventing the limitations inherent withthermal amplification microdroplet partitioning and fluorescence-based detection. Based upon preliminaryresults for the detection of cancer-associated ctDNA AC3 offers a detection limit of 50 zM and a measurementof mutant allele frequency of <0.001%. Importantly AC3 utilizes a small and inexpensive (~ $7K) detectioninstrument. In this project we will apply AC3 for characterization of plasma ctDNA biomarkers across sixmutations and characterize performance using spiked-in calibration standards and in banked human plasmasamples. We will rigorously characterize the sensitivity selectivity and repeatability of AC3 compared to dropletdigital PCR (ddPCR). We envision AC3 as a complement to tissue-based NGS applied to routine initial cancerscreening for therapy selection monitoring the effects of treatments and as a remission monitoring tool.Compared with alternatives the inherently greater sensitivity of AC3 offers opportunities to perform earlier cancerdetection integrate higher levels of multiplexing and reduce plasma volume requirements. 391467 +No NIH Category available Affect;Behavioral;Breast Cancer Risk Factor;Breast Feeding;Classification;Code;Early Diagnosis;Epidemiology;Ethnic Population;Future;Grain;Health;Image;Incidence;Intake;Mammography;Outcome;Pathology;Pathway interactions;Performance;Population;Prevention strategy;Recording of previous events;Risk;Risk Factors;Risk Reduction;Statistical Methods;Stratification;Time;Update;Variant;Vegetables;Woman;black women;breast cancer diagnosis;cohort;digital;follow-up;improved;insight;malignant breast neoplasm;novel;racial population;risk prediction;targeted treatment;triple-negative invasive breast carcinoma Dynamic prediction incorporating time-varying covariates for the onset of breast cancer PROJECT NARRATIVEThe objective of this proposal is to propose and apply novel statistical methods to dynamicallypredict the risk of triple negative breast cancer (TNBC) that disproportionately affects Black womenrelative to White women. Successful completion of the study can provide insights in identifyingnovel targets for TNBC that could open new pathways for early prevention strategies and futuretreatment options and improve the early detection of TNBC. NCI 10709203 8/21/23 0:00 PAR-22-114 3R37CA256810-03S1 3 R37 CA 256810 3 S1 "DIVI, RAO L" 7/1/21 0:00 6/30/25 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 15871925 "JIANG, SHU " Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 210216 NCI 135187 75029 PROJECT SUMMARYTriple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limitedtreatment options and poor survival. Approximately 12% to 17% of women with breast cancer arediagnosed with TNBC. Women with TNBC have relatively poor outcomes and cannot be treatedwith targeted therapies. However the risk of TNBC is not uniform across all race-ethnic groups ofthe US population. Review of epidemiologic risk factors and TNBC incidence shows limited insightto variation in risk or risk reduction with the exception of history of breast feeding and highervegetable and grain intake. We aim to bring personalized dynamic prediction to improve thecurrent TNBC risk classification paradigm to make full use of the longitudinal information inaddition to the baseline information where risk prediction/stratification can be updated as newobservations are gathered to reflect the womans latest health- and behavioral-related status.Specifically we aim to investigate 5- and 10-year TNBC risk prediction performance by proposingnovel statistical methods that fully utilize the personalized mammogram-based risk factors fromrepeated mammogram images. The proposed study capitalizes on the WashU TNBC cohort withrich digital mammograms with well-studied BC risk factors 10 years of follow-up and pathologyconfirmed incident TNBC. All proposed statistical methods will be supplemented by R code that wewill make publicly available. 210216 +Behavioral and Social Science; Bioengineering; Biotechnology; Cancer; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Emerging Infectious Diseases; Hepatitis; Hepatitis - C; Infectious Diseases; Liver Disease Acute;Antibody Response;Archives;Biological Assay;Blood specimen;Characteristics;Chronic;Chronic Hepatitis C;Development;Evaluation;Exposure to;Expression Library;FDA approved;Fingers;Generations;HCV screening;Hepatitis C;Hepatitis C virus;Home;Human;Immune response;Individual;Lateral;Mining;Morbidity - disease rate;Output;Patients;Performance;Proteome;Proteomics;Public Health;Reproducibility;Sensitivity and Specificity;Serum;Specimen;Technology;Tertiary Protein Structure;Validation;antibody test;assay development;base;clinical diagnosis;cross reactivity;detection limit;experimental study;home test;immunogenic;individual response;innovation;lateral flow assay;mortality;prototype;rapid test;screening;self testing;tool A Simple at-home test for rapid and accurate screening for Hepatitis C Virus (HCV) exposure n/a NCI 10709130 75N91022C00027-0-9999-1 N43 9/20/22 0:00 9/19/23 0:00 78874918 "MANOHAR, JOHN " Not Applicable 4 Unavailable 832427822 GAEYBFGAB1N9 832427822 GAEYBFGAB1N9 US 42.022225 -93.639475 10025238 "PATHOVACS, INC." AMES IA Domestic For-Profits 500110001 UNITED STATES N R and D Contracts 2022 393833 NCI Development and feasibility demonstration of a prototype rapid and accurate Lateral Flow Assay (LFA) to self-screen qualitatively for exposure to Hepatitis C Virus (HCV) in at-home settings is proposed. The LFA employing conserved immunogenic domains of proteins comprising the HCV human immunoproteome will detect host antibody responses to such immunogenic protein domains in user-generated finger-prick blood samples. Preliminary validation / feasibility will be demonstrated using archived human serum specimens from patients clinically diagnosed to have had acute chronic or resolved HCV infection. The highly sensitive and specific assay will be simple enough for self-use and output results that can be read visually by the end-user within 30 mins. It is anticipated that the resulting LFA will positively impact global public health by accurately identifying exposed individuals for further evaluation and contribute significantly to reducing HCV morbidity and mortality; hence the LFA will be a valuable addition to the armamentarium of available tools for effective management of individuals with active HCV infection. 393833 +No NIH Category available 2019-nCoV;Address;Affect;Area;Autoimmune Diseases;Basic Science;COVID-19;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;California;Caring;Characteristics;Chronic Disease;Clinical;Clinical Sciences;Cohort Studies;Collaborations;Communities;Coronavirus;Data;Data Analyses;Data Collection;Disease;Enrollment;Ensure;Epidemiologist;Evaluation;Evaluation Studies;Exposure to;Foundations;Funding;Goals;Health;Health Personnel;Health system;Healthcare Systems;Home;Immune;Immunity;Immunologist;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Knowledge;Los Angeles;Malignant Neoplasms;Metabolic Diseases;Minority;Molecular Profiling;Natural History;Nature;Outcome;Patients;Pattern;Persons;Population Heterogeneity;Population Sciences;Populations at Risk;Predisposition;Public Health;Publishing;Recovery;Recovery of Function;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;Scientific Advances and Accomplishments;Scientist;Seeds;Seroprevalences;Signal Transduction;Structure;Subgroup;Techniques;Therapeutic;Translational Research;Viral;Virus;Vulnerable Populations;World Health Organization;base;biobank;clinical phenotype;disorder risk;experience;immune function;immune reconstitution;innate immune function;insight;novel;operation;pandemic disease;programs;racial and ethnic;recruit;response;severe COVID-19;trait;translational scientist Admin-Core-001 NARRATIVE: OverviewOur study will be centered on the ethnically/racially diverse population served by our health system in LosAngeles given then critical need for more knowledge regarding the determinants of COVID-19 related risks inthese minority subgroups. Leveraging our collective experience resources and infrastructure at major academicinstitutions from across Southern California (Cedars Sinai UCSD UCLA and USC) we will advance thescientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidatethe natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure infectionrecovery and clinical immunity patterns across the spectrum of persons at risk; Project 2 will investigate thedeterminants of SARS-CoV-2 response in persons with altered innate immune function with a focus onindividuals with pre-infection susceptibility traits (e.g. metabolic disease states); and Project 3 will investigatethe determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus onindividuals with immune-altered status arising from select malignancies autoimmune disease and/or theirdirected therapies. NCI 10709124 9/22/22 11:51 RFA-CA-20-038 3U54CA260591-02S2 3 U54 CA 260591 2 S2 "PATRIOTIS, CHRISTOS F" 9/1/22 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 9960 9537080 "FIGUEIREDO, JANE C." "KARIN, MICHAEL ; MERCHANT, AKIL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 195001 116767 78234 ASBTRACT OverviewEvery day Californians continue to experience high levels of exposure to the novel severe acute respiratorycoronavirus 2 (SARS-CoV-2) virus. There is an ever-growing urgent need to better understand the nature ofexposures course of illness and recovery and potential for immunity among persons at particularly heightenedrisk for the worst COVID-19 outcomes. As part of a rapid scientific response to the present public health crisiswe convened on March 18 2020 a collaborative of frontline clinicians and scientists to form the Coronavirus RiskAssociations and Longitudinal Evaluation (CORALE) studies (corale-study.org). We established two base studycohorts with enrollment centered on (i) patients with suspected or confirmed COVID-19 treated in our healthsystem (currently N>8300) and on (ii) healthcare workers directly or indirectly involved in delivering their care(currently N=6679). In response to NIH RFA-CA-20-038 we are now highly motivated and prepared to leverageour existing infrastructure to directly address the critical need for comprehensive longitudinal data collection andanalyses to advanced our understanding of SARS-CoV-2 risks the course of disease the nature of recoveryand the potential for immunity across populations at risk. By establishing the CORALE-SeroNet U54 programour goal will be to form a robust and sustainable structure of academic activities centered on investigating theresponses elicited by SARS-CoV-2 exposure and the extent to which carefully phenotyped clinical and molecularprofiles can signal robust immune reconstitution and complete functional recovery. Our study will be centeredon the ethnically/racially diverse population served by our health system in Los Angeles given then critical needfor more knowledge regarding the determinants of COVID-19 related risks in these minority subgroups. Ourscientific objectives will be achieved by an outstanding collaborative team of clinician-scientists epidemiologistsimmunologists basic and translational scientists analytical chemists and biostatisticians. Leveraging ourcollective experience resources and infrastructure at major academic institutions from across SouthernCalifornia (Cedars Sinai UCSD UCLA and USC) we will advance the scientific enterprise through the threedistinct yet closely integrated research Projects: Project 1 will elucidate the natural history and longitudinaltrajectories that represent the diversity of SARS-CoV-2 exposure infection recovery and clinical immunitypatterns across the spectrum of persons at risk. Project 2 will investigate the determinants of SARS-CoV-2response in persons with altered innate immune function with a focus on individuals with pre-infectionsusceptibility traits (e.g. metabolic disease states); and Project 3 will investigate the determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus on individuals with immune-altered status arising from select malignancies autoimmune disease and/or their directed therapies. As a wholethis research program will integrate population clinical translational and basic science resources with a world-class investigator team to meet the urgent need for new mechanistic insights and therapeutic approaches toaddress key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity. +No NIH Category available 2019-nCoV;Address;Affect;Area;Autoimmune Diseases;Basic Science;COVID-19;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;California;Caring;Characteristics;Chronic Disease;Clinical;Clinical Sciences;Cohort Studies;Collaborations;Communities;Coronavirus;Data;Data Analyses;Data Collection;Disease;Enrollment;Ensure;Epidemiologist;Evaluation;Evaluation Studies;Exposure to;Foundations;Funding;Goals;Health;Health Personnel;Health system;Healthcare Systems;Home;Immune;Immunity;Immunologist;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Knowledge;Los Angeles;Malignant Neoplasms;Metabolic Diseases;Minority;Molecular Profiling;Natural History;Nature;Outcome;Patients;Pattern;Persons;Population Heterogeneity;Population Sciences;Populations at Risk;Predisposition;Public Health;Publishing;Recovery;Recovery of Function;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;Scientific Advances and Accomplishments;Scientist;Seeds;Seroprevalences;Signal Transduction;Structure;Subgroup;Techniques;Therapeutic;Translational Research;Viral;Virus;Vulnerable Populations;World Health Organization;base;biobank;clinical phenotype;disorder risk;experience;immune function;immune reconstitution;innate immune function;insight;novel;operation;pandemic disease;programs;racial and ethnic;recruit;response;severe COVID-19;trait;translational scientist Admin-Core-001 NARRATIVE: OverviewOur study will be centered on the ethnically/racially diverse population served by our health system in LosAngeles given then critical need for more knowledge regarding the determinants of COVID-19 related risks inthese minority subgroups. Leveraging our collective experience resources and infrastructure at major academicinstitutions from across Southern California (Cedars Sinai UCSD UCLA and USC) we will advance thescientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidatethe natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure infectionrecovery and clinical immunity patterns across the spectrum of persons at risk; Project 2 will investigate thedeterminants of SARS-CoV-2 response in persons with altered innate immune function with a focus onindividuals with pre-infection susceptibility traits (e.g. metabolic disease states); and Project 3 will investigatethe determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus onindividuals with immune-altered status arising from select malignancies autoimmune disease and/or theirdirected therapies. NCI 10709118 9/22/22 11:48 RFA-CA-20-038 3U54CA260591-02S1 3 U54 CA 260591 2 S1 "PATRIOTIS, CHRISTOS F" 9/1/22 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 9955 9537080 "FIGUEIREDO, JANE C." "KARIN, MICHAEL ; MERCHANT, AKIL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 440000 263473 176527 ASBTRACT OverviewEvery day Californians continue to experience high levels of exposure to the novel severe acute respiratorycoronavirus 2 (SARS-CoV-2) virus. There is an ever-growing urgent need to better understand the nature ofexposures course of illness and recovery and potential for immunity among persons at particularly heightenedrisk for the worst COVID-19 outcomes. As part of a rapid scientific response to the present public health crisiswe convened on March 18 2020 a collaborative of frontline clinicians and scientists to form the Coronavirus RiskAssociations and Longitudinal Evaluation (CORALE) studies (corale-study.org). We established two base studycohorts with enrollment centered on (i) patients with suspected or confirmed COVID-19 treated in our healthsystem (currently N>8300) and on (ii) healthcare workers directly or indirectly involved in delivering their care(currently N=6679). In response to NIH RFA-CA-20-038 we are now highly motivated and prepared to leverageour existing infrastructure to directly address the critical need for comprehensive longitudinal data collection andanalyses to advanced our understanding of SARS-CoV-2 risks the course of disease the nature of recoveryand the potential for immunity across populations at risk. By establishing the CORALE-SeroNet U54 programour goal will be to form a robust and sustainable structure of academic activities centered on investigating theresponses elicited by SARS-CoV-2 exposure and the extent to which carefully phenotyped clinical and molecularprofiles can signal robust immune reconstitution and complete functional recovery. Our study will be centeredon the ethnically/racially diverse population served by our health system in Los Angeles given then critical needfor more knowledge regarding the determinants of COVID-19 related risks in these minority subgroups. Ourscientific objectives will be achieved by an outstanding collaborative team of clinician-scientists epidemiologistsimmunologists basic and translational scientists analytical chemists and biostatisticians. Leveraging ourcollective experience resources and infrastructure at major academic institutions from across SouthernCalifornia (Cedars Sinai UCSD UCLA and USC) we will advance the scientific enterprise through the threedistinct yet closely integrated research Projects: Project 1 will elucidate the natural history and longitudinaltrajectories that represent the diversity of SARS-CoV-2 exposure infection recovery and clinical immunitypatterns across the spectrum of persons at risk. Project 2 will investigate the determinants of SARS-CoV-2response in persons with altered innate immune function with a focus on individuals with pre-infectionsusceptibility traits (e.g. metabolic disease states); and Project 3 will investigate the determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus on individuals with immune-altered status arising from select malignancies autoimmune disease and/or their directed therapies. As a wholethis research program will integrate population clinical translational and basic science resources with a world-class investigator team to meet the urgent need for new mechanistic insights and therapeutic approaches toaddress key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity. +No NIH Category available 2019-nCoV;Acute;Address;African American population;Agonist;Antibodies;Antigen Targeting;Attention;Award;B-Lymphocytes;Biopsy;Blood;COVID-19;COVID-19 diagnosis;COVID-19 patient;COVID-19 test;Cancer Patient;Caucasians;Cells;Clinical;Collaborations;Communities;Convalescence;Data;Data Set;Disease;Elderly;Evaluation;Female;Hispanic Americans;Human;Immune;Immune response;Immune system;Immunity;Immunologic Memory;Immunologics;Individual;Infection;Institution;Knowledge;Laboratories;Longitudinal Studies;Mucosal Immune Responses;Mucous Membrane;Nose;Patient Recruitments;Patients;Peripheral Blood Mononuclear Cell;Phenotype;Physicians;Plasma;Plasma Cells;Populations at Risk;Prognosis;Protocols documentation;Research;Risk;Route;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Science;Serology;Severity of illness;Site;T cell response;T-Lymphocyte;Testing;Tissue Sample;Toll-like receptors;Translational Research;Translations;Vaccination;Validation;Viral Antigens;adaptive immune response;adaptive immunity;base;clinical development;cohort;data sharing;immune checkpoint blockade;interest;male;medically underserved;medically underserved population;member;mucosal site;novel therapeutic intervention;pandemic coronavirus;pandemic disease;patient population;research clinical testing;response;tool;vaccine candidate;vaccine trial;young adult Admin-Core-001 OVERALL: NARRATIVEWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world. We willemphasize deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanningserological B cell and T cell responses; analysis of immune responses in the blood as well as mucosal tissuesites; comparing immune responses induced by infection to those induced by candidate vaccines; and payingparticular attention to the understanding the clinical needs and immune responses of underservedunderrepresented and at-risk patient populations. Within these parameters we will attempt to determine thefactors that result in effective and durable immunity to SARS-CoV-2 infection and provide useful knowledge andtools for physicians and patients. NCI 10709110 9/22/22 11:41 RFA-CA-20-038 3U54CA260517-02S1 3 U54 CA 260517 2 S1 "LIU, YIN" 9/1/22 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 9949 10429455 "BOYD, SCOTT DEXTER" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 440000 328879 111121 OVERALL: SUMMARYWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world.Our Center will be based on four scientific pillars: Deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanning serological B cell and T cell responses Analysis of immune responses in the blood as well as mucosal sites Comparing immune responses induced by infection to those induced by candidate vaccines and Studying medically underserved underrepresented and at-risk patient populationsWithin these parameters we will attempt to determine the factors that result in effective and durable immunityto SARS-CoV-2 infection.We are dedicated to broad collaboration rapid sharing of data and technical knowledge nimbleness inresponding to the rapidly changing pandemic and rapid translation of research findings to CLIA Lab clinicaltesting and development of new therapeutic approaches. We feel these are the best routes forward foraddressing gaps in our understanding of the determinants of protective immunity to SARS-CoV-2 andproviding useful tools for physicians and patients. +Cancer; Cancer Genomics; Colo-Rectal Cancer; Digestive Diseases; Genetics; Health Disparities; Hematology; Human Genome; Liver Cancer; Liver Disease; Minority Health; Rare Diseases; Rehabilitation Admin-Core-001 n/a NCI 10709107 9/22/22 11:33 PA-21-071 3U2CCA252981-02S1 3 U2C CA 252981 2 S1 "MECHANIC, LEAH E" 9/1/22 0:00 8/31/26 0:00 ZCA1(M1) 9948 2110411 "COLDITZ, GRAHAM A." "DING, LI ; DRAKE, BETTINA F.; FIELDS, RYAN C" 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Other Research-Related 2022 28540 18159 10381 The overall goal of the WU-PE-CGS is to build a rigorous scientific evidence base for approaches direct engagement of cancer patients and post-treatment cancer survivors as participants in cancer research. Our focus is on rare and understudied cancer populations with significant disparities including cholangiocarcinoma multiple myeloma and colorectal cancer under age 50. Participant engagement strategies are most effective when they are adapted and implemented in real-world settings in partnership with community and patient advocacy stakeholders. +No NIH Category available interdisciplinary approach;tumor immunology Multidisciplinary Approaches to Tumor Immunology PROJECT NARRATIVEThe incidence of neoplasia and death resulting from this disease remains a significant public health challengeglobally and it has become increasingly evident that immune-based approaches will have a substantial impactin our understanding of cancer prevention diagnosis prognosis and treatment. Pre-doctoral training providedby the Tumor Immunology Training Program (TITP) is directly pertinent to public health. The continued primarymission of the TITP is to educate train and prepare the next generation of talented scientists with theconcepts knowledge and skills of fundamental and translational tumor immunology which provides thenecessary foundation to develop and advance innovative approaches to human cancer biology and therapy. NCI 10709095 7/7/23 0:00 PA-20-142 2T32CA085183-21 2 T32 CA 85183 21 "LIM, SUSAN E" 7/1/01 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1915642 "ABRAMS, SCOTT I." Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 144099 NCI 146092 10398 PROJECT SUMMARY/ABSTRACTThe overarching goals of the Tumor Immunology Training Program (TITP) at Roswell Park ComprehensiveCancer Center Graduate Division are to educate train and prepare talented pre-doctoral trainees for aprofession in cancer immunology research. Driven by significant advances in understanding how the immunesystem can be weaponized against cancer future leaders in tumor immunology will not only be well-trained inthe discipline but also will have a strong appreciation of the potential translational impact to human cancerbiology and therapy. The unique cancer-focus of the TITP introduces trainees to an advanced didactic andconceptual cancer immunology educational paradigm that encapsulates knowledge spanning the continuum ofbasic science to clinical application. The uniqueness of this TITP is further enhanced by the integration of anacademic environment comprised of diverse faculty concentrated within a prestigious NCI-designatedComprehensive Cancer Center. Throughout the program trainees are continually exposed to acomprehensive portfolio of themes and concepts in tumor immunology responsible conduct of research andthe principles of rigor and reproducibility. Trainees conduct their doctoral research with TITP mentors withexpertise in basic translational and clinical tumor immunology. The primary mission of the TITP is to supportcompetitively selected trainees during their third and fourth years of study. The funds requested coverstipends and tuition for 4 pre-doctoral trainees per year. This funding is crucial to continue the upwardtrajectory experienced for nearly 20 years of NRSA support in the quality and diversity of pre-doctoral traineesfocused on complex and challenging immunologic questions in cancer. NRSA-supported trainees areprepared for a competitive biomedical career through didactic lectures and concept-driven learning in tumorimmunology and biology grant writing responsible conduct of research and rigor and reproducibility. Aftertrainees complete all formal course work and pass a qualifying exam degree conferral is dependent uponfulfilling a first-authored publication requirement and passing the dissertation defense reflecting the novel andoriginal findings of the trainees body-of-work. Trainees who complete this TITP will be well-versed in all majorfacets of tumor immunology and will have the solid foundation upon which to build cancer-focused careersguided by a clear vision of its impact on human cancer biology and treatment. 144099 +No NIH Category available Acceleration;Adopted;Adoptive Cell Transfers;Advanced Development;Benchmarking;Biomedical Engineering;CTLA4 gene;Cell Survival;Cell Therapy;Cell physiology;Cells;Cellular immunotherapy;Chromosomal translocation;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Complex;Cytoplasmic Tail;DNA;DNA Transposons;Disease;Dissection;Electroporation;Elements;Engineering;Face;Functional disorder;Gene Delivery;Gene Transduction Agent;Generations;Genomics;Hematopoietic Neoplasms;Immune;Immunologic Receptors;Immunologics;Immunology;Immunotherapeutic agent;Joints;Laboratory Research;Lentivirus Vector;Ligands;Malignant Neoplasms;Measures;Memory;Messenger RNA;Metabolic;Molecular;Nature;Output;Pathway interactions;Patients;Performance;Process;Retroviral Vector;Risk;Signal Transduction;Sleeping Beauty;Solid Neoplasm;System;T-Lymphocyte;TP53 gene;Tail;Technology;Therapeutic;Toxic effect;Transposase;Tumor Antigens;Validation;adeno-associated viral vector;anticancer research;cell type;cellular engineering;chimeric antigen receptor;chimeric antigen receptor T cells;cytokine;design;exhaustion;gene delivery system;genome editing;genomic aberrations;genotoxicity;improved;in vivo;knockout gene;monomer;neoplastic cell;new technology;novel;programs;promoter;prototype;receptor;research and development;success;technology development;technology validation;therapeutic development;tool;transgene expression;tumor Advanced development of composite gene delivery and CAR engineering systems Project Narrative (Relevance)Cancer is a complex disease involving various molecular cellular and immunological processes. In this projectwe will perform advanced development and validation of composite gene delivery and CAR engineeringsystems. Our systems will enable broad applications in engineering of diverse cancer and immune cell types toaccelerate cancer research and advance engineering of cellular immunotherapy against cancer. NCI 10709085 9/15/23 0:00 RFA-CA-22-002 1R33CA281702-01 1 R33 CA 281702 1 "OSSANDON, MIGUEL" 9/15/23 0:00 8/31/26 0:00 ZCA1-TCRB-5(M1) 11348646 "CHEN, SIDI " Not Applicable 3 GENETICS 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/15/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 417075 NCI 249000 168075 SUMMARY | Cellular immunotherapy such as chimeric antigen receptor (CAR) T cells involves engineering andadoptive transfer of cells to directly target tumor cells in patient and demonstrated clinical success. Howevercurrent cell forms of cell therapies face multiple major hurdles centering around efficient generation of potentspecific and safe therapeutic immune cells. This R33 will address this significant problem by developingand rigorously validating two sets of versatile gene delivery and cell engineering toolkits to ease thetherapeutic cell generation issue and to offer a simple yet distinct approach to achieve high potency. Aim1. Advanced development of MAJESTIC a highly efficient composite gene delivery system. A vital part ofcellular immunotherapies is therapeutic cell generation. Current approaches including lentiviral or g-retroviralvectors AAV mRNA DNA transposons and genome editing such as CRISPR/Cas all have their ownlimitations. In the first part of this R33 we will perform advanced development and validation of MAJESTICtechnology (mRNA AAV-Sleeping-Beauty Joint Engineering of Stable Therapeutic Immune Cells). This systemcan transduce diverse immune cell types with minimal cellular toxicity leading to highly efficient and stabletherapeutic cargo delivery. Aim 2. Advanced development of synthetic fusion tails to enhance therapeuticcell function. Despite success in CAR-T therapy in hematopoietic malignancies major challenges still existsuch as tumor antigen loss T cell exhaustion T cell dysfunction and poor in vivo persistence that hampered itswidespread clinical potential. We seek to develop and validate a distinct approach for cellular engineering toadd to the armamentarium of tools to enhance CAR immune cells against cancer. In the second part of this R33we will advance the development of TAILFUSE technology a novel and unique CAR engineering approach bycytoplasmic tail (CT) fusions which reprograms CAR-T function and substantially enhanced in vivo anti-tumorefficacy. We achieved proof-of-concept development of the technologies (R21/R61 equivalent). In this projectwe will perform robust validation optimization extension and advanced development (R33). This R33 will maturethese versatile tools for gene delivery and synthetic cell engineering including quantitative performancemeasures benchmarking new capability extension and validation of broader applications to cancer-related celltypes. Success of this R33 will lead to novel technologies that will bring new capabilities with substantialimprovements over existing technologies. We anticipate wide-spread use of such technologies in laboratoryresearch and therapeutic development settings by the field to reach transformative impact. 417075 +No NIH Category available Advanced Development;Angiogenesis Inhibitors;Animals;Apoptosis;Autophagocytosis;Binding;Cancer Biology;Cancer Model;Caspase Inhibitor;Cell Death;Cell Death Induction;Cells;Cessation of life;Characteristics;Chemotherapy and/or radiation;Clear cell renal cell carcinoma;Clinic;Clinical Management;Clinical Trials;Combined Modality Therapy;Cytoprotection;Deferoxamine;Development;Disease;Dose;Dose Limiting;Drug Industry;Drug resistance;Elements;Formulation;Funding;Future;Genitourinary system;Goals;Grant;Human;Hypoxia Inducible Factor;Immune checkpoint inhibitor;Immunooncology;In Vitro;Industry Standard;Inherited;International;Intracellular Accumulation of Lipids;Investigational Drugs;Investments;Iron;Iron Chelation;Iron Overload;Lead;Lipid Peroxidation;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Medical Oncologist;Molecular Target;Mus;Necrosis;Neoplasm Metastasis;Oral;Oral Administration;Pathogenesis;Patient-Focused Outcomes;Patients;Perfusion;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Play;Polymorph;Population;Predisposition;Production;Property;Proteins;Refractory;Renal carcinoma;Rodent;Role;Safety;Series;Small Business Innovation Research Grant;Sodium Chloride;Solid Neoplasm;Solubility;Source;Specialist;Starvation;Structure-Activity Relationship;Sulfur;Survival Rate;Therapeutic;Tissues;Toxic effect;Toxicology;Translational Repression;Translations;Tumor Suppressor Proteins;Tyrosine Kinase Inhibitor;Von Hippel-Lindau Syndrome;Work;Xenograft procedure;candidate marker;carcinogenesis;checkpoint inhibition;clinical development;commercialization;constitutive expression;cytotoxic;drug development;experience;first-in-human;improved;in vivo;inhibitor;innovation;manufacturability;mouse model;next generation;novel;novel strategies;novel therapeutic intervention;programmed cell death protein 1;reconstitution;response;scale up;screening;small molecule;synergism;therapeutic target;tumor;tumor growth;tumor xenograft Development of a novel dual HIF- inhibitor and inducer of ferroptosis for kidney cancer Project NarrativeKidney cancer is among the most drug resistant of solid tumors and current treatments do not provide long-lasting benefit for most patients. Kuda Therapeutics has identified a new treatment strategy to both block theproduction of the hypoxia-inducible factors (HIFs) known tumor drivers and to induce cancer cell death througha novel strategy of promoting excessive iron accumulation. The proposed project will facilitate the advancementof this paradigm-shifting treatment approach towards first-in-human clinical trials for patients with kidney cancer. NCI 10708992 7/28/23 0:00 PA-21-259 5R44CA217385-04 5 R44 CA 217385 4 "DJEMIL, SARRA" 6/1/18 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-T(10)B] 16420059 "LIPPERT, ROBERT " Not Applicable 1 Unavailable 80116475 WAH4VVM57875 80116475 WAH4VVM57875 US 33.203646 -117.386529 10042655 "KUDA THERAPEUTICS, INC." Salt Lake City UT Domestic For-Profits 841032206 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 625000 NCI 533555 51664 AbstractKidney cancer is the 8th most common cancer in the US population of which clear cell renal cell carcinoma(ccRCC) is the most common subtype. ccRCC is highly refractory to standard chemotherapy and radiation andpatients with advanced or metastatic tumors have a 5-year survival rate of just 14%. ccRCC is typically initiatedby inactivation of the von Hippel Lindau (VHL) tumor suppressor which results in the constitutive activation ofthe hypoxia inducible factors HIF-1 and HIF-2. The HIFs are promising therapeutic targets for ccRCC due totheir known involvement in the pathogenesis of the disease and their lack of expression in normal well-perfusedtissue. Additionally the intracellular accumulation of lipids which is a defining characteristic of ccRCC rendersthem uniquely susceptible to cell death associated with iron-dependent lipid peroxidation or ferroptosis. Throughefforts to optimize selective HIF-2 inhibitors in the predicate SBIR Phase I project Kuda Therapeutics hasidentified a series of novel compounds including lead KD061 that decrease both HIF-1 and HIF-2 and induceferroptosis in vitro and in vivo by binding to the novel molecular target Iron Sulfur Cluster Assembly 2 (ISCA2).ISCA2 inhibition triggers the iron starvation response which inhibits iron-responsive element (IRE)-dependenttranslation of HIF-2 and triggers iron overload which results in ferroptotic death. Strikingly pVHL-deficientccRCC cells have decreased ISCA2 levels and are more sensitive to ISCA2 inhibition compared to cells withpVHL reconstitution suggesting a therapeutic window for the selective targeting of pVHL-deficient ccRCC cellswith minimal toxicity to normal pVHL-proficient tissue. In mice KD061 treatment mediates significant >60%inhibition of RENCA syngeneic xenograft tumor growth through oral administration with no detectable toxicitiesat the therapeutic dose validating this novel approach for the treatment of ccRCC. The objective of this SBIRPhase II project is to further characterize the efficacy and safety of Kudas dual HIF- inhibitor and ferroptosisinducer lead KD061. This work will advance its development towards Investigational New Drug (IND) filing andfirst-in-human studies for the initial treatment of patients with ccRCC. Our first aim is to optimize KD061 drugsubstance formulation and synthesis. Here we will perform salt screening polymorph screening and formulationstudies to identify the optimal form of KD061 for oral delivery in vivo then scale-up synthesis for efficacy andtoxicology studies. Our second aim is to characterize the in vivo anti-tumor efficacy of KD061 as a single agentin multiple mouse models of ccRCC and in combination with sunitinib or PD-1 immune checkpoint inhibition inthe RENCA syngeneic kidney cancer model. Our third aim is to determine in vivo toxicology of KD061 in a rodentand non-rodent species by performing industry standard non-GLP and GLP studies to identify the starting dosesand sources of dose limiting toxicities for human clinical trials. At Phase II completion we will have produced theoptimal KD061 drug substance and characterized its efficacy and safety significantly advancing KD061 towardsIND filing and first-in-human trials where it can begin to make a difference in the lives of patients with ccRCC. 625000 +No NIH Category available ATAC-seq;Address;Algorithms;Antibodies;Bar Codes;Cell Nucleus;Cells;ChIP-seq;Clinical;Combination immunotherapy;Computer Analysis;Computer software;DNA;Data;Data Set;Epigenetic Process;Fluorescence;Fluorescent Antibody Technique;Freezing;Genes;Image;Image Analysis;Immune;Individual;Kinetics;Label;Location;Maps;Methods;Modeling;Names;Pathologic;Patients;Pattern;Population;Proteins;Proteome;Proteomics;Registries;Reporting;Research;Research Personnel;Resolution;Resources;Running;Scientist;Series;Slice;Specimen;Stains;System;Systems Biology;Techniques;Technology;Time;Tissue imaging;Tissues;Training;Training Programs;Transcript;Tumor Tissue;Validation;biobank;cancer cell;cost;cost effective;data warehouse;digital;epigenetic profiling;experience;fluorescence imaging;genome-wide;high throughput analysis;human tissue;image processing;imaging informatics;inhibitor;innovation;interest;kinetic model;meter;mouse model;multiple omics;nano-string;next generation sequencing;operation;preservation;programs;prospective;spatiotemporal;technology development;tissue fixing;tissue slice preparation;tool;transcriptome;tumor Core 2: Tissue Imaging and Profiling Core n/a NCI 10708933 8/30/23 0:00 RFA-CA-21-048 5U54CA274509-02 5 U54 CA 274509 2 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9921 9372328 "FAN, RONG " Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 294177 229222 64955 Core 2. Imaging and Spatial Profiling Core Project Summary:Central technologies of the ST-Analytics U54 program are tissue imaging and profiling platforms including twosets of tools for highly multiplex multi-omic analysis of tumor tissue specimens including clinical archival FFPEand lightly preserved frozen tissues and associated image analysis & informatics software. These Coreresource technologies are used extensively by both ST Analytics Projects. The first spatial profiling tool is the well-established commercial Nanostring Digital Spatial Profiling (DSP)system which permits analysis of regions of interest (ROIs) containing as few as 10-20 cells for detecting around1000 genes or around 50 proteins (Lee 2017 Lu 2021). Adjacent slices from an FFPE block are prepared. Thefirst is subjected to H&E staining for pathological analysis while the second is stained with fluorescent antibodiesto identify ROIs (for example immune cell rich or cancer cell rich regions). Those ROIs are then interrogated atthe transcriptome or proteome level. We have extensive experience with this tool for analysis of FFPE preservedpatient tumor tissues (Lu 2021). The second profiling tools are those recently developed and reported by the Fan group (Deng 20212021 Liu 2020). These powerful tools permit highly multiplex (up to 300-plex) proteomics and genome--widetranscriptome mapping at a resolution of 10 micrometers in tissue slices prepared from FFPE blocks. They alsopermit spatially resolved ATAC-seq and ChIP-seq type epigenetic profiling (Chen 2017; Chen 2018) at a similarspatial resolution in lightly fixed tissue slices. In particular this epigenetic profiling capacity is unique to thesetools. Similar to DSP adjacent tissue slices can be H&E stained and low-plex fluorescent imaging can beemployed on the same slice for identification of nuclei as well as immune rich and immune poor regions foralignment validation. These methods can enable high throughput and cost-effective profiling of tissues andsome technology development to that end is described. The Core will continue to develop new spatial profilingtools to meet the emergent needs in the two projects as they advance in the next 5 years thus serving as aTechnoloy Innovation Hub for the U54 center and for the CSBC consortium as well. +No NIH Category available Adoptive Cell Transfers;Antigen Presentation;Biopsy;CD8-Positive T-Lymphocytes;Cell Line;Child;Clinical;Clinical Data;Combination immunotherapy;Combined Modality Therapy;Cutaneous Melanoma;Data;Data Analyses;Educational process of instructing;Immune;Immune Evasion;Immune checkpoint inhibitor;Immunocompetent;Immunologic Factors;Lead;MAP Kinase Gene;MEKs;Melanoma Cell;Metastatic Melanoma;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Mus;Mutation;Pathway interactions;Patients;Protocols documentation;Recurrence;Regimen;Resistance;Services;Standardization;Testing;Therapeutic;Tissues;Treatment Protocols;Triplet Multiple Birth;Tumor Immunity;Up-Regulation;Validation;anti-CTLA4;anti-PD-1;anti-PD-L1;biobank;clinical development;clinical heterogeneity;combat;combinatorial;immune checkpoint blockade;immunogenic cell death;in vivo;inhibitor;inhibitor therapy;melanoma;mouse model;neoplastic cell;novel;posters;prevent;programmed cell death ligand 1;resistance mechanism;response;spatiotemporal;subcutaneous;success;targeted treatment;tumor;tumor-immune system interactions Core 1: Mouse Model and Tissue Biobank Core n/a NCI 10708931 8/30/23 0:00 RFA-CA-21-048 5U54CA274509-02 5 U54 CA 274509 2 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9920 1890098 "LO, ROGER S" Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 250014 211654 38360 Murine and Clinical Tumors (MCT) Core services. Project SummaryThe simultaneous combination of anti-PD-L1 with BRAFV600MUT and MEK inhibitors (so-called triplet therapy)in early clinical data appears beneficial and has recently been approved for patients with BRAFV600MUT melanoma(13). This is first mutation-immune co-targeted therapy to be approved but the data on this triplet appear mixedwith other trials not meeting key endpoints (14) suggesting that simultaneous combination is not optimal.Importantly retrospective clinical data analysis and in vivo therapeutic modeling using syngeneic models ofmurine melanoma showed that a regimen of anti-PD-1/L1 ( anti-CTLA-4) lead-in before MAPKi combinationaugments the efficacy of triplet therapy by enhancing MAPKi durability (and overcoming innate resistance toimmune checkpoint blockade) (12). Thus the realization that immune factors drive resistance to MAPKi therapyopens the door to immune-based strategies such as adoptive cell therapy (ACT) (Project 1 Aim 3) ascombinatorial agents to prevent MAPKi resistance.Building on this recent progress this Murine and Clinical Tumors (MCT) Core will offer Projects 1 and 2 modeland clinical tumors to obtain multi-scale (spatiotemporal) profiles of the tumor immune microenvironment (TIME)early and late on single-agent (MAPKi or anti-PD-1/L1) therapy (Project 1 Aim 1). These early data will provideinputs to the agent-based models (ABMs) being developed in Project 1 Aim 2 and late data will help validatepredictions. Profiles from more successful combination strategies will be compared against less successfulcombination strategies to teach the ABM on optimized TMEs. This core will also offer clinical tissues fortranslational validation (Project 1 Aim 4) and tumor models to test predicted novel combination therapies(Project 2 Aim 3). +No NIH Category available Address;Administrator;Collaborations;Combination immunotherapy;Combined Modality Therapy;Communities;Computer Models;Coupled;Creativeness;Development;Disease;Diverse Workforce;Education;Education and Outreach;Effectiveness;Feedback;Goals;Immunooncology;Immunotherapy;Institution;Internships;K-12 Education;Learning;Learning Module;Los Angeles;Medicine;Next Generation Science Standards;Occupations;Participant;Policies;Population;Problem Solving;Professional Education;Research;Research Personnel;Resources;STEM field;Science Technology Engineering and Mathematics Education;Solid Neoplasm;Students;System;Systems Biology;Teacher Professional Development;Thinking;Washington;Work;academic standard;cancer immunotherapy;design;designbuildtest;experience;improved;inhibitor;insight;melanoma;outreach;outreach program;programs;recruit;school district;spatiotemporal;teacher;teacher community;tumor Outreach Core n/a NCI 10708930 8/30/23 0:00 RFA-CA-21-048 5U54CA274509-02 5 U54 CA 274509 2 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9919 10723559 "LUDWIG, CLAUDIA " Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 148432 78953 69479 Outreach. Project Summary.The ST-Analytics scientific program is designed to take a systems biology approach towards addressing thequestion of how to effectively administer targeted-inhibitor immunotherapy sequential combinations for thetreatment of solid tumors with an emphasis on melanoma. ST Analytics incorporates state-of-the-artexperimental and computational programs advancing in close feedback with each other towards a robustsolution. The ST-Analytics Outreach Program is designed as a highly complementary program with STEMoutreach goals that are aligned with the core scientific theme of the U54. The Outreach program takes advantageof ISBs Systems Education Experiences teacher Educational Programs that promote systems approaches toscientific problem solving through the development of educational modules that have provided positive STEMlearning experiences for millions of students worldwide and in each of the 50 states. A strong emphasis isplaced on providing systems immuno-oncology internships and experiences to student populations traditionallyunder-represented in the STEM fields. The basic approach is to integrate these interns with ST-Analyticsresearchers to incorporate systems immuno-oncology concepts into two existing or in-development educationalmodules entitled Systems Medicine Module 3 - Personalizing Disease Treatments and Gaining Insight throughSystems Thinking and Computational Modeling. While those modules are designed to meet Next GenerationScience Standards (NGSS) the professional educators who are tasked with implementing those standards oftendo not have the proper background or supporting materials for the job. Thus our outreach programs are alsodesigned to provide that background and support. For example we provide research-based reality-drivenprofessional development for more than 1000 teachers and 80 district administrators annually impacting overtwo-thirds of students in Washington. Thus the potential impact of an ST-Analytics outreach program is largeand is achieved by leveraging extensive existing resources and relationships that extend throughout the state ofWA and up and down the U.S. west coast. A program that solicits creative engagement from all participantswithin our proposed U54 program at all levels is described. +No NIH Category available AIDS prevention;Address;African;Age;Applications Grants;Area;Cancer Burden;Cancer Control;Cancerous;Caregivers;Cervical Cancer Screening;Clinic;Collection;Communities;Community Health Aides;Community Participation;Country;Daughter;Development;Dissemination and Implementation;Dose;Economic Models;Elements;Female;Goals;Government;Group Structure;HIV;Health Services Accessibility;Human Papilloma Virus Vaccination;Human Papillomavirus;Human papillomavirus 6;Immunization Programs;Individual;Interdisciplinary Study;Intervention;Knowledge;Laboratories;Learning;Lesion;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medical Research;Methods;Modeling;Morbidity - disease rate;Mothers;National Cancer Institute;Nigeria;Nigerian;Participant;Population;Prevention;Prevention strategy;Preventive measure;Primary Prevention;Problem Solving;Proctor framework;Quality-Adjusted Life Years;Randomized Controlled Trials;Recommendation;Records;Research;Research Infrastructure;Resource-limited setting;Risk;Sampling;Secondary Prevention;Services;Specimen;State Government;Strategic Planning;Techniques;Time;United States;United States National Institutes of Health;Vaccination;Woman;Work;Youth;anticancer research;cancer prevention;cancer vaccination;community based participatory research;community clinic;community engagement;cost effectiveness;crowdsourcing;design;direct application;dissemination science;effectiveness evaluation;experience;experimental study;girls;health communication;implementation evaluation;implementation outcomes;implementation process;implementation research;implementation science;implementation strategy;improved;learning community;low and middle-income countries;mortality;mother-daughter relationship;older women;preference;premalignant;prevention service;primary outcome;programs;public health relevance;recruit;risk perception;scale up;screening;screening program;secondary outcome;self testing;social cognitive theory;treatment as usual;uptake;vaccine acceptance Actions for Collaborative Community Engaged Strategies for HPV (ACCESS HPV) PUBLIC HEALTH RELEVANCEAlthough there is a substantial burden of cervical cancer among Nigerian women there are significant gaps inimplementing both primary and secondary HPV prevention strategies. The study will engage young girls andtheir mothers to increase uptake of essential HPV prevention services. The findings from this study will berelevant to other resource-constrained settings that are expanding HPV vaccination and screening programs. NCI 10708926 8/18/23 0:00 PAR-19-274 5R01CA271033-02 5 R01 CA 271033 2 "RICCIARDONE, MARIE D" 9/22/22 0:00 8/31/27 0:00 Health Promotion in Communities Study Section[HPC] 9545342 "IWELUNMOR, JULIET " "EZECHI, OLIVER CHUKWUJEKWU; TUCKER, JOSEPH DAVID" 1 PSYCHOLOGY 50220722 JNBLLTBTLLD8 50220722 JNBLLTBTLLD8 US 38.633829 -90.213138 7915401 SAINT LOUIS UNIVERSITY SAINT LOUIS MO SCHOOLS OF PUBLIC HEALTH 631032006 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 517441 NCI 406508 110933 ABSTRACTCervical cancer is a major cause of morbidity and mortality in many sub-Saharan countries including Nigeria.Expanding human papillomavirus (HPV) vaccination for young girls/women ages 9-26 years (primaryprevention) and HPV self-collection for cervical cancer screening for older women ages 30-49 (secondaryprevention) are both critical to achieving WHO and Nigerian goals for reducing the cervical cancer burden. TheNigerian government now recommends HPV vaccination and self-collection yet uptake is poor. As suchcontext-specific targeted and culturally relevant implementation strategies are needed. We focus on HPVvaccination among girls and self-collection among women because of the substantial burden of cervicalcancer. Mother-daughter relationships in Nigeria can be leveraged to increase HPV vaccination uptake amongyoung girls and HPV self-collection among mothers. Mothers (or similar female caregivers) profoundlyinfluence decisions and preferences about young girls vaccine uptake in the Nigerian cultural context. At thesame time maternal choices about HPV self-collection can be reinforced in discussions with their daughters. Inthe proposed study Actions for Collaborative Community-Engaged Strategies for HPV (ACCESS-HPV) we willuse participatory crowdsourcing methods to drive HPV prevention among mother-daughter dyads.Crowdsourcing open calls will allow us to identify locally relevant messages and dissemination techniques toincrease uptake of HPV prevention. Then participatory learning communities will build capacity for community-led implementation of selected strategies. Informed by social learning theory and the PEN-3 cultural model ourmulti-disciplinary research team proposes the following specific aims: (1) to develop a new combinedcampaign to increase HPV vaccination for young girls (ages 9-26) and HPV self-collection for mothers (ages30-49) using crowdsourcing open calls and participatory learning communities; (2) to determine theeffectiveness of a final combined campaign on uptake of HPV vaccination among young girls/women and HPVself-collection among their mothers using a stepped-wedge randomized controlled trial; (3) to estimate theimpact and cost-effectiveness of the crowdsourced campaign. Our primary outcome will be vaccine uptake(ascertained by clinic records of vaccine uptake) among young girls and HPV self-collection (ascertained bylaboratory receipt of specimens) among their mothers. The strong support of the Nigerian Institute for MedicalResearch (NIMR) alongside national HPV programs creates a rich research infrastructure and increases thelikelihood of successful implementation. Our multi-disciplinary research team has experience organizingimplementation research focused on crowdsourcing and community participation in Nigeria. This study willenhance our understanding of HPV prevention in resource-constrained settings. This grant application directlyresponds to strategic priorities of the United States government the National Institutes of Health the NationalCancer Institute and NOT-CA-20-025. 517441 +No NIH Category available Adoptive Cell Transfers;Aftercare;Antigens;Area;Biopsy;Cancer Histology;Child;Clinical;Clinical Data;Clinical Trials;Clonal Expansion;Combination immunotherapy;Combined Modality Therapy;Cutaneous Melanoma;Data;Data Analyses;Data Set;Dose;Engineering;Environment;Formalin;Foundations;Freezing;Goals;Immune;Immune system;Immunocompetent;Immunologic Factors;Immunotherapy;Inflammatory;Lead;MAP Kinase Gene;MEKs;Malignant Neoplasms;Metastatic malignant neoplasm to brain;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Molecular;Multiomic Data;Mus;Mutation;Oncogenes;Outcome;Paraffin Embedding;Pathway interactions;Patients;Physiological;Progression-Free Survivals;Regimen;Resistance;Resistance development;Resolution;Resources;Retrospective Studies;Role;Sampling;T cell therapy;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Therapy trial;Time;Tissues;Treatment Efficacy;Triplet Multiple Birth;Tumor Antigens;Tumor Immunity;Tumor-associated macrophages;Validation;Work;anti-CTLA4;anti-PD-1;anti-PD-L1;biobank;clinical development;clinically relevant;combinatorial;computational pipelines;data resource;design;driver mutation;engineered T cells;immune checkpoint blockade;immunogenic cell death;immunotherapy trials;improved;in vivo;inhibitor;inhibitor therapy;insight;melanoma;movie;multiple omics;mutant;neoantigens;neoplastic cell;overexpression;posters;prevent;rational design;resistance mechanism;response;spatiotemporal;subcutaneous;targeted treatment;therapy outcome;tool;treatment response;tumor;tumor-immune system interactions PROJECT 1: TIME-Based Spatiotemporal Cancer Immunograms Predictive for Immunotherapy-Targeted Therapy Sequential Combinations n/a NCI 10708924 8/30/23 0:00 RFA-CA-21-048 5U54CA274509-02 5 U54 CA 274509 2 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9917 8126809 "HEATH, JAMES R." Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 752351 554221 198130 Project 1 Summary/AbstractCombining immunotherapy with other therapy regimens particularly targeted therapy is a highly active area ofexploration with the goal of improving anti-tumor efficacy and extending therapeutic benefits to more patients ortumor types. As the first mutation-immune co-targeted therapy the simultaneous combination of anti-PD-L1 withBRAFV600MUT and MEK inhibitors (so-called triplet therapy) has been approved for patients with BRAFV600MUTmelanoma. However the data on this triplet appear mixed with other trials not meeting key endpointssuggesting that simultaneous combination is not optimal. Our recent work in syngeneic murine melanomamodels showed uniformly across tumor models of distinct driver mutations and cancer histologies that aregimen of 1-week anti-PD-1/L1 ( anti-CTLA-4) pretreatment augments the efficacy of triplet therapy byenhancing MAPKi durability and dramatically suppressing melanoma brain metastasis. The improved therapyefficacy resulted from the promotion of pro-inflammatory polarization of tumor-associated macrophages and theelicitation of robust T cell clonal expansion and clonotypic convergence within the tumor-immunemicroenvironment (TIME) induced by the anti-PD-1/L1 lead-in. This is consistent with observations in the clinicaltrial data that prior immunotherapy before MAPKi is associated with improved progression-free survival. Theseresults highlight the vital role of the sequence/timing of each therapy component in the rational design ofcombination therapies and also point to the need for a mechanistic understanding of the early-stage impact ofeach combinatorial therapy component on the TIME.However the design of such sequential combination therapy trials is challenging because of the sheer numberof variables (sequence order dosing and timing) to be tested. The level of complexity calls for a predictiveframework to significantly reduce the parameter space and inform the identification of effective sequentialimmunotherapy-targeted inhibitor combinations. Herein we hypothesize that a spatiotemporal multi-omicsanalysis of early-stage (few days) monotherapy-induced changes in the TIME can provide deep insightsfor greatly simplifying the design of immunotherapy-targeted inhibitor sequential combination trials. Thegoal of Project 1 is to provide a data set that can be mined to inform the design of effective sequential combinationregimens. We will leverage state-of-the-art spatial multi-omics tissue profiling tools to build a spatiotemporalmovie of the evolving TIME in established syngeneic melanoma tumor models and their associated brainmetastases after treatment with each of the combinatorial therapy components. The resultant spatiotemporalmulti-omic data will be analyzed to extract a number of highly informative TIME features from which agent-basedmodels (Project 2) for predicting effective sequential combination regimens can be constructed. Retrospectivestudies of clinical tumor biopsies are proposed to validate the model findings. +No NIH Category available Acceleration;Accountability;Advocate;Awareness;Biological;Cancer Biology;Clinic;Clinical;Clinical Oncology;Combination immunotherapy;Combined Modality Therapy;Communication;Communities;Cutaneous Melanoma;Data;Education and Outreach;Educational Materials;Educational process of instructing;Engineering;Environment;Evaluation;Faculty;Feedback;Funding;Goals;Immunotherapy;Infrastructure;Institution;Intellectual Property;Learning;Logistics;Malignant Neoplasms;Mentors;Monitor;Patients;Persons;Pilot Projects;Process;Program Description;Protocols documentation;Reagent;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;STEM field;Schedule;Scientist;Self-Examination;Series;Solid Neoplasm;Specimen;Structure;Students;Systems Biology;Talents;Thinking;Tissues;Training Support;Translations;Underrepresented Minority;Underrepresented Populations;biobank;collaborative environment;design;flexibility;inhibitor;meetings;mouse model;multiple omics;outreach program;programs;spatiotemporal;targeted treatment;teacher;tool;translational goal;translational potential;tumor Administrative Core n/a NCI 10708920 8/30/23 0:00 RFA-CA-21-048 5U54CA274509-02 5 U54 CA 274509 2 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9915 8126809 "HEATH, JAMES R." Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 378467 203870 174597 Administration and Coordination CoreProject SummaryThe administrative and coordination core of the proposed U54 Center for Spatiotemporal Tumor Analytics forGuiding Sequential Targeted Inhibitor : Immunotherapy Combinations (ST-Analytics is designed topromote and support the integrated research efforts of scientists from the ISB Yale and UCLA as well as ourOutreach program our Pilot Projects and Cross-Consortium Projects. The scientific programs of ST-Analyticsare designed to resolve how to best harness immunotherapy/targeted therapy sequential combinations for thetreatment of solid tumors in the clinic starting with a focus on metastatic cutaneous melanoma. This requiresbringing together a cross-disciplinary mix of clinical biological physical engineering and computationalscientists as well as state-of-the-art multiomic profiling tools syngeneic mouse models and a rich bio-repositoryof highly relevant patient tissues. Meeting the ST-Analytics scientific goals requires a responsive administrativestructure that (i) promotes and enables effective communication and resource sharing between the ST-Analyticsresearchers and the broader Cancer Systems Biology Consortium (CSBC) (ii) establishes a highly interactiveenvironment wherein ST-Analytics researchers can be good students and teachers of each other (iii) promotesachieving the program specific aims in a timely manner (iv) intervenes as early as possible when scientific andlogistic conflicts arise (v) promotes diversity in our scientific workforce through various mechanisms includingbut not limited to seed project funding outreach programs and raising awareness of these critical issues duringour remote and in-person meetings and (vi) monitoring the scientific integrity and robustness of scientificdesigns. The ST-Analytics administrative CORE should facilitate the free flow of data new ideas experimentalprotocols customized reagents and biospecimens between the institutions. It should establish workingrelationships with other funded centers. It should facilitate clinical or commercial translation and educationaloutreach. It should encourage flexible thinking in anticipation of new opportunities or unexpected roadblocks.Finally it should facilitate a healthy environment of self-evaluation. +No NIH Category available Acceleration;Address;Adoptive Cell Transfers;Algorithms;Automobile Driving;Biological;Biopsy;Calibration;Cell physiology;Cells;Clinical;Clinical Data;Clinical Trials;Clinical Trials Design;Combination immunotherapy;Combined Modality Therapy;Communities;Coupled;Data;Databases;Development;Dimensions;Disadvantaged;Disease model;Distal;Dose;Education and Outreach;Educational Models;Environment;Environment Design;Epigenetic Process;Evaluation;Genetic Transcription;Immune;Immune system;Immunologic Factors;Immunooncology;Immunotherapy;Individual;Internships;K-12 Education;Kinetics;Knowledge;Lead;Leadership;Malignant Neoplasms;Measurement;Metastatic malignant neoplasm to brain;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Nature;Neoplasm Metastasis;Outcome;Patients;Pharmaceutical Preparations;Pilot Projects;Play;Primary Neoplasm;Proteomics;Research;Research Personnel;Research Project Grants;Resistance;Resources;Role;Science;Science Technology Engineering and Mathematics Education;Scientist;Self-Examination;Series;Structure;System;Systems Biology;Therapeutic;Time;Tissues;Visual;Work;biobank;cancer immunotherapy;combinatorial;computing resources;demographics;design;immune checkpoint blockade;in silico;in vivo;inhibitor;inhibitor therapy;medical schools;melanoma;model design;mouse model;multiple omics;outreach;outreach program;prevent;programs;recruit;spatiotemporal;tool;transcriptomics;tumor;tumor-immune system interactions Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor: Immunotherapy Combinations (ST-Analytics) Overall NarrativeThe proposed U54 program Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor --Immunotherapy Combinations (ST-Analytics) is designed to develop the recent conceptual advance thattargeted inhibitor + cancer immunotherapy (IT) combination treatments may yield significantly greater patientbenefit if those treatments are administered in sequence rather than as monotherapies or as simultaneouslyadministered combinations. NCI 10708901 8/30/23 0:00 RFA-CA-21-048 5U54CA274509-02 5 U54 CA 274509 2 "ZAMISCH, MONICA" 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M2) 8126809 "HEATH, JAMES R." Not Applicable 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2548990 NCI 1764533 784457 Overall Project SummaryThe proposed U54 program Spatiotemporal Tumor Analytics for Guiding Sequential Targeted-Inhibitor --Immunotherapy Combinations (ST-Analytics) is designed to develop the recent conceptual advance thattargeted inhibitor + cancer immunotherapy (IT) combination treatments may yield significantly greater patientbenefit if those treatments are administered in sequence rather than simultaneously. Analysis of retrospectiveclinical data coupled with in vivo therapeutic modeling using syngeneic models of murine melanoma stronglysupport this concept. In fact the picture that has emerged in melanoma is that immune factors can play a strongrole in driving resistance to MAPK inhibitor (MAPKi) therapy and that lead-in immune checkpoint blockade (ICB)can prime both the primary tumor and distal metastases (including brain metastases) for eradication when theIT is subsequently combined with MAPKi. This observation opens the doors for immune based strategies suchas ICB or adoptive cell therapy (ACT) as sequential combinatorial agents to prevent MAPKi resistance.However this concept introduces a number of new variables including dosing sequence and timing. This canmake the design and execution of clinical trials that can yield statistically significant outcomes impractical. Thisis the scientific and translational problem we address in the proposed ST-Analytics U54.The ST-Analytics U54 center is populated by leading scientists at the ISB the UCLA Geffen School of Medicineand Yale and is comprised of two research projects and two research cores with each project integrating bothstate-of-the-art experimentation and computational work. This structure is further designed to bring together thescientific experimental and computational and administrative resources to develop a data base that capturesthe kinetics of lead-in monotherapy tumor priming and apply that data base to the development of predictive insilico models that can inform the design of such targeted inhibitor immunotherapy sequence combinations forclinical trials. This requires close integration and cycles of iteration between of state-of-the-art experimentationleading edge computation and realistic disease models continuously calibrated through the analysis of highlyrelevant biopsied patient tumors. The resulting science also provides exciting opportunities for high impactSTEM outreach. We propose to act on those opportunities by leveraging a long-standing systems educationoutreach program at ISB that already has impacted K-12 STEM education in all 50 states and places anemphasis on those communities that have been historically under-represented in STEM. 2548990 +No NIH Category available Aberrant DNA Methylation;Ablation;Algorithms;Aneuploidy;Award;Barrett Esophagus;Biological Assay;Biological Markers;Biopsy;Breakthrough device;Cessation of life;Chromosomes;Classification;Clinical;Complication;DNA;DNA Markers;DNA Methylation;DNA analysis;Detection;Devices;Diagnosis;Diagnostic;Disease;Disease Progression;Disease remission;Distal;Dysplasia;Early Detection Research Network;Early Diagnosis;Effectiveness;Endoscopy;Enrollment;Esophageal Adenocarcinoma;Esophageal Neoplasms;Esophagectomy;Esophagus;Excision;FDA approved;Face;Frequencies;Future;Guidelines;High grade dysplasia;Histology;Image;Immunohistochemistry;Incidence;Individual;Intestinal Metaplasia;Laboratories;Lesion;Longitudinal Studies;Malignant Neoplasms;Malignant neoplasm of esophagus;Medical;Methods;Methylation;Molecular;Morbidity - disease rate;Natural History;North Carolina;Pathologist;Patients;Periodicals;Phase;Prevention;Prospective Studies;Publishing;Recommendation;Recording of previous events;Recurrence;Recurrent disease;Residual Neoplasm;Retrospective Studies;Risk;Role;Sampling;Societies;Squamous Epithelium;TP53 gene;Technology;Testing;Tissues;Universities;Validation;Vimentin;biobank;biomarker panel;biomarker performance;biomarker validation;commercialization;cost;digital imaging;disorder risk;epigenetic marker;falls;follow-up;high risk;liquid biopsy;molecular marker;mortality;neoplastic;new epidemic;next generation sequencing;overtreatment;patient stratification;patient subsets;phase 3 study;phase 4 study;predictive marker;premalignant;prevent;progression risk;prospective;risk stratification;routine practice;surveillance study;validation studies Validation of Biomarkers for predicting Barrett's esophagus that will or will not: i) progress towards cancer or ii) recur after ablation Project NarrativeInterception of esophageal adenocarcinoma (EAC) by eradication dysplasia when detected in its precursorBarretts esophagus (BE) is required for a cancer whose rate has more than sextupled in the past three decades.Biomarkers that can a) effectively identify dysplasia and risk-stratify patients with BE who are at risk forprogression to cancer and those who are not; and b) effectively identify those who are likely to recur aftersuccessful ablative therapy for dysplastic BE and those who are not will prevent unnecessary ablative therapyand minimize costs by decreasing the frequency of endoscopy after successful ablative therapy. NCI 10708890 8/28/23 0:00 RFA-CA-21-033 5U01CA271867-02 5 U01 CA 271867 2 "YOUNG, MATTHEW R" 9/22/22 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 1888502 "MARKOWITZ, SANFORD D." "BETTEGOWDA, CHETAN ; CHAK, AMITABH ; SHAHEEN, NICHOLAS J; WANI, SACHIN " 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1028348 NCI 733713 294635 AbstractThis EDRN-CVC proposal is aimed at the validation of molecular biomarkers for distinguishing high versus lowrisk esophageal neoplasias (Barretts esophagus) for the purpose of guiding selection and management ofpatients for endoscopic eradication therapy (EET). Two validation studies are proposed: the first a phase 4prospective study to identify a patient group at low progression risk who can be spared EET; the second a phase3 retrospective study to distinguish individuals who following EET are at low versus high risk of diseaserecurrence. Barretts esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EAC) a cancerwith 80% lethality whose incidence has increased more than 7-fold in the past three decades. BE progresses toEAC in a step-wise fashion from non-dysplastic BE to low grade dysplasia (LGD) to high grade dysplasia (HGD)and finally cancer. EAC prevention is based on using EET to ablate HGD BE before it can progress to EAC.However increasingly EET is also becoming the default therapy for LGD a highly imprecise diagnosis aboutwhich expert pathologists frequently disagree and which is applied to as many as 40% of BE patients at somepoint during their course. As EET has a 9% complication rate the result is an emerging epidemic of overtreatmentof BE with LGD. In a prior EDRN-BDL award our team developed the BAD technology for early detection ofBE progression. In BAD we used a brushing device to sample a patients full BE esophageal segment. We thenanalyzed the DNA from this sample using next-generation sequencing technology (developed for liquid biopsyassays) to instead detect presence of BE clones that had acquired gains or losses on specific driverchromosomes associated with EAC. Detection of driver chromosome changes (dubbed Very-BAD) typified EACand HGD. In contrast 28% of LGD showed complete absence of any chromosomally aberrant clones (dubbedNot-BAD). We will now validate Not-BAD as a biomarker that identifies LGD at such low progression risk as tonot require EET. We will do this by partnering with the SURVENT trial that will be the first U.S. prospective studyto follow LGD patients managed by surveillance not ablation. A second major challenge with EET is that over25% of patients recur following ablation (with either high risk BE HGD or EAC). These patients face a substantialburden of post-EET surveillance endoscopies initially at every 3-month intervals. In our prior EDRN-BDL ourteam identified a panel of methylated DNA biomarkers for sensitive molecular early detection of BE (currentlyawarded FDA breakthrough device designation). We have further identified that these markers remain retainedin a subset of patients post-EET. We accordingly now propose a retrospective Phase 3 study to further validatethese DNA markers for molecular assessment of minimal residual disease whose post-EET elimination identifiesindividuals achieving complete molecular eradication of BE and hence at low risk of disease recurrence and notin need of intense post-EET surveillance. We do this by partnering with the unique UNC-BEECAB biorepositoryof post-EET esophageal biopsies from patients whose disease did or did not recur following ablation. 1028348 +No NIH Category available Active Learning;Adult;African American;African American population;Anxiety;Area;Attitude;Award;Behavior;Behavioral;Behavioral trial;Belief;Breast;Cancer Burden;Clinic;Colorectal;Communication;DNA Sequence Alteration;Data;Death Rate;Development;Diet;Educational Status;Educational workshop;Ethnic Population;Evaluation;Extended Family;Face;Faith;Family;Family Caregiver;Family health status;Focus Groups;Future;Generations;Genetic;Genetic Counseling;Germ-Line Mutation;Goals;Grant;Health;Health behavior;Health education;Hereditary Breast and Ovarian Cancer Syndrome;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Individual;Inherited;Intervention;Intervention Studies;K-Series Research Career Programs;Knowledge;Learning;Life;Longitudinal Studies;Malignant Neoplasms;Manuscripts;Medical Genetics;Mental Health;Mentored Research Scientist Development Award;Mentors;Modification;Outcome;Outcome Study;Pattern;Persons;Physical activity;Politics;Population;Positioning Attribute;Process;Public Health;Recommendation;Recording of previous events;Reporting;Research;Research Personnel;Resources;Risk;Self Determination;Smoking;Social Work;Social status;Spirituality;Test Result;Testing;United States;Writing;acceptability and feasibility;behavior change;cancer genetics;cancer health disparity;cancer risk;cancer type;career;career development;commune;communication theory;contextual factors;coping;eHealth;economic disparity;experience;genetic information;genetic testing;health disparity;hereditary risk;high risk;improved;improved outcome;intervention program;lifestyle intervention;motivational enhancement therapy;pilot test;post-doctoral training;psychosocial;racial population;randomized clinical trials;response;screening;skills;symposium;tailored messaging;testing uptake;theories;therapy design;therapy development;transmission process;uptake Family Centered Approaches to Promoting Cascade Screening for Hereditary Cancer Syndromes among African Americans PROJECT NARRATIVEAfrican Americans are less likely to receive genetic testing to determine if they have a genetic mutationassociated with increased risk for certain cancers. When testing is done it is important to share informationwith relatives to help them determine whether or not they too would benefit from testing; however it can bedifficult to share this information within families. This project will develop and test an intervention specificallytailored for African American families to support their communication about cancer genetic testing resultscommunication about behaviors that can reduce their cancer risk and future decisions about whether or not tocomplete cancer genetic testing. NCI 10708884 8/31/23 0:00 PAR-21-296 5K01CA255137-02 5 K01 CA 255137 2 "VAHEDI, SHAHROOZ" 9/21/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 11314088 "ELLIS, KATRINA RENEE" Not Applicable 6 NONE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI GRADUATE SCHOOLS 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 172800 NCI 160000 12800 Research has shown that African Americans are less likely than other racial groups to engage in genetictesting for hereditary cancer syndromes which can uncover genetic mutations that increase cancer risk.African Americans also have lower rates of cancer cascade testing a process for providing genetic counselingand testing for relatives of African Americans who are known carriers of specific cancer-related geneticmutations. As clinical genetic testing becoming increasingly available it is critically important to designinterventions to reach all populations especially those that have been traditionally underserved. Tailoredstrategies are particularly useful for increasing intervention access and uptake where health disparities exist.This career development award provides Dr. Ellis the opportunity to develop and test a family-tailoredintervention to increase cancer cascade testing among African Americans. This award focuses onstrengthening the investigators skills in intervention research and cancer genetics. Her long-term career goalis to become an independent investigator with expertise in conducting family-based intervention research toimprove cancer outcomes among African Americans. Dr. Ellis graduate-level training in public health (healthbehavior and education) and social work (interpersonal practice with individuals and families) and postdoctoraltraining in cancer health disparities puts her in a unique position to develop interventions that attend to boththe psychosocial and behavioral aspects of cancer genetic testing for African American families. The careerdevelopment goals and mentoring plan include courses and workshops; guided mentoring including directedreadings with mentors; experiential learning including shadowing in a cancer genetics clinic and interventiondevelopment testing and evaluation; tailored health messaging development; attendance and participation atprofessional conferences; and manuscript and grant writing and submissions. These activities support theexecution of the specific aims which are to: (1) Identify intrapersonal and interpersonal facilitators and barriersto African American family communication about genetic testing and cascade testing through eight focusgroups; (2) Develop a tailored eHealth intervention for African American families that encourages uptake ofrecommended cascade genetic testing by improving communication about genetic testing results and targetingdrivers of and barriers to behavior change (e.g. knowledge attitudes skills for communication and testing); (3)Conduct a pilot test of the intervention with 30 families to evaluate intervention feasibility acceptability andengagement and explore its potential impact on cascade testing. Dr. Ellis mentoring team has expertise ineach of her key developmental areas. At the completion of this K01 award Dr. Ellis will have the expertise tobecome an independent investigator who conducts family-based intervention research to improve canceroutcomes with African American families with increased cancer risk. 172800 +No NIH Category available AXIN1 gene;Active Immunotherapy;Adult;Advanced Malignant Neoplasm;Animal Model;Biological Models;Breast Adenocarcinoma;Breast Cancer cell line;Cancer Cell Growth;Cancer Model;Cancer cell line;Cell Proliferation;Cells;Chromosome 8;Chromosome Arm;Chromosome Deletion;Chromosomes;Clinical;Clinical Management;Clustered Regularly Interspaced Short Palindromic Repeats;Colon;Colon Adenocarcinoma;Colorectal Cancer;Colorectal Neoplasms;Complex;Data;Dependence;Diploidy;Disease;Disease Progression;Distal;Drug resistance;Engineering;Enzymes;Family member;Gene Silencing;Genes;Genetic Models;Genetic Transcription;Genome;Goals;Growth;Heterozygote;Homeostasis;Human;Hyperactivity;Immunocompetent;Intestines;Lead;Link;Lung Adenocarcinoma;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measures;Modeling;Molecular Target;Mus;Mutation;Normal Cell;Normal tissue morphology;Oncogenic;Organ;Organoids;Pathway interactions;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Process;Proteins;Proteomics;Regulation;Safety;Series;Signal Pathway;Signal Transduction;Solid Neoplasm;System;TNKS gene;TP53 gene;Tankyrase;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Transgenic Organisms;WNT Signaling Pathway;Work;beta catenin;body system;bone;cancer cell;cancer therapy;cancer type;cell type;cellular engineering;chromosome 8p loss;colorectal cancer treatment;efficacy evaluation;genetic approach;genome editing;in vivo;inhibitor;injury and repair;innovation;malignant breast neoplasm;molecular targeted therapies;mouse model;novel;novel strategies;novel therapeutic intervention;pharmacologic;pre-clinical;precision oncology;preclinical study;resistance mechanism;response;small hairpin RNA;small molecule;small molecule inhibitor;stem cells;targeted treatment;therapeutic target;therapy resistant;tissue regeneration;treatment response;tumor;tumor progression Tumor selective inhibition of the WNT pathway PROJECT NARRATIVEMany cancers are driven by increased activation of a signaling pathway called WNT. Drugs that block WNT oftencause damage to normal organs and have so far been difficult to use in a clinical setting. Here we will test anew approach that aims to exploits genetic changes in cancer cells and allow cancer-specific suppression ofWNT treatment of colorectal cancer. NCI 10708875 8/31/23 0:00 PA-20-185 5R01CA273106-02 5 R01 CA 273106 2 "XU, WANPING" 9/22/22 0:00 8/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 10295556 "DOW, LUKAS EDWARD" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 568218 NCI 374075 194143 PROJECT SUMMARYWNT pathway hyperactivation is a dominant oncogenic driver in colorectal cancer (CRC) and directly linked todisease progression and drug resistance in many other cancer types including lung (LUAD) breast and prostatecancer. Indeed there is strong evidence from pre-clinical model systems that targeting hyperactive WNTsignaling can provide significant therapeutic benefit in multiple cancer models. We and others have shown thatblocking the function of redundant Tankyrase enzymes (TNKS and TNKS2) can suppress hyperactive WNTsignaling impede cancer cell proliferation and drive differentiation particularly in CRC. However WNT signalingis also critical for the homeostatic maintenance of multiple organ systems. Consequently drugs that effectivelyblock WNT like TNKS inhibitors have shown a range of on-target toxicities in essential tissues such as theintestine and bone. Defining a strategy for tumor-restricted WNT pathway suppression is a major goal in precisiononcology.Advanced cancers often contain significant disruptions to their genomes including gains and losses of largechromosome segments. These large-scale alterations encompassing many genes are presumed to supportcancer cell growth. However they also lead to loss of passenger genes that do not drive cancer progressionbut may unintentionally rewire the signaling networks. Such cancer-specific collateral damage may provideopportunities for therapeutic intervention. We will test the hypothesis that a large chromosomal deletion onchromosome 8p which induce loss of TNKS create a tumor-specific dependency on TNKS2 that can beexploited to block WNT only in cancer cells. Because normal cells express both redundant family members theyshould remain unaffected by selective targeting. In Aim 1 using a panel of CRC LUAD and breast cancer celllines and patient-derived organoids in combination with CRISPR-based genome editing we will determine howheterozygous and homozygous chromosome deletions impact the response to TNKS2 inhibition. Further we willdefine downstream protein targets that are most sensitive to TNKS disruption and TNKS2 suppression. In Aim2 we will exploit a unique transgenic shRNA system we developed to define the safety of systemic and selectiveTNKS2 inhibition in vivo and determine the efficacy of selective TNKS2 inhibition in immunocompetent animalmodels of aggressive CRC and LUAD. Aim 3 will determine the efficacy of novel TNKS2-selective smallmolecules in cancer cell lines and organoid models and evaluate potential mechanisms of therapy resistance toTNKS2 inhibition.Identifying a safe and effective approach to block hyperactive WNT signaling in multiple tumor types could havea profound impact on the clinical management of advanced cancers. Thus we believe our work will contributesubstantially to the overall goal of developing safe and effective targeted therapies for WNT-driven cancers. 568218 +No NIH Category available Address;Award;Budgets;Cells;Cellular biology;Clinical;Clinical Investigator;Complement;Comprehensive Cancer Center;Core Facility;Data;Development;Development Plans;Direct Costs;Early Diagnosis;Education;Educational workshop;Electronic Mail;Extramural Activities;Faculty;Female;Foundations;Funding;Funding Agency;Genitourinary system;Goals;Grant;Institution;International;Kidney;Leadership;Manuscripts;Medical center;Mentors;Mentorship;Minority Groups;Mission;Molecular;Pathologist;Pathology;Preparation;Prevention;Publications;Qualifying;Renal carcinoma;Reproduction spores;Research;Research Personnel;Scientist;Seasons;Selection Criteria;Talents;Texas;Training;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;anticancer research;career;career development;design;experience;innovation;interest;meetings;member;mid-career faculty;minority scientist;next generation;novel;outreach;professor;programs;recruit;research study;role model;skills;success;symposium;synergism;translational cancer research;translational potential Career Enhancement Program n/a NCI 10708861 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 9893 10377720 "KAPUR, PAYAL " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 88157 53754 34403 Project SummaryThe CEP provides seed funding for early-stage investigators whose research addresses important objectives inkidney cancer. The goal of the CEP is to attract talented typically early-career investigators with novel ideasand/or experimental approaches in translational kidney cancer research. The CEP is led by an energeticleadership team who represent the spectrum of academic experience have complementary research expertiseand offer diverse perspectives. They include a clinical pathologist Dr. Kapur Professor of Pathology and Directorof Genitourinary Pathology; a molecular biologist Dr. Zhang Associate Professor of Pathology; and a cellbiologist Dr. Conacci-Sorrell Assistant Professor of Cell Biology. Dr. Conacci-Sorrell a previous CEP recipientis a member of an underrepresented minority (URM) group and a role model. The CEP is committed to recruitingand training the next generation of researchers who are focused on translational kidney cancer research withan emphasis on attracting women and URMs. The CEP partners with the Office of Faculty Diversity andDevelopment and the Office of Womens Careers to recruit women and URM faculty. CEP proposals are solicitedby Core A via campus-wide email. Submitted proposals are reviewed by at least 4 reviewers including membersof the SPORE leadership IAB/EAB and other UTSW faculty with relevant expertise. Criteria for selection includesignificance innovation approach investigator qualifications (and mentorship) and translational potential. Thehighest-scoring proposals are funded following approval by the SPORE Executive Committee. The CEP willassist awardees by: (a) providing preferential access to all SPORE Cores (b) assigning mentors (c) formulatinga career development plan that includes relevant career development workshops seminars and educationalcourses (d) assisting in identifying other funding sources and putting together competitive applications and (e)providing forums for brainstorming and synergy. Metrics of success include presentations at scientific meetingssuccessful competition for independent grant support publication of original research studies and promotionthrough the academic ranks. Enabling an expansion of the CEP/DRP SPORE funding is complemented by fundsfrom the Simmons Comprehensive Cancer Center (SCCC) and UTSW which provide $400000/year in directcosts. The CEP plans to award 3 to 6 projects per year. The CEP will accomplish its mission through the followingAims. Aim 1. Promoting translational kidney cancer research by recruiting and supporting junior faculty. Aim 2.Attracting seasoned investigators to refocus their expertise on kidney cancer. Aim 3. Promoting diversity byrecruiting women and underrepresented minorities. Aim 4. Mentoring new investigators in the kidney cancerfield through traditional and innovative mechanisms. Illustrating our commitment to supporting an exceptionalCEP and highlighting our successful outreach efforts 19 CEP awards were funded including 7 women and 3underrepresented minorities during the first 5 years. +No NIH Category available Award;Budgets;Cancer Patient;Cellular biology;Clinical;Clinical Trials;Collaborations;Complement;Comprehensive Cancer Center;Dedications;Development;Electronic Mail;Ethnic Population;Faculty;Faculty Recruitment;Fostering;Foundations;Funding;Future;Grant;Hematology;Immune system;Institution;Internal Medicine;International;Kidney;Lead;Leadership;Letters;Medical center;Mentorship;Minority Groups;Mission;Nephrology;Oncology;Patient-Focused Outcomes;Peer Review;Physicians;Physiology;Preparation;Program Research Project Grants;Publications;Qualifying;Renal carcinoma;Reproduction spores;Research;Research Personnel;Research Project Grants;Resources;Scientific Advances and Accomplishments;Scientist;Selection Criteria;Texas;Translating;Translational Research;Translations;Underrepresented Minority;United States National Institutes of Health;Universities;Work;anticancer research;arm;cancer research center director;experience;high reward;improved;improved outcome;innovation;interest;meetings;member;mid-career faculty;multidisciplinary;novel therapeutics;professor;programs;racial population;recruit;research study;success;symposium;synergism;translational cancer research;translational impact;translational potential;trend;tumor Developmental Research Program n/a NCI 10708855 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 9892 1879305 "BRUGAROLAS, JAMES " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 206550 125945 80605 Project SummaryThe DRP provides seed funding for promising research projects with translational projection and potential tosignificantly impact kidney cancer research. The DRP funds pilot and/or high-impact/high-reward projects. Itserves as a pipeline to support the mission of the SPORE. The DRP is led by Dr. Brugarolas Professor ofInternal Medicine/Hematology-Oncology and SPORE Director together with Dr. Denise Marciano AssociateProfessor of Nephrology and Cell Biology. Dr. Brugarolas brings to bear his expertise in renal cancer and Dr.Marciano a deep understanding of kidney physiology and cell biology. Their combined research experience aswell as their track record in program building and mentorship provides them the expertise to successfully leadthe DRP program. DRP proposals are solicited by Core A via a campus-wide email. Each submitted proposal isreviewed by at least 4 reviewers. Criteria for selection include significance innovation approach investigatorqualifications and translational potential (or synergism with existing projects). Priority is given to proposals withthe potential to become full SPORE projects. The highest-scoring proposals are funded following approval bythe SPORE Executive Committee. DRP awardees have preferential use of SPORE Shared Core resources andbenefit from the expertise and leadership of SPORE investigators. They participate in SPORE conferenceswhere they regularly present their work. Metrics of success for DRP recipients include: invitations to present atscientific meetings; publication of original research studies; successful competition for independent externalgrant support; promotion of the projects to full SPORE projects; and institutional recognition by promotionthrough the academic ranks. Over the 5 years of our SPORE 16 DRP awards were funded. One DRP projectset the foundation for SPORE Project 3 of the renewal application. For the next funding period we seek tocontinue to attract and support a pipeline of diverse research interests and expertise relevant to kidney cancerin particular from under-represented minority (URM) groups. These projects will enlarge the breadth and depthof innovative Kidney Cancer Program/SPORE translational research and serve as potential SPORE projects inthe future. Enabling an expansion of the DRP/CEP NCI/SPORE funding will be complemented by funds fromSimmons Comprehensive Cancer Center (SCCC) and UTSW providing $400000/year. The DRP will aim toaward 3 to 6 projects per year. The DRP will accomplish its mission through the following Aims. Aim 1. Expandtranslational kidney cancer research by providing seed funding for promising translational projects. Aim 2.Identify and recruit a pool of promising scientists and physician-scientists. Aim 3. Nurture the development andprogress of the DRP projects and facilitate the transition of successful projects into competitive applications forpeer-reviewed funding. Aim 4. Support SPORE DRP awardees to ensure that scientific advances are translatedinto improved outcomes for kidney cancer patients. +No NIH Category available Bioinformatics;Biological;Biological Markers;Biometry;Biostatistics Shared Resource;Cell Line;Cells;Clinical;Clinical Data;Clinical Oncology;Collection;Communication;Communities;Complex;Comprehensive Cancer Center;Computerized Medical Record;Computing Methodologies;Core Facility;Data;Data Analyses;Data Analytics;Data Science;Data Set;Database Management Systems;Development;Ensure;Experimental Designs;Faculty;Funding;Genomics;Immune;Immunology;Individual;Journals;Kidney;Kidney Neoplasms;Lead;Link;Malignant Neoplasms;Manuscripts;Medical center;Methodology;Methods;Modeling;Nature;Neoplasm Metastasis;Patients;Population Sciences;Publications;Publishing;Renal carcinoma;Reporting;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Resources;Sampling;Science;Statistical Data Interpretation;Texas;Tissue Banks;Translations;Universities;Update;Visualization;Work;anticancer research;biobank;cancer cell;career;data integration;data management;design;experience;innovation;member;metabolomics;mid-career faculty;novel;professor;programs;sound;success;tool;transcriptome sequencing;tumor;web-accessible Core C: Data Analytics Core Project NarrativeThe Data Analytics Core will provide biostatistics bioinformatics and data management support to all threeSPORE projects the CEP and DRP as well as to the SPORE Cores. The Core will ensure that the appropriatestatistical design is incorporated into all studies from inception that the data are properly analyzed using thestate-of-the-art data methods and that all results are interpreted on statistical as well as biological significance.The Core also supports the SPORE through a state-of-the-art data management platform. NCI 10708848 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 9890 8328345 "AHN, CHUL W" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 236705 144332 92373 Project SummaryThe Data Analytics Core (Core C) brings together a team of experienced professionals to assist with biostatisticsand bioinformatics methodologies as well as data management for the UT Southwestern Medical Center (UTSW)Kidney Cancer Program (KCP) SPORE. The Core is directed by Dr. Ahn who is also the Director of theBiostatistics Shared Resource of the NCI-designated UTSW Simmons Comprehensive Cancer Center (SCCC).Core C is co-directed by Venkat Malladi M.S. who is the Director of the UTSW Department of BioinformaticsCore Facility and supervises genomics analyses (>3000 WES/RNA-Seq datasets). It is also co-directed byAlana Christie M.S. who is the Co-Leader of Biostatistics for the KCP and oversees data management andKidney Cancer Explorer (KCE) a pioneering tool that automatically extracts information from the electronicmedical record self-updates and links this information to experimental genomics as well as a state-of-the-artBioBank in OpenSpecimen. During Years 1 6 Core members assisted with study design bioinformatics datamanagement and data analysis for individual Projects the Career Enhancement Program (CEP) and theDevelopmental Research Program (DRP) and jointly published 30 manuscripts including in high-impact journals.The Core also made significant contributions by developing novel biostatistics and bioinformatics methodologieswith direct impact on SPORE Projects. For the next funding period (Years 7 12) the Core will provide state-of-the-art biostatistics and bioinformatics support as well as database management. Core members will work withSPORE investigators to ensure that the appropriate statistical design is incorporated into all studies from theirinception that the data are appropriately linked and validated and that all results are interpreted on statisticalas well as biological significance. In addition the Core will expand KCE by increasing functionality and linking itto external resources/datasets. To support the kidney cancer SPORE Core C will assist with the followingSpecific Aims. Aim 1: To provide strong biostatistical support for experimental design with power calculationstatistical analysis and interpretation for all KCP SPORE research activities. Aim 2: To provide strongbioinformatics support for genomic metabolomic and immune repertoire data preprocessing analysisinterpretation and visualization for all KCP SPORE research activities. Aim 3: To maintain and expand upon apioneering kidney cancer web-accessible tool clinical data integration with a unique BioBank (including live tumorsamples and a vast number of TGs) and extensive experimental genomics to support SPORE investigators andmore broadly the kidney cancer research community. In summary Core C investigators support the SPORE byensuring sound methodology rigor and reproducibility tailored new methodologies and providing an ever-expanding state-of-the-art data management platform linking clinical information experimental genomics andthe tissue bank. +No NIH Category available Academia;Address;Adult;Advisory Committees;Animal Model;BRAF gene;Basic Science;Benchmarking;Biological Assay;Biological Specimen Banks;Black race;Blood;CLIA certified;Cancer Biology;Cell Culture Techniques;Cell Line;Clinic;Clinical;Clinical Data;Clinical Trials;Collaborations;Communication;Communities;Complement;Comprehensive Cancer Center;Cryopreserved Tissue;DNA;DNA copy number;Dana-Farber Cancer Institute;Data;Development;Dimethyl Sulfoxide;Evaluation;FDA approved;Fostering;Freezing;Gene Expression;Generations;Genetic;Genitourinary system;Genomics;Goals;Hispanic;Histologic;Histology;Human;Image Analysis;Immunoassay;Immunohistochemistry;Implant;In Situ Hybridization;Industry;Infrastructure;Institution;Journals;Kidney;Kidney Neoplasms;Laboratories;Letters;Link;Malignant Neoplasms;Medical center;Metabolic;Metabolism;Modeling;Molecular;Mus;Mutation;National Cancer Institute;National Comprehensive Cancer Network;Nature;Neoplasm Metastasis;Nutrient;Oncology;Paraffin Embedding;Pathologic;Pathologist;Pathology;Pathway interactions;Patient Care;Patients;Pharmaceutical Preparations;Primary Neoplasm;Principal Investigator;Protocols documentation;Publishing;Quality Control;RNA;Radiation;Renal Cell Carcinoma;Renal Mass;Renal carcinoma;Research;Research Personnel;Resources;SNP array;Sampling;Services;Small Interfering RNA;Specimen;Stable Isotope Labeling;Standardization;Stimulator of Interferon Genes;Testing;Texas;Therapeutic;Tissue Banks;Tissue Microarray;Tissue Preservation;Tissue Procurements;Tissues;Tracer;Transgenic Organisms;Translational Research;Tropism;Tumor Bank;Tumor Cell Line;Tumor Markers;Universities;Validation;assay development;biobank;brca gene;cancer cell;clinical practice;cohort;digital pathology;drug sensitivity;drug testing;ethnic diversity;exome sequencing;experience;federated learning;human model;improved;in vivo;innovation;interdisciplinary approach;knockout animal;laser capture microdissection;member;patient derived xenograft model;personalized diagnostics;personalized medicine;pre-clinical;precision medicine;preservation;programmed cell death ligand 1;programs;racial diversity;radiotracer;rare condition;repository;stem;tissue processing;tissue resource;transcriptome sequencing;translational goal;tumor;whole slide imaging Core B: Biospecimen and Pathology Resources Core Project NarrativeAll of the proposed SPORE projects are dependent on the pathology and tissue resources provided by theBiospecimen and Pathology Resources Core (Core B). The Core B Director is a pathologist withhistomorphologic and research expertise in adult kidney cancers and with extensive experience in biobanking.The proposed Core infrastructure will further strengthen our ongoing translational mission and has the potentialto revolutionize personalized medicine in renal cancer. NCI 10708846 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 6719 10377720 "KAPUR, PAYAL " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 357195 217802 139393 Project SummaryThe aims of the Biospecimen and Pathology Resources (BPR) Core (Core B) are to facilitate the storage anddistribution of comprehensively annotated high-quality biospecimens and their derivatives and to provideprofessional and technical pathology services to the principal investigators and collaborators of our SPORE andKidney Cancer Program. All three SPORE projects utilize Core B which is critical to achieving their aims. It isan indispensable component of our SPORE and leverages and expands (without duplicating) existing pathologyresources in our National Cancer Institute (NCI)-designated Simmons Comprehensive Cancer Center. Wedeliver basic histology immunohistochemistry (IHC) in situ hybridization (ISH) tissue microarrays whole slideimaging image analysis and laser-capture microdissection services and make available unique cancer tissuederivatives such as primary cancer cell cultures and cell lines cryopreserved tissues DNA RNA and patient-derived xenografts (PDX or tumorgrafts TG). These efforts are complemented by several national initiatives ledby the Core. This Core provides expertise in histomorphologic evaluation of human kidney tumors humantumorgrafts in mice kidney tumors in transgenic and knockout animal models and in the interpretation of IHCand ISH and multiplex immunoassays. The BPR Core develops IHC and molecular assays and has experiencein the deployment of CLIA-certified laboratory tests such as our PD-L1 IHC. The BPR Core currently has fresh-frozen renal tumor and paired-normal kidney (or blood) tissues for >1700 racially and ethnically diverse patients;a unique live-tissue repository of >1900 kidney tumor tissues preserved viable in DMSO for mechanistic studiesto address questions arising from genomic and other studies of inert tissues; >200 independent TG lines; 47primary tumor cell lines representing a wide variety of tumors; and integrated genomic analyses (exomesequencing RNA-Seq and SNP arrays) of >500 RCC patients. Specimen data is linked to the institutional tissuebank and to comprehensive patient clinical data through Kidney Cancer Explorer (Core C). The BPR Coreprovides routine quality control for SPORE investigators to ensure that the tissues are optimal and several ofour protocols have been published in Nature Protocols and serve as benchmarks in the fields of tissue processingfor integrated genomic analyses and TG utilization for preclinical drug testing. Our repository has had significantutilization with >1000 samples having been shipped to collaborators both internally as well as externally. TGshave been extensively utilized to evaluate RCC drug sensitivity study radiation responsiveness explore tumorbiomarkers understand cancer biology (including rare syndromes) and dissect metabolic derangements inRCC. Studies with these tissues have been published in high-impact journals such as Nature Genetics NatureCommunications and Lancet Oncology. Our Core promotes flourishing collaborations among our SPOREinvestigators investigators from other SPOREs and other investigators in academia and industry. +No NIH Category available Adaptive Immune System;Antigen Presentation;Biological Availability;Biological Sciences;Biopsy;Blood specimen;Cancer Patient;Clinical;Clinical Trials;Complement;Cytosol;DNA;Development;Dose Limiting;Future;Gene Expression;Goals;Immune;Immune checkpoint inhibitor;Immune system;Immunotherapy;In complete remission;Inflammation;Innate Immune System;Interferons;Intervention;Label;Ligands;Maintenance;Medical;Medical center;Metastatic Renal Cell Cancer;Natural Immunity;Neoadjuvant Therapy;Nivolumab;Pathway interactions;Patients;Pharmacodynamics;Phase;Phase II Clinical Trials;Physiological;Positioning Attribute;Positron-Emission Tomography;Prize;Production;Progressive Disease;Radiation;Randomized;Regimen;Renal Cell Carcinoma;Renal carcinoma;Research;STING agonists;Safety;Second Messenger Systems;Site;Stable Disease;Stimulator of Interferon Genes;Survival Rate;Texas;Therapeutic Intervention;Tissue Sample;Tissues;Toxic effect;Universities;Work;adaptive immune response;analog;anti-PD-L1;arm;design;experience;immunogenic cell death;improved;improved outcome;innate immune sensing;innovation;insight;ipilimumab;molecular imaging;novel;patient population;phase I trial;phase II trial;programmed cell death ligand 1;programs;radiotracer;response;standard of care;success;tool;trial comparing;tumor Project 3: Maximizing Anti-tumor Activity through Simultaneous Activation of the Innate and Adaptive Immune System in Kidney Cancer Project NarrativeImmune checkpoint inhibitor combinations have shown considerable promise but the majority of metastatickidney cancer patients are not cured. We propose to engage both the innate and the adaptive immune systemarms to improve the outcome of immune checkpoint inhibitors for patients with metastatic kidney cancer. NCI 10708841 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 6718 11144278 "HANNAN, RAQUIBUL " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 339344 206917 132427 Project SummaryImmune checkpoint inhibitors (ICI) have the potential to cure patients with metastatic renal cell carcinoma (RCC).For those experiencing a complete response (CR) induction Ipilimumab (Ipi)/ Nivolumab (Nivo) followed bymaintenance Nivo results in overall survival (OS) rates of 97% at 4 years. However CR rates occur in ~10% ofpatients. Survival rates plummet in patients with progressive disease (PD) and even stable disease (SD). DespiteNivo maintenance patients with SD after induction (36%) show significantly reduced 4-year OS rates (55% vs97%). While by comparison to PD patients (OS rates ~20%) patients with SD derive some benefit from ICI thefull potential of immunotherapy is not realized. We hypothesize that the addition of complementary immunestrategies will increase responses and eventually cure rates for patients with SD after induction. This representsan unmet medical need. Most immunotherapy approaches to date have focused on amplifying an adaptiveimmune response (i.e. ICI) but more effective strategies may result from simultaneously activating the innateand adaptive immune arms as it normally occurs physiologically. To unleash the full potential of the immunesystem we propose to induce innate immunity by stimulating antigen presentation (through immunogenic celldeath triggered by stereotactic radiation) and promoting inflammation (with a novel STING agonist wediscovered). Pioneering research at UT Southwestern Medical Center (UTSW) identified a novel innate immune-sensing pathway the cGAS-cGAMP-STING pathway leading to the Breakthrough Prize in Life Sciences in 2019and the development of IMSA101 a novel STING agonist. A phase 1 trial of IMSA101 (NCT04020185) at UTSWand elsewhere showed that IMSA101 is safe and active. Herein we propose a novel adaptive clinical trial toevaluate the impact of stereotactic ablative radiation (SAbR)/ IMSA101 added to standard-of-care (SOC) Nivomaintenance in patients with SD following induction Ipi/Nivo to harness the full potential of the immune system.To accomplish this goal we will conduct a randomized phase 2 trial comparing this regimen to SOC maintenanceNivo. The study is powered to detect a clinically meaningful difference in response rates from 5% to 35% whichcan be accomplished with 50 patients. We will explore the impact of the intervention through pharmacodynamicstudies involving not only sophisticated tissue analyses but also an innovative PD-L1 PET. We are uniquelypositioned to carry out these studies given: (i) the discovery of the cGAS-cGAMP-STING pathway anddevelopment of IMSA101; (ii) our pioneering development of SAbR applications for RCC with possibly the largestSAbR RCC program globally; (iii) our prior success executing clinical trials combining SAbR with ICI in RCCpatients; and (iv) our pioneering work leveraging PD-L1 PET in renal cancer. If successful this study will harnessthe full potential of the immune system through simultaneous activation of the innate and adaptive arms of theimmune system in a patient population with modest benefit from ICI and which represents an unmet medicalneed. +No NIH Category available Address;Bypass;Carbon;Cathepsins;Cell physiology;Cells;Citric Acid Cycle;Clear Cell;Clear cell renal cell carcinoma;Clinic;Collaborations;Cytotoxic T-Lymphocytes;Data;Dependence;Drug Targeting;Enzymes;Equilibrium;Event;Failure;Generations;Germ-Line Mutation;Glucose;Glutaminase;Glutamine;Glycogen;Growth;Human;Immune;Immunocompetent;Implant;Infusion procedures;Intervention;Knowledge;Label;Link;Lipids;Malignant Neoplasms;Mediating;Medical center;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Mus;Neoplasm Metastasis;Nitrogen;Non-Malignant;Nutrient;Oxidation-Reduction;Oxidative Phosphorylation Deficiency;Pathway interactions;Patients;Pharmacologic Substance;Phenotype;Predisposition;Process;Reaction;Renal Cell Carcinoma;Renal carcinoma;Reporting;Resistance;Role;Source;Testing;Texas;Therapeutic;Translating;Tumor Promotion;Tumor Tissue;Universities;cell type;drug development;genetic approach;in vivo;inhibitor;innovation;insight;metabolomics;mouse model;neoplastic cell;next generation;nitrogen metabolism;novel;novel strategies;oxidation;small molecule;therapeutic target;treatment response;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumorigenesis Project 2: Defining Targetable Metabolic Dependencies in Human Renal Cell Carcinoma Project NarrativeClear cell renal cell carcinoma (ccRCC) is characterized by altered metabolic pathways that promote tumorgrowth but may render the tumors susceptible to metabolic inhibitors. In this Project we will apply our discoveriesof metabolic pathways that promote ccRCC progression and metastasis in patients to test whether inhibitingthese pathways with novel metabolic inhibitors suppresses tumor growth in a panel of human-derived ccRCCtumors growing in mice. Further we will test the impact of these inhibitors on both the tumor cells and immunecells in the tumor microenvironment (TME) in novel syngeneic models of kidney cancer in immunocompetentmice. NCI 10708840 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 9887 1900629 "DEBERARDINIS, RALPH J" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 339343 206917 132426 Project SummaryMetabolic reprogramming in cancer is an attractive source of therapeutic targets because it fuels tumor growthand metastasis through enzymes that are in principle amenable to inhibition with small molecules. Metabolicreprogramming is intrinsic to renal cell carcinoma (RCC). In fact few tumors are as profoundly linked to metabolicderangement as RCC and in particular clear cell RCC (ccRCC). This is shown by: the clear cell phenotypewhich arises from lipid/glycogen accumulation; direct metabolic reprogramming by the ccRCC signature eventVHL inactivation; and the observation that germline mutations in metabolic enzymes cause RCC but few othertumor types. The two main barriers to targeting metabolic reprograming are the lack of knowledge about RCCmetabolism in patients and the absence of validated translational platforms. To address these challenges weexecuted 5 major activities in Years 1 5. First we pioneered intraoperative infusions of 13C-labeled nutrients inpatients to directly report on RCC metabolism in humans which revealed among others suppressed glucoseoxidation. Second we showed mechanistically that suppressed glucose oxidation is due to deficient oxidativephosphorylation. Third we determined that additive-free orthotopically implanted patient tumors (tumorgraftsTG) are valid models to study human RCC metabolism. Fourth we established the In Vivo Metabolism Laban innovative translational platform to detect metabolic reprogramming in human tumors nominate therapeuticstrategies test them in TG models and primary human tumor tissue and advance the most promising leads.Fifth we demonstrated that both primary ccRCC tumors and metastases use glutamine to maintain redoxbalance and produce essential biosynthetic intermediates. Building upon discoveries by us and others implicatingglutamine in cancer the CB-839 glutaminase inhibitor was developed. However results in ccRCC trials havebeen disappointing. One possible explanation is that glutaminase is only one of several enzymes that catabolizeglutamine. Our new data not only explain CB-839 lack of efficacy but also identify new opportunities forintervention. Indeed while CB-839 inhibits carbon metabolism by targeting glutaminase glutamine is also asource of nitrogen in RCC which is processed via amidotransferases which are not inhibited by CB-839. Inpreliminary data we show that pan-glutamine inhibition with JHU-083 not only effectively inhibitsamidotransferase reactions but also significantly blocks ccRCC TG growth. To advance effective glutaminetargeting to the clinic in Years 6 10 we will pursue the following Aims. Aim 1. Probing the role ofamidotransferases in mediating resistance to CB-839 glutaminase inhibitor. Aim 2. Targeting IDH enzymes tomaximize glutamine blockade. Aim 3. To maximize the impact of glutamine targeting by leveraging the tumormicroenvironment using next-generation models. +No NIH Category available Advocacy;Advocate;Automobile Driving;Award;Cancer Center;Cancer Patient;Cancer Research Project;Cancer Survivor;Caregivers;Caring;Clinic;Clinical;Common Neoplasm;Communication;Communities;Complex;Comprehensive Cancer Center;Core Facility;Country;County Hospitals;Development;Education;Event;Faculty;Faculty Recruitment;Fostering;Foundations;Funding;Future;Goals;Health Resources;Healthcare;Hospitals;Incidence;Institution;Interdisciplinary Study;Kidney;Leadership;Malignant Neoplasms;Medical center;Mission;Monitor;Office of Administrative Management;Organizational Objectives;Patient advocacy;Patients;Program Evaluation;Renal carcinoma;Reporting;Research;Research Personnel;Resource Allocation;Role;Services;Structure;Texas;Translating;Underrepresented Minority;Universities;anticancer research;cancer care;career;data management;equity diversity and inclusion;experience;innovation;multidisciplinary;patient population;programs;recruit;role model;sound;success;synergism;volunteer Core A: Administrative Core n/a NCI 10708829 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 9886 1879305 "BRUGAROLAS, JAMES " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 145930 88982 56948 Project SummaryFor reasons unknown Texas has one of the highest incidence rates of kidney cancer in the US. UT SouthwesternMedical Center (UTSW) together with its affiliates the county hospital Parkland Memorial Hospital (staffed byUTSW faculty) and Texas Health Resources cares for 57% of all new kidney cancer patients in the Dallas-FortWorth metroplex. At UTSW Simmons Comprehensive Cancer Center (SCCC) kidney cancer is the 5th mostcommon tumor type. In 2013 the Kidney Cancer Program (KCP) was inaugurated. Recognized with a Leadersin Clinical Excellence Program Award and a finalist for the metroplex Innovation in Healthcare Award the KCPhas been a trailblazer. Directed by Dr. Brugarolas and with the goal to promote collaborative interdisciplinaryresearch to translate discovery and technical innovation at UTSW the KCP provides a foundation for theUTSW Kidney SPORE and serves as a vehicle for its integration within UTSW/SCCC. As the coordinating hubof the SPORE the Administrative Core provides essential administrative services and organizational support tothe SPORE as a whole. The Director of the Core Dr. Brugarolas will continue to provide overall direction andscientific leadership promote multidisciplinary interactions and oversee fiscal management and reporting. Hisscientific background experience across the research continuum and administrative roles enable him to serveas an effective overall SPORE PI and Director of the Administrative Core. Dr. Kapur Co-Leader of the KCP andpreviously SPORE PI successor has been promoted to SPORE PI and Core A Co-Director. Dr. Conacci-Sorrellan underrepresented minority and Co-Leader of the CEP will also be joining the Administrative Core as Co-Director. An Executive Committee comprised of representatives from all Projects and Cores provides advice onSPORE strategic directions departmental and administrative interactions faculty recruitment and resourceallocation. A Patient Advocacy team representing the spectrum of the cancer experience (from current patientsto cancer survivors and caregivers) is actively engaged in leading community and educational eventsfundraising and perhaps most inspiringly volunteering at SCCC clinics to assist other patients. An InternalAdvisory Board made up of institutional leaders serves as a sounding board and an External Advisory Boardof leaders in their fields with complementary expertise assists by evaluating progress and providing input onfuture directions. The KCP/SPORE benefits from a strong commitment from both UTSW and the SCCC witheach committing $200000 yearly to promote kidney cancer research thereby extending the reach of the CEPand DRP programs as well as $1100000 in recruitment funds. Core A will continue to fulfill its objectives throughthe following Aims. Aim 1: Partnering with the SCCC and UTSW to advance a program of excellence in kidneycancer. Aim 2: Serving and engaging the kidney cancer patient population. Aim 3: Furthering a state-of-the-arttranslational kidney cancer research program. Aim 4: Recruiting investigators through successful DevelopmentalResearch and Career Enhancement Programs. Aim 5: Supporting and leading national initiatives. +No NIH Category available Affinity;Binding;Biological Markers;Biopsy;Biotechnology;Chemicals;Chemistry;Clear cell renal cell carcinoma;Clinical;Clinical Trials;Collaborations;DNA Binding;Data;Dependence;Dissociation;Dose Limiting;Down-Regulation;Drug Targeting;Drug resistance;Evaluation;FDA approved;Fluorine;Funding;Future;Generations;Genes;Genetic Transcription;HIF1A gene;Human;Hypoxia Inducible Factor;Imaging Device;Institutional Review Boards;Integrin alphaVbeta3;Ligands;Malignant Neoplasms;Measurable;Measures;Mediating;Medical center;Messenger RNA;Modeling;Monitor;Mus;Mutation;Nature;Neoplasm Transplantation;Oncology;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase I Clinical Trials;Positron-Emission Tomography;Proteins;RNA Interference;Radiology Specialty;Renal Cell Carcinoma;Renal carcinoma;Reporting;Resistance;Resistance development;Sagittaria;Small Interfering RNA;Specificity;Testing;Texas;Therapeutic;Toxic effect;Transplantation;Universities;Visualization;Work;analog;biomarker identification;cancer type;cohort;dosimetry;experimental study;imaging biomarker;implantation;in vivo;inhibitor;innovation;mRNA Transcript Degradation;manufacture;molecular imaging;mutant;novel;novel therapeutics;phase 1 study;phase I trial;pre-clinical;programs;radioligand;radiotracer;resistance mutation;small molecule inhibitor;standard of care;success;therapeutic siRNA;transcriptome sequencing;tumor;tumor growth Project 1: Targeting HIF2 in Renal Cell Carcinoma Project NarrativeHaving identified the first core dependency in kidney cancer and having developed a drug now approved by theFDA we propose to develop a second-generation drug able to target resistant tumors along with a highlyinnovative radiology test enabling visualization of target engagement in patients. NCI 10708828 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8 6716 1879305 "BRUGAROLAS, JAMES " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 339342 206916 132426 Project SummaryHIF2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC) the most common kidneycancer type. Discovered at UT Southwestern Medical Center (UTSW) and regarded as undruggable structuralstudies revealed a vulnerability that was exploited leading to the identification of small molecule inhibitors andthe founding of a biotech company Peloton Therapeutics Inc. which developed several analogues (PT2385PT2399 and PT2977). PT drugs bind to HIF2 leading to its dissociation from its obligatory partner HIF1thereby inhibiting HIF2-mediated transcription. Preclinical and clinical work during the previous funding periodadvanced the field significantly. Using tumorgraft (TG) models of patient ccRCCs transplanted in mice weshowed that: HIF2 is a valid target; approximately 50% of ccRCC are dependent on HIF2; HIF2-sensitive tumorsare characterized by high HIF2 which may serve as a biomarker; and resistance develops as a result ofacquired HIF2 mutations. In addition we led accrual to the phase 1 trial which showed that PT2385 was welltolerated and active. Furthermore we showed that: (i) PT2385 specifically targeted HIF2 in patient tumors (butnot HIF1); (ii) HIF2 targeting resulted in inhibition of HIF2 target genes; and (iii) prolonged therapy led to theacquisition of resistance mutations we predicted in TGs. These data identified HIF2 as the first core dependencyin ccRCC. The success of the program culminated with the approval by the FDA of PT2977 (belzutifan). For thenext funding period we seek to co-develop: (i) an siRNA-based HIF2 drug (siHIF2) that targets both wild-typeand resistant-mutant HIF2; and (ii) a molecular imaging tool that can enable non-invasive HIF2 monitoring inpatients. Developed by Arrowhead Pharmaceuticals Inc. siHIF2 is a synthetic stabilized chemically modifieddouble-stranded RNAi trigger specifically targeting HIF2 mRNA conjugated to a high-affinity ligand for integrinsv3 and v5 which are broadly expressed in ccRCC. siHIF2 will be co-developed with a novel imaging toolwe generated to enable HIF2 quantification and which will be deployed to measure siRNA-mediated targetdepletion. We leveraged the high specificity of PT2385 and by substituting a native fluorine atom converted itinto a PET radiotracer ([18F]PT2385). Since the original submission a year ago we received an IND for([18F]PT2385) obtained IRB approval and began dosimetry studies in humans. We also advanced the siHIF2phase 1 trial to the last planned cohort revealing good tolerability showing that siHIF2 downregulates HIF2 inpatient tumor biopsies and providing preliminary evidence of activity. Having successfully launched a HIF2inhibitor now FDA approved we propose to develop a second-generation inhibitor targeting wild-type and drug-resistant HIF2. If successful this may lead to a new drug for ccRCC and possibly the first siRNA-basedtherapeutic in oncology. +No NIH Category available ABL1 gene;Address;Adopted;Affect;Alleles;American Society of Clinical Oncology;Area;B-Cell Acute Lymphoblastic Leukemia;Benign;Birth;Cancer Etiology;Catalogs;Child;Childhood;Classification;ClinVar;Clinical;Collaborations;DNA Sequence Alteration;Data;Databases;Development;Diagnosis;Disease;Environment;Event;Funding;Genes;Genetic;Genetic Databases;Genome;Genomics;Goals;Grant;Guidelines;Human Genetics;Informatics;Inherited;Knowledge;Laboratories;Link;Los Angeles;Lymphoblastic Leukemia;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Molecular;Molecular Profiling;Mutation;National Institute of Child Health and Human Development;Pathway interactions;Pediatric Hospitals;Pediatric Neoplasm;Phenotype;Philadelphia;Policies;Population;Prediction of Response to Therapy;Procedures;Process;Process Assessment;Professional Organizations;Prognosis;Publications;Registries;Reproducibility;Research Personnel;Resources;Somatic Mutation;Testing;Translating;United States National Institutes of Health;Universities;Variant;Washington;accurate diagnosis;actionable mutation;adjudication;anticancer research;cancer diagnosis;clinical application;clinical decision-making;clinically actionable;clinically relevant;clinically significant;crowdsourcing;data curation;data exchange;data hub;data standards;experience;genetic counselor;genetic variant;genome-wide;genomic data;information display;knowledgebase;novel;novel strategies;precision oncology;repository;response;treatment response;tumor;user-friendly;working group;young adult Genomic Expert Curation Panels for Pediatric Malignancies Project NarrativeChildhood cancers are caused by genetic mutations inherited at birth or acquired during cancer development.Understanding these mutations is critical for accurate diagnosis and treatment of children and young adultswith cancer but they are currently under-represented in public genetic databases. We will develop proceduresand expert panels to fill this gap by performing focused curation of mutations found in childhood cancers. NCI 10708799 7/25/23 0:00 PAR-20-101 5U24CA258115-02 5 U24 CA 258115 2 "OSSANDON, MIGUEL" 9/22/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-GGG-B(50)R] 11091560 "GRIFFITH, OBI L." "GRIFFITH, MALACHI ; RACA, GORDANA " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 283182 NCI 242072 41110 Project Summary/AbstractThe goal of this proposal is to develop expert panels focused on curating evidence for the clinical application ofsomatic mutations associated with childhood cancers. Tumors in the pediatric population have unique geneticprofiles that can affect their diagnosis prognosis and treatment. There is currently a gap in representationof somatic variants for childhood tumors in public cancer databases and knowledgebases. Newapproaches for evidence curation are needed to identify important mutations in childhood cancers for bothdiagnosis and therapy response. To address these gaps our application builds on two prominentdevelopments in the field led by our team. First as the ClinGen Somatic Clinical Domain Working Group(CDWG) we developed the Minimal Variant Level Data (MVLD) standard to promote sharing and use of genevariants in precision oncology. Second we developed the Clinical Interpretation of Variants in Cancer (CIViC)expert crowdsourced platform for somatic curation and clinical interpretation. Our goals are to: (1)systematically catalog the clinical relevance of common rare and novel variants identified throughgene-specific and genome-scale testing in childhood cancers; (2) partner with ClinGen ClinVarguideline-setting professional organizations and other relevant global efforts to translate and present theknowledge derived from genome researchers and clinical laboratories; and (3) develop informatics support forvariant assessment of clinical actionability information display interfacing with relevant databases anddissemination. To accomplish these goals we developed a collaboration over the past three years through theClinGen Somatic CDWG among researchers at Washington University Georgetown University and ChildrensHospital Los Angeles that includes clinical and molecular geneticists genetic counselors bioinformaticiansand genomic database experts to advance the use of genomic data in childhood cancers. Specifically we willestablish pilot variant curation expert panels (VCEPs) to assess clinical relevance and actionability of somaticvariants in pediatric cancers. Our initial focus will be on two disease areas with timely relevance pediatricmalignancies with NTRK fusions and BCR-ABL1 (Philadelphia)-like B-lymphoblastic leukemia (Ph-like B-ALL).We will adopt ClinGens existing VCEP policies and processes for assessing variants of strong clinicalsignificance potential clinical significance unknown clinical significance and benign or likely benign variants inchildhood cancers. We will adapt and enhance the CIViC platform to support these expert panels. The CIViCplatform will also provide the curated evidence in standard formats for exchange of data with ClinVar andClinGen resources. Finally we will seek FDA recognition for the evidence repository developed and curatedthrough this grant. 283182 +No NIH Category available Affect;Aftercare;Age;Antibiotics;Anxiety;Attention;Attenuated;Biological;Biological Markers;Biopsy;Blood;Blood Tests;Blood specimen;Cancer Detection;Cessation of life;Clinical;Clinical Data;Cohort Studies;Colorectal;Complex;Data;Decision Making;Detection;Diagnosis;Disease;Early Diagnosis;Elderly;Ensure;Ethnic Origin;Future;Genes;Genetic Variation;Goals;Guidelines;Head;Human;Image;Individual;Kinetics;Kininogenase;Knowledge;Ligands;Liquid substance;Lung;MSMB gene;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Monitor;Neoplasm Metastasis;Outcome;Ovarian;PSA level;PSA screening;Patients;Pattern;Peptide Hydrolases;Population;Population Study;Predictive Value;Primary Care Physician;Promoter Regions;Prostate;Prostate Cancer therapy;Prostate specific antigen measurement;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Prostate-Specific Antigen;Prostatic;Proteins;Publishing;Race;Recommendation;Research;Research Personnel;Risk;Risk Marker;Role;Sampling;Screening for Prostate Cancer;Single Nucleotide Polymorphism;Specific qualifier value;Specificity;Staging;Statistical Models;Technology;Test Result;Testing;Time;United Kingdom;United States;Urology;Variant;alpha 1-Antichymotrypsin;blood-based biomarker;cancer biomarkers;cancer risk;chymotrypsin;clinical care;clinical decision-making;clinical practice;cohort;cost;diagnostic value;evidence base;head-to-head comparison;improved;individual variation;innovation;insight;men;middle age;molecular marker;multi-ethnic;novel;patient subsets;population based;programs;prospective;prostate biopsy;prostate cancer risk;randomized trial;risk prediction;risk prediction model;risk stratification;screening;tool;treatment trial Influence of intra-individual variability in serial screening samples on clinical decision-making for risk stratification and biopsy by a single PSA and additional markers PROJECT NARRATIVEWhile prostate-specific antigen (PSA) testing is used commonly in early detection programs for prostatecancer a single test result may be unreliable due to the tendency of PSA levels to fluctuate (both biologicaland analytical variation). False-positive PSA elevations are a cause of significant concern that may lead toanxiety unnecessary antibiotic use additional and costly clinical-work up with imaging and/or risky invasiveprostate biopsies. We will analyze blood samples and clinical data from the world's largest randomized trials ofprostate cancer screening and treatmentthe United States Prostate Lung Colorectal and Ovarian(PLCO) Cancer Screening Trial the Swedish Gteborg population-based screening trials (Gteborg-1 andGteborg-2) and the United Kingdom's Prostate Testing for Cancer and Treatment (ProtecT) trialas wellas biomarker and clinical data from the Multiethnic Cohort (MEC) to better understand these fluctuations inPSA levels how to distinguish between aggressive and insignificant prostate cancers and when to performprostate biopsy. NCI 10708766 8/3/23 0:00 PAR-18-913 5U01CA266535-02 5 U01 CA 266535 2 "ZHU, CLAIRE" 9/22/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M1) 14342018 "CARLSSON, SIGRID " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 386067 NCI 243272 142795 Testing for prostate-specific antigen (PSA) in blood has enabled early detection of prostate cancer andreduced metastasis and death from diseasebut also contributed to overdetection of low-risk cancers.Although no PSA concentration confers zero risk of finding cancer at prostate biopsy a single PSAmeasurement at midlife is a remarkably strong predictor of the risk of developing lethal prostate cancerdecades later. PSA is a proteolytic enzyme that is non-catalytic in blood and it occurs in multiple forms. Astatistical model based on four kallikrein (4K) markers (free total and intact PSA plus human kallikrein-relatedpeptidase-2 [hK2]) improves specificity in detecting high-grade prostate cancer among men with elevated PSA(reducing unnecessary biopsies) and is also a strong predictor of the risk of lethal prostate cancer decadeslater. While intra-individual fluctuations in PSA levels are common an excessive degree of variability is highlyproblematic as temporary false positive elevations reduce the specificity of PSA as a cancer markerattenuate the diagnostic value of PSA kinetics and lead to the use of unnecessary antibiotics. Less studied butsimilarly abundant in prostatic fluid as PSA the concentration of microseminoprotein- (MSP MSMB) in bloodis inversely associated with prostate cancer risk and a single nucleotide polymorphism (SNP rs10993994) inthe promoter region of the MSMB gene is also associated with prostate cancer risk but the role of thesemarkers in clinical decision-making is unclear. Similarly a SNP in the SERPINA3 gene is significantlyassociated with blood levels of PSA and the encoded protein alpha-1-antichymotrypsin (ACT) is thepredominant stable complexing ligand to PSA in the blood. However the clinical value of these makers isundetermined and it remains unclear whether ACT levels in blood influence the predictive value of a baselinePSA value or affect intra-individual variation in PSA. Additionally the intra-individual variation of the 4K-panelis currently unknown but could be determined using high-quality serial samples. As the role of these differentmolecular markers in combined risk-prediction models of aggressive prostate cancer is not well understood weplan to delineate the influence of intra-individual variability in serial screening samples on clinical decision-making for risk stratification and biopsy by a single PSA value and additional markers. Using blood samplesfrom the PLCO Gteborg-1 & -2 trials and Multiethnic Cohort (MEC) we plan to: 1) quantify the patterns ofvariation in the 4K markers + MSP in serial measurements; 2) determine the relationship between a statisticalmodel based on 4K markers + MSP and subsequent risk of lethal prostate cancer then independently validatethe clinical utility of the markers in decision-making and risk stratification before treatment decisions in arandomized trial of prostate cancer treatments (ProtecT); and 3) compare head-to-head the clinical utility ofpre-biopsy biomarkers versus magnetic resonance imaging on cancer detection rates. The resulting insightswill shed light on how to improve the specificity of prostate cancer screening and early detection. 386067 +No NIH Category available Appointment;Clinical;Collaborations;Core Facility;Development;Development Plans;Education;Educational Curriculum;Eligibility Determination;Exhibits;Faculty;Funding;Goals;Individual;Institution;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of pancreas;Memorial Sloan-Kettering Cancer Center;Mentors;Mentorship;New York City;Pancreas;Peer Review;Physicians;Positioning Attribute;Postdoctoral Fellow;Publications;Qualifying;Recording of previous events;Research;Research Personnel;Research Project Grants;Research Support;Schedule;Scientist;Talents;Therapeutic;Training;Training and Education;Translating;Translational Research;Underrepresented Populations;Universities;Woman;anticancer research;career;career development;clinically relevant;design;diversity and inclusion;health care disparity;inter-institutional;interest;medical schools;meetings;member;programs;recruit;skills;success;symposium;tenure track Career Enhancement Program NARRATIVENot applicable. NCI 10708764 8/15/23 0:00 PAR-20-305 5P50CA257881-02 5 P50 CA 257881 2 "NOTHWEHR, STEVEN F" 9/20/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9871 1865744 "IACOBUZIO-DONAHUE, CHRISTINE A" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 65293 37521 29000 PROJECT SUMMARY/ABSTRACT CEPThe goal of the Career Enhancement Program (CEP) of the MSK Pancreas SPORE is to support and mentorthe most promising and motivated early-career investigators to prepare them for independent careers intranslational research focused on malignancies arising in the pancreas. The CEP leadership team has a strongpublication record a history of successful mentorship and a sustained commitment to education/training. TheCEP will: 1) recruit early-career investigators to the field of translational research in pancreatic cancer to enhancethe overall translational research capability of the SPORE and bring fresh ideas and new talent to our programand 2) provide these individuals the scholarly basis and mentorship needed for effective translational researchin pancreatic cancer. CEP funds supplemented by institutional funds will allow us to support up to twoexceptional candidates each year. Early-career investigators (applied and basic scientists clinicians andphysician-scientists within 2 years of their faculty appointment) with a demonstrated interest in pancreatic cancerresearch from MSK from institutions within the Tri-Institutional Program (Weill Cornell Medical College orRockefeller University) or institutions within and outside of New York City will be eligible to apply.Applications will be peer-reviewed by the CEP/DRP Selection Committee which is composed of the SPOREPIs DRP and CEP Leaders select MSK Departmental and Divisional Chairs and representatives from theMSK Equality Diversity & Inclusion Council. The most promising candidates with the most meritoriousmentored research projects based on defined review criteria will be selected. Special emphasis will be placedon recruiting qualified women and members of underrepresented populations and on projects focused onissues pertaining to health care disparities in pancreatic cancer. CEP awardees will prepare an individualizeddevelopment plan with their clinical and/or laboratory mentor(s) and take part in various educationalprograms conferences and curricula at MSK that support their career development. CEP awardees will havefull access to all SPORE Core facilities and expertise and will be an integral part of monthly SPOREmeetings where they will present their research. CEP recipients will be formally evaluated annually andtraining will be modified when appropriate. Metrics of success for CEP awardees include presentation/publication of original research successful competition for independent research support establishment ofnew collaborations and institutional recognition by academic promotion. +No NIH Category available Award;Clinical Trials;Collaborations;Combined Modality Therapy;Data;Development;Doctor of Philosophy;Eligibility Determination;Extramural Activities;Faculty;Funding;Genomics;Goals;Immunotherapeutic agent;Individual;Institution;Investigation;Islet Cell Tumor;Leadership;Malignant neoplasm of pancreas;Memorial Sloan-Kettering Cancer Center;Outcome;Pancreas;Participant;Patient Care;Peer Review;Pilot Projects;Program Research Project Grants;Publications;Qualifying;Recording of previous events;Request for Proposals;Research;Research Personnel;Research Support;Resources;Translational Research;Underrepresented Populations;United States National Institutes of Health;Universities;Vision;Women's Group;anticancer research;base;biomarker development;clinical care;diversity and inclusion;innovation;medical schools;novel strategies;pancreatic neoplasm;preference;programs;radiomics;stem;success;translational cancer research;translational goal Developmental Research Program NARRATIVENot applicable. NCI 10708758 8/15/23 0:00 PAR-20-305 5P50CA257881-02 5 P50 CA 257881 2 "NOTHWEHR, STEVEN F" 9/20/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9870 7614079 "LEWIS, JASON S." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 108724 62521 48250 PROJECT SUMMARY/ABSTRACT DRPThe goals of the Developmental Research Program (DRP) of the MSK Pancreas SPORE are to expand thebreadth of the translational pancreatic cancer research base and to encourage highly innovative investigationsthat have major potential to impact pancreatic cancer outcomes. DRP funds supplemented by institutional fundswill allow us to support 2 exceptional pilot projects each year. We will request proposals for pilot projects with aclear translational focus and with potential to ultimately impact clinical care of patients with pancreaticneoplasms. Investigators (MD MD/PhD DO or PhD) with a demonstrated history of pancreas cancer researchappointed at MSK or a neighboring institution Weill Cornell Medical College and the Rockefeller University willbe eligible to apply. Applications will be peer-reviewed by the CEP/DRP Selection Committee which iscomposed of the SPORE PIs DRP and CEP Leaders select MSK Departmental and Divisional Chairs andrepresentatives from the MSK Equality Diversity & Inclusion Council. The most meritorious projects based ondefined review criteria will be selected. Preference will be given to projects that advance the long-term researchgoals of the SPORE and have high potential to become full SPORE projects. We will prioritize projects submittedby early-stage investigators and are committed to promoting diversity and strengthening the participation ofwomen and underrepresented groups in translational research. DRP awardees will have full access to SPORECore resources will benefit from the expertise of the SPORE investigative team and will be active participantsin the SPORE. The scientific progress of DRP projects will be evaluated every six months by the DRP Leaders.Long-term metrics of success for DRP awardees include presentation/publication of original research successfulcompetition for independent research support successful development and completion of clinical trials stemmingfrom DRP research establishment of new collaborations and institutional recognition by academicpromotion. DRP projects that make significant progress towards their translational goals will be eligible for asecond year of funding and have the potential to be promoted to full SPORE projects. +No NIH Category available Address;Attention;Bioinformatics;Biological Assay;Biostatistics Core;Clinical Data;Clinical Research;Clinical Trials;Consult;Data;Data Analyses;Data Analytics;Data Set;Dedications;Development;Ensure;Experimental Designs;Formulation;Goals;Graph;Individual;Laboratories;Leadership;Malignant neoplasm of pancreas;Manuscripts;Memorial Sloan-Kettering Cancer Center;Methodology;Methods;Modification;Molecular;Molecular Profiling;Nature;Outcome Assessment;Outcome Study;Pancreas;Population;Preparation;Procedures;Program Research Project Grants;Protocols documentation;Publications;Randomized;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Role;Sample Size;Sampling;Science;Statistical Data Interpretation;Statistical Methods;Validation;Work;analytical method;career;comparison group;computerized data processing;data format;design;experience;human tissue;imaging modality;imaging study;laboratory experiment;member;molecular marker;novel;potential biomarker;predict clinical outcome;predictive marker;primary endpoint;radiomics;research study;secondary endpoint;translational goal;treatment response Biostatistics Core NARRATIVE BIOSTATISTICS COREThe Biostatistics Core will provide investigators of the Memorial Sloan Kettering Cancer Center PancreasSPORE with computational and statistical support for their research efforts including the design and analysis oflaboratory experiments molecular profiling assays clinical trials and imaging studies. Its support is critical forthe successful completion of all research projects in the Pancreas SPORE and will be available to support CareerEnhancement and Developmental Research Program projects. NCI 10708756 8/15/23 0:00 PAR-20-305 5P50CA257881-02 5 P50 CA 257881 2 "NOTHWEHR, STEVEN F" 9/20/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9869 8795308 "CAPANU, MARINELA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 108724 62521 48250 PROJECT SUMMARY/ABSTRACT BIOSTATISTICS COREThe role of the Biostatistics Core is to support the investigators of the Memorial Sloan Kettering Cancer CenterPancreas SPORE in the computational and statistical aspects of their research efforts including the design andanalysis of laboratory experiments clinical trials molecular profiling studies and imaging studies. Prior to theinitiation of all studies Core staff will consult with SPORE investigators to discuss the underlying scientificpremise and translational goals of the project to help the investigators select the most efficient and robustanalytical methods and to estimate sample sizes to ensure adequate power to address study objectives. Inlaboratory experiments Core members will assist in the formulation of the experimental design and in theanalysis and interpretation of the data at the conclusion of the study. For clinical studies Core members will workwith SPORE investigators to outline the major scientific objectives; the population to be studied; primarysecondary and exploratory endpoints; experimental design; analysis plans; and a targeted sample size justifiedin probabilistic terms. At the conclusion of the trial data analyses will be performed to assess the outcomes ofthe study. For molecular studies using human tissues Core members will closely interface with the teammembers performing bioinformatics analysis and will have primary responsibility for merging molecular andclinical data and for performing appropriate statistical and bioinformatics analyses. The members of theBiostatistics Core will also work with SPORE investigators to format data for publication. For imaging studiesCore members will assess the ability of different imaging modalities to localize pancreatic cancer. Imagingstudies and radiomics analysis will also be employed to identify potential biomarkers of response to treatment.As the research studies proceed Core staff will suggest modifications to the design and analysis plans asappropriate. They will also assist investigators with the preparation of any necessary graphs and tables theinterpretation of results the preparation of presentations and manuscripts and will consult on the design ofsubsequent research. If current statistical methodology does not adequately address a research questionalternative methodologies will be developed. The experienced and collaborative Biostatistics Core is wellconfigured to provide the SPORE with a high level of statistical leadership and support that will enhance theefficiency quality and quantitative rigor of its science. +No NIH Category available Adjuvant Therapy;American;Basic Science;Biological Assay;Biological Specimen Banks;Blood;CLIA certified;Cancer Patient;Cell Line;Cell Survival;Clinical;Collaborations;Collection;Consent;Databases;Diagnosis;Documentation;Effectiveness;Enrollment;Ensure;Evaluation;Excision;Formalin;Freezing;Generations;Genomics;Goals;Heterogeneity;Human;Immunohistochemistry;Infrastructure;Institution;Laboratories;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Memorial Sloan-Kettering Cancer Center;Microdissection;Microscopic;Molecular Analysis;Morphology;Mutation;Neoadjuvant Therapy;Normal tissue morphology;Organoids;Pancreas;Pancreatic Ductal Adenocarcinoma;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patient-Focused Outcomes;Patients;Plasma;Play;Protocols documentation;Quality Control;Randomized Controlled Trials;Recording of previous events;Reproducibility;Research;Research Personnel;Research Project Grants;Resistance;Resources;Role;Sampling;Serum;Services;Specimen;Standardization;System;Techniques;Therapeutic Research;Tissue Banks;Tissue Microarray;Tissue Sample;Tissues;Translational Research;Treatment Protocols;Tumor Tissue;Work;adjudication;anticancer research;biobank;cancer cell;college;cost effective;data quality;design;diagnostic value;exome sequencing;follow-up;human tissue;laser capture microdissection;molecular diagnostics;molecular oncology;mouse model;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;participant enrollment;peripheral blood;programs;prospective;quality assurance;relational database;response;single cell sequencing;treatment response;tumor Biospecimen Core NARRATIVE BIOSPECIMEN COREThe Biospecimen Core will support the work of the Memorial Sloan Kettering Cancer Center (MSK) PancreasSPORE by playing a critical role in the collection annotation and storing of all tumor samples and blood frompatients with pancreatic neoplasms enrolled in research protocols at MSK. The core will provide centralizedexpertise in pathological diagnosis tissue selection for molecular analysis and interpretation of ancillarytechniques to assist the translational research goals of the SPORE investigators. NCI 10708755 8/15/23 0:00 PAR-20-305 5P50CA257881-02 5 P50 CA 257881 2 "NOTHWEHR, STEVEN F" 9/20/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9868 11613502 "BASTURK, OLCA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 108723 62520 48250 PROJECT SUMMARY BIOSPECIMEN COREThe Biospecimen Core is designed to provide expert support to the translational research efforts of theMemorial Sloan Kettering Cancer Center (MSK) Pancreas SPORE. The Core will leverage and extend the veryactive tissue banking program and molecular diagnostics capabilities of the MSK Precision PathologyBiobanking Core (PPBC) which anchors 4 other MSK SPOREs and the MSK Center for Pancreatic CancerResearch. The SPORE Biospecimen Core will play an essential role in collection annotation storagedistribution and tracking of pancreatic cancer biospecimens (tissue and blood) from patients enrolled ininstitutional biospecimen banking protocols and therapeutic research protocols. Detailed biospecimenannotation including documentation of preanalytic processing variables pathology findings and patient clinicalhistory information will be recorded in robust relational databases. We will conduct rigorous data qualityassurance and quality control measures and standardized longitudinal follow-up of all consented patients withmaterials in the pancreatic cancer biospecimen repository. The Core will also provide SPORE investigatorswith expert histopathological evaluation of tumor samples as well as assistance in performing and interpretingimmunohistochemical assays selecting tissue for microdissection for downstream analysis constructing tissuemicroarrays and facilitating patient-derived organoid creation. The specific aims of the core are to (1) maintainand expand the collection annotation and storage of biospecimens for pancreatic cancer research (2) performsystematic pathologic evaluation of all relevant ductal pancreatic adenocarcinoma samples and to prepareappropriate biospecimens for use by SPORE investigators and (3) provide systematic microscopicassessment of response to therapy. Given the significant heterogeneity of pancreatic cancers each of theseaims requires expertise beyond what existing resources can provide underscoring the need for this Core. Allof the research projects will rely extensively on the Biospecimen Core to achieve their translational researchobjectives. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;Albumins;Antitumor Response;Biological Markers;Biology;CD8-Positive T-Lymphocytes;Cancer Patient;Canis familiaris;Cell Density;Cells;Clinic;Clinical;Clinical Trials;Coculture Techniques;Combined Modality Therapy;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Drug Delivery Systems;Drug Kinetics;Drug Targeting;Genetic Transcription;Half-Life;Human;Immunity;Immunologics;Immunotherapy;Infiltration;Interleukins;Knowledge;Laboratory Study;Lead;Life Extension;Liver;Lung;Lymphocyte;Lymphoid Cell;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Memorial Sloan-Kettering Cancer Center;Metastatic Adenocarcinoma;Modeling;Molecular;Morals;Mus;Nature;Neoplasm Metastasis;Organoids;PD-1 blockade;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Peritoneum;Pharmaceutical Preparations;Pharmacology;Phenotype;Pre-Clinical Model;Primary Neoplasm;Proteins;Recombinant Interleukins;Recombinants;Reporter;Resistance;Safety;Sampling;Signal Transduction;Site;Specimen;Survivors;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Tissues;Toxicology;Translating;Translations;Tumor Expansion;Tumor Immunity;Work;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;biomarker driven;biomarker identification;cancer immunotherapy;cancer therapy;checkpoint inhibition;chemokine;clinic ready;cohort;cytokine;cytotoxicity;design;first-in-human;immune checkpoint;inhibiting antibody;lymph nodes;molecular subtypes;mouse model;neoplastic cell;novel;novel strategies;novel therapeutics;pre-clinical;programmed cell death protein 1;rare cancer;receptor;recruit;refractory cancer;response;transcriptomics;tumor;tumor growth;tumor-immune system interactions Recombinant Interleukin-33 Immunotherapy for Pancreatic Cancer NARRATIVE RP3As all current immunotherapies fail in pancreatic cancer new approaches are needed. We have discovered thatinterleukin-33 (IL33) is a novel effective pancreatic cancer immunotherapy in preclinical models. We will nowdevelop an IL33 drug identify target patient cohorts and mechanisms of action and launch a first-in-humanclinical trial. NCI 10708752 8/15/23 0:00 PAR-20-305 5P50CA257881-02 5 P50 CA 257881 2 "NOTHWEHR, STEVEN F" 9/20/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 8036 9594184 "BALACHANDRAN, VINOD P" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 542269 312078 240410 PROJECT SUMMARY RP3Immunotherapies can induce durable responses in advanced cancer patients and are the most exciting newcancer treatments. However as current immunotherapies directly reinvigorate preexisting anti-tumor T cellsthey are ineffective in T cell-poor (cold) cancers such as pancreatic ductal adenocarcinoma (PDAC). Newimmunotherapies that stimulate de novo immunity are therefore needed for PDAC. To identify such strategieswe discovered that compared to the majority of PDACs that are T-cell poor and cold T-cell rich hot tumorsfrom rare long-term PDAC survivors are infiltrated by higher densities of group 2 innate lymphoid cells (ILC2s)a recently discovered lymphocyte with tissue-specific anti-tumor function. Higher densities of tumor ILC2s andhigher expression of the ILC2-activating cytokine interleukin-33 (IL33) correlated with higher CD8+ T cell densitygreater T cell cytolytic activity and 2-fold longer survival in human PDAC. Using PDAC mouse models we foundthat systemic delivery of recombinant IL33 (rIL33) activated tumor ILC2s to produce the chemokine Ccl5 recruitintratumoral dendritic cells amplify intratumoral CD8+ T cells 10-fold and restrict tumor growth. In addition likeactivated T cells rIL33-activated ILC2s upregulated the inhibitory immune checkpoint PD-1 and combining rIL33with PD-1 antibody blockade maximally restricted tumor growth and prolonged survival in PDAC mouse models.Thus our laboratory studies identify rIL33 as a novel therapeutic cytokine that stimulates de novo anti-tumorimmunity in PDAC both as a mono- and as a combination therapy with PD-1 blockade. However as there arecurrently no drugs that target the IL33-ILC2 axis and as human PDAC tumors are immunologicallyheterogeneous the appropriate drug delivery strategy and target patient cohorts to rationally translate thesefindings to PDAC patients are unknown. We will address these key knowledge gaps through three specific aimsto determine if rIL33 has anti-tumor efficacy (1) in immunologically heterogeneous PDAC molecular subtypes(2) in immunologically heterogeneous PDAC primary tumors and metastases and (3) as half-life extended clinic-compatible drugs. We will complete these aims and thereby establish the principles to translate rIL33 to patientsusing mechanistic studies in orthotopic PDAC mice deficient in components of the IL33-ILC2 axis patient-derivedorganoid models of the tumor immune microenvironment cellular and transcriptional analyses of matched multi-site human PDAC primary tumors and metastases and IND-enabling toxicology studies. Through these studieswe will identify the target patient cohorts the mechanisms of action and the optimal drug to inform the design ofa first-in-human rIL33 clinical trial in PDAC patients by the end of the study period. This work will thereforecritically expand our knowledge of preclinical and translational biology of the novel IL33-ILC2 therapeutic axisaccelerate its translation to patients and address the unmet need for effective PDAC immunotherapy. +No NIH Category available Administrator;Authorization documentation;Clinical;Collaborations;Communication;Communities;Data;Decision Making;Development;Doctor of Philosophy;Education;Ensure;Fostering;Genomics;Goals;Grant;Human Resources;Infrastructure;Institution;Link;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Manuscripts;Medical;Memorial Sloan-Kettering Cancer Center;Molecular;Monitor;National Cancer Institute;Occupational activity of managing finances;Office of Administrative Management;Pancreas;Principal Investigator;Program Research Project Grants;Publications;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Services;Training;Translational Research;United States National Institutes of Health;Work;authority;career;compliance behavior;data management;editorial;experience;meetings;member;operation;patient privacy;programs;scientific organization;sound Administrative Core NARRATIVENot applicable. NCI 10708745 8/15/23 0:00 PAR-20-305 5P50CA257881-02 5 P50 CA 257881 2 "NOTHWEHR, STEVEN F" 9/20/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9864 1865744 "IACOBUZIO-DONAHUE, CHRISTINE A" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 167852 96557 74457 SUMMARY/ABSTRACT ADMINISTRATIVE COREThe Administrative Core will support the translational research objectives of the Memorial Sloan Kettering CancerCenter (MSK) Pancreas SPORE by providing: (1) centralized administrative support of the daily activities of theSPORE Program and (2) coordination for all educational and scientific activities of the SPORE including threeresearch projects two cores a Developmental Research Program (DRP) and a Career Enhancement Program(CEP). This work will be performed under the direction of the SPORE Principal Investigators Christine Iacobuzio-Donahue MD PhD and Eileen M. OReilly MD who will share overall authority for the scientific andadministrative decision-making. The Administrative Core will also include a team of experienced personneltrained in financial management operations grants administration medical editing and data management.Administrative Core members will work as a team to ensure the effective financial and administrativemanagement of the SPORE. The Administrative Core will be responsible for financial management submissionof all reports and non-competing renewal applications to the NIH/NCI coordination of the DRP and CEP andcoordination of meetings for consistent scientific review of ongoing SPORE research. The Core will also beresponsible for annual solicitation of new applications for the DRP and CEP as well as fostering communicationand collaborative research within our SPORE with other SPOREs in Pancreas or Gastrointestinal Cancers andthe wider scientific community and sharing genomic and other molecular data and linked clinical annotation ina manner that assures patient privacy and compliance with all Federal and State regulations. The centralizedservices of the Administrative Core will ensure the effective financial and administrative management of theSPORE. +No NIH Category available Adipocytes;Adipose tissue;Advanced Malignant Neoplasm;Atlases;Biological Assay;Biopsy;Blood;Blood Vessels;Body Weight;Body Weight decreased;Cancer Etiology;Cancer Patient;Cardiac;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;Complex;Development;Eating;Event;FDA approved;Family;Fractionation;Genetic Models;Human;Immune;In Vitro;Inflammation;Inflammatory;Institutional Review Boards;Interleukin-6;Knockout Mice;LIF gene;Lipase;Lipids;Lipolysis;Malignant Neoplasms;Metabolic;Modeling;Molecular;Molecular Target;Mus;Muscular Atrophy;Pathway interactions;Patients;Peripheral;Phenotype;Phosphorylation;Play;Process;Protocols documentation;Quality of life;Recombinants;Regimen;Regulation;Resolution;Role;STAT3 gene;Sampling;Signal Pathway;Signal Transduction;Syndrome;TNF gene;Thinness;Triglycerides;adipokines;allotransplant;cancer cachexia;cancer survival;cellular targeting;cytokine;ghrelin;improved;inhibitor;leukemia inhibitory factor receptor;mouse model;new therapeutic target;programs;sarcopenia;single molecule;transcriptome;tumor;wasting Identifying the Cellular and Molecular Targets of JAK/STAT-Driven Adipose Wasting to Reverse Cancer Cachexia Adipose inflammation plays a significant role in the wasting of cancer cachexia but is poorly understood. In thisproposal we will dissect the cellular and molecular contributors to a JAK-dependent Tumor-Cytokine-AdiposeAxis that increases lipolysis and subsequent wasting in cancer cachexia. Validating this axis in longitudinalcancer patient samples and optimizing inhibition of this axis will improve cancer cachexia patient quality of lifeand survival. NCI 10708737 8/28/23 0:00 PA-20-185 5R01CA266900-02 5 R01 CA 266900 2 "PERLOFF, MARJORIE" 9/22/22 0:00 8/31/27 0:00 Tumor Cell Biology Study Section[TCB] 12664042 "INFANTE, RODNEY E" "IYENGAR, PUNEETH " 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 528437 NCI 322218 206219 ABSTRACT/NARRATIVECancer cachexia (CCX) wasting of muscle and/or adipose is associated with 20-30% of all cancer relateddeaths.1 Our clinical studies have shown that the presence of CCX is associated with a 50% decrease in mediansurvival (14 months vs 28 months p<0.001) independent of tumor-directed therapies.2-3 There are no FDA-approved CCX regimens with a majority of trials focused on limiting sarcopenia. Using multiple establishedmurine CCX mouse models we consistently observed significant adipose tissue loss compared to muscleatrophy. Furthermore blocking adipocyte lipolysis using global lipase null mice limited both adipose wasting andsarcopenia in murine models of CCX. Understanding upstream mechanisms cancers use to provoke adiposelipolysis and wasting could offer novel therapeutic targets to reverse CCX syndrome. The complex intracellular (stromal vascular immune and adipocyte) interactions within adipose tissueultimately regulate CCX wasting by altering the relative signals of adipocyte triglyceride lipolysis and synthesis.To understand the convergence of these interactions we developed an in vitro CCX adipocyte assay to screensecreted factors from CCX lines that increase adipose inflammation and wasting by inducing adipocyte lipolysisand identified the cytokine leukemia inhibitory factor (LIF).5 Through the JAK-dependent inflammatoryreprogramming of adipose tissue in mice recombinant LIF caused a decrease in adipose mass by >50% leanmass and body weight by >10% recapitulating CCX. LIF also altered the adipose expression and systemiclevels of other cyto/adipokines to amplify this inflammation and alter food intake. Use of JAK inhibitors in murineCCX models led to decreased adipose inflammation (decreased STAT3 phosphorylation) adipocyte lipolysisand adipose/muscle wasting all increasing survival. To understand the contributions of adipose intracellularsignaling in the regulation of CCX adipose inflammation we selectively silenced the LIF receptor (LIFR) orSTAT3 in adipocytes. Both mouse models doubled their adipose mass compared to littermate controls duringdevelopment highlighting an inverse CCX phenotype. When allotransplanted with CCX tumors both models stilldemonstrated adipose inflammation with persistent STAT3 phosphorylation resulting in a partial suppression ofCCX and defining the non-adipocyte cellular contributions of adipose to CCX wasting. FACS analysis verifiedlongitudinal enrichment of immune cells during CCX progression offering additional tumor/cytokine targetssupporting CCX adipose inflammation and wasting. We hypothesize that CCX adipose inflammation occurs viaa JAK-dependent Tumor-Cytokine-Adipose Axis that reprograms adipose through JAK/STAT signaling ofmultiple cellular subtypes to increase adipocyte lipolysis and alter secretion of cyto/adipokines resulting inwasting. SA1-2 will dissect the multiple cellular/molecular signaling components of this axis facilitating adiposeinflammation in support of this CCX wasting. SA3 will validate associations between JAK/STAT signaling eventsin human adipose to CCX induction in patients. 528437 +No NIH Category available Applications Grants;Award;Basic Science;Biometry;California;Cancer Biology;Cancer Etiology;Clinic;Clinical;Clinical Trials Design;Collaborations;Department chair;Development;Development Plans;Diagnosis;Disabled Persons;Discipline of obstetrics;Doctor of Philosophy;Early Diagnosis;Education;Educational Status;Ethics;Extramural Activities;Faculty;Feedback;Financial Support;Fostering;Funding;Gynecology;Image;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of pancreas;Medicine;Mentors;Minority;Nebraska;North Carolina;Outcome;Pancreas;Patient Care;Population Sciences;Prevention;Professional Competence;Research;Research Personnel;Research Support;System;Training;Translational Research;Universities;Washington;Woman;anticancer research;career;career development;improved;multidisciplinary;next generation;novel strategies;novel therapeutic intervention;pancreatic cancer patients;peer;programs;recruit;research and development;skills training;success;synergism Career Enhancement Program PROJECT NARRATIVEContinued improvement in outcomes for pancreatic cancer patients requires recruitment and support of newindependent investigators in the field of translational pancreatic cancer research. To accomplish this objectivethe CEP will provide financial support didactic training and mentored research opportunities to promotemultidisciplinary translational research as well as diversity through the recruitment of women minority anddisabled faculty. NCI 10708580 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9848 1938279 "GILLANDERS, WILLIAM E." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 179655 115534 64121 PROJECT SUMMARYThe SPORE in Pancreatic Cancer Career Enhancement Program (CEP) aims to recruit and support newindependent investigators in translational pancreatic cancer research. Along with the Developmental ResearchProgram (DRP) the CEP will provide financial support didactic training and mentored research opportunities toprepare investigators for independent careers in translational pancreatic cancer research. The CEP will extendcurrent efforts to promote diversity in pancreatic cancer research through recruitment of women minority anddisabled faculty. We propose the following specific aims:Specific Aim 1: Recruit and support new investigators in translational pancreatic cancer research. Inaddition to the NCI funds a total of $323000 in institutional support is committed in support of the CEP program.CEP awards will provide $75K per year for 2 years. Awardees will be junior faculty beginning their researchcareers or transitioning into translational pancreatic cancer research. Funded initiatives are expected to have amajor translational component and focus on pancreatic cancer etiology prevention diagnosis early detectiontreatment or population science.Specific Aim 2: Train and mentor junior faculty in translational pancreatic cancer research. All CEPawardees will be mentored by both a senior basic science and clinical mentor and will craft an individualizedcareer development plan that includes didactic coursework patient care and career skills training. We willleverage institutional educational opportunities to include courses in clinical trial design biostatistics and ethics.The SPORE CEP Steering Committee will track and evaluate CEP awardees research and career development.Specific Aim 3: Foster inter-SPORE collaborations. An educational exchange with our peer Pancreatic or GISPORE institutions (University of Nebraska Mayo Clinic John Hopkins University of North Carolina Universityof California System) allows CEP awardees to present their research receive expert feedback meet peerSPORE leadership and develop collaborations. Content experts from peer SPORE institutions will performcritical reviews and provide formal feedback for CEP awardees extramural grant applications.Specific Aim 4: Promote participation of women minority and disabled investigators in pancreaticcancer research. Diversity Advisor Bettina Drake PhD MPH will guide recruitment training and retention ofwomen minority and disabled investigators in pancreatic cancer research at all training levels. We have alsoadded two diversity advisors to the Internal Advisory Board (IAB) to synergize the SPORE efforts with the WUSMwide initiative to hire and retain faculty of diverse backgrounds underrepresented in medicine.Relevance: These aims will support research the next generation of PDAC researchers and project to improveour understanding of pancreatic cancer biology and develop new therapeutic approaches +No NIH Category available Area;Award;Cancer Biology;Cancer Research Project;Clinical;Clinical Trials;Collaborations;Development;Disabled Persons;Early Diagnosis;Epidemiology;Extramural Activities;Faculty;Fostering;Funding;Future;Goals;Grant;Group Meetings;Image;Institution;Malignant Neoplasms;Malignant neoplasm of pancreas;Mentors;Minority;Minority Groups;Minority Recruitment;Peer Review;Prevention;Program Research Project Grants;Refractory;Research;Research Personnel;Research Project Grants;Translating;Translational Research;Underrepresented Minority;Universities;Washington;Woman;Work;Writing;anticancer research;cancer prevention;career;design;improved;innovation;meetings;minority investigator;pancreas development;pancreatic cancer patients;programs;recruit;success Developmental Research Program PROJECT NARRATIVEThe Developmental Research Program (DRP) will recruit and support innovative early stage research inpancreatic cancer. NCI 10708579 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9847 8182718 "FIELDS, RYAN C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 230194 148035 82159 PROJECT SUMMARYThe goal of the SPORE in Pancreatic Cancer Developmental Research Program (DRP) is to recruit and supportdevelopmental research projects in pancreatic cancer for future incorporation as full SPORE projects or as thebasis for applications for other nationally competitive peer-reviewed funding. The types of pancreatic cancerresearch projects that will be supported include basic translational clinical epidemiologic and cancerprevention. Projects supported under the DRP will expand the scope of translational research and increase thenumber of investigators committed to pancreatic cancer research. The DRP is open to institutions participatingin the SPORE (WUSM UPenn) and any of their collaborators. The DRP will work in tandem with the CareerEnhancement Program (CEP) to assist in developing junior investigators and recruiting/mentoring minorityinvestigators. These objectives will be accomplished by performing four specific aims.Aim 1: Support the development of pancreatic cancer research projects for future incorporation as fullSPORE projects or for new independent peer-reviewed funding. The DRP will solicit new research projectsannually. In addition to NCI funds a total of $375000 in institutional support has been committed in support ofthe DRP. DRP awards will provide up to $75000 for 1 year with a competitive renewal allowed for a secondyear of funding. Two to three awards per year are anticipated. Institutional funds will make the NCI funds($25000/year) committed to underrepresented minorities equivalent to other DRP awards.Aim 2: Foster collaborations between basic and clinical researchers. The DRP directors will facilitateinteractions between basic and clinical researchers through shared weekly meetings the annual SPORE retreatand small group meetings.Aim 3: Mentor junior faculty and new faculty involved in pancreatic cancer research. All investigatorssubmitting applications to the DRP will receive a written scientific and statistical review and the DRP directorswill be available to discuss the projects in detail. Where appropriate mentors will be identified to work with juniorfaculty or collaborate with faculty whose primary research area is outside of pancreatic cancer. All DRP awardeeswill present their research progress to the SPORE steering committee twice per year.Aim 4: Promote the participation of women minorities and disabled investigators in pancreatic cancerresearch and facilitate the recruitment of minorities into clinical pancreatic cancer trials. The DRPdirectors will implement initiatives that enhance the participation of women minorities and disabled persons inSPORE clinical trials and promote the participation of diverse groups in pancreatic cancer research.Impact: The proposed work will improve our understanding of pancreatic cancer biology and will identify newstrategies for early detection prevention imaging and treatment for this refractory malignancy. +No NIH Category available Adverse event;Bioinformatics;Biometry;Cancer Center;Clinical Cancer Center;Clinical Trials;Collaborations;Computing Methodologies;Consult;Consultations;Data;Data Analyses;Data Collection;Data Set;Databases;Development;Ensure;Genomics;High Performance Computing;Malignant neoplasm of pancreas;Output;Pancreas;Quality Control;Reporting;Reproducibility;Research;Research Design;Research Personnel;Resource Sharing;Role;Statistical Methods;Statistical Study;System;Tissue Sample;Training;Universities;Visualization;Washington;Work;anticancer research;bioinformatics pipeline;bioinformatics tool;career;data integration;data management;data sharing;design;epidemiology study;experience;genomic data;laboratory experiment;medical schools;meetings;member;multidimensional data;programs Core C: Biostatistical and Bioinformatics Core PROJECT NARRATIVEThe development and application of new computational methodology for cancer research has expanded rolesfor statisticians and computational experts. The Biostatistics and Bioinformatics Core provides the statisticalbioinformatics and computational support for all SPORE in Pancreatic Cancer investigators. Core C will supportconsultation and collaboration on all aspects of study design database development and quality control anddata analysis interpretation and presentation of data. NCI 10708578 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9846 2110411 "COLDITZ, GRAHAM A." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 225881 145261 80620 PROJECT SUMMARYThe Biostatistics and Bioinformatics Core (Core C) facility will provide study design pipeline development datamanagement and computational support for all SPORE in Pancreas investigators and projects. The Biostatisticscomponent of the Core will perform consultation and collaboration on all aspects of statistical study designdatabase development and quality control and data analysis and interpretation. The Bioinformatics componentof the Core will perform consultation and collaboration on all aspects of genomics and bioinformatics studydesign pipeline development omics data integration visualization interpretation and genomic data sharingthrough controlled access systems. Core C will provide bioinformatics and biostatistics collaborations for SPOREprojects Developmental Research Program (DRP) studies and other Cores to ensure that robust statisticalmethods and robust reproducible omics analyses are available to support SPORE investigators. Core C will alsoprovide bioinformatics and biostatistical support and training to junior investigators through the CareerEnhancement Program (CEP). The Biostatistics and Bioinformatics components of Core C will work togetherclosely to ensure their efforts are integrated and complementary. +No NIH Category available Adenocarcinoma Cell;Aftercare;Attention;Biological Models;Biological Specimen Banks;Biology;Biopsy;Blood;Cancer Biology;Cancer Center;Clinical;Clinical Data;Collaborations;Collection;Communities;Consent;Cryopreservation;DNA amplification;Data;Databases;Dedications;Detection;Diagnosis;Disease;Enrollment;Ensure;Epidemiology;Evolution;Freezing;Funding;Future;Genomic DNA;Genomics;Goals;Grant;Harvest;Immune system;Immunologics;Informatics;Institution;Institutional Review Boards;Investigation;Lesion;Liquid substance;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Metadata;Molecular;Newly Diagnosed;Normal tissue morphology;Operative Surgical Procedures;Organoids;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Pathologic;Pathologist;Pathology;Patient-Focused Outcomes;Patients;Peripheral Blood Mononuclear Cell;Plasma;Population;Prevention;Process;Proteins;Protocols documentation;Quality Control;RNA;Radiation;Research;Research Personnel;Resected;Resource Informatics;Resources;Sampling;Science;Serum;Solid;Solid Neoplasm;Source;Specimen;Testing;Time;Tissue Banks;Tissue Expansion;Tissue Procurements;Tissues;Transcript;Translational Research;Tumor Bank;Tumor Biology;Tumor Cell Line;Tumor Tissue;Universities;Urine;Washington;Xenograft procedure;anticancer research;biobank;bioinformatics infrastructure;biomedical informatics;cancer cell;cell free DNA;chemotherapy;clinical database;cohort;follow-up;improved;in vivo Model;individual patient;medical schools;neoplasm resource;neoplastic cell;novel strategies;pancreatic cancer patients;patient derived xenograft model;peripheral blood;premalignant;preservation;programs;prospective;research study;sample collection;success;therapy resistant;tissue culture;tissue processing;tissue registry;treatment response;tumor;tumor microenvironment;whole genome Core B: Biospecimen Core PROJECT NARRATIVEThe biospecimen core will support the proposed SPORE projects that will lead to both an improvedunderstanding of the pathogenesis and new approaches for the detection prevention and treatment ofpancreatic ductal adenocarcinoma. NCI 10708577 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9845 8182718 "FIELDS, RYAN C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 244765 162384 82381 PROJECT SUMMARYThe controlled collection and processing of clinical specimens from patients with pancreatic ductaladenocarcinoma (PDAC) is a critical activity for an efficient and comprehensive program in translational researchin the context of a SPORE grant. Accordingly the Biospecimen Core (Core B) has one overarching aim: We willcollect store process and distribute biospecimens from patients with a diagnosis of PDAC seen at this institutionto facilitate biospecimen-based translational research: We will collect malignant cell populations from tumors(from pre-surgical and surgical biopsies). We will also collect normal pancreas pre-malignant pancreatic lesionsand peripheral blood from PDAC patients. Serum and plasma will be collected for correlative and future studies.Specimens will be collected throughout each patient's disease course (initial presentation pre-treatment post-treatment/follow-up) and where appropriate archival specimens from previous biopsies/etc. will be retrieved.Particular attention to specimen procurement (e.g. rapid processing of tissue to preserve transcript profiles) andquality control will be practiced. Specimens will be processed to cellular RNA genomic DNA whole genomeamplified DNA and protein extracts as required for each study. We will also collect longitudinal patient cell-freeDNA samples for downstream analysis. Cellular populations will also be viably frozen or immediately processedfor patient-derived xenograft and/or organoid creation. Importantly we will ensure that all specimens used forresearch are extensively and accurately annotated with clinical (pre-treatment treatment and follow-up) dataand metadata utilizing the bioinformatics infrastructure at our institution. Expert pathologic review from adedicated GI pathologist will ensure high-quality annotation. The aims of this Core will be accomplished bycontinuing the scope of our well-established Cancer Center Tumor Bank and prior PDAC SPORE Core Bsuccesses and an on-going funded effort to collect solid gastrointestinal malignancies at our institution.Specifically Core B will expand the number of PDAC patients from whom biospecimens will be collected andserve as a conduit (through data and specimen sharing) to allow for a broader variety of translational researchstudies in PDAC malignancies using new and previously banked biospecimens. +No NIH Category available Ablation;Aftercare;Animal Model;Autoimmune Diseases;Autophagocytosis;Blood specimen;Cachexia;Cell Death;Cells;Cessation of life;Chemotherapy-Oncologic Procedure;Clinic;Clinical;Clinical Research;Clinical Trials;Combination Drug Therapy;DNA;Development;Diagnosis;Disease;Dizziness;Dose;Ensure;Enzymes;Exhibits;Exposure to;Fibrosis;Fluorouracil;Future;Genetic;HSPB1 gene;Headache;Human;Immune;Immunohistochemistry;Immunologics;Immunologist;Immunotherapeutic agent;Immunotherapy;Inflammatory Response Pathway;Infrastructure;Institution;KPC model;Knockout Mice;Lead;Leucovorin;MAPKAPK2 gene;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mediator;Mitogen-Activated Protein Kinases;Mus;Oncology;Operative Surgical Procedures;Oral;Pancreatic Ductal Adenocarcinoma;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phenotype;Phosphotransferases;Physicians;Predisposition;Prognosis;Protein Array Analysis;Protein Kinase;Publishing;Recommendation;Records;Regimen;Reporting;Research;Resistance;Resistance development;Rheumatoid Arthritis;Safety;Sampling;Scientist;Signal Transduction;Stress;TNF gene;Techniques;Testing;Toxic effect;Translational Research;Treatment Efficacy;Treatment-related toxicity;Tumor Immunity;Tumor-associated macrophages;Tumor-infiltrating immune cells;Universities;Washington;Work;anti-cancer;autocrine;biological adaptation to stress;cancer cell;chemotherapy;clinical trial protocol;combinatorial;conditional knockout;cytokine;effector T cell;experience;gastrointestinal;improved;inhibitor;investigator-initiated trial;irinotecan;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;oxaliplatin;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pre-clinical;preclinical efficacy;prevent;resistance mechanism;response;safety assessment;safety testing;single-cell RNA sequencing;targeted treatment;therapy outcome;translational medicine;treatment response;tumor;tumorigenic Project 3: Targeting Stress-induced MK2 as Novel Strategy in Pancreatic Cancer PROJECT NARRATIVEExtreme resistance to chemotherapy is one of the major factors that underlies the poor prognosis of pancreaticcancer. Using an unbiased protein array analysis we have identified a novel mechanism of resistance governedby MK2 kinase that when overcome renders chemotherapy effective. In this study we propose to conduct aphase 1 clinical trial combining a novel MK2 inhibitor ATI-450 with FOLFIRINOX chemotherapy for patients withmetastatic pancreatic cancer and to develop a novel immunotherapeutic strategy that can be tested in the future. NCI 10708576 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9844 12479630 "LIM, KIAN H" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 359091 230927 128164 PROJECT SUMMARYWe propose a phase 1 clinical trial to test the safety and preliminary efficacy of a new therapeutic strategy thataims at augmenting the efficacy of standard chemotherapy in pancreatic cancer. To date combinationchemotherapies remain the mainstay treatment of pancreatic cancer. FOLFIRINOX is a combinationchemotherapy regimen with the best track record for treatment of pancreatic cancer that cannot be treated withsurgery; however even with the best treatment the majority of the patients will still succumb to the diseasewithin one to two years of diagnosis. This is in part due to pancreatic cancer cells developing resistance to thechemotherapy drugs. Another reason for poor survival and unsuccessful clinical experience of immunotherapyis because of the dense non-cancer cells that surround the pancreatic cancer not only prevent the chemotherapydrugs from reaching the cancer cells but also incapacitate anti-tumor immune cells. These challenges supportthe need for further research into overcoming resistance to combination chemotherapy and improving the effectof immunotherapy in pancreatic cancer.Using an unbiased protein array analysis we found that pancreas cancer cells dramatically upregulate MK2enzyme and its partnering molecule Hsp27 when exposed to FOLFIRINOX chemotherapy. Both MK2 and Hsp27protect pancreas cancer cells from cell death when their DNA is hit by chemotherapy. When MK2 was blockedby ATI-450 pancreatic cancer cells became much more vulnerable to chemotherapy-induced death. In anaggressive pancreas cancer mouse model (KPC mice) the combination of ATI-450 plus FOLFIRINOX potentlyablated the cancer an observation that to our best knowledge has not been reported. Furthermore ATI-450causes immune cells surrounding the cancer to be converted to the types that were more susceptible toimmunotherapy paving the way for development of an immunotherapy regimen which we will establish in thisproposal. Importantly ATI-450 is now already in clinical trial for patients with moderate to severe rheumatoidarthritis and is very well-tolerated except for infrequent mild dizziness and headaches which lessens ourconcerns of added toxicities when combined with FOLFIRINOX.In this proposal we will conduct a phase I clinical trial to establish the safety of combining ATI-450 withFOLFIRINOX in patients with inoperable pancreatic cancer (Aim 1). We will determine a safe tolerable dose ofATI-450 in combination with FOLFIRINOX and get an early indication on whether this combination is moreeffective than FOFIRINOX alone. We plan to obtain tumor and blood samples in patients who are receiving ATI-450 and FOLFIRINOX on this trial and analyze those to confirm that the addition of ATI-450 was useful toovercome the resistance to FOLFIRINOX and changed the immune cells surrounding the cancer as it did inanimal models (Aim 2). Lastly we made discovery that MK2 activates anti-cancer immunity. By analyzing patientsamples treated with MK2 inhibitor and generating new state-of-the art genetic mouse models we will investigatethe mechanism and develop a novel MK2 inhibitor-based immunotherapy strategy for pancreatic cancer (Aim3). +No NIH Category available Address;Adjuvant Chemotherapy;Agonist;Algorithms;Biology;Biomedical Research;CD8B1 gene;Clinical Trials;Clinical Trials Design;Correlative Study;Coupled;DNA Vaccines;Data;Development;Dimensions;Enrollment;FLT3 ligand;Functional disorder;Funding;Generations;Human;Immune response;Impairment;Licensing;Malignant Neoplasms;Malignant neoplasm of pancreas;Neoadjuvant Therapy;Operative Surgical Procedures;Pathway interactions;Patients;Peptide Vaccines;Phase I Clinical Trials;Pre-Clinical Model;Publishing;Resistance;Role;Signal Transduction;Software Tools;Specimen;Synthetic Antigens;T cell receptor repertoire sequencing;T cell response;T-Lymphocyte;TNFRSF5 gene;Testing;Therapeutic;Tumor Immunity;Tumor Tissue;Universities;Vaccination;Vaccine Design;Vaccine Therapy;Vaccines;Washington;anti-PD1 antibodies;anti-tumor immune response;antigen-specific T cells;cancer immunobiology;cancer immunotherapy;early phase clinical trial;exhaustion;functional improvement;functional status;improved;in vivo;innovation;manufacture;neoantigen vaccine;neoantigens;pancreatic ductal adenocarcinoma model;patient population;peripheral blood;pre-clinical;predict clinical outcome;resistance mechanism;response;restraint;safety assessment;single-cell RNA sequencing;success;translational study;trial design;tumor;tumor microenvironment;vaccine platform Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC PROJECT NARRATIVECancer neoantigens are important targets of cancer immunotherapy. Neoantigen vaccines have generatedgreat enthusiasm as a potential safe and effective strategy to induce/enhance the immune response topancreatic cancer. We have obtained funding to test optimized neoantigen vaccines in a window trial inpancreatic cancer and propose preclinical and human translational studies to assess the mechanisms ofresponse and resistance to neoantigen vaccines in pancreatic cancer. NCI 10708575 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9843 6331590 "HAWKINS, WILLIAM G" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 336881 216644 120237 ABSTRACTWe have made important contributions to the immunobiology of cancer neoantigens and have developed arobust publically available and frequently downloaded suite of software tools for neoantigen prediction. Withsupport from our previous SPORE in Pancreatic Cancer and SU2C we have now completed enrollment to twophase 1 clinical trials in PDAC testing neoantigen DNA vaccines (NCT03122106) and synthetic long peptide(SLP) vaccines (NCT03956056). Preliminary analyses confirm that both neoantigen vaccine platforms caninduce robust immune responses and suggest that PDAC patients treated with neoantigen vaccines havebetter than predicted clinical outcomes. We recently developed algorithms for the prioritization of class IIneoantigens and demonstrated that optimized vaccines incorporating both class I and II neoantigens improvethe success of neoantigen vaccines. With funding from Leidos Biomedical Research we are currently testingoptimized neoantigen SLP vaccines in PDAC patients using a window trial design (NCT05111353).Aim 1: Test the hypothesis that optimized neoantigen vaccines can increase the number and improvethe function of neoantigen-specific T cells in PDAC. We are currently testing optimized neoantigenvaccines in PDAC patients following neoadjuvant chemotherapy in the window prior to surgery(NCT05111353). The window clinical trial design provides the opportunity to study neoantigen-specific T cellresponses in the tumor microenvironment (TME) after vaccination. In Aim 1 we will use biospecimens from thetrial to rigorously assess the functional biology of neoantigen-specific T cells present in the TME using coupledsingle-cell RNA sequencing (scRNA-seq) and TCR sequencing.Aim 2: Test innovative strategies to address the paucity of cDC1 in PDAC. We have made importantcontributions to understanding the development and biology of cDC1. We recently demonstrated that cDC1orchestrate CD4 and CD8 immune responses in cancer and that PDAC impairs development of cDC1restraining antitumor immunity. We are currently testing an innovative strategy to expand and license cDC1 inPDAC (NCT04536077). We will test innovative strategies to enhance neoantigen vaccine therapy in PDAC byexpanding and licensing cDC1 in vivo. We will also test biospecimens from NCT05111353 and NCT04536077to evaluate the impact of cDC1 paucity on the response to neoantigen vaccines.Aim 3: Test the hypothesis that the TIGIT pathway restrains the response to optimized neoantigenvaccines in PDAC. We and others have generated data using human specimens and preclinical modelssuggesting that the TIGIT pathway restrains antitumor immune responses in PDAC. We propose correlativestudies to determine if TIGIT signaling also restrains neoantigen-specific T cell responses in human PDAC.These studies have immediate translational relevance given that anti-TIGIT and anti-PD-1 antibodies arecurrently being tested in early phase clinical trials +No NIH Category available Abraxane;Agonist;Biological;Biological Markers;Blood;Cell Lineage;Cellular Immunity;Clinical;Clinical Research;Clinical Trials;Colorectal Cancer;Combination immunotherapy;Combined Modality Therapy;Correlative Study;Data;Dimensions;Disease Progression;Drug Combinations;Elements;Event;Exclusion;Functional disorder;Genetically Engineered Mouse;Human;IL8RA gene;ITGAM gene;Immunity;Immuno-Chemotherapy;Immunologic Memory;Immunologics;Immunotherapy;Impairment;Infiltration;Integrins;Interferons;Laboratory Study;Lead;Macrophage;Macrophage Colony-Stimulating Factor Receptor;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of pancreas;Molecular;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;PD-1 blockade;Pancreatic Ductal Adenocarcinoma;Patients;Phase;Phase I Clinical Trials;Pre-Clinical Model;Publishing;Research Personnel;Resistance;Safety;Signal Pathway;Signal Transduction;Site;Slice;System;T-Lymphocyte;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Translating;Treatment Efficacy;Tumor Immunity;Tumor-associated macrophages;Universities;Washington;cancer type;checkpoint therapy;chemokine receptor;combat;gemcitabine;granulocyte;improved;monocyte;novel strategies;novel therapeutics;p65;pancreatic ductal adenocarcinoma model;participant enrollment;pembrolizumab;pre-clinical;programmed cell death protein 1;programs;recruit;resistance mechanism;response;safety testing;success;targeted agent;targeted treatment;tumor;tumor microenvironment;unpublished works;validation studies Project 1: Employing CD11b-Agonists to Render PDAC Responsive to Immunotherapy PROJECT NARRATIVEThese studies seek to understand if targeting integrins on myeloid cells can impact therapeutic responsivenessto immunotherapy in pancreas cancer. They include studies clinically testing an integrin agonist in PDAC patientsand correlative and laboratory studies to understand mechanism of resistance. NCI 10708574 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9842 8710339 "DENARDO, DAVID G" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 357273 229757 127516 PROJECT SUMMARYThe potential of checkpoint immunotherapy to combat cancer has been established in several cancer types.However in pancreatic ductal adenocarcinoma (PDAC) checkpoint immunotherapy has not yet led to clinicalbenefits. Although multiple factors likely contribute to checkpoint resistance one significant factor is extensiveinfiltration of PDACs by multiple lineages of immunosuppressive myeloid cells. These myeloid cells whichinclude tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) drive T cellexclusion and dysfunction. Thus one promising therapeutic strategy is to reprogram these myeloid cells toimprove T cell-mediated immunity. Our team has recently developed an allosteric AGONIST of CD11b GB1275.Our published data demonstrate that CD11b-agonism rapidly repolarizes TAMs to support anti-tumor immunityand combining CD11b-agonists with checkpoint immunotherapy leads to tumor regression and long-term survivalin pre-clinical PDAC models. These strong data drive our hypothesis that CD11b agonism reprograms thePDAC tumor microenvironment to overcome resistance to checkpoint immunotherapy. To test thishypothesis we will:Aim 1: Determine the safety and efficacy of GB1275 Gemcitabine and Abraxane and PD-1 blockade inmetastatic PDAC patients.Aim 2: Determine the biomarkers of exposure response and resistance to GB1275 therapy in PDACpatients.Aim 3: Determine how tumor-intrinsic and extrinsic factors regulate the impact of CD11b agonist therapy.Impact: These studies will investigate a novel approach to render PDAC responsive to immunotherapy. +No NIH Category available Address;Advocacy;Animals;Bioinformatics;Biometry;Clinical Services;Clinical Trials;Collaborations;Communication;Community Health Education;Community Outreach;Contracts;Dedications;Development;Disparity;Documentation;Ensure;Faculty;Feedback;Funding;Grant;Group Meetings;Guidelines;Human;Institution;Leadership;Malignant neoplasm of pancreas;Manuscripts;Minority Participation;Minority Recruitment;Monitor;National Cancer Institute;Participant;Patient advocacy;Patients;Peer Review;Progress Reports;Protocols documentation;PubMed;Publications;Research;Research Personnel;Resource Sharing;Resources;Sampling;Travel;Underrepresented Minority;Universities;Update;Washington;anticancer research;career;meetings;member;peer;programs;web site;working group Core A: Administrative Core PROJECT NARRATIVEThis shared resource will provide administrative support necessary for the translational pancreatic cancerresearch proposed in this SPORE and will facilitate collaboration between other SPORE institutions. NCI 10708573 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 9841 6331590 "HAWKINS, WILLIAM G" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 131302 84438 46864 PROJECT SUMMARYThe Administrative Core aims to provide executive oversight and administrative support for all SPORE inPancreatic Cancer projects and cores. The Administrative Core will monitor the activities of all programcomponents ensure compliance with local and federal grant administration guidelines and facilitatecommunication and collaboration among program members. The specific aims of the Administrative Core are:Aim 1: Facilitate intra- and inter-SPORE communication collaboration and meetings. This core will beresponsible for distributing SPORE-related materials agendas regulatory information progress reports andpublications to SPORE faculty and staff. We will coordinate bi-monthly working group meetings monthly SPORESteering Committee meetings and an annual retreat to facilitate exchange of ideas and use of shared resources.We will coordinate the External Advisory Board and Internal Advisory Board. We will maintain a dedicatedwebsite to provide progress updates and contact information distribute quarterly updates to investigatorshighlighting resources available through the Biospecimen (Core B) and Biostatistics & Bioinformatics (Core C)Cores and facilitate bidirectional flow of biospecimen samples and information. This core will also provideadministrative oversight of multi-institution SPORE clinical trials.Aim 2: Provide administrative and fiscal oversight and support for all SPORE components. We will interactwith Washington University's Grants and Contracts Office and National Cancer Institute staff to prepare andsubmit annual progress reports and complete other projects as needed.Aim 3: Coordinate the SPORE Developmental Research Program and Career Enhancement Programadministrative activities. This core will solicit applications and coordinate review for the Career EnhancementProgram (CEP) and Developmental Research Program (DRP). This core will monitor awardee progresscoordinate awardees travel to peer SPORE institutions and facilitate use of core resources by awardees.Aim 4: Enhance participation of underrepresented minorities in all SPORE activities. The Core will overseeDRP and CEP initiatives to promote minority participation in SPORE clinical trials and pancreatic cancerresearch. We will accomplish this through leadership community outreach and education clinical servicesclinical trial accrual auditing support of disparities research retention and recruitment of minorities andcommunication with institutional disparities resources.Aim 5: Ensure advocacy issues are addressed in all aspects of research with patient participants. TheCore will ensure that all SPORE components properly incorporate advocacy issues or concerns. We willaccomplish this in two ways including patient advocacy and patient feedback.Aim 6: Assist investigators in preparing scholarly presentations publications regulatory documentsand all other SPORE-related products. This core will be responsible for completing documentation requiredfor investigators presenting at local and national meetings and submitting of documents to institutional regulatorybodies (e.g. human and animal studies protocols) publications and final peer-reviewed manuscripts supportedby SPORE funds to PubMed Central immediately upon acceptance. +No NIH Category available Agonist;Basic Science;Bioinformatics;Biometry;California;Cancer Biology;Cancer Center;Cancer Research Project;Clinic;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communities;Development;Diagnosis;Disease;Drug resistance;Ensure;Environment;Ethics;Faculty;Fostering;Funding;Genomics;Goals;ITGAM gene;Image;Immunologics;Immunology;Immunotherapeutic agent;Immunotherapy;Individual;Infrastructure;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of pancreas;Mentors;Metabolic;Minority;Mission;Nebraska;North Carolina;Pancreatic Ductal Adenocarcinoma;Patient Participation;Patient-Focused Outcomes;Patients;Pennsylvania;Quality of life;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Specialized Program of Research Excellence;Stress;Testing;Therapeutic Clinical Trial;Therapeutic Trials;Training;Translational Research;Translations;Universities;Washington;bench-to-bedside translation;cancer genomics;cancer type;career;clinical care;clinical practice;design;drug development;gastrointestinal;immune resistance;improved;improved outcome;innovation;inter-institutional;leukemia;medical schools;multidisciplinary;neoantigen vaccine;novel;novel diagnostics;novel strategies;novel therapeutic intervention;patient population;programs;recruit;resistance mechanism;translational applications;translational cancer research;translational impact;translational potential;treatment strategy Washington University SPORE in Pancreatic Cancer PROJECT NARRATIVEThe goal of this SPORE is to develop and test novel therapeutic strategies for the treatment of pancreas ductaladenocarcinoma (PDAC) with the ultimate goal of improving survival. The SPORE team will recruit and trainnew investigators and build resources to be shared with the PDAC research community. NCI 10708572 8/30/23 0:00 PAR-20-305 1P50CA272213-01A1 1 P50 CA 272213 1 A1 "NOTHWEHR, STEVEN F" 8/28/23 0:00 6/30/28 0:00 ZCA1-RPRB-6(M1)S 6331590 "HAWKINS, WILLIAM G" "DENARDO, DAVID G" 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/28/23 0:00 6/30/24 0:00 397 Research Centers 2023 2065042 NCI 1332980 732062 PROJECT SUMMARYThe Washington University Specialized Program of Research Excellence (SPORE) in Pancreatic Cancer is ahighly translational cancer research program focused entirely on the deadliest form of the disease pancreaticductal adenocarcinoma (PDAC). Our outstanding investigators have complementary expertise in basic andclinical studies and our teams leverage individual expertise in immunology cancer biology drug developmentgenomics and clinical care to develop novel diagnostic and therapeutic approaches for PDAC. This SPORE application includes three research projects an administrative core (Core A) two shared-resource cores [Biospecimen Core (Core B) and Biostatistics and Bioinformatics Core (Core C)] anddevelopmental research (DRP) and career enhancement (CEP) programs. In collaboration with our External(EAB) and Internal (IAB) Advisory Boards we intentionally selected projects with the greatest potential to impactthe outcome for patients with PDAC. Basic research at WUSM and UPenn has led to the development of thefollowing three research projects all of which feature innovative investigator-initiated therapeutic trials for PDAC.All projects deemed to have the most potential for translational impact and share an immunologic theme in theirapproach. This immunologic theme leverages institutional strengths and highlights our teams expertise andleadership in this field. Thus far the immunologic and metabolic therapies that have been increasingly successfulfor controlling other cancer types have not been impactful in PDAC. Our project leaders have made noteworthycontributions to elucidate the mechanisms underlying this immunologic resistance and drug resistance in PDACand developed several exciting strategies with potential to overcome these obstacles. The three projects in thisapplication are designed to have significant potential to change clinical practice within 5 years.Project 1. Employing CD11b-agonists to render PDAC responsive to immunotherapyProject 2. Mechanisms of Resistance to Neoantigen Vaccines in PDACProject 3. Targeting Stress-induced MK2 as Novel Strategy in Pancreatic Cancer Our long-term goals are to improve the survival and the quality of life of patients diagnosed with PDAC. Toachieve this goal we will promote institutional and inter-institutional collaborative research with an emphasis ontranslation. We anticipate that no singular approach will solve PDAC and fully commit to supporting thedevelopment of novel research concepts as well as highly promising young investigators. Our SPORE willprovide access to pancreatic cancerspecific resources to facilitate this mission. 2065042 +No NIH Category available Adult;Antineoplastic Agents;Childhood;Training Programs;drug development;drug discovery Pediatric and Adult Translational Cancer Drug Discovery and Development Training Program (PACT-D3) NarrativeThe goal of the PACT-D3 training program is focused on grooming the next generation of diverse basic andtranslational researchers with interests in cancer drug discovery and development. It will allow us to educate thenext generation of investigators focusing both on pediatric and adult cancer drug discovery and developmentand is unique for the IU system and NCI. NCI 10708526 8/29/23 0:00 PA-20-142 1T32CA272370-01A1 1 T32 CA 272370 1 A1 "DAMICO, MARK W" 9/1/23 0:00 8/31/28 0:00 ZCA1-RTRB-R(M1) 1899304 "KELLEY, MARK R." "CLAPP, DAVID W" 7 PEDIATRICS 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 158847 NCI 151048 7799 AbstractThis training program is unique for our institution creating the next generation of basic and clinical investigatorswho focus their efforts on strategic and comprehensive drug discovery and development in cancer. This programcapitalizes on a strong infrastructure and institutional commitment to the training of graduate student trainees forcareers in pediatric and adult drug discovery and development. The addition of a pediatric cancer focusaddresses an unmet need as well as a major focus of NCI as determined by the NCI's board of scientificadvisors and the resulting Childhood Cancer Data (CCDI) initiative. The wealth of adult experience and pediatricresearchers is uniquely being used in this T32 to develop novel approaches in pediatric drug discovery. Thereare no current NCI T32s with an emphasis on both pediatric and adult cancer drug discovery and developmenttraining. Cancer remains the leading cause of disease-related death in children. For the many children whoexperience relapses of their malignant solid tumors curative treatment options are scarce. The pediatric effortswill dovetail with the multi-institutional Developmental and HyperActive Ras Tumor (DHART) SPORE led bymulti-PI Dr. Wade Clapp focusing on neurofibromatosis type 1 (NF1)the most common human genetic cancerpredisposition syndrome. Findings in this SPORE have led to new clinical trials for pediatric patients and it isanticipated additional new drugs will need to be developed that is beyond the scope of the SPORE. In additionthe NIH/NICHD-funded P50 Specialized Centers in Research in Pediatric Developmental Pharmacology isusing precision genomics strategies and in vivo modeling to design efficacious and safe combination therapiesfor relapsed solid tumors such as osteosarcoma and additional new targets for potential drug development arebeing identified. This highlights our focus and opportunity to identify new drug targets and develop new drugsspecifically for pediatric patients. This program will be supported by collaborative efforts from other programs atthe IU School of Medicine (IUSM) including the NCI designated IU Simon Comprehensive Cancer Center(IUSCCC); the Cancer Drug Discovery and Development (CDDD) center which is embedded in the IUSCCCExperimental and Developmental Therapeutics (EDT) program; the TaRget Engagement to Accelerate TherapyDevelopment for Alzheimer's Disease (TREAT-AD) Center and the Indiana CTSI Preclinical Innovation ThinkTank program. We will focus on graduate students as trainees who will be recruited from two centralizedprograms that oversee graduate student recruitment and guide trainees in selecting mentors and homedepartments. These two programs are the Indiana BioMedical Gateway (IBMG) program which enrolls ~36graduate students per year and MSTP which enrolls ~10 per year. Eighteen mentors are intimately involved inthis program and drug development efforts at the school. The goal of PACT-D3 is focused on grooming the nextgeneration of diverse basic and translational researchers with interests in pediatric and adult cancer drugdiscovery and development. 158847 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Patient Safety Cancer Therapy Evaluation Program;Contractor;Contracts;Databases;Extracellular Matrix;Government;Logistics;Maintenance;Pamphlets;Persons;Pharmaceutical Services;Pharmacologic Substance;Policies;Recovery;Regulation;Research Personnel;Services;programs SUPPORT SERVICES FOR THE CTEP PHARMACEUTICAL MANAGEMENT BRANCH (PMB) n/a NCI 10708327 75N91022C00012-0-9999-1 N02 9/1/22 0:00 8/31/23 0:00 78754535 "GRAY, ARIE " Not Applicable 11 Unavailable 43690788 CAM5K35PN6D7 43690788 CAM5K35PN6D7 US 38.934471 -77.428684 10022495 "EDJ ASSOCIATES, INC." RESTON VA Domestic For-Profits 201911244 UNITED STATES N R and D Contracts 2022 1853905 NCI The objective of the Support Services for the Pharmaceutical Management Branch (PMB) contract is to provide logistical and administrative support to Government staff within PMB and across multiple Programs within DCTD. The Contractor supports PMB functions by primarily providing support of IND agent management and distribution (e.g. order processing transfers local destruction investigator brochure distribution stock recovery notice distribution etc.) person registration processing and maintenance curation of a database [Enterprise Core Module (ECM)] containing an NCI list of organizations associated with NCI trials as well as helpdesks for managing the investigator sub-investigator associate and organizations databases in compliance with IND regulations and DCTD policies. 1853905 +No NIH Category available Hematology;Pediatric Oncology;Research Training Lab Research Training in Pediatric Oncology-Hematology Project NarrativeThis program provides postdoctoral education training and experience in field-leading laboratory research onchildhood cancers for pediatric oncology-hematology physician-scientists. It ensures that a pipeline of well-trained physician-scientists can continue the progress that has been made in the treatment of these life-threatening diseases affecting children. NCI 10708308 6/30/23 0:00 PA-20-142 2T32CA060441-31A1 2 T32 CA 60441 31 A1 "LIM, SUSAN E" 9/30/93 0:00 7/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1876542 "FRIEDMAN, ALAN D" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 585732 NCI 653048 50644 Project SummaryTo continue to make progress for pediatric oncology patients we need to perpetuate the pool of talented andtrained pediatric oncology-hematology physician-scientists who will make relevant discoveries and provideinvestigative leadership. This has become ever more challenging in the field of pediatric oncology as therecontinues to be a shortage of young investigators with extensive laboratory research expertise. Fortunately weare able to attract candidates willing to spend the time in the laboratory under the tutelage of outstandinginvestigators who are able to inculcate them with the culture of research that predominates at Johns HopkinsMedical (JHM) and the National Cancer Institute (NCI) despite the current challenging funding climate. Thisgrant institutional funds and additional funding obtained by many trainees after two years in the laboratoryallows the large majority of trainees to continue for at least three years with many staying on at the Instructorlevel for additional time until they are fully ready to establish their own laboratory. In the current funding period(07/2018 09/2022) this grant has supported superb laboratory research training for an outstanding group of17 physician-scientists (12 MD and 5 MD/PhD) who have demonstrated a high degree of productivity andcommitment to careers in cancer research. Three of the MDs enrolled in a PhD graduate program while alsoreceiving T32 training and we anticipate more will do so in the future. This application seeks continued supportfor 8 interdisciplinary postdoctoral research positions per year. On average we anticipate that 3 new traineeswill be appointed to this T32 Program each year. These highly selected physician-scientists will have completedthe clinical year of their fellowship. These strongly qualified trainees will be provided intensive three-yearresearch experiences that will prepare them for careers in cancer research. Trainees work on projects relevantto the full range of childhood cancers in the laboratories of leading scientists. Areas of faculty research expertiseinclude pediatric leukemias lymphomas sarcomas brain tumors neuroblastoma cancer genetics andepigenetics cancer immunotherapy stem cell transplantation and small molecule drug development. The T32trainees will receive extensive mentorship not only from their primary laboratory mentor but also from the T32Executive Committee and members of their Scholarship Oversight Committee will participate in grant-writingworkshops and have their grants reviewed by a T32 faculty committee and will receive instruction in biostatisticsthe responsible conduct of research and additional topics in courses selected by the trainees. They will beprovided career guidance via presentations from former T32 trainees now pursuing pediatric oncology researchcareers in academia industry and government will be given the opportunity to present their research in multipleforums to develop their oral and critical thinking skills and will participate in a pediatric oncology laboratoryresearch-specific Journal Club. The trainees and their mentors participate in an interactive dynamic researchenvironment bridging the JHM and the NIH with an emphasis on translational approaches in pediatric oncology. 585732 +No NIH Category available 3-Dimensional;Algorithms;Animal Model;Atlases;Automobile Driving;Biological;Biological Models;Biology;Cancer Biology;Cells;Clinical;Coculture Techniques;Collaborations;Computer Analysis;Computer software;Computing Methodologies;Data;Data Analyses;Data Coordinating Center;Data Science;Data Set;Development;Disease;Ensure;Evolution;Experimental Designs;Fee-for-Service Plans;Gene Expression;Generations;Genetic Heterogeneity;Genetic Transcription;Genomics;Goals;Heterogeneity;Human;Imaging technology;Immune;Lead;Lesion;Machine Learning;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Meta-Analysis;Methods;Modeling;Molecular;Mucinous Neoplasm;Oncogenic;Oncology;Organoids;Outcome;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Papillary;Pre-Clinical Model;Premalignant Cell;Process;Proteomics;Regulation;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Sampling;Scientist;Standardization;Stromal Cells;T cell receptor repertoire sequencing;Techniques;Technology;Three-Dimensional Imaging;Validation;algorithm development;analysis pipeline;anticancer research;cancer cell;cancer initiation;cancer invasiveness;cancer type;cell behavior;computerized tools;computing resources;data harmonization;data integration;data sharing;data standards;data submission;data wrangling;design;exome sequencing;experience;experimental study;flexibility;genomic data;high dimensionality;high throughput analysis;improved;interoperability;meetings;method development;multiple omics;novel;novel imaging technology;novel therapeutic intervention;premalignant;programs;single cell technology;synergism;technology development;tool;transcriptomics;transfer learning;tumor;tumor initiation;tumor microenvironment Multiscale Computational Oncology Research Core n/a NCI 10708204 9/5/23 0:00 RFA-CA-21-054 5U54CA274371-02 5 U54 CA 274371 2 9/21/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9684 9551759 "FERTIG, ELANA JUDITH" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 239894 239894 0 MULTISCALE COMPUTATIONAL ONCOLOGY RESEARCH CORE (M-CORE) AbstractThe Multiscale Computational Oncology Research Core (M-CORE) provides computational oncologyexpertise from initial experimental design and power studies to ongoing data generation and analysis to datadeposition and sharing for single-cell and genomics data. Core Leader Dr. Fertig is a leader in single-cell multi-omics for applications to cancer with a particular focus on translational pancreatic cancer research applications.The M-CORE will support high-throughput data analysis in all three Tri-State Pancreatic Adenocarcinoma TBEL(Tri-PACT) Center Projects and Collaborative Projects. Methods will be applied to bridge spatial and temporalscales to identify cell intrinsic mechanisms underlying pre-malignant lesions progression into invasive cancers.These will be extended to analyze cell extrinsic intercellular interactions that mediate malignancy developmentand tumor initiation incorporating new three-dimensional imaging technologies from Tri-PACT. Many of thesemethods were recently developed by the Core leader and new algorithms will be developed specifically to meetthe TBEL needs and provide synergy across Projects. Research Projects will be testbeds for new single-cellmethods for dynamic spatial processes and novel imaging technologies and computational CollaborativeProjects will benefit from M-CORE resources. Standardization in the Core will harmonize data to enable meta-analyses between biological models and human precursor lesions biological mechanisms from the Projectsand novel mechanisms associated with precancer through cross-disease analysis in the broader TBELconsortium in collaboration with the Coordinating and Data Management Center (CDMC). The Core Leader willparticipate in all regular Center meetings and collaborate closely with the TBEL CDMC to ensure amplecomputational resources for new research directions. The Core will partner with the TBEL CDMC to assist withdata standards and harmonization data validation data wrangling and overall data deposition data andsoftware sharing and genomic data sharing. In summary the M-CORE will support the overall TBEL researchobjectives by providing computational methods to characterize the mechanisms of malignancy initiation andprogression into invasive tumors; to analyze spatial and temporal data to infer interactions and crosstalk betweenpre-malignant cells with stromal cells and other cells in the microenvironment; and to perform integrativeanalyses to promote Tri-PACT and Consortium synergy by identifying shared mechanisms. +No NIH Category available 3-Dimensional;Abdomen;Accounting;Affect;Alleles;Biochemical;Biogenesis;Cell Line;Cell Survival;Collaborations;Colorectal Cancer;Cyst;Cystic Lesion;Data;Dependence;Diagnosis;Drops;Excision;Exhibits;Fibroblasts;Frequencies;Genetic;Genetic Engineering;Histopathology;Human;Image;In Vitro;Indolent;Intervention;KRAS2 gene;Knockout Mice;Lesion;Location;Malignant Neoplasms;Malignant neoplasm of pancreas;Membrane Potentials;Metabolic Control;Metabolic Pathway;Metabolism;Mitochondria;Modeling;Molecular;Molecular Biology Techniques;Morphology;Mucinous Neoplasm;Mus;Mutate;Mutation;Nature;Operative Surgical Procedures;Organ;Organelles;Organoids;Oxidative Phosphorylation;Pancreas;Pancreatic Cyst;Pancreatic Ductal Adenocarcinoma;Pancreatic cystic neoplasia;Papillary;Pathogenesis;Patients;Phase I Clinical Trials;Phosphorylation Inhibition;Pre-Clinical Model;Prevalence;Probability;Property;Proteins;Quality Control;Recording of previous events;Reporter;Reporting;Respiration;Role;Site;Solid;TP53 gene;Testing;Tissues;WNT Signaling Pathway;Wood material;cancer invasiveness;clinic ready;clinical application;conditional knockout;endoplasmic reticulum stress;functional loss;genetic approach;genetically modified cells;high risk;improved;in vitro Model;in vivo;inhibitor;insight;mitochondrial metabolism;mouse model;mutant;neoplastic;novel;pancreatic ductal adenocarcinoma model;pharmacologic;proteostasis;reconstruction;response;tool;tumor;tumor microenvironment;tumor progression TBEL Project 2 n/a NCI 10708202 9/5/23 0:00 RFA-CA-21-054 5U54CA274371-02 5 U54 CA 274371 2 9/21/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9682 7626839 "MAITRA, ANIRBAN " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 331974 225095 106879 PROJECT 2 ABSTRACTThe estimated prevalence of pancreatic cystic neoplasms (PCNs) is between 2030% with intraductal papillarymucinous neoplasm (IPMNs) accounting for half of them. Depending on the morphology location and geneticsIPMNs can be of high-risk developing pancreatic ductal adenocarcinoma (PDAC) and as such significantlydiminishing patients survival. While RNF43 is only mutated in a small fraction of PDAC RNF43 mutations areprevalent in a high frequency in IPMNs. Although RNF43 has been identified as a negative regulator of Wntsignaling in colorectal cancers and other preclinical models including PDAC a phase 1 clinical trial of a Wntinhibitor in patients with RNF43 mutated solid cancers (including PDAC) has been proven disappointing. Otherlikely organ specific functions of RNF43 might be of great advantage for IPMN progression. Utilizing a conditionalknockout mouse model of RNF43 in context of Kras mutation we found that RNF43 abrogates the mitochondrialproperties and functions while loss of RNF43 improved mitochondrial quality control increased unfolded proteinresponse (UPR) and ER stress. These findings let us hypothesize that loss of RNF43 may deregulate thecrosstalk of these organelles in order to maintain proteostasis metabolic control and cell survival.Employing an autochthonous mouse model for functional loss of RNF43 in the context of Kras (generated in theDr. Maitra lab) primary genetically engineered cell lines (generated in the Dr. Lyssiotis lab) and human IPMNderived organoids (generated in the Dr. Wood lab; see Project 3) we propose to pursue the following aims:First we will investigate whether RNF43 regulates mitochondrial dynamics including biogenesis fission fusionand mitophagy to inhibit IPMN pathogenesis (Aim 1). Further we will investigate whether RNF43 blocks IPMNpathogenesis by limiting ER stress through management of ER-mitochondrial dynamics (Aim 2). Lastly we willdetermine whether loss of RNF43 creates a synthetic essentiality for sustained OXPHOS (Aim 1) andwhether/how OXPHOS inhibition impacts the multistep progression in an autochthonous KRC model ofpancreatic cystic neoplasia (Aim 3). Overall these studies will elucidate the functional role of RNF43 inmitochondria quality control ER-mitochondrial dynamics and how this impacts IPMN pathogenesis andprogression. +No NIH Category available Adherence;Administrator;Advocacy;Advocate;Agreement;Awareness;Biometry;Budgets;Cancer Center;Collaborations;Communication;Communities;Consultations;Data;Data Coordinating Center;Decision Making;Dedications;Doctor of Philosophy;Ensure;Foundations;Funding;Goals;Grant;Human Resources;Hybrids;Information Dissemination;Institution;Lead;Leadership;Lesion;Malignant Neoplasms;Malignant neoplasm of pancreas;Manuscripts;Michigan;Molecular Biology;Monitor;Oncology;Pancreas;Pancreatic Adenocarcinoma;Patients;Persons;Preparation;Productivity;Progress Reports;Publications;Regulation;Reporting;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Schedule;Science;Site;Site Visit;Transfer Agreement;Universities;University of Texas M D Anderson Cancer Center;Update;Wood material;anticancer research;career;data integrity;design;experience;implementation facilitation;material transfer agreement;meetings;member;molecular pathology;operation;pancreatic neoplasm;professor;programs;quality assurance;tumor microenvironment;virtual;web site;working group TBEL Admin Core n/a NCI 10708200 9/5/23 0:00 RFA-CA-21-054 5U54CA274371-02 5 U54 CA 274371 2 9/21/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9680 7626839 "MAITRA, ANIRBAN " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 424952 246816 178136 ADMINISTRATIVE CORE - AbstractThe Administrative Core (AC) will provide all of the administrative and communications support to the Tri-StatePancreatic Adenocarcinoma TBEL (Tri-PACT) Center investigators and form the central hub for productiveinteractions within the NCI TBEL community. The title of our Tri-PACT Center proposal is TumorMicroenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer and our Center incorporates threeinstitutions UT MD Anderson cancer Center (UTMDACC) University of Michigan (UMich) and Johns HopkinsUniversity (JHU) in a collaborative and integrated U54 endeavor to study early pancreatic neoplasia. The Tri-PACT Center AC will be led by overall Contact PI Dr. Anirban Maitra and Co-PI Dr. Marina Pasca di Maglianoand housed within the Sheikh Ahmed Center for Pancreatic Cancer Research at UTMDACC. The AC will besupported by a PhD-level Core Administrator with experience with multi-investigator grants. Further Dr. YuShen Professor and Chair ad interim of Biostatistics at UTMDACC will provide comprehensive statisticalsupport for the Tri-PACT Center and will be assisted by a senior statistical analyst. Dr. Maitra and the AC haveconsiderable experience in overseeing and participating in multi-investigator grants that include programmaticNCI U01 P01 and P50 Grants. The overall goals of the AC will be (a) to monitor research progress and toprovide stable and continuous leadership that advances integration communication and collaboration amongthe Tri-PACT Center investigators participating in the three proposed projects and shared resource core(Multiscale Computational Oncology Research Core or M-CORE) and (b) to ensure productive interactions withother concurrently funded TBEL U54 sites and the TBEL CDMC through formal and informal collaborativeendeavors under the TBEL umbrella. The AC will leverage the wide-ranging research expertise of both theInternal Advisory Board (IAB) and the External Advisory Board (EAB) in critical decision-making steps such aschanges in research directions of currently proposed projects. The AC will ensure fiscal management includingpersonnel budgets and effort oversight facilitate organization of virtual and in-person work-in-progressmeetings for Tri-PACT center investigators engage in manuscript preparation and provide federally mandatedprogress and other reports to the NCI. The AC will facilitate attendance for the PIs and Tri-PACT investigatorsto the semi-annual TBEL consortium meetings and ensure our participation in other network activities includingTBEL working groups trans-network collaborations and dissemination of results within and beyond the TBELcommunity. The AC will serve as a liaison with the TBEL CDMC in ensuring the transfer of TriPACT Center-generated data and materials under appropriate transfer agreements. The AC will also ensure timelycommunication and consultation with the NCI Program Directors for both adherence and deviations from statedprogrammatic goals. Last but not the least the AC will also enhance awareness of pancreatic cancer earlylesion research and advocacy in the community through public-facing websites and and publications. +No NIH Category available 3-Dimensional;Accounting;Animal Model;Architecture;Basic Science;Biology;Cancer Biology;Cancer Center;Cancer Etiology;Cessation of life;Collaborations;Communication;Computational Biology;Credentialing;Cues;Data Analyses;Data Science;Dependence;Disease;Disease Progression;Distant;Early Diagnosis;Epithelium;Event;Excision;Fibroblasts;Genetic;Genetic Engineering;Genome;Goals;Heterogeneity;Histologic;Histology;Human;Immune;Individual;Institution;Interleukins;KRAS2 gene;Lesion;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Mediator;Metabolic;Michigan;Mitochondria;Modeling;Molecular;Mucinous Neoplasm;Mus;Mutation;Neoplasms;Oncology;Operative Surgical Procedures;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pancreatic cystic neoplasia;Papillary;Pathogenesis;Pathway interactions;Patients;Play;Pre-Clinical Model;Process;Quality Control;Research;Research Personnel;Resolution;Resource Sharing;Role;Seminal;Signal Transduction;Site;Specificity;Survival Rate;Testing;Translational Research;United States;Universities;Validation;cancer genomics;cytokine;data analysis pipeline;data harmonization;data sharing;dimensional analysis;endoplasmic reticulum stress;high dimensionality;improved;improved outcome;member;molecular pathology;mortality;pancreatic neoplasm;paracrine;premalignant;programs;prototype;reconstruction;response;tool;translational study;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumor progression;ubiquitin-protein ligase Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer OVERALL PROJECT NARRATIVEImproved understanding of the biology and heterogeneity of precursor lesions including the interactions thatthese lesions harbor with the surrounding microenvironment are a prerequisite for improving outcomes inpancreatic cancer the third most common cause of cancer related deaths. The TriState PancreaticAdenocarcinoma TBEL (Tri-PACT) Center brings together a collaborative group of investigators from threeinstitutions who will use credentialed animal models and patient-derived materials to pursue three highlyinterdependent projects on basic and translational research in pancreatic cancer precursor lesions. NCI 10708199 9/5/23 0:00 RFA-CA-21-054 5U54CA274371-02 5 U54 CA 274371 2 "BERA, TAPAN K" 9/21/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 7626839 "MAITRA, ANIRBAN " "PASCA DI MAGLIANO, MARINA " 9 PATHOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1600526 NCI 1315511 285015 OVERALL - ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the 3rd most common cause of cancer-related mortality in theUnited States with the overhwhelming majority of patients presenting advanced stage disease. Invasiveneoplasia in the pancreas represents the culmination of a multistep progression that begins with non-invasiveprecursor lesions which remain an untapped window of opportunity for early detection and cancer interception.Two major histological subtypes of precursor lesions are recognized - the more common non-cystic pathwayrepresented by pancreatic intarepithelial neoplasia or PanIN lesions estimated to precede ~90% of PDAC andthe cystic pathway most commonly represented by intraductal papillary mucinous neoplasms or IPMNsaccounting for the remaining 10%. While members of this team have played a seminal role in characterizing thehistology and genetics of PanINs and IPMNs much remains to be elucidated in terms of the moleculardependencies that sustain early pancreatic neoplasia and how signaling cues from these early lesionsreprogram the precursor microenvironment (PME) including precursor-associated fibroblasts (PAFs). Thegoal of our Tri-state Pancreatic Adenocarcinoma TBEL (Tri-PACT) Center - incorporating UT MD AndersonCancer Center (UTMDACC) University of Michigan (UMich) and Johns Hopkins University (JHU) - is to createa collaborative and integrated U54 center to conduct basic and translational studies in early pancreatic neoplasia.The Tri-PACT Center will be led by Dr. Anirban Maitra (UTMDACC) and Co-PI Dr. Marina Pasca di Magliano(UMich). The title of our Tri-PACT Center proposal is Tumor Microenvironment Crosstalk Drives Early Lesionsin Pancreatic Cancer and we are proposing three projects (two basic one translational) each of which will besupported by a Multiscale Computational Oncology Research Core (M-CORE) and an Administrative Core (AC).Project 1 (basic) will study the functional requirement of a pivotal cytokine interleukin IL-33 which is induced inthe PAF and epithelial compartments of PanINs and IPMNs in response to KRAS and GNAS mutationsrespectively in disease progression and reprogramming of the PME. Project 2 (basic) will study a uniquemetabolic synthetic essentiality centered on mitochondrial quality control created in cystic precursors thatharbor loss of RNF43 a E3 ubiquitin ligase lost in ~50% of IPMNs. Notably the Tri-PACT investigators havedeveloped genetically engineered models (GEMs) of pancreatic preneoplasia that recapitulate the cognatehuman lesions and will be extensively leveraged in the two basic projects with cross-species validation inpatient-derived preclinical models. Project 3 (translational) will deploy a unique 3D reconstruction tool (CODA)paired with multi-region sequencing of human precursor lesions to map the evolutionary trajectory of individualprecursors at an unprecedented resolution and correlate subclonal architecture with high dimensional analysisof the immune and PAF composition within the PME. Cumulatively these projects will enhance ourunderstanding of the drivers of early pancreatic neoplasia and a seedbed for early detection approaches. 1600526 +No NIH Category available Carcinoma;Cell Communication;Cell Death Induction;Cells;Clinic;Clinical;Clinical Research;Coculture Techniques;Collagen;Collagen Fiber;Collagen Receptors;Collagen Type I;Complex;DDR1 gene;Data;Deposition;Desmoplastic;Environment;Equilibrium;Excision;Extracellular Matrix;Extracellular Matrix Proteins;Failure;Fiber;Fibroblasts;Goals;Growth;Human;Immune;Immune checkpoint inhibitor;Immunity;Immunologic Surveillance;Immunosuppression;Length;Ligands;Liver;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Mediating;Mediator;Metabolic;Metabolism;Metastatic Neoplasm to the Liver;Mus;Neoplasm Metastasis;Nutrient availability;Pancreatic Ductal Adenocarcinoma;Patients;Physical Restraint;Progression-Free Survivals;Receptor Signaling;Regulation;Research;Resistance;Resolution;Role;Signal Pathway;Signal Transduction;Site;Slice;Specimen;Starvation;Testing;Therapeutic Intervention;Tumor Immunity;Tumor Promotion;Tumor Suppression;Vascular blood supply;Visceral metastasis;antitumor effect;clinical translation;immune activation;immune cell infiltrate;immune checkpoint blockade;immune clearance;improved;indexing;individualized medicine;mouse model;novel;novel strategies;novel therapeutics;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;rational design;receptor;refractory cancer;single-cell RNA sequencing;synergism;targeted treatment;therapy development;therapy resistant;tool;trait;transcriptomics;translational scientist;tumor;tumor growth;tumor metabolism Regulation of PDAC metabolism and immunity by collagen and its cleavage products PROJECT NARRATIVEInteractions between malignant epithelial cells and cancer associated fibroblasts (CAF) are key determinants ofpancreatic ductal adenocarcinoma (PDAC) growth metastatic spread and therapy resistance. However CAFcan either restrict or stimulate PDAC growth and CAF targeting therapies had failed in the clinic. Our project willfocus on CAF-produced type I collagen its cleavage and receptors that sense the balance between intact andcleaved collagens as novel approaches for converting CAF-mediated tumor promotion and immunosuppressionto tumor growth inhibition and enhanced anti-tumor immunity. NCI 10708168 9/5/23 0:00 RFA-CA-21-041 5U01CA274295-02 5 U01 CA 274295 2 "MERCER, NATALIA" 9/21/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M1) 1861927 "KARIN, MICHAEL " "LOWY, ANDREW M; SCHWABE, ROBERT F." 50 PHARMACOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 955015 NCI 723015 232000 ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic and therapy-resistant cancer. The role ofthe desmoplastic stroma in PDAC remains elusive with studies supporting both tumor-promoting or tumor-restricting functions. The failure of stroma targeting therapies suggests that a deeper understanding of thecomplex cancer-stroma interaction is needed. Type I collagen (Col I) the major ECM protein in PDAC canphysically restrain tumors and limit nutrient availability. Yet PDAC cells adapt and exploit the surrounding stromato acquire more advanced malignant traits. Moreover the desmoplastic collagen-rich stroma may suppressimmunosurveillance and activate tumor-promoting mechanosensitive signaling. It is likely that tumor-promotingand tumor-suppressive effects of CAF and ECM occur in parallel and that their balance determines the net effecton PDAC growth. We seek to better understand these opposing functions by focusing on Col I as a key mediatorof stroma-PDAC crosstalk. Clinical studies show improved progression-free survival (PFS) after resection inpatients with inert stroma characterized by extensive ECM deposition and low fibrolytic activity whereas highlyfibrolytic stroma is associated with much shorter PFS times. Based on this finding we hypothesize that ratherthan the sheer quantity of CAF and stroma collagen fibrolysis and differential effects of receptors thatdiscriminate between intact and cleaved Col I dictate tumor growth and immunity. Our preliminary data supportthis hypothesis indicating differential regulation of cancer cell metabolism by intact and cleaved collagen througha specific receptor DDR1; as well as high expression of the inhibitory Col I receptor LAIR1 on immune cells anda role for Col I in immune cell infiltration and activation in PDAC spread to the liver the most common site ofmetastasis and a suppressor of systemic anti-tumor immunity. Our long-term goal is to develop therapies thattarget collagen receptors and shift the balance from immunosuppression and tumor promotion by cleavedcollagen to tumor starvation growth inhibition and enhanced anti-tumor immunity rather than CAF depletion ormodulation which so far had resulted in untoward effects. Our interdisciplinary team of basic and clinical-translational investigators will utilize clinical specimens tumor slice cultures single cell RNA-sequencing spatialtranscriptomics mouse models and PDAC-ECM co-cultures to elucidate the role of collagen receptor signalingvia two closely integrated specific aims: 1. Test the hypothesis that collagen fragments and fibers antagonisticallycontrol PDAC metabolism through the PDAC-intrinsic collagen receptor DDR1 whose inhibition can switch offtumor metabolism and induce cell death. 2. Test the hypothesis that stimulatory and inhibitory collagen receptorscontrol anti-PDAC immunity and can be combined with immune checkpoint inhibitors to increase anti-tumorimmunity. The successful completion of these research goals will provide us with novel tools for convertingstroma-mediated tumor growth and immunosuppression to growth inhibition and anti-tumor immunity. 955015 +No NIH Category available Animal Model;Automobile Driving;Biotechnology;Cancer Patient;Cell Line;Cell Proliferation;Cell Survival;Cells;Cessation of life;Clustered Regularly Interspaced Short Palindromic Repeats;Defect;Development;Disease Resistance;Event;Frequencies;Future;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genomics;Genotype;Goals;Histologic;In Vitro;KRAS oncogenesis;KRAS2 gene;Knowledge;Lead;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mediating;Messenger RNA;Methods;Mission;Modality;Modeling;Molecular;Monitor;Mus;Mutation;Oligonucleotides;Oncogenic;Oncoproteins;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacogenomics;Phenocopy;Play;Pre-Clinical Model;Precision therapeutics;Predisposition;Protein Isoforms;Public Health;RNA Splicing;Research;Resistance;Role;Sampling;Scientific Advances and Accomplishments;Signal Transduction;Spliceosomes;Study models;TP53 gene;Testing;Therapeutic;Therapeutically Targetable;Treatment Efficacy;Tumorigenicity;Work;chemotherapeutic agent;clinical investigation;design;driver mutation;drug sensitivity;gain of function;gain of function mutation;improved;in vivo;inhibitor;innovation;loss of function;molecular subtypes;mouse model;mutant;new therapeutic target;novel;novel therapeutics;pancreatic cancer patients;pancreatic ductal adenocarcinoma cell;personalized medicine;refractory cancer;response;screening;small molecule;small molecule inhibitor;synergism;targeted treatment;therapeutic target;therapy development;therapy outcome;therapy resistant;transcriptome;transcriptome sequencing;treatment response;tumor;tumor growth;tumorigenesis;tumorigenic;ultrasound Understanding and targeting mutant splicing factors in pancreatic cancer PROJECT NARRATIVEThis project is relevant to public health because identifying mutations that drive pancreatic cancer could revealnovel targets to treat this deadly and currently therapeutic-resistant disease. We recently identified a group ofmutations related to RNA splicing that can be blocked with both existing and emerging therapies that impedetumor growth and extend survival in animal models. In the proposed work we will 1) determine the role of thesemutations in driving pancreatic cancer development 2) identify and correct the RNA splicing defects requiredfor the mutations to exert their effects and 3) test two types of novel therapies to restore normal RNA splicingand determine anti-tumor efficacy. NCI 10708159 9/8/23 0:00 PA-20-185 5R01CA274355-02 5 R01 CA 274355 2 "MAAS, STEFAN" 9/21/22 0:00 8/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 15056131 "ESCOBAR HOYOS, LUISA " Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 396332 NCI 278328 118004 Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer that is resistant tocurrently available therapies. Notably we discovered that PDACs are exquisitely susceptible to a range oftherapies directed at RNA splicing. However it is unknown how alterations in RNA splicing drive PDACtumorigenesis or impact therapeutic responses. Thus identification of the role of aberrant RNA splicing inPDAC tumorigenesis could reveal novel therapeutic targets for PDAC. Our long-term goal is to identifydesign and test novel mechanistic-based targeted therapies for highly aggressive tumors such as PDAC. Themain objective of this proposal is to characterize the role of RNA splicing factor mutations in PDACpathogenesis and treatment response. Recently we identified that the most common gain-of-function drivermutations found in 50% of PDACs (mutant KRAS and p53) synergize and cooperate through altered RNAsplicing. While >90% of PDAC cases harbor mutant KRAS only 50% co-occur with mutant p53. Weperformed mutual exclusivity analysis among hundreds of annotated mutations in PDACs and identified twomutant splicing factors SF3B1 and RBM10 that co-occur with mutant KRAS but do not co-occur with mutantp53 and are mutually exclusive between each other. Additionally our proof-of-concept studies using newlygenerated genetically engineered mouse models oligo-therapy and RNA splicing inhibitors demonstrated thatRNA splicing is a therapeutic target. Our central hypothesis is that persistent RNA splicing defectsdownstream of SF3B1 and RBM10 mutations are a required adaptive mechanism for KRAS-mediatedtumorigenicity and represent a therapeutic target for PDAC. We aim to 1) determine the role of aberrant RNAsplicing in PDAC tumorigenesis 2) identify the function and correct RNA splicing defects in pancreaticcancer and 3) evaluate the impact of mutant RNA splicing factors on the therapeutic efficacy of spliceosomeinhibitors and chemotherapeutic agents. Our expected outcomes include identification of 1) how aberrantRNA splicing underlies major cancer-driving events 2) novel therapeutic targets for our newly generatedoligo-therapy or small molecule inhibitors and 3) a previously overlooked mechanism for how cancer canevolve through multiple mutations converging at a common mechanistic function. We will use innovativenewly generated genetically engineered mouse models co-expressing KRAS and splicing-factor mutations inthe pancreas leading to autochthonous PDAC resembling patient tumors and we will employ novelcomputational and genetic biotechnologies to identify and correct RNA splicing defects. These results willuncover a fundamental yet novel non-mutational mechanism required for PDAC pathogenesis: altered RNAsplicing. This will provide a strong basis for future approaches to treat PDAC which would significantly impactpersonalized therapies and patient outcomes. This research directly aligns with NCIs mission to advancescientific knowledge of drivers and targets of cancer to improve patients lives. 396332 +No NIH Category available Adjuvant;Animals;Calibration;Characteristics;Clinical;Clinical Trials;Collaborations;Commercial grade;Complex;Computer software;Deposition;Detection;Devices;Documentation;Dose;Dose Limiting;Dose Rate;Electron Beam;Electronics;Electrons;Engineering;Ensure;Environment;Event;Goals;Grant;Human;Image;Industry;Interruption;Kansas;Location;Measures;Medical;Medical center;Medicine;Methods;Modification;Monitor;Normal tissue morphology;Operative Surgical Procedures;Output;Patients;Performance;Persons;Phase;Physics;Physiologic pulse;Positioning Attribute;Protons;Radiation;Radiation Monitoring;Radiation Oncology;Radiation therapy;Research;Resolution;Resources;Risk;Running;Safety;Scanning;Schools;Sea;Series;Speed;Structure;Synchrocyclotron;System;Testing;Tissues;Toxic effect;Translations;Treatment outcome;United States;Universities;Validation;Work;cancer therapy;chemotherapy;cherenkov imaging;clinical implementation;clinical research site;clinical translation;conventional therapy;curative treatments;design;detection method;detection platform;dosimetry;efficacy clinical trial;image guided;imaging system;improved;irradiation;maltreatment;millisecond;performance tests;preclinical study;proton beam;prototype;risk minimization;risk mitigation;sensor;spatiotemporal;tool;translation to humans;translational potential;treatment planning;tumor Ultra-fast imaging for the safe delivery of electron FLASH radiation therapy NarrativeThe recent advances in FLASH radiotherapy mark a sea change in the way radiotherapy could be delivered butalso have the potential to introduce new dangers. Tools to monitor and verify the accurate and consistentdelivery of FLASH do not exist today. At DoseOptics we leverage our world leading Cherenkov detectionsystem BeamSite for conventional radiation therapy and develop BeamSite ULTRA a system suitable toaccurately characterize of treatment beams temporally and spatially for the ultra-high dose rates used inFLASH. By developing the system for both electron and proton treatments BeamSite ULTRA will help to ensureaccurate delivery reduce misadministration events and improve treatment outcomes. NCI 10708158 8/1/23 0:00 PA-21-259 5R44CA268466-03 5 R44 CA 268466 3 "ZHAO, MING" 9/16/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Z(10)B] 15121007 "BRUZA, PETR " Not Applicable 2 Unavailable 79605332 QERKPUEMGKH3 79605332 QERKPUEMGKH3 US 43.717363 -72.26448 10037749 "DOSEOPTICS, LLC" LEBANON NH Domestic For-Profits 37661441 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 999998 NCI 674637 259941 AbstractRadiation therapy is a supplementary curative treatment used adjuvant with most surgery and chemotherapybeing delivered to nearly 1 out of every 4 people in their lifetime. While image guidance and conformal planningreduced the dose to healthy tissue there is still a substantial risk of tissue damage that sets the upper limit ofdose deposited to the tumor. Recently the minimization of healthy tissue damage was demonstrated to occurwhen ultra-high dose rates (UHDR) were used for irradiation known as the FLASH effect. UHDR are defined asa complex set of high average dose rates (>40 Gy/s) instantaneous dose rates (>106 Gy/s) total dose values(>8Gy) and temporal pulse structures. FLASH promises a reduction in normal tissue toxicity by 20-50% and ourclinical site partner Dartmouth-Hitchcock has been the first to demonstrate routine weekly delivery of FLASH ona clinically used linac. This modification shows enormous translational potential to deliver electron FLASH(eFLASH) in any radiotherapy center using existing systems. However while most research in the field is focusedon elucidating the radiobiological mechanisms of FLASH work towards mitigating the risks of FLASH is largelyuntouched yet will be pivotal for wider clinical implementation. New techniques for detection monitoring ofradiation need to be developed due to the millisecond timescales at which FLASH operates which maketraditional methods unsuitable. In this project we have leveraged our camera platform BeamSite the worldsfirst video system for radiotherapy now FDA cleared and in use clinically to developed BeamSite-ULTRAspecifically for imaging FLASH. In our Phase I grant we successfully demonstrated the ability to image at thehigh frame rates and transfer speeds necessary to capture a single beam pulse energy in phantoms and ontissue. In this Phase II we will advance BeamSite-ULTRA as a robust manufacturable and FDA clearablecommercial system. We will quantify both spatial and temporal pulse structures demonstrate beam-on andgating-off potential of the system and establish the capabilities in both proton and electron FLASH clinicalsettings. The work includes an extensive team of industry and academic medicine colleagues using the eFLASHresources at Dartmouth-Hitchcock Medical Center and the proton treatment facilities at the University of KansasMedical Center. 999998 +No NIH Category available Achievement;Advisory Committees;Advocacy;Applications Grants;Award;Basic Science;Bioinformatics;Biometry;Breast;Categories;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Sciences;Data;Development;Diagnosis;Direct Costs;Disabled Persons;Discipline;Disease;Ensure;Evaluation;Extramural Activities;Faculty;Funding;Future;Goals;Grant;Individual;Laboratories;Leadership;Mayo Clinic Cancer Center;Mentors;Minority;Mission;Monitor;Pathology;Policies;Population;Population Sciences;Positioning Attribute;Prevention;Procedures;Process;Productivity;Qualifying;Reporting;Research;Research Personnel;Research Project Grants;Resources;Science;Scientist;Talents;Translational Research;Veterans;Wages;Woman;Work;anticancer research;bench to bedside;career;community engaged research;convict;diversity and inclusion;expectation;health equity;improved;malignant breast neoplasm;mortality;multidisciplinary;next generation;patient registry;programs;recruit;skills;success;translational scientist;women with disabilities Career Enhancement Program NARRATIVEThe Career Enhancement Program is focused on identifying supporting and mentoring the most highlyqualified investigators in basic science population science and clinical research who have the greatestpotential to conduct meaningful translational research in breast cancer and develop independent researchprograms directed at reducing the burden and mortality from breast cancer. NCI 10708098 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC 9662 7570767 "GOETZ, MATTHEW PHILIP" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 83247 52361 30886 PROJECT SUMMARYThe Career Enhancement Program (CEP) of the Mayo Clinic Breast Cancer SPORE is committed to identifyingand mentoring junior faculty with the greatest potential of developing independent programs in translationalbreast cancer research. This is accomplished through a rigorous review process aimed at identifying the mosttalented and promising candidates followed by an intensive rigorous and effective mentoring program. Thementoring program is based on the establishment and optimal functioning of a Multidisciplinary MentoringCommittee led by a senior investigator with the scientific expertise and commitment to developing the nextgeneration of translational breast cancer researchers. The Multidisciplinary Mentoring Committee will becomposed of the primary mentor and the complementary clinical and/or basic investigator necessary for acomprehensive mentoring program plus a statistician. It is viewed as crucial to the success of the awardee thatthe mentoring be ongoing and robust. This will be accomplished by close oversight by the Director of the CEPof the mentoring process and progress of the awardee. Dr. Goetz the Director of the CEP and SPORE Directorwill report to the SPORE Executive Committee. This intensive oversight process was established because of thefirm conviction of the SPORE Director that the development of independent investigators and translational breastcancer research is central to the SPORE mission. The explicit expectation is that the awardees will utilize theresources made available to them for the development of independent research programs and acquisition ofindependent funding in breast cancer research. We are requesting $50000 per year (direct costs) to supportthis program. This will be supplemented by $50000 (direct costs) of Mayo Clinic Cancer Center support. Oneaward of $100000 per year will be made which can be used for salary technician support and supplies. Oneawardee will be supported per year and a given awardee can be supported for up to two years providingsatisfactory progress is demonstrated. To date the CEP has been successful in that of the 10 awardees fivehave successfully competed to become either SPORE Project Co-Leaders in full Projects or Co-Directors ofCores. Additionally half have been women (three) or minority (two). Further of the 3 women 2 have beenpromoted into leadership positions in the SPORE including Core B Co-Director and Core C Co-Director. +No NIH Category available Achievement;Advisory Committees;Advocacy;American Association of Cancer Research;American Cancer Society;Applications Grants;Award;Breast;Breast Cancer Patient;Cancer Center;Clinic;Clinical;Clinical Research;Collaborations;Data;Decision Making;Detection;Development;Diagnosis;Direct Costs;Disabled Persons;Disease;Ensure;Ethnic Population;Evaluation;Extramural Activities;Foundations;Funding;Future;Generations;Goals;Grant;Human Resources;Incidence;Institution;Journals;Laboratory Study;Leadership;Letters;Manuscripts;Mayo Clinic Cancer Center;Mentors;Minnesota;Minority;Monitor;Peer Review;Performance;Pilot Projects;Policies;Population Study;Prevention;Procedures;Process;Productivity;Program Research Project Grants;Progress Reports;Publications;Publishing;Qualifying;Quality of life;Regenerative Medicine;Research;Research Personnel;Research Project Grants;Selection Criteria;Site Visit;Testing;Translating;Translational Research;Universities;Utilization Review;Veterans;Woman;anticancer research;career;clinical center;diversity and inclusion;expectation;experience;innovation;interdisciplinary collaboration;malignant breast neoplasm;meetings;member;mortality;originality;programs;racial population;recruit;research and development;success;symposium;translational potential;translational study Development Research Program NARRATIVEThe Developmental Research Program supports innovative and scientifically meritorious research projectsthat have the greatest potential to be translated into clinically important applications for the preventiondiagnosis and treatment of women with breast cancer. NCI 10708093 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC 9660 8084551 "HAWSE, JOHN R." Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 268068 168611 99457 PROJECT SUMMARYThe goal of the DRP is to support innovative and scientifically meritorious research projects that can be translatedinto clinically important applications impacting diagnosis and management of breast cancer to decrease theburden and mortality from this disease. The DRP will: 1) encourage and solicit innovative translational laboratorypopulation and clinical study proposals; 2) encourage and support interdisciplinary collaboration in translationalresearch in breast cancer; and 3) generate new hypotheses that can be tested in larger-scale research projects.This support will expand the research portfolio of the SPORE. The Developmental Research Program will provide$50000 direct costs for one year ($25000 from SPORE funds and $25000 from Mayo Clinic Cancer Center) toeach of six projects. Additionally the DRP will provide an additional $25000 direct costs/year for each of the 5years to support one project led by an investigator from an underrepresented racial and ethnic group. This willbe matched with an additional 25K from the Mayo Clinic Cancer Center or our collaborating institutionsUniversity of Minnesota Masonic Cancer Center and Emory Cancer Center. In all cases there will be theexpectation of a second year of support contingent on sufficient progress. A process has been establishedinvolving a call for applications and a formal peer review utilizing the expertise of the Internal Scientific AdvisoryCommittee and other experienced investigators. Criteria for selection of projects for funding are based uponscientific merit originality qualifications of the applicant and translational potential. It is expected that supportof developmental research projects will result in generation of data that will serve as the basis for additionalSPORE-sponsored projects or support through peer-reviewed external grant support. The three main metrics forproductivity of the DRP are advancement of DRP projects to a full Project in the SPORE acquisition of extramuralfunding and publications by the project awardees. There have been 41 DRP awardees with four awards beingmade on September 1 2020. Six of the eleven SPORE projects in the current grant (two) previous grant (two)and renewal (two) have a Co-Leader who was a DRP awardee. The 36 DRP awardees (before September 12020) have obtained 17 R01s nine Foundation grants three Komen grants one State of Minnesota grant oneR21 one American Association for Cancer Research grant one American Cancer Society grant one Eaglesgrant one Regenerative Medicine Minnesota grant and three Breast SPORE Career Enhancement Awards inaddition to the five awardees who have advanced to Co-Leadership of a full project in the Breast SPORE. These36 awardees have published 115 manuscripts related to their DRP projects in peer-reviewed journals. The DRPhas been highly successful in identifying cadre of investigators that has expanded and enriched the scientificportfolio of the SPORE and provided a mechanism for development of Co-Leaders in full Projects. +No NIH Category available Address;African American;Antibodies;Antigen Targeting;Antigens;B cell repertoire;B-Cell Antigen Receptor;B-Lymphocytes;Benign;Biological Response Modifiers;Biopsy;Blood;Blood specimen;Breast;Breast Cancer Cell;Breast Cancer Prevention;Breast Cancer Prevention Trial;Breast Cancer Risk Factor;Breast Diseases;Cancer Center;Cells;Cessation of life;Chemopreventive Agent;Clinic;Clinical;Clinical Trials;Collaborations;Contralateral Breast;Development;Diagnosis;Disease;Division of Cancer Prevention;ERBB2 gene;Eligibility Determination;Estrogen receptor positive;Frequencies;Future;Immune;Immune response;Immune system;Immunity;Immunization;Immunologics;Incidence;Investigation;Link;Lobule;MAGEA3 gene;Mammary Gland Parenchyma;Methods;Mucin 1 protein;Non-Malignant;Patients;Peripheral;Phase;Phase Ib Clinical Trial;Phase Ib Trial;Phenotype;Prevention;Prevention strategy;Prevention trial;Primary Prevention;Randomized;Research;Research Personnel;Risk Reduction;Sampling;Specificity;T-Cell Development;T-Cell Receptor;T-Lymphocyte;Tissues;Translational Research;Tumor Antigens;Vaccination;Vaccine Antigen;Vaccine Clinical Trial;Vaccines;Widespread Disease;Woman;blood-based biomarker;breast cancer progression;cancer subtypes;case control;cohort;cost;digital;early phase clinical trial;experimental study;high dimensionality;high risk;immunogenic;improved;innovation;malignant breast neoplasm;mammaglobin;member;minimally invasive;mortality;novel;novel vaccines;overexpression;potential biomarker;premalignant;prevention clinical trial;response;response biomarker;side effect;success;survivin;targeted sequencing;tissue resource;tumor progression;vaccination strategy;vaccine delivery;vaccine development;vaccine response;vaccine trial Project 3 NARRATIVEThis project supports the development of a vaccine for the primary prevention of breast cancer in two ways.First in premalignant breast tissues potential vaccine targets will be evaluated as well as their association withfuture breast cancer. Second samples will be evaluated from an early clinical trial of the prevention vaccine inorder to determine what type of immune responses are generated by the vaccine both in blood and breasttissue and whether those immune responses can aid in further development of the vaccine and act aspotential biomarkers of disease protection. A vaccine to prevent breast cancer is expected to lead to asignificant reduction in deaths and costs associated with this widespread disease. NCI 10708077 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC 9654 9447131 "DEGNIM, AMY C" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 475671 423350 52321 ABSTRACTVaccine-based prevention of breast cancer is a promising strategy for substantially reducing the impact ofdisease incidence treatment and mortality because vaccines can induce highly specific immune responses thatself-regulate in the absence of disease. Ongoing clinical trials of vaccines targeting antigens expressed by breastcancer cells including ongoing trials from members of this research group have shown that vaccines can induceT-cell-based immunity that can last for years. Effective implementation of a prevention vaccine will requireidentification of which antigens are associated with breast cancer risk and progression and definition of tissue-and blood-based metrics of vaccine response. The experiments presented in this project will pair with our newPhase Ib trial of a novel multi-antigen prevention vaccine to advance it toward a clinical prevention trial. In ourfirst Specific Aim we will draw upon an extensive tissue resource of women diagnosed with benign breastdisease at the Mayo Clinic and at the Karmanos Cancer Center to assess which of the antigens in the preventionvaccine are expressed in premalignant breast tissue and which are most associated with subsequent breastcancer development. This information will be critical for identifying which antigens should be included in thefuture prevention trial and which patients are most likely to benefit from it. In our second Specific Aim we willevaluate blood-based antibody and cellular immune responses to the multiantigen vaccine in our current Phase1b clinical trial. We will use high dimensional cellular analysis and targeted sequencing approaches informationthat will provide minimally invasive endpoints of immune response for a larger scale future prevention trial. Inour third Specific Aim we will assess pre- and post-vaccine background normal breast tissues from patients inthe clinical trial to identify how changes in antigen expression are associated with activation of specific immunecell subtypes and changes in the T- and B-cell repertoire. This information will inform the future prevention trialby defining how the vaccine and its specific components impact antigen expression and immune response innonmalignant breast tissue. Successful completion of this project will define which vaccine components shouldbe advanced to a larger vaccine-based breast cancer prevention clinical trial which has the potential to drivesignificant reductions in overall disease incidence burden and mortality. +No NIH Category available Anatomy;Bioinformatics;Biological;Biology;Blood;Characteristics;Clinical Data;Collaborations;Data;Data Commons;Data Set;Diagnostic;Digital Imaging and Communications in Medicine;Dose;Ensure;Factor Analysis;Goals;Human;Image;Immune;Immune response;Immunologic Markers;Infrastructure;Learning;Link;Machine Learning;Magnetic Resonance Imaging;Maps;Methods;Mission;Modeling;Molecular;Molecular Profiling;Multivariate Analysis;Operative Surgical Procedures;Patients;Pattern;Peripheral Blood Mononuclear Cell;Phenotype;Privatization;Publications;Radiation;Radiation therapy;Reaction Time;Rectal Cancer;Research;Resources;Specimen;Training;X-Ray Computed Tomography;anticancer research;data ecosystem;data exchange;data quality;data sharing;digital;innovation;insight;microbiome;multimodality;novel;radiomics;tool;transcriptomics;treatment planning;tumor Data Sharing and Integrative Analysis Core n/a NCI 10708072 9/14/23 0:00 RFA-CA-21-040 5U54CA274291-02 5 U54 CA 274291 2 9/21/22 0:00 7/31/27 0:00 ZCA1-SRB-X 9652 1858119 "DEASY, JOSEPH O" Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 195488 152775 42713 This Data Sharing and Integrative Analysis (DSIA) Core will support the overall mission of the Center throughthree interlocking functions: (Aim 1) to ensure effective data quality and full computability (Aim 2) to provideinnovative integrative analyses to support the scientific goals of this ROBIN center and (Aim 3) to ensureseamless data sharing for inter-ROBIN network collaborations as well as to the NCI Cancer Research DataEcosystem. Aim 1. To ensure effective data quality and computability. Under this Aim we will collect harmonizeand make accessible the digital data collected in this ROBIN Center including the Molecular CharacterizationTrial as well as Projects 1 and 2. These diverse sets of data include: 1) clinical data (de-identified patient andtumor characteristics Immunoscore of the diagnostic rectal cancer specimen etc.) imaging data (MRI / CTimages at baseline and prior to surgery) 2) radiotherapy treatment planning data (DICOM images dosedistributions to the contoured anatomic structures) and 3) biological data resulting from the two scientific projectsassociated with the MCT (e.g. spatial transcriptomics microbiome immune biomarkers in circulating bloodetc.). We will curate and transfer data from the Molecular Characterization Trial (MCT) and Scientific Projects 1and 2 and will fully link all ROBIN data within NCI Cloud Resource FireCloud workspaces and the Imaging DataCommons with imputation where necessary providing fully computable subject data profiles. Aim 2. To conductinnovative integrative analyses to support the scientific goals of this ROBIN center. Under this Aim we will applyboth unbiased/non-parametric and machine learning integrative (multi-datatype) analyses to identify criticalimmune phenotypes and their tumor/immune molecular signatures using the full spectrum of available biologicaland imaging data. To identify biological and imaging/radiomics signatures or subtypes we will apply innovativeclustering using network optimal mass transport methods. To understand the impact of radiation on PeripheralBlood Mononuclear Cells (PBMCs) we will conduct systematic multivariate analyses using machine learningapproaches. To understand subtypes of RT response we will apply a novel non-linear machine-learningintegrative phenotypic mapping tool (iPhenMap) based on sparse Bayesian factor analysis modeling thatintegrates molecular and functional multimodal patterns. Aim 3. To support seamless data sharing for inter-ROBIN network collaborations and cross-training. Under this Aim we will document and demonstrate our toolsdata and rerunnable analysis workflows in FireCloud and Imaging Data Commons infrastructure to supportinter-ROBIN network collaborations as well as inter-disciplinary cross-training. +No NIH Category available Adjuvant Study;Adjuvant Therapy;Aromatase Inhibitors;Binding;Biological;Biological Availability;Biopsy;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer therapy;Breast-Conserving Surgery;CDK4 gene;Cancer Burden;Cell Proliferation;Cessation of life;Characteristics;Clinic;Clinical;Clinical Research;Cohort Studies;Collaborations;Cyclin D1;Data;Developed Countries;Development;Diabetes Mellitus;Diagnosis;Disease;Disease Resistance;Disease-Free Survival;Distant;Dose;Down-Regulation;E2F transcription factors;ERBB2 gene;ESR1 gene;Early Diagnosis;Endocrine;Estrogen Receptor alpha;Estrogen receptor positive;Estrogens;Event;Exemestane;Foundations;Genes;Goserelin;Heart Diseases;Hyperlipidemia;Hypertension;In Vitro;Incidence;Laboratories;Mammary Neoplasms;Mediating;Menopause;Molecular;Morbidity - disease rate;Mutation;Neoadjuvant Therapy;Newly Diagnosed;North Central Cancer Treatment Group;Oncoproteins;Operative Surgical Procedures;Oral;Osteoporosis;Outcome;Ovarian;Pathway interactions;Patients;Pharmacodynamics;Phase;Phase II Clinical Trials;Phosphotransferases;Postmenopause;Predictive Value;Premature Menopause;Premenopause;Prognostic Marker;Progression-Free Survivals;Quality of Life Assessment;Quality of life;Randomized;Recommendation;Regimen;Residual Cancers;Resistance;Role;Signal Transduction;Tamoxifen;Testing;Text;Therapeutic;Toxic effect;Uterus;Woman;anti-cancer;arm;bone;cancer diagnosis;chemotherapy;cohort;hormone therapy;improved;in vivo;inhibitor;kinase inhibitor;malignant breast neoplasm;novel;optimal treatments;pharmacologic;phase II trial;preclinical study;predictive marker;prevent;primary endpoint;prognostic value;prospective;protein expression;response;secondary endpoint;side effect;standard of care;therapy resistant;transcriptome sequencing;tumor Project 2 PROJECT NARRATIVEPremenopausal women diagnosed with ER+/HER2- breast cancer tend to have a more aggressive form ofdisease compared to women diagnosed in the postmenopausal setting and as such are aggressively treatedwith chemotherapy ovarian function suppression and aromatase inhibitors. While this therapeutic strategyimproves breast cancer specific outcomes it is associated with substantial morbidity. This proposal focuses ondeveloping an alternative endocrine approach for premenopausal breast cancer patients using endoxifen withoutovarian function suppression and aims to mechanistically understand the basis for endoxifens superioranticancer effects. NCI 10708071 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC 9651 7570767 "GOETZ, MATTHEW PHILIP" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 248563 160726 87837 PROJECT SUMMARY/ABSTRACTBreast cancer (BC) remains the most commonly diagnosed cancer in premenopausal women (pre-MW)worldwide and its incidence is increasing in developed countries. BCs in pre-MW are more likely to be of anaggressive intrinsic subtype higher grade and advanced stage compared to BCs in post-MW. Pre-MW withER+/HER2- BC are commonly treated with chemotherapy (CT) endocrine therapy (ET) and ovarian functionsuppression (OFS). Long-term data from the SOFT and TEXT adjuvant trials demonstrated that aromataseinhibitors (AI)+OFS improved disease free survival but have yet to improve overall survival (OS) compared totamoxifen (TAM) or TAM+OFS. Furthermore in one study (ABCSG 12) AI+OFS led to worse OS compared toTAM+OFS. The lack of a survival benefit in these studies may relate to the detrimental side-effects of prematuremenopause (PM) known to be associated with higher rates of cardiac disease hypertension diabeteshyperlipidemia osteoporosis and death. Therefore alternative endocrine strategies for pre-MW with ER+/HER2-BC are critically needed especially for pre-MW who cannot tolerate OFS. Endoxifen (ENDX) is an active TAMmetabolite and the PIs have led the development of ENDX as a novel ET for BC. Through completion of phaseI and II trials we have demonstrated that ENDX is safe well-tolerated has substantial oral bioavailability and issuperior to TAM in endocrine therapy (ET) resistant BC. Furthermore the PIs have identified a novel mechanisticbasis for the superior anti-cancer effects of ENDX; namely the novel ENDX target PKCI. Here we build uponthis foundation by performing a prospective neoadjuvant endocrine study comparing ENDX without OFS vsAI+OFS in the neoadjuvant treatment of pre-MW with ER+/HER2- BC. We will also extensively study the rolesof PKCI in mediating ENDX efficacy given our preliminary data demonstrating that ENDX uniquely binds PKCIand targets it for proteasomal degradation resulting in downregulation of ER cyclin D1 and E2F1 protein levelsconcurrent with marked inhibition of BC cell proliferation. Importantly these effects are not observed with PKCIkinase inhibitors suggesting novel non-kinase related functions of PKCI. Furthermore they are not observedwith TAM or AI. Based on these data the central hypothesis of this proposal is that ENDX is a superior ET inpart due to its ability to dually target both ER and PKCI. We further hypothesize that the optimal treatment ofpre-MW with ER+/HER2- BC can be achieved using ENDX monotherapy without the need for OFS. To test ourhypotheses we will 1) develop ENDX for pre-MW with ER+/HER2- BC; 2) elucidate the mechanisms by whichPKCI contributes to ENDX responsiveness in endocrine sensitive disease; and 3) determine the predictive andprognostic value of PKCI in ER+/HER2- BC patients treated with TAM and ENDX. Given the increasingincidence of BC in pre-MW along with the known morbidity associated with OFS the proposed studies are ofcritical importance towards improving the endocrine management of ER+/HER2- BC in pre-MW. +No NIH Category available ATM gene;Address;Adjuvant;Adjuvant Therapy;African;African American;African American population;Age;BARD1 gene;BRCA1 gene;BRCA2 gene;Benign;Biological Assay;Breast;Breast Cancer Detection;Breast Cancer Patient;Breast Cancer Risk Factor;CDH1 gene;CHEK2 gene;Caring;Categories;Classification;Clinic;Clinical;Clinical Trials;Colorectal;Contralateral Breast;DNA;Data;Disease-Free Survival;ERBB2 gene;Eligibility Determination;Estrogen Receptor Status;Estrogen Receptors;Estrogen receptor positive;FDA approved;General Population;Genes;Genetic;Germ-Line Mutation;High Risk Woman;Histologic;Histopathology;Individual;Magnetic Resonance Imaging;Mammary Neoplasms;Medical Genetics;Methods;Molecular;Mutate;NF1 gene;Operative Surgical Procedures;Ovarian;PALB2 gene;PTEN gene;Pancreas;Participant;Pathogenicity;Predisposition;Prevention;Progesterone Receptors;Prognosis;Prognostic Factor;Prognostic Marker;Proteins;Qualifying;RAD51C gene;Recurrence Score;Risk;Risk Assessment;Risk Estimate;Risk Management;Screening for cancer;Second Primary Cancers;Selection for Treatments;Susceptibility Gene;TP53 gene;Test Result;Variant;Woman;age related;brca gene;cancer clinical trial;cancer predisposition;cancer risk;chemotherapy;clinical risk;clinical subtypes;clinically relevant;cohort;genetic testing;high risk;high risk population;hormone therapy;improved;insight;lifetime risk;malignant breast neoplasm;oncotype;population based;predictive marker;research clinical testing;response;risk variant;screening;success;triple-negative invasive breast carcinoma;tumor;variant of unknown significance;virulence gene Project 1 PROJECT NARRATIVEThe risk estimates for primary and contralateral breast cancers associated with pathogenic variants (PVs) inestrogen receptor positive breast cancer predisposition genes for women of all ages from the general populationand high-risk population will substantially improve risk assessment and management of these individuals.Reclassification of variants of uncertain significance in these genes as pathogenic or benign will also improvethe utility of genetic testing results. Furthermore determination of the influence of PVs in ER-positivepredisposition genes on disease free survival and overall survival in response to adjuvant therapy and whetherthese PVs are correlated with Oncotype Dx Breast Recurrence Scores will provide substantial insight into theselection of therapy for women with PVs in these genes. NCI 10708067 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC 9650 1899922 "COUCH, FERGUS JOSEPH" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 370692 251155 119537 PROJECT SUMMARYGermline pathogenic variants (PV) in the BRCA1 BRCA2 and PALB2 cancer predisposition genes are associatedwith high risks of breast cancer (lifetime risks to age 80 of >50%) whereas PVs in ATM and CHEK2 are associatedwith moderate lifetime risks of 20-25%. Of these PVs in ATM BRCA2 CHEK2 and PALB2 are predominantlyassociated with estrogen receptor positive (ER+) breast cancer. While much is known about ER+ breast canceroverall little is known about the contribution of PVs in these predisposition genes to ER+ breast cancer risks andto the influence of these PVs on prognosis. Here we aim to address some of the important clinical questions thatremain unanswered for these ER+ breast cancer predisposition genes. In Aim #1 we propose to assess age-relatedrisks of cancers associated with ER+ breast cancer predisposition gene PVs. Specifically while overall risks ofbreast cancer are well established age-related risks of breast cancer in 5-10 year categories and risks ofcontralateral breast cancer are not known for the ATM CHEK2 and PALB2 genes. In the absence of thisinformation the overall risks of cancer associated with PVs are of limited clinical value. We will use information fromvery large population-based including targeted studies of African Americans and West Africans and from high-riskbreast cancer studies to estimate these cancer risks. In Aim #2 we propose to establish the influence of PVs in ER-positive breast cancer predisposition genes on prognosis. It is not currently known whether breast cancers drivenby ER+ predisposition genes other than BRCA2 display specific responses to standard therapy (such aschemotherapy endocrine therapy or HER2 directed therapy). We propose to screen germline DNA fromparticipants in large breast cancer adjuvant clinical trials for PVs in the ER+ breast cancer predisposition genesand to assess the influence of PVs on disease free survival and overall survival in response to adjuvant therapy.In addition we will determine whether the PVs are correlated with the Oncotype Dx Breast Recurrence Scorewhich is an effective prognostic and predictive biomarker for ER+ breast cancer patients. In Aim #3 we propose todetermine the clinical relevance of Variants of Uncertain Significance (VUS) in ER-positive breast cancerpredisposition genes. Individuals carrying germline VUS which are predominantly missense variants cannotbenefit from enhanced risk assessment and cancer screening or make informed decisions about surgicalprevention or screening. We will conduct individual and high-throughput functional assay studies and apply rules-based FDA-approved ClinGen methods for determination of the clinical relevance of many VUS in these genes. +No NIH Category available Advisory Committees;Advocacy;Advocate;Breast;Clinic;Collaborations;Communication;Development;Extramural Activities;Funding;Future;Goals;Human Resources;Infrastructure;Leadership;Malignant Neoplasms;Mayo Clinic Cancer Center;Monitor;National Cancer Institute;Organ;Performance;Positioning Attribute;Production;Program Development;Progress Reports;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Scientist;Structure;Translational Research;United States National Institutes of Health;Visit;Woman;Work;anticancer research;career;career development;innovation;instrument;malignant breast neoplasm;meetings;operation;programs;translational cancer research;translational research program Administrative Core NARRATIVEThe Administration Core provides the organizational infrastructure necessary to perform the work proposed inthis SPORE application. NCI 10708063 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC 9648 7570767 "GOETZ, MATTHEW PHILIP" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 218064 137160 80904 PROGRAM SUMMARY/ABSTRACTThe overall goals of the Mayo Clinic Breast SPORE are to identify significant and innovative SPORE ResearchProjects; identify Developmental Research Projects with the greatest potential for advancing to full SPOREResearch Projects; through the Career Development Program identify scientists with the greatest potential fordeveloping independent translational research programs and advancing to future leadership positions in theSPORE; and finally to maximize collaborations with other SPOREs (breast and other organ-based) and otherNIH-funded instruments both intra- and extra-murally. The Administrative Core has facilitated progress towardthese goals by serving as the organizational hub of the Mayo Breast SPORE during Years 1-15 of funding.During the next funding period (Years 16-20) it will continue to provide organizational and communicationssupport for the SPORE leadership research projects scientific cores and developmental programs[Developmental Research Program (DRP) and Career Enhancement Program (CEP)]. Specifically theAdministrative Core will: (1) Maximize breast cancer translational research through provision of leadership andoversight of the SPORE Research Projects and Cores; 2) Facilitate the activities of the SPORE ExecutiveCommittee through organization of meetings and development of materials related to oversight andprogrammatic development; 3) Organize meetings of the SPORE Advocacy Advisory Committee facilitatecollaborations between the Mayo Breast SPORE advocacy committee and advocates involved in otherSPOREs; 4) Organize meetings of the SPORE Internal Scientific Advisory Committee; 5) Organize meetings ofthe SPORE External Advisory Committee 6) Provide administrative support to the Director of theDevelopmental Research Program 7) Provide administrative support to the Director of the Career DevelopmentProgram; 8) Organize monthly SPORE scientific meetings 9) Organize monthly SPORE Key PersonnelMeetings 10) Organize twice-monthly SPORE Operations Committee meetings; 11) Coordinate and facilitateinvestigator participation in NCI Translational Science Meetings as well as the Translational Breast CancerResearch Consortium; 12) Monitor manage and coordinate fiscal activities of the SPORE program 13) Serveas a liaison between the Breast SPORE the National Cancer Institute the Mayo Clinic Cancer Center (MCCC)and Mayo Clinic; 14) Identify and facilitate development of inter-breast SPORE collaborations 15) Preparereports relating to Breast SPORE activities including annual Progress Reports and the competitive renewalapplication and finally 16) Coordination of visiting scientists. +No NIH Category available Acceleration;Affect;Bioinformatics;Biological;Biology;Blood specimen;Cell Death;Cells;Cellular Stress;Clinical;Clinical Data;Clinical Trials;Colon;Communities;Data;Databases;Doctor of Philosophy;Equilibrium;Foundations;Future;Genomics;Goals;Image;Immune;Immune response;Immune system;Immunologics;Incidence;International;Intervention;Intervention Trial;Irradiated tumor;Laboratories;Magnetic Resonance Imaging;Malignant Neoplasms;Maps;Modeling;Molecular;Molecular Analysis;Mucous Membrane;Multimodal Imaging;Neoadjuvant Therapy;Normal tissue morphology;Operative Surgical Procedures;Outcome;Output;Oxidative Stress Induction;Pathologic;Pathway interactions;Patients;Pattern;Proteomics;Quality of Life Assessment;Radiation;Radiation therapy;Radio;Radiobiology;Rectal Cancer;Research;Research Personnel;Research Priority;Robin bird;Specimen;Standardization;Structure;Testing;Time;Tissues;Tumor Tissue;United States National Institutes of Health;data integration;data sharing;fitness;host microbiome;insight;international center;longitudinal analysis;lymph nodes;microbiome;multiple omics;novel;prospective;racial disparity;radiomics;response;simulation;spatial integration;stool sample;tumor Molecular Characterization Trial of Irradiated Rectal Cancer n/a NCI 10708055 9/14/23 0:00 RFA-CA-21-040 5U54CA274291-02 5 U54 CA 274291 2 9/21/22 0:00 7/31/27 0:00 ZCA1-SRB-X 9645 16174425 "GOLDEN, ENCOUSE " Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 370435 344225 26210 ABSTRACTMolecular Characterization TrialThe Molecular Characterization Trial (MCT) is a clinical platform to enable tissue acquisition to perform cuttingedge laboratory and imaging research to advance the field of radiation biology. The MCT overarching hypothesisis that the contribution of radiotherapy (RT) to the outcome of cancer depends on the balance of the crosstalkamong the irradiated tumor and normal tissue the host microbiome and the hosts immune system. Rectalcancer is an ideal model to test this hypothesis since imaging and specimens from patients undergoing astandard short course radiotherapy (SCRT) treatment are accessible and available at pre- and post RTtreatment as well as at time of surgery. As such the RT effects can be analyzed longitudinally in each singletissue and then be integrated globally into a model to correlate biological and imaging data with clinical outcome.Rectal cancer is also a research priority because of its disparity in racial incidence and outcome.The ROBIN P.I.s have assembled an international team of established investigators to conduct the same trialconcurrently at seven centers to accelerate accruals and discovery. As such the MCT represents the ROBINfoundation on which both Project 1 and Project 2 rely to answer fundamental questions regarding RT biology.Novel bioinformatic approaches will be applied to integrate clinical and biological data with imaging data toenhance the potential for discovery. The initial MCT will create a supporting structure for future trials iterativelytesting new interventions informed by the results of the associated scientific projects. Project 1 will focus on themolecular analyses of tumor and patients matched non-tumor tissue with the goals of defining the local immuneresponse to RT and the genomic changes induced by RT and elucidate how the treatment affects the pathwaysinvolved in cell fate decisions and its effects on the local colonic mucosal microbiome. Project 2 will use bloodspecimens and lymph nodes collected inside or outside the radiation field to quantify RT-induced oxidativestress and the biological outcome of it on each immune cell subpopulation. Pathways associated with cellularstress responses cell death and immunological fitness will also be evaluated. Additionally stool samplescollected before and after RT will be analyzed to qualitatively and quantitatively map changes in the microbiome.Both projects will address these pivotal questions using state-of-the-art genomic and proteomic approachesintegrated with the patients clinical data and multi-modal imaging from an orthogonal radiomic study. After standardization and upload all laboratory clinical and imaging data will be harmonized and cured bythe Data Sharing and Integrative Analysis Core (DSIA). Data will then be analyzed using novel integrativebioinformatics approaches to identify previously undetectable patterns related to radio-responsiveness andassess their association with clinical outcomes. The final output will converge into NIH/NCI databases andbecomes available to the ROBIN network and to the scientific community at large. +No NIH Category available Archives;Authorization documentation;Collaborations;Communication;Communities;DNA Repair;Decision Making;Elements;Ensure;Evaluation;Fostering;Goals;Grant;Human Resources;Individual;Infrastructure;Institution;Malignant neoplasm of prostate;Manuscripts;Medical;Memorial Sloan-Kettering Cancer Center;National Cancer Institute;Occupational activity of managing finances;Office of Administrative Management;Principal Investigator;Program Research Project Grants;Publications;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Running;Schedule;Services;Structure;Training;Work;authority;editorial;meetings;member;programs;scientific organization Administrative Core n/a NCI 10708054 9/5/23 0:00 PAR-18-290 5P01CA228696-04 5 P01 CA 228696 4 9/1/19 0:00 8/31/25 0:00 ZCA1-RPRB-6 9644 1941089 "KANTOFF, PHILIP W" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 99438 61635 37803 PROJECT SUMMARY/ABSTRACTThe goal of the Administrative Core based at Memorial Sloan Kettering Cancer Center (MSK) is to supportthe proposed Program Project (P01) grant The Impact of DNA Damage Repair Abnormalities in ProstateCancer by integrating and providing administrative fiscal and scientific oversight to the program overall andeach individual project and core. The interactive structure of the Core will also facilitate communication andcollaboration among the program investigators at the participating institutions. The specific aims of theAdministrative Core are to (1) provide seamless budgetary oversight for the projects and cores; (2) scheduleand support the program meetings as well as facilitate evaluation and communications among the projects; (3)distribute and archive the publications reports and grant elements from the components of the P01 and (4)schedule facilitate and manage the meetings of the Principal Investigators and the Scientific Advisory Board.The services centralized in the Administrative Core will provide the following administrative andcommunications infrastructure that will serve all components of the proposed P01 program. Financial Management: serve as the centralized budgetary coordinator and financial manager Grants Administration: serve as administrative liaison to the National Cancer Institute ensuring the timely submission of all required reports and compliance with institutional and federal regulations Editorial Services: provide editorial services for manuscript publication and grants coordination Meetings Coordination: organize the scientific review of ongoing research projects and cores Communication: foster communication and collaborative research within our proposed P01 program as well as with the wider scientific communityThe Administrative Core will be led by Philip W. Kantoff MD and Mark M. Pomerantz MD PrincipalInvestigators of the proposed P01 program. They will share overall authority for the scientific andadministrative decision-making and for the day-to-day running of the program. The Administrative Core willalso include personnel trained in financial management grants administration and medical editing. Coremembers will work as a team to ensure the effective financial and administrative management of the proposedP01 program.1 of 1 AdminCore_Summary_v1a.docx 05/19/17 +No NIH Category available Achievement;Adjuvant Radiotherapy;Adverse event;Advocate;Age;Award;Charge;Clinical Trials;Collaborations;Colorectal;Communication;Data;Data Analyses;Data Element;Data Scientist;Descriptor;Discipline;Electronic Mail;Ensure;Equilibrium;Ethics;Europe;Evaluation;Feedback;Funding;Future;Gender;Generations;Grant;Image;Immune;Immune response;Immune system;Immunity;Immunology;Immunooncology;Infrastructure;Institution;Intellectual Property;Investigation;Legal;Link;Malignant Neoplasms;Medicine;Modeling;Molecular;Monitor;Nature;Neoadjuvant Therapy;Newsletter;Patients;Performance;Physicians;Pilot Projects;Process;Radiation;Radiation Oncology;Radiation therapy;Radiobiology;Radiometry;Rectal Cancer;Reporting;Research;Research Project Grants;Resource Sharing;Rest;Robin bird;Role;Running;Scientist;Secure;Self Assessment;Site;Specific qualifier value;Specimen;Tissues;Training;Training Activity;Tumor stage;candidate identification;community building;data sharing;design;experience;international center;meetings;member;microbiome;novel;organizational structure;programs;prospective;radiation effect;radiomics;recruit;success;tool;tumor Administrative Core n/a NCI 10708052 9/14/23 0:00 RFA-CA-21-040 5U54CA274291-02 5 U54 CA 274291 2 9/21/22 0:00 7/31/27 0:00 ZCA1-SRB-X 9643 6095791 "FORMENTI, SILVIA C." Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 343328 228665 114663 The ROBIN Administrative Core (AC) provides administrative and communication infrastructure to the ROBINgrant. Led by the three P.I.s the AC is supported by an executive committee composed by the leaders of theCores of the Molecular Characterization Trial (MCT) and of the scientific projects. The AC has a prestigiousExternal Advisory Board (EAB) with members who represent all the disciplines and expertise relevant to thisROBIN. A team of experienced patients advocates completes the organizational chart. An Executive Directorwill be recruited if the ROBIN is funded in charge of maintaining communication and coordination of all ROBINactivities. To this scope the ROBIN Tracker will be introduced adapted from an IT tool developed at Weill CornellMedicine for electronic communication of activities and tasks of large grants (like SPORE or PPG). An importantrole of the AC is to develop a semestral evaluation plan and share it with the EAB and if necessary at ad hocmeetings when important decisions need to be made. Metrics of success will include the timely achievement ofcompletion of MTAs and other legal steps to enable transfer between academic institutions of researchspecimens in the US and of research data both in the US and Europe. Planned accruals to the MCT generationof preliminary data from the scientific projects and successful integration of trainees within the ROBIN programsare additional metrics of success. The iterative nature of ROBIN will also be assessed as it is expected that theresults of the first MCT and the associated scientific projects (converged with the feedback and results from theother centers in the ROBIN network) will inspire the design of one or more new MCT around year 3. These newMCT will be implemented during the last two years of the award through the existing Immunology and RadiationOncology Network (IRON) that will run the proposed first MCT. Another important role of the AC consists ofassessing the Cross Training Core (CTC). While metrics of success of the CTC are defined in detail in its plannedself-assessment the AC will monitor the CTC to ensure a harmonious integration of the different disciplines andexpertise that characterize ROBIN and are indispensable to a cross training in Radiation and Immunity theoverarching theme of this ROBIN proposal. A central duty of the AC is to identify potential collaborations withinand beyond the ROBIN network and participate in the process of actualizing the restricted fund pilot projectsprogram of the ROBIN network. The ROBIN newsletter proposed in the CTC with distribution across the networkwill advertise the RFA. In addition each of the ten academic institutions involved in this ROBIN will use theirinternal communication mechanisms to solicit applications. We expect the applications to be evaluated by acommittee formed by representatives of each funded ROBIN. The AC will select representation from this ROBINbased on the need of the committee with consideration to ensure its diversity (gender balance diversity ofexpertise and seniority etc.). Finally the AC leaders will participate in the executive activities of the ROBINnetwork and will be the link for bidirectional communication between this ROBIN and the rest of the network. +No NIH Category available Address;Adjuvant;Antigen Targeting;Antigens;Aromatase Inhibitors;BRCA2 gene;Benign;Bioinformatics;Biometry;Blood;Breast;Breast Cancer Prevention;Breast Cancer Risk Factor;Breast Diseases;CHEK2 gene;CRISPR/Cas technology;Cell Cycle Progression;Classification;Clinic;Clinical;Clinical Trials;Collaborations;Colorectal;Contralateral Breast;Cyclin D1;DNA;Data;Development;Diagnosis;Disease;Dose;Down-Regulation;Drug Targeting;E2F transcription factors;ERBB2 gene;Economic Burden;Endocrine;Estrogen Receptor alpha;Estrogen receptor positive;Estrogens;Extramural Activities;Funding;Future;Genes;Goals;Immune response;Immunologic Markers;Incidence;Knock-in;Laboratories;Leadership;Malignant Neoplasms;Mammary Gland Parenchyma;Mayo Clinic Cancer Center;Medical;Mentors;Methodology;Morbidity - disease rate;National Surgical Adjuvant Breast and Bowel Project;Oncogenic;Organ;Ovarian;PALB2 gene;Pancreas;Pathogenicity;Pathology;Performance;Phase III Clinical Trials;Positioning Attribute;Premenopause;Prevention;Prevention strategy;Principal Investigator;Prognosis;Protein Degradation Induction;Proteins;RAD51C gene;Recommendation;Recurrent Malignant Neoplasm;Reproduction spores;Research;Research Personnel;Research Project Grants;Risk;Risk Assessment;Sampling;Science;Scientist;Second Primary Cancers;Susceptibility Gene;Systemic Therapy;Tamoxifen;Translating;Translational Research;United States National Institutes of Health;Uterus;Vaccine Antigen;Vaccine Clinical Trial;Vaccines;Variant;Vision;Woman;Work;age related;bone;breast cancer vaccine;cancer recurrence;cancer subtypes;career;clinically relevant;deprivation;faculty support;first-in-human;high throughput screening;hormone therapy;improved;in vivo;innovation;instrument;malignant breast neoplasm;mortality;novel;novel strategies;novel therapeutics;novel vaccines;patient registry;phase 1 study;population based;premalignant;prognostic;programs;response;success;translational cancer research;translational research program;treatment response;tumor;vaccine trial;variant of unknown significance Mayo Clinic Breast Cancer SPORE NarrativeThe Mayo Clinic Breast Cancer SPORE addresses significant problems relating to breast cancer with the goalof reducing morbidity and mortality from the disease. This will be accomplished through projects focusing onbreast cancer risk prevention and development of a novel approach to treat premenopausal ER+/HER2-breast cancer. The proposed research addresses vitally important issues to an enormous number of womenboth with and at risk of developing breast cancer. NCI 10708025 9/4/23 0:00 PAR-20-305 5P50CA116201-17 5 P50 CA 116201 17 "BASA JANAKIRAM, NAVEENA" 7/1/05 0:00 8/31/27 0:00 ZCA1-SRC(99) 7570767 "GOETZ, MATTHEW PHILIP" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2285993 NCI 1599339 686654 Program Summary/AbstractThis third renewal application of the Mayo Clinic Breast Cancer SPORE is being submitted with the visionthat the burden of breast cancer (BC) can be reduced through the performance of innovative translationalresearch addressing issues of high significance for women. The science of the SPORE includes threetranslational research projects. Project 1: The influence of variants in ER-positive BC predisposition genes onBC risk and response to therapy. This project builds upon the work from the prior funding period where theprincipal investigators (PIs) identified that certain BC predisposition genes (ATM CHEK2 and PALB2) wereassociated mainly with the risk of ER+ BC. The Pis will assess pathogenic variants in ATM BRCA2 CHEK2PALB2 and determine a) age-related risks the risks of contralateral BC and second cancers (ovariancolorectal pancreatic etc.) b) the prognostic effects of these PV and c) the clinical relevance of variants ofuncertain significance in ATM CHEK2 and PALB2. Project 2: Improving the endocrine management ofpremenopausal ER+/HER2- BC brings forward a new ER-targeting drug Z-endoxifen (ENDX) forpremenopausal ER+ BC based on new data that ENDX dually targets both ER and PKC1 with potentprotein downregulation of ER Cyclin D1 and E2F1. This dual targeting is not only unique to ENDX but atthe dosing proposed in the clinical trial ENDX is able to completely block the stimulatory effects ofpremenopausal levels of estrogen. Project 3: Development of a novel multi-antigen BC prevention vaccinefor women with premalignant disease is based on pioneering work of Mayo investigators to develop a novelvaccine that targets six antigens collectively expressed by all BC subtypes. The work in this project will providecritical information that will allow the investigators to a) understand the expression of target antigens duringprogression from normal breast tissue to BC; and b) in the phase I study evaluate blood and breast tissuebiomarkers of immune response. Successful completion of this project will establish the parameters for a phase IIIclinical trial of the vaccine for BC prevention in women with benign breast disease (BBD) with the enormouspotential to drive significant reductions in overall BC incidence and mortality. These research projects aresupported by three highly interactive cores: Core A: Administrative Core Core B: Biospecimen and PathologyCore and Core C: Biostatistics Bioinformatics and Patient Registry Core. A Developmental ResearchProgram will continue to identify and develop research projects that hold the greatest promise to advance tofull SPORE projects and a Career Enhancement Program will continue to identify and support facultyinvestigators in BC translational research that have the greatest potential to become future SPORE leaders.The investigators cores and the research programs in the SPORE are all integrated in the Mayo Clinic CancerCenter. Collectively our SPORE will make discoveries and translate them into the clinic for the benefit ofwomen with or at risk of BC. 2285993 +No NIH Category available Acceleration;Address;Advocate;Affect;Age;Artificial Intelligence;Biological;Biology;Biopsy;Blood;Blood specimen;Cells;Cementation;Clinic;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Colonoscopy;Colorectal;Communities;Complex;Computers;Consent;Data;Dedications;Descriptor;Discipline;Environment;Europe;Feces;Fertilization;Foundations;Future;Gender;Generations;Grant;Harvest;Human;Image;Imaging Techniques;Immune;Immune response;Immune system;Immunity;Immunologist;Immunology;Immunophenotyping;Institution;International;Investigation;Ionizing radiation;Irradiated tumor;Knowledge;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Modeling;Molecular;Neoadjuvant Therapy;Newly Diagnosed;Normal tissue morphology;Operative Surgical Procedures;Outcome;Oxidative Stress Induction;Patients;Peripheral Blood Mononuclear Cell;Physics;Preparation;Procedures;Process;Publications;Radiation;Radiation Oncology;Radiation therapy;Radiobiology;Radiometry;Rectal Cancer;Regulation;Research;Resource Sharing;Sampling;Scientist;Sorting;Specimen;Standardization;Structure;Survivors;System;Technology;Testing;Tissue Banks;Tissues;Training;Translations;Tumor Tissue;Tumor stage;biobank;bioinformatics tool;biological effect of radiation;data acquisition;data harmonization;data sharing;design;effective therapy;experience;insight;international center;longitudinal analysis;lymph nodes;meetings;microbiome;multiple omics;next generation;novel;prospective;radiation effect;radiomics;response;simulation;standard care;stool sample;study characteristics;synergism;tumor Dynamics of Immune Response in Irradiated Rectal Cancer NARRATIVEThe current ROBIN proposal addresses a knowledge gap on how standard radiotherapy affects the patientsimmune system. By inviting patients newly diagnosed with rectal cancer to donate for research small tumor stooland blood samples collected during standard colonoscopy procedure (before and after standard treatment) wewill create a bio-repository (a bank of tissues) to study the characteristics of the tumors that respond to radiationand those that dont: this insight may help avoiding additional treatments in future patients and select others formore effective treatments. We have converged a team of outstanding scientists physicists clinicians and patientadvocates to carry out this task. NCI 10708019 9/14/23 0:00 RFA-CA-21-040 5U54CA274291-02 5 U54 CA 274291 2 "VIKRAM, BHADRASAIN" 9/21/22 0:00 7/31/27 0:00 ZCA1-SRB-X(M1) 6095791 "FORMENTI, SILVIA C." "DEASY, JOSEPH O; WEICHSELBAUM, RALPH R" 12 RADIATION-DIAGNOSTIC/ONCOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 1477107 NCI 1123956 353151 ABSTRACTDespite the recognition of the contribution of the immune system to cancer response to ionizing radiationsuccessful translation to the clinic is lagging. We are proposing to adapt the ROBIN mechanisms of research toenable a deep dive into the field of radiation (RT) and immunity. Representatives from seven internationalacademic centers already engaged in RT and immunity research have converged to participate in a smallprospective clinical trial (accrual: 25 patients in US and 25 patients in Europe) to synergize and acceleratediscovery. The setting of preoperative short course radiotherapy (SCRT) in rectal cancer has emerged as idealfor the scientific questions posed. SCRT is a standard treatment preceded and followed by colonoscopies torespectively assess tumor baseline extent and response (at the end of RT): during each colonoscopy consentingpatients can donate a tumor biopsy as well as stool and blood (PBMC) samples. The same set of specimenscan be harvested six weeks later at surgery where research sampling of lymph nodes will also be possiblewithin and outside the RT field. These sequential sets of tissues will enable us to conduct cutting edge multipleomics approaches to study irradiated normal and cancer tissue and the microbiome in the RT field. The PBMCanalysis will allow correlation at a single cell level between RT-induced oxidative stress changes inimmunophenotype and PBMC biology. Similarly the ability to analyze lymph nodes harvested inside and outsidethe radiation field will allow to pinpoint at the single cell level the RT effects on each immune subpopulation. Thelongitudinal analysis on cancer biopsy collected before and after RT and at surgery will give a snapshot on theRT-induced omics changes. An orthogonal radiomic study will analyze MR images obtained before SCRT andbefore surgery (also standard imaging procedures in rectal cancer) together with images obtained at CTsimulation. Compliance with international regulations for data sharing standardization of procedures and dataacquisition and harmonization of uploaded data will be essential to this effort. Advanced bioinformatics tools willbe applied through a dedicated Data Sharing and Integrative Analysis Core capable to deconvolute and interpretcomplex biological and imaging data sorted by utilizing NCI FireCloud workspaces. By converging experiencedclinical investigators bio-scientists and bio-informaticians to address fundamental radiation biology questionsthis ROBIN will rapidly enable unprecedented discovery that will be shared with the ROBIN network and thescientific community at large.Finally since inception ROBIN has revealed an optimal environment for cross-training and cross-fertilization ofthe scientists and clinicians involved in the grant preparation and has created a robust foundation for theproposed Cross Training Core a novel structure to form future leaders in radiation oncology and biology a taskeach of the three P.I.s consider crucial to the future of our discipline. 1477107 +No NIH Category available Area;Basic Science;Biology;Biometry;Cancer Biology;Clinical;Clinical Research;Education;Epidemiology;Ethics;Exposure to;Faculty;Funding;Institution;Laboratory Research;Malignant neoplasm of prostate;Memorial Sloan-Kettering Cancer Center;Mentors;Participant;Physicians;Prostate;Research;Research Personnel;Resources;Schedule;Scientist;Teacher Professional Development;Training;Translational Research;Visit;anticancer research;cancer genetics;career;design;experience;inter-institutional;interest;knowledge base;lectures;member;professor;programs;recruit;symposium Career Enhancement Program n/a NCI 10708008 8/29/23 0:00 PAR-20-305 5P50CA092629-22 5 P50 CA 92629 22 9/14/01 0:00 8/31/27 0:00 ZCA1-RPRB-8 9625 7076419 "EASTHAM, JAMES A" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 70802 39944 30858 PROJECT SUMMARY/ABSTRACTThe SPORE Career Enhancement Program (CEP) prepares physicians and scientists for independent careersas investigators in translational research in prostate cancer. We have designed the CEP to form both aninterdepartmental and an interinstitutional training ground to produce investigators who will become intellectualleaders in their fields of interest. By combining the research and academic resources available throughoutMemorial Sloan Kettering Cancer Center and at our affiliated institutions we have a long tradition of successfulfaculty development. Recruiting and/or developing the career of junior faculty members committed totranslational research in prostate cancer is a centerpiece of our program. Over the next 5 years we willcontinue to recruit and develop the careers of junior faculty members and experienced investigatorsfromboth basic research and clinical backgroundscommitted to translational research in prostate cancer. +No NIH Category available Animal Model;BRCA2 gene;CHD1 gene;Cell Line;Clinical;Collaborations;DNA;Disease;Doctor of Philosophy;ERBB2 gene;Engineering;Epithelial Cells;Funding;Generations;Genes;Genetic Engineering;Genetically Engineered Mouse;Goals;Histologic;Human;In Vitro;Knock-in Mouse;Knock-out;Malignant neoplasm of prostate;Modeling;Molecular;Mouse Strains;Mus;Mutation;NRG1 gene;Oncogenic;Organoids;PIK3CG gene;Pathway interactions;Patients;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Prostate;Proteins;RNA;Research Personnel;Resources;Services;Tissues;Transgenic Organisms;Translational Research;biobank;castration resistant prostate cancer;design;homologous recombination;human disease;in vivo Model;interest;mouse model;neuroendocrine differentiation;novel;patient derived xenograft model;preclinical trial;prostate cancer model;repository;success;therapy resistant;trial design;validation studies Core D: Preclinical Models Core PROJECT NARRATIVEThe study of prostate cancer has been limited by a lack of quality models that accurately recapitulate itsmolecular and phenotypic diversity. The Preclinical Models Core (Core D) is an essential component of ourSPORE in Prostate Cancer because it will provide unparalleled access to state-of-the-art patient-derived andgenetically engineered models. The core will also provide expert histopathologic analyses and preclinical trialdesign. NCI 10707994 8/29/23 0:00 PAR-20-305 5P50CA092629-22 5 P50 CA 92629 22 9/14/01 0:00 8/31/27 0:00 ZCA1-RPRB-8 9620 8725597 "CHEN, YU " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 212401 119943 92458 PROJECT SUMMARY/ABSTRACTThe overall purpose of the Preclinical Models Core is to facilitate the accomplishment of the translationalresearch goals and objectives of the SPORE by providing investigators with a biobank of state-of-the-artpatient-derived and genetically engineered mouse models (GEMMs) of prostate cancer. These models include23 patient-derived organoid (PDO) lines and 14 patient-derived xenograft (PDX) lines as well as GEMMs ofgenetic alterations studied in the SPORE projects and organoids derived from these models. In addition thePreclinical Models Core will provide assistance in the design and generation of transgenic andknockout/knockin mouse strains and will serve as a centralized repository for these mouse strains andmaterials of common interest such as dissected tissues DNA RNA and protein extracts from these strains.The Preclinical Models Core will generate characterize and maintain clinically and molecularly annotatedPDOs and PDXs for use by SPORE investigators; generate and provide a repository of GEMMs and murineengineered prostate organoid models; and provide histopathologic analyses and design preclinical trials. ThePreclinical Models Core will collaborate with RP-1 to use unique PDOs with mutations in homologousrecombination genes as well as mouse organoids with BRCA2 deletion for validation studies of determinants ofPARP inhibitor sensitivity; with RP-2 to provide genetically defined models for preclinical trials to evaluatetargeting of the NRG1-HER2/3-PI3K pathway and to provide GEMMs to study the prostate microenvironment;and with RP-3 to provide PDX PDO and genetically engineered mousederived organoid models of lineageplasticity. +No NIH Category available Address;Area;Bioinformatics;Biometry;Clinical;Clinical Trials;Clinical Trials Design;Collaborations;Computing Methodologies;Data;Data Analyses;Development;Doctor of Philosophy;Experimental Designs;Formulation;Genomics;Individual;Laboratories;Laboratory Research;Malignant neoplasm of prostate;Memorial Sloan-Kettering Cancer Center;Methodology;Outcome Assessment;Phase;Population;Procedures;Protocols documentation;Randomized;Research;Research Methodology;Research Personnel;Role;Sample Size;Statistical Data Interpretation;advanced prostate cancer;anticancer research;clinical trial analysis;data quality;design;improved;laboratory experiment;member;pre-clinical;preclinical study;preclinical trial;primary endpoint;quality assurance;secondary endpoint;trial design;working group Core C: Biostatistics & Bioinformatics Core PROJECT NARRATIVEThe Biostatistics and Bioinformatics Core assists the research efforts of the Memorial Sloan Kettering CancerCenter SPORE in Prostate Cancer investigators contributing to the design and analysis of clinical genomicand laboratory research and the development of valid conclusions. The core provides statistical analysis andconsultancy as well as ongoing quality assurance. The core has also established a data quality working groupto improve the quality of SPORE data. NCI 10707987 8/29/23 0:00 PAR-20-305 5P50CA092629-22 5 P50 CA 92629 22 9/14/01 0:00 8/31/27 0:00 ZCA1-RPRB-8 9618 6878965 "GONEN, MITHAT " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 212401 119943 92458 PROJECT SUMMARY/ABSTRACTThe role of the Biostatistics and Bioinformatics Core is to support investigators of the SPORE in ProstateCancer at Memorial Sloan Kettering Cancer Center in their research efforts including laboratory experimentsthe design and analysis of clinical trials and bioinformatics analyses. For preclinical studies core members willassist in the formulation of the experimental design and in the analysis and interpretation of the data at theconclusion of the studies. A core member will conduct a protocol review with SPORE investigators during theclinical trial design phase. Based on this review we will provide a statistical section for the protocol outliningmajor scientific objectives population to be studied primary and secondary endpoints experimental design arandomization procedure if necessary analysis plans and a targeted sample size justified in probabilisticterms. At the conclusion of the trial data analyses will be performed to assess outcomes of the primary andsecondary endpoints stated in the protocol. A similar strategy will be employed for genomic analyses and coremembers will be integrated to the individual studies early on remain involved and carry full responsibility for allquantitative aspects. +No NIH Category available Acidosis;Adjuvant;Aftercare;Arteries;Biological Markers;Biopsy Specimen;Biosensor;Cancer Etiology;Catheters;Cell Density;Cells;Cellularity;Cessation of life;Chemoembolization;Classification;Clinical;Clinical Treatment;Collaborations;Combination immunotherapy;Combined Modality Therapy;Data Pooling;Decision Making;Development;Environment;Goals;Grant;Graph;Guidelines;Habitats;Hepatocyte;Human;Image;Image Analysis;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunobiology;Immunologics;Immunotherapy;Individual;Intervention;Joints;Learning;Lesion;Liver;Liver neoplasms;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Manuals;Maps;Measurement;Measures;Medical Oncology;Metabolic;Metabolism;Methods;Modality;Modeling;Multimodal Imaging;Neoadjuvant Therapy;New Zealand;Oryctolagus cuniculus;Outcome Assessment;Palliative Care;Pathology;Patient Care;Patients;Pattern;Phase;Phenotype;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Recurrence;Resolution;Standardization;Structure;Therapeutic;Time;Tissues;Translating;Tumor Volume;Western World;X-Ray Computed Tomography;automated segmentation;biomarker development;cancer therapy;chemotherapy;clinical decision-making;clinical outcome assessment;cohort;cone-beam computed tomography;contrast enhanced;convolutional neural network;deep learning;design;extracellular;feeding;graph neural network;image guided;image registration;imaging biomarker;imaging informatics;immune activation;improved;in vivo;innovation;intrahepatic cancer;ischemic injury;learning strategy;liver cancer model;machine learning method;magnetic resonance imaging biomarker;magnetic resonance spectroscopic imaging;metabolic imaging;minimally invasive;neoplastic cell;non-invasive imaging;novel;novel strategies;outcome prediction;permissiveness;pre-clinical;predicting response;radiomics;random forest;recruit;response;spatiotemporal;spectroscopic imaging;therapy outcome;treatment strategy;treatment stratification;tumor;tumor microenvironment;tumor progression Quantitative Multimodal Imaging Biomarkers for Combined Locoregional and Immunotherapy of Liver Cancer Project NarrativeThis grant is aimed at enhancing our ability to study and assess liver cancer treatment using locoregional therapyin combination with systemic immune therapy. At the core of this effort is the unmet need for advanced imag-ing which can track the combined locoregional and immune therapies and to that end we will develop evaluateand translate advanced imaging machine learning and image analysis methods to predict and assess clinicaloutcome with non-invasive imaging biomarkers based on characterization of liver tumor microenvironment. Theresulting predictions and assessments will lead to improved patient care through more informed treatment strati-cation and clinical decision making. NCI 10707985 8/8/23 0:00 PAR-19-158 5R01CA206180-07 5 R01 CA 206180 7 "ESPEY, MICHAEL G" 8/1/16 0:00 8/31/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 1878213 "DUNCAN, JAMES S" "MADOFF, DAVID C" 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 576314 NCI 378485 197829 Project SummaryLiver cancer is the fourth most common cause of cancer-related death worldwide. Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer and is on the rise in the western world. Minimally inva-sive catheter-based locoregional therapies (LRT) such as transarterial chemoembolization (TACE) are now themainstay treatments for intermediate to advanced stage HCC and are included in all management guidelines.TACE is a palliative therapy that prolongs survival by controlling intra-hepatic tumor progression via targeted is-chemic injury paired with the delivery of highly concentrated chemotherapy into the tumor-feeding artery. Morerecently systemic immunotherapies (IMT) specically immune checkpoint inhibitors have emerged as an im-portant treatment option for HCC to boost the body's own immune response against the tumor. While IMT ispromising for many cancers only 15-30% of HCC patients respond to this type of therapy. TACE is increasinglyused in conjunction with IMT both in neoadjuvant and adjuvant scenarios. Recent efforts show that TACE candramatically alter the tumor microenvironment (TME) to become more immune-permissive enabling more ef-fective immune cell recruitment against the tumor through IMT. Thus the LRT+IMT combination is a likely pathforward for HCC treatment strategies. In this context there is an urgent and unmet clinical need for robust non-invasive quantitative biomarkers to help guide therapeutic decision making and assess therapeutic outcome earlyduring treatment. Previously our team developed clinical and preclinical advanced imaging image analysis andimaging biomarkers to study guide and assess HCC treatment with TACE alone using multiparameter magneticresonance imaging (mpMRI) and magnetic resonance spectroscopic imaging (MRSI). We developed randomforests and convolutional neural networks for liver segmentation tissue classication and nonrigid registration tomap these results into the clinical treatment environment. Using graph convolutional neural networks we pre-dicted and assessed therapeutic outcomes. In a rabbit model of liver cancer (VX2) using Biosensor Imaging ofRedundant Deviation in Shifts (BIRDS) we successfully characterized the metabolic state of the TME with respectto extracellular acidosis before and after TACE. We now propose to develop robust quantitative biomarkers forcombined LRT+IMT assessment and outcome prediction in humans. We will develop novel image analysis (JointDomain Learning with Structure-Consistent Embedding by Disentanglement) and characterize the changing TMEover the course of LRT+IMT by deriving information from longitudinal mpMRI (with liver-specic contrast) and/ormultiphase computed tomography (mpCT) learning across modalities via domain adaptation. Since LRT+IMT isexpected to reduce extracellular acidosis in treated liver tumors we propose to develop high-resolution advancedBIRDS in the rabbit VX2 model with novel machine learning to spatially characterize changes in extracellularacidosis due to LRT+IMT enabling focus on the peritumoral region where immune activation is most enhanced.These developments will ultimately facilitate personalized HCC treatment stratication. 576314 +No NIH Category available Antibodies;Bioinformatics;Biological;Biological Assay;Biological Markers;Biological Specimen Banks;Biometry;Biopsy;Blood;Blood specimen;Cancer Intervention;Characteristics;Clinical;Clinical Chemistry;Clinical Laboratory Improvement Amendments;Clinical Trials;Collaborations;Communities;Consent;Credentialing;Diagnostic;Disease model;Documentation;Evaluation;Formalin;Freezing;Gene Expression Profiling;Genes;Genetic;Genomics;Germ Lines;Goals;Guidelines;Image;In Situ Hybridization;Individual;Institutional Review Boards;Laboratories;Malignant neoplasm of prostate;Measures;Methodology;Microdissection;Morphology;Mus;Needle biopsy procedure;Neoplasm Metastasis;Nucleic Acids;Paraffin Embedding;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Performance;Pharmacogenomics;Phenotype;Pilot Projects;Plasma;Play;Pre-Clinical Model;Preparation;Process;Prostate;Proteomics;Protocols documentation;Publications;Quality Control;Radical Prostatectomy;Recording of previous events;Research;Research Personnel;Research Project Grants;Research Support;Role;Sampling;Scanning;Serum;Services;Specimen;Stains;Standardization;System;Tissue Embedding;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translational Research;Tube;Validation;Whole Blood;Work;Xenograft Model;animal tissue;anticancer research;data quality;design;digital;exosome;follow-up;human tissue;improved;mouse model;neoplasm resource;novel;novel marker;participant enrollment;prospective;prostate cancer model;quality assurance;relational database;tissue archive;tumor;web site Core B: Biospecimen Repository PROJECT NARRATIVEThrough the work of the MSK SPORE in Prostate Cancer supported by the Biospecimen Repository Core wehope to increase our understanding of the clinical biologic and genetic basis of prostate cancer to improvepatient outcomes; to facilitate a range of scientific activities that could lead to new genomic- and proteomic-based interventions for cancer including target identification and validation; and to develop new biomarkersdiagnostics and pharmacogenomic analyses. NCI 10707981 8/29/23 0:00 PAR-20-305 5P50CA092629-22 5 P50 CA 92629 22 9/14/01 0:00 8/31/27 0:00 ZCA1-RPRB-8 6611 10395091 "GOPALAN, ANURADHA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 247801 139943 107858 PROJECT SUMMARY/ABSTRACTThe Biospecimen Repository Core is designed to provide support to the basic translational research efforts ofthe SPORE. The Core will continue to play a central role in collecting annotating storing distributing andtracking prostate cancer tissue and blood biospecimens from patients enrolled in research protocols. Detailedbiospecimen annotation including documentation of pre-analytic processing variables pathology findings andpatient clinical history information will be recorded in robust relational databases. We will conduct rigorous dataquality assurance and quality control measures and standardized longitudinal follow-up of all consentedpatients with materials in the prostate biospecimen repository. The Core will provide SPORE investigators withexpert histopathological evaluation of tumor samples both from patients enrolled on research protocols andfrom xenograft models. The Core will also provide assistance in performing and interpretingimmunohistochemical and in situ hybridization assays in selecting tissue for microdissection and constructionof arrays and in collaborating with project leaders and the directors of the Biomarkers Core and theBiostatistics and Bioinformatics Core. This project will maintain and expand a model prostate cancer resourceto collect annotate store and distribute biospecimens for translational prostate cancer research; performsystematic pathologic evaluation of all human and animal tissue samples and preparation of appropriatetissues for use by SPORE investigators; and collect process annotate store and distribute blood specimensunder Clinical Laboratory Improvement Amendments (CLIA)regulatory conditions for use by SPOREinvestigators. +No NIH Category available Acetates;Address;Adjuvant Study;Androgen Receptor;Androgens;Automobile Driving;Basic Science;Cells;Clinical;Clinical Sciences;Clinical Trials;Cytokine Receptors;DNA Sequence Alteration;Data;Dependence;Development;Disease;Disease Progression;Doctor of Philosophy;ERBB2 gene;Epithelial Cells;Generations;Genes;Genetically Engineered Mouse;Goals;Growth Factor;Hormones;Human;Individual;Ligands;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Mediating;Mediator;Metastatic Prostate Cancer;Molecular;Mus;Neoadjuvant Therapy;Neuregulin 1;Nonmetastatic;PI3K/AKT;PIK3CG gene;PTEN gene;Pathologic;Pathway interactions;Patients;Phase;Phase III Clinical Trials;Play;Population;Population Dynamics;Pre-Clinical Model;Precision medicine trial;Prevalence;Prior Therapy;Prostate;Prostate Cancer therapy;Prostatectomy;Proto-Oncogene Proteins c-akt;Radical Prostatectomy;Receptor Inhibition;Receptor Signaling;Recurrence;Reporting;Resistance;Role;Science;Shapes;Signal Transduction;Specimen;Stromal Cells;Technology;Therapeutic;Time;Tissue-Specific Gene Expression;Work;abiraterone;advanced prostate cancer;androgen deprivation therapy;antagonist;cancer cell;cancer initiation;castration resistant prostate cancer;cell growth;clinical development;cytokine;disorder control;early phase clinical trial;enzalutamide;high risk;improved;inhibitor;men;novel;novel strategies;phase III trial;precision medicine;preclinical trial;primary endpoint;prostate cancer cell;prostate cancer model;prostate cancer risk;receptor;response;single cell sequencing;single-cell RNA sequencing;synergism;targeted treatment;therapeutic target;tumor microenvironment Project 2: Overcoming Microenvironment-Mediated Resistance to AR Pathway Inhibition in High-Risk Prostate Cancer PROJECT NARRATIVEAndrogen blockade forms a main pillar of prostate cancer treatment but even potent second-generationandrogen receptor signaling inhibitors are only effective for a limited time with most cancers ultimatelyprogressing. We recently discovered a cellular growth factor neuregulin 1 secreted by the local prostatecancer microenvironment that promotes the survival of prostate cancer cells under conditions of androgenblockade. We aim to 1) study whether targeting neuregulin 1 can make androgen-directed therapies moreeffective 2) discover other microenvironment-mediated mechanisms driving resistance to androgen-targetedtherapies and 3) develop therapeutic strategies to overcome these mechanisms to improve the cure rates formen with high-risk prostate cancer. NCI 10707969 8/29/23 0:00 PAR-20-305 5P50CA092629-22 5 P50 CA 92629 22 9/14/01 0:00 8/31/27 0:00 ZCA1-RPRB-8 6609 7835134 "CARVER, BRETT STEWART" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 371701 209943 161758 ABSTRACT/SUMMARYThe majority of prostate cancers are dependent on androgen receptor (AR) signaling across clinical diseasestates. While initially approved for patients with metastatic castration-resistant prostate cancer recent phase IIItrials have shown that second-generation AR pathway inhibitors (abiraterone acetate enzalutamideapalutamide darolutamide) convey even greater benefit when used earlier in the disease course in patientswith metastatic hormone-sensitive and non-metastatic castration-resistant prostate cancer. Indeed thisconcept has also extended to the neoadjuvant treatment of patients with locally advanced high-grade primaryprostate cancer. However despite potent AR inhibition complete pathologic response rates have remainedlow. Thus there is a significant need to further define the mechanisms driving resistance to AR-targetedtherapies in this unique context and develop therapeutic strategies that enhance response rates in patientswith high-risk localized prostate cancer to shift the treatment paradigm from disease control to cure.Through single-cell RNA sequencing studies of human and mouse prostates we recently discovered thatneuregulin 1 (NRG1) is an AR-regulated gene in normal prostate stromal cells critical to sustaining survival ofnormal luminal epithelial cells. Parallel studies in prostate cancer preclinical models revealed that stromal-derived NRG1 in the prostate cancer microenvironment promotes cancer cell persistence following AR-targeted therapies. Secreted NRG1 promotes resistance through HER2/3-PI3K/AKT-mediated signaling inprostate cancer epithelial cells. We are now poised to define the NRG1 downstream signaling nodes drivingcancer cell persistence to AR targeted therapies and optimize therapeutic strategies targeting the NRG1 axis incombination with AR inhibition. We will investigate the effects of targeting individual nodes of the NRG1-HER2/3-PI3K pathway to overcome resistance to AR-targeted therapies in preclinical trials using clinical-gradeinhibitors of NRG1 HER2/3 PI3K and AKT in combination with AR antagonists. Furthermore in the proposedproject we will take a comprehensive approach to defining the microenvironmental mechanisms contributing toprostate cancer cell persistence after AR-targeted therapy. Using single-cell sequencing technology we willdefine the changes in prostate cancer microenvironmental cell populations following AR inhibition and evaluatedifferential gene expression within these cell populations to identify novel cytokine-receptor pairs contributingto cancer cell persistence in primary and metastatic prostate cancers. Finally we will conduct a phase Ib/IIneoadjuvant clinical trial of PI3K (copanlisib) and androgen-deprivation therapy prior to prostatectomy inpatients harboring loss of PTEN an established mediator of resistance to AR-targeted therapies. Our collectivework will set the path for novel precision medicinebased neoadjuvant trials to improve the cure rates of menwith high-risk localized prostate cancer. +No NIH Category available Accounting;Affinity;Amino Acids;Apoptosis;Apoptotic;Autophagocytosis;BRAF gene;Binding;Biological;Biological Process;C-terminal;Cancer Cell Growth;Cancer cell line;Cell Proliferation;Cell Respiration;Cell membrane;Cells;Consumption;Cytoplasm;Development;Dimerization;Disease;Eating;Epithelium;Exhibits;FRAP1 gene;Family member;Fatty Acids;GTP Binding;Genetically Engineered Mouse;Goals;Grant;Growth;Guanosine Triphosphate Phosphohydrolases;Heterodimerization;Homodimerization;Human;Incidence;Inhibition of Cancer Cell Growth;Inhibition of Cell Proliferation;KRAS oncogenesis;KRAS2 gene;KRASG12D;Laboratories;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mediating;Membrane;Metabolic;Mutation;N-terminal;Neoplasm Metastasis;Nuclear;Nutrient;Oncogenic;Organelles;Ovarian Carcinoma;Ovarian Serous Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Peptides;Physiological;Prevalence;Prognosis;Proteins;RAS driven cancer;RAS inhibition;Ras Inhibitor;Recurrent disease;Role;STK11 gene;Serous;Signal Induction;Signal Pathway;Signal Transduction;Site;Surface;Testing;Therapeutic;Tumor Suppressor Proteins;Xenograft procedure;cancer cell;cell growth;cell motility;cell transformation;cellular engineering;dimer;inhibition of autophagy;inhibitor;migration;monomer;mutant;myristoylation;nanocluster;new therapeutic target;novel;novel strategies;novel therapeutic intervention;novel therapeutics;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;prenylation;rare cancer;response;stapled peptide;targeted treatment;treatment strategy;tumor DIRAS3 disrupts K-RAS clustering and signaling enhancing autophagy and response to autophagy inhibition KRAS drives transformation and growth of human cancers from several sites including pancreatic ductaladenocarcinoma (PDAC) and low-grade serous ovarian cancer (LGSOC) but therapy targeting KRAS remainsa work in progress. Upon completion of this grant we will better understand the role for DIRAS3 a tumorsuppressor in targeting KRAS inducing autophagy and potentiating the pro-apoptotic activity of autophagyinhibitors in PDAC and LGSOC opening a new approach to treating KRAS mutant cancers by inhibiting KRASdimerization/nanoclustering increasing autophagy and enhancing sensitivity to autophagy inhibitors. NCI 10707965 8/10/23 0:00 PA-20-185 5R01CA266187-02 5 R01 CA 266187 2 "SALNIKOW, KONSTANTIN" 9/21/22 0:00 8/31/27 0:00 Tumor Cell Biology Study Section[TCB] 2717823 "BAST, ROBERT C" "LU, ZHEN " 9 MISCELLANEOUS 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 667020 NCI 461473 205547 Mutant KRAS drives human cancers from several sites including pancreatic ductal adenocarcinoma (PDAC)and low-grade serous ovarian cancer (LGSOC). Despite the prevalence of RAS mutations in different cancerseffective RAS-targeted treatment remains a challenge. KRAS monomers form homodimers and nanoclusters inthe cell membrane to optimize signaling and to transform cells efficiently. Dimerization of KRAS is required forRAS-driven transformation and cancer growth. Agents that disrupt mutant RAS dimers and clusters can blockoncogenic activity. Recent evidence indicates that inhibition of RAS signaling induces autophagy and enhancesthe response to anti-autophagic therapy. Despite four decades of effort development of effective strategies forthe treatment for mutant KRAS-driven cancers remains a work in progress. Our laboratory has discovered anovel endogenous physiological RAS inhibitor designated DIRAS3 a 26 KDa GTPase sharing 50-60% homologywith classical RAS family members but with a distinctive 34 amino acid N-terminal extension that reverses RASfunction. Like RAS DIRAS3 is prenylated at the C-terminal CAAX site binds GTP with high affinity exhibitsweak GTPase activity and requires membrane association for its biological function. DIRAS3 is downregulatedin a number of cancers including PDAC and LGSOC and re-expression of DIRAS3 blocks cancer cellproliferation inhibits motility and importantly induces autophagy by multiple mechanisms. Recently we havefound that DIRAS3 and a DIRAS3-derived stapled peptide from its 5 domain interact directly with mutant KRASreducing KRAS dimerization and nanoclustering and inhibiting KRAS signaling. Both intact DIRAS3 andDIRAS3-derived stapled peptide induce autophagy and potentiate the pro-apoptotic activity of autophagyinhibitors in PDAC and LGSOC cells. In this proposal we will study the effect of DIRAS3 on KRAS-dependentcell growth migration and effector signaling in MEF cells and genetically engineered mouse model with mutantKRAS as well as in KRAS-driven PDAC and LGSOC better defining the mechanism by which DIRAS3 inhibitsKRAS (Aim 1). We will investigate the mechanisms by which DIRAS3 induces autophagy in KRAS-driven PDACand LGSOC (Aim 2). Finally we will test the ability of DIRAS3 or a DIRAS3-derived stapled peptide incombination with autophagy inhibitors (CQ/DC661) to enhance apoptosis and growth inhibition in PDAC andLGSOC (Aim3). These studies will not only lay the groundwork for exploring new therapeutic strategies targetingKRAS-mutant cancers but also contribute to a fundamental understanding of the mechanisms by which DIRAS3as a tumor suppressor inhibits mutant KRAS activity and induces autophagy. 667020 +No NIH Category available Acceleration;Adult;Cancer Center;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cancer Survivor;Caring;Data;Effectiveness;Electronic Health Record;Equity;Health;Health Care Costs;Intervention;Malignant Neoplasms;Methods;Modification;NCI-Designated Cancer Center;National Cancer Institute;Oncology;Outcome;Patients;Policies;Primary Care;Principal Investigator;Program Effectiveness;Recovery;Research;Senior Scientist;Smoke;Smoking;Smoking Cessation Intervention;Smoking treatment;System;Treatment outcome;cancer care;cancer therapy;cigarette smoking;clinical care;contextual factors;cost;cost effectiveness;demographics;design;evidence base;experience;implementation context;implementation strategy;improved;intervention delivery;patient engagement;pragmatic implementation;programs;smoking cessation;tool;treatment program Leveraging the National Cancer Institutes Cancer Center Cessation Initiative (C3I) Program to Evaluate and Transform Smoking Cessation Treatment in Cancer Care PROJECT NARRATIVESmoking is both common among adult patients with cancer and undertreated despite strong evidence thatquitting smoking markedly improves the health of cancer patients and survivors. Too few patients with cancerwho smoke are offered and provided effective smoking treatment by their cancer care teams. The proposedresearch will identify and disseminate effective and feasible smoking treatment programs for cancer centers toincrease the rates at which cancer patients who smoke quit smoking and improve their cancer recovery. NCI 10707958 8/8/23 0:00 PAR-21-333 5R35CA197573-09 5 R35 CA 197573 9 "REYES-GUZMAN, CAROLYN" 8/1/15 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 1891151 "FIORE, MICHAEL C" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 914341 NCI 588001 326340 PROJECT SUMMARY/ABSTRACTCigarette smoking is both common and undertreated among oncology patients. Although smoking is a leadingcause of cancer and results in worse cancer prognoses only half of cancer patients who smoke are offeredhelp in quitting during cancer care and it is unclear that the help they are offered is effective. This R35proposal is designed to transform oncology practice so that smoking cessation is an integral part of treatmentfor all cancer patients who smoke. Electronic health records (EHRs) have tremendous potential to accelerateimprovements in clinical care by facilitating such treatment delivery. EHR modifications can also increasediscovery by enhancing assessment of smoking treatment reach costs equity and effectiveness both in termsof helping patients quit and improving cancer outcomes. The Principal Investigator has 30 years of experienceleading research and policy efforts to promote the treatment of smoking. Over the past 7 years he has led ateam that developed and evaluated new EHR-based tools and workflows that markedly increase the proportionof adult patients who receive evidence-based smoking cessation treatment in primary care. The new R35proposal will similarly identify intervention strategies that increase smoking treatment engagement andeffectiveness when implemented in oncologic care. Over the last 4 years the Principal Investigator has servedas Senior Scientist for NCIs Moonshot-supported Cancer Center Cessation Initiative (C3I) a nationwide effortof 52 NCI-designated cancer centers to develop and implement programs to aid their patients who smoke. Yetthis incredibly important initiative has not been systematically assessed in terms of which EHR-enabledinterventions enhance a smoking programs reach patient engagement implementation cessationeffectiveness and benefits. This R35 renewal is designed to do just that by systematically assessing bestpractices via EHR data extraction of intervention delivery healthcare costs short-term cancer treatmentoutcomes overall and by patient demographics. These EHR data will be supplemented by qualitative analysisof C3I smoking treatment components delivery adaptations and contexts in a mixed-methods approach.Higher- and lower-performing smoking treatment programs will be identified and rigorous methods will then beused to select best practice programs from cessation- and cost-effectiveness perspectives. Furtherassessment will identify implementation strategies and contextual factors that may contribute to theeffectiveness of these programs. Best practices from these programs will be implemented in lower-performingC3I programs with research team support in adaptation and implementation. Pragmatic implementation guidesand strategies will be used to disseminate best practices to cancer care programs nationwide. Thus theproposed project seeks to extend and adapt transformative EHR-facilitated system changes that enhancesmoking treatment in primary care to the high-priority cancer care context. The project will demonstrate thebenefits of such system changes to cancer patients in terms of costs smoking cessation and cancer recovery. 914341 +No NIH Category available Area;Bioinformatics;Biological Assay;Biological Markers;Biological Process;Biopsy;Cancer Etiology;Cell Line;Cessation of life;Chronotherapy;Circadian Rhythms;Clinic;Clinical;Clinical Research;Clinical Trials;Code;Colon Carcinoma;DNA Repair;DNA biosynthesis;Data;Data Science;Decision Making;Detection;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Dose;Effectiveness;Endoscopic Biopsy;Event;Excision;Genes;Goals;Heterogeneity;Hour;Human;Incidence;Individual;Individuation;Knowledge;Learning;Link;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Maps;Medicine;Methods;Molecular;Molecular Abnormality;Molecular Profiling;Motivation;Operative Surgical Procedures;Organ;Organoids;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathologic;Pathway interactions;Patients;Pattern;Periodicity;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Precision therapeutics;Prognosis;Proteins;Protocols documentation;Randomized;Research;Retroperitoneal Space;Role;Sampling;Shapes;Solid Neoplasm;Source;Technology;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Treatment Efficacy;Tumor Tissue;Variant;Work;cancer subtypes;cancer type;chemotherapy;circadian;circadian pacemaker;clinical application;disease prognosis;drug efficacy;effective therapy;fighting;high reward;high risk;improved;innovation;insight;inter-individual variation;interest;malignant breast neoplasm;next generation sequencing;novel;novel therapeutic intervention;pancreatic ductal adenocarcinoma cell;personalized approach;personalized medicine;pre-clinical;precision medicine;preclinical study;response;screening;side effect;standard of care;therapeutic target;transcriptomics;treatment strategy;tumor Development of a precision medicine platform for circadian based therapeutics in pancreatic cancer NarrativePancreatic ductal adenocarcinoma (PDA) is a deadly cancer for which there are few effective treatmentoptions. Multiple targetable pathways in cancer show circadian rhythmicity in a tumor specific manner.Therefore the time of treatment (chronotherapy) can influence the efficacy of therapies in PDA. To advancemore targeted personalized circadian medicine approaches for PDA patients there is a critical need to gainknowledge of normal pancreatic rhythms and identify tumor specific rhythms and markers to guidechronotherapy. We propose to develop and optimize new pre-clinical protocols using normal pancreas andpatent derived organoid cultures to inform the way treatment decisions are made within the context of PDA. NCI 10707929 8/16/23 0:00 RFA-RM-21-017 5R01CA279487-02 5 R01 CA 279487 2 "AMIN, ANOWARUL" 9/21/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-BST-J(70)R] 11204459 "BISHEHSARI, FARAZ " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 68610245 C155UU2TXCP3 68610245 C155UU2TXCP3 US 41.87506 -87.668327 6644301 RUSH UNIVERSITY MEDICAL CENTER CHICAGO IL SCHOOLS OF MEDICINE 606123833 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 703616 OD 451664 251952 AbstractPancreatic ductal adenocarcinoma (PDA) is among the most fatal of all cancers and is on track to become thesecond-leading cause of cancer-related death in the US by 2030. There is significant heterogeneity among PDAtumors mitigating the effectiveness of conventional chemotherapy and highlighting the need for moreindividualized approaches to treatment. Personalized medicine (PM) strategies which take tumor and/or patient-specific data into account when deciding on a course of treatment have shown great promise within the contextof many different types of cancers in recent preclinical and clinical studies. However most PM approaches relyon molecular profiling data that require relatively large samples of tumor tissue. Unlike other cancers in whichsurgical resection is standard-of-care PDA patients rarely undergo surgery at diagnosis. In the absence ofupfront surgery in the majority of PDA patients access to sufficient tumor tissue for comprehensive molecularand drug profiling in PDA is limited. Patient-derived organoids (PDOs) represent a unique opportunity tocircumvent this limitation. Patient-derived organoids can be successfully established from the scant tissuecollected during endoscopic biopsies which are routine in PDA diagnosis. Moreover such organoids canrecapitulate the phenotype of their tissue of origin and can predict patient drug response in clinic. The primarygoal of the current proposal is to establish pre-clinical predictors of tumor-specific circadian clock dynamics andchronotherapeutic efficacy using normal human pancreas tissue well characterized PDA cell lines and patient-specific biopsy-based PDOs. Specifically we will: (1) characterize baseline molecular rhythms and clockdynamics in the normal human pancreas over 24 hours; (2) determine the role of PDA cancer events in tumorclock perturbations and patient survival and (3) validate the use of molecular and drug response profiling datafrom PDOs to inform time-based drug treatment (chronotherapy) strategies. Altogether these studies will helpadvance the use of tumor specific circadian profiles in clinical settings with particular implications for bringingmore individualized and targeted time/circadian-based strategies to PDA patients. 703616 +No NIH Category available Algorithms;Animals;Artificial Intelligence;Biocompatible Materials;Biology;Board Certification;Caring;Cell Line;Cell Therapy;Cells;Clinical;Collaborations;Data;Data Set;Development;Ensure;Film;Goals;Histopathology;Human Resources;Image;Individual;Ions;Laboratories;Machine Learning;Maintenance;Measures;Methodology;Methods;Modification;Molecular;Normal tissue morphology;Pathologist;Radiation;Radiation Oncology;Radiation therapy;Radiobiology;Reagent;Reproducibility;Research;Resource Sharing;Resources;Sampling;Serum;Services;Site;Specimen;Standardization;Techniques;Therapeutic Index;Tissues;Tumor Tissue;X-Ray Computed Tomography;cell repository;clinically relevant;design;dosimetry;experimental study;image guided;improved;irradiation;novel;oncology trial;pre-clinical;programs;technique development;treatment planning;tumor Translational Biology Core Project Narrative (Core B)Core B the Translational Biology core of this program project provides support to the projects for the executionof common methods including animal radiotherapy and histopathological analysis maintenance and forstandardization of cell lines and shared resources. It is also responsible for development of improved methodsfor target identification and treatment planning to improve the accuracy and reproducibility of small animalirradiation. These are essential services that are common to all projects. NCI 10707919 8/24/23 0:00 PAR-20-077 5P01CA257907-02 5 P01 CA 257907 2 9/21/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q 9598 2049271 "GRAVES, EDWARD E" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 278659 185952 92707 Project Abstract (Core B)In this revised application modifications from the previous submission are marked in blue.Core B is designed to provide support to the projects by standardizing common methods and resources ensuringconsistency and quantitative accuracy across the Program Project. Each service of the Core is relevant to andwill be utilized by each project. In addition to providing state-of-the-art preclinical radiotherapy and histopathologyservices in order to bring accurate and reproducible methodology across the program project we will alsoleverage the data generated in this effort in order to develop automated target delineation and treatment planningalgorithms using machine learning and artificial intelligence approaches. The goals of Core B are fourfold andencompass both service and technique development efforts:Specific Aim 1: Treat tumors and normal tissues in small animals with radiation using clinically relevant conformal image-guided techniques.Specific Aim 2: Utilize artificial intelligence and machine learning techniques to automate tissue and tumor segmentation and radiation treatment plan definition.Specific Aim 3: Perform histopathologic analysis of tissue specimens collected from experimental subjects.Specific Aim 4: Provide a centralized repository of cell lines animal strains media and serum for eachproject. +No NIH Category available Administrator;Animals;Applications Grants;Area;Bioinformatics;Biometry;Biostatistics Core;Collaborations;Computer software;Data Analyses;Doctor of Philosophy;Ensure;Expenditure;Goals;Grant;Human Resources;Infrastructure;Institution;Leadership;Malignant Neoplasms;Molecular;Monitor;National Cancer Institute;Office of Administrative Management;Persons;Preparation;Principal Investigator;Program Research Project Grants;Progress Reports;Protocols documentation;Publications;Radiation Oncology;Radiation therapy;Reagent;Regulation;Reporting;Research;Research Design;Research Personnel;Resource Allocation;Resources;Role;Science;Therapeutic;Therapeutic Index;Time;Work;Writing;experience;meetings;member;operation;programs;success;virtual Administration Core Narrative (Core A)The success of a Program Project Grant involves statistical assistance fiscal support administrativemanagement and coordination between the projects and cores. In addition the increased administrativerequirements have driven the need for an administrative core. This core will work to ensure that all project andcore leaders have adequate support and time to focus on their science. NCI 10707913 8/24/23 0:00 PAR-20-077 5P01CA257907-02 5 P01 CA 257907 2 9/21/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q 9597 6592029 "LE, QUYNH-THU XUAN" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 387743 254467 133276 Abstract (Core A)Core A functions to provide the leadership interaction and coordination between the different projects of theProgram Project Grant (PPG) in order to help them meet their scientific goals. Core A will work to ensure: (1)that robust and timely statistical support is provided to all projects and Core B (2) that the resources of the PPGare distributed fairly among the projects (3) that the regulations of the National Cancer Institute (NCI) are fulfilledand (4) that technical support for hardware and software is supplied. It can be divided into two sections: scientificsupport and administrative support.Support for biostatistics and bioinformatics is crucial for study design and data interpretation; thus it is animportant scientific function of Core A. A large team of highly experienced biostatisticians and bioinformaticians(Ying Lu Ph.D. Rie vonEyben M.S. Andre Shultz Ph.D. and Subarna Sinha Ph.D.) will provide the neededstatistical support to all PPG members. In addition Dr. Lu who is the co-director of the Stanford Cancer InstituteBiostatistics Core is able to mobilize additional statistical support from this larger core to assist the PPG asneeded. Other important functions of the scientific support will be: (1) to organize and hold regular meetings ofthe project/ core leaders and key personnel (2) to convene Executive Committee meetings to review theprogress and scientific direction of the grant and (3) to organize an annual retreat with the members of theExternal Advisory Board (EAB) to review the progress of the PPG as a whole. Mr. Frank Chavez will act as theAdministrative Coordinator of this PPG. He is currently the research program manager in the Department ofRadiation Oncology and has been working closely with the principal investigators (PIs) project and core leadersin the preparation of the grant application. He has also been coordinating their bi-weekly meetings/ calls in thelast year. Mr. Eric Alemany will provide the technical support for all software and hardware problems andquestions. He has served in this role for 10 years in a previous PPG within the department and therefore isfamiliar with the needed IT support and infrastructure. The administrative core will also be responsible forsubmitting the yearly PPG progress report to the NCI including the written report of the EAB.An important aspect of administrative support will be to monitor the dispersion of financial resources and researchallocations. The PPG Executive Committee which is composed of all four project leaders will meet twice a year toreview expenditures and resource allocations for the projects and cores. Ms. Joyce Chao who has been afinance analyst in the Department of Radiation Oncology for the past 6 years will serve as the financialadministrator for this proposed PPG.An additional function of the administrative core will be to disseminate information on Stanford seminars that arebroadly related to the scientific directions of the PPG. A final aspect of the scientific support will be to ensure thatall investigators are using common reagents to maintain uniformity in animal and experimental protocols. +No NIH Category available Adopted;Antibiotic Resistance;Bacteria;Bar Codes;Basic Science;Biological Assay;Biopsy;Blinded;Blood;Blood Circulation;Blood specimen;Cancer Biology;Cancer Detection;Cancer Patient;Carcinogens;Cells;Clinic;Clinical;Clinical Management;Clinical Trials Design;Colonoscopy;Consent;Coupled;DNA;DNA sequencing;Detection;Discipline;Disease;Early Diagnosis;Early Intervention;Engineering;Experimental Designs;Genes;Hematopoietic Neoplasms;Human;Individual;Institutional Review Boards;KRAS2 gene;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Methods;Microbiology;Molecular;Monitor;Mus;Mutation;Mutation Detection;Neoplasm Circulating Cells;Oncogenic;Oncologist;Pathologist;Patients;Performance;Point Mutation;Population;Protocols documentation;Publishing;Radiology Specialty;Recurrence;Recurrent disease;Reporting;Reproducibility;Research Personnel;Resected;Sampling;Scientist;Screening for cancer;Source;Stream;Technology;Testing;Tissues;Translating;Tumor Tissue;biobank;cancer care;cancer cell;cancer type;clinical care;clinical development;deep sequencing;detection assay;detection limit;detection sensitivity;driver mutation;experience;extracellular vesicles;head-to-head comparison;high risk;improved;innovation;liquid biopsy;mutant;mutational status;new technology;next generation sequencing;novel strategies;prospective;research study;resistance mutation;screening;targeted sequencing;tumor;tumor DNA Adapting K-MDS to detect KRAS-mutant ctDNA PROJECT NARRATIVEEarly detection of cancer holds great promise as a way to identify cancer at a curative stage or recurrent diseasebefore radiologically visible to initiate treatment at a more vulnerable stage of disease. As such our approachto develop an ultra-sensitive method to detect cancer DNA in the bloodstream has significant clinical implications. NCI 10707899 8/14/23 0:00 RFA-CA-21-003 5R21CA257816-02 5 R21 CA 257816 2 "HODGES, NICHOLAS AARON" 9/21/22 0:00 8/31/25 0:00 ZCA1-TCRB-D(J1) 6388871 "COUNTER, CHRISTOPHER M" "ABBRUZZESE, JAMES L." 4 PHARMACOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 184406 NCI 114538 69868 PROJECT SUMMARY/ABSTRACTDNA shed from tumors into the blood stream termed circulating tumor DNA (ctDNA) is an easily obtained sourceof tumor material. As most ctDNA is identical to normal DNA some distinguishing feature is needed to demarka cancer origin. In this regard a fifth or more of all human cancers harbor a cancer-causing (oncogenic) pointmutation in the gene KRAS. This raises the exciting possibility that sequencing for the presence of KRAS-mutantctDNA could be used to detect many types of cancers from a simple blood draw. Indeed the Guardant360ctDNA-detection assay is used for just this purpose in the clinical care of cancer patients. The challenge todetecting ctDNA is that this form of DNA is found at vanishingly low levels in the blood. This limitation is borneout in our own clinical experience at Duke where we find that the Guardant360 assay successfully detectedKRAS-mutant ctDNA in only half the cases in which the patient's cancer was documented to be KRAS mutation-positive by direct sequencing of resected or biopsy tumor tissue. Thus while Guardant360 is real-world proofthat ctDNA can be used as a `liquid biopsy' in the clinic there is clearly much room for improvement. In thisregard we adopted the Maximum Depth Sequencing (MDS) technology originally developed in the microbiologyfield to detect rare antibiotic-resistance mutations in bacteria populations to detect oncogenic mutations inKRAS. By barcoding the original KRAS template and making multiple first-strand replicates thereof coupledwith ultra-deep sequencing of these targeted DNA products we were able to detect mutations engineered intoKRAS templates at a limit of 5x10-7 which is 2500 to 50000 times more sensitive than the detection limit of1x10-3 to 2x10-4 reported for the Guardant360 assay. Given this we will combine the basic research of Dr.Counter into this KRAS-specific MDS (K-MDS) assay with the clinical and translational expertise of oncologistDr. Abbruzzese to optimize the K-MDS assay for blood samples (aim 1) and then evaluate K-MDS toGuardant360 a prospective clinical comparison (aim 2). Completion of this study will thus provide an newtechnology to screen for KRAS-mutant ctDNA in the blood of cancer patients at a sensitivity orders ofmagnitude greater than current clinical assays initially to monitor either recurrence of KRAS-mutant cancersor detect such cancers in high-risk patients but more long term in combination with screening for other hotspotmutations and using different sources of tissue for the early detection of multiple cancer types. 184406 +No NIH Category available Anabolism;Cancer Model;Cancer Patient;Cell Line;Chest;Clinical;Clinical Trials;Collaborations;Complement Inactivators;Complement Receptor;Databases;Development;Dose;Esophagus;Free Radicals;Future;Genetic Complementation Test;Genomics;Genotype;Glutaminase;Glutamine;Goals;Head and Neck Cancer;Human;In Vitro;KRAS2 gene;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Mus;Mutagenesis;Mutation;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Operative Surgical Procedures;Pathogenicity;Patient Selection;Patients;Play;Publishing;Radiation;Radiation Oncology;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Recurrence;Resistance;Role;System;Systemic Therapy;Techniques;Testing;Therapeutic Index;Toxic effect;Translating;Work;cancer imaging;cell killing;cell type;cohort;experimental study;high risk;improved;in vivo;inhibitor;irradiation;molecular marker;mutant;mutation screening;mutational status;novel;personalized strategies;personalized therapeutic;predictive marker;protein function;radiation delivery;radiation resistance;radioresistant;side effect;tumor Project 3: Targeting KEAP1-Mediated Radioresistance in Lung Cancer Project Narrative (Project 3)In this study we will test a precision radiation oncology approach for specifically radiosensitizing a radioresistantsubset of non-small cell lung cancers. Our long-term objective is to develop personalized radiation sensitizationstrategies based on tumor genotypes that will broaden the therapeutic index of radiotherapy by maximizing curerates and minimizing side effects. NCI 10707897 8/24/23 0:00 PAR-20-077 5P01CA257907-02 5 P01 CA 257907 2 9/21/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q 9593 10253790 "DIEHN, MAXIMILIAN " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 363155 236836 126319 Abstract (Project 3)Radiation therapy (RT) plays a critical role in the treatment of non-small cell lung cancer (NSCLC). Whileadvances in tumor imaging and radiation delivery techniques have significantly improved RT advances ingenomic and molecular understanding of tumors have largely failed to impact management of patients treatedwith RT. Therefore development of precision radiation oncology approaches defined as the use of molecularbiomarkers to personalize RT remains a major unmet need. Our long-term goal is to develop novelmolecularly-based precision radiation oncology approaches for NSCLC patients treated with RT. We previouslydemonstrated that NSCLCs with KEAP1 or NFE2L2 mutations are radioresistant and have high rates of localrecurrence after RT. In this proposal we will develop a personalized radiosensitization strategy forKEAP1/NFE2L2 mutant tumors based on inhibition of glutaminase which plays a critical role in biosynthesis ofcellular free radical defenses. Prior studies have found conflicting results regarding the ability of glutaminaseinhibition to radiosensitize NSCLC. Our central hypothesis is that glutaminase inhibition can radiosensitizeKEAP1/NFE2L2 mutant but not wildtype NSCLCs and if correct would help explain the previous conflictingresults. We will therefore test if our genotype-specific radiosensitization approach has efficacy in KEAP1/NFE2L2mutant but not wildtype NSCLC in vivo. We will also test if our approach increases normal tissue toxicity.Additionally we will identify specific KEAP1 mutations that cause radioresistance in order to enable identifyingpatients with radioresistant tumors. In collaboration with Project 1 we will also test if the complement inhibitorPMX205 can serve as an additional radiosensitizer for KEAP1/NFE2L2 mutant NSCLC. Finally in collaborationwith Project 2 we will test if glutaminase inhibition can radiosensitize NFE2L2-mutant head and neck cancers.If successful our project will establish glutaminase inhibition as a precision radiation oncology strategy forpersonalized radiosensitization of KEAP1/NFE2L2 mutant NSCLC. This approach could widen the therapeuticindex of RT since it would only expose patients at highest risk of local recurrence to the potential additionaltoxicities of adding a radiation sensitizer. Our results will serve as the basis for developing clinical trials to attemptto translate this strategy. These trials will involve genotyping of NSCLC patients undergoing RT in order to selectpatients with KEAP1/NFE2L2 mutations for concurrent treatment with RT and glutaminase inhibitors. Importantlyour findings will serve as proof-of-principle that can likely also translate to other tumor types with frequentKEAP1/NFE2L2 mutations. +No NIH Category available Address;Adult;Aldehydes;Ames Assay;Apoptosis;Cancer Patient;Cells;Chemopreventive Agent;Chemotherapy and/or radiation;Chest;Clinic;Clinical Trials;Collaborations;Complication;Cytoprotection;Data;Deglutition;Dental caries;Dermatitis;Dose;Eating;Enzyme Activation;Enzymes;Epithelium;Esophageal mucous membrane;Esophagitis;European Organization for Research and Treatment of Cancer;Functional disorder;Genes;Genetic;Gland;Glutaminase;Goals;Head and Neck Cancer;Head and neck structure;In Vitro;Injections;Intensity-Modulated Radiotherapy;Intestinal Mucosa;Knowledge;Location;Mass Fragmentography;Maximum Tolerated Dose;Measures;Mitochondria;Molecular;Morbidity - disease rate;Morphology;Mucositis;Mus;Natural Products;Normal tissue morphology;Oral;Oral Administration;Oral mucous membrane structure;Outcome;Parotid Gland;Pathway interactions;Patient Outcomes Assessments;Patients;Pharmaceutical Preparations;Phase;Plant Extracts;Plasma;Platinum;Procedures;Production;Quality of life;Questionnaires;Radiation;Radiation Injuries;Radiation Protection;Radiation Tolerance;Radiation induced damage;Radiation therapy;Radiosensitization;Reactive Oxygen Species;Recurrence;Rest;Risk;Safety;Saliva;Salivary;Salivary Glands;Skin;Statistical Data Interpretation;Submandibular gland;Survivors;Terpenes;Testing;Therapeutic Index;Time;Tissues;Toxic effect;Work;Xenograft Model;Xenograft procedure;Xerostomia;aldehyde dehydrogenases;bone;cancer cell;cancer radiation therapy;cancer therapy;carcinogenicity;cell killing;chemoradiation;clinical candidate;clinical translation;comparison group;cost;draining lymph node;follow-up;head and neck cancer patient;implantation;improved;in vivo;instrument;irradiation;limonene;mouse model;mutant;novel;novel strategies;oral infection;patient prognosis;phase I trial;preservation;primary endpoint;radioprotected;safety testing;saliva function;side effect;small molecule;stem cell self renewal;stem cell survival;stem cells;treatment duration;tumor growth Project 2: ALDH3A1 Activation for Radioprotection of Salivary Glands and Other Head and Neck Epithelial Tissues Project NarrativeRadiation-induced dry mouth is the most common side effect of head and neck cancer (HNC) treatment and itcan lead to inability to eat a normal meal recurring mouth infection swallowing dysfunction and rare damage tothe jawbone. We have previously found that adult salivary glands harbor stem/ progenitor cells (SSPCs) thatexpress high level of an enzyme called ALDH3A1 and activation of this enzyme with d-limonene (a naturalproduct compound) protects these cells from radiation damage without protection of cancer cells and improvessaliva function after radiation. Therefore we propose to conduct a small clinical trial to test the safety of d-limonene given with radiation and chemotherapy in HNC patients and to identify the maximum dose that istolerable to these patients; at the same time we will also study its effect on protecting other normal tissues fromradiation damage and collaborate with the other projects to develop novel ways to protect salivary glands andother tissues from radiation injury. NCI 10707889 8/24/23 0:00 PAR-20-077 5P01CA257907-02 5 P01 CA 257907 2 9/21/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q 8431 6592029 "LE, QUYNH-THU XUAN" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 392627 257286 135341 Project Abstract (Project 2)Hyposalivation or dry mouth is the most common complication of radiotherapy (RT) in head and neck cancer(HNC). It adversely impacts patients quality of life and places them at risk for significant late morbidities. Currentstrategies to mitigate hyposalivation are costly and ineffective. Intensity modulated radiotherapy (IMRT) whichaims to spare one parotid gland has resulted in improved stimulatory salivary function but it cannot spare thesubmandibular glands which are crucial for resting salivary function throughout the day because of their locationadjacent to the draining lymph nodes. We and others have found that salivary stem/progenitor cells (SSPCs)exist in adult glands and that injection of ~200 of these cells into irradiated murine submandibular glands (SMG)could restore saliva function. We have also found that ALDH3A1 expression is upregulated in SSPCs andthat activation of this enzyme with a small molecular activator before during and after RT resultedincreased SSPC yield and preservation of saliva function after RT. Mechanistically activation ofALDH3A1 enhanced clearance of aldehyde after RT leading less SSPC apoptosis resulting in functionalpreservation. The use of ALHD3A1 activator did not protect HNC from radiation cell kill in a xenograft modeland high expression of this enzyme did not affect the prognosis of patients treated with chemoradiation. Wehave performed a screen from plant extracts and identified a natural product d-limonene which provesto be a highly selective activator of ALDH3A1. Oral administration of d-limonene before during and after RTresulted in preservation of saliva function in mice after RT but did not protect HNC cells from RT cell kill. Mostimportantly d-limonene has been studied as a chemoprevention agent and an anti-cancer therapy in cancerpatients and found to be well tolerated. Because of its favorable safety profile d-limonene is a promising clinicalcandidate for clinical translation.Based on these data from the main objectives of this proposal are: (1) To determine the maximum tolerateddose of d-limonene in patients undergoing chemoradiation for HNC in a phase I dose escalation trial and toobtain preliminary data on the effect of the drug on saliva production and patient quality of life (2) To identify themechanism by which activation of ALDH3A1 in the absence of RT leads to increased SSPC self-renewal (3) Toassess the effect of d-limonene and/or C5aR1 inhibition on radioprotection of other epithelial tissues includingskin oral mucosa and esophageal mucosa. Our ultimate goals are to test whether ALDH3A1 activation withd-limonene can mitigate RT-induced xerostomia in HNC patients and to develop novel approaches toprotect normal tissues from head and neck and thoracic irradiation. +No NIH Category available Animal Model;Apoptosis;Attenuated;Cancer Model;Cell Culture Techniques;Cell Survival;Cells;Clinic;Collaborations;Colorectal Cancer;Colorectal Neoplasms;Complement;Complement Receptor;Data;Dependence;Disease;Ensure;Epithelium;Exhibits;Gastrointestinal tract structure;Genetic;Histologic;Immune;Immunity;In Vitro;Interleukin-10;Intestines;Lung;Macrophage;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Mus;Natural Immunity;Normal tissue morphology;Pathway interactions;Phosphorylation;Population;Process;Proto-Oncogene Proteins c-akt;Radiation;Radiation Protection;Radiation induced damage;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Role;Salivary Glands;Schedule;Signal Transduction;Site;Small Intestines;Stress;TP53 gene;Therapeutic;Therapeutic Index;Tissues;Toxic effect;Tumor Promotion;Tumor Tissue;angiogenesis;antagonist;cell killing;clinical effect;colon cancer cell line;complement pathway;complement system;crypt cell;data sharing;dosimetry;effectiveness evaluation;gastrointestinal;gastrointestinal epithelium;gastrointestinal system;improved;in vivo;inhibitor;intestinal injury;irradiation;molecular targeted therapies;neoplastic cell;pharmacologic;radiation response;radioprotected;recruit;response;targeted treatment;tumor;tumor progression Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors Narrative (Project 1 - Oxford)The main focus of this proposal is to explore how inhibition of the complement pathway regulates the radiationresponse of tissues and tumors and our data show that targeting complement receptor C5aR1 improves radiationresponse in colorectal cancer models while reducing radiation-induced toxicity. No study has evaluated the effectof complement inhibition on both tumor and normal tissue radiation response. Our data therefore suggest thatgenetically or pharmacologically targeting C5aR1 can improve radiation response in colorectal tumor modelswhile reducing radiation-induced small bowel toxicity so together these findings suggest that targetingcomplement could be a promising approach to increasing the therapeutic window of radiotherapy. NCI 10707880 8/24/23 0:00 PAR-20-077 5P01CA257907-02 5 P01 CA 257907 2 9/21/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q 9587 1886037 "GIACCIA, AMATO J." Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 227826 211532 16294 Abstract (Project 1 - Oxford)Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies against cancer-associated pathways. The complement system is an innate immunity pathway with emerging roles in cancerprogression. No study has evaluated the effect of complement inhibition on both tumor and normal tissueradiation response. Here we show that targeting complement receptor C5aR1 improves radiation response incolorectal cancer models while reducing radiation-induced toxicity. Targeting C5aR1 increases IL-10 secretionwhich attenuates NF-B signaling and enhances apoptosis in tumor cells. IL-10-dependent apoptosis isobserved both in vivo and in vitro suggesting a non-canonical stress-specific and likely immune-independent rolefor C5aR1 in regulating apoptosis. Importantly we find that C5aR1 depletion results in decreased small intestinalhistologic damage crypt cell apoptosis and increased survival of mice following irradiation. In the small intestineC5aR1 depletion results in increased IL-10 expression in both non-immune and immune cell populations. IL-10signaling in CX3CR1+ macrophages is important for intestinal injury defense and C5aR1-/- mice have significantlyhigher levels of CX3CR1+ macrophages than WT mice. In response to irradiation C5aR1 depletion does notattenuate NF-B signaling but instead increases AKT activation correlating with decreased apoptosis occurringin an IL-10-depedent manner. Our data therefore indicate that genetically or pharmacologically targeting C5aR1can improve radiation response in colorectal tumor models while reducing radiation-induced small bowel toxicity.Together these findings suggest that inhibiting complement could be a promising approach to increasing thetherapeutic window of radiotherapy. In this Project we propose four specific aims to better understand the roleof C5aR1 in radioprotection and radiosensitization. Aim 1 will determine the broad versus specific protection ofnormal epithelium (intestines salivary glands and lung epithelium) by C5aR1-/- mice in response fractionatedand hypofractionated radiotherapy in collaboration with Projects 2 3 4 and Core B. In Aim 2 we will investigatethe mechanistic basis of radioprotection when C5aR1 is inhibited. Our preliminary data indicates that this is anIL-10 dependent mechanism and involves recruitment of CX3CR1+ macrophages that promote survival andangiogenesis. Aim 3 will determine how C5aR1 promotes tumor cell killing in combination with radiotherapy.The hypothesis based on our preliminary data is that C5aR1 inhibition increases IL-10 secretion whichattenuates NF-B signaling resulting in IL-10 dependent tumor cell killing both in cell culture and in animalmodels. Aim 4 will determine the effect of clinical grade C5aR1 inhibitors on radioprotecting intestine salivaryglands and lungs and sensitizing colorectal tumors to radiotherapy. I intend to return to Stanford on a monthlyor bimonthly schedule and will share this data with my colleagues at Stanford. At Oxford we perform our owndosimetry and will cooperate with Core B at Stanford to ensure comparability of methods. +No NIH Category available Abdomen;Animals;Artificial Intelligence;Biology;Cancer Cell Growth;Cancer Model;Cancer Patient;Cell Line;Cervical;Clinic;Clinical;Clinical Research;Clinical Trials;Collaborations;Complement;Data;Development;Dioxygenases;Doctor of Medicine;Doctor of Philosophy;Drug Targeting;Effectiveness;Epithelium;Family;Feedback;Future;Gastrointestinal Neoplasms;Genomics;Glutaminase;Glutamine;Goals;Grant;Head and Neck Cancer;Head and neck structure;Ionizing radiation;Knowledge;Knowledge acquisition;Lead;Lung;Machine Learning;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Mediating;Metabolism;Molecular;Mutation;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Nutraceutical;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phenotype;Program Research Project Grants;Protein Inhibition;RNA;Radiation;Radiation Protection;Radiation Tolerance;Radiation induced damage;Radiation therapy;Radiosensitization;Role;Safety;Salivary;Salivary Glands;Serum;Solid Neoplasm;Specimen;Structure of parenchyma of lung;Techniques;Testing;Therapeutic Effect;Therapeutic Index;Time;Tissues;Toxic effect;Translating;Tumor Biology;Tumor Tissue;Work;Xerostomia;aldehyde dehydrogenases;alpha ketoglutarate;cell repository;clinical care;clinically relevant;complement pathway;epitranscriptomics;fat mass and obesity-associated protein;head and neck cancer patient;image guided;improved;inhibitor;innovation;limonene;member;mutant;neoplastic cell;novel;novel therapeutics;overexpression;personalized approach;programs;radiation effect;radiation mitigation;radiation resistance;radiation response;radioprotected;radioresistant;stem cell survival;stem cells;treatment planning;tumor Molecular Strategies to Widen the Therapeutic Index of Radiotherapy Narrative (Overall)Acquired knowledge the tumor its microenvironment and the surrounding normal tissues has allowed us toidentify innovative and unique means for normal tissue protection while enhancing tumor sensitivity toradiotherapy. At the same time we augment the precision of these approaches by enriching for patients whowould benefit from radiosensitization. This Program Project Grant focusses on widening the therapeutic index ofradiotherapy through the activation of the Aldehyde Dehydrogenase 3A1 pathway in the treatment of head andneck cancers the inhibition of the Complement C5aR1 pathway in the management gastrointestinal tumorstargeting KEAP1-mediated radioresistance in lung cancer and inhibiting the Fat mass and obesity-associatedprotein (also known as alpha-ketoglutarate-dependent dioxygenase FTO) in cervical lung and head and neckcancers. NCI 10707879 8/24/23 0:00 PAR-20-077 5P01CA257907-02 5 P01 CA 257907 2 "PRASANNA, PAT G" 9/21/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q(O1)S 6592029 "LE, QUYNH-THU XUAN" "DIEHN, MAXIMILIAN " 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 2021847 NCI 1381187 640660 Abstract (Overall)The central hypothesis of this program project grant is that our knowledge of tumor genomics and themicroenvironment combined with our understanding of normal tissue biology can be exploited to protect normaltissues from radiation (RT) damage while selectively killing tumor cells leading to an improved therapeutic index.The projects and cores that comprise this grant represent a highly integrated effort with a single focus ofwidening the therapeutic index of radiotherapy. Project 1 (Giaccia) will modulate the radiosensitivity oftumors and radioprotection of normal tissues via the complement pathway and will aim to understand themechanistic basis of how inhibition of C5aR1 serves to sensitize gastrointestinal (GI) tumors and protectabdominal tissues from RT. They will also explore the role of C5aR1 inhibition in other normal tissues incollaboration with the other projects and cores. Project 2 (Le) will focus on activating Aldehyde Dehydrogenase-3A1 (ALDH3A1) to mitigate RT-induced severe dry mouth in head and neck cancer (HNC) patients by testing d-limonene a novel ALDH3A1 activator identified by their group in a phase I clinical trial. While focusing on HNCthey will evaluate the effect of d-limonene in radioprotecting other normal tissues in collaboration with the otherprojects and cores. Project 3 (Diehn) will develop a personalized radiosensitization strategy for patients withKEAP1/NFE2L2 mutant non-small cell lung cancer (NSCLC) based on their prior work that identified mutationsin this pathway as key determinants of radioresistance in NSCLC patients. They will test the hypothesis thatglutaminase inhibition preferentially radiosensitizes KEAP1 mutant NSCLC without enhancing normal lung tissuetoxicity. While concentrating on NSCLC they will also evaluate the effects of glutaminase inhibition in otherKEAP1/NFE2L2 mutant tumors and its effect on normal tissues in collaboration with other projects and cores.Project 4 (Rankin) tests the hypothesis that inhibition of FTO (Fat mass and obesity-associated protein) an RNAdemethylases would enhance the efficacy of RT in multiple solid tumors. This is based on their preliminary datashowing that FTO is overexpressed in many cancers including cervical lung and HN cancers that FTO inhibitionreduces cancer cell growth and enhances RT sensitivity through the inhibition of glutamine metabolism. Theywill determine the therapeutic effects and mechanism of action of FTO inhibition in combination with RT inmultiple cancer models in collaboration with the other projects and cores. They will also study the effect of FTOinhibition on normal tissue response to RT. If successful D-limonene a nutraceutical can be rapidly tested inlarger phase II and III clinical trials for future clinical use. Similarly PMX 205 (a C5aR1 inhibitor) and CB-839 (aglutaminase inhibitor) are currently being evaluated in clinical trials for other clinical indications while drugstargeting FTO are in active development. Thus the proposed projects could rapidly lead to clinical studies thatcould impact the management of cancer patients. 2021847 +Cancer; Cervical Cancer; Radiation Oncology; Social Determinants of Health; Women's Health 3-Dimensional;Affect;Brachytherapy;Cancer Burden;Clinical;Collaborations;Complex;Disease;Ensure;High-Dose Rate Brachytherapy;Human;Malignant neoplasm of cervix uteri;Medical center;Phase;Problem Solving;Process;Radiation therapy;Recurrence;Resource-limited setting;Resources;Site;Small Business Innovation Research Grant;Treatment outcome;automated segmentation;commercialization;improved;innovation;low and middle-income countries;novel;software systems;standard of care;therapeutically effective;tool;treatment planning PROJECT TITLE: AUTOMATIC TREATMENT PLANNING OF CERVICAL CANCER HIGH-DOSE RATE BRACHYTHERAPY FOR LOW-RESOURCE SETTINGS n/a NCI 10707838 75N91022C00022-0-9999-1 N43 9/15/22 0:00 9/14/23 0:00 78859067 "LIANG, RON " Not Applicable 10 Unavailable 117165024 L267GZS3JE28 117165024 L267GZS3JE28 US 30.448785 -97.818678 10056320 VELOXAI LLC AUSTIN TX Domestic For-Profits 787261455 UNITED STATES N R and D Contracts 2022 400000 NCI Cervical cancer is a major disease globally and 85% of the cancer burden occurs in low- and middle-income countries (LMICs). Standard of care is external-beam radiotherapy with high dose-rate brachytherapy (HDRBT). Adding brachytherapy to the treatment course improves overall survival by 12% and reduces local recurrence. HDRBT treatment planning is a complex process. Brachytherapy in low-resource settings often do not have adequate human expertise for this task limiting the wide-spread use of this effective therapeutic form and significantly affecting treatment outcomes. Aiming at solving this problem VeloxAI a spin-off of UT Southwestern Medical Center (UTSW) proposes a Phase-I SBIR project in collaboration with clinical experts at UTSW to develop AutoBrachy the world first software system to realize fully automatic treatment planning of cervical cancer HDRBT. We will pursue two specific aims: Aim1 to develop automatic segmentation tools and rigorously refactor AutoBrachy to plan for commercialization; Aim2 to implement AutoBrachy at multiple participating sites including those in LMICs to evaluate its feasibility and merit. The innovation of our project is that it enhances HDRBT of cervical cancer in low-resource settings by utilizing novel computational approaches. Deliverability is ensured by extensive preliminary studies and the partnership with complementary expertise and resources. 400000 +Cancer; Clinical Research; Immunotherapy Air Pressure;Cell Therapy;Cells;Cellular immunotherapy;Cyclic GMP;Enrollment;Guidelines;Human;Industry;Infrastructure;Infusion procedures;Manufacturer;Patients;Pharmaceutical Preparations;Phase;Primary Cell Cultures;Primary Neoplasm;Sterility;Tissues;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;base;design;human subject TIL Rosenberg Modular Processing Facility (T30 building) n/a NCI 10707821 1ZIICO030001-05 1 ZII CO 30001 5 78871692 "KHOSHBIN, JEAN " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 3016111 NCI The NIH / NCI TIL cGMP Modular facility project is a state of the art 10 module standalone facility to be constructed at the NIH campus and will be used to aseptically isolate and expand Tumor Infiltrating Lymphocytes (TILs) cell culture from the primary tumors of enrolled patients as well as patient individualized cellular immunotherapy products for safe infusion into human subjects in compliance with FDA cGMP requirements. The facility opened for cellular processing and manufacturing in February 2022 and provides the much needed cGMP and Cell Processing space and support infrastructure that meets the FDA guidelines for manufacturing Phase 1 and early Phase 2 cellular therapies. 3016111 +Cancer; HIV/AIDS Area;Contractor;Contracts;Emergency Situation;Ensure;Grant;Institutes;Mission;Monitor;National Cancer Institute;Process;Property;Services;Time;United States National Institutes of Health;cost;cost effective;design;innovation;operation;programs;symposium Space and Facilities Management n/a NCI 10707820 1ZIICO020002-14 1 ZII CO 20002 14 78871692 "KHOSHBIN, JEAN " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 21769668 NCI The National Cancer Institute's (NCI) Office of Space and Facilities Management (OSFM):1. Acquires and manages real property assets in support and furtherance of the NCI mission;2. Coordinates NCI acquisitions for space and facilities;3. Develops and maintains the NCI Space Master Plan;4. Support the NCIs office of Grant Management in managing the NCI Construction Grants Program;5. Manages and monitors all assets and costs associated with NCI facilities leases utilities space and renovations/construction;6. Provides daily support to facilities in the area of operations and function by managing the facilities and space allocated to the Institute to ensure that it is fully utilized and suited to the needs of the occupants; and by acting as the Institute's contact point for space and facilities management activities and coordinates these activities with NIH offices involved in the acquisition renovation and management of space. 21769668 +Bioengineering; Biotechnology; Cancer; HIV/AIDS; Immunization; Infectious Diseases; Nanotechnology; Prevention; Vaccine Related; Vaccine Related (AIDS) Acquired Immunodeficiency Syndrome;Animals;Biomedical Research;Cancer Etiology;Clinical;Communities;Congresses;Development;Diagnostic tests;Disease;Funding;Goals;Government;Healthcare;Home;Investments;Laboratories;Laboratory Research;Lead;Malignant Neoplasms;Nanotechnology;New Drug Approvals;Patients;Persons;Pharmaceutical Preparations;Private Sector;Research;Research Personnel;Scientist;Services;Speed;Technology;Time;Translations;Universities;Vaccines;Washington;animal facility;base;cancer care;cancer therapy;commercialization;cost;evidence base;flexibility;health care delivery;improved;meetings;nonhuman primate;novel diagnostics;programs;prototype;public-private partnership;research and development;response;technology development;vaccine evaluation NCI-Frederick Support and Technical Services n/a NCI 10707818 1ZICCO020007-14 1 ZIC CO 20007 14 78871689 "KOMSCHLIES MCCONVILLE, KRISTIN " Not Applicable n/a Unavailable "OFFICE OF THE DIRECTOR, NCI" Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2480548 NCI NCI-Frederick is designated by Congress as one of 43 Federally Funded Research and Development Centers. These centers provide a rapid response and flexible capability in meeting federal research and development goals that cannot be met effectively by other means.Our campus 50 miles north of Washington D.C. is home to a wealth of expertise including that of our own cancer and AIDS researchers our technology development teams and our regulatory liaisons and commercialization partners. This combination gives us a unique perspective that spans laboratory discovery technology development and healthcare delivery.NCI-Frederick quickly adapts to changing R&D priorities by curtailing or ending programs when necessary to maintain a strategic focus and keep pace with new discoveries development opportunities and healthcare priorities.With our collaborators we are answering the call from Congress and the public to show how taxpayer investments in biomedical research are helping to ease and to end the suffering caused by cancer AIDS and other diseases. The intramural project supports efforts that OSO must fund through the government mechanism on the Bethesda Campus. 2480548 +Precision Medicine Admin-Core-001 n/a NCI 10707804 9/20/22 17:42 PA-20-272 3U54CA261719-02S1 3 U54 CA 261719 2 S1 "NADEAU, CHRISTINE FRANCES" 9/1/22 0:00 8/31/26 0:00 ZCA1(M1) 9582 10842134 "CURTIS, CHRISTINA N" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 116475 75000 41475 No abstract available +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Immunization; Immunotherapy; Neurosciences; Pediatric; Pediatric Cancer; Rare Diseases; Vaccine Related Admin-Core-001 n/a NCI 10707767 9/20/22 15:52 PA-21-071 3U54CA232561-01A1S5 3 U54 CA 232561 1 A1S5 "BOURCIER, KATARZYNA" 5/1/22 0:00 8/31/24 0:00 9575 1884239 "CRIPE, TIMOTHY P" "MARDIS, ELAINE R" 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 5/1/22 0:00 8/31/24 0:00 Research Centers 2022 172073 127542 44531 Enhancing antigen and cytokine expression to break immune tolerance and improve antitumor response Gliomas like other solid tumors restrict immune recognition of aberrant cancer cells. Further complicating this pediatric cancers also have lower mutation rates than adult tumors making them more difficult to generate an immunotherapeutic response. This proposal addresses three mechanisms contributing to immune resistance in pediatric tumors: 1) low mutational loads 2) myeloid immunosuppressive environment and 3) MHC downregulation (immuno-editing). We have developed a multimodal virus based vaccine platform that uses the viruss natural ability to recruit immune cells and break immune tolerance to improve immune activity against the tumor. By encoding tumor associated self-antigens within the viral genome so that they are expressed during infection our results show that we can convert the antiviral response into an anti-tumor response. The studies described in our proposal seek to improve our virus-based multi-modal vaccine approach to overcome immune restriction in one of the most difficult to treat solid tumors malignant glioma. We propose testing our hypothesis that: Engineered viral modifications that enhance native and adoptive immune cell activity will improve durable anti-tumor activity in treatment resistant pediatric gliomas by the following aims. +Cancer; Immunotherapy; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Admin-Core-001 n/a NCI 10707766 9/20/22 15:50 PA-20-272 3U54CA232561-01A1S4 3 U54 CA 232561 1 A1S4 "BOURCIER, KATARZYNA" 4/18/22 0:00 8/31/24 0:00 9574 1884239 "CRIPE, TIMOTHY P" "SORENSEN, POUL H.B.; STEIN, LINCOLN D." 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 4/18/22 0:00 8/31/24 0:00 Research Centers 2022 225752 146592 79160 This application describes the Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center created in response to the RFA as a second nidus for the Pediatric Immunotherapy Discovery and Development Consortium (PI-DDN). To complement the funded U54 (Maris and Mackall MPI) of the PI-DDN that largely seeks to harness adaptive immunity to further develop CAR-T cells against newly identified antigens we propose to harness innate immunity to target pediatric cancers to circumvent resistance to conventional therapy and to further enable adaptive/hybrid immune approaches +Cancer Admin Core n/a NCI 10707762 9/20/22 15:39 RFA-CA-15-014 3U54CA217376-05S1 3 U54 CA 217376 5 S1 "DUECK, HANNAH RUTH" 4/12/18 0:00 3/31/23 0:00 ZCA1-RTRB-B(O2) 5147 6486040 "MALEY, CARLO " Not Applicable 4 Unavailable 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ Domestic Higher Education 852876011 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 Research Centers 2022 78529 56605 21924 Admin Core Project SummaryWe propose to establish the Arizona Cancer and Evolution Center (ACE). Arizona State University will lead the Arizona Cancer and Evolution Center effort. Drs. Maley and Shibata co-principal investigators will direct the Center in collaboration with NCI program staff. ACE integrates a team of modelers evolutionary biologists and cancer biologists with a successful track-record of collaborations. The objective of the Arizona Cancer and Evolution Center Administrative Core is to provide the necessary infrastructure for the overall organization and effective management of the Center to achieve the objectives of the CSBC and the NCI as well as realize the scientific goals of the Center. The ACE Administrative Core will accomplish four Specific Aims during this funding period: Aim 1 Create and maintain a knowledgeable skilled and interdisciplinary leadership team that is connected to the research and the wider network; Aim 2 Design and implement a clear and effective communication plan across the Center; Aim 3 Identify and foster pilot projects; Aim 4 Solicit coordinate and respond to external advice for the scientific direction and opportunities for ACE. IMPACT: The Administrative Core will enable the Arizona Cancer and Evolution Center to transform current understanding and management of cancer by developing the theory models and measures of cancer that will be applicable and clinically relevant across cancers and species. +Cancer; Health Disparities; Minority Health Administrative Core n/a NCI 10707761 9/20/22 15:34 PAR-18-767 3U54CA137788-14S1 3 U54 CA 137788 14 S1 "GEBREAB, SAMSON YIKEALO" 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 6652 8906241 "AHLES, TIM ALAN" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 243191 137396 105795 Administrative CoreThe Administrative Core includes the four PIs Drs. Ahles and Gany (MSKCC) and Drs. Hubbard and Barabino (CCNY) Research Education Core Leaders Dr. Hricak (MSKCC) with Dr. Hubbard PCORE Leaders Dr. Leng (MSKCC) and Dr. Dorn (CCNY) Linguistic and Cultural Responsiveness Shared Resource Core Leaders Drs. Gany and Diamond (MSKCC) and Drs. Uyar and Riob (CCNY) and the Administrative Core staff from both CCNY and MSKCC. The U54 Administrative Core coordinates all of the Partnership activities and ensures that the Partnership continues to function effectively and efficiently. Specifically the Administrative Core will: 1) coordinate biweekly meetings of Partnership PIs quarterly meetings of the Administrative Committee which includes the leaders of the Research Education Core and Partnership Community Research and Education Core and quarterly IAC meetings as well as the Annual Program Steering Committee meeting; 2) meet with the Executive Committee on an annual basis to evaluate the potential synergy between Partnership goals and new institutional initiatives including recruitment of new faculty; 3) provide support for both institutions research resources and facilities and to provide access to and awareness of these resources for Partnership investigators faculty and students; 4) coordinate with GMap Region 4 (CDRN) to ensure that Partnership students have access to regional career resources; 5) coordinate student placements at either CCNY or MSKCC in research laboratories or service-based learning projects and to provide administrative support for faculty that teach in Partnership courses; 6) provide fiscal planning and management for all aspects of the Partnership including the distribution of developmental funds; and 7) maintain and update a manual of Standard Operating Procedures. +No NIH Category available Admin-Core-001 n/a NCI 10707759 9/8/23 0:00 PAR-18-767 5U54CA132378-15 5 U54 CA 132378 15 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 9573 1922320 "HUBBARD, KAREN " "HRICAK, HEDVIG " 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 309295 204891 104404 Administrative CoreThe Administrative Core includes the four PIs Drs. Ahles and Gany (MSKCC) and Drs. Hubbard and Barabino (CCNY) Research Education Core Leaders Dr. Hricak (MSKCC) with Dr. Hubbard PCORE Leaders Dr. Leng (MSKCC) and Dr. Dorn (CCNY) Linguistic and Cultural Responsiveness Shared Resource Core Leaders Drs. Gany and Diamond (MSKCC) and Drs. Uyar and Riob (CCNY) and the Administrative Core staff from both CCNY and MSKCC. The U54 Administrative Core coordinates all of the Partnership activities and ensures that the Partnership continues to function effectively and efficiently. Specifically the Administrative Core will: 1) coordinate biweekly meetings of Partnership PIs quarterly meetings of the Administrative Committee which includes the leaders of the Research Education Core and Partnership Community Research and Education Core and quarterly IAC meetings as well as the Annual Program Steering Committee meeting; 2) meet with the Executive Committee on an annual basis to evaluate the potential synergy between Partnership goals and new institutional initiatives including recruitment of new faculty; 3) provide support for both institutions research resources and facilities and to provide access to and awareness of these resources for Partnership investigators faculty and students; 4) coordinate with GMap Region 4 (CDRN) to ensure that Partnership students have access to regional career resources; 5) coordinate student placements at either CCNY or MSKCC in research laboratories or service-based learning projects and to provide administrative support for faculty that teach in Partnership courses; 6) provide fiscal planning and management for all aspects of the Partnership including the distribution of developmental funds; and 7) maintain and update a manual of Standard Operating Procedures. +No NIH Category available Admin-Core-001 n/a NCI 10707758 9/20/22 15:28 PA-20-272 3U54CA132378-14S1 3 U54 CA 132378 14 S1 "WALI, ANIL" 9/1/22 0:00 8/31/24 0:00 ZCA1(A1)-R 9572 1922320 "HUBBARD, KAREN " "HRICAK, HEDVIG " 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 410666 265075 145591 No abstract available +No NIH Category available Affect;Alabama;Automobile Driving;Biological;Black American;Black race;Cancer Biology;Cells;Clinical;Collaborations;Comprehensive Cancer Center;DNA;DNA Methylation;Data;Deep South;Diagnosis;Disparate;Disparity;Environment;Environmental Risk Factor;Epigenetic Process;Ethnic Population;Formalin;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Generations;Genes;Genetic;Genetic study;Genome;Genomics;Goals;Guidelines;Health;Hormones;Immune system;Incidence;Individual;Institution;Lasers;Life Style;Malignant Neoplasms;Malignant neoplasm of pancreas;Methods;Modernization;Modification;Morehouse School of Medicine;Mutation;Normal tissue morphology;Outcome;Pancreas;Paraffin Embedding;Pathway interactions;Patients;Population;Race;Research;Resolution;Sampling;Severity of illness;Stains;Stress;System;Testing;Tissue Microarray;Universities;bisulfite sequencing;black patient;chemical group;cohort;comparative;epigenetic regulation;experience;gene network;gene product;genomic profiles;patient population;protein biomarkers;racial population;socioeconomics;stressor;transcriptome;tumor Admin-Core-001 n/a NCI 10707755 8/16/23 0:00 PAR-18-767 5U54CA118948-18 5 U54 CA 118948 18 "RODRIGUEZ, LARITZA MARIA" 9/23/05 0:00 8/31/26 0:00 ZCA1-SRB-2 9571 7008046 "MANNE, UPENDER " "RIVERS, BRIAN M.; YATES, CLAYTON " 7 Unavailable 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL Domestic Higher Education 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 181909 122498 59411 PNETs are cancers that arise from hormone-producing cells of the pancreas. They are usually diagnosed in late stages with few treatments available. PNETs are the second most common pancreatic cancer and are rapidly increasing in incidence. Black pNET patients have worse survival and higher rates of cancer spread associated with smaller tumors than White patients. These clinical disparities suggest a biologic difference between these two patient groups. Guidelines for treating pNETs are mostly based on data from White patients and may not apply to Black patients. Differences in cancer biology between racial groups that affect disease severity has been discovered in other cancers. Notably there are differences in epigenetic modifications between different ethnic and racial groups. Epigenetic regulation of gene expression including DNA methylation (whereby chemical groups are added to DNA to alter the generation of gene product) is an important mechanism by which environmental factors lifestyle and stress can affect an individuals genes. pNETs are known to have high rates of epigenetic dysregulation. However nothing is known about the differences in the (epi)genetics of pNETs between Black and White patients as Black patients represent under 1% of patients included in genetic studies of pNETs. Other key differences may exist between how tumor from different patient populations interact with the normal tissue environment or the patients immune system. The goal of this project is to investigate the causes of the clinical outcomes differences between Black and White patients with pNETs. These differences may be at the (epi)genetic level how the tumor interacts with surrounding cells or environmentally influenced. The proposed research will compare the genomes and gene regulation systems between the two patient groups to find what is driving the clinical differences seen at a cellular level. This will demonstrate if the clinical outcome differences could be due to how the body keeps the tumor at bay and determine what key stressors exist today in the Black pNET patient population in the Deep South. While this study is aimed at understanding the ways in which epigenetic and gene expression changes affect pNETs in Black patients the findings will profoundly impact the direction of both pNET treatment and research for the entire patient population. +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Social Determinants of Health Admin-Core-001 n/a NCI 10707753 9/20/22 15:24 PA-20-272 3U54CA118948-17S1 3 U54 CA 118948 17 S1 "RODRIGUEZ, LARITZA MARIA" 9/1/22 0:00 8/31/26 0:00 ZCA1(A1)-S 9570 7008046 "MANNE, UPENDER " "RIVERS, BRIAN M.; YATES, CLAYTON " 7 Unavailable 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL Domestic Higher Education 352940001 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 185625 125000 60625 PNETs are cancers that arise from hormone-producing cells of the pancreas. They are usually diagnosed in late stages with few treatments available. PNETs are the second most common pancreatic cancer and are rapidly increasing in incidence. Black pNET patients have worse survival and higher rates of cancer spread associated with smaller tumors than White patients. These clinical disparities suggest a biologic difference between these two patient groups. Guidelines for treating pNETs are mostly based on data from White patients and may not apply to Black patients. Differences in cancer biology between racial groups that affect disease severity has been discovered in other cancers. Notably there are differences in epigenetic modifications between different ethnic and racial groups. Epigenetic regulation of gene expression including DNA methylation (whereby chemical groups are added to DNA to alter the generation of gene product) is an important mechanism by which environmental factors lifestyle and stress can affect an individuals genes. pNETs are known to have high rates of epigenetic dysregulation. However nothing is known about the differences in the (epi)genetics of pNETs between Black and White patients as Black patients represent under 1% of patients included in genetic studies of pNETs. Other key differences may exist between how tumor from different patient populations interact with the normal tissue environment or the patients immune system. The goal of this project is to investigate the causes of the clinical outcomes differences between Black and White patients with pNETs. These differences may be at the (epi)genetic level how the tumor interacts with surrounding cells or environmentally influenced. The proposed research will compare the genomes and gene regulation systems between the two patient groups to find what is driving the clinical differences seen at a cellular level. This will demonstrate if the clinical outcome differences could be due to how the body keeps the tumor at bay and determine what key stressors exist today in the Black pNET patient population in the Deep South. While this study is aimed at understanding the ways in which epigenetic and gene expression changes affect pNETs in Black patients the findings will profoundly impact the direction of both pNET treatment and research for the entire patient population. +Aging; Behavioral and Social Science; Cancer; Prostate Cancer; Urologic Diseases Core A: Administrative Project Narrative Administration Core AThe Administrative Core A provides for the overall administration of the grant encompasses fiscal and scientific responsibilities and serves to integrate the four Projects and four Cores of the Program Project. NCI 10707732 9/20/22 15:10 PAR-16-457 3U19CA214253-05S1 3 U19 CA 214253 5 S1 "DAEE, DANIELLE L" 7/5/18 0:00 6/30/24 0:00 ZCA1-RPRB-6(O1) 5458 8474689 "HAIMAN, CHRISTOPHER ALAN" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 Non-SBIR/STTR 2022 73392 44480 28912 Abstract Administration Core AThe Administration Core A will provide the necessary administrative and scientific oversight for the Program Project to ensure close interaction and effective integration of the Projects and Cores. More specifically Core Awill provide leadership to the primary components of the Program Project through an Executive Committee (EC) comprised of the principal investigators (PIs) of the Projects and Cores as well as senior investigators. The ECwill oversee scientific progress planning and management and will be responsible for making decisionsregarding scientific direction to promote and achieve scientific coherence. This Core will also be responsible forenhancing scientific interaction and communication amongst the PIs and co-investigators of the Projects and Cores to ensure optimal utilization and integration of the clinical and genomic data across Projects. The Core will assemble an External Advisory Committee (EAC) comprised of scientists clinicians and advocates representing the African American community to provide advice on scientific direction recruitment strategies as well as communication and dissemination of results with the broader community. Core A will also coordinate all program activities including fiscal oversight of the individual Projects/Cores and subcontracts the preparation of progress reports regular communication with NCI and the compliance with regulatory institutional and governmental policies regarding data sharing. +Cancer; Clinical Research Admin-Core-001 n/a NCI 10707727 9/20/22 14:56 PA-20-272 3U10CA180888-09S1 3 U10 CA 180888 9 S1 "MOONEY, MARGARET M" 3/1/22 0:00 2/28/25 0:00 ZCA1(O1) 9553 6765159 "BLANKE, CHARLES D." Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 2502196 2285714 216482 No abstract available +No NIH Category available Ablation;Academia;Algorithms;Appearance;Area;Benchmarking;Biological;Biological Markers;Bladder;Cancer Biology;Characteristics;Charge;Chemicals;Clear cell renal cell carcinoma;Collaborations;Colon;Complex;Conventional (Clear Cell) Renal Cell Carcinoma;Coupled;Data;Development;Devices;Diagnosis;Diagnostic;Disease;Early Diagnosis;Electrodes;Electrospray Ionization;Electrostatics;Environment;Feces;Gases;Generations;Histologic;Image;Imaging Techniques;Imaging technology;Industry;Inflammatory Response;Intervention;Ions;Irrigation;Isomerism;Kidney;Knowledge;Lasers;Lipids;Liquid Chromatography;Lung;MRI Scans;Malignant Epithelial Cell;Malignant Neoplasms;Measures;Metabolism;Microscope;Molecular;Names;Neoplasm Metastasis;Noise;Ovarian;Pathway Analysis;Pathway interactions;Pattern;Performance;Pharmaceutical Preparations;Phase;Physical condensation;Physiologic pulse;Play;Positioning Attribute;Principal Investigator;Process;Proteomics;Reaction;Renal Cell Carcinoma;Renal carcinoma;Renal pelvis;Reproducibility;Research;Resolution;Role;Sampling;Signal Transduction;Source;Specificity;Spectrometry Mass Electrospray Ionization;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stream;Survival Rate;Symptoms;Techniques;Technology;Testing;Thinness;Time;Tissue Sample;Tissues;Tumor Tissue;United States;Universities;Urine;Uterus;Vendor;Water;X-Ray Computed Tomography;anticancer research;biobank;biomarker discovery;cancer cell;cancer imaging;cancer therapy;detection limit;electric field;experimental study;imaging approach;improved;inflammatory marker;instrument;ion mobility;ion source;ionization;kidney biopsy;lipid metabolism;lipid structure;lipidome;lipidomics;mass spectrometer;mass spectrometric imaging;metabolic phenotype;metabolome;metabolomics;nano;nano-electrospray;oxidized lipid;pi bond;prevent;tandem mass spectrometry;tool;transcriptomics;tumor;tumor growth;tumor progression;urinary;voltage Triboelectric Ambient Mass Spectrometry Imaging of Renal Cell Carcinomas Principal Investigator: FM Fernndez Triboelectric Ambient Mass Spectrometry Imaging of Renal Cell Carcinomas Mass spectrometry imaging (MSI) is a powerful tool used in cancer research to study biomarkersin tumors and to develop new cancer treatment drugs. Current MSI techniques are powerful but stillsuffer from some drawbacks such as not having sufficient sensitivity and not being able to ionize allcompounds in a tissue sample. We propose a new generation of MSI technology that uses triboelectricnanogenerators coupled to laser ablation to improve on existing MSI techniques; this technology willhave higher sensitivity and higher coverage than existing tools improving our understanding of cancerbiology. NCI 10707686 9/20/23 0:00 RFA-CA-22-001 1R61CA281667-01 1 R61 CA 281667 1 "MCKEE, TAWNYA C" 9/20/23 0:00 8/31/26 0:00 ZCA1-TCRB-5(M1)R 8306133 "FERNANDEZ, FACUNDO MARTIN" Not Applicable 5 CHEMISTRY 97394084 EMW9FC8J3HN4 97394084 EMW9FC8J3HN4 US 33.781897 -84.404009 676603 GEORGIA INSTITUTE OF TECHNOLOGY ATLANTA GA SCHOOLS OF ARTS AND SCIENCES 303320415 UNITED STATES N 9/20/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 215136 NCI 140251 74885 Principal Investigator: FM Fernndez Triboelectric Ambient Mass Spectrometry Imaging of Renal Cell Carcinomas Understanding complex chemical and biological alterations in cancer requires detailedknowledge of the molecular composition of cancer tissues and the changes in these alterations overtime and following interventions. Mass spectrometry imaging (MSI) is the tool of choice for probing thintissue sections when femto- to attomole sensitivity is required with simultaneous exquisite specificity.In this project it is proposed to develop a proof-of-concept MSI ion source based on a triboelectricnanogenerator (TENG) and benchmark its performance against standard MSI techniques such asmatrix-assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI)using de-identified clear cell renal carcinoma tissue sections. These are lipid-rich cancer tumors wherelipid metabolism plays a major role in disease development. TENG when coupled to MS have shownhigher sensitivity than standard nanoelectrospray ionization particularly for difficult to ionize lowpolarity lipids and metabolites. TENG can also be used to yield structural information about importantmolecules such as lipids by enlarging the TENG electrode area which allows to carry out controlledgas-phase ion molecule reactions that yield diagnostic fragmentation patterns. Tissue sections to beexamined by TENG MSI will be selected from the biobank maintained by Prof. John Petros a long-standing collaborator at Emory University. The TENG MSI ion source will be coupled to an ion mobility-mass spectrometer to enable distinguishing lipid isobars during imaging experiments in collaborationwith the instrument vendor (Waters). Co-registration of TENG images with MALDI and DESI imageswill be conducted with algorithms developed with collaborators at Georgia Tech (Kemp). Improvementsto the TENG MSI ion source will be achieved using a symbolic regression approach that will enable thesimultaneous optimization of several quantitative performance metrics such as spatial resolutionoverall sensitivity the number of detected spectral features the number of lipid/metabolite chemicalclasses detected and the number of oxidized lipids. Overall this project will develop an MSI technologythat will become an invaluable tool for investigating lipid-rich tissues of importance in cancer research. 215136 +No NIH Category available ABL1 gene;Adult;Area;Biological Assay;Biopsy;Blood;Breast;Cancer Patient;Cell Line;Cells;Central Nervous System;Clinical;Clinical Laboratory Improvement Amendments;Colon;DNA;Detection;Development;Devices;Diagnostic;Diameter;Disease;Disease Progression;Encapsulated;Enzyme-Linked Immunosorbent Assay;Excision;Fibroblast Growth Factor Receptors;Gene Frequency;Gene Fusion;Genes;Glioma;Goals;Guidelines;High Density Lipoproteins;Introns;Knowledge;Label;Laboratories;Length;Lipids;Low-Density Lipoproteins;Lung;Magnetism;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of thyroid;Membrane Lipids;Messenger RNA;Methods;Modality;Modeling;Molecular Profiling;Molecular Weight;NRG1 gene;Nanosphere;Nanotechnology;National Comprehensive Cancer Network;Non-Invasive Detection;Oncologist;Operative Surgical Procedures;Pathologic;Patient-Focused Outcomes;Patients;Performance;Phase;Plasma;Plasma Proteins;Point Mutation;Positioning Attribute;Proteins;RNA;RNA Degradation;ROS1 gene;Reading;Receptor Protein-Tyrosine Kinases;Recommendation;Ribonucleases;Sampling;Solid Neoplasm;Surface;Technology;Therapeutic;Time;Tissue Sample;Tissues;Transcript;Tropomyosin;Tumor Weights;Tumor-Derived;Ultracentrifugation;Validation;Very low density lipoprotein;Western Blotting;clinically actionable;cohort;compliance behavior;cost;cost effective;detection limit;detection sensitivity;diagnostic assay;extracellular vesicles;fusion gene;genetic variant;hepatobiliary cancer;hybrid gene;inhibitor therapy;innovation;kinase inhibitor;liquid biopsy;malignant stomach neoplasm;minimally invasive;molecular diagnostics;nanopore;nanoprobe;operation;particle;pediatric patients;precision medicine;preservation;receptor;response;screening;screening services;sequencing platform;single molecule;targeted treatment;technology platform;testing services;transcriptome;tumor;variant detection Non-invasive detection of tumor NTRK gene fusions via rapid efficient and low-cost extracellular vesicle isolation method NarrativePan-tropomyosin receptor kinase (TRK) inhibitors larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) havedramatically transformed the therapeutic landscape for cancer patients harboring NTRK gene fusion. Wepropose to develop a fast blood-based NTRK fusion screening assay to find NTRK inhibitor responders. NCI 10707684 5/24/23 0:00 PA-22-176 1R43CA275629-01A1 1 R43 CA 275629 1 A1 "LOU, XING-JIAN" 6/1/23 0:00 5/31/24 0:00 Special Emphasis Panel[ZRG1-MCST-U(11)B] 15205074 "HE, HONGZHANG " Not Applicable 15 Unavailable 80805442 JS3HJ4EHJ9J8 80805442 JS3HJ4EHJ9J8 US 40.765641 -77.887425 10047426 CAPTIS DIAGNOSTICS STATE COLLEGE PA Domestic For-Profits 168012468 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 SBIR/STTR 2023 400000 NCI 361274 21398 SUMMARY/AbstractCancer patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusions who took Larotrectinib(Vitrakvi) and Entrectinib (Rozlytrek) lived significantly longer without disease progression regardlessof the disease origin and its gene fusion partners. Currently detection of NTRK fusions is recommendedby multiple National Comprehensive Cancer Network (NCCN) guidelines including those for colon non-small cell lung breast central nervous system pancreatic thyroid gastric hepatobiliary and ovarian cancers.However current diagnostic assays for NTRK gene fusions require highly invasive tissue samples which areoften limited by tumor position patient compliance sample amount and tumor inaccessibility in cancers suchas lung cancer gliomas and pancreatic cancers. Liquid biopsy allows for minimally invasive molecular profilingwhen tissue biopsies are scarce or unreachable. This means that patients tumors can be molecularlyprofiled for precision medicine with a simple blood draw instead of a surgical procedure. The significantclinical benefit of targeted tropomyosin receptor kinase (TRKs) inhibitor therapies towards cancer patientsbearing NTRK fusions bolsters the urgent unmet need for a liquid biopsy method to screen pathologicalNTRK fusions to identify the TRK inhibitor responders.Extracellular vesicles (EVs) in the blood plasma of cancer patients encapsulate the entire cancer transcriptomevia long and high-quality mRNA fragments up to 20 kbp. EVs harbor cancer-associated mRNA transcriptstherefore perfectly for NTRK fusion detection. To meet the urgent unmet clinical challenge of detecting NTRKfusions we propose to vertically integrate our proprietary one-component lipid nanoprobe (1C-LNP) technologyfor isolating total EV from plasma a new wild-type blocker amplification (wtBA) technology to NTRK fusions inEV RNA from a high background of wildtype RNA and the Oxford Nanopore Technologies long-read sequencingplatform for reading NTRK fusions. We will develop a minimally invasive NTRK fusion detection technology withtwo Aims. In Aim 1 we will optimize the 1C-LNP technology for total EV isolation in plasma. In Aim 2 we willdevelop and integrate 1C-LNP and wtBA to isolate high-molecular weight tumor mRNA from EVs enrich mRNAsequence with NTRK fusions perform single-molecule long-reads sequencing analysis using the OxfordNanopore Flongle device and further validate the feasibility of NTRK fusion variants detection using samplesisolated from tissue and plasma EV. We anticipate significant impacts in two areas of molecular diagnostics andliquid biopsy: (1) We will create the most sensitive state-of-the-art method to identify NTRK fusions at low variantallele frequencies; (2) We will create a minimally invasive NTRK fusion screening assay for plasma whichidentifies NTRK inhibitors responders and can have an incredible impact on the patient outcomes. Phase IIactivities will focus on expanding this 1C-LNP integrated wtBA technology platform to other clinical actionablegene fusions such as ROS1 ALK NRG1 RET ETS EWS FGFR ABL1 and subsequently perform the clinicalvalidation of the gene fusion panel. Upon completion of clinical validation we will launch this minimally invasiveNTRK fusion screening test service through the Clinical Laboratory Improvement Amendments (CLIA) laboratoryfor oncologists. 400000 +Cancer; Clinical Research; Dissemination and Implementation Research; Health Services; Prevention The Implementation Science Center for Cancer Control Equity - Admin Core n/a NCI 10707678 9/20/22 13:41 RFA-CA-19-006 3P50CA244433-04S1 3 P50 CA 244433 4 S1 "D'ANGELO, HEATHER" 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(A1) 5910 1863832 "EMMONS, KAREN M." Not Applicable 7 Unavailable 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA Domestic Higher Education 21156028 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 190280 190280 Abstract - Admin CoreThe Administrative Core provides scientific and administrative leadership to ensure an integrated and sustained focus on the Centers aims to create an implementation science (IS) ecosystem focused on health equity in community health centers across MA. The Core provides governance and coordination of center scientific administrative and networking activities and will evaluate Center processes outcomes scientific and clinical impacts. The Core has three primary components. The Administrative team brings strong scientific community health and administrative leadership as required to ensure a substantive and enduring focus on cancer health equity and implementation science by: (1) assembling a transdisciplinary team with scientific and community-based expertise; (2) providing strong transdisciplinary input through our governance and Advisory Board structure; (3) maintaining rigorous standards for community-engaged research quality of scientific and practice-based products and ethical standards; and (4) providing strong coordination and fiscal administration of Center activities.The Network Unit connects the Center to other ISCCCs and Cancer Moonshot implementation centers and to state and national community health center leadership by: (1) creating a mechanism for directly engaging investigators from Moonshot and other relevant IS into the planning and research functions of the Center; and (2) extend our networking to include national CHC leadership and care delivery structures.The Evaluation Unit is responsible for creating a data and evaluation ecosystem to evaluate and establish the Centers impact including: (1) establishing short and long-term metrics for productivity for all Center components; (2) collecting reviewing and providing feedback on Center wide and project specific metrics; (3) providing statistical support for evaluating pilot outcomes; and (4) creating a robust data repository that includes clinical as well as community contextual data.The Administrative Core has been built to provide: (1) strong and inclusive governance; (2) mechanisms to articulate the scientific vision and thematic foci of the center; (3) coordinated and collaborative activitiesacross the Center and other relevant University resources; and (4) advancement of the Centers themesthrough administrative support and continuous evaluation of Center activities. +Cancer; Cervical Cancer; Clinical Research; Health Services; Prevention; Sexual and Gender Minorities (SGM/LGBT*) Admin-Core-001 n/a NCI 10707677 9/20/22 13:37 PA-21-071 3P50CA244289-04S1 3 P50 CA 244289 4 S1 "CZAJKOWSKI, SUSAN" 9/1/22 0:00 8/31/24 0:00 ZCA1(A1) 9544 7895491 "DEVOE, JENNIFER E" "HUGUET, NATHALIE " 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 68114 44230 23884 The proposed research project work is a pre-implementation study that will fill gaps in our knowledge around cancer screening and risk reduction services among gender-expansive patients (individuals who identify as transgender and those whose gender is broadened from societys notion of gender) compared to cisgender patients. With this supplement the BRIDGE-C2 Center has two main aims: Aim 1: Examine the experience and patterns of care for cervical cancer screening and results and tobacco use status and cessation services among gender-expansive patients compared to cisgender patients seen in OHSU primary care clinics. Aim 2: Provide mentored research training and career development to Mr. Chen a post-masters degree trainee by implementing didactic coursework experiential activities opportunities to attend and present at conferences mentorship for research and professional skills and clinical shadowing. +Cancer; Digestive Diseases; Liver Cancer; Liver Disease; Rare Diseases Core A: Administrative Core The Administrative Core will provide infrastructure for managing finances planning meetings booking travel arrangements and communications. The objective is to support the SPOREs goals in general operations in order for the SPORE to function more efficiently; this will allow the translational scientific goals to be achieved and advances in superior patient care to be attained. NCI 10707676 9/20/22 13:24 PAR-14-353 3P50CA210964-05S1 3 P50 CA 210964 5 S1 "NOTHWEHR, STEVEN F" 9/10/18 0:00 8/31/24 0:00 ZCA1-RPRB-N(O1) 5541 1864291 "MC NIVEN, MARK A." Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 137617 137617 0 Core A the Administrative Core of Mayo Clinics Hepatobiliary Cancer SPORE will provide an overall organizational infrastructure to encourage collaboration manage finances and coordinate the review of progress of the research projects scientific cores and developmental programs (Developmental Research Program and Career Enhancement Program). The Administrative Core will also ensure optimal function of all SPORE components and encourage communication between the SPORE Mayo Clinic Cancer Center Mayo Clinic as a whole other Hepatobiliary SPOREs other Mayo SPOREs SPORE collaborations with non-SPORE funding instruments and the National Cancer Institute. In addition the Administrative Core will consult with the members of the SPORE committees including the External and Internal Advisory boards in order to achieve maximum potential for translational objectives. Core As specific aims are to: 1) Provide leadership and collaboration between the Research Projects and Cores of the SPORE; 2) Assure incorporation and participation of the Hepatobiliary Cancer SPORE in the activities of Mayo Clinic Cancer Center; 3) Establish monthly meetings of SPORE investigators and the Internal Advisory Board; 4) Arrange yearly research retreats and 2x/year meetings of the External Advisory Board; 5) Coordinate meetings of the Mayo Clinic Cancer Center SPORE Directors Working Group as needed; 6) Provide administrative support to the Developmental Research Program and to the Career Enhancement Program; 7) Facilitate investigator trips to relevant SPORE meetings; 8) Enable activities of the Hepatobiliary Cancer SPORE advocates; 9) Prepare the yearly non-competing SPORE application; 10) Serve as the administrative liaison between the Mayo Clinic SPORE and the NCI SPORE Program other SPOREs and collateral organizations; 11) Maintain the Mayo Hepatobiliary Cancer SPORE Websites that will be useful to investigators inside and outside the SPORE as well as patients; 12) Coordinate information and communication about SPORE research developments to the Mayo Clinic SPORE investigators the scientific community at large and the public. +No NIH Category available Administrator;Advocacy;Animals;Bioinformatics;Biometry;Cancer Patient;Charge;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Decision Making;Development;Doctor of Philosophy;Ethics;Fostering;Institution;Institutional Review Boards;Leadership;Malignant Neoplasms;Malignant neoplasm of prostate;Mentorship;Michigan;Mission;Monitor;Occupational activity of managing finances;Pathology;Pathway interactions;Patient advocacy;Productivity;Prostate;Research;Research Personnel;Role;Therapeutic;Tissue Banks;Translational Research;Universities;Vision;career;clinical application;clinical database;clinical development;community engagement;data management;design;meetings;minority communities;programs;quality assurance;success;synergism;translational cancer research;translational goal;translational pipeline;translational progress Admin-Core-001 The Administration Core is responsible for the leadership guidance and management of the Michigan Prostate SPORE. In fulfilling these responsibilities the Administration Core provides the framework to support the success and mission of the Michigan Prostate SPORE as a cohesive group of investigators committed to supporting translational research in prostate cancer. NCI 10707666 8/22/23 0:00 PAR-18-313 5P50CA186786-10 5 P50 CA 186786 10 "ARNOLD, JULIA T" 9/11/14 0:00 8/31/24 0:00 ZCA1-RPRB-7 9536 1866290 "CHINNAIYAN, ARUL M" "HEATH, ELISABETH IIJAS; PALAPATTU, GANESH S" 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 255130 190029 107521 The Michigan Prostate SPORE Administration Core is responsible for the leadership guidance and management of this proposal. The Administration Core oversees all aspects and performs numerous duties across the wide scope of the SPORE to support the translational goals of the investigators. The SPORE Administration Core is guided by the following Specific Aims: Specific Aim 1: Provide scientific programmatic and administrative leadership to all aspects of the SPORE. Specific Aim 2: Develop facilitate and monitor progress of translational aims with project Co-Leaders. Specific Aim 3: Identify support and facilitate scientific collaborations. The Administration Core is charged with creating a culture of collaboration through fostering and helping to establish and maintain successful collaborations. Specific Aim 4: Facilitate communication between investigators and groups within the Michigan Prostate SPORE as well as with other institutional SPOREs the SPORE network outside the University of Michigan (U-M) Karmanos Cancer Institute (KCI) NCI and investigators across the spectrum of translational cancer research. Specific Aim 5: Perform fiscal and data management functions. Specific Aim 6: Coordinate patient advocacy and provide functional and ethical oversight to projects and cores. The Core provides support and oversight to ensure that all investigators have IRB and animal approvals in place to conduct research. The Core will develop and maintain an advocacy portal for our prostate cancer patient community. Arul M. Chinnaiyan MD PhD (U-M) serves as Core Director. Ganesh Palapattu MD (U-M) and Elisabeth Heath MD (KCI) will serve as Core Co-Directors of the Administrative Core and provide overall scientific oversight. Dr. Chinnaiyan will be responsible for overall program organization and fiscal oversight as well as the Biostatistics/Bioinformatics and Biospecimen/Pathology Cores. Dr. Palapattu will be responsible for mentorship and development of collaborators and trainees oversight of the Career Enhancement Program and synergies between U-M and KCI programs. Dr. Heath will oversee clinical trials and therapeutics patient advocacy minority community engagement and the Developmental Research Program. Ms. Jill Miller has served as the Michigan Prostate SPORE administrator since 1998 and will continue in this role. This Core provides the framework to support the success and mission of the Michigan Prostate SPORE as a cohesive group of investigators committed to supporting translational research in prostate cancer. +Cancer; Clinical Research; Prostate Cancer; Urologic Diseases Admin-Core-001 The Administration Core is responsible for the leadership guidance and management of the Michigan Prostate SPORE. In fulfilling these responsibilities the Administration Core provides the framework to support the success and mission of the Michigan Prostate SPORE as a cohesive group of investigators committed to supporting translational research in prostate cancer. NCI 10707664 9/20/22 13:17 PAR-18-313 3P50CA186786-09S1 3 P50 CA 186786 9 S1 "ARNOLD, JULIA T" 9/1/22 0:00 8/31/24 0:00 ZCA1-RPRB-7(M1) 9535 1866290 "CHINNAIYAN, ARUL M" "HEATH, ELISABETH IIJAS; PALAPATTU, GANESH S" 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 351000 225000 126000 The Michigan Prostate SPORE Administration Core is responsible for the leadership guidance and management of this proposal. The Administration Core oversees all aspects and performs numerous duties across the wide scope of the SPORE to support the translational goals of the investigators. The SPORE Administration Core is guided by the following Specific Aims: Specific Aim 1: Provide scientific programmatic and administrative leadership to all aspects of the SPORE. Specific Aim 2: Develop facilitate and monitor progress of translational aims with project Co-Leaders. Specific Aim 3: Identify support and facilitate scientific collaborations. The Administration Core is charged with creating a culture of collaboration through fostering and helping to establish and maintain successful collaborations. Specific Aim 4: Facilitate communication between investigators and groups within the Michigan Prostate SPORE as well as with other institutional SPOREs the SPORE network outside the University of Michigan (U-M) Karmanos Cancer Institute (KCI) NCI and investigators across the spectrum of translational cancer research. Specific Aim 5: Perform fiscal and data management functions. Specific Aim 6: Coordinate patient advocacy and provide functional and ethical oversight to projects and cores. The Core provides support and oversight to ensure that all investigators have IRB and animal approvals in place to conduct research. The Core will develop and maintain an advocacy portal for our prostate cancer patient community. Arul M. Chinnaiyan MD PhD (U-M) serves as Core Director. Ganesh Palapattu MD (U-M) and Elisabeth Heath MD (KCI) will serve as Core Co-Directors of the Administrative Core and provide overall scientific oversight. Dr. Chinnaiyan will be responsible for overall program organization and fiscal oversight as well as the Biostatistics/Bioinformatics and Biospecimen/Pathology Cores. Dr. Palapattu will be responsible for mentorship and development of collaborators and trainees oversight of the Career Enhancement Program and synergies between U-M and KCI programs. Dr. Heath will oversee clinical trials and therapeutics patient advocacy minority community engagement and the Developmental Research Program. Ms. Jill Miller has served as the Michigan Prostate SPORE administrator since 1998 and will continue in this role. This Core provides the framework to support the success and mission of the Michigan Prostate SPORE as a cohesive group of investigators committed to supporting translational research in prostate cancer. +No NIH Category available Academy;Address;Admission activity;Adolescence;Advanced Malignant Neoplasm;Area;Basic Cancer Research;Biomedical Research;Cancer Biology;Cancer Control;Cancer Death Rates;Cancer Research Project;Cancer Science;Cancer Survivor;Career Choice;Caring;Cause of Death;Cessation of life;Childhood;Clinical;Critical Thinking;Death Rate;Dedications;Detection;Development;Discipline;Education;Educational Curriculum;Evaluation;Exposure to;Face;Funding;Future;Goals;Health;Image;Immunooncology;Incidence;Individual;Institution;Internet;Knowledge;Laboratory Research;Link;Malignant Neoplasms;Medical;Medical Students;Medicine;Mentors;Mentorship;Methodology;Modality;Modeling;Morbidity - disease rate;Occupations;Outcome;Pathway interactions;Persons;Physicians' Offices;Positioning Attribute;Postbaccalaureate;Prevalence;Prevention;Professional Competence;Program Sustainability;Radiation Oncology;Research;Research Personnel;Research Training;Resources;Risk;Role;STEM field;Science;Scientist;Structure;Students;Talents;Technical Expertise;Techniques;Therapeutic;Training;Training and Infrastructure;United States;Universities;anticancer research;cancer care;cancer diagnosis;cancer prevention;cancer risk;cancer therapy;cancer type;career;career development;cohort;didactic education;education research;evidence base;experience;falls;graduate school;improved;innovation;interest;laboratory experience;medical schools;meetings;model development;mortality;network models;neuro-oncology;next generation;outreach;peer;peer coaching;peer networks;precision oncology;premature;programs;recruit;skills;success;summer research;tool;undergraduate student;virtual;virtual platform Duke PRIME Cancer Research Program NARRATIVE/RELEVANCE STATEMENTInnovations in cancer prevention treatment and cure are at risk because an insufficient number of people areentering and persisting in the biomedical research workforce. To address this we have launched the DukePreparing Research scholars In bioMEdical sciences (PRIME): Cancer Research Program a sustainableprogram that will develop a pipeline in academic careers and enhance their success by providing earlyexposure to cancer research experiences mentorship skills-building and scientific networks. This program willrecruit and prepare the next generation of scientists to advance cancer care and will serve as a model forexpanding across disciplines to develop the biomedical workforce and meet the nations needs for innovationin medicine. NCI 10707608 9/19/23 0:00 PAR-21-279 1R25CA275731-01A1 1 R25 CA 275731 1 A1 "ELJANNE, MARIAM" 9/19/23 0:00 8/31/28 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1931205 "BLOBE, GERARD C" "SOMARELLI, JASON ANDREW" 4 INTERNAL MEDICINE/MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 196839 NCI 182258 14581 ABSTRACTThe U.S. is facing a biomedical workforce crisis starting with attrition from STEM majors inundergraduate training. The result is a lack of innovative solutions to advance health outcomes. Cancerremains a significant cause of morbidity and mortality. The prevalence of cancer diagnoses and survivors inthe U.S. was more than 19 million in 2020 with 9.9 million cancer-related deaths worldwide. Duke Universityis uniquely positioned to address this critical problem by building a robust pipeline of future academiccancer researchers. The Duke Cancer Institute (DCI) is nationally recognized for its research programs in theareas of cancer biology; cancer prevention and control; cancer risk detection and interception; immune-oncology; neuro-oncology; precision cancer medicine and investigational therapeutics; and radiation oncologyand imaging. Our recently established Office of Physician Scientist Development (OPSD) offers a sustainablestructure for mentorship professional development and research funding. By leveraging these institutionalstructures we are well positioned to support the development implementation and evaluation of a programthat links resources across the training spectrum to introduce undergraduate students to varied cancerresearch career opportunities. To address the cancer research workforce gap we propose the DukePreparing Research scholars In bioMEdical sciences (PRIME): Cancer Research Program whichwill recruit cohorts of undergraduate students and provide them with research skills-building andmentored research experiences in cancer research. We will provide evidence-based professionaldevelopment activities and sustained engagement through virtual platforms and the opportunity for programalumni to return in peer-to-peer mentor roles. The Duke PRIME: Cancer Research Program will achieveour long-term goal addressing barriers that limit the recruitment and retention of a cancer research workforcethrough early exposure to intensive research experiences an innovative didactics curriculum and peernetworking. The program focuses on 1) providing a mentored summer research intensive experience forundergraduates; 2) providing a parallel OPSD PRIME Academy enrichment curriculum to enhanceunderstanding of FDQFHU research concepts and career paths in research; and 3) developing a peer networkingmodel with sustained engagement throughout the academic year. Successful implementation of theproposed program will lead to a scalable model for development of a robust pipeline for a diversebiomedical research workforce across disciplines. 196839 +No NIH Category available Ablation;Address;Affect;CASP1 gene;CASP8 gene;CRISPR/Cas technology;Carcinoma;Caspase;Caspase Inhibitor;Catalytic Domain;Cell Culture Techniques;Cell Death;Cells;Child;Chronic;Cyclic AMP-Dependent Protein Kinases;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Disputes;Engineering;Exhibits;Exons;Extrahepatic;Family;Fibrolamellar Hepatocellular Carcinoma;Future;Gene Fusion;Genes;Genomics;Heat shock proteins;Hepatocarcinogenesis;Hepatocyte;IL18 gene;Immune;Immune signaling;Immunity;Infiltration;Inflammasome;Inflammation;Inflammatory Response;Injections;Knock-out;Link;Liver;Liver Stem Cell;Liver neoplasms;Lytic;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Modeling;Mus;Mutation;Natural Immunity;Nature;Oncogenic;Ontology;Organoids;PRKACA gene;Pathogenesis;Patients;Phenotype;Prognosis;Proteins;Publications;Publishing;Recurrence;Risk;Role;Signal Pathway;Signal Transduction;Tail;Testing;Time;Veins;Work;anakinra;curative treatments;effective therapy;fusion gene;genome editing;hepatobiliary cancer;immune cell infiltrate;in vivo;inhibitor;insight;interest;liver transplantation;mouse model;novel;preservation;prevent;programs;stem cells;tool;transcriptome;transcriptomic profiling;transcriptomics;translational study;tumor;tumorigenesis;virtual;young adult Innate Immune Signaling in Fibrolamellar Carcinoma Fibrolammellar Carcinoma (FLC) is a rare and severe form of liver cancer that afflicts children and young adultsfor which the only present cure is liver transplantation. Without exception patients with FLC have a unique fusionof two genes in liver cells. We have engineered liver cells to harbor the FLC fusion gene and have discoveredalterations in these cells that suggest that they are prone to eliciting inflammation. Our work will define thismechanism and determine whether it contributes to forming liver tumors in a mouse model of FLC. NCI 10707605 9/14/23 0:00 PAR-20-052 1R03CA270278-01A1 1 R03 CA 270278 1 A1 "LUO, RUIBAI" 9/15/23 0:00 8/31/25 0:00 ZCA1-SRB-A(M2)S 6720953 "HANSEN, STEEN HENNING" Not Applicable 7 Unavailable 76593722 Z1L9F1MM1RY3 76593722 Z1L9F1MM1RY3 US 42.337481 -71.104964 1504801 BOSTON CHILDREN'S HOSPITAL BOSTON MA Independent Hospitals 21155724 UNITED STATES N 9/15/23 0:00 8/31/25 0:00 396 Non-SBIR/STTR 2023 177000 NCI 100000 77000 Fibrolammellar Carcinoma (FLC) is a rare form of liver cancer that afflicts children and young adults. At the timeof diagnosis the cancer is stage IV in ~60% of patients without effective treatment option. For the remaining40% liver transplantation is the only curative therapy providing a suitable donor can be found in time and eventhen with significant risks for short- and long-term complications.Virtually all patients with FLC have a genomic alteration on Chr. 19 resulting in fusion of exon 1 of DNAJB1 ofthe Hsp40 family to exons 2-10 of PRKACA a catalytic subunit of PKA. The resulting DNAJB1-PRKACA fusiongene encodes a Dnajb1-Prkaca protein with preserved catalytic activity. Using CRISPR/Cas9 technologycombined with hydrodynamic tail vein injection we and others have shown conclusively that a syntenic Dnajb1-Prkaca fusion gene on mouse Chr. 8 is sufficient to elicit liver cancer with hallmarks of FLC.FLC is thought to arise from liver stem cells but the mechanisms whereby Dnajb1-Prkaca promotes oncogenictransformation are not well understood. To permit functional studies in a developmentally relevant context weused CRISPR/Cas9 technology to engineer syntenic Dnajb1-Prkaca in mouse liver organoids. We discoveredthat liver organoids expressing Dnajb1-Prkaca are prone to undergoing lytic cell death. Next we performedextensive transcriptome analyses that revealed an innate immune signature prominently featuring constituentsof the NLRC4 inflammasome. We moreover determined that Dnajb1-Prkaca expressing liver organoids exhibitsignificantly elevated levels of cleaved caspase-8 consistent with its potent activation.In this work we will first test if the NLRC4 inflammasome is activated by Dnajb1-Prkaca in mouse liver organoidsand establish its role in lytic cell death. We will then determine if the Nlrc4 and/or Casp-8 genes are necessaryfor tumorigenesis elicited by engineering of the Dnajb1-Prkaca fusion gene in the mouse liver. The latter wouldrepresent a major breakthrough in understanding the pathogenesis of FLC. 177000 +Breast Cancer; Cancer; Women's Health Advocate;Animal Cancer Model;Annual Reports;Area;Biochemistry;Biophysics;Breast Cancer Patient;Breast Cancer Treatment;Breast Oncology;Budgets;California;Cancer Center;Charities;Clinical Medicine;Clinical Trials;Clip;Collaborations;Communication;Communication Programs;DNA;Data;Deaminase;Development;Diagnosis;Educational workshop;Electronic Mail;Elements;Endocrine;Ensure;Enzymes;Event;Family;Family member;Feedback;Foundations;Geography;Goals;Grant;Growth Factor;HIV;Human Resources;Institutes;Institution;Investigation;Investigational Therapies;Laboratories;Leadership;Logistics;Mammary Neoplasms;Medial;Medical;Minnesota;Molecular Biology;Mutagenesis;Neoadjuvant Therapy;Online Systems;Patients;Persons;Pharmaceutical Preparations;Physicians;Postdoctoral Fellow;Production;Program Development;Publications;Reagent;Reporting;Research;Research Personnel;Resource Sharing;Role;Science;Scientist;Seeds;Services;Signal Pathway;Site;Somatotropin;System;Technology;Telephone;Travel;Universities;Update;Videoconferencing;Virus;Voting;Work;Xenograft Model;base;experience;falls;frontier;graduate student;hormonal signals;innate immune mechanisms;malignant breast neoplasm;material transfer agreement;meetings;member;multidisciplinary;operation;organizational structure;outreach;payment;pre-clinical;professor;programs;repository;social;stem;success;symposium;training opportunity;web site Administrative-Core-001 NARRATIVECore A Administration provides critical support for all administrative activities of the Program including budgetary and fiscal operations logistical assistance and reporting activities. Core A strives to facilitate scientific progress toward the overall goal of diagnosis and treatment of patients with APOBEC-driven breast cancer. It does so by providing strong and consistent leadership; productive administrative services to Program scientists collaborators and External Advisory Board members; and coordinated Program communicationsacross all relevant sites which will include meetings workshops and outreach efforts. NCI 10707575 9/20/22 9:31 PAR-18-290 3P01CA234228-04S1 3 P01 CA 234228 4 S1 "READ-CONNOLE, ELIZABETH LEE" 8/1/22 0:00 7/31/24 0:00 ZCA1-RPRB-L(M1) 9508 8004071 "HARRIS, REUBEN S" "YEE, DOUGLAS " 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Non-SBIR/STTR 2022 95930 82180 13750 ABSTRACTThe primary goals of Core A Administration are to provide leadership logistical support and coordinated communication for all Program members and collaborators in order to expedite the successful completion of the Programs scientific aims. The PI of Core A is Douglas Yee and the Co-I is Reuben Harris. The specific aims of the Core are to 1) provide strong and consistent leadership; 2) provide services to Program scientists collaborators and External Advisory Board members; and 3) coordinate Program communications including meetings workshops and outreach efforts. The efficient administration of this bi-institutional multi-investigator Program is essential to its success and has proved to be effective over the 7 years that this team has been working together.Yee and Harris both have experience managing multi-investigator matrixed grants and they meet monthly to coordinate Program management. They are supported by a Program Manager Jane Balster who provides day-to-day administrative support and coordinates meetings workshops and other communication and outreach activities. The Executive Leadership Team which consists of Project and Core PIs meets monthly to review the status of scientific progress and budgets. In-person Program Workshops which include Project and Core PIs Co-Is postdocs graduate students and other personnel will continue to be held twice each year alternating between the University of Minnesota (fall) and University of California San Diego (spring). The External Advisory Board which consists of 5 expert scientists and 3 patient advocates regularly participates in weekly meetings and meets twice each year in conjunction with the bi-annual in-person Program Workshop.Additional meetings of PIs Project personnel Core personnel outside collaborators and all Program-associated personnel occur on a weekly or monthly basis. Web-based conferencing facilitates the participation of team members who are geographically dispersed. +No NIH Category available Affect;Affinity;Albumins;Animal Model;Animals;Binding;Biochemical;Cancer Etiology;Cells;Cellular biology;Cessation of life;Chemoresistance;Chromosomal Instability;Clinic;Clinical;Clinical Trials;Combined Modality Therapy;Data;Drug resistance;FDA approved;Genes;Genetic;Genetic Epistasis;Genetic Transcription;Goals;Growth;HDAC4 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;Immune;Immunocompetent;In Vitro;KPC model;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Maps;Mediating;Metabolism;Methods;Microtubules;Mitotic;Molecular;Outcome;Paclitaxel;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphorylation Site;Phosphotransferases;Prognostic Marker;Proteins;Recurrence;Regulation;Resistance;Role;Serine;Signal Pathway;Signal Transduction;Survival Rate;Testing;Text;Therapeutic;Transcription Coactivator;Translating;Treatment outcome;Tubulin;United States;Vorinostat;antitumor agent;cancer cell;cancer therapy;cancer type;cell growth;chemotherapy;cytotoxicity;drug sensitivity;efficacy outcomes;gemcitabine;histone deacetylase 2;improved;in vivo;malignant breast neoplasm;mortality;nanoparticle;novel;pancreatic cancer patients;pancreatic ductal adenocarcinoma cell;patient derived xenograft model;patient response;pre-clinical;programs;response;therapeutic target;upstream kinase Targeting MARK2-HDAC signaling to overcome paclitaxel resistance in pancreatic cancer n/a NCI 10707545 9/8/23 0:00 RFA-CA-21-052 5U54CA274329-02 5 U54 CA 274329 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9501 10491869 "DONG, JIXIN " Not Applicable 5 Unavailable 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK Domestic Higher Education 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 260950 260950 0 Abstract TextMany antitubulin agents such as paclitaxel (Taxol) have been used extensively for treatment of several typesof cancer including breast ovarian lung and pancreatic cancers. Despite their wide use in cancer treatmenthowever patient response is highly variable and drug resistance remains a major clinical issue. It is thereforeessential to identify prognostic markers to predict the patient response and to enhance drug sensitivity.Through biochemical and cell-based kinome-wide screens we identified MARK2 (microtubule affinity-regulating kinase 2) as a critical regulator for Taxol chemosensitivity in PDAC (pancreatic ductaladenocarcinoma) cells. We show that MARK2 is phosphorylated in response to antitubulin chemotherapeutics.We further identified the corresponding kinase and mapped phosphorylation sites. MARK2 determines Taxolcytotoxicity in PDAC cells without affecting growth under normal conditions. Mechanistically our findings alsosuggest that MARK2 controls Taxol chemosensitivity by regulating class IIa HDACs (histone deacetylase).MARK2 directly phosphorylates HDAC4 upon Taxol treatment. MARK2-phosphorylated HDAC4 positivelyregulates YAP (yes-associated protein) activity and controls expression of YAP target genes specificallyinduced by Taxol. Inhibition of HDACs sensitizes PDAC cells to Taxol treatment in vitro and inimmunocompetent animals. Our hypothesis is that the MARK2-HDACs axis functions as a therapeutic targetfor overcoming Taxol resistance in PDAC patients. We will test our central hypothesis by three specific aims.Aim 1: Determine the role and regulation of MARK2 in response to antitubulin chemotherapeutics; Aim 2:Elucidate the downstream effectors and mechanisms of MARK2 in response to Taxol chemotherapeutics; Aim3: Targeting HDACs and serine metabolism to overcome Taxol resistance in PDAC. The identification of newregulators and/or signaling pathways triggered by antitubulin drugs will shed light on the mechanismsunderlying chemoresistance. Our study suggests that combining HDAC inhibitors with antitubulin agents (e.g.Taxol) will have enhanced efficacy in treatment of drug-resistant and/or recurrent PDAC patients. +No NIH Category available Affect;Apoptosis;Biological;Biological Products;Breast;Cells;Cisplatin;Collaborations;Colorectal;Data;Distant;Drug resistance;Estrogen Receptors;Etoposide;Fibroblasts;Future;Gene Expression Profile;Gene Expression Profiling;Genetic Transcription;Genomics;Head and neck structure;Immune;Immunofluorescence Immunologic;Immunotherapy;Induction of Apoptosis;Inhibition of Apoptosis;Invaded;Laboratories;Location;Longevity;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediator;Metabolic;Molecular;Molecular Target;Mucin 1 protein;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Paclitaxel;Pancreas;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Primary Neoplasm;Process;Property;Radiation;Resistance;Role;Sampling;Signal Transduction;Site;Stomach;Tamoxifen;Techniques;Tissues;Trastuzumab;Up-Regulation;cancer stem cell;cancer type;cell motility;chemotherapy;exosome;gemcitabine;glucose metabolism;glucose uptake;insight;kidney cell;knock-down;lenalidomide;neoplastic cell;novel;pancreatic cancer cells;pancreatic cancer patients;programs;refractory cancer;single-cell RNA sequencing;therapy resistant;transcription factor;transcriptomics;translational study;tumor;tumor growth;tumor microenvironment;virtual MUC1 in Therapy Resistance n/a NCI 10707543 9/8/23 0:00 RFA-CA-21-052 5U54CA274329-02 5 U54 CA 274329 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9499 1891494 "HOLLINGSWORTH, MICHAEL A." Not Applicable 5 Unavailable 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK Domestic Higher Education 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 260950 260950 0 Abstract. Pancreatic cancer arises as an innately therapy-resistant cancer that is capable of rapidly acquiringadditional resistance to therapy upon treatment. We and others have demonstrated that high levels of expressionof MUC1 contribute to both inherent and acquired resistance of pancreatic cancer (and other lethal cancers) totherapies. Evidence that MUC1 plays a critical role in resistance to therapy comes from unbiased analysis ofgene expression profiles in different tumors and results of many experimental knockdown studies which haverevealed that high levels of MUC1 are associated with resistance to radiation cisplatin estrogen receptor targetslenalidomide paclitaxel tamoxifen trastuzumab gemcitabine FOLFIRINOX etoposide and other experimentaldrugs in numerous cancers including pancreatic breast colorectal gastric head and neck hepatocellular non-small cell lung cancer renal cell and multiple types of cancer stem cells. MUC1 is known to affect oncogenicsignaling and transcriptional programs through interactions and effects with signaling effectors and transcriptionfactors. Our collaboration with Pankaj Singh's group has shown that MUC1 stabilizes and activates HIF-1a andincreases glucose uptake and metabolism and that upregulation of MUC1 in Gemcitabine resistant cells andconcomitant stabilization of HIF induces anabolic glucose metabolism to impart Gemcitabine resistance topancreatic cancer cells. Recent results from our laboratory presented below have provided provocative datashowing that: MUC1 is expressed on tumor cell derived exosomes; that MUC1 expressing exosomes fromtumors contain cargoes distinct from exosomes that do not express MUC1; that MUC1 derived exosomes areselectively taken up by cancer associated fibroblasts immune cells other tumor cells and cells that comprisethe premetastatic niche of pancreatic cancer. Additional data show that MUC1 containing exosomes alter thebiological properties of cells that take them up in ways that enhance tumor growth at primary and metastaticsites and increase drug resistance of tumors growing at those sites. This leads us to the OverarchingHypothesis for the studies in this application: Exosomes from pancreatic cancer cells induce resistanceto chemotherapy and immunotherapy by reprogramming metabolic and functional features of tumorcells cancer associated fibroblasts and immune cells in the primary tumor and at distant metastaticsites. To investigate this hypothesis we propose two aims: Specific Aim 1. Elucidate the molecular features ofMUC1 positive exosomes that cause therapy resistance through reprogramming of tumor cells cancerassociated fibroblasts and immune cells at local or metastatic sites.; Specific Aim 2. Evaluate expressionsignatures and pathways of therapy resistance in matched sets of primary tumors and metastatic lesions fromuntreated and treated patients (from our tissue core) by utilizing spatial transcriptomics (single cell RNAseq) andby performing multiplexed immunofluorescence. +No NIH Category available Acute;Adrenal Glands;Archives;Ascites;Autopsy;Benign;Biological;Biopsy;Cancer Center;Cell Culture Techniques;Cell Line;Chronic;Clinical;Clinical Data;Clinical Trials;Collaborations;Collection;Core Facility;DNA;Database Management Systems;Dedications;Diagnostic;Diagnostic Procedure;Disease;Disease Resistance;Disease model;Duodenum;Eligibility Determination;Ensure;Fibrosis;Fresh Tissue;Goals;Growth;Histologic;Human;Informed Consent;Intercellular Fluid;Large Intestine;Liquid substance;Liver;Lung;Lymphocyte;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Medical center;Modeling;Muscle;Nebraska;Neoplasm Metastasis;Neuroendocrine Tumors;Oncology;Operative Surgical Procedures;Organ;Organ Procurements;Organoids;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic carcinoma;Pancreatitis;Patient Care;Patient Monitoring;Patients;Peripheral Blood Lymphocyte;Plasma;Procedures;Quality Control;Recording of previous events;Reproducibility;Research;Research Activity;Research Personnel;Resistance;Resources;Respiratory Diaphragm;Risk;Sampling;Scientist;Sequence Analysis;Serum;Small Intestines;Specimen;Spleen;System;Tissue Banks;Tissues;Translational Research;Universities;Writing;Xenograft procedure;biobank;lymph nodes;multidisciplinary;neoplastic;novel;peripheral blood;programs;repository;research study;resistance mechanism;sample archive;therapy resistant Tissue Core-UNMC Rapid Autopsy Program n/a NCI 10707538 9/8/23 0:00 RFA-CA-21-052 5U54CA274329-02 5 U54 CA 274329 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9494 8731990 "GRANDGENETT, PAUL M" Not Applicable 5 Unavailable 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK Domestic Higher Education 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 96643 92528 4115 Project Summary AbstractAll projects in this ARTNet application will use deidentified human specimens for research directed atunderstanding acquired resistance to therapy in pancreatic ductal adenocarcinoma. In order to provide thenecessary specimens a Tissue Core has been developed in cooperation with and under the auspices of theUniversity of Nebraska Medical Center (UNMC) Tissue Bank with the goal of providing a coordinated andcentralized core dedicated to procuring processing and distributing biological specimens and associated de-identified clinical data. The Rapid Autopsy Program (RAP) core facility stores normal benign (i.e. acuteand/or chronic fibrosing pancreatitis) and malignant pancreatic tissues (including both primary and metastaticpancreatic carcinomas as well as neuroendocrine tumors) and peripheral blood lymphocytes plasma andserum from patients undergoing surgical procedures for pancreatic malignancies and from deceasedpatients with a history of pancreatic cancer (rapid autopsy). Non-cancer donor whole pancreata spleenduodenum liver lung muscle lymph node and adrenal tissue are also collected in collaboration with localorgan procurement agencies. The RAP biorepository also coordinates with surgery and oncology as well asseveral well-established UNMC patient monitoring programs such as the PCDC and PCCR to developrobust longitudinal collections of pre early and end-stage tissue and biofluid sample sets. Importantly thecurrently archived samples available from the rapid autopsy program are a UNMC-based resourcerepresenting the exact sample sets necessary to investigate acquired resistance in PDAC disease andcontinued growth of the resource will only serve to enhance UNMCs ability to study disease resistance. Thecore also maintains a cache of various resources available to all cancer investigators such as disease andnormal TMAs donor sample sequence analysis and fresh tissue acquisition. The bank includes amechanism for database management and specimen distribution (Freezerworks) and a uniform system ofprioritization of requested materials has been defined and used by the Tissue Bank Oversight Committee.This core facility is intended to benefit the specific research activities of the ARTNet as well as the researchactivities of other scientists within and outside of UNMC who are concentrating on translational researchissues and resistance mechanisms.Only specimens obtained from clinically indicated surgeries after all other diagnostic procedures havebeen performed will be submitted to the UNMC ARTNet tissue bank for resistance research. Thespecimens would otherwise be discarded or disposed. Eligible patients have the opportunity to participateby submitting written informed consent. There is no risk to the patient or compromise to the patient's careas all the procedures performed would be performed for diagnostics regardless of the collection need.. +No NIH Category available Address;Algorithm Design;Algorithms;Award;Cloud Computing;Code;Communities;Complex;Computer software;Computing Methodologies;Conscious;Data;Data Analyses;Development;Diffusion;Documentation;Education;Genomics;Goals;Guidelines;High Performance Computing;Libraries;Malignant Neoplasms;Memory;Methods;Play;Process;Research;Research Personnel;Research Project Grants;Resource Allocation;Role;Services;Software Design;Software Tools;Speed;Statistical Computing;Statistical Methods;Techniques;Technology;Testing;Work;cluster computing;code development;computing resources;design;experience;implementation process;member;multithreading;novel;parallel computer;programs;simulation;software development;success;tool Core C: Computation and Software Development Core Core C: Project NarrativeCore C has the overall goal of providing researchers of the program project with support andguidance for all their computational needs. A consequence of our work implementing statisticalmethods developed by the project will be the design and creation of novel computationalresources that enable those analyses. We anticipate that we will create numerous new librariesand software packages that will not only support our own developments but also serve the entirescientific community. NCI 10707475 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L 9460 8694737 "MARJORAM, PAUL " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 251402 156164 95238 Core C: Computation and Software Development CoreThe overall goal of Core C is to provide researchers involved with the Program Project withsupport and guidance for all their computational needs while developing their code as well asassistance with implementation of algorithms in the form of scientific software. As such Core Cwill play a central role in the success and impact of each of the research projects. We haveorganized the Core activities into two main aims: High-Performance Computing [HPC] andScientific Code Development. In doing so we are conscious of two key concepts: Reliability andScalability.Our first Specific Aim focuses on high-performance computing. The Core will be involved inactivities ranging from developing and allocating resources for computation to actively reviewingor developing new methods for dealing with data that may be both big and complex. Specificallywe will focus on the use of parallel computing cloud computing technologies and out-of-memorydata analysis techniques.Our second Specific Aim focuses on scientific code development. Software tools are a corner-stone component when it comes to the diffusion and wide-spread use of novel statistical methods.The Core will assist members in developing the code for such software with a special emphasison the efficient implementation of algorithms based on two fundamental principles reliability andscalability. To this end we will develop standards and guidelines on scientific softwaredevelopment--including themes such as documentation version control continuous integrationand unit tests--to be followed by the project members. Furthermore Core C will both advise andactively participate in the implementation process of the methods developed by each project.Ultimately the Core will be involved throughout the process all the way from initial algorithmicdesign and implementation of the methods up to final software design packaging and publicrelease.Additionally the Core will play a number of other key roles supporting the other Program Projectcomponents. Examples of these include resource allocation simulation of test data anddevelopment of computational-methods tutorials that can be distributed in partnership with theeducational efforts of Core D. +No NIH Category available Advisory Committees;Bioinformatics;Biometry;Budgets;Categories;Collaborations;Committee Members;Communication;Computer software;Discipline;Education;Educational workshop;Elements;Ensure;Epidemiology;Financial Activity;Genetic;Genomics;Goals;High Performance Computing;Human Resources;Infrastructure;Leadership;Life;Malignant Neoplasms;Monitor;Nature;Occupational activity of managing finances;Postdoctoral Fellow;Progress Reports;Reporting;Research;Research Personnel;Research Project Grants;Role;Schedule;Statistical Methods;Students;Travel;Work;cancer genetics;conflict resolution;design;experience;genetic epidemiology;meetings;programs;recruit;synergism;trend;web site Core A: Administrative Core NarrativeThe Administrative Core will provide scientific oversight enhance communications amonginvestigators and support all of the day-to-day administrative needs of this program. It will workproactively to assure complete synergy across the Research Projects and Cores around the theme ofstatistical methods for integrative genomics that is the focus of the Program. NCI 10707469 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L 9457 1964858 "GAUDERMAN, WILLIAM JAMES" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 267047 161847 105200 Core A: Administrative CoreAbstractThe administrative core is designed to coordinate and support all the activities of this Program. Itwill work pro-actively to assure complete integrations across the Research Projects and Coresaround the theme of integrative genomics that is the focus of the program. The Core will beresponsible for overseeing the day-to-day activities of this program and assuring that the overallgoals of the program are achieved. Among other activities this Core will organize biweeklymeetings of the entire research team coordinate scientific seminars and workshops and hold anannual retreat. We have assembled an External Advisory Committee (EAC) comprising expertsfrom outside USC in statistical genetics cancer genetic epidemiology integrative genomicsbioinformatics and high-performance computing. We have also assembled an Internal AdvisoryCommittee (IAC) drawing on the deep expertise of our colleagues across these same disciplineswithin USC. The Core will coordinate an annual meeting of the EAC and quarterly meetings ofthe IAC and it will facilitate additional interactions with EAC or IAC members throughout the yearas needed. The Core will coordinate travel purchase supplies monitor budgets handlepersonnel issues submit annual progress reports and facilitate recruitment of new investigatorspost docs and students.As co-directors of this core Drs. Gauderman and Siegmund will jointly assume responsibility forall organizational and financial activities of the project. In addition Dr. Gauderman will assumespecific leadership of Project activities and Dr. Siegmund specific leadership of Core activities.These Project- and Core-specific roles will guarantee that both important elements of the overallprogram are being adequately administered. They will also establish the infrastructure neededfor effective communications and collaboration across the Projects and Cores. They will co-chairour IAC and plan one annual meeting of the EAC as well as a separate annual scientific retreatwith all program and core investigators. Leveraging their experience as Director of the Divisionof Biostatistics (Dr. Gauderman) and Director of our Biostatistics and Epidemiology EducationProgram (Dr. Siegmund) they will assure that the ambitious goals of this program are fullycoordinated and supported. +No NIH Category available Biological;Cancer cell line;Cells;Collaborations;Computer software;Computing Methodologies;DNA Methylation;Data;Data Analyses;Databases;Dependence;Development;Epigenetic Process;Family;Gene Silencing;Genes;Genetic;Genome;Genomics;Health;Heterogeneity;Human;Hypermethylation;Joints;Knowledge;Libraries;Life;Malignant Neoplasms;Maps;Measures;Methods;Methylation;Modeling;Normal tissue morphology;Ontology;Pathologist;Pathway Analysis;Pathway interactions;Phenotype;Phylogenetic Analysis;Play;Recording of previous events;Research Personnel;Resources;Role;Science;Specificity;Statistical Data Interpretation;Statistical Methods;Structure;Translating;Translations;Trees;Variant;Work;bisulfite sequencing;cost;data to knowledge;drug sensitivity;epigenome;experimental analysis;functional genomics;gene function;gene interaction;genetic analysis;genome-wide;improved;interest;lens;member;model building;novel;personalized medicine;programs;public database;query tools;tool;tumor;whole genome Statistical Methods for Genome Characterization Project NarrativeUnderstanding the role that genes play in life is a key issue in biomedical sciences yet theoverwhelming majority of sequences in public databases remain uncharacterized. Functionalannotation is important for a variety of downstream analyses of genetic data yet experimentalcharacterization of function remains costly and slow. This project therefore proposes three Aimsfocused on improving our understanding of functional genomics thereby allowing bettertranslation of data to knowledge impacting human health. NCI 10707463 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L 9455 8694737 "MARJORAM, PAUL " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 283461 171794 111667 Project 3: Statistical Methods for Genome CharacterizationAbstractUnderstanding the role that genes play in life is a key issue in biomedical sciences yet theoverwhelming majority of sequences in public databases remain uncharacterized. Functionalannotation is important for a variety of downstream analyses of genetic data. Yet experimentalcharacterization of function remains costly and slow making computational prediction animportant endeavor. This project therefore proposes three Aims focused on functional genomics.In our first Specific Aim we propose to develop a probabilistic evolutionary model built uponphylogenetic trees and experimental Gene Ontology functional annotations that allows automatedprediction of function for unannotated genes. We will develop a probabilistic hierarchical modelingframework that that will allow joint inference and borrowing of strength across a family of relatedtrees. We expect this to significantly improve overall accuracy. Our approach will provide ascalable computational method that will enable gene annotation to be kept up to date regardlessof the flow of new experimental data. Our second Aim focuses on the development of improvedstatistical methods for pathway analysis. Such methods aim to detect over-representation ofmembers of a super-structure such as a genetic pathway in a list of objects of interest from anexperimental or statistical analysis. However pathway definitions are not consistent betweenresources with the overlap between two definitions of the same pathway on differing resourcesbeing as low as 30%. In this Aim we will develop methods that focus on the network structureitself which is much more robust. Our third Aim focuses on analysis of epigenetic conservation.The epigenome dictates cell phenotype and it is increasingly possible to infer which genes aresilenced or expressed by measuring the epigenome of a cell. Cancers are characterized bymultiple genes that show both hypermethylation and hypomethylation relative to normal tissues.We will develop advanced statistical methods to assess how conservation of DNA methylationvaries along the genome and validated using measures of essentiality taken from the CancerDependency Map and drug sensitivity data taken from the Genomics of Drug Sensitivity in Cancer(GDSC) Project. +No NIH Category available Accounting;Address;Affect;Alcohols;Biological;Biological Markers;Cancer Etiology;Cancer Prognosis;Clinical Research;Clinical Trials;Code;Collaborations;Colon;Colorectal Cancer;Complex;Data;Data Analyses;Dimensions;Environment;Environmental Exposure;Gene Expression;Genes;Genome Scan;Genomics;Genotype;Joints;Linkage Disequilibrium;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Measures;Meat;Methods;Methylation;Modeling;Molecular;Normal tissue morphology;Obesity;Organoids;Outcome;Pathway interactions;Patient-Focused Outcomes;Process;Questionnaires;Research Design;Research Personnel;Resources;Risk;Risk Factors;Sampling;Software Tools;Source;Statistical Methods;Statistical Models;Step Tests;Structure;Techniques;Testing;Time;Tobacco;Translating;Treatment outcome;Work;cancer therapy;cancer type;case control;clinical investigation;cohort;colon cancer patients;data resource;design;empowerment;epidemiology study;gene discovery;gene environment interaction;guided inquiry;high dimensionality;improved;malignant breast neoplasm;metabolome;metabolomics;method development;microbiome;multi-ethnic;novel;screening;simulation;trait;transcriptome;transcriptomics;user friendly software Integration of Omic Data in the Analysis of Gene x Environment Interaction Project 2: Narrative The availability of high-volume omic data including gene expression metabolome methylation and microbiome provides new opportunities to identify gene-environment (GE) and omic E interactions. This project will develop statistical methods to leverage omic data to improve power for identifying novel interactions as well as to inform the biological mechanism by which genes and exposures affect cancer outcomes. NCI 10707459 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L 9454 1964858 "GAUDERMAN, WILLIAM JAMES" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 282237 171053 111184 Project 2: Integration of Omic Data in the Analysis of Gene x Environment Interaction Abstract The availability of high-volume omic data including gene expression metabolome methylation and microbiome provides exciting opportunities to identify novel gene-environment (GE) and omic E interactions affecting cancer and other complex traits. For example the FIGI colorectal cancer consortium has generated transcriptomic (gene expression) data on both normal tissue and colon organoids to inform the discovery of GE and expression E interactions for colorectal cancer in a sample of over 130000 cases and controls with exposure data on established risk factors including tobacco alcohol obesity and red meat. The multi-ethnic cohort includes over 215000 subjects followed for up to 30 years with biomarkers metabolomic and microbiome data available on selected subsamples and nested case-control samples of breast and colorectal cancer. In addition to potentially improving power for identifying novel interactions the use of omic data holds promise to inform the biological mechanisms by which genes and exposures affect a particular trait. This project will develop two types of novel methods that leverage omic data to identify interactions in a genomewide scan. The first (Aim 1) considers one factor at a time (e.g. one SNP one gene) and uses novel two-step screening/testing methods to discover GE or omic E interactions. The second (Aim 2) approach is a joint model considering SNPs and omic data simultaneously using novel hierarchical modeling techniques to guide the discovery of GE and omic E interactions. For both Aims 1 and 2 we will consider the various types of exposure data that may be available ranging from simple yes/no indicators from questionnaires to integrated exposure measures constructed using statistical models with or without relevant omic data. Aim 3 will focus on applying the methods from Aims 1 and 2 to several cancer-related data resources including epidemiological investigations such as FIGI and MEC and a clinical trial examining modifiers of treatment outcomes in colorectal cancer patients. Overall this project will develop statistical methods to use both integrative omic and environmental exposure approaches to improve power for identifying novel GE and omic E interactions as well as to inform the biological mechanism by which these factors affect the risk or prognosis of cancer. We will leverage our collaborations on several cancer-related studies to guide our methods development process to design realistic simulation studies for evaluating the methods and to assure that methods we develop are translated into real-data applications. +No NIH Category available Area;Automobile Driving;Biological;Biological Markers;Biology;Cancer Etiology;Colorectal Cancer;Complex;Computer software;Data;Data Set;Development;Disease;Disease Outcome;Etiology;Exposure to;FAIR principles;Gene Expression;Genes;Genetic;Genomics;Goals;Heterogeneity;Individual;Investigation;Joints;Malignant Neoplasms;Malignant neoplasm of prostate;Mathematics;Measurement;Measures;Mediating;Mediation;Mediator;Methodology;Methods;Modeling;Molecular;Multiomic Data;Outcome;Pathway interactions;Phenotype;Population;Population Study;Process;Proteomics;Research;Risk;Risk Factors;Specific qualifier value;Statistical Methods;Structure;Subgroup;Techniques;Technology;Testing;The Cancer Genome Atlas;Time;Tissues;Translations;cancer genomics;data integration;data reduction;feature selection;genome wide association study;innovation;instrument;interest;metabolomics;microbiome;multidimensional data;multiple data types;multiple omics;novel;phenomics;pleiotropism;programs;statistics;trait;transcriptomics;user friendly software Integration of Omic Data to Estimate Mediation or Latent Structures Project 1: Integration of Omic Data to Estimate Mediation or Latent Structures Project NarrativeThis project focuses on the development of statistical approaches for the integration of multiple omics data that are suspected a priori to act on a disease or trait outcome via mediation or a latent structured model. The approaches span the analysis of studies with multiple omic measures on the same individuals to summary statistics from omic data measured from multiple studies. These methods will have a direct impact on applied investigations by facilitating a better understanding of potential biological mechanisms driving underlying cancer etiology via identifying novel factors estimating connections between those factors and identifying subgroups of individuals with potentially different associated mechanisms. NCI 10707453 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L 9452 8644273 "CONTI, DAVID V" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 255643 154935 100708 Project 1: Integration of Omic Data to Estimate Mediation or Latent Structures AbstractThe omic era is upon us and population-based studies are moving rapidly to measure multiple types of data to explore the underlying connection between risk factors and outcomes. Integration of data from complementary avenues of research using novel statistical approaches will result in discoveries within each area of research probe the area between and push innovation forward. Overall this project focuses on the development of statistical approaches for the integration of multiple omics data that are suspected a priori to act on a disease or trait outcome via mediation or a latent structured model. The approaches span the analysis of studies with multiple omic measures on the same individuals to summary statistics from omic data measured from multiple studies. In Aim 1 we will develop a multi-omic causal inference test (CIT) to facilitate its application to large multi-omic datasets measured on individuals to simultaneously model multiple risk factors and multiple mediators. In Aim 2 we will develop an integrative model to estimate latent unknown clusters aiming to incorporate multiple types of omic measures either measured cross-sectionally or at multiple time points to jointly estimating subgroups relevant to the outcome of interest. In Aim 3 we will estimate joint causal effects of intermediate factors or latent-outcome associations using summary statistics for multiple SNPs and multiple intermediates. We will leverage methodological developments from other projects within the overall program project and using expertise and assistance from the computational and translation cores we will developrobust computationally efficient and user-friendly software for application to applied projects. Overall these methods will have a direct impact on applied investigations by facilitating a better understanding of potential biological mechanisms driving underlying cancer etiology via identifying novel factors estimating connections between those factors and identifying subgroups of individuals with potentially different associated mechanisms. +No NIH Category available Address;Assessment tool;Biological;Chromosome Mapping;Colorectal Cancer;Complex;DNA;DNA Integration;Data;Data Analytics;Data Correlations;Data Set;Diagnostic;Disease;Disease Outcome;Elements;Enhancers;Evaluation;Event;Gene Expression;Gene Expression Profiling;Genes;Genetic Transcription;Genomics;Goals;Joints;Knowledge;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mediating;Methods;Modeling;Molecular;Outcome;Pathway interactions;Performance;Play;Population;Regulatory Element;Risk Factors;Role;Scanning;Statistical Methods;Time;Transcriptional Regulation;Untranslated RNA;Variant;Work;computerized tools;data integration;diagnostic signature;diagnostic tool;epigenomics;feature selection;flexibility;genome wide association study;high dimensionality;improved;insight;novel;predictive modeling;prognostic;prognostic signature;prognostic tool;tool;trait;transcriptomics High-Dimensional Regression for Data Integration Project 1: NarrativeAssociated with high-dimensional omic features there is a rich set of functional and regulatory annotations pathway information and disease-specific knowledge from previous studies that is routinely used to interpret analyses of omic data. In this project we propose to develop integrative high-dimensional regression methods capable of incorporating this array of external information a priori to improve prediction performance selection of predictive and associated features and to gain insight into potential biological mechanisms. NCI 10707448 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L 9450 10811142 "LEWINGER, JUAN PABLO " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 275336 166870 108466 Project 1: High-Dimensional Regression for Data Integration AbstractAssociated with high-dimensional omic (e.g. genomic transcriptomic epigenomic) features there is arich set of functional and regulatory annotations pathway information and disease-specific knowledge from previous studies that is routinely used to interpret analyses of omic data. In this project we propose to develop integrative regression methods capable of incorporating this array of external information a priori rather than post hoc to improve prediction performance selection of predictive and associated features and to gain insight into potential biological mechanisms in studies with highdimensional omic data. In our first Specific Aim we propose a general high-dimensional mixed modelling framework for integrating meta-features (e.g. functional annotations pathways) into omic studies with the flexibility to handle quantitative categorical and time-to-event outcomes as well as the ability to accommodate correlated data through the inclusion of random effects. Our proposed approach brings together mixed modeling high-dimensional regularized regression and an empirical Bayes strategy that makes the direct estimation of tuning penalty parameters from the data analytically and computationally tractable. The proposed integrative models can be deployed in predictive mode to develop diagnostic and prognostic signatures or in discovery mode to identify omic features associated with disease outcomes. We also propose an accompanying set of tools for inference and model interpretation. Our second Specific Aim focuses on integrative high-dimensional regression models for transcription-wide association studies (TWAS). We propose to leverage recent advances linking enhancers and other DNA regulatory elements and their proximal target genes to improve the prediction of genetically regulated gene expression with the goal of boosting the power and localization ability of TWAS. In our third Specific Aim we focus on applications of the methods in Aims 1 and 2 toseveral cancer datasets. +No NIH Category available Address;Area;Automated Annotation;Big Data;Bioinformatics;Biological;Cancer Etiology;Cancer Prognosis;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Communities;Complex;Computer software;Constitution;Constitutional;Core Facility;DNA Methylation;Data;Data Analyses;Data Set;Databases;Development;Disease;Environmental Risk Factor;Epidemiologist;Etiology;Foundations;Gene Expression;Gene set enrichment analysis;Generations;Genes;Genetic Transcription;Genome;Genomics;Genotype;Genotype-Tissue Expression Project;Goals;Heredity;Infrastructure;Intervention;Knowledge;Malignant Neoplasms;Measures;Mediation;Methodology;Methods;Modeling;Multiomic Data;Ontology;Pathway interactions;Phylogenetic Analysis;Prognosis;Proteome;Research Personnel;Research Project Grants;Resources;Risk Factors;Sample Size;Scanning;Software Tools;Source;Spectrum Analysis;Statistical Data Interpretation;Statistical Methods;Structure;Therapeutic Intervention;Time;Tissues;Training;Translational Research;Translations;Work;anticancer research;bioinformatics resource;cancer epidemiology;cancer genetics;cancer risk;cancer therapy;data integration;data resource;design;epidemiologic data;epidemiology study;feature selection;gene environment interaction;gene function;genetic association;genetic epidemiology;genome wide association study;genomic variation;high dimensionality;longitudinal analysis;member;metabolome;metabolomics;methylome;microbiome;modifiable risk;multiple data types;novel;novel strategies;predictive modeling;preventive intervention;programs;risk prediction;risk prediction model;simulation;software development;statistics;tool;trait;transcriptome;transcriptomics;user friendly software Statistical Methods for Integrative Genomics in Cancer Overall Program NarrativeThis Program Project will develop novel statistical methods for integrating multiple data types toaddress the etiology and prognosis of cancer through a collaboration across four closely relatedprojects drawing upon the resources of three shared facility cores and coordinated by anadministrative core. This goal will be achieved by a combination of methodological developmentssimulation studies closely keyed to real data projects user-friendly software packages thatimplement new methods and applications to several studies of cancer. NCI 10707446 9/8/23 0:00 PAR-20-077 5P01CA196569-08 5 P01 CA 196569 8 "ROTUNNO, MELISSA" 7/1/16 0:00 8/31/27 0:00 ZCA1-RPRB-L(J1)S 1964858 "GAUDERMAN, WILLIAM JAMES" "SIEGMUND, KIMBERLY D" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2047749 NCI 1244859 802890 OVERALL ABSTRACTThe overall goal of this Program Project is to develop novel statistical methods for integratingmulti-omic data to address etiology prognosis and treatment of cancer through a collaborationof four closely related projects and fourshared cores (see inset). The fourprojects can be broadly described asspanning the spectrum of analysischallenges including feature selectionmediation interaction andcharacterization. The first of theseHigh-Dimensional Regression for DataIntegration develops new strategiesfor the analysis of longitudinal -omicdata incorporating external functionalinformation maintaining a rigorousinferential foundation. The secondproject Integration of Omic Data toEstimate Mediation or LatentStructures develops novel latent factorand mediation models using high-dimensional omic data or GWAS summary statistics to identifyand distinguish genotype exposure and omic effects. The third project Integration of OmicData in the Analysis of Gene x Environment Interaction incorporates gene expression andother -omics data into powerful multi-step approaches to scan for interactions leveragingexposure or disease marginal associations. Project 3 will also add novel approaches to identifytranscriptional interactions hierarchical GxE models with heredity constraints (i.e. requiringinteractions to include the corresponding main effects) and extensions to longitudinal survivaland quantitative traits. The fourth project Statistical Methods for Genome Characterizationautomates annotation of gene function using phylogenetic inference to identify new cancer-specific regions of conserved DNA methylation. Project 4 also proposes a novel approach foragnostic pathway gene set enrichment analysis. These projects will be supported by four cores:Administrative Core (A) Functional Annotation Core (B) Computation and SoftwareDevelopment Core (C) and Data Analysis and Research Translation Core (D). Core B willmaintain up-to-date copies of key bioinformatics resources and will develop a softwareapplication that will provide a single unified portal for creating annotation files that integratesdata from multiple resources. Core C will assist with high-volume computing needs and willdevelop user-friendly software packages that implement novel methods. Core D will focus ontranslation of new methods both by supporting applications to real cancer datasets and bydeveloping materials for training outside investigators in the use of our methods and software.Our proposed work will have both methodological and substantive importance. On the onehand we will develop novel statistical methods that will be applicable to a wide range of cancerepidemiology studies and clinical trials. These methods will for example allow more powerfuldiscovery of genetic associations and interactions through leveraging biological information fromother sources. They will have translational significance in the areas of risk prediction andtargeted interventions. Our program is designed to be highly integrative with the variousprojects and cores being inter-related so that together they will be more informative than any ofthem could be on their own. Program members have access to extraordinary data resources atUSC and elsewhere assuring that the methods we develop will be motivated by and applicableto important questions arising in current cancer research. 2047749 +No NIH Category available Animal Model;Antibodies;Antibody Therapy;Antibody-drug conjugates;Biopsy;Bone Marrow;Bone Marrow Aspiration;Bone Marrow Neoplasms;Cancer Patient;Carcinoma;Cell Death;Cell Proliferation;Cell Therapy;Cell surface;Cells;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Coculture Techniques;Collagen;Complex;Coupled;Data;Disease;Disseminated Malignant Neoplasm;Economics;Endothelial Cells;Endothelium;Environment;Failure;Future;Human Resources;Hydrogels;Immune;Induction of Apoptosis;Investments;Malignant Bone Marrow Neoplasm;Malignant Neoplasms;Measures;Mediating;Metastatic Neoplasm to the Bone;Modeling;Natural Killer Cells;Neoplasm Metastasis;Oncology;Osteoblasts;Osteoclasts;Outcome;Patients;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Phase II/III Clinical Trial;Physiology;Play;Positioning Attribute;Prediction of Response to Therapy;Prognosis;Prostatic Neoplasms;Resistance;Resources;Role;SN-38;Sampling;Selection for Treatments;Solid Neoplasm;Stimulus;Stromal Cells;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Microarray;Topoisomerase Inhibitors;Topoisomerase-I Inhibitor;Toxic effect;Treatment Efficacy;Treatment outcome;Vascularization;bone;cancer cell;cancer type;castration resistant prostate cancer;cell type;cytotoxic;design;effective therapy;efficacy clinical trial;environmental change;humanized antibody;improved;in vitro Model;in vivo;induced pluripotent stem cell;innovation;men;monocyte;multidisciplinary;neoplastic cell;novel therapeutics;patient population;patient stratification;peripheral blood;phase II trial;phase III trial;pre-clinical;predicting response;receptor;responders and non-responders;response;screening;success;synergism;targeted treatment;therapy development;therapy resistant;tool;transcriptomics;treatment responders;treatment response;trial design;tumor;tumor growth;tumor microenvironment Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics Project NarrativeThere is a critical unmet need for improved models to enable more effective clinical trial design.This proposal will test the utility of a bone marrow tissue chip to identify patients with metastaticcastrate resistant prostate cancer most likely to have a response to a candidate new cell-surface targeted therapeutic agent currently in Phase II/III clinical trials. NCI 10707411 8/1/23 0:00 RFA-TR-19-014 5UH3CA260692-04 5 UH3 CA 260692 4 "MCKEE, TAWNYA C" 9/15/20 0:00 8/31/25 0:00 ZTR1-TC-7(01) 1923039 "BEEBE, DAVID J" "LANG, JOSHUA MICHAEL" 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 777500 NCATS 83634 46416 Project Summary: Rates of FDA approval for oncology drugs in clinical trials are low and often clinical trialfailures are driven by pre-screening of therapies in models that cannot adequately replicate patient physiology.The tumor microenvironment (TME) is highly complex consisting of multiple cell types including stromal cellsimmune cells and vasculature. The interplay between tumor cells and neighboring cells in the TME results inenvironmental changes that can support tumor growth vascularization and metastasis and thus plays animportant role in prognosis and treatment efficacy (e.g. by modulating resistance). It is important for clinicalprescreening models to include the TME to assess how treatment efficacy can be impacted by this multicellularcrosstalk. For men with advanced castrate resistant prostate cancer (CRPC) that have progressed tometastasis the disease is invariably lethal as current therapies are not curative. 90% of these patients havedeveloped bone metastases but the bone microenvironment has been historically difficult to model in animalmodels or traditional co-culture. Therefore in vitro models of the bone marrow TME are urgently needed toimprove pre-screening of novel therapeutics improve clinical trial design outcomes and expedite muchneeded treatments to the clinic. Here we propose to create a tissue chip model of the bone marrowmicroenvironment for testing metastatic CRPC therapeutics. Patient-derived prostate tumor spheroids modelthe solid tumor embedded in a collagen hydrogel surrounded by multiple resident bone marrow stromal cellsderived from bone marrow aspirates immune cells and iPSC endothelial cell vasculature. Cell-surface targetedtherapies such as IMMU-132 have great potential for treatment of metastatic cancers. IMMU-132 is anantibody drug conjugate with an antibody against Trop 2 a receptor expressed on tumor cells coupled to thedrug SN-38. SN-38 is a topoisomerase inhibitor that induced apoptosis in rapidly proliferating cells. We haveaccess to samples and data from a Phase II trial of IMMU-132 in metastatic CRPC which will allow us tovalidate our bone marrow tissue chip model. In the UG3 phase we will optimize our bone marrow tissue chipmodel and demonstrate that normal and disease chip environments replicate the in vivo physiology. We willalso validate the chip for measuring responses to cell surface targeted therapies. In the UH3 we will useclinical trial data to build tissue chips that represent patients who respond and do not respond to IMMU-132and validate these models. These chips will be used to determine mechanisms of TME-induced treatmentresistance and identify signatures of response for use in stratifying patients for more efficient clinical trials. Thechips can also be used to screen multiple different cell-surface targeted therapies helping direct therapy choicein future trials. The bone marrow tissue chips can be easily adapted for any cancer type that has bonemetastases and can measure a range of cell surface targeted therapies. These chips have the potential to be apowerful tool for improving clinical trial success rates in therapies for metastatic cancer. 130050 +No NIH Category available Animal Model;Antibodies;Antibody Therapy;Antibody-drug conjugates;Biopsy;Bone Marrow;Bone Marrow Aspiration;Bone Marrow Neoplasms;Cancer Patient;Carcinoma;Cell Death;Cell Proliferation;Cell Therapy;Cell surface;Cells;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Coculture Techniques;Collagen;Complex;Coupled;Data;Disease;Disseminated Malignant Neoplasm;Economics;Endothelial Cells;Endothelium;Environment;Failure;Future;Human Resources;Hydrogels;Immune;Induction of Apoptosis;Investments;Malignant Bone Marrow Neoplasm;Malignant Neoplasms;Measures;Mediating;Metastatic Neoplasm to the Bone;Modeling;Natural Killer Cells;Neoplasm Metastasis;Oncology;Osteoblasts;Osteoclasts;Outcome;Patients;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Phase II/III Clinical Trial;Physiology;Play;Positioning Attribute;Prediction of Response to Therapy;Prognosis;Prostatic Neoplasms;Resistance;Resources;Role;SN-38;Sampling;Selection for Treatments;Solid Neoplasm;Stimulus;Stromal Cells;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Microarray;Topoisomerase Inhibitors;Topoisomerase-I Inhibitor;Toxic effect;Treatment Efficacy;Treatment outcome;Vascularization;bone;cancer cell;cancer type;castration resistant prostate cancer;cell type;cytotoxic;design;effective therapy;efficacy clinical trial;environmental change;humanized antibody;improved;in vitro Model;in vivo;induced pluripotent stem cell;innovation;men;monocyte;multidisciplinary;neoplastic cell;novel therapeutics;patient population;patient stratification;peripheral blood;phase II trial;phase III trial;pre-clinical;predicting response;receptor;responders and non-responders;response;screening;success;synergism;targeted treatment;therapy development;therapy resistant;tool;transcriptomics;treatment responders;treatment response;trial design;tumor;tumor growth;tumor microenvironment Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics Project NarrativeThere is a critical unmet need for improved models to enable more effective clinical trial design.This proposal will test the utility of a bone marrow tissue chip to identify patients with metastaticcastrate resistant prostate cancer most likely to have a response to a candidate new cell-surface targeted therapeutic agent currently in Phase II/III clinical trials. NCI 10707411 8/1/23 0:00 RFA-TR-19-014 5UH3CA260692-04 5 UH3 CA 260692 4 "MCKEE, TAWNYA C" 9/15/20 0:00 8/31/25 0:00 ZTR1-TC-7(01) 1923039 "BEEBE, DAVID J" "LANG, JOSHUA MICHAEL" 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 777500 NCI 416366 231084 Project Summary: Rates of FDA approval for oncology drugs in clinical trials are low and often clinical trialfailures are driven by pre-screening of therapies in models that cannot adequately replicate patient physiology.The tumor microenvironment (TME) is highly complex consisting of multiple cell types including stromal cellsimmune cells and vasculature. The interplay between tumor cells and neighboring cells in the TME results inenvironmental changes that can support tumor growth vascularization and metastasis and thus plays animportant role in prognosis and treatment efficacy (e.g. by modulating resistance). It is important for clinicalprescreening models to include the TME to assess how treatment efficacy can be impacted by this multicellularcrosstalk. For men with advanced castrate resistant prostate cancer (CRPC) that have progressed tometastasis the disease is invariably lethal as current therapies are not curative. 90% of these patients havedeveloped bone metastases but the bone microenvironment has been historically difficult to model in animalmodels or traditional co-culture. Therefore in vitro models of the bone marrow TME are urgently needed toimprove pre-screening of novel therapeutics improve clinical trial design outcomes and expedite muchneeded treatments to the clinic. Here we propose to create a tissue chip model of the bone marrowmicroenvironment for testing metastatic CRPC therapeutics. Patient-derived prostate tumor spheroids modelthe solid tumor embedded in a collagen hydrogel surrounded by multiple resident bone marrow stromal cellsderived from bone marrow aspirates immune cells and iPSC endothelial cell vasculature. Cell-surface targetedtherapies such as IMMU-132 have great potential for treatment of metastatic cancers. IMMU-132 is anantibody drug conjugate with an antibody against Trop 2 a receptor expressed on tumor cells coupled to thedrug SN-38. SN-38 is a topoisomerase inhibitor that induced apoptosis in rapidly proliferating cells. We haveaccess to samples and data from a Phase II trial of IMMU-132 in metastatic CRPC which will allow us tovalidate our bone marrow tissue chip model. In the UG3 phase we will optimize our bone marrow tissue chipmodel and demonstrate that normal and disease chip environments replicate the in vivo physiology. We willalso validate the chip for measuring responses to cell surface targeted therapies. In the UH3 we will useclinical trial data to build tissue chips that represent patients who respond and do not respond to IMMU-132and validate these models. These chips will be used to determine mechanisms of TME-induced treatmentresistance and identify signatures of response for use in stratifying patients for more efficient clinical trials. Thechips can also be used to screen multiple different cell-surface targeted therapies helping direct therapy choicein future trials. The bone marrow tissue chips can be easily adapted for any cancer type that has bonemetastases and can measure a range of cell surface targeted therapies. These chips have the potential to be apowerful tool for improving clinical trial success rates in therapies for metastatic cancer. 647450 +No NIH Category available Active Sites;Address;Antineoplastic Agents;Architecture;Binding;Biochemical;Biological Assay;Cancer Patient;Cardiovascular Diseases;Catalytic Domain;Cell Death;Cell Line;Cells;Chromatin;Chromatin Remodeling Factor;Chromatin Structure;Clinic;Clinical;Complex;Cryoelectron Microscopy;DNA;DNA Binding;DNA Damage;DNA Repair;DNA Repair Pathway;Defect;Development;Drug Targeting;Effectiveness;Environment;Enzymes;Glutamates;Goals;Histones;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Mediating;Molecular;Molecular Chaperones;Molecular Conformation;Nuclear;Nuclear Proteins;Nucleosomes;Patients;Pharmaceutical Preparations;Phase III Clinical Trials;Poly(ADP-ribose) Polymerase Inhibitor;Polymers;Process;Property;Proteins;Radiation therapy;Relaxation;Research;Resistance;Ribose;Role;Serine;Shapes;Signal Transduction;Structure;Substrate Specificity;Therapeutic;Variant;Zinc Fingers;assay development;biophysical properties;brca gene;cancer cell;cancer therapy;chemotherapy;chromatin remodeling;clinical application;crosslink;design;dosage;drug efficacy;experimental study;improved;inhibitor;innovation;insight;nervous system disorder;neurotensin mimic 1;next generation;particle;patient population;polymerization;prevent;recruit;repaired;resistance mechanism;response;stoichiometry;structural biology;success;targeted cancer therapy;tumor Structure and Mechanism of Chromatin-Bound PARP1 NARRATIVEPARP1 is a validated target for cancer therapy in DNA repair-compromised tumors with four clinically approveddrugs and many ongoing phase III clinical trials. We propose to study the structure activity inhibition anddownstream effects of PARP1 bound to chromatin DNA. Our quantitative structural and mechanisticapproaches will aid in the development of the next generation of PARP inhibitors. NCI 10707396 7/21/23 0:00 PA-20-185 5R01CA218255-07 5 R01 CA 218255 7 "WEINREICH, MICHAEL DALE" 8/1/17 0:00 7/31/27 0:00 Macromolecular Structure and Function C Study Section[MSFC] 6409573 "LUGER, KAROLIN " Not Applicable 2 CHEMISTRY 7431505 SPVKK1RC2MZ3 7431505 SPVKK1RC2MZ3 US 40.013296 -105.251932 1199902 UNIVERSITY OF COLORADO Boulder CO GRADUATE SCHOOLS 803031058 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 440083 NCI 288305 151778 PROJECT SUMMARYInhibitors of the nuclear enzyme PARP1 (PARPi) are in clinical use and advanced trials as therapeutics forcancers with DNA damage repair defects. PARP1 is a highly abundant protein that shapes chromatin structurebut upon detecting damaged DNA becomes enzymatically active and builds chains of poly(ADP)-ribose (PAR)on itself. PARylation of other nuclear proteins such as histones is mediated by the recently discovered HistonePARylation Factor 1 (HPF1). PARylation relaxes compact chromatin and serves as a signal to recruit the DNArepair machinery but access of the DNA damage repair machinery also relies on the action of ATP-dependentchromatin remodeling factors and histone chaperones. The efficacy of PARP inhibitors in cancer patients isattributed to synthetic lethality: Simultaneously shutting down PARP-mediated DNA repair in patients withdeficiencies in DNA repair pathways (i.e. BRCA1/2 negative) or with induced DNA damage (i.e. chemo- orradiotherapy) leads to overwhelming DNA damage and cancer cell death. Despite the success of existinginhibitors of PARP1 high effective dosages poor correlation of drug efficacy with inhibition of PARP1 activity incancer cells and resistance to PARPi suggest room for improvement.Our goal is to use rigorous quantitative structural and mechanistic approaches to investigate how PARP1interacts differently with damaged vs. intact DNA in the context of chromatin and in the presence or absence ofits accessory protein HPF1. We aim to discover whether next-generation PARPi should be optimized for bindingmore tightly to the PARP1-HPF1 complex or instead prevent this complex from forming and whether theseproperties should differ for different clinical applications (i.e. cancer vs. cardiovascular or neurological diseases).We also seek to investigate whether selective inhibition of the DNA-bound active conformation of PARP1 is apotential approach to lowering the amount of drug one would need to administer by illuminating theconformational diversity of PARP1 bound to intact vs. damaged chromatin through structural biology. Finally wewill determine the effect of PARylation on the ability of chromatin remodelers to provide better access to the DNArepair machinery. Our mechanistic studies will yield key insights into how to design better screens or assays forthe development of more selective and mechanism-based PARP inhibitors. Altogether our proposed researchwill inform the development of the next generation of PARP inhibitors for use in cancer therapy. 440083 +No NIH Category available Antibodies;Antigens;Binding;Biological Markers;Biosensor;Blood;Bone Marrow;Breast Cancer Patient;Cancer Detection;Cells;Clinical;Detection;Disease;Engineering;Estrogen receptor positive;Future;Genetic;Growth;Image;In complete remission;Libraries;Life;Lung;Malignant Neoplasms;Medicine;Memory;Meta-Analysis;Methods;Micrometastasis;Monitor;No Evidence of Disease;Patients;Peptide Hydrolases;Peptides;Phenotype;Proteolysis;Recurrence;Relapse;Relative Risks;Reporting;Risk;Sensitivity and Specificity;Site;Sleeping Beauty;Symptoms;T cell therapy;T-Cell Activation;T-Lymphocyte;Technology;Therapeutic Intervention;Tumor Antigens;Urine;angiogenesis;cancer immunotherapy;cancer type;design;engineered T cells;extracellular;hormone therapy;in vivo;malignant breast neoplasm;neoplastic cell;receptor;screening;sensor;treatment response;tumor Finding Sleeping Beauty: T Cell Biosensors for Dormant Cancer Detection PROJECT NARRATIVESome types of cancers as exemplified by estrogen receptor positive breast cancer can recur as metastaticdisease many years or even decades following a dormancy period where the patient displays no clinicalsymptoms. This proposal seeks to engineer T cells as ultrasensitive biosensors to detect dormant cancer andwhen they reawaken. NCI 10707371 8/8/23 0:00 RFA-RM-21-015 5DP1CA280832-02 5 DP1 CA 280832 2 "SORG, BRIAN S" 9/20/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-BCMB-N(50)R] 10554748 "KWONG, GABRIEL A" Not Applicable 5 ENGINEERING (ALL TYPES) 97394084 EMW9FC8J3HN4 97394084 EMW9FC8J3HN4 US 33.781897 -84.404009 676603 GEORGIA INSTITUTE OF TECHNOLOGY ATLANTA GA BIOMED ENGR/COL ENGR/ENGR STA 303320415 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 1107400 OD 700000 407400 PROJECT SUMMARYSome types of cancers as exemplified by estrogen receptor positive breast cancer can recur as metastaticdisease many years or even decades following a dormancy period where the patient displays no clinicalsymptoms. Late recurrence is thought to arise from disseminated tumor cells (DTCs) that were not killed by initialtreatment and that lie dormant at metastatic sites such as the bone marrow until they reawaken. Strikingly meta-analysis of over 60000 early-stage ER-positive breast cancer patients treated with endocrine therapy revealedthat the relative risk of recurrence progressively increases over a period of at least 20 years indicating thatpatients in complete remission with no evidence of disease could harbor dormant cancer and remain at risk ofmetastatic relapse for the remainder of their life. Currently there is no widely used method to monitor the dormantstate nor its reawakening. The arrival of cancer immunotherapy has revealed exciting possibilities usingengineered T cells as living medicines. T cells designed with tumor-targeting receptors and sophisticated geneticcircuits have led to striking treatment responses in patients with certain types of cancers that were previouslyuntreatable. This moment is an opportunity to not only build a future where T cells are engineered as therapiesbut also as living sensors that can detect cancer with sensitivities and specificities beyond what is currentlypossible. The activation and growth of dormant tumor cells into micro-metastases require the hallmarkexpression of proteases during key steps such as angiogenesis. To exploit protease dysregulation this projectwill develop engineered receptors that sense proteolysis to detect reawakening. These contain an extracellularsingle chain antibody that is blocked by a peptide mimotope such that they can bind to their cognate antigensonly after the blocking peptide is removed by proteolysis restricting T cell activation to the specific conditionwhere the cognate protease and tumor antigen are both present. Following activation T cell sensors amplify therelease of synthetic biomarkers (blood urine and imaging) for detection. Genetically encoded libraries (>10^4)of protease-activatable receptors will allow in vivo screening of 1000s of candidate T cell sensors to positivelyand negatively select for constructs that can report on awakening in different microenvironments such as thebone marrow and lungs. The adoptive transfer of T cell sensors with memory phenotype could lead to life-longT cell sensors that continuously monitor for future disease. These technological breakthroughs will have hugeimplications in understanding how and when dormant cells reawaken and guide therapeutic interventions at theearliest stages of reactivation. 1107400 +No NIH Category available Aftercare;Area;Atlases;Cancer Biology;Cancer Center;Cell Communication;Cells;Clinic;Clinical Trials;Collaborations;Collection;Core Biopsy;Data;Diagnosis;Disease;Disease Management;Doctor of Philosophy;Environment;Fine needle aspiration biopsy;Formaldehyde;Funding;Goals;Human;Image;Immune system;Immunofluorescence Immunologic;Journals;Laboratories;Lead;Licensing;Methods;Microscopy;Molecular;Morphology;Mus;Paraffin Embedding;Patients;Periodicity;Pharmacology;Play;Protocols documentation;Public Domains;Publications;Publishing;Research;Research Support;Resolution;Role;Slide;Solid Neoplasm;Specialist;Specimen;Staging;Structure;System;Technology;Three-Dimensional Imaging;Tissue Preservation;Tissue imaging;Tissues;Transcript;Work;cancer imaging;cancer initiation;cell type;design;digital pathology;high dimensionality;high resolution imaging;immunological synapse;improved;insight;invention;mass spectrometric imaging;novel strategies;performance site;protein biomarkers;research and development;technology development;treatment response;tumor;tumor progression Advancing technologies for the collection and analysis of high dimensional immunoprofiles and tumor images NARRATIVEThe acquisition of detailed molecular and spatial data on human tumors using highly multiplexedmicroscopy promises to improve fundamentally our understanding of cancer initiation andprogression particularly the critical role played by interactions between tumors the immunesystem. Advancing the state of the art in tissue imaging is also likely to impact digital pathologyin the clinic leading to better diagnosis and disease management. NCI 10707358 8/29/23 0:00 PAR-21-285 5R50CA274277-02 5 R50 CA 274277 2 "MAZURCHUK, RICHARD V" 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-1(M1) 11757698 "LIN, JIA-REN " Not Applicable 7 NONE 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF DENTISTRY/ORAL HYGN 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 174710 NCI 103074 71636 SUMMARY-ABSTRACT The overall goal of this proposal is to use highly multiplexed high-resolution imaging oftissues and tumors to deeply characterize the microenvironments of diverse solid tumors beingstudied by NCI-funded collaborators at the Harvard Laboratory of Systems Pharmacology(LSP) Dana Farber/Harvard Cancer Center and four other NCI cancer centers. The PI of thisproposal Research Specialist Jerry Lin PhD invented tissue-based cyclic immunofluorescence(CyCIF) in 2018 and has made it the leading public domain (license-free) method for performinghigh-plex tissue analysis. He has adapted the method to high resolution 3D imaging of selectedfields of view (~103 cells using deconvolution microscopy) as well as rapid analysis of wholeslides (~106 cells) at lower resolution. As developed CyCIF can collect data from 20-60 proteinmarkers from a single specimen making it possible to identify cell types and states in apreserved tissue environment. It can also image structures as small as immune synapsesallowing cell-cell interactions to be analyzed at a functional level. Dr. Lins work directly supportsresearch by 18 NCI-funded laboratories and the CyCIF protocols he has published are used bymultiple other labs working independent of the HMS team. Dr. Lin also performs his ownresearch as part of a Human Tumor Atlas Network Trans Network Project that conceived andnow leads. These activities have resulted in 20 collaborative publications over the past threeyears including several in high impact journals with Dr. Lin as first or co-first author. As part of this R50 proposal Dr Lin will engage in three primary activities. First he willcontinue to collaborate with research groups to acquire CyCIF data at different stages beforeand after treatment. This is will make it possible to identify molecular and morphological featuresassociated with disease initiation progression and therapeutic response. Second he willcontinue to improve the CyCIF method and integrate it with other methods for spatialinterrogation of human and murine tumors (e.g. transcript profiling and imaging massspectrometry). Dr. Lin will also continue to lead an HTAN TNP designed to compare spatialprofiling methods across technologies and performance sites. This research has already led tounexpected insights into adequately powering spatial profiles as well as the relative merits ofwhole-slide 2D and 3D imaging. Third he will continue to develop and validate new approachesto tissue imaging particularly those that are applicable to digital pathology workflows in thesetting of clinical trials and patient diagnosis. This builds on the proven ability of CyCIF to collecthigh quality data from the formaldehyde-fixed paraffin embedded (FFPE) specimens routinelyacquired for patient diagnosis and staging (including core biopsies and fine needle aspirates).This combination of collaborative and original research and technology development isexpected to have a high impact on an emerging area of translational cancer biology and is fullyconsistent with the roles expected of a laboratory-based R50 Research Specialist. 174710 +No NIH Category available Address;Biological;Biological Factors;Biological Markers;Biological Process;Biology;Black race;Breast Cancer Risk Factor;Cancer Biology;Cancer Etiology;Cancer health equity;Cardiovascular system;Cells;Chronic;Clinical;Clinical Data;Community Actions;Cross-Sectional Studies;Data;Development;Diagnosis;Diagnostic;Disease;Disparity;Ethnic Origin;Ethnic Population;Exhibits;Exposure to;Health;Hispanic;Immune;Incidence;Individual;Inequity;Inflammatory;Intervention;Knowledge;Latinx;Link;Literature;Long-Term Effects;Longterm Follow-up;Malignant Neoplasms;Mammary Neoplasms;Measures;Mediating;Mediator;Metabolic;Modeling;National Health and Nutrition Examination Survey;Neighborhoods;Nested Case-Control Study;Not Hispanic or Latino;Outcome;Participant;Pathway interactions;Phenotype;Physiological;Prevention strategy;Process;Prospective cohort;Public Health;Public Policy;Publishing;Race;Racial Segregation;Risk;Risk Factors;Sampling;Sampling Studies;Socioeconomic Status;Stress;Structural Racism;System;Testing;Time;Tissues;United States;Weather;Woman;Women's Health;allostatic load;biopsychosocial;black women;breast cancer diagnosis;cancer biomarkers;cancer epidemiology;cancer prevention;cancer risk;cohort;contextual factors;cost;deprivation;design;economic disparity;epidemiologic data;evidence base;experience;improved;malignant breast neoplasm;marginalized population;mortality risk;neighborhood association;novel;perceived stress;prospective;racial population;residential segregation;response;social factors;socioeconomics;stressor;structural determinants;triple-negative invasive breast carcinoma;tumor Impact of Allostatic Load and Neighborhood Contextual Factors on Breast Cancer in the Women's Health Initiative PROJECT NARRATIVEThis study is relevant to public health because it will prospectively examine the impact of disadvantageousneighborhood contextual factors (rooted in structural racism) and allostatic load (as an intermediate biologicalprocess/mechanism between neighborhood context and health) on breast cancer in a large diverse studysample. The successful accomplishment of the proposed aims will contribute new knowledge about the impactof long-term exposures to disadvantageous neighborhoods and how chronic cumulative stress becomesbiologically embedded in cells and tissues thereby impacting breast cancer biology and etiology. NCI 10707352 8/24/23 0:00 PAR-21-190 5R01CA274564-02 5 R01 CA 274564 2 "SIMONDS, NAOKO ISHIBE" 9/20/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-PSE-N(91)S] 10513738 "LLANOS WILSON, ADANA A.M." "ADAMS-CAMPBELL, LUCILE LAUREN" 13 PUBLIC HEALTH & PREV MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF PUBLIC HEALTH 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 364178 NCI 257751 106427 PROJECT SUMMARY/ABSTRACTNon-Hispanic Black (NHB) and Hispanic/Latinx women are disproportionately diagnosed with breasttumor exhibiting more aggressive phenotypes; and NHB women are dying from breast cancer at rateshigher than every other racial/ethnic group in the United States (US). Due to structural racism (and itsdownstream effects) NHB and Hispanic/Latinx women experience more chronic stressors comparedto non-Hispanic White (NHW) women. Emerging data from our group and others show that social andbiologic factors contribute to the development of breast cancers with more aggressive tumor featuresthat lead to the poorer outcomes. Evidence supports allostatic load a measure of dysregulation acrossmajor physiologic systems including metabolic cardiovascular and immune/inflammatory systems as a measure of cumulative physiologic stress and risk factor for adverse health outcomes. Data froma nationally representative sample of US women showed that allostatic load is inversely associatedwith socioeconomic status (SES) and positively associated with breast cancer among Black womenbut not White women. No prior study has prospectively explored the impact of allostatic load andneighborhood contextual factors (simultaneously) on breast cancer in a large diverse study sample.Here we propose to examine the impact of pre-diagnostic allostatic load score (ALS) and objectivelymeasured neighborhood contextual factors on breast cancer incidence and phenotype in a largenested case-control study of NHB NHW and Hispanic/Latinx participants in the Womens HealthInitiative (WHI). Our central hypothesis is that risk of breast cancer and aggressive tumors areattributable to the impact of higher ALS and socioeconomically deprived and racially segregatedneighborhood context. Further we hypothesize that allostatic load mediates the associations ofneighborhood context with breast cancer which differ by race/ethnicity. Leveraging WHIs prospectivedesign rich epidemiologic and clinical data and long-term follow-up to test these hypotheses throughthe following aims: 1) Investigate associations of allostatic load with breast cancer risk and tumorphenotype; 2) Investigate associations of neighborhood contextual factors with breast cancer risk andtumor phenotype; and 3) Evaluate whether independent associations of allostatic load andneighborhood context with breast cancer differ by race/ethnicity. This study will have a high impact byyielding novel prospective data on the impact of unfavorable neighborhood contextual factors andallostatic load (as an intermediate biological process/mechanism between neighborhood context andhealth) on breast cancer. Findings from this study will contribute new knowledge about the biologicalbasis of long-term effects of structural racism and utility of ALS as a biomarker of cancer risk. Thesedata are essential to developing evidence-based prevention strategies to improve cancer health equity. 364178 +No NIH Category available Antibodies;Antigens;Automobile Driving;B Cell Proliferation;B-Cell Antigen Receptor;B-Cell Lymphomas;B-Lymphocytes;BLNK gene;Cells;Characteristics;Clinical;Complex;Cytotoxic Chemotherapy;Data;Dependence;Development;Diffuse Large-Cell Lymphoma;Drug resistance;Epstein Barr Virus B cell lymphoma;Epstein-Barr Virus Infections;Epstein-Barr Virus-Related Lymphoma;Failure;Gene Expression;Growth;HIV;Hodgkin Disease;Human Herpesvirus 4;Immunocompromised Host;Immunoglobulin Class Switching;Immunoglobulin G;Immunoglobulin Isotypes;Immunoglobulin M;Impairment;In Vitro;Individual;Knowledge;Lymphocyte Activation;Lymphoma;Lymphomagenesis;Mediating;Mediator;Morbidity - disease rate;Non-Hodgkin's Lymphoma;Oncogenes;Oncogenic;Outcome;Pathway interactions;Persons;Pharmaceutical Preparations;Plasma Cells;Play;Predisposition;Process;Proliferating;Proteins;Receptor Signaling;Resistance;Role;Signal Induction;Signal Pathway;Signal Transduction;Signaling Molecule;Testing;Therapeutic;Therapeutic Intervention;Tissue-Specific Gene Expression;Viral;Viral Oncogene;antiretroviral therapy;cell transformation;clinical predictors;design;high risk;humanized mouse;improved;in vivo;infected B cell;inhibitor;lymphoblastoid cell line;mortality;mutant;novel;nuclear factors of activated T-cells;pharmacologic;response;stem;targeted agent;targeted treatment;transforming virus;transmission process;tumorigenesis Role of Epstein-Barr virus LMP2A protein in maintaining oncogenic IgM signaling in EBV+ B cell lymphomas PROJECT NARRATIVESubversion of the B cell receptor (BCR) signaling pathway is a cardinal feature of B cell lymphoma. This pro-posal investigates how the Epstein-Barr virus (EBV) LMP2A oncogene interacts with the BCR maintaining it inits growth promoting IgM isotype and creating dependence upon antigen-induced signaling for EBV trans-formed cells expressing LMP2A. Completion of this proposal will provide a framework of knowledge defininginteractions between LMP2A and the BCR and identify strategies for targeting dependencies of EBV+ lympho-mas on the antigen-induced signaling pathway. NCI 10707312 6/27/23 0:00 PAR-21-348 5U01CA275247-02 5 U01 CA 275247 2 "DASCHNER, PHILLIP J" 9/20/22 0:00 7/31/27 0:00 ZCA1-SRB-P(M2) 6712292 "JOHANNSEN, ERIC C" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 436538 NCI 284287 152251 PROJECT SUMMARYEpstein-Barr virus (EBV) causes a wide spectrum of lymphomas including Hodgkin Burkitt and diffuse largecell lymphomas (DLBCL). The proportion of EBV+ lymphomas rises sharply as does morbidity and mortality inHIV-infected persons despite combined antiretroviral therapy (cART) suggesting specific failure to control viraldriven lymphomas. However the mechanistic processes contributing to EBV-driven lymphomagenesis remainpoorly understood. This proposal will investigate a conceptually novel hypothesis that the LMP2A viraloncogene interacts with the B cell receptor (BCR) serving to maintain it in its growth promoting IgM isotype.This hypothesis predicts that EBV transformed cells expressing LMP2A are dependent upon their constitutiveactivation of cellular mediators of antigen-induced signaling and thus will be susceptible to agents that targetthis signaling cascade whereas EBV-transformed cells that do not express LMP2A will be resistant to suchdrugs. Our proposal stems from two exciting observations that we have made about lymphoblastoid cells(LCLs) transformed by an EBV mutant that lacks LMP2A (LMP2A-EBV). First we discovered that unlikenormal LCLs the growth of LMP2A-LCLs is not dependent on mediators of antigen-induced signaling likeBLNK and BTK. Second in contrast to normal LCLs LMP2A-LCLs fail to maintain the growth promoting IgMform of the BCR and instead express the IgG-BCR. Since antigen signaling through IgG-BCR promotesdifferentiation into plasma cells which secrete high levels of antibodies but have limited proliferative potentialour central hypothesis is that LMP2A contributes to lymphomagenesis by facilitating outgrowth of EBVtransformed B lymphocytes expressing the growth promoting IgM-BCR. This proposal will analyze mechanisticpathways and gene expression profiles in EBV-transformed LCLs and test lymphoma formation in humanizedmice in order to distinguish the direct contributions of LMP2A from those mediated by the IgM-BCR andassess the therapeutic vulnerability that arise from each. Specifically we will (1) Investigate intersection ofLMP2A and BCR Ig isotype on B lymphocyte transformation (2) Characterize impact of antigenic stimulation inthe presence or absence of LMP2A expression and (3) Determine LMP2A-mediated susceptibility totherapeutic inhibition of signaling molecules. Together these studies provide a framework for how LMP2Ainteracts with the BCR to promote EBV transformation and provide new opportunities for therapeuticintervention in EBV-associated lymphomas. 436538 +No NIH Category available Antigens;Area;CRISPR/Cas technology;Cancer Biology;Cancer Control;Cancer Model;Cancer Patient;Cancer Vaccines;Cells;Data Set;Development;Disease Progression;Dissociation;Evolution;Foundations;Functional disorder;Gene Expression;Genes;Genetic Engineering;Genetically Engineered Mouse;Human;Immune;Immune system;Immunotherapy;In Situ;Laboratories;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Methods;Modeling;Molecular;Nature;Organoids;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Pre-Clinical Model;Preventative vaccination;Research;Specimen;System;T cell response;T-Cell Activation;T-Lymphocyte;Time;Vaccine Therapy;cancer cell;cancer type;cell type;clinical translation;experimental study;genetic profiling;genome editing;human model;improved;mouse model;novel;novel therapeutic intervention;response;single cell analysis;technology development;tool;transcriptomics;tumor;tumor microenvironment;tumor progression;vaccine strategy Studying factors controlling cancer progression and immune recognition in mouse models Project NarrativeThe Jacks laboratory has pioneered the use of genetic engineering and genome editing to develop highlysophisticated models of human cancer. This proposal highlights novel research directions in the areas oftumor evolution and tumor-immune interactions. Results from these studies are expected to inform newstrategies for treating human cancer. NCI 10707303 8/8/23 0:00 PAR-21-333 5R35CA274464-02 5 R35 CA 274464 2 "LIU, YIN" 9/20/22 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 3128332 "JACKS, TYLER E." Not Applicable 7 MISCELLANEOUS 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA ORGANIZED RESEARCH UNITS 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 934920 NCI 588000 346920 SummaryOver the past three decades the Jacks laboratory has been a recognized leader in the development andcharacterization of genetically engineered mouse models of cancer among other pre-clinical models.The laboratory has also studied human cancer specimens and datasets to validate finding from theirexperimental systems and to advance discoveries toward clinical translation. While Jacks laboratory hasinvestigated many cancer types over time this proposal is focused on models of lung adenocarcinomaand pancreatic ductal adenocarcinoma. By developing and deploying tools of genetic engineering andgenetic profiling such as CRISPR-based methods and single-cell analysis the laboratory has pioneerednew models and analytical approaches that have allowed for a deeper understanding of diseaseprogression including interactions between developing tumors and the immune system. This proposalbuilds on this foundation at the intersection of cancer biology and technology development to explore indetail the molecular and cellular aspects of tumor evolution. Single-cell profile methods will be augmentedby spatial transcriptomics to characterize the changes in gene expressionin cancer cells as well asother cell types within the tumor microenvironmentin situ rather than in dissociated cells. Genes andpathways implicated by this analysis will be subjected to functional analysis using organoid-based modelsas well as in the autochthonous setting. A second major theme of this proposal is the further explorationof tumor-immune interactions in lung cancer which the laboratory has been studying for several years.Following up on experiments investigating the factors that control T cell activation and dysfunction in thesetting of lung and pancreas cancer development the laboratory will explore methods to provokeeffective anti-tumor T cell responses as well as an improved response to immunotherapy. These studieswill investigate the nature of the antigens and antigen combinations that induce effective T cell primingand activation including through prophylactic and therapeutic vaccinations. Results of these experimentswill inform new therapeutic approaches including novel cancer vaccine strategies in human cancerpatients. 934920 +No NIH Category available Adjuvant Chemotherapy;Adjuvant Therapy;Aftercare;Agreement;Axilla;Biological;Biological Markers;Breast;Breast Cancer Patient;Breast-Conserving Surgery;Clinical;Clinical Trials;Data;Diffusion;ERBB2 gene;Endocrine;Enrollment;Estrogen Receptors;Estrogens;Evaluation;Event;Excision;Functional Imaging;Genes;Goals;Hormonal;Hybrids;Image;Knowledge;Magnetic Resonance Imaging;Mammary Neoplasms;Mammography;Measures;Mediating;Metastatic breast cancer;Metastatic/Recurrent;Methods;Mission;Modality;Morbidity - disease rate;Multicenter Trials;Mutation;Neoadjuvant Therapy;Newly Diagnosed;Operative Surgical Procedures;Outcome;Palpation;Patient-Focused Outcomes;Patients;Perfusion;Phase;Phase II Clinical Trials;Physicians;Positron-Emission Tomography;Pre-Clinical Model;Prediction of Response to Therapy;Predictive Value;Prior Therapy;Progesterone Receptors;Progestins;Proliferating;Protocols documentation;Reader;Reference Standards;Research;Resistance;Safety;Scanning;Signal Transduction;Staging;Techniques;Testing;Translating;Treatment Efficacy;Treatment outcome;Tumor Burden;Tumor Markers;United States National Institutes of Health;Woman;Work;X-Ray Computed Tomography;Xenograft procedure;adjuvant endocrine therapy;antagonist;breast imaging;care outcomes;chemotherapy;deprivation;drug sensitivity;efficacy evaluation;hormone receptor-positive;hormone therapy;imaging agent;imaging approach;imaging modality;improved;improved outcome;in vivo;individualized medicine;innovation;malignant breast neoplasm;men;molecular subtypes;mortality;multiparametric imaging;novel diagnostics;personalized approach;personalized care;phase 2 study;pre-clinical;precision medicine;predicting response;prospective;quantitative imaging;radioligand;receptor;receptor expression;resistance mechanism;response;standard of care;success;tool;treatment optimization;treatment planning;treatment response;tumor;tumor growth;tumor xenograft;ultrasound;uptake Precision Imaging of Breast Cancer for Guiding Neoadjuvant Endocrine Therapy PROJECT NARRATIVETools to help physicians tailor treatments to match the biologic aggressiveness and drugsensitivity of each patients breast cancer are urgently needed to achieve precision medicine.The proposed research will lay the groundwork for translating a new functional imaging-basednon-invasive approach to assess early response to neoadjuvant endocrine therapy for patientswith hormone receptor positive primary breast cancer. A direct method of measuring functionalendocrine sensitivity is relevant to the NIHs mission and is expected to have significant clinicalimpact by better informing decisions for optimal individualized therapy and ultimately byreducing breast cancer morbidity and mortality. NCI 10707285 8/16/23 0:00 PAR-21-033 5R01CA272571-02 5 R01 CA 272571 2 "ZHANG, HUIMING" 9/20/22 0:00 8/31/27 0:00 Clinical Translational Imaging Science Study Section[CTIS] 12175956 "FOWLER, AMY " Not Applicable 2 RADIATION-DIAGNOSTIC/ONCOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 600877 NCI 386416 214461 Accurate non-invasive biomarkers are urgently needed to identify which patients with hormonereceptor positive (HR+) breast cancer will respond to neoadjuvant endocrine therapy. Lack ofdirect knowledge of the endocrine sensitivity of each patients breast cancer impedes optimaltailored therapy. Without a more personalized approach many women and men will continue tosuffer from the current morbidity and mortality of breast cancer. The overall objective of theproposed clinical trial is to investigate the ability of quantitative hybrid functional imaging forassessing hormonal sensitivity estrogen receptor (ER) functional inhibition and early responseto neoadjuvant endocrine therapy. The long-term goal is to develop functional imagingapproaches to directly test tumor sensitivity to endocrine therapy in breast cancer patients forindividualized treatment plans and improved outcomes. The proposed research will investigateearly changes in expression of a classic estrogen-regulated target gene as a surrogate measureof endocrine sensitivity: progesterone receptor (PR) using a progestin-based radioligand 21-[18F]fluorofuranylnorprogesterone (FFNP) and quantitative simultaneous breast positronemission tomography/magnetic resonance imaging (PET/MRI). The central hypothesis is thatFFNP uptake in primary breast tumors will show dynamic changes in response to presurgicalendocrine therapy which will correlate with treatment response and exceed inherent technicalvariability. The proposed clinical trial is a prospective single-center study that will enroll womenwith newly diagnosed ER+/PR+/HER2- invasive breast cancer who will undergo simultaneousbreast PET/MRI with FFNP before and after a short course of endocrine therapy prior to surgicalexcision. The study aims to determine 1) the efficacy of FFNP PET/MRI for predicting responseto presurgical endocrine therapy and 2) the quantitative reliability of FFNP breast PET/MRI. Theproposed research is innovative because it will use functional imaging with simultaneous breastPET/MRI to improve the success of neoadjuvant endocrine therapy. Imaging treatment-inducedchanges in estrogen-regulated signaling events using FFNP PET/MRI will have a significantpositive impact by enabling early assessment of endocrine therapy response mediated throughER before changes in tumor size can be measured using conventional techniques such asmammography ultrasound and palpation. Once validated this approach can easily beintegrated into the preoperative evaluation of patients with primary HR+ breast cancer toindividualize neoadjuvant and adjuvant treatment plans for improved patient outcomes. 600877 +No NIH Category available Aerodigestive Tract;Algorithms;Biochemical;Biological;Biological Assay;Biological Markers;Biological Models;Biopsy Specimen;Blood specimen;Carbon;Cell Line;Cells;Characteristics;Chemicals;Cisplatin;Clinical;Clinical Trials;Coenzymes;Coupled;Data;Detection;Development;Diagnostic Neoplasm Staging;Disease;Dose;Early Diagnosis;Effectiveness;Evaluation;Exposure to;Failure;Feedback;Genomics;Genotoxic Stress;Glycolysis;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Human;Image;In Vitro;Knowledge;Lactate Dehydrogenase;Link;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Measurable;Measurement;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mission;Modeling;Molecular;Mutagens;NADH;NADP;Neoadjuvant Therapy;Neoplasm Circulating Cells;Nicotinamide adenine dinucleotide;Non-Invasive Detection;Normal tissue morphology;Oxidation-Reduction;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Pyruvate;Recycling;Regimen;Research;Resistance;Solid Neoplasm;Spectrum Analysis;Systemic Therapy;Testing;Therapeutic;Time;Toxic effect;Treatment Failure;Tumor Biology;Tumor Burden;Tumor Markers;United States National Institutes of Health;Work;Xenograft procedure;biomarker identification;chemoradiation;chemotherapy;clinical decision-making;design;drug testing;effective therapy;imaging approach;in vitro Assay;in vivo;malignant oropharynx neoplasm;metabolic imaging;metabolic phenotype;minimally invasive;mortality;neoplastic cell;non-invasive imaging;novel;oxidation;phase 2 study;pre-clinical;precision oncology;prospective;real-time images;relative effectiveness;response;success;transcriptomics;treatment optimization;treatment response;tumor;tumor growth;tumor metabolism Quantification of cisplatin sensitivity and resistance using metabolic imaging and circulating tumor cell (CTC) biomarkers n/a NCI 10707179 8/31/23 0:00 RFA-CA-21-052 5U54CA274321-02 5 U54 CA 274321 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9357 1880052 "LAI, STEPHEN Y" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 269807 166548 103259 PROJECT 3 SUMMARYCisplatin (CDDP) remains the gold-standard for chemotherapeutic treatment for multiple solid tumors includinghead and neck squamous cell carcinoma (HNSCC). High rates of treatment failure result from the developmentof acquired resistance following this relatively toxic chemotherapy. Despite the frequent use of CDDP no robustpredictors of tumor response or development of acquired resistance exist. Treatment failure is uniformly fatal.Given the critical unmet need for predictors of tumor response and acquired resistance we have focused ourefforts on the assessment of tumor response with minimally invasive imaging (hyperpolarized magneticresonance imaging; HP-MRI) and detection of biological shifts in circulating tumor cells (CTCs) while patientsare undergoing cisplatin-based therapy. We have shown that CDDP and other genotoxic agents triggermeasurable fluctuations in tumor cell metabolism detectable by both conventional biochemical assays and HP-MRI with [1-13C]-pyruvate. The recycling of key coenzymes in several reductive metabolic pathways links theeffects of genotoxic stress to carbon flux from pyruvate into lactate via lactate dehydrogenase (LDH). Wepreviously showed that genotoxic agents alter the intracellular redox state shift pyruvate/lactate metabolismand suppress the apparent rate of pyruvate conversion to lactate (kPL) in a manner that correlates with anti-tumoreffectiveness. Genomic and transcriptomic analysis of regulatory shifts associated with the acquisition of cisplatinresistance in CTCs will re-enforce the imaging-based quantification of cisplatin sensitivity and resistance. Basedon these preliminary data we hypothesize that metabolic reprogramming driven by Nrf-2 in cisplatin-resistant HNSCC is detectable using a combination of non-invasive imaging of carbon flux (kPL- via HP-MRI) and scCTC analysis. To assess this premise we will use well-characterized preclinical models of HNSCCthat are sensitive and resistant to cisplatin. Alterations in glycolytic metabolism will be measured at baseline andfollowing cisplatin administration through hyperpolarized imaging and biochemical assays. These measurementswill be validated with biochemical assays in vitro and in vivo (Aim 1). We will also measure treatment responsein HNSCC patients relative to alterations in tumor kPL by acquiring HP-MRI data prior to and following inductionchemotherapy (Aim 2). Biological confirmation will be performed in CTCs to identify biomarkers associated withcisplatin resistance through genomic and transcriptomic analysis. Successful completion of this study willestablish HP-MRI as a minimally invasive imaging approach to characterize relative tumor resistance to cisplatinand provide real-time feedback to optimize treatment. CTC biomarker analysis will provide critical biologicalsupport for the imaging findings. This work has the potential to change the basis for clinical decision-makingregarding the use of cisplatin in HNSCC and related aerodigestive tract cancers. As a noteworthy first steptowards a precision oncology approach the proposed research is relevant to the part of the NIHs mission thatpertains to developing and applying fundamental knowledge that will help to reduce the burdens of human illness. +No NIH Category available Animal Model;Biological Markers;Biological Specimen Banks;Blood;Cancer cell line;Cell Line;Cell Maintenance;Clinical;Collaborations;Collection;Cytology;Database Management Systems;Databases;Development;Diagnosis;Drug or chemical Tissue Distribution;Ensure;Evaluation;Fine needle aspiration biopsy;Fostering;Genomics;Guidelines;Harvest;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Health Insurance Portability and Accountability Act;Human Resources;Immunohistochemistry;Individual;Laboratories;Lead;Leadership;Link;Malignant - descriptor;Medicine;Modeling;Mus;Nucleic Acids;Pathologic;Pathology;Patients;Preparation;Process;Research;Research Personnel;Resistance;Resources;Sampling;Secure;Services;Specimen;Techniques;Tissue Banks;Tissue Microarray;Tissue Sample;Tissues;United States National Institutes of Health;University of Texas M D Anderson Cancer Center;Western Blotting;college;cytokine;immunosuppressed;innovation;patient derived xenograft model;peripheral blood;programs;repository;tumor Tumor Model and Biospecimen Repository Core n/a NCI 10707167 8/31/23 0:00 RFA-CA-21-052 5U54CA274321-02 5 U54 CA 274321 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9354 6218975 "EL-NAGGAR, ADEL K." Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 67245 41509 25736 Tumor Model and Biospecimen Repository Core (Core C) SUMMARYTumor Model and Biospecimen Repository Core (Core C) led by Dr. Adel K. El-Naggar (Core Leader) and Dr.Jeffrey Myers (Core Co-Leader) will provide H-CARR investigators with a centralized facility that ensures thesystematic collection processing storage and distribution of peripheral blood surrogate and specializedspecimens and samples of head and neck squamous cell carcinoma (HNSCC) from patients diagnosed treatedand followed at The University of Texas MD Anderson Cancer Center (MD Anderson) at Baylor College ofMedicine (BCM). Core C also provides expert preparation and distribution of high-quality samples and ancillarytechniques to optimize utilization of patients materials by H-CARR investigators. Procurement and distributionof the samples to individual investigators will follow the guidelines established by the H-CARR Center ExecutiveLeadership Committee and in compliance with HIPAA. Core C leadership will provide detailed pathologicevaluation of all tumor samples to investigators through the secure pathology database system linked to the H-CARR database and server. Core C will perform specialized services including tissue microarray (TMA)construction qualitative and quantitative biomarker analyses both in tissue [e.g. immunohistochemistry (IHC)Western blotting] and non-tissue (e.g. blood-based cytokine profiles) specimens nucleic acid extractions anddevelopment and maintenance of cell lines. Core C will also provide well-characterized genomicallyauthenticated head and neck cancer cell lines well-characterized patient-derived xenograft (PDX) models andheterotopic and orthotopic animal models in immunosuppressed or syngeneic mice and autochthonous tumormodels of HNSCC to investigators. The leadership and personnel of Core C and its centralized organization willensure the highest quality tissue samples and related analyses to all H-CARR investigators and to collaboratingresearchers participating in other NIH/NCI-sponsored programs. +No NIH Category available ATAC-seq;Advisory Committees;Big Data;Bioinformatics;Biological Markers;Cell Line;ChIP-seq;Cisplatin;Code;Collaborations;Communities;Consult;Data;Data Analyses;Data Set;Development;Drug resistance;Ensure;Funding Agency;Generations;Genomics;Head and Neck Squamous Cell Carcinoma;Human;Individual;Institution;Metadata;Methodology;Modeling;Molecular and Cellular Biology;Multiomic Data;Neoplasm Circulating Cells;Policies;Process;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resistance;Resistance development;Site;Solid Neoplasm;Source Code;System;Technology;Time;United States National Institutes of Health;University of Texas M D Anderson Cancer Center;Visualization;Work;advanced analytics;complex data;data acquisition;data dissemination;data integration;data pipeline;data sharing;data streams;design;human data;metabolic imaging;metabolomics;mid-career faculty;multiple omics;open source;prevent;programs;response;sharing platform;single-cell RNA sequencing;success;synergism;transcriptomics Systems Bioinformatics Core n/a NCI 10707163 8/31/23 0:00 RFA-CA-21-052 5U54CA274321-02 5 U54 CA 274321 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9353 11079182 "COARFA, CRISTIAN " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 63080 63080 0 Systems Bioinformatics Core (Core B) SUMMARYH-CARR is designed to interrogate the genomic transcriptomic and metabolomic drivers of acquired cisplatinresistance in HNSCC. Projects 1 2 and 3 are designed to synergize with the ultimate dual objective of: 1)identifying reliable biomarkers of cisplatin resistance and 2) developing strategies for preventing its developmentor acquisition. Project 1 will generate steady state and flux metabolomic data which will be integrated with thegenomic and transcriptomic data generated in Project 2. Together the datasets will then be validated againsthuman data acquired using non-invasive metabolic imaging and genomic and transcriptomic analysis of humanHNSCC circulating tumor cells (CTCs). Core B is envisioned as a Systems Bioinformatics Core which will coalesce the datastreams from all 3Projects into one coherent multi omics understanding of cisplatin response and development of resistance. CoreB led by Dr. Coarfa is tasked with performing the complex data analysis proposed in each individual Project anddeveloping pipelines for data acquisition analysis and interpretation which can be rapidly deployed within H-CARR and the broader ARTNet scientific community. Core B in collaboration with Core A (Administrative) willdevelop a near real time reporting system for both model (PDX cell line) generation analytical pipelines andraw and processed data sharing with other investigators. The Core will leverage existing institutional expertisewith big data analysis along with Dr. Coarfas established scientific relationships with the other investigators todevelop a state of the art analytical platform that can be deployed to characterize and understanding acquiredresistance across multiple solid tumors and systemic agents. +No NIH Category available 3-Dimensional;Abdomen;Acceleration;Adoption;Affect;Angiomyolipoma;Benign;Biological;Biological Markers;Biopsy;Breathing;Cellularity;Cessation of life;Chromophobe Renal Cell Carcinoma;Clear cell renal cell carcinoma;Clinical;Collagen;Data;Databases;Development;Diagnosis;Diagnostic;Differential Diagnosis;Dimensions;Economic Burden;Eligibility Determination;Evaluation;Excision;Exhibits;Fatty acid glycerol esters;Financial Hardship;Fingerprint;Goals;Graph;Health Care Costs;Healthcare Systems;Heterogeneity;Histologic;Histology;Image;Image Analysis;Imaging Techniques;Kidney;Kidney Diseases;Lipids;Machine Learning;Magnetic Resonance;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of kidney;Maps;Measurement;Measures;Medicare;Methodology;Methods;Morbidity - disease rate;Morphologic artifacts;Motion;Neoplasm Metastasis;Normal Range;Operative Surgical Procedures;Oxyphilic Adenoma;Papillary;Patient Selection;Patients;Positioning Attribute;Predisposition;Procedures;Property;Psychosocial Stress;Publications;Relaxation;Renal Cell Carcinoma;Renal Mass;Renal carcinoma;Reporting;Reproducibility;Resolution;Risk;Sampling;Sensitivity and Specificity;Slice;Societies;Standardization;Techniques;Technology;Three-Dimensional Imaging;Time;Tissues;Unnecessary Surgery;Up-Regulation;Validation;biological heterogeneity;clinical practice;comorbidity;convolutional neural network;cost;data acquisition;deep learning;diagnostic accuracy;follow-up;healthy volunteer;human old age (65+);imaging biomarker;imaging capabilities;improved;kidney imaging;learning strategy;lipid metabolism;machine learning method;mortality;novel;older patient;overtreatment;predictive modeling;prospective;quantitative imaging;soft tissue;spatiotemporal;tissue mapping;tool;treatment strategy;tumor Development of Magnetic Resonance Fingerprinting in Kidney for Evaluation of Renal Cell Carcinoma Project NarrativeRenal cell carcinoma (RCC) is the most common malignant renal neoplasm which often presents as anincidentally detected incompletely characterized renal mass. Due to the limited capability of current imagingtechniques many of these patients with incidental renal mass undergo direct surgery or biopsy without furtherimaging evaluation which adds to unnecessary morbidity and health care cost. In this study we propose toleverage our expertise in Magnetic Resonance Fingerprinting machine learning and body MR imaging todevelop a novel free-breathing multi-parametric MR imaging technique which upon successful developmentcould make MRI a more powerful tool for the diagnosis and characterization of these patients with incidentalrenal mass with the ultimate goal to eliminate unnecessary biopsy/surgery in eligible patients and provideguidance towards the most appropriate treatment strategy. NCI 10707150 8/22/23 0:00 PA-20-185 5R01CA266702-02 5 R01 CA 266702 2 "KIM, BOKLYE" 9/20/22 0:00 8/31/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 12144227 "CHEN, YONG " "TIRUMANI, SREE HARSHA " 11 RADIATION-DIAGNOSTIC/ONCOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 516077 NCI 382253 133824 AbstractKidney cancer is expected to affect 76080 new patients with 13780 deaths in the U.S. in the year 2021. Renalcell carcinoma (RCC) is the most common type of kidney cancer which imposes significant economic burdenon healthcare system. A recent study based on SEER Medicare database reported that the total healthcarecost per RCC patient was $23489 with a weighted total economic burden of $2.1 billion. RCC often presentsas an incidentally detected incompletely characterized renal mass. Many of these patients with incidental renalmass either undergo direct surgery or biopsy without further imaging evaluation as accurate histologicdiagnosis with current imaging techniques is not always possible. However upfront surgery or biopsy is notideal as nearly 25% incidental renal masses are either benign (angiomyolipoma oncocytoma) or low-grade(chromophobe RCC low-grade clear cell RCC) and overtreatment of such masses adds to unnecessarymorbidity and health care cost. Prior studies have shown low-grade RCC can be managed conservatively withactive surveillance in select patients (elderly patients and patients who are poor surgical candidates) but atpresent there is a no non-invasive way to separate low-grade RCC from aggressive RCC (high-grade clear cellRCC papillary RCC). Accordingly there is an emergent need to develop novel non-invasive quantitativebiomarkers for accurate characterization of renal masses so that more patients eligible for active surveillancecould be identified. Recent studies have shown that MR tissue relaxometry mapping including T1 T2 and T2*mapping and fat fraction quantification can provide improved characterization of kidney diseases and correlatewith tumor grade and biologic aggressiveness in RCC. However the current kidney relaxometry mappingtechniques still suffer from long breath-holds limited spatial resolutions/coverage and ability to mostly captureone tissue property at a time. Further the quantitative measures are often susceptible to motion artifacts withpoor repeatability and reproducibility. In this study we propose to utilize the novel MR Fingerprinting (MRF)technique together with machine learning methods to mitigate aforementioned limitations in kidney imaging. Inparticular we will develop a new 3D free-breathing kidney MRF method for simultaneous T1 T2 T2* and fatfraction quantification (Aim 1). We will combine this kidney MRF acquisition with novel deep learningapproaches to accelerate data acquisition and improve tissue mapping efficiency (Aim 2). Finally we will applythe MRF technique in patients with RCC to explore its diagnostic strength in characterizing kidney cancer (Aim3). Upon successful development the multi-parametric quantitative measures acquired with MRF could makeMRI a more powerful tool for the diagnosis and predicting of tumor grade in RCC with the ultimate goal toeliminate unnecessary biopsy/surgery in eligible patients with benign/low-grade RCCs and provide guidancetowards the most appropriate treatment strategy. 516077 +No NIH Category available Basic Science;Biopsy;Biopsy Specimen;Cancer cell line;Cause of Death;Cell Death Induction;Cell Differentiation process;Cells;Chemotherapy and/or radiation;Chromosome abnormality;Clinical;Communication;Complex;Cystine;DNA copy number;DNA sequencing;Data;Disease;Drops;Esophageal Adenocarcinoma;Excision;Fibroblasts;Fluorescent in Situ Hybridization;Future;Gene Expression;Gene Expression Profile;Genes;Genomics;Goals;Healthcare;Heterogeneity;Hypoxia;Image;Immune;In complete remission;Iron;KRAS2 gene;Link;MDM2 gene;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Maps;Mediating;Molecular;Morbidity - disease rate;Myeloid Cells;Neutrophil Infiltration;Nonmetastatic;Operative Surgical Procedures;Organoids;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Positron-Emission Tomography;Pre-Clinical Model;Preclinical Testing;Radiation therapy;Refractory;Regimen;Resistance;Resolution;Risk;Role;Sampling;Selection for Treatments;Signal Pathway;Societies;Solid Neoplasm;Stromal Cells;Survival Rate;Technology;Testing;Time;Tracer;Transplant Recipients;Treatment outcome;Treatment-related toxicity;Tumor-infiltrating immune cells;base;cancer cell;cancer therapy;care burden;chemoradiation;curative treatments;cytokine;data integration;determinants of treatment resistance;differential expression;humanized mouse;improved;innovation;insight;irradiation;molecular imaging;mortality;mouse model;neoplastic cell;neutrophil;predicting response;predictive tools;radiation resistance;response;single-cell RNA sequencing;therapy development;therapy resistant;tissue mapping;tool;trait;transcriptome;transcriptomic profiling;treatment response;tumor;tumor microenvironment Role of genomic and microenvironment factors in conferring acquired resistance to ferroptosis to chemoradiation in esophageal adenocarcinoma n/a NCI 10707135 8/31/23 0:00 RFA-CA-21-052 5U54CA274220-02 5 U54 CA 274220 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 8887 10298380 "LIN, STEVEN HSESHENG" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 284543 175644 108899 Project 3 SummaryEsophageal cancer is the sixth most common cause of deaths worldwide with a 5-year survival rate of less than20%. Similar to other intrathoracic malignancies such as lung cancer chemoradiation therapy (CRT) is aneffective tool for treating esophageal adenocarcinoma (EAC). However CRT leads to complete responses inEAC in only approximately 25% of patients. Thus characterizing the cellular and molecular changes that occurin the tumor and tumor microenvironment during CRT can provide highly accurate predictive tools to identifywhich EAC patients will develop acquired resistance to therapy. CRT induces the cell death pathway ferroptosisin cancer cells and the hypothesis that ferroptosis is a key regulator in acquired radiation therapy resistance isa central theme of the Acquired Resistance to Therapy and Iron (ARTI) Center. Project 3 will contribute tothis central theme by bridging the basic science mechanisms in preclinical models discovered in Project 1 andProject 2 with clinical EAC tumor biopsies collected at baseline (before treatment) and during the middle of theCRT regimen. These EAC tumor biopsies will undergo single cell transcriptome profiling to identify expressionof ferroptosis-related genes and to provide an understanding of the complex communications between tumorcells and cells of the tumor microenvironment that may drive and/or regulate ferroptosis (Aim 1). Identificationof transcriptomes that are directly or indirectly related to ferroptosis may help to prognose EAC patients whomay or may not respond to CRT. Further spatial cellular mapping and deciphering the relationship of differentiallyexpressed genes with ferroptosis will provide evidence for the tumors ability to evade ferroptosis uponirradiation. Aim 2 will focus on determining whether adaptive resistance to therapy occurs due to selection ofrare but pre-existing tumor cells or due to de novo acquisition of alterations in genes directly or indirectly relatedto ferroptosis signaling pathways. Aim 3 will focus on elucidating the tumor microenvironment mechanisms thatmay confer ferroptosis resistance to CRT such as fibroblasts which have been shown to regulate the cystinetransporter SCL7A11 that promotes ferroptosis resistance. In addition tumor-infiltrated immune cells withhypoxic signatures will be analyzed for their association with ferroptosis resistance to CRT. In EAC tumorsresistant to CRT myeloid cell expansion was observed and the phenotype and activation status of myeloid cellswill be assessed using orthotopically transplanted patient derived EAC tumors. Further application of aninnovative positron emission tomography tracer from the Molecular Imaging Core of the ARTI Center to assessoxidative potential of tumors as related to the myeloid cell expansion observed in resistant tumors will helpdiscover molecular and cellular pathways related to ferroptosis. Project 3 will iteratively strengthen and supportthe basic science/mechanistic Projects 1 and 2 and Project 3 will significantly contribute to the ARTI Center goalof identifying patients who are at greatest risk to develop acquired radiation resistance. +No NIH Category available 3-Dimensional;Anabolism;Anatomy;Area;Basic Science;Cancer cell line;Cause of Death;Cell Death;Cell Death Induction;Cell physiology;Clinical;Combined Modality Therapy;Cultured Tumor Cells;Cystine;DNA Damage;Data;Disease;Environment;Esophageal Adenocarcinoma;Esophageal Neoplasms;FDA approved;Family;Genes;Genetic;Genetic Transcription;Glutathione;Goals;Hyperbaric Oxygen;Hyperbaric Oxygenation;Hypoxia;Hypoxia Inducible Factor;In Vitro;Ionizing radiation;Iron;Lipid Peroxidation;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Measures;Mediating;Mediator;Monitor;Mus;Neoplasm Metastasis;Organoids;Oxygen;Oxygen Therapy Care;Pathway interactions;Patient Selection;Play;Positron-Emission Tomography;Proliferating;Radiation;Radiation Tolerance;Radiation induced damage;Radiation therapy;Regulation;Resistance;Role;Signal Pathway;Site;Solid;Testing;Therapeutic;Time;Tracer;Tumor Oxygenation;Up-Regulation;Vascular blood supply;acquired factor;activating transcription factor 4;biological adaptation to stress;bioluminescence imaging;cancer cell;cancer therapy;cancer type;cell type;chemoradiation;design;efficacy evaluation;epithelial to mesenchymal transition;in vivo;inhibitor;member;molecular imaging;neoplastic cell;pharmacologic;pre-clinical;radiation resistance;response;small molecule;small molecule inhibitor;solute;therapeutically effective;therapy resistant;transcription factor;tumor;tumor growth;tumor hypoxia;tumor metabolism;tumor microenvironment;tumor xenograft Tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition n/a NCI 10707129 8/31/23 0:00 RFA-CA-21-052 5U54CA274220-02 5 U54 CA 274220 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9340 1939997 "KOONG, ALBERT " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 288757 178245 110512 Project 2 SummaryTumor hypoxia defined as low intratumoral oxygen tension is common to most solid malignancies includinglung and esophageal cancer. Lung and esophageal cancer treatments include radiation therapy (RT); howeverclinically these cancers develop acquired resistance to RT. The mechanisms of acquired resistance to RT areunknown but may involve a type of cell death called ferroptosis which is the overarching theme of the proposedAcquired Resistance to Therapy and Iron (ARTI) Center. Project 2 will contribute to this overarching themeby determining whether hypoxia drives ferroptosis resistance thereby promoting the acquired resistance to RT.Project 2 will utilize lung and esophageal cancer cell lines generated in Project 1 that are deficient in theferroptosis resistance-mediator Solute Carrier Family 7 Member 11 (SLC7A11) and one of its transcriptionfactors: activating transcription factor 4 (ATF4). The transcription of genes including hypoxia-related genes maybe dynamically regulated within tumor cells and cells of the tumor microenvironment during chemoradiationtherapy (CRT) of esophageal adenocarcinoma which is a focus of Project 3. In order to determine whetheroxygen is required for ferroptosis induction by RT lung and esophageal cancer cells will be subjected to varyingoxygen concentrations and radiosensitivity lipid peroxidation (i.e. driver of ferroptosis) and SLC7A11expression will be measured (Aim 1). Aim 2 will focus on the delineation of the mechanisms of hypoxia-drivenferroptosis resistance during acquired RT resistance by determining whether SLC7A11 expression is dependenton ATF4 under hypoxic conditions during RT. Furthermore as hypoxia inducible factors (HIFs) have been shownto promote radioresistance the effect of hypoxia-induced HIF activation in acquired resistance to ferroptosis willbe investigated. To test the hypothesis that enhanced tumor oxygenation through hyperbaric oxygen treatment(HBOT) as well as small molecule HIF and ATF4 inhibitors can overcome acquired radioresistance by enhancingferroptosis induction lung tumor and esophageal tumor xenografts in mice will be treated with RT in combinationwith HBOT or HIF/ATF4inhibitors(Aim 3). Tumor growth after RT will be monitored with weekly noninvasivebioluminescence imaging at the Molecular Imaging Core (MIC). Furthermore in the MIC hypoxic regions withintumors will be monitored in real-time by performing positron emission tomography (PET) using the PET tracer18F-Fluoroazomycin arabinoside (FAZA). Overall the differential regulation of ferroptosis and acquired RTresistance by poorly oxygenated and well oxygenated areas in tumors discovered in Project 2 will iterativelystrengthen and support the basic science/mechanistic Project 1 and the preclinical/translational Project 3 byhelping identify tumor regions that may develop acquired resistance to RT that could aid in patient selection forsubsequent treatments. +No NIH Category available Anabolism;Automobile Driving;CRISPR screen;Cell Death;Cell Line;Complement;Cystine;Data;Glutathione;Goals;Immunotherapy;Iron;Link;Lipid Peroxidation;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of thorax;Mediating;Modeling;Normal Cell;Normal tissue morphology;Outcome;Pathway interactions;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Recurrent disease;Resistance;Role;TP53 gene;Testing;Therapeutic;Therapeutic Effect;Therapeutic Studies;Toxic effect;Translating;Tumor Suppression;Xenograft procedure;cancer cell;cancer therapy;comparative;effectiveness evaluation;innovation;mutant;novel;novel therapeutic intervention;radiation resistance;radiation-induced injury;radioresistant;therapeutically effective;therapy resistant;tumor;tumor microenvironment Ferroptosis resistance as a key driver in acquired radiation resistance n/a NCI 10707126 8/31/23 0:00 RFA-CA-21-052 5U54CA274220-02 5 U54 CA 274220 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9339 9939858 "GAN, BOYI " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 279166 172325 106841 Project 1 SummaryFerroptosis is a form of regulated cell death that is triggered by iron-dependent lipidperoxidation. Previous studies by us and others identified ferroptosis as a critical tumor suppressionmechanism and suggested that inducing ferroptosis holds promise for cancer treatment. Recently we andothers showed that radiotherapy (RT) can potently induce ferroptosis and identified ferroptosis inducers(FINs) as radiosensitizers to tumors with intrinsic radioresistance (such as KEAP1 or p53 mutant tumors).However the mechanistic and therapeutic relevance of ferroptosis to acquired radioresistance remainslargely unexplored. Our long-term goals are to understand the mechanistic basis of ferroptosis in acquiredtherapy resistance and to rationally target ferroptosis in acquired resistance and disease recurrence incancer treatment. The objectives of this application are to determine the mechanisms by whichferroptosis resistance contributes to acquired radioresistance in thoracic cancers (including lung andesophageal cancers) and to assess FINs as a therapeutic strategy to overcome acquiredradioresistance in these cancers. Our preliminary data support the central hypotheses that (i) ferroptosisresistance represents a key mechanism underlying acquired radioresistance in lung andesophageal cancers and (ii) combining FINs with immunotherapy is an effective therapeutic strategy toovercome acquired radioresistance without causing significant damage to normal tissues. To test ourhypotheses we will pursue the following specific aims: Specific Aim 1. To define the mechanisms bywhich ferroptosis resistance drives acquired radioresistance. Specific Aim 2. To determine theeffectiveness of combining FINs with RT in overcoming acquired tumor radioresistance. Specific Aim 3. Todetermine the potential effects of FINs on radiation-induced toxicity in normal cells and tissues. It isexpected that our proposed studies will identify novel mechanisms of ferroptosis and acquired radioresistanceand identify effective new therapeutic strategies to overcome acquired radioresistance in thoraciccancer treatment. Our proposal is highly innovative because it focuses on previously unexploredpathways linking ferroptosis to acquired radioresistance. Our proposed studies will have a significantimpact on both our understanding of the fundamental mechanisms of ferroptosis and therapy resistanceand our ability to target ferroptosis in acquired radioresistance in cancer treatment. +No NIH Category available 3-Dimensional;3D ultrasound;Acoustics;Address;Algorithms;Anatomy;Animal Model;Biomedical Engineering;Cancer Patient;Clinical;Computer Simulation;Data;Data Analytics;Data Science;Dedications;Deposition;Detection;Development;Dose;Dose Rate;Electron Beam;Electrons;Emerging Technologies;Ensure;FarGo;Film;Geometry;Height;Image;Imaging Techniques;Institution;Ionizing radiation;Ions;Lesion;Machine Learning;Malignant Neoplasms;Maps;Measures;Methods;Modality;Monitor;Monte Carlo Method;Morphology;Mus;Noise;Normal tissue morphology;Outcomes Research;Patient Care;Patients;Penetration;Performance;Physics;Physiologic pulse;Play;Positioning Attribute;Pre-Clinical Model;Protons;Quality of life;Radiation;Radiation Biophysics;Radiation Oncology;Radiation Physics;Radiation therapy;Radiology Specialty;Rattus;Real-Time Systems;Resolution;Risk;Role;Safety;Signal Transduction;Structure;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Translations;Treatment Efficacy;Treatment-related toxicity;Ultrasonography;Width;X-Ray Computed Tomography;absorption;acoustic imaging;anatomic imaging;attenuation;cancer radiation therapy;clinical implementation;clinical translation;cost effective;deep learning;deep learning algorithm;design;detector;dosimetry;ex vivo imaging;experimental study;falls;image guided;imaging approach;imaging modality;imaging system;improved;in silico;in vivo;in vivo Model;in vivo imaging;interoperability;irradiation;machine learning algorithm;multidisciplinary;pre-clinical;preclinical study;proton beam;quality assurance;real time monitoring;reconstruction;risk minimization;soft tissue;spatiotemporal;temporal measurement;tool;tumor;ultrasound An Ionizing Radiation Acoustics Imaging (iRAI) Approach for guided Flash Radiotherapy NARRATIVEWe propose to address the current challenges of effective and safe FLASH-RT clinical delivery by developing animage-pulse guidance system utilizing technological advances in radiation acoustic imaging and machinelearning algorithms. Our approach is based on developing a general-purpose real-time radiation acoustic andultrasound dual-modality imaging system with deep learning reconstruction and error detection algorithms forguiding and safeguarding electron and proton FLASH-RT deliveries. The feasibility and versatility of the dualimage-guidance system will be evaluated using computer simulations phantoms and in vivo preclinical modelstowards clinical translation. NCI 10707124 8/16/23 0:00 PA-20-185 5R01CA266803-02 5 R01 CA 266803 2 "OBCEMEA, CEFERINO H" 9/20/22 0:00 8/31/27 0:00 Imaging Technology Development Study Section[ITD] 8704258 "EL NAQA, ISSAM M." "BORTFELD, THOMAS R.; WANG, XUEDING " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 652743 NCI 560030 92713 SUMMARYAn emerging radiotherapy (RT) modality that utilizes ultra-high dose rate known as FLASH-RT hasdemonstrated unprecedented ability for improving RT therapeutic ratio in preclinical studies and early clinicalcases. Because of lack of appropriate image-guidance technologies these studies have been limited to superficialirradiations and simplistic cases where monitoring of delivered dose is permissible using existing methods. Thisseverely handicaps the prospects of FLASH-RT and largely limits its promising impact for deep seated tumorswhich constitute most of RT cancer cases. It is widely recognized that currently used dosimetry technologies fallshort of providing the necessary guidance to deliver FLASH-RT in a practical clinical setting without exposingthe patient to tremendous risks that go far beyond the traditional RT delivery. Undoubtedly there is an unmetneed to develop in vivo image-guidance techniques to safeguard FLASH-RT accurate delivery. We hold that thesechallenges can be resolved by refining the emerging technology of ionizing radiation-induced acoustic imaging(iRAI) which can be intrinsically paired with FLASH-RT delivery systems. iRAI is based on the knownthermoacoustic phenomenon in radiation physics where acoustic waves are generated from thermoelasticexpansion of a substance following absorption of penetrating pulsated high energy radiation. Building upon ourmulti-institutional multidisciplinary team with expertise in ultrasound (US) imaging RT physics data analyticsand our promising preliminary results we hypothesize that: (1) a dual-modality imaging system comprised ofiRAI and US (iRAI-US) can simultaneously image both tissue morphology and 3D dose deposition duringFLASH-RT delivery with high spatio-temporal resolutions; and (2) machine learning based reconstruction andanomaly detection can effectively improve imaging quality and mitigate errors respectively for clinicaltranslation. Therefore in this project we aim to exploit the technological potentials of iRAI-US and machinelearning for developing an image-guidance platform for effective and safe FLASH-RT delivery. We willdemonstrate its efficacy with electron and proton beams using computer simulations (in silico) tissue mimickingphantoms and relevant preclinical in vivo models. Specifically we will (1) develop and test a dual-mode imagingsystem for 3D radiation-acoustics dosimetry and US imaging for FLASH-RT; (2) evaluate the in vivoperformance of iRAI-US dual imaging during electron and proton FLASH-RT deliveries; and (3) adapt andimprove iRAI volumetric representation temporal resolution and error detection for FLASH-RT using deepmachine learning algorithms (DeepRAI) towards effective clinical implementation.Impact: Our proposed image-guided FLASH-RT once validated will offer a practical robust cost-effectiveand unique system for safeguarding FLASH-RT delivery. These advancements will address the currentchallenges impeding the clinical translation of FLASH-RT and enable achieving its promise of limitingradiotherapy toxicity to normal tissues and thereby improving cancer patient care and quality of life. 652743 +No NIH Category available Achievement;Advisory Committees;Basic Science;Benchmarking;Cancer Patient;Clinical;Cloning;Collaborations;Combined Modality Therapy;Communication;Data;Development;Direct Costs;Doctor of Philosophy;Ensure;Esophageal Adenocarcinoma;Evaluation;Faculty;Funding;Genomics;Goals;Guidelines;Human;Hypoxia;Image;Imaging Device;Immunotherapy;Infrastructure;Institution;Intellectual Property;Iron;Knowledge;Leadership;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Measures;Mus;Myeloid Cells;National Cancer Institute;Office of Administrative Management;Patients;Performance;Policies;Pre-Clinical Model;Principal Investigator;Process;Production;Progress Reports;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Reporter Genes;Research;Research Project Grants;Resistance;Resource Sharing;Resources;Risk;Role;Sampling;Students;Technology;Testing;Therapeutic Agents;Training;Transfection;Transgenic Organisms;Translating;Translational Research;Wages;Work;Xenograft Model;anticancer research;cancer cell;cancer type;chemoradiation;cohort;conflict resolution;data management;data sharing;esophageal cancer patient;interest;meetings;member;molecular imaging;neoplastic cell;novel therapeutics;outreach;peer;programs;radiation resistance;stable cell line;standard of care;therapy resistant;tool;tumor;tumor growth;tumor hypoxia;web site Administrative Core n/a NCI 10707118 8/31/23 0:00 RFA-CA-21-052 5U54CA274220-02 5 U54 CA 274220 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E 9337 9939858 "GAN, BOYI " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 313499 193518 119981 ADMINISTRATIVE CORE SUMMARYThe proposed Acquired Resistance to Therapy and Iron (ARTI) Center is focused on the role of ferroptosisin acquired resistance to radiation therapy. Radiation therapy is used to treat approximately 50% of cancerpatients and is standard of care treatment for lung cancer and esophageal cancer patients. The ARTI Center willfocus on these cancer types and comprise three research projects. Project 1 will focus on identifying themechanisms of ferroptosis in acquired resistance to radiation therapy and testing ferroptosis inducers (FINs) asradiosensitizers. Project 2 will focus on determining whether hypoxia-induced resistance to ferroptosiscontributes to acquired tumor resistance to radiation therapy and whether FINs re-sensitize hypoxic tumor cellsto radiation treatment. Project 3 will focus on understanding the role of genomic and microenvironment factorsin acquired resistance to ferroptosis to chemoradiation in esophageal adenocarcinoma. The three researchprojects will be supported by one shared Molecular Imaging Core (MIC) which will provide imaging tools andanalyses for measuring tumor growth assessing the ability to overcome acquired radiation resistance usingcombination therapies (e.g. FINs with radiation therapy or immunotherapy) identifying intratumoral hypoxicregions and evaluating myeloid cell expansion in conferring ferroptosis resistance to chemoradiation therapy.To support the MIC and these three projects the Administrative Core (AC) will be established as part of theARTI Center infrastructure that will support coordinate and facilitate all activities aimed at achieving andevaluating milestones across the projects and core. The AC will establish and maintain engagement andcommunication among ARTI Center and ARTNet members and program officials in Aim 1. In Aim 2 the AC willfacilitate ARTI Center evaluation support the timely and quality development and submission of progressreports and maintain proper and transparent stewardship of funds. The AC will develop and implement aninternal solicitation and prioritization process for Pilot and Trans-Network Projects in Aim 3. In Aim 4 the ACwill serve as the central infrastructure to build a website and manage data materials resources conflictresolution and issues of intellectual property for technologies and tools. The multiple Principal Investigators(mPIs) of the ARTI Center Boyi Gan PhD and Albert Koong MD PhD will serve as AC Co-Leaders. Undertheir leadership the AC will be able to leverage institutional and divisional resources; to establish and maintainan ARTI Center Advisory Committee; to encourage the development of junior faculty trainees and students incancer research; to promote collaborations across ARTNet; and to ensure abidance by the ARTNet governanceand resource and data sharing policies. Overall the AC will be the central juncture for the ARTI Center tointegrate with other ARTNet centers as well as other National Cancer Institute-funded programs and initiatives. +No NIH Category available Achievement;Advisory Committees;Basic Science;Cancer Center;Cancer Patient;Cancer cell line;Cell Death;Cell Death Induction;Cells;Clinical;Clinical Trials;Cloning;Collaborations;Communication;Cystine;Data;Development;Drug resistance;Esophageal Adenocarcinoma;Failure;Family;Feedback;Fostering;Foundations;Future;Genes;Genomics;Goals;Grant;Guidelines;Human;Hypoxia;Hypoxia Inducible Factor;Image;Imaging Device;Immune;Immunologics;Immunotherapy;Infrastructure;Iron;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of thorax;Mediating;Medical;Modality;Modeling;Monitor;Mus;National Cancer Institute;Nature;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Patient-Focused Outcomes;Patients;Play;Policies;Positron-Emission Tomography;Pre-Clinical Model;Production;Prognostic Marker;Radiation;Radiation Oncology;Radiation therapy;Radiation-Sensitizing Agents;Reagent;Recurrence;Recurrent disease;Reporter Genes;Research;Research Project Grants;Resistance;Resource Sharing;Resources;Risk;Role;Sampling;Techniques;Testing;Therapeutic;Therapeutic Agents;Tracer;Transfection;Transgenic Organisms;Translating;Translational Research;Tumor Suppression;University of Texas M D Anderson Cancer Center;Xenograft Model;activating transcription factor 4;bioluminescence imaging;cancer cell;cancer imaging;cancer therapy;cancer type;chemoradiation;clinically significant;cohort;determinants of treatment resistance;drug sensitivity;effective therapy;hormone therapy;imaging program;improved;individual patient;member;molecular imaging;multidisciplinary;novel;novel therapeutic intervention;novel therapeutics;pre-clinical;programs;radiation resistance;radioresistant;single cell sequencing;solute;stable cell line;synergism;targeted treatment;therapy resistant;treatment strategy;tumor;tumor growth;tumor hypoxia;tumor microenvironment Acquired Resistance to Therapy and Iron (ARTI) Center Project NarrativeThe Acquired Resistance to Therapy and Iron (ARTI) Center at The University of Texas MD Anderson CancerCenter will establish a foundation for understanding the role of iron in cancer resistance to therapies and willfocus on deciphering the mechanisms of acquired resistance to radiation therapy which can be extrapolated toother types of cancer therapy. The overarching goals of the ARTI Center are: 1) to bridge the basic sciencemechanism of a novel type of iron-dependent cell death called ferroptosis in acquired resistance to radiationtherapy with translational research in preclinical models and human patient samples; 2) to identify cohorts ofpatients who are at greatest risk to develop acquired radiation therapy resistance; and 3) to investigate the abilityof novel therapeutic agents to re-sensitize cancer cells to radiation by inducing ferroptosis. The long-termoutcomes from the ARTI Center will foster collaborations with other centers in the Acquired Resistance toTherapy Network (ARTNet) build upon and iteratively feedback into research projects focused on drugresistance and sensitivities and ultimately lead to cancer treatment strategies tailored to the individual patient. NCI 10707117 8/31/23 0:00 RFA-CA-21-052 5U54CA274220-02 5 U54 CA 274220 2 "KAI, MIHOKO" 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-E(M1) 9939858 "GAN, BOYI " "KOONG, ALBERT " 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 1356931 NCI 837612 519319 Overall SummaryApproximately 50% of cancer patients are treated with radiation therapy (RT) but local recurrence can still occureven with the use of advanced RT techniques. This local recurrence which commonly develops in 30-50% ofcancer cases is exacerbated by the acquisition of RT resistance. This RT resistance is especially true forpatients with locally advanced thoracic cancers such as lung and esophageal cancers. RT can lead to an iron-dependent cell death modality called ferroptosis but whether ferroptosis resistance occurs within tumors givingrise to acquired RT resistance is not known and is the central theme of the proposed Acquired Resistance toTherapy and Iron (ARTI) Center. The overarching goals of the ARTI Center are: 1) to bridge the basic sciencemechanisms of ferroptosis in acquired resistance with translational research in preclinical models and humanpatient samples; 2) to identify cohorts of patients who are at greatest risk to develop acquired RT resistance;and 3) to investigate the ability of novel therapeutic agents to re-sensitize lung and esophageal cancer cells toradiation by inducing ferroptosis. The ARTI Center comprises two basic/mechanistic projects (Project 1 andProject 2) one preclinical/translational project (Project 3) and one shared resource core (Molecular ImagingCore [MIC]). Project 1 will focus on elucidating whether ferroptosis evasion is a key driver in acquired RTresistance using radioresistant lung cancer and esophageal cancer cell lines and xenograft models that will beused in Project 2. Project 2 will test the hypothesis that hypoxia a long-recognized driver of tumorradioresistance suppresses ferroptosis induction during RT and contributes to RT-induced acquired resistanceto ferroptosis. Furthermore expression of hypoxia-related genes and other targets of acquired RT resistance willbe analyzed by single-cell sequencing in Project 3. Project 3 investigates changes in immune cells in the tumormicroenvironment of humanized tumor models derived from chemoradiation therapy-responsive or -non-responsive esophageal adenocarcinoma patients. These ferroptosis-mediated immunologic changes in thetumor microenvironment may serve as prognostic biomarkers for identifying tumors that may acquire RTresistance and predicting cancer patient outcomes which could in the future be modulated by the ferroptosis-inducing agents tested in Projects 1 and 2. Projects 1 2 and 3 will be supported by the MIC that utilizesbioluminescence imaging to monitor tumor growth positron emission tomography (PET) tracers to monitorcystine transporter activity and to identify hypoxic regions within tumors as well as novel redox-tuned PETtracers for identifying activated innate immune cells. The ARTI Center will develop an Administrative Core foreffective communication and collaboration between the ARTI Center Project and Core Leaders and Co-Leaderswith National Cancer Institute (NCI) of Acquired Resistance to Therapy Network (ARTNet) program staff as wellas other ARTNet centers to synergize ARTI Center-related activities. 1356931 +No NIH Category available Architecture;Basic Science;Big Data;Biometry;Cells;Chromosome Mapping;Clinical;Code;Collection;Colon;Colonic Adenoma;Communication;Communities;Complex;Computed Tomographic Colonography;Data;Data Analyses;Data Set;Data Storage and Retrieval;Databases;Elements;Ensure;Faculty;Fred Hutchinson Cancer Research Center;Gene Expression;Genomics;Histology;Histopathology;Human;Image;Immunohistochemistry;Institution;Investments;Knowledge;Laboratories;Lesion;Longitudinal cohort;Medicine;Metagenomics;Molecular;Molecular Profiling;Molecular Target;Mus;Nucleic Acids;Oncology;Pathology;Patient Care;Patients;Pattern;Polyps;Population;Protein Analysis;Radiology Specialty;Research;Research Personnel;Resolution;Resources;Sampling;Science;Services;Site;Specimen;Structure;Sum;System;Techniques;Technology;Tissues;Translational Research;Universities;Washington;Wisconsin;adenoma;analytical tool;clinically significant;cohort;data harmonization;data sharing;data visualization;design;digital;exome sequencing;gut microbiome;human tissue;innovative technologies;interoperability;methylomics;multidimensional data;multiple omics;nano-string;next generation sequencing;novel;programs;protein expression;serial imaging;spectrograph;statistics;success;tool;transcriptomics;translational goal;translational medicine Translational Pathology and Data Analysis Core (TPDAC) n/a NCI 10707115 9/8/23 0:00 RFA-CA-21-054 5U54CA274374-02 5 U54 CA 274374 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9336 11271190 "MATKOWSKYJ, KRISTINA A" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 171020 161878 9142 SUMMARYAccomplishment of the translational and basic science aims of each Translational and Basic Science ofAdenomas Center (TBAC) project will depend on reliable access to the biospecimens analytic and data servicesthat will be provided by the Translational Pathology and Data Analysis Core (TPDAC). The TPDAC facilitatesthe utilization of existing resources/facilities in the University of Wisconsin (U WI) Department of Pathology &Laboratory Medicine Translational Research Initiatives in Pathology (TRIP) Laboratory and Fred HutchinsonCancer Research Center (FHCRC) along with faculty expertise in the U WI Departments of Pathology &Laboratory Medicine Radiology Oncology and Biostatistics. The complementarity between the populations attwo public research institutions will allow intra- and inter-TBAC investigators to access biospecimens that will notonly advance our knowledge of early colonic lesions but also ensure adequate representation of patient diversityin our studies. In addition TBAC U54 Project studies require analytic resources that use innovative technologiessuch as Digital Spatial Profiling Single cell Seq and multispectral imaging. The availability of technology andexpertise in the UW TRIP Lab permits quantitative analysis of multiple molecular targets at single-cell resolutionin a single tissue section. Finally the commitment of the TPDAC ensures consistent implementation of big dataanalysis and statistics to enhance the TBACs translational goals which include providing high-dimensionaldatasets for cross-TBEL collaborative studies. Under U54 support the TPDAC will contain the expertise neededto help identify optimize and implement the newest technology for early colon lesion research. The TPDAC draws upon elements from biospecimen science research pathology imaging and data analysisservices units at U WI UWCCC FHCRC and Univ of Washington. The additive and complementary expertiseand resources at the two research institutions will be capable of providing investigators of early colonic lesionsin all of the TBAC Projects with a wide array of pathology and analytic services to support translational and basicresearch. The Specific Aims are:Aim 1) To collect organize and distribute annotated polyps and imaging data from computed tomographycolonography (CTC) to facilitate research in early colonic lesions.Aim 2) To support multi-omics analysis of nonadvanced and advanced colonic adenomas and matched normalcolon samples from the ColoCare and GiCaRes cohorts.Aim 3) To support spatial and molecular profiling projects with a comprehensive array of pathology services andanalytic tools.Aim 4) To support analysis and integration of high dimensional data generated from multi-omics studies. +No NIH Category available Acute Pain;Address;Adult;Affect;American Society of Clinical Oncology;Analgesics;Benefits and Risks;Cancer Pain Management;Cancer Patient;Cancer Survivor;Chills;Chronic;Clinical;Consensus;Coupled;Databases;Disease;Disease remission;Evaluation;Event;Exclusion;Future;Guidelines;Health;Health Insurance;Health Personnel;Health Policy;Hospitals;Indolent;Insurance;International;Intervention;Life Expectancy;Link;Long Term Survivorship;Long-Term Survivors;Machine Learning;Malignant Neoplasms;Maps;Measures;Medicare;Mining;Oncologist;Oncology;Opioid;Outcome;Overdose;Pain;Pain management;Patients;Pattern;Persons;Pharmacy facility;Policies;Policy Maker;Population;Practice Guidelines;Primary Care;Proliferating;Provider;Risk;Specialist;Survivors;Treatment-Related Cancer;active method;advanced disease;anticancer treatment;cancer care;cancer diagnosis;cancer therapy;care coordination;care providers;chronic pain;chronic pain management;clinical development;clinical encounter;dosage;experience;health care service organization;health plan;high risk;innovation;interest;medical specialties;non-cancer chronic pain;non-opioid analgesic;opioid epidemic;opioid policy;opioid therapy;opioid use;patient subsets;prescription monitoring program;prescription opioid;primary care provider;response;therapy development;treatment risk Opioid Treatment of Pain in People with Cancer: Intended and unintended consequences of state policies addressing opioid prescribing PROJECT NARRATIVEState policies addressing opioid prescribing may have profound influences on opioid use and painmanagement among patients with cancer leading to both intended and unintended consequences. Theproposed study will shed light on the extent to which two prominent state policies mandates for prescriberparticipation in the Prescription Drug Monitoring Programs and legislative limits on opioids prescribed for acutepain had intended and unintended effects among three clinically important subpopulations of patients withcancer. Findings will inform continued development of clinical and policy guidelines and interventions atprescriber provider organization pharmacy health plan and policy levels that will support optimal opioidprescribing and pain management for cancer patients. NCI 10707114 8/21/23 0:00 PAR-21-190 5R01CA267996-02 5 R01 CA 267996 2 "HALPERN, MICHAEL TOUBER" 9/20/22 0:00 8/31/26 0:00 Organization and Delivery of Health Services Study Section[ODHS] 8740041 "BAO, YUHUA " Not Applicable 12 PUBLIC HEALTH & PREV MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 379977 NCI 224175 155802 ABSTRACTChronic cancer-related pain is highly prevalent and international guidelines have long supported the use ofopioid therapy for moderate to severe pain related to active disease. The strength of such consensus isstrongest for patients experiencing advanced disease and limited life expectancy. For patients experiencinglong-term remission or stable or indolent disease without the need for ongoing anti-cancer treatment (long-term survivorship) there is emerging consensus that opioid therapies should be addressed in a similarmanner as for patients with chronic non-cancer pain. There is mounting ambiguity regarding best practices forpatients receiving active anti-cancer treatment intended for cure. In the wake of the opioid epidemic statepolicies have proliferated in an effort to reduce unsafe opioid prescribing. Prominent recent policies includestate mandates for prescriber participation in the Prescription Drug Monitoring Programs (PDMPs) and statelegislative limits on duration and/or dosage of opioid prescriptions for acute pain. These policies vary in theirintended applicability to subpopulations of cancer patients and coupled with the ambiguity regarding clinicalbest practices may have inadvertently impacted opioid use and related outcomes among the differentsubpopulations of people with cancer. We propose a study to evaluate intended and unintended consequencesof the two types of state policies for opioid prescriptions and pain- and opioid-related adverse health eventsamong cancer patients with advanced disease long-term survivors and patients receiving active cancertreatment. To help elucidate mechanisms underlying changes in response to policies we will also explore thetrajectories of opioids dispensed and clinical encounters within each subpopulation using an innovative patternmining approach. We will use the SEER-Medicare linked database and a large national commercial insurancedatabase to achieve study aims. Findings will inform consensus-building guideline and interventiondevelopment and policy and practice changes by providers health care organizations and policymakers inoptimizing opioid prescribing and pain management for cancer patients. 379977 +No NIH Category available Architecture;Area;Automobile Driving;Bacteria;Basic Science;Behavior;Biology;Cells;Collaborations;Colon;Colonic Adenoma;Colonoscopy;Colorectal;Colorectal Adenoma;Colorectal Cancer;Data;Fibroblasts;Fusobacterium nucleatum;Future;Genes;Genetic;Gnotobiotic;Health;Human;Image;In Situ;Individual;Indolent;Intervention;Knowledge;Lesion;Link;Longitudinal cohort;Machine Learning;Mediating;Mediation;Metagenomics;Modeling;Molecular;Molecular Profiling;Monitor;Mus;Natural History;Oncogenic;Organoids;Phenotype;Role;Testing;Tissues;Translations;Up-Regulation;Visual;adenoma;clinical care;colorectal cancer prevention;deep sequencing;design;experimental study;genomic signature;gut bacteria;gut microbes;gut microbiome;host microbiome;individualized prevention;insight;microbiome;novel;pathobiont;screening;senescence;tumor;tumorigenesis;tumorigenic The gut microbiome interactions with primed colon states and effects on adenoma formation and progression n/a NCI 10707109 9/8/23 0:00 RFA-CA-21-054 5U54CA274374-02 5 U54 CA 274374 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9335 9311392 "DEY, NEELENDU " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 286209 162619 123590 Project SummaryEmerging data have linked the gut microbiome to colorectal adenomas the established early lesions incolorectal cancer (CRC) and de facto targets during screening colonoscopy. However deficit in our knowledgeof the basic science of the gut microbiome and the specific driver mechanisms for inducing adenoma formationand progression has impeded translation. We hypothesize that the microbiome is an adenoma nonautonomousinducer of colorectal priming the term we use in this application to refer to molecular/cellular alterationscritical for adenoma formation and progression. The near-term objective of this proposal is to define whetherand how the microbiome and the primed colon act in concert to drive adenoma formation. The long-termobjective of this proposal is to develop microbiome-based strategies for precision prevention of adenomas andultimately CRC. In Aim 1 we will identify interdependencies of the microbiome and the primed colon. We willleverage insights from a novel validated metagenomic analysis. Using gnotobiotic mice we will studyinteractions between a primed colon tumorigenic gut bacteria and tumorigenesis. We use analytic approachessuch as mediation analysis to quantify the extent to which the microbiome and a primed colon each mediatethe others tumorigenic effects. In Aim 2 we will identify the adenoma-associated gut microbiome features thatcharacterize aggressive vs indolent adenomas in humans. We will analyze a unique cohort of longitudinallymonitored adenomas through deep sequencing in situ bacterial imaging rigorously defined genetic/molecularprofiles generated in Project 1 and machine learning to identify adenoma-associated microbiome features thatinteract with primed colon attributes to drive adenoma progression. In Aim 3 we will determine if microbiome-induced senescent fibroblasts drive progression behavior in adenoma cells in ex vivo adenoma organoidsthrough specific CRC-associated senescence-associated secretory phenotype (SASP) factors. Using primarycolon fibroblasts derived from gnotobiotic mice colonized with a CRC-associated bacterial consortium we willassess oncogenic effects on adenoma progression behavior in an ex vivo organoid model. We will determinewhether tumorigenic effects of the microbiome are mediated through induction of the senescent colon primedstate and we will mechanistically test roles for candidate CRC-associated SASP factors in driving progressionbehavior of adenoma cells in ex vivo human adenoma organoids. Our findings could serve as the basis forbiology-backed intervenable precision prevention of adenomas and ultimately CRC. +No NIH Category available APC gene;APC mutation;Acceleration;Affect;Architecture;Cancerous;Carcinoma;Cells;Cessation of life;Chemopreventive Agent;Collection;Colon;DNA sequencing;Development;Epithelial Cells;Event;Fibroblasts;Gene Expression;Genes;Genetic;Individual;KRAS2 gene;Label;Malignant Neoplasms;Modernization;Molecular;Mus;Mutation;Normal tissue morphology;PIK3CA gene;Paracrine Communication;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Proliferating;Regulatory Pathway;Risk;Role;Signal Transduction;Solid;Stromal Cells;TP53 gene;Technology;Testing;Tissues;Tumor Suppressor Genes;United States;adenoma;cancer risk;design;gut microbiome;high risk;innovation;migration;mosaic;mouse model;mutant;neoplastic cell;prevent;progenitor;senescence;stem cells;success;transcriptomics;tumor;tumor heterogeneity;tumor progression;tumorigenic Features of the early adenoma and adjacent colon that drive progression: the role of mutation burden in normal tissue senescent cells and tumor clonal architecture n/a NCI 10707105 9/8/23 0:00 RFA-CA-21-054 5U54CA274374-02 5 U54 CA 274374 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9334 1983438 "HALBERG, RICHARD BROTT" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 311475 311475 0 PROJECT SUMMARYCRC persists as a heavy burden in the United States and throughout the world with over 1.93 million newcases and 0.95 million deaths in 2020. Our study is designed to identify autonomous and non-autonomousattributes of the early adenoma and the surrounding colon that drive adenoma progression to malignancy. Inthis project we mimic in mice a primed colon with pre-existing mutant clones (Aim 1) or overloaded withsenescent cells (Aim 2) to determine whether these altered states enhance adenoma formation andprogression. Such attributes can be detected with modern technology so individuals could be screened todetermine their personal risk of developing CRC. We propose that adenomas emerging from a primed coloncan have a multi-ancestral origin being derived from multiple progenitors. Interactions among intermingledclones could alter gene expression in the participating clones in a manner that favors adenoma progression(Aim 3). Such interactions could potentially be disrupted with new chemopreventive agents or repurposedcommon drugs. Thus individuals having a primed colon and consequently at a high risk of CRC could beidentified surveilled more frequently and potentially treated to prevent cancers from forming +No NIH Category available Aberrant DNA Methylation;Architecture;Atlases;Biological;Biological Markers;Biological Models;Biology;Cells;Classification;Clinical;Collection;Colon;Colonic Adenoma;Complex;DNA Methylation;DNA Sequence Alteration;Development;Ecosystem;Environment;Epigenetic Process;Epithelial Cells;Epithelium;Evaluation;Fibroblasts;Fostering;Gene Mutation;Gnotobiotic;Histologic;Indolent;Infrastructure;Lesion;Malignant Neoplasms;Mediating;Methods;Microbe;Modeling;Molecular Profiling;Monitor;Oncogenic;Organism;Outcome;Patients;Phenotype;Play;Process;Research Personnel;Resolution;Resources;Role;Sampling;Testing;Tissues;Tumor Promotion;adenoma;biobank;cancer prevention;cell type;cohort;colon cancer patients;colorectal cancer prevention;colorectal cancer screening;deep sequencing;digital;driver mutation;dysbiosis;gut microbiome;gut microbiota;insight;methylation pattern;methylome;microbiome;microbiota;multiple omics;permissiveness;premalignant;programs;prospective;recruit;risk prediction;risk stratification;senescence;tissue biomarkers;tumor-immune system interactions Comprehensive atlas of advanced adenomas and their surrounding primed colon: A multi-omics evaluation and clinical impact assessment n/a NCI 10707100 9/8/23 0:00 RFA-CA-21-054 5U54CA274374-02 5 U54 CA 274374 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9333 1865649 "GRADY, WILLIAM MALLORY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 503414 309939 193475 SUMMARYColon adenomas account for 80-85% of the CRC precancerous lesions and can progress to CRC. Yet themajority of these early lesions remain in an indolent early state and only 5-10% are aggressive and progress toCRC. Although the adenoma progression sequence was initially proposed to be driven mainly by the serialaccumulation of gene mutations and epigenetic alterations in colon epithelial cells based on increasingly detailedanalyses of the cancer-causing alterations that characterize CRC it has becoming apparent that these samealterations can also be found in indolent adenomas and even in the histologically normal colon epithelium. Theseobservations indicate that DNA alterations alone are not sufficient to drive adenoma progression. Emergingstudies indicate that factors that mediate adenoma progression can be derived from histologically normal colontissue primed to foster adenoma progression into cancer. We hypothesize that the adenoma progression isdriven by both cell-autonomous and non-autonomous mechanisms and the primed colon promotes adenomaprogression by providing a permissive tissue environment. We further hypothesize that the distinct features ofa primed colon may be developed as biomarkers to predict the likelihood of adenoma progression to cancer.AIM 1A: To identify molecular signatures of adenoma progression (aggressive or indolent) by performing amutli-omics evaluation of a unique collection of adenomas followed longitudinally with defined progressionoutcomes; AIM 1B: To determine the aggressiveness of adenomas in an independent cohort using themolecular signature of progression derived from Aim 1A.AIM 2: To directly determine the distinct features of a primed colon that associate with adenoma progression.(1) increased senescent fibroblast load and associated SASP factor expression; (2) oncogenic immunemicroenvironment; (3) increased cancer driver gene mutation burden; (4) altered CRC associated methylomeand (5) the dysbiotic CRC-associated microbiome state.AIM 3A: To identify and evaluate DNA methylation-based tissue biomarkers to determine whether they predictthe risk of aggressive adenoma occurrence using a highly precise and sensitive droplet digital PCR method.AIM 3B: To determine if the cancer driver gene mutation burden in the primed colon associates with aggressiveadenoma occurrence using a high fidelity and ultra-deep sequencing method.This translational Project 1 will provide an unprecedented high-quality characterization of the early lesion andthe surrounding primed colon that enables its progression. This project aligns with the expertise of theinvestigators involved the access to precious sample biorepositories and the infrastructure provided by the U54mechanism. The significance findings from Project 1 will be functionally interrogated in Project 2&3 and otherU54 projects leading to an iterative process to advance our understanding of the adenoma biology and thedevelopment of personalized biomarkers for CRC prevention. +No NIH Category available Administrative Coordination;Architecture;Basic Science;Biology;Cancer Biology;Cancer Intervention and Surveillance Modeling Network;Collaborations;Communication;Communities;Data Analyses;Data Commons;Data Coordinating Center;Education;Funding;Goals;Industrialization;Institution;Investigation;Mission;Pathology;Process;Productivity;Rana;Research;Research Personnel;Structure;System;Teleconferences;Tissues;Translational Research;United States National Institutes of Health;adenoma;cancer genomics;data dissemination;data harmonization;data sharing;data submission;gut microbiome;industry partner;innovation;meetings;member;operation;organizational structure;programs;protocol development;translational goal Administrative Core n/a NCI 10707097 9/8/23 0:00 RFA-CA-21-054 5U54CA274374-02 5 U54 CA 274374 2 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9332 1865649 "GRADY, WILLIAM MALLORY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 335868 190834 145034 SUMMARYThe Administrative Core of our Translational and Basic Science of Adenomas Center (TBAC) will serve tooptimize and integrate the investigative processes of the Project Labs between each other and the Project Labswith the Cores. The Administrative Core will provide logistical support enhance communication facilitate datadissemination and create a system for structured oversight of the projects by the PIs. The Administrative Corewill also provide administrative support to facilitate collaborations and communications between the other TBELCenters the Coordinating and Data Management Center (CDMC); NCI staff collaborating industrial andacademic partners and collaborating NCI programs (e.g. CISNET NIST etc.). The Administrative Core willprovide guidance and enhance communication for and between the TBAC TBEL Community members andexternal partners. The TBAC is comprised of three teams of investigators in the Project Labs: Project 1 (Grady Yu Maroni-Rana Dai Carter) Project 2 (Halberg Spengler Snow Newton) and Project 3 (Dey Morella LaChance) andthe Translational Pathology and Data Analysis Core (Matkowskyj Pickhardt Sun Kendziorski Dinh) who willfunction as a seamless unit though the coordination of the Administrative Core. The TBAC will interact closelywith other TBEL Centers and the CDMC in its core mission to elucidate the translational and early biology ofadenomas. The TBAC will also have collaborations with industrial partners and academic partners as needed toadvance the Projects studies. The TBAC other TBEL Centers TBEL CDMC industrial partners and academicpartners will collaborate on the studies in this proposal as well as on any resulting derivative studies that arisefrom the TBACs highly innovative productive and significant program of investigation of the basic andtranslational biology of adenomas. The Administrative Core has the following Specific Aims/Goals:Specific Aim 1: To provide the organizational structure for supporting the key objectives of the TBACSpecific Aim 2: To provide efficiency in management of large-scale collaborative research efforts involvingmultiple institutions and multiple PDs/PIsSpecific Aim 3: To coordinate with the TBEL CDMC and the TBEL community protocol developmentbiospecimen sharing biospecimen blinding data analysis data sharing data harmonization data depositionpopulating any data commons and any other relevant functions deemed necessary for TBAC operations as wellas for the larger TBEL community. +No NIH Category available Aberrant DNA Methylation;Affect;Architecture;Atlases;Basic Cancer Research;Behavior;Biological Markers;Biology;Cancer Etiology;Cancer Research Project;Cells;Cessation of life;Clinic;Clinical;Collaborations;Colon;Colonic Adenoma;Colorectal Adenoma;Colorectal Cancer;DNA Sequence Alteration;Data Set;Epigenetic Process;Epithelial Cells;Fibroblasts;Gene Mutation;Goals;Human;Immune;Individual;Indolent;Lesion;Light;Malignant Neoplasms;Mission;Molecular;Multiomic Data;Mutation;Natural History;Pathogenesis;Patients;Persons;Positioning Attribute;Recording of previous events;Research Personnel;Science;Sessile Lesion;Technology;Testing;Tissues;Translational Research;Translations;Tumor Promotion;adenoma;cancer genetics;cancer type;clinical application;cohort;colon cancer patients;colorectal cancer prevention;colorectal cancer progression;deep sequencing;dysbiosis;experience;gut microbiome;human disease;innovation;methylation pattern;methylome;microbiome;mouse model;mutant;novel;premalignant;risk prediction;senescence;translational cancer research Understanding adenoma progression: Interplay among tissue microenvironment clonal architecture and gut microbiome NARRATIVEAdenomas are early lesions of colorectal cancer but only a subset of adenomas progress and become cancer.In light of the well characterized clinical natural history of adenomas we plan to study them as early lesions andto determine the mechanisms involved in the formation and progression of early precancerous lesions. Wehypothesize that adenoma progression requires a suite of hallmark behaviors and that these behaviors areinduced by adenoma autonomous factors (e.g. cancer driver gene mutations) and adenoma nonautonomousfactors from the primed colon or adenoma microenvironment. Our proposed studies will integrate basic andtranslational cancer research projects to iteratively examine the direct causal relationships and interactions ofadenomas the colon primed microenvironment and host-systemic factors as co-organizers of adenomainitiation and/or progression. NCI 10707096 9/8/23 0:00 RFA-CA-21-054 5U54CA274374-02 5 U54 CA 274374 2 "PATRIOTIS, CHRISTOS F" 9/20/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 1865649 "GRADY, WILLIAM MALLORY" "DEY, NEELENDU ; HALBERG, RICHARD BROTT" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 1607986 NCI 1136745 471241 SUMMARYColorectal cancer (CRC) affects ~145000 people/year in the US and is the 3rd most common cause of cancerrelated deaths. CRC arises from early lesions that are pre-cancerous; these early lesions are colon adenomasand serrated sessile lesions (SSL). Colon adenomas account for 80-85% of the CRC precancerous lesions andprogress to CRC via an early adenomaadvanced adenomaCRC sequence. In light of the well characterizedclinical natural history of adenomas we plan to study them as early lesions and to determine the mechanismsinvolved in the formation and progression of early precancerous lesions. Notably only a few early adenomas willprogress to advanced adenomas (AA) and even fewer will progress to CRC. Our group and others have shownthat mutations alone are not sufficient to cause adenoma initiation and/or progression in the majority of cases.There are likely multiple adenoma nonautonomous mechanisms that cooperate with the DNA alterations in theadenomas to cause progression and these mechanisms are likely operative in discrete subsets of affectedindividuals. We and others have observed alterations such as tissue senescence high cancer driver genemutation loads aberrant DNA methylation patterns and dysbiotic gut microbiomes in the normal colon of peoplewith advanced adenomas and CRC patients. We have termed normal colons with these features primed colonsand propose that these features are plausible mechanisms that affect adenoma initiation and progression.Based on these observations and our prior studies we hypothesize that early lesion progression requires a suiteof hallmark behaviors and that these behaviors are induced by adenoma autonomous factors (e.g. cancer drivergene mutations) and adenoma nonautonomous factors from the primed colon or adenoma microenvironment. Our proposed studies will integrate basic and translational cancer research Projects to iteratively examine thedirect causal relationships and interactions of adenomas the colon primed microenvironment and host-systemic factors as co-organizers of adenoma initiation and/or progression. The Specific Aims are:Aim 1) To determine the adenoma cell autonomous molecular factors that distinguish nonadvanced adenomasfrom advanced adenomas and that regulate nonadvanced adenoma progression. (Projects 1 and 2)Aim 2) To determine the adenoma nonautonomous factors from the primed colon and from the adenomamicroenvironment that associate with advanced human colon adenomas and regulate adenoma progression.These factors will include the following primed colon states: 1. senescence state; 2. cancer driver gene mutationburden; 3. gut microbiome state; 4. colon methylome and 5. colon immune activity state. (Projects 1-3)Aim 3)To determine how adenoma autonomous and nonautonomous factors from the adenomamicroenvironment and the primed colon cooperate to drive adenoma formation and progression.(Projcts 1-3) 1607986 +No NIH Category available Address;Affect;Attention;Automobile Driving;Breast;Breast Cancer Patient;Cardiovascular Diseases;Cessation of life;Characteristics;Chronic Disease;Code;Colorectal;Colorectal Cancer;Communicable Diseases;Computer software;Data;Data Sources;Development;Diagnostic;Disease;Disease Surveillance;Ensure;Epidemiologic Monitoring;Epidemiologist;Epidemiology;Funding;Future;Goals;HIV Infections;HIV/HCV;Individual;Intuition;Log-Linear Models;Malignant Neoplasms;Manufacturer;Medical Records;Methodology;Methods;Modeling;Monitor;Monitoring for Recurrence;Motivation;Pathway interactions;Patients;Performance;Population;Predictive Value;Prevalence;Property;Protocols documentation;Recurrence;Recurrent Malignant Neoplasm;Registries;Reproducibility;Research Design;Research Personnel;Research Project Grants;Sampling;Sensitivity and Specificity;Signal Transduction;Specific qualifier value;Statistical Methods;Stream;Surveillance Program;System;Techniques;Training;Tuberculosis;Uncertainty;Validation;Viral;analytical method;cancer recurrence;comparative;data streams;data visualization;design;disease registry;flexibility;follow-up;improved;malignant breast neoplasm;mortality;multiple data sources;neoplasm registry;novel;pathogen;patient registry;simulation;surveillance data;surveillance study;theories;tool Refined Capture-Recapture Methods for Surveilling Cancer Recurrence Project NarrativeThe proposed research project will develop principled and accessible statistical frameworks toward improvedand more transparent capture-recapture (C-R) methods for effective use of multiple overlapping data streamsfor disease surveillance. A key goal of the project is an appropriate merging of statistical with epidemiologicdesign and implementation principles to fully harness the power of C-R for enhanced validity and precision inthe estimation of case counts while adjusting for false positive signals. These developments draw on currentsurveillance initiatives and provide immediate applications to improve estimates of breast and colorectal cancerrecurrence totals over defined follow-up periods among patients in US-based cancer registries. NCI 10707088 8/25/23 0:00 PA-20-185 5R01CA266574-02 5 R01 CA 266574 2 "HOWLADER, NADIA" 9/20/22 0:00 8/31/26 0:00 Biostatistical Methods and Research Design Study Section[BMRD] 9256347 "LYLES, ROBERT H" "WALLER, LANCE A" 5 BIOSTATISTICS & OTHER MATH SCI 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF PUBLIC HEALTH 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 341843 NCI 223623 118220 Project Summary/AbstractThe monitoring of disease prevalence and estimation of the number of affected individuals in a definedpopulation are among the crucial goals of epidemiologic surveillance for chronic and infectious diseases. Thisproposal aims to provide novel and reliable statistical tools to improve best practices for design and analysis ofsuch surveillance studies. We take specific motivation from timely challenges associated with the registry-based monitoring of cancer recurrences in the state of Georgia Cancer Registry (GCR).We focus on customizing capture-recapture (C-R) methods which are ever increasingly used tools forestimating total numbers of cases or deaths based on multiple epidemiologic surveillance streams. We clarifyunderappreciated pitfalls associated with widely popular log-linear model-based C-R techniques and proposean accessible approach to sensitivity analysis with data visualization that promotes a general strategy for moreappropriate propagation of uncertainty into ultimate estimates of case totals. This in turn provides a gateway toa broad class of useful models whereby practitioners can transparently encode assumptions about howsurveillance streams operate relative to one another at the population level. As a next step we consider thecase in which one surveillance stream is implemented by means of a well-controlled sampling design. Underappropriate conditions this provides what we refer to as an anchor stream whereby otherwise ever-presentinherent uncertainties in specifying a defensible C-R model are overcome. In this setting we will promote beststatistical practices for estimating case totals by means of a novel C-R estimator that harnesses the power ofthe principled sampling behind the anchor stream while offering markedly enhanced precision. We propose toextend this approach to account for misclassification which is inevitable in the case of our motivating study ofcancer recurrence and in any setting in which surveillance streams identify cases in an error-prone manner.We will tailor proposed methodology toward breast and colorectal cancer recurrence monitoring via theongoing Cancer Recurrence Information and Surveillance Program (CRISP) based on the GCR. CRISP isactively compiling informative but potentially false-positive recurrence signals from up to 6 data streams andconducts validation sampling through protocol-based medical record review to confirm true cases amongsignaled recurrences. We will use such validation data to adjust for misclassification in estimating C-R-basedrecurrence counts. In particular the current project will implement a principled anchor stream random sampleof 200 GCR patients for validation through medical record review leading to valid and demonstrably preciseestimates of true recurrence counts over the study period that are free of misclassification bias. 341843 +No NIH Category available Abscopal effect;Activated Natural Killer Cell;Adaptor Signaling Protein;Address;Antigens;Autoimmunity;Automobile Driving;Blood;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Circulation;Cross Presentation;Cytosol;DNA;DNA Binding;DNA Damage;DNA Methylation;Data;Dendritic Cells;Disseminated Malignant Neoplasm;Distal;Dose;Exposure to;Fostering;Generations;Goals;Growth Factor;Home;Human;Hybrids;IFNAR1 gene;Immune;Immune response;Immunotherapy;Impairment;Infiltration;Interferon Activation;Interferon Type I;Interferon-beta;Interferons;Intervention;Irradiated tumor;Knowledge;Literature;Malignant neoplasm of lung;Mediating;Mitochondrial DNA;Mus;Mutation;NK Cell Activation;Natural Killer Cells;Neoplasm Metastasis;Nucleic Acids;Pathway interactions;Patient Selection;Patients;Phenotype;Play;Pre-Clinical Model;Process;Production;Publishing;RNA;Radiation;Radiation therapy;Role;Sampling;Second Messenger Systems;Serum;Signal Transduction;Site;Stimulator of Interferon Genes;Stimulus;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Tumor Promotion;Tumor-infiltrating immune cells;Work;anti-CTLA-4 therapy;cancer cell;candidate identification;candidate marker;cell type;checkpoint therapy;chemokine;effector T cell;extracellular vesicles;fractionated radiation;immune checkpoint blockade;immunogenic;improved;in situ vaccine;in vitro testing;in vivo;ipilimumab;knock-down;micronucleus;novel;overexpression;patient response;pseudotoxoplasmosis syndrome;radiation response;recruit;response;single cell analysis;tumor;tumor microenvironment Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation NARRATIVE Radiation therapy applied to one tumor has the ability to induce anti-tumor T cell responses that incombination with immune checkpoint blockade therapy cause systemic tumor regression. The goal of thisproposal is to understand the mechanisms that enable the immune response elicited at the irradiated tumorsite to be effective against non-irradiated metastases. This information will fill knowledge gaps about the role ofradiotherapy in enhancing responses to immunotherapy and possibly identify candidate biomarkers andactionable targets to improve cancer patients selection and treatment. NCI 10706961 9/12/23 0:00 PA-20-185 5R01CA201246-07 5 R01 CA 201246 7 "AHMED, MANSOOR M" 1/19/16 0:00 8/31/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6487050 "DEMARIA, SANDRA " Not Applicable 12 RADIATION-DIAGNOSTIC/ONCOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 397076 NCI 234263 162813 Recent evidence indicates that the presence of conventional dendritic cells type 1 (cDC1) in the tumormicroenvironment (TME) is required for response to immune checkpoint blockade (ICB) therapy. In addition to cross-presenting cancer cell-derived antigens to CD8+ and CD4+ T cells cDC1 promote tumor infiltration by effector T cellsand support their survival and function. Thus interventions that improve cDC1 recruitment to the TME could enhancepatient responses to ICB. Focal radiation therapy (RT) increases responses to ICB therapy at least in part by inducingtype I interferon (IFN-I) and driving cDC1 into the irradiated tumor. We have previously shown that cDC1 are essentialfor immune-mediated regression of irradiated and synchronous non-irradiated tumors (abscopal effect) in mice treatedwith RT and ICB. Abscopal responses have also been achieved in metastatic cancer patients treated with RT and ICB butless reliably than expected and the determinants of such responses remain unclear. We hypothesize that a previouslyunexplored barrier to abscopal responses is the limited infiltration of poorly immunogenic tumors by cDC1 whichprecludes effector T cells generated at the irradiated tumor site from rejecting non-irradiated tumors. Moreover wehypothesize that activation of a strong IFN-I response in the irradiated tumor is essential for achieving systemicactivation of natural killer (NK) cells which can home to non-irradiated tumors and foster the recruitment of cDC1. Thishypothesis is supported by a strong scientific premise which is based on the recent literature and on our extensivepublished and unpublished data including the fact that increased serum IFNb post-RT was the top predictor for abscopalresponses in metastatic lung cancer patients treated with RT+anti-CTLA4 (Nat Med 2018). To test this hypothesis threeindependent but related aims that address different mechanistic questions are planned. Aim 1 will investigate the roleof RNA:DNA hybrids which accumulate in the cytosol of irradiated cancer cells and in the cargo of small extracellularvesicles (sEV) they produce in activating the IFN-I pathway via cGAS/STING in cancer cells and locoregional DCs. The roleof RT-induced IFNb in systemic NK cell activation will be confirmed by using IFNAR1-deficient NK cells. Aim 2 willdetermine the contribution of sEV to RT-induced IFN-I activation in vivo by using Rab27a-deficient cancer cells. Aim 3 willdirectly address the role of NK cells in driving cDC1 infiltration in abscopal tumors and abscopal responses to RT+ICB. Inaddition NK cell functional subsets present in the blood of lung cancer patients with abscopal response to RT+anti-CTLA4 will be investigated by single cell analysis. Results of proposed studies will identify a novel mechanism wherebylocal IFN-I induction by RT activates a systemic cross-talk between NK cells and cDC1 required for T-cell mediatedrejection of abscopal tumors. 397076 +No NIH Category available Academic Medical Centers;Address;Age;Antibodies;Area;Arizona;Back;Binding;Biological Assay;Biological Markers;Blinded;Blood;COVID-19;COVID-19 assay;Cancer Control;Cancer Etiology;Cancer Patient;Caring;Cervical Cancer Screening;Clinical;Clinical Management;Clinical Research;Collaborations;Collection;Controlled Clinical Trials;DNA;Data;Detection;Development;Diagnosis;Diagnostic;Dryness;Early Detection Research Network;Early Diagnosis;Enrollment;Enzyme-Linked Immunosorbent Assay;Feasibility Studies;Fingers;Foundations;Funding;Gender;General Population;Geographic Locations;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;High Risk Woman;Home;Human;Human Papillomavirus;Human papillomavirus 16;Immune;Immunoglobulin G;Incidence;Individual;Infection;Infrastructure;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methodology;Methods;Morbidity - disease rate;Newly Diagnosed;Nucleic Acid Amplification Tests;Nucleic Acids;Oncoproteins;Oral health;Oropharyngeal;Participant;Patients;Peer Review Grants;Performance;Phase;Phase III Clinical Trials;Plasma;Population;Predictive Value;Prevalence;Prospective Studies;Publications;Reagent;Recurrent Malignant Neoplasm;Research;Research Design;Research Institute;Resources;Risk;Risk Assessment;Saliva;Salivary;Sampling;School Dentistry;Screening for cancer;Serology;Serology test;Serum;Specimen;Speed;Spottings;System;Technology;Testing;Texas;Universities;Vaccination;Vaccines;Validation;Viral;advanced disease;aggressive therapy;anticancer research;assay development;biobank;biomarker development;biomarker performance;biomarker validation;blood-based biomarker;cancer biomarkers;cancer prevention;cancer recurrence;carcinogenesis;circulating biomarkers;clinical application;cohort;comparative;coronavirus disease;design;digital;experience;feasibility testing;human migration;immunogenicity;improved;innovation;instrument;malignant oropharynx neoplasm;men;migration;mortality;novel;operation;patient population;peripheral blood;programs;prospective;public health priorities;repository;research clinical testing;response;risk prediction;saliva diagnostic;saliva sample;salivary assay;sample collection;screening;screening program;serological marker;success;underserved community;validation studies Southwest EDRN Clinical Validation Center for Head and Neck Cancer Project NarrativeWe will rigorously evaluate existing immune and viral biomarkers in blood and saliva to develop clinical screening paradigmsfor the early detection of HPV-associated head and neck cancers. NCI 10706931 7/25/23 0:00 RFA-CA-22-054 1U01CA281660-01 1 U01 CA 281660 1 "WANG, WENDY" 8/1/23 0:00 7/31/28 0:00 ZCA1-SRB-P(J2) 1931214 "ANDERSON, KAREN S." "STURGIS, ERICH MADISON" 4 MISCELLANEOUS 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ ORGANIZED RESEARCH UNITS 852876011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 747673 NCI 588206 159467 Project Summary/AbstractThe goal of the EDRN Southwest Clinical Validation Center for Head and Neck Cancer is to improve oropharyngeal cancerscreening through the rigorous validation of salivary biomarkers. The scientific approach of our Center is based on severalfundamental principles. First that human papillomaviral (HPV) infection and persistence induces carcinogenesis in theoropharynx over decades generating well-documented circulating and salivary viral nucleic acid and serologic biomarkers.These biomarkers have not yet been tested in rigorous prospective studies with centralized CLIA/CAP biomarker validation.Second the low incidence requires that effective screening paradigms for oropharyngeal cancers (OPC) use novel systemsfor large-scale prospective studies using self-collection sampling digital enrollment and distributive systems to enableenrollment in underserved communities. Third that the clinical management of positive biomarkers be rigorously addressed.Our proposal builds on our extensive experiences with cancer biomarker development verification validation innovativeclinical study management and expertise in HPV oropharyngeal cancer screening. Our previous results on HPV serologicbiomarkers have been confirmed in blinded phase 2 multicenter validation studies. Our results have shown that multiplexedpanels of IgG antibodies for HPV16 are required for adequate predictive value. Our Meso Scale Diagnostics LLC. (MSD)team has fielded over 3000 instruments worldwide and over 700 commercially available biomarker assay kits. Theirexpertise at serologic assay development led to one of their V-PLEX serology panels being selected by Operation WarpSpeed as the basis of its standard binding assays for immunogenicity assessments in all funded Phase III clinical trials ofCOVID vaccines. We will use the MSD MULTI-ARRAY platform to migrate the HPV serologic markers for target clinicalapplications in saliva. This represents an ongoing collaboration with experts in large-scale self-collection salivary biomarkerscreening at Arizona State University experts on head and neck cancer screening at Baylor University Medical Center andAT Still University (ATSU) School of Dentistry and Oral Health. We will generate high-quality well-characterized samples tovalidate circulating and salivary biomarkers to enhance oropharyngeal cancer screening. Adhering to the principles ofPRoBE design we will perform Phase 2 validation of HPV serology and nucleic acid testing with cancer patient and controlsera and saliva followed by developing and testing the methodology needed to conduct a prospective Phase 4 salivaryscreening study. We will provide a resource for expertise and clinical repository for the rigorous validation of salivary andcirculating biomarkers for cancer screening. 747673 +No NIH Category available Automobile Driving;Binding;Biochemistry;Bioluminescence;Breast Cancer Cell;CXCL11 gene;CXCR3 gene;CXCR4 Receptors;CXCR4 gene;Cell Proliferation;Cell surface;Cells;Chemotaxis;Complex;Computer Models;Coupling;Data Set;Drug Targeting;Environment;Event;Exhibits;Extracellular Matrix;Fluorescence Microscopy;Future;G-Protein-Coupled Receptors;Heterogeneity;Human;Image;Image Analysis;Imaging Device;Imaging technology;Immune;Invaded;Investigation;Ligands;Malignant Neoplasms;Measures;Mediator;Methods;Molecular;Neoplasm Metastasis;Organism;Output;Pathway interactions;Patients;Pattern;Performance;Phosphotransferases;Positioning Attribute;Process;Proliferating;Protein Isoforms;Receptor Signaling;Reporter;Research;Research Personnel;Resolution;Role;Shapes;Signal Transduction;Signaling Molecule;Site;Spatial Distribution;Specificity;Stromal Cell-Derived Factor 1;Stromal Cells;System;Technology;Testing;Tumor Biology;angiogenesis;bioluminescence imaging;cancer cell;cancer therapy;cell motility;cell type;cellular imaging;chemokine;chemokine receptor;chemokine therapy;clinical translation;complement system;drug development;extracellular;fluorescence imaging;high dimensionality;image processing;imaging study;improved;innovation;intercellular communication;large scale data;live cell imaging;malignant breast neoplasm;molecular imaging;multiplexed imaging;quantitative imaging;receptor;receptor binding;recruit;response;scavenger receptor;targeted treatment;technology development;therapy design;tool;treatment optimization;tumor Integrated Imaging Tools for Intercellular Chemokine Signalling We will develop a new suite of quantitative molecular imaging tools to measure spatial andtemporal changes of distribution of signaling molecules known as chemokines in multicellularenvironments. These tools will allow investigators to answer basic questions about howchemokines signal and function and cancer which will open opportunities to better target thesemolecules for cancer therapy. NCI 10706896 8/9/23 0:00 RFA-CA-22-001 1R61CA281657-01 1 R61 CA 281657 1 "AMIN, ANOWARUL" 8/9/23 0:00 7/31/26 0:00 ZCA1-TCRB-5(M1)R 1974298 "LUKER, GARY D" Not Applicable 6 RADIATION-DIAGNOSTIC/ONCOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/9/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 218790 NCI 140250 78540 Chemokines and their G-protein coupled receptors (GPCRs) are key mediators of intercellularsignaling between cancer cells and multiple stromal cell types. Cancer cell proliferation localinvasion systemic metastasis recruitment of immune cells and angiogenesis all are regulated byspatial and temporal dynamics of chemokines. The central role of chemokines in tumor biologyhas made them an attractive target for therapies designed to inhibit or enhance chemokinesignaling. However much of the complex biochemistry of chemokines remains to be discovereddue to the technical challenges of tracing their presence and function in living systems.Chemokines are effective at signaling at very low levels and their spatial distribution is complexdue to their ability to bind to cell surfaces and extracellular matrix. Furthermore internalization ofchemokines by GPCRs and scavenger receptors shape local chemokine gradients bysequestering and degrading chemokines. Experimental evidence and computational modeling byour lab show that short-range steep local gradients of chemokine CXCL12 over distances of asingle cell most effectively drive signaling and chemotaxis through receptor CXCR4. To enabletransformative studies of chemokines and ultimately advance applications of drugs targetingchemokines in cancer we propose to develop a new suite of quantitative molecular imaging toolsto measure the spatial and temporal dynamics of chemokine distribution association andsignaling in hundreds of single cells. These tools will allow us to measure cell signaling patternsduring chemotaxis and identify potential mechanisms underlying intercellular heterogeneity inresponses to chemokines. We will 1) Generate an integrated multiplexed bioluminescence andfluorescence microscopy toolbox for single-cell imaging of extracellular and intracellular steps inchemokine signaling; and 2) Test our chemokine imaging technology as a generalizablequantitative approach applicable to patient-derived cells. We will uniquely combine dynamicsingle-cell bioluminescence and fluorescence microscopies technologies to measure numerousmolecular events cells use to convert chemokine inputs into signaling outputs and chemotaxis.We will couple our multiplexed imaging readouts with advanced image processing methods togenerate high-dimensional quantitative data sets needed for basic studies of chemokines andintegration with other large-scale data. Our innovative imaging tools will allow an unprecedentedview of chemokine gradients and heterogeneity of cellular responses in complex environments.This technology will transform investigations of chemokines in cancer and advance ongoingefforts to target chemokines for therapy. 218790 +No NIH Category available 2019-nCoV;Address;Award;COVID-19;COVID-19 pandemic;Cellular Phone;Common Data Element;Communities;Computer Analysis;Computerized Medical Record;Contracts;Data;Data Analyses;Data Discovery;Data Set;Deposition;Development;Future;Goals;Health Technology;Institution;Laboratories;Learning;Link;Modeling;National Cancer Institute;National Institute of Biomedical Imaging and Bioengineering;Quality Control;RADx;Research;Research Personnel;Source;Standardization;Surveys;Technology;United States National Institutes of Health;Virus;computerized tools;conditioning;data de-identification;data hub;data integration;data management;data modeling;data pipeline;data repository;digital health;digital repositories;insurance claims;machine learning model;multiple data sources;pandemic disease;population health;predictive modeling;privacy preservation;programs;quality assurance;response;tool;wearable sensor technology Digital Health Technologies Data Hub n/a NCI 10706850 ACO21003001-1-0-1 Y01 78869434 "DICKHERBER, TONY " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 2129500 NCI C6 In May 2020 in response to the rapidly expanding pandemic caused by the SARS-CoV-2 virus the National Cancer Institute (NCI) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) launched a program called Digital Health Solutions for COVID-19. The goal of this initiative was to support the development of digital health tools that could leverage multiple data sources privacy-preserving technologies and computational tools to assist in managing population health during the COVID-19 pandemic. NCI and NIBIB awarded eight contracts to companies and academic institutions to develop such tools. These projects acquired large amounts of data from a broad set of sources including but not limited to wearable sensors smartphones electronic medical records insurance claims data and survey instruments. A key aspect of this initiative was to make the data available and accessible to researchers to enable current and future research. MIT Lincoln Laboratory (MIT-LL) was awarded the current contract to establish a data hub for the collected data. Analysis of the data by the broader research community will provide an opportunity to develop and refine predictive models generating new learnings from the datasets to address the COVID-19 pandemic and future pandemics. 2129500 +No NIH Category available Acceleration;Acids;Address;Adult;Affect;African American;Asian;Body mass index;Breast Carcinoma;Cancer Patient;Cells;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Colorectal Cancer;Consultations;Coupled;Cytometry;Data;Detection;Disease;Ethnic Origin;Fatty Acids;Frequencies;Functional disorder;Future;G-Protein-Coupled Receptors;GTP-Binding Proteins;Growth;High Fat Diet;High Prevalence;Hispanic;Hispanic Populations;Human;Immune;Incidence;Learning;Lipids;Macrophage;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Maps;Molecular;Mus;Non obese;Not Hispanic or Latino;Obese Mice;Obesity;Obesity associated cancer;Oleic Acids;Pancreatic Adenocarcinoma;Patients;Phenotype;Play;Population;Primary carcinoma of the liver cells;Production;Race;Risk;Risk Factors;Role;Sampling;Signal Transduction;Surface;TNF gene;Testing;Therapeutic Intervention;Time;Tissues;Tumor Immunity;Tumor-associated macrophages;Tumor-infiltrating immune cells;Weight;cancer health disparity;cytokine;diet-induced obesity;experience;experimental study;indexing;innate immune mechanisms;lipid metabolism;malignant breast neoplasm;molecular targeted therapies;mouse model;neoplasm immunotherapy;neoplastic cell;new therapeutic target;novel;obese patients;obesogenic;parent grant;parent project;single-cell RNA sequencing;spatial relationship;tumor;tumor growth;tumor metabolism;tumor microenvironment Innate Immune Mechanisms Contributing to Cancer Growth in Obesity Project NarrativeObesity which is more common among African American and Hispanic populations increases the risk ofdeveloping and dying from certain cancers such as breast and colon cancer. We discovered in obese mice withcancer that this increased risk is caused by a molecule on immune cells called GPR65 and that eliminatingGPR65 results in markedly reduced cancer growth. In this project we will determine if GPR65 is present in thecancers of obese but not nonobese patients and whether its presence differs between African AmericanHispanic Asian and non-Hispanic White populations. NCI 10706825 8/31/23 0:00 PAR-22-114 3R01CA262361-03S1 3 R01 CA 262361 3 S1 "KUO, LILLIAN S" 7/1/21 0:00 6/30/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 1862821 "ENGLEMAN, EDGAR G. " Not Applicable 16 PATHOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 231825 NCI 150000 81825 Supplement Project SummaryObesity (body mass index 30 kg/m2) which affects at least one-third of the U.S. population is more prevalentamong African American and Hispanic populations and increases the risks of both developing and dying fromcertain cancers. However the cellular and molecular mechanisms underlying these risks are unknown. Ourstudies demonstrate that colorectal cancer (CRC) and other tumors grow considerably faster in diet-inducedobese mice due to the immunosuppressive actions of the acid-sensing receptor G-protein coupled 65 (GPR65)on tumor-associated macrophages (TAMs). In the parent project we are analyzing the intracellular signals fromGPR65 that alter TAM function and tumor growth in obese mice identifying the mechanism by which a high-fatdiet (HFD) promotes GPR65 signaling in TAMs and assessing the effects of targeting GPR65 for tumorimmunotherapy in obese and non-obese mice. Data from the parent project indicate that altered lipid metabolismis responsible for upregulating GPR65 expression on TAMs in the tumors of obese mice. Since the lipid profilein tumors of obese humans is nearly identical to that of tumors from obese mice we believe there is a highlikelihood that tumors from obese humans will display a similar immune profile. In the proposed supplementproject we will extend our studies to human cancers including CRC hepatocellular carcinoma (HCC) pancreaticadenocarcinoma (PDAC) and breast carcinomas in order to test the hypothesis that GPR65 expression on TAMsis associated with obesity altered TAM function and alterations of other immune cells in the tumormicroenvironment. We further hypothesize that these effects of obesity on immune cells in cancer are equivalentin African American Hispanic Asian and non-Hispanic White populations and not determined on the basis ofrace or ethnicity. To analyze the tumors we will use mass cytometry (CyTOF) to examine the frequenciessurface and cytokine profiles of immune cells in the tumor use single cell RNA sequencing (scRNA seq) toanalyze the functional profiles of these cells and use CODEX to analyze the spatial relationships between TAMsand other immune cells. We will then compare the results between tumors from patients of different racial andethnic backgrounds. The results of these experiments are expected to confirm both of our hypotheses andprovide a strong rationale for future studies in which these hypotheses are tested in larger populations and noveltherapies targeting GPR65 are developed and evaluated in clinical trials. 231825 +No NIH Category available 2019-nCoV;Address;Affect;Area;Autoimmune Diseases;Basic Science;COVID-19;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;California;Caring;Characteristics;Chronic Disease;Clinical;Clinical Sciences;Cohort Studies;Collaborations;Communities;Coronavirus;Data;Data Analyses;Data Collection;Disease;Enrollment;Ensure;Epidemiologist;Evaluation;Evaluation Studies;Exposure to;Foundations;Funding;Goals;Health;Health Personnel;Health system;Healthcare Systems;Home;Immune;Immunity;Immunologist;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Knowledge;Los Angeles;Malignant Neoplasms;Metabolic Diseases;Minority;Molecular Profiling;Natural History;Nature;Outcome;Patients;Pattern;Persons;Population Heterogeneity;Population Sciences;Populations at Risk;Predisposition;Public Health;Publishing;Recovery;Recovery of Function;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;Scientific Advances and Accomplishments;Scientist;Seeds;Seroprevalences;Signal Transduction;Structure;Subgroup;Techniques;Therapeutic;Translational Research;Viral;Virus;Vulnerable Populations;World Health Organization;base;biobank;clinical phenotype;disorder risk;experience;immune function;immune reconstitution;innate immune function;insight;novel;operation;pandemic disease;programs;racial and ethnic;recruit;response;severe COVID-19;trait;translational scientist Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2 NARRATIVE: OverviewOur study will be centered on the ethnically/racially diverse population served by our health system in LosAngeles given then critical need for more knowledge regarding the determinants of COVID-19 related risks inthese minority subgroups. Leveraging our collective experience resources and infrastructure at major academicinstitutions from across Southern California (Cedars Sinai UCSD UCLA and USC) we will advance thescientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidatethe natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure infectionrecovery and clinical immunity patterns across the spectrum of persons at risk; Project 2 will investigate thedeterminants of SARS-CoV-2 response in persons with altered innate immune function with a focus onindividuals with pre-infection susceptibility traits (e.g. metabolic disease states); and Project 3 will investigatethe determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus onindividuals with immune-altered status arising from select malignancies autoimmune disease and/or theirdirected therapies. NCI 10706736 9/22/22 0:00 RFA-CA-20-038 3U54CA260591-02S2 3 U54 CA 260591 2 S2 "PATRIOTIS, CHRISTOS F" 9/30/20 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 9537080 "FIGUEIREDO, JANE C." "KARIN, MICHAEL ; MERCHANT, AKIL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Research Centers 2022 195001 NCI 116767 78234 C6 Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in immunocompromised populations. To do so requires large datasets of well-defined populations with clinical information and a robust collaborative infrastructure able to evolve as new research questions arise during the pandemic. Therefore we propose to mimic the NA-ACCORD strategy of pooling cohorts at multiple sites in North America. In this Pooling Project we will merge data from both (i) electronic medical record (EMRs) as well as (ii) prospective cohorts from 11 geographically disperse SeroNet sites across the U.S. Data harmonization efforts will be streamlined and analyses will be divided by research area across all sites to allow multiple publications to occur simultaneously. 195001 +No NIH Category available 2019-nCoV;Address;Affect;Area;Autoimmune Diseases;Basic Science;COVID-19;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;California;Caring;Characteristics;Chronic Disease;Clinical;Clinical Sciences;Cohort Studies;Collaborations;Communities;Coronavirus;Data;Data Analyses;Data Collection;Disease;Enrollment;Ensure;Epidemiologist;Evaluation;Evaluation Studies;Exposure to;Foundations;Funding;Goals;Health;Health Personnel;Health system;Healthcare Systems;Home;Immune;Immunity;Immunologist;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Knowledge;Los Angeles;Malignant Neoplasms;Metabolic Diseases;Minority;Molecular Profiling;Natural History;Nature;Outcome;Patients;Pattern;Persons;Population Heterogeneity;Population Sciences;Populations at Risk;Predisposition;Public Health;Publishing;Recovery;Recovery of Function;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;Scientific Advances and Accomplishments;Scientist;Seeds;Seroprevalences;Signal Transduction;Structure;Subgroup;Techniques;Therapeutic;Translational Research;Viral;Virus;Vulnerable Populations;World Health Organization;base;biobank;clinical phenotype;disorder risk;experience;immune function;immune reconstitution;innate immune function;insight;novel;operation;pandemic disease;programs;racial and ethnic;recruit;response;severe COVID-19;trait;translational scientist Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2 NARRATIVE: OverviewOur study will be centered on the ethnically/racially diverse population served by our health system in LosAngeles given then critical need for more knowledge regarding the determinants of COVID-19 related risks inthese minority subgroups. Leveraging our collective experience resources and infrastructure at major academicinstitutions from across Southern California (Cedars Sinai UCSD UCLA and USC) we will advance thescientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidatethe natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure infectionrecovery and clinical immunity patterns across the spectrum of persons at risk; Project 2 will investigate thedeterminants of SARS-CoV-2 response in persons with altered innate immune function with a focus onindividuals with pre-infection susceptibility traits (e.g. metabolic disease states); and Project 3 will investigatethe determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus onindividuals with immune-altered status arising from select malignancies autoimmune disease and/or theirdirected therapies. NCI 10706735 9/21/22 0:00 RFA-CA-20-038 3U54CA260591-02S1 3 U54 CA 260591 2 S1 "PATRIOTIS, CHRISTOS F" 9/30/20 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 9537080 "FIGUEIREDO, JANE C." "KARIN, MICHAEL ; MERCHANT, AKIL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Research Centers 2022 440000 NCI 263473 176527 C6 Patients receiving cancer therapy experience iatrogenic immunosuppression which makes them more susceptible to severe COVID and simultaneously blunts their response to vaccines against SARS-CoV-2. Treatment related immunosuppression is often transient and/or cyclical which raises critical questions about how to optimally time vaccines and boosters in patients who are undergoing active cancer therapy. In our U54 SeroNet project we have focused on accruing cancer patients undergoing active treatment. While patients with any cancer type were eligible we oversampled patients either receiving B lineage depleting treatments bone marrow transplant and PD-1/PD-L1 immune check point inhibitors as we hypothesized these treatments were most likely to create immune altered states that would alter responses to SARS-CoV-2 vaccine or infection. As of July 8 2022 we have enrolled 826 patients with cancer in our study 738 (89%) of whom have received their primary vaccine series 543 (74% of vaccinated) have received their first booster and 177 (33% of single boosted) have received their second booster. Our cohort is racially and ethnically diverse with 20% Hispanic 9% Black 9% Asian and 6% mixed/other races reflecting the diversity of patients who live in Los Angeles county. Among a subset of 657 cancer patients with serology data available 53.9% and 38.1% of solid and hematologic cancer patients achieve high (IgG(S-RBD) >590 BAU/ml) antibody levels after completion of the primer series which improves to 76.8% and 65.2% after boosting. Among patients with no seropositivity after priming 83.3% seroconverted after a booster immunization (25.0% with high IgG-(S-RBD)). These data demonstrate that booster doses can improve serologic responses in patients immunosuppressed due to cancer therapy however a substantial number of patients still have suboptimal serologic responses. Durability of the serological response T cell/cellular immunity and resistance to breakthrough infection in this cohort are largely unknown 440000 +No NIH Category available 2019-nCoV;ACE2;Adult;Advocate;Age;Aggressive course;Antibodies;Antibody Response;Bioinformatics;Biology;Biometry;Budgets;COVID-19;COVID-19 mortality;COVID-19 patient;COVID-19 susceptibility;COVID-19 vaccination;COVID-19 vaccine;Cancer Patient;Cardiopulmonary;Cells;Characteristics;Clinical;Clinical Sciences;Clinical Trials;Complement;Contracts;Control Groups;Cytoprotection;Data Science;Data Science Core;Demographic Factors;Development;Disease;Doctor of Philosophy;Epithelial Cells;Ethnic Origin;Fatality rate;Gender;Histology;Immune;Immune response;Incidence;Individual;Infection;Informatics;Kinetics;Knowledge;Longevity;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Morbidity - disease rate;Normal tissue morphology;Patient Recruitments;Patients;Persons;Play;Population Control;Predisposition;Race;Recording of previous events;Research;Risk Factors;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Science;Serology;Seroprevalences;Smoking;Smoking History;Tobacco;Vaccination;Vaccines;Viral;Viral Load result;Virus;Virus Diseases;Virus Replication;base;cancer therapy;cigarette smoking;comorbidity;data dissemination;human subject;inter-individual variation;lung cancer cell;member;multidisciplinary;neoplastic cell;neutralizing antibody;patient population;programs;protective efficacy;public database;response;sample collection;tumor;vaccine trial Vulnerability of SARS- CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses OVERALL: Vulnerability of SARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody AnalysesProgram Director: Fred R. Hirsch MD PhD; Co-PI: Adolfo Garcia-Sastre PhD. PROJECT NARRATIVEThe overarching research theme for the Serological Center of Excellence at Mount Sinai NY is to understandfactors contributing to the vulnerability of SARS-CoV-2 infection in patients with lung cancer through serologicalanalysis of antibody response and to characterize and compare the antibody response to SARS-CoV-2 infectionor SARS-CoV-2 vaccines in patients with lung cancer compared to a matched healthy control group. NCI 10706729 9/22/22 0:00 RFA-CA-20-038 3U54CA260560-02S1 3 U54 CA 260560 2 S1 "MARQUEZ, GUILLERMO" 9/30/20 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 7822511 "HIRSCH, FRED R" "GARCIA-SASTRE, ADOLFO " 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Research Centers 2022 120079 NCI 94061 26018 C6;Reg-CV As a supplement to our existing U54 we propose that Mount Sinai serve as a coordinating site for aggregating and analyzing demographic clinical and molecular data from multiple lung cancer studies supported by SeroNet. These studies from prominent institutions across the country have been investigating the intersection of lung cancer and SARS-CoV-2 to explore the impact of the combined diseases on patient health investigate the underlying biology that leads to poor outcomes and understand the effects of lung cancer disease and/or treatments on SARS-CoV-2 vaccination-induced immune responses. To accomplish this goal we will leverage the considerable expertise and experience of the Mount Sinai Bio-informatics group led by Joseph Finkelstein and the data analysis capabilities of our partners at the Vanderbilt Department of Statistics. 120079 +No NIH Category available 2019-nCoV;Antibodies;Automobile Driving;Bar Codes;Biological Assay;Biology;COVID-19;COVID-19 monitoring;COVID-19 pandemic;COVID-19 patient;COVID-19 risk;COVID-19 severity;COVID-19 vaccine;Cancer Patient;Cardiovascular system;Cells;Cessation of life;Clinical;Complex;Data;Disease;Enzyme-Linked Immunosorbent Assay;Flow Cytometry;General Population;Hematologic Neoplasms;Hematological Disease;Hematology;Hematopathology;Hematopoietic Neoplasms;Immune;Immune response;Immunoassay;Immunoglobulin G;Immunoglobulin M;Immunosuppression;Institutional Review Boards;Laboratories;Lymphopenia;Malignant Neoplasms;Measurement;Measures;Mediating;Medicine;Memorial Sloan-Kettering Cancer Center;Microfluidics;Molecular;Monitor;Motivation;Multiple Myeloma;Multiple Organ Failure;Myelosuppression;Pathology;Patient Monitoring;Patients;Peripheral Blood Mononuclear Cell;Plasma;Plasma Proteins;Population;Production;Prospective cohort;Proteins;Public Health;Research Personnel;Retrospective cohort;Risk;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Sampling;Serology;Serology test;Severities;Specimen;Stains;Technology;Testing;Time;Tissue Banks;Vaccination;Vaccines;Validation;Vulnerable Populations;angiogenesis;blood treatment;cell type;chemokine;clinical translation;cohort;combat;coronavirus disease;cytokine;density;design;effective therapy;high risk;high throughput screening;immune activation;immune function;improved;individualized medicine;lung injury;microchip;novel;peripheral blood;personalized strategies;protein biomarkers;response;success;synergism;thrombotic;transcriptome sequencing;vaccine efficacy;vaccine evaluation;vaccine response Immuno-Serological Assays for Monitoring COVID19 in Patients with Hematologic Malignancies PROJECT NARRATIVEThis project aims to develop two novel immuno-serological assays for highly informative measurement of plasmaprotein markers and single-cell cytokine signatures in order to identify molecular correlates with COVID-19 riskseverity vaccine response in patients with hematologic malignancies. They can be applied to monitoring ofCOVID-19 patients without a malignancy or other cancers and potentially guide the design of effective treatments.This project is of vital importance and urgency to public health during the COVID-19 pandemic. NCI 10706726 9/21/22 0:00 RFA-CA-20-039 3U01CA260507-02S1 3 U01 CA 260507 2 S1 "SORBARA, LYNN R" 9/30/20 0:00 8/31/25 0:00 ZCA1-RTRB-C(A1) 9372328 "FAN, RONG " "HALENE, STEPHANIE " 3 ENGINEERING (ALL TYPES) 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT BIOMED ENGR/COL ENGR/ENGR STA 65208327 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Non-SBIR/STTR 2022 76742 NCI 45816 30926 C6 We propose a two-year collaborative project to synchronize data harmonization efforts and analyses of individual-level data in immunocompromised populations to assess effectiveness of vaccine boosters and immune responses using data from 11 Serological Sciences Network (SeroNet) institutions. Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in these vulnerable populations. To do so requires large datasets of well-defined populations with clinical information and a robust collaborative infrastructure able to evolve as new research questions arise during the pandemic. Therefore we propose to mimic the NA-ACCORD strategy of pooling cohorts at multiple sites in North America (https://naaccord.org). The foundational work of the NA-ACCORD enabled them to rapidly pivot to establish the CIVET-II cohort collaboration during the pandemic. To be time- and cost-efficient we propose a single pooling project that merges data from both (i) electronic medical records as well as (ii) prospective cohorts from SeroNet sites across the U.S. The cooperation of many SeroNet sites is crucial and will allow results to be more generalizable to the wider U.S. population including investigation of sources of heterogeneity (e.g. age sex race/ethnicity and geography). Data harmonization efforts will be streamlined and analyses will be divided by research area across all sites to allow multiple publications to occur simultaneously. 76742 +No NIH Category available 2019-nCoV;Address;Affect;Age;Antibodies;Antibody Response;Antibody-mediated protection;Antigens;Basic Science;Biometry;COVID-19;COVID-19 patient;COVID-19 severity;Cell surface;Cells;Cessation of life;Clinical;Clinical Sciences;Collaborations;Communicable Diseases;Complement;Complex;Coupled;Data Analyses;Development;Diabetes Mellitus;Disease;Ensure;Enzyme-Linked Immunosorbent Assay;Epidemiologic Monitoring;Epidemiology;Ethnic Origin;Evaluation;Flow Cytometry;Foundations;Gender;Goals;HIV;Health;Healthcare Systems;Heart Diseases;Human;Immune;Immune response;Immunity;Immunoglobulin Class Switching;Immunology;Immunomodulators;Infant;Infection;Inflammasome;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Leadership;Mediating;Metabolic;Methods;Mission;Modeling;Monoclonal Antibody Therapy;Myeloid-derived suppressor cells;Outcome;Pathogenesis;Pathologic;Pathology;Patients;Peripheral Blood Mononuclear Cell;Persons;Population;Prospective cohort;Proteins;Protocols documentation;Public Health;Race;Reagent;Regimen;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Respiratory Tract Infections;Risk;SARS-CoV-2 antibody;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sampling;Science;Serology;Serology test;Severity of illness;Sex Differences;Solid;Stains;Statistical Data Interpretation;Statistical Models;Surrogate Markers;Symptoms;T-Lymphocyte;Testing;Therapeutic;Training;Translational Research;Ursidae Family;Vaccine Design;Viral;Viral Pathogenesis;Virus;age difference;antibody-dependent cell cytotoxicity;base;biosafety level 3 facility;comorbidity;experimental study;gender difference;innate immune sensing;insight;intersectionality;male;neutralizing antibody;new therapeutic target;novel;novel marker;organ transplant recipient;pandemic disease;racial difference;rational design;response;sample fixation;severe COVID-19;sex;single cell analysis;therapeutic evaluation;therapy development;vaccine candidate;vaccine development;vaccine evaluation;virology Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS) Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)Overall NarrativeThe goal of the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)is to define the immune responses that can either protect or harm during infection. The JH-EPICS team willevaluate the immune responses required to detect the presence of SARS-CoV-2 initiate inflammatoryresponses eliminate infected cells and engage the antibody responses against the virus in COVID-19patients. Using statistical analyses and modeling JH-EPICS will identify the variables such as demographic(e.g. age sex gender race and ethnicity) and clinical (e.g. severity of COVID-19 and comorbidities) factorsthat predict COVID-19 immune responses and outcomes. NCI 10706725 9/22/22 0:00 RFA-CA-20-038 3U54CA260492-02S1 3 U54 CA 260492 2 S1 "KUO, LILLIAN S" 9/30/20 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 3088131 "KLEIN, SABRA L." "COX, ANDREA L" 7 MICROBIOLOGY/IMMUN/VIROLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF PUBLIC HEALTH 212182680 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Research Centers 2022 119719 NCI 73111 46608 C6;Reg-CV Johns Hopkins has broad expertise in the science of human health with viral immunity pathogenesis epidemiology biostatistics and surveillance emerging as integral components of the multidisciplinary research mounted at Johns Hopkins during the current pandemic. We have operated a Serological Sciences Center of Excellence: the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS). The overarching goal of JH-EPICS since 2020 with ongoing projects to distinguish immune responses that protect from those that cause pathology during infection and to analyze vaccine induced immune responses. We have resources and samples available to systematically evaluate innate T cell and antibody responses to SARS-CoV-2 in peripheral blood mononuclear cells and serological samples from COVID-19 vaccine recipients and patients sampled longitudinally. JH-EPICS contains three interconnecting Research Projects (RPs). RP1 focuses on innate immune sensing and activation of the human inflammasome by SARS-CoV-2 with evaluation of how anti-SARS-CoV-2 antibodies modulate innate sensing. RP2 uses traditional techniques to assess T cell responses including ELISpot and a novel flow-cytometry based platform that enables single cell analysis of cell surface markers combined with intracellular staining for proteins involved in metabolic programming. In RP3 the magnitude duration and class switching of SARS-CoV-2-specific antibody isotypes as well as virus-specific neutralizing antibody responses is analyzed and compared with non-neutralizing antibody functions e.g. complement fixation and antibody-dependent cellular cytotoxicity using a novel core set of serological assays. A centralized Virology Reagent Core provides antigen for ELISAs reagents to identify virus-specific immune cell populations inactivated SARS-CoV-2 viruses methods for quantifying SARS-CoV-2 and access to biosafety level 3 facilities and training needed to perform any experiments involving live SARS-CoV-2. The Analysis Resource Core provides statistical modeling and analysis to frame and test hypotheses about the mechanisms mediating the severity of COVID-19 as well as the intersectionality of sex gender age and racial differences in immune mechanisms of COVID-19 disease and vaccination. In concert with the trans-network collaborations this research provides significant insights into pathologic immune responses to SARS-CoV-2 and elucidates mechanisms of immunity against SARS-CoV-2 infection and vaccination. By uncovering the correlates of protective immunity following boosting JH-EPICS research will further enhance vaccine design and evaluation of vaccine candidates. 119719 +No NIH Category available 2019-nCoV;Acute;Address;African American population;Agonist;Antibodies;Antigen Targeting;Attention;Award;B-Lymphocytes;Biopsy;Blood;COVID-19;COVID-19 diagnosis;COVID-19 patient;COVID-19 test;Cancer Patient;Caucasians;Cells;Clinical;Collaborations;Communities;Convalescence;Data;Data Set;Disease;Elderly;Evaluation;Female;Hispanic Americans;Human;Immune;Immune response;Immune system;Immunity;Immunologic Memory;Immunologics;Individual;Infection;Institution;Knowledge;Laboratories;Longitudinal Studies;Mucosal Immune Responses;Mucous Membrane;Nose;Patient Recruitments;Patients;Peripheral Blood Mononuclear Cell;Phenotype;Physicians;Plasma;Plasma Cells;Populations at Risk;Prognosis;Protocols documentation;Research;Risk;Route;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Science;Serology;Severity of illness;Site;T cell response;T-Lymphocyte;Testing;Tissue Sample;Toll-like receptors;Translational Research;Translations;Vaccination;Validation;Viral Antigens;adaptive immune response;adaptive immunity;base;clinical development;cohort;data sharing;immune checkpoint blockade;interest;male;medically underserved;medically underserved population;member;mucosal site;novel therapeutic intervention;pandemic coronavirus;pandemic disease;patient population;research clinical testing;response;tool;vaccine candidate;vaccine trial;young adult Mechanisms and Duration of Immunity to SARS-CoV-2 OVERALL: NARRATIVEWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world. We willemphasize deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanningserological B cell and T cell responses; analysis of immune responses in the blood as well as mucosal tissuesites; comparing immune responses induced by infection to those induced by candidate vaccines; and payingparticular attention to the understanding the clinical needs and immune responses of underservedunderrepresented and at-risk patient populations. Within these parameters we will attempt to determine thefactors that result in effective and durable immunity to SARS-CoV-2 infection and provide useful knowledge andtools for physicians and patients. NCI 10706724 9/21/22 0:00 RFA-CA-20-038 3U54CA260517-02S1 3 U54 CA 260517 2 S1 "LIU, YIN" 9/23/20 0:00 8/31/25 0:00 ZCA1-GRB-I(A) 10429455 "BOYD, SCOTT DEXTER" Not Applicable 16 PATHOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Research Centers 2022 440000 NCI 328879 111121 C6 Primary immune deficiency disorders (PID) affect 1 in 2000 individuals in the U.S. twice the prevalence of non-Hodgkin lymphoma. PID patients are at risk for severe COVID-19 and impaired responses to vaccination. Research into vaccine boosting in these individuals is clearly of importance for public health. Study of these patients many of which have single-gene inborn causes for their phenotype offers the valuable opportunity to correlate genotypes with immunological phenotypes in humans. Dr. Boyd will collaborate with Dr. Charlotte Cunningham-Rundles a world expert in PID at the Mount Sinai School of Medicine in New York to analyze the serological and B and T lymphocyte responses to vaccination and boosting using previously-collected plasma and peripheral blood mononuclear cells from a cohort of 142 PID patients whose disorders affect adaptive immune responses with a range of severity and whose immunological phenotypes can include autoreactivity in addition to impaired protective immunity. The most common diagnosis in this cohort is Common Variable Immune Deficiency (CVID). These patients generate suboptimal vaccine responses but some can still mount specific antibody titers after vaccination. We will carry out an in-depth systemsimmunology characterization of serological responses and B cell and T cell populations in these patients characterizing the frequencies cellular phenotypes B cell and T cell receptor sequences and antigen epitopes targeted by antigen-specific B cells using a panel of 14 different DNA-tagged SARS-CoV-2 variant antigen tetramers. Examination of T cell responses in the PID patients will include analysis of vaccine antigen-stimulated T cell frequencies and TCR sequences and detailed flow cytometric immunophenotyping. These data will provide clinically relevant information about SARS-CoV-2 vaccination and boosting responses in PID patients to potentially contribute to clinical guidance as new Omicron variant-containing vaccine boosters are implemented and should provide insights into the immunological genes pathways and cell populations that contribute to adaptive immune responses and memory formation after mRNA vaccination in human patients. 440000 +Cancer; Colo-Rectal Cancer; Digestive Diseases; Esophageal Cancer; Health Disparities; Minority Health; Prevention; Rare Diseases; Women's Health Accounting;Address;Advocate;Animals;Award;Biometry;Case Management;Colon Adenocarcinoma;Colon Carcinoma;Communities;Community Medicine;Comprehensive Cancer Center;Core Facility;Development;Early Diagnosis;Educational workshop;Ensure;Esophageal Adenocarcinoma;Evaluation;Faculty;Funding;Grant;Human Experimentation;Individual;Informatics;Intellectual Property;Leadership;Malignant neoplasm of gastrointestinal tract;Methods;Monitor;Oral;Patients;Performance;Policies;Prevention;Principal Investigator;Process;Program Development;Progress Reports;Quality Control;Regulation;Reporting;Research;Research Project Grants;Resource Sharing;Risk;Safety;Training;United States National Institutes of Health;Visit;career;career development;community organizations;data management;hospital organization;medical schools;meetings;programs;research study;success Administrative Core PROJECT NARRATIVEThe Case GI SPORE provides for an integrated program in developing new methods for addressing riskprevention early detection and treatment of GI cancers principally colon cancer and adenocarcinoma of theesophagus. The Administrative Core will provide for overall direction coordination and administration of allSPORE activities. NCI 10706702 9/23/22 0:00 PA-20-272 3P50CA150964-10S1 3 P50 CA 150964 10 S1 "NOTHWEHR, STEVEN F" 9/14/11 0:00 7/31/23 0:00 9263 1888502 "MARKOWITZ, SANFORD D." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 8/1/21 0:00 7/31/22 0:00 Research Centers 2022 664839 412944 251895 PROJECT SUMMARY/ABSTRACTThe Administrative Core will provide for overall direction coordination and administration of the Case GISPORE. The Administrative Core will include: The SPORE Principal Investigator (Core Director) the SPORECo-Principal Investigator (Core Co-Director) and the SPORE Administrative Coordinator. The AdministrativeCore will oversee the functioning of: the SPORE Executive Committee the SPORE Internal Advisory Board theSPORE External Advisory Board and the SPORE Patient Advocates Advisory Board. It will be responsible forfacilitating coordinating stimulating monitoring and maintaining scientific and financial oversight for all SPOREactivities. It will provide the central forum for interaction among all SPORE components and all SPORE faculty.It will provide the central mechanism for monitoring progress and evaluating performance of all SPOREcomponents. It will provide the coordinating mechanism between the SPORE faculty and the SPORE Internaland External Advisory Boards. And it will provide the mechanism for one of the key functions of the SPORE thedecision on when to re-allocate SPORE funds. The Administrative Core will maintain liaison between the GISPORE the Case Comprehensive Cancer Center and the School of Medicine leadership as well as withexternal organizations including NCI other GI SPOREs and the SPORE community in general. Coreresponsibilities will include: Oversee conduct of all SPORE activities; Convene monthly meetings of the SPORE Executive Committee; Coordinate twice yearly progress presentations of all SPORE components to the Executive Committee; Organize twice yearly meetings and SPORE progress reviews by the SPORE Internal Advisory Board; Organize annual visits and SPORE progress reviews by the SPORE External Advisory Board; Oversee administration coordination and quality assessment of all SPORE Core Facilities; Coordinate all SPORE seminars and the SPORE annual retreat; Organize and coordinate meetings of the SPORE Patient Advocate Advisory Board Coordinate solicitation and evaluation of developmental research awards and career enhancement awards; Oversee management and accounting of grant funds; assure monthly reconciliation of all accounts; Assure compliance and maintain documents for all institutional regulatory requirements for humanexperimentation animal utilization toxic material and safety training and utilization; Ensure compliance and coordination with all SPORE reporting regulations; Manage all intellectual property affairs arising from SPORE-sponsored research; Represent the SPORE in interactions with other Centers Departments and the School of Medicine; Coordinate and assure participation of the Case GI SPORE in National SPORE meetings. +Biotechnology; Cancer; Clinical Research; Prostate Cancer; Urologic Diseases Ablation;Administrative Supplement;Bone Marrow;Bone Matrix;Bone neoplasms;Cancer Center;Cancer Patient;Cell Survival;Cessation of life;Clinical;Clinical Trials;Clinical/Radiologic;Combined Modality Therapy;Conditioned Culture Media;Disease Progression;Generations;Genes;Goals;Hormones;Immature Bone;In Vitro;Integrins;KDR gene;Lead;Ligands;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Molecular Profiling;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Oral;Osteoblasts;Osteogenesis;PTK2 gene;Pathway interactions;Patients;Pharmacodynamics;Phenotype;Phosphorylation;Play;Progression-Free Survivals;Proteins;Radiation;Recurrence;Refractory;Resistance;Resolution;Role;Serum;Signal Transduction;Structure;Study models;Symptoms;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Treatment Efficacy;Xenograft Model;Xenograft procedure;antiangiogenesis therapy;bone;bone imaging;bone lead;castration resistant prostate cancer;chemotherapy;disorder control;docetaxel;improved;in vivo;inhibitor;men;mortality;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;osteogenic;paracrine;patient derived xenograft model;patient population;predictive marker;prostate cancer cell;release factor;resistance mechanism;response;serum PSA;standard of care;targeted treatment;theories;therapeutic target;therapy resistant;tumor;tumor growth;tumor microenvironment Targeting Tumor Microenvironment-Induced Therapy Resistance in Prostate Cancer Bone Metastasis NARRATIVE (Project 2) While several new therapeutic agents have prolonged the lives of men with metastatic castrate resistant prostate cancer (mCRPC) resistance invariably develops leading to death. This proposal tests the novel concept that newly formed bone induced by metastatic prostate cancer cells forms a resistance niche by releasing osteocrines soluble molecules that confer resistance to therapies for mCRPC. Inhibitors that block osteocrine-induced resistance will prolong survival of men with mCRPC. NCI 10706699 9/23/22 0:00 PA-20-272 3P50CA140388-10S1 3 P50 CA 140388 10 S1 "ARNOLD, JULIA T" 9/2/09 0:00 8/31/23 0:00 9260 1896778 "LIN, SUE-HWA " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/20 0:00 8/31/21 0:00 Research Centers 2022 113022 69767 43255 PROJECT SUMMARY (Project 2) Metastatic castrate resistant prostate cancer (mCRPC) in bone is almost universally fatal. While new targeted therapeutics have improved patient survival resistance invariably develops. Treatment refractory bone metastases lead to morbidity and mortality in patients with mCRPC. Long-term goals of this proposal are to understand mechanisms of therapy resistance and strategies to overcome them. Studies of this proposal focus on resistance mediated from the bone microenvironment. Specifically using an osteogenic prostate cancer xenograft MDA-PCa-118 we found that treatment with cabozantinib an oral multi-kinase inhibitor with potent activity against p-MET and p-VEGFR-2 demonstrated striking initial responses. However resistance rapidly occurs as first evidenced by viable cells tumor cells found in proximity to newly formed bone matrix. Because prostate cancer bone metastasis presents with a unique bone-forming phenotype we hypothesize that factors released from tumor-induced bone lead to pre-existing resistance in which the microenvironment has already contributed factors that mediate resistance prior to application of therapy. To study the mechanisms of this form of resistance a secretome analysis was performed on conditioned medium from prostate cancer-induced bone which identified 121 bone-secreted proteins. Many of these bone-secreted proteins activate integrins through paracrine effects increasing tumor cell survival. We term these osteoblast-secreted paracrine factors osteocrines. Consistent with the involvement of integrins in therapy resistance we found that FAK the downstream effector of integrin signaling is highly activated in therapy-resistant tumor cells. Thus we hypothesize that osteocrines released from prostate cancer-induced bone form a pre-existing resistance niche that mediates therapy resistance of prostate cancer cells through activation of FAK. We will test this hypothesis by: (1) Examining the ability of selected osteocrines to confer therapy resistance through activation of FAK; (2) Examining the effects of second-generation FAK inhibitors (VS-6063 or VS- 4718) on overcoming osteocrine-induced therapy resistance in xenograft mouse models; and (3) Conducting a clinical trial to examine the toxicity and efficacy of a FAK inhibitor (VS-6063 or VS-4718) in men with treatment- refractory bone-metastatic castrate-resistant prostate cancer. The studies would be paradigm shifting by demonstrating that the tumor microenvironment can provide a niche of pre-existing resistance a mechanism of resistance in addition to tumor adaptation to therapy which is likely applicable to multiple therapies in mCRPC. The studies would also demonstrate the potential efficacy of FAK inhibitors for treatment of bone-metastatic CRPC. In addition delineating mechanisms of this pre-existing resistance will provide new predictive markers to guide therapeutic strategies to overcome resistance. +Aging; Cancer; Prostate Cancer; Urologic Diseases Address;Administrative Supplement;Awareness;Bioinformatics;Biometry;Budgets;Cancer Center;Cancer Patient;Collaborations;Communication;Communities;Complex;Consult;Country;County;Decision Making;Deposition;Development;Discipline;Ensure;Expenditure;Extramural Activities;Funding;Goals;Grant;Human Resources;Institution;Interdisciplinary Study;Leadership;Malignant neoplasm of prostate;Manuscripts;Medical center;Minority;Monitor;Pathology;Patient advocacy;Preparation;Prostate;Quality Control;Recommendation;Regulation;Reporting;Reproduction spores;Research;Research Activity;Research Personnel;Research Project Grants;Role;Supervision;Texas;Time;Translational Research;Work;anticancer research;base;career;data quality;data sharing;experience;interdisciplinary collaboration;medically underserved;meetings;minority communities;programs;quality assurance;success;translational research program;underserved community Administrative Core PROJECT NARRATIVE (Administrative Core) The principal role of the Administrative Core of the MD Anderson Cancer Center Prostate Cancer SPORE is to expand the integration of investigators from diverse scientific disciplines who have joined the translational research effort in prostate cancer and to provide continuous leadership and general administrative support for all SPORE-related activities. NCI 10706693 9/23/22 0:00 PA-20-272 3P50CA140388-10S1 3 P50 CA 140388 10 S1 "ARNOLD, JULIA T" 9/2/09 0:00 8/31/23 0:00 9254 1941224 "LOGOTHETIS, CHRISTOPHER J." Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/20 0:00 8/31/21 0:00 Research Centers 2022 156239 96444 59795 PROJECT SUMMARY (Administrative Core) The Administrative Core provides essential support to the MD Anderson Cancer Center Prostate Cancer SPORE (Prostate Cancer SPORE) PIs and investigators to maximize success. It is directed by Drs. Christopher J. Logothetis and Timothy C. Thompson and co-directed by Dr. Sue-Hwa Lin who co-chair the Executive Committee and provide overall supervision of 4 Projects 2 additional Cores Developmental Research (DRP) and Career Enhancement (CEP) Programs and scientific direction of the SPORE. The Core Directors and co-Director rely on the extensive broad-based scientific research and SPORE experience of the Advisory Boards in critical decision-making. Success of the complex interdisciplinary research in the SPORE depends in part on integration of diverse prostate cancer research approaches. The Core will overcome barriers to interdisciplinary collaboration and data sharing and ensure a unified translational research effort. The SPORE is founded on planning integration and translational research efforts supported by this Core. Its leadership and staff will be responsible for monitoring/planning scientific activities; providing scientific direction; ensuring emphasis on translational research; ensuring interdisciplinary and inter-SPORE integration with major prostate programs within/outside MD Anderson and other broad translational research activities; and providing administrative and fiscal management (eg personnel budgets office oversight communication organization of meetings manuscript preparation and progress and other reports to the NCI and SPORE committees and support of Cores and Programs). Specific responsibilities of the Administrative Core are to: monitor research activity and provide stable and continuous leadership and direction; promote integration communication and collaboration among the SPORE and collaborating investigators at MD Anderson and other Texas Medical Center institutions; monitor scientific integrity and ensure overall compliance with all institutional state federal and NCI regulations and requirements as well as assurance for data quality control for the Biostatistics and Bioinformatics and Biospecimen and Pathology Cores; provide oversight for completion of DRP and CEP goals; convene staff and manage all necessary meetings; oversee expenditures and maintain budgets; communicate and consult with the NCI Translational Research Program Director and staff including reports; increase awareness of prostate cancer research and patient advocacy in the community; address ongoing needs of minority and underserved communities in Houston and Harris County (Texas); and encourage and facilitate translational prostate cancer research by extramural groups within the region and throughout the US. +No NIH Category available Acetates;Address;Administrative Supplement;Aging;Behavior;Bifidobacterium;Caloric Restriction;Cell physiology;Data;Development;Dietary Intervention;Dietary intake;Disease;Epigenetic Process;Food;Funding;Genes;Goals;Grant;Health;Health Benefit;Immune;Immune response;Immunity;Immunotherapy;Inflammatory;Laboratories;Link;Mammals;Mediating;Metabolic;Mitochondria;Molecular;Oral;Oxidative Phosphorylation;Parents;Physiological;Physiology;Play;Recording of previous events;Research;Role;Solid Neoplasm;Supplementation;System;T memory cell;Testing;Tumor Immunity;Volatile Fatty Acids;Work;cancer immunotherapy;design;dietary restriction;dietary supplements;gut microbiota;immune function;immunoregulation;improved;in vivo;insight;melanoma;member;microbiota;microbiota metabolites;microorganism;novel;parent grant;prevent;rational design Harnessing oral acetate supplementation to enhance anti-tumor immunity Project NarrativeCaloric restriction enhances the ability of memory T cells to control melanoma. While the molecular determinantsand mechanisms remain unclear my preliminary data indicates a critical role for acetate producing members ofthe intestinal microbiota. The mechanistic insights derived from this work have the potential to optimize cancerimmunotherapies and lead to the design of rational nutritional interventions that prevent and treat disease. NCI 10706665 4/7/23 0:00 PA-20-227 3R00CA252443-03S1 3 R00 CA 252443 3 S1 "DASCHNER, PHILLIP J" 7/6/20 0:00 3/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 16145314 "COLLINS, NICHOLAS " Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 310 Non-SBIR/STTR 2023 169500 OD 100000 69500 Abstract for Administrative Supplement (The Office of Dietary Supplements)Mammals and their microbiota have co-evolved for millennia through periods of fluctuating or limited foodavailability. As such restricting dietary intake could have the potential to restore our physiological state to onecompatible with our evolutionary history. Consistent with this mild or transient dietary restriction (DR) improvesmany aspects of health and aging. Emerging evidence from us and others has demonstrated that DR alsooptimizes the development and quality of immune responses. Therefore our work has the potential to revealunique fundamental insights into the physiological factors and mechanisms involved in promoting optimalimmune responses. Our primary goal is to harness these mechanisms in the design of novel cancerimmunotherapies.New data from my laboratory (funded by parent R00 grant) indicate that enhanced immune function and hostprotection during DR is dependent on the gut microbiota. The microbiota is comprised of trillions ofmicroorganisms that co-evolved with mammals and play a critical role in regulating host physiology behaviorand immunity. Such effects can be mediated by microbiota-derived metabolites such as the highlyimmunomodulatory short-chain fatty acids (SCFA). These include acetate which has been shown to regulateimmune responses via metabolic and epigenetic mechanisms. Thus gut microbiota-derived metabolites providea key link between dietary intake and immunoregulation. Our preliminary data suggest that acetate produced bythe gut commensal Bifidobacteria is critical for optimizing immune function and host protection during DR. Thisfinding led us to hypothesize that acetate supplementation alone will enhance anti-melanoma immune responsesvia metabolic and epigenetic mechanisms. To receive an Office of Dietary Supplements administrativesupplement grant will be essential for us to address this question and will significantly enhance the parent grant.In this proposal we will use novel in vivo systems to directly test whether acetate supplementation promotesimmune cell function by regulating 1) mitochondrial oxidative phosphorylation and 2) the expression of pro-inflammatory genes. Further we will 3) harness acetate supplementation to optimize immunotherapy againstestablished solid tumors. The preliminary described here was acquired via funding from the parent grant andthe new proposed research objectives remains within the scope of this parent grant. Altogether this proposalhas the potential to promote a greater understanding of how dietary supplements can benefit health and be usedto prevent and treat disease. 169500 +Autoimmune Disease; Bioengineering; Biotechnology; Cancer; Colo-Rectal Cancer; Dietary Supplements; Digestive Diseases; Inflammatory Bowel Disease; Microbiome; Nanotechnology; Nutrition; Obesity; Prevention Adipose tissue;Apoptosis;Apoptotic;Bacteria;Bile Acids;Biological Availability;Butyrates;Cancer Model;Cells;Chemoprevention;Chemopreventive Agent;Colon Carcinoma;Colorectal Cancer;Cultured Cells;Deoxycholic Acid;Development;Diet;Early Intervention;Encapsulated;Excipients;Exposure to;Fermentation;Fiber;G-Protein-Coupled Receptors;Gastrointestinal Diseases;Genes;Histone Deacetylase;Histone Deacetylase Inhibitor;Homing;Hydrophobicity;Immune;Inflammatory Bowel Diseases;International;Intervention;Intestines;Legal patent;Life Style;Link;Malaria;Methods;Mus;Names;Nutrient;Oral;Organ;Patients;Pharmaceutical Preparations;Play;Polymers;Polyvinyl Alcohol;Preclinical Drug Development;Prevention Protocols;Production;Program Development;Property;Propionates;Publications;Research;Retinaldehyde;Retinoids;Role;Sample Size;Shapes;Signal Pathway;Site;Solubility;Testing;Travel;Tretinoin;Valerates;Volatile Fatty Acids;amphiphilicity;base;cancer cell;carcinogenicity;cell killing;colorectal cancer prevention;covalent bond;dietary;dysbiosis;esterase;experimental study;extracellular;gut dysbiosis;gut microbiome;gut microbiota;hydrophilicity;improved;microbial;mimicry;mouse model;nanodrug;nanoparticle;obese person;obesity risk;pre-clinical;receptor-mediated signaling;retinaldehyde dehydrogenase;sex;treatment strategy;tumorigenic TASK ORDER TITLE: MICROBIAL METABOLITE MIMICRY A NANO-DRUG FOR COLON CANCER PREVENTIONPREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFF n/a NCI 10706658 75N91019D00022-0-759102200003-1 N01 9/15/22 0:00 3/14/24 0:00 78868006 "CLAPPER, MARGIE " Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N R and D Contracts 2022 702469 NCI Approximately 75% of colorectal cancer (CRC) cases are sporadic (occurring in patients not genetically predisposed to CRC) suggesting environmental and lifestyle influences. Because diet shapes the gut microbiota WD-induced gut dysbiosis and related carcinogenic metabolites such as the secondary bile acid deoxycholic acid (DCA) have been suggested to play a critical role in the CRC development. Dysbiosis of the gut microbiome leads to reduced synthesis of dietary nutrient metabolites in particular short-chain fatty acids (SCFAs). Indeed one of the factors linking the WD-induced gut dysbiosis and increased risk of obesity inflammatory bowel disease (IBD) and CRC is the reduced level of SCFA synthesis. Gut dysbiosis-targeted chemoprevention strategy could advance the field of CRC prevention. An effective drug would be orally delivered to mitigate the dysbiosis induced by a WD thereby preventing CRC in obese populations.Bacterial fermentation of fiber results in the production of SCFAs including butyrate (BU) propionate and valerate. Extracellularly SCFAs exert functions through G-protein coupled receptor (GPCR)-mediated signaling pathways in the immune cells adipose tissue and other organ sites. Intracellularly BU and other SCFAs show histone deacetylase (HDAC) inhibitory properties resulting in the activation of retinaldehyde dehydrogenase 1A (ALDH1A) and the enhanced conversion of retinaldehyde into all-trans retinoic acid (RA) in the gut which regulates the gut homing of immune cells. It has been shown that WD-fed mice have a reduced concentration of BU as well as the copy number of the bcoA which is a BU-producing gene found in the intestinal bacteria.It is possible that a combination of RA and HDAC inhibitor (HDACi) such as BU may be anti-tumorigenic as has been suggested by our previous studies that showed a combination of a retinoid and a HDACi can induce apoptosis of colon cancer cells. In order to further test this approach in preclinical CRC models a nanoparticle RA-based HDACi named BURA has been synthesized (US Patent Application No. 17/522405; International Publication No. WO 2020/232399 A1).By itself RA does not typically have an apoptotic cancer cell killing effect however an apoptotic effect on cultured cells was noted when RA was used in combination with a HDACi. The treatment strategy is to co-deliver BU and hydrophobic RA using hydrophilic polyvinyl alcohol (PVA) as an excipient. PVA is proven to improve stability and bioavailability as well as generate the sustained release of oral drugs to treat gastrointestinal diseases such as malaria and inflammatory bowel disease. The resulting nanodrug forms an amphiphilic polymer in which BU and RA are aggregated and encapsulated and thereby protected in the center of a nanoparticle with hydrophilic moieties exposed to increase solubility. In this way the free drugs BU and RA will be released together by encountering endogenous esterase that breaks the covalent bonds. 702469 +No NIH Category available Advanced Malignant Neoplasm;Androgen Receptor;Biological Assay;Biopsy;Blood;Blood Tests;Blood specimen;Breast;Cell Fraction;Circulation;Clinical;Collaborations;Collection;DNA;DNA sequencing;Dedications;Detection;Development;Estrogen receptor positive;Genes;Goals;Hemorrhage;Infection;Institution;Knowledge;Libraries;MEKs;Malignant Neoplasms;Malignant neoplasm of prostate;Manuscripts;Metastatic breast cancer;Multiple Myeloma;Mutate;Mutation;Pain;Patients;Performance;Plasma;Ploidies;Process;Prognosis;Proto-Oncogene Proteins c-akt;Protocols documentation;Publications;Quality of life;Reproducibility;Research;Research Personnel;Risk;Role;Running;Sampling;Sensitivity and Specificity;Specimen;Testing;Therapeutic;Therapeutic Clinical Trial;Therapeutic Trials;Time;Tissue Banks;Tube;Tumor-Derived;Validation;Work;antagonist;assay development;cancer type;castration resistant prostate cancer;cell free DNA;computational pipelines;cost effective;genome sequencing;genomic biomarker;improved;ineffective therapies;inhibitor;innovation;liquid biopsy;malignant breast neoplasm;minimally invasive;patient oriented;patient response;pembrolizumab;prospective;success;survival outcome;therapy outcome;time interval;treatment response;triple-negative invasive breast carcinoma;tumor;tumor DNA;whole genome Assay Validation of Cell-Free DNA Shallow Whole Genome Sequencing To Determine 'Tumor Fraction' in Advanced Cancers PROJECT NARRATIVEWe developed a cost-effective minimally-invasive approach to determine the amount of tumor-derived DNA inblood through shallow (ultra low-pass) whole genome sequencing of cell-free DNA from a single bloodsample. In this proposal we will analytically validate our cell-free DNA assay (UH2 portion) then establishclinical validity and prospectively evaluate performance in metastatic breast cancer through two large tissuecollection and two therapeutic clinical trials (UH3 portion). The ultimate goal of this research is to utilize thiscell-free DNA genomic biomarker to guide therapy in metastatic breast and other cancers. NCI 10706596 8/22/23 0:00 PAR-18-317 5UH3CA239105-04 5 UH3 CA 239105 4 "DEY, SUMANA MUKHERJEE" 9/19/22 0:00 8/31/25 0:00 ZCA1-SRB-X(J2)S 12484626 "LENNON, NIALL JOHN" "ADALSTEINSSON, VIKTOR ; STOVER, DANIEL G." 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 274067 NCI 234950 39117 PROJECT SUMMARYThe overarching goal of this research is to utilize a plasma-based genomic biomarker of cell-free DNA (cfDNA)to guide therapy in metastatic breast and other cancers. In our approach we use a cfDNA ultra low passwhole genome sequencing (ULP-WGS) assay with computational pipeline (ichorCNA) to determine theamount of tumor DNA in circulation (tumor fraction; TFx). Changes in TFx may serve as an early identifier forpatients responding or failing to respond to therapy and cfDNA ULP-WGS provides a cost-effectiveminimally-invasive approach to determine TFx. Our ULP-WGS cfDNA assay allows rapid precise quantitationof TFx from a single blood sample without prior knowledge of tumor mutations. While most liquid biopsyapproaches to date have focused on tracking known alterations or commonly mutated genes in cancer ourapproach is mutation agnostic and broadly applicable across advanced cancers.This proposal developed through deep collaboration between three primary investigators working on concerton the development and application of a cell-free DNA assay to guide prognosis and therapy in advancedcancers. To date we have performed the research version of this assay on over 3000 patients samples and inthree publications to date we demonstrate clinical utility in metastatic breast and prostate cancer as well asmultiple myeloma. We bring expertise in clinical breast cancer sequencing assay development and CLIAsequencing at scale with a strong track record of collaboration with multiple shared publications. All three PIsare dedicated to the success of this proposal with distinct yet complementary roles and responsibilities.In this proposal we will analytically validate our cfDNA ULP-WGS assay (UH2 portion) then establish clinicalvalidity and prospectively evaluate performance in therapeutic clinical trials (UH3 portion). In the UH2 portionwe will determine the sensitivity and specificity of ULP-WGS using serial dilutions of patient samples thenassess reproducibility repeatability and reportable range. We will then determine performance in the contextof real world pre-analytic variability including blood collection tube type amount of plasma and detectionthresholds with respect to DNA input quantity. In the UH3 portion we will establish clinical validity byevaluating TFx in 700 clinical plasma specimens from patients with metastatic breast cancer then advance ourunderstanding of cfDNA by evaluating the association of TFx with patient response to therapy and survivaloutcomes. Finally we will evaluate ULP-WGS in two prospective therapeutic clinical trials of metastatic triple-negative breast cancer evaluating association with response to therapy. 274067 +No NIH Category available Aftercare;Agonist;Antibodies;Antigen-Presenting Cells;Antigens;Autologous;Bilateral;Biological Assay;Biometry;Brain;Brain Neoplasms;Breast;CD14 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Capsid;Cell Density;Cell Separation;Cell physiology;Cells;Chemosensitization;Childhood;Clinical;Communicable Diseases;Complement;Cytolysis;Data;Dendritic Cells;Fatty acid glycerol esters;Flow Cytometry;Gene set enrichment analysis;Glioblastoma;Glioma;Goals;Human;Immune response;Immune system;Immunity;Immunization;Immunize;Immunobiology;Immunologic Stimulation;Immunologic Surveillance;Immunotherapy;Infiltration;Inflammation;Inflammatory;Injections;Ligation;Macrophage;Malignant Neoplasms;Measures;Mediating;Memory;Mentors;Modeling;Molecular Target;Monitor;Mus;Myeloid Cell Activation;Myeloid Cells;Natural Immunity;Natural Killer Cells;Oncolytic poliovirus;Ovum;PTPRC gene;Pathway interactions;Patients;Pattern recognition receptor;Phase;Phenotype;Play;Poliomyelitis;Poliovirus Vaccines;Poly I-C;Postdoctoral Fellow;Principal Component Analysis;Public Health;Qi;Recurrence;Research;Role;Route;SILV gene;STING agonists;Slice;T-Lymphocyte;TNFRSF5 gene;Testing;Tetanus;Tetanus Helper Peptide;Tetanus Toxoid;Tetanus Vaccine;Therapeutic;Tumor Antigens;Tumor Immunity;Tumor-associated macrophages;Vaccinated;Vaccination;Vaccines;Virotherapy;Work;adaptive immunity;antitumor effect;cancer immunotherapy;cancer therapy;cancer type;cell type;clinical translation;clinically actionable;cytokine;design;differential expression;draining lymph node;granulocyte;immunogenic;melanoma;neoplasm immunotherapy;neoplastic cell;novel;novel therapeutics;pathogen;programs;response;subcutaneous;success;synergism;targeted cancer therapy;transcriptome;transcriptome sequencing;tumor;tumor growth;tumor microenvironment Reviving cancer immune surveillance with CD4 T cell help Project NarrativeCD4+ T cell help is required for optimal effector CD8+ T cell function; however therapies that enlist CD4+ T cellsfor cancer immunotherapy are lacking. I discovered that intratumor activation of childhood vaccine CD4+ T cellrecall responses inflame the tumor microenvironment and mediate antitumor efficacy. This work will defineinflammatory reprogramming CD8+ T cell potentiating and `helper' functions induced by CD4+ T cell recall withintumors to leverage CD4+ T cells for cancer immunotherapy. NCI 10706593 6/8/23 0:00 PA-20-188 5R00CA263021-03 5 R00 CA 263021 3 "LIU, YIN" 7/8/21 0:00 6/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 10983362 "BROWN, MICHAEL CLAVON" Not Applicable 4 NEUROSURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Non-SBIR/STTR 2023 246243 NCI 153158 93426 AbstractThe immune system is capable of eliminating advanced malignant tumors yet cancer immunotherapy successhas been limited to a subset of cancer types. Conventional CD4 or `helper' T cells play an integral role inorchestrating immune responses and can potentiate the function of antitumor immunity: both via activation andpotentiation of antigen presenting cell function and antitumor CD8 T cells. My postdoctoral work demonstratedthat reactivating childhood vaccine-specific CD4 T cells after intratumor injection of recall antigen (e.g. poliocapsid or tetanus toxoid) mediates antitumor efficacy and causes both innate and adaptive inflammation withintumors. The antitumor efficacy of intratumor recall responses were partially dependent upon CD8 T cells andcoincided with infiltration of activated granulocytic macrophages with phenotypes distinct from tumor associatedmacrophages after direct innate stimulation with Poly IC. Thus inducing CD4 T cell recall represents a noveltherapeutic opportunity with a distinct mode of inflammatory and antitumor potential. We hypothesize thatintratumor childhood vaccine-specific CD4+ T cell recall responses instigate distinct and durable inflammatoryreprograming of myeloid cells to potentiate antitumor CD8+ T cell function and mediate antitumor efficacy. Totest this hypothesis we will define reprogramming of innate immunity after triggering intratumor recall responsesand determine its role in mediating antitumor efficacy (Aim 1) and test if polio vaccine-specific CD4+ T cell recallresponses `help' antitumor CD8+ T cells (Aim 2). These analyses will inform clinically actionable routes to developrecall antigen-based therapies that enlist CD4 T cell help within tumors (the goal of the independent R00 phase).The clinical translation of these findings will be informed by identifying therapeutic strategies such as combinedinnate pattern recognition receptor agonist therapy that may synergize with recall antigens in mediating systemicantitumor efficacy; as well as identifying more targeted molecular routes to recapitulate CD4 T cell help in tumorstherapeutically (Aim 3). The K99 phase of this work will be mentored by several distinguished experts in tumorimmunobiology and cancer immunotherapy: including Drs. Darell Bigner (primary Mentor cancer immunotherapyof brain tumors) Simon Gregory (computational expert) Qi Jing-Li (T cell biologist using transcriptome analysesto gauge T cell function) Amy Heimberger (tumor associated myeloid cell expert who has previously appliedtranscriptome analyses to define activation/suppressive features of tumor associated myeloid cells) and JamesHerndon II (biostatistical support). This proposal will enable clinical translation of recall antigens to cancerpatients and will seed a research program that leverages the potent immune-stimulating effects of CD4+ T cellhelp to develop novel cancer therapies. 246243 +No NIH Category available Adult;African Burkitt's lymphoma;Age;Animal Model;B lymphocyte immortalization;B-Cell Lymphomas;B-Cell NonHodgkins Lymphoma;B-Lymphocytes;Behavior;Biological Markers;Cell Separation;Cell model;Cells;Clinical Trials;Coupled;Cytotoxic T-Lymphocytes;DNA Damage;Data;Development;Epstein Barr Virus B cell lymphoma;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Exhibits;Failure;Frequencies;Ganciclovir;Gene Expression;Genetic;Goals;Growth;HIV Infections;Herpesviridae;Heterogeneity;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;Human Herpesvirus 4;Immune;Immunosuppression;In Vitro;Individual;Infection;Latent virus infection phase;Lymphoma;Lymphoma cell;Lymphomagenesis;Lytic;Lytic Virus;Mediating;Minor;Modeling;Molecular;Monitor;Non-Hodgkin's Lymphoma;Oncogenic;Oncogenic Viruses;Organ Transplantation;Outcome;Pathogenesis;Phenotype;Phosphotransferases;Plasmablast;Population;Predisposition;Proliferating;Protein Kinase;Regulation;Repression;Research;Rest;Role;T cell response;Testing;Therapeutic;Therapeutic Intervention;Tumor Tissue;Valganciclovir;Viral;Viral Proteins;Virus;Work;Xenograft Model;cell killing;epstein barr virus mediated immortalization;experimental study;gene product;in vivo;infected B cell;innate immune sensing;large cell Diffuse non-Hodgkin's lymphoma;latent infection;lymphoblastoid cell line;mouse model;neoplastic cell;novel therapeutics;programs;response;sensor;single-cell RNA sequencing;success;transforming virus;tumor;tumor heterogeneity;tumor progression;tumorigenesis;virtual Defining and exploiting EBV-infected cell heterogeneity in non-Hodgkin lymphomas PROJECT NARRATIVEEpstein-Barr virus promotes lymphomas in the immune suppressed. These studies will characterize and exploitthe underlying single cell heterogeneity in these tumors to develop new therapies. NCI 10706553 8/3/23 0:00 PAR-21-348 5U01CA275306-02 5 U01 CA 275306 2 "DASCHNER, PHILLIP J" 9/19/22 0:00 8/31/27 0:00 ZCA1-SRB-P(M2) 9242914 "LUFTIG, MICAH A." Not Applicable 4 GENETICS 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 555946 NCI 345308 210638 Epstein-Barr virus (EBV) was the first human tumor virus discovered over 50 years ago in the context ofendemic African Burkitt lymphoma. However we now know it is also a common herpesvirus that persists as alifelong latent infection in virtually all adults worldwide. Early work in the field led to a model for EBV infectionpromoting B-cell lymphomas as evidenced by the growth transformation or immortalization of primary restinghuman B cells into lymphoblastoid cell lines (LCLs). In vivo EBV latent infection is met with a robust cytotoxicT-cell response keeping most infected individuals protected from the oncogenic potential of the virus. As suchEBV-associated B-cell lymphomas occur at significantly higher rates in the setting of immune suppression.Studies of viral and cellular gene expression in EBV-infected cells in vitro and in vivo have led to a model oflymphomagenesis characterized by the full expression of EBV latency gene products. However the phenotypesin bulk culture and tumor tissue lack the nuanced detail of cellular heterogeneity and the consequences of minorfrequency phenotypes on cancer progression. Our recent single cell RNAseq experiments have characterizedgene expression within individual EBV-infected B cells leading to an appreciation of cell fate trajectories anddynamic gene expression behavior of individual cells that we will integrate with human tumor analysis and mousemodels of lymphomagenesis. It is our ultimate goal to define the importance of specific EBV-infected cellpopulations on the progression of B-cell non-Hodgkin lymphomas of the immune suppressed. In this proposalwe aim to define how EBV-infected cell heterogeneity including innate antiviral restriction and plasmablastdifferentiation impacts lymphomagenesis and can be exploited for therapy. Our central hypothesis is that EBV-infected B cells toggle between different states that can restrict or promote lymphomagenesis as well as rendercells susceptible to virus-specific therapeutic intervention. We formulated our central hypothesis based onpreliminary data including single-cell RNA sequencing of EBV-infected primary B cells early after infection andin LCLs as well as characterization of cell fate dynamics regulating plasmablastic differentiation and lyticreactivation. We also provide evidence supporting a recent clinical trial using the kick and kill strategy ofpromoting EBV lytic reactivation with histone deacetylase inhibition coupled with ganciclovir to kill lymphomacells that activate viral kinases. Thus the rationale for the proposed research is that understanding EBVregulation of infected B-cell fates will dissect mechanisms of pathogenesis and reveal new therapeutic avenuesto target EBV-positive B-cell lymphomas. We plan to test our central hypothesis and complete the objectives inthis proposal through the following three specific aims: i) to define the role of innate immune sensors andeffectors in EBV-mediated immortalization and lymphomagenesis ii) to determine the role of plasmablastdifferentiation in suppressing EBV-mediated lymphomagenesis and iii) to define the mechanism by which HDACinhibition promotes susceptibility of EBV+ DLBCL to killing by ganciclovir. 555946 +No NIH Category available Actins;Activated Lymphocyte;Atomic Force Microscopy;Biochemical;Bioinformatics;Biophysics;Blood Vessels;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Breast cancer metastasis;CD8B1 gene;Calcium;Cancer Biology;Cancer Model;Cells;Cessation of life;Chemicals;Clinical;Clinical Data;Coculture Techniques;Complement Factor B;Confocal Microscopy;Coupled;Cytoplasmic Granules;Cytoskeleton;Data;Data Analyses;Data Set;Diagnosis;Disease;Doxycycline;Flow Cytometry;Future;Genes;Genetic;Genetic Epistasis;Genetic Transcription;Genomics;Goals;Histologic;Human;Image;Immune;Immune response;Immune system;Immunity;Immunocompetent;Immunocompromised Host;Immunologic Surveillance;In Situ;In Vitro;Infiltration;Invaded;Knowledge;Ligands;Lung;Lymphocyte;Lymphocyte Activation;Machine Learning;Malignant Neoplasms;Measures;Mechanics;Mediator;Metastatic Neoplasm to the Lung;Metastatic breast cancer;Methods;Modeling;Molecular;Mus;Natural Killer Cells;Neoplasm Metastasis;Nuclear;Oncogenic;Organ;Organoids;Patients;Phosphorylation;Prevalence;Process;Prognosis;Proteins;Publishing;Regulation;Research Design;Sampling;Serum Response Factor;Structure;Surface;System;T-Cell Activation;T-Lymphocyte;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutically Targetable;Tissue Sample;Woman;Work;biophysical properties;cancer cell;cell motility;cell transformation;clinically relevant;cytotoxic;experimental study;factor A;immune checkpoint blockade;immunological synapse formation;in vivo;inducible gene expression;interdisciplinary approach;junctophilin;malignant breast neoplasm;mechanical signal;mechanical stimulus;melanoma;mouse model;multiplexed imaging;mutant;myocardin;novel;novel therapeutics;overexpression;palliative;patient derived xenograft model;pharmacologic;prevent;receptor;therapeutic target;transcription factor;transcriptomics;treatment strategy MECHANOSURVEILLANCE IN BREAST CANCER METASTASIS PROJECT NARRATIVE - MECHANOSURVEILLANCE IN BREAST CANCER METASTASISMetastasis is the leading cause of breast cancer related deaths but the majority of treatment options thattarget known abnormalities in cancer cells are not curative. In our effort to identify additional abnormalities incancer cells for therapeutic targeting we found that the immune system could sense and destroy cancer cellsbased on cancer cells altered biophysical stiffness. In this project we aim to close the knowledge gap in ourmolecular understanding of this novel mode of immune surveillance which we termed mechanosurveillance inorder to facilitate clinical progress in metastatic breast cancer treatment. NCI 10706552 8/28/23 0:00 PA-20-185 5R37CA269370-02 5 R37 CA 269370 2 "NADEAU, CHRISTINE FRANCES" 9/16/22 0:00 8/31/27 0:00 Tumor Microenvironment Study Section[TME] 12312939 "ER, EKREM EMRAH " Not Applicable 7 PHYSIOLOGY 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL SCHOOLS OF MEDICINE 606124305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 354889 NCI 224175 130714 PROJECT SUMMARY/ABSTRACT - MECHANOSURVEILLANCE IN BREAST CANCER METASTASISMetastatic breast cancer is a devastating disease that impacts the lives of tens of thousands of women eachyear. Unfortunately the majority of treatment options for patients diagnosed with metastatic breast cancer arepalliative. Current treatment strategies often target cancer cells genetic and biochemical abnormalities butcancer cells also undergo profound changes in their biophysical properties such as cellular stiffness. Targetingbiophysical properties offers exciting new therapeutic avenues but the basic knowledge on the relationshipbetween cancer cell stiffness and regulation of metastasis is incomplete. Emerging evidence suggests thatcancer cell stiffness acts as a mechanical input for activation of cytotoxic lymphocytes that destroy cancercells. Thereby stiffness becomes an immune vulnerability of cancer cells during the metastatic cascade. Thisprocess where mechanical inputs activate the immune surveillance is termed mechanosurveillance and it isstrongly regulated by the expression of Myocardin related transcription factors A and B (MRTFA/B) in cancercells. Based on the published and the preliminary data the overarching hypothesis of this project is thatMRTFA driven calcium influx increases cancer cell stiffness and thereby activates mechanosurveillance duringbreast cancer metastasis. The long-term goal of this project is to determine the molecular mediators of MRTFAassociated mechanosurveillance and thereby inform pharmacological methods to exploit this cancer cellvulnerability for better treatment of patients with metastatic breast cancer. The research design includes a setof interdisciplinary approaches such as transcriptomic and genomic analyses of patient samples and cancermodels atomic force microscopy on patient derived xenograft organoids (PDXos) and on immunocompetentmodels of metastatic colonization and histological analyses of human breast cancer metastases. The specificaims of this project are:1) to determine the contribution of MRTFA driven calcium influx on cancer cell stiffness in PDXos in vitro and in situ mouse models by using atomic force microscopy and confocal microscopy.2) to determine the degree of cytotoxic lymphocyte activation by MRTFA and the associated stiffness in vivo by using multiplexed imaging and machine learning on metastatic tissue samples from patients and by using flow cytometry in metastases in syngeneic mouse models.3) to determine how to exploit MRTFA associated mechanosurveillance to target metastases by testing the impact of clinically relevant immune checkpoint blockade treatments on metastasis bearing mice.This work will uncover mediators of mechanosurveillance and demonstrate its prevalence in human cancer.Thus results of this work will impact the immediate use of immune checkpoint blockade and the futurestrategies to enhance mechanosurveillance in patients with metastatic breast cancer. 354889 +No NIH Category available Anticonvulsants;Apolipoprotein A-I;Binding;Binding Proteins;Biological;Biological Assay;Cancer Patient;Canis familiaris;Cell membrane;Cells;Certification;Chemotherapy-induced peripheral neuropathy;Cholesterol;Chronic;Cisplatin;Clinical;Clinical Research;Cyclic GMP;Data;Dependence;Development;Development Plans;Dose;Drug Kinetics;Endotoxins;Ensure;Epidemic;Excision;Formulation;Future;Healthcare;Helping to End Addiction Long-term;Immune response;Inflammation;Inflammatory;Injury;Macrophage;Mediating;Membrane Microdomains;Methods;Microglia;Modeling;Monitor;Mus;NOEL;National Institute of Neurological Disorders and Stroke;No-Observed-Adverse-Effect Level;Nociceptors;Non-Steroidal Anti-Inflammatory Agents;Opioid;Organ;Outcome;Pain;Pain management;Patients;Peripheral Nerves;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology;Phase;Phenotype;Preparation;Process;Proteins;Qualifying;Quality of life;Rattus;Regulation;Research;Risk;Rodent;Safety;Small Business Innovation Research Grant;Specific qualifier value;Spinal;Spinal Ganglia;Spinal nerve root structure;Sterility;Surface;TLR4 gene;Therapeutic;Toxic effect;Toxicology;Translating;United States National Institutes of Health;Vertebral column;addiction;biobank;cGMP production;cancer therapy;chemotherapy;chronic pain;clinical development;design;drug standard;effective therapy;experimental study;first-in-human;ganglion cell;human study;lead candidate;manufacture;manufacturing process;manufacturing scale-up;medication safety;meetings;neuroinflammation;non-opioid analgesic;nonhuman primate;novel;novel strategies;opioid misuse;pain relief;painful neuropathy;particle;pharmacologic;pre-Investigational New Drug meeting;preclinical evaluation;preclinical study;process optimization;programs;research clinical testing;response;safety study;scale up;side effect;success;systemic toxicity Novel biologic to treat chemotherapy-induced neuropathic pain NARRATIVEChronic pain is a major healthcare problem. Because no effective therapy is available the misuse of opioidscontributes to the growing epidemic of addiction. Capitalizing on the discovery of a novel mechanism involved inthe development of chemotherapy-induced peripheral neuropathy (CIPN) this project is to advance a non-opioidfirst-in-class therapeutic which effectively reverses CIPN associated pain toward IND and clinical testing. NCI 10706551 8/28/23 0:00 RFA-NS-20-011 5R44CA271904-02 5 R44 CA 271904 2 "BOZZA, WILLIAM PATRICK" 9/19/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-ETTN-S(14)B] 14475737 "KOGAN, YAKOV " Not Applicable 51 Unavailable 81343492 KD1LJTFV7DN8 81343492 KD1LJTFV7DN8 US 32.899179 -117.196665 10052906 "RAFT PHARMACEUTICALS, LLC" SAN DIEGO CA Domestic For-Profits 921213938 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 279 SBIR/STTR 2023 1049997 NINDS 908357 76219 PROJECT SUMMARYChemotherapy-induced peripheral neuropathy (CIPN) has a profound negative impact on quality of life of nearly70% of cancer patients receiving chemotherapy. While systemic administration of opiates NSAIDs andanticonvulsants can relieve pain for short intervals they are not suitable for chronic therapy. Aside from efficacymany of the potent agents are beset with limiting side effects and issues related to dependence and addiction.RAFT Pharmaceuticals (RAFT) proposes a Direct-to-Phase 2 SBIR proposal presenting a novel approach toreversal of preexisting neuropathic pain via regulation of lipid rafts in spinal and dorsal root ganglia (DRG) cells.Our lead candidate RFT1081 which is a modified apoA-I binding protein (AIBP) promotes removal ofcholesterol selectively from the plasma membrane of activated and inflammatory cells. This targeting is due toAIBP binding to Toll-like receptor 4 (TLR4) which is highly expressed on the surface of inflammatory microgliamacrophages and activated DRG nociceptors. RFT1081-mediated disruption of lipid rafts harboring activatedTLR4 abrogates the facilitatory cycle of neuroinflammation and nociceptors spontaneous activity and alleviateschronic pain phenotypes. In a prior project we developed a non-GMP scaled-up upstream and downstreammanufacturing process for RFT1081 and conducted its detailed characterization; conducted pharmacokineticsstudies of spinally delivered RFT1081 in mice and designed pharmacodynamics assays to evaluate RFT1081target engagement; established dose-dependent efficacy profile for AIBP treatment in CIPN mice; and conducteda non-GLP dose-range tolerability study of RFT1081 in rats. These data provide support and justify furtherdevelopment of RFT1081 in the proposed Direct-to-Phase 2 SBIR studies. In this milestones-driven project weplan to manufacture a RFT1081 drug product lot for toxicology studies using a cGMP-compatible process andanalytical assays. The RFT1081 drug product lot conforming to RAFTs specifications and in optimizedformulation will be thoroughly characterized for storage and in-use stability. The initial single-dose toxicologystudies will be performed in rats. We will then also evaluate the pharmacology local and systemic toxicity andimmune response to repeated i.t. administration of RAFT1081 in rats dogs and non-human primates to furtherstudy the safety of the drug and to select a pharmacologically relevant non-rodent species for further IND-enabling preclinical evaluation. RFT1081 will also be evaluated in a model of cisplatin cancer therapy to ensureit does not interfere with chemotherapy action. The project will conclude with developing a detailed synopsis ofan integrated first-in-human study and an overall indication-supporting clinical strategy followed by preparationfor and conducting a pre-IND meeting with the FDA. We expect that this Phase 2 SBIR project outcomes willinclude: 1) successful scale-up of RFT1081 suitable for future cGMP manufacturing 2) completion of dose-ranging toxicology studies and selection of a relevant non-rodent species and 3) a viable IND-enabling andclinical development strategy vetted with the FDA to de-risk future steps of RFT1081 development. 1049997 +No NIH Category available Accounting;Address;Angiogenesis Inhibitors;Antigen Presentation;Area;Bioinformatics;Biological Markers;Biotechnology;Bypass;Carbon;Cell Proliferation;Cell Survival;Cessation of life;Chemicals;Citric Acid Cycle;Clear Cell;Clear cell renal cell carcinoma;Collaborations;Comprehensive Cancer Center;Computerized Medical Record;Core Facility;Data Analytics;Dependence;Development;Diagnosis;Disease;Drug Screening;Education;Enzymes;Evaluation;Failure;Foundations;Funding;Generations;Genes;Genomics;Germ-Line Mutation;Glutaminase;Glutamine;Glycogen;Growth;Heart failure;Hypertension;Image;Immune checkpoint inhibitor;Immune system;Immunotherapy;In complete remission;Individual;Inflammation;Infusion procedures;Innate Immune System;International;Isotope Labeling;KDR gene;Link;Lipids;Medical;Medical center;Metabolic;Metabolism;Modeling;Nitrogen;Nivolumab;Nutrient;Pathology;Pathway interactions;Patient Care;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Phosphotransferases;Physiological;Prize;Process;Production;Proteinuria;Radiation;Recording of previous events;Renal Cell Carcinoma;Renal carcinoma;Research;Research Personnel;Resistance;STING agonists;Sagittaria;Small Interfering RNA;Structure;Survival Rate;Technology;Texas;Therapeutic;Toxic effect;Tracer;Translating;Translations;Tumor Bank;Tumor Promotion;Tyrosine Kinase Inhibitor;Universities;Update;VHL mutation;Vascular Endothelial Growth Factors;angiogenesis;anticancer research;arm;career;clinical practice;data management;immunogenic;in vivo;inhibitor;innovation;mortality;mutant;novel therapeutic intervention;novel therapeutics;palliative;patient population;phase I trial;predictive marker;programs;radiotracer;real time monitoring;resistance mutation;safety and feasibility;side effect;stemness;success;targeted treatment;tool;transcription factor;tumor;tumorigenesis University of Texas Southwestern Medical Center SPORE in Kidney Cancer Overall NarrativeKidney cancer is expected to be diagnosed in over 75000 individuals in the US in 2021 and is particularlyprevalent in Texas. Approximately 30% of patients develop metastatic disease and 5-year survival rates are12%. To address this unmet medical need the UT Southwestern Medical Center Kidney Cancer SPORE hasdeveloped a comprehensive program to explore and translate therapeutic opportunities with established andnew treatment approaches. NCI 10706530 7/18/23 0:00 PAR-20-305 5P50CA196516-07 5 P50 CA 196516 7 "KUZMIN, IGOR A" 8/1/16 0:00 7/31/27 0:00 ZCA1-RPRB-8(M1)S 1879305 "BRUGAROLAS, JAMES " "KAPUR, PAYAL " 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 2173408 NCI 1325251 848160 Overall SummaryParticularly prevalent in Texas renal cell carcinoma (RCC) is lethal when metastatic. To address this unmetmedical need the UTSW Kidney Cancer SPORE has developed a comprehensive therapeutic program in proven(targeted therapies and immunotherapy) and innovative (metabolism-directed) areas. Arguably the mostimportant driver of RCC is HIF2. Discovered at UTSW and regarded as undruggable structural studiesrevealed a vulnerability that was exploited through a chemical screen leading to the founding of PelotonTherapeutics in the UTSW BioCenter and the development of PT2385 and PT2977. During the previous fundingperiod Project 1 investigators validated HIF2 as a target identified putative biomarkers of dependencyexecuted a phase 1 trial identified resistance mutations and established HIF2 as a core dependency.Culminating the vertical collaboration and program success Peloton was acquired by Merck and PT2977 (alsocalled belzutifan) gained FDA approval. During the next period an innovative siRNA-based second-generationinhibitor targeting both wild-type and resistant mutant HIF2 will be co-developed together with a ground-breaking imaging radiotracer enabling HIF2 evaluation in patients. Project 2 investigators exploit a profoundlink between RCC and metabolism. Using pioneering isotope-labeled nutrient infusions Project 3 investigatorsestablished during years 1-5 that glutamine is a key nutrient fueling RCC growth in patients. In years 7-12 theywill deploy the authenticated In Vivo Metabolism Lab to target glutamine bypass pathways likely explainingthe recent failure of glutaminase inhibitors. Finally by leveraging Breakthrough Prize-recognized research atUTSW leading to a new innate immune system-activating drug Project 3 investigators propose a paradigm shiftin immunotherapy development involving the coordinated activation of the adaptive and innate arms (as it occursphysiologically). Together with previously commended development and career-enhancing programs SPOREinvestigators are supported by four Cores. A forward-looking Administrative Core (Core A) serves as a hub. APathology Core (Core B) brings to bear one of the largest and most sophisticated RCC tumor banks andexpertise supporting national efforts. A Data Analytics Core (Core C) assists with statistical supportbioinformatics and data management with an avant-garde tool that automatically extracts information from theelectronic medical record self-updates and links this information to experimental genomics and the tumor bank.An Imaging Core (Core D) delivers enabling technologies including IND-holding innovative tracers andunqualified expertise. Building upon the Simmons Comprehensive Cancer Center Kidney Cancer Program andits history of collaborative interdisciplinary cancer research SPORE Projects and Cores provide an engine ofdiscovery innovation and translation supporting national and international efforts to advance patient careresearch and education. 2173408 +No NIH Category available Adjuvant Study;Affect;Aftercare;Antibodies;Archives;Biology;Biopsy;Cell Communication;Cells;Cellular Structures;Clinical;Clinical Trials;Coculture Techniques;Complex;Data;Dermal;Disease Progression;Disease Resistance;Evolution;Exhibits;Fibroblasts;Gene Expression;Genetic Screening;Genetically Engineered Mouse;Genomic approach;Growth Factor;Heterogeneity;Human;Hypoxia;Immunofluorescence Immunologic;Impairment;Investigation;Isogenic transplantation;Ligands;Liver;Malignant Neoplasms;Malignant neoplasm of pancreas;Mesenchymal;Metastatic Neoplasm to the Liver;Modeling;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Nutrient;Organ;Organoids;Pancreatic Ductal Adenocarcinoma;Patients;Pattern;Pericytes;Pharmaceutical Preparations;Phenotype;Play;Population;Prior Therapy;Process;Protein Secretion;Resistance;Role;Sampling;Shapes;Signal Transduction;Specimen;Stromal Cells;TGFB1 gene;Testing;Therapeutic;Tumor Subtype;Work;biobank;cancer cell;cell type;chemotherapy;cytokine;differential expression;digital;functional genomics;innovation;insight;member;multidisciplinary;neoplastic cell;novel;novel strategies;novel therapeutic intervention;programs;response;single nucleus RNA-sequencing;single-cell RNA sequencing;standard of care;therapeutic target;therapy resistant;transcriptome;translational scientist;transplant model;treatment response;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity Project NarrativeThe overarching hypothesis of this Project is that reciprocal signaling between tumor cells andCAFs shapes malignant cell and CAF phenotypes that affect tumor progression and therapyresponses. Identifying and characterizing these interactions will provide new insights into thisbiology and identify new approaches to target PDAC. NCI 10706519 8/31/23 0:00 RFA-CA-21-041 5U01CA274276-02 5 U01 CA 274276 2 "BERA, TAPAN K" 9/19/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M1) 1925058 "HAHN, WILLIAM C" "AGUIRRE, ANDREW JAMES; DOUGAN, STEPHANIE " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 1037023 NCI 599999 437024 AbstractUnlike many cancers pancreatic ductal adenocarcinoma (PDAC) is characterized by a hypoxic nutrient-deprived immunosuppressive tumor microenvironment (TME) and a fibrotic stroma that may impair treatmentresponse. Recent single-cell studies suggest a complex interplay between malignant tumor cells and other celltypes within the TME with crosstalk between tumor and stromal cell types influencing malignant cell phenotypesincluding responses to therapy. Understanding these interactions will provide insight into PDAC progression andtherapy resistance.In particular cancer-associated fibroblasts (CAFs) are a major non-immune cell component of the TME and arecomprised of several distinct subtypes that vary based on tumor subtype and the surroundingmicroenvironmental niche. In this proposal we bring together a multidisciplinary team of basic and translationalinvestigators that will build upon our prior studies to investigate the Tumor-TME co-organizer model with a focuson interrogating interactions between PDAC tumor cells and CAFs in the TME. Specifically we will examine theoverarching hypothesis that reciprocal signaling between tumor cells and CAFs shapes malignant cell and CAFphenotypes in a context-specific manner that can be modulated by prior therapy and the organ-specific niche.We will leverage multiple built-in capabilities including genetically engineered mouse models (GEMMs) patient-derived organoid (PDO) and matched fibroblast models functional genetic screens and clinical trials with serialbiopsies to study the PDAC TME continuum in disease progression and resistance to therapy. Specifically wepropose (1) to determine whether targeting organ-specific PDAC-CAF interactions enhances therapeuticresponses (2) to interrogate novel vulnerabilities resulting from tumor cell and CAF reprogramming during PDACtherapy and (3) investigate whether TGFB blockade disrupts tumor cell-CAF crosstalk and sensitizes PDAC tochemotherapy. In pursuing these studies we will work with other members of the PDAC Stromal ReprogrammingConsortium (PSRC) to pursue collaborative studies to understand how PDAC and TME interactions programtumor progression and therapy responses. 1037023 +No NIH Category available Adoptive Cell Transfers;Adoptive Immunotherapy;Antigen Targeting;Antigens;CD4 Positive T Lymphocytes;Cancer Model;Cells;Clinical;Clinical Trials;Data;Disease remission;Dose;Endogenous Retroviruses;Endowment;Ensure;Enzymes;Extracellular Matrix;Foundations;Future;Genes;Helper-Inducer T-Lymphocyte;Heterogeneity;Human;Immune response;Immunity;Infiltration;Interferon alpha;Interleukin-9;Leukocytes;MME gene;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Modeling;Mus;PPBP gene;Patients;Penetration;Phenotype;Production;Recurrence;Relapse;Resistance;Role;Signal Transduction;Solid Neoplasm;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;TLR3 gene;TRAF6 gene;Therapeutic Index;Tumor Antigens;Work;cancer cell;chimeric antigen receptor;effector T cell;exhaust;extracellular;in vivo;innovation;melanoma;monocyte;mouse model;neoplastic cell;novel;pre-clinical;prevent;proto-oncogene protein Spi-1;response;restraint;stem-like cell;therapy resistant;tumor;tumor eradication;tumor heterogeneity The Unique Roles of Tumor-Specific Th9 Cells for Solid Tumor Eradication Project NarrativeIn this project we will determine the roles of specialized white blood cells called tumor-specific interleukin 9-producing T cells in promoting an immune response against solid tumors in mice and determine their potentialfor use in cancer adoptive cell immunotherapy. We hypothesize that transfer of these tumor-specific T cells willeradicate large established tumors and prevent recurrence in vivo in both mouse and human tumor modelsdue to their ability to 1) directly kill the tumor cells; 2) penetration into stroma-rich solid tumors and 3) restrainrelapse caused by acquired resistance due to high heterogeneity in tumor antigen expression. NCI 10706513 3/21/23 0:00 PA-20-185 5R01CA258477-03 5 R01 CA 258477 3 "LIU, YIN" 3/1/21 0:00 2/28/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 12114837 "LU, YONG " Not Applicable 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 388802 NCI 244833 143969 Project SummaryOur early studies have characterized IL-9-producing CD4+ T helper (Th9) cells as an antitumor T cell subset.Recently we also revealed Th9 cells as a novel T cell paradigm for ACT they are less exhausted fullycytolytic and hyperproliferative; and efficiently kills targeted antigen-positive tumor cells. In the current projectwe will use tumor models that faithfully recapitulate the clinical scenario of ACT in solid tumors to uncoverunique features of tumor-specific Th9 cells that enable them to efficiently eradicate advanced solid tumors. Wehypothesize that anti-solid tumor activity of Th9 cells are mainly attributed to both enhanced Th9 cellpenetration into stroma-rich solid tumors and restrain relapse caused by acquired resistance due to highheterogeneity in tumor antigen expression. Aim 1 will determine the role of Pu.1-dependent MMP12 productionin Th9 cells for their efficient penetration into solid tumors to exert antitumor functions. Aim 2 will determine therole of Th9 cells in promoting an eATP-enriched milieu to eradicate the TANTs in solid tumors and preventacquired resistance. Our proposed studies will identify tumor-specific Th9 cells as the first antitumor T cellsubset that are endowed with the capacity to eliminate solid tumors with the heterogeneity in tumor antigenexpression. This translationally relevant work holds promise to significantly advance the therapeutic index ofACT in solid tumors and could then lay the foundation for future clinical trials. 388802 +No NIH Category available 3-Dimensional;Address;Air;Anti-CD47;Area;Automobile Driving;Biological;Biological Assay;Brain;Brain Neoplasms;CRISPR library;CRISPR screen;CRISPR/Cas technology;Cancer Model;Cause of Death;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Communication;Development;Disease;Engineering;Epithelial Cells;Epithelium;Genetic;Genetic Screening;Genomics;Goals;Human;Immune;In Vitro;Information Dissemination;Interruption;Invaded;Investigation;Knock-out;Libraries;Life;Liquid substance;Lymphoid;Malignant Neoplasms;Mass Spectrum Analysis;Metastatic malignant neoplasm to brain;Microglia;Modeling;Molecular;Molecular Profiling;Mus;Neoplasm Metastasis;Neuroimmune;Occupational activity of managing finances;Organism;Organoids;Pathway interactions;Patients;Pattern;Peptides;Phagocytes;Physiological;Play;Positron-Emission Tomography;Post-Translational Protein Processing;Production;Proliferating;Protein Analysis;Protein Glycosylation;Proteome;Proteomics;Qualifying;Research;Resources;Sampling;Scientist;Signal Transduction;Study models;Survival Rate;T-Lymphocyte;Techniques;Technology;Therapeutic;Tissue Banks;Tissues;Tumor-Associated Process;Vision;brain tissue;candidate identification;cell motility;cytokine;empowerment;experience;experimental study;functional genomics;glycoproteomics;glycosylation;improved;in vitro Model;induced pluripotent stem cell;innovation;insight;migration;neoplastic cell;neuropathology;new technology;next generation;novel;preservation;radiation response;reconstitution;response;synergism;tool;transcriptomics;tumor;tumor-immune system interactions;vaccine development;vaccine strategy TOOLKIT Core n/a NCI 10706501 9/7/23 0:00 RFA-CA-20-029 5U54CA261717-03 5 U54 CA 261717 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 9204 1927477 "KUO, CALVIN J" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 83944 65530 37616 PROJECT SUMMARY TOOLKIT COREThe majority of cancer-related deaths are caused by metastatic disease highlighting the glaring deficiency inour understanding of the processes of tumor dissemination. Research is substantially hampered by lack ofphysiologically-relevant tumor models and molecular tools necessary for discovering life-saving therapies. TheStanford Brain Metastasis Consortium (SBMC) is focused on identifying the genetic underpinnings regulatingbrain metastases a disease with limited treatment options and meager survival rates. In support of this goal theToolkit Core provides innovative experimental solutions from leading experts in organoid modeling (Dr. CalvinKuo) genomic functional screens (Dr. Michael Bassik) and glycoproteomics (Dr. Sharon Pitteri) to executethe projects proposed within the SBMC.The Toolkit Core team has diverse yet complementary areas of expertise and is qualified to specifically addressthe unmet needs outlined in this RFA: Metastasis Research Network by providing novel experimental organoidmodels and cutting-edge CRISPR and proteomic tools for characterizing and manipulating the poorlyunderstood signaling nodes driving brain metastatic disease. Specifically the Kuo lab will provide patient andmurine-derived brain metastatic 3D organoids to study radiation response in Project 1 explore the intricatecrosstalk between metastatic epithelium and the immune microenvironment in Projects 1 and 2 and developnovel lymphoid organoids for modeling T-cell priming in Project 3. The Bassik lab will provide innovativeCRISPR tools for targeted genetic screens in Project 1 to explore the interaction between tumor-associatedmicroglia and metastatic epithelial cells along with engineering iPSCs for Project 3 to develop vaccine strategiesfor brain metastasis. The Pitteri lab will provide proteomic analysis for Projects 13 to characterizeglycosylation patterns and features in brain metastatic tissue and organoids thus providing critical biologicalinsights into metastatic disease. Together these resources will empower the diverse investigations of the SBMCtoward improved therapeutic approaches. +No NIH Category available 3-Dimensional;Ablation;Adoptive Transfer;Air;Antigen Presentation;Antigen-Presenting Cells;Antigens;Antitumor Response;Autologous;Biological Assay;Brain;Brain Drains;Brain Neoplasms;Breast;Breast Cancer Cell;CD8-Positive T-Lymphocytes;Cancer cell line;Cell Communication;Cells;Cephalic;Cytotoxic T-Lymphocytes;Data;Distal;Drops;Exhibits;Flow Cytometry;Future;ITGAM gene;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunomodulators;Immunosuppression;Immunotherapy;Infiltration;Injections;Interferon Type II;Interruption;Intracranial Neoplasms;Kidney;Knock-out;Knockout Mice;Lesion;Liquid substance;Lung;Lymphocyte;Malignant Neoplasms;Measurement;Measures;Mediating;Metastatic malignant neoplasm to brain;Modeling;Monitor;Mus;Myelogenous;Myeloid Cells;Neoplasm Metastasis;Neuroimmune;Organoids;Pathologic;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Pluripotent Stem Cells;Positron-Emission Tomography;Production;Prognosis;Proliferating;Role;Signal Transduction;Site;Skin;Specimen;Splenocyte;T cell clonality;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;Testing;Therapeutic;Transforming Growth Factor beta;Transgenic Mice;Tropism;Tumor-associated macrophages;Vaccinated;Vaccination;Vaccines;anti-PD-1;anti-PD1 therapy;anti-tumor immune response;cancer cell;cancer infiltrating T cells;cytotoxic;design;draining lymph node;immune checkpoint;immune checkpoint blockade;immunoregulation;induced pluripotent stem cell;inhibitor;insight;lung cancer cell;lymph nodes;melanoma;migration;mouse model;novel;personalized immunotherapy;reconstitution;recruit;spatiotemporal;subcutaneous;synergism;treatment strategy;tumor;tumor progression;vaccination strategy Optimizing systemic immunotherapy for personalized brain metastasis treatment n/a NCI 10706497 9/7/23 0:00 RFA-CA-20-029 5U54CA261717-03 5 U54 CA 261717 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 9202 9245419 "LIM, MICHAEL " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 347313 271125 155637 ABSTRACT PROJECT 3By definition when patients develop brain metastasis (BM) from their systemic cancer they become stage IVand their prognosis drops to under a year. While the mechanism behind brain-tropism of different tumors (Project1) and the role of resident immune cells in supporting brain metastasis (Project 2) need to be elucidated thereis also a gap in our understanding of how brain tumors represent an inflection point in patient survival and anti-tumor response. We have previously observed evidence of intracranial metastases dampening the immuneresponse mounted by cytotoxic T lymphocytes. Understanding the mechanism by which tumor-associatedmacrophages (TAMs) recruited to BMs exert said immunosuppression is crucial for the successful treatment ofbrain metastasis. We propose to study the role of TAMs in dampening T cell priming via a TGF- mediatedpathway. We hypothesize that TGF- released by TAMs in the BM act at the level of the draining lymph nodesto induce global immunosuppression. We believe that blockade of TGF- at the lymph nodes will augment anantitumor immune response induced by checkpoint-blockade or vaccination strategies (such as with inducedpluripotent stem cells or iPSCs). To test our hypothesis we will investigate the: i) migration of TAMs to BMs andtumor draining lymph nodes and its effects on T cell priming ii) role of TGF- secreted by the TAMs in mediatingsaid immunosuppression at the level of the draining lymph nodes and iii) synergy of inhibiting TGF- signalingand iPSC vaccines to treat BMs. We expect that the data generated from these studies will provide novel insightsinto a previously unexplored mechanism by which BM-infiltrating TAMs exert systemic immunosuppression andopen new avenues for the design of future therapeutic strategies to treat patients with brain metastasis. +No NIH Category available 3-Dimensional;Affect;Air;Animal Model;Anti-CD47;Antigen Presentation;Architecture;Biological Assay;Bone Marrow Transplantation;Brain;Brain Neoplasms;Busulfan;CD47-SIRP;CRISPR library;CSF1 gene;Cell Communication;Cell Death;Cells;Cerebrospinal Fluid;Circulation;Clustered Regularly Interspaced Short Palindromic Repeats;Coculture Techniques;Complex;Data;Disease Progression;Disseminated Malignant Neoplasm;Distant;Epithelium;Evaluation;Exhibits;Extracellular Matrix;Generations;Genes;Growth;Human;Immune;Immunologic Surveillance;Immunological Models;Immunotherapy;Inflammatory;Inflammatory Response;Interleukin-6;Interruption;Intrinsic factor;Invaded;Knock-out;Knowledge;Ligands;Liquid substance;Macrophage;Macrophage Activation;Malignant Neoplasms;Measures;Mediating;Messenger RNA;Metalloproteases;Metastatic malignant neoplasm to brain;Methods;Microglia;Modeling;Monitor;Mus;Myeloid Cells;Neoplasm Metastasis;Neuroimmune;Neurologic;Organoids;Phagocytosis;Phenotype;Population;Positioning Attribute;Primary Neoplasm;Production;Prognosis;Proliferating;Property;Protocols documentation;Publishing;RNA analysis;Recurrence;Resistance;Role;Sampling;Signal Transduction;T-Cell Activation;T-Lymphocyte;Technology;Testing;Therapeutic;Tumor Cell Invasion;Tumor Immunity;Tumor-associated macrophages;cancer cell;cytokine;human disease;immune cell infiltrate;implantation;in vitro Model;innovation;migration;mortality;multidisciplinary;neoplastic cell;neuropathology;novel;novel strategies;receptor;single-cell RNA sequencing;small molecule;transcriptome;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;weapons Investigate and inhibit microglia support of brain metastases n/a NCI 10706495 9/7/23 0:00 RFA-CA-20-029 5U54CA261717-03 5 U54 CA 261717 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 9201 10312066 "HAYDEN GEPHART, MELANIE " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 355555 277560 159330 1 ABSTRACT PROJECT 2 2 Brain metastases are highly aggressive treatment resistant malignancies with debilitating neurological sequelae 3 and a grave prognosis. Efforts to understand and modulate the metastatic brain tumor microenvironment (TME) 4 have great therapeutic potential. Studies have suggested that polarization of macrophages (M1 or M2) may be5 helpful or harmful in cancer progression (1 2). Microglia the brains myeloid cells function in immune 6 surveillance and mediate the tumor-related inflammatory response including within the context of the metastatic 7 brain tumor microniche (tumor-associated macrophages and tumor-associated microglia). We hypothesize 8 brain metastases are supported in part by native microglia (3) and that these interactions can be 9 manipulated for therapeutic benefit. The role of microglia in brain metastases has been difficult to investigate10 given the relative inaccessibility of brain metastases samples inability to isolate human tumor-associated11 microglia or monitor their interactions within the TME and lack of models that include or allow manipulation of12 microglia while still reliably recapitulating the human disease. To overcome these critical hurdles we employ the13 following innovative methods: (i) single cell RNA-sequencing (scRNA-seq) on fresh human brain metastases14 and normal surrounding brain (Neuropathology Core)(4 5); (ii) isolation and dynamic array sequencing of cell15 free messenger RNA (cfRNA) from human cerebrospinal fluid (6 7); (iii) generation of human and murine-derived16 brain metastasis 3D air-liquid interface (ALI) organoids that include tumor-associated microglia/macrophages17 (Toolkit Core); and (iv) repopulation of microglia with circulation derived microglia-like cells (CDMCs) with18 greater than 90% efficiency throughout the entire brain. These four innovative methods allow us to investigate19 the role of tumor-associated microglia in human brain metastases model immune cell interactions and20 manipulate their function in an animal model of metastatic malignancy. Our multidisciplinary team is uniquely21 positioned to test the following three aims: (1) Test the extent to which tumor-associated microglia create an22 immunosuppressive TME supporting brain metastasis. In addition to relating microglia function to brain23 metastasis local recurrence and distant progression we will cross-reference our findings with cancer cell intrinsic24 factors (Project 1) and systemic macrophage reactivity (Project 3); (2) Model tumor-associated microglia within25 the brain metastatic TME using ALI organoids. We will model tumor and tumor-associated microglia/macrophage26 interactions and determine the impact of immunotherapy on microglia/macrophage activation and phagocytosis27 T-cell activation states and cell death. Our findings will be integrated with expanding knowledge of cell-intrinsic28 factors (Project 1) and brain-periphery immune interactions (Project 3); (3): Determine how high efficiency29 microglia replacement with CDMCs inhibits brain metastasis. We will replace microglia with weaponized30 CDMCs to inhibit cancer cell implantation and disease progression.31 +No NIH Category available 3-Dimensional;Address;Advanced Malignant Neoplasm;Anti-CD47;Biological;Biological Models;Brain;Brain Neoplasms;Cells;Cellular Tropism;Characteristics;Clinical;Complement;Computer Models;Data;Data Set;Disease Progression;Early Diagnosis;Foundations;Genes;Genomic Instability;Genomics;Goals;Growth;Immune;Immunologic Surveillance;Incidence;Interruption;Link;Macrophage;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Metastatic Neoplasm to the Central Nervous System;Metastatic malignant neoplasm to brain;Microglia;Modeling;Molecular;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Neuroimmune;Neurologic;Operative Surgical Procedures;Organoids;Outcome;Pathway interactions;Patients;Peripheral;Play;Prediction of Response to Therapy;Primary Neoplasm;Prognostic Marker;Radiation;Radiation Tolerance;Radiation therapy;Recording of previous events;Resected;Resources;Risk;Role;Sampling;Selection for Treatments;Statistical Models;Testing;Treatment Efficacy;Treatment outcome;Tropism;biobank;brain cell;cancer genome;cancer type;cell type;differential expression;functional status;genomic biomarker;genomic data;genomic predictors;genomic signature;high risk;imaging modality;in vitro testing;insight;mortality;multiple omics;neuropathology;predictive marker;predictive modeling;pressure;programs;radioresistant;response;screening;standard of care;translational study;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Determine the mechanisms of acquired brain-tropism n/a NCI 10706493 9/7/23 0:00 RFA-CA-20-029 5U54CA261717-03 5 U54 CA 261717 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 9200 8471415 "JI, HANLEE P" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 347715 271439 155817 ABSTRACT PROJECT 1For patients with advanced cancer 30% will be afflicted with brain metastases the cause of devastatingneurologic morbidity and mortality. As a result the incidence of brain metastasis is 170000 new cases per ayear. For screening MRI is the preferred imaging modality for brain metastasis but is prohibitively expensiveand lacks relevant molecular information. We lack predictive models to identify patients at high risk for brainmetastases for screening as treatment efficacy and morbidity are linked to early detection. Treatment involvessurgery and radiotherapy but with a noticeable lack of prognostic or predictive biomarkers for diseaseprogression or treatment. Our central hypothesis is that there are common intrinsic features to the tumor andextrinsic features to the brain microenvironment relevant for cancer brain tropism and response to therapies.We will determine these features association to microglia (Project 2) and peripheral immune surveillance(Project 3) leveraging biological models to test these discoveries. We will identify intrinsic cellular genomicfeatures relevant for brain metastasis that can be generalized across many primary tumor types. Likewise wehypothesize there are extrinsic features of the tumor cellular milieu in the brain that facilitate the seeding andmaintenance of these metastases. (1) For determining extrinsic cellular tropism we will characterize the immunecell types states and function in the brain metastasis tumor microenvironment. Using single cell genomics wewill determine the distribution and functional status of the TME microglia and macrophages across different tumortypes that have CNS metastasis. In parallel using three dimensional organoids we will determine the TME-based macrophage response to anti-CD47 a potent modulator of macrophage function. Our results willdetermine the cellular genomic characteristics and functional status of TME macrophages/microglial cells andtheir regulatory states. (2) For intrinsic tropism factors we will analyze genomic features of the primary tumorand extrinsic features of the brain that indicate increased propensity for brain metastasis. We will conductgenomic sequencing analysis on matched primary and metachronous brain metastasis with complete treatmentexposure patient history. With this data we will determine critical cancer genome features such as the extent ofgenomic instability intratumoral clonal diversity treatment selection pressure and TME immune cell compositionthat are associated with brain metastatic risk. Our results will identify genomic biomarkers indicative of increasedrisk of brain metastasis across different tumor types. (3) Finally we will use the overlapping data set for intrinsicgenomic factors to determine if there are predictive genomic signatures of radioresistant brain metastases. Wehypothesize there are specific genomic features of primary tumors that are radiotherapy predictors. Theseresults may yield potential candidates for increasing sensitivity to this mode of treatment that can be tested invitro. +No NIH Category available Accountability;Adherence;Advocate;Basic Science;Brain;Cancer Patient;Cementation;Collaborations;Communication;Communities;Consultations;Data;Data Analyses;Effectiveness;Ensure;Equity;Ethics;Foundations;Future;Generations;Goals;Grant;Human;Human Subject Research;Individual;Interruption;Malignant Neoplasms;Metastatic malignant neoplasm to brain;Neuroimmune;Occupational activity of managing finances;Office of Administrative Management;Participant;Patients;Policies;Postdoctoral Fellow;Process;Productivity;Program Development;Research;Research Design;Research Personnel;Resources;Science;Scientist;Self-Examination;Services;Specimen;Statistical Data Interpretation;Structure;Training;Translational Research;Universities;Work;data management;design;improved;innovation;meetings;next generation;organizational structure;programs;statistical service;success;timeline Administrative and Data Management Core n/a NCI 10706492 9/7/23 0:00 RFA-CA-20-029 5U54CA261717-03 5 U54 CA 261717 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 9199 10312066 "HAYDEN GEPHART, MELANIE " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 218047 170216 97710 ABSTRACT ADMINISTRATIVE AND DATA MANAGEMENT COREThe Administrative Core of the Stanford Brain Metastasis Consortium (BMC) is structured to enhance efficiencyquality and productivity while promoting integrated and effective collaboration and communication amongConsortium participants network partners our local community cancer networks and the public in general.BMCs Administrative Core aims to minimize the administrative burden of Consortium activities and servicescentralize statistical consultation (study design and data interpretation) cement integration of projects throughregular meetings communicate accomplishments to the community via Patient Advocates and encouragemetrics-driven continuous improvement of all Consortium functions.We have unified brain and cancer experts in the singular goal of improving our understanding and treatment ofbrain metastases. To accomplish the above goal we have: (1) designed an organizational structure that supportsscientists in our integrated Projects enhancing efficiency and productivity within both the BMC and greaterStanford University network; (2) established policies and practices that ensure accurate data-based self-evaluation for continuous improvement and developed communication channels with scientists patients andcompanies most likely to benefit from and build upon our results; (3) created a seed grant program driven by theunderlying goals of quality equity innovation efficiency and effectiveness.In summary the Administrative and Data Management Core will provide fully integrative administrative servicesfor the management communications coordination and financial administration of the BMC MetNet Center. TheCore will ensure productive collaborations through efficient management active reflection and strongcommunication leveraging the expert administrative and financial management resources of StanfordUniversity ensuring Stanford Brain Metastasis Consortiums generation of outstanding high impact research. +No NIH Category available Address;Advocate;Biology;Brain;Brain Neoplasms;CRISPR library;Cancer Patient;Clinical;Clinical Trials;Communication;Communities;Data;Dedications;Deterioration;Development;Diagnostic;Disease model;Ensure;Exclusion;Experimental Models;Foundations;Goals;Human;Immune system;Immunotherapy;In Vitro;Incidence;Interruption;Malignant Neoplasms;Mediator;Metastatic malignant neoplasm to brain;Methods;Microglia;Modeling;Molecular;Mus;Neoplasm Metastasis;Neuroimmune;Neurologic;Office of Administrative Management;Organoids;Patient risk;Patients;Physicians;Primary Neoplasm;Production;Productivity;Quality of life;Research;Sampling;Scientist;Site;Specimen;Technology;Testing;Therapeutic;Translating;Translations;Tropism;Tumor Tissue;Work;brain cell;data management;design;experience;glycoproteomics;high throughput screening;human disease;human tissue;improved;in vivo Model;innovation;insight;interest;multidisciplinary;neoplastic cell;neuropathology;new therapeutic target;novel;organizational structure;programs;synergism;therapy resistant;tool;tumor;tumor microenvironment Deconvolution and interruption of the cancer-neuro-immune axis facilitating brain metastases NARRATIVE OVERALL COMPONENTThe Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improvingour understanding and treatment of brain metastases a currently increasing yet underserved subset of cancerpatients. To accomplish the above goal we have developed highly innovative and complementary Projects tounderstand and disrupt the cancer-neuro-immune axis supporting brain metastases and created ResearchCores to make human specimens and cutting-edge technologies readily accessible to participating scientists.We expect to identify and target key mediators of brain metastasis with therapeutic benefit for patients. NCI 10706491 9/7/23 0:00 RFA-CA-20-029 5U54CA261717-03 5 U54 CA 261717 3 "GRIL, BRUNILDE M" 9/21/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y(M1) 10312066 "HAYDEN GEPHART, MELANIE " Not Applicable 16 NEUROSURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1476762 NCI 1152816 661760 1 ABSTRACT OVERALL COMPONENT 2 3 The development of brain metastases experienced by up to 40% of cancer patients marks a clear inflection 4 point in survival and quality of life. The inaccessibility of brain tumor tissue has stymied progress in our 5 understanding and treatment of brain metastases and patients are regularly excluded from clinical trials. The 6 Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improving our 7 understanding and treatment of brain metastases a currently increasing yet underserved subset of cancer 8 patients. To accomplish the above goal we have: (1) designed an organizational structure that supports 9 scientists in our integrated work; (2) developed highly innovative and complementary Projects to understand10 and disrupt the cancer-neuro-immune axis supporting brain metastases; and (3) created NeuroPathology11 and ToolKit Cores to make human specimens and cutting-edge technologies readily accessible to participating12 scientists. We expect to identify and target key mediators of brain metastasis with therapeutic benefit for13 patients.14 Little is known about the distinct mechanisms that drive tumor cells to the brain and allow them to grow in this15 unique microenvironment supported in part by normal brain cells. Streamlined access to human brain16 specimens combined with innovations in modeling and manipulation of the tumor microenvironment create this17 collaborative opportunity for fundamental advancement. Our expert integrated team of productive collaborators18 aims to understand how the intrinsic features of tumor cells (Project 1) resident microglia (Project 2) and the19 systemic immune system (Project 3) contribute to the onset and progression of brain metastases. These projects20 are facilitated by centralized access to human patient brain metastases samples (NeuroPathology Core) and21 novel multiplexed analyses and disease modeling (ToolKit Core). Our multidisciplinary physician Consultant22 Network provides clinical insight and helps in the rapid translation of our findings into clinical trials for patients23 with brain metastases. The Administrative and Data Management Core will provide the operational support24 necessary to successfully achieve the goals of the program. Our Patient Advocates help to integrate and25 communicate our work to the greater scientific and patient communities.26 We have formed one of the few groups with the expertise interest and capacity to address the underlying27 mechanisms of and therapeutic opportunities for brain metastases. Only through this combined synergy would28 this project be possible. These innovative methods will ensure our findings are reflective of and translatable to29 the human disease enabling our multidisciplinary team to lay the foundation for diagnostic and therapeutic30 advancements. 1476762 +Cancer; Networking and Information Technology R&D (NITRD); Radiation Oncology Automation;Benign;Brain;Characteristics;Classification;Code;Computer software;Computerized Medical Record;Data;Diagnosis;Diagnostic;Diagnostic Imaging;Dictionary;Health Insurance Portability and Accountability Act;Histopathology;Information Technology;Infrastructure;Laboratories;Licensing;Malignant - descriptor;Malignant Neoplasms;Manuals;Medical;Methods;Operative Surgical Procedures;Pathology;Pathology Report;Process;Radiation Oncology;Records;Registries;Reporting;SEER Program;Savings;Secure;Site;Source;System;Terminology;Text;Travel;base;cancer registrars;data management;data registry;electronic data;flexibility;neoplasm registry;operation;transmission process THE OVERALL SCOPE OF THIS REQUIREMENT IS TO SUPPORT AND MAINTAIN THE CURRENT ELECTRONIC PATHOLOGY REPORTING INFRASTRUCTURE INCLUDING MAINTAINING CONT n/a NCI 10706415 75N91020P00886-P00005-0-1 N02 9/26/20 0:00 9/25/23 0:00 77865903 "LLOYD, MARK " Not Applicable 14 Unavailable 65807152 HDMJWAC1CK23 65807152 HDMJWAC1CK23 US 27.945464 -82.504638 10038540 "INSPIRATA, INC." TAMPA FL Domestic For-Profits 336092771 UNITED STATES N R and D Contracts 2022 866300 NCI The overall scope of this requirement is to support and maintain the current electronic pathology reportinginfrastructure including maintaining continuity of electronic pathology reporting licenses for thefacilities listed in Attachment 2 SEER ePath Sites and to install and maintain new license installationsas required by the NCI to support the SEER program. 866300 +No NIH Category available Aberrant DNA Methylation;Adult;African American;African American population;Alcohol consumption;Alcohols;Anatomy;Biological Markers;Biopsy;Black race;Businesses;Cancer Burden;Cause of Death;Chronic;Classification;Clinical;Combined Modality Therapy;DNA;DNA Methylation;DNA Sequence Alteration;Data;Dental;Detection;Developed Countries;Development;Diagnosis;Diagnostic;Disparity;Distant;Early Diagnosis;Epigenetic Process;Etiology;Evaluation;Event;Exhibits;Frequencies;Gender;Gene Expression;Gene Silencing;Genes;Genetic;Genetic Predisposition to Disease;Genomics;Head and Neck Squamous Cell Carcinoma;Hospitals;Human Papillomavirus;Hypermethylation;Incidence;Infection;Inflammation;Latino;Lesion by Stage;Link;Location;Low Income Population;Malignant Neoplasms;Metastatic Neoplasm to Lymph Nodes;Methylation;Modification;Molecular;Monitor;Mutation;Newly Diagnosed;Oncogenes;Operative Surgical Procedures;Oral Diagnosis;Oral Stage;Outcome;PAX5 gene;Patients;Performance;Preventive;Primary Neoplasm;Process;Prognosis;Prognostic Marker;Promoter Regions;Publishing;Race;Recommendation;Recording of previous events;Recurrence;Research;Resource-limited setting;Risk;Saliva;Salivary;Small Business Innovation Research Grant;Specificity;Survival Analysis;Survival Rate;TP53 gene;Technology;Testing;The Cancer Genome Atlas;Tissues;Tobacco;Tumor Cell Invasion;Tumor Promotion;Tumor Suppressor Genes;United States;Virus Diseases;Visit;advanced disease;cancer health disparity;cancer subtypes;commercialization;cost;diagnostic accuracy;early detection biomarkers;epigenomics;genetic testing;health difference;high risk;improved;low and middle-income countries;low income country;malignant mouth neoplasm;methylation biomarker;methylation testing;methylome;molecular subtypes;mouth squamous cell carcinoma;patient stratification;personalized screening;premalignant;prevent;prognostic;prognostication;promoter;risk stratification;rural area;rural patients;rurality;saliva sample;salivary assay;screening;social health determinants;tobacco control;tobacco exposure;tumor Precision DNA methylation test to reduce oral cancer disparities in African Americans patients residing in low-resource settings NarrativeWe propose to examine the feasibility for the commercialization of the OralMethDX Test a rapid saliva test fororal cavity squamous cell carcinoma (OSCC) that enables the identification of patients with early-stage lesionsand advanced disease. A highly sensitive and specific precision screening test will reduce oral cancerdisparities in low-income populations worldwide. NCI 10706376 9/20/23 0:00 PA-22-176 1R44CA281719-01 1 R44 CA 281719 1 "ZHAO, MING" 9/20/23 0:00 2/29/24 0:00 Special Emphasis Panel[ZRG1-HSS-J(10)B] 8374819 "GUERRERO-PRESTON, RAFAEL " Not Applicable 98 Unavailable 968756119 GGR9ABCTBGG5 968756119 GGR9ABCTBGG5 US 18.417375 -66.061221 10029873 "LIFEGENE-BIOMARKS, INC." SAN JUAN PR Domestic For-Profits 9091833 UNITED STATES N 9/20/23 0:00 2/29/24 0:00 394 SBIR/STTR 2023 292486 NCI 195251 78100 Project SummaryA diagnosis of Head and neck squamous cell carcinoma (HNSCC) includes many cancer subtypes. We willfocus on the oral cavity squamous cell carcinoma (OSCC) subtype on the proposed project. OSCC is the 11thmost common malignancy in the world. Despite advances in treatments the 5-year survival rates for OSCChave not improved for the past 25 years. OSCC is a very aggressive tumor and the majority of patientsdisplays a locoregionally advanced disease at diagnosis for which multimodality therapy is required. Tumorinvasion lymph node metastasis and high rates of locoregional recurrence besides development of secondprimary tumors are the leading causes of death for OSCC patients. At least 50% of patients with locallyadvanced OSCC develop locoregional or distant relapses which usually occur within the first 2 years oftreatment completion. Treatment in high-quality hospitals is associated with improved survival for patients withOSCC. However African American patients are less likely to be treated in high-quality hospitals comparedwith non-Latino white patients in US as well as poor patients worldwide. Most HNSCC cases worldwide aredetected at later stage of cancer because screening is not routinely conducted leading to disparities atdiagnosis based on rurality race and gender which can be reduced by targeted screening. OSCC is one ofthe tumors in which the most glaring disparities exist worldwide. The dramatic disparity in incidence ratesbetween high- and low-income countries is due primarily to differential access to effective screening and pre-cancer or preventive treatment. Similar disparities also exist within developed countries like the US wherethe burden of OSCC is highest in low-income populations. OSCC molecular screening should be included indental visits for adults because early detection of OSCC is associated with better survival. The development ofOSCC is a multistep process requiring the accumulation of multiple DNA alterations influenced by a patient'sgenetic predisposition as well as by environmental influences including tobacco alcohol chronicinflammation and infection with Human Papilloma Virus. DNA alterations consist of two major types:alterations in tumor suppressor genes which promote tumor development when inactivated; and alterations inoncogenes which promote tumor development when activated. Tumor suppressor genes can be inactivatedthrough genetic events or by epigenetic modifications such as DNA methylation. Gene silencing by aberrantDNA methylation is an important epigenetic event in cancer development and progression which has greatpotential as a biomarker for early diagnosis tumor molecular subtyping prognosis monitoring and therapy. Inthis Fast Track SBIR project we propose to demonstrate the feasibility for the commercialization of a precisionDNA methylation test the OralMethDx Test to stratify patients at high risk of OSCC. Our business plan is toevaluate the performance of the OralMethDx Test for two separate indications: A saliva test for riskstratification in screening and early detection; and tissue biopsy test for diagnosis and prognostication. 292486 +No NIH Category available 3-Dimensional;Acceleration;Address;Animal Model;Antibiotics;Attenuated;Bacteria;Bacterial Genes;Bacteriophages;Biosensor;CT26;Cancer Model;Cell Death;Cells;Chemoresistance;Coculture Techniques;Colon;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Complex;Computer Models;Coupled;Development;Disease Progression;Dose;Engineered Gene;Engineering;Environment;Feedback;Fusobacterium nucleatum;Genes;Goals;Growth;Homing;Human body;Hypoxia;Immunologic Surveillance;In Situ;In Vitro;Intelligence;Libraries;Malignant Neoplasms;Mammalian Cell;Methods;Microbe;Microscopy;Modeling;Monitor;Mus;Necrosis;Oncogenic;Organism;Oxygen;Patients;Peptides;Phase;Plasmids;Population;Postdoctoral Fellow;Prevalence;Production;Proliferating;Rapid screening;Repression;Research;Research Project Grants;Research Proposals;Risk;Role;Salmonella typhimurium;Solid Neoplasm;Specificity;System;Technology;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;Toxic effect;Treatment Efficacy;Tropism;Tumor Promotion;Tumor Tissue;Work;cancer cell;cancer therapy;clinical candidate;clinical translation;colorectal cancer progression;colorectal cancer treatment;commensal microbes;cytotoxic;delivery vehicle;dynamic system;effective therapy;gut microbes;gut microbiota;improved;in vivo;microbial;microbiome research;microbiota;mouse model;next generation;novel;novel strategies;pathogen;response;sensor;skills;spatiotemporal;synthetic biology;therapeutic candidate;therapy outcome;tool;tumor;tumor hypoxia;tumor microbiota;tumor microenvironment;tumor progression Engineering tumor-targeting bacteria to sense and deliver therapeutics Project NarrativeThe engineering of living cells as programmable therapeutic system is poised to transform therapeutic paradigmsparticularly for cancer where some bacteria selectively colonize solid tumors. A central challenge for developingliving microbial therapies is the inaccessibility to study this dynamical system consisting of interacting populationsof bacteria and cancer cells. This research proposal leverages 3D multicellular coculture technologies and syn-thetic biology tools to engineer novel bacterial systems that sense and express therapeutics specifically in tumors. NCI 10706350 8/28/23 0:00 RFA-CA-19-057 5K00CA253756-04 5 K00 CA 253756 4 "DAMICO, MARK W" 8/10/20 0:00 8/31/26 0:00 ZCA1-SRB-H(M1) 16004342 "HARIMOTO, TETSUHIRO " Not Applicable 5 NONE 82359691 LN53LCFJFL45 82359691 LN53LCFJFL45 US 42.369697 -71.11193 3212901 HARVARD UNIVERSITY CAMBRIDGE MA ORGANIZED RESEARCH UNITS 21385369 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 88627 NCI 82062 6565 Project SummaryThe ability to engineer living cells as intelligent therapeutic agents is poised to transform current cancer treatmentparadigms. Based on the inherent growth specificity of some natural and exogenous bacteria to solid tumorsmicrobes have been explored as programmed vehicles to deliver therapeutics to tumor environments. Howevera universal challenge for developing this next-generation living therapy is the lack of tools to study the dynami-cally interacting population of bacteria and cancer cells. Consequently the vast majority of the past studies haverelied on animal models that only test a handful of therapeutic candidates and provide limited spatiotemporalinformation. To address this challenge I have recently developed a 3D multicellular coculture platform that ena-bles high-throughput characterization of bacteria in tumor spheroids assessing dynamics of multicellular inter-actions and predicting therapeutic efficacy in vivo. In this proposal I will leverage the 3D coculture technologies and synthetic biology tools to construct novelbacterial systems that sense and express therapeutics specifically in tumors. In the F99 phase I will engineertumor-homing bacteria to dynamically regulate production of cytotoxic molecules in response to tumor shrinkage.Specifically as the cancer cell death increases the level of oxygen in the tumor core I will engineer a bacterialbiosensor circuit to monitor this change in the tumor microenvironment. By detecting rises in oxygen levelswhich indicate extensive therapeutic progression this gene circuit will reduce the therapeutic level producedminimizing off-target toxicity. In the K00 phase I will repurpose tumor-homing bacteria to target and eradicateoncogenic F. nucleatum in colorectal cancer. I will apply the 3D coculture platform to screen anti-F. nucleatumpeptides delivered by bacteria to tumor spheroids. Orthotropic mouse cancer models will be used to assess theF. nucleatum elimination effect on commensal microbiota and cancer progression. Collectively the proposedwork will utilize a novel engineering framework to develop effective bacterial cancer therapies towards clinicaltranslation. 88627 +No NIH Category available Advocate;Agreement;Area;Award;Benign;Bioinformatics;Biological Specimen database;Biometry;Bispecific Antibodies;Cancer Research Project;Clinic;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Communities;Complement;Comprehensive Cancer Center;Development;Early Diagnosis;Faculty;Fostering;Foundations;Functional disorder;Funding;Genetic;Goals;Grant;Group Meetings;Hematologic Neoplasms;Immune response;Individual;Infrastructure;Institution;Integration Host Factors;Interdisciplinary Study;Joints;Laboratories;Malignant - descriptor;Malignant Neoplasms;Mayo Clinic Cancer Center;Mentors;Mentorship;Minority;Multiple Myeloma;NCI-Designated Cancer Center;Patients;Peer Review;Peer Review Grants;Prevention;Productivity;Prognosis;Publications;Regimen;Research;Research Personnel;Research Project Grants;Research Proposals;Research Support;Resources;Risk;Series;Site;System;Training Activity;Translating;Translational Research;Tumor Biology;Vesicular stomatitis Indiana virus;Virotherapy;Wages;Woman;base;candidate selection;career;clinical database;design;high risk;improved;innovation;interest;multidisciplinary;multiple omics;novel;programs;sound;success;survivorship;translational cancer research;translational scientist;tumor microenvironment Career Enhancement Program PROJECT NARRATIVEThe purpose of this program is to support and mentor young investigators at the junior faculty level so that theycan become outstanding translational investigators with a primary focus on multiple myeloma. Each individualselected for the project is provided 2 years of salary support ($50000 per year). Each awardee is expected tospend the 2 years engaged in multiple myeloma translational research under the aegis of a suitable mentor.Again support for only one of these individuals is being requested by the grant. Developmental funds from theMayo Comprehensive Cancer Center will. NCI 10706335 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9195 6878806 "FONSECA, RAFAEL " Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 133293 90234 47932 PROJECT SUMMARYThe Career Enhancement Program is designed to increase the translational investigator base in the MayoMyeloma SPORE by identifying and fostering the early careers of young investigators who have an interest inmultiple myeloma translational research. In particular this program provides much-needed support forpromising young laboratory or clinical investigators early in their careers so that they can focus their energieson research projects related to multiple myeloma research. The SPORE CEP provides $50000 for one year($90000 from SPORE funds and institutional support of $50000 from the Mayo Clinic cancer Center) for 2-3awards per year. A second year of support is possible based on progress and successful re-competition.Mayo as part of its commitment through the Mayo Comprehensive Cancer Center has agreed to match thesefunds. The Career Enhancement Program makes maximal use of the scientific expertise within the Mayocommunity. The Career Enhancement Program Committee is responsible for organizing the program andreviewing research proposals as submitted. During the prior funding period (years 1-5) the SPORE hassupported 12 investigators each for 1 year. All of them remain involved in translational research in myelomaand related hematologic malignancies and 10 of 12 are still involved in our SPORE and one is at another NCIdesignated Cancer Center.During the next funding period the SPORE will maintain: a stringent candidate selection system that encourages applications from minorities and women comprehensive trainee guidance by a mentor support through a scientific mentor group (the Individual Trainee Mentorship Committee) comprised of investigators with expertise in each trainees area of interest multi-disciplinary research courses and on-going training activities such as the Multidisciplinary Cancer Seminar Series and Myeloma Group meetings encouragement of collaboration with investigators at all Mayo sites opportunities for further research enhancement through the Developmental Research Program and fullProjects. +No NIH Category available Affect;Anemia;Anti-Inflammatory Agents;Automobile Driving;BIRC2 gene;BRAF gene;Benign;Blood;Bone Marrow;CDKN2C gene;Cells;Chromosome abnormality;Chronic;Clinic;Clinical;Clinical Trials;Collection;Combined Modality Therapy;Cytogenetics;DNMT3a;Data;Diagnosis;Disease;Early Diagnosis;Early intervention trials;Early treatment;Enhancers;Enrollment;Event;FGFR3 gene;Genetic;Growth;Heart Diseases;Hematopoiesis;Hypercalcemia;IL6 gene;Immunoglobulin Genes;Individual;Inflammation;Intervention;Intervention Trial;KRAS2 gene;Kidney Failure;Lesion;Life;Lymphoma;MAP Kinase Gene;MDM2 gene;Malignant - descriptor;Malignant Neoplasms;Molecular Abnormality;Monoclonal gammopathy of uncertain significance;Multiple Myeloma;Mus;Mutation;Myeloid Cells;NF-kappa B;NF1 gene;Nature;Organ;Outcome;PTPN11 gene;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Plasma Cell Neoplasm;Plasma Cells;Population;Prevention;Prognosis;Proteins;RB1 gene;Recurrence;Reporting;Research;Risk;Role;Sampling;Subgroup;TNF receptor-associated factor 3;TP53 gene;TRAF2 gene;Time;Tumor Burden;biobank;bone;clinical biomarkers;cohort;disability;gene translocation;high risk;immune modulating agents;improved;inflammatory marker;malignant state;mouse model;mutant;next generation sequencing;novel therapeutics;pre-clinical;prevent;progression risk;prospective;randomized clinical trials;therapeutic target;treatment response;tumor microenvironment Project 3: Early detection and prevention of MM progression PROJECT NARRATIVERecent data suggests that the early detection and treatment of multiple myeloma results in improved clinicaloutcomes. The proposed research will develop a genetic definition of multiple myeloma that will improve earlydetection. This will lead to early treatment aimed at reducing illness preventing disability and prolonging life. NCI 10706331 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9193 9046430 "CHESI, MARTA " Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 380400 285176 110626 PROJECT SUMMARYMultiple myeloma (MM) is a malignant plasma cell neoplasm leading to anemia hypercalcemia renalinsufficiency and bone lesions. It is preceded by a common benign monoclonal plasma cell expansion calledmonoclonal gammopathy of undetermined significance (MGUS) that shares the same initiating events seen inMM. These include recurrent immunoglobulin gene translocations and hyperdiploidy. There is a third clinicalentity in between these two smoldering multiple myeloma (SMM) in which there has been more extensiveplasma cell expansion than MGUS but the malignant features of MM are not seen. This project is focused onusing genetics to more precisely demarcate benign from malignant plasma cells and develop a patho-geneticdefinition of MM. We hypothesize that an accumulation of secondary genetic events mark the progression froma benign to malignant state. These events involve a handful of pathways common to many cancers:MYC/MAX MAPK (NRAS KRAS BRAF FGFR3 PTPN11 NF1) NFKB (TRAF3 TRAF2 CYLD BIRC2/3MAPK3K14) TP53/MDM2 RB1/CDKN2C Others (DIS3 FAM46C). One of these pathways is dysregulated in>95% of MM and <5% of MGUS and we postulate that individually or in combination they can be used todefine malignant plasma cells. There is also increasing evidence of a role of the tumor microenvironment inprogression of SMM and recently clonal hematopoiesis has been associated with increased inflammation andmore rapid progression of MM. We will use next generation sequencing to identify clonal hematopoiesis and tocharacterize the genetic events present in patients with MGUS SMM and MM and correlate these with theclinical course. We will validate our findings in an independent cohort of patients with SMM enrolled onprospective randomized clinical trials. Ultimately we hope that a genetic definition will allow both the earlydetection and prompt treatment of MM resulting in the prevention of the malignant consequences of MM andprolonged survival for patients. +No NIH Category available Alaska Native;American Indians;Area;Basic Science;Biometry;Cancer Center Planning Grant;Cancer Research Project;Cessation of life;Cherokee Indian;Clinical;Clinical Sciences;Collaborations;Colorectal Cancer;Development;Disparity;Early Diagnosis;Endowment;Epidemiology;Etiology;Face;Faculty;Feedback;Foundations;Fred Hutchinson Cancer Research Center;Functional disorder;Funding;Goals;Government;Grant;Health Services;Incidence;Infrastructure;Institution;Investments;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Manuscripts;Medical center;Monitor;Morbidity - disease rate;Native-Born;Outcome;Patients;Persons;Phase;Population;Population Study;Prevention;Primary carcinoma of the liver cells;Prognosis;Program Research Project Grants;Quality of life;Reporting;Research;Research Personnel;Research Project Grants;Research Proposals;Resources;Scientist;Site;Source;Structure;Talents;Texas;Therapeutic;Translational Research;Travel;Universities;Washington;Woman;Work;anticancer research;cancer health disparity;cancer therapy;design;disparity elimination;ethnic diversity;experience;feasibility testing;gender diversity;improved;innovation;interest;malignant breast neoplasm;medical schools;meetings;member;men;mortality;multidisciplinary;novel;programs;racial diversity;research study;survivorship;translational approach;translational goal;tribal health Developmental Research Program While deaths related to lung breast prostate and colorectal cancer have declined dramatically by 40-53%between 1990 and 2016 hepatocellular carcinoma (HCC) is the only major malignancy whose mortality is risingin both men and women and has had the highest average annual percentage change. American Indian/AlaskaNative (AI/AN) people face a disproportionally high burden of HCC with 2.4 times higher HCC incidence and 2.5times higher HCC-related mortality than white persons. Our aim is to apply novel innovative translationalapproaches to surveillance and early detection of HCC that are informed by unique aspects of HCCpathophysiology and epidemiology in AI/AN people in order to eliminate disparities improve early detection andultimately reduce HCC-related mortality. NCI 10706329 8/24/23 0:00 RFA-CA-19-034 5P20CA252732-03 5 P20 CA 252732 3 9/6/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 9192 8615691 "IOANNOU, GEORGE " Not Applicable 7 Unavailable 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA Domestic Higher Education 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 63883 41109 22815 ABSTRACT: DEVELOPMENTAL AND RESEARCH PROGRAM COREThe Developmental Research Program (DRP) of the Liver Cancer in American Indians/Alaska Natives (AI/AN)Disparities (Li-CAD) P20 Program will support early-phase projects that have the potential to open new areas oftranslational liver cancer research and ultimately contribute to reducing morbidity and mortality and improvingquality-of-life for patients with hepatocellular carcinoma (HCC). Projects funded under the DRP are intended torapidly advance a new idea or concept that has the potential to substantially impact our understanding of livercancer to eliminate disparities and improve surveillance early detection and treatment of HCC in AI/AN personsand thereby reduce or eliminate HCC-related mortality. The infrastructure of the DRP will establish mechanismsto quickly respond to translational research opportunities within the Li-CAD P20 Program institutions that requiresupport to advance hypotheses or confirm feasibility in order to justify larger resource investments.Developmental projects will include research in basic science clinical science and population-based studiesand will build collaborations between Li-CAD sites and other institutions with P20 Programs and SPOREs in livercancer and disparities research.Developmental projects may encompass a wide range of liver cancer research and treatment areas includingbasic science etiology and prevention (primary and secondary) early detection prognosis therapeutics andsurvivorship. Collectively the DRP is structured to strengthen collaborations between Li-CAD sites and initiateinteractions with other institutions with P20 Programs and SPOREs in liver cancer. DRP proposals will besupported based on their potential to mature an original idea or concept into a translational research project thatwill successfully attain independent funding either within a subsequent P50 or from other government orfoundation sources. In addition the DRP is designed to attract senior investigators with diverse scientificexpertise and junior investigators new to translational liver cancer research.The Specific Aims for the Developmental Research Program are to: 1. Stimulate the development of innovative impactful early-phase research studies that include multidisciplinary interactions with basic clinical and population scientists across the Li-CAD institutions; 2. Provide funding (1-2 years) and infrastructure (e.g. biospecimens biostatistical support) to rapidly test the feasibility of original investigator-initiated projects in all areas of HCC research; 3. Prioritize funding to rapidly exploit new opportunities or support specific areas of strategic importance for advancing the translational research goals of the Li-CAD P20 Program; and 4. Monitor (and facilitate) the progress of each DRP project and consider their advancement to a full P50 SPORE project. +No NIH Category available Accounting;Address;Atlases;Automobile Driving;Biological;Blood;Bone Marrow;Caring;Cells;Clinic;Clinical;Clinical Data;Clinical Trials;Collaborations;Complex;Complex Analysis;Core Facility;DNA;DNA sequencing;Data;Data Analyses;Data Analytics;Data Set;Disease;Disease Outcome;Environment;Epigenetic Process;Event;Evolution;Generations;Genes;Genetic;Genome;Genomics;Goals;Immune;Immuno-Chemotherapy;Immunophenotyping;Individual;Link;Maps;Marrow;Mass Spectrum Analysis;Mononuclear;Multiomic Data;Multiple Myeloma;Mutation;Network-based;Outcome;Pathogenesis;Pathway interactions;Patients;Pattern;Phase II Clinical Trials;Phenotype;Pilot Projects;Population;Positioning Attribute;Process;Proteome;RNA;Relapse;Resistance;Resolution;Resources;Rewards;Role;Sampling;Sampling Studies;Series;Specimen;Technology;Time;Variant;Work;biobank;bioinformatics tool;clinical database;clinical phenotype;clinical risk;data integration;data resource;deep learning;design;drug sensitivity;epigenome;experience;gene environment interaction;gene interaction;high risk;high risk population;immunoregulation;improved;insight;lipidome;mRNA sequencing;metabolome;multidisciplinary;multiple omics;neoplastic cell;patient population;personalized approach;response;single cell analysis;therapeutically effective;transcriptome;transcriptomics;translational clinical trial;treatment response;tumor;tumor-immune system interactions;ultra high resolution;whole genome Project 2: Multi-Omics of high-risk MM PROJECT NARRATIVEWhile our studies have confirmed the significant role of the disrupted genome in Multiple Myeloma (MM) theyhave also re-emphasized the gaps in understanding and the importance of immune regulation and gene-environment interaction. To address this we will leverage a carefully studied and homogeneously treated high-risk group of double hit patients to create the first unbiased multi-omics atlas of MM. We will perform a seriesof complex analyses to identify MM-associated changes in and across the genome transcriptome epigenomeimmune environment proteome lipidome and metabolome. This will reveal insights into biological pathwaysinfluencing MM responsiveness to therapy and subsequent outcomes and create the High Definition MMScientific resource a unique data compendium derived from blood and marrow samples linked to a detailedclinical trial data set. NCI 10706328 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9191 10011530 "BRAGGIO, ESTEBAN " Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 322219 270878 65971 PROJECT SUMMARY/ABSTRACTWhile our own extensive studies have confirmed the significant role of the disrupted genome in MultipleMyeloma (MM) they have also re-emphasized the gaps in understanding and the importance of immuneregulation and gene-environment interaction. It is indeed likely that the evolution of MM both before or duringtherapy is the result of a complex interplay of biological perturbations driven by genetic changes andenvironmental influences. Our past work has also demonstrated that studying small numbers of patients atgreat depth can be as rewarding for scientific understanding as studies of superficial genomic events inthousands of patients. Thus we will strive to generate the first longitudinal translational clinical trial andcomprehensive data resource of environmental genetic interactions for the highest-risk MM population. It isthese patients who continue to rapidly fail highly effective therapeutics for reasons which are still completelyopaque. New and bold approaches using state-of-the-art technology are required to reverse this decades-oldlack of progress.Our hypothesis is that analysis of data capturing gene-environment interactions at high resolution will revealinsights into biological pathways influencing MM responsiveness to therapy and subsequent outcomes. Firstwe will leverage a carefully studied and homogeneously treated high-risk group of double hit patients in aPhase 2 clinical trial with large control clinical databases and bio-repositories to derive for each patient adetailed map of environmental gene interactions linked to clinical outcome over time. Second we will perform aseries of complex analyses to identify MM-associated changes in and across the genome transcriptomeepigenome immune environment proteome lipidome and metabolome. Third we will study these samples atthe highest resolution technically feasible today and seek to define gene-environment interaction changesover time that associate with response to therapy. Finally high resolution data capturing these interactionchanges and clinical response data will be linked to improve our understanding of the mechanisms underlyingMM variability among patients in regards to disease outcomes. This comprehensive resource will enable amore individualized approach to clinical surveillance and therapy for MM. +No NIH Category available Antibodies;Antibody Therapy;Antibody titer measurement;Cell Death;Cells;Clinic;Clinical;Combined Modality Therapy;Cyclophosphamide;Cytolysis;Cytotoxic T-Lymphocytes;Data;Disease remission;Dose;Engineering;Frequencies;Funding;Gene Expression Profile;Goals;Grant;Hematologic Neoplasms;Hour;Immune;Immune response;Immune system;Immunosuppression;Infection;Inflammation;Inflammation Mediators;Inflammatory;Infusion procedures;Interferon-beta;Interferons;Intravenous;Intravenous infusion procedures;Kinetics;Lymphoma;Measures;Mediating;Modality;Modeling;Monitor;Multiple Myeloma;Mutation;Normal tissue morphology;Oncolytic;Patients;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Phase Ib Clinical Trial;Positron-Emission Tomography;Radiation therapy;Regimen;Regulatory T-Lymphocyte;Research Personnel;SLC5A5 gene;Safety;Saliva;Seroprevalences;Serum;Signal Transduction;Specificity;Systemic Therapy;T cell response;T-Cell Lymphoma;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Tracer;Tumor Antigens;Urine;Vesicular stomatitis Indiana virus;Viral;Viral Genome;Viremia;Virotherapy;Virus;Virus Diseases;anti-PD-1;anti-PD1 antibodies;anti-tumor immune response;cancer therapy;cell killing;exhaustion;exome;first-in-human;human study;immune checkpoint blockade;immune modulating agents;intravenous administration;mouse model;neoantigens;neoplastic cell;novel;oncolytic Vesicular Stomatitis Virus;oncolytic virotherapy;pharmacodynamic biomarker;pharmacokinetics and pharmacodynamics;pre-clinical;response;therapy outcome;transcriptome sequencing;tumor Project 1: Optimizing a VSV-based virotherapy-based regimen for advanced MM PROJECT NARRATIVELive replication competent viruses propagate specifically in tumors causing cell death and activation of thehost immune system to ideally induce long term tumor control. Here we have engineered a replicatingVesicular Stomatitis Virus to infect tumor cells specifically. The virus has been given by intravenous infusion topatients with myeloma with no safety concerns. In this grant we propose to combine virotherapy with drugs.The goal is to inhibit the immune system transiently to allow the virus to infect and spread in the tumorfollowed by addition of immune enhancing antibody or radiation therapy to enhance overall therapeuticoutcome. The timing and sequencing of these immune modulating drugs will be tested in this proposal as wellas the safety and immune responses to the virus and tumor. NCI 10706326 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9190 6192205 "LACY, MARTHA Q" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 279766 295740 0 PROJECT SUMMARYOncolytic virotherapy is a two-stage therapy. In the oncolytic phase (short-lived) the infection spreads in thetumor killing infected cells and inflaming the microenvironment. In the immune phase (prolonged) priming andamplification of tumor-specific cytotoxic T cells (CTLs) by inflammatory mediators and phagocytosed debrisfrom dead or dying tumor cells leads to killing of uninfected tumor cells. VSV-IFN-NIS is a fast-replicatingoncolytic Vesicular Stomatitis Virus (VSV) that causes inflammatory tumor cell killing. During the first MyelomaSPORE funding period we launched an investigator initiated first-in-human study of single dose single agentintravenous (IV) VSV-IFN-NIS in patients with hematological malignancies. There is good tolerability andencouraging signs of antitumor activity. Extensive correlative analyses have been conducted to characterizethe kinetics of the antitumor immune responses and their relationship to patient-specific baseline parameters.During the second Myeloma SPORE funding period we seek to maximize the potency of intravenousVSVIFN-NIS therapy by combining (i) repeat virus administration (ii) early suppression of the antiviralimmune response and (iii) late boosting of antimyeloma T cells by using a combination of immune suppressionand immune activating regimens with the overall goal to achieve a durable response using VSV virotherapy inpatients with multiple myeloma. +No NIH Category available Address;Alaska Native;American Indians;Bayesian Method;Biological Markers;Biometry;Biostatistics Core;Blinded;Cessation of life;Colorectal Cancer;Communication;Communication Methods;Communities;Data Analyses;Data Element;Data Management Resources;Data Scientist;Data Set;Data Sources;Development;Early Diagnosis;Ensure;Epidemiology;Evaluation;Evaluation Studies;Face;Functional disorder;Funding;Future;Goals;Guidelines;Health Sciences;Hepatitis B Virus;Home;Incidence;Individual;Institution;International;Leadership;Machine Learning;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Methods;Modeling;Mutation;Native-Born;Pathology;Patients;Persons;Phase;Play;Population;Primary carcinoma of the liver cells;Public Health;Publications;Reporting;Reproducibility;Research;Research Design;Research Personnel;Resources;Role;Screening for Hepatocellular Cancer;Screening for cancer;Services;Statistical Data Interpretation;Systematic Bias;Validation;Visualization software;Woman;Work;biobank;biomarker development;biomarker discovery;cancer health disparity;clinical application;clinically relevant;cohort;computerized data processing;data harmonization;data management;data visualization;design;disparity elimination;early detection biomarkers;experience;improved;innovation;interest;malignant breast neoplasm;men;mortality;novel;prospective;risk prediction model;sample collection;translational approach Biostatistics Core While deaths related to lung breast prostate and colorectal cancer have declined dramatically by 40-53%between 1990 and 2016 hepatocellular carcinoma (HCC) is the only major malignancy whose mortality is risingin both men and women and has had the highest average annual percentage change. American Indian/AlaskaNative (AI/AN) people face a disproportionally high burden of HCC with 2.4 times higher HCC incidence and 2.5times higher HCC-related mortality than white persons. Our aim is to apply novel innovative translationalapproaches to surveillance and early detection of HCC that are informed by unique aspects of HCCpathophysiology and epidemiology in AI/AN people in order to eliminate disparities improve early detection andultimately reduce HCC-related mortality. NCI 10706325 8/24/23 0:00 RFA-CA-19-034 5P20CA252732-03 5 P20 CA 252732 3 9/6/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 9189 2110020 "FENG, ZIDING " Not Applicable 7 Unavailable 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA Domestic Higher Education 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 94220 94315 0 ABSTRACT: BIOSTATISTICS COREThe Biostatistics Core (BC) will support the study design data processing and analysis needs for individualprojects as well as enhance interactions among all the projects in the P20. Experience has shown thatinvolvement of biostatisticians and data scientists from the concept phase yields studies that are betterdesigned more likely to answer the scientific questions of interest and ultimately more compelling in theirconclusions. The goal of the Biostatistics Core is to support the investigators through all phases of their studiesfrom design to publication via the following Specific Aims.Specific Aim 1: Study DesignThe BC will employ the 5-phase early detection biomarker development guideline as well as the PRoBE studydesign standards in order to help the P20 team establish a road map and research strategies for improvingliver cancer early detection in AI/AN patients. The use of the 5-phase guideline will allow P20 investigators tostrategize and make long-term plans helping move biomarkers from discovery phases 1-2 to validation phases3-5 fulfilling the translational continuum. Adhering to PRoBE standards will guide the study design driven byintended clinical application reducing systematic bias and ensuring a high likelihood of reproducible andclinically relevant study conclusions.Specific Aim 2: Analysis and InterpretationThe BC will play a leadership role in statistical analysis and interpretation for the proposed Li-CAD P20 projects.The BC will identify and implement quantitative methods to address the scientific questions of interest andprovide valid statistical inferences about the evidence addressing the various study hypotheses. For exampleParametric Empirical Bayesian (PEG) and Multivariate Fully Bayesian (mFB) approaches will be used to modellongitudinal biomarkers which will be used to build risk prediction models for the early detection of HCC in AI/ANpopulation. Additionally data visualization will be conducted to investigate HBV mutations and state-of-the-artmachine learning approaches will be utilized to develop and validate HCC risk prediction models in AI/ANpersons. The BC will also work with study investigators to clearly communicate methods and results in studypublications and insure that reported conclusions are justified.Specific Aim 3: Promote Interactions with DRP and Other CoresThe BC will interact with the DRP as well as the Biospecimen and Pathology Core to ensure efforts within theLi-CAD P20 are on track including all proposed P20 projects as well as DRP projects. The BC leader willcommunicate directly with the P20 Executive Committee to ensure any decision that has statistical implicationshas appropriate and timely inputs from the Core. +No NIH Category available Address;Area;Award;Basic Science;Bioinformatics;Biological;Biological Specimen database;Biometry;Cell model;Clinic;Clinical;Clinical Management;Clinical Sciences;Clinical Trials;Collaborations;Collection;Common Data Element;Communities;Complement;Complex;Consultations;Core Facility;Correlative Study;Country;Data;Data Analyses;Data Collection;Data Element;Data Management Resources;Data Set;Data Sources;Databases;Development;Ensure;Experimental Designs;Faculty;Funding;Future;Genes;High Performance Computing;In Vitro;Individual;Informatics;Information Management;Infrastructure;Institution;K-Series Research Career Programs;Laboratories;Laboratory Study;Machine Learning;Malignant Neoplasms;Mayo Clinic Cancer Center;Methodology;Modeling;Monitor;Multiomic Data;Multiple Myeloma;Outcome Measure;Pathway Analysis;Pathway interactions;Patient Care;Patients;Phase;Problem Solving;Procedures;Publications;Quality Control;Research;Research Design;Research Personnel;Scientist;Security;Source;Specific qualifier value;Specimen;Statistical Data Interpretation;System;Techniques;Testing;Time;Translating;Translational Research;Work;archive data;bioinformatics infrastructure;career development;clinical database;computerized data processing;data archive;data handling;data integration;data management;data resource;data sharing;data standards;deep learning;design;experience;genetic variant;high risk;in vivo;informatics infrastructure;innovation;instrument;member;mouse model;multidimensional data;multiple omics;novel;programs;research and development;research study;statistics;synergism;tool;tumor registry;web portal Biostatistics & Bioinformatics Core PROJECT NARRATIVEThe Biostatistics & Bioinformatics Core will provide the SPORE Investigators access to statistical andbioinformatics expertise that includes state-of-the-art statistical analysis; bioinformatics preprocessinganalysis and interpretation; novel methodology development; and data management resources. It provides amechanism for consistent and compatible data handling among all projects and ensures analysis acrossSPORE projects is accomplished in a timely manner. In providing centralized statistical bioinformatics anddata management support this Core enables synergies and efficiencies for programmatic initiatives beyondwhat can be achieved with individual statistical and bioinformatics teams for each project. NCI 10706323 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9188 6854103 "GEYER, SUSAN MICHELLE" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 167372 176929 0 PROJECT SUMMARY/ABSTRACTThe Biostatistics & Bioinformatics Core (BSI) is responsible for all statistical bioinformatics and datamanagement activities for each of the SPORE projects the developmental research and career developmentprojects and the cores. The BSI not only supports the projects and cores but also solves problems thereforeserves the broader scientific community. The Core deliberately leverages and builds upon strong existinginstitutional infrastructure as well as infrastructure created during the prior funding cycle of this SPORE byproviding investigators access to statistical and bioinformatics expertise and extensive Mayo Clinic CancerCenter (MCCC) and Division of Biomedical Statistics and Informatics infrastructure. Each of the projectspresented in this application reflects input from members of the BSI on the design and an appropriate analysisplan. The research studies will be conducted across different platforms with different data management needsfrom in vitro cell models and in vivo murine models to phase Ib/II adaptive clinical trials to multi-omicscorrelative studies of biospecimens from clinical trials and an existing tumor registry. Biostatisticians willprovide statistical expertise including experimental design for laboratory studies and clinical trials.Bioinformaticians will provide support for data preprocessing quality control annotations and long-termstorage and planning future analysis needs. Biostatisticians and Bioinformaticians will work together oncorrelative studies involving clinical trial specimens and modeling and analyses of all data. The BSI employs acomplex array of tools and approaches in the space of machine-learning/deep-learning network analysis andhigh-performance computing to address the significant challenges in analyzing integrating and interpretingmulti-omics datasets; Members of the BSI in consultation with the biostatistics and bioinformatics faculty in theDivision of Biomedical Statistics and Informatics will explore develop and implement appropriate designs andanalyses to address the aims of the individual projects. The Core will oversee the data management andintegration of existing and newly collected data through consistent and compatible data handling. In additionmembers of this Core will complement and assist the efforts of other Cores such as the Biospecimens &Clinical Database Core with superior data management and experience with institutional databases. Thestrengths of the Biostatistics & Bioinformatics Core are our collaborative relationships with each of the projectsand cores established in the prior funding cycle; the operational statistical and bioinformatics infrastructuresalready in place in the MCCC and the Division of Biomedical Statistics and Informatics; and the diverse andextensive statistical and bioinformatics experience of the Core members. Overall the Biostatistics &Bioinformatics Core builds upon the innovative and time-tested procedures and systems developed by one ofthe largest statistical and bioinformatics groups in the country which has supported more than 13000 clinicaltranslational and basic science research studies since 1966. +No NIH Category available Accelerometer;Adherence;Adolescent and Young Adult;Aftercare;Age;Behavior Therapy;Biological Assay;Biological Markers;Blood;Cancer Burden;Cardiometabolic Disease;Cardiomyopathies;Cardiopulmonary;Caring;Cellular Phone;Chronic;Communities;Competence;Control Groups;Data;Devices;Dyslipidemias;Enrollment;Evaluation;Exercise;Fasting;Fatigue;Future;Goals;Guidelines;Health;Health Insurance;Health behavior;Health education;Heart Rate;Home;Hospitals;Inflammatory;Instagram;Insulin Resistance;Insurance;Intervention;Interview;Knowledge;Lipids;Maintenance;Mediating;Mediation;Modeling;Morbidity - disease rate;Obesity;Participant;Patient Self-Report;Patients;Pediatric Oncology Group;Phase;Physical Function;Physical activity;Physiological;Pilot Projects;Population;Privatization;Procedures;Quality of life;Randomized;Randomized Controlled Trials;Research;Rest;Risk;Rural;Sampling;Site;Social Functioning;Support Groups;Survivors;Text;Treatment Efficacy;adipokines;behavioral health intervention;cancer therapy;cardiometabolic risk;cardiometabolism;cardiovascular health;childhood cancer survivor;comparison control;cost;design;disparity reduction;efficacy evaluation;efficacy testing;exercise intervention;fitbit;fitness;glucose metabolism;health disparity;health related quality of life;heart rate monitor;improved;indexing;instrument;intervention participants;intervention refinement;mHealth;medical specialties;patient subsets;peer;peer support;personalized approach;physical inactivity;portability;predictive marker;preference;primary outcome;psychologic;randomized trial;recruit;secondary outcome;sedentary;social;social media;survivorship;tool;uptake;virtual A Randomized Trial of a Mobile Health and Social Media Physical Activity Intervention Among Adolescent and Young Adult Childhood Cancer Survivors PROJECT NARRATIVEChildhood cancer survivors are generally sedentary and have a lifelong increased risk of chronic healthconditions post-treatment that would be improved by physical activity. This project in adolescent and youngadult childhood cancer survivors evaluates the efficacy of a physical activity intervention consisting of awearable activity tracker (i.e. Fitbit) integrated with individualized goal setting and a private Instagram accountto increase physical activity improve biomarkers of cardiovascular health and improve quality of life. Ifefficacious this portable and scalable intervention would be a much-needed tool to reduce the morbidity fromcancer treatment and improve quality of life among survivors in the months years and decades after treatmentends. NCI 10706322 8/15/23 0:00 RFA-CA-19-033 5U01CA246665-05 5 U01 CA 246665 5 "CZAJKOWSKI, SUSAN" 9/19/19 0:00 8/31/24 0:00 ZCA1-RTRB-E(A1) 7753669 "KADAN-LOTTICK, NINA S" "MENDOZA, JASON A" 98 NONE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC ORGANIZED RESEARCH UNITS 200570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 541058 NCI 455208 85850 PROJECT SUMMARYInterventions to increase physical activity (PA) are vitally needed in adolescent and young adult childhood cancersurvivors (AYA survivors) who are largely inactive but are at lifelong elevated risk of cardiomyopathy insulinresistance and other cardiometabolic disorders. To reach AYA survivors their desire for peer connectionsalmost ubiquitous use of smartphones and social media and strong preferences to exercise in their homes andcommunities and as part of social activity must be leveraged. The intervention must also be accessible andaffordable for patients without private health insurance as they are less likely to receive survivorship care andmore likely to have greater morbidity. The transdisciplinary study team has completed two recent pilot studiesamong AYA survivors that provide substantial scientific premise for the proposed research by demonstratingthat the intervention is feasible has high rates of uptake and adherence and appears promising for increasingPA. The proposed multi-site randomized controlled trial (RCT) will enroll 384 AYA survivors currently ages 15.0-20.9 years who are 3-36 months off therapy and not meeting PA guidelines. The 12-month trial will test theefficacy of a 6-month intensive multi-level PA intervention combining a wearable Fitbit PA tracker (intrapersonallevel) with integration of activity data leading to individualized goal setting by text (intrapersonal level) and aprivate Instagram account serving as a virtual peer support group of survivors (interpersonal and communitylevel) followed by a 6-month maintenance phase to improve PA in AYA survivors. Given the ubiquity of PAtracking devices and apps the control group will receive the Fitbit only without integration of Fitbit data in otheractivities. A nationwide sample of patients drawn from rural urban community and academic centers will berecruited using the Childrens Oncology Group consortium of >200 hospitals. This rigorously designed multi-siteRCT will test the efficacy of the mobile health (mHealth) behavioral intervention compared to the control groupto achieve the following Specific Aims among AYA survivors over 12 months: Aim 1 - To increase PA; Aim 2 -To improve biomarkers predictive of cardiometabolic health; and Aim 3 - To improve health-related quality of life.Analyses of hypothesized mediation factors for Aims 1-3 and post-trial qualitative interviews among participantswith and without private health insurance will provide explanatory knowledge to help refine interventionprocedures and tailor the intervention for future RCTs among patient subgroups who will most benefit. If shownto be efficacious this mHealth intervention to improve PA in AYA survivors is highly scalable becausesmartphones and social media are widespread PA trackers are popular and affordable goal setting can beautomated and social media activities do not require specialized staff. 541058 +No NIH Category available Algorithms;Aliquot;Area;Arizona;Bioinformatics;Biological;Biological Specimen database;Biometry;Blood;Blood specimen;Bone Marrow;Bortezomib;COVID-19 pandemic;Cancer Center;Classification;Clinic;Clinical Data;Clinical Research;Clinical Trials;Collection;Data;Data Collection;Data Set;Databases;Dedications;Development;Disease;Early Diagnosis;Electronics;Florida;Funding;Geographic Locations;Goals;Grant;Individual;Information Systems;Infrastructure;Institution;Institutional Review Boards;K-Series Research Career Programs;Laboratories;Light-Chain Immunoglobulins;Link;Medicine;Metadata;Monoclonal gammopathy of uncertain significance;Multi-Institutional Clinical Trial;Multiple Myeloma;Natural Language Processing;Outcomes Research;Pathogenesis;Pathology;Patient Recruitments;Patients;Performance;Plasma Cells;Prevention;Process;Protocols documentation;Quality Control;Records;Regimen;Research;Research Personnel;Research Project Grants;Resources;Risk Factors;Safety;Sampling;Services;Specimen;System;Time;Tissue Banks;Translational Research;Tumor Tissue;Vesicular stomatitis Indiana virus;Virotherapy;Visit;Waldenstrom Macroglobulinemia;archive data;base;career;clinical database;clinical practice;clinical translation;data archive;data handling;data harmonization;design;high risk;innovation;migration;multiple omics;peripheral blood;primary amyloidosis of light chain type;programs;research and development;therapy outcome;translational study;treatment response;user-friendly Biospecimen & Clinical Database Core PROJECT NARRATIVEEffective myeloma research requires blood and tumor tissue connected to patient records for translationalresearch. The Biospecimens Pathology & Clinical Database Core coordinates all specimen-related researchfor projects in the Myeloma SPORE. This Core has developed new innovations in natural language processingthat will enable investigators to expand myeloma research in the next funding period. NCI 10706319 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9186 6878806 "FONSECA, RAFAEL " Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 428116 405870 44168 PROJECT SUMMARY/ABSTRACTThis Biospecimens Pathology and Clinical Database Core will not only furnish essential services for theindividual projects by managing patient data safety and samples but it will provide a link between clinical dataand research outcomes and interface with the Biostatistics and Bioinformatics Core to allow for formalinteractions between existing datasets to develop relational networks. It will accomplish its goals by integratingwith and building upon existing successful infrastructure housed at the Mayo Clinic making the Core anefficient integral component of this SPORE.The significant patient referral base and clinical practice at the Mayo Clinic (>10000 patient visits annually withmultiple myeloma and related conditions) will allow substantial patient recruitment to the clinical trials andtranslational studies in this Mayo SPORE in multiple myeloma. The already extant 12000+ bone marrowsamples in our Biospecimens Core make SPORE and DRP projects possible. The on-going initiative ofcollecting data and research specimens from additional myeloma patients will feed into all SPORE projects andmake Development Research and Career Development Award Programs possible. The Aims of the Core are: 1. to provide support for collection transport processing and storage of samples; 2. to supply the data system infrastructure to track all SPORE patients and samples; 3. to provide coordination and oversight of distribution of samples to SPORE investigators; and 4. to serve as a resource of expertise collaborative support and service for full projects as well as Career Enhancement and Developmental Research Awardee research.This Core provides a mechanism of consistent and compatible data handling thereby facilitating managementof collected data and integration with data from existing Mayo resources. Areas of data support includedatabase development data form development and processing quality control data collection and entry anddata archiving. This Core is unique not only in its scope and potential but also in that it will be built on existing(but currently unfunded) tissue banking facilities and processes at the Mayo Clinic in Rochester and in Arizonaguaranteeing successful performance. Finally the Core will interface with the clinical research components ofother SPORE grantees and cancer centers to facilitate multi-institutional clinical research arising out of nationalmyeloma research efforts. +No NIH Category available Abbreviations;Alaska Native;American Indians;Biological;Categories;Cessation of life;Cirrhosis;Colorectal Cancer;Development;Early Diagnosis;Epidemiology;Face;Feasibility Studies;Foundations;Functional disorder;Genetic;Genotype;HBV Genotype;Hepatitis B Infection;Hepatitis B Virus;Incidence;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Modeling;Mutation;Native-Born;Patients;Persons;Pilot Projects;Primary carcinoma of the liver cells;Protocols documentation;Randomized Controlled Trials;Reporting;Research;Risk;Risk Factors;Role;Testing;Ultrasonography;Veterans Health Administration;Woman;cancer health disparity;clinically significant;cost effective;disparity elimination;high risk;imaging modality;improved;individual patient;innovation;machine learning algorithm;malignant breast neoplasm;men;mortality;novel;patient stratification;prospective;risk stratification;screening;surveillance strategy;translational approach Risk stratification strategies and abbreviated MRI-based surveillance for early detection of HCC in high-risk AI/AN patients While deaths related to lung breast prostate and colorectal cancer have declined dramatically by 40-53%between 1990 and 2016 hepatocellular carcinoma (HCC) is the only major malignancy whose mortality is risingin both men and women and has had the highest average annual percentage change. American Indian/AlaskaNative (AI/AN) people face a disproportionally high burden of HCC with 2.4 times higher HCC incidence and 2.5times higher HCC-related mortality than white persons. Our aim is to apply novel innovative translationalapproaches to surveillance and early detection of HCC that are informed by unique aspects of HCCpathophysiology and epidemiology in AI/AN people in order to eliminate disparities improve early detection andultimately reduce HCC-related mortality. NCI 10706318 8/24/23 0:00 RFA-CA-19-034 5P20CA252732-03 5 P20 CA 252732 3 9/6/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 9185 8615691 "IOANNOU, GEORGE " Not Applicable 7 Unavailable 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA Domestic Higher Education 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 200664 183820 17030 ABSTRACT: PROJECT 2. Risk Stratification and abbreviated MRI-based surveillanceThis translational project will first investigate further the clinical significance of an HCC pathogenetic mechanismthat we described which is particularly important in AI/AN patients i.e. HBV genotype-specific mutations. Wewill then use AI/AN-specific HCC risk factors described by our group (including HBV genotype and genotype-specific mutations) to develop AI/AN-specific HCC Risk Calculators for HCC risk stratification and risk-basedsurveillance. Finally we will use HCC Risk Calculators to identify high-risk patients for more intensivesurveillance strategies using abbreviated MRI which will be tested in a pilot and feasibility RCT. The project willaccomplish the following specific aims:SA1. Investigate the role of genotype-specific HBV mutations in the development of HCC in Alaska Nativepatients: Determine the development of HBV genotype-specific mutations in AN patients with different HBVgenotypes prior to the occurrence of HCC compared to appropriate controls without HCC and the excess HCCrisk associated with these mutations.SA2. Develop and validate HCC Risk Calculators in AI/AN patients with HBV or cirrhosis using biological anddemographic predictors specific to AI/AN patients for the purpose of risk stratification identification of high-riskpatients and personalized HCC surveillance strategies.SA3. Perform a pilot and feasibility randomized controlled trial of abbreviated MRI (aMRI) versusultrasonography (US) for HCC screening in 200 AI/AN patients who have high HCC risk.SIGNIFICANCE. This project will set the foundation for precision HCC screening based on estimating HCCrisk in individual patients using HCC Risk Calculators risk stratifying patients according to their HCC risk anddeveloping specific HCC surveillance strategies for different categories of HCC risk. This will be developed andpursued further in a subsequent P50 application +No NIH Category available Achievement;Advisory Committees;Advocate;Arizona;Awareness;Clinic;Collaborations;Communication;Communities;Detection;Development;Ensure;Florida;Fostering;Funding;Goals;Grant;Growth and Development function;Guidelines;Infrastructure;Leadership;Methods;Multiple Myeloma;Occupational activity of managing finances;Patients;Prevention;Procedures;Reporting;Reproduction spores;Research;Research Activity;Research Personnel;Research Project Grants;Site;Structure;System;Teleconferences;Translational Research;Translations;Work;career;design;operation;organizational structure;programs;systematic review Administrative Core PROJECT NARRATIVEThe Administration Core provides administrative support for all SPORE research activities and assures there isexcellent communication between all Mayo sites all participating investigators and staff and the NCI. TheAdministration Core also ensures the patient advocates participation in annual retreats and their inclusion in allkey decisions. The Core is a necessary component for a successful SPORE. NCI 10706317 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 9184 1967810 "BERGSAGEL, PETER LEIF" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 116873 87759 33854 PROJECT SUMMARY/ABSTRACTThe overall goal of the Mayo Clinic Multiple Myeloma SPORE (SPORE) Administration Core is to stimulateresearch in myeloma and to expedite the translation of discoveries into new and better methods of preventiondetection and treatment of myeloma. The Administration Core has served well as the organizational hub ofSPORE during the prior funding period. During the next grant period it will continue to provide anorganizational structure designed to coordinate the activities of the research projects scientific cores anddevelopmental programs (Developmental Research Program Career Enhancement Program). TheAdministration Core will be responsible for coordinating the function of the SPORE committees including theExecutive Committee the External Advisory Committee and the Patient Advocate Group. Drs. Leif Bergsageland Vincent Rajkumar will serve as Co-Directors of the Administration Core. Bergsagel and Rajkumarfunctioned well as a team during the prior funding period and will continue to work collaboratively to provideoversight of SPORE activities. The Administration Core will: 1) Provide leadership organizational support and financial management for SPORE investigators 2) Coordinate communication and collaboration between Mayo Clinic Arizona Rochester and Florida including support for exchange of ideas between investigators design of new projects conduct of translational research and reporting of translational research findings 3) Provide information transfer to the scientific community and the public 4) Provide leadership and organizational support for interactions with the External Advisory Committee as well as external and internal review for SPORE research projects 5) Provide the structure for the establishment and nurture of collaborations to facilitate and expand myeloma research including interactions between Mayo sites 6) Work closely with SPORE patient advocates so that they are aware of the progress of the SPORE and facilitate their ability to provide input at all levels 7) Foster young investigator development 8) Communicate with the NCI. +No NIH Category available Adjuvant;Adjuvant Therapy;Adoption;Binding;Bioinformatics;Biological Markers;Biopsy;California;Cancer Biology;Categories;Cessation of life;Characteristics;Clear Cell;Clear cell renal cell carcinoma;Clinical;Clinical Trials;Collaborations;Complex;Copper;Coupled;Data;Development;Discipline;Disease;Disease-Free Survival;Educational workshop;Electron Transport;Environment;Excision;Future;Gene Expression;Gene Proteins;Genes;Goals;Histologic;Immunohistochemistry;Immunotherapy;Individual;Inductively Coupled Plasma Mass Spectrometry;K-Series Research Career Programs;Kidney Neoplasms;Knowledge;Laboratories;Laboratory Scientists;Los Angeles;Major Histocompatibility Complex;Malignant Neoplasms;Measurement;Measures;Mentors;Mentorship;Metabolic;Metabolic Pathway;Metformin;Methods;Mitochondria;Molecular;Molecular Sieve Chromatography;Necrosis;Neoplasm Metastasis;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Population;Postoperative Period;Primary Neoplasm;Prognosis;Prognostic Marker;Publishing;Quantitative Reverse Transcriptase PCR;Recurrence;Recurrent Malignant Neoplasm;Relapse;Renal Cell Carcinoma;Renal carcinoma;Research;Research Personnel;Respiration;Ribosomal Proteins;Risk;Risk Assessment;Risk Reduction;Sampling;Serum;Specific qualifier value;Staging System;Stratification;The Cancer Genome Atlas;Therapeutic Clinical Trial;Tissues;Tobacco smoking behavior;Toxicant exposure;Training;Transcript;Translational Research;Tyrosine Kinase Inhibitor;United States Food and Drug Administration;Universities;Validation;Vascular Endothelial Growth Factors;biomarker development;biomarker identification;biomarker validation;cancer recurrence;career;career development;clinically relevant;cohort;cytochrome c oxidase;early experience;experience;experimental study;functional genomics;genetic signature;high risk;immunological status;improved;improved outcome;inhibitor;metabolomics;molecular marker;novel;novel therapeutic intervention;novel therapeutics;patient stratification;precision medicine;predictive modeling;prognostic;prognostic signature;prognostic significance;prognostic value;prospective;relapse risk;side effect;skills;transcriptome sequencing;transcriptomics;translational approach;translational cancer research;tumor Combination of Transcriptomic and Metallomic Biomarkers for Risk Assessment in Locoregional Clear Cell Renal Cell Carcinoma PROJECT NARRATIVEAlthough significant progress has been made in developing new drugs in kidney cancer there are no biomarkersto guide treatment decisions post-operatively in patients with localized kidney cancer. Majority patientsparticularly those with high-risk features in their tumors relapse after surgery; therefore making it necessary todevelop a biomarker to help identify these patients as well as to guide treatment in the adjuvant setting. In thisproposal I will investigate strategies to identify novel transcriptomic and metallomic biomarkers of poor-riskkidney cancer to determine if we can identify patients most likely to benefit from adjuvant therapies minimizeexposure of toxic drugs to those at low risk of recurrence and overall improve the outcomes of patients withkidney cancer. NCI 10706315 8/1/23 0:00 PA-20-203 5K08CA273542-02 5 K08 CA 273542 2 "BIAN, YANSONG" 9/16/22 0:00 7/31/27 0:00 Career Development Study Section (J)[NCI-J] 16171159 "GULATI, SHUCHI " Not Applicable 4 INTERNAL MEDICINE/MEDICINE 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 261072 NCI 241733 19339 PROJECT SUMMARYThe overall goal of this K08 Mentored Career Development proposal is to provide me with the essentialmentorship and career development opportunities necessary to become an independent investigator withexpertise in translational research. Kidney cancer is among the top ten most common cancers with an estimated76000 new cases every year in the Uniter States. Management of patients with localized or locally advancedclear cell renal cell carcinoma (ccRCC) involves surgical resection following which half of the patients will havea recurrence within five years. Adoption of adjuvant therapies to lower this risk has been poor due to inconsistentresults across trials. There is a lack of biomarkers to predict the recurrence risk accurately a critical barrier indirecting adjuvant therapies to this group of patients. This proposal will investigate novel translational approachesto identify patients at high risk of relapse after surgical removal of the primary kidney tumor. In Specific Aim 1 Ihypothesize that a prognostic transcriptomic signature comprised of genes corresponding to electron transportchain (ETC) mitochondrial ribosomal proteins (MRP) and major histocompatibility complex-II (MHC-II) will resultin stratification of localized ccRCC tumors into the two subtypes- those at risk of early relapse vs. not. In SpecificAim 2 I hypothesize that Cu-bound to mitochondrial cytochrome c oxidase (Cu-COX) measured by sizeexclusion chromatography inductively coupled plasma mass spectrometry will be indicative of mitochondrialrespiration and will be predictive of early relapse thus making for a simple and inexpensive biomarker. Inaddition we will be evaluating the clinical relevance of different pools of copper in serum as predictors of highcopper content in corresponding ccRCC tumors thus enabling a serum-based biomarker to detect aggressiveccRCC. Data generated from this proposal will allow me to perform additional research including validation ofthese biomarkers in larger studies development of novel clinical-trials to direct adjuvant therapies in a biomarkerspecified population at high risk of relapse and ultimately improve outcomes for patients with kidney cancer.University of Cincinnati provides me collaborative opportunities with several laboratory and clinical researchersthus making this an ideal environment to conduct my research while providing clinical and administrative support.My background in clinical and translational cancer research including experience in collaborating with laboratoryscientists and focus on biomarker development will help me to successfully attain my short-term goals includingtraining in the fields of cancer biology functional genomics and bioinformatics. To this end I have assembled ateam of mentors and advisors all of whom are expert investigators in these disciplines. To supplement mytraining aims I plan on completing relevant workshops. Through the K08 Career Development Award ProgramI will generate data and enhance knowledge and skills in translational research to submit an R01 applicationand ultimately transition to an independent investigator. 261072 +No NIH Category available Advocate;Area;Arizona;Basic Science;Benign;Bioinformatics;Biological Specimen database;Biology;Biometry;Bispecific Antibodies;Cancer Center;Cancer Research Project;Caring;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Complement;Comprehensive Cancer Center;Development;Early Diagnosis;Florida;Foundations;Functional disorder;Funding;Genetic;Goals;Immune response;Immunotherapy;Infrastructure;Institution;Integration Host Factors;International;Joints;Laboratories;Leadership;Malignant - descriptor;Minnesota;Multiple Myeloma;Ontario;Patients;Peer Review;Peer Review Grants;Phase I Clinical Trials;Prevention;Productivity;Prognosis;Publications;Regimen;Research;Research Personnel;Research Project Grants;Research Support;Resources;Risk;Site;Translating;Tumor Biology;Tumor Markers;Vesicular stomatitis Indiana virus;Virotherapy;Work;career;clinical database;clinical epidemiology;high risk;immunoregulation;improved;innovation;multiple omics;novel;oncolytic virotherapy;prognostic index;programs;sound;success;survivorship;translational cancer research;translational clinical trial;translational scientist;treatment optimization;tumor microenvironment;tumor-immune system interactions Mayo Clinic Multiple Myeloma SPORE PROJECT NARRATIVEThe Mayo Clinic Multiple Myeloma SPORE is a highly productive research program based at the NCI-designated Mayo Clinic Comprehensive Cancer Center located in Minnesota Florida and Arizona and thePrincess Margaret Cancer Centre in Toronto Ontario. The goal of the SPORE is to support investigators at allthree sites with expertise in basic myeloma biology genetics clinical research and epidemiology as they worktogether to translate basic science advances into improved care for myeloma patients. SPORE researchprojects focus on oncolytic virotherapy the myeloma tumor microenvironment myeloma immunotherapy earlydetection of myeloma requiring treatment prevention of myeloma progression and using genetics to optimizetherapy of high-risk myeloma. NCI 10706314 9/4/23 0:00 PAR-18-313 5P50CA186781-08 5 P50 CA 186781 8 "UJHAZY, PETER" 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N(M1)P 1967810 "BERGSAGEL, PETER LEIF" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1976442 NCI 1708357 360355 PROJECT SUMMARY/ABSTRACTThe Mayo Clinic Multiple Myeloma SPORE (SPORE) is a dynamic productive translational cancer researchprogram based at all three Mayo Clinic sites (Rochester MN Jacksonville FL Phoenix AZ) now with input fromthe Princess Margaret Cancer Centre in Toronto Ontario. From 2003-2013 we participated in the jointDFCI/Mayo Clinic Multiple Myeloma SPORE and since 2015 in the Mayo Clinic Multiple Myeloma SPORE. Atthe center of the ongoing success of the SPORE is the collaborative interaction between investigatorsthroughout the Mayo Foundation as well as SPORE basic laboratory translational and clinical investigatorsand patient advocates focused on MM. The overall goal of the SPORE is to support innovative interactiverigorous translational myeloma research that leverages the expertise of laboratory translational and clinicalexpertise. Over the last funding period the SPORE has been highly productive as demonstrated byidentification of new tumor markers and prognostic indices that are being used clinically; scientific findings thatled to innovative clinical trials both within and outside the SPORE; multiple publications with many authored byinvestigators from multiple sites; and brisk accrual to translational clinical trials. The SPORE was involved inmultiple productive vertical and horizontal collaborations with other national and international academicinstitutions and organizations. For example with leadership of clinical efforts in patient-focused clinical trialsfrom the Multiple Myeloma Research Foundation International Myeloma Foundation and MyelomaCrowd. Thecurrent proposal includes 3 major research projects. Two of the projects are new based on research resultsobtained over the past funding period while Project 1 is a continuation of efforts to investigate ways ofmodulating the immune micro-environment to improve the efficacy of oncolytic viral therapy in MM in a phase Iclinical trial. Project 2 is an integrated multi-omic analysis of high-risk MM with associated clinical trial highlyfocused on identifying promising approaches in this group of patients that have not benefited from recentadvances. Project 3 is investigating the genetic and microenvironmental mechanisms of progression ofsmoldering MM to MM to enable early detection of MM requiring treatment. The SPORE also includesDevelopmental Research and Career Enhancement Programs to pursue novel translational concepts in MMresearch and new investigators through the programs respectively. Finally the SPORE will enhance theinfrastructure that supports translational MM research through shared core resources in AdministrationBiostatistics & Bioinformatics and Biospecimens & Clinical Database. 1976442 +No NIH Category available AFP gene;Age;Alaska;Alaska Native;Algorithms;American Indians;Bayesian Method;Bayesian Modeling;Biological Markers;Case/Control Studies;Caucasians;Cells;Cessation of life;Characteristics;Cirrhosis;Collection;Colorectal Cancer;Cross-Sectional Studies;DNA;DNA Markers;DNA Methylation;Diagnostic;Early Diagnosis;Environmental Exposure;Epidemiology;Epigenetic Process;Ethnic Population;Etiology;Face;Functional disorder;Future;Gender;Genetic;Genetic Polymorphism;Genomics;HBV Genotype;HCV Cirrhosis;Hepatitis B Virus;Image;Incidence;Indian reservation;Liver diseases;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measurement;Methylation;Modeling;Mutation;Native-Born;Patients;Pattern;Performance;Persons;Phase;Plasma;Population;Primary carcinoma of the liver cells;Proteins;Research Design;Risk;Science;Serum;Serum Proteins;Severities;Specialized Center;Specificity;Testing;Tumor Tissue;Woman;biomarker development;biomarker panel;biomarker performance;biomarker validation;blood-based biomarker;cancer health disparity;cohort;design;disparity elimination;epigenetic marker;epigenetic profiling;epigenomics;imaging facilities;improved;innovation;liquid biopsy;malignant breast neoplasm;men;molecular marker;mortality;novel;novel marker;performance tests;peripheral blood;phase 2 study;phase 3 study;prospective;racial population;screening;translational approach;tribal community;tumor;tumor DNA Novel biomarker strategies for HCC early detection in AI/AN patients While deaths related to lung breast prostate and colorectal cancer have declined dramatically by 40-53%between 1990 and 2016 hepatocellular carcinoma (HCC) is the only major malignancy whose mortality is risingin both men and women and has had the highest average annual percentage change. American Indian/AlaskaNative (AI/AN) people face a disproportionally high burden of HCC with 2.4 times higher HCC incidence and 2.5times higher HCC-related mortality than white persons. Our aim is to apply novel innovative translationalapproaches to surveillance and early detection of HCC that are informed by unique aspects of HCCpathophysiology and epidemiology in AI/AN people in order to eliminate disparities improve early detection andultimately reduce HCC-related mortality. NCI 10706313 8/24/23 0:00 RFA-CA-19-034 5P20CA252732-03 5 P20 CA 252732 3 9/6/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 9183 1865649 "GRADY, WILLIAM MALLORY" Not Applicable 7 Unavailable 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA Domestic Higher Education 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 136284 133541 2879 ABSTRACT: PROJECT 1 Novel Biomarker StrategiesPeripheral blood-based HCC biomarker panels are an essential component of early detection strategiesespecially in remote AI/AN tribal communities and Indian reservations that are very far from any imaging facilities.Additionally blood-based biomarker screening achieves greater compliance than imaging-based screeningeven when imaging is readily available.Promising serum biomarker panels have been undergoing phase 2 and 3 studies of biomarker validation in thelast 5-7 years such as the GALAD test by Fujifilm-Wako and the methylated DNA marker (MDM) panel byEXACT Sciences which raises the possibility of a liquid biopsy for early detection of HCC. Unfortunately noneof these panels have ever been tested in AI/AN patients. It is likely that the performance of these biomarkers willbe significantly different in AI/AN patients than what was described in predominantly Caucasian populations inwhom they were developed.The overarching aim of Project 1 is to use a translational approach to develop novel biomarker strategies forearly detection of HCC that are designed specifically for AI/AN through 3 interconnected specific aims:SA1: Determine if hepatocellular carcinoma (HCC) in AI/AN patients is associated with unique or enrichedgenomic and/or epigenomic alterations or patterns of alterations compared to other racial/ethnic groups inorder to identify molecular markers including circulating free methylated DNA (cf mDNA) markers that can beused for surveillance in AI/AN patients at risk of HCC.SA2: (Phase 2 study of biomarker development). Perform a case-control study of 100 cases with T1 or T2HCC (n=50 AI/AN n=50 other racial/ethnic groups) and 100 at-risk control patients without HCC with cirrhosisor HBV (n=50 AI/AN n=50 other racial/ethnic groups) matched by liver disease etiology and cirrhosis severityto determine and compare the performance characteristics (sensitivity specificity AUROC) of the followingnovel HCC screening biomarker panels: Circulating methylated DNA marker (MDM) panel (EXACT sciences) Serum protein-based biomarker panel GALAD (FujiFilm-Wako Diagnostics)If necessary we will modify GALAD to optimize its performance for AI/AN persons and consider if itsperformance can be further improved by combining it with cf mDNA markers.SA3: (Phase 3 study of biomarker development). Develop and validate HCC early detection algorithms in anAlaska cohort of AI/AN patients with HCV-cirrhosis or HBV using longitudinal (serial) AFP or GALAD ormodified GALAD developed in SA2 specifically for AI/AN patients modeled by a Parametric EmpiricalBayesian (PEB) and Multivariate Fully Bayesian (mFB) approach. +No NIH Category available Achievement;Advocacy;Alaska Native;American Indians;Biometry;Biostatistics Core;Cessation of life;Cherokee Indian;Collaborations;Colorectal Cancer;Communication;Communities;Development;Disparity;Dissemination and Implementation;Early Diagnosis;Education;Epidemiology;Evaluation;Face;Fostering;Fred Hutchinson Cancer Research Center;Functional disorder;Funding;Grant;Health Services;Incidence;Infrastructure;Institution;Japan;Leadership;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mission;Monitor;National Cancer Institute;Native-Born;Outcome;Persons;Primary carcinoma of the liver cells;Productivity;Program Research Project Grants;Research;Research Personnel;Research Project Grants;Resources;Schedule;Structure;Texas;Tribes;United States National Institutes of Health;Universities;Washington;Woman;Work;biobank;cancer health disparity;career;community involvement;data dissemination;design;disparity elimination;disparity reduction;improved;innovation;malignant breast neoplasm;men;mortality;novel;organizational structure;outreach;programs;structured data;success;symposium;translational approach;tribal community;tribal health Administrative Core While deaths related to lung breast prostate and colorectal cancer have declined dramatically by 40-53%between 1990 and 2016 hepatocellular carcinoma (HCC) is the only major malignancy whose mortality is risingin both men and women and has had the highest average annual percentage change. American Indian/AlaskaNative (AI/AN) people face a disproportionally high burden of HCC with 2.4 times higher HCC incidence and 2.5times higher HCC-related mortality than white persons. Our aim is to apply novel innovative translationalapproaches to surveillance and early detection of HCC that are informed by unique aspects of HCCpathophysiology and epidemiology in AI/AN people in order to eliminate disparities improve early detection andultimately reduce HCC-related mortality. NCI 10706311 8/24/23 0:00 RFA-CA-19-034 5P20CA252732-03 5 P20 CA 252732 3 9/6/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 9182 8615691 "IOANNOU, GEORGE " Not Applicable 7 Unavailable 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA Domestic Higher Education 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 190815 136568 54386 ABSTRACT: ADMINISTRATIVE COREThe Administrative Core of our Liver Cancer in American Indians and Alaska Natives and Disparities (Li-CAD)P20 program will serve to optimize the work of discovery conducted by the P20 Projects and Cores throughadministrative support enhancement of communication data dissemination and structured oversight. TheAdministrative Core will provide guidance and enhance communication for and between the following groups: Li-CAD Executive Committee Li-CAD External and Internal Advisory Boards Participating Institutions (University of Washington [UW]; Fred Hutchinson Cancer Research Center [FHCRC]; Alaska Native Tribal Health Consortium [ANTHC]; Cherokee Nation Health Service [CNHS]; University of Texas Southwestern [UTSW]; Kumamoto University Japan) AI/AN Leadership Council (ANTHC and CNHS) Discovery Team (Research Projects; Developmental Research Program; Biorepository; Biostatistics) Education and Advocacy Team (AI/AN Advocacy Committee Education and Conference Committee; Career Enhancement Program) National Institutes of Health (NIH) and National Cancer Institute (NCI) representativesThe Li-CAD P20 is comprised of a unique collaboration of multiple entities (Figure 1). Investigators from eachentity have demonstrated prior success in collaborative research and will partner in this program to establishthe infrastructure to develop a highly innovative productive and significant program of discovery whose aim itis to reduce disparities in liver cancer outcomes among Alaska Native and American Indian people. The Corehas the following Specific Aims:Specific Aim 1: To provide the organizational structure for supporting the key objectives of the Li-CAD P20 andto promote AI/AN-appropriate research objectives community involvement and dissemination of findingsSpecific Aim 2: To integrate the Li-CAD P20 with the host institutions (UW FHCRC ANTHC CNHS andUTSW) and AI/AN Tribal and Research organizations at ANTHC and CNHS.Specific Aim 3: To provide oversight for the Li-CAD P20 Program Research Projects and Cores throughstructured and transparent evaluation of all P20 Program activities and prepare the transition to P50 SPORE. +No NIH Category available Abbreviations;Air Pollutants;Alaska Native;American Indians;Biological Markers;Biometry;Biostatistics Core;Cancer Biology;Cancer Etiology;Carcinogens;Cessation of life;Chad;Characteristics;Chemoprevention;Cherokee Indian;Cirrhosis;Clinical;Clinical Research;Collaborations;Colorectal Cancer;Continuity of Patient Care;Development;Diabetes Mellitus;Disparity;Early Diagnosis;Effectiveness;Epidemiology;Epigenetic Process;Exposure to;Face;Functional disorder;Genetic;HBV Genotype;Health Services;Health system;Hepatitis B;Hepatitis B Infection;Hepatitis C;Hepatology;High Prevalence;Incidence;International;Liver;Liver diseases;Longitudinal cohort;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Modeling;Mutation;Native-Born;Obesity;Outcome;Particulate Matter;Pathology;Patients;Performance;Persons;Prevalence;Prevention strategy;Primary carcinoma of the liver cells;Protocols documentation;Radiology Specialty;Recurrence;Research;Risk;Risk Factors;Role;Testing;Tribes;United States;Viral hepatitis;Woman;alcohol use disorder;biobank;biomarker development;biomarker panel;cancer genetics;cancer health disparity;chronic liver disease;data repository;disparity elimination;fine particles;high risk;improved;innovation;malignant breast neoplasm;men;mortality;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel marker;prognosis biomarker;programs;prospective;risk stratification;screening;surveillance strategy;translational approach;treatment response;tribal health Liver Cancer Disparities in Alaska Native and American Indian People While deaths related to lung breast prostate and colorectal cancer have declined dramatically by 40-53%between 1990 and 2016 hepatocellular carcinoma (HCC) is the only major malignancy whose mortality is risingin both men and women and has had the highest average annual percentage change. American Indian/AlaskaNative (AI/AN) people face a disproportionally high burden of HCC with 2.4 times higher HCC incidence and 2.5times higher HCC-related mortality than white persons. Our aim is to apply novel innovative translationalapproaches to surveillance and early detection of HCC that are informed by unique aspects of HCCpathophysiology and epidemiology in AI/AN people in order to eliminate disparities improve early detection andultimately reduce HCC-related mortality. NCI 10706310 8/24/23 0:00 RFA-CA-19-034 5P20CA252732-03 5 P20 CA 252732 3 "WALLACE, TIFFANY A" 9/6/21 0:00 8/31/24 0:00 ZCA1-RPRB-M(M1)P 8615691 "IOANNOU, GEORGE " "GRADY, WILLIAM MALLORY; MCMAHON, BRIAN JAMES" 7 INTERNAL MEDICINE/MEDICINE 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 828416 NCI 720803 108343 ABSTRACT: OVERALL COMPONENT - LIVER CANCER DISPARITIES IN AI/ANHCC is the fastest-rising major malignancy in the United States. While deaths related to lung breast prostateand colorectal cancer have declined dramatically by 40-53% between 1990 and 2016 HCC is the only majormalignancy whose mortality is rising in both men and women and has had the highest average annualpercentage change2. HCC is now the 6th leading cause of cancer-related death in the U.S. It is projected tosurpass breast and colorectal cancer to become the 3rd leading cause of cancer-related death by 2030.American Indian/Alaska Native (AI/AN) people face a disproportionally high burden of HCC. AI/AN people have2.4 times higher HCC incidence and 2.5 times higher HCC-related mortality than white persons. AI/AN peoplehave a very high incidence and prevalence of conditions that cause HCC such as viral hepatitis C and B alcoholuse disorders NAFLD/NASH obesity and diabetes. Additionally AI/AN patients have unique risk factors andpathogenetic mechanisms for HCC development such as high prevalence of infection with HBV genotype F1bunique mutations in the core region of HBV genotype F1b and high exposure to air pollutants (particulate matter<2.5m or PM2.5) which are recognized carcinogens.The main focus of our Liver Cancer in AI/AN Disparities (Li-CAD) P20 program is to eliminate disparities inEARLY DETECTION. We believe that the most critical disparities and deficiencies in HCC management andthe greatest opportunities for improvement lie in early detection. The overarching aim of this P20 Program isto apply novel innovative translational approaches to surveillance and early detection of HCC that are informedby unique aspects of HCC pathophysiology and epidemiology in AI/AN people in order to eliminate disparitiesimprove early detection and ultimately reduce HCC-related mortality. The overarching strategy is to introducePrecision HCC Screening based on HCC risk stratification and risk-based surveillanceThe P20 Li-CAD program will achieve the following AIMS:1. PROJECT 1. Transform biomarker-based surveillance for early detection of HCC in medium and low-riskAI/AN patients. We will test and adapt exciting biomarker panels in AI/AN patients and develop innovativelongitudinal (Bayesian) biomarker modeling strategies to maximize the performance characteristics of biomarker-based surveillance.2. PROJECT 2. Develop novel risk stratification strategies and test abbreviated MRI-based surveillance for earlydetection of HCC in high-risk AI/AN patients. We will elucidate the role of HBV genotype-specific mutations inHCC; develop AI/AN-specific HCC Risk Calculators for HCC risk stratification and risk-based surveillance; anduse these HCC Risk Calculators to identify high-risk patients for more intensive HCC surveillance strategiesutilizing novel abbreviated MRI protocols which will be tested in a small pilot and feasibility RCT 828416 +No NIH Category available 3-Dimensional;Androgen Receptor;Aneuploidy;Bioinformatics;Biological Assay;Biological Models;Bone Marrow;Breast Cancer Cell;Bulla;Castration;Cell Separation;Cessation of life;Chromosomal Instability;Clonal Expansion;Cytoplasm;Diagnostic;Disease;Down-Regulation;Epithelium;Exhibits;Expression Profiling;Family;Funding;Genes;Genetic Transcription;Genetically Engineered Mouse;Genome;Genomic Instability;Goals;Growth;Histologic;Histology;Human;Hypoxia;Longterm Follow-up;Malignant neoplasm of prostate;Membrane Proteins;Mesenchymal;Metastatic Prostate Cancer;Methods;Molecular;Mus;Needle biopsy procedure;Neoplasm Circulating Cells;Neoplasm Metastasis;Neurosecretory Systems;Newly Diagnosed;Nuclear;Nuclear Envelope;Nuclear Inner Membrane;Patients;Phenotype;Ploidies;Population;Primary Neoplasm;Process;Property;Prostate;Prostatic Neoplasms;Receptor Signaling;Reporting;Resistance;Role;Shapes;Signal Transduction;Specific qualifier value;Stimulus;Tissue Grafts;Tissues;Variant;Xenograft procedure;castration resistant prostate cancer;chromosome missegregation;cohort;drug-like compound;emerin;extracellular vesicles;genomic data;human data;human model;human tissue;in vivo;inhibitor;inhibitor therapy;men;micronucleus;neoplastic cell;novel;novel marker;novel therapeutic intervention;pressure;prognostic;programs;prostate cancer cell;prostate cancer metastasis;regeneration model;single cell analysis;small molecule;stemness;tissue regeneration;transcription factor;tumor growth;tumor heterogeneity Mechanisms of Prostate Cancer Metastasis PROJECT NARRATIVE (PROJECT 4)The overall goal of Project 4 is to understand the relationship between expression and activation of the masterregulator transcription factor ONECUT2 (OC2) lineage plasticity chromosome instability and nuclear shapeinstability. We have found these to be shared features of both treatment-nave de novo metastatic prostatecancer (PC) and metastatic castration-resistant PC suggesting these properties are inherent to one or moresubtypes of aggressive PC. We will use model systems human data and tissues and a range of molecular andcomputational approaches to identify new therapeutic approaches to lethal forms of PC.Project Narrative Page 700 NCI 10706309 9/8/23 0:00 PAR-20-077 5R01CA271750-03 5 R01 CA 271750 3 "AULT, GRACE S" 9/17/21 0:00 8/31/26 0:00 ZCA1-SRB-5(J1) 1883557 "FREEMAN, MICHAEL R" "GARRAWAY, ISLA PEARL" 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 426934 NCI 338375 88559 Contact PD/PI: Freeman Michael R Project-004 (511)ABSTRACT (PROJECT 4)Aggressive prostate cancers (PC) exhibit phenotypic changes through a poorly-understood process termedlineage plasticity (LP). LP typically occurs as a result of secondary resistance to androgen receptor signalinginhibitor (ARSI) therapy and is identified by variant histology and emergence of stemness neuroendocrine (NE)and epithelial-mesenchymal transition features. LP can be a driver of genome and chromosome instability (CIN).In the previous P01 cycle we were the first to report that the transcription factor ONECUT2 (OC2/HNF6) is amaster regulator that specifies an NE transcriptional program in certain castration-resistant prostate cancers(CRPC). OC2 suppresses androgen receptor (AR) target genes and acts as a survival factor. We developed anovel class of small molecule OC2 inhibitors that inhibit growth and metastasis of AR-V7-positive mCRPCxenografts. OC2 is thus a previously unknown driver of LP in aggressive PC that can be targeted with a drug-like compound. Evidence from genetically engineered mouse models and tissue regeneration modelsdemonstrate that OC2 is upregulated under conditions that produce CIN. In the previous funding cycle we usedmodel systems genomics data and studies of human PC tissues and circulating tumor cells (CTCs) to assembleevidence that CIN OC2 activation and nuclear shape instability (NSI) are shared features of both treatment-nave de novo metastatic PC and mCRPC. These findings suggest these are inherent to one or more aggressivePC classes and may even occur in the absence of selection from ARSI. Using these observations as a scientificpremise we hypothesize that OC2 CIN and NSI act coordinately to drive LP and PC lethality. The SpecificAims are: Aim 1. Determine the role of CIN in OC2-driven lineage plasticity. OC2 will be enforced in vivo inhuman PC tissue regeneration assays to determine whether OC2 activity is dependent on CIN and whether OC2promotes LP CIN or NSI. Graft tissues from intact and castrated mice will be analyzed for CIN LP and NSIusing histologic immunohistochemical RNA expression profiling and bioinformatics methods. LP will be inducedin human mCRPC 2D and 3D human models by hypoxia and bone marrow stromal secretions to determinewhether these stimuli promote NSI and CIN. Aim 2. Identify mechanisms of NSI that promote lineage plasticity.Tissue regeneration assays will be used to determine whether NSI induced by silencing the nuclear membraneprotein emerin (EMD) promotes CIN LP and OC2 activation. We will determine whether EMD silencing canelicit or cooperate with CIN to drive tumor growth LP and castration resistance. Aim 3. Investigate OC2activation CIN and NSI in parallel across primary and metastatic tumor cell populations. An established singlecell analysis approach will be used to determine whether CIN NSI and OC2 activation co-exist in human PCcells isolated from de novo metastatic and mCRPC cases.Project Summary/Abstract Page 699Contact PD/PI: Freeman Michael R Project-004 (511) 426934 +Cancer; Cervical Cancer; Clinical Research; HIV/AIDS; Health Services; Infectious Diseases; Prevention; Sexually Transmitted Infections; Women's Health Address;Adoption;Appointment;Biomedical Research;Cervical;Cervical Cancer Screening;Clinic;Clinical;Clinical Practice Guideline;Collection;Complex;Diagnosis;Evaluation;Goals;Human Papillomavirus;Intervention;Laboratories;Malignant neoplasm of cervix uteri;Methods;Monitor;National Cancer Institute;Positioning Attribute;Professional Organizations;Provider;Public Health;Regulatory Pathway;Research;Research Design;Sampling;Specimen;Speculums;Testing;Time;United States Food and Drug Administration;Woman;Work;anticancer research;base;cervical cancer prevention;design;geographic inaccessibility;health disparity;improved;industry partner;practice setting;programs;public-private partnership;sample collection;screening;socioeconomic disparity COORDINATING CENTER FOR THE NCI CERVICAL CANCER LAST MILE INITIATIVE SELF-SAMPLING FOR HPV TESTING TO IMPROVE CERVICAL CANCER PREVENTI n/a NCI 10706294 75N91019D00024-P00001-759102100014-1 N01 9/14/21 0:00 8/31/25 0:00 78377495 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 1888290 NCI the twentieth century rates have plateaued for the past two decades. Despite the availability of highly sensitive screening methods such as human papillomavirus (HPV) testing over 13000 women continue to be diagnosed with and over 4000 women continue to die of cervical cancer annually in the US. Over half of all new cervical cancer cases are among women who have either never been screened or who have been infrequently screened reflecting substantial socio-economic disparities and barriers due to geographic inaccessibility. An alternative screening approach under evaluation to overcome these barriers is self-collection of samples (self-sampling) by women themselves and sending the sample for HPV testing. This approach offers several benefits including ease of collection at a time/place of womens choice without a need for a clinic appointment or a speculum examination. This intervention has significant potential to expand cervical cancer screening to never screened or under-screened women and address a pressing public health concern of lack of access to screening as a health disparity.The National Cancer Institute (NCI) has developed the Cervical Cancer Last Mile Initiative as a public private partnership between several stakeholders (including federal agencies industry partners and professional societies/clinical practice guidelines organizations) to validate self-sampling-based HPV testing as a comparable (non-inferior) alternative to provider-collected cervical specimen for HPV testing in cervical cancer screening and facilitate regulatory approvals and broader adoption of this approach in real world practice settings. Towards this goal the NCI will support a nationwide multicentric screening trial the Self-sampling for HPV testing to Improve Cervical Cancer Prevention (SHIP) Trial (SHIP Trial) in diverse delivery settings. Pending discussions with the US Food and Drug Administration (FDA) and the industry partners the SHIP Trial may be designed as a pre-approval trial or a post-approval trial dependent on the approved regulatory pathways. This document assumes a study design of a post-approval trial 1888290 +Cancer; Cancer Genomics; Genetics; Human Genome Bioinformatics;genome wide association study;genome-wide analysis ADVANCED STATISTICAL AND BIOINFORMATIC ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES (GWAS) n/a NCI 10706291 75N91020D00008-P00001-759102100001-1 N02 9/16/21 0:00 9/15/23 0:00 78379285 "GREENE, JOHN " Not Applicable Unavailable 171830748 VZHBEXPGE6G3 171830748 VZHBEXPGE6G3 US -444345 MCLEAN VA Other Domestic Non-Profits 221023838 UNITED STATES N R and D Contracts 2022 557366 NCI ADVANCED STATISTICAL AND BIOINFORMATIC ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES (GWAS) 557366 +Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Immunotherapy; Lung; Lung Cancer Address;Advanced Development;Biological Markers;Cancer Patient;Combination immunotherapy;Image Analysis;Immune;Immunologic Monitoring;Immunotherapy;Investigation;Malignant neoplasm of lung;Maps;Methods;Non-Small-Cell Lung Carcinoma;Phase;Platinum;Positron-Emission Tomography;Pre-Clinical Model;Scanning;Signal Transduction;Small Business Innovation Research Grant;Standardization;T-Lymphocyte;Technology;Testing;anti-PD-1;anti-PD-L1;cancer imaging;cancer immunotherapy;cancer therapy;chemotherapy;clinical imaging;imaging biomarker;quantitative imaging;response;response biomarker;treatment response;tumor SBIR PHASE II - TOPIC 396 - IMAGING FOR CANCER IMMUNOTHERAPIES n/a NCI 10706239 75N91022C00015-0-9999-1 N44 9/16/22 0:00 9/15/24 0:00 78856062 "LEVI, JELENA " Not Applicable 11 Unavailable 832714898 E3UQXACGFR43 832714898 E3UQXACGFR43 US 37.775975 -122.392972 10025200 "CELLSIGHT TECHNOLOGIES, INC." SAN FRANCISCO CA Domestic For-Profits 941079107 UNITED STATES N R and D Contracts 2022 1995174 NCI Immunotherapy has transformed cancer treatment but therapy response remains low for certain tumor types. Despite the vital significance of immune activity within tumors there are currently no non-invasive immunomonitoring methods for assessment of immune contexture and assessment of response to therapy. To address this urgent need Cellsight Technologies is developing a PET agent specific for activated T cells [18F]F-AraG as an imaging biomarker of immunotherapy response. In Phase I we demonstrated in preclinical models the ability of [18F]F-AraG to provide an early assessment of response to both mono and combinatorial immunotherapy. In Phase II we focus on optimization and standardization of clinical image analysis and quantitation as the crucial components of [18F]F-AraGs suitability to serve as a biomarker of immunotherapy response. In this project we will determine treatment-independent variability in lung cancer patients to accurately define a threshold that indicates therapy-induced signal changes. This threshold will be used for automated quantitative analysis of [18F]F-AraG scans and creation of response maps in lung cancer patients undergoing combinatorial immunotherapy. The results of the planned investigations will address some of the most critical issues in quantitative image analysis and strongly advance development of [18F]F-AraG as an imaging biomarker for response to immunotherapies. 1995174 +Cancer; Dental/Oral and Craniofacial Disease; Digestive Diseases; Health Disparities; Prevention; Rare Diseases; Rural Health; Social Determinants of Health Address;Developed Countries;Diagnosis;Disease Progression;Early Diagnosis;FDA approved;Image;Lesion;Light;Malignant - descriptor;Malignant Neoplasms;Modality;Morbidity - disease rate;Mus;Oral;Oral Stage;Oropharyngeal Squamous Cell Carcinoma;PUVA Photochemotherapy;Patients;Performance;Photochemistry;Research;Resource-limited setting;Screening for Oral Cancer;Small Business Innovation Research Grant;Stage at Diagnosis;Survival Rate;System;Technology;Time;United States National Institutes of Health;Xenograft Model;base;cost;high risk;high risk population;low and middle-income countries;malignant mouth neoplasm;mortality;premalignant;rural area;subcutaneous;success SBIR TOPIC 431 - MOBILE ORAL-CANCER SCREENING AND TREATMENT (MOST) SYSTEM FOR LOW-RESOURCE SETTINGS n/a NCI 10706238 75N91022C00019-0-9999-1 N43 9/15/22 0:00 9/14/23 0:00 78858764 "LIANG, RONGGUANG " Not Applicable 6 Unavailable 80295846 L4E8EXJDSUH5 80295846 L4E8EXJDSUH5 US 32.294565 -110.848018 10042405 "LIGHT RESEARCH, INC." TUCSON AZ Domestic For-Profits 857506064 UNITED STATES N R and D Contracts 2022 399862 NCI Oral and oropharyngeal squamous cell carcinoma (OSCC) together rank as the sixth most common cancer worldwide it is the most common cancer in some low- and middle- income countries (LMICs). The poor survival rate in LMICs and rural regions in developed countries is mainly due to late diagnosis and the resultant progression of disease to an advanced stage at diagnosis. Motivated by the successes in the two different NIH UH2/UH3 projects for detecting and treating pre- and early oral cancers Light Research Inc (LRI) proposes to develop and commercialize a new integrated mobile oral-cancer screening and treatment (MOST) system optimized for low-resource settings (LRS). It combines dual-modal oral cancer screening technology and photochemistry-based FDA approved photodynamic therapy (PDT) modality. We will first develop the MOST system (Aim 1) and then demonstrate the imaging and treatment performance of MOST system with murine subcutaneous xenograft model (Aim 2). This project is significant because early diagnosis of oral cancers and timely treatment can reduce disease progression reduce morbidity and mortality and cut costs. It addresses the major barrier to screen high-risk population and treat patients with high risk oral premalignant and malignant lesions (OPML) and early-stage oral cancer in LRS. 399862 +No NIH Category available Address;Algorithms;Artificial Intelligence;Artificial Intelligence platform;Benchmarking;Benign;Biological Markers;Biopsy;Biostatistical Methods;Blood;Breast;Cancer Center;Cancer Detection;Classification;Clinical;Clinical Data;Collaborations;Colon;Communication;Complement;Comprehensive Cancer Center;Cutaneous;Data;Dedications;Development;Diagnosis;Diagnostic;Discrimination;Disease;Early Detection Research Network;Early Diagnosis;Electronic Medical Records and Genomics Network;Environment;Funding;Goals;Guidelines;Housing;Image;Individual;Indolent;Institution;Lung;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mammography;Measurement;Medical Imaging;Modality;Modeling;Mutation;Nodule;Operative Surgical Procedures;Organ;Ovary;Pancreas;Performance;Play;Population;Prediction of Response to Therapy;Process;Productivity;Prostate;Recurrence;Research;Resected;Resources;Risk;Risk Marker;Role;Sampling;Screening for cancer;Shapes;Site;Subcategory;Subgroup;Sum;Techniques;Technology;Texture;Tissues;Validation;Vascularization;Woman;bioimaging;breast density;breast imaging;cancer biomarkers;cancer diagnosis;clinical imaging;data repository;deep learning;diagnostic biomarker;experience;image archival system;imaging biomarker;improved;interest;learning strategy;lung cancer screening;lung imaging;malignant breast neoplasm;non-invasive imaging;novel;overtreatment;patient population;personalized cancer care;prognostication;quantitative imaging;radiomics;repository;risk prediction;screening;standard of care;success;treatment response;tumor;working group Quantitative Imaging Clinical Validation Center at Moffitt Cancer Center PROJECT NARRATIVECancer screening modalities are often associated with false positives high rates of indeterminate findingsoverdiagnosis and overtreatment which are all serious limitations that can be addressed with imaging. Ourgroup pioneered image biomarker approaches leveraged in the prior funding cycle to create the first and onlyEDRN Clinical Validation Center (CVC) to dedicated to the validation of image biomarkers to improve earlydetection of cancer. In this renewal application we build on our initial progress to bring practical automatedsolutions to these pressing screening problems. NCI 10706028 9/22/23 0:00 RFA-CA-22-054 2U01CA200464-06A1 2 U01 CA 200464 6 A1 "MAZURCHUK, RICHARD V" 7/22/16 0:00 8/31/28 0:00 ZCA1-SRB-P(J2) 2277719 "HEINE, JOHN J" "SCHABATH, MATTHEW B." 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 881620 NCI 549996 376747 PROJECT SUMMARY/ABSTRACTAn overarching goal of cancer screening is to detect cancer at an early stage while it is localized treatable andcurable. However cancer screening is associated with false positives high rates of indeterminate findingsoverdiagnosis and overtreatment which are serious limitations that need to be addressed to improve earlydetection efforts. Because medical imaging is a key component of early detection for many cancers quantitativeimaging/radiomics can provide biomarkers to address many of these limitations with early detection. Our groupQuantitative Imaging Clinical Validation Center at Moffitt Cancer Center (QICVC-MCC) helped pioneer imagebiomarker approaches leveraged in the prior funding cycle to create the first and only EDRN Clinical ValidationCenter (CVC) dedicated to the validation of image biomarkers. For breast cancer we validated several breastdensity-type risk markers and diagnostic models in women classified as BI-RADS 4 noting the threesubcategories within this classification were strong diagnostic markers and constructed a bio-image repositoryfor this subgroup. For lung cancer we conducted extensive studies applying conventional radiomics for riskprediction discrimination between malignant and benign nodules distinguishing between indolent andaggressive lung cancers predicting tumor mutations and predicting treatment response. In this renewal we willexpand our CVC from validated conventional feature-based radiomics as a benchmark to compare end-to-enddeep learning (DL) methods expand to other populations and implement AI platforms for analyzing breast lungand other organ site images. In breast imaging (Aim 1) we will expand our efforts from parametric modeling tomachine learning/DL for improved risk early detection and diagnostic predictions and continue our datarepository developments. In lung imaging (Aim 2) we will expand our efforts from lung cancer screening toincidentally detected nodules and surgically resected early-stage lung cancer. Additionally in Aim 3 we will seekout additional opportunities within the EDRN to conduct studies of image biomarkers in other organ sites beyondbreast and lung (e.g. prostate pancreas and cutaneous) to address emerging Network objectives. The EDRNhas proven that it is greater than the sum of the individual projects. As such in Aim 4 we propose to build arepository for the housing and sharing of images algorithms radiomics clinical data and information onbiospecimens. In this CVC renewal we will systematically validate radiomic features and novel image metricsin the early detection of cancer. This research is significant because such information may be able to complementexisting clinical guidelines and lead to new strategies to apply noninvasive image biomarkers. The research ofthe QICVC-MCC is performed at an NCI-Designated Comprehensive Cancer Center which is an outstandingenvironment to conduct such studies given the access to large patient populations and outstanding resourcesand the clinical setting to deploy such biomarkers for improved personalized cancer care. 881620 +No NIH Category available Address;Adolescent;Age;Amendment;Area;Code;Communication;Complement;Computer software;Data;Educational workshop;Electronic cigarette;Ensure;Epidemic;Exclusion;Facebook;Future;Genus Mentha;Goals;Health;Hour;Industry;Instagram;Investigation;K-Series Research Career Programs;Laws;Learning;Legal;Menthol;Mentors;Methodology;Methods;Nicotine;Outcomes Research;Pathway Analysis;Persons;Policies;Policy Analysis;Policy Maker;Procedures;Process;Publications;Recommendation;Regulation;Research;Research Methodology;Sales;Social Network;Source;Statutes and Laws;Surveys;Taxes;Techniques;Technology;Time;Tobacco;Tobacco Industry;Tobacco use;Training;Twitter;Youth;career development;certificate program;electronic cigarette use;experience;gaps in access;improved;innovation;population based;prevent;public policy on tobacco;response;social media;symposium;timeline;tobacco advertising;tobacco control;tobacco products;tobacco regulation;young adult Loopholes Enforcement Challenges and Tobacco Industry Interference with Tobacco Control Policies PROJECT NARRATIVETobacco access laws are intended to prevent youth and young adults from initiating and using all tobaccoproducts; however research about policy efficacy enforcement challenges and communication the tobaccoindustry has with the public about federal tobacco regulatory laws has only been explored through limitedtraditional research methodologies. The training and proposed research in this career development awardapplication will use publicly available social media (e.g. Twitter Facebook) data to organically andsystematically examine policy loopholes that circumvent policy efficacy key challenges related to enforcementand tobacco industry interference among emerging youth access laws (e.g. Tobacco 21 Flavor restrictionpolicies a maximum nicotine level law). This innovative research would provide the FDA with prompt action-oriented recommendations about these policies which can enable the FDA to make meaningful responses tocritical issues including policy loopholes enforcement practices and industry interference. NCI 10705827 8/16/23 0:00 RFA-OD-20-008 5K01CA267967-02 5 K01 CA 267967 2 "RADAEV, SERGEY" 9/16/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-VH-K(90)S] 16270754 "DOBBS, PAGE D." Not Applicable 3 PUBLIC HEALTH & PREV MEDICINE 191429745 MECEHTM8DB17 191429745 MECEHTM8DB17 US 36.069922 -94.176965 1471102 UNIVERSITY OF ARKANSAS AT FAYETTEVILLE FAYETTEVILLE AR EARTH SCIENCES/RESOURCES 727013214 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 77 Other Research-Related 2023 160990 OD 149065 11925 PROJECT SUMMARY/ABSTRACTBackground. Enactment of tobacco control policies is a vital response to the ongoing epidemic of adolescente-cigarette use in the US and is believed to have contributed to the decline in youth e-cigarette use from 2019to 2020. During 2019-2020 two federal laws were enacted: (1) Tobacco 21 (increased the minimum legalsales age for tobacco to 21 years; T21) and (2) a partial Flavor Restriction law eliminated pod/cartridge-basede-cigarette products that contained flavors other than mint/menthol. While traditional policy evaluations (e.g.compliance checks document analyses and surveys) have been employed to evaluate policy impactcomplementary and innovative social media-based methodologies can be used to systematically examineorganic public discussion about policy-relevant issues. Such data are particularly valuable due to the ability touncover critical policy-relevant information taking less time than traditional methodologies. Building on myexperience and learning from my research mentors expertise I will conduct the first comprehensive socialmedia assessment aimed at uncovering highly valuable yet often difficult-to-ascertain information regardingemerging tobacco access laws (that have already been enacted or are currently being discussed) in threeareas: policy efficacy enforcement challenges and industry interference. Research. The overarching goal ofthe proposed investigation is to reduce youth/young adult access to tobacco products. Therefore in thisproposal we will (1) identify loopholes that may circumvent emerging federal tobacco access laws; (2) identifykey challenges related to enforcement of FDA regulated tobacco access laws; and (3) investigate tobaccoindustry supported interference with emerging FDA regulated tobacco access laws. To achieve these aims wewill use a specialized software and a comprehensive list of social media-optimized search terms to collect datafrom several social media platforms (e.g. Twitter Instagram Reddit Facebook). Using a two-step process wewill ensure search strings are comprehensive feasible specific and informal. After developing a codebook toexplore sentiment (positive negative neutral and mixed/both) about tobacco youth access laws two trainedindependent coders will code a sub-sample of collected data stratifying by month day and time. Finallycontent analyses and social network analyses will be used to explore loopholes enforcement challenges andinterference with emerging tobacco access laws. Training. Pedagogically the training plan for this proposedK01 is comprised of didactic training (certificate program workshop coursework seminars) mentoring(directed research conference calls in-person contact hours readings) and dissemination deliverables(publications presentations and proposals) required to complete the project on the projected timeline.Outcomes from these research aims will complement my career-development aims (i.e. developing expertisein tobacco control policies social media analysis and social network analysis) that focus on the intersectionbetween health policy communication and technology. 160990 +No NIH Category available Activities of Daily Living;Address;Adherence;Aerobic;Animals;Anthracycline;Attenuated;Cancer Center;Cancer Patient;Cancer Survivor;Cardiac Output;Cardiac rehabilitation;Cardiopulmonary;Cardiotoxicity;Cardiovascular Physiology;Cardiovascular system;Clinical Trials;Cognitive;Communities;Comprehensive Cancer Center;Data;Data Analyses;Enrollment;Event;Exercise;Exercise Tolerance;Fatigue;Feedback;Focus Groups;Fostering;Functional disorder;Funding;Goals;Health;Heart failure;Home;Hospitalization;Human;Immunocompromised Host;Impaired cognition;Individual;Instruction;Intervention;Interview;Knowledge;Left Ventricular Dysfunction;Left Ventricular Function;Life Style;Lymphoma;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Methods;Morbidity - disease rate;Myocardial dysfunction;Non-Hodgkin's Lymphoma;North America;Outcome;Oxygen;Participant;Patients;Peripheral;Phase;Physical Exercise;Physical Performance;Physical activity;Physical shape;Physiological;Prognosis;Property;Quality of life;Randomized;Rehabilitation Centers;Research Personnel;Structure;Survivors;Testing;Time;Translating;Travel;Treadmill Tests;Treatment-Related Cancer;United States National Institutes of Health;Walking;adverse outcome;arm;cancer initiation;cancer therapy;cardiovascular risk factor;chemotherapy;clinical practice;cognitive function;design;exercise capacity;exercise intervention;exercise intolerance;exercise program;exercise training;experience;functional decline;health related quality of life;heart function;improved;individualized medicine;insight;intervention refinement;mortality;non-Hodgkin's lymphoma patients;novel;participant enrollment;physical inactivity;preservation;primary outcome;programs;randomized clinical trials;screening;secondary outcome;sedentary lifestyle;treadmill;trend Improving Exercise Capacity with a Tailored Physical Activity Intervention in Lymphoma Patients Undergoing Treatment PROJECT NARRATIVELymphoma survivors are increasingly experiencing morbidity and mortality due to cardiovascular events thatoften result from the anthracycline-based chemotherapy used to treat their cancer. Our team of experiencedinvestigators will test the utility of a patient-centric individually tailored physical activity interventionimplemented throughout chemotherapy to attenuate physical inactivity reduce fatigue and preserve exercisecapacity cardiac and cognitive function strength and health-related quality of life: all metrics that associatewith or reduce cardiovascular risk. By fostering a lifestyle that maintains or increases physical activity andexercise capacity this project seeks to reduce overall cardiovascular morbidity and mortality of lymphomasurvivors and thereby improve their overall survival and quality of life. NCI 10705825 8/15/23 0:00 PAR-18-307 5R33CA226960-04 5 R33 CA 226960 4 "DIMOND, EILEEN" 12/1/18 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-RPHB-W(55)R] 6855679 "HUNDLEY, WILLIAM GREGORY" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 350221 NCI 313823 36398 Cardiovascular (CV) events related to the receipt of potentially cardiotoxic anthracycline-based chemotherapy(Anth-bC) are emerging as leading causes of morbidity and mortality for survivors of lymphoma (the 5thmost common cancer in North America). The objective of our proposal is to reduce this cancer treatmentrelated CV morbidity by developing enabling and testing a physical activity intervention that commences andcontinues throughout receipt of Anth-bC for the purpose of attenuating physical inactivity preserving exercisecapacity CV & cognitive function strength and health-related quality of life (HRQOL) for those with lymphoma.The need for and the design of this program is based in part on feedback from lymphoma survivor focusgroups treated in our NIH funded Comprehensive Cancer Center - preliminary pilot data (Section 3.C.1).Several novel features of this proposal include:1) Performance of physical activity during receipt of cancer treatment where exercise intolerance originates.2) Creation of patient communities that enable cancer patients to support one another during treatment.3) Administration of aerobic & strength activities suited to one's individual lifestyle in the home guided by instruction provided from 4 close to home cardiac rehabilitation facilities experienced in exercising immunocompromised individuals and those with other pre-existing activity limitations due to cancer.4) Utilization of newly developed magnetic resonance cardiopulmonary exercise treadmill testing methods to measure the two components (cardiac function and peripheral factors) that contribute to peak VO2 (a measure of maximal exercise capacity). This new information will provide mechanistic insight into how physical activity helps preserve exercise capacity and reduce fatigue.5) Assessment of the relationships between cognitive function activity and exercise capacity thereby helping to unravel the association between physical activity HRQOL and cognitive function in cancer patients.In this application we propose to refine the physical activity intervention during the R21 Phase in patients whoparticipate in the intervention for 6 months. If suitable milestones are achieved we will conduct a randomizedclinical trial in the R33 Phase to test the utility of the integrated physical activity intervention for sustaining peakV02 6-min walk distance cardiac and cognitive function strength activity and HRQOL.If we achieve our study goals this proposed intervention could reduce CV mortality and heart failure relatedhospital admissions translate into clinical practice via extension through cardiac rehabilitation centers (oftenlocated close to cancer centers) increase health-related quality of life reduce fatigue to perform activities ofdaily living and attenuate cognitive function decline in lymphoma survivors. The results of this study could helpto change existing sedentary behavior paradigms during receipt of chemotherapy and ultimately lead toimproved long term outcomes for those with lymphoma and potentially other forms of cancer. 350221 +No NIH Category available Address;Baltimore;Benign;Biological Assay;Biological Markers;Biopsy;Blinded;Body Fluids;CLIA certified;Cancer Etiology;Categories;Cells;Cessation of life;Characteristics;Clinical;Collaborations;DNA Methylation;Detection;Development;Diagnostic Procedure;Diameter;Disease;Early Detection Research Network;Early Diagnosis;Ensure;Evaluation;Exhibits;Funding;Healthcare;Image;Knowledge;Laboratories;Lesion;Longterm Follow-up;Lung;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maryland;Methodology;Methods;Methylation;Morbidity - disease rate;Nodule;Operative Surgical Procedures;Participant;Patients;Performance;Plasma;Population;Predictive Value;Procedures;Quality Control;Reagent;Reproducibility;Research Personnel;Sampling;Screening Result;Specificity;Standardization;Technology;Testing;Time;Universities;Validation;arm;assay development;biomarker development;biomarker validation;candidate marker;experience;flexibility;laboratory development;liquid biopsy;lung cancer screening;methylation biomarker;mortality;multidisciplinary;prospective;sample collection;screening;wasting Core - Biomarker Reference Laboratory (BRL) n/a NCI 10705806 8/8/23 0:00 RFA-CA-21-035 5U2CCA271885-02 5 U2C CA 271885 2 9/16/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 9106 6365905 "HERMAN, JAMES G." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 197728 123399 74329 The Biomarker Reference Laboratory (BRL) will be led by Dr. Sanford Stass and as acomponent of the BCC will develop refine and standardize the biomarkers assays developedby the Biomarker Development Laboratory. This BRL is a continuation of the University ofMaryland Baltimore Biomarker Reference Laboratory. UMB-BRL has for the past 15 yearsprovided active support of the EDRN including testing of candidate biomarkers development ofassays and technologies and standardization of assay methods in collaboration with multipleinvestigators in the EDRN. The proposed BRL includes a multi-disciplinary team of directors/co-investigators and staff with broad knowledge experience and expertise in application oftechnology for biomarkers including reagent and assay development and implementationvalidation of laboratory methodology and assays quality control for reagents and technologiesevaluation of accuracy precision reproducibility and characteristics of performance includingsensitivity specificity and positive and negative predictive values. The BRL will bring DNAmethylation biomarkers from the BDL into a CLIA compliant laboratory using developedstandard operating procedures (SOPs) and extensive experience in collaborative studies inbiomarker validation. +No NIH Category available Anatomy;Apoptotic;Benign;Biological;Biological Markers;Blood;Body Fluids;Breast;Cancer Detection;Cancer Etiology;Categories;Classification;Clinical;Collection;Colorectal;DNA;DNA Methylation;Data;Detection;Development;Diagnosis;Diagnostic;Diagnostic Procedure;Diameter;Early Detection Research Network;Early Diagnosis;Epigenetic Process;Event;Funding;Genetic;Head and neck structure;Healthcare;High Prevalence;Histology;Laboratories;Location;Low Prevalence;Lung;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Methods;Methylation;Molecular;Monitor;Necrosis;Nodule;Nucleic Acids;Pancreas;Participant;Patients;Performance;Plasma;Process;Prostate;Reporting;Research Design;Research Personnel;Sampling;Screening for cancer;Sensitivity and Specificity;Source;Specimen;Standardization;Testing;The Cancer Genome Atlas;Tissues;United States;Validation;biomarker development;bisulfite;cancer biomarkers;cancer type;circulating DNA;clinical implementation;computed tomography screening;cost effective;design;detection assay;detection method;digital;improved;laboratory development;low dose computed tomography;lung cancer screening;methylation biomarker;mortality;multidisciplinary;neoplastic cell;novel;performance tests;prospective;screening;tumor;tumor DNA;tumorigenesis;wasting Core - Biomarker Development Laboratory (BDL) n/a NCI 10705802 8/8/23 0:00 RFA-CA-21-035 5U2CCA271885-02 5 U2C CA 271885 2 9/16/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 9105 6365905 "HERMAN, JAMES G." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 382381 308052 74329 As part of a Biomarker Characterization Center the Biomarker Development Laboratorywill develop improved methods to detect DNA methylation changes for the early detectionof lung cancer. Led by Dr. James Herman and Dr. Tza-Huei Jeff Wang a multidisciplinaryteam of investigators will develop improved panels of DNA methylation alterations able todetect circulating tumor DNA (ctDNA) changes in plasma to determine the origin ofctDNA from lung cancer or other common malignancies and to continue improvementsin methylation detection methods to better detect the small amounts of ctDNA present inplasma. This EDRN Biomarker Development Laboratory will use high qualityprospectively collected biospecimens to develop highly sensitive specific andquantitative approaches for the detection of tumor-specific DNA methylationabnormalities in plasma. These methods will be transferred to the Biomarker ReferenceLaboratory to be standardized and tested for performance in a CLIA setting. +No NIH Category available Biological Markers;Blood;Budgets;Clinical;Communication;Complex;Comprehensive Cancer Center;DNA Methylation;Detection;Development;Early Detection Research Network;Funding;Goals;Individual;Institution;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Maryland;Pennsylvania;Preparation;Progress Reports;Research Personnel;Resources;Sampling;Schedule;Screening for cancer;Site;Site Visit;Testing;Travel;Universities;Validation;biomarker development;biomarker validation;innovative technologies;laboratory development;material transfer agreement;meetings;methylation biomarker;multidisciplinary;programs;research clinical testing Administrative Core n/a NCI 10705801 8/8/23 0:00 RFA-CA-21-035 5U2CCA271885-02 5 U2C CA 271885 2 9/16/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 9104 6365905 "HERMAN, JAMES G." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 299550 225221 74329 The development and validation of biomarkers for the early detection of cancer requires a teamof investigators and resources to move from discovery through stages of validation to the ultimategoal of a clinically approved and useful test. This Biomarker Characterization Center proposesto develop and validate blood-based cancer specific DNA methylation biomarkers by bringingtogether investigative teams from three NCI designated Comprehensive Cancer Centers (TheUMPC Hillman Comprehensive Cancer Center at the University of Pittsburgh The Sidney KimmelComprehensive Cancer Center at Johns Hopkins and The University of Maryland Marlene &Stewart Greenebaum Comprehensive Cancer Center) to accomplish this complex task. Tocoordinate and support these efforts an administrative core will integrate activities of EDRN BCCinvestigators. The administrative core of this Biomarker Characterization Center overseescoordinates and supports the activities of this multidisciplinary program. Through overseeing andsupporting these activities the individual components of the Biomarker Development Laboratoryand the Biomarker Reference Laboratory are able to effectively accomplish their objectives andintegrate their activities with other components of the BCC (BDL and BRL) with other NCIprograms and with other EDRN centers (BCCs CVCs and the DMCC). +No NIH Category available APAF1 gene;Abscopal effect;Affect;Allografting;Antigens;Apoptosis;BAX gene;BCL1 Oncogene;CASP9 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Caspase;Cell Death;Cell Line;Cell Membrane Permeability;Cell Nucleus;Cells;Clear cell renal cell carcinoma;Computer Models;Cytosol;Dimensions;Distant;Ecosystem;Engineering;Epigenetic Process;Evolution;Gene Expression;Genetic Engineering;Genetically Engineered Mouse;Goals;Human;Immune;Immune response;Immune system;Immunofluorescence Immunologic;Immunologic Memory;Immunologics;Immunotherapy;In complete remission;Inflammatory;Inner mitochondrial membrane;Interferon Type I;Label;Lead;Luciferases;Melanoma Cell;Memorial Sloan-Kettering Cancer Center;Mitochondria;Mitochondrial DNA;Modeling;Molecular;Mus;Mutation;Necrosis;Neoplasm Metastasis;Outer Mitochondrial Membrane;Pathway interactions;Patients;Probability;Process;Protein Family;RNA;Recurrent tumor;Renal Cell Carcinoma;Research Personnel;Resolution;Sampling;Stimulator of Interferon Genes;System;Systems Biology;T cell receptor repertoire sequencing;T-Lymphocyte;T-cell receptor repertoire;The Cancer Genome Atlas;Therapeutic;Transplantation;Tumor Immunity;adaptive immune response;anti-CTLA-4 therapy;anti-PD-1;cancer care;cancer cell;cancer type;cell type;cytochrome c;draining lymph node;immune checkpoint blockade;immunogenic;immunogenic cell death;immunogenicity;improved;in vivo;insight;melanoma;mouse model;multiple omics;novel;programs;response;success;survival outcome;tumor;tumor heterogeneity;tumor progression Project III: Engineering immunogenic cell death in melanoma and renal cell carcinoma. n/a NCI 10705788 8/22/23 0:00 RFA-CA-21-048 5U54CA274492-02 5 U54 CA 274492 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9936 7039912 "CHENG, EMILY H" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 495600 280000 215600 Project III. Engineering immunogenic cell death in melanoma and renal cell carcinomaExperimental Lead: ChengComputational Lead: LeslieExperimental Co-Investigator: LiPROJECT SUMMARYRecent approval of immune checkpoint blockade (ICB) in multiple cancer types has revolutionized cancer carebut only a small fraction of patients achieve a durable complete response. Hence there is an urgent need fornovel immunotherapy-based therapeutic strategies to enhance response and offer long-term survival benefits.We hypothesize that induction of immunogenic cancer cell death is one of such strategy. Necroptosis andpyroptosis two forms of programmed necrosis are pro-inflammatory and probably immunogenic. By contrastmitochondrial apoptosis is generally considered immunologically silent. The BCL-2 family proteins are centralregulators of mitochondrial apoptosis. BAX and BAK once activated by BH3-only molecules triggermitochondrial outer membrane permeabilization (MOMP) which releases cytochrome c to activate theapoptosome and caspases. Recent paradigm-shifting discoveries have shown that BAX/BAK activation in theabsence of caspases can trigger the release of mitochondrial DNA to the cytosol through a process calledmitochondrial inner membrane permeabilization (MIMP) which activates the cGAS/STING pathway and type Iinterferon response. These findings indicate that this form of BAX/BAK-dependent caspase-independent celldeath which we termed mimptosis is highly inflammatory. Here we engineer models of inducible cell death inmurine melanoma and genetically engineered mouse models (GEMMs) of clear cell renal cell carcinoma(ccRCC) to compare the immune response to apoptosis mimptosis pyroptosis and necroptosis in vivo. Ourgoal is to identify the most immunogenic cell death that not only kills cancer cells but also instructs the immunesystem to enhance ICB response and elucidate the underlying molecular mechanisms using a comprehensivesystems biology approach. In Aim 1 we will characterize the impact of different kinds of engineeredimmunogenic cell death (ICD) on tumor-immune ecosystem dynamics melanoma using integrated single-cellmultiome paired single-cell RNA and T cell receptor (TCR) sequencing and multiplexed immunofluorescence.Computational modeling will define immune cell gene expression and regulatory programs in response to ICDto inform therapeutic strategies to improve ICB. In Aim 2 we will determine whether and how immunogenic cellabrogates tumor progression and metastasis and generates immunological memory against tumor rechallengein GEMMs of ccRCC. A comprehensive multidimensional assessment and computational modeling of tumor-immune ecosystem evolution T cell epigenetic and functional states and TCR repertoire in response to differenttypes of cell death will unravel mechanisms that promote anti-tumor immunity. TCGA analysis revealed that lowexpression of apoptosome components APAF1 and Caspase-9 is associated with better survival outcomessuggesting that caspase-independent mimptosis may activate anti-tumor immunity and confer survival benefitsin ccRCC. We will assess this hypothesis by performing single-nucleus multiome and MxIF in patient ccRCCsamples to characterize tumor-immune cross-talk comparing ccRCC with low vs high apoptosome expression. +No NIH Category available Adenocarcinoma Cell;Alzheimer's Disease;Apoptosis;Astrocytes;Basement membrane;Binding;Blood Vessels;Brain;Breast Cancer Cell;Cancer Patient;Cell Communication;Cells;Clinical;Communication;Complex;Disease associated microglia;Disseminated Malignant Neoplasm;ERBB2 gene;Exclusion;Extracellular Matrix Proteins;Factor Analysis;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Growth;Homeostasis;Immune;Immune system;Immunologist;Label;Laminin;Lead;Learning;Logic;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator;Memorial Sloan-Kettering Cancer Center;Metastatic malignant neoplasm to brain;Microglia;Modeling;Morbidity - disease rate;Natural Immunity;Nature;Neoplasm Metastasis;Neural Cell Adhesion Molecule L1;Patients;Phenotype;Physicians;Primary Neoplasm;Research;Research Personnel;Resistance;Sampling;Shapes;Signal Transduction;System;Systems Analysis;Systems Biology;Testing;Therapeutic Intervention;Tissues;Transcriptional Regulation;autocrine;brain cell;brain shape;cancer cell;cell type;cerebral capillary;contextual factors;differential expression;knowledge of results;lung colonization;malignant breast neoplasm;mortality;mouse model;multiple omics;pharmacologic;prevent;programs;response;single cell analysis;single-cell RNA sequencing;spatial relationship;spatiotemporal;therapeutic development;therapeutic evaluation;triple-negative invasive breast carcinoma;tumor;tumor growth;unpublished works Project I: Systems analysis of tumor-stroma interactions in brain metastasis n/a NCI 10705775 8/22/23 0:00 RFA-CA-21-048 5U54CA274492-02 5 U54 CA 274492 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9088 1894200 "MASSAGUE, JOAN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 495600 280000 215600 Project I. Systems Analysis of Tumor-Stroma Interactions in Brain MetastasisExperimental Lead: MassaguComputational Lead: PeerPROJECT SUMMARYThe overall goal of this project is to apply systems-level computational approaches to mouse models and clinicalsamples to unravel strategies that metastatic cancer cells employ to colonize the brain. Brain metastasis is amajor cause of morbidity and mortality in breast and lung cancer patients. The Massagu Lab pioneered studiesto identify mediators of brain metastasis and relevant cell-cell interactions and are subjecting this problem tosystems-level analysis with the Peer Lab. We recently found that brain metastatic lesions of triple-negativebreast cancer (TNBC) HER2+ breast cancer (HER2BC) and lung adenocarcinoma (LUAD) in mouse modelsand patient samples display remarkable differences in the spatial relationship between cancer cells and the hosttissue. TNBC and LUAD cells spread along brain capillaries via L1CAM forming perivascular colony networksthat intermingle with microglia and astrocytes. In sharp contrast HER2BC cells colonize the brain by formingcompact spheroidal colonies that exclude brain parenchymal cells. High expression of specific extracellularmatrix proteins by HER2BC cells drives this spheroidal growth. Notably the perivascular and spheroidal coloniestrigger distinct disease-associated microglia (DAM) innate immunity stages previously defined in Alzheimersdisease. Aim 1 is to elucidate the DAM regulatory mechanisms in metastasis-associated microglia. Wewill resolve transcriptional regulation of the homeostasis-to-DAM transition in brain metastasis by analyzingsingle-cell multiomic profiles of metastasis-associated microglia. We will dissect how cancer cells trigger andmodulate DAM responses by testing the hypothesis that HER2BC apoptosis triggers stage 2 DAM whereasenhanced survival of TNBC retains stage 1 DAM. We will identify drivers of TNBC-intrinsic resistance toapoptosis by computationally guided search for autocrine pro-survival signaling in TNBC cells. We will determinehow stage 1 DAM supports tumor growth. We will seek to connect metastasis-associated microglia to activatedmicroglia states across contexts by supervised gene set analysis. Aim 2 is to define spatiotemporalprogression and multicellular communication in brain metastasis by a systems-level analysis. We andothers have shown the engagement of multiple cell types besides microglia to support brain metastasis. Theseinteractions call for a comprehensive interrogation of the various ensembles of multicellular communication thatshape brain metastasis. We will leverage our LUAD-to-brain metastasis models to study what cell types andprograms constitute multicellular communication ensembles. We will analyze intact metastatic colonies to learnwhere the cells are localized and which programs are differentially expressed. We will unravel how the cellsand programs shape metastasis by computationally inferring the formation and impact of multicellular ensemblesfrom snapshots of metastatic colonies. We will perturb the inferred ensembles to test therapeutic interventionparadigms. The resulting knowledge enriched with the input of the CSBC Research Center immunologists andphysicians will ultimately guide the development of therapeutic interventions to target brain metastases.1 +No NIH Category available Administrative Efficiency;Adopted;Advisory Committees;Award;Collaborations;Communication;Communities;Data;Ensure;Faculty;Feedback;Funding;Goals;Human Resources;Immune system;Infrastructure;Leadership;Malignant Neoplasms;Measures;Memorial Sloan-Kettering Cancer Center;Mentors;Pilot Projects;Postdoctoral Fellow;Procedures;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Review Committee;Structure;System;Systems Biology;Training;Work;data management;data sharing;high school;multidisciplinary;next generation;organizational structure;outreach;programs;tool;tumor;tumor immunology;undergraduate student Administrative Core n/a NCI 10705771 8/22/23 0:00 RFA-CA-21-048 5U54CA274492-02 5 U54 CA 274492 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 9086 8049199 "LESLIE, CHRISTINA S" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 407100 230000 177100 Administrative CoreSUMMARYThe Administrative Core of the Center for Tumor-Immune Systems Biology will work collectively to support andaccomplish the proposed goals of the center. The administrative core will provide the organizational support andleadership to the Research Projects Shared Resource Core and Outreach Core to accomplish their goals anddisseminate the accomplishments of each Project and Research Center lab to all Research Center investigatorsand the scientific community at large. The Research Center Administration will also serve as the nexus forResearch Center communication provide budgetary review and scientific oversight and fulfill reportingrequirements to the NCI. The leadership team of the multiple PIs Drs. Christina Leslie and Alexander Rudenskywill oversee the research teams and the shared resource administrative and outreach cores. The ScientificDirector (Dr. Lalitha Ramanthapuram) and Data Manager (Dr. Tal Nawy) will work with the core leaders to fulfillthe administrative project management and data management responsibilities of the center. +No NIH Category available Achievement;Anatomy;Area;Basic Science;Behavior;Biological Markers;Biology;Biomedical Engineering;Biometry;Cancer Biology;Caring;Characteristics;Clinical;Clinical Investigator;Committee Members;Dana-Farber Cancer Institute;Development;Diagnosis;Discipline;Disease;Disease model;Doctor of Philosophy;Ensure;Equilibrium;Faculty;Foundations;Funding;Funding Mechanisms;Genetic;Genetic Predisposition to Disease;Genomics;Genotype;Goals;In Vitro;Individual;Institution;Interdisciplinary Study;Investigational Therapies;Laboratories;Leadership;Learning;Life Expectancy;Medical;Medical Oncologist;Medical Oncology;Medicine;Mentors;Mentorship;Minority;Molecular;Nature;Operative Surgical Procedures;Pathologist;Pathology;Patients;Pediatric Oncology;Phenotype;Productivity;Qualifying;Quality of life;Radiation;Radiation Oncologist;Radiation Oncology;Records;Rejuvenation;Research;Research Personnel;Research Support;Science;Scientist;Solid;Source;Specialist;Surgeon;Surgical Oncology;Talents;Time;Training;Translational Research;Universities;Uterine Leiomyosarcoma;Validation;Woman;cancer type;care coordination;career;career development;design;experience;human capital;improved;in vitro Model;in vivo Model;innovation;insight;integrated care;interdisciplinary approach;leiomyosarcoma;member;multidisciplinary;novel strategies;novel therapeutic intervention;pressure;programs;recruit;sarcoma;soft tissue;success;translational cancer research;translational scientist;translational study;tumor Career Enhancement Program n/a NCI 10705765 8/22/23 0:00 PAR-20-305 5P50CA272170-02 5 P50 CA 272170 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-N 9084 11841939 "DEMICCO, ELIZABETH " Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 87209 49369 37840 Career Enhancement Program (CEP): Project Summary / AbstractBy its very nature leiomyosarcoma (LMS) demands a multi-disciplinary approach to care and research. LMS arehighly aggressive tumors which frequently present at high stage and require the coordinated and integratedcare of surgeons radiation oncologists and medical oncologists. In addition the diverse nature of the anatomicsites of presentation the differential behavior and molecular characteristics of soft tissue and uterine LMS andgenotypic and phenotypic overlap with other pleomorphic sarcomas demands the involvement of anatomic andmolecular pathologists. This SPORE will be uniquely poised to provide career development opportunities andmentorship for young investigators in all of these disciplines. In particular the SPORE CEP will recruit andpromote promising young researchers to pursue careers in translational studies of LMS or genetic predispositionfor sarcoma/LMS. The SPORE mechanism will provide these CEP awardees with rich opportunities to interactwith and learn from basic translational and clinical sarcoma researchers from key disciplines. Elizabeth G. Demicco MD PhD (University of Toronto) and Jonathan A. Fletcher MD (Dana FarberCancer Institute) will serve as co-directors for the SPORE CEP committee. The CEP committee will assist theco-directors in ensuring that the CEP meets its goals and that awardees are progressing in their careerdevelopment and being adequately mentored. The committee represents the multi-disciplinary natureof translational sarcoma research with particular expertise in sarcoma biology target discovery andvalidations genomics experimental therapeutics biostatistics surgery radiation medicinebiomarkers and pathology. The committee members are academic leaders at the SPORE memberinstitutions with experience in LMS. As seen across sarcoma-relevant medical and surgical disciplineswomen and minorities continue to be underrepresented. It is a priority for this SPORE that diversity isenhanced in sarcoma research and we have endeavored to contribute to this effort by including womenas members of all SPORE Committees and in the program leadership. Providing research support and protected time for young investigators is essential in translationalresearch particularly in sarcoma research where funding mechanisms are few. The SPORE CEP will facilitatetransition of awardees to independent investigator status and will prioritize funding early career scientists whoseek to advance quality of life through research on disease mechanisms. Specific aims that assist the SPORECEP in achieving these goals include: 1. Identifying and providing exceptional science and career mentorship toyoung sarcoma researchers; 2. Enforcing adequate protected time for clinically-oriented investigators to facilitatetheir development into independent translational researchers; 3. Recruiting highly qualified minority and womeninvestigators from diverse clinical and scientific backgrounds into translational LMS research; and 4. Promotingmulti-disciplinary research by encouraging young investigators to participate in scientific retreats. +No NIH Category available Archives;Area;Bioinformatics;Biological Assay;Biometry;Cancer Biology;Cancer cell line;Case Report Form;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Cohort Studies;Collaborations;Collection;Communication;Complement;DNA Damage;Data;Data Analyses;Data Collection;Data Set;Data Sources;Databases;Dedications;Dependence;Development;Diagnosis;Encyclopedias;Ensure;Epidemiology;Experimental Designs;Generations;Genetic;Genomics;Human Resources;Information Dissemination;Infrastructure;Institution;Investigational Therapies;Knowledge;Li-Fraumeni Syndrome;Link;Location;Malignant Neoplasms;Manuscripts;Maps;Methodological Studies;Methodology;Michigan;Molecular;Nature;Patients;Policies;Population Database;Prospective cohort;Quality Control;Registries;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Resources;Sampling;Source;Time;Universities;Utah;Work;adverse event monitoring;career development;computational platform;data access;data management;data mining;data quality;data standards;drug sensitivity;epidemiology study;experience;experimental study;genomic data;health data;improved;leiomyosarcoma;member;multidisciplinary;novel strategies;programs;public repository;radiomics;research study;response;sample collection;single-cell RNA sequencing;transcriptome sequencing;translational study;trial design Core C- Data Analysis Core n/a NCI 10705756 8/22/23 0:00 PAR-20-305 5P50CA272170-02 5 P50 CA 272170 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-N 9081 9060637 "BALADANDAYUTHAPANI, VEERABHADRAN " Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 174574 136734 37840 Core C Data Analysis Core - Summary/Abstract:The objective of the Data Analysis Core (DAC) is to provide a comprehensive multidisciplinary resource forthe research associated with the SPORE. The needs of these projects require a wide breath of biostatistics andbioinformatics analytical knowledge as well as computational expertise. The DAC will provide biostatistical andbioinformatic collaboration in support of the discovery translational and clinical studies associated with theSPORE research activities. The comprehensive nature of this core assures each SPORE investigator access toexpertise that includes collaborative development of study designs collection and management of datageneration of analysis plans support for clinical trials analysis of data interpretation of data development ofcomputational platforms for data mining and dissemination of results (e.g. abstracts presentationsmanuscripts). Furthermore the DAC will facilitate knowledge-sharing among the projects and cores by identifyingand communicating best practices standardizing data when possible centralizing data for use across theprojects and conveying results to SPORE investigators in a timely fashion. Finally the core is poised to developnew methodology when needed to support the SPORE research as well as to adapt to changes in researchstrategy in response to new or unexpected findings. In summary to support all proposed SPORE projects theCareer Development and Developmental Research Programs the other cores and related SPORE researchthe DAC will (1) provide biostatistics and bioinformatics collaboration for all SPORE research activities (2)facilitate data collection management integration and storage for SPORE research activities and (3) developand implement methodology that enhances the research across the SPORE projects.The members of DAC will work closely with team members of each of the projects. In addition they willcollaborate closely with bioinformatics personnel within the research teams of the project PIs to ensure alignmentof the statistical aspects with the bioinformatics efforts and allow the integration of bioinformatics data acrossprojects. The members of DAC will engage in regular communication with SPORE projects other Cores SPOREPIs. +No NIH Category available Address;Age;Apoptotic;Benign;Bioinformatics;Biological;Biological Assay;Biological Markers;Blood;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Categories;Cessation of life;Classification;Clinical;Clinical Pathology;Communication;Complement;DNA;DNA Markers;DNA Methylation;DNA Sequence;DNA analysis;Data;Detection;Diagnosis;Diagnostic Procedure;Diameter;Dreams;Early Detection Research Network;Early Diagnosis;Event;Frequencies;Funding;Genes;Goals;Healthcare;High Prevalence;Histology;Human;Hypermethylation;Laboratories;Lung;Lung Neoplasms;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Methods;Methylation;Molecular;Necrosis;Nodule;Nucleic Acids;Organ;Participant;Patients;Performance;Plasma;Population;Preparation;Process;Prospective cohort;Protocols documentation;Radiology Specialty;Reagent;Reporting;Reproducibility;Research Personnel;Risk;Sampling;Screening for cancer;Sensitivity and Specificity;Signal Transduction;Site;Source;Specimen;Standardization;Testing;The Cancer Genome Atlas;Time;United States;Work;biomarker development;bisulfite;cell free DNA;circulating DNA;clinical practice;cohort;computed tomography screening;cost;detection assay;detection method;detection platform;improved;laboratory development;lung cancer screening;methylation biomarker;mortality;neoplastic cell;novel;novel strategies;operation;prospective;screening;tumor;tumor DNA;wasting Optimizing Ultrasensitive DNA methylation detection for lung cancer and other malignancies This proposal for a Biomarker Characterization Center seeks to improve upon the managementof lung cancer and other malignancies through detection of tumor specific abnormal DNAmethylation in plasma. The Biomarker Development Lab will discover new loci with a highprevalence of cancer specific methylation in lung cancer and others and develop new and moresensitive methods of detection. These approaches will be transferred to the BiomarkerReference Lab for testing in a clinical setting and operations of these two components and theircommunication facilitated by the Administrative Core. NCI 10705752 8/8/23 0:00 RFA-CA-21-035 5U2CCA271885-02 5 U2C CA 271885 2 "WANG, WENDY" 9/16/22 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 6365905 "HERMAN, JAMES G." "STASS, SANFORD A; WANG, TZA-HUEI JEFF " 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 879659 NIDCR 37326 12674 This proposal for a Biomarker Characterization Center (BCC) for the Early Detection ResearchNetwork (EDRN) seeks to improve the management of lung cancer through detection of cancer-specific DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) whichwill optimize the methylation detection methods implementation of these methods for clinical usethrough a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testingin a clinical setting and an Administrative Core facilitating the interactions between the BDL andBRL and with other EDRN investigators and the NCI. Previous work by the applicants hasdemonstrated the potential of DNA methylation detection for cancer diagnostics and they havedeveloped extremely sensitive assays for the detection of hypermethylated DNA sequences andoptimized the isolation and processing of circulating cell-free DNA from tumors for these novelassays. The approach has been used to detect circulating cancer-specific DNA methylationchanges for the early diagnosis of lung cancer in patients with screen-detected pulmonarynodules. Although sensitivity and specificity of the assay are promising additional improvementsin the performance are required for implementation of this approach in the setting of cancerscreening. In this BCC detection of cancer-specific DNA methylation changes in the plasma willbe further improved and new approaches developed and implemented to address the challengesof ultrasensitive detection of DNA methylation in the blood. In addition we will assess the potentialof these methods to detect other common and lethal malignancies. Our bioinformatic analysis ofDNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequentcancer-specific methylation events common to all cancers including lung cancer that will bedeveloped into universal cancer detection assays. The use of TCGA data has also resulted in theidentification of other methylation alterations that allow determination of the origin (organ site) ofthis cancer-specific signal. The combination of optimal sample processing ultrasensitivemethylation detection developed with universal cancer and histology specific loci detection willallow improved lung cancer early detection in the setting of CT screening and management ofdetection of other cancer-specific DNA methylation from blood. 50000 +No NIH Category available Address;Age;Apoptotic;Benign;Bioinformatics;Biological;Biological Assay;Biological Markers;Blood;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Categories;Cessation of life;Classification;Clinical;Clinical Pathology;Communication;Complement;DNA;DNA Markers;DNA Methylation;DNA Sequence;DNA analysis;Data;Detection;Diagnosis;Diagnostic Procedure;Diameter;Dreams;Early Detection Research Network;Early Diagnosis;Event;Frequencies;Funding;Genes;Goals;Healthcare;High Prevalence;Histology;Human;Hypermethylation;Laboratories;Lung;Lung Neoplasms;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Methods;Methylation;Molecular;Necrosis;Nodule;Nucleic Acids;Organ;Participant;Patients;Performance;Plasma;Population;Preparation;Process;Prospective cohort;Protocols documentation;Radiology Specialty;Reagent;Reporting;Reproducibility;Research Personnel;Risk;Sampling;Screening for cancer;Sensitivity and Specificity;Signal Transduction;Site;Source;Specimen;Standardization;Testing;The Cancer Genome Atlas;Time;United States;Work;biomarker development;bisulfite;cell free DNA;circulating DNA;clinical practice;cohort;computed tomography screening;cost;detection assay;detection method;detection platform;improved;laboratory development;lung cancer screening;methylation biomarker;mortality;neoplastic cell;novel;novel strategies;operation;prospective;screening;tumor;tumor DNA;wasting Optimizing Ultrasensitive DNA methylation detection for lung cancer and other malignancies This proposal for a Biomarker Characterization Center seeks to improve upon the managementof lung cancer and other malignancies through detection of tumor specific abnormal DNAmethylation in plasma. The Biomarker Development Lab will discover new loci with a highprevalence of cancer specific methylation in lung cancer and others and develop new and moresensitive methods of detection. These approaches will be transferred to the BiomarkerReference Lab for testing in a clinical setting and operations of these two components and theircommunication facilitated by the Administrative Core. NCI 10705752 8/8/23 0:00 RFA-CA-21-035 5U2CCA271885-02 5 U2C CA 271885 2 "WANG, WENDY" 9/16/22 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 6365905 "HERMAN, JAMES G." "STASS, SANFORD A; WANG, TZA-HUEI JEFF " 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 879659 NCI 619346 210313 This proposal for a Biomarker Characterization Center (BCC) for the Early Detection ResearchNetwork (EDRN) seeks to improve the management of lung cancer through detection of cancer-specific DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) whichwill optimize the methylation detection methods implementation of these methods for clinical usethrough a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testingin a clinical setting and an Administrative Core facilitating the interactions between the BDL andBRL and with other EDRN investigators and the NCI. Previous work by the applicants hasdemonstrated the potential of DNA methylation detection for cancer diagnostics and they havedeveloped extremely sensitive assays for the detection of hypermethylated DNA sequences andoptimized the isolation and processing of circulating cell-free DNA from tumors for these novelassays. The approach has been used to detect circulating cancer-specific DNA methylationchanges for the early diagnosis of lung cancer in patients with screen-detected pulmonarynodules. Although sensitivity and specificity of the assay are promising additional improvementsin the performance are required for implementation of this approach in the setting of cancerscreening. In this BCC detection of cancer-specific DNA methylation changes in the plasma willbe further improved and new approaches developed and implemented to address the challengesof ultrasensitive detection of DNA methylation in the blood. In addition we will assess the potentialof these methods to detect other common and lethal malignancies. Our bioinformatic analysis ofDNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequentcancer-specific methylation events common to all cancers including lung cancer that will bedeveloped into universal cancer detection assays. The use of TCGA data has also resulted in theidentification of other methylation alterations that allow determination of the origin (organ site) ofthis cancer-specific signal. The combination of optimal sample processing ultrasensitivemethylation detection developed with universal cancer and histology specific loci detection willallow improved lung cancer early detection in the setting of CT screening and management ofdetection of other cancer-specific DNA methylation from blood. 829659 +No NIH Category available Address;Adult;Biological Assay;Biological Specimen Banks;Blood;Cancer Biology;Cells;Child;Clinical Research;Collaborations;Collection;Data;Databases;Dermis;Diagnosis;Doctor of Philosophy;Ensure;Future;Gastrointestinal tract structure;Genetic;Genomics;Guidelines;Heart;Histology;Hospitals;Human;Immunohistochemistry;Institution;Leadership;Limb structure;Malignant Neoplasms;Nature;Neoplasm Metastasis;Nucleic Acids;Organ;Pathologist;Pathology;Patients;Pediatric Hospitals;Physician Executives;Population;Procedures;Prognosis;Protocols documentation;Qualifying;Quality Control;Research;Research Institute;Research Personnel;Residual state;Resolution;Resources;Retroperitoneal Space;Sampling;Services;Slide;Smooth Muscle;Soft tissue sarcoma;Stains;Standardization;Surgical Pathology;Tissue Microarray;Tissues;Translational Research;Uterus;Veins;Woman;Work;accurate diagnosis;biobank;bone;diagnostic accuracy;digital imaging;experience;imaging system;improved;innovation;leiomyosarcoma;medical schools;novel strategies;participant enrollment;professor;rare cancer;sarcoma;success;technological innovation;translational goal;tumor Core B- Biospecimen Core Core B Biospecimen Core - Narrative:Leiomyosarcoma (LMS) is a rare and aggressive soft tissue sarcoma that can be difficult to diagnose and treat.The Biospecimen Core will support the LMS SPORE investigators by conducting expert pathology review andfacilitating the collection specialized processing storage and distribution of high quality biospecimens. Anyresidual biospecimens will be banked and made available following review to qualified investigators who haveinnovative ideas. NCI 10705751 8/22/23 0:00 PAR-20-305 5P50CA272170-02 5 P50 CA 272170 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-N 9079 15971263 "HORNICK, JASON " Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 254438 216598 37840 Core B Biospecimen Core: Summary/Abstract:The projects of this LMS SPORE will use leiomyosarcoma (LMS) biospecimens for translational research. A keyfunction of this Core will be ensuring the accuracy of diagnosis of LMS. To that end Jason Hornick MD PhDan expert sarcoma pathologist will Co-Direct the Biospecimen Core along with Nilsa Ramirez MD an expert inbiospecimen repositories and banking. The functions of the Biospecimen Core will include pathology reviewbiospecimen procurement from the institutions participating in the LMS SPORE clinical studies basic andspecialized processing management of biospecimen-related data and distribution of biospecimens and data toproject investigators. Biospecimens collected for this LMS SPORE will be prioritized to distribute to the LMSSPORE investigators for the defined projects. After the needs of the planned research have been addressedresidual banked biospecimens can be distributed to other investigators using existing mechanisms establishedby the Administrative Core/MPI of this LMS SPORE.The Biospecimen Core will provide the latest biorepository-based technological innovations and best practicesresulting in constant improvements in operational capabilities investigator access to biospecimens and thestewardship of these precious resources. Dr. Nilsa Ramirez who has extensive experience in the managementof biospecimen quality control processing and banking will oversee all activities of the Biospecimen Core andwill provide guidance to the Project leaders regarding biospecimen best practices. Dr. Hornick will oversee thereview of pathology and histology assessments to confirm diagnosis of all cases of LMS and will be the arbiterin case of discrepancy in the diagnosis.The Biospecimen Core will work closely with the Administrative Core and the project leadership to ensure thesuccess of the planned research. The collaborative nature of this LMS SPORE is necessary for the study of thissubtype of rare malignancies where only multi-institutional cooperation can facilitate the acquisition of sufficientbiospecimen resources vital to make progress. The biospecimens banked in the Biospecimen Core will providean essential resource for the LMS SPORE team as well as future investigators. +No NIH Category available Adult;Anesthesia procedures;Biological Markers;Biology;Biopsy;Biopsy Specimen;Blood;Blood specimen;Cancer Biology;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinical;Clinical Research;Clinical Trials;Clonal Evolution;Collection;Consensus;Correlation Studies;Cytotoxic Chemotherapy;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Disease Resistance;Doxorubicin;Evolution;Future;Gene Mutation;Genetic;Genomics;Heterogeneity;Image;In Vitro;Lesion;Malignant Neoplasms;Metastatic Leiomyosarcoma;Modality;Modeling;Mutation;Newly Diagnosed;Oncologist;Operative Surgical Procedures;Outcome;Patient Selection;Patient-Focused Outcomes;Patients;Pattern;Pilot Projects;Plasma;Prognosis;Prognostic Factor;Prognostic Marker;Progression-Free Survivals;Proxy;Radiology Specialty;Recurrence;Regimen;Relapse;Research;Research Personnel;Resistance;Risk;Safety;Sampling;Single Nucleotide Polymorphism;Smooth Muscle;Soft tissue sarcoma;Solid;Systemic Therapy;Technology;Testing;Time;Toxic effect;Treatment Failure;Treatment Futility;Unresectable;Validation;Variant;burden of illness;chemotherapy;clinical care;clinical decision-making;cohort;deep sequencing;design;disease natural history;disorder control;docetaxel;experience;experimental study;gemcitabine;genomic profiles;high risk;improved;improved outcome;in vivo;insight;leiomyosarcoma;liquid biopsy;next generation sequencing;novel;novel strategies;novel therapeutic intervention;participant enrollment;patient derived xenograft model;patient subsets;personalized medicine;prevent;prognostic;prospective;radiation risk;radiological imaging;resistance mechanism;response;side effect;single cell sequencing;therapy resistant;treatment response;treatment strategy;tumor;tumor DNA;tumor heterogeneity;tumor progression PROJECT 3: Applying Liquid Biopsy Technologies to Detect Clinical Response and Mechanisms of Resistance in the Treatment of LMS Project 3: Project NarrativeLeiomyosarcoma (LMS) is an aggressive soft tissue sarcoma that remains difficult to cure even with intensivechemotherapy and surgery. In this study blood samples from patients with metastatic LMS will be used to profilecirculating tumor DNA to identify genomic features that are associated with a high-risk of treatment failure.Results from this study will enable the development of new risk-based and personalized treatment strategies forpatients with LMS. NCI 10705742 8/22/23 0:00 PAR-20-305 5P50CA272170-02 5 P50 CA 272170 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-N 9077 9552082 "CROMPTON, BRIAN " Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 541504 503664 37840 Project 3: Project Summary / AbstractLeiomyosarcoma (LMS) is an aggressive soft tissue sarcoma (STS) with evidence of smooth muscledifferentiation and is one of the most common STS in adults. Nearly half of patients will develop metastaticdisease either prior to diagnosis or during their clinical care. Chemotherapy is the primary modality for treatmentof metastatic LMS and the standard chemotherapy regimens use doxorubicin or gemcitabine. Thesechemotherapy agents carry a significant risk of toxicity yet only 15-20% of patients will experience an objectiveresponse and only 5-10% will achieve long-term disease control. The median progression-free survival forpatients with metastatic LMS treated with either doxorubicin or a gemcitabine-based regimen is 6 months.Despite intensive research efforts to understand the biology of LMS most studies have been underpowered tocorrelate recurrent genomic features at diagnosis with clinical outcomes. Patterns of tumor evolution that giverise to relapse and chemotherapy resistance have remained unstudied due to the safety concerns associatedwith anesthesia and surgery to obtain serial tumor biopsies for research. Newly available liquid biopsytechnologies enable the detection of circulating tumor DNA (ctDNA) in the blood of patients with cancer. In somemalignancies ctDNA levels correlate with prognosis and changes in ctDNA levels correspond to diseaseresponse and progression. In Project 3 a prospective collection of blood samples from patients with metastaticLMS receiving doxorubicin or gemcitabine/docetaxel chemotherapy will be used to study the correlation betweenctDNA levels and clinical outcomes in patients with newly diagnosed metastatic LMS as Aim 1. Data from thebiomarker study will also validate ctDNA as a novel prognostic biomarker. Copy number alterations of genes inLMS from patients enrolled in the biomarker study in Aim 1 will also be examined as potential prognostic factorsand biomarkers of resistance to front-line chemotherapy. Recent studies show that deep sequencing of ctDNAcan be used as a proxy for sequencing of tumor biopsy samples. Evidence suggests that genomic profiles fromctDNA better represent genomic heterogeneity in patients with metastatic disease than any single biopsy sample.In Aim 2 we propose to profile serial ctDNA samples to identify recurrent patterns of tumor heterogeneity anddisease evolution in LMS and to validate identified acquired genetic changes associated with chemotherapyresistance using patient-derived xenograft models. These studies will have a major impact on development of abiomarker for LMS and LMS treatment and will fundamentally broaden the understanding of LMS and the naturalhistory of this disease. Validation of mechanisms of evolution that give rise to resistant disease could lead todevelopment of novel therapeutic approaches designed to prevent the emergence of resistance and improveoutcomes for patients with metastatic LMS in the near future. +No NIH Category available African American population;Aliquot;Anthropometry;Bayesian Modeling;Biological Markers;Blood;Blood specimen;Calibration;California;Cancer health equity;Cessation of life;Chemicals;Chronic Disease;Clinical;Cohort Studies;Computerized Medical Record;Consultations;Cost efficiency;Cryopreservation;Cultural Diversity;Data;Data Analyses;Data Management Resources;Data Security;Data Set;Databases;Diagnosis;Diagnostic;Dietary intake;Disease Outcome;Energy Intake;Energy Metabolism;Ensure;Environment;Environmental Epidemiology;Environmental Exposure;Environmental Risk Factor;Epigenetic Process;Ethnic Origin;Ethnic Population;Etiology;Funding;Genetic;Genomics;Genotype;Geographic Locations;Grant;Hawaii;Health;Health behavior;Hospitals;Incidence;Indirect Calorimetry;Infrastructure;Intake;Japanese American;Latino Population;Leadership;Life Style;Lymphocyte;Maintenance;Malignant Neoplasms;Measurement;Measures;Medical;Medicare/Medicaid;Methodology;Native Hawaiian;Neighborhoods;Normal tissue morphology;Oral;Outcome;Paper;Participant;Phenotype;Physical activity;Physiological;Pilot Projects;Planning Techniques;Postdoctoral Fellow;Prospective cohort study;Publishing;Questionnaires;Race;Registries;Research;Research Methodology;Research Personnel;Research Project Grants;Residual state;Resources;Rest;Risk Factors;Saliva;Sampling;Science;Slide;Social Environment;Specimen;Structural Racism;Students;Testing;Tissue Banks;Tissue Sample;Training;Tumor Tissue;United States National Institutes of Health;Urine;Vertebral column;Vital Statistics;Woman;actigraphy;biobank;blood product;climate change;cohort;complex data;computerized;data harmonization;data sharing;database of Genotypes and Phenotypes;design;dietary;digital repositories;disorder prevention;epigenomics;ethnic difference;ethnic disparity;ethnic diversity;ethnic health disparity;ethnic minority;follow-up;genetic risk factor;genome wide association study;improved;indexing;innovation;member;men;metabolomics;microbiome research;multi-ethnic;neoplasm registry;novel strategies;nutrition;programs;prospective;racial disparity;racial diversity;racial health disparity;racial minority;racial population;social health determinants;stool sample;tumor;tumor registry;web platform;willingness Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study This renewal application seeks support for the infrastructure maintenance of the Multiethnic Cohort (MEC)Study established in 1993-1996 to continue a well-integrated program of research testing innovativehypotheses aimed at ensuring that racial/ethnic disparities are investigated and progress in disease preventionapplies to major US racial/ethnic minorities. By including 215251 men and women mostly of 5 racial/ethnicpopulations (African Americans Japanese Americans Latinos Native Hawaiians and Whites) the MEC is themost racially and ethnically diverse cancer cohort and its value for etiologic research on chronic diseases iswidely recognized. Leadership of the MEC entails a highly interactive team-science approach; investigatorshave amply demonstrated willingness to share data and samples. NCI 10705732 8/30/23 0:00 PAR-20-294 5U01CA164973-12 5 U01 CA 164973 12 "MAHABIR, SOMDAT" 9/1/12 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 1898900 "LE MARCHAND, LOIC " "HAIMAN, CHRISTOPHER ALAN; WILKENS, LYNNE R" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2398162 NCI 1920498 477664 This renewal application seeks support for the infrastructure of the Multiethnic Cohort (MEC) Study which wasestablished in Hawaii and southern California in 1993-1996 to study risk factors for cancer and other chronicdiseases. The study was designed to take advantage of the ethnic and cultural diversity of the two geographicareas as well as the expertise of the investigators in nutrition ethnic/racial disparities studies and genetics. Itis the most ethnically diverse cancer cohort in existence. It achieves high cost-efficiency by significantlysupplementing active follow-up information with computerized linkages to SEER cancer registries vitalstatistics hospital-discharge diagnoses medical claim data electronic medical records and geospatialinformation. At baseline the cohort included information on 215000 men and women comprised almostentirely of five ethnic/racial populations: Japanese Americans Latinos Whites African Americans and NativeHawaiians. The resource was later expanded to include a prospective biorepository of blood specimens from~70000 of the participants and urine specimens on a large subset. Leadership of the MEC entails a highlyinteractive team-science approach and the investigators have amply demonstrated their willingness to sharedata/samples and to participate actively in consortia. Research accomplishments include significantcontributions to understanding both genetic and environmental risk factors for cancer. Over 291 papersdescribing our findings have been published during the current grant cycle. In addition over the last 28 years129 NIH grants/supplements have been built around the MEC (77 were active in the current cycle) and morethan 136 students and postdoctoral fellows have been trained on the study. This application describes ouraims over the next 5 years for maintaining and enhancing the infrastructure of the MEC as well as plans formethodological research. We project adding 7253 incident cancer cases in the new 5 years to the current48064 cases; 2670 of these cases will have pre-diagnostic blood samples to be added to the current 10957cases. We will add 6K FFPE tumor samples to the current ~13K. In addition this grant renewal will makepossible the continuation of a well-integrated program of research aimed at evaluating lifestyle environmentaland genetic risk factors and social determinants of health for cancer and other common chronic diseasestaking advantage of new approaches such as dietary quality indices exposomics genomics epigenomicsmicrobiomics metabolomics and multilevel exposures including spatial environment structural racism andclimate change. The MEC will allow the testing of innovative research hypotheses aimed at ensuring thatracial/ethnic health disparities are investigated and that progress in disease prevention applies to all major USracial/ethnic minorities. 2398162 +No NIH Category available American;American Cancer Society;Area;Basic Science;Bioinformatics;Biological Assay;Biometry;Cancer Biology;Cancer Etiology;Cataloging;Cells;Clinical;Clinical Trials Design;Cloud Computing;Collaborations;Communication;Communities;Computational Biology;Cues;Data;Data Collection;Data Coordinating Center;Data Science;Data Storage and Retrieval;Dedications;Desmoplastic;Diagnosis;Disease;Disease Outcome;Ecosystem;Education;Education and Outreach;Educational Activities;Educational workshop;Elements;Ensure;Extracellular Matrix;Fibroblasts;Funding;Genetic;Goals;Group Meetings;Growth;Heterogeneity;Immune;Infrastructure;Intranet;Lymphovascular;Malignant Neoplasms;Malignant neoplasm of pancreas;Mentorship;Mission;Molecular;Outcome;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Pathology;Patients;Persons;Policies;Procedures;Reagent;Registries;Regulation;Research;Research Activity;Research Personnel;Role;Secure;Site;Site Visit;Solid;Specificity;Stromal Neoplasm;System;Therapeutic;Time;Tissues;Transfer Agreement;Translational Research;Tumor Promotion;Twitter;Underrepresented Minority;United States;United States National Institutes of Health;analytical tool;biobank;cancer genetics;computing resources;data dissemination;data exchange;data harmonization;data management;improved;innovation;material transfer agreement;meetings;member;microbiome;minority trainee;molecular pathology;mortality;multidisciplinary;multimodal data;neoplastic cell;pancreas visualization;pancreatic tumorigenesis;programs;research study;response;shared database;social media;success;survival outcome;symposium;tumor;tumor immunology;tumor microenvironment;virtual;web site;working group PASSCODE (Pancreatic Adenocarcinoma Stromal Reprograming ConSortium COordination Data Management and Education) PROJECT NARRATIVEThe goal of the interdisciplinary PASSCODE (Pancreatic Adenocarcinoma Stromal Reprograming ConSortiumCOordination Data Management and Education) is to serve as an organizing hub for coordinationcommunication and collaboration within the Pancreatic Cancer Stromal Reprogramming Consortium (PSRC).The PASSCODE will provide administrative support facilitate communication and collaboration provide acentralized venue for data management analysis and storage and serve as a platform for consortium outreachand educational activities. Through its efforts PASSCODE will significantly enhance the meaningful progressmade by PSRC in improving survival outcomes for pancreatic cancer. NCI 10705730 8/29/23 0:00 RFA-CA-21-042 5U24CA274274-02 5 U24 CA 274274 2 "UJHAZY, PETER" 9/16/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M1) 7626839 "MAITRA, ANIRBAN " "LEE, J. JACK " 9 PATHOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 972000 NCI 600000 372000 ABSTRACTA defining feature of Pancreatic ductal adenocarcinoma (PDAC) is the presence of a host stromal responsewhich is characteristically more robust (desmoplastic) than many solid cancers. Stromal elements includingcancer-associated fibroblasts (CAFs) and the extracellular matrix are pivotal components of the tumormicroenvironment (TME) ecosystem in PDAC which also includes immune cells the lymphovascular systemand the intra-tumoral microbiome. In recent years the role of the PDAC stroma (and CAFs in particular) hasmorphed to one characterized by profound heterogeneity plasticity and context-specificity. The newly createdPancreatic Cancer Stromal Reprogramming Consortium (PSRC) will fund a team of six U01 sites to conductbasic and translational research studies on the role of the stroma and other TME constituents in PDACpathogenesis and outcomes. We have collated a multidisciplinary team of investigators at UT MD Anderson withthe goal of creating PASSCODE (Pancreatic Adenocarcinoma Stromal Reprograming ConSortiumCOordination Data Management and Education Center) that will serve as an organizing hub for coordinationcommunication and collaboration within the PSRC and support the newly funded U01 sites. PASSCODE will beco-led by Dr. Anirban Maitra an expert in PDAC pathology genetics and cancer biology and Dr. J. Jack Leean expert in biostatistics clinical trial design and data science. PASSCODE proposes four aims: First we willsupport the administrative infrastructure of the PSRC and ensure effective communication and collaborationbetween consortium investigators the NCI program office and other trans-NCI networks including facilitating allof the PSRC-approved in-person and virtual meetings. We will also provide operational support for material anddata transfer agreements that are germane to the collaborative studies within the PSRC. Second we will developa framework for a PSRC virtual biorepository as a registry database for shared biospecimen access across theconsortium and develop SOPs for processing storage cataloging and distribution of annotated biospecimensand de-identified clinical demographic and molecular information. Third we will provide centralized datamanagement and data storage capabilities for the PSRC with the overarching goal of data harmonization anddissemination within and beyond the consortium. As part of this aim PASSCODE will provide dedicatedbiostatistical and bioinformatics analytical tools and multimodal data visualization for PSRC investigatorsincluding for approved collaborative projects. Fourth PASSCODE will be responsible for developing andmaintaining both a public facing PSRC website and other social media outlets as well as a secure intranet site.We will organize seminars and workshops that highlight progress within the PSRC and provide a platform foreducational/mentorship opportunities especially with regards to enhancing the participation of underrepresentedminority trainees. Cumulatively PASSCODEs activities will be geared towards ensuring the success of theconsortiums mission of improving PDAC survival through innovative and collaborative research endeavors. 972000 +No NIH Category available Address;Aftercare;Biochemical;Biological;Biological Assay;Biological Markers;Biopsy;CRISPR interference;CRISPR screen;CRISPR-mediated transcriptional activation;Cancer Biology;Cell Line;Cells;Chromosomal Instability;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Compensation;Coupled;Cytotoxic Chemotherapy;Cytotoxic agent;DNA;DNA Damage;Data Analyses;Defect;Dependence;Diagnosis;Dose;Doxorubicin;Enzymes;Essential Genes;Evaluation;Event;Family;Genes;Genetic;Genetic Transcription;Genomics;Genotoxic Stress;Goals;Guide RNA;Heterogeneity;In Vitro;Investigational Therapies;Libraries;Mediating;Metastatic Leiomyosarcoma;Minority;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;PIK3CG gene;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphotransferases;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Protein Kinase;Proteins;RB1 gene;Reproducibility;Resistance;Resources;Safety;Science;Specimen;TP53 gene;Testing;Therapeutic;Time;Toxic effect;Validation;chemotherapy;clinical translation;ds-DNA;gene repression;genomic profiles;genotoxicity;homologous recombination;improved;inhibitor;inhibitor therapy;insight;leiomyosarcoma;member;novel strategies;pre-clinical;preclinical study;predicting response;protein kinase inhibitor;repaired;resistance mechanism;response;sarcoma;targeted treatment;therapy development;transcriptome sequencing;validation studies PROJECT 1: Genomic Vulnerabilities in Leiomyosarcoma (LMS) Project 1: NarrativeProject 1 seeks to develop therapies that maximize intrinsic LMS genotoxic stress by targeting the key DNAdamage response enzyme DNA protein kinase. We have shown that most LMS have chromosomal instability(CIN) which creates hyper-dependence on this enzyme. The initial clinical trial in this Project tests the hypothesisthat a very low dose of doxorubicin sensitizes LMS cells to DNA-PKi and PARPi thereby converting CIN into aliability while minimizing nonneoplastic cell toxicity. NCI 10705729 8/22/23 0:00 PAR-20-305 5P50CA272170-02 5 P50 CA 272170 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-N 5512 1898859 "FLETCHER, JONATHAN ALFRED" Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 487565 449725 37840 Project 1: Summary/AbstractLeiomyosarcoma (LMS) is one of the most common sarcomas and is a considerable therapeutic challengebecause 50% of patients develop metastases for which current chemotherapy provides clinical benefit to only asmall minority. We have shown that most LMS have chromosomal instability (CIN) which results in part fromdefects in homologous recombination and from ubiquitous TP53 and RB1 inactivation. Our recent studies showthat these CIN aberrations are associated with hyper-dependency on DNA protein kinase (DNA-PK) which along with ATM and ATR is a member of the PI3K-like kinase family of DNA damage response (DDR) enzymes.DNA-PK is a key repair mechanism for double-strand DNA damage thereby maintaining CIN below genotoxicthresholds.In Project 1 we wish to develop therapies that maximize intrinsic LMS genotoxic stress particularly be targetingDNA-PK and by discovering more selective ways to target the DNA-PK pathway. To this end Aim 1 determineswhether relevant biomarkers (biochemical DNA-PK pathway activation DNA damage response and genomicevidence of CIN) are found homogeneously within a metastasis and in different metastases from a given patient.Aim 1 also determines whether partially vs. completely inactivating TP53 mutations have differing impact on LMSCIN and DNA-PK activation levels and therefore differing predictive relevance with respect to therapies targetingDNA-PK and DNA integrity. By determining if assays of DNA-PK activation and DNA damage are effectivelydemonstrated by LMS IHC and genomic profiles Aim 1 shows whether these assays can be used as robust andreproducible correlative science assessments for our subsequent (Aim 3b) clinical trial combining low-dosedoxorubicin and DNA-PK inhibition. Aim 2 provides biologic insights needed to achieve efficacy and selectivityfor DNA-PK inhibition and other DDR-targeted therapies in LMS. These in vitro studies include DDR CRISPR-iand CRISPR-a screens which are performed with/without DNA-PKi PARPi and doxorubicin treatment. TheCRISPR screens aim to discover DNA-PK inhibitor synthetic lethals and resistance mechanisms and the biologicinsights from these screens are enhanced by performing RNAseq and phosphoproteome profiles in the sameLMS conditions and by characterizing LMS cells with acquired resistance to DNA-PKi or doxorubicin. Aim 3 isthe clinical translation for Project 1 which encompasses in vitro and murine preclinical validations and an initialclinical trial of doxorubicin coupled with DNA-PK inhibition. Here we test the hypothesis that a very low dose ofdoxorubicin sensitizes LMS cells to DNA-PKi thereby converting CIN into a liability while minimizingnonneoplastic cell toxicity. +No NIH Category available Africa;Africa South of the Sahara;Age;Area;Benign;Biological Assay;Biology;Biopsy;Biopsy Specimen;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Patient;Cell Count;Chronic;Clinical;Code;Collaborations;Country;Cytology;DNA;DNA Methylation;DNA methylation profiling;Data;Development;Diagnosis;Disease;Epidemiology;Epigenetic Process;Europe;Exogenous Factors;Funding;Future;Gene Expression;Genotype;Goals;HIV;HIV Infections;HPV-High Risk;Health care facility;High Prevalence;Hospitals;Human Papillomavirus;Immune System Diseases;Immune system;Immunologic Deficiency Syndromes;Individual;Inflammation;Inherited;Intervention;Lesion;Literature;Longitudinal Studies;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medicine;Modification;Mouthwash;Nigeria;Nigerian;Oncogenic;Oral;Oral Sex;Oral cavity;Outcome;Participant;Patients;Persons;Predisposition;Prevalence;Prevention;Preventive;Public Health;Radiation Oncology;Research;Resources;Risk;Risk Factors;Role;Sampling;Satellite Hospitals;Screening for Oral Cancer;Screening for cancer;Sex Behavior;Site;Swab;Testing;Tissues;United States;Universities;Viral;Viral Load result;Virus;Virus Diseases;antiretroviral therapy;biomarker development;cancer biomarkers;co-infection;cohort;college;cost effective;early detection biomarkers;epigenetic marker;experience;follow-up;genome-wide;hazard;improved;malignant mouth neoplasm;malignant oropharynx neoplasm;methylation biomarker;novel strategies;oncology service;oral HPV;predictive marker;premalignant;prognostic;progression risk;prospective;recruit;screening;sex;specific biomarkers;therapeutic target;transmission process;trend;tumor;virus related cancer;young adult Epigenetic study of oral HPV infection-associated oral cancer in people living with HIV in Nigeria NARRATIVEThis proposed research is responding to RFA-DE-22-003 and aims to better understand the epidemiology andbiology of oral HPV infection as well as its acquisition and persistence in people living with HIV (PLWH) andelucidate mechanisms related to HPV-associated oral and oropharyngeal cancers (OOPC) in the context ofHIV. We propose to study the role of epigenetic biomarkers in HPV-associated OOPC in PLWH in Nigeria acountry with high HIV prevalence to help develop potential non-invasive screening and early detectionbiomarkers of OOPC in PLWH. Identifying epigenetic markers predictive of the progression of precancerouslesions into OOPC will also provide opportunities for developing future preventive and therapeutic targets formanaging precancerous lesions and OOPC in PLWH. NCI 10705727 8/24/23 0:00 RFA-DE-22-003 5R01CA274952-02 5 R01 CA 274952 2 "LIDDELL HUPPI, REBECCA" 9/16/22 0:00 8/31/26 0:00 ZDE1-TO(15) 9243845 "HOU, LIFANG " "MORHASON - BELLO, IMRAN ; MURPHY, ROBERT LEO" 5 PUBLIC HEALTH & PREV MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 825457 NCI 646028 179429 PROJECT SUMMARY/ABSTRACTThe long-term goals of this project are to a) understand the epidemiology of Human papillomavirus virus (HPV)-associated oral and oropharyngeal cancers (OOPC) among people living with HIV (PLWH) as well as the role ofepigenetic biomarkers in OOPC and b) to develop potential targeted interventions to improve prevention andearly detection of OOPC. HPV causes ~5% of cancers worldwide including an increasing proportion of OOPCs;our recent data showed that 17% of OOPC samples have HPV infections. This worsening public health problemis even more serious in countries with high HIV prevalence such as Nigeria. The impact of HIV infection onimmune dysfunction promotes transmission and reactivation of oncogenic HPV co-infections. HIV-HPV co-infection then synergistically increases the prevalence of oral potentially malignant disorders (OPMDs) and thehazards of progression to OOPC among PLWH. As HIV is controlled with antiretroviral therapy (ART) PLWHlive longer with chronic inflammation and continued immunodeficiency making them even more susceptible toHPV infection and its cancer-promoting consequences. Epigenetic biomarkers represent a field with untappedpotential for identifying HPV-infected PLWH who are at risk of progression to invasive OOPC. DNA methylation(DNAm) modifications are a well-studied epigenetic mechanism in cancer including OOPC. DNAm modificationsare inducible by exogenous factors including HIV and HPV infection and their associated cancers. Countrieslike Nigeria provide unique resources and opportunities to study HPV-associated cancers in PLWH particularlylongitudinal studies of the progression of OPMDs into malignant OOPCs. We hypothesize that oral HPV infectionmay induce DNAm changes in PLWH some of which are mechanisms in OOPC development. Such changesmay differ by HPV subtype and can be seen in OPMDs that predict the progression to invasive OOPC. We planto examine tissue-specific epigenetic biomarkers in 4 groups of HIV(+) patients: 1) HPV(+) OOPC (n=150); 2)HPV(-) OOPC (n=150); 3) HPV(+) with benign warts (n=100) and 4) HPV(+) with OPMDs (n=400). Recruitmentwill be conducted at the College of Medicine University of Ibadan/University College Hospital (COMUI/UCH) inNigeria West Africa as well as 10 other hospital satellite recruitment sites. COMUI/UCH is the largest radiationoncology referral site in Nigeria and one of the leading centers for oncological services in the region. We will alsostudy HIV (-) OOPC patients derived from our existing cohort (SHINI) in the same area. Our primary Aims areto: 1) Understand the epidemiology of HPV-associated OOPCs in PLWH; 2) Identify DNAm biomarkers of HPV-associated OOPCs in PLWH; and 3) Examine DNAm biomarkers for OOPC aggressiveness and OPMDprogression during follow up. Our research team has a long and successful collaboration record and theNorthwestern University MPIs have extensive experience studying HPV-associated cervical cancer in PLWHthrough an NCI-funded U54 consortium in Nigeria. 825457 +No NIH Category available Address;Algorithmic Analysis;Anti-Inflammatory Agents;Astrocytes;Award;Blood Vessels;Brain;CD8-Positive T-Lymphocytes;Cancer Biology;Cancer Center;Caspase;Cell Death;Cells;Chromatin;Clear cell renal cell carcinoma;Colon Carcinoma;Colorectal Cancer;Complex;Computational Biology;Computing Methodologies;Data;Data Set;Dendritic Cells;Development;Disease associated microglia;Distal;Ecosystem;Education and Outreach;Educational workshop;Engineering;Functional disorder;Genetic Transcription;Human;Immune;Immune response;Immune system;Immunofluorescence Immunologic;Immunological Models;Immunologics;Immunology;Immunotherapeutic agent;Immunotherapy;In complete remission;Invaded;Investigation;Ligands;Link;Liver;Lung Adenocarcinoma;Malignant Neoplasms;Mediating;Melanoma Cell;Memorial Sloan-Kettering Cancer Center;Metastatic Neoplasm to Lymph Nodes;Metastatic Neoplasm to the Leptomeninges;Methods;Mismatch Repair;Mitochondria;Modality;Modeling;Molecular Analysis;Multiomic Data;Organ;Patients;Process;Refractory;Regulator Genes;Renal Cell Carcinoma;Research;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Role;Scientific Advances and Accomplishments;Scientist;Solid Neoplasm;System;Systems Biology;T cell response;T memory cell;T-Lymphocyte;Technology;Therapeutic;Training;Training Activity;Training Programs;Tumor Immunity;anti-cancer;cancer care;cancer cell;cancer immunotherapeutics;cancer immunotherapy;clinical care;computer studies;design;experimental study;graduate student;immune checkpoint blockade;immunogenic;immunogenic cell death;improved;innovation;insight;learning strategy;lectures;machine learning model;malignant breast neoplasm;mouse model;multidisciplinary;multiple omics;novel;novel strategies;optical imaging;programs;receptor;refractory cancer;response;standard of care;success;symposium;tissue regeneration;tool;transcriptomics;tumor;tumor immunology;tumor-immune system interactions;undergraduate student The Center for Tumor-Immune Systems Biology at MSKCC The Center for Tumor-Immune Systems Biology at MSKCCNARRATIVECancer immunotherapies are designed to harness the human immune system to attack cancer cells andeliminate tumors. Breakthroughs in cancer immunotherapy such as checkpoint blockade agents haverevolutionized cancer care but only a fraction of patients with specific tumor types respond to these newtreatments. Our proposed Research Center will deploy tools from systems biology to improve our fundamentalunderstanding of tumor-immune interactions in contexts where current immunotherapies fail and to developnovel strategies for enhancing responses in contexts where they have only partial success. NCI 10705726 8/22/23 0:00 RFA-CA-21-048 5U54CA274492-02 5 U54 CA 274492 2 "ZAMISCH, MONICA" 9/16/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M2) 8049199 "LESLIE, CHRISTINA S" "RUDENSKY, ALEXANDER Y" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2601900 NCI 1470000 1131900 The Center for Tumor-Immune Systems Biology at MSKCCSUMMARYThe advent of cancer immunotherapies based on immune checkpoint blockade (ICB) has revolutionized clinicalcare in multiple solid tumor types and demonstrated the power of the immune system to target and eliminatecancer cells. Despite these breakthroughs the efficacy of ICB-based immunotherapy is limited to a subset ofcancers and even in tumors where ICB is now the standard of care only a fraction of patients achieve durablecomplete responses. Addressing these limitations requires (1) improving our fundamental understanding oftumor-immune interactions in immunological contexts where current immunotherapies fail and (2) developingnovel strategies for enhancing responses in contexts where they have only partial success. The Center forTumor-Immune Systems Biology at MSKCC has assembled a multi-disciplinary team of leading investigatorsin computational biology immunology and cancer biology to tackle these challenges. The Center is organizedaround three Research Projects that integrate computational and experimental studies in mouse models andmolecular analyses in patient tumors in both immunotherapy-resistant and -responsive contexts exploiting novelmachine learning modeling of single-cell multiome highly multiplexed optical imaging using confocalimmunofluorescence and spatial transcriptomic data sets. We will investigate distinct immunemicroenvironments where cancers are refractory to ICB: metastatic colonization of the brain an immune-privileged organ where the interplay of cancer cells astrocytes and different states of disease-associatedmicroglia dictate modes of invasion (Project I); and mismatch-repair proficient primary colon cancer wheretumors reside in a tolerizing microenvironment and interact with complex cellular circuits of regulatory andconventional T cells together with metastases to the lymph node and liver (Project II). We will also carry out asystems biology interrogation of cancer cell death mechanisms in models of ICB-responsive melanoma andrenal cell carcinoma based on findings that engineering mitochondrial damage-dependent but caspase-independent cell death elicits anti-cancer immunity and protection against tumor rechallenge (Project III). AShared Resource Core will interact with all three Research Projects to develop computational methods andestablish technologies for spatial analyses of the tumor-immune microenvironment. These studies will advanceour fundamental understanding of tumor-immune ecosystems in ICB-refractory microenvironments and ofimmune responses to therapeutically induced immunogenic cancer cell death in ICB-responsive settingsultimately leading to novel immunotherapeutic targets and combination strategies. Our team will build on thesuccesses of our previous CSBC U54 Center award for the Center for Cancer Systems Immunology at MSKCCwhich produced numerous high-impact studies at the forefront of systems biology and cancer immunology. OurResearch Center will also carry out innovative outreach and training activities to disseminate research findingsin tumor-immune systems biology and to train young scientists in this critical field. 2601900 +No NIH Category available Acetylation;Affect;Affinity;Automobile Driving;Binding;Binding Sites;CDKN2A gene;CRISPR/Cas technology;Carcinogens;Cell Cycle Proteins;Cell Line;Cells;Cessation of life;Chromatin;Chronic;Communities;Cyclin-Dependent Kinase Inhibitor 2A;DNA;DNA Methylation;DNA Methylation Inhibition;DNA Modification Process;DNA Sequence Alteration;Data;Development;Drug Combinations;EP300 gene;Enhancers;Environmental Risk Factor;Enzymes;Epigenetic Process;Genes;Genetic Induction;Genomic Segment;Genomics;Goals;Guide RNA;Histone Acetylation;Histones;Human;Hypermethylation;Inhibition of Cell Proliferation;Invaded;Laboratories;Large Cell Carcinoma;MYC gene;MYC-Family Oncogene;Malignant Neoplasms;Measures;Methylation;Modification;Neoplasm Metastasis;Oncogenes;Oncogenic;Patients;Phenotype;Play;Positioning Attribute;Pre-Clinical Model;Proliferating;RNA Polymerase II;Risk;Role;Sampling;Signal Transduction;Skin;Skin Cancer;Specimen;Testing;Therapeutic;Tumor Promotion;Tumor Suppressor Proteins;UV Radiation Exposure;UV induced;Ultraviolet Rays;United States;Untranslated RNA;Visualization;demethylation;detection assay;driver mutation;epigenome editing;epigenomics;genome editing;genomic locus;histone modification;in vivo;inhibitor;innovative technologies;malignant phenotype;migration;new technology;novel strategies;novel therapeutic intervention;overexpression;p14ARF Protein;patient derived xenograft model;promoter;rational design;recruit;skin organogenesis;skin squamous cell carcinoma;small molecule inhibitor;targeted treatment;tool;transcription factor;tumor;tumor growth;ultraviolet Targeting epigenetic abnormalities to inhibit cutaneous squamous cell carcinoma Project NarrativeUltraviolet radiation is the most prevalent carcinogen in humans leading to the development of skin cancer withover 5 million cases annually in the United States. This environmental factor induces genetic mutations andepigenetic abnormalities that affect the expression of cancer-relevant genes but it remains unclear how theseepigenetic abnormalities drive skin malignancies. Using genome and epigenome editing tools we aim toelucidate the contribution of epigenetic abnormalities to malignant phenotypes with the goal of developing noveltherapeutic strategies to target epigenetic aberrations and inhibit cutaneous squamous cell carcinoma. NCI 10705718 8/8/23 0:00 PA-20-185 5R01CA272482-02 5 R01 CA 272482 2 "WEINREICH, MICHAEL DALE" 9/15/22 0:00 8/31/27 0:00 Cancer Etiology Study Section[CE] 9758220 "KAWASUMI, MASAOKI " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 395669 NCI 224175 171494 Project Summary/Abstract Chronic ultraviolet (UV) radiation induces not only genetic mutations but also aberrant epigeneticmodifications that affect the expression of transcription factors oncogenes and tumor suppressors leading tothe development of cutaneous squamous cell carcinoma (cSCC) the second most common cancer in the UnitedStates. A better understanding of the mechanisms underlying UV-associated epigenetic abnormalities willprovide novel approaches to inhibit skin malignancies. Strikingly chronic UV exposure induces DNA hypermethylation at the promoter of CDKN2A gene whichencodes tumor suppressors p16INK4A and p14ARF. This epigenetic alteration silences CDKN2A promoting tumorgrowth and metastasis. However it remains unclear whether the reversal of this epigenetic aberration canreactivate CDKN2A and inhibit malignant phenotypes of cSCC. In Aim 1 we will use our CRISPR-Cas9-basedepigenome editing tools to specifically demethylate the CDKN2A promoter and investigate the effect of targetedDNA demethylation on cancer phenotypes. UV radiation increases the expression of Myc which is an oncogenic transcription factor. Myc activation is acancer hallmark and the Myc oncogene family is deregulated in many human cancers. When overexpressedMyc binds to noncanonical (low-affinity) motifs invading enhancers and potentially activates super-enhancers(noncoding genomic regions defined by unusually high levels of H3K27 acetylation). Cancer-specific super-enhancers strongly upregulate oncogenes driving malignancies. However it remains elusive how aberrantsuper-enhancers are formed in cSCC. We hypothesize that overexpressed Myc binds to low-affinity Myc bindingsites recruits histone acetyltransferase p300 and generates aberrant super-enhancers that drive malignancy.In Aim 2 we will determine the role of overexpressed Myc in super-enhancer formation in cSCC. A subset of cSCC displays poor differentiation which correlates with poor patient survival. However it remainsunclear what confers the aggressiveness of poorly differentiated cSCC. We hypothesize that small-moleculeinhibitors of DNA methylation and/or Myc suppress poorly differentiated cSCC in vivo by reactivating CDKN2Aand/or inhibiting Myc-associated super-enhancers. In Aim 3 we will use poorly differentiated cSCC patient-derived xenografts as preclinical models to assess the effects of these inhibitors on tumor growth and metastasis. Innovative technologies will be used for epigenetic analyses: PIXUL-ChIP (high-throughput chromatinshearing for robust ChIP signals) and EVA (epigenetic visualization assay that detects specific DNAmethylation at the single-cell level). With our epigenome editing tools the proposed study will elucidate thecontribution of epigenetic abnormalities to cSCC aggressiveness and reveal therapeutic potential of modulatingepigenetic marks to suppress cSCC. 395669 +No NIH Category available 2-butenal;4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol;7alpha hydroxylase;Acetylcysteine;Acrolein;African American population;Biological;Biological Markers;Blood;Cadmium;Clinical;Clinical Research;Clinical Trials;Collection;Conduct Clinical Trials;Cotinine;Data;Dose;Erythrocytes;Ethnic Origin;Ethnic Population;Exposure to;Genetic;Genotype;Goals;Hawaii;Hour;Human Resources;IL8 gene;Individual;Inflammation;Inflammatory;Inhalation;Inhalation Drug Administration;Interleukin-6;Japanese American;Laboratories;Linoleic Acids;Malignant neoplasm of lung;Measures;Metabolic;Metabolism;Minnesota;Native Hawaiian;Nicotine;Not Hispanic or Latino;Oral;Oral Administration;Oxidative Stress;Participant;Pathway interactions;Patient Recruitments;Peroxidases;Plasma;Procedures;Program Research Project Grants;Race;Research;Risk;Running;Sampling;Services;Site;Smoker;Stable Isotope Labeling;Time;Tobacco;Training;Urine;Variant;alpha Tocopherol;biomarker panel;blood-based biomarker;caucasian American;cigarette smoking;clinical biomarkers;clinical implementation;clinical trial participant;clinical trial recruitment;cohort;cost;cost effective;ethnic difference;former smoker;multi-ethnic;never smoker;non-smoking;phenanthrene;programs;propylene oxide;racial difference;racial population;recruit;sample collection;smoking cessation;urinary Core B. Clinical & Biomarkers Core PROJECT NARRATIVEThe purpose of the Clinical Trial and Biomarker Core is to conduct the clinical trials and collect biologicalsamples for Project 2-4 and analyze biomarkers of exposure and potential harm for all Projects proposed inthis P01. NCI 10705704 9/7/23 0:00 PAR-20-077 5P01CA138338-12 5 P01 CA 138338 12 12/1/09 0:00 8/31/27 0:00 ZCA1-SRB-K 9060 2403789 "HATSUKAMI, DOROTHY K" Not Applicable 5 Unavailable 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN Domestic Higher Education 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 642684 481934 160750 ABSTRACTThe Clinical and Biomarkers Core is critical for the studies in this program project renewal proposal. The Corewill run clinical trials to collect biological samples and will carry out analyses of tobacco constituent biomarkers.The Clinical Trial component of this Core includes trained personnel with clinical research and implementationexpertise that will be applied to conduct the clinical trials proposed in Projects 2 and 4. Both trials include theuse of stable isotope-labeled constituents. Project 2 will use oral administration of [pyridyl-D4]-nicotine to developa CYP2A6 genetic score that will allow to predict nicotine metabolism in smokers. This study will recruit 400smokers (Native Hawaiians Japanese Americans Whites and African Americans) in Hawaii and Minnesota.Project 4 will administer [D10]phenanthrene and [13C18]linoleic acid to 50 never smokers and 50 formers smokersto investigate the potential contribution of metabolic and inflammatory pathways to the elevated risk for lungcancer in former smokers. The Biomarkers component of the Core will analyze a panel of biomarkers of exposureand effect. These will include total nicotine equivalents cotinine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol phenanthrene tetraol and mercapturic acids of acrolein crotonaldehyde and propylene oxide andurinary cadmium (Cd) in urine samples collected in clinical trials. Plasma nicotine metabolite ratio will be alsomeasured. Results of these analyses will be used by Projects 2 3 and 4. In addition biomarkers of potentialharm (urinary and blood-based biomarkers relevant to oxidative stress and inflammation) will be measured forProjects 3 and 4. The Core will also assess urinary Cd in 1000 samples from Project 1. The biological samplesand biomarker results generated by this Core will be used by all projects. +No NIH Category available Advisory Committees;Analytical Biochemistry;Biometry;Biostatistics Core;California;Cancer Center;Collaborations;Communication;Ensure;Epidemiology;Goals;Government;Grant;Hawaii;Laboratories;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Mass Spectrum Analysis;Minnesota;Molecular;National Cancer Institute;Office of Administrative Management;Persons;Policies;Preparation;Prevention;Principal Investigator;Program Research Project Grants;Progress Reports;PubMed;Publications;Regulation;Reporting;Research;Research Personnel;Resource Sharing;Scientist;Sexual Harassment;Specialist;United States National Institutes of Health;Universities;Videoconferencing;cancer risk;cigarette smoking;data quality;equity diversity and inclusion;ethnic difference;ethnic diversity;experience;lung cancer prevention;meetings;multidisciplinary;novel strategies;operation;professor;programs;quality assurance;racial difference;racial population;symposium;tobacco control;virtual Core A. Administrative Core A PROJECT NARRATIVEThis program brings together highly respected scientists with expertise ranging from epidemiology andbiostatistics to molecular aspects of tobacco control to determine why lung cancer risk from cigarette smokingis significantly different among five diverse ethnic/racial groups. The multidisciplinary team in this programfollows this important lead to determine new approaches toward prevention of lung cancer the leading cancerkiller in the U.S. NCI 10705702 9/7/23 0:00 PAR-20-077 5P01CA138338-12 5 P01 CA 138338 12 12/1/09 0:00 8/31/27 0:00 ZCA1-SRB-K 9059 1865674 "HECHT, STEPHEN S" Not Applicable 5 Unavailable 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN Domestic Higher Education 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 5627 3630 1997 ABSTRACTThe Administrative Core will provide professional coordination and oversight to all projects and cores of thisprogram project grant. It will ensure smooth collaborative progress toward our research goals whilemaintaining a high level of communication among our investigators and advisors and the National CancerInstitute ensuring compliance with all regulations and working together with all relevant university units asrequired for the timely completion of our research. Plans for organizational and administrative managementscientific and fiscal management and coordination and communication are presented. The Specific Aimsinclude convening and leading regular formal meetings of the investigators in this program project grantmaintaining communication among the investigators convening meetings of the External Scientific AdvisoryBoard and Internal Advisory Committee reporting research results in annual Progress Reports to the NCIprocessing reimbursements and other related expenses assisting in communication among the investigatorsand with the NCI compliance with all relevant university and government policies coordination of data qualityassurance and processing of publications. +No NIH Category available 4 hydroxynonenal;4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol;Acetylcysteine;Acrolein;Aromatic Polycyclic Hydrocarbons;Bay Region;Biochemical;Biological Markers;C-reactive protein;CYP1A1 gene;Cancer Etiology;Cells;Chemicals;Chronic;Clinic;Clinical Research;Cohort Studies;Cytochromes;DNA;DNA Adduction;DNA Adducts;DNA Damage;Data;Dose;Environmental Carcinogens;Epoxy Compounds;Exposure to;Glycols;IL8 gene;Inflammation;Inflammatory;Inhalation;Inhalation Drug Administration;Interleukin-6;Label;Leukocytes;Linoleic Acids;Lipid Peroxidation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolic Activation;Oral;Oxidative Stress;Participant;Pathway interactions;Peroxidases;Phenols;Plasma;Pleural;Predisposition;Process;Production;Progress Reports;Prostaglandins;Pulmonary Inflammation;Questionnaires;Relative Risks;Risk;Sampling;Serum;Smoker;Smoking;Testing;Toxic effect;Tumor Promotion;Urine;Volatilization;adduct;alpha Tocopherol;black lung;cancer risk;carbonyl compound;carcinogenesis;carcinogenicity;cigarette smoking;ethnic difference;former smoker;high risk;innovation;insight;lung cancer prevention;multi-ethnic;never smoker;non-smoker;oxidative damage;particle;phenanthrene;potential biomarker;racial difference;recruit;smoking cessation;theories;toxicant;urinary Carcinogenesis biomarkers in former smokers of the Multi Ethnic Cohort Study NARRATIVEFormer smokers remain at high risk for lung cancer even 25 years after quitting yet little is known about thebiochemical mechanisms leading to lung cancer in former smokers. This project investigates the hypothesisthat exposure to ubiquitous environmental carcinogens can be very damaging to former smokers because ofparticles and other changes in their lungs and that chronic inflammation in former smokers is also involved intheir high cancer susceptibility. Specific chemical biomarkers will be used to test these theories. NCI 10705695 9/7/23 0:00 PAR-20-077 5P01CA138338-12 5 P01 CA 138338 12 12/1/09 0:00 8/31/27 0:00 ZCA1-SRB-K 9057 1865674 "HECHT, STEPHEN S" Not Applicable 5 Unavailable 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN Domestic Higher Education 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 326478 210631 115847 ABSTRACTFormer smokers remain at high risk for lung cancer for years after quitting smoking with at least 3-fold relativerisk compared to never smokers even 25 years after quitting. More lung cancer cases in the U.S. (50.8%) nowoccur in former smokers than in current smokers (36.7%) yet we know little about the relevant biochemicalmechanisms and related potential biomarkers that could ultimately be used to identify those at high risk. Thisproject proposes to investigate chemical and metabolic biomarkers in former smokers.The Specific Aims are to: 1) Perform a clinical study of inhaled [D10]phenanthrene ([D10]Phe) to determine the ratio of urinary [D10]phenanthrene tetraol ([D10]PheT) to [D9]phenanthrene phenols ([D9]PhOH) as an indicator of increased metabolic activation of PAH in the lungs of former smokers compared to never smokers possibly due to pleural anthracosis (the accumulation of black particles in the lungs of smokers which persist in former smokers; 2) Perform a clinical study of inhaled [13C18]linoleic acid to determine levels of [13C]mercapturic acids of acrolein 4-hydroxynonenal and related -unsaturated carbonyl compounds in the urine of former smokers compared to never smokers to investigate the hypothesis that pulmonary inflammation leads to production of these urinary metabolites; 3) Quantify the inflammation and oxidative damage-related adducts 1N6-etheno-dA 3N4-etheno-dC -OH- propano-dG and 8-oxo-dG in DNA from oral cells and leukocytes of former smokers compared to never smokers; and 4) Working together with Core B quantify biomarkers of potential harm - myeloperoxidase activity in plasma IL-6 IL-8 and C-reactive protein levels in serum and urinary levels of 8-epi-PGF2 and prostaglandin E metabolite (PGEM) in former and never smokers. Serum levels of -tocopherol protective against lung cancer will also be quantified.Collaborative studies with Projects 1 and 3 are also proposed. These innovative studies are expected toprovide important new insights on lung cancer mechanisms in former smokers and potentially identify newbiomarkers of lung cancer susceptibility. +No NIH Category available Biological;Biology;Biometry;Biostatistics Core;Collaborations;Combined Modality Therapy;Communication;Data;Data Analyses;Data Collection;Development;Elements;Ensure;Experimental Designs;Funding;Genotype;Goals;Individual;Label;Methodology;Play;Quality Control;Research;Research Design;Research Personnel;Research Project Grants;Resources;Sample Size;Services;Site;Statistical Data Interpretation;Techniques;The Wistar Institute;anticancer research;cost effective;cost efficient;data integration;data management;data quality;experience;experimental analysis;experimental study;flexibility;forging;genetic signature;inhibitor;melanoma;novel strategies;programs;response;statistical service;synergism;targeted treatment Biostatistics Core ProjectNarrativeCoreD ThisCoreispivotaltoensurethattheexperimentaldesignanddataanalyseswithintheProjectsaredonein a rigorous integrated fashion and to forge new directions in the translational components of the Program Project. This Core has a wealth of experience in cancer research that is used by the Program Project. The quantitative data analyses done by the Core allow us to better understand the associations between the studiedinhibitorsandgenotypesofmelanomaaswellasmechanismsofvariouscombinationtherapies. NCI 10705672 9/6/23 0:00 PAR-18-290 5P01CA114046-15 5 P01 CA 114046 15 4/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-F 9048 10936184 "LIU, QIN " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 168617 105027 63590 ProjectSummaryCoreD The primary objective of the Biostatistics Core in this P01 is to facilitate the understanding of the biology of melanomas and the development of novel strategies for melanoma treatment based on the most stringent and highest quality of statistical data analyses and inferences. The Biostatistics Core is well organized and equipped to achieve this goal. This Core will provide expertise on experimental design and critical analytical services to Investigatorsthatare tailored to eachproject andprovided ina timelyand cost-effective manner. The biostatisticians in this Core will meet regularly with project investigators to developanalytic strategies assess the statistical needs for each particular project on an ongoing basis and to modify analysis plans as the research evolves. Since many elements of the statistical analysis plans will be specific to a particular studyeachproject willbenefitfromthe centralized resource including individuals who canprovideexpertise in study design biostatistics methodology and specialized data analysis techniques and who have had significant experience in solving statistical issues in biological cancer research. This level of collaboration between Core biostatisticians and project Investigators will ensure that the quality and validity of each research project will be of the highest degree. In addition to the statistical services provided to each project this Core is the essential centralized resource to integrate the data across all projects in this program and synthesize study findings. Using state-of-the-art statistical techniques combined with high-throughput data garnered from each project the Core will provide a clear and complete view of the associations between studied inhibitors and genotypes and provide quantitative assessment regarding the development of novel strategiesofmelanomatreatmentinthisP01. +No NIH Category available 3-Dimensional;Alleles;Animals;Antibodies;Architecture;Autologous;Autologous Transplantation;Biological;Biological Assay;Biology;CD34 gene;Cell Adhesion Molecules;Cell Aggregation;Cell Communication;Cell Culture Techniques;Cell Line;Cell Lineage;Cells;Cellular biology;Clinical;Collaborations;Collagen;Complex;Cutaneous;DNA;Data;Databases;Dermis;Development;Disease;Endothelial Cells;Environment;Epidermis;Exclusion;Exposure to;Fetal Liver;Fibroblasts;Fingerprint;Funding;Generations;Genes;Genetic;Genetic Status;Genomics;Grant;Growth;Growth Factor;Hematopoietic;Human;Immune;Immune system;In Vitro;Infrastructure;Injections;Invaded;Investigation;Laboratories;Lentivirus Vector;Libraries;Lung;Malignant Neoplasms;Melanoma Cell;Metastasis Induction;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic malignant neoplasm to brain;Methodology;Mission;Modeling;Monoclonal Antibodies;Mus;Mutation;Neoplasm Metastasis;Neural Crest;Normal Cell;Oncogenes;Pathologic;Pathology;Patients;Phenotype;Primary Neoplasm;Proteins;RNA;Recording of previous events;Research;Research Personnel;Research Project Grants;Research Support;Resources;Robotics;Services;Site;Skin;Specimen;Stress;T-Lymphocyte;Technology;Testing;Therapeutic;Thymus Gland;Tissues;Training;Training Programs;Tumor-Infiltrating Lymphocytes;Virus;cancer infiltrating T cells;cancer stem cell;exome sequencing;experimental study;genome-wide;human fetal hematopoietic stem cells;human model;humanized mouse;in vivo;in vivo Model;induced pluripotent stem cell;keratinocyte;lymph nodes;melanocyte;melanoma;melanoma biomarkers;member;mouse development;neoplastic cell;patient derived xenograft model;programs;reconstitution;repository;screening;stem cells;stem-like cell;subcutaneous;targeted treatment;three-dimensional modeling;tool;transcriptome sequencing;tumor growth Biology Core ProjectNarrativeCoreC This core supports the research projects with cell- and animal-based experimental tools and models but also conducts experiments. The infrastructure encompasses libraries of human melanoma cell lines viruses and antibodies skin and tumor growth models each reflecting different aspects of melanoma biology in patients. Most recent developments have added the capacity of the core to conduct testing of compounds and to investigatehostcell-tumorcellinteractions. NCI 10705671 9/6/23 0:00 PAR-18-290 5P01CA114046-15 5 P01 CA 114046 15 4/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-F 8434 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 272984 209394 63590 ProjectSummaryCoreC The Cell Biology Core provides major resources to the program project investigators including normal human cellsanextensivelibraryofcharacterizedmelanomacelllinesandpatient-derivedxenografts(PDX)(Objective 1). The melanoma cell line library encompasses >400 cell lines at least 200 with known genetic status. To exclude cross-contamination all experimental cell lines are fingerprinted. Our normal cell panel includes: melanocytes keratinocytes fibroblasts endothelial cells and skin-derived stem cells. The PDX panel encompasses now >500 specimens. They have been characterized for metastasis formation and ~250 have beenanalyzedformutationsin108cancer-relatedgenes.Approximate50havebeensubjectedtoWholeExome Sequencingand RNAseq. >350PDXhave beenanalyzed forexpressionof>300 proteins. Weexpect thatall PDXwillbeanalyzedduringthecourseofthegrantatagenomewidelevelforabnormalitiesattheDNARNA and protein levels. Other resources include a lentiviral vectors for growth factors adhesion molecules and oncogenesandmonoclonalantibodiestomelanoma-associatedbiomarkers. Three-dimensionalculturesofnormalhumanskin(skinequivalentsororganotypicculturesofskin)withadermis of fibroblasts embedded in collagen and an epidermis of melanocytes/melanoma cells and keratinocytes are alsocontinuouslyavailabletotheprograminvestigators(Objective2).Thisthree-dimensionalmodelissuperior to standard cell culture techniques because it mimics the in vivo microenvironment for the melanocytes/melanoma cells. For screening studies the Core is providing a robotics-assisted spheroid culture modelthatallowsinvestigationsonmelanomacellsdisplayinginvivorelevantarchitecturecell-to-cellcontacts and invasion inthepresence ofa collagen support matrix. Spheresare enriched in cancer stem-like cellsand canbeusedinsteadofspheroids.TheCoreadditionallyprovidessubcutaneousmelanomagrowthmodelsfor standard experiments including patient-derived xenografts that are exclusively maintained in vivo and using tissuesprovidedbythePathologyCoreB.Avarietyofmetastasismodelsareavailableasarehumanizedmice tostudytheinteractionsofimmunecellswithtumorcells. +No NIH Category available Accounting;Address;Adult;Age;Antibiotic Resistance;Asian population;Black Populations;Calibration;Cancer Burden;Cancer Control;Cancer Etiology;Cancer Model;Caring;Categories;Cessation of life;Clinical;Country;Curative Surgery;Data;Databases;Diagnosis;Disparity;Ethnic Origin;Excision;Future;Gastric Adenocarcinoma;Goals;Helicobacter Infections;Helicobacter pylori;Hispanic Populations;Incidence;Individual;Intervention;Lesion;Malignant Neoplasms;Methodology;Modeling;Neoplasms;Outcome;Patients;Persons;Policies;Population;Positioning Attribute;Prevalence;Prevention;Prevention strategy;Primary Care;Primary Prevention;Prospective Studies;Publications;Race;Randomized Controlled Trials;Recommendation;Regimen;Research;Risk;Risk Factors;Screening for Gastric Cancer;Second Primary Cancers;Secondary Prevention;Smoking;Stomach;Study models;Subgroup;Survival Rate;Variant;Vulnerable Populations;Work;World Health Organization;burden of illness;cancer care;cancer health disparity;cancer prevention;comparative;cost effective;cost effectiveness;disease natural history;early onset;experience;gastric cancer prevention;gastric intestinal metaplasia;high risk;high risk population;improved;innovation;malignant stomach neoplasm;minority communities;model development;models and simulation;mortality;neglect;population health;premalignant;progression risk;racial population;screening;sex;simulation;smoking cessation;surveillance strategy;tool;transmission process;trend;young woman Comparative modeling of gastric cancer disparities and prevention in the US and globally Gastric cancer is the fifth most common cancer and the third leading cause of cancer death globally. In theU.S. there are stark disparities in gastric cancer incidence and mortality with many vulnerable minoritycommunities bearing much of the disease burden. We propose to perform comparative modeling to providecritical evidence to improve the prevention and early detection of gastric cancer and cancer control policy. NCI 10705668 9/1/23 0:00 RFA-CA-20-043 5U01CA265729-03 5 U01 CA 265729 3 "ZHU, LI" 9/15/21 0:00 8/31/26 0:00 ZCA1-SRB-F(A1)R 7040249 "HUR, CHIN " "LANSDORP-VOGELAAR, IRIS ; YEH, JENNIFER M." 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 810184 NCI 703068 107116 Gastric cancer (GC) specifically gastric adenocarcinoma is the fifth most common cancer and the thirdleading cause of cancer death globally and has been categorized as a neglected cancer by the World HealthOrganization. In the U.S. there are stark disparities with Blacks Hispanics and Asians having a nearly two-fold greater risk of developing or dying from GC compared to Whites reflecting differences in risk factors suchas Helicobacter pylori (H. pylori) infection and smoking as well as access to primary prevention and care.Several factors are changing the landscape of GC prevention including a better understanding of the diseasenatural history new evidence on prevention from prospective studies and anticipated results from randomizedcontrolled trials. As early GC detection can improve survival by allowing for curative surgical or noninvasiveendoscopic resection new targeted approaches to GC prevention have the potential to markedly improvepopulation health and reduce GC disparities within the U.S. Although H. pylori has been the primary focus ofglobal GC prevention efforts to date substantial variation by subpopulation in H. pylori prevalence in the U.S.and the world has accentuated the need to optimize H. pylori screen-and-treat interventions for vulnerablegroups. One approach is targeted endoscopic screening of high-risk individuals. For instance persons found tohave gastric intestinal metaplasia a precursor lesion associated with a high progression risk to gastricneoplasia are recommended to undergo endoscopic surveillance in many countries. A critical need exists toidentify effective and cost-effective strategies to address these clinical challenges in the U.S. as wellas globally. This proposed work builds upon prior GC work spanning GC and H. pylori simulation modelingstudies GC secondary database analyses and relevant methodologic and global cancer modelingpublications. The research team for this proposal has a vast collective experience in simulation andcomparative modeling for cancer control clinical expertise across the spectrum of GC prevention and careand a demonstrated track record and commitment to informing cancer care and policy. The proposed threemodeling groups are well-positioned to perform and successfully complete the highly relevant project aims.The overarching goal of the proposed research is to produce innovative and paradigm-shiftingchanges to cancer care through a disparities-focused modeling approach targeting the mostvulnerable high-risk populations that bear the greatest burden of GC in the US and the world. We willaccomplish this goal by performing comparative modeling and completing the following aims: 1) Develop GCsimulation models to estimate GC outcomes for subgroups by race and ethnicity in the U.S.; 2) Assess theimpact of risk factor trends and primary prevention strategies on GC disparities; 3) Evaluate targetedsecondary prevention strategies for reducing early onset-related mortality and GC disparities and 4) Adapt themodels to evaluate GC prevention policies in the global setting. 810184 +No NIH Category available Cancer Center;Collection;Communication;Communities;Data;Effectiveness;Ensure;Environment;Fostering;Goals;Guidelines;IACUC;Infrastructure;Institution;Institutional Review Boards;Leadership;Output;Policies;Progress Reports;Regulation;Reporting;Research;Research Personnel;Resources;Role;Series;Services;Structure;Technology;The Wistar Institute;Vertebrates;Work;conflict resolution;data sharing;design;human subject;lectures;meetings;melanoma;programs;symposium;targeted treatment Administrative Core n/a NCI 10705667 9/6/23 0:00 PAR-18-290 5P01CA114046-15 5 P01 CA 114046 15 4/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-F 9045 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 146166 82575 63591 ProjectSummaryCoreA TheessentialservicesprovidedbytheCoreinclude:administrativesupportforalloftheinvestigatorsineach project and core; fiscal management and oversight for all components of the Program Project; and organization and communication of all Program Project meetings and activities. The overall goal of this Core is efficient stewardship of the P01. The rolesof the Core Director and administrative staffare to facilitate communication while stimulating scientific andtechnological interactions. This will beachieved by 1) Establishing an administrative structure to provide support and management for all Program Project activities. 2) Fostering collaborative research and 3) Ensuring compliance with regulatory and governmental guidelines. Overall The Administrative Core A of this Program Project is designed to provide scientific leadership effective communication and an administrative support structure to ensure the coordinationofallProgramProjectactivities. +No NIH Category available 3-Dimensional;Address;Animals;Autologous;Autophagocytosis;BRAF gene;Biology;Bromodomains and extra-terminal domain inhibitor;Cancer Center;Cells;Clinical;Complex;Cutaneous Melanoma;Data;Development;Drug Tolerance;Drug resistance;ERBB2 gene;Epigenetic Process;Feedback;Fibroblasts;Future;Gene Expression Profile;Genes;Genetic Transcription;Goals;Growth Factor Receptors;Human;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunotherapy;In Vitro;Incidence;Lipid Peroxidation;MAPK3 gene;MEK inhibition;MEKs;Macrophage;Malignant Neoplasms;Mediating;Melanoma Cell;Mesenchymal;Mission;Modeling;Mus;Neuregulins;Oncogenic;Organoids;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Pennsylvania;Population;Production;Protein Tyrosine Kinase;Proteins;Proteomics;Reader;Receptor Protein-Tyrosine Kinases;Repression;Research;Resistance;Salvage Therapy;Series;Signal Transduction;Skin Cancer;Stress;T-Lymphocyte;Translating;Tumor Immunity;Tumor Promotion;Xenograft procedure;age effect;anti-PD-1;anti-PD1 therapy;biological adaptation to stress;cancer type;cell growth;combinatorial;effective therapy;efficacy testing;immune checkpoint;improved;in vivo;inhibitor;melanoma;mouse model;mutant;neoplastic cell;patient derived xenograft model;pre-clinical;programmed cell death ligand 1;programmed cell death protein 1;resistance mechanism;response;standard of care;targeted agent;targeted treatment;treatment strategy;tumor;tumor growth;tumor microenvironment Overcoming primary and secondary resistance in wild-type BRAF melanoma ProjectNarrativeProject4 In Pennsylvania (the state served by our Cancer Centers) the 5 year incidence of melanoma is above the national average and is the fastest rising across cancer types. This proposal aims to address the issue of increased melanoma by providing the preclinical basis for targeted inhibitor and epigenetic inhibitor combinationswithinsubsetsofgenetically-definedwild-typeBRAFmelanomapatients. NCI 10705664 9/6/23 0:00 PAR-18-290 5P01CA114046-15 5 P01 CA 114046 15 4/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-F 8491 6717521 "APLIN, ANDREW ERIC" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 441736 378145 63591 ProjectSummaryProject4 Melanomaisthedeadliestformofskincancer.Whilesignificantprogresshasbeenmadetreatingmelanoma drug resistant represents one of the greatest challenges to achieve optimal responses and improve patient outcomes. Our long-term goal is to understand mechanisms underlying dysregulated signaling and drug resistance in melanoma to form the pre-clinical basis for improved treatment options. In this project we are focusing on a clinical unmet need the treatment of cutaneous melanomas that are wild-type (WT) for BRAF (both WT BRAF/WT NRAS and mutant NRAS). MEK-ERK1/2 signaling is activated in WT BRAF melanoma but the response to MEK inhibitors is poor. Furthermore immune checkpoint agents elicit responses in only 30-40% of cases and patients who are non-responsive have no effective treatment options. The goals of this project are to identify drugtolerance mechanisms in subsetsof WTBRAF melanomas to provide the basis for new strategies to improve targeted inhibitor treatments and provide salvage options for melanomas that are non-responsive to immune checkpoint agents. Our preliminary data indicate that MEK inhibition triggers a receptor tyrosine kinase-mediated adaptive response in WT/WT melanoma. Based on these data we hypothesize that the efficacy of MEK inhibitors will be improved with agents targeting either adaptive ErbB3 responses or epigenetic BET/BRD reader proteins as these epigenetic readers regulate multiple receptor kinasetyrosinekinaseandoncogenicpathwaysassociatedwithdrugresistance.Weaimtoidentifyandtarget mechanisms underlying enhanced activation of the growth factor receptor ErbB3 in MEK inhibitor-treated melanoma. Additionally we will test the efficacy of BET inhibitor-based combinations to mitigate stress/therapytolerancemechanismsanddevelopoptimalcombinatorialapproachestooffsetdrugresistance. We will primarily focus on WT/WT melanomabut where possible extend our observation to mutant NRAS melanoma. To achieve these goals we will leverage our unique genetically and clinically annotated models including in vitro 3D/T cell autologous organoids immune checkpoint inhibitor-resistant patient-derived xenografts and syngeneic mouse models. Through synergistic interactions withother projects and cores in the P01 we will identify mechanisms underlying tumor cell intrinsic and stromal-mediated adaptive responses to targeted and immune therapy and inform future combinatorial targeted/epigenetic inhibitor strategies that can be translated into effective treatments. This project meets the NCI mission by conducting research into the treatmentofthedeadliestformofskincancer. +No NIH Category available 3-Dimensional;Acidity;Acids;Address;Affect;Animals;Antimalarials;Antineoplastic Agents;Autologous;Autophagocytosis;BRAF gene;Binding Proteins;Biological Assay;Cell Communication;Cell Death;Cell-Mediated Cytolysis;Cells;Cellular Assay;Chemicals;Chloroquine;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Critiques;Data;Enzymes;Family;Fibroblasts;Future;Genetic study;Goals;Hydroxychloroquine;Immunocompetent;Immunotherapy;In Vitro;Knock-out;Knowledge;Length;Lipids;Literature;Lysosomes;MEKs;Macrophage;Malignant Neoplasms;Mediating;Melanoma Cell;Metabolic;Modeling;Molecular Target;Neoplasm Metastasis;Normal Cell;Nude Mice;Nutrient;Pathway interactions;Patient-Focused Outcomes;Patients;Penetration;Pharmaceutical Preparations;Phenotype;Post-Translational Protein Processing;Primary Neoplasm;Protein Inhibition;Proteins;Quinacrine;Refractory;Reporting;Resistance;Role;Signal Transduction;Solubility;Stress;T-Cell Activation;T-Lymphocyte;Testing;The Cancer Genome Atlas;Tumor Immunity;Tumor Promotion;Tumor-associated macrophages;Water;Xenograft procedure;aged;analog;anti-cancer;aqueous;cancer cell;cancer therapy;cell type;clinical development;conditional knockout;cytotoxicity;dimer;immunosuppressive macrophages;improved;in vivo;in vivo evaluation;inhibition of autophagy;inhibitor;innovation;lipid transport;melanoma;mouse model;neoplastic cell;new therapeutic target;next generation;novel;novel therapeutics;overexpression;palmitoylation;prevent;programmed cell death protein 1;resistance mechanism;response;targeted treatment;therapy resistant;thioesterase PPT1 gene product;three dimensional cell culture;tool;translational potential;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;tumorigenic Targeting PPT1 in the Tumor Microenvironment ProjectNarrativeProject2 This project will address a critical unmet need for new therapeutics for treat refractory advanced melanoma patients. We will utilize new chemical approaches to determine how best to inhibit a new target in melanoma we have identified PPT1. We will utilize the P01 platform to study the effects of PPT1 inhibition both in the melanomacellanditsimpactonthetumormicroenvironment. NCI 10705658 9/6/23 0:00 PAR-18-290 5P01CA114046-15 5 P01 CA 114046 15 4/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-F 9041 8183362 "AMARAVADI, RAVI K" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 481705 418113 63592 ProjectSummaryProject2 Therapyresistanceinmelanomaisamajorhurdletoimprovedsurvival.Thisprojectwilldetermineiftherapy resistance can be reversed by targeting the lysosomal enzyme protein palmitoyl thioesterase 1 (PPT1). Autophagy is a lysosome-dependent pathway that promotes tumor growth and resistance to therapy in melanoma.Autophagyinhibitionwithchloroquine(CQ)derivativesaugmentstheefficacyofmanyanticancer therapies but has limited activity as a single agent. Clinical trials involving HCQ in melanoma show promising activity but concerns have been raised about the potency of HCQ and its poorly understood mechanism of action. We have prepared dimeric antimalarial compounds that are 10-1000 fold more potent in vitro and in vivo than CQ or HCQ. Dimeric quinacrines (DQs) (Rebecca Cancer Discovery 2017) and dimeric chloroquines (DCs) (Rebecca Cancer Discovery in revision) look especially promising as both tool compounds and potential clinical drugs. In the current cycle we have found that extending the linker length of these dimeric compounds increases lysosomal localization and anti-melanoma activity. These DQs and DCs with longer linkers as well as CQ were used to pull a new lysosomal target PPT1 which is overexpressed in cancer especially in metastatic lesions. Efforts to target the lysosome and autophagy in cancer cells have focused on the effects within cancer cells but recent literature suggests targeting this pathway in immunosuppressive cells within the TME also contributes to antitumor activity. We will leverage innovative collaborations with Projects1 3 and4 andheavy support from the P01 cores to understand the effects of PPT1 inhibition in both tumor cells the interaction between tumor cells and fibroblasts tumor associatedmacrophagesandTcells.Theproposalisbasedonextensivenewpreliminarydatainresponse to the reviewers critiques from the September 2017 submission. We will test the hypothesis that targeting PPT1 intumor cellsand macrophages overcomes therapy resistance in melanomathrough completion of3 aims: Aim 1 will develop innovative new compounds by introducing heteroatom substitutions into the linker and developing the first ever dimeric ferroquine derivatives that could have better penetration in the acidic TME. We willalsodevelopanovel assay forPPT1 that is compatible with live cells and animal studies. Aim 2 will leverage collaborations within the P01 to study the role of PPT1 in blocking lipid trafficking from aged fibroblasts to melanoma cells and reversing resistance to targeted therapy. Aim 3 will study the effects of PPT1 inhibition on tumor cell interactions with T cells and macrophages in 3D culture immunocompetent mouse models and a new conditional KO model of Ppt1 with the goal of reversing resistance to immunotherapy. The impact of these studies will be to unravel a deeper mechanistic understanding of the consequencesoflysosomalinhibitionwithintheTMEwhichwillsupportclinicaldevelopmentoftheseagents inthefuture.Knowledgegainedwillultimatelyleadtoimprovedpatientoutcomes. +No NIH Category available Address;Advisory Committees;Ally;American Indians;Awareness;Bachelor's Degree;Cancer Burden;Cancer Center;Career Choice;Cherokee Indian;Cherokee Nation Oklahoma;Collaborations;Communities;Country;County;Development;Discipline;Disparity;Education;Education and Outreach;Educational Curriculum;Educational Status;Educational workshop;Enrollment;Evaluation;Exposure to;Face;Fostering;Foundations;Goals;Grant;Health;Health Disparities Research;Health Sciences;Immersion;Individual;Institution;Knowledge;Leadership;Location;Malignant Neoplasms;Manuscripts;Maps;Medicine;Mentors;Mentorship;Monitor;National Cancer Institute;Oklahoma;Outcomes Research;Peer Review;Pilot Projects;Positioning Attribute;Publishing;Research;Research Activity;Research Methodology;Research Personnel;Reservations;Resources;Schools;Secondary Schools;Series;Services;Site;Strategic Planning;Students;Support System;Sustainable Development;Time;Tobacco;Training;Training Programs;Tribes;Universities;Work;age group;anticancer research;cancer health disparity;career;career development;college;cultural competence;curriculum development;design;disparity reduction;education pathway;education research;experience;faculty mentor;falls;graduate student;hands on research;health disparity;health disparity populations;health equity;high school;innovation;inter-institutional;interest;lectures;member;outreach;professional students;programs;resilience;skills;undergraduate student Cancer Research Education Program NARRATIVEAddressing American Indian (AI) cancer health disparities requires increasing the representation of AIindividuals in cancer research. The overall goal of the Cancer Research Education Program is to train andsupport AI students and researchers to meaningfully engage in cancer health research with Cherokee Nation. NCI 10705646 8/11/23 0:00 PAR-18-911 5P20CA253255-04 5 P20 CA 253255 4 9/14/20 0:00 8/31/24 0:00 ZCA1-SRB-T 8850 1980749 "KHAN, SOHAIL IMRAN" Not Applicable 2 Unavailable 77345494 TBAHL1WANLF3 77345494 TBAHL1WANLF3 US 35.85318 -94.99067 673901 CHEROKEE NATION TAHLEQUAH OK Other Domestic Non-Profits 744651669 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 18589 74213 871 PROJECT ABSTRACTAmerican Indian (AI) individuals face significant cancer-related health disparities yet are severelyunderrepresented in the scientific and cancer research workforce. A key component to eliminating healthdisparities includes increasing the pool of well-trained scientific investigators from diverse backgrounds anddisciplines. AI students have significant challenges in navigating the educational pipeline. Disparities are seenat all levels and are most prominent as AI students move from high school to post-secondary education.Cherokee Nation is the largest federally-recognized tribe in the country with an estimated 378371 registeredmembers of whom 138087 reside within the reservation's 14 counties in northeastern Oklahoma. CherokeeNation faces significant cancer disparities and through a longstanding partnership with Stephenson CancerCenter (SCC) at the University of Oklahoma Health Sciences Center (OUHSC) Cherokee Nation has madeincreasing efforts to build capacity and expand cancer health disparities research conducted at the tribe. Tofurther the work of the partnership we have established the Cherokee Nation Cancer Research EducationProgram (C-REP) through a unique Collaborative among the SCC Cherokee Nation and newly engagedacademic partner Oklahoma State University (OSU). As a Carnegie Very High Research Activity UniversityOSU brings a significant pool of AI trainees and faculty mentors to the C-REP. The C-REP has three maincomponents: 1) Research experiences that include research experiences through pilot projects formalmentorship of Early Stage Investigators and a select number of students and a Summer Immersion Programfor undergraduate graduate or professional students; 2) Curriculum development using a curriculum mappingapproach and a newly developed Cancer Research Methods Training Series with components offered at eachlocation; and 3) Outreach education including but not limited to a newly developed Reducing Cancer Burden inAmerican Indian Communities Lecture Series: RAISE conducted at the SCC OSU and Cherokee Nation and aformal Cherokee Nation Outreach and Engagement Series: Resilience Against Cancer (CN-RAC) conducted atCherokee Nation. Throughout the program the C-REP will receive guidance from the Collaborative 'sLeadership Team and Internal Advisory Committee and will participate in evaluation and tracking activities tomonitor the progress and outcomes of the research experiences curriculum development and outreachactivities. With the C-REP the Cherokee Nation/OSU and SCC Collaborative is well-positioned to expand thepool of AI students researchers and collaborators who meaningfully engage in tribal cancer health disparitiesresearch. This project will lay the foundation for a large-scale inter-institutional training program and anexpanded trainee pipeline. +No NIH Category available Accounting;Adult;Age;American Indians;Area;Cancer Center;Cancer Patient;Cancer Survivor;Career Mobility;Caring;Cessation of life;Cherokee Indian;Cherokee Nation Oklahoma;Chronic;Clinic;Consolidated Framework for Implementation Research;Counseling;Data;Diagnosis;Enrollment;Ethnic Population;Evidence based intervention;Future;General Population;Goals;Health Expenditures;Health system;Healthcare;High Prevalence;Incidence;Individual;Intervention;Intervention Studies;Interview;Malignant Neoplasms;Mental Health;Mentors;Methods;Morbidity - disease rate;National Health Interview Survey;Oklahoma;Oncologist;Oncology;Participant;Patients;Persons;Pharmaceutical Preparations;Population;Prevalence;Primary Care;Provider;Relapse;Reporting;Research;Research Personnel;Reservations;Resources;Risk;Role;Second Primary Cancers;Smoking;Survivors;System;Time;Tobacco;Tobacco Use Cessation;Tobacco use;Tobacco-Related Carcinoma;Tribes;United States;United States Indian Health Service;Universities;Work;anticancer research;cancer care;cancer diagnosis;care systems;compare effectiveness;education research;evidence base;experience;former smoker;future implementation;graduate student;health care service;health disparity;implementation research;implementation strategy;improved;insight;medical specialties;member;mortality;primary care provider;productivity loss;professional students;programs;quitline;racial population;reduce tobacco use;smoking cessation;success;tobacco cessation intervention;tobacco user;tribal health;undergraduate student;vaping Tobacco Cessation among American Indian Cancer Survivors in Cherokee Nation NarrativeThis study will identify common barriers and facilitators in receiving smoking cessation counseling and/ortreatment among Cherokee Nation cancer survivors. We expect to identify implementation strategies that areacceptable to survivors and providers and plan for future interventions studies. These results will facilitate carebetween the tribal health system and external specialty care clinics. NCI 10705638 8/11/23 0:00 PAR-18-911 5P20CA253255-04 5 P20 CA 253255 4 9/14/20 0:00 8/31/24 0:00 ZCA1-SRB-T 9036 12030569 "GARRETT, BRADY " Not Applicable 2 Unavailable 77345494 TBAHL1WANLF3 77345494 TBAHL1WANLF3 US 35.85318 -94.99067 673901 CHEROKEE NATION TAHLEQUAH OK Other Domestic Non-Profits 744651669 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 11186 37541 2224 AbstractTobacco use is the leading cause of morbidity and mortality in the US accounting for 30% of cancer deathsand resulting in more than $300 billion in annual health care expenditures and productivity loss. AmericanIndian (AI) adults continue to have a higher prevalence of tobacco use (32%) compared to any otherrace/ethnic group (13%-25%) in the US and experience disproportionate rates of tobacco-related morbidity andmortality. In addition AI individuals in Oklahoma have the highest age-adjusted cancer incidence (637 per100000) and mortality (255 per 100000) rates compared to other racial groups. Continued use of tobaccoafter a cancer diagnosis increases the risk of secondary cancers and mortality compared to non-tobacco users.Cherokee Nation is the largest tribe in the United States with more than 378000 enrolled members andreducing tobacco use is one of the tribe's top priorities. Cherokee Nation works with Indian Health Service(IHS) to provide healthcare services for the AI population within their reservation area. Because of this systemany referral for specialty care not provided by Cherokee Nation must obtain approval through the IHSPurchased and Referred Care system which may complicate oncology care. Furthermore it is unclearwhether AI cancer survivors routinely receive tobacco cessation treatment during their oncology care or whilereceiving primary care within the Cherokee Nation Health System. Our long-term goal is to reduce theprevalence of tobacco use among cancer survivors in Cherokee Nation. Our study aims to 1) evaluate tobaccocessation experiences among AI cancer survivors in Cherokee Nation; 2) identify current tobacco cessationpractices in primary care and oncology settings along with facilitators and barriers to delivering cessationtreatment to Cherokee Nation cancer patients; and 3) develop tailored strategies to increase implementationand reach of tobacco cessation treatment for cancer survivors in Cherokee Nation. This study will provideinsight into current practices and needs related to tobacco cessation for AI cancer survivors in CherokeeNation. This project will provide preliminary data for an R01 proposal to compare the effectiveness ofimplementation strategies aimed at improving tobacco cessation treatment provided to cancer survivors. It willalso provide opportunities for future implementation research focused on other evidence-based interventionsfor cancer survivors in Cherokee Nation. +No NIH Category available Adult;Affect;Alaska Native;American Indians;Biochemical;Birth;Carbon Monoxide;Cessation of life;Characteristics;Cherokee Indian;Childbirth;Cigarette;Consumption;Cotinine;Data;Devices;Disease;Disparity;Electronic cigarette;Elements;Ethnic Population;Exhalation;Fetus;First Pregnancy Trimester;Future;General Population;Goals;Health;Health Services;High Prevalence;Individual;Infant;Intervention;Investigation;Knowledge;Literature;Longitudinal Studies;Low Birth Weight Infant;Low Prevalence;Lung;Medical Records;Nicotine;Outcome;Pattern;Perception;Persons;Pilot Projects;Population;Pregnancy;Pregnant Women;Premature Birth;Prenatal care;Prevalence;Race;Reporting;Risk;Risk Factors;Safety;Smoke;Smoking;Smoking Status;Surveys;Third Pregnancy Trimester;Tobacco;Tobacco use;Toxicant exposure;Toxin;Woman;acceptability and feasibility;adverse birth outcomes;adverse outcome;anticancer research;cigarette smoke;cigarette smoking;e-cigarette cessation;electronic cigarette use;electronic cigarette user;insight;maternal outcome;modifiable risk;never smoker;news;nicotine exposure;observational cohort study;pregnant;racial population;recruit;retention rate;risk perception;smoking cessation;smoking during pregnancy;smoking prevalence;tobacco exposure;vapor Electronic Cigarette Use among American Indian Women NarrativeElectronic cigarettes (e-cigarettes) are increasingly being used by people who want to reduce or quit smokingand these products have the potential to reduce the risks related to smoking including the risks of smokingduring pregnancy. However these products still contain components that are associated with toxins that leadto poorer birth outcomes. It is important to understand the prevalence of e-cigarette use among pregnantwomen and implications for birth outcomes especially among American Indian/Alaska Native pregnantwomen a population disproportionately affected by tobacco-related diseases. NCI 10705631 8/11/23 0:00 PAR-18-911 5P20CA253255-04 5 P20 CA 253255 4 9/14/20 0:00 8/31/24 0:00 ZCA1-SRB-T 9035 12620796 "COMIFORD, ASHLEY " Not Applicable 2 Unavailable 77345494 TBAHL1WANLF3 77345494 TBAHL1WANLF3 US 35.85318 -94.99067 673901 CHEROKEE NATION TAHLEQUAH OK Other Domestic Non-Profits 744651669 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 11951 39852 2437 AbstractSmoking during pregnancy is associated with serious and adverse outcomes for mothers and their infants.American Indian/Alaska Native (AI/AN) women have higher prevalence of smoking and poorer tobacco-relatedbirth outcomes compared to other racial/ethnic populations. People who smoke are increasingly usingelectronic cigarettes (e-cigarettes) to quit smoking or reduce cigarette consumption. Since e-cigarettes havesubstantially lower levels of certain toxins compared to cigarettes pregnant women may switch to theseproducts in order to reduce the known risks associated with smoking. While e-cigarettes contain fewer toxinscompared to cigarettes these products still contain elements that may be harmful to the fetus includingnicotine. Yet relatively few studies have evaluated e-cigarette use in pregnancy or the effects of e-cigaretteuse on birth outcomes. Further no studies have assessed e-cigarette use among AI pregnant women apopulation disproportionately affected by tobacco-related poorer birth outcomes. This observational cohortstudy will provide new insight into e-cigarette use and its association with birth outcomes and harm versusbenefit perceptions during pregnancy among 300 American Indian women receiving prenatal care at CherokeeNation Health Services using biochemical verification of toxicant exposure and smoking cessation includingcotinine metabolite of nicotine carbon monoxide and survey data. We will pursue the following specific andexploratory aims: 1) Describe baseline prevalence of e-cigarette and other tobacco use cotinine levels andpatterns of e-cigarette use among adult pregnant AI women in their first trimester; 2) Describe the baselineperceptions about the health risks related to tobacco and e-cigarette use during pregnancy and how they areassociated with tobacco and e-cigarette use patterns; 3) Among the group of AI women in SA1 who usedtobacco or e-cigarettes at baseline or within 3 months of pregnancy explore the feasibility of reassessingsmoking and e-cigarette use and cotinine exposures in the third trimester of pregnancy. We will explore thefeasibility of recruiting and retaining pregnant AI women in a longitudinal study to assess product switchingchanges in cigarettes smoked per day change in nicotine exposure and smoking cessation throughpregnancy; 4) Assess the prevalence of low birth weight and preterm birth among infants born to AI women bye-cigarette and tobacco use status. We will explore the feasibility and acceptability of using medical records toassess birth outcomes overall and by baseline e-cigarette use and smoking status. E-cigarette use maypotentially mitigate some of the health effects associated with cigarette use. Our project promises to illuminatepatterns of e-cigarette use and its association with toxicant exposure in pregnancy and birth outcomes in aracial subpopulation disproportionately affected by tobacco-related diseases. +No NIH Category available Address;Advanced Malignant Neoplasm;Advisory Committees;Ally;Cancer Center;Cancer health equity;Cherokee Indian;Cherokee Nation Oklahoma;Collaborations;Communication;Complex;Decision Making;Education;Educational Activities;Ensure;Evaluation;Fostering;Foundations;Funding;Future;Goals;Grant;Growth;Infrastructure;Institution;Joints;Leadership;Malignant Neoplasms;Mentorship;Monitor;Oklahoma;Pilot Projects;Procedures;Program Evaluation;Research;Research Activity;Site;Structure;Students;Tobacco;Training Activity;Tribes;Underrepresented Students;Universities;Work;anticancer research;cancer education;cancer health disparity;data sharing;design;education research;experience;health disparity populations;implementation process;innovation;novel;programs;success Administrative Core n/a NCI 10705624 8/11/23 0:00 PAR-18-911 5P20CA253255-04 5 P20 CA 253255 4 9/14/20 0:00 8/31/24 0:00 ZCA1-SRB-T 9033 1980749 "KHAN, SOHAIL IMRAN" Not Applicable 2 Unavailable 77345494 TBAHL1WANLF3 77345494 TBAHL1WANLF3 US 35.85318 -94.99067 673901 CHEROKEE NATION TAHLEQUAH OK Other Domestic Non-Profits 744651669 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 15496 49775 3612 AbstractThe Administrative Core of the Cherokee Nation/Oklahoma State University (OSU) and StephensonCancer Center (SCC) Collaborative Partnership for Cancer Research (the Collaborative) provides theorganizational hub for the jointly conducted cancer-related research and cancer research education activities ofthis planning project. The Collaborative is novel yet organizationally complex as it enhances the success of aprior Cherokee Nation-SCC partnership through the addition of OSU as an academic ally for the tribe. Toaddress this complexity the Administrative Core establishes shared leadership between the participatinginstitutions an Internal Advisory Committee and procedures for regular communication and decision makingwithin the partnership. The research and training activities of the Collaborative are integrated and mutuallyreinforcing with the ultimate goal of providing Cherokee Nation with the capacity to pursue independentresearch in cancer disparities focusing on tobacco. The Administrative Core specific aims are to: 1) Provide joint leadership and infrastructure to provide the operational support including fiscal management to ensure the integration of the diverse components of the Collaborative; 2) Conduct rigorous planning and implementation processes for pilot research and cancer research education; 3) Conduct program evaluation to gauge overall success of the Collaborative in achieving targets and milestones; and 4) Pursue funding to ensure sustainability of our efforts to address cancer disparities at Cherokee Nation for both research and cancer research education.A major goal of this feasibility grant is to build the foundation for future tribally engaged cancer research. TheAdministrative Core proposed herein is essential to this effort as it ensures that all aspects of the program areintegrated into a collaborative effort addressing cancer disparities for Cherokee Nation. +No NIH Category available Applications Grants;Area;Award;Basic Cancer Research;Biomedical Engineering;Budgets;Cancer Control;Cellular biology;Clinical Research;Collaborations;Development;Early Diagnosis;Early treatment;Epigenetic Process;Evaluation;Extramural Activities;Faculty;Foundations;Funding;Genetic;Goals;Historically Black Colleges and Universities;Immunology;Immunotherapy;Incidence;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of pancreas;Mission;Modeling;Monitor;North Carolina;Pancreas;Participant;Peer Review;Population Research;Population Study;Program Research Project Grants;Program Reviews;Publications;Research;Research Personnel;Research Support;Resources;Review Committee;Signal Transduction;Sister;Technology;Testing;Therapeutic;Time;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;anticancer research;cancer cell;cancer imaging;cancer prevention;cancer therapy;career;career development;drug development;experience;flexibility;improved outcome;innovation;insight;meetings;mortality;novel therapeutic intervention;pre-clinical;programs;success;translational goal;translational potential;tumor immunology SToP Cancer SPORE: Developmental Research Program DEVELOPMENTAL RESEARCH PROGRAM: PROJECT NARRATIVEThe Developmental Research Program of the UNC Pancreatic Cancer SPORE supports developmental researchinto causes and treatment of pancreatic cancer. Announcements for funding will be widely distributed to all UNCfaculty and to partner institutions. Evaluation of projects will be performed by the DRP review committee. NCI 10705611 8/21/23 0:00 PAR-20-305 5P50CA257911-02 5 P50 CA 257911 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9029 1861018 "BALDWIN, ALBERT SIDNEY" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 120543 77540 43003 DEVELOPMENTAL RESEARCH PROGRAM: ABSTRACTThe Developmental Research Program (DRP) is critical to the UNC SToP Cancer SPORE mission to advancebasic understanding of pancreatic cancer development and progression and to develop new therapeuticapproaches. The overarching goal of the SPORE DRP is to identify and provide research support for innovativeprojects that provide key insight into critical areas of pancreatic cancer research. Funded DRP projects shouldprovide compelling evidence of potential to develop into full projects within the SPORE and/or to be funded bypeer-reviewed federal (NIH/NCI DOD) or foundation resources. Each year with institutional support the DRPintends to fund up to three projects of approximately $100000 with a second year of funding dependent onprogress in the first year. Budget flexibility will be built in if the senior leadership determines that a projectis particularly promising. RFAs for the UNC SToP Cancer SPORE developmental projects will be offered oncea year with proposals solicited from UNC and our sister institutions which include NC State University(NCSU) and NC Central University (NCCU a historically black college/university). The DRP ReviewCommittee (DRPRC) will review applications focused on pancreatic cancer basic research (such as cancercell signaling cell biology and genetics); translational research (biomedical engineering [BME]cancer imaging cancer immunology/immunotherapy and therapeutic approaches); and populationresearch including cancer prevention and control. +No NIH Category available 13-Butadiene;4 hydroxynonenal;7alpha hydroxylase;Acetylcysteine;Acrolein;Adult;African American population;American Cancer Society;Aromatic Polycyclic Hydrocarbons;Automobile Driving;Biochemical;Biochemistry;Biological;Biological Markers;Biometry;Biostatistics Core;Cancer Center;Cancer Etiology;Carcinogens;Cessation of life;Chemistry;Chronic;Cigarette;Cigarette Smoker;Clinical;Cohort Studies;Collaborations;DNA Damage;DNA Methylation;Deuterium;Disease;Epidemiology;Epigenetic Process;Ethnic Population;Frequencies;Genetic;Genetic Markers;Goals;Hemoglobin;Incidence;Individual;Inflammation;Inflammatory Response;Inhalation;Japanese American;Label;Latino Population;Lead;Linoleic Acids;Lipid Peroxidation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Metabolic;Metabolic Activation;Metabolism;Methodology;Molecular;Molecular Epidemiology;Molecular Epidemiology of Cancer;Native Hawaiian;Nicotine;Persons;Phenols;Prevention;Prevention approach;Productivity;Program Research Project Grants;Relative Risks;Research;Research Personnel;Risk Marker;Scientist;Smoke;Smoker;Smoking;Tobacco smoke;Tobacco-Associated Carcinogen;Tobacco-Related Carcinoma;Urine;Variant;Woman;addiction;cancer risk;carbonyl compound;carcinogenesis;catalyst;cigarette smoking;design;enzyme activity;epigenetic marker;ethnic difference;ethnic diversity;experience;exposure to cigarette smoke;former smoker;genetic variant;high risk;improved;insight;lung cancer prevention;men;mortality statistics;multi-ethnic;multidisciplinary;never smoker;novel;novel strategies;phenanthrene;programs;racial difference;racial population;response;smoking cessation;statistics;tobacco carcinogenesis;tobacco control;urinary Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to Cigarette Smoking PROJECT NARRATIVEThis program brings together highly respected scientists with expertise ranging from epidemiology andbiostatistics to molecular aspects of tobacco control to determine why lung cancer risk from cigarette smokingis significantly different among five diverse ethnic/racial groups. The multidisciplinary team in this programfollows this important lead to determine new approaches toward prevention of lung cancer the leading cancerkiller in the U.S. NCI 10705605 9/7/23 0:00 PAR-20-077 5P01CA138338-12 5 P01 CA 138338 12 "MAHABIR, SOMDAT" 12/1/09 0:00 8/31/27 0:00 ZCA1-SRB-K(J1)S 1865674 "HECHT, STEPHEN S" Not Applicable 5 PATHOLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2189974 NCI 1739614 450360 ABSTRACTLung cancer is the leading cause of cancer death in the U.S. This renewal application for years 11-15 of ourProgram Project Grant entitled Mechanisms of Ethnic/Racial Differences in Lung Cancer Due to CigaretteSmoking brings together our team of renowned experts in cancer molecular epidemiology tobacco controlmechanisms and biochemistry of tobacco carcinogenesis and biostatistics to continue our groundbreakingresearch on biochemical molecular and epigenetic mechanisms by which cigarette smoking causes lungcancer. We will build on our significant findings from ongoing studies which include important advances in theepigenetics of lung cancer biochemistry of nicotine leading to addiction and cancer DNA damage by tobaccosmoke carcinogens including acrolein and 13-butadiene and tobacco carcinogen biomarker studies whichexpand and explain the dramatic differences in lung cancer incidence among cigarette smokers from 5 ethnicgroups African Americans Native Hawaiians Whites Latinos and Japanese Americans. Project 1 Geneticand epigenetic risk markers for lung cancer in former smokers proposes to identify these markers of lungcancer risk in people who have quit smoking and improve our understanding of the ethnic/racial differences inlung cancer risk among former smokers. Project 2 CYP2A6 genetic score nicotine metabolism and lungcancer will focus on the primary catalyst of nicotine metabolism which is critical because people with lowactivity of this enzyme smoke fewer cigarettes and smoke those less intensely because they need lessnicotine which is proposed to lead to lower lung cancer risk. Project 3 Untargeted adductomics tocharacterize ethnic differences in the exposome of smokers hypothesizes that biological responses towardscigarette smoke exposure differ among individuals and ethnic groups due to genetic and/or epigenetic factorsthat lead to differences in metabolic and inflammatory responses to smoking. Project 4 Carcinogenesisbiomarkers in former smokers of the Multiethnic Cohort Study will use a unique approach to determine themetabolic activation of polycyclic aromatic hydrocarbons as well as lipid peroxidation in the lungs of formersmokers compared to never smokers. These 4 projects will be supported by 3 outstanding Cores:Administrative Core Clinical and Biomarkers Core and Biostatistics Core. Thus our experienced investigatorspropose to continue their superb and unique teamwork to make significant progress in understanding lungcancer mechanisms among present and former cigarette smokers leading to new insights for prevention offatal lung cancer. 2189974 +No NIH Category available Address;Animals;Applications Grants;Biometry;Characteristics;Clinical;Clinical Data;Clinical Protocols;Clinical Trials;Clinical Trials Design;Data;Development;Documentation;Ensure;Faculty;Future;Gene Expression Profiling;Genomics;Human;Individual;Maintenance;Malignant neoplasm of pancreas;Medicine;Methodology;Methods;Mission;Molecular;Outcome;Participant;Pathology;Portraits;Preparation;Program Development;Proteomics;Public Health;Publications;Quality Control;Reporting;Reproducibility;Research Design;Research Personnel;Research Project Grants;Sample Size;Science;Services;Statistical Data Interpretation;Statistical Methods;Technical Expertise;Time;Tissue Procurements;Translational Research;analytical tool;biomarker discovery;career development;clinical decision-making;data integration;data management;database design;design;diverse data;genomic data;genomic platform;high dimensionality;individual patient;innovation;machine learning method;multiple data types;patient response;patient subsets;research study;response;skills;treatment response;treatment strategy;tumor Core C - Integrated Quantitative Science (IQS) CORE C: PROJECT NARRATIVEThe Integrated Quantitative Sciences Core participates in the design of all clinical trials animal studies andtranslational research proposed in the SPORE to ensure that all relevant studies are well powered utilizeappropriate statistical methods and are properly designed to address relevant hypotheses of study aims. Inthis manner the Core supports the rigor and reproducibility of all results that are generated by the SPOREwhich in turn has significant impacts in the fields of public health and medicine. Expert analysis of project dataand clear reporting of scientific results are of similar importance for addressing scientific hypotheses andsimilarly have strong implications in public health. NCI 10705601 8/21/23 0:00 PAR-20-305 5P50CA257911-02 5 P50 CA 257911 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 9026 1901846 "KOSOROK, MICHAEL R" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 187072 122289 64783 CORE C: ABSTRACTThe mission of the Integrated Quantitative Science (IQS) Core is to provide state-of-the-art data managementstudy design and statistical analysis support for the UNC Pancreatic Cancer SPORE translational researchprojects. This centralized core will provide the technical skills for the statistical analysis of clinical translationaland multi-platform genomic data from individual research projects to provide a broad clinical and molecularportrait of pancreatic cancer. Results from each project will inform the design and analysis of a future SMARTtrial which will involve state-of-the-art clinical trial design and machine learning methods to determine the bestsequence of treatments tailored to individual patient-level characteristics. Complementary skills possessed bythe Core faculty will also lead to the application and development of (as needed) cutting-edge approaches forcross-platform data integration and high-dimensional biomarker discovery to facilitate patient subtyping andoptimize clinical decision-making. This Core will provide appropriate input into design management andanalysis to ensure that SPORE investigators pursue the most promising lines of translational research. +No NIH Category available Bioinformatics;Cellularity;Clinical;Clinical Data;Clinical Laboratory Information Systems;Code;Collaborations;Collection;Comprehensive Cancer Center;Core Facility;DNA;DNA sequencing;Data;Data Analyses;Data Storage and Retrieval;Databases;Development;Doctor of Philosophy;Ensure;Environment;Evaluation;Fostering;Genomics;Histologic;Hospitals;Infrastructure;Laboratories;Leadership;Link;Malignant neoplasm of pancreas;Management Information Systems;Methods;Normal tissue morphology;Pancreas;Pathologic;Pathology;Process;Proteins;RNA;Reproducibility;Research Activity;Research Personnel;Resource Sharing;Sampling;Science;Services;Specimen;System;Technology;Tissue Banks;Tissue Procurements;Tissues;Translational Research;Tumor Tissue;Update;analysis pipeline;computer cluster;data de-identification;data management;data sharing;distributed data;genomic data;improved;pancreatic cancer patients;public repository;sample collection;transcriptome sequencing Core B - Tissue Procurement Pathology and Genomics CORE B: PROJECT NARRATIVEThe Tissue Procurement Pathology and Genomics (TPPG) Core will assist SPORE projects with expertise andguidance in pathology genomics and data analysis and will provide investigators with research specimens andclinical data. TPPG will provide database support for collecting tracking and distributing data and will ensurerigor reproducibility and transparency within all SPORE projects. NCI 10705595 8/21/23 0:00 PAR-20-305 5P50CA257911-02 5 P50 CA 257911 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 8369 14408862 "IUGA, ALINA " Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 195917 126025 69892 CORE B: ABSTRACTCore B Tissue Procurement Pathology and Genomics will be led by Drs. Alina Iuga MD and Katherine A.Hoadley PhD. This core will support the SPORE projects through sample collection tracking translationalpathology genomics and data analysis. The core takes advantage of existing infrastructure supported by theLineberger Comprehensive Cancer Center to provide SPORE investigators with access to quality samples anddata. The development of an integrated laboratory information system and database tracking and managementsystem will allow for easy tracking and transition of data and information from the hospital to tissue banking topathology and genomic services. The PIs of the core bring expertise in pancreatic cancer pathology andgenomics and will provide guidance and data analysis for the projects. +No NIH Category available 3-Dimensional;Affect;Architecture;Binding;Biology;Cancer Biology;Cell Nucleolus;Cell Nucleus;Cell Wall;Cells;Centromere;Characteristics;Chromatin;Chromosome Segregation;Chromosomes;Cis-Acting Sequence;Clinical Trials;Complex;Cytology;DNA;Data;Data Set;Disease;Dissociation;Eukaryota;Event;Frequencies;Gene Dosage;Gene Expression;Genetic Transcription;Genome;Genome Stability;Genomics;Goals;Health;Heterochromatin;Histones;Human;Human Chromosomes;Human Genome;Immune;Immune signaling;Infection;Inflammatory;Innate Immune System;Interphase Cell;Investigation;Kinetics;Label;Learning;Link;Lipopolysaccharides;MAP Kinase Gene;Macrophage;Malignant Neoplasms;Maps;Measurement;Mediating;Methods;Mitotic spindle;Modification;Molecular;Mus;Natural Immunity;Neoplasm Metastasis;Normal Cell;Nuclear;Nucleolar Proteins;Organelles;Phase;Prevalence;Process;Property;Proteins;RNA;RNA-Binding Proteins;Repetitive Sequence;Research Personnel;Ribosomal RNA;Ribosomes;Role;Satellite DNA;Series;Shapes;Signal Pathway;Signal Transduction;Site;Stimulus;Stress;Structure;Surface;System;Testing;Therapeutic;Transducers;Untranslated RNA;anticancer treatment;cancer cell;carcinogenesis;carcinogenicity;cell type;cellular targeting;chromatin modification;chromosome missegregation;chromosome movement;deep sequencing;environmental stressor;experimental study;extracellular;functional outcomes;genetic manipulation;genome-wide;genomic locus;histone modification;malignant phenotype;member;monocyte;neoplastic cell;novel;p38 Mitogen Activated Protein Kinase;pathogen;recruit;response;therapeutic lead compound;tool;tumor xenograft The role of the nucleolus in human genome organization in normal and disease states 8. Project Narrative / Relevance.The nucleolus is not only the site of ribosome assembly but also a dynamic genomic organization hub thatrecruits interactions with specific loci. We have found that several types of genomic interactions at the nucleolussurface are altered during events important for human health including signaling of infections differentiationprocesses or during carcinogenesis and responses to anticancer treatment. We plan to use genome-scalemethods to analyze how these interactions are altered and to determine the mechanisms underlying thesehigher-order chromosome movements. These studies will provide invaluable tools and datasets for studying howhuman chromosomes respond to a variety of environmental stresses. NCI 10705594 9/1/23 0:00 RFA-RM-20-005 5U01CA260699-04 5 U01 CA 260699 4 "FINGERMAN, IAN M" 9/21/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CB-S(70)R] 1928401 "KAUFMAN, PAUL D." "FOLTZ, DANIEL RICHARD; HUANG, SUI " 2 ANATOMY/CELL BIOLOGY 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 544839 OD 516250 114761 7. Project Summary / Abstract In all eukaryotes the largest nuclear body is the nucleolus a phase-separated non-membrane boundorganelle specialized for the synthesis of ribosomal RNAs and their assembly into ribosomes. Additionally theexterior of the nucleolus is a hub for interactions with multiple specific DNA loci thereby contributing to thethree-dimensional architecture of the eukaryotic nucleus. Nucleolus-genome interactions are intimately connected to processes central to human health. Forexample nucleolar-associated DNA is highly enriched in centromeric repetitive sequences. Centromeres thesites of chromosome attachment to mitotic spindles are fundamentally important for proper chromosomesegregation. Several nucleolar proteins have been implicated in centromere-nucleolar interactions and severalcentromeric proteins prominently reside in nucleoli in interphase cells. We have found that the nucleolar-centromeric interactions are regulated during cellular differentiation and are greatly increased in cancer cells.However the mechanisms that regulated these interactions remain unknown. Not only do cancer cells display increased centromere-nucleolar interactions they also frequently contain aperinucleolar compartments (PNC) a complex cytological feature that is absent in non-tumor cells. PNCs arelocated on the surface of nucleoli and contain multiple RNA species and RNA-binding proteins. Wedemonstrate here that these bodies also contain specific DNA loci some of which encode non-coding RNAsretained within PNCs. A candidate cancer therapeutic termed metarrestin was isolated based on its ability todissociate PNCs; metarrestin is currently in clinical trials based on its ability to reduce metastasis in humantumor xenograft experiments. Importantly for this proposal we have observed that metarrestin also perturbscentromere-nucleolar interactions. We also present data that centromere-nucleolus interactions are perturbed in macrophages upon exposurethe bacterial lipopolysaccharide (LPS) a canonical stimulus for the innate immune system. We also show thatthis response is blocked upon inhibition of specific signaling pathways. These changes are accompanied byaltered nuclear distribution of the H3K27me3 a histone modification characteristic of facultativeheterochromatin. Altogether the central theme of this proposal is that the factors that govern centromere-nucleolusinteractions are important for understanding chromosome missegregation metastasis and innate immunity.We plan a series of synergistic experiments to learn more about the underlying mechanisms. For example wewill test whether the centromeric activity of neocentromeres generates nucleolar associations or if instead thatis a property of centromeric satellite repeats regardless of activity. We will take candidate and unbiasedapproaches to finding centromeric proteins required for nucleolar interactions. We will characterize howmetarrestin affects association of DNA loci with PNCs and nucleoli and we will define cis-acting loci involved inPNC association. We will characterize the signaling pathways required for signaling-mediated disruption ofnucleolar-centromeric interactions in macrophages. Results from these studies will allow for subsequent testingof universality. For example do signaling components in macrophages also operate in tumor cells whentreated with the therapeutic metarrestin? In this manner this collaborative proposal will unite questions fromdiverse experimental systems to answer questions about the fundamental links between nuclear organizationand human health. 544839 +No NIH Category available Address;Adopted;Adoption;Affect;Age;Algorithms;Artificial Intelligence;Asian;Black race;Breast;Breast Cancer Detection;Breast Cancer Model;Breast Cancer Surveillance Consortium;Breast Cancer Treatment;Breast Cancer survivor;Cancer Detection;Clinical;Community Practice;Data;Disparity;Early Diagnosis;Education;Ensure;Equity;Ethnic Origin;Ethnic Population;Event;Failure;Funding;Future;Goals;High Risk Woman;Hispanic;Housing;Image;Image Analysis;Incidence;Income;Individual;Intervention;Malignant Neoplasms;Mammary Gland Parenchyma;Mammographic screening;Mammography;Measures;Meta-Analysis;Modeling;Morbidity - disease rate;Neighborhoods;Observational Study;Outcome;Pacific Islander;Performance;Physicians;Policies;Population;Quality of life;Race;Racial Equity;Recommendation;Recording of previous events;Recurrence;Registries;Resources;Risk;Specificity;Surveillance Modeling;Survivors;Technology;Testing;Training;Validation;Woman;Work;artificial intelligence algorithm;breast cancer diagnosis;cancer diagnosis;deep learning;head-to-head comparison;health equity;high risk;improved;malignant breast neoplasm;mortality;predictive tools;primary endpoint;programs;quantitative imaging;racial population;radiologist;risk prediction;risk prediction model;risk stratification;screening;secondary endpoint;social health determinants;surveillance imaging;surveillance strategy Project 3 PROJECT NARRATIVE Project 3 Surveillance mammography is recommended every year for all breast cancer survivors who still have breast tissue. Unfortunately it does not work well for all survivorswith 3 out of every 10 second breast cancers missed. This Project focuses on improving imaging surveillance after breast cancer treatment by: testing a risk model for breast cancer survivors to receive additional imaging if they are at high risk; validating artificial intelligence algorithms to see if they can help find more cancers on mammography; and understanding if conditions where women are born grow live work and age affect how we find and treat second breast cancers. NCI 10705593 8/10/23 0:00 PAR-20-077 5P01CA154292-12 5 P01 CA 154292 12 9/27/11 0:00 5/31/27 0:00 ZCA1-SRB-K 9024 8686032 "LEE, JANIE M" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 192575 165459 27116 PROJECT SUMMARY Project 3 The incidence of second breast cancer in survivors is seven times higher than first breast cancer incidence in women without this history; these cancers are associated with increased morbidity and breast-cancer specific mortality. Annual surveillance mammography is recommended for survivors for early detection of a second breast cancer to reduce morbidity and mortality. However surveillance mammography is imperfect. Survivors have 4x higher surveillance failure rates (cancers diagnosed within 12 months of a negative mammogram) than women without a history of breast cancer. Project 3s overarching goal is to reduce surveillance failures in breast cancer survivors through equitably predicting women at high risk of a surveillance failure (i.e. interval 2nd breast cancer) improving cancer detection through artificial intelligence (AI) and examining social determinants of health as multilevel drivers of surveillance failures and targets for future interventions. Having an accurate surveillance failure risk prediction tool across broad populations of survivors would support a future of targeted surveillance imaging. Understanding whether predictive performance differs by race is critical to validating an accurate risk prediction model. External validation is also key to ensuring the generalizability of the model. Additionally acceptability of future risk-based surveillance strategies for referring physicians and women is important to consider and has not yet been evaluated. In the current P01 we developed the first risk model of surveillance failures that can be applied to individual survivors. In the next funding cycle our Aim 1 will address feasibility of adopting the BCSC 5-year surveillance failure risk prediction model by assessing performance equity by race group external generalizability and acceptability. Our Aim 2 will evaluate whether AI algorithms improve sensitivity at a fixed specificity equivalent to that of BCSC radiologists. Commercially available AI algorithms for mammography interpretation are already being implemented. However these algorithms were developed in screening populations and have not yet been validated in survivors. Lastly our Aim 3 will identify the relative contribution of selected multilevel social determinants of health that contribute to surveillance failures. Multiple studies have shown social determinants of health including income education housing and race are associated with higher rates of second breast cancers and mortality. No prior study has evaluated how multilevel social determinants of health that may be amenable to intervention are associated with interval second breast cancers in survivors. Understanding the relative contribution of multilevel factors to surveillance failures can be used to guide future targeted interventions to decrease surveillance failures. Together this Project will generate evidence to improve surveillance through a multipronged effort to reduce surveillance failures at the points of risk stratification and imaging interpretation and an overall examination of key social determinants of health as multilevel drivers of surveillance failure and targets for future interventions. +No NIH Category available 3-Dimensional;Affect;Aging;Astrocytes;Automobile Driving;Autophagocytosis;Bioinformatics;Biology;Biometry;Biostatistics Core;Brain;Cancer Model;Catabolism;Cell Death;Cell Death Induction;Cells;Clinical;Collaborations;Communication;Complex;Data;Data Analyses;Dendritic Cells;Drug resistance;Endothelial Cells;Evolution;Experimental Designs;Fibroblasts;Funding;Genes;Genetic;Goals;Grant;Heat-Shock Proteins 70;Human;Immune;Immunotherapy;Individual;Knowledge;Lipids;Lymphocyte;Melanoma Cell;Metabolism;Myeloid-derived suppressor cells;Outcome;Paper;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Population;Post-Translational Protein Processing;Predisposition;Production;Productivity;Publications;Publishing;Quinacrine;Research Personnel;Research Support;Resistance;Resistance development;Role;Sampling;Signal Pathway;Signal Transduction;Skin;Stromal Cells;Testing;Transgenic Model;Translating;Work;advanced disease;aged;cancer cell;cell growth;cell type;design;dimer;humanized mouse;improved;in vitro Model;inhibitor;lipid biosynthesis;lipid metabolism;melanoma;neoplastic cell;normal aging;novel;novel therapeutics;patient derived xenograft model;prevent;programs;proteostasis;response;senescence;small molecule inhibitor;success;synergism;targeted treatment;therapy design;therapy resistant;thioesterase PPT1 gene product;tool;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;uptake Targeted Therapies in Melanoma ProjectNarrative-OverallThis program project is a renewal from a highly productive team of investigators which produced 107publications >70% of which are collaborations among the team. Overall our findings in the 2013-2018 cyclehave led to a natural evolution of our studies where we found that the aged microenvironment is a keycontributortotherapyresistanceandthatlipidmetabolismisacriticalregulatorofbothtumorcellandimmunecell response resulting in forms of cell death such as ferroptosis. Using the tools we have developed in thecurrent funding cycle (dimeric quinacrines HSP70 inhibitors) and our new understanding of the role of thetumor microenvironment in therapy resistance this Program focuseson how toovercome resistance and lackofresponsetotherapybytargetingnotjustthetumorbutalsothemicroenvironment. NCI 10705591 9/6/23 0:00 PAR-18-290 5P01CA114046-15 5 P01 CA 114046 15 "FORRY, SUZANNE L" 4/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-F(M1) 2795105 "HERLYN, MEENHARD F" "WEERARATNA, ASHANI T" 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 2478587 NCI 1969859 508728 ProjectSummary-OverallThe clinical landscape of melanoma is evolving rapidly however a significant fraction of individuals fail torespond to frontline therapy and another significant fraction of melanoma patients develop resistance. Inorder to improve the response to frontline therapies we have previously focused on inhibiting survivalpathways including autophagy senescence and proteostasis. In the new funding cycle we extend thisfocustowardtargetingthemelanomamicroenvironment.Targeted therapies designed to inhibit tumor-intrinsic signaling do not contemplate the influences of themicroenvironment and the recent success of immunotherapy is a reminder of how important theconsideration of the microenvironment is. Our data are revealing that the normal aging of stromal cellscreates a microenvironment that promotes the activation of signaling pathways that circumvent thosetargeted by therapies such as vemurafenib making the one gene one drug approach less likely to besuccessful. Additionally the crosstalkbetweenstromal and immunecells in the tumor microenvironment isvastly underexplored. We believe that genetic drivers in the tumor cell or specific checkpoints onimmune cells cannot be effectively targeted without the consideration of the crosstalk betweenthosecellpopulationsandothercellsinthemicroenvironment.TheProgram consistsoffour well-integratedprojects fromateam thathas workedextremely welltogetherover the last five years publishing numerous high-impact collaborative papers. The evolution of this P01into its new form is truly a reflection of these concerted efforts evolving from targeting cell fate to arealization that cell fate can be differentially affected by its microenvironment. The four Projects aredesigned in order to achieve a fully coordinated understanding of how multiple factors (but with a focus onaging) in the tumor microenvironment contribute to therapy resistance. The alteration of lipid profiles instromal immune and tumor cells isemerging asa keydriverof resistance. TheProjects will worktogetherto understand the impact of lipid production accumulation uptake metabolism and catabolism in tumorcells. Using the novel compounds developed within the current funding cycle of the grant we will targettumor/TMEcrosstalkandexplorenovelwaysinwhichtodisruptit. 2478587 +No NIH Category available Accreditation;Address;Advanced Malignant Neoplasm;Advisory Committees;Affect;Ally;American Indians;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer health equity;Cherokee Indian;Cherokee Nation Oklahoma;Clinical;Collaborations;Communities;Country;Disparity;Education;Education Projects;Education and Outreach;Educational Activities;Ensure;Environment;Evaluation;Foundations;Future;Goals;Grant;Health Services;High Prevalence;Hospitals;Infrastructure;Institution;Joints;Link;Malignant Neoplasms;Mentors;Mission;Monitor;National Cancer Institute;Oklahoma;Osteopathic Medicine;Persons;Population;Positioning Attribute;Psychologist;Psychology;Public Health;Research;Research Activity;Research Personnel;Research Priority;Research Project Grants;Reservations;SEER Program;Scientist;Site;Students;System;Tobacco;Tobacco use;Training;Tribes;Underserved Population;United States;Universities;Work;anticancer research;cancer health disparity;cancer risk;curriculum development;early experience;education research;educational atmosphere;experience;graduate student;health care delivery;improved;innovation;interest;medical schools;mortality;neoplasm registry;next generation;outreach;professional students;programs;success;tobacco control;tribal Nation;undergraduate student 2/2 Cherokee Nation/OSU and SCC Collaborative Partnership for Cancer Research NarrativeAmerican Indian communities suffer disproportionately from cancer disparities. This planning grant will expandauthentic tribal capacity to address cancer disparities through a coordinated program of jointly executed pilotresearch directly providing research experiences for early-stage investigators and students and throughspecific cancer research curriculum development and outreach education activities. NCI 10705587 8/11/23 0:00 PAR-18-911 5P20CA253255-04 5 P20 CA 253255 4 "RODRIGUEZ, LARITZA MARIA" 9/14/20 0:00 8/31/24 0:00 ZCA1-SRB-T(M1)S 1980749 "KHAN, SOHAIL IMRAN" Not Applicable 2 Unavailable 77345494 TBAHL1WANLF3 77345494 TBAHL1WANLF3 US 35.85318 -94.99067 673901 CHEROKEE NATION TAHLEQUAH OK Other Domestic Non-Profits 744651669 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 57222 NCI 201381 9144 AbstractA serious shortage of scientists conducting AI cancer disparities research persists which may have contributedto cancer disparities affecting tribal nations. Cherokee Nation and the Stephenson Cancer Center havepartnered to build tribal cancer research capacity through a previous Partnerships to Advance Cancer HealthEquity (PACHE) P20 planning grant. However it was recognized that further expansion and sustainability ofCherokee Nation's cancer research workforce requires increased access to an academic ally with a largenumber of AI students entering scientific fields. Oklahoma State University fulfills this need as one of thenation's leading universities for AI students and Early Stage Investigators (ESIs). The overall mission of theproposed Cherokee Nation/Oklahoma State University (OSU) and Stephenson Cancer Center (SCC)Collaborative for Cancer Research is to develop durable research capacity within the context of an AmericanIndian (AI) tribal nation to address cancer disparities. To achieve this goal the four Specific Aims of theCollaborative are:1. to strengthen administrative infrastructure including a joint Internal Advisory Committee that ensures integration of cancer research education and outreach and pilot research activities among Cherokee Nation OSU and the SCC;2. to conduct innovative pilot research in tobacco use and cancer risk capable of seeding large-scale research projects performed by AI researchers within the Cherokee Nation setting;3. to educate the next generation of cancer researchers to engage meaningfully with Cherokee Nation in the context of this research focusing on ESIs graduate professional and undergraduate students; and4. to evaluate activities of the partnership including monitoring progress of pilot research projects and the cancer research education program (C-REP). This evaluation will inform future jointly executed efforts to reduce AI cancer disparities.The Collaborative provides a crucial opportunity to solidify the foundation for tribal capacity in cancerdisparities research. The addition of OSU strengthens the Collaborative by its remarkable success in theeducation of AI ESIs and students in scientific fields. Moreover Cherokee Nation and OSU have brokenground at Cherokee Nation on the first tribally affiliated medical school in the US. The Collaborative thereforeprovides an unprecedented environment in which a tribe a university and a research-intensive cancer centerwill work synergistically to reduce the unacceptable burden of cancer that continues to affect AI people. 57222 +No NIH Category available Academy;Adherence;Adopted;Adoption;Advanced Malignant Neoplasm;Artificial Intelligence;Attention;Automobile Driving;Benchmarking;Breast;Breast Cancer Detection;Breast Cancer Surveillance Consortium;Cancer Burden;Cancer Detection;Cancer Intervention and Surveillance Modeling Network;Caring;Communities;Community Practice;Data;Diagnosis;Diagnostic;Diffusion;Digital Breast Tomosynthesis;Digital Mammography;Disease;Disparity;Education;Enabling Factors;Equilibrium;Equity;Ethnic Origin;Evaluation;General Population;Image Analysis;Imaging technology;Income;Individual;Inequity;Insurance;Intervention;Low income;Malignant Neoplasms;Mammography;Medicine;Minority Women;Morbidity - disease rate;National Institute on Minority Health and Health Disparities;Neighborhoods;Outcome;Performance;Policy Maker;Population;Quality of Care;Registries;Reporting;Research;Research Design;Resources;Risk;Rural Population;Screening for cancer;Sensitivity and Specificity;Services;Site;Societies;Structural Racism;Technology;Time;Training;Underserved Population;United States National Institutes of Health;Woman;Work;artificial intelligence algorithm;black women;breast imaging;cancer health disparity;cancer invasiveness;case control;clinical practice;cohort;cost;design;ethnic minority;experience;follow-up;health care delivery;health equity;health equity promotion;image guided;imager;imaging facilities;improved;innovation;malignant breast neoplasm;models and simulation;mortality;multilevel analysis;new technology;observational cohort study;patient navigation;racial minority;radiologist;routine screening;rural residence;screening;screening disparities;social health determinants;structural determinants;tool;underserved community Project 2 PROJECT NARRATIVE Project 2 Women of minority race/ethnicity lower income lower education and rural residence have limited access to higher quality breast cancer screening and newer technologies that can detect more cancer and reduce unnecessary diagnostic follow-up. The proposed study will comprehensively evaluate how targeted facility- level changes including the use of artificial intelligence for automated mammography interpretation can promote greater equity in breast cancer screening outcomes. This study will generate evidence to guide practitioners and policymakers in optimizing the quality of care in cancer screening and reducing the unequal burden of cancer in our society. NCI 10705584 8/10/23 0:00 PAR-20-077 5P01CA154292-12 5 P01 CA 154292 12 9/27/11 0:00 5/31/27 0:00 ZCA1-SRB-K 9022 11373261 "LEE, CHRISTOPH I" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 312352 285236 27116 PROJECT SUMMARY Project 2 Underserved breast cancer screening populations including those that are predominantly composed of racial/ethnic minorities lower income lower educated and rural populations continue to have a higher breast cancer morbidity and mortality burden than their counterparts. These populations tend to have lower follow-up rates after abnormal screening more missed cancers and more advanced stage disease at the time of diagnosis. Drivers of inequities are likely multi-factorial and include not only woman-level enabling factors but also neighborhood-level social determinants of health and facility-level factors that influence access to and use of high quality screening timely diagnostic evaluation and treatment. The National Institute of Minority Health and Health Disparities on behalf of the NIH reports that a major barrier in achieving health equity is that prior disparities research efforts have focused on individual enabling factors rather than neighborhood or healthcare delivery factors. Understanding the impact of breast imaging facility-level drivers of inequities is particularly important as new screening technologies including artificial intelligence (AI) are rapidly adopted in clinical practice. If newer technologies do not diffuse equitably across communities persistent breast cancer disparities may be further exacerbated. Our overall project objective is to identify modifiable breast imaging facility-level factors that drive breast cancer screening disparities. Using an observational cohort study design and simulation modeling we will explore how targeted facility-level changes that aim to increase access to and use of routine screening and targeted use of AI for improved imaging interpretation accuracy can promote greater equity in screening outcomes. We will leverage the robust longitudinal multi-level Breast Cancer Surveillance Consortium data across eight regional U.S. breast imaging registries to pursue the following specific aims: Aim 1) Perform multi-level analyses to identify facility-level factors (e.g. on-site technologies) that drive disparities in screening performance and outcomes. Aim 2) Using a retrospective matched case control design and five commercially available AI technologies evaluate whether commercially available AI tools for automated mammography interpretation can aid low-performing facilities to meet or exceed national mammography performance benchmarks. Aim 3) Using three established microsimulation models and results from Aims 1 and 2 estimate the long-term population-level benefits harms and costs of enacting facility-level quality-of-care interventions (e.g. AI for higher performance) for the overall U.S. screening population and for underserved subpopulations. Elevating the quality-of-care at low-performing facilities has the potential to tip the balance towards greater screening benefits and less harms at the population-level while also promoting health equity. +No NIH Category available Address;Adverse event;Antibodies;Antibody Specificity;Antigen Targeting;Antigens;B lymphoid malignancy;B-Lymphocytes;Biological Availability;CD19 Antigens;CD276 gene;Caspase;Cell Therapy;Cell physiology;Cell surface;Cells;Clinical;Clinical Research;Cross Reactions;Data;Desmoplastic;Dose Limiting;Endoplasmic Reticulum;Engineering;Enzymes;Epitopes;Evaluable Disease;Evaluation;Extracellular Matrix;Family;Genetic;Goals;Growth;Heat-Shock Proteins 90;Hematologic Neoplasms;Heparan Sulfate Proteoglycan;Human;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunotherapy;In Vitro;Infiltration;Infusion procedures;Integral Membrane Protein;Invaded;Macrophage;Malignant lymphoid neoplasm;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Molecular Chaperones;Molecular Conformation;Mus;Myelogenous;Myeloid-derived suppressor cells;Nature;Normal tissue morphology;North Carolina;Oral;PD-1 blockade;PD-1/PD-L1;PDL1 pathway;Pancreatic Ductal Adenocarcinoma;Patients;Penetration;Phase;Phase I Clinical Trials;Pre-Clinical Model;Prognosis;Proteins;Reaction;Receptor Protein-Tyrosine Kinases;Refractory;Reporting;Safety;Shapes;Signal Transduction;Solid Neoplasm;T cell therapy;T-Lymphocyte;Testing;Therapeutic;Time;Tissues;Toxic effect;Tumor Escape;Tumor Promotion;Universities;cancer cell;cancer type;chimeric antigen receptor;chimeric antigen receptor T cells;effector T cell;extracellular;first-in-human;glucose-regulated protein 94;heparanase;immune cell infiltrate;immunosuppressive macrophages;in vivo;inhibitor;leukemia;malignant breast neoplasm;melanoma;member;mouse model;neoplastic cell;novel;pancreatic cancer cells;pancreatic ductal adenocarcinoma model;patient prognosis;phase 1 study;pre-clinical;preclinical study;prevent;programs;receptor expression;response;safety assessment;small molecule inhibitor;success;suicide gene;tumor;tumor microenvironment;tumorigenesis;tumorigenic Project 2: Combined CAR-T cell therapy PROJECT 2: PROJECT NARRATIVEWe have had success in treating patients with hematological malignancies by using their own immune cellsmodified with a chimeric molecule that eliminates tumor cells but spare part of the immune B-lymphocytes. Weare now extending this approach to solid tumors such as pancreatic cancer that remains a tumor with poorprognosis. In this project we intend test in a Phase I clinical trial the safety persistence and in vivo functionalityof these cells that have been modified to persist target an antigen expressed by pancreatic cancer cells. NCI 10705578 8/21/23 0:00 PAR-20-305 5P50CA257911-02 5 P50 CA 257911 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 8367 8141432 "DOTTI, GIANPIETRO " Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 483710 311149 172561 PROJECT 2: ABSTRACTRemarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cellsredirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However developing CAR-Tsfor the treatment of solid tumors including pancreatic ductal adenocarcinoma (PDAC) is challenging because:(1) PDAC-associated antigens that are targetable by CAR-Ts are limited generally not exclusively expressedby PDAC and act as passengers not as drivers of tumorigenesis allowing for antigenic drift; (2) CAR-Ts aredefective in their capacity to invade stroma-rich tumors such as PDAC; (3) PDAC tumor microenvironment(TME) is highly immunosuppressive. In this proposal we aim at solving these critical issues. We have identifiedB7-H3 (CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in PDAC. B7-H3 is a tumor-promoting transmembrane protein aberrantly expressed in 60% to 93% of PDAC melanoma leukemia breastprostate and ovarian cancer while limited expression is seen on normal healthy tissues. We have developedand tested B7-H3.CAR-Ts in xenogeneic and immunocompetent mouse models of PDAC showing antitumoractivity and safety. Thus in Aim 1 we propose to develop a phase I clinical study in patients with PDAC toassess safety and antitumor activity of B7-H3.CAR-Ts that also include the inducible caspase9 (iC9) as asafety switch to terminate the activity of B7-H3.CAR-Ts in case of toxicity. In Aim 2 we propose to develop inpreclinical models CAR-Ts in which T cells are not be only rendered tumor specific through the CARexpression but are also equipped to overcome the desmoplastic nature of PDAC. Specifically B7-H3.CAR-Tswill be further engineered to re-express the enzyme heparanase (HPSE) which is defective in CAR-Tsgenerated for clinical use. Furthermore we will explore if the glucose-regulated protein of 94 kDa (gp96 orGrp94) which is a member of the heat shock protein (HSP) 90 family (HSP90B1) can also be used asadditional target in PDAC to prevent tumor escape due to antigen loss when one single antigen is targeted. InAim 3 we propose to reprogram macrophages and myeloid derived suppressor cells (MDSC) to a non-immunosuppressive state by using potent and orally bioavailable TAM RTK small molecule inhibitorsdeveloped at University of North Carolina (IND #128236). We will thus perform preclinical studies to evaluatewhether TAM RTK signaling inhibition in macrophages and MDSC would favor the antitumor activity of B7-H3.CAR-Ts. If successful this strategy will be included into a second phase of the proposed Phase I clinicalstudy with B7-H3.CAR-Ts. +No NIH Category available Advanced Malignant Neoplasm;Age;Algorithms;American Joint Committee on Cancer;Area;Artificial Intelligence;Biopsy;Black race;Breast Cancer Detection;Breast Cancer Risk Factor;Breast Cancer Surveillance Consortium;Breast Microcalcification;Cancer Intervention and Surveillance Modeling Network;Cessation of life;Characteristics;Clinical;Collaborations;Community Practice;Data;Diagnosis;Discrimination;Effectiveness;Equity;Ethnic Origin;Focus Groups;Frequencies;Funding;Goals;Guidelines;Harm Reduction;High Risk Woman;Image;Incidence;Intervention;Interview;Life;Magnetic Resonance Imaging;Mammographic screening;Mammography;Modality;Modeling;Modernization;Outcome;Output;Pathologic;Patient Self-Report;Performance;Physicians;Population;Provider;Race;Racial Equity;Recommendation;Registries;Risk;Risk Factors;Services;Statistical Methods;Woman;Women's Group;advanced breast cancer;aged;artificial intelligence algorithm;breast cancer diagnosis;breast imaging;cancer invasiveness;cancer risk;clinical practice;clinical risk;comparative effectiveness;discrete time;ethnic disparity;experience;high risk;improved;improved outcome;malignant breast neoplasm;models and simulation;mortality;novel;predictive modeling;prognostic;racial disparity;randomized trial;risk prediction;risk prediction model;routine screening;screening;social health determinants;targeted imaging Project 1 PROJECT NARRATIVE Project 1 Project 1 will develop and validate new models to predict womens advanced breast cancer risk and evaluate the comparative effectiveness of screening interventions based on advanced cancer risk. Our findings will inform clinical practice and national guidelines by determining how equitable breast cancer screening strategies can be targeted based on womens advanced cancer risk to maximize benefits while minimizing harms. NCI 10705576 8/10/23 0:00 PAR-20-077 5P01CA154292-12 5 P01 CA 154292 12 9/27/11 0:00 5/31/27 0:00 ZCA1-SRB-K 9020 2072556 "KERLIKOWSKE, KARLA M" Not Applicable 4 Unavailable 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA Domestic Higher Education 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 152166 125049 27117 PROJECT SUMMARY Project 1 Screening mammography results in lower breast cancer mortality by reducing the incidence of advanced breast cancer. Advanced cancer occurs in about 22% of routinely screened women diagnosed with breast cancer with advanced cancer rates more than 2-fold higher in Black vs. White women. We have identified advanced cancer rate as a key screening outcome because it best discriminates who has the highest risk of breast cancer death. Identifying women at increased advanced cancer risk and targeting them with effective screening strategies could reduce breast cancer mortality. Thus Project 1 aims to advance a new risk-based screening paradigm that identifies womens absolute advanced cancer risk to inform screening intensity and supplemental imaging decisions. Aim 1) Using Breast Cancer Surveillance Consortium data on screening exams from women aged 40-74 years and advanced breast cancers we will develop evaluate and validate new risk prediction models to identify women at high risk of advanced breast cancer. We will combine clinical breast cancer risk factors self-reported race/ethnicity imaging features and Artificial Intelligence output to estimate cumulative 6-year advanced cancer risk using novel discrete time survival models incorporating modern data-adaptive modeling approaches for annual and biennial screeners and examine model predictive equity by race/ethnicity. Aim 2) We will statistically emulate a randomized trial within a causal inference framework to evaluate annual vs. biennial mammography screening on breast cancer mortality among the general screening population according to advanced cancer risk. Aim 3) Three established breast cancer simulation models will be used to evaluate the long-term benefits (breast cancer deaths averted and life years gained) and harms (e.g. false positives and biopsies) of population-level screening strategies that target mammography frequency (annual biennial) and supplemental MRI based on advanced cancer risk. This proposal will answer: 1) Which women undergoing screening mammography are at high risk of advanced cancer and require an alternative strategy to biennial mammography and which women are at low risk and can be screened less often? 2) What advanced cancer risk levels require annual mammography vs. biennial mammography for similar reductions in breast cancer mortality? 3) Does a risk-based screening strategy using advanced cancer risk to inform screening frequency and modality improve outcomes compared to an agebased strategy? Therefore this project will provide evidence to guide women and providers towards equitable screening strategies based on advanced cancer risk to maximize screening benefits while minimizing harms. +No NIH Category available Acute;Aftercare;Automobile Driving;Autophagocytosis;BRAF gene;Biological Markers;Biopsy;CRISPR/Cas technology;Caring;Cells;Chronic;Clinical;Clinical Trials;Combined Modality Therapy;Cytostatics;Development;Eating;Evaluation;Future;Gene Expression;Genes;Genetic;Genome;Genomic Library;Glycolysis;Goals;Growth;Growth Inhibitors;Hydroxychloroquine;Immune;Immune response;Impairment;KRAS2 gene;MEK inhibition;MEKs;Malignant Neoplasms;Malignant neoplasm of pancreas;Metabolic;Metabolism;Mitochondria;Mitogen-Activated Protein Kinases;Modeling;Mus;Mutation;Normal tissue morphology;Nutrient;Oncology;Organelles;Organoids;Paclitaxel;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Phenocopy;Pre-Clinical Model;Process;Protein Kinase;Publishing;Randomized;Recycling;Resistance;Signal Transduction;Source;Toxic effect;Up-Regulation;advanced pancreatic cancer;anti-tumor immune response;arm;cancer cell;clinical efficacy;cytokine;cytotoxic;cytotoxicity;effective therapy;effectiveness evaluation;experimental study;gemcitabine;genetic profiling;improved;inhibition of autophagy;inhibitor;innovation;loss of function;macromolecule;mouse model;mutant;novel;pancreatic cancer model;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pharmacologic;phase 2 study;research clinical testing;resistance gene;resistance mechanism;response;response biomarker;small molecule libraries;standard of care;targeted treatment;therapeutic target;therapeutically effective;tumor;tumorigenic Project 1: Targeting autophagy for the treatment of KRAS-mutant PDAC PROJECT 1: PROJECT NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS-dependent tumorigenic growth. Werecently determined that the treatment of PDAC with inhibitors of the key KRAS effector pathway the RAF-MEK-ERK mitogenic activated protein kinase cascade unexpectedly caused further elevation of the metabolic processautophagy rendering PDAC acutely dependent on autophagy and hypersensitive to autophagy inhibition. Wepropose studies to facilitate further clinical advancement of novel combination anti-autophagy strategies with thegoal of identifying effective treatments for PDAC. NCI 10705570 8/21/23 0:00 PAR-20-305 5P50CA257911-02 5 P50 CA 257911 2 9/16/22 0:00 8/31/27 0:00 ZCA1-RPRB-8 8366 1860326 "DER, CHANNING J." Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 415212 308317 106895 PROJECT 1: ABSTRACTAutophagy is a self-degradation process whereby cancer cells recycle defective organelles and macromoleculesas a nutrient source to support their increased metabolic needs. Autophagy is elevated and essential for thetumorigenic growth of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) providing the rationale forclinical evaluation of the autophagy inhibitor hydroxychloroquine (HCQ) for PDAC. Disappointingly when usedas monotherapy in combination with standard of care HCQ has shown limited to no clinical efficacy for PDAC.We recently determined that the treatment of PDAC with inhibitors of the key KRAS effector pathway the RAF-MEK-ERK mitogenic activated protein kinase cascade unexpectedly caused further elevation of autophagyrendering PDAC acutely dependent on autophagy and hypersensitive to autophagy inhibition. We determinedthat ERK inhibition impaired other critical metabolic processes (glycolysis mitochondrial function) that then ledto compensatory upregulation of autophagy. Our findings together with essentially identical conclusions byanother independent co-published study has led to our initiation of two clinical trials evaluating two approvedMEK inhibitors (trametinib binimetinib) in combination with HCQ for PDAC. Since our recent studies suggestthat ERK inhibitors will have superior activity in PDAC this has prompted our initiation of a phase II clinical trialwith the ERK inhibitor LY3214996 in combination with HCQ for metastatic PDAC (Aim 1). While earlyobservations from compassionate care utilization of this combination support a significant clinical impact for thiscombination our preliminary studies (Aims 2 and 3) support our premise that we can improve upon this therapy.Aim 2 studies are based on our application of a 2500-gene druggable genome CRISPR-Cas9 genetic-loss-of-function screen to identify genes that modulate HCQ anti-tumor activity. The identified hits that either enhanceor reduce HCQ growth inhibitor activity represent candidate combinations or biomarkers for HCQ resistancerespectively. The biomarkers for response can then be applied to tumor biopsies collected in the Aim 1 clinicaltrial evaluation. Aim 3 studies involve our application of a chemical library screen using a 525-oncology drug setto identify combinations that enhance the cytotoxicity of HCQ. Together combinations that arise from Aims 2and 3 studies will then be advanced to Aim 4 studies where we will apply PDAC organoid or orthotopic mousetumor models to identify combinations for future clinical evaluation. Since we have found that ERK MAPKinhibition causes tumor-associated gene expression changes that can lead to an improved anti-tumor immuneresponse we will also evaluate the impact of our combinations on tumor cytokine expression and on tumor-associated immune cells. In summary our studies will develop novel combination therapies to target autophagyfor the treatment of KRAS-mutant PDAC. +No NIH Category available Address;Administrative Supplement;Ancillary Study;Antiestrogen Therapy;Atherosclerosis;Atypical hyperplasia;Benefits and Risks;Black race;Breast Cancer Risk Factor;Breast Cancer survivor;Breast Diseases;Cardiovascular system;Chemoprevention;Cholesterol;Chronic;Chronic Disease;Clinical;Clinical Data;Decision Aid;Diabetes Mellitus;Dyslipidemias;Electronic Health Record;Equity;Evaluation;Event;Fast Healthcare Interoperability Resources;Future;Goals;Health;High Risk Woman;Hispanic;Hypertension;Individual;Intervention Trial;Medical Records;Not Hispanic or Latino;Online Systems;Outcome;Patients;Pharmaceutical Preparations;Pilot Projects;Primary Prevention;Randomized Controlled Trials;Recommendation;Reduce health disparities;Research;Risk;Risk Assessment;Risk Factors;Risk Reduction;Southwest Oncology Group;Testing;Woman;Work;base;breast lesion;cancer health disparity;cardiovascular disorder risk;comorbidity;ethnic difference;ethnic diversity;health data;health literacy;high risk;improved;lobular breast carcinoma in situ;malignant breast neoplasm;multi-ethnic;prevent;racial difference;racial diversity;response;risk perception;uptake;usability Cancer Disparity Collaborative Supplement: Integrating electronic health record and patient-generated health data for breast cancer and cardiovascular disease risk assessment among diverse multiet... PROJECT NARRATIVEThe overall objective of this administrative supplement is to develop equitable strategies for risk assessment ofbreast cancer and atherosclerotic cardiovascular disease (ASCVD) to improve health outcomes and reducehealth disparities. We propose to refine an existing RealRisks decision aid which is actively being evaluated inon ongoing multicenter SWOG trial to facilitate breast cancer and ASCVD risk assessment amongracially/ethnically diverse high-risk women with atypical hyperplasia or lobular carcinoma in situ. We hypothesizethat juxtaposing ASCVD and breast cancer risk with statin and chemoprevention uptake respectively mayenhance the use of these medications for primary prevention. NCI 10705493 8/24/23 0:00 PAR-22-114 3UG1CA189974-10S1 3 UG1 CA 189974 10 S1 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1(M1) 6765159 "BLANKE, CHARLES D." "HERSHMAN, DAWN ; TANGEN, CATHERINE M." 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 253250 NCI 246750 6500 PROJECT SUMMARY/ABSRACT This supplement is being submitted in response to PAR-22-114 to conduct an ancillary study to SWOG 1904a multicenter randomized controlled trial of chemoprevention decision support among women with atypicalhyperplasia (AH) or lobular carcinoma in situ (LCIS). Our overall objective is to develop an equitable and efficientapproach for risk assessment of breast cancer and atherosclerotic cardiovascular disease (ASCVD). Womenwith high-risk breast lesions such as AH or LCIS have up to a 4- to 10-fold increased risk of invasive breastcancer compared to women with non-proliferative breast disease and derive a 70-80% relative breast cancerrisk reduction with anti-estrogen therapy for chemoprevention. A potential barrier to chemoprevention uptakeincludes competing comorbidities such as ASCVD. Racial/ethnic differences exist for multiple chronic diseases;for example Black and Hispanic women are at lower risk for breast cancer but have poorer clinical outcomescompared to non-Hispanic Whites but they are at higher risk for ASCVD risk factors including hypertensiondyslipidemia and diabetes. Current recommendations are for individuals at intermediate-high risk for ASCVD toreceive cholesterol-lowering medications with statin therapy for the primary prevention of cardiovascular events.Among racially/ethnically diverse women with AH or LCIS we found that mean 10-year risk of breast cancer washigher than ASCVD (9.14% vs. 6.69% p<0.001); however among women at high-risk for both conditions uptakeof statins was higher compared to anti-estrogen therapy for chemoprevention (58% vs. 21% p<0.001). Toaddress under-utilization of chemoprevention among women at high-risk for breast cancer the risks and benefitsof anti-estrogen therapy could be placed in the context of medications used to treat or prevent other chronicconditions such as statins for ASCVD. We have developed a web-based RealRisks decision aid (DA) which includes personalized breast cancerrisk assessment and decision support for chemoprevention. The DA is available in English and Spanish and hasbeen rigorously tested in racially/ethnically diverse women with varying health literacy. Using Fast HealthcareInteroperability Resources (FHIR) we have developed a RealRisks user interface (UI) which allows patients toaccess and verify their medical records to facilitate breast cancer risk assessment. Our current aims are: 1) Toconduct user evaluations in up to 24 high-risk women with AH or LCIS to develop a FHIR-enhanced RealRisksUI to assess both breast cancer and ASCVD risk by extracting clinical data from the electronic health record(EHR); 2) To assess the effect of the FHIR-enhanced RealRisks UI on patient activation risk perceptions andusability in a feasibility pilot study among 55 diverse multiethnic high-risk women with AH or LCIS. Thispreliminary work will inform a future intervention trial through the SWOG NCORP Research Base which may beapplied to both high-risk women and breast cancer survivors. Our goal is to develop equitable strategies for riskassessment of multiple chronic diseases to improve health outcomes and reduce health disparities. 253250 +No NIH Category available ABCG2 gene;Address;Aftercare;Aminolevulinic Acid;Area;Award;Biological;Brain Neoplasms;Cancer Patient;Cell Death;Cell Line;Characteristics;Clinical;Conventional Surgery;Excision;Exhibits;FDA approved;Flow Cytometry;Fluorescence;Fluorescence Microscopy;Fluorescence Spectrometry;Fluorescent Probes;Funding;Future;Genetic Engineering;Genotype;Glioma;Goals;Heterogeneity;Human;Image;In Vitro;Isocitrate Dehydrogenase;Light;Malignant Neoplasms;Measurement;Measures;Metabolic;Modeling;Molecular Probes;Mutation;Normal tissue morphology;Operative Surgical Procedures;PUVA Photochemotherapy;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phototherapy;Recurrence;Research;Resolution;Skin Cancer;Solid Neoplasm;Structure;Students;Surgeon;Surgical Oncology;Surgical margins;Testing;Time;Training;Tumor Tissue;U118;base;brain tissue;cancer surgery;common treatment;cytotoxicity;design;enzyme biosynthesis;experience;ferrochelatase;fluorescence imaging;fluorescence microscope;glioma cell line;graduate student;hands on research;heme biosynthesis;imager;improved;in vivo;kinase inhibitor;lapatinib;neoplastic cell;overexpression;preservation;protoporphyrin IX;response;subcutaneous;surgery outcome;treatment choice;treatment response;tumor;tumor growth;undergraduate student Optimization of aminolevulinic acid-protoporphyrin IX for fluorescence-guided tumor resection and treatment This project focuses on the optimization of aminolevulinic acid for fluorescence-guided resection ofgliomas. This research is directly related to the goal of conquering cancer by improving cancersurgery outcomes. NCI 10705406 1/25/23 0:00 PAR-19-134 6R15CA268200-03 6 R15 CA 268200 3 "WANG, CHIAYENG" 6/1/22 0:00 12/31/25 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 8136828 "CHEN, BIN " Not Applicable 3 PHARMACOLOGY 75495937 YGSGAA2XKP71 75495937 YGSGAA2XKP71 US 39.993744 -75.239641 7862501 SAINT JOSEPH'S UNIVERSITY PHILADELPHIA PA SCHOOLS OF PHARMACY 191311308 UNITED STATES N 6/1/22 0:00 12/31/25 0:00 394 Non-SBIR/STTR 2022 422018 NCI 291047 130971 The long-term goal of our research is to determine tumor phenotypic and genotypic characteristics that reducetumor protoporphyrin IX fluorescence and design mechanism-based approaches to overcome these limitingfactors this first renewal builds on progress made in our initial funding period. Surgery is the most commontreatment for all types of solid tumors. A successful cancer surgery is to completely remove tumor tissues andmaximally preserve normal structures. To improve cancer surgery accuracy and precision fluorescent molecularprobes have been developed and are being increasingly used in the oncological surgery. Fluorescence fromintraoperative molecular probes enables surgeons to visualize tumor tissues in real time and performfluorescence-guided resection (FGR). It has been well demonstrated that FGR leads to more complete tumorresection and better surgical outcomes than conventional surgery under white light. Aminolevulinic acid (ALA) isone of a few FDA-approved intraoperative fluorescent probes and the only molecular probe based on themetabolic alterations in tumor cells. ALA has no fluorescence on its own and needs to be metabolized in theheme biosynthesis pathway in tumor cells to produce a fluorescent and photosensitizing metaboliteprotoporphyrin IX (PpIX) which enables tumor fluorescence imaging and photodynamic therapy (PDT). AlthoughALA-PpIX has been clinically used for tumor FGR its applications are limited by low tumor PpIX fluorescencehigh tumor fluorescence heterogeneity and low tumor-to-normal tissue fluorescence contrast. Studies in theinitial funding period of this award have led to the identification of ABCG2 transporter activity as a critical factorin reducing tumor PpIX fluorescence. Importantly we have identified clinically used agents to suppress ABCG2activity to enhance tumor PpIX fluorescence. In this renewal we will use an FDA-approved drug lapatinib (Lap)the most potent one we have identified for the enhancement of tumor PpIX fluorescence and hypothesize thatlapatinib improves the use of ALA for FGR and PDT of gliomas. We chose to study this enhancement strategyin gliomas because ALA is now primarily used for guiding the resection of gliomas and more importantly ABCG2expression elevation is a common feature in human gliomas. To this end we will evaluate Lap in combinationwith ALA for the enhancement of PpIX fluorescence and PDT response in human glioma cell lines with differentgenotype and phenotype (Aim 1) and glioma tumor models (Aim 2). Through this research we hope todemonstrate that Lap in combination with ALA enhances tumor PpIX fluorescence and PDT response. Thesuccessful completion of this research will lead to an optimized use of ALA for FGR and PDT treatment ofgliomas. 422018 +Cancer; Chronic Obstructive Pulmonary Disease; Lung; Lung Cancer; Prevention; Tobacco; Tobacco Smoke and Health Advanced Malignant Neoplasm;Affinity;Air Movements;Alveolus;Apoptosis;Binding;Cancer Etiology;Cancer Patient;Cancer cell line;Canis familiaris;Cell Proliferation;Chronic Obstructive Pulmonary Disease;Development;Diagnosis;Dimerization;Dose;Family;Immune response;Incidence;Individual;Inflammation;Inflammatory;Interleukin-17;Interleukin-6;Lung;Lung Adenocarcinoma;Malignant neoplasm of lung;Non-Small-Cell Lung Carcinoma;Oral;Oral Administration;Particulate;Patients;Phase I Clinical Trials;Phosphorylation;Plasma;Prevention;Preventive;Protein Tyrosine Kinase;Rattus;Risk;Safety;Severity of illness;Smoker;Stat3 protein;Therapeutic;Toxic effect;base;candidate marker;cigarette smoking;cytokine;design;efficacy evaluation;former smoker;high risk;inhibitor;interleukin-22;member;mortality;mouse model;mutant;pathogen;prevent;smoke inhalation;src Homology Region 2 Domain;transcription factor;tumor TARGETING STAT3 TO PREVENT NON-SMALL CELL LUNG CANCER (NSCLC) IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) n/a NCI 10705395 75N91019D00021-0-759102200002-1 N01 9/15/22 0:00 3/14/25 0:00 78859058 "BROWN, POWELL " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N R and D Contracts 2022 1097981 NCI Lung cancer is the leading cause of cancer mortality worldwide due to its high incidence and low cure rate. Cigarette smoking (CS) which causes a dysregulated inflammatory microenvironment is the principal cause of lung cancer. Chronic Obstructive Pulmonary Disease (COPD) is another morbid consequence of CS that results from inflammation induced by inhaled smoke particulates and infecting pathogens that leads to structural changes in airways and alveoli resulting in reduced airflow. Between 50-80% of patients diagnosed with Non-Small Cell Lung Cancer (NSCLC) have preexisting COPD and the annual incidence of lung cancer arising from COPD is 0.8-1.7%. Current and former smokers with COPD display a 3- to 10-fold increased risk of lung cancer based on their disease severity. Therefore strategies to prevent lung cancer in its earliest stages among high-risk individuals such as smokers and COPD patients are urgently needed to reduce the public burden of lung cancer. Signal transducer and activator of transcription 3 (STAT3) is one of the seven members of a family of transcription factors that regulates cell proliferation differentiation apoptosis and the immune response. Increased levels of activated STAT3 (pY-STAT3 Tyr 705) have been demonstrated in lungs of COPD patients in tumors of NSCLC patients including KRas mutant lung adenocarcinoma (KM-LUAD) and several NSCLC cell lines. Several cytokines that activate STAT3 including IL-6 IL-22 and IL-17A are shown to be generated during inflammation in mouse models of LUAD including KM-LUAD and a COPD-like mouse model. TTI-101 an orally bioavailable inhibitor of STAT3 (Tvardi Therapeutics) binds to the SH2 domain of STAT3 with high affinity and inhibits the proteins dimerization and phosphorylation. It does not target other tyrosine kinases provides good plasma exposure following oral administration and produces no detectable toxicity when administered for a period of 28 days in rats and dogs. It is currently being evaluated in a Phase I clinical trial in patients with advanced cancers (https://clinicaltrials.gov/show/NCT03195699). The purpose of this Task Order is to evaluate the efficacy of TTI-101 for the prevention of NSCLC associated with COPD in a mouse of model of COPD-associated LUAD. 1097981 +No NIH Category available Abstinence;Address;Adoption;Africa South of the Sahara;Agreement;Assessment tool;Baltimore;Biochemical;Botswana;Cancer Burden;Cancer Control;Caring;Case Manager;Clinic;Clinical effectiveness;Control Groups;Demographic and Health Surveys;Development;Effectiveness;Evidence based intervention;Formularies;Fostering;Government;HIV;HIV Infections;HIV/AIDS;Health;Health care facility;Health system;Information Systems;Infrastructure;Intervention;Malignant Neoplasms;Malignant neoplasm of lung;Maryland;Monitor;Nurses;Outpatients;Participant;Persons;Pharmaceutical Preparations;Policies;Population;Premature Mortality;Prevalence;Prevention strategy;Program Sustainability;Psychological reinforcement;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Research Design;Sample Size;Smoking Cessation Intervention;Southern Africa;Structure;Time;Tobacco;Tobacco use;Training;United States National Institutes of Health;Universities;Work;cancer prevention;care systems;clinical research site;combustible tobacco;comorbidity;cost effectiveness;design;effectiveness evaluation;effectiveness/implementation study;evidence base;follow-up;implementation fidelity;implementation science;implementation strategy;indexing;intervention delivery;intervention program;low and middle-income countries;programs;routine practice;screening brief intervention referral and treatment;smoking abstinence;smoking cessation;smoking prevalence;standard of care;syndemic;tobacco products;trial comparing;varenicline Botswana Smoking Abstinence Reinforcement Trial (BSMART) NARRATIVELung cancer is the most common non-AIDS defining malignancies among people living with HIV/AIDS. Thisimplementation science study integrates a smoking cessation intervention which is lacking in Botswana into areal-world HIV care system. NCI 10705316 8/17/23 0:00 RFA-CA-21-056 5U01CA275048-02 5 U01 CA 275048 2 "VEDHAM, VIDYA" 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M2) 7693593 "CHARURAT, MANHATTAN E" "HIMELHOCH, SETH S; MBONGWE, BONTLE " 7 INTERNAL MEDICINE/MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 701239 NCI 546112 155127 PROJECT ABSTRACTTobacco use is highly prevalent among people living with HIV/AIDS (PLWH) especially in southern Africa whereHIV is most heavily concentrated. Among PLWH tobacco use impacts HIV-related co-morbidities and is theleading cause of premature mortality from non-HIV related malignancies such as lung cancer which account for20% of the cancer burden. Integrating an evidence-based intervention such as Screening Brief Intervention andReferral to Treatment (SBIRT) into a HIV care system presents an important opportunity to establish andevaluate a modifiable cancer prevention strategy into a low- and middle-income country (LMIC) setting whereboth lay health workers (LHW) and non-physician clinicians are widely used. Botswana where the University ofMaryland Baltimore (UMB) has worked since 2015 oversees a wide network of HIV care clinics for its citizens.Demographic Health Surveys from sub-Saharan Africa show that smoking prevalence among PLWH ranges12.5-44.3%. Yet based on our pilot data the system of care is highly unprepared to meet the challenge ofintegrating evidence-based smoking cessation treatment into routine HIV care. The Government of Botswanawants more to be done to assist its citizen in smoking cessation. To meet this challenge the Botswana SmokingAbstinence Reinforcement Trial (BSMART) proposes to use a Type 2 hybrid effectiveness-implementation studydesign to evaluate the effectiveness and implementation of a well-established SBIRT intervention consisting ofthe 5As (Ask Advise Assess Assist Arrange) delivered by trained LHW case managers followed by referralto treatment with varenicline (a medication demonstrated to be efficacious for smoking cessation amongPLWH1-3 and on formulary in Botswana) prescribed and monitored by trained nurse prescribers-dispensers inthe network of outpatient HIV care facilities in Botswana. The specific aims guided by the RE-AIM Frameworkand informed by an Implementation Governance Structure are to: 1) Assess Reach and Effectiveness ofBSMART; 2) Assess the Adoption and Implementation indexed by quality and consistency of interventiondelivery; 3) Assess whether the intervention becomes Maintained as part of routine practices; 4) Determine thepreliminary cost-effectiveness of BSMART. 701239 +No NIH Category available Adaptive Immune System;Adenosine;Agonist;Binding;Biological Availability;Breast;Breast Cancer Model;CTLA4 gene;Canis familiaris;Cells;Cisplatin;Clinical;Clinical Trials;Cyclic GMP;Cytosol;DNA;Development;Drug Kinetics;Drug resistance;Enzymes;FDA approved;Family member;Funding;Gene Expression;Goals;Growth;Half-Life;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunosuppression;Immunotherapy;In Vitro;Innate Immune Response;Innate Immune System;Intercept;Laboratories;Lead;Malignant Neoplasms;Modeling;Mus;Neoplasm Metastasis;Oncology;Oral;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Performance;Pharmaceutical Preparations;Pharmacology;Phase;Phase I Clinical Trials;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Private Sector;Prognosis;Proteins;Radiation;Rattus;Regimen;Safety;Signal Transduction;Site;Small Business Innovation Research Grant;Stimulator of Interferon Genes;Surface;Tablets;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;Toxicology;Work;adaptive immune response;anti-cancer;arm;cancer cell;cancer therapy;cancer type;cell motility;chemotherapy;data modeling;dosage;efficacy evaluation;extracellular;first-in-human;immune cell infiltrate;inflammatory milieu;inhibitor;malignant breast neoplasm;manufacture;mouse model;novel;overexpression;pharmacokinetics and pharmacodynamics;phosphoric diester hydrolase;plasma cell membrane glycoprotein PC-1;pre-clinical research;preclinical development;preclinical evaluation;preclinical study;prevent;programmed cell death protein 1;programs;pyrophosphatase;side effect;small molecule inhibitor;standard of care;stingray;success;synergism;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Development of a potent and selective oral ENPP1 inhibitor for oncology PROJECT NARRATIVECurrent immunotherapies activate only the adaptive immune system and prove ineffective when cancer silencesthe innate immune response the other central arm of immunity. Stingray Therapeutics has developed a novelpotent small-molecule inhibitor of ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase family member1) a dual checkpoint regulator of innate and adaptive immune responses that alone or in combination withimmune checkpoint inhibitors or standard of care treatments may produce superior outcomes in patients withhigh ENPP1-expressing tumors such as triple-negative breast cancer. This Direct to Phase II SBIR applicationaims to complete non-GLP and GLP preclinical studies on our lead ENPP1 inhibitor SR-8541A necessary toseek IND acceptance for a first-in-human Phase I clinical trial. NCI 10705273 7/18/23 0:00 PA-21-259 5R44CA278144-02 5 R44 CA 278144 2 "LOU, XING-JIAN" 9/15/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-T(10)B] 10393089 "KAADIGE, MOHAN RAO" "SHARMA, SUNIL " 18 Unavailable 81096756 XNADTMZYJMP5 81096756 XNADTMZYJMP5 US 29.705032 -95.407546 10050165 "STINGRAY THERAPEUTICS, INC." HOUSTON TX Domestic For-Profits 770212039 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 836231 NCI 791346 44885 ABSTRACTCompelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator ofINterferon Genes) pathway is necessary to elicit potent anti-cancer innate immune responses. Ectonucleotidepyrophosphatase/phosphodiesterase 1 (ENPP1) is the STING pathway's only known direct negative regulatorexpressed in many tumor types and when it is overexpressed tumors show limited efficacy to front-linetherapies. Such as in triple-negative breast cancer (TNBC) high ENPP1 expression is associated with drugresistance and poor prognosis. If a safe and efficacious ENPP1 inhibitor were available it would havewidespread utility for multiple cancer types and if used in combination with other cancer therapies may enhancetheir performance. Towards this end we have developed an orally bioavailable potent small-molecule inhibitorof ENPP1 called SR-8541A. It inhibits hENPP1 activity with an IC50 of 3.6 nM (Ki=1.9 nM) and demonstratesrobust selectivity. We have established that it activates the STING pathway promotes immune cell infiltrationand inhibits cancer spheroid growth. Furthermore in syngeneic tumor mouse models SR-8541A demonstratesa synergistic effect with radiation and a preliminary study also shows synergy with checkpoint inhibitors. Todate we have completed preclinical development activities on SR-8541A that include API development andmanufacturing stability pharmacokinetics tolerability and preliminary toxicology (mouse rat dog). The overallgoal of this Direct to Phase II SBIR application is to complete non-GLP and GLP preclinical studies for our leadmolecule SR-8541A with TNBC as our initial focus. In Aim 1 we will evaluate the efficacy of SR-8541A incombination with FDA-approved drug regimens (e.g. cisplatin anti-mCTLA-4 anti-mPD-1 PARP inhibitor) in4T-1 and EMT-6 breast cancer mouse models. In Aim 2 we will conduct IND enabling GLP toxicology study indogs as the rat GLP study is complete. In Aim 3 we will develop and manufacture cGMP clinical-grade tabletsnecessary to conduct a Phase 1 clinical trial. Direct to Phase II SBIR success will result in the completion of therequired preclinical studies to seek IND acceptance for a first-in-human Phase I clinical trial and to engage withprivate-sector investors in funding clinical trials in TNBC. If SR-8541A is approved for patient use it would bethe first-in-class molecule to modulate the innate immune system expanding the benefits of immunotherapy tomore patients. 836231 +No NIH Category available Adoption;Adoptive Immunotherapy;Animals;Award;Biomedical Technology;CD19 gene;Cell Therapy;Cells;Chemicals;Clinical;Clinical Trials;Collaborations;Contracts;Control Groups;Cryopreservation;Cryopreserved Cell;Data Set;Development;Devices;Dimethyl Sulfoxide;Endotoxins;Engineering;Evaluation;Feedback;Foundations;Future;Glycerol;Goals;Good Manufacturing Process;Health;Human;Ice;Impairment;In Vitro;Industry;Laboratories;Letters;Liquid substance;Mammalian Cell;Marketing;Missouri;Molecular;Mus;Natural Killer Cells;Nature;Nitrogen;Osmolar Concentration;Outcome;Polysaccharides;Practice Guidelines;Process;Production;Proteins;Protocols documentation;Qualifying;Reagent;Research;Research Contracts;Research Personnel;Safety;Secure;Serum;Serum Albumin;Small Business Innovation Research Grant;Standardization;Sterility;T-Lymphocyte;Technology;Testing;Tissues;Trademark;United States National Institutes of Health;Universities;Viscosity;Work;Xenograft Model;biobank;biomaterial compatibility;cancer immunotherapy;cancer therapy;cell type;chimeric antigen receptor T cells;commercial prototype;commercialization;cytotoxicity;efficacy evaluation;efficacy testing;evaluation/testing;experience;extracellular;improved;in vivo;in vivo evaluation;innovation;leukemia;manufacturing organization;migration;mouse model;nanoscale;novel;precision medicine;preservation;prevent;safety testing;success Innovation of Biobanking for Cellular Adoptive Immunotherapies Based on a First-in-Class Biocompatible Cryopreservation Technology for T and NK Cells and Their CAR-Engineered Products NARRATIVEThe long-term vision of CryoCrate LLC related to this project is to commercialize a First-in-Class biocompatiblecryopreservation medium product for biomedical applications associated with cell-based therapies for cancers.The product OdinSol eliminates the need for any toxic cell permeating cryoprotectant (e.g. DMSO) any liquidnitrogen facilities any animal or human products (e.g. animal serum or human serum albumin) which areunfortunately required by traditional cryopreservation medium products and protocols. In this project we willobtain qualifications associated with Good Manufacturing Practice production biocompatibility safety andefficacy testing and secure 510(k) clearance to pave the path to commercialization. NCI 10705271 7/20/23 0:00 PA-21-259 5R44CA278579-02 5 R44 CA 278579 2 "BOZZA, WILLIAM PATRICK" 9/15/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-V(13)B] 10518133 "HAN, XU " Not Applicable 3 Unavailable 78602139 MXHXWLBMUZL7 78602139 MXHXWLBMUZL7 US 38.932745 -92.337305 10032735 "CRYOCRATE, LLC" COLUMBIA MO Domestic For-Profits 652110001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 864173 NCI 727173 81000 SUMMARYPrevious support from NIH SBIR and Coulter Foundation awards allowed the CryoCrate team to develop a first-in-class biocompatible cryopreservation medium product that doesnt need any cell permeating and toxiccryoprotectant. The product is trademarked as OdinSol and has been approved to provide significantlyimproved efficiency in cryostorage of cell types that are essential for cell-based adoptive immunotherapies. TheOdinSol technology also removes the requirement of serum and human products and secures long-term storagein regular -80oC deep freezers.Based on our former experience in FDA 510(k) submission in this project we organized the collaboration withour regulatory consultant (Cardinal Health) contract manufacturing organizations (Bryllan) contract researchorganization (WuXi AppTec) academic subcontract collaborator (the Center for Precision Medicine at Universityof Missouri) to achieve the following milestones:I. The production of OdinSol meets GMP qualifications and biocompatibility assessment shows compliance with FDA guidance for 510(k) submission as a storage device for transfusable cells;II. The in vitro and in vivo evaluation of safety and efficacy demonstrates the OdinSol technology to be superior to existing cryopreservation protocols with respect to preserving viability and functionalities of T NK and CAR-T cells;III. Based on those qualifications we will complete of the 510(k) submission and finalize of the production line based on further FDA feedback before the end of the project period.We expect future clinical use of the OdinSol technology within three years after the FDA clearance providingthe industry of cell therapies with a highly efficient biocompatible cryostorage platform. 864173 +No NIH Category available Achievement;Agammaglobulinaemia tyrosine kinase;Apoptotic;B lymphoid malignancy;B-Cell Leukemia;BCL2L1 gene;Biological Assay;Chronic Lymphocytic Leukemia;Clinical;Clinical Trials;Combined Modality Therapy;Data;Dependence;Disease;Elderly;Elements;Family member;Flow Cytometry;Future;Generations;Genes;Genomics;Genotype;Goals;Grant;Head;Heme;In complete remission;Karyotype;Laboratories;Laboratory Study;MCL1 gene;Maps;Mitochondria;Monoclonal Antibody CD20;Multi-Institutional Clinical Trial;Mutation;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Phenotype;Phosphorylation;Phosphotransferases;Population;Principal Investigator;Progression-Free Survivals;Protein Family;Protein Phosphatase 2A Regulatory Subunit PR53;Proteins;Regimen;Research Personnel;Residual Neoplasm;Resistance;Resistance development;Rest;Risk;Safety;Sampling;Sampling Studies;Somatic Mutation;Subgroup;TP53 gene;Technology;Testing;Therapeutic;Therapy trial;Time;Toxic effect;Triplet Multiple Birth;Tyrosine Kinase Inhibitor;Writing;anti-CD20;chronic lymphocytic leukemia cell;clinical predictors;comorbidity;design;efficacy evaluation;experience;genomic predictors;high risk;individualized medicine;inhibitor;innovation;leukemia treatment;leukemia/lymphoma;next generation sequencing;novel;optimal treatments;personalized decision;predicting response;protein B;resistance mechanism;response;response biomarker;standard of care;survival prediction;targeted agent;therapy duration;tositumomab;treatment duration;treatment response Optimizing novel agent combination therapy for previously untreated high risk chronic lymphocytic leukemia PROJECT NARRATIVEDespite the recent approval of targeted agents such as acalabrutinib (A) venetoclax (V) and obinutuzumab(O) outcomes for patients with high risk TP53-aberrant chronic lymphocytic leukemia (CLL) remainsuboptimal. This project aims to evaluate through a phase 2 investigator-initiated clinical trial whether atriplet combination regimen of AVO is effective as time-limited therapy for previously untreated patients withhigh risk CLL. We will utilize innovative functional laboratory tests such as BH3 profiling and high-throughputkinase activity mapping as well as genomic analyses to study samples from the patients on the trial to predictwhich patients will respond best to the AVO regimen and what resistance mechanisms emerge in patientstreated with this novel regimen. NCI 10705268 7/17/23 0:00 PAR-21-033 5R01CA266298-02 5 R01 CA 266298 2 "HENDERSON, LORI A" 9/15/22 0:00 6/30/27 0:00 Clinical Oncology Study Section[CONC] 10331504 "DAVIDS, MATTHEW S" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 395400 NCI 237710 157690 SUMMARY/ABSTRACTPatients with high-risk TP53 aberrant chronic lymphocytic leukemia (CLL) have a shorter survival than otherCLL patients. We previously found that the BTK inhibitor acalabrutinib (A) and the BCL-2 inhibitor venetoclax(V) are highly effective at killing CLL cells ex vivo. We developed AVO a new time-limited triplet combinationregimen combining AV with an anti-CD20 antibody obinutuzumab (O). The AVO clinical trial and correlativelaboratory studies on primary samples from this trial comprise the key elements of this project.The first aim of the project is to determine the efficacy of the AVO combination regimen in patients withpreviously untreated TP53 aberrant CLL. We hypothesize that AVO will be a highly efficacious and well-tolerated novel agent triplet regimen with individualized therapy duration guided by achievement ofundetectable minimal residual disease (uMRD). This hypothesis will be tested through determining theproportion of patients who achieve complete response (CR) with uMRD as well as characterizing the safety ofthe regimen in an investigator-initiated phase 2 multicenter clinical trial of AVO in patients with previouslyuntreated CLL.The second aim of the project is to assess whether MRD clonal dynamics pre-treatment mitochondrial primingor genomic complexity predict clinical response to AVO. We will utilize a next-generation sequencing (NGS)based technology Adaptive ClonoSEQ to assess whether MRD clonal dynamics with this assay can moreaccurately predict survival and guide treatment duration decisions compared with conventional flow cytometry-based MRD. Through functional interrogation of CLL cell mitochondria by BH3 profiling we hypothesize thatpatients with higher levels of mitochondrial priming at baseline and/or early on treatment will achieve a higherrate of CR with uMRD on AVO. Genomic predictors of response will also be assessed through stimulatedkaryotype and mutational profiling with a 95-gene NGS rapid heme panel (RHP).The third aim of the project is to elucidate mechanisms of resistance to AVO including acquired somaticmutations modulation in mitochondrial priming alterations in phosphorylation and kinase activity. We will useRHP to evaluate the pattern of somatic mutations as they develop. We will also evaluate whether CLL cellsthat are typically dependent on BCL-2 at baseline will develop alternative survival dependencies on other anti-apoptotic proteins at progression. In addition we will assess whether BCL-2 family protein phosphorylationmay represent a functional resistance mechanism and whether PP2A activators can help reverse this andthereby restore sensitivity. And we will use high-throughput kinase activity mapping (HT-KAM) to identify whichkinases are activated in resistant patients to identify new potentially therapeutically actionable targets.Elucidating resistance mechanisms will inform the design of future novel agent combination therapy trials withthe goal of decreasing the risk of acquired therapy resistance in CLL and eventually other B cell malignancies. 395400 +No NIH Category available Administrator;Advocacy;Animals;Bioinformatics;Biometry;Cancer Patient;Charge;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Decision Making;Development;Doctor of Philosophy;Ethics;Fostering;Institution;Institutional Review Boards;Leadership;Malignant Neoplasms;Malignant neoplasm of prostate;Mentorship;Michigan;Mission;Monitor;Occupational activity of managing finances;Pathology;Pathway interactions;Patient advocacy;Productivity;Prostate;Research;Research Personnel;Role;Therapeutic;Tissue Banks;Translational Research;Universities;Vision;career;clinical application;clinical database;clinical development;community engagement;data management;design;meetings;minority communities;programs;quality assurance;success;synergism;translational cancer research;translational goal;translational pipeline;translational progress Administration Core The Administration Core is responsible for the leadership guidance and management of the Michigan ProstateSPORE. In fulfilling these responsibilities the Administration Core provides the framework to support the successand mission of the Michigan Prostate SPORE as a cohesive group of investigators committed to supportingtranslational research in prostate cancer. NCI 10705249 8/22/23 0:00 PAR-18-313 5P50CA186786-10 5 P50 CA 186786 10 9/11/14 0:00 8/31/24 0:00 ZCA1-RPRB-7 8959 1866290 "CHINNAIYAN, ARUL M" Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 120274 115039 47655 The Michigan Prostate SPORE Administration Core is responsible for the leadership guidance andmanagement of this proposal. The Administration Core oversees all aspects and performs numerous dutiesacross the wide scope of the SPORE to support the translational goals of the investigators. The SPOREAdministration Core is guided by the following Specific Aims: Specific Aim 1: Provide scientific programmaticand administrative leadership to all aspects of the SPORE. Specific Aim 2: Develop facilitate and monitorprogress of translational aims with project Co-Leaders. Specific Aim 3: Identify support and facilitate scientificcollaborations. The Administration Core is charged with creating a culture of collaboration through fosteringand helping to establish and maintain successful collaborations. Specific Aim 4: Facilitate communicationbetween investigators and groups within the Michigan Prostate SPORE as well as with other institutionalSPOREs the SPORE network outside the University of Michigan (U-M) Karmanos Cancer Institute (KCI) NCIand investigators across the spectrum of translational cancer research. Specific Aim 5: Perform fiscal and datamanagement functions. Specific Aim 6: Coordinate patient advocacy and provide functional and ethicaloversight to projects and cores. The Core provides support and oversight to ensure that all investigators haveIRB and animal approvals in place to conduct research. The Core will develop and maintain an advocacy portalfor our prostate cancer patient community. Arul M. Chinnaiyan MD PhD (U-M) serves as Core Director.Ganesh Palapattu MD (U-M) and Elisabeth Heath MD (KCI) will serve as Core Co-Directors of theAdministrative Core and provide overall scientific oversight. Dr. Chinnaiyan will be responsible for overallprogram organization and fiscal oversight as well as the Biostatistics/Bioinformatics andBiospecimen/Pathology Cores. Dr. Palapattu will be responsible for mentorship and development ofcollaborators and trainees oversight of the Career Enhancement Program and synergies between U-M andKCI programs. Dr. Heath will oversee clinical trials and therapeutics patient advocacy minority communityengagement and the Developmental Research Program. Ms. Jill Miller has served as the Michigan ProstateSPORE administrator since 1998 and will continue in this role. This Core provides the framework to supportthe success and mission of the Michigan Prostate SPORE as a cohesive group of investigators committed tosupporting translational research in prostate cancer. +No NIH Category available Acceleration;Advertisements;African American;Attention;Award;Basic Science;Brain;Brain Neoplasms;Charge;Clinical;Clinical Research;Clinical Sciences;Clinical and Translational Science Awards;Collaborations;Communities;Dedications;Development;Diagnosis;Eligibility Determination;Ensure;Evolution;Faculty;Feedback;Fostering;Funding;Funding Mechanisms;Goals;Grant;Individual;Infrastructure;Institution;Journals;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of brain;Medical;Medicine;Minority;Minority Recruitment;Patient-Focused Outcomes;Patients;Peer Review;Prevention;Primary Brain Neoplasms;Probability;Process;Progress Reports;Research;Research Personnel;Research Project Grants;Resources;Rotation;Scientist;Source;Teacher Professional Development;Testing;Translating;Translational Research;Tumor Biology;United States National Institutes of Health;Universities;Update;Woman;Work;bench to bedside;experience;improved;improved outcome;innovation;interest;medical schools;meetings;member;neuro-oncology;novel;novel strategies;professor;programs;recruit;success;translational potential;tumor diagnosis;women faculty Developmental Research Program PROJECT NARRATIVE Developmental Research ProgramThe Developmental Research Program is a critical component of the Duke SPORE in Brain Cancer and meetsthe NIH requirement for all SPOREs. It will take maximum advantage of new research opportunities in braintumors attract new outstanding investigators and collaborators to the field of neuro-oncology provide supportfor novel research and serve as a source of new translational projects for the SPORE. By providing support fornovel neuro-oncology research this program will accelerate discovery and expand the breadth of researchseeking to improve outcomes for patients with primary brain tumors. NCI 10705248 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0 8958 15321972 "ASHLEY, DAVID M." Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 109645 68117 41551 ABSTRACT Developmental Research ProgramThe Developmental Research Program (DRP) is a critical component of the Duke SPORE in Brain Cancersupporting (1) pilot research projects with translational potential relevant to brain tumors and (2) theparticipation of experienced investigators from other fields to work in brain tumor research. Projects areencouraged to test novel concepts and paradigms that bring new approaches into the field to advanceunderstanding of brain tumor biology and improve brain tumor diagnosis treatment and/or prevention. TheDRP will support two to three promising projects each year with the option of renewed funding for oneadditional year with excellent progress. Projects that have a strong likelihood of either developing into fullSPORE projects or projects that can receive funding as independent research projects (e.g. R01s) will bespecifically targeted for support. Both individual investigator and collaborative research are eligible. TheSpecific Aims of this DRP are: 1) To identify and support meritorious basic translational or clinical researchprojects that have a high probability of impacting the diagnosis treatment or prevention of brain tumors; 2) Toattract new outstanding and experienced investigators currently not working on brain tumors to pursue braintumor research; 3) To facilitate collaborative research to test novel concepts and paradigms relevant to braintumor biology diagnosis treatment or prevention and 4) To evaluate progress on funded projects andfacilitate their evolution into full SPORE projects or into independently funded projects. Through these Aimsthe DRP helps to ensure success in the Duke Brain SPORE's charge to translate research findings from thebench to the bedside of brain tumor patients. +No NIH Category available Animal Model;Antigens;Antitumor Response;B-Lymphocytes;Brain Neoplasms;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cancer Vaccines;Cells;Clinical;Cross Presentation;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Diagnosis;Excision;FLT3 ligand;Future;Genes;Glioma;Goals;Growth;Human;Immune response;Immunity;Immunotherapy;In Situ;Injections;Interferon Type II;Isocitrate Dehydrogenase;Macrophage;Malignant neoplasm of brain;Mediating;Mediator;Mus;Mutation;Natural Killer Cells;Pathway interactions;Patients;Pediatric Neoplasm;Phase I Clinical Trials;Population;Prevalence;Primary Brain Neoplasms;Recurrence;Resectable;Resected;Safety;Secondary to;Signal Transduction;Spleen;T cell response;Testing;Therapeutic;Time;Tumor Immunity;Vaccination;cell type;childhood cancer mortality;cost effective;dosage;driver mutation;immunogenic;immunogenicity;improved;improved outcome;melanoma;migration;monocyte;mouse model;mutant;neoplastic cell;novel;novel vaccines;patient population;radiological imaging;response;traditional therapy;tumor;vaccination outcome;vaccination strategy;vaccine efficacy;vaccine strategy;young adult A novel cellular tumor vaccine strategy for mutant IDH1 glioma PROJECT NARRATIVE Project 3Primary brain tumors are the most frequent cause of cancer death in children and young adults. Brain tumorstypically begin as slow growing low grade gliomas (LGGs) that transform in almost all cases to a universallylethal high grade glioma (HGGs) within 10 years. Traditional therapies do not prevent the ultimate progressionfrom LGG to HGG. This project proposes a cell-based vaccine strategy to target a mutation in isocitratedehydrogenase 1 (IDH1) found in the vast majority of LGGs and secondary HGGs. This vaccine strategy hasthe potential to significantly improve outcomes in patients with mutant IDH1-expressing gliomas. NCI 10705246 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0 8956 1912312 "GUNN, MICHAEL D" Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 291140 180871 110331 ABSTRACT Project 3The progression of primary brain tumors in children from low grade (LGGs) to lethal high grade gliomas(HGGs) typically occurs over a 10 year period and is not prevented by traditional therapies. Althoughimmunotherapy seems to be an ideal alternative therapeutic approach for LGG tumors due to the ample timewindow between resection and recurrence during which anti-tumor immunity can be stimulated attempts todevelop the approach have been unsuccessful. The most common mutation found in LGGs IDHR132H islocated in the isocitrate dehydrogenase 1 (IDH1) gene and is ubiquitously expressed in all tumor cells.Unfortunately although its prevalence and ubiquity make IDHR132H an excellent tumor vaccine target it hasproven to be very poorly immunogenic especially in generating CTL responses. This Project aims to overcomethis hurdle by establishing proof of principle for a novel monocyte vaccination strategy for IDHR132H+ gliomas.The approach exploits an endogenous antigen (Ag) cross-presentation presentation pathway that usesresident splenic dendritic cells (DC) to significantly improve the survival of mice bearing intracranial IDH1R132H+CT2A tumors. Our preliminary data suggest that this strategy may stimulate anti-IDH1R132H CD8+ T cellresponses. Building on these findings and additional preliminary data showing that Flt3L markedly improvesmonocyte vaccine efficacy in mouse models of melanoma the Project will test the hypotheses that monocytevaccination can induce effective anti-IDH1R132H CTL responses in mice that these responses can be increasedby Flt3L administration and that monocyte vaccination will safely stimulate robust anti-IDH1R132H immuneresponses in humans. The objectives of this project are to determine the specific mechanisms by whichmonocyte vaccination inhibits IDH1R132H glioma growth (Aim 1) to determine if Flt3L improves the efficacy ofmonocyte vaccination for IDH1R132H-expressing gliomas in mice (Aim 2) and to determine if IDH1R132Hmonocyte vaccination is safe and immunogenic in humans (Aim 3). These studies are expected to provideproof of principle that an entirely novel vaccine strategy monocyte vaccination possibly in combination withFlt3L administration provides superior efficacy to alternative strategies in animal models of IDH1R132H gliomasdetermine the mechanisms by which this efficacy is achieved and demonstrate that this strategy is safe andimmunogenic in a relevant patient population. If successful this Project will provide the rationale and criticalinformation needed for future studies of monocyte vaccination which has the potential to significantly improveoutcomes in patients with IDH1R132H-expressing gliomas. +No NIH Category available Automobile Driving;Benign;Biocompatible Materials;Biological;Blood;Clinical;Clinical Data;Clinical Research;Clinical Trials;Common Data Element;Confidentiality of Patient Information;Consultations;DNA;Data;Databases;Development;Diagnosis;Diagnostic Neoplasm Staging;Donor person;Emerging Technologies;Fluorescent in Situ Hybridization;Formalin;Freezing;Genitourinary system;Goals;Guidelines;High-Throughput Nucleotide Sequencing;Histologic;In Situ Hybridization;Informatics;Informed Consent;Infrastructure;Institutional Review Boards;Link;Maintenance;Malignant neoplasm of prostate;Measures;Medical Oncology;Michigan;Mission;Molecular;Molecular Analysis;Morbidity - disease rate;Morphology;Mutation;National Cancer Institute;Organoids;Outcome;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patients;Play;Prostate;Prostatic Diseases;Proteins;Protocols documentation;RNA;Radiation Oncology;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Serum;Services;Source;Specimen;Technology;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translational Research;Urine;Urology;anticancer research;cDNA Library;clinical care;clinical sequencing;clinically relevant;data de-identification;design;genome sequencing;genomic biomarker;hormone refractory prostate cancer;informatics infrastructure;innovation;laser capture microdissection;mortality;new technology;participant enrollment;patient derived xenograft model;patient oriented research;preservation;programs;relational database;single cell analysis;single molecule;success;technology development;tissue fixing;transcriptome;tumor;welfare Core 2 Biospecimen/Pathology Core The Michigan Prostate SPORE Biospecmen / Pathology Core collects annotates and stores critical prostatecancer related biospecimens required for patient-oriented research. It also has the capabilities for themorphological analysis of tissues and molecular analysis of tissues and biofluids. Our continued goal is todecrease the morbidity and mortality of prostate cancer through innovative research that is supported bybiospecimen resources database and informatics support. NCI 10705244 8/22/23 0:00 PAR-18-313 5P50CA186786-10 5 P50 CA 186786 10 9/11/14 0:00 8/31/24 0:00 ZCA1-RPRB-7 8955 9313950 "KUNJU, LAKSHMI PRIYA" Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 153250 124721 70949 The goal of Michigan Prostate SPORE Biospecimen/Pathology Core is to collect biological materials withassociated clinical information to facilitate translational prostate cancer research. The Core places patientconfidentiality and clinical care as a top priority. As a coordinated effort between pathology urology medicaloncology radiation oncology and Michigan Prostate SPORE researchers the Core has developed a unifiedinformatics infrastructure that provides researchers a wide range of annotated samples. The specific goals ofthe Core include: (1) Protection of patient welfare. The highest priority is given to assure that no research protocolcompromises pathology diagnosis or tumor staging. (2) Acquisition and processing of prostate tissues forresearch. The Core assures that the widest range of prostate tissues and derived biomolecules are availablefrom various sources including benign prostate tissue from patients without any known prostatic diseaseclinically localized prostate cancer and metastatic hormone refractory prostate cancer (Michigan Legacy TissueProgram). (3) High quality pathologic review of prostate tissues. Expert GU pathologists assure uniform reviewof prostate tissue samples. (4) Pathology consultation for the purpose of designing translational researchprojects. This service focuses on determining the types of tissues and amount required for the successfulcompletion of the research projects. (5) Quality assessment of prostate tissues and clinical data. TheBiospecimen/Pathology Core staff regularly evaluates frozen and formalin fixed tissues for adequacy. (6)Development of technology appropriate for pathology-based translational research. New technologies such asintegrative high-throughput sequencing RNA in situ hybridization and single-cell analysis have been introduced.(7) Provide support to ongoing clinical studies. The Core will continue to provide tissue procurement servicesand/or high-quality pathology reviews of specimens from patients enrolled in various clinical trials and studies.(8) Maintenance of clinical and pathology data with links to molecular studies. The Core will continue to expandthe detailed clinical and pathology database conforming to the NCI's Common Data Elements (CDE) guidelinespermitting queries between molecular findings and clinically relevant outcomes. In summary the Core willprovide SPORE investigators with a wealth of carefully annotated samples for translational research whilemaintaining the highest level of clinical care and patient confidentiality. +No NIH Category available Acquired Immunodeficiency Syndrome;Antitumor Response;Area;Biological Assay;Biological Markers;Blood;Bone Marrow;CD4 Lymphocyte Count;Cell Count;Cell surface;Cells;Chemistry;Circulation;Clathrin;Clinical;Contracts;Cytoplasm;Data;Endocytosis;Excision;Exhibits;Foundations;G-Protein-Coupled Receptors;Glioblastoma;Goals;Human;Immune System Diseases;Immunotherapeutic agent;Immunotherapy;Implant;In Vitro;Intervention;Investigation;Knock-in;Knock-in Mouse;Knockout Mice;Licensing;Ligands;Lung;Lymphopenia;Malignant - descriptor;Malignant neoplasm of brain;Marrow;Mediating;Methods;Mus;Newly Diagnosed;Nobel Prize;Patients;Phenotype;Plasma;Primary Brain Neoplasms;Process;Radiation;Recurrence;Research Personnel;Resistance;Serine;Sphingosine-1-Phosphate Receptor;Spleen;Surface;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Variant;Wild Type Mouse;Work;beta-arrestin;biomarker identification;combinatorial;design;efficacy study;improved;inhibitor;lymphoid organ;malignant breast neoplasm;melanoma;mouse model;novel;novel strategies;patient population;pharmacologic;predictive marker;prevent;receptor;receptor internalization;recruit;small molecule;small molecule inhibitor;success;temozolomide;transcriptome sequencing;translatable strategy;tumor;uptake 'Arresting' bone marrow T cell sequestration in patients with GBM PROJECT NARRATIVE Project 2Glioblastoma (GBM) is both the most common and the most malignant primary brain tumor with a mediansurvival of < 21 months. Despite treatment advances it remains nearly uniformly lethal. Immunotherapiescontinue as an active and promising area of investigation but clinical success has been limited by GBMssurprisingly potent capacities for eliciting severe local and systemic immune dysfunction including profoundlylow circulating T cell counts. Building on our findings that these low counts are in part due to S1P1-mediatedsequestration of T cells in the bone marrow this project will determine how T cell sequestration varies withcurrent GBM treatments identify biomarkers to improve selection of GBM patients for intervention and screennovel agents that can release T cells from the bone marrow as promising immunotherapeutic adjuncts. NCI 10705243 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0 8954 10540180 "FECCI, PETER " Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 252382 158491 93946 ABSTRACT Project 2Glioblastoma (GBM) elicits severe local and systemic immune dysfunction including T cell lymphopenia whichhas remained unexplained and unaddressed for nearly 40 years. Foundational studies characterizing T celldisappearance from the blood and lymphoid organs of both patients and mice with GBM reveal AIDS-level CD4counts (< 200 cells/l) substantial reductions in spleen volume (mean of 30%) and up to 5-fold increases innave T cell counts in bone marrow. Additional work has connected these observations to the loss of sphingosine1-phosphate receptor 1 (S1P1) from the T cell surface. Specifically loss of S1P1 results in sequestration of Tcells preferentially in the bone marrow in the context of regressing lymphoid organs such as spleen. In micehowever S1P1 can be stabilized on T cells by knocking in a receptor with disrupted cytoplasmic serines toprevent -arrestin recruitment an early step toward receptor internalization. Importantly -arrestin-inhibitedS1P1-stabilized mice implanted with GBM exhibit long-term survival when administered T cell-activatingtherapies that were previously ineffective. Likewise -arrestin2 knockout mice specifically prove resistant to Tcell sequestration in the setting of GBM. Building on these findings Project 2 proposes to set the groundwork fordesigning translatable strategies to inhibit -arrestin2 and stabilize S1P1 as a novel anti-tumor platform. Likewisethe project has an early focus on elucidating biomarkers that correctly identify those patients most likely to benefitfrom intervention and when. The project will test the hypothesis that systemically administered -arrestin2 smallmolecule inhibitors developed by the group will effectively hinder S1P1 internalization stabilize surface T cellS1P1 free T cells from sequestration and newly license T cell anti-tumor capacities. This hypothesis will betested by the following Specific Aims: Aim 1: Assess in patients the longitudinal variation in T cell sequestrationwith tumor resection and treatment and establish predictive biomarkers and contributory mechanisms for T cellS1P1 loss; Aim 2: Establish the relative contribution of -arrestin2 to S1P1 internalization and screen candidate-arrestin2 small molecule inhibitors for their ability to stabilize S1P1 and abrogate T cell sequestration; Aim 3.Initiate IND-enabling toxicity and efficacy studies with our leading -arrestin2 small molecule inhibitor. This studyis expected to provide a foundation for therapeutic approaches enabling T cell release which our data suggestwould allow immunotherapies to render a more successful antitumor response. +No NIH Category available ATM Gene Mutation;Ablation;Alleles;Allografting;Bioinformatics;Biological;Biological Markers;C-terminal;CCND1 gene;CRISPR screen;Cancer Biology;Cancer Patient;Cell Cycle;Cell Line;Cell physiology;Characteristics;Classification;Clinical;Clinical Data;Clinical Trials;Clonal Expansion;Collection;Complex;Correlative Study;Credentialing;Cyclin-Dependent Kinases;Cyclins;DNA biosynthesis;Diploidy;Disease;Exhibits;Gene Expression Profile;Gene Fusion;Genes;Genetic;Genome Stability;Genomic Instability;Genomics;Growth;Immune checkpoint inhibitor;Immune response;Immunogenomics;Immunotherapy;In Vitro;Knockout Mice;Lead;Link;Loss of Heterozygosity;Maintenance;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metastatic Prostate Cancer;Methods;Michigan;Mismatch Repair Deficiency;Modeling;Molecular;Mus;Mutation;Nivolumab;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Phenotype;Phosphorylation;Population;Property;Prostate;Prostatic Neoplasms;RNA;Recurrence;Role;Sampling;T cell infiltration;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Transcription Elongation;Transcriptional Regulation;advanced prostate cancer;anti-PD-1;cancer subtypes;castration resistant prostate cancer;checkpoint therapy;cohort;experience;experimental study;homologous recombination;immune cell infiltrate;immune checkpoint blockade;immunogenic;improved;in vivo;individual patient;individualized medicine;ipilimumab;molecular subtypes;mouse model;mutant;neoantigens;next generation sequencing;novel;novel therapeutics;personalized medicine;phase 2 study;phase II trial;precision oncology;prostate carcinogenesis;rational design;recombinational repair;response;response biomarker;targeted treatment;trafficking;treatment strategy;tumor;tumor growth;tumor microenvironment;tumorigenesis Project 1: Targeting Metastatic Prostate Cancer Patients with Biallelic Loss of CDK12 Large-scale genomic studies have shown that metastatic castration-resistant prostate cancer (mCRPC) iscomprised of several molecular subtypes that can be targeted through rational precision oncology approaches.We recently identified a novel subtype of prostate cancer enriched in metastatic disease that is typified by biallelicinactivation of CDK12 which leads to genomic instability increased neoantigen burden and an active immuneresponse. In this proposal we will explore this newly defined immunogenic subtype of mCRPC at the mechanisticlevel and also for the first time evaluate targeted therapeutics for CDK12-mutant mCRPC patients focusing onimmune checkpoint blockade agents. NCI 10705240 8/22/23 0:00 PAR-18-313 5P50CA186786-10 5 P50 CA 186786 10 9/11/14 0:00 8/31/24 0:00 ZCA1-RPRB-7 8952 1866290 "CHINNAIYAN, ARUL M" Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 188229 181928 48721 With the wide-spread integration of next-generation sequencing technology over the past several yearscomprehensive genomic studies have shown that prostate cancers can be classified into different molecularsubtypes. Identification of these subtypes and molecular drivers of pathogenesis represents an opportunity todesign rational precision oncology approaches for treatment. To this end we have recently identified andcharacterized a novel molecular subtype of prostate cancer typified by biallelic inactivation of CDK12 and shownthat it is enriched in cases of metastatic castration-resistant prostate cancer (mCRPC). CDK12-mutant prostatecancers exhibit a distinct genomic instability pattern from other prostate cancer subtypes including homologousrecombination and mismatch repair-deficient that is associated with a focal tandem duplication (FTD)phenotype. Importantly CDK12-FTDs lead to an elevated neoantigen burden from increased gene fusions andthis is mirrored by an active immune response and increased T cell trafficking in the tumor microenvironment.Accordingly preliminary results from mCRPC patients in our cohort suggest that they may have a higherlikelihood of response to immune checkpoint blockade. We therefore hypothesize that inactivation of CDK12results in an immunogenic class of mCRPC that may benefit from immune-directed therapies. This hypothesiswill be explored through the following Specific Aims:Aim 1: Define the functional relevance of CDK12 loss to prostate cancer biology and identify synthetic lethaltargets. Experiments in this Aim will focus on in vitro methods bioinformatics analyses and a CRISPR screento examine how CDK12 loss impacts prostate cancer pathogenesis and drives the emergence of animmunogenomic phenotype.Aim 2: Determine the impact of Cdk12 ablation on prostate tumor growth and immune response in vivo. We willgenerate several Cdk12-null mouse prostate models to directly evaluate the role of Cdk12 in prostatetumorigenesis and response to immune checkpoint blockade.Aim 3: Identify molecular determinants of response in the first clinical trials of immune checkpoint blockade forCDK12-mutant mCPRC patients. Using samples from our Phase II trial (IMPACT) of nivolumab and ipilimumabin CDK12-mutant patients we will analyze changes in the immune response and determine tumor-intrinsicbiomarkers of response.Together completion of these Aims will define the role of CDK12 in prostate tumorigenesis and assess precisiononcology approaches for this recently identified subtype of prostate cancer. +No NIH Category available Antigens;Avastin;Bioinformatics;Biometry;Bone Marrow;Brain;Brain Neoplasms;Cancer Vaccines;Case Report Form;Certification;Clinic;Clinical;Clinical Data;Clinical Management;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Conduct Clinical Trials;Conflict of Interest;Consent;Databases;Dedications;Development;Doctor of Medicine;Doctor of Philosophy;Documentation;Electronics;Enrollment;Ensure;Evaluation;Family;Federal Government;Gliadel;Glioblastoma;Glioma;Goals;Health system;Immune;Immunologic Monitoring;Individual;Infrastructure;Interdisciplinary Communication;International;Investigation;Laboratories;Laboratory Finding;Leadership;MGMT gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Manuscripts;Methodology;Mutate;Newly Diagnosed;Pathology;Patient Recruitments;Patient-Focused Outcomes;Patients;Population Heterogeneity;Preparation;Primary Brain Neoplasms;Procedures;Process;Protocols documentation;Publications;Regulatory T-Lymphocyte;Research;Research Design;Research Support;Safety;Services;Specialist;T-Lymphocyte;Therapeutic Clinical Trial;Tissues;Training;Translating;Translational Research;United States Food and Drug Administration;Universities;biobank;career;clinical material;cost effective;data acquisition;data management;electronic data;follow-up;improved;innovation;interdisciplinary collaboration;meetings;monocyte;multidisciplinary;neoantigen vaccine;neuro-oncology;operation;participant enrollment;patient population;programs;promoter;protocol development;quality assurance;recruit;screening;temozolomide;translational goal;vaccine strategy Clinical Trial Operations Core PROJECT NARRATIVE Clinical Trial Operations Core (Core 2)Malignant primary brain tumors are generally fatal with devastating consequences for patients and theirfamilies. The Duke SPORE in Brain Cancer proposes a coordinated program of scientific discovery andtranslational research to enhance treatment of brain tumors and minimize their sequelae. In support of theSPORE's goals this Clinical Trial Operations Core provides clinical leadership infrastructure and expertise forthe proposed research and clinical trials with patients. NCI 10705233 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0 8948 9858268 "DESJARDINS, ANNICK " Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 266230 165396 100892 ABSTRACT Clinical Trial Operations Core (Core 2)The Clinical Trial Operations Core provides critical research support to promote seamless and efficientdevelopment recruitment and conduct of the clinical trials in the Duke Brain SPORE's three projects andclinical studies proposed by Developmental and Career Enhancement awardees. Bringing strong expertise inneuro-oncology and clinical trial operations to the SPORE the Core ensures the safe and efficient conduct ofclinical studies (Aim 1) and recruitment consent and enrollment of a diverse group of subjects for biospecimencollection and clinical studies (Aim 2). Through these Aims the Core provides critical oversight of the full rangeof clinical trial activities including study design protocol preparation research staff training patientrecruitment patient evaluation during treatment and follow-up assessment and treatment of complicationsand evaluation of patient outcomes. To ensure rigorus trial conduct the Core mainatins a full portfolio ofstandard operating procedures (SOPs). In addition the Core is fully integrated with other Duke Brain SPOREcomponents to ensure seamless research coordination. For example in partnership with the AdministrativeCore this Clinical Trial Operations Core provides regulatory specialists to meet the requirements of the federalgovernment Duke University Health System (DUHS) and Duke Cancer Institute (DCI) and avoid conflict ofinterest (COI). This Core also collaborates with the Biostatistics and Bioinformatics Core (Core 1) in thedevelopment of the protocol electronic case report forms (eCRFs) study database data management qualityassurance and summarization of clinical data for presentation at international meetings and manuscriptpublications. Finally the Clinial Trial Operations Core supplies electronic data acquisition and documentationservices for the Biostatistics and Bioinformatics Core (Core 1) and facilitates tissue biobanking with theBiospecimen and Immune Monitoring Core (Core 3). By enchancing interdisciplinary communictation andcollaboration in this way the Core supports the the SPORE's commitment to both translate laboratory findingsto the clinic and collect clinical material to be studied in the laboratory. +No NIH Category available Address;American Indians;Anxiety;Area;Cancer Burden;Cancer Care Facilities;Cancer Death Rates;Cancer Patient;Caregivers;Caring;Censuses;Chairperson;Cheyenne;Collaborations;Communities;Community Health Aides;Dedications;Development;Economic Conditions;Education;Emergency department visit;Enrollment;Family;Family member;Future;General Hospitals;Goals;Great Plains;Health;Health Personnel;Healthcare;Healthcare Systems;Home;Hospitalization;Hospitals;Inpatients;Intervention;Interview;Knowledge;Leadership;Malignant Neoplasms;Massachusetts;Methods;Modeling;Montana;North Dakota;Outcome;Outcome Assessment;Outcome Measure;Pain;Palliative Care;Patients;Phase;Population;Population Intervention;Preparation;Protocols documentation;Provider;Quality of Care;Quality of life;Quasi-experiment;Research;Rural;Rural Health;Rural Population;School Nursing;Service delivery model;Services;Social Conditions;South Dakota;Spirituality;Symptoms;Testing;Teton Sioux Indian;Time;Translating;Transportation;Tribes;United States;United States Indian Health Service;Universities;Walking;Work;cancer care;care coordination;care delivery;care systems;design;effectiveness evaluation;end of life;experience;health care service utilization;improved;improved outcome;innovation;member;mortality;multidisciplinary;novel;novel strategies;palliative;patient engagement;programs;rural area;rural dwellers;rural healthcare;rural setting;rural underserved;satisfaction;socioeconomics;tribal health;tribal healthcare;tribal lands;tribal leader;urban area Advancing Palliative Care in Northern Plains American Indians American Indians in the Northern Plains experience high rates of cancer mortality inadequateaccess to cancer care and adverse social conditions making the development of an innovativeand culturally appropriate model of palliative care delivery a priority for tribes providers andhealth care systems in Western South Dakota. In this application we propose a two-phasestudy that will develop and evaluate a novel culturally appropriate approach to the delivery ofpalliative care services that builds upon existing work in the Northern Plains and advances inpalliative delivery in other settings. This proposal leverages a collaboration across 8organizations committed to improving the health of American Indians in Western South Dakotaan extraordinary opportunity to address a key aspect of the quality of cancer care in one of themost underserved rural populations in the US. NCI 10705232 8/22/23 0:00 RFA-CA-18-026 5R01CA240080-06 5 R01 CA 240080 6 "WEAVER, SALLIE JAYNE" 7/1/22 0:00 8/31/24 0:00 ZCA1-SRB-2(M1)R 2087173 "ARMSTRONG, KATRINA " "PETEREIT, DANIEL G" 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 472072 NCI 452759 19313 The quality of cancer care in the rural United States (US) is inadequate. The Northern Plains is one of the mostrural areas of the US including three states with the highest proportion of rural residents in the 2010 census(South Dakota North Dakota and Montana). In the Northern Plains the burden of cancer is not distributedequally with substantially higher cancer mortality among American Indians (AI) than Whites. Annual cancerdeath rates in this region are 338 per 100000 for American Indians compared to 223 for Whites. One of the greatest areas of need in cancer care for AIs in the Northern Plains is palliative care.Defined as the services needed to live well with serious illness access to palliative care by this population isalmost non-existent particularly in areas like western South Dakota where many tribal lands are located.Because of distance to the nearest cancer care facility inadequate transportation and lack of community-based palliative care support most AIs with cancer living on tribal lands are separated from their familiesduring inpatient cancer care and die either alone in a hospital or at home suffering unnecessarily fromsymptoms such as pain and anxiety. This situation is particularly unacceptable given the the US governmentalresponsibility for tribal health care the adverse socioeconomic conditions experienced by the tribes and theimportance the tribes place on spiritual preparation and community support at the end of life. This proposal arises from a collaboration of 8 programs dedicated to improving cancer care among AIsin Western South Dakota: the Walking Forward program of Avera Health the Oglala Sicangu and CheyenneRiver Lakota tribes the Great Plains Tribal Chairmen's Health Board the School of Nursing at South DakotaState University the Indian Health Service Great Plains Region and the Rural Health and Palliative Careprograms at Massachusetts General Hospital (MGH). These groups have come together to propose a two-phase study that will lead to a sustainable culturally tailored and effective palliative care program for AI cancerpatients in Western South Dakota. In Phase 1 we will build upon formative work understanding palliative careneeds barriers and opportunities in American Indians in this area palliative care educational programsdeveloped at MGH/Harvard and innovations in care delivery and patient engagement ongoing at MGH andelsewhere to create a culturally appropriate intervention for this population focusing on two key componentsprioritized by stakeholders: (1) multidisciplinary provider education and (2) in-home support and carecoordination through a palliative care focused community health worker program. In Phase 2 we will evaluatethese components using an innovative quasi-experimental factorial design examining the combined andindependent impact of the interventions on patient and caregiver outcomes as well as provider knowledge andcomfort. All phases of the project will be guided by a community advisory board composed of tribal healthleaders and representative enrolled members from the three tribes. 472072 +No NIH Category available Antibodies;Bioinformatics;Biometry;Bone Marrow;Brain;Brain Neoplasms;Cancer Vaccines;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Consult;Correlative Study;Data;Data Analyses;Databases;Development;Doctor of Philosophy;Ensure;Family;Flow Cytometry;Genotype;Glioblastoma;Glioma;Goals;Health system;Immunologic Monitoring;Immunologic Tests;Immunotherapeutic agent;Individual;Infrastructure;Laboratories;Leadership;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Manuscripts;Monitor;Pathology;Patients;Phenotype;Practice Management;Preparation;Primary Brain Neoplasms;Program Development;Publications;Quality Control;Randomized;Records;Regulatory T-Lymphocyte;Reporting;Reproducibility;Reproducibility of Results;Reproduction spores;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Role;Safety;Sample Size;Security;Services;Source;Specimen;Stains;Statistical Data Interpretation;T cell receptor repertoire sequencing;T-Lymphocyte;Test Result;Tissues;Translational Research;Universities;Vaccines;Work;biobank;career;career development;clinical infrastructure;cost effective;data integration;data integrity;data management;data quality;design;experience;improved;member;monocyte;mutant;neoantigens;novel;novel therapeutic intervention;operation;programs;quality assurance;synergism;vaccine strategy Biostatistics and Bioinformatics Core PROJECT NARRATIVE Biostatistics and Bioinformatics (Core 1)Malignant primary brain tumors are generally fatal with devastating consequences for patients and theirfamilies. The Duke SPORE in Brain Cancer proposes a coordinated program of scientific discovery andtranslational research to enhance treatment of brain tumors and minimize their sequelae. This Biostatistics andBioinformatics Core will provide biostatistical and bioinformatics expertise to support all studies in the SPOREin Brain Cancer to ensure that reliable reproducible results are generated that have maximal impact. NCI 10705231 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0 8947 7759547 "HERNDON, JAMES E" Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 212658 132114 80590 ABSTRACT Biostatistics and Bioinformatics Core (Core 1)The Biostatistics and Bioinformatics Core will serve as an essential central resource to support the commonquantitative needs of the three translational projects (Projects 1-3) as well as research developed within theDevelopmental Research (DRP) and Career Enhancement Programs (CEP). Building on decades ofcollaborative experience with Duke Brain SPORE investigators the Core will use their expertise to helpinvestigators frame study objectives and to ensure rigorous research design conduct analysis and inference.The Core will provide biostatistical leadership and expertise in the study design conduct sample sizecalculations randomization monitoring analysis and reporting of clinical studies in brain cancer bycollaborating at all project stages from study design to interpretation and publication of results (Aim 1). Inaddition Core 1 will contribute bioinformatics expertise to the conduct analysis and reporting of correlativestudies associated with clinical trials (Aim 2). Expertise is provided for the analysis of data from polychromaticflow cytometry intracellular staining and TCR sequencing data. Finally the Core will facilitate integration ofclinical laboratory and correlative data generated by Projects and Cores and to promote data integrity (Aim3). In partnership with the Administrative Core an exemplary research culture will be promoted where the bestdata management practices will be used throughout the SPORE in order to ensure data integrity provenanceand security and reproducibility of study findings. Though oversight of quality control and quality assurance isprovided by the Administrative Core each individual Core has a role in maintaining data quality and providingan infrastructure within which reliable and valid data is gathered. This Core will provide infrastructure for theClinical Trial Operations Core (Core 2) and the Biorepository Pathology and Immune Monitoring Core (Core 3)to collect quality data and will be responsible for the integration of data from various sources for statisticalanalyses. Taken together the Biostatistics and Bioinformatics Core's contributions to investigating the safetyactivity and mechanisms of novel immunotherapeutic approaches to the treatment of patients with glioma arecritical to the achieving our shared goals of improving treatment of GBM. +No NIH Category available Academy;Acceleration;Accounting;Address;Administrator;Brain;Brain Neoplasms;Cancer Etiology;Cancer Patient;Clinical Sciences;Clinical Trials;Collaborations;Communication;Complex;Data;Data Commons;Data Provenance;Department chair;Development;Doctor of Philosophy;Ensure;Evaluation;Expenditure;Funding;Goals;Grant;Home;Human Resources;Infrastructure;Institution;International;Leadership;Malignant Neoplasms;Malignant neoplasm of brain;Medicine;Molecular;Monitor;Occupational activity of managing finances;Office of Administrative Management;Patient-Focused Outcomes;Patients;Policies;Preparation;Primary Brain Neoplasms;Procedures;Process;Productivity;Publications;Recommendation;Regulation;Regulatory Affairs;Reporting;Reproduction spores;Research;Research Design;Research Personnel;Research Project Grants;Research Subjects;Resource Sharing;Resources;Schedule;Specimen;Training;Translational Research;United States National Institutes of Health;Universities;Vertebrates;Visit;career;childhood cancer mortality;clinical development;conflict resolution;data integrity;data management;data sharing;experience;human subject;improved;improved outcome;medical schools;meetings;neuro-oncology;neurosurgery;operation;patient population;professor;programs;quality assurance;success;therapeutic development;young adult Administrative Core PROJECT NARRATIVE Administrative CorePrimary brain tumors are the most frequent cause of cancer death in children and young adults. ThisAdministrative Core provides infrastructure leadership coordination integration and oversight for the DukeSPORE in Brain Cancer to enable its translational research designed to improve outcomes for patients withprimary brain tumors. NCI 10705227 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0 8945 15321972 "ASHLEY, DAVID M." Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 342725 212920 129880 ABSTRACT Administrative CoreThe Administrative Core provides comprehensive administrative and scientific management for all componentsof the Duke Brain SPORE including research Projects 1-3 three Shared Resource Cores and bothDevelopmental Research and Career Enhancement Programs. Programmatic oversight will be provided by theAdministrative Core Co-Leads as well as an Executive Committee consisting of Project and Core Leads andInternal and External Advisory Boards. The functions of the Administrative Core will be carried out through thefollowing Specific Aims: 1) Provide administrative management and oversight; 2) Provide financialmanagement and ensure compliance with fiscal and research policies; 3) Provide oversight of all dataoperations; 4) To promote integration within the SPORE and the Institution; 5) Maintain and support access toan adequate cancer patient population; and 6) Provide scientific management and evaluate researchprogress. Through these Aims the Core ensures the full range of support required to provide administrativemanagement; promote integration communication and collaboration; ensure fiscal and regulatory compliance;and oversee data operations scientific rigor and research progress. By serving these functions theAdministrative Core allows SPORE investigators to focus on conducting and advancing the translationalscience supported by the SPORE. +No NIH Category available Address;Agonist;Antibodies;Antigens;Arrestins;Award;Basic Science;Bioinformatics;Biological Assay;Biometry;Bone Marrow;Brain;Brain Neoplasms;Cancer Etiology;Cancer Vaccines;Cessation of life;Clinical;Clinical Trials;Collaborations;Communication;Communities;Complementary therapies;Cytomegalovirus Vaccines;Data Commons;Development;Ensure;Environment;Epitopes;Evaluation;Excision;FLT3 ligand;Faculty;Feeds;Fostering;Future;Glioblastoma;Glioma;Goals;Heterogeneity;Human;Immune;Immune response;Immunobiology;Immunologic Monitoring;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Infrastructure;Lead;Leadership;Licensing;Life;Link;Lymphopenia;Malignant - descriptor;Malignant neoplasm of brain;Mus;Outcome;Pathology;Pathway interactions;Patients;Pilot Projects;Population;Positioning Attribute;Primary Brain Neoplasms;Recording of previous events;Regulatory T-Lymphocyte;Renal carcinoma;Reporting;Research;Research Project Grants;Resource Sharing;Resources;Sampling;Scientist;Surface;T cell response;T-Cell Depletion;T-Lymphocyte;Testing;Therapeutic Trials;Tissues;Toxic effect;Translational Research;Universities;Vaccination;Vaccines;Variant;Work;biobank;career;childhood cancer mortality;clinical translation;design;immunogenic;improved;innovation;melanoma;monocyte;mutant;neoantigens;neuro-oncology;novel;novel strategies;novel therapeutic intervention;operation;patient population;predictive marker;programs;recruit;response;small molecule inhibitor;therapy development;translational goal;translational impact;translational physician;tumor;vaccine strategy;young adult Duke SPORE in Brain Cancer PROJECT NARRATIVE OverallMalignant primary brain tumors like glioblastoma (GBM) are the most frequent cause of cancer death inchildren and young adults and account for more deaths than cancer of the kidney or melanoma. Moreovercurrent therapy is incapacitating and limited by non-specific toxicity to systemic tissue or surrounding eloquentbrain. The research proposed in this application focuses on the development of and improvement of novelimmunotherapeutic platforms against GBM and low grade glioma takes basic science and recent clinicalfindings to the next level of clinical translation feeds the development of future high-impact translationalresearch in immunotherapy for brain tumors and expands the research community addressing brain tumors. NCI 10705225 8/15/23 0:00 PAR-18-313 5P50CA190991-10 5 P50 CA 190991 10 "HUBBARD, LEAH" 9/24/14 0:00 8/31/24 0:00 ZCA1-RPRB-0(O1) 15321972 "ASHLEY, DAVID M." "ALI-OSMAN, FRANCIS " 4 NEUROSURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2087855 NCI 1302002 786306 ABSTRACT OverallBuilding on the Duke Brain Tumor Program's longstanding focus on development refinement and testing ofimmunotherapies to treat low-grade gliomas and glioblastoma (GBM) this renewal of the Duke SPORE inBrain Cancer continues work to develop new or improve existing therapies to improve the life of patients withprimary malignant brain tumors. To achieve this goal the Program provides the infrastructure oversight andresources to conduct innovative translational research relevant to these treatments (Aim 1). Innovativeresearch proposed includes: 1) studies of potent neoantigen and Cytomegalovirus vaccines in the context ofregulatory T cell depletion using a novel approach targeting CD27 to overcome both host immunosuppressionand antigenic heterogeneity endemic to GBM (Project 1); 2) studies employing a novel therapeutic strategy toreverse the recently discovered phenomenon of T cell sequestration in patients with GBM and overcome thelimitations imposed on immunotherapy by longstanding lymphopenia in this population (Project 2); and 3)studies examining the mechanisms and efficacy of a novel cellular tumor vaccine strategy that uses antigen-loaded monocytes and an endogenous antigen transfer pathway to stimulate potent anti-tumor T cellresponses (Project 3). To support this work the SPORE ensures the availability of expertise through threeShared Resource Cores all continued from the current award: a Biostatistics and Bioinformatics Core(Core 1) Clinical Trial Operations Core (Core 2) and a Biorepository Pathology and ImmuneMonitoring Core (Core 3) (Aim 2). Research central to the theme of the SPORE is further enhanced by theProgram's commitment to seeding developmental research and implementing approaches to grow theresearch community through its Developmental Research and Career Enhancement Programs (Aim 3).Finally the Duke SPORE in Brain Cancer continues to participate in and lead inter-SPORE activities toenhance collective impact (Aim 4). Contributions include continuing leadership of an active inter-SPOREcollaboration in Immune Monitoring that is working to establish common standards and to harmonize assaysand proposed contributions to the NCI's new Functional Data Commons effort. Taken together the Duke BrainSPORE is ideally positioned to address and overcome limitations in existing malignant brain tumor therapiesand enhance collective research environment to advance shared research community goals. 2087855 +No NIH Category available Ablation;Address;Androgen Receptor;Area;Autophagocytosis;Bioinformatics;Biological Assay;Biometry;Biotechnology;Bone Pain;Bromodomains and extra-terminal domain inhibitor;Cancer Patient;Cells;Clinic;Clinical;Clinical Investigator;Clinical Management;Clinical Trials;Collaborations;Communities;Complement;DNA Repair;DNA Repair Gene;Data;Dedications;Defect;Development;Diagnosis;Disease;Dreams;Early Detection Research Network;Early Diagnosis;Ensure;Extramural Activities;Fostering;Foundations;Funding;Gene Fusion;Genetic;Goals;Grant;Individual;Infrastructure;Institution;Intervention;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of prostate;Mentors;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Michigan;Morbidity - disease rate;Mutation;Nature;Oncogenic;Oncology;Pathology;Phase II Clinical Trials;Pilot Projects;Play;Poly(ADP-ribose) Polymerase Inhibitor;Prevention;Prostate;Prostate Cancer therapy;Recording of previous events;Recurrence;Reproduction spores;Research;Research Personnel;Resources;Role;Science;Scientific Advances and Accomplishments;Scientist;Screening for Prostate Cancer;Southwest Oncology Group;Sum;Testing;Therapeutic;Training;Translations;Underserved Population;Universities;University resources;Untranslated RNA;Urine;Washington;advanced prostate cancer;anticancer research;bench to bedside;cancer cell;career;career development;castration resistant prostate cancer;clinical diagnostics;clinical efficacy;clinically actionable;flexibility;inhibitor;innovation;men;mortality;multidisciplinary;next generation;next generation sequencing;novel;patient population;peptidomimetics;phase II trial;programs;prostate cancer risk;recruit;success;therapeutic target;transcription factor;translational impact;translational research program;tumorigenesis Michigan Prostate SPORE The Michigan Prostate SPORE seeks to decrease the morbidity and mortality associated with prostate cancerby making scientific advances that address critical questions in prostate cancer tumorigenesis and treatment. Inthe Michigan Prostate SPORE renewal four translational projects together identify and address major barriersand challenges that exist for the diagnosis and clinical management of prostate cancer and progression tometastatic disease. These projects are highly collaborative with respect to the multidisciplinary nature andexpertise of the Co-Leaders. NCI 10705224 8/22/23 0:00 PAR-18-313 5P50CA186786-10 5 P50 CA 186786 10 "SCROGGINS, BRADLEY TODD" 9/11/14 0:00 8/31/24 0:00 ZCA1-RPRB-7(M1) 1866290 "CHINNAIYAN, ARUL M" "HEATH, ELISABETH IIJAS; PALAPATTU, GANESH S" 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1346108 NCI 1192329 535563 Since inception in 1995 the University of Michigan (U-M) Prostate SPORE has endeavored to tap the vastintellectual and physical resources of the U-M community to decrease the morbidity and mortality of prostatecancer (PCa). In this renewal application U-M joins forces with Karmanos Cancer Institute (KCI) to propose aMichigan Prostate SPORE leveraging our institutions' respective areas of strength. KCI has a non-overlappingpatient population as U-M which includes an underserved population. The Michigan Prostate SPORE supportsan interactive group of basic and clinical investigators in a translational research program that has led to majordiscoveries in the diagnosis prevention and treatment of PCa. Successful translation of discoveries in themost recent grant period include: 1) The ETS gene fusions (which were discovered by this SPORE program)have been established as a urine test for the early detection of PCa (JAMA Oncology 2017 3:1085) and havebeen therapeutically targeted with peptidomimetic inhibitors (Cancer Cell 2017 31:844). 2) Our SPORE programplayed a significant role in defining the clinically actionable landscape of metastatic castration-resistant prostatecancer (mCRPC) (Cell 2015 162:454) which led to the discovery that upwards of 20-25% of mCRPC harbordefects in DNA repair genes. As part of the TO-PARP study we showed that mCRPC patients with DNA repairdefects preferentially respond to PARP inhibitors (NEJM 2015 373:1697). 3) Established that BET bromodomaininhibitors may be useful in the treatment of advanced PCa by blocking oncogenic transcription factor activity(Nature 2014 510:278). 4) Several PCa-associated long non-coding RNAs including PCAT1 Schlap1 (NatureGenetics 2013 45:1392) and ARlnc1 (Nature Genetics 2018 50:814) were discovered and characterized. Thesebench-to-bedside applications were aided by horizontal collaborations with the University of WashingtonDana Farber Memorial Sloan-Kettering and Weill-Cornell Prostate SPOREs as well as the EDRN and verticalcollaborations with SWOG and biotech companies. This application consists of four projects: Project 1:Targeting mCRPC Patients with Biallelic Loss of CDK12; Project 2: Integrating a Novel MiPS-Based Next-Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk PCa; Project 3: ExploringAblation of the Androgen Receptor as a Therapeutic Approach for mCRPC; Project 4: Targeting Autophagy inthe Treatment of mCRPC. These projects are complemented by strong ongoing institutional commitments ofmoney and space successful Career Development and Developmental Research Programs and threecores: Administration Biostatistics/Bioinformatics and Biospecimen/Pathology. The Michigan ProstateSPORE continues to place premiums on rigorous scientific review of its translational research programs pairingof basic and clinical investigators drawing on expertise of scientists from within and from outside the PCa fieldand utilizing flexibility to fund promising new research approaches. The interaction of our multidisciplinary groupof investigators clearly makes the Michigan Prostate SPORE greater than the sum of its individual parts. 1346108 +No NIH Category available Affect;Anxiety;Award;Behavioral;Cancer Patient;Classification;Clinical;Clinical Investigator;Clinical Oncology;Communication;Comprehensive Cancer Center;Computerized Medical Record;Confusion;DNA Sequence Alteration;Data;Decision Making;Dedications;Development;Diffuse;Dimensions;Early Diagnosis;Early treatment;Ensure;Foundations;Frequencies;Fright;Funding;Future;Genetic Services;Genomic medicine;Genomics;Goals;Guidelines;Health;Health system;Healthcare Systems;Human;Individual;Institutional Practice;Intervention;Interview;Investigation;Knowledge;Length;Literature;Longitudinal Studies;Malignant Neoplasms;Measures;Medical;Medical Genetics;Mentorship;Methods;Minority Groups;Oncology;Operative Surgical Procedures;Outcome;Patient Care;Patient Outcomes Assessments;Patients;Perception;Phase;Practice Guidelines;Prevalence;Professional Practice;Program Sustainability;Provider;Psychometrics;Public Health Informatics;Qualitative Methods;Recommendation;Recontacts;Reporting;Research;Risk;Sampling;Site;Source;Structure;Subgroup;Surgical Management;Survey Methodology;Surveys;Test Result;Testing;Time;Training;Uncertainty;Underrepresented Minority;Underserved Population;United States;Update;Validation;Variant;Work;apprenticeship;cancer prevention;career;clinical decision-making;clinical translation;clinically relevant;clinically significant;cohort;cost;design;ethnic diversity;ethnic minority population;evidence based guidelines;experience;genetic technology;genetic testing;genetic variant;genome sequencing;improved;instrument;mutation carrier;novel;patient population;psychosocial;psychosocial wellbeing;racial diversity;racial minority population;screening;sociodemographics;therapy design;tool;translational genomics;variant of unknown significance Multilevel investigation of uncertain and reclassified genomic variants in clinical oncology PROJECT NARRATIVEAs genomic sequence data are being produced faster and at lower cost the most significant challenge inclinical genetic testing today is accurate variant classification and communication of that information to patientswhich is being adversely affected by variants of unknown significance (VUS) which comprise of a substantialpercentage of all genetic variants in clinical oncology. VUS along with other confirmed variants are beingreclassified with increasing availability of more ethnically diverse reference data yet there is a lack ofunderstanding on how practicing clinicians and patients are impacted by and manage these variants. Toprovide empirical data to fill this critical knowledge gap and potentially inform patient care I will conduct anational survey of oncology providers about how their variant reclassification related practices develop a toolfor measuring patient reported uncertainty in genomics and evaluate the clinical utility of VUS reclassificationamong cancer patients and at-risk individuals. NCI 10705219 8/10/23 0:00 RFA-CA-20-014 5R00CA256216-04 5 R00 CA 256216 4 "CAGA-ANAN, EMILIE CHARLISSE F" 3/1/21 0:00 8/31/25 0:00 ZCA1-RTRB-U(O1) 15594841 "MAKHNOON, SUKH " Not Applicable 30 PUBLIC HEALTH & PREV MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 195053 NCI 151811 97159 PROJECT SUMMARY/ABSTRACTThe overarching goal of this award is to prepare the applicant for an independent sustained program ofresearch that incorporates psychosocial behavioral and clinical concepts and methods to understand anddesign interventions to guide clinical translation of uncertain and reclassified genomic variants. Variants ofuncertain significance (VUS) introduce uncertainty and can confuse clinical decision making for patients andproviders. VUS are also frequently reclassified especially in racial/ethnic minority populations and can informclinical decision making. However insufficient evidence around the influences and outcomes of uncertain andreclassified variants presents a challenge for more diffuse clinical translation of these genetic variants. Suchunderstanding is particularly important in clinical oncology as identification of mutation carriers cansignificantly alter cancer prevention screening surgery recommendations and treatment. The K99 phase isdesigned to augment the candidate's prior research experience though coursework apprenticeships anddirected readings with specific training in: 1) clinical health informatics 2) psychometrics and surveymethodology and 3) advanced qualitative methods. The proposed research will collect patient reported andelectronic medical record data from six healthcare systems that provide clinical genetic services to aracially/ethnically diverse patient population. Aim 1 (K99 phase) surveys a national sample of oncologyproviders to understand their practices related to variant reclassification and recontact. Aim 2 (K99 phase)interviews patients to identify dimensions of reclassification associated psychosocial well-being. Aim 3 (R00phase) uses data from aim 2 and existing literature to develop and pilot an instrument to measure genomicuncertainty in patients. Aim 4 (R00 phase) evaluates the clinical utility of variant reclassification. This work willgenerate evidence to inform institutional and professional practice around variant reclassification. Takentogether the findings from this study will contextualize and provide tools for a future longitudinal study todetermine the behavioral psychosocial and clinical consequences of receiving uncertain genetic test results.This project is a critical building block for the applicant's long-term research goal to develop and testinterventions (at the levels of provider patient and healthcare system) to facilitate the clinical translation ofgenomics into diverse health systems and into underserved populations. The proposed award will providetraining mentorship and research experience that will serve as the foundation for the applicant's career as anindependently funded clinical investigator dedicating to improving health outcomes in translational genomicsfor underrepresented minority populations. 195053 +No NIH Category available 2 arm randomized control trial;Acute;Architecture;Behavioral;Biopsy;Biopsy Specimen;Cessation of life;Clinic;Clinical;Confidence Intervals;Data;Diagnosis;Diagnostic;Exercise;Exercise Therapy;Freezing;Future;Genomic Instability;Grant;Histology;Home;Hypoxia;Image;Incidence;Intervention;Investigation;Local Therapy;Localized Disease;Magnetic Resonance Imaging;Malignant neoplasm of prostate;Molecular;Monitor;Nature;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Observational Study;Operative Surgical Procedures;Outcome;PSA screening;Pathologic;Pathologist;Patient Care;Patient Self-Report;Patients;Phase II/III Trial;Physical activity;Quality of life;Radiology Specialty;Random Allocation;Randomized;Randomized Controlled Trials;Research;Safety;Sample Size;Sampling;Screening Result;Structure;Symptoms;Telemedicine;Testing;Therapeutic Intervention;Time;Toxic effect;Translating;Untranslated RNA;Walking;Width;arm;clinical risk;conventional therapy;cost;exercise capacity;genome sequencing;genome-wide;health related quality of life;high risk;improved;men;mouse model;novel;overtreatment;post intervention;preclinical study;prevent;primary endpoint;programs;progression marker;prospective;prostate biopsy;prostate cancer model;prostate cancer progression;prostate cancer risk;randomized trial;response;serum PSA;standard of care;transcriptome sequencing;treadmill;treatment as usual;trial design;tumor progression;whole genome Randomized Trial of Exercise Therapy on Markers of Progression in Localized Prostate Cancer: Project narrativeIn this grant we will investigate for the first time whether and how exercise alters molecular clinical andsymptom outcomes in men with localized prostate cancer. As such if successful the findings of this study couldsignificantly enhance the management of men initiating active surveillance as well as provide essential formativeinformation to guide larger definitive trials. NCI 10705201 8/21/23 0:00 PAR-21-035 5R01CA272678-02 5 R01 CA 272678 2 "PERNA, FRANK" 9/15/22 0:00 7/31/27 0:00 Lifestyle Change and Behavioral Health Study Section[LCBH] 8070359 "JONES, LEE W" "BOUTROS, PAUL CHRISTOPHER" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 679692 NCI 506829 172863 AbstractWidespread use of serum prostate-specific antigen (PSA) screening results in 50% of new cases of prostatecancer being diagnosed with low-grade localized disease. Standard of care for these cases is to defer immediatetreatment in favor of active surveillance (AS) a low-toxicity management which entails close monitoring withPSA tests repeat prostate biopsies and multi-parametric MRI (mpMRI). Around 30% of men on AS progress orelectively undergo definitive treatment within two years of diagnosis. Efficacious low-cost low-toxicity strategiesto limit exit from AS are needed to reduce over-treatment and improve health-related quality of life (QOL). Accordingly in this proposal we will test whether and how exercise alters prostate cancer molecularlandscape. Using a two-arm RCT design 122 men initiating AS (e.g. inactive diagnostic biopsy <6 months) willbe randomly allocated (1:1 ratio) to exercise therapy intervention (n=61) or usual care (plus general physicalactivity advice; n=61) for 12 months. Exercise therapy will consist of home-based treadmill walking five dayseach week at 65-75% of their personal baseline exercise capacity. All sessions will be implemented usingTeleMed-X a novel telemedicine platform pioneered in our program. Our central hypothesis is that exercisetherapy will reduce the number of nimbosus features to collectively inhibit clinical progression. This centralhypothesis is tested in three distinct but complementary aims: Aim 1. Determine effects of exercise therapy onmolecular nimbosus hallmarks; Aim 2. Determine effects on the radiologic and pathologic nimbosus hallmarks;and Aim 3. Delineate the precision of estimating rates of clinical progression at 18 months. 679692 +No NIH Category available Address;Advocate;Affect;Area;Collaborations;Common Data Element;Communities;Dedications;Development;Development Plans;Education;Ensure;Environment;Equipment;Equity;Ethics;Evaluation;Faculty;Funding;Future;Goals;Grant;Individual;Infrastructure;Institution;Institutional Policy;Lead;Manuscripts;Mentors;Modeling;Outcome;Policies;Research;Research Infrastructure;Research Personnel;Research Support;Science;Scientist;Teacher Professional Development;Underrepresented Minority;United States National Institutes of Health;Woman;Work;Writing;career;career development;cohort;collaboratory;community building;community engagement;community organizations;design;diversity and inclusion;equity diversity and inclusion;health disparity;innovation;member;men;minority scientist;multidisciplinary;peer;programs;recruit;social;success;virtual UAB/TU FIRST Faculty Development Core n/a NCI 10705183 9/11/23 0:00 RFA-RM-20-022 5U54CA267746-03 5 U54 CA 267746 3 9/22/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 8940 1883865 "FOUAD, MONA N." Not Applicable 7 Unavailable 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL Domestic Higher Education 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 203606 140000 63606 The UAB/TU FIRST Partnerships Faculty Development Core has aligned its proposed aims andactivities to include each of the levels of influence described by the Social Ecological Model. Specifically wewill: 1) facilitate development of innovative independent research among Benjamin-Carver Scientists throughindividual and cluster development plans augmented by a) scientific mentoring through Principal Mentors andmentoring teams; b) individual and group career coaching; c) personal sponsorship by an established leader;and d) professional development opportunities with immersive community engagement; 2) institute an Officeof Integrated Research Support to provide research navigation to Benjamin-Carver Scientists and fast-trackadministrative support; 3) develop a Research Community Collaboratory to inspire and challenge Benjamin-Carver Scientists by augmenting peer clusters with established mid- and senior-level scientists and communitystakeholders to facilitate collaboration and team science; 4) revise and implement institutional policiespractices and programs related to recruitment promotion and personal/career development to reduceisolation build community and create an inclusive equitable environment for Benjamin-Carver Scientists aswell as current and future diverse research-intensive faculty; and 5) work with the Evaluation Core to evaluatethe UAB/TU FIRST Partnership and for common data elements needed by the FIRST Coordination andEvaluation Center to assess impact of the FIRST Cohort Program. Both UAB and TU are committed to supporting our Scientists so that they can become successfulindependent researchers. We will promote their career development by funding dedicated Principal Mentors toprovide scientific guidance and to lead multidisciplinary mentoring teams supported by Research Navigatorsand Sponsor advocates; offering individual career coaching and group coaching sessions to reduce isolationand provide support; and facilitating involvement in professional development opportunities across fourdomains. We will remove barriers to success by fast tracking the infrastructure support of our Scientists and byproviding Research Navigators through an institutionally supported Office of Integrated Research Support. Wewill integrate investigators within clusters across areas of research and with community organizations throughour Research Community Collaboratory and networking activities. We will ensure retention by institutingpolicies at both institutions that reflect positive changes initiated by this program and by implementing diversityequity and inclusion programming to enhance and sustain a culture of diversity and inclusive excellence. We are confident that our decades of collaboration combined with our current adeptness to interactvirtually will allow us to provide the support and integration our Benjamin-Carver Scientists need to besuccessful. Together we can create the systemic and sustainable culture change needed to ameliorate ourregions significant health disparities. +No NIH Category available Acceleration;Address;Advocate;Affect;Alabama;Area;Cardiovascular Diseases;Collaborations;Communities;Complement;Development;Development Plans;Diabetes Mellitus;Ensure;Environment;Evaluation;Faculty;Fostering;Foundations;Goals;Grant;Health Status;Individual;Infrastructure;Institution;Institutional Policy;Location;Logistics;Malignant Neoplasms;Mentors;Modeling;Neurosciences;Obesity;Outcome;Policies;Positioning Attribute;Research;Research Personnel;Research Support;Research Training;Resources;Rural;Scientist;Series;Surgeon;Testing;United States National Institutes of Health;Universities;Washington;Work;career;career development;cohort;collaboratory;community building;diversity and equity;diversity and inclusion;early-career faculty;equity diversity and inclusion;experience;health disparity;improved;interest;model design;peer networks;peer support;programs;recruit;social;success UAB/Tuskegee Faculty Institutional Recruitment for Sustainable Transformation (UAB/TU FIRST) Partnership (NIH U54) Project NarrativeWe propose to create systemic and sustainable culture change to support inclusive excellence in research byrecruiting clusters of faculty focused on health disparities specifically in the areas of cancer obesity anddiabetes cardiovascular disease and neuroscience. We will recruit and select 12 junior faculty who arecommitted to diversity and provide supportive institutional environments to facilitate their development ofsuccessful independent research programs. Support will include individual career development infrastructureand assistance opportunities for networking and collaboration and changes to policy and environment toreduce isolation build community and increase retention. NCI 10705176 9/11/23 0:00 RFA-RM-20-022 5U54CA267746-03 5 U54 CA 267746 3 "CALZOLA, JESSICA MARIE" 9/22/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(51)R] 1883865 "FOUAD, MONA N." "DURANT, RAEGAN WINSTON; TURNER, TIMOTHY " 7 INTERNAL MEDICINE/MEDICINE 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 4380881 OD 3270520 1110361 The overarching goal of the University of Alabama at Birmingham (UAB)/Tuskegee University (TU)Faculty Institutional Recruitment for Sustainable Transformation (FIRST) Partnership is to create systemic andsustainable culture change to further support inclusive excellence in research at both institutions. Within ourtheme of Health Disparities we will build a community of scientists committed to inclusive excellence byrecruiting 12 early-career faculty committed to promoting diversity and inclusion and interested in addressinghealth disparities. These faculty will be hired across 3-4 clusters representing areas of research strength andopportunity across our institutions: cancer obesity and diabetes cardiovascular disease and neuroscience.Program hires will be designated as Benjamin-Carver Scientists in honor of two barrier-breaking investigatorleaders Regina Benjamin MD and George Washington Carver. Our Scientists will be surrounded by acomprehensive support infrastructure including sponsors mentors career coaches institutional researchnavigators and professional development opportunities to help them mitigate the difficulties experienced bynew hires and accelerate the development of collaborative networks and peer support. We have targeted our activities and support mechanisms to ensure that they impact all levels ofinfluence in the Social Ecological Model including Individual Interpersonal Organizational Community andPolicy. All levels are reflected in the following specific aims: 1) recruit and hire clusters of Benjamin-CarverScientists who are committed to advancing diversity equity and inclusion in areas of shared research needand support them by implementing individual career development plans enhanced with scientific mentoringcareer coaching and advocate sponsorship; 2) provide enhanced support for new faculty through an Office ofIntegrated Research Support in which Research Navigators will help new faculty coordinate sponsor mentorand career coaching support; connect new faculty to existing support resources; and assist new faculty withlogistic fiscal and regulatory matters related to proposal development and grants management; 3) provideextended opportunities for professional development and networking including a diverse and inclusiveResearch Community Collaboratory to help faculty build a collaborative network of peers; 4) expand a series ofdiversity and inclusion programs at both UAB and Tuskegee to help foster systemic and sustainable culturalchange; 5) institute changes to institutional policies and environment to support sustainable institutional culturechange including initiatives to support diverse and inclusive hiring and retention; and 6) evaluate the UAB/TUFIRST Partnership and work with the FIRST Coordination and Evaluation Center (CEC) to determine whetherthis cohort and cluster design model of faculty hiring sponsorship continual mentoring and professionaldevelopment embedded within programs to create academic cultures of inclusive excellence producessignificant change in metrics of institutional culture. 4380881 +No NIH Category available Allogenic;Apoptotic;Bar Codes;Biological Markers;Bone Marrow Transplantation;Cells;Clinical;Clinical Trials;Complication;Databases;Development;Disease;Eligibility Determination;Evaluation;Gastrointestinal tract structure;Hematopoietic Stem Cell Transplantation;Hour;Human;In Vitro;Intestines;Link;Malignant - descriptor;Modality;Modeling;Molecular;Mus;Organoids;Pathway interactions;Patients;Process;Quality Control;Reporting;Research;Sampling;Services;Site;Tube;arm;biobank;clinical database;computer program;curative treatments;data reduction;flexibility;gastrointestinal;patient screening;stem cells;therapeutically effective;tv watching Core 2: Biorepository Biomarker Analysis and GI Organoids CORE 2 NARRATIVEAllogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignantdiseases whose applicability has been impeded by the development of its most serious complicationGI GVHD. Strategies that strengthen the target cells in the GI tract will allow for better harnessing ofthis effective therapeutic modality. Core 2 provides support for organoid models biomarker analysisand computer programming and is used by all three projects. NCI 10705168 9/8/23 0:00 PAR-20-077 5P01CA039542-34 5 P01 CA 39542 34 9/10/97 0:00 8/31/27 0:00 ZCA1-RPRB-J 6109 1876461 "FERRARA, JAMES L. M." Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 474345 280678 193667 CORE 2 ABSTRACTIn this renewal all three projects share an integrated synergistic focus on GI GVHD. Core 2 hasdeveloped new services related to GI GVHD in both clinical and experimental BMT in order to meet thisfocus of all three projects. The core continues to maintain and curate the MAGIC biorepository (objective1). During this cycle we collected and processed more than 30000 research samples from 3000 patients.Samples are aliquoted into barcoded tubes that are linked to the patient date and sample type. The corealso continues to provide central analysis for both human and mouse biomarkers (objective 3). We havedeveloped rigorous quality control processes for real time screening of patient samples for clinical trialeligibility and reporting of results to all participating sites within 24 hours.The first new service provided by this core (objective 2) is the use of computer programming to enhancethe flexibility of the MAGIC biorepository and database. This programming reduces data errors andfacilitates rapid creation of contemporaneous controls for single arm clinical trials. The second newservice (objective 4) establishes and analyzes gastrointestinal organoid cultures. These cultures permitthe analysis and quantification of intestinal stem cells in models of GVHD damage in vitro that permitevaluation of key survival and apoptotic pathways.The objectives therefore are:1. To maintain and curate the MAGIC biorepository.2. To use computer programming to enhance the flexibility of the MAGIC biorepository and facilitate its linkage to the clinical database.3. To provide central analyses of both human and mouse biomarkers.4. To provide a central process for the establishment and analysis of GI organoids. +No NIH Category available Accountability;Acute Graft Versus Host Disease;Allogenic;Biological Markers;Biometry;Bone Marrow Transplantation;Categories;Cells;Clinical;Clinical Trials Design;Committee Members;Complication;Data;Data Coordinating Center;Databases;Development;Disease;Doctor of Philosophy;Experimental Designs;Experimental Models;Gastrointestinal tract structure;Generations;Hematopoietic Stem Cell Transplantation;Individual;Laboratories;Malignant - descriptor;Modality;Molecular;Monitor;Patients;Process;Reporting;Research;Sample Size;Services;Statistical Data Interpretation;clinical database;cost effective;curative treatments;data sharing;innovation;operation;programs;statistical service;therapeutically effective Admin Core: Administration Biostatistics and Data Coordinating Center CORE 1 NARRATIVEAllogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignantdiseases whose applicability has been impeded by the development of its most serious complicationGI GVHD. Strategies that strengthen the target cells in the GI tract will allow for better harnessingof this effective therapeutic modality. Core 1 contains the administrative biostatistical support anddatabase operations support for all three projects. NCI 10705165 9/8/23 0:00 PAR-20-077 5P01CA039542-34 5 P01 CA 39542 34 9/10/97 0:00 8/31/27 0:00 ZCA1-RPRB-J 8929 1876461 "FERRARA, JAMES L. M." Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 580591 353013 227578 CORE 1 ABSTRACTThe Administration Biostatistics and Clinical Database Core provides support for all three projects withinthe P01. The PI Dr. Ferrara is responsible for the overall conduct of this research program. An executivecommittee of members (the three project and core leaders) is chaired by the PI. The executive committeemeets formally on a monthly basis to review progress of the individual projects to monitor the function ofthe cores and to resolve any potential logistical difficulties. Umut zbek Ph.D. provides biostatisticaloversight to all projects with expertise in three categories of statistical services: 1) statistical analysis ofclinical and biomarker data; 2) experimental design sample size calculations and analyses inexperimental models; and 3) clinical trial design and monitoring. Dr. Levine oversees the activities of thedata coordinating center which provides a number of innovative and cost effective services. The MAGICdatabase currently contains data for 5000 HCT recipients and 2300 acute GVHD cases; ~700 patients(300 with GVHD) per year. This core has developed rigorous processes to minimize data errors bothbefore and after data entry.The Core 1 objectives are as follows:1. To provide administrative and fiscal oversight to all projects and cores and to facilitate optimal interactions including centralized data sharing document generation organization monitoring financial reports and accountability to all internal and external agencies.2. To provide advanced biostatistical support for analysis of clinical and laboratory data and assist in the biostatistical design of experiments in all projects.3. To oversee the creation and curation of the MAGIC database. +No NIH Category available Address;Algorithms;Allogenic;Biological Markers;Bone Marrow Transplantation;Categories;Cells;Clinical;Clinical Trials;Complication;Data;Development;Disease;Dose;Exhibits;Exposure to;Frequencies;Gastrointestinal tract structure;Hematopoietic Stem Cell Transplantation;Infection;Intestines;Malignant - descriptor;Measures;Modality;Molecular;Monitor;Morbidity - disease rate;Multi-Institutional Clinical Trial;Outcome;Patient Outcomes Assessments;Patients;Phase;Phase II Clinical Trials;Physical Function;Population;Pre-Clinical Model;Probability;Quality of life;RIPK1 gene;Reproducibility of Results;Risk;Running;Safety;Serum;Severities;Site;Steroids;Symptoms;Testing;Time;cohort;comparison control;curative treatments;disease natural history;efficacy testing;gastrointestinal;graft vs host disease;hematopoietic cell transplantation;high risk;improved;improved outcome;inhibitor;innovation;mortality;outcome prediction;overtreatment;patient subsets;phase II trial;predict clinical outcome;prevent;response;response biomarker;stem cells;therapeutically effective;treatment response;treatment strategy Project 3: Risk Adapted Clinical Trials of GVHD Treatment PROJECT 3 NARRATIVEAllogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignantdiseases whose applicability has been impeded by the development of its most serious complication GIGVHD. Strategies that strengthen the target cells in the GI tract will allow for better harnessing of thiseffective therapeutic modality. Project 3 will conduct two clinical trials of primary treatment based on theamount of GI damage at the time of treatment as determined by serum biomarkers. NCI 10705159 9/8/23 0:00 PAR-20-077 5P01CA039542-34 5 P01 CA 39542 34 9/10/97 0:00 8/31/27 0:00 ZCA1-RPRB-J 6107 6475012 "LEVINE, JOHN " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 677070 416929 260141 PROJECT 3 ABSTRACTGastrointestinal (GI) graft-vs-host disease (GVHD) remains the major cause of non-relapse mortality(NRM) after hematopoietic cell transplant but GVHD symptom severity at onset predicts outcomes toopoorly to guide treatment and thus all patients are treated with prolonged courses of high dose systemicsteroids under treating some and over treating others. Steroid treatment for GVHD is itself a major causeof morbidity and complications include infections reduced physical function and poor quality of life(QOL). In the current cycle we developed and validated the MAGIC algorithm probability (MAP) whichcombines two serum GI GVHD biomarkers into a single value that measures the extent of GI cryptdamage. The MAP predicts clinical outcomes such as response to treatment and NRM more accuratelythan clinical severity alone and thresholds categorize patients into high or low risk groups. Patients withhigh risk GVHD (35% of GVHD) account for 75% of NRM. In contrast our preliminary data show that asubset of patients with low risk GVHD who exhibit both clinical and biomarker responses during the firsttwo weeks of treatment represent an ultra-low risk population with 91% response to steroids and 2%NRM. Ultra-low risk patients comprise 40% of all GVHD. Our central hypothesis is that biomarker-guidedrisk adapted treatment of GVHD will improve outcomes. We will test this hypothesis in two clinical trials.Specific Aim 1 leverages the discovery in Project 2 that activation of RIPK1 causes destruction ofintestinal stem cells and its inhibition can both prevent and reverse GI GVHD in preclinical models. In thisAim we will conduct a multicenter Phase 2 clinical trial to test whether the addition of a RIPK1 inhibitorto steroid treatment in patients with high risk GVHD increases treatment response rates and decreasesNRM. In Specific Aim 2 we will conduct a Phase 2 multicenter clinical trial that tests whether ultra-lowrisk GVHD can be successfully treated with a brief exposure to steroids. We will use real-time clinical andbiomarker monitoring to reduce steroid exposure by more than 50%. We will quantify the efficacy of thisapproach by comparing the frequency of severe infections in trial patients to a well matchedcontemporaneous control cohort. In a subaim we will test whether our approach improves QOL asmeasured by patient reported outcomes in cases compared to controls. These two trials thus useinnovative and complementary risk-adapted treatment strategies to treat both high and low risk GVHD.If the trials are successful we will have devised new treatments for the large majority of patients whodevelop GVHD and will have addressed the under-treatment of high risk GVHD as well as the over-treatment of low risk GVHD.. +No NIH Category available Academia;Address;Administrative Coordination;Attention;Awareness;Budgets;Clinic;Clinical;Collaborations;Combined Modality Therapy;Communication;Communities;Consultations;Critiques;Data;Development;Education;Elements;Ensure;Equipment and supply inventories;Fertilization;Funding;Future;General Hospitals;Geographic Locations;Goals;Grant;Healthcare;Human Resources;Image;Immune;Immune checkpoint inhibitor;Immune response;Immunology;Individual;Industry;Institution;Intellectual Property;International;Joints;Laboratories;Leadership;Logistics;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Massachusetts;Medical;Mentors;Molecular;PUVA Photochemotherapy;Persons;Physicians;Physics;Play;Positioning Attribute;Postdoctoral Fellow;Pre-Clinical Model;Preparation;Principal Investigator;Process;Program Development;Publications;Published Comment;Quality Control;Reporting;Research;Research Project Grants;Resources;Role;Schedule;Science;Scientist;Series;Services;Site;Societies;Students;Techniques;Technology;Technology Transfer;Teleconferences;Therapeutic;Training;Training Programs;Translations;United States National Institutes of Health;Visit;Work;academic program;anticancer research;aspirate;cancer therapy;career development;checkpoint inhibition;clinical translation;commercialization;data sharing;equity diversity and inclusion;experience;experimental study;follow-up;global health;image guided;industry involvement;innovation;insight;interest;knowledge base;lectures;medical schools;meetings;member;next generation;programs;public-private partnership;response;skills;success;timeline;tumor;web site Core A: Administration Integration Education and Career Development Administrative CORE A- NarrativeCore A is mandated for all P01s and is an essential element of the application which ensures maximal integrationand utilization of diverse skills and resources to develop new treatments for cancers that are a burden to societyin different ways yet allowing synergistic skills to come regardless of the geographic location of individuals. Thelimited budget available (<$100K) make it incumbent for the core to leverage essential services that are notdirectly funded by the P01 and offered by the Massachusetts General Hospital (MGH) or Harvard Medical School(HMS) but are crucial to the success of the Program. Although the Core was noted for being highly integrated itcontinues to focus on enhancing this along with a succession plan for future planning so that at the end wehave a more economical approach to healthcare. NCI 10705158 9/13/23 0:00 PAR-20-077 5P01CA084203-18 5 P01 CA 84203 18 12/1/99 0:00 8/31/27 0:00 ZCA1-RPRB-J 8926 1877772 "HASAN, TAYYABA " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 98756 73083 25673 ABSTRACT - CORE AThe current proposal takes a new direction of including immune checkpoint inhibition (ICI) therapy within theexisting P01 theme of Photodynamic Therapy (PDT)-based combinations guided by molecular mechanisms andimaging. The renewal application has been revised and each of the critique comments have been addressedunder introduction section and elaborated further under research strategy section. Infact the theme isphotodynamic priming (PDP) of tumors to make them immune sensitive. This priming enables tumors that weresilent to immune checkpoint inhibitors (ICI) sensitive at lower concentrations with increased efficiency andtolerability. The P01 has a diversity of skills and geographical locations and the Administrative Core is essentialto ensure an integrated conduct facile exchange of information and a coordinated use of resources for themaximal utilization of institutional and NCI-supported resources. The budgets are very limited (average~$150/year ~ 50% of an average R01) and therefore the Core and its efforts at coordination of multiple sitesquality control and project data become critical. An aspiration of the Program is to create an ethos for maximalintegration of the components to better serve this P01 the field of PDT cancer research training of the nextgeneration clinical translation and the community at large. To this end the PIs have brought together a team ofnew and existing scientists and physicians who already collaborate enthusiastically. The Core also takes aleadership role in mid-course correction as became necessary with clinical pancreatic cancer project in the lastcycle. In addition to the two broad functions of Scientific and Administrative coordination the renewal applicationretains the goals of career development intellectual property (IP) development and data sharing for this Core.The scientific coordination will be maintained through a variety of mechanisms that will include regular intra- andinter-Project/Scientific Core meetings (Zoom or in person). This Core will: a) perform monthly reviews and identifyobstacles; b) coordinate meetings with selected collaborators and key personnel; c) organize and follow up onaction plans; d) organize annual SAB meeting and core/project specific discussions; e) As resources permitachieve scientific enhancement by inviting speakers with larger perspectives on cancer therapeutics relevant tothe Program but not directly in PDT. Technologies will get IP protection where appropriate using institutionalresources and find development partners consistent with one of the goals of the NIH Roadmap. In response tothe reviewers critiques a succession plan and a Scientific Advisory Board (SAB)is added instead of the ScientificAdvisory Group. The Core was viewed as successful in the past cycle. Specially noted strengths were careerdevelopment efforts numerous joint publications and leadership. The aims were appreciated for clarityconstruction and for promoting better communications across all projects and cores. The revised proposaladdresses all the concerns expressed by the reviewers notably the lack of a succession plan and the absenceof an explicit SAB which are now included. We hope that the reviewers will now deem this Core superior. +No NIH Category available Acceleration;Allogeneic Bone Marrow Transplantation;Allogenic;Animal Model;Apoptosis;Apoptotic;Biological Markers;Biopsy;Bone Marrow Transplantation;Cause of Death;Cell Death;Cell Line;Cells;Cessation of life;Collaborations;Complement;Complex;Complication;Data;Development;Disease;Enzymes;Experimental Models;Gastrointestinal tract structure;Genetic Complementation Test;Hematopoietic Stem Cell Transplantation;Histopathology;Human;Inflammatory;Intestines;Leukemic Cell;Malignant - descriptor;Mediating;Metabolic;Methods;Mitochondria;Modality;Modeling;Molecular;Morbidity - disease rate;Mus;Natural regeneration;Organoids;Outcome;Patients;Protein Kinase Interaction;Proteins;RIPK1 gene;RIPK3 gene;Receptor Activation;Receptor Inhibition;Regenerating islet derived protein 3-Gamma;Role;Scanning;Severities;TNF gene;cell injury;curative treatments;graft vs host disease;graft vs leukemia effect;high risk;in vivo;inhibitor;mortality;mouse model;mutant;novel strategies;pharmacologic;phase II trial;pre-clinical;prevent;regenerative;restoration;stem cells;therapeutically effective Project 2: Inhibition of RIPK1 Mediated Cell Death to Prevent GVHD PROJECT 2 NARRATIVEAllogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignantdiseases whose applicability has been impeded by the development of its most serious complication GIGVHD. Strategies that strengthen the target cells in the GI tract will allow for better harnessing of thiseffective therapeutic modality. Project 2 uses animal models to investigate the role of enzyme RIP1 thatcauses death of intestinal stem cells and methods to inhibit RIP1 activation and thereby reduce GVHD. NCI 10705156 9/8/23 0:00 PAR-20-077 5P01CA039542-34 5 P01 CA 39542 34 9/10/97 0:00 8/31/27 0:00 ZCA1-RPRB-J 8925 1876461 "FERRARA, JAMES L. M." Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 479401 283669 195732 PROJECT 2 ABSTRACTGI GVHD remains the major cause of morbidity and non-relapse mortality (NRM) after HCT. Wediscovered that a major cause of GI crypt destruction is the accelerated death of intestinal stem cells(ISCs) which is mediated by activation of receptor interacting protein kinase 1 (RIPK1). Our data showthat inhibition of RIPK1 with two compounds specific for RIPK1 Necrostatin-1s and GNE684 preventISC damage in organoid culture and in two experimental models of GVHD. We have also shown that thePaneth cell protein regenerative 3 (REG3) that is lost from the crypt during GVHD is a critical anti-apoptotic protein and inhibits the activation of RIPK1 rescuing ISCs from GVHD and reducing mortality.These findings support the central hypothesis of Project 2 that inhibition of RIPK1 activation prevents ISCloss and allows regeneration of crypts thus reducing GVHD. Our three specific aims will investigate thishypothesis. Specific Aim 1: To determine the role of RIPK1 activation in ISC damage and GVHD. Wewill first use systemic administration of pharmacological inhibitors of RIPK1 in well-defined mouse modelsto treat and prevent GVHD with detailed analyses of GVHD severity of the GI tract correlating metricsof crypt histopathology RIPK1 expression and activation. We will complement these analyses usingmutant HCT recipient mice with inactive forms of RIPK1 and RIPK3 proteins. We will also analyze theeffect of RIPK1 inhibitors on GVL effects using two leukemic cell lines. In human GI biopsies we willanalyze phospo-RIPK1 expression as a biomarker of GVHD severity and as a predictor of long termoutcomes. These studies will complement and expand the preclinical data that form the rationale for thePhase 2 trial of RIPK1 inhibition in high risk patients in Project 3. Specific Aim 2: To analyze the effect ofREG3 on RIPK1 activation. This specific aim will investigate the role of REG3 on the expression ofComplex I/II components and the role of TNF and RIPK1 on REG3 expression. In summary thesestudies will illuminate the key mechanisms by which inhibition of RIPK1 prevents the inflammatory celldeath that causes GI crypt damage during GVHD and thus will lead to novel strategies to control thismajor cause of NRM after allogeneic BMT. +No NIH Category available 3-Dimensional;Abscopal effect;Adverse effects;Animals;Area;Autologous;Bilateral;Biological Markers;Blinded;Blood Vessels;Categories;Cell Line;Cell Survival;Chemoresistance;Clinical;Collaborations;Combination Drug Therapy;Combined Modality Therapy;Data;Diameter;Dimensions;Disease;Dose;Eligibility Determination;FDA approved;Fine needle aspiration biopsy;Future;Generations;Goals;Heterogeneity;Human;Image;Immune;Immune response;Immunocompetent;Immunologic Monitoring;Immunologics;Immunotherapeutic agent;Immunotherapy;Intervention;KPC model;Light;Literature;Lymphocytic Infiltrate;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metabolic;Microsatellite Instability;Modeling;Molecular Target;Monitor;Mus;Neoplasm Metastasis;Operative Surgical Procedures;Organoids;Outcome;PD-1/PD-L1;PUVA Photochemotherapy;Pancreatic Ductal Adenocarcinoma;Pathologist;Patients;Performance;Peripheral Blood Mononuclear Cell;Permeability;Pharmaceutical Preparations;Phenotype;Photosensitizing Agents;Pre-Clinical Model;Process;Radiation;Radiology Specialty;Receptor Protein-Tyrosine Kinases;Refractory;Reporting;Research;Resolution;Study models;Survival Rate;Technology;Testing;Therapeutic;Time;Toxic effect;Treatment-related toxicity;Tumor Immunity;Tumor Volume;Tumor-Infiltrating Lymphocytes;Tumor-infiltrating immune cells;Tyrosine Kinase Inhibitor;Validation;Verteporfin;Visualization;anti-PD-1;anti-PD-L1;anti-PD-L1 therapy;anti-PD1 therapy;anti-tumor immune response;cancer imaging;checkpoint inhibition;chemotherapy;cytokine;design;dosage;dosimetry;efficacy evaluation;functional status;high resolution imaging;image guided;imaging capabilities;imaging platform;imaging system;immune cell infiltrate;immune checkpoint blockade;immune resistance;immunogenic;immunogenic cell death;immunoregulation;in vivo;innovation;insight;migration;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;pancreatic cancer model;pancreatic cancer patients;pancreatic ductal adenocarcinoma cell;patient population;pembrolizumab;pharmacologic;point of care;preclinical study;radioresistant;response;statistics;subcutaneous;success;synergism;therapy design;therapy outcome;three-dimensional modeling;tool;treatment response;treatment strategy;tumor;tumor growth;tumor microenvironment;validation studies Project 3: Immune Checkpoint Inhibition Therapy Enhanced by Integrated Photodynamic Treatment and Image Guidance in Preclinical Models of Pancreatic Cancer NarrativePancreatic cancer is a devastating disease with poor response to most therapies including immunotherapywhich is the new hope for cancer management. Therefore we propose a new treatment approach to overcomethe major obstacle of non-responsiveness of pancreatic cancers to immunotherapy by transforming non-responding immunologically cold tumors to hot responsive ones using red light activation of a drug alreadyFDA approved with no serious reported toxicities. Combined with a novel real-time high-resolution imagingsystem this strategy is expected to provide the ideal timing of immunotherapy drugs thus enhancing efficacyreducing toxicities and expanding the immunotherapy eligible pancreatic cancer patient population (presentlyonly 1-3%). NCI 10705154 9/13/23 0:00 PAR-20-077 5P01CA084203-18 5 P01 CA 84203 18 12/1/99 0:00 8/31/27 0:00 ZCA1-RPRB-J 8924 1877772 "HASAN, TAYYABA " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 176620 150945 25675 The statistics for pancreatic ductal adenocarcinoma (PDAC) remain dismal despite advances in combinationchemotherapies. It is largely chemo and radiation resistant and surgery the only curative option is availableto only ~20% of patients. Immune checkpoint inhibition (ICI) has brought hope but in PDAC even the modestsuccess (anti-PD1: Pembrolizumab) is limited to only 1-3% of patients displaying microsatellite instability. Themajority of tumors lack the immune infiltration necessary for effective ICI. Based on our data and the literaturewe hypothesize that Photodynamic Priming (PDP) a process that is a fallout of photodynamic therapy (PDT)and our main research focus alters the tumor microenvironment to sensitize it to enhance ICI therapy. PDPinduces immunogenic cell death and enhances tumor infiltrating lymphocyte (TIL) migration augmented byPDP-induced higher tumor permeability.. We capture this priming effect for designing a non-empiric approachfor a PDT-ICI combination. We are greatly helped in this by our recent innovation of hyperspectral imagingcapable for the first time of monitoring 6 biomarkers simultaneously in live tumor bearing animals; it allows usto quantify TILs (and subsets) along with PD1/PD-L1 expression changes to generate an immunoscore (IS).We posit that ICI administration will be most beneficial when the tumor has been PDP-stimulated to be thehottest thus minimizing ICI dose and associated toxicities similar to that observed for PDP-chemotherapycombinations. The hypothesis will be tested in 3 aims. Aim 1 will identify in orthotopic murine tumors PDP-dosimetry and optimal timing for IS modulation to establish the time for maximal benefits of anti-PD1 therapy(increased survival decreased metastasis) and increased tolerability. Aim 2 informed by aim 1 will use bothorthotopic and a bilateral subcutaneous PDAC murine model to determine abscopal effects of PDP-ICItherapy. A comparison of optimally timed single dose ICI therapy with multiple dosages along with acomparison of single immune checkpoint blockade (anti-PD1) with dual blockade (anti-PD1/anti-PD-L1) willalso be established. Aim 3 will utilize patient derived tumor immune organoids (PDIO) to recapitulateheterogeneity and evaluate the combination therapy outcomes. PDP induced IS will inform optimally timedanti-PD1/anti-PD-L1 therapy guidance for PDIOs. Relevance and Impact 1) it sensitizes non-immuneresponsive tumors to responsive ones and expands the eligible PDAC patients (currently only at 3%). 2) Anon-empiric approach is introduced. 3) Combined with imaging-enabled dose reduction of anti-PD1 it reducestoxicities of immune drugs as reported with chemotherapy and receptor tyrosine kinase inhibitors. 4) It providesa broad imaging platform for in vivo real-time multiple-marker information at cellular resolution and serves as ageneral point-of-care tool by enabling simultaneous visualization of several molecular targets (e.g. tumorimmune cell phenotypes and cytokines/stromal/metabolic signatures) for designing new therapies for manyother diseases and with potential to expand the use of fine needle aspirate biopsy for PDAC ICI dosimetry. +No NIH Category available Award;Cancer Center;Clinical;Dana-Farber Cancer Institute;Evaluation;Faculty;Funding;Goals;Individual;Infrastructure;Mentors;Mentorship;Monitor;Process;Program Evaluation;Program Reviews;Renal carcinoma;Research Personnel;career;next generation;programs;success;translational scientist Career Enhancement Program (CEP) CEP Narrative:The CEP aims to attract and develop the next generation of translational investigators in kidney cancer. NCI 10705148 8/9/23 0:00 PAR-18-313 5P50CA101942-19 5 P50 CA 101942 19 9/18/03 0:00 8/31/25 0:00 ZCA1-RPRB-J 8922 1886242 "KAELIN, WILLIAM G." Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 134683 98905 39545 CEP Project SummaryThe investigators assembled in the DF/HCC Kidney Cancer SPORE have a substantial record in mentorshipand enhancement of junior faculty working in the kidney cancer field (detailed below). The goal of the CareerEnhancement Program (CEP) of our SPORE is to build upon this record and continue a formal process forthe identification selection funding and mentoring of individuals pursuing careers in the study of the basictranslational and clinical aspects of kidney cancer. This Program will rely on the infrastructure created by theAdministrative Evaluation and Planning Core (Admin Core) to:1. Solicit CEP Award Applications2. Evaluate Applicants and Select Awardees3. Conduct CEP Evaluation and Review4. Mentor CEP Awardees and promote Career Progress +No NIH Category available Abscopal effect;Adverse event;Area;Basal Cell Cancer;Biological Markers;Blood Vessels;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Cessation of life;Characteristics;Clinic;Clinical;Combined Modality Therapy;Common Terminology Criteria for Adverse Events;Development;Disease;Distant Metastasis;Endoscopic Ultrasonography;Fiber Optics;Fine needle aspiration biopsy;Flow Cytometry;Fluorescence;Goals;Granzyme;Hour;Image;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Stimulation;Immunotherapy;Inflammatory Infiltrate;Intravenous;Intravenous Bolus;Left;Light;London;Lymph Node Tissue;Lymphocyte;Lymphocyte Subset;Malignant Neoplasms;Malignant Squamous Cell Neoplasm;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Measurement;Metastatic Neoplasm to the Lung;Microsatellite Instability;Molecular;Monitor;Mus;Necrosis;Necrosis Induction;Needles;Neoplasm Metastasis;Oral mucous membrane structure;Outcome;PUVA Photochemotherapy;Pancreatic Ductal Adenocarcinoma;Pancreatic carcinoma;Patients;Pattern;Perfusion;Perioperative;Peripheral;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase II Clinical Trials;Photosensitizing Agents;Population;Primary Lesion;Primary Neoplasm;Process;Progression-Free Survivals;Quality of Life Assessment;Recurrent Malignant Neoplasm;Regulatory T-Lymphocyte;Research;Residual Neoplasm;Resistance;Sampling;Signal Transduction;Skin Cancer;Skin Neoplasms;T-Cell Activation;T-Lymphocyte;Therapeutic;Toxic effect;Universities;Verteporfin;Work;X-Ray Computed Tomography;advanced pancreatic cancer;aspirate;cancer recurrence;chemotherapy;clinical outcome assessment;college;cytotoxic;dosimetry;image guided;immune checkpoint blockade;improved;in vivo;indexing;lymph nodes;melanoma;microendoscopy;optical fiber;pancreatic cancer model;pancreatic cancer patients;pancreatic neoplasm;pembrolizumab;peripheral blood;phase 2 study;predicting response;programmed cell death ligand 1;programmed cell death protein 1;radiomics;recruit;response;tumor;tumor progression Project 2: Intratumoral PDT Induces PDP-based Enhancement of PD-1 Inhibition in Pancreatic Carcinoma NARRATIVE Project 2Pancreatic cancer is a deadly disease that is very resistant to chemotherapy partly because the tumor is encased ina fibrous shell that helps the cancer disguise itself from the body's immune system. The purpose of this project is tocreate an immunologically-based treatment that first damages the primary pancreatic tumor using a light activateddrug that disrupt the fibrous shell (allowing chemotherapeutic treatments to reach the cancer) and also causes thetumor to release damage signals that permit the patients' own immune system to identify and attack the cancer. Thisresearch could help immune-activating drugs (currently ineffective on their own) to become more effective fortreating pancreatic cancer both the primary lesions as well as distant metastases. NCI 10705146 9/13/23 0:00 PAR-20-077 5P01CA084203-18 5 P01 CA 84203 18 12/1/99 0:00 8/31/27 0:00 ZCA1-RPRB-J 5804 79383317 "CHANDRASEKHARA, VINAY " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 245034 219359 25675 ABSTRACT - Project 2Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and typically presents atadvanced stages. Progress in treating these cancers has been slow and has produced only very modestincreases in survival. One of the few positive developments has been the use of immune checkpoint inhibitors(ICI) in the setting of PDAC with microsatellite instability (MSI). Unfortunately MSI is uncommonly found inthese cancers. The goal of this project is to expand the usage of ICI to the majority of PDAC tumors bystimulating the immune system via photodynamic priming (PDP) of the primary tumor using the intravenousphotosensitizer Verteporfin which is activated by light delivered via an optical fiber delivered though a fineneedle into the tumor under endoscopic ultrasound or CT guidance. This initiates PDP a process thatactivates immune cell recruitment into the tumor and educates T-cells to mount a response against theprimary PDAC as well as peripheral metastasis. We had a patient in whom a pulmonary metastasis regressedafter PDP treatment of the primary cancer without any additional chemotherapy or immunotherapy. Inaddition we were able to show an increase in tumor-directed T cells (responsive to ICI) in the peripheralblood of another patient 72 hours after we administered PDP for pancreatic cancer. In Project 2 we willperform a Phase II study using combination therapy with PDP (Veteporfin and red light) followed by ICI(pembrolizumab). Aim 1 will assess this combination treatment in 25 patients with locally advanced oradvanced pancreatic cancer (oligometastasis) for its ability to increase overall and disease specific survivalproduce necrosis of the primary tumor and regression of metastatic disease; we will also monitor for anytoxicities. Dosimetry for PDP will be based on vascular perfusion of the tumor on CT scans as well asfluorescence measurements from the buccal mucosa (with Core C) avoiding direct measurements in thetumor which were found to be unreliable previously. Aim 2 will use a PDP radiometric index (found in residualtumor after PDP) to predict response to ICI. The index is based on changes in tumor characteristics related tothe degree of inflammatory infiltrate that is reflected in tumor heterogenity. We will also use hyperspectralfluorescence microendoscopy to evaluate lymphocytes from lymph nodes with metastatic diseaseinvolvement (Core B) to determine if this correlates with the subpopulations found by flow cytometry. FinallyAim 3 will focus on PDP-stimulated immune cell changes in peripheral blood lymphocytes of our PDACpatients to determine if these changes correlate with post-PDP changes in lymphocyte sub-populationsobserved after PDP in skin tumors (Project 1) that are known to be immune sensitive (squamous cell cancer)and those that are not (basal cell cancer). Finally in a group of 5 patients we will be sampling large metastaticlymph nodes 3 days after PDP to assess the changes in immune cells in order to determine whether ICIresponsive tumor directed T-cells will increase. +No NIH Category available 3-Dimensional;Aminolevulinate;Basal cell carcinoma;Biological Models;Blood;Blood Vessels;Blood specimen;Cancer Patient;Cells;Clinical Research;Clinical Trials;Collaborations;Combined Modality Therapy;Cytometry;Data;Dimensions;Dose;Ensure;Excision;Exposure to;Fluorescence;Fluorouracil;Future;Goals;Healthcare;Histologic;Human;Image;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Markers;Immunologics;Immunotherapy;Inbred HRS Mice;Induced Mutation;Lymphocyte;Macrophage;Malignant Epithelial Cell;Malignant Neoplasms;Measures;Metabolic Clearance Rate;Modeling;Mohs Surgery;Molecular;Mononuclear;Morbidity - disease rate;Mus;Nature;Neoadjuvant Therapy;Neutrophil Infiltration;Operative Surgical Procedures;Optics;Oral;Organoids;PUVA Photochemotherapy;Patient Recruitments;Patients;Pattern;Peripheral Blood Mononuclear Cell;Photosensitizing Agents;Pilot Projects;Population;Proteins;Regimen;Risk;Safety;Skin Cancer;Skin Carcinoma;Skin Neoplasms;Societies;Squamous cell carcinoma;Subgroup;T-Cell Activation;T-Lymphocyte;TP53 gene;Techniques;Testing;Therapeutic;Three-dimensional analysis;Time;Tissues;Toxic effect;Treatment Failure;Treatment Protocols;Treatment outcome;Tumor-Infiltrating Lymphocytes;Tumor-infiltrating immune cells;UV induced;Verteporfin;Vitamin D;anti-PD1 antibodies;anti-tumor immune response;arm;cancer infiltrating T cells;cancer therapy;care burden;checkpoint inhibition;checkpoint therapy;comparative;cytotoxic;design;dosimetry;experimental study;image guided;immune activation;immune cell infiltrate;immune checkpoint;immunogenic cell death;immunomodulatory therapies;improved;in vitro Model;innovation;mortality;mouse model;neoplastic cell;neutrophil;novel strategies;novel therapeutic intervention;optimal treatments;organ transplant recipient;overexpression;patient subsets;pre-clinical;preclinical study;programmed cell death protein 1;recruit;skin squamous cell carcinoma;therapy resistant;three dimensional cell culture;three-dimensional modeling;treatment response;tumor;tumor microenvironment Project 1: 5FU and Vitamin D as Neoadjuvants for Photodynamic Priming to Enhance Skin Cancer Therapy NARRATIVE Project 1This project will advance new therapeutic approaches that use photodynamic therapy (PDT) 5-fluorouraciland Vitamin D as immune-priming agents with subsequent addition of immune checkpoint inhibition (ICI) forthe treatment of advanced squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) which togetherrepresent the most common of all human cancers. Preclinical experiments in mouse models and clinicalstudies in patients with SCC and BCC will be done with the aid of advanced optical fluorescence techniquesprovided by Core B and Core C to detect changes in initial photosensitizer levels and immune cell recruitmentpost-PDT. These experiments will allow us to determine the precise timing of increased checkpoint moleculeexpression and recruitment of specific populations of immune cells into tumors after PDT treatment therebyestablishing a rationale and a therapeutic window for designing a new combination treatment regimen that willbenefit patients by improving treatment outcomes for advanced SCC and BCC. NCI 10705142 9/13/23 0:00 PAR-20-077 5P01CA084203-18 5 P01 CA 84203 18 12/1/99 0:00 8/31/27 0:00 ZCA1-RPRB-J 5803 1888790 "MAYTIN, EDWARD V" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 234921 209246 25675 ABSTRACT Project 1Project 1 will explore how photodynamic therapy (PDT) can be used for immunological priming in newcombination treatments for skin cancer. Nonmelanoma skin cancers (NMSC) comprising squamous cellcarcinoma (SCC) and basal cell carcinoma (BCC) are the most common of all human cancers representing asignificant healthcare burden (>3 million U.S. cases/year) with increased lethality for certain patient subsetse.g. organ transplant recipients. We showed previously that aminolevulinate (ALA)-based PDT can be effectivefor NMSC patients and that 5-fluorouracil (5FU) and Vitamin D (VitD) further improve treatment outcomes; yettumor clearance rates remain poor for large and advanced NMSC. To ameliorate this situation we propose toexploit the concept of photodynamic priming (PDP) a natural consequence of PDT. PDT triggers immunogeniccell death enhances influx of tumor infiltrating lymphocytes (TILs) and induces an adaptive anti-tumor immuneresponse sensitizing the tumor microenvironment to the effects of immune checkpoint inhibition. Ourpreliminary data show that a low-intensity PDT regimen can clear tumors in a murine SCC modelaccompanied by induction of damage-associated molecular patterns (DAMPs) and recruitment of neutrophilsmacrophages and TILs along with altered expression of immune checkpoint molecules such as PD-1. Thesefindings set the stage for a further combination approach using PDT and immune checkpoint inhibitors (ICI). InAim 1 (preclinical) we will evaluate in murine SCC and BCC models the therapeutic response to variouscombinations of PDT 5FU VitD and ICI agents and measure specific timing of TIL recruitment checkpointmolecule expression and tumor clearance. In Aim 2 (clinical studies) we will determine the nature and timingof immune responses in BCC and SCC patients post-PDT. Tumors will be subjected to PDT (guided by CoreC dosimetry to measure photosensitizer levels); then after 1-to-14 days the tumor will be surgically excised andanalyzed for checkpoint molecule expression and intratumoral immune cell infiltration using the histologicalimmunoscore (IS; Project 3). Systemic T-cell activation in circulating blood will be measured in collaborationwith Project 2. Another arm of these studies will test effects of 5FU or VitD pretreatment of NMSC tumors uponthe magnitude of anti-tumoral immune responses. Aim 3 will feature exploratory studies to validate the ISapproach for measuring TIL recruitment in human SCC tumor models in vitro. In collaboration with Project 3and Core B 3D patient-derived tumor-immune organoids (PDIOs) consisting of stratified SCC culturesadmixed with PBMCs (lymphocytes) will be tested for differential immune cell activation following PDT usingcutting-edge hyperspectral optical cytometry techniques developed in Core B that can image multiple immunemarkers simultaneously. Relevance and Impact: Overall this Project will benefit patients by providing thebasis for a new approach that combines photodynamic priming 5FU VitD and ICI immunotherapy to improvetreatment outcomes for difficult and advanced cases of NMSC. +No NIH Category available Acute;Address;Air;Alveolar;Antibodies;Antibody-drug conjugates;Area;Bioinformatics;Biology;Biopsy;Blood Vessels;CD44 gene;CD47 gene;CD47-SIRP;CRISPR screen;Cancer Patient;Cell Communication;Cells;Clinical;Clinical Treatment;Clustered Regularly Interspaced Short Palindromic Repeats;Development;Drug Interactions;Drug resistance;Endothelium;Engineering;Epidermal Growth Factor Receptor;Epithelium;Exhibits;Extracellular Matrix;Fibroblasts;Gefitinib;Genetic;Glucuronic Acids;Glycosaminoglycans;Goals;Grant;Histology;Human;Immune;In Vitro;Infiltration;KRAS2 gene;Lethal Genes;Liquid substance;Lung;Macrophage;Mass Spectrum Analysis;Modality;Modeling;Molecular;Mus;Mutation;Myelogenous;Nature;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;PDL1 pathway;PTPNS1 gene;Pathway interactions;Patients;Penetrance;Phagocytes;Phagocytosis;Pharmacology Study;Primary Neoplasm;Production;Progressive Disease;Proteins;Proteoglycan;Proteome;Proteomics;ROS1 gene;Refractory Disease;Regulation;Relapse;Residual state;Resistance;Role;Sampling;Series;Shapes;Signal Transduction;System;Technology;Testing;Therapeutic;Treatment Efficacy;acquired drug resistance;advanced disease;anticancer treatment;carcinogenesis;cell type;drug sensitivity;immune reconstitution;improved;in vivo;inhibitor;lead candidate;molecular targeted therapies;mutant;neoplastic;novel;patient derived xenograft model;phosphoproteomics;preservation;programs;prospective;reconstitution;resistance mechanism;response;single-cell RNA sequencing;small molecule;synthetic lethal interaction;targeted agent;targeted treatment;therapy resistant;translational approach;tumor;tumor microenvironment;tumor xenograft;virtual Organoid Acquired Resistance n/a NCI 10705134 9/20/23 0:00 RFA-CA-21-052 5U54CA224081-06 5 U54 CA 224081 6 9/30/17 0:00 8/31/27 0:00 ZCA1-SRB-E 8916 10525461 "BANDYOPADHYAY, SOURAV " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 208555 171148 37407 PROJECT SUMMARYThe overall goal of Project 3 of this U54 application is the organoid-based definition of mechanisms of acquiredresistance (AR) to targeted therapy in non-small cell lung cancer (NSCLC). The treatment of NSCLC employsnumerous therapies directed against the EGFR ALK KRAS G12C ROS1 and PD-1/PD-L1 pathways. Howeverdespite initial responses these molecularly-targeted therapies are not curative and virtually all patientseventually succumb to progressive disease. Acquired resistance features prominently in relapse such as withEGFR T790M or C797S mutations following gefitinib or osimertinib treatment; however known AR mechanismscannot be identified for a significant proportion of patients receiving targeted therapy. Further compounding thisdilemma are the distinct contributions of tumor-intrinsic versus tumor microenvironmental (TME) influences. TheTME in particular contains extracellular matrix (ECM) fibroblast vascular and immune components that canvitally impact the development and manifestations of AR. The study of TME-dependent and -independentmechanisms of AR have been further hindered by a distinct lack of in vitro human experimental systems allowingholistic recapitulation of the TME in patient biopsies. Our application leverages the synergistic strengths of the Sourav Bandyopadhyay and Calvin Kuo groupsin organoid and proteomics technology to address mechanisms of EGFR and KRAS G12C AR in NSCLC. Weconduct advanced proteomic approaches and organoid culture both from primary tumor biopsies at acquiredresistance (from Project 1) as well as from patient-derived xenograft (PDX) tumors grown in human immunereconstituted mice (from Project 2). Our organoids are either epithelial-only or novel air-liquid interface (ALI)organoid cultures that co-preserve tumor epithelium en bloc with tumor-infiltrating fibroblasts and immunesubsets (T B NK myeloid). Aim 1 leverages the results of a NSCLC organoid CRISPR screen to determine ifosimertinib-sensitizing loci can overcome delay or alter acquired resistance in clinical biopsy/PDX AR organoidsemphasizing hits with TME mechanisms. Aim 2 uses our mass spectrometry platforms to characterize totalproteome and phospho-proteomic changes in treatment-naive residual and acquired resistance organoids andPDX while pursuing lead candidate TROP2 and new target nominations by genetic mechanistic andpharmacologic studies. Lastly Project 1 has identified MIF/CD74/CD44 and CD47/SIRPa tumor-fibroblast-macrophage pathways upregulated during AR which are then functionally explored in Aim 3 using ALI organoidsfrom AR clinical biopsies and PDX tumors. Overall we propose a comprehensive translational approach thatexploits complementary organoid and proteomics expertise to directly study biopsies and PDX from NSCLCpatients with acquired resistance to targeted therapy towards development of improved therapeutic approaches. +No NIH Category available BRCA1 gene;Biological Assay;Biological Markers;CDK4 gene;CRISPR screen;Cell Death;Cell Line;Cells;Clear cell renal cell carcinoma;Clinic;Clinical;Clinical Trials;Compensation;Dana-Farber Cancer Institute;Data;Dependence;Drosophila genus;Event;Funding;Generations;Genes;Genetic;Genome;Growth;Human;Infection;Insecta;Laboratories;Lead;Libraries;Malignant Epithelial Cell;Mutation;Noise;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase I/II Trial;Play;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Predisposition;Proteins;RB1 gene;RNA Interference;Relapse;Renal carcinoma;Resistance;Role;Sampling;Signal Transduction;Synthetic Genes;Time;Tissue Sample;Tumor Suppressor Genes;Tumor Tissue;VHL Gene Inactivation;VHL gene;Validation;Vegf Inhibitor;cancer cell;cancer therapy;candidate marker;druggable target;experience;genetic approach;inhibitor;interest;mutant;new therapeutic target;novel therapeutics;paralogous gene;pharmacologic;pre-clinical;predictive marker;resistance mechanism;response;standard of care;synthetic lethal interaction;therapeutic target;therapy resistant;transcription factor;translational goal;tumor;whole genome Project 1:Targeting HIF2 and VHL Synthetic Lethal Interactions in Kidney Cancer NarrativeMost clear cell renal cells carcinomas the most common form of kidney cancer are caused by mutation(alteration) of the VHL gene and resulting activation of a protein called HIF2. Drugs that inhibit HIF2 appearpromising but not all patients respond to them and it is highly unlikely they will be curative when used as singleagents. This project seeks to understand how clear cell renal cell carcinomas become resistant to HIF2inhibitors and to identify other proteins that like HIF2 are selectively required by kidney cancer cells lackingVHL. NCI 10705129 8/9/23 0:00 PAR-18-313 5P50CA101942-19 5 P50 CA 101942 19 9/18/03 0:00 8/31/25 0:00 ZCA1-RPRB-J 6051 1886242 "KAELIN, WILLIAM G." Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 276139 240360 39546 Summary Inactivation of the VHL tumor suppressor gene is the initiating genetic event in mostclear cell renal cell carcinomas (ccRCCs) and increases the abundance of HIF2 which drivesccRCC growth. HIF2 inhibitors are active against some but not all VHL-/- ccRCCs inpreclinical models. In the last funding cycle we and others showed that HIF2 inhibitors (e.g.PT2977) have promising antitumor activity in pretreated ccRCC patients. While the efficacysignal seen with PT2977 has justified the launch of a pivotal trial that could lead to its regulatoryapproval some ccRCC patients fail to respond to HIF2 blockade. Moreover the patients thatdo respond to PT2977 monotherapy eventually relapse in most cases. We need biomarkersthat identify patients who are likely to respond to HIF2 inhibitors (predictive biomarkers) and tounderstand the mechanisms of resistance to such agents. Finally de novo and acquiredresistance is also a problem with standard of care kidney cancer therapies (e.g. VEGFinhibitors). We therefore need new therapeutic targets in kidney cancer. Ideally drugs againstthese new targets would be active as single agents and could be combined with existing agentswith the combinations increasing response rates and decreasing therapeutic resistance. Two genes are synthetically lethal with one another when mutation of either gene aloneis tolerated but inactivation of both genes causes cell death. This paradigm has been validatedin the clinic with the activity of PARP inhibitors against BRCA1 mutant tumors. In our lastfunding cycle we discovered that VHL and CDK4/6 have a synthetic lethal relationship.Moreover we showed that the hyperdependence of VHL-/- ccRCC cells was NOT driven byHIF2. In keeping with the latter we showed that CDK4/6 inhibitors were active against VHL-/-ccRCCs irrespective of their HIF2 dependence and enhanced the activity of PT2977 againstHIF2-dependent VHL-/- ccRCC. In aim 1 of this proposal we will conduct a phase 1/2 trial of the CDK4/6 inhibitorabemaciclib alone and in combination with PT2977. In aim 2 we will search for additionalgenes that are synthetic lethal with VHL. We will leverage our ability to do synthetic lethalscreens in both human cells and drosophila cells as a means of identifying genetic interactionsthat are likely to be robust. In aim 3 we will use genetic approaches to identify the mechanismsby which cells become resistant to HIF2 inhibitors. This aim could eventually yield new ways ofpredicting which ccRCC patients will respond to HIF2 inhibitors as well as new ways tocircumvent resistance. +No NIH Category available Acceleration;Acute Graft Versus Host Disease;Allogenic;Animal Model;Bioenergetics;Biological Markers;Biology;Biopsy;Bone Marrow Transplantation;Cancer Patient;Cell Death;Cessation of life;Clinical Trials;Collaborations;Complication;Data;Defect;Development;Disease;Dose;Enzymes;Gastrointestinal tract structure;Goals;Hematopoietic Stem Cell Transplantation;Human;Inflammatory;Intestines;Laboratories;Malignant - descriptor;Measures;Mitochondria;Molecular;Morbidity - disease rate;Natural regeneration;Organ;Outcome;Pathway interactions;Patients;Phase II Clinical Trials;Protein Kinase Interaction;RIPK1 gene;Resistance;Risk;Role;Sampling;Serum;Steroids;Succinate Dehydrogenase;T-Cell Depletion;Testing;Therapeutic;Translating;curative treatments;gastrointestinal;graft vs host disease;hematopoietic cell transplantation;inhibitor;innovation;insight;intestinal crypt;intestinal epithelium;mortality;novel;novel therapeutic intervention;phase II trial;pre-clinical;prevent;real time monitoring;stem cells;synergism;translational model;translational progress Cellular and Molecular Studies of Bone Marrow Transplant OVERALL NARRATIVEThe three projects of this P01 focus on allogeneic hematopoietic stem cell transplantation as a potentiallycurative therapy for many malignant diseases whose applicability has been impeded by the developmentof its most serious complication GI GVHD. Projects 1 and 2 focus on the role of mitochondrial damagein intestinal stem cells and the role of the enzyme RIP1 that causes their death. Project 3 conducts tworisk adapted clinical trials that determine treatment based on GI damage as measured by serumbiomarkers. NCI 10705124 9/8/23 0:00 PAR-20-077 5P01CA039542-34 5 P01 CA 39542 34 "HENDERSON, LORI A" 9/10/97 0:00 8/31/27 0:00 ZCA1-RPRB-J(M1)S 1876461 "FERRARA, JAMES L. M." Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 2520987 NCI 1643869 877118 OVERALL ABSTRACTGraft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneichematopoietic cell transplant (HCT) and prevents this curative therapy from wider application in cancerpatients. This P01 consists of three projects and two cores and its goal is to significantly reduce GVHDby: (1) elucidating its basic biology; (2) developing new laboratory strategies to predict its long termoutcomes; and (3) translating these insights into novel therapeutic strategies in Phase 2 clinical trials.Gastrointestinal (GI) GVHD is the target organ that is most resistant to steroid treatment and acute GVHDin the GI tract accounts for the vast majority non-relapse mortality. The focus on mechanisms of damageto the GI crypt during GVHD and enhancing its regeneration unifies all three projects during this cycle ofthe P01. Project 1 investigates the key bioenergetic pathways in intestinal stem cells (ISCs) that arealtered during GVHD. Preliminary data have identified a profound defect in the key mitochondrial enzymeSuccinate Dehydrogenase A (SDHA) that is specifically depleted by the T cell attack on intestinal epitheliumduring GVHD. Project 1 will analyze the role of SDHA in ISCs and will also evaluate SDHA expression inhuman GI biopsies in a collaboration study with Project 2. Project 2 also explores the regeneration ofcrypts by ISCs during GVHD focusing on the key enzyme receptor-interacting protein kinase I (RIPK1)that controls the inflammatory cell death pathway. A collaboration with Genentech leverages their deepexpertise in this field to explore RIPK1 biology in animal models and human samples. Project 2 shares asubaim with Project 1 to investigate the interactions of SDHA with the RIPK1 pathway in ISCs duringGVHD. Project 3 translates insights from the preclinical projects into two highly innovative clinical trials.The first trial will test a Genentech RIPK1 inhibitor in a Phase 2 trial. The second trial uses novel real-time monitoring with serum biomarkers to identify a group of patients with minimal GI crypt damage whocan be safely treated with much lower doses of steroids. This P01 thus represents a translationalprogression of exploration of GVHD biology from basic through translational models to clinical trials thatleverage multiple synergies between projects with the goal to accelerate transformative therapeuticstrategies for GVHD patients. 2520987 +No NIH Category available Antitumor Response;Area;Automobile Driving;CD44 gene;CD47 gene;CSF1 gene;Cancer Etiology;Cell Communication;Cell Survival;Cells;Chronic;Clinical;Clinical Treatment;Communication;Coupled;Drug Tolerance;Ecosystem;Epidermal Growth Factor Receptor;Evolution;Extracellular Matrix;Fibroblasts;Funding;Future;Genetic;Goals;Heterogeneity;Immune;Integrins;KRAS2 gene;Knowledge;Ligands;Macrophage;Malignant Neoplasms;Mediating;Migration Inhibitory Factor;Modeling;Molecular;Non-Small-Cell Lung Carcinoma;Oncogenes;Oncogenic;PDGFRB gene;PTK2 gene;Paracrine Communication;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Platelet-Derived Growth Factor;Proteomics;Research Project Grants;Residual Neoplasm;Resistance;Role;Signal Transduction;Specimen;Therapeutic;Work;biomarker driven;biomarker identification;cancer cell;cancer subtypes;cell type;clinical translation;combat;cytokine;immunosuppressive checkpoint;improved;improved outcome;inhibitor;innovation;insight;molecular targeted therapies;mortality;mutant;neoplastic cell;paracrine;pharmacologic;programmed cell death protein 1;programs;resistance mechanism;response;spatial relationship;targeted agent;therapeutic target;translational approach;translational goal;treatment response;tumor;tumor microenvironment;tumor progression Clinical specimen tumor-TME acquired resistance n/a NCI 10705122 9/20/23 0:00 RFA-CA-21-052 5U54CA224081-06 5 U54 CA 224081 6 9/30/17 0:00 8/31/27 0:00 ZCA1-SRB-E 8917 9547125 "BIVONA, TREVER G" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 305261 189016 116245 Project Summary/Abstract: The goal of this translational Project within BAATAAR-UP is to characterize themechanisms of and therapeutically counteract acquired resistance to molecular therapies in non-small cell lungcancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem and its plasticity duringtreatment. Acquired resistance (AR) is defined as tumor progression that occurs during active therapy and afteran initial therapy response. The overarching hypothesis is that AR can be therapeutically counteracted bydefining the cellular and signaling networks allowing tumors to survive and grow during therapy. The use ofmolecularly targeted therapies that inhibit oncogenic driver alterations such as mutant EGFR and KRAS andblock immunosuppressive checkpoints such as PD1/L1 is improving outcomes for patients with aggressivetumors including NSCLC which nonetheless remains the leading cause of cancer mortality. Despite profoundprogress a major challenge to transforming NSCLC into a chronic or curable cancer is AR that enables lethaltumor progression in patients. Understanding the mechanisms driving AR is essential to develop strategies tocounteract it and induce sustained anti-tumor responses to improve patient survival. Critical knowledge gaps arewhether and how tumor cell/TME cell interactions and spatial relationships promote AR. Another aspect of theevolution of AR that is poorly defined is the basis of the incomplete response and residual disease that is typicalduring therapy. This residual disease contains drug tolerant cancer cells and interactive TME cells that evolvetogether to promote the aggressive transition into AR. Defining how this transition occurs could provide strategiesto thwart it. Our work accomplished during the prior U54 funding period showed that oncogene-driven NSCLCscontain a rich cellular ecosystem that evolves during molecular treatments (e.g. EGFR ALK and RAS pathwaytargeted agents). We discovered heterogeneity and plasticity in tumor cells and TME cells including immuneand non-immune cell types and spatial relationships at different clinical treatment states including at AR that wehypothesize contribute collectively to AR. These include bi-directional interactions between tumor macrophagesand cancer cells and tumor fibroblasts and cancer cells via discrete signaling circuits that promote cancer cellsurvival and remodel the TME into a more pro-tumor phenotype at AR. Examples include cytokine (CSF1 TNFaIL1b) and CD47 signaling between tumor macrophages and cancer cells and macrophage migration inhibitoryfactor (MIF)-CD74/CD44 and extracellular matrix (ECM)/integrin signaling between tumor fibroblasts and cancercells at AR. Our goal is to define and therapeutically target these and additional cancer cell and TME cellnetworks to therapeutically thwart AR. We focus on clinically important and prevalent NSCLC subtypes definedby oncogenic mutant EGFR and KRAS and current clinical targeted inhibitors against these major oncogenicdrivers. Two Specific Aims are proposed. Our work will highlight mechanisms driving AR across the tumor-TMEcontinuum in EGFR- and KRAS-driven NSCLCs and identify counteracting therapeutic strategies for translation. +No NIH Category available Acceleration;Animals;Automobile Driving;Behavior;Biological Markers;Budgets;Categories;Clinical;Clinical Research;Clinical Trials;Collaborations;Combined Modality Therapy;Development;Diagnostic;Disease;Dose;Economic Burden;Eligibility Determination;Endoscopic Ultrasonography;Endoscopy;Environment;Excision;Fibroblasts;Fluorouracil;Future;Human;Image;Imaging Device;Immune;Immune checkpoint inhibitor;Immune response;Immunocompetent;Immunologic Monitoring;Immunologics;Immunotherapy;Incidence;Industry;Infiltration;Intelligence;Knowledge;Learning;Lesion;Literature;Lymphocyte Subset;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Microsatellite Instability;Modeling;Molecular;Molecular Target;Monitor;Morbidity - disease rate;Mus;Optics;Organoids;Outcome;PD-1/PD-L1;PUVA Photochemotherapy;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pancreatic carcinoma;Pathway interactions;Patients;Pattern;Peer Review;Permeability;Pre-Clinical Model;Process;Prognosis;Program Research Project Grants;Proteins;Publications;Radiology Specialty;Regimen;Research;Research Project Grants;Skin Cancer;Skin Carcinoma;T-Cell Activation;T-Lymphocyte Subsets;Techniques;Therapeutic;Time;Toxic effect;Tumor Escape;Tumor-Infiltrating Lymphocytes;United States;Verteporfin;Visible Radiation;Vitamin D;Work;X-Ray Computed Tomography;anti-PD-1;cancer therapy;cancer type;checkpoint inhibition;chemotherapy;clinical translation;cohort;confocal imaging;conventional therapy;cost;cytotoxic;design;dosimetry;high resolution imaging;image guided;immune cell infiltrate;immune checkpoint;immunogenic cell death;immunoregulation;improved;innovation;lymph nodes;mortality;mouse model;novel;optical imaging;pancreatic cancer model;pancreatic cancer patients;patient subsets;pembrolizumab;pharmacologic;pre-clinical;preclinical study;programmed cell death protein 1;programs;radiomics;recruit;response;side effect;success;symposium;tool;treatment response;treatment strategy;tumor;tumor microenvironment;ultrasound Photodynamic Priming of Cancer and Image-guidance for Optimal Immune Response NARRATIVE - OVERALLThis P01 aims to improve therapy for Pancreatic cancer one of the most lethal of cancers and nonmelanomaskin cancer the most ubiquitous cancer in the United States. We use visible light activation to not only destroythe cancer itself but also to increase the efficacy of other treatments such as chemotherapy andimmunotherapy while minimizing the toxicity associated with the latter. Our overall strategy includes two clinicaltrials (in Projects 1 and 2) and preclinical studies (Project 3) which together will ultimately allow patientcustomized combination treatments that will benefit even those patients whose disease has stoppedresponding to any of the conventional treatments. NCI 10705121 9/13/23 0:00 PAR-20-077 5P01CA084203-18 5 P01 CA 84203 18 "BUCHSBAUM, JEFFREY" 12/1/99 0:00 8/31/27 0:00 ZCA1-RPRB-J(M1)S 1877772 "HASAN, TAYYABA " "MAYTIN, EDWARD V" 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 1202445 NCI 1048401 154044 OVERALL PROGRAM SUMMARYFor optimal cancer therapy combination approaches that are mechanistically complementary and directedat non-overlapping molecular targets are needed. Strategically combinations should be selected such thatthe first treatment primes the tumor for the second treatment. Building upon our own findings and work onphotodynamic therapy (PDT) in pancreatic adenocarcinoma (PDAC) and nonmelanoma skin cancer (NMSC)along with recent advances in immunotherapy we hypothesize that the damage-related processes triggeredby PDT can form the basis for Photodynamic Priming (PDP) to promote an immune-based combinationtherapy. PDP induces immunogenic cell death enhances influx of tumor infiltrating lymphocytes (TILs) andsensitizes the tumor microenvironment to immune checkpoint inhibition (ICI). We will capture the PDP effectto design a non-empiric approach for PDT-ICI combination therapy. We will be helped in this effort by ourrecent innovation of hyperspectral confocal imaging that can monitor 6 biomarkers simultaneously in livetumor bearing animals and allow quantification of TIL subsets along with PD1/PD-L1 expression changes.We posit that ICI will be most beneficial when immunologically cold tumors can first be converted to hottumors via PDP treatment thereby minimizing the ICI dose required and reducing toxicity. Our Program has 3Research Projects and 2 scientific Cores plus an Administrative Core. Projects 1 and 2 are largely clinicalwhile Project 3 is exclusively pre-clinical driving fundamental findings that form the basis of the hypothesis.Project 1 introduces a double-priming strategy for the treatment of NMSC; the tumor is first treated pharmaco-logically with 5-fluorouracil or Vitamin D to enhance PDT priming which in turn increases the efficacy of ICI.Project 2 focuses on PDP in pancreatic cancer patients who are unresponsive to chemotherapy. PDT isdelivered under endoscopic ultrasound (EUS) guidance and timing of ICI delivery is informed by findings fromProject 3 and by examining subpopulations of TILs in metastatic lymph nodes in some patients. Project 3looks in-depth at PDP induction of TILs in a PDAC murine model and in patient-derived immune organoids(PDIOs). Cores are critical. Core B will assist Projects 1 and 3 with high resolution imaging in preclinicalmodels and PDIOs and Core C will support all projects with dosimetry techniques to monitor tumor treatmentresponse including radiomics to garner new information from CT scans in PDAC patients. Wepropose t h a t new combinations o f PDT with immune checkpoint inhibition (ICI) if done in a rational waythat is informed by optical imaging to monitor molecular responses at the cellular level and in real time willreduce a major barrier to ICI therapy (the lack of effective immune cell infiltration into the tumor). Impact andRelevance: This program positively impacts the treatment of two cancers PDAC and NMSC at oppositeends of the spectrum of high mortality/morbidity and high incidence. Both cancers inflict a heavy societalburden of cost and suffering. Findings from this work could also be translatable to other types of cancer. 1202445 +No NIH Category available Animals;Area;Bioinformatics;Biometry;Cancer Center;Clinical;Clinical Research;Collaborations;Computer software;Computing Methodologies;Consultations;Correlative Study;Data;Data Analyses;Data Collection;Databases;Development;Ensure;Experimental Designs;Genomics;Goals;Laboratories;Methods;Outcome;Process;Program Development;Quality Control;Renal carcinoma;Reporting;Reproduction spores;Research;Research Activity;Research Design;Research Personnel;Resource Sharing;Role;Translational Research;anticancer research;career development;cost effective;data framework;data integrity;data management;data modeling;design;epidemiology study;high standard;programs;quality assurance;research and development;translational scientist DF/HCC Kidney Cancer SPORE Biostatistics and Bioinformatics Core 1 Narrative:Organizing Biostatistical and Bioinformatic expertise as a shared resource core is a cost-effective approach toensure that collaboration is readily available to SPORE investigators and an effective strategy to guarantee ahigh degree of integration among projects with interrelated analytic goals and needs. The primary role of theBiostatistics and Bioinformatics (B&B) Core of this kidney cancer SPORE is to ensure that research conductedin the SPORE benefits from efficient experimental design and data analysis; quantitative methods used inSPORE research are appropriate for the design of the study and for the data and assumptions required forthese methods are evaluated and data collected in the Projects are managed and subjected to rigorous qualitycontrol to minimize the possibility of errors and are organized within an overall data model and framework thatfacilitates inter-project collaboration. NCI 10705118 8/9/23 0:00 PAR-18-313 5P50CA101942-19 5 P50 CA 101942 19 9/18/03 0:00 8/31/25 0:00 ZCA1-RPRB-J 8911 1888029 "CATALANO, PAUL J" Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 235593 199815 39546 SUMMARYThe Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE in Kidney Cancer Biostatistics andBioinformatics Core (Core 1) collaborates and provides consultation on all research activities within theSPORE including SPORE Projects the Developmental Research and Career Development Programs andother SPORE Cores - to ensure the highest standards of scientific rigor in areas of study design datamanagement and integrity and data analysis and interpretation. The specific aims are to: (1) Providebiostatistical and bioinformatic expertise for the planning and design conduct analysis and reporting oflaboratory genomic animal translational clinical (including associated correlative studies) andepidemiological studies for SPORE Projects Developmental Research and Career Development Programprojects and other SPORE Cores. (2) Provide consultation on all issues of data management and integrityincluding data collection storage transfer and quality assurance on statistical and bioinformatic software andprograms and on coordination of laboratory results with parameters and outcomes from clinical studies orclinical/translational research databases. (3) Provide short-term biostatistical and bioinformatic consulting toSPORE researchers. Organizing biostatistical and bioinformatic expertise as a shared resource core is a cost-effective approach to ensure that collaboration is readily available to SPORE investigators and an effectivestrategy to guarantee a high degree of integration among projects with interrelated analytic goals and needs.The development of new statistical and computational methodologies for cancer research has resulted in anexpanded role for the statistician bioinformatician and computational biologist in the research process and ahigher standard for what constitutes acceptable scientific evidence in a study. Biostatisticians andcomputational biologists are professionally committed to staying on top of these developments and apply theirexpertise to check assumptions assure appropriate use and interpret results and limitations--a challengebeyond what can reasonably be expected of translational investigators. +No NIH Category available Advocate;American Association of Cancer Research;American Society of Clinical Oncology;Animal Experimentation;Area;Basic Science;Biology;Budgets;Cancer Advocacy;Chemicals;Clinical;Clinical Research;Collaborations;Communication;Communities;Data;Data Coordinating Center;Data Science Core;Disputes;Doctor of Philosophy;Ensure;Epidermal Growth Factor Receptor;Evaluation;Event;Evolution;Feedback;Funding;Generations;Goals;IACUC;Institution;Institutional Review Boards;Interpersonal Relations;KRAS2 gene;Knowledge;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Organoids;Patient advocacy;Patients;Progress Reports;Reporting;Research;Research Personnel;Resistance;Resource Sharing;Role;Signal Transduction;Teleconferences;Therapeutic;Translational Research;Travel;Update;Work;Xenograft procedure;data sharing;human subject;meetings;molecular targeted therapies;patient advocacy group;programs;single cell analysis;symposium;targeted treatment;therapy resistant;timeline;tumor;tumor microenvironment Administrative Core n/a NCI 10705113 9/20/23 0:00 RFA-CA-21-052 5U54CA224081-06 5 U54 CA 224081 6 9/30/17 0:00 8/31/27 0:00 ZCA1-SRB-E 8909 10803618 "BLAKELY, COLLIN M" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 187261 115951 71310 Project Summary/Abstract: The main goal of the BAATAAR-UP ARTNet Admin Core is to ensure regularcommunication between the leaders and teams involved in Project 1 led by Dr. Bivona and Dr. Blakely (Clinicaltumor-TME acquired resistance) Project 2 led by Dr. Roth and Dr. Bivona (PDX tumor-TME acquiredresistance) Project 3 led by Dr. Bandyopadhyay and Dr. Kuo (PDO tumor- TME acquired resistance) and theData Science Core led by Dr. Wang and Dr. Bandyopadhyay. Additional goals include ensuring regularcommunication with the NCI and other ARTNet centers as well as with the basic translational and clinicalscientific stakeholders and with lung cancer advocacy groups and the public at large. These goals will beaccomplished through three specific aims. The first aim will be to effectively manage and integrate scientificprojects and budgets. The Admin Core will create a Leadership Team consisting of the Project and DataScience Core Leads which will evaluate the progress and impact of research accomplished through regularmonthly team meetings as well as an annual retreat. The Admin Core will also oversee the submission ofscientific progress reports to the NCI in collaboration with the Leadership Team. The second aim of the AdminCore will be to organize intra and trans-institutional activities to ensure regular communication between theproject teams with each other and with the Data Sciences Core. The Admin Core will ensure resource anddata sharing between each Project and with the Data Science Core. The Admin Core will also ensure regularcommunication between the Leadership Team and the Scientific Advisory Board (SAB) as well as the broaderscientific and patients advocacy community. This will be accomplished by organizing an annual researchretreat in which project teams will present research progress and receive feedback and guidance from theSAB. The SAB will include a range of experts with extensive knowledge of EGFR and KRAS biology andacquired resistance to molecular targeted therapies as well as clinical and patient expertise. The Admin Corewill also ensure regular presentation of our findings by coordinating travel and presentations at scientificconferences. Finally the Admin Core will ensure engagement with patient advocacy groups and the generallay community. In these events our scientific team will communicate our research to a diverse lay audienceas well as seek input and observations from the community for our work. The third aim of the Admin Core isto organize interactions with the NCI and other national ARTNet Centers. The Admin Core will spearheadcoordination and communication directly with the ARTNet Coordinating and Data Management Center(CDMC) and NCI scientific staff as well as coordinate teleconferences with other ARTNet centers and/or theNCI scientific staff to communicate updates on the progress of the Research Program and enhance thestrength of interpersonal interactions among all ARTNet stakeholders. +No NIH Category available Address;Bioinformatics;Bioinformatics Shared Resource;Biometry;Biostatistics Core;Biostatistics Shared Resource;Cancer Center;Clinical;Clinical Trials;Collaborations;Computer software;Data Analyses;Development;Educational workshop;Ensure;Experimental Designs;Funding;Human Resources;Individual;Information Storage;Laboratory Study;Maintenance;Malignant Neoplasms;Manuscripts;Methodology;Methods;Participant;Pilot Projects;Publications;Quality Control;Questionnaire Designs;Reporting;Research;Research Design;Research Personnel;Retrieval;Role;Sample Size;Services;Statistical Data Interpretation;Tennessee;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Training;Universities;Work;Writing;cancer health disparity;data cleaning;data quality;data visualization;database design;design;experimental study;investigator training;medical schools;member;multidimensional data;posters;power analysis;relational database;symposium Biostatistics Core n/a NCI 10705108 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2 8906 15288922 "LU, TAO " Not Applicable 7 Unavailable 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN Domestic Higher Education 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 81572 96166 40577 PROJECT SUMMARY: BIOSTASTICS AND BIOINFORMATICS SHARED RESOURCE COREIn this application we propose to intensify the role of our existing Meharry Medical College/Vanderbilt-IngramCancer Center/Tennessee State University Cancer Partnership (MVTCP) Bioinformatics and BiostatisticsShared Resource Core (BBSRC). The BBSRC will support two full projects and one pilot project; detailed andspecific biostatistical and bioinformatic analysis plans are provided for each specific aim/sub-aim within eachproject. Sample size for each primary experiment is computed to provide high power to detect clinically orbiologically relevant effects. For projects with high-dimensional data analyses the methods described in theResearch Strategy will be applied to assess data quality and then perform statistical analysis only afterpreprocessing to address quality issues. BBSRC support is required for all MVTCP studies with biostatisticiansand bioinformaticians from this core assigned to each project. BBSRC personnel have worked and will continueto work closely with project leaders to ensure the Biostatistics and Bioinformatics Shared Resource Coreprovides state-of-the-art statistical/bioinformatic support to the MVTCP. +No NIH Category available Advocacy;African American;African American population;Anatomy;Antigens;Awareness;Basic Science;Bioinformatics Shared Resource;Biological Markers;Biometry;Biopsy Specimen;Blood;Cancer Center;Cells;Clinical Trials;Collaborations;Collection;Communities;Consultations;DNA;Development;Doctor of Philosophy;Drug or chemical Tissue Distribution;Education;Equity;Fee-for-Service Plans;Fluorescence;Formalin;Foundations;Future;General Hospitals;Genomics;Goals;Histologic;Histology;Histopathology;Human;Immune;In Situ;Institution;Malignant Neoplasms;Medical Research;Messenger RNA;Minority Groups;Molecular Biology;Morphology;Normal tissue morphology;Operative Surgical Procedures;Paraffin Embedding;Pathology;Pilot Projects;Population;Population Research;Process;Proteomics;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Services;Slide;Stains;Techniques;Technology;Tennessee;Time;Tissue Banks;Tissue Sample;Tissues;Translational Research;Universities;Work;animal tissue;anticancer research;cancer health disparity;clinical diagnostics;design;human tissue;imaging capabilities;liquid biopsy;medical schools;microscopic imaging;molecular diagnostics;neoplastic;outreach;repository;tissue processing Translational Pathology Core n/a NCI 10705106 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2 8905 8934618 "BALLARD, BILLY RAY" Not Applicable 7 Unavailable 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN Domestic Higher Education 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 230490 198515 87146 PROJECT SUMMARY: TRANSLATIONAL PATHOLOGY SHARED RESOURCE COREThe Translational Pathology Shared Resource Core (TPSRC) provides collaborative and fee-for service supportto enhance basic and translational research efforts for Meharry Medical College (MMC) Vanderbilt-IngramCancer Center (VICC) and Tennessee State University (TSU) investigators. The TPSRC integrates the HumanTissue Acquisition Histology/Immunohistochemical/Histopathology and Morphology Cores centrally located atMMC to provide a comprehensive suite of continually expanding high-quality services including human cancerresearch tissue banking and distribution human and animal tissue processing sectioning routine and specialstaining immune-based cell antigen staining mRNA and DNA in-situ localization histological andhistopathological review and interpretation and a variety of state of the art imaging capabilities. The collectionof well-characterized human tissue for correlative research and molecular biology studies is a critical part ofcancer research and is the foundation for the development of effective translational medical research andpersonalized molecular diagnostics and treatment. The TPSRC works collaboratively with the researchcommunity and designs implements and validates new Core approaches and services. To facilitate integrationwith the Biostatistics and Bioinformatics Shared Resource Core MMC provides an on-campus office for in-houseconsultation purposes for investigators who routinely utilize the TPSRC. Our collaboration with the CancerOutreach Core in an advocacy and educational role enhances awareness of research efforts to eliminate cancerdisparities in African American and minority groups. The TPSRC will work closely with the Population ResearchAnd Clinical Trials In Cancer Equity (PRACTICE) Shared Resource Core for biospecimen collection. Further theTPSRC will actively engage with the MVTCPsponsored research projects proposed by Josiah Ochieng PhD(Project 2) and Anil Shanker PhD (Pilot Project) to provide tissues and pathology services to support theirresearch initiatives. +No NIH Category available Academia;Acceleration;Address;Affect;Applications Grants;Area;Bioinformatics Shared Resource;Biometry;Black race;Breast Cancer Risk Factor;Cancer Burden;Cancer Center;Cancer health equity;Censuses;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;County;Development;Dissemination and Implementation;Education and Outreach;Educational Materials;Ensure;Equity;Evaluation;Faculty;Feedback;Fostering;Foundations;Funding;Goals;Grant;Healthcare;Institution;Knowledge;Learning;Learning Module;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mentorship;Methodology;Minority Participation;Multicultural Education;Outreach Research;Ownership;Participant;Pathology;Patients;Pilot Projects;Policies;Population;Population Research;Prevention;Process;Public Health Education;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Risk Assessment;Rural Community;Scanning;Source;Students;Support Groups;Technology;Tennessee;Testing;Training Activity;Universities;Work;anticancer research;biobank;cancer care;cancer health disparity;cancer prevention;cancer risk;community based participatory research;community building;community engaged research;community engagement;community organizations;design;dissemination science;education research;ethnic minority;evidence base;health equity;health inequalities;implementation science;innovation;interest;medical schools;meetings;member;men;metropolitan;mobile application;mortality disparity;new technology;online resource;outreach;programs;racial minority;research study;social media;survivorship;training opportunity;underserved community;web-based tool Cancer Community Outreach Core n/a NCI 10705105 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2 8904 11321532 "ERVES, JENNIFER C." Not Applicable 7 Unavailable 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN Domestic Higher Education 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 82873 97059 40985 PROJECT SUMMARY: CANCER OUTREACH COREThe Cancer Outreach Core (COC) will apply a community-engaged research (CEnR) framework to facilitate andnurture integration and partnership between the institutions in our Meharry Medical College/Vanderbilt-IngramCancer Center/Tennessee State University Cancer Partnership (MVTCP). The COC will engage with ourcommunity partners to incorporate meaningful community engagement into research and outreach to ensurethat MVTCP activities are reflecting the needs and concerns of those populations that are most affected bycancer health disparities in the 14-county Nashville Metropolitan Statistical Area. The overarching goal of theCOC is to facilitate the reduction of cancer health disparities by leveraging the strengths of community partners tosupport and enhance cancer research and outreach efforts which will be addressed by the following Specific Aims:1) enhance community collaborations to accelerate research and implementation of programs and policydesigned to reduce cancer burden and disparities; 2) facilitate strategic research and diverse/inclusive clinicaltrial participation relevant to community needs; and 3) develop innovative outreach and education strategies tosupport capacity building of MVTCP stakeholders. These aims will be achieved through the collaboration of theCOC with other MVTCP cores through a robust Community Advisory Board (CAB) and through regularlyconsulting with MVTCP research projects. Given the significant regional mortality disparity among Black (comparedto white) men with prostate cancer a CAB member representing the Prostate Cancer Coalition of Tennesseecollaborated on the pilot work that led to the submission of a full project in this renewal on prostate cancer. The higherregional rates of ovarian cancer led to the formation of an ovarian cancer support group established through a CABmember enabling ongoing support of a pilot project focused on ovarian cancer. During the last grant period COChelped to foster incorporation of dissemination and implementation science into the CEnR which contributed to thefull project in this renewal focused on breast cancer risk assessment. The COC will facilitate bi-directionalcommunications bringing community input to the projects and disseminating results to the community. FurthermoreMVTCP investigators leading research projects will provide presentations to the CAB and receive feedback onpresenting to lay audiences. With coordination through the Administrative Core the COC will collaborate withthe Translational Pathology and Population Research and Clinical Trials in Cancer Equity Shared ResourceCores to develop an educational module about biospecimen donation. With the Research Education Corestudents will be engaged in community outreach utilizing new technologies aiming to reduce cancer disparities.The Biostatistics and Bioinformatics Shared Resource Core will provide input on quantitative analyses requiredfor CEnR projects. The Planning and Evaluation Core will participate in the +No NIH Category available Address;Area;CD47 gene;Cancer Etiology;Cancer Patient;Cell Survival;Cells;Chronic;Clinical;Communities;Cues;Data Science Core;Data Set;Development;Disease;Drug resistance;Ecosystem;Ensure;Epidermal Growth Factor Receptor;Event;Extracellular Matrix;Fibroblasts;Foundations;Funding;Future;Geography;Goals;Human;Immune;KRAS2 gene;Link;Lung;Lung Adenocarcinoma;Macrophage;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of lung;Medicine;Methods;Modeling;Molecular;NF-kappa B;Nature;Non-Small-Cell Lung Carcinoma;Oncogenic;Organoids;PD-1/PD-L1;PDPK1 gene;Paracrine Communication;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Process;Progress Reports;Proteomics;Public Health;Refractory;Research;Research Project Grants;Resistance;Signal Transduction;Specimen;System;Testing;Therapeutic;acquired drug resistance;cancer cell;cancer therapy;cancer type;clinical translation;cytokine;data sharing;humanized mouse;immunosuppressive checkpoint;improved;improved outcome;innovation;molecular targeted therapies;mortality;mouse model;mutant;neoplastic cell;patient derived xenograft model;precision oncology;prevent;programs;resistance mechanism;response;success;targeted treatment;therapeutic evaluation;therapy resistant;treatment strategy;tumor;tumor microenvironment;tumor progression;tumor xenograft BAY AREA & ANDERSON TEAM AGAINST ACQUIRED RESISTANCE - U54 PROGRAM (BAATAAR-UP) Project Narrative: Cancer is a substantial public health burden. Despite recent progress through the use ofprecision cancer medicines that have improved outcomes for cancer patients the development of acquiredresistance to these medicines has impeded transforming most cancers into chronic or curable conditions. ThisNCI ARTNet Research Program aims to understand the basis of acquired drug resistance to improve cancertreatments and patient survival. NCI 10705103 9/20/23 0:00 RFA-CA-21-052 5U54CA224081-06 5 U54 CA 224081 6 "KONDAPAKA, SUDHIR B" 9/30/17 0:00 8/31/27 0:00 ZCA1-SRB-E(M1) 9547125 "BIVONA, TREVER G" "ROTH, JACK " 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 1067511 NCI 832999 234512 Project Summary/Abstract: The goal of this BAATAAR-UP renewal program application within the NCI ARTNetis to characterize the mechanisms of and therapeutically counteract acquired resistance to molecular therapiesin non-small cell lung cancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem andits plasticity during treatment. Acquired resistance is defined as tumor progression that occurs during therapyand after an initial tumor response. The overarching hypothesis is that acquired resistance to molecular therapiescan be thwarted by defining and exploiting vulnerabilities in the cellular signaling and geographic tumorecosystem networks that allow tumors to survive and grow during therapy. In lung cancer and other cancer typesthe use of targeted therapies that inhibit important and common oncogenic driver alterations such as mutantEGFR and KRAS (G12C) and block immunosuppressive checkpoints such as PD1/PDL1 is improving patientoutcomes. A major challenge to transforming cancers into chronic or curable diseases is acquired resistancewhich enables lethal cancer progression in patients. Understanding the mechanisms underlying acquiredresistance is essential to develop counteracting strategies that improve patient survival. During the prior NCIU54 DRSC funding period our team uncovered several mechanisms of acquired resistance to targeted therapyin human NSCLC by studying clinical specimens and innovative patient-derived models including humanizedmurine models bearing patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) with an intactTME. Our expert team proposes to investigate these mechanisms and identify others synergistically anditeratively via 3 Research Projects and optimal interactions with 2 Cores. A Data Science Core will analyzeharmonize centralize and share data obtained across the basic and translational continuum using innovativemethods. An Administrative Core will ensure optimal project integration and internal and external interactionswith the ARTNet Consortium and scientific and lay communities. Project 1 (Clinical tumor-TME acquiredresistance) is translational and uses clinical specimens and patient-derived models to test the hypothesis thattumor macrophages and tumor fibroblasts promote acquired resistance via paracrine signaling interactionsincluding cytokine CD47 and extracellular matrix (ECM) cues sensed by cancer cells and converging on survivalpathways such as YAP and NF-kB. Project 2 (PDX tumor-TME acquired resistance) is translational and useshumanized mouse models to test the hypothesis that an immune-suppressive TME and activation of macrophageand fibroblast signaling circuits that support tumor cell survival via PDK1 YAP and NF-kB signaling promoteacquired resistance. Project 3 (PDO tumor-TME acquired resistance) is basic and uses synthetic lethal andproteomic profiling in PDOs with a TME to test the hypothesis that signaling interactions involving the ECMTROP2 and CD47 promote acquired resistance. Synergistic iterative interactions to study these mechanismsacross projects and systems will yield robust translatable treatment strategies to counteract acquired resistance. 1067511 +No NIH Category available African American;American;Biology;Cancer Biology;Cancer Center;Career Choice;Chemistry;Clinical;Cognitive;Communities;Community Developments;Community of Practice;Development;Disparity;Doctor of Philosophy;Educational workshop;Ensure;Environment;Evolution;Goals;Growth and Development function;High School Student;Institution;Laboratory Research;Latinx;Maintenance;Malignant Neoplasms;Master of Public Health;Medical Students;Mentors;Pathway interactions;Population;Population Heterogeneity;Population Sciences;Psychosocial Assessment and Care;Research;Research Personnel;Research Project Grants;Research Support;Resources;Schools;Science;Self Efficacy;Series;Students;Talents;Tennessee;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Training and Education;Underrepresented Minority;Underrepresented Students;Universities;anticancer research;cancer health disparity;career;career development;doctoral student;education research;experience;faculty mentor;graduate student;high school;innovation;interest;learning materials;medical schools;peer coaching;programs;psychosocial resources;recruit;social;student participation;success;theories;translational cancer research;undergraduate student;underrepresented minority student Education and Training Core n/a NCI 10705101 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2 8902 1877605 "ADUNYAH, SAMUEL EVANS" Not Applicable 7 Unavailable 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN Domestic Higher Education 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 110456 123731 41896 PROJECT SUMMARY: RESEARCH EDUCATION COREThe goal of the Meharry Medical College/Vanderbilt-Ingram Cancer Center/Tennessee State Cancer Partnership(MVTCP) Research Education Program is to facilitate the growth and career development of a new populationof outstanding underrepresented minority (URM) cancer researchers. Our current Pathway to Discovery programbegins with cancer research education for high school students continues for undergraduate Biology/Chemistrymajors at Tennessee State University (TSU) and culminates with support for graduate students (PhD MSPHand MPH) at Meharry Medical College (MMC) and TSU. The program also includes research support for medicalstudents at MMC and Vanderbilt University (VU). This program has proven to be very successful in supportingthe progression of a diverse population of students into cancer research careers. We propose to enhance theefficacy of the Pathway to Discovery program by including psychosocial resources derived from social cognitivecareer theory (SCCT). Research experience will engage students in the development and evolution of self-efficacy (SE) as well as a sense of being part of the scientific research community [science identity (SI)]. SCCTresearch shows that strong SE and SI are especially crucial to URM students entering and completing thenecessary programs to pursue research careers including cancer research. We propose a program groundedin SCCT that provides psychosocial resources and research experiences needed to develop and sustain SE andSI. MVTCP is particularly suited to target African American and Latinx undergraduate students (at TSU)graduate (at TSU and MMC) and medical students (at MMC). High school students come from two local STEMmagnet schools with predominant URM student populations. To achieve our goals we propose the followingaims: 1) Provide psychosocial resources for high school (8 students 4 juniors and 4 seniors) and undergraduatestudents (12 students 3 at each level freshmen through seniors) engaged in continuous academic year andsummer cancer research experiences to ensure development of SI and SE by leveraging the cancer researchand support resources at our Partnership institutions. Development of SE and SI will be accomplished byproviding opportunities for laboratory research and communities of practice (CoP) and a series of workshopsbased in SCCT. 2) Recruit and support a diverse population of graduate students (2 MPH/3 PhD students eachyear) who will evolve strengthen and maintain a strong SI and SE as they engage in cancer research with theultimate goal of enhancing the diversity of the cancer research workforce. SCCT-based workshops andresources targeted at the evolution and maintenance of SE and SI in our graduate students will be implemented.3) Provide educational research opportunities workshops and CoP to medical students (4 students each yearat MMC/4 at VU) to ensure successful evolution strengthening and maintenance of their SI and SE and tosustain their interest in clinical population sciences and translational cancer research with a focus on disparities. +No NIH Category available Advanced Malignant Neoplasm;Advisory Committees;Cancer Center;Cancer health equity;Collaborations;Collection;Communication;Data;Data Analyses;Data Collection;Data Reporting;Decision Making;Development;Education;Ensure;Evaluation;Feedback;Fostering;Funding;Goals;Grant;Health;Institution;Investments;Leadership;Logic;Malignant Neoplasms;Measurable;Measures;Methods;Modeling;Monitor;Nature;Outcome;Output;Performance;Practice Management;Principal Investigator;Process;Program Evaluation;Publications;Quality of life;Recommendation;Research;Research Personnel;Resources;Respondent;Services;Students;Teacher Professional Development;Techniques;Tennessee;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Time;Universities;Work;cancer health disparity;data management;design;health inequalities;improved;innovation;medical schools;programs;recruit;success;theories;tool Planning/Evaluation Core n/a NCI 10705099 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2 8901 8714275 "MARSHALL, DANA ROBIN" Not Applicable 7 Unavailable 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN Domestic Higher Education 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 22576 55618 22129 PROJECT SUMMARY/ABSTRACT: PLANNING AND EVALUATION COREThe Planning and Evaluation Core (PEC) will ensure that planning monitoring evaluation and tracking ofpartnership activities will be comprehensive to the needs of the Meharry Medical College/Vanderbilt-IngramCancer Center/Tennessee State University Cancer Partnership (MVTCP) and utilize evaluation activities toensure that the MVTCP is successful in contributing to the broad goals of the Comprehensive Partnerships toAdvance Cancer Health Equity (CPACHE) program. The information we garner through our evaluationprocesses will be used to guide the investment of resources into projects programs and institutional-levelstrategies such as recruitment and leveraging of resources that support the goals of the partnership. At a timein which cancer health disparities and inequities in research and education remain as major barriers to improvinghealth and quality of life for all ensuring that the efforts of the MVTCP are successful is paramount. Conductinghigh-quality continuous evaluation of the MVTCP provides the opportunity to document our efforts measure oursuccesses and attend to our weaknesses for the purposes of program improvement. During the past fundingcycle the PEC worked with all cores of the MVTCP to develop logic models that are used to identify programtheory as well as the measurable outputs and outcomes of each core. The metrics identified through this processwere then harmonized with the CPACHE-wide evaluation indicators to create an integrated outcome frameworkdesigned to capture the broader impact of the MVTCP. In the next funding cycle we will build on this work todevelop evaluation tools and processes to ensure high-quality implementation of funded projects integrationamong projects and cores and dissemination of methods and findings that demonstrate the impact of theMVTCP. The work of the evaluation core will be guided by the following aims: 1) foster on-going coordinationfacilitated by the Administrative Core with the Internal Advisory Committee and Program Steering Committee toensure the MVTCP is receiving expert feedback and guidance on cores projects and the performance of theMVTCP as a whole; 2) use a combination of established and innovative evaluation techniques to assess theMVTCP and its accomplishment of short- and long-term goals; 3) develop a culture of evaluation within theMVTCP that is committed to the use of data to support decision making drive quality improvement and informdissemination. +No NIH Category available Advisory Committees;Annual Reports;Basic Science;Belief;Cancer Center;Clinical;Clinical Sciences;Collaborations;Communication;Community Outreach;Data;Disparity;Doctor of Philosophy;Educational workshop;Ensure;Ethnic Origin;Evaluation;Expenditure;Faculty;Faculty Recruitment;Fostering;Funding;Funding Agency;Funding Opportunities;Geography;Goals;Growth and Development function;Guidelines;Human Resources;Infrastructure;Institution;Leadership;Malignant Neoplasms;Mentorship;Mission;Monitor;National Cancer Institute;Occupational activity of managing finances;Office of Administrative Management;Phase;Population Sciences;Preparation;Principal Investigator;Process;Productivity;Progress Reports;Race;Regulation;Reporting;Reproducibility;Research;Research Activity;Research Personnel;Research Project Grants;Resource Sharing;Resources;Services;Socioeconomic Status;Strategic vision;Tennessee;Training and Education;United States National Institutes of Health;Universities;Vision;Work;anticancer research;cancer health disparity;career development;experience;faculty mentor;implementation strategy;innovation;medical schools;programs;recruit;responsible research conduct;symposium;synergism MMC Admin Core n/a NCI 10705091 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2 8896 1877605 "ADUNYAH, SAMUEL EVANS" Not Applicable 7 Unavailable 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN Domestic Higher Education 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 263585 221260 97496 PROJECT SUMMARY/ABSTRACT: ADMINISTRATIVE COREIn this competing renewal application we propose to continue support of the longstanding Meharry MedicalCollege/Vanderbilt-Ingram Cancer Center/Tennessee State Cancer Partnership (MVTCP) that promotes abalanced focus on basic clinical and population science research to eliminate cancer disparities. TheAdministrative Core (AC) as a team from all three institutions are jointly responsible for supporting all MVTCPcomponents and investigators through overall management and coordination of resources communication andengagement. Importantly the AC fosters manages and supports interactions among and within the partnerinstitutions components and investigators internal and external advisory committees and the National CancerInstitute (NCI). The administrative teams from the partner institutions interact and collaborate extensively toenhance productivity and support the needs of the MVTCP. The AC is comprised of the Principal Investigators(PIs) from all three institutions Samuel Adunyah PhD [Meharry Medical College (MMC) contact PI] DuaneSmoot MD (MMC Co-PI) Tuya Pal MD [Vanderbilt-Ingram Cancer Center (VICC) contact PI] Ann RichmondPhD (VICC Co-PI) Margaret Whalen PhD [Tennessee State University (TSU) contact PI] and VenkataswarupTiriveedhi MD PhD (TSU Co-PI). An experienced administrative team from each institution provides day-to-day administrative oversight and supports the PIs and the Partnership. Through effective leadership the ACteam 1) provides vision and support as well as implements the overall direction of the Partnership; 2) facilitatesnew and ongoing review processes of Research projects funded through the Partnership; 3) ensures promotesand actively coordinates integration and synergy across the Cores and Shared Resources to support the projectsand grow additional disparities-focused efforts; 4) collaborates with institutional leadership to ensure appropriatelevels of institutional support; and 5) coordinates and prepares required annual reports and any additionalrequired reporting and data for the NCI in close coordination with the Planning and Evaluation Core. The ACdevelops and coordinates activities in support of planning and evaluation engages in faculty recruitment andmentoring develops and executes workshops seminars and the Annual MVTCP Cancer Health DisparitiesSymposium. To ensure fulfillment of the goals of the MVTCP the AC engages regularly with the Internal AdvisoryCommittee (IAC) Program Steering Committee (PSC) NCI leadership Partnership Cores Shared Resourcesand funded Research Projects. The AC is committed to providing necessary leadership and services to supportefficient working relationships across and within the Partnership with senior institutional leaders and other keypersonnel as well as with the PSC and NCI. The AC team shares the belief that this Partnership is at a criticaljuncture in its maturation and have worked together to develop strategic initiatives and an implementationstrategy for the next phase of growth and development to fulfill its mission to Eliminate Cancer Health Disparities. +No NIH Category available Address;Area;Award;Awareness;Basic Science;Behavioral;Big Data;Bioinformatics;Bioinformatics Shared Resource;Biological Factors;Biometry;Cancer Center;Cancer Patient;Cancer Research Project;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Community Health;Comprehensive Cancer Center;Development;Discipline;Disparity;Education;Effectiveness;Environment;Equity;Ethnic Origin;Evaluation;Extramural Activities;Faculty;Financial Hardship;Fostering;Geographic Locations;Geography;Goals;Growth;Health Educators;Immunooncology;Incidence;Inequity;Infrastructure;Institution;Intervention Trial;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medical Students;Minority;Minority-Serving Institution;Mission;Oncology;Outcome;Pathology;Pathway interactions;Patient Participation;Peer Review;Population Research;Population Sciences;Prevalence;Publications;Race;Reduce health disparities;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Series;Tennessee;Training;Translational Research;Underrepresented Minority;United States;Universities;anticancer research;cancer clinical trial;cancer health disparity;cancer initiation;career;collaborative approach;community based participatory research;community organizations;education research;evidence base;graduate student;health care disparity;high school;improved;malignant breast neoplasm;medical schools;minority communities;mortality;multidisciplinary;outcome disparities;outreach;outreach program;programs;recruit;screening;socioeconomics;survivorship;treatment trial;undergraduate student;underserved community 1/3) MMC VICC and TSU: Partners in Eliminating Cancer Disparities PROJECT NARRATIVE: OVERALLThe well-established Meharry Medical College/Vanderbilt-Ingram Cancer Center/Tennessee State UniversityCancer Partnership (MVTCP) triad provides an exceptional environment to identify and address health careinequities in cancer seen in underrepresented minorities. The proposed research projects cores and sharedresource cores will grow research and propose evidence-based solutions address to these inequities. Furtherthe development of expanded research infrastructure at MMC and TSU enhancement of minority educationprograms and improvement to the effectiveness of cancer-related activities will address health care disparitiesin the greater Nashville geographical region with the ultimate goal of contributing to reducing health disparitiesamong cancer patients in minority and underserved communities. NCI 10705089 8/23/23 0:00 PAR-18-767 5U54CA163069-13 5 U54 CA 163069 13 "WALI, ANIL" 9/26/11 0:00 8/31/26 0:00 ZCA1-SRB-2(A1)S 1877605 "ADUNYAH, SAMUEL EVANS" "SMOOT, DUANE T." 7 BIOCHEMISTRY 41438185 DLTJBDQBGBC9 41438185 DLTJBDQBGBC9 US 36.166904 -86.806149 5050201 MEHARRY MEDICAL COLLEGE NASHVILLE TN SCHOOLS OF MEDICINE 372083501 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1485821 NCI 1429918 607613 PROJECT SUMMARY: OVERALLCancer health disparities based on factors such as race and ethnicity are the result of a combination ofsocioeconomic environmental behavioral and biological factors. These disparities impact cancer incidenceprevalence mortality survivorship financial burden and screening rates. The long-standing and mature MeharryMedical College (MMC) Vanderbilt-Ingram Cancer Center (VICC) Tennessee State University (TSU) CancerPartnership (MVTCP) continues to provide and expand upon an exceptional cancer research and trainingenvironment to support the efforts of diverse investigators in addressing disparities. These efforts span acrossmultiple disciplines to study the determinants of cancer health disparities at an NCI-designated comprehensivecancer center (VICC) along with enhancing research infrastructure capacity-building and impact at two minority-serving institutions (MMC and TSU). Collectively over the past twenty years of partnership these collaborativeefforts provide a robust infrastructure to address and overcome cancer disparities while expanding researchopportunities recruitment and training. Our Triad has benefited from sustained and strong collaborativeinteractions between the three partner institutions resulting in robust community and educational outcomes.Moreover the geographical placement of this Triad in Tennessee a region with some of the highest cancerincidence and mortality rates in the United States also provides a unique opportunity for our Partnership topositively impact outcomes for cancer patients in this geographical region. This region continues to havesignificant cancer health disparities in lung breast prostate and colorectal cancers. In order to meet our ultimategoals of overcoming cancer disparities while simultaneously strengthening research impact the overallobjectives of this competing renewal application are to: 1) increase the participation in traditional investigator-initiated cancer research projects awarded to MMC and TSU faculty with collaborative guidance by senior VICCfaculty; 2) increase the number of investigator-initiated awards to VICC junior faculty that address cancerdisparities; 3) recruit train and retain early-stage investigators to become independent leaders in cancer healthdisparities and cancer research and training; 4) expand MVTCP participation in national oncology treatment andinterventional trials; 5) strengthen the physical and intellectual infrastructure for research at MMC and TSU; 6)facilitate partnerships between community organizations and academic researchers leading to hypothesis-driven research projects that include the involvement of a community health educator; 7) increase the numberof MMC and TSU trainees engaged in cancer research; and 8) increase awareness of cancer researchopportunities and careers for minority high school undergraduate graduate and medical students through thePathway to Discovery program. 1485821 +No NIH Category available Archives;Automobile Driving;Biological Markers;Biology;Biopsy;Cell Line;Cells;Clinical;Clinical Management;Complex;Critical Pathways;Data;Diagnostic Neoplasm Staging;Disease;Disease Outcome;Distant;Distant Metastasis;Education;Electronic Medical Records and Genomics Network;Event;Evolution;Excision;Exhibits;Freezing;Generations;Goals;Human;Image;Immune;Immunity;Immunologic Markers;Immunologic Surveillance;Immunologics;Immunosuppression;Interferon Type I;Interferons;Investigation;Knockout Mice;Knowledge;Localized Disease;Lymph;Lymph Node Dissections;Lymph Node Subcapsular Sinus;Lymph Node Tissue;Lymphatic Endothelial Cells;Malignant Neoplasms;Maps;Melanoma Cell;Metastatic Neoplasm to Lymph Nodes;Modeling;Molecular;Mus;Neighborhoods;Neoplasm Metastasis;Operative Surgical Procedures;Organ;Outcome;Patient risk;Patient-Focused Outcomes;Patients;Phenotype;Recurrence;Regional Disease;Research;Research Personnel;Resources;Rest;Retrospective cohort;Role;Sentinel Lymph Node;Signal Transduction;Site;Solid Neoplasm;Staging;Systemic disease;Testing;Time;Tissues;Tumor Biology;Tumor Immunity;Validation;Work;cancer cell;clinical care;clinically relevant;cohort;computational pipelines;computerized tools;draining lymph node;experimental study;high dimensionality;improved;innovation;interest;liquid crystal polymer;lymph nodes;malignant breast neoplasm;melanoma;melanoma biomarkers;melanomagenesis;mouse model;multiplexed imaging;neoplastic cell;novel;outcome disparities;patient stratification;patient subsets;permissiveness;personalized strategies;prognostic;programs;risk stratification;spatial integration;transcriptomics;treatment response;tumor;tumor immunology;tumor initiation;tumor progression;tumor-immune system interactions Project 3: The Evolving Role of Regional Lymph Nodes in Melanoma Progression n/a NCI 10705088 8/7/23 0:00 RFA-CA-20-029 5U54CA263001-02 5 U54 CA 263001 2 9/15/22 0:00 7/31/27 0:00 ZCA1-RTRB-U 6640 12071678 "LUND, AMANDA W." Not Applicable 12 Unavailable 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY Domestic Higher Education 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 365671 215735 149936 PROJECT 3 SUMMARYCancers commonly spread from their primary site and colonize regional lymph nodes (LNs) representing ahallmark of progression and a key parameter for staging. The prognostic impact of LN metastasis and utility ofcomplete LN dissection in patients with micrometastatic LN disease however varies between solid tumor typesand patient subsets. The clinical observation that removal of micrometastatic LN disease does not by definitionimprove survival has highlighted a gap in our understanding of regional LN metastasis and calls into questionthe simple model of sequential metastasis. Given that LNs are both an early site of metastasis and immunologicalorgans the interplay between dissemination and immunity may be critical to understanding how LNs impactoutcome. Here we will investigate the biology of tumor-draining LNs to ask whether regional draining LNs act asan educational site that ultimately shifts the systemic macroenvironment to favor distant tumor outgrowth.In this proposal we test the hypothesis that sentinel LNs undergo a cascade of cellular and molecular eventsthat prime the host to be receptive to tumor progression. To test this hypothesis we will build an unbiasedtemporally and spatially resolved map of regional draining LNs. This will enable us to identify clinically relevantmechanisms that determine outcome by integrating a deep mechanistic understanding of lymphatic and LNbiology together with high-dimensional imaging and novel computational tools in mice and humans. To buildthis map we will leverage fresh frozen LNs from surgical cases archived FFPE matched primary and metastasispairs and a clinically relevant mouse model and determine the early changes that support tumor cell seedingand the melanoma cell states that first arrive in LNs (Aim 1). We will further test causal programs including typeI interferon signaling that may functionally initiate this tumor permissive state and install local mechanisms ofadaptive immune suppression that limit systemic immune surveillance and thereby distant metastasis (Aim 2).Finally we will leverage the extensive resource and expertise of Core B to investigate the utility of immunemarkers to stratify patient risk from archived sentinel LN tissue and thereby predict recurrence in Stage II and IIImelanoma patients (Aim 3). The work we propose here promises to significantly reimagine the role of the sentinelLN in systemic melanoma progression. This conceptual shift may inform personalized strategies to manage localdisease and thereby mobilize anti-tumor immunity and systemic tumor control across solid tumor types andidentify immune-based LN features to stratify risk for recurrence in melanoma and guide clinical care.The resources and knowledge generated through this proposal will be made publicly accessible through NYULHMetNet Center Cores B and C which will enable extension of these observations to other solid tumor types (e.g.breast cancer) through the broader Metastasis Research Network and therefore enable a significantly expandedunderstanding of LN metastasis and progression. +No NIH Category available ATAC-seq;Address;Adjuvant Therapy;Behavior;Benign;Cancer Control;Cancerous;Cell Communication;Cell Lineage;Cells;ChIP-seq;Characteristics;Chromatin;Clinical;Clinical Data;Congenic Mice;Cytokine Signaling;Data;Dermis;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Distal;Environment;Epidermis;Epigenetic Process;Extracellular Matrix;Fibroblasts;Gene Cluster;Genes;Genetic Engineering;Genetic Transcription;Growth;Growth Factor;Heterogeneity;Histones;Human;Human Pathology;IGF1 gene;IGF1R gene;Immune;Immune system;Immunofluorescence Microscopy;Immunohistochemistry;Invaded;Ligands;Link;Lymphatic;Malignant Neoplasms;Maps;Melanoma Cell;Metastatic Melanoma;Metastatic Neoplasm to Lymph Nodes;Modeling;Molecular;Mus;Neoplasm Metastasis;Organ;Pathologic;Pathway Analysis;Pathway interactions;Patient Selection;Patients;Pattern;Phenotype;Play;Population;Primary Neoplasm;Process;Prognostic Marker;Regulation;Regulator Genes;Regulatory Element;Research;Resolution;Resources;Role;Signal Pathway;Signal Transduction;Solid Neoplasm;Spatial Distribution;Specimen;Stromal Cells;Technology;Testing;Time;Tissues;Tomatoes;cancer cell;cancer type;cell type;chemokine;clinically relevant;cytokine;differential expression;draining lymph node;genetic manipulation;in vivo;insight;melanocyte;melanoma;metastatic process;migration;molecular marker;morphogens;mouse model;neoplastic cell;pancreatic cancer model;prevent;prognostic value;programs;receptor;single-cell RNA sequencing;stem cells;synergism;targeted treatment;therapeutic target;tool;transcription factor;transcriptome;transcriptomics;tumor;tumor heterogeneity;tumor initiation;tumor progression;tumorigenesis Project 2: Contribution of the Stromal Microenvironment to Early Dissemination n/a NCI 10705081 8/7/23 0:00 RFA-CA-20-029 5U54CA263001-02 5 U54 CA 263001 2 9/15/22 0:00 7/31/27 0:00 ZCA1-RTRB-U 6639 9827515 "ITO, MAYUMI " Not Applicable 12 Unavailable 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY Domestic Higher Education 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 346819 204613 142206 PROJECT 2 SUMMARYMetastasis initiates early in melanoma and coincides with phenotypic and functional changes in tumor cellssurrounding stromal cells and extracellular matrix components. Amongst the stromal cell types cancerassociated fibroblasts (CAFs) are emerging as a particularly relevant cell population. Although they aregenetically stable CAFs are phenotypically and functionally diverse and distinct subsets of CAFs were found tosupport or inhibit cancerous growth in pancreatic cancer models. Although these findings suggest functionallydiverse sets of CAFs could also exist in other cancers they have yet to be defined in most other cancer types.Furthermore because specific CAFs might be valuable prognostic markers or therapeutic targets it is becomingincreasingly important to better understand their development and regulation. Here we propose to investigatehow signals between melanoma cells and fibroblasts create heterogeneity within tumors and how thisheterogeneity unleashes metastatic behaviors in a subset of melanoma cells. To test this hypothesis wedeveloped genetically engineered congenic mouse models that allow us to genetically manipulate melanocytestem cells to initiate tumors that faithfully recapitulate the pathology of human melanoma and to independentlyinhibit specific genes in melanoma cells or CAFs. These models will uniquely enable us to investigate howspecific signaling mechanisms influence CAF functions in melanoma development and metastasis. We proposeto couple our mouse models with single-cell RNA sequencing spatial transcriptomics ATAC-seq and ChIP-seqapproaches to transcriptionally define distinctive CAF states. We will also use them along with melanomaspecimens from patients with and without metastatic progression to map specific CAFs and their proximity toother cell types with highly multiplexed immuno-histochemistry (Aim 1). Next we will use these tools and data todiscover cell state specific receptor-ligand interactions and study how IGF1-IGF1R signaling between melanomacells and CAFs one model pathway our preliminary studies identified influences intratumor heterogeneity andmetastatic progression in vivo (Aim 2). Project 2 will leverage the pathological technological and analytical resources of Cores B and C. It willsynergize with Project 1 to determine whether and how melanoma cells interact with distinctive CAFs and howthese interactions allow for metastatic dissemination. Project 2 will also enhance Project 3 by shedding new lightonto CAF-secreted cytokines that modulate tumor draining lymph nodes and make immune cells tolerant tometastasizing melanoma cells. Once we understand these processes on a molecular level and link them toclinical characteristics we can begin to inform patient selection for adjuvant therapy in early-stage melanomaand catalyze a rational development of targeted therapies that prevent or treat metastatic dissemination in early-stage melanoma and other cancer types. +No NIH Category available Adjuvant Therapy;Animal Model;Anoikis;Automobile Driving;Bar Codes;Behavior;Biology;Candidate Disease Gene;Cell model;Cells;Cessation of life;Classification;Clinical;Correlation Studies;Cutaneous Melanoma;Data;Dermal;Development;Diagnosis;Epigenetic Process;Evolution;Exhibits;Gene Expression Profile;Genetic;Genetic Engineering;Genetic Transcription;Genetically Engineered Mouse;Goals;Heterogeneity;Human;Immunohistochemistry;Individual;Information Dissemination;Invaded;Laboratories;Link;Maintenance;Malignant Neoplasms;Melanoma Cell;Mesenchymal;Metastatic Melanoma;Modeling;Molecular;Monitor;Mus;Neoplasm Metastasis;Neural Crest;Nuclear Receptors;Outcome;Output;Pathogenesis;Pathologic;Patient-Focused Outcomes;Patients;Phenotype;Population;Primary Neoplasm;Prognostic Marker;Property;Protein Isoforms;Reporting;Research;Research Project Grants;Resected;Resources;Risk;Sampling;Signal Transduction;Site;Technology;Testing;Tissues;Transcript;Transcriptional Regulation;Tropism;Tumor stage;Variant;apoAI regulatory protein-1;cancer cell;candidate identification;data integration;falls;high risk;human disease;human model;improved;innovation;melanocyte;melanoma;metastatic process;migration;millimeter;mouse model;neoplastic cell;novel;novel therapeutic intervention;patient prognosis;prevent;programs;prospective;screening;single-cell RNA sequencing;transcriptomics;treatment response;tumor;tumor heterogeneity;tumorigenesis;tumorigenic Project 1: Tumor Cell Intrinsic Determinants of Early Dissemination in Melanoma n/a NCI 10705072 8/7/23 0:00 RFA-CA-20-029 5U54CA263001-02 5 U54 CA 263001 2 9/15/22 0:00 7/31/27 0:00 ZCA1-RTRB-U 6638 9107364 "HERNANDO, EVA " Not Applicable 12 Unavailable 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY Domestic Higher Education 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 323305 190741 132564 PROJECT 1 SUMMARYIncreasing data suggest that phenotypic and transcriptional plasticity are important features that contribute tometastatic progression tropism and response to therapy of cancer cells. We and others have providedcompelling evidence that intratumoral heterogeneity exists in primary melanomas suggesting it is an earlyfeature important for tumorigenesis. Further recent reports demonstrate that melanoma cells can switchbetween phenotypic states some of which are associated with more aggressive biology implicatingtranscriptional plasticity in this phenotypic variation. However the evolution of tumor cell intrinsic featuresassociated with melanoma progression remains largely uncharacterized. The studies that have evaluatedtranscriptomic and epigenetic features involved in melanoma metastasis have typically focused on individualmolecular features restricted to a specific cell population and have fallen short of integrating the metastaticprocess as a whole. We hypothesize that emergence of transcriptional heterogeneity that gives rise to distinctcell states in primary cutaneous melanoma is a critical step driving early metastatic dissemination and that cellswith a specific transcriptional program harbor the bulk of metastatic potential. The goal of Project 1 is toinvestigate the timing and function of molecular drivers of metastasis the emergence and evolution oftranscriptional heterogeneity and metastatic trajectories of cell states. We will do this in novel geneticallyengineered mouse models that reflect human disease as well as in clinically annotated patient samples. Usingan innovative approach that integrates genetic bar coding single cell RNA sequencing spatial transcriptomicsand highly-multiplexed immunohistochemistry we will assess the presence of specific transcriptional cell stateswithin murine and human primary melanomas and assess their influence on metastatic potential using animalmodels and statistical correlates to known patient outcomes (Aim 1). We will then study the mechanisms drivingthese transcriptional cell states by testing the contribution of individual candidate genes to their emergence andmaintenance and their impact on metastatic potential (Aim 2).This research project will leverage the pathological technological and analytical resources of Cores B and C.Integration with Projects 2 and 3 will dissect the evolving bidirectional crosstalk between melanoma cells andtheir microenvironment that culminates in a metastasizing tumor. Understanding the contribution of specific cellstates and the molecular programs underlying early dissemination can improve our ability to subclassify patientsdiagnosed with primary melanoma by their risk of metastasis and identify those patients who could benefit mostfrom increased surveillance or adjuvant therapies. Our studies might also provide a rationale for noveltherapeutic approaches to prevent or target metastasis. Finally findings from this research may apply to othertumor types wherein early dissemination results on increased metastatic potential and worse outcomes. +No NIH Category available Accounting;Award;Cancer Center;Cancer Center Support Grant;Cell Nucleus;Collaborations;Communication;Community Outreach;Disease model;Ensure;Evaluation;Federal Government;Fostering;Funding;Goals;Health;Incidence;Infrastructure;Institution;Institutional Policy;Invaded;Leadership;Local Government;Monitor;Neoplasm Metastasis;New York;Occupational activity of managing finances;Patients;Pilot Projects;Policies;Primary Neoplasm;Process;Progress Reports;Race;Reagent;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Site;Solid Neoplasm;Strategic Planning;Thick;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;community engagement;cost effectiveness;data integration;geographic barrier;material transfer agreement;meetings;melanoma;outreach;programs;quality assurance;synergism Administrative Core n/a NCI 10705069 8/7/23 0:00 RFA-CA-20-029 5U54CA263001-02 5 U54 CA 263001 2 9/15/22 0:00 7/31/27 0:00 ZCA1-RTRB-U 8892 9107364 "HERNANDO, EVA " Not Applicable 12 Unavailable 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY Domestic Higher Education 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 141354 83395 57959 ADMINISTRATIVE CORE SUMMARYThe Administrative Core (Core A) will execute the administrative needs of the NYU Langone Health MetastasisResearch Network (NYULH MetNet) Center investigators and collaborators optimize the utilization of resourcesavailable to the projects and synergize the intellectual depth of NYULH investigators to achieve the researchgoals of the NCIs Metastasis Research Network. The four overarching goals of the Administrative Core includeNYULH MetNet Center governance intra-programmatic and inter-programmatic communication oversightfinancial and scientific reporting management and conscientious public outreach.Specifically the Admin Core aims to: 1) Provide strategic planning for the execution of the NYULH MetNetCenters research goals administrative support for full research and pilot projects and policies to continuouslymonitor all Center activities. 2) Develop a review and award process for pilot projects that encourages juniorunderrepresented minority and women investigators to conduct metastasis research. 3) Establish and maintainpolicies for prudent financial management and maximize efficient resource use and sharing by leveragingadministrative and scientific infrastructures of the NYU Melanoma SPORE and NYU Perlmutter Cancer Center(PCC) across all MetNet Center activities for cost-effectiveness quality assurance and Center integration. 4)Fulfill the NYULH MetNet Center governance responsibilities including regulatory compliance fiscal oversightand account management of NYULH MetNet Center activities. 5) Augment our community outreach andengagement programs to integrate a broad patient perspective taking into consideration financial racial andgeographic barriers.As the administrative nucleus for the NYULH MetNet Center the Admin Core leadership will organize intra-programmatic meetings as well as attend all Metastasis Research Network meetings. The Admin Core inaccordance with federal and local governments NIH and institutional policies will manage the budgetaryaccounting of all Center activities. Finally the Admin Core will be responsible for sustaining communication andcooperation with the NYULH PCC and NCI/NIH administration and overseeing the timely submission of allrequired progress reports. +No NIH Category available Behavior;Cells;Clinical;Collaborations;Complex;Computational Biology;Data;Databases;Dermal;Development;Disease;Distant;Environment;Evolution;Financial Support;Frequencies;Genes;Genetic;Genetic Diseases;Genetic Transcription;Genetically Engineered Mouse;Genomics;Heterogeneity;Human;Immune Evasion;Immune response;Immunologic Surveillance;Infrastructure;Institution;Intercept;Knowledge;Link;Malignant - descriptor;Malignant Neoplasms;Maps;Mediating;Methods;Modeling;Molecular;Molecular Evolution;Neoplasm Metastasis;Non-Malignant;Organ;Output;Patient Care;Patient-Focused Outcomes;Patients;Population;Productivity;Recurrence;Research;Research Personnel;Resources;Risk;Sampling;Signal Transduction;Site;Skin;System;Testing;Therapeutic;Therapeutic Intervention;Thick;Tissues;Tumor stage;biomarker identification;cancer type;cell behavior;cell type;clinically relevant;computer framework;draining lymph node;epigenetic regulation;improved;innovation;lymph nodes;melanoma;melanoma biomarkers;millimeter;mouse genetics;mouse model;multidisciplinary;neoplastic cell;new therapeutic target;novel;novel therapeutics;participant enrollment;permissiveness;prevent;programs;prospective;stem cell biology;survival outcome;synergism;temporal measurement;transcriptomics;tumor;tumor immunology;tumor microenvironment;tumor progression;tumorigenic NYULH Metastasis Research Network Center (NYULH MetNet Center) OVERALL NARRATIVEThe NYULH MetNet Center will leverage the complementary expertise of the NYU Melanoma programinvestigators to build an in-depth transcriptional and cellular characterization of tumor-microenvironmentinteractions that dictate early dissemination using novel clinically relevant mouse models and well-annotatedpatient biospecimens. NCI 10705068 8/7/23 0:00 RFA-CA-20-029 5U54CA263001-02 5 U54 CA 263001 2 "NADEAU, CHRISTINE FRANCES" 9/15/22 0:00 7/31/27 0:00 ZCA1-RTRB-U(J1) 9107364 "HERNANDO, EVA " "OSMAN, IMAN " 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 1654459 NCI 976082 678377 OVERALL SUMMARYConventional views of cancer as a predominantly genetic disease that proceeds in a step-wise linear mannerhave ceded to an understanding that tumor progression involves a multifaceted set of tumor cell-intrinsic andmicro-environmental adaptations that co-evolve dynamically and non-linearly. However much remains to bediscovered about how different cell populations in the local environment drive metastatic behavior at differentstages of tumor progression. Primary melanomas that are only millimeters thick can disseminate to lymph nodesand distant organs. This clinical feature suggests that egress of tumor cells from a primary site occurs early inmelanoma development making melanoma an exceptional model to study these dynamic adaptations during theearliest stages of tumor progression. Our central hypothesis is that melanoma metastasis is driven by acombination of tumor cellintrinsic features and interactions with micro-environmental compartmentsthat govern early dissemination and immune evasion in the regional draining lymph nodes. To test thishypothesis we propose three inter-related projects supported by three cores that will collectively build an in-depth transcriptional and cellular map of critical compartments in the tumor microenvironment during earlymelanoma dissemination in both mouse models and patient biospecimens. Successful completion of theseprojects will identify genes and transcriptional programs within those compartments that drive and maintaintumorigenic adaptations and ultimately metastatic dissemination. Our aims are to: 1. Map the cellular andmolecular evolution of primary melanomas and their local and regional microenvironments to identify criticalswitches that drive non-linear tumor progression; 2. Mechanistically dissect the emergence and functionalrelevance of transcriptionally defined cell state heterogeneity of malignant and non-malignant cell populations;3. Identify novel therapeutic vulnerabilities to intercept early dissemination mobilize systemic immunesurveillance and improve patient outcomes; and 4. Leverage the information gained to define new biomarkersof melanoma metastasis. We expect that knowledge generated through our approach may define newbiomarkers of melanoma metastasis and therapeutic strategies to manage early disease. Our approach canserve as a roadmap to study early tumor progression at an unprecedented level of cellular spatial and temporalresolution. It will provide a comprehensive picture of interactions both within the tumor microenvironment andtumor draining lymph nodes that influence tumor cell behavior and condition the host to be receptive to metastaticspread. We will leverage the complementary and synergistic expertise of our research team with an establishedrecord of productive collaboration our novel genetically engineered mouse model that recapitulates earlyprogression of human melanoma and our access to high quality clinically annotated patient samples from over4700 patients enrolled in a prospective clinicopathological database. The scope and scalability of the knowledgegained will serve other sites of the Metastasis Research Network. 1654459 +No NIH Category available Achievement;Advisory Committees;Animal Model;Applications Grants;Area;Award;Basic Science;Bioinformatics;Biometry;Cancer Center;Cancer Research Project;Clinic;Clinical Sciences;Communities;Data;Development;Diagnosis;Disabled Persons;Disease;Eligibility Determination;Ensure;Environment;Extramural Activities;Faculty;Funding;Future;Goals;Grant;Individual;Leadership;Malignant neoplasm of ovary;Manuscripts;Mayo Clinic Cancer Center;Medicine;Mentors;Mentorship;Minority;Monitor;Ovarian;Patient advocacy;Peer Review;Policies;Population Sciences;Prevention;Procedures;Process;Productivity;Published Comment;Publishing;Qualifying;Reporting;Research;Research Personnel;Resources;Role;Scientist;Secure;Series;System;Translational Research;Woman;Work;Writing;anticancer research;base;candidate selection;career;career development;diversity and inclusion;expectation;improved;interest;meetings;multidisciplinary;patient registry;programs;recruit;skills;success;translational scientist Career Enhancement Program NARRATIVE CAREER ENHANCEMENT PROGRAM (CEP)The Career Enhancement Program seeks to identify and mentor new and developing investigators in ovariancancer research. The SPORE assists these individuals by providing mentoring teams actively integrating theawardee into the SPORE and providing access to Core resources while encouraging each awardee togenerate sufficient data and a trajectory toward independent funding in ovarian cancer research. NCI 10705058 9/8/23 0:00 PAR-18-313 5P50CA136393-13 5 P50 CA 136393 13 7/1/09 0:00 8/30/26 0:00 ZCA1-RPRB-8 8891 1899922 "COUCH, FERGUS JOSEPH" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 73935 46500 27435 ABSTRACT CAREER ENHANCEMENT PROGRAM (CEP)The purpose of the Mayo Clinic SPORE in Ovarian Cancer is to stimulate organize and facilitate rigoroustranslational research that will meaningfully reduce the burden of ovarian cancer. A critical part of this processis to increase the quality and depth of the translational investigator base in ovarian cancer. During Years 6-10of funding five individuals received Career Enhancement Program (CEP) awards and were supported with 1-2years of funding (one awardee with 2 years of funding; four with 1 year of funding) mentoring teams and fullaccess to SPORE resources. Our awardees have been highly successful with 39 peer-reviewed manuscriptspublished by Year 6-10 awardees and 3 have successfully secured subsequent funding. All five Year 6-10awardees relied upon the Biostatisics and Bioinformatics Core (Core C) four awardees also partnered with theBiospecimens and Patient Registry (Core B) and three with the Animal Models Core (Core D). The ultimateobjectives of the Career Enhancement Program (CEP) continue to be the identification and mentoring of newand developing investigators in ovarian cancer who demonstrate clear potential to become independenttranslational researchers as well as attracting established scientists who wish to refocus on ovarian cancer.The CEP provides up to $100000 for one year of support ($50000 from SPORE funds and a matching$50000 from Mayo Clinic Cancer Center); a second year is possible based on progress and continuedtranslational trajectory. Special emphasis is placed on attracting highly qualified individuals underrepresentedin medicine including women minorities and persons with disabilities. Identifying and selecting CEPawardees is accomplished through a rigorous review process followed by intense mentoring integration intoongoing SPORE activities and close oversight of each individuals progress. In addition to a primary mentorawardees have complementary mentors in clinical basic or population sciences necessary to ensuredevelopment of a translational research career. This capitalizes on numerous strengths present within theMayo environment. The CEP directorship reports to the Executive Committee of the Mayo Clinic OvarianCancer SPORE. During the next funding period the Ovarian SPORE CEP will continue to maintain: (1) Astringent candidate selection system; (2) comprehensive trainee guidance by a primary mentor; (3) supportthrough a scientific mentoring group (each awardees Individual Trainee Mentorship Committee) comprised ofinvestigators with expertise in each awardees area of interest; and (4) full integration into the SPOREincluding access to all scientific Cores. Mayo Clinic provides an exceptional environment for developingcareers in translational research in ovarian cancer. The CEP allows us to identify mentor and support younginvestigators who will become future leaders in ovarian cancer research. +No NIH Category available Advisory Committees;Award;Cancer Patient;Chicago;Clinic;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Communities;Creativeness;Data;Development;Direct Costs;Disabled Persons;Disease;Extramural Activities;Facilities and Administrative Costs;Fostering;Funding;Goals;Grant;Human Resources;Individual;Institution;Intervention;Laboratory Study;Letters;Malignant neoplasm of ovary;Mayo Clinic Cancer Center;Measures;Minnesota;Minority;Monitor;Ovarian;Patient advocacy;Patients;Peer Review;Pilot Projects;Policies;Population;Population Study;Process;Program Research Project Grants;Publications;Qualifying;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Stimulus;System;Testing;Translating;Translational Research;United States National Institutes of Health;Universities;Woman;Work;anticancer research;base;clinically relevant;experience;improved;innovation;interdisciplinary collaboration;interest;originality;programs;research and development;sound;success;timeline;translational goal;translational pipeline;translational potential Development Research Program NARRATIVE DEVELOPMENTAL RESEARCH PROGRAM (DRP)The Developmental Research Program supports young investigators or those new to ovarian cancer researchwith the goal of identifying promising pilot studies. The objective of these preliminary studies is to generatenew ideas that could be tested in larger projects or in clinical trials for ovarian cancer patients. NCI 10705054 9/8/23 0:00 PAR-18-313 5P50CA136393-13 5 P50 CA 136393 13 7/1/09 0:00 8/30/26 0:00 ZCA1-RPRB-8 8890 6405112 "CLIBY, WILLIAM A" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 147870 93000 54870 ABTRACT DEVELOPMENTAL RESEARCH PROGRAM (DRP)The purpose of the Developmental Research Program (DRP) in the Mayo Clinic SPORE in Ovarian Cancer isto support innovative scientifically sound research projects from which findings can be translated into clinicallyrelevant interventions that will reduce the burden of ovarian cancer. This program has been highly successfulwith support going to 38 DRP projects in Years 6-10. Among the DRP project teams 21 (11 funded in Years 1-5 and 10 funded in Years 6-10) have received additional funding outside of the SPORE in Years 6-10 based ontheir DRP project and 5 provided data instrumental for the selection of the full research projects in this renewal.In our second funding period the DRP generated 74 associated publications and contributed to 7 SPORE-associated clinical trials. We will build on the successes of our SPORE DRP which has attracted investigatorsnew to ovarian cancer research who ultimately became co-Leaders or co-Investigators of full Projects includedin this SPORE application Core co-Leaders or were awarded NIH funding outside of the SPORE. The DRPwill 1) foster innovative laboratory population and clinical study proposals that have strong translationalpotential; 2) encourage and support interdisciplinary collaboration in translational research in ovarian cancer;and 3) generate new hypotheses that can be tested in larger scale research projects or clinical trials in ovariancancer. The DRP will provide $200000 annually ($100000 from the SPORE and a matching $100000 fromMayo Clinic) to support at least 4 meritorious projects with $50000 each to be used within one year. Inaddition between August 2014 and July 2020 we raised philanthropic support for ovarian cancer research atMayo Clinic that supported 18 DRP awards above and beyond the 20 originally projected during Years 6-10;and we will continue to seek additional support for ovarian cancer research in the years to come. Dependingon the progress of any given project the possibility of a second year of support exists via competitive review ofboth new and continuation projects. The DRP will continue to utilize a defined process to call for applicationson an annual basis and to review submissions utilizing the expertise of the Internal Scientific AdvisoryCommittee Executive Committee Patient Advocacy Advisory Committee and other experienced investigatorsas needed. Criteria for DRP awards include: The likelihood that the work will impact major challenges inovarian cancer scientific merit originality translational potential qualifications of the key personnel andinteractivity. As experienced in our second funding period it is anticipated that support of DRP projects throughthis program will generate new hypotheses that progress to full SPORE translational projects or to peer-reviewed external grant support. +No NIH Category available 3-Dimensional;Address;Affect;Animal Model;Antitumor Response;BRCA mutations;Base Excision Repairs;Bioinformatics;Biological Assay;Biological Markers;Biometry;CRISPR screen;Cancer Patient;Cancer cell line;Cell Line;Clinic;Clinical;Code;Cohort Studies;Correlative Study;DNA Damage;DNA Repair;DNA Repair Gene;DNA Repair Pathway;Data;Defect;Development;Disease;Disease Resistance;Dose;Drug Kinetics;Excision;Excision Repair;FDA approved;Future;Gene Mutation;Genes;Genotype;Goals;Immune system;Immunocompetent;In Vitro;Individual;Libraries;Maintenance Therapy;Malignant neoplasm of ovary;Mitochondria;Modeling;Mus;Mutation;Non-Small-Cell Lung Carcinoma;Oxidative Phosphorylation;Pathway interactions;Patient Selection;Patients;Pharmaceutical Preparations;Phase;Phase Ib Clinical Trial;Phase Ib Trial;Phenotype;Phosphotransferases;Plasma;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Process;Production;Progression-Free Survivals;Protein Tyrosine Kinase;Proteins;Reactive Oxygen Species;Recurrence;Relapse;Reporting;Resistance;Respiration;Safety;Sampling;Serous;Therapeutic;Time;Toxic effect;Woman;XRCC1 gene;base;biomarker identification;brca gene;cancer cell;cancer therapy;cohort;cytotoxic;cytotoxicity;design;homologous recombination;improved outcome;in vivo;in vivo Model;inhibitor;insight;kinase inhibitor;loss of function;novel;novel therapeutics;partial response;patient derived xenograft model;patient registry;phase II trial;potential biomarker;preclinical study;predicting response;prevent;repaired;response;response biomarker;safety assessment;small molecule;synergism;tissue culture;tumor Project 3: Repurposing Ceritinib for Ovarian Cancer Therapy NARRATIVE PROJECT 3Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been FDA approved as maintenance therapy toextend progression-free survival in ovarian cancer. Here we study the effect of combining PARP inhibitors withan FDA-approved drug (the ALK inhibitor ceritinib) that is not currently used to treat high-grade serous ovariancancer (HGSOC). Based on a novel mechanism of action we have discovered and the synergistic activity ofthe ceritinib + PARP inhibitor combination we propose additional preclinical studies to better understand themechanism by which this combination kills ovarian cancer cells in tissue culture and in ovarian cancer patient-derived xenografts in vivo. In addition we propose to perform a phase 1b clinical trial of ceritinib in combinationwith the PARP inhibitor olaparib with an expansion phase in HGSOC to assay toxicity assess potential activityand explore biomarkers of response identified in the mechanistic and PDX studies. NCI 10705048 9/8/23 0:00 PAR-18-313 5P50CA136393-13 5 P50 CA 136393 13 7/1/09 0:00 8/30/26 0:00 ZCA1-RPRB-8 5392 1921891 "KARNITZ, LARRY M" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 237155 149154 88001 ABSTRACT PROJECT 3The 5-year survival for advanced high-grade serous ovarian cancer (HGSOC) is <30%. The introduction ofpoly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) has increased progression-free survival in patientsand may increase overall survival in some patients; however the emergence of PARPi-resistant disease is anescalating clinical problem. Accordingly there is a pressing need to identify novel therapies that enhance PARPiactivity in HGSOC. Here we show that ceritinib a small molecule kinase inhibitor approved for the treatment ofALK-positive non-small cell lung cancer synergizes with PARPis. This synergy is not due to ceritinib-induceddisruption of homologous recombination (HR) or ALK inhibition. Instead ceritinib synergizes with PARPis atleast in part by inhibiting mitochondrial respiration which induces the production of reactive oxygen species(ROS) and consequent induction of DNA damage that is repaired via the PARP-dependent base excision report(BER) pathway. Consistent with this mechanism of action we show that a ceritinib + PARPi combination issynergistic in HR-proficient and -deficient ovarian cancer cell lines. Moreover in HGSOC patient-derivedxenograft (PDX) models ceritinib + olaparib (C+O) induces tumor regressions and extends mouse survival moreeffectively than olaparib alone. These observations raise the possibility that C+O will extend progression-freesurvival or prevent the emergence of PARPi resistance in HGSOC. Despite this progress it remains uncleari) whether C+O can be safely given to patients ii) whether C+O has activity against HGSOC in patients andiii) how to identify the ovarian cancers that will be most responsive to C+O. To begin the process of repurposingceritinib for ovarian cancer we propose to i) perform a phase Ib trial of C+O with an expansion cohort andcorrelative studies in platinum-sensitive relapsed ovarian cancer; ii) identify genes and pathways including DNArepair pathways that affect C+O cytotoxicity in order to provide additional insight into the action of thiscombination and potentially identify biomarkers of response; and iii) use PDX models to assess potentialgenotypic and phenotypic differences that correlate with antitumor responses to C+O. The overarching goals ofthese studies are to better understand the mechanism(s) of action of the C+O combination and identify ovariancancers most likely to respond to this combination in a future phase II trial in HGSOC. These studies whichutilize the Biospecimens Biostatistics and Bioinformatics and Animal Models Cores are designed to facilitatethe repurposing of ceritinib in combination with PARPis as a new therapy to improve the outcomes of PARPi-treated HGSOC. +No NIH Category available ABCG2 gene;Address;Affect;Animal Model;Antibodies;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Biochemical;Bioinformatics;Biological Markers;Biometry;Biopsy;CRISPR screen;Cancer Model;Cancer Patient;Cell Line;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;DNA Damage;DNA Repair Enzymes;Development;Diagnostic Reagent;Disease;Disease Resistance;Dose;Epithelial ovarian cancer;Excision;Exhibits;FDA approved;Failure;Formulation;Generations;Genes;Genetic;Genomics;Germ-Line Mutation;In Vitro;Infusion procedures;Investigation;Laboratories;Maintenance Therapy;Malignant neoplasm of ovary;Mammalian Oviducts;Marrow;Modeling;Mutation;NKTR gene;Neoplasm Circulating Cells;Neoplasms;Ovarian;PARP inhibition;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Polyethylene Glycols;Polymerase;Pre-Clinical Model;Process;Prodrugs;Progression-Free Survivals;Recurrence;Refractory;Regimen;Relapse;Reporting;Resistance;SN-38;Sampling;Schedule;Serous;Site;Somatic Mutation;Testing;Therapeutic;Topoisomerase I inhibition;Topoisomerase-I Inhibitor;Topotecan;Toxic effect;Type I DNA Topoisomerases;Woman;antibody detection;antitumor effect;bevacizumab;cell free DNA;cell killing;chemosensitizing agent;clinical practice;cohort;cytotoxicity;design;drug action;efficacy evaluation;genomic profiles;homologous recombination;improved;in vivo;inhibitor;insight;irinotecan;nanoparticle;neoplastic cell;next generation;novel therapeutics;overexpression;patient derived xenograft model;peritoneal cancer;phase II trial;pre-clinical;preclinical study;protein expression;recombinational repair;resistance mechanism;response;synergism;treatment response;tumor Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian Cancer NARRATIVE PROJECT 2Treatment options are limited for women whose ovarian cancer has become resistant to platinum drugs andPARP inhibitors. Clinical studies have shown that prolonged schedules of DNA topoisomerase I (TOP1) inhibitorscan be effective in some platinum-resistant ovarian cancers. Our preclinical studies have also shown that PARPinhibitors can enhance the antitumor effects of TOP1 inhibitors in vitro and in ovarian cancer patient derivedxenograft (PDX) models despite resistance to the antitumor effects of PARP inhibitor alone. These observationswhich reflect the fact that PARP inhibition and PARP inhibitor-induced tumor cell killing are related but separableprocesses provide the opportunity to use PARP inhibitors as chemosensitizing agents in ovarian cancers thatare PARP inhibitor resistant. Accordingly this project will study the action of a promising 3rd generation ultra-long acting TOP1 inhibitor PLX038 in combination with the PARP inhibitor rucaparib in preclinical models andin a phase II clinical trial in platinum- and PARP inhibitor-resistant high grade serous ovarian cancer. NCI 10705044 9/8/23 0:00 PAR-18-313 5P50CA136393-13 5 P50 CA 136393 13 7/1/09 0:00 8/30/26 0:00 ZCA1-RPRB-8 5391 1861030 "KAUFMANN, SCOTT H" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 262125 164859 97266 ABSTRACT PROJECT 2 Inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) are highly active in homol-ogous recombination (HR)-deficient ovarian cancers especially those with BRCA1 or BRCA2 (BRCA1/2) muta-tions. Even in this setting however 40-80% of cases become PARP inhibitor (PARPi) resistant most often asa result of genetic or biochemical changes that restore HR. Among other genomic subsets of ovarian cancerPARPi resistance is even more prevalent. The observation that most common mechanisms of acquired PARPiresistance do not result from a failure to inhibit PARP1 raises the possibility that PARPis can potentially beutilized as chemosensitizing agents in this setting if suitable combinations can be identified. Accordingly thepresent project seeks to enhance the efficacy of the PARPi rucaparib and extend its use by combining it with a3rd generation topoisomerase I (TOP1) inhibitor (TOP1i). Recent studies have shown that nanoparticleformulations such as PLX038 a polyethylene glycol-conjugated ultra-long acting form of the TOP1i 7-ethyl-10-hydroxycamptothecin (SN-38) exhibit less marrow toxicity and greater efficacy than conventional TOP1is inpreclinical cancer models. Our preliminary studies show that sustained release TOP1is including PLX038 areactive against five of seven PARPi-resistant ovarian cancer patient-derived xenografts (PDXs) tested. Moreoverusing a unique antibody that detects TOP1-DNA covalent complexes (TOP1ccs) which are intermediates in theTOP1i-induced killing process we have shown that TOP1ccs are diminished or undetectable in PDXs that areresistant to the TOP1i/PARPi combination providing a starting point for understanding ovarian cancer resistanceto this treatment. Collectively these results lead to the hypothesis that a readily identifiable subset of HR-proficient ovarian cancers will exhibit sustained antitumor effects when treated with a next generationTOP1i alone or in combination with a PARPi. To test this hypothesis we now propose to i) assess the efficacyof PLX038 alone and in combination with the PARPi rucaparib in a cohort of genomically profiled high gradeserous ovarian cancer PDXs with intrinsic or acquired resistance to single agent PARPis to identify the spectrumof ovarian cancers that could potentially benefit from PLX038 or the combination; ii) identify mechanisms ofresistance to the TOP1i/PARPi combination in PDXs and cell lines; and iii) examine the association between theformation of drug-stabilized TOP1-DNA covalent complexes in tumor cells and the response of ovarian cancerpatients to the PLX038/rucaparib combination in a phase II clinical trial. Collectively these studies will not onlyprovide insight into the genomic and biochemical factors that affect response to a 3rd generation TOP1i in ovariancancer but also determine whether it is possible to use PARPis as chemosensitizing agents in settings wherethey are no longer active as single agents. If successful this project will point to a new therapy for the growingnumber of women with PARPi-resistant ovarian cancer. +No NIH Category available Advisory Committees;Advocate;Clinic;Clinical Management;Clinical Trials;Collaborations;Collection;Communication;Communities;Detection;Development;Disease;Funding;Goals;Infrastructure;Leadership;Malignant Neoplasms;Malignant neoplasm of ovary;Mayo Clinic Cancer Center;Methods;Minority;Monitor;Occupational activity of managing finances;Ovarian;Patient advocacy;Performance;Population Research;Prevention;Procedures;Progress Reports;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Structure;Translational Research;Translations;Woman;Work;career;design;innovation;meetings;member;programs;recruit;research and development;research study Administration Core NARRATIVE ADMINISTRATIVE COREThe Administration Core provides the organizational infrastructure necessary to perform the work proposed inthis SPORE application. NCI 10705035 9/8/23 0:00 PAR-18-313 5P50CA136393-13 5 P50 CA 136393 13 7/1/09 0:00 8/30/26 0:00 ZCA1-RPRB-8 8883 1861030 "KAUFMANN, SCOTT H" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 127579 80238 47341 ABSTRACT ADMINISTRATIVE COREThe overall goals of the Mayo Clinic SPORE in Ovarian Cancer are to stimulate innovative research in ovariancancer and to expedite the translation of discoveries into new and better methods of prevention detection andtreatment of this disease. The Administrative Core has facilitated progress toward these goals by serving as theorganizational hub of the Mayo Ovarian SPORE during Years 6-10 of funding. Major changes during the past 5years have included the i) development of a new co-leader Jamie Bakkum-Gamez for the Core andii) recruitment of several new External Advisory Board (EAB) Members reflecting new directions in the SPOREprojects. During the next funding period (Years 11-15) the Administrative Core will continue to provideorganizational and communications support for the SPORE leadership research projects scientific cores anddevelopmental programs [Developmental Research Program (DRP) and Career Enhancement Program (CEP)].Specifically the Administrative Core will: 1) Provide leadership and organizational support to SPOREinvestigators; 2) oversee formal procedures for scientific review of SPORE research projects; 3) oversee andfacilitate the efforts of all cores; 4) manage and coordinate SPORE fiscal activities; 5) monitor accrual includingminority accrual to all Mayo Ovarian SPORE clinical trials population research studies and biospecimencollections; 6) provide guidance and administrative support to the DRP and CEP leadership; 7) facilitate theactivities of the Executive Committee and implement its decisions; 8) facilitate engagement of the SPOREadvocates; 9) facilitate reviews of the SPORE by the EAB and Internal Scientific Advisory Committee (ISAC);10) organize monthly SPORE scientific meetings seminars and the annual retreat; 11) assure ongoingintegration of the Ovarian SPORE with the Mayo Clinic Cancer Center and its Womens Cancer Program;12) serve as the administrative liaison between the Mayo Ovarian SPORE the NCI SPORE Program otherMayo SPOREs and external collaborators; 13) identify and catalyze research collaborations in ovarian cancerincluding collaborations with the other Ovarian SPOREs; 14) communicate SPORE-related researchdevelopments and opportunities to Mayo investigators; and 15) assist the SPORE Director in preparing reportsof Ovarian SPORE activities including annual progress reports and the competitive renewal application. +No NIH Category available Acceleration;Adjuvant;Adoptive Immunotherapy;Allogenic;Animal Model;Basic Science;Biochemical;Bioinformatics;Biological;Biometry;Biostatistics Core;Cancer Biology;Cancer Model;Cancer Patient;Cancer Therapy Evaluation Program;Cancer cell line;Cellular immunotherapy;Cessation of life;Clinic;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Collaborations;Complementary DNA;DNA Repair Pathway;Data;Dendritic Cell Vaccine;Dendritic Cells;Development;Disease;Enrollment;Epithelial ovarian cancer;FDA approved;FOLR1 gene;Fostering;Funding;Future;Generations;Genes;Genomics;Goals;Grant;Homing;Immune;Immune response;Immune system;Immunologic Stimulation;Immunotherapy;Leadership;Malignant Female Reproductive System Neoplasm;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mammalian Oviducts;Mediating;Mentors;Metformin;Methods;Minnesota;Mission;Mitochondria;Natural Killer Cells;Organ;Ovarian;Pathway interactions;Patients;Peer Review;Peptides;Peritoneum;Phase I Clinical Trials;Phenotype;Physiologic pulse;Pilot Projects;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Publications;Reactive Oxygen Species;Recurrence;Relapse;Research;Research Personnel;Research Project Grants;Resistance;Resources;Respiration;Serous;Signal Transduction;Survival Rate;TOP1 gene;Techniques;Testing;Therapeutic;Therapeutic Agents;Therapeutic Studies;Therapeutic Trials;Translational Research;United States National Institutes of Health;Universities;Vaccines;Woman;anticancer research;cancer therapy;career;cellular engineering;design;effective therapy;follow-up;homologous recombination;improved;inhibitor;innovation;insight;kinase inhibitor;mTOR Inhibitor;mortality;next generation;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;patient registry;peritoneal cancer;phase 1 study;phase I trial;phase II trial;pre-clinical;programs;research clinical testing;safety testing;taxane;transcriptomics;translational pipeline;translational research program;translational scientist;treatment response;tumor;tumor microenvironment;vaccine response;vaccine strategy Mayo Clinic Ovarian Cancer SPORE NARRATIVE OVERALLWith an estimated 22000 new cases and 14000 deaths each year cancer of the ovary fallopian tube orperitoneum (termed ovarian cancer in this application) remains the most lethal of the gynecologicalmalignancies. The Mayo Clinic SPORE in Ovarian Cancer provides support for translational research projectsthat are intended to have a rapid impact for ovarian cancer patients. Specifically we will develop and test fournovel therapeutic approaches designed to i) stimulate the immune system (Project 1) ii) introduce a NextGeneration TOP1 inhibitor for ovarian cancer (Project 2) iii) repurpose the FDA-approved kinase inhibitorceritinib as an ovarian cancer therapeutic (Project 3) and iv) provide a new form of adoptive immune cell therapy(Project 4). NCI 10705034 9/8/23 0:00 PAR-18-313 5P50CA136393-13 5 P50 CA 136393 13 "BASA JANAKIRAM, NAVEENA" 7/1/09 0:00 8/30/26 0:00 ZCA1-RPRB-8(M1)P 1861030 "KAUFMANN, SCOTT H" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1752990 NCI 1207893 545097 PROJECT SUMMARY OVERALLThis revised application of the Mayo Clinic SPORE in Ovarian Cancer (OC) builds on translational research con-ducted during Years 6-10 of funding. Our accomplishments over the past five years include i) identification of aunique vaccine strategy that in a phase I study led to 39% recurrence free survival at 49 months in high gradeserous OC ii) new understanding of the genomic and biochemical changes that limit the action of PARPinhibitors (PARPis) in OC iii) distribution of over 9600 biospecimens for OC research and iv) publication of 220articles. The Developmental Research Program (DRP) has contributed to two of the four projects in this renewal;and the Career Enhancement Program (CEP) contributed to leadership of two projects. The overall goal of theSPORE remains to support innovative interactive translational OC research that leverages the expertise of bas-ic and translational investigators. This renewal contains four translational projects designed to investigate OCbiology and enhance therapeutic response building on recent clinical advances and promising preclinical results: P1 (Development of a Th17-Inducing Dendritic Cell [DC] Vaccine for OC): Based on our study showing that DCs pulsed with Folate Receptor peptides and matured to a Th17-inducing phenotype induced immune re- sponses in all patients and long-term recurrence-free survival in 39% we will identify determinants of long- term vaccine response in a phase II trial and elucidate mechanisms of immune escape from this vaccine. P2 (Next Generation TOP1 Inhibition for the Treatment of OC): Building on our observation that TOP1 inhib- itors are active in PARPi-resistant OC models and this activity can be enhanced by PARPi treatment even in the face of PARPi resistance this project will identify determinants of sensitivity to TOP1 inhibitor/PARPi combinations and conduct a phase II trial of the ultra-long acting TOP1i PLX038 with the PARPi rucaparib. P3 (Repurposing Ceritinib for OC Therapy): Based on the finding that ceritinib a kinase inhibitor used for ALK- rearranged lung cancer inhibits mitochondrial respiration increases reactive oxygen species and sensitizes OC cell lines and PDXs to PARPis independent of ALK status we will identify pathways that mediate these effects and conduct a phase I trial of the ceritinib/olaparib combination. P4 (Treatment of Advanced OC Using Gene-Edited CAR NK Cells): Building on a prior developmental research project this team located at the University of Minnesota will apply advanced cellular engineering techniques to generate activated NK cells with enhanced tumor homing and persistence then test the safety and efficacy of administering this allogeneic adoptive immunotherapy in a phase I clinical trial in platinum-resistant OC.These impactful projects are supported by four highly interactive cores: Core A (Administrative) Core B (Biospec-imens/Patient Registry) Core C (Biostatistics/Bioinformatics) and Core D (Animal Models). A DRP and CEP willbe used to nurture the next generation of translational OC investigators. Collectively these SPORE activities willprovide new insight into OC biology while examining potential therapeutic advances for this lethal disease. 1752990 +No NIH Category available ARID1A gene;Admixture;Advanced Malignant Neoplasm;Affect;African;Asian;Asian population;Award;Behavioral;Biological;Black Populations;Black race;Breast;CTNNB1 gene;Cancer Etiology;Case/Control Studies;Cessation of life;Characteristics;Cirrhosis;Clinic;Clinical Data;Colon;Communities;DNA Sequence Alteration;Data;Data Analyses;Data Set;Diagnosis;Disease;Disparity;Educational workshop;Enrollment;Epidemiologic Factors;European;Fibrosis;Financial Hardship;Florida;Foundations;Funding;Future;Genes;Genetic;Genetic Determinism;Genetic Variation;Genetic study;Genome;Genomics;Genotype;Goals;Haplotypes;Hepatobiliary;Hispanic;Hispanic Populations;Individual;Inflammation;Institution;Internships;K-Series Research Career Programs;Knowledge;Laboratories;Link;Liver diseases;Malignant Neoplasms;Malignant neoplasm of liver;Mentors;Mentorship;Minority;Modeling;Mutate;Native American Ancestry;Native Americans;Not Hispanic or Latino;Outcome;Participant;Pathway interactions;Patient-Focused Outcomes;Patients;Performance;Persons;Phenotype;Physicians;Population;Population Heterogeneity;Prevalence;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Prognosis;Prospective cohort;Prostate;Race;Research;Research Personnel;Risk;Risk Factors;Scientist;Survival Analysis;TP53 gene;The Cancer Genome Atlas;Time;Training;Training Activity;Tumor Biology;United States;United States National Institutes of Health;biobank;cancer risk;cancer survival;chromosomal location;chronic liver disease;clinical epidemiology;clinical phenotype;cohort;disorder control;ethnic minority;experience;gene environment interaction;genetic analysis;genetic epidemiology;hazard;health care disparity;health disparity;hepatobiliary cancer;high risk;improved;innovation;mortality;multidisciplinary;novel;patient oriented;patient oriented research;personalized approach;phenotypic data;precision medicine;predictive modeling;prognostication;progression risk;racial difference;racial disparity;racial minority;risk prediction model;risk stratification;risk variant;screening;skills;social determinants;social factors;social health determinants;socioeconomic diversity;survival disparity;survival prediction;tool;treatment strategy The Impact of Genetic Ancestry on Racial Disparities in Hepatocellular Carcinoma Risk and Mortality PROJECT NARRATIVEHepatocellular carcinoma (HCC) also known as primary liver cancer disproportionately affects minorities andthe burden of this deadly disease has increased significantly. The proposed study will determine if geneticdifferences in African European or Native American ancestry are responsible for the significant racialdifferences in liver cancer risk and survival either directly or indirectly by interacting with other risk factors orsocial factors. Understanding which genetic features increase liver cancer risk or worsen survival couldpotentially improve our ability to (1) identify those people who are at highest risk and (2) develop screening andtreatment strategies that are based on a persons individualized risk. NCI 10705026 9/6/23 0:00 PAR-18-337 5K08CA255413-02 5 K08 CA 255413 2 "RODRIGUEZ, LARITZA MARIA" 9/15/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 11113614 "JONES, PATRICIA DENISE" Not Applicable 27 INTERNAL MEDICINE/MEDICINE 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 237065 NCI 219505 17560 PROJECT SUMMARYHepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the United States and worldwide.There are significant racial disparities in HCC risk. Blacks Hispanics and Asians all have increased risk of HCCcompared to non-Hispanic Whites. Also Blacks consistently have the lowest survival after HCC diagnosis. Likelygenetic variation and gene-environment interactions modify HCC risk and may also contribute to racialdifferences in HCC survival. The objective of this proposal is to leverage our established cohort of diversepatients with chronic liver disease cirrhosis and HCC to identify how genetic variation including geneticancestry drives disparities in HCC risk and mortality in the context of known risk factors and social determinantsof health. This career development award will provide Dr. Patricia Jones a skilled hepatologist with experiencein clinical epidemiology with the opportunity to gain additional training in genetic epidemiology genetic analysislongitudinal data analysis and predictive modeling. Understanding how genetic ancestry drives HCC riskand outcomes is the first step towards identifying specific ancestry-associated genes and pathways thatare linked to increased risk and/or poor survival. In Aim 1 we will define the relationship between geneticancestry and HCC risk by genotyping 200 participants with HCC 400 participants with chronic liver disease cirrhosis and 400 healthy controls from the NIH All of Us study. We will define how HCC risk differs based ongenetic ancestry across the genome (global) and at specific chromosomal locations for commonly mutated genesin HCC e.g. TERT ARID1A RB CTNNB1 TP53 PNPLA3 and IDH1/2. We will also explore new genetictargets as they emerge from ongoing genetic studies. We will build and validate an HCC risk-prediction modelthat incorporates genetic ancestry. By integrating genetic and clinical data with individual social factors and socialdeterminants of health the proposed project will improve our ability to accurately predict HCC risk. Bydistinguishing patients at highest risk our risk stratification tool could transform the current HCC screeningparadigm. In Aim 2 we will use genotype data from 200 participants with HCC to develop a survival predictionmodel that incorporates genetic ancestry social determinants and clinical data. We will validate the final survivalmodel in two separate cohorts of HCC patients. The knowledge gained from our comprehensive survival analysisin Aim 2 will improve our understanding of the genetic determinants of survival disparities and could lead to moreprecise estimates of prognosis a key patient-centered outcome. The formal and experiential training receivedthrough coursework internships and workshops will enable Dr. Jones to develop an ancestry-informed HCC riskprediction model that will form the basis of a future R01 application. With guidance from a strong multidisciplinarymentoring team with expertise in tumor biology hepatobiliary malignancies genetic epidemiology and socialdeterminants Dr. Jones will develop new and complementary skills enabling her to become an independentinvestigator who conducts integrative patient-oriented research that bridges the community clinic and laboratory. 237065 +No NIH Category available Acceleration;Alleles;Amino Acid Substitution;Animal Cancer Model;Animal Model;Behavior;Biology;Breeding;Cancer Etiology;Cancer Model;Cell division;Cessation of life;Clinical;Colitis;Collaborations;Community Clinical Oncology Program;Cryopreservation;DNA Polymerase II;DNA Sequence Alteration;DNA biosynthesis;DNA-Directed DNA Polymerase;Development;Dextran Sulfate;Endometrial Carcinoma;Exhibits;Frequencies;Generations;Genetic;Genetic Engineering;Genetically Engineered Mouse;Genomics;Growth;Hereditary Nonpolyposis Colorectal Neoplasms;Histology;Housekeeping;Human;Immune response;Inflammation;Inflammatory Bowel Diseases;Inherited;Intestinal Cancer;Intestinal Diseases;Intestinal Neoplasms;Intestinal Polyposis;Intestines;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Methods;Mismatch Repair;Mismatch Repair Gene Inactivation;Modeling;Monitor;Morphology;Mus;Mutation;Mutation Spectra;Organoids;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Polymerase;Process;Role;Survival Analysis;Tissues;Translational Research;Tumor Biology;Woman;aged;base;behavioral response;beta catenin;checkpoint therapy;gastrointestinal;gastrointestinal carcinoma;genome sequencing;improved;interest;men;model building;mouse model;neoantigens;novel;response;tool;transcriptome sequencing;translational cancer research;translational model;treatment response;tumor;tumor behavior;tumor heterogeneity;tumor progression;whole genome Polymerase epsilon-based mouse and derived organoid models of intestinal cancer PROJECT NARRATIVEA major limitation of animal models of intestinal cancer is their inability to recapitulate the high mutation(base substitution) rates inherent to human intestinal cancers which define many aspects of tumor biologyand clinical behavior. Here we propose to efficiently overcome this constraint by recapitulating theultramutator phenotype recently described in a wide range of human malignanciesparticularlygastrointestinal cancersand study the impact of induced inflammation on this novel intestinal cancer model.This project will catalyze the creation of a wide range of intestinal cancer mouse models that are effectivelyhumanized with respect to mutation rate ennabling a wide range of translational investigations. NCI 10705025 9/1/23 0:00 PAR-20-131 5R01CA265884-02 5 R01 CA 265884 2 "WATSON, JOANNA M" 9/15/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-OTC1-J(55)R] 6099001 "CASTRILLON, DIEGO H" Not Applicable 30 PATHOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 484055 NCI 295156 188899 PROJECT SUMMARY/ABSTRACT Intestinal cancer is the 3rd most common malignancy and cause of cancer-related deaths in both men andwomen. Unfortunately recent advances in our understanding of the underlying intestinal biology and cancer-related pathways have not translated to significantly improved patient outcomes. While numerous animalmodels of intestinal cancer have been developed mostly based on misregulation of the -catenin pathwaysome key features of human cancers (particularly tumor mutational burden) now known to be critical for tumorprogression and therapy response have not been adequately modelled or investigated in animal models ofintestinal cancer. More recently genome sequencing efforts led to the discovery of an intestinal cancer mutator phenotypewhere single amino acid substitutions within proofreading domains of the housekeeping DNA polymerasesresult in the highest mutation rates described in human cancers (ultramutation). Unlike human cancers genetically-engineered animal models exhibit very low mutation rates limiting theirutility for studies of intratumoral heterogeneity and competition immune responses and immune checkpointtherapies now known to be essential aspects of human tumor biology. We propose to overcome theselimitations in intestinal cancer animal models by building upon 1) a strong track record in the generation ofcancer animal models and novel genetic tools for their development 2) a well-characterized conditional PoleP286Rallele that we previously used to develop a robust model of endometrial cancer and 3) expertise in genomicsinflammation intestinal cancer and mouse models of intestinal disease. These models will be useful not onlyto recapitulate POL-driven intestinal cancers but also to humanize any intestinal cancer mouse model withrespect to mutational burden. This proposal is submitted in response to PAR-20-131 to expand and improve thedevelopment of mammalian models for translational cancer research. 484055 +Cancer Data;Data Analytics;Methodology;National Cancer Institute;SEER Program;cohort;design SPECIALIZED ANALYTIC DATA SUPPORT for SEER-MHOS DATA EXPANSIONS n/a NCI 10704983 75N91021F00279-P00003-0-1 N02 9/24/21 0:00 9/23/23 0:00 78388091 "BOGGS, ABBEY " Not Applicable 4 Unavailable 4868105 JJHCMK4NT5N3 4868105 JJHCMK4NT5N3 US 35.9138 -78.848911 6939101 RESEARCH TRIANGLE INSTITUTE RESEARCH TRIANGLE PARK NC Research Institutes 277092194 UNITED STATES N R and D Contracts 2022 187891 NCI The purpose of this solicitation is to obtain specialized analytic data support to demonstrate the utility of recentSEER-MHOS data expansions and to investigate new methodological approaches taking advantage of the MHOSrepeated multi-cohort design. 187891 +No NIH Category available Actins;Adjuvant Chemotherapy;Aftercare;Anatomy;Animal Model;Award;Behavior;Biology;Blood Vessels;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Carcinoma;CSF1 gene;Cancer Etiology;Cell Communication;Cells;Cellular biology;Chemoresistance;Clinical;Collaborations;Coupled;Cyclophosphamide;Development;Dichloromethylene Diphosphonate;Disseminated Malignant Neoplasm;Distant;Doxorubicin;Education;Endothelial Cells;Ensure;Environment;Ephrins;Frequencies;Funding;Generations;Genetic;Goals;Hematogenous;Histopathology;Imaging Device;Immune;In Vitro;Infiltration;Intervention;Laboratories;Literature;Lung;MDA MB 231;Macrophage;Mammary Neoplasms;Mediating;Medicine;Mentors;Metastasis Induction;Metastatic Neoplasm to the Lung;Microanatomy;Microscopy;Modality;Modeling;Molecular;Mus;Neoadjuvant Therapy;Neoplasm Circulating Cells;Neoplasm Metastasis;Outcome;Paclitaxel;Pathway interactions;Patients;Phase;Phenotype;Physicians;Primary Neoplasm;Property;Protein Isoforms;Publications;Reporter;Research;Role;Scientist;Secondary to;Signal Pathway;Signal Transduction;Site;Stem Cell Research;System;Testing;Touch sensation;Training;Transgenic Animals;Transgenic Organisms;Translational Research;Transplantation;Tumor-associated macrophages;Universities;Xenograft procedure;cancer cell;cancer stem cell;career development;chemotherapy;clinical care;college;conditional knockout;density;design;experimental study;genetic regulatory protein;improved;in vitro Assay;in vivo;inhibitor;interest;intravital imaging;malignant breast neoplasm;metastatic process;microscopic imaging;mortality;mouse model;multi-photon;multiphoton microscopy;neoplastic cell;notch protein;novel diagnostics;novel therapeutics;patient derived xenograft model;pharmacologic;predictive marker;recruit;response;side effect;stem;stem cell biology;stem cell biomarkers;stem cell niche;stem cells;stemness;tissue fixing;tool;translational medicine;treatment strategy;tumor;tumor growth;tumor initiation;tumor microenvironment Prometastatic Effects of Neoadjuvant Chemotherapy in Breast Cancer Project NarrativeThis project investigates the underlying mechanisms related to the acquisition of de novo pro-metastaticproperties in breast tumor cells after treatment with neo-adjuvant chemotherapy. Outcomes will reveal how thetumor microenvironment influences the generation of cancer cell subpopulations that have the ability to bothdisseminate and seed a new tumor at the metastatic site. Findings will be applied toward new diagnostic andtherapeutic tools for counteracting this unwanted side-effect of neo-adjuvant chemotherapy. NCI 10704749 8/29/23 0:00 PA-18-398 5R00CA237851-04 5 R00 CA 237851 4 "O'HAYRE, MORGAN" 9/14/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 12648238 "KARAGIANNIS, GEORGE S" Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 246673 NCI 148214 100786 Project SummaryMetastasis the dissemination of cancer cells from the primary tumor to secondary sites is the leading cause ofcancer-related mortality. Although chemotherapy improves overall survival in early breast cancer it does notprovide definite cure for metastasis. Paradoxically chemotherapy induces pro-metastatic changes in the tumormicroenvironment if given in the pre-operative (neo-adjuvant) setting. These pro-metastatic changes areprimarily initiated via infiltration of tumors by pro-angiogenic Tie2Hi macrophages which are essentialcomponents of cancer cell intravasation sites called Tumor MicroEnvironment of Metastasis (TMEM). Onlyinvasive and migratory cancer cell expressing MenaINV can disseminate via TMEM. In mouse mammarycarcinoma and patient derived xenografts neo-adjuvant chemotherapy increases (i) TMEM assembly (ii) thedensity of cancer cells expressing MenaINV (iii) the number of circulating tumor cells and (iv) lung metastases.This proposal will elucidate molecular mechanisms by which chemotherapy exerts these pro-metastaticchanges in the breast tumor microenviroment so that predictive biomarkers and targetable signaling pathwaysof chemotherapy-induced metastasis can be identified. We hypothesize that macrophages recruited totumors upon neo-adjuvant chemotherapy educate tumor cells not only to become dissemination-competent byinducing MenaINV expression through juxtacrine interactions but also to obtain tumor-initiating capabilitiesresponsible for tumor growth initiation at distant sites. In Aim 1 we will investigate whether macrophage-cancercell interaction is required for induction of MenaINV and MenaINV-mediated pro-metastatic phenotypes upontreatment with neo-adjuvant chemotherapy. This will be accomplished using established macrophage depletionstudies in vivo coupled with advanced microscopy. In Aim 2 we will investigate whether breast tumor cellsexpressing MenaINV-Hi also harbor stem cell capabilities. MDA-MB-231 cells expressing a fluorescent stem cellreporter (SORE6) will be used to generate xenografts for multiphoton intravital imaging microscopy and fixed-tissue multichannel immune-fluorescent microscopy and study the effects of neo-adjuvant chemotherapy ontumor cell stemness. Aim 3 is designed to unravel the signaling pathways responsible for the aforementionedpro-metastatic phenotypes. Transgenic and pharmacological inhibition mouse models targeting the relevantjuxtacrine pathways will be developed to eliminate macrophage-tumor cell interactions and study whetherthese pathways are instrumental in chemotherapy-induced metastasis. The research environment at the AlbertEinstein College of Medicine offers outstanding opportunities for collaborations scientific discussion andcareer development. The proposed studies and career development training coupled with an exceptional teamof Dr. Condeelis expert in advanced microscopy Dr. Oktay physician scientist Dr. Wakefield a pioneer instem cell research and Dr. Richard Stanley leader in macrophage biology will ensure that I achieve my goalof establishing a successful independently-funded lab at a major university. 246673 +No NIH Category available Affect;Anorexia;Antineoplastic Agents;Cachexia;Caloric Restriction;Cancer Biology;Cancer Model;Cancer Patient;Cell Death;Cell Signaling Process;Cells;Circulation;Communication;Consumption;Dependence;Desire for food;Desmoplastic;Development;Development Plans;Diet;Diet and Nutrition;Diet therapy;Dietary Factors;Dietary Fats;Dietary Intervention;Dietary Practices;Digestion;Drug Combinations;Drug Targeting;Educational process of instructing;Environment;Epidemiology;Exocrine pancreatic insufficiency;Extracellular Matrix;Fatty acid glycerol esters;Food;Foundations;Genes;Goals;Growth;Impairment;Intercellular Fluid;Learning;Lipid Peroxidation;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mentors;Metabolic;Metabolic Pathway;Metabolism;Molecular;Mus;Nutrient;Nutrient availability;Pancreatic Ductal Adenocarcinoma;Pancreatic enzyme;Patient Care;Patients;Peripheral;Polyunsaturated Fatty Acids;Positioning Attribute;Quality of life;Recommendation;Reducing diet;Research;Research Personnel;Research Proposals;Science;Scientist;Shapes;Stromal Cells;Survival Rate;Technology;Testing;Therapeutic;Tissues;Trace Elements Nutrition;Training;Translations;Treatment Efficacy;Work;cancer cell;cancer therapy;career development;chemotherapy;diet and cancer;dietary;enzyme replacement therapy;fatty acid metabolism;food restriction;improved;in vivo;inhibitor;lipid metabolism;lipidomics;metabolomics;mouse model;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;response;skills;stable isotope;standard of care;synergism;transcriptome sequencing;treatment response;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;wasting Understanding the effects of dietary interventions on pancreatic ductal adenocarcinoma therapy cancer Project NarrativePancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is associated with dysregulatedtumor and whole-body metabolism that impacts therapy and quality of life. An opportunity for better exploitingmetabolic vulnerabilities in PDAC for cancer treatment is to systematically examine how dietary interventionsimpact PDAC progression therapy responses and survival. This proposed research will elucidate themetabolic mechanisms underlying potential synergies between dietary factors and standard-of-care oremerging PDAC therapies in an effort to provide scientific evidence that can benefit patients with guidance onhow to best incorporate diet and nutrition into PDAC treatment. NCI 10704739 9/1/23 0:00 PA-20-188 5R00CA255928-03 5 R00 CA 255928 3 "XI, DAN" 4/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11626616 "LIEN, EVAN CHEN" Not Applicable 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 248982 NCI 131043 117939 Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment optionsthat has a five-year survival rate of <10%. PDAC progression is associated with dysregulated tumor and whole-body metabolism that impacts therapy and quality of life which has motivated research on how to best exploitmetabolic dependencies in PDAC for better cancer treatment. Nutrient utilization by cancer cells is regulated inpart by the availability of metabolites in the environment and the PDAC tumor microenvironment in particular ishighly desmoplastic consisting of stromal cells extracellular matrix and nutrient-poor interstitial fluid. Thesemicroenvironmental factors can impact therapy response suggesting that the efficacies of metabolism-targeteddrugs can be improved by manipulating components of the PDAC tumor microenvironment. One determinant ofmetabolite levels in the tumor microenvironment is diet and how diet affects cancer progression and treatmentis an important question for many patients. Since dietary recommendations to patients must be made in thecontext of therapies being received the value of any dietary intervention likely lies in its ability to enhance tumorresponses to cancer therapies. Understanding the molecular mechanisms that drive synergistic interactionsbetween diet and cancer therapies is critical for the translation of dietary recommendations into patient care. The main objective of this proposal is to identify dietary interventions that synergize with cancer therapiesto impair PDAC progression. Mouse PDAC models will be used to examine how different diets enhance theefficacies of standard-of-care FOLFIRINOX chemotherapy (Aim 1) lipid metabolism inhibitors in developmentfor cancer treatment (Aim 2) and inducers of ferroptosis a non-apoptotic form of cell death being explored forPDAC treatment (Aim 3). Mass spectrometry-based metabolomics and lipidomics stable isotope nutrient tracingand RNA sequencing will be used to determine how diet-mediated changes to nutrient levels in the tumormicroenvironment alter the metabolism of PDAC tumors to shape their responses to these therapies. Elucidatingthe metabolic mechanisms that underlie synergistic diet-drug combinations will provide scientific evidence thatcan benefit patients with guidance on how to best incorporate diet and nutrition into cancer therapy. The proposed training plan will help me transition into an independent academic position. A team ofoutstanding scientists will mentor me to help me achieve this goal: Dr. Tyler Jacks a leader in mouse cancermodels; Dr. Omer Yilmaz a leader in dietary effects on cancer progression; Dr. Caroline Lewis a leader in massspectrometry-based metabolomics and lipidomics technologies; and Dr. Brian Wolpin a leader in PDACepidemiology. My training plan also outlines activities that will help me cultivate mentors improve my scientificskillset improve science communication skills develop teaching and mentoring skills build my network andlearn lab management skills. Together the research proposal and career development plan will provide me withthe expertise needed to become a successful independent investigator and educator in the cancer biology field. 248982 +No NIH Category available Bar Codes;Bioinformatics;Biological Assay;Biological Markers;Biometry;Cell Survival;Cells;Chairperson;Clinical;Clinical Research;Clinical Trials;Collaborations;Combined Modality Therapy;Computational Biology;Data;Data Analyses;Data Collection;Data Management Resources;Dedications;Ensure;Flow Cytometry;Generations;Genes;Genomics;Health Sciences;Immunogenomics;Immunologic Monitoring;Immunologics;Immunology;Immunology procedure;Immunooncology;Immunophenotyping;Immunotherapy;Laboratories;Molecular;Mutation;Pathologic;Pathology;Pathway Analysis;Pathway interactions;Performance;Peripheral Blood Mononuclear Cell;Plasma;Procedures;Process;Proteomics;Quality Control;Radiation;Reporting;Research Design;Research Personnel;Research Project Grants;Resources;Sampling;Sequence Analysis;Specimen;Standardization;Statistical Data Interpretation;T-Lymphocyte;T-cell receptor repertoire;Technology;Tissue Procurements;Translational trial;Treatment Efficacy;Tumor Tissue;Whole Blood;biobank;computing resources;data harmonization;data management;data resource;differential expression;empowerment;human leukocyte antigen testing;interoperability;multidisciplinary;neoantigens;preclinical study;programs;radiation response;radiomics;response;screening;transcriptome;transcriptomics;translational goal;treatment response Translational and Clinical Trial Correlates Core n/a NCI 10704716 7/31/23 0:00 RFA-CA-21-040 5U54CA274513-02 5 U54 CA 274513 2 9/14/22 0:00 7/31/27 0:00 ZCA1-SRB-X 8830 7910647 "DIAZ-MONTERO, CLAUDIA MARCELA" Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 298207 250268 47939 PROJECT SUMMARYThe goal of the Translational & Clinical Correlates Core (TCCC) is to provide the expertise and resources neededto conduct quality correlative analyses for the research projects and clinical studies proposed as part of ourROBIN Program. To accomplish this we have assembled a multidisciplinary team with expertise in tissueprocurement and biobanking immune assays immunogenomics proteomics radiomics and state-of-the-artcomputational biology and biostatistics approaches. In Aim 1 the TCCC will provide highly standardized andvalidated procedures to procure process and biobank specimens. This will ensure availability of well-cataloguedand clinically annotated samples with optimal cell viability. In Aim 2 the TCCC will facilitate access to state-of-the-art platforms for the comprehensive molecular pathologic and immunologic profiling of collectedbiospecimens. This will provide a broad molecular assessment of the changes that occur in response totreatment and their contributions to response. In Aim 3 the TCCC will provide access to cutting-edgecomputational resources for the processing analysis and interpretation of high-throughput data. Advancedbioinformatics will be provided by the Center for Immunotherapy and Precision Immuno-OncologysComputational Immunology Platform and the Department of Quantitative Health Sciences (QHS) will assist withthe statistical analyses. To facilitate harmonization of data management and analysis each participating institutewill have a designated Data Resource Manager (Kattan for CC/Switchenko for Emory). This centralizedapproach will ensure optimal data collection analysis and sharing among projects and clinical studies. +No NIH Category available ATM Gene Mutation;Antibodies;Antibody-drug conjugates;Biological Response Modifiers;Bladder;Blood;Cancer Patient;Cells;Cessation of life;Cisplatin;Clinical;Clinical Trials;Clonality;Combined Modality Therapy;DNA Damage;Data;Diagnosis;Dissection;Ecosystem;Evolution;Genes;Genetic;Genetic Transcription;Genomics;Goals;Image;Immune;Immune checkpoint inhibitor;Immunologics;Kinetics;Malignant neoplasm of urinary bladder;Modality;Molecular;Mutation;Operative Surgical Procedures;Organ;Outcome;Pathogenesis;Patient Care;Patients;Phenotype;Population;Prospective Studies;Radiation;Radiation therapy;Research Project Grants;Research Project Summaries;Resistance;Sampling;Somatic Mutation;TP53 gene;Testing;Therapeutic;Transurethral Resection;Treatment Efficacy;Urothelium;Variant;antitumor effect;cancer cell;cell injury;checkpoint therapy;chemoradiation;chemotherapy;driver mutation;immune activation;immune cell infiltrate;improved;improved outcome;irinotecan;muscle invasive bladder cancer;neoplastic cell;next generation;overexpression;preservation;prospective;radiation effect;radiation response;resistance mechanism;response;single cell sequencing;standard of care;treatment effect;tumor;tumor-immune system interactions Project 1 Genetic and Immunologic Mechanisms Underlying Combination Sacituzumab plus Radiation Therapy for Bladder Cancer n/a NCI 10704713 7/31/23 0:00 RFA-CA-21-040 5U54CA274513-02 5 U54 CA 274513 2 9/14/22 0:00 7/31/27 0:00 ZCA1-SRB-X 8827 9306964 "CHAN, TIMOTHY AN-THY" Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 164648 116709 47939 PROJECT SUMMARYResearch Project 1 An organ sparing standard-of-care for patients with muscle invasive bladder cancer (MIBC) involvesconcurrent chemotherapy plus radiation (RT). However even after receiving current therapies (surgery orchemoradiation) bladder preservation and overall survival remains low at approximately 50-60%. Themolecular pathogenesis of bladder cancer and the mechanisms of resistance to chemoradiation remain poorlyunderstood. Our long-term goal is to understand the mechanisms of efficacy and resistance of bladder cancerto radiation plus sacituzumab or cisplatin and to use this information to develop better therapeutic modalitiesfor bladder cancer patients. Perhaps one of most promising immunomodulatory biologicals used with radiationis the antibody-drug conjugates (ADC). Sacituzumab govitecan (SG) is an antibody drug conjugate thatcombines the anti-TROP2 antibody with an active metabolite of irinotecan. ADCs act by inducing tumor celldamage as well as immune activation. The central hypothesis of this application is that specific genetic andimmune determinants underlie sensitivity and resistance to radiation-based combination therapies with SGADC versus cisplatin in MIBC patients. Our hypothesis has been formulated based on strong preliminary datafrom our group. We plan to accomplish our objectives with 3 specific aims. In Aim 1 we will elucidate thegenetic and microenvironmental mechanisms that drive efficacy and resistance to combined sacituzumab plusradiation therapy in bladder cancer. The working hypothesis here is that combinations of distinct tumordeterminants such as somatic mutations in DDR genes and microenvironmental features may be importantfor the anti-tumor effects of RT+SG. We will systematically elucidate the molecular genetic and immunologiceffects of treatment with standard-of-care radiation + cisplatin versus radiation + ADC. We will also utilizesingle cell sequencing to reveal treatment-related changes in the tumor ecosystem in MIBC undergoing eachapproach. In Aim 2 we will characterize tumor clonal dynamics immune repertoire editing and imagingchanges following treatment with sacituzumab plus radiation. We postulate that ADC therapy may inducesculpting of both the tumor clonal variants and the immune microenvironment and associate with an improvedresponse to radiation treatment. We will reveal adaptive changes to radiation + cisplatin versus radiation +ADC using comprehensive genomic transcriptional and immunologic profiling. We will integrate the temporalkinetics of tumor clonality and immune repertoire editing with tumor genomics and imaging. In Aim 3 we willexamine the mechanisms of acquired resistance to radiation plus cisplatin versus radiation plus sacituzumab.We will uncover the differential effects of these two treatment approaches systematically characterizeemergence of driver mutations changes in the tumor clonal composition immune reprogramming and identifymolecular and cellular mechanisms of acquired resistance. +No NIH Category available Accounting;Animal Experimentation;Animals;Cancer Center;Clinic;Clinical;Clinical Management;Clinical Trials;Collaborations;Combined Modality Therapy;Communication;Comprehensive Cancer Center;Core Facility;Data;Development Plans;Documentation;Education;Enrollment;Ensure;Feedback;Florida;Funding;Genomics;Goals;Grant;Human;Human Resources;Human Subject Research;Individual;Institution;Investigation;Laboratories;Leadership;Manuscripts;Monitor;Multi-Institutional Clinical Trial;Multicenter Trials;National Cancer Institute;Office of Administrative Management;Oral;Performance;Preparation;Progress Reports;Radiation;Research;Research Personnel;Resources;Schedule;Services;Site;Study Subject;System;Time;Training;Treatment Efficacy;Universities;Work;Writing;experience;human subject;innovation;meetings;operation;programs Administrative Core n/a NCI 10704708 7/31/23 0:00 RFA-CA-21-040 5U54CA274513-02 5 U54 CA 274513 2 9/14/22 0:00 7/31/27 0:00 ZCA1-SRB-X 8825 9306964 "CHAN, TIMOTHY AN-THY" Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 247394 199455 47939 PROJECT SUMMARYAdministrative Core The Administrative Core is responsible for the overall leadership management and execution of theROBIN center and it will provide overall organizational administrative scientific and clinical management. TheAdministrative Core will oversee and coordinate all ROBIN program components and centrally monitor andevaluate their performance. In addition the Administrative Core will facilitate all interactions with the ExternalAdvisory Board (EAB) the Steering Committee and the other sites of the national ROBIN program. ThisROBIN center involves 3 institutions (Cleveland Clinic Emory University and Case Western ReserveUniversity) with multiple enrollment sites (Cleveland Clinic system Cleveland Clinic Florida system EmoryUniversity system) across 2 NCI-designated Comprehensive Cancer Centers (Case Comprehensive CancerCenter Emory Cancer Center) with representation across these institutions as project and core leaders. TheAdministrative Core personnel will be led by Drs. Chan Yu and Scott with collaboration from the trial andproject leads. Both Drs. Chan and Yu (ROBIN PIs) have extensive experience in managing multi-institutionclinical trial and laboratory-based research programs. The specific aims for the Administrative Core are asfollows. In Aim 1 the Core will provide all organizational administrative educational and scientificcoordination for the ROBIN center projects and cores by cultivating and promoting the ROBIN team throughinnovation and excellence collaboration leveraging resources and providing constructive feedback.In Aim 2 the Core will provide centralized administrative management for all fiscal aspects of the ROBINcenter including but not limited to clinical trial execution accounting of grant funds progress reportscommunication meeting scheduling and minutes and manuscript and grant preparation. In Aim 3 the Corewill evaluate research progress through oral and written documentation with regular input from the EABSteering Committee and National Cancer Institute (NCI) leadership to ensure that each project meets itsobjectives within the proposed time frame and to facilitate interactions with other ROBIN sites for trans-ROBINcenter projects. In Aim 4 the Core will ensure integration across ROBIN components including projects andcores across all sites and provide interaction through scientific exchanges coordination of an annual scientificretreat and through training and development plans that will ensure state-of-the-art practices. In Aim 5 theCore will ensure and monitor best practices for human subjects and animal research for all ROBIN centerprojects and cores as well as clinical and data operations and to ensure adequate human and animalbiospecimens for all projects (with the Translational and Clinical Correlates Core). +No NIH Category available Address;African American;African ancestry;Androgen Receptor;BRCA2 gene;Bioinformatics;Biomedical Research;Biostatistical Methods;Boston;CHD1 gene;Cancer Biology;Cancer Center;Code;DNA Sequence;Dana-Farber Cancer Institute;Data;Data Analyses;Education;Educational workshop;Fees;Frequencies;Genetic Transcription;Genomic approach;Genomics;Goals;Infrastructure;Institution;Instruction;Learning;Malignant neoplasm of prostate;Massachusetts;Minority-Serving Institution;Modeling;Outcome;Population;Prostatic Neoplasms;Quantitative Reverse Transcriptase PCR;RNA;Receptor Signaling;Research;Research Design;Research Personnel;Resources;Risk;SNP genotyping;Structure;Students;Technology;Training;Underrepresented Populations;Underrepresented Students;Universities;Untranslated RNA;anticancer research;cancer health disparity;cancer initiation;cancer risk;cost;design;education research;experience;genomic data;health disparity populations;innovation;instrumentation;men;nano-string;next generation sequencing;novel;outreach;personalized cancer therapy;programs;single cell sequencing;therapy resistant;tool;tumor progression Genomics Core n/a NCI 10704706 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2 8823 1894128 "MACOSKA, JILL A." Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 129738 85965 45132 SUMMARYA critical gap often exists at institutions serving underserved health disparity populations and underrepresentedstudents (ISUPS) between access to Genomics technologies and the high costs associated with the requiredinstrumentation technical proficiency and analytical expertise. The Genomics Core (GC) addresses this gapby providing expert and affordable access to high-throughput genomics technologies on a reduced fee basisfor all Partnership investigators. The GC benefits the entire Partnership by providing innovative approaches toexplore early project ideas and by working with Partnership investigators and their trainees to facilitate the useof genomics technologies to build sustainable cancer biology and cancer disparities research. To accomplishthese goals the GC (through the auspices of the Center for Personalized Cancer Therapy CPCT) providesfront-line genomics-related technologies as well as bioinformatics support for data analysis to Partnershipinvestigators through an affordable reimbursement model. The GC proposes to accomplish these goalsthrough the pursuit of four specific aims designed to build capacity for biomedical and cancer research andtraining at UMass Boston by bridging a gap in the availability of cutting-edge genomics-based tools; supportPartnership investigators who wish to pursue early project ideas especially those that require innovativeand/or technically challenging genomics approaches; bridge a training gap between students and high-levelgenomics-based technologies and provide bioinformatics analysis of data generated in the core. In thisapplication the GC specifically supports FP2: Targeting androgen receptor signaling in prostate cancer in menwith African Ancestry Steven Balk (DF/HCC - BIDMC) and Changmeng Cai (UMass Boston) and PP2: Highfrequency of CHD1 loss in BRCA2-deficient African American prostate tumors drives treatment resistance Zoltan Szallasi (DF/HCC - BCH) and Shailja Pathania (UMass Boston). +No NIH Category available 19 year old;Address;Adolescence;Adolescent;Adolescent and Young Adult;Age;Age Years;Alcohol consumption;Behavior;Black race;Boston;Cancer Center;Cancer Control;Cancer Control Research;Cancer Prevention Intervention;Collaborations;Communities;Community of Practice;Consultations;Dana-Farber Cancer Institute;Data;Development;Early Intervention;Education;Equity;Evidence based intervention;Goals;Health;Health Promotion;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Inequity;Infrastructure;Institution;Internships;Intervention;Latino;Link;Literature;Low Income Population;Low income;Malignant Neoplasms;Massachusetts;Methods;Minority Groups;Modeling;Persons;Population;Prevention strategy;Research;Research Design;Research Methodology;Research Project Grants;Science;Services;Shapes;Students;Tobacco use;Training;Universities;Work;Youth;adolescent health;anticancer research;cancer health disparity;cancer prevention;cancer risk;career;community center;community engaged research;community engagement;community organizations;education research;emerging adulthood;ethnic minority;ethnic minority population;experience;health care availability;health care service;healthy weight;implementation science;innovation;next generation;outreach;prevent;programs;racial minority;racial minority population;structural determinants;theories;underrepresented minority student;underserved community Outreach Core n/a NCI 10704705 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2 8822 10928340 "DONALDSON, SHERRY TIFFANY" Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 83279 55500 29138 Summary. Background: Use of existing cancer prevention strategies could have prevented over half of theroughly 1.7 million new cases of cancer expected in the US in 2019. It is critical to intervene with adolescentsand young adults (AYAs) around key behaviors including avoiding alcohol and tobacco use maintaininghealthy weight and receiving the human papillomavirus vaccine given a) their potential to shift cancertrajectories and b) the establishment of these behaviors during AYA developmental stages. However AYAsare not engaging in these behaviors at desired levels. For racial and ethnic minorities and low-incomeindividuals periods of adolescence (ages 10-19) and emerging adulthood (ages 20-25) are often marked byinconsistent healthcare access and structural factors that place them at greater risk for cancer.Goal: The Outreach Core connects implementation science outreach and community engagement to addresstwo key divides that hinder cancer prevention among underserved AYAs: (1) the research-practice dividewhich limits the impact of evidence-based interventions (EBIs) for underserved communities and (2) the cancerworkforce divide in which the communities most impacted by cancer inequities are least represented in thecancer research workforce. To address these divides we will use participatory approaches to conduct theproject in collaboration with a Community Advisory Board thus increasing the impact and relevance ofproposed solutions.Methods: The study is organized around four aims. With Aim 1 we will build on the existing board whichincludes representatives from the Black and Brazilian communities of Greater Boston and the Latinocommunity of Greater Lawrence MA (communities experiencing cancer inequities) and add AYAs and expertsin AYA health and youth-engaged research. With Aim 2 we will support community organizations to adapt anddeliver EBIs focusing on alcohol and tobacco use maintaining healthy weight and HPV vaccination amongunderserved AYAs. With Aim 3 we will train the next generation of Black Latino Brazilian and Nativescholars in the theory and practice of community-engaged research and community-centered interventions.With Aim 4 we will co-create products and services with the Community Advisory Board to disseminatefindings and integrate community and equity considerations into Partnership activities.Innovations and impact: We link outreach engagement and implementation science to develop a platform toshape research conducted at UMB and the seven partner institutions of the DF/HCC serving as a modelinfrastructure for cancer prevention and control in partnership with populations experiencing cancer inequities. +No NIH Category available Address;American;Area;Behavioral Sciences;Black Populations;Boston;COVID-19 pandemic;Cancer Center;Color;Communication;Communities;Dana-Farber Cancer Institute;Development;Disabled Persons;Discipline;Discipline of Nursing;Disparity;Doctor of Philosophy;Education;Educational Status;Enrollment;Ethnic Population;Faculty;Fellowship;Fostering;Genomics;Graduate Degree;Grant;Group Affiliation;Growth;Health;Health Disparities Research;Healthcare;Individual;Infrastructure;Institutional Racism;Intervention;Investments;Knowledge;Latinx;Low Income Population;Malignant Neoplasms;Manuscripts;Massachusetts;Mentors;Methods;NCI Center for Cancer Research;Native Americans;Peer Review;Phase;Population;Population Heterogeneity;Postbaccalaureate;Postdoctoral Fellow;Preparation;Process;Productivity;Publications;Research;Research Design;Research Personnel;Research Project Grants;Science;Science Enrichment;Scientific Advances and Accomplishments;Scientist;Students;Training;Underrepresented Populations;Underrepresented Students;Universities;Work;behavioral and social science;cancer health disparity;career;career development;design;education research;evidence base;experience;graduate school;graduate student;health communication;health disparity;improved;innovation;interest;multidisciplinary;outreach;personalized cancer therapy;physical science;programs;racial population;research and development;research study;skills;success;undergraduate student Research Education Core n/a NCI 10704704 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2 8821 77954170 "ESCALERA, LIYA " Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 539998 354988 186369 PROJECT SUMMARYThe UMass Boston Dana-Farber/Harvard Cancer Center Partnerships Research Education Core (REC) aimsto bridge the divide that exists in the biomedical workforce by increasing the number of UMass Bostonstudents particularly those from underrepresented populations to pursue graduate degrees and cancer/cancerhealth disparities research careers. Utilizing evidence-based training that fosters the growth and persistence ofunderrepresented students in the sciences the REC provides trainees with science enrichment education andmentored research experiences which emphasize professional development inclusive support and teamscience across multiple disciplines. The framework of the REC focuses on three areas that are critical to thedevelopment of research scientists: (1) acquisition of scientific knowledge; (2) development of communicationskills; and (3) individualized career development. The Core will provide four research education programs:undergraduate post-baccalaureate graduate and post-doctoral. Over the course of the grant cycle the RECseeks to support 60 undergraduates (15-20 per year minimum one semester or summer 90% multi-semester) 30 graduate students (6-8 per year most multi-semester) 15 post-baccalaureate students (3 peryear for 1-2 years) and 2 nursing post-doctoral scientists (1 per two-year fellowship) in innovative researcheducation programming. Partnership faculty will mentor trainees and fellows at all levels. Recognizing that theneeds of individuals vary and that they change at each educational level the REC will provide individualizedand developmentally appropriate experiences aimed at preparing students/trainees for the next phase of theiracademic and research careers. The REC will continue to provide research opportunities for students at theintersection between the natural/physical sciences and social/behavioral sciences. Over the past 15 years theResearch Education Core (REC) has provided 347 trainees/fellows across the scientific preparation levels withmentored research experiences and scholarly scientific and professional development that prepares them topursue advanced degrees & fellowships and then to become cancer health disparities and/or biomedicalscience researchers. The REC will continue to use innovative methods to assess the extent to which thePartnership research education program is preparing trainees and fellows to successfully pursue a productivecancer/cancer health disparities research career. The REC will also advance scientific knowledge on effectiveresearch education programs through the submission of manuscripts to peer-reviewed publications regardingthe impact of Partnership activities on the diversity of the biomedical workforce and effective strategies fordeveloping research scientists from underrepresented backgrounds. +No NIH Category available Address;Advisory Committees;Area;Boston;Cancer Center;Collaborations;Databases;Decision Making;Development;Education;Ensure;Evaluation;Faculty;Funding;Funding Opportunities;Glues;Goals;Grant;Growth;Infrastructure;Institution;Logic;Malignant Neoplasms;Massachusetts;Modeling;Monitor;Outcome;Performance;Process;Progress Reports;Reporting;Research;Research Personnel;Research Project Grants;Resources;Scientific Inquiry;Universities;Vision;cancer health disparity;design;experience;innovation;outreach;programs;senior faculty;success;synergism;training opportunity Planning and Evaluation Core n/a NCI 10704702 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2 8820 8606765 "COLON-CARMONA, ADAN " Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 172724 114153 59930 SUMMARYThe Planning and Evaluation (P&E) Core of the University of Massachusetts Boston (UMass Boston) andDana-Farber/Harvard Cancer Center (DF/HCC) Partnership enables cutting-edge cancer and cancerdisparities research through the solicitation evaluation and selection of new research projects. The P&E Corebrings senior faculty early stage investigators and trainees together to design and pursue significant researchprojects. This process is vetted by a robust Internal Advisory Committee (IAC) comprising senior facultyinstitutional leaders core leaders and current and former project investigators. The P&E Core utilizes a logicmodel framework and outcomes database to carefully monitor assess and report the progress of researchprojects programs and cores. Key assessment metrics used by the core include impact disseminationtraining opportunities and sustainability. The P&E Core engages key institutional leaders and faculty at UMassBoston and DF/HCC to provide effective and well-integrated programmatic and scientific management that ismutually beneficial. These efforts are focused on bridging the gaps between scientific inquiry and societalimplementation to treat cancer and reduce cancer disparities.The specific aims of the Planning and Evaluation Core are to: 1) Facilitate and promote cutting-edge research;2) Build and maintain a robust IAC and utilize this expertise and that of the Program Steering Committee (PSC)to monitor Partnership progress and inform decision making; 3) Evaluate and track research projects andcores; 4) Document Partnership activity and oversee reporting to the NCI; 5) Identify grant opportunities andsupport proposal development; and 6) Expand the Partnership into areas of high potential impact throughcollaboration and development of synergies with other institutional activities and initiatives. +No NIH Category available AR gene;Address;Affect;African American population;African ancestry;American;Androgen Receptor;Androgen Therapy;Androgens;Apoptotic;Basic Science;Biological;Boston;CAG repeat;Cancer Center;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Clinical;Combined Modality Therapy;Critical Pathways;DNA Damage;DNA Sequence Rearrangement;Dana-Farber Cancer Institute;Dependence;Development;Dose;European ancestry;Genetic;Genetic Polymorphism;Genetic Transcription;Genomics;Glutamine;Grant;High Prevalence;KDM1A gene;Lead;Length;Ligands;Malignant neoplasm of prostate;Massachusetts;Modeling;Molecular Target;Mutation;N-terminal;Nuclear;Outcome;Pathway interactions;Patients;Play;Population;Proteins;Receptor Signaling;Research;Risk Factors;Role;Testing;Therapeutic;Translational Research;Universities;cancer health disparity;cancer initiation;men;polyglutamine;programs;prostate cancer cell;prostate cancer cell line;prostate cancer model;racial disparity;repaired;response;targeted agent;targeted treatment;transcription factor;tumor progression Targeting androgen receptor signaling in prostate cancer in men with African ancestry n/a NCI 10704700 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2 8818 10275601 "CAI, CHANGMENG " Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 147328 97500 51187 ABSTRACTProstate cancer (PCa) is the second leading cause of cancer-related death in American men. Although men withEuropean ancestry (EA) still represent the largest population of PCa patients men with African ancestry (AA)are disproportionately affected by PCa with higher prevalence and worse outcomes. Androgen receptor (AR) aligand-dependent nuclear transcription factor plays a pivotal role in PCa development and there are well-established genetic differences in the AR gene and associated pathways between EA versus AA men. Howeverit remains unclear how these genetic differences alter AR interaction with associated proteins and their potentialrole in PCa development and response to AR targeted therapies. In this study we hypothesize that differencesin AR signaling contribute to the biological differences between PCa in AA versus EA men and that PCa in AAmen may have distinct AR-dependencies and be vulnerable to therapies that combine AR-targeted therapieswith other targeted agents. To test these hypotheses Aim 1 will assess the effect of androgen stimulation onPCa cells from AA versus EA patients and in isogenic cells reflecting the genetic difference of AR. Aim 2 willidentify vulnerabilities generated in response to AR-targeted therapies in AA versus EA PCa models. +No NIH Category available Address;Administrator;Advisory Committees;Area;Basic Science;Boston;Budgets;Cancer Center;Cell Nucleus;Clinical Sciences;Collaborations;Colon;Color;Communication;Communities;Complex;Dedications;Development;Education;Educational Activities;Electronic Mail;Ensure;Faculty;Foundations;Funding;Goals;Grant;Growth;Infrastructure;Institution;Institutional Review Boards;Joints;Lead;Leadership;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Newsletter;Participant;Population Sciences;Postdoctoral Fellow;Research;Research Personnel;Research Project Grants;Resources;Role;Running;Structure;Training;Universities;Update;cancer health disparity;education research;equity diversity and inclusion;experience;innovation;meetings;member;multidisciplinary;outreach;programs;recruit;social media;success;symposium;synergism;web site Administrative Core n/a NCI 10704697 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2 8815 8606765 "COLON-CARMONA, ADAN " Not Applicable 8 Unavailable 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA Domestic Higher Education 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 253012 166801 87570 Summary: The Administrative Core of the University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC) Partnership takes an integrated approach to operational structure tosupport the growth of broad-based transdisciplinary cancer and cancer disparities research at both institutions.Partnership PIs Drs. K Vish Viswanath and Gregory Goyo Abel from DF/HCC and Drs. Adn Coln-Carmona and Jill Macoska from UMass Boston lead the Administrative Core and provide complementaryexpertise and abiding dedication to the sustained success of this research program. As the nucleus of theleadership and administrative teams the PIs with the support of effective internal (Internal AdvisoryCommittee (IAC)) external (Program Steering Committee (PSC)) and institutional leaders provide rigorousoversight for the research projects programs and cores to maximize the impact of the Partnership at theinstitutional level. In addition a single Partnership Program Manager shared by both institutions createsoperational synergies in the management of this multi-institutional research collaboration.The aims of the Administrative Core are to: 1) Provide administrative and fiscal oversight for Partnership coresand research projects and ensure responsible stewardship of funds; 2) Coordinate joint Partnership activitiesat UMass Boston and DF/HCC and facilitate networking opportunities; 3) Ensure proper infrastructural supportfor funded projects and cores; 4) Manage Partnership communications with all critical stakeholders in greaterBoston; 5) Support a new institutionally-funded DEI Manager who will leverage the expertise of the PartnershipCores to begin to investigate reasons for faculty of color attrition train a dedicated group of mentors for beforeand after hire and develop a new network for diverse post-docs in the Boston metro area; and 6) Trackinstitutional commitment in support of Partnership initiatives particularly toward recruitment efforts for EarlyStage Investigators (ESIs) and leverage institutional resources for this effort. +No NIH Category available 3-Dimensional;Address;Air;Breast;Breast Cancer Model;Breast Cancer Patient;Breast cancer metastasis;CRISPR interference;CRISPR-mediated transcriptional activation;CRISPR/Cas technology;Cancer Biology;Cancer Relapse;Carcinoma;Cell Communication;Cell Line;Cells;Characteristics;Clinical;Clinical Pathology;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Communication;Consent;Cryopreservation;Development;Disease;Drug Modelings;Drug Targeting;Drug resistance;Epithelial Cells;Epithelium;Experimental Models;Feedback;Genes;Genetic;Genetic Engineering;Genomics;Goals;Heterogeneity;Histologic;Histology;Human;Immune;Immune Evasion;Immunological Models;Impairment;Information Dissemination;Liquid substance;Macrophage;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Metastatic breast cancer;Methods;Modeling;Mus;Mycoplasma;Neoplasm Metastasis;Occupational activity of managing finances;Organoids;Pathology;Patients;Pattern;Phagocytosis;Pharmaceutical Preparations;Physiological;Population;Positioning Attribute;Primary Neoplasm;Production;Property;Proteomics;Protocols documentation;Qualifying;Quality Control;Research;Research Personnel;Resources;Services;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Standardization;Study models;System;Technology;Testing;Tissues;Tumor Tissue;Work;anticancer research;biobank;breast cancer genomics;cancer subtypes;cell type;digital;functional genomics;genome sequencing;glycosylation;in vitro Model;malignant breast neoplasm;mammary;molecular subtypes;nano-string;next generation;novel;patient derived xenograft model;reconstitution;response;single-cell RNA sequencing;synergism;therapeutic target;therapy resistant;tool;transcriptome;tumor;tumor microenvironment;tumor-immune system interactions;whole genome Core 2: Stanford Breast Metastasis Center Organoid Core n/a NCI 10704695 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 8814 1927477 "KUO, CALVIN J" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 189355 120302 69053 Abstract/Project SummaryBreast cancer research is substantially hampered by lack of experimental models that efficiently reflectphysiological disease necessary to provide a comprehensive understanding of metastatic disease. Conventionalcell lines and PDX models have contributed greatly to our understanding of breast cancer biology but areinefficiently derived do not fully capture the heterogeneity across breast cancer subtypes and rarely mimicclinical observations. Advancements in 3D organoid models from our lab and others have shown that patient-derived organoids (PDOs) can be generated efficiently retain histologic and genetic features of originating tumorclosely mimic patient drug response and are amendable to scale for genomic functional screens. Recently theKuo lab developed next generation PDOs by developing an Air-Liquid Interface (ALI) culture system that enablesculture of tumor epithelium en bloc with endogenous immune stroma (Cell 2018). The advent of ALI organoidculture provides critical experimental models for studying the tumor microenvironment. Here the Organoid Coreprovides essential patient derived organoid models for identifying the evolutionary dynamics andmicroenvironmental determinants of metastatic breast cancer for Stanford Breast Metastasis Centerinvestigators. Co-led by breast cancer genomics expert Dr. Christina Curtis and organoid pioneer Dr. Calvin Kuothe Stanford Breast Metastasis Center Organoid Core is uniquely positioned and qualified to address theunmet needs highlighted in this RFA: Metastasis Research Network by providing novel experimental models tostudy metastatic dissemination patterns cellular microenvironment crosstalk and drug response. Here theorganoid core will provide patient-derived breast cancer submerged organoids from primary and metastatictissue to study targeted drug resistance and to define specific metastatic patterns of breast cancer sub-clonesin Project 1 along with genomic functional screens using CRISPR/CAS9 and macrophage-mediatedphagocytosis in Project 3. Novel human breast cancer ALI organoid models will be extensively characterizedas compared to originating tissue in collaboration with Projects 1 and 2. Further ALI culture conditions will beoptimized for functional tumor-immune crosstalk studies with Project 3. Upon successful completion novelorganoid models will provide critical experimental tools for defining metastatic driver genes and identifyingtherapeutic targets to overcome drug resistance and immune evasion. +No NIH Category available Address;Bar Codes;Biological Assay;Biopsy;Blood;Blood specimen;Breast;Breast Cancer Patient;Breast Oncology;Breast cancer metastasis;Cancer Relapse;Cell Survival;Cellularity;Clinical;Clinical Data;Clinical Trials;Consent;Correlative Study;Cryopreservation;Data;Databases;Diagnosis;Disease;Disease Progression;Distant Metastasis;ERBB2 gene;Early treatment;Emergency Department patient;Estrogen receptor positive;Evolution;Formalin;Generations;Genomics;Goals;Immune;Immunohistochemistry;Institutional Review Boards;Laboratories;Link;Location;Longitudinal cohort;Longterm Follow-up;Mammary Gland Parenchyma;Mammary Neoplasms;Management Information Systems;Medical Oncologist;Metadata;Metastatic breast cancer;Modernization;Molecular;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Oncology;Organoids;Outcome;Pathologic;Pathologist;Pathology;Patient Recruitments;Patients;Pattern;Phase II Clinical Trials;Phase Ib Trial;Principal Investigator;Procedures;Process;Proteomics;Protocols documentation;Qualifying;Quality Control;Recurrence;Relapse;Research;Research Personnel;Resolution;Sampling;Scanning;Secure;Site;Slide;Source;Specimen;Standardization;Subgroup;Surgeon;Survival Rate;Tissue Banks;Tissue Microarray;Tissues;Translational Research;Tumor Markers;Tumor Tissue;Tumor-Infiltrating Lymphocytes;bean;biobank;biomarker driven;breast cancer survival;clinical trial recruitment;clinically relevant;cohort;design;electronic data;experience;follow-up;high risk;improved;insight;malignant breast neoplasm;metastatic process;multidisciplinary;multiple omics;new therapeutic target;novel therapeutic intervention;preservation;prospective;relapse risk;routine care;sample collection;sample fixation;spatiotemporal;therapy resistant;transcriptomics;triple-negative invasive breast carcinoma;tumor Core 1: Stanford Breast Metastasis Center Biospecimen and Pathology Core n/a NCI 10704692 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 8812 9189991 "BEAN, GREGORY " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 57457 36504 20953 Project Summary/AbstractIn order to investigate the processes of breast cancer metastatic relapse longitudinal cohorts of breast tumortissue with detailed clinical information are needed. Thus an integral function of the Stanford Breast MetastasisCenter (SBMC) will be the acquisiton processing clinical annotation and curation of hundreds of breast tumorscollected across multiple sites and stages of disease progression. To this end this project describes the aimsand functions of the SBMC Biospecimen and Pathology Core. The Core will be led by experienced breastpathologist Dr Gregory Bean who will implement and iteratively improve standard operating procedure protocolsfor processing pathologic review and generation of tissue microarrays for the Core samples. The lab of principalinvestigator Dr Christina Curtis will assist in sample collection and processing to enable numerous downstreammulti-omic protocols in which they have extensive expertise as well as breast organoid generation. Breastmedical oncologist Dr Jennifer Caswell-Jin and breast surgeon Dr Irene Wapnir will recruit participants toprospective tissue acquisition protocols and will design and review clinical annotation procedures. The Core willdraw samples from six established efforts including two completed clinical trials (TRIO B07 and TONIC) twoprospectively recruiting clinical trials (NCT04504331 and TERPSICHORE) an existing Institutional ReviewBoard (IRB)-approved protocol whereby archival tumor specimens are collected retrospectively and an existingIRB-approved protocol whereby prospective serial tumor and blood samples are collected from consentedpatients with breast cancer undergoing routine care. In Aim 1 longitudinal tumor samples throughout treatmentand metastasis will be collected from these sources. Prospectively collected samples will be subjected to rapidprocessing to include formalin fixation cryopreservation and preservation of viable cells for organoids; H&Eslides will be scanned and reviewed for tumor cellularity and tumor-infiltrating lymphocytes; standardizedimmunohistochemistry will be performed; and detailed information about location and orientation will berecorded. In Aim 2 a highly integrated database will be constructed to provide linkage of these collectedbiospecimens with high quality demographic clinical pathologic and treatment data. This secure Research andElectronic Data Capture database will include detailed clinical information and will link biospecimens viabarcodes to the Laboratory Information Management System where information on all downstream assaysperformed on samples is stored. In Aim 3 a framework for sharing high quality de-identified biospecimens andclinical data within the SBMC will be established. Summaries of de-identified clinical metadata that can be sharedwith investigators across the SBMC will be generated and rapid identification of project-specific cohorts enabled.Successful completion of these Aims will result in an annotated longitudinal breast cancer biospecimen cohortwith unprecedented molecular and clinical annotation and the potential to reveal new insight into the metastaticniche and breast cancer evolution. +No NIH Category available 3-Dimensional;Breast;Breast Cancer Cell;Breast Cancer Risk Factor;Breast Cancer cell line;CD47 gene;CRISPR interference;CRISPR screen;CRISPR-mediated transcriptional activation;Cancer Model;Cancer Patient;Candidate Disease Gene;Cell Communication;Cell Line;Cells;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Dependence;Development;Drug Targeting;Drug resistance;Effectiveness;Engineering;Estrogen receptor positive;Exhibits;Fluorescent Probes;Gene Combinations;Gene Expression;Gene Expression Profile;Gene Targeting;Genes;Genetic;Genetic Transcription;Genomics;Growth;Immune Evasion;Immune system;Immunosuppression;Immunotherapy;In Vitro;Individual;Infiltration;MCF10A cells;MCF7 cell;Macrophage;Magnetism;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Mediating;Metastatic breast cancer;Modeling;Molecular;Nature;Neoplasm Metastasis;Organoids;Outcome;Patients;Phagocytes;Phagocytosis;Phenotype;Post-Translational Protein Processing;Process;Property;Proteins;Proteomics;Relapse;Repression;Resistance;Resistance development;Role;Signal Transduction;Subgroup;System;Testing;Therapeutic;Trastuzumab;Tumor Escape;Tumor-associated macrophages;adaptive immune response;anti-cancer;anticancer activity;biomarker driven;breast cancer progression;cancer cell;cancer therapy;candidate identification;differential expression;druggable target;experimental study;genome-wide;high risk;hormone therapy;improved;in vivo;malignant breast neoplasm;mammary epithelium;neoplastic cell;next generation;novel;overexpression;receptor;relapse risk;resistance mechanism;sialylation;targeted treatment;therapeutic target;therapy resistant;three dimensional cell culture;transcriptomics;treatment response;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis Project 3: Systematic characterization of factors controlling breast cancer progression and resistance n/a NCI 10704691 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 8811 2186789 "BASSIK, MICHAEL C" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 345678 219618 126060 Abstract/Project SummaryMetastatic breast cancer and relapse following therapy are dependent on (1) resistance to recognition anddestruction of cancer cells by the immune system and (2) development of intrinsic resistance to targeted andendocrine therapies. The study of these processes using in vitro cancer models have been limited in scale andoften lack key properties of the tumor microenvironment. We recently developed a scalable cancer spheroidsystem that enabled the first genome-wide CRISPR screens in 3D culture; phenotypes in this system muchbetter reflect in vivo tumors (Nature 2020). In addition we developed a magnetic separation strategy to rapidlyidentify regulators of phagocytosis by macrophages (Nature Genetics 2018) and have successfully extendedthis strategy to study macrophage-tumor cell interactions. Here we will use these systems to identifyregulators of therapeutic relapse and immune evasion in metastatic breast cancer. To investigate mechanisms of relapse after therapy we will focus on four ER+ breast cancer subgroups withhigh relapse risk previously identified by the Curtis Lab (Project 1). This has formed the basis of a biomarker-driven clinical trial targeting the presumed candidate drivers in these high-risk subgroups. Since the ampliconsdefining these subgroups each contain multiple genes we will use functional CRISPR perturbations to test whichgenes (or combinations thereof) are the true drivers. Further we will build on the comprehensive characterizationof these tumors from transcriptomics (Project 1) and spatial proteomics (Project 2) adding functionalmeasurements of the requirement for each altered factor in growth and resistance to therapy using high-throughput CRISPR screens. Together these studies will dramatically enhance our understanding of whichgenes are critical targets for improved therapies in high-relapse risk breast cancers. To investigate how metastatic tumors evade the immune system we will focus on macrophage-tumorinteractions. Surprisingly although macrophages comprise 50% of the cell mass of some tumors breastcancer cells appear resistant to macrophage killing. This is largely due to anti-phagocytic signals expressed bycancer cells including CD47; however accumulating evidence points to the existence of additionalunidentified anti-phagocytic signals in breast cancer. In addition tumor-associated macrophages (TAM) arere-wired to support tumor development and have reduced phagocytosis. It remains unclear however whichgenes mediate resistance to phagocytosis in high-risk IC subtypes and which macrophage genes underlieimmunosuppression by metastatic breast cancers. Here we will systematically identify genes limiting anti-canceractivity by macrophages by conducting CRISPR screens in both macrophages and cancer cells making use ofsophisticated ALI patient-derived organoid models to validate hits. These complementary approaches willfunctionally define breast cancer driver genes and therapeutic targets that control therapeutic response andimmune evasion informing the next generation of clinical trials. +No NIH Category available Address;Adult;Brain;Brain Neoplasms;Breathing;Butterflies;Cancerous;Cell Differentiation process;Cells;Childhood Brain Neoplasm;Computer Simulation;Computing Methodologies;Cues;Data;Deep Brain Stimulation;Deglutition;Development;Diffuse;Diffuse intrinsic pontine glioma;Diffusion;Drug Targeting;Electrodes;Embryonic Development;Environment;Excision;Exercise;Fatality rate;Glioma;Growth;Implanted Electrodes;In Vitro;Intervention;Invaded;Knowledge;Location;Malignant Neoplasms;Malignant neoplasm of brain;Mastication;Messenger RNA;Methods;Modeling;Molecular;Mus;Neurons;Operative Surgical Procedures;Outcome;Patients;Pattern;Pharmaceutical Preparations;Physiologic pulse;Pontine structure;Population;Positioning Attribute;Radio;Research;Resectable;Safety;Shapes;Site;Therapeutic;Therapeutic Effect;Time;Tissues;Volition;Xenograft Model;brain tissue;cancer cell;cancer therapy;cell motility;curative treatments;design;electric field;glioma cell line;improved;in vivo;innovation;insight;minimally invasive;neoplastic cell;novel strategies;palliative;patient population;pediatric patients;pharmacologic;prevent;rational design;response;standard of care;transcriptomics;tumor;tumor microenvironment;voltage;wound healing Tumor 'tractor beam' for diffuse cancers PROJECT NARRATIVE Currently there are few options for treating diffuse cancers particularly those that arisein sensitive tissues (i.e. not amenable to resection) in tissues in which drug diffusion is limitedor in patients for whom typical interventions incur unacceptable sequelae (e.g. pediatricpatients). Using as basis one of the most aggressive forms of pediatric brain tumor DiffuseIntrinsic Pontine Glioma (DIPG) we propose the use of safe electrical fields to move and/orconsolidate DIPG cells electrotaxis and thus provide a strategy to for making diffuse cancersamenable to surgical removal and/or chemo/radio therapeutic treatment. NCI 10704689 8/11/23 0:00 RFA-RM-20-013 5R01CA271304-03 5 R01 CA 271304 3 "COUCH, JENNIFER A" 9/23/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-BST-J(70)R] 2129862 "BELLAMKONDA, RAVI V." Not Applicable 5 BIOLOGY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF ARTS AND SCIENCES 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 371688 OD 237500 134188 PROJECT SUMMARY Currently there are few options for treating diffuse cancers. This is a particular challengefor diffuse cancers that arise in sensitive tissues (i.e. not amenable to resection) in tissues inwhich drug diffusion is limited or in patients for whom typical interventions incur unacceptablesequelae (e.g. pediatric patients). Here we investigate a novel approach: guiding cells with electrical fields (electrotaxis) toconsolidate the diffuse cancer cells to one or few locations (making them less diffuse) oralternately move these cells to a less critical location. As a basis for our approach we will useone of the most aggressive forms of pediatric brain tumor Diffuse Intrinsic Pontine Glioma(DIPG) which is emblematic of the challenges inherent in treating diffuse cancers. The need fornew treatments for DIPG is particularly critical as it arises in the ponsa site that hosts criticalcenters for breathing chewing heartbeat and swallowingand incurs a dismal median survivaltime of 9 months and is fatal in more than 99% of patients. We propose to quantify using transcriptomics and pharmacological inhibition underlyingmechanisms of electrotactic tumor cell response. This will reveal electrotactic drug targets andprovide controls to manipulate/enhance further electrotaxis. We will investigate in vivo theeffects of various electrode montages to shape and steer infiltrative DIPG cells in both thecortex and pons. To support our approach we will apply computational methods to iterativelymodel and design stimulation montages in response to observed patterns of growth after fieldapplication. These studies will provide a novel approach to addressing the general problem of adiffuse cancer so that they can become more amenable to standard-of-care therapies. 371688 +No NIH Category available 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine;Antibodies;Automobile Driving;Avidity;Binding;Biopsy;Breast cancer metastasis;CRISPR interference;Cell Communication;Cells;Clinical;Collagen;Data;Data Set;Deaminase;Disease Progression;Distant;Enzymes;Estrogen receptor positive;Excision;Extracellular Matrix;Family;Fibroblasts;Frequencies;Hydroxylation;Image;Immune;Immune Evasion;Immunosuppression;Invaded;Label;Libraries;Location;Machine Learning;Macrophage;Maps;Mass Spectrum Analysis;Metabolic;Metals;Metastatic breast cancer;Methods;Mixed Function Oxygenases;Modeling;Modification;Molecular;Morphology;Multiplexed Ion Beam Imaging;Neighborhoods;Neoplasm Metastasis;Nivolumab;Normal tissue morphology;Operative Surgical Procedures;Organoids;Outcome;Pathogenesis;Patients;Peptide Hydrolases;Peptides;Play;Polysaccharides;Population;Process;Procollagen-Proline Dioxygenase;Protein Glycosylation;Proteins;Proteomics;Resolution;Resources;Risk;Role;Sampling;Site;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stains;Stromal Cells;Structure;Testing;Therapeutic;Time;Tissue Sample;Tissue imaging;Tissues;Tumor Cell Migration;Visualization;Work;biobank;breast cancer progression;breast imaging;cell type;clinically significant;collagenase;crosslink;glycosylation;glycosyltransferase;high risk;imaging modality;immune activation;malignant breast neoplasm;mass spectrometric imaging;neoplastic cell;permissiveness;prevent;receptor;recruit;response;sialylation;tool;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Project 2: Cellular topography and function of the breast cancer tissue microenvironment n/a NCI 10704687 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 8809 11579647 "ANGELO, ROBERT MICHAEL" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 341484 231583 109901 Abstract/Project SummaryBreast cancer (BC) metastasis is an emergent feature that occurs when the tumors ability to recruit metabolicresources avoid immune activation and disseminate to distant sites exceeds the capacity of surrounding normaltissue to prevent these processes. In line with this work over the last decade has demonstrated the crucial roleplayed by the tumor microenvironment (TME) in promoting or deterring BC progression. Tumor cell migrationand immune recruitment have both been shown to be heavily influenced by fibroblasts and the surroundingextracellular matrix (ECM) they produce. Additionally protein glycosylation has been shown to modulate theseinteractions. To understand how tumor glycosylation and ECM remodeling interact to potentiate BC metastasiswe will use spatial transcriptomics and two complementary mass spectrometry methods MIBI-TOF and MALDIto identify glycan-dependent cell-cell and cell-ECM interactions that shift the TME toward tumor permissivestates. All three analyses will be performed on spatially-coregistered serial sections from the same tissue blocks.In doing so comprehensive single-cell maps of each tissue sample constructed by MIBI-TOF can be directlysuperimposed with de novo proteomic and transcriptomic data. We will map and enumerate the lineage andmajor functional subsets of tumor and stromal cells with respect to relevant therapeutic and molecularparameters to understand how the BC TME evolves with disease progression. These features will be overlaidwith de novo imaging of tissue glycans to identify potential mechanisms of immune evasion that involve tumorsialoglycans and macrophage-bound SIGLECs. The frequency and spatial enrichment of these features will becorrelated with spatial transcriptomics data to identify regulatory glycosyltransferases promoting theseinteractions. Next ECM-MALDI and MIBI-TOF data will be used to identify how collagen type hydroxylation andcrosslinking shift in coordination with the collagen structure and function of neighboring cell populations. Inparticular we will focus on understanding how the activity of two families of enzymes prolyl and lysylhydroxylases drive structural changes in the ECM that promote BC metastasis. The clinical significance of theseextracted cellular and molecular definitions of ECM remodeling will be assessed with respect to metastatic riskstage and IC subtype. Taken together this work will provide an unprecedented view into how TME structureand cell-cell interactions between tumor and stroma relate to specific facets of the tumor ECM and glycome. +No NIH Category available 11q13;17q23;8q24;ATAC-seq;Address;Aftercare;Bar Codes;Biological Markers;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;CCND1 gene;CDK4 gene;Cancer Relapse;Cell surface;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Clinical;Clinical Data;Clinical Trials;Collaborations;Colorectal Cancer;Computer Models;Cues;Data;Data Set;Diagnosis;Disease;Distant;EIF4EBP1 gene;ERBB2 gene;Endocrine;Engineering;Estrogen receptor positive;FGF3 gene;FGFR1 gene;FRAP1 gene;Fibroblast Growth Factor Receptors;Genomics;HBXAP gene;Immune;Immunosuppression;In Situ;In Vitro;Link;Longitudinal cohort;Longterm Follow-up;Lymphocyte;MCF10A cells;Macrophage;Malignant neoplasm of lung;Measures;Metastatic breast cancer;Modeling;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Oncogenic;Organoids;PVT1 gene;Patients;Pattern;Polysaccharides;Primary Lesion;Primary Neoplasm;Prognosis;Progression-Free Survivals;Proto-Oncogene Proteins c-akt;RNA;Recurrence;Relapse;Resistance;Route;Sampling;Site;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Subgroup;Techniques;Testing;Time;Tissues;Xenograft procedure;biomarker driven;breast cancer progression;cohort;digital;genomic data;glycosyltransferase;high risk;hormone therapy;improved;in silico;in vivo;inhibitor;malignant breast neoplasm;mathematical model;monocyte;nano-string;neoplastic cell;new therapeutic target;novel therapeutic intervention;overexpression;predictive modeling;prospective;receptor expression;relapse risk;resistance mechanism;response;spatiotemporal;targeted sequencing;targeted treatment;transcriptomics;treatment response;triple-negative invasive breast carcinoma;tumor;tumor progression Project 1:Evolutionary dynamics and drivers of breast cancer metastasis and relapse n/a NCI 10704684 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 8808 10842134 "CURTIS, CHRISTINA N" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 338601 215121 123480 Abstract/Project Summary While prognosis for early stage breast cancer (BC) has improved dramatically 20-30% of patients recur atdistant sites and ultimately succumb to their disease. To date the spatial and temporal patterns of BC relapsehave been difficult to predict. Moreover when and how metastatic potential is determined is largelyunknown. To address these questions we have developed spatial computational and mathematical models oftumor progression to infer the time of metastatic seeding. Application of these techniques to paired primarybreast cancers with matched metastases yielded quantitative evidence for early metastatic seeding often 2-4 years before the primary lesion is detectable (Nat Gen 2020) consistent with experimental and clinical dataindicating that BC cells can disseminate early and persist. In parallel we defined the rates and routes of relapse across 11 Integrative Clusters (ICs) in ananalysis of 2000 early-stage BCs with long-term follow-up (METABRIC cohort: Nature 2019; 2012). Theseinclude two triple negative BC subgroups with distinct relapse trajectories and four ER+/HER2- ICs (1 2 6 and9) with high and persistent risk of relapse up to 20 years after diagnosis. Collectively these high-risksubgroups account for 26% of all ER+/HER2- tumors and the majority of BC relapses. The pattern of copynumber amplification (CNA) and overexpression in these high-risk ICs echoes that seen for HER2+ BC eachharboring druggable clonal genomic drivers. This breakthrough discovery led to a biomarker-driven clinicaltrial evaluating new targeted therapies in early-stage high-risk BC patients. However the definitive drivers andmechanisms of progression in these subgroups have yet to be characterized. Moreover how the local tissuemicroenvironment (TME) varies across the ICs and contributes to immune suppression disseminationdormancy and relapse is unknown We hypothesize that the oncogenic drivers of the high-risk ICs drive tumor progression and relapse bydictating immune contexture and remodeling the cell surface glycoproteome potentiating tolerogenic cell statesas further functionally evaluated in Projects 2 and 3 in collaboration with Michael Angelo and MichaelBassik. Additionally we hypothesize that these amplicons confer intrinsic endocrine resistance necessitatingnew therapeutic strategies. We test these hypotheses in the following Specific Aims: Aim 1- Characterizes theTME in longitudinal BC cohorts and evaluate the association between IC glycosyltransferase expressionresponse to therapy and relapse. Aim 2 - Quantifies the dynamics of BC relapse and the response to clinicaltherapies across the ICs. Aim 3 - Measures clonal dynamics and identify mechanisms of resistance to targetedand endocrine therapies in high-risk ER+ BC patient-derived organoids from primary and metastatic lesions. +No NIH Category available Advisory Committees;Advocate;Archives;Bioinformatics;Breast;Breast cancer metastasis;Calendar;Cancer Biology;Communication;Communities;Computational Biology;Data;Ensure;Evaluation;Event;Fostering;Future;Hearing;Immunology;Interdisciplinary Study;Link;Logistics;Medical Oncology;Metastatic breast cancer;Methods;Modeling;Monitor;Neoplasm Metastasis;Operative Surgical Procedures;Pathology;Patients;Performance;Process;Productivity;Progress Reports;Recommendation;Research;Research Personnel;Resolution;Site;Update;Work;dashboard;data exchange;design;experience;flexibility;functional genomics;meetings;multidisciplinary;organizational structure;programs;repository;statistics;success;web site;working group Stanford Breast Metastasis Center Administrative Core n/a NCI 10704683 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 8807 10842134 "CURTIS, CHRISTINA N" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 259581 164917 94664 Abstract/Project SummaryThe Stanford Breast Metastasis Center (SBMC) Administrative Core will operate by upholding the principle thatour success relies on a well coordinated and focused multidisciplinary team executing premier research. Ourcore team has an established track record of working on large scale projects with scientific investigators frommultiple fields including cancer biology immunology functional genomics computational biology bioinformaticsand statistics breast medical oncology pathology surgery. Through our Administrative Core we will provideoversight that identifies and responds to short-term and long-term needs by executing three aims. Our first aimis to establish and maintain an effective and responsive organizational structure that provides propercommunication and coordination of activities within the NCI Metastasis Network. For internal oversight we willconvene an Executive Committee including patient advocates External Advisory Committee Internal AdvisoryCommittee and Steering Committee that will meet regularly to review current progress make recommendationsand monitor future progress. All SBMC investigators and staff will be expected to attend bi-weekly SBMCmeetings where we will have general announcements by PIs Project Leads and Core Leads review ourmilestones hear updates and an in-depth presentation from one of our investigators followed by discussion. Wewill maintain updated mailing lists and a website to disseminate announcements archive summary notes frommeetings host a calendar of activities and provide links to data and model repositories. Our second aim is toestablish and maintain a communication and logistics strategy for transparent and responsive interactions withinthe SBMC the NCI MetNet and the broader scientific community. To foster exchange of data and methods withinother centers comprising the MetNet we will actively participate in annual MetNet investigator meetings andcontribute to the activities of the MetNet by organizing and participating in collaborative activities and workinggroups. Our third aim is to facilitate the evaluation of Center interim milestones and if needed implementprocesses to revise milestones with NCI MetNet Program Manager approval. We will monitor progress at bi-weekly SBMC team meetings through our SBMC Milestones Dashboard which will summarize progress in ourthree Projects and Cores. We will also report progress on milestones at NCI MetNet annual meeting. Thirdly wewill host an onsite evaluation of our Centers performance during annual NCI Site Reviews. Finally in the unlikelyevent that we experience a delay in meeting our milestones we will engage a resolution strategy that will involveour team and Steering Committee and as needed the EAC IAC colleagues in other MetNet Centers and theNCI. +No NIH Category available Address;Antigens;Antioxidants;Blood;Blood Pressure;Blood Vessels;Cancer Model;Cancer Patient;Cell Line;Cell Respiration;Cell Transplantation;Cells;Chemoresistance;Chemotherapy and/or radiation;Chronic;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Complex;DNA sequencing;Data;Data Set;Databases;Dependence;Dose;Drops;Effectiveness;Electron Transport;Engineering;Enrollment;Equilibrium;Erectile dysfunction;FDA approved;Future;Gastrointestinal tract structure;Gene Expression;Genes;Genetic;Genetic Transcription;Human;Hypoxia;Image;Immune;Immunocompetent;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Intervention;Intravenous infusion procedures;Lead;Lung;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of lung;Maximum Tolerated Dose;Metabolic;Metabolism;Mitochondria;Modality;Modeling;Mus;Muscle relaxants;Mutation;Neoplasm Transplantation;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Oncogenic;Outcome;Oxidative Phosphorylation;Oxygen;Oxygen Consumption;PD-1 blockade;Papaverine;Parents;Pathway interactions;Patient-Focused Outcomes;Patients;Perfusion;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase I Clinical Trials;Phenotype;Physiology;Population;Pre-Clinical Model;Process;Radiation;Radiation therapy;Radio;Radioimmunotherapy;Radiosensitization;Refractory;Reporter;Research Personnel;Resistance;Safety;Side;Smooth Muscle;System;T cell infiltration;T-Cell Activation;T-Lymphocyte;Testing;The Cancer Genome Atlas;Theft;Therapeutic;Tumor Oxygenation;Up-Regulation;Vascular resistance;Vasospasm;anti-PD-1;anti-PD1 therapy;cancer therapy;chemoradiation;chemotherapy;design;driver mutation;exhaust;exhaustion;imaging study;immune cell infiltrate;immune checkpoint blockade;improved;in vitro testing;inhibitor;innovation;mRNA sequencing;migration;mitochondrial metabolism;mutant;neoplastic cell;novel;novel strategies;pharmacologic;phase I trial;phosphoric diester hydrolase;progenitor;prognostic indicator;programs;radiation resistance;radiation response;response;standard of care;theories;treatment response;tumor;tumor DNA;tumor hypoxia;tumor microenvironment;vascular bed Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism PROJECT NARRATIVESome lung cancer patients respond well to therapy while others do not. We are investigating the repurposing ofan FDA-approved drug to enhance the effectiveness of established radiation and immunotherapy for lung cancer. NCI 10704677 8/21/23 0:00 PAR-18-560 5R01CA262388-03 5 R01 CA 262388 3 "VIKRAM, BHADRASAIN" 9/22/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OTC-L(02)M] 1933683 "DENKO, NICHOLAS C." "LI, ZIHAI ; WILLIAMS, TERENCE MARQUES" 3 RADIATION-DIAGNOSTIC/ONCOLOGY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 627890 NCI 408582 219308 PROJECT SUMMARYMany groups are investigating why some lung cancer patients respond well to radio- and immuno-therapies andsome do not. One variable is tumor hypoxia and many groups have shown it can significantly inhibit theeffectiveness to these therapeutic modalities. Clinical studies have identified hypoxia as an independentprognostic indicator of poor patient outcomes but even though this connection has been known for decades noFDA-approved intervention exists to clinically overcome hypoxia. Some investigators have tried to deliver moreoxygen to the tumor but this approach remains constrained due to the poorly formed tumor vasculature. Wehave taken an innovative approach and asked if we can reduce demand for rather than increase supply ofoxygen to reduce hypoxia. We have found that the FDA-approved vasorelaxant papaverine (PPV) has an off-target ability to inhibit mitochondrial complex 1 and reduce oxygen consumption rapidly in low micromolarconcentrations in every cell line tested in vitro. We have also shown that PPV can enhance the effectiveness ofradiation and immune checkpoint blockade (ICB) in preclinical models of lung and other cancers withoutsensitizing well-oxygenated normal tissue. Reducing hypoxia reverses immune privilege decreases terminally-exhausted T cells and increases progenitors that are responsive to PD-1 blockade. We have more recentlydeveloped new derivatives of PPV that have lost their vasorelaxant capability and increased their duration ofaction so that they can be improved immuno-sensitizers. We now propose to test the hypothesis that PPV caneffectively enhance the radio- and immuno-therapeutic treatment of preclinical models of lung cancer and thatit is feasible to add PPV to standard of care therapy for advanced non-small cell lung cancer (NSCLC). We haveexamined TCGA databases and found that lung cancer driver mutations in the KEAP1/NRF2 pathway lead tohigh levels of mitochondrial gene expression that can cause elevated oxygen metabolism contributing to hypoxia.In Aim 1 we will investigate the effects of oncogenic NRF2 activation human and murine cells and model tumorsto determine the dependence of these cells on mitochondrial function how increased oxygen metabolismcontributes to tumor hypoxia and if therapy-refractory tumors are sensitized by PPV or its derivatives. In Aim 2we will examine the effect of tumor hypoxia on the migration and activation of T-cells in model tumors and howthe immune infiltrate changes after reduction of hypoxia with PPV or its derivatives. Finally in Aim 3 we willperform a phase 1 clinical trial to determine if the addition of PPV is feasible for patients receiving standard ofcare chemoradiation followed by immunotherapy for advanced NSCLC. We will look for effectiveness in changingtumor oxygenation using paired blood level oxygen determination (BOLD) MRIs and for changes in immunepopulations of peripheral blood mononuclear cells. These studies will let us know if and how to use PPV or itsnovel derivatives in future clinical trials for the treatment of NSCLC. 627890 +No NIH Category available African American;Area;Basic Science;Biochemistry and Cellular Biology;Bioethics;Biometry;Cell Therapy;Cells;Cessation of life;Clinical;Clinical Investigator;Clinical Research;Collaborations;Complex;Dedications;Development;Doctor of Philosophy;Education;Ensure;Environment;Epidemiologist;Epidemiology;Equity;Ethics;Evaluation;Faculty;Female;Fostering;Funding;Future;Genetic;Goals;Healthcare;Hispanic Americans;Hospitals;Immunology;Incentives;Individual;Investments;Laboratories;Lead;Learning;Lymphoma;Medicine;Mentors;Mentorship;Methodist Church;Methods;Minority;Molecular and Cellular Biology;Monitor;Pathologic;Pathology;Peer Review;Pharmacology;Physicians;Pilot Projects;Private Practice;Process;Production;Productivity;Publishing;Research;Research Personnel;Research Project Grants;Science;Scientist;Selection Criteria;Therapeutic Studies;Training;Training Programs;Translational Research;Translations;Underrepresented Minority;Woman;Work;bench to bedside;career;college;design;editorial;equity diversity and inclusion;gene therapy;improved;lectures;member;patient oriented research;programs;recruit;role model;skills;success;tool;translational scientist;vector Career Enhancement Program PROJECT NARRATIVEThe goal of this program is to provide training in translational research in lymphoma for a diverse group ofyoung investigators or established investigators who wish to refocus their career on lymphoma. ThisLymphoma SPOREs Career Enhancement Program aims to increase the number of promisinginvestigators working in this field in the future through tailored learning programs expert mentorship andindividualized training in the translation of cell and gene therapies for lymphoma. NCI 10704675 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6 8805 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 88808 57591 31217 PROJECT SUMMARYThe goal of the Lymphoma SPOREs Career Enhancement Program is to provide support for younginvestigators pursuing careers in translational lymphoma research as well as for established investigatorswho wish to refocus their work on lymphoma. The program is led by Drs. Helen Heslop Martha Mims and SidGanguly and will be co-ordinated by the Administrative Core with oversight from the Executive Committeeand Internal and External Advisory Boards. Continually improved throughout the previous funding cycles ourestablished Career Enhancement Program has well-defined processes and for candidate recruitment. We willcontinue to collaborate with the Baylor Office of Diveristy Equity and Inclusion to devote significant effort torecruit women and minorities to our program and the field of lymphoma research an initiative that has beensuccessful in the past funding periods when 53% of trainees were female and 37% were under-representedminorities (Hispanic or African American). Both MD and PhD trainees will be able to take advantage of coursesavailable through the Clinical Scientist Training Program at Baylor College of Medicine and will have a stronggroup of mentors with broad translational expertise. We have developed mentoring strategies focued on theunique challenges of moving cell and gene therapies from the bench-to-the-bedside as well as the dynamicsof team science that enhance the overall training program. Specifically these strategies include providingtrainees with multiple mentors that possess complementary skills individualized training plans and multipleopportunities to participate in learning courses and attend lectures relevant to the field. Additionally traineeshave access to the SPORE cores (Clinical Research and Biostatistics Cell Processing and Vector ProductionBiospecimen and Pathology) with unique expertise in cell and gene therapy and clinical research. In the last14 years19 awardees have been selected for this Program seven of whom are now incorporated into theSPORE program with 4 as project leaders in the current renewal . This Program will therefore ensure that theSPORE will continue to train promising investigators who will contribute to translational lymphoma researchinto the future. +No NIH Category available Advisory Committees;Award;Budgets;Cancer Center;Chronic Lymphocytic Leukemia;Clinical;Clinical Research;Collaborations;Data;Development;Diagnosis;Eligibility Determination;Ensure;Evaluation;Feedback;Female;Funding;Future;Goals;Home;Hospitals;Institution;Investments;Laboratory Research;Longterm Follow-up;Lymphoma;Malignant Neoplasms;Medical center;Medicine;Methodist Church;Minority;Monitor;Nature;Non-Malignant;Peer Review;Performance;Pilot Projects;Program Research Project Grants;Publications;Recommendation;Reproducibility;Research;Research Personnel;Research Project Grants;Rice;Scientist;Secure;Selection Criteria;Source;Talents;Testing;Texas;Translating;Translational Research;Underrepresented Minority;Universities;Woman;bench to bedside;college;feasibility research;flexibility;improved;innovation;meetings;minority investigator;novel;novel strategies;programs;research study;success;synergism;technology/technique;tool;translational potential;treatment strategy Developmental Research Program 1 NARRATIVEOur successful Lymphoma SPORE Developmental Research Program (DRP) will continue to support pilotprojects of novel translational ideas in lymphoma research with the long-term goal of incorporating theseprojects into the SPORE or seeking independent funding for them in the future. The eight DRP projects (ledby 5 women and 2 minority PIs) supported in our last funding cycle have already amassed $8.65 milliondollars in external peer-reviewed funding. With the addition of a new co-leader in Dr. George Carrum weaim to continue this successful track record while increasing diversity among our DRP awardees. NCI 10704671 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6 8803 1884819 "BRENNER, MALCOLM K." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 124660 80841 43819 PROJECT SUMMARYThe goal of the Lymphoma SPORE Developmental Research Program (DRP) is to support innovativetranslational research projects that may in the future develop into full projects. To achieve this objective theDRP will solicit submission of novel projects with translational potential in lymphoma and chronic lymphocyticleukemia (CLL). The program will be led by directors Drs. Malcolm Brenner and Margaret Goodell whocontinue as DRP leaders and new co-leader Dr George Carrum who brings with him clinical expertise and acommitment to increasing diversity among DRP awardees. Candidate projects will be reviewed by a panelwith expertise in translational research and the most promising proposals will be selected for support. Ourgoal for each supported project is that it will either develop into a full SPORE project or secure peer-reviewedfunding as an independent project. We will continue to achieve this goal by fully incorporating the leaders ofdevelopmental projects into the SPORE enabling them to take advantage of the expertise of SPOREinvestigators in translating their project from the bench to bedside. In the last four years our Lymphoma SPORE DRP has supported a broad portfolio of 9 projects bydiverse investigators from five different Departments and Centers within Baylor College of Medicine as wellas other institutions in the Texas Medical Center (one award to Texas A&M and one to Rice University) andnationally (one award to Moffitt Cancer Center). Five female and two underrepresented minority investigatorshave led the nine DRP projects supported in most recent funding period and have already been leveraged toobtain $8.65 million in peer-reviewed funding from an initial investment of $450000. Long-term follow up ofthe 28 projects funded in the first two cycles of our SPORE shows 46 publications that have been cited over4300 times and over $18.4 million dollars in peer-reviewed funding from an investment of $1.4 million throughour DRP. In collaboration with the Administrative Core the DRP directors will continue to use this program totest and develop novel strategies for the treatment of lymphoma and CLL and will also collect data to evaluatethe success of the DRP program including seeking the feedback and advice of our internal and externaladvisory boards. +No NIH Category available Accreditation;Address;Adverse reactions;American;Antigen-Presenting Cells;Area;Australia;Cell Therapy;Cells;Chemistry;Clinical;Clinical Laboratory Improvement Amendments;Clinical Protocols;Clinical Research;Clinical Trials;Contracts;Dedications;Development;Documentation;Effector Cell;Environmental Monitoring;Equipment;Europe;Far East;Flow Cytometry;Foundations;Generations;Genes;Genetic;Good Manufacturing Process;Immune;Individual;Infrastructure;International;Investigational Drugs;Investigational New Drug Application;Knowledge;Laboratories;Lymphoma;Medicine;Modification;National Heart Lung and Blood Institute;Outcome;Pathologist;Phase;Plants;Population;Preparation;Procedures;Process;Production;Qualifying;Quality Control;Quality Indicator;Reagent;Records;Regulation;Research;Research Personnel;Resource Sharing;Services;Somatic Cell;Source;System;Testing;Therapeutic;Training;Translations;United States Food and Drug Administration;Validation;Viral Vector;cell bank;cell preparation;college;experience;gene therapy;manufacture;pre-clinical;programs;quality assurance;translational study;vector Core C: GMP Cell and Vector Production PROJECT NARRATIVEThe Cell and Vector Production Core (Core C) is essential for the clinical protocols proposed in each of theSPORE projects. The Core will be responsible for the preparation of therapeutic grade viral vectors and formanufacturing the various cellular therapy products that will be used in the proposed clinical trials. It willadditionally assist in the translation of pre-clinical procedures into clinical scale manufacturing and testing.Core C will also provide the quality control and assurance services required to support the GoodManufacturing Practices infrastructure. NCI 10704663 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6 8799 10011571 "LAPTEVA, NATALIA " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 280115 181652 98463 PROJECT SUMMARYThe three projects comprising this application use immune effector cells to treat lymphoma. Food and DrugAdministration (FDA) regulations require that therapeutic cell populations must be manufactured undercurrent Good Manufacturing Practices (cGMP). Core C (Cell and Vector Production) will provide theinfrastructure necessary to meet this requirement. The cGMP facility at the Center for Cell and Gene Therapyconsists of 22 ISO 7 clean rooms fully equipped for the preparation of cell and gene therapy products. Overthe last 23 years our staff have manufactured more than 7000 cellular therapy final products (and countlessintermediates) and >70 clinical grade viral vectors and master and working cell banks in support of more than60 IND studies and international clinical protocols. During this period the facility was designated as a NationalGene Vector Laboratory and as a National Somatic Cell Processing Facility under a contract from NHLBIProduction Assistance for Cellular Therapy (PACT) program. Manufacturing services are supported by adedicated specialized flow cytometry laboratory which performs >13000 tests annually; a quality controllaboratory performing in-house testing and environmental monitoring (>25000 tests/year); and anindependent quality assurance group which oversees compliance. The program is accredited by theFoundation for the Accreditation of Cellular Therapy the College of American Pathologists and under theClinical Laboratory Improvements Amendments. The Cell and Vector Production facility is registered with theFDA. In addition to manufacturing responsibilities the Core staff are experienced in transitioning researchprocesses into GMP-compliant procedures and providing regulatory advice. This experience will be essentialin supporting the clinical components of this Lymphoma SPORE application. +No NIH Category available Antibody-drug conjugates;Automobile Driving;Biography;Biological Markers;Biological Products;Bladder;Breast Cancer Patient;Cancer Patient;Chemotherapy and/or radiation;Cisplatin;Clinic;Clinical;Combined Modality Therapy;DNA Damage;Data;Disease;Event;Foundations;Gene Expression;Genetic;Genetic Transcription;Genomics;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Immune;Immune checkpoint inhibitor;Immune system;Immunologic Factors;Immunologics;Immunotherapy;International;Malignant neoplasm of urinary bladder;Modality;Molecular;Mutation;Oncology;Outcome;Pathogenesis;Patients;Radiation;Radiation Tolerance;Radiation therapy;Radiobiology;Research;Research Personnel;Resistance;Robin bird;Roentgen Rays;Testing;Therapeutic;Treatment Efficacy;Work;antitumor effect;cancer therapy;cancer type;checkpoint therapy;chemotherapy;immune checkpoint blockade;improved;improved outcome;innovation;insight;multidisciplinary;multimodality;next generation;preservation;programs;radiation effect;radiation resistance;radiation response;radiomics;response;standard of care;treatment strategy;tumor Genomic and Microenvironmental Determinants Temporal Dynamics and Treatment Efficacy of Radiation-Based Combination Therapies PROJECT NARRATIVEOverall Section This proposal focuses on elucidating the genomic and microenvironmental determinants and temporaldynamics underlying efficacy of radiation-based combination therapies. We will use an innovative molecularcharacterization trial testing radiation plus antibody-drug conjugate in bladder cancer and radiation plusimmunotherapy in head and neck cancer to characterize the mechanistic drivers underlying these nextgeneration RT-based therapies. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. NCI 10704661 7/31/23 0:00 RFA-CA-21-040 5U54CA274513-02 5 U54 CA 274513 2 "VIKRAM, BHADRASAIN" 9/14/22 0:00 7/31/27 0:00 ZCA1-SRB-X(M1) 9306964 "CHAN, TIMOTHY AN-THY" "YU, DAVID SUNG-WEN" 11 INTERNAL MEDICINE/MEDICINE 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 1473606 NCI 1138034 335572 PROJECT SUMMARYOverall Section Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants andtemporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT) alone orin combination with other treatments is used to treat about two-thirds of all cancer patients. Despite thewidespread use of radiation therapy in oncology our understanding of the mechanisms driving response andresistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy andresistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus onusing combination therapies in which radiation is used with systemic agents highlighting the urgent need tounderstand the drivers of efficacy. Among the most promising new biologics being studied for use withradiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use aninnovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI inhead and neck cancer to characterize the mechanistic drivers underlying these next generation RT-basedcombinations. The central hypothesis of this U54 application is that specific genetic and immunologicmechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will addressthese questions through 3 specific aims. In Aim 1 we will work to understand the molecular mechanisms thatunderlie efficacy of treatment with radiation plus ADC. Here our working hypothesis is that specific genetic andimmunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage ourmolecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservationtherapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT +SG. In Aim 2 we will improve identification of patients who are sensitive or resistant to RT-based therapiesbased on new insights into transcriptional dynamics and temporal reprogramming during treatment withradiation-based therapies. Here we will leverage our molecular characterization trial treating head and necksquamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG orICI. We will build on recent experimental and clinical breakthroughs led by our research groups which haveidentified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim3 we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT +immune checkpoint blockade. Here using our head and neck trial (Part B) we will uncover the unique geneticand immunologic factors that govern response to RT when combined with these two classes of agents. Wewill elucidate the differential molecular effects of the two approaches immune reprogramming andmechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal radiation-based definitive treatment strategies. 1473606 +No NIH Category available Address;Architecture;Benchmarking;CRISPR/Cas technology;Cancer Model;Cancer Patient;Cells;Chemotherapy and/or radiation;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Colostomy Procedure;Combination Drug Therapy;Cytotoxic Chemotherapy;Data;Development;Diagnosis;Disease;Drug Screening;Effectiveness;Epigenetic Process;Evaluation;Evolution;Excision;Experimental Models;Foundations;Genetic;Genomics;Genotype;Goals;Human;Implant;In complete remission;Infrastructure;Institution;Instruction;KRAS2 gene;Laboratories;Light;Malignant Neoplasms;Mentors;Methods;Modeling;Mutation;Neoadjuvant Therapy;Operative Surgical Procedures;Organoids;Pathologic;Patients;Phenotype;Radiation therapy;Rectal Cancer;Rectal Neoplasms;Rectum;Research;Resistance;Sampling;Specimen;Structure;TP53 gene;Techniques;Thick;Time;Training;Treatment outcome;Tumor Volume;Variant;Xenograft Model;advanced disease;career development;chemoradiation;chemotherapy;design;drug sensitivity;epigenomics;experience;genome-wide;high-throughput drug screening;improved;innovation;knowledge base;lymph nodes;mutant;neoplastic cell;non-genetic;novel;novel therapeutic intervention;patient derived xenograft model;patient subsets;radioresistant;rectal;resistance mechanism;response;screening;single-cell RNA sequencing;standard care;subclonal heterogeneity;success;targeted treatment;therapeutic target;therapy resistant;treatment strategy;trend;tumor;tumor eradication Harnessing treatment-induced tumor evolution and collateral sensitivities using a human rectal cancer co-clinical platform Advanced rectal tumors are treated with combined chemotherapy and radiation therapy (chemoradiation) priorto surgery but there is wide variation in the magnitude of tumor response. Optimizing non-surgicalchemoradiation-based treatments could spare some patients the need to undergo a morbid surgery but willrequire a detailed understanding of how chemoradiation causes evolution of tumor subpopulations as well asthe development of unique approaches to therapeutically target these evolving subpopulations. This project willuse cutting-edge techniques to dissect tumor responses to chemoradiation as well as an innovative approachto identify new treatment strategies for locally advanced rectal cancer. NCI 10704660 9/12/23 0:00 PA-20-203 5K08CA263300-02 5 K08 CA 263300 2 "BIAN, YANSONG" 9/13/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 9304087 "EYLER, CHRISTINE ELISSA" Not Applicable 4 RADIATION-DIAGNOSTIC/ONCOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 240840 NCI 223000 17840 PROJECT SUMMARY/ABSTRACTLocally advanced rectal cancer defined by spread to lymph nodes or extension through the full rectal wallthickness is diagnosed in over 15000 US patients yearly. Standard treatment for locally advanced rectalcancer in the US involves chemotherapy and radiation therapy (chemoradiation CRT) prior to surgical removalof the entire rectum. Patients may experience undesirable post-surgical consequences such as permanentcolostomy or altered anorectal function. In light of this much ongoing research focuses on strategies to avoidsurgical intervention in the subset of patients who might be cured with CRT alone. At the time of surgery 10-30% of tumors are eradicated by CRT (i.e. they demonstrate a pathologic complete response) while othertumors show little to no response. This variability in response is incompletely understood but likely relates tothe fact that one tumor may contain numerous different tumor cell subpopulations all with different genotypesand epigenetic (or non-genetic) features. These diverse subpopulations and variable genetic/epigeneticfeatures can interact resulting in a dynamic and evolving tumor cell network that is poorly understood. In anincreasing number of cancers there is evidence supporting the emergence of treatment-induced evolutionarytraps or collateral sensitivities where resistance to one therapy results in sensitivity to another therapy.Whether this occurs in rectal cancer and how to leverage it into treatment strategies is unclear. To addressthese questions it is crucial to select a representative experimental model. Thus the current proposalleverages an already-established co-clinical pipeline from which patient derived tumor samples are used togenerate paired patient-specific organoid and xenograft models. Two broad analytic approaches will beundertaken to identify trends in CRT-induced tumor evolution and elucidate potential synergistic approaches toimprove CRT response. Specific Aim 1 will dissect CRT-induced changes using genomic epigenomic andsingle cell profiling techniques including an advanced method combining single cell RNA-seq with lineagetracing. Specific Aim 2 employs an innovative iterative paired CRISPR/high throughput drug screen approachto identify evolving collateral sensitivities in CRT-treated rectal cancer. To validate the findings in both Aimsadvanced patient-derived rectal cancer organoid and xenograft models will be utilized. Research scientificinstruction and career development will be supported by an expert panel of mentors and collaborators and astructured training plan. Successful completion of both Aims will be promoted by the expertise and existingscreening and genomic infrastructure in the co-mentors laboratories and leverages a unique co-clinicalplatform already established by close institutional collaborators. This research will establish a patient-derivedplatform for interrogating CRT-induced tumor evolution establishing a scientific niche to facilitate successduring the transition to scientific independence. 240840 +No NIH Category available Absenteeism;Address;Advanced Malignant Neoplasm;Area;Biology;Boston;Cancer Center;Cancer Control;Cancer Science;Cancer health equity;Charge;Color;Communities;Community Networks;Community Outreach;Creativeness;Data;Data Set;Dedications;Discipline;Disparity;Education;Ethnic Origin;Experimental Designs;Faculty;Foundations;Funding;Genomics;Goals;Government;Grant;Health Disparities Research;Incidence;Infrastructure;Institution;Joints;Lasers;Leadership;Malignant Neoplasms;Massachusetts;Mentors;Methods;Modeling;Morbidity - disease rate;Phase;Population;Population Group;Population Heterogeneity;Population Sciences;Postdoctoral Fellow;Race;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Solid;Source;Students;Training;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;anticancer research;cancer health disparity;career;career development;community engagement;community organizations;dissemination science;education research;experience;experimental study;implementation science;innovation;member;mortality;outreach;outreach program;programs;research and development;research study;socioeconomic disparity;translational model;translational potential 1/2 The University of Massachusetts Boston - Dana-Farber/Harvard Cancer Center U54 Comprehensive Partnership for Cancer Disparities Research PROJECT NARRATIVEThe University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC)Partnership is committed to further developing a shared rigorous and collaborative transdisciplinary cancer anddisparities-related research program that is primed for Bridging the Divides: Innovations to Address Gaps inCancer Disparities Research Education Outreach and Infrastructure. Sophisticated research projects areproposed across several areas of basic biomedical and population sciences that will employ evidence andmethods to converge upon and impact cancer and cancer health disparities at multiple levels of analysis.These projects together with state-of-the-art Outreach and Research Education Cores and creative ResearchDesign and Analysis Core and Genomics Cores will serve to build research capacity and infrastructure atUMass Boston expand the cancer disparities platform and community outreach programs at DF/HCC; andmake at an elevated level significant advances to the science of cancer control. NCI 10704659 8/3/23 0:00 PAR-18-767 5U54CA156734-13 5 U54 CA 156734 13 "WALI, ANIL" 9/28/10 0:00 8/31/26 0:00 ZCA1-SRB-2(A1)S 8606765 "COLON-CARMONA, ADAN " "MACOSKA, JILL A.; VISWANATH, KASISOMAYAJULA " 8 BIOLOGY 808008122 CGCDJ24JJLZ1 808008122 CGCDJ24JJLZ1 US 42.313703 -71.062976 850902 UNIVERSITY OF MASSACHUSETTS BOSTON BOSTON MA SCHOOLS OF ARTS AND SCIENCES 21253300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1483629 NCI 980000 514500 SUMMARYThe University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC)Partnership is primed for Bridging the Divides: Innovations to Address Gaps in Cancer DisparitiesResearch Education Outreach and Infrastructure. Our goal is to pursue Partnership activities andresearch that will bridge the divides in cancer disparities science research education and outreach throughinnovative research training and practice serving as models for translation at the state and national level. ThePartnerships to Advance Cancer Health Equity (PACHE) program itself is a prime example of bridged divides:partnerships formed between institutions have enhanced the education of underrepresented population groupsand provided well-established cancer centers with the necessary resources and research infrastructure toaddress cancer disparities.The specific aims of the UMass BostonDF/HCC Partnership are to: 1) Advance Partnership transdisciplinarycancer and cancer health disparities research programs reflecting the theme Bridging the Divides; 2) Developeducational experiences for students and trainees from a diverse population typically underrepresented inbiomedical careers; 3) Promote hiring and retention of diverse scholars particularly those fromunderrepresented populations by leveraging institutional resources; 4) Bridge research-community dividesthrough innovative platforms: forming and engaging networks of community-based organizations to advanceoutreach drawing on state of the science from dissemination and implementation sciences (D&I); 5) Developcutting-edge approaches to address data-absenteeism the lack of representation of underserved groups inpopulation- community- and genomics-based cancer and cancer disparities datasets and projects; and 6)Promote sustainability of partnership activities by reinforcing institutional support and grant matching with NIH-mechanisms and other sources of government foundation and philanthropic support. 1483629 +No NIH Category available Address;Adverse event;Annual Reports;Biological Products;Biometry;Biostatistics Core;Clinical;Clinical Data;Clinical Management;Clinical Research;Clinical Research Protocols;Clinical Trials;Collaborations;Complex;Comprehensive Cancer Center;Conduct Clinical Trials;Consent Forms;Consultations;Data;Data Analyses;Data Collection;Data Reporting;Databases;Dedications;Enrollment;Ensure;Futility;Good Clinical Practice;Human Resources;Individual;Infrastructure;Institution;Institutional Review Boards;Intranet;Lymphoma;Medicine;Monitor;Notification;Nursing Research;Outcome;Patient Care;Patient Recruitments;Patients;Physicians;Preparation;Principal Investigator;Procedures;Protocol Compliance;Protocols documentation;Quality Control;Randomized;Regulation;Regulatory Affairs;Reporting;Research;Research Design;Research Infrastructure;Research Personnel;Research Support;Resource Sharing;Resources;Review Committee;Safety;Science;Services;Statistical Methods;Statistical Study;System;Toxic effect;Training;Update;Work;care providers;clinical development;college;data management;design;experience;experimental study;meetings;operation;pre-clinical;preclinical study;programs;protocol development;quality assurance;research study;searchable database;web site Core B: Clinical Research NARRATIVEThe Clinical Research and Biostatistics Core supports the SPORE clinical research studies to ensure theyare conducted safely accurately and in accordance with applicable regulations. This Core (Core B) alsoprovides all SPORE projects with statistical support for preclinical experiments and clinical trials. NCI 10704656 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6 6184 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 143257 92901 50356 PROJECT SUMMARYThis core provides all projects with centralized clinical trial support and the infrastructure of personnel andservices essential to safely and effectively support such research to meet Good Clinical Practice (GCP)standards. Core services will be provided in Regulatory Affairs Study Co-ordination Quality Assurance (QA)and Control (QC) and Data Safety Monitoring (DSM) leveraging the clinical research infrastructure of the DanL Duncan Comprehensive Cancer Center (DLDCCC) at Baylor College of Medicine. The Regulatory Affairscomponent collaborates with investigators to develop and submit all required regulatory documents includinginitial and revised submissions to the IRB IBC and FDA and the subsequent annual reports and adverseevent notifications as required. This core has extensive experience with IND submissions successfullysubmitting over 100 studies of complex biological agents on over 50 INDs: the completed studies haveenrolled over 1200 patients. The Study Co-ordination group arranges meetings of investigators attendingphysicians research nurses and data managers; provides training on the standard operating procedures(SOPs) for each protocol; and offers research coordinator support to ensure that clinical studies are conductedsafely accurately and efficiently to GCP standards using the OnCore clinical trials management system. TheQC program will ensure that the standard operating procedures for protocol development conduct of clinicaltrials data collection and management of clinical trials are followed. The QA program will audit each studyafter the first patient is enrolled; subsequent audits are held in a randomized way to ensure that studies followGood Clinical Practices. Data Safety monitoring is provided through the DLDCCC Data Review Committee orexternal DSMB operating under an NCI-approved data safety monitoring plan which is responsible forreviewing and evaluating toxicity and any other study-relevant safety-related data for clinical research studies.Finally the core provides comprehensive and centralized biostatistical support to projects including studydesign data analysis and data management for preclinical and clinical studies. Centralized biostatisticalsupport facilitates efficient use of these services and promotes collaboration between biostatisticians andinvestigators in the design conduct analysis and interpretation of results for all projects. This ensures theconduct of high-quality projects that incorporate appropriate and state-of-the-art statistical methods from theirdesign to their analysis. +No NIH Category available Address;Advanced Malignant Neoplasm;Area;Basic Cancer Research;Benchmarking;Biomedical Research;Cancer Biology;Cancer Center;Collaborations;Communication;Communities;Data;Data Commons;Deposition;Division of Cancer Biology;Education and Outreach;Educational workshop;Effectiveness;Ensure;Evaluation;FAIR principles;Fostering;Funding;Glues;Hybrids;Knowledge;Knowledge Portal;Learning;Malignant Neoplasms;Metadata;Modeling;Outcomes Research;Persons;Qualifying;Research Personnel;Resource Sharing;Resources;Science;Scientist;Software Tools;System;Systems Biology;Training;Validation;Work;anticancer research;community building;community engagement;data harmonization;data sharing;diversity and inclusion;evidence base;experience;ideation;improved;informatics infrastructure;innovation;interdisciplinary approach;interdisciplinary collaboration;interoperability;meetings;metadata standards;next generation;outreach;programs;public repository;special interest group;success;tool;translational cancer research;usability;working group Multi-Consortia Coordinating Center (MC2 Center) for Cancer Biology: Building Interdisciplinary Scientific Communities Coordinating Impactful Resource Sharing and Advancing Cancer Research Project NarrativeAdvancing our understanding of cancer requires teams of scientists working together but many labs andresources remain siloed. The proposed MC2 Center will catalyze collaboration improve the usability of shareddata and tools and ensure wide dissemination of resources to the broader cancer research community. Theresulting collaborative network of diverse researchers will power the next generation of cancer discoveries andtreatments. NCI 10704654 8/18/23 0:00 RFA-CA-21-049 5U24CA274494-02 5 U24 CA 274494 2 "TURNER, MICHELLE C" 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M2) 1891838 "BLETZ, JULIE A" "EDDY, JAMES A" 7 Unavailable 830977117 TPALZA9N4M11 830977117 TPALZA9N4M11 US 47.62803 -122.330082 10023027 SAGE BIONETWORKS SEATTLE WA Other Domestic Non-Profits 981211031 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 1867064 NCI 1273154 593910 Project SummarySystems Biology has been an instrumental approach to overcoming challenges in biomedical research wheresolutions arise from interdisciplinary efforts shared resources (data tools models expertise) and integrativeanalyses. The NCI Division of Cancer Biology (DCB) has created multiple consortia comprising interdisciplinarycommunities of scientists who aim to integrate approaches data and tools to address important questions inbasic and translational cancer research. The Multi-Consortia Coordinating (MC2) Center for Cancer Biology willwork across programs to motivate engagement and collaboration support resource sharing and disseminateknowledge and resources to the broader scientific community.The MC2 Center will operate through three hubs. The Collaboration Hub will use evidence-based strategies tocatalyze interactions and new collaborations. An evaluation framework will be developed with quantitative andqualitative metrics to ensure the center continuously improves its impact. Community engagement activities willinclude working groups special interest groups DREAM Challenges and Ideation Jams all of which will havemechanisms for ensuring inclusion and promoting diversity. To facilitate sharing of resources from DCBprograms the Resource Coordination Hub will ensure all resources are findable accessible interoperable andreusable (FAIR); it will identify or develop open and FAIR standards and best practices; provide training onhow to implement these standards and practices in the cancer research community; and provide tooling andinterfaces to facilitate resource sharing curation and deposition in public repositories. Finally the OutreachHub will enhance dissemination of knowledge and resources through training materials to maximize utilizationof tools and short courses and workshops that bring concepts and resources from across the DCB programstogether enabling the broader community to experience the power of an integrative interdisciplinary approachto cancer.The Cancer Complexity Knowledge Portal will continue to provide open access to all data tools and otherresources generated through the DCB and MC2 highlighting discoveries and enabling exploration into themany valuable resources generated by DCB programs. 1867064 +No NIH Category available 3-Dimensional;Address;Biological Models;Breast;Breast Cancer Model;Breast Cancer Patient;Breast cancer metastasis;CRISPR screen;CRISPR/Cas technology;Cancer Relapse;Cell Communication;Cells;Classification;Clinical;Collection;Computer Models;Data;Dependence;Development;Diagnosis;Disease;ERBB2 gene;Estrogen receptor positive;Experimental Models;Genomic approach;Genomics;Goals;Image;Immune;Immune system;In Situ;Lead;Longitudinal cohort;Machine Learning;Macrophage;Malignant Neoplasms;Metastatic breast cancer;Modeling;Molecular;Molecular Profiling;Multiplexed Ion Beam Imaging;Nature;Neoplasm Metastasis;Non-linear Models;Oncogenic;Organoids;Outcome;Pathologist;Pathology;Patients;Phagocytosis;Population;Primary Neoplasm;Process;Property;Relapse;Research Project Grants;Research Support;Resistance;Resolution;Resource Sharing;Sampling;Site;Spatial Distribution;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stromal Cells;Subgroup;System;Systems Biology;Technology;Therapeutic;Time;Tissue Model;Tissue Sample;Tissues;Tumor Tissue;Vision;Visualization;bean;biobank;breast cancer progression;cancer cell;cohort;computer framework;computerized tools;data integration;disease heterogeneity;functional genomics;genome-wide;high risk;hormone therapy;innovation;invention;malignant breast neoplasm;multidisciplinary;neoplastic cell;prospective;relapse risk;response;single cell technology;targeted treatment;therapeutic target;therapy resistant;tissue resource;triple-negative invasive breast carcinoma;tumor Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer Project NarrativeMetastatic breast cancer and relapse following therapy are dependent on (1) development of intrinsic resistanceto targeted and endocrine therapies and (2) resistance to recognition and destruction of cancer cells by theimmune system. The Stanford Breast Metastasis Center (SBMC) is focused on (1) quantifying the timing ofmetastatic dissemination in breast cancer (2) functionally delineating the contribution of cellular andmicroenvironmental crosstalk on metastatic proclivity and (3) characterizing the mechanisms of responses bymetastatic cells to therapies. To achieve these goals we harness an integrated systems biology functionalgenomic and evolutionary dynamic approach applied to longitudinal breast cancer tissue cohorts and patient-derived organoid models. NCI 10704647 8/10/23 0:00 RFA-CA-20-029 5U54CA261719-03 5 U54 CA 261719 3 "NADEAU, CHRISTINE FRANCES" 9/14/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y(M1) 10842134 "CURTIS, CHRISTINA N" Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1532156 NCI 988045 544111 Abstract/Project SummaryMetastatic breast cancer and relapse following therapy are dependent on (1) development of intrinsic resistanceto targeted and endocrine therapies and (2) resistance to recognition and destruction of cancer cells by theimmune system. The Stanford Breast Metastasis Center (SBMC) is focused on (1) quantifying the timing ofmetastatic dissemination in breast cancer (2) functionally delineating the contribution of cellular andmicroenvironmental crosstalk on metastatic proclivity and (3) characterizing the mechanisms of responses bymetastatic cells to therapies. In order to achieve these goals mechanistic computational models that capture dynamic andemergent tumor cell intrinsic and extrinsic properties are needed as are clinically annotated longitudinaltissue cohorts and experimental models that capture disease heterogeneity. The SBMC addresses each of theseoutstanding challenges. First we have established an unparalleled collection of clinically annotated breastcancer cohorts sampled through treatment and metastasis including both prospective and retrospectivelongitudinal cohorts with multiple metastatic sites. We leverage a living biobank of breast cancer patient-derived organoids (PDOs) from primary tumors and metastases that recapitulate the heterogeneity ofdisease high-risk of relapse subgroups and tumor-immune interactions and greatly facilitating the proposedfunctional studies. We characterize these vast tissue resources and model systems using state-of-the-artmolecular profiling technologies to probe tumor tissue in situ at single cell and subcellular resolution. Specificallywith Multiplexed Ion Beam Imaging by Time of Flight (MIBI-TOF) and matrix-assisted laser desorption ionizationimaging (MALDI) we simultaneously visualize the composition lineage function and spatial distribution of tumorand stromal cell populations and perform co-registered analysis of the glycome. We integrate these data withinthe genomic landscape of metastatic disease and analyze these data within robust machine learning andcomputational frameworks to uncover disease dynamics and features associated with clinical outcomes.Lastly we conduct genome-scale CRISPR screens in 3D breast cancer models to systematically defineoncogenic dependencies therapeutic vulnerabilities and macrophage-tumor cell interactions. This integrated systems biology and functional genomics approach will contribute to a quantitative andmechanistic understanding of metastatic breast cancer and the dynamic relationship between tumor cells andthe host with implications for therapeutic targeting. 1532156 +No NIH Category available Acceleration;Address;Adoptive Cell Transfers;Allogenic;Antigens;Autologous;Automobile Driving;B lymphoid malignancy;B-Lymphocytes;Back;Behavior;CAR T cell therapy;Cell Lineage;Cell Therapy;Cells;Clinic;Clinical;Clinical Data;Clinical Research;Cyclic GMP;Dasatinib;Disease Progression;Engineering;Ensure;Frequencies;Funding;Genes;Goals;Hematopoietic Stem Cell Transplantation;Homing;Immune;Learning;Lymphoma;Malignant - descriptor;Modification;Outcome;Patients;Peripheral;Persons;Phase;Phase I Clinical Trials;Population;Property;Protocols documentation;Receptor Signaling;Recurrent disease;Refractory;Relapse;Resistance;Safety;T cell differentiation;T cell therapy;T memory cell;T-Cell Lymphoma;T-Cell Receptor Genes;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Therapeutic;Tyrosine Kinase Inhibitor;Undifferentiated;anti-cancer;arm;cell preparation;chimeric antigen receptor;chimeric antigen receptor T cells;clinically significant;donor stem cell;first-in-human;fitness;graft vs host disease;improved;improved outcome;inhibitor;lymph nodes;manufacture;novel;patient subsets;pharmacologic;pre-clinical;preservation;receptor;receptor expression;response;success;therapy resistant;tumor Project 2: CAR-T cell therapy for T cell lymphoma NARRATIVEPatients who have T-cell lymphoma that does not respond to or comes back after treatment do not have goodoprions for treatment. We have shown that the patients own non-cancerous T cells can be modified with a genethat allows them to recognize and kill their malignant counterparts. We will now make these anti-cancer T cellsmore efficient and then modify them further so that they can be made from healthy people in advance andstored ready to use immediately for anyone with a T cell lymphoma. NCI 10704642 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6 6182 1884819 "BRENNER, MALCOLM K." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 328022 212719 115303 PROJECT SUMMARY/ABSTRACTIn this project we will improve the outcome and the accessibility of adoptive cell therapy with engineered CD5-specific chimeric antigen receptor (CAR) T-cells in patients with refractory or relapsed T-cell lymphoma (r/r TCL).These studies build on the promising results obtained in the Phase I clinical trial funded in the previous SPOREwhere autologous CD5 CAR T-cells produced robust clinical responses in 44% of patients with recalcitrant TCLenabling three out of nine patients to proceed with allogeneic hematopoietic stem cell transplantation (HSCT).These responses were achieved by CAR T-cell products enriched for minimally differentiated T-cell subsets. Wewill now overcome the remaining barriers to success and accessibility identified from our previous study namelythe rapid loss of potency of ex vivo expanded CD5 CAR T-cells induced by tonic CAR signaling low frequencyand poor fitness of patient-derived T-cells and rapid disease progression due to lengthy manufacturing ofautologous cell products. We will use several complementary strategies to improve the clinical potency of CD5CAR T-cell products and to enable patients to rapidly receive these products as banked (off the shelf) cells. Inclinical studies in Aim 1 we use pharmacologic inhibitors to reversibly inhibit tonic CAR signaling and theresultant terminal differentiation of CD5 CAR T-cells during cGMP manufacturing and evaluate CD5 CAR T-cells generated from HSCT (i.e. normal) donors for patients whose disease relapsed after allogeneic HSCT. Wepredict these improvements will preserve the beneficial undifferentiated T-cell subsets and thus improveexpansion and anti-lymphoma activity of CD5 CAR T-cell products; this hypothesis is supported by our earlyclinical data. To further maximize clinical potency of CD5 CAR T-cells and expedite treatment of patients withrapidly progressing disease in Aim 2 we will develop banked CD5 CAR T-cells for off-the-shelf therapy.Leveraging our latest preclinical findings we will engineer these CD5 CAR T-cells to eliminate alloreactivity(using TCR gene editing) and resist host immune rejection by arming them with a novel alloimmune defensereceptor ADR. These modifications should ensure the safety and functional persistence of allogeneic CD5 CART-cells in patients. We will manufacture and bank highly potent ADR-armed TCR-edited CD5 CAR T-cells inAim 3 and initiate a Phase I clinical trial in patients with treatment-resistant TCL. Overall these studies shouldprovide a safe and effective cell therapy for patients with r/r T-cell lymphoma who have few alternative options. +No NIH Category available ATR gene;Address;Alkylating Agents;Alkylation;Apoptosis;Biological Markers;Brain;Brain Neoplasms;Cancer Therapy Evaluation Program;Carmustine;Cell Cycle;Cells;Clinic;Clinical Trials;Clinical Trials Design;Collaborations;Combined Modality Therapy;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;DNA analysis;DNA lesion;Data;Defect;Disease;Dose;Double Strand Break Repair;Drug Kinetics;FDA approved;Futile Cycling;Glioblastoma;Goals;In Situ;In Vitro;Lead;Lesion;Lomustine;Mediating;Methylation;Methyltransferase;Methyltransferase Gene;Mismatch Repair;Modeling;Molecular;Molecular Profiling;Newly Diagnosed;Newly Diagnosed Disease;Operative Surgical Procedures;Pathway interactions;Patients;Pharmacologic Substance;Phase;Phase 0/1 Trial;Phosphotransferases;Proteins;Radiation therapy;Recommendation;Recurrence;Recurrent disease;Research;Resistance;Sampling Studies;Signal Transduction;Site;Therapeutic;Therapeutic Index;Tissues;Translations;Vertebral column;Work;adduct;ataxia telangiectasia mutated protein;base;blood-brain barrier penetration;chemotherapy;clinically relevant;crosslink;cytotoxicity;design;genotoxicity;improved;in vivo;inhibitor;innovation;multidisciplinary;new combination therapies;novel;novel therapeutic intervention;patient derived xenograft model;phosphoproteomics;promoter;repaired;replication stress;response;safety testing;standard of care;synergism;temozolomide;tumor Novel DNA damage response inhibitor and alkylator combinations for GBM n/a NCI 10704630 9/7/23 0:00 RFA-CA-20-047 5U19CA264362-03 5 U19 CA 264362 3 9/1/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 9363 11263286 "BINDRA, RANJIT " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 278878 290108 51167 PROJECT DESCRIPTION/ABSTRACT PROJECT 1Alkylating chemotherapies are part of the backbone of standard-of-care therapy in newly diagnosed diseaseand they are also used in the recurrent setting. We and others have demonstrated that these agents each induceunique spectra of DNA damage which engage specific DNA damage response (DDR) pathways depending onthe status of key DNA repair pathways. The most commonly used agents are temozolomide (TMZ) amonofunctional alkylator that induces methyl-adducts on discrete DNA base sites and lomustine andcarmustine which are bifunctional alkylators that induce both mono-adducts and DNA cross-links. The differentDNA lesions induced by these and other alkylating therapies trigger distinct DNA damage responses criticallymodulated by ataxia-telangiectasia mutated (ATM) and ATM/Rad3-related (ATR) kinases which orchestrate thecellular response to a broad array of genotoxic insults. Over the past few years we have collaborated with theNCI Cancer Therapy Evaluation Program and multiple pharmaceutical companies (AstraZeneca Vertex MerckKGaA Bayer) to evaluate multiple highly brain penetrant ATM and ATR inhibitors in combination with radiationtherapy and alkylating chemotherapies. Our preliminary data demonstrate robust synergy between TMZ andATR inhibitors specifically in GBM models lacking. Mechanistically unrepaired O6-methyguanine lesionsinduced by TMZ cause replication stress and activation of the ATR signaling axis. In contrast synergisticinteractions of ATR inhibitors with lomustine were independent of MGMT status which reflects a distinct set ofalkylation lesions that are relatively unaffected by MGMT repair activity. Overall our extensive preliminary datasupport the fundamental scientific premise that monofunctional and bifunctional alkylator therapies trigger distinctfunctional and temporal activation of DNA damage response pathways governed by ATM and ATR.Understanding these relationships can be used to define optimal combinations of ATR or ATM inhibitors withvarious alkylating agents for GBM. +No NIH Category available Address;Agar;Biochemical;Biological Assay;Biomedical Engineering;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cells;Clinical Trials;Collaborations;DNA Damage;Data;Development;Double Minutes;Drug Exposure;Drug Kinetics;Evaluation;Funding;Heterogeneity;Human;Imaging technology;Immunofluorescence Immunologic;Infiltration;Laboratories;Liquid Chromatography;Massachusetts;Measures;Minnesota;Modeling;Mus;Normal tissue morphology;Pathway interactions;Periodicity;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacy (field);Phase 0/1 Clinical Trial;Process;Proteomics;Radiology Specialty;Recording of previous events;Regimen;Research;Research Personnel;Sampling;Schedule;Signal Pathway;Spatial Distribution;Systems Analysis;TP53 gene;Technology;Therapeutic;Therapeutic Agents;Therapy Evaluation;Tissue Sample;Tissue imaging;Tissues;Tumor Tissue;Tumor Volume;Universities;Validation;Work;ataxia telangiectasia mutated protein;combinatorial;design;drug development;drug distribution;drug efficacy;effective therapy;forest;inhibitor;innovation;mass spectrometric imaging;mid-career faculty;neurosurgery;novel therapeutics;pharmacodynamic biomarker;pharmacokinetics and pharmacodynamics;pharmacologic;phosphoproteomics;physical science;professor;programs;response;tandem mass spectrometry;therapeutically effective;transcriptomics;tumor Pharmacology Core n/a NCI 10704629 9/7/23 0:00 RFA-CA-20-047 5U19CA264362-03 5 U19 CA 264362 3 9/1/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 9362 1858108 "ELMQUIST, WILLIAM " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 372823 357578 77642 PROJECT DESCRIPTION/ABSTRACT PHARMACOLOGY CORE The Pharmacology Core will work closely with the project teams and the Therapy Evaluation Core to providecomprehensive pharmacology support for all proposed studies. The studies supported by the PharmacologyCore will address key pharmacologic issues and will inform crucial go-no go decisions in novel drugdevelopment for GBM including issues surrounding blood-brain barrier (BBB). Understanding the ability of drugsto distribute across the BBB into tumor tissue and surrounding normal brain infiltrated by GBM cells is criticallyimportant for the development of effective therapies especially those treatments that could lead to long-termsurvival. The proposed Center projects are focused on developing combinatorial regimens using DNA damageresponse (DDR) inhibitors targeting the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR)signaling pathways (Project 1) or the p53/murine-double minute 2 (MDM2) pathway (Project 2). Efficacy of thesecombination strategies is dependent on adequate drug exposure at optimal times throughout the tumor volumeincluding the infiltrative regions. Further both projects will use a rigorous spatial evaluation of pharmacokinetic(PK) processes and resulting pharmacodynamic (PD) effects of these drugs within normal brain and throughoutbrain tumor tissues to design and implement the most efficacious combination regimens. The PharmacologyCore is led by Dr. William Elmquist who is a Professor of Pharmaceutics at the University of Minnesota and aworld expert in the PK of drug distribution across the blood-brain barrier (BBB) into normal brain and braintumors. His key co-investigators include Dr. Forest White from Massachusetts Institute of Technology and Dr.Nathalie Agar from Harvard University. These three research groups have an extensive collaborative historyand many of the strategies planned have been rigorously validated through this close collaboration across thethree laboratories. The specific functions of this Pharmacology Core can be divided into three specific Aims:Specific Aim 1: Pharmacokinetic and CNS distribution analyses of novel therapeutic agentsSpecific Aim 2: Support the development of pharmacodynamic biomarkersSpecific Aim 3: Support human Phase 0/1 clinical trial development +No NIH Category available Administrator;Advisory Committees;Advocate;Award;Budgets;Cells;Characteristics;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Data;Development;Disputes;Ensure;Equipment;Evaluation;Funding;Genome;Goals;Group Meetings;Immune;Immunogenetics;Individual;Institution;Leadership;Link;Lymphoma;Measures;Medical center;Medicine;Monitor;Patients;Performance;Principal Investigator;Process;Productivity;Recommendation;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Texas;Work;career;career development;college;cost;equity diversity and inclusion;lectures;meetings;member;operation;programs;proteogenomics;response;single cell analysis;synergism;timeline;transcriptome;tumor Administrative Core NARRATIVEThe Administrative Core supports the leadership of the overall Lymphoma SPORE to facilitate cooperationand communication between all Projects and Cores for the successful completion of the proposed research.This Core organizes meetings to monitor progress and promote collaboration and obtains external adviceon program performance from Internal and External Scientific Advisory Boards. The Administrative Corealso co-ordinates input from patient advocates and the Baylor College of Medicine Office of Diversity. NCI 10704628 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6 8780 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 177597 115170 62427 PROJECT SUMMARYThe goals of the Administrative Core are to provide all projects within the Lymphoma SPORE withcentralized leadership and administrative support and to ensure effective communication among allProjects and Cores. Through this work the Administrative Core will ensure the Programs overall objectivesare being met. To achieve this goal Core leaders Drs. Helen Heslop and Malcolm Brenner will arrangeinternal group meetings including a monthly investigator meeting executive committee meetings andinvited research lectures. The Core will oversee the overall fiscal and budgetary management of theSPORE and assist each project and core leader to achieve their goals with a particular focus on assistingbudgetary planning. Over the last 14 years of funding this Core has monitored each project with input fromthe Executive Committee and Internal and External Advisory Boards and modified projects andincorporated new directions as necessary. For the current proposal the Administrative Core leaders willensure continued SPORE oversight by convening meetings of the Scientific Advisory Board which consistsof both internal and external investigators with expertise in the field and assessing and implementing theirrecommendations. The Core also coordinates input from patient advocates and liaises with the BaylorOffice of Diversity to ensure diversity in projects the Career Enhancement Program (CEP) theDevelopmental Research Program (DRP) and all clinical research conducted under the SPORE. This Corewill also coordinate the administration of the Developmental Research and the Career EnhancementPrograms to ensure that the objectives of these programs are being met. This Core has the discretionaryfunds to support new research opportunities or unexpected costs. Finally the Administrative Core willcommunicate with the NCI program staff and encourage and facilitate collaboration with other NCItranslational initiatives. +No NIH Category available Address;Adult;Allogenic;Antibodies;Antigen Targeting;Antigens;Autologous;B-Cell Lymphomas;Biological;CD19 gene;Cell Therapy;Cells;Cellular immunotherapy;Child;Clinic;Clinical;Clinical Investigator;Clinical Research;Combined Modality Therapy;Cytotoxic T-Lymphocytes;Dasatinib;Dinoprostone;Down-Regulation;EBV specific T-cells;Effector Cell;Elements;Engineering;Ensure;Epstein-Barr Virus-Related Lymphoma;Foundations;Frequencies;Future;Genes;Genetic;Glycolipids;Goals;Graft Rejection;Hodgkin Disease;Hospitals;Human Herpesvirus 4;Immune;Immune Evasion;Immune response;Immune system;Immunotherapy;In complete remission;Interleukin 7 Receptor;Interleukin-15;Investigation;Laboratories;Laboratory Scientists;Laboratory Study;Length;Licensing;Licensure;Lymphoma;Lymphoma cell;MHC Class II Genes;Mediating;Medicine;Methodist Church;MicroRNAs;Morbidity - disease rate;Multicenter Trials;Natural Killer Cells;Non-Hodgkin's Lymphoma;Orphan Drugs;Outcome;Patients;Phase I/II Trial;Process;Productivity;Property;Records;Research;Research Personnel;Research Support;Residual Neoplasm;Resistance;Resources;Safety;Signal Transduction;Source;Specificity;Stress;T cell therapy;T memory cell;T-Cell Activation;T-Cell Lymphoma;T-Lymphocyte;TNFRSF8 gene;Technology;Technology Transfer;Testing;Toxic effect;Transforming Growth Factor beta;Translational Research;Treatment Efficacy;Treatment-related toxicity;Tumor Antigens;Tumor-associated macrophages;Viral Antigens;Virus;alpha-beta T-Cell Receptor;anti-tumor immune response;beta-2 Microglobulin;cancer cell;cell bank;cell preparation;checkpoint inhibition;chimeric antigen receptor;chimeric antigen receptor T cells;clinical translation;college;comparative trial;early phase clinical trial;effector T cell;first-in-human;fitness;genetically modified cells;improved;in vivo;insight;invariant chain;knock-down;manufacture;mortality;neoplastic cell;novel;novel strategies;pre-clinical;precision medicine;programs;receptor;recruit;response;small hairpin RNA;small molecule;standard of care;success;tumor;tumor microenvironment;tumor-immune system interactions SPORE in Lymphoma OVERALL NARRATIVECellular immunotherapy has enormous potential to improve the therapy of lymphoma. The SPORE researchplan outlined in this renewal application seeks to develop more effective cellular immunotherapies byincreasing their antitumor activity against lymphomas in children and adults reducing treatment-relatedcomplications and simplying therapies to use banked allogeneic products that are immediately available.Results of these studies will lay the foundation for future comparative trials and licensing investigations. NCI 10704624 9/8/23 0:00 PAR-20-305 5P50CA126752-17 5 P50 CA 126752 17 "KUZMIN, IGOR A" 9/11/07 0:00 8/31/27 0:00 ZCA1-RPRB-6(M1)S 2413379 "HESLOP, HELEN E" "BRENNER, MALCOLM K." 9 PEDIATRICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2048062 NCI 1375498 672564 OVERALL PROJECT SUMMARYThe long-term goal of this SPORE renewal is to develop in the laboratory and test in the clinic novel cellularimmunotherapies mediated by genetically modified immune effector cells to treat non-Hodgkin lymphoma (NHL)and Hodgkin lymphoma (HL). We have assembled an integrated team of laboratory scientists and clinicalinvestigators with strong track records of productive translational research supported by four shared coreresources. To address the persistent challenges of suboptimal long term lymphoma control and unacceptablerates of treatment-related toxicity in lymphoma investigators in this program have proposed three projects eachinvolving early-phase clinical trials. All projects address the following five distinct lines of research: 1) Use highlyspecific T or NKT cell immunotherapies to target multiple lymphoma antigens. This objective will be pursued ineach project using either native or chimeric antigen receptors (CARs) or both. 2) Increase the potency of the Tor NKT cell immunotherapies for lymphoma. This theme includes targeting multiple antigens (Projects 1 and3) manufacturing changes to increase T cell fitness (Project 2) and adding a constitutive IL7 receptor to improvethe expression and persistence of Epstein Barr Virus-specific T cells (Project 3). 3) Overcome the immuneevasion tactics of lymphoma cells and their microenvironment. Project 1 will take advantage of the ability of NKTcells to overcome the immunosuppressive microenvironment to boost response rates. Project 2 will use analloimmune defense receptor to remove alloreactive cells from the tumor microenvironment and prolong survivalof banked CAR T cells. Project 3 investigators will exploit a constitutive IL7 receptor to enable T cells to sustainactivation and expansion in the presence of immunosuppressive molecules and will also evaluate combinationtherapy with Panobinostat (4) Make T and NKT cell immunotherapy more broadly applicable by using bankednormal donor cells. To make cells immediately available we will evaluate several sources of banked cellsincluding banked NKT cells as an off-the-shelf product (Project 1) knock down of TCR (Project 2) andbanked EBV specific T cells (Project 3). 5) Ensure transferred banked immune effectors are not rejected by thehost immune system. We will enable infused immune effectors to be resistant to the host immune response by;evaluating knock down of 2 microglobulin (B2M) to diminish MHC Class 1 expression and of the MHC Class IIinvariant chain (Project 1); adding a novel alloimmune defense receptor (Project 2); or taking advantage of theability of a CD30 CAR to target alloreactive T cells (Project 3). At the conclusion of these proposed studies wewill have evaluated the clinical activity and safety of several strategies with genetically modified immune effectorcells in NHL and HL and gained insight into immune and tumor factors that correlate with clinical outcome.Successful completion of these studies should increase the potency and improve accessibility of these cellularimmunotherapies for lymphoma. 2048062 +No NIH Category available Biological;Cell model;Cells;Code;Computer software;Custom;Data;Data Analyses;Deposition;Development;Ecosystem;Elements;Environment;Generations;Genetic;Infrastructure;Lead;Libraries;Link;Maps;Ontology;Pathway Analysis;Proteomics;Publications;Publishing;Pythons;Research;Research Personnel;Resources;Scientist;Services;Software Framework;Software Tools;Visualization;Work;cancer cell;data dissemination;data exchange;data resource;digital object identifier;infrastructure development;network models;protein protein interaction;protein structure;public repository;repository;software infrastructure;tool;web app;web interface;web portal;web services;web site Core 2: Software Infrastructure for Network Models and Cell Maps n/a NCI 10704622 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8777 7036028 "IDEKER, TREY " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 77419 77419 0 CCMI v2.0Core 2: Software Infrastructure for Network Models and Cell MapsCore Lead: Trey Ideker; Co-Investigator: Dexter PrattSUMMARYThe Software Infrastructure for Network Models and Cell Maps Core will support the CCMI Projects at allstages of research and publication. The core will provide infrastructure and assistance towards three mainelements: (1) the Cytoscape desktop application along with tools and services from the Cytoscape Ecosystem;(2) NDEx the Network Data Exchange; and (3) infrastructure for the development and deployment of webservices and applications. First we will support center investigators in use of the Cytoscape Ecosystem foranalysis and visualization of biological networks including protein--protein interaction networks from Project 1genetic interaction networks from Project 2 and multiscale cancer cell maps from Project 3. The CytoscapeEcosystem includes the well-known Cytoscape desktop environment the HiView multiscale cell model viewerthe IQuery pathway analysis tool multiple R and Python libraries and the CDAPS software framework for thegeneration of multiscale cell models. Second we will facilitate the use of NDEx by center investigators to publishCCMI cell maps interaction data and other products as live network data that can be immediately visualizedand used. We will also provide assistance in the use of NDEx to share pre-publication network data betweencenter investigators including direct programmatic access from Jupyter notebooks and other software. Thirdwe will provide assistance to Project 3 investigators in the creation of web interfaces and back-end services.For all projects we will facilitate programmatic access to resources hosting of websites the use of Dockersoftware containers and the management of CCMI Github repositories. Finally we will maintain and extend theCCMI web portal to provide access to (1) CCMI public networks and cell maps via the NDEx networks cloud (2)CCMI software tools and resources (3) custom websites and web applications CCMI v2.0 +No NIH Category available Affinity;Affinity Chromatography;Atlas of Cancer Mortality in the United States;Bioinformatics;Biological Assay;Biological Sciences;Breast;CRISPR/Cas technology;Cancer Model;Cancer cell line;Cell Line;Cell model;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complex;Computational Biology;Core Facility;Coupled;Cryoelectron Microscopy;Data;Dependence;Disease;Education;Generations;Genes;Genetic;Genetic Screening;Genomic medicine;Genomics;Goals;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Infrastructure;Knock-in;Knock-out;Lead;Mali;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Measures;Mentors;Modeling;Molecular;Mutate;Mutation;Outcome;PIK3CG gene;Pathogenesis;Pathology;Pathway Analysis;Pathway interactions;Phenotype;Physiological;Point Mutation;Protein Binding Domain;Protein Complex Subunit;Protein-Protein Interaction Map;Proteins;Proteomics;Recurrence;Reproducibility;Research Personnel;Research Project Grants;Research Support;Specificity;Squamous Cell Lung Carcinoma;Structure;Systems Biology;TP53 gene;Technical Expertise;Technology;Tertiary Protein Structure;Training;Variant;cancer cell;cancer type;cell type;combinatorial;comparative;crosslink;experimental study;fitness;functional genomics;gain of function;insight;interest;loss of function;migration;mutant;network models;novel;outreach;patient stratification;protein complex;protein expression;protein function;protein protein interaction;protein purification;protein structure;reverse genetics;software infrastructure;stoichiometry;targeted cancer therapy;targeted treatment;tumor progression;tumorigenesis Core 1: Functional Genomics and Proteomics n/a NCI 10704617 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8776 8727857 "KROGAN, NEVAN J" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 260287 175909 84378 CCMI v2.0Core 1: Functional Genomics and Proteomics CoreCore Lead: Nevan Krogan; Co-Investigator: Prashant MaliSUMMARYSystematic characterization of protein-protein interactions (PPIs) and genetic interaction networks of cancerdrivers is critical for the identification of functional complexes for patient stratification and targeted cancertherapies. Proteomic approaches that determine PPIs and protein complex stoichiometry and topology canprovide strategic insight into the dynamic cancer landscape and help guide tailored genetic screens to assessfunctional relevance of newly characterized PPIs. The Functional Genomics and Proteomics Core (Core 1)will provide the infrastructure and technical expertise essential to the completion of the overall CCMI objectives.With support of two Core facilities the Functional Genomics and Proteomics Core will provide its expertisein CRISPR genetic screens (Institute for Genomic Medicine (IGM) Genomics Center UCSD) and proteomictechnologies (Thermo Fisher Scientific Proteomics Facility for Disease Target Discovery UCSF QuantitativeBiosciences Institute (QBI) Gladstone Institute) for the generation of high-quality protein-protein (Aim 2; insupport of Project 1) and genetic (Aim 1; in support of Project 2) interaction data which will be integrated usingsystems biology approaches in Project 3 and Core 2. Our goal is to provide functional and structuralcharacterization of cancer driver networks model their functional interactions in three different cancers (breasthead and neck lung cancer) and determine consequences of introducing point mutations. Finally we will use aunique platform for Endogenous Network/Dynamic Structure (EN/DS) determination (Aim 3) that will useCRISPR-based genetics to introduce point mutations and FLAG-affinity tags into the endogenous loci of selectedgenes to study endogenous protein complex stoichiometry and structure using mass spectrometry and cryo-EM(in support of Project 1). +No NIH Category available Adult;Area;Biological Sciences;Cancer Patient;Child;Communities;Data Set;Dedications;Education;Educational workshop;Engineering;Event;Faculty;Family;Festival;General Population;Goals;Institution;Leadership;Learning;Link;Malignant Neoplasms;Maps;Medicine;Patients;Persons;Play;Postdoctoral Fellow;Public Opinion;Research;Research Activity;Research Personnel;Research Project Grants;Role;Science;Scientist;Site;Societies;Systems Biology;Taste Perception;Technical Expertise;Techniques;Training;Training Activity;Work;anticancer research;bioinformatics tool;cancer cell;clinical translation;forgetting;graduate student;member;next generation;outreach;programs;recruit;symposium;web portal Outreach Core n/a NCI 10704615 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8775 1859822 "BACHELDER, ROBIN ELIZABETH" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 156555 126420 30135 Outreach Core Core Leads: Jason Kreisberg and Antoine ForgetSUMMARYThe CCMI Outreach Core will use a multifaceted approach to promote the use of systems biology in cancer research and clinical translation. We will also devote significant efforts to educating the general public from children to adults and including patients and patients families. The result will be a motivated community of cancer systems biology researchers an enthusiastic next generation of scientists and clinicians and a more informed general public open to supporting further systems biology research. First to build and enrich a strong and diverse community of cancer systems biology researchers in the Bay Area and San Diego the CCMI v2.0 will play a major role in recruiting new faculty and training junior scientists at UCSF Stanford and UCSD. We have and will continue to work closely with our institutional leadership to recruit new faculty members with expertise in cancer systems biology several of whom are integral to the present proposal. We will draw on significant matched institutional support at both UCSF and UCSD to continue what is now a 5-year-long program of Cancer Systems Biology Trainees. This program has enabled us to recruit and support top graduate students and postdoctoral fellows at both UCSF and UCSD. Second to provide a broad portfolio of educational opportunities in cancer systems biology we will organize workshops to provide hands-on expert advice for learning and applying bioinformatics tools and systems biology techniques to cancer research. These events will leverage the operational know-how built and refined in CCMI v1.0 during which we organized 7 symposia and 20 workshops and tutorials. Third in recognition of the vital role that the scientific community plays in educating lay people and influencing public opinion the CCMI will support a wide array of public outreach activities. These activities will leverage the strong partnerships we have established with organizations and events of proven track record. These include science festivals such as the Bay Area Science Festival and the San Diego Festival for Science and Engineering as well as the Taste for the Cure: A Taste of Science yearly event which offers educational opportunities to cancer patients. These events will both educate the public and provide members of the CCMI opportunities to share their enthusiasm for science and medicine. Finally to disseminate information describing our research and training activities we have built and will continue to maintain a dedicated CCMI web portal. Visitors to the site will be provided with up-to-date information about the major research projects links to sites for downloading primary data sets and bioinformatics tools and online forms to register for CCMI events. In addition we have partnered with the Quantitative Biosciences Institute (QBI) Media & Events team at UCSF to produce content and organize events for researchers and lay audiences. +No NIH Category available Affect;Affinity Chromatography;Architecture;Biological;Biological Assay;Biological Markers;Breast;Cancer Model;Cell model;Cells;Cellular Structures;Clinical;Clinical Data;Complex;Cryoelectron Microscopy;DNA Sequence Alteration;Data;Data Analyses;Data Set;Development;ERBB3 gene;Evaluation;Expert Systems;FRAP1 gene;Funding;Generations;Genes;Genetic;Head and Neck Cancer;Head and Neck Neoplasms;Head and neck structure;Heterogeneity;Human;Image;Immunofluorescence Immunologic;Knowledge;Learning;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Medicine;Methodology;Methods;Modeling;Molecular;Mutate;Mutation;Organelles;PIK3CA gene;Pathway interactions;Patients;Phenotype;Population;Protein Dynamics;Proteins;Research Personnel;Resolution;Risk;Sampling;Somatic Mutation;Structural Models;Structure;System;Techniques;Training;Translations;Treatment outcome;Work;Xenograft procedure;cancer cell;cancer genome;cancer therapy;cancer type;clinical translation;clinically relevant;combinatorial;computer framework;confocal imaging;crosslink;data modeling;deep learning;design;drug response prediction;improved;machine learning model;malignant breast neoplasm;multimodality;neoplastic cell;patient derived xenograft model;precision medicine;predictive modeling;protein complex;protein distribution;response;structural biology;three-dimensional modeling;transfer learning;tumor Project 3: From Networks and Structures to Hierarchical Whole Cell Models of Cancer n/a NCI 10704611 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8774 7036028 "IDEKER, TREY " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 476818 403323 73495 CCMI v2.0Project 3: From Networks and Structures to Hierarchical Whole-Cell Models of CancerProject Leads: Trey Ideker and Andrej Sali; Co-Investigators: Emma Lundberg Jennifer Grandis J. SilvioGutkind and Laura van t VeerSUMMARYOne of the striking discoveries of the cancer genome projects is that each tumor presents a unique set of geneticmutations and molecular alterations. To understand how these alterations give rise to cancer and treatmentoutcomes the Cancer Cell Map Initiative (CCMI) has launched systematic efforts to map the physical andfunctional architecture of tumor cells capturing the molecular components and pathways on which cancermutations converge. While parts of this effort are experimental this Project 3 presents the central computationalframework.A first computational theme concerns methods to assemble the structure of the multiscale tumor cell map. Aim1 focuses on creating 3D models of cancer-associated protein complexes. It will apply established methods ofintegrative structural biology to data from other projects including cryo-electron microscopy (cryo-EM) affinitypurification mass spectrometry (AP-MS) cross-linking mass spectrometry (XL-MS) and genetic interactiondatasets. Initial efforts will focus on PIK3CA-HER3 and mTOR complexes identified in previous work by theCCMI then move to new protein complexes identified by our ongoing mapping activities. Aim 2 focuses onmapping tumor cellular components at scales at and above the protein complex extending to larger cellularcomponents compartments and organelles. It will expand on a compelling proof-of-concept for creating anunbiased hierarchical map of human cell components by integration of AP-MS data with protein distribution datafrom immunofluorescence confocal images. These whole-cell maps will be analyzed to reveal specific cellularcomponents under mutational selection in breast head-and-neck and lung cancers.A second computational theme concerns methods to integrate tumor cell maps with functional analysis andpredictive medicine. Aim 3 uses the maps to build interpretable deep learning systems for prediction of drugresponses. This aim draws from our previous work to establish visible learning models (DCell and DrugCell)which are not black boxes but have internal organization determined by prior knowledge of biological structure.We will construct such models from CCMI tumor cell maps incorporating key improvements over our first-generation pilots. Finally Aim 4 will use visible deep learning systems alongside other machine learning modelsto design and evaluate combinatorial biomarkers for breast head-and-neck and lung tumors in the patient-derived xenograft (PDX) and clinical settings. Clinical samples and data will be drawn from moleculartumor boards and the I-SPY breast cancer trial. PDX and clinical data will be used for further optimizationof our predictive models using nascent techniques from transfer learning.Through these aims we will advance our basic knowledge of the structure and function of tumors whileembedding this knowledge within intelligent systems for precision medicine. +No NIH Category available Biological Assay;Breast Cancer Patient;CRISPR screen;CRISPR/Cas technology;Cell Line;Cell Proliferation;Cells;Cessation of life;Chromosome Mapping;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Data;Development;Disease;Drug Interactions;Drug Targeting;Engineering;Event;Face;Gene Deletion;Gene Targeting;Genes;Genetic;Genetic Epistasis;Genetic Screening;Genomics;Head and Neck Squamous Cell Carcinoma;Intervention;Knock-out;Libraries;Link;Logic;Mali;Malignant Neoplasms;Maps;Measurement;Measures;Methodology;Methods;Molecular;Mutate;PIK3CG gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacogenetics;Phenotype;Predisposition;Protein-Protein Interaction Map;Proteins;Reporter;Reporting;Research Personnel;Resistance;Signal Transduction;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;System;TP53 gene;Technology;Testing;Time;Treatment Efficacy;arm;cancer cell;cancer subtypes;cell behavior;clinical translation;combinatorial;experimental study;in vivo;individualized medicine;malignant breast neoplasm;member;new technology;novel therapeutic intervention;patient derived xenograft model;precision medicine;precision oncology;prospective test;response;reverse genetics;spatiotemporal;synthetic lethal interaction;therapeutic target;tumor;tumor progression;tumorigenesis Project 2: Functional Genetic Networks for Systems-Guided Precision Medicine n/a NCI 10704609 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8773 12467130 "FRALEY, STEPHANIE IRENE" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 501398 445700 55698 CCMI v2.0Project 2: Functional Genetic Networks for Systems-Guided Precision MedicineProject Leads: Prashant Mali and Stephanie Fraley; Co-Investigators: Alan Ashworth Jennifer GrandisSilvio Gutkind Trey Ideker and Laura van t Veer.SUMMARYPrecision medicine aims to tailor therapies to the genetic and molecular background of a patients tumor. Thedevelopment of such therapies faces numerous obstacles many deriving from our ignorance of the geneticnetworks underlying tumorigenesis and the mechanisms of possible interventions. To clarify the genetic logicthat governs therapeutic efficacy Project 2 will use CRISPR/Cas9 genetic perturbation methodologies in anensemble of combinatorial functional and mechanistic screens. Screens will focus on the PI3K pathway thep53 tumor suppressor and the protein systems mutated in invasive breast cancer (BRCA) head and necksquamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC) pathways and diseases thattogether result in well over one million deaths each year worldwide. This focus will enable us to interrogate abroad collection of cell lines experiments and microenvironmental conditions. First we will build on significantpreliminary data to establish maps of synthetic lethal and epistatic genetic interactions centered on frequentlymutated genes and therapeutic targets in the above pathways and cancer subtypes (Aim 1). Second we willcouple CRISPR/Cas9 screening to a panel of scalable functional assays for large-scale measurement of cancerphenotypes beyond cell proliferation (Aim 2). Third we will pilot a new technology STAG-CRISPR to linkCRISPR/Cas9 screening to real time molecular events in living cells providing access to an even deeper arrayof phenotypes that have been recalcitrant to systems genetics thus far (Aim 3). Finally to facilitate clinicaltranslation of the identified gene-gene gene-phenotype gene-mechanism and gene-drug interactions we willapply our extensive library of BRCA HNSCC and LUSC patient-derived xenograft (PDX) models to testcompelling leads in vivo. We will also validate the identified interaction networks with patient data from the BRCAI-SPY 2 trial and from HNSCC patients at UCSD (Aim 4). Taken together our integrated approach establishesa network of extensively validated interactions among genes drugs and multiple phenotypic endpoints toadvance the practice of precision oncology. +No NIH Category available Address;Affect;Biological Assay;Biological Markers;Cancer Model;Cancer Patient;Cancer Prognosis;Cancer cell line;Cell Communication;Cell Cycle;Cell model;Cells;Clinical Trials;Colorado;Companions;Complex;Cyclin D1;Data;Disease;Dose;Drug Kinetics;Drug resistance;Evaluation;FDA approved;FRAP1 gene;Failure;Genes;Goals;Growth;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Home;Human;Human Papillomavirus;Hypoxia;Immune;Immune Evasion;Immune Targeting;Immunity;Immunologic Deficiency Syndromes;Immunologic Surveillance;Immunotherapy;In Vitro;Internal Ribosome Entry Site;Invaded;Ligands;Malignant Neoplasms;Measures;Mediating;Messenger RNA;Minority;Modality;Modeling;Molecular Target;Mus;Mutation;Oncogenic;Oncoproteins;Outcome;PIK3CG gene;Papillomavirus Transforming Protein E6;Pathway interactions;Patients;Pharmaceutical Preparations;Predictive Value of Tests;Predisposition;Production;Property;Protein Biosynthesis;Protein Synthesis Inhibition;Proteins;Proteome;Proteomics;Proto-Oncogene Proteins c-myc;Radiation therapy;Relapse;Reporting;Resistance;Rest;Ribosomes;Sampling;Signal Transduction;Stress;T-Lymphocyte;Testing;Therapeutic;Therapeutic Index;Tissue Banks;Tissues;Toxic effect;Translations;Treatment Efficacy;Treatment Failure;Tumor Bank;Tumor-infiltrating immune cells;Work;cancer cell;cancer infiltrating T cells;cancer therapy;efficacy testing;fitness;gene product;humanized mouse;in vivo;in vivo Model;inhibitor;mouse model;novel therapeutics;patient derived xenograft model;pembrolizumab;pharmacologic;predictive marker;programmed cell death ligand 1;programmed cell death protein 1;protein expression;ribosome profiling;small molecule;stemness;synergism;tool;transcription factor;tumor;tumor growth;tumor microenvironment;tumor progression Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer NARRATIVE. Major limitations in understanding the cancer-host interaction and in finding drugs that will help usstop cancer progression include either simply culturing cancer cells on plastic dishes or injecting cells on micethat have no human immunity. To study a new drug (SVC112) that inhibits production of proteins vital to cancercells while addressing these limitations we are proposing to use assays that include active human immune cellsand a humanized mouse model which can actually mimic what happens in a patient more closely and will makethe testing of SVC112 more robust. Our goal is to determine if modulating protein synthesis with SVC112 willenhance the efficacy of radiation and immune therapy the two main modalities in use in early and late head andneck cancers. NCI 10704601 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6 5436 8665415 "JIMENO, ANTONIO " Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 328151 224865 103286 SUMMARY. Radiation therapy (RT) and immunotherapy with PD-1 inhibitors are used in early and relapsedhead and neck squamous cell cancers (HNSCC) respectively; RT failures are common and most patients donot respond to PD-1 inhibition. Both impact the tumor microenvironment (TME) but studying the TME is limitedby the availability of models with human immune cells. PI3K/mTOR signaling regulates protein synthesis throughtranscription factors such as Myc or SOX2 that dictate growth invasion and drug resistance in HNSCC. SVC112is a fully synthetic small molecule that inhibits protein synthesis at the elongation step by inhibiting eEF2. SVC112had greater effect on cancer over non-cancer cells and was more potent and selective than homoharringtonin(HHT) an FDA-approved translation elongation inhibitor. Cancer cells had higher eEF2 than non-cancer cellsand the most susceptible strain had the highest eEF2 expression. SVC112 depleted SOX2 Myc and Cyclin D1in HNSCC cells at concentrations that had minimal effect on the rest of the proteome. SVC112 decreasedspheres in vitro reduced tumor growth in vivo in patient-derived xenografts (PDX) and induced tumor regressionwhen given with RT in three out of four PDX models. SVC112 also reduced the E6 oncoprotein in humanpapillomavirus-driven cells. Lastly SVC112 decreased PD-1 ligand (PD-L1) resulting in decreased PD-L1:PD-1interactions leading to increased sphere T cell invasion while having no effect on T cell fitness or function. ThusSVC112 can target multiple key pathways (SOX2 Myc PD-L1) and can influence the TME to reverse immuneevasion. To test SVC112s therapeutic potential in HNSCC several unique tools will be used including 1) spherescontaining cancer cells and T cells (iSpheres) that enable studying TME interactions and immunotherapy in vitro2) syngeneic mouse models of HNSCC and 3) humanized mouse (HM) models developed by the PI that enablestudying TME interactions and immunotherapy in vivo. The hypothesis that SVC112s discriminating effect isdue to selective depletion of key proteins will be tested by ribosome profiling (to identify mRNA targets) andproteomics analysis (to identify proteins targets). Then we will test the mechanism of SVC112 synergy with RTand if the modulation of the TME by SVC112 will further enhance RT efficacy. Lastly the hypothesis thatreduction of PD-L1 by SVC112 in HNSCC will alter the tumor-immune interaction will be tested by defining theeffect of SVC112 on the expression of proteins critical for the TME T cell tumor infiltration and cancer-immunecrosstalk. The effect of SVC112 on T cell fitness and function will be examined aiding SVC112 translation. Wewill assess SVC112 and PD-1 inhibition in iSphere and HM models and explore their efficacy when both arecombined. Lastly we will test the predictive value of eEF2 in SVC112 susceptibility and we will assess eEF2expression in human tumors to enable identifying a companion biomarker to SVC112 using a HNSCC tissuebank with 1250 patient cases. This project will propel the translation of SVC112 a drug discovered in Coloradoby dissecting the basis for its effect studying its toxicity and testing predictive biomarkers to aid clinical trials. +No NIH Category available Acceleration;Affinity;Antibodies;Atlas of Cancer Mortality in the United States;Atlases;Biological Markers;Biology;Breast;CRISPR interference;Cancer Biology;Catalogs;Cell Line;Cell model;Cells;Chromosome Mapping;Clinical;Clinical Cancer Center;Clinical Data;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Complement;Complex;Coupled;Coupling;Cryoelectron Microscopy;DNA Sequence Alteration;Data;Development;Drug Combinations;Drug usage;ERBB3 gene;Exhibits;Genes;Genetic Predisposition to Disease;Genetic study;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Human;Image;In Vitro;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Modeling;Molecular;Molecular Biology;Mutate;Mutation;Oncogenic;PIK3CG gene;Pathway interactions;Pattern;Pharmaceutical Preparations;Precision therapeutics;Prediction of Response to Therapy;Protein-Protein Interaction Map;Proteins;Proteomics;Recurrence;Regulation;Research;Research Personnel;Resolution;Resources;Sampling;Small Interfering RNA;Spatial Distribution;Squamous Cell Lung Carcinoma;Structure;TP53 gene;Technology;Testing;Therapeutic;Tissues;Validation;Work;cancer cell;cancer imaging;cancer therapy;cancer type;candidate marker;crosslink;experimental study;functional genomics;genomic data;high throughput screening;in vivo;in vivo imaging;innovation;insight;metaplastic cell transformation;mouse model;mutant;new technology;novel;patient derived xenograft model;patient population;protein complex;protein protein interaction;structural biology;targeted cancer therapy;therapeutic target;treatment response;tumor;tumor heterogeneity;tumor progression;tumorigenesis Project 1: Systematic Physical and Spatial Mapping of Cancer Driver Networks n/a NCI 10704599 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8769 15401017 "LUNDBERG, EMMA " Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 535563 395275 140288 CCMI v2.0Project 1: Systematic physical and spatial mapping of driver networks in cancerProject Leads: Nevan Krogan and Emma Lundberg; Co-Investigators: Alan Ashworth Jean-Philippe CoppeJennifer Grandis Silvio Gutkind Natalia Jura and Laura van t VeerSUMMARYTumors display complex mutational profiles that appear as a random pattern of mutations in genetic studies.However it is their non-random combination and convergence on cancer pathways that lead to transformation.Specific pathways such as the PI3K or p53 axis are recurrently mutated in a majority of cancers but besidessuch pan-cancer mutated pathways each tumor harbors 20 to over 1000 additional mutations that are rarelyseen across the patient population. Tumor heterogeneity tissue of origin and degree of progression give eachcase a unique subset of altered pathways and has hampered the development of targeted cancer therapies.Mapping genetic mutations onto previously identified cellular pathways can provide insights for clinicalcharacterization. To efficiently leverage pathway networks for therapeutic strategies in Project 1 we will identifyand characterize cancer driver pathways.To this end we will combine physical and spatial protein interactions with large scale genomic data and apply asuite of proteomic technologies with in vitro imaging through cryo-electron microscopy (cryo-EM) tosystematically map protein networks in an orthogonal (cancer specific) or transversal (across cancers) manner.Specifically we will systematically identify the network of key regulators of the PI3K pathway and p53 acrossbreast (BRCA) head and neck (HNSCC) and lung squamous cancers (LUSC) and complement our previouswork on HNSCC and BRCA by identifying driver networks in LUSC. Guided by proteomic approaches coupledwith sophisticated imaging and high-resolution structural analysis of key complexes with functional validationProject 1 will gain insights into the underlying molecular biology of these cancers and unravel geneticvulnerabilities of therapeutic relevance. In Aim 1 we will map the protein-protein interactions (PPIs) of 30proteins (and 12 mutants in 6 of those proteins) of the PI3K pathway and 10 mutants of p53 across HNSCCBRCA and LUSC. We will also define the physical interactions of the 30 most recurrently altered proteins (and20 associated mutants in 9 of the proteins) in LUSC complementing our previous work on HNSCC and BRCA.Using the Human Protein Atlas resource of antibodies Aim 2 will focus on macroscopic mapping of the spatialsubcellular organization of key oncogenic drivers and their interactors defined in Aim 1. Aim 3 will exploit recentadvances in cryo-EM to structurally characterize key complexes including those in the PI3K pathway. Finallypredictions from the previous aims will be tested in Aim 4 in cell lines primary cells and mouse models and withclinical data. +No NIH Category available Adhesions;Affect;Autoimmune;Beds;Biological Assay;Blood Vessels;Blood specimen;Cell Communication;Cell Proliferation;Cell Survival;Cell physiology;Cells;Clinical Trials;Coculture Techniques;Colorado;Cytometry;Cytoplasmic Tail;Cytoskeleton;Data;Disease;Embryonic Development;Endothelial Cells;Endothelium;Environment;EphB4 Receptor;Ephrin-B2;Flow Cytometry;Genetic;Genetically Engineered Mouse;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Human;Image;Immune;Immune Evasion;Immune Targeting;Immune checkpoint inhibitor;Immunocompetent;Immunofluorescence Immunologic;Immunofluorescence Microscopy;Immunologics;Immunosuppression;Immunotherapeutic agent;Implant;In Vitro;Infiltration;Intervention;L-Selectin;Ligands;Macrophage;Macrophage Activation;Malignant Neoplasms;Mediating;Mediator;Methods;Molecular;Molecular Target;Outcome;Participant;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phenotype;Phosphorylation;Play;Population;Pre-Clinical Model;Process;Proto-Oncogene Proteins c-akt;Publishing;Radiation;Radiation therapy;Receptor Protein-Tyrosine Kinases;Regulatory T-Lymphocyte;Research;Resistance;Role;STAT3 gene;Sampling;Signal Transduction;Smoking History;Specimen;Stress Fibers;System;T cell response;Target Populations;Testing;Tissues;Tumor Promotion;Tumor-associated macrophages;Tumor-infiltrating immune cells;Vascular Endothelial Cell;angiogenesis;anti-tumor immune response;biomarker identification;cancer cell;cell motility;chemoradiation;cytokine;effector T cell;head and neck cancer patient;high risk;immunological status;immunoregulation;immunotherapy trials;in vivo;inhibitor;intravital microscopy;knock-down;migration;monocyte;neoplastic cell;novel;participant enrollment;pharmacologic;potential biomarker;pre-clinical;predictive marker;radiation response;radiological imaging;receptor;recruit;response;response biomarker;side effect;therapeutic target;therapy resistant;trafficking;transcriptome sequencing;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Targeting EphB4-ephrinB2 to decrease immunosuppression in HNSCC NARRATIVE Project 1In the treatment of head and neck cancer radiation contributes to an immunologic phenotypic change and actto promote tumor growth and progression. Immunosuppressive cells including regulatory T cells (Tregs) andmonocytes which are precursors for tumor associated macrophages (TAMs) are recruited after radiation andrepresent a primary driver of resistance to therapy by generating an immune suppressive microenvironment. Inthis proposal we examine how interactions between EphB4-ephrin-B2 at endothelial-immune cell interface inthe context of radiation selectively enable a Treg- and TAM-rich microenvironment switching it to a tumor-supportive phenotype. NCI 10704596 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6 5434 6491204 "KARAM, SANA " Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 324670 208790 115880 SUMMARY Project 1Treatment resistance remains a challenging problem for high-risk head and neck cancer (HNSCC) patients.Current trials with immune checkpoint inhibitors have yielded sub-optimal response rates. This could be due toTME factors that substantially modulate the immune landscapes composition phenotype and function.Preferential recruitment of unique immunosuppressive cell subtypes to the tumor bed may play an important rolein contributing to the promotion of tumor growth and progression. The tumor endothelium can act as a selectivebarrier that regulates entry stability and activation status of immune cells but the mechanistic underpinningsremain poorly understood. The EphB4 receptor tyrosine kinase and its ligand EFNB2 define novel moleculartargets. Although they have been studied in cell migration and angiogenesis in early embryonic developmentlittle has been published on their role in modulating the cancer immune microenvironment. Our preliminary datashow that HNSCCs are enriched in regulatory T-cells (Tregs) and tumor associated macrophages (TAMs) bothof which contribute to resistance after RT. EFNB2 is upregulated on tumor vasculature after RT whereas EphB4is expressed on Tregs and TAMs and among all immune cells Tregs and TAMs are most sensitive to eitherpharmacologic inhibition with TNYL-RAW or genetic knockdown of endothelial EFNB2 in the context of RT. Wetherefore hypothesize that RT upregulates EFNB2 on tumor vascular endothelial cells which actspreferentially to recruit EphB4 expressing Tregs and TAMs. Blockade of EphB4-EFNB2 signaling at thetumor endothelial barrier will hinder Tregs and TAMs ability to infiltrate and promote cancer cell survivalor suppress Teff function. In Aim1 we will analyze the mechanistic outcome of the interaction between immunecell EphB4 and endothelial EFNB2 on immune trans-endothelial trafficking survival polarization anddifferentiation of immune cells as well as vascular normalization of endothelial cells in response to RT. We willuse pharmacological inhibitors as well as GEMMs with EFNB2 deletion on endothelial cells or EphB4 deletionon Tregs or TAMs. Aim 2 will study the cellular and molecular mechanisms triggered by the interaction betweenendothelial EFNB2 and EphB4-expressing immune cells on immune cell processes in response to RT usingendothelial-immune cells co-culture assays. Targeted inhibition of STAT3 AKT and Erk pathway will be donewith pharmacological inhibitors based on our preliminary data. Aim 3 will use tissue from a human clinical trialwith sEphB4-HSA (an inhibitor currently in Phase I and II trials) before and after drug alone or drug andchemoradiation alone. This will serve to identify the molecular mediators that drive the anti-tumor immuneresponse to this therapy. These studies will also collectively elucidate the molecular and cellular parameters ofEphB4-EFNB2 inhibitors and will allow for the identification of potential predictive markers for this using EphB4-EFNB2 inhibitors. +No NIH Category available Address;Administrator;Advisory Committees;Agreement;Area;Budgets;Catalogs;Cells;Collaborations;Communication;Communities;Complement;Custom;Data;Data Set;Documentation;Education;Educational Status;Ensure;Equilibrium;Event;Faculty;Funding;Gender;Goals;Institution;Journals;Link;Malignant Neoplasms;Maps;Mission;Monitor;Nature;Pilot Projects;Productivity;Publications;Qualifying;Research;Research Personnel;Resource Sharing;Resources;San Francisco;Schedule;Science;Scientist;Secure;Software Tools;Systems Biology;Talents;Training;United States National Institutes of Health;Woman;anticancer research;cancer cell;data interoperability;data sharing;diversity and inclusion;high risk;innovation;interest;meetings;member;network models;outreach;programs;response;software infrastructure;web portal;web site;working group Administrative Core n/a NCI 10704593 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8766 8727857 "KROGAN, NEVAN J" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 313371 248579 64792 CCMI v2.0Administrative CoreCore Leads: Nevan Krogan and Trey IdekerSUMMARYThe mission of the Administrative Core is to promote the scientific and outreach goals of the Cancer Cell MapInitiative (CCMI) v2.0 and to connect the CCMI to the broader cancer systems biology community and the NCI.Amongst its responsibilities the Core will perform the following: serve as the primary contact for all internallogistical and organizational aspects of the CCMI; serve as the primary contact for external interactions withother centers in the Cancer Systems Biology Consortium (CSBC) the NCI and the cancer research community;implement strategies to enhance diversity and inclusion in cancer systems biology; manage the solicitationreview and funding of Research Center pilot projects; and ensure timely sharing of data and resources producedby all Research Center Projects and Cores through the U24 Coordinating Center and NIH/NCI resources. Day-to-day activities will be coordinated by a cross-campus team consisting of the Co-Directors Assistant DirectorResearch Center Administrators and Data Managers. The Core will organize a Steering Committee to evaluatethe progress and needs of each CCMI component review and possibly modify priorities and identify areasdeserving of extra focus. To facilitate communication amongst Center members the Core will organize a varietyof regularly scheduled meetings some specifically for members of the Steering Committee and others for theentire CCMI. The Core will also facilitate communication with the CSBC and NCI especially around key eventssuch as the CSBC Annual Meeting the Junior Investigators Meeting and the various CSBC Working Groups.To enhance diversity and inclusion in cancer systems biology the Core will ensure that opportunities areprovided to a diverse set of researchers whether that opportunity is to present at a CCMI-organized event or asa recipient of CCMI research funds. The Core will also manage the solicitation review and funding of pilotprojects of faculty members wishing to develop and apply systems biology approaches to address a compellingbiomedical question in cancer in collaboration with CCMI investigators. Finally to ensure the timely sharing ofdata and resources we have designated two qualified Data Managers one in San Francisco with experimentalexpertise and one in San Diego with computational expertise who will interact with the consortium to facilitatethe timely sharing of interoperable datasets and community accessible resources. In addition the CCMI webportal will be maintained as a collaborative effort among the Administrative Core Outreach Core andSoftware Infrastructure for Network Models and Cell Maps Core (Core 2). It provides researchers with acentral access point for CCMI networks and cell maps; custom websites in support of CCMI publications;and a catalog of software tools tutorials and links to documentation. +No NIH Category available Archives;Biological;Biological Specimen Banks;Body Fluids;CLIA certified;Cancer Center;Chemopreventive Agent;Classification;Clinical;Clinical Trials;Collaborations;Colorado;Computer Assisted;Consent;Core Facility;Cytogenetics;DNA;Data;Data Analyses;Data Science Core;Databases;Dedications;Development;Diagnostic;Disease;Disease Progression;Drug or chemical Tissue Distribution;Extramural Activities;Generations;Genetic;Goals;Guidelines;Head and Neck Cancer;Health Insurance Portability and Accountability Act;Histologic;Histology;Human;Human Resources;Image;Image Analysis;Immune;Immunohistochemistry;Immunologic Monitoring;Individual;Infrastructure;Institutional Review Boards;Knowledge;Laboratories;Leadership;Link;Medical;Methodology;Molecular;Molecular Analysis;Morphology;Outcome;Participant;Pathologic;Pathologist;Pathology;Patients;Performance;Practice Guidelines;Procedures;Process;Proteins;Protocols documentation;Publishing;RNA;Reproduction spores;Research;Research Design;Research Personnel;Resource Sharing;Resources;Service provision;Services;Solid;Specimen;Specimen Handling;Standardization;System;Techniques;Technology;Testing;The University of Colorado Cancer Center;Therapeutic;Time;Tissue Sample;Tissues;Translating;Translational Research;United States National Institutes of Health;Universities;Work;biobank;biological specimen archives;cancer clinical trial;career development;design;experience;human tissue;improved;laser capture microdissection;member;molecular pathology;operation;organizational structure;patient derived xenograft model;prevent;preventive intervention;research study;skills;success;thyroid neoplasm;tissue archive;tissue processing;tissue resource;tool;treatment response Colorado HNC SPORE Biospecimen/Pathology Core NARRATIVE BPCThe Biospecimen/Pathology Core (BPC) is essential to the success of the Colorado Head and Neck CancerSPORE. The BPC is a central service that obtains tissues and information from patients with head and neckcancer. The collected tissue and information is stored and processed so that researchers have the bestpossible materials and information for their projects. In addition the BPC provides unique skills and expertisein pathology and analysis technology to be successful in the execution of their projects. NCI 10704591 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6 5433 1866026 "LUCIA, M. SCOTT" Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 219170 143932 75238 SUMMARY BPCThe Biospecimen/Pathology Core (BPC) is the central repository of specimens established to provide support tothe Head and Neck Cancer (HNC) SPORE to aid in the successful execution of the proposed studies. Throughthe BPC we will establish a comprehensive resource of tissue specimens body fluids and tissue isolates(DNA/RNA) that will support the SPORE and can be used by extramural investigators to improve ourunderstanding of the underlying mechanisms in the onset development and progression of head and neckcancer and improve treatment options to aid the clinician in patient management. The main goals of the BPCare to procure characterize analyze and process and distribute specimen. The provision of these servicestakes advantage of a close working relationship with the existing facilities infrastructure and personnel forbiobanking and histology operations of the University of Colorado Cancer Center Tissue Biobanking andProcessing Shared Resource and the University of Colorado Biorepository Core Facility. Specimens arecollected as archival tissue or SPORE trial associated specimens that are obtained under IRB approvedprotocols. The BPC will also collect correlative clinical and biologic information that can be included in specimendistributions. The BPC provides histologic interpretation performs immunohistochemistry (IHC) andquantification of IHC by image analysis prepares biospecimen isolates (RNA DNA protein) and providesmolecular analysis on selected specimens required by the SPORE projects. This includes histologic review andclassification by up-to-date published WHO classification systems by the pathologist leadership of the core. Thecore designs its activities to meet the needs of each of the SPORE projects as outlined in the proposal. In orderto meet the tissue needs and achieve the goals of the projects the BPC collects and processes tissues in aspecific manner as determined via collaboration with project investigators. The BPC also collaborates in theperformance of project related studies in which expertise of BPC personnel can benefit study design datageneration and data analysis. The BPC will provide the necessary experience and expertise to be able todevelop CLIA certified testing to translate research findings into clinical utility. +No NIH Category available Algorithms;Alleles;Automobile Driving;Cells;Chromatin Loop;Chromatin Structure;Complex;DNA;DNA Repair;DNA copy number;Data;Defect;Development;Evolution;Gene Rearrangement;Genome;Genomic Segment;Genomics;Graph;Haplotypes;Homologous Gene;Individual;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Modality;Modeling;Mutation;Ovarian Adenocarcinoma;Pattern;Phase;Phylogenetic Analysis;Positioning Attribute;Prognostic Marker;Prostate Adenocarcinoma;Recurrence;Single-Stranded DNA;Structure;Systemic Therapy;Taxonomy;Technology;Tissue Sample;Variant;Work;cancer genome;computer framework;computerized tools;data structure;dosage;driver mutation;genome sequencing;genomic profiles;new technology;novel;repaired;tool;tumor;whole genome Inferring the structure and evolution of tandem duplication towers PROJECT NARRATIVEComplex structural variants are a frequent but underexplored aspect of cancer genomes that may driveaggressive tumors and reflect treatable defects in DNA repair. While long-range and single cell genomic profilingtechnologies have matured algorithms for inferring complex structural variants from these data are lacking. Thisproposal will develop such algorithms and apply them to study the evolution of pyrgo a recently identifiedcomplex structural variant class prevalent in ovarian and prostate cancer. NCI 10704590 5/18/23 0:00 PA-21-049 5F30CA268747-02 5 F30 CA 268747 2 "DAMICO, MARK W" 7/1/22 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15119698 "CHOO, ZI-NING " Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARYComplex structural variants (SVs) are a class of mutations consisting of clustered DNA copy number changesand rearrangements. These alterations can produce driver mutations in cancer but have been underexploreddue to the analytical limitations of bulk short read sequencing. There is an urgent need for new computationaltools that can apply long-range and single cell genomic profiles to structural variant analysis. Genome graphsare a computational framework that can be extended to these new data modalities to study the allelic structureand evolution of complex SVs. Recent genome graph analysis of pan-cancer whole genomes by our lab identifieda novel complex structural variant pattern termed pyrgo. Pyrgo consist of towers of clustered tandemduplications and are enriched in prostate and ovarian adenocarcinomas. In Aim 1 we will construct haplotypegraphs to characterize the allelic structure of pyrgo. Haplotype graphs represent allele-specific genomicsegment and junction copy numbers and will be inferred from long range profiling data. Using these graphs wewill characterize the parental and somatic allele structure of pyrgo duplications in pan-cancer genomes. We willidentify associations between allelic structure and cell-of-origin prior systemic therapy and genomic featuressuch as chromatin loops and replication timing. In Aim 2 we will construct single cell genome graphs thatrecapitulate the evolution of pyrgo. Single cell genome graphs are a set of phylogenetically linked genomegraphs representing the structural variants present in individual cells along with the ancestral subclone in whicheach aberrant genomic junction first arose. These graphs will be inferred from single cell whole genome profiles.We will use single cell genome graphs to model the acquisition of tandem duplications comprising pyrgo duringtumor evolution in ovarian adenocarcinoma tissue samples. 52694 +No NIH Category available Advanced Malignant Neoplasm;Area;Atlas of Cancer Mortality in the United States;Attention;Binding;Bioinformatics;Biological Assay;Biology;Breast;California;Cancer Center;Cataloging;Catalogs;Cell Line;Cell Proliferation;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Complex;Copy Number Polymorphism;Cryoelectron Microscopy;Data;Dependence;Disease;Expert Systems;FDA approved;Faculty;Funding;Gene Mutation;Genes;Genetic Diseases;Genetic Screening;Head and Neck Neoplasms;Heterogeneity;Image;Immunofluorescence Microscopy;Information Networks;Institution;Laboratories;Logic;Lung;Malignant Neoplasms;Maps;Mind;Mission;Modeling;Molecular;Mutation;NCI Center for Cancer Research;Neoplasm Metastasis;Other Genetics;PIK3CA gene;Pathogenesis;Pathway interactions;Patients;Pattern;Phenotype;Physiological;Point Mutation;Principal Investigator;Proliferating;Proteins;Research Personnel;Resources;Science;Scientist;Sister;Squamous Cell;Structural Models;Structure;System;Systems Biology;TP53 gene;Techniques;The Cancer Genome Atlas;Time;Training;Translating;Universities;anticancer research;cancer cell;cancer genome;cell motility;combinatorial;computerized tools;deep learning;driver mutation;drug response prediction;experimental study;genome-wide;interest;knockout gene;molecular modeling;mouse model;neoplastic cell;next generation;patient response;personalized medicine;precision medicine;precision oncology;pressure;protein complex;rare cancer;scale up;simulation;spatiotemporal;training opportunity;transfer learning;treatment response;tumor;tumor initiation The Cancer Cell Map Initiative v2.0 THE CANCER CELL MAP INITIATIVE v2.0OVERALL NARRATIVEAlthough much attention has been devoted to mapping the tumor genome understanding cancer requires thatwe move beyond simply cataloguing the genes associated with it. It is critical to understand the many interactionsamong these genes and the corresponding proteins and how these complex networks give rise to tumorinitiation progression and metastasis. The Cancer Cell Map Initiative (CCMI) is applying systematic approachesto comprehensively map the molecular networks that underlie cancer and to use these maps as key resourcesfor precision medicine. NCI 10704587 8/21/23 0:00 RFA-CA-21-048 5U54CA274502-02 5 U54 CA 274502 2 "DUECK, HANNAH RUTH" 9/14/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M2) 8727857 "KROGAN, NEVAN J" "IDEKER, TREY " 11 OTHER BASIC SCIENCES 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2321411 NCI 1872625 448786 THE CANCER CELL MAP INITIATIVE v2.0OVERALL SUMMARYThe Cancer Genome Atlas and sister projects have now sequenced over 20000 tumor genomes providing acatalog of gene mutations copy number variants and other genetic alterations associated with cancer. Thesedata have made it clear that every cancer is a distinct genetic disease with tumors that look physiologicallysimilar often driven by patterns of gene mutations that are strikingly different. Due to this molecular heterogeneityit is typically unclear what are the key driver mutations or dependencies in a given cancer and how theseinfluence pathogenesis and response to therapy. One key observation for interpreting tumor genomes is that themany rare tumor mutations can be shown to converge on common molecular networks. Based on this premisewe created the Cancer Cell Map Initiative (CCMI) whose mission is to create comprehensive maps of cancermolecular networks and to use these maps in intelligent systems for personalized therapy. In 2017 the CCMIwas funded as an NCI U54 Research Center for Cancer Systems Biology integrating expertise in networkmapping bioinformatic analysis and cancer research from leading academic laboratories at two University ofCalifornia campuses (UCSF and UCSD). We have since generated comprehensive networks of proteininteractions in breast and head-and-neck tumor cells and from these data identified several hundred proteincomplexes under selective mutational pressure in cancer (NeST v1.0). We have piloted deep learning systems(DCell DrugCell and TCRP) that can use this protein network information to translate a patients tumor mutationprofile to a predicted drug response including FDA-approved and exploratory agents. We have implemented arich portfolio of training opportunities and leveraging UC institutional support expanded the CCMI consortiumto include more than a dozen faculty at UC and most recently Stanford. In the next five years the CCMI willseek to: (1) Generate comprehensive protein interaction networks centered on key cancer driver genes in lungsquamous cells (in healthy and diseased states) as well as the PIK3CA and TP53 pathways which are centralto many tumor types; (2) Systematically extend the CCMI collection of cancer protein interaction data with proteinimmunofluorescent imaging and cryo-electron microscopy to formulate multi-scale cancer cell maps; (3) Dissectthe functional logic of these networks and maps by systematic genetic screening experiments in the same tumortypes and pathways using a panel of scalable cell proliferation phenotype and pathway readouts; (4)Significantly advance and harden our DrugCell interpretable deep learning system for cancer precision medicine;(5) Train the current and next generation of scientists in network biology and its applications to cancer research;and (6) Continue to build a cadre of leading investigators to expand CCMI into a global coordinated partnership. 2321411 +No NIH Category available Animal Experiments;Area;Award;Basic Science;Bioinformatics;Bioinformatics Shared Resource;Biological Markers;Biometry;Categories;Cells;Clinic;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Colorado;Communication;Community of Practice;Data Analyses;Data Collection;Data Science;Data Science Core;Development;Doctor of Philosophy;Ensure;Epidemiologist;Evaluation;Experimental Designs;Extramural Activities;Faculty;Focus Groups;Formulation;Genetic;Genetic Transcription;Genomics;Grant;Head and Neck Cancer;Head and neck structure;Human Resources;Immunological Models;Immunotherapy;In Vitro;Informatics;Investigation;Laboratories;Lead;Leadership;Link;Malignant Neoplasms;Manuscripts;Methods;Mission;Multiomic Data;Mus;Observational Study;Outcome;Paper;Pathology;Peer Review;Play;Population Study;Predictive Value;Preparation;Process;Proteins;Proteomics;Publishing;Radiation;Recording of previous events;Reporting;Reproduction spores;Research;Research Design;Research Methodology;Research Personnel;Research Support;Resources;Retrieval;Ribosomes;Role;Sample Size;Services;Speed;Statistical Models;Structure;T cell receptor repertoire sequencing;T-Lymphocyte;Techniques;Testing;The University of Colorado Cancer Center;Therapeutic;Translating;Translation Process;Translational Research;Universities;anticancer research;career;data management;database design;density;design;effectiveness research;electronic data capture system;experience;experimental study;improved;in vivo;individual responsibility;innovation;large datasets;member;next generation;novel;pre-clinical research;preclinical study;predictive modeling;prognostic value;programs;quality assurance;response;single cell mRNA sequencing;single-cell RNA sequencing;small molecule;software development;therapeutic target;tool;trafficking;translational study;whole genome Colorado HNC SPORE Data Sciences Core NARRATIVE Data Science CoreThe Data Science Core is designed to increase the speed and efficiency of support and scientific input withwhich head and neck cancer research is translated from the lab to the clinic. Core personnel have extensiveexperience in design and analysis of translational studies. Integrating personnel within a Core to support allSPORE programs will maximize the available resources and scientific impact. NCI 10704585 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6 8763 10313522 "GAO, DEXIANG " Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 134586 86550 48036 SUMMARY Data Science CoreThe University of Colorado Head and Neck Cancer (CO HNC) SPORE Data Science Core (DSC) providesservices for biostatistics informatics bioinformatics and other data science related analyses. The DSC staff iscomprised of five Ph.D. and one Masters level researchers who collectively offer substantial expertise in clinicaltrial design and analysis; statistical genetics multi-omics data analysis; software development; predictivemodeling; and cancer-focused bioinformatics. The core includes a comprehensive team of biostatisticiansbioinformaticians and an epidemiologist that form a hub of researchers with the common denominator of beingengaged in HNC research through exisiting collaborations. The DSC has the overarching objective to build acommunity of practice related to HNC data science. All staff are operationally managed and overseen by theDSC Director Dexiang Gao Ph.D and like all faculty in the CO HNC SPORE the DSC faculty are members ofthe University of Colorado Cancer Center (UCCC) specifically the Biostatistical and Bioinformatics sharedresource (BBSR). The BBSR has a long-standing history of collaboration with the Head and Neck research teamover the past 10 years. Faculty biostatisticians and bioinformaticians are engaged in the development of novelmethods and tools that enhance the HNC SPORE. Since 2015 faculty within the DSC published ~20 peer-reviewed manuscripts (with an additional 5 in preparation) and collaborated on 9 peer-reviewed extramural R01grants with HNC SPORE investigators 4 of which are active awards. By harnessing these establishedcollaborations the DSC can effectively and efficiently support CO HNC SPORE projects. Integrating personnelwithin a Core to support all SPORE programs will maximize available resources to increase the DSCs scientificimpact. Specifically the DSC will provide assistance with research hypotheses formulation clinical trial designssample size determination analytical and database design data collection analyses management and storage.This support will continue through management and coordination of accumulating research and clinical dataanalyses assistance with manuscript preparation and clinical trial reports in relation to key quantitative findingsand rigorous scientific conclusions. Thus the DSC will play a critical role in clinical trials as well as basic scienceand translational studies. +No NIH Category available Academia;Acceleration;Adherence;Advocate;Award;Awareness;Benchmarking;Cancer Research Project;Clinic;Clinical;Clinical Trials;Collaborations;Colorado;Communication;Communities;Community Outreach;Development;Discipline;Ensure;Evaluation;Goals;Guidelines;Head and Neck Cancer;Human Resources;Industrialization;Industry;Institution;Institutional Policy;Intellectual Property;Intervention;Leadership;Oncology Group;Organ;Outcomes Research;Pathology;Patients;Policies;Progress Reports;Publications;Reproduction spores;Research;Research Personnel;Resources;Schedule;Scientist;Services;Site;Southwest Oncology Group;Tissues;Translating;Translational Research;United States National Institutes of Health;Visit;Work;Writing;anticancer research;career;community engagement;data sharing;head and neck cancer patient;innovation;interdisciplinary approach;lectures;meetings;member;organizational structure;programs;success;symposium Colorado HNC SPORE Administrative Core NARRATIVE Administrative CoreThe Administrative Core of the Colorado Head and Neck Cancer (HNC) SPORE will provide the operationaladministration to ensure the success of our SPORE as a whole. The benchmark of our success is to translateinnovative research into clinical interventions for HNC patients. NCI 10704582 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6 8761 8665415 "JIMENO, ANTONIO " Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 296018 190365 105653 SUMMARY Administrative CoreThe goal of the Administrative Core of the Colorado Head and Neck Cancer (HNC) SPORE is to facilitateinnovative translational science that will accelerate the application of new discoveries to the clinic for HNCpatients. The primary objective of the Administrative Core is to provide scientific leadership administrativeservices and financial oversight and to function as a communication hub for all SPORE-related activities. TheAdministrative Core will support investigators and personnel in projects 1-3 the Biospecimen/Pathology Corethe Developmental Research Program (DRP) the Career Enhancement Program (CEP) and the Tissue UseCommittee. The Administrative Core personnel interact with the patient advocates to coordinate their activitiesand integrate their participation in SPORE activities and provides support to the External and Internal AdvisoryBoards as well as visiting scientists fellows and all collaborating investigators from academia and industry. TheAdministrative Core provides each of these groups with centralized organization and support for their activitiesand helps each group stay informed about activities meetings opportunities and other information pertinent tothe SPORE. The Administrative Core will be responsible for communication with NCI and will provide supportfor all collaborations. Continuity of support provided by the staff will result in efficient and effective administrationfor the CO HNC SPORE. +No NIH Category available Adenocarcinoma;Aggressive behavior;Androgen Receptor;Animal Model;Binding;Bioinformatics;Cessation of life;Clinical;Clinical Data;Clinical Trials;Compensation;Complex;Data Set;Dependence;Detection;Development;Diagnostic;Differentiation and Growth;Disease;Family;Foundations;Gene Amplification;Gene Expression;Genes;Genetic Transcription;Growth;Hormonal;Human;Immunohistochemistry;Malignant neoplasm of prostate;Measures;Medicine;Methods;Molecular;Molecular Profiling;Multiprotein Complexes;Multivariate Analysis;Nature;Needle biopsy procedure;Neoplasm Metastasis;Neuroendocrine Carcinoma;Neurosecretory Systems;Oncoproteins;Outcome;Pathway interactions;Patient Selection;Patients;Pharmaceutical Chemistry;Phase I Clinical Trials;Pre-Clinical Model;Prostate;Proteins;Reporting;Resistance;Role;Sampling;Specimen;Testing;Therapeutic;Up-Regulation;Variant;Xenograft Model;Xenograft procedure;androgen deprivation therapy;biophysical techniques;castration resistant prostate cancer;clinically relevant;experimental study;genome-wide;high throughput screening;in silico;inhibitor;men;neural;neuroendocrine differentiation;novel;novel therapeutic intervention;pharmacologic;programs;promoter;prostate cancer cell;prostate cancer progression;quantitative imaging;receptor expression;receptor function;safety testing;small molecule;targeted treatment;therapeutic target;therapy resistant;transcription factor;tumor Project 4: A Targetable Master Regulator of Lethal Prostate Cancer PROJECT NARRATIVEThis project will test the hypothesis that the developmental transcription factor ONECUT2 is a genome-widemodulator of androgen receptor function a driver of a neural differentiation program and a clinically relevanttherapeutic target in castration-resistant prostate cancer (CRPC). The objectives are to understand the functionalrole of ONECUT2 in CRPC identify clinical scenarios where ONECUT2 operates and develop pathways totherapeutic targeting of this protein that will lead to a clinical trial. NCI 10704579 9/15/23 0:00 PAR-18-313 5P50CA092131-20 5 P50 CA 92131 20 9/15/02 0:00 8/31/24 0:00 ZCA1-RPRB-7 8760 1883557 "FREEMAN, MICHAEL R" Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 308680 244707 63973 PROJECT SUMMARY/ABSTRACTCastration-resistant prostate cancer (CRPC) emerges following androgen deprivation therapy (ADT) wherevariable degrees of dependence on the androgen receptor (AR) are observed and features of neuroendocrine(NE) carcinoma often arise. We have identified the developmental transcription factor ONECUT2 (OC2/HNF6)as a master regulator of AR networks in metastatic (m)CRPC. OC2 governs a lethal differentiation programdrives metastasis and interacts with the AR at several levels including as a multiprotein complex and atranscriptional regulator of AR target genes. Our studies indicate that OC2 appears to override AR-dependentmechanisms in a subset of mCRPC and activates an NE differentiation program within the context ofadenocarcinoma. To inhibit OC2 we developed a novel class of small molecules that bind OC2 directly andsuppress growth and metastasis of AR/AR-V7-positive mCRPC xenografts. Additionally we have developedprofiling and immunohistochemistry (IHC) methods to identify OC2 activity in clinical specimens laying afoundation for an OC2-targeted treatment approach in select patients. This project will test the hypothesis thatOC2 is an actionable target in a subset of aggressive prostate cancer where OC2 is active. The Specific Aimsare: Aim 1. Study the mechanism by which OC2 activity promotes aggressive behavior of CRPC. Determinewhether OC2 can compensate for AR in CRPC. Determine whether OC2 upregulation can confer independencefrom AR. Determine whether OC2 interactors in AR-dependent and AR-independent transcription complexes aredistinct. Determine whether OC2 is required for NE differentiation and growth of NE-CRPC. Aim 2. Develop andoptimize OC2 inhibitors for use in patients with early mCRPC. Synthesize and test derivatives of the OC2targeting compound CSRM617. Perform in silico and high-throughput screening for structurally unrelated OC2inhibitors. Test the safety and efficacy of OC2 inhibitors in pre-clinical models. Aim 3. Identify the clinicalscenarios where OC2-driven tumors emerge. Refine multiplex IHC detection of OC2/AR expression in OC2-active tumors. Determine the correlation between OC2 activity and IHC detection of OC2 and AR in independentsets of clinical samples. Evaluate OC2 activity along the clinical spectrum of prostate cancer progressionincluding sequential pre/post-ADT tumor specimens metastases and xenograft models. Measure OC2/ARactivity in diagnostic prostate needle biopsies (PNBX) of untreated men with high-grade prostate cancer anddetermine the impact of OC2 activity on clinical outcome in univariate and multivariate analyses. Theseexperiments will help clarify the role of alternative drivers of progression and ADT resistance that emerge tocause lethal disease. They will also advance toward a phase I clinical trial a therapeutic approach against anovel master regulator that we estimate operates in 1/3 or more of all patients with CRPC tumors. +No NIH Category available Address;Advisory Committees;Applications Grants;Attention;Award;Basic Science;Cancer Center;Certification;Clinical;Clinical Investigator;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communities;Dedications;Detection;Development;Disease;Education;Educational Curriculum;Educational workshop;Electronic Mail;Ensure;Environment;Extramural Activities;Faculty;Feedback;Female;Financial Support;Fostering;Funding;Future;Gender Issues;Generations;Goals;Grant;Growth;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Health Sciences;Home;Infrastructure;Institution;Malignant Neoplasms;Mentors;Mentorship;Mission;Oral;Peer Review;Performance;Positioning Attribute;Prevention;Process;Program Development;Publishing;Reporting;Reproduction spores;Request for Applications;Research;Research Personnel;Research Project Grants;Science;Scientist;Secure;Study Section;Training;Training Programs;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Writing;career;career development;career preparation;design;disability;education research;experience;follow-up;improved;medical schools;meetings;member;next generation;programs;recruit;responsible research conduct;skills;success;translational scientist;web site;women faculty Career Enhancement Program PROJECT NARRATIVE CAREER ENHANCEMENT PROGRAM (CEP) The Hillman Cancer Center HN SPORE Career Enhancement Program (CEP) is designed to foster thegrowth of a new diverse generation of diverse scientists dedicated to head and neck squamous cell carcinoma(HNSCC) research leading to improvements in the prevention detection and therapy of this deadly disease.To accomplish this we have established collaborations with Johns Hopkins Howard University EmoryUniversity and Meharry Medical College to increase the representation of underrepresented minorities in theHN SPORE in addition to several internal initiatives to increase the diversity of the CEP to the benefit of theentire HNSCC research community. NCI 10704570 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6 8757 8581860 "BAKKENIST, CHRISTOPHER J." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 73865 46500 27415 PROJECT SUMMARY CAREER ENHANCEMENT PROGRAM (CEP) Despite recent gains driven in part by Hillman Cancer Center (HCC) HN SPORE-funded researchtranslational research in head and neck squamous cell carcinoma (HNSCC) lags that of many othermalignancies. The HCC HN SPORE is uniquely positioned to build upon its past successes and foster the nextgeneration of translational scientists studying HNSCC. The Career Enhancement Program (CEP) of the HCCHN SPORE has been designed to attract educate and mentor a new diverse group of scientists committed tounderstanding and eradicating HNSCC. HCC and the University of Pittsburgh have committed substantialfunding and infrastructure to this endeavor with institutional matching to double the number of CEP awardsgiven annually. Moreover the HCC HN SPORE is committed to diversity and has recently establishedcollaborations with Johns Hopkins Howard University Emory University and Meharry Medical College toincrease the participation of under-represented minorities in the HCC HN SPORE CEP and indeed throughthe entirety of the program. In addition we have appointed Dr. Tullia Bruno as Co-Director of the CEP. She isa previous CEP awardee member of the HCC Womens Task Force (an initiative launched by Dr. Ferris in late2017 which addresses gender issues among the female faculty at the Cancer Center) and co-leader of thePittsburgh Chapter of the Association for Women in Science to assist in increasing our number of femaleapplicants and awardees. Potential CEP awardees will be new to the study of HNSCC either because they are junior faculty who areestablishing their careers; established investigators studying other scientific questions who wish to transition toHNSCC; or clinical investigators well versed in the design and performance of clinical trials who wish tobroaden their translation research experience. The selection process for these awards are rigorous and includeall aspects of HNSCC research. Once awarded the CEP grantee will meet regularly with a more establishedHNSCC investigator with an established record of successful mentorship as well as a mentoring team. Theywill be encouraged to participate in courses in clinical and translational research and participate in mock studysections where their extramural funding applications will be scored by their mentoring team. The goal of thisprogram is to develop CEP awardees research into larger projects as well as diverse next generation ofHNSCC researchers. +No NIH Category available Adopted;Applications Grants;Area;Basic Science;Bioinformatics;Biometry;Clinical Investigator;Clinical Research;Clinical Trials;Cloud Computing;Collaborations;Computer software;Consultations;Custom;Data;Data Analytics;Development;Education;Ensure;Evaluation;Experimental Designs;Flow Cytometry;Gene Chips;Genomics;Goals;Individual;Leadership;Malignant neoplasm of prostate;Manuscripts;Methodology;Pathway Analysis;Preparation;Prostate;Proteomics;Publications;Quality Control;RNA;Reporting;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resources;Services;Statistical Data Interpretation;T cell receptor repertoire sequencing;Technology;Tissue Microarray;Translational Research;anticancer research;design;exome;gang;high dimensionality;member;power analysis;preclinical study;programs;tool;translational study Core 2: Biostatistics and Bioinformatics Core NARRATIVEThe Biostatistics and Bioinformatics core for the UCLA Prostate Cancer SPORE will ensure high quality researchthroughout the program by providing investigators with support in biostatistics and bioinformatics. This supportwill include the design of research projects development of data analytic plans carrying out statistical andbioinformatics analyses and assisting with publication of scientific manuscripts based on the results of analyses. NCI 10704569 9/15/23 0:00 PAR-18-313 5P50CA092131-20 5 P50 CA 92131 20 9/15/02 0:00 8/31/24 0:00 ZCA1-RPRB-7 8756 7919439 "ELASHOFF, DAVID " Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 136811 87699 49112 PROJECT SUMMARY/ABSTRACTThe Biostatistics and Bioinformatics Core (BBC) will facilitate translational research in prostate cancer byproviding UCLA investigators and their colleagues with state of the art biostatistical bioinformatics and clinicaltrials support. The BBC provides a centralized network of biostatistics and bioinformatics support for prostatecancer researchers at UCLA and their collaborators. The overall goal of the Core is to provide statistical andbioinformatic support to basic and clinical investigators in the SPORE. The statistical consulting will be led byDr. David Elashoff and supported by Dr. Gang Li and will include consultation on power analyses andexperimental design for planning of preclinical and clinical studies. The core will collaborate on the developmentof statistical analysis plans and assist with carrying out those plans. The Bioinformatics component will be ledby Dr. Thomas Graeber and supported by Dr. Paul Boutros. The Core provides analytical services for allgenomics research including RNA/whole exome/T-cell receptor sequencing and proteomic analysis within theSPORE. For these data types the core will assist with data preprocessing pipeline development and cloudcomputing quality control evaluation and both standard and custom integrative and network analysis. The corewill assist with the reporting of research findings in manuscripts. Finally the Biostatistics and Bioinformatics Coreprovides yearly educational seminars and courses to all SPORE investigators. +No NIH Category available Acceleration;Aftercare;Award;Back;Basic Science;Biochemical;Biological Assay;Biological Models;Biology;Biomedical Research;Bypass;Cancer Biology;Cancer Model;Cancer Patient;Cell Line;Cell physiology;Chemicals;Chemistry;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Coupled;Coupling;Data;Development;Diagnostic;Discipline;Disease;Elements;Engineering;Epigenetic Process;Foundations;Future;Gene Mutation;Generations;Genetic;Genomic approach;Genomics;Goals;Individual;Investments;Label;Link;Malignant - descriptor;Malignant Neoplasms;Maps;Measurement;Methodology;Methods;Modality;Molecular;Monitor;Mutation;Normal Cell;Oncogene Activation;Oncogenic;Outcome;Patient-Focused Outcomes;Patients;Post-Translational Protein Processing;Prediction of Response to Therapy;Primary carcinoma of the liver cells;Protein Biochemistry;Proteins;Proteome;Proteomics;Reagent;Reporting;Research;Research Personnel;Resources;Sampling;Signal Pathway;Solid Neoplasm;Technology;Therapeutic;Therapeutic Intervention;Tissue Banks;Tissue Sample;Translation Alteration;Translations;Tumor Biology;Tumor Cell Biology;Visit;Visualization;anticancer research;behavioral response;bench to bedside;cancer cell;cancer genetics;cancer genomics;cancer initiation;cancer therapy;cancer type;chemoproteomics;clinical decision-making;cofactor;design;diagnostic technologies;driver mutation;drug development;drug discovery;empowerment;gene product;genetic approach;genetic predictors;genetic profiling;imaging approach;imaging probe;improved;innovation;innovative technologies;insight;neoplastic cell;new technology;new therapeutic target;novel;novel therapeutics;patient subsets;precision medicine;precision oncology;protein degradation;protein function;response;targeted treatment;technology platform;therapeutic development;therapeutic target;tool;transcriptomics;translational potential;treatment response;treatment strategy;tumor Unlocking the Chemical Space of Cancer-Associated Perturbations Genomic technologies fail to directly capture the molecular complexity and plasticity of the tumor proteome thatdictates cancer initiation progression and therapeutic response. However methodologies and tools toquantitatively visualize and identify the molecular and biochemical features of tumor cell dynamics to inform ontherapeutic mechanism of action and motivate targeted therapy and diagnostic discovery are needed. Thisproposal describes the creation of the Probe Enabled Activity Reporting (PEAR) platform technology thatleverages chemical biology approaches to monitor proteome driven changes necessary for tumor cell functionas a means to predict therapeutic responses and discover unexplored liabilities. NCI 10704558 8/4/23 0:00 RFA-RM-21-017 5R01CA280833-02 5 R01 CA 280833 2 "AMIN, ANOWARUL" 9/14/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-BST-J(70)R] 9736845 "BRADY, DONITA C" "BURSLEM, GEORGE ; BUSINO, LUCA ; GADE, TERENCE P; WITZE, ERIC S." 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 431789 OD 265716 166073 The prevailing approach to precision cancer medicine relies on genetic profiling of patients followed byidentification of the malignant gene product and delineation of the mechanisms of that protein product in causingdisease. As a result much of the future of precision oncology is built on the hope of tailoring therapeuticinterventions based on diagnostic technologies that acquire complex genomic and transcriptomic data. Despitethe focus on cancer genetics the unique functional capabilities acquired by normal cells during tumordevelopment are driven by the aberrantly activated tumor cell proteome that arises not only from gene mutationsbut also from epigenetic reprogramming post-translational alterations or rewiring of signaling pathways.Unfortunately integrating traditional measurements of protein biochemistry that reflect tumor cell biology and thetherapeutics to which a tumor would respond into clinical decision-making for cancer patients is challenging dueto the uniqueness of each protein and limitations in existing technologies. Thus our proposal focuses onmechanism-based cancer research at the interface of chemistry and cancer biology to develop quantitativeapproaches that evaluate dynamic changes in the proteome in order to characterize unique features of tumorbiology with the long-term goal of motivating novel targeted therapies. Specifically we aim to establish aninnovative new development and discovery platform termed Probe Enabled Activity Reporting (PEAR) for tumorproteome profiling by leveraging chemical biology approaches to understand the molecular complexity ofproteomic changes necessary for tumor cell function as well as cellular adaptations to cancer therapy. Thefoundation of our bedside-to-bench and back again approach is rooted in the hypothesis that novel chemicalprobe reactomes exist in cancer cells themselves and changes in the reactome profile in response to cancertherapeutics will reflect alterations in protein function that drive cancer cell adaptations and thus would be idealfor new treatment modalities in the future. In interconnected and interdisciplinary discovery and elucidationmodules we will utilize state-of-the-art patient derived cancer models to both visualize and identify the proteintargets of chemical biology probes in pre- and post-treatment with the hypothesis that the differential reactomeswill be indicative of proteomic liabilities therapeutic response and unique aspects of tumor cell biology. Themajor outcomes from investing in PEAR for tumor proteome profiling to enable therapeutic development will bedevelopment of methodology to visualize reactive targets identification of treatment induced reactive targets andestablishing their functional relevance and unraveling unique tumor cell biology based on a novelcompartmentalized reactive target method. Taken together our proposal will establish and validate novelconcepts and methodologies that can be applied across the broad spectrum of solid tumors and as an extensionholds the potential to provide fundamental insights into tumor biology and transform precision oncology byproviding a platform to improve existing paradigms for drug discovery. 431789 +No NIH Category available Agreement;Area;Award;Breast;Cancer Research Project;Clinical;Development;Doctor of Philosophy;Environment;Exposure to;Faculty;Fellowship;Goals;Grant;Individual;Laboratories;Laboratory Research;Mentors;Positioning Attribute;Process;Productivity;Research;Research Personnel;Research Project Grants;Role;Time;Training;Translational Research;anticancer research;candidate selection;career;clinical investigation;clinical practice;course development;design;experience;malignant breast neoplasm;programs;skills Career Enhancement Program (CEP) NarrativeThe central goal of our translational research is to get the most up to date laboratory research and the mostcurrent clinical experience to talk productively to each other for the most rapid and efficient progress towardcontrolling and eliminating breast cancer. Thus we have designed this career enhancement program toexpose young researchers to the full range of the breast cancer research experience in a vigorouslytranslational environment whatever their initial training was as they move towards research independence. NCI 10704556 9/11/23 0:00 PAR-18-313 5P50CA186784-09 5 P50 CA 186784 9 9/19/14 0:00 7/31/25 0:00 ZCA1-RPRB-6 8752 1883878 "FUQUA, SUZANNE AW" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 86387 53992 32395 Abstract The purpose of this Career Enhancement Program is to support promising investigators who will participatein translational breast cancer research projects. There are one to two awardees at any one time who may beeither MD's or PhD's. Candidates are selected based on their previous accomplishments and their potential anddesire to pursue a career in academic breast cancer research. While our primary focus is to support promisingyoung investigators at the junior faculty level it is possible that more established investigators may also beappropriate for support. The general outline of each awardees research will have been discussed by the applicant and the SelectionCommittee as a part of the selection process and a principal mentor from the Program Faculty will be agreedupon. Awardees will receive further guidance from the Executive Committee and the selected mentor indeveloping their translational research projects throughout the award period. They will also participate in anextensive set of seminars professional development courses and clinical opportunities. The research environment at the Baylor Breast Center is ideal for supporting translational activities. Scientificexcellence in breast cancer research continues to be reaffirmed by the award of both individual and collaborativegrants while both national and local programs of clinical investigation are well established at the Baylor BreastCenter and can serve to assist in the translation of research findings into clinical practice. This is an excellentsetting for enhancing and focusing the careers of outstanding investigators on productive translational researchin breast cancer. Indeed of the 21 young investigators who received partial support from this program in the 26years since our first SPORE award most are active in academic research positions in breast cancer and fourhave important roles in this new SPORE proposal including one project leader. +No NIH Category available Pathology;anticancer research Opportunities for Pathology Trainees in Cancer Research Project NarrativeThis application is a renewal of our T32 training program Opportunities for Pathology Trainees In Cancerresearch (OPTIC) which supports postdoctoral trainees developing research-oriented careers in cancerpathology. The program is open to a highly select group of clinical trainees allowing them to conduct in-depthlaboratory projects and participate in educational activities geared towards preparing them for leadership rolesin academic pathology and laboratory-based cancer research. NCI 10704553 9/6/23 0:00 PA-20-142 5T32CA193145-08 5 T32 CA 193145 8 "LIM, SUSAN E" 9/21/15 0:00 8/31/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 10098443 "LOTAN, TAMARA LEVIN" "EBERHART, CHARLES G" 7 PATHOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 111986 NCI 312292 22743 Project Summary/AbstractPathologists are uniquely positioned to contribute to cancer research. Their familiarity with disease classificationsand pathogenesis physical manifestations of tumors in tissue and clinical challenges in cancer care mean thatthese investigators can provide important perspectives in developing experimental models that recapitulate keyaspects of human disease. The Opportunities for Pathology Trainees In Cancer research (OPTIC) programat the Johns Hopkins University School of Medicine (JHUSOM) supports postdoctoral trainees developingresearch-oriented careers in cancer pathology and is geared towards preparing them for leadership roles inacademic pathology and laboratory-based cancer research. Over the first funding period the mandate of theOPTIC program has been to attract and recruit the brightest pathology trainees interested in cancer research; topair them with faculty mentors representing the remarkable breadth and diversity of cancer research at JHUSOM;to protect their time for an immersive experience in the research laboratory; and to involve them in a unique andprogram-specific educational curriculum. With four postdoctoral trainees each year the program is overseen byinternal and external oversight committees consisting of highly successful academic pathologists in cancerresearch. Fellows select a research mentor from participating faculty a stellar group recruited from the fullspectrum of cancer research fields at the institution. All are accomplished investigators with an expertise inexperimental cancer research and strong track records of laboratory-based mentorship. In addition to pursuinga rigorous research program trainees participate in program-specific didactics and workshops to develop skillsfor their independent careers and enroll in other course work tailored to their individual interests and chosen tocomplement their previous experiences. Fellows create an Independent Development Plan with their mentoreach trainee convenes meetings of an Individual Progress Committee members of which provide feedback ontheir progress recommend specific near-term research goals and training activities and are generally beavailable as career mentors and advocates. Fellows leave the program poised for transitions to mentored andindependent faculty positions in academic pathology departments and fully prepared to conduct high impactcancer research. 111986 +No NIH Category available Affect;Antibodies;Antibody-drug conjugates;Biological Markers;Cancer Burden;Cancer Etiology;Cancer Model;Child;Clinic;Clinical Trials;Clinical Trials Design;Clonal Evolution;Coupled;Cytotoxic Chemotherapy;DNA;Development;Diagnostic;Ecosystem;Epigenetic Process;Evolution;Genetic Predisposition to Disease;Genetic Screening;Genomics;Goals;Health;Human;Immune Evasion;Immunogenomics;Immunotherapeutic agent;Knowledge;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Mission;Morbidity - disease rate;Motivation;Neuroblastoma;Newly Diagnosed;Oncogenic;Pathway interactions;Patient-Focused Outcomes;Patients;Probability;Public Health;Relapse;Research;Solid;Susceptibility Gene;Sympathetic Nervous System;T cell therapy;Therapeutic;Translating;United States National Institutes of Health;Variant;attributable mortality;design;drug development;epigenomics;evidence base;genetic approach;genomic data;high risk;improved;individualized medicine;innovation;multidisciplinary;neurodevelopment;novel therapeutic intervention;pressure;programs;standard of care;targeted treatment;therapy development;therapy resistant;translational research program;treatment response;tumor;tumorigenesis Discovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomes Project NarrativeThe research program proposed here is relevant to public health because it seeks to discover fundamentalprinciples of cancer etiology evolution and response to therapy focusing on the childhood malignancyneuroblastoma. The research is highly relevant to the NIH mission and the urgent unmet need of developingrational evidence-based therapeutic strategies to reduce the health burden of cancer. The proposed researchis designed to discover the basic oncogenic mechanisms of high-risk neuroblastoma that are amendable tonovel therapeutic strategies designed to dramatically improve cure rates with decreased morbidity. NCI 10704552 7/25/23 0:00 PAR-16-411 5R35CA220500-07 5 R35 CA 220500 7 "UNDALE, ANITA H" 9/30/17 0:00 8/31/24 0:00 ZCA1-GRB-I(M2) 1938303 "MARIS, JOHN M" Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 821084 NCI 588000 423360 Project SummaryAfter stunning improvements in patient outcomes for most childhood cancers in the latter half of the lastcentury cure rates have plateaued. Children with metastatic solid malignancies continue to have a less than50% chance of survival despite being treated with highly intensive cytotoxic therapies. Neuroblastoma (NB) adiverse malignancy affecting very young children that arises from the developing sympathetic nervous systemis responsible for a disproportionate amount of morbidity and mortality attributable to childhood cancer and isthe main focus of the Maris translational research program. Our primary motivation is to improve patientoutcomes and we also deem NB an outstanding model of cancer in general such that discoveries of basicmechanisms of tumorigenesis are broadly applicable to other human malignancies. Over the next seven yearsthe Maris lab will seek to substantively improve cure rates for patients with through a multidisciplinary andcollaborative research program. Our broad goal is to discover the fundamental mechanisms that subvertnormal neural development and orchestrate NB tumorigenesis and then to translate this knowledge intopatient-specific therapies that will be more effective and less toxic. We thus have a comprehensive approachwith six highly integrated major research efforts planned over the next seven years. 1) Genetic susceptibility toNB. Our lab has discovered the majority of NB predisposition genes using genetic approaches. We will nowdefine the mechanisms by which DNA variation cause malignant transformation via epistatic deregulation ofnormal developmental pathways using epigenomics approaches. 2) NB genomics and clonal evolution. Our labhas led the collaborative efforts to define the genomic landscape of diagnostic high-risk NB. We will now focuson NB as a dynamic ecosystem defining how tumors adapt to the selective pressure of therapy. 3) NB drugdevelopment. The Maris lab has utilized genomic data and genetic screens to define oncogenic vulnerabilitiesand many of these have been translated to the clinic. We will now focus on defining mechanisms of therapyresistance to both standard of care agents and the targeted therapies we develop. 4) Immunogenomics. TheMaris lab has used an integrative approach to discover several new immunotherapeutic targets in NB. We willnow intensively focus on developing antibodies antibody drug conjugate and adoptive T-cell therapies to thesetargets designed to eradicate NB safely. 5) Precision NB therapies. We have developed biomarker-directedclinical trials for children with relapsed NB and will continue our efforts here both in the relapse and newlydiagnosed setting using clinical trials designed to enrich for patients most likely to benefit. We think that ourresearch program proposes a variety of innovative experimental strategies to uncover basic mechanisms ofoncogenesis kinome reprogramming epigenetic adaptation and immune evasion and is steadfastlytranslational. The significance of the proposed program is the discovery of fundamental mechanisms of NBtumorigenesis that will lead to markedly improved probability of cure coupled with reduced morbidity. 821084 +No NIH Category available Address;Anatomy;Basic Science;Biological Models;Biopsy;Breathing;Cancer Model;Caring;Cell Survival;Cell physiology;Cells;Clinic;Clinical Sciences;Clinical Trials;Colorado;Combination immunotherapy;Communication;Cyclin D1;Data;Data Science;Dedications;Development;Disabled Persons;Discipline;Endothelium;Epithelial-Stromal Communication;Eragrostis;Faculty;Fostering;Genetically Engineered Mouse;Goals;Grant;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Human;Human Papillomavirus;Immune;Immune Evasion;Immunocompetent;Immunosuppression;Immunotherapy;Infiltration;Investigational Therapies;Lead;Malignant neoplasm of salivary gland;Malignant neoplasm of thyroid;Modeling;Molecular;Morbidity - disease rate;Mus;Oncogenic;Organ;Pathogenesis;Pathology;Patients;Pharmaceutical Preparations;Phase;Postdoctoral Fellow;Prognostic Marker;Proteins;Quality of life;Radiation therapy;Recurrence;Regimen;Regulatory T-Lymphocyte;Reproduction spores;Research;Research Personnel;Research Project Grants;Resistance;Sampling;Signal Transduction;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Therapeutically Targetable;Tissues;Tobacco;Transforming Growth Factor beta;Translating;Translational Research;Translations;Treatment Efficacy;Tumor-associated macrophages;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Vascular Endothelial Cell;anticancer research;base;cancer cell;cancer survival;cancer therapy;cancer type;career;chemoradiation;clinical application;design;head and neck cancer patient;humanized mouse;improved;improved outcome;in situ vaccination;in vitro Model;in vivo;inhibitor;innovation;monocyte;mortality;novel;novel therapeutic intervention;optimal treatments;palliation;participant enrollment;patient derived xenograft model;pharmacologic;phase I trial;pre-clinical;predictive marker;prognostic;prognostic significance;programmed cell death ligand 1;programs;recruit;research and development;research clinical testing;synergism;targeted treatment;therapeutic target;therapy development;translational cancer research;tumor;tumor microenvironment Colorado Head and Neck Cancer SPORE PROJECT NARRATIVE OverallThe ultimate goal of the Colorado (CO) Head and Neck Cancer (HNC) SPORE is to advance translationalresearch to improve survival and quality of life for HNC patients. The strategies to accomplish this goal will takeadvantage of our expertise in basic and clinical sciences and unique model systems to identify novel molecularand cellular mechanisms of HNC pathogenesis that may be targeted for therapeutic interventions. NCI 10704550 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 "HUBBARD, LEAH" 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6(M1)P 8665415 "JIMENO, ANTONIO " "WANG, XIAO-JING " 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1817388 NIDCR 213969 114031 PROJECT SUMMARY OverallThe main goal of the Colorado (CO) Head and Neck Cancer (HNC) SPORE is to advance translational researchto improve survival and quality of life for HNC patients. Optimal treatment for HNC patients is critically importantbecause the head and neck organs support critical functions such as breathing nourishing and communicatingand thus HNC can lead to significant morbidity and mortality. The CO HNC SPORE takes advantage of ourexpertise in basic and clinical sciences and uses unique model systems to identify novel molecular and cellularmechanisms of HNC pathogenesis targetable by therapeutic interventions to treat all cancer types arising fromhead and neck anatomic sites. Three projects cover the treatment spectrum of head and neck squamous cellcarcinoma (HNSCC) and include both tobacco-related and human papillomavirus (HPV)-related HNSCC.Project 1 studies novel immunotherapy mechanisms by inhibiting EphB4-EFNB2 interactions between immunecells and the endothelium. It will test if blockade of EphB4-EFNB2 signaling at the tumor endothelial barrierhinders Tregs' and TAMs' ability to infiltrate and promote cancer survival or suppress Teff function. Theapplicability of pre-clinical data to clinic will be assessed in samples from HNSCC patients treated with an EphB4-EFNB2 inhibitor during a window trial. Project 2 investigates if dual inhibition of TGF/PD-L1 combined withradiation therapy (RT) induces in situ vaccination reverses immune suppression and overcomes RT resistance.It will translate its findings with a trial of the TGF/PD-L1 dual inhibitor M7824 combined with RT in locallyrecurrent and oligometastatic HNSCC patients. Project 3 will study mechanisms of protein elongation inhibitionin HNSCC identifying key proteins targeted by the novel inhibitor SVC112 (a drug discovered in Colorado thatis nearing clinical testing) and translating our findings by testing the distribution and prognostic significance ofits target (eEF2) in patient samples. It will use immune relevant models including syngeneic and humanized miceto study immune-dependent and independent mechanisms of SVC112 and study if protein elongation inhibitionimpacts the tumor microenvironment and enhances RT in HNSCC. The developmental research program (DRP)is designed to attract current HNC researchers and researchers from other fields to conduct innovative researchin all types of cancers arising from head and neck tissues. The career enhancement program (CEP) is designedto solicit junior researchers to develop research projects to transition into independent HNC researchers. Weencourage underrepresented minority (URM) and people with disabilities to apply for DRP and CEP projects.The CO HNC SPORE also includes Biospecimen/Pathology Data Science and Administrative Cores. Insum the CO HNC SPORE will solidify in-depth HNC translational research and expand our team of dedicatedHNC researchers. These activities will improve the care spanning the entire spectrum of HNC treatment fromimproving cures to developing innovative palliation strategies for HNC patients. 328000 +No NIH Category available Address;Anatomy;Basic Science;Biological Models;Biopsy;Breathing;Cancer Model;Caring;Cell Survival;Cell physiology;Cells;Clinic;Clinical Sciences;Clinical Trials;Colorado;Combination immunotherapy;Communication;Cyclin D1;Data;Data Science;Dedications;Development;Disabled Persons;Discipline;Endothelium;Epithelial-Stromal Communication;Eragrostis;Faculty;Fostering;Genetically Engineered Mouse;Goals;Grant;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Human;Human Papillomavirus;Immune;Immune Evasion;Immunocompetent;Immunosuppression;Immunotherapy;Infiltration;Investigational Therapies;Lead;Malignant neoplasm of salivary gland;Malignant neoplasm of thyroid;Modeling;Molecular;Morbidity - disease rate;Mus;Oncogenic;Organ;Pathogenesis;Pathology;Patients;Pharmaceutical Preparations;Phase;Postdoctoral Fellow;Prognostic Marker;Proteins;Quality of life;Radiation therapy;Recurrence;Regimen;Regulatory T-Lymphocyte;Reproduction spores;Research;Research Personnel;Research Project Grants;Resistance;Sampling;Signal Transduction;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Therapeutically Targetable;Tissues;Tobacco;Transforming Growth Factor beta;Translating;Translational Research;Translations;Treatment Efficacy;Tumor-associated macrophages;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Vascular Endothelial Cell;anticancer research;base;cancer cell;cancer survival;cancer therapy;cancer type;career;chemoradiation;clinical application;design;head and neck cancer patient;humanized mouse;improved;improved outcome;in situ vaccination;in vitro Model;in vivo;inhibitor;innovation;monocyte;mortality;novel;novel therapeutic intervention;optimal treatments;palliation;participant enrollment;patient derived xenograft model;pharmacologic;phase I trial;pre-clinical;predictive marker;prognostic;prognostic significance;programmed cell death ligand 1;programs;recruit;research and development;research clinical testing;synergism;targeted treatment;therapeutic target;therapy development;translational cancer research;tumor;tumor microenvironment Colorado Head and Neck Cancer SPORE PROJECT NARRATIVE OverallThe ultimate goal of the Colorado (CO) Head and Neck Cancer (HNC) SPORE is to advance translationalresearch to improve survival and quality of life for HNC patients. The strategies to accomplish this goal will takeadvantage of our expertise in basic and clinical sciences and unique model systems to identify novel molecularand cellular mechanisms of HNC pathogenesis that may be targeted for therapeutic interventions. NCI 10704550 8/29/23 0:00 PAR-18-313 5P50CA261605-03 5 P50 CA 261605 3 "HUBBARD, LEAH" 9/1/21 0:00 8/31/26 0:00 ZCA1-RPRB-6(M1)P 8665415 "JIMENO, ANTONIO " "WANG, XIAO-JING " 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1817388 NCI 971591 517797 PROJECT SUMMARY OverallThe main goal of the Colorado (CO) Head and Neck Cancer (HNC) SPORE is to advance translational researchto improve survival and quality of life for HNC patients. Optimal treatment for HNC patients is critically importantbecause the head and neck organs support critical functions such as breathing nourishing and communicatingand thus HNC can lead to significant morbidity and mortality. The CO HNC SPORE takes advantage of ourexpertise in basic and clinical sciences and uses unique model systems to identify novel molecular and cellularmechanisms of HNC pathogenesis targetable by therapeutic interventions to treat all cancer types arising fromhead and neck anatomic sites. Three projects cover the treatment spectrum of head and neck squamous cellcarcinoma (HNSCC) and include both tobacco-related and human papillomavirus (HPV)-related HNSCC.Project 1 studies novel immunotherapy mechanisms by inhibiting EphB4-EFNB2 interactions between immunecells and the endothelium. It will test if blockade of EphB4-EFNB2 signaling at the tumor endothelial barrierhinders Tregs' and TAMs' ability to infiltrate and promote cancer survival or suppress Teff function. Theapplicability of pre-clinical data to clinic will be assessed in samples from HNSCC patients treated with an EphB4-EFNB2 inhibitor during a window trial. Project 2 investigates if dual inhibition of TGF/PD-L1 combined withradiation therapy (RT) induces in situ vaccination reverses immune suppression and overcomes RT resistance.It will translate its findings with a trial of the TGF/PD-L1 dual inhibitor M7824 combined with RT in locallyrecurrent and oligometastatic HNSCC patients. Project 3 will study mechanisms of protein elongation inhibitionin HNSCC identifying key proteins targeted by the novel inhibitor SVC112 (a drug discovered in Colorado thatis nearing clinical testing) and translating our findings by testing the distribution and prognostic significance ofits target (eEF2) in patient samples. It will use immune relevant models including syngeneic and humanized miceto study immune-dependent and independent mechanisms of SVC112 and study if protein elongation inhibitionimpacts the tumor microenvironment and enhances RT in HNSCC. The developmental research program (DRP)is designed to attract current HNC researchers and researchers from other fields to conduct innovative researchin all types of cancers arising from head and neck tissues. The career enhancement program (CEP) is designedto solicit junior researchers to develop research projects to transition into independent HNC researchers. Weencourage underrepresented minority (URM) and people with disabilities to apply for DRP and CEP projects.The CO HNC SPORE also includes Biospecimen/Pathology Data Science and Administrative Cores. Insum the CO HNC SPORE will solidify in-depth HNC translational research and expand our team of dedicatedHNC researchers. These activities will improve the care spanning the entire spectrum of HNC treatment fromimproving cures to developing innovative palliation strategies for HNC patients. 1489388 +No NIH Category available Address;Cancer Patient;Clinic;Clinical;Communication;Community Clinical Oncology Program;Complex;Conflict (Psychology);Consensus;Decision Aid;Decision Making;Dependence;Development;Diagnosis;Education;Electronics;Genes;Genetic Counseling;Goals;Hereditary Neoplastic Syndromes;Human Resources;Improve Access;Individual;Inherited;Institution;Intention;Knowledge;Level of Evidence;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Measures;Medical Oncologist;Oncologist;Outcome;Pathogenicity;Patients;Performance;Population Heterogeneity;Procedures;Process;Productivity;Professional counselor;Provider;Research Design;Resources;Risk;Syndrome;Test Result;Testing;Time;Update;Variant;acceptability and feasibility;cancer care;effectiveness evaluation;effectiveness/implementation study;efficacy evaluation;gene panel;genetic counselor;genetic panel test;genetic testing;implementation outcomes;innovation;pancreatic cancer patients;patient population;preference;randomized trial;randomized clinical trials;satisfaction;shared decision making;standard of care;targeted treatment;tool;tumor;uptake Development and Implementation of ElectronicDecision Aids for Genetic Testing in Inherited Cancer Syndromes PROJECT NARRATIVEThe goal of this project is to develop evaluate and implement a new electronic decision aid toolfor individuals referred for genetic testing for an inherited cancer syndrome. We propose thatsuch a decision aid can facilitate quality decisions around genetic testing reduce the dependenceupon formal genetic counseling and improve access to genetic testing. The tools will beevaluated broadly in both academic and community oncology clinics at multiple institutions. NCI 10704549 8/24/23 0:00 RFA-CA-20-006 5U01CA243695-04 5 U01 CA 243695 4 "NELSON, WENDY" 9/14/20 0:00 8/31/25 0:00 ZCA1-TCRB-T(A1) 2046025 "CHUNG, DANIEL C" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 737088 NCI 603739 301351 PROJECT SUMMARYThe indications and demand for genetic testing in cancer care are rapidly growing. Hereditary cancersyndromes are more common than previously appreciated and genetic testing is standard of care toestablish these diagnoses. Genetic test results are also critical to guiding targeted therapies in patientswith established tumors such as ovarian and pancreatic cancer. Genetic counselors have traditionallymanaged the testing process but there is a critical shortage of counselors and they are not able to meetthe demand for testing. Without a genetic counselor effective communication of testing options outcomesand risks could be compromised. One of the most challenging decisions is the choice of gene panel. Multi-gene panels are now the norm but panels can include as few as 5 or as many as 125 genes. Panels caninclude genes associated with a single tumor type or multiple tumor types and genes with weaker evidencefor pathogenicity may also be included. There is no consensus on what constitutes an ideal panel andthe choice of panel is therefore highly individualized. Innovative strategies to support patients facing thesetime-sensitive and complex pre-test decisions are needed.Decision aids are well-suited to address this challenge by providing education facilitating the process ofinformed choice clarifying personal preferences and promoting shared decision making. We propose todevelop an electronic decision aid to assist individuals in choosing a multi-gene panel with their medicaloncologist instead of a genetic counselor. We will test the hypothesis that a decision aid without a geneticcounselor can facilitate quality decisions around the selection of a specific multi-gene panel. In additionto positive changes in knowledge shared decision making and decisional conflict we anticipate that thedecision aid will increase access to genetic testing in a timely manner. Utilizing an effectiveness-implementation hybrid study design we propose these specific aims: (1) To develop and pilot electronicdecision aids for selection of a multi-gene panel in ovarian and pancreatic cancer patients. (2) To evaluatethe efficacy of the decision aid with an oncologist versus a traditional genetic counselor session for multi-gene panel testing in a randomized clinical trial at multiple institutions. (3) To evaluate the effectiveness ofimplementation of the decision aid in multiple diverse populations.These decision aids will establish a much needed and new paradigm for quality decision making andcommunication around multi-gene panel testing for inherited cancer syndromes. This format will uniquelyaddress the current barriers that include the complex decision of which multi-gene panel to select limitedgenetic counselor resources and lack of time and expertise on the part of practicing oncologists. 737088 +No NIH Category available Aftercare;Animals;Applications Grants;Bayesian learning;Bioinformatics;Biological;Biometry;Biostatistics Core;Cancer Center;Clinic;Clinical;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Computer Analysis;Data;Data Analyses;Development;Experimental Designs;Genomics;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Immunohistochemistry;Immunologics;In Vitro;Individual;Laboratories;Machine Learning;Malignant Neoplasms;Manuscripts;Methods;Nature;Patients;Preparation;Program Development;Protocols documentation;Quality Control;Reporting;Reproducibility;Reproduction spores;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Services;Skin Cancer;Specimen;Techniques;Translational Research;Visualization;Work;Writing;anticancer research;career development;compare effectiveness;data management;data quality;data quality/integrity;data sharing;design;experience;experimental study;in vivo;innovation;member;multidimensional data;stem;translational study Core C: Biostatistics and Bioinformatics Core PROJECT NARRATIVE BIOSTATISTICS/BIOINFORMATICS CORE (CORE C) The Biostatistics/Bioinformatics Core (Core C) provides specialized analysis services to the clinicallaboratory translational and -omics research projects of the UPMC Hillman Cancer Center HN SPORE toensure that experiments are efficiently designed and data are analyzed in a rigorous and reproducible fashionby analysts familiar with cancer in general and head and neck squamous cell carcinoma in particular. NCI 10704548 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6 8750 15181523 "BAO, RIYUE " Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 211292 133014 78423 PROJECT SUMMARY BIOSTATISTICS/BIOINFORMATICS CORE (CORE C) The Biostatistics/Bioinformatics Core (Core C) of the Hillman Cancer Center (HCC) HN SPORE providesservices for the design of experiments and the analysis of in vitro in vivo clinical translational and -omicsdata. The investigators and staff of both segments of the Core have significant experience in research in headand neck cancers so that data are analyzed in the appropriate scientific context increasing the Core'sefficiency and effectiveness compared to general purpose data analysis services. Biostatistics andBioinformatics combines classic statistical techniques with contemporary Bayesian machine learning andgenomics methods to ensure that every research project Developmental Research Program and CareerDevelopment Program awardee in the SPORE has access to the most appropriate analyses. The Core willalso work closely with Core A (OSD) and Core B to ensure that data flows between laboratories clinics andanalysts are efficient and that data and resource sharing can be effective and comprehensive. This Core C Co-Directors are Dr. Daniel Normolle (Biostatistics) and Dr. Riyue Bao (Bioinformatics) whohave assembled an excellent team to help achieve the goals of the HN SPORE. +No NIH Category available Address;Appearance;Benign;Biological;Biological Markers;Biology;Biopsy;Breast;Breast Cancer Detection;Calibration;Cancer Biology;Classification;Clinical;Clinical Management;Clinical Trials;Computer Assisted;Computer Vision Systems;Creativeness;Data;Databases;Decision Making;Development;Diagnosis;Diagnostic;Diagnostic Imaging;Dimensions;Disease;Disease Progression;Epigenetic Process;Evolution;Excision;Failure;Fostering;Foundations;Goals;Growth;Harm Reduction;Health;Health Care Costs;Histopathology;Image;In Situ Lesion;Indolent;Joints;Lead;Lesion;Malignant Neoplasms;Mammographic screening;Mammography;Mathematics;Measures;Methods;Mission;Modality;Modeling;Monitor;Morbidity - disease rate;Noninfiltrating Intraductal Carcinoma;Operative Surgical Procedures;Outcome;Pathology;Patient Monitoring;Patient risk;Patients;Pattern;Performance;Practice Guidelines;Predictive Value;Prognosis;Public Health;Research;Resources;Risk;Surgical Oncology;Testing;Time;Tissue Sample;Tissues;Uncertainty;United States;United States National Institutes of Health;Woman;Work;breast lesion;calcification;clinical decision-making;clinical practice;cohort;follow-up;imaging biomarker;improved;infiltrating duct carcinoma;innovation;malignant breast neoplasm;molecular clock;multidisciplinary;neoplastic;overtreatment;personalized medicine;predictive marker;prognostic;prognostic model;prospective;psychological distress;radiological imaging;radiologist;radiomics;risk stratification;screening;screening guidelines;screening program;serial imaging;tissue biomarkers;treatment planning;tumor Dynamic imaging and tissue biomarker models to delineate indolent from aggressive breast calcifications PROJECT NARRATIVEThis proposal aims to develop innovative new methods to improve the clinical management of breastcalcifications detected on screening mammograms. The proposed research is relevant to public health becauseit seeks to reduce the harms of mammography screening and to facilitate more personalized treatment planningfor women diagnosed with early-stage breast cancer. The proposed research is relevant to the part of NIHsmission that seeks to foster creative discoveries to improve health. NCI 10704546 8/29/23 0:00 PAR-19-264 5R01CA271237-02 5 R01 CA 271237 2 "MAZURCHUK, RICHARD V" 9/15/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-E(59)R] 14871586 "GRIMM, LARS J" "RYSER, MARC " 4 RADIATION-DIAGNOSTIC/ONCOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 458632 NCI 306444 152188 ABSTRACT. Breast cancer screening programs suffer from false positive mammograms unnecessary biopsiesoverdiagnosis and overtreatment. A major contributor to the poor performance of screening mammography isthe diagnostic and prognostic uncertainty of mammographically detected calcifications. Breast calcificationsrepresent a biological continuum from benign disease to ductal carcinoma in situ (DCIS) to aggressive cancer.Radiologists struggle to correlate their imaging appearance with the underlying pathology and roughly two-thirdsof biopsied calcifications return with a benign pathology. Although calcifications evolve dynamically over timethe current management strategy relies heavily on the static appearance of calcifications from the most recentmammogram. Most women in screening programs have multiple mammograms yet this temporal information isconsistently underutilized in clinical decision making. There is thus an urgent need to quantify the dynamics ofcalcifications from serial mammograms and to characterize the relationship between calcification trajectoriesand disease biology. In the absence of such innovation increasingly sensitive screening modalities are expectedto further increase the burden of unnecessary diagnostic work-up and breast cancer overdiagnosis. The centralhypothesis of this proposal is that dynamic imageable and tissue biomarkers contain actionable diagnostic andprognostic information about mammographic calcifications. The use of established diagnostic imaging(mammography) in conjunction with investigational imageable biomarkers will enable testing of this hypothesis.Key to this proposal will be the creation of a large database of retrospectively and prospectively collected cohortsof patients with serial mammograms tissue samples and clinical outcomes. This proposal will consist of threespecific aims: (1) Develop a static model of breast calcifications to improve the clinical performance ofmammography screening; 2) Develop a dynamic model of breast calcifications to predict histopathology andDCIS prognosis; and 3) Combine the dynamic calcification model with tissue-based biomarkers of the underlyingevolutionary dynamics to delineate DCIS prognosis. The proposed research is highly innovative because it addsthe temporal dimension to computer-assisted classification of mammographic calcifications yields a jointcharacterization of calcification growth trajectories and lesion biology and develops dynamic risk models topredict invasive progression in women undergoing active monitoring for DCIS. This proposal will be co-led byDr. Grimm (breast radiologist) and Dr. Ryser (mathematical modeler) supported by a highly collaborativemultidisciplinary team with expertise in cancer biology computer vision and surgical oncology. The overallobjective of this proposal is to develop a dynamic imageable biomarker that delineates lethal cancer from non-lethal disease by leveraging the temporal dimension of serial mammograms. Ultimately the long-term goal ofour work is to better identify which calcifications to biopsy (reduce unnecessary biopsies) and if pre-invasiveDCIS is found to predict whether it will remain indolent or progress to lethal cancer (reduce overtreatment). 458632 +No NIH Category available ERBB2 gene;Intervention;Research;Therapeutic;Translational Research;chemotherapy;endoplasmic reticulum stress;immune checkpoint;malignant breast neoplasm;novel therapeutic intervention;sensor;targeted treatment;tumor-immune system interactions Targeting Endoplasmic Reticulum Stress Sensor IRE1 to Enhance Chemotherapy Sensitivity in MYC-driven breast cancer NARRATIVEAfter the introduction of successful HER2 directed therapeutics most fatal cases of breast cancer areassociated with chemotherapy-insensitive triple-negative or luminal B breast cancer. Our research will establish endoplasmic reticulum stress sensor IRE1-targeted therapy as a novel therapeutic approach to enhance chemotherapy sensitivity and reverse the immunosuppressive microenvironment in the presence of chemotherapy that sensitizes MYC-driven breast cancers to immune checkpoint intervention. NCI 10704545 9/11/23 0:00 PAR-18-313 5P50CA186784-09 5 P50 CA 186784 9 9/19/14 0:00 7/31/25 0:00 ZCA1-RPRB-6 8749 12011233 "CHEN, XI " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 332039 207524 124515 ABSTRACTLimited sensitivity to chemotherapy and an immunosuppressive tumor microenvironment drives breast cancer mortality in HER2 negative breast cancer. We have identified the IRE1/XBP1 branch of the Unfolded Protein Response (UPR) or endoplasmic reticulum (EnR) stress response as a previously unexplored therapeutic vulnerability in MYC-driven breast cancer that enhances chemotherapy sensitivity and reverses the immunosuppressive tumor microenvironment. IRE1 is amplified in ~10% of human breast cancer and frequently co-amplified with the MYC oncogene. Activation of MYC is synthetic lethal with IRE1/XBP1 pathway inhibition. We found that inhibition of the IRE1/XBP1 pathway with a highly selective first-in-class IRE1 RNaseinhibitor ORIN1001 suppresses MYC-high-expressing (MYChigh) but not MYC-low-expressing (MYClow) tumor growth in patient-derived xenograft (PDX) models. ORIN1001 substantially enhances the docetaxel efficacy resulting in rapid tumor regression and complete eradication of the MYChigh PDX tumors. Furthermore the ORIN1001 plus docetaxel therapy triggers massive cytotoxic T-cell infiltration depletion of immunosuppressive myeloid-derived suppressor cells (MDSCs) and substantial upregulation of PD-L1 in the tumor microenvironment. Non-human primate toxicology testing showed that ORIN1001 has excellent safety profile and is well-tolerated. These preclinical data prompt us to hypothesize that inhibition of the IRE1/XBP1 pathway with the IRE1 inhibitor ORIN1001 compromises MYChigh breast cancers by inhibiting obligatory UPR stress adaptation required for cellular viability. This therapeutic effect of ORIN1001 is associated with a marked increase in taxane sensitivity. In addition MDSCs are also selectively depleted by ORIN1001 in the presence of a taxane thus reversing immunosuppression and potentially sensitizing MYChigh breast cancers to immune checkpoint intervention. A pre-clinical phase study in breast cancer models will be conducted in parallel with aPhase 1 clinical trial. In Aim 1 we will establish diagnostic tests to determine eligibility for a clinical trial of ORIN1001 plus taxane combination therapy. Aim 2 will exploit the immunomodulatory effects of ORIN1001 plus docetaxel therapy in breast cancer by testing the addition of anti-PD-L1 immunotherapy. In Aim 3 we will conduct a phase I dose escalation study of ORIN1001 alone then in combination with paclitaxel followed by expansion cohorts in 4 subsets of breast cancer. The overarching objective of this proposal is to design and open a Phase 2 clinical trial in MYC-positive metastatic breast cancer with eligibility and endpoints to be defined by the execution of the research aims. +No NIH Category available Area;Automobile Driving;Biological;Biological Assay;Blood;Cancer Center;Cancer Patient;Cellular Assay;Characteristics;Chromatin;Clinical;Collection;Communication;Consent;Coupled;Data;Data Analyses;Data Collection;Databases;Dedications;Development;Evaluation;Flow Cytometry;Free Will;Generations;Genomics;Goals;Head;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Histologic;Histology;Histopathology;Image;Image Analysis;Immunohistochemistry;Individual;Institution;Joints;Laboratories;Link;Malignant neoplasm of thyroid;Organ;Pathologic;Pathologist;Pathology;Patient imaging;Patients;Policies;Preparation;Process;Proteomics;Publications;Raja;Recurrence;Reproduction spores;Research;Research Personnel;Research Project Grants;Resources;Sampling;Scanning;Science;Services;Specimen;Squamous cell carcinoma;Surgeon;Techniques;Technology;Testing;Tissue Microarray;Tissues;Translational Research;Transposase;Triage;Work;X-Ray Computed Tomography;central database;cluster computing;data exchange;digital;exome sequencing;experience;fluorescence imaging;improved;meetings;multiple omics;nano-string;programs;prospective;radiomics;recruit;repository;sample collection;single-cell RNA sequencing;spectrograph;standard of care;tissue preparation;transcriptome sequencing;transcriptomics;tumor;tumor-immune system interactions Core B: Tissue Histology and Imaging Core PROJECT NARRATIVE TISSUE/HISTOLOGY/IMAGING CORE (CORE B) The Tissue/Histology/Imaging Core (Core B) is critical for achieving the goals of the UPMC HillmanCancer Center Head and Neck (HN) SPORE by acquiring and storing biospecimen and patient imagingprocessing both and performing of a large variety of cutting-edge analysis techniques to support all HNSPORE projects. NCI 10704537 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6 8747 9593641 "CHIOSEA, SIMION I." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 286179 180157 106219 PROJECT SUMMARY TISSUE/HISTOLOGY/IMAGING CORE (CORE B) The Tissue/Histology/Imaging Core (Core B) of the UPMC Hillman Cancer Center (HCC) HN SPORE isresponsible for the acquisition and processing of biospecimens and computed tomography (CT) scans for HNSPORE-sponsored projects. Core B is co-led by Drs. Raja Seethala Simion Chiosea and Rivka Colen withDr. Colen specifically recruited to bring imaging and radiomics expertise to the HN SPORE. Core B willcontinue to work with surgeons and coordinators to facilitate the acquisition and efficient use of head andsquamous cell carcinoma (HNSCC) biospecimens and provide specialized histologic evaluation of thesetissues for the SPORE research projects and developmental programs. As previously Core B is responsiblefor collection triage processing and distribution or storage of specimen and tissue histopathology tissuemicroarray generation immunohistochemistry (IHC) and interpretation. However Core Bs function hasexpanded to facilitating multiple -omics-based analysis including whole exome and transcriptomesequencing single cell RNA sequencing single-cell Assay for Transposase-Accessible ChromatinSequencing NanoString digital spatial (DSP) profiling multi-parameter flow cytometry and multi-spectralfluorescent imaging. Additionally as part of Core Bs expanding capabilities standard of care CT images forHNSCC patients can now be easily acquired processed with extraction and analysis of radiomics features inthe service of HN SPORE-sponsored research. Information derived from Core B will freely flow to Core C foradditional analysis with key variables and information linked to the organ specific database (OSD) in Core Aa detailed searchable repository of over 12000 HNSCC patients. The overarching goal of Core B is to provideand facilitate the testing of clinically derived data to achieve the goals of the HN SPORE and improve the livesof patients suffering from HNSCC. +No NIH Category available Acceleration;Advanced Malignant Neoplasm;Alaska Native;Award;Biological;Biological Markers;Cancer Burden;Cancer Center;Cancer Patient;Cancer Prevention Trial;Chemoprevention;Chemopreventive Agent;Clinic;Clinical;Clinical Chemoprevention;Clinical Trials;Clinical Trials Network;Collaborations;Development;Division of Cancer Prevention;Dose;Dysplasia;Formulation;Funding;Genetic Predisposition to Disease;Goals;Histologic;Immunologics;Immunoprevention;Individual;Infrastructure;Institution;Intervention;Investments;Lead;Malignant Neoplasms;Medical center;Minority Groups;Molecular Target;National Cancer Institute;Neoplasms;Organ;Organizational Affiliation;Participant;Patients;Performance;Pharmacodynamics;Phase;Population;Populations at Risk;Positioning Attribute;Prevention;Prevention program;Prevention trial;Preventive;Preventive measure;Principal Investigator;Process;Productivity;Puerto Rico;Recommendation;Recording of previous events;Reproducibility;Research;Research Personnel;Risk;Science;Screening procedure;Site;Special Population;Testing;Time;Tissues;Underrepresented Minority;Universities;Vaccines;Wisconsin;cancer care;cancer chemoprevention;cancer clinical trial;cancer prevention;cancer therapy;clinical effect;clinically relevant;clinically significant;cost effective measures;design;drug repurposing;epidemiologic data;experience;first-in-human;healthy volunteer;high risk;high risk population;improved;innovation;medical specialties;member;multidisciplinary;novel;phase I trial;pilot trial;prevent;prevention clinical trial;research clinical testing;targeted agent;tumor progression;vaccine trial The MW Cancer Prevention Clinical Trials Network NARRATIVEThe purpose of the CP-CTNet site at the University of Wisconsin Carbone Cancer Center ChemopreventionProgram (UWISC) is to promote and conduct research in early phase cancer prevention trials (Phase 0 1 2) inorder to determine potential viable prevention agents for at-risk populations. The CP-CTNet site will serve as themain organization to develop design conduct and analyze early phase prevention trials. The CP-CTNet site willuse novel or re-purposed agents in various target organs to investigate their effects on pertinent biomarkers withthe overarching goal of reducing the cancer burden by preventative measures. NCI 10704531 8/16/23 0:00 RFA-CA-19-031 5UG1CA242635-04 5 UG1 CA 242635 4 "JOHNSEY, DONALD" 9/3/20 0:00 7/31/25 0:00 ZCA1-SRB-X(J3) 1877637 "BAILEY, HOWARD H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1627637 NCI 1112608 515029 ABSTRACTThe need to provide safe and cost-effective measures to prevent Cancer is self-explanatory. The University ofWisconsin (UWISC) as the Lead Academic Organization (LAO) together with our collaborating institutions(Affiliated Organizations/AOs) propose to continue performing early phase cancer prevention trials for theNational Cancer Institute (NCI) Division of Cancer Prevention (DCP) as a Cancer Prevention Clinical TrialsNetwork (CP-CTNET) site funded as a UG1 Consortium as described in RFA-CA-18-031. Our overarching goalis to evaluate the effects of novel preventive agents/interventions on pertinent biological endpoints in order toefficiently determine their appropriateness for further testing and potential viability toward becomingrecommended societal interventions to lessen the burden of cancer. We will pursue this overarching goal viathe following specific aims: (1) Efficiently design conduct and perform Phase 0 1 2 Chemoprevention ClinicalTrials of novel and/or re-purposed immunologic-based or molecular targeted agents assessing their effects uponrelevant biological (biomarkers/clinical effects) endpoints. (2) Build upon existing consortium infrastructure tocomplete Aim 1 via intra- or inter-consortium (CP-CTNET) multi-institutional collaborations in concert withNCI/DCP contributing three to four new Phase 0 1 or 2 clinical trials and accrual of 40-50 subjects per year.We are well positioned to successfully achieve the above aims due to our combined experience with preventionagent development (consortium members currently hold >90 DCP sponsored R U or PREVENT awards) andour consortium's staffing organization and management which results in the timely development performanceand completion of impactful multi-institutional early phase cancer prevention trials. Our enhanced consortiumconsists of >10 NCI-designated Cancer Centers institutions providing access to robust numbers of at-riskpatients (e.g. Mayo Clinics Seattle Cancer Care Alliance) and expanded access to at-risk under-representedminorities and special populations (e.g. University of Puerto Rico Alaska Native Medical Center). Supported bythe Carbone Cancer Center the University of Wisconsin CP-CTNet site is determined to contribute to advancingthe field of Cancer prevention through performance of early phase prevention trials. 1627637 +No NIH Category available Cause of Death;Cessation of life;Estrogen receptor positive;NF1 gene;Patients;Resistance;Role;Translational Research;Treatment Efficacy;improved;malignant breast neoplasm Project 1: Co-Targeting ER and Kinome Deregulation in Breast Cancers with Neurofibromin Deficiency PROJECT NARRATIVEEstrogen receptor-positive breast cancer is the largest contributor to death from breast cancer which now exceeds a half million annually worldwide. The major cause of death is resistance to treatment. Therefore this project aims to study a powerful resistance driver neurofibromin (encoded by the NF1 neurofibromatosis type 1 gene) to define its role in resistance and to seek a vulnerability that can be targeted to greatly improve treatment efficacy and enhance patient survival. NCI 10704529 9/11/23 0:00 PAR-18-313 5P50CA186784-09 5 P50 CA 186784 9 9/19/14 0:00 7/31/25 0:00 ZCA1-RPRB-6 8487 1955335 "ELLIS, MATTHEW J" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 330481 209784 120697 PROJECT SUMMARYOver 250000 cases of breast cancer are diagnosed annually in the US alone and about 80% of these will be estrogen receptor- positive (ER+). Despite great progress in treating this ER+ disease by endocrine therapy resistance to this treatment remains a major problem causing the majority of deaths from breast cancer. Our clinical studies on resistance have found that inactivation of the NF1 (for neurofibromatosis type 1) gene which may occur in as much as 20% of primary ER+ breast cancer patients correlates with a poor outcome in tamoxifen-treated patients. NF1 encodes neurofibromin best known as a Ras repressor (a GTPase Activating Protein or GAP) but the scientific premise of this project stems from our discovery that besides activating Ras loss of NF1 also globally enhances estradiol (E2)-dependent gene expression thus permitting the cells to grow in lower levels of E2 or even in tamoxifen because NF1 also directly interacts with ER as a transcriptional corepressor. In contrast to their lack of response to E2-deprivation or tamoxifen treatment NF1-depleted cells still respond to fulvestrant a SERD (Selective ER Degrader) and although the reduced repression of Ras-Raf signaling in NF1-depleted cells still allows promotion of cell survival/growth this in turn could be blocked pharmacologically by FDA-approved kinase inhibitors. This project will therefore investigate the hypothesis that NF1-deficient ER+ breast tumors should be treated by a SERD together with inhibitors blocking the Ras-Raf pathway. To assess whether NF1-status in patient tumors can differentiate treatment responses to various endocrine agents Aim 1 will first establish an effective diagnosis for NF1-deficiency and then analyze how NF1-status impacts long-term treatment responses in two large randomized neoadjuvant clinical trials ALTERNATE and P024. The former compares fulvestrant vs. AI (anastrozole) while the latter compares tamoxifen vs. another AI (letrozole). In addition we propose that NF1-deficient ER+ breast cancer should be treated by a SERD combined with kinase inhibitors targeting the Ras-Raf pathway so that Aim 2 will conduct preclinical modeling to examine new generation oral SERDs and Ras effector kinase inhibitors to find the best combination to drive clinical trial design and encourage pharma interest in trial support. A Phase-2 clinical trial to further this treatment concept has been planned for which we already have pharma interest and commitment. We will support this trial here by developing technologies to assess how NF1-heterogeneity impacts treatment response. Finally Aim 3 will analyze kinome reprograming after SERD treatment in primary NF1-deficient patients (Aim 1) and in preclinical models (Aim 2) by a mass spectrometry-based micro-scaled platform called KiP (Kinome Profiling). While our primary objective is to assess whether the use of a SERD in NF1-depleted tumors can lead to compensatory Ras-Raf activation the KiP platform is intrinsically unbiased and may also discover additional kinases driving SERD resistance. The successful execution of this project may stop the progression of the NF1-deficient subset of ER+ aggressive breast cancer early in its tracks. +No NIH Category available Animal Model;Animals;Bar Codes;Biological Assay;Biological Process;Blood;Bone Marrow;COL1A2 gene;Cancer Cell Growth;Cancer Patient;Castration;Cell model;Cells;Chick;Circulation;Clinical;Collaborations;Cre-LoxP;Data;Diameter;Disease;Disease Progression;Endothelium;Fibroblasts;Foundations;Gene Deletion;Genes;Genetic Transcription;Gleason Grade for Prostate Cancer;Goals;Growth;Heterogeneity;Human;Image;In Vitro;Indolent;Intervention;Invaded;Knock-out;Laboratories;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator;Membrane;Metastasis Induction;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Methods;Modeling;Molecular;Morphogenesis;Neoplasm Metastasis;Nonmetastatic;Oncogenic;Oncology;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Plasma;Play;Population;Positioning Attribute;Predisposition;Process;Prostate;Reporter;Resistance;Role;SPI1 gene;Signal Transduction;Site;Solid;Specimen;System;Testing;Tissues;Tumor Promotion;Tumor-Derived;Vesicle;Work;androgen sensitive;angiogenesis;cancer cell;cancer type;castration resistant prostate cancer;clinically significant;conditioning;exosome;experimental study;extracellular vesicles;genome editing;host neoplasm interaction;in vivo;innovation;intercellular communication;machine learning method;men;molecular oncology;nano-string;novel;programs;prostate cancer cell;prostate cancer metastasis;prostate cancer model;prostate cancer progression;response;trafficking;tumor;tumor growth;tumor microenvironment;tumor progression;uptake Molecular Mechanisms of Large Oncosome-Induced Prostate Cancer Progression and Metastasis PROJECT NARRATIVEIn this project we will perform functional tests of a newly-identified class of tumor-derived extracellular vesiclereferred to as large oncosomes. These shed vesicles are products of metastatic prostate cancer cells and wehave obtained evidence that they are potent effectors of conditioning of the tumor microenvironment in amanner that promotes disease progression. Here we will examine their potential role in stroma-supportedtumor progression and metastasis and the novel molecular mechanisms underlying this process. NCI 10704523 9/7/23 0:00 PA-18-484 5R01CA234557-05 5 R01 CA 234557 5 "WOODHOUSE, ELIZABETH" 8/1/19 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-OBT-D(02)M] 8903399 "DI VIZIO, DOLORES " Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 432034 NCI 262077 169957 AbstractProstate cancer (PC) is one of the most frequent tumors in men. Despite recent progress the disease is still incurableonce resistance to castration therapy occurs. Tumor progression is strongly mediated by altered molecularexchanges between cancer cells and the surrounding milieu that originate at the primary sites. However themechanisms regulating the response of the stroma to the tumor which ultimately promote PC progression arestill largely unknown. Our laboratory discovered a new type of tumor-derived extracellular vesicle (EV) which arereferred to as large oncosomes (LO) can harbor more abundant molecular cargo that is distinct and more potentlybioactive than that carried by exosomes. The rationale for this proposal derives from our preliminary observations inpatients that LO abundance in the circulation correlates with PC progression. Our functional data demonstrate thatLO can activate oncogenic signaling in fibroblasts which respond to LO uptake by activating MYC and SPI1 and byinduce a transcriptional program that promotes angiogenesis and stimulates tumor growth. The overarching goal ofthis project is to determine the functional role of LO in PC progression and metastasis. We hypothesize that LOfunctionally reprogram normal prostate-associated fibroblasts (NAF) toward a phenotype that is driven by MYC andSPI1 activation. These results strongly suggest that tumor-derived LO might activate intercellular responses that arespecific to this subtype of extracellular vesicle. Our hypothesis will be tested with three Specific Aims: Aim 1: Toinvestigate the role of LO-induced fibroblast activation in PC progression. Aim 2: To find evidence that the LO-induced transcriptional program is active in PC patients with clinically significant disease. Aim 3: To test if LOand/or Exo derived from PC patient and PDX specimens promote castration resistance and/or bone metastasis.We will use a combination of complementary in vitro and animal orthotopic models as well as focusedapproaches involving genome editing molecular barcodes and a Cre-Lox reporter in vivo system. Our study willdetermine if the transcriptional program induced by LO in vitro drives tumor progression and metastasis in vivo.Additionally we will determine if this transcriptional program can also be identified in patient specimens and if itindicative of tumor progression. Finally our study will provide evidence for LO abilities to induce metastasis ofindolent PC cells. 432034 +No NIH Category available Aftercare;Area;Biological Markers;Biology;Biopsy;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Cancer Patient;Cell physiology;Cell surface;Cells;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Data;Development;Disease;Excision;Exhibits;Functional disorder;Genetic Transcription;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Homeostasis;IL6 gene;Immune;Immune System Diseases;Immune response;Immunotherapeutic agent;Immunotherapy;Inflammation;Link;Malignant Neoplasms;Mediating;Metalloproteases;Metastatic/Recurrent;Minority;Molecular;NRP1 gene;Neoadjuvant Therapy;Nivolumab;Operative Surgical Procedures;PD-1 blockade;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Personal Communication;Phenotype;Plasma;Proliferating;Randomized;Regulation;Research Personnel;Resistance;Series;Surface;T cell receptor repertoire sequencing;T-Cell Activation;T-Cell Immunologic Specificity;T-Cell Proliferation;T-Lymphocyte;Therapeutic Clinical Trial;Tissues;Tumor Immunity;Tumor Tissue;Validation;anti-PD-1;anti-PD1 therapy;arm;biomarker identification;cancer imaging;cohort;combinatorial;cytokine;effector T cell;immune resistance;immunotherapy trials;improved;innovation;insight;interest;mouse model;novel;patient population;patient response;peripheral blood;predict responsiveness;programmed cell death protein 1;programs;receptor;receptor expression;resistance mechanism;response;response biomarker;single-cell RNA sequencing;spectrograph;standard of care;synergism;targeted treatment;therapeutic target;tocilizumab;transcriptomics;tumor;tumor microenvironment Project 3: Determining biomarkers for responsiveness to immunotherapy targeting LAG3/PD1 in HNSCC PROJECT NARRATIVE PROJECT 3 Although great strides have been made with immunotherapy for head and neck squamous cell carcinoma(HNSCC) only a minority of patients respond to anti-PD1 monotherapy. Thus there is an imperative need tofind better treatment options for these patients. LAG3 limits effector T cell function and exhibits synergy withanti-PD1 in mouse models of cancer and thus is a logical therapeutic target to increase anti-tumor immunity incombination with anti-PD1. There are now 10+ LAG3-targeting therapeutic clinical trials in the US and yet westill know very little about how LAG3 blockade alone or in combination with anti-PD1 impacts the immuneresponse to cancer and whether biomarkers exist which could predict responsiveness. NCI 10704522 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6 8745 8461537 "BRUNO, TULLIA CARMELA" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 316388 199175 117432 PROJECT SUMMARY PROJECT 3 Although great strides have been made with immunotherapy for head and neck squamous cell carcinoma(HNSCC) there is a strong imperative to [i] gain a better understanding of the mechanism(s) of action forcurrent standard-of-care (SOC) immunotherapies (e.g. anti-PD1) and novel immunotherapeutic treatments inclinical trials (e.g. anti-LAG3); [ii] determine biomarkers of responsiveness that could predict patient outcomesto immunotherapy; and [iii] determine if there are mechanisms of resistance that can be overcome. Tumor-specific inhibitory mechanisms such as inhibitory receptors (IRs) represent major obstacles to effective anti-tumor immunity highlighting the importance of understanding their cell intrinsic and extrinsic mechanisms andoptimal combinations to improve immunotherapies. Although LAG3 is the third checkpoint to be targeted with>10 agents in clinical trials we still know very little about how LAG3 blockade alone or with anti-PD1 impactsthe immune response to HNSCC. Our over-arching hypothesis is that LAG3/PD1 dual blockade synergizes topromote CD8+ T cell function in the tumor and peripheral blood (PBL) of HNSCC patients and a LAG3-dominant IR module in peripheral CD8+ T cells downregulates T cell function and ultimately patient responseto PD1-targeted therapy. We ask two major questions in this area. What is the mechanism of anti-PD1 (nivo)and anti-LAG3 (rela) on the anti-tumor function of CD8+ T cells? We are accruing to a novel neoadjuvantwindow trial which randomizes treatment-nave locally advanced HNSCC patients to two arms relevant to thisAim: [i] nivo monotherapy or [ii] nivo plus rela followed by surgery after initiation of treatment. We hypothesizethat T cell activation and proliferation pathways are differentially regulated by anti-PD1 vs. anti-LAG3 in CD8+ Tcells and that unique synergistic molecular programs will be revealed by this immunotherapeutic combinationin treatment-nave patients with HNSCC. Secondly we ask whether cytokines drive a LAG3-dominant IRmodule in peripheral naive CD8+ T cells and does it predict responsiveness to immunotherapy? We recentlymade a series of novel findings regarding IR expression in peripheral CD8+ T cells implying a novelmechanism of immune resistance. We hypothesize that cytokine-driven systemic immune dysfunction andsubsequent resistance to anti-PD1 therapy is driven by a LAG3-dominant IR module and that this dysfunctioncan be ameliorated by anti-LAG3+PD1 blockade. This project will [i] define biomarkers of response andresistance to nivo and nivo/rela [ii] potentially identify a patient population that will optimally benefit fromLAG3-based therapies and [iii] lead to the development novel combinatorial immunotherapy trials of increasedefficacy in HNSCC. +No NIH Category available Bioinformatics;Biometry;Computational Biology;Ensure;Medical Informatics;Methods;Mission;Resources;Translational Research;data management;malignant breast neoplasm;translational goal Biostatistics Information and Computational Biology PROJECT NARRATIVEThis Core provides comprehensive and essential statistical bioinformatics medical informatic and data management support to all projects to the DRP and CEP and to the other Cores. Our mission is to bring the best possible methods to bear and to help ensure that the translational goals of the SPORE will be met while making efficient use of resources. NCI 10704521 9/11/23 0:00 PAR-18-313 5P50CA186784-09 5 P50 CA 186784 9 9/19/14 0:00 7/31/25 0:00 ZCA1-RPRB-6 8744 2408334 "HILSENBECK, SUSAN G." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 271083 169428 101655 PROJECT SUMMARYIn this renewal SPORE application the former Biostatistics and Data Management Core is renamed to better reflect our expanded services. We have considerable experience working as a team with groups of investigators in general and this group of SPORE investigators in particular. All projects in our SPORE application will require statistical support for a range of preclinical and clinical experiments. All three projectspropose clinical trials and we have a strong track record of electronic clinical trial data management for both small single institution trials and more complex randomized multi-institution trials. All projects will also benefit from our expanded support for bioinformatics and integrative proteogenomic analysis. We also provide data management support to Core 1 (Pathology and Biobanking). New informatic development in support of biobanking and clinical annotation undertaken and cost shared with several other large projects is a significant benefit to the SPORE. In our experience centralized quantitative science support ensures that the biostatisticians bioinformaticians and informatics professionals are completely familiar with all aspects of the Projects and Cores. This provides continuity increases efficiency and ensures that appropriate methods are applied. This also increases cross-Project data sharing. The Informatics and Statistics Core (ISC) will provide three broad types of services: (1) Comprehensive biostatistical consultation experimental design data analysis and reporting; (2) Integrative proteome-genomic bioinformatic consultation experimental design data analysis and reporting; (3) Development customization integration and maintenance of databases and data management systems to support data management needs of SPORE projects and cores. As a by-product when necessary the Core can also develop new methods or adapt existing methods from other arenas to meet the unique needs of the SPORE.The SPORE benefits greatly from having a dedicated and experienced team with a range of skills. The Core can also draw flexibly on the resources and personnel in the Cancer Center Biostatistics and Informatics Shared Resource and the Zhang Lab to augment expertise or alter access to resources as needs change. Sample size considerations experimental designs and overviews of planned analyses for all projects were prepared in collaboration with the Core. In addition deep understanding of SPORE data and analysis needs in turn drives database and application development ensuring that informatic solutions meet the broad as well as project-specific needs of the SPORE. A hallmark of SPOREs is flexibility to terminate futile studies and pursue new leads. With dedicated Core personnel we can also help investigators design new studies and test new hypotheses that may arise by cross-fertilization of these related projects. +No NIH Category available 3-Dimensional;4T1;Ablation;Address;Binding;Binding Proteins;Biological Assay;Breast;Breast Cancer Model;Breast Cancer Patient;Breast cancer metastasis;Calcium;Calcium Binding;Cause of Death;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Co-Immunoprecipitations;Data;Detection;Development;Disease;Distal;Dominant-Negative Mutation;EF-Hand Domain;GTPase-Activating Proteins;Goals;Growth;Guanosine Triphosphate;Guanosine Triphosphate Phosphohydrolases;Immunohistochemistry;Immunoprecipitation;In Vitro;Injections;Invaded;Knockout Mice;Ligation;MDA MB 231;Malignant Neoplasms;Malignant neoplasm of prostate;Mass Spectrum Analysis;Matrix Metalloproteinases;Measurement;Mediating;Messenger RNA;Mitochondria;Mitochondrial Membrane Protein;Modeling;Molecular;Myosin ATPase;Myosin S-2;Neoplasm Metastasis;Neuroglia;Neurons;Normal tissue morphology;Organ;Organelles;Outer Mitochondrial Membrane;Pancreas;Patients;Phenocopy;Phenotype;Primary Neoplasm;Process;Production;Proliferation Marker;Prostate;Recombinant Proteins;Role;Sampling;Secondary to;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;System;Tertiary Protein Structure;Testing;Tissues;Transfection;Tumor Cell Invasion;Tumor Promotion;United States;Work;cell motility;cell type;hazard;in vitro Assay;in vivo;in vivo Model;in vivo imaging system;interest;knock-down;live cell imaging;mRNA Expression;melanoma;neoplastic cell;new therapeutic target;novel;novel therapeutics;pancreatic cancer cells;pharmacologic;prostate cancer cell line;protein function;rho GTP-Binding Proteins;rho GTPase-activating protein;small hairpin RNA;targeted treatment;therapeutic target;trafficking;tumor;tumor growth;tumorigenesis;tumorigenic The role of MIRO2 in tumor cell invasion and metastasis Project Narrative Ninety percent of cancer related deaths are due to metastatic dissemination to distal organs thus it isof great interest to study molecular mechanisms that contribute to metastases. Of interest mitochondria haveemerged as important organelles in tumorigenesis and metastasis. This project seeks to gain a mechanisticunderstanding of a novel mitochondrial signaling pathway that positively influences tumor cell invasion andmetastasis which would serve as the basis for new therapeutics targeting metastatic disease. NCI 10704512 3/24/23 0:00 PA-21-051 5F31CA271652-02 5 F31 CA 271652 2 "ODEH, HANA M" 4/1/22 0:00 3/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 14632230 "BOULTON, DILLON " Not Applicable 6 NONE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO UNIVERSITY-WIDE 800452571 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 398 "Training, Individual" 2023 37154 NCI 37154 0 Project Abstract/Summary Cancer is the second leading cause of death in the United States. Overall survival for patients with tumorsthat remain localized to the tissue of origin remain relatively high while it is estimated that 90% of all cancerrelated deaths are due to metastatic dissemination to secondary sites. This underscores the importance ofidentifying signaling pathways that promote metastasis. Mitochondria are multifunctional organelles withimportant roles in regulating many cellular processes outside of ATP production and are recognized for theirroles in tumorigenesis and metastasis. This project seeks to define a novel mechanism that promotes tumor cellinvasion and metastasis through a previously unidentified signaling pathway between Mitochondrial Rho GTPase2 (MIRO2) and atypical myosin IXB (MYO9B). MIRO2 is an outer-mitochondrial membrane protein that is a part of the MIRO subfamily of Ras GTPases.MIROs were first characterized in neurons where they are involved in the anterograde and retrograde traffickingof mitochondria. MIRO2 has been shown by several groups to be dispensable for mitochondrial trafficking inmany non-neuronal cell types. Our lab has previously shown that MIRO2 mRNA is enriched in tumorigenictissues in many tumor types when compared to normal tissue. Additionally we have shown in prostate cancerthat MIRO2 is important in tumor cell viability anchorage-dependent and -independent growth and tumor growthin vivo. Despite this initial evidence it remains unknown if MIRO2 exclusively impacts the primary tumor or if thisis also important in metastasis. My initial results show that loss of MIRO2 reduces the invasive capacity of tumorcells from many tumor types including breast melanoma pancreas and prostate. Furthermore I have shownout of the top newly identified MIRO2 binding partners loss of MYO9B reduces invasive capacity to the greatestextent. MYO9B is known to control cell motility by localizing to the leading edge of migrating cells and inactivatingRhoA through MYO9Bs Rho GTPase activating protein (GAP) domain. Excitingly I show that loss of both MIRO2and MYO9B result in increased active RhoA. Given this evidence I hypothesize MIRO2 promotes tumor cellinvasion and metastasis through positively regulating MYO9B GAP activity. In this proposal I will 1) determine the role of MIRO2 in tumor cell invasion and metastasis and 2)determine the mechanism in which MIRO2 regulates tumor cell invasion. This proposal will utilize many modelsincluding but not limited to: 2D/3D in vitro invasion systems live cell imaging of migrating cells in vivo breastcancer metastasis models cell-free GTPase assays co-immunoprecipitation and proximity ligation assays.Overall the goal of this proposal is to serve as the basis for the development of novel therapeutics to targetmetastatic disease. 37154 +No NIH Category available Advocacy;Charge;Communication;Goals;Services;Translational Research;malignant breast neoplasm;member;synergism Administration and Advocacy NARRATIVE The Administrative Core is charged with facilitating communication and sustaining integration among the SPORE members and projects as well as providing efficient support services for all of the SPORE components in order to maximize synergy in achieving our translational research goals NCI 10704511 9/11/23 0:00 PAR-18-313 5P50CA186784-09 5 P50 CA 186784 9 9/19/14 0:00 7/31/25 0:00 ZCA1-RPRB-6 8742 1955335 "ELLIS, MATTHEW J" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 181002 113125 67877 SUMMARY Our Breast SPORE consists of three full research projects as well as developmental projects career development and specialized core resources. An Administrative Core is needed to efficiently utilize administrative personnel and to provide common services for these projects and cores. Dr. Matthew Ellis as Principal Investigator of the SPORE will direct this Administrative Core. The Core will support communication and integration among SPORE members organize regular SPORE membership meetings as well as conferences and seminars and assist in coordinating clinical trials management within the SPORE projects. The Core also provides a pool of services which are common to all components of the SPORE including: financial administration of grant funds and the Directors discretionary funds organization of conferences and seminars administrative processing of review and funding of Developmental Projects management and review of Developmental Projects coordination of travel report preparation monitoring Human Subjects training conflict of interest reporting and management and assurance of compliance with all NIH and institutional grant regulations. The Core will also coordinate the services of our Internal Advisory Board and Advocates Committee and arrange for the visits of our External Advisory Board members to review our progress and make recommendations. In summary consolidation of common support and administrative functions relieves individual projects of many minor but important tasks and assures quality control in record-keeping services and compliance issues. Core personnel are highly experienced and the Core provides well-organized and cost-effective support to all components of the SPORE +No NIH Category available Affect;Aftercare;American Society of Clinical Oncology;Animal Model;Automobile Driving;Award;Cell physiology;Cells;Clinical Research;Clinical Trials;Clinical Trials Design;Combination immunotherapy;Data;Development;Disease;Environment;Equilibrium;Exhibits;Functional disorder;Future;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Hypoxia;Image;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunologics;Immunotherapy;Malignant Neoplasms;Metabolic;Metabolism;Metastatic/Recurrent;Metformin;Minority;Modeling;Nivolumab;Outcome;Oxidative Phosphorylation;Patients;Pharmaceutical Preparations;Phenotype;Phosphorylation Inhibition;Pre-Clinical Model;Productivity;Repression;Reproduction spores;Research;Research Personnel;Resistance;Sampling;Scanning;T-Lymphocyte;Testing;Therapeutic Clinical Trial;Tissues;Tumor Immunity;X-Ray Computed Tomography;anti-CTLA4;anti-PD-1;anti-PD1 therapy;cell type;checkpoint inhibition;clinical practice;combinatorial;design;immune cell infiltrate;immune checkpoint blockade;immunotherapy trials;improved;inhibitor;insight;ipilimumab;next generation;novel;novel therapeutics;patient population;pembrolizumab;personalized immunotherapy;pre-clinical;predicting response;programmed cell death protein 1;programs;radiomics;receptor;recruit;resistance mechanism;response;rosiglitazone;standard of care;targeted treatment;transcriptome sequencing;tumor;tumor hypoxia;tumor metabolism;tumor microenvironment Project 1: Hypoxia and metabolic dysregulation as a targetable barrier to immunotherapy in head and neck squamous cell carcinoma (HNSCC) PROJECT NARRATIVE PROJECT 1 Despite the promise of immune checkpoint inhibition in head and neck squamous cell carcinoma (HNSCC)only a minority of patients ultimately benefit. Continuing Project 1 has already identified tumor metabolism andhypoxia as potential drivers of anti-PD-1 resistance in this disease and now seek to examine the interactionbetween tumor hypoxia and metabolism combinatorial immunotherapy and response. The goal of this projectwill be to identify the next generation of metabolically driven immunotherapy combination for clinical trial. NCI 10704505 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6 8740 10043437 "DELGOFFE, GREG M." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 316751 199404 117566 PROJECT SUMMARY PROJECT 1 In recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) immune checkpointblockade has changed the standard of care with trials from HN SPORE PI Dr. Robert Ferris and co-I (Project2) Dr. Barbara Burtness pioneering the use of anti-PD-1 in this setting. Unfortunately only a minority ofpatients benefit due to resistance to anti-PD-1 therapy pointing to an urgent need to better understand thetumor microenvironment. With HN SPORE support first through a Developmental Research Program awardand later following elevation to Continuing Project 1 we have identified a connection between tumormetabolism hypoxia and T cell dysfunction that may be partially driving resistance to anti-PD-1 (Zandberg etal ASCO 2020). To further investigate this question we are proposing to conduct two newly designed noveltherapeutic clinical trials within Project 1 in R/M HNSCC nave to anti-PD-1 (HCC 18-190/NCT04114136) orprogressed on anti-PD-1 (HCC 18-156/NCT04326257). The former is a trial of metabolic modulators and anti-PD1 the latter a trial of anti-PD-1 combined with either anti-CTLA4 or anti-LAG3. Utilizing these trials and pre-clinical models of HNSCC we will examine the following questions. First what is the relationship betweenanti-PD-1 resistance tumor metabolism and hypoxia in HNSCC? With the assistance of Core B we willaddress this question via multiplexed tissue analysis in R/M HNSCC samples from our clinical trials as well asradiomics-based approaches of determining tumor hypoxia. Second does hypoxia promote resistance tocombinatorial immunotherapy in HNSCC? We will test how hypoxia may impede immunotherapy withnivolumab plus relatlimab (anti-LAG3) or ipilimumab (anti-CTLA4) in R/M HNSCC patients who haveprogressed on anti-PD-1 evaluating tissue before and after therapy. Third can metabolically targeted therapybe combined with anti-PD-1 to overcome anti-PD1 resistance in HNSCC? We will evaluate tumor samplesobtained before and after treatment with anti-PD-1 plus either metformin or rosiglitazone and determinechanges in tumor metabolism and hypoxia. We will also test combinatorial immunotherapy (as in Aim 2) withmetabolic modulation in pre-clinical HNSCC models rendered anti-PD1 resistant. Our trial of metabolicinhibitors combined with anti-PD1 therapy if positive will directly lead to larger scale clinical studies openingup an entirely novel avenue of combinatorial immunotherapy; while the project as a whole will also provide aplatform for developing future personalized immunotherapy trials by adding metabolic analysis and/ormodulation as a component. +No NIH Category available Advocacy;Cancer Center;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Data;Data Security;Databases;Development;Discipline;Disease;Ensure;Environment;Evaluation;Expedite Dissemination;Expenditure;Fostering;Funding;Goals;Guidelines;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Housing;Human Resources;Image;Individual;Institution;International;Leadership;Letters;Medical Oncologist;Monitor;Organ;Participant;Patients;Periodicals;Physicians;Productivity;Publications;Radiation Oncologist;Records;Reproduction spores;Research;Research Personnel;Research Project Grants;Resource Allocation;Resources;Scientist;Surgeon;Translational Research;Translations;Underrepresented Minority;Universities;Work;career;clinical database;college;data exchange;improved;individual patient;industry partner;interdisciplinary approach;interest;meetings;multidisciplinary;operation;organizational structure;outreach;outreach program;programs;prospective;recruit;translational progress;website development Core A: Administrative Core PROJECT NARRATIVE ADMINISTRATIVE CORE (CORE A) The Administrative Core (Core A) is critical in coordinating the efforts of the HCC HN SPORE by providingoversight on all aspects HN SPORE activities as well as housing and improving the HN SPORE organ specificdatabase (OSD) which includes data collected from over 12000 patients with head and neck cancer. NCI 10704502 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6 8739 1900219 "FERRIS, ROBERT L" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 446778 281259 165827 PROJECT SUMMARY ADMINISTRATIVE CORE (CORE A) The Administrative Core (Core A) is co-led by HN SPORE PIs Drs. Robert Ferris and Heath Skinner as wellas by Dr. Dan Zandberg with support from the Hillman Cancer Center (HCC) fiscal and administrative staffsupported jointly by the HN SPORE and the HCC (see Letter of Institutional Commitment). The primaryfunction of Core A is to serve the administrative and oversight needs of each Project and Core with thespecific responsibility of ensuring each aspect of the HN SPORE is progressing to its individual translationalclinical or career enhancement goal. Due to the centrality of this Core and its associated administrativefunction the organ specific database (OSD) a large longitudinal prospectively collected easily searchableclinical database is now housed in Core A. It is directly supported by the HN SPORE with over 12000individual patients and clinical records. The Core A directors will oversee data requests from the OSD as wellas the integration of additional -omics and imaging functionality that is ongoing and will be completed over thecourse of the proposed HN SPORE period. The Core A directors will also oversee the work of the Core AClinical Research Coordinator who along with institutional support coordinates the clinical trials of the HNSPORE. The Core A Co-Directors will also facilitate interactions between full projects DevelopmentalResearch Projects Career Enhancement Program Awardees and Cores identifying new opportunities andpotential changes in direction of each study performed within the HN SPORE. Collectively the Core Aleadership team monitor expenditures coordinate monthly HN SPORE meetings invited speakers at least bi-annual Executive Committee meetings Internal and External Advisory Board meetings and Inter-SPOREmeetings. Core A is also the primary point of contact for all NCI inter-and extra-institutional communicationsand coordinates multi-noninstitutional clinical trials. Additionally Core A coordinates research and laypublications website development HNSCC advocacy activities fund-raising and additional outreach efforts(including our outreach program with Johns Hopkins Howard University Emory and Meharry College toincrease participation of under-represented minorities in the HN SPORE). Core A is critical to the coordinationof the HN SPORE specifically working to ensure the successful completion of the HN SPORE aims as well asmore generally fostering a continued culture of highly impactful translational research at HCC with a goal ofchanging practice in the management of HNSCC. +No NIH Category available Address;Adjuvant Radiotherapy;American College of Radiology Imaging Network;American Society of Clinical Oncology;Antidiabetic Drugs;Automobile Driving;Award;Bioinformatics;Biological Markers;Biometry;Biopsy;Cancer Center;Cancer Center Support Grant;Cisplatin;Clinical;Clinical Data;Clinical Trials;Clinical Trials Design;Collaborations;Combination immunotherapy;Combined Modality Therapy;Cytometry;Data;Databases;Development;Diagnosis;Dose;Eastern Cooperative Oncology Group;Ensure;Exercise;Funding;Future;Generations;Genes;Genomics;Gifts;HPV oropharyngeal cancer;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Historically Black Colleges and Universities;Hypoxia;IL6 gene;Image;Immune;Immunologist;Immunooncology;Immunotherapy;Industrialization;Institution;Investments;Low risk HPV;Measures;Metabolic;Metformin;Minority Groups;National Clinical Trials Network;Neoadjuvant Therapy;Nivolumab;Operative Surgical Procedures;Oral;Organ;Outcome;PD-1 blockade;Pathologic;Patients;Positioning Attribute;Primary Neoplasm;Program Research Project Grants;Quality of life;Radiation therapy;Radiogenomics;Recurrence;Reporting;Reproduction spores;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Risk;Robotics;Site;Subgroup;T-Lymphocyte;Technology;Testing;Thyroid Nodule;Time;Tissues;Toxic effect;Translational Research;Underrepresented Minority;Universities;Woman;X-Ray Computed Tomography;anti-PD-1;anti-PD1 therapy;anticancer research;biobank;career;chemoradiation;chemotherapy;cohort;design;flexibility;follow-up;high dimensionality;high risk;improved;inhibitor;innovation;medical schools;minimally invasive;multidisciplinary;next generation;novel;outreach;precision oncology;predict responsiveness;predictive signature;prevent;programmed cell death protein 1;programs;prospective;radiomics;recruit;response;rosiglitazone;single cell sequencing;standard of care;success;technology platform;transcriptome sequencing;transcriptomics;trial comparing;tumor Head and Neck Cancer SPORE PROJECT NARRATIVE OVERALL The research Projects and supporting state-of-the-art supporting Cores of the UPMC Hillman Cancer CenterHead and Neck SPORE are directed at solving key remaining problems in head and neck squamous cellcarcinoma treatment debilitating toxicities low immunotherapy response rates and the need for precisiononcology. The SPOREs Developmental Research and Career Enhancement Programs will ensure continuousinvigoration and increased diversity of the SPORE and the field of translational head and neck cancerresearch. NCI 10704501 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 "HUBBARD, LEAH" 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6(O1)S 1900219 "FERRIS, ROBERT L" "SKINNER, HEATH DEVIN" 12 OTOLARYNGOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2112973 NCI 1220052 694257 PROJECT SUMMARY OVERALL For more than 15 years the UPMC Hillman Cancer Center (HCC) Head and Neck SPORE has facilitatedpractice change in diagnosis and treatment of head and neck squamous cell carcinomas (HNSCC) and otherhead and neck cancers. For the renewal period the SPORE will focus on the remaining problems ofdebilitating toxicities low immunotherapy response rates and the need for precision oncology in HNSCCtreatment. Through its multidisciplinary project teams four clinical trials and analysis of a completed clinicaltrial the SPORE will investigate: 1) how hypoxia and metabolic dysregulation leads to PD-1 immunotherapyresistance and how it can be overcome 2) how patients with human papillomavirus-positive oropharyngealcancers can be optimally selected for deintensified therapy and 3) which biomarkers can be used forpredicting responsiveness to combined immunotherapy with PD-1 and LAG3 inhibitors. The studies will beconducted with the support of state-of-the-art Cores that provide access to over 6400 well-characterizedclinically annotated biospecimens; biostatistical and bioinformatics support; and advanced technologyplatforms that include multiplexed cytometry and imaging next generation and single sequencing; andradiomic and radiogenomic analyses based on features extracted from patient CT scans. Through theSPOREs Developmental Research Program (DRP) and Career Enhancement Program (CEP)translational head and neck cancer research will be further advanced with new ideas research strategies andinvestigators. These programs will focus heavily on increasing diversity by attracting and advancing projectsfrom woman and underrepresented minorities groups via internal initiatives and external collaborations. Criticalto the success of the research is the wealth of longitudinal clinical data collected on nearly 12000 patients withlongitudinal 30 years of clinical follow up in the SPOREs Organ Specific Database (OSD) which is now beenexpanded to include quality of life measures as well as extensive genomics radiomics and transcriptomicdata. Established horizontal and vertical collaborations with other Cancer Centers national cooperative trialgroups industrial partners enable and extend the efforts of the SPORE investigators. Submission of thisrenewal application was intentionally taken off cycle separating its renewal cycle from the HCC CCSG P30 tomaximize institutional resources that could be devoted to both applications as well as to provide additionaltime for newly recruited SPORE leaders to collaborate and solidify their interactions as a team at HCC. HCCshas continued to support the HN SPORE including soliciting CEP and DRP awards highlight its strongcommitment to its renewal. 1912973 +No NIH Category available Address;Adjuvant Radiotherapy;American College of Radiology Imaging Network;American Society of Clinical Oncology;Antidiabetic Drugs;Automobile Driving;Award;Bioinformatics;Biological Markers;Biometry;Biopsy;Cancer Center;Cancer Center Support Grant;Cisplatin;Clinical;Clinical Data;Clinical Trials;Clinical Trials Design;Collaborations;Combination immunotherapy;Combined Modality Therapy;Cytometry;Data;Databases;Development;Diagnosis;Dose;Eastern Cooperative Oncology Group;Ensure;Exercise;Funding;Future;Generations;Genes;Genomics;Gifts;HPV oropharyngeal cancer;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Historically Black Colleges and Universities;Hypoxia;IL6 gene;Image;Immune;Immunologist;Immunooncology;Immunotherapy;Industrialization;Institution;Investments;Low risk HPV;Measures;Metabolic;Metformin;Minority Groups;National Clinical Trials Network;Neoadjuvant Therapy;Nivolumab;Operative Surgical Procedures;Oral;Organ;Outcome;PD-1 blockade;Pathologic;Patients;Positioning Attribute;Primary Neoplasm;Program Research Project Grants;Quality of life;Radiation therapy;Radiogenomics;Recurrence;Reporting;Reproduction spores;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Risk;Robotics;Site;Subgroup;T-Lymphocyte;Technology;Testing;Thyroid Nodule;Time;Tissues;Toxic effect;Translational Research;Underrepresented Minority;Universities;Woman;X-Ray Computed Tomography;anti-PD-1;anti-PD1 therapy;anticancer research;biobank;career;chemoradiation;chemotherapy;cohort;design;flexibility;follow-up;high dimensionality;high risk;improved;inhibitor;innovation;medical schools;minimally invasive;multidisciplinary;next generation;novel;outreach;precision oncology;predict responsiveness;predictive signature;prevent;programmed cell death protein 1;programs;prospective;radiomics;recruit;response;rosiglitazone;single cell sequencing;standard of care;success;technology platform;transcriptome sequencing;transcriptomics;trial comparing;tumor Head and Neck Cancer SPORE PROJECT NARRATIVE OVERALL The research Projects and supporting state-of-the-art supporting Cores of the UPMC Hillman Cancer CenterHead and Neck SPORE are directed at solving key remaining problems in head and neck squamous cellcarcinoma treatment debilitating toxicities low immunotherapy response rates and the need for precisiononcology. The SPOREs Developmental Research and Career Enhancement Programs will ensure continuousinvigoration and increased diversity of the SPORE and the field of translational head and neck cancerresearch. NCI 10704501 9/7/23 0:00 PAR-20-305 5P50CA097190-17 5 P50 CA 97190 17 "HUBBARD, LEAH" 7/1/04 0:00 8/31/27 0:00 ZCA1-RPRB-6(O1)S 1900219 "FERRIS, ROBERT L" "SKINNER, HEATH DEVIN" 12 OTOLARYNGOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2112973 NIDCR 127555 72584 PROJECT SUMMARY OVERALL For more than 15 years the UPMC Hillman Cancer Center (HCC) Head and Neck SPORE has facilitatedpractice change in diagnosis and treatment of head and neck squamous cell carcinomas (HNSCC) and otherhead and neck cancers. For the renewal period the SPORE will focus on the remaining problems ofdebilitating toxicities low immunotherapy response rates and the need for precision oncology in HNSCCtreatment. Through its multidisciplinary project teams four clinical trials and analysis of a completed clinicaltrial the SPORE will investigate: 1) how hypoxia and metabolic dysregulation leads to PD-1 immunotherapyresistance and how it can be overcome 2) how patients with human papillomavirus-positive oropharyngealcancers can be optimally selected for deintensified therapy and 3) which biomarkers can be used forpredicting responsiveness to combined immunotherapy with PD-1 and LAG3 inhibitors. The studies will beconducted with the support of state-of-the-art Cores that provide access to over 6400 well-characterizedclinically annotated biospecimens; biostatistical and bioinformatics support; and advanced technologyplatforms that include multiplexed cytometry and imaging next generation and single sequencing; andradiomic and radiogenomic analyses based on features extracted from patient CT scans. Through theSPOREs Developmental Research Program (DRP) and Career Enhancement Program (CEP)translational head and neck cancer research will be further advanced with new ideas research strategies andinvestigators. These programs will focus heavily on increasing diversity by attracting and advancing projectsfrom woman and underrepresented minorities groups via internal initiatives and external collaborations. Criticalto the success of the research is the wealth of longitudinal clinical data collected on nearly 12000 patients withlongitudinal 30 years of clinical follow up in the SPOREs Organ Specific Database (OSD) which is now beenexpanded to include quality of life measures as well as extensive genomics radiomics and transcriptomicdata. Established horizontal and vertical collaborations with other Cancer Centers national cooperative trialgroups industrial partners enable and extend the efforts of the SPORE investigators. Submission of thisrenewal application was intentionally taken off cycle separating its renewal cycle from the HCC CCSG P30 tomaximize institutional resources that could be devoted to both applications as well as to provide additionaltime for newly recruited SPORE leaders to collaborate and solidify their interactions as a team at HCC. HCCshas continued to support the HN SPORE including soliciting CEP and DRP awards highlight its strongcommitment to its renewal. 200000 +No NIH Category available Adverse effects;Adverse event;Amino Acids;Animal Model;Animals;Binding;Biological;Biopsy;Brain;Cancer Etiology;Cancer Patient;Canis familiaris;Carcinoma;Cessation of life;Chemistry;Clinical;Clinical Data;Clinical Management;Clinical Trials;Contrast Media;Cyclic GMP;Data;Decision Making;Detection;Development;Diagnosis;Diagnostic;Diagnostic Procedure;Differential Diagnosis;Disease;Disease Progression;Dose;Drug Kinetics;Drug resistance;Early Diagnosis;Economics;Excretory function;Exhibits;Extracellular Matrix;FDA approved;FOLH1 gene;Fibronectins;Formulation;Funding;Future;Goals;Grant;Guidelines;Healthcare;Human;Image;Imaging technology;Institutional Review Boards;Invaded;Investments;Kidney;Kilogram;Lead;Legal patent;Lesion;Liquid substance;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Mission;Modeling;Mole the mammal;Molecular;Monitor;Neoplasm Metastasis;Normal tissue morphology;Ohio;Oncoproteins;PET/CT scan;PSA screening;Patient Schedules;Patients;Pelvis;Peptides;Phase;Phase I Clinical Trials;Phase II/III Trial;Physicians;Precision therapeutics;Privatization;Procedures;Proliferating;Protocols documentation;Quality of life;Radical Prostatectomy;Rattus;Recommendation;Resolution;Risk;Safety;Secure;Sensitivity and Specificity;Signal Transduction;Site;Small Business Innovation Research Grant;Specific qualifier value;System;Therapeutic Intervention;Tissues;Toxic effect;Work;accurate diagnosis;accurate diagnostics;active method;aggressive therapy;analytical method;angiogenesis;cGMP production;cancer cell;cancer imaging;cancer risk;clinical application;clinical development;clinical diagnostics;cohort;commercialization;cost;cost effective;design;drug resistance development;epithelial to mesenchymal transition;healthy volunteer;high risk;image guided;imaging agent;imaging approach;imaging modality;improved;in vivo;manufacture;manufacturing scale-up;men;meter;molecular imaging;mortality;non-invasive imaging;noninvasive diagnosis;novel;open label;overexpression;personalized intervention;pharmacologic;phase I trial;pre-Investigational New Drug meeting;pre-clinical;pre-clinical assessment;preclinical safety;prostate biopsy;prostate cancer cell;prostate cancer risk;risk stratification;safety testing;scale up;soft tissue;stemness;theranostics;tool;treatment response;tumor Commercialization of an MRI contrast agent for differential diagnosis of prostate cancer Narrative:A novel cancer-specific MRI contrast agent will be developed for MRI of high-riskprostate cancer to improve the healthcare and treatment of the patients. The imagingagent can be implemented in the existing MRI systems and protocols and has thepotential to provide non-invasive accurate detection risk-stratification and activesurveillance of PCa and to reduce false positives suffered by current diagnosticmethods. NCI 10704488 8/31/23 0:00 PA-21-260 5R44CA265626-02 5 R44 CA 265626 2 "REGMI, SAROJ GOPAL" 9/14/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-R(11)B] 10166422 "GAO, SONGQI " "TWEEDLE, MICHAEL F" 11 Unavailable 79282660 L1VLYM9HZNK3 79282660 L1VLYM9HZNK3 US 41.489266 -81.490318 10035907 "MOLECULAR THERANOSTICS, LLC" BEACHWOOD OH Domestic For-Profits 441221765 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1000000 NCI 862907 71760 Abstract Prostate cancer is a highly heterogeneous disease and the second most cause of cancer death of menin the USA. Current methods to assess prostate cancer risk combine prostate specific antigen (PSA)screening and random prostate biopsy. Unfortunately this strategy fails to reveal the lesions location anddoes not accurately differentiate between invasive and non-invasive prostate cancers. As a result mostpatients will receive unnecessary active treatment for low-risk prostate cancer. Thus development of non-invasive and accurate diagnostic imaging technology to localize and differentiate high-risk prostate canceroffers a new tool to assist physicians in risk-stratification and decision-making and to spare millions ofpatients with low-risk cancer from unnecessary aggressive treatment. The mission of Molecular Theranostics is to commercialize a novel molecular imaging approach thattargets an oncoprotein associated with epithelial-to-mesenchymal transition (EMT) cancer cell stemnessangiogenesis proliferation and metastasis. The oncoprotein has a high expression in the tumorextracellular matrix of high-risk prostate cancer low in low-grade tumor and none in normal tissues. Theultimate goal of this project is to commercialize a targeted contrast agent MT218 for accurate earlydetection localization and differential diagnosis of high-risk prostate cancer with MRI. We have optimizedand identified a lead targeted MRI contrast agent proven it effective in various animal in vivo tumor modelsand completed the chemistry manufacturing and control (CMC) work for the preclinical batches. Moreoverwe demonstrated the GLP preclinical safety of MT218 according to the FDAs guidelines for an INDsubmission. MT218 has shown rapid and complete clearance via renal excretion with no detectable brainretention and low pharmacological risk and toxicity in rats and dogs. An IND was approved by the FDA inMarch 2021 for phase 1 clinical trial in Ohio. The first two dosing cohorts have shown no adverse effectsand rapid excretion from the body as the clinical contrast agents. The proposed work in this SBIR project will allow the company to carry out the proof-of-concept phase2a clinical trial in the patents with confirmed high-risk prostate cancer. The specific aims are 1) to performopen-label phase 2a clinical trial to investigate initial imaging efficacy of MT218 in diagnostics MRI in PCapatients; 2) to develop a liquid phase synthetic procedure for scale-up cGMP production. Successfuldevelopment of our imaging technology has the potential to accurately detect localize and diagnoseprostate cancer with MRIs < 1 mm spatial resolution reduce the use of invasive prostate biopsy and soimprove decision-making in clinical management of prostate cancer. It also has the potential for accuratenon-invasive Active Surveillance of prostate cancer and timely monitoring of disease progression as wellas image-guided focal therapy. Clinical application of MT218 promises to improve the healthcare and thequality of life of PCa patients and will thus have highly significant clinical economic and societal impact. 1000000 +No NIH Category available Address;Administrative Supplement;Androgen Antagonists;Androgen Receptor;Awareness;Basic Science;Bioinformatics;Biometry;Biopsy;Budgets;Cancer Center;Cancer Patient;Carboplatin;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Combined Modality Therapy;Communication;Communities;Consult;Country;County;DNA Damage;Development;Disease;Down-Regulation;Endothelial Cells;Endothelium;Ensure;Expenditure;Extramural Activities;Funding;Gene Expression;Generations;Genes;Genetic Transcription;Goals;Homing;Human;Immunotherapy;In Vitro;Incidence;Informatics;Infrastructure;Institution;International;Laboratory Study;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Medical center;Metastatic Neoplasm to the Bone;Minority;Molecular;Monitor;Morbidity - disease rate;Osteoblasts;Pathology;Patient advocacy;Patients;Phenotype;Population Sciences;Pre-Clinical Model;Principal Investigator;Process;Prognostic Marker;Prostate Cancer therapy;Quality Control;Radiopharmaceuticals;Randomized;Refractory;Refractory Disease;Regulation;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resistance;Resources;Role;Secure;Signal Transduction;Techniques;Testing;Texas;Tissue Sample;Tissues;Translating;Translational Research;United States;University of Texas M D Anderson Cancer Center;anticancer research;base;bone;career;castration resistant prostate cancer;chemotherapy;clinical practice;cofactor;cytotoxicity;data quality;disorder risk;evidence base;experience;genetic signature;in vivo;inhibitor;innovation;medically underserved;meetings;men;mortality;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overtreatment;patient derived xenograft model;predictive marker;predictive tools;programs;prostate cancer cell;prostate cancer model;prostate cancer risk;quality assurance;resistance mechanism;response;response biomarker;targeted treatment;translational research program;treatment response;tumor;tumor microenvironment;underserved community Administrative Supplement to MD Anderson Cancer Center Prostate Cancer SPORE PROJECT NARRATIVEDespite substantive strides in detecting and treating prostate cancer this disease continues to take anunacceptable toll on the lives of tens of thousands of men in the United States. The MD Anderson CancerCenter Prostate Cancer SPORE will address the critical gaps in our understanding and treatment of thisdevastating disease by (1) developing predictive tools to better inform prostate cancer patients with low-riskdisease to make evidence-based decisions and thereby eliminate overtreatment; (2) developing a clearunderstanding of the molecular mechanisms of resistance to currently available diverse therapies for castrate-resistant prostate cancer (CRPC) including 2nd generation inhibitors of androgen signaling immunotherapychemotherapy and bone-homing radiopharmaceuticals and developing combination therapies to overcomethese resistance mechanisms; and (3) developing novel therapeutic options for men with CRPC andtreatment-refractory prostate cancer. Our laboratory and clinical studies build on the vast experienceexpertise and infrastructure of MD Anderson Prostate Cancer SPORE investigators. NCI 10704453 9/23/22 0:00 PA-20-272 3P50CA140388-10S1 3 P50 CA 140388 10 S1 "SCROGGINS, BRADLEY TODD" 9/2/09 0:00 8/31/23 0:00 1941224 "LOGOTHETIS, CHRISTOPHER J." "THOMPSON, TIMOTHY CHARLES" 9 DENTISTRY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/20 0:00 8/31/23 0:00 397 Research Centers 2022 664838 NCI 410394 254444 PROJECT SUMMARY/ABSTRACTThrough this application The University of Texas MD Anderson Cancer Center seeks funding for renewal ofits Prostate Cancer SPORE. This application is submitted under the Multiple Principal Investigator plan (MPI)by Principal Investigators Drs. Christopher J. Logothetis and Timothy C. Thompson who are recognizedinternationally for their research in prostate cancer The MD Anderson Prostate Cancer SPORE has created astable and dynamic infrastructure for translational research to meet and successfully address specificchallenges in reducing suffering and mortality rates for men with prostate cancer. We continue to build on ourcapacity to conduct novel innovative clinical trials and believe that new research projects conducted by ourtranslational research team will yield substantial progress and meaningful changes in clinical practice. In thecurrent proposal we define our translational research challenges and goals as (1) quantitative definition ofprostate cancer risk to eliminate overtreatment of low-risk prostate cancer (2) development of noveltherapeutic approaches to overcoming resistance of castration-resistant prostate cancer (CRPC) to availabletherapies and (3) development of novel alternative strategies for CRPC and treatment-refractory disease. Wewill achieve these translational research goals by identifying and testing novel predictive and prognosticbiomarkers to determine the need for therapy in patients with early-stage prostate cancer developing andtesting novel immunotherapy for CRPC developing and testing a novel approach to overcoming osteocrine-mediated resistance of bone metastasis to therapy and developing and testing lead-in combination therapy tomaximize DNA damage response-targeted therapy for CRPC. We will accomplish our goals via 4 researchprojects (including one population science research project) 3 support cores (Administrative Biostatistics andBioinformatics and Biospecimen and Pathology) a dynamic Developmental Research Program and aneffective Career Enhancement Program. We are optimistic that our research efforts will contribute toreductions in the incidence morbidity and mortality of this devastating disease by translating basic researchfindings into clinical practice. 664838 +No NIH Category available Award;Barrett Esophagus;Bioinformatics;Biological Markers;Biometry;Cancer Center;Cancer Etiology;Cessation of life;Chemopreventive Agent;Clinical Research;Clinical Trials;Colitis associated colorectal cancer;Collection;Colorectal Adenocarcinoma;Colorectal Cancer;Comprehensive Cancer Center;Conduct Clinical Trials;DNA;Data;Deglutition;Dependence;Detection;Development;Devices;Distal;Drug Combinations;Early Diagnosis;Enzymes;Esophageal Adenocarcinoma;Esophagus;Evaluation;Financial Support;Freezing;Funding;Glutaminase;Glutamine;Human;Infrastructure;Jordan;Lesion;Magnesium;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mediator of activation protein;Metabolic;Metabolism;Methods;Molecular;Mutation;Nature;PIK3CA gene;PIK3CG gene;Pathway interactions;Patients;Phase II Clinical Trials;Pre-Clinical Model;Prevention;Progression-Free Survivals;Property;Publications;Research Personnel;Research Project Grants;Resource Development;Resources;Sampling;Science;Secondary Prevention;Series;Special Population;Specialized Program of Research Excellence;Technology;Temperature;Therapeutic Effect;Translational Research;addiction;anticancer research;base;biomarker development;biomarker identification;capecitabine;colitis associated cancer;design;enzyme activity;inhibitor;inhibitor therapy;molecular diagnostics;molecular marker;mortality;mutant;novel;nutrient deprivation;phase 1 study;phase 2 study;preclinical development;preclinical study;programs;research study;screening;small molecule;targeted therapy trials;targeted treatment;translational medicine;tumor;tumor microenvironment Case GI SPORE OVERALL NARRATIVEThis Case GI SPORE renewal application provides for a cutting edged Specialized Program of ResearchExcellence in gastrointestinal malignancies with emphasis on colorectal cancers pancreas cancers andadenocarcinoma of the esophagus. Colorectal cancers are the second leading cause of cancer deaths andesophageal cancers and pancreas cancers are highly lethal with 80% mortality. This program is aimed at makingimportant and significant translational advances to reduce mortality from these three malignancies. NCI 10704292 9/23/22 0:00 PA-20-272 3P50CA150964-10S1 3 P50 CA 150964 10 S1 "NOTHWEHR, STEVEN F" 9/14/11 0:00 7/31/23 0:00 1888502 "MARKOWITZ, SANFORD D." Not Applicable 11 RADIATION-DIAGNOSTIC/ONCOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 7/1/22 0:00 7/31/23 0:00 397 Research Centers 2022 664839 NCI 412944 251895 OVERALL SUMMARY/ABSTRACTThis Case GI SPORE supplement application provides for a cutting edged Specialized Program of ResearchExcellence in gastrointestinal malignancies with emphasis on colorectal cancers pancreas cancers andadenocarcinoma of the esophagus. This comprehensive program builds on the resources of the CaseComprehensive Cancer Center to supplement 3 translational Research Projects to bring new molecularadvances to patients with GI Cancers. A series of 3 supplemented core resources support these projects andestablish a strong infrastructure for translational research in GI cancers. We will further supplement a continuedDevelopmental Research Project. These 4 supplemented SPORE translational research studies constitute noveland cutting edge approaches to GI cancers and include studies of: i) Prevention of colitis associated colon cancerusing 15-PGDH inhibitor agents (Project 1 Drs. Markowitz and Berger);; ii) Development of molecular markersand non-endoscopic methods for early detection of Barrett's esophagus (BE) and esophageal adenocarcinomas(Project 3 Drs. Chak Willis and Markowitz); iii) Development of targeted treatment of PIK3CA mutant colorectalcancers (Project 4 Drs. Wang and Bajor); iv) Development of targeted therapy for pancreas cancer based oneffects of the tumor microenvironment that a) via nutrient deprivation create metabolic addiction to wild-typeIDH1 enzyme activity and b: via low magnesium levels activate the mutant IDH1 inhibitor drug ivosidenib tobecome an potent inhibitor of wild-type IDH1 (continuation DRP Project Dr. Winter). These projects are built onmajor advances from the SPORE's current funding period that include: i) publication in Science TranslationalMedicine of development of a novel non-endoscopic swallowable device for targeted sampling of the distalesophagus together with development of a methylated DNA panel for BE detection on non-endoscopic samples;ii) publication Cancer Research of results of Phase I study of a glutaminase inhibitor CB-839 for treating PIK3CAmutant colorectal cancer; iii) publication in Nature Cancer of discovery of sensitivity of pancreas cancers to IDH1inhibitors. These projects are advantaged by special populations for conducting clinical trials of BE and forconducting clinical trials of targeted therapies as well as cancer center resources for development of biomarkersand molecular diagnostics. The strength of these investigators and these resources will insure this program leadsto significant translational advances. 664839 +No NIH Category available Ablation;Address;Androgen Receptor;Area;Autophagocytosis;Bioinformatics;Biological Assay;Biometry;Biotechnology;Bone Pain;Bromodomain;Cancer Patient;Clinic;Clinical;Clinical Investigator;Clinical Management;Clinical Trials;Collaborations;Communities;Complement;DNA Repair;DNA Repair Gene;Data;Defect;Development;Diagnosis;Disease;Dreams;Early Detection Research Network;Early Diagnosis;Ensure;Extramural Activities;Fostering;Foundations;Funding;Gene Fusion;Genetic;Goals;Grant;Individual;Infrastructure;Institutes;Institution;Intervention;Malignant Neoplasms;Malignant neoplasm of prostate;Mentors;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Metastatic to;Michigan;Morbidity - disease rate;Mutation;Nature;Oncogenic;Oncology;Pathology;Phase II Clinical Trials;Pilot Projects;Play;Prevention;Prostate;Prostate Cancer therapy;Recording of previous events;Recurrence;Research;Research Personnel;Resources;Role;Science;Scientific Advances and Accomplishments;Scientist;Screening for Prostate Cancer;Southwest Oncology Group;Sum;Testing;Therapeutic;Training;Translations;Underserved Population;Universities;University resources;Untranslated RNA;Urine;Washington;advanced prostate cancer;anticancer research;base;bench to bedside;cancer cell;career;career development;castration resistant prostate cancer;clinical diagnostics;clinical efficacy;clinically actionable;flexibility;inhibitor;innovation;men;mortality;multidisciplinary;next generation;next generation sequencing;novel;patient population;peptidomimetics;phase II trial;programs;prostate cancer cell;prostate cancer progression;prostate cancer risk;recruit;success;therapeutic target;transcription factor;translational impact;translational research program;tumorigenesis Michigan Prostate SPORE The Michigan Prostate SPORE seeks to decrease the morbidity and mortality associated with prostate cancerby making scientific advances that address critical questions in prostate cancer tumorigenesis and treatment. Inthe Michigan Prostate SPORE renewal four translational projects together identify and address major barriersand challenges that exist for the diagnosis and clinical management of prostate cancer and progression tometastatic disease. These projects are highly collaborative with respect to the multidisciplinary nature andexpertise of the Co-Leaders. NCI 10704248 9/16/22 0:00 PAR-18-313 3P50CA186786-09S1 3 P50 CA 186786 9 S1 "SCROGGINS, BRADLEY TODD" 9/11/14 0:00 8/31/24 0:00 ZCA1-RPRB-7(M1) 1866290 "CHINNAIYAN, ARUL M" "HEATH, ELISABETH IIJAS; PALAPATTU, GANESH S" 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 353 Research Centers 2022 351000 NCI 225000 126000 Since inception in 1995 the University of Michigan (U-M) Prostate SPORE has endeavored to tap the vastintellectual and physical resources of the U-M community to decrease the morbidity and mortality of prostatecancer (PCa). In this renewal application U-M joins forces with Karmanos Cancer Institute (KCI) to propose aMichigan Prostate SPORE leveraging our institutions' respective areas of strength. KCI has a non-overlappingpatient population as U-M which includes an underserved population. The Michigan Prostate SPORE supportsan interactive group of basic and clinical investigators in a translational research program that has led to majordiscoveries in the diagnosis prevention and treatment of PCa. Successful translation of discoveries in themost recent grant period include: 1) The ETS gene fusions (which were discovered by this SPORE program)have been established as a urine test for the early detection of PCa (JAMA Oncology 2017 3:1085) and havebeen therapeutically targeted with peptidomimetic inhibitors (Cancer Cell 2017 31:844). 2) Our SPORE programplayed a significant role in defining the clinically actionable landscape of metastatic castration-resistant prostatecancer (mCRPC) (Cell 2015 162:454) which led to the discovery that upwards of 20-25% of mCRPC harbordefects in DNA repair genes. As part of the TO-PARP study we showed that mCRPC patients with DNA repairdefects preferentially respond to PARP inhibitors (NEJM 2015 373:1697). 3) Established that BET bromodomaininhibitors may be useful in the treatment of advanced PCa by blocking oncogenic transcription factor activity(Nature 2014 510:278). 4) Several PCa-associated long non-coding RNAs including PCAT1 Schlap1 (NatureGenetics 2013 45:1392) and ARlnc1 (Nature Genetics 2018 50:814) were discovered and characterized. Thesebench-to-bedside applications were aided by horizontal collaborations with the University of WashingtonDana Farber Memorial Sloan-Kettering and Weill-Cornell Prostate SPOREs as well as the EDRN and verticalcollaborations with SWOG and biotech companies. This application consists of four projects: Project 1:Targeting mCRPC Patients with Biallelic Loss of CDK12; Project 2: Integrating a Novel MiPS-Based Next-Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk PCa; Project 3: ExploringAblation of the Androgen Receptor as a Therapeutic Approach for mCRPC; Project 4: Targeting Autophagy inthe Treatment of mCRPC. These projects are complemented by strong ongoing institutional commitments ofmoney and space successful Career Development and Developmental Research Programs and threecores: Administration Biostatistics/Bioinformatics and Biospecimen/Pathology. The Michigan ProstateSPORE continues to place premiums on rigorous scientific review of its translational research programs pairingof basic and clinical investigators drawing on expertise of scientists from within and from outside the PCa fieldand utilizing flexibility to fund promising new research approaches. The interaction of our multidisciplinary groupof investigators clearly makes the Michigan Prostate SPORE greater than the sum of its individual parts. 351000 +No NIH Category available Address;Affect;Animal Model;Autologous;Bioinformatics;CD8-Positive T-Lymphocytes;Cancer Model;Cell surface;Cells;Charge;Consultations;Crossbreeding;Cytokine Network Pathway;Cytokine Signaling;Data;Data Analyses;Dendritic Cells;Detection;Dissection;Dose;Ensure;Fibroblasts;Flow Cytometry;Fluorescence-Activated Cell Sorting;Fostering;Genetically Engineered Mouse;Goals;Growth;Head and Neck Squamous Cell Carcinoma;Human;IL17 gene;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunocompromised Host;Immunotherapy;Individual;Inflammation;Inflammatory;Infrastructure;Interferon-beta;Interferons;KRASG12D;Kinetics;Knock-in Mouse;Libraries;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mission;Modeling;Molecular;Mouse Strains;Mus;Myeloid Cells;Outcome;Pathway interactions;Peripheral Blood Mononuclear Cell;Procedures;Protocols documentation;Research Personnel;Resistance;Role;STAT2 gene;Sampling;Services;Shapes;Signal Pathway;Standardization;Sting Injury;Suspensions;Testing;Th1 Cells;Therapeutic;Tissues;Transcend;Transforming Growth Factor beta;Tumor Biology;Tumor Cell Line;Tumor Immunity;Tumor Promotion;Tumor Tissue;Work;Xenograft Model;cancer type;cell type;checkpoint therapy;chemotherapy;cytokine;design;experience;experimental study;fluorophore;humanized mouse;immune checkpoint blockade;improved;in vivo;inflammatory milieu;instrumentation;member;mouse model;novel therapeutic intervention;patient derived xenograft model;pre-clinical;pre-clinical assessment;programs;response;single cell sequencing;tissue preparation;tool;transcriptome sequencing;transcriptomics;treatment response;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor progression;tumor xenograft Core B: Animal Model and Immunotyping Core Project NarrativeCore B is part of a Program Project that aims to investigate how intratumor inflammation affects tumorprogression and responses to therapy. Core 1 is designed to facilitate the testing of novel therapeutic strategiesin preclinical cancer models to enable uniform sample processing for characterizing intratumor inflammationand to foster interactions among the constituent projects including analytics assistance. NCI 10704234 8/18/23 0:00 PAR-20-077 5P01CA272161-02 5 P01 CA 272161 2 9/13/22 0:00 8/31/27 0:00 ZCA1-RPRB-L 8673 1860778 "HAMILTON, THOMAS A." Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 384934 239089 145845 Project SummaryOur preliminary data suggested a shared paradigm for the impact of the STING-IFN-/TGF/IL-17 cytokinenetwork on tumor progression and responses to therapy which transcends the tissue origins of each cancer.Our goal to unravel the crosstalk and define the paradigms necessitates standardization of the protocols andprocedures used by each constituent project in order to unify our approaches in establishing preclinical tumormodels and measuring tumor responses to therapy. Our ability to reach meaningful conclusions critically hingeson comparable execution of in vivo studies. Furthermore a common readout shared by all three constituentprojects is the inflammatory status in the TME. While immune-supportive inflammation (CD8 Th1 and dendriticcells) is associated with favorable responses to immune checkpoint inhibitor therapy an immune-suppressiveinflammatory environment (immature myeloid cells and fibroblasts) can antagonize anti-tumor immunity.Accurate detection characterization and quantification of multiple cell types by flow cytometry and single-cellsequencing are crucial for assessing the state of intra-tumoral inflammation. A shared infrastructure that enablesreliable analysis of the TME is essential for studying cytokine crosstalk. Taken together the Animal Model andImmunotyping Core will be charged with two missions. First the Core will provide technical and experimentalinfrastructure to enable uniform and standard in vivo analyses including preclinical assessment of cancertherapeutics and characterization of the TME. Secondly the Core will function as a hub for interaction amongthe constituent projects including analytics assistance and scientific consultation on analyses of the TME. +No NIH Category available Animal Model;Automobile Driving;Award;Binding;CD8-Positive T-Lymphocytes;Cells;Chemoresistance;Chronic;Cisplatin;Collaborations;Collagen;Cutaneous;Data;Deposition;Development;Dissection;Environment;Epidermal Growth Factor Receptor;Exclusion;Fibroblasts;Genes;Genetic;Goals;HIF1A gene;Head and Neck Squamous Cell Carcinoma;Human;IL17 gene;Immune;Immune checkpoint inhibitor;Immunotherapy;Infiltration;Inflammation;Inflammatory;Interleukins;Knowledge;Link;MAPK7 gene;Malignant Neoplasms;Mediating;Messenger RNA;Molecular;Mus;Myeloid-derived suppressor cells;Pathogenicity;Population;Process;Prognosis;Proteins;RNA Binding;Refractory;Reporting;Resistance;Role;Shapes;Signal Transduction;Solid Neoplasm;Squamous cell carcinoma;Standardization;Statistical Data Interpretation;Stromal Cells;Testing;Therapeutic;Transcript;Transforming Growth Factor beta;Translations;Tumor Promotion;Work;antagonist;anti-PD-1;anti-PD1 therapy;cancer cell;cancer cell differentiation;cancer therapy;chemotherapy;cytokine;design;improved;in vivo;insight;neoplastic cell;novel therapeutic intervention;oxidation;pre-clinical assessment;prevent;programs;response;single cell analysis;stem;stem cells;stemness;synergism;therapeutic target;therapy resistant;tool;transcriptome;transcriptomic profiling;treatment response;tumor;tumor microenvironment;tumor progression;tumorigenesis;wound healing IL-17-driven mechanisms for tumor progression and resistance to therapies Project NarrativeThis proposal aims to study the relationship between inflammation and cancer. Specifically we will investigatethe pathogenic role of pro-inflammatory interleukin-17 in tumor progression and resistance to anti-cancertherapies including chemotherapy and checkpoint inhibitors. The completion of the proposal will inform thedesign of novel therapeutic strategies and identify potential therapeutic targets that improve the therapeuticresponse in otherwise refractory tumors. NCI 10704232 8/18/23 0:00 PAR-20-077 5P01CA272161-02 5 P01 CA 272161 2 9/13/22 0:00 8/31/27 0:00 ZCA1-RPRB-L 8671 1860778 "HAMILTON, THOMAS A." Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 512644 318412 194232 Project SummaryWhile the relationship between chronic inflammation and cancer is well recognized knowledge of the cellularand molecular mechanisms that link these processes continues to evolve. Intratumoral interleukin 17A (IL-17)levels are associated with poor prognosis for a variety of solid tumors in human. The overall goal of thisapplication is to investigate the mechanisms of IL-17-mediated cancer progression focusing on tumor responsesto anti-cancer therapies. Our recent preliminary data revealed that IL-17 engages both cancer cells and tumormicroenvironment to synergistically promote cancer progression. Firstly work supported by this award identifieda non-canonical IL-17-induced EGFR-mediated ERK5 signaling cascade critical for tumorigenesis. Our newpreliminary study revealed an Lrig1+ stem-like tumor cell population in squamous cell carcinoma that are highlyresponsive to IL-17 with EGFR-ERK5 activation. Transcriptomic profiling revealed a link between IL-17-ERK5axis in human and mouse Lrig1+ stem-like tumor cells with NRF2-mediated antioxidation and Wnt5a-dependentinduction of stemness. Lineage tracing showed that IL-17 rendered these Lrig1+ stem-like tumor cells resistanceto chemotherapy which were also enriched by anti-PD1 treatment. Secondly we found that canonical IL-17signaling operates in both tumor cells and stromal cells to dictate a tumor-promoting and immune suppressiveenvironment. In tumor cells IL-17 synergizes with other inflammatory cytokines to orchestrate an intratumoralcancer promoting inflammation via the induction of specific effector molecules. In cancer-associated fibroblastsIL-17 signaling helps to establish an immune exclusion zone to prevent the infiltration of CD8+ T cells. Deletionof IL-17R in CAFs rendered these tumors sensitive to immune therapy. Based on these observations wehypothesize that canonical and non-canonical IL-17 signaling in cancer cells and CAFs coordinately drive cancerprogression and resistance to therapies. To test this hypothesis we will (1) Investigate how IL-17R-EGFR axisin Lrig1+ stem-like tumor cells renders resistance to anti-cancer therapies; (2) Elucidate the mechanism by whichIL-17 shapes the pro-tumor immune exclusive tumor microenvironment. Program Interactions: This Project willbe critically informed by and also provide necessary information to the other Projects in the Program at multiplelevels. Project 1 and Project 2 will investigate the antagonistic interplay between IFN and TGF in cancer celldifferentiation. Informed by those studies we will determine whether STING-induced IFN can be used toeradicate Lrig1+ cells to improve responses to anti-cancer therapies. We will take advantage of the AnimalModel Immunotyping and Analytics Core B to standardize our in vivo analyses including preclinicalassessment of cancer therapeutics and characterization of the tumor microenvironment (TME). Statisticalanalyses will be performed by Program Biostatistician Dr. Bo Hu and Program Bioinformatician Dr. Fulai Jin(Core B). +No NIH Category available Adjuvant Chemotherapy;Animal Model;Binding;Binding Sites;Breast Cancer Model;Breast cancer metastasis;Cells;Chromatin;Clinical;Combined Modality Therapy;Dissection;Epithelium;Equilibrium;Family;Gene Expression;Genes;Genetic Transcription;Goals;IL17 gene;Immune;Immune checkpoint inhibitor;Immune system;Immunosuppression;Immunotherapy;Impairment;Interferon Activation;Interferon-beta;Interferons;Interleukin-6;MADH3 gene;Malignant Neoplasms;Mediating;Mesenchymal;Messenger RNA;Molecular;Neoadjuvant Therapy;Patient-Focused Outcomes;Patients;Phosphorylation;Production;RNA Binding;Recurrence;Recurrent Malignant Neoplasm;Regulation;Repression;Resistance development;STAT1 gene;STAT2 gene;STAT3 gene;Signal Transduction;Specimen;Standardization;Sting Injury;Stromal Cells;TGFB1 gene;Testing;Threonine;Time;Transforming Growth Factor beta;Translations;Treatment Failure;Tumor Immunity;Viral;aggressive breast cancer;autocrine;breast cancer progression;cancer cell;cancer cell differentiation;cancer invasiveness;cancer recurrence;cancer therapy;cell behavior;chemotherapy;cytokine;epigenomics;immune system function;improved;improved outcome;in vivo;mimicry;novel;novel therapeutic intervention;novel therapeutics;paracrine;prevent;programs;receptor;refractory cancer;response;restoration;sensor;standard of care;stem;synergism;therapy resistant;triple-negative invasive breast carcinoma;tumor;tumor initiation;tumor microenvironment Shifting the balance between IFN-I and TGF-beta to improve cancer therapy PROJECT NARRATIVETwo important factors that regulate Triple Negative Breast Cancer (TNBC) metastasis and recurrence are: (i)the differentiation status of the cancer cells and (ii) the functionality of anti-tumor immunity both of which arehighly influenced by the cytokines Transforming Growth Factor-beta (TGFB) and Interferon-beta (IFNB). Wefind that the actions of TGFB and IFNB oppose one another in regulating both cancer cell differentiation andimmune system function within the tumor microenvironment. We propose here to define how TGFB and IFNBantagonize one another and test novel therapeutic approaches to shift the balance towards active IFNB andaway from TGFB signaling with the goal of improving outcomes for patients with metastatic TNBC NCI 10704231 8/18/23 0:00 PAR-20-077 5P01CA272161-02 5 P01 CA 272161 2 9/13/22 0:00 8/31/27 0:00 ZCA1-RPRB-L 8670 9492815 "JACKSON, MARK W." Not Applicable 11 Unavailable 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH Domestic Higher Education 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 393225 244239 148986 PROJECT SUMMARY/ABSTRACTTherapy failure remains an overarching clinical challenge for patients with aggressive Triple Negative BreastCancer (TNBC). Two important factors that regulate TNBC metastasis and recurrence are: (i) the differentiationstatus of the cancer cells and (ii) the functionality of anti-tumor immunity both of which are highly influenced bythe tumor microenvironment (TME). We find that the TME cytokines Transforming Growth Factor (TGF) andInterferon (IFN) oppose one another in regulating both cancer cell differentiation and immune system functionin TNBC. TGF and its receptors are frequently upregulated in aggressive therapy-resistant cancers such asTNBC. Mechanistically we find that TGF effector SMAD3 cooperates with STAT3 an important effector of theIL-6 family of cytokines to induce stem-like/mesenchymal reprogramming which enhances TNBC invasivenesstumor-initiating capacity and therapeutic resistance. At the same time TGF strongly suppresses IFNproduction. Since IFN promotes a less aggressive cancer cell state and activates anti-tumor immunity theTGF-mediated suppression of IFN and its downstream effectors STAT1 and STAT2 is an importantcontributor to TNBC progression and immune system impairment. Importantly restoration of IFN signalingresults in the reversal of TGF-mediated stem-like/mesenchymal program and re-engages anti-tumor immunity.We hypothesize that the relative amounts of TGF and IFN cytokine activity in both cancer and immune cellsdictate TNBC aggressiveness and ultimately patient outcomes. The purpose of our study is to define themolecular mechanisms by which TGF and IFN antagonize one another in regulating stem-like/mesenchymalreprogramming and anti-tumor immunity. Our Project has strong connections with Project 1 which will assess theregulation of STAT2 by a novel threonine phosphorylation and with Project 3 which will examine how TGFsynergizes with another pro-tumor cytokine IL-17 to amplify the signals critical for repressing IFN production.The unifying studies proposed in our Program will (i) identify common molecular mechanisms that promote thedevelopment of resistance to chemo- and immune-therapies and (ii) assess novel therapeutic combinationsaimed at shifting the equilibrium of IFN and TGF/IL-17 signaling in the TME. By shifting this balance wepropose to induce the differentiation of cancer cells and enhance anti-tumor immunity to increase the sensitivityof hard-to-treat cancers to chemo- and immuno-therapy. +No NIH Category available Acceleration;Address;Affect;Agar;Anchorage-Independent Growth;Automobile Driving;Biological Assay;Breast;Breast cancer metastasis;Cancer Etiology;Cell Line;Cells;Cessation of life;Characteristics;Circulation;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Disease Progression;Distal;Doxycycline;Early identification;Future;Gene Expression Profile;Genes;Genetically Engineered Mouse;Glutathione S Transferase A;Glutathione S-Transferase;Glutathione Transferase Inhibitor;Growth;Human;Hydrophobicity;In Vitro;Incidence;Invaded;Lesion;Liver;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metastatic Adenocarcinoma;Modality;Modeling;Molecular;Neoplasm Metastasis;Outcome;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Pattern;Play;Primary Neoplasm;Proteins;Reduced Glutathione;Research;Role;Solid Neoplasm;Specimen;Stains;Survival Rate;System;TP53 gene;Testing;Therapeutic;Tissue-Specific Gene Expression;Tissues;Validation;Work;cancer cell;cell growth;differential expression;efficacy testing;experimental study;human tissue;in vivo;inhibitor;insight;knock-down;lung metastatic;malignant breast neoplasm;mortality;mouse model;non-genetic;novel;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pre-clinical;self-renewal;small hairpin RNA;small molecule inhibitor;therapeutic target;transcriptome sequencing;tumor;tumor growth Role of Gstt1 in metastatic maintenance and self-renewal in PDA PROJECT NARRATIVEThe primary cause of cancer-related mortality is distal metastasis particularly in pancreatic cancer patientswhere the high incidence of extra-pancreatic metastasis upon diagnosis results in poor patient outcomes. Whilethe genetic mutations that cause pancreatic cancer have been extensively studied there has been little workdone to explain the mechanisms behind metastatic tumor growth and as a consequence limited treatmentmodalities to treat this disease. Here we have identified Gstt1 as a regulator of metastasis and this proposalwill provide insight into Gstt1-driven vulnerabilities to treat pancreatic cancer metastasis. NCI 10704159 9/7/23 0:00 PA-19-130 5R00CA252600-04 5 R00 CA 252600 4 "AULT, GRACE S" 9/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11756641 "FERRER, CHRISTINA " Not Applicable 7 PHARMACOLOGY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 161165 87835 PROJECT SUMMARYOnly 0.01% of cancer cells enter circulation survive & produce metastasis however metastatic diseaseaccounts for 90% of cancer-related deaths. In pancreatic ductal adenocarcinoma (PDA) the majority of patientspresent with extra-pancreatic invasion and metastatic disease for which the there is a dismal five-year survivalrate and no specific therapeutic strategies directed at the treatment of metastatic disease. Notably much of theresearch into the mechanisms of metastasis has been focused on identifying early drivers within primary tumorshowever the identification of central drivers of metastatic outgrowth within established lesions largely remainunexplored. Recently we have demonstrated that SIRT6 inactivation dramatically accelerates PDAdevelopment resulting in highly aggressive metastatic disease in the Kras-p53 GEM model. Employing thishighly aggressive PDA metastasis model in addition to an established breast cancer metastasis model thisstudy aims to identify potential vulnerabilities of metastatic lesions that could be exploited to treat patients withadvanced metastatic disease. Performing unbiased RNA-Seq on matched primary and metastatic tissuesfollowed by a newly developed 96-well soft agar screen we identified factors that are uniquely required foranchorage-independent growth of established metastatic cells. Utilizing this functional screen and validation wehave identified Gstt1 (glutathione S-transferase theta 1) as a top candidate driver of metastatic outgrowth inmultiple mouse models of metastasis. Preliminary data demonstrates that Gstt1 is differentially expressed inmetastatic cell lines compared to matched primary-derived cell lines and inhibition of Gstt1 significantly reducedmetastatic potential of metastases-derived cells without affecting primary tumor growth suggesting an importantrole for Gstt1 in the outgrowth of established metastatic lesions. Additionally within metastatic lesions Gstt1shows a heterogenous expression pattern where Gstt1high cells represent an aggressive non-proliferative sub-population. Additionally we have demonstrated that Gstt1 is required for the formation of tumor spheres in breastand PDA metastatic-derived cell lines in vitro suggesting a role for Gstt1 as a driver of self-renewal in metastaticcells. In this proposal we seek to identify characteristics unique to Gstt1high PDA-derived metastatic lesions. Theproposed studies will provide important preclinical demonstration of whether Gstt1 and its downstream targetsare required for sustained growth of metastatic tumors thus identifying a possible therapeutic window for thissubset of metastatic PDA. 249000 +No NIH Category available Address;Algorithms;Antibodies;Appearance;Architecture;Automobile Driving;Bayesian learning;Biopsy;CD8-Positive T-Lymphocytes;Cancer Patient;Carcinoma;Cell Communication;Cells;Clear Cell;Clear cell renal cell carcinoma;Clinical;Clinical Investigator;Conventional (Clear Cell) Renal Cell Carcinoma;Data;Development;Dissection;Environment;Gene Expression;Genetic Transcription;Goals;Human;Image;Immune;Immune checkpoint inhibitor;Immunotherapy;Intervention;Kidney;Knowledge;Learning;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of ovary;Methods;Microsatellite Instability;Modeling;Molecular;Molecular Analysis;Morphology;Mus;Mutation;Outcome;Ovarian;Ovarian Clear Cell Tumor;Ovarian Endometrioid Adenocarcinoma;Ovarian Serous Adenocarcinoma;Patient Selection;Patients;Phenotype;Property;Proteomics;Sample Size;Signal Transduction;Stromal Cells;Systems Analysis;Systems Biology;TP53 gene;Testing;Tissue Microarray;Transgenic Model;Translations;Tumor Tissue;Validation;Work;cancer cell;cancer type;cell type;cellular imaging;checkpoint therapy;computer framework;data resource;experience;human disease;imaging platform;immunogenic;improved;indexing;innovation;learning strategy;mouse model;novel;novel marker;objective response rate;pembrolizumab;predicting response;predictive marker;preservation;rare cancer;response;single-cell RNA sequencing;transcriptome sequencing;treatment response;tumor;tumor behavior;tumor microenvironment;tumor-immune system interactions Systems analysis of mechanisms driving response to immunotherapy in clear cell cancers Clear cell ovarian cancer is a rare and lethal malignancy with limited treatment options.Molecularly it is similar to much more frequent clear cell renal carcinomas of which around25% respond to immunotherapy. We will take a systems biology approach to identifysimilarities in the ovarian and renal clear cell cancer tumor environments and how cellularcrosstalk in these environments drives therapy response. NCI 10704140 9/1/23 0:00 PAR-19-287 5U01CA264611-02 5 U01 CA 264611 2 "DUECK, HANNAH RUTH" 9/13/22 0:00 8/31/27 0:00 ZCA1-RTRB-R(M2) 9261375 "GENTLES, ANDREW J." Not Applicable 16 PATHOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 502504 NCI 345556 160309 Clear cell ovarian cancer (ccOC) is a rare and lethal cancer with few treatment options. Based on molecularanalysis ccOC appears intrinsically immunogenic but with an immunosuppressive tumor microenvironmentsimilar to other ovarian cancer types. However ccOC is very distinct from high grade serous ovariancarcinoma. Strikingly it is similar in gene expression profiles to more frequent clear cell renal cell carcinomas(ccRCC) suggesting that clear cell cancers share intrinsic mechanistic or microenvironment properties not justmorphological appearance. Around 25% of ccRCC respond well to immune checkpoint inhibitors (ICIs) butmarkers for predicting response are lacking. The objective response rate for monotherapy pembrolizumab inone study was 33.3% for ccOC patients; but in general it is unknown which clear cell cancer patients couldbenefit from ICI treatment. Recent work has shown that tumor behavior is driven not just by cellularcomposition but also by the spatial organization of different cell types including immune and stromal cells aswell as malignant cells themselves. Knowledge of clear cell cancer tumor microenvironments and their spatialarchitecture is lacking. Addressing this gap will improve our understanding of mechanisms of response to ICIsin clear cell cancers including rare ones like ccOC and improve selection of patients for immunotherapy.This study will use systems biology approaches to (i) elucidate and compare the cell types and theirtranscriptional states present in ccOC and ccRCC; (ii) characterize the spatial architecture of these cells withintumors using the CODEX (CODetection by indEXing) single cell proteomic imaging platform; and (iii) modeland validate cell-cell interactions in the spatial tumor microenvironment that drive clear cell cancer response toimmunotherapy through extensions of causal signaling inference algorithms to incorporate spatial context andto optimize experimental validations in mouse models that maximize the information gain about interactionnetworks. Similar intrinsic and tumor microenvironmental features shared by ccOC and ccRCC will nominatecommon mechanisms of immunotherapy response and identify the subset of both who might benefit fromtreatment with ICIs. Successful development and application of these methods to clear cell cancers willestablish a framework that can be applied to other cancer types notably to rare ones.The expected outcome of this proposal is a comprehensive definition and dissection of the tumormicroenvironment of ccRCC and ccOC. It will identify common features and mechanisms between these clearcell cancers providing a basis to extend the approach to other classes of cancer opening new avenues fortreatment particularly in rare cancer types. 502504 +No NIH Category available Adult;Affective;Age;Applications Grants;Award;Cigar;Cigarette;Cognitive;Communication;Communication Research;Cues;Development;Educational workshop;Effectiveness;Electronic cigarette;Elements;Emotions;Experimental Designs;Focus Groups;Goals;Image;Intervention;K-Series Research Career Programs;Lead;Mental Health;Mentorship;Methods;Myocardial Infarction;Nicotine;Nicotine Dependence;Pattern;Performance;Prevalence;Randomized;Randomized Controlled Trials;Reaction;Research;Research Activity;Respiratory Disease;Risk;Risk Factors;Sampling;Self Efficacy;Smoker;Socioeconomic Status;Stroke;Symptoms;Testing;Text Messaging;Time;Tobacco;Tobacco Dependence;Tobacco use;Training;United States;Work;Youth;apprenticeship;arm;behavioral outcome;cardiovascular risk factor;career;communication theory;design;eHealth;effectiveness testing;experimental study;hands on research;health communication;high risk;innovation;interest;low socioeconomic status;prevent;preventable death;reduce symptoms;substance use;theories;tobacco control;tobacco products;tobacco user Communication Messages to Reduce Youth Multiple Tobacco Product Use PROJECT NARRATIVEMultiple tobacco product (MTP) useor the concurrent use of two or more tobacco productsis the dominantpattern of tobacco use among youth in the United States however little research has been conducted oncommunication messages that could prevent and reduce youth MTP use. Using rigorous and innovatemethods the overarching goal of the proposed research is to develop and evaluate messages about the harmsof MTP use. This research would make significant and timely contributions to the development of tobaccocontrol communication strategies in the United States and is responsive to FDAs interest in communicationsresearch. NCI 10704138 8/4/23 0:00 RFA-OD-20-011 5K01CA265886-02 5 K01 CA 265886 2 "RADAEV, SERGEY" 9/13/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-VH-K(90)S] 14634156 "KOWITT, SARAH " Not Applicable 4 FAMILY MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 77 Other Research-Related 2023 156688 OD 145334 11354 PROJECT SUMMARY/ABSTRACTTobacco use remains the leading cause of preventable death in the United States. Almost 50% of youthtobacco users now concurrently use two or more tobacco productsdefined as multiple tobacco product(MTP) use. Youth MTP use is concerning because it associated with a two-fold increase in nicotinedependence symptoms decreased likelihood of successful quitting and increased risk of other substance useand mental health problems. Many communication messages exist to warn youth of the harms of specifictobacco products like e-cigarettes or cigarettes. However almost all tobacco communication messagesfocus on one tobacco product at a time which could lead MTP users to consume the tobacco product thatis not the target of the messages. Moreover these communication messages may not work well with MTPusers who are more likely than single tobacco users to underestimate the harms of tobacco be moredependent on nicotine and be of lower socioeconomic status (SES). The overarching goal of the proposedK01 project is to develop and evaluate messages about the harms of MTP use. The primary hypothesis is thatMTP messages will increase intentions to quit using all tobacco products more than existing messages thatfocus only on single tobacco products and control messages. A secondary goal is to determine the impact ofmessages among youth at higher risk of MTP use specifically youth of lower SES. In Aim 1 I will identifyeffective themes for youth-oriented messages that communicate the harms of MTP use. In Aim 2 I willdevelop a set of high impact messages that discourages MTP use among youth and determine whether othermessage elements (e.g. testimonials quitting approach self-efficacy cue) increase tobacco quit intentionsusing a discrete choice experiment (DCE) with youth MTP users. Finally in Aim 3 I will conduct a three-armpilot randomized controlled trial (RCT) with youth MTP users (50% lower SES) to see if the MTP messagesdelivered as text messages over a two-week period increase tobacco quit intentions more than existingmessages that focus only on single tobacco products and control messages. This research would makesignificant and timely contributions to the development of tobacco control communication strategies in theUnited States and is responsive to FDAs interest in communications research. My long-term career goal is toconduct independent research that focuses on preventing and reducing youth tobacco use through healthcommunication interventions. This career development award will help me reach this goal by providing newtraining in a) health communication theory and message development b) experimental design for healthcommunication research including design of discrete choice experiments and c) eHealth interventions foryouth. My training plan includes apprenticeships with my mentorship team formal coursework hands-onresearch activities and workshops. This award will culminate in a R01 application for a full-scale RCT testingthe effectiveness of MTP messages on quit attempts and other behavioral outcomes among youth MTP users. 156688 +No NIH Category available Adult;Alleles;Animals;Antibodies;Area;Attention;Award;Back;Bioinformatics;Biological;Biological Markers;Biometry;Black Populations;Black race;Blood;Brain Neoplasms;Caring;Central Nervous System Neoplasms;Clinic;Clinical;Clinical Trials;Collaborations;Creativeness;Data;Data Set;Development;Disease;Environment;Epigenetic Process;European;Fostering;Funding;Genetic;Genomics;Glioblastoma;Glioma;Glycolysis;Goals;Grant;Hispanic;Hispanic Populations;Home;Human;Hypoxia;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunologics;Immunotherapeutic agent;Impairment;Incidence;Incubators;Malignant neoplasm of brain;Malignant neoplasm of central nervous system;Mentors;Metabolic;Minority;Minority Groups;Mission;Molecular;Molecular Abnormality;Molecular Profiling;Mutation;Oncolytic viruses;Operative Surgical Procedures;Outcome;Oxidative Phosphorylation;PIK3CG gene;Pathogenesis;Pathology;Patient-Focused Outcomes;Patients;Pattern;Persons;Phase I/II Clinical Trial;Phase II Clinical Trials;Phosphorylation Inhibition;Population Study;Positron-Emission Tomography;Prognosis;Prognostic Marker;Radiation Tolerance;Radiation therapy;Records;Research;Research Personnel;Research Project Grants;Resources;Risk;Safety;Sampling;Science;Single Nucleotide Polymorphism;Source;Stress;TNFSF4 gene;Testing;The Cancer Genome Atlas;Therapeutic;Time;Tissues;Translating;Translational Research;University of Texas M D Anderson Cancer Center;Virus;Work;bench to bedside;biobank;cancer diagnosis;career;chemotherapy;epidemiology study;first-in-human;flexibility;genome wide association study;home test;improved;improved outcome;inhibitor;innovation;meetings;minority patient;multidisciplinary;next generation;novel;oncolysis;oncolytic adenovirus;pembrolizumab;personalized approach;phase II trial;population based;predictive marker;programs;racial disparity;repository;research clinical testing;success;targeted agent;targeted treatment;translational research program;translational scientist;treatment response;treatment strategy;tumor;underserved minority SPORE in Brain Cancer NARRATIVE: OVERALLOver the past 20 years advances in the treatment of glioblastoma the most common malignant brain tumorhave been only incremental. If successful the research proposed in this Brain Cancer SPORE renewalapplication will legitimize novel mechanistically unique therapies and decipher the genomic landscape ofgliomas in minority populations thereby changing the standards of care for all patients with human gliomasincluding underserved minorities. NCI 10704137 8/21/23 0:00 PAR-18-313 5P50CA127001-15 5 P50 CA 127001 15 "HUBBARD, LEAH" 9/1/08 0:00 8/31/24 0:00 ZCA1-RPRB-7(J1) 2190844 "LANG, FREDERICK F" "FUEYO, JUAN " 9 NEUROSURGERY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2051421 NCI 1364437 686984 SUMMARY: OVERALLThe overarching goal of this Brain Cancer SPORE renewal application is to improve the notoriously poor outcomeof patients with glioblastoma (GBM). This goal will be achieved through the development of a multidisciplinaryand highly translational research program that seeks to discover and rapidly translate novel and mechanisticallydiverse treatment strategies including biological immunological and targeted strategies and by developingprognostic and predictive biomarkers that inform individualized approaches to GBM treatment while alsoexploring pathogenesis and risk through genetic-based epidemiological studies in minority populations. Bypursuing the strategies of this research program all projects in the current funding period (2013-18) havesuccessfully transitioned from the bench to clinical trials including testing of a novel oncolytic virus Delta-24-RGD in multiple clinical trials; completing a biological-endpoint Phase II clinical trial of a PI3K-targeted agentBKM-120; meeting IND requirements for a first-in-human trial of a new immune-modulatory p-STAT-3 inhibitorWP1066; and validating prognostic biomarkers in clinical trial datasets while also testing a molecular predictorof radiation sensitivity. In this renewal application we propose three translational research projects thatorganically evolved from the successes of our current SPORE and which are supported by four mission-criticalCores (Administrative Pathology/Biorepository Biostatistics/ Bioinformatics Animal). Our DevelopmentalResearch Program (DRP) and Career Enhancement Program (CEP) continue as incubators of new projects andportals for new investigators. The aims of our projects are:Project 1: Exploit the capacity of Delta-24-RGD to activate anti-glioma immunity by completing a clinical trialcombining Delta-24-RGD with Pembrolizumab and by testing next-generation Delta-24-RGD viruses that arearmed with immune stimulatory molecules: OX40L GITRL and 4-1BBL while analyzing anti-Ad5 antibodies asa biomarker in response to therapy.Project 2: Attack metabolic vulnerabilities of GBMs through the development and clinical testing of a novelinhibitor of oxidative phosphorylation (OxPhos) IACS-010759 that efficiently kills GBMs harboring genetic orepigenetic mutations that impair glycolysis (e.g. ENO1 deletions) and by evaluating a new hypoxia-responsivePET probe 18F-FAZA as a readout of OxPhos inhibition and target engagement of IACS-010759.Project 3: Decipher germline and somatic genomic landscape of gliomas in Black and Hispanic minoritypopulations whose prognosis and survival differ than GBM patients of White European descent. Germline SNPdata will be combined with extensive molecular profiling in case-matched tumors. A detailed analysis will beperformed to determine ancestry composition and how it influences risk for gliomas and clinical outcome inminorities. 2051421 +No NIH Category available Award;BARD1 gene;BRCA1 gene;BRCA2 gene;Biochemical;Biological Assay;Biology;Cancer Biology;Cells;Chemicals;Chromosome abnormality;Companions;DNA;DNA Double Strand Break;DNA Repair;DNA biosynthesis;DNA lesion;DNA replication fork;Development;Double Strand Break Repair;Extramural Activities;Filament;Funding;Gene Mutation;Genome;Genomic Instability;Growth;Health;Invaded;Investigation;Laboratories;Lead;Leadership;Maintenance;Malignant Neoplasms;Mediating;Mentors;Neoplastic Cell Transformation;Pathway interactions;Play;Positioning Attribute;Postdoctoral Fellow;Process;Productivity;Research;Role;Specialist;System;Texas;Therapeutic;Training;Tumor Suppressor Proteins;Universities;Wages;biophysical analysis;career;doctoral student;graduate student;homologous recombination;insight;mid-career faculty;novel;preservation;presynaptic;programs;reconstitution;repaired;small molecule;structural biology;symposium;tool;tumorigenesis BRCA-dependent Mechanisms of Genome Maintenance and Repair Project NarrativeThe main objective of this R50 proposal is to seek support for a Research Specialist Dr. YounghoKwon to apply his class-leading expertise to enhance the productivity and impact of a long-standingNCI-funded research program at University of Texas Health San Antonio and to enable Dr. Kwonto achieve higher autonomy and further career growth. Our NCI-funded program is aimed atdeciphering the mechanistic underpinnings of DNA break repair and DNA replication forkpreservation via the homologous recombination (HR) pathway that is mediated by several tumorsuppressors including BRCA1-BARD1 and BRCA2. The continual involvement and leadership ofDr. Kwon will exert a broader impact in DNA repair studies and the cancer biology field at thenational level and will also furnish the intellectual and experimental framework for the developmentof cancer therapeutics. NCI 10704127 8/16/23 0:00 PAR-21-285 5R50CA265315-02 5 R50 CA 265315 2 "SHARMAN, ANU" 9/13/22 0:00 8/31/27 0:00 ZCA1-SRB-1(M1) 10196239 "KWON, YOUNGHO " Not Applicable 20 BIOCHEMISTRY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 164435 NCI 106087 58348 ABSTRACTDNA double-strand breaks (DSBs) are among the most deleterious of DNA lesions and if nothandled properly can lead to gross chromosome aberrations neoplastic transformation of cells andtumorigenesis. The NCI-funded research program of the Unit Director Dr. Patrick Sung has focusedon elucidating conserved homologous recombination (HR) mechanisms by which DSBs are beingfaithfully repaired. Through a transdisciplinary approach encompassing biochemical reconstitutionbiophysical analysis structural biology and cell-based investigations the Sung laboratory hasprovided insights into critical steps of HR. The available experimental and intellectual frameworkideally positions us to continue delineating the mechanistic intricacy of HR and DSB repair processesto provide actionable information for explaining why HR gene mutations lead to genome instabilityreplication fork demise neoplastic cell transformation and cancer.As Research Associate Professor I have been making contributions in elucidating the underlyingmechanisms of three critical stages of HR namely RAD51 presynaptic filament assembly DNAstrand invasion and repair DNA synthesis. I have also played a key role in the training and mentoringof graduate students and research fellows in the Sung laboratory. In this R50 Research SpecialistAward application I request salary support to enable me to help drive research endeavors directedat elucidating the multifaceted roles that the tumor suppressors BRCA1-BARD1 BRCA2 FANCJand their companion HR factors fulfill in the aforementioned stages of the HR process and in DNAreplication fork preservation. As such the R50 Research Specialist Award will not only help advanceour research objectives but will also exert a broader impact in the DNA repair and cancer biologyfields as I continue to devise novel biochemical assays and systems reconstituted with purified HRfactors to facilitate the studies of other laboratories and will help identify novel targets and pathwaypivot points to spur the development of small molecule compounds as chemical biology tools andpotential cancer therapeutics. I will continue to advise the Unit Director in all matters concerningthe general directions of our research program take on major responsibilities in mentoring andtraining of doctoral students and postdoctoral fellows and act as the main conduit with intramuraland extramural collaborators. I will serve as the corresponding author on studies in which I haveplayed a leadership role attend major conferences to disseminate my research findings anddevelop a national reputation based on my own merit. 164435 +No NIH Category available Acute Myelocytic Leukemia;Adverse effects;Adverse event;Aftercare;Amendment;Apoptotic;Autophagocytosis;Award;Biological Markers;Cancer Center;Cell Death;Ceramides;Chloroquine;Clinical;Clinical Research;Clinical Trials;Data;Disease Progression;Disease remission;Dose;Dose Limiting;Drug Kinetics;Effectiveness;Erythrocytes;Experimental Leukemia;Foundations;Funding;Genomics;Gifts;Grant;Histone Deacetylase;Hydrophobicity;In Vitro;Institutional Review Boards;Legal patent;Lipids;Malignant Neoplasms;Mediating;Medical;Membrane;Memorial Sloan-Kettering Cancer Center;Metabolism;Methods;Microtubules;Modeling;N-caproylsphingosine;NCI-Designated Cancer Center;Orphan Drugs;Participant;Pathogenesis;Patients;Pharmaceutical Preparations;Phase;Physiological;Plasma;Platelet Transfusion;Privatization;Prognosis;Prognostic Marker;Proteomics;Protocols documentation;Publishing;Quality of life;Recommendation;Refractory;Regimen;Relapse;Research;Research Personnel;Running;Sampling;Site;Solid Neoplasm;Specialist;Sphingolipids;Sphingosine;Supportive care;Surrogate Markers;Survival Rate;System;Testing;Therapeutic;Therapeutic Intervention;Toxic effect;United States National Institutes of Health;Universities;University of Virginia Cancer Center;Validation;Vinblastine;Virginia;clinical investigation;combinatorial;commercialization;cost;design;disorder control;drug candidate;effective therapy;improved;in vivo;inhibitor;innovation;leukemia treatment;lipidomics;liposomal delivery;manufacture;nano;nanoliposome;novel;novel strategies;novel therapeutics;patient biomarkers;phase 1 study;phase I trial;phase II trial;pre-clinical;predictive marker;prognostic;research clinical testing;safety testing;sphingosine 1-phosphate;success;therapeutic biomarker;trafficking;translational medicine;trial design;virtual Ceraxa (Ceramide NanoLiposome) and Vinblastine For the Improved Treatment of Relapsed or Refractory Acute Myeloid Leukemia Keystone Nano in partnership with the University of Virginia Cancer Center Memorial Sloan Kettering CancerCenter and Penn State Hershey Cancer Center is developing Ceraxa (Proprietary Ceramide NanoLiposome)and Vinblastine as a new treatment for relapsed / refractory AML patients. These patients have a three-yearsurvival rate of only ten percent and new therapies are urgently needed. The Ceraxa/Vinblastine combinationis novel never tried therapeutic intervention based on very exciting preclinical data and strongly supportivemechanistic data. This testing builds on a highly successful dose escalation study of Ceraxa supported by theNCI. The project team will conduct clinical testing advancing the therapies for AML patients and conductingresearch to support translational medicine and new discovery. NCI 10704116 9/8/23 0:00 PA-21-260 5R44CA275609-02 5 R44 CA 275609 2 "LOU, XING-JIAN" 9/14/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-T(10)B] 79095306 "ADAIR, BERNADETTE MCMAHON" Not Applicable 15 Unavailable 610435070 M5STD1CK7FC3 610435070 M5STD1CK7FC3 US 40.772906 -77.890972 10007876 "KEYSTONE NANO, INC." State College PA Domestic For-Profits 16803 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 999628 NCI 764623 169609 ABSTRACT: This grant supports the clinical study of Keystone Nanos (KN) Ceraxa (C6 CeramideNanoLiposome) and Vinblastine (VBL) in patients with relapsed/refractory Acute Myeloid Leukemia (AML) atleading NCI cancer centers. A recently completed NCI-supported Phase 1 study in solid tumor patients (NCT02834611) has shown no Dose Limiting Toxicities and only modest adverse events with Ceraxa at doses up to323 mg/m2 a dose five times the planned dose for the proposed AML trial. The rationale for the proposed uniqueand innovative combinatorial strategy of administration of Ceraxa plus Vinblastine is based upon findings from arecently renewed NIH NCI P01 grant (CA171983-06A1) awarded to KN Chief Technical Officer and co-founderDr. Mark Kester where dysfunctional sphingolipid metabolism was shown to contribute to the pathogenesis ofAML. Published mechanistic data document that Vinblastine disrupts autophagy leading to the induction ofCeraxa-mediated autophagic-cell death and shunting Ceraxa metabolism into pro-apoptotic sphingolipidmetabolites. The objectives of this grant are to: 1) establish a recommended dose of Ceraxa for AML patientsand test preliminary efficacy as a monotherapy 2) establish a Recommended Phase 2 Dose to test Ceraxa incombination with Vinblastine and 3) test the safety of Ceraxa plus Vinblastine at the RP2D. Secondaryobjectives of the grant are to: 1) obtain estimates of effectiveness (CR PR) 2) assess the pharmacokinetics(PK) of Ceraxa and VBL 3) obtain estimates of the overall survival (OS) at 90 days after treatment with thecombination of Ceraxa and VBL 4) validate putative lipid-based prognostic or therapeutic biomarkers frompatient plasma samples; 5) determine the number of red blood cell (RBC) and platelet transfusions needed forsupportive care and 6) estimate the quality of life of participants prior during and following treatment withCeraxa and VBL. KN has an open IND 142902 and IRB approval (IRB-HSR 22000) for the monotherapy study.This grant integrates important translational medicine opportunities with three research universities acompany a supporting PO1 team and a private foundation (Commonwealth Foundation of Virginia)cooperatively conducting research and clinical investigations including exploring genomic proteomic andlipidomic impacts of a new AML treatment with a smart clinical trial. All studies will be completed through twospecific aims: 1) Manufacture Ceraxa as a Clinical Drug Product; 2) Conduct Ceraxa clinical trials for AMLpatients at leading cancer centers. 999628 +No NIH Category available Affect;Aromatase Inhibitors;Benchmarking;Biochemistry;Bioinformatics;Biological Assay;Biological Markers;Biological Models;Breast Cancer Model;Breast Cancer cell line;Breast Cancer therapy;CDK4 gene;CRISPR/Cas technology;Cancer Model;Caring;Cause of Death;Cell Cycle Inhibition;Cell Line;Cells;Cessation of life;Characteristics;Clinic;Clinical;Clinical Trials;Comparative Genomic Analysis;DNA Damage;DNA Repair;DNA Sequence Alteration;Data;Data Set;Dependence;Detection;Development;Diagnosis;Disease;Disease Resistance;Disseminated Malignant Neoplasm;Drug Combinations;Drug resistance;ERBB2 gene;ESR1 gene;Eligibility Determination;Endocrine;Enzymes;Estrogen Antagonists;Estrogen Receptors;Estrogen receptor positive;Estrogens;FAT gene;Family;Genes;Genetic;Genomic Instability;Genomics;Immune response;Immunohistochemistry;Immunologics;Individual;Kinetics;Knock-out;Large-Scale Sequencing;Link;Malignant Neoplasms;Mediating;Medical;Metastatic breast cancer;Methods;Minority;Modeling;Mutagenesis;Mutagens;Mutation;NF1 gene;Neoplasm Metastasis;Newly Diagnosed;Pathogenesis;Pathogenicity;Patients;Pattern;Phenotype;Positioning Attribute;Prevalence;Primary Neoplasm;Process;RB1 gene;Recurrence;Regimen;Resistance;Resistance development;Sampling;Series;Shapes;Systemic Therapy;Tamoxifen;Testing;Therapeutic;Time;Translating;United States;Viral;Woman;acquired drug resistance;antagonist;breast cancer diagnosis;cancer cell;cancer genome;cancer therapy;cell free DNA;chromatin remodeling;curative treatments;deprivation;dominant genetic mutation;genomic profiles;hormone therapy;immune checkpoint blockade;inhibitor;innovation;insight;knock-down;malignant breast neoplasm;mortality;multimodality;next generation sequence data;novel strategies;overexpression;patient derived xenograft model;prevent;refractory cancer;resistance allele;resistance mutation;therapeutic target;transcription factor;tumor;tumor DNA;tumor progression Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer Relevance: Metastatic breast cancer is one of the leading causes of death among women in the United Stateswith mortality linked to the disease becoming resistant to hormonal therapies. Analyses of breast cancers thatare metastatic reveal the presence of pathogenic DNA mutations originating from the mutagenesis processinduced by the activity of the APOBEC family of antiviral enzymes. This project will facilitate clinicalidentification of cancers in which APOBEC is or will become active elucidate how APOBEC promotes drugresistance and develop new methods for treating APOBEC positive tumors. NCI 10704108 8/7/23 0:00 PAR-18-313 5P50CA247749-04 5 P50 CA 247749 4 8/13/20 0:00 7/31/25 0:00 ZCA1-RPRB-8 6280 9257605 "CHANDARLAPATY, SARAT " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 436454 329266 107188 Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast CancerSummary: Although the majority of early stage estrogen receptor (ER)-positive breast cancers are curedthrough multimodality care metastatic ER-positive breast cancer remains a lethal disease. Insights into thisdiscrepancy have come through comparative genomic analyses of primary and metastatic tumors. We andothers have identified several mutations affecting specific genes that are more prevalent in metastatic cancersthan in their primary counterparts including ESR1 ERBB2 and NF1. These mutations result in resistance tofront-line endocrine treatments that are the mainstay systemic therapy in ER-positive breast cancer. Evenmore striking than such individual mutations however has been the finding that certain `mutational signatures'are enriched in metastatic disease as compared to primary breast cancers. These mutational signaturesrepresent the DNA damage and repair processes that shape the cancer genome and can give rise to suchmutations and the transformed phenotypes they convey. A glaring and consistent finding from multiple large-scale sequencing studies has been that the APOBEC mutational signature is both enriched and highlyprevalent in ER-positive metastatic disease comprising the dominant mutational signature for these drug-resistant and ultimately lethal cancers. Our preliminary data confirm that APOBEC activation can promote thedevelopment of endocrine resistance in ER-positive cancer models and is associated with characteristicAPOBEC-mutational changes in many drug resistance alleles. Together these results point to the APOBECmutational process as a key driver in the development and pathogenesis of ER-positive metastatic breastcancer and endocrine therapy resistance. In this highly collaborative and innovative project we propose threespecific aims to advance the APOBEC mutational process as a biomarker and therapeutic target in breastcancer. (1) We will develop and utilize robust bioinformatic methods to detect the presence and the timing ofonset of the APOBEC mutational signature from clinical NGS datasets of both tumor and cell free DNA(cfDNA). We will further ascertain if a promising IHC assay for the A3B enzyme can identify those ER-positivecancers likely to subsequently develop an APOBEC mutational signature. (2) We will determine themechanisms and kinetics of APOBEC's contribution to endocrine resistance. We will use isogenic cell linemodels and patient derived xenografts to dissect the types of resistance patterns that are caused by APOBECas well their timing and whether the endocrine therapy itself contributes to the induction of APOBEC activity.(3) We will assess both immunologic and synthetic lethal approaches to targeting tumors in which APOBECactivity is induced and determine their capabilities in killing APOBEC-positive cancers. We anticipate that ourfindings will uniquely position our team to launch clinical trials testing specific approaches to diagnoseAPOBEC-positive tumors to prevent the development of resistance to endocrine therapies and to target thelargest subset of ER-positive endocrine-resistant metastatic breast cancers. +No NIH Category available Address;Adenosine;Adjuvant Chemotherapy;Autophagocytosis;Behavior;Biological Markers;Biological Specimen Banks;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast cancer metastasis;Cell Death;Cell Senescence Induction;Cell physiology;Cells;Cellular Immunity;Chromosomal Instability;Chromosome Segregation;Chromosomes;Chronic;Clinical;Colon Carcinoma;Cyclic AMP;Cytoplasm;Cytosol;Cytotoxic Chemotherapy;DNA;Data;Development;Disease;Distant;Encapsulated;Epithelial Cells;Exposure to;Extracellular Space;Flow Cytometry;Generations;Genomic DNA;Genomic Instability;Genomics;Goals;Human;Hydrolysis;Immune;Immune Evasion;Immune signaling;Immunohistochemistry;Immunologic Surveillance;Immunophenotyping;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Inflammation;Inflammatory;Interferon Activation;Interferon Type I;Interferons;Malignant Neoplasms;Mammary Neoplasms;Measures;Mediating;Metabolic;Metastatic breast cancer;Metastatic/Recurrent;Microdialysis;Mitosis;Modeling;Mus;Mutation;Neoadjuvant Therapy;Neoplasm Metastasis;Nuclear;Organ;Paclitaxel;Pathologic;Pathology;Pathway interactions;Patient-derived xenograft models of breast cancer;Patients;Preclinical Testing;Prediction of Response to Therapy;Recurrence;Research;Resistance;Role;Rupture;Sampling;Second Messenger Systems;Signal Transduction;Source;Specimen;Stimulator of Interferon Genes;System;T-Lymphocyte;Techniques;Testing;Therapeutic;Tumor Subtype;Validation;Viral;Work;Xenograft procedure;aggressive breast cancer;cancer cell;cancer subtypes;cancer therapy;chemotherapy;chromosome missegregation;ds-DNA;ecto-nucleotidase;extracellular;first-in-human;genetic manipulation;inhibitor;innate immune pathways;malignant breast neoplasm;melanoma;micronucleus;mouse model;neoplastic cell;new therapeutic target;novel;novel marker;novel therapeutic intervention;patient derived xenograft model;pharmacologic;pre-clinical;predicting response;predictive marker;prevent;prospective;response;response biomarker;senescence;single-cell RNA sequencing;therapy resistant;tool;treatment response;triple-negative invasive breast carcinoma;tumor;tumor-immune system interactions;viral DNA Targeting innate immune pathways in breast cancers with chromosomal instability PROJECT NARRATIVEChromosomal instability (CIN) is a hallmark of aggressive breast cancer yet how it contributes to the ability ofcancer cells to resist therapy and spread to distant organs remains poorly understood. Our research identifiedthat CIN promotes aggressive cancer behavior by sustaining chronic inflammation. Here we will exploit thisfinding to test whether a tool compound that inhibits inflammation can suppress breast cancer metastasis andto develop novel biomarkers predictive of response to chemotherapies and immunotherapies already approvedfor the treatment of breast cancer. NCI 10704103 8/7/23 0:00 PAR-18-313 5P50CA247749-04 5 P50 CA 247749 4 8/13/20 0:00 7/31/25 0:00 ZCA1-RPRB-8 6279 12142996 "BAKHOUM, SAMUEL F" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 462250 290611 171639 PROJECT SUMMARY/ABSTRACTWhile considerable progress has been made in treating primary breast cancers metastatic breast cancers re-main a challenge. Metastatic breast cancer cells typically have chromosomal instability (CIN) that involveschromosome-level alterations leading to genomic copy number abnormalities. A major challenge in targetingbreast cancers driven by CIN is the lack of known targetable alterations. We recently found that CIN pro-motes chronic inflammatory signaling in cancer cells. As chromosomes missegregate they often become en-capsulated in micronuclei. Subsequent micronuclear rupture exposes genomic double-stranded DNA to thecytosol. Cytosolic DNA activates anti-viral innate immune pathways chief among which is cGAS-STING signal-ing. Under normal circumstances cGAS-STING activation promotes type I interferon and facilitates cell-mediated immunity. Engagement of STING in normal epithelial cells induces senescence and cell death. Wehave shown that cancer cells however are intrinsically resistant to cGAS-STING activation by virtue of theirchronic exposure to cytosolic DNA. Instead they upregulate alternative pathways downstream of STING suchas NF-B signaling. The extent to which cancer cells depend on chronic inflammatory signaling is poorly un-derstood. More importantly how they subvert innate immune signaling to avoid immune surveillance remainsunknown. Our ongoing work reveals that cGAS-STING signaling is sequestered in cancer cells away from thehost. Furthermore human breast tumors upregulate ENPP1 a negative regulator of cGAS-STING signaling.ENPP1 enables immune evasion by degrading cGAMP the second messenger produced by cGAS only in theextracellular space. As such ENPP1 prevents host STING activation in response to tumor-to-host cGAMPtransfer. Strikingly pharmacologic inhibition of STING suppresses metastasis in syngeneic models of melano-ma breast and colon cancers. We postulate this is because its inhibition in tumor cells outweighs its protectiverole in the host. Building on this work we will expand our pre-clinical testing of STING inhibition in breast can-cer probing its efficacy in delaying metastasis and therapeutic resistance (Aim 1). We will then examinewhether cGAMP contributes toward the formation of an immune suppressive microenvironment through meta-bolic breakdown in the extracellular space (Aim 2). Finally we will develop cGAS-STING-based biomarkers inprospectively collected tumor specimens. We will test whether the status of cGAS-STING signaling andENPP1 levels can predict response to neoadjuvant chemotherapy and atezolizumab an immunotherapeuticrecently approved for the treatment of metastatic breast cancer (Aim 3). Our work addresses a clinically unmetneed by targeting a subset of breast cancers with CIN and for which there are limited therapeutic options. Ifsuccessful it will provide pre-clinical rationale for first-in-human testing of STING inhibitors for the treatment ofcancer metastasis as well as the development of novel CIN-related biomarkers to predict therapeutic response. +No NIH Category available Antibodies;Antigens;Architecture;Biological Markers;Cell Ontogeny;Cells;Cellular Structures;Consultations;Data;Detection;Development;Disease;Early Diagnosis;Ensure;Epithelium;Frequencies;Generations;Genetic;Goals;Human;Human Resources;Image;Immune;Immune Evasion;Immune system;Individual;Laboratories;Learning;Link;Malignant neoplasm of pancreas;Maps;Methods;Monitor;Mus;Neighborhoods;Pancreas;Population;Public Health;Quality Control;Reagent;Research;Research Personnel;Resources;Retrieval;Role;Services;Signal Transduction;Stains;Stereotyping;Time;Tissue Procurements;Tissue imaging;Tissues;Work;cancer cell;cancer therapy;candidate identification;cell type;cost;effective therapy;health goals;human tissue;immunoregulation;in vivo;indexing;mouse model;pancreas imaging;programs;single-cell RNA sequencing;spatial relationship;stem cells;tissue preparation;tool;treatment response;tumor;tumor growth;ultrasound Core C: CODEX Core PROJECT NARRATIVE (Core C)In order to understand the roles of specific types of cells including immune cells in pancreatic cancer this core will use a new method developed at Stanford called Co-Detection by indexing (CODEX) which enables us to define the frequency spatial relationships and activation states of cell types within tumors and to learn how these parameters change over time and in response to treatment. This core will work closely with all 3 projects to support their studies of mouse and human tissues thereby helping this Program to meet the public health goals of the NCI by discovering biomarkers that enable early diagnosis and more effective treatment for cancer. NCI 10704098 9/11/23 0:00 PAR-20-077 5P01CA244114-03 5 P01 CA 244114 3 8/1/21 0:00 7/31/26 0:00 ZCA1-RPRB-H 8657 1927492 "KIM, SEUNG K" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 333560 211667 121893 ABSTRACT (Core C)A central focus of our program is understanding the roles of specific cell types including immune cell populations throughout the initiation development and spread of PDAC in mouse models and in humans. A key aspect of this effort is to define the frequency spatial relationships and activation states of cell types within tumors and to learn how these parameters change over time and in response to therapy. Additionally while each project focuses on a different aspect of PDAC a comprehensive understanding of the role of the epithelial compartment and the immune system in PDAC will require simultaneous analysis of each of these cell types in multiple tissues. To achieve these goals we will use CO-Detection by indEXing (CODEX) a new method generated by Dr. Nolans group at Stanford. CODEX will allow cytometric imaging of tissue sections with dozens of antibodies. CODEX data from this Core can then be linked to complementary data from CyTOF and scRNASeq used in individual projects. The Specific Aims of Core C for human and mouse pancreas studies are:1. Provide CODEX processing to investigators including staining imaging and quality control2. Provide CODEX analysis including antigen clustering cell type annotation and neighborhood mapping3. Develop new antibodies and reagents for CODEX in consultation with P01 investigators4. Develop standard workflows for tissue procurement processing storage and retrieval in partnership with the human pancreas tissue core (Core B).Projects 1 2 and 3 will specifically use the CODEX core platform for studies of both mouse and human tissues. Core C will work closely with the Human Tissue Core B to ensure appropriate human tissue preparation to support CODEX analysis. Thus Core C will provide services technically difficult and not available in most laboratories materials not available commercially or impossible to obtain elsewhere and services more reliably and cost-effectively performed than if performed in an individual investigators laboratory. This CODEX Core would be new and unique at Stanford. +No NIH Category available Address;Administrator;Biology;Biostatistics Core;Cancer Biology;Cells;Collaborations;Communication;Communities;Consultations;Dedications;Development;Disease;Education;Ensure;Environment;Faculty;Genetic;Goals;Human Resources;Immune;Knowledge;Lead;Maintenance;Malignant neoplasm of pancreas;Medical Students;Pathway interactions;Patient Care;Postdoctoral Fellow;Productivity;Public Health;Research;Research Personnel;Resource Sharing;Resources;Role;Science;Training and Education;Translating;Universities;burden of illness;career development;graduate student;immunoregulation;improved;member;operation;programs;statistics;web site Administrative and Biostatistics Core Project Narrative (Core A) This P01 application from investigators at Stanford University seeks to discover apply and translate science about pancreatic cancer (PDAC) with the ultimate goal of improving care for patients with this disease. To address fundamental persistent questions about the biology of PDAC we have assembled a superb interactive team of productive collaborators to lead our Projects and Research Cores. This team will identify genetic and immune cell-based interactions and pathways that regulate the inception and progression of PDAC. Advances from studies proposed here could broadly impact pancreas cancer biology and drive translational efforts in PDAC. NCI 10704093 9/11/23 0:00 PAR-20-077 5P01CA244114-03 5 P01 CA 244114 3 8/1/21 0:00 7/31/26 0:00 ZCA1-RPRB-H 8654 1927492 "KIM, SEUNG K" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 181668 115281 66387 ABSTRACT (Core A-Administrative and Biostatistics Core) This application seeks support for its efforts to discover apply and translate scientific knowledge about pancreatic cancer to improve public health by reducing the burden of this disease. The Administrative and Statistics Core will coordinate allocate and oversee resources and provide oversight to ensure the smooth operation of the Projects and shared resource Cores comprising this program project. Coordination of these activities will be facilitated through the maintenance and curation of a program website by this Core. Core personnel include the Lead (Director) the co-Lead (Co-Director) a Program Manager a biostatistician and a Financial Administrator. The Director assumes responsibility for the scientific and educational directions of the program. The Co-Director will assist the Director in the operation of the program and will assume full responsibility when the Director is not present. The roles of other Core personnel are detailed below. This Core is responsible for: 1) oversight and allocation of center resources to each Project (three in this program) 2) oversight and allocation of Research Core resources 3) coordinating interactions within the P01 and with the relevant community of science through the program website and 4) coordinating statistical support for the Projects. +No NIH Category available Affect;Agonist;Antibodies;Antigen-Presenting Cells;Automobile Driving;Base Composition;Biological Assay;CDKN2A gene;Cell Line;Cells;Complement;DNA Sequence Alteration;Data;Development;Disease Progression;Duct (organ) structure;Ductal Epithelial Cell;Environment;Enzyme-Linked Immunosorbent Assay;Exhibits;Frequencies;Genetic;Genetically Engineered Mouse;Genomics;Genotype;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;Human;Immune;Immune response;Immune system;Immunobiology;Immunologics;Immunotherapy;KRAS2 gene;Lesion;Ligands;MADH4 gene;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Methods;Modeling;Molecular;Mus;Mutation;Organism;Pancreatic Ductal Adenocarcinoma;Pancreatic duct;Pattern recognition receptor;Property;Quantitative Reverse Transcriptase PCR;Resistance;Role;Shapes;Signal Pathway;Specimen;System;T-Cell Activation;T-Lymphocyte;TP53 gene;Testing;Therapeutic;Transplantation;Treatment Efficacy;Tumor Promotion;Tumor-Derived;Tumor-associated macrophages;Tumor-infiltrating immune cells;Variant;Work;analytical tool;antitumor effect;cancer cell;cell type;cytokine;driver mutation;effective therapy;exome sequencing;high dimensionality;immune cell infiltrate;immune checkpoint blockade;immune function;immunoregulation;improved;molecular subtypes;mouse dectin-2;mouse model;mutational status;neoplastic cell;neutralizing antibody;pancreatic ductal adenocarcinoma model;patient population;pharmacologic;programs;receptor;recruit;response;single-cell RNA sequencing;targeted treatment;therapy resistant;transplant model;treatment response;tumor;tumor growth;tumor microenvironment Project 3: Impact of tumor genetics on PDAC immunobiology and responses to macrophage-targeted immunotherapy PROJECT NARRATIVE (Project 3)Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive infiltration of immune cells and inparticular macrophages are abundant in the PDAC stroma contributing to disease progression as well asresistance to treatment. However the factors contributing to the immune landscape within the tumormicroenvironment (TME) and throughout the host during PDAC development and progression are poorlyunderstood. In this project we seek to delineate the role of somatic cancer cell alterations cell type of originand tumor molecular subtype in modulating the local and systemic immune profiles during PDAC developmentand to investigate the mechanisms by which the immune landscape of the TME and the host are altered inresponse to therapy that reprograms immunosuppressive tumor-associated macrophages intoimmunostimulatory antigen-presenting cells. NCI 10704089 9/11/23 0:00 PAR-20-077 5P01CA244114-03 5 P01 CA 244114 3 8/1/21 0:00 7/31/26 0:00 ZCA1-RPRB-H 8653 1862821 "ENGLEMAN, EDGAR G. " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 421608 267539 154069 ABSTRACT (Project 3)Pancreatic ductal adenocarcinoma (PDAC) an aggressive malignancy that is poorly responsive to treatmentis characterized by a prominent infiltration of immune cells. In particular macrophages are abundant within thetumor microenvironment (TME) in PDAC and contribute to disease progression and treatment resistance.However the factors affecting the recruitment and distribution of immune cells including macrophages inPDAC remain largely unknown. Recently our collaborators in Project 1 found that tumors differing in theirTrp53 status exhibited different immune profiles. Our collaborators further observed that the cell type of origin(acinar or ductal) influenced the tumor molecular subtype (classical or basal-like) which is also known to beshaped by the immune composition of the tumor. We postulate that somatic alterations in cancer cells the celltype of origin and tumor molecular subtype influence the immune landscape within the TME and throughoutthe host during PDAC progression. To test this hypothesis we will determine immune cell frequencydistribution and function in the TME and throughout the host using high-dimensional analytical tools (CODEXand CyTOF) on genetically engineered mouse models (GEMMs) of PDAC that vary in their driver mutationsand cell type of origin (developed by Project 1). Additionally we will use molecular methods to identifyimmunomodulatory factors regulating immune cell recruitment in the context of different genetic mutations andcell type of origin and we will use genetic pharmacological and neutralizing antibody-based approaches toconfirm the functional effects of these factors in driving PDAC progression. Importantly we will validatefindings from these studies in human PDAC specimens and in cell lines derived from human pancreatic ductalcells. Finally we recently found that the pattern recognition receptor Dectin-2 is expressed on tumor-associated macrophages (TAMs) in an aggressive transplantable model of PDAC. Notably administration ofnatural Dectin-2 ligands induces sustained PDAC regression in a T-cell dependent manner by reprogrammingimmunosuppressive TAMs into immunostimulatory antigen-presenting cells (APCs). We hypothesize thatPDAC can be effectively treated by reprogramming Dectin-2+ TAMs into immunostimulatory APCs. We willtreat autochthonous tumors arising in the GEMMs developed by Project 1 with Dectin-2 ligands to test thishypothesis. Furthermore to identify mechanisms by which Dectin-2 stimulation is therapeutically efficaciouswe will use CODEX and CyTOF to observe changes to the immune landscape occurring within the TME andthroughout the host upon treatment. Molecular approaches will be used to identify immunomodulatory factorsresponsible for mediating therapeutic efficacy. Together these studies will improve our understanding of howthe immune system is altered during PDAC development in the context of variation in genetic mutations celltype of origin and molecular subtype and in response to TAM reprogramming. +No NIH Category available Acinar Cell;Affect;Cell Communication;Cells;Chemoresistance;Chronic;Communication;Development;Disease;Ductal Epithelial Cell;Early Diagnosis;Environment;Epigenetic Process;Experimental Models;Feedback;Fibroblasts;Fibrosis;Genetic;Genetic Engineering;Goals;Growth;Human;Immune;Immune signaling;In Vitro;Infiltration;Inflammation;Lead;Link;LoxP-flanked allele;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Methods;Mus;Neoplasm Metastasis;Oncogenic;Pancreas;Pancreas Transplantation;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pancreatic duct;Pancreatitis;Pathway interactions;Patients;Peripheral;Phenotype;Platelet-Derived Growth Factor alpha Receptor;Play;Population;Process;Prognosis;Property;Radiation therapy;Recurrence;Regulation;Resistance;Risk Factors;Role;STAT3 gene;Sampling;Shapes;Signal Pathway;Signal Transduction;Stromal Cells;Survival Rate;TP53 gene;Tamoxifen;Testing;Therapeutic;Tumor Promotion;Tumorigenicity;Work;acute pancreatitis;cancer cell;cancer stem cell;cancer subtypes;carcinogenesis;chemotherapy;chronic pancreatitis;dimensional analysis;driver mutation;genetic approach;immunoregulation;improved;in vivo;insight;interleukin-22;molecular targeted therapies;mouse model;novel;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic stellate cell;pharmacologic;receptor;selective expression;single-cell RNA sequencing;stemness;synergism;therapeutic evaluation;therapeutic target;tissue repair;tumor microenvironment;tumor progression;tumorigenic Project 2: Immune signals promoting pancreas cancer stemness and progression PROJECT NARRATIVE (Project 2) Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of less than 5%. The extremely poor prognosis in PDAC is attributed to lack of early detection complexity and aggressiveness of the disease and importantly resistance to conventional chemotherapy radiotherapy and molecularly targeted therapy. This is due to the complexity in PDAC characterized by several genetic epigenetic alterations dense fibrosis and a dynamic immune environment that cross-talk with each other to drive cancer progression and chemoresistance. Our study proposes to examine immune signals that facilitate communication between immune cancer and stromal cells to promote cancer progression. Our preliminary results have identified a novel pro-tumorigenic signaling pathway that links immune cells cancer cells and stroma in PDAC. Using human samples and experimental models of PDAC we will study the mechanisms involved and examine the possibility of therapeutically blocking this pathway to treat PDAC. NCI 10704088 9/11/23 0:00 PAR-20-077 5P01CA244114-03 5 P01 CA 244114 3 8/1/21 0:00 7/31/26 0:00 ZCA1-RPRB-H 8652 7810696 "ARTANDI, STEVEN E" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 414571 263074 151497 ABSTRACT (Project 2) There is an urgent need to discover improved therapies for pancreatic ductal adenocarcinoma (PDAC) which require a better understanding of mechanisms underlying development and recurrence. Chronic inflammation is a feature and an independent risk factor for PDAC. Interactions between immune cells cancer associated fibroblasts (CAFs) and cancer cells can promote PDAC development and progression. However little is known about how immune cells or immune cell-related signals affect PDAC development. Our long-term goal is to identify signaling nodes that facilitate the crosstalk between immune cells cancer cells and CAFs to promote PDAC progression. In healthy subjects IL-22 is expressed by immune cells while its receptor IL22RA1 is selectively expressed in non-immune cells. IL-22 and IL-22RA1 expression are both elevated in PDAC but little is known about the role of this signaling axis in PDAC. We have recently demonstrated high heterogeneous expression of IL-22RA1 in human and mouse PDAC. Importantly high IL-22RA1 expression is associated with poor prognosis of PDAC patients. Furthermore we showed that IL-22RA1high cells in PDAC have cancer stem cell properties including high tumorigenicity in vivo. We found that IL-22 stimulates IL22RA1 expression through STAT3 activation in PDAC cells and postulate that this positive feedback loop enhances stemness and tumorigenicity of PDAC cancer cells. Thus IL-22RA1/STAT3 signaling might provide a therapeutic target to treat PDAC with high IL-22RA1. We will use different mouse models of PDAC to study the effects of genetic deletion of IL-22RA1 in acinar cells or PSCs on PDAC growth metastasis and stemness in vivo. We will use novel multi- dimensional analysis methods to analyze if inflammation drives carcinogenesis via IL-22 IL-22 expression in immune cell populations in PDAC mouse models and test therapeutic benefit of blocking IL-22 signaling in PDAC using pharmacologic and genetic approaches. We will determine the expression and role of IL-22/IL-22RA1 axis in human PDAC. Using primary human pancreatic ductal epithelial cells with defined PDAC genetic driver mutations we will study the contribution and regulation of IL-22/IL-22RA1 signaling in human PDAC development. Our proposed studies will novel insights into how genetic drivers and inflammation orchestrate functional connection and communication between immune and non-immune components in PDAC. Further we will gain mechanistic understanding of how (1) immune cell CAF and cancer cell interactions mediated by the IL-22/IL-22RA1 axis lead to PDAC development and (2) inhibition of the IL-22/IL-22RA1 signaling axis provides a therapeutic strategy that targets cancer stemness a major factor in therapy resistance and the dismal prognosis associated with PDAC. +No NIH Category available Abstinence;Adherence;Adoption;Adult;Behavior Therapy;Behavioral;Biochemical;Caring;Cellular Phone;Cigarette;Clinical;Clinical Treatment;Collaborations;Communicable Diseases;Cost Effectiveness Analysis;Cost Measures;Data;Effectiveness;Epidemic;HIV;Health Services;Home;Income;India;Individual;International;Intervention;Measures;Medical center;Modeling;Outcome;Patients;Penetration;Persons;Pharmaceutical Preparations;Pharmacotherapy;Population;Positioning Attribute;Proctor framework;Provider;Randomized;Reporting;Research;Research Personnel;Resources;Safety;Self Efficacy;Site;Smoke;Smokeless;Smokeless Tobacco;Smoker;Smoking;Testing;Tobacco;Tobacco Dependence;Tobacco Use Cessation;Tobacco smoke;Tobacco use;Viral;Work;antiretroviral therapy;bidis;brief advice;care systems;clinical research site;comparison intervention;cost;cost effective;cost effectiveness;design;effective therapy;effectiveness evaluation;effectiveness study;effectiveness testing;health communication;hookah;implementation evaluation;implementation process;implementation strategy;interest;low and middle-income countries;mHealth;medication compliance;models and simulation;novel;open label;programs;quitline;randomized trial;randomized clinical trials;scale up;smokeless tobacco cessation;smokeless tobacco use;smoking prevalence;social cognitive theory;stakeholder perspectives;standard care;success;theories;timeline;tobacco abstinence;tobacco cessation intervention;tobacco control;tobacco smokers;tobacco user;treatment program;two-arm trial;varenicline;years of life lost Varenicline and mobile behavioral assistance for tobacco cessation in HIV care in India NarrativeThere is an urgent need to adapt and implement effective tobacco cessation interventions in HIV careprograms in low- and middle-income settings. This study will evaluate the effectiveness and cost-effectivenessof an integrated varenicline and mobile behavioral intervention among smokers and dual tobacco users in HIVcare in Chennai India. Combining a scalable mobile health intervention with cost-effective pharmacotherapycould reduce the harmful impacts of tobacco among people living with HIV. NCI 10704086 8/28/23 0:00 RFA-CA-20-037 5U01CA261614-04 5 U01 CA 261614 4 "RICCIARDONE, MARIE D" 9/23/21 0:00 8/31/26 0:00 ZCA1-SRB-2(M1) 11990793 "KRUSE, GINA RAE" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 634040 NCI 551908 82132 AbstractThere is an urgent need to implement effective tobacco cessation interventions in HIV care programs in low-and middle-income countries (LMICs) where most tobacco users and people with HIV live. India is animportant setting in which to test tobacco cessation interventions with an estimated 275 million tobacco usersand 2 million people living with HIV (PWH). Effective medications and behavioral interventions have not beenwell tested in HIV care settings in LMICs. In high income settings Positively Smoke Free (PSF) a theory-based behavioral intervention has demonstrated efficacy among PWH and been adapted for mobile phonedelivery (PSF-M). Mobile health interventions offer scalability and may be more effective among PWH thanface-to-face. Varenicline is the cessation medication with the strongest evidence of efficacy in PWH butachieving sufficient adherence to sustain long-term success is a challenge. We propose to combine the twomost promising cessation interventions among PWH varenicline and PSF-M enhanced with vareniclineadherence support. They will be tested at the Voluntary Health Services (VHS) Infectious Disease MedicalCenter Chennai Antiviral Research and Treatment Clinical Research Site where 24% of patients new to HIVcare are current smokers or dual users of smoked and smokeless tobacco and 83% own mobile phones. Inthis setting we propose the following specific aims: (1) To demonstrate the effectiveness of an integratedintervention combining varenicline plus mobile behavioral treatment among tobacco users in HIV care onbiochemically verified tobacco abstinence at 24 weeks compared to a standard care control; (2): To evaluatethe implementation processes of the integrated intervention in an LMIC HIV practice; and (3): To measure thecosts and cost-effectiveness of an integrated intervention with varenicline and PSF-M. To accomplish theseaims PSF-M will be adapted to the VHS context and novel content about smokeless tobacco and medicationadherence self-efficacy will be added. A randomized two-arm trial will compare the combination of vareniclineand PSF-M to a standard care control. We will evaluate implementation processes within HIV care workflowsincluding acceptability appropriateness feasibility and costs and conduct cost-effectiveness analysis to assessthe clinical impact and value of the integrated intervention if scaled-up. The work proposed is responsive to thespecific interests in RFA-CA-20-037 by testing the effectiveness of tobacco cessation interventions withdemonstrated efficacy in other settings and adapted for an LMIC context evaluating the implementationprocess from multiple stakeholder perspectives in an HIV care practice and assessing the clinical impact andvalue of the integrated intervention if implemented at scale. The successful completion of this work will movethe field forward by advancing our understanding of the effectiveness of an integrated tobacco cessationintervention in HIV care settings and projecting the population level impacts of implementing the integratedintervention for PWH in India or other LMICs. 634040 +No NIH Category available Acinar Cell;Affect;Aging;Alleles;Bar Codes;CDKN2A gene;CRISPR/Cas technology;Cells;Chromosome Mapping;Clinical;Clinical Management;Clonal Expansion;Data;Development;Disease;Duct (organ) structure;Ductal Epithelial Cell;Early Diagnosis;Early treatment;Epithelial Cells;Event;Evolution;Gene Expression;Gene Expression Profile;Genetic;Genetic Determinism;Genetically Engineered Mouse;Genotype;High-Throughput Nucleotide Sequencing;Homeostasis;Human;Immune;Intervention;KRAS oncogenesis;KRAS2 gene;KRASG12D;Knowledge;Lesion;MADH4 gene;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metaplasia;Modeling;Molecular;Mus;Mutate;Mutation;Oncogenic;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pancreatitis;Pathway interactions;Positioning Attribute;Process;Recurrence;Research;Research Personnel;Risk;Risk Factors;Role;Route;System;TP53 gene;Testing;Tumor Suppressor Genes;Tumor-Suppressor Gene Inactivation;Variant;Viral;cancer care;cancer cell;cancer genetics;cancer initiation;carcinogenesis;cell type;chronic pancreatitis;design;genome editing;genome sequencing;immunoregulation;improved;in vivo;innovation;insight;mortality;mouse model;mutant;neoplastic;novel;premalignant;reduce symptoms;regenerative;repaired;single-cell RNA sequencing;somatic cell gene editing;synergism;transcriptome;transdifferentiation;tumor;tumor initiation;tumor microenvironment Project 1: Elucidating the genetics and cell of origin of pancreatic cancer initiation PROJECT NARRATIVE (Project 1)Pancreatic cancer is particularly deadly because few symptoms manifest until late in disease development andbecause treatment options are ineffective. Developing improved early diagnosis strategies is therefore critical.This research aims to gain a detailed understanding of the earliest steps of pancreatic cancer development bydefining the cell type from which it originates and the genetic events involved essential first steps towardreducing mortality from this disease. NCI 10704080 9/11/23 0:00 PAR-20-077 5P01CA244114-03 5 P01 CA 244114 3 8/1/21 0:00 7/31/26 0:00 ZCA1-RPRB-H 8650 1885021 "ATTARDI, LAURA D" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 409455 259827 149628 ABSTRACT (Project 1)Pancreatic ductal adenocarcinoma (PDAC) is a prevalent and almost uniformly fatal malignancy. Human PDACgenome sequencing has identified recurrent mutations in Kras and several major tumor suppressor genes(TSGs) but the impact of these alterations in the initiation and evolution of human PDAC development remainpoorly understood at the molecular level. Understanding the basis of tumor initiation and development has criticalimplications for improving early diagnosis and therapy. While PDACs were originally thought to arise from ductalcells evidence from mouse models suggests that acinar cells can give rise to PDACs through a regenerativetransdifferentiation process known as Acinar to Ductal Metaplasia (ADM). ADM is stimulated by chronicpancreatitis a known risk factor for PDAC and generates premalignant Pancreatic Intraepithelial Neoplasias(PanINs) which lead to PDAC. Our preliminary data suggest that the p53 TSG can inhibit ADM and that p53inactivation in acinar cells expressing oncogenic KrasG12D drives PDAC. However expression of oncogenicKrasG12D and p53 inactivation in ductal cells can also induce PDAC suggesting alternate routes of PDACcarcinogenesis. Interestingly we find that acinar cell-derived and ductal cell-derived tumors resemble theclassical and basal-like subtypes of human PDAC respectively. These results underscore the unique value ofmouse models in uncovering the determinants that dictate different paths of PDAC evolution to provide insightinto human PDAC. The roles of other common PDAC TSGs in early stage pre-neoplastic lesions includingwhether they normally function in acinar cells and/or ductal cells however remains unclear. Furthermoreoncogenic Kras mutations are diverse in PDAC yet it is unknown whether different mutations have distinctimpacts on PDAC development from different pancreatic epithelial cell types. We hypothesize that the cell typeof origin and tumor genotype cooperate to drive different paths of PDAC development and to test this idea wewill systematically inactivate several major PDAC TSGs and express different Kras alleles in both putative celltypes of origin. We will characterize the transcriptomes and the cellular milieu of early lesions and tumors andemploy innovative approaches like somatic genome editing and molecular barcoding. We will compare ourstudies in tractable mouse models to studies of human PDAC development. Together these transformativestudies will establish how genetic determinants and cell-of-origin influence the molecular pathways and thecellular microenvironment during PDAC evolution in mice and humans critical knowledge for better clinicalmanagement of this deadly disease. +No NIH Category available Acceleration;Acinar Cell;Address;Affect;Amplifiers;Biology;Biostatistics Core;Cancer Biology;Carcinoma;Cell Compartmentation;Cell Ontogeny;Cells;Chronic;Collaborations;Conceptions;Data;Data Analyses;Data Set;Dedications;Dependence;Detection;Development;Disease;Duct (organ) structure;Ductal Epithelial Cell;Epithelial Cells;Epithelium;Evolution;Fibroblasts;Frustration;Generations;Genetic;Genetically Engineered Mouse;Genotype;Goals;Human;Image;Imaging technology;Immune;Immune Evasion;Immune response;Immune signaling;Immunobiology;Immunotherapeutic agent;Immunotherapy;Infiltration;Inflammation;Inflammatory;Investigation;KRAS2 gene;Lead;Learning;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Metaplasia;Molecular;Mus;Mutation;Neoplasm Metastasis;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pathway interactions;Patient Care;Preparation;Prevention strategy;Process;Productivity;Research;Research Personnel;Resistance;Resource Sharing;Resources;Risk;Role;Science;Shapes;Signal Transduction;Therapeutic;Tissue Procurements;Tissues;Translating;Universities;Work;cancer cell;candidate identification;cell type;diagnostic strategy;driver mutation;empowerment;genetic resource;high dimensionality;human tissue;immunoregulation;improved;indexing;infrastructure development;innovation;lymph nodes;medical schools;member;mouse model;novel;novel diagnostics;pancreas development;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;programs;response;search engine;stem cells;stemness;targeted treatment;tool;translational impact;tumor;tumor microenvironment Pancreatic Cancer Development: Genetic and Immune Regulation Project Narrative (Overall):This P01 application from investigators at Stanford University seeks to discover apply and translate scienceabout pancreatic cancer (PDAC) with the ultimate goal of improving care for patients with this disease. Toaddress fundamental persistent questions about the biology of PDAC we have assembled a superbinteractive team of productive collaborators to lead our Projects and Research Cores that will identify geneticimmune cell and cancer-associated fibroblasts based interactions and pathways that regulate the inceptionand progression of PDAC. Advances from studies proposed here could broadly impact pancreas cancerbiology and drive translational efforts in PDAC. NCI 10704071 9/11/23 0:00 PAR-20-077 5P01CA244114-03 5 P01 CA 244114 3 "MERCER, NATALIA" 8/1/21 0:00 7/31/26 0:00 ZCA1-RPRB-H(J1)P 1927492 "KIM, SEUNG K" "ATTARDI, LAURA D" 16 ANATOMY/CELL BIOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 1982541 NCI 1258059 724482 Abstract (Overall):Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease whose mechanisms of development remainincompletely understood. Evidence suggests that pancreatic cancers may arise from acinar cells undergoing aprocess called acinar to ductal metaplasia (ADM) or from ductal cells to give rise to Pancreatic IntraepithelialNeoplasias (PanINs). How mutations or combinations of mutations promote PDAC development and the role ofinflammation in the process still remains unclear. Moreover interactions between immune cells cancer-associated fibroblasts (CAFs) and cancer cells can promote PDAC development and progression but muchremains to be learned about how signaling between cells in the tumor microenvironment (TME) affects the stemcell compartment (`stemness') thought to underlie PDAC development and promotes immune evasion. Thusmultiple questions about fundamental mechanisms governing PDAC development persist.To address these challenges our superb and highly interactive team will identify genetic and stromal (immunecells and CAFs) interactions and pathways that regulate the inception and progression of PDAC using innovativemouse models and human tissue-based approaches. We propose three Projects to address the following overallaims:1. Identify the originating cell(s) and deconstruct genetic pathways underlying PDAC initiation2. Discover immune signals that cross-talk with epithelial cells and CAFs to promote pancreas cancerdevelopment and stemness3. Investigate the impact of tumor genetics on PDAC immunobiology and response to macrophage-targetedimmunotherapyEffort on these projects will be organized through an Administrative and Biostatistics Core (A) and empoweredby two Research Cores focused on human tissue procurement (Core B) and use of high-dimensional imagingto measure cell and signaling interactions in tissues (CODEX; Core C).The participating investigators on this P01 lead teams that have collaborated productively for years and havegenerated compelling preliminary data that support the potential for unraveling the genetic and immune signalingmechanisms underlying PDAC development and developing new immunotherapeutic strategies for PDACwhich has proven frustratingly resistant to immuno-based therapies.Our studies should broadly impact pancreas cancer biology and importantly elucidate the reciprocal interactionsbetween immune and non-immune compartments (epithelial CAFs) in shaping the tumor microenvironmentduring disease evolution. accelerate discovery of novel diagnostic or preventive strategies for early-stagedisease or therapeutics for advanced PDAC. 1982541 +No NIH Category available Alleles;Animals;Antigen Presentation;Antigen Presentation Pathway;Antigen Targeting;Antigens;Basic Science;Biological Response Modifiers;Biopsy;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Breast Melanoma;CD8-Positive T-Lymphocytes;Cell Line;Clinic;Clinical;Clinical Data;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Data;Down-Regulation;Elements;Estrogen receptor positive;HLA-A gene;Human;Immune;Immune response;Immunocompetent;Immunosuppression;Immunotherapy;Individual;Inflammatory;Institution;Laboratories;Laboratory Research;MAP Kinase Gene;MEK inhibition;MEKs;Major Histocompatibility Complex;Malignant Neoplasms;Mediating;Mediator;Metastatic breast cancer;Molecular;Molecular Target;Mus;Outcome;PD-1/PD-L1;Pathway interactions;Patients;Resistance;Rodent Model;Role;Schedule;Signal Transduction;Solid Neoplasm;Testing;Therapeutic;Translating;Tumor Antigens;Tumor Escape;Tumor Immunity;Up-Regulation;Validation;Work;anti-PD-1;anti-PD-1/PD-L1;anti-PD-L1;anti-PD-L1 antibodies;cancer immunotherapy;clinical biomarkers;clinical efficacy;colon cancer patients;cytokine;drug sensitivity;efficacy testing;improved;in vivo;inhibitor;laboratory experiment;malignant breast neoplasm;melanoma;metastatic colorectal;mouse model;neoplastic cell;novel;novel marker;patient stratification;preclinical study;predicting response;programmed cell death protein 1;response;response biomarker;synergism;targeted agent;targeted treatment;tissue resource;translational approach;translational study;treatment optimization;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Targeting antigen presentation to improve immunotherapy responses in breast cancer PROJECT NARRATIVE: TARGETING ANTIGEN PRESENTATION TO IMPROVEIMMUNOTHERAPY RESPONSES IN BREAST CANCERThis is a translational proposal that seeks to extend our preclinical studies which identified synergy betweenMEK inhibitors and anti-PD-L1 immunotherapy to two (2) human metastatic breast cancer trials testing the samecombination. Tumor correlates associated with MEK inhibition in animals and subsequent response toimmunotherapy will be evaluated in paired patient tumor biopsies; furthermore we will perform laboratoryexperiments to optimize therapy sequence and schedule and confirm the functionality of MHC-II expression(induced by MEK inhibition) in tumor cells as a mediator of immunologic response. Successful completion of thiswork will elucidate possible clinical biomarkers for response or resistance to immunotherapy in breast canceras well as novel mechanisms of tumor immune-evasion. NCI 10704061 8/8/23 0:00 PAR-18-313 5P50CA098131-21 5 P50 CA 98131 21 8/7/03 0:00 7/31/24 0:00 ZCA1-RPRB-7 8644 10166490 "BALKO, JUSTIN M" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 335158 197206 138044 PROJECT SUMMARY/ABSTRACT: TARGETING ANTIGEN PRESENTATION TO IMPROVEIMMUNOTHERAPY RESPONSES IN BREAST CANCERCancer immunotherapies particularly those targeting the PD-1/L1 axis are revolutionizing treatment paradigms.Although these therapies have proven effective in a wide variety of solid tumors response rates to single agentanti-PD-1/L1 in breast cancer have been underwhelming centering around 5%-15% of treated patients.However given the durable responses observed in other tumor types finding ways to increase breast cancersensitivity to immunotherapy is a valuable endeavor. Our recent work in breast cancer and melanoma hasidentified an important role for major histocompatibility complex-II (MHC-II) expression on tumor cells as amediator of enhanced anti-tumor immunity and subsequent response to immunotherapies targeting the PD-1/PD-L1 axis. Furthermore our preliminary studies suggest that both MHC-I and MHC-II expression (antigen-presenting molecules) on breast tumor cells directly influences the tumor microenvironment through expandedanti-tumor immunity. We found that activation of the Ras/MAPK pathway suppresses the expression of bothMHC-I and MHC-II and therefore may be an actionable target for enhancing antigen presentation to promoteanti-tumor immunity and potentiate immunotherapy responses. Based on these data we have initiated trials inboth metastatic triple-negative breast cancer (TNBC) and ER+ breast cancer testing the efficacy of thiscombination. In this proposal we will perform clinical validation of the molecular effects of MEK inhibition withanti-PD-L1 in ongoing clinical trials at our institution as well as perform direct translational studies exploring theimmune mechanism behind MEK inhibition that promotes anti-tumor immunity. Our central hypothesis is thattherapeutic modulation of antigen presentation via MEK inhibition will promote immunotherapy response inbreast cancer through enhanced MHC-I and MHC-II responses. The proposed studies will elucidate mechanismvalidate clinical utility and identify new targets for combinations of therapies that promote anti-tumor immunitythrough enhancing antigen presentation. Thus this proposal will use a translational approach to bring rationalcombinations of immunotherapy and molecularly targeted agents to breast cancer patients. +No NIH Category available Address;Adoption;Algorithms;Architecture;Biology;Centromere;Cloud Service;Collaborations;Communities;Community Outreach;Computer software;Computing Methodologies;DNA Repair;DNA analysis;Data;Dedications;Democracy;Development;Diagnostic;Drug resistance;Ecosystem;Education and Outreach;Environment;Evolution;Feedback;Genes;Genetic Heterogeneity;Genomics;Goals;Heterogeneity;High Performance Computing;Hour;Lead;Letters;Libraries;Malignant Neoplasms;Maps;Mediating;Memory;Metaphase;Methods;Nature;Normal Cell;Oncogenes;Optics;Pathogenicity;Research;Resources;Running;Sampling;Stains;Structure;Tumor Promotion;Visualization;Work;anticancer research;automated segmentation;chromothripsis;cloud platform;computational platform;computer infrastructure;deep neural network;design;extrachromosomal DNA;genome sequencing;improved;nanopore;novel;novel therapeutics;outreach;patient prognosis;reconstruction;single molecule;supercomputer;technology platform;tool;tumor;user-friendly;whole genome Software and algorithms for elucidating the structure function and evolution of extrachromosomal DNA Project NarrativeIncreased activity of cancer-causing genes (onco-genes) is often due to increased copy numbers mediatedby extrachromosomal DNA (ecDNA). We propose to enhance our software and algorithms for elucidatingthe structure function and evolution of ecDNA and make them available to the research community as user-friendly tools. The resulting resource will enable advances in ecDNA biology and help identify new therapeuticvulnerabilities in currently intractable cancers. NCI 10704060 8/9/23 0:00 RFA-CA-20-009 5U24CA264379-03 5 U24 CA 264379 3 "LI, JERRY" 9/1/21 0:00 8/31/26 0:00 ZCA1-RTRB-R(M3) 7612243 "BAFNA, VINEET " Not Applicable 50 BIOSTATISTICS & OTHER MATH SCI 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF ARTS AND SCIENCES 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 611201 NCI 463671 259835 Project SummarySomatic copy number amplification (SCNA) of tumor promoting oncogenes and focal copy number amplifi-cations specifically are a major driver of cancer pathogenicity. Recent results have revealed that that focaloncogene amplification is mediated to a large extent by extrachromosomal DNA (ecDNA) i.e. large (1.3 Mbon average) highly amplified oncogene-containing circular molecules that occur in nearly 25% of cancersacross all sub-types but rarely in normal cells. Unresolved questions regarding the formation evolution het-erogeneity and pathogenicity of ecDNA are becoming central to uncovering vulnerabilities that can be targetedfor diagnostics and therapy. The proposed project will enhance and disseminate Software and algorithmsfor elucidating the structure function and evolution of extrachromosomal DNA. Specifically we will (1) de-velop CAPER (a Community Accessible Pipeline for EcDNA Reconstruction) by leveraging the GenePatternecosystem to provide an easy point and click interface to running the CPU memory and storage heavy soft-ware; (2) design and implement novel algorithmic improvements to the CAPER work flow including supportfor long-reads and integration of Omics data; and (3) enable the broad adoption of CAPER through strategiccollaborations outreach and education. 611201 +No NIH Category available 3-Dimensional;Address;Affect;BRCA mutations;BRCA1 gene;BRCA2 gene;Biological Markers;Breast;Breast Cancer Patient;Cancer Patient;Cell Culture Techniques;Cell division;Cisplatin;Clinic;Clinical;Clinical Treatment;Clinical Trials;Clinical effectiveness;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Gene;DNA biosynthesis;DNA replication fork;Data;Defect;Double Strand Break Repair;Drug Combinations;Drug Controls;Drug Efflux;Ensure;Enzymes;Equilibrium;Genes;Genetic;Genetic Recombination;Genomic Instability;Genomics;Goals;Ionizing radiation;Malignant Neoplasms;Malignant neoplasm of ovary;Metastatic breast cancer;Mutate;Mutation;Organoids;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Prevalence;Proteins;Proteome;Proteomics;Research;Resistance;Safety;Testing;Therapeutic;Therapeutic Intervention;Treatment Efficacy;Tumor Tissue;Work;biological adaptation to stress;brca gene;cancer cell;cancer therapy;cell growth;clinical investigation;clinically relevant;genetic analysis;improved;in vitro Model;inhibitor;kinase inhibitor;malignant breast neoplasm;mutant;neoplastic cell;patient derived xenograft model;patient response;pre-clinical;prevent;repaired;replication stress;resistance mechanism;response;restoration;side effect;therapeutic evaluation;triple-negative invasive breast carcinoma;tumor;tumorigenesis Targeting and DNA damage response in breast cancer PROJECT NARRATIVE: TARGETING DNA DAMAGE RESPONSES IN BREAST CANCER Poly-ADP-ribose polymerase (PARP) inhibitors are useful in the treatment of cancers with defects in select DNA repair mechanisms. This project will test the hypothesis that fork protection is an important determinant of therapeutic efficacy of PARP inhibitors identify mechanisms of resistance and test therapeutic strategies to overcome resistance. NCI 10704059 8/8/23 0:00 PAR-18-313 5P50CA098131-21 5 P50 CA 98131 21 8/7/03 0:00 7/31/24 0:00 ZCA1-RPRB-7 8643 2436424 "CORTEZ, DAVID K" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 325240 209858 115480 PROJECT SUMMARY/ABSTRACT: TARGETING DNA DAMAGE RESPONSE IN BREAST CANCER The increased genome instability caused by DNA repair defects can be exploited using synthetic lethal approaches. For example poly-ADP-ribose polymerase (PARP) inhibitors including olaparib have been approved to treat breast and ovarian cancer patients harboring mutations in BRCA1 or BRCA2. These drugs are thought to work by targeting defects in homology-directed repair (HR) of double-strand breaks (DSBs). However HR proteins including BRCA1 and BRCA2 moonlight to regulate replication fork stability and there is increasing evidence that these replication fork functions can be important determinants of PARP inhibitor outcomes independently of HR. Importantly PARP inhibitor resistance is an increasing clinical problem. Thus defining clinically relevant resistance mechanisms biomarkers of resistance and ways to overcome or prevent resistance are important research goals. This proposal addresses these issues both at the mechanistic and patient levels. Our overall goal is to improve patient outcomes by defining the mechanisms by which HR proteins regulate replication fork stability understanding the contribution of replication fork dynamics to PARP inhibitor sensitivity and identifying drug combinations that can be used to overcome resistance. We will use cell culture and patient-derived xenograft models to define mechanisms that influence PARP inhibitor sensitivity utilize patient-derived 3D-ex vivo organoid cultures to examine mechanisms of PARP inhibitor resistance and explore rational drug combinations that can overcome resistance mechanisms in clinical trials. Completing these studies will test the hypothesis that fork protection is an important determinant of therapeutic efficacy of PARP inhibitors identify therapeutic strategies to overcome resistance and potentially provide a rationale for expansion of PARP inhibitor use for clinical investigation and treatment. +No NIH Category available Address;Affect;Bioinformatics;Biological Assay;Biological Markers;Biological Specimen Banks;Biometry;Breast;Cancer Center;Cancer Patient;Cells;Cellular Assay;Cellular Immunity;Clinical;Clinical Research;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Correlative Study;Data Set;Effectiveness;Ensure;Flow Cytometry;Future;Gene Expression;Genetic;Genetic Markers;Genetic Polymorphism;Genomics;Genotype;Goals;Haplotypes;Health;Hematology;Histopathology;Image;Imaging Techniques;Immune;Immune checkpoint inhibitor;Immune system;ImmunoPET;Immunofluorescence Immunologic;Immunologic Markers;Immunologic Monitoring;Immunology procedure;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Inflammatory;Informatics;Intervention;Knowledge;Malignant Neoplasms;Measurement;Methods;Mission;Molecular;Mus;Oncology;Other Genetics;Pathology;Patients;Pattern;Phenotype;Population;Process;Quality Control;Resources;Safety;Sampling;Scientific Inquiry;Solid;Specimen;Standardization;Structure;T cell receptor repertoire sequencing;Technology;Therapeutic;Tissues;Toxic effect;Tumor Immunity;United States National Institutes of Health;Universities;anti-tumor immune response;biomarker identification;cancer clinical trial;cancer imaging;cancer immunotherapeutics;cancer immunotherapy;cancer therapy;cancer type;clinical efficacy;clinically relevant;cytokine;exome sequencing;genetic analysis;genetic signature;imaging science;immune checkpoint blockade;immune imaging;immune resistance;immune-related adverse events;immunotherapy clinical trials;immunotherapy trials;improved;in vivo;innovation;malignant breast neoplasm;murine antibody;next generation;participant enrollment;patient response;phase 1 study;preclinical study;predictive marker;rational design;resistance mechanism;response biomarker;success;transcriptome sequencing;tumor;tumor-immune system interactions Immuno-Phenotyping Core PROJECT NARRATIVE: IMMUNOPHENOTYPING COREIn concordance with the mission statement of NIH this proposal seeks to obtain knowledge of cancer therapyand cancer management by generating clinically pertinent biomarkers derived from samples from theVanderbilt-Ingram Cancer Center SPORE in Breast Cancer clinical trials. The Immunophenotyping Core willcharacterize these biospecimens for the purpose of enhancing the health of cancer patients. NCI 10704047 8/8/23 0:00 PAR-18-313 5P50CA098131-21 5 P50 CA 98131 21 8/7/03 0:00 7/31/24 0:00 ZCA1-RPRB-7 8639 8932513 "KIM, YOUNG J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 173864 102301 71611 PROJECT SUMMARY/ABSTRACT: IMMUNOPHENOTYPING COREThe promising clinical efficacy of immune checkpoint inhibitors for a significant number of cancer types has beendogged by inconsistent biomarkers incomplete toxicity profiles and non-validated correlative studies that havenot fostered next generation of clinical trials based on clear mechanistic studies to address immune resistancemechanisms. For breast cancer immunotherapy-based trials have expanded but predictive biomarkers remainpoorly defined. Thus there remains an unmet need for a comprehensive characterization of clinically relevantbiomarkers for breast cancer immunotherapy-based trials. In this SPORE proposal we have introduced twoimmunotherapy-based trials (Projects 2 and 4) and another trial that can be interrogated for future combinationwith immune checkpoint inhibitors (Project 3). Given the critical need for a concerted and coordinated analysisplatform for immune monitoring and assessment we propose to establish an Immunophenotyping Core (IPC).We have both well established and state-of-the-art immunological assay platforms that can analyzebiospecimens collected from ongoing clinical trials to enable rational translational efforts of combinatorialimmunotherapy and to provide comprehensive clinical toxicity profiling on patients undergoing theseimmunotherapy trials. IPC proposes to provide validated analytic platforms to include CyTOF robust single cellTCR sequencing multispectral immunofluorescence flow cytometry whole exome and RNA sequencing.Vanderbilt has recently led the efforts to comprehensively characterize the clinical toxicity profile of immunecheckpoint inhibitors and we will synchronize these efforts to standardize immune toxicity profiling on patientsenrolled in breast cancer immunotherapy clinical trials. IPC will also incorporate translational technologies fromVanderbilt University Institute of Imaging Science (VUIIS) to promote immuno-imaging methods to advance non-invasive tumor correlative studies in conjunction with the proposed clinical trials. IPC will help to establishclinically relevant biomarkers and immune-toxicity profiles that can precisely define the therapeutic window forbreast cancer immunotherapeutic platforms and potentially define the next generation of breast cancerimmunotherapy-based studies. +No NIH Category available Activated Natural Killer Cell;Biology;Blocking Antibodies;Cell Communication;Cell physiology;Cells;Cellular biology;Clinical;Combined Modality Therapy;Cytolysis;Cytometry;Data;Desmoplastic;Epithelial Cells;Exhibits;Fibroblasts;Fibrosis;Flow Cytometry;Future;Genetic Transcription;Growth;Human;Human Cell Line;Image;Immune;Immunologics;Immunosuppression;Immunotoxins;In Vitro;Inflammatory;Innate Immune System;Invaded;Knowledge;Laboratories;Ligands;Link;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mica;Molecular;Mus;Myofibroblast;Natural Killer Cells;Outcome;Pancreatic Ductal Adenocarcinoma;Patients;Phenotype;Population;Property;Receptor Cell;Rest;Role;Survival Rate;System;T-Lymphocyte;Therapeutic;Therapeutic Agents;Therapeutic Effect;Tissue Microarray;Tumor Burden;Tumor Promotion;Tumor Tissue;Tumor Volume;Work;anti-tumor immune response;antitumor effect;cancer cell;cell motility;cytotoxic;fibroblast-activating factor;immune resistance;immunogenic;in vivo;mouse model;neoplastic cell;novel;novel therapeutic intervention;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic stellate cell;prevent;resistance mechanism;single-cell RNA sequencing;spatial relationship;tissue repair;translational potential;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions Pancreatic Stellate Cell (PSC) Engagement of Natural Killer (NK) cells in the Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment PROJECT NARRATIVETumor-promoting pancreatic stellate cells (PSCs) may suppress the ability of natural killer (NK) cells to attackmalignant pancreatic ductal adenocarcinoma (PDAC) cells therefore I aim to examine the molecularmechanisms that regulate the interactions of NK cells with fibroblast activation protein (FAP)+ expressing PSCs.I also will deplete FAP+ PSCs to determine if this unleashes NK cell mediated tumor lysis in vivo. Successfulexecution of this project will provide a novel therapeutic strategy to effectively treat PDAC. NCI 10704009 9/6/23 0:00 PA-21-051 5F31CA261125-02 5 F31 CA 261125 2 "BOULANGER-ESPEUT, CORINNE A" 9/1/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16500969 "MALCHIODI, ZOE XENOS" Not Applicable 98 INTERNAL MEDICINE/MEDICINE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 34994 NCI 34994 0 PROJECT SUMMARY/ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with a 5-year survivalrate of less than 10%. One of the hallmarks of PDAC is immune suppression which is mediated in part by aheterogenous cancer-associated fibroblast (CAF) population also termed pancreatic stellate cells (PSCs). PSCscan exist as both tumor-promoting and tumor-restrictive subpopulations. Our laboratory recently showed thathuman natural killer (NK) cells interact with and lyse activated PSCs via a NKG2D-MICA/B NK cell receptor-ligand interaction. NK cells are cytotoxic components of the innate immune system; their functions are highlyunderstudied in PDAC. Our laboratory also had made the novel and potentially important observationsthat activated cytotoxic NK cells are relatively abundant in the PDAC tumor microenvironment (TME)and that high expression of NK cell markers correlates with better PDAC patient survival. Based on theseobservations I hypothesize that one important role of PSCs is to divert NK cells from malignant epithelialPDAC cells in the tumor microenvironment (TME) protecting tumors from immune attack. Therefore thisprojects first aim is to explore the interactions between fibroblast activation protein (FAP)+ PSCs with NK cellsin PDAC. NK cell receptor-ligand interactions that regulate NK cell-mediated lysis of FAP+ PSCs will be furtherstudied in vitro. The spatial relationships between NK cells and FAP+ PSCs will also be defined using a humanPDAC tumor microarray by Imaging Mass Cytometry. The second aim is to examine the impact of NK cells andFAP+ PSCs on tumor growth. In a murine PDAC model FAP+ PSCs will be depleted using a FAP-specificcatalytic immunotoxin to assess the impact of FAP+ PSC depletion on PDAC and NK cell invasion phenotypeand function. NK cells will also be selectively depleted in a murine PDAC model in order to determine their impacton tumor growth FAP+ PSC phenotype and function in the PDAC TME. This work will employ single-cell RNAsequencing analysis to assess transcriptional changes in the PDAC TME as a function of these depletion studies.Combinations of NK cell enhancement/activation with FAP+ PSC depletion will define the potential translationalrelevance for future therapy strategies. Successful completion of these aims will elucidate the relevance of NKcell-PSC interactions in PDAC and will lay the groundwork for exploiting the innate immune system to increasethe efficacy of the anti-tumor immune response. 34994 +No NIH Category available ALK gene;Accounting;Address;Autoantibodies;Biological Assay;Biological Markers;Biology;Blood;Child;Childhood;Childhood Lymphoma;Chromosome abnormality;Clinical;Clinical Trials;Detection;Development;Disease;Disease Progression;Early identification;Enrollment;Future;Genetic;Goals;Human;Immune response;Inflammatory Pseudotumor;Ki-1 Large-Cell Lymphoma;Lead;Lesion;Lymphoma;Malignant Neoplasms;Malignant neoplasm of lung;Mature T-Lymphocyte;Mediating;Methods;Modeling;Molecular;Monitor;Mutation;NPM1 gene;Neuroblastoma;Newly Diagnosed;Non-Hodgkin's Lymphoma;Patients;Pediatric Oncology Group;Plasma;Play;Population;Prognosis;Prognostic Marker;Prophase;Protein Tyrosine Kinase;Randomized;Receptor Protein-Tyrosine Kinases;Recurrence;Relapse;Research;Research Personnel;Residual Neoplasm;Residual Tumors;Resources;Risk;Role;Sampling;Subgroup;T-Cell Lymphoma;Therapeutic Agents;Time;Toxic effect;Transcript;anaplastic lymphoma kinase;base;chemotherapy;circulating biomarkers;cohort;crizotinib;digital;experience;high risk;minimally invasive;multidisciplinary;novel;novel therapeutics;peripheral blood;personalized diagnostics;phase 2 study;prognostic;prognostic significance;prognostic value;prognostication;relapse risk;response;specific biomarkers;t(2;5)(p23;q35);targeted treatment;treatment response;tumorigenesis Circulating biomarkers of ALK+ anaplastic large cell lymphoma Project Narrative: NPM-ALK+ anaplastic large cell lymphomas are aggressive forms of pediatric mature Tcell lymphoma and over 30% of patients experiences disease progression or relapse without robustprognostic biomarkers. The studies in this proposal will lead to development of simple blood-based robustand sensitive quantitatve assays that will help facilitate decisions about discontinuation of treatment andidentify patients with risk of relapse. NCI 10703855 11/23/22 0:00 PA-21-268 7R01CA255350-03 7 R01 CA 255350 3 "AGRAWAL, LOKESH" 10/1/22 0:00 7/31/25 0:00 Cancer Biomarkers Study Section[CBSS] 7518345 "LIM, MEGAN S." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 10/1/22 0:00 7/31/23 0:00 394 Non-SBIR/STTR 2022 388157 NCI 219877 168280 Project SummaryAnaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the ALK gene located on 5q35.Structural alterations including translocations copy number gains and activating mutations targeting ALKoccur in many types of human cancer including lung cancer non- Hodgkin lymphomas Spitzoidmelanocytic lesions neuroblastoma and inflammatory myofibroblastic tumor. In over 80% of pediatricanaplastic large cell lymphoma (ALCL) the most common form of mature T cell lymphoma in this populationthe chromosomal aberration t(2;5)(p23;q35) results in the expression of the constitutively active tyrosinekinase NPM-ALK. NPM-ALK positive lymphoma has served as a model for understanding ALK-mediatedoncogenesis and development of targeted therapies thus NPM-ALK related studies carry profoundimplications for the cancer field in general. Unfortunately even with current intensive combinedchemotherapy approximately 30% of patients experiences disease progression or recurrence within twoyears of treatment. However clinical or genetic factors that cause ALCL relapse are not known.Furthermore prognostic biomarkers that can be easily obtained using non-invasive methods have not beenclearly defined in patients receiving targeted therapies in ALCL. Our central hypothesis is that sensitive andspecific quantitative assessment of circulating NPM-ALK transcript using digital droplet (dd)PCR inconjunction with plasma levels of ALK auto- antibody will serve as unique disease-specific biomarkers thatwill provide an opportunity for assessment of response to therapy and lead to prognostic biomarkers thatmay identify patients with high risk for relapse. Using plasma samples from uniformly treated patientsenrolled in a Children's Oncology Group (COG) Phase II study of Brentuximab Vedotin and Crizotinib withnewly diagnosed ALCL we address our hypothesis through the following specific aims: 1) Determine theutility of ddPCR for minimal disease detection and disease monitoring in ALK+ ALCL 2) Determine theprognostic utility of anti-ALK immune response in ALK+ ALCL 3) Investigate the prognostic significance of amultivariate model combining ddPCR and immune response to ALK in patients with ALK+ ALCL. Thedevelopment of sensitive and precise assessment of minimal disseminated disease and/or minimal residualdisease will play an important role in management of patients with ALK+ ALCL and facilitate decisions aboutdiscontinuation of treatment and identifying patients at risk of relapse/progression. 388157 +No NIH Category available Address;B-Lymphocytes;Biologic Characteristic;Biological;Biological Assay;Biological Markers;Blinded;Blood;Blood specimen;Bone Marrow;Bone Marrow Involvement;Categories;Cells;Characteristics;Clinical;Clonality;DNA Sequence Alteration;Detection;Development;Diagnosis;Disease;Early Diagnosis;Future;Gene Mutation;Genes;Genomics;Goals;High-Throughput Nucleotide Sequencing;Immunoglobulin Gene Rearrangement;Immunoglobulin Genes;Lymphoma;Malignant Neoplasms;Modeling;Monitor;Mononuclear;Mutate;Mutation;Mutation Analysis;Mutation Detection;Operative Surgical Procedures;Patients;Performance;Peripheral Blood Involvement;Peripheral Blood Mononuclear Cell;Population;Prospective cohort;Recurrence;Research;Residual Neoplasm;Retrospective cohort;Risk;Sampling;Spleen;Splenectomy;Splenic Tissue;Techniques;Testing;Tissues;Training;Tumor Tissue;accurate diagnosis;base;clinical diagnosis;cohort;diagnostic accuracy;disease diagnosis;early detection biomarkers;exome sequencing;genome sequencing;genomic aberrations;genomic biomarker;immunohistochemical markers;improved;novel;peripheral blood;prospective;virtual;whole genome Genomic biomarkers of splenic lymphoma Project Narrative: Splenic marginal zone lymphoma is the most common form of cancer arising in thespleen. Current diagnosis is based on histopathologic criteria and requires splenectomy despite the fact thatvirtually all cases involve peripheral blood. We and others have recently determined the genomic aberrationsthat characterize this disease and propose to employ stateof-the-art and sensitive genomic sequencingapproaches to achieve early and accurate disease diagnosis. The studies in this proposal will lead todevelopment of simple blood-based assays that will improve early detection and promote implementation ofearly and appropriate treatment. NCI 10703846 12/2/22 0:00 PA-21-268 7R01CA255655-03 7 R01 CA 255655 3 "SORBARA, LYNN R" 10/1/22 0:00 11/30/25 0:00 Cancer Biomarkers Study Section[CBSS] 6097193 "ELENITOBA-JOHNSON, KOJO S. J." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 10/1/22 0:00 11/30/22 0:00 394 Non-SBIR/STTR 2022 194502 NCI 109888 84614 PROJECT SUMMARYGENOMIC BIOMARKERS OF SPLENIC LYMPHOMASplenic marginal zone lymphoma (SMZL) is the most common form of primary cancer in the spleen. SMZLtypically involves the bone marrow and peripheral blood (PB) at presentation. The diagnosis is invariablyestablished in late stages of disease via a splenectomy which is a surgical procedure carrying major risk.Additionally the diagnosis of SMZL is subjective because there are no specific histopathologic orimmunohistochemical biomarkers of the disease. Consequently early diagnosis of SMZL is challenging andnot achieved in most clinical scenarios. Further SMZLs are among the least reproducibly diagnosed categoryof lymphomas. The suboptimal diagnostic accuracy necessitates the development of qualitative and objectivebiomarkers of SMZL. Importantly while all cases of SMZL are characterized by PB involvement at diagnosishowever this biologic feature has not been leveraged for the reliable early detection of the disease. Usingwhole genome and exome sequencing we and others defined the genomic landscape of SMZL and identifiedrecurrently mutated genes in SMZL. An unmet clinical need is the development of reliable biomarkers for theearly and accurate diagnosis of the disease based on the characteristic genomic alterations of SMZL. Wepropose in this application to develop a genomic-based approach that utilizes and validates peripheral blood asfor early and accurate diagnosis of the disease. The overall impact of the application is the establishment of aparadigm for early sensitive and accurate disease diagnosis by analysis of peripheral blood therebypermitting early and appropriate treatment for the disease. 194502 +No NIH Category available Address;Aggressive Clinical Course;Antineoplastic Agents;Behavior;Biological Assay;Biological Markers;Biological Process;Blood;CD4 Positive T Lymphocytes;CLIA certified;Chemicals;Clinical;Cutaneous T-cell lymphoma;Data;Detection;Development;Diagnosis;Diagnostic;Disease;Early Diagnosis;Exhibits;Flow Cytometry;Gene Expression;Goals;Histone Code;Histone Deacetylase Inhibitor;Histone Deacetylation;Histones;Individual;Indolent;Laboratories;Learning;Life Expectancy;Lymphoid;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Modeling;Modification;Mycosis Fungoides;Nature;Neoplasm Circulating Cells;Outcome;Pathogenesis;Patients;Peripheral;Pharmaceutical Preparations;Prospective cohort;Resources;Retrospective cohort;Sampling;Sezary Syndrome;Skin;Skin Cancer;Staging;T-Cell Lymphoma;Testing;Therapeutic Effect;Time;Tumor Burden;Validation;Variant;accurate diagnosis;base;biomarker signature;cohort;diagnostic accuracy;diagnostic biomarker;diagnostic criteria;diagnostic tool;improved;improved outcome;indexing;innovation;mortality;neoplastic cell;novel;patient response;predict responsiveness;predicting response;predictive marker;response;skin lesion;targeted treatment;treatment response Epiproteomics of Sezary Syndrome Project NarrativeCutaneous T-cell lymphomas (CTCL) are a common form of skin cancer with highly variable clinical behaviorand without robust tests that can be used for unequivocal diagnosis or predict who will have aggressivedisease or response to therapy. Szary Syndrome is an aggressive form of CTCL with poor outcomes andour laboratory recently developed a strategy to identify histone post-translational marks that will offer arobust strategy for provide better diagnostic tools and predict response to histone deacetylase inhibitors. Thestudies in this proposal will lead to development of simple blood-based assays that will improve earlydetection and predict response to therapies. NCI 10703845 2/9/23 0:00 PA-21-268 7R01CA251764-04 7 R01 CA 251764 4 "MCKEE, TAWNYA C" 6/1/20 0:00 5/31/25 0:00 Cancer Biomarkers Study Section[CBSS] 6097193 "ELENITOBA-JOHNSON, KOJO S. J." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 2/7/23 0:00 5/31/23 0:00 394 Non-SBIR/STTR 2022 528744 NCI 317035 211709 PROJECT SUMMARYEPIPROTEOME OF SEZARY SYNDROMEPeripheral T-cell lymphomas including cutaneous T-cell lymphomas (CTCL) are poorly understood andmany subtypes exhibit aggressive clinical course and high mortality with short (2-year) life expectancy afterdiagnosis. Poor understanding of mechanisms underlying the pathogenesis of CTCLs contributes tosuboptimal diagnostic subcategorization and lack of targeted therapies. Mycosis fungoides (MF) and Szarysyndrome (SS) are two major forms of CTCL. Clinical staging and outcome of MF and SS is dependent onthe quantity of neoplastic cells in the blood. While SS is an aggressive disease with poor overall survival(42.3% at 5 years and is by definition diagnosed at late stage disease there are many patients with lowtumor burden (Early-stage CTCL) who suffer from delay in diagnosis due to the subjective nature of thediagnostic criteria. The mean diagnostic delay (measured as the time from emergence of skin lesions to thediagnosis of SS) is long (4.2 year; median 2.8 years) with a significant variation (1 month to 32 years). Thesuboptimal diagnostic accuracy and imprecision of disease detection necessitates the developmentof qualitative and objective biomarkers of SS. Histone deacetylase inhibitors (HDACi) have beenintroduced as anti- cancer agents which achieve their therapeutic effect in part by inhibiting deacetylation ofhistones. However despite the fact that CTCLs including SS were the first diseases which received FDAapproval for treatment with HDACi responses to the drugs in each patient are markedly variable. An unmetclinical need is the absence of reliable biomarkers directly interrogating the histone PTMs that can predictresponse to the drugs. We recently developed a novel mass spectrometry (MS)-based strategy for unbiasedidentification of histone PTMs and demonstrated its applicability for the analysis of primary samples of SS.Importantly these epiproteomic profiling studies reveal distinctive histone PTM marks that distinguish SSfrom CD4+ T-cells from healthy individuals. It is our central hypothesis that epiproteomic modifications(the histone code) of SS can be utilized for the early diagnosis and as predictors of response toHDACi. Accordingly we propose to investigate the utility of MS-based epiproteomic profiling for the earlydiagnosis of SS and for the prediction of response to HDACi. The overall impact of this proposal is theestablishment of novel epiproteomic biomarkers that will improve outcomes particularly in aggressiveCTCLs. 528744 +No NIH Category available Aggressive Clinical Course;Behavior;Bioinformatics;Biological Assay;Biological Markers;Biometry;Blood;Classification;Clinical;Cutaneous T-cell lymphoma;DNA Sequence Alteration;Detection;Development;Diagnosis;Diagnostic;Disease;Early Diagnosis;Environment;Epigenetic Process;Exhibits;Gene Mutation;Genetic;Genomics;Goals;High-Throughput Nucleotide Sequencing;Indolent;Laboratories;Learning;Life Expectancy;Lymphoma;Measures;Methods;Modeling;Mutation;Mycosis Fungoides;Nature;Neoplasm Circulating Cells;Oncogenic;Outcome;Pathogenesis;Pathway interactions;Patients;Pennsylvania;Performance;Peripheral;Population;Prognosis;Prognostic Marker;Prospective cohort;Recurrence;Research;Research Personnel;Retrospective cohort;Sampling;Sezary Syndrome;Skin;Skin Cancer;Staging;Subgroup;T cell receptor repertoire sequencing;T-Cell Lymphoma;T-Cell Receptor Genes;T-Lymphocyte;Testing;Time;Tumor Burden;Universities;Variant;accurate diagnosis;base;chromatin remodeling;cohort;comparative;comparative genomic hybridization;diagnostic biomarker;diagnostic criteria;diagnostic panel;diagnostic tool;disorder risk;exome sequencing;genome sequencing;genomic biomarker;improved;indexing;leukemia;mortality;neoplastic cell;next generation sequencing;novel;patient subsets;prognostic;prognostic significance;prognostic tool;prognostication;risk stratification;skin lesion;specific biomarkers;targeted treatment;tumor;whole genome Genomic biomarkers for cutaneous T-cell Lymphoma Project Narrative: Cutaneous T-cell lymphomas are incurable forms of skin cancer with highlyvariable clinical behavior without robust genomic tests that can be used for early diagnosis orpredict who will have aggressive disease. Our laboratory recently identified genetic alterationsin CTCL that will offer us with a strategy for developing better diagnostic and prognostic tools.The studies in this proposal will lead to development of simple blood-based genetic assays thatwill improve early detection and predict their clinical behavior. NCI 10703843 11/21/22 0:00 PA-21-268 7R01CA238552-04 7 R01 CA 238552 4 "THURIN, MAGDALENA" 10/1/22 0:00 1/31/25 0:00 Cancer Biomarkers Study Section[CBSS] 7518345 "LIM, MEGAN S." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 10/1/22 0:00 1/31/23 0:00 394 Non-SBIR/STTR 2022 174591 NCI 109484 65107 PROJECT SUMMARYPeripheral T-cell lymphomas including cutaneous T-cell lymphomas (CTCL) are poorly understood and manysubtypes exhibit aggressive clinical course and high mortality with short (2-year) life expectancy afterdiagnosis. Poor understanding of mechanisms underlying the pathogenesis of CTCLs contributes tosuboptimal diagnostic subcategorization and lack of targeted therapies. Mycosis fungoides (MF) and Sezarysyndrome (SS) are two major forms of CTCL. Clinical staging and outcome of MF and SS is dependent onthe quantity of neoplastic cells in the blood. While SS is an aggressive disease with poor overall survival(42.3% at 5 years and is by definition diagnosed at late stage disease there are many patients with lowtumor burden (Early-stage CTCL) who suffer from delay in diagnosis due to the subjective nature of thediagnostic criteria. The mean diagnostic delay (measured as the time from emergence of skin lesions to thediagnosis of SS) is long (4.2 year; median 2.8 years) with a significant variation (1 month to 32 years).Thus there is a critical need for improved methods for early disease detection. Furthermore theidentification of genomic disease biomarkers that would establish early diagnosis and provide prognosticinformation would clearly have benefit for patients with this form of aggressive CTCL. Until recentlyrecurrent genetic alterations that can be exploited as diagnostic and prognostic biomarkers have not beendescribed in these tumors. Our laboratory and other investigators recently described the genomiclandscape of CTCL utilizing a comprehensive integrated strategy including whole genome sequencingwhole exome sequencing and array comparative gnomic hybridization. Highly recurrent gene mutationstargeting epigenetic and chromatin remodeling and JAK-STAT and other pathways were identified in pre-treatment samples of CTCL. Based on these results it is our central hypothesis that somatic alterationsinvolved in the pathogenesis of CTCL in conjunction with high-throughput sequencing (HTS) of the T-cellreceptor (TCR) can be utilized for early diagnosis and that genetic profiles and sensitive andquantitative detection of clonal T-cell populations can serve as prognostically-relevant biomarkers ofCTCL. Accordingly in Specific Aim 1 we propose to investigate the utility of a multivariate model based ontargeted next generation sequencing (NGS) and HTS-TCR assays for the diagnosis of ES-CTCL and Late-stage CTCL (SS). In Specific Aim 2 we will investigate the impact of the genetic mutations and HTS-TCRon the prognosis of ES-CTCL and SS using a retrospective cohort. In Specific Aim 3 we will assessthe performance of the multivariate model for assessing the prognosis of ES-CTCL and SS using aprospective cohort. The overall impact of this proposal is the development of targeted genomic assays thatwill lead to early and accurate diagnosis of CTCL and improve methods to assess early disease detectionand prognosis. 174591 +No NIH Category available Address;Bioinformatics;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CTLA4 gene;Carcinoma;Cell Nucleus;Cells;Clinical;Clinical Data;Combined Modality Therapy;Data;Down-Regulation;Epithelial Cells;Equilibrium;Family;Genomics;Human;IL6 gene;Immune;Immune checkpoint inhibitor;Immunosuppression;In Vitro;Infection;Interleukin-1;Interleukin-13;Interleukins;Link;Lung;Mediating;Messenger RNA;Modeling;Molecular;Mus;PD-1 blockade;Pattern;Play;Regulation;Regulatory T-Lymphocyte;Role;Signal Transduction;Skin;Solid Neoplasm;T-Lymphocyte;Testing;Therapeutic Effect;Thinness;Tissues;Treatment Efficacy;Tumor Cell Line;Tumor Escape;Tumor Tissue;Tumor-Derived;anti-tumor immune response;antitumor effect;base;cancer immunotherapy;cancer therapy;cytokine;design;exhaustion;immune checkpoint blockade;immunogenic;improved;in vivo;interleukin-21;interleukin-21 receptor;member;mouse model;neoplasm immunotherapy;neoplastic cell;novel;prevent;programmed cell death protein 1;receptor;response;tool;tumor;tumor growth;tumor microenvironment Study of the IL-33-driven immune cell organization underpinning responses to immune checkpoint blockade cancer therapy Understanding the immune cellular organization driven by IL33 in the TME open doors to rationale design ofnovel combinational therapy to meet the pressing clinical need for improvement of responses to current cancerimmunotherapy. NCI 10703824 11/23/22 0:00 PA-21-268 7R01CA254274-03 7 R01 CA 254274 3 "LIU, YIN" 9/13/22 0:00 5/31/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6955073 "LU, BINFENG " Not Applicable 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 9/13/22 0:00 5/31/23 0:00 396 Non-SBIR/STTR 2022 244207 NCI 163747 80460 The immune checkpoint blockade cancer therapy (ICB) can greatly prolong survival in responders.However significant improvement of the response rate of ICB is in urgent need. We have found that IL33 isexpressed in normal epithelial cells of lining tissues such as lung and skin but drastically down-regulated in high-grade tumor cells in multiple human carcinomas. These clinical data support the notion that down-regulation ofIL33 is a major mechanism of tumor immune evasion. How IL-33 contributes to responses to current ICB therapyis not explored. Interestingly our bioinformatics analysis revealed that the IL33 receptor ST2 mRNA isupregulated in human tumor tissues after successful PD-1 blockade treatment. Using mouse models we showedthat the IL33/ST2 signaling was required for therapeutic effect of ICB therapy. In addition we demonstrated thatIL33 was highly induced in immunogenic murine tumor cells during ICB tumor therapy and tumor-expressed IL33was required for responses to ICB therapy. Despite these strong evidence supporting an antitumor function ofboth endogenous and administered IL33 the underlying molecular and cellular mechanisms are not wellunderstood. Our preliminary data showed that ICB-induced tumor-expressed IL33 drove conspicuous immunecell re-organization in the tumor microenvironment (TME). We further demonstrated that the antitumor effect ofIL33 is dependent on DC1 and CD8+ T cells suggesting their role in anchoring the antitumor effect of IL33.Interestingly IL33 also led to accumulation of ST2+ Treg cells in the TME which might counteract the antitumoreffect of IL33 and maintain an immune equilibrium. We hypothesize that tumor-derived IL33 underpins responsesto ICB tumor immunotherapy through promoting a drastic reorganization of the immune cellular network in theTME. SA1 Determine how IL33 expression is induced in tumor cells by ICB tumor therapy. SA2. We will definehow IL33 organizes the immune cellular network that mediates responses to ICB tumor therapy. SA3. Determinethe mechanisms how ST2 signaling in regulatory T cells (Tregs) limits antitumor activities of IL33. 244207 +No NIH Category available Advanced Malignant Neoplasm;Affect;Ancillary Study;Area;Benchmarking;Benign;Biological Assay;Biopsy;Blood Tests;Cell Separation;Cells;Centrifugation;Certification;Chemistry;Chest wall structure;Clinical;Collection;Cytology;Cytopathology;DNA;Data;Diagnosis;Diagnostic;Evaluation;Experimental Designs;Formalin;Gene Frequency;Gene Rearrangement;Genes;Goals;Guidelines;Hematoxylin and Eosin Staining Method;Inflammatory;Laboratories;Libraries;Liquid substance;Literature;Lung;Malignant Neoplasms;Malignant Pleural Effusion;Measures;Microsatellite Instability;Molecular;Molecular Analysis;Mutation;Nucleic Acids;Oncogenes;Oncogenic;Paraffin Embedding;Pathologic;Pathologist;Patients;Plasma;Pleural;Pleural effusion disorder;Positioning Attribute;Preparation;Procedures;Process;Protocols documentation;Publishing;Reproducibility;Research;Sampling;Serum;Slide;Source;Specimen;Speed;Stains;Surface;Techniques;Temperature;Testing;Therapeutic;Thoracentesis;Time;Tissues;Tumor Tissue;Urine;Validation;Variant;cancer cell;cell free DNA;clinical practice;detection test;experimental study;gene panel;genetic testing;improved;insertion/deletion mutation;liquid biopsy;molecular pathology;multidisciplinary;mutant;neoplastic cell;next generation sequencing;reduce symptoms;research clinical testing;success;theories;time interval;tumor;tumor heterogeneity Comprehensive Analysis of Best Practices for Clinical Testing of Malignant Pleural Effusion Specimens PROJECT NARRATIVEA malignant pleural effusion (MPE) is an abnormal fluid collection between the lung and chest wall containingcancer cells that often develops in patients with advanced cancers. We hypothesize that cell-free DNA (cfDNA)within the supernatant fraction of an MPE represents an abundant accessible and efficient source of nucleicacids for downstream molecular testing. The goal of our project is to use our CLIA/CAP certified pan-cancergene panel to optimize and define best practices for pre-analytical processing of cfDNA from MPE for clinicalmolecular testing. NCI 10703794 9/5/23 0:00 PAR-22-049 1U01CA275514-01A1 1 U01 CA 275514 1 A1 "AGRAWAL, LOKESH" 9/5/23 0:00 8/31/28 0:00 ZCA1-TCRB-9(M1) 6865859 "DEVINE, WALTER PATRICK" "KHANAFSHAR, ELHAM ; VAN ZIFFLE, JESSICA " 11 PATHOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/5/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 369431 NCI 228750 140681 PROJECT SUMMARY/ABSTRACTPatients with advanced cancers often develop malignant pleural effusions (MPEs) a collection of fluid thatdevelops between the surface of the lung and the chest wall that contains malignant tumor cells and benigninflammatory cells. In many cases percutaneous or transbronchial tissue biopsies may be pauci-cellular ordifficult to obtain thus MPEs may be the only specimen available for pathologic evaluation and molecular testing.Thoracentesis removes this fluid alleviating symptoms and also providing diagnostic material that can be usedfor downstream molecular analysis. In current clinical practice the thoracentesis fluid is typically centrifuged andthe cell-rich pellet is used to generate a formalin fixed paraffin embedded (FFPE) cell pellet that is subsequentlyused to make a hematoxylin & eosin (H&E) stained slide for diagnosis along with additional unstained slides forancillary studies. Recent studies have highlighted the fact that pleural fluid samples often contain abundant cell-free DNA (cfDNA) within the supernatant fraction and this may represent an alternative source of DNA formolecular testing. Similar to cfDNA isolated from plasma cfDNA isolated from MPEs could in theory circumventthe problem of intra-tumoral heterogeneity and tissue accessibility while at the same time obviate the timeneeded to create a cell block and reduce/eliminate the labor-intensive steps of scraping and extracting DNA fromunstained slides. Despite its promise there are no established guidelines for the collection storage processingand molecular testing of cfDNA isolated from MPEs. Our proposal systematically tests several preanalyticalvariables as well as directly compares three different cfDNA isolation techniques to identify the best practices forprocessing cfDNA from MPEs. We predict that optimization and harmonization of the these preanalytical stepswill lead to reduced false negative results increased reproducibility improved efficiency and reduced turn-around-time in the testing of MPEs. We will leverage our collective expertise in cytopathology molecularpathology and test validation to develop standard operating procedures that can be easily adapted into existingclinical workflows. Finally we will validate these pre-analytical protocols using a CLIA/CAP certified multi-genesequencing assay. 369431 +No NIH Category available Affect;Bioinformatics;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;CTLA4 gene;Cancer Patient;Cell Nucleus;Cells;Combination Drug Therapy;Data;Development;Down-Regulation;Epithelial;Epithelial Cells;Family;Flow Cytometry;Genes;Genetic Transcription;Histologic;Human;Immune;Immune Tolerance;Immune response;Immunologic Surveillance;Immunotherapy;Infection;Inflammation;Interleukin-1;Interleukins;Link;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Microscopy;Modality;Modeling;Molecular;Monoclonal Antibodies;Mus;Mutate;Mutation;Paclitaxel;Plasmids;Regulatory T-Lymphocyte;Resistance;Role;Signal Transduction;Signaling Molecule;Site;Solid Neoplasm;TP53 gene;Testing;Th1 Cells;The Cancer Genome Atlas;Therapeutic;Therapeutic Effect;Tissues;Transgenic Mice;Translations;Treatment Efficacy;Tumor Escape;Tumor Immunity;Tumor Suppression;Tumor Suppressor Genes;Tumor Tissue;Work;anti-CTLA4;anti-PD-1;anti-tumor immune response;base;cancer immunotherapy;cancer survival;cancer therapy;cell mediated immune response;chemotherapy;clinically relevant;cytokine;cytotoxic;gain of function;gene delivery system;gene therapy;genetic approach;high dimensionality;immune checkpoint blockade;immunogenic;improved;loss of function;lung cancer cell;lung tumorigenesis;member;mouse model;neoplasm immunotherapy;neoplastic cell;novel;overexpression;programmed cell death protein 1;resistance mechanism;response;systemic toxicity;tumor;tumor growth;tumor microenvironment;tumor progression;tumorigenesis Study of Interleukin 33 as a new immunotherapy of lung cancer NarrativeCancer immunotherapy has been shown recently to be a promising modality of cancer therapy. Currentproposal is aim to boost antitumor immunity by delivering a potent antitumor cytokine IL-33 to cancer tissues. NCI 10703786 2/17/23 0:00 PA-21-268 7R01CA239716-05 7 R01 CA 239716 5 "BOURCIER, KATARZYNA" 9/13/22 0:00 6/30/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6955073 "LU, BINFENG " "LI, SONG " 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 9/13/22 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2022 266925 NCI 191456 75469 The immune suppressive tumor microenvironment (TME) has limited the response rate of Immune checkpointblockade (ICB) therapy. Lack of immune stimulatory danger signal molecules in TME can be a major factorcontributing to resistance to tumor immunotherapy. Therefore reprogramming the TME by over-expression ofalarmin represents a novel and promising tumor immunotherapy. We have found that IL-33 which is adanger signal is expressed in normal lung epithelial cells but drastically down-regulated in human malignantlung cancer cells. Our bioinformatics analysis of the TCGA data has suggested that loss of tumor protein p53(TP53) is responsible for IL-33 down-regulation in epithelial cells during tumorigenesis of multiple humancancers. In addition IL-33 expression was reduced in p53 deficient compared to p53 WT murine lung tumorcells. These data suggest that down-regulation of IL-33 is a major mechanism of tumor immune evasion. Usingmouse tumor models we demonstrated that IL-33 was highly expressed in immunogenic murine tumor cellsand its level could be further increased during ICB tumor therapy. Importantly we showed that the ST2/IL-33Rsignaling was required for therapeutic effect of ICB therapy. Furthermore we showed that tumor tissueexpression of IL-33 synergized with both chemotherapy and ICB in inhibiting lung tumor growth. And theincreased therapeutic efficacy was associated with increases in function and number of CD103+CD8+ T cellsas well as decreases in Treg. We hypothesize that a novel immunotherapy based on reprogramming TME byalarmin IL-33 synergizes with chemotherapy and ICB immunotherapy through promoting tumoralCD103+CD8+ T cells. SA1. Test the hypothesis that loss of the tumor suppressor gene p53 causes the down-regulation of epithelial IL-33 expression leading to reduced tumor immune surveillance of lung tumor andaccelerated lung tumor progression. SA2. We will focus on development of an improved therapy that is basedon codelivery of IL-33 expressing plasmid and paclitaxel (PTX) alone or in combination with either PD1 mAbsor CTLA-4 mAbs-based ICB. 266925 +Cancer; Clinical Research; Prevention Affect;Asian population;Award;Baltimore;Basic Science;Behavior;Biology;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Catchment Area;Cigarette;Cities;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Comprehensive Cancer Center;County;Dentistry;Detection;Discipline of Nursing;Doctor of Medicine;Faculty;First Independent Research Support and Transition Awards;Flow Cytometry;Funding;Future;Genomics;Grant;Head Cancer;Human;Image;Institutes;Investigational Therapies;Investments;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maryland;Medical;Medical center;Middle School Student;Minority;Minority Groups;Mission;Molecular;Molecular Biology;Names;National Cancer Institute;Neck Cancer;Participant;Pathology;Patient Care;Patients;Pharmacy Schools;Pharmacy facility;Population;Population Research;Population Sciences;Positioning Attribute;Prevention;Prevention Research;Prevention strategy;Public Health Schools;Reporting;Research;Research Activity;Research Design;Research Personnel;School Dentistry;School Nursing;Schools;Screening for cancer;Services;Structure;Students;System;Talents;Therapeutic;Therapeutic Trials;Training;Translational Research;Translations;Underrepresented Minority;Universities;Work;acronyms;anticancer research;biobank;cancer care;cancer health disparity;cancer therapy;clinical care;clinical phenotype;clinically relevant;college;community based research;design;fundamental research;health disparity;hormone related cancer;innovation;medical schools;member;minority communities;mortality;multidisciplinary;neoplasm immunotherapy;news;prevent;programs;racial and ethnic;racial diversity;science education;standard of care;structural biology;tumor immunology;tumor registry;virology UNIVERSITY OF MARYLAND GREENEBAUM CANCER CENTERSUPPORT GRANT 1.1 Project Narrative: OverallThe mission of the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center(UMGCCC) is to undertake innovative basic and clinical and population research that will impact theunderstanding and treatment of cancer around the world and to provide state-of-the-art clinical care to cancerpatients in Maryland and beyond. NCI 10703756 9/15/22 0:00 PAR-20-043 3P30CA134274-15S3 3 P30 CA 134274 15 S3 "BELIN, PRECILLA L" 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 1967833 "CULLEN, KEVIN J." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 397 Research Centers 2022 251835 NCI 163000 88835 1.0 Abstract: OverallOur strategy at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center(UMGCCC) is to take advantage of discoveries in basic cancer biology in conjunction with clinical populationand prevention research to (a) develop and apply innovative therapeutic and preventive strategies to cancerpatients (b) describe the molecular mechanisms involving specific clinical phenotypes and behaviors (c) applydiscoveries and strategies to the Maryland community with a specific focus on cancer disparities and (d) providetraining in cancer biology and cancer care for students fellows clinicians and staff. These strategies collectivelywill serve the clinical and research missions of the Cancer Center for the Maryland community well into thefuture. In this application UMGCCC seeks the second competitive renewal of the Cancer Center Support Grant(CCSG) which was first awarded to UMGCCC in August 2008; Comprehensive designation was awarded in2016. For this application UMGCCC is represented by 137 full and 88 associate members working in 5 researchprograms unchanged since our 2015 application. The application describes seven shared services. UMGCCCprovides an effective structure to support the multidisciplinary cancer research activities of this talented group ofinvestigators. Total direct cancer funding is $79.1 million with $14.2 million from the National Cancer Institute.Direct cancer funding has increased 70 percent in the last cycle. In 2019 UMGCCC served 3095 new cancerpatients. In the last funding cycle a total of 9702 patients participated in clinical trials. Fifty-six percent of allparticipants in clinical trials were minorities reflecting UMGCCC's unique position and mission to involve theminority community in state-of-the-art clinical and translational research. This includes 48.2 percentunderrepresented minorities as well as 7.8 percent Asians the latter reflecting clinical trials examining healthdisparities in that group. Underrepresented minority accrual to therapeutic trials is 34.7 percent. UMGCCCcontinues to make outstanding contributions to understanding cancer biology and important recent work fromUMGCCC labs and clinics is now the standard of care or in advanced clinical trials. The U.S. News & WorldReport ranking of U.S. cancer programs has named UMGCCC in the top 50 for 13 consecutive years. Reflectingremarkable and continued progress UMGCCC seeks to renew its CCSG to enhance and expand its efforts andsupport high-quality and clinically relevant cancer research. 251835 +No NIH Category available 3q29;Affinity;Affinity Chromatography;B cell differentiation;B-Cell Development;B-Cell Lymphomas;B-Lymphocyte Subsets;B-Lymphocytes;BCL2 gene;BCL6 gene;Biochemical;Biological;Biological Process;Birth;Cancer Etiology;Cell Differentiation process;Cell Line;Cell physiology;Cells;Cellular biology;Cessation of life;Characteristics;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Complement;Constitutional;Cullin Proteins;Data;Development;Event;F Box Domain;Family;Gene Targeting;Genes;Genetic;Genomics;Growth;Guanine Nucleotide Exchange Factors;Hour;Human;Knock-in;Knock-out;Lymphoma;Lymphomagenesis;MS4A1 gene;Malignant Neoplasms;Mediating;Molecular;Molecular Biology Techniques;Mus;Mutagenesis;Neoplasms;Oncogenic;Pathogenesis;Pharmacology;Play;Proteolysis;Proteomics;RNA;RNA Interference;Recurrence;Research;Resources;Role;Sampling;Structure of germinal center of lymph node;Tamoxifen;Testing;Time;Transgenic Mice;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumorigenicity;Ubiquitin-mediated Proteolysis Pathway;Update;Xenograft Model;cohort;genome sequencing;in vivo;insight;large cell Diffuse non-Hodgkin's lymphoma;member;mouse model;novel;novel therapeutic intervention;prognostic;proteogenomics;screening;small hairpin RNA;tandem mass spectrometry;targeted treatment;treatment strategy;ubiquitin ligase;ubiquitin-protein ligase;whole genome Role of FBXO45 in Diffuse Large B Cell Lymphoma Pathogenesis Project narrativeDeregulation of ubiquitin ligases and their substrates is increasingly being recognized to play asignificant role in the pathogenesis of cancer. In this proposal we will investigate theinvolvement of a ubiquitin ligase known as FBXO45 in the development of diffuse large B-celllymphoma the most frequent form of lymphoma death in the U.S. Our studies will lead to abetter understanding of the function of FBXO45 and offer insights into novel therapeuticstrategies for treatments of DLBCL. NCI 10703746 11/16/22 0:00 PA-21-268 7R01CA231021-05 7 R01 CA 231021 5 "JHAPPAN, CHAMELLI" 10/1/22 0:00 6/30/24 0:00 Molecular Oncogenesis Study Section[MONC] 6097193 "ELENITOBA-JOHNSON, KOJO S. J." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 10/1/22 0:00 6/30/23 0:00 396 Non-SBIR/STTR 2022 511096 NCI 288755 222341 PROJECT SUMMARYTHE ROLE OF FBXO45 IN DIFFUSE LARGE B-CELL LYMPHOMA PATHOGENESISDiffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma and represents themost common form of malignant lymphoma in the western hemisphere. The biologic eventsunderlying the pathogenesis of DLBCL are not completely understood. We have recentlyidentified functional inactivation of FBXO45 an E3 ubiquitin ligase in DLBCL. In thisapplication we will utilize transgenic mouse models to explore the biological roles forFBXO45 in B-cell differentiation and lymphomagenesis. Further we will employbiochemical and molecular biology techniques to better understand the role FBXO45 in thepathogenesis of DLBCL. Accordingly we propose in the first aim of this application to utilizenewly created transgenic mouse models to functionally interrogate the role of FBXO45 in B-cell development and lymphomagenesis. In the second aim we will identify the globalcellular substrates of FBXO45 in B cell contexts. These studies will establish the role ofFBXO45 in the pathogenesis of DLBCL and establish the mechanisms by which itsderegulation contributes to DLBCL. 511096 +Cancer; HIV/AIDS Academic Medical Centers;Administrator;Budgets;Cancer Center;Cancer Center Support Grant;Cells;Charge;Clinical Data;Clinical Protocols;Collaborations;Communication;Comprehensive Cancer Center;Data;Decision Making;Development;Documentation;Ensure;Environment;Equipment;Evaluation;Faculty Recruitment;Funding;Funding Mechanisms;Goals;HIV-1;Human Resources;Individual;Information Systems;Information Technology;Leadership;Malignant Neoplasms;Mission;Monitor;Outcomes Research;Pilot Projects;Process;Progress Reports;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Services;Strategic Planning;Vision;data management;experience;faculty support;meetings;member;operation;programs Cancer Center Administration Core n/a NCI 10703661 9/14/22 0:00 PA-20-272 3P30CA142543-12S1 3 P30 CA 142543 12 S1 "BELIN, PRECILLA L" 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 8576 1894038 "ARTEAGA, CARLOS L" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2022 250000 152439 97561 The overarching goal of the Simmons Comprehensive Cancer Center (SCCC) Administration is to provide anefficient and effective administrative environment that nurtures and supports the Center's mission and vision.Administration's specific goals are to deliver value-added support to Cancer Center members by providing stellaradministrative support and leadership in facilitating collaborative transdisciplinary and multi-investigatorresearch; decision-making data from its information technology platforms; strategic planning implementationand monitoring; and support for the other CCSG components essential to SCCC such as shared resourcesclinical protocol and data management developmental funds and planning and evaluation. Administration'sservices include: Management of the CCSG application progress reports and supplements Financial coordination and oversight including budgeting and management of philanthropic resources Management of the membership processes research and grants activities and SCCC space Coordination of pilot funding mechanisms Oversight and management of operational aspects of the shared resources Representation of SCCC among UTSW institutional entities and collaboration with their representatives Support for faculty recruitment retention promotion and tenure Coordination and documentation of Center meetings Human resource management for CCSG personnel +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Immunotherapy; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases 19 year old;Adjuvant;Adult;Aftercare;Age;Alabama;Archives;Biological;Biopsy;Brain Neoplasms;Cancer Etiology;Caregivers;Cells;Child;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Clinical;Clinical Research;Clinical Trials;Coupled;Cyclic GMP;Data;Development;Developmental Delay Disorders;Diagnosis;Diffuse intrinsic pontine glioma;Dose;Dose-Limiting;Embryonal Neoplasm of the CNS;Engineering;Ependymoma;Exclusion Criteria;Foundations;Future;G207;Genetic Transduction;Glioblastoma;Glioma;Herpesvirus 1;Immune;Immune checkpoint inhibitor;Immune response;Immunohistochemistry;Immunologics;Immunotherapy;In Vitro;Infection;Infiltration;Inflammatory;Infusion procedures;Institution;Investigation;Knowledge;Laboratories;Lead;Long-Term Survivors;Magnetic Resonance Imaging;Malignant neoplasm of brain;Measures;Meta-Analysis;Modality;Nature;Nervous System Physiology;Newly Diagnosed;Normal Cell;Oncogenic Viruses;Oncolytic;Orphan Drugs;Outcome;Patients;Pediatric Hospitals;Phase;Phase I Clinical Trials;Phase I/II Clinical Trial;Phase II Clinical Trials;Phase II/III Clinical Trial;Primitive Neuroectodermal Tumor;Process;Progression-Free Survivals;Psyche structure;Publishing;Quality of life;Radiation;Radiation Dose Unit;Radiation therapy;Recurrence;Recurrent disease;Reporting;Research Support;Safety;Sampling;Simplexvirus;Site;Small Business Innovation Research Grant;Specimen;Supratentorial Neoplasms;Survivors;Testing;Therapeutic;Toxic effect;Training;Transgenic Mice;Tumor-infiltrating immune cells;Universities;Virotherapy;Virus;anti-tumor immune response;antitumor effect;arm;base;brain tissue;chemotherapy;childhood cancer mortality;commercialization;effective therapy;efficacy trial;experience;immune activation;immune function;improved;improved outcome;in vivo;irradiation;medulloblastoma;mouse model;neoplastic cell;neurotoxicity;oncolytic herpes simplex virus;oncolytic virotherapy;patient derived xenograft model;patient population;phase I trial;phase II trial;pre-clinical;preclinical study;programs;radiological imaging;response;standard of care;targeted treatment;therapeutic effectiveness;tumor Phase II Clinical Trial of G207 HSV To Treat Children with High Grade Gliomas Treovir LLC is requesting Direct-to-Phase II SBIR support to conduct a Phase I/II clinical trial in 32 children withrecurrent high-grade malignant brain tumors to evaluate the safety and efficacy of a single intratumoral infusionof an oncolytic Herpes Simplex Virus G207 followed within 24 hrs with a single 5 Gy dose of radiation to thetumor. Based on a remarkable increase in survival of 10 children with recurrent gliomas coupled with a strikingimmune cell-related infiltration of their tumors after G207 therapy we believe that this combination virotherapy(G207 plus 5Gy radiation) will be proven to have improved efficacy leading to long-term survival responses withlittle to no serious toxicities. We have obtained Orphan Drug Designation for G207 for several types of pediatricbrain tumors and will seek Breakthrough Status Designation to accelerate the approval of G207 with radiationas a safe and effective therapy for children harboring these fatal malignant brain tumors. NCI 10703636 9/13/22 0:00 PA-19-273 3R44CA250883-02S1 3 R44 CA 250883 2 S1 "EVANS, GREGORY" 9/1/20 0:00 11/30/23 0:00 Special Emphasis Panel[ZRG1-OTC-L(12)B] 16151077 "GILLESPIE, GEORGE YANCEY" Not Applicable 7 Unavailable 117087257 P3MKE8JK22Q8 117087257 P3MKE8JK22Q8 US 40.009959 -75.240485 10055553 "TREOVIR, INC" Birmingham AL Domestic For-Profits 352031865 UNITED STATES N 1/1/22 0:00 11/30/22 0:00 395 SBIR/STTR 2022 1625 NCI 1625 0 Treovir LLC is requesting Small Business Innovation Research (SBIR) support to conduct a single arm Phase IIclinical trial in children (age 3-18 years) who have been diagnosed with recurrent or progressive high gradeglioma (HGG). We propose to determine efficacy of a cGMP-produced (clinical grade) G207 Herpes SimplexVirus (HSV) in children with recurrent HGG. Our rationale is based on a Phase I clinical trial of G207 in childrenwith recurrent HGG that has (1) established safety of intratumoral infusion of G207 HSV alone or with a 5Gyfraction of radiotherapy and (2) resulted in an apparent significant increase in overall survival. We have orphandrug designations for G207 HSV for treatment of HGG (glioblastoma multiforme Ependymomas)Medulloblastoma and Primitive Neuroectodermal Tumors (PNETs). G207 has been used safely in 3 clinicaltrials in 35 adults with recurrent HGG with 17 obvious radiographic responses and at least 2 long term survivors(>5.5 years) in a patient population with an expected median survival of 5.56.5 months. We have publishedcompelling preclinical data using in vitro cultures and mouse models of pediatric brain tumors that demonstratedan increased sensitivity to G207 compared with adult brain tumors. In children with HGG we have observedradiographic neuropathologic and/or clinical responses in 9 of 10 patients and a median survival of 12.2 months(95% CI=5.0519.4) with 3 patients surviving long-term (18.3 20+ and 32+ months). A recent meta-analysis(Kline et al. 2018) reported an average median survival of 5.6 months (95% CI=3.9-7.3) for 129 children withrecurrent HGG in 17 clinical trials. G207 is not just producing an oncolytic effect but is obviously eliciting a potentimmune inflammatory cell-based response. Immunohistochemical examination of 4 paired samples (pre- vs.post-virus tumor) revealed extensive infiltration of immune-related inflammatory cells in all 4 post-treatmenttumor even 5 months post-G207. We propose that G207 infection of tumor cells converts an immunologicallycold tumor to a hot one. We propose to conduct a Phase II trial to determine efficacy of a single intratumoralG207 infusion plus a single 5Gy fraction of radiation. The lead institution will be Children's of Alabama Universityof Alabama at Birmingham together with other Pediatric Hospitals with experience in immunotherapy/virotherapyfor brain tumors. This Phase II trial will involve a total of 32 subjects accrued according to the sameinclusion/exclusion criteria as in the current Phase I trial (NCT02457845). The Recommended Phase II Dose(RP2D) will be 1 x 108 plaque-forming units (pfu) infused into multiple sites of the enhancing portions of the braintumor in a total volume of 2.4cc. The overall clinical PI will be Gregory K. Friedman MD who has conducted thePhase I trial with G207 provided by Treovir LLC. We hypothesize that 38 (both Phase I and II) subjects willprovide >85% power to detect a significant difference (p<0.05) in overall survival over standard of care therapiesfor recurrent HGG patients with few associated serious toxicities of G207. This trial will lay the foundations forsingle/multiple dosing clinical trials leading to eventual registration of G207 for commercialization. 1625 +Breast Cancer; Cancer; Genetics; Health Disparities; Lung; Lung Cancer; Minority Health; Women's Health Affect;Apoptosis;Biochemical;Biological Assay;Biological Models;Brain;Breast Cancer Treatment;Bypass;Cancer Patient;Cells;Chemicals;Cisplatin;Cyclin-Dependent Kinases;Data;Development;Disease;Disseminated Malignant Neoplasm;Dose;Drug Kinetics;Drug Targeting;Drug Tolerance;Drug resistance;ERBB2 gene;Enhancers;Enzymes;Epigenetic Process;Epithelial;Evaluation;FRAP1 gene;Fatty acid glycerol esters;Future;Genes;Genetic Transcription;Goals;Growth Factor Receptors;Image;Immune system;Immunocompetent;Investigational Drugs;KRAS2 gene;Lead;Ligands;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mesenchymal;Metabolism;Mission;Modeling;Molecular;Molecular Probes;Mutation;Neoplasm Metastasis;New Agents;Non-Small-Cell Lung Carcinoma;Oncogenes;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Property;Proteomics;Receptor Signaling;Reporter;Reporting;Research;Resistance;Resistance development;Role;Signal Transduction;Solubility;Stress;Structure;Testing;Transcription Alteration;Transcription Process;Transcriptional Regulation;Trastuzumab;United States National Institutes of Health;Work;Xenograft Model;acquired drug resistance;analog;anti-cancer;anti-cancer therapeutic;anticancer activity;base;cancer cell;chemotherapy;clinical development;combat;design;disability;epigenetic regulation;first-in-human;fluorescence imaging;immune resistance;immunoregulation;improved;in vivo;ineffective therapies;inhibitor;innovation;insight;kinase inhibitor;lung cancer cell;malignant breast neoplasm;mammary;neoplastic cell;novel;novel strategies;novel therapeutics;overexpression;patient derived xenograft model;phosphoproteomics;pre-clinical;prevent;programs;research clinical testing;resistance mechanism;response;safety assessment;single-cell RNA sequencing;small molecule;stressor;success;targeted agent;targeted treatment;therapy resistant;three-dimensional modeling;transcriptome sequencing;translational approach;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers Project NarrativeAlthough targeted anti-cancer therapeutics have improved patient outcomes benefits can be short-lived andnew approaches are needed to prevent the emergence of drug resistance. We aim to determine if CDK12/13inhibition can prevent drug resistance in combination with targeted agents and use our new inhibitors to revealthe complexities of acquired drug resistance. Thus the proposed research is directly relevant to NIHs mission to fuel discovery reduce illness and disability. NCI 10703529 9/15/22 0:00 PA-20-185 3R01CA262530-02S1 3 R01 CA 262530 2 S1 "AGYIN, JOSEPH KOFI" 7/12/21 0:00 6/30/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 9621640 "DUCKETT, DEREK RONALD" "HAURA, ERIC B.; MONASTYRSKYI, ANDRII " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 395 Non-SBIR/STTR 2022 74145 NCI 44003 30142 Project SummaryAlthough the development of targeted therapies has improved overall cancer patient survival adaptiveresponses by tumor cells can render these treatments ineffective. The development of agents that block adaptiveresponses thereby increasing treatment durability is desperately needed. We and others have demonstratedthat inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidatesto combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcometherapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overallobjective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiringand develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis isthat CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for thisproject posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticityas an adaptive stress resistance mechanism and (ii) elucidation of mechanisms underpinning compound actionwill offer a strong scientific framework that will facilitate future clinical development of these new agents forimproved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimizethe drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanismswhereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3)Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitorresistance in NSCLC. Accordingly using a battery of approaches we will: a) optimize key CDK12/13 inhibitorparameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translationalmechanisms whereby SR-4835 provokes resensitization to chemotherapy and c) validate cell-basedobservations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovativeas our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecularprobes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii)evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting moredurable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drivedrug resistance. The proposed research is highly significant and provides a strong scientific rationale for thecontinued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinningsof the master effectors of CDK12 and CDK13-driven signaling together with an optimized CDK12/13 inhibitorwill offer new opportunities for improved combination treatments for breast and lung cancer. 74145 +No NIH Category available Aberrant DNA Methylation;Acceleration;Age;Aging;Alcohols;Americas;Anatomy;Area;Behavioral;Biological;Biological Aging;Biological Markers;CD4 Lymphocyte Count;Cancer Etiology;Chronic;Clinical;Clinical Data;Collaborations;Country;Data;Dental Care;Dental Hygiene;Development;Early Diagnosis;Exclusion;Funding;Future;Goals;Grant;HIV;HIV therapy;HPV oropharyngeal cancer;Human Herpesvirus 4;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immune;Immune System Diseases;Incidence;Infection;Inflammation;Infrastructure;Integration Host Factors;Knowledge;Latin America;Latin American;Literature;Location;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Measures;Methods;Methylation;Natural History;Nested Case-Control Study;Oncogenic;Oral;Oral health;Patients;Periodontal Diseases;Persons;Policies;Population;Predictive Factor;Prevention;Prevention strategy;Primary Prevention;Prospective Studies;Recording of previous events;Reproducibility;Research;Risk;Risk Factors;Secondary Lesion;Secondary Prevention;Services;Sex Behavior;Specimen;Testing;Tobacco use;Tooth Loss;Tumor Suppressor Genes;Vaccination;Vaccines;Viral;Visit;Woman;biomarker identification;cancer risk;carcinogenesis;co-infection;disorder risk;efficacy evaluation;epigenetic marker;follow-up;high risk;human old age (65+);male;malignant mouth neoplasm;malignant oropharynx neoplasm;men;modifiable risk;multidisciplinary;novel;oral HPV;oral HPV infection;oral infection;premalignant;prevent;programs;progression risk;screening;social factors Oral HPV Research Among Latin Americans Living with HIV (ORAL - H Study) PROJECT NARRATIVEHuman papillomavirus (HPV) related oropharyngeal cancer (OPC) is increasing in incidence globally and isdisproportionately higher among people living with HIV (PLWH). Unlike cervical and anal cancers caused byHPV no screening tests are available for OPC. Therefore in this application we propose to study oral HPVnatural history among PLWH to obtain data urgently needed to inform the development of future prevention/earlydetection strategies. NCI 10703511 8/11/23 0:00 RFA-DE-22-003 5R01CA274950-02 5 R01 CA 274950 2 "LIDDELL HUPPI, REBECCA" 9/12/22 0:00 8/31/27 0:00 ZDE1-TO(15) 1872587 "GIULIANO, ANNA R." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 664434 NCI 499112 165322 ABSTRACTOropharyngeal cancer (OPC) is predominantly caused by HPV 16 and other oncogenic HPV types anddisproportionately impacts men and people living with HIV (PLWH). There is no reliable method to detect OPCpre-cancerous lesions for secondary prevention. Trials assessing efficacy of the 9vHPV vaccine to prevent OPCare ongoing by our team: NCI-funded U54 grant Research on Oral and Cervical Cancer HPV and HIV in theAmericas [ROCCHHA] Trial 201 among men with HIV and the Merck v503-049 trial among HIV-uninfectedmen. While HPV vaccination is a promising approach for the primary prevention of OPC vaccination may not beavailable to those in greatest need as most countries exclude males in their national programs and may not havepolicies for PLWH vaccination. Additional methods to prevent OPC and identify PLWH at highest risk forsurveillance are urgently needed particularly given that OPC incidence rates are significantly increasing in theUS and Latin America. To inform prevention strategies the identification of modifiable risk factors and easilymeasured biomarkers identifying those at highest risk is needed. Development of HPV-related OPC is multi-factorial. Sexual behavior leading to an oral oncogenic HPV infection is a necessary step. Regardless ofanatomic site of infection only a proportion of infections persist and progress to cancer. Multiple interplayingfactors influence viral persistence. We are among the few groups that have conducted large oral HPV naturalhistory studies contributing to this literature. Results from ours and other studies indicate that older age poororal health immune dysregulation such as occurs among PLWH and aberrant DNA methylation influence oralHPV persistence. Exacerbating this is the fact that PLWH are living to older ages which results in lifelong immunedysfunction that may accelerate biological aging increase risk of acquiring or reactivating a multitude ofinfections such as EBV and ultimately lead to reduced oncogenic viral control. Social factors compound thisscenario as PLWH have lower utilization of dental care and other services resulting in prolonged untreated oralinfections subsequent chronic oral inflammation periodontal disease and tooth loss factors that potentiallypromote oral HPV carcinogenesis and have independently been associated with HPV-OPC risk. We areconducting two large studies as part of our ROCCHHA grant among PLWH that obtain clinical data and oralgargle specimens at bi-annual study visits which we will leverage to study oral HPV natural history. The goal ofthis application is to define the natural history of oncogenic oral HPV infection among PLWH. The centralhypothesis of the Oral HPV Research Among Latin Americans Living with HIV (ORAL H2) Study is thatamong PLWH advanced biological age dental health and viral factors are associated with persistent oraloncogenic HPV. We will estimate oral HPV 16 and oncogenic HPV infection assess factors associated with viralpersistence and determine the optimal combination of biomarkers and behavioral factors that predict oraloncogenic HPV persistence. 664434 +No NIH Category available Accounting;Animals;Automobile Driving;Avidity;Binding;Biochemical;Biological Assay;Bioluminescence;Cell Death;Cell membrane;Cells;Cessation of life;Chemoresistance;Chronic;Complement;Complex;Computer Models;DNA Damage;Data;Data Set;Disease;EGF gene;Endocytosis;Endosomes;Engineering;Epidermal Growth Factor Receptor;Equilibrium;Exons;Glean;Glioblastoma;Goals;Grain;Hybrids;Hypoxia;Image;Impairment;In Vitro;Intervention;Least-Squares Analysis;Ligation;Location;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Measurement;Measures;Mediating;Membrane;Modeling;Monitor;Mutate;Mutation;NF1 mutation;Oncogenes;Oncogenic;Organelles;PIK3CA gene;PTEN gene;PTPN11 gene;Pathway interactions;Patients;Phenotype;Phosphorylation;Phosphotyrosine;Pinocytosis;Proliferating;Proteins;Proto-Oncogene Proteins c-akt;Proto-Oncogenes;Receptor Protein-Tyrosine Kinases;Regulation;Reporter;Research Personnel;Role;Route;Signal Transduction;Signaling Protein;Stress;System;Systems Analysis;Systems Biology;Testing;Transplantation;Tyrosine Phosphorylation;Work;combinatorial;data-driven model;epidermal growth factor receptor VIII;experimental study;immunocytochemistry;improved;in vivo;inhibitor;intermolecular interaction;interoperability;novel strategies;phosphoproteomics;predictive modeling;protein protein interaction;receptor-mediated signaling;refractory cancer;src Homology Region 2 Domain;tool EGFR signaling network adaptations to overcome RAS-induced membrane stress in glioblastoma n/a NCI 10703483 8/9/23 0:00 RFA-CA-21-048 5U54CA274499-02 5 U54 CA 274499 2 9/12/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8543 8200505 "LAZZARA, MATTHEW J" Not Applicable 5 Unavailable 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA Domestic Higher Education 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 364251 239404 124847 SUMMARYThe most common genetic alteration in glioblastoma (GBM) is amplification of the receptor tyrosine kinaseEGFR. In GBM some amplified EGFR further mutates to yield exon-deleted EGFRvIII which is constitutivelyactive and endocytosis impaired thereby signaling to effector pathways that favor survival over proliferation. Itis not clear why EGFRvIII is specifically selected for in this disease but GBM cells poorly tolerate unbridledsignaling from the EGFR effector RAS. Chronic RAS signaling places an oncogene-induced stress on cellmembranes that gives rise to excessive micropinocytosis and vacuolization concluding with an alternativeform of cell death called methuosis. The objective of this work is to reconcile EGFR amplification andEGFR/RAS-induced membrane stress through EGFRvIII and the signaling intermediates they share.Preliminary evidence suggests that EGFRvIII may achieve stress-relieving signaling adaptations by rewiringthe network of protein-protein interactions at different subcellular locations within GBM cells. Our hypothesis isthat EGFRvIII is a GBM-specific adaptive mechanism for overcoming methuosis. We will build a computationalmodel of EGFR/EGFRvIII signaling that tests this hypothesis by accounting for the network of proteininteractions and signaling relevant for the methuosis phenotype. The specific aims are to 1) define the keyintermolecular interactions in the EGFR signaling network and mechanistically predict the consequences ofnetwork adaptations to EGFRvIII expression; 2) map differential EGFR signaling network activation amongglioblastoma cells to the methuosis phenotype through a hybrid mechanistic and data-driven computationalmodel; and 3) test model predictions about signaling control of methuosis in vitro and in vivo using new tools tomonitor RAS-ERK and AKT activities concurrently and noninvasively. This project brings together a team ofinvestigators with complementary expertise in mechanistic and data-driven computational models of receptor-mediated signaling protein-protein interactions in vivo transplantations of GBM and treatment of GBMpatients using investigational approaches. By quantitatively testing the hypothesis about EGFRvIII as a keyregulator of oncogene-induced plasma membrane stress in glioblastoma our collaborative project holdspromise for identifying conceptually new approaches for driving alternative cell-death phenotypes in a highlychemotherapy-resistant cancer for which durable therapies are desperately needed. +No NIH Category available Acetyl Coenzyme A;Address;Anabolism;Area;Bacteria;Biochemical Pathway;Butyrates;Cellular Metabolic Process;Circulation;Citric Acid Cycle;Colorectal Cancer;Complex;Computer Models;Data;Dependence;Dietary Intervention;Environment;Event;Exhibits;Exposure to;Feeds;Generations;Glycolysis;Growth;HCT116 Cells;Hepatic;Hepatocyte;Heterogeneity;Human;Injections;Inner mitochondrial membrane;KRAS oncogenesis;KRAS2 gene;Liver;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of pancreas;Mammalian Cell;Membrane;Membrane Potentials;Metabolic;Metabolism;Metastatic Neoplasm to the Liver;Microbe;Mitochondria;Mitochondrial Matrix;Mitochondrial Proteins;Modeling;Mutation;Neoplasm Metastasis;Nutrient;Oncogenes;Oncogenic;Organelles;Oxidative Phosphorylation;Pancreatic Ductal Adenocarcinoma;Patients;Primary Neoplasm;Process;Proliferating;Publishing;Reaction;Research Project Grants;Role;Shapes;Signal Transduction;Site;Stress;Structure;Surface;System;Systems Analysis;Systems Biology;Testing;Tissues;Tumor Promotion;Volatile Fatty Acids;Work;Xenograft procedure;adenoma;cancer cell;cancer initiation;colon cancer cell line;colorectal cancer metastasis;fatty acid metabolism;gut bacteria;gut microbiota;host microbiota;human model;in vivo;knowledge integration;liver metabolism;metastatic colorectal;nutrient metabolism;predictive modeling;programs;tumor;tumor growth;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumor progression;tumorigenesis A systems-metabolism approach to identify mitochondria-dependent vulnerabilities in colorectal cancer n/a NCI 10703479 8/9/23 0:00 RFA-CA-21-048 5U54CA274499-02 5 U54 CA 274499 2 9/12/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8542 8831084 "KASHATUS, DAVID FRANCIS" Not Applicable 5 Unavailable 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA Domestic Higher Education 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 382698 239505 143193 PROJECT ABSTRACT/SUMMARYDuring tumorigenesis mitochondrial function is altered by fusion/fission dynamics that control organellestructure and impact overall cell metabolism. Signaling from oncogenic RAS fragments mitochondrial tubulesand causes metabolic changes that support tumor growth. However the precise role of these oncogene-driven mitochondrial changes on cancer metabolism is unclear especially when considering the diversemetabolic environments in which tumors develop. For example colorectal cancer (CRC) initiates in the gutwhere the microbiota produces high quantities of short chain fatty acids (SCFAs) that are metabolized bynormal colonocytes. During CRC tumorigenesis mutations in the KRAS oncogene occur at the transition toadenomas suggesting that mitochondrial adaptation in the gut may be critical for progression of primarytumors. And yet the primary site of CRC metastasis is the liver which provides a very different set of nutrientsfor metabolism and growth. Recognizing the complexity of metabolic networks both inside and outside adeveloping tumor we propose a systems biology approach to examine the role of RAS-induced mitochondrialfission in CRC. Specifically our objective is to identify metabolic adaptations that permit mitochondriallyfragmented CRC cells to grow in the unique metabolic environment of the gut and metastatic CRC cells togrow in the liver. While the fragmentation of the mitochondrial network can impact tumor metabolism inmultiple ways we hypothesize that RAS-induced mitochondrial fragmentation leads to hyper-compartmentalization of specific metabolic reactions within the mitochondrial matrix that depend on low-abundance mitochondrial proteins. We predict that these adaptations create unique vulnerabilities in CRCcells as they switch from normal SCFA metabolism to promote biosynthesis and energy generation. Thespecific aims are to 1) curate a metabolic model of human CRC cells that incorporates the system-wide impactof mitochondrial fragmentation and the availability of microbe-derived SCFAs; 2) instantiate metabolic modelsof CRC with data characterizing in vivo metabolic states to assess impacts of gut microbiota metabolism andmitochondrial fragmentation; and 3) evaluate the impact of metabolic adaptations to mitochondrial organellestress on CRC colonization and growth as liver metastases. Successful completion of this project will providea better understanding of CRC metabolism that may one day point to dietary interventions or shifts in the gutmicrobiota that predictably influence organelle adaptation. +No NIH Category available Ablation;Acute Myelocytic Leukemia;Address;Affect;Alleles;Automobile Driving;CRISPR/Cas technology;Cells;Chemicals;Clinical;Clinical Trials;Clonal Evolution;Coculture Techniques;Communication;DNA Sequence Alteration;DNMT3a;Dependence;Development;Disease;Disease Progression;Doctor of Philosophy;Epigenetic Process;Event;FDA approved;FLP recombinase;FLT3 gene;FLT3 inhibition;FLT3 inhibitor;Foundations;Future;Gene Frequency;Genes;Genetic;Genetic Transcription;Genomics;Goals;Grant;Head;Hematologic Neoplasms;Heterogeneity;Human;In complete remission;Intervention;Laboratories;Lead;Lesion;Leukemic Cell;Link;Maintenance;Malignant - descriptor;Malignant Neoplasms;Membrane;Memorial Sloan-Kettering Cancer Center;Mentors;Methods;Minor;Modeling;Molecular;Mutate;Mutation;Myeloid Leukemia;NPM1 gene;Oncogene Activation;Oncogenes;Oncogenic;Oncology;Outcome;Pathogenesis;Patients;Pharmaceutical Preparations;Phase;Postdoctoral Fellow;Predisposition;Process;Prognostic Marker;Protein Tyrosine Kinase;Receptor Protein-Tyrosine Kinases;Recurrent disease;Relapse;Reporter;Research;Research Institute;Resistance;Resources;Role;Signal Transduction;Site;Somatic Mutation;System;Technical Expertise;Testing;Therapeutic;Treatment Efficacy;anticancer research;career;career development;clinically relevant;efficacious treatment;epigenetic drug;epigenome;fitness;genetic epidemiology;genetic variant;improved;in vivo;inhibitor;insight;leukemia;leukemia treatment;leukemic transformation;leukemogenesis;member;mouse model;mutant;novel;novel therapeutics;patient subsets;programs;recombinase;relapse patients;research and development;response;skills;small molecule;success;therapeutic target;tool;tool development;treatment response;tumor microenvironment Interrogating oncogene-dependency and mutation order in FLT3 mutant AML PROJECT NARRATIVEWhile the spectrum of genetic mutations in myeloid leukemia has been comprehensively studied the relevanceof the diversity of mutations within a single patient remains a significant hurdle in delivering efficacious therapyto patients. The proposed research here will use mouse models to identify contexts in which oncogenic FLT3mutations are necessary for disease progression. These studies will provide insights into improved therapeuticstrategies for patients with FLT3-mutant acute myeloid leukemia. NCI 10703473 8/14/23 0:00 PA-19-130 5R00CA248460-04 5 R00 CA 248460 4 "KLAUZINSKA, MALGORZATA" 9/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11011862 "BOWMAN, ROBERT LYLE" Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 245326 NCI 153231 95769 PROJECT ABSTRACT/SUMMARYCANDIDATE: I am a postdoctoral fellow in the laboratory of Dr. Ross Levine in the Human Oncology andPathogenesis Program at Memorial Sloan Kettering Cancer Center. My previous PhD research offered me theopportunity to develop the experimental and computational skills necessary to assess cellular crosstalk in thetumor microenvironment. My current research extends these skills to the study of mutation order andoncogene-dependency in subpopulations of leukemic cells. To gain insights into these processes I developednovel multi-recombinase mouse models of oncogene-activation and dependency as well as new lineage tracingtools that allow for functional interrogation of clonal evolution. My proposed research will provide a strongfoundation for independent research following the K99 phase of this grant. My long-term career goal is toidentify molecular mechanisms driving leukemogenesis including interactions between AML subclones in vivoand the role of sequential mutational acquisition. To achieve these goals I have developed a career plan thatwill 1) bolster my technical skills and scientific scope 2) improve my presentation and communication skills 3)cultivate professional relationships and networking and 4) prepare me for mentoring future trainees.RESEARCH: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloidleukemia. Mutations in FLT3 are often found with low variant allele frequency suggesting these mutationsoccur as late subclonal events. Despite their presence as a minor clone FLT3 mutations are poor prognosticmarkers and the target of several recently approved clinical compounds. These inhibitors lead to sometransient clinical success yet patients invariably relapse and develop resistant calling into question thenecessity of FLT3 mutation in disease progression. I aim to determine the dependency of FLT3 mutations indisease and propose methods to assess the functional contributions of subclonal mutations to diseaseprogression. The specific aims are: 1) determining the genomic context for FLT3 oncogene-dependency inAML 2) identifying novel therapeutic vulnerabilities in FLT3-driven AML and 3) investigating the role ofmutation order and clonal crosstalk in leukemic disease.ENVIRONMENT: The Levine laboratory is a part of the Human Oncology and Pathogenesis Program(HOPP) at Memorial Sloan Kettering Cancer Center a state of the art cancer research institute. The Levine labis also a member of the Center for Epigenetic Research and the primary mentor Dr. Levine is the head of theCenter for Hematologic Malignancies. These affiliations provide a rich set of collaborative technical andscientific resources to execute the research and career development proposed here. 245326 +No NIH Category available Administrative Supplement;Administrator;Awareness;Biological Models;Charge;Communication;Communities;Complement;Coupled;Couples;Data;Data Set;Decision Making;Deposition;Ensure;Evaluation;Event;Face;Faculty;Funding Mechanisms;Future;Goals;Health system;Hearing;Individual;Institutionalization;Internet;Lead;Leadership;Logistics;Maintenance;Malignant Neoplasms;Mentors;Mentorship;Mission;Monitor;Names;Organelles;Output;Ownership;Pilot Projects;Postdoctoral Fellow;Productivity;Request for Applications;Research;Research Activity;Research Personnel;Resources;Role;Schedule;Scientist;Site Visit;Stress;System;Systems Analysis;Systems Biology;Time;Training;U-Series Cooperative Agreements;United States National Institutes of Health;University of Virginia Cancer Center;Vision;Voice;Woman;Work;anti-racism;anticancer research;career;cost;data management;data modeling;data sharing;disadvantaged background;expectation;experience;improved;marginalization;marginalized population;meetings;member;next generation;organizational structure;outreach;programs;racism;recruit;repository;success;synergism;timeline;virtual Administrative Core n/a NCI 10703472 8/9/23 0:00 RFA-CA-21-048 5U54CA274499-02 5 U54 CA 274499 2 9/12/22 0:00 8/31/27 0:00 ZCA1-RTRB-F 8538 9677317 "JANES, KEVIN A" Not Applicable 5 Unavailable 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA Domestic Higher Education 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 557044 344810 212234 PROJECT SUMMARY/ABSTRACTThe SASCO Administrative Core will bring together the activities of the Center under the leadership of theMPIs with the support of experienced staff for research center administration and data management. Wesupplement the Administrative Core with i) an Inclusion Lead that will monitor the Centers Plan to EnhanceDiverse Perspectives ii) a Leadership Team for centralized decision-making and iii) a Resource ManagementTeam in charge of data sharing and model accessibility. The intra-center pilot project program will bemanaged by the Leadership Team as a vehicle for welcoming junior faculty and postdoctoral fellows fromhistorically marginalized groups. The Administrative Core is conscientious about long-term stewardship of theCenter and has clear criteria for the External Advisory Board that it will recruit. Collectively the AdministrativeCore will facilitate communication and logistics among Center components and with the broader CancerSystems Biology Consortium. +No NIH Category available Adopted;Aneuploidy;Automobile Driving;Cancer Biology;Cancer Model;Cell Culture Techniques;Cell membrane;Cells;Cellular biology;Charge;Chromosomes;Chronic;Clinical and Translational Science Awards;Collaborations;Colorectal Cancer;Complex;Couples;Cultured Cells;Data;Decision Making;Dedications;Defect;Disease;Ecosystem;Education;Elements;Epidermal Growth Factor Receptor;Eukaryota;Faculty;Fostering;Genetically Engineered Mouse;Genomics;Glioblastoma;Goals;Growth;Image;Immunofluorescence Immunologic;Indirect Immunofluorescence;Institution;Joints;KRAS2 gene;Lead;Leadership;Length;Lesion;Life;Malignant Neoplasms;Malignant neoplasm of brain;Mentorship;Metabolic;Metaphase;Metastatic Neoplasm to the Liver;Mitochondria;Mitotic;Modeling;Mutation;NCI Center for Cancer Research;Neoplasm Metastasis;Oncogene Activation;Oncogenes;Oncogenic;Organelles;Pathway interactions;Phase;Phenotype;Pilot Projects;Play;Positioning Attribute;Primary Neoplasm;Process;Proliferating;Records;Recurrence;Research;Research Personnel;Research Project Grants;Resolution;Resource Sharing;Resources;Rest;Role;Secondary to;Signal Transduction;Site Visit;Standardization;Stress;Structure;System;Systems Analysis;Systems Biology;Testing;Training;Universities;Virginia;Vision;cancer cell;cancer type;career;cell type;clinical practice;cost;experimental study;feature detection;feature extraction;image registration;innovation;interoperability;learning strategy;malignant breast neoplasm;mitochondrial membrane;multidisciplinary;mutant;outreach;programs;repaired;residence;response;success;summer research;transcription factor;tumor;tumorigenesis;undergraduate research experience Systems Analysis of Stress-adapted Cancer Organelles (SASCO) Center PROJECT NARRATIVECancers cannot initiate or progress if their subcellular components are unable to overcome the stresses thataccompany uncontrolled proliferation and growth. This Center seeks a predictive understanding of subcellularadaptations that must take place to accommodate and subvert the stresses that naturally occur in response tocancer-causing genetic alterations. Successful models of such adaptations will lead to secondary inferencesabout where cancer cells become vulnerable as a result of their internal adaptations. NCI 10703471 8/9/23 0:00 RFA-CA-21-048 5U54CA274499-02 5 U54 CA 274499 2 "DUECK, HANNAH RUTH" 9/12/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M2) 9677317 "JANES, KEVIN A" "LAZZARA, MATTHEW J" 5 BIOMEDICAL ENGINEERING 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2081447 NCI 1320746 760701 PROJECT SUMMARY/ABSTRACTOncogene activation is modulated by normal subcellular compartments that execute specialized functionsrelated to hallmark cancer phenotypes. These organelles must adapt to oncogenic stress in order for tumorsto initiate and progress but there is little to no systems-level understanding of how such adaptations occur andwhat vulnerabilities might be created. The Systems Analysis of Stress-adapted Cancer Organelles (SASCO)Center at the University of Virginia will address this challenge by mechanistic modeling of organellar processesthat iterates with quantitative experiments in disease-relevant cell cultures and primary tumors. The workingSASCO Center hypothesis is that organelle-specific adaptation to oncogenic stress occurs through a fewcritical bottlenecks which become identifiable once the relevant signaling metabolic and transport pathwayshave been properly integrated. The Center brings together 14 investigators with primary and collaborativetrack records in cancer biology systems biology genetically engineered mouse models of cancer and clinicalpractice. Three Research Projects and one Shared Research Core will pursue a common research strategywhich leverages mechanistic models to test competing alternative hypotheses about how organelles adapt tostresses from proximal oncogenes that drive specific types of cancer. The Projects are organizedhierarchically as organelle stresses downstream of proliferation-inducing oncogenes. Project 1 will examinethe chromosome passenger complex and its regulated phase separation during metaphase as an organellethat senses and repairs spindle defects to suppress breast cancer aneuploidy driven by mitotic transcriptionfactors. Project 2 will evaluate the metabolic consequences of chronic mitochondrial fragmentation caused bymutant KRAS in primary colorectal cancers and secondary liver metastases. Project 3 will investigate localizedsignal-transduction rebalancing as a mechanism for alleviating plasma-membrane stress caused by EGFRamplification in glioblastoma. All Research Projects will rely on the High-Content Imaging & Analysis Core toobtain iterative multichannel immunofluorescence data with organelle-level resolution and quantification. TheSASCO Outreach Core amplifies ongoing programs at the University of Virginia to provide summer researchexperiences for undergraduates and faculty scholars from historically underrepresented backgrounds as wellas introductory systems biology modeling materials for clinicians across the Commonwealth of Virginia. TheSASCO Center will thus create a national headquarters for subcellular cancer systems biology within thebroader Cancer Systems Biology Consortium. 2081447 +No NIH Category available Acceleration;Address;Aftercare;Age;Age Years;Aging;American Society of Clinical Oncology;Archives;Area;Behavioral;Biological Markers;Blood;Blood specimen;Breast;Cancer Patient;Cancer Survivor;Cancer Survivorship;Clinical;Collection;Colorectal;Communities;Consensus;Data;Data Analyses;Databases;Development;Diagnosis;Elderly;Endometrial;Enrollment;Event;Female;Funding;Geriatric Assessment;Health;Home visitation;Impaired cognition;Infrastructure;Institute of Medicine (U.S.);Investments;Knowledge;Life;Longevity;Lung;Lymphoma;Malignant Neoplasms;Measurement;Measures;Medical;Methods;Newly Diagnosed;Older Population;Outcome;Ovarian;Participant;Patient Outcomes Assessments;Patient Self-Report;Performance;Phenotype;Physical Function;Population;Prevalence;Process;Protocols documentation;Psyche structure;Recurrence;Research;Research Design;Research Infrastructure;Research Personnel;Research Priority;Resources;Risk Factors;Safety;Second Primary Cancers;Silver;Solid Neoplasm;Specimen;Survivors;Tissues;Treatment Efficacy;Tsunami;Tumor Tissue;United States;Woman;Women's Health;age related;aging population;cancer diagnosis;cancer therapy;cohort;comorbidity;comparison group;design;follow-up;frailty;functional decline;functional loss;health assessment;health data;human old age (65+);infancy;leukemia;melanoma;neoplasm resource;older patient;performance based measurement;potential biomarker;resilience;social;survivorship;tumor;virtual Life and Longevity After Cancer (LILAC): The Women's Health Initiative Cancer Survivor Cohort PROJECT NARRATIVETo address compelling issues of cancer and aging we propose to enhance the Life and Longevity AfterCancer (LILAC) cohort by continuing to enroll older (70+ year old) cancer survivors from the Womens HealthInitiative (WHI) by establishing measures of frailty creating age-matched cancer-free controls and in a subsetof participants conducting a geriatric assessment and collecting a new post-diagnosis blood collection in asubset of participants to assess biomarkers of aging. Further by making these resources broadly availableLILAC will provide the research infrastructure needed to examine many emerging questions aroundaccelerated aging and resilience in cancer patients. NCI 10703462 8/23/23 0:00 PAR-17-233 5U01CA173642-11 5 U01 CA 173642 11 "GALLICCHIO, LISA M" 2/15/13 0:00 8/31/24 0:00 ZCA1-RTRB-4(M1) 1867583 "ANDERSON, GARNET L." "CAAN, BETTE J; PASKETT, ELECTRA D." 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1308977 NCI 876706 432271 SUMMARY/ABSTRACTThere are 16 million cancer survivors in the United States and approximately 60% are age 65 years and over.By 2040 it is estimated that the number of cancer survivors will grow to 26 million with 73% age 65 and olderand almost 50% age 75 and older. Despite this so-called silver tsunami of older cancer survivors there aresignificant knowledge gaps regarding how cancer and cancer treatment impacts the aging process. There isalso a growing consensus regarding the need for studies of cancer in older adults because of the prevalence ofcomorbidities functional losses cognitive impairment and frailty and particularly for those age 75 for whomthere are virtually no data. Studies are needed to better understand how cancer and its treatment interact withunderlying vulnerabilities which in turn impacts the feasibility safety and efficacy of interventions in thispopulation. The Life and Longevity After Cancer (LILAC) project is a cancer survivor cohort embedded withinthe Womens Health Initiative to support studies of cancer survivorship in an aging population. During the initialfunding period we developed the LILAC cohort of 13453 WHI cancer survivors who were diagnosed with oneof eight LILAC designated cancers: invasive breast colorectal endometrial melanoma leukemia lunglymphoma melanoma or ovarian. We collected information on first course of treatment clinical and patientreported outcomes as well as archival tissue from 4351 solid tumors. With a minimum of 20 years of data onthese women and a current age-range of 70 to101 years the LILAC population is poised to provide keyinformation on cancer and aging to advance our cancer and aging research agenda. To accomplish this wepropose to enhance the LILAC resource through several mechanisms designed to support analyses ofemerging questions. Specifically we propose: 1) To fill critical gaps in knowledge regarding the self-reportedphysical mental and social health of older female cancer survivors by continuing to enroll newly diagnosedsurvivors (N=2685) and follow the LILAC cohort; 2) To develop the analytic framework to assess trajectories ofaging including an accelerated aging phenotype in the WHI/LILAC database; 3) To establish cohorts of age-matched WHI participants with similar data who have remained cancer free to help us understand thediagnosis of cancer and its treatment on the trajectories of aging the accelerated aging phenotype and age-related comorbidities; 4) To obtain performance-based measures of physical function and new post-treatmentblood samples to assess potential biomarkers of accelerated aging; and 5) To maximize the use and impact ofthis resource. Given the aging of the US population the increase in the number of cancer survivors and theassociation between cancer and aging these strategic and timely investments in the LILAC infrastructure willhelp to fill many of these critical research gaps. 1308977 +No NIH Category available Address;Age;American;Barrett Esophagus;Biological Markers;Biometry;Biopsy;Cancer Center;Clinical;Columnar Metaplasia;Comprehensive Cancer Center;Computing Methodologies;Country;Data;Development;Diagnosis;Disease;Distal;Dysplasia;Environment;Environmental Exposure;Environmental Risk Factor;Epidemiology;Epigenetic Process;Esophageal Adenocarcinoma;Esophageal Tissue;Esophagus;Etiology;Funding;Gastroenterology;Gastroesophageal reflux disease;Gene Expression;Genetic;Genetic Predisposition to Disease;Genetic Risk;Genome;Genotype;Genotype-Tissue Expression Project;Goals;Guidelines;Heritability;Incidence;Individual;Indolent;Leadership;Length;Lesion;Life Style;Link;Malignant Neoplasms;Maps;Mediating;Mediation;Mediator;Meta-Analysis;Methodology;Methods;Modeling;Molecular;Molecular Abnormality;Molecular Probes;Multiomic Data;Non-Steroidal Anti-Inflammatory Agents;Obesity;Pathway interactions;Patients;Population;Predisposition;Prevalence;Prevention;Public Health;Publishing;Reflux;Research;Resources;Risk;Risk Factors;Risk Reduction;Role;Sample Size;Smoking;Specimen;Survival Rate;Susceptibility Gene;Tissues;analytical method;bead chip;biobank;cancer prevention;candidate validation;cohort;college;cost;deep neural network;epidemiologic data;epigenetic marker;epigenome;epigenome-wide association studies;epigenomics;genetic association;genetic risk factor;genome wide association study;genome-wide;high risk;high risk population;improved;innovation;methylome;multiple omics;novel;polygenic risk score;predictive marker;predictive modeling;prevent;preventive intervention;progression marker;rare cancer;risk prediction;risk prediction model;risk stratification;risk variant;screening;sex;trait;transcriptome;transcriptome sequencing;transcriptomic profiling;tumor progression Genetics Epigenetics and Risk Prediction for Esophageal Adenocarcinoma PROJECT NARRATIVEThis project integrates transcriptome and methylome of Barretts esophagus (BE) the key cancer precursor ofesophageal adenocarcinoma (EAC) with existing genetic and environmental risk factor data in genome-wideassociation studies. The goal is to identify new genetic and epigenetic loci underlying susceptibility anddevelop prediction models for EAC. Findings are anticipated to aid in the identification of individuals who are atelevated risk of EAC and may benefit most from preventive interventions ultimately helping to reduce thepublic health burden of this deadly cancer. NCI 10703461 8/28/23 0:00 PA-20-185 5R01CA266386-02 5 R01 CA 266386 2 "HANISCH, RACHEL ANN" 9/12/22 0:00 8/31/27 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 1861221 "KOOPERBERG, CHARLES L" "BUAS, MATTHEW FRANK" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 710221 NCI 570262 139959 PROJECT SUMMARY/ABSTRACTEsophageal adenocarcinoma (EAC) is one of the most lethal cancers with a 5-year survival rate less than20%. Incidence of EAC has risen sharply in the U.S. and other Western countries over the past four decadeslargely due to rising prevalence of two risk factors gastroesophageal reflux disease and obesity. EACdevelops from Barretts esophagus (BE) a cancer precursor defined by a specialized columnar metaplasia ofthe distal esophagus. Although BE follows an indolent course in most patients 5-10% eventually progress tocancer and a sizable fraction of BE remain undetected in the population. A critical unmet need is to identifyindividuals with high-risk BE who are most likely to develop EAC and thus benefit from screening andendoscopic surveillance. Conversely identifying the majority who are unlikely to progress will reduce risks andcosts associated with unnecessarily frequent surveillance. Biomarker-assisted risk stratification howevercontinues to be hindered by our limited understanding of the molecular pathways underlying early steps in thedevelopment of EAC. In recent years genome-wide association studies (GWAS) have identified ~20 novelgenetic susceptibility loci yet most heritability remains unexplained and only one SNP is linked specifically toBEEAC progression. The epigenome an important interface between the environment and the genome hasnot been studied for its potential mediating roles in relation to genotypes strong environmental risk factors andprogression to EAC. To address these gaps overcome sample size limitations for a rare cancer and invigorateexisting research efforts newer molecular and statistical approaches are needed to systematically integratemulti-omics data with established disease exposures. In this project we will conduct the most comprehensivemulti-omics study of BE the key cancer precursor profiling the transcriptome and methylome of 500 biopsiesfrom the NCI-funded Barretts and Esophageal Adenocarcinoma Consortium and Roswell Park ComprehensiveCancer Center and perform integrative analyses leveraging genotypes and environmental risk factors alreadyavailable through the largest GWAS meta-analysis for BE/EAC (n27000). The goal is to identify new geneticrisk loci through eQTL mapping and transcriptome-wide association study (Aim 1) new epigenetic locimediating and predicting the risk of BE progression to EAC (Aim 2) and develop risk prediction modelsintegrating genome-wide polygenic risk score and environmental exposures (Aim 3). The unifying theme of thethree aims is development and implementation of innovative analytical strategies leveraging transcriptome andmethylome data. Ultimately genetics epigenetics and environmental exposures will be incorporated to identifyhigh-risk populations for tailored screening and surveillance and prevent cancer development. 710221 +No NIH Category available Acquired Immunodeficiency Syndrome;Address;Anti-Retroviral Agents;Area;B-Lymphocytes;Cancer Etiology;Cancer cell line;Cell Line;Cell Proliferation;Cells;Cessation of life;Cicatrix;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Disorder;DNA-Directed DNA Polymerase;Data Set;Dependence;Disease;Double Strand Break Repair;Ensure;Epstein-Barr Virus Infections;Epstein-Barr Virus-Related Lymphoma;Exhibits;FDA approved;Gene Expression Profile;Gene Expression Profiling;Genome;Goals;HIV;Herpesviridae;Human;Human Herpesvirus 4;Immunocompromised Host;Impairment;Individual;Investigation;Janus kinase;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Modeling;Mutation;Non-Hodgkin's Lymphoma;Oncogenic;Oncogenic Viruses;Oncoproteins;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Predisposition;Process;Proliferating;Property;Regimen;Research;S phase;Shapes;Stat3 protein;Testing;Therapeutic;Therapeutic Agents;Transcript;Translating;Xenograft Model;Xenograft procedure;antiretroviral therapy;brca gene;cancer cell;cancer specimen resource;cell transformation;clinical risk;clinically actionable;drug action;gene regulatory network;genome-wide;high risk;homologous recombination;improved outcome;in vivo;in vivo Model;inhibitor;innovation;insight;large cell Diffuse non-Hodgkin's lymphoma;lymphoblastoid cell line;malignant breast neoplasm;multiple omics;novel;novel therapeutic intervention;personalized medicine;predicting response;predictive marker;predictive signature;repaired;response;targeted agent;therapeutic target;transcription factor;transforming virus;tumor Synthetic lethal targeting of EBV-positive diffuse large B cell lymphomas in persons living with HIV PROJECT NARRATIVEDiffuse large B-cell lymphoma (DLBCL) the most common type of non-Hodgkin lymphoma (NHL) continues tobe a leading cause of cancer-related death in HIV-infected individuals. Notably those with DLBCLs that areinfected with the opportunistic cancer-causing Epstein-Barr virus (EBV) suffer from worse overall survivalcompared to their EBV-negative counterparts highlighting the importance of focusing on EBV-associatedfactors and pathways. In this application we address how EBV rewires cellular DNA repair to make DLBCLsvulnerable to innovative synthetic lethal therapies with the ultimate goals of developing clinically actionablesignatures to predict therapeutic responsiveness of individual tumors and improving outcomes for those withEBV+ HIV-DLBCL. NCI 10703446 8/8/23 0:00 PAR-21-348 5U01CA275310-02 5 U01 CA 275310 2 "DASCHNER, PHILLIP J" 9/12/22 0:00 8/31/27 0:00 ZCA1-SRB-P(M2) 6885288 "BHADURI-MCINTOSH, SUMITA " "MCINTOSH, MICHAEL T" 3 PEDIATRICS 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 750686 NCI 509153 241533 PROJECT SUMMARYDiffuse large B-cell lymphoma (DLBCL) the commonest type of non-Hodgkin lymphoma (NHL) is highlyaggressive and despite antiretrovirals continues to be a leading cause of cancer-related death in persons livingwith HIV. Notably up to 90% of HIV-DLBCL are positive for the cancer-causing Epstein-Barr virus (EBV). Thusunderstanding how EBV contributes to cancer is essential to discovering new therapeutic approaches.Cancer cells require DNA repair but how EBV engages and reshapes cellular DNA repair is an underexploredarea. Our studies on EBV-cancer cells and EBV-transformed human B cells (lymphoblastoid cell lines) the latteran important model of EBV-driven lymphomas in immunosuppressed hosts converge on STAT3. Anoncoprotein STAT3 is frequently activated in cancer. Several studies have also shown that EBV+ HIV-DLBCLfrequently exhibit activating mutations in the Janus kinase (JAK)-STAT3 pathway. We have found that EBVactivates STAT3 to circumvent the S phase checkpoint barrier thereby ensuring cell proliferation but in theprocess loses homologous recombination (HR) that repairs DNA double strand breaks (DSB). As a result EBV-transformed and cancer cells become dependent on other forms of DNA repair in particular the error-pronemicrohomology-mediated end-joining (MMEJ) type of repair. This creates a therapeutic vulnerability to syntheticlethal agents that would otherwise be non-toxic to cells with intact HR. PARP [poly (ADP-ribose) polymerase]inhibitors are among such synthetic lethal agents that target MMEJ. Indeed we find that EBV-transformed andcancer cells are highly susceptible to MMEJ inhibitors that target PARP and the MMEJ-specific DNA polymerasePOL. Supporting this dependence on MMEJ EBV-transformed cells exhibit genome-wide scars of MMEJrepair and EBV+ HIV-DLBCL display higher abundance of STAT3 and POLQ transcripts compared to EBV-tumors; POLQ encodes POL. Further by multiomic analyses of several hundred cancer cell lines we haveidentified a STAT3-related gene expression signature that points to a mechanistic link between STAT3 andreliance on MMEJ repair while predicting susceptibility to synthetic lethal therapies.We now propose to investigate how EBV uses the JAK-STAT3 pathway to reshape DNA repair and render EBV+HIV-DLBCL vulnerable to synthetic lethal therapeutic targeting. Using cell lines xenografts and patient-derivedEBV+ & EBV- HIV-DLBCL from the NCI AIDS and Cancer Specimen Resource (ACSR) we investigate the linkbetween JAK-STAT3 pathway and DSB repair in EBV+ HIV-DLBCL (Aim 1) and synthetic-lethally exploit JAK-STAT3-dependent DNA repair deficiency to kill EBV+ HIV-DLBCL (Aim 2).These studies specifically address PAR-21-348 by identifying mechanisms and generating new paradigms toreveal how EBV contributes to NHL. In the long-term these mechanistic insights will uncover novel vulnerabilitiesand enable the prediction of responses to synthetic lethal therapies to improve outcomes for EBV+ DLBCL inpersons living with HIV. 750686 +No NIH Category available African American;African American population;Age;Aging;Biological;Black race;Chronology;Cohort Studies;DNA;Data;Development;Diagnosis;Disease;Early Diagnosis;Elderly;Family history of;Frequencies;Genetic;Genomics;Germ-Line Mutation;Goals;Health;Hematologic Neoplasms;Hematopoietic Neoplasms;Immune;Immune system;MALDI-TOF Mass Spectrometry;Malignant Neoplasms;Measures;Molecular;Monoclonal Gammapathies;Monoclonal gammopathy of uncertain significance;Morbidity - disease rate;Multiple Myeloma;Organ;Outcome;Participant;Patient Self-Report;Patients;Peripheral Blood Mononuclear Cell;Persons;Population;Populations at Risk;Prevalence;Prevention;Process;Progression-Free Survivals;Prospective cohort study;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Race;Recording of previous events;Risk;Risk Factors;Role;Sampling;Serum;Source;T cell receptor repertoire sequencing;T-Lymphocyte;T-cell diversity;Therapeutic Intervention;Tissue Banks;Tissues;Translating;biobank;cancer risk;carcinogenesis;case control;cohort;data integration;gammopathy;genome sequencing;genomic signature;high risk;high risk population;improved;novel;risk stratification;screening;sex;tool;whole genome Molecular prediction of myeloma in African Americans NARRATIVEThe overarching goal of this application is to translate novel risk mechanisms into tools for cancer interception.By defining the risk of developing MM precursors at the genomic level and not just basing risk on race and familialhistory we can more precisely identify the specific populations at risk and develop focused strategies of earlyinterception. NCI 10703438 8/24/23 0:00 PAR-18-913 5U01CA271492-02 5 U01 CA 271492 2 "ZHU, CLAIRE" 9/12/22 0:00 8/31/27 0:00 ZCA1-RTRB-F(M1) 8436435 "GHOBRIAL, IRENE M." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 855498 NCI 516021 339477 "SUMMARYMultiple Myeloma (MM) is almost always preceded by early precursor conditions: monoclonal gammopathy ofundetermined significance (MGUS) and smoldering myeloma (SMM). About 3% of the population >50 yearshave MGUS making it a very common precursor condition. The risk is 2-3 times higher in people with a familyhistory of MM or who are Black/African American (AA). Here we believe that instead of defining risk by race andfamilial history only we will define risk as specific genomic signatures some of which are related to race. Byscreening at-risk populations for MGUS one can develop early prevention and interception strategies for patientswho would benefit from early therapeutic interventions. Our preliminary data identified an MGUS prevalence of~13% in high-risk populations; the data came from two sources: our prospective cohort study (the PROMISEstudy) that is screening 30000 participants at-risk of developing MM and a large retrospective tissue bankingstudy the Mass-General Brigham (MGB) biobank with 123000 subjects. However what is lacking is theidentification of biological cancer risk mechanisms in MM and translating these discoveries into cancerinterception and early therapeutic interventions. This approach will allow the field to transition from a purelydemographic definition of risk to a biological one. We believe that samples from the PLCO study along with ourcurrent study cohorts can help define the mechanistic underpinnings of the carcinogenesis process leading toMGUS/MM. Our overarching hypothesis is that defining the risk of developing MM precursors at thegenomic level can more precisely identify specific populations at risk than demographic attributes anddefine focused strategies for early interception. In Specific Aim 1 we define the prevalence of monoclonalgammopathies in high-risk participants in the PLCO study along with MGB/PROMISE cohorts and characterizetheir impact on long-term health outcomes. In Specific Aim 2 we identify germline variants that predispose todeveloping MGUS/MM. We aim to characterize the genetic underpinnings of risk related to race and familyhistory of disease. We expect that this approach will allow us to move past using self-reported race status forrisk stratification. In Specific Aim 3 we assess the role of immune aging in developing MGUS/MM. MM istraditionally thought of as a disease of the elderly but the risk may be better explained by the ""aging tissue"" oforigin rather than chronological age.This approach will allow us to transition from a purely demographic definitionof risk to a biological one." 855498 +No NIH Category available Acceleration;Address;Adolescent;Adolescent and Young Adult;Adult;Age;Area;Behavioral Research;Behavioral Sciences;Blood;Blood specimen;Caring;Child;Childhood;Clinical;Clinical Data;Clinical Research;Clinical Trials;Communication;Communities;Computational Biology;Computer Analysis;Consent;Country;Dana-Farber Cancer Institute;Data;Data Reporting;Data Science;Databases;Decentralization;Development;Diagnostic Procedure;Disease;Economics;Electronics;Enrollment;Ensure;Ethnic Origin;Failure;Feedback;Future;Genome;Genomics;Goals;Hemangiosarcoma;Intervention;Intervention Trial;Knowledge;Leadership;Literature;Malignant Neoplasms;Medical Records;Metastatic Prostate Cancer;Metastatic breast cancer;Minority;Molecular;Morbidity - disease rate;Outcome;Participant;Patient Recruitments;Patient-Focused Outcomes;Patients;Phase;Population;Population Heterogeneity;Prevention strategy;Process;Protocols documentation;Race;Rare Diseases;Reach Effectiveness Adoption Implementation and Maintenance;Research;Rural;Saliva;Site;Smooth Muscle;Specimen;Survival Rate;Testing;Time;Tissue Sample;Translating;Translational Research;Translations;Tumor Tissue;Underrepresented Populations;United States;Work;anticancer research;bone;cancer clinical trial;clinical database;data de-identification;efficacy trial;ethnic minority;experience;genomic data;improved;leiomyosarcoma;literacy;member;novel;osteosarcoma;outreach;participant enrollment;patient engagement;racial minority;rare cancer;recruit;rural area;rural dwellers;saliva sample;sarcoma;shared database;social;success;targeted treatment;treatment strategy;tumor;tumor DNA;understudied cancer;web site;young adult Engagement Optimization Unit n/a NCI 10703417 9/15/23 0:00 RFA-CA-19-045 5U2CCA252974-04 5 U2C CA 252974 4 9/1/20 0:00 8/31/26 0:00 ZCA1-TCRB-O 8212 7337203 "MACK, JENNIFER W" Not Applicable 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 357891 468928 161875 Osteosarcoma (OS) and leiomyosarcoma (LMS) are exceedingly rare cancers both subtypes of sarcomathat arise in bone and smooth muscle respectively. There has been a failure to improve survival rates or decreasetreatment-related morbidity in OS/LMS due to insufficient characterization of the genomic landscape resultingin a lack of targeted therapeutic approaches diagnostic methods and preventive strategies. There is an urgentneed for a large shared database of clinical and genomic data in OS and LMS. Yet because of the rarity ofthese tumor types as well as other challenges in patient recruitment and the genomic characterization of thesetumors to date it has been difficult to generate this data. The overarching goal of this proposal is to engageadult and pediatric participants with OS and LMS as partners to generate a shared database of clinicalgenomic molecular and patient-reported data. This should accelerate discoveries that drive novel treatmentstrategies new clinical trials and new standards of care. The Count Me In PE-CGS U2C Research Center willleverage our experience in patient engagement genome characterization computational analysis andbehavioral research to create and launch two patient-partnered projects to generate this clinicogenomicdata. We will build two websites with patients in the OS and LMS communitiesthe Osteosarcoma Project(OSproject) and the Leiomyosarcoma Project (LMSproject)and consent 3000 patients over the course of thestudy. We will collect medical records patient-reported data archival tumor tissue samples and saliva and bloodfor genomic analysis. We will generate clinically annotated genomic data from at least 750 tumor specimens500 circulating tumor DNA specimens and corresponding germline specimens and share the de-identified datawidely. At the same time we will study and optimize the approach to patient engagement in cancer researchparticularly among rural and minority participants and participants across a range of literacy levels ages andstages in development. To accomplish these goals we will build on a well-established interdisciplinary team fromthe Broad Institute and Dana-Farber Cancer Institute with members who have pioneered these approaches. Ourleadership (Wagle Janeway) and Units are comprised of experts in patient-partnered cancer research (WaglePainter) sarcoma clinical and translational research (Janeway George Crompton Raut) genomecharacterization analysis and clinical interpretation (Gabriel Getz Van Allen Wagle Janeway)computational biology/data science (Getz Van Allen Philippakis) and behavioral science (Mack Rebbeck).Our Center will uncover the key clinicogenomic features of OS/LMS integrate them into a single comprehensivedatabase with a goal of accelerating research and improving the lives of these patients. In doing so we alsoaim to present a general approach to patient-partnered research that can be disseminated broadly and appliedto other tumors types and patient communities. +No NIH Category available Acceleration;Adult;Age;Back;Behavioral Research;Behavioral Sciences;Biological Assay;Blood;Cancer Center;Caring;Child;Childhood;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Communities;Computational Biology;Computer Analysis;Consent;Dana-Farber Cancer Institute;Data;Data Analytics;Data Files;Data Reporting;Data Science;Databases;Development;Diagnostic Procedure;Failure;Family;Funding;Genome;Genomics;Goals;Infrastructure;Leadership;Malignant Neoplasms;Medical Records;Minority;Molecular;Morbidity - disease rate;National Human Genome Research Institute;Participant;Patient Participation;Patient Recruitments;Patients;Prevention strategy;Process;RNA;Reporting;Research;Rural;Saliva;Sampling;Smooth Muscle;Specimen;Survival Rate;The Cancer Genome Atlas;Time;Tissue Sample;Translational Research;Tumor Tissue;analytical tool;anticancer research;bone;cancer genome;cancer genomics;cell free DNA;childhood sarcoma;clinical database;clinically relevant;computerized data processing;data de-identification;exome sequencing;experience;genome sequencing;genomic data;genomic platform;improved;leiomyosarcoma;literacy;member;novel;osteosarcoma;patient engagement;programs;rare cancer;sarcoma;shared database;targeted treatment;tool;transcriptome;treatment strategy;tumor;tumor DNA;web site;whole genome Genome Characterization Unit n/a NCI 10703412 9/15/23 0:00 RFA-CA-19-045 5U2CCA252974-04 5 U2C CA 252974 4 9/1/20 0:00 8/31/26 0:00 ZCA1-TCRB-O 8211 7897640 "GABRIEL, STACEY " Not Applicable 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 693888 1272729 161876 Osteosarcoma (OS) and leiomyosarcoma (LMS) are exceedingly rare cancers both subtypes of sarcomathat arise in bone and smooth muscle respectively. There has been a failure to improve survival rates or decreasetreatment-related morbidity in OS/LMS due to insufficient characterization of the genomic landscape resultingin a lack of targeted therapeutic approaches diagnostic methods and preventive strategies. There is an urgentneed for a large shared database of clinical and genomic data in OS and LMS. Yet because of the rarity ofthese tumor types as well as other challenges in patient recruitment and the genomic characterization of thesetumors to date it has been difficult to generate this data. The overarching goal of this proposal is to engageadult and pediatric participants with OS and LMS as partners to generate a shared database of clinicalgenomic molecular and patient-reported data. This should accelerate discoveries that drive novel treatmentstrategies new clinical trials and new standards of care. The Count Me In PE-CGS U2C Research Center willleverage our experience in patient engagement genome characterization computational analysis andbehavioral research to create and launch two patient-partnered projects to generate this clinicogenomicdata. We will build two websites with patients in the OS and LMS communitiesthe Osteosarcoma Project(OSproject) and the Leiomyosarcoma Project (LMSproject)and consent 3000 patients over the course of thestudy. We will collect medical records patient-reported data archival tumor tissue samples and saliva and bloodfor genomic analysis. We will generate clinically annotated genomic data from at least 750 tumor specimens500 circulating tumor DNA specimens and corresponding germline specimens and share the de-identified datawidely. At the same time we will study and optimize the approach to patient engagement in cancer researchparticularly among rural and minority participants and participants across a range of literacy levels ages andstages in development. To accomplish these goals we will build on a well-established interdisciplinary team fromthe Broad Institute and Dana-Farber Cancer Institute with members who have pioneered these approaches. Ourleadership (Wagle Janeway) and Units are comprised of experts in patient-partnered cancer research (WaglePainter) sarcoma clinical and translational research (Janeway George Crompton Raut) genomecharacterization analysis and clinical interpretation (Gabriel Getz Van Allen Wagle Janeway)computational biology/data science (Getz Van Allen Philippakis) and behavioral science (Mack Rebbeck).Our Center will uncover the key clinicogenomic features of OS/LMS integrate them into a single comprehensivedatabase with a goal of accelerating research and improving the lives of these patients. In doing so we alsoaim to present a general approach to patient-partnered research that can be disseminated broadly and appliedto other tumors types and patient communities. +No NIH Category available Acceleration;Address;Adult;Age;Behavioral Research;Behavioral Sciences;Biology;Blood;Bone neoplasms;Cancer Patient;Caring;Child;Childhood;Clinical;Clinical Data;Clinical Research;Clinical Trials;Communities;Computational Biology;Computer Analysis;Consent;Country;Dana-Farber Cancer Institute;Data;Data Reporting;Data Science;Databases;Development;Diagnostic Procedure;Disparate;Failure;Genome;Genomics;Geography;Goals;Incidence;Institution;Intervention Studies;Leadership;Malignant Neoplasms;Medical Records;Mesenchymal;Minority;Modeling;Molecular;Morbidity - disease rate;Observational Study;Participant;Patient Recruitments;Patients;Prevention strategy;Primary Neoplasm;Research;Risk Factors;Rural;Saliva;Sampling;Smooth Muscle;Specimen;Survival Rate;Time;Tissue Sample;Translational Research;Tumor Tissue;Work;anticancer research;bone;cancer type;cell free DNA;clinical database;data de-identification;empowerment;exome;experience;genomic data;improved;leiomyosarcoma;literacy;member;novel;osteosarcoma;patient engagement;patient population;primary bone cancer;prognostic indicator;public database;rare cancer;sarcoma;shared database;social media;targeted treatment;therapeutic biomarker;therapy resistant;transcriptome;treatment response;treatment strategy;tumor;tumor DNA;web site;whole genome Count Me In: Partnering with patients to define the clinical and genomic landscape of rare aggressive sarcomas in children and adults Rare cancers comprise over 25% of tumors in U.S. adults but due to low incidence and geographically dispersedpatient populations they are challenging to study leading to significant unmet clinical needs. This proposal willform a Research Center that will directly engage patients with two such rare cancers osteosarcoma andleiomyosarcoma as partners in research in order to generate a large shared database of clinical genomicmolecular and patient reported data. We hope that this work can accelerate discoveries that drive noveltreatment strategies new clinical trials and new standards of care and also serve as a model for patient-partnered research in other cancer types and patient communities. NCI 10703401 9/15/23 0:00 RFA-CA-19-045 5U2CCA252974-04 5 U2C CA 252974 4 "GILLANDERS, ELIZABETH" 9/1/20 0:00 8/31/26 0:00 ZCA1-TCRB-O(M1) 10848298 "JANEWAY, KATHERINE A" "GEORGE, SUZANNE ; MACK, JENNIFER W; VAN ALLEN, ELIEZER M" 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 1849405 NCI 2875297 647505 Osteosarcoma (OS) and leiomyosarcoma (LMS) are exceedingly rare cancers both subtypes of sarcomathat arise in bone and smooth muscle respectively. There has been a failure to improve survival rates or decreasetreatment-related morbidity in OS/LMS due to insufficient characterization of the genomic landscape resultingin a lack of targeted therapeutic approaches diagnostic methods and preventive strategies. There is an urgentneed for a large shared database of clinical and genomic data in OS and LMS. Yet because of the rarity ofthese tumor types as well as other challenges in patient recruitment and the genomic characterization of thesetumors to date it has been difficult to generate this data. The overarching goal of this proposal is to engageadult and pediatric participants with OS and LMS as partners to generate a shared database of clinicalgenomic molecular and patient-reported data. This should accelerate discoveries that drive novel treatmentstrategies new clinical trials and new standards of care. The Count Me In PE-CGS U2C Research Center willleverage our experience in patient engagement genome characterization computational analysis andbehavioral research to create and launch two patient-partnered projects to generate this clinicogenomicdata. We will build two websites with patients in the OS and LMS communitiesthe Osteosarcoma Project(OSproject) and the Leiomyosarcoma Project (LMSproject)and consent 3000 patients over the course of thestudy. We will collect medical records patient-reported data archival tumor tissue samples and saliva and bloodfor genomic analysis. We will generate clinically annotated genomic data from at least 750 tumor specimens500 circulating tumor DNA specimens and corresponding germline specimens and share the de-identified datawidely. At the same time we will study and optimize the approach to patient engagement in cancer researchparticularly among rural and minority participants and participants across a range of literacy levels ages andstages in development. To accomplish these goals we will build on a well-established interdisciplinary team fromthe Broad Institute and Dana-Farber Cancer Institute with members who have pioneered these approaches. Ourleadership (Wagle Janeway) and Units are comprised of experts in patient-partnered cancer research (WaglePainter) sarcoma clinical and translational research (Janeway George Crompton Raut) genomecharacterization analysis and clinical interpretation (Gabriel Getz Van Allen Wagle Janeway)computational biology/data science (Getz Van Allen Philippakis) and behavioral science (Mack Rebbeck).Our Center will uncover the key clinicogenomic features of OS/LMS integrate them into a single comprehensivedatabase with a goal of accelerating research and improving the lives of these patients. In doing so we alsoaim to present a general approach to patient-partnered research that can be disseminated broadly and appliedto other tumors types and patient communities. 1849405 +Clinical Research; Health Disparities; Networking and Information Technology R&D (NITRD); Rural Health Agricultural Health Study;Agriculture;Budgets;Communication;Computers;Contractor;Contracts;Data;Data Linkages;Data Set;Databases;Development;Educational workshop;Information Systems;Institutional Review Boards;Kidney;Licensing;Longitudinal cohort;Maintenance;Medicare;Newsletter;Participant;Phase;Preparation;Records;Reporting;Schedule;Secure;Services;United States;Update;cohort;data cleaning;data management;follow-up;meetings;member;mortality;neoplasm registry;operation;web site Agricultural Health Study Phase 5 n/a NCI 10703340 261201800029C-P00009-9999-1 N02 9/23/18 0:00 9/22/23 0:00 15713160 "DUNN, MARSHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2022 130000 NIEHS In the fifth phase of the Agricultural Health Study (AHS) contract the Contractor shall serve as the coordinating center for all study activities of cohort maintenance and follow-up. They will be responsible for handling the daily operations of the study scheduling regular and ad hoc meetings maintaining secure data records and updating cohort member contact information. The Contractor shall conduct data linkages to state cancer registries mortality files other types of records as needed (e.g. Medicare United States Renal Data System Internal Revenue Service Drivers Licenses LexisNexis). The Contractor shall conduct communication activities to the cohort and stakeholders maintain and update the studys website and develop the layout of an annual newsletter. They shall also facilitate preparation of compliance documents and manage the studys financial budgets. The overall objective of the contract is to continue to follow and update this longitudinal cohort for the purposes of studying agricultural exposures. 130000 +No NIH Category available Adoption;Aftercare;Antitumor Response;Biological;Biological Markers;Biopsy;Cancer Patient;Characteristics;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Computer Vision Systems;Computers;Development;Diagnosis;Disease Progression;Early identification;Early treatment;Eastern Cooperative Oncology Group;Environment;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immuno-Chemotherapy;Immunotherapeutic agent;Immunotherapy;Inflammatory;Institution;Letters;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Molecular;Monitor;Morphology;Mutation;Nature;Neoadjuvant Therapy;Nivolumab;Nodule;Non-Small-Cell Lung Carcinoma;Outcome;PD-1/PD-L1;Pathologic;Pathway interactions;Patient Selection;Patients;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Phenotype;Predictive Value;Publishing;Radiology Specialty;Reporting;Resected;Scanning;Shapes;Site;Testing;Texture;Time;Tissues;Toxic effect;Training;Treatment outcome;Tumor Biology;Tumor-Infiltrating Lymphocytes;Validation;X-Ray Computed Tomography;anti-PD-1;anti-PD-1/PD-L1;anti-PD-L1;cost;imaging biomarker;immune- related response criteria;immunotherapy clinical trials;immunotherapy trials;industry partner;inhibitor therapy;non-invasive imaging;novel;phase III trial;predicting response;predictive marker;primary endpoint;prognostic;prognostic of survival;prognostic value;prognostication;programmed cell death ligand 1;prospective;radiological imaging;radiomics;responders and non-responders;response;success;survival outcome;survival prediction;tool;treatment response;tumor;tumor behavior;tumor heterogeneity Novel Radiomics for Predicting Response to Immunotherapy for Lung Cancer RELEVANCE: Only 1 in 5 lung cancer patients treated with immunotherapy (IO) has a favorable response.Additionally the cost of IO is extremely high >$200K/year per patient. The goal of this project is to develop novelcomputational radiomic tools which in conjunction with routine CT scans from IO clinical trials will allow for (1)identifying pre-IO therapy as to which non-small cell lung cancer patients could potentially benefit from immunecheckpoint inhibitors and (2) quantitatively monitor serial changes in tumor heterogeneity during IO treatment forearly identification of responders and non-responders. NCI 10703255 6/26/23 0:00 PA-20-185 5R01CA257612-03 5 R01 CA 257612 3 "ESPEY, MICHAEL G" 4/2/21 0:00 3/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(03)M] 8352708 "MADABHUSHI, ANANT " "VELCHETI, VAMSIDHAR " 5 BIOMEDICAL ENGINEERING 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 394 Non-SBIR/STTR 2023 1 NCI 1 0 ABSTRACT: In 2019 an estimated 228150 patients in the US are expected to be diagnosed with non-small celllung cancer (NSCLC). A recent landmark development has been the approval of the immune checkpointinhibitors (anti-PD-1 and anti-PD-L1) for the treatment of locally advanced and metastatic NSCLC. Theseimmunotherapy (IO) drugs have an excellent toxicity profile and have the potential to induce durable clinicallymeaningful responses. However only 1 in 5 NSCLC patients treated with IO will have a favorable response.Unfortunately the current tissue based biomarker approach to selecting patients for these treatments is sub-optimal due to the dynamic nature of the interaction of the immune system with the tumor. Given the prohibitivecosts associated with IO (>$200K/year per patient) there is a critical unmet need for predictive biomarkers toidentify which patients will not benefit from IO. Additionally the current clinical standard to evaluating tumorresponse (i.e. RECIST and irRC which evaluate change in tumor size and nodule disappearance) is sub-optimalin evaluating early clinical benefit from IO drugs. This is due at least in part to the fact that some patientsundergoing IO present apparent disease progression (pseudo-progression) on post-treatment CT scans. Unlike the standard canon of radiomics (computer extracted features from radiographic scans) thatassess textural or shape patterns our group has been developing novel computer vision strategies to capturepatterns of peri-tumoral heterogeneity (outside the tumor) and tumor vasculature from CT scans. In N>300patients our group has shown that (1) radiomics of vessel tortuosity on baseline pre-treatment CT for NSCLCpatients undergoing IO were significantly different between responders (less tortuous) and non-responders(more tortuous) (2) serial changes in these measurements were better predictors of early response to IOcompared to clinical response criteria such as RECIST and irRC and (3) these radiomic attributes wereassociated with PD-L1 expression and degree of tumor infiltrating lymphocytes on baseline biopsies. Criticallythese radiomic features predicted response for NSCLC patients treated with 3 different IO agents from 3 sites. In this project we will further develop vasculature peri- and intra-tumoral radiomic features for monitoringand predicting benefit and early response for NSCLC patients treated with IO. We will uniquely train our radiomicsusing a set of N>180 resected NSCLC patients treated with first line IO and for whom we will have majorpathologic response (MPR) as primary endpoint. In addition we will establish the biological underpinnings ofthese predictive radiomic signatures by evaluating their association with the morphology immune landscape(from biopsies) and molecular pathways of the tumor. In addition we have access to N>700 NSCLC patientstreated on completed clinical trials via our industry partners (Astrazeneca Bristol-Myers Squibb) for toolvalidation. Finally we will deploy LunIOTx within the ECOG-5163 (INSIGNA) trial (N>600) the first time thatradiomics will be evaluated within a prospective cooperative group clinical trial for IO. 1 +No NIH Category available 3-Dimensional;Accounting;Behavior;Cancer Biology;Cancer Etiology;Cell Culture Techniques;Cell Separation;Cell fusion;Cells;Cessation of life;Characteristics;Circulation;Colorectal Cancer;Data;Development;Disease;Distant;Epigenetic Process;Evaluation;Evolution;Exhibits;Foundations;Future;Gene Expression;Genes;Genotype;Goals;Heterogeneity;Hybrid Cells;Hybrids;Immune;Immune Tolerance;Immunofluorescence Immunologic;In Vitro;Institution;Invaded;Investigation;Knock-out;Knowledge;Label;Laboratories;Large Intestine Carcinoma;Macrophage;Malignant Neoplasms;Mediating;Medical;Meditation;Methods;Migration Assay;Molecular;Monitor;Morbidity - disease rate;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;Pathway interactions;Patients;Periodicity;Phenotype;Physicians;Population;Primary Neoplasm;Property;Research;Research Proposals;Role;Sampling;Scientist;Site;System;Tissue-Specific Gene Expression;Training;Tumor-Derived;Validation;Work;Xenograft procedure;Zebrafish;acute myeloid leukemia 1 protein;burden of illness;cancer type;career;cell motility;early detection biomarkers;epithelial to mesenchymal transition;hematopoietic stem cell differentiation;hybrid gene;improved;in vivo;in vivo Model;innovation;live cell imaging;lymphatic vessel;mRNA Differential Displays;migration;mortality;neoplastic;neoplastic cell;novel;peripheral blood;peripheral blood vessel;prevent;protein expression;single-cell RNA sequencing;therapeutic target;transcription factor;translational oncology;tumor;tumor microenvironment;tumor progression Mechanisms of Neoplastic Hybrid Cell Dissemination in Colorectal Cancer Project NarrativeMetastatic disease is the primary cause of cancer morbidity and mortality accounting for more than 90% ofcancer-related deaths yet the molecular mechanisms underlying neoplastic cell metastasis remains poorlyunderstood. The proposed research herein will integrate single cell RNA sequencing novel methods of cyclicimmunofluorescence and cell-based mechanistic studies to identify how discrete subtypes of neoplastic cellsdefined by co-expression of immune and tumor characteristics disseminate in patients with colorectal cancer.Identification and validation of these mechanisms will contribute to our understanding of tumor progression andthe development of metastatic disease with the potential to uncover therapeutic targets aimed to prevent orreduce neoplastic cell dissemination. NCI 10703215 9/7/23 0:00 PA-21-052 5F31CA271676-02 5 F31 CA 271676 2 "DIBELLO, ANTHONY THOMAS" 9/8/22 0:00 9/7/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 15638753 "ANDERSON, ASHLEY NICOLE" Not Applicable 1 ANATOMY/CELL BIOLOGY 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/8/23 0:00 9/7/24 0:00 398 "Training, Individual" 2023 39967 NCI 39967 0 Project Summary Metastatic disease is the primary cause of cancer morbidity and mortality resulting in >10 million deathsworldwide in 2020. Despite recent advances in our knowledge of metastatic tumor development there is a criticalneed to understand the molecular mechanisms by which discrete subpopulations of neoplastic cells successfullyenter circulation to improve strategies for monitoring and reducing metastatic disease burden. Our teamdiscovered a unique disseminated neoplastic cell subtype characterized by co-expression of neoplastic andimmune cell genotypes and phenotypes that can form from neoplastic-macrophage cell fusion. These hybridcells are found in peripheral blood at numbers greater than other circulating tumor-derived cells (CTCs) andexhibit increased migratory and invasive potential as well as the ability to seed and expand at metastatic sites atrates greater than CTCs. However the mechanisms by which hybrid cells do so is currently unknown. In mypreliminary analyses of hybrid cell gene expression I identified upregulated components from the Runt-relatedtranscription factor 1 (RUNX1) pathway in hybrid cells compared to tumor cells. RUNX1 is a transcription factorthat regulates hematopoietic stem cell differentiation and macrophage migration and has been shown to mediatemetastatic conversion of tumor cells by facilitating epithelial-to-mesenchymal transition in colorectal cancer. In ahybrid cell RUNX1 may integrate the functional behaviors of both macrophages and tumor cells into a singlecell and facilitate their successful dissemination. Therefore I hypothesize that disseminated subpopulations ofneoplastic hybrid cells display differential RUNX1 meditated ~omics and functional expression that facilitatesenhanced tumor dissemination. This project proposes to first assess the gene expression and phenotypic profiles of hybrid cells in colorectalcancer tumors and peripheral blood to identify characteristics of hybrid cells that successfully disseminate.Additionally this project will evaluate the functional role of RUNX1 in facilitating enhanced hybrid cell migrationand dissemination. Successful completion of these studies will define the molecular underpinnings of neoplastichybrid cell migration and dissemination and will provide the basis for future exploration of this unique neoplasticsubtype as a biomarker for the detection of early metastatic disease and tumor evolution. Furthermore this application proposes a comprehensive and interdisciplinary training plan within a prominentacademic medical and research institution that seamlessly integrates with the research proposal providingessential training in systems and molecular cancer biology to support the candidates career goal of maintainingan academic translational oncology laboratory as a physician scientist. 39967 +No NIH Category available Algorithms;Architecture;Attention;Basement membrane;Biological Assay;Biological Markers;Biopsy;Blood;Breast;Calibration;Cancer Prognosis;Classification;Clinic;Collagen Fiber;Collection;Color;Desmoplastic;Development;Diagnostic;Disease Marker;Early Diagnosis;Epidermal Growth Factor Receptor;Epithelium;Estrogen Receptors;Goals;Health;Histopathology;Human;Image;Imaging Device;Imaging technology;Interference Microscopy;Interobserver Variability;Invaded;Investigation;Light;Malignant Neoplasms;Mammary Neoplasms;Maps;Measures;Mediating;Methodology;Microscope;Microscopic;Microscopy;Molecular;Morphologic artifacts;Morphology;Non-Malignant;Operative Surgical Procedures;Optics;Outcome;Pathologist;Pathology;Patient Care;Patient risk;Patients;Performance;Phase;Physicians;Preparation;Procedures;Progesterone Receptors;Prognosis;Prognostic Marker;Prostate;Quantitative Microscopy;Research;Role;Scanning;Signal Transduction;Site;Slice;Slide;Specimen;Stains;TP53 gene;Techniques;Technology;Testing;Thick;Time;Tissue Stains;Tissues;Training;Translating;Treatment Protocols;Tumor Cell Invasion;Wisconsin;Woman;Work;automated segmentation;biomarker evaluation;cancer cell;clinically relevant;diagnostic accuracy;image processing;imaging biomarker;immunohistochemical markers;improved;instrument;malignant breast neoplasm;microscopic imaging;mosaic;nanoscale;new technology;novel;outcome prediction;personalized medicine;prognostic;prognostic tool;prototype;response;risk stratification;tool;treatment and outcome;tumor initiation;tumor microenvironment;whole slide imaging Quantitative histopathology for cancer prognosis using quantitative phase imaging on stained tissues Project NarrativeThis project proposes to develop a staining-invariable whole slide imaging (WSI) instrument for breast cancerprognosis that integrates with the current pathology workflow. We will advance the Spatial Light InterferenceMicroscopy technology to work on existing stained tissues and provide both color bright field and quantitativephase images from an upgraded commercial optical microscope. The outcome of this project is an imagingand analysis instrument that will yield pathology outcome information to help the pathologist inferprognosis free of artifacts due to variability in staining and tissue sectioning. NCI 10703212 6/16/23 0:00 PAR-18-206 5R01CA238191-05 5 R01 CA 238191 5 "OSSANDON, MIGUEL" 7/12/19 0:00 6/30/24 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 2205403 "ANASTASIO, MARK A" "ELICEIRI, KEVIN WILLIAM; LIU, ZHENG GEORGE" 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 467172 NCI 337603 129569 Project SummaryAbout 1 in 8 U.S. women will develop invasive breast cancer over the course of her lifetime. Early diagnosisand prognosis are key to improving health outcomes. Prognostic markers in tissue biopsies help cliniciansmake treatment decisions and refine the patient risk stratification. New research expands the currentprognostic markers to better deliver personalized treatment regimens. However the variability of preanalyticalfactors (biopsy collection processing and storage) can have a significant impact on biomarkers evaluationwhich can result in potentially serious consequences in terms of patient care. There is an identified need fordeveloping clinically relevant biomarkers that are invariant to biospecimen preparation.This project proposes a technical solution to extracting intrinsic tissue morphology information unaffected byvariability in tissue staining slice thickness or sectioning errors. Spatial Light Interference Microscopy(SLIM) was shown to provide prognostic markers derived from tumor microenvironment usingnanoscale organization of the non-malignant tissue adjacent to cancer cells i.e. the stromal response tocancer. Preliminary results indicate that SLIM can distinguish between pairs of matched patients (good vs.bad outcome) and has the capability to eliminate false positives and help the clinician assign the appropriatetreatment.For this project we will validate color SLIM (cSLIM) capabilities as a prognostic tool for existingstained histopathology slides. cSLIM will render simultaneously bright field and quantitative phaseimages in a single scan. cSLIM will be implemented in a whole slide imaging (WSI) instrument with the colorbright field image familiar to pathologists while maintaining a stain-independent signal which has intactprognosis value. The WSI instruments high sensitivity to stroma and collagen fibers will be used to developrobust markers for breast prognosis which are independent of tissue slice thickness color variability within thesame stain type (say H & E) and across stains (H & E various immunochemical stains etc). With this newinstrument we will test the staining-invariance performance on 196 TMA cases and validate with 300biopsies. The work is the results of combining expertise in imaging pathology and image processing acrossfour sites: UIUC Beckman Institute the Mills Breast Cancer Institute in Urbana UIC Pathology and U.Wisconsin. 467172 +No NIH Category available Acute Myelocytic Leukemia;Alleles;Antisense Oligonucleotides;Arginine;Catalysis;Cells;Chronic Lymphocytic Leukemia;Data;Disease;Drug Targeting;Dysmyelopoietic Syndromes;Evaluation;Event;Gene Expression;Genes;Genetic;Health;Heterozygote;In Vitro;Individual;Leukemic Cell;Malignant Neoplasms;Mediating;Methylation;Modeling;Molecular;Mutation;Myeloid Leukemia;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phenotype;Point Mutation;Process;Protein Inhibition;Protein Methylation;Protein Splicing;Protein-Arginine N-Methyltransferase;Proteins;Proteome;RNA Splicing;RNA methylation;RNA-Binding Proteins;RNA-targeting therapy;Refractory;Safety;Small Nuclear Ribonucleoproteins;Solid Neoplasm;Spliceosome Assembly Pathway;Spliceosomes;Therapeutic;Therapeutic Effect;Uveal Melanoma;Work;cancer cell;cancer type;cell killing;clinical development;curative treatments;early phase clinical trial;efficacy evaluation;in vivo;inhibitor;leukemia;mRNA Precursor;mutant;myeloid leukemia cell;novel therapeutic intervention;novel therapeutics;pharmacologic;preclinical development;small molecule;snRNP Structural Core Protein;synthetic lethal interaction Therapeutic targeting of RNA splicing catalysis through inhibition of Protein Arginine Methylation NARRATIVERecent work from our groups and others has shown that cancer cells bearing mutations in genes controlling aprocess known as RNA splicing are exquisitely sensitive to drugs that block the machinery that carries outRNA splicing. Because the safety and efficacy of this specific class of drugs is not yet known here we proposeto study an additional means to target RNA splicing by inhibiting a process known as protein argininemethylation. This study may have great therapeutic potential because a number of drugs targeting proteinarginine methylation are entering early phase clinical trials now. NCI 10703206 4/27/23 0:00 PA-19-056 5R01CA249204-04 5 R01 CA 249204 4 "VENKATACHALAM, SUNDARESAN" 5/15/20 0:00 4/30/25 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 14078747 "GUCCIONE, ERNESTO " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 375903 NCI 229027 146876 SUMMARYMutations in splicing factors (SF) are highly enriched in a variety of cancer types particularly myelodysplasticsyndromes (MDS) acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in addition to solidtumors such as uveal melanoma. Our group has identified that cells bearing SF mutations cannot toleratefurther perturbations to splicing catalysis and consistent with this we have identified that spliceosomal mutantcancer cells are preferentially sensitive to small molecules that disrupt pre-mRNA splicing.While the above effort has resulted in an ongoing phase I clinical trial of a spliceosome modulatory compoundfor patients with refractory myeloid leukemias we do not currently know the safety or efficacy of pharmacologicmodulation of core spliceosome function. To this end our group has also recently identified that inhibitingspliceosomal assembly through inhibition of arginine methylation of Sm proteins provides an alternate meansof therapeutic splicing inhibition. We have identified that inhibiting either symmetric arginine methylation(mediated by the protein arginine methyltransferase 5 (PRMT5)) or asymmetric dimethyl arginine methylation(mediated by type I PRMTs (PRMT1 4 and 6)) reduces splicing fidelity resulting in strong preferential killing ofSF-mutant leukemias over their wildtype counterparts.Here we aim to determine if in leukemia SF-mutations portend greater vulnerability to a second hit targetingsplicing through inhibition of type I (PRMT1/4/6) and/or type II (PRMT5) PRMTs. In Aim 1 we will define thetherapeutic potential of inhibiting PRMT5 type I PRMTs and core spliceosome function alone or together inleukemia models with or without a SF mutation. In addition we will understand the consequences of combinedPRMT inhibition on RNA splicing and gene expression relative to inhibiting PRMT5 or Type I PRMTs alone.In parallel to the above studies in Aim 2 we will define the molecular basis for the cooperation between PRMTinhibition and SF mutations by first determining the methylation substrates of PRMT5 or Type I PRMTs andsecondly by determining if individual spliceosomal changes mediated by inhibiting PRMTs or core spliceosomefunction can be mimicked by anti-sense oligonucleotides thereby providing an orthogonal novel therapeuticapproach to eliminate SF-mutant cancer cells.The significance of these studies is that inhibitors of PRMTs are now entering phase I clinical trials in patientswith a variety of cancer types and defining the mechanistic effects and therapeutic utility of PRMT inhibitors forspecific genetic subsets of cancers may have incredible therapeutic importance. The health relatedness isthat our studies may identify new therapeutic opportunities for a variety of cancer types that have no curativetherapies for the majority of patients with these diseases currently. 375903 +Biotechnology; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health Agreement;Area;Bioinformatics;Biological;Biomedical Research;Biometry;Biotechnology;CCR;Clinical Research;Communities;Computer software;Contracts;Cost Savings;Data;Databases;Dissection;Educational workshop;Event;Funding;Funding Mechanisms;Gene Expression Profiling;Genomics;Image;Individual;Investigation;Journals;Laboratories;Licensing;Mammalian Cell;Mediation;Microarray Analysis;Pathway interactions;Principal Investigator;Private Sector;Protein Analysis;Proteins;Proteomics;Publications;Reporting;Research;Research Personnel;Resources;Science;Scientist;Services;Signal Transduction;Statistical Data Interpretation;Technology;Technology Transfer;Training;Transfer Agreement;Translational Research;United States National Institutes of Health;Work;assay development;base;bioinformatics tool;biomarker development;clinical application;cost;experimental study;high throughput analysis;high throughput technology;metabolomics;nanoscale;new technology;next generation sequencing;programs;protein expression;response;single cell analysis;therapeutic target;transcriptomics Science and Technology Resources n/a NCI 10703149 1ZIKBC010857-16 1 ZIK BC 10857 16 9414524 "GOLDSTEIN, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 4202597 NCI The OSTR is supporting a number of protein characterization analyses in mammalian cells for CCR investigators through the Laboratory of Protein Characterization at the Frederick National Lab (FNL). The OSTR continues to evaluate all commercially available platforms for protein and gene expression profiling and other high throughput technologies. To make the latest advances easily accessible to CCR researchers the OSTR has established a number of arrangements with companies providing genomic and metabolomic profiling technologies and services. These agreements have led to far lower cost and an efficient and easy way for CCR investigators to access these technologies. A subsidy program has been established providing subsidies to support CCR investigator access to advanced genomic proteomic metabolomic and bioinformatic technologies. This funding mechanism has helped to extend the limited research dollars available to CCR laboratories and has permitted our researchers to conduct experiments that might otherwise be cost prohibitive. Many of the funded projects have led to important publications in top-tier journals. Most recently the OSTR has been involved in CCR's efforts to access the next generation sequencing technologies including the setting up of a new single cell analysis facility now located building 41 which is available to any CCR investigator. In response to CCR's rapidly growing need to manage and analyze large sets of genomic and proteomic data the OSTR has developed several partnerships with bioinformatics companies. At significant cost savings to NCI OSTR negotiated a variety of license agreements on behalf of all NCI researchers for universal access to sophisticated tools for bioinformatic and statistical analysis of microarray experiments proteomic profiling studies and genomic analysis including next-generation sequencing data. In addition the OSTR has made a number of software applications for the investigation of pathways and biological association networks available to all of NCI. The OSTR continues to assess CCR's requirements in the area of bioinformatics and biostatistics. We continue to work with Leidos Biomedical Research (LBR) to create a CCR dedicated Bioinformatics Program to provide support to CCR investigators. Support for analysis of high throughput genomic and proteomic data is being made available through this new program which is located on the Bethesda campus. Most recently the OSTR has taken on the management of the NanoScale Proteomics section of the Collaborative Protein Technology Resource. This Core is an open to all CCR investigators and dedicated to developing and implementing cutting-edge protein-based technologies to facilitate discovery translational and clinical research in CCR/NCI/NIH. This Core offers expertise and provides state-of-the-art technologies to accommodate the demands of CCR/NCI/NIH investigators for: Rapid and precise protein analysis; Comprehensive and quantitative cell signaling event dissection; Nanoscale quantitative proteomics assessment; Biomarker development and therapeutic target identification; and Clinical applicable assay development and applications. Most recently the CPTR is offering spatial proteomics and transcriptomics to the CCR community. This Core is reported separately. 4202597 +Cancer; HIV/AIDS Advocate;Awareness;Benchmarking;CCR;Clinical;Clinical Research;Clinical Trials;Communication;Communities;Congresses;Development;Division of Cancer Epidemiology and Genetics;Division of Cancer Treatment and Diagnosis;Education and Outreach;Employee;Ensure;Facebook;Government;Internet;Interview;Intramural Research;Journals;Malignant Neoplasms;Medical;Mission;Modernization;Multimedia;Paper;Peer Review;Press Releases;Production;Publications;Research;Research Personnel;Scientific Advances and Accomplishments;Taxes;Training;Twitter;United States National Institutes of Health;Visit;Work;career;clinical center;faculty research;faculty support;interest;migration;news;programs;recruit;social media;web site CCR Education and Outreach n/a NCI 10703146 1ZIJBC011285-13 1 ZIJ BC 11285 13 14732225 "BRONEZ, MELISSA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 89655 NCI This project is important because it provides the public Congress and scientific communities with an understanding of the research advances that are being made with U.S. tax dollars and about opportunities to participate in clinical research. The publication and dissemination of research results is a critical component of what the CCR Office of Communications does. Education and outreach are key components to our ability to achieve our mission. Accomplishments this year include: Production of the Milestones publication in print and on line which highlight CCR's most noteworthy research advances. Dozens of summaries of important peer-reviewed journal papers written for the lay public announcements of new clinical trials opening and other activities were shared via the website: https://ccr.cancer.gov/news. The office worked with NCI's Office of Communications and Public Liaison to disseminate press releases and to inform the media about the research progress being made within CCR. CCR also disseminated information to the public through social media including Twitter and NCI's Instagram and Facebook and through video production. The office also worked collaboratively with many other NCI and NIH organizations including the Division of Cancer Treatment and Diagnosis; Division of Cancer Epidemiology and Genetics; Office of Congressional and Government Relations; NCI at Frederick; the NIH Office of Intramural Research; and the NIH Clinical Center. The office supported visits by interested Congressional staff advocates scientific collaborators and dignitaries. A major undertaking this year was the migration of CCR's public website to an upgraded Drupal platform and a redesign that is modern and meets many of the federal website benchmarks. 89655 +Cancer; HIV/AIDS Biology;CCR;Equipment;Goals;Leadership;Modification;Procedures;Professional counselor;Recommendation;Research Personnel;Resources;Services;Strategic Planning;animal facility;square foot CCR New Space Activation n/a NCI 10703144 1ZIIBC011234-14 1 ZII BC 11234 14 10274929 "HENDERSON, DARREN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 5499878 NCI On average my office relocates around 100 scientific and administrative staff every year. This number will fluctuate depending on the needs and priorities of the CCR leadership. These relocations involve the planning of new space renovations of existing space procurement and installation of furnishings planning and installation of LAN and telecom equipment and final punch list completion per end user. The renovation projects that occur on a yearly basis range from simple office modifications to complete refurbishment of lab space in the thousands of square feet. This includes basic biology labs computational spaces and in some cases animal facility upgrades. The need for renovations and relocations for the scientific staff is driven by the strategic planning between my office and the CCR leadership as well as recommendations from the Board of Scientific Counselors. 5499878 +Bioengineering; Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Genetics; Human Genome; Networking and Information Technology R&D (NITRD); Women's Health Bioinformatics;Breast Cancer Model;ChIP-seq;Chromatin Interaction Analysis by Paired-End Tag Sequencing;Collaborations;Complex;Computing Methodologies;Data;Data Analyses;Data Set;Epigenetic Process;Gene Expression;Genetic;Genome;Germ-Line Mutation;Goals;Metastatic Neoplasm to the Lung;Methylation;Modeling;Molecular;Mus;Neoplasm Metastasis;Patients;Post-Transcriptional Regulation;Primary Neoplasm;Proteomics;Public Domains;RNA immunoprecipitation sequencing;Research;Research Personnel;Series;Somatic Mutation;The Cancer Genome Atlas;Tissues;Variant;Work;bisulfite sequencing;exome sequencing;genetic analysis;genome sequencing;interest;mathematical model;melanoma;metabolomics;transcriptome sequencing;treatment response;tumor progression;whole genome Integrated analyses of genetics epigenetics and gene expression n/a NCI 10703138 1ZIHBC011703-07 1 ZIH BC 11703 7 9692363 "LEE, MAXWELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1197293 NCI We have worked with many high-throughput datasets including the data generated by NCI investigators and those from public domains. In particular we have worked with a series of mouse mammary tumor models and melanoma models with the data generated by many NCI investigators. The data span many platforms including whole genome sequencing exome sequencing RNAseq DHS ChIP-seq bisulfite-sequencing ChIA-PET RIP-seq RPPA metabolomics and involve multiple tissues primary tumors and lung metastasis. We are currently doing integrated analyses including integrating sequence variants with DHS and gene expression; integrating methylation with gene expression and genome sequence features; integrating gene expression with therapeutic response data. Similarly we have also conducted integrated analyses for TCGA data involving collaborations with many NCI investigators. We are also developing computational methods and mathematical modeling to empower the data analyses. 1197293 +Cancer; HIV/AIDS; Networking and Information Technology R&D (NITRD) Animals;Bioinformatics;Budgets;Clinical Research;Clinical Trials;Clinical trial protocol document;Collaborations;Collection;Computer software;Data;Data Analyses;Data Collection;Data Storage and Retrieval;Databases;Development;Disease;Division of Cancer Epidemiology and Genetics;Documentation;Equipment and supply inventories;Funding;Future;Goals;Human;Human Resources;Information Technology;Institutional Review Boards;Iris;Medical;Methods;NCI Center for Cancer Research;Online Systems;Postdoctoral Fellow;Principal Investigator;Process;Protocols documentation;Research;Research Personnel;Series;Site;Standardization;Study Subject;System;Systems Analysis;Technology;Time;Tissues;United States National Institutes of Health;Validation;Videoconferencing;base;cancer type;clinical center;clinical trial participant;lectures;prevent;programs;web app;web site;website development;wiki Support of NCI CCR Clinical Research and Bioinformatics n/a NCI 10703137 1ZIHBC011235-14 1 ZIH BC 11235 14 14732217 "LEVINE, JASON " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 5066393 NCI This program is involved in many aspects of information technology support for the NCI Center for Cancer Research (CCR). Projects which we develop and/or maintain include the following: 1) Labmatrix a tissue research and inventory system for managing both the collection and storage of tissues as well as data resulting from the research analysis of these tissues. Tissues are from numerous types of cancers and other diseases. 2) iRIS a protocol lifecycle management system used for all CCR human and animal protocols as well as DCEG Special Studies IRB-managed protocols. 3) CCR Protocol View a website for NCI and NIH Clinical Center distribution of our clinical trials protocols. 4) Confluence wiki which facilitates standardized documentation collaboration and simple website development for CCR scientific and administrative staff. Confluence acts as an interface to our DB Quick technology allowing ultra fast development of simple web-based database applications. 5) JIRA issue management software used to support those groups in the CCR that need to manage user requests. 6) Future Fellows a web application for the collection and review of C.V.s submitted by potential postdoctoral fellows. 7) Budget Management System used to allocate funds to CCR principal investigators and core research groups. 8) Redesign and reengineering of the CCR website to a Drupal-based site. 9) CCR Referrals. This provides a standardized way to manage potential clinical trial participants and their medical information as it pertains to being qualified to participate in CCR clinical trials. 10) PA Tracker for the tracking of human resource packages through the approval process. 11) Video conference support for scientific presentations including the CCR Grand Rounds Lecture series as well as many smaller scientific collaborations. 11) Section 508 compliance of CCR-managed websites. 12) Scribe a method of collecting study data directly from study subjects and having that data go through real-time validation and entry into a researcher's data collection system. 5066393 +Biotechnology; Cancer Address;Adjuvant;Animals;Antineoplastic Agents;Biological;Biotechnology;CCR;Cancer Biology;Canis familiaris;Clinical;Clinical Data;Clinical Protocols;Clinical Trials;Collaborations;Common Terminology Criteria for Adverse Events;Communities;Complement;Conceptions;Contracts;Data;Data Reporting;Development;Development Plans;Drug Industry;Enrollment;Extramural Activities;Foundations;Goals;Good Clinical Practice;Human;Infrastructure;Institution;Investigation;Leadership;Lymphoma;Malignant Neoplasms;Multi-Institutional Clinical Trial;Nature;North America;Oncologist;Oncology;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Play;Positioning Attribute;Process;Property;Protocols documentation;Publications;Publishing;Reporting;Research Personnel;Resources;Rewards;Risk;Role;Structure;System;TOP1 gene;Therapeutic;Therapeutic Agents;Time;Update;Veterinary Schools;Work;anticancer research;base;bridge program;cancer clinical trial;catalyst;comparative;cost;data management;design;drug development;inhibitor;mTOR inhibition;member;novel;novel anticancer drug;novel therapeutics;oncology program;oncology trial;osteosarcoma;pet animal;pharmacokinetics and pharmacodynamics;programs Comparative Oncology Trials Consortium n/a NCI 10703135 1ZIGBC011689-07 1 ZIG BC 11689 7 14280471 "LEBLANC, AMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 108586 NCI "The core component of the COP is the Comparative Oncology Trials Consortium (NCI-COTC) which is an infrastructure uniting study sponsors such as pharmaceutical and biotechnology companies with 24 academic veterinary centers within North America to support multicenter clinical trials of investigational therapeutics wherein centralized trial support and data management is provided by the NCI. This clinical trial infrastructure supports the integration of pet dogs with cancer into the development path of new cancer drugs. The COTC initiates pet animal trials in collaboration with other NCI investigators academic institutions and/or the pharmaceutical industry. These trials are implemented through the collective caseloads of the consortium membership with COTC member institutions united through a single Memorandum of Understanding (MOU). These trials are typically small and focused on relevant biological endpoints associated with drug development. The pet animal trials are intended to answer specific questions regarding the properties of a drug and results are to be rapidly integrated into the development plans for novel therapeutic agents by the sponsor. The data generated through these studies are available to COTC members to facilitate larger investigator-initiated pet animal trials that may further complement this translational process. The COP provides leadership oversight and management of trials. Trial sponsors most often pharmaceutical companies support the clinical costs of studies conducted by the COTC. This support is paid directly to COTC centers by the sponsor through collectively defined contracts and this process has been streamlined so as to not create a barrier to the trial. A requirement is that the scientific question related to human drug development must be explicitly and clearly stated in the protocol. Due to the unique positioning of the COP the framework of these questions is usually guided by the COP as many outside investigators are unfamiliar with this process. Trials conducted by the COTC are designed to include clinical and biological endpoints i.e. pharmacokinetics and pharmacodynamics so as to optimally inform the design of early phase human trials and assist in the difficult transitions between early and later phase human trials. The process of trial initiation and scientific development is led by the COP but involves detailed and iterative discussions with the trial sponsor and COTC investigators. The infrastructure that exists to implement trials within the COTC is leveraged against existing structures within the CCR. For example in collaboration with Jeff Shilling/Pamela Asangong (CCR) we maintain a ""dog friendly"" version of the CCR's C3D (Oracle Clinical) data reporting system. This allows real-time data entry and review under Good Clinical Practice (GCP) by COTC investigators and sponsors exactly analogous to the forms used in human trials. This enables sponsors to quickly assess study results and use them in FDA submissions. The first completed COTC trial was published in 2009 and the 30th trial concept is currently open for enrollment. The detail and scientific rigor mandated for COTC studies is exemplified in our trial protocols. Examples of our open trial protocols are provided under Section V/Clinical Protocol Summary. Despite the progress made in the field of comparative oncology the concept of evaluating new therapeutics in large animals that naturally develop cancer and share strong similarities to human cancers is still considered novel. A significant need in the field is to present this opportunity its risks and potential rewards to various stakeholders not least of which is Pharma. Not all questions should or can be asked through this approach and thus COP plays an important role in providing stewardship over these resources. This expertise has recently been disseminated in the form of a Perspectives piece in Clinical Cancer Research addressing the questions and associated value of comparative oncology studies as well as an invited review in Nature Reviews Cancer. With regard to specific clinical trial activities we recently published the results of a Morris Animal Foundation trial that evaluated adjuvant mTOR inhibition as an anti-metastatic approach in canine osteosarcoma as well as an NCI-sponsored clinical trial of 3 novel TOP1 inhibitors in canine lymphoma. The results of this publication directly impacted and informed the IND submissions for these agents to be assessed in the human Phase 1 setting. Finally we recently worked with our team of extramural COTC investigators to publish an updated version of the Veterinary Common Terminology Criteria for Adverse Events (V-CTCAE) to harmonize standard for AE reporting across comparative oncology studies conducted in our program and across the community." 108586 +Cancer; HIV/AIDS; Hematology; Immunization; Infectious Diseases; Lymphatic Research; Lymphoma; Prevention; Rare Diseases; Urologic Diseases; Vaccine Related; Vaccine Related (AIDS) Acquired Immunodeficiency Syndrome;Acute;Animal Experimentation;Animal Model;Animals;B-Cell Lymphomas;Basal Cell;Basic Science;Brain;Breast;Cancer Center;Cervical;Clinical;Colon;Communities;Cutaneous Melanoma;Development;Fostering;Future;Genetically Engineered Mouse;HIV;HIV/AIDS;Head and neck structure;Hematopoietic Neoplasms;Imaging technology;Intramural Research Program;Kidney;Liver;Lung;Lymphoma;Malignant Neoplasms;Molecular Target;Multiple Myeloma;Myelogenous;NCI Center for Cancer Research;National Cancer Institute;Ovarian;Pancreas;Pre-Clinical Model;Preclinical Testing;Principal Investigator;Prostate;Rana;Rattus;Research;Research Personnel;Skin Neoplasms;Squamous cell carcinoma;Thyroid Gland;Training and Education;Validation;Zebrafish;animal resource;melanoma;nonhuman primate;novel;pre-clinical;pre-clinical research;programs;technology development Basic and Preclinical Animal Models in support of Cancer and HIV-AIDS Research n/a NCI 10703133 1ZIGBC010856-16 1 ZIG BC 10856 16 9414522 "CUSTER, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 20018915 NCI The Center for Cancer Resarch animal program fosters cutting edge basic and preclinical research for creation and use of novel genetically engineered mouse models as well as other animal models including non-human primates rats zebrafish frogs etc. for cancer and HIV/AIDS. The program determines needs of CCR Principal Investigators seeks to fulfill them and facilitates their implementation. The program provides animal resources training and education imaging and technology development in support of moving basic science discoveries to the clinical setting. Keywords: preclinical models molecular targets cancers: including plasma cell myeloma acute myeloid lymphoma B cell lymphoma breast lung kidney prostate pancreas thyroid brain colon head and neck liver melanoma skin cervical ovarian AIDS HIV molecular targets 20018915 +Cancer; Clinical Research; Health Services Area;Basic Science;Cancer Biology;Chest;Clinical;Clinical Data;Clinical Research;Clinical Services;Conduct Clinical Trials;Data Analyses;Disease;Educational Curriculum;Educational process of instructing;Endocrine;Environment;Evaluation;Exposure to;Fellowship;Foundations;Funding;Future;Hepatobiliary;Laboratories;Literature;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Methods;Modernization;Molecular;National Cancer Institute;Operative Surgical Procedures;Outpatients;Patient Care;Patients;Peritoneal;Postoperative Care;Research;Research Project Grants;Rotation;Science;Scientist;Series;Side;Speed;Statistical Data Interpretation;Surface;Surgeon;Surgical Oncologist;Surgical Oncology;Time;Tissues;Training;Training Programs;Translational Research;United States National Institutes of Health;base;bench to bedside;cancer therapy;clinical center;design;direct patient care;follow-up;gastrointestinal;interest;laboratory experience;lectures;meetings;molecular oncology;multidisciplinary;programs;symposium;translational study;tumor Surgical Oncology Program Training Program n/a NCI 10703131 1ZIEBC012097-01 1 ZIE BC 12097 1 78858651 "BLAKELY, ANDREW " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 4132753 NCI The Surgical Oncology Research Fellowship at the National Cancer Institute is a fully-funded 2- or 3-year program designed to educate and develop future leaders in the field of Surgical Oncology. This includes 18 months of bench laboratory experience in one of the many NCI laboratories with the option to extend for an additional year. The fellowship connects fundamental basic science research in cancer biology to translational studies in patients and patient-derived tissues. Fellowship training involves 3 components: 1) Focused laboratory-based and clinical research in cancer biology particularly related to surgical aspects of the disease; 2) Formal didactic teaching in modern cancer biology including the molecular basis of cancer and mechanisms of current cancer therapies and 3) Operative clinical rotations in key surgical oncology subspecialties. In addition to bench research Fellows participate in clinical research projects and have first-hand exposure to the design and conduct of clinical trials including statistical analyses of clinical data. All Fellows participate in a formal didactic lecture and discussion curriculum Foundations of Modern Cancer Biology designed to quickly bring surgical residents up to speed in understanding the current state of molecular oncology. The curriculum covers current and historical breakthroughs in cancer and cancer treatment through a series of lectures and literature-based discussions focusing on experimental methods and data interpretation in tumor types of particular interest to surgical oncologists. Finally Fellows participate on surgical rotations in the areas of gastrointestinal hepatobiliary endocrine thoracic and peritoneal surface and gynecologic malignancies. Fellows actively participate in all aspects of patient care including conducting the pre-operative evaluation performing the operative procedure and providing post-operative care and subsequent outpatient follow-up. In addition to daily rounds with the attending surgeons clinical training is further enhanced by a series of weekly conferences including multidisciplinary molecular-based tumor boards a weekly clinical service meeting a diverse array of talks on the latest topics in cancer and biomedical science in general by some of the world's most outstanding scientists through lecture series and Grand Rounds held across the entire NIH campus. For fiscal year 2022-2023 there are 13 fellows within the Program 6 in their first year 6 in their second year and 1 in her third year. 4132753 +Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Patient Safety Address;Adopted;Advanced Practice Nurse;American;American Nurses' Association;Back;Biological;Canada;Certification;Collaborations;Community of Practice;Competence;Country;Data;Data Analyses;Delphi Study;Developing Countries;Development;Discipline of Nursing;Distance Education;Education;Educational Curriculum;England;European;European Union;Faculty;Finland;Funding;Genetic;Genomics;Goals;Graduate Degree;Grant;Guidelines;Health;Health education;Healthcare;Hospital Planning;Hospitals;Indiana;Institutes;Intervention;Knowledge;Leadership;Learning;Left;Licensure;Los Angeles;Malignant Neoplasms;Measures;Mentors;Methodology;Methods;Modeling;National Health Services;National Human Genome Research Institute;National Institute of Nursing Research;Natural regeneration;Nurse Midwives;Nurse Practitioners;Nurses;Nursing Education;Nursing Faculty;Nursing Research;Outcome;Output;Paper;Patient Recruitments;Pharmacogenomics;Phase;Postdoctoral Fellow;Precision Health;Protocols documentation;Published Comment;Publishing;Registered nurse;Regulatory Element;Reporting;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Science;Scientist;Services;Strategic Planning;Stream;Surveys;Teacher Professional Development;Technology;Testing;Text;Time;Training;Training Programs;Translations;United Kingdom;United States National Institutes of Health;Universities;Update;Voting;Wales;Work;Workforce Development;academic preparation;arm;base;clinical practice;college;coronavirus disease;design;digital;doctoral student;education planning;evidence base;falls;follow-up;implementation study;instrument;international partnership;invention;medical specialties;meetings;pandemic disease;pilot test;recruit;science education;skills;success;symptom science;tool;training opportunity;university student;usability;web site;webinar Genomic Competency Initiative n/a NCI 10703129 1ZIEBC011912-04 1 ZIE BC 11912 4 16162371 "CALZONE, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 105292 NCI Project 1-Nursing Capacity in Pharmacogenomics: The national study of advanced practice nurses assessing pharmacogenomic capacity is being done collaboration with Dr. Cathy Fulton at Indiana University. The instrument was pilot tested and the protocol approved as Exempt at Indiana University and the NIH 000990. The study recruited participants from the Coalition of Advanced Practice Registered Nurses of Indiana (CAPNI) and the American Association of Nursing Practitioners annual meeting. CAPNI disseminated the survey electronically will end recruitment in August 2022. Once CAPNI completes recruitment data analysis will begin. Thus far we been unsuccessful in having the American Association of Colleges of Nursing disseminate a faculty specific pharmacogenomic survey. We are exploring other mechanisms to gather faculty data on pharmacogenomic capacity and curricular content. Project 2-Omics Nursing Science and Education Network (ONSEN): The National Institute of Nursing Research (NINR) Director has changed. The current director changed NINR reserarch priorities to not include genomics or other biologic correlatives. The new strategic plan reflects this direction and NINR funding for studies that include biologic correlatives has been discontinued as has the Summer Genetics Institute (SGI). The intramural symptom science investigators have left NINR. Funding for the ONSEN was discontinued and the website is being taken down though I have navigated moving the website to the University of Pittsburgh (UPitt). The National Human Genome Research Institute (NHGRI) asked me to update the Genomic Nursing Science Blueprint. I discussed that NINR will not participate and there is no mechanism to both train nursing scientists to integrate genomics into their research nor a funding stream to support this work. NHGRI asked the NINR Director to speak at Council and Drs. Brody and Green plan to meet with her in follow-up given concerns they have and I have met with Dr. Brody at his request to provide some background information. I am moving forward with the Blueprint on a global scale through G2NA (Project 3) and will work with UPitt to expand ONSEN for global use. If there is a US funding stream for genomic nursing science (many are symptom science) then I will explore mechanisms for regenerating the Summer Genetics Institute as a possible NCI/NHGRI collaboration. Project 3-Global Genomics Nursing Alliance (G2NA): G2NA established in 2017 has grown to 146 nursing leaders. The G2NA website https://g2na.org/ has funding and support from the University of South Wales (USW); sustains quarterly education webinars; grown the countries represented; established a strategic plan; communicates through a listserv; completed or are conducting research projects described below. Three Communities of Practice received the most votes from G2NA constituents to move forward: Workforce Development; Clinical Practice; and Overcoming Barriers. However the pandemic has slowed the launch. The current action plan is to launch one and evaluate success. Two primary research outputs from G2NA the Roadmap and the Maturity Matrix have both been adopted by England National Health Service and Health Education England in their country wide genomic implementation initiative. This effort is still in the early phases i.e. the faculty training program was July 2022 despite being planned 3 years ago. As this implementation moves ahead large scale usability data on the Maturity Matrix and Roadmap will be conducted to refine both tools. Establishing a Global Genomic Nursing Science Blueprint is still in place but delayed. This project starts with a systematic evidence review with a doctoral student from USW working with me. She had both personal and health problems but is finally back at it. But we needed an updated search. The first 6388 papers have had abstract reviews. The second updated search is in Covidence and there are 5 reviewers. 995 new abstracts need review 331 have 1 vote and 490 full text in Covidence need review. The plan is to have the remainder of abstracts/papers reviewed by October 1. The doctoral student will coalesce the evidence at which time G2NA will convene a panel to establish a Global Genomic Nursing Research Blueprint. The project to establish the Global Minimal Genomic Competencies for nurses and midwives was unable to move ahead in this reporting period due to COVID as panelists include academic educators who had to transition to and back out of remote education. Methods have been established and the project now will launch late fall 2022 or spring 2023. Lastly a team from Finland United Kingdom Canada and myself a COST Action European Union grant which provides funding for European and global research and capacity building initiatives. This will be submitted 10/2022 with 15 country partners besides the submission team. If funded this will facilitate the ability to convene the meetings for establishing the Blueprint but also a research consortium and genomic capacity building initiatives and establishing evidence-based best practices and a resource toolkit. Project 4-The Genomic Nursing Competency (GNC) Update: With my collaborator Laurie Badzek we submitted a proposal to the American Nurses Association for a national nursing precision health and genomic competency initiative which was approved and has launched. The previously updated but not published Genomic Nursing Competencies will be disseminated for public comment in August 2022. Changes will be integrated and ANA will digitally publish them followed by integration into Scope and Standards of Practice so the existence of Competencies will no longer be required. ANA is also supporting the update the Genetic and Genomic Competencies for Graduate Nurses. This will use the same methodology as the original competency update a Delphi study. The Delphi reviewers have been selected and the list approved by ANA. Invitations will be go out September 2022. The Delphi Survey will launch once the Delphi panel is fully populated. Competencies will be revised based on the findings of the different rounds to Delphi then disseminated for public comment and digitally published once all comments are addressed followed by integration into Scope and Standards. An additional project arm is to conduct a national precision health and genomics nursing competency assessment to inform whether a national nursing genomic education initiative is required. The genomics questions will use the Genetic and Genomic Nursing Practice Survey (my instrument). Questions for precision health are being crafted and validated by the Precision Health team. Once completed with regulatory review and approval the survey will be disseminated as a single instrument. The decision about education inventions will be determined based on the findings. A genomic implementation study will be conducted at Cedars Sinai building on my original MINC study and use the Roadmap and Maturity Matrix Tool. MINC-2 will be cancer focused and a phased project. Phase 1 will be conducted at the primary Cedars in Los Angeles. Phase 2 will roll out to all hospitals with cancer services within the Cedars conglomerate. This project will measure competency and implementation at baseline and at the conclusion of the study and compare usual hospital planned education/competency initiatives to the intervention same hospital. Cedars leadership approval is in place. A genomic post doc funded by NHGRI and ACMG has been with me and our Cedars collaborator B *TRUNCATED* 105292 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Pancreatic Cancer; Rare Diseases CCR;Chest;Clinic;Clinical;Clinical Skills;Clinical Trials;Goals;Instruction;Interest Group;Journals;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Malignant neoplasm of thorax;Medical Oncologist;Medical Oncology;Mission;Patient-Focused Outcomes;Patients;Primitive foregut structure;Protocols documentation;Research Personnel;Surgical Oncology;Training;improved outcome;interest;mesothelin;oncology program;symposium;treatment response;tumor Clinical Support n/a NCI 10703128 1ZIEBC011653-08 1 ZIE BC 11653 8 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 13011 NCI The Thoracic and Gastrointestinal Malignancies Branch (TGMB) and Surgical Oncology Program (SOP) have a number of ongoing clinical trials for patients with mesothelin-expressing malignancies. I participate as an Associate Investigator on these trials by seeing trial patients and assessing patient clinical response to therapy. Training new researchers is an important part of the NCI mission. I provide instruction to CCR Medical Oncology fellows that rotate through the GI and Thoracic clinics. I participate in GI Cancer Journal Clubs and also in Foregut Tumor Board which is an interbranch conference for clinicians interested in GI malignancies. I organize an interdisciplinary pancreas cancer journal club monthly for the Pancreatic Cancer Interest Group. 13011 +Cancer; Childhood Leukemia; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Hematology; Neuroblastoma; Neurosciences; Pediatric; Pediatric AIDS; Pediatric Cancer; Rare Diseases Accreditation;Adolescent and Young Adult;Adult;Cause of Death;Central Nervous System Neoplasms;Child;Childhood;Clinical;Clinical Research;Clinical Services;Disease;Education;Endocrine Gland Neoplasms;Fellowship;Institution;Joints;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical;Mentors;Minor;Mission;Neuroblastoma;Nurse Practitioners;Patient Care;Patients;Pediatric Oncology;Physicians;Quality of life;Scientist;Soft tissue sarcoma;Survivors;Training;Training Programs;Translating;Translational Research;United States National Institutes of Health;clinical care;clinical center;graduate medical education;improved;leukemia/lymphoma;melanoma;osteosarcoma;pediatric patients;rare cancer;therapy development;tumor Pediatric Oncology Branch Clinical Care and Education n/a NCI 10703127 1ZIEBC011516-10 1 ZIE BC 11516 10 14732189 "GLOD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 6538219 NCI The Clinical Director of the Pediatric Oncology Branch oversees the pediatric oncology clinical service at the NIH Clinical Center and has budgetary and supervisory responsibility for the clinical fellows nurse practitioners and patient care coordinators. The NCI fellowship training program is a joint training program with Johns Hopkins Medical Institutions. The joint training program is accredited by the Accreditation Council for Graduate Medical Education (ACGME). Together we oversee the mentoring and training of 20 fellows. 6538219 +Cancer; Genetics; HIV/AIDS Accreditation;Anatomy;Area;Autopsy;Biological Assay;COVID-19;Case Study;Clinical;Clinical Research;Clinical Trials;Clonality;Communicable Diseases;Consult;Consultations;Cytopathology;DNA Methylation;DNA analysis;Diagnosis;Diagnostic;Digestive System Disorders;Disease;Disease Management;Educational process of instructing;Enrollment;Etiology;Exposure to;Extramural Activities;Flow Cytometry;Fluorescent in Situ Hybridization;Functional disorder;Funding;Gene Mutation;Genes;Genetic study;Hematopathology;Institutes;Investigation;Kidney Diseases;Laboratories;Learning;Lymphoid;Malignant Neoplasms;Medicine;Mission;Molecular Genetics;Mutation;Oncology;Outcome;Pathogenesis;Pathologic;Pathology;Patient Care;Patients;Philosophy;Play;Protocols documentation;Publications;Research;Research Activity;Research Training;Residencies;Role;Services;Surgical Pathology;Techniques;Tissues;Training;Training Programs;United States National Institutes of Health;base;cancer therapy;clinical center;disease diagnosis;epidemiology study;experience;improved;insight;molecular diagnostics;neoplastic;nervous system disorder;neuropathology;next generation sequencing;novel;programs;recruit;research clinical testing;soft tissue;urologic Anatomic Pathology Residency Program n/a NCI 10703126 1ZIEBC011384-12 1 ZIE BC 11384 12 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2039628 NCI Residents in the Anatomic Pathology Residency Program contribute to the clinical research program of the NCI and the NIH. Through their efforts as anatomic pathology residents in training they help illuminate the pathological changes associated with initial presentation and therapy of both neoplastic and non-neoplastic diseases and explore new techniques to improve diagnosis of these diseases. These residents are critical to the patient care activities of the NCI and the NIH and contribute to the diagnosis and management of disease especially COVID-19 this year. Residents have also contributed to publications dealing with characterization diagnosis and pathogenesis of a number of disease entities. 2039628 +Cancer; Clinical Research; HIV/AIDS; Hematology Academy;Accreditation;American;Appointment;Career Choice;Child;Clinical;Clinical Research;Communication;Communities;Consultations;Credentialing;Data;Dedications;Diagnosis;Diagnostic;Diagnostic Services;Disease;District of Columbia;Educational Curriculum;Environment;Exposure to;Faculty;Fellowship;Fellowship Program;Flow Cytometry;Functional disorder;Future;Goals;Head;Hematology;Hematopathology;Hospitals;Immune System Diseases;International;Investigation;Journals;Laboratories;Literature;Lymphoma;Medical;Medical center;Medicine;Mentors;Occupations;Oral;Paper;Pathology;Patient Care;Patients;Peer Review;Philosophy;Positioning Attribute;Procedures;Publishing;Research;Research Project Grants;Review Literature;Rotation;Services;Techniques;Time;Training;Training Programs;Translational Research;United States;United States National Institutes of Health;University Hospitals;Washington;career;clinical center;experience;individual patient;medical specialties;meetings;member;molecular diagnostics;neoplastic;posters;programs;skills;success;symposium Hematopathology Fellowship n/a NCI 10703125 1ZIEBC011241-14 1 ZIE BC 11241 14 9692515 "JAFFE, ELAINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 657455 NCI "All the Clinical Fellows become involved in research projects while their fellowship. Fellows hone their presentation skills through their participation in Journal clubs and Data clubs held on a monthly basis. At these meetings fellows discuss recent papers from the published literature and present results of their ongoing projects. These conferences help them transition to their future career path with most of them remaining in the academic sector. In addition to our daily interactions while fellows are on service we have more formal meetings at least twice each year to discuss career goals and job opportunities. More frequent meetings are held to discuss their current research projects at least monthly. We hold regular conferences with clinical branches treating patients with lymphoma and other immune disorders. Mentoring of trainees and Lab members has been a major focus of our group and the success that our trainees have had since leaving the NIH is evidence of our dedication to these goals. Since my appointment as Head of the Hematopathology Section in 1980 we have trained more than 60 Clinical Fellows in Hematopathology. Dr. Pittaluga is Program Director a position held since 2005. While the fellowship is sponsored by the Hematopathology Section LP NCI fellows spend a considerable portion of their time in rotations in different units to broaden their educational experience. The ""credentialing year"" of the ACGME accredited program includes rotations in the Hematopathology Section LP (4 months) the Hematology Service of the Department of Laboratory Medicine Clinical Center (DLM CC) (4 months) Flow Cytometry Unit (1 month) Molecular Diagnostics Unit (1 month) Hematopathology Division of the Johns Hopkins Hospital (1 month) with optional rotations at the Children's National Medical Center Washington DC and George Washington University Hospital. In the second year of the program fellows have 7 months of protected research time and enhance their diagnostic skills through an additional five months of diagnostic service in the Hematopathology Section LP and the Hematology Service DLM CC. Each of the fellows is sponsored to attend the week-long Tutorial in Neoplastic Hematopathology an experience that further rounds out the educational curriculum. 100% of our fellows have passed on the first attempt the examination in Hematology offered by the American Board of Pathology Since 2015 trainees in the Hematopathology Section have authored more than 50 articles in the peer-reviewed literature. Fellows present at one of the scientific meetings related to our specialty most often the United States and Canadian Academy of Pathology (USCAP). This year three of the four fellows in the program presented papers at the USCAP meeting two of which were selected for oral presentations and one for poster." 657455 +Cancer; Clinical Research; HIV/AIDS; Hematology; Infectious Diseases; Lymphatic Research; Lymphoma; Orphan Drug; Rare Diseases AIDS related cancer;Acquired Immunodeficiency Syndrome;Adult;Ambulatory Care;American Cancer Society;American Society of Clinical Oncology;Anti-Retroviral Agents;Appointment;Area;Basic Science;Board Certification;Bone Marrow Examination;Cancer Control;Centers for Disease Control and Prevention (U.S.);Clinic;Clinical;Clinical Oncology;Clinical Research;Clinical Sciences;Communities;Comprehensive Cancer Center;Development;Diagnostic Procedure;Disease;Division of Cancer Prevention;Drug Industry;Educational Curriculum;Educational process of instructing;Ensure;Fellowship;Fellowship Program;First Year Experience;Goals;Hematological Disease;Hematologist;Hematology;Hodgkin Disease;Hospitals;Human;Industry;Intramural Research;Investigation;Journals;Laboratories;Laboratory Research;Leadership;Lymphoma;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maryland;Medical;Medical Oncology;Medicine;NCI Center for Cancer Research;National Cancer Institute;National Heart Lung and Blood Institute;Oncologist;Oncology;Outpatients;Paracentesis;Patients;Peer Review;Physicians;Positioning Attribute;Publications;Renal Cell Carcinoma;Research;Research Activity;Research Personnel;Research Project Grants;Rotation;Scientist;Series;Stem cell transplant;Thoracentesis;Time;Training;Translational Research;United States;United States National Institutes of Health;Universities;Washington;Work;anticancer research;base;cancer therapy;career;chemotherapy;chronic leukemia;clinical care;clinical center;clinical diagnostics;design;drug testing;experience;experimental study;inpatient service;interest;lectures;meetings;member;neoplastic;next generation;novel strategies;novel therapeutics;patient oriented;patient population;programs;recruit;skills;symposium NIH Hematology Oncology Fellowship Program n/a NCI 10703123 1ZIEBC010843-16 1 ZIE BC 10843 16 78858344 "KANAKRY, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 7681463 NCI The NIH Hematology Oncology Fellowship Program provides a unique opportunity for physicians interested in academic careers to develop and integrate both their clinical and basic research interests. This program combines hematology and medical oncology into a series of clinical rotations encompassing 18 months of fellow's training. The clinical portion of the training consists of primary responsibility for the clinical care of inpatients and outpatients with a board spectrum of adult malignancies and hematologic diseases. During the first clinical year there is an emphasis on exposing fellows to the basic science and clinical hematology and oncology. During the research years the fellow will join one of the several hundred available investigators within the NIH to acquire the skills necessary to become an independent biomedical investigator. The NIH works hard to guarantee at least two years of protected research time to all of its fellows. During the first year of training fellows devote 100% of their time to clinical training in inpatient and outpatient care at the NIH Clinical Center (NIH-CC) Georgetown University's Lombardi Comprehensive Cancer Center MedStar Washington Hospital Center. University of Maryland and the Johns Hopkins University. This ensures that fellows undergo comprehensive clinical training and extend their experience with a wide spectrum of human cancers and hematologic diseases. Training in clinical diagnostic procedures such as bone marrow examination thoracentesis and paracentesis is a routine part of the first-year experience. Following completion of this 18-month clinical period the fellow does laboratory or clinical research for up to 4 years of fellowship along with continued outpatient clinical duties. The remaining time in the second and third years is protected time for research in any of the NCI or NHLBI Clinical Teams or any NIH laboratory. Offered throughout the Program are lectures research seminars conferences journal club teaching rounds and conferences relevant to clinical hematology and oncology and cancer research. Most of these are organized specifically for hematology oncology fellows. These include a core curriculum lecture series in clinical hematology and oncology which meets once a week throughout the year and offers lectures by members of the senior staff across the spectrum of issues in neoplastic disease. Fellows are responsible for preparing case presentations and lecture material. In addition there are 10 to 15 research seminars and lectures given per day throughout the NIH; these are advertised in a weekly announcement and are regularly open to the entire NIH community. It is expected that each fellow's research activities will lead to at least one abstract presentation at a national meeting and one or more peer-reviewed publication. All fellows are expected to actively engage in a hypothesis-driven research project(s) in a clinical translational or basic science. The NIH-CC emphasizes the development of new approaches to the treatment of cancer and its complications. Current areas of clinical emphasis include prostate cancer ovarian cancer renal cell carcinoma lymphomas Hodgkin's disease chronic leukemia new drug testing stem cell transplantation and AIDS and its associated malignancies. Patients with AIDS and AIDS associated malignancies constitute approximately 5% of the total patient population; nearly all these patients are involved in studies of experimental antiretroviral compounds and chemotherapy. 7681463 +Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health; Neurosciences; Precision Medicine; Rare Diseases Brain Neoplasms;Cancer Diagnostics;Central Nervous System Neoplasms;Classification;Clinical;Clinical Pathology;Collaborations;DNA Methylation;DNA sequencing;Development;Diagnosis;Diagnostic;Europe;Fluorescence;Formalin;Gene Fusion;Goals;Histopathology;Human;Immunohistochemistry;Laboratories;Lead;Malignant Neoplasms;Methods;Methylation;Modality;Molecular;Mutation;New York;North America;Paraffin Embedding;Pathology;Patient Care;Patients;Process;Publishing;RNA;Resources;Series;Solid Neoplasm;Specimen;Techniques;Tissue Sample;United States;Universities;Update;base;clinical practice;diagnostic accuracy;diagnostic criteria;improved;individual patient;molecular diagnostics;next generation sequencing;personalized diagnostics;precision oncology;programs;standard of care;tumor;tumor diagnosis;virtual;whole genome Classification of tumors using whole-genome methylation profiling n/a NCI 10703120 1ZIDBC012090-01 1 ZID BC 12090 1 78858639 "ABDULLAEV, ZIED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 213667 NCI Given the emphasis at the NCI on precision cancer medicine the NCI-Laboratory of Pathology has implemented methylation-based modality for routine diagnostic on all brain tumor cases. While this technique is being used at several centers in Europe to our knowledge we are one of only 3 centers in North America (in addition to the University of Toronto and New York University) where this has been implemented for brain tumor diagnosis. The goals of the brain tumor diagnosis program at the NCI-Laboratory of Pathology are to serve as a precision diagnostic modality for patients seen at the NCI and as a resource for diagnostic applications for difficult-to diagnose brain tumors throughout the United States. An advantage of this platform in a pathology practice is that it is technically robust on routinely processed formalin-fixed paraffin embedded (FFPE) tissue samples making this applicable to virtually any brain tumor specimen encountered in daily practice. Overall methylation classifier for brain tumors is perhaps the most exciting development in solid tumor cancer diagnostics since the advent of techniques such as immunohistochemistry and fluorescence in-sit hybridization (FISH). Going forward methylation classifiers are being developed for additional tumor types using the same platform increasing its utility and application across the spectrum of human cancer. The NCI Laboratory of Pathology is poised in collaboration with partners in Europe and North America to help lead this effort for a new era in precision cancer diagnostics. 213667 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Genetic Testing; Genetics; Health Services; Human Genome; Precision Medicine; Rare Diseases Address;Advisory Committees;Award;Back;Bioethics;Blood specimen;CCR;CDH1 gene;Cities;Classification;Clinical;Clinical Services;Collaborations;Communities;Community of Practice;Companions;Complex;Consent;Consult;Consultations;Continuing Education;Contracts;Data;Development;Disclosure;Doctor of Philosophy;Education;Education Gap;Educational Curriculum;Electronic Mail;Enrollment;Extramural Activities;Fellowship;Film;Funding;Future;Genes;Genetic;Genetic Counseling;Genetic Services;Genome;Genomics;Goals;Health behavior;Healthcare;Hematopathology;Hematopoiesis;Historically Black Colleges and Universities;Hour;Individual;Infrastructure;Inherited;Institutes;Interview;Label;Laboratories;Leadership;Learning;Longterm Follow-up;Lung;Lymphoma;Malignant Neoplasms;Manuscripts;Medical;Medical Genetics;Mentors;Mesothelioma;National Human Genome Research Institute;Outcome Assessment;Pathology;Patient Schedules;Patients;Persons;Phase;Positioning Attribute;Preparation;Professional counselor;Prostate;Protocols documentation;Provider;Reporting;Research;Resources;Role;Rotation;Saliva;Sampling;Schedule;Services;Ships;Societies;Standardization;Students;Swab;Telemedicine;Telephone;Testing;Therapeutic;Time;Training;Training Programs;Tumor Pathology;United States National Institutes of Health;Universities;Urologic Cancer;Urologic Oncology;Variant;Vocational Guidance;Work;Workload;active duty;base;cancer genetics;cancer genomics;clinical center;clinical infrastructure;clinically relevant;cohort;cost;design;empowerment;evidence base;exome sequencing;experience;genetic counselor;genetic testing;genetic variant;improved;interest;journal article;malignant stomach neoplasm;medically underserved;meetings;member;multidisciplinary;novel;online community;precision oncology;programs;protocol development;research study;simulation;skills;student mentoring;symposium;tumor;underserved community;working group Clinical Cancer Genomics Program n/a NCI 10703116 1ZIDBC011908-04 1 ZID BC 11908 4 16162371 "CALZONE, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1579391 NCI The Clinical Cancer Genetics Service (CCGS) is partially staffed with 1-parttime and 2 full-time cancer genetic counselors (GC). Our clinical cancer geneticist Dr. Chimene Kesserwan decided to pursue a hematopathology fellowship starting 7/1/2022. On 6/30/202 she transitioned to an NIH Research Collaborator position continues to provide clinical genetic expertise consultation and contributes to clinical and T/N WES germline variant curation. She will be conducting a Clonal Hematopoiesis study once the exemption is approved. The CCGS conducts weekly case conferences with fellows students and others for testing decisions result interpretations and to discuss complex patients. Dr. Sheila Rajagopal attends our case conference and provides medical support which Dr. Meltzer agreed she had the expertise needed. The CCGS has achieved the following: 1) Genetic Counselor Training Program: The MOU with the National Human Genome Research Institute (NHGRI) for the NIH Genetic Counseling Training Program (GCTP) was renegotiated signed April 2022. In this renewal NHGRI declined to expand the cohort of annual student beyond the 2 funded by CCR. The 4th cohort begins 8/2022 and the 2nd expanded cohort will graduate 12/2022. The NCI funded GCTP Assistant Director continues as an active member of the City of Hope cancer genetic Community of Practice. This year working with Drs. Biesecker and Meltzer she developed and conducted a Precision Oncology GC course and applied to Johns Hopkins Department of Health Behavior and Society to obtain credit approval. She created a cancer genetic standardized patient (SP) rotation that included scripting 7 patient cases actor training outcome assessments and identifying additional preceptors. She is working with GCTP leadership to develop a manuscript about SP best practices. She also designed and taught a companion course aimed at improving genetic counseling students' case preparation skills in the cancer. She participated in an outside consultant curriculum review and continues to interview and rank applicants. CCGS GCs accepts students for clinical experiences mentoring and thesis advising. Dr. Jamal continues 50% effort with the NIH Department of Bioethics. 2) CCGS provides protocol development support and clinical services to manage genomic results and provides genetic counseling/testing. Our request to be a formal consult service in 2019 was not approved. CCGS maintains a central email and phone line for consult requests and worked with NHGRI so cancer consults submitted to the NHGRI consult service are referred back to us. Drs. Gulley and Levine are exploring ways to address this. From 7/10/2021-7/9/2022 CCGS saw 216 consults (not includingT/N WES [data below]) with an additional 125 requests for chart and/or genetic test report reviews. Most germline tests are conducted by outside laboratories i.e. Invitae. Test request forms for outside labs are completed by the GC that saw the patient. Our group enters all POTS my CAN pays for the test then quarterly reconciles with the PI CAN. Invitae has laid off 1000 staff as part of restructuring which in the future may change our contract genetic test cost. Dr. Gulley is exploring options with LP to expand their testing platform to include clinical grade germline testing. CCGS continues to see patients mostly using telemedicine without compromising consult availability or quality. Patients are seen in person when clinically indicated and to retrieve blood samples for laboratory shipment. Most germline samples are collected using saliva or buccal swabs. GCs are embedded in four services based on consult numbers and/or protocols requiring germline testing: Prostate; Lung; Mesothelioma; and Inherited Gastric Cancer. From 7/10/2021-7/9/2022 there were 49 CCR for T/N WES. Dr. Calzone and GC Yi Liu participate in the weekly paired T/N WES signout meeting conducted by LP. Our team is the primary reviewer of all germline variants in QCI provides the initial variant classification and crafts the initial variant interpretation section on the germline report.. The CCGS GC Assistant is the central contact for T/N WES consent requests and patient scheduling for all NIH. An additional 47 T/N WES cases not for CCGS were scheduled with most (44) going to the CCR POB/NOB GC. For T/N WES encounter occurs when the patient is not at the Clinical Center saliva or buccal swab kits are mailed to the patient with a return Fedex label. CCGS currently covers all kit purchases and mailing costs. On 6/15/2022 Dr. Calzone met with the CCR Lymphoma team including Drs. Roschewski and Staudt. They have obtained approval from Dr. Ken Aldape to perform T/N WES on all patients seen by this team. The estimate provided is approximately 250 T/N WES cases/year from the lymphoma team. CCGS conducted a workload study from 4/1/2022-4/29/2022. These data are being used to establish current workload begin to establish genetic counselor time for activities such as T/N WES consent/result disclosure and average counselor time based for general consults based on case complexity. However this assessment was conducted prior to Dr. Kesserwan announcing her departure. Therefore a second assessment of the time/workload associated with variant curation when done by the GC followed by confirmation by Dr. Kesserwan review is underway. These data will help inform whether we can accommodate this significant increase in T/N WES cases including variant curation with existing staff. Continuing education efforts included a program in collaboration with the Urologic Oncology Branch which ran 9/2020-6/2022. Weekly one-hours sessions open to intramural and extramural providers awarded 1 CE and were taped for future use. Topics included basic cancer genomics genetic counseling fundamentals urologic cancer genetics including therapeutics review of journal articles and clinical cases. CCGS is creating a Global Genetics and Genomics Community online unfolding case https://www.genomicscases.net/en with NHGRI funding. The case has been filmed and is in the final phases of going up online. This webite will move to genome.gov this year. CCGS also supports education and mentoring of students interested in a genetic counseling career. GC Grace-Ann Fasaye co-founded the Genetics Opportunities Learning Development Empowerment and Networking (GOLDEN) Program for students at Historically Black Colleges and Universities interested in pursuing a GC career. GOLDEN aims to increase the profession diversity and improve genomic service access in medically underserved communities. CCR supported a GOLDEN post-bacc Elise Travis who started 1/3/2022. She completed an inherited gastric cancer cascade testing study and has been accepted into a PhD/GC program which begins 8/2022. 3) Genomic Variant Curation: Interpreting genomic variants is a challenge. ClinGen has built a central resource to define the clinical relevance of genomic variants and convened several Working Groups (WG) Task Forces (TF) Gene Curation Expert Panels and Variant Curation Expert Panels (VCEP) which CCGS actively participates. With Dr. Kesserwan's departure for the fellowship the CCGS representation on these panels is limited. Grace Fasaye continues as a member on the CDH1 VCEP. 1579391 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunotherapy; Minority Health; Neurosciences; Orphan Drug; Precision Medicine; Radiation Oncology; Rare Diseases Adult;American Society of Clinical Oncology;Angiogenesis Inhibitors;Antineoplastic Agents;Basic Science;Belief;Biological Response Modifiers;Biology;Biotechnology;Brain;Brain Neoplasms;Cancer Center;Cardiology;Central Nervous System;Central Nervous System Neoplasms;Characteristics;Child;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Complement;Complex;Consultations;Dana-Farber Cancer Institute;Disease;Doctor of Medicine;Double-Blind Method;Endocrinology;Ensure;Environment;Fellowship;Freedom;Genetic;Glioblastoma;Glioma;Group Practice;Health;Health system;Healthcare;Hospitals;Immune checkpoint inhibitor;Immune response;Immunocompetence;Immunologic Monitoring;Infrastructure;Institution;Intramural Research Program;Journals;Kansas;Laboratories;Leadership;Malignant Glioma;Malignant Neoplasms;Measures;Medical;Medical Oncology;Medical center;Medicine;Methodist Church;Microscopic;Mission;Molecular;Monitor;Morphology;National Cancer Institute;National Heart Lung and Blood Institute;National Institute of Mental Health;National Institute of Neurological Disorders and Stroke;Neurocognitive Deficit;Neurology;Neurosurgeon;New England;Newly Diagnosed;Nivolumab;North Carolina;Nurse Practitioners;Nursing Research;Ohio;Oncologist;Oncology;Ophthalmology;Pain;Pathology;Patient Agents;Patient Care;Patient-Focused Outcomes;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Pharmacologic Substance;Physical Medicine;Physicians;Placebo Control;Primary Brain Neoplasms;Privatization;Psychiatry;Publishing;Quality of life;Radiation Oncologist;Radiation Oncology;Radiation Therapy Oncology Group;Randomized;Research;Research Personnel;Research Project Grants;Resources;Role;Running;Second Opinions;Site;Social Work;South Carolina;Specialist;Specimen;Spinal Cord Neoplasms;Stratification;Symptoms;Testing;Texas;Therapeutic;Tissues;Training Programs;Translational Research;Treatment Efficacy;Tumor Tissue;United States National Institutes of Health;Universities;Utah;Washington;anti-CTLA4;anti-PD-1;anticancer research;base;bevacizumab;cancer care;clinical care;clinical center;clinical investigation;cognitive function;collaborative trial;design;drug development;effective therapy;improved;individual patient;individualized medicine;innovation;ipilimumab;medical schools;member;multidisciplinary;neuro-oncology;neurosurgery;novel;novel diagnostics;novel therapeutics;oncology service;palliation;personalized medicine;phase III trial;programs;prototype;safety testing;standard care;survival outcome;tool;translational research program;treatment arm;tumor Brain Tumor Clinical and Clinical Research Program n/a NCI 10703111 1ZIDBC011642-08 1 ZID BC 11642 8 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2214994 NCI "The NOB has made substantial progress towards building an infrastructure necessary for fulfilling its mission of developing new and improved therapies for children and adults with brain and spinal cord tumors. Since Dr. Gilbert's arrival at the NIH in November 2014 he has rebuilt the Brain Tumor Clinical and Clinical Research Program: a highly collaborative robust translational research program centered on finding treatments for brain and other central nervous system tumors. In addition to conducting basic and translational research the NOB has become a nationally recognized resource for patient information and referrals for second opinions. In addition to seeing and treating brain tumor patients Dr. Gilbert currently runs a significant number of national clinical trials and helps organize and administrate over several large national Neuro-Oncology translational science initiatives. Importantly Dr. Gilbert led RTOG 0825 which evaluated the role of the anti-angiogenic agent bevacizumab in patients with newly diagnosed glioblastoma in a double-blind placebo controlled randomized phase III trial. This study accrued 973 patients and successfully incorporated upfront stratification by two molecular parameters as there was 100% compliance with tumor tissue submission. This study which did not demonstrate a survival benefit for bevacizumab demonstrated neurocognitive decline and worsened symptom burden and quality of life in the patients treated with bevacizumab. This study was presented at the Plenary Session at ASCO and published in the New England Journal of Medicine. These efforts have led to his leadership of NRG BN002 a clinical trial that is testing the safety of adding the immune checkpoint inhibitors ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with newly diagnosed glioblastoma. This is the prelude to an NOB study that will help determine whether these immune checkpoint inhibitors have efficacy in glioblastoma by determining if patients who demonstrate a peripheral immune response have improved survival outcomes. A critical component of the trial will be the immunologic monitoring which will comprise testing of tumor tissue for mediators of immune-reactivity and serial monitoring of peripheral blood mononuclear cells as an indicator of the impact of treatment on ""immune competence"". Dr. Gilbert has also transitioned the Brain Tumor Trials Collaborative (BTTC) from M. D. Anderson Cancer Center. This is a national consortium that was founded on philanthropic support. The mission of the BTTC is to rapidly develop and complete innovative clinical trials for patients with primary brain tumors. To date the BTTC has completed a study that used a factorial design (8 treatment arms were evaluated simultaneously) and a trial that used an adaptive randomized design (patient allocation based on treatment efficacy using patient by patient rebalancing). This effort is currently being transferred from the M. D. Anderson Cancer Center to the NCI. There are currently 3 active studies and once relaunched and addition study concepts are anticipated. The list of participating sites is provided below: Aurora Advanced Healthcare National Institutes of Health Baylor University Northwestern University Feinberg School of Medicine Case Western Reserve SOM Ohio State University Cedar-Sinai Medical Center Rush University Cancer Center Cleveland Clinic Texas Oncology Columbia University The Methodist Hospital Dana Farber Cancer Institute University of North Carolina Henry Ford Health System University of Kansas Medical University of South Carolina University of Utah Orlando Health University of Washington Mayo Clinic UT M. D. Anderson Cancer Center Northshore University Health System UT Southwestern Medical Center at Dallas. The NOB has created a vibrant robust and clinically busy center for neuro-oncology excellence that serves as a national resource for patients with CNS malignancies (regardless of their ability to pay) for information consultation clinical trials or referrals to their local centers of excellence for clinical care and NCI-sponsored trials. This was an important accomplishment because: Part of the mission of the NCI is to provide expertise to patients and physicians for a lethal tumor type not frequently seen in the community and for whom standard treatment options are limited. A busy clinical program ensures a steady flow of patients with primary CNS tumors imperative for stimulating clinical and translational research by ensuring rapid patient accrual to clinical trials efficient acquisition of tissue for basic and translational research and for enticing pharmaceutical/biotechnology companies to co-develop novel CNS tumor agents with the NOB and the NCI at large. A multi-disciplinary tumor board convenes every other week and is attended by neuro-oncologists radiation oncologists neurosurgeons neuropathologists and laboratory investigators. Complex and challenging patients are presented and discussed optimizing individual patient care and leading to many collaborative interactions and research projects. This Tumor Board is complemented by a bi-weekly pathology review where NIH neuropathologists prepare specimens from active clinical patients that are examined microscopically and morphologic and genetic features are discussed in conjunction with members of the Brain Tumor Clinical Team. Additionally a Molecular Tumor Board has been incorporated into the Pathology Review that reviews all of the available molecular information from individual patient's tumors so that therapies can be considered in the context of this information. Below are partial lists of accomplishments in the building of an NIH-wide multidisciplinary Brain Tumor Clinic with active participation from three different NCI Branches (ROB MOCRU CCRLP) five different NIH Institutions (NCI NINDS NEI NHLBI NIMH) and six different Clinical Center Programs (Neuroradiology Psychiatry Pain and Palliation Rehabilitation Medicine Social Work). Expertise represented in the clinic includes Medical Oncology Radiation Oncology Neurosurgery Neurology Ophthalmology Cardiology Psychiatry Endocrinology Social Work and Rehabilitation Medicine; Assembled a primary neuro-oncology clinical care/research team which now consists of 6 neuro-oncologists 5 nurse practitioners 5 research nurses 2 clinical fellows 1 clinical collaborator 3 patient coordinators 4 clinical trials specialists; Additionally the NOB provides neuro-oncology services for Walter Reed Medical Center in Bethesda; established close collaborative clinical programs with Johns Hopkins Medical Center George Washington Medical Center Fairfax Inova and Washington Hospital Center and a wide array of private neurosurgical radiation and oncology practice groups locally and nationally; created a neuro-oncology fellowship training program between the NIH and the Johns Hopkins Medical Center. Since the Brain Tumor Clinical and Clinical Research Program re-initiated in 2015 the NOB launched 18 clinical trials." 2214994 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Immunotherapy; Liver Cancer; Liver Disease; Lung; Lung Cancer; Orphan Drug; Pancreatic Cancer; Rare Diseases; Women's Health Antibodies;Antibody-drug conjugates;CCR;Chelating Agents;Chest;Clinical;Clinical Research;Clinical Trials;Conduct Clinical Trials;Drug Targeting;Goals;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotoxins;Label;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Malignant neoplasm of thorax;Malignant neoplasm of thymus;Medical;Non-Small-Cell Lung Carcinoma;Patients;Radiation therapy;Research Personnel;Scientist;Thorium;Tumor Antigens;base;chimeric antigen receptor T cells;drug development;gastrointestinal;innovation;lung small cell carcinoma;mesothelin;novel;preclinical study;standard care;treatment program Thoracic and Gastrointestinal Malignancies Branch Clinical Core n/a NCI 10703109 1ZIDBC011540-09 1 ZID BC 11540 9 6189074 "HASSAN, RAFFIT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1461857 NCI The medical TGMB has a robust clinical program for treatment of patients with advanced thoracic and GI cancers who have failed standard therapies. The thoracic team is conducting innovative studies for patients with non-small cell lung cancer small cell lung cancer malignant mesothelioma and thymic cancers. These include use of novel treatments developed by scientists at the NCI. A major focus of our team is the development of drugs targeting the tumor antigen mesothelin that is highly expressed in many cancers. We are using an immunotoxin -LMB-100 an antibody drug conjugate- BAY 94-9343 thorium-227 labeled antibody-chelator conjugate-BAY 2287411 and mesothelin targeting CAR-T cells to treat these cancers. In addition we are conducting clinical trials using immunotherapy agents including immune checkpoint inhibitors to treat patients with thoracic cancers who have failed standard treatments. The TGMB is also conducting studies for treatment of gastrointestinal cancers with a special emphasis on liver and pancreatic cancer. Investigators within the TGMB have established a robust program for treatment of patients with liver cancer including use of immunotherapy agents either alone or in combination with radiation therapy or locally ablative therapies for liver cancer. The gastrointestinal group is also conducting clinical trials of novel agents for treatment of pancreatic cancer. 1461857 +Behavioral and Social Science; Biotechnology; Cancer; Childhood Leukemia; Chronic Pain; Clinical Research; Clinical Trials and Supportive Activities; Emerging Infectious Diseases; HIV/AIDS; Hematology; Immunotherapy; Infectious Diseases; Mental Health; Neurofibromatosis; Neurosciences; Orphan Drug; Pain Research; Pediatric; Pediatric AIDS; Pediatric Cancer; Prevention; Rare Diseases; Social Determinants of Health; Transplantation Acute Myelocytic Leukemia;Adolescent;Adolescent and Young Adult;Adrenal Glands;Adult;Advance Care Planning;Apple;Apple watch;Attitude;B lymphoid malignancy;Behavioral Sciences;Brain Neoplasms;CAR T cell therapy;CCR;CD19 gene;CD22 gene;CDK4 gene;COVID-19 impact;COVID-19 pandemic;Cancer Patient;Caregivers;Cellular Phone;Central Nervous System Diseases;Cessation of life;Characteristics;Child;Child Development;Childhood;Chronic Disease;Clinic;Clinical;Clinical Trials;Clinical trial protocol document;Cognitive;Cranial Irradiation;Cutaneous;Data;Diagnosis;Discipline;Distress;Docking;Dysmyelopoietic Syndromes;Emotional;Enrollment;Evaluation;Family;Fatigue;Gastrointestinal Stromal Tumors;Hairy Cell Leukemia;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Hydrogen;Imatinib;Immune checkpoint inhibitor;Incidental Findings;Individual;Infusion procedures;Institutes;Intervention;Interview;Investigation;Journals;Leadership;MAP2K1 gene;Malignant Neoplasms;Measures;Medical;Mental Health;Morals;NF1 gene;Natural History;Neoplasm Metastasis;Neurocognitive;Neurofibromatoses;Neurofibromatosis 1;Neurologic Symptoms;Neuropsychology;Outcome;Outcome Measure;Pain;Palliative Care;Parents;Patient Outcomes Assessments;Patient Self-Report;Patients;Pediatric Oncology;Phase;Phase II Clinical Trials;Physical Function;Pilot Projects;Plexiform Neurofibroma;Protocols documentation;Psychosocial Assessment and Care;Psychosocial Factor;Publications;Publishing;Quality of life;RUNX1 gene;Rare Diseases;Reaction Time;Recommendation;Recurrence;Refractory;Relapse;Reporting;Research;Research Support;Services;Siblings;Sickle Cell Anemia;Site;Social Workers;Solid Neoplasm;Stem cell transplant;Sulfate;Surveys;Symptoms;Technical Expertise;Transplantation;Treatment Protocols;United States National Institutes of Health;Voice;base;behavioral health;behavioral health intervention;behavioral outcome;care providers;checkpoint therapy;chimeric antigen receptor T cells;chronic graft versus host disease;chronic pain patient;clinical center;cognitive function;cognitive testing;computerized;design;diet and exercise;flexibility;gut microbiome;health care availability;high risk;inhibitor;medication compliance;medullary thyroid carcinoma;melanoma;mobile sensor;neurobehavioral;neurocognitive test;neurofibroma;neurotoxicity;next generation sequencing;pain outcome;programs;psychosocial;rare cancer;remote assessment;research study;response;sensor technology;social;social skills;stressor;student training;tumor;young adult Pediatric Oncology Branch Behavioral Science Core n/a NCI 10703108 1ZIDBC011517-10 1 ZID BC 11517 10 14732189 "GLOD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1225916 NCI Recommendations for patient-reported outcome measures assessing quality of life and social skills endpoints in NF clinical trials (2021). Impact of COVID-19 on the impact of COVID-19 on mental health and access to health care in adults with neurofibromatosis from an anonymous online survey (2022) Publication of the impact of COVID-19 on the moral distress of pediatric palliative care providers and social workers. First national outcome data on the use of Voicing My CHOiCES an advance care planning guide for adolescents and young adult developed in the POB. Co-edited and published a Special Issue in the Journal Children on Psychosocial Considerations for Children and Adolescents Living with a Rare Disease. Developed an app The Clinical Center Treasure Tour preparing children coming to the NIH Clinical Center Support Intramural PIs: Assessing neurotoxicity using computerized neurocognitive testing and a neurologic symptom checklist that we developed in a phase I/II study of CD33 CAR T-cell infusions in pediatric and adolescent and young adult patients with relapsed/refractory acute myeloid leukemia (PI: Nirali Shah) Assessing neurotoxicity using computerized neurocognitive testing and a neurologic symptom checklist that we developed in a POB phase I CD22 CAR treatment protocol for children with recurrent B-cell malignancies including CNS disease (PI:Shah) Assessing neurotoxicity using computerized neurocognitive testing and a neurologic symptom checklist that we developed and revised based on the CD22 CAR results in the POB phase I CD19/22 CAR treatment protocol for children with recurrent B-cell malignancies (PI:Shah) Assessing neurotoxicity using computerized neurocognitive testing neurologic symptom checklist and patient-reported outcomes on a CD22 CAR trial in adults with Hairy Cell Leukemia (PI:Krietman) Developing a limited-site pilot study to investigate the cognitive aftereffects (subacute and long-term) of neurotoxicity in children and young adults with relapsed/refractory hematologic malignancies who receive CAR T-cell therapy including remote assessments (PI:Shalabi) Assessing patient reported outcomes in children undergoing CAR T therapy and their caregiver through self-report and qualitative interviews (PI: Haneen Shalabi; LAI: Lori Wiener) Collecting subject-reported symptom data prior to infusion of CD33 CAR T-cell infusions and weekly in the month following (PI:Shah) Assessing psychosocial and behavioral outcomes in a longitudinal and natural history study of children and young adults with Medullary Thyroid Carcinoma (MTC) (PI:Widemann) Assessing psychosocial and behavioral outcomes in a longitudinal and natural history study of children and adults with RUNX1 FPD (PI:Liu) Assessing psychosocial and behavioral outcomes in longitudinal and natural history study of children and adults with Adrenal Cortical Cancer (PI:Del Rivero) Assessing psychosocial factors stressors and needs of children and adults with Gastrointestinal Stromal Tumor (GIST) that attend the NIH GIST clinic (PI:Glod) Assessing psychosocial factors stressors and needs of children and adults with Medullary Thyroid Carcinoma (MTC) that attend the NIH MTC clinic (PI:Glod) Investigating the natural history of neuropsychological functioning QOL and pain in children adolescents and young adults with NF1 (PI:Widemann) Analyzing the long-term patient-reported outcome (PRO) data of pain physical function and quality of life in a registration phase II clinical trial of selumetinib in children with NF1 and inoperable plexiform neurofibromas which contributed to FDA approval of selumetib (koselugo) in April 2020 (PI:Widemann) Assessing patient-reported outcomes of pain physical function and quality of life in a phase II clinical trial of selumetinib in adults with NF1 and inoperable plexiform neurofibromas Assessing medication adherence in a phase II clinical trial of selumetinib in children with NF1 and inoperable plexiform neurofibromas (PI:Widemann) Administering the patient-reported outcomes measures for a pilot study of the MEK1/2 inhibitor selumetinib (AZD6244 Hydrogen Sulfate) for adults with neurofibromatosis type 1 and cutaneous neurofibromas (PI:Gross) Assessing patient-reported outcomes measures for a phase I/II study to evaluate the Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib for Neurofibromatosis Type I (NF1) Related Atypical Neurofibromas (PI:Gross) Planning the patient-reported outcomes and neurocognitive assessment for a new natural history study of individuals with NF1 and high risk tumors (PI:Gross) Investigating neurocognitive functions pain and quality of life in several protocols of children adolescents and adults with sickle cell anemia undergoing stem cell transplant (PIs: Courtney Fitzhugh John Tisdale) Identifying patient and parent attitudes toward the use of next generation sequencing (NGS) for diagnosing and managing cancer and the return of results and incidental findings (PI: Rosie Kaplan) Evaluating the effects of whole-brain radiation on the neurocognitive functioning of adults with brain tumor metastases (PI: Kevin Camphausen) Assessing psychosocial characteristics of children in a natural history study of clinical factors in children with chronic GVHD (PI: Steven Pavletic) Assessing a core set of patient-reported outcomes to assess children adolescents and adults with rare solid tumors as part of the POB natural history rare tumor initiative (PI: Jaydira Del Rivero) Conducting two cognitive test batteries (low and high functioning) for a natural history study to examine the cognitive social and emotional development of children and young adults with RASopathies (PI: Doug Stewart) Conducted qualitative interviews on order of transplant in siblings undergoing transplant for DOCK8 Deficiency (PI: Nirali Shah) Assessing symptom burden and quality of life in patients undergoing related and unrelated donor Hematopoietic Stem Cell Transplant for Dock 8 Deficiency (PI: Corina Gonzalez) Conducting qualitative interviews pre and 1 year post Hematopoietic Stem Cell Transplant for Dock 8 Deficiency (PI: Corina Gonzalez) Conducting evaluations to investigate the feasibility of mobile sensor technologies using an Apple iPhone and Apple Watch to assess general symptomology (e.g. fatigue pain) and cognitive function (e.g. cognitive flexibility reaction time) of cancer patients (PI: James Gulley) Designing and implementing a behavioral health intervention and patient-reported outcomes in a protocol assessing the effect of diet and exercise on the gut microbiome and response to immune checkpoint inhibitor therapy in patients with melanoma (PI: James Gulley) Assessing quality of life in a natural history protocol for Myelodysplastic Syndromes (PI: Kathy L McGraw). Assessing patient report outcomes and quality of life in a study of Imatinib to increase RUNX1 activity in patients with germline RUNX1 deficiency (PI: Lea Cunningham) Core-Initiated Investigations Establishing and disseminating recommendations on working with patients with chronic pain during the COVID-19 pandemic Assessing the impact of COVID-19 on mental health and access to health care in adults with neurofibromatosis from an anonymous online survey Developed a study to assess the impact of COVID-19 on pediatric palliative care providers and programs within the US and a 2nd study to assess the impact globally Evaluating the psychosocial support needs of parents before and after the death of their child Assessing the barriers and facilitat *TRUNCATED* 1225916 +Cancer; Clinical Research; HIV/AIDS; Urologic Diseases Acquired Immunodeficiency Syndrome;Adult;Affect;Childhood;Clinical;Collaborations;Consult;Consultations;Emergency Situation;Goals;HIV;Hospitals;Hour;National Cancer Institute;Operative Surgical Procedures;Patients;Play;Research Personnel;Role;Tissue Procurements;Tissues;United States National Institutes of Health;Urologic Oncology;Urologic Surgeon;Urologic Surgical Procedures;Urology;clinical center;coronavirus disease;design;surgical service;urologic Urologic Oncology Branch Consult Core n/a NCI 10703105 1ZIDBC011092-15 1 ZID BC 11092 15 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 544151 NCI Investigators in the Urologic Oncology Branch of the National Cancer Institute are the urologic surgeons and general urology consultants to the entire National Institutes of Health. In this role we see patients in consultation for all pediatric and adult urologic surgical problems. The Urologic Oncology Branch answers all emergency as well as elective urologic surgical consultations and provides 24 hour coverage for urologic surgical emergencies that may arise in the Clinical Center Hospital. Increasing surgery in AIDS patients is being performed. The Urologic Oncology Branch also collaborates in the procurement of tissue for studies required by other investigative units. The degree of involvement of the Urologic Oncology Branch in the planning and execution of these studies is variable. The Urologic Oncology Branch often plays an instrumental role in the design of these studies while in other collaborations the Urologic Surgical Service merely provides tissue. Approximately 30% of the clinical surgical effort of the Urologic Oncology Branch is devoted to these consultative and collaborative studies. The Core supports all patients seen at the NIH Clinical Center including HIV+ patients and those affected with COVID. 544151 +Behavioral and Social Science; Biomedical Imaging; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Genetic Testing; Genetics; HIV/AIDS; Health Services; Kidney Disease; Patient Safety; Prevention; Prostate Cancer; Rare Diseases; Urologic Diseases Admission activity;Affect;Amendment;Appointment;Appointments and Schedules;Archives;Bilateral;Blood;Businesses;Cancer-Predisposing Gene;Cardiology;Clinical;Clinical Data;Clinical Management;Clinical Nursing;Clinical Nursing Research;Clinical Oncology;Clinical Research;Clinical Trials;Communication;Communities;Complement 3d;Complex;Conduct Clinical Trials;Consent;Consult;Consultations;Contracts;Counseling;DNA;Data;Databases;Dermatology;Diagnosis;Discharge Plannings;Discipline of Nursing;Disease;Education;Educational Materials;Educational process of instructing;Eligibility Determination;Endocrine;Enrollment;Ethics;Evaluation;Family;Family Study;Film;Follow-Up Studies;Generations;Genetic;Genetic Counseling;Genetic Predisposition to Disease;Genetic Risk;Genotype;Goals;Good Clinical Practice;Growth;Guidelines;Health Promotion;Heart;Hereditary Disease;Hereditary Leiomyomatosis and Renal Cell Cancer;Heritability;Human Resources;Image;Informed Consent;Inherited;Institutional Review Boards;Intake;Internal Medicine;Kidney Neoplasms;Knowledge;Letters;Literature;Location;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measurement;Medical;Medical Genetics;Medical History;Medical Records;Mentors;Mentorship;Methods;Modality;Natural History;Neurology;Nursing Research;Operating Rooms;Operative Surgical Procedures;Paper;Papillary;Patient Admission;Patient Appointment;Patient Care;Patient Education;Patient Recruitments;Patient Schedules;Patients;Persons;Physician Assistants;Physicians;Policies;Positron-Emission Tomography;Postoperative Period;Practice Guidelines;Predisposition;Principles of law and justice;Procedures;Process;Professional Practice;Protocols documentation;Quality of life;Questionnaires;Recommendation;Renal Cell Carcinoma;Renal carcinoma;Reporting;Research;Research Support;Resources;Risk;Schedule;Scientist;Services;Slide;Social Work;Societies;Specialist;Support Groups;Surgeon;Surgical Management;Syndrome;System;Telephone;Test Result;Time;Tissue Procurements;Tissues;Travel;United States National Institutes of Health;Urine;Urologic Cancer;Urologic Oncology;Urology;Visit;Work;X-Ray Computed Tomography;bone imaging;clinical center;compliance behavior;data integrity;data management;demographics;diaries;follow-up;genetic counselor;genetic pedigree;genetic testing;human model;human subject protection;imaging study;meetings;member;nephrogenesis;novel;operation;patient expectation;programs;psychosocial;recruit;success;surveillance strategy;tumor Clinical Nursing and Data Management Core n/a NCI 10703104 1ZIDBC011089-15 1 ZID BC 11089 15 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 544151 NCI The heart of the Urologic Oncology Branch is our clinical program- we study the human model of kidney cancer prostate cancer and bladder cancer. The Urologic Oncology Clinical Core is comprised of a genetic counselor / protocol manager clinical research nurses patient care coordinators (PCC) a senior data manager and data managers. RESEARCH NURSES: Clinical trials Research nurse specialists coordinate / manage the operations of our clinical trials in kidney cancer prostate cancer and bladder cancer. Their responsibilities include: kidney cancer prostate cancer and bladder cancer patient recruitment participate in the informed consent process; perform patient education; create patient-specific protocol schedule; schedule blood and urine studies CT scan MRI; PET CT internal medicine neurosurgical ENT consults; register patient with CRO; collect / review diaries with patients; assess patient compliance; rapid and accurate data capture; Q/A data entries in c3D; report AEs to NCI IRB and sponsor according to protocol requirements; submit annual Continuing Reviews to IRB; maintain regulatory binder; participate in clinical trial meetings. Familial Kidney Cancer A key component of the UOB Branch is the study of families who have rare inherited conditions such as von Hippel-Lindau Hereditary Papillary Renal Cell Cancer Birt-Hogg-Dub Syndrome and Hereditary Leiomyomatosis and Renal Cell Carcinoma which predispose to development of kidney cancer. Research nurse specialists and a genetic counselor provide protocol oversight for our natural history protocols in kidney cancer prostate cancer and bladder cancer. Responsibilities include: patient recruitment; telephone intake covering pedigree; initiation of informed consent process to include purpose of study; provide information about NIH the study objectives assess patients expectations; initial medical history; determine appropriate clinical studies; communicate with PCCs re: appointment and indicated studies; assist PCC in obtaining pertinent medical records; tissue slides films; obtain informed consent; assure patient has adequate understanding of information received during visit; prepare/submit annual Continuing Review to NCI IRB. Prostate Cancer and Bladder Cancer The prostate cancer and bladder cancer program is supported by research nurse specialists who have overall oversight of patients with localized prostate or bladder cancer. Responsibilities include: telephone intake to include; purpose of study; information about NIH the study objectives assess patients expectations; initial medical history; initiate informed consent process; determine appropriate clinical studies; communicate with PCCs re: appointment and indicated studies; obtain informed consent in person; patient teaching; follow-up visit; assure Quality of Life questionnaires are submitted /received by patients at multiple time points; work with data managers to assure data is captured and submitted. GENETIC COUNSELING: A Genetic Counselor actively participates in pursuit of the research questions about known genetic syndromes or unknown familial renal cancer. Responsibilities include: family recruitment through professional genetic societies; develop a 3-generation pedigree; complete a personal medical history; determine the genetic test to be performed; perform literature searches contribute to the identification of novel clinical manifestations of rare heritable malignant disorders. Patients with or at risk for an inherited kidney cancer cancer susceptibility disorder undergo an extensive counseling / education session. Topics generally covered during these sessions include: Clinical aspects and natural history of the suspected disorder; if the disorder is unknown the differential clinical and genetic evaluation plan is presented; psychosocial risks of genetic testing; implications of potential genetic test results; clinical management of condition and /or multiple bilateral renal tumors; health promotion strategies; provide supportive counseling at-risk or affected patients; provide written educational material and medical papers if appropriate; provide information about support groups; discuss familial communication. Genetic test results are provided per patient preferred modality; a counseling letter is sent with DNA result and recommended surveillance strategies. PROTOCOL MANAGER: Overall protocol management is the responsibility of our Genetic Counselor. Protocol manager responsibilities include: draft natural history protocols; prepare and submit protocol amendments; submit Continuing Reviews for natural history and tissue procurement protocols; remain informed about the IRB process as well as the ethical / legal aspects of clinical research; serve as a resource/ mentor to the UOB about protocols and the IRB process PHYSICIANS ASSISTANT: The in-patient and Urology consult service is managed by our Physician Assistant (P.A.). Responsibilities include: manage surgical patients upon decision for surgery; determine with surgical Fellows the appropriate pre-operative work-up; arrange in-patient admission; schedule / enter orders for operative admission including imaging studies consultations; refer patients to NIH social service for potential Family Lodge availability; perform H & P upon admission; conduct regular and frequent patient rounds; handle patient concerns while surgeons in operating room; schedule post-operative follow up visit; collaborate with nursing /social service re: discharge plan; see consult patient during post-op visit. The Urology consult service offered to the entire NIH community is managed by our P.A. Responsibilities include: initially see / evaluate all consult patients; assess patient and in concert with UOB Fellows identify probable diagnosis; recommendations to referring service; see all consults at follow-up visits; submit consult note into CRIS system. PATIENT CARE COORDINATORS: The complex task of scheduling multiple appointments and clinical studies is the responsibility of our PCCs. PCC responsibilities include: schedule new and follow- up patient appointments; communicate with patients regarding reimbursement / travel policy; admission procedures; enter patient information into ATV system; schedule all studies such as CT MRI. bone scan PET CT; arrange coordinate consultations with internal medicine neurology endocrine dermatology cardiology consults etc.; develop patient schedule; send letter of invitation; copy of protocol consent appointment schedule; obtain relevant tissue slides imaging studies and medical records; track / oversee recommendation by UOB physicians for follow-up visits and recommended studies for follow-up visits. DATA MANAGEMENT: Senior Data Manager Overall management of UOB data is the responsibility of our senior Data Manager. His responsibilities include: adapt LabMatrix to UOB data needs; maintain extensive UOB database; responsible for data integrity; query requested reports; Q/A entered data; capture and track: demographics; tumor measurements; clinical manifestations; genetic test results / genotype; provide mentorship to contract data personnel. Data management staff: One data management staff is responsible for tracking/ identifying tumor size and location; growth rates of tumors; captures images for UOB archives. Two contract data staff members are responsible for entering / QA data collected from natural history and clinical trials; tracking enrollment; works closely with research nurses and CRO to assu *TRUNCATED* 544151 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; HIV/AIDS; Hematology; Lymphatic Research; Lymphoma; Pediatric; Pediatric Cancer; Radiation Oncology; Rare Diseases; Urologic Diseases Brain Neoplasms;Breast;Cancer Patient;Clinic;Clinical;Clinical Research;Collaborations;Consultations;Head and neck structure;Histologic;Intramural Research Program;Journals;Lung;Lymphoma;Malignant Neoplasms;Malignant lymphoid neoplasm;Medical;Medical Oncology;Medical center;Mission;New Agents;Nursing Faculty;Oncology;Operative Surgical Procedures;Patient Care Management;Patients;Pediatric Oncology;Pediatrics;Physicians;Physics;Private Practice;Prostate;Protocols documentation;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Radiobiology;Research;Residencies;Scientist;Subgroup;Talents;Training;Translational Research;United States National Institutes of Health;Urologic Oncology;Writing;bench to bedside;cancer care;clinical center;design;lectures;neuro-oncology;next generation;oncology program;pre-clinical research;programs;success Radiation Oncology Branch - Radiation Clinic n/a NCI 10703102 1ZIDBC010990-15 1 ZID BC 10990 15 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 9449660 NCI The ROB is critical to the overall care of cancer patients in the Intramural Research Program and provides radiation therapy as well as general oncology consultation for patients admitted to the clinical center. This has allowed numerous collaborations and/or interactions with the Surgery Branch Urologic Oncology Branch Pediatric Oncology Branch Medical Oncology Clinical Research Unit (GU GI Head and Neck Breast Gyn cancers) Neuro Oncology Branch Lymphoid Malignancies Branch and the Radiation Biology Branch. These collaborations extend beyond merely treating patients with radiation in that the talented physician/scientists assembled in the ROB are outstanding oncology research scientists who can articulate the latest findings in radiation biology research to the larger oncology paradigm. The ROB maintains a strong radiation oncology residency program in association with radiation oncology departments at Walter Reed Medical Center training the next generation of radiation oncologists/scientists. The residents receive clinical training in a one on one setting with the clinical faculty as well as participate in multiple settings that include lectures didactics journal clubs and formal classes in medical physics and radiobiology. Trainees from the Radiation Oncology Residency Program have enjoyed significant success in both academic and private practices. 9449660 +Cancer; Clinical Research; Organ Transplantation; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Caring;Clinical;Clinical Research;Clinical Trials Design;Collection;Data Analyses;Data Collection;Goals;Hematopoietic Stem Cell Transplantation;Individual;Infrastructure;Malignant Neoplasms;Patient Care;Patient Recruitments;Policies;Translational Research;Transplant Recipients;Transplantation;Transplantation Immunology;career development;clinical care;design;member;programs;transplantation therapy ETIB Clinical Research Core n/a NCI 10703100 1ZIDBC010963-15 1 ZID BC 10963 15 9692325 "GRESS, RONALD " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1307759 NCI The Experimental Transplantation and Immunology Branch (ETIB) clinical transplantation program has as goals the cure of cancer through hematopoietic stem cell transplant therapies conducting outstanding translational research and providing the highest level of excellence in clinical care. The ETIB Clinical Core provides interactions activities and support across the branch. It represents a collection of individuals each with particular expertise in clinical transplantation and clinical research. While the section functions as a coordinated effort it is also designed for individual career development and professional advancement for members. Specific aims include developing a supportive infrastructure for the conduct of clinical transplantation trials establishing consistent clinical policies and practices in the care of transplantation patients in order to achieve excellence in clinical care and providing and promoting educational opportunities in hematopoietic stem cell transplantation. 1307759 +Cancer; Clinical Research; HIV/AIDS; Health Services Accreditation;Adherence;American;Anatomy;Archives;Area;Autopsy;Benchmarking;Biocompatible Materials;Biopsy;CCR;CLIA certified;Certification;Childhood;Chromosomes;Clinical;Clinical Laboratory Information Systems;Clinical Management;Clinical Pathology;Clinical Research;Clinical Services;Cytology;Cytopathology;Data;Databases;Diagnosis;Diagnostic;Diagnostic Services;Dissection;Elements;Ensure;Ethics;Flow Cytometry;Genomics;Goals;Health care facility;Hematopathology;Histology;Histopathology;Hospital Information Systems;Human Resources;Individual;Institutes;Institution;Institutional Review Boards;Joints;Label;Laboratories;Leadership;Legal;Medical;Mission;Molecular;Monitor;Operative Surgical Procedures;Pathologist;Pathology;Pathology Report;Patient Care;Patients;Performance;Process;Protocols documentation;Quality Control;Recommendation;Reporting;Research;Research Personnel;Resected;Ribonucleases;Scanning;Scientist;Services;Slide;Specialist;Specimen;Stains;Surgical Pathology;System;Telepathology;Testing;Time;Tissue Procurements;Tissues;United States National Institutes of Health;clinical center;clinical diagnostics;clinical material;college;high standard;imaging program;improved;operation;patient safety;programs;quality assurance;research facility;statistics;tissue archive;tissue processing;tissue resource;whole slide imaging Clinical Operations for Laboratory of Pathology n/a NCI 10703098 1ZIDBC010686-18 1 ZID BC 10686 18 14732101 "CHINQUEE, JOSEPH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1099118 NCI The Laboratory of Pathology (LP) supports the clinical and research missions of the NIH and the NCI by providing anatomic pathology and tissue processing services to the Clinical Center and to all of the NIH institutes. LP's clinical sections provide services in surgical pathology autopsy pathology hematopathology cytopathology chromosome pathology pediatric pathology flow cytometry and a dynamic and growing genomic pathology service. Clinical Operations is the administrative and technical core of the clinical component of the Laboratory of Pathology. The Clinical Operations section: oversees the regulatory compliance and accreditation of all clinical sections; manages the Quality Management program; provides core laboratory services in tissue procurement processing and gross analysis of clinical specimens; manages the clinical administrative functions; supports human resource management for clinical and technical staff; supports operations of the Laboratory Information System (LIS); whole slide imaging; and maintains the clinical diagnostic tissue archives of the laboratory. ACCREDITATION AND REGULATORY COMPLIANCE: LP is CLIA-certified and maintains a Certificate of Accreditation. LP is inspected every two years for compliance with regulatory standards by the College of American Pathologists with our last onsite accreditation inspection in March 2022. During that onsite inspection seven laboratory specialists evaluated more than 1200 standards in all of LP's clinical services with minimal recommendations. Continued accreditation is required for CLIA compliance but also demonstrates that the department's quality in patient care is of the highest standards. TISSUE PROCUREMENT HISTOLOGY and SURGICAL PATHOLOGY Support: Clinical Operations' pathologists assistants perform tissue division for clinical and research tissue sections and perform gross analysis dissection and processing of clinical biopsy and resected tissues from NIH patients for anatomic pathology diagnosis. Patients who undergo surgery at the NIH Clinical Center frequently have tissue divided between research and diagnostic purposes as dictated by IRB-approved protocols. For clinical cases the diagnostic material is processed and special stains are performed by the Histopathology section and distributed to LP's pathologists for diagnostic interpretation. After pathology diagnoses are rendered Clinical Operations staff provide pathology reports to requesting clinicians internal and external to the NIH. TISSUE RESOURCE REQUESTS: Clinical Operations staff manage the Tissue Processing and Procurement Facility and have oversight of the Tissue Resource Requests. As a service to investigators throughout the NIH Clinical Operations staff process requests from scientists for tissues to be used for research from the clinical archives while ensuring appropriate ethical approval (from their IRB or from the OHSR). During the fiscal year approximately 15000 individual biospecimens (unstained slides special stains tissue shavings and tissue slides processed with RNAse precautions) were provided to researchers from our tissue archive. The Clinical Operations section also processed approximately 1000 medical-legal requests which involved retrieving and processing approximately clinical slides and/or blocks that were forwarded to other healthcare or research facilities at the request of clinicians or patients. LABORATORY INFORMATION SYSTEM (LIS): The LIS is part of the SoftLab system used by the Clinical Center and it interfaces with the hospital information system so that anatomic pathology results are available online. As part of the tissue request process and to support requests for pathology reports from patients and clinicians we conduct searches of the pathology database and provide lists of cases that match the requested criteria. The LIS is used by Clinical Operations to generate benchmark data and quality assurance statistics for managing and continuously improving the clinical diagnostic services. QUALITY MANAGEMENT: The LP Quality Management Program monitors LP's performance with key benchmarks such as: cytology molecular surgical and biopsy turnaround times; specimen adequacy labeling and identification compliance; and quality control performance of special stains. Annual QM reports are provided to LP's leadership to identify areas that have demonstrated improvements but also show areas that need continuous improvement and monitoring. Annual QM reports are provided to the NIH Clinical Center's Office of Patient Safety and Clinical Quality as one element needed to demonstrate an ongoing quality assurance and process improvement program for clinical services that is required for Joint Commission accreditation. WHOLE SLIDE IMAGING: The Clinical Operations staff performed whole slide imaging for more than 1800 clinical cases with 18460 slides scanned which is a 100% increase from the previous year. The whole slide imaging program provides telepathology capability for LP's pathologists and collaborative projects with NCI investigators working with whole slide imaging and analyses. 1099118 +Bioengineering; Biotechnology; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Immunotherapy; Nanotechnology; Orphan Drug; Rare Diseases ABCB1 gene;Adult;Agonist;Antineoplastic Agents;Astrocytoma;Azacitidine;BAY 54-9085;Binding Proteins;Biological;Biological Assay;Biological Availability;Bortezomib;CCR;Camptothecin;Cancer Cell Growth;Carboplatin;Cells;Child;Cisplatin;Clinical Pharmacology;Clinical Research;Clinical Trials Design;Collaborations;Communities;Complex;Concentration measurement;Conduct Clinical Trials;Coupled;Cyclophosphamide;Data;Depsipeptides;Detection;Development;Disseminated Malignant Neoplasm;Dose;Drug Costs;Drug Exposure;Drug Formulations;Drug Interactions;Drug Kinetics;Equation;Erlotinib;Esters;Etoposide;Excretory function;Extramural Activities;Finasteride;Fluorescence;Frequencies;Future;Glioma;Goals;Guidelines;High Pressure Liquid Chromatography;Hodgkin Disease;Imatinib;Immune checkpoint inhibitor;Immunotherapy;Immunotoxins;Interleukin-15;Intervention;Ketoconazole;Laboratories;Liquid substance;Locally Advanced Malignant Neoplasm;MEKs;MS-275;Mathematics;Measures;Melphalan;Mesothelioma;Metabolism;Midazolam;Modeling;Modification;Molecular Target;Monoclonal Antibodies;Mus;Natural Products;Nelfinavir;Nivolumab;Oncology;Oral;Paclitaxel;Patients;Pharmaceutical Economics;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Phase I Clinical Trials;Phase I/II Trial;Phase II Clinical Trials;Phenylacetates;Phenylbutyrates;Phyllanthus;Physiological Processes;Plants;Plicamycin;Population;Pre-Clinical Model;Pregnancy;Prodrugs;Program Development;Radiation therapy;Randomized;Randomized Clinical Trials;Recombinants;Recurrence;Refractory;Regimen;Relapse;Renal Cell Carcinoma;Reproducibility;Research Personnel;Rhabdoid Tumor;Route;SU 5416;Sampling;Scheme;Solid Neoplasm;Stress;Suramin;TNP470;Tamoxifen;Tariquidar;Testing;Thalidomide;Therapeutic;Time;Tissues;Topoisomerase-I Inhibitor;Topotecan;Toxic effect;United States National Institutes of Health;Unresectable;Valproic Acid;Visit;Xenograft Model;abiraterone;absorption;analog;analytical method;antagonist;anti-PD-1;aurora kinase A;base;bevacizumab;cancer therapy;chronic graft versus host disease;clinical center;clopidogrel;comparative trial;cost;cytotoxicity;detector;docetaxel;drug clearance;drug development;drug disposition;drug metabolism;first-in-human;flavopiridol;improved;in silico;inhibitor;instrument;intraperitoneal;irinotecan;kinase inhibitor;lapatinib;lenalidomide;mass spectrometer;mesothelin;method development;mucosal melanoma;nanoparticle;nanoparticle drug;nonhuman primate;novel anticancer drug;novel therapeutics;pediatric patients;pembrolizumab;pharmacodynamic model;pharmacokinetic model;pharmacokinetics and pharmacodynamics;phase 1 study;phase 2 study;phase I trial;phase II trial;pomalidomide;pre-clinical;programs;prospective;simulation;temozolomide;trial comparing;tumor;virtual patient Using Clinical Pharmacology Principles to Develop New Anticancer Therapies n/a NCI 10703095 1ZICSC006537-29 1 ZIC SC 6537 29 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1537766 NCI Over the years the CPP has developed analytical methods for a wide range of therapeutics that include the following: depsipeptide TNP-470 phenylacetate phenylbutyrate tamoxifen UCN-01 CAI thalidomide COL-3 suramin melphalan erlotinib perifosine SU5416 2ME MS-275 ketoconazole lenalidomide romidepsin AZD2281 gemicitabine sorafenib finasteride nelfinavir 17-DMAG clopidogrel Hsp90 inhibitor PF-04928473 irinotecan (its active metabolite SN38 and glucuronidated SN38) Trk kinase inhibitor AZD7451 pomalidomide olaparib sorafenib belinostat cediranib abiraterone cabozantinib carfilzomib midazolam lapatinib temozolomide perifosine valproic acid temozolomide cyclophosphamide and its 4-hydroxycyclophosphamide metabolite NLG207 (formerly CRLX-101 nanoparticle-drug conjugate of camptothecin) and ONC206. The CPP has provided PK support for various agents in phase I/II trials: suramin TNP-470 CAI UCN-01 docetaxel flavopiridol thalidomide lenalidomide pomalidomide intraperitoneal cisplatin/carboplatin paclitaxel 17-DMAG imatinib sorafenib nelfinavir bevacizumab romidepsin clopidrogrel bortezomib TRC-105 vandetanib olaparib topotecan irinotecan mithramycin durvalumab abiraterone belinostat with cisplatin and etoposide temozolomide seviteronel selumetinib and immunotoxin LMB-100. During the current fiscal year the CPP provided PK support for several phase I/II clinical studies including a first-in-human phase I study of LMB-100 in patients with mesothelioma and other solid tumors expressing mesothelin; phase I trial of zotiraciclib in combination with temozolomide for patients with recurrent high-grade astrocytomas; phase I study of lenalidomide and radiotherapy in children with gliomas; phase II trial of M6620 (a first-in-class competitive inhibitor of ATR) and topotecan in relapsed SCLC patients; phase II study of pomalidomide in patients with refractory chronic graft-versus-host disease; phase I/II of cabozantinib and docetaxel in patients with mCRPC; checkpoint inhibitor immunotherapy during pregnancy for relapsed-refractory Hodgkin lymphoma; phase I study of single agent NIZ985 a recombinant heterodimeric IL-15 agonist in adult patients with metastatic or unresectable solid tumors; phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors. Over the years we have conducted population PK (popPK) modeling of the following compounds: depsipeptide romidepsin sorafenib olaparib docetaxel in combination with the p-glycoprotein antagonist tariquidar TRC105 TRC102 belinostat mithramycin and seviteronel. Recent efforts have focused on characterizing the complex PK of NLG207 a nanoparticle-drug conjugate of the potent topoisomerase I inhibitor camptothecin (CPT) in order to better describe CPT release from nanoparticles using a popPK model. In collaboration with Drs. Mark Ratain and Daniel Goldstein we're evaluating in silico-based extended dosing regimens for monoclonal antibody immune checkpoint inhibitors. Based on patient-specific estimates for clearance optimal alternative dosing strategies can be simulated to lower drug and cost burden yet maintain therapeutic levels especially as the clearance of the drug decreases over time. We hypothesize that longer dosing intervals than those currently approved (without commensurate dose increases) will maintain efficacy. To this end we are collaborating on a multi-institutional randomized non-inferiority trial to investigate the PK of standard interval dosing compared to extended interval dosing of nivolumab or pembrolizumab in locally advanced or metastatic cancers. The primary objective is to assess the noninferiority of extended interval dosing relative to standard dosing as assessed by drug trough levels above the target concentration of 1.5 ug/ml for both nivolumab and pembrolizumab. Nivolumab and pembrolizumab anti-programmed cell death protein 1 monoclonal antibodies have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that 95% of patients maintained greater than or equal to 1.5 ug/mL at steady state which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in 95% of patients. Extended dosing regimens of nivolumab 240 mg every 4 weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated showing that 95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50% thus substantially reducing patient visits (as well as costs) while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing and ultimately an efficacy-driven comparative trial. The CPP participates in several preclinical pharmacology projects in order to study drug metabolism PK drug formulation and bioavailability as well as efficacy in preclinical models of drug development to allow for more accurate dosing estimates for future first-in-human studies. The CPP has validated assays and conducted PK analysis for the following compounds: 3-deazaneplanocin (DZ-Nep) PV1162 schweinfurthin G englerin A aza-englerin XZ-419 aurora kinase A/B inhibitor SCH-1473759 and a long-acting prodrug of talazoparib. We have conducted bioavailability studies for schweinfurthin G englerin A and aza-englerin. We collaborate with both intramural and extramural investigators to evaluate the preclinical PK of various novel therapeutics in mouse tumor models and/or non-human primate (NHP) models including 5-azacytidine pexidartinib photo-activatable paclitaxel prodrug and panobinostat. We evaluated the preclinical PK of sapanisertib (mTORC1/2 inhibitor) and trametinib (MEK inhibitor) in mucosal melanoma xenograft models. We also investigated how dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors. In collaboration with the Molecular Targets Laboratory and the Natural Products Branch the CPP provided preclinical PK support to study the bioavailability of two new classes of analogs of englerin A (extracted from the Tanzanian plant Phyllanthus engleri Pax on the basis of its high potency and selectivity for inhibiting renal cancer cell growth). The first class of analogs are modified at the esters to improve stability and oral bioavailability while the second class of analogs are modified on the bridgehead of the seven-membered ring within the main englerin body of the compound. Replacement of the isopropyl group by other larger substituents yielded compounds *TRUNCATED* 1537766 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS Ascites;Aspirate substance;Bar Codes;Biological;Biological Specimen Banks;Blood;Bone Marrow;CCR;COVID-19;Cerebrospinal Fluid;Clinic;Clinical;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;DNA;Data;Data Collection;Databases;Development;Ensure;Extramural Activities;Human;Laboratories;Life Cycle Stages;Methods;Mission;Pleural effusion disorder;Procedures;Process;Protocols documentation;Research;Research Design;Resources;Saliva;Sampling;Services;Ships;Specimen;Specimen Handling;Time;Urine;Validation;biobank;pandemic disease;pharmacokinetics and pharmacodynamics;repository;sample collection;software systems Biospecimen Processing and Biorepository n/a NCI 10703094 1ZICSC006536-29 1 ZIC SC 6536 29 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1537766 NCI For the current fiscal year the BPC provides support to over 130 clinical trials and receives and processes over 50000 biological samples including blood urine cerebrospinal fluid pleural effusion aspirate ascites saliva and bone marrow aspirate. This Core is responsible for the management and repository of samples from the CCR clinics. Upon arrival all samples are processed according to the clinical protocol (per standard operating procedures) barcoded and entered into a database for sample handling and storage purposes and cataloged into a software system. The BPC handles urgent same-day and routine sample shipments to both intramural and extramural laboratories. The BPC provides a broad range of services including the development and validation of procedures for specimen processing analyses and DNA extraction to establish protocols that optimize specimen integrity and consistency. In addition to laboratory services the Core serves as a resource for clinicians seeking advice on study design including specimen collection and storage methods as well as all protocol-associated study worksheets related to data and sample collection. The BPC provides services related to sample processing barcoding and storage of pharmacokinetic (PK) and pharmacodynamic (PD) biospecimens for all trials. Staff provides support to clinical teams throughout the life cycle of their protocols including assistance with ensuring time-sensitive samples are collected appropriately and with provision of sample data and shipment logs. During the pandemic the BPC provided support and remains involved in processing research bloods for COVID-19 clinical protocols. 1537766 +Cancer; Clinical Research; Health Services; Prevention Address;Adult;Age;Biological;Biological Markers;Cancer Etiology;Cohort Studies;Computerized Medical Record;Data;Development;Division of Cancer Epidemiology and Genetics;Drug Prescriptions;Future;Health Maintenance Organizations;Length;Medical;Medical Records;Military Personnel;Outcome;Participant;Population;Procedures;Questionnaires;Recording of previous events;Records;Research;Resources;Risk Factors;Running;Sampling;System;Time;Tumor Tissue;Vertebral column;Work;biobank;cancer risk;clinical infrastructure;cohort;cost effective;follow-up;next generation;novel;prospective;sample collection;tissue archive;working group Cohort and Biobank Development n/a NCI 10703093 1ZICCP010226-09 1 ZIC CP 10226 9 15666500 "GARCIA-CLOSAS, MONTSERRAT " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 6525753 NCI DCEG has a long history of developing and running major cohort studies and these form the backbone of the research portfolio in the division. Existing cohorts including but not limited to AARP PLCO and USRT have been extremely productive and have generated a wealth of information about potential cancer risk factors and biological markers. In the next decade these cohorts will reach the end of their natural lifetime due to the length of time since the baseline questionnaire the average age of the participants and the depletion of biological samples. There is the need therefore to start planning now for the next generation of cohorts that will be able to continue to address current and future hypotheses about the etiology of cancer. A working group within DCEG was formed to discuss potential settings and Health Maintenance Organizations (HMOs) like Kaiser Permanente (KP) and the US Military were selected as some of the most promising for further exploratory work. Major advantages of HMOs and the Military are the availability of electronic medical records a passive follow-up system that is both cost effective and highly complete existing clinical infrastructure for specimen collection and the long-term stability of the population. Furthermore many of the HMOs have archived tissue available and the electronic records provide extensive and reliable information on drug prescriptions medical conditions and procedures. 6525753 +Bioengineering; Biotechnology; Cancer; Estrogen; Women's Health Androgens;Biological Assay;Biomedical Research;Development;Division of Cancer Epidemiology and Genetics;Estrogens;Hormones;Human;Infrastructure;Laboratories;Measurement;Measures;Population Study;Production;Proteomics;Techniques;Technology;liquid chromatography mass spectrometry;method development Endogenous Hormone Measurement Production Assay Infrastructure at the FNLCR n/a NCI 10703092 1ZICCP010223-11 1 ZIC CP 10223 11 15666502 "HENDERSON, MARIANNE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 152823 NCI Dedicated support for production level assays for estrogen and androgen metabolites measured in human biofluids at the Leidos Biomedical Research Inc. Laboratory of Proteomics and Analytical Technologies. This project provides the dedicated production assay support (labor and materials and supplies) and some new assay methods development for the collaborative activities with the Laboratory of Proteomics and Analytical Technologies (LPAT) associated with the development of liquid chromatography-mass spectrometry techniques/assays for the measurement of endogenous hormone metabolites(estrogens and androgens) for population studies in DCEG. 152823 +Cancer; Clinical Research; Genetics; HIV/AIDS Biological Assay;Biological Specimen Banks;Collection;DNA;Division of Cancer Epidemiology and Genetics;Genotype;Infrastructure;Laboratories;Methods;Molecular Epidemiology;Population;Research;Sampling;Services;biobank;epidemiology study;repository Biorepository Processing Storage and Research n/a NCI 10703091 1ZICCP010192-15 1 ZIC CP 10192 15 15188145 "BLACK, AMANDA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 727593 NCI The main objective of this project is to investigate current and alternative methods for efficient collecting processing storing and retrieving biospecimens in order to and to establish baseline standards that can be used in molecular epidemiology studies. Other primary objectives are to perform DNA extraction genotyping assays and other laboratory services for biospecimen samples and to provide infrastructural support and management of the Division of Cancer Epidemiology and Genetics biospecimen repository. Efficiencies in collection processing and storage at the DCEG repository and within the population collections are an important focus of this project this year. 727593 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Address;Advanced Technology Center;Area;Basic Science;Biological;Biological Assay;Cancer Etiology;Candidate Disease Gene;Custom;DNA;DNA sequencing;Data;Data Analytics;Data Storage and Retrieval;Division of Cancer Epidemiology and Genetics;Employment;Epidemiologist;Equipment and supply inventories;Family;Gene Chips;Genetic;Genetic Fingerprintings;Genetic Markers;Genetic Variation;Genotype;Germ Lines;Heritability;Human;Informatics;Information Management;Intramural Research Program;Laboratories;Laboratory Research;Malignant Neoplasms;Management Information Systems;Medical Genetics;Mission;NCI Center for Cancer Research;Outcome;Predisposition;Preparation;Principal Investigator;Process;Quality Control;Residual state;Sampling;Scientist;Series;Signal Transduction;Statistical Methods;System;Technology;Work;analytical tool;cancer genetics;cancer genomics;design;genetic analysis;genetic linkage analysis;genome wide association study;high risk;instrument;new technology;next generation sequencing;operation;population based;quality assurance;translational genomics;whole genome Cancer Genomics Research Laboratory n/a NCI 10703090 1ZICCP010178-21 1 ZIC CP 10178 21 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 781327 NCI NCI's Advanced Technology Center (ATC) established for the implementation of novel technologies to address biological clinical and genetic questions pertinent to human cancers includes the Cancer Genomics Research Laboratory which is overseen by DCEG. The LTG is adjacent to the CGR and consists of three principal investigators and their respective laboratories which work closely with the expertise in the CGR and DCEG. The aim of the CGR is to meet the genotyping and selected DNA sequencing needs of the DCEG and NCI's Center for Cancer Research. The facility performs high-throughput genotyping and sequencing to support genetic analysis for a broad range of projects for the intramural research program of the NCI. Working in concert with epidemiologists biostatisticians and basic research scientists in the intramural research program the CGR has developed the capacity to conduct genome-wide association studies and candidate gene approaches to identify the heritable determinants of various forms of cancer. The Cancer Genomics Research Laboratory(CGR) offers a wide variety of sample preparation and genotyping operations. All samples received must meet minimum requirements and are taken through the Sample Handling pipeline prior to completing any genotyping. The Sample Handling pipeline includes DNA quantification and genetic fingerprinting. Also offered is current Whole Genome Amplification (WGA) technology designed to increase available DNA from samples with minimal residual DNA. The genotyping platforms cover a wide-range of size and scope. The CGR operates the Illumina BeadLab system which supports Illumina assay technologies including the whole genome genotyping Infinium assays custom GoldenGate OPA assays and Custom Infinium (iSelect) assays. The CGF operates next generation sequencing with two 454/Roche instruments with high throughput analytical capacity for targeted regions identified in GWAS and linkage studies. In addition the CGR offers Affymetrix GeneChip arrays and uniplex TaqMan genotyping. Informatics at the CGR is focused on two main areas: Information Management the electronic storage and retrieval of data and Analytics the employment of the most appropriate statistical methods to effectively and accurately draw conclusions from the data generated by the laboratory. 781327 +Biotechnology; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health Affect;Basic Science;Bioinformatics;Biological;Biological Assay;Cell Culture Techniques;Cell Line;Cell Lineage;Cell Surface Proteins;Cell model;Cells;Chromatin;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Complex;Consultations;Detection;Development;Disease;Enrollment;Gene Expression Profiling;Genes;Genetic;Genetic Transcription;Genomics;Goals;Heterogeneity;Immune;Immunotherapy;Individual;Interest Group;Laboratory Research;Molecular;NCI Center for Cancer Research;Patients;Phenotype;RNA Sequences;Receptor Cell;Research Personnel;Role;Sampling;Technology;Therapeutic;Tissue Sample;Transcript;United States National Institutes of Health;Work;cell type;experience;functional genomics;insight;member;mouse model;multimodality;peripheral blood;pre-clinical;single cell analysis;single cell sequencing;tumor microenvironment Single Cell Analysis Facility n/a NCI 10703089 1ZICBC012123-01 1 ZIC BC 12123 1 78858607 "KELLY, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1804229 NCI Over the past year SCAF has supported over 110 projects from more than 40 NCI Center for Cancer Research laboratories which involved the sequencing of roughly 3.3 million single cells. This work included studies to understand mechanism and potential limitations of immunotherapy and cellular therapeutics in pre-clinical cell culture and mouse models as well as from samples of patients enrolled in clinical trials. Collaborative support from SCAF also enabled a better understand the composition of cell types and cell phenotypes within the tumor microenvironment and peripheral blood in multiple disease states by utilizing single cell sequencing to examine heterogeneity within tissue samples. Utilizing high throughput CRISPR-enabled functional genomic screens insight was gained as to how individual or sets of target genes affect transcriptional phenotypes in model cell lines to help better understand their role in normal development and their dysregulation in disease. Members of the SCAF team also promoted better understanding of available technologies and how they can be utilized through individual consultations hosting and presenting seminars and support for relevant scientific interest groups at NIH. 1804229 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics Autologous;Cell Count;Cells;Centrifugation;Clinical;Cytomegalovirus;Evaluation;Goals;Intention;Lentivirus;Methods;Muromonab-CD3;Mus;Operative Surgical Procedures;Patients;Population;Process;Production;Protocols documentation;Recording of previous events;Retroviral Vector;Retroviridae;System;Systems Development;T-Lymphocyte;Therapeutic;Time;Transfection;Viral Vector;Virus;cellular transduction;clinically relevant;exhaust;experimental study;gene therapy;improved;manufacturing process;promoter;protocol development;transgene delivery;vector Use of lentivirus in individualized cell-gene therapy n/a NCI 10703086 1ZICBC012051-02 1 ZIC BC 12051 2 15687510 "BEYER, RACHEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 217324 NCI This is a new project as of January 2021. The initial experiments are centered around establishing a baseline for comparison to the proposed lentiviral system and the development of the system and protocols to generate lentivirus suitable for clinical T-cell transductions. Critical variables of the lentivirus evaluation is the selection of promoter (EF1a CMV or MSCV LTR) lentivirus production method (concentrated vs unconcentrated) transduction protocol (incubation vs spinoculation) and use (or concentration) of OKT3 required for T-cell stimulation and activation. Lentivirus production parameters have been determined and at-scale cell experiments have been performed with the intention of transitioning to a GMP production platform. The newly developed cell production process has reduced the T cell production time to 14 days and requires only 3 manipulations during that time frame. The T cell repertoire at the end of the new shorter process more closely mimics the starting T cell sub-population ratios with a continued bias towards younger naive T cells. Mouse experiments are underway with a gamma-retroviral comparator to demonstrate clinical relevance of using lentivirus for TCR transgene delivery. 217324 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics Allogenic;Autologous;Biological Assay;Cells;Certification;Clinical;Complex;Contracts;Control Groups;Data;Detection;Development;Disease Progression;Endotoxins;Ensure;Failure;Individual;Infusion procedures;Lead;Microbiology;Mycoplasma;Operative Surgical Procedures;Patient Schedules;Patients;Plasmids;Production;Quality Control;Research;Residual state;Retroviridae;Safety;Specificity;Sterility;Testing;Time;Treatment Protocols;Viral;Virus;base;cellular transduction;endonuclease;gene therapy;mutant;neoantigens;personalized medicine;transduction efficiency;vector QC and Release Testing of Clinical Vector and Cell Gene Therapy Products n/a NCI 10703085 1ZICBC012049-02 1 ZIC BC 12049 2 15687510 "BEYER, RACHEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 434646 NCI The SBQC team executes multiple assays to demonstrate conformance of viral and cell products manufactured both at the Surgery Branch and from external labs such as Contract Manufacturing Organizations (CMOs). All assays are executed according to specific GMP compliant SOPs and the specifications for product use are captured on the Certificate of Analysis (COA). These assays are complex cell-based multi-day assays that are executed under time constraints to meet clinical patient treatment schedules - as each product (virus or cell) is unique and intended for a single unique patient. Both the vector (encoding a patient specific TCR targeting a mutant neoantigen) and the cells transduced with this vector must conform to the COA specifications. Release of Vector: The assays required to demonstrate that a vector produced at the SB or other facility is appropriate safe and meets specification for clinical use are: vector titer TCR specificity and presence (absence) of replication competent retrovirus residual plasmid residual benzonase endonuclease and sterility (microbiology endotoxin and mycoplasma). All assays except the sterility assays are performed by the SBQC group. Release of Cell Products: The assays required to demonstrate that cellular products manufactured at the SB is appropriate safe and meets specification for clinical use are: transduction efficiency TCR specificity presence (absence) of replication competent retrovirus residual plasmid residual benzonase endonuclease vector copy number (per cell) and sterility (microbiology endotoxin and mycoplasma). All assays except the sterility assays are performed by the SBQC group. The SBQC unit since its inception in 2018 has performed testing on 70 individual vector products and 40 individual cellular products. An unfortunate consequence of personalized therapies with long lead times from discovery of patient specific TCRs through to a vetted patient treatment is that many vector products are made but not used as the patient becomes ineligible due to disease progression before the treatment is ready. This is the primary cause for the discrepancy in vectors tested for clinical use versus patient products generated for treatment/infusion. Other unique factors of the trials supported by this project are that some vectors are made for allogeneic use (TCR identified in another patient but vector used in manufacturing of patient autologous cells for treatment) as well as some TCRs are transferred to clinical vector production but the data generated by the research team is either incomplete or cannot be replicated using the GMP-qualified assays. 434646 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD) ATAC-seq;Algorithms;Antibodies;Area;Bioinformatics;Biological;Biological Assay;Biology;CCR;Cells;ChIP-seq;Classification;Clinical;Communities;Computational Biology;Contractor;Cooperative Research and Development Agreement;Custom;DNA;DNA analysis;DNA sequencing;Data;Data Analyses;Detection;Development;Enhancers;Epigenetic Process;Foundations;Funding;Gene Rearrangement;Genes;Genetic;Genome;Goals;Immunogenomics;Industrialization;Intention;Internet;Laboratories;Left;Machine Learning;Malignant Neoplasms;Mediating;Methods;Micrococcal Nuclease;Molecular Profiling;Molecular Target;Mutation Detection;Oncogenes;Positioning Attribute;Proteomics;Protocols documentation;RNA;Research;Research Personnel;Resources;Sequence Analysis;Structure;T-Lymphocyte;Technology;Training;Tumor Antigens;United States National Institutes of Health;Validation;Work;assay development;base;biomarker development;clinical biomarkers;convolutional neural network;epigenetic regulation;exome sequencing;genome sequencing;innovation;mass spectrometric imaging;member;new technology;next generation sequencing;operation;recruit;response;screening;single-cell RNA sequencing;targeted sequencing;technology development;tool;transcriptome sequencing;tumor;whole genome Omics Technology facility n/a NCI 10703083 1ZICBC012031-02 1 ZIC BC 12031 2 9692475 "CAO, LIANG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 822832 NCI As the project was started in this fiscal year the main effort was focused on the establishment of operation and in the development of core technologies. A. Team formation: 1. Web lab: Two additional members were transferred to us in April of FY22 from the previous Molecular Profile/Clinomics Core one of which had since left NCI in June 22. We'll fill in this vacate position in FY23. 2. IT team: Two members were recruited to the IT team via the NCI Frederick contractor. This IT team is currently helping to establish the pipelines for Next Generation Sequencing (NGS) data analysis. B. Core technology development. We are mainly focused on establishing NGS-based technologies for discovery cancer drivers and for understanding biological mechanisms. Specifically the following technologies are established or near establishment. 1. NGS for cancer mutation detection. We adapted methods for both DNA and RNA Exome sequencing aimed for detection SNV deletion an insertion. 2. NGS for expression and fusion detection. The staff in the lab were trained for RNA Exome seq for the detection of fusions and for expression analysis. 3. Epigenetic regulation. We adapted two different methods for chip-seq including antibody-mediated DNA cutting by micrococcal nucleases and transposes. 4. Targeted sequencing of cancer gene panels 5. Customized assay development and sequencing of genes involved in T-cell mediated responses against tumor antigens 6. Validation of the NGS methods for their intended research or clinical use respectively 7. Refining the analytical pipelines for NGS data analysis 822832 +Autoimmune Disease; Bioengineering; Cancer; Crohn's Disease; Digestive Diseases; Immunotherapy; Inflammatory Bowel Disease; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Prostate Cancer; Urologic Diseases Affinity;Aftercare;Architecture;Artificial Intelligence;Award;Benign;Biological Assay;Biopsy;CASP3 gene;CD3 Antigens;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cell Density;Cells;Clinical;Clinical Protocols;Collaborations;Colon;Combination immunotherapy;Crohn's disease;Cytokeratin;Data;Data Set;Development;Disease Outcome;Drops;Epidermis;Equilibrium;Etiology;FOXP3 gene;Family;Fluorescence;Fluorescent Antibody Technique;Frequencies;G-Protein-Coupled Receptors;GPR15 gene;GTP-Binding Protein alpha Subunits Gs;Generations;Genetic Transcription;Grant;Graph;HIV;Home;Homeostasis;Homing;Hospitals;Human;Image;Immune;Immunofluorescence Immunologic;Immunologics;Immunooncology;Immunotherapeutic agent;Immunotherapy;Impairment;Infiltration;Inflammatory Bowel Diseases;Intestines;Laboratories;Lamina Propria;Large Intestine;Lymphocyte;MS4A1 gene;Malignant Neoplasms;Malignant neoplasm of prostate;Manuscripts;Metadata;Methods;Modeling;Molecular;Mus;Mutation;NCAM1 gene;Natural Killer Cells;Nature;Neoadjuvant Therapy;Nivolumab;Pathogenicity;Pathology;Patient imaging;Patients;Pattern;Performance;Pharmaceutical Preparations;Physiological;Play;Population;Preparation;Procedures;Process;Protocols documentation;Publishing;RNA;Radical Prostatectomy;Regulatory T-Lymphocyte;Research;Research Project Grants;Role;S-Phase Fraction;SIV;Sampling;Sanitation;Scanning;Set protein;Signal Transduction;Small Intestines;Stains;Study models;T-Lymphocyte;Technology;Time;Tissue Stains;Tissues;Training;Tumor Tissue;Tumor-infiltrating immune cells;Ulcerative Colitis;Woman;Work;advanced prostate cancer;autoencoder;base;bevacizumab;cancer immunotherapy;cell motility;chemotherapy;cohort;convolutional neural network;cost;cytokine;cytotoxic;cytotoxicity;deep learning;early onset;effector T cell;gut inflammation;image processing;immunoregulation;interest;learning strategy;machine learning model;medical schools;mouse model;murine colitis;neoplastic cell;novel;patient response;posters;pre-clinical;prostate biopsy;protein biomarkers;protein expression;response;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;unsupervised learning;whole slide imaging Tumor Immune MicroEnvironment Facility n/a NCI 10703081 1ZICBC012029-02 1 ZIC BC 12029 2 78355765 "LASSOUED, WIEM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 131232 NCI "We added 1 more patient to our cohort of 6 patients having local advanced prostate cancer and undergoing radical prostatectomy (RP). These patients were treated with neoadjuvant PROSTVAC and Nivolumab (NCT 02933255). We investigated the immune modulation in TIME after treatment using multiplex immunofluorescence (Opal Method). FFPE sections from matched pre-treated prostate biopsies and post-treated RP samples were stained with our validated T cell panel1. Combination immunotherapy significantly increased CD4+ T cells and CD8+ T cells densities in the invasive margin intratumoral and the benign compartments. 6/7 and 5/7 patients showed more than 2Xincrease of CD4 and CD8 T cells in the TIME respectively in at least one of the three compartments showing more effect that Prostvac alone. Increased proliferative indices in CD4+ and CD8+ T cells were also seen after treatment. Tregs were present in low frequencies in TIME (maximum of 12 cells/mm2) with no significant changes. Moreover a significant drop in tumor cell Ki67 after treatment suggests that the combination may control tumor growth. The combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patient. This work was presented as a poster at SITC in November 2021. We are developing new IF-multiplex panels for mouse tissues to support the preclinical team at the center or immuno-oncology (CIO). The preclinical team is treating mice bearing different tumor models with different drugs in solo and in combination. To look at the effect of these drugs on TIME and correlate we are developing 6 multiplex panels using IF each of these panels include 6 markers and DAPI. We have a collaboration with Dr. Michael Lenardo's laboratory to explore the immune modulation in patients with inflammatory bowel disease (IBD) and having GPR15 mutations. GPR15 a G protein-coupled receptor originally identified as a high affinity coreceptor for HIV/SIV was recently shown to home lymphocytes to murine colon and developing epidermis. The effect of Gpr15 deficiency on murine colitis varied in different mouse models but the studies demonstrated the critical role of GPR15 in homing Treg and Teff cells to the large intestine lamina propria (LILP). In addition the physiological and pathogenic roles of GPR15 in human have not been determined. Dr Lenardo's group has identified 3 families with GPR15 mutations and severe early onsets of IBD. In order to look at the effect of this mutation on the immune cells present in colon of these patients we developed 5 multiplex fluorescence panels using the opal technology. The panels we developed are the following: Panel 1 (CD8 KI67 GRANZYME B PRO-CASPASE 3 AND PAN-CK) PANEL 2 (CD3 GPR15 GPR15L CD4 PAN-CK) PANEL 3 (CD4 FOXP3 PRO-CASPASE 3 KI67 PAN-CK) PANEL 4 (CD4 FOXP3 KI67 CLEAVED CASPASE 3 CD20 PAN-CK) and panel 5 (CD3 GRANZYME B CD8 CD56 CD4). Our studies showed that the GPR15 mutations led to impaired GPR15L-induced signal transduction and T cell migration perturbing the normal T cell distribution in the patient small intestine and colon. We also identified a unique group of CD56+GZMB+ cells that was upregulated in our patient intestine. This population was not observed in ulcerative colitis Crohn's disease and healthy controls without GPR15 mutations indicating these cells may be unique to the GPR15-deficient IBD etiology. Finally we showed that loss of GPR15 in primary NK cells significantly upregulated GZMB expression and cytotoxicity. Thus our study not only demonstrates GPR15's role in maintaining lymphocyte homeostasis but also uncovers the role of NK cells in gut inflammation which has not been studied to the best of our knowledge. A manuscript is in preparation to publish this data. We have a collaboration with Dr. George Zeki from NFL and Drs. Shaban Mohammed and Faisal Mahmood from Harvard Medical School and the Division of Computational Pathology at the Brigham and Women's Hospital. During the first seven months of the award of the grant : Artificial Intelligence Based Analysis of Tumor Immune MicroEnvironment (TIME) in Patients Treated with Immune Therapy Agents we have successfully accomplished several tasks in terms of data generation and image processing related to our first AIM: ""Stratify the tumor immune cell patterns in Multiplex Immunofluorescence MxIF images using unsupervised learning approaches based on Convolution Neural Networks and Graph Convolution Neural Networks and GCNN"". For this grant we are using pre and post treated tumor tissue section from 42 patients treated with Bintrafusp alfa. These tissue sections were immuno-stained using our validated panels using multiplex fluorescence assays and then scanned. For every patient three fluorescence panels were performed. Each panel contains six multiplex immunofluorescent markers and DAPI. For every section we select regions of interest (ROIs) that we scan using 40X objectives the clinical protocol requires the scanning of selected regions of interest (ROIs) crops that are about 1500 * 1500 * 7 images from the whole slide. Additionally for the purpose of the LDER (Laboratory Director Exploratory Research) grant we are also scanning all the crops available in the section which takes more significant scanning time. We have implemented a standard operating procedure to collect the relevant metadata for every patient section and panel. This metadata includes the time of acquisition tissue type patient response and type of the section (tumor/biopsy). With the increasing number of images sections and panels these metadata would be crucial as develop analyze and evaluate the machine learning models generated by this research. We also defined and implemented a data and metadata anonymization and sharing protocols. These protocols enabled us to share the generated data with our external collaborators from Brigham and Women's hospital and to automate the data sanitation and transfer process to be able to track and process thousands of files generated during the period of the grant. In summary the data generation is moving forward with a pace that allows us to move forward with the image processing tasks related to AIM1. Another aim in this project is to define a new method for an Automated prediction/generation of a marker using a combination of other markers can help to reduce the time and cost to prepare a MxIF panel. As a proof of concept Dr Mohammed has developed a deep learning method that takes a set of protein markers (CD4 CD8 CD56 CD68 CD163 and DAPI) and predicts the Cytokeratin (CK) marker. This method uses an autoencoder architecture to first down sample the set of the input markers into a latent representation then synthesize the Cytokeratin marker. He trained and evaluated the proposed method on an in-house pilot dataset of 1300 images (1024x1024 pixels). We provided images from this panel without CK and with CK to be used as ground truth. The proposed method has shown reliable performance both in terms of quantitative and qualitative results. The structural similarity between generated and the real CK markers is 98%. We further compared the CK+ and CK- cells in generated and the real CK markers. The proposed method achieves average precision and F1 score (which is a parameter to compare the performance of 2 classifiers) of 0.87 and 0.75 respectively. Now we are generated new set of images from patient's tissues stained with our va *TRUNCATED*" 131232 +Biotechnology; Cancer; Congenital Structural Anomalies; Genetics; Pediatric Address;Animal Model;Apoptotic;Behavior;Biochemical;Biological Assay;Biological Models;Blood;Breeding;CCR;CRISPR/Cas technology;Cancer Biology;Cardiovascular system;Cartilage;Cell Cycle;Cell Survival;Cells;Cellular Structures;Cephalic;Cilia;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Collection;DUSP6 protein;Defect;Deubiquitinating Enzyme;Development;Developmental Biology;Disease;Disease model;Drug Targeting;Effectiveness;Embryo;Exhibits;Familial disease;Fibroblasts;Future;Gene Expression Profiling;Gene Targeting;Gene Transfer Techniques;Generations;Genes;Genetic;Goals;Heart;Hematopoietic;Hematopoietic stem cells;Homologous Gene;Human;Human Characteristics;Hypertrophic Cardiomyopathy;Image;In Situ Hybridization;Injections;Kinesin;Knock-out;Laboratories;MAP Kinase Gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Membrane Fusion;Methods;Mission;Molecular;Monitor;Motor;Motor Neurons;Mus;Mutation;Ohio;Orthologous Gene;Patients;Pediatric Oncology;Pharmaceutical Preparations;Pharmacotherapy;Phenocopy;Phenotype;Play;Preparation;Process;Protein Analysis;Protein Overexpression;Proteins;Publishing;RNA;Rana;Reporter;Reporting;Research;Research Personnel;Resources;Role;Severities;Signal Pathway;Signal Transduction;Signaling Protein;Stains;Structure;Subcellular structure;System;Technical Expertise;Techniques;Technology;Therapeutic;Time;Tissues;Training Support;Transgenic Organisms;Transmission Electron Microscopy;United States National Institutes of Health;Universities;Validation;Vascular System;Vertebrates;WASP protein;Work;Xenograft procedure;Zebrafish;Zinc Fingers;cancer cell;cancer genetics;cardiofaciocutaneous syndrome;causal variant;cell motility;ciliopathy;cilium biogenesis;convergent extension;design;developmental disease;egg;genetic approach;genetic manipulation;human disease;in vivo imaging;knock-down;knockout gene;mutant;neoplastic cell;novel;novel therapeutics;overexpression;programs;protein expression;replication stress;response;reverse genetics;single-cell RNA sequencing;skeletal;the sun;timeline;tool;tumor behavior;tumor microenvironment;tumor progression Zebrafish core n/a NCI 10703079 1ZICBC011956-03 1 ZIC BC 11956 3 77857653 "KETTENHOFEN, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 755762 NCI Project summaries and research accomplishments for the zebrafish Core in 2021/2022 are listed below: 1. The facility is collaborating with Dr. Christopher Westlake's group (LCDS NCI-CCR) on several projects utilizing the zebrafish model system to study primary cilia formation and ciliary signaling. These studies involve the use of morpholino CRISPR and protein overexpression approaches combined with the biochemical analysis of protein expression and imaging of developmental structures by immunofluorescent staining and confocal or transmission electron microscopy. Using these approaches we completed a project in FY2022 that was initiated by Dr. Huiji Zhao in Dr. Westlake's group. A gene product that was identified by Dr. Zhao in a cellular screen for regulators of mammalian multiciliogenesis was characterized and its functional requirements compared to that of homologues in human mouse zebrafish and frog cells the latter of which was conducted in collaboration with Dr. Ira Daar's group (Cancer and Developmental Biology Laboratory NCI-CCR). This work was completed and published at EMBO Reports (Zhao H. Sun J. et al. 2022). In a second project being conducted with Dr. Saurabh Shakya we are studying the effects of novel mutations in a signaling protein known to play an important role in ciliogenesis. Dr. Shakya will characterize the effect and/or function of the mutant proteins in fibroblasts derived from human patients while we will compare their function in the zebrafish model system. Using a combination of morpholino and overexpression/rescue approaches we will determine whether embryos expressing the mutant proteins present any cilia formation defects and associated ciliopathy phenotypes. This work will be included in a manuscript that is currently under preparation. In a third project the facility is collaborating with Dr. Lu to study the function of a group of proteins involved in membrane fusion and determine whether they function in ciliogenesis. Finally in conjunction with Dr. Westlake the facility collaborated with two groups at Ohio State University (OSU). Working with Dr. Monica Venere's lab we investigated the function of a kinesin motor protein associated with familial diseases that exhibit overlapping clinical features with ciliopathies. Using a CRISPR/Cas9 approach developed by the OSU Zebrafish Facility embryos lacking the kinesin gene were generated following which the embryos were assessed for potential cell cycle aberrations and for ciliary defects that phenocopied the characteristics of the human disease. This work will be included in a manuscript that is currently in preparation. In collaboration with Dr. Matthew Summers at OSU the facility used a morpholino approach to study the apoptotic function of USP37 a deubiquitinating enzyme that controls responses to replication stress. This work was completed and published at J. Biol. Chem. (Stromberg BR. et al. 2021). 2. In collaboration with Dr. Russell Smith in Dr. Deborah Morrison's group (LCDS and the NCI-RASopathy Initiative NCI-CCR) we explored the function and localization of novel B-Raf mutants associated with the cardiofaciocutaneous syndrome (CFC) one of a group of developmental disorders known collectively as the RASopathies. In this study we determined whether early cell migrations and phenotypical defects induced by overexpression of the B-Raf mutants in zebrafish correlated with the corresponding disease presentation in humans and whether the observed phenotypes were specific to the causative mutation. This work is currently under review at Molecular Cell. 3. To support a future collaboration with Dr. Marielle Yohe (Pediatric Oncology and the NCI-RASopathy Initiative NCI-CCR) the facility has developed assays using several fluorescent reporter transgenic lines (Tg) to assist in the analysis of RASopathy-associated mutant proteins. In particular Tg(Col2a1:GFP) and Tg (Islet1:GFP) are used to characterize abnormalities in cartilage/skeletal and cranial motor neuron organization during development and Tg(Dusp6:GFP) will be used as a reporter line for RAS/MAPK signaling in studies evaluating the effects of specific drug treatments. Work with the Tg(Col2a1:GFP) line was used in the manuscript from Dr. Morrison's lab currently under review. Collaborative studies between the Morrison and Yohe groups and the NCI-RASopathy Initiative will also take advantage of the zebrafish convergent-extension cell movements assay to analyze any previously uncharacterized RASopathy mutants identified through the NCI-RASopathies Initiative. This assay will be an important tool to obtain critical information regarding the severity of the mutation and the effectiveness of various drug treatments. Additionally a novel assay to identify the presence of hypertrophic cardiomyopathy (HCM) in mutant zebrafish embryos is currently under development. Two transgenic lines Tg(Myl7:GFP) and Tg(cmlc2:GFP) were recently acquired to characterize heart looping defects. The goal of this collaboration will be to use the zebrafish system to accelerate the development of patient-specific therapeutic approaches. 4. In collaboration with Dr. Orri Gudmundsson in Dr. Jonathan Keller (Mouse Cancer Genetics Program NCI-CCR) the facility is continuing a project started in FY2020 aimed at analyzing the functional requirement of the zinc finger protein Pogz in zebrafish hematopoietic stem cells (HSCs). Embryos lacking pogz were generated using CRISPR/Cas9 and validation of the knockout was confirmed. Mutant embryos will be analyzed at different developmental stages by in situ hybridization in order to monitor the expression of genes specific for hematopoietic cells and to confirm the reduction or loss of specific blood lineages in the knockouts. In addition the pogz knockout strain will be subject to FACS analysis. If defects are detected in HSCs and/or hematopoietic lineages we will determine downstream gene targets that may be critical for Pogz function by conventional or single cell RNA-sequencing. 5. In collaboration with Dr. Esta Sterneck (LCDS NCI-CCR) the facility is working on the development of a xenograft assay to study the metastatic behavior of human tumor cells in zebrafish when embryos are treated with drugs that target various cancer-associated signaling pathways. The goal of this research is to identify classes of drugs that will enhance or reduce tumor cell survival. In the future the behavior of tumor cells will also be studied using a modified xenograft approach to observe whether cells leave the circulatory system and extravasate into surrounding tissues using a transgenic line marking the vascular system. 755762 +Bioengineering; Biomedical Imaging; Biotechnology; Brain Cancer; Brain Disorders; Cancer; Kidney Disease; Orphan Drug; Prevention; Rare Diseases Abdomen;Aftercare;Algorithms;Animals;Bacteria;Biochemical;Biological;Biological Markers;Biopsy;Blood;CCR;Cancer Detection;Cancer Model;Carcinogenesis Mechanism;Cells;Certification;Chemical Shift Imaging;Chemicals;Chills;Chromatography;Clinic;Clinical;Data Collection;Detection;Deuterium;Development;Dose;Electron Spin Resonance Spectroscopy;Glucose;Glycolysis;Goals;Head;Human;Image;Immune system;In Situ;Infusion procedures;Investigation;Ions;Isotope Labeling;Isotopes;Label;Lead;Lipids;Magic;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Malignant neoplasm of brain;Malignant neoplasm of prostate;Mammals;Mass Spectrum Analysis;Metabolic;Metabolism;Methodology;Methods;Monitor;NMR Spectroscopy;Nuclear;Operative Surgical Procedures;Oxygen;Pathway interactions;Patients;Physiologic pulse;Plants;Positron-Emission Tomography;Preparation;Procedures;Production;Publications;Pyruvate;Pyruvic Acid;Renal Cell Carcinoma;Renal carcinoma;Research;Resolution;Resources;Sampling;Scanning;Specimen;Sterility;Succinate Dehydrogenase;TOCSY;Therapeutic Intervention;Time;Tissues;Toxic effect;Tracer;Tumor-Derived;United States National Institutes of Health;Urine;X-Ray Computed Tomography;cancer biomarkers;cancer diagnosis;cancer imaging;cancer prevention;cancer recurrence;cancer therapy;clinical center;design;experimental study;fluorodeoxyglucose;glucose uptake;imaging capabilities;imaging study;in vivo;inhibitor;instrument;isotope incorporation;mass spectrometer;metabolic imaging;metabolomics;method development;molecular imaging;multimodality;new therapeutic target;novel;novel strategies;novel therapeutics;pre-clinical;small molecule;solid state;spectroscopic imaging;stable isotope;tumor;tumor metabolism;ultra high resolution Metabolomics Core n/a NCI 10703077 1ZICBC011932-03 1 ZIC BC 11932 3 77857650 "CROOKS, DANIEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2218771 NCI This facility is focused on the application of targeted ultra-high resolution stable isotope-resolved metabolomics as well as critical careful sample extraction and preparation methodologies designed to obtain as much information as possible from clinical specimens. The initial mass spectrometer is a Thermo Orbitrap Fusion Lumos capable of 1000000 resolving power. This spectrometer is equipped with an Advion Nanomate direct infusion electrospray module as well as an Ion Chromatography module which together allow for resolution of a wide range of intermediary metabolites. The ultra-high resolution capability of this spectrometer allows for resolution of metabolites that are multiply-labeled with different isotopes (e.g. 13C 15N 2H) in a single specimen. We are currently developing a workflow tailored for targeted quantitation of approximately 120 cellular metabolites with the capability for multiple heavy isotope labels in a single experiment. The facility is also equipped with a powerful 700MHz NMR magnet with with a triple inverse resonance cryoprobe and high-capacity chilled autosampler available for targeted and untargeted isotope-resolved studies of polar and non-polar metabolite and lipid extracts. In situ solid-state tissue metabolite analysis is also available via magic angle spinning (MAS-NMR) Examples include the determination of the global fate of intracellular 13C tracer molecule metabolism in tumor-derived cells such as succinate dehydrogenase-deficient renal cell carcinoma (Saxena et al. 2016) and global assessment of lipid isotope incorporation using 1D and 2D HSQC pulse sequences (Crooks et al. 2018; Lin et al. 2021). In addition positional determination of metabolite isotope labeling can be determined using 1D and 2D NMR pulse sequences such as 1H-1H TOCSY (Kishimoto et al. 2019). Data collection and method development for NMR analysis of metabolite extracts from clinical tissue specimens obtained during surgical and biopsy procedures in the NIH Clinical Center are currently underway analyses performed using this instrument have already resulted in numerous CCR publications. Pre-clinical metabolic imaging resources are available for dynamic small animal metabolic imaging via Dynamic Nuclear Polarization (hyperpolarization) as well as non-hyperpolarized deuterium and 13C metabolic imaging using image deconvolution algorithms developed at CCR. Additionally pre-clinical PET-CT imaging capability will be available in 2021. Recent research highlights include quantitative assessment of the relationship between tumor glycolysis and oxygenation status by multimodal sequential application of electron paramagnetic resonance imaging of tumor oxygen levels hyperpolarized MRI to assess tumor lactate production rates and 18FDG-PET imaging to assess tumor glucose uptake (Yamamoto et al. 2020). In addition a tensor decomposition post-processing algorithm developed at CCR was applied to MRI chemical shift imaging experiments in order to visualize the metabolism of 13C-glucose in tumors in vivo and assess tumor glycolytic propensities without the need for tracer hyperpolarization (Brender et al. 2019). Finally the activity of a novel therapeutic LDH inhibitor molecule developed at CCR was assessed in vivo using hyperpolarized 13C-pyruvate infusion before and after treatment revealing potent on-target efficacy and a rapid rewiring of tumor metabolism following therapy (Oshima et al. 2020). Clinical 13C-hyperpolarized metabolic imaging with the investigational agent 1-13C-pyruvic acid will be conducted at NCI in patients with renal prostate and brain cancers using a SPINLab clinical polarizer and specialized 13C MRI scanner located in the Molecular Imaging Clinic. Clinical head abdominal and endorectal coils are currently under development. Construction of a sterile filling room in the Molecular Imaging Clinic has been completed to facilitate preparation of clinical 13C1-pyruvate doses required for hyperpolarized imaging studies and the sterile filling facility is currently undergoing certification so that an IND can be cross-filed and scanning of patients can begin. 2218771 +Cancer; Cancer Genomics; Genetics; Human Genome Address;Administrator;Animal Experimentation;Animal Model;CCR;Cell Line;Certification;Clinical Research;Clinical Trials;Computers;Consent Forms;Data;Data Element;Data Reporting;Databases;Development;Ensure;Environment;Feedback;Funding;Genomics;Human;Human Cell Line;Infectious Agent;Informed Consent;Infrastructure;Intramural Research;Iris;Laboratories;Language;Lead;Learning;Link;Logistics;Maintenance;Malignant Neoplasms;Modification;Monitor;Notification;Online Systems;Organism;Participant;Periodicity;Policies;Policy Compliance;Policy Developments;Positioning Attribute;Process;Protocols documentation;Rare Diseases;Reporting;Research;Research Personnel;Resolution;Resources;Retrieval;Review Committee;Role;Science Policy;Services;Source;Subgroup;Supervision;System;Testing;Time;Training;United States National Institutes of Health;Update;Work;arm;base;dashboard;data integrity;data management;data portal;data sharing;data submission;database of Genotypes and Phenotypes;genomic data;genomic platform;improved;meetings;migration;programs;prospective;repository;response;statistics;timeline;wiki;working group Genomic Data Sharing n/a NCI 10703076 1ZICBC011931-03 1 ZIC BC 11931 3 16162371 "CALZONE, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 947634 NCI The NIH Genomic Data Sharing Policy (GDS) applies to NIH-funded research that generates large-scale human or non-human genomic data. The CCR Director mandates genomic data sharing for rare diseases/cancers with no minimum thresholds. The GDS Policy expanded 11/1/2018 to include public access to Genomic Summary Results. The Office of Science Policy (OSP) released the NIH Policy for Data Management and Sharing (DMS Policy) 10/29/2020 that expands scientific data sharing from NIH-funded or conducted research effective 1/25/2023. OSP convened a Clinical Research Subgroup of the Trans NCI DMS Implementation Working Group and Dr. Calzone has been assigned. At the inaugural meeting it was shared that Genomic Program Administrations (GPA) will NOT be involved in DMS policy implementation except through the working group term. GPAs and GPA Administrators will only be involved in GDS content. The Office of Intramural Research (OIR) will lead DMS policy implementation the intramural Data Management and Sharing Plan template mechanisms for plan submission and will monitor for compliance. This subgroup meets monthly until the DMS policy launch. Investigator Resources: Dr. Calzone is the Genomic Program Administrator (GPA) and primary contact for CCR investigators. The GPA Administrator (GPA-A) position was vacant until Margaux Seyler-Schmidt started 2/7/2022. She serves the secondary contact for CCR investigators the primary contact for CBIIT and assists with data pulls study registrations and now auditing old and new portal data. Between 7/6/2021-2/6/2022 all activities were handled by Dr. Calzone. The role of the GPA and GPA-A include attendance at the OSP and ODS periodic meetings to learn about new policy developments that will impact CCR investigators. The GPA works with the GDS regulatory aspects leads the CCR Sensitivity Review committee with assistance of the GPA A and reviews all entered determinations and discusses with the committee if there are issues. She enters final sensitivity determinations in iRIS in time for scientific review. She serves as the interface when the need arises to engage ODS. She handles any CCR Exception Requests which this year involved one investigator that has not yet moved forward with submission of the exception justification. Lastly she maintains and updates all the CCR GDS SOPs with the assistance of the GPA-A. The GPA-A serves as lead for logistical computer and portal issues. She's been trained and works under GPA's supervision to: complete the initial reviews of GDSP and IC submissions in the portal provide timely feedback to investigators if modifications are required and enter dbGaP study registrations and supports investigators in the data sharing process; enter studies into the Genomic Summary Result online system for review by the CCR Sensitivity Review committee; maintains the CCR GDS Wiki page the online GDS key information source for CCR investigators; and enters data into the portal tracking database enabling rapid response to investigator queries about the status of a given project or any possible report requests. Project Summary: Genomic Data Sharing Infrastructure: Critical to the infrastructure needed to facilitate investigator Genomic Data Sharing (GDS) is the development and maintenance of CCR GDS Portal https://service.cancer.gov/gds/. The GDS Policy mandates prospectively a Genomic Data Sharing Plan (GDSP) and/or an Institutional Certification (IC) be completed based on whether the study involves human or non-human organisms or cell lines. The GDSP documents data type(s) repository for submission and proposed submission and release timeline. This form is required of human (including human cell lines) model organisms non-human cell lines and infectious organisms. The IC documents consent for data sharing data use limitations and whether Genomic Summary Results (GSR) must be maintained in a controlled access environment based on a sensitivity determination. The portal (version 4) launched this year provides the platform for GDS form creation review approval revision if indicated and retrieval. Version 4 was required because the existing platform Jira was no longer going to be supported by NCI so there was a required transition to Service Now with the transition handled by CBIIT. Portal activities this past year included the rebuild of the portal in Service Now which also addressed the following issues: 1-GDSP's and ICs are linked to a project. 2-Improve portal login issues for the GPA and GPA Admin which greatly reduced the load time. The GDS Tracking Database moved into the existing GDS portal though the tracking arm is not visible to end users. The portal is organized by project which can be clinical or animal research protocols or laboratory projects of any organism or cell line. Portal projects and documents are established by the investigator or their designee. Despite multiple tests prior the launch of Version 4 there have been several problems including integrity of data migration from Version 3 completed forms not accurately linked to the project incorrect status reports on form completion and inconsistency in notifications to the investigator and GPA/GPA Admin that there are documents that require review and sign off. Unfortunately given the magnitude of the problems including problems which were CBIIT reportedly fixed but persist or new problems arising ultimately resulted in us escalating this to the supervisor Larry Brem. This had some limited impact initially but there remain unresolved problems. The GPA and GPA Admin meet weekly with CBIIT representative Jae Song to resolve ongoing issues. Statistics from 7/3/2021-7/4/2021: During data pulls from the new dashboard we identified additional issues that still require resolution which impact some of the numbers we can report. For example when the studies were migrated to the new portal the date the migration occurred became the data the study was created. In addition form migration from the old to new portal continues as an issue which also impacts data accuracy. So while we are reporting data below we plan perform a full audit of all forms/data elements which will begin in 8/2022. Tracking Portal: 514 studies are in the GDS Tracking portal. 39 GDSP's were reviewed and 37 approved. 31 IC's were reviewed 27 approved. No exception requests were submitted in this reporting period however preliminary discussions with Dr. Aldape about submitting an exception but he has not provided the justification. Since version 4 launched mid 3/1022 there have been 12 projects created with 24 GDSPs and 28 ICs. New Studies: GSR Sensitivity Determinations: 63 studies were reviewed 27 Sensitive 36 Not Sensitive. Data Sharing: 465 studies are registered in dbGaP 408 are minimal registrations 18 in the past year and 57 full registrations 5 in the past year. Data was submitted on 40 studies 8 in the past year. Three new versions of existing studies were submitted this year. Lastly there are 14 closed studies without data submission which are awaiting data submission by the PI. With the move to DMS policy when compliance will be overseen by OIR we will work with these investigators to data share before OIR oversight starts 1/31/2023. 947634 +Biotechnology; Cancer; Emerging Infectious Diseases; Immunization; Immunotherapy; Infectious Diseases 2019-nCoV;American Association of Cancer Research;Antibodies;Antibody Therapy;Antibody-drug conjugates;Antigen Receptors;Antigens;Area;Award;Bacteriophages;Binding;Binding Proteins;Camels;Cell Surface Receptors;Cell surface;Cells;Characteristics;Clinic;Clinical Research;Clinical effectiveness;Communicable Diseases;Communication;Communities;Complex;Consult;Diagnostic;Epitopes;GPC3 gene;Generations;Glypican;Hepatology;Histocompatibility Antigens Class I;Human;Hybridomas;Immunoglobulin G;Immunoglobulins;Immunotherapy;Immunotoxins;Intramural Research;Ion Channel;Laboratory Research;Lassa virus;Libraries;Ligand Binding;Malignant Neoplasms;Mammalian Cell;Methodology;Methods;Molecular;Monoclonal Antibodies;Mus;NCI Center for Cancer Research;Names;National Cancer Institute;Nature;Oryctolagus cuniculus;Paper;Peptide/MHC Complex;Peptides;Phage Display;Procedures;Production;Property;Proteins;Proteome;Protocols documentation;Publishing;Research;Research Personnel;Resources;SARS-CoV-2 spike protein;Scientist;Services;Shark;Signal Transduction;Site;Source;Surface;System;T-Cell Receptor;Technology;Therapeutic;Therapeutic Uses;Therapeutic antibodies;United States National Institutes of Health;Validation;Virus;Virus Diseases;antibody engineering;antibody libraries;antigen binding;base;cancer immunotherapy;cancer therapy;cancer type;chimeric antigen receptor;chimeric antigen receptor T cells;human disease;innovation;interest;mesothelin;nanobodies;new technology;novel;preclinical study;programs;technology development Antibody Engineering Program n/a NCI 10703075 1ZICBC011891-04 1 ZIC BC 11891 4 9692203 "HO, MITCHELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 588522 NCI While antibody-based therapeutics have emerged as a major component in cancer treatment the generation of antibodies to important targets such as cell surface receptors and ion channels remains difficult. These proteins contain buried functional sites that are often unreachable by classical mouse or human IgG-based antibodies. Single domain antibodies have shown a promising ability to target difficult antigens and hidden epitopes. Dr. Mitchell Ho at the NCI has demonstrated that single domain antibodies are capable of targeting buried functional sites in cancer signaling complexes [Feng et al. PNAS 2013; Gao et al Nature Communications 2015; Li et al. PNAS 2017; Li et al. Hepatology 2019]. The Ho lab has constructed large shark and camel single-domain ('nanobody') libraries and isolated binders to a wide range of antigens [Feng et al. Antibody Therapeutics 2019] indicating that the phage-displayed single domain antibody libraries can be a valuable source to isolate therapeutic antibodies. Two areas of research are being pursued at the AEP with collaborators using the shark and camel single domain phage libraries created by the Ho lab. One is focused on targeting intracellular cancer targets via binding of nanobodies to the MHC associated peptide complexes. The other is to isolate nanobodies to important and emerging viruses such as Lassa virus and SARS-CoV-2. In FY22 the AEP published three review articles [Duan and Ho. Molecular Cancer Therapeutics 2021; Duan and Ho. Antibody Therapeutics 2022; Yerabham and Ho. Antibody Therapeutics 2022] and one methodology paper [Duan et al. Current Protocols 2022]. Antibody-based immunotherapies show clinical effectiveness in various cancer types. However the target repertoire is limited to surface or soluble antigens which are a relatively small percentage of the cancer proteome. Most proteins of the human proteome are intracellular. Short peptides from intracellular targets can be presented by MHC class I (MHC-I) molecules on cell surface making them potential targets for cancer immunotherapy. Antibodies can be developed to target these peptide/MHC complexes similar to the recognition of such complexes by the T-cell receptor (TCR). These antibodies are referred to as T-cell receptor mimic (TCRm) or TCR-like antibodies. Ongoing preclinical and clinical studies will help us understand their mechanisms of action and selection of target epitopes for immunotherapy. Our review article published in Molecular Cancer Therapeutics (AACR) [Duan and Ho 2021] summarized and discussed the selection of intracellular antigens production of the peptide/MHC complexes isolation of TCRm antibodies for therapeutic applications limitations of TCRm antibodies and possible ways to advance TCRm antibody-based approaches into the clinic. Single-domain antibodies including the antigen-binding variable domains of the shark immunoglobulin new antigen receptor and the camelid variable region of the heavy chain are the smallest antigen recognition domains (15 kDa) and have unique characteristics compared to conventional antibodies. They are capable of binding epitopes that are hard to access for classical antibodies and can also be used for therapeutics or diagnostics or as modular building blocks for multi-domain constructs antibody-drug conjugates immunotoxins or chimeric antigen receptor therapy. Our method paper contains detailed procedures for the purification and validation of two single-domain antibodies (one shark and one camel) which bind to the S2 subunit of the SARS-CoV-2 spike protein using both bacterial and mammalian cell expression systems [Duan et al. Current Protocols. 2022]. It provides a comprehensive reference for the production of single-domain antibodies with high yield good quality and purity. In FY2022 the AEP also published two research papers as co-authors [Hong et al. PNAS 2022; Pan et al. Molecular Cancer Therapeutics 2022]. 588522 +Cancer; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health APOCEC3G gene;Acquired Immunodeficiency Syndrome;Affinity;Amino Acids;Binding;Catalytic Domain;Cells;Complex;Conflict (Psychology);Cryoelectron Microscopy;Crystallization;Cytosine deaminase;DNA;DNA Sequence Alteration;Defense Mechanisms;Electron Microscopy;Epitopes;Evolution;Goals;HIV;HIV Genome;HIV-1;HIV/AIDS;Human;Infection;Magnetism;Malignant Neoplasms;Modification;Mutate;Mutation;Nuclear;Nucleotides;Pathway interactions;Prognosis;Proteins;Publishing;RNA;Reaction;Research;Research Project Grants;Role;Signal Transduction;Single-Stranded DNA;Source;Spectrum Analysis;Stable Isotope Labeling;Structure;Techniques;Testing;Ubiquitin;Virion;X-Ray Crystallography;Zebularine;analog;base;cancer therapy;cancer type;inhibitor;multicatalytic endopeptidase complex;novel therapeutics;pathogen;protein structure;response;therapy resistant;tumor;tumor growth;tumor progression;ubiquitin-protein ligase Structural studies of biomolecules related to cancer and HIV-AIDS n/a NCI 10703074 1ZICBC011849-05 1 ZIC BC 11849 5 14732013 "MATSUO, HIROSHI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 694954 NCI APOBEC3G (A3G) and APOBEC3H (A3H) are single-stranded DNA cytosine deaminase that can restrict HIV-1 infection by mutating HIV-1 genome. HIV-1 developed a counter defense mechanism by which virion infectivity factor (Vif) leads the degradation of A3G/A3H through ubiquitin-proteasome pathway. Our ultimate goal is to generate small compounds which inhibit the degradation of A3G/A3H. Previously we had determined NMR and crystal structures of domains of A3 proteins including the VIf-binding domain and the catalytic domain. In addition we had determined co-crystal structures of the A3's catalytic domain-ssDNA complex. During 2021-2022 we have developed a technique to selectively stable-isotope label Vif in complex with A3G and assigned NMR signals of Vif to identify amino acid residues in the interfaces with A3G (published in JMR 2022). We have made progress in determining the structure of the A3H-Vif E3 ubiquitin ligase complex by using cryoEM which will provide epitopes to be targeted by small compounds which inhibit formation of the complex. Dysregulation of APOBEC3A (A3A) and APOBEC3B (A3B) proteins contributes a major endogenous source of DNA mutations traced in approximately 75% of cancer types and 50% of all cancers analyzed. A3A/A3B proteins can cause DNA mutations either alone or as the response to cancer therapies which can drive evolution of cancers and A3A/A3B related mutations maybe associated with poor prognosis and therapeutic resistance in cancers. We are developing ssDNA based A3A/A3B inhibitors as ssDNA is the natural substrate for their catalytic reaction. A transition state analogue 2'-deoxy-zebularine was incorporated into the target ssDNA sequence of A3A/A3B and yielded promising affinity and inhibitory effect. We are currently testing modification of nucleotides in order to resist degradation in cells. 694954 +Cancer Accreditation;American;Anatomy;Autopsy;Biocompatible Materials;Biomedical Research;Cancer Center;Clinical;Clinical Research;Collaborations;Collection;Complex;Consult;Critical Thinking;Databases;Diagnosis;Diagnostic;Exposure to;Freezing;Frozen Sections;Genetic Materials;Goals;Histology;Human;Journals;Knowledge;Laboratories;Medical center;Military Personnel;Mission;Operating Rooms;Operative Surgical Procedures;Pathologist;Pathology;Patients;Peer Review;Primary Neoplasm;Process;Protocols documentation;Publications;Research;Research Ethics;Research Personnel;Research Support;Resources;Rotation;Services;Slide;Specimen;Stains;Standardization;Students;System;Technical Expertise;Time;Tissue Banks;Tissue Preservation;Tissue Procurements;Tissues;Training;United States National Institutes of Health;Virginia;Work;biobank;clinical center;college;data resource;demographics;experience;laboratory facility;medical schools;meetings;operation;preservation;programs;skills;standard of care;tissue processing;tissue resource Tissue Procurement Processing Facility and Biorepository n/a NCI 10703072 1ZICBC011731-07 1 ZIC BC 11731 7 14732101 "CHINQUEE, JOSEPH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 219824 NCI The Tissue Processing and Procurement Facility (TPPF) of the Laboratory of Pathology (LP) is staffed by two Pathologists Assistants (PAs for Pathology) and a Technical Laboratory Manager (TLM) who each also supports the Clinical Operations and Histology services. The TPPF also houses LP's frozen section room and is contiguous to the Clinical Center's Operating Rooms. The connection to the OR allows LP's PAs to support time-sensitive tissue procurement inside the operating room or immediately following collection and delivery to the TPPF. This allows immediate processing and preservation of tissues procured for diagnosis and research. The PAs act as liaisons between OR staff research teams and pathology staff by coordinating tissue procurements in the operating room (OR) which entails facilitation of the complex procurements that often involve multiple investigators and multiple protocols simultaneously. PAs work with investigators identifying what tissues need to be procured how they are to be stabilized and what protocols allow the tissue procurement to occur all while preserving the diagnostic integrity of the tissue. The PA also works with the senior resident and between them perform most of the procurements. This system allows as many investigators as possible to benefit all while meeting the standard-of-care for anatomic pathology. During the past fiscal year TPPF staff processed more than 3770 specimens to support 1388 tissue procurements during surgery which were distributed to more than 260 NIH investigators in 12 ICs under approximately 185 protocols. The WRNMMC tissue bank collection has amassed just over 600 frozen and FFPE blocks from more than 300 anonymized cases. This additional biomaterial and associated clinical information expand upon the resources available for utilization by NIH investigators. Each request for specimens is reviewed by a Tissue Resource Committee of Pathologists and regulatory administrative staff in LP prior to distribution. Materials acquired from the TRC program were instrumental resources for data comparison and collection leading to publications in peer review journals. In support of our academic and research missions the TPPF PAs accepted 2 Pathologists' Assistant students this year from Eastern Virginia Medical School (EVMS). The students gain exposure to biomedical research in anatomic pathology. During their clinical rotations the students shadow for one month through LP and work with our PA's and residents to hone their grossing autopsy and frozen section skills while being introduced to the unique field of tissue procurement. The PA students gain experience in research ethics relating to biospecimen procurement technical skills with tissue procurement and processing and in the research and translational laboratory sections in LP. Exposure to procurements allows the students to apply didactic knowledge to real-time situations requiring critical thinking catered to meet the needs of each specific case and research need. In addition to the two PA students the PA's also train new clinical residents each year in tissue procurement and frozen sections for intra-operative consults. 219824 +Cancer; Genetics; Health Disparities; Minority Health; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Affect;Amino Acid Sequence;Binding;Binding Proteins;Brain;CCAAT-Enhancer-Binding Proteins;Cellular biology;Consensus;CpG dinucleotide;Cyclic AMP-Responsive DNA-Binding Protein;Cytosine;DNA;DNA Binding;DNA Sequence;DNA-Directed DNA Polymerase;Dimerization;Dioxygenases;Epigenetic Process;Family;Family member;Foundations;Gene Expression;Genes;Goals;Helix-Turn-Helix Motifs;Leucine Zippers;Mediating;Methylation;Modification;N-terminal;Oxides;Property;Response Elements;Single-Stranded DNA;Site;Specificity;Structure;TCF7L2 gene;Thymine DNA Glycosylase;Tissues;USF1 gene;Variant;Work;ZIP protein;activating transcription factor 1;cell type;demethylation;ds-DNA;in vivo;stem cells;transcription factor Effects of Cytosine Modifications on Transcription Factor Binding n/a NCI 10703071 1ZICBC011724-07 1 ZIC BC 11724 7 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 35346 NCI Sequence-specific DNA binding of transcription factors (TFs) is the foundation of regulated gene expression. Two recent observations have broadened the lexicon of sequence-specific DNA binding of mammalian TFs: the first is that methylated cytosines (5mC) are iteratively oxidized by the ten-eleven-translocation family of dioxygenases to 5-hydroxymethylcytosine (5hmC) 5-formylcytosine (5fC) and 5-carboxycytosine (5caC). 5fC and 5caC are removed by thymine DNA glycosylase completing the DNA demethylation cycle. However 5hmC is found accumulatesd in several tissues suggesting it may have a regulatory function. The second finding is that 5mC can occur outside of CG dinucleotides initially being observed in stem cells and later in the brain. 5mC in CG dinucleotides is known to inhibit or enhance the DNA binding of B-ZIP proteins. The cAMP response element-binding protein (CREB1) regulates expression of cellular genes by binding to its consensus CRE sequence (TGAC'GTCA) and its variants including the CRE/CEBP chimeric site (TGAC'GCAA). Double-stranded cytosine methylation of the CG dinucleotide at the center of the CRE motif inhibits CREB1 binding leading to suppression of gene expression. In contrast methylation of the central CG dinucleotide in the C/EBP motif TTGC'GCAA increases DNA binding of C/EBP family members. While the effect of 5mC and 5hmC in CG dinucleotides on sequence-specific DNA binding of transcription factors has been explored their effect outside of CG dinucleotides on DNA binding has not been examined. The B-ZIP family of transcription factors have a bipartite structure with the leucine zipper region mediating dimerization and the N-terminal basic region mediating sequence specific DNA binding. The structural determinants of leucine zipper domain mediated B-ZIP dimerization specificity and stability have been investigated in detail. However the relationship between the amino acid sequence of the B-ZIP basic region and the DNA sequences they bind including those with modified cytosines has not been explored. T7 DNA polymerase can efficiently incorporate 5mC and 5hmC into DNA when double-stranding single-stranded DNA. We exploited this property to double-strand single-stranded DNA 60-mers on an Agilent microarray using 5mC or 5hmC creating double-stranded DNA sequences containing an asymmetric distribution of 5mC and 5hmC that mimics what occurs in several cell types in vivo. Using these protein binding microarrays containing either cytosines on both DNA strands or a combination of cytosines on one strand and 5mC or 5hmC on the second strand we started to examined the sequence specific binding of a number of B-ZIP and helix-loop-helix transcription factors in addition to CREB1: i.e. ATF1 C/EBP JUND TCF4 USF1 and ZTA. 35346 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Neurosciences; Orphan Drug; Precision Medicine; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human Animal Experiments;Animal Model;Animals;Area;Biological;Biological Markers;Biological Process;Biology;Biopsy;Biotechnology;Brain Neoplasms;Breeding;Cancer cell line;Categories;Cell Line;Cells;Central Nervous System Neoplasms;Characteristics;Clinic;Clinical;Clinical Drug Development;Clinical Investigator;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Convection;Cooperative Research and Development Agreement;Cytostatics;Data;Development;Developmental Therapeutics Program;Diagnostic;Dose;Drug Delivery Systems;Drug Screening;Drug Targeting;Evaluation;Extramural Activities;Future;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Generations;Genetic;Genomics;Glioma;Growth;Human;Image;Immunotherapeutic agent;In Vitro;Institution;Intracarotid;Investigational Therapies;Label;Laboratories;Magnetic Resonance Imaging;Magnetism;Metabolic;Methods;Mission;Modeling;Molecular;National Institute of Neurological Disorders and Stroke;Operative Surgical Procedures;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Program Development;Progression-Free Survivals;Property;Protective Agents;RNA;Radiation-Sensitizing Agents;Research;Research Design;Research Personnel;Resources;Sampling;Schedule;Serum;Serum Markers;Services;Specimen;Surrogate Markers;Technology;Testing;Therapeutic;Tissues;Translational Research;Tumor Cell Line;Tumor Stem Cells;Tumor Tissue;United States National Institutes of Health;Work;Xenograft procedure;angiogenesis;antitumor agent;antitumor drug;base;blood-brain barrier disruption;cancer stem cell;clinical center;clinical development;cytotoxic;design;early phase clinical trial;endothelial stem cell;expectation;experimental study;glioma cell line;human disease;imaging science;in vivo;mouse model;neural;novel;novel therapeutics;pre-clinical;precision medicine;preclinical development;programs;protein biomarkers;repository;research facility;response;screening;screening program;stem cell biology;stem cells;subcutaneous;targeted treatment;translational study;tumor;tumor progression;vasculogenesis Pre-clinical Translational Research Facility n/a NCI 10703070 1ZICBC011641-08 1 ZIC BC 11641 8 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2362658 NCI The major mission of the PTRF is to provide services for clinical investigators to evaluate potential new anti-glioma agents in vitro and in vivo. The NOB Lab has collaborated with pharmaceutical companies and academic institutions and the NCI Developmental Therapeutics Program in the preclinical and clinical development of several new anti-glioma agents. The first step in the development pipeline is screening of the agent through the PTRF that provides the professional service for screening these agents both in vitro and in vivo using both standard subcutaneous and stereotactic intracranial models. Furthermore PTRF provides experimental and technical support to other investigators both within and outside of the NOB for evaluating newly developed therapeutics. These extended studies involved stereotactic-based intracranial models looking at various dose and administration schedules as well as combination trials of the new drug with other agents. For example the PTRF has helped to generate the RNA for gene expression profiles for given glioma cell lines treated with a specific class of agents. Once characteristic patterns are identified that correspond with anti-tumor activity then clinical trials can/will be devised to administer one of these agents to patients with brain tumors immediately prior to biopsy/surgery in order to attempt and identify a similar genetic profile clinically. In collaboration with the NOB Lab and the Genomics Core team gene expression signatures are being generated in all of glioma cell lines and GIC/GSCs for all compounds tested within the PTRF. In addition several newer drug delivery technologies including intra-carotid administration delivery with or without selective or gross blood-brain barrier disruption convection delivery etc. have been evaluated in animal models within the PTRF. Many of the new classes of anti-tumor therapeutics will have cytostatic rather than cytotoxic properties. Evaluating which of these agents will have biologic activity in humans in small early clinical trials is a challenge since the standard response criteria are based on the determination of cytotoxic responses. The only truly valid clinical parameter available for evaluating the activity of a truly cytostatic agent is patient survival or tumor progression-free survival. These however are not useful parameters for screening drug activity in small early phase clinical trials. Thus if surrogate markers of biologic activity could be identified one could utilize these as early endpoints for screening out agents with little or no clinical activity. Toward that end the PTRF is actively working to develop surrogate markers of drug anti-tumor activity that can be utilized and validated in clinical trials which includes three major areas:1) Imaging; 2) Gene expression profiling; 3) Proteinomics/Serum markers. For example in collaboration with investigators in NOB NINDS and the Clinical Centers program of experimental imaging science noninvasive MR imaging has been used to image magnetically labeled endothelial progenitor cells in vivo to directly identify vasculogenesis in a glioma model. Finally the PTRF stores representative tumor tissue and serum samples from animals treated with each new compound tested with the expectations that new candidate tissue and/or serum-based protein markers of drug activity tumor activity and/or some tumor biological process (i.e. angiogenesis) may be found. This will be an invaluable preclinical resource for validating such claims in the future. As described above a major effort of the NOB is to develop human glioma cell lines that more closely model primary human gliomas both biologically and molecularly. The PTRF is actively involved in the generation of primary human glioma cell lines and GIC/GSC lines from fresh surgical specimens for glioma patient operated on at the NIH. Working closely with the cancer stem cell biologists for the growth propagation and characterization of each of these cell lines and animal xenografts the PTRF uses these well-characterized cell lines (described above in the project Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas) as screens for two major categories of drugs; 1) The most promising drugs from the first levels of in vitro and in vivo screens using the more conventional established glioma cell lines; 2) The drugs that target pathways that may not be well represented by the biology of standard glioma cell lines but are reproduced in the GIC/GSCs. The laboratory expertise utilizing these cells and the large resources of different GIC/GSC lines are a potent enticement for potential partnerships between NCI and the pharmaceutical/ biotechnology community given their growing appreciation of the limitation of standard cancer cell lines and the promise of cancer stem cells for better representing the human disease. Since PTRF initiated in 2016 four clinical trials have activated as a direct result of translational work performed within the NOB all of which had preclinical animal studies performed within the facility. Furthermore we have identified 4 compounds solely through the preclinical screening program that have since been brought forward to clinical trials at the NIH (Regadenoson TG02 LB100 ONC206). PTRF is further extending the translational studies such as experimental immunotherapeutics synthetic lethality for the Precision Medicine Program and metabolic targeting therapeutics as well as the experimental therapeutics for rare CNS tumors PTRF is further extending the translational studies such as experimental immunotherapeutics synthetic lethality for the Precision Medicine Program and metabolic targeting therapeutics as well as the experimental therapeutics for rare CNS tumors (Animal Study Proposal: NOB001 005 007 008 021 023 and 024). 2362658 +Biotechnology; Cancer 3D Print;COVID-19;Collaborations;DNA;Development;Disease;Experimental Pathology;Fixatives;Freezing;Goals;Head;Histology;Image Analysis;Immunohistochemistry;In Situ Hybridization;Laboratories;Legal patent;Methodology;Microdissection;Pathologist;Pathology;RNA;Reporting;Research;Research Personnel;Research Support;Science;Services;System;Technology;Tissue Microarray;Tissue Preservation;Tissues;cancer type;instrument;invention;laser capture microdissection;member;method development;prevent;tool;whole slide imaging Experimental Pathology Laboratory (EPL) n/a NCI 10703069 1ZICBC011638-08 1 ZIC BC 11638 8 10274463 "HEWITT, STEPHEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1050159 NCI Long-term research efforts in the EPL in support of translational pathology include: developments of new hardware for the construction of tissue microarrays the development of a tissue microarray instrument for frozen tissue refinement of technologies for tissue micro-dissection. Additional efforts in the EPL focus on tissue preservation and storage with efforts in the development of non-formaldehyde containing tissue fixatives refinement to tissue impregnation systems to prevent tissue degradation and development of methods for freezing and storing tissue that prevent degradation. We filed invention reports in this fiscal year both of which will be filed as preliminary patent applications. The research we support involves numerous types of cancers and other diseases including COVID-19. 1050159 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Genetics; HIV/AIDS; Human Genome; Immunotherapy; Networking and Information Technology R&D (NITRD); Prevention; Urologic Diseases ATAC-seq;Acquired Immunodeficiency Syndrome;Area;Atlases;Authorship;Basic Science;Biochemistry;Bioinformatics;Biological;Biology;Businesses;CCR;CRISPR/Cas technology;Cancer Biology;Cell Therapy;Cells;Cellular biology;ChIP-seq;Collaborations;Computer software;Computers;Consultations;Core Facility;DNA;DNA Sequence;DNA Sequencing Facility;Data;Data Analyses;Data Science;Data Storage and Retrieval;Development;Developmental Therapeutics Program;Dideoxy Chain Termination DNA Sequencing;Doctor of Medicine;Ensure;Enzymes;Experimental Designs;Gene Expression;Genes;Genetic;Genitourinary system;Genomics;Grant;HIV;Head;Human;Immune;Immunology;Immunotherapy;Individual;Information Technology;Institutes;Interest Group;Journals;Laboratories;Laboratory Research;Libraries;Liquid substance;Malignant Neoplasms;Malignant lymphoid neoplasm;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of thorax;Manuscripts;Messenger RNA;Mission;Molecular Biology;Molecular Profiling;Molecular and Cellular Biology;Mus;Names;National Heart Lung and Blood Institute;National Human Genome Research Institute;National Institute of Allergy and Infectious Disease;National Institute of Arthritis and Musculoskeletal and Skin Diseases;National Institute of Child Health and Human Development;National Institute of Diabetes and Digestive and Kidney Diseases;National Institute of Neurological Disorders and Stroke;Operative Surgical Procedures;Pathogenesis;Pathology;Pediatric Oncology;Peer Review;Plasmids;Policies;Principal Investigator;Procedures;Process;Production;Proteins;Provider;Publications;Quality Control;RNA;RNA library;Radiation Oncology;Radiobiology;Reaction;Receptor Biology and Gene Expression;Recovery;Research;Research Personnel;Resources;Reverse Transcriptase Polymerase Chain Reaction;Robotics;Running;Sampling;Schedule;Science;Scientist;Secure;Services;Surgical Oncology;System;Systems Analysis;Technology;Thoracic Surgical Procedures;Time;Training;Transplantation;United States National Institutes of Health;Urogenital Cancer;Urologic Oncology;Vaccines;Vendor;Woman;Work;bioinformatics resource;biomedical informatics;cancer genetics;cancer genomics;cancer immunotherapy;carcinogenesis;cellular oncology;cost;data standards;design;digital;genome integrity;innovation;instrument;instrumentation;liquid biopsy;meetings;member;nano-string;nanopore;neuro-oncology;next generation sequencing;oncology program;outreach;programs;resource guides;seal;single cell sequencing;spelling;transcriptome;transcriptome sequencing;tumor immunology;virtual CCR Genomics Core n/a NCI 10703068 1ZICBC011623-08 1 ZIC BC 11623 8 14280419 "CONNER, ELIZABETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 3231619 NCI CCR Genomics Core lists over 700 registered members in its iLab management and scheduling software. So far in FY22 there are 410 active users; 166 research groups of which 134 are from NCI and the remaining 32 from 9 other NIH institutes. These institutes include NEI NHGRI NHLBI NIA NIAID NIA NIAID NIAMS NICHD NIDDK and NINDS. Of the 45 labs/branches/programs listed under CCR 38 utilize our services (84%). Those labs include: Basic Research Laboratory Cancer Data Science Laboratory Cancer Innovation Laboratory Developmental Therapeutics Branch Experimental Immunology Branch Experimental Transplantation and Immunotherapy Branch Genetics Branch Genitourinary Malignancies Branch HIV and AIDS Malignancy Branch Immune Deficiency Cellular Therapy Program Laboratory of Biochemistry and Molecular Biology Laboratory of Cancer Biology and Genetics Laboratory of Cell Biology Laboratory of Cellular and Molecular Biology Laboratory of Cellular Oncology Laboratory of Genitourinary Cancer Pathogenesis Laboratory of Genome Integrity Laboratory of Human Carcinogenesis Laboratory of Immune Cell Biology Laboratory of Integrative Cancer Immunology Laboratory of Molecular Biology Laboratory of Pathology Laboratory of Receptor Biology and Gene Expression Lymphoid Malignancies Branch Mouse Cancer Genetics Program Neuro-Oncology Branch Pediatric Oncology Branch Radiation Biology Branch Radiation Oncology Branch Surgery Branch Surgical Oncology Program Thoracic and GI Malignancies Branch Thoracic Surgery Branch Urologic Oncology Branch Vaccine Branch Women's Malignancies Branch and the Office of Science Technology Resource. Core instrumentation and services include: Sanger Sequencing (2 ABI 3500xL and 1-3730 xL DNA sequencers). The Core prepares the sequencing reaction or the user can provide their own sequencing reaction. Data are typically analyzed and made available within one business day. Illumina Next-Generation Sequencing (1-iSeq 1-MiSeq 2- NextSeq550 2- NextSeq2000)- Researchers meet with the core prior to discuss the best experimental designs costs turn-around time and data analysis needs and submit pre-made libraries or purified DNA/RNA for library construction and subsequent sequencing. Samples we had sequenced includes 10X single cell sequencing full plasmid sequencing ChIP-Seq RNA-Seq amplicon sequencing ATAC-Seq END-Seq and targeted panel sequencing. Nanopore Sequencing (Oxford Nanopore MinION MinIT MinION Mk1C). A sequencing technology that generates ultra-long reads some of them more than 100kb. Here single DNA (or RNA) molecules are sequenced without the need for PCR amplification. Digital Gene Expression (Nanostring nCounter Analysis System). Direct quantification of individual mRNAs in a biological sample without the use of enzymes or amplification. NanoString designs each CodeSet and then investigators bring their samples to the core to be processed. Digital Droplet PCR (Bio-Rad QX200 Droplet Digital PCR System). This technology is the absolute quantification of a PCR reaction. Customers bring prepared samples in a sealed plate ready to be applied to Automatic Droplet Generator. Results are usually available within 24 h. Data analysis software is available for use on customers' own computer. DNA/RNA & Library QC (Agilent TapeStation 4150 & 4200 Fragment Analyzer QuantStudio RT-PCR system Pippen HT Pippin HT (spelling)). Every sample submitted to the Genomics Core for sequencing undergoes a variety of quality control (QC) procedures to verify the integrity of samples and to ensure that every sequencing run produces the best quality data possible. QC is also performed for customers submitting samples to the Sequencing Facility in Frederick or outside vendors. Digital Spatial Profiling (NanoString GeoMx DSP). This platform combines spatial and molecular profiling technologies by generating digital whole transcriptomes and profiling data. This technology is offered in collaboration with the Collaborative Protein Technology Resource (CPTR). In addition the CCR Genomics Core functions as a support lab containing instruments for various applications for use by CCR investigators. The Core has several robotic liquid handlers to include the Agilent Bravo and the Formulatrix. Analytical software for the various technologies is also made available. So far in FY22 the Core has managed over 3500 iLab requests and processed over 17000 samples for Sanger sequencing 516 for Nanostring 8985 for ddPCR and 11703 for tapestation. The Core has been involved in over 368 different NGS projects featuring the MiSeq NextSeq 550 and 2000 platforms. Projects included 10X single cell sequencing full plasmid sequencing ChIP-Seq RNA-Seq amplicon sequencing ATAC-seq END-SEQ and targeted panel sequencing amongst others. The NanoString GeoMx DSP is our newest platform that continues to advance. This new spatial profiling technology is being offered through a cooperation with the CPTR under Dr. Noemi Kedei and relies heavily on each Core's expertise. Workflows are now being offered for NGS utilizing NanoString's newest releases of the Cancer Genomics Atlas (CTA 1800 genes) and the Whole Transcriptome Atlas (WTA 18000 genes). The CPTR and the GC are presently working with 7 investigators on DSP projects. Thus far 9 nCounter and 26 NGS (23 CTA and 3 WTA) runs have been performed on the DSP. Our work with Dr. Chen Zhao M.D. in the Thoracic and GI Malignancies Branch has resulted in a recent manuscript currently in accepted in Journal for ImmunoTherapy of Cancer. The two Cores are continuing to work on off-instrument data analysis and storage which is an important area for further development. Toward this end the Cores are in discussion with both the CCR Collaborative Bioinformatics Resource and NCI Center for Biomedical Informatics & Information Technology (CBIIT) to establish standardized data workflows to ease the burden on individual PI laboratories. In addition the Core collaborates with NCI investigators on the long-read technology utilizing the Oxford NanoPore MinION. Outreach efforts of the core facility have included active membership in the NIH Single Cell Interest Group virtual participation in CCR-FYI Colloquium Staff Scientist and Principal Investigator Retreats Genetics Branch Annual Retreat as well as the annual meetings of the ABRF and the AGBT. In in lieu of Annual Core Open House the Core in cooperation with CPTR put together a NCI Core Resource Guide which was posted to CCR Central of more than 20 Cores from Buildings 37 41 and Frederick. Three vendor Core-sponsored virtual seminars were held one with Fisher Scientific on online tools for CRISPR-CAS9 gene editing Illumina on Liquid biopsy using RNA and Nanostring on exploring spatial biology. The Core also held demos on the I.DOT liquid dispenser and the Absolute Q digital PCR system from Thermo Fisher. As we are open-access Core it is not a requirement that we be collaborators for investigators to use our facility nor do we ask that our names be included as authors on publications. We do ask that users acknowledge the facility if they use data generated from the Core in a publication but we do not require it. Overall the CCR Genomics Core was acknowledged in 5 peer reviewed publications with co-authorship of Core members in 6 manuscripts in this review period. 3231619 +Bioengineering; Cancer Binding;CCR;Cells;Cellular Structures;Computers and Advanced Instrumentation;Custom;Equipment;Fluorescence Microscopy;Fluorescence Recovery After Photobleaching;Fluorescence Resonance Energy Transfer;Light;Maps;Measures;Methods;Microscope;Microscopy;Mission;Molecular;Optics;Proteins;Research Personnel;Resolution;Specimen;Surveys;System;Techniques;Technology;Testing;Time;United States National Institutes of Health;Vision;Work;base;experimental study;fluorescence imaging;instrument;instrumentation;light microscopy;nano;nanomachine;prospective;single molecule;tool LRBGE Optical Microscopy Core n/a NCI 10703066 1ZICBC011574-09 1 ZIC BC 11574 9 12448468 "KARPOVA, TATIANA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 608675 NCI The Core mission is to provide state-of-the-art light microscopy instrumentation to anyone in the CCR and NIH who requires assistance with fluorescence imaging. Present work in the Core revolves around several established techniques: structural and morphometrical studies based on colocalization of different fluorescent markers by high-resolution and super-resolution techniques 4D and 5D time-lapse analysis to follow how cellular components change over time and how cellular structures nanomachines and proteins interact fluorescence recovery after photobleaching to measure mobility and binding of cell molecules and fluorescence resonance energy transfer to measure molecular interactions in live or fixed specimens. For that the Core is maintaining and upgrading high-end commercial microscopes. Currently the Core maintains wide-field optical sectioning microscope Delta Vision Elite Carl Zeiss LSM780 and 880 confocal microscopes and Lattice Light Sheet 3I microscope and Carl Zeiss SIM/dSTORM Elyra Super-resolution microscope MINFLUX microscope. The Core develops Single Molecule Tracking technique utilizing custom-built HILO microscopes and MINFLUX. The system adapts MINFLUX nano-resolution technique for molecular maps of proteins in cells. The Core constantly surveys the demands for the state-of-the art technology tests and arranges demonstrations of the new instruments for OMC users and advertises new microscopy methods that may be useful for specific needs of the current and prospective customers. 608675 +Cancer; Genetics Binding;Binding Sites;Biophysics;Cell Nucleus;Cells;Cellular biology;Chromatin;Copper;Custom;DNA;DNA Sequence;Data;Data Analyses;Enhancers;Ensure;Event;Fluorescent in Situ Hybridization;Gene Expression;Genes;Genetic Models;Genetic Transcription;Goals;Heavy Metals;Hour;Image;In Situ;Individual;Mammalian Cell;Measures;Messenger RNA;Metallothionein;Metals;Methods;Modeling;Molecular;Periodicity;Pharmaceutical Preparations;Process;Regulatory Element;Research;Response Elements;Role;Site;Stress;Techniques;Time;Transcription Process;Transcriptional Regulation;Ultradian Cycle;Yeasts;chromatin remodeling;circadian;fluorescence imaging;in vivo;instrument;interest;mRNA tagging;promoter;recruit;residence;response;single molecule;stem;transcription factor Transcription factor mobility n/a NCI 10703065 1ZICBC011571-09 1 ZIC BC 11571 9 12448468 "KARPOVA, TATIANA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 260861 NCI "Expression of many important genes is cyclical and may incorporate multiple cycles at the different time scale such as circadian or ultradian cycles on the scale of hours and fast and short bursts of transcription on the scale of minutes. The mechanisms of this cycling are poorly understood but very important for the correct application of the drugs. At the transcription level gene expression is controlled by the accessibility of the regulatory elements within DNA - promoters and enhancers. Research in yeast and mammalian cells indicates that modulation of chromatin accessibility occurs through interaction of transcription factors (TF) and chromatin remodelers. Binding of certain TF to their target DNA sequences is highly dynamic on the scale of seconds. Also some TF undergo the ""slow"" cycling on the scale of minutes which consist of alternating ""ON"" and ""OFF"" gene states. It is unclear how this TF cycling is related to the transcriptional cycling. We are interested in molecular mechanisms of the TF cycling on promoters and its correlation with transcription cycles. We use as a model a yeast gene CUP1 encoding metallothionein expressed in response to heavy metal stress. CUP1 is activated by copper-bound TF Ace1p. Our previous studies demonstrated two types of Ace1p cycling at CUP1: fast - on the scale of seconds and slow - on the scale of minutes. The fast cycling occurs within the slow cycle. The slow cycle of binding may be quantified in individual cells by the regular fluorescence imaging and the fast cycling - by Single Molecule Tracking (SMT). Previously we have built a custom instrument for SMT and optimized SMT data interpretation. We have developed methods for SMT in yeast cell nuclei and methods of performing SMT on specific promoters. By SMT we have measured binding parameters of a chromatin remodeler RSC and TF Ace1p to specific sites (Metal Response Elements MRE) within CUP1 promoter. Transcription of CUP1 may be observed either by smFISH (Fluorescence In Situ Hybridization) or by live imaging of the fluorescently tagged mRNA. Recently we correlated the transcriptional activity of CUP1 promoter by smFISH with changes in the search for the binding sites and the specific residence time of TF. We demonstrated that the transient recruitment of TFs is regulated by fast cyclical chromatin remodeling events to ensure the best dynamic transcriptional response. Our current goal is to corroborate these findings with analysis of the transcription in live cells. Preliminary observations indicate that the slow cycle of transcription consists of the fast cycles (bursts) of expression on individual genes. This kind of observations cannot be made by smFISH in fixed cells and provides new information about transcription. This is the first genetic model where the superimposed slow and fast cycles of transcription correlate with superimposed slow and fast cycling of the transcriptional factor. We are working on modeling of the slow and fast transcription cycles by live TS and corroborating the observations by smFISH modeling. Ultimately these studies will lay the groundwork for the analysis of in vivo interactions of the components of the transcriptional machinery. The smFISH data are corroborated by the live transcription quantification in situ by a stem-loop approach. Live TS imaging revealed transcription bursting on two different scales - slow and fast. Notably slow cycle of transcription correlates with slow cycle of TF binding. Currently we are characterizing fast spikes of transcription and the role of TF in those short spikes. The technique of correlation of the TF biophysics with transcription modeling that we are in process of developing may be applied to a number of other problems of cellular biology where the information for molecular regulation of transcription is desired." 260861 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Immunotherapy Activated Lymphocyte;Address;Adoptive Cell Transfers;Antigens;Area;Autologous;B-Lymphocytes;Back;Biological Response Modifiers;Biopsy;Blood;Blood specimen;Candidate Disease Gene;Carcinoma;Cell Therapy;Cell physiology;Cells;Characteristics;Cholangiocarcinoma;Clinical;Clinical Trials;Colorectal Cancer;Competence;Computer software;Core Facility;Cryopreservation;Cyclic GMP;Data;Dendritic Cell Vaccine;Development;Disseminated Malignant Neoplasm;Documentation;Effectiveness;Enrollment;Ensure;Environmental Monitoring;Equipment;Excision;Extramural Activities;Future;Gene-Modified;Genes;Goals;Human;Human Papillomavirus;Human Resources;Immunologics;Immunotherapy;Industrialization;Infusion procedures;Institution;Laboratories;Lymphocyte;Malignant Neoplasms;Mission;Mutation;National Cancer Institute;Neoplasms;Operative Surgical Procedures;Patients;Peptides;Peripheral Blood Lymphocyte;Physiologic pulse;Procedures;Process;Production;Protocols documentation;Research;Research Personnel;Research Project Grants;Research Support;Resected;Sampling;Sleeping Beauty;Somatic Mutation;Source;Specialist;Supporting Cell;System;T cell therapy;T-Lymphocyte;Testing;Time;Training Programs;Translating;Tumor Antigens;Tumor Tissue;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Vendor;Viral Vector;anti-cancer;cancer cell;cancer therapy;clinical translation;design and construction;gene delivery system;improved;interest;lymphoid neoplasm;malignant breast neoplasm;manufacturing facility;melanoma;neoantigens;novel;novel therapeutics;operation;programs;square foot;success;synovial sarcoma;therapy development;tool;transfusion medicine;tumor;tumor immunology Cell Production Core Facility n/a NCI 10703064 1ZICBC011569-09 1 ZIC BC 11569 9 78355702 "HALAS, HYUNMI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1501220 NCI The mission of this core laboratory is to provide support to the immunotherapy program established by the Surgery Branch of the National Cancer Institute. The laboratory is overseen by Dr. Hyunmi Halas. The main effort of the laboratory involves the production of large numbers of human anti-cancer T lymphocytes ex vivo to treat patients with advanced metastatic cancer enrolled on Surgery Branch clinical trials. Cancer targeting lymphocytes are either isolated directly from biopsied material or are generated by genetically modifying T lymphocytes from a patient's blood. 32 patients each underwent a resection between 01-Aug-2021 01-July 2022. Of the 32 total resections processed by CPF 16 resections were processed in the new Cell Production Facility (T30) which began clinical GMP manufacturing and processing on 24 Feb 2022. The 16 resections processed in T30 provided potential source of tumor-infiltrating lymphocytes (TIL) and 16 were research resection from which initial fragments as potential source of tumor-infiltrating lymphocytes (TIL) were not performed. 70% of the 16 resections processed for fragments and subsequent TIL cells during this time provided sufficient tumor tissue to provide 10+ fragments which were cryopreserved. 3 patient resections yielded reactive fragments with tumor specific reactivity to generate TIL cell which can be expanded in culture cultures for potential treatments. 2 of these patients were resected in mid 2022 and most of the resections with expanded fragments are currently being screened for reactivity as potential future therapies. 4 patient resections were identified reactive fragments as well as candidates for gene modified T lymphocyte therapies. 5 patients were found to not have reactive fragments but were found to have reactive neoantigens for gene modified T lymphocyte therapies identified from the tumor resection and gene modified therapies to provide TCR known to recognize the cancer cells were identified. Nine(9) cell products delivered to patients enrolled on 2 clinical trials were used to treat patients with autologous cell therapies generated by this core laboratory since opening the new facility in Feb 2022 to July 2022. A second critical function of this core lab is to collect process and curate samples from patients enrolled in Surgery Branch protocols. These samples are used to generate the cancer therapies described above and are also used by investigators in the Surgery Branch cell therapy program to evaluate the progress of each clinical trial as well as to address research questions that identify changes that can be implemented to improve these trials. In addition the samples from these trials facilitate research that generates new patient therapies. These research projects include 1) Transducing patients' T cells with genes whose products will better target tumors or enhance endogenous tumor activity 2) Evaluating the ability of infused anticancer lymphocytes to function and survive in patients 3) Identifying new cancer-associated antigens that can be targeted by anticancer cells 4) Identifying novel patient-specific antigens that are created by somatic mutations and selecting cultures that recognize these mutations for use in personalized T cell therapies 5) Identifying characteristics of infused anticancer cells that are associated with objective tumor regression 6) Identifying characteristics of patients who are most likely to respond to anticancer T cell therapies 7) Evaluating selected biological response modifiers tested in Surgery Branch clinical trials 8) Evaluating new gene delivery systems such as the sleeping beauty transposon 9) Producing dendritic cell vaccines that are pulsed with peptides representing a patient's own unique mutanome. Finally the core laboratory maintains and curates all source documents data protocols and expertise associated with cGMP manufacturing and the clinical translation of anticancer cell therapies. Due to the success of these therapies developed by the Surgery Branch investigators within the Surgery Branch intramural NCI laboratories extramural regulatory agencies industrial and academic partners and other interested parties increasingly want access to these data protocols and advice. There is a need to develop new tools for curating data from older trials. There is a need to convert existing data into a format that can be read by newer software packages it is essential that existing is not lost as older file types become obsolete. The Surgery Branch Cell Production Facility has implemented several programs since the development of a Quality Management Systems (QMS) in 2016 and oversight from the Office of Research Support and Compliance (ORSC). These programs include 1. Independent QA - Established through a memorandum of understanding with the Department of Transfusion Medicine who oversees the program. The program has a total of 7 QA specialists to manage the program. 2. Quality Management System (QMS) that governs all operations. 3. A materials management program to ensure that all products/materials that are used in the manufacture or come in to contact with patient therapies are of highest quality and free from adulteration. 4. An environmental monitoring program that ensures the facility is maintained in the highest possible state of cleanliness. 5. Equipment management program that ensures that all equipment used in manufacturing operations is functioning and is maintained appropriately. 6. A document management program that ensures all personnel are working from vetted and approved procedures. 7. A personnel training program that ensures competency and emphasizes the responsibilities and duties of all personnel involved in manufacturing cell therapies in the Surgery Branch. The facilities and QMS is audited annually by third party vendors through ORSC. 3 The former primary cell production facility 3W/TIL lab is no longer used for manufacturing as of Dec 2020. New facilities have been qualified and validated for cGMP cellular manufacturing on the NIH campus. These include Trailer 10B which will provide clinical cell supporting capabilities; 1B42 in building 10 which will support viral vector manufacturing; and T30 a 5000 square foot modular building that will serve as the main manufacturing facility for Surgery Branch Cell Therapies which was completed in March 2021. Cell Processing Facility staff were actively involved in the review of all design and construction documents as well as in drafting and reviewing the commissioning documentation that is being generated for these facilities and are responsible for the cGMP operations of these facilities. 1501220 +Cancer; Cancer Genomics; Genetics; HIV/AIDS; Health Disparities; Human Genome; Minority Health; Networking and Information Technology R&D (NITRD); Rare Diseases Area;Bioinformatics;Biological;CCR;CLIC4 gene;Cells;Collaborations;Communities;Computer software;Custom;Data;Data Analyses;Data Correlations;Databases;Epigenetic Process;Genes;Genome;Genomics;Goals;Head and Neck Squamous Cell Carcinoma;Human Herpesvirus 8;Information Technology;Infrastructure;Knock-out;Laboratories;Malignant neoplasm of liver;Metadata;Methylation;MicroRNAs;Microarray Analysis;Minority Groups;Modeling;Modification;Mutation;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Primary Neoplasm;Principal Investigator;Publications;Reporting;Research;Research Personnel;Resources;Scientist;Somatic Mutation;Statistical Data Interpretation;System;Tissues;United States National Institutes of Health;Update;Viral;Visualization;Yang;base;bioinformatics resource;biomedical informatics;cancer cell;cancer genomics;cancer health disparity;comparative genomic hybridization;data integration;data mining;exome sequencing;experimental study;health disparity;improved;mathematical analysis;next generation sequence data;operation;secondary analysis;survival outcome;transcriptomics CCR Collaborative Bioinformatics Resource n/a NCI 10703061 1ZICBC011532-10 1 ZIC BC 11532 10 9414524 "GOLDSTEIN, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2554457 NCI The CCR Collaborative Bioinformatics Resource (CCBR) is an organizational umbrella which provides a mechanism for CCR researchers to obtain many different types of bioinformatics assistance to further their research goals. This entity pulls together many different bioinformatics expertise within NCI with strengths in a broad range of bioinformatics topics. The CCBR currently is providing support to over 80 Principal Investigators within CCR and are working on 120 projects related to several different general areas including support to a wide variety of cancer genomics areas. The newest efforts have been in the area of single-cell genomics. Examples of collaborations leading to high-end publications include: 1) Regulatory relationships between CLIC4 and miR-142-3p in head and neck squamous cell cancers (Yuspa); 2) The first complete knockout of viral ORF57 gene from all copies of KSHV genome in BCBL-1 cells (Zheng); 3) Demonstration of the differences in methylation between metastases and primary tumors demonstrating the effect of DNMT3B in epigenetic modifications allowing cancer cells to colonize different tissues (Yang); 4) The transcriptomic data of liver cancer used to identify four unique patient clusters which were found to have different survival outcomes (Wang); and 5) Primary and secondary analyses of the exome-seq data as well as integrative visualizations including somatic mutations germline ancestry and mutational signatures analyses to demonstrate health disparities in cancer among minority populations (Ryan). 2554457 +Bioengineering; Biotechnology; Cancer; Genetics; Nanotechnology; Rare Diseases American Association of Cancer Research;Antibodies;Apoptosis;Atlases;Bar Codes;Bioinformatics;Biological Assay;Biological Markers;Biological Sciences;Blood capillaries;CCR;Capillary Electrophoresis;Cardiovascular Diseases;Cell Cycle Checkpoint;Cell Death;Cell Proliferation;Cells;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Collaborations;Communities;Consumption;Custom;Data;Data Analyses;Data Storage and Retrieval;Detection;Development;Drug Targeting;Evaluation;Extramural Activities;Fluorescent Antibody Technique;Freezing;Genes;Genomics;Human;Image;Image Analysis;Immune;Immunoassay;Immunofluorescence Immunologic;Immunologic Monitoring;Immunooncology;Individual;Industry Collaboration;Inflammation;International;Laboratories;Liver neoplasms;Lymphoid Tissue;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Measurement;Measures;Metabolic Diseases;Metastatic Neoplasm to the Lung;Methods;Molecular Profiling;Monitor;Mus;Neighborhoods;Neurosciences;Oncology;Optics;Organ;Pathway interactions;Performance;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Plasma;Post-Translational Protein Processing;Preparation;Program Development;Protein Analysis;Proteins;Protocols documentation;Publishing;RNA;Regulation;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Running;Sample Size;Sampling;Science;Services;Signal Transduction;Signaling Molecule;Site;Societies;Specialist;Specimen;System;Technology;Tissue Microarray;Tissue imaging;Tissues;Transcript;Tumor Tissue;United States National Institutes of Health;Validation;Vendor;Walking;Work;anticancer research;base;biomarker validation;cancer immunotherapy;cancer therapy;clinical application;clinical practice;cost;cost estimate;cytokine;data infrastructure;data sharing;digital;digital pathology;experience;experimental study;image processing;improved;indexing;innovative technologies;instrument;interest;malignant breast neoplasm;meetings;melanoma;multidisciplinary;nanoimmunoassay;nanoscale;neoplastic cell;neurofibroma;ovarian neoplasm;pre-clinical;preclinical study;preservation;protein biomarkers;response;therapeutic target;tool;transcriptome;treatment response;tumor immunology;tumor microenvironment Collaborative Protein Technology Resource - Nano-Scale Protein Analysis Section n/a NCI 10703056 1ZICBC011434-11 1 ZIC BC 11434 11 78355738 "KEDEI, NOEMI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1090698 NCI In the past years we have established 1) the SimpleWesternTM capillary nano-immunoassay (CNIA) system; 2) the bead-based Luminex xMAP multiplexed-immunoassay system for high-performance quantitative protein measurement with small sample consumption; 3) the CO-Detection by Indexing (CODEX) technology for quantitative detection of up to 40 protein markers in tissues at single cell level; and 4) GeoMx Digital Spatial Profiler (DSP) enabling detection of up to 100s of protein and thousands of RNA targets from a single tissue. 1) The SimpleWesternTM CNIA system is an automated capillary immunoassay system for highly quantitative reproducible detection of target proteins and their post-translational modifications in a format that is applicable to very small sample sizes. The CNIA analysis platform fills a need for high-performance assays for comprehensive and quantitative signaling molecule profiling at the protein level and facilitates transferring those assays from discovery research into preclinical/clinical practice. CPTR is one of the earliest adopters of the CNIA technology. We established assay conditions for more than three hundred signaling molecules covering key pathways including targets in apoptosis/cell death cell cycle and checkpoint control gene and RNA regulation cell proliferation and development. Collaborating with CCR investigators we have successfully developed protocols/strategies supporting multiple clinical trial and drug-development programs including the validation of a panel of 120 CNIA assays in peripheral blood mononuclear cells (PBMCs) allowing analysis of samples collected with non-invasive methods and monitoring of protein levels and state of activation at more frequent intervals. In the 2021-2022 fiscal year we have been working with 6 PIs to support their projects. The data generated facilitates preparation of multiple manuscripts (three have been submitted). 2) The Luminex xMAP bead-based multiplex-immunoassay system provides a highly-quantitative multiplex-analysis of cytokines metabolites and other serum/plasma biomarkers. The technology has been broadly applied in life-science research including cancer immunology cardiovascular disease metabolic disease and inflammations with clinically applicable assay performance. Using this technology we have been supporting projects on clinical and pre-clinical studies to monitor immune or other treatment responses in cancer therapies. In addition to full support for the technology we also offer walk-up access to the instrument so users do not need to sustain multiple individual instruments at high cost in their laboratories. This fiscal year we have been working with 3 PIs on their research projects. 3) For the last two years we offer the CO-Detection by Indexing (CODEX) spatial ultra-highplex immunofluorescence technology as service for CCR/NCI/NIH branches/laboratories. The ability to quantitatively measure up to 40 protein targets from the same tissue at single cell level preserving spatial context allows for deep phenotyping of immune cells in the tumor microenvironment characterize their interaction with tumor cells and identify cellular neighborhoods determining cancer fate and progression as well as response to cancer treatment. CPTR is an early adopter of the CODEX technology and became one of most advanced sites spearheading the development and implementation of improved imaging processing and data analysis workflows. We have assessed CODEX assay performance and feasibility in multiple human/mouse organ and tumor tissues (such as lung and breast cancers ovarian and liver tumors melanoma neurofibroma lung metastasis lymphoid tissues etc.). Previously most of our experience has been with imaging fresh frozen tissues this year we successfully implemented assay protocols for the clinically more relevant FFPE tissues and tissue microarrays. Collaborating with CCR/NCI/NIH investigators we customized multiple antibodies to extend the commercially available antibody panel to better support cancer research and therapy. We established a 39-plex antibody panel to characterize the tumor microenvironment of human liver tumors. There is increased interest in using the technology in basic as well as clinical studies. This fiscal year we continued to work with 8 PIs to support their research projects. Our work has been presented at several national and international meetings such as the American Association for Cancer Research (AACR) annual meeting Society for Immunotherapy of cancer (SITC) etc. Several manuscripts are in-preparation close to be submitted. We also have been actively working with multi-disciplinary teams of experts involving other CCR technology and bioinformatics specialists and industry collaborators to establish the infrastructure for data storage collaborative data sharing and analysis and implementing image viewing and quantitative analysis tools such as and NCI HALO 2D digital pathology image analysis platform. With the help and support from CCR Office of Science and Technology Resource (OSTR) and in collaboration with CCR Genomics Core recently we established the GeoMx Digital Spatial Profiler (DSP) platform at CPTR. GeoMx DSP combines standard immunofluorescence techniques with the nCounter digital optical barcoding or NGS readout to perform highly-multiplexed spatially-resolved protein and transcript profiling of tissues. Both RNA and protein panels have been developed by the vendor for immune-oncology cancer pathways and neuroscience as well as the 1800-target 'cancer transcriptome atlas' (CTA) and whole transcriptome atlas (WTA) RNA panel. This fiscal year we have supported 10 intra and extramural investigators for cancer discovery research projects and clinical specimen profiling. The data were included in two published/accepted manuscripts with multiple other in preparation. 1090698 +Biotechnology; Cancer; Cancer Genomics; Genetics; HIV/AIDS; Human Genome; Prevention 7-methylguanosine;ADP ribosylation;Acetylation;Apoptosis;Autophagocytosis;Basic Science;Binding;Biological;Breast Epithelial Cells;CCR;CD4 Positive T Lymphocytes;CD47 gene;CD8B1 gene;Caspase;Cell Cycle;Cell Death;Cells;Cellular biology;ChIP-seq;Chromatin;Chromosome Condensation;Chromosome Structures;Collaborations;Communication;Communities;Complex;Cues;Cysteine;Cytolysis;DNA Repair;DNA-protein crosslink;Data Analyses;Deacetylase;Development;Developmental Therapeutics Program;Digestion;ERCC3 gene;Enhancers;Enzymes;Epigenetic Process;Experimental Designs;Genes;Genetic Transcription;Genomic Segment;HIV;HIV Infections;HMGN Proteins;HMGN1 gene;HMGN2 gene;Hi-C;Immune;Immunology;Immunoprecipitation;Inductively Coupled Plasma Mass Spectrometry;Inflammation;Interleukin-6;Investigation;Isotope Labeling;Journals;Knock-in;Knock-out;Knockout Mice;Laboratories;Laboratory Research;Lipids;Lysine;MCM Protein;MCM2 gene;Manuscripts;Mass Spectrum Analysis;Mediating;Membrane;Metals;Methods;Methylation;MicroRNAs;Molecular;Molecular Biology;Molecular and Cellular Biology;National Institute of Diabetes and Digestive and Kidney Diseases;Nature;Nuclear;Nuclear Export;Nucleic Acids;Nucleosomes;Organelles;Outcome;Oxidation-Reduction;Pathology;Pathway interactions;Phosphorylation Site;Post-Translational Protein Processing;Pre-Replication Complex;Preparation;Process;Protein Conformation;Proteins;Proteolysis;Proteomics;Publications;Publishing;RNA;RUNX3 gene;Regulation;Repression;Research;Research Personnel;Resources;Role;SIRT1 gene;Sampling;Science;Signal Transduction;Site-Directed Mutagenesis;TOP1 gene;Techniques;Technology;Transcriptional Regulation;Translational Research;UBQLN1 gene;United States National Institutes of Health;Vaccines;Work;XDH gene;Xenopus;base;butyrophilin;cell type;chromatin protein;chromatin remodeling;crosslink;design;egg;epigenetic regulation;experimental study;exportin 1 protein;extracellular vesicles;follow-up;histone modification;lipid metabolism;loss of function;mammary epithelium;poly ADP-ribose glycohydrolase;prevent;promoter;protein aggregation;receptor;recruit;repaired;small molecule inhibitor;thioester;trafficking;transcription factor;transcription factor TFIIH;transcriptome sequencing CPTR - Mass Spectrometry Unit n/a NCI 10703055 1ZICBC011430-11 1 ZIC BC 11430 11 11593641 "JENKINS, LISA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1134792 NCI Overall the expertise of the Mass Spectrometry Unit is being used to further the research of multiple groups within the NIH. In FY22 we collaborated in 64 different projects from 36 different investigators with over 2500 samples processed and analyzed. Among these are projects to characterize the post-translational modifications of target proteins including sites of phosphorylation acetylation and methylation to better understand signal transduction protein regulation and the effects of small molecule inhibitors. The resource is also being used to identify protein interactors of both proteins and nucleic acids. Mass spectrometry is additionally being used extensively for large-scale quantitative proteomics projects using both isotopic labeling and label-free approaches. Structural mass spectrometry applications such as crosslinking and limited proteolysis methods are used to investigate protein conformation. Finally the resource is using inductively-coupled plasma mass spectrometry (ICP-MS) to quantify the level of metals in biological samples. In the past year ten collaborative studies have been published; several other projects are nearing completion or manuscripts are under review. One publication resulted from collaboration with Dr. Yves Pommier Developmental Therapeutics Branch. Both used mass spectrometry to characterize interactors of proteins as a means to better understand their function. In the first the role of poly(ADP)-ribosylation (PARylation) in the regulation of the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) was investigated. Mass spectrometry analysis of TOP1 interactors revealed that PARP1 is pulled down with TOP1 even in the absence of CPT consistent with the fact that PARP1 and TOP1 are associated under unperturbed conditions and that PARP1 promptly PARylates TOP1-DPCs without the requirement for replication or transcription. Other work showed that PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Poly(ADP-ribose) glycohydrolase (PARG) was shown to be a repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs which suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs. This research was published in Nature Communications. Global proteomics methods were used in a collaborative project with Dr. Roberto Weigert Laboratory of Cellular and Molecular Biology to understand the effects of Butyrophilin 1A1 (BTN1A1) knockout in mammary epithelium. BTN1A1 has been implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor in a secretion complex with the redox enzyme xanthine oxidoreductase (XDH). Combination of RNAseq and global proteomics analysis of wildtype and Btn1a1-/- knock-out mice demonstrated effects on proteins involved in inflammation and IL-6 signaling autophagy the cell cycle apoptosis membrane-bounded organelles lipid metabolism and transport functions. Evidence was found for the involvement of several pathways responsible for cell death in the knock-out mice including caspase signaling autophagy and pStat3-mediated lysosomal lysis. This research was published in FABSEB BioAdvances. In collaboration with Dr. David Roberts Laboratory of Pathology mass spectrometry was used to investigate potential mechanisms by which CD47 regulates the trafficking of specific RNAs to extracellular vesicles. Interaction of CD47 and its cytoplasmic adapter ubiquilin-1 with components of the exportin-1/Ran nuclear export complex were identified and shown to have functional consequences for nuclear to cytoplasmic trafficking of 5'-7-methylguanosine-modified microRNAs and further transport into extracellular vesicles. This research was published in the Journal of Cell Communication and Signaling. SIRT1 chromatin interactome analyses were performed in collaboration with Dr. Mirit Aladjem Developmental Therapeutics Branch to better understand the differential molecular cues that distinguish dormant origins from baseline origins. In examining the interactome of SIRT1 the MCM protein were identified as binding partners for SIRT1 on chromatin; these proteins are known to be key components of pre-replication complexes. Further analysis of the interactome of MCM2 revealed the reciprocal interaction; phosphorylated SIRT1 was also able to interact with several MCM proteins. Further experiments demonstrated that dormant origins can be distinguished from baseline origins by their preferential association with two phosphoforms of MCM2. This research was published in Nucleic Acids Research. In collaboration with Dr. Alexander Kelly Laboratory of Molecular Biology mass spectrometry was used to investigate the mechanism of condensing engagement with and action on chromatin. Mass spectrometry analysis of immunoprecipitations of the XPB subunit of TFIIH revealed that it was responsible for TFIIH recruitment to condensed chromatin helping to demonstrate a new role for the TFIIH complex in chromosome condensation. Further experiments demonstrated that the TFIIH complex is continuously required to establish and maintain a compacted chromosome structure in transcriptionally silent Xenopus egg extracts. This research was published in eLife. The transcription factor Thpok is essential for development of CD4+ T cells but the mechanisms by which it do so are not well defined. Working with of Dr. Remy Bosselut Laboratory of Immune Cell Biology mass spectrometry was used to analyze the proteins that interact with Thpok in primary CD4+ T cells. These experiments identified components of the nucleosome remodeling and deacetylase complex (NuRD). Further investigation revealed three residues of Thpok that are required for interaction with NuRD and subsequent repression of CD8+ lineage genes including Runx3. These results were published in Science Immunology. With the lab of Dr. Michael Bustin Basic Research Laboratory mass spectrometry was used to investigate whether HMGN proteins regulate higher order chromatin status. ChIP-MS experiments were performed to identify HMGN1 and HMGN2 interactors on chromatin. Among proteins consistently observed and enriched above background in the analysis were proteins related to epigenetic regulation and histone modification transcriptional regulation chromatin remodeling and DNA damage repair. Hi-C Promoter Capture Hi-C and ChIP-seq experiments revealed that HMGN proteins occupy genomic regions involved in cell-type-specific long-range promoter-enhancer interactions but do not cause structural changes in higher order chromatin. These findings were published in Epigenetics & Chromatin. In addition to the above projects mass spectrometry has been used to investigate the mechanism of action of SAMT-247 a thioester molecule developed to prevent and treat HIV infection. Working with Drs. Genoveffa Franchini Vaccine Branch and Daniel Appella NIDDK mass spectrometry experiments have demonstrated that SAMT-247 covalently modifies cysteine and lysine residues in HIV Gag resulting in protein aggregation and loss of function. Additionally new work has identified a host protein that can also be targeted by SAMT-247 resulting in decreased HIV infection of cells. 1134792 +Bioengineering; Biotechnology; Cancer; Health Disparities; Minority Health Advanced Malignant Neoplasm;Aerosols;Baltimore;Bioinformatics;COVID-19 pandemic;Calendar;Cell Line;Cell Separation;Cell fusion;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Computer software;Consultations;Containment;Core Facility;Custom;DNA Damage;Data Analyses;Development;Drug Targeting;Education;Emergency Situation;Ensure;Epithelial;Exercise;Flow Cytometry;Fluorescence-Activated Cell Sorting;Fluorochrome;Future;Generations;Genomics;Goals;Guidelines;Hour;Housing;Image;Immune response;Institutes;Laboratories;Laboratory Research;Lasers;Lead;Libraries;Lymphocyte;Lymphoma;Methods;Mission;Modernization;Molecular Biology;NCI Center for Cancer Research;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Policies;Procedures;Research Personnel;Reservations;Resource Sharing;Resources;Safety;Sampling;Schedule;Services;Sorting;Students;Supporting Cell;System;T-Cell Development;T-Lymphocyte;Technical Expertise;Technology;Thymus Gland;Time;Training;United States National Institutes of Health;Visit;Work;advanced system;analytical tool;anticancer research;base;design;digital;dimensional analysis;experimental study;flexibility;follow-up;foot;genome integrity;high dimensionality;innovation;instrument;instrumentation;investigator training;member;mutant;new technology;novel;operation;pandemic disease;response;screening;single cell analysis;tool;tumor;user-friendly CCR LGI Flow Cytometry Core n/a NCI 10703054 1ZICBC011428-11 1 ZIC BC 11428 11 14732145 "LIVAK, FERENC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1677497 NCI The mission of the CCR LGI Flow Cytometry Core in Building 37 (FC37) is to offer up-to-date instrumentation and technical expertise to CCR investigators to assist cancer research. The core provides full-scale state-of-the-art flow cytometry services including analytical sample acquisition data analysis imaging flow cytometry fluorescent cell sorting and experimental planning and consultation. The core is committed to the dissemination of novel flow cytometry-based technologies through continuous education of investigators and participating in the NCI-wide flow cytometry training course with active contributions from director Ferenc Livak and staff members Karen W. Wolcott and Caiyi Li. The Core also works together with other NCI Flow Cytometry cores and facilities to take advantage of a shared bioinformatics expert who was hired and started in FY22 to support high dimensional flow cytometry data analysis at NCI. Director Ferenc Livak and staff member Shafiuddin Siddiqui together wrote a chapter on design and execution of high dimensional flow cytometry for the upcoming edition of Methods in Molecular Biology Vol 2580 T-Cell Development section. This chapter offers users a step-by-step guide in planning and setting up successful high dimensional flow cytometry analytical experiments. The LGI FC37 provides instrumentation for a wide variety of flow cytometry technologies. The core is equipped with seven analytical instruments: a state-of-the-art BD FACSymphony A5 flow cytometer equipped with five lasers and the capacity to identify 27 fluorochromes also equipped with a high throughput sampler (HTS) attachment that accommodates 96-well plates to further increase the capacity of the instrument. Two high end BD LSRFortessa cytometers with identical configuration equipped with five lasers and the capacity to identify 18 fluorochromes. One of these instruments LSRFortessa SORP1 is also equipped with HTS attachment. The core also has a three-laser digital BD FACSCanto II cytometer. The LGI FC37 has been a pioneer in introducing the novel technology of spectral flow cytometry to NCI and currently operates a 4-laser/32-channel Sony SA3800 and a 5-laser/144 channel Sony ID7000 spectral analyzer. It is anticipated that the ID7000 instrument will fully replace the smaller and older SA3800 analyzer by the end of FY22. In addition the Core operates a dual-camera 4-laser ImageStream MarkII imaging flow cytometer equipped with HTS attachment. To support cell sorting the Core operates two BD FACSAria IIu instruments equipped with 3-4 lasers to simultaneously identify 11-12 fluorochromes. Both of these sorters are enclosed in flexible BioBubble Benchtop Biocontainment units. The Core also operates one BD FACSAria Fusion cell sorter housed in a custom-designed Class II type A2 biosafety cabinet which is equipped with five lasers with the capacity to identify 18 fluorochromes. The old Beckman Coulter MoFlo Astrios EQ instrument has been replaced with a newer much more user-friendly Sony MA900 cell sorter housed in a custom-designed Class II biosafety cabinet. The biosafety cabinets combined with the separate housing in a dedicated laboratory space in Room 6008A allow the LGI FC37 to operate in full compliance with NIH Policy for Biosafety of Cell Sorters (July 28 2012) to perform all sorts at a BSL-2 with enhanced precautions aerosol containment level. In FY22 utilization of the Core began to return to pre-pandemic levels. The new Sony ID7000 spectral analyzer has been installed and with staff member Karen Wolcott's expert training exercises it has now almost completely replaced the older Sony SA3800 analyzer. Ferenc Livak and Karen Wolcott working with James Galentine of NCI Office of Space and Facilities Management developed a detailed plan to expand and renovate the Core's physical space in BG37. These plans have been approved however work has not begun yet. It is hoped that this renovation can proceed urgently as the Core has continuously expanded its instrumentation repertoire and user base in the past years and now has reached the limits of its physical space. The new expanded space will allow users and staff to maintain minimum 6-foot physical distancing and would give the Core the opportunity to introduce another high-end cell sorter in the coming years in a separate lab space that can continue to operate even in case of future emergency situations. In FY22 the LGI FC7 purchased and installed a new online calendar and tracking software iLab from Agilent Technologies. This software replaces the suddenly discontinued LabShare system. After several weeks of intense training and user support the Core has successfully switched to this modern and more versatile online scheduling platform which will hopefully provide our more than 200 users with more robust and reliable online reservation mechanism than the previous LabShare-based system did. The LGI FC37 served 286 users from 85 CCR laboratories as well as from 3 additional laboratories of three other NIH institutes in FY22. Many of these laboratories heavily depend on the services of the Core in conducting high-dimensional analyses aimed at better understanding of lymphocyte development and activation (Ashwell Samelson labs (LICB] thymus epithelium development (Bhandoola lab [LGI]) and tumor-associated immune responses (Goldszmid lab [CIP] Gilbert and Zhuang labs [NOB]). Single cell sorting helps the rapid generation of CRISPR-induced mutant cell lines and is becoming an essential tool in single cell genomic analyses and CRSIPR library screening (Nussenzweig and Lazzerining-Denchi labs [LGI] Bosselut lab [LICB] Casellas lab [NIAMS/NCI]). The LGI FC37 provides unique support in imaging flow cytometry technology by offering the only Amnis ImageStream instrument on campus to the study of lymphoma drug targeting (Staudt lab [LMBr]) thymic selection and innate-like cell development (Takahama and Lazarovic labs [EIB]) advanced AI-assisted image-based T-cell characterization (Jiang lab [CDSL]) and DNA damage response (Nussenzweig lab [LGI]). The LGI FC37 has trained 70 new users in FY22 on analytical instruments and has also trained three new users for cell sorting. New users are instructed to review instrument and software training tutorials before attending a 4-hor hands-on training session that includes startup and shut down procedures for the cytometers setting up experiments basic instrument troubleshooting and data analysis. Using a completely Webex-based remote training schedule allows the Core to offer training while observing the NIH guidelines on physical distancing. Core staff also provides follow-up assistance and helps new users develop confidence in using the technology correctly. Cell sorter training is offered to select users who need frequent possibly after hour sorting time. The LGI FC37 has designed policies to ensure safe fair and equitable access of Core resources to all registered users. Despite recent challenges associated with the immediate aftermath of the COVID-19 pandemic the LGI FC37 remains committed to be a leader of flow cytometry services at CCR by offering the highest quality reliable support to the largest number of NCI investigators on campus The LGI FC37 is dedicated to the introduction of innovative flow cytometry-based technologies to further advance the cutting-edge cancer research conducted at NIH. 1677497 +Bioengineering; Cancer; Genetics; HIV/AIDS; Nanotechnology ADORA2A gene;Affect;Agonist;Amines;Apoptosis;Binding;Biological;Biological Assay;Biomimetics;Cell Adhesion;Cell Surface Receptors;Cell membrane;Cells;Cilengitide;Clinical;Collaborations;Cyclic Peptides;DNA;Development;Drug Targeting;Endothelium;Equilibrium;Extracellular Matrix;Extracellular Matrix Proteins;Family;Glioblastoma;Goals;HIV;Human;Hybrids;Infiltration;Integrin alpha Chains;Integrin alphaVbeta3;Integrins;Investigation;Laboratories;Libraries;Ligands;Malignant Neoplasms;Mediating;Melanoma Cell;Membrane;Metastatic Neoplasm to the Lung;Molecular Conformation;Molecular Target;Nanotechnology;National Institute of Diabetes and Digestive and Kidney Diseases;Nerve Degeneration;Nucleic Acids;Parkinson Disease;Peptide Nucleic Acids;Peptides;Periodicity;Pharmaceutical Preparations;Phase;Positioning Attribute;RGD (sequence);RNA;Surface;Synthesis Chemistry;Tandem Repeat Sequences;Technology;Time;Vertebral column;Work;Xanthines;angiogenesis;antagonist;base;cancer cell;cancer therapy;density;dimer;drug development;echistatin;inhibitor;interest;migration;molecular size;monomer;mouse model;neovascular;overexpression;peptide analog;programs;receptor;scaffold;tumor HIV NCp7 inhibitors and Multivalent Inhibition of Membrane Receptors n/a NCI 10703053 1ZICBC011380-12 1 ZIC BC 11380 12 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 35346 NCI This project is in collaboration with the laboratory of Dr. Daniel Appella (LBC/NIDDK) which specializes in synthetic chemistry of biomimetics. This is an extension of their work developing hybrids of DNA and Peptide Nucleic Acid (PNA) molecules as programmable scaffolds for the multivalent display of biological ligands. PNAs are oligomeric molecules with peptide-like backbones and nucleic acid-type bases i.e. the A G C & T/U of DNA and RNA for sidechains. Thus by adjusting the sequence of the monomers PNAs can be programmed to bind in a helical conformation to a single or tandem repeated complementary sequence in DNA. Specific ligands are positioned anywhere along the PNA/DNA scaffold by the programmed addition of bridging linkers to the synthesized PNA backbone. For a proof of principle we focused on the conserved RGD sequence in extracellular matrix proteins that is a preferential ligand of Integrin alphaVbeta3. We used a 5-residue cyclic-peptide analog of this sequence that is similar to the drug Cilengitide (MerckSerono) which is currently under Phase II investigation for Glioblastoma and other cancers. To determine the optimal configuration the Appella lab generated a library of hybrid molecules with systematically-varied ligand positions and densities and then screened it on a melanoma cell binding assay. Balancing molecular size and potency a construct with 5 PNA segments each presenting three RGD ligands was judged the optimal inhibitor. Using a radiolabled echistatin displacement assay this optimal construct was found to bind 400 times stronger to alphaVbeta3 than the monomeric RGD control. Finally this optimal PNA/DNA inhibitor was also found to outperform monomeric cyclic-RGD in blocking lung metastasis of melanoma cells in a mouse model. Recently we have expanded this project to target the human A2a adenosine receptor for multivalent binding of agonists and antagonists. Recently we expanded the application of this technology to the A2a adenosine receptor a drug target for Parkinson's disease and other neurodegenerative conditions. Using a multivalent library of attached anatagonist ligands (Xanthine Amine Congener) we were able to identify the receptor in both dimer and higher order configurations in the cell membrane. 35346 +Biotechnology; Cancer; Cancer Genomics; Genetics; HIV/AIDS; Human Genome Automation;Bioinformatics;Biological Sciences;Chromatin;Communicable Diseases;Communities;DNA;Data;Deoxyribonucleases;Ensure;Failure;Future;Generations;Genomic DNA;High-Throughput Nucleotide Sequencing;Laboratories;Libraries;Liquid substance;Manuals;Maps;Messenger RNA;MicroRNAs;Mission;NCI Center for Cancer Research;Neck;Preparation;Principal Investigator;Process;RNA;Reagent;Resources;Sampling;Stretching;System;Technology;Time;Transcript;anticancer research;bisulfite;cancer type;coronavirus disease;cost;data quality;exome;genomic variation;instrument;microbial;next generation sequencing;operation;single molecule CCR Sequencing Facility n/a NCI 10703052 1ZICBC011331-13 1 ZIC BC 11331 13 9414524 "GOLDSTEIN, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 5570884 NCI Over the last year the CCR-SF has sequenced several hundred samples for dozens of different NCI principal investigators generated Terabases of mappable data and has completed numerous projects. Sample types from various cancer types and infectious diseases including COVID have been successfully sequenced include: whole genomic DNA exome capture DNA Chromatin Immuno-Precipitated DNA (ChIP) DNase HS DNA 4C DNA mRNA short hairpin DNA microRNA and Bisulfite samples. The labor intensive library preparation step is the major workflow bottle neck. To reduce library preparation costs and increase library preparation throughput and the efficiency of laboratory operations the CCR-SF team has implemented Beckmans SPRIworks Fragment Library System (SPRI-TE). The SPRI-TE has the capability to produce three times the number of libraries prepared by a technician uses a tightly controlled micro fluidics system to reduce manual liquid transfer variability and the reagent costs are currently at or below the cost of the Illumina library preparation reagents before optimization. CCR-SF bioinformatics has implemented standard analyses on all applications. These analyses have been incorporated into an automation pipeline providing additional time to bioinformatics staff for optimizing the data quality and automation process. CCR-SF bioinformatics takes all new customers through an Introduction to Illumina session complete with a document for future reference. This course has been given across NCI. The CCR-SF Quality Management team has implemented a robust QC workflow to help identify potential failures as early as possible further conserving resources and increasing overall efficiency. 5570884 +Bioengineering; Biotechnology; Cancer; Immunization; Neuroblastoma; Neurosciences; Rare Diseases Agreement;Antibody-drug conjugates;Biology;CCR;CD276 gene;Cancer Biology;Carbamates;Cell Separation;Cells;Chemicals;Chemistry;Clinical Research;Clone Cells;Collaborations;Computer software;Consult;Coumarins;Cytometry;Data;Data Collection;Deposition;Development;Developmental Biology;Ensure;Equipment;Evaluation;Festival;Flow Cytometry;Hematopoietic stem cells;Hour;Human;ID2 gene;Immunophenotyping;Individual;Laboratories;Laboratory mice;Life Cycle Stages;Maintenance;Malignant Neoplasms;Masks;Measures;Microfluidics;Molecular;National Institute of Allergy and Infectious Disease;Neuroblastoma;Parkinson Disease;Price;Publications;RNA;Reagent;Reporting;Research;Research Personnel;Sampling;Scientist;Secure;Services;Signal Transduction;Sorting;Students;Technology;Testing;Training;Training Programs;Vendor;Work;alpha synuclein;antibody conjugate;antibody libraries;assay development;cancer genetics;chimeric antigen receptor;cyanine;exhaustion;functional group;high throughput analysis;immune function;in vivo;innovation;instrument;investigator training;operation;posters;programs;quality assurance;sound;spectrograph;structural biology CCR-Frederick Flow Cytometry Core n/a NCI 10703049 1ZICBC011236-14 1 ZIC BC 11236 14 77857619 "CARRELL, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 365069 NCI To date in FY2022 the Core has performed 236 billable services including 432 individual samples sorted and 1023 hours billed. The core's cytometers were used for 1573 sessions totaling more than 4300 hours. The Core recorded 99 individual users from numerous CCR programs including the Cancer Innovation Laboratory Mouse Cancer Genetics Program Chemical Biology Laboratory RNA Biology Laboratory Cancer & Developmental Biology Laboratory Center for Structural Biology and Laboratory of Cell & Developmental Signaling. The core also provided services for the Collaborative Clinical Research Branch (NIAID) the Office of Scientific Operations and the FNL Molecular Characterization Lab. The core trained 28 new users (scientists fellows students and technicians) from 7 different labs to use flow cytometry in their work. To keep up with evolving cytometry technology and ensure uninterrupted service as old instruments are declared obsolete by vendors core staff evaluates new instruments and software and meets regularly with flow facility leaders across NCI to harmonize instrument offerings and secure favorable pricing for equipment and service maintenance agreements. Recent live evaluations include the Miltenyi Tyto microfluidic sorter (Oct 2021) Thermo Bigfoot cell sorter (May 2022) and BDBiosciences FACSplore spectral & imaging cytometer (Jul 2022). The core added 96 and 384-well sampling capabilities to an additional instrument (May 2022); with 3 instruments now configured for high throughput analysis investigators may screen large libraries for antibody discovery. The core also built bespoke hardware for depositing sorted cells in Terasaki microwells for hematopoietic progenitor single cell cloning (Jun 2022). The Core presented a technical poster describing data spill-spread phenomena in multicolor cytometry at the USAMRDC Spring Research Festival April 2022. The core was acknowledged for technical contributions to these 2021/2022 publications: 1) ID2 and HIF-1a collaborate to protect quiescent hematopoietic stem cells from activation differentiation and exhaustion. Jakubison BL et al. J Clin Invest 2022 132(13): e152599. PMID: 35775482 2) Alpha synuclein the culprit in Parkinson disease is required for normal immune function. Alam Md et al. Cell Reports 2022 38:110090. PMID: 35021075 3) Coumarins to Cyanines: Synthesis of Hemicyanines. Caldwell DR et al. Org. Lett 2021 23:8857. PMID: 34752112 4) Targeted Fluorgenic Cyanine Carbamates Enable In Vivo Analysis of Antibody-Drug Conjugate Linker Chemistry. Usama SM et al. J Am Chem Soc 2021 143:21667. PMID: 34928588 5) Cyanine Masking: A Strategy to Test Functional Group Effects on Antibody Conjugate Targeting. Thapaliya ER et al. Bioconjugate Chem 2022 33:718. PMID: 35389618 6) An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma. Tian M et al. J Clin Invest 2022 In press PMID: 35852863. 365069 +Cancer; Genetics Affinity;Apoptosis;Architecture;Arginine;Binding;Biochemical Pathway;C-terminal;CREBBP gene;Cancer Biology;Cell Cycle Arrest;Cell Cycle Kinetics;Cellular Stress;Chemicals;Chromatin;Collaborations;Complex;DNA Damage;Development;EP300 gene;Electrostatics;Genes;Genetic Transcription;Histone Acetylation;Hydrophobicity;Laboratories;Lead;MDM2 gene;Mediating;Modification;Monitor;Mutation;N-substituted Glycines;N-terminal;Normal Cell;Pattern;Peptides;Peptoids;Phosphorylation;Play;Post-Translational Protein Processing;Proteins;Role;Series;Serine;Signal Pathway;Signal Transduction;Site;Structure;Surface;TP53 gene;Thermodynamics;Threonine;Transactivation;Work;Zinc;alpha helix;base;design;drug development;histone acetyltransferase;inhibitor;interest;molecular modeling;molecular targeted therapies;novel;promoter;protein protein interaction;recruit;response;scaffold;structural biology;transcription factor Molecular Modeling of Interactions Regulating the Activity of the p53 Protein n/a NCI 10703043 1ZICBC011077-15 1 ZIC BC 11077 15 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 141384 NCI This project continues a long-standing collaboration with the Laboratory of Dr. Ettore Appella (LCB/NCI). Initially we focused on the inactivation of p53 by the binding of the MDM2 and MDMX proteins to the N-terminal transactivation domain. This work lead to the development of two types of competitive inhibitor molecules. The first based on a poly N-substituted glycine scaffold was the proof of principle that such peptoids could be designed against a protein target. The second easier to produce molecule was based on a novel N-acylpolyamine (NAPA) scaffold. This latter molecule was optimized to have a binding affinity comparable to the well-known MDM2 inhibitor Nutlin (Hoffman-La Roche). However superior to Nutlin our inhibitor is potent against both MDM2 and MDMX. Subsequently we have concentrated on the functional interactions of p53 with the histone acetyltransferase coactivator homologs CREB-binding protein (CBP) and p300. Chromatin-bound p53 recruits these proteins to the gene promoter resulting in localized acetylation of the histones and thus the required unwinding of the chromatin needed for transcription. CBP and p300 are each composed of seven distinct domains arranged in a common architecture. Among these are two transcriptional adaptor zinc-binding domains Taz1 (C/H1) and Taz2 (C/H3) which mediate protein-protein interactions important for transcription. While both these domains were known to interact with both transactivation domains of p53 (TAD1 & TAD2) nothing was known of the structural details. In collaboration with Drs. Hanqiao Feng and Yawen Bai (LBMB/NCI) we were the first to elucidate the structure of the interaction of the TAD1 of p53 with the Taz2 domain of p300. In the complex the p53 peptide forms a short helix and interacts with the Taz2 domain through an extended surface. The specific way in which the helix is bound is different from what has been observed in complexes with other proteins most notably with MDM2 and MDMX. While the complex is primarily stabilized by hydrophobic bonds electrostatic interactions also play a role. Our additional studies involving NMR mutations and thermodynamics indicated how the structure of the complex shifts and is further stabilized upon phosphorylation of p53 at residues Ser15 and Thr18 which was known as post-translational modification signals for the recruitment of CBP and p300. By revealing the specific interactions of the phosphorylated residues of p53 with proximal arginine residues of Taz2 we were able to explain the structural basis for this important signaling pathway. Currently we are pursuing the structure of the complex of the p300 Taz2 domain with TAD2 the second transactivation domain of p53. This is of particular interest because unlike the first the interaction is not altered by phosphorylation of the analogous serine and threonine residues in the p53 sequence. Finally we have at least two new directions we are gearing-up to pursue. One is to evaluate the formation of a putative stabilizing alpha-helix in the C-terminal regulatory domain and to determine the effect of modifications on the stabilization of the p53 tetramer. The other is to monitor directly in cells the kinetics of the site-specific chemical modifications of p53 and the resultant series of molecular interactions that follow different types of cellular stresses. Recently we finished refining and analyzing the NMR structure of the p300-Taz2/p53-TAD2 complex. 141384 +Bioengineering; Cancer 3-Dimensional;ABCB1 gene;ATP-Binding Cassette Transporters;Address;Adenosine;Antibodies;Binding;Carrier Proteins;Cells;Chemotherapy-Oncologic Procedure;Computing Methodologies;Crystallization;Data;Effectiveness;Electron Microscopy;Electrons;Environment;Experimental Designs;Exposure to;Family;Genetic Polymorphism;Goals;Homologous Protein;Human;Hydrolysis;Hydrophobicity;Integral Membrane Protein;Knowledge;Label;Lipids;Membrane;Methods;Modeling;Molecular Conformation;Multi-Drug Resistance;Mus;Mutation;Pattern;Proteins;Pump;Roentgen Rays;Sequence Alignment;Site-Directed Mutagenesis;Structural Models;Structure;Substrate Specificity;Transmembrane Domain;X-Ray Crystallography;analog;base;cancer therapy;chemotherapy;crosslink;design;experimental study;extracellular;flexibility;human model;in vivo;mathematical methods;member;molecular modeling;nucleotide analog;small molecule inhibitor;stem;three dimensional structure;tripolyphosphate Molecular Modeling of the Human P-glycoprotein Transporter Protein n/a NCI 10703042 1ZICBC011075-15 1 ZIC BC 11075 15 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 176730 NCI Like many transmembrane proteins determination of the structure of P-gp by X-ray crystallography has proven very difficult. This stems from the problems encountered forming sufficient-quality crystals that maintain the native physiochemical environments for the different parts of the protein and thus the native conformations. After many years of endeavor a structure of the closely-related mouse P-gp protein has become available. However many questions remain as to how close the crystal structure relates to the protein in vivo and how the conformation changes as part of the transport function. To address these questions we are striving to integrate all available X-ray crystal and electron microscopy determined and indirect experimental data with physiochemically-based mathematical methods to produce advanced models of the structures. Fortunately over three decades of study has provided a wealth of information about P-gp from which we can gleam structural information. In addition to mouse P-gp crystallographic structures are available from homologous proteins: especially bacterial Sav1866 and the MsbA lipid flippase. Examples of useful indirect experimental data include the effects of site-directed mutagenesis naturally occurring polymorphisms and residue cross-linking. Examples of theoretical physiochemically-based methods include examining the patterns of residue conservation and polarity/hydrophobicity within the family of closely related MDR proteins and the superfamily of ABC transporters. This information helps predict which residues are exposed to the core and headgroup layers of the membrane which residues line the pore and which are at the interfaces of the two transmembrane domains. To this end we are developing a grand sequence alignment of homologous families and the superfamily. The results of this will also enable the determination of patterns of correlated mutations which help identify groups of residues that are proximal in the 3-dimensional structure of the protein. We have used our 3-D structural modelling of human P-gp to determine where to put electron paramagentic probes to experimentally determine different conformational states over the functional cycle of the protein. Additionally we will use computational methods with our P-gp models to select nucleotide analogs and labeling agents to interact with and further elucidate the structure and functional mechanisms. Most recently we have use the models to explain the experimentally-determined binding-effects of 5'-fluorosulfonylbenzonyl-5'-adenosine (FSBA) an ATP analogue on the functional mechanisms of P-gp. We have also used computational methods to better account for the membrane environment on the protein. Recently the models were used to design and interpret experiments that revealed the functional flexibility of the P-gp binding pocket. That is mutation of known substrate-binding residues identified alternative sub-pockets that allow for functional transport. We have also used computational methods to predict the binding of antibodies to the extracellular loops of human Pgp. 176730 +Cancer; HIV/AIDS; Health Disparities; Minority Health; Women's Health Anatomy;Ancillary Study;Breast;Cell Count;Cell Line;Central Nervous System;Clinical;Clinical Protocols;Clinical Research;Cytology;Cytopathology;Diagnosis;Diagnostic;Diagnostic Services;Duct (organ) structure;Evaluation;Fellowship;Fine needle aspiration biopsy;Flow Cytometry;Goals;Gynecologic;Investigation;Irrigation;Malignant Neoplasms;Molecular;Molecular Analysis;Morphology;Nature;Organ;Organism;Pathologic;Pathology;Patients;Pericardial cavity;Peritoneal;Pleural;Prognosis;Protocols documentation;RNA;Research Technics;Residencies;Respiratory System;Sampling;Specimen;System;Techniques;Technology;Testing;Therapeutic;Time;Training;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;base;coronavirus disease;diagnosis evaluation;experience;human disease;immunocytochemistry;immunosuppressed;neoplastic cell;patient population;prognostic;research study;urogenital tract Cytopathology Core n/a NCI 10703041 1ZICBC011052-15 1 ZIC BC 11052 15 9692483 "FILIE, ARMANDO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1996514 NCI Cytopathology provides diagnostic evaluation of cytology specimens that direct patient management and treatment. The Cytopathology Section provides complete diagnostic service in cytopathology for the various clinical protocols at the NIH. We specialize in the application of ancillary techniques (i.e. immunocytochemistry flow cytometry and molecular testing) to patient material for the confirmation of morphologic diagnoses evaluation for protocol entry criteria and collaborative investigations. The Cytopathology Section evaluates cytology specimens from the central nervous system pleural/peritoneal/pericardial cavities respiratory tract genitourinary tract gynecologic system fine needle aspiration (FNA) samples of various organs and other less common cytology specimens. Due to the nature of the specimen material evaluated by our Section often our cases require immunocytochemical and/or other ancillary studies. The immunosuppressed nature of our patient population at the NIH dictates that a significant proportion of our cases require special studies for pathologic organisms. The relatively high rate of pathologic findings combined with the diversity of types of exfoliative and FNA specimens provide a broad experience in diagnostic cytopathology for anatomic pathology residency and cytopathology fellowship training. The Cytopathology Section is involved in numerous clinically related research studies many of which utilize FNA or non-gynecologic exfoliative samples with immunocytochemistry and/or molecular techniques to provide additional ancillary diagnostic prognostic therapeutic or protocol required information. A partial list of such studies includes: (1) morphologic and immunocytochemical evaluation of tumor infiltrating lymphocytes samples for possible tumor cell contamination prior to therapy; (2) FNA material for subsequent analysis by molecular technologies; (3) evaluation of cell lines by morphology and immunocytochemistry; (4) application of RNA-based molecular technique to non-gynecologic and FNA cytology samples to enhance diagnosis prognosis and patient management; and (5) morphologic evaluation of breast ductal lavage samples for diagnosis and cell count needed for protocol research studies. 1996514 +Aging; Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Genetics; Hematology; Human Genome; Lymphatic Research; Lymphoma; Prostate Cancer; Rare Diseases; Urologic Diseases; Women's Health Amendment;Animal Care and Use Committees;Animal Genetics;Animal Model;Animals;Area;B-Cell Lymphomas;Bioluminescence;Breeding;Cancer Biology;Cancer Model;Communities;Computer software;DNA;Equipment;Foundations;Genetic;Genomics;Genotype;Goals;Image;Laboratories;Malignant neoplasm of prostate;Monitor;Multiple Myeloma;Mus;National Cancer Institute;Neoplasm Metastasis;Pharmaceutical Preparations;Plasma Cell Neoplasm;Plasma Cells;Preclinical Testing;Preparation;Process;Research;Research Personnel;Research Support;Ships;Skin Carcinogenesis;Techniques;Technology;Western Blotting;Writing;anticancer research;cancer genetics;cancer initiation;design;experimental study;gel electrophoresis;malignant breast neoplasm;melanoma;mouse model;new technology;tool;tumor;tumor progression;tumorigenesis Animal Model and Genotyping Core Support Facility n/a NCI 10703040 1ZICBC011047-15 1 ZIC BC 11047 15 16162291 "DU BOIS DE VROYLANDE, WENDY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1219865 NCI The mouse model animal and genotyping core provides support to investigators in the Laboratory of Cancer Biology and Genetics in several areas all relating to mouse models of B cell lymphoma myeloma plasma cell tumorigenesis skin carcinogenesis melanoma breast cancer and prostate cancer all of which have been developed by various investigators in the group. In the animal core we maintain the genetic integrity and oversee all of the breeding strategies required to maintain the many different lines of mice. The core staff carries out all genetic monitoring/genotyping. We routinely perform DNA extraction genotyping of all mouse lines by PCR and gel electrophoresis. We are in the process of outfitting the lab so that we can do Western Blot experiments. We actively participate in the planning design execution and analysis of various types of experiments using animal models and in setting up and executing preclinical testing of various drugs for their anti-tumor activity.. We have acquired a Lumina II imaging machine and can now carry out tumor/drug studies using bioluminescence technology. We write many of the original Animal Study Proposals and associated amendments and assure that they are kept up to date and in compliance with the NCI Animal Care and Use Committee. We actively participate in preparation for all inspections by the ACUC and AALAC. The animal core is responsible for coordinating the shipment of mouse lines as well as tumor lines to investigators all over the world thus providing useful research tools to others in the cancer research community. The combination of animal and genomic expertise in the core assists our investigators in their mechanistic studies of cancer initiation cancer progression and cancer metastasis. 1219865 +Biotechnology; Cancer; Immunotherapy Adoptive Immunotherapy;Aliquot;Annual Reports;Aspirate substance;Biological Assay;Biopsy;Blood;Blood Circulation;CD19 gene;Cells;Cellular immunotherapy;Clinic;Clinical;Clinical Treatment;Clinical Trials;Collaborations;Collection;Cooperative Research and Development Agreement;Data;Data Analyses;Development;Documentation;Equipment;Extramural Activities;Flow Cytometry;Generations;Genotype;Immune checkpoint inhibitor;Immunohistochemistry;Immunologics;Immunology procedure;Immunotherapy;Infusion procedures;Lymphocyte;Manuscripts;Marrow;Molecular;Monitor;Outcome;PD-1/PD-L1;Patients;Performance;Principal Investigator;Procedures;Process;Protocols documentation;Publishing;RNA;Reagent;Receptor Cell;Research;Research Personnel;Research Support;Role;Sampling;Services;Ships;Site;Specimen;Structure;System;T cell therapy;T-Cell Receptor;T-Lymphocyte;TNFRSF8 gene;Testing;Therapeutic Trials;Tissues;Transgenic Organisms;Translations;Transplantation;Validation;Viral;base;cellular transduction;chimeric antigen receptor;clinical implementation;innovation;peripheral blood;preclinical development;preservation;product development;therapy outcome;transfusion medicine;transplantation therapy;tumor Preclinical development and clinical monitoring of adoptive immune therapy n/a NCI 10703037 1ZICBC011029-15 1 ZIC BC 11029 15 78355705 "FLOMERFELT, FRANCIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 710207 NCI SUMMARY: The Preclinical Development and Clinical Monitoring Facility (PDCMF) of the Experimental Transplantation and Immunotherapy Branch supports the development and implementation of new protocols involving adoptive immune cell therapies through preclinical development translational implementation of clinical products and preservation and analysis of patient blood and tissues during clinical trials. PDCMF staff working within the Cell Processing Service of the Department of Transfusion Medicine have documented patient data and aliquots of cells for RCR/RCL testing (15-C-0141 PI: James Kochenderfer; 20-C-0051 PI: Christian Hinrichs) for James Kochenderfer's Chimeric Antigen Receptor (CAR) therapies and for Christian Hinrichs's transgenic T cell products in fulfillment of FDA requirements. As per our role in ZIC BC 010934 the PDCMF processes and preserves peripheral blood marrow aspirates and tumor biopsies as well as the research aliquots of the starting and final cell products for this Project. We collaborate with the Cell Processing Service of DTM the ETIB Flow Cytometry Facility and ETIB T Cell Facility and we routinely ship specimens to extramural labs for RCR/RCL testing and for a multicenter CRADA trial (16-C-0025 16-C-0091 19-C-0046; PI: James Kochenderfer). Our further contribution to the protocols can be distinguished on the basis of their principal investigators James Kochenderfer and Christian Hinrichs. James Kochenderfer's clinical trials can be subdivided by the target molecules of their CAR constructs: CD30 (17-C-0048) CD19 (10-C-0054 16-C-0054) BCMA (14-C-0168 18-C-0125) and SLAM-F7 (19-C-0102). The manuscript described in the 2019 Annual Report was published in 2020 describing the clinical outcomes of 16-C-0054 and our characterization of CAR+ cells in the infusion product and in peripheral blood. Dr. Christian Hinrichs has therapeutic trials for treatment of viral-induced tumors either by checkpoint inhibitors of the PD-1/PD-L1 system with or without TGFb blockade (16-C-0160 and 19-C-0002 and in collaboration 17-C-0125 PI: Mark Roschewski) or adoptive immunotherapy utilizing expanded T cells transduced to express a transgenic T cell receptor (16-C-0154 17-C-0116 and 19-C-0091). The PDCMF has especially supported these protocols by the collection of tumor biopsies in coordination with Dr. Hinrichs's researchers. The biopsies are sectioned and apportioned for downstream applications such as viral genotyping RNA-based analysis and immunohistochemistry with each requiring its own processing and storage conditions. 710207 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health; Networking and Information Technology R&D (NITRD); Radiation Oncology Advanced Technology Center;Analysis of Variance;Back;Bacterial Genes;Base Sequence;Basic Science;Bioinformatics;Biometry;Chromosomes;Clinical Research;Collaborations;Communities;Computer Analysis;Computer software;Computing Methodologies;Consult;Consultations;Core Facility;Custom;Data;Data Analyses;Data Set;Databases;Detection;Development;Educational workshop;Equipment;Experimental Designs;Extramural Activities;Gene Chips;Gene Expression;Gene Expression Profiling;Genes;Housekeeping Gene;Human Resources;Image;Information Centers;Information Resources;Information Resources Management;Information Technology;Internet;Joints;Journals;Label;Literature;Loss of Heterozygosity;Maintenance;Malignant Neoplasms;Maps;Measurement;Meta-Analysis;Methods;Microarray Analysis;Mining;NCI Center for Cancer Research;National Cancer Institute;Odds Ratio;Pathway Analysis;Positioning Attribute;Process;Publications;Quality Control;RNA;Radiation Oncology;Regression Analysis;Research;Research Personnel;Resources;Risk Estimate;Running;Sampling;Services;Signal Transduction;Statistical Data Interpretation;Statistical Methods;Students;Sum;Survival Analysis;System;Technology;Testing;Tissue-Specific Gene Expression;Training;United States National Library of Medicine;Validation;Work;advanced analytics;analytical method;beta Actin;comparative;data format;data mining;data visualization;differential expression;experimental study;gel electrophoresis;genetic profiling;high throughput analysis;in silico;innovation;meetings;member;multidisciplinary;population based;preference;public repository;reference genome;repository;sound;symposium;technology development;tool;tool development;user-friendly Radiation Oncology Branch - Microarray Facility n/a NCI 10703035 1ZICBC010991-15 1 ZIC BC 10991 15 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 934582 NCI "Core services: As an integral component of the ROB research framework the MCF has contributed to the scientific excellence of the ROB investigators. The Core has been utilized by all ROB investigators and a few external collaborators leading to many joint publications. The MCF provides two main services: 1) Affy microarray service and 2) bioinformatics and biostatistics analysis. a. Microarray service. The core specializes in the use and analysis of microarrays for large-scale gene expression profiling and genetic profiling and provides full core lab services for Affymetrix GeneChip arrays. The process begins with a research hypothesis and the development of a sound experimental design in consultation with the primary researcher. Basic gene expression service begins by providing the core with total RNA. The core will first run the samples on gel electrophoresis or on an Agilent 2100 bioanalyzer to assess sample quality. If the samples pass QC the core processes the samples through each step culminating with a comprehensive dataset. Users will be provided with all the array files associated with their runs. In addition the files are uploaded to a shared microarray database (mAdb) system (http://madb.nci.nih.gov) developed by National Cancer Institute's (NCI) Center for Cancer Research (CCR) in collaboration with the Center for Information Technology. b. Data analysis service. Collaborative statistical support on multidisciplinary projects is provided to basic and clinical research investigators. Analysis of high throughput studies involves a wide range of statistical methods begins with consultation regarding experimental design. Microarray results are directly influenced by the experimental design; therefore it is suggested that the researcher control for as many experimental factors as possible. Arrays are initially evaluated for basic quality control. In the case of Affymetrix chips a set of bacterial gene (BioC bioD and cre) spike-in controls are used to evaluate hybridization efficiency. A set of internal housekeeping gene (GAPDH and B-Actin) controls are used to assess the quality of the synthesis of labeled cRNA. The data are normalized by the Lowess (cDNA array) MAS5.0 scaling method Robust Multichip Average (RMA) or other methods depending on attributes of the experiment or the user's preference. The data are formatted to show probe-gene identities aligned with log2 signal intensity measurements and detection p-values for each gene of each array experiment. In the case of sequencing data computational analysis of reference genome alignment quality filtering annotation to map the aberrations to cancer specific and population based sequences and comparative analysis are performed. Whenever possible data are normalized copy number is computed and segmented and loss of heterozygosity is calculated. Data are also visualized to see gains and losses across chromosomes. The primary users are consulted after the initial analysis of the data that may for example include a statistical analysis whereby Student's t-test or Wilcoxon rank-sum may be used to assess the significance of differential expression of genes between two groups or more than two groups (e.g. ANOVA Kruskal-Wallis) followed by false discovery correction (e.g. Benjamini and Hochberg method). After consultation with the primary user advanced analytical objectives such as data visualization and mining differential expression analyses pathway analyses and in silico independent validation of results (meta-analysis using information available in the literature and in expression databases) to draw meaningful conclusions from the ""omic"" technologies. Support for clinical studies involves methods to estimate risk ratios odds ratios survival analysis and cox regression analysis. The analytical methods for the analysis of high throughput data are continuously evolving and to keep abreast of the latest developments and best practices the core works in collaboration with members of CCR bioinformatics core as needed in statistical methods. Personnel also attend scientific conferences and participate in advanced workshops at the meetings. In addition the core organizes weekly journal club discussions of new innovations within the bioinformatics community. c. Information resources and management service Uma you said the core does two things in the intro and now you are introducing a third The core has unique interdisciplinary expertise and is in a good position to generate and maintain information resources including customized technology development projects not found in commercial software. Microarray processes generate large amounts of data. Information including the images image quantitation data and attributes of the samples are quite valuable. Generally only a fraction of the results generated by microarray experiments can be further investigated by a single workgroup. Unlike the research samples generated by the investigators the information generated by these experiments represents a resource that should be widely shared. The maintenance and dissemination of this resource requires specialized equipment and expertise. For the gene expression microarrays processed in the core the results of all array experiments are stored in the mAdb shared repository accessed and used by ROB investigators and their collaborators. In addition accompanying publication the raw and processed data analyzed at the core will be submitted to public repositories as required by the scientific journals (e.g. Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo )) and be available to researchers globally. After publication information and processed data are maintained at the microarray array core. These data along with data from public resources are used to generate user friendly tools with an advantage of: 1) presenting data with common standards and 2) mining the integrated data for added confidence of a particular result and help conserve resources by redirecting investigators research efforts in other directions. This is accomplished using MySQL database components configured with custom software written by bioinformatics staff in the core. The database is maintained locally and backed up remotely by NCI-maintained servers." 934582 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics; Immunotherapy Autologous;Clinic;Clinical;Colon Carcinoma;Core Facility;Epithelial Cells;Gene Delivery;Generations;Goals;Individual;Lentivirus Vector;Malignant neoplasm of lung;Mediating;Metastatic Melanoma;Mutation;Oncogenes;Operative Surgical Procedures;Patients;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Production;Reagent;Research;Retroviral Vector;Solid Neoplasm;T cell therapy;T-Cell Receptor;T-Lymphocyte;Testing;Time;Tumor-Infiltrating Lymphocytes;Viral;Viral Vector;cancer cell;cell bank;cellular transduction;chimeric antigen receptor;cost;gene therapy;gene therapy clinical trial;immunogenic;improved;individualized medicine;malignant breast neoplasm;meetings;neoantigens;nonsynonymous mutation;novel;novel strategies;programs;tumor;vector Clinical production of viral vectors for cancer gene therapy n/a NCI 10703034 1ZICBC010989-15 1 ZIC BC 10989 15 15687510 "BEYER, RACHEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 434646 NCI The Surgery Branch Vector Production Facility (SBVPF) was established to provide clinical-grade retroviral and lentiviral vectors to support of our gene therapy clinical trials with the goal of providing GMP quality products while reducing production time and cost. These products both retroviral and lentiviral vectors will be used to introduce novel T cell receptors (TCR) or chimeric antigen receptors (CAR) to genetically modify T cells to make them specifically recognize and kill tumor. This lab provides all the clinical viral reagents for our clinical gene therapy program. Our current focus is to isolate T cell receptors targeting nonsynonymous mutations presented by tumors from tumor infiltrating lymphocytes residing within the given tumor and testing the hypothesis that immunogenic mutations (neoantigens) presented on a patient's tumor mediate tumor regression by TIL. In some cases TIL cannot be generated but TCRs can still be cloned. We use a gene therapy approach to treat patients by introducing neoantigen-specific TCRs into autologous PBMC using these viral vectors expanding the transduced cells ex vivo and administering to the patient. We have developed a small scale transient vector production platforms (gammaretroviral) that support GMP-compliant transient vector production for single individualized patient treatments targeting neoantigens. Since the opening of dedicated GMP space in October 2019 the SB GMP VPF has produced 40 novel individual vectors encoding patient specific TCRs meeting the specifications required for clinical use. 434646 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Coronaviruses; Coronaviruses Diagnostics and Prognostics; Emerging Infectious Diseases; Genetic Testing; Genetics; Immunotherapy; Infectious Diseases; Precision Medicine; Prevention ACE2;Aneuploidy;Animal Model;Antibody-drug conjugates;Antigen Presentation;Biological Assay;Biological Markers;Blood;Bone Marrow Transplantation;COVID-19;COVID-19 pandemic;COVID-19 test;Cancer Gene Mutation;Chromosome abnormality;Chromosomes;Clinical Data;Clinical Drug Development;Clinical Management;Clinical Research;Clinical Trials;Collaborations;Data;Detection;Development;Disease;Dose;Drug Kinetics;Evaluation;Goals;Human Papillomavirus;Immune response;Investigation;Investigational Therapies;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Monitor;Mutation;Mutation Analysis;National Institute of Child Health and Human Development;Neoplasms;Pathogenicity;Patient Monitoring;Patient Selection;Patient-Focused Outcomes;Patients;Performance;Pharmaceutical Preparations;Pharmacodynamics;Phase;Pregnant Women;Process;Publishing;Research;Research Personnel;Resistance;SARS-CoV-2 variant;Screening for cancer;Serology test;Somatic Mutation;T cell response;T cell therapy;Technology;Test Result;Testing;Therapeutic;Therapeutic Agents;Time;Tumor Antigens;Tumor Markers;United States National Institutes of Health;Vaccination;Validation;Work;antigen test;assay development;base;biomarker-driven;cell free DNA;clinical center;clinical development;clinical investigation;cytokine;design;drug development;early detection biomarkers;genotyped patients;graft vs host disease;improved;mesothelin;new technology;new therapeutic target;novel;novel marker;patient safety;pre-clinical;receptor binding;resistance mechanism;response;specific biomarkers;targeted therapy trials;technology development;treatment response;tumor;tumor DNA Biomarker Investigations for Clinical Trials n/a NCI 10703033 1ZICBC010981-15 1 ZIC BC 10981 15 9692475 "CAO, LIANG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 822832 NCI Related to the specific biomarker goals above we conducted various studies to support biomarker driven early-stage drug development: 1. Application of new or novel biomarkers in early-stage trials of highly unique therapeutic agents. A) We supported correlative marker investigations of Dr. Raffit Hassan on his mesothelin-targeted novel therapies including traditional antibody drug conjugate therapies and T cell therapies using the assay that we have previously developed (JCO Precis Oncol. doi: 10.1200/PO.17.00282 2018). Significant responses were seen in many patients where our tumor antigen tests were performed in near real time to provide investigators with timely information on responses and on progression. B) We provided continues biomarker support of clinical trials by Dr. Andrea Apolo and some of the work was published (Girardi DM Clin Cancer Res doi: 10.1158/1078-0432. 2022). C) We developed a cell free DNA detection for cervical cancer and use it for treatment monitoring minimum residue disease (MRD) detection cancer genotyping for patient selection. We support HPV-targeted therapy trials by Dr. Scott Norberg. Some of the recent work was focused on using NGS with cell free DNA for resistance mechanisms against T cell therapies. D) Somatic mutation analysis with cell free DNA in pregnant women with abnormal chromosome test results. In working with Christina Annunziata and Dr. Diana Bianchi of NICHD we performed some pioneer work to uncover tumor specific somatic mutation informing on cancer origins on common pathogenic processes and on treatment drug options. Interim results presented some significant novel knowledge in the field which could impact the patient clinical management and inform on the feasibility of using chromosome aneuploidy for cancer screening. 2. Identification of new biomarkers. A) In working with Dr. Steven Pavletic we developed new cytokine tests for the investigation of graft vs host disease (Curtis LM Blood. 137:896-907. 2021; Goklemez S Bone Marrow Transplant. doi: 10.1038/s41409-021-01419-2. 2021). B) Preclinical investigation of tumor biomarker in animal models. The work with Dr. Christine Alewine is to better design the clinical study and to improve the value of the biomarker investigation. Some of the research was published (Zhang X Transl Oncol doi: 10.1016/j.tranon.2022.101440. 2022) with others to follow. 3. Assay development and validation. A) In response to COVID-19 pandemic we developed a high-performance serology test for COVID-19. In addition we also developed a test to evaluate an assay to evaluate the ACE2 receptor binding of various SARS-cov-2 variants. We generated extensive clinical data with donors who had COVID-19 or vaccination in collaboration with Dr. Kamille West of NIH Clinical Center (Yu Y Sci Rep 12:2628. doi: 10.1038/s41598-022-06629-2. 2022). 4. New technology development. A) We focus on the development of a circulating tumor DNA based technology for determining cancer gene mutations associated with treatment responses and for the identification of mutations associated with resistance. We successfully developed new NGS-based assays to examine somatic mutations involved in the process of antigen presentation and T cell response using cell free DNA. The work is to support trials by Dr. Christian Hinrichs who was succeeded by Dr. Scott Norberg. B) We are working on cell free DNA test for the investigation of potential neoplasia in pregnant women presented with abnormal NIPT test results in a trial led by Dr. Christina Annunziata and Dr. Diana Bianchi of NICHD. 822832 +Bioengineering; Biomedical Imaging; Biotechnology; Brain Cancer; Brain Disorders; Cancer; Networking and Information Technology R&D (NITRD); Prostate Cancer; Rare Diseases; Urologic Diseases 3-Dimensional;Adult;Basic Science;Blood Circulation;Brain;Brain region;Breast;CCR;Cells;Child;Clinical Research;Collaborations;Colorectal;Communities;Computers;Confocal Microscopy;Core Facility;Differentiation Antigens;Distant;Educational process of instructing;Elements;Embryo;Epithelial Cells;Equipment;Genomics;Gleason Grade for Prostate Cancer;Glioblastoma;Goals;Human;Image;Image Analysis;Indolent;Label;Laboratories;Lasers;Lymph;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of thyroid;Manuscripts;Measures;Microdissection;Microscope;Microscopy;Mission;Modeling;Molecular;Mus;Neoplasm Metastasis;Optics;Organ;Organoids;Ovarian;Pathogenesis;Patients;Postdoctoral Fellow;Preparation;Process;Prostate;Proteins;Radical Prostatectomy;Research;Research Personnel;Resolution;Role;Scanning;Scientist;Signal Pathway;Signaling Molecule;Slide;Speed;Stains;Stomach;Structure;Surveys;System;TNF gene;Techniques;Time;Tubular formation;Urogenital Cancer;Visualization;Xenograft Model;Zebrafish;anticancer research;cancer cell;castration resistant prostate cancer;cell motility;cohort;empowered;experimental study;fluorescence imaging;fluorescence microscope;gang;high resolution imaging;imaging capabilities;imaging software;interest;novel therapeutic intervention;patient derived xenograft model;progression marker;prostate cancer metastasis;real time model;residence;stem-like cell;summer student;three dimensional cell culture;trafficking;transcriptomics;tumor progression;two-dimensional;virtual imaging;whole slide imaging Laboratory of Genitourinary Cancer Pathogenesis Microscopy Core Facility n/a NCI 10703028 1ZICBC010947-15 1 ZIC BC 10947 15 14732110 "LAKE, ROSS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 636877 NCI The Core Facility houses a Carl Zeiss LSM 780 laser scanning module mounted on an Axio Observer Z1 motorized fluorescent microscope. It also has two Zeiss Axio Observer Z1 fluorescent microscopes with attached computers equipped with Zen software for image acquisition. The Core also has a Nikon TI2E Epiflourescent microscope with attached computer with Nikon Elements software for image acquisition and analysis. Finally the facility has two Carl Zeiss AxioScan Z.1 slide scanning microscope with bright-field and fluorescence imaging capabilities for creating virtual images of whole slides. Researchers from over forty different laboratories (approximately 60 users) in the NCI are currently using the LGCP Microscopy Core Facility. The research focus of the scientists using the facility includes ovarian breast prostate colorectal gastric glioblastoma and thyroid cancer progression and metastasis. In the Laboratory of Genitourinary Cancer Pathogenesis (LGCP) 20 scientists including postdoctoral fellows post baccalaureate fellows and summer students routinely use the Core Facility in their research efforts. In Dr. Kathy Kelly's laboratory postdoctoral and baccalaureate fellows are using microscopy to study the molecular mechanisms and identify differentiation markers and signaling molecules on both primary murine and human prostate cells in order to elucidate the signaling pathways involved in prostate cancer metastasis. They are using whole slide scanning to characterize normal and transformed prostate epithelial cells stained with progression markers and signaling molecules in 2 and 3 dimensional cultures. Confocal microscopy is also being used for observing the localization of these components in the spherical and tubular structures that grow in 3D culture. Dr Adam Sowalsky's lab is comparing the genomic and transcriptomic profiles of high grade prostate cancers (that have progressed to Gleason score 7 or higher) to indolent cancers (Gleason score 6 prostate cancers from an active surveillance cohort). Researchers from the Sowalsky lab use whole slide scanning to process hundreds of immunohistochemically stained radical prostatectomy slides inorder to identify the regions of interest which require further microdissection and analysis. Scientists from several other branches or laboratories are currently using the Core as an integral part of their research. Below are some examples of ongoing projects using the Core Facility. The Tofilin Lab is using the Core slide scanning microscope in their study of glioblastoma (GBM) stem-like cells (GSCs). They are able to obtain high quality images to survey the entire brain from a number of replicate mice at a resolution that allows them to make quantitative measures of the labeled cells in discrete brain regions. The study would have taken a prohibitive amount of time to acquire on any other microscope they had access to. Postdoctoral fellows in Dr. Zheng-Gang Liu's laboratory are using the Core to investigate TNF-induced necroptosis. Confocal microscopy is being used by this group to investigate the role and cellular localization of the necroptosis related proteins MLKL and RARgamma. The Tanner Lab is investigating mechanisms of metastasis using zebrafish models. While the conceptual framework describing cancer cell trafficking through the lymph and circulation systems to colonize distant organs is well accepted actual visualization of this process has proven difficult. Dr. Tanner exploits the use of optically transparent embryonic zebrafish injected with human cancer cells as a xenograft model for real-time visualization of the metastatic cascade. Dr. Tanner uses a variety of equipment within the Core to obtain high-resolution images in which cancer cell migration speeds residence times and interactions with host cells have been characterized to better understand the metastatic spread of cancer. Apart from collaborating on projects involving the microscopy core facility teaching scientists various aspects of microscopy and maintaining the equipment in the core I am conducting research in collaboration with the branch Chief of LGCP Kathy Kelly on castrate-resistant prostate cancer (mCRPC) patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). 636877 +Cancer; Hematology; Orphan Drug; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Acute;Affect;Allogenic;Annual Reports;Antithymoglobulin;Aspirate substance;Autologous;Biological Assay;Biopsy;Blood Circulation;Blood Tests;Cell Lineage;Cells;Chimerism;Clinical;Clinical Protocols;Collection;Cyclophosphamide;Data;Dose;Enrollment;Flow Cytometry;Functional disorder;Gene Expression;Goals;Hematologic Neoplasms;Hematology;Hematopoietic Stem Cell Transplantation;Homologous Transplantation;Immune;Infection;Investigation;Laboratories;Leukocytes;Link;Longterm Follow-up;Lymphocyte;Lymphocyte Depletion;Lymphocyte Subset;Manuscripts;Marrow;Measures;Medicine;Monitor;Morbidity - disease rate;Mutation;Patients;Pattern;Plasma;Population;Predisposition;Preparation;Process;Protocols documentation;Publishing;Regimen;Research;Research Support;Residual state;Role;Sampling;Secure;Services;Specificity;Stem cell transplant;T-Lymphocyte;T-cell receptor repertoire;Time;Tissues;Transplantation;Transplantation Immunology;United States National Institutes of Health;Vaccines;Work;arm;base;chronic graft versus host disease;cohort;congenital immunodeficiency;curative treatments;cytokine;graft vs host disease;gut microbiome;immune reconstitution;leukemia/lymphoma;monocyte;mortality;peripheral blood;post-transplant;preclinical development;preservation;reconstitution;research study;response;stool sample;tumor Immune reconstitution following autologous and allogeneic stem cell transplant n/a NCI 10703025 1ZICBC010934-15 1 ZIC BC 10934 15 78355705 "FLOMERFELT, FRANCIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 236736 NCI SUMMARY: The Preclinical Development and Clinical Monitoring Facility (PDCMF) projects have developed from transplantation protocols developed within ETIB. The PDCMF processes and preserves peripheral blood marrow aspirates and tumor and CGVHD tissue biopsies from all ongoing ETIB protocols. In close collaborative relationships with the Cell Processing Service of DTM the ETIB Flow Cytometry Facility the ETIB T Cell Facility and the laboratory of Ronald Gress we have evaluated lymphocyte subsets cytokine content T cell receptor repertoire diversity and gene expression to support research studies of clinical protocols. All data are incorporated into protocol-specific spreadsheets linking samples to protocol arms and transplant time points and are accessible by Branch clinicians over secure NIH networks. These routine tasks describe the Facility's role in support of any ETIB protocol currently in the stages of long-term follow-up including 11-C-0136 (PI: Chris Kanakry). The Facility provides additional services unique to other studies. Those transplant-related protocols can be categorized as: 1) myeloablative transplant for leukemias and lymphomas and 2) transplantation for monogenic immune deficiencies. 19-C-0112 (PI: Christopher Kanakry) is currently the only ETIB transplant protocol to treat hematologic malignancies and tests the effects of varying dose levels and timing of post-transplant cyclophosphamide. To our past strategies to characterize immune reconstitution and graft-versus-host-disease (GVHD) we will add the assessment of changes in the gastrointestinal microbiome based on the collection of stool samples pre- and post-transplant. Several protocols employing allogeneic transplants as a curative therapy for primary immunodeficiencies are conducted by ETIB. This Facility monitors the repopulation of deficient cell lineages especially by preparing samples at post-transplant intervals for the ETIB Flow Cytometry Facility (William Telford) to then be assessed for subset-specific donor chimerism by the Hematology Service of the Department of Laboratory Medicine. 16-C-0003 18-C-0135 and 19-C-0085 (PI: Jennifer Kanakry) enroll an array of patients with various defined mutations. The manuscript described in the 2019 Annual Report encompassing an entire cohort of 16-C-0003 has been published. Similar studies are ongoing for 18-C-0135 and 19-C-0085 in addition to assaying residual anti-thymocyte globulin (ATG) levels and specificity in the plasma collected from patients enrolled in those protocols. 236736 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Immunotherapy; Orphan Drug; Patient Safety; Rare Diseases Activated Lymphocyte;Address;Adoptive Cell Transfers;Air;Antigens;Area;Autologous;B lymphoid malignancy;Back;Biological Response Modifiers;Biopsy;Blood;Blood specimen;Candidate Disease Gene;Carcinoma;Cell Therapy;Cell physiology;Cells;Characteristics;Cholangiocarcinoma;Clinical;Clinical Treatment;Clinical Trials;Colorectal Cancer;Computer software;Contracts;Cryopreservation;Cyclic GMP;Data;Dendritic Cell Vaccine;Development;Disseminated Malignant Neoplasm;Documentation;Effectiveness;Employee;Enrollment;Ensure;Environmental Monitoring;Excision;Extramural Activities;Gene-Modified;Genes;Goals;Human;Immunologics;Immunotherapy;Industrialization;Industry;Infusion procedures;Institution;Laboratories;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Manufactured Materials;Manufacturer;Mission;Mutation;National Cancer Institute;Neoplasm Metastasis;Operative Surgical Procedures;Patients;Peptides;Peripheral Blood Lymphocyte;Physiologic pulse;Procedures;Process;Production;Program Effectiveness;Protocols documentation;Quality Control;Quarantine;Regulation;Research;Research Personnel;Research Project Grants;Research Support;Resected;Sampling;Sanitation;Services;Sleeping Beauty;Somatic Mutation;Source;Surface;System;T cell therapy;T-Lymphocyte;Testing;Time;Tissues;Training;Translating;Tumor Antigens;Tumor Tissue;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Update;adverse event monitoring;anti-cancer;authority;base;cancer cell;clinical translation;expiration;gene delivery system;gene therapy;improved;interest;malignant breast neoplasm;melanoma;microbial;neoantigens;novel;novel therapeutics;operation;patient safety;prevent;programs;quality assurance;response;success;synovial sarcoma;therapy development;tool;trend;tumor;tumor immunology Surgery Branch Cell Prep Core n/a NCI 10703023 1ZICBC010905-15 1 ZIC BC 10905 15 78355702 "HALAS, HYUNMI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1501220 NCI The mission of this core laboratory is to provide support to the immunotherapy program established by the Surgery Branch of the National Cancer Institute. The laboratory has been managed by Dr. Hyunmi Halas. The main effort of the laboratory involves the production of large numbers of human anti-cancer T lymphocytes ex vivo to treat patients with advanced metastatic cancer enrolled in Surgery Branch clinical trials. Cancer-targeting lymphocytes are either isolated directly from biopsied cancer metastases or are generated by genetically modifying T lymphocytes from a patient's blood. 26 patients each underwent a resection between 01-July-2021 and 01-Aug-2021 with 1 patient undergoing 3 independent resections. Of the 28 total resections processed by CPF 15 resections provided potential source of tumor-infiltrating lymphocytes (TIL) and 13 were research resection from which initial fragments as potential source of tumor-infiltrating lymphocytes (TIL) were not performed. 70% of the 15 resections processed for fragments and subsequent TIL cells during this time provided sufficient tumor tissue to provide 11+ fragments which were cryopreserved. 5 patient resections yielded reactive fragments with tumor specific reactivity to generate TIL cell which can be expanded in culture for potential treatments. 2 patient resections were identified reactive fragments as well as candidates for gene modified T lymphocyte therapies. 3 patients were found to not have reactive fragments but were found to have reactive neoantigens for gene modified T lymphocyte therapies identified from the tumor resection and gene modified to provide TCR known to recognize the cancer cells. Sixteen (16) cell products delivered to patients enrolled on 5 clinical trials were used to treat patients with autologous cell therapies generated by this core laboratory during FY20 through December 2020. A second critical function of this core lab is to distribute resected cancer tissue leftover after the clinical treatment needs have been fulfilled. These samples are used by investigators in the Surgery Branch cell therapy program to evaluate the progress of each clinical trial as well as to address research questions that identify changes that can be implemented to improve these trials. In addition the samples from these trials facilitate research that generates new patient therapies. These research projects include 1) Transducing patients' T cells with genes whose products will better target tumors or enhance endogenous tumor activity 2) Evaluating the ability of infused anticancer lymphocytes to function and survive in patients 3) Identifying new cancer-associated antigens that can be targeted by anticancer cells 4) Identifying novel patient specific antigens that are created by somatic mutations and selecting cultures that recognize these mutations for use in personalized T cell therapies 5) Identifying characteristics of infused anticancer cells that are associated with objective tumor regression 6) Identifying characteristics of patients who are most likely to respond to anticancer T cell therapies 7) Evaluating selected biological response modifiers tested in Surgery Branch clinical trials 8) Evaluating new gene delivery systems such as the sleeping beauty transposon 9) Producing dendritic cell vaccines that are pulsed with peptides representing a patient's own unique mutanome. Finally the core laboratory maintains and curates all source documents data protocols and expertise associated with cGMP manufacturing and the portion of the clinical translation of anticancer cell therapies carried out in the core lab. Due to the success of these therapies developed by the Surgery Branch investigators within the Surgery Branch intramural NCI laboratories extramural regulatory agencies industrial and academic partners and other interested parties increasingly want access to these data protocols and advice. There is a need to develop new tools for curating data from older trials. There is a need to convert existing data into a format that can be read by newer software packages it is essential that existing data generated in the core lab is not lost as older file types become obsolete. In response to two independent audits of the Surgery Branch cell production facility in early 2016 several programs and systems have been developed to comply with NIH FDA and industry guidance/best practices. We have established an independent Quality Assurance (QA) program. This QA program functions independently of the cell processing facility and has the authority to stop production or prevent the release of cell-based therapies manufactured by the Surgery Branch cell processing facility when deemed necessary. Additionally the QA program performs internal audits to ensure compliance with SOPs and procedures and approves the new employee and annual training of the facility staff. These programs ensure that patient safety along with generating clinically effective anti-cancer cells is a primary concern of all employees involved in the manufacture of cell-based therapies. A crucial component of the QA program is document control. The document management system used by NCI SB Operations and Quality Assurance group MediaLab is employed to ensure that all staff has access to the most update version of SOPs forms and regulations used by the cell processing facility. MediaLab allows full tracking of all document versions and changes to ensure better compliance and training for all cell processing facility SOPs and regulations. A cleaning service that specializes in cleanroom sanitation has been contracted by the Office of Research Support and Compliance (ORSC) to clean all NIH aseptic facilities including NCI SB manufacturing and support facilities Trailer 10B and T30. The effectiveness of this program is tracked with a newly implemented environmental monitoring program that tracks and trends air and surface quality/cleanliness within the manufacturing areas of the facility. This program identifies potential sources of microbial contamination before they can impact the overall manufacturing operation. The final component of efforts to develop a robust QA system is the development of a materials management program. Materials management controls the acquisition quarantine acceptance and release of all manufacturing materials. The goal of this program is to increase patient safety by improving documentation of source lot number and expiration date and quality control of all materials used to manufacture cell products within the Surgery Branch cell processing facility. This program is crucial in identifying patient's whose past or pending treatments are associated with a manufacturer recall. The materials management program allows all patients impacted by a recall to be identified and monitored for adverse events. Dr. Xu Zhao is currently the facility manager of the Cell Production Facility at the Surgery Branch of the National Cancer Institute in Bethesda USA where the main interest is to establish successful gene therapies and cell-based treatments for patients with advanced metastatic cancer. 1501220 +Bioengineering; Biomedical Imaging; Cancer 3-Dimensional;Architecture;Authorship;Brain;CCR;Cell Differentiation process;Cells;Communities;Core Facility;Custom;Educational process of instructing;Elements;Gene Expression;Image;Image Analysis;Imaging Techniques;Interest Group;Licensing;Methodology;Methods;Microscope;Microscopy;Molecular Structure;Monitor;Motion;Mus;Neoplasm Metastasis;Organoids;Positioning Attribute;Protein Dynamics;Publications;Research;Research Personnel;Resolution;Services;Site;Techniques;Time;Training;Tumor Cell Invasion;United States National Institutes of Health;Zebrafish;anticancer research;cancer stem cell;chromatin modification;image processing;imaging software;in vivo imaging;induced pluripotent stem cell;instrument;light microscopy;neoplastic cell;outreach;tumor;two-photon CCR Microscopy Core n/a NCI 10703022 1ZICBC010858-16 1 ZIC BC 10858 16 9692243 "KRUHLAK, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1112954 NCI The NCI microscopy core is used consistently by a wide range of NCI researchers with 145 users from 30 labs in the past year. Among the techniques now in use within our CCR microscopy core are methods to visualize live cells in three dimensions over time including the tracking of cell motion in three-dimensions in vivo imaging of differentiated induced pluripotent stem cells in 3D spheroids spontaneous fusion and asymmetric division of cancer stem cells super-resolution imaging of chromatin modifications in metastatic tumor cells monitoring protein dynamics in sub-cellular macromolecular structures using FRAP and multi-position time lapse imaging of live iPS cells with induced gene expression upon cell differentiation. Our Zeiss Z.1 lightsheet microscope has been used to study tumor cell invasion in live zebrafish cellular differentiation and organization in tumor organoids and tumor architecture in cleared mice brains. The number of projects supported represents the diversity of cancer research pursued by CCR investigators. 1112954 +Cancer; Clinical Research; HIV/AIDS Acquired Immunodeficiency Syndrome;Autopsy;Biopsy;COVID-19 pandemic;Clinic;Clinical;Clinical Research;Consult;Consultations;Core Facility;Cytopathology;Data;Diagnosis;Diagnostic;Dissection;Evaluation;Growth;Hematopathology;Histopathology;Immunohistochemistry;Infection;Laboratories;Malignant Neoplasms;Microscope;Microscopic;Microscopy;Microtomy;Mission;Operative Surgical Procedures;Pathologist;Pathology;Patients;Preparation;Process;Protocols documentation;Reporting;Research;Research Activity;Research Personnel;Research Support;Rotation;Scanning;Services;Slide;Specimen;Stains;Surgical Pathology;Techniques;Time;Tissue Procurements;Tissues;Training;United States National Institutes of Health;clinical center;coronavirus disease;digital imaging;digital pathology;human tissue;laboratory experience;laboratory experiment;methylation testing;molecular diagnostics;novel;pandemic disease;tissue processing Histology Core Laboratory n/a NCI 10703021 1ZICBC010687-18 1 ZIC BC 10687 18 14732101 "CHINQUEE, JOSEPH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 3077531 NCI The Histopathology (Histology) section of the Laboratory of Pathology (LP) is devoted to supporting the clinical activities of LP which involves tissue procurement processing and distribution of patient reports to inhouse and submitting clinicians. The Histology Lab does not conduct primary research but supports the activities of many investigators. The laboratory processes a large variety of tissue specimens from NIH and non-NIH patients including a wide variety of malignancies AIDS-related diagnostic specimens COVID-related biospecimens infections and surveillance biopsies. This consists of accessioning human tissues removed at surgery or in clinics processing the tissues preparing and staining slides for microscopy by LP's pathologists clinical fellows and residents. Pathology residents are trained by LP's Pathologists Assistants (PAs) in techniques of gross dissection and taught to evaluate large and small specimens in preparation for microscopic evaluation during Histology rotations. The Histology lab serves Immunohistochemistry Surgical Pathology Hematopathology Postmortem Pathology and Cytopathology sections as well as the Specialized / Molecular Diagnostics Unit. During the past fiscal year the Histopathology section processed approximately 27000 tissue blocks prepared microtomy of 85000 slides and more than 10000 special stains. During this period LP's Pathologists Assistants performed and trained residents in gross analysis and selection of the most diagnostically relevant sections for tissues collected from over 12 300 inhouse biopsy and surgical tissues. The laboratory processed over 55000 consult slides and 12500 blocks from over 4500 cases that were submitted to LP's pathologists for clinical consultation or review for patients being admitted to the NIH Clinical Center or entry on protocol. There has been a steady increase in consult cases since over the past two years attributed to the growth in volumes of the novel methylation testing provided by our Molecular Diagnostics laboratory. The Histology section continued its services throughout the COVID pandemic and pathology case material and research tissues were provided to pathologists and investigators uninterrupted throughout the pandemic. 3077531 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; HIV/AIDS; Neurosciences; Rare Diseases Acquired Immunodeficiency Syndrome;Arts;Autopsy;Brain Stem Glioma;COVID-19 mortality;Categories;Cause of Death;Cessation of life;Chest;Clinical;Clinical Investigator;Clinical Pathology;Clinical Protocols;Clinical Research;Databases;Dementia;Demyelinating Diseases;Disease;Genetic;Glioma;Goals;Hematologic Neoplasms;Hospitals;Hour;Human;Immunologic Deficiency Syndromes;Information Systems;Institutes;Intramural Research Program;Investigation;Laboratories;Magnetic Resonance Imaging;Malignant Neoplasms;Mission;Multiple Sclerosis;Normal tissue morphology;Pathologic;Pathology;Patient Care;Patients;Procedures;Process;Protocols documentation;Reporting;Research;Research Personnel;Research Project Grants;Research Subjects;Research Support;Science;Services;Specimen;System;Text;Time;Tissues;Training;United States National Institutes of Health;clinical care;clinical center;clinical investigation;graft vs host disease;human tissue;neoplastic cell;nervous system disorder;quality assurance;quality of death;tool;treatment response;tumor;urologic Postmortem Pathology n/a NCI 10703020 1ZICBC010685-18 1 ZIC BC 10685 18 12499012 "KLEINER, DAVID ERWIN" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1145681 NCI The Postmortem Pathology Section provides a complete 24 hour per day 365 days per year service in autopsy pathology for the Clinical Center. All patients on protocols for any of the Institutes or the Clinical Center may have an autopsy performed by the Laboratory of Pathology at the discretion of the principle investigator. The results from autopsies are used to assess treatment response to answer clinical questions at the time of death to identify pathology that was unknown or misdiagnosed prior to death and to provide for hospital and protocol quality assurance. In addition when the use and study of human pathological material is requested by research staff of any of the categorical institutes the Postmortem Section makes every effort to collaborate with and/or supply the researchers with the human tissues upon approved request. (The Laboratory of Pathology has a standard procedure for tissue requests.) The autopsy material is utilized by NIH staff and fellows for research projects involving clinicopathological correlation and characterization of disease processes. Currently several collaborative projects are on-going: COVID-19 related deaths; clinical-pathological studies in dementia; culture of tumor cells from post-mortem tumor specimens following rapid autopsy; brain stem gliomas; MRI correlations with normal tissue and de-myelinating disease (multiple sclerosis); investigation into non-HIV immunodeficiencies and complications of graft-versus-host disease. A partial database of major autopsy findings from 1953 through the present is available and all findings from March 1999 on are available on-line through the Laboratory of Pathology's Information System. This system contains the full text of all autopsy reports. Texts of final reports are also available in the Clinical Research Information System (CRIS) after sign-out. In addition to its primary clinical responsibilities and research support function the Post-mortem Pathology section is responsible for training pathology residents in the art and science of autopsy pathology. Diseases with deaths investigated in this fiscal year include AIDS hematological malignancies non-heatological malignancies (particularly thoracic and urological tumors) gliomas and non-AIDS immunodeficiencies.. 1145681 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics; Health Disparities; Minority Health; Orphan Drug; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Transplantation Allogenic;Animal Model;Autologous;Bone Marrow;Bone Marrow Cells;Bone Marrow Stem Cell;Canis familiaris;Cells;Child;Clinical Trials;Complication;Defect;Detection;Disease;Dog Diseases;Flow Cytometry;Future;Gene Expression;Gene Transfer;Gene-Modified;Generations;Genetic;Genetic Diseases;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homologous Transplantation;Human;ITGB2 gene;Individual;Lentivirus Vector;Leukocyte Adhesion Deficiency;Leukocytes;Membrane;Methods;Modeling;Patients;Pre-Clinical Model;Regimen;Retroviral Vector;Spumavirus;Study models;Surface;Testing;Transgenes;Transplantation;Viral;Viral Genes;Viral Vector;bone;canine model;clinical phenotype;conditioning;disease phenotype;donor stem cell;gene correction;gene replacement;gene therapy;gene transfer vector;genotoxicity;graft vs host disease;immune reconstitution;promoter;receptor;stem cell biology;stem cell gene therapy;success;vector Hematopoietic Stem Cell Gene Therapy for Leukocyte Adhesion Deficiency n/a NCI 10703015 1ZIASC010384-22 1 ZIA SC 10384 22 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 128092 NCI These studies aim to identify new methods of gene transfer into hematopoietic stem cells using the genetic disease canine leukocyte adhesion deficiency (CLAD) as a model. We are using the canine model to identify new vectors for gene transfer and conditioning regimens to enable sufficient numbers of gene modified hematopoietic stem cells to engraft and reverse the disease phenotype. The canine form of this disease is an optimal model for these studies since: 1) the defect involves a membrane receptor on the surface of leukocytes flow cytometry allows fascile detection and analysis of the number of gene corrected cells; 2) low levels of gene-corrected cells result in reversal of the disease phenotype; and 3) studies in the canine model have been predictive of success in humans in the field of hematopoietic stem cell biology. The presence of a human counterpart to the canine disease allows the results from the animal model to be directly extrapolated to humans. The long-term objective of these studies is to develop strategies that will allow levels of expression of CD18 in hematopoietic cells of children with leukocyte adhesion deficiency (LAD) that are sufficient to reverse the clinical phenotype. We have utilized this model to test retroviral and foamy viral gene transfer into the bone marrrow cells of dogs. The foamy viral vector demonstrated greater efficacy and a more favorable integration profile than the conventional retroviral vectors. The foamy viral vector-treated dogs are being followed for the durability of the correction and for any possible genotoxicity from the vector. To date there has been no genotoxicity. These results represent the first successful use of a foamy virus (FV) vector to treat a genetic disease and they suggest that foamy virus vectors will be effective in treating human hematopoietic diseases. We are currently testing third-generation foamy viral vectors and lentiviral vectors with cellular promoters and lentiviral vectors with cellular rather than viral promoters in our canine model. 128092 +Cancer; Childhood Leukemia; Genetics; Hematology; Pediatric; Pediatric Cancer; Rare Diseases Acute Myelocytic Leukemia;B-Lymphocytes;Base Sequence;Biological Assay;Biological Models;CCR;CDKN1A gene;Cell Line;Chemoresistance;Chromosomal Rearrangement;Chromosomal translocation;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;DNA Double Strand Break;DNA Insertion Elements;DNA copy number;DNA replication fork;Development;Event;Fusion Oncogene Proteins;Gene Amplification;Genes;Genomic Segment;Goals;Human;Lead;MLL gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Mediating;Molecular;Mus;NUP98 gene;Nonhomologous DNA End Joining;Oncogenes;Oncogenic;PTEN gene;Pathway interactions;Phenotype;Process;Production;Proteins;Proto-Oncogenes;Publishing;Recurrence;Resistance development;Structure;T-Cell Leukemia;Tumor Suppressor Genes;Work;acute T-cell lymphoblastic leukemia cell;cancer cell;chemotherapy;childhood sarcoma;driver mutation;experimental study;fusion gene;in vivo Model;interstitial;leukemia;prevent;thyroid neoplasm Mechanisms of Chromosomal Translocation n/a NCI 10703014 1ZIASC010379-22 1 ZIA SC 10379 22 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 199741 NCI "Previous work highlighting DNA double strand breaks that colocalized with chromosome translocation hotspots within the MLL and NUP98 genes done in collaboration with Dr. Andre Nussenzweig was previously published. We recently developed an in vivo model in which mice with decreased expression of Mcm2 (Mcm2 hypomorph) develop leukemia with recurrent copy number alterations (CNA) involving known or suspected cancer-related genes. Nucleotide sequence of the breakpoints primarily interstitial deletions revealed features of NHEJ at the deletion junctions and further showed that the deletions were enriched for mononucleotide repeats consistent with the possibility that replication fork pausing caused by limiting amounts of Mcm2 protein preferentially led to DNA double strand breaks at mononucleotide repeats. These experiments were done in collaboration with CCR colleagues Drs. Meltzer and Nussenzweig and a manuscript describing these findings was recently published. As discussed in detail under ""Collaborative Pathways that Lead to Leukemia [ZIA BC 010982]"" mice that are deficient for Mcm2 develop a specific mutator phenotype that involves recurrent acquired DNA copy number losses. These losses can both inactivate tumor suppressor genes (CDKN1A PTEN) as well as activate oncogenes (Notch1) and lead to B and T cell leukemias in mice. Less commonly the leukemias that develop in Mcm2 hypomorphic mice are accompanied by copy number gains; one recurrent gain that we have characterized leads to a fusion between Nup214 and Abl1; of note Nup214-Abl1 fusions are recurrent events associated with B and T-ALL in humans. We are pursuing the mechanisms by which Mcm2 deficiency leads to this mutator/deletor phenotype by using a CRISPR-mediated structure/function assessment of Mcm2. In addition it is well-established that many leukemias are initially sensitive to chemotherapy but ultimately develop resistance. We have a panel of Mcm2 deficient and control Mcm2 proficient T-ALL cell lines. We are in the process of developing derivatives of this panel of cell lines that are chemotherapy resistant. Chemotherapy resistant cell lines will then be assayed for acquired SNV and CNA to determine important events in developing chemotherapy resistance. Chromosomal translocations and the mechanisms by which they occur are highly relevant for childhood cancer. In fact one of the cancer moonshot goals ""Fusion Oncoproteins in Childhood Cancers (FusOnC2)"" is focused on fusion oncoproteins. Fusion oncoproteins are well-known critical ""driver"" mutations in a wide spectrum of childhood cancers from leukemias including acute myeloid leukemia to childhood sarcomas to thyroid tumors. The vast majority of fusion oncoproteins are produced by recurrent non-random chromosomal translocations." 199741 +Biotechnology; Cancer; Childhood Leukemia; Genetics; Hematology; Pediatric; Pediatric Cancer; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Animal Model;Animals;B cell differentiation;B-Cell Leukemia;B-Lymphocytes;Cell Line;Cells;Child;Childhood Acute Myeloid Leukemia;Chromosomal Rearrangement;Chromosomal translocation;Clinical;Clinical Trials;Collaborations;Data;Development;Erythroid;Generations;Genes;Genetic;Genetic Predisposition to Disease;Hematologic Neoplasms;Hematopoietic;Immunophenotyping;Lesion;Life;Link;Lymphocyte;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Molecular;Mus;Mutate;Mutation;Myeloid Leukemia;NUP98 gene;Nodal;Oncogenic;Pathway interactions;Patients;Phenotype;Point Mutation;Pre-Clinical Model;Process;Proto-Oncogenes;Publishing;Recurrence;Sequence Analysis;Series;Surveys;T-Lymphocyte;TAL1 gene;TSLP gene;Testing;Time;Transgenes;Transgenic Mice;Translocation Breakpoint;Yeasts;chemotherapy;chromosome missegregation;exome;expression vector;fusion gene;gene cloning;improved;in vivo;in vivo Model;leukemia;leukemic transformation;mouse model;novel;novel diagnostics;offspring;overexpression;preclinical study;premalignant;progenitor;receptor;response;stem cell self renewal Activation of Proto-Oncogenes by Chromosomal Translocation n/a NCI 10703013 1ZIASC010378-22 1 ZIA SC 10378 22 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 599222 NCI We generated mice that expressed a NUP98-PHF23 (NP23) fusion in hematopoietic cells. Almost 100% of these mice develop leukemia within 1 year of life; the leukemic phenotype is very broad including T and B cell leukemias myeloid leukemias and erythroid leukemias. A subset of NP23 mice developed a leukemia of B1 progenitor origin. These leukemias had a B1 progenitor immunophenotype and preferential usage of V regions utilized by B1 lymphocytes. Similar to normal B1 progenitors these pro B1 leukemias express CRLF2 a subunit for the TSLP receptor. Interestingly CRLF2 is overexpressed due to chromosomal rearrangement in over 10% of B cell precursor acute lymphocytic leukemia patients; a preliminary survey suggest that patients with CRLF2 overexpression preferentially utilize V regions used in B1 lymphocytes suggesting that these B cell precursor acute lymphocytic leukemia may be derived from B1 progenitors. Finally whole exome sequence (WES) analysis of these leukemias revealed that all have mutations involving Bcor and Jak/Stat pathway genes suggesting a genetic mechanism for this disease. The NP23 fusion leads to stem cell self renewal the Bcor mutation blocks B cell differentiation and the Jak/Stat mutation leads to hyperproliferation. Manuscripts describing these findings and the utility of this model for pre-clinical studies were published in FY 2018-2020. Ongoing studies are focused on using these in vivo models to inform clinical trials of B-cell precursor acute lymphocytic leukemia. In addition a manuscript describing the molecular basis for NP23 oncogenic effects was published in FY2020. NP23 leukemias consistently overexpress a novel gene designated Bahcc1 (for Bromo Adjacent Homology Domain And Coiled-Coil Containing 1). Publicly available expression data indicates that BAHCC1 is overexpressed in several distinct subsets of acute myeloid leukemia. We have generated transgenic mice that overexpress the Bahcc1 gene in hematopoietic cells and are currently studying hematopoietic development and leukemic transformation in these mice. Preliminary studies have demonstrated that two of the founder mice and several offspring have developed hematologic malignancy. A large series of pediatric acute myeloid leukemia patients has demonstrated that over 5% of patients have a NUP98-NSD1 fusion and that this fusion predicts a poor response to chemotherapy. We have cloned a NUP98-NSD1 fusion into the Vav1 expression vector and generated mice that have incorporated the transgene. Three of the founders developed acute myeloid leukemia. Unexpectedly acute myeloid leukemia is not increased in the F1 generation; we have recently generated another group of founder mice: one of these has developed acute myeloid leukemia thus far and we are studying F1 offspring of this founder. In collaboration with Dr. Munira Basrai of the Genetics branch we have generated mice that overexpress CENPA in the hematopoietic compartment. CENPA overexpression in yeast and cultured cell lines leads to chromosomal mis-segregation; the transgenic mice will enable us to determine if the mis-segregation takes place in primary cells as well. Moreover CENPA overexpression has been linked to several malignancies these mice will enable us to determine if CENPA overexpression is oncogenic in vivo. A portion of these results were published in FY2021. Leukemia (predominantly acute myelocytic leukemia and acute lymphocytic leukemia) is the most common malignancy in children. The results of these studies are relevant for improving our understanding of childhood cancer and have led to new diagnostics (the SIL-TAL1 fusion) and generated mouse models that can be used for pre-clinical studies. 599222 +Cancer; Health Disparities; Infectious Diseases; Minority Health Achievement;Acquired Immunodeficiency Syndrome;Acute;Antineoplastic Agents;Apoptosis;Apoptotic;Arthritis;Autoimmune Diseases;Biological;Breast Cancer Model;COVID-19;Cell Death;Cell Proliferation;Cell Surface Proteins;Cells;Cessation of life;Chronic;Crohn's disease;Development;Diagnosis;Disease;Dose;Equilibrium;Event;Future;Glucose;Goals;Human;Inflammation;Inflammatory Response;KRAS2 gene;Knowledge;Laboratories;Life;Light;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator of activation protein;Molecular;Necrosis;Neoplasm Metastasis;Pathogenesis;Pathway interactions;Physiological;Play;Production;Proteins;Regulation;Research;Rheumatoid Arthritis;Role;Septic Shock;Signal Pathway;Signal Transduction;Specific qualifier value;T-Lymphocyte;TNF gene;Therapeutic;Tissues;Transforming Growth Factors;Translating;Virus Diseases;Work;apoptosis inducing factor;cancer therapy;cancer type;chronic inflammatory disease;cytokine;cytokine release syndrome;cytotoxicity;deprivation;genetic regulatory protein;improved;neoplastic cell;novel;response;tumor;tumorigenesis TNF Signaling Cell Death and Cancer n/a NCI 10703012 1ZIASC010376-22 1 ZIA SC 10376 22 9417013 "LIU, ZHENG-GANG " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1519723 NCI "The research goal of our laboratory is to understand the molecular mechanism of tumor necrosis factor (TNF) signaling and the regulation of cell death and the role of cell death in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events including cell proliferation differentiation and cell death. TNF is also involved in many types of diseases including cancer. Inappropriate production of TNF plays a critical role in the pathogenesis of both acute and chronic inflammatory diseases such as septic shock acquired immunodeficiency syndrome (AIDS) and arthritis. The development of anti-TNFalpha therapy is arguably the most significant achievement in the treatment of autoimmune-diseases such as rheumatoid arthritis and Crohn's disease. Opposing effects of TNF on cancer have been described: a high dose of TNF (acute inflammation) has anti-neoplastic effects such as direct cytotoxicity on certain types of cancer while an endogenous low-dose of TNF (chronic inflammation) promotes cancer development. Studies from many laboratories have demonstrated that the diverse TNF-mediated biological responses are achieved through activating multiple signaling pathways (see below). Although much information about TNF signaling has been obtained in recent years many molecular aspects of TNF signaling and its role in inflammation and cancer development remain unknown. Therefore uncovering the molecular mechanism of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to understand its role in inflammation and cancer development. In last year we have made several significant contributions to the understanding of the molecular mechanism regulating TNF signaling and the regulation of cell death. In the future we will continue to investigate the regulation of TNF signaling particularly the molecular mechanisms of TNF-induced cell death and to explore the role of cell death in tumorigenesis as specified in the following: Studying the regulation of TNF-induced cell death and the involvement of key cell death regulatory proteins in tumorigenesis Aim1: Investigating the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein ATIA and its potential role in tumorigenesis. a) Understanding the underlying mechanism of the anti-apoptotic effect of ATIA. b) Demonstrating the importance of ATIA in tumorigenesis. Aim 2: Identifying and studying novel players in tumor necroptosis and exploring the role of necroptosis in tumorigenesis. Understand the regulation of tumor necroptosis. a) Investigate the mechanism of MLKL-mediated necroptosis. b) identifying new components of tumor necroptosis. Study the role of tumor necrosis in tumor development and tumor metastasis. Recently we have found that necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis. we found that tumor necroptosis is induced by glucose deprivation but not TNF and that ZBP1 not RIPK1 mediated tumor necroptosis during tumor development in breast cancer models. Most recently we found that one of the mechanisms for necroptosis's metastasis promoting effect is that shedding of cell surface proteins of necroptotic tumor cells inhibits the anti-tumor activities of T cells resulting in more aggressive tumor metastasis. Currently we are developing potential therapeutics PROTACs for treating tumor metastasis by targeting key mediators of necroptosis. We are also exploring the role of necroptosis in the inflammatory response particularly ""cytokine storm"" of COVID-19. For the ATIA project we found that ATIA is a key factor for tumor growth and could serve as a diagnosis marker of multiple types of cancers." 1519723 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Minority Health; Neurosciences; Orphan Drug; Patient Safety; Radiation Oncology; Rare Diseases Acute;Address;Adverse event;Agreement;Anticonvulsants;Biological;Biopsy;Blood;Bone Marrow;Brain Neoplasms;Brain Stem;Cancer Therapy Evaluation Program;Clinic;Clinical;Clinical Trials;Collaborations;Common Terminology Criteria for Adverse Events;Complication;Computer software;Cooperative Research and Development Agreement;DNA;Data;Databases;Development;Dose;Dose Fractionation;Enrollment;European;European Organization for Research and Treatment of Cancer;Excision;Fractionation;Hepatotoxicity;Image;Industry;Institutes;Intramural Research Program;Investigation;Laboratories;Location;Long-Term Survivors;Measures;Metabolic;Molecular Target;Morbidity - disease rate;Nature;Necrosis;Neurologic;Neurologic Symptoms;Neurological Models;Newly Diagnosed;Newly Diagnosed Disease;Normal tissue morphology;Operative Surgical Procedures;Optic Nerve;Oral;Organ;Pancreas;Patients;Pattern;Perception;Performance Status;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Probability;Progression-Free Survivals;Protocols documentation;Publications;Publishing;Radiation;Radiation Dose Unit;Radiation Oncologist;Radiation Therapy Oncology Group;Radiation therapy;Radiation-Sensitizing Agents;Recommendation;Recurrence;Recurrent tumor;Regimen;Reporting;Research;Respondent;Retreatment;Risk;Role;Running;Schedule;Scheme;Serum;Structure;Surveys;Systemic Therapy;Time;Toxic effect;Translating;Tumor Volume;United States National Institutes of Health;Valproic Acid;Work;acute toxicity;arm;base;chemotherapy;clinical care;clinical center;clinical development;clinical practice;clinically relevant;inhibitor;irradiation;mathematical model;novel;novel therapeutics;patient response;phase 1 study;phase 3 study;phase II trial;phase III trial;preclinical study;radiological imaging;success;synergism;targeted agent;time interval;treatment planning;trial comparing;tumor The Synergy Between Radiotherapy and Molecularly Targeted Agents n/a NCI 10703010 1ZIASC010373-22 1 ZIA SC 10373 22 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1398197 NCI Recently we reported on our Phase II trial of Valproic Acid/ RT/TMZ in patients with newly diagnosed GBM. Briefly 37 patients with newly diagnosed GBM were enrolled and administered VPA 25 mg/kg orally divided into two daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. We used this one week run in period to escalate the VPA dose as the final VPA dose could have had pancreatic/hepatic toxicity. VPA and TMZ related acute toxicities were evaluated using the Cancer Therapy and Evaluation Program Common Toxicity Criteria (CTC) Version 3.0 for toxicity and adverse event reporting as well as the RTOG/EORTC Radiation Morbidity Scoring Scheme. Although VPA has been used for 40 years as an anti-convulsant often in combination with RT/TMZ it is typically used at a much lower dose (5-10mg/kg). Overall 67% of patients completed the VPA/RT/TMZ according to protocol. The patient's median overall survival (OS) was 29.6 months (21-63.8m) and median progression free survival (PFS) was 10.5m (6.8-51.2m). Additionally the combination was well tolerated; the most common grade 3/4 acute toxicities of VPA/RT/TMZ were blood/bone marrow toxicity (32%) neurological (11%) and metabolic/laboratory (8%). Interestingly the serum VPA levels were not correlated with the measured grade 3/4 toxicities and most of the toxicities could be attributed to the concurrently administered TMZ. Overall there were 16 (43%) acute grade 3-5 toxicities significantly lower than the 6 other Phase II sensitizer/RT/TMZ studies (reviewed in Krauze 2015) which had grade 3-5 toxicities rates ranging from 62-142%. As the pattern of recurrence for GBM is 85% local the use of re-RT is commonly prescribed. However the appropriate features of the tumor patient and previous radiation doses that might impact on the success of re-irradiation are not well understood. To develop this understanding we pursued two lines of investigation: the first was surveying Radiation Oncologists that primarily treat patients with recurrent brain tumors. We asked 13 experts in brain tumor re-irradiation (8 US and 5 European) to rate 11 clinical factors impacting their decision to offer re-RT. From this we found a heterogeneous treatment pattern including the prescribed doses and volumes but the clinical factors used most often to decide on the appropriateness of offering re-irradiation were: time since previous radiation therapy (92%) recurrent tumor volume (85%) previously administered dose to organs at risk (77%) and patient performance status (69%). These factors have been previously mentioned in multiple publications but this is the first time a ranking of the various clinical factors has been published. Additional findings included a split in the fractionation schedules most often recommended with 25% offering SRS or standard fractionation (2Gy) and 50% offering hypo-fractionated regimens. There was also a difference in the clinical practice of these respondents for the time required between the two courses of radiotherapy with 50% requiring 6m and 50% requiring 12m before they would consider offering re-RT. An additional common perception was that if re-RT is given earlier in the re-treatment schema the patients responded better. Our second investigation was a report of the results for the re-irradiation of patients with brain tumors performed within the ROB. To properly evaluate every patient primary treatment plans and re-treatment plans we loaded into the current Eclipse software to create cumulative tumor doses and cumulative doses to the organs at risk (OAR). We found a 15% variance in the OAR volumes when comparing the original treatment plan volumes to those generated from the combination of treatment plans. In the 31 patients that had both plans available the median cumulative Biological Effective Dose 2Gy (BED) combining the two treatments was 96Gy (range 72-112Gy). Using the doses from the combined plans and the mathematical model Normal Tissue Complication Probability (NTCP) we would have expected complication rates of 25% for the chiasm 21% for the right optic nerve and 59% for the brainstem. Thus 25-60% of our patients should have had a long term neurological toxicity. Yet with a median overall survival of 6m (range 0.7-103m) we had no documented grade 3-5 toxicities in any OAR nor evidence of necrosis in the re-RT treatment fields. This included 13 patients that had concurrent chemotherapy with the re-RT course. This underscores the disconnect that we currently have between the mathematical models of neurological toxicity (NTCP or QUANTEC) and the toxicity that is observed in the clinic. Our two publications highlight some of the current issues in GBM re-RT: what is the appropriate total dose and fractionation; the optimal interval between irradiation courses; the role of concomitant therapy with re-RT; and the potential toxicity of the re-RT? 1398197 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Hematology; Neurosciences; Orphan Drug; Radiation Oncology; Rare Diseases Address;Adjuvant Chemotherapy;Affect;Anticonvulsants;Biological Markers;Biopsy;Blood - brain barrier anatomy;Brain Neoplasms;Bypass;Cells;Characteristics;Chemicals;Clinic;Clinical;Clinical Trials;Collaborations;DNA;Data;Development;Diagnosis;Dose;Dose Fractionation;Drug Kinetics;Drug Screening;Evaluation;Excision;FDA approved;Failure;Foundations;Functional disorder;Future;Glioblastoma;Glioma;Glycolysis;Goals;Histone Deacetylase Inhibitor;Image;In Vitro;Lead;Long-Term Survivors;MGMT gene;Megakaryocytes;Metabolism;Modeling;Molecular;Molecular Classification of Tumors;National Center for Advancing Translational Sciences;Newly Diagnosed;Operative Surgical Procedures;Oral;Pathologic;Patients;Penetrance;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pre-Clinical Model;Primary Neoplasm;Publishing;Radiation;Radiation Tolerance;Radiation therapy;Radiation-Sensitizing Agents;Recurrence;Research;Role;Site Visit;Surrogate Markers;Testing;Therapeutic;Thrombocytopenia;Toxic effect;Toxicology;Translating;Translations;Valproic Acid;Warburg Effect;Work;chemoradiation;clinically relevant;cost;drug development;experience;improved;in vivo;inhibitor;interest;irradiation;metabolic imaging;model development;molecular imaging;neoplastic cell;novel;novel marker;novel therapeutics;pre-clinical;preclinical development;preclinical study;predictive modeling;programs;radiation response;randomized trial;response;temozolomide;tumor Pre-clinical Development of Radiation Sensitizers for Patients with Glioblastoma n/a NCI 10703009 1ZIASC010372-22 1 ZIA SC 10372 22 9692373 "CAMPHAUSEN, KEVIN " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 599228 NCI Glioblastoma multiforme (GBM) is the most common and most aggressive type of brain tumor with a median survival of 14 months. Currently the diagnosis of GBM requires surgical resection and pathological examination followed by concurrent chemoradiotherapy then adjuvant chemotherapy using oral temozolomide (TMZ). Despite this treatment most tumors recur within the irradiation field thus GBM continues to represent a significant therapeutic challenge. As such we have focused on the development of drugs that can sensitize GBM to irradiation. We and others have shown that multiple HDACi from diverse chemical backgrounds can sensitize tumor cells to radiation (RT). Our previous work focused on valproic acid (VPA) for several reasons: it is currently used in the clinic as an anti-convulsant; VPA pharmacology including its blood-brain-barrier (BBB) penetrance is well known; and VPA has a low cost per dose. Our group was the first to show that VPA had HDACi activity that could sensitize glioma cells to irradiation both in vitro and in vivo and that maximal radiosensitivity occurred when the HDACi was present both prior to and following irradiation. This preclinical data formed the foundation for our recently published clinical trial of VPA/RT/TMZ in patients with newly diagnosed GBM. The logical next step would be to initiate a randomized trial of VPA/RT/TMZ through one of the cooperative groups. However that trial is currently not planned. It is not planned for several reasons including a lack of understanding of how the tumor molecular classification (i.e. MGMT(+) versus MGMT(-)) from the patients in our study affected VPA-induced radioresponse. Second newer HDAC inhibitors may have improved pharmacokinetics and thus be more effective with less toxicity than VPA. Third there is a question whether VPA and TMZ have a synergistic toxic effect against megakaryocytes leading to thrombocytopenia. My group is addressing these pre-clinical issues in Project 1 Aim 1. There was also a concern that the addition of a radiation sensitizer to the RT/TMZ combination would lead to late CNS effects in long term survivors which will be addressed in Project 2. In addition to HDAC inhibitors there are other classes of molecules that can sensitize GBM to irradiation that will be studied in our preclinical models including two that should progress to clinical trial shortly. The first is the DNA-pK inhibitor from Vertex Pharmaceuticals shown to enhance GBM radiosensitivity both in vitro and in vivo. The second is the XPO1 inhibitor Selinexor. Additionally we are interested in drugs that are known to cross the blood-brain-barrier but are not currently known as radiation sensitizers. We will screen these drugs for an enhancement of radiosensitivity through an off-target effect through a collaboration with NCATS. As most GBM fail within the first year there is a need for the development of models of recurrent GBM to test novel therapies. As re-irradiation (re-RT) is often offered as a therapeutic option additional studies are needed to understand the effects of re-RT in pre-clinical models. The Tofilon lab has recently developed a model of primary GBM RT failure that we will expand to study re-irradiation of recurrent GBM. Questions of dose fractionation and the addition of radiation sensitizers will be addressed in these pre-clinical models and used to guide future clinical trials. As brain tumors are difficult to evaluate through serial biopsy the development of surrogate biomarkers from biofluids or imaging would potentially offer information about the tumor that is currently unavailable. Since the last site visit our evaluation of novel GBM biomarkers has been focused on molecular imaging. As it is assumed that gliomas bypass standard glycolysis through the Warburg effect and that the metabolism of different gliomas contributes to the efficacy of our current therapy our biomarker studies will focus on the use of 13C hyperpolarized molecular imaging in both the primary and recurrent GBM models. Thus my section is focused on the pre-clinical development of radiation sensitizers for both primary and recurrent GBM the use of novel metabolic imaging and the translation of these pre-clinical findings into clinical trials. Specific Research Aims: 1. To continue the development of VPA as a radiation sensitizer. To determine if the molecular characteristics of GBM tumors are predictive of VPA-RT response we will extend our previous pre-clinical studies by exploring the role of VPA as a radiation sensitizer in MGMT(-) GSCs. This will include both in vitro and in vivo studies. As newer HDACi may have improved pharmacology compared to VPA new HDAC inhibitors (128) will be screened in combination with RT in a collaboration with the National Center for Advanced Translational Sciences (NCATS) program using a post-IR ?-H2AX screen. Furthermore additional toxicology including work on megakaryocyte dysfunction will include both TMZ and VPA/TMZ combinations. 2. To test novel radiation sensitizers in models of primary GBM. In order to maximize the potential for Selinexor to be successfully translated to the clinic we will perform additional preclinical work including combination studies with TMZ studies of the timing of Selinexor with irradiation and tumor pharmacokinetic studies using RNAscope. The DNA-pK inhibitor VX-984 will also be studied in our pre-clinical orthotopic models using a clinically relevant combination of RT/TMZ. An additional screen of all FDA approved BBB penetrant drugs will be conducted in collaboration with NCATS to identify agents already known to penetrate the BBB that can act as radiosensitizers. 3. The development of a model for GBM re-irradiation. Questions from our clinical experience that will be tested in the GBM re-RT model include: does more dose of re-RT improve overall survival; is a single or fractionated dose more effective; does the timing of re-RT after failure affect survival (early versus late); and lastly does the addition of TMZ or novel radiation sensitizers in the setting of reirradiation improve overall survival? 599228 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Clinical Research; Genetic Testing; Genetics; Human Genome; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Neuroblastoma; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Precision Medicine; Rare Diseases 1p36;Age;Algorithms;Amino Acids;Biological;Cell Culture Techniques;Cessation of life;Chemicals;Childhood Soft Tissue Sarcoma;Clinical;Collaborations;Companions;Custom;DNA Sequence Alteration;Data;Databases;Diagnosis;Disease-Free Survival;Enrollment;FOXO1A gene;Fingerprint;Gene Amplification;Gene Deletion;Gene Expression Profiling;Genes;Genetic;Genomics;Goals;Histology;Incidence;International;Isotopes;Isotopically-Coded Affinity Tagging;Label;Light;MYCN gene;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Measurement;Mesenchymal Cell Neoplasm;Methods;Molecular;Mutation;Neural Crest;Neuroblastoma;Outcome;Pathway interactions;Patients;Pattern;Pattern Recognition;Pediatric Oncology Group;Phosphorylation;Ploidies;Prognosis;Prognostic Marker;Property;Proteins;Proteomics;Reagent;Recurrent disease;Research;Research Design;Rhabdomyosarcoma;Sampling;Series;Somatic Mutation;Stable Isotope Labeling;Survival Analysis;Survival Rate;Techniques;Therapeutic;Tissues;Tumor Biology;United Kingdom;aggressive therapy;artificial neural network;base;biomarker development;cDNA Arrays;cancer genomics;cell type;conventional therapy;diagnostic biomarker;differential expression;driver mutation;effective therapy;exome sequencing;genetic variant;genome sequencing;genomic biomarker;genomic profiles;high risk;insertion/deletion mutation;next generation;next generation sequencing;outcome prediction;phosphoproteomics;predicting response;prognostic;protein expression;risk stratification;targeted treatment;therapeutic target;transcriptome sequencing;treatment group;tumor;whole genome Predicting Response Prognosis in Pediatric Cancers n/a NCI 10703008 1ZIASC010366-22 1 ZIA SC 10366 22 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 170862 NCI Neuroblastomas are cancers of neural crest origin with variable prognoses depending on age at presentation stage histology presence of MYCN amplification chromosomal ploidy and deletion status of 1p36. Very little is known of the molecular mechanisms that confer good or poor prognosis in this and other malignancies. We have demonstrated that cancers can be diagnosed on the basis of gene expression profiling using cDNA microarrays and sophisticated pattern recognition algorithms such as Artificial Neural Networks. The Oncogenomics Section has expanded this study in collaboration with the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) group to perform more extensive genomic analysis using next generation whole genome exome and transcriptome sequencing on a series of clinically annotated neuroblastoma samples. With these methods we are identifying somatic mutations and tumor-specific expression patterns or fingerprints that uniquely identify a poor prognostic group as well as those associated with specific genetic aberrations including MYCN amplification. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Despite aggressive therapy the 5-year survival rate for patients with metastatic or recurrent disease remains poor and beyond PAX-FOXO1 fusion status no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. Patients and Method: Tumor samples collected from patients enrolled on Children's Oncology Group (COG) trials and United Kingdom patients enrolled on Malignant Mesenchymal Tumour (MMT) and RMS2005 trials were subjected to custom capture sequencing. Mutations indels gene deletions and amplifications were identified and survival analysis will be performed. We will produce a searchable companion database (https://clinomics.ccr.cancer.gov/clinomics/public/) containing all genomic variants and clinical annotation including survival data. By these techniques we hope to classify genomic profiles that correlate with prognosis and hence identify the genes that confer these biological properties. Isotope-coded affinity tags (ICAT) stable isotope labeling by amino acids in cell culture (SILAC) and phospho-proteomic analysis allows the quantitative measurement of protein expression levels and the phosphorylation status in different cell types and tissues. In these methods proteins from two samples can be compared by chemically labeling both samples with the light and heavy isotopic forms of a reagent respectively. With this and other proteomic method we plan to sequence and identify up to 3000-4000 differentially expressed proteins between tumors with poor (death) and good (event free survival 3yrs) outcome. These proteins and their phosphorylation status indicates potential targets for therapy diagnostic and prognostic markers for high-risk patients as well as provide important clues on the biology of these tumors that fail to respond to conventional therapy. 170862 +Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Genetics; Health Disparities; Minority Health; Precision Medicine; Prevention; Prostate Cancer; Urologic Diseases 10q;Age-Years;American;BRCA1 gene;BRCA2 gene;Biochemical;Biology;Biopsy;CHEK2 gene;Cancer Etiology;Cancer Patient;Cessation of life;Clinical Laboratory Improvement Amendments;Clinical Research;DNA Damage;Data;Detection;Diagnostic Neoplasm Staging;Disease;Enrollment;Evaluation;FOLH1 gene;Fanconi Anemia Complementation Group A Protein;Future;Genes;Genetic Risk;Genitourinary system;Genomics;Hereditary Nonpolyposis Colorectal Neoplasms;Histology;Hormonal;Image;Imaging Techniques;Individual;Institution;Intramural Research Program;Investigation;Laboratories;Laboratory Study;Lesion;Link;Localized Disease;MLH1 gene;MSH2 gene;MSH6 gene;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Measures;Modernization;Mutation;NCI Center for Cancer Research;Neoadjuvant Study;Neoadjuvant Therapy;Neoplasm Metastasis;Newly Diagnosed;Noninfiltrating Intraductal Carcinoma;Nuclear;Operative Surgical Procedures;Outcome;PALB2 gene;PET/CT scan;PMS2 gene;Pathogenicity;Pathology;Patients;Population;Positron-Emission Tomography;Principal Investigator;Prior Therapy;Progression-Free Survivals;Prostate-Specific Antigen;Prostatectomy;Prostatic Neoplasms;Publishing;Recurrence;Research;Research Personnel;Rest;Role;Series;Site Visit;Sodium Fluoride;Specimen;TP53 gene;Time;United States National Institutes of Health;Variant;Work;advanced disease;base;cancer clinical trial;cancer diagnosis;castration resistant prostate cancer;clinical practice;cohort;collaborative environment;exceptional responders;ferumoxytol;genetic variant;high risk;high risk population;hormone therapy;imaging program;imaging study;improved;improved outcome;industry partner;meetings;men;molecular imaging;mortality;novel therapeutics;programs;prospective;prostate cancer risk;response;screening;small molecule;tumor The Evaluation of Novel Therapeutics for Genitourinary Malignancies n/a NCI 10703003 1ZIASC010098-20 1 ZIA SC 10098 20 8900432 "DAHUT, WILLIAM L." Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 426153 NCI 1. Completed the first study to integrate targeted mpMRI biopsies spatially linked to prostatectomy specimens in men treated with intensive neoadjuvant hormonal therapy prior to surgery and provided the first evidence that a defined set of 4 genomic/histology features may help predict both outcome and genomic diversity. Prior studies of neoadjuvant therapy in prostate cancer have not used targeted biopsies or sequential mpMRI to evaluate changes in unique lesions. Utilizing the ability of the MIP to perform serial mpMRIs the impact of therapy on targeted individual prostate tumors was evaluated for the first time both from an imaging perspective as well as genomically. Tumor response both per lesion and per patient could be reliably measured and was integrated with pathology. In addition in my study the presence of 10q loss intraductal carcinoma (IDC) nuclear ERG and TP53 mutations distinguished exceptional responders (ERs) from the rest of the cohort and predicted tumor genomic diversity. 2. Demonstrated that the combination of durvalumab plus olaparib has greater than expected activity in prostate cancer patients with DNA damage response (DDR) abnormalities. My previously published data demonstrated that the combination of durvalumab plus olaparib had activity in an unselected population of men with mCRPC. Importantly while on trial all patients had biopsies of metastatic lesions for genomic profiling. Further accrual demonstrated that much of the activity was driven by the BRCA2 and NBN populations with 12 of the 13 patients in this cohort having a significant decline in prostate-specific antigen (PSA). In addition both the median progression-free survival (PFS) (16.5 months) and overall survival (OS; not reached) appear to be very promising. Conversations are ongoing with the FDA and our industry partners on next steps. 3. Accrued 178 patients in my study (2019-2022) which prospectively uses mpMRI to screen a high-risk population of men with known germline genetic variants. As Principal Investigator (PI) I enrolled patients from 30-75 years of age with a germline variant (i.e. pathogenic/likely pathogenic) in prostate cancer risk-related genes as documented by a laboratory certified by the Clinical Laboratory Improvement Amendments: BRCA1 and BRCA2 MMR genes (MLH1 MSH2 MSH6 PMS2 and EPCAM) associated with Lynch syndrome as well as HOXB13 ATM NBN TP53 CHEK2 PALB2 RAD51D BRIP1 or FANCA without a prior prostate cancer diagnosis. Sixteen patients had findings which led to a targeted biopsy and 5 of those were found to have cancer (PSA range 0.69-2.49 ng/mL). This is the first study to prospectively screen men in this population using PSA as well as modern imaging. It would be difficult to conduct such a study outside of the NIH. 4. Completed a series of trials that are helping to define the role of molecular imaging in prostate cancer. One of the strengths of the NCI intramural program is the ability to study patients using molecular imaging. Since the last review a series of studies have been completed which are defining the field for ferumoxytol [18F] sodium fluoride PET/CT and more recently PSMA-based PET/CTs. The work comparing [18F] sodium fluoride and PSMA PET/CT showing discordance in the same lesion quantifying the ability of 18F-DCFPyL PET/CT to detect disease in biochemically recurrent prostate cancer and comparing 18F-DCFPyL PET/CT with mpMRI could not be done easily at other institutions and will have a very meaningful impact on the field. 426153 +Cancer; Genetics 3T3 Cells;Acute;Affinity;Alleles;Binding;Binding Sites;Biological Assay;Birth;Cell Cycle;Cell Cycle Progression;Cells;Chimeric Proteins;Chromatin;Chromatin Loop;Chromatin Structure;Collaborations;Complex;DNA;DNA Binding Domain;DNA Sequence;DNA Structure;DNA-Binding Proteins;DNA-Directed RNA Polymerase;DNA-Protein Interaction;Dangerousness;Development;Differentiation and Growth;Dimensions;Disease;ERCC3 gene;Elements;Embryo;Epigenetic Process;Excision;FBP interacting repressor;FUBP3 gene;Family;Family member;Feedback;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomics;Goals;Hematopoietic;Heterogeneous-Nuclear Ribonucleoprotein K;Human;Hypersensitivity;Impairment;In Vitro;KH Domain;Knock-in;Knock-out;Knockout Mice;Laboratories;Lymphocyte Activation;Malignant Neoplasms;Measures;Mechanical Stress;Mediating;Mediator of activation protein;Modeling;Molecular;Molecular Conformation;Molecular Machines;Monitor;Movement;Mus;Mutate;Mutation;Normal Cell;Nuclear;Nucleosomes;Nucleotide Excision Repair;Oncogenes;Output;Pathologic;Pathology;Pathway interactions;Phenotype;Physiologic pulse;Physiological;Property;Proteins;RNA;RNA Interference;Regulation;Regulatory Element;Reporter;Repression;SP1 gene;SS DNA BP;Series;Serum;Signal Pathway;Signal Transduction;Single-Stranded DNA;Site;Small Interfering RNA;Stress;System;T7 RNA polymerase;Testing;Torque;Torsion;Transact;Transcript;Transcription Coactivator;Transcription Repressor;Variant;Work;X-Ray Crystallography;Xeroderma Pigmentosum;c-myc Genes;c-myc Proto-Oncogenes;cancer cell;cell growth;cell type;chromatin immunoprecipitation;experimental study;flexibility;genetic corepressor;genome-wide;helicase;in vivo;insight;knock-down;melting;nuclease;prevent;promoter;prospective;rapid test;response;tool;transcription factor;transcription factor TFIIH;transmission process Mechanisms of transcription factor integration at the c-myc promoter n/a NCI 10702997 1ZIASC009144-38 1 ZIA SC 9144 38 9692465 "LEVENS, DAVID L." Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 601272 NCI "We have been studying regulatory elements that are single-stranded when the human c-myc proto-oncogene is expressed and have been characterizing the conformation and topology sensitive DNA binding proteins that interact with these elements. First a cell type differentiation specific positive cis-element FUSE 1.5 kb upstream of promoter P1 is single stranded when c-myc is expressed in vivo and is devoid of nucleosomes except when c-myc is repressed. This element specifically binds FBP a sequence specific single strand DNA binding protein. FBP's amino terminus is a potent transcriptional repressor which interacts with TFIIH while the carboxyl is a powerful transcription activator. The activation domain of FBP binds directly with the p62 subunit and the p89 helicase subunit of TFIIH. A co-repressor with FBP FIR binds the central domain of FBP and interacts with TFIIH. FIR increases the affinity of FBP for binding with the FUSE element. FBP activation is defective in xeroderma pigmentosum cells mutated in TFIIH subunits. So endogenous c-myc expression is unresponsive to FBP in XP cells. In XPB cells we have discovered that tight regulation of c-myc is lost and remarkable cell-to-cell variation in MYC levels occur. The XPB mutation prevents FUSE from looping and interacting with the major P2 promoter as a result both the induction and shutoff of c-myc in response to serum addition and removal are impaired. Thus the same mutation that disables nucleotide excision repair also deregulates a dangerous oncogene. Moreover we have discovered that this mutation also disturbs normal cell cycle progression and leads to an accummulation of cells in G2/M. Knockdown of FIR with siRNA provokes a similar cell cycle alteration and similarly disturbs the serum response of the c-myc gene. Along with FBP two other family members FBP2 and FBP3 probably form a basis set to adjust the steady levels of important genes. The central domain of FBP mediates interaction with FUSE. This portion of the protein is composed of repeated ""KH"" motifs which comprise a bi-partite DNA binding domain. Sub-domains constituted of the amino-terminal two KH repeats or the carboxyl pair of KH motifs bind weakly and strongly respectively with upstream and downstream contiguous sequence segments of FUSE. SELEX studies have identified specific DNA sequences interacting with FBP's KH domains and have enabled a genomic analysis of prospective FBP binding sites. Upon binding with FIR the weak binding sub-domain of FBP recognizes the upstream segment of FUSE with increased affinity. Both FBP and FIR have been shown to control levels of endogenous c-myc expression. FIR repression of c-myc also fails in XP cells. ChIP (chromatin immunoprecipitation)-Seq studies are revealing that the FBP-FIR system is a commonly used molecular machine that controls the output of a large number of genes. NMR studies of a complex between the strong binding sub-domain and the downstream segment of FUSE suggest that FBP is truly a DNA binding protein as particular features of the complex are unique to DNA-protein interactions. X-ray crystallography in collaboration with Dr. Demetrios Braddock revealed new features of the FBP-FIR-FUSE system. Recent evidence in collaboration with Leonie Quinn (Melbourne) shows that FBP is likely to also interact with the Mediator complex. All of these interactions occur both in vivo and in vitro. The mechanism of transcriptional modulation by the FBP/FIR/TFIIH/repressor/co-activator complex reveals that FBP hastens RNA polymerase movement through earliest stages of transcript elongation. In contrast FIR delays the transition of RNA polymerase into its elongation mode. mechanisms. The relevance of FBP and FIR to the regulation of c-myc has been established using RNAi. Additional experiments have exposed the presence of multiple signals embedded within FBP targeting the protein to multiple nuclear compartments. We have developed an FBP knockout mouse that dies just before birth and seems to display hematopoietic abnormalities. MEF and 3T3 cells from FBP ko embryos have been developed to study the molecular mechanisms targets and cell dynamics that are under the control of FBP. We have also developed a a c-myc-EGFP knock-in that is the best reporter system yet developed to study the regulation and deregulation of c-myc expression. combined with our studies of FIR and FBP via DNA topology these studies provide an extra dimension to our understanding of gene regulation. We are using this system to provide new insights for the identification and understanding of MYC targets during lymphocyte activation. Recent studies in the lab have established that FUBP2/KHSRP another FBP family cooperates with FBP/FUBP1 to control MYC levels. The properties of FBP and hnRNP K that each bind to both single stranded DNA and RNA prompted examination of c-myc regulatory cis-elements in vivo and in vitro to determine how these sites become melted. Using actively transcribing T7 RNA polymerase to generate torque experiments indicate that the dynamic transmission of mechanical stress destabilizes particular elements such as FUSE and CT-elements even in the absence of defined topological boundaries. Recent experiments have been devised to measure the level of superhelical stress transmitted into DNA by ongoing transcription. The level attained is close to the theoretical limit and is suprisingly high high enough to disturb chromatin and DNA structures and so may of regulatory consequence. Recent studies are establishing the the equivalence of our in vitro and in vivo studies. Because single-stranded DNA is much more flexible to torsion and flexion than is duplex interposing CT-elements between genetically interacting sites facilitates these interactions. Therefore one function of regulated single-stranded cis-elements is to serve as protein-DNA hinge. Recent work suggests that competition between hnRNP K and SP1 at the CT element may be mediated by a conformation switch. To explore the interplay between these DNA conformation sensitive factors and the multitude of conventional transcription factors that regulate c-myc we have knocked EGFP as a chimeric protein into the c-myc locus. This knock-in allele is fully functional as homozygous myc-EGFP mice are phenotypically normal. The EGFP allows us to monitor MYC levels in single living cells. This will allow us to describe the distribution of cell-to-cell variation in MYC levels with the quantitative precision necessary to develop a predictive mechanistic model if how the c-myc promoter works. Why is c-myc regulation so complicated? We have determined that even a brief pulse of forced MYC expression can cause cells to undergo several cycles of cell division. Therefore expression must be held to close tolerances. Using a new nuclease assay developed by us we are commencing the the analysis of the differential utilization of cis-reguatory modules that control MYC expression in helath and disease. We demonstrated that MYC levels have precise and epigentically fixed set points in different cells and that these set points are disturbed in cancer. With low level stimulation cells induce MYC while respecting a ceiling that is epigenetically bounded but with high level stimulation this ceiling may be breeched and pathological MYC levels ensue. The high-MYC cells are primed for a rapid response to stimulii." 601272 +Breast Cancer; Cancer; Clinical Research; Women's Health Agonist;Animals;Antibodies;Apoptosis;Binding Proteins;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Breast Cancer cell line;Caspase;Cell Death;Cell Death Induction;Cells;Cessation of life;Clinical Trials;Collaborations;Combined Modality Therapy;Data;Drug usage;Endometrial Carcinoma;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epigenetic Process;Family;Gene Proteins;Genetic;Induction of Apoptosis;Ligands;Mediating;Mitochondria;National Center for Advancing Translational Sciences;Necrosis;Pathway interactions;Patients;Peptide Hydrolases;Pharmaceutical Preparations;Phase II Clinical Trials;Protein Tyrosine Kinase;Resistance;TNF gene;TNFRSF10A gene;TNFRSF10B gene;Toxic effect;Trastuzumab;Tumor Necrosis Factor Ligand Superfamily Member 6;Tumor Necrosis Factor Receptor;Work;cancer cell;cancer subtypes;cell killing;chemotherapeutic agent;functional genomics;malignant breast neoplasm;member;novel;novel drug class;pre-clinical;preclinical study;receptor;recruit;targeted agent;targeted treatment;tumor Activating Cell Death Pathways in Breast Cancer Cells n/a NCI 10702995 1ZIASC007263-30 1 ZIA SC 7263 30 14821366 "LIPKOWITZ, STANLEY " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1018140 NCI Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. TNF family death receptors (e.g. TNFR Fas DR3 TRAIL Receptor 1 and TRAIL Receptor 2) induce apoptosis in cells by recruiting and activating caspases upon activation by their respective ligands (e.g. TNF Fas Ligand and TRAIL). We are investigating the expression and function of TRAIL death receptors (members of the TNFR family) and their ligands (e.g. TRAIL and agonistic antibodies) in breast cancer cells in order to selectively trigger apoptosis in the cancer cells. In our early work we found that most breast cancer cell lines are resistant to the induction of apoptosis by TRAIL. We have demonstrated that a subset of breast cancer cells those with triple-negative/basal-like features are very sensitive to TRAIL-induced apoptosis while other breast cancer subtypes are relatively resistant to TRAIL-induced apoptosis. This subset of breast cancers is particularly aggressive and most in need of targeted therapies. Further we found that TRAIL Receptor 2 and not TRAIL Receptor 1 is required for TRAIL induced apoptosis in the sensitive breast cancer cells. This latter finding will help in the selection of TRAIL agonists for eventual clinical trials in breast cancer patients. In addition we have found that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents targeted agents such as trastuzumab and EGFR inhibitors. More recently we have demonstrated that inhibition or loss of the G2/M checkpoint tyrosine kinase Wee1 enhances TRAIL-mediated apoptosis in basal-like breast cancer cells. Together these studies are beginning to provide clear preclinical rationales for studies of TRAIL ligands alone or in combination with other drugs in patients with breast cancer. Ongoing work is: 1) using functional genomics to identify and characterize the genes and proteins that regulate apoptosis induced by TRAIL receptor agonists in breast cancer cells. 2) characterizing novel TRAIL receptor agonists in breast cancer cells 3) evaluating the effects on the immunogenecity of breast cancer cells. In a spin off projject we are characterizing the mechanism of action of ClpP agonists. The latter drug was described to work via the TRAIL pathway. However our data suggest that it works independent of the TRAIL pathway to kill breast cancer and other cancer cells. Our ongoing work includes 1) characterizing the mchanism of death induced by ClpP agonists on breast cancer cells; 2) in collaboration with NCATS we conducted a screen to identify drugs that synergize with ClpP agonists in breast cancer cells and are validating hits from that screen to credential combination therapies that will be useful with ClpP agonists. 3) investigating the effects of ClpP agonists on breast cancer tumor initiating cells. 1018140 +Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Clinical Research; Genetics; Health Disparities; Human Genome; Microbiome; Minority Health; Prevention; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Women's Health 16S ribosomal RNA sequencing;Actinobacteria class;Address;African American;Age of Onset;Aneuploidy;Architecture;Atypia;Atypical Ductal Breast Hyperplasia;Autologous;Bacteroidetes;Basic Research Breast Cancer;Biological;Breast;Breast Cancer Prevention;Breast Cancer Risk Factor;Breast Carcinogenesis;Breast Magnetic Resonance Imaging;CCR;Caucasians;Cells;Cellularity;Characteristics;Chemoprevention;Chronic;Classification;Clinical;Clinical Research;Collection;Complement;Control Groups;Core Facility;Cytologic Atypia;Cytology;DNA;DNA Methylation;DNA amplification;Development;Doctor of Medicine;Duct (organ) structure;Ductal Carcinoma;Ductal Epithelial Cell;Ductal Epithelium;Early identification;Endoscopy;Epithelial;Epithelial Cells;Evaluation;Feasibility Studies;Flow Cytometry;Freezing;Future;Gene Chips;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Genomic Instability;Genomics;Goals;High Risk Woman;Hispanic Americans;Histology;Immune;Immunologic Surveillance;Individual;Inflammation;Inflammatory;Institutional Review Boards;Internet;Irrigation;Laboratory Study;Loss of Heterozygosity;Lymphocyte;Magnetic Resonance Imaging;Malignant Neoplasms;Mammary Gland Parenchyma;Methods;MicroRNAs;Modeling;Molecular;Molecular Profiling;Monitor;Mutation;Pathway interactions;Patients;Pharmaceutical Preparations;Pilot Projects;Play;Population;Proteins;Protocols documentation;Publications;Publishing;RNA;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Review Literature;Risk;Risk Assessment;Role;Saline;Sampling;Sampling Studies;Signal Pathway;Source;Suspensions;Telomere Shortening;Time;Tumor Suppressor Proteins;Woman;anticancer research;cancer stem cell;carcinogenicity;caucasian American;cell type;clinical prognostic;clinically significant;design;differential expression;exome sequencing;follow-up;high risk;immune checkpoint;improved;intraepithelial;malignant breast neoplasm;mammary;microbiome;microbiome research;progenitor;racial disparity;sample collection;stem cells;whole genome Molecular Characterization of Breast Duct Epithelium at Risk for Breast Cancer n/a NCI 10702991 1ZIASC006663-33 1 ZIA SC 6663 33 6572190 "DANFORTH, DAVID " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 449713 NCI This project is designed to define the cytologic ductal architectural and molecular characteristics of breast ducts and ductal epithelial cells of women at normal risk and at high risk for breast cancer including Caucasian Hispanic and African American women. This information is needed to define the early changes in the carcinogenic pathway for breast cancer to develop an improved classification and molecular signature of preneoplastic breast tissue for risk assessment to identify new targets and to facilitate selection and monitoring of women for breast cancer prevention and to define the molecular basis for disparities in the development and presentation of breast cancer. This project includes the following clinical and laboratory study: Protocol 02-C-0077 Characterization of High-Risk Breast Duct Epithelium by Cytology Breast Duct Endoscopy and Gene Expression Profile (DN Danforth PI). This protocol examines by ductal lavage and ductal endoscopy the breast ducts and ductal epithelium of women at normal risk and at high risk for breast cancer. One hundred fifty-five subjects have been studied 75 high risk subjects and 80 subjects at normal risk. A significantly improved method of ductal epithelial cell sampling has been developed under this study which provides multiple samples of pure (90%) ductal epithelial cells with high cellularity. The details of this sampling method were recently published (Danforth DN et al Breast Cancer: Basic and Clinical Research 9:31-40 2015). Extraction of a single ductal lavage sample provided DNA and RNA suitable for multiple downstream molecular studies including whole genome DNA amplification arrayCGH analysis microarray gene expression profiling and RT-PCR of miRNA species. This method significantly expands our ability to characterize the molecular characteristics of ductal cells according to breast cancer risk including women at normal risk for breast cancer a critical control group for defining the multiple molecular characteristics of women at high risk for breast cancer. To compliment and guide the molecular studies in this protocol a comprehensive literature review was conducted to identify and define genomic changes in normal breast tissue at normal risk (NR) and at high risk (HR) for breast cancer (Danforth DN. Breast Cancer: Basic and Clinical Research 10:109 2016). This indicated that normal risk breast tissues contain evidence of early breast carcinogenesis including loss of heterozygosity DNA methylation of tumor suppressor and other genes and telomere shortening. In normal breast tissues at high risk for breast cancer these changes persist and are increased and accompanied by aneuploidy increased genomic instability a wide range of gene expression differences development of large cancerized fields and increased proliferation. A model for the carcinogenic pathway in normal risk and in high risk normal breast tissue is proposed in this publication. The studies conducted under protocol 02-C-0077 have also provided important clarification of the clinical and prognostic role of cytologic atypia in women at risk for breast cancer. Cytologic studies of ductal cells under this protocol have revealed the presence of atypical epithelial cells in 22.9% of HR and 25.7% of NR subjects. Ductal endoscopy was performed in 89 subjects with the very important finding that the ducts of 40.4% of women at high risk contained intraductal fibrous webbing suggesting chronic inflammation compared with only 5.6% of normal risk subjects (P2 = 0.0004). Chronic inflammation has long been recognized as an important factor promoting the development of cancer as well as promoting expression of immune checkpoint proteins which can inhibit lymphocytes and immunosurveillance. This has been reviewed in a recent publication (Danforth DN. Cancers 13:3918 2021) Immune cells are clearly instrumental in the development of chronic inflammation and to help define the role of immune cells in normal breast tissue we have recently published a review of this relationship (SL Goff and DN Danforth. Clinical Breast Cancer 21:63-732021). Characterization of intraductal chronic inflammatory changes are important topics for future studies. Our studies have further defined the presence of intraductal cytologic atypia. In normal risk subjects cytologic atypia was present in 25.7% but was not associated with altered gene expression by microarray profiling or with abnormalities on ductal endoscopy or on breast MRI or on follow-up providing the important observation that cytologic ductal atypia in normal risk subjects does not appear to be of clinical significance. In high-risk subjects atypia was present in 22.9% and follow-up MRI revealed a ductal carcinoma in 13.7% of patients indicating the importance of ductal evaluation in high-risk subjects. These findings have recently been reported [Danforth DN. et al. Characteristics of breast ducts in normal risk and high-risk women and their relationship to ductal cytologic atypia. Cancer Prev Res 2020;13:1027-36]. The ductal samples we are collecting are single cell suspensions of ductal cells which should be very amenable to separation by flow cytometry. This is being studied and will allow detailed characterization of each ductal cell type both epithelial and immune and further define normal risk high risk and atypical cell states. To complement these studies a review of the molecular profile of atypical ductal hyperplasia of the breast was recently published (Danforth DN. Breast Canc Res Treat 167:9 2018). An important secondary objective of the study is to determine the presence of mammary stem cells in the ductal microenvironment. Mammary stem cells (MSC) are considered the progenitors of all ductal cell types. Importantly mammary stem cells may also be transformed into cancer stem cells (CSC) the origin of breast cancer. Identification of MSCs or CSCs in the breast ductal cellular compartment could have important implications for understanding early breast carcinogenesis. Recent evidence has also indicated the presence of a microbiome in breast tissue. We recently performed a pilot study in which 8 frozen ductal samples were analyzed by 16s rRNA sequencing through the CCR Microbiome Core Facility. We identified microbia in all samples with the following relative distribution according to phylum: Bacteroidetes Firmacutes Protobacteria Actinobacteria. This confirmed the feasibility of studying the microbiome in our normal risk and high-risk breast ductal samples. Further characterization of the microbiome in our ductal samples will clarify the relation of the intraductal microbiome to breast cancer risk and as a potential cause of chronic intraductal inflammation which we have observed in the high-risk ducts. Lastly to complement our studies of the basis of racial disparities a comprehensive review of the literature has recently been published proposing for the first time a model describing the relationship of biological and nonbiological factors to the initiation and development of the major disparities in breast cancer between African American and Caucasian women (Danforth DN. Breast Cancer Research 15:208-220 2013). This model identified multiple molecular differences in breast cancer between African American and Caucasian women and these differences are important drivers of the disparities in age of onset more advanced stage more aggressive histology and worse survival in African American vs. Caucasian wom *TRUNCATED* 449713 +Biotechnology; Cancer; Clinical Research Affect;Alkaloids;Angiogenesis Inhibitors;Angiogenesis Pathway;Anti-Inflammatory Agents;Antineoplastic Agents;Aorta;Benzamides;Binding;Biological Assay;Biological Markers;Biological Models;C-terminal;Chemical Structure;Chick Embryo;Clinical;Collaborations;Complex;Crystallization;Cullin Proteins;Cysteine;Cytochrome P450;Development;Disease;Docking;Drug Design;EP300 gene;Elements;Endothelial Cells;Energy Metabolism;FDA approved;Fluorescence;Hematologic Neoplasms;Histidine;Human;Hypoxia;Hypoxia Inducible Factor;Immunomodulators;In Vitro;Inflammation;Isoenzymes;Laboratories;Legal patent;Libraries;Ligase;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic Biotransformation;Modeling;Molecular;Molecular Target;Multiple Myeloma;Natural Products;New Agents;New Zealand;Pathway interactions;Pharmacology;Pharmacology Study;Pharmacology and Toxicology;Porifera;Property;Pyrroloiminoquinones;Rattus;Regimen;Regulation;Reporting;Research;Saphenous Vein;Series;Solid Neoplasm;Structure;Structure-Activity Relationship;Substrate Specificity;Teratogens;Thalidomide;Therapeutic;Toxic effect;Toxicology;Transactivation;Tube;Tumor Angiogenesis;United States National Institutes of Health;Work;Xenograft Model;Zebrafish;analog;angiogenesis;base;cancer therapy;cell motility;chemotherapy;cytotoxicity;design;drug development;high throughput screening;hypoxia inducible factor 1;immunoregulation;improved;in silico;in vivo;in vivo Model;inhibitor;inhibitor therapy;interest;knock-down;model development;novel;pharmacophore;pleiotropism;pre-clinical;preclinical study;protein expression;protein protein interaction;rational design;repository;research clinical testing;secondary analysis;side effect;small molecule inhibitor;targeted treatment;therapeutically effective;tumor growth;ubiquitin ligase Development of Anticancer Agents n/a NCI 10702990 1ZIASC006538-29 1 ZIA SC 6538 29 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 730131 NCI Development of immunomodulatory drugs. The antiangiogenic properties of thalidomide reported by D'Amato and colleagues prompted its clinical evaluation in various solid tumors including prostate cancer. Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenesis pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort in our laboratory. Previously we showed that one of the products of cytochrome P450 2C19 isozyme biotransformation of thalidomide 5'-OH-thalidomide is responsible for the drug's antiangiogenic activity. Based on the chemical structure of this metabolite we collaborate with Drs. Nigel Greig (NIA NIH) and Michael Gutschow to synthesize novel thalidomide analogs evaluate them using in vitro and in vivo models to assess activity and characterize their structure-activity-relationships for further rational drug design. We have synthesized over 315 novel analogs of thalidomide and screened them for inhibition of inflammation and angiogenesis using various in vitro ex vivo and in vivo drug development models (e.g. rat aorta ring model human saphenous vein model cultured endothelial cells migration and tube formation assays). In collaboration with Dr. Neil Vargesson we conduct an in vivo screen of a library of new analogs to determine which agents demonstrate activity using the in vivo zebrafish and chicken embryo model systems. We identified the most potent of these agents and have patented them. We continue to develop these compounds which appear to have minimal side effects in initial preclinical toxicology studies and may have improved pharmacology over the two FDA approved thalidomide analogs. We have optimized for both antiangiogenic and anti-inflammatory properties of these immunomodulatory drugs (IMiDS) which means the clinical indication can go beyond hematological malignancies and could have activity in solid tumors. This work in antiangiogenic/anticancer drug development serves not only to advance the field of antiangiogenic therapy but also to discover new treatment paradigms that focus on immunomodulation for advanced metastatic disease. We have recently completed characterization of the cytotoxicity antiangiogenic and anti-inflammatory properties of polyfluorinated benzamides as well as adamantyl and noradamantyl phthalimidines in multiple myeloma models. Efforts are ongoing to identify potential leads for in vivo toxicology and pharmacology studies in xenograft models as well as understand the mechanisms of action since the compounds are structurally similar to thalidomide but lacks binding to cereblon (CRBN). CRBN is a substrate recruiter element of the E3 cullin 4-RING ubiquitin ligase complex and a binding target of thalidomide and IMiDs. CRBN is responsible for the pleiotropic effects of IMiDs yet its function in angiogenesis and in mediating the antiangiogenic effects of IMiDs remains unclear. The binding of these IMiDs to CRBN alters the substrate specificity of the ligase thereby mediating multiple effects that are exploited in cancer therapy. We have previously demonstrated that knockdown of CRBN caused a corresponding increase in AGO2 and SALL4 protein expression and IMiD treatment was able to rescue the siCRBN effect to increase the CRBN expression. These findings suggest one potential mechanism of action that likely involves a tightly coordinated regulation of CRBN with endothelial cell targets and highlight the need to further elucidate the mechanism(s) which could include cereblon-independent pathways through which IMiDs exert their antiangiogenic effects. Due to its antiangiogenic and anti-immunomodulatory activity thalidomide continues to be of clinical interest despite its teratogenic actions and efforts to synthesize safer clinically active thalidomide analogs are continually underway. We conducted a structure-activity relationship study to evaluate the antiangiogenic activity and in silico CRBN binding analysis of novel thalidomide analogs. We use in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon and multiple targets and mechanisms of action may be involved. Development of HIF-1alpha inhibitors. The hypoxia-inducible factor (HIF) is fundamentally involved in tumor angiogenesis invasion and energy metabolism. Inhibition of HIF-1 represents an attractive therapeutic strategy for targeting hypoxia a hallmark of many solid tumors and tumor angiogenesis. One promising approach for directly inhibiting HIF-1 activity is by disrupting the tight binding between HIF-1alpha and p300. Previously our laboratory developed an in vitro fluorescence binding assay that can be used in a high-throughput screen to identify small-molecule inhibitors of HIF-1a through inhibiting the binding interaction between the C-terminal transactivation domain (CTAD) of HIF-1a and the cysteine/histidine-rich 1 (CH1) domain of p300. Using our HIF-1alpha/p300 assay we performed high-throughput screen of NCI's Natural Products Repository in collaboration with the Molecular Targets Laboratory (NCI). This effort led to the discovery of a series of pyrroloiminoquinone alkaloids including discorhabdin and makaluvamine alkaloids originating from a Latrunculia sp. of marine sponge as potential HIF-1a/p300 inhibitors. Efforts are ongoing to extract more discorhabdins from New Zealand sponges in order to continue preclinical studies to further understand the mechanisms of these novel compounds. 730131 +Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Clinical Research; Clinical Trials and Supportive Activities; Genetics; HIV/AIDS; Human Genome; Immunization; Immunotherapy; Microbiome; Pediatric; Pediatric AIDS; Prevention; Vaccine Related; Vaccine Related (AIDS); Women's Health Adenoviruses;Adjuvant;Affinity;Age;Agonist;Allogenic;Antibodies;Antigens;Arylsulfatases;Autologous;Avidity;Binding;Biotechnology;CCR;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cancer Vaccines;Cells;Cholesterol;Clinic;Clinical;Clinical Trials;Combined Vaccines;Cooperative Research and Development Agreement;Cytotoxic T-Lymphocytes;Data;Dose;ERBB2 gene;Endometrial Carcinoma;Epitopes;Equilibrium;Evaluable Disease;Extracellular Domain;Failure;Glycolipids;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;HLA-A2 Antigen;Helper-Inducer T-Lymphocyte;Histocompatibility;Human;Immune checkpoint inhibitor;Immune response;Immunity;Immunologic Surveillance;Immunology;Immunotherapy;Interleukin-12;Interleukin-13;Interleukin-15;Interleukin-17;KDR gene;Knockout Mice;Lead;Ligands;Lipids;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Mammary Neoplasms;Mediating;Metastatic Neoplasm to the Lung;Microbe;Modification;Mucosal Immunity;Mucous Membrane;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Omega-3 Fatty Acids;PD-1 blockade;PD-L1 blockade;PPBP gene;Pathway interactions;Patients;Peptides;Phase I Clinical Trials;Phase I/II Trial;Primary Neoplasm;Process;Publishing;Purinergic P1 Receptors;Rattus;Regulation;Regulatory T-Lymphocyte;Research;Role;Safety;Sampling;Skin;Stimulant;Structure;Sulfoglycosphingolipids;T cell response;T-Cell Depletion;T-Lymphocyte;TLR3 gene;Testing;Therapeutic Effect;Tissues;Toll-like receptors;Transforming Growth Factor beta;Transgenic Mice;Translating;Translations;Transmembrane Domain;Trastuzumab;Tropism;Tumor Antigens;Tumor Immunity;Vaccine Adjuvant;Vaccine Design;Vaccinee;Vaccines;Vaccinia virus;Viral Cancer;Virus;Virus Diseases;Work;alpha-galactosylceramide;analog;anergy;anti-PD-1;anti-PD-L1;base;cancer immunotherapy;cell killing;cytokine;gut microbiome;immunoregulation;improved;inhibitor;malignant breast neoplasm;melanoma;microbiome;neoplastic cell;novel;novel strategies;phase I trial;phase II trial;preclinical study;prevent;receptor for advanced glycation endproducts;recruit;response;scavenger receptor;synergism;transcriptome sequencing;tumor;tumor growth;vaccine efficacy;vaccine immunogenicity;vaccine strategy;viral transmission Vaccine and immunotherapy strategies for cancer and viruses causing cancer n/a NCI 10702986 1ZIASC004020-45 1 ZIA SC 4020 45 6572144 "BERZOFSKY, JAY A" Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 960045 NCI The strategies above involve 5 steps that together comprise a push-pull approach to optimize antigen structure improve quantity and quality of the response and remove regulatory barriers. Regulation of tumor immunity by NKT cells: NKT cells are true T cells recognizing glycolipid antigens presented by CD1d. We discovered a novel immunoregulatory pathway in which NKT cells suppress tumor immunosurveillance using IL-13 to induce myeloid cells to make TGF-b that suppresses immunity. We completed a phase I trial of anti-TGF-b with clinical benefit in melanoma patients. We discovered synergy between TGF-b blockade and cancer vaccines in mice. Blockade of TGF-b1 / 2 (without 3) was sufficient to enhance immunosurveillance and vaccine efficacy further amplified by PD-1 blockade. Type I (invariant-TCR) NKT cells promote tumor immunity whereas we found that type II (diverse-TCR) NKT cells suppress tumor immunity. We discovered these subsets cross-regulate each other defining a new immunoregulatory axis. We are investigating relationships with other regulatory cells/ molecules. Both type II NKT cells and Treg cells can suppress tumor immunity concurrently but type I inhibit type II NKT cells leaving Tregs as the dominant suppressor unless type I NKT cells are blocked or absent. Thus the balance between 2 regulatory cells is determined by a 3rd cell that regulates the regulators. Moreover we found distinct regulatory cells dominate in the same tumor in the lung and skin. Thus tissue context determines cancer immunity for the same tumor implying that immunotherapy for primary tumors and metastases in different tissues may need to be different not widely recognized. . We are performing a structure-function study of sulfatide analogs to activate or inhibit type II NKT cell activities. One sulfatide analog stimulates type II NKT cells when not processed but type I NKT cells when processed by DCs and under that condition can prevent instead of promote cancers. Endosomal processing by arylsulfatase A converts sulfatide to b-GalCer not expected to be active but which turned out to be a strong type I NKT cell stimulant. This is the first case of glycolipid processing that changes cell tropism and reverses function. We identified a new class of agonist for type I NKT cells b-ManCer that inhibits tumors by a mechanism distinct from that of a-GalCer synergizes with a-GalCer is much less anergy-inducing than a-GalCer and stimulates human NKT cells also. Studies using structure-specific antibodies showed that b-ManCer could assume a structure resembling a-GalCer. All of these studies are aimed to remove the roadblocks to allow cancer vaccines to successfully induce tumor regression. Epitope enhancement in cancer vaccine strategies and translation to clinical trials: We first devised and carried out epitope enhancement (sequence modification to improve MHC binding) on an HLA-A2-binding epitope we discovered in a novel prostate and breast cancer antigen TARP. The enhanced epitope induces human T cells that kill human tumor cells. We translated this to a phase I clinical trial of 2 peptides in stage D0 prostate cancer. 74% of vaccinees had a decreased PSA slope and tumor growth rate at 1 year (p = 0.0004). All 6 vaccinated patients in the safety lead-in for a phase 2 trial had flat or reduced PSA slope. We studied preclinically and published a novel adenovirus-based HER-2 vaccine expressing the extracellular (EC) and transmembrane (TM) domains of rat neu (ErbB2) which prevents tumor growth in the neu-transgenic mice and cures large established TUBO mammary tumors (2 cm) and established lung metastases. The therapeutic effect in mice is purely antibody mediated through inhibiting ErbB-2 function unlike trastuzumab which is FcR dependent so may work in trastuzumab failures. We translated to a clinical autologous DC vaccine transduced with an Ad5f35 expressing the EC and TM domains of human HER2 and have now published a phase I/II trial of this human vaccine. At vaccine doses of 10-40 million DCs 7/21 (33%) evaluable patients showed clinical benefit (CR PR or SD) and complete safety. A new study combining this vaccine with checkpoint inhibitors (anti-PD-1 a VEGFR inhibitor and an enhanced IL-15) in endometrial cancer is under review. We also compared combinations of checkpoint inhibitors and anti-TGF-b in enhancing cancer vaccine efficacy in mice and found preliminary data for synergy among anti-TGFb anti-LAG3 anti-TIGIT and anti-PDL1. Without the vaccine the checkpoint inhibitors don't work without anti-TGFb. We also found vaccine efficacy enhancement by blockade of PD-L1 and TIGIT a combination further enhanced by CD4 T cell depletion so we are investigating the role of CD4 Treg cells. Thus the vaccine is essential but the other inhibitors of negative regulation amplify the efficacy in mice. We invented a new modified a-GalCer (PLS-a-GalCer) that is more potent in treating mouse tumors and are investigating the mechanism involving targeting a scavenger receptor by PLS. We also carried out a CRADA-collaborative study in mice of an intratumoral therapy that we found induces a T cell response necessary for regression. This has been translated to the clinic by our collaborators. Recently we began examining the effects of cholesterol and omega-3 lipids in regulating tumor growth in mice. Tumor growth is slowed in mice that genetically make more omega-3 lipids and cancer vaccine efficacy is enhanced. We also initiated a CRADA with BriaCell to test the ability of semi-allogeneic DCs to act as more effective cancer vaccine vehicles by recruiting allogeneic help. Also we just opened a CRADA with Portage Biotech to examine the ability of their agents that block RAGE or adenosine receptors and activate the STING pathway to enhance cancer vaccine efficacy initially in mice and ultimately in the clinic. Cytokines as vaccine adjuvants for induction of high avidity T cells: Our earlier work showed that high avidity T cells were more effective at clearing viral infections and cancers. We discovered ways to induce them with cytokines and TLR ligands. The quality of response proved more important than the quantity. We found using a novel adjuvant CAF09 that we could lower the vaccine dose sufficiently to induce higher avidity CD4 T cells to better clear virus infection. We also found that IL-1b induces Th17 helper cells that do not help Tc1 CD8 T cells that protect against vaccinia virus. Rather they skew the CD8 response to Tc17 cells that make IL-17 and do not protect. TGF-b blockade can prevent this problem. We also examined combinations of cytokines and TLR ligands as vaccine adjuvants and found greatest efficacy of IL-15 + TLR3 and TLR9 agonists but also some efficacy of IL-12 + GM-CSF. Mucosal immunity microbiome: We are also examining the effect of the gut microbiome on cancer. We are examining the effect of NKT cells on the gut microbiome and the downstream effect on cancer. We have bred Ja18 knockout (KO) mice that lack type I NKT cells only and CD1d KO mice that lack both type I and type II NKT cells along with wild type B6 mice that have both types in the same facility. We collected their gut microbiome samples at ages 14 23 30 60 and 90 days and done 16S RNA sequencing through the CCR Microbiome Core. We are analyzing the changes in microbiome with age. Then we have cohoused some of these pairwise from day 30 to day 90 and examined the ability of microbes to be transferred. We are finding micr *TRUNCATED* 960045 +Cancer; Cancer Genomics; Genetics; Hematology; Human Genome; Lymphatic Research; Lymphoma; Pediatric; Pediatric Cancer; Rare Diseases 1p36;Adult;Affect;American;Awareness;B-Cell Neoplasm;B-Lymphocytes;BCL2 gene;Behavior;Benign;Biology;Bone Marrow Involvement;CREBBP gene;Categories;Cell Proliferation;Cells;Cellular Structures;Centrocyte;Cervix Uteri;Characteristics;Child;Childhood;Chromatin;Classification;Clinical;Clinical Management;Consensus;Cutaneous;DNA Methylation;Derivation procedure;Diagnosis;Diffuse Pattern;Disease;Disease remission;European;Extranodal;Female genitalia;Follicular Lymphoma;Functional disorder;Gene Rearrangement;General Population;Genes;Genetic;Genomic approach;Genomics;Goals;Heel;Hematologic Neoplasms;Histiocytic and Dendritic Cell Neoplasms;Histologic;Immune system;Indolent;International;Knowledge;Limited Stage;Localized Disease;Loss of Heterozygosity;Lymphoid;Lymphoma;MAP2K1 gene;Malignant Neoplasms;Methylation;Minor;Modification;Molecular;Morphology;Mutate;Mutation;Nature;Nodal;Nomenclature;Oral;Pathogenesis;Pathologic;Pathologist;Pathology;Patients;Process;Prognosis;Progressive Disease;Publications;Publishing;Recurrence;Relapse;Reporting;Residual state;Risk;Scientist;Series;Signal Pathway;Skin;Structure of germinal center of lymph node;Terminology;Translating;Update;Vagina;Variant;Work;base;clinical practice;diagnostic criteria;diagnostic tool;disease classification;exome sequencing;follow-up;genetic approach;herpesvirus entry mediator;improved;insight;large cell Diffuse non-Hodgkin's lymphoma;lymphoid neoplasm;male;meetings;next generation sequencing;novel diagnostics;pediatric follicular lymphoma;prevent;reproductive tract;treatment response;tumor;unnecessary treatment;young adult Lymphoma Disease Discovery and Definition n/a NCI 10702983 1ZIASC000550-42 1 ZIA SC 550 42 9692515 "JAFFE, ELAINE " Not Applicable n/a Unavailable DIVISION OF CLINICAL SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 920437 NCI Pediatric nodal marginal zone lymphoma (PNMZL) is an uncommon B-cell neoplasm affecting mainly male children and young adults. This indolent lymphoma has distinct characteristics that differ from conventional nodal marginal zone lymphoma (NMZL). Clinically it shows overlapping features with pediatric-type follicular lymphoma (PTFL). To explore the differences between PNMZL and adult NMZL and its relationship to PTFL a series of 45 PNMZL cases was characterized morphologically and genetically using an integrated approach including whole exome sequencing in a subset of cases targeted next generation sequencing and copy number (CN) and DNA methylation arrays. Fourteen cases (31%) were diagnosed as PNMZL whereas 31 cases (69%) showed overlapping histological features between PNMZL and PTFL including a minor component of residual serpiginous germinal centers reminiscent of PTFL and a dominant interfollicular B-cell component characteristic of PNMZL. All cases displayed low genomic complexity (1.2 alterations/case) with recurrent 1p36/TNFRSF14 copy number-neutral loss of heterozygosity alterations and CN loss (11%). Similar to PTFL the most frequently mutated genes in PNMZL were MAP2K1 (42%) TNFRSF14 (36%) and IRF8 (34%) DNA-methylation analysis showed no major differences between PTFL and PNMZL. Genetic alterations typically seen in conventional NMZL were absent in PNMZL. In summary we demonstrated overlapping clinical morphological and molecular findings including low genetic complexity recurrent alterations in MAP2K1 TNFRSF14 and IRF8 and similar methylation profiles. Our results indicate that PNMZL and PTFL are likely part of a single disease with variation in the histological spectrum. As a single entity it could designated as pediatric-type follicular lymphoma with or without marginal zone differentiation. Extranodal forms of follicular lymphoma differ from nodal follicular lymphoma based on the frequent absence of BCL2-rearrangement (BCL2-R) and the tendency to remain confined to the skin without dissemination. The nature of other extranodal follicular lymphoma including those of the lower female genital tract is not well defined. We studied 15 cases of follicular lymphoma of the lower female genital tract involving cervix and vagina to determine their clinicopathological and molecular characteristics. All patients had localized disease with no evidence of bone marrow involvement. The majority of cases had a diffuse pattern and large centrocytes were a prominent feature. This led to the concern for diffuse large B-cell lymphoma by most referring pathologists. All the cases had a follicle center derivation. The majority (91%) were negative for BCL2 gene rearrangement by FISH. NGS showed these cases specifically lacked mutations in chromatin modifying genes (CREBBP and KMT2D) which are hallmark of nodal FL. The most mutated gene was TNFRSF14(60% cases). None of the patients had progressive disease with all achieving durable complete remission regardless of the treatment received. Median follow-up period was 7.8 years (range: 0.2-20.5 years and mean: 8.9 years) with 100% overall survival. Together these findings show that this tumor distinct from nodal FL and is clinicopathologically and molecularly like primary cutaneous follicle center lymphoma. Despite component of large cells it is characterized by limited stage presentation and invariably benign behavior. Awareness and recognition of this entity is very important to distinguish it from higher grade lymphomas and to prevent unnecessary treatment as it remains localized with low risk of progression and relapse. This work was presented orally at the pathology meetings in 2022 and is being prepared for final publication. Since the publication of the Revised European-American Classification of mature lymphoid neoplasms in 1994 subsequent updates of the classification of mature lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists geneticists molecular scientists and clinicians. Significant progress in the characterization of malignancies of the immune system in the last years with many new insights provided by genomic studies have changed the definition of some entities and have led to the recognition of other entities. With my collaborators I have led a major international effort to update the classification of lymphoid neoplasms. We have followed the same process that was successfully used for the 3rd and 4th editions of the WHO classification of hematological neoplasms. The definition recommended studies and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional are now upgraded to definite entities. Terminology of some diseases has been revised to adapt nomenclature to the current knowledge of their biology but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in our published report in 2022 as the proposed International Consensus Classification (ICC) of mature lymphoid histiocytic and dendritic cell tumors. 920437 +Cancer; Cervical Cancer; Clinical Research; HIV/AIDS; HPV and/or Cervical Cancer Vaccines; Immunization; Infectious Diseases; Prevention; Sexually Transmitted Infections; Vaccine Related; Women's Health Adult;Africa South of the Sahara;Anogenital cancer;Antibodies;Anus;Biological Assay;Blood;Cancer Control;Cancer Intervention;Country;Development;Dose;Effectiveness;Enrollment;Etiology;Evaluation;Focus Groups;Future;Gardasil;Genotype;Goals;HIV;HIV Seronegativity;HIV Seropositivity;Health;High Risk Woman;Human;Human Papilloma Virus Vaccination;Immune;Immunity;Immunization Programs;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mass in breast;Natural History;Observational Study;Oral;Palpable;Participant;Population;Prevalence;Prevention;Questionnaires;Recording of previous events;Research;Research Project Grants;Risk Factors;Rwanda;Sexual Health;Specimen;Testing;Underserved Population;Vaccinated;Vaccination;Vaccines;Validation;Virus;Woman;Women's Group;cervicovaginal;cohort;low and middle-income countries;malignant mouth neoplasm;new technology;novel strategies;prevent;programs;prophylactic;risk prediction;screening;symptom science;unvaccinated;vaginal microbiome Global Cancer Health n/a NCI 10702969 1ZIACP101237-01 1 ZIA CP 101237 1 10687280 "CASTLE, PHILIP " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1033509 NCI My research program and group are focused on discovery development and evaluation/validation of new technologies for the prevention and control of cancer in underserved populations globally. Our current objectives are 1) to optimize screening and prophylactic HPV vaccination to prevent anogenital cancers especially in those living with HIV 2) developing novel strategies to oral cavity cancer; 3) risk prediction of and intervention for cancers of the upper aerodigestive track; 4) management of palpable breast masses in low- and middle-income countries; and 5) symptom science and etiology.This ZIA currently includes research for the research project below:HPV Natural History in HIV-positive and HIV-negative Women: The Long-Term Human Papillomavirus Vaccination (HPV) Effectiveness and Immunity in Rwandan Women Living with and without Human Immunodeficieny Virus (HIV) study is an observational study of women living with HIV (WLWH) and HIV-negative women who did and did not receive the HPV vaccine in Rwanda. Rwanda is a high-burden cervical cancer country where the prevalence of HIV is 3.7% among adult women. In 2011 Rwanda implemented a national HPV vaccination program with Gardasil. To answer questions about HPV effectiveness in WLWH 757 vaccinated WLWH 757 unvaccinated WLWH and 757 vaccinated HIV-negative women will be enrolled in the study. Participants will provide blood anal oral and cervicovaginal specimens and complete a questionnaire on sexual health and history. Cervicovaginal anal and oral specimens will be HPV genotyped using type-specific genotyping assays. Blood will be antibody tested to compare the immune resonse in WLWH and HIV-negative women and the impact of switching from 3 doses to 2 doses of Gardasil in 2015. Participants who test HPV positive at baseline will return in six months to assess type-specific HPV persistence. Risk factors for HPV persistence including vaginal microbiome will also be studied. A long-term goal of the study is to establish a cohort of WLWH in whom we can examine the long-term effectiveness of HPV vaccination in WLWH now and in the future. This research is significant as it will establish the population effectiveness of HPV vaccination in WLWH in sub-Saharan Africa the group of women at the highest risk of cervical cancer for which there is a dearth of evidence. 1033509 +Cancer; Genetics Alleles;Data;Disease susceptibility;Genetic Structures;Haplotypes;Libraries;Link;Linkage Disequilibrium;Measures;Multiomic Data;Online Systems;Pattern;Population;Population Group;Research Personnel;Susceptibility Gene;Variant;Visualization;design;flexibility;interest;open source;tool LDlink webtool for examining patterns of linkage disequilibrium in diverse popul n/a NCI 10702968 1ZIACP101236-02 1 ZIA CP 101236 2 78381935 "MACHIELA, MITCHELL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 168903 NCI Exploring linkage disequilibrium (LD) across ancestral populations is a powerful approach for investigating population-specific genetic structure as well as functionally mapping regions of disease susceptibility. LDlink is a suite of web-based applications designed to easily and efficiently interrogate linkage disequilibrium in population groups. LDlink consists of several modules for interactively exploring linkage disequilibrium including LDassoc LDexpress LDhap LDmatrix LDpair LDpop LDproxy LDtrait SNPchip and SNPclip. Modules are designed with an emphasis on ease of use query flexibility and interactive visualization of results. Haplotype tables and interactive plots generated by LDlink are tailored for investigators interested in mapping common and uncommon disease susceptibility loci with a focus on linking correlated alleles and highlighting potentially functional variants. 168903 +Cancer; Clinical Research; Emerging Infectious Diseases; HIV/AIDS; Infectious Diseases; Prevention Acquired Immunodeficiency Syndrome;Aging;Behavior;Chronic;Chronic Disease;Disease;Etiology;General Population;HIV;HIV Infections;Health Services Accessibility;Hepatitis B Virus;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immunosuppression;Incidence;Individual;Infection;Inflammation;Intervention;Malignant Neoplasms;Natural History;Oncogenic Viruses;Outcome;Persons;Role;Socioeconomic Status;Tobacco smoking behavior;Virus;antiretroviral therapy;cancer biomarkers;cancer diagnosis;cancer prevention;cancer therapy;immunosuppressed;improved;prevent;risk stratification;screening;treatment disparity Studies of HIV infection and its contribution to the natural history and outcome n/a NCI 10702967 1ZIACP101235-02 1 ZIA CP 101235 2 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1700139 NCI People living with HIV have an elevated incidence of cancer due to a complicated range of issues related to AIDS-related immunosuppression chronic inflammation infection with oncogenic viruses behavior factors including tobacco smoking and poor socioeconomic status. Examples of important cancer-causing viruses include human papillomavirus (HPV) Epstein-Barr virus Kaposi sarcoma-associated herpesvirus and hepatitis viruses B and C. Studies of these factors in people living with HIV can contribute to understanding their role in other immunosuppressed individuals and in the general population. Many of these factors also contribute to poor access to treatment and disparities in outcomes following a cancer diagnosis. As people with HIV infection live longer with better antiretroviral therapies they are aging which is contributing to an increase in the burden of chronic diseases including cancer. There is a major need to develop improved cancer prevention screening and treatment for people living with HIV. This project includes multiple studies of cancer in people living with HIV. 1700139 +Cancer; Cancer Genomics; Clinical Research; Genetics; Health Disparities; Human Genome; Minority Health; Prevention Cancer Etiology;Data;Environmental Epidemiology;Epidemiology;Genetic study;Genomics;Histologic;Malignant Neoplasms;Methods;Mission;Molecular Profiling;Research;Risk Factors;genetic epidemiology;genomic epidemiology;molecular pathology;tumor;tumor progression Studies of Genetic and Environmental Epidemiology n/a NCI 10702964 1ZIACP101231-05 1 ZIA CP 101231 5 15666293 "LANDI, MARIA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2916460 NCI The Integrative Tumor Epidemiology Branch (ITEB) employs molecular pathology somatic and germline genomics and epidemiology to identify environmental and germline risk factors for cancer.Research MissionThe mission of ITEB is to advance understanding of cancer etiology and progression through integrative analyses of environmental and germline risk factors with comprehensive data on histological and molecular profiling of tumors and their precursors including somatic genomic analyses. The branch also develops methods to support this cutting-edge research. 2916460 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Prevention Affect;Age;Bioinformatics;Biological;Biology;Cell Line;Chromosome Fragility;Clinical Research;Collaborations;Consult;Data;Data Pooling;Data Set;Disease;Disease susceptibility;Division of Cancer Epidemiology and Genetics;Elements;Epidemiologist;Epidemiology;Epigenetic Process;Etiology;Event;Family;Gene Mutation;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genetic study;Genome;Genomics;Genotype-Tissue Expression Project;Haplotypes;Health;Human Cloning;Human Genome;Individual;Inherited;Interdisciplinary Study;International;Investigation;Laboratories;Laboratory Research;Maintenance;Malignant Neoplasms;Methodological Studies;MicroRNAs;Modeling;Molecular;Molecular Epidemiology;Molecular Evolution;Mosaicism;Mutation;Normal tissue morphology;Outcome;Pathway interactions;Persons;Phenotype;Population Genetics;Population Study;Predictive Value;Predisposition;Regulatory Element;Research;Research Personnel;Resources;Risk;Risk Factors;Scientist;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Somatic Mutation;Susceptibility Gene;The Cancer Genome Atlas;Therapeutic Intervention;Time;Transcript;Tumor Tissue;Uniparental Disomy;Ursidae Family;Variant;cancer genomics;cancer heterogeneity;cancer risk;cancer subtypes;cohort;deep sequencing;design;epidemiology study;follow-up;gene environment interaction;genetic analysis;genetic architecture;genetic epidemiology;genetic variant;genome wide association study;genome-wide;high risk;insight;interdisciplinary approach;large scale data;methylation pattern;novel;public database;tumor;validation studies Laboratory of Genetic Susceptibility n/a NCI 10702960 1ZIACP010227-08 1 ZIA CP 10227 8 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 743760 NCI The Laboratory of Genomic Susceptibility (LGS) in the Division of Cancer Epidemiology and Genetics (DCEG) is committed to understanding the biological basis for genetic susceptibility to cancer including identification and characterization of cancer susceptibility alleles characterization of the scope of genetic mosaicism and its contribution to cancer risk investigation of the genetic architecture of cancer susceptibility and determination of how germline variation informs our understanding of somatic alterations in cancer. LGS scientists participate in genetic epidemiologic clinical and methodological studies of populations families and persons at risk for cancer. In addition they collaborate and consult with experts in statistical genetics bioinformatics genetic epidemiology and molecular epidemiology in interdisciplinary studies. Using large-scale genome-wide association studies familial linkage studies in high-risk families and publically available databases such as TCGA TARGET ENCODE and GTEx investigators continue to identify loci within the human genome that are associated with cancer risk. The laboratory is at the forefront of applications in bioinformatics and advanced genetic analyses with new platforms designed to evaluate the biological effects of dense sets of single nucleotide polymorphisms (SNPs) which are the most common genetic variants in the human genome. Specifically the laboratory has integrated approaches to identify and validate common SNPs and ancestral haplotypes which could be used to dissect the genetic basis of disease susceptibility. Together with NCIs Cancer Genomics Research Laboratory LGS carries out genome-wide association studies (GWAS). Using data from large-scale GWAS that evaluate millions of SNPs investigators at the LGS are able to identify in great detail new regions in the human genome that are associated with cancer risk and to estimate the magnitude of effect of these risks. GWAS have been instrumental in the discovery of new regions of the genome which influence the basic etiological risk factors. In addition these novel findings may at a later time also bear important predictive value for disease particularly in developing a polygenic model as well as highlight potential molecular pathways related to both disease etiology and perhaps therapeutic intervention. To understand the biology underlying these associations investigators are following up with focused validation studies deep-sequencing and functional analyses such as analyses of expression levels and methylation patterns. This research relies on multidisciplinary approaches from population genetics epidemiology and molecular evolution. Investigation of GWAS signals requires extensive bioinformatic follow-up to examine unannotated transcripts regulatory elements as well as functional elements for novel transcripts. Regulatory effects are queried with respect to the alteration of gene levels epigenetics and long-ranging effects on other genes at a distance using cell lines normal tissue and tumor tissue as well as resources from the TCGA and ICGC. The LGS is also investigating several possible biologic mechanisms including whether variations in these identified regions may affect regulatory elements of neighboring genes the impact of miRNA polymorphisms acting upon fragile chromosomal sites and epigenetic effects across multi-susceptibility regions. We have developed a series of collaborations with leading epidemiologists and biostatisticians in the Division of Cancer Epidemiology and Genetics (DCEG) the NCI Cohort Consortium and multiple other international molecular epidemiologic consortia. Data pooling is being used to achieve the statistical power necessary to detect associations between genomic variants and a variety of health outcomes as well as gene-environment interactions. An interesting outcome from GWAS studies at LGS has been the identification of a sizeable fraction of apparently healthy individuals that harbor large scale (2MB) mosaic events detected as copy number changes or copy-neutral uniparental disomies. Investigating human clonal mosaicism has the potential to offer new insights into genomic maintenance as individuals age as well as explain a portion of the phenotypic heterogeneity of cancer subtypes. With the accumulation of cancer susceptibility regions from GWAS and large new datasets of tumor sequencing data it is now possible to investigate the interplay between inherited germline genetics and acquired somatic mutations. The expertise of LGS staff and collaborations with DCEG experts enables for novel investigation of how germline genetics combined with somatically acquired mutations may affect susceptibility to cancer. 743760 +Cancer; Digestive Diseases; Prevention; Rare Diseases Barrett Esophagus;Biological Markers;Biopsy;Biopsy Specimen;Blood;Blood specimen;Clinic;DNA Sequence Alteration;Data;Data Analyses;Disease;Dysplasia;Early Diagnosis;Endoscopes;Endoscopy;Esophagus;Gastroesophageal reflux disease;Genetic Polymorphism;Genetic Transcription;Germ Lines;Goals;Hormones;Laboratories;Medical center;Patients;Pattern;Periodicity;Pharmaceutical Preparations;Pilot Projects;Proteomics;Questionnaires;Registries;Risk Factors;Sampling;Serum;Study of serum;Testing;Time;Tissue Sample;Tissues;base;blood-based biomarker;comparison group;follow-up;genotyped patients;patient registry;screening;stomach cardia;tissue archive;tissue biomarkers Barrett's esophagus early detection project n/a NCI 10702959 1ZIACP010225-11 1 ZIA CP 10225 11 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 74683 NCI The goal of this project is to identify a practical blood-based biomarker(s) that can be used as a screening test to determine who has Barrett's esophagus (BE) and who does not. Secondary goals of the project are to characterize germ line and tissue biomarkers associated with BE and compare biomarkers in non-BE patients with and without GERD. Tertiary goals are to explore associations between biomarkers in blood or tissue and progression from BE to dysplasia or EAC and to assess the stability of proteomic patterns over time. This study will be conducted among patients in the Barrett's Esophagus Registry (currently with 206 registrants) established at the National Naval Medical Center (NNMC) in Bethesda beginning in 1992 as well as a comparison group of approximately 600 matched non-BE patients endoscoped in the GI clinic at NNMC for other conditions. Blood and tissue samples will be collected as well as questionnaire data on risk factors and medications as well as GERD. Data analyses will be based primarily on laboratory testing of newly collected esophageal biopsies brush samples and blood samples but secondarily will also include use of archival tissue biopsy samples. Follow-up of BE Registry patients will include standard periodic surveillance endoscopies additional blood samples and ascertainment of disease status (i.e. progression). To distinguish BE versus non-BE patients we will: (i) assess predictability of BE status from serum proteomic patterns; (ii) characterize esophageal biopsies and brush samples for selected DNA alterations RNA expression and proteomic profiles; (iii) genotype patients for selected polymorphisms potentially associated with BE; (iv) compare blood and tissue biomarkers in non-BE patients with and without GERD; (v) explore the association of biomarkers with progression from BE to dysplasia or EAC; and (vi) assess proteomic pattern stability over time in BE patients. Recent studies in this project have (i) profiled and compared tissue RNA expression differences among BE cardia and normal squamous tissues in BE cases; (ii) compared serum hormones in BE cases versus noncases; and (ii) conducted a pilot study of serum proteomics in BE cases and noncases. 74683 +Cancer; Cancer Genomics; Digestive Diseases; Esophageal Cancer; Genetics; Human Genome; Prevention; Rare Diseases; Stomach Cancer Area;Biological Specimen Banks;Blood;Blood specimen;Cancer-Predisposing Gene;Case/Control Studies;Cells;County;DNA;Disease;Etiology;Family;Family Study;Fingers;Genetic;Genetic Markers;Genetic Polymorphism;Genome Scan;Goals;Hot Spot;Individual;Lesion by Morphology;Malignant Neoplasms;Malignant neoplasm of esophagus;Microsatellite Repeats;Molecular;Morphology;Normal Range;Population;Risk;Role;Sampling;Specimen;Testing;Venous;cancer biomarkers;cancer genetics;candidate marker;density;esophageal cancer prevention;exome sequencing;gene environment interaction;genome wide association study;genomic biomarker;high risk;malignant stomach neoplasm;microbiome research;premalignant;stomach cardia;tumor Esophageal cancer genetic project n/a NCI 10702958 1ZIACP010224-11 1 ZIA CP 10224 11 2062427 "GOLDSTEIN, ALISA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 480168 NCI The overall goal of this project is to understand the role of genetics in the etiology and prevention of esophageal cancer and gastric cancer. Five different but complementary approaches have been used to identify esophageal cancer susceptibility genes. First a tumor/nontumor study has been conducted in which a biological specimen bank consisting of samples (tumor nontumor venous blood finger stick blood and buccal cells) from several hundred cases of esophageal cancer and gastric cancer (both cardia and body) was developed in Taiyuan for the identification of esophageal cancer and gastric cancer susceptibility genes and potential early genetic markers of these cancers. High-density genome-wide scans with microsatellite markers have been conducted to identify potential hot spots and further testing of these hot spots and other candidate markers in additional tumor/nontumor samples is in progress. Premalignant morphologic lesions will also be examined. Second blood samples for DNA have been collected from several hundred healthy individuals from high-risk (Yangcheng County) and low-risk (Beijing) areas to examine potential population differences in polymorphisms for selected genomic markers. Third a large case-control study with cases of esophageal cancer and gastric cancer (both cardia and body) has been conducted and is being used to evaluate polymorphisms in the candidate markers identified in other components of this project and to evaluate gene-environment interactions. Fourth a family study is in progress which will permit linkage of candidate markers with cancer in families having 2 or more cases with esophageal cancer or gastric cancer. Finally an endoscopic study is being conducted to obtain specimens from a morphologic spectrum of disease ranging from normal to early invasive esophageal cancer in order to characterize molecular progression. Recent studies have emphasized UGI cancer GWAS and post-GWAS analyses exome sequencing of subjects in the family study profiling of UGI cancer tumors and studies of the microbiome of UGI cancers. 480168 +Biomedical Imaging; Brain Cancer; Brain Disorders; Cancer; Childhood Leukemia; Health Disparities; Hematology; Minority Health; Neurosciences; Patient Safety; Pediatric; Pediatric Cancer; Prevention; Radiation Oncology; Rare Diseases Adult;Age;BRAF gene;Benefits and Risks;Benign;Brain;Brain Neoplasms;Child;Childhood;Childhood Leukemia;Cohort Studies;Data;Databases;Dose;Epidemiology;Etiology;Exposure to;Gender;Histopathology;Hospitals;Incidence;International;Intervention;Investigation;Ionizing radiation;KRAS2 gene;Life;Lymphoma;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of thyroid;Methods;Molecular;NRAS gene;Organ;Papillary Carcinoma;Patients;Physicians;Population Study;Procedures;Publications;Publishing;RAS genes;Radiation;Radiation Dose Unit;Radiation exposure;Radiation-Induced Cancer;Research Personnel;Risk;Roentgen Rays;Scientist;Statistical Models;Techniques;Technology;Time;Tissues;Tumor Tissue;United States;X-Ray Computed Tomography;base;cancer risk;case control;clinical diagnostics;cohort;computed tomography screening;improved;in utero;infancy;leukemia;molecular marker;radiation effect;radiation risk;response;thyroid neoplasm;tool Studies of Populations Exposed to Diagnostic Medical Radiation n/a NCI 10702957 1ZIACP010222-12 1 ZIA CP 10222 12 15187082 "BERRINGTON DE GONZALEZ, AMY " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 155579 NCI Computed Tomography Organ Dose Calculations - New tools and methods are being developed by using Monte Carlo transport technique to calculate organ dose for pediatric and adult patients undergoing computed tomography examinations. The organ dose estimates are being used for retrospective epidemiologic cohort and case-control studiesCancer Risks from CT Scan Use in the United States - We are estimating the potential radiation-related cancer risks that may be related to current levels of CT use in adults and also conducting radiation risk-benefit analyses for CT screening examinations.Early Life Radiation and the Risk of Child Cancer - Studying radiation exposure during early life is of particular importance given that many tissues are more susceptible to radiation effects in utero and at younger age of exposure. Results of our analysis published in February 2011 showed some indication of a slight non-significant increase in risk for all childhood cancer and leukemia with exposure to ionizing radiation in utero and potential increased risk of lymphoma following exposure to x-rays in early infancy based on small numbersPediatric CT Scans - REB initiated an international cohort study of 180000 children to evaluate the potential risk of cancer associated with radiation exposure from pediatric CT scans. A comprehensive organ CT dose database was developed in support of a study of pediatric cancer risk and CT exposure. The results from this study published in 2012 suggested for the first time that there are increased risks of leukemia and brain tumors after CT scans in childhood.Pooled Analysis of Radiation-Related Brain Tumors - Preliminary arrangements have been made to conduct a pooled analysis of the risk of radiation-related malignant and benign brain tumors including data from studies worldwide that have information on radiation dose to the brain for individualsMolecular and Histopathologic Clues to the Understanding of Thyroid Cancer Incidence - Thyroid cancer incidence has increased significantly over the last few decades. We are evaluating whether alterations in molecular markers and histopathology of papillary carcinoma have changed over the last three decades using thyroid tumor tissue collected from one US hospital. Molecular markers under investigation are BRAF N-RAS K-Ras H-Ras and RET/PTC.Pooled analysis of Radiation-Related Thyroid Cancer- To improve our understanding of the etiology of thyroid cancer REB scientists have set up an international consortium to study radiogenic thyroid cancer in children and adults. Statistical models of the radiation dose-response will be assessed as well as potential interaction with gender age at exposure attained age and time since exposure. Results for children were submitted for publication in 2012. 155579 +Cancer; Clinical Research; Digestive Diseases; Esophageal Cancer; Prevention; Rare Diseases Adenocarcinoma;Algorithms;Androgens;Barrett Epithelium;Barrett Esophagus;Case/Control Studies;Cells;Chemicals;Clinical;Cohort Studies;Costs and Benefits;Databases;Diagnosis;Disease;Endoscopy;Epithelial;Epithelial Cells;Equation;Esophageal Adenocarcinoma;Esophagitis;Esophagus;Estrogens;Etiology;Exposure to;Gastroenterology;Gastroesophageal reflux disease;General Population;General Practices;Goals;Hepatology;Hormones;Incidence;Individual;Journals;Laboratories;Lesion;Malignant Neoplasms;Malignant neoplasm of esophagus;Manuscripts;Medical History;Medicare;Metabolic syndrome;Metaplasia;Modality;Natural History;Patients;Population;Prognostic Marker;Publications;Publishing;Reflux;Research;Research Personnel;Resources;Risk;Risk Factors;Squamous Cell;Staging;Survival Rate;Testing;Tissues;Triage;United States;base;bile salts;billing data;cancer epidemiology;cancer risk;case control;clinical practice;cohort;comparative;data harmonization;diagnostic biomarker;diagnostic value;disease natural history;disorder control;follow-up;genotoxicity;high risk;indexing;inflammatory marker;mortality risk;prognostic Barrett's Esophagus n/a NCI 10702956 1ZIACP010220-12 1 ZIA CP 10220 12 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 23869 NCI This project covers a broad range of studies which focus on elucidating risk factors for and the natural history of esophageal adenocarcinoma (esophageal cancer) and the precursor lesion Barretts esophagus (aka Barrett esophagus). Barretts esophagus is a metaplastic change in the lower esophagus which is characterized by the replacement of the native squamous cell epithelium with a glandular-type of epithelium. This metaplastic change is thought to be primarily the result of genotoxic damage induced by gastroesophageal refluxacid and bile salts reflux up into the esophagus exposing cells not equipped to deal with these reactive chemicals. Re-epithelization with the metaplastic Barretts epithelium provides for a tissue which is better able to withstand the exposure to such compounds. However it also increases the risk of esophageal adenocarcinoma approximately 10-50 fold that of the general population. The incidence of esophageal adenocarcinoma has increased over 650% in the United States over the last 35 years and most individuals present with late stage malignancies resulting in a 5-year survival rate of less than 20%. This indicates that researchers need to be able to better identify those at high risk and Barretts esophagus is a good starting point. However although this metaplasia greatly increases the risk of esophageal adenocarcinoma relative to the general population the absolute risk remains low at around 0.5% or 1 in 200 patient years of follow-up. This is because approximately 90% of individuals who develop esophageal adenocarcinoma are diagnosed at their first (index) endoscopy. Thus not only do we need to be able to better identify those with high risk (Barretts esophagus) in the general population we also need to be able to triage these individuals into high and low risk groups so that surveillance resources can be focused on those who most need them which would make the cost-benefit equation of surveillance endoscopy more attractive. Therefore the ultimate goals of all the studies within this project seek to better understand the natural history of this disease risk factors for progression diagnostic markers and modalities with high sensitivity and prognostic biomarkers for efficient triaging of risk.The Barrett's Esophagus Consortium project (CAS ID:10593) is a pooling project that brings together and harmonizes data from eight case-control studies of Barrett's esophagus and fourteen case-control studies of esophageal adenocarcinoma. The consortium has published many articles details of which can be seen at http://beacon.tlvnet.net/ The Esophageal Cancer in SEER-Medicare project (CAS ID:10633) is assessing metabolic syndrome in relation to Barrett's esophagus (published in Journal of Clinical Gastroenterology) and esophageal adenocarcinoma (manuscript submitted) as well as the comparative utility of staging modalities in relation to survival following diagnosis of esophageal adenocarcinoma (published in Cancer). We are also assessing whether there is are demographic medical history and survival differences in esophageal adenocarcinoma by whether there was a prior diagnosis of the precursor condition Barrett's esophagus (submitted for publication). A new project will assess whether we can develop an algorithm to accurately identify diagnoses of esophageal adenocarcinoma using Medicare billing data alone.The CPRD EAC Progression Study has assessed whether metabolic syndrome is a risk factor for progression from Barretts esophagus to esophageal adenocarcinoma. This analysis is based in the Clinical Practice Research Datalink (CPRD) which was formerly called the General Practice Research Database (GPRD). The manuscript has been published in Cancer Epidemiology. In the Hormones in Barrett's Esophagus project (CAS ID:10638) we have assessed circulating androgens and estrogens in Barrett's esophagus patients compared with gastroeosphageal reflux disease controls in the BEEDS study based at the Walter Reed (published in Clinical Gastroenterology and Hepatology). We are currently assessing similar exposures in a second Barrett's esophagus population for external replication (manuscript being drafted) as well as expansion to esophageal cancer (adenocarcinoma) using three cohort studies.The Kaiser BE Cohort project has enabled us to assess cancer and mortality risks amongst a large Barretts esophagus cohort. These analyses will provide evidence that is directly applicable for a Barretts esophagus population undergoing surveillance. The manuscript has been submitted for publication.The inflammation markers and esophageal adenocarcinoma (CAS 10731) is beinging together esophageal adenocarcinoma cases and controls from seven cohorts. We are assessing a suite of circulating inflammation markers and testing whether these are associated with risk of developing esophageal adenocarcinoma. Laboratory analyses are currently being conducted. All of these projects are closely aligned to the aims of elucidating the etiology of Barrett's esophagus and esophageal adenocarcinoma as well as providing potential utility for diagnostics and prognostics. 23869 +Brain Cancer; Brain Disorders; Cancer; Childhood Obesity; Clinical Research; Congenital Structural Anomalies; Dietary Supplements; Nutrition; Obesity; Pediatric; Pediatric Cancer; Prevention; Radiation Oncology; Rare Diseases; Women's Health Asthma;Back;Body mass index;Cancer Patient;Child;Childhood Leukemia;Chinese;Chronic;Country;County;Data;Data Set;Disease;Enrollment;Environmental Exposure;Etiology;European;Evaluation;Family;Folic Acid;Gallbladder;Genetic;Hospitals;Incidence;Individual;Interview;Life Style;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of thyroid;Mission;Mothers;Neural Tube Defects;Obesity;Persons;Pilot Projects;Play;Population Programs;Prospective Studies;Province;Publications;Publishing;Radiation Tolerance;Research;Risk;Risk Factors;Role;Sampling;Site;Thyroid Gland;Work;cancer subtypes;case control;cohort;community intervention;effectiveness evaluation;epidemiology study;feasibility testing;folic acid supplementation;intervention program;mortality;offspring;rare cancer;tumor;waist circumference Studies of other risk factors for radiosensitive tumors n/a NCI 10702955 1ZIACP010219-12 1 ZIA CP 10219 12 14721304 "KITAHARA, CARI " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 257024 NCI Thyroid cancer incidence rates have been increasing for the last 3 decades in the US and the reasons for this are largely unknown. We have been studying potential risk factors for the disease in a pooled analysis of 5 NCI prospective studies. This pooling project provided some of the strongest evidence to date that obesity may be a risk factor for thyroid cancer and the rising obesity rates could therefore be part of the explanation for the rise in thyroid cancer incidence rates. We are now expanding this pooling project to include data from 15 European and US cohorts to examine the relationship in more detail including the risk associated with central adiposity and the relationship between obesity and rarer thyroid cancer subtypes.NCI Cohort Consortium BMI Pooling Project - We built a rich dataset of lifestyle risk factor and mortality data from 20 prospective studies and over 1.5 million people to study the relationship between BMI and all cause mortality. The results from this detailed analysis published in 2010 suggested that optimal BMI was in the range 20-25. We are currently exploring the association between waist circumference and all cause mortality and expanding the pooling project to look at cancer incidence for rare cancers including thyroid and gallbladder. These cancers are typically difficult to study in individual cohorts because the numbers of cases is limited.Childhood Cancer In Chinese Children and Family Cohorts -We are conducting two pilot studies to test the feasibility of (1) follow and participation in interviews of a sample of 500 families from two county sites where the Community Intervention Program (CIP) was carried out in the mid-1990s and (2) identification of incident pediatric cancers arising among thoseborn during 1994-96 in hospitals serving the CIP population and ability to link these pediatric cancer patients back to the CIP population. The CIP community intervention program trial which was carried out during 1994-96 in three large counties northeast and south of Beijing evaluated the effectiveness of periconceptional folic acid supplements in reducing neural tube defects. There were dramaticreductions in neural tube defects among offspring of mothers who took folic acid supplements during thepericonceptional period. Publications from case-control epidemiologic studies in the past 10 years from Western countries have shown that periconceptional folic acid supplements may reduce risks of pediatric leukemia and potentially other pediatric cancers in offspring of mothers who take these supplements. Otherstudies have shown statistical associations with periconception folic acid and other serious chronic diseasesof offspring including asthma. The pilot studies will attempt to trace enroll and interview 500 families fromTaicang Jiangsu Province and Laoting Hebei Province and will seek to identify all pediatric cancers diagnosedduring 1994 to the present among children born during 1994-96 and link these children back to the CIP cohort. 257024 +Cancer; Clinical Research; Digestive Diseases; Digestive Diseases - (Gallbladder); Emerging Infectious Diseases; Health Disparities; Infectious Diseases; Liver Cancer; Liver Disease; Minority Health; Rare Diseases Bile fluid;Biliary Tract Cancer;Biochemical;Biological;Cancer Patient;Chile;Cholelithiasis;Collection;Complement;DNA;Diet;Enrollment;Epidemiology;Etiology;Evaluation;Gender;Goals;Heavy Metals;Location;Malignant Neoplasms;Malignant neoplasm of gallbladder;Medical History;Molecular;Patients;Pilot Projects;Population;Questionnaires;Reproductive History;Risk Factors;Salmonella typhi;Sampling;Serum;Smoking;Structure;Tissue Sample;Validation;drinking;high risk;insight;multidisciplinary Etiology of Biliary Tract Cancer n/a NCI 10702954 1ZIACP010218-12 1 ZIA CP 10218 12 11613123 "KOSHIOL, JILL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2809823 NCI This project includes two studies: 1) the Shanghai Biliary Tract Cancer Study 2)the Chile Gallbladder Cancer Study. These studies complement each other and will provide unique insight into the etiology of biliary tract cancer. The Shanghai Study includes more than 3000 subjects including over 600 biliary tract cancer patients 900 gallstone patients and 1000 healthy controls randomly selected from the population. A structured questionnaire was used to elicit information on epidemiologic risk factors including smoking drinking diet medical history and reproductive factors. The study had a strong biochemical and molecular component with an extensive collection of biological samples including serum DNA gallstones bile and tissue samples. The Chile Gallbladder Cancer Study includes a pilot study of 120 subjects. The full-scale study will include 4000 cases of gallbladder cancer and 4000 controls enrolled from 12 locations in Chile which has the highest risk of gallbladder cancer in the world. Similar to the Shanghai Study the Chile Study will incorporate extensive biospecimen collection. It will complement the Shanghai Study by allowing replication and validation of previous findings as well as evaluation of unique exposure (i.e. salmonella typhi and heavy metals). 2809823 +Biotechnology; Cancer; Cervical Cancer; Clinical Research; Clinical Trials and Supportive Activities; HPV and/or Cervical Cancer Vaccines; Health Disparities; Immunization; Infectious Diseases; Minority Health; Orphan Drug; Prevention; Rare Diseases; Sexually Transmitted Infections; Vaccine Related; Women's Health Acquired Immunodeficiency Syndrome;Age;Antibodies;Antibody Avidity;Anus;Blinded;Cervical;Cervix Neoplasms;Cervix Uteri;Clinical;Collaborations;Communities;Costa Rica;Cytology;DNA;Dose;Effectiveness;Enrollment;Evaluation;Frequencies;Funding;HIV Infections;HIV Seropositivity;Head and Neck Cancer;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Human papillomavirus 18;Immune response;Immunologics;Infection;Lesion;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Measures;Medical;Methodology;Molecular Conformation;Natural History;Oncogenic;Participant;Phase;Phylogenetic Analysis;Population;Population Group;Preventative vaccination;Public Health;Randomized;Randomized Controlled Trials;Research;Resource-limited setting;Safety;Series;Site;Structural Protein;System;United States National Institutes of Health;Vaccinated;Vaccination;Vaccinee;Vaccines;Viral;Virus-like particle;Woman;Women's Health;Work;base;dosage;efficacy evaluation;follow-up;high risk;immunogenic;immunogenicity;infection rate;men who have sex with men;premalignant;prevent;screening program;unvaccinated;vaccine formulation;vaccine trial;virtual HPV Vaccine Trial n/a NCI 10702953 1ZIACP010217-12 1 ZIA CP 10217 12 10687321 "KREIMER, AIMEE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 9094976 NCI Infections with oncogenic types of HPV cause virtually all cases of cervical cancer worldwide and subsets of various other anogenital and head and neck cancers. Prophylactic vaccination against HPV-16 and HPV-18 two of the most important HPV types could protect against a large majority of the cases of cervical cancer globally and a considerable proportion of other HPV-associated cancers. Vaccines based on the L1 structural protein of HPV that self-assemble into conformationally-correct VLPs have been shown to be generally safe immunogenic and effective at preventing precancerous lesions of the cervix associated with HPV-16/18. A community-based phase 3 randomized controlled trial of an HPV16/18 VLP vaccine was conducted in Costa Rica. Costa Rica was chosen for the trial because of our extensive successful scientific collaborations there the high risk of cervical cancer the universal medical system providing national linkage and the likelihood of very high participation over the many needed years of close clinical follow-up. Randomization and 3-dose vaccination of 7466 women enrolled into the HPV-16/18 Vaccine Trial in Costa Rica has been successfully completed. Women have been followed actively on an annual or semi-annual basis in the first four years of follow-up and every two years thereafter. Women have completed their first four years of follow-up in the blinded phase of the trial and have been enrolled in the extended (up to 10 years) follow-up phase of the study. Cross-over vaccination was offered to trial participants at the end of the four-year blinded phase of the trial. Results from this study have shown that 1) the vaccine is highly effective at preventing new infections with HPV types 16 or 18 2) the vaccine confers partial protection against HPV types phylogenetically related to HPV 16 or 18 3) the vaccine does not help treat existing infections 4) fewer than 3 doses of the vaccine protects as well as the full 3-dose series for at least 4 years 5) the vaccine protects against HPV infection at the anus 6) Vaccine impact declines with increasing age at vaccination 7) vaccination induces cross-neutralizing potential in sera of vaccinated individuals 8) modest levels of antibodies generated by natural HPV infection provide partial protection against re-infection and 9) antibody levels generated in vaccines from regions with high HIV infection rates are comparable to those observed among participants in our trial in Costa Rica. In support of the vaccine trials a variety of methodologic and ancillary projects are underway or planned that will maximize the yield of the main effort. This includes evaluation of immunological correlates of protection including viral neutralization total type-specific antibodies and measures of antibody avidity. Immunological correlates of protection among naturally infected women are being examined and studies are underway to better understand why vaccinated women might be protected against HPV types not included in the vaccine formulation and why a single vaccine dose (prime-only) appears to protect for several years. Several analyses are underway or planned to evaluate the natural history of HPV infection at cervical and other sites and of cervical neoplasia in vaccinated and unvaccinated women. This effort is sponsored by Intramural NCI funds and by the NIH Office of Research on Women's Health (ORWH). It was formerly associated with Project Z01 CP010177. 9094976 +Cancer; Clinical Research; Dental/Oral and Craniofacial Disease; Digestive Diseases; Infectious Diseases; Rare Diseases; Sexually Transmitted Infections Cross-Sectional Studies;Etiology;Goals;Head and Neck Cancer;Human Papillomavirus;Human papilloma virus infection;Incidence;India;International;Lesion;National Health and Nutrition Examination Survey;Natural History;Population;Prevalence Study;Research Project Grants;cancer site;malignant oropharynx neoplasm;molecular marker;oral HPV infection;screening;trend Studies of Head and Neck Cancers n/a NCI 10702951 1ZIACP010213-13 1 ZIA CP 10213 13 10687326 "CHATURVEDI, ANIL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1365665 NCI Research projects in the past year have focused on evaluating incidence trends for HPV-related and HPV-unrelated head and neck cancer sites internationally; investigating historical trends in the proportion of oropharynx cancers attributable to HPV infection in the US; characterizing the proportion of oropharynx cancers attributable to HPV infection in India a region with very high incidence of head and neck cancers; and studying the prevalence and predictors of oral HPV infection within the U.S. NHANES a representative cross-sectional survey of the U.S. civilian population. 1365665 +Cancer; Clinical Research; Dental/Oral and Craniofacial Disease; Genetics; Prevention Affect;Antibodies;Antibody Specificity;Behavioral;CYP2E1 gene;Case/Control Studies;Caucasians;Childhood;China;Chinese;Chromosome 14;Clinical;Clinical Markers;DNA Repair;DNA Repair Gene;Development;Dust;Environmental Risk Factor;Enzymes;Etiology;Evaluation;Exposure to;Family;Family Study;Formaldehyde;GEM gene;Gene Expression;General Population;Genes;Genetic;Geography;Human Herpesvirus 4;Immune;Individual;Infection;Intake;Integration Host Factors;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Nasopharyngeal Neoplasms;Nitrites;Nitrosamine Metabolism;Nitrosamines;Normal Cell;Occupational;Occupational Exposure;Pathogenesis;Pattern;Population;Risk;Risk Factors;Serology;Taiwan;Testing;Tissues;Variant;Viral;Weaning;Wood material;base;cancer risk;cigarette smoking;dietary;follow-up;high risk;neoplastic cell Viral and Host Factors Associated with NPC n/a NCI 10702949 1ZIACP010211-13 1 ZIA CP 10211 13 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 550379 NCI Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer other factors both genetic and exogenous are also thought to be important. To investigate genetic dietary occupational and behavioral factors related to the etiology of NPC several studies were conducted in including a case-control study of approximately 1000 individuals and a multiplex family study of approximately 3000 individuals (350 families) in Taiwan. To date our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes specific patterns of HLA and KIR genes and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk; in contrast formaldehyde exposure was not a significant risk factor. Exogenous risk factors identified within our family study were similar to those observed from our case-control study. Evaluation of gene expression profiles from nasopharynx tumor and normal cells suggest that genes involved in DNA repair and in the metabolism of nitrosamines are involved in NPC pathogenesis. Results from our tissue-based expression studies also suggest the possibility of loss-of-heterozygosity on the telomeric end of chromosome 14 in NPC and that EBV gene expression within NPC tumor cells affect the expression of host genes involved in immune presentation. This suggests a possible mechanism by which EBV manages to evade immune surrveillance in NPC. Uaffected individuals from NPC multiplex families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To follow-up on this finding we have evaluated the value of EBV serology to predict subsequent NPC risk among unaffected individuals from NPC multiplex families. We observed that individual with elevated antibody levels against several EBV markers are at a 4 to 6-fold increased risk of developing NPC within 10 years but the low specificity of the antibodies evaluated suggest that improvements are required before such serology-based tests can be used clinically. 550379 +Cancer; Cervical Cancer; Clinical Research; Genetics; Health Disparities; Immunization; Infectious Diseases; Minority Health; Prevention; Sexually Transmitted Infections; Vaccine Related; Women's Health Adenocarcinoma Cell;Affect;Antibodies;Case/Control Studies;Cervical;Cervical Adenocarcinoma;Cervix Neoplasms;Cohort Studies;Contraceptive Usage;DNA;Development;Etiology;Evaluation;Funding;GEM gene;Genes;Genetic;Genetic Polymorphism;Goals;HIV;Head and Neck Cancer;Histologic;Histology;Hormonal;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immune;Immunity;Immunologic Factors;Individual;Infection;Knowledge;Lesion;Longitudinal Studies;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Menstrual cycle;Molecular Epidemiology;Mucosal Immunity;Natural History;Oral Contraceptives;Predisposition;Prevention;Prevention strategy;Risk Factors;Role;Sex Behavior;Squamous cell carcinoma;Taiwan;Testing;Vaccination;Variant;Viral;Virus Diseases;Woman;Work;cervical cancer prevention;epidemiology study;novel;response;screening HPV cervical neoplasia and vaccination n/a NCI 10702948 1ZIACP010210-13 1 ZIA CP 10210 13 10687321 "KREIMER, AIMEE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 125787 NCI HPV is known to be a necessary cause of cervical cancer and a subset of other anogenital and head and neck cancers including many cancers (e.g. cervical and anal cancers) that are elevated in the context of HIV. However while HPV infection is common development of cancer is rare. This suggests that in additional to HPV infection co-factors are important for the development of cervical cancer. This project aims to elucidate the role of HPV and co-factors in the etiology of cervical cancer and its precursors to define whether risk factors are similar or different for different histological forms of cervical cancer and to apply knowledge gained to novel prevention strategies. Several studies have been conducted to date to achieve our goals including a multicenter case-control study of cervical adenocarcinomas and squamous cell carcinomas in the US a longitudinal study of women with low-grade HPV-induced cervical lesions and a cohort study of HPV and cervical cancer in Taiwan. Results from these studies to date have shown that 1) while HPV infection is required for the development of all histological types of cervical cancer the distribution of HPV types/variants observed in cancers vary by histology 2) co-factors associated with distinct histological types of cervical cancer differ and while all histological forms of cervical cancer are associated with sexual behavior variables that predispose to HPV infection cervical adenocarcinomas appear to be preferentially associated with risk factors that indicate hormonal involvement 3) polymorphisms in immune-related genes (including HLA and KIR genes) are associated with the development of cervical cancer and 4) HPV DNA testing is a useful screening test for the prevention of cervical cancer. In addition we have conducted molecular epidemiology studies that have shown that 1) antibodies generated in response to natural infections protect against re-infection with HPV and 2) markers of mucosal immunity vary across the menstrual cycle and are affected by oral contraceptive use suggesting that studies of local immunity and its role in predisposition to HPV persistence and progression need to account for these changes. This effort is sponsored by Intramural NCI funds. 125787 +Cancer; Cervical Cancer; Clinical Research; Dental/Oral and Craniofacial Disease; Digestive Diseases; HPV and/or Cervical Cancer Vaccines; Immunization; Infectious Diseases; Prevention; Rare Diseases; Sexually Transmitted Infections; Vaccine Related; Women's Health Address;Anus;Biological;Cancer Etiology;Cervical;Cervix Uteri;Cutaneous;Cytology;Data;Diagnosis;Epidemiology;Evaluation;Genotype;Goals;HIV;HPV-16/18 Vaccine;Head and Neck Cancer;Head and Neck Neoplasms;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Individual;Infection;Infection prevention;Infectious Agent;Larynx;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Multiple Anatomic Sites;Natural History;Oral;Oropharyngeal;Population;Prevalence;Preventive vaccine;Recurrent Malignant Neoplasm;Research;Role;Site;Skin;Specimen;Testing;Vagina;Vulva;Work;carcinogenicity;cohort;conjunctiva;efficacy evaluation;immunosuppressed;infection risk;malignant mouth neoplasm;men;oral HPV infection;penis;prospective;sample collection;tumor;vaccine efficacy;vaccine trial HPV and cancer at multiple anatomic sites n/a NCI 10702947 1ZIACP010209-13 1 ZIA CP 10209 13 10687321 "KREIMER, AIMEE " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 526734 NCI Human papillomaviruses are one of the principal infectious agents known to cause cancers in humans; it is estimated that approximately 5% of cancers worldwide are attributable to HPV infection. HPV-associated cancers occur at particularly high rates among immunosuppressed individuals especially HIV-infected individuals. While it is well established that HPV is a necessary cause of cervical cancer world experts agree that for HPV16 the most carcinogenic of the HPV genotypes data show a causal role in cancers outside the cervix including the vulva vagina penis and anus and some head and neck tumors in the oropharynx. Other cancers hypothesized to be related to HPV infection but for which a causal association has yet to be shown include cancers of the oral cavity larynx conjunctiva and for cutaneous HPV types skin. To that end considerable research within the IIB focuses on the role of HPV infection in cancer at extra-cervical sites. We have many on-going studies whose aims are to: 1) evaluate the natural history of HPV infections at non-cervical sites 2) determine the prevalence and biologic activity of HPV infection in tumors from these sites 3) assess the prospective association between HPV infection and risk of extra-cervical prevalent incident and recurrent cancers 4) evaluate the efficacy of the HPV16/18 prophylactic vaccine against extra-cervical infection 526734 +Aging; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Lung; Lung Cancer; Ovarian Cancer; Prevention; Prostate Cancer; Rare Diseases; Urologic Diseases; Women's Health Benign Prostatic Hypertrophy;Biochemical;Blood;Cells;Cessation of life;Collaborations;Colonic Polyps;Colorectal Cancer;Computers;Contracts;Data Collection;Data Set;Development;Disease;Division of Cancer Epidemiology and Genetics;Division of Cancer Prevention;Extramural Activities;Follow-Up Studies;Genetic;Individual;Investigation;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Medical Records;NCI Executive Committee;Participant;Pathologic;Population;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Questionnaires;Randomized;Records;Research Personnel;Risk;Risk Factors;Saliva;Sampling Studies;Scientist;Screening for Prostate Cancer;Study Subject;Support Contracts;Test Result;Tissues;Update;Woman;aged;base;clinical center;cohort;effectiveness evaluation;follow-up;indexing;men;neoplasm registry;screening;usual care arm;volunteer PLCO EEMS and Extended Follow Up n/a NCI 10702946 1ZIACP010207-13 1 ZIA CP 10207 13 11613071 "FREEDMAN, NEAL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 407995 NCI 10513 - To oversee the field support and computer support contracts responsible for annual follow-up of study subjects from the PLCO trial and construct analyzable data sets for use by investigators throughout the division. The Division of Cancer Prevention (DCP formerly DCPC) under extramural contracts to 10 U.S. clinical centers is evaluating the effectiveness of screening for prostate lung colorectal and ovarian cancer (The PLCO Trial). In 1996 the NCI Executive Committee approved the expansion of the PLCO Trial to collect additional materials and to conduct additional studies. About 74000 men and 74000 women aged 55-74 years have been randomized on a 50/50 basis into screening or usual care arms. Additional blood is collected from screened subjects and saliva for buccal cells from control subjects. Pathologic tissues are obtained for selected cases that develop cancer or selected related diseases (e.g. colon polyps benign prostatic hyperplasia). Additional questionnaire-based risk and disease-related information is also collected with confirmation of disease status from medical records. Genetic biochemical and questionnaire-based risk information will be related to the development of cancer and other diseases in this population. Volunteers who provide samples for these studies will not routinely receive their individual results from the Additional Investigation. Subjects requesting such information however will be provided their test results. In 2009 the NCI Executive Committee approved the Extended Follow-up of subjects beyond the original 13-year follow-up period. Participants will be reconsented for the release of records to a single NCI-Designated Central Data Collection Center (CDCC) which will administer the annual mailings containing the annual study update questionnaire and a brief (1-2 page) risk factor questionnaire. Individuals who do not consent to release their identifiers to the CDCC will be followed up passively through linkage to state cancer registries and the National Death Index. l Death Index. 407995 +Cancer; Clinical Research; Nutrition; Obesity; Physical Activity; Prevention Binding Proteins;Biological;Biological Markers;Body Weight decreased;Cancer and Nutrition;Colorectal Cancer;Energy Intake;Estrogens;Etiology;Goals;Growth Factor;Incidence;Inflammatory;Insulin-Like Growth Factor Binding Protein 3;Insulin-Like Growth Factor I;Interleukin-6;Malignant Neoplasms;Malignant neoplasm of pancreas;Obesity;Output;Phenotype;Physical activity;SHBG gene;TNF gene;Testosterone;Weight Gain;cancer prevention;cancer risk;cytokine;energy balance;improved;malignant breast neoplasm;metabolomics;multidisciplinary;novel;sedentary lifestyle;steroid hormone Physical Activity Energy Balance and Cancer n/a NCI 10702940 1ZIACP010197-16 1 ZIA CP 10197 16 9414784 "ALBANES, DEMETRIUS " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1136383 NCI The goals will be achieved by a) evaluating obesity energy balance and physcial activity in relation to cancer incidence and survival; b) Improving assessment of energy intake output and body phenotype; c) Evaluating biomarkers to determine mechanisms including inflammatory cytokines (CRP IL-6 TNF-alpha) growth factors and their major binding proteins (IGF-1 and IGFBP-3) steroid hormones (testosterone estrogen SHBG) in relation to cancer and intermediate outs comes such as weight loss and weight gain d) evaluate novel such as metabolomics in assessing obesity energy balance and physical activity and body phenotype and in relation to cancer risk. Although this project is for all cancer its particular cancer includes breast colorectal and pancreatic cancer. 1136383 +Cancer; Cancer Genomics; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Genetics; Health Disparities; Human Genome; Lung; Lung Cancer; Minority Health; Nutrition; Prevention; Prostate Cancer; Rare Diseases; Tobacco; Tobacco Smoke and Health; Urologic Diseases Age;All-Trans-Retinol;Antioxidants;Area;Beta Carotene;Biochemical;Biochemical Genetics;Biological;Biological Markers;Bladder;Bronchi;Cancer Etiology;Cancer Intervention;Carbon;Carotene;Carotenoids;Categories;Caucasians;Cessation of life;Chest;Cigarette;Cohort Analysis;Collaborations;Colon;Colorectal;Colorectal Cancer;Data;Diagnosis;Diet;Dietary Questionnaires;Dimensions;Disease;Epidemiology;Erythrocytes;Evaluation;Extramural Activities;Film;Finland;Folic Acid;Follow-Up Studies;Food;Freezing;Genetic;Genetic Polymorphism;Genome Scan;Genotype;Glioma;Goals;Gonadal Steroid Hormones;Growth Factor;Habits;Head and neck structure;Health;High Density Lipoprotein Cholesterol;Human;Human Resources;Institutes;Insulin;International;Intervention;Investigation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measurement;Medical;Medical Records;Metabolic;Metabolism;Molecular;National Cancer Institute;Nested Case-Control Study;Nutrient;Nutritional;Occupational;Pancreas;Participant;Pathology;Phase;Phenotype;Placebos;Pleura;Population Registers;Procedures;Prospective Studies;Prostate;Public Health;Randomized;Randomized Controlled Trials;Rectum;Renal carcinoma;Research;Research Personnel;Research Project Grants;Resources;Risk;Sampling;Selenium;Serum;Slide;Smoker;Smoking;Specialized Center;Specimen;Structure of nail of toe;Supplementation;Surveys;Testing;Thoracic Radiography;Trachea;Visit;Vitamin D;Vitamin E;Vitamin E Acetate;Vitamins;Whole Blood;alpha Tocopherol;base;cancer prevention;capsule;case control;cohort;design;diet and cancer;dietary;effectiveness testing;energy balance;epidemiology study;follow-up;genetic analysis;genetic variant;genome wide association study;group intervention;interest;intervention effect;male;malignant breast neoplasm;malignant stomach neoplasm;men;metabolomics;neoplasm registry;nutrition;population based;post intervention;prevent;prostate cancer risk;recruit;side effect;web site Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study n/a NCI 10702938 1ZIACP010195-16 1 ZIA CP 10195 16 9414784 "ALBANES, DEMETRIUS " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 712278 NCI The ATBC Cohort Follow-up Study has been in place since 1994. Male smokers between the ages of 50 and 69 were recruited from southwestern Finland between April 1985 and June 1988. A total of 29133 men were randomly assigned to one of four intervention groups: 50 mg/day alpha-tocopherol (as dl-alpha-tocopheryl acetate); 20 mg/day beta-carotene; both alpha-tocopherol and beta-carotene; or placebo. They were followed for five to eight years during the trial until death or 30 April 1993 when intervention was stopped (median follow-up 6.1 years). Follow-up for endpoints was continued postintervention. Following invitation for participation and recruitment through a population-based postal survey the trial randomly assigned 29133 Caucasian 50-69 year old male smokers of 5 cigarettes daily to one of four intervention groups based on a 2x2 factorial design: beta-carotene (20 mg/day) vitamin E (50 mg/day as dl-alpha-tocopheryl acetate) both agents or placebo. At entry medical dietary smoking and occupational data were obtained along with physical measurements a chest x-ray and serum and toenail samples. Diet was captured through a 276 food item dietary questionnaire that was developed and validated for the trial. Baseline serum was collected frozen and stored for all participants and vitamin E beta-carotene retinol and total and HDL cholesterol were determined. Follow-up serum and whole blood were collected for all active participants later in the study as were additional serum and red blood cell samples from selected subsets. Active intervention continued for 5-8 years with three study visits annually during which participants were asked about their health and possible subjective side effects capsule compliance and smoking habits since the last visit. Chest films were taken at 2-3 year intervals and at the end of the trial. All incident cancers were identified through the nationwide Finnish Cancer Registry medical records/pathology slides were reviewed / abstracted and deaths/underlying causes were identified through the National Population Register. The ATBC Cohort Follow-up Study has had the overall aim of conducting cancer etiologic research and post-intervention cancer surveillance based on the original trial cohort of 29133 men. Cohort analyses nested case-control investigations analyses of genetic polymorphisms and other molecular parameters and studies of the biological effects of the intervention agents on relevant biomarkers have been conducted and are the focus of ongoing research. Current cumulative totals of diagnosed cases through 2012 include approximately 3900 lung 2700 prostate 900 colorectal 800 bladder 400-500 each for stomach pancreas and kidney cancers and 450 head and neck. Cancer etiologic research in the ATBC Study has evolved naturally from the focus on supplementation into several areas of concentration that reflect both our research interests and the availability of study resources to a continually growing number of highly productive investigators both at NCI and elsewhere. A public website (http://atbcstudy.cancer.gov/) provides information regarding the project's research data personnel and resources including procedures for initiating collaborations. The high-quality study data biological specimens and ongoing endpoint ascertainment have been applied to testing biochemical and genetic hypotheses related to nutritional and other factors having potentially high attributable risks in prostate (based on 2500 cases) lung (3500 cases) colorectal (700 cases) pancreatic (400 cases) and other cancers. GWAS studies of risk for prostate lung renal and bladder cancers as well as NHL and glioma are completed. We have completed investigations of vitamins D E A and selenium status; carotenoids and other antioxidants; one-carbon metabolism; energy balance insulin and growth factors; sex steroids; and genetic variants impacting these exposures. GWAS studies of nutrition phenotypes such as serum vitamin D status are being conducted. Evaluation of these factors within the context of the controlled vitamin supplementation design has afforded us unique opportunities to investigate biological and biochemical interactions.Another important dimension of the ATBC Study has been collaborations with extramural researchers in cancer epidemiological consortia. These include: the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) PanScan the Pooling Project of Prospective Studies of Diet and Cancer and the Harvard Specialized Center on Folate One-Carbon Nutrients Gene Variants and Colorectal Cancer. We contribute scientific expertise data and cohort resources and intramural support to these powerful high-impact studies. 712278 +Breast Cancer; Cancer; Clinical Research; Health Disparities; Infectious Diseases; Lung; Lung Cancer; Minority Health; Prevention; Women's Health Breast Cancer Risk Assessment Tool;Breast Cancer Risk Factor;Calibration;California;Cause of Death;Cessation of life;Clinical Research;Cox Models;Data;Development;Disease;Electronic Health Record;Evaluation;Family Study;Genotype;Goals;Human Papillomavirus;Incidence;Latina;Left;Literature;Logistics;Lung CAT Scan;Malignant neoplasm of lung;Methods;Modeling;National Cancer Institute;New Mexico;Pap smear;Publishing;Registries;Relative Risks;Risk;Risk Estimate;Risk Factors;Single Nucleotide Polymorphism;Smoker;Statistical Methods;Statistical Models;Testing;Validation;Woman;base;cancer prevention;case control;cohort;data registry;disorder risk;improved;interest;lung cancer screening;malignant breast neoplasm;method development;personalized predictions;population based;risk prediction;risk stratification;screening Risk prediction methods n/a NCI 10702935 1ZIACP010188-18 1 ZIA CP 10188 18 8770483 "GAIL, MITCHELL H" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 367682 NCI "We continued to develop refine and evaluate the National Cancer Institutes Breast Cancer Risk Assessment Tool (BCRAT). Dr. Mateo Banegas a NCI Cancer Prevention Fellow developed a new model for absolute invasive breast cancer risk for Latina women. There is interest in determining whether adding information from single nucleotide polymorphisms (SNPs) can increase the discriminatory accuracy and usefulness for screening of risk models. We demonstrated improved risk stratification of breast cancer by adding SNPs to a variety of more standard risk factors. Using data from 1.4 million women undergoing HPV testing and Pap smears in Kaiser Permanente Northern California (KPNC) we published on: (1) estimating absolute risks based on HPV genotyping tests; (2) calculating and comparing risk versus those in the New Mexico HPV/Pap Registry and (3) calculating risks among those with equivocal Pap smears. We developed and validated models for risk of lung cancer incidence and death and used them to project the impact of risk-based selection of smokers for CT lung-cancer screening in the US. We developed absolute risk models appropriate under left/interval/right-censoring data occurring for screen-detected disease which occurs for electronic health record data called the ""logistic-Weibull"" and the ""logistic-Cox"" models. We explained why a method sometimes used to assess absolute risk models in case-control data does not assess calibration but only fits of relative risk." 367682 +Aging; Biotechnology; Brain Cancer; Brain Disorders; Breast Cancer; Cancer; Cancer Genomics; Colo-Rectal Cancer; Digestive Diseases; Genetic Testing; Genetics; Human Genome; Lung; Lung Cancer; Ovarian Cancer; Prevention; Prostate Cancer; Rare Diseases; Urologic Diseases; Uterine Cancer; Women's Health Brain Neoplasms;Carcinogenesis Mechanism;Cessation of life;Colorectal Cancer;Early Diagnosis;Endometrial Carcinoma;Genes;Genetic Markers;Genetic Research;Genome Scan;Genomics;Goals;Human Genetics;Inherited;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Non-Hodgkin's Lymphoma;Predisposition;Prevention;Renal carcinoma;Research Personnel;Single Nucleotide Polymorphism;Susceptibility Gene;Technology;Variant;Work;breast cancer progression;cancer genetics;cancer risk;cancer therapy;gene environment interaction;genome annotation;human genome sequencing;insight;malignant breast neoplasm;meetings;new technology;novel strategies;tool Cancer Genetic Markers of Susceptibility n/a NCI 10702934 1ZIACP010187-18 1 ZIA CP 10187 18 9712952 "CHANOCK, STEPHEN J." Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 210831 NCI To help meet the Challenge Goal of eliminating suffering and death from cancer by 2015 the NCI must capitalize on the extraordinary momentum generated by advances in human genetic research. The sequencing of the human genome and the annotation of common variations together with new technologies for analyzing single nucleotide polymorphisms (SNPs) have provided the tools for investigators to actively search for inherited variants in genes that can increase or modify cancer risk. The C-GEMS proposal will use the latest genomic technologies to perform dense whole genome scans to identify and validate susceptibility genes in the induction and progression of breast and prostate cancer and clarify gene-gene and gene-environment interactions. This work will provide new insights into mechanisms of carcinogenesis and point the way to novel strategies for meeting the 2015 Challenge Goal by accelerating the prevention early detection and treatment of cancer.Prostate cancer lung cancer bladder cancer breast cancer colorectal cancer kidney cancer non-Hodgkin's lymphoma (NHL) ovarian cancer brain tumors and endometrial cancer are the main focus of current and planned replication studies. 210831 +Breast Cancer; Burden of Illness; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Health Disparities; Minority Health; Nutrition; Ovarian Cancer; Prevention; Rare Diseases; Stomach Cancer; Uterine Cancer; Women's Health Affect;Amoxicillin;Antibiotic Therapy;Ascorbic Acid;Biometry;Breast;Breast Cancer Detection;Cancer Control;Case/Control Studies;China;Cohort Studies;Collaborations;Collection;Consult;Control Groups;Data;Data Collection;Development;Division of Cancer Epidemiology and Genetics;Egypt;Endometrial Carcinoma;Enrollment;Epidemiology;Female;Follow-Up Studies;Garlic;Helicobacter pylori;Histopathology;Hospitals;Incidence;Inpatients;Intervention Trial;Lead;Lesion;Malignant neoplasm of nasopharynx;Malignant neoplasm of ovary;Measurement;Morocco;National Cancer Institute;Nebraska;Northern Africa;Omeprazole;Paper;Paraffin Embedding;Participant;Population;Procedures;Province;Publishing;Questionnaires;Randomized;Rural;Saliva;Selenium;Stomach;Subgroup;Supplementation;Time;Translations;Tumor Tissue;Tunisia;Universities;Woman;Work;cohort;digital;field study;follow-up;gastric cancer prevention;gastric carcinogenesis;inflammatory breast cancer;malignant breast neoplasm;malignant stomach neoplasm;member;mortality;premalignant;prevent Epidemiologic Field Studies n/a NCI 10702931 1ZIACP010182-20 1 ZIA CP 10182 20 8770483 "GAIL, MITCHELL H" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 733103 NCI BCDDP: Breast Cancer Detection Demonstration Project follow-up study (01030). This study follows about 60000 former participants in the Breast Cancer Demonstration Project (BCDDP). Current analyses include a variety of cohort consortium pooling projects. Gastric cancer: Randomized multi-intervention trial to inhibit precancerous gastric lesions in Linqu Shandong Province (00446). We gathered fifteen year follow-up data from an 8-year trial in rural China to determine whether any of three treatments would affect gastric cancer incidence or specific causes of mortality. The treatments were long-term vitamin (C E and selenium) supplementation and garlic supplementation given from 1995 to 2003 and one time administration of amoxicillin/omeprazole given in 1995. A paper published in 2012 showed that amoxicillin/omeprazole treatment reduced gastric cancer incidence by 39% over a fifteen year period. We examined subgroups and determined that antibiotic treatment was effective for older members of the population and for members with advanced precancerous gastric lesions at the beginning of the study despite the fact that Helicobacter pylori is thought to act on early stages of gastric carcinogenesis. Thus antibiotic treatment can be applied broadly to prevent gastric cancer and need not be restricted to the young or to those with mild histopathology. This work was published in 2014. Inflammatory breast cancer (IBC) case-control study (00314) This case-control study includes approximately 250 IBC cases accrued at 5 centers in North Africa (1 center in Tunisia 2 in Egypt and 2 in Morocco). Two control groups are being included: 1) 250 non-IBC breast cancer cases and; 2) 250 visitor controls (excluding first-degree relatives) to randomly selected female inpatients (excluding those with breast ovarian endometrial and nasopharyngeal cancer) in the study hospitals. The study involves the administration of a questionnaire anthropometric measurements saliva collection digital photographs of the breasts of IBC cases and the collection of paraffin-embedded tumor tissue for IBC cases and non-IBC breast cancer controls. The study has been conducted as a collaboration with the University of Nebraska with forms development and translation coordinated at the National Cancer Institute-USA. The NCI-DCEG is responsible for developing study procedures at the study centers in Egypt Tunisia and Morocco. Data collection began in March 2009 in Egypt August 2009 in Tunisia and January 2011 in Morocco. Data collection in Egypt and Tunisia stopped on 09/30/2013. Data collection for the project will end in Morocco by August 2016. 733103 +Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Colo-Rectal Cancer; Digestive Diseases; Genetics; Human Genome; Lung; Prevention; Women's Health Address;Area;Biological Markers;Biometry;Blood;Breast;Breast Cancer Detection;Breast Cancer Education;Bronchi;Calibration;Cancer Detection;Categories;Cervical Cancer Screening;Colon;Colorectal Cancer;Complex;Computer software;Data;Data Analyses;Differential Equation;Dimensions;Disease;Division of Cancer Epidemiology and Genetics;Dose;Electronic Health Record;Environmental Risk Factor;Epidemiologic Methods;Equilibrium;Family;Genes;Genetic;Genetic Markers;Genomics;Genotype;Household;Individual;International;Left;Lung;Malignant neoplasm of lung;Measurement;Methods;Mission;Modeling;National Health and Nutrition Examination Survey;Outcome;Pathway Analysis;Pleura;Procedures;Rectum;Research;Risk;Risk Estimate;Sampling;Surveys;Testing;The Cancer Genome Atlas;Trachea;Vitamin D;Weight;base;beta diversity;design;detection limit;disorder risk;electronic data;epidemiology study;genetic variant;improved;malignant breast neoplasm;member;method development;microbiome;novel;novel strategies;population based;protective effect;response;screening guidelines;semiparametric;statistics;trait Methods for Epidemiology Studies n/a NCI 10702930 1ZIACP010181-20 1 ZIA CP 10181 20 15187126 "ALBERT, PAUL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 714877 NCI Extensions of likelihood-based sufficient dimension reduction methods were proposed and studied for analyzing biomarkers that are left and/or right censored due to lower or upper limits of detection. These methods apply generally to any type of outcome including continuous and categorical outcomes. Bias of estimates of exposure effects conditional on covariates was assessed when summary scores of confounders instead of the confounders themselves were used to analyze observational data. Two scores the propensity score (PS) and the disease risk score (DRS) were studied in detail. New procedures were developed for seasonal adjustment and calibration of blood measurements of vitamin D to support the multicenter international Vitamin D Pooling Project for Breast and Colorectal Cancer. These methods were used to guide the analysis on the associations of blood levels of Vitamin D with the risk of breast and of colorectal cancer with findings that indicate protective effects for colorectal cancer. Parametric and semi-parametric mixture models have been proposed for analyzing left or interval-censored data from electronic health records. The new approach was used for risk estimates that underlie current U.S. risk-based cervical cancer screening guidelines. A multiple imputation approach based on Additive Regression Bootstrapping and Predictive mean matching (ARBP) methods was introduced to accurately impute the missing values for steps collected in the 2003-2004 National Health and Nutrition Examination Survey NHANES. A novel class of functional data analysis models based hierarchical stochastic differential equations was developed to address some limitations by existing methods. An efficient Hardy Weinberg Equilibrium test was developed to analyze genetic data collected from population-based household surveys utilizing pairwise composite likelihood methods that incorporate the sample weighting effect and genetic correlation induced by the complex sample designs. A general procedure was developed for conducting gene and pathway analysis that uses only SNP-level summary statistics in combination with genotype correlations estimated from a reference panel of individual-level genetic data. A family of multi-locus testing procedures were developed for detecting the composite association between a set of genetic markers and two traits based on a random effect model with two variance components with each presenting the genetic effect on one trait. A likelihood-based test was developed for mutual exclusivity analysis in detection of cancer driver gene and applied to TCGA data as well as a DCEG lung cancer study. A statistical framework and a computationally efficient software package were developed for identifying host genetic variants associated with microbiome beta diversity with or without interacting with an environmental factor. 714877 +Aging; Cancer; Clinical Research; Genetics; Human Genome; Nutrition; Prevention; Prostate Cancer; Urologic Diseases 8q24;Africa;African;Androgen Metabolism;Androgens;Biochemical;Biological;Biological Assay;Biological Markers;Blood;Burkitt Lymphoma;Case Series;Central obesity;China;Cities;Classification;Clinical;Collection;Colorectal;Consent;Data;Databases;Diagnosis;Dietary Factors;Dietary Practices;Epidemiology;Ethnic group;Fasting;Freezing;Fresh Tissue;Gene Expression;Genes;Genetic;Genetic Markers;Genotype;Ghana;Health;Hormonal;Hormonal Carcinogenesis;Hormones;Human;Human Genetics;Insulin;Insulin-Like Growth Factor I;Interview;Isoflavones;Life Style;Link;Low-Density Lipoproteins;Lung;Malaria;Malignant neoplasm of prostate;Manuscripts;Medicare;Meta-Analysis;Methodological Studies;Molecular;Molecular Genetics;Nature;Nested Case-Control Study;Non-Steroidal Anti-Inflammatory Agents;Nutritional;Obesity;Outcome;Ovarian;Pathway interactions;Pharmaceutical Preparations;Population;Predisposition;Prevalence;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Prostatic Diseases;Publishing;Questionnaires;Recurrence;Research;Resources;Risk;Risk Factors;Role;Sampling;Series;Serum;Stage at Diagnosis;Stains;Study Subject;Surveys;TMPRSS2 gene;Techniques;Testosterone;Time;Tissue Banks;Tissue Microarray;Tissue Sample;Tissues;Tumor Markers;Variant;androgenic;base;cancer risk;cancer type;case control;clinical practice;clinically relevant;cohort;design;dietary;follow-up;genetic risk factor;genetic variant;genome wide association study;indexing;insight;men;metabolic profile;mortality;multi-racial;multidisciplinary;novel;population based;population survey;prostate cancer risk;prostate carcinogenesis;racial and ethnic;racial difference;recruit;resistance gene;soy;tumor;western diet Prostate Cancer Studies n/a NCI 10702929 1ZIACP010180-21 1 ZIA CP 10180 21 9414784 "ALBANES, DEMETRIUS " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 189155 NCI In Ghana Africa we have conducted a population-based survey of men to assess the population prevalence of prostatic disease (CAS ID:01130). We have also collected consented into the study a clinical series of men diagnosed with prostate cancer. This dynamic epidemiologic design of a population survey combined with a larger case series is enabling us to assess the burden of prostate cancer in African men as well as assess risk factors associated with prostate cancer in an important and understudied population. Biological samples collected from the 1038 healthy men in the population survey component will allow us to establish the nutritional hormonal and genetic profiles of African men. In addition linking interview data from these 1038 healthy subjects with biomarkers will produce insights into whether westernization in African men is associated with an adverse metabolic profile (obesity; abdominal obesity; higher levels of insulin low-density lipoprotein and insulin-like growth factor I) which has been associated with excess prostate cancer risk. The additional 677 prostate cancer cases that we recruited through the clinical component has enabled us to conduct a genome wide association study (GWAS) of prostate cancer in this unique population (published in Human Genetics). In addition we have sequenced the 8q24 region and identified several novel variants (published in Prostate) as well contributed to a pooled fine-mapping study of this region in African Men (published in JNCI) and an imputation and subset based meta-analysis of chr5p15.33 across multiple cancer types (published in Human Molecular Genetics). We have also contributed data to multi-racial GWAS and have identified 23 novel genetic (SNP) associations with prostate cancer (published in Nature Genetics). We have recently contributed to an integrative analysis to identify candidate functional SNPs at prostate cancer susceptibility regions of the geonome (published in Human Molecular Genetics). We are now extending this GWAS effort to include additional cases and controls that were recruited for this study. We are also using the population component of the Ghana Prostate Study to assess the prevalence of malaria-resistance genes with a view to uncovering the genetic risk factors of Burkitt lymphoma in Africa. We are assessing whether IFNL4 is also prominent in African men by genotyping the IFNL4 variant in 350 population-based controls in the Ghana Prostate Study. We are also assessing whether this variant can be imputed using the existing GWAS data. We are assessing whether IFNL4 is associated with age and/or stage at diagnosis of prostate cancer in the Ghana Prostate Study. We are also currently assessing the prevalence of TMPRSS2-ERG fusions in prostate cancer tissues of these African prostate cancer cases (manuscript being drafted). We have also begun analyses of questionnaire components of this study to further elucidate associations of prostate cancer in this novel population. We have conducted a multidisciplinary study in China to assess risk factors for prostate cancer in a low-risk population in order to understand more clearly the reasons for the large racial differences in prostate cancer risk (CAS ID:01140). That study involved the collection of multiple biologic samples with a primary aim of assessing risk factors and how westernization influences the risk of prostate cancer. The study also involved the collection of tissue samples from prostate cancer tumors to permit precise tumor classification as well as assays of tumor biomarkers in some cases using newly developed tissue microarray techniques. In addition to specific dietary factors dietary patterns will be identified and compared with those of controls to evaluate whether a western-style diet in China is related to excess prostate cancer risk. The study is also assessing biological correlates of westernization to look for potential biological links between westernization and excess prostate cancer risk. Data on genotypes and circulating levels of hormones provide a unique opportunity to investigate the interrelationships between serum hormones and genetic variants to gain insights into the functional significance of these genetic markers. In another study of prostate cancer in 15 cities in China we are assessing the role of soy in prostate cancer by developing a dietary isoflavone index. In addition several nested case-control studies in large cohorts including Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial the SEER-Medicare database total Medicare and Clinical Practice Research Datalink (CPRD) we are assessing the relationships of hormone-related factors with subsequent risks of prostate cancer and prostate cancer-specific mortality. A methodologic study is currently underway to evaluate whether circulating levels of androgens reflect intraprostatic androgenicity a key issue in hormonal carcinogenesis of the prostate (CAS ID:01072). This methodologic study has collected samples of fasting blood and snap-frozen fresh tissue (over 3000 pieces) from 600 study subjects in three racial/ethnic groups. Data from this study will provide a unique opportunity to investigate the interrelationships among serum and tissue hormones and variants in genes involved in the androgen metabolism pathways to provide critical data for determining the functional significance of these genetic markers. The collection of tissue samples also will provide a unique opportunity for gene expression studies. This manuscript is currently being drafted.In continuing the theme of hormonal perturbations in relation to prostate cancer we are also using a large health database to assess whether testosterone replacement medications are associated with prostate cancer risk (CAS ID: 10667). For more accurate and detailed follow up in PLCO to enable prostate recurrence analyses and analyses of outcomes post-diagnosis in this resource we are currently extending the follow-up time beyond the first year post-diagnosis to capture all clinically relevant data (CAS ID: 10515). Biochemical recurrence is being assessed in relation to tissue IHC stains.Lastly we are using data from AARP to investigate the association of NSAID use and subsequent risk of cancer including prostate cancer (CAS ID: 10547) the manuscript of which is currently under review. 189155 +Cancer; Clinical Research; Digestive Diseases; Emerging Infectious Diseases; HIV/AIDS; Health Disparities; Hematology; Infectious Diseases; Lymphatic Research; Lymphoma; Malaria; Minority Health; Pediatric; Pediatric Cancer; Prevention; Rare Diseases; Urologic Diseases; Vector-Borne Diseases 20 year old;Acquired Immunodeficiency Syndrome;Affect;African Burkitt's lymphoma;Age;Anogenital cancer;Antibodies;Antigens;Bar Codes;Biological;Biological Markers;Black Populations;Breast;Burkitt Lymphoma;Cancer Etiology;Case/Control Studies;Categories;Cell Cycle Progression;Child;Clinical;Code;Cohort Studies;Collaborations;Comparative Study;Confidence Intervals;Data;Data Analyses;Development;Diagnosis;Disease;Enrollment;Epidemiology;Etiology;Extramural Activities;Falciparum Malaria;Fostering;General Population;Genetic Predisposition to Disease;Genetic Variation;Ghana;Goals;HIV;HIV Seronegativity;HIV Seropositivity;HIV diagnosis;Head and Neck Cancer;Helicobacter pylori;Hepatitis B;Hepatitis C virus;Hispanic Populations;Hodgkin Disease;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immune response;Immunity;Immunologics;Incidence;Individual;Infection;Infectious Agent;Injecting drug user;Institutes;Kaposi Sarcoma;Laboratories;Light;Link;Liver;Lymphoma;Malaria;Malawi;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of penis;Malignant neoplasm of testis;Measures;Modeling;Molecular;Mutation;Natural History;Non-Burkitt's Lymphoma;Non-Hodgkin's Lymphoma;Oncornaviruses;Organ Transplant Research;Pathogenesis;Pathway interactions;Patients;Persons;Plasmodium falciparum;Population;Population Attributable Risks;Privatization;Proteins;Residual state;Risk;Role;SEER Program;Saliva;Specimen;Stomach;T cell factor 3;TCF3 gene;Testing;Time;Tissue Banks;Tissue Microarray;Tissues;Transplant Recipients;Tumor Tissue;United States;Virus;age group;cancer risk;cancer therapy;cancer transplantation;comparative;data registry;detection method;disorder risk;experience;high risk;infection risk;malaria infection;malignant breast neoplasm;malignant stomach neoplasm;men who have sex with men;metropolitan;mortality;multidisciplinary;neoplasm registry;novel;pathogen;peripheral blood;population based;prospective;rational design;seropositive;tumor;viral transmission;virus related cancer Epidemiology and Natural History of Cancer-Associated Viruses n/a NCI 10702928 1ZIACP010176-22 1 ZIA CP 10176 22 10693148 "MBULAITEYE, SAM M" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1727582 NCI This project consists of several overlapping comprehensive multidisciplinary population-based cohort and/or case-control studies to quantify the association between cancer-causing viruses (oncoviruses) with linked cancers. The projects include the HIV-AIDS Cancer Match (HACM) Study that links some 780000 people with HIV-AIDS in 14 U.S. states and metropolitan regions with cancer registry data to examine cancer risk among HIV-infected individuals and the Transplant Cancer Match (TCM) Study that links some 175000-transplant recipients to cancer registry data in 13 cancer for comparative studies. In addition focused projects on BL include the Ghana BL Study and the EMBLEM Study with broad goals to study the role of infections including HIV immune responses to EBV and Plasmodium falciparum malaria and genetic susceptibility in the etiology to BL. The studies focus on the role of the role of immunological alteration infection and risk for cancer including BL NHL Hodgkin lymphoma Kaposi sarcoma lung cancer cervical cancer head and neck cancer testicular cancer breast cancer penile cancer and gastric cancer. Biological specimens (peripheral blood saliva tumor tissues) when available are used to measure load of infectious agents including HIV EBV and KSHV also called HHV8 Pf malaria and genetic variation in the pathogens a or the host to characterize association of biomarkers with cancer. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses. Study of the US HACM provides continuing evidence of strong and durable impact of HIV on cancer risk in HIV infected persons. Using cancer incidence rates for the United States HIV-infected and general populations and applying Poisson models to linked HIV and cancer registry data and from Surveillance Epidemiology and End Results program data an estimated 7760 (95% confidence interval [CI] = 7330 to 8320) cancers occurred in 2010 among HIV-infected people. Of these 3920 cancers (95% CI = 3480 to 4470) or 50% (95% CI = 48 to 54%) were in excess of expected. The most common excess cancers were non-Hodgkin's lymphoma (NHL; n = 1440 excess cancers occurring in 88% excess) Kaposi's sarcoma (KS n = 910 100% excess) anal cancer (n = 740 97% excess) and lung cancer (n = 440 52% excess). The proportion of excess cancers that were AIDS defining (ie KS NHL cervical cancer) declined with age and time since AIDS diagnosis (both P .001). For anal cancer 83% of excess cases occurred among men who have sex with men and 71% among those living five or more years since AIDS onset. Among injection drug users 22% of excess cancers were lung cancer and 16% were liver cancer. An analysis of risk of cancers associated with infection persons diagnosed HIV in the United States in 2008 showed that 40% (95% CI 39-42) of the cancers are attributable to an infection particularly Kaposi sarcoma herpes virus Epstein-Barr virus and human papillomavirus which together were responsible for 90% of the new cancers (mainly Kaposi sarcoma lymphomas and ano-genital cancers). The infection attributable fraction was highest in the age group 20-29 years (69% 95% CI 65-72) and in men who have sex with men (48% 95% CI 46-50). Further analysis of data from HACM also showed that HIV-infected patients with cancer experienced higher cancer-specific mortality than in HIV-uninfected patients regardless of the cancer stage or receipt of cancer treatment. A study to investigate the role of protective immunity to Plasmodium falciparum (Pf) malaria in Burkitt lymphoma (BL) using data from Ghana was completed. Cases were children with Burkitt lymphoma enrolled in Ghana during 1965-1994 and controls were healthy children from the same village as the cases. Malaria immunity was measured using novel antibodies to HRP-II (an antigen believed to mark recent malaria) and Pf SE36 (thought to be protective) in 354 cases and 384 matched controls. BL was positively associated with HRP-II seropositivity (OR = 1.60; 95% CI 1.08-2.36) and inversely associated with SE36 seropositivity (OR = 0.37; 95% CI = 0.21-0.64) after control for confounding factors. Furthermore BL risk was 21 times higher (95% CI = 5.8-74) in HRP-II-seropositive and SE36-seronegative responders compared with HRP-II-seronegative and SE36-seropositive responders suggesting that individuals with evidence of recent malaria who lack protective antibodies are at highest risk for this disease. Using a sensitive and specific 24 SNP Pf molecular-barcode array developed by the Broad Institute BL cases from Malawi were shown to have greater genetic diversity than non-BL cancers from Malawi (mean genetic diversity score: 153.9 [se=5.8] versus 133.1 [se=7.7] t-test p=0.036). This suggested that there is a positive correlation between genetic diversity score of Pf malaria infection in BL in Malawi shedding new light on how infections might drive risk for an AIDS defining cancer such as BL. In studies focusing on BL tumor tissues study novel mutations were discovered in the transcription factor TCF3 (E2A) its negative regulator ID3. The mutations in TCF3/ID3 were present in about 70% of HIV-associated and sporadic BL and 40% of endemic BL while mutations in CCND3 which codes for proteins that drive cell cycle progression were present in 38% of sporadic BL but in only 1.8% of endemic BL. These results point to novel pathways for BL pathogenesis which can be targeted rational design of simpler and less toxic treatment for BL. To understand the role of EBV in BL in the US 91 confirmed BL tissues from the SEER Residual Tissue Repository (SRTR)were studied by tissue microarray (TMA). About one-third of the BL cases were EBV tumor positive. EBV positivity was lowest in cases aged 20 years and 60 years higher in Blacks/Hispanics compared to Whites and higher HIV positive cases compared to those who were HIV negative. These results suggest that EBV positive and EBV negative BL are distinct types whose distribution is different in different demographic groups. 1727582 +Aging; Breast Cancer; Cancer; Cervical Cancer; Clinical Research; Colo-Rectal Cancer; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Estrogen; Genetic Testing; Genetics; Health Disparities; Lung; Lung Cancer; Minority Health; Nutrition; Obesity; Ovarian Cancer; Prevention; Prostate Cancer; Rare Diseases; Urologic Diseases; Women's Health Adolescent;Adult;Androgens;Asia;Asian;Asian Americans;Asian population;Biochemical Pathway;Biological;Biological Assay;Biological Markers;Blood;Body of uterus;Breast Cancer Cell;Breast Cancer Risk Factor;Breast Carcinogenesis;Cancer Etiology;Carbon;Carotenoids;Case/Control Studies;Categories;Childhood;Cohort Studies;Collaborations;Colorectal Adenoma;Colorectal Cancer;Communities;DNA biosynthesis;Data;Diagnosis;Diet;Dietary Practices;Disease;Environmental Exposure;Enzymes;Epidemiology;Erythrocytes;Estrogen Metabolism;Estrogens;Etiology;Family;Folic Acid;Follow-Up Studies;Food;Fruit;Genes;Genetic;Genetic Markers;Genetic Polymorphism;Genotype;Goals;Hawaiian;Health;Height;Homocysteine;Hormonal;Hormones;Human;Hydroxyestrones;Incidence;Individual;Indolent;Insulin-Like Growth Factor Binding Protein 3;Insulin-Like Growth Factor I;Intake;International;Interview;Japanese;Life Style;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Manuscripts;Measurement;Measures;Metabolic;Metabolism;Methionine;Methylation;Methylenetetrahydrofolate reductase (NADPH);Micronutrients;Migrant;Mothers;Mutation;NCI Center for Cancer Research;Nested Case-Control Study;Nutritional;Obesity;Papillomavirus;Participant;Pathway interactions;Pattern;Physiological;Phytoestrogens;Plasma;Play;Population;Population Study;Postmenopause;Premenopause;Principal Component Analysis;Procedures;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Proteomics;Publishing;Recording of previous events;Relative Risks;Reproducibility;Riboflavin;Risk;Risk Factors;Role;Sampling;Sensitivity and Specificity;Series;Serum;Sexually Transmitted Diseases;Smoking;Societies;Somatomedins;Testing;Tissues;Urine;Variant;Vegetables;Vitamin B6;Weight Gain;Woman;alpha-carotene;base;beta-cryptoxanthin;cancer risk;cohort;design;diet and cancer;dietary;epidemiology study;folic acid metabolism;fruits and vegetables;genetic variant;liquid chromatography mass spectroscopy;lung cancer prevention;lycopene;malignant breast neoplasm;men;methyl group;migration;multidisciplinary;nutrition;pre-clinical;prospective;prostate cancer cell;prostate cancer risk;protective effect;repaired;soy Nutrition Metabolism and Cancer n/a NCI 10702926 1ZIACP010169-21 1 ZIA CP 10169 21 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 282826 NCI FOLATE AND ONE-CARBON METABOLISM Folate is essential for one-carbon (methyl group) metabolism a biochemical pathway involved in DNA synthesis repair and methylation. Efficient one-carbon metabolism also requires vitamins B-6 and B-12 riboflavin and optimal activity of 10-20 enzymes. In a community-based case-control study of invasive cervical cancer we showed that high serum homocysteine was associated with a statistically significant 100-200% increase in risk and low serum or red blood cell folate with only a 20-60% increase. This pattern suggests that circulating homocysteine may be an integratory measure of insufficient folate in tissues or a biomarker of disruption of one-carbon metabolism. Variant forms of two common polymorphisms in the methylene tetrahydrofolate reductase gene and a common polymorphism in the methionine synthase gene were each associated with elevated cervical cancer risk. Risk generally increased as copies of the variant gene increased. These results suggest that both genetic variability in the one-carbon metabolism pathway and micronutrient inadequacy can contribute to increased risk of cervical cancer. Additional polymorphisms in pathway genes are now being assayed. We are also exploring the role of one-carbon metabolism in the etiology of both colorectal and breast cancer in the Prostate Lung Colorectal and Ovarian Cancer (PLCO) cohort. The large number of advanced colorectal adenomas (1200) identified will allow us to systematically search for main effects of polymorphic variation in key one-carbon metabolism genes using spaced polymorphisms as biomarkers of genetic change. The relationships among circulating levels of homocysteine and various folate forms and genotype will also be explored.VEGETABLES FRUITS AND CAROTENOIDS The protective effect of vegetables and fruits is frequently touted as the most persuasive finding to emerge from epidemiologic studies of diet and cancer with evidence strongest for lung and colorectal cancer. Individual carotenoids measured in diet or blood are reliable measures of intake of a variety of vegetables and fruits. In a nested case-control study of lung cancer in a cohort of Hawaiian Japanese men individual carotenoids were measured in prediagnostic sera. Low serum levels of beta-cryptoxanthin lycopene and alpha-carotene but not beta-carotene were each modestly associated with elevated lung cancer risk (smoking-adjusted RRs = 1.3-1.5). There was no evidence of combined or synergistic effects for individual carotenoids. Thus carotenoids at physiologic levels may not contribute substantially to lung cancer prevention. In the PLCO screening trial we are investigating the relationship of vegetable and fruit intake with quantity and variety assessed in several ways to risk of colorectal adenoma. Greater intake of fruits and some vegetables particularly deep yellow and dark green vegetables is modestly but significantly associated with decreased risk for colorectal adenoma. Pyramid servings a more comprehensive and quantitative approach to estimating food group intake did not produce substantially different results than the more traditional number of servings/day.BREAST CANCER AND PROSTATE CANCER IN ASIAN-AMERICAN POPULATIONS International variation in breast cancer incidence and migrant studies indicate that modifiable factors play a major role in breast cancer etiology although the specific lifestyles and environmental exposures remain elusive. We designed a large population-based case-control study of breast cancer in Asian-American women to take advantage of their diversity in lifestyle and breast cancer risk. Childhood adolescent and adult exposures were assessed by interviewing both study participants and their mothers. We observed a six-fold gradient in breast cancer incidence by migration patterns comparable to the international differences in breast cancer incidence rates. Using the blood and urine samples that were collected we initially focused on relationships in the controls between endogenous hormones and migration patterns. Estrogens did not differ significantly between Asian-American women born in Asia and the West. However androgen levels were higher among Asian-Americans born in Asia. Thus further efforts to understand the hormonal mechanisms underlying breast carcinogenesis should consider androgens as well as estrogens. The ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone an indicator of estrogen metabolism pathways was consistently lower (by 20%) in Asian-American women born in the West. The 2:16alpha ratio may reflect Asian lifestyles that influence estrogen metabolism and reduce breast cancer risk. We are now analyzing insulin-like growth factors (IGFs). Adiposity and weight gain in the decade preceding diagnosis as well as height were critical determinants of breast cancer risk in these Asian-American women. We are seeking biologic explanations with emphasis initially on the IGFs.Childhood adolescent and adult soy intake were each independently associated with reduced risk of breast cancer. The strongest effect was seen for childhood soy intake with a statistically significant 60% reduction in risk between extreme tertiles. Further analysis of the dietary and cultural pattern information collected will clarify whether soy seems uniquely protective or may only be serving as an indicator of other Asian lifestyles. Preliminary results suggest that the relative risk of breast cancer for a positive family history is similar in Asian-American women at different levels of Westernization. This constancy implies that the lifestyles responsible for lower risk among Asians may also modify genetically determined breast cancer risk.Foci of prostate cancer cells like foci of breast cancer cells seem to advance more rapidly in Western societies than in Asian societies. Elevated IGF-I has been postulated as a biomarker of more rapid progression and possibly a cause. With prospectively stored serum samples from a cohort of Hawaiian Japanese men we are exploring the relationship of IGF-I IGFBP-3 free IGF-I PSA and proteomic patterns to risk of prostate cancer. Two important questions are whether IGF-I is equally predictive of indolent and aggressive prostate cancer and whether it is a true risk factor preceding diagnosis by many years or simply an early marker of preclinical disease.ENDOGENOUS HORMONE MEASUREMENT We have published a series of manuscripts on the reproducibility and utility of the commercial kits currently used to measure estrogens estrogen metabolites and androgens in blood and urine from premenopausal women postmenopausal women and men. While some of the assays are sufficiently reliable to discriminate among individuals others are more problematic. In collaboration with Drs. Xia Xu and Timothy Veenstra at NCI-Frederick and Dr. Larry Keefer in the NCI Center for Cancer Research we have developed a robust relatively rapid liquid chromatography/mass spectroscopy procedure that can measure simultaneously 16 estrogens and estrogen metabolites in 0.5 ml of urine. A formal test of reproducibility sensitivity and specificity in a range of samples is being implemented. We anticipate that our approach can be extended to estrogen metabolite measurement in serum/plasma and tissue and that it can be modified to also measure androgens and phytoestrogens.NATIONAL HEALTH EPIDEMIOLOGIC FOLLOW-UP STUDY With prospective dietary data from the nationally representative U.S. Health Examination Epidemiological Follow-up Study we used principal component analysis to explore the role of dietary patterns in the etiology of prostate cancer. 282826 +Breast Cancer; Cancer; Clinical Research; Conditions Affecting the Embryonic and Fetal Periods; Contraception/Reproduction; Diethylstilbestrol (DES); Endocrine Disruptors; Estrogen; Health Disparities; Maternal Health; Minority Health; Pediatric; Perinatal Period - Conditions Originating in Perinatal Period; Pregnancy; Prevention; Rare Diseases; Vaginal Cancer; Women's Health AFP gene;Adult;Adult Children;Androstenedione;Animal Model;Behavioral;Biological Assay;Birth;Birth Weight;Blood specimen;Body of uterus;Boston;Breast Cancer Risk Factor;Categories;China;Cohort Studies;Collaborations;Collection;Contractor;Data;Daughter;Dehydroepiandrosterone Sulfate;Diethylstilbestrol;Disease;Estradiol;Estriol;Estrogens;Estrone;Europe;Exposure to;Female;Functional disorder;Gestational Age;Health Sciences;Hormones;Immune system;Insulin-Like Growth Factor Binding Protein 3;Label;Laboratories;Link;Louisiana;Malignant Neoplasms;Maternal Age;Medical Records;Medical center;Mothers;National Institute of Child Health and Human Development;Pathology Report;Perinatal;Pharmaceutical Preparations;Phase;Placenta;Pre-Eclampsia;Pregnancy;Pregnant Women;Premature Birth;Preneoplastic Conditions;Prevention;Progesterone;Prolactin;Questionnaires;Reporting;Risk;Risk Factors;Ships;Son;Spontaneous abortion;Standardization;Testosterone;Twin Multiple Birth;Umbilical Cord Blood;Umbilical cord structure;Universities;Uterine Diseases;Work;cancer risk;cohort;dehydroepiandrosterone;early life exposure;follow-up;high risk;in utero;male;medical schools;member;neoplasm registry;offspring;prenatal exposure;prostate cancer risk;reproductive;vaginal clear cell adenocarcinoma Early Life Exposures and Subsequent Cancer Risk n/a NCI 10702925 1ZIACP010168-22 1 ZIA CP 10168 22 15666500 "GARCIA-CLOSAS, MONTSERRAT " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 777366 NCI 00020 - Diethylstilbestrol (DES) a drug first synthesized in 1938 was administered to several million pregnant women in the U.S. and Europe for the prevention of spontaneous abortion and premature delivery. In 1971 Herbst reported a strong association between DES use in pregnancy and the occurrence of vaginal clear cell adenocarcinoma (CCA) in exposed female offspring. Animal models have demonstrated a range of DES effects on offspring exposed in utero including reproductive dysfunction immune system changes behavioral and sexual abnormalities and increases in various reproductive cancer in males and females. NCI in collaboration with five field centers reassembled previously studied cohorts of DES-exposed and unexposed mothers daughters and sons and identified subjects with documented exposure status who had not been studied previously through familial links within the cohorts. Standardized baseline questionnaires were mailed to cohort members to ascertain the risk of cancer and other disorders. Pathology reports were collected for reported cancers and preneoplastic conditions. Theree separate phases of follow-up have been conducted. The purpose of this study is to continue the follow-up by means of mailed questionnaires and medical record collection which was begun during the the first phase of the study. Concern has arisen that DES-exposed daughters may be at higher risk of breast cancer. Exposure to high levels of endogenous estrogen in utero has been hypothesized to increase the risk of breast cancer and DESis a potent estrogen. Cacner risk in the sons will also continure to be assessed especailly for increased risks of prostate cancer. since the offspring who were exposed to DES in utero are currently reaching their late forties when cancer rates begin to rise it is important to continue the follow-up of these cohorts to determine if there are long-term increases in cancer risk. 10039 - The proposed study involves collecting maternal and cord blood samples from monochorionic twin dichorionic twin and singleton pregnancies of similar gestational age to quantify differences in concentrations of several hormones and other pregnancy products including estriol estradiol estrone testosterone androstenedione dehydroepiandrosterone (DHEA) DHEA-sulfate progesterone AFP prolactin IGF and IGF-binding protein 3. Data from medical records and pathology reports will be abstracted to provide information on the mother baby pregnancy and placenta. The work will be done at Dartmouth Hitchcock Medical Center Dartmouth Medical School. Blood samples labeled with a unique ID number only will be sent to Bioreliance NCI's contractor for preperation and shipment to the laboratory that will perform the hormone assays. NCI will receive the abstracted data in electronic form. no personal identifying information will be received by NCI or its contractor. The study has been approved by Dartmouth Medical School. 10041 - The Norwegian birth and cancer registries will be used to investigate the association of several pregnancy and perinatal factors and risk of cancer in adult offspring. 10032 - Collaboration with NICHD on a study of preeclampsia conducted at Louisiana State University Health Sciences Center. Blood samples are being collected from mothers and from umbilical cords with and without preeclampsia. The relationship of pregnancy hormone levels and preeclampsia will be analyzed. 01132 - In this study using data from a cohort study of preeclamptic and uncomplicated pregnancies at the University of Pittsburgh we are analyzing maternal and cord blood samples from preeclamptic and normal pregnancies of similar gestational age to quantify differences in levels of various hormones. We will evaluate associations of several maternal perinatal and pregnancy factors such as maternal age and birth weight with hormone levels in normal pregnancies. In addition we will determine how well maternal levels represent levels in cord blood. 00043 - Umbilical cord blood samples were collected from 75 pregnancies in Boston MA and 175 in Shanghai China. Pregnancy hormone concentrations will be determined and correlated with putative breast cancer risk factors. 777366 +Breast Cancer; Cancer; Clinical Research; Immunization; Prevention; Vaccine Related; Women's Health Area;Breast;Case/Control Studies;Categories;Characteristics;Clinical;Collaborations;Colon;Development;Disease;Environmental Risk Factor;Epidemiology;Exposure to;Follow-Up Studies;Genetic;Health;Hormonal;Hospitals;Immune System Diseases;Immune system;Immunization;Immunize;Individual;Infectious Agent;Laboratories;Life Style;Long-Term Effects;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Maryland;Medical Staff;National Cancer Institute;Occupations;Persons;Positioning Attribute;Recording of previous events;Rectum;Risk;base;case control;cohort;disorder risk;experience;genetic risk factor;genome wide association study;malignant breast neoplasm;mortality;osteosarcoma;pathogen;reproductive General Studies of Epidemiology n/a NCI 10702924 1ZIACP010167-22 1 ZIA CP 10167 22 15666500 "GARCIA-CLOSAS, MONTSERRAT " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1367776 NCI 00015 - Breast cancer and prostate cancer cases occuring within the PLCO cohort will be evaluated in a nested case-control manner to assess risks associated with early reproductive characteristics including likely early hormonal profiles (via genetic inference) 00022 - The National Cancer Institute is studying the health effects among persons receiving large numbers of immunizations while employed as civilians at Fort Detrick Maryland. These individuals were employed in a variety of positions which required them to enter areas where they were potentially exposed to a variety of infectious agents. To protect individuals against these exposures immunizations were administered to them by the medical staff at the Fort whenever their job required entry to particular areas. Some individuals received as many as 50 or more immunizations to a particular agent and some persons were immunized to as many as 30 different infectious agents. While these immunizations protected the individuals against specific pathogens the long term effects of such challenges to the immune system are unknown. A study of 100 persons receiving multiple immunizations at this facility found no immediate clinical illness as a result of their immunizations. However the study did show several laboratory aberrations following intensive immunizations that suggest the possibility of long term deleterious effects. We are conducting a follow-up study of this hyper-immunized cohort to examine their mortality experience relative to their immunization history. The results of this study may add to our understanding of the effects of high levels of immune stimulation and disease development including cancer. 00400 - a multi-center case-control study of bladder cancer 1978. There are 10 SEER centers. 00028 - A hospital based case-control study of osteosarcoma was conducted in the 1990s and is still under analysis relating lifestyle environmental and genetic risk factors to risk of this disease. This study will be participating in the first Genome-Wide Association Studies (GWAS) of osteosarcoma in collaboration with several other groups. 1367776 +Aging; Biotechnology; Breast Cancer; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Genetics; Health Disparities; Lung; Lung Cancer; Minority Health; Nutrition; Ovarian Cancer; Prevention; Prostate Cancer; Rare Diseases; Tobacco; Tobacco Smoke and Health; Urologic Diseases; Women's Health 2-Amino-1-Methyl-6-Phenylimidazo[45-b]pyridine;8q24;Address;Age;Aromatic Amines;Biochemical;Biocompatible Materials;Biological Assay;Bladder;Blood specimen;Breast;Breast Cancer Risk Factor;Bronchi;Calcium-Sensing Receptors;Cancer Etiology;Candidate Disease Gene;Categories;Cells;Collaborations;Collection;Colon Carcinoma;Colonic Adenoma;Colorectal Adenoma;Colorectal Cancer;Contracts;Cooking Practices;Cytogenetics;DNA Repair;Data;Databases;Demographic Factors;Development;Dietary Fiber;Disease;Disease Marker;Division of Cancer Epidemiology and Genetics;Division of Cancer Prevention;Early Diagnosis;Equipment and supply inventories;Etiology;Food;Frequencies;Gene-Modified;Genetic Markers;Genetic Polymorphism;Genetic study;HIV;High temperature of physical object;Immune system;Incidence;Individual;Institutes;Insulin-Like Growth Factor I;Intake;Investigation;Kidney;Lung;Lymphoma;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Meat;Medical;Metabolism;Molecular Epidemiology;Nutritional;Pancreas;Participant;Pathologic;Pathway interactions;Pleura;Predisposition;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Questionnaires;Reporting;Research;Research Activity;Research Personnel;Resources;Risk;Risk Factors;SHBG gene;Sampling;Scientist;Screening for cancer;Selenium;Serum;Smoker;Somatomedins;Special Population;Tissue Microarray;Tobacco smoke;Tobacco use;Trachea;United States;Validation;Vegetables;Vitamin E;adenoma;alpha Tocopherol;arm;biobank;calcium intake;cancer genetics;clinical center;cohort;cooking;cruciferous vegetable;dietary;follow-up;genetic analysis;genetic variant;genome wide association study;lycopene;malignant breast neoplasm;meetings;member;mortality;prostate cancer risk;randomized trial;recruit;research study;screening;steroid hormone;volunteer PLCO Trial Etiologic and Early Marker Study n/a NCI 10702922 1ZIACP010152-23 1 ZIA CP 10152 23 11613071 "FREEDMAN, NEAL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1264772 NCI The Prostate Lung Colorectal and Ovarian Cancer (PLCO) Screening Trial is a large randomized trial to determine if screening for these cancers reduces mortality. The Trial is carried out by the NCI under contract with investigators at ten clinical centers in the United States. The study includes approximately 155000 volunteers (recruited from 1993 through 2001 ages 55-74 equally distributed to the screening and control arms of the Trial). The PLCO Etiology and Early Markers Study (EEMS) supports etiologic and early detection studies of cancers and other conditions. EEMS uses data and samples collected in the context of the PLCO Trial including:1. Baseline demographic and risk factor information on all participants2. Food Frequency Questionnaires(FFQ) on all participants3. Fractionated blood specimens at each of six screening rounds from screened participants4. Buccal cell samples from control participants and5. Information on all-cancer incidence and selected other medical conditions.The very large size of the study and biorepository allows examination of both common and less common cancers as well as special populations such as HIV infected individuals and cancers which are found in excess in these individuals and those with compromised immune systems. Investigations in PLCO EEMS have shown dietary-related factors associated with adenoma risk including dietary fiber meat cooking practices serum selenium low calcium intake and a gene variant in the calcium-sensing receptor. Tobacco use was strongly related to adenoma risk with evidence of risk modification by genes involved in the metabolism of PAH and aromatic amine constituents of tobacco smoke. Other factors associated with risk of colorectal adenoma included insulin-like growth factors and selected DNA repair-related polymorphisms. Prostate cancer risk was related to vegetable intake particularly cruciferous vegetables while dietary and serum lycopene were unrelated to risk. Supplemental vitamin E and serum alpha-tocopherol were related to risk only in smokers consistent with other reports; serum selenium was also related to risk in smokers only. High-temperature cooked meat containing 2-amino-1-methyl-6-phenylimidazo[45-b]pyridine (PhIP) led to increased risk while only the highest levels of insulin-like growth factor-1 (IGF-1) were related to prostate cancer. Genetic studies of candidate genes in the PLCO Trial have revealed associations with SNPs in SHBG and risk of prostate cancer. Through the Breast and Prostate Cancer Cohort Consortium (BPC3) are evaluating prostate and breast cancer risks related to gene variants in steroid hormone and insulin-like growth factor pathways. Investigations in BPC3 and the Cancer Genetic Markers of Susceptibility (CGEMS) project are identifying prostate cancer risks associated with gene variants in the 8q24 region. Colon adenoma studies are now being expanded to consider the etiology of colon cancer also in collaboration with other research groups. Genome wide association studies (GWAS) have been condicted for canccers of the lymphoma kidney pancreas bladder prostate breast and lung. 1264772 +Cancer; Clinical Research; Digestive Diseases; Hematology; Infectious Diseases; Lymphatic Research; Lymphoma; Prevention; Rare Diseases Address;Autoimmunity;Development;Division of Cancer Epidemiology and Genetics;Elderly;HIV;HIV/AIDS;Hodgkin Disease;Human Papillomavirus;Immune;Immunity;Immunologic Epidemiology;Immunosuppression;Infection;Inflammation;Kaposi Sarcoma;Link;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Medicare;Multiple Myeloma;National Cancer Institute;Non-Hodgkin's Lymphoma;Organ Transplantation;Persons;Population;Population-Based Registry;Renal carcinoma;Risk;Risk Factors;Role;Skin Carcinoma;Tissues;Transplant Recipients;cancer risk;cancer transplantation;chronic infection;data registry;immunosuppressed;interest;melanoma;neoplasm registry Infections immunity and inflammation in cancer n/a NCI 10702921 1ZIACP010150-23 1 ZIA CP 10150 23 7030470 "ENGELS, ERIC A" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2075667 NCI Infection immune disturbances and inflammation overlap in the ways that they damage tissues and promote development of cancer. Major studies under this project include the HIV/AIDS Cancer Match Study and Transplant Cancer Match Study which link population-based registries of HIV infected people and transplant recipients to cancer registries in the U.S. Additional studies characterize risk factors for specific cancers in HIV-infected people and transplant recipients. Risk of non-Hodgkin lymphoma and lung cancer is elevated in immunosuppressed populations and these two malignancies are an important focus of study. Other cancers of interest because they are associated with HIV or organ transplant include Kaposi sarcoma liver cancer cancers related to human papillomavirus (such as cervical cancer and anal cancer) Hodgkin lymphoma melanoma non-melanoma skin cancers kidney cancer and multiple myeloma. Some studies under this project address the role of HIV other chronic infections immune disturbance and inflammation in these and other cancers. Other studies which focus on cancer risk in the elderly related to immune and other conditions involve analyses of linked SEER-Medicare registry data. 2075667 +Brain Cancer; Brain Disorders; Cancer; Climate-Related Exposures and Conditions; Genetics; Health Disparities; Lung; Lung Cancer; Minority Health; Neurosciences; Prevention; Rare Diseases; Women's Health Acoustic Neuroma;Adult;Agreement;Apoptosis;Behavioral Genetics;Benign;Biological;Biological Assay;Brain Neoplasms;Cancer Etiology;Cancer Patient;Carbon Tetrachloride;Case/Control Studies;Cell Cycle Regulation;Cellular Phone;Colon;DNA Damage;DNA Repair;DNA Repair Gene;Data;Diagnostic;Division of Cancer Epidemiology and Genetics;Electromagnetic Energy;Electromagnetic Fields;Environment;Epidemiology;Etiology;Exposure to;Female;Future;Genes;Genetic Polymorphism;Glioma;Hour;Incidence;International Agency for Research on Cancer;Ionizing radiation;Lead;Lung;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Measures;Mutation;Neomycin;Nonionizing Radiation;Occupational;Occupational Exposure;Ovary;Oxidative Stress;Pathway interactions;Pesticides;Phenotype;Pilot Projects;Population;Predictive Value;Prostate;Questionnaires;Radiation;Radiation exposure;Radiation-Induced Cancer;Radiology Specialty;Reporting;Reproducibility;Research Personnel;Risk;Sampling;Skin;Skin Cancer;Solvents;Source;Specimen;Testing;Time;Time Study;Time trend;UV Radiation Exposure;Ultraviolet Rays;Woman;base;cancer diagnosis;cancer risk;carcinogenicity;cytokine;diaries;dosimetry;epidemiology study;farmer;follow-up;genetic analysis;genome wide association study;improved;magnetic field;meningioma;radio frequency;response;screening;solar ultraviolet radiation;trend;volunteer Studies of Non-Ionizing Radiation-Related Cancer n/a NCI 10702916 1ZIACP010135-27 1 ZIA CP 10135 27 15666236 "CAHOON, ELIZABETH " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 359570 NCI Case referent study of brain tumors - 04030 The etiology of brain tumors and brain cancer is poorly understood and recorded incidence rates have increased dramatically over the past several decades. In response to these findings and to advance understanding of environmental behavioral and genetic causes of brain tumors we conducted a case-control study of malignant and benign brain tumors (glioma meningioma and acoustic neuroma). Excess risks of glioma were found among electricians and farmers and an elevated risk of meningioma was seen among auto-body painters. Detailed occupational exposure assessments were conducted for electromagnetic radiation lead and pesticides. No associations were seen for electromagnetic radiation but an association was suggested for meningioma and lead. No consistent evidence was found of an association between any of six chlorinated solvents and risk of glioma or meningioma although there was limited evidence of an association between carbon tetrachloride and risk of glioma. Recent genetic analyses have indicated associations between brain tumor risk and polymorphisms in cytokine apoptosis/cell cycle control DNA repair and oxidative stress genes. Findings for these pathways are being followed up in larger and more comprehensive studies. Cellular Telephone Use and Cancer Risks Ionizing radiation is known to increase cancer risks but there is no consistent evidence that non-ionizing radiofrequency radiation (cell phones) or magnetic field (power lines and electrical appliances) exposures increase cancer risk. As a result of public and Congressional concern the Radiation Epidemiology Branch (REB) launched an early case-control study and found no relationship between cell phone use and risk of glioma meningioma or acoustic neuroma. A study of time trends in glioma incidence in the U.S. led by REB showed no rise despite dramatic increases in cell phone use. A subsequent REB assessment demonstrated that the elevated glioma risks associated with cell phone use in a Swedish study that influenced IARCs conclusion of possible carcinogenicity was not consistent with U.S. incidence trends though incidence trends could be consistent with the small excess of glioma in the highest level users in the Interphone study. UV Dosimetry - 10262 A pilot study of 125 volunteer radiologic technologists was performed by REB investigators in which daily diaries and polysulfone UV dosimeters were used to develop better questionnaire approaches to ascertain environmental UV exposure for future studies of skin and other cancers in this largely female occupational population. The volunteers were queried 6 months later to test the reproducibility of responses to time outdoors. Agreement between reported time on weekdays was significantly higher than for weekends and the reproducibility of hour-based compared to activity-based questionnaires was poorer in adult women. Improved exposure assessment may enable us to characterize more quantitatively the effects of UV and ionizing radiation on skin and other cancers. PLCO Lung DNA Damage Study - 10334 It is unclear whether the reported associations between functional assays and increased lung cancer risk represent a true association because the tests were performed on biologic specimens collected after cancer diagnosis. It may be that they are measuring the consequence rather than the underlying cause of cancer (termed reverse causation bias). Several DCEG investigators are participating in the effort to determine the predictive value of multiple phenotypic or functional assays in pre-diagnostic samples from lung cancer patients included in the Prostate Lung Colon and Ovary (PLCO) screening trial. Primary study findings were that neomycin mutation sensitivity was associated with increased lung cancer risk. Further study of DNA repair genes will be done using existing GWAS data. 359570 +Bioengineering; Biomedical Imaging; Breast Cancer; Cancer; Clinical Research; Digestive Diseases; Health Disparities; Hematology; Minority Health; Pediatric; Perinatal Period - Conditions Originating in Perinatal Period; Physical Injury - Accidents and Adverse Effects; Prevention; Radiation Oncology; Rare Diseases; Women's Health Accidents;Age;Aircraft;Alcohols;Basal cell carcinoma;Binding Sites;Biological Markers;Body of uterus;Brain;Breast;Breast Cancer Risk Factor;Bronchi;Case/Control Studies;Categories;Central Nervous System;Cessation of life;Chernobyl Nuclear Accident;Chromosome abnormality;Chronic;Chronic Lymphocytic Leukemia;Circadian Rhythms;Cohort Studies;Colon;Contracts;Cosmic Radiation;Data;Development;Diagnostic Procedure;Diet;Discipline of Nuclear Medicine;Disease;Disease Outcome;Dose;Dose-Rate;Employment;Endocrinology;Excess Mortality;Exposure to;External Beam Radiation Therapy;Faculty;Feedback;Female;Fluorescent in Situ Hybridization;Flying body movement;Focus Groups;Frequencies;General Population;Hematological Disease;Incidence;Individual;Interview;Ionizing radiation;Joints;Length;Literature;Lung;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pharynx;Malignant neoplasm of thyroid;Maternal Exposure;Medical;Medicine;Methods;National Cancer Institute;Nervous System;New York;Nuclear;Occupational;Occupational Groups;Occupations;Organ;Paper;Patients;Pattern;Pleura;Plutonium;Population;Population Study;Procedures;Publishing;Radiation;Radiation Dose Unit;Radiation exposure;Radiation-Induced Cancer;Radiation-Induced Leukemia;Radiology Specialty;Recording of previous events;Rectum;Reporting;Research;Risk;Role;Scientist;Seasons;Site;Skin;Skin Carcinoma;Solid;Source;Suicide;Survivors;Testing;Time;Trachea;Travel;Ukraine;United States;Universities;Update;Vitamin D;Vitamins;Woman;Work;Workplace;atomic bomb;base;biodosimetry;cancer risk;case control;cohort;comparison group;design;dosimetry;experience;follow-up;improved;in utero;leukemia;malignant breast neoplasm;malignant mouth neoplasm;melanoma;mortality;mortality risk;pilot test;radiation carcinogenesis;radiation effect;reconstruction;response;telomere;trend;work-study Studies of Populations Exposed to Occupational Sources of Radiation n/a NCI 10702915 1ZIACP010133-27 1 ZIA CP 10133 27 14721304 "KITAHARA, CARI " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2099548 NCI Markers of Cosmic Radiation Exposure Among Flight Crew A biodosimetry study study was conducted to determine if there were differences in the frequency of chromosome aberrations by assess cosmic radiation exposure and frequency of chromosome aberrations by fluorescence in situ hybridization among 83 pilots (given their increased levels of cosmic radiation exposure) and 51 university faculty with minimal flying experience. The mean frequency of translocations did not differ between the airline pilots and a comparison group of university faculty however there was a significant increasing trend among the pilots for number of years flying commercial aircraft and translocation frequency. In addition radiation exposure from personal diagnostic procedures among the pilots was positively associated with translocation frequencies after adjustment for age and number of years flying. Some diet and vitamin supplements were also associated with translocation frequency. Cancer and Other Mortality Risks in a Cohort of U.S. Radiologic Technologists In 1982 the REB initiated a nationwide cohort study of all cancer incidence and mortality among 146022 U. S. radiologic technologists who were certified during 1926-1980. The cohort with 73% females. From work history data (collected 1983-89 1994-98 2003-2005 and beginning in 2012) along with tracing and matching with death information we found significantly elevated incidence risks for breast cancer leukemias other than chronic lymphocytic leukemia basal cell carcinoma of the skin melanoma and circulatory diseases among technologists first working before 1950 and a suggested increase in thyroid cancer in those first working before 1960. The and very high response rates and development of the first comprehensive historical occupational dose reconstruction offers a rare opportunity to study effects of occupational protracted low- to moderate-dose radiation exposure on breast and thyroid cancer the two most sensitive organ sites for radiation carcinogenesis in women. All other cancer and non-cancer serious disease outcomes are also being evaluated in relation to protracted low-to-moderate dose exposures. Cancer Mortality in Russian Nuclear Workers A cohort of 26000 Mayak nuclear facility workers is being studied because they comprise a unique occupational group for protracted exposure to external radiation at high doses and for exposure to plutonium. Improved dosimetry and updated mortality data confirm earlier findings of external dose-response relationships for leukemia and for all solid cancers. Mortality analyses have clearly demonstrated that risks for lung cancer liver cancer and bone cancer increase with increasing dose from plutonium. Dose-response analyses of cancer mortality in relation to in utero radiation exposure from maternal employment at the Mayak facility provide no evidence of an effect. Chernobyl Leukemia Study This is a joint US-Ukrainian case-control study of leukemia and other hematological diseases in a cohort of clean-up workers in Ukraine following the Chornobyl accident carried out from 1986 to 2006 - one of the largest analytical studies performed in Chornobyl liquidators taking into account the whole period of observation since the accident cohort size (approximately 110000) and collective dose. A total of137 cases of leukemia have been ascertained in the cohort. With a case-control ratio of 1:5 this number of cases provides adequate power to test the hypothesis of an association between radiation and leukemia risk. The study should also have adequate power to test the hypothesis that the risk is different from that seen in the atomic bomb survivors study if the previously pattern of CLL increases observed in the Chornobyl liquidators from Ukraine is confirmed. The study is conducted by scientists of the Ukrainian Research Center for Radiation Medicine (RCRM) scientists from the U.S. National Cancer Institute (NCI) and scientists and consultants from Columbia University New York (through a contract with NCI). The field work for the study has been completed. A paper has been published reporting a significant increase risk of both chronic lymphocytic leukemia and other types of leukemia. Dosimetry for Nuclear Medicine Patients Despite the growing use of nuclear medicine procedures in the United States very little is known regarding patterns of exposure in medical radiation workers. 20% of radiologic technologists in the U.S. radiologic technologist (USRT) study have reported working as nuclear medicine technologists at some time in their job history. In November 2010 REB held a focus-group discussion in which 8 to 10 experts provided input on historical practices. Based on these findings as well as the literature we have developed a detailed interview work module for radiologic technologists working with nuclear medicine procedures. We plan to refine this module based on feedback from additional feedback from focus group attendees and other experts and to perform extensive pilot testing of the new nuclear medicine module. Studies of UV and cancer at various sites in the USRT cohort This project is designed to facilitate study of the role of UV/ vitamin D in relation to several cancers. We recently completed an analysis in a USRT subpopulation of the UV and other determinants of circulating 25(OH)D which is in press in AJE. An additional analysis of how well 25(OH)D tracks in individuals across seasons will soon be submitted to J Clin Endocrinology. Other analysis planned involve the relationship between 25(OH)D and telomere length. We also plan to examine the relationship between specific UV wavelengths and various skin and other cancers. Leukemia and Other Cancer Incidence in Baltic Clean-up Workers Workers received an average radiation dose of approximately 10 cGy. No clear evidence of increased risk was seen for leukemia thyroid cancer or radiation-related cancer sites combined relative to incidence in the general population. An elevated risk was found for cancers of the pharynx esophagus central nervous system and a broad category of alcohol-related sites. Excess mortality was observed for cancer of the mouth and pharynx alcohol-related sites taken togetherand suicide. Twenty-five years of follow-up suggest that non-radiation determinants of cancer incidence and mortality predominate over direct effects of radiation in this cohort. Incidence of Cancers in Female Flight Attendants Flight attendants may be at increased risk of breast and other cancers due to work-place exposures including cosmic radiation and circadian rhythm disruption from traveling across multiple time zones. We are investigating the risk of breast and other cancers in 9631 female flight attendants and whether the risk is cosmic radiation dose-related. 2099548 +Bioengineering; Brain Cancer; Brain Disorders; Cancer; Childhood Injury; Climate-Related Exposures and Conditions; Clinical Research; Conditions Affecting the Embryonic and Fetal Periods; Dietary Supplements; Health Disparities; Minority Health; Nutrition; Pediatric; Pediatric Cancer; Perinatal Period - Conditions Originating in Perinatal Period; Physical Injury - Accidents and Adverse Effects; Prevention; Rare Diseases; Unintentional Childhood Injury; Women's Health Accidents;Affect;Animals;Area;Belarus;Benign;Case/Control Studies;Cessation of life;Chernobyl Nuclear Accident;Child;Childhood;Clinical;Cohort Studies;Collection;Consumption;Country;Coupled;Data;Data Analytics;Data Set;Databases;Development;Dose;Environment;Environmental Exposure;Ethnic group;Etiology;Event;Exposure to;External Beam Radiation Therapy;Fertility;Focus Groups;General Population;Genes;Genetic Predisposition to Disease;Glioma;Group Interviews;Gynecologist;Head circumference;Health;Hormones;Human;I131 isotope;Individual;Interview;Investigation;Ionizing radiation;Kazakhstan;Length;Life;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of thyroid;Manuscripts;Measurement;Measures;Medical;Methodology;Milk;Mothers;National Health and Nutrition Examination Survey;National Institute of Child Health and Human Development;Nature;Neonatal;Newborn Infant;Nuclear;Nuclear Accidents;Occupational Exposure;Organ;Persons;Play;Population;Population Study;Pregnancy;Pregnant Women;Preparation;Prevention;Province;Publishing;Questionnaires;Radiation;Radiation Accidents;Radiation Dose Unit;Radiation Protection;Radiation exposure;Radiation-Induced Cancer;Radioactive;Radioactive Fallout;Radioactive Iodine;Radioactive Waste;Radioisotopes;Radiology Specialty;Records;Resources;Risk;Risk Estimate;Risk Factors;Rivers;Role;Russia;Site;Skin Cancer;Skin Carcinoma;Solid;Source;Statistical Data Interpretation;Structure;Sunlight;System;Techniques;Testing;Testosterone;Thyroid Diseases;Thyroid Gland;Time;UV Radiation Exposure;Ukraine;Uncertainty;Vitamin D;Vitamins;Work;base;cancer risk;cohort;computer program;design;dosimetry;drinking water;environmental radiation;epidemiology study;feeding;fetal;field study;follow-up;genome wide association study;improved;in utero;internal radiation;leukemia;medical countermeasure;melanoma;member;mortality;neoplasm registry;offspring;population based;prenatal;prenatal exposure;prospective;racial and ethnic;radiation effect;reconstruction;reproductive function;reproductive outcome;response;screening;solar ultraviolet radiation;study population;the sun;ultraviolet;weapons Studies of Populations Exposed to Environmental Sources of Radiation n/a NCI 10702914 1ZIACP010132-27 1 ZIA CP 10132 27 15666236 "CAHOON, ELIZABETH " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1742818 NCI Cancer Mortality Among Populations Exposed to Radioactive Waste in the Techa River by Mayak Nuclear Facility Cancer mortality is being evaluated in a cohort of approximately 30000 people who lived by the banks of the Techa River in the Southern Urals of Russia and had protracted environmental radiation exposure from radioactive waste released into the river by the Mayak nuclear facility. Current efforts focus on statistical analyses using the recent follow-up data and dosimetry system and manuscript preparation. Significant dose-response relationships have been observed for both solid cancer and leukemia mortality. Chernobyl Thyroid Study in Belarus/Ukraine The Chernobyl accident in Ukraine contaminated large parts of Belarus northwestern Ukraine and bordering Russian provinces. Two case-control studies with individual dose estimates demonstrated a statistically significant link between thyroid cancer and environmental radiation dose from fallout related to the accident. REB and collaborators organized follow-up screening studies of benign and malignant thyroid disease among those exposed as children to fallout from the accident in Belarus and in Ukraine. The thyroid glands of approximately 12000 subjects in each country have been screened biennially for four cycles in Ukraine and three cycles in Belarus. The projects have transitioned from active screening to other forms of follow-up using existing national cancer registries. Cohort-based GWAS of Glioma We have completed a cohort-based genome wide association study of glioma including 18 studies from the Cohort Consortium with the aim of confirming gene regions associated with glioma risk identifying new regions of genetic susceptibility that may be more apparent in a cohort setting and conducting targeted gene-environment analyses based on the covariate data available from cohorts. Development of Computer Program for Organ Dose Calculations The computer program is based on Monte Carlo transport technique coupled with computational human phantoms to provide organ dose estimates for individuals exposed to radiological accidents or terrorist events. Dose reconstruction and Health Effects of In-utero and Early Life Radiation Exposure Appropriate medical countermeasures for prevention of adverse health effects following radiological or nuclear incidents are critical to radiation protection of exposed populations and are of particular scientific medical and public concern when pregnant women and their offspring are involved. Several thousands of children born in Belarus during the period from April 26 1986 through February 28 1987 were exposed in utero and in early life as a result of the Chernobyl accident. This study will establish a cohort of about 2500 Belarusian individuals exposed in utero and in early life to radioactive iodine and other radioactive isotopes from Chernobyl fallout reconstruct doses to the thyroid gland from internal and external radiation exposure ascertain thyroid cancer and other thyroid diseases and assess radiation dose-responses. NHANES III: Prospective Vitamin Study The NHANES III data set with measured vitamin D levels on about 20000 people is a resource that allows investigation of the relationship between vitamin D and specific causes of mortality. This cohort includes actual vitamin D measurements and about 2253 deaths of which nearly 900 are cancer deaths. In a published study of this data we found no relationship between circulating 25(OH)D and cancer mortality across racial/ethnic groups. The dataset also allows examination of relationships between 25(OH)D and other circulatinf hormones (e.g. testosterone) which we are reviewing. Skin Cancer in Radiologic Technologists Exposure to ultraviolet (UV) radiation from sunlight plays a predominant role in the etiology of melanoma and non-melanoma skin cancer but the nature of the relationship is not fully understood. We recently completed questionnaire-based collection of lifetime UV sun-related radiation exposure from more than 70000 U.S. radiologic technologists and have undertaken analyses to assess risks of specific forms of cancer in relation to exposure. We also plan to evaluate whether skin cancer risks associated with occupational exposures to ionizing radiation might be modified by questionnaire-derived estimates of UV radiation exposures. Study to Improve Thyroid Doses from Fallout Exposure in Kazakhstan This builds on an existing study of radiation exposure and thyroid disease among individuals in Kazakhstan exposed during childhood to radioactive fallout from nuclear tests conducted at the Semipalatinsk Nuclear Test Site between 1949 and 1962. High thyroid doses to this population from both internal and external radiation sources present a unique opportunity to quantify and compare the two types as risk factors for thyroid disease in a single population. A field study using focus group interviews has been conducted to investigate aspects of typical village life in areas affected by fallout that might influence individual radiation doses to the thyroid gland. We collected retrospective information about factors influencing radiation dose to the thyroid gland in children of two distinct ethnic groups including milk and milk product consumption seasonal practices of pasturing and supplemental feeding of dairy animals at the time of the nuclear tests time spent outdoors and radiation shielding provided by buildings. These data will fill key gaps in the current dose-reconstruction methodology and should result in improved dose estimates providing the basis for evaluating and quantifying dosimetric uncertainty and related biases in risk estimates. NICHD_NCI_Health Effects of in Utero Exposure to I-131 in Chernobyl Fallout The population-based epidemiologic study was designed to evaluate potential adverse reproductive outcomes associated with prenatal exposure to Iodine-131 as a result of radioactive releases from the April 1986 Chernobyl nuclear accident. The study population is a well-defined cohort of 2582 mother-child pairs from contaminated areas of northern Ukraine originally assembled to investigate the risk of benign and malignant thyroid disease through in-depth clinical screening examinations of the offspring and structured interviews with the mothers carried out in 2003-2006. Data for the current study of reproductive outcomes were ascertained by retrieving and reviewing cohort members' prenatal delivery and newborn records. Data were recorded on an Abstract Form designed with the help of study gynecologists and registered in analytic data base. Individual estimates of fetal thyroid Iodine-131 dose are available for all subjects. Statistical analyses to examine the relationship of fetal I-131 dose with neonatal anthropometrics and length of gestation have been carried out on a subset of cohort members with complete data (N=1167). Preliminary results show dose-dependent relationships with head circumference and gestational length. We are currently carrying out more extensive analyses to pursue these initial findings. We are also extending the work to explore radiation effects on reproductive function/fertility among the in-utero exposed offspring. 1742818 +Aging; Breast Cancer; Cancer; Diabetes; Digestive Diseases; Estrogen; Infertility; Liver Cancer; Liver Disease; Nutrition; Obesity; Orphan Drug; Ovarian Cancer; Prevention; Rare Diseases; Uterine Cancer; Women's Health Age;Anti-Inflammatory Agents;Antidiabetic Drugs;Aspirin;Benign;Breast Cancer Risk Factor;Cardiovascular system;Central Nervous System Neoplasms;Chemopreventive Agent;Chemoprophylaxis;Cholesterol;Chronic;Clinic;Clomiphene;Collaborations;Consumption;Data;Data Set;Development;Diabetes Mellitus;Diagnostic Factor;Dose;Drug usage;Endometrial Carcinoma;Estrogens;Etiology;Evaluation;Event;Exposure to;Fertility;Fertility Agents;Fertilization;Fertilization in Vitro;Fibroid Tumor;Fracture;Gender;Gynecologic;Hepatotoxicity;Hormonal;Hormones;Hypertension;Incidence;Individual;Infertility;Inflammation;International Agency for Research on Cancer;Intervention;Investigation;Lead;Link;Literature;Liver diseases;Long-Term Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of ovary;Medical;Medicare;Menopause;Metabolic syndrome;Metformin;Methodology;Michigan;Modeling;Non-Steroidal Anti-Inflammatory Agents;Norway;Obesity;Overweight;Pattern;Persons;Pharmaceutical Preparations;Pharmacology;Population;Preparation;Primary carcinoma of the liver cells;Progestins;Publications;Publishing;Regimen;Research;Research Personnel;Risk;Risk Factors;Risk Reduction;Severities;Therapeutic;Therapeutic Intervention;Thinness;Thyroid Diseases;Time;United States National Institutes of Health;Weight;Woman;Women's Health;bone loss;cancer risk;clinical practice;cohort;endometriosis;follow-up;high risk;hormone related cancer;hypertension treatment;insight;interest;liver development;malignant breast neoplasm;neoplasm registry;prospective;protective effect;rare cancer;reproductive;therapeutic evaluation Therapeutic and Diagnostic Factors as Related to Cancer Risk n/a NCI 10702912 1ZIACP010128-27 1 ZIA CP 10128 27 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 313017 NCI A large part of our portfolio within this Project has focused on the effects on cancer risk of exogenous hormones. Descriptive analyses using data from SEER documented increases in endometrial cancer incidence after 2002 when results from the Womens Health Initiative (WHI) Trial were published. We hypothesized that this reflected widespread decreases in continuous estrogen plus progestin (E+P) MHT use (the therapy linked with increased breast cancer risk within WHI) given that this is an exposure that we as well as others have documented as leading to reductions in endometrial cancer risk in overweight and obese women. In contrast in another analysis we found long-term sequential E+P use (which involves substantial exposure to unopposed estrogens) is associated with increased risk; this association was restricted to thin-to-normal weight women presumably reflecting their lower endogenous estrogen levels. In an additional investigation focused on ovarian cancer we found that both sequential and continuous E+P usage was associated with ovarian cancer risk increases. In fact in a descriptive study we noted an accelerated decline in ovarian cancer incidence among women 50 years and older in age-period-cohort models following the marked reduction in MHT use that occurred after publication of the WHI results. The notable gender discrepancy in rates of liver cancer has suggested that hormones influence risk leading to an interest in the effects of MHT use. However in the Liver Cancer Pooling Project (LCPP) we found no evidence that liver cancer risk was related to MHT use although we had limited information of the specific types of preparations used.In addition to MHT we have also been concerned regarding the long-term use of fertility drugs. In an extended followup of our large U.S. infertility cohort we saw no relationship of clomiphene use to either ovarian or endometrial cancers. However women exposed to 12 or more clomiphene cycles were at an increased risk of invasive breast cancers. In an evaluation of the long-term effects of in vitro fertilization (IVF) undertaken in collaboration with investigators at one of Israelis largest HMOs we saw no significant associations with breast endometrial or ovarian cancer risk but a significant reduction in cervical cancer presumably reflecting increased surveillance and treatment of precursor conditions among women availing themselves of reproductive assistance. We also collaborated on a study in Norway that evaluated cancer risk following IVF exposures. There were no increases in risk for most cancer although some elevated risk of breast cancer for the subjects followed for the longest periods of time. In addition some increases in risk were also observed for central nervous system tumors and for ovarian cancers among women who remained childless. To continue the evaluation of long-term cancer risks following IVF exposure we are conducting a retrospective linkage of nationwide IVF fertility clinic data with the national cancer registry. Once completed we will be able to evaluate both maternal and childhood cancer risk following IVF treatment.In 1999 the International Agency for Research on Cancer (IARC) reviewed the existing literature on OC use and hepatocellular carcinomas (HCC) and concluded that there was sufficient evidence of a causal relationship. However the number of studies included in the review was small and the number of cases per study modest. In the LCPP which involved large numbers we found no evidence that OC use was related to an increased risk of HCC. The increasing recognition of the importance of chronic inflammation in the etiology of ovarian cancer has prompted an interest in risk associated with usage of non-steroidal anti-inflammatory drug (NSAID) usage. In the NIH-AARP study we evaluated aspirin use and ovarian cancer risk but did not find an association possibly due to limited information on use patterns. In a large pooled analysis of individual data within the ovarian cancer association consortium (OCAC) a significant reduction in ovarian cancer risk was associated with regular aspirin use with evidence that the reduced risk was strongest for daily low-dose (100 mg) usage. This suggested that the same aspirin regimen proven to protect against cardiovascular events and associated with risk reduction of several cancers might have chemopreventive implications for ovarian cancer. We are following up on our aspirin finding for ovarian cancer using pooled prospective data in the ovarian cancer cohort consortium (OC3). [Ovarian cancer studies are described in Z01 CP010126 Hormone-related Cancers]The majority of risk factors for HCC cause chronic inflammation; thus we hypothesized that use of NSAIDs might be related to reduced risk. In analyses within the NIH-AARP study we found that aspirin but not non-aspirin NSAID use was significantly inversely associated with HCC risk. As most aspirin use in the population was on a daily basis the result suggested that consuming an 80 mg dose for cardiovascular chemoprophylaxis might also lead to a reduction in HCC risk.In an analysis that we conducted in the SEER-Medicare dataset we demonstrated that metabolic syndrome is a risk factor for HCC. As high cholesterol levels are one of the defining conditions of metabolic syndrome we sought to determine whether use of cholesterol-lowering drugsstatins--would decrease risk. In an analysis within the Henry Ford HMO in Detroit Michigan we did indeed find that persons who took statins were at significantly decreased risk of developing HCC. A subsequent analysis within the U.K.s Clinical Practice Research Datalink (CPRD) confirmed the inverse association between statin use and liver cancer risk. Analyses restricted to higher-risk individuals (i.e. those with pre-existing liver disease and those with diabetes) found similarly strong inverse associations suggesting that the observed risk reduction associated with statins was unlikely to reflect confounding by contraindication (concerns about hepatotoxicity with the use of statins that may result in biased prescribing patterns) and that statins may be beneficial even among persons at high-risk for liver cancer.A number of prior studies had suggested that use of metformin an anti-diabetic drug is inversely associated with development of liver cancer. Most of these studies however have compared metformin use to that of all other anti-diabetes medications. However anti-diabetic medications are strongly linked to diabetes duration and severity. To assess whether the apparent protective effect of metformin was due to it being a first line therapy we conducted an analysis in the CPRD that compared HCC cases with diabetes to controls with diabetes. Our analysis found that metformin was not strongly inversely associated with the development of HCC and has offered important methodologic insights related to the use of appropriate comparison populations while studying cancer risk associated with pharmacologic exposures. [Liver cancer studies are described in Z01 CP010158 Studies of Rare-Cancers] 313017 +Cancer; Chronic Liver Disease and Cirrhosis; Clinical Research; Diabetes; Dietary Supplements; Digestive Diseases; Emerging Infectious Diseases; Hepatitis; Hepatitis - B; Hepatitis - C; Infectious Diseases; Liver Cancer; Liver Disease; Lung; Lung Cancer; Nutrition; Obesity; Prevention; Rare Diseases Alcohols;Anatomy;Asian;Asian population;Awareness;Breast;Cancer Etiology;Coffee;Colon;Colorectal;Databases;Diabetes Mellitus;Diet;Dietary Component;Etiology;Fatty acid glycerol esters;Fruit;Glioma;Glucose;Goals;Hepatitis B;Hepatitis C;Incidence;Insulin;Iron;Juice;Life Style;Link;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Measures;Meat;Medicare;Metabolic Diseases;Nested Case-Control Study;Non-Steroidal Anti-Inflammatory Agents;Nutrition Disorders;Obesity;Pernicious Anemia;Physical activity;Process;Prospective cohort study;Reflux;Resources;Risk Factors;Role;Serum;Site;Smoking;Stomach;Ulcer;United States National Institutes of Health;Vitamin D;Work;cancer risk;cohort;diet and cancer;dietary;drinking;energy balance;fruits and vegetables;lifestyle factors;melanoma;mortality Etiologic Studies of Diet and Cancer n/a NCI 10702911 1ZIACP010127-27 1 ZIA CP 10127 27 11613071 "FREEDMAN, NEAL " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 117650 NCI Studies of diet and obesity with liver cancer: Liver cancer is the third leading cause of cancer-related mortality worldwide. Numerous hypotheses link different aspects of the diet e.g. alcohol meat fat fruits and vegetables coffee fruit juice with liver cancer. However of that list only alcohol is an established risk factor. In addition to dietary components there is a growing awareness of the importance of energy balance including obesity diabetes and physical activity with liver cancer. We are investigating these dietary and energy balance hypotheses taking advantage of large prospective cohort studies. In the past couple of years we have measured Hepatitis B (HBV) and Hepatitis C (HCV) positivity in several of our studies. HBV and HCV are strong risk factors for liver cancer and so now we can take account of these possible risk factors in our analyses. We have also measured several other analytes including insulin glucose vitamin D and serum iron and aim to determine the association of these analytes with cancer. We are also in the process of examining associations with specific dietary components such as meat fat coffee and fruits and vegetables. Finally we are examining lifestyle factors such as smoking and NSAID use.SEER-Medicare. We have worked to create a nested-case control study in the SEER-Medicare database in which to examine the association of diet and obesity related exposures with cancer risk. The very large size of the SEER-Medicare database allows us to examine hypotheses which are difficult to conduct other places-- for example the association of diabetes with particular anatomic sub-sites of the colon. We have developed the database and examined an initial set of exposures including obesity diabetes smoking ulcers gastric reflux and pernicious anemia.Coffee. Finally our work has potentially implicated coffee drinking in the etiology of liver and other cancers. Therefore we are comprehensively examining the association between coffee drinking and a wide range of different cancers including liver colorectal melanoma glioma breast and lung in the NIH-AARP and other studies. 117650 +Aging; Breast Cancer; Cancer; Clinical Research; Congenital Structural Anomalies; Endocrine Disruptors; Estrogen; Health Disparities; Minority Health; Ovarian Cancer; Pediatric; Prevention; Rare Diseases; Sexual and Gender Minorities (SGM/LGBT*); Urologic Diseases; Uterine Cancer; Women's Health Address;African;African American population;American;Androgens;Area;Atypical hyperplasia;Biological;Biological Assay;Breast Cancer Risk Factor;Case/Control Studies;Catechols;Caucasians;Characteristics;Clinical;Collaborations;Cryptorchidism;Data;Development;Diagnosis;Disease;Endometrial Carcinoma;Endometrial Hyperplasia;Epidemiology;Estradiol;Estrogen receptor negative;Estrogens;Etiology;Exhibits;Female Genital Neoplasms;Finland;GTP-Binding Protein alpha Subunits Gs;Genetic;Gestational Diabetes;Ghana;Glucuronides;Gynecologic Oncology Group;Health Maintenance Organizations;Heterogeneity;High Prevalence;Histologic;Hormonal;Hormones;Hydroxylation;Hypospadias;Impairment;Incidence;Individual;Inguinal Hernia;Investigation;Israel;Knowledge;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of esophagus;Malignant neoplasm of male breast;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of testis;Mammographic Density;Mammography;Measures;Medical Records;Menopause;Metabolic;Metabolic Pathway;Methods;Methylation;Mothers;Natural History;Nested Case-Control Study;Parents;Participant;Physical activity;Polishes;Postmenopause;Prepaid Health Plans;Prognosis;Prognostic Factor;Questionnaires;Reporting;Research;Research Personnel;Rest;Risk;Risk Factors;Role;Sampling;Site;Spermatogenesis;Standardization;Sweden;Syndrome;Terminal Ductal Lobular Unit;Testicular Dysgenesis Syndrome;Testicular Germ Cell Tumor;Urine;Woman;Women's Health;anxious;base;bisphenol A;boys;cancer risk;clinical prognostic;cohort;congenital anomaly;design;genotoxicity;hormone related cancer;interest;liquid chromatography mass spectrometry;male;malignant breast neoplasm;multidisciplinary;novel;programs;reproductive system disorder;screening;tumor;urinary Hormone-Related Cancers n/a NCI 10702910 1ZIACP010126-27 1 ZIA CP 10126 27 15187078 "GIERACH, GRETCHEN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 9342840 NCI This project covers a broad base of studies aimed at assessing the epidemiology of the majority of hormonally-related cancers. Major efforts are underway for breast cancer endometrial cancer ovarian cancer and testicular cancer. We also have an active research program on prostate cancer covered in a separate report (Z01 CP010180-02). Our efforts for all of these cancers relate to a variety of environmental genetic and hormonal predictors of risk. It is well recognized that breast cancers that occur among Africans and African-Americans tend to exhibit different clinical characteristics as compared with Caucasians including a higher prevalence of estrogen receptor negative and triple negative tumors cancers associated with a generally poor prognosis. To better understand the reasons for the occurrence of these cancers we are conducting a case-control study in Ghana where incidence rates of breast cancer have been increasing. The study has been designed to evaluate some novel etiologic hypotheses as well as to relate risk factors to carefully defined subtypes of breast cancers. We have also had a major interest in studying a number of intermediate markers of breast cancer risk including mammographic breast density and terminal duct lobular unit involution. We have developed and used some novel methods for measuring both of these presumed breast cancer precursors and have related breast cancer risk factors to varied measures. We are also examining how these measures relate to subsequent breast cancers. In collaboration with the Gynecologic Oncology Group we have administered a standardized questionnaire to women in a large endometrial cancer trial. This has enabled analyses which have demonstrated that there is great etiologic heterogeneity of endometrial cancer across histologic subtypes. We have also assessed how these factors relate to survival after adjusting for other clinical prognostic factors. We have learned much about the natural history of cervical cancer (as described in another project report) and are now anxious to expand our knowledge in this area to address the natural history of another gynecologic tumor namely endometrial cancer. Endometrial hyperplasias are recognized to increase the subsequent risk of endometrial cancer but data with which to accurately predict risk are lacking and it is unknown how other factors might influence those risks. We have conducted a nested case-control study within a prepaid health plan to better understand the risk of endometrial cancer in women diagnosed with endometrial hyperplasia. Data from this study have supported the notion that atypical hyperplasia is strongly related to subsequent endometrial cancer risk. We are also conducting a study to assess early markers which may be important to the development of ovarian cancer and endometrial cancer. To further our understanding of testicular cancer we have conducted a number of studies regarding Testicular Dysgenesis Syndrome (TDS) a group of etiologically related male reproductive disorders which included cryptorchidism hypospadias impaired spermatogenesis and testicular germ cell tumors (TGCTs). While the associations among cryptorchism impaired spermatogenesis and TGCT have been widely acknowledged the linkage of hypospadias to the rest of the syndrome has been unclear. To examine this question we analyzed linked medical records data from Sweden and found that hypospadias was significantly associated with both cryptorchidism and TGCT. We also found that another congenital anomaly inguinal hernia was significantly associated thereby suggesting that both hypospadias and inguinal hernia should be included in TDS. Given that a previous study in Finland found that boys born to mothers with gestational diabetes were at an increased risk of cryptorchidism we examined the association in a health maintenance organization (HMO) in Israel However we found no association between gestational diabetes and either congenital cryptorchidism or hypospadias. This project has also included a focus on the etiologic role of endogenous hormones for a variety of tumor sites. We have established a close collaboration with a laboratory in Frederick which has developed a liquid chromatography/mass spectrometry assay that measures 15 estrogen metabolities. We have assessed the relationship of these metabolites to breast cancer risk in three large cohorts. Although there were some differences across these studies in terms of the effects of individual metabolites all three showed significant associations of risk with high estradiol levels. Several of the studies suggested that increased 2- or 4-hydroxylation of parent estrogens might lower postmenopausal breast cancer risk of interest given that this metabolic pathway involves less extensive methylation of potentially genotoxic catechols. We have also contributed our data to several consortial efforts that have further clarified the effects of endogenous hormones on breast cancer risk.To address mounting concerns regarding a possible link between bisphenol A (BPA) and breast cancer risk we used an assay that we recently helped develop and validate to measure its primary excreted metabolic conjugateBPA-glucuronide (BPA-G). Using urine samples collected in our Polish Breast Cancer Study (PBCS) we found that BPA-G concentrations were higher among women reporting extended use of menopausal hormones and a prior screening mammogram but there was no relationship with breast cancer risk. We are currently collaborating with investigators of the Womens Health Initiative to measure estrogens in relation to ovarian and endometrial cancers that developed among participants in the observational component of that investigation. We also have measured estrogens and androgens in relation to male breast testicular and esophageal cancers. Finally in the Polish study we have measured urinary estrogens among the control subjects in order to more fully understand relationships with identified risk factors including physical activity levels that have been objectively determined. . 9342840 +Cancer; Childhood Leukemia; Clinical Research; Health Disparities; Health Effects of Indoor Air Pollution; Hematology; Kidney Disease; Lung; Lung Cancer; Minority Health; Pediatric; Pediatric Cancer; Prevention; Rare Diseases; Rural Health; Social Determinants of Health; Tobacco; Tobacco Smoke and Health; Women's Health African American population;Agricultural Health Study;Agriculture;Animal Feed;Asian;Benzene;Blood;Breast;California;Carcinogens;Case/Control Studies;Cells;Child;Childhood Leukemia;China;Collaborations;Colon Carcinoma;Data;Diesel Exhaust;Employment;Environmental Exposure;Environmental Pollution;Environmental Risk Factor;Equipment;Ethnic group;European;Evaluation;Exposure to;Farm;Female;Goals;Hispanic;Incidence;Industrialization;Industry;Institutes;Iowa;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Melatonin;Minority;Monitor;Municipal Government;New England;Occupational;Occupational Exposure;Occupations;Ovarian;Participant;Passive Smoking;Pesticides;Population;Prospective cohort study;Renal Cell Carcinoma;Renal carcinoma;Reporting;Research;Risk;Risk Factors;Role;Sampling;Spouses;Thyroid Gland;Universities;Urine;Wife;Woman;Women's Health;base;cancer risk;cancer type;cigarette smoking;drinking water;epidemiology study;farmer;leukemia;leukemia/lymphoma;men;mortality;non-smoking;operation;pesticide exposure;population based;racial and ethnic;racial disparity;respiratory;shift work Occupational and Environmental Determinants of Cancer among Women and Minorities n/a NCI 10702907 1ZIACP010123-27 1 ZIA CP 10123 27 15666226 "HOFMANN, JONATHAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 398807 NCI Traditionally occupational research has focused primarily on white men even though women comprise nearly half of the U.S. civilian workforce and minorities are often employed in jobs with hazardous exposures. The OEEB has undertaken a number of population-based epidemiologic studies which include women and minorities during the past year with a substantial focus in occupation . In the Agricultural Health Study a prospective cohort study of more than 90000 subjects including approximately 32000 women and 2000 minorities both direct occupational exposure and indirect environmental exposure to pesticides and other exposures are being evaluated for association with breast ovarian thyroid and other cancers. Diesel exhaust from farm equipment has also been evaluated for associations with lung cancer among the spouses of farmers. In addition living near concentrated animal feeding operations (CAFOs) are being evaluated for associations with several cancer types including lung and other respiratory cancers. The Shanghai Women's Study is a prospective cohort study of 75000 women conducted by Vanderbilt University in collaboration with NCI and the Shanghai Cancer Institute. Blood/buccal cell and urine samples have been collected from nearly 90% of participants. Exposure assessment to benzene has been based on industrial monitoring data maintained by the Shanghai municipal government and is being evaluated for associations with leukemia and lymphoma. Cancer risk in relation to occupation and industry of employment is being evaluated including a recent report of lung cancer risk associated with employment in certain occupations that may have exposure to potential industrial carcinogens. Two studies have also been conducted within this study focused on the effect of night shift work on melatonin levels and on overall cancer risk. The New England Bladder Cancer study a large multicenter case-control study of bladder cancer is on-going to examine environmental and occupational risk factors and the reasons for the consistently elevated incidence and mortality of this cancer in New England and includes the largest number of women of any previous case-control study. The U.S. kidney cancer study is the first study of this cancer that included a sufficient number of African Americans for separate evaluation of their risks and the contribution of environmental and occupational risk factors to the racial disparity in incidence of this cancer. NCI is leading the environmental sampling component of the California childhood leukemia case-control study. The approximately 40% Hispanic and 10% Asian participants in this study provide an opportunity to evaluate agricultural and other risk factors among these minorities. In the Iowa Women's Health Study environmental contaminants in drinking water are being evaluated for associations with cancers of the bladder ovary pancreas and colon. 398807 +Agent Orange & Dioxin; Bioengineering; Brain Cancer; Brain Disorders; Cancer; Climate-Related Exposures and Conditions; Clinical Research; Endocrine Disruptors; Health Effects of Indoor Air Pollution; Pediatric; Pediatric Cancer; Rare Diseases; Social Determinants of Health 24-Dichlorophenoxyacetic Acid;Air;Algorithms;Aromatic Amines;Aromatic Polycyclic Hydrocarbons;Arsenic;Asbestos;Asian;Atrazine;Benzene;Benzene Exposure;Biological Markers;Brain;Breast;Cadmium;Carbon Black;Carcinogens;Case/Control Studies;Chemicals;Childhood Malignant Brain Tumor;Chlorinated Hydrocarbons;Chromium;Classification;Code;Cohort Studies;Computer software;Cross-Sectional Studies;Data;Databases;Development;Diesel Exhaust;Dose;Dust;Electromagnetic Fields;Ewings sarcoma;Exposure to;Formaldehyde;Gasoline;Germ cell tumor;Goals;Hormonal;Human;Immune;Individual;Kidney;Larynx;Lead;Link;Lung;Lymphatic;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of urinary bladder;Measurement;Metals;Methodological Studies;Methods;Modeling;Neoplasms;New England;Occupational;Occupational Epidemiology;Occupational Exposure;Occupations;Participant;Particulate;Pattern;Performance;Pesticides;Physical activity;Polychlorinated Biphenyls;Population Study;Procedures;Publishing;Questionnaires;Renal carcinoma;Reporting;Solvents;Spain;Specificity;System;Techniques;Text;Training;Trichloroethylene;Urine;Validation;Woman;Wood material;Work;air monitoring;base;case control;cohort;data mining;design;exhaust;farmer;gender difference;genotoxicity;improved;lead exposure;leukemia;mathematical model;men;novel;population based;programs;response;urinary Occupational Exposure Assessment n/a NCI 10702906 1ZIACP010122-27 1 ZIA CP 10122 27 10271059 "FRIESEN, MELISSA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 130681 NCI Assessment of occupational exposures is a crucial factor in evaluating dose-response relationships and most human population-based studies conducted by the Branch have an extensive exposure assessment component. Major assessment efforts in cohort studies have involved exposures to pesticides benzene polycyclic aromatic hydrocarbons and diesel exhaust fumes and to a broad range of exposures in a cohort study of women in Shanghai and shipyard workers. Cross-sectional studies are being conducted to study the effect of benzene diesel exhaust trichloroethylene and atrazine on genotoxic immune and hormonal parameters. In the case-control design jobs have been evaluated for a wide variety of exposures including solvents (including chlorinated hydrocarbons aromatic and other solvents) metals (arsenic chromium cadmium lead) electromagnetic fields polychlorinated biphenyls dusts (wood dust and other types) asbestos formaldehyde physical activity nitrosoamines polycyclic aromatic hydrocarbons gasoline and diesel exhausts aromatic amines and pesticides. These exposures have been evaluated in studies of cancer of the bladder brain breast kidney lung larynx and the lymphatic and hemtopoietic system and of childhood brain cancer germ cell tumor cancer and leukemia Ewings sarcoma and possible associations with parental occupations. Methodologic studies are also conducted to improve exposure assessment techniques and to understand exposure patterns such as peak exposures. A study has been conducted in Shanghai to evaluate assessments made from detailed occupational questionnaires with air measurements. A report describing the exposure assessment procedures for evaluating EMF exposures in a brain cancer case-control study has been published. Reports describing the occurrences of pesticides polychlorinated biphenyls chlorinated and aromatic solvents wood dust lead cadmium and nitrosoamines are being prepared. Detailed questionnaires have been developed for several case-control studies: a kidney cancer study in the US a bladder cancer study in New England a NHL study in the US and a bladder cancer study in Spain and neoplasmic lyphomas in four Asian centers (AsiaLymph Study). A comparison of assessments to pesticides has been compared to pesticide metabolites in the urine. Important determinants of exposure to 24-D has been evaluated using urinary levels. Historical benzene and lead exposure estimates have been developed using a novel framework that combines job-exposure matrices with databases of inspection measurements to predict exposure for a population-based cohort of women in Shanghai. Air monitoring of particulate black carbon and bioaerosol exposures is being conducted on farmers. Data mining models have been used to extract decision rules from questionnaire responses and previously assessed exposure metrics for occupational diesel exhaust exposure so that the decision rules can be used in subsequent studies. The same data mining approaches is being used for other agents including lead and chlorinated solvents. An algorithm-based approach that efficiently links expert-based exposure decisions to participants responses to exposure-oriented modules was developed to estimate occupational diesel exhaust exposure and was compared to estimates from an expert review of each individual job. Exposure estimates for lead and cadmium exposure are being developed for the kidney cancer study. Occupational questionnaire data was used to evaluate gender differences in work tasks and exposure within men and women reporting the same job title. A software program to automatically assign occupation codes based on free-text entries of job title has been developed to improve the efficiency of conducting occupational epidemiology; a revised algorithm is being developed by expanding the training database. 130681 +Brain Cancer; Brain Disorders; Breast Cancer; Cancer; Clinical Research; Dental/Oral and Craniofacial Disease; Digestive Diseases; Health Disparities; Health Effects of Indoor Air Pollution; Hematology; Kidney Disease; Lung; Lung Cancer; Minority Health; Pancreatic Cancer; Prevention; Rare Diseases; Women's Health Aircraft;Benzene;Biochemical;Body of uterus;Brain;Cancer Etiology;Carcinogenesis Mechanism;Case/Control Studies;Categories;Cessation of life;Chemicals;Chronic;Coast Guard;Cohort Studies;Colon;Diesel Exhaust;Electromagnetic Fields;Employment;Etiology;Europe;Exposure to;Formaldehyde;Hour;Individual;Industrial Health;Industrialization;Industry;Investigation;Iowa;Kidney Diseases;Link;Liver Cirrhosis;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Malignant neoplasm of nasopharynx;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Measures;Medical;Meleagris gallopavo;Mesothelioma;Methodological Studies;Methods;Myeloid Leukemia;Nervous System;Occupational;Occupational Exposure;Occupational Malignant Neoplasm;Occupations;Organic solvent product;Pattern;Pesticides;Poland;Population;Predisposition;Pulmonary Emphysema;Rectum;Renal carcinoma;Reporting;Rheumatic Heart Disease;Risk;Rubber;Russia;Ships;Silicon Dioxide;Spain;Techniques;Telecommunications;Textile Industry;Time;Trichloroethylene;Uterine Diseases;Woman;cancer risk;carcinogenicity;cohort;combustion product;design;follow-up;improved;leukemia;malignant breast neoplasm;mortality;repaired;response;trend;urinary Studies of Occupational Cancer n/a NCI 10702904 1ZIACP010120-27 1 ZIA CP 10120 27 10271053 "LAN, QING " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1210861 NCI Major etiologic investigations focus on working populations exposed to benzene trichloroethylene other organic solvents formaldehyde diesel exhausts combustion products electromagnetic fields pesticides and silica. Findings linking cancer with occupational exposures included an excess of nasopharyngeal cancer and leukemia among workers exposed to formaldehyde. Results from two studies suggest an association with myeloid leukemia. The first an industrial cohort study of workers in formaldehyde industries indicate an association with myeloid leukemia with risks that were persistently elevated over 40 years of follow-up time. In the second study a case-control study of workers in the funeral industry an elevated OR was found for those whose estimated cumulative formaldehyde exposure exceeded 9253 parts per million hours (OR = 3.1; 95% CI = 1.0 to 9.6 P = .047). Nasopharyngeal cancer was also associated with formaldehyde as measured by average intensity peak exposure cumulative and duration of exposure (p-trend = 0.066 0.025 0.001 and 0.147 respectively). Breast cancer among women in Shanghai was associated with employment in the textile industry medical profession and the telecommunications industry. A cohort of U.S. Coast Guard shipyard workers was found to have elevated mortality from emphysema lung cancer and mesothelioma while a cohort of Coast Guard marine inspectors who carry out ship inspections involving exposure to a variety of chemicals showed excess deaths from cirrhosis of the liver and chronic rheumatic heart disease. Among other industrial studies a cohort of workers engaged in the repair and maintenance of aircraft and missiles showed no clear exposure-response gradient for TCE with any cancer but did show an approximately two-fold excess of renal disease. In a case-control study in Europe evaluated the risk of renal cancer increased risk was observed among subjects ever TCE-exposed (OR=1.63;(1.04-2.54) compared to those never exposed. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR=1.38;(0.81-2.35); OR=2.34;(1.05-5.21) p-trend=0.02). We have also reported findings from a variety of case-control studies that have examined occupation and cancer risks including bladder cancer in Spain kidney cancer in Europe lung cancer in Russia and Turkey pancreas cancer in Iowa and breast cancer in Poland. Other studies are evaluating brain cancer risk from electromagnetic fields (EMF) relying on quantitative exposure estimates from job-specific modules. Methodologic studies dealt with confounding and exposure misclassification quantitative exposure assessment and exposures and urinary mutagenicity in rubber workers. 1210861 +Cancer; Climate-Related Exposures and Conditions; Clinical Research; Endocrine Disruptors; Health Disparities; Health Effects of Indoor Air Pollution; Minority Health; Prevention; Rare Diseases; Rural Health; Women's Health 24-Dichlorophenoxyacetic Acid;Agricultural Health Study;Agriculture;Agrochemicals;Aromatic Amines;Biological;Birth;Blood;Carbaryl;Case/Control Studies;Cells;Chemicals;Child;Chronic Disease;Computer Assisted;Data;Defect;Diet;Disease;Dust;Enrollment;Epigenetic Process;Etiology;Evaluation;Exposure to;Family history of;Farm;Future;Gardenal;Genomic DNA;Home;Insecta;Insecticides;Iowa;Length;Life;Limb structure;Link;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of thyroid;Malignant neoplasm of urinary bladder;Medical;Methodology;Molecular;Multiple Myeloma;National Institute of Environmental Health Sciences;North Carolina;Occupational Exposure;Occupational Malignant Neoplasm;Organophosphates;Outcome;Paper;Participant;Pesticides;Plants;Population;Prospective cohort study;Public Health;Publishing;Questionnaires;Research Personnel;Risk;Rodent;Self Administration;Source;Specimen;Spouses;Telephone Interviews;Update;Woman;cancer risk;cohort;commercial application;design;early life exposure;epidemiology study;farmer;interest;lifestyle factors;malignant breast neoplasm;men;offspring;pesticide exposure;programs;recruit;statistics;telomere;vector control Studies of Occupational Cancer (Pesticides) n/a NCI 10702903 1ZIACP010119-27 1 ZIA CP 10119 27 11613066 "BEANE FREEMAN, LAURA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2060486 NCI There are several studies within this project. However the largest of these is the Agricultural Health Study (AHS). This prospective cohort study was designed to evaluate the relationship between pesticides and other agricultural factors and the risk of cancer and other diseases. Enrollment in this study includes about 90000 men and women from Iowa and North Carolina. From 1993-1997 detailed information was obtained by self-administered questionnaire and from 1998 through September 2003 and again from 2004 through 2010 computer assisted telephone interviews updated the information collected at enrollment. Telephone interviews include questions on pesticides used and other agricultural exposures lifestyle factors medical and family history of disease and diet. A questionnaire focused on chronic disease other than cancer was administered in 2010-2015 and focused on chronic disease other than cancer was led by investigators from NIEHS. The AHS has provided information on a number of pesticide-cancer associations over the years. In this FY several papers were published including one on bladder cancer showing a link between aromatic amine pesticides and bladder cancer risk in the pesticide applicators. Another evaluation showed an increased association between metolachlor use and liver cancer which had been previously linked to liver cancer in rodents. The AHS spouses represent an important population in which to evaluate lower exposure levels as well as cancer among women. A study among this group showed an increased risk of thyroid and ovarian cancers with exposure to specific organophosphate insecticides. Buccal cells are available from approximately 50% of the cohort and provides a source of genomic DNA for GXE studies and studies of epigenetic mechanisms. Smaller sub-studies have biological specimens for the evaluation of intermediate effects of exposure and outcome. This year a study was published evaluating the association between telomere length and a number of pesticides and showed an association between 24-D use and shorter telomeres. There is currently an effort underway to recruit 1600 farmers within the AHS to update exposure information and collect blood and other biological specimens and dust for the purpose of evaluating several hypotheses related to pesticide exposure. A paper describing the methodology and preliminary statistics was published this year. The AHS has been a productive study with which to evaluate many hypotheses related to pesticides. However early life exposures and future cancer risk are of great interest. At enrollment AHS participants provided information on their offspring. A new effort was launched to enumerate these offspring and follow them with the purpose of evaluating their early life pesticide and other farm exposures and future cancer risk. The AHS also contributes data to AGRICOH the consortium of agricultural cohorts. An initial paper describing the harmonization of exposure across studies was published this year with etiologic results focused on lymphohematopoietic malignancies to follow. Pooled studies of breast and prostate cancer have also been initiated within the consortium. Other studies within the Branch are also evaluating risks associated with pesticide exposure. A pooled study of case-control studies of multiple myeloma demonstrated an increased risk associated with the use of DDT carbaryl and captan. maternal occupational exposure to agricultural chemicals may increase the risk of giving birth to a child with limb defects. 2060486 +Aging; Breast Cancer; Cancer; Cancer Genomics; Climate-Related Exposures and Conditions; Clinical Research; Genetics; Hematology; Human Genome; Microbiome; Prevention; Rare Diseases; Women's Health Age;Area;Asian;Attention;Autoimmune Diseases;Autoimmunity;BRAF gene;Blood;Brain;Breast Cancer Genetics;Breast Cancer Patient;Breast Cancer Risk Factor;Canada;Cancer Hospital;Candidate Disease Gene;Case/Control Studies;Categories;Cells;Characteristics;Childhood Medulloblastomas;China;Chinese;Chordoma;Chronic;Clinic;Clinical;Cohort Effect;Complement;Complex;Country;Cutaneous Melanoma;DNA;Data;Dentistry;Development;Dysplastic Nevus;Eating;Embryo;Epidemiologist;Estrogen Receptor Status;Estrogen receptor negative;Estrogen receptor positive;Estrogens;Etiology;Exposure to;Expression Profiling;Family;Family Study;Family history of;General Population;Genes;Genetic;Genetic Diseases;Genetic Research;Goals;Hematologic Neoplasms;High-Risk Cancer;Hong Kong;Human Microbiome;Immune;Incidence;Individual;Investigation;Italy;Korea;Lesion;Link;Malaysia;Malaysian;Malignant Bone Neoplasm;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical;Melanocortin 1 Receptor;Melanocytic nevus;Menopausal Status;Metabolism;Molecular;Molecular Profiling;Monoclonal gammopathy of uncertain significance;Morphology;Multiple Myeloma;Mutation;Neoplasm Metastasis;Neoplasms;Nervous System;Nevi and Melanomas;Nevus;Normal tissue morphology;Not Hispanic or Latino;Oncogenes;Outcome;Pathogenesis;Pathway interactions;Patients;Pattern;Philadelphia;Pilot Projects;Play;Polishes;Population;Predisposition;Process;Prognostic Factor;Protocols documentation;Questionnaires;Receptor Gene;Recording of previous events;Registries;Regulation;Reporting;Research Personnel;Rest;Risk;Risk Factors;Role;Rural;Sampling;San Francisco;Sarawak;Scandinavia;Singapore;Site;Skeleton;Skin;Smoker;Somatic Mutation;Spain;Specimen;Structure;Suggestion;Sun Exposure;Sunscreening Agents;Susceptibility Gene;Taiwan;Tea;Terminal Ductal Lobular Unit;Testing;Time;Tissue Sample;Tissues;Tumor Subtype;Tumor Tissue;Ulcerative Colitis;United States;United States National Institutes of Health;Universities;Variant;Woman;age effect;base;cancer subtypes;cancer type;carcinogenesis;case control;cdc Genes;cohort;comorbidity;data registry;disorder risk;drinking;early onset;environment related cancer;exome sequencing;follow-up;genetic epidemiology;genome wide association study;high risk;human disease;individualized medicine;malignant breast neoplasm;medical schools;melanoma;microbiome;molecular subtypes;neoplasm registry;non-smoker;older women;oral microbiome;parity;polygenic risk score;population based;preservation;rare variant;rate of change;receptor;risk variant;stem cells;tanning booths;telomere;the sun;tumor;tumor DNA;young woman Genetic Epidemiology n/a NCI 10702901 1ZIACP005803-28 1 ZIA CP 5803 28 2062427 "GOLDSTEIN, ALISA " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2399238 NCI Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies.Analyses of a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco showed modest non-significant decreased risk of melanoma among susceptible individuals who used sunscreens most of the time. Young women were the individuals most likely to use tanning beds and use was related to melanoma risk. Those who used tanning beds were more likely to have melanomas in sites not usually exposed to sun. These observations may help explain the increasing rates and changing distribution of melanoma among young women in the general population. Questionnaire data tumor and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy showed a strong association between germline variants in the melanocortin-1 receptor (MC1R) gene and melanoma with somatic mutations in the BRAF oncogene in subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage. We confirmed this association in an independent population. Data from other Mediterranean populations have been collected and harmonized to extend the analyses of association between melanoma risk and several risk factors also including immune-related genes. In this combined sample we identified suggestive evidence for a role of telomere-related genes in the etiology of melanoma. Moreover a genome-wide association study (GWAS) of melanoma cases from Mediterranean countries and appropriate controls is ongoing. A polygenic risk score analysis using the GWAS data and additional data from melanoma consortia is also ongoing. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure body site nevi count susceptibility genes and molecular alterations is planned. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway we are currently collecting multiple tissue samples of normal skin common melanocytic nevi dysplastic nevi melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. A project was developed to collect personal and family medical history buccal cells and tumor tissue from sporadic chordoma patients from the United States and Canada. Using DNA from 100 sporadic chordoma patients in this study we identified several common and rare variants in the T gene that are related to disease risk providing more evidence for the importance of the T gene in the pathogenesis of both familial and sporadic chordoma. Currently we are using whole-exome sequencing (WES) to identify additional susceptibility genes in chordoma families without T duplication and sporadic chordoma cases. The WES analysis identified several genes that are potentially related to chordoma predisposition and functional follow-up is in process. We are also collaborating with cancer hospitals in Beijing China to collect germline DNA and chordoma tumor tissues from Chinese chordoma patients to follow up on variants we identify from the WES project. Alterations in the normal microbiome are increasingly recognized to play a role in human disease. Using protocols adapted from the NIH Human Microbiome Project we conducted pilot studies with investigators from the School of Medicine and Dentistry University of Rochester to evaluate differences in the oral microbiome between smokers and nonsmokers. Analysis of the resultant microbiome data is in progress. Using data we collected from the Polish Breast Cancer Study and breast cancer association consortium we demonstrated that risk factors for breast cancer and morphology and molecular characteristics of terminal duct lobular units (TDLUs) the structures from which breast cancers arise varied by molecular subtypes. In addition we found that parity-related molecular changes were preserved in breast cancer patients with ER-positive tumors but disrupted in patients with ER-negative tumors a finding that may partially account for the observed differential effect of parity in these two tumor subtypes. We are currently analyzing the expression profiling data to identify molecular signatures for TDLU involution and parity. Recently we initiated several breast cancer projects with clinicians and epidemiologists in Asian countries to study breast cancer among Asian women. Using data collected from Sarawak Malaysia we showed that the overrepresentation of early-onset and ER-negative tumors among Malaysian women was largely due to the disproportionally lower incidence of late-onset ER-positive tumors rather than an absolute increase in ER-negative cancers. We extended this finding using cancer registry data from several Asian countries (Singapore Taiwan Hong Kong China Korea) and reported that after the adjustment of period and cohort effects the age effects of breast cancer may be more similar between Asian and Western women than previously recognized. Our results also showed that rapidly rising cohort specific rates have narrowed the historic disparity between Chinese and US NHW breast cancer populations particularly in regions with the lowest baseline rates (such as rural China) and among older women. We developed a new tissue-based breast cancer study in Hong Kong and plan to collect breast tumor and adjacent normal tissues from up to 1000 breast cancer cases with the goal of identifying molecular changes that are related to risk and clinical factors for breast cancer subtypes among Chinese women in Hong Kong. Using the Hong Kong data we collected we found a complex relationship between tea drinking and breast cancer risk that is modified by menopausal status age at tea drinking and possibly ER status. We also identified an interesting association between nighttime eating and increased breast cancer risk among Hong Kong women.We are continuing to conduct studies of hematologic malignancies using the Swedish linked registry data to complement the family studies in GEB. However the current level of activity of these studies is low. We have recently completed a study with some additional data added which describes the effect of prior autoimmune diseases on survival of patients with MGUS and multiple myeloma (MM). As expected in control individuals autoimmune diseases lower overall survival. We also found that survival of MGUS and MM patients was decreased in patients with pre-existing autoimmune diseases. When analyzing different types of autoimmune diseases a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors or that patients with a personal history of autoimmunity develop more severe cases of MM and MGUS or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM and underlines the need for studies aimed at tailoring therapy according to comorbidity. 2399238 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Esophageal Cancer; Health Disparities; Infectious Diseases; Minority Health; Nutrition; Prevention; Rare Diseases; Stomach Cancer Ablation;Acetaldehyde;Adult;Age;Animals;Antibodies;Area;Aromatic Polycyclic Hydrocarbons;Beta Carotene;Beverages;Biopsy;Black Tea;Brazil;Cancer Etiology;Cardiovascular system;Carotenoids;Case/Control Studies;Cessation of life;Characteristics;China;Clinic;Clinical;Cohort Studies;Consumption;County;DNA;Death Rate;Dental Hygiene;Development;Diagnosis;Dietary Intervention;Disease;Dose;Dysplasia;Early Diagnosis;Early treatment;Enrollment;Environmental Risk Factor;Esophageal Squamous Cell Carcinoma;Esophageal Tissue;Esophagus;Etiology;Evaluation;Evaluation Studies;Excision;Feasibility Studies;Freezing;Fumonisins;Gastric Cardia Adenocarcinoma;General Population;Genetic Polymorphism;Genetic Risk;Geography;Glucuronides;Goiter;Helicobacter pylori;High grade dysplasia;Human Papillomavirus;Human papillomavirus 16;Human papillomavirus 18;In complete remission;Individual;Intervention Trial;Iodine;Iran;Kenya;Laboratories;Lesion;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Measures;Methods;Minerals;Neighborhoods;Participant;Partner in relationship;Patient Self-Report;Patients;Persons;Population;Prevention;Prevention strategy;Prognosis;Province;Radiofrequency Interstitial Ablation;Randomized;Residual state;Resolution;Risk;Risk Factors;Role;Ruminants;Sampling;Selenium;Serology;Serum;Specimen;Stains;Stomach;Stroke;Supplementation;Symptoms;Tea;Techniques;Temperature;Testing;Tissues;Tobacco use;Tooth Loss;Upper digestive tract structure;Vital Status;Vitamin E;Vitamins;Zinc;alpha Tocopherol;base;cancer risk;cancer therapy;carcinogenesis;case control;cohort;design;drinking;field study;follow-up;genetic risk factor;high risk population;human papilloma virus oncogene;insight;low socioeconomic status;malignant stomach neoplasm;microendoscopy;modifiable risk;molecular marker;mortality;opium use;response;screening;stomach cardia;tumor;upper gastrointestinal cancer;urinary Upper Gastrointestinal Cancer Studies n/a NCI 10702898 1ZIACP000185-18 1 ZIA CP 185 18 8770361 "DAWSEY, SANFORD M" Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2680713 NCI BACKGROUND: Gastric cancer and esophageal cancer are the second and sixth most common causes of cancer death worldwide. Both of these upper gastrointestinal tract (UGI) cancers have a very poor prognosis largely because symptoms usually do not occur until late in the disease. Significant reduction in UGI cancer mortality will probably require development of new prevention strategies based on identification of new modifiable risk factors and development of new methods to diagnose and treat more cases at earlier more curable stages of disease. PURPOSE: The aims of this project are (1) to examine hypotheses relating to the etiology and prevention of upper gastrointestinal cancers and (2) to develop successful clinical strategies for the early detection and treatment of these cancers. METHODS: Both etiologic and early detection studies are most efficiently done in high-risk populations so many of the studies in this project are performed in such populations. (1) Etiologic studies: (a) China: Between 1985 and 1991 we conducted two randomized nutrition intervention trials (NIT) in Linxian China a county where cumulative death rates due to esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) exceed 20%. These trials with a combined enrollment of nearly 33000 people evaluated the effect of supplementation with several vitamin/mineral combinations on UGI cancers and found significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium beta-carotene and vitamin E. Since 1991 we have followed the NIT participants as a cohort and have performed nested studies evaluating the association between baseline characteristics and later development of UGI cancers. In addition we have performed other etiologic studies specifically designed to evaluate individual exposures such as polycyclic aromatic hydrocarbons (PAHs) acetaldehyde human papillomavirus (HPV) and Helicobacter pylori (H. pylori). (b) Iran: We have recently performed two etiologic studies in Golestan Province Iran another population with very high rates of ESCC. Between 2003 and 2007 the Golestan Case-Control Study enrolled 300 ESCC cases 571 neighborhood controls and 300 clinic controls and between 2004 and 2008 the Golestan Cohort Study enrolled 50000 participants. Comparing results from high-risk populations in Iran and China which are quite distinct geographically ethnically and culturally should give us insight into which environmental and genetic risk factors are most important for the development of this disease. (c) Brazil: We have performed several studies evaluating PAH exposure in a high ESCC risk population in southern Brazil; (d) Kenya: We have completed a feasibility study for a case-control study of ESCC in western Kenya which has high rates of this disease and the unusual occurrence of 8% of the cases in individuals younger than 30 years old. (2) Early Detection of Esophageal Cancer: This part of the project includes three studies: (a) the Primary Screening Studies to develop practical and accurate primary screening tests for esophageal squamous dysplasia and early ESCC; (b) Endoscopic Evaluation Studies to develop methods for endoscopic localization and evaluation of esophageal squamous dysplasia; and (c) Endoscopic Therapy Studies to evaluate new techniques for endoscopic treatment of high-grade squamous dysplasia and early ESCC. PROGRESS: (1) Etiologic studies: (a) China: Recent follow-up through 10 years after the end of the Linxian General Population Nutrition Intervention Trial has shown continued significant reductions in total mortality and gastric cancer mortality among those taking a combination of selenium beta-carotene and vitamin E especially among those who were less than the median age (55 years) at the beginning of the trial. Results from nested studies in the NIT cohort have shown: (i) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (ii) no relation between serum carotenoids and risk of UGI cancers; (iii) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (iv) a strong association between low tissue zinc levels and increased ESCC risk; (v) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (vi) no association between positive serology for HPV 16 HPV 18 or HPV 73 and ESCC gastric cardia cancer or non-cardia gastric cancer; (vii) no relation between fumonisin exposure and ESCC risk; (viii) an association between tooth loss and risk of UGI cancers; (ix) an association between self-reported goiter and non-cardia gastric cancer; and (x) associations between several genetic polymorphisms and risk of ESCC and/or gastric cardia cancer. We also found no evidence of HPV DNA or HPV oncogene activity in fresh-frozen tumor samples from 272 consecutive ESCC resection specimens in Linxian. (b) Iran: Results from the Golestan Case-Control Study have shown an significant associations between case status and tobacco use opium use or both; poor oral hygiene; drinking hot-temperature black tea; ruminant animal contact; and various measures of low socioeconomic status. Comparison of normal esophageal tissue biopsies from cases and controls has shown a striking dose-response relationship between PAH exposure in the esophageal tissue (measured by intensity of immunohistochemical staining with anti-PAH antibodies) and case status consistent with a causal role for PAH exposure in ESCC carcinogenesis. The participants in the Golestan Cohort Study are being followed annually for vital status and cancer endpoints; through June 2013 there have been 3537 deaths (34% cardiovascular 22% cancer 17%stroke) and 1127 incident cancers (19% esophagus 15% stomach) and fewer than 1% of the cohort has been lost to follow-up. (c) Brazil: Recent results from southern Brazil have show an association between urinary 1-hydroxypyrene glucuronide (a PAH metabolite) and consumption of mate a local tea which has consistently been associated with ESCC risk. Laboratory analysis of dry mate leaves and mate beverages have shown high levels of PAHs in both. (d) Kenya: We have recently finished a feasibility study for the case-control study of ESCC in western Kenya and will soon begin the full study of 300 cases and 300 controls. (2) Early Detection of Esophageal Cancer: (a) Primary Screening Studies: We recently completed the first endoscopic screening study of asymptomatic adults in Western Kenya; preliminary results from the 300 participants show that 3% had high-grade and 11% had low-grade esophageal squamous dysplasia. We are currently planning evaluation of several new primary screening tests in China using molecular biomarkers. (b) Endoscopic Evaluation Studies: We recently completed the first field study of high resolution microendoscopy (HRME) for endoscopically distinguishing dysplastic from non-dysplastic Lugol's iodine unstained lesions in the squamous esophagus; analysis of this study which was performed in China is ongoing. (c) Endoscopic Therapy Studies: We recently completed the first study of radiofrequency ablation (RFA) for treatment of flat high-grade squamous dysplasia and early invasive ESCC in China; preliminary results from the first 100 patients show complete response (defined as no residual high-grade dysplasia or ESCC in the treated area) at 3 months (after one ablation session) in 72% and complete response at 12 months (after 1-3 ablation sessions) in 90% of patients. 2680713 +Cancer; Health Disparities; Health Effects of Indoor Air Pollution; Lung; Lung Cancer; Microbiome; Minority Health; Nutrition; Prevention; Women's Health Antioxidants;Arsenic;Biochemical;Biological;Biological Specimen Banks;Cancer Etiology;Carotenoids;Cessation of life;Cohort Studies;DNA Sequence Alteration;Detection;Disease;Early Diagnosis;Environmental and Occupational Exposure;Etiology;Evaluation;Exposure to;Future;Goals;Heterogeneous-Nuclear Ribonucleoproteins;Human papilloma virus infection;Incidence;Localized Disease;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Methods;Modality;Molecular;Monoclonal Antibodies;Occupational Exposure;Patients;Pilot Projects;Radon;Research;Sampling;Selenium;Serum;Smelts;Smoking;Sputum;Sputum Cytology Screening;Survival Rate;Thoracic Radiography;Tin;Tobacco;Tocopherols;Update;Validation;cancer biomarkers;case control;cohort;data repository;dietary;experience;follow-up;genetic risk factor;high risk;lung cancer screening;microbiome;microbiome research;mortality;screening;screening program;serological marker;tumor Biologic Specimen Bank for Early Lung Cancer Markers n/a NCI 10702897 1ZIACP000176-18 1 ZIA CP 176 18 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 484735 NCI OBJECTIVE: The overall goal of this project is to identify strategies to reduce lung cancer incidence and mortality. Specific objectives are to 1) establish a biologic specimen bank and data bank that can be used for the validation and refinement of potential early markers of lung cancer and 2) establish a cohort for the study of environmental (including dietary) and genetic risk factors for lung cancer. BACKGROUND: Lung cancer is the leading cause of cancer death in the U.S. While relative survival rates for localized disease are dramatically better than for nonlocalized disease most patients are not diagnosed early enough for present therapies to be effective and early detection by screening with conventional modalities (i.e. chest x-ray and/or sputum cytology) has not been shown to be beneficial. Potential strategies to reduce the incidence and mortality of lung cancer include new methods of early detection and identification and alteration of etiologic factors. METHODS: Miners in the Yunnan Tin Corporation have an extraordinary rate of lung cancer due to exposure to radon arsenic and tobacco. Over 7000 high-risk miners (40+ years old with 10+ years of underground and/or smelting experience)have been the target of an annual lung cancer screening program (CXR and sputum cytology)for the past 20+ years. Between 1992 and 1999 sputum samples were collected and stored annually for future early marker research and new cases of lung cancer ascertained. Prediagnostic sputum and other biologic samples are stored for analysis for potential early markers (e.g. biochemical molecular or monoclonal antibody markers) utilizing a nested case-control approach. PROGRESS: Over 450 lung cancer were identified through 1999 in this cohort. Analyses to date have evaluated occupational exposures (arsenic and radon) smoking and medical conditions; a number of serum antioxidants (carotenoids selenium tocopherols); and one potential marker in sputum (Mab 703D4 in the detection of hnRNP). New follow-up has been initiated to update vital and cancer status through 2005. New studies initiated in the YTC cohort include: (i) an analysis of serologic markers of HPV infection in relation to lung cancer; (ii) studies of the microbiome in sputum samples collected as part of the YTC lung cancer screening to include evaluation of the relation of the microbiome to lung cancer etiology early detection and environmental and occupational exposures (tobacco radon arsenic); and (iii) a pilot study to compare DNA alterations in sputum and tumors in lung cancer cases. 484735 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Esophageal Cancer; Health Disparities; Infectious Diseases; Lung; Minority Health; Nutrition; Prevention; Rare Diseases; Stomach Cancer Age;Beta Carotene;Biological;Blood;Bronchi;Cancer Death Rates;Carotenoids;Categories;China;Cohort Studies;Consumption;Cytology;Cytology Histology;Data Analyses;Death Rate;Dietary Intervention;Disease;Double-Blind Method;Dysplasia;Esophagus;Etiology;Food;Fumonisins;General Population;Genetic Polymorphism;Genetic Risk;Goiter;Helicobacter pylori;Human Herpesvirus 4;Human Papillomavirus;Human papillomavirus 16;Incidence;Ingestion;Intervention;Intervention Studies;Intervention Trial;Lung;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Micronutrients;Millet;Minerals;Nitrosamines;Nutrient;Participant;Patient Self-Report;Persons;Placebo Control;Play;Pleura;Prevention;Randomized;Risk;Role;Selenium;Serology;Serum;Silicon Dioxide;Specimen;Stomach;Structure of nail of toe;Supplementation;Testing;Tissues;Tooth Loss;Trachea;Trauma;Vegetables;Vitamin E;Vitamins;Zinc;alpha Tocopherol;cancer risk;carcinogenesis;esophageal cancer prevention;follow-up;histological specimens;malignant stomach neoplasm;mortality;post intervention;stomach cardia Nutrition Intervention Trials n/a NCI 10702896 1ZIACP000112-18 1 ZIA CP 112 18 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 317786 NCI OBJECTIVE: The primary objective of this project is to determine if supplementation with multiple vitamin-minerals reduces the incidence and mortality of esophageal cancer gastric cancer and total mortality. Secondary objectives are to assess supplement effects on intermediate endpoints in carcinogenesis and to examine new hypotheses relating to the etiology and prevention of esophageal cancer and gastric cancer. BACKGROUND: Probably the highest worldwide rates of esophageal cancer occur in Linxian China where cumulative death rates to age 75 for this cancer exceed 20%. Widespread deficiencies of multiple nutrients are considered the most likely cause but consumption of pickled vegetables moldy foods and nitrosamines and physical trauma from silica fragments in ingested millet may play a role. METHODS: Two double-blind placebo-controlled randomized intervention studies were conducted to evaluate multiple vitamins/minerals in the prevention of esophageal and other cancers. The Dysplasia Trial evaluated 3318 persons with cytologic evidence of dysplasia supplemented for 6 years while the General Population Trial evaluated 29584 persons supplemented for 5 1/4 years. Biologic specimens (blood toenails cytology and histology specimens) were collected periodically throughout the trials. PROGRESS: TRIALS - Both trials concluded in 1991 and results showed that the combination of beta-carotene/vitamin E/selenium significantly reduced total mortality total cancer mortality and stomach cancer incidence and mortality. Results from endoscopic and cytologic examinations suggested that multiple vitamins/minerals may decrease proliferation and enhance cytologic reversion to nondysplasia. POST-TRIAL FOLLOW-UP - Analysis of data from 10 years of post-intervention followup (through May 2001) indicate that for the General Population Trial the beneficial effects of the beta-carotene/vitamin E/selenium supplementation continued after termination of the intervention and that the benefits were greater in the younger participants. None of the four factors tested influenced lung cancer death rates. ETIOLOGY STUDIES - A number of nested case-cohort studies relating baseline serum values of micronutrients fumonisins Helicobacter pylori HPV and EBV to cancer have recently been completed. Results of recent analyses have shown: (1) an especially strong association with increased risk for esophageal cancer and gastric cardia cancer among subjects with low serum selenium levels; (2) no relation of serum carotenoids with esophageal cancer or gastric cancer; (3) a strong association for low serum alpha-tocopherol levels and esophageal cancer risk; (4) a strong association between low tissue zinc levels and increased esophageal cancer risk; (5) increased risk for H pylori exposure for gastric cancer both cardia as well as body; (5) no relation of fumonisin exposure with esophageal cancer risk; (6) an association between tooth loss and risk of esophageal cancer and gastric cancer; (7) associations between several genetic polymorphisms and risk of esophageal cancer and gastric cardia cancer; (8) increased risk of gastric noncardia cancer in persons with self-reported goiter; and (9) no relation for HPV 16 18 or 73 serology and esophageal cancer or gastric cancer. 317786 +"Aging; Alcoholism, Alcohol Use and Health; Breast Cancer; Cancer; Clinical Research; Colo-Rectal Cancer; Complementary and Integrative Health; Dietary Supplements; Digestive Diseases; Estrogen; Health Disparities; Minority Health; Nutrition; Obesity; Physical Activity; Prevention; Substance Misuse; Women's Health" Age;Alcohol consumption;Alcohols;Androstenedione;Antioxidants;Ascorbic Acid;Autoantibodies;Beta Carotene;Biological Availability;Breast Cancer Risk Factor;Calories;Cardiovascular Diseases;Carotenoids;Chemopreventive Agent;Clinical Nutrition;Clinical Trials;Colorectal Cancer;DNA Damage;Dehydroepiandrosterone Sulfate;Diet;Diet Records;Diet and Nutrition;Dietary Alcohol;Dietary Fats;Dose;Drug Kinetics;Energy Intake;Energy Metabolism;Estradiol;Estrogens;Estrone-Sulfate;Evaluation;Food;Frequencies;Hormones;Human;Insulin-Like Growth Factor I;Intake;Intervention;Leptin;Lipids;Lipoproteins;Malignant Neoplasms;Malignant neoplasm of esophagus;Menstrual cycle;Menstruation;Metabolic;Methodological Studies;Micronutrients;Nulliparity;Nutritional Study;Observational Study;Oxidative Stress;Physical activity;Plasma;Postmenopause;Pregnancy;Premenopause;Questionnaires;Research;Role;SHBG gene;Safety;Selenium;Serum;Statistical Models;Testosterone;United States Department of Agriculture;Woman;age related;alpha-carotene;cancer chemoprevention;cardiovascular risk factor;dehydroepiandrosterone;dietary;doubly-labeled water;feeding;high-fat/low-fiber diet;improved;insulin sensitivity;malignant breast neoplasm;men;parous;urinary;zeaxanthin Human Studies of Diet and Nutrition n/a NCI 10702895 1ZIACP000101-18 1 ZIA CP 101 18 15187057 "ABNET, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 139497 NCI OBJECTIVE: The objectives of this research are to evaluate the metabolic effects of dietary changes relevant to cancer and to assess the safety pharmacokinetics bioavailability and mechanisms of action of macro- and micronutrients with cancer chemoprevention potential. BACKGROUND: Clinical nutrition studies provide information that helps bridge the gap between observational research and clinical trials by assessing potential mechanisms of action and other parameters important in developing intervention strategies. METHODS: Since 1983 collaborative efforts with the Beltsville Human Nutrition Research Center of the USDA in clinical nutrition research has resulted in conduct of over 10 studies focused primarily on antioxidant and hormone research. Studies have evaluated the dose bioavailability and safety of selenium carotenoids and vitamin C and the potential modulating role of dietary fat and alcohol on hormones. PROGRESS: PAST STUDIES - (1) Evaluation of carotenoids in premenopausal women on and off alcohol on the same controlled diet showed that plasma levels of both beta- and alpha-carotene were higher on alcohol while lutean/zeaxanthin levels were lower. (2) In another controlled diet study all plasma carotenoid levels were found to vary over the menstrual cycle: concentrations were lowest at menses and each peaked following the peak of its lipoprotein carrier. (3) Hormone evaluations in premenopausal women have shown that taller women have higher estradiol (E2) that pregnancy may modify the age-related changes in E2 levels (E2 decreases with age in parous women but increases in nulliparous) that energy intake is inversely related to serum levels of androstenedione and DHEAS and P:S ratio is inversely related to E2 and E1 levels. (4) In men a controlled high-fat/low-fiber diet resulted in higher plasma levels of total and SHBG-bound testosterone higher urinary testosterone and lower urinary estrogens compared to a low-fat/high-fiber diet. RECENT STUDIES - (1) A recently completed controlled alcohol feeding study in postmenopausal women determined that alcohol ingestion led to increased levels of both estrone sulfate and DHEA sulfate providing support for one possible mechanism of action for the observed relation of alcohol to breast cancer risk. In other analyses from this study alcohol consumption reduced lipid-related risk factors for cardiovascular diseases bioavailable IGF-1 and serum B12 levels; improved insulin sensitivity; increased serum leptin and some markers of oxidative stress; and did not affect autoantibodies to DNA damage. Dietary methodology studies conducted as part of this study compared energy expenditure from four physical activity questionnaires with doubly labeled water estimates and documented calorie intake misreporting by diet record and food frequency questionnaires (also in relation to doubly labeled water). (2) A study of the pharmacokinetics of selenium a particularly promising chemopreventive agent has been completed and statistical modeling is ongoing. 139497 +Biotechnology; Cancer; Digestive Diseases; Genetics; Immunotherapy; Pancreatic Cancer; Rare Diseases Adaptive Immune System;Adoptive Cell Transfers;Aftercare;Antigens;Biological Assay;Brefeldin A;Cancer cell line;Cell Proliferation;Cell Therapy;Cell physiology;Cells;Conflict (Psychology);Cytotoxic T-Lymphocytes;Exhibits;Flow Cytometry;Gene Expression;Gene Proteins;Genes;Genetic;Growth;HLA-A11;Human;Immune;Immune response;Immunohistochemistry;Implant;In Vitro;Injections;Interleukin-2;KRAS2 gene;KRASG12D;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Metabolism;Mitogen-Activated Protein Kinases;Modeling;Modification;Muromonab-CD3;Mus;Mutation;Oncogenic;Operative Surgical Procedures;PIK3CA gene;PTEN gene;Pancreas;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Pharmacology;Phosphoric Monoester Hydrolases;Production;Property;Proto-Oncogene Proteins c-akt;Role;Sampling;Signal Pathway;Signal Transduction;Stains;T cell differentiation;T cell therapy;T-Cell Proliferation;T-Cell Receptor;T-Lymphocyte;Testing;Transcript;Translations;Tumor Suppressor Proteins;Tumor-infiltrating immune cells;Vertebral column;Viral Vector;Western Blotting;anti-tumor immune response;base;cancer cell;clinically relevant;comparative efficacy;cytokine;gain of function mutation;genetic approach;in vivo;inhibitor;knock-down;loss of function mutation;neoplastic cell;pancreatic cancer cells;pre-clinical;preclinical study;programmed cell death protein 1;protein transport;receptor;small hairpin RNA;small molecule inhibitor;subcutaneous;success;transport inhibitor;tumor;tumor growth;vector Retroviral genetic modification of PBLs to optimize expansion for cell therapy n/a NCI 10702893 1ZIABC012121-01 1 ZIA BC 12121 1 78858404 "KLEMEN, NICHOLAS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 823426 NCI Cytotoxic T cells respond to antigen by reprogramming their metabolism to support cellular proliferation differentiation and effector functions. These changes are induced by changes in gene expression induced by intracellular signaling pathways including the PI3K-AKT pathway and the MAP kinase (MAPK) pathway. These pathways are essential for T cell function but oncogenic alterations in cancers stimulate proliferation through these same networks. Gain of function mutations in PIK3CA or KRAS can drive gastrointestinal cancers; many tumors also exhibit loss of function mutations in PTEN a tumor suppressor and negative regulator of PI3K signaling. Preclinical studies have suggested that combining immune-based approaches with inhibitors of the PI3K or MAPK pathways can promote anti-tumor immune responses and inhibit tumor growth. Despite a substantial body of preclinical evidence supporting this approach there has been little discernible success at translation. Between these studies there are conflicting results and it is not clear whether the effects are specific to T cells cancer cells both or neither. In order to better understand how these shared pathways influence interactions between the adaptive immune system and cancer cells we propose to investigate phosphatases that regulate the PI3K and MAPK pathways in a clinically relevant adoptive cell transfer model. 823426 +Cancer; Cancer Genomics; Genetics; Human Genome; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Non-Human Adult;Atlases;Biological Assay;Cell Lineage;Cell Ontogeny;Cell Transplantation;Cells;Clover;Coupling;Development;Embryo;Embryonic Development;Gene Expression;Goals;Homeostasis;Individual;Light;Mediating;Molecular;Natural regeneration;Organism;Planarians;Platyhelminths;Pluripotent Stem Cells;Process;Property;Regulation;Research Personnel;Source;Tissues;base;cell behavior;comparative;experimental study;in silico;innovation;irradiation;pluripotency;postnatal;programs;regenerative;single-cell RNA sequencing;stem cell fate specification;transcriptomics Adult pluripotent stem cell specification during planarian embryogenesis n/a NCI 10702892 1ZIABC012120-01 1 ZIA BC 12120 1 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 389969 NCI This project is a team-driven effort led by NCI iCURE Postdoctoral Researcher Dr. Kayla Titialii-Torres with the assistance of postbaccalaurate researcher Clover Stubbert and bioinformaticist Laura Paez Baena. Our working hypothesis is that cycling piwi-1+ cells in early embryos are the cellular antecedents of adult pluripotent stem cells (aPSCs). We posit that stage-dependent changes in gene expression correlate and are potentially causative in effecting the embryonic to adult pluripotency transition. We are collecting single cell RNA-Seq whole-embryo atlases for stages bookending this key cell fate transition and are focused on characterizing the changing lineage repertoire for the piwi-1+ cells during embryogenesis and in performing trajectory analysis to generate testable hypothesis about key regulators of this process. In tandem we have been developing functional assays that will answer key questions about piwi-1+ cell behavior during embryogenesis including whether cells at different stages are clonogenic and multipotent and whether pluripotency is an individual or collective property of piwi-1+ cells at different stages. These studies will also shed light on the contribution and regulation of nascent aPSCs to the establishment of livelong whole-body regenerative abilities late in embryogenesis. 389969 +Cancer; Estrogen; Genetics; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Adult;Amputation;Anatomy;Area;Atlases;Biological Markers;Biological Models;Candidate Disease Gene;Cells;Embryonic Development;Female;Future;Genetic;Germ Cells;Gonadal structure;Homeostasis;Imaging Techniques;Morphogenesis;Natural regeneration;Organ;Outcome;Platyhelminths;Process;Protocols documentation;Reaction;Regulation;Reproductive system;Resources;Signal Induction;Source;Starvation;Structure;Techniques;Time;Tissues;Transgenic Organisms;Ursidae Family;cell type;falls;germline stem cells;gonad development;imaging modality;male;nano;postnatal;programs;reproductive;screening;segregation;self assembly;self organization;sexual dimorphism;single-cell RNA sequencing;stem cell fate;stem cells;transcriptomics Inductive germ cell specification and self-assembly of sexually dimorphic gonads n/a NCI 10702891 1ZIABC012119-01 1 ZIA BC 12119 1 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 259980 NCI Dr. Xintao Fan has made steady progress since the initiation of this project in Fall 2021 and has brought new techniques to bear in this emerging model system. He developed hybridization chain reaction protocols to visualize candidate aPSC and early germ cell biomarkers including nanos and vasa homologs. He has characterized both postnatal and de novo gonad formation following amputation or starvation using cell type-specific markers on fixed tissue. He has identified conditions critical to the capture of biologically impactful time points for single cell RNA-Seq transcriptomic analysis as part of a collaborative atlas-building project to identify cellular constituents of the reproductive system and candidate genes for future functional perturbation. A key area of focus in the upcoming fiscal year will be generating transgenic lines that allow us to visualize and track the dynamics of adult PSCs and the outcome of asymmetric divisions giving rise to germline stem cells. We will develop live imaging methods to observe gonad morphogenesis in different adult contexts and will begin functional screening of candidate genes implicated in the establishment of germline stem cell fate(s). 259980 +Aging; Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Prostate Cancer; Urologic Diseases Biochemical;Biological Markers;Cancer Patient;Canes;Collaborations;Data;Developmental Therapeutics Program;Disease Progression;Enrollment;FOLH1 gene;Goals;Image;Malignant neoplasm of prostate;Natural History;Patients;Pharmacodynamics;Population;Positron-Emission Tomography;Process;Prostate;Protocols documentation;Recurrence;Research;Scanning;Toxic effect;men;molecular imaging;new technology;overtreatment Natural History of Biochemically Recurrent Prostate Cancer n/a NCI 10702890 1ZIABC012118-01 1 ZIA BC 12118 1 10687105 "MADAN, RAVI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 123362 NCI This protocol is a collaboration with the Molecular Imaging Branch and the Developmental Therapeutics Branch (Translational Pharmacodynamics Research Group). This protocol will enroll men with recurrent prostate cancer and track their imaging including CT Tc99 and PSMA PET imaging. We will also track PSA and evaluate biomarkers as well. This study is approved by the scientific review process and will hopefully open later in 2022. Even though PSMA PET imaging was approved in prostate caner in recent years there is no natural history data to accompany this new technology. This likely leads to over-treatment of patients. Data is needed to better understand who requires therapy in this population and who can be spared the toxicity of such therapies. 123362 +Biotechnology; Cancer; Hematology; Immunotherapy; Rare Diseases Acute Myelocytic Leukemia;Adoptive Cell Transfers;Adoptive Transfer;Appointment;Blood;Bone Marrow;Cell Therapy;Cells;Characteristics;Clinical Protocols;Development;Dysmyelopoietic Syndromes;Equipment;Hematologic Neoplasms;Immune;Malignant Neoplasms;Myelogenous;Myeloproliferative disease;NCI Center for Cancer Research;National Cancer Institute;Patient Transfer;Patients;Postdoctoral Fellow;Prevalence;Process;Reagent;Research;Research Project Grants;T cell response;T-Lymphocyte;Technology;Training;Validation;base;cohort;neoantigens;next generation sequencing;programs;recruit;research study;translational goal;tumor Targeting cancer neoantigens in patients with myeloid malignancies n/a NCI 10702888 1ZIABC012116-01 1 ZIA BC 12116 1 78858397 "LEKO, VID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 70927 NCI Following my recent (July 24 2022) appointment at the National Cancer Institute Center for Cancer Research I am currently in the process of establishing my lab within the Immune Deficiency Cellular Therapy Program. This includes acquiring key reagents and the necessary equipment and technology for carrying out my research and completing the required training. I am also taking steps to recruit a post-doctoral fellow or post-baccalaureate fellows. I anticipate initiating research studies before the end of the fiscal year. 70927 +Cancer; Cancer Genomics; Digestive Diseases; Genetics; Human Genome; Liver Disease; Prostate Cancer; Urologic Diseases ASCL1 gene;Adenocarcinoma;Adrenal Glands;Androgen Receptor;Androgens;Animal Model;Biology;Bone Marrow;Bone Tissue;Bromodeoxyuridine;CDH1 gene;CDKN1A gene;Castration;Cell Lineage;Cell Survival;Cells;Clinical;Communication;Computer software;Cytokeratin-8 Staining Method;Development;Diffuse;Euthanasia;Goals;Heterogeneity;Histologic;Human;Image;Image Analysis;Incidence;Injections;Interferons;Investigation;Kidney;Liver;Malignant neoplasm of prostate;Marrow;Metastatic Neoplasm to the Bone;Metastatic Neoplasm to the Liver;Modeling;Mus;NR3C1 gene;Neoplasm Metastasis;Organoids;Osteoblasts;Osteoid;Paralysed;Pathway Analysis;Pathway interactions;Patients;Phenotype;Physiology;Primary Neoplasm;Proliferation Marker;RB1 gene;Receptor Signaling;Recovery;Resistance;Role;Sampling;Scanning;Signal Transduction;Stains;TP53 gene;Tissue-Specific Gene Expression;Tissues;Tumor Burden;advanced prostate cancer;bioluminescence imaging;bone;clinical phenotype;deprivation;experience;gastrointestinal;in vivo;inhibitor;interest;metastatic process;molecular phenotype;neoplastic cell;novel therapeutic intervention;prostate cancer metastasis;quantitative imaging;receptor expression;single-cell RNA sequencing;soft tissue;spine bone structure;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor heterogeneity Biology of AR+ prostate cancer metastases and the role of the microenvironment n/a NCI 10702884 1ZIABC012111-01 1 ZIA BC 12111 1 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 467174 NCI LuCaP 136 model establishment and initial characterization: Following intracardiac injection of single cells bone metastasis can be visualized using bioluminescence imaging (BLI) by 3 weeks after inoculation and tumors grow exponentially with mice requiring euthanasia between 6-7 weeks. A large percentage of mice are paralyzed due to the outgrowth of metastasis in vertebrae. Metastasis also can be found in liver adrenal and kidney but the predominant burden is in bone. Castration results in a dramatic slowing in tumor burden accumulation and importantly a general shift to heterogeneous tumor phenotypes. Of particular interest we determined that soft tissue liver metastases are enriched for the NE phenotype compared to bone following castration (see below) and similar to human mPC. Tumor phenotypes: Serial sections of tissues containing metastasis were stained for eight markers including BrdU and pHH3 proliferation markers. One form of analysis co-registered sections using HALO quantitative image analysis software where 70 micron bins from the image scans were aggregated to analyze co-expression of markers. Bins containing multidimensional marker quantifications were subsequently clustered by similarity and projected in 2D space as UMAPs. There is a dramatic phenotypic shift and gain in heterogeneity from the intact to late castration tumors with relatively few marker positive cells at the early castration stage. Intact tumor cells lose AR and proliferation markers while small clusters of NR3C1(GR) positive cells are either maintained or newly gained. Late castration metastases diffusely express SOX2 as expected and in addition we discovered CDKN1A (p21) is frequently observed in SOX2+ metastases. Of interest ASCL1 and SYP are expressed predominantly in non-identical or non-adjacent cells within SOX2+ tumors and proliferation is more associated with the ASCL1 subpopulation suggesting SYP+ differentiation-associated quiescence. Molecular phenotypes: Molecular phenotyping of metastases are ongoing using bulk and single cell transcriptomic analyses. To gain sufficiently in-depth sequences for tumor cells we determined that depletion of mouse cells from tumor-bearing bone marrows is the optimal approach. We have analyzed intact and early and late castrated samples as well as orthotopic tumors via RNAseq. Because of the quality and depth of sequencing in bulk samples differential gene expression (DGE) in even small subpopulations are observable. DGE and pathway analysis revealed loss of AR signaling in castrated samples as expected. IFN and NFkB signaling was induced with castration and neuro as well as gastrointestinal pathways became prominent in late vs early castration demonstrating lineage plasticity. We have begun single cell (sc) RNAseq analyses in order to associate transcriptomic and pathway analyses with specific subpopulations of heterogeneous tumor cells. Of particular interest is the finding that the MYC pathway is overrepresented in most bone metastasis cellular phenotypic clusters as compared to matched adrenal clusters. Importantly MYC pathway enrichment has been demonstrated previously in human and mouse bone metastases relative to primary tumors In the second model of interest LuCaP23.1 have altered TP53 (TP53-/mut) and WNT (APC-/mut) pathways. LuCaP23.1 is a relatively slow growing model with bone metastasis detected two months after tumor cell inoculation in about 30% of mice. Tumor bearing mice can survive up to 6 months. Histologically osteoblastic bone metastases occur mainly in vertebrae with extensive osteoid matrix surrounding marrow spaces that contain tumor cells. ARPC LuCaP23.1 tumors (CK8+CDH1+) maintain strong AR expression in the bone microenvironment. Because clonally-derived osteoblastic metastases have not been investigated previously our initial goal is to determine the cross-communication between tumor cells and the osteoblast lineage cells in the bone marrow. 467174 +Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Intellectual and Developmental Disabilities (IDD); Neurosciences; Pediatric; Rare Diseases; Rett Syndrome Acute;Brain;Cell division;Chromatin;DNA Methylation;Development;Disease;Epigenetic Process;Face;Genetic Transcription;Genome;Genomic approach;Goals;Impairment;Lead;Learning;Longevity;Malignant Neoplasms;Memory;Methyl-CpG-Binding Protein 2;Modification;Molecular;Mus;Mutation;Neurodevelopmental Disorder;Neurologic;Neurons;Organism;Proteins;Reader;Regulation;Research;Research Personnel;Research Project Grants;Rett Syndrome;Role;cell type;experimental study;genome integrity;insight;nervous system disorder;postnatal Chromatin Regulation in Brain Development and Disease n/a NCI 10702883 1ZIABC012110-01 1 ZIA BC 12110 1 78858390 "BOXER, LISA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 993549 NCI As a recently established investigator at NCI only very preliminary results on these research projects can be presented. In one research project we are using molecular and genomic approaches to understand the function of these neuron-specific forms of DNA methylation. We are investigating why these modifications accumulate in neurons what proteins associate with these modifications how these modifications regulate transcription and genome integrity and how mutations in regulators of DNA methylation lead to neuorodevelopmental disorders and cancer. Another project is focused on a specific methyl-DNA-binding protein MeCP2 mutations in which cause the neurodevelopmental disorder Rett syndrome. To investigate the function of MeCP2 we have developed an approach to rapidly degrade the MeCP2 protein in the mouse brain. We are using this approach to distinguish the immediate molecular consequences of acute MeCP2 loss from the secondary consequences of neurological impairment. These experiments will lend insight into the primary function of MeCP2 and this approach can be broadly applied to other proteins implicated in neurological disease. 993549 +Cancer; Cancer Genomics; Genetics; Human Genome; Infectious Diseases; Microbiome; Networking and Information Technology R&D (NITRD) Algorithms;Bacterial Genome;Communities;Complex;Consensus;Environment;Gene Cluster;Graph;Horizontal Gene Transfer;Human;Metagenomics;Metaphase;Methods;Natural Products;Neurofibrillary Tangles;Pathogenicity;Phase;Phenotype;Resolution;Shotguns;Variant;Virus Integration;Work;gut microbiome;insight;metagenome;metagenomic sequencing;microbiome;pressure;skin microbiome Algorithms for strain-resolved metagenomics n/a NCI 10702882 1ZIABC012109-01 1 ZIA BC 12109 1 78858383 "KOLMOGOROV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 282015 NCI Long-read metagenomic sequencing has recently been used to recover complete bacterial genomes from various complex metagenomic communities. Metagenome assembly algorithms however are still facing challenges in deconvolution of closely-related species and strains. De novo assemblies of highly heterogeneous bacterial species typically result in tangled assembly graphs where some sequences could be strain-specific while others represent species-level consensus. Such partially-collapsed representation of bacterial strains does not take full advantage of the ability of long reads to phase small variants. In this work we develop an algorithm called MetaPhase that extends metagenomic phasing approaches to assembly graphs. The new method will allow for profiling of human metagenomes on the finest level of resolution and provide insights into microbiome dynamics. In addition complete bacterial assemblies facilitate discovery of known and new biosynthetic gene clusters that encode important natural products. 282015 +Cancer; Cancer Genomics; Genetics; Human Genome Algorithms;Complex;DNA;Data;Detection;Drug resistance;Genomics;Haplotypes;Human Genome;Malignant Neoplasms;Methods;Molecular Weight;Patients;Role;Sampling;Technology;Variant;Work;actionable mutation;cancer genome;cancer genomics;chromothripsis;design;drug development;human pangenome;improved;success;telomere;therapeutic target;tumor heterogeneity;tumor progression Complex rearrangement detection in cancer genomes using long reads n/a NCI 10702881 1ZIABC012108-01 1 ZIA BC 12108 1 78858383 "KOLMOGOROV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 282015 NCI Many recent studies highlighted the improved capability of long-read sequencing to detect structural variation in the human genome. For example these technologies was also recently utilized to produce the first complete assembly of the human genome by the Telomere-to-Telomere consortium. Further Human Pangenome Reference Consortium has recently released 47 nearly-complete haplotype-resolved human genomes from diverse backgrounds. A few recent studies have utilized long-read sequencing to discover complex genomic changes such as chromothripsis or ecDNA formation. However the broad application of the technology is facing additional hurdles such as patient sample availability high-molecular weight DNA extraction tumor heterogeneity and purity among others. Compared to short-read sequencing there are little-to-no existing computational approaches to analyze cancer long-read data either. In this project we aim to capitalize on the recent successes of long-read sequencing for germline variation analyzis and develop a set of methods for profiling cancer genomes using long reads. This work will open possibilities to detect structural variants and complex rearrangements in cancer genomics with high confidence study their role in cancer progression and development of drug resistance and potentially discover new actionable mutations and therapeutic targets. 282015 +Cancer Biogenesis;Biological;Biology;Biomedical Research;Categories;Cell surface;Cells;Classification;Communities;Development;Diagnostic;Disease;International;Knowledge;Language;Macromolecular Complexes;Methodology;Nomenclature;Ontology;Pathway interactions;Process;Research;Research Personnel;Societies;Structure;Terminology;Therapeutic;design;exosome;extracellular;extracellular vesicles;improved;liquid biopsy;metrology;molecular diagnostics;response;tool Classification and Ontology of Macromolecular Complexes in Liquid Biopsies n/a NCI 10702880 1ZIABC012107-01 1 ZIA BC 12107 1 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 76763 NCI "This is a new project started in 2021-2022 in response to ongoing requests from researchers across the biomedical research space to provide input on the design and interpretation of ""exosome"" studies pertaining to various diseases. Although the International Society for Extracellular Vesicles the largest society of EV and ""exosome"" researchers defines ""exosomes"" in terms of how these structures are produced by cells researchers studying EVs and ""exosomes"" in liquid biopsies generally have no tools with which to determine whether an extracellular vesicle in a biofluid arose from an intraluminal body and released (via a pathway for exosome biogenesis) or whether an extracellular vesicle was shed from the surface of the cell. Moreover several additional categories of extracellular macromolecular complexes such as exomeres and supermeres have been identified for which researchers encounter similar challenges of ontologic clarity. The first steps for this project will be to assess the state of the field and delineate potential next steps towards harmonized terminologies. This will be a large collaborative initiative encompassing the EV biology and Liquid Biopsy/Molecular Diagnostics communities and will engage with regulatory communities working with ""exosome"" metrology diagnostics and therapeutics." 76763 +Biotechnology; Cancer; Clinical Research; HIV/AIDS; Immunotherapy; Infectious Diseases Acquired Immunodeficiency Syndrome;Affect;Area;B-Lymphocytes;Biology;Blood;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Cancer Patient;Cells;Clinical;Clinical Trials;Collaborations;DNA Vaccines;Dendritic Cells;Development;Disease;Disseminated Malignant Neoplasm;Effector Cell;Gene Expression;Gene Expression Profile;Goals;Growth Factor;HIV;HIV Infections;HIV therapy;Immune;Immune response;Immune system;Immunotherapeutic agent;Immunotherapy;Infiltration;Interleukin-15;Intervention;Light;Location;Lymphocyte;Lymphocyte Activation;Lymphocyte Function;Lymphoid Cell;Macaca;Malignant Neoplasms;Mediating;Methods;Modeling;Mus;Myeloid Cells;Natural Killer Cells;Pathway interactions;Plasma;Population;Production;Property;Proteomics;Protocols documentation;Regulation;Regulatory T-Lymphocyte;Reporting;SIV;SIV Vaccines;Site;Technology;Testing;Therapeutic Agents;Viral;Viral reservoir;Viremia;Virus;anti-PD-1;arm;base;cancer immunotherapy;clinical application;combinatorial;cytokine;cytotoxic;design;first-in-human;gene therapy;immunoregulation;inhibitor;interest;lymph nodes;migration;mouse model;prevent;recruit;response;simian human immunodeficiency virus;transcriptomics;tumor;viral RNA Examining IL-15 as an immunotherapy agent in cancer and AIDS n/a NCI 10702878 1ZIABC012105-01 1 ZIA BC 12105 1 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 704873 NCI Understanding of the cellular mechanisms controlling expression shed new light in the biology and regulation of IL-15 led to the identification of the bioactive heterodimeric form of IL-15 and provided methods for the efficient production and clinical application of this cytokine (Bergamaschi J. Biol. Chem. 283: 4189 2008; Bergamaschi Blood 120: e1-8 2012; Bergamaschi Cancers 13 2021). We have shown that hetIL-15 greatly increases lymphocyte infiltration in several tumors in mouse models and in macaques suggesting a general method to increase lymphocyte infiltration which is associated with anti-tumor activity. We have performed first-in-human clinical trials of hetIL-15 in metastatic cancers (Conlon JITC:e003388. 2021) and also in combination with anti-PD-1 check point inhibitor (NCT02452268; collaboration with Novartis). hetIL-15 is extensively studied in mouse tumor models where we demonstrated the rapid interaction of lymphoid and myeloid cell networks resulting in changes in numbers and migration of different cell populations. Extensive transcriptomics and proteomics analysis has revealed additional pathways affected by hetIL-15 (Bergamaschi J. Immunother. Cancer: 8:e000599 2020; Bergamaschi Cancers 13 2021). We have studied the effects of hetIL-15 in the number and properties of Dendritic Cells (DC) in tumors which increase upon hetIL-15 treatment. DC participate in a network of cells that are induced during hetIL-15 treatment and in turn support more recruitment of effector cells in tumor sites. Studies in mouse orthotopic models show that DC populations correlate with tumor regression and reveal additional beneficial effects of hetIL-15 in inducing or enhancing long term protective immune response against tumors. Thus hetIL-15 a cytokine directly affecting lymphocytes and inducing cytotoxic cells has also an indirect rapid and significant effect on the recruitment of myeloid cells initiating a cascade for tumor elimination though innate and adoptive immune mechanisms. In addition to cancer immunotherapy IL-15 has generated strong interest for clinical use to treat HIV infection especially in protocols targeting viral eradication or a functional cure. The use of IL-15 as an immune therapeutic agent against HIV infection is based on its effects as a growth factor and key regulator of cytotoxic responses mediated by both the innate (NK cells) and the adaptive (CTL) arms of the immune system. Importantly hetIL-15 treatment promotes the entrance of cytotoxic (GrzB+) CD8+ T cells in the B cell follicles areas within the LN where CTL are typically excluded and where SIV/HIV infected follicular helper CD4+ T cells reside. hetIL-15 treatment led to significant decrease in cell-associated viral RNA within the LN as well as in plasma viremia in SHIV infected macaques (Watson PLoS Pathog. 14: e1006902 2018). In a collaborative effort we further reported that a IL-15 transcriptional signature response to a viral RhCMV/SIV vaccine strongly correlated with protection (Barrenas PLoS Pathog 17:e1009278; 2021). We have expanded this concept and are testing the contribution of a combinatorial treatment including hetIL-15 in reducing reservoir in the SIV infected ART-treated macaques. 704873 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Nanotechnology Alzheimer's disease related dementia;Biological Sciences;Cell Line;Cells;Computer software;Data;Genome;Genomics;Goals;Haplotypes;Human Genome;Methods;Methylation;Phase;Pilot Projects;Protocols documentation;Reference Standards;Repetitive Sequence;Sensitivity and Specificity;Technology;Tissue Sample;Variant;base;brain tissue;cost;genome sequencing;improved;nanopore;open source;whole genome Assembly-based methods to detect germline structural variation using long reads n/a NCI 10702877 1ZIABC012104-01 1 ZIA BC 12104 1 78858383 "KOLMOGOROV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 141007 NCI Long-read sequencing technologies substantially overcome the limitations of short-reads but have to date been a combination of too expensive not scalable enough or too noisy to be considered a feasible replacement at scale. Here we develop an efficient and scalable wet lab and computational protocol for nanopore long-read sequencing that seeks to provide a true alternative to short-reads for whole genome sequencing. We applied this protocol to cell lines and brain tissue samples as part of a pilot project for the Centers for Alzheimer's and Related Dementias (CARD). Using a single PromethIon flow cell we can detect SNPs with sensitivity/specificity better than Illumina short-read sequencing (standard for large scale genomic projects) discover structural variants (SVs) comparably to state of the art long-read based de novo assembly methods involving Pacific Biosciences HiFi sequencing and trio information but at a much lower cost and far greater throughput and combine and phase small and SV variants at megabase scales. The protocol also produces highly accurate haplotype specific methylation calls. This protocol uses a de novo assembly-based framework for structural valiant discovery that improves over reference-based methods. We provide the protocol and software as open source pipelines for generating variant calls and assemblies. 141007 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Cancer cell line;Cell Line;Clustered Regularly Interspaced Short Palindromic Repeats;Databases;Exons;Genes;Genetic;Genetic Screening;Genomics;Guide RNA;Human Genome;Hybrids;Individual;Libraries;Maps;Modification;Property;Resources;Signal Transduction;Site;System;Testing;Time;Variant;Work;base;combinatorial;design;experimental study;fitness;genetic element;genome editing;genome-wide;improved;knockout gene;mouse genome;nuclease;online resource;paralogous gene;promoter;screening;searchable database;tool Improving editing efficiency and guide design of CHyMErA screening platform n/a NCI 10702876 1ZIABC012102-01 1 ZIA BC 12102 1 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 334004 NCI We have cloned and established multiple cell lines for various Cas12a variants in the context of our CHyMErA screening Cas9/Cas12a screening platform. We have screened the different CHyMErA variants in multiple cell lines with a hgRNA library allowing us to compare editing efficiency as well as precision of the Cas12a variants in the context of our screening system. Our results revealed editing improvements with new Cas12a variants which were confirmed with focused experiments. Genome-scale screens are currently performed with the enhanced screening platform to map fitness genes across various cancer cell lines. In parallel we have been collecting all possible Cas9 and Cas12a target sites in the human and mouse genome have scored guide sequences for on- and off-target properties and have uploaded guide sequences genomic features and scores to an online data base. Current work focuses on making those data bases searchable in a time-effective fashion. The online tool will eventually allow for facile and efficient design of individual or large-scale guide design for Cas9 and Cas12a nuclease for numerous genome editing applications. 334004 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Prevention Ablation;Binding Sites;Biological Process;Biomedical Research;CRISPR screen;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Coupled;DNA cassette;Data;Disease;Engineering;Genes;Genetic;Genetic Screening;Genomics;Guide RNA;Hybrids;Link;Modification;Phenotype;Poly A;Proteins;Protocols documentation;Reagent;Role;System;Technology;Therapeutic Intervention;Transcript;Work;combinatorial;cost;cost effective;design;experimental study;expression vector;gene function;genetic element;genome-wide;genomic platform;improved;indexing;insight;loss of function;novel;prevent;response;screening;single cell analysis;single-cell RNA sequencing;therapeutic candidate;transcriptome;transcriptomics Establishing combinatorial screening platform coupled to single-cell analysis n/a NCI 10702875 1ZIABC012101-01 1 ZIA BC 12101 1 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 111335 NCI Hybrid guide RNA cassettes have been engineered to harbor capture sequences within Cas9 and Cas12a guide RNAs which make them amenable to capture using 10x Genomics protocols and reagents during single-cell analysis. Pilot experiments have been performed to assess capture efficiency of hgRNAs along with polyadenylated transcripts. Current work includes further modifications of the hgRNA expression cassettes to improve the simultaneous capture of Cas9 and Cas12a guides while retaining efficient editing efficiency of our combinatorial system. Once the guide design is fully optimized we will perform genetic screening with single-cell transcriptomic readouts thereby allowing us to gain mechanistic insights into the cellular rewiring in response to single or combined genetic perturbations. 111335 +Biotechnology; Cancer; Genetics CRISPR interference;CRISPR-mediated transcriptional activation;Cell Line;Cell surface;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNA Damage;Flow Cytometry;Gene Expression;Gene Targeting;Genes;Genetic Transcription;Individual;Malignant Neoplasms;Pathway interactions;Repression;System;Testing;Tissues;Transcription Coactivator;Transcription Repressor;Variant;Western Blotting;Work;cell type;combinatorial;expression vector;genome editing;knockout gene;nuclease;promoter;recruit;response;screening Combinatorial CRISPR transcriptional perturbation screening platform n/a NCI 10702874 1ZIABC012100-01 1 ZIA BC 12100 1 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 334004 NCI Transcriptional repressor domains have been cloned into lentiviral expression vectors carrying various CRISPR-Cas nucleases (Cas9 and Cas12a variants). HAP1 and RPE1 cells have been transduced with CRISPRi constructs (single and Cas9/Cas12a pairs) and nuclease expression has been verified by western blotting. Editing efficiency of individual CRISPRi effectors have been verified by assessing expression of cell surface markers by flow cytometry. Currently work is in progress to test combinatorial transcriptional repressor activities in our CRISPRi cell lines. Transcriptional activator domains have been cloned into lentiviral expression vectors carrying various CRISPR-Cas nucleases (Cas9 and Cas12a variants). HAP1 cells have been transduced with CRISPRa constructs (single and Cas9/Cas12a pairs) and nuclease expression has been assessed by western blotting. Editing efficiency of combined CRISPRa effectors have been tested by assessing expression of cell surface markers by flow cytometry. Current work is focused on modifying the CRISPRa effectors to enhance nuclease expression and hence genome editing efficiency. 334004 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Kidney Disease; Rare Diseases Biological Assay;CCR;Cell Line;Cells;Chromosome Mapping;Clustered Regularly Interspaced Short Palindromic Repeats;Dependence;Genes;Genetic;Genome;Goals;Libraries;Malignant Epithelial Cell;Maps;Metabolic;Patients;Regulation;Renal Cell Carcinoma;Somatic Mutation;Therapeutic;Translations;Validation;Western Blotting;Work;combinatorial;fitness;functional genomics;genome-wide;insight;knockout gene;novel;nuclease;screening Genetic interaction screening in renal cell carcinoma n/a NCI 10702873 1ZIABC012099-01 1 ZIA BC 12099 1 78858378 "AREGGER, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 334004 NCI We have obtained 6 patient-derived renal cell carcinoma (RCC) cell lines harboring somatic mutations in metabolic genes from the lab of Marston Linehan (UOB/CCR/NCI). We have transduced those RCC lines with CRISPR-Cas nucleases amenable to our CHyMErA combinatorial genome perturbation platform. Expression of Cas nucleases have been verified by western blotting and work is in progress to assess editing efficiency of the cell lines. Once cell lines have been validated through those assays and cell line identify have been confirmed by STR pofiling cell lines will be screened with genome-scale gene knockout libraries to identify fitness genes across the various genetic backgrounds. 334004 +Cancer; Genetics; Lung; Lung Cancer 3' Untranslated Regions;Adaptor Signaling Protein;Adenocarcinoma;Affect;Alleles;Animals;Apoptosis;Area;BRAF gene;Binding;Binding Proteins;Binding Sites;Biogenesis;CCAAT-Enhancer-Binding Protein-beta;Cancer Etiology;Cancer cell line;Cell Aging;Cells;Collaborations;Complex;Cytoplasm;Cytostatics;DNA Damage;Data;Dependence;Development;Disabled Persons;Disease;Docking;Elements;Endosomes;Exhibits;Fibroblasts;Future;Genes;Genotype;Goals;Human;Individual;Inflammatory;Investigation;KRAS2 gene;KRASG12D;KSR gene;Laboratories;Lesion;Lung Neoplasms;MAPK3 gene;MDM2 gene;Malignant - descriptor;Malignant Neoplasms;Mediating;Messenger RNA;Modeling;Molecular and Cellular Biology;Mus;Mutate;Mutation;Neoplastic Cell Transformation;Nonsense-Mediated Decay;Nuclear;Oncogenes;Oncogenic;Oncoproteins;Pathway interactions;Phenotype;Phospholipids;Phosphorylation;Phosphotransferases;Population;Post-Translational Protein Processing;Proteins;RAS genes;RNA;RNA Decay;Regulation;Research;Ribosomal RNA;Ribosomes;Series;Signal Transduction;Site;Substrate Specificity;TOLLIP gene;TP53 gene;Testing;Tissues;Transcript;Transgenes;Translating;Translational Activation;Translations;Tumor Burden;Tumor Cell Line;Untranslated Regions;Work;antitumor agent;cancer cell;experimental study;high resolution imaging;in vivo;insight;lung tumorigenesis;mRNA Decay;mutant;neoplastic cell;novel;phosphoproteomics;prevent;ras Oncogene;recruit;response;scaffold;senescence;small molecule;transcription factor;transcriptome;transcriptome sequencing;transmission process;tumor;tumor progression;ubiquitin ligase Control of Oncogenic Signaling Through Spatial Organization of Kinases and mRNAs n/a NCI 10702872 1ZIABC012098-01 1 ZIA BC 12098 1 8777578 "JOHNSON, PETER F" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1556503 NCI "Our research is divided into two main subprojects. The first focuses on how 3'UTRs of mRNAs encoding proteins that are targets of oncogenic kinases such as ERK and CK2 regulate mRNA localization in tumor cells. This subcellular mRNA compartmentalization can either inhibit or stimulate phosphorylation of the encoded protein. Secondly we are studying how kinases partition to the perinuclear cytoplasm in tumor cells to form perinuclear signaling centers or PSCs. Our work indicates that PSCs serve as critical signaling engines that drive malignant transformation and cancer. 1.3'UTR regulation of protein activity (UPA) and its underlying mechanisms. 3'UTR regulation of protein activity was discovered through our earlier observation that the CEBPB 3'UTR inhibits RAS-induced post-translational activation of C/EBPb in tumor cells where the 3'UTR effectively uncouples C/EBPb from RAS signaling. UPA thus constrains the pro-senescence activity of C/EBPb and its ability to induce pro-inflammatory senescence-associated secretory phenotype (SASP) genes. UPA requires a long G/U-rich element (GRE) motif in the 3'UTR and its cognate binding protein HuR/ELAV1. These components exclude CEBPB mRNAs from a perinuclear cytoplasmic compartment containing endosome-associated ERK1/2 and CK2 thus preventing newly translated C/EBPb from accessing its activating kinases. More recently we found that the RNA decay proteins UPF1 and Staufen (STAU1/2) are essential UPA factors enriched within the perinuclear cytoplasm. Together with HuR and the nonsense-mediated decay factors SMG6 and 7 these proteins promote perinuclear mRNA decay (PMD) of CEBPB transcripts. Depletion of UPF1 or STAU in tumor cells increased the nuclear-proximal population of CEBPB transcripts leading to C/EBPb activation and senescence. High resolution imaging showed that these perinuclear CEBPB mRNAs frequently colocalize with CK2 foci. These observations suggest that when UPA is disabled C/EBPb undergoes co-translational phosphorylation which is contingent on close proximity of CEBPB transcripts with activating kinases. We identified a STAU binding site (SBS) adjacent to the GRE which when deleted activated the pro-senescence functions of C/EBPb but not its ability to induce SASP genes. This observation and other data imply that distinct 3'UTR sequences are involved in repressing the two C/EBPb functions most likely by inhibiting different PTMs. We propose that various mRNA decay factors (e.g. STAU) which recognize discrete 3'UTR sequences are tethered to different types of signaling endosomes (e.g. those carrying ERK CK2 or other kinases). Hence individual 3'UTR elements may promote mRNA decay in the vicinity of particular kinases and thereby inhibit protein phosphorylation on specific sites. Future work will expand upon this novel relationship between modular 3'UTR motifs mRNA decay near perinuclear kinases and inhibition of specific PTMs on the encoded protein. To examine the in vivo relevance of UPA we generated mice with a deletion that removes the Cebpb GRE and part of the adjacent SBS. This strain was tested in a Kras model of lung tumorigenesis. Although overall lung tumor burdens in deltaGRE mice were similar to WT animals regions of malignant adenocarcinoma were significantly reduced. These findings provide the first in vivo evidence that UPA constrains C/EBPb activity and thus facilitates tumor progression to carcinomatous lesions. We are currently performing senescent cell analysis and RNA-seq studies on tumors of different stages in the two genotypes to assess whether the delGRE mutation increases senescence and how this allele alters the C/EBPb transcriptome. A key goal of our work is to determine whether UPA is a general mechanism that regulates many other proteins. p53 is one such candidate as it undergoes activation by oncogenic RAS in OIS cells and its 3'UTR harbors a U-rich element (URE) that binds HuR. We found that the TP53 3'UTR suppresses the cytostatic activity of a p53 transgene expressed in p53-deficient RAS tumor cells without affecting p53 protein levels. Like C/EBPb the 3'UTR excludes TP53 mRNA from the kinase-rich perinuclear region and appears to inhibit p53 phosphorylation on an activating CK2 site Ser392. RNA FISH showed that endogenous TP53 transcripts also partition away from the nuclear-proximal area in tumor cells but are perinuclear in senescent fibroblasts. Similarly TP53 mRNA undergoes perinuclear translocation in cancer cells treated with chemotherapeutic DNA damaging agents (which induce p53-dependent senescence or apoptosis) correlating with increased Ser392 phosphorylation. Depletion of the p53 ubiquitin ligase MDM2 also caused p53 transcripts to become perinuclear indicating that MDM2 restrains p53 activity both directly through p53 degradation and indirectly by enforcing UPA. Our findings demonstrate that 3'UTR-dependent changes in mRNA localization control p53 function. 2. Mechanisms and function of RAS pathway perinuclear signaling centers (PSCs) as key signaling engines in cancer cells. Oncogenic RAS induces perinuclear translocation of the effector kinases p-ERK and CK2 and the signaling scaffold KSR1. These proteins form signaling hubs on endosomes tethered to the ER network termed ""perinuclear signaling centers"". PSCs are critical to the UPA mechanism and are widely present in cancer cell lines and tissues. We propose that PSCs are also key signaling engines that drive cancer allowing oncogenic kinases to access targets that are important for neoplastic transformation. We found that the endosomal adaptor TOLLIP is required for perinuclear localization of RAB11A+ endosomes harboring CK2 and KSR1 but not ERK which resides on a different class of signaling endosome. TOLLIP is perinuclear in human cancer cells and KRasG12D-driven mouse tumors but is pan-cytoplasmic in non-transformed cells coinciding with the presence of PSCs. TOLLIP associates with KSR1 through a conserved region that binds to the KSR1 pseudo-kinase domain. This interaction recruits CK2 signaling complexes to endosomes. We performed a series of phosphoproteomics experiments which show that perinuclear CK2 phosphorylates selective substrates including proteins involved in ribosome biogenesis and translation. One such target is the atypical kinase RIOK1 which regulates 18S rRNA processing and 40S subunit maturation. Mutant analysis suggests that phosphorylation on Ser22 by perinuclear CK2 is essential for RIOK1 activity in tumor cells. We observed that KRasG12D-driven lung tumors in Tollip-/- mice progress less efficiently to the malignant adenocarcinoma stage. Furthermore tumor cell lines carrying KRAS mutations but not HRAS or BRAF lesions require TOLLIP for proliferation/survival. TOLLIP is therefore a key signaling adaptor in KRAS tumor cells whose inhibition is a potential vulnerability of these cancers. TOLLIP contains a phospholipid binding domain (C2) that likely determines its association with particular classes of endosomes. in collaboration with Dr. Nadya Tarasova (CIL) to identify small molecules that are projected to dock in predicted TOLLIP pockets. Compounds verified to bind TOLLIP and that disrupt PSCs in tumor cells may be considered for further development as potential antitumor agents. As cancer cells driven by mutant HRAS BRAF and other oncogenes display reduced dependence on TOLLIP but nevertheless exhibit perinuclear CK2 we believe that an additional adaptor protein(s) provides a redundant perinuclear tetheri *TRUNCATED*" 1556503 +Bioengineering; Cancer; Clinical Research; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Radiation Oncology Address;Algorithms;Area;Biological;Biological Markers;Blood;Clinical;Collaborations;Data;Data Collection;Data Set;Dose;Ecosystem;Failure;Future;Goals;Histology;Image;Infrastructure;Link;Location;Methodology;Methods;Modeling;Normal tissue morphology;Oncology;Outcome;Patient imaging;Patient-Focused Outcomes;Patients;Pilot Projects;Proteomics;Protocols documentation;Radiation Oncology;Radiation therapy;Radiometry;Resources;Site;Testing;Tumor Biology;Tumor Tissue;United States National Institutes of Health;Urine;Validation;Work;artificial intelligence algorithm;data cleaning;data framework;data harmonization;design;improved;improved outcome;prognostic;response;standard of care;tissue biomarkers;treatment optimization;tumor Advancing clinically meaningful AI algorithms to improve oncologic outcomes n/a NCI 10702871 1ZIABC012096-01 1 ZIA BC 12096 1 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171676 NCI "The goals are to: 1) generate a ""toolkit"" of algorithms that directly link RT biology tumor response/failure to clinical areas of need to improve patient outcomes 2) define and create optimal methodology linking RT dose/volumes to AI to outcomes and 3) identify surrogates for response/failure as pertaining to radiation oncology ie. biomarkers. Current work involves building connections and collaboration with AI resources using existing data to pilot projects to generate a gap analysis and build data framework and create a functional query ready radiation oncology study platform in the NIH AI ecosystem to allow for streamlining of analysis. Algorithms are being developed at the clinical imaging and proteomic level for future aggregation. Future protocol will be aimed at validating promising algorithms." 171676 +Cancer; Clinical Research; Data Science; Radiation Oncology Aftercare;Artificial Intelligence;Biological Markers;Clinical Data;Data;Data Aggregation;Data Analyses;Data Collection;Dose;Genomics;Goals;Image;Infrastructure;Laboratories;Location;Maintenance;Methods;Oncology;Pathology;Patients;Pattern;Proteomics;Radiation;Radiation therapy;Resistance;Testing;Time;Tissues;Work;data cleaning;data framework;data harmonization;data streams;exhaustion;large scale data;response;usability Generating a multi-channel data framework for AI analysis in Radiation therapy n/a NCI 10702870 1ZIABC012095-01 1 ZIA BC 12095 1 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171676 NCI Following exhaustive data gap analysis of location extent and usability of data streams several have now been successfully aggregated and work is ongoing in particular with respect to imaging and radiation therapy data which are particularly siloed. The current goal is to gather data in robust manner that allows for a queriable and scalable format and then to develop AI methods for the curation and cleaning of data to create buildable infrastructure for robust data collection and harmonization of oncology patients. 171676 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Neurosciences; Precision Medicine; Radiation Oncology; Rare Diseases Adjuvant;Agreement;Behavior;Biological;Biological Markers;Brain Neoplasms;Clinic;Clinical;Clinical Data;Data;Dose;Dose Fractionation;Excision;Glioblastoma;Glioma;Image;Immunotherapy;Methodology;Neurologic;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Predictive Value;Proteins;Proteome;Proteomics;Protocols documentation;Radiation therapy;Recurrence;Signal Transduction;Staging;Steroids;Stratification;Systemic Therapy;The Cancer Genome Atlas;Time;Valproic Acid;base;biomarker discovery;brain magnetic resonance imaging;clinical application;clinical predictors;follow-up;improved;improved outcome;large scale data;novel;predictive signature;prognostic;prognostic signature;prognostic value;response;standard of care;temozolomide;tumor Prognostic and predictive clinical and proteomic biomarker discovery in GBM n/a NCI 10702869 1ZIABC012094-01 1 ZIA BC 12094 1 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171676 NCI The objectives are to define biological behaviors survival and response in glioma through clinical data features and proteome driven stratification in order to optimize radiation therapy management and patient outcomes. 1) Exploring differential biomarker expression post-radiation therapy in relationship to recurrence and survival and existing data on proteins associated with predictive and/or prognostic value; 2) Replicating and extending possible differential proteomic biomarker expression pre- vs post-radiation therapy across large scale data sets (TCGA CGGA); 3) Explore existing and novel statistical methodology in as pertaining to proteomic signals and merging these with clinical data. 171676 +Biomedical Imaging; Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Neurosciences; Orphan Drug; Precision Medicine; Radiation Oncology; Rare Diseases Adjuvant;Age;Agreement;Algorithms;Artificial Intelligence;Biological;Biological Assay;Biological Markers;Blood;Brain Neoplasms;Clinic;Clinical;Clinical Data;Data;Data Set;Diagnosis;Dose;Dose Fractionation;Early treatment;Eligibility Determination;Enrollment;Excision;Fostering;Gender;Genomics;Glioblastoma;Glioma;Image;Immunotherapy;Institutional Review Boards;Ionizing radiation;Literature;Malignant Neoplasms;Metabolism;Methods;Neurologic;Operative Surgical Procedures;Outcome;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Predictive Value;Prognosis;Proteins;Proteomics;Protocols documentation;Radiation therapy;Recurrence;Resources;Serum;Steroids;Systemic Therapy;Technology;The Cancer Genome Atlas;The Cancer Imaging Archive;Time;Treatment Failure;Urine;Validation;Work;angiogenesis;aptamer;base;biomarker discovery;brain magnetic resonance imaging;clinical application;clinical predictors;clinically relevant;follow-up;improved;predictive signature;prognostic;prognostic signature;prognostic value;proteogenomics;proteomic signature;radiation resistance;radiation response;radiological imaging;response;standard of care;stemness;temozolomide;tumor Proteogenomic characterization and biomarker discovery in glioblastoma n/a NCI 10702868 1ZIABC012093-01 1 ZIA BC 12093 1 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171676 NCI Methods: 82 pts diagnosed with pathology proven glioblastoma (2005-2013) were enrolled on IRB approved protocol 04-C-0020 and treated with concurrent chemoirradiation with blood and urine biospecimens obtained prior to and following completion of radiation therapy. Serum was then screened using the aptamer-based SOMAscan proteomic assay technology for changes in expression of 7000 protein analytes. Employing each patient as their own control biomarker expression was initially analysed using Graphpad and IPA to identify preliminary proteomic signatures representative of biological mechanisms involved in ionizing radiation and hallmarks of cancer including angiogenesis stemness and metabolism. These were then correlated using clinical data (pt age gender) tumor related factors (extent of resection) radiation therapy volumes (GTV PTV) outcomes (PFS OS). Further work will be aimed at: 1) Replicating and extending possible differential proteomic biomarker expression pre vs post radiation therapy. 2) Connecting large scale proteomic data to upstream pathways and genomic analysis to identify proteogenomic clusters defining radiation resistance and response and prognosis. 3) Validation with large scale public data sets (eg TCGA/TCIA and others). 4) Exploring differential biomarker expression prior to radiation therapy as compared to glioma subtypes described in the literature. 5) Exploring differential biomarker expression post radiation therapy in relationship to recurrence and survival and existing data on proteins associated with predictive and/or prognostic value. 6) Aggregating proteomic and proteogenomic results with AI driven progression criteria in glioma (currently subject of imaging analysis with Artificial Intelligence Resource (AIR)) and validation with large scale public data sets. 171676 +Bioengineering; Biomedical Imaging; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Immunotherapy; Machine Learning and Artificial Intelligence; Neurosciences; Patient Safety; Radiation Oncology; Rare Diseases Address;Adjuvant;Agreement;Algorithms;Artificial Intelligence;Brain;Brain Neoplasms;Classification;Clinic;Clinical;Custom;Data Set;Diagnosis;Ensure;Excision;Fostering;Glioblastoma;Glioma;Image;Immunotherapy;In complete remission;Institutional Review Boards;Magnetic Resonance Imaging;Maps;Methodology;Neurologic;Operative Surgical Procedures;Patient imaging;Patient-Focused Outcomes;Patients;Protocols documentation;Radiation therapy;Resources;Secondary to;Selection for Treatments;Stable Disease;Steroids;Testing;Time;Toxic effect;Treatment Efficacy;Treatment Failure;United States National Institutes of Health;base;brain magnetic resonance imaging;cohort;follow-up;improved outcome;neuro-oncology;novel;partial response;response;standard of care;temozolomide;treatment optimization;tumor progression Using artificial intelligence and MRI to address limitations in glioblastoma n/a NCI 10702867 1ZIABC012092-01 1 ZIA BC 12092 1 78858371 "KRAUZE, ANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171676 NCI We hypothesize that MRI images of patients with glioma when subjected to change over time analysis (at diagnosis prior to and post radiation therapy) can identify features predictive of treatment failure helping guide patient management in the clinic. Successful algorithms can be validated using large scale publicly available data sets fostering the secondary advancement of currently lacking ground truth data sets for glioma progression. Our methodology will include MRI (Magnetic Resonance Imaging) of the brain using standard of care sequences generally carried out at most centers will initially be employed to ensure transferrable findings. However we would like to identify and test additional features including ADC and CBV maps that may enhance the predictive ability of algorithms to identify true progression vs. pseudoprogression acknowledging that these may not be consistently carried out outside of centers of excellence secondary to limitations in resources and expertise. The patient cohort initially employed consists of glioblastoma patients treated on IRB approved ROB protocols at NCI NIH for whom biospecimens for correlative omic analysis are available. 171676 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Precision Medicine; Urologic Diseases Address;African American population;Bladder;Bladder Neoplasm;Cell Line;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Computer Analysis;DNA;DNA Sequence Alteration;Data;Deaminase;Disease Outcome;Enzymes;Genes;Goals;In Vitro;Intrinsic factor;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Modeling;Molecular;Multiomic Data;Mus;Mutagenesis;Mutation;Natural Immunity;Neoadjuvant Therapy;Neoplasm Metastasis;Organoids;Outcome;Pathway interactions;Patients;Process;Prognosis;Role;Sequence Read Archive;Testing;The Cancer Genome Atlas;Therapeutic;Translational Research;Tumor Subtype;Untranslated RNA;Woman;base;cancer cell;cancer therapy;cell transformation;database of Genotypes and Phenotypes;epithelial to mesenchymal transition;genetic manipulation;improved;in vivo;molecular phenotype;mouse model;multiple omics;new therapeutic target;prevent;programs;response biomarker;therapy resistant;tool;transcriptome sequencing;tumor;tumor microenvironment;tumor-immune system interactions;tumorigenesis;whole genome Investigating mechanisms of bladder tumorigenesis n/a NCI 10702866 1ZIABC012091-01 1 ZIA BC 12091 1 78858369 "BANDAY, ABDUL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1142525 NCI Our lab mines multi-omics data of bladder cancer available through The Cancer Genome Atlas Sequence Read Archive dbGAP etc. We are in the process of performing whole-genome and whole-transcriptome sequencing of bladder tumors - treatment-naive and neoadjuvant from diverse ancestries through collaborations. Through these studies we also aim to address disparities associated with prognosis and disease outcomes of bladder cancer in African Americans and women. We have begun functional testing of some specific hypotheses based on computational analysis of tumor -omics data. We are using cell lines and are planning to generate organoids mouse models and ex vivo tumor cultures for further explorations. Specially we are performing CRISPR-I screen to identify target genes of non-coding mutations found in bladder tumors and are establishing syngeneic mouse tumor models for exploring role of APOBECs in modulating tumor micro-environment. Our ultimate goal is to identify new druggable targets and biomarkers for response and resistance to therapies and survival in patients with cancer. 1142525 +Bioengineering; Cancer; Nanotechnology 3-Dimensional;Address;Algorithms;Biological;Catalysis;Cells;Computer software;Cryoelectron Microscopy;Crystal Formation;Data;Development;Electron Beam;Electron Microscopy;Electrons;Growth;Heterogeneity;Image;Image Analysis;Individual;Investigation;Ligands;Liquid substance;Maps;Masks;Methodology;Methods;Microscope;Morphology;Performance;Population;Positioning Attribute;Property;Reaction;Research;Resolution;Rotation;Route;Sampling;Science;Series;Shapes;Structure;Substrate Interaction;Surface;Thermodynamics;Time;Time Series Analysis;Variant;automated segmentation;base;density;detector;expectation;experimental study;graphene;improved;insight;nanocrystal;nanoparticle;nanoscale;particle;quantitative imaging;reconstruction Algorithms for atomic-resolution structure identification of nanocrystals n/a NCI 10702864 1ZIABC012088-01 1 ZIA BC 12088 1 78858365 "ELMLUND, HANS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 401856 NCI "Ensembles of synthesized ligand-protected nanocrystals each with a unique atomic structure can be imaged tumbling in solution using Graphene-Liquid Cell Electron Microscopy (GLC-EM). Projection images of differently rotated nanocrystals are acquired using a direct electron detector with high temporal ( 2.5 ms) resolution. The analysis of time-series data of nanocrystals imaged in solution to obtain 3D structural information is an emerging field of research with great potential for improving our understanding of the physiochemical properties of nanocrystals which thermodynamically deviate from the expectations derived from the bulk material. We previously developed a ""one-particle 3D reconstruction method"" based on imaging of individual Pt nanocrystals rotating in solution and the use of Single-Particle Analysis (SPA) to obtain an ensemble of 3D reconstructions (Science 2015 & 2020). However the standard SPA workflow cannot straightforwardly be applied to reconstruct atomic- resolution 3D density maps of the nanocrystals. A number of critical steps need to be addressed: (1) the individual nanocrystals need to be accurately tracked throughout the time-series and robust tracking algorithms have proven difficult to develop (2) the strong interfering background of the GLC needs to be subtracted (3) low-quality images that result from the nanocrystals moving vertically out of the narrow depth of focus of the aberration-corrected microscope need to be identified and rejected and (4) tailored strategies for 2D and 3D alignment and averaging that differ from those used in biological cryo-EM are needed." 401856 +Bioengineering; Biomedical Imaging; Cancer; Data Science Algorithm Design;Cells;Cryo-electron tomography;Cryoelectron Microscopy;Data;Data Analyses;Data Collection;Data Set;Electron Microscopy;Feedback;Future;Goals;Image;Image Analysis;Intelligence;Liquid substance;Manuals;Methods;Microscope;Preparation;Procedures;Research Personnel;Robotics;Sampling;Stream;Time;Tissues;base;computational platform;computerized tools;computing resources;data acquisition;data quality;experimental study;image processing;image reconstruction;imaging modality;improved;instrument;movie;nanocrystal;particle;statistics;success Unsupervised image processing methods for cryoEM analysis in real time n/a NCI 10702863 1ZIABC012087-01 1 ZIA BC 12087 1 78858365 "ELMLUND, HANS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 401856 NCI Traditionally imaging experiments involve a linear workflow with sample preparation followed by data acquisition and analysis. In this workflow data acquisition is often conducted manually-a researcher sits at a microscope and decides which particle cell or tissue section to image. These procedures not only make imaging experiments incredibly time and labour intensive they also limit the volume of data that can be acquired and can create biased data sets. With the advent of robotics for sample preparation and completely automated microscopes it is now time to upscale imaging experiments to generate larger and better data sets through integration of analysis during data acquisition. 401856 +Cancer; Genetics Aspartate;Biochemical;Camptothecin;Chemicals;Crystallization;DNA;DNA Damage;DNA Repair;DNA biosynthesis;DNA replication fork;DNA-protein crosslink;Data;Dimerization;Enzymes;Goals;Hydrophobic Interactions;Movement;Peptide Hydrolases;Pharmaceutical Preparations;Protease Domain;Proteins;Regulation;Roentgen Rays;Serine Protease;Structure;Valine;cancer cell;crosslink;dimer;experimental study;improved;in vivo;inhibitor;mutant;prevent DNA Replication and Repair n/a NCI 10702862 1ZIABC012086-01 1 ZIA BC 12086 1 78858363 "MACHIDA, YUICHI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1181073 NCI We have solved X-ray crystal structures of the FAM111A serine protease domain (SPD). The structural information will help us determine potential mechanisms that regulate the protease activity of FAM111A. Our biochemical and structural studies suggested that FAM111A SPD forms a homodimer through the alpha-1 helix at the N-terminus where two subunits are held together through hydrophobic interactions. We found that substitution of valine on the dimerization interface with aspartate disrupted dimer formation and diminished its protease activity. These data suggest that the dimerization of the enzyme domain is crucial for the activity of FAM111A. Supporting the importance of the dimer formation our in vivo experiments suggested that the monomeric mutant was defective in preventing DPC accumulation and failed to promote DNA replication at DPCs induced by camptothecin. These results raise a new concept that chemicals that can block dimer formation could be used as an inhibitor of FAM111A. 1181073 +Bioengineering; Cancer Biological;Computer Simulation;Data;Dependence;Dissection;Entropy;Free Energy;Goals;Hydrogen Bonding;Hydrophobicity;Modeling;Molecular;Nucleic Acids;Paper;Protein Denaturation;Proteins;Publishing;Solvents;Source;Temperature;Testing;Thermodynamics;Water;Work;enthalpy;functional group;hydrophilicity;insight;mechanical force;molecular dynamics;protein complex;protein folding;solute;theories Computer Simulation Studies of Solvation Thermodynamics n/a NCI 10702861 1ZIABC012085-01 1 ZIA BC 12085 1 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 106039 NCI In this period we published a paper that extended our previous work by examining the temperature-dependence of free energies and forces among small model hydrophilic and hydrophobic functional groups of proteins. For the hydrophilic solutes different relative orientations were used to distinguish between direct inter-solute hydrogen bonds and solutes simultaneously hydrogen bonding to a solvent water bridge. Interestingly the temperature dependencies of the hydrophobic and directly hydrogen bonding solutes turned out to be opposite to that of the bridged hydrophilic solutes: with the delta-G becoming more negative for the former and less negative for the latter with increasing temperature. Dissection of the free energy curves into enthalpy and entropy contributions and further separation of the enthalpy term into solute-solute solute-solvent and solvent-solvent components provided insight into the physical molecular causes for the distinctive thermodynamic results. Finally it was reasoned how the opposite temperature dependencies of the two types of hydrophilic interactions provides a rational for the cold denaturation of proteins. 106039 +Acquired Cognitive Impairment; Aging; Alzheimer's Disease; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Brain Disorders; Cancer; Dementia; Neurodegenerative; Neurosciences Alzheimer's Disease;Amyloid beta-Protein;Atomic Force Microscopy;Data;Dimensions;Electrons;Gamma synuclein;Goals;Image;Ion Channel;Lipoproteins;Modeling;Neurons;Paper;Parkinson Disease;Peptides;Publishing;Side;Synuclein Family;Tubular formation;alpha synuclein;amyloid structure;beta barrel;drug development;monomer;phosphoneuroprotein 14 Modeling Oligomeric Structures of Amyloid forming Peptides n/a NCI 10702860 1ZIABC012084-01 1 ZIA BC 12084 1 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 106039 NCI In this period we published two papers. In the first we proposed a range of concentric beta-barrel models and compare their dimensions to image-averaged electron micrographs of Beta-Amyloid42. The smaller oligomers have 6 8 12 16 and 18 monomers. These beads string together to form necklace-like beaded-annular-protofibrils (bAPFs). These gradually morph into smooth-APFs in which a S3 beta-barrel is shielded on one or both sides by beta-barrels formed from S1 and S2 segments. In the second we extend our beta-amyloid peptide models of oligomers annular protofibrils tubular protofibrils lipoproteins and ion channels to the alpha beta and gamma synuclein family which has been implicated in Parkinson's Disease. 106039 +Cancer; Digestive Diseases; Immunotherapy; Liver Cancer; Liver Disease; Machine Learning and Artificial Intelligence; Orphan Drug; Rare Diseases Aftercare;Automobile Driving;Cell Communication;Cells;Consensus;Evolution;Goals;Immunologic Surveillance;Immunotherapy;Machine Learning;Molecular;Non-Malignant;Patients;Play;Process;Role;Time;Treatment Failure;base;liver cancer patient;malignant state;neoplastic cell;novel;osteopontin;patient prognosis;response;transcriptomics;treatment response;tumor;tumor heterogeneity;tumor microenvironment;tumorigenesis Tumor evolution in response to treatment n/a NCI 10702859 1ZIABC012083-01 1 ZIA BC 12083 1 78858358 "MA, LICHUN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 175226 NCI Tumor evolution is a dynamic process with continuous changes of tumor cells and the interactions with the tumor microenvironment. Based on single-cell transcriptomic profiles from liver cancer patients before and after treatment we developed a novel machine learning-based consensus clustering approach to track cellular states of malignant and non-malignant cells. We demonstrated that a tumor's evolutionary trajectory may change over time in response to immunotherapy. We suggest osteopontin may be a candidate regulator of tumor evolution in response to treatment. 175226 +Cancer; Cancer Genomics; Digestive Diseases; Genetics; Human Genome; Liver Cancer; Liver Disease; Prevention; Rare Diseases Biological Assay;Cancer Intervention;Cells;Early Diagnosis;Failure;Goals;Heterogeneity;Malignant Neoplasms;Malignant neoplasm of liver;Methods;Nature;Neoplasm Metastasis;Outcome;Patient-Focused Outcomes;Patients;Secondary to;Solid;Technology;Therapeutic;cancer cell;cancer therapy;improved;novel strategies;single cell analysis;transcriptome;transcriptomics;tumor;tumor heterogeneity Tumor heterogeneity in liver cancer n/a NCI 10702858 1ZIABC012079-01 1 ZIA BC 12079 1 78858358 "MA, LICHUN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 175226 NCI Tumor heterogeneity is a key factor in therapeutic failures and lethal outcomes of solid malignancies. Uncovering the nature behind the phenomenon of heterogeneity is critical for developing effective cancer treatments. We demonstrated that vast transcriptomic heterogeneity occurs both intertumor and intratumor in liver cancer using single-cell analysis. We developed a method to determine transcriptomic clusters of malignant cells as functionally unique states within a tumor using single-cell transcriptomes and found that tumors with a higher number of functional states are associated with worse patient outcomes. 175226 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Comparative Effectiveness Research; Patient Safety Address;Advocacy;Age-Years;Basic Science;CCR;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Caring;Clinical;Clinical Research;Clinical Trials;Clinical trial protocol document;Common Terminology Criteria for Adverse Events;Conduct Clinical Trials;Data;Data Analyses;Data Collection;Development;Devices;Disease;Doctor of Medicine;Drug Approval;Drug Evaluation;Enhancement Technology;Evaluation;Foundations;Funding;Future;Glean;Grant;Infrastructure;Institutes;Label;Lead;Malignant Neoplasms;Measures;Mission;NCI Center for Cancer Research;Outcome;Outcome Measure;Outcomes Research;Palliative Care;Patient Care;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Performance;Persons;Phase;Phase I/II Trial;Phase II/III Trial;Population;Positioning Attribute;Process;Protocols documentation;PubMed;Questionnaires;Regimen;Reporting;Research;Symptoms;System;Technology;Testing;Therapeutic;Toxic effect;Translational Research;Treatment Efficacy;United States National Library of Medicine;anticancer research;associated symptom;base;cancer therapy;clinical outcome assessment;common symptom;design;drug development;early phase clinical trial;early phase trial;electronic data;experience;improved;infrastructure development;innovation;insight;neglect;novel;novel therapeutic intervention;novel therapeutics;patient oriented;phase I trial;phase III trial;programs;response;success;symptom management;timeline;tool development;tumor;virtual reality Office of Patient-Centered Outcomes Research (OPCORe) n/a NCI 10702857 1ZIABC012078-01 1 ZIA BC 12078 1 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 465049 NCI The mission of CCR is to improve the lives of all cancer patients by solving important challenging and neglected problems in cancer research and patient care through a world-leading basic translational and clinical research and patient care program. Integral to this is the development and evaluation of novel therapeutic approaches evaluated in early-phase trials. Importantly in these early phase clinical trials toxicity and tolerability are the primary questions being addressed. Standard toxicity assessments provide only limited or inadequate information whereas patient-focused approaches using clinical outcomes assessments (COAs) in which information is gathered on the impact of treatment on the person and not only on tumor response would markedly enhance the understanding of the patient experience in these trials. Patients are uniquely positioned to inform understanding of the therapeutic context for drug development and evaluation of these outcomes. The FDA has noted the need for more systematic ways of gathering patient perspective on their condition and patient experience related to novel therapies on how they feel and function through the use of COAs. COAs can broadly be classified into four distinct groups based on how data is collected including information taken directly from the patient (Patient-reported outcomes or PROs) information gleaned from clinical observation (ClinROs); other observer reported outcomes (ObsROs) and data from performance on a task or test (PerfOs) (http//www.fda.gov/media/104969/download ). In cancer-related clinical trials PROs are increasingly encouraged by regulatory agencies and advocacy groups alike to describe the clinical benefit of a therapeutic regimen. This includes information on disease-associated symptom or functions as a component of determining treatment efficacy and in understanding treatment-associated symptomatic toxicities. These measures which collect information directly from the patient without interpretation by somebody else provides further understanding of the patient perspective about the impact of treatment. The incorporation of PROs in early phase clinical trials is increasingly important as there has be a shift in the clinical trial landscape towards early-phase studies where data from well-designed and pivotal phase I/II trials is leading to accelerated drug approval. Therefore having PROs incorporated in these early phase trials can inform the primary trial objective and provide critical information that can be used to support labeling claims in the future. There are many examples where the value of outcomes measures has been instrumental in assessing treatment efficacy in both Phase II and III trials. Additionally these measures also provide valuable insights about the impact of the disease and its treatment that are critical in improving patient care even when the treatment does not prove to have sufficient activity against the cancer. A recent study of 248 patients participating in Phase I trials at M.D. Anderson Cancer Center revealed that 67% of the patients had seven or more concurrent symptoms and more than half of the patients reported that at least 3 of these symptoms were rated as moderate-to-severe. Surprisingly this was more frequent in the younger patients compared to those over 65 years of age highlighting the need for systematic evaluation (starting before treatment) in order to get an accurate assessment of the impact and tolerability of treatment on patients. https://pubmed.ncbi.nlm.nih.gov/31761957/ . The NCI has a long-standing commitment to patient-centered research. This has included development of tools to measure outcomes such as the development of a PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) with demonstrated validity in early phase trials https://pubmed.ncbi.nlm.nih.gov/33392443/ in addition to supporting development of other PRO questionnaires funded through R Grant and other mechanisms. Inclusion of these outcomes has been encouraged and is considered standard in NCI sponsored cooperative group trials and in CTEP-sponsored Phase III trials. The clinical research program of CCR is uniquely poised to lead efforts in systematic integration of these measures in early phase clinical trials and to align with guidance from the NCI and FDA on the importance of these efforts. The proposed program would systematically integrate COAs into the clinical trials conducted at the CCR provided valuable insight into the patient experience and provide opportunity for evaluation of innovative approaches to data collection and analysis. A centralized CCR program will be created through formation of the Section of Patient Centered Outcomes within the program of the NCI Clnical Director within CCR. As outlined below the program would be instituted in several phases starting first with Core Module development for inclusion in all trials engagement of key stakeholders and agencies and infrastructure development. The use of a core set of symptoms common across cancers in addition to treatment-specific symptomatic toxicities will be foundational for Phase II and III in which novel integration of measures use of technology and integration of care can be incorporated. The proposed plan and timeline is as follows: PHASE I (YEAR 1) Establish Stakeholder Advisory Board set up infrastructure for electronic data capture and reporting develop core construct set of outcomes measures Develop template for incorporation into ongoing and future clinical trial protocols for selected clinical branches and cancers pilot and evaluate system with established metrics of feasibility and success. PHASE II (YEAR 2-3) Expand core construct use throughout CCR clinical research develop process for enhanced core concepts based on population or target launch enhanced core concept development as part of scientific review. PHASE III (YEAR 3-5) Develop enhanced technology platform to enable incorporation of these devices (smart wearables virtual reality as examples) into assessment plan Integrate symptom management into assessment core align CCR Outcomes initiative with early phase protocols (ie integrated palliative care) or across stand-alone studies. 465049 +Autoimmune Disease; Cancer; Cerebrovascular; Clinical Research; Clinical Trials and Supportive Activities; Genetics; Hematology; Orphan Drug; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Acute;Age;Allogenic;Anemia;Blood Platelets;Bone Marrow;Bone Marrow Cells;Bone marrow failure;Busulfan;Cessation of life;Characteristics;Classification;Clinical;Cutaneous;Cyclophosphamide;Development;Disease;Dose;Drug Kinetics;Dysmyelopoietic Syndromes;Dysplasia;Ear;Eligibility Determination;Engraftment;Enzymes;Erythroid Progenitor Cells;Fever;Genes;Genetic;Glucocorticoids;Hematologic Neoplasms;Hematology;Hematopoietic Stem Cell Transplantation;Inflammatory;Link;Lung;Marrow;Methionine;Morbidity - disease rate;Mosaicism;Musculoskeletal;Mutation;Myelogenous;Myeloproliferative disease;Names;Neutropenia;Nose;Participant;Patients;Plasma Cell Neoplasm;Polyarteritis Nodosa;Prednisone;Prophylactic treatment;Recurrence;Refractory;Regimen;Relapsing polychondritis;Research;Research Personnel;Secondary to;Sirolimus;Somatic Mutation;Steroids;Sweet's Syndrome;Syndrome;Temporal Arteritis;Testing;Thrombocytopenia;Time;Transfusion;Ubiquitin-Activating Enzymes;United States National Institutes of Health;Vacuole;Whole-Body Irradiation;autoinflammatory;base;clinical phenotype;conditioning;cytopenia;design;fludarabine;graft vs host disease;inflammatory marker;mortality;mycophenolate mofetil;novel;patient population;phase 2 study;post-transplant;skin lesion;systemic inflammatory response Hematopoietic Stem Cell Transplant for VEXAS n/a NCI 10702856 1ZIABC012075-01 1 ZIA BC 12075 1 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 256183 NCI "We opened a trial ""A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects With VEXAS Syndrome"" NCT05027945 in August 2021. Our research objectives are: To determine whether allogeneic hematopoietic stem cell transplantation (HSCT) results in sustained donor engraftment at day 100 and one-year post-HSCT. To determine whether allogeneic HSCT results in reversal of the clinical phenotype of VEXAS at one year and two years post-HSCT without requiring interval prednisone at greater than 0.5 mg/kg per day for reasons other than graft-versus-host disease (GVHD). Eligibility: Recipients ages 18-75 year-old with or without a somatic mutation in UBA1 who have: 1) the clinical phenotype for VEXAS with refractory cutaneous pulmonary musculoskeletal and/or other recurrent acute inflammatory manifestations and 2) require greater than 0.5 mg/kg per day of prednisone for inflammatory manifestations OR have cytopenia (transfusion dependent anemia transfusion dependent thrombocytopenia/platelets less than 75000 neutropenia less than 1000/uL) or myeloid neoplasm (by WHO criteria) or being intolerant or refractory to use steroids. Have an 8/8 or 7/8 HLA-matched related or unrelated donor or a haploidentical related donor. Design: For Recipients with 8/8 HLA Matched Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 40 mg/m2 IV once daily for four days on days -6 -5 -4 -3 and Busulfan IV for three days on days -6 -5 -and -4 followed by HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (3.2 mg/kg IV per day will be the default dose). For Recipients with 7/8 HLA Matched Donors or Haploidentical Related Donors: Participants will receive reduced intensity conditioning with the following regimen: fludarabine 30 mg/m2 IV once daily for five days on days -6 -5 -4 -3 and -2 cyclophosphamide 14.5 mg/kg for two days on days -6 and -5 200 cGy total body irradiation (TBI) on day -1 busulfan IV once daily for two days on days -4 and -3 and HSCT on day 0. The busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to an AUC of 3600-4800 microMol*min/L (52-65 mg*h/L) (3.2 mg/kg IV per day will be the default dose). For Post-Transplant GVHD Prophylaxis: Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4 along with mycophenolate mofetil from day +5 to approximately day +35 and sirolimus from day +5 to approximately day +180." 256183 +Behavioral and Social Science; Bioengineering; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Depression; Health Services; Mental Health; Mental Illness; Networking and Information Technology R&D (NITRD); Neurosciences; Rare Diseases; Sleep Research; Telehealth Acute;Adrenal Cortex Hormones;Affect;Anxiety;Brain Neoplasms;Central Nervous System Neoplasms;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical Trials;Collection;Diagnosis;Distress;Emotional;Enrollment;Environment;Equipment and supply inventories;Feeling;Health;Health Technology;Heart Rate;Home;Individual;Intervention;Learning;Measurement;Measures;Mental Depression;Mental disorders;Moods;National Comprehensive Cancer Network;Participant;Patient Recruitments;Patient Self-Report;Patient-Focused Outcomes;Patients;Personal Satisfaction;Persons;Phase;Population;Primary Brain Neoplasms;Questionnaires;Reporting;Sleep;Sleep disturbances;Stress;Surveys;Symptoms;Technology;Thermometers;affective disturbance;anxiety states;base;computer generated;death anxiety;depressive symptoms;diaries;emotional symptom;experience;falls;fitbit;improved;indexing;physical symptom;preference;research clinical testing;sleep health;sleep quality;telehealth;tumor;tumor diagnosis;virtual reality;virtual reality headset;virtual reality intervention;wearable device Implementation of telehealth and health technology to improve patient outcomes n/a NCI 10702854 1ZIABC012073-01 1 ZIA BC 12073 1 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 746895 NCI We have recently initiated three clinical trials using telehealth and health related technologies to improve patient experience for those with primary brain tumors (PBTs) or primary central nervous system tumors (PCNSTs): The first trial will use describe sleep disturbances and circadian disruption in people with PBT using Fitbits to learn more about sleep disruptions caused by tumors. Participants in this trial will receive a Fitbit which they will wear for one month to track sleep heart rate and activity they will keep a sleep diary for one week and complete 4 surveys with questions about the patient's quality of sleep their ability to fall asleep and stay asleep how the quality of their sleep affects their daily activities and their sleep hygiene and preferences. We will assess the feasibility of using smart wearable devices to measure the impact of oncologic therapy on sleep and circadian rhythms in the PBT population. We will also assess if reported quality of sleep collected with the PROMIS Sleep Indices are comparable between clinical evaluation and collection at-home if patient chronotype as measured by the Morningness-Eveningness Questionnaire (MEQ) are more pronounced in individuals with circadian disruption or sleep disturbances as measured by smart wearables or if circadian rhythm variables (Amplitude and Phase onset/offset) are dampened or phase shifted in patients with moderate to severe levels of sleep disturbances (as measured by the MDASI-BT score of =5). This trial has begun enrolling participants by invitation. The second trial will assess whether a type of therapy called CALM can help patients with PCNST manage distress symptoms and the emotional challenges experienced with a tumor diagnosis. Participants will fill out 7 electronic surveys asking about physical and emotional symptoms depression feelings about death and dying feelings about close relationships and general well-being. Participants will be assigned to a CALM therapist and will have 3 to 6 individual therapy sessions in 6 months. To assess the effects of the CALM intervention in reduction of depressive symptoms we will compare PROMIS-Depression scale results in PCNST participants from baseline to 6 months. We will also assess the effects of CALM intervention on death anxiety at both 3 and 6 months using the Death and Dying Distress Scale (DADDS) and the feasibility of implementing CALM remotely in a PCNST population. This trial has begun enrolling participants by invitation. The third trial will assess if virtual reality (VR) technology can help reduce stress and improve mood in people with PBTs. Participants will receive a VR headset by mail which they will use to view computer-generated environments and they will complete questionnaires at 4 timepoints during the study. At the end of the study we will assess the number of participants who completed the study the effects of a VR intervention on self-reported mood disturbance (as measured by PROMIS -Anxiety PROMIS -Depression Short Forms) and symptom burden and interference (as measured by the MD Anderson Symptom Inventory Brain Tumor [MDASI-BT]) if the effects VR has on distress and anxiety are more pronounced in those with high distress (based on DT cut-off score of greater than or equal to 5) compared those with to low distress (based on DT scores of 0 4) Measurement of Distress the effects of a VR intervention on self-reported acute and subacute distress (as measured by the NCCN Distress Thermometer [DT]) and anxiety (as measured by the State Anxiety Inventory [STAI-6]) in PBT patients and if the effects VR has on distress and anxiety are more pronounced in those individuals not on systemic corticosteroids (CS) compared to those who are not. This trial has begun recruiting participants. 746895 +Cancer; Cancer Genomics; Clinical Research; Genetic Testing; Genetics; Human Genome; Prevention; Rare Diseases Adult;Agarose Chromatography;Age;Algorithms;Biological Assay;Cancer Patient;Cancer Personalized Profiling by Deep Sequencing;Caring;Catecholamines;Cells;Child;Citric Acid Cycle;Classification;Cluster Analysis;Collaborations;Collection;DNA;DNA Methylation;Data;Data Science;Data Set;Detection;Dioxygenases;Disease;Early Diagnosis;Enrollment;Enzyme Inhibition;Enzymes;Excision;Family;Freezing;Fumarates;Gastrointestinal Stromal Tumors;Gender;Genes;Genome;Glycolysis;Goals;High Pressure Liquid Chromatography;High-Risk Cancer;Hour;Hybrids;Hypermethylation;Kidney;Laboratories;Literature;Localized Disease;Magnetic Resonance Imaging;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Methods;Methylation;Modeling;Molecular;Mutation;Natural History;Paraganglioma;Patient Care;Patients;Pediatric Oncology;Pentosephosphate Pathway;Pheochromocytoma;Plasma;Predictive Value;Proteins;Protocols documentation;Publishing;Renal Cell Carcinoma;Reporting;Research;Sampling;Screening for cancer;Serum;Solid Neoplasm;Somatic Mutation;Succinate Dehydrogenase;Succinates;TP53 gene;Technology;Testing;Time;Training;Urine;alpha ketoglutarate;base;cancer type;cell free DNA;cohort;demethylation;detection limit;digital;genetic variant;indexing;inhibitor;metabolic profile;metabolomics;methylation pattern;model building;model development;mutant;objective response rate;participant enrollment;patient population;patient screening;peripheral blood;predictive signature;programmed cell death ligand 1;prospective test;rare cancer;rare variant;screening;screening guidelines;small molecule;tumor;tumor DNA;tumor behavior Early Detection of Cancer Patients with Germline SDH Deficiency n/a NCI 10702853 1ZIABC012072-01 1 ZIA BC 12072 1 14732189 "GLOD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 408639 NCI The initial training set will include 40 patients with SDH-deficient GIST 40 patients with SDH-deficient paraganglioma and 40 patients matched for gender and SDH subunit mutation enrolled on the Rare Tumor Natural History Study. Peripheral blood and urine samples will be collected at the second void of the day at three separate time points separated by at least one month for each patient to minimize the impact of normal variability in the metabolic profiling. All patients will continue to be followed using the current standard screening recommendations. Cell free DNA will be isolated from plasma. Urine cfDNA will be isolated using a Q-Sepharose chromatography protocol which has been shown in the literature to outperform other published and commercial urine cfDNA isolation methods for trans-renal cfDNA yield. PDL-1 methylation has been demonstrated to regulate PDL-1 expression and DNA methylation patterns have been shown to match or exceed TMBs predictive value for PDL-1 inhibition. When sufficient cfDNA is isolated PDL-1 methylation status will be assessed using previously published probes and digital PCR enhanced Methylight technology. This technology's minimal DNA input is 3ng with limits of detection approaching 0.03%. PDL-1 methylation status would be compared to objective response rates for predictive value as a stand-alone assay as well as when integrated with cfDNA derived TMB using a synergistic index. While the genome of SDH-deficient GIST typically contain very few somatic mutations other cancer-associated genes including p53 and RB have been observed particularly in patients with more aggressive tumor behavior. In addition to methylation analysis cfDNA variant allele detection and copy number alterations will also be assessed using a CAPP-seq approach. Previously validated and optimized probe sequences will be incorporated into a targeted hybrid capture NGS panel (cancer personalized profiling by deep sequencing (CAPP-Seq)). Using integrated digital error suppression CAPP-seq limit of detections for rare variants approaches 0.0025% (2.5 in 105 molecules). Metabolomic analysis will be performed in collaboration with the laboratory of Dr. Naomi Taylor through the Mass Spectrometry (Protein and Small Molecule) core at NCI at Frederick. Paired serum and urine samples will be collected and frozen within 2 hours of collection. Metabolic profiling of batched samples will be performed via HPLC-Mass spectrometry including quantitation of TCA cycle pentose phosphate shunt and glycolysis metabolites. AIM 2: Model building will be performed in collaboration with the NCI's Cancer Data Science Laboratory. The combination of DNA methylation and metabolomic data will provide a robust data set for model development using standard algorithms for unsupervised cluster analysis. If possible the model will be refined and simplified to use only better-discriminating features. AIM 3: A testing data set will be generated through ongoing enrollment of patients with germline SDH deficiency on the Rare Tumor Natural History Study. Metabolomic and cfDNA methylation data will be collected from newly enrolled patients with GIST PHEO/PGL and without evidence of cancer (20 in each group). The model will be tested and refined using this dataset. 408639 +Cancer Biological Process;Cellular Membrane;Collaborations;Complex;Cryoelectron Microscopy;Genetic Transcription;Membrane;Molecular;Molecular Conformation;Nucleic Acid Folding;Proteins;RNA;RNA Folding;Signal Transduction;Structure;T-Cell Development;Technology;Translations;structural biology Structural biology collaborations n/a NCI 10702851 1ZIABC012070-01 1 ZIA BC 12070 1 78355629 "LEA, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 208555 NCI We are using the expertise and the state of the art cryoEM technology in the Center of Structural Biology to assist our intramural collaborators on a number of projects. Specific projects include: 1) trying better to understand how the complexes formed under the cellular membrane drive T-cell development; 2) how protein-RNA complexes regulate translation and transcription and 3) how folded RNAs regulate activity by shifting conformational space. We anticipate additional projects over the coming year. 208555 +Brain Disorders; Cancer; Huntington's Disease; Neurodegenerative; Neurosciences; Rare Diseases Anti-Bacterial Agents;Binding;Carrier Proteins;Cells;Disease;Ensure;Goals;Health;Human;Huntington Disease;Infection;Malignant Neoplasms;Membrane Proteins;Pharmaceutical Preparations;Proteins;Publishing;Signal Transduction;Structure;Therapeutic Agents;Work;anti-cancer;improved;novel;protein folding;small molecule;structural biology Eukaryotic Protein Maturation and Transport n/a NCI 10702850 1ZIABC012069-01 1 ZIA BC 12069 1 78355629 "LEA, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 625665 NCI Control of entry of molecules to the cell is fundamental to cellular health as is ensuring that proteins are correctly folded and incorporated in the right cellular compartment. We are using structural biology to dissect the membrane proteins that achieve these goals. This year we have published structures that now form the start point for larger studies of drug-bound forms that will enable redesign of therapies for both cancer and novel anti-bacterial agents. Additionally we have extended our work to delineate the structural basis for the association with disease of expansions of the HTT protein in Huntington's Disease. 625665 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics; Immunotherapy; Infectious Diseases; Orphan Drug; Precision Medicine; Rare Diseases; Sexually Transmitted Infections Affinity;Antibodies;Antigens;Cell Therapy;Chromosomal translocation;Chronic;Clinical Trials;Common Neoplasm;Disease;Engraftment;Epitopes;Goals;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Infusion procedures;Malignant Neoplasms;Mutate;Proto-Oncogenes;Safety;Signal Transduction;T cell therapy;T-Cell Development;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;T-Lymphocyte Epitopes;Therapeutic;Tumor Antigens;Viral Oncogene;base;cancer therapy;chimeric antigen receptor;conditioning;gene therapy;genetically modified cells;melanoma;personalized cancer therapy;premalignant;synovial sarcoma;targeted treatment;therapeutic target;treatment strategy;tumor Cellular Therapy n/a NCI 10702849 1ZIABC012067-01 1 ZIA BC 12067 1 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 286212 NCI T cell receptor (TCR) gene therapy is a personalized cancer treatment strategy that can precisely and potently target a wide variety of tumor antigens. It is based on the infusion of T cells that are genetically engineered ex vivo to express a TCR directed against a tumor antigen. This strategy enables tumor targeting with a large number of T cells that express a high affinity TCR. It also permits pretreatment host conditioning to enhance anti-tumor T cell engraftment and function. TCR gene therapy has shown encouraging results in melanoma synovial cell sarcoma and human papillomavirus-associated cancers. In contrast to antibody and chimeric antigen receptor (CAR) therapy TCR gene therapy can target intracellular antigens which is important because many of attractive oncological therapeutic targets (e.g. mutated protooncogenes viral oncogenes driver chromosomal translocations and cancer germline antigens) localize to the intracellular compartment. The goal of this project is to catalyze the discovery and development of TCR gene therapy for a wide-array of cancers including human papillomavirus-positive cancers and premalignant diseases caused by chronic HPV infection. 286212 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Hematology; Immunotherapy; Infectious Diseases; Lymphatic Research; Lymphoma; Orphan Drug; Patient Safety; Prevention; Rare Diseases; Regenerative Medicine; Transplantation Allogenic;American;American Society of Clinical Oncology;Antithymoglobulin;Award;Cell Therapy;Cells;Clinical Trials;Correlative Study;Data;Disease;Distal;Engraftment;Enrollment;Equus caballus;Goals;Grant;HIV;Hematologic Neoplasms;Infection;Infection Control;Infection prevention;Institutional Review Boards;Kinetics;Malignant Neoplasms;Oral;Organ;Patients;Peripheral;Process;Prophylactic treatment;Publications;Radiation;Regimen;Research Personnel;Societies;Survivors;T-Cell Lymphoma;Toxic effect;Transplant Recipients;arm;conditioning;disorder control;efficacy evaluation;expectation;follow-up;graft vs host disease;hematopoietic cell transplantation;immune reconstitution;novel;novel strategies;pharmacokinetics and pharmacodynamics;transplantation therapy Reduced toxicity allogeneic hematopoietic cell transplantation in malignancies n/a NCI 10702847 1ZIABC012065-01 1 ZIA BC 12065 1 78858344 "KANAKRY, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 146091 NCI In this fiscal year a study of reduced-intensity transplant for patients with peripheral T cell lymphoma has enrolled an arm of the study with 1 year of follow-up of survivors and is in the process of being written for publication. The study results have been presented in oral form at the American Society for Transplantation and Cell Therapy. The correlative studies of the project including the study of horse ATG pharmacokinetics and pharmacodynamics have begun with preliminary data submitted in a successful ASCO Young Investigator Award grant earned by Dr. Kamil Rechache. The peripheral T cell lymphoma study has expanded to enroll patients on a new arm to further study and optimize this novel reduced intensity approach. A new study for patients with hematologic malignancies requiring allogeneic hematopoietic cell transplantation and who are living with HIV has been written and is in the process of IRB review with the expectation of being open to enrollment by the end of the fiscal year. 146091 +Cancer; Cancer Genomics; Genetics; Human Genome; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Address;Adult;Algorithms;Anatomy;Animals;Atlases;Behavior;Bioinformatics;Biological;CCR;Cell Lineage;Cells;Collection;Data;Data Set;Development;Dissociation;Dyes;Embryo;Embryonic Development;Female;Fluorescence-Activated Cell Sorting;Foundations;Gene Expression;Genes;Genetic Transcription;Germ Cells;Heterogeneity;Homeostasis;In Situ Hybridization;Internships;Laboratories;Lead;Manuscripts;Morphology;Natural regeneration;Nuclear;Oregon;Peer Review;Platyhelminths;Pluripotent Stem Cells;Preparation;Protocols documentation;Publications;Regulation;Reporting;Reproductive system;Resources;Sampling;Scientist;Sexual Maturation;Stains;System;Technology;Time;Tissue-Specific Gene Expression;Tissues;Treatment Protocols;Universities;Validation;Work;analysis pipeline;cell fate specification;cell type;comparative;differential expression;digital;falls;germline stem cells;irradiation;male;programs;regenerative;research facility;single-cell RNA sequencing;specific biomarkers;transcriptomics Anatomical and gene expression resource for Macrostomum lignano n/a NCI 10702840 1ZIABC012055-02 1 ZIA BC 12055 2 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 389969 NCI The Macrostomum lignano (Mlig) postembryonic anatomical atlas is a collaborative team effort. Dr. Matthew Voas has optimized cell dissociation vital nuclear dye staining and fluorescence activated cell sorting protocols required for sample preparation and he is producing pilot 10x scRNA-Seq data sets in conjunction with Dr. Sevilay Turan and Dr. Bao Tran's team at the CCR Sequencing Facility at the NCI-Frederick Advanced Technology Research Facility. Postdoctoral Scientist Dr. Xintao Fan has determined the developmental time points from hatchling to sexually mature adult that are most biologically impactful for sequencing and he determined the irradiation treatment regimen necessary for complete elimination of adult pluripotent stem cells and germ cells. University of Oregon Masters intern Laura Paez Baena has developed a scRNA-Seq analysis pipeline tailored to Mlig expression data and she will be the lead bioinformatic analyst for the project. We anticipate collection of necessary data sets including biological replicates for all wild type time points and irradiated animals in fall 2022 and will proceed with analysis and validation of cell/tissue-type specific biomarkers. In tandem Laura will work to create an interactive Shiny app that integrates digital and spatial gene expression data for differentially expressed genes defining anatomical entities captured in our analysis. We anticipate preprinting and submitting a manuscript for peer-reviewed publication on this resource by summer 2023. 389969 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Genetics; HIV/AIDS; Health Disparities; Human Genome; Immunization; Immunotherapy; Infectious Diseases; Microbiome; Minority Health; Nanotechnology; Prevention; Vaccine Related; Vaccine Related (AIDS) ALVAC;Acute;Adjuvant;Affect;Affinity;Agonist;Animals;Antibiotics;Antibodies;Antigens;Avidity;Back;Binding;Blood Platelets;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cell Line;Cells;Citrobacter;Clinical Trials;Colitis;Collaborations;Colon;Cross Presentation;Cytotoxic T-Lymphocytes;DNA;Data;Dose;Endosomes;Epigenetic Process;Epitopes;Fertilization;Funding;Genes;Genetic Transcription;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Gut Mucosa;HIV;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;HIV/SIV vaccine;Helper-Inducer T-Lymphocyte;Histocompatibility;Home;Homing;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunization;Immunodominant Epitopes;Immunology;Immunotherapy;Infection;Interferon Type II;Interferons;Interleukin-12;Interleukin-15;Interleukin-17;Large Intestinal Mucosa;Large Intestine;Ligands;Macaca;Malignant Neoplasms;Memory;Modeling;Modification;Mucosal Immunity;Mucous Membrane;Mus;Myeloid-derived suppressor cells;Natural Immunity;Oral;PPBP gene;Patients;Phase;Predisposition;Proteins;Regulation;Research;Risk;Role;SIV;SIV Vaccines;STAT1 gene;Safety;Site;Small Intestines;Stomach;Structure;Surface;T cell response;T-Cell Depletion;T-Lymphocyte;TLR3 gene;Testing;Textbooks;Time;Toll-like receptors;Training;Transforming Growth Factor beta;Translating;Translations;Tretinoin;Vaccine Adjuvant;Vaccine Design;Vaccines;Vaccinia virus;Vagina;Viral;Viral Antigens;Viral Load result;Virus;Virus Diseases;Work;aluminum sulfate;anti-PD-L1;base;cancer immunotherapy;carboxypeptidase C;chemokine receptor;cytokine;design;gp160;gut microbiota;immune activation;imprint;improved;in vivo;lymphoid structures;melanoma;microbicide;microbiome;monocyte;mucosal vaccine;nanoparticle;nanoparticle delivery;novel;novel strategies;prevent;receptor expression;rectal;response;simian human immunodeficiency virus;single-cell RNA sequencing;synergism;trafficking;transcriptome sequencing;transmission process;vaccine delivery;vaccine efficacy;vaccine immunogenicity;vaccine strategy;vaginal mucosa;viral detection;viral transmission Vaccine strategies for HIVAIDS n/a NCI 10702839 1ZIABC012054-02 1 ZIA BC 12054 2 6572144 "BERZOFSKY, JAY A" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2640125 NCI "The strategies above involve several steps that together comprise a push-pull approach to optimize antigen structure improve quantity and quality of the response and remove regulatory barriers. Blocking negative regulation in HIV and vaccine strategies: We carried out epitope enhancement (sequence modification to improve MHC binding) to increase MHC binding of epitopes from several viral antigens including HIV and showed these improved vaccine efficacy. We have pioneered the use of anti-TGFb as a novel checkpoint inhibitor given that TGFb is one of the most immunosuppressive cytokines known. We even showed preliminary evidence of efficacy and safety in a clinical trial in melanoma patients. We have also compared combinations of checkpoint inhibitors and anti-TGF-b in enhancing vaccine efficacy in mice and found preliminary data for synergy among anti-TGFb anti-LAG3 anti-TIGIT and anti-PDL1. These strategies are applicable to both HIV and cancer. Cytokines as vaccine adjuvants for HIV and induction of high avidity T cells: Our earlier work first showed that high avidity T cells were more effective at clearing viral infections. We found ways to induce them with cytokines and TLR ligands including expressing IL-15 in the vaccine and inclusion of costimulatory molecules in collaborations with Tom Waldmann and with Jeff Schlom respectively. The quality of response proved more important than the quantity. We recently found using a novel adjuvant CAF09 that we could lower the vaccine dose sufficiently to induce higher avidity CD4 T cells to better clear HIV-gp160-expressing virus infection in mice. We also found that IL-1b induces Th17 helper cells that do not help Tc1 CD8 T cells that protect against vaccinia virus expressing HIV gp160. Rather they skew the CD8 response to Tc17 cells that make IL-17 and do not protect. TGF-b blockade can prevent this problem. We are examining the epigenetic and transcriptional mechanisms behind high avidity T cells by carrying out a single-cell RNAseq study of high vs low avidity T cell lines generated against the same antigen. We also found that IL-21 synergizes with IFN-g to induce IFN-stimulated genes and clear Citrobacter colitis through an effect on STAT1. We also examined combinations of cytokines and TLR ligands as vaccine adjuvants and found greatest efficacy of IL-15 + TLR3 and TLR9 agonists but also some efficacy of IL-12 + GM-CSF. Mucosal immunity microbiome and HIV/SIV vaccines: About 85% of HIV transmission is mucosal. We found that a mucosal T cell vaccine can impact the initial mucosal nidus of infection. We are studying induction and trafficking of T cells DCs and MDSCs among mucosal compartments to optimize mucosal vaccine efficacy. In mice we found that T cells could be directly primed in the vaginal mucosa despite lack of organized lymphoid structures contrary to textbook dogma. We also discovered that colonic DCs can imprint CD8 T cells to home back to the colon preferentially based on differential retinoic acid expression vs. small intestine DCs. We are currently examining the mechanism of this effect in terms of chemokine receptor expression and homing activity. We discovered that altering a cathepsin S cleavage site could protect an immunodominant epitope of HIV gp120 from degradation in endosomes during cross-presentation providing proof of concept for a novel mechanism of virus escape for HIV that infects mostly non-APCs. Using NHP models we found that activated mucosal T cells determine susceptibility to SIV/HIV infection (transmission) eclipse time prior to systemic viral detection and acute viral load. We found that even in naive animals gut microbiota can strongly affect susceptibility to transmission by immune activation and also affect vaccine efficacy. We are exploring the mechanisms by testing the effect of antibiotics on multiple cell subsets in the large compared to the small intestine. Further we found that vaccines can induce MDSCs that counteract vaccine protection and also infection can affect trafficking of MDSCs. We also demonstrated for the first time that MDSCs could be infected by SHIV in vivo. As most HIV transmission is through mucosal surfaces and HIV homes to the gut mucosa we have designed and invented a nanoparticle vaccine delivered orally but coated to pass through the stomach intact and to be released selectively in the large intestine where it induces CTL responses in the large intestine and vaginal mucosa and protects against rectal or vaginal challenge with a virus. We translated our oral nanoparticle (NP) approach to macaque SIV vaccines finding reduced risk against SHIV rectal acquisition in 2 studies. Surprisingly we discovered that protection against SIV acquisition in 3 studies can occur without anti-envelope antibodies. While T cell immunity was induced it did not correlate with protection and protection was not abrogated by CD8 T cell depletion. Rather protection correlated with trained innate immunity involving monocyte ""memory"" for SIV in induction of cytokines maintained by epigenetic changes. We have carried out RNAseq to determine what changes occur in monocytes after immunization leading to new mechanistic hypotheses including an unexpected role for platelets. Also we are combining an SIV vaccine and mucosal NP boost to increase mucosal immunity with a microbicide to reduce the viral inoculum in an OAR-funded study. Our hypothesis is that priming and boosting with mucosally delivered nanoparticles containing V2 loop antigens will both increase mucosal immunity to protect against intrarectal SIV challenge and selectively expand immune responses against the V2 loop that have been shown to correlate with protection in the RV144 phase III human trial. Initial results show that priming and boosting orally with NPs containing a V2-loop pentamer can increase protection compared to the base vaccine alone consisting of SIV gag and env DNA ALVAC expressing gp120 and deltaV1 gp120 protein in alum. Immune correlates are under study." 2640125 +Bioengineering; Biotechnology; Cancer; Cerebrovascular; Neurosciences ABCB1 gene;ABCC1 gene;ABCG2 gene;ATP-Binding Cassette Transporters;Astrocytes;Biological Assay;Biological Models;Blood;Blood - brain barrier anatomy;Brain;Caring;Cells;Collaborations;Consumption;Data;Drug Delivery Systems;Drug resistance;Embryo;Firefly Luciferases;Fishes;Glial Fibrillary Acidic Protein;Goals;Homologous Gene;Human;Incubated;Kidney;Knockout Mice;Light;Liver;Luciferases;Malignant Neoplasms;Measures;Modeling;Monitor;Mus;National Center for Advancing Translational Sciences;Nature;Permeability;Play;Property;Resistance;Role;Signal Transduction;Site;Study models;Substrate Specificity;System;Testing;Time;Transgenic Organisms;Variant;Work;Zebrafish;base;blood-brain barrier crossing;blood-brain barrier permeabilization;coelenterazine;high throughput analysis;high throughput screening;improved;inhibitor;luciferin;luminescence;mouse model;nanoluciferase;novel;prevent;promoter Zebrafish model of blood-brain barrier to improve drug delivery to the brain n/a NCI 10702837 1ZIABC012052-02 1 ZIA BC 12052 2 9414470 "GOTTESMAN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 607518 NCI Not only are ABC transporters responsible for drug resistance in cancer but they are a major component of the blood-brain barrier (BBB) and blood-placental barrier. The three most prominent transporters at the blood-brain barrier are ABCB1 ABCC1 and ABCG2. We previously developed a murine model for analysis of ABCG2 expression at the blood-brain barrier based on the fact that luciferin is an ABCG2 substrate and its entry into the brain is prevented by transporter expression. In this model firefly luciferase is under the expression of the GFAP promoter leading to its expression in the astrocytes. When mice are injected with luciferin no light signal from the brain is detected due to ABCG2 preventing luciferin from crossing the blood-brain barrier. However when luciferin is coadministered with an ABCG2 inhibitor it can cross the blood-brain barrier and react with luciferase expressed in the astrocytes to produce light which can be quantitatively measured. Because studies of the BBB in mice are time-consuming and expensive we are developing homologous models in the zebrafish as components of the zebrafish BBB appear to be very similar to those of the mammalian BBB. Two transgenic zebrafish lines have been developed with either firefly luciferase or nanoLuc under the control of the GFAP promoter. Luciferin is the substrate for firefly luciferase and is transported by ABCG2 while coelenterazine is one of the substrates for nanoLuc and is transported by both ABCB1 and ABCG2. Thus either model could potentially be used to study the role of transporters at the blood-brain barrier but they could also be used to screen compounds that might increase permeability of the barrier irregardless of the mechanism. If zebrafish are to be considered an appropriate model for study of transporters at the blood-brain barrier the zebrafish homologs of human transporters must be carefully characterized. Zebrafish do not have a direct homolog of human ABCB1 but instead have 2 similar variants-Abcb4 and Abcb5. Expression of these transporters in heterologous systems has enabled their detailed characterization and inhibition properties. In collaboration with Matthew Hall at NCATS we have found that zebrafish Abcb4 is nearly identical to human ABCB1 in conferring resistance to 90 known ABCB1 substrates. Abcb5 is also a functional transporter and confers resistance to many ABCB1 substrates but has a slightly narrower substrate specificity. While zebrafish Abcb4 is the only homolog that localizes to the BBB Abcb4 and Abcb5 are expressed at other barrier and excretory sites in zebrafish such as the gut liver and kidneys. Zebrafish also have 4 homologs of human ABCG2-Abcg2a Abcg2b Abcg2c and Abcg2d. We have determined that Abcg2a is the only ABCG2 homolog expressed at the zebrafish BBB and a detailed characterization of the substrate specificity of the transporters is underway. Preliminary data in transfected cells suggest that Abcg2a has the most similar substrate specificity to human ABCG2 but they are not identical. As the light signal from nanoLuc is significantly brighter than that of firefly luciferase we initially focused on the nanoLuc transgenic fish. Native coelenterazine and several of its derivatives are compatible with the nanoLuc system and we identified furimazine and coelenterazine h as the brightest. Both furimazine and coelenterazine h were found to be transported by zebrafish Abcg2a but not Abcb4. When embryonic fish were incubated with coelenterazine h in the presence of the ABCG2 inhibitor Ko143 we noted higher levels of luminescence compared to fish incubated with coelenterazine h alone a proof-of-concept result. Further work will include testing other nanoLuc substrates as well as other known inhibitors. 607518 +Bioengineering; Biotechnology; Cancer; Gene Therapy; Genetics; Hematology; Immunotherapy; Lymphatic Research; Lymphoma; Rare Diseases ABL1 gene;AML/MDS;Acute Lymphocytic Leukemia;Address;Alleles;Antigen Targeting;Antigen-Presenting Cells;Antigens;B lymphoid malignancy;Biological Assay;Brachyury protein;CCR;CD22 gene;CD8B1 gene;Categories;Cell Line;Cells;Chordoma;Clinic;Collaborations;Data;Databases;Disease;Dose;Engineering;Epitopes;Evaluation;Frequencies;Fusion Oncogene Proteins;Goals;HLA-A gene;HLA-A2 Antigen;HLA-B Antigens;HLA-C Antigens;Hematologic Neoplasms;Hematological Disease;Human;Immunology;Immunotherapeutic agent;In Vitro;Interleukin-12;International;Legal patent;Love;MS4A1 gene;Manuscripts;Mass Spectrum Analysis;Mature B-Lymphocyte;Mediating;Membrane;Methods;Modeling;Molecular Abnormality;Mus;Mutation;Myeloproliferative disease;National Institute of Child Health and Human Development;Normal tissue morphology;Oncogenic Viruses;Pathway interactions;Patients;Peptide/MHC Complex;Peptides;Peripheral Blood Mononuclear Cell;Population;Pre-Clinical Model;Proteins;Rare Diseases;Receptor Signaling;Recurrence;Research;Safety;Science;Somatic Mutation;T cell therapy;T-Cell Receptor;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Translating;United States National Institutes of Health;Virus;Xenograft Model;base;cancer cell;chimeric antigen receptor T cells;clinical translation;clinically relevant;cross reactivity;cytokine;cytokine release syndrome;cytotoxicity;early phase clinical trial;engineered T cells;expression vector;improved;interest;leukemia;leukemia treatment;leukemia/lymphoma;neoantigens;novel;pre-clinical;preclinical development;preclinical safety;prospective;receptor expression;screening;technology development;therapy development;vector TCR engineered T cell therapies for hematologic malignancies n/a NCI 10702834 1ZIABC012045-02 1 ZIA BC 12045 2 78355631 "ISHII, KAZUSA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 701185 NCI Activity 1: TCR class I and II epitope discovery for myeloid malignancies (AML/MDS/MPN): The objective of this activity is to discover epitopes that can be targeted with T cell receptors. The project is pursued in collaboration with Dr. Josh Elias (Stanford/Chan Zuckerberg Biohub). Recurrent somatic mutations or chromosomal breakpoints shared across patients with frequencies of at least 2% in a given disease category were curated using the publicly accessible COSMIC database. A total of 47 such genetic abnormalities were chosen and expression vectors for tandem minigenes (as described by Tran E et al. Science 2014) encoding these genetic abnormalities were manufactured. Then a panel of artificial antigen presenting cells expressing tandem minigene with one or two HLA class I or II alleles were engineered. A total of sixty cell lines were established which cover 12 most frequent HLA class I and II alleles in the US population. These artificial cell lines were lysed peptide-MHCs were pulled down and the lysates are currently being analyzed by mass spectrometry by Dr. Elias' team. The initial assay identified multiple new epitopes derive from PRAME restricted by HLA-A*02:01 HLA-B*08:01 HLA-C*07:02 HLA-B*07:02 an BCR-ABL1 fusion onco-protein-derived epitope restricted by HLA-B*08:01 and several TMG-encoded neoantigen-derived epitopes. Top candidate epitopes identified in this project will be used for TCR discovery using reverse immunology approaches. ------Activity 2: Pre-clinical development of HLA-A*02:01-restricted CD22TCR: We have discovered T cell receptor that recognizes HLA-A*02:01-restricted epitope of CD22 which is an antigen expressed broadly by mature B-cell malignancies and a portion of acute lymphoblastic leukemia. The CD22TCR demonstrates promising pre-clinical anti-leukemia/lymphoma activity against multiple cell lines in both CD22- and HLA-A2-restricted manner. Furthermore the CD22TCR does not demonstrate severe cross-reactivity that would cause off-target toxicities on normal tissues. We have filed the EIR and patent for the CD22 TCR (Patent Application No. 63/149795 Filed: February 16 2021 International Patent Application No. International Patent Application No. PCT/US2022/016561 filed February 16 2022). Extensive pre-clinical safety evaluation was completed which confirmed that the CD22 TCR-T cells do not cross-react with peptides derived from other human proteins. In NSG xenograft models (BV173-ffLuc-GFP and DG75-ffLuc-Thy1.1) CD22 TCR-T cells mediated anti-leukemia/lymphoma cytotoxicity at clinically relevant cell doses. Leukemia clearance by CD22 TCR-T cells was not associated with systemic cytokine elevation. In contrast CD22 CAR-T was not able to control leukemia at its clinically relevant dose. The CD22 CAR-T cells at higher cell dose (500-fold higher than the dose feasible/safe in humans) cleared leukemia but the treatment was associated with systemic IFNg elevation reminiscent of cytokine release syndrome. These data support that the CD22 TCR-T cells is an active and potentially safer alternative cell-based treatment for B-cell malignancies and the data warrant clinical translation of the TCR. We have submitted an NCI DCTD NExT proposal for GMP-grade vector manufacturing for CD22 TCR awaiting review result. ------Activity 3: Establishment of TCR cross-reactivity screening strategy: Using a panel of murine TCRs recognizing HLA-A*02:01-restricted epitope of CD20 we established a method of prospectively identifying the cross-reactivity that could cause prohibitive toxicities if translated into clinic. The method was summarized as a manuscript which was submitted and currently under review. ------Activity 4: Discovery of TCRs against HLA class I-restricted epitopes of brachyury and PRAME: Using in vitro stimulation of human PBMCs we have isolated multiple TCRs against HLA class I-restricted epitopes of brachyury and PRAME. We currently vetting the antigens and these TCRs for further clinical translation. ------Activity 5: Development of technologies to safely enhance the potency of TCR-T cell therapies: In this activity we are evaluating various methods of improving the therapeutic potency of TCR-engineered T-cell therapies developed in activity #2 and #4. Methods being developed and evaluated include 1) membrane-anchored IL-12 (collaboration with Dr. Ling Zhang CIO CCR NCI) 2) CD8 co-receptor expression augmentation and 3) modulation of TCR signaling by introducing CD3z mutation (collaboration with Dr. Paul Love NICHD NIH). 701185 +Cancer; Infectious Diseases Antibiotics;Bacteria;Bacteriophages;Cryoelectron Microscopy;Disease;Environment;Future;Goals;Health;Human;Infection;Medical;Methods;Molecular;Multiprotein Complexes;Pathogenesis;Pathway interactions;Play;Protein Secretion;Proteins;Research;Resistance;Role;System;Work;X-Ray Crystallography;cell motility;genetic information;human pathogen;novel;pathogen;structural biology;uptake Structural biology of host-pathogen interactions n/a NCI 10702833 1ZIABC012043-02 1 ZIA BC 12043 2 78355629 "LEA, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1251330 NCI We are studying Bacterial systems required for pathogenesis chiefly secretion and motility systems. These two functions are often achieved via a single large apparatus such as in the bacterial flagellar system which is also a protein secretion system. We are using structural biology and functional studies to dissect systems relevant for infection by a variety of human pathogens. Another range of systems we are starting to investigate include protein assemblies associated with uptake of genetic information from the environment and resistance to phages 1251330 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Orphan Drug; Pancreatic Cancer; Rare Diseases Acinar Cell Carcinoma;Affect;Area;CCR;Clinical;Clinical Research;Clinical Trials;Collaborations;Correlative Study;Disease model;Engineering;Exocrine pancreas;Extramural Activities;Goals;Histologic;Histology;Immune;Intervention;Malignant neoplasm of pancreas;Molecular Profiling;Molecular Target;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Exocrine Neoplasm;Pancreatic carcinoma;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase;Pre-Clinical Model;Reporting;Research;Sampling;Site;Testing;Therapeutic;Variant;Work;base;cancer diagnosis;improved outcome;inhibitor;overexpression;phase II trial;prospective;rare cancer;small molecule;tumor Rare Exocrine Tumors of the Pancreas n/a NCI 10702831 1ZIABC012041-02 1 ZIA BC 12041 2 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 260221 NCI GOAL#1) Improving outcomes for patients with adenosquamous carcinoma of the pancreas (ASCP). ASCP is a highly aggressive variant of PDAC that consists of at least 30% squamous component on a background of typical glandular PDAC component. Recent work by extramural collaborators (Von Hoff & Han) demonstrated that myc overexpression drives ASCP and that the small molecule drug Minnelide (Minneamrita Therapeutics LLC) is a superenhancer inhibitor that suppresses myc expression in ASCP. Based on these results we have initiated a Phase 2 single-site CCR-sponsored study to test the anti-tumor activity of Minnelide in patients with advanced previously treated ASCP (PI Alewine). Correlative studies examining drug bioactivity affect on immune components and ASCP molecular fingerprint will be performed by collaborators with expertise in these areas. Accrual is in progress. GOAL#2) Improving outcomes for patients with pancreatic acinar cell carcinoma (PACC). PACC is an ultra-rare tumor type that is histologically and genetically distinct from PDAC. Aim 1: Develop pre-clinical models of PACC. We have initiated a collaboration with CAPR Frederick (S. Kozlov) to engineer a PACC GEMM. Aim 2: Identify new treatments for PACC. We have initiated a Phase 2 trial to test olaparib in patients with PACC based on research by us and others suggesting that PACC is an ID3 deficient tumor and that deficiency of ID3 leads to PARP inhibitor sensitivity. 260221 +Biotechnology; Cancer; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; HIV/AIDS; Immunization; Infectious Diseases; Prevention; Vaccine Related; Vaccine Related (AIDS) 2019-nCoV;ACE2;Antibodies;Antibody Response;Antibody-Dependent Enhancement;Binding;Binding Sites;Epitopes;Family member;Goals;Human;In Vitro;Knowledge;Laboratories;Light;Molecular Conformation;Monoclonal Antibodies;Proteins;Research;SARS coronavirus;SARS-CoV-2 antibody;SARS-CoV-2 infection;SARS-CoV-2 spike protein;Therapeutic;Transgenic Mice;Vaccines;Variant;Virus;betacoronavirus;design;improved;prevent Antibody responses to viruses n/a NCI 10702828 1ZIABC012038-02 1 ZIA BC 12038 2 77857435 "MAYER, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 9313 NCI This research was primarily carried out by the cooperating laboratories. One study characterized several monoclonal antibodies targeting distinct epitopes on the SARS-CoV2 spike protein. One especially potent antibody XG014 was capable of neutralizing SARS-CoV2 as well as its variants and related viruses (e.g. SARS-CoV) in vitro without displaying an antibody-dependent enhancement (ADE) effect seen for some SARS-CoV2 antibodies. XG014 also protected hACE2 transgenic mice from SARS-CoV2 infection. Structural analyses revealed that XG014 has a unique mode of action by recognizing a conserved epitope outside the ACE2 binding site thereby locking the spike protein in a conformation unable to bind ACE2. In contrast other antibody family members directly contacted the ACE2 binding site to prevent ACE2 binding. This research shed new light into the human antibody response to SARS-CoV2 and helped to understand the mechanism of action of a broadly neutralizing beta coronavirus antibody. 9313 +Cancer; Cancer Genomics; Genetics; Human Genome; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human A549;Alternative Splicing;Bar Codes;Biomedical Research;CRISPR screen;CRISPR/Cas technology;Cancer cell line;Cataloging;Cell Maintenance;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Consequentialism;Coupled;Custom;Data;Development;Disease;Dropout;Elements;Engineering;Ensure;Event;Exons;Future;Genes;Genetic;Genomics;Goals;Guide RNA;HCT116 Cells;Hematologic Neoplasms;High-Throughput Nucleotide Sequencing;Human;Hybrids;Individual;K-562;Libraries;Link;MDA MB 231;Malignant Neoplasms;Messenger RNA;Molecular;Names;Neurodevelopmental Disorder;Nuclear;Nuclear Localization Signal;Output;Pathway interactions;Phenotype;Physiology;Play;Polyadenylation;Process;Protein Isoforms;Protocols documentation;RNA;RNA Processing;RNA Splicing;RNA-Binding Proteins;Resolution;Role;System;Testing;Tissues;Transcript;United States National Institutes of Health;Vertebral column;Work;base;cancer cell;combinatorial;computational pipelines;design;embryonic stem cell;fitness;functional genomics;genomic locus;genomic platform;improved;insight;nuclease;pluripotency;polyadenylated messenger RNA;preservation;programs;screening;single-cell RNA sequencing;stem cells;tool;transcriptome;transcriptomics High-throughput phenotypic screening for functionally characterizing alt. exons n/a NCI 10702825 1ZIABC012033-02 1 ZIA BC 12033 2 77857482 "GONATOPOULOS-POURNATZIS, THOMAS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 581974 NCI Aim A In recent work performed at NCI/NIH we have applied molecular engineering strategies to further boost the editing efficiency of CHyMErA. We have shown that addition of 6 nuclear localization signals at the C-terminus of Cas12a stimulates the editing efficiency of CHyMErA by promoting nuclear accumulation and stabilization of Cas12a nuclease. We are currently applying the improved CHyMErA screening platform to identify alternative exons that impact on cell fitness and proliferation in cancer cells. Comprehensive deletion of frame-preserving alternative exons will be performed using the CHyMErA screening platform across a panel of 7 diverse human cancer cell lines (A375 HCT116 MDA-MB-231 A549 Jurkat K562 HAP1). These screens will enable the systematic cataloguing of the core and context-specific alternative fitness exons along with providing insights into the functional complexity of the transcriptome. Aim B We have previously developed CHyMErA a powerful and versatile tool for combinatorial perturbation of genomic loci which is based on the expression of hybrid Cas9 and Cas12a gRNAs. This tool has been successfully applied for dropout and enrichment cell fitness screens. Compared to conventional single-cell transcriptomics CRISPR screens coupled to scRNA-Seq require the capture of non-polyadenylated gRNAs in addition to the capture of mRNA in order to assign perturbations to consequential transcriptomic outputs. CHyMErA in its current form does not allow capturing of guide sequences using any scRNA-Seq platform. Therefore we aim to transform CHyMErA to a perturbation tool that is amenable to capturing both the mRNA transcriptome and gRNAs at the single-cell level. To achieve this we will introduce capture sequences in the middle of the tracrRNA of Cas9 and at the end of Cas12 gRNAs. These capture sequences will be recognized by customized RT barcoded primers during the first step of generating scRNA-Seq libraries. In parallel barcoded polyT RT primers will be used to capture polyadenylated mRNA. Capture sequences have recently been used for a Cas9-based CRISPR platform and made available for use with the 3 Direct Capture 10x Genomics platform. We aim to use these capture sequences in our system but need to ensure that their incorporation does not impact the editing efficiency of CHyMErA. To test the suitability of scCHyMErA for combinatorial CRISPR perturbations coupled to scRNA-Seq we will generate a small library targeting 450 genes using dual-targeting hgRNAs directing both Cas9 and the Cas12a to target the same gene. Two independent hgRNAs will be designed per gene resulting in 1000 library elements (including controls) that will be cloned as a pool into a lentiviral backbone following protocols that we have mastered in the past. For our first screen we will focus on targeting genes encoding RNA binding proteins (RBPs) which regulate RNA processing events including alternative splicing and polyadenylation. These processes underlie important cell fate decisions and their disruption is linked to numerous diseases including hematological malignancies. The hgRNA library will be transduced into embryonic stem cells and subsequently subjected to single-cell RNA-Seq analysis profiling using standard 10x Genomics protocols.The transcriptomes will be sequenced on a NovaSeq 6000 S2 flow cell resulting in 4 billion reads equal to 50k reads per profiled cell and data will be analyzed using established computational pipelines. These data will not only establish scCHyMErA-Seq as a tool for CRISPR perturbation with scRNA-Seq readout but also may uncover genes and RNA-related pathways that play an important role in stem cell maintenance and pluripotency. Future screens will be focused on targeting tissue-regulated alternative cassette exons with scCHyMErA-Seq in order to uncover the postranscriptional splicing events that underlie developmental trajectories. 581974 +Biotechnology; Cancer; HIV/AIDS; Health Disparities; Immunization; Infectious Diseases; Minority Health; Prevention; Vaccine Related; Vaccine Related (AIDS) ALVAC;Adjuvant;Antibodies;Antigens;Binding;CD4 Positive T Lymphocytes;Communicable Diseases;DNA;DNA Vaccines;Development;Engineering;Epidemic;Epigenetic Process;Exposure to;Goals;Government;Grant;HIV;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Human;Hydroxides;Immune response;Immune system;Immunity;Inflammatory;Intellectual Property;Invertebrates;Investigation;Lead;Legal patent;Licensing;Macaca;Malignant Neoplasms;Mediating;Memory;Modeling;Natural Immunity;Natural Killer Cells;Phase;Preparation;Private Sector;Production;Proteins;Recombinants;Risk;SIV;T cell response;Testing;Thailand;Training;Translating;Vaccination;Vaccines;Virus;aluminum sulfate;antibody-dependent cell cytotoxicity;base;design;efficacy trial;gp160;monocyte;nonhuman primate;novel;pathogen;programs;trait;vaccine efficacy;vaccine platform;vaccine trial Phase I HIV vaccine trial with DNAALVAC-HIV gp120 delta V1 vaccines n/a NCI 10702823 1ZIABC012025-02 1 ZIA BC 12025 2 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 9055951 NCI The project will exploit the DNA/ALVAC-HIV vaccine platform's ability to induce lasting trained monocyte memory in combination with a clade AE (A244 strain) V1-deleted HIV-gp160 prime and a novel V1-deleted HIV gp120/alum protein boost. The deletion of V1 from the gp120 envelope will be specially engineered to minimize antibody interference and elicit a high level of antibodies to V2 the primary correlate of risk in RV144. Alum hydroxide will be used as adjuvant for its ability to maximize the induction of trained immunity (through its ability to induce IL-1B) and CD4+ T-cell responses that constituted the secondary correlate of decreased risk of HIV acquisition in RV144. The overall objective of this proposal is to design and produce both a novel HIV V1-deleted A244 gp160 (A244 DeltaV1 gp160) DNA vaccine and a novel HIV V1-deleted A244 gp120 (A244 DeltaV1 gp120) in GMP conditions for testing in a phase I human HIV vaccine trial. These immunogens will first be tested in macaques to assess whether this approach also induces long-lasting non-interfering antibodies innate monocyte memory and adaptive CD4+ T-cells with a low inflammatory profile in humans. The investigation of protective monocyte or NK memory trained immunity will prove beneficial in combatting additional infectious diseases and cancer. Evolutionary conserved from invertebrates trained immunity is an ancient trait of the human immune system that is defined by durable epigenetic reprogramming of monocytes providing the first line of defense against pathogens .This will lead not only to the production and testing of a novel HIV vaccine but also to the thorough investigation of unexplored host protective immune responses in non-human primates (NHP) whose immune system mirrors that of humans. 9055951 +Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Acquired Immunodeficiency Syndrome;Address;Aneuploidy;Animal Model;Binding;Biochemical;Biological;Biological Assay;C-terminal;Cell Cycle;Cell model;Cell physiology;Cells;Centrioles;Centrosome;Complex;Cultured Cells;Data;Development;Disease;Electron Microscopy;Etiology;Event;Genome Stability;Goals;HIV;HIV-1;HIV-2;HIV/AIDS;Human;Immune system;Incidence;Infection;Investigation;Lead;Light;Link;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Molecular;Nature;Organelles;PLK1 gene;Pathogenesis;Persons;Phosphotransferases;Physiological;Process;Proteins;Proteomics;Research;Research Priority;Risk;Role;Scaffolding Protein;Specificity;Structure;Tissues;United States National Institutes of Health;WD Repeat;X-Ray Crystallography;base;cancer risk;carcinogenesis;cellular targeting;chromosome missegregation;comorbidity;cryogenics;design;experience;high risk;inhibitor;interest;novel strategies;prevent;scaffold Unraveling the molecular link between HIVAIDS and cancer n/a NCI 10702822 1ZIABC012024-02 1 ZIA BC 12024 2 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 276385 NCI Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein VprBP via its C-terminal cryptic polo-box. Strikingly HIV-1 Vpr which binds to the WD40 domain (1003-1400) of VprBP greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the formation of the ternary complex appeared to augment Plk4-mediated centriole duplication. Consistent with these findings VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that when cells are infected with HIV-1 Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4 indicating the specificity of HIV-1 Vpr-induced events. Based on these observations we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore it may offer a new paradigm in understanding the increased cancer risk in people living with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Furthermore our efforts to determine the quaternary structure of the Vpr-VprBP-Plk4 complex have been moving along well. Once the quaternary structure is determined we will be interested in designing inhibitors that could disrupt the complex and thus help prevent HIV-1-induced centrosomal abnormalities and their associated human disorders such as cancer. 276385 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Neurosciences; Precision Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Alternative Splicing;Animal Behavior;Biological Process;CRISPR screen;Cell Cycle Regulation;Cells;Complex;Disease;Event;Exons;Genetic;Human Genome;Individual;Libraries;Malignant Neoplasms;Mammalian Cell;Mediating;Names;Neurons;Phenotype;Physiology;Play;Process;RNA Splicing;RNA-Binding Proteins;Regulation;Regulatory Pathway;Role;Series;Synaptic Transmission;System;cognitive function;combinatorial;design;gain of function mutation;gene regulatory network;nervous system disorder;neurogenesis;next generation sequencing;novel;precision medicine;stem cell differentiation;transcriptome;transcriptomics Investigating the regulation of alternative splicing and its role in disease n/a NCI 10702820 1ZIABC012019-03 1 ZIA BC 12019 3 77857482 "GONATOPOULOS-POURNATZIS, THOMAS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 581974 NCI Identification of RNA-binding proteins (RBPs) underlying cell fate decisions. To systematically identify RBPs with important roles in normal physiology and disease we will couple CHyMErA-mediated genetic perturbations of RBPs with phenotypically rich transcriptome profiling read-outs in single cells during a series of stem cell differentiation towards the neuronal lineage. Furthermore we will extend these studies by combinatorially targeting RBPs and elucidating complex gene regulatory networks. Towards this we will exploit CHyMErA genetic interaction mapping capabilities and design a library that will target several hundreds of RBPs individually and combinatorially. 581974 +Cancer; Genetics; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human Apoptosis;Cell Cycle Arrest;Cells;Chromosomes;DNA Damage;Data;Defect;Development;Functional disorder;Genomic Instability;Goals;Knowledge;Malignant Neoplasms;Pathway interactions;Pluripotent Stem Cells;Process;Research Project Grants;Work;cancer cell;cell type;embryonic stem cell;genetic manipulation;response;stem cells;telomere;tumor Mechanism of end protection in stem cells n/a NCI 10702816 1ZIABC012015-03 1 ZIA BC 12015 3 10105415 "LAZZERINI DENCHI, EROS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 666510 NCI When telomeres become critically short they become dysfunctional and elicit activation of the DNA damage response pathway at chromosome ends. Cells with dysfunctional telomeres can either undergo programmed cell death enter into an irreversible cell cycle arrest or accumulate genome instability and eventually transform into an aggressive cancer cell. Using conditional deletion of shelterin components we have shown that the differentiation status has a major impact on the cellular response to telomere dysfunction (Lazzerini Denchi et al. 2006; Lobanova et al. 2017; Pinzaru et al. 2016). We have demonstrated that in response to the same type of genetic manipulation certain cell types accumulate genome instability and eventually develop into aggressive tumors. In contrast others never overcome the proliferation barrier imposed by telomere dysfunction (Lobanova et al. 2017; Pinzaru et al. 2016). Given the importance of telomere-driven genome instability in the development of cancer these data highlight a significant gap in knowledge in a critical tumor-initiating process. Our ongoing work aimed at understanding the connection between telomere dysfunction and the differentiation status revealed that unexpectantly pluripotent embryonic stem cells (ESCs) could survive in the absence of essential shelterin components. This unexpected finding opens a set of outstanding questions regarding the mechanism of telomere protection in pluripotent stem cells 666510 +Biotechnology; Cancer; Emerging Infectious Diseases; Genetics; HIV/AIDS; Health Disparities; Hematology; Immunization; Immunotherapy; Infectious Diseases; Lymphatic Research; Lymphoma; Minority Health; Orphan Drug; Prevention; Rare Diseases; Vaccine Related AIDS related cancer;Acquired Immunodeficiency Syndrome;Acute;B cell repertoire;B-Cell Lymphomas;B-Lymphocytes;Cancer Burden;Cancer Etiology;Cause of Death;Cells;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Codon Nucleotides;Complex;Development;Disease;Elements;Engineering;Enrollment;Epithelial Cells;Flow Cytometry;Genes;Genome;Goals;Guide RNA;HIV;HIV/AIDS;Herpesviridae;Herpesvirus Vaccines;Human Herpesvirus 4;Human Herpesvirus 8;Immune;Immune response;Immunomodulators;Immunotherapy;Individual;Infection;Infection prevention;Intervention;Kaposi Sarcoma;Life;Lymphoma;Lymphoproliferative Disorders;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Methods;Molecular;Morbidity - disease rate;Mus;Mutate;Mutation;Oncogenic;Patients;Peripheral Blood Mononuclear Cell;Persons;Pre-Clinical Model;Process;Repetitive Sequence;Research;Risk;Sampling;Site;System;T cell response;T-Lymphocyte;Technology;Therapeutic Intervention;United States;Vaccination;Vaccines;Viral Genes;Viral Genome;Viral Load result;Virus;Virus Replication;adaptive immune response;antiretroviral therapy;chemotherapy;design;effective therapy;gammaherpesvirus;gene complementation;gene product;high risk;lytic gene expression;malignant stomach neoplasm;mortality;next generation sequencing;novel;novel vaccines;pathogen;patient response;post-transplant;prevent;primary effusion lymphoma;programs;recombinant virus;response;success;therapeutic gene;tumorigenesis;vaccine candidate;vaccine strategy;viral genomics Novel interventions for gammaherpesvirus infection and AIDS-Related Malignancies n/a NCI 10702815 1ZIABC012014-03 1 ZIA BC 12014 3 9786523 "KRUG, LAURIE T" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 255740 NCI (1) To overcome current challenges in the development of herpesvirus vaccines my collaborators and I devised a codon-shuffled complementing gene method to grow high titer replication-dead virus stocks. This replication-dead virus is mutated in a critical gene common to KSHV that is essential for lytic gene expression. We determined that two administrations of this vaccine candidate generate virus-specific B and T cell responses. We also found that vaccination is protective against acute virus replication upon wild-type virus challenge. Building upon the success of this initial approach we have designed new recombinant viruses that inactivate other viral genes essential to replication and latency of gammaherpesvirus including KSHV. This is a novel vaccine strategy to generate a wide repertoire of B and T cells against structural and non-structural gene products. Our goal is to reduce oncogenic viral loads and associated-cancer burdens in infected individuals especially high-risk individuals with HIV/AIDS. (2) In a second project CRISPR is a gene-editing system that we are developing to neutralize gammaherpesviruses in the cells they infect. This system must be engineered for precision to prevent off-target damage to the host for efficiency to inactivate multiple copies of herpesvirus genomes. We successfully reduced murine gammaherpesvirus replication by CRISPR editing of viral genomic elements. We next applied a modified strategy to deliver guide RNAs that target viral genes and repetitive elements in the multiple sites of the EBV genome. Next generation sequencing is being used to characterize the types of mutations generated and we are examining how this CRISPR system impacts latency and reactivation of EBV in a broad array of B cells and epithelial cells that EBV is known to infect and transform. (3) I am analyzing the host immune response in the peripheral blood mononuclear cells of patients in HAMB clinical trials. We are using flow cytometry to examine if the innate and adaptive immune response differs between HIV+ and HIV- patients. We also study if the immune response changes with the chemotherapies and immunotherapies that are used to treat these patients in the clinical trials. The goal is to identify immune correlates of the clinical response for non-responders and responders to find effective therapies for AIDS associated malignancies. 255740 +Cancer; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Non-Human Adult;Anatomy;Animal Model;Animals;Anterior;Competence;Cues;Defect;Development;Embryo;Embryonic Development;Failure;Genetic;Genetic Transcription;Genomics;Head;Injury;Instruction;Natural regeneration;Organogenesis;Pathway interactions;Pattern;Planarians;Platyhelminths;Pluripotent Stem Cells;Positioning Attribute;Production;Property;RNA Interference;Regenerative engineering;Regulation;Reverse engineering;Signal Pathway;Source;Structure;System;Tissues;Work;adult stem cell;beta catenin;blastema;cell type;hatching;inhibitor;knock-down;regenerative;stem cell fate specification;stem cells;wound Mechanisms underlying establishment of regeneration competence n/a NCI 10702811 1ZIABC012009-03 1 ZIA BC 12009 3 77857470 "DAVIES, ERIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 259980 NCI Planarian regeneration requires adult pluripotent stem cells the source of all new tissues and instructive cues from pre-existing tissues to re-establish polarity patterning and orchestrate differentiation of missing cell types. When and how embryos acquire regenerative abilities was not known. We discovered that regeneration competence emerges gradually during embryogenesis and that development of somatic tissue(s) necessary for context-dependent regulation of stem cell dynamics after injury is rate-limiting establishment of regenerative abilities. We observe stage- and axial position-dependent effects on regenerative abilities late in embryogenesis culminating in the production of a fully regeneration-competent animal at hatching. Regeneration-incompetent animals while able to regenerate posterior body structures were incapable of regenerating new anterior (head) tissue. Ongoing work suggests that stem cell specification is not rate-limiting for establishment of regeneration competence: stem cells were present cycling and capable of producing differentiating progeny for pre-existing tissues in regeneration-incompetent animals. We discovered that failure to reset the anterior-posterior axis underlies the head regeneration defect. RNAi knock-down of the Wnt pathway effector Beta-catenin-1 induced precocious head formation in regeneration-incompetent embryos suggesting that high Wnt pathway activity inhibits anterior regeneration. Consistent with this result and in contrast to what was observed in regeneration-competent embryos regeneration-incompetent embryos did not express Wnt pathway inhibitors like notum in anterior-facing blastemas. We are currently investigating how development of tissues that are transcriptionally responsive to wounding including the body wall musculature impinge on axial polarity re-establishment and acquisition of regeneration competence. Our results suggest that regeneration is regulated hierarchically with master regulators of axial polarity governing regional patterning and organogenesis. 259980 +Cancer; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; Infectious Diseases 2019-nCoV;Antigen Presentation;Antigen Presentation Pathway;Antigens;Cells;Coronavirus;Coronavirus Infections;Cross Presentation;Defect;Family;Goals;Human;Image;Immune;Immune response;Immunologics;Immunology;Life Cycle Stages;Lysosomes;Methodology;Modality;Monitor;Monomeric GTP-Binding Proteins;Natural Killer Cells;Pathway interactions;Patients;RNA Viruses;Reporter;Severe Acute Respiratory Syndrome;T-Cell Activation;Virus;Virus Diseases;betacoronavirus;inhibitor;insight;interest;novel therapeutics;trafficking;virus envelope Dynamics of viral infection n/a NCI 10702809 1ZIABC012007-03 1 ZIA BC 12007 3 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 222774 NCI Beta-Coronaviruses are a family of positive-strand enveloped RNA viruses that include the severe acute respiratory syndrome-CoV2 (SARS-CoV2). While much is known regarding their cellular entry and replication pathways their mode of egress remains uncertain; however this is assumed to be via the biosynthetic secretory pathway by analogy to other enveloped viruses. Using imaging methodologies in combination with virus-specific reporters we demonstrated that beta-Coronaviruses utilize lysosomal trafficking for egress from cells. This pathway is regulated by the Arf-like small GTPase Arl8b; thus virus egress is insensitive to inhibitors of the biosynthetic secretory pathway. Coronavirus infection results in lysosome deacidification inactivation of lysosomal degradation and disruption of antigen presentation pathways. This coronavirus-induced exploitation of lysosomes provides insights into the cellular and immunological abnormalities observed in patients and suggests new therapeutic modalities. 222774 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Emerging Infectious Diseases; HIV/AIDS; Infectious Diseases; Orphan Drug; Patient Safety; Rare Diseases AIDS related cancer;African;Animal Disease Models;Anti-Retroviral Agents;Antibodies;Antineoplastic Agents;BAY 54-9085;CDK4 gene;CYP3A4 gene;Cell Cycle;Clinical;Clinical Pharmacology;Cyclin D1;Cyclin-Dependent Kinase Inhibitor;Cyclins;Cytotoxic Chemotherapy;Dose;Drug Exposure;Drug Interactions;Drug Kinetics;Endothelial Cells;Endothelium;Gastrointestinal tract structure;Goals;HIV;HIV Seronegativity;HIV diagnosis;HIV therapy;Human;Human Herpesvirus 8;Interleukin 6 Receptor;Kaposi Sarcoma;Laboratories;Liposomal Doxorubicin;Lung;Lymph Node Involvement;Malignant Neoplasms;Metastatic breast cancer;Modeling;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Oral;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Phase;Phosphorylation;Phosphotransferases;Polypharmacy;Proteins;Recurrence;Refractory;Relapse;Retinoblastoma;Retinoblastoma Protein;Ritonavir;Role;Safety;Signal Pathway;Skin;Therapeutic;Therapeutic Agents;Treatment Protocols;Umbilical vein;bone;comorbidity;cyclin D3;improved;interest;pomalidomide;therapeutic target;tocilizumab;tumor Clinical Pharmacology and Drug-Drug Interactions in HIV-Associated Malignancy n/a NCI 10702799 1ZIABC011996-03 1 ZIA BC 11996 3 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 439362 NCI Our laboratory is interested in studying the pharmacokinetics (PK) of therapeutic agents in the absence and presence of concomitant HIV drugs to better understand if there are clinically meaningful changes in drug exposure of either the HIV or non-HIV therapeutic such that dose adjustments would be warranted. We have previously evaluated the safety and drug-drug interactions between sorafenib and ritonavir an HIV medication with strong CYP3A4 inhibitory activity. We also evaluated the PK of tocilizumab a humanized anti-IL-6 receptor (gp80) antibody in patients with Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease. In a separate study the PK of pomalidomide and liposomal doxorubicin were analyzed to assess for any potential drug interactions in patients with KSHV. Furthermore we have investigated the role of polypharmacy in Sub-Saharan African to understand drug-drug interactions between antiretroviral and anti-cancer drugs. Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor caused by Kaposi sarcoma-associated herpesvirus that most frequently involves the skin but may also involve lymph nodes lungs bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV associated KS have worse survival than HIV-infected patients without KS. As it is a relapsing and remitting condition patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS. Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins including cyclin D kinases (CDKs) cyclins and retinoblastoma (Rb)-E2F signaling pathway. Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. KS is an endothelial tumor and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 uM. The CPP will be involved in determining the PK of abemaciclib in a phase I/II study of patients with HIV-associated and HIV-negative KS. 439362 +Biotechnology; Cancer; Coronaviruses; Emerging Infectious Diseases; Genetics; Health Disparities; Infectious Diseases; Minority Health 2019-nCoV;Address;Alveolar;Amino Acids;Antiviral Agents;Biological Assay;Biological Markers;Blood;Blood Cells;COVID-19;COVID-19 detection;COVID-19 mortality;COVID-19 patient;Cloning;Collaborations;Critical Illness;DNA Sequence Alteration;Data Analyses;Detection;Development;Disease;Donor Selection;Drug resistance;Extramural Activities;Future;General Population;Genetic;Genetic Variation;Goals;HIV;Lower Respiratory Tract Infection;Measurement;Measures;Medical center;Methods;Minor;Mutation;Outpatients;Pathogenesis;Patients;Peripheral Blood Mononuclear Cell;Plasma;Population;Population Genetics;Preventive;RNA;RNA Viruses;Research Personnel;Resistance;Resources;Role;SARS-CoV-2 genome;SARS-CoV-2 pathogenesis;Sampling;Severity of illness;Testing;Time;Tissues;Universities;Vaccines;Variant;Viral;Viral Load result;Viremia;Virion;Virus;Virus Replication;Whole Blood;assay development;experience;experimental study;genome sequencing;in vivo;predict clinical outcome;therapy resistant;transmission process;virus genetics Assessment of SARS-Coronavirus-2 Levels and Genetics in Vivo n/a NCI 10702798 1ZIABC011995-03 1 ZIA BC 11995 3 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 190956 NCI We investigated whole blood plasma and peripheral blood mononuclear cells from patients at the University of Pittsburgh Medical Center. In collaboration with investigators at the University of Pittsburgh including Drs. John Mellors and Jana Jacobs we detected CoV-2 RNA in the majority of samples from hospitalized donors and in few of the samples from outpatients. We found that levels of CoV-2 RNA in blood plasma were highly associated with disease pathogenesis and that CoV-2 RNA can be packaged in virus particles in the blood. We also characterized the population genetics of CoV-2 in the U.S. to establish a prevaccination baseline for viral genetic diversity and to profile the emergence of mutations prior to the introduction of the vaccines to the general public. Such a baseline allowed for the identification of mutations that were selected for by the introduction of the vaccine. My role in these studies was to advise on the development of a quantitative CoV-2 RNA assay the development of CoV-2 sequencing assays the selection of donor samples and the interpretation of the results. I advised extramural investigators to modify our HIV Single-Copy Assay to quantify levels of CoV-2 RNA in the plasma of donors with COVID-19. My lab also assisted in modifying our HIV single-genome sequencing assays to CoV-2 for studies of intrapatient viral diversity and possible emergence of drug resistance. A CoV-2 SGS assay will allow for the detection of minor variants in vivo that may harbor mutations rendering resistance to therapies and preventives including current vaccines. The CoV-2-adapted assays were carried out in the labs of my collaborators at the University of Pittsburgh Drs. Mellors Jana Jacobs and Kevin McCormick. With the exception of a limited scope of experiments such as cloning some fragments of the CoV-2 genome testing primers for the CoV-2 SCA and uSGS assays and validating the assays on CoV-2 RNA we do not anticipate performing these studies in my lab. However we assisted in the analyses of data obtained by our collaborators as requested to aid in our understanding CoV-2 pathogenesis the efficacy of future antivirals and the potential emergence of resistance to future treatments and vaccines. My commitment in time and resources were limited as the goal is to transfer our experience in assay development and with RNA viruses to those focused on studies of CoV-2. _____ACCOMPLISHMENTS: ____Using our SARS-CoV-2 plasma viral load assay we found that plasma SARS-CoV-2 RNA levels are a biomarker of lower respiratory tract infection in critically ill patients with COVID-19 (Jacobs et al. JID 2022) ____ We also found that SARS-COV-2 viremia is associated with disease severity and predicts clinical outcomes (Jacobs et al. CID 2022) ____By analyzing publicly available sequences we demonstrated that the genetic diversity of SARS-CoV-2 tripled in the U.S. in 2020 and included the emergence and persistence of 54 amino acid changes in the population (Capoferri et al. Viruses 2021). ____ In a review article we described the Tterapeutic implications of ongoing alveolar viral replication in COVID-19 (McGonagle D et al. Lancet Rheumatol. 4: e135-e144 2022). 190956 +Cancer; Cancer Genomics; Clinical Research; Genetics; Health Disparities; Hematology; Human Genome; Immunotherapy; Minority Health; Orphan Drug; Pediatric; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Age;Alkylating Agents;Allogenic;Busulfan;Cells;Chimerism;Clinical;Cyclophosphamide;Defect;Disease;Dose;Eligibility Determination;Engraftment;HLA-A gene;Hematological Disease;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Immune;Infection;Life;Marrow;Myeloid Cells;Organism;Participant;Patients;Prophylactic treatment;Recording of previous events;Recovery;Regimen;Resolution;Safety;Source;T-Lymphocyte;Tacrolimus;Transplantation Conditioning;Whole-Body Irradiation;alemtuzumab;cohort;conditioning;congenital immunodeficiency;curative treatments;design;disease phenotype;donor stem cell;efficacy evaluation;exome sequencing;fludarabine;gain of function mutation;genome sequencing;hematopoietic transplantation;immune function;loss of function;mycophenolate mofetil;neutrophil;post-transplant;programs;reconstitution;response;whole genome Allogeneic Hematopoietic Transplantation for Primary Immunodeficiency Diseases n/a NCI 10702797 1ZIABC011994-03 1 ZIA BC 11994 3 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1024731 NCI Background: With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected immune deficiency the number of recognized PID has increased in recent years to over 400 distinct immune defects. Allogeneic hematopoietic stem cell transplantation represents a potentially curative therapy for many hematologic diseases. Hematopoietic stem cell transplant is now an accepted standard or an appropriate experimental approach for treatment of an increasing number of PID The use of conditioning regimens containing high doses of alkylating agents often in combination with total body irradiation are considered myeloablative and are essential and for suppression of the host-versus-graft response to the donor stem cells (i.e. rejection) We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with primary immunodeficiency diseases. 1024731 +Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Precision Medicine; Rare Diseases 19q;Biological;Blood;Cancer Patient;Cell Lineage;Cells;Clinical;Cluster Analysis;Communication;DNA Methylation;Data Set;Diffuse;Environment;Epigenetic Process;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Epistasis;Genome;Glioma;Goals;Immune;Individual;Malignant Neoplasms;Mesenchymal;MicroRNAs;Modification;Mutation;Oncogenic;Outcome;Patients;Phenotype;Precision therapeutics;Process;Publishing;Reporting;Role;Therapeutic;base;cancer cell;cell type;clinical phenotype;clinically significant;computerized tools;epigenomics;gene function;gene interaction;macrophage;monocyte;mutational status;oncostatin M;patient prognosis;programs;receptor;survival outcome;trend;tumor Gene interactions in cancer n/a NCI 10702790 1ZIABC011984-03 1 ZIA BC 11984 3 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 164959 NCI 1. We have contributed to a project in Aldape lab now published in Acta Neuropathologica Communications. We estimated immune cell type-specific gene expression profiles in 3 large clinically annotated glioma datasets using CIBERSORTx and LM22/LM10 blood-based immune signatures and found that the proportions and estimated gene expression patterns of specific immune cells significantly varied according to IDH mutation status. When IDH-WT and IDH-MUT tumors were considered separately cluster-of-cluster analyses of immune cell gene expression identified groups with distinct survival outcomes. We then showed a significant association of monocytic lineage cell gene expression clusters with patient survival and with mesenchymal gene expression scores. Integrating immune cell-based gene expression with previously described malignant cell states in glioma demonstrated that macrophage M0 abundance significantly correlated with mesenchymal state in IDH-WT gliomas with evidence of a previously implicated role of the Oncostatin-M receptor and macrophages in the mesenchymal state. Among IDH-WT tumors that were enriched for the mesenchymal cell state the estimated M0 macrophage expression signature coordinately also trended to a mesenchymal signature. We also examined IDH-MUT tumors stratified by 1p/19q status showing that a mesenchymal gene expression signature the M0 macrophage fraction was enriched in IDH-MUT non-codeleted tumors. Overall these results highlight the biological and clinical significance of the immune cell environment related to IDH mutation status patient prognosis and the mesenchymal state in diffuse gliomas. 2. We are now continuing with the above project with goal of specifically identifying functional interactions between specific processes/states across cell types much like gene-gene interaction approach we have previous published in Cell Reports. 3. A third project we have now initiated with the goal of assessing whether known oncogenic mutations' effect on the clinical phenotype depends on the epigenomic background of the genome. This has implications on precision therapy. 164959 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Coronaviruses; Emerging Infectious Diseases; Genetics; Human Genome; Infectious Diseases; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Women's Health 2019-nCoV;BUB1 gene;Benchmarking;Biological;Biology;Breast;COVID-19;COVID-19 patient;COVID-19 severity;Cell Cycle;Cell Line;Cells;Computer software;Data;Data Set;Development;Drug Targeting;G1/S Transition;Gene Cluster;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Genotype;Hematologic Neoplasms;Hematopoietic;Human;Immunology;Infection;Kidney;Knowledge;Length;Link;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Measures;Mediating;Messenger RNA;Metabolism;Methods;MicroRNAs;Modeling;Mus;Network-based;Noise;Nucleotides;Pathogenesis;Performance;Peripheral Blood Mononuclear Cell;Phenotype;Play;Poly(A) Tail;Post-Transcriptional Regulation;Process;Protocols documentation;Publishing;RNA Interference;RNA Sequences;Reporting;Resolution;Reverse Transcription;Role;SARS-CoV-2 infection;Sampling;Skin;TIAM1 gene;Testing;Tissues;Training;Untranslated RNA;Validation;Virus;Work;base;biological systems;cancer type;cell type;differential expression;gene network;gene regulatory network;human disease;human tissue;leukocyte activation;machine learning model;malignant breast neoplasm;migration;new technology;novel;open source;phthalocyanine;response;single-cell RNA sequencing;tool;transcription factor;transcriptome sequencing;transcriptomics;tumor Machine learning network-based models for gene expression activity function n/a NCI 10702789 1ZIABC011981-03 1 ZIA BC 11981 3 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 329917 NCI We have several subprojects to report on here: 1. We have developed a machine learning tool -- miRSCAPE -- to infer miRNA expression in a sample from its RNA-seq profile. We establish miRSCAPE's accuracy separately in 10 tissues comprising 10000 tumor and normal bulk samples and demonstrate that miRSCAPE accurately infers cell type-specific miRNA activities (predicted vs observed fold-difference correlation 0.81) in two independent datasets where miRNA profiles of specific cell types are available (HEK-GBM Kidney-Breast-Skin). When trained on human hematopoietic cancers miRSCAPE can identify active miRNAs in 8 hematopoietic cell lines in mouse with a reasonable accuracy (auROC = 0.67). Finally we apply miRSCAPE to infer miRNA activities in scRNA clusters in Pancreatic and Lung cancers as well as in 56 cell types in the Human Cell Landscape (HCL). Across the board miRSCAPE recapitulates and provides a refined view of known miRNA biology. miRSCAPE is freely available and promises to substantially expand our understanding of gene regulatory networks at cellular resolution. This work is now accepted at iScience. 2. Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast exploiting curated biological network our PathExt tool identifies central genes from the differentially active paths mediating global transcriptomic response. We apply PathExt to multiple cell line infection models of SARS-CoV-2 and other viruses as well as to COVID-19 patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines were uniquely enriched for ATP metabolic process G1/S transition leukocyte activation and migration. In contrast PBMC response reveals dysregulated cell-cycle processes. In PBMC the most frequently central genes are associated with COVID-19 severity. Importantly relative to differential genes PathExt-identified genes show greater concordance with several benchmark anti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2 ADSL OCRL TIAM1 PBK and BUB1 and potential drugs targeting these genes such as Bemcentinib Phthalocyanine and Conivaptan. This work is now published at Front Immunology. 3. Knowledge of genes that are critical to a tissue's function remains difficult to ascertain and presents a major bottleneck toward a mechanistic understanding of genotype-phenotype links. Here we present the first machine learning model-FUGUE-combining transcriptional and network features to predict tissue-relevant genes across 30 human tissues. FUGUE achieves an average cross-validation auROC of 0.86 and auPRC of 0.50 (expected 0.09). In independent datasets FUGUE accurately distinguishes tissue or cell type-specific genes significantly outperforming the conventional metric based on tissue-specific expression alone. Comparison of tissue-relevant transcription factors across tissue recapitulate their developmental relationships. Interestingly the tissue-relevant genes cluster on the genome within topologically associated domains and furthermore are highly enriched for differentially expressed genes in the corresponding cancer type. We provide the prioritized gene lists in 30 human tissues and an open-source software to prioritize genes in a novel context given multi-sample transcriptomic data. This work is published at PLoS Comp Biology. 329917 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Neurosciences Affect;Binding;Binding Sites;Biological Process;Cell Line;Cell Nucleus;Central Nervous System Diseases;ChIP-seq;Code;Cognition;Collaborations;Complex;Computer Analysis;Data;Data Set;Deposition;Developmental Process;Effectiveness;Embryo;Enhancers;Evolution;Exhibits;Gene Expression;Gene Expression Regulation;Genes;Genetic Polymorphism;Genetic Transcription;Genome;Genomics;Glean;Goals;Housekeeping;Human;Incidence;Interneurons;Macaca;Malignant Neoplasms;Malignant neoplasm of prostate;Methods;Mutation;Neocortex;Nucleotides;Pattern;Pongidae;Prefrontal Cortex;Process;Property;Race;Sampling;Single Nucleotide Polymorphism;Somatic Mutation;Untranslated RNA;Variant;Work;base;cancer initiation;cancer type;deep learning model;driver mutation;experimental study;genome sequencing;neocortical;neural;novel;racial disparity;stem cells;tool;trait;transcription factor;trend;tumor;tumor progression;whole genome Identifying non-coding drivers of cancer n/a NCI 10702788 1ZIABC011979-03 1 ZIA BC 11979 3 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 247437 NCI We have made major progress in the developing the methods and tools and showing its efficacy in identifying mutations in the non-coding regions of the genome during human diversification from other great apes that presumably have created novel regulatory enhancers active in the developing prefrontal cortex. Using deep learning model of embryonic neocortical enhancers and human and macaque embryonic neocortex H3K27ac data we identified 4000 enhancers gained de novo in the human largely attributable to single-nucleotide essential mutations. The genes near de novo gained enhancers exhibit increased expression in human embryonic neocortex relative to macaque are involved in critical neural developmental processes and are expressed specifically in the progenitor cells and interneurons. The gained enhancers especially the essential mutations are associated with central nervous system disorders/traits. Integrative computational analyses suggest that the essential mutations establish enhancer activities through affecting binding of key transcription factors of embryonic neocortex. Overall our results suggest that non-coding mutations may have led to de novo enhancer gains in the embryonic human neocortex that orchestrate the expression of genes involved in critical developmental processes associated with human cognition. This work is now on BioRxiv and currently under review. Encouraged by the effectiveness of the method in prioritizing non-coding mutations during evolution we are now in the process of evaluating the non-coding mutations in cancer. The challenge has been identifying matched healthy and tumor whole genome sequence data in sufficient numbers. We have now identified 10 such matched datasets in Esophaegeal cancer. Also for lack of whole genome sequencing data we have utilized the H3K27AC ChIP-seq data in these samples to identify non-coding mutations. We have also initiated a new collaboration to prioritize race-specific polymorphisms in the enhancer regions to understand the racial disparity in prostate cancer incidence. These efforts are still in the early stages. Additional activity under this projects involves a collaboration where we analyze the spatial organization ofTranscription factor (TF) binding in the nucleus. We find that in multiple cell line contexts TFs form two groups such that TFs within a group 'attract' each other and those across the groups 'repel'. The same trend is also seen in the linear organization of the TF binding on the genome suggesting a co-evolution of the linear genome with the spatial organization. Attractive TF pairs exhibit significantly more physical interactions suggesting an underlying mechanism. The two TF groups differ significantly in their genomic and network properties as well in their function-while one group regulates housekeeping function the other potentially regulates lineage-specific functions that are disrupted in cancer. We also show that weaker binding sites tend to occur in spatially interacting regions of the genome. Our results suggest a complex pattern of spatial cooperativity of TFs that has evolved along with the genome to support housekeeping and lineage-specific functions. This work is deposited in BioRxiv and is currently under review. 247437 +Cancer; Genetics Alternative Splicing;Brain;Cancer Patient;Cancer cell line;Cells;Collaborations;Data;Deposition;Development;Embryo;Embryonic Development;Event;Exhibits;Exons;FDA approved;FOXM1 gene;Foundations;Gene Expression;Genes;Genetic Transcription;Goals;HepG2;Human;Intracellular Transport;Link;Liver;Logic;Malignant Neoplasms;Manuscripts;Mediating;Mesenchymal;Mus;Mutation;Natural regeneration;Neoplasm Metastasis;Oncogenic;Organ;Organogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Process;Proteins;Publications;RNA Splicing;Reporting;Resistance;Role;Schwann Cells;Side;Spliced Genes;Tissue Differentiation;Transmembrane Domain;Work;Writing;base;biological adaptation to stress;cancer cell;cancer risk;cancer type;comparative;experimental study;gene conservation;glycosylation;knock-down;melanoblast;melanoma;novel;small hairpin RNA;stem cells;theories;transcription factor;transcriptomics;tumor;tumor microenvironment;tumor progression;tumorigenesis;wound healing Developmental origins of cancer n/a NCI 10702787 1ZIABC011978-03 1 ZIA BC 11978 3 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 412396 NCI We have three subprojects to report. 1. Leveraging temporal transcriptomic data during development in multiple human organs we demonstrate that the 'embryonic positive (EP)' alternative splicing events specifically active during human organogenesis are broadly reactivated in the organ-specific tumor. EP events are associated with key oncogenic processes and their reactivation predicts proliferation rates in cancer cell lines as well as patient survival. EP exons are significantly enriched for nitrosylation and transmembrane domains coordinately regulating splicing in multiple genes involved in intracellular transport and N-linked glycosylation respectively known critical players in cancer. We infer critical splicing factors (CSF) potentially regulating these EP events and show that CSFs exhibit copy number amplifications in cancer are mutational hotspots and somatic drivers in multiple cancer types and upregulated specifically in malignant cells in the tumor microenvironment. Mutational inactivation of CSFs in cancer patients and shRNA knockdown in HepG2 cell line results in decreased EP splicing supporting their causal role. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of CSFs in brain and liver which can be potentially targeted using FDA approved drugs. Our study provides the first comprehensive demonstration of a splicing-mediated link between development and cancer and suggest novel targets including splicing events splicing factors and transcription factors. This works was deposited in BioRxiv and is currently under review. 2. In collaboration with Merlino lab@NCI we have analyzed the in-house single cell transcriptomics data of developing melanoblasts in mouse at 2 developmental timepoints - E11.5 and E15.5. We have identified several cellular states among the developing melanoblasts and show that some of the Schwann cell progenitor and Mesenchymal states are recapitulated in the melanoma metastasis. Through an extensive analysis of publicly available data we show that these states are associated with patient survival in human melanoma and are associated with vemurafenib and ICB resistance. This is very exciting development and we are currently starting to write the manuscript. 3. As a side project we have also started analyzing the links between oncogenesis and three key homeostatic processes namely Stress response Wound Healing and Regeneration. We have compiled genes associated with these processes from original perturbation experiments in multiple species. We show that indeed known human cancer drivers highly overlap with these processes are proximal to these processes in the protein-interaction network and very interestingly we show that based simply on the proximity from these processes in the protein interaction network we can predict known cancer drivers from other genes. This work is close to finishing and we will start writing the manuscript in a couple of months. We have also contributed to a publication by Ruppin lab that perform a comparative analysis across multiple species relating gene conservation and cancer risk to identify cancer-resistance associated genes that may mediate human cancer risk. 412396 +Arthritis; Autoimmune Disease; Cancer; Cancer Genomics; Digestive Diseases; Genetics; Human Genome; Immunotherapy; Infectious Diseases; Pancreatic Cancer; Rare Diseases 2019-nCoV;Adopted;Adoptive Transfer;Animals;Ankylosing spondylitis;Apoptotic;Autoimmune;Autoimmune encephalitis;Blocking Antibodies;CD4 Positive T Lymphocytes;CXCL3 gene;Cell Surface Receptors;Cells;Colitis;Couples;Death Domain;Disease;Evaluation;Granulocyte-Macrophage Colony-Stimulating Factor;Immune response;Inflammation;Inflammatory;Innate Immune Response;Interferon Type II;Interleukin-10;Interleukin-17;Interleukin-4;Knockout Mice;Malignant Neoplasms;Minor;Modeling;Mus;Pancreatic Ductal Adenocarcinoma;Pathogenicity;Pathologic;Pathway interactions;Psoriasis;Receptors Tumor Necrosis Factor Type II;Regulation;Regulatory T-Lymphocyte;Rheumatoid Arthritis;Role;Shapes;Signal Transduction;T-Lymphocyte;T-bet protein;TNF gene;TNFRSF1A gene;TNFRSF1B gene;Tumor Necrosis Factor Receptor;Tumor-infiltrating immune cells;Virus Diseases;adaptive immune response;anti-tumor immune response;cytokine;in vivo;macrophage;response;single-cell RNA sequencing;transcriptome sequencing;transcriptomics;tumor TNF and inflammation n/a NCI 10702785 1ZIABC011976-03 1 ZIA BC 11976 3 9692263 "ASHWELL, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 423767 NCI "CD4+ T cells are ""skewed"" to different ""T helper"" (Th) fates by activating them in the presence of certain cytokine cocktails. Among the best studied Th subsets are Th1 (master transcription factor: T-bet signature cytokine: IFN-gamma) Th2 (GATA-3 and IL-4) and Th17 (RORgt and IL-17). Th17 cells can be further roughly divided into non-pathogenic and pathogenic cells. The former express immunosuppressive IL-10 whereas the latter express inflammatory products such as GM-CSF and CXCL3. We have found that when naive CD4+ murine T cells are skewed in the presence of TNF as the primary cytokine they adopt an inflammatory Th17 state. We have used both antibody-blocking and the analysis of knockout mice to determine that TNFR2 (the minor TNF receptor) is responsible for this. In addition in vivo studies of various autoimmune inflammatory models (e.g. experimental autoimmune encephalopathy (EAE) and colitis due to adoptive transfer of Treg-depleted T cells) with the corresponding TNFR knockout mice have demonstrated a role for TNF signaling in pathological Th skewing. Evaluation of the composition of immune cell infiltrates as well as transcriptomic analysis both bulk RNA sequencing (RNA-seq) and single cell RNA sequencing (scRNA-seq) has provided a precise picture of how TNF regulation of Th skewing and how it alters the adaptive and innate immune responses. These studies have shown that TNF signaling is upstream of inflammatory Th responses and exacerbates autoimmune/inflammatory diseases. The major and best-studied TNF receptor is TNFR1. We have found that mice deficient in TNFR1 are better able to deal with inflammatory tumors such as pancreatic ductal adenocarcinoma (PDAC). This is due to an enhanced anti-tumor immune response. We are exploring this phenomenon in vivo using mice that spontaneously develop PDAC and are characterizing the innate and adaptive immune response in these animals." 423767 +Autoimmune Disease; Cancer Address;Affinity;Antibody Affinity;Antigen Receptors;Apoptosis;Autoimmune Diseases;B cell differentiation;B-Cell Antigen Receptor;B-Lymphocytes;BCL2 gene;Biological Assay;Bone Marrow;Cell Compartmentation;Cell Death;Cells;Dangerousness;Development;Genes;Goals;Immunologist;Longevity;Lymphocyte Biology;Memory B-Lymphocyte;Mouse Strains;Mus;Mutation;Plasma Cells;Process;Production;Proliferating;Reaction;Role;Seeds;Specificity;Structure of germinal center of lymph node;Transgenic Mice;anergy;antigen binding;autoreactivity;human disease;immunoregulation;mouse model;overexpression;systemic autoimmunity The role of apoptosis in B lymphocyte biology n/a NCI 10702784 1ZIABC011975-03 1 ZIA BC 11975 3 77857435 "MAYER, CHRISTIAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 922085 NCI B lymphocytes assemble the genes encoding for the antigen receptor (B cell receptor BCR) during their development in the bone marrow. Once a diverse repertoire of naive B cells has been generated only those B cells that can best respond to an antigenic challenge become activated start to proliferate and some of those clones may also seed a germinal center (GC) reaction. GC B cells introduce further mutations into the BCR-encoding genes to generate and select for cells with increased antigen binding affinity. During these dynamic processes memory B cells and high-affinity antibody producing plasma cells are also generated. Because BCR assembly in the bone marrow and BCR mutation in GCs are random processes both can result in the production of self-reactive B cells. How these potentially dangerous cells are controlled is a long-standing question that has puzzled immunologists. Several different mechanisms have been proposed including revision of the BCR specificity anergy and cell death. Many of these discoveries were made using transgenic mouse strains in which B cells produced a defined self-reactive BCR. However the precise quantity timing and role of B cell apoptosis in mice with a diverse BCR repertoire remain poorly understood. Interference with apoptosis by overexpression of Bcl-2 throughout the B cell compartment results in systemic autoimmunity indicating the existence of at least one apoptosis-dependent checkpoint for self-reactivity. While we previously identified such a checkpoint in memory B cells and plasma cells it remains unclear if apoptosis has additional roles in earlier stages of the B lymphocyte life span and if these contribute to the censoring of autoimmune diseases. To address these questions we have developed and are currently employing new mouse models to interrogate the role of apoptosis in mice with a normal B lymphocyte repertoire. We have also successfully developed new assays to screen for autoreactivity that will benefit this project. 922085 +Cancer; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; Genetics; Health Disparities; Infectious Diseases; Minority Health 2019-nCoV;Affect;Antiviral Agents;Biological Assay;COVID-19;Cells;Chymase;Containment;Coronavirus;Development;Enzymes;FDA approved;Genes;Genetic Translation;Genome;Human;Nonstructural Protein;Open Reading Frames;Papain;Peptide Hydrolases;Pharmaceutical Preparations;Polyproteins;Population;Protease Inhibitor;Proteins;RNA;RNA Viruses;RNA replication;RNA-Directed RNA Polymerase;SARS coronavirus;SARS-CoV-2 inhibitor;SARS-CoV-2 protease;Site;Structural Protein;Toxic effect;Translating;Viral;Viral Genome;Virus;Virus Replication;absorption;base;high throughput screening;improved;in vitro Assay;small molecule Development of Cell-based Assays to Identify SARS-CoV-2 Protease Inhibitor n/a NCI 10702780 1ZIABC011969-03 1 ZIA BC 11969 3 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 113267 NCI Coronaviruses are positive-strand RNA viruses with exceptionally large genomes (27-32 kb). All coronaviruses encode the enzymes required for their replication in genes 1a and 1b. Genes 1a and 1b are translated as polyproteins; 1b is expressed by -1 frameshifting at the end of the 1a open reading frame. In both SARS-CoV and SARS-CoV-2 the 1a polyprotein contains two proteases a papain-like (PL) protease and a 3-chymotrypsin-like (3CL) protease. Together these proteases cleave polyprotein at 14 sites (3 for PL protease 11 for 3CL protease) generating 16 nonstructural proteins (nsps). These proteins include viral enzymes required for RNA replication including RNA-dependent RNA polymerase. The RNA replication machinery not only generates more copies of the viral genome but also generates subgenomic RNAs that act as mRNAs for the translation of structural proteins. Thus the PL and 3CL proteases are critical for viral replication which make them excellent targets for antivirals. ___We have developed a human cell-based assay that can be used to identify inhibitors of the SARS-CoV-2 3CL protease. This assay has advantages over other protein-based assays that are often affected by in vitro assay conditions and do not account for compound absorption and toxicity issues. Furthermore this assay can be used in BSL-2 containment making it far more accessible than the existing BSL-3 replication-competent virus assays which are not amenable to high-throughput platforms. We are currently modifying the assay to make it suitable to determine the 3CL protease activity of multiple coronaviruses that can infect the human population. 113267 +Cancer; Coronaviruses; Emerging Infectious Diseases; Health Disparities; Infectious Diseases; Minority Health 2019-nCoV;ATP phosphohydrolase;Address;Binding;Binding Proteins;Biogenesis;Cell Surface Receptors;Cells;Cellular Membrane;Collaborations;Coronavirus;Coronavirus spike protein;Cryo-electron tomography;Development;E-Selectin;Endothelial Cells;Epithelial Cells;Family;Genes;Goals;HIV;HIV envelope protein;HIV-1;Human;Immune;Immune response;Infection;Innate Immune Response;Integration Host Factors;Interferon Type II;Interferons;L-Selectin;Measures;Mediating;Membrane;Membrane Glycoproteins;Middle East Respiratory Syndrome Coronavirus;National Institute of Environmental Health Sciences;Natural Immunity;P-Selectin;P-selectin ligand protein;Play;Proteins;Publishing;Role;SARS coronavirus;Structure;Surface;Tertiary Protein Structure;Therapeutic Intervention;Tissues;Vaccine Design;Vaccines;Viral;Virion;Virus;Virus Diseases;Virus Replication;Virus-like particle;Work;adaptive immunity;airway epithelium;antagonist;antiviral drug development;cell motility;cell type;experience;guanylate;insight;mutant;neutralizing antibody;particle;protein transport;trafficking;ubiquitin-protein ligase;viral entry inhibitor;viral transmission Antagonism of Coronavirus Spike Proteins by Cellular Host Factors n/a NCI 10702779 1ZIABC011968-03 1 ZIA BC 11968 3 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 247114 NCI In a structural and functional analysis of the SARS-CoV-2 S protein that we recently started we have determined that MARCH8 but not a catalytically inactive MARCH8 mutant targets the S proteins of SARS-CoV MERS-CoV and SARS-CoV-2 for degradation. We also showed that human airway epithelial cells express MARCH8 upon treatment with IFN. The work on MARCH protein-mediated antagonism may reveal new opportunities for therapeutic intervention with S protein trafficking and incorporation into virus particles. This work was recently published (mBio 12: e00219-21 2021). _____In a separate study we showed that virion incorporation of PSGL-1 on SARS-CoV and SARS-CoV-2 pseudovirions blocks S protein-mediated virus attachment and infection of target cells. These results demonstrate that PSGL-1 can serve as an IFN-regulated host factor that restricts CoV infectivity. This work was recently published (Viruses 13: 46 2020). _____We are now focusing on defining the mechanism by which MARCH E3 ubiquitin ligases antagonize the SARS-CoV-2 S protein evaluating the antiviral activity of GBP ATPases against the SARS-CoV-2 S protein and measuring the expression of host cell anti-SARS-CoV-2 S protein antagonists in relevant cell types. 247114 +Cancer; Coronaviruses; Emerging Infectious Diseases; Health Disparities; Infectious Diseases; Minority Health 2019-nCoV;ACE2;Binding;Cell Culture Techniques;Cell Line;Cell membrane;Cell surface;Cells;Cholesterol;Complement;Coronavirus Infections;Data;Endosomes;Exhibits;Goals;HIV;Human;IFITM1 gene;Immune;Infection;Influenza A virus;Journals;Mediating;Ohio;Pathway interactions;Peptide Hydrolases;Play;Proteins;Protocols documentation;Publishing;Research;Role;Route;SARS coronavirus;SARS-CoV-2 infection;SARS-CoV-2 spike protein;SARS-CoV-2 variant;Severity of illness;TMPRSS2 gene;Universities;Vesicular stomatitis Indiana virus;Virus;Work;base;human coronavirus;in vivo;mutant;novel coronavirus;protein function;receptor;respiratory virus;variants of concern Deciphering the Double-Edged Role of IFITM3 during SARS-CoV-2 Infection n/a NCI 10702778 1ZIABC011967-03 1 ZIA BC 11967 3 15201721 "COMPTON, ALEX " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 69947 NCI We have successfully produced HIV-based and VSV-based pseudovirus bearing the spike protein of SARS-CoV-1 and SARS-CoV-2 variants and produced cell lines that are permissive to these pseudoviruses. We have developed a protocol for transiently transfecting human ACE2 (the receptor for SARS-CoV-1 and SARS-CoV-2) and TMPRSS2 (a protease that activates the fusion potential of SARS-CoV-1 and SARS-CoV-2 spike proteins) into HEK293T cells stably expressing human IFITM1 IFITM2 IFITM3 and mutants thereof. We then challenged these cells with the pseudoviruses and found that the human IFITM proteins inhibit both SARS-CoV-1- and SARS-CoV-2-mediated entry into cells albeit to different extents. Whereas IFITM3 strongly inhibits SARS-CoV-1-mediated entry it only slightly inhibits that driven by SARS-CoV-2. Furthermore if target cells express TMPRSS2 the inhibitory effect of IFITM3 is negligible. These results suggest that viruses utilizing TMPRSS2 have decreased sensitivity to IFITM proteins indicating that TMPRSS2 usage may alter the virus entry route into the cell and may be a means for the virus to evade intrinsic immune barriers. To complement our studies we are collaborating with Jacob Yount at Ohio State University where infections with replication-competent SARS-CoV-2 can be performed. The first chapter of our collaborative work was published in the EMBO Journal (Shi et al. EMBO J. 2021). Interestingly we found that IFITM3 localized to endosomes restricts SARS-CoV-2 infection while IFITM3 at the plasma membrane promotes SARS-CoV-2 infection. This finding demonstrated that SARS-CoV-2 may coopt IFITM3 at the cell surface for its own benefit and provides yet another explanation for why SARS-CoV-2 exploits a cell entry pathway at the cell surface while SARS-CoV-1 does not. Currently we are investigating the mechanisms by which IFITM3 promotes SARS-CoV-2 fusion at the plasma membrane and we are assessing whether the recently evolved variants of concern including Omicron exhibit the same capacity to use IFITM3 for its own benefit. We will explore how the amphipathic helix and its cholesterol binding activity contribute to the promotion of SARS-CoV-2 infection by IFITM3. 69947 +Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Lung; Minority Health Acinar Cell;Adrenocortical carcinoma;Biology;Blood;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Chromatin;Clinic;Collaborations;Data;Data Set;Endothelial Cells;Engineering;Environment;Future;Gene Expression;Genes;Genetic Transcription;Goals;Hydrocortisone;Immune;Individual;Interleukin-12;KRASG12D;Learning;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mus;Mutation;Myeloid Cells;Neoplasm Metastasis;Non-Malignant;Oncogenic;Pancreas;Patients;Pharmaceutical Preparations;Phenocopy;Population;Primary Neoplasm;Publications;Publishing;T-Cell Development;T-Lymphocyte;The Cancer Genome Atlas;Thinking;Thymus Gland;Time;Tissues;To specify;Work;base;cancer cell;cancer type;cell type;clinical prognosis;cohort;computational pipelines;cytokine;design;differential expression;exhaust;experimental study;prognostic;single-cell RNA sequencing;small molecule;transcriptome;transcriptomics;tumor;tumor microenvironment Transcriptomic origins of cancer n/a NCI 10702775 1ZIABC011964-03 1 ZIA BC 11964 3 77857423 "HANNENHALLI, SRIDHAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 494875 NCI "Since the publication of or Edge cell work we have extended the project in three directions. 1. The project has led us to thinking about reversible cell states and how oncogenic or tumor-promoting cell states in the tumor microenvironment can be altered by drugs (small molecules or cytokines). We are currently developing a computational pipeline to do so. We learn each drugs effect on the global transcriptome in a specific cell types (from public datasets like CCLE and CytoSig) and by comparing that with the transcriptional difference between two cell states (say exhausted T cells versus active T cell states) we attempt to prioritize individual drugs by their potential to reverse cell state. This approach recovers for instance IL12 as a potential therapy to alter pre-metastatic niche in lung cancer (previously identified by our collaborator Dr Rosie Kaplan). The work is under progress. 2. In our edge cell work we had made an intriguing observation that the transcriptional effect of KRASG12D mutations in pancreatic cells (in independent experiments) is highly concordant with the transcriptional difference between our detected edges cells and non-edge cells in the non-malignant (also unmutated) pancreatic acinar cells. This suggests existence of transcriptional ""phenocopy"" of KRASG12D mutation. This has led to design of a new subproject (not yet started) where we will define such phenocopies for various key oncogenic mutations in different cancer types and assess its efficacy in clinical prognosis. This will substantially expand the scope of the current mutation-based approaches in practice in the clinic. 3. We have made substantial progress in analyzing and characterizing the tumor and adjacent normal micro-environment of lung and liver metastasized Adrenal Cortical Carcinoma (ACC) tumors in the NCI cohort. This work is done in collaboration with Dr. Rosie Kaplan. Bulk (80%) of the work is completed and we have found several cell type-specific states in the metastasis and adjacent normal microenvironment (for example Tip and Stalk endothelial cells Exhausted T cell etc) uniquely found in met and adjacent environments that are prognostic of patient survival in TCGA. We have also observed substantive functional differences between the Cortisol-producing and non-cortisol-producing malignant cells that could explain their differential aggressiveness." 494875 +Biotechnology; Cancer; Emerging Infectious Diseases; Genetics; HIV/AIDS; Health Disparities; Hematology; Infectious Diseases; Lymphatic Research; Lymphoma; Minority Health; Rare Diseases Acquired Immunodeficiency Syndrome;Animal Model;Animals;Area;B cell repertoire;B-Lymphocytes;Basic Science;Binding Proteins;Biochemical;Biological;Biopsy;Bypass;Cancer Burden;Cause of Death;Cell Culture System;Cell Culture Techniques;Cell Line;Cell Nucleus;Cell Proliferation;Cells;Clinical;Clinical Trials;Clonal Expansion;Clonality;Collaborations;Complex;DNA biosynthesis;Data;Data Set;Development;Disease;Endothelial Cells;Enrollment;Etiology;Event;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Recombination;Genetic Risk;Genome Stability;HIV;HIV/AIDS;Herpesviridae;Herpesviridae Infections;Host Defense;Human;Human Herpesvirus 4;Human Herpesvirus 8;Immunoglobulins;Implant;Individual;Infection;Interferons;Interphase Cell;Intervention;Investigation;Kaposi Sarcoma;Knock-out;Knowledge;Laboratories;Life;Lytic;Malignant - descriptor;Malignant Neoplasms;Molecular;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Mus;Nuclear;Nucleotides;Oncogenic;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Process;Property;RRM1 gene;Reporting;Research;Research Personnel;Risk;Role;STAT1 gene;STAT3 gene;Sampling;Series;Signal Transduction;Source;Structure;Structure of germinal center of lymph node;System;T-Lymphocyte;Therapeutic;Trans-Activators;Transgenic Mice;Viral;Viral Genome;Viral Pathogenesis;Viral Proteins;Virus;Xenograft procedure;antiretroviral therapy;base;cell transformation;cohort;conditional knockout;cytokine;dUTP pyrophosphatase;differential expression;gammaherpesvirus;infected B cell;lymph nodes;mortality;mouse model;next generation sequencing;novel;nucleotide metabolism;pathogen;patient derived xenograft model;pre-clinical;pre-clinical research;primary effusion lymphoma;programs;protein metabolism;rational design;receptor;response;transcriptome sequencing;tumor;uracil-DNA glycosylase;viral DNA;virus host interaction Investigation of viral and host determinants of gammaherpesvirus pathogenesis n/a NCI 10702769 1ZIABC011953-03 1 ZIA BC 11953 3 9786523 "KRUG, LAURIE T" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1449199 NCI (1) STAT3 activation is associated with gammaherpesvirus latency and cancer in cell culture systems but the target genes that drive latency proliferation and transformation are not well-defined. As a prelude to studying the effects of STAT3 activation in KSHV itself we used transgenic mice with a B cell-specific knock-out of STAT3 to determine that STAT3 signaling is critical for the establishment of gammaherpesvirus latency in primary B cells of the host. We also determined that the viral lytic gene transactivator RTA interacts with STAT3 in a cytokine-dependent manner. Our central hypothesis is that gammaherpesviruses require STAT3 to promote B cell latency. To define the STAT3-dependent gene expression program of infected B cells we are performing RNAseq to compare the gene expression profile in infected cells with and without STAT3. Thus far we have identified a pro-viral role of STAT3 in dampening the interferon response in B cells via STAT3 inhibition of STAT1/2 and numerous antiviral interferon-stimulated genes. We will merge differentially expressed genes from all available gammaherpesvirus datasets to identify and prioritize common STAT3-regulated pathways and target genes. These will lead to further investigations of latency reactivation and transformation in KSHV and murine cell culture systems using conditional knock-out approaches. (2a) The numerous herpesvirus genes involved in nucleotide metabolism indicate that the nucleotide pool is a major restriction point in non-dividing cells. We recently reported that the enzymatic properties of the viral uracil DNA glycosylase (UNG) synergize with the viral nucleotide metabolism protein dUTPase to promote pathogenesis and counter recombination-based deletions in the viral genome. We are currently exploring protein binding partners of the viral UNG. In collaboration with Kevin McBride we are examining the differential biochemical properties of the viral and host UNG. (2b) Also in collaboration with the McBride lab we analyzed the immunoglobulin repertoire of infected and uninfected B cells from infected mice using next generation sequencing. This analysis revealed that gamamherpesvirus-infected cells undergo clonal expansion yet only a few clones were shared between the infected and uninfected germinal center B cells. There is also evidence for receptor editing and clear bias for specific IghV genes in the infected B cells. These novel data indicate the gammaherpesviruses occupy a distinct niche in the infected host and takes an active role in subverting the immunoglobulin repertoire in the B cells that it infects. This supports the existence of a critical strategy that is shared with KSHV and EBV namely that these viruses bypass normal selection processes placing the B cells at risk for genetic instability and for producing immunoglobulins with pathologic potential. I am also collaborating with other NCI investigators and clinicians in HAMB to analyze the B cell repertoire of KSHV-infected cells in HIV-associated primary effusion lymphoma and lymph node material of HIV-infected KSHV-multicentric Castleman disease patients enrolled in HAMB clinical trials. This will enable us to examine the clonality and source of the B cell transformation. Importantly this might inform the possible etiology of these diseases which often occur in a concurrent or sequential manner in people living with HIV. (3) We are examining the mechanism by which the viral ribonucleotide reductase large subunit relocalizes host nuclear defense factors termed PML-NB into track-like structures. We hypothesize that this relocalization by the virus neutralizes their antiviral functions and promotes productive infection. (4) With regard to the development of direct animal models of Kaposi sarcoma a hallmark tumor of AIDS I am collaborating with clinicians in the HIV and AIDS Malignancy Branch and in the Center for Advanced Preclinical Research (CAPR) of NCI Frederick in more translational projects towards the establishment of a patient-derived xenograft model. KS biopsy material from HIV infected patients in the HAMB clinical cohorts is being implanted into immunodeficient animals. Thus far we observe KSHV-infected endothelial cell proliferation and expansion in the xenografts. Cell lines derived from this system that maintain KSHV infection and drive tumors in mice will be a tremendous advancement for the field since there is no way to maintain KSHV+ endothelial cells upon explant and there is no pre-clinical animal model of Kaposi sarcoma to screen for effective drug interventions of this AIDS-defining cancer. 1449199 +Cancer; Clinical Research; Coronaviruses; Emerging Infectious Diseases; Health Disparities; Hematology; Immunization; Infectious Diseases; Lymphatic Research; Lymphoma; Minority Health; Prevention; Rare Diseases; Vaccine Related Acute;Antibody Formation;Antigens;B-Lymphocytes;COVID-19 pandemic;COVID-19 patient;Clone Cells;Data;Genes;Hematologic Neoplasms;Immune;Immune response;Immune system;Immunoglobulins;Malignant Neoplasms;Multiple Myeloma;Mutate;Outcome;Patients;Pattern;Persons;Population;Publications;SARS-CoV-2 antibody;Symptoms;Testing;Time;Vaccination;Vaccines;Variant;coronavirus disease;experience;large cell Diffuse non-Hodgkin's lymphoma Patterns of immune response in COVID-19 patients n/a NCI 10702768 1ZIABC011952-03 1 ZIA BC 11952 3 6212020 "KREITMAN, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 335156 NCI At this time data from all projects is being analyzed. For the 1st project involving patients without active malignancy who are acutely infected with COVID we found a broad distribution of responding B-cell clones without noticeable skewing of IGHV gene usage. Some patients demonstrated monoclonal populations carrying highly mutated IGHV rearrangements indicating antigen experience at a few or all of the time points tested including even before anti-SARS-CoV2 antibodies were detected. We did not find a particular pattern of immune response correlating with outcome. For the 2nd project a total of 129 patients with COVID19 have been tested including 115 with HCL 5 with HCL variant (HCLv) 1 with HCL and multiple myeloma 1 with diffuse large B-cell lymphoma and 7 without hematologic malignancy. We found striking differences in the immune response to COVID with respect to antibody production with respect to recent treatment and presence of normal B-cells. We found similar results in the larger project of the study of the immune response to vaccine in patients with HCL. 335156 +Biotechnology; Cancer; Clinical Research; Coronaviruses; Coronaviruses Therapeutics and Interventions; Coronaviruses Vaccines; Emerging Infectious Diseases; Genetics; Health Disparities; Immunization; Immunotherapy; Infectious Diseases; Minority Health; Prevention; Vaccine Related 2019-nCoV;Antibodies;Antibody Response;Antigens;Biological;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;COVID-19;Disease Outcome;Dose;Evaluation;Evolution;Frequencies;Future;Generations;Genes;Genetic;Genome;Immune Response Genes;Immune response;Individual;Infection;Molecular;Mutation;Participant;Proteins;Research Personnel;SARS-CoV-2 infection;SARS-CoV-2 variant;Sampling;T cell response;T memory cell;T-Lymphocyte;Testing;Therapeutic Monoclonal Antibodies;Vaccinated;Vaccination;Vaccinee;Vaccines;Variant;Viral;booster vaccine;comparative;cytotoxicity;effector T cell;genetic association;genetic resistance;preservation;response;vaccine-induced antibodies;variants of concern Host genetic resistance to COVID-19 n/a NCI 10702766 1ZIABC011949-03 1 ZIA BC 11949 3 9414396 "CARRINGTON, MARY N." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 156177 NCI The SARS- CoV-2 Omicron variant (B.1.1.529) was the cause of a new surge of infections globally. With as many as 36 substitutions in the viral spike protein and 59 mutations in total throughout its genome Omicron has been found to evade neutralization by infection- and vaccine-induced antibodies with unprecedented frequency and escape neutralization by most therapeutic monoclonal antibodies. Additional booster vaccine doses partially compensate for this effect but the durability of such protective antibody response remains to be determined. Utilizing samples from prior SARS-CoV-2 infected vaccinated and both prior infected and vaccinated individuals it was shown that circulating effector T cell responses and both CD4+ and CD8+ memory T cell responses were generally preserved to the Omicron variant. However distinct from previous variants of concern (VOCs) such as Delta a subset of individuals had reduced effector and memory T cell recognition to the Omicron spike protein relative to wild-type spike with a particularly noticeable effect on spike-specific CD8+ T cell memory re- sponses. Booster doses enhanced the magnitude of responses to wild-type and Omicron spike although did not completely mitigate the comparatively reduced T cell reactivity to Omicron in individual participants. These findings also raise the prospect that future SARS-CoV-2 variants may variably escape from antibody or T cell responses. They therefore support continued evaluation of second-generation vaccine approaches that induce robust T cell responses that target both variant spike and nonspike antigens in order to overcome current and future SARS-CoV-2 evolution. 156177 +Biotechnology; Cancer; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; Health Disparities; Immunization; Infectious Diseases; Minority Health 2019-nCoV;ACE2;Affinity;Bacteriophages;Binding Proteins;Biological;COVID-19;Camels;Cells;Complex;Cryoelectron Microscopy;Data;Development;Dose;Dromedaries;Human;K-18 conjugate;Libraries;Molecular Conformation;Nurses;Phage Display;Proteins;Publishing;Research;SARS-CoV-2 B.1.351;SARS-CoV-2 B.1.617.2;SARS-CoV-2 antibody;SARS-CoV-2 spike protein;SARS-CoV-2 variant;Shark;Site;Structure;Surface;Therapeutic;Therapeutic antibodies;Transgenic Mice;Variant;Viral;Virus;Work;global health;nanobodies;neutralizing antibody;novel;pandemic disease;receptor binding;therapeutic target Development of neutralizing nanobodies against SARS-CoV-2 n/a NCI 10702762 1ZIABC011943-03 1 ZIA BC 11943 3 9692203 "HO, MITCHELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 45270 NCI During the pandemic Dr Ho has evaluated the challenges for developing antibody therapeutics targeting SARS-Cov-2 and wrote a review/perspective article [Ho Antibody Therapeutics 2020; PMID: 32566896]. SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore the S protein is the primary target for neutralizing antibodies. In FY2022 we summarized our work on isolation of dromedary camel nanobodies against SARS-CoV-2 and published the data in PNAS [Hong et al. Proc Natl Acad Sci U S A. 2022]. With the emergence of SARS-CoV-2 variants there is an urgent need to develop broadly neutralizing antibodies. We isolated two VHH nanobodies (7A3 and 8A2) from dromedary camels by phage display which have high affinity for the receptor-binding domain (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants. Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike regardless of the RBD conformational state. 7A3 at a dose of 5 mg/kg efficiently protects K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2 suggesting that the nanobody has promising therapeutic potential to curb the COVID-19 surge with emerging SARS-CoV-2 variants. 45270 +Bioengineering; Cancer; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; Health Disparities; Infectious Diseases; Minority Health; Nanotechnology 2019-nCoV;CCR;COVID-19;COVID-19 pandemic;COVID-19 treatment;Collaborations;Communities;Computer software;Detection;Disease;Flow Cytometry;HIV;Laboratories;Malignant Neoplasms;Manuscripts;Measurement;Methods;Molecular Analysis;Monitor;Physiologic pulse;Protocols documentation;Research;Resources;SARS-CoV-2 infection;Technology;Update;Viral;Virus;Virus Diseases;exosome;extracellular vesicles;nano;nanobiologic;nanobiology;open source;particle;programs;tool;web site Translational Nanobiology Approaches to Viral Diseases (HIV HTLV SARS-CoV2) n/a NCI 10702761 1ZIABC011942-03 1 ZIA BC 11942 3 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 76763 NCI We established and are maintaining an open-access resource at nano.ccr.cancer.gov wherein protocols and methods for virus and extracellular vesicle (EV) detection or characterization that is developed in this program are shared with the worldwide research community. Since launch of the website we have been posting updates on a near-weekly basis. Additional open source software relating to extracellular vesicles particles research has been added in 2022 and will be presented in upcoming manuscripts. New 2022 software includes 1) an updated FCMpass package for single EV flow cytometry 2) post acquisition analysis software for resistive pulse sensing measurements and 3) multiplex EV repertoire analysis software 76763 +Bioengineering; Biotechnology; Cancer; Coronaviruses; Coronaviruses Vaccines; Emerging Infectious Diseases; Health Disparities; Immunization; Infectious Diseases; Lung; Lung Cancer; Minority Health; Nanotechnology; Nutrition; Prevention; Vaccine Related 2019-nCoV;ACE2;Adjuvant;Affect;Angiotensin II;Animal Model;Animals;Antibodies;Antibody Specificity;Antibody titer measurement;Antigens;Appearance;B-Lymphocyte Epitopes;Binding;Bioinformatics;Body Weight decreased;Bronchoalveolar Lavage;Bronchoalveolar Lavage Fluid;CD8-Positive T-Lymphocytes;COVID-19;COVID-19 vaccine;Cancer cell line;Cell Line;Cells;Cholesterol;Coupled;DNA Vaccines;Dendritic Cells;Diet;Disease;Dose;Electroporation;Engineering;Epithelial Cells;FDA Emergency Use Authorization;Formulation;HIV vaccine;Hamsters;Human;Human Cell Line;Immune;Immunity;Immunize;Immunoglobulin A;Immunoglobulin G;In Vitro;Industrialization;Infection;Infection prevention;Interferon Type I;Interferons;Interleukin-15;Ligands;Lung;Macaca;Macaca mulatta;Malignant neoplasm of lung;Medical center;Methods;Modeling;Morbidity - disease rate;Mucosal Immunity;Mucous Membrane;Mus;Myeloid Cells;Nasal cavity;Natural Immunity;Non-Small-Cell Lung Carcinoma;Nose;Obesity;Omega-3 Fatty Acids;Persons;Play;Predisposition;Production;Proteins;Publishing;Recombinants;Respiratory Mucosa;Risk;Role;Route;SARS-CoV-2 B.1.351;SARS-CoV-2 spike protein;SARS-CoV-2 variant;SIV Vaccines;Serum;Site;T cell response;T-Lymphocyte;TLR3 gene;TMPRSS2 gene;Testing;Texas;Time;Transgenic Mice;Universities;Vaccination;Vaccines;Variant;Vascular Endothelial Cell;Viral;Viral Vaccines;Virus;Work;airway epithelium;aluminum sulfate;base;chemokine;coronavirus disease;cytokine;dimer;experience;immunogenicity;immunopathology;improved;in vivo;lung cancer cell;mucosal vaccine;nanoparticle;neutralizing antibody;nonhuman primate;preclinical study;receptor;receptor binding;respiratory challenge;respiratory virus;response;transmission process;vaccine candidate;vaccine trial;viral transmission Studies of the SARS-CoV-2 Spike Protein n/a NCI 10702760 1ZIABC011941-03 1 ZIA BC 11941 3 6572144 "BERZOFSKY, JAY A" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1200057 NCI In vitro studies in macaque bronchioalveolar lavage cells: We found some effects in vitro on these cells of stimulating them with recombinant spike protein to affect expression of ACE2 and of interferons that may play a role in infection. Little effect was seen on other cytokine or chemokine production. We recently published that S1 protein acts on macaque lung bronchoalveolar lavage cells to downregulate expression of the ACE2 receptor and also inhibit type I interferon production. Type I interferons have been shown to be essential for protection against SARS-CoV-2 and ACE2 besides being a receptor for spike protein also protects the lung against respiratory viruses by cleaving angiotensin II so downregulating these could worsen COVID-19. In vivo vaccine studies in macaques: Rhesus macaques have been primed IM with spike in different adjuvants and boosted systemically with spike in alum or mucosally intranasally with spike in nanoparticles with IL-15 and TLR ligand adjuvants. We have found and published that nanoparticles containing S1 spike protein delivered intranasally can boost macaques primed IM with S1 in alum and result in better protection against respiratory challenge with SARS-CoV-2 than can the IM vaccine alone even though the S1-binding and neutralizing antibody levels are lower. Other mechanisms must play a role and we have found correlations with mucosal IgA dimeric IgA and type I interferon production in the lung and certain types of myeloid cells. We then tested a mucosal nanoparticle boost with the B1.351 (South African) variant S1 protein to protect against this SARS-CoV-2 variant in macaques. The beta variant was the most difficult to neutralize before the appearance of the omicron variant which had not been identified at the time. The beta variant mucosal nanoparticle vaccine given 1 full year after the animals had last been boosted systemically or mucosally with the original Wuhan strain induced a 3-log increase in both IgG binding antibody in both the serum and bronchoalveolar lavage fluid (BAL representing response in the lung). Further it boosted the titer to the original Wuhan strain as much as to the beta variant. Neutralizing antibody titers were also similar against both virus variants. IgA and dimeric IgA to both strains were also increased. This suggests a role for original antigenic sin in determining the fine specificity of antibodies at the time of first primary vaccination. When challenged the animals were well protected against intranasal challenge with the beta variant SARS-CoV-2. Thus a variant intranasal vaccine can induce strong protective immunity in the lungs and nasal cavity and eliminate virus from these sites. These studies suggest that a human intranasal nanoparticle COVID-19 vaccine given to people who had been previously immunized systemically with one of the approved vaccines could improve protection against infection and reduce the risk of forward transmission to others by reducing intranasal virus which is especially a problem with the new delta and omicron variants This second NHP study was also published. In addition two more studies were carried out in a hamster model as hamsters get COVID disease more like humans. The intranasal vaccine was able to markedly reduce weight loss in the immunized animals compared to controls. In vivo studies in mice: ACE2-transgenic mice have been purchased despite delays and are being bred. In wild type B6 mice we have immunized with recombinant spike protein S1 S1+S2 or RBD in several different adjuvants to determine the best formulation. The best combination so far is S1 antigen with IL-15 + ligands for TLR3 and 9 for both antibody and T cell responses. Studies are in progress to determine which components contribute the most to protection. The DNA vaccine with spike protein coupled to a chemokine has been constructed and initial results show that it can induce a strong CD8 T cell response. Human cell lines: We have received the immortalized human lung epithelial cell lines which express ACE2 from John Minna at UTSW as well as some of his non-small-cell lung cancer cell lines that also express ACE2. We have obtained an antibody to ACE2 to verify expression. Initial results show that omega-3 fatty acids and cholesterol differentially affect ACE2 expression on lung cancer cells as well as TMPRSS2 expression and may help explain how diet and obesity as well as lung cancer can affect susceptibility to SARS-CoV-2. 1200057 +Biotechnology; Cancer; Coronaviruses; Coronaviruses Vaccines; Emerging Infectious Diseases; Health Disparities; Immunization; Immunotherapy; Infectious Diseases; Minority Health; Precision Medicine; Prevention; Vaccine Related 2019-nCoV;Antibodies;Antigens;Binding;Biological Markers;Biology;COVID-19;COVID-19 vaccination;COVID-19 vaccine;CXCL10 gene;Cancer Patient;Cells;Development;Disease;Effectiveness;Goals;Hematologic Neoplasms;Humoral Immunities;IL7 gene;Immune response;Immunity;Immunocompromised Host;Individual;Infection;Innate Immune Response;Interferon Type II;Interleukin-10;Interleukin-15;Interleukin-6;Internships;Longevity;Longitudinal cohort;Malignant Neoplasms;Messenger RNA;Nature;Patients;Pattern;Persons;Pfizer-BioNTech COVID-19 vaccine;Population;SARS-CoV-2 immune response;SARS-CoV-2 infection;Secondary Immunization;Shapes;TNF gene;Transplant Recipients;Vaccinated;Vaccination;Vaccine Design;Vaccinee;Vaccines;Virus;chemokine;cohort;cytokine;frontier;high risk;individual patient;microorganism;neutralizing antibody;novel;prognostic;research and development;response;vaccine efficacy;vaccine strategy COVID-19 vaccine in naive individuals and cancer patients n/a NCI 10702759 1ZIABC011940-03 1 ZIA BC 11940 3 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 704873 NCI We have been studying the immune response of COVID-19 cohorts longitudinally to characterize the nature and longevity of immune response (Rosati M Am J Hematol: 97:E3 2022; Rosati Frontiers Immunol 12: 793953 2021; Thomopoulos Viruses 1:1844; 2021; Terpos Eur J Intern Med 89:872021; Pappa Microorganisms 9 806 2021; Terpos Microorganisms. 8:1885 2020). The analysis of natural infection is providing important information for the design of vaccine strategies. To characterize adaptive and innate immune responses in SARS-CoV2 vaccinated persons we identified early responses to vaccination that are important in shaping both humoral and cellular protective immunity (Bergamaschi Cell Rep 36:109504; 2021; Bergamaschi Frontiers Immunol 3:899972 2022). We characterized the cytokine and chemokine responses to BNT162b2 mRNA (Pfizer/BioNtech) vaccinations in antigen-naive and in previously COVID-19-infected individuals and in patients with hematological malignancies (NCT04743388). We identified a systemic signature including IL-15 IFN-gamma IP-10/CXCL10 TNF-alpha and IL-6. Transient increases in IL-15 and IFN-gamma levels early after boost correlated with Spike antibody levels supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We expanded our studies to immunocompromised individuals including patients with hematological malignancies a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. Overall the patients showed heterogeneous adaptive and innate responses with lower humoral (binding and neutralizing antibodies) and reduced innate cytokine responses (IFN-gamma IL-15 and IP-10/CXCL10 signature) to vaccination compared to naive vaccine recipients. Changes in IFN-gamma and IP-10/CXCL10 at priming vaccination and IFN-gamma IL-15 IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies. We are expanding our research of the development of adaptive and innate immune responses upon COVID-19 vaccination to other cancer cohorts. 704873 +Cancer; Cancer Genomics; Clinical Research; Clinical Trials and Supportive Activities; Genetics; Human Genome; Kidney Disease; Rare Diseases; Urologic Diseases Adenocarcinoma;Affect;Bladder;Bladder Adenocarcinoma;Bladder Squamous Cell Carcinoma;Caring;Clinical;Clinical Research;Clinical Trials;Collecting Ducts of Bellini Carcinoma;Country;Data;Data Pooling;Disease;Duct (organ) structure;Genitourinary system;Histologic;Histology;Human;Immune;Incidence;Individual;Literature;Malignant Neoplasms;Malignant neoplasm of penis;Malignant neoplasm of testis;Malignant neoplasm of urinary bladder;Mutation;Nivolumab;Patients;Penis carcinoma;Peripheral Blood Mononuclear Cell;Persons;Pharmaceutical Preparations;Phase;Rare Diseases;Renal carcinoma;Resources;Science;Skin Appendage Carcinoma;Small Cell Carcinoma;Squamous cell carcinoma;Transitional Cell Carcinoma;Tumor Expansion;United States National Institutes of Health;Urethra;Urogenital Cancer;Variant;base;bladder Carcinoma;bone;cancer type;cohort;exome sequencing;ipilimumab;phase 1 study;phase 2 study;rare cancer;recruit;response;transcriptome sequencing;tumor;urogenital tract Rare genitourinary tumors projects n/a NCI 10702756 1ZIABC011928-04 1 ZIA BC 11928 4 10687150 "APOLO, ANDREA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 396442 NCI A phase 2 study of Ipilimumab CabOzantinib and NIvolumab in rare genitourinary (GU) cancers (ICONIC) The phase 1 study of combination CaboNivo and CaboNivoIpi included patients with rare GU histologies. Objective responses were seen in patients with adenocarcinoma of the bladder/urachal squamous cell carcinoma of the bladder small cell carcinoma of the bladder penile cancer sarcomatoid RCC chromophobe RCC and renal medullary carcinoma leading to multiple rare tumor expansion cohorts. The final data for these rare tumors and the pooled data from the phase 1 and expansion cohorts are currently being analyzed. Based on these data I initiated a phase 2 study through the Alliance cooperative group of CaboNivoIpi in patients with rare GU tumors which includes 12 cohorts: bladder squamous cell carcinoma bladder small cell carcinoma bladder adenocarcinoma bladder plasmacytoid bladder sarcomatoid urethra (all histologies) penile cancer sarcomatoid RCC collecting duct RCC renal medullary carcinoma bone-only non-prostate GU tumor and miscellaneous rare GU tumors. As of September 2020 the trial has accrued 100 patients (44% accrued). Preliminarily in this study we have seen confirmed responses in the bladder squamous cell carcinoma bladder small cell carcinoma bladder adenocarcinoma urethra penile cancer sarcomatoid RCC renal medullary carcinoma and testicular adnexal carcinoma. An extensive number of translational correlatives are being conducted in this study with baseline and serial subsequent cycles of therapy. We will analyze the immune subsets of circulating PBMCs and ctDNA and use whole-exome sequencing to define the relationship between tumor mutational burden in each histologic subtype and response to the trial drugs. We will also use RNA sequencing to define the relationship between expression-based subtypes the immune context of the tumors and response to study drugs. Having a rare tumor clinical trial developed through the NIH and available nationally through a cooperative such as the Alliance builds on our center's recruitment strength and on our collaborative science. If this trial shows clinical activity it may provide a potential new treatment option for patients with rare GU tumors. 396442 +Biotechnology; Cancer; Genetics; Human Genome; Prevention; Prostate Cancer; Urologic Diseases Adenocarcinoma;CRISPR library;CRISPR/Cas technology;Castration;Epigenetic Process;Gene Silencing;Genes;Genetic Predisposition to Disease;Genotype;Growth;Guide RNA;Individual;LNCaP;Malignant Neoplasms;Mediating;Mediator of activation protein;Metastatic Prostate Cancer;Modeling;Neuroendocrine Prostate Cancer;Organoids;Process;Prostate;RB1 gene;Resistance;Screening Result;TP53 gene;design;genetic manipulation;neuroendocrine phenotype;screening;therapeutic target;transcription factor;transdifferentiation Identifying genetic vulnerabilities in neuroendocrine prostate cancer n/a NCI 10702751 1ZIABC011919-04 1 ZIA BC 11919 4 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 350381 NCI We will utilize CRISPR/CAS9 mediated gene inactivation to identify viability factors required for the growth of NEPC. We are screening PDX-derived organoid models using CRISPR/CAS9 libraries directed against transcription factors or epigenetic modulators. By screening in various metastatic prostate cancer classes we are determining lineage-specific and genotype specific viability factors. Our main focus has been on RB1 deficient models which express lineage plasticity encompassing adenocarcinoma double negative and neuroendocrine phenotypes. We also have produced and characterized genetically-manipulated models to produce RB1 deficiencies in adenocarcinomas (LNCaP and LuCAP 167). We have identified transcription factors that selectively are required for viability in double negative prostate carrying RB1/TP53 loss genotypes. We are currently validating screen results with individual guide RNAs. 350381 +Cancer; Genetics; Regenerative Medicine APC gene;Address;Adult;Animal Model;Animals;Apoptosis;Attenuated;Binding;Biochemical Reaction;Biochemistry;Biological Process;Cardiovascular Diseases;Cell Communication;Cell Compartmentation;Cell Cycle Arrest;Cell Surface Receptors;Cell membrane;Cell physiology;Cell surface;Cells;Cellular biology;Chemosensitization;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Complex;Cues;Defect;Dental;Development;Diabetes Mellitus;Disease;Down-Regulation;Embryo;Embryonic Development;Epithelial;Evolution;FDA approved;Family;Family member;Gene Amplification;Gene Family;Genetic Screening;Goals;Growth Factor;Haploidy;Helix-Turn-Helix Motifs;Heparan Sulfate Proteoglycan;Homeostasis;Human;Hyperactivity;Instruction;Language;Leucine Zippers;Life;Ligand Binding;Ligands;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Mediator of activation protein;Mesenchymal;Modeling;Molecular;Morphogenesis;Mutate;Natural regeneration;Neoplasm Metastasis;Neurodegenerative Disorders;Oncogenic;Organ;Organism;Organoids;Outcome;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Physiological;Process;Property;Proteins;Regulator Genes;Regulatory Element;Reporter;Research;Research Project Grants;Role;Signal Pathway;Signal Transduction;Site;Therapeutic;Tissues;Transcription Coactivator;Transcriptional Activation;Ubiquitin;Ubiquitination;Vertebrates;WNT Signaling Pathway;Xenopus laevis;base;beta catenin;cancer type;casein kinase;comparative;fascinate;forward genetics;gastric cancer cell;genetic analysis;genome wide screen;malformation;member;migration;prevent;programs;receptor;response;self-renewal;skeletal;stem cells;therapeutic target;tissue regeneration;tissue stem cells;transcription factor;tumor;ubiquitin ligase;zygote New regulatory mechanisms of WNT signaling in development stem cells and cancer n/a NCI 10702742 1ZIABC011901-04 1 ZIA BC 11901 4 16162143 "LEBENSOHN, ANDRES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1460473 NCI New regulatory mechanisms in WNT signaling: Through forward genetics screens in haploid human cells harboring a fluorescent reporter of WNT signaling we discovered regulators of the intact pathway as well as those selectively required to sustain hyperactive oncogenic signaling. This study (Lebensohn et al. eLife 2016) comprised seven genome-wide screens systematically interrogating the pathway including screens for positive negative and attenuating regulators of ligand-induced signaling as well as suppressor screens following disruption of key regulators commonly mutated in WNT-driven tumors such as the tumor suppressor APC. A comparative analysis of the screens revealed new regulatory mechanisms for ligand reception signal transduction and transcriptional activation as well as new gene regulatory elements (Patel Lebensohn et al. PLoS One 2019). Our current goal is to elucidate the molecular underpinnings of these new regulatory mechanisms understand their physiological functions and evaluate their potential as therapeutic targets. The following research projects are aimed at elucidating some of these new regulatory mechanisms and evaluating their therapeutic potential. 1) The transcription factor TFAP4 is a new limiting component of the WNT signaling pathway. Our genetic screens uncovered a basic helix-loop-helix leucine zipper transcription factor called TFAP4 as a potential regulator of WNT signaling (Lebensohn et al. eLife 2016). We have shown that TFAP4 acts downstream of b-catenin the principal transcriptional co-activator in the WNT pathway and is a limiting component for signaling activity. Furthermore excess TFAP4 can promote ectopic activation of WNT signaling during Xenopus laevis development causing the formation of a secondary body axis. Interestingly TFAP4 expression is tightly linked to malignancy in gastrointestinal cancers: TFAP4 is upregulated in colorectal cancer where it mediates epithelial-mesenchymal transition (EMT) and metastasis and its down-regulation in gastric cancer cells inhibits proliferation induces cell cycle arrest and promotes apoptosis. We are dissecting the molecular mechanism by which TFAP4 regulates WNT signaling and evaluating its potential as a therapeutic target. 2) A new function of the b-catenin destruction complex regulating WNT signaling through the ubiquitin ligase HUWE1. HUWE1 is a HECT-domain ubiquitin ligase involved in dozens of cellular processes through the ubiquitination of diverse substrates. Both oncogenic and tumor suppressive functions have been ascribed to HUWE1. HUWE1 has been postulated as a negative regulator of WNT signaling through at least two distinct mechanisms. However in our unbiased forward genetic screen for mediators of hyperactive WNT signaling induced by loss of the b-catenin destruction complex kinase casein kinase 1a we identified HUWE1 as a positive regulator of the WNT pathway (Lebensohn et al. eLife 2016). We also demonstrated that HUWE1 potentiates WNT signaling in cells and in Xenopus laevis embryos. We have now found that HUWE1 promotes WNT/b-catenin signaling through a mechanism independent of the control of b-catenin protein stability. Potentiation of WNT signaling by HUWE1 requires its ubiquitin ligase activity and a subset of b-catenin destruction complex components. These results reveal a new role for some destruction complex components in mediating WNT signaling through HUWE1 distinct from their established activity in controlling b-catenin stability. New regulatory mechanisms in R-spondin signaling: Some WNT responses during embryonic development and in stem cell compartments depend on a second signal provided by the R-spondin family of secreted growth factors only present in vertebrates. R-spondins are key regulators of WNT signaling strength but the mechanisms by which they transduce signals are not fully understood and how the four different members of the family control distinct physiological functions is unknown. We discovered that R-spondins 2 and 3 can uniquely potentiate WNT signaling in cells lacking their only known cell-surface receptors LGRs 4-6 through an alternative interaction with heparan sulfate proteoglycans (HSPGs) (Lebensohn & Rohatgi eLife 2018; Dubey et al. eLife 2020). This finding is transformative because LGRs were thought to be required to transduce all R-spondin signals and hence determine their site of action but now we know that R-spondins can also signal in tissues where LGRs are not expressed. The following research projects are aimed at elucidating the molecular mechanisms and physiological functions of 'LGR-independent' signaling by R-spondins. 3) Molecular mechanisms of LGR-independent signaling by R-spondins. A central question regarding any signal transduction mechanism is how binding of the ligand to the receptor communicates the signal across the plasma membrane and into the cell. In the prevailing model simultaneous binding of R-spondins to their LGR receptors and to the transmembrane ubiquitin ligases ZNRF3 or RNF43 triggers their internalization. This prevents ZNRF3 and RNF43 from targeting WNT receptors for ubiquitin-mediated degradation thus increasing their abundance on the cell surface and enhancing sensitivity to WNT ligands. We are investigating the molecular mechanisms whereby R-spondins transduce signals in the absence of LGRs through their alternative HSPG receptors to potentiate WNT signaling. 4) Physiological roles for LGR-dependent and LGR-independent signaling by R-spondins during embryonic development and in stem cells. Gene amplifications followed by neo- or sub-functionalization of different gene family members underlie much of the functional diversification generated during evolution. Yet paralogues are often deemed to be redundant and drastically different phenotypes resulting from their loss are simply attributed to tissue-specific patterns of expression. This is the prevailing view regarding the four members of the R-spondin family which potentiate WNT signaling during embryonic development and in adult tissue stem cells. However the markedly distinct phenotypes caused by the loss of different R-spondins or their LGR receptors could also be due to intrinsic differences in the capacity of these R-spondins to signal through LGR-dependent and LGR-independent mechanisms. We are investigating in what contexts these two modes of signaling are used during development tissue homeostasis and regeneration. We are also trying to understand what unique properties make LGR-dependent and LGR-independent R-spondin signaling specifically suited to their physiological functions. 1460473 +Cancer; Clinical Research; Genetics; Health Disparities; Immunization; Immunotherapy; Minority Health; Prostate Cancer; Radiation Oncology; Urologic Diseases; Vaccine Related Cancer Vaccines;Cell Line;Cells;Chemotherapy and/or radiation;Clinical;Collaborations;DNA;Development;Dose;Evaluation;Goals;Histones;Immune;Immune checkpoint inhibitor;Immune response;Immunotherapy;Interleukin-12;Malignant neoplasm of prostate;Mutation;Necrosis;Newly Diagnosed;Patients;Phase;Phenotype;Population;Pre-Clinical Model;Progression-Free Survivals;Prostate Cancer therapy;Radiation;Radiation Oncology;Renal carcinoma;Research;Toxic effect;Tumor-infiltrating immune cells;base;castration resistant prostate cancer;chemotherapy;clinical efficacy;cytokine;docetaxel;melanoma;necrotic tissue;programs;standard of care;synergism;systemic toxicity;therapeutic evaluation;tumor;tumor microenvironment;tumor-immune system interactions;vaccine trial Evaluation of Immune-based Combinations in Prostate Cancer n/a NCI 10702739 1ZIABC011897-04 1 ZIA BC 11897 4 10687105 "MADAN, RAVI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 493445 NCI Current studies are exploring a combination of standard of care chemotherapy with an immunocytokine combination treatment. Unlike checkpoint inhibitors which may require T-cell infiltration or high tumor mutational burden to be effective cytokines provide an opportunity to impact multiple immune cell lines within the prostate cancer microenvironment and convert them broadly from immune suppressive to a more anti-tumor phenotype. Indeed cytokines have been a key part of immune treatments for kidney cancer and melanoma before the development of checkpoint inhibitors but the potential systemic toxicity of high doses of cytokines often limited treatment delivery and thus efficacy. Immunocytokines are able to deliver smaller doses of cytokines in a targeted fashion to the tumor microenvironment thereby limiting systemic toxicity and perhaps enhancing clinical efficacy. NHS-IL12 (M9241) has been developed clinically within the GMB Immunotherapy Section and specifically targets histones of exposed DNA in necrotic tissue. This capability forms the basis of a key strategy within my research program. By using standard therapies for prostate cancer such as radiation and chemotherapy to induce necrosis the goal is to use NHS-IL12 to alter the pleiotropic immune microenvironment including multiple immune cell populations shifting it to a more anti-tumor phenotype. We have completed the phase 1 portion of 21-c-0001 which has established a safe dose of docetaxel with M9241. We will now explore immune responses in this study as we move into the phase 2 portion of the study that will focus on metastatic castration resistant prostate cancer. We are also about to open a new study combining M9241 and radiation in patients with newly diagnosed and localized prostate cancer in a collaboration with the Radiation Oncology Branch. This is based on the potential synergy of radiation and M9241 established in preclinical models. 493445 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunotherapy; Microbiome; Minority Health; Prostate Cancer; Urologic Diseases Agreement;Androgen Antagonists;Area;Biochemical;COVID-19 pandemic;Cancer Patient;Castration;Cells;Clinical;Clinical Trials;Collaborations;Combination immunotherapy;Data;Data Analyses;Development;Evaluation;FDA approved;Future;Goals;Image;Immune;Immunologics;Immunotherapy;Industry;Investigational Therapies;Kinetics;Malignant neoplasm of prostate;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Nonmetastatic;Outcome;Patients;Phase;Population;Positron-Emission Tomography;Prostate;Protocols documentation;Publications;Quality of Life Assessment;Quality of life;Radiation;Radiopharmaceuticals;Radium;Recurrence;Safety;Science;Surveys;androgen deprivation therapy;castration resistant prostate cancer;cohort;enzalutamide;follow-up;microbiome;novel;phase II trial Evaluation of novel treatments in biochemically recurrent prostate n/a NCI 10702738 1ZIABC011896-04 1 ZIA BC 11896 4 10687105 "MADAN, RAVI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 616806 NCI Two protocols have been completed. 13-c-0153: Enzalutamide in Combination With PSA-TRICOM in Patients With Non-Metastatic Castration Sensitive Prostate Cancer has completed the data analysis phase and is pending publication. Enzalutamide alone extends PSA suppression in patients with non-metastatic castration resistant prostate cancer and future studies are planned ti further evaluate this. Furthermore immune changes were noted after enzalutamide therapy as well. 16-c-0035: Prostvac in Patients With Biochemically Recurrent Prostate Cancer: This study has completed accrual at the NCI Dana Farber and Sloan Kettering and is now being prepared for publications. Of note late PSA declines were seen in 15-20% of patients. 18-c-0005: Phase II Trial of Combination Immunotherapy in Biochemically Recurrent Prostate Cancer: This study has completed the safety phase of the trial and now is in the main cohort of non-metastatic castration resistant prostate cancer patients and is accruing at the NCI. We are approximately 2/3 of the way through accrual and expect to compete accrual in the next 6-10 months. 20-c-0010 Radium 233 in biochemically recurrent prostate cancer is evaluating the immune impact of an FDA-approved radiopharmaceutical in patients with micro-metastatic (only PET scan positive) prostate cancer. This study had its accrual held through much of the COVID pandemic but is now approximately 1/3 of the way through accrual with rapid accrual in recent months. Additional studies are being planned with other non-toxic immunotherapy strategies. The uniform use of PET imaging is part of the GMB's programmatic approach to developing clinical trials in BCRpc. All current and future BCRpc studies are evaluating the impact of PSA kinetics on these patients using validated quality of life survey. In addition the immunologic impact of these treatments on circulating immune cell subsets. And in a collaboration with Dr. Heidi Kong of NIAMS we are evaluating the microbiome to better understand how baseline the microbiome may be associated with clinical outcomes while also evaluating the influence of experimental therapies on the microbiome in BCRpc. 616806 +Cancer; Health Disparities; Minority Health; Prostate Cancer; Urologic Diseases FOLH1 gene;Future;Human;Pharmaceutical Preparations;Radiation Dose Unit;Radiopharmaceuticals;Testing;base;improved;prostate cancer cell;radioligand;side effect;tumor Improving PSMA-based radioligand therapy via combination radioligand therapy n/a NCI 10702737 1ZIABC011895-04 1 ZIA BC 11895 4 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171864 NCI The approach taken by this proposal is to combine the PSMA drug with other radioactive drugs that also selectively target prostate cancer cells. If this approach is proven to be successful we will be able to increase the radiation dose give to tumors without causing additive worsening of side effects. Furthermore this combinational approach could become the new paradigm for which all radioactive drugs are given in the future. We expect this approach to be ready for testing in humans in about 5 years. 171864 +Basic Behavioral and Social Science; Behavioral and Social Science; Cancer; Neurosciences; Radiation Oncology; Sleep Research Animals;Behavior;Behavioral;Behavioral Model;C57BL/6 Mouse;Central Nervous System;Central Nervous System Neoplasms;Computer software;Cranial Irradiation;Data;Data Analyses;Dose;Eating;Exposure to;Foundations;Genes;Genetic Polymorphism;Goals;Graph;Grooming;Hour;Human;Hypersomnias;Hypersomnolence;Individual;Light;Low Dose Radiation;Monitor;Mus;Patients;Phase;Phenotype;Pre-Clinical Model;Procedures;Quality of life;Radiation;Radiation Dose Unit;Radiation therapy;Rest;Rodent;Sleep;Symptoms;System;Testing;Time;Travel;Walking;behavior measurement;early onset;experience;experimental study;irradiation;male;mouse model;radiation effect;sleep behavior;standard of care;tumor Behavioral Correlates in Mouse Model of CNS radiation-induced hypersomnia n/a NCI 10702735 1ZIABC011893-04 1 ZIA BC 11893 4 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 497931 NCI Radiation therapy is the standard of care for both primary and secondary central nervous system tumors tumors. A majority of patients experience radiation induced hypersomnia (RIH) which may impact life quality and treatment tolerance. Currently there is no mouse model of RIH that measures behavioral sleep and activity. Previously we demonstrated that Ethovison software can be used to effectively monitor differences in the sleep behavior of mice. Here we test the dose effect of radiation in mice using our system prior to introducing tumor. Aims: Establish the optimal radiation dose to recapitulate symptoms experienced by patients who receive cranial irradiation such as heightened daytime sleep and reduced activity. Experimental Procedure: Animals: Male young (6wk) C57BL/6 mice were individually housed in Phenotyper cages Monitored for 10 days pre-irradiation and 11 days post irradiation under 12:12 light dark conditions. 24 non-tumor bearing C57BL/6 mice received whole brain radiation at one of 4 doses (sham 2Gy 5Gy and 15Gy) using a single fraction Ethovision XT Software automatically generate general activity data as total distance travelled over time. Mouse Behavior recognition module scored Sleep/Rest Walking Grooming and Eating. Data Analysis: General activity was examined for total activity across 24 hours for 11 days between doses.Behaviors were compared between doses for three days (Day 8-10). Groups were analyzed between high (5&15Gy) and low (0&2Gy) doses. Baseline Analysis: Baseline activity was not significantly different between groups (F(3.23) = 0.649 p=0.593). As expected activity levels are higher during the dark period (active period) while sleep is higher during the light period (inactive period). Post-Irradiation Activity Analysis: Activity levels were unchanged less than 5% difference for sham and 2Gy however high doses 5Gy and 15Gy were suppressed by 10% Suppression of activity started after 2 days in 15Gy and 5 days in 5Gy mice. Data was corrected to baseline which is represented by zero in the graph Post-Irradiation Behavioral Analysis: Across three days (8-10) 5Gy and 15Gy (1987sec) had more sleep during their active phase (t=2.27 p=0.03) than sham or 2Gy (17618 sec). Grooming was significantly higher (t=2.588 p=0.017) for low radiation dose during the active phase. There are no effects on amount of time spent eating or the amount of time spent walking Animals had no significant difference in baseline activity or sleep between groups. Shams and 2Gy had activity levels similar to baseline while 5 and 15Gy had decreased activity levels post-radiation. Mice exposed to 15Gy radiation had an earlier onset of radiation induced hypersomnolence with decreases starting three days before 5Gy mice. Significant effects for sleep and grooming were observed during the active phase with animals exposed to high radiation doses having more sleep and less grooming. No changes were observed for eating or total walking time between groups. Our study demonstrates that cranial irradiation causes a clear increase in sleep during the active period and decrease in activity both factors that recapitulate the human RIH experience. Activity and sleep are impacted by irradiation in patients. A good behavioral model to observe these changes has not yet been developed in rodents. Here we demonstrate a reliable system to collect and analyze activity and sleep parameters in mice exposed to irradiation that will serve as the foundation for ongoing experiments. 497931 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Bioinformatics;Cell Density;Cell Fraction;Cell Lineage;Cells;Clone Cells;Copy Number Polymorphism;Coupling;Data;Double-Blind Method;Gene Expression Profiling;Genomics;Geography;Hematoxylin and Eosin Staining Method;Human;Image;Immune;Knowledge;Ligands;Methods;Mining;Modeling;Pathology;Pathway interactions;Sampling;Scheme;Spottings;Stromal Cells;Technology;Tissues;Visualization;anticancer research;base;cancer cell;cell type;design;receptor;transcriptomics;tumor;tumor progression Computational approaches for the analyses of spatial profiling technologies n/a NCI 10702733 1ZIABC011890-04 1 ZIA BC 11890 4 16162128 "JIANG, PENG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 512397 NCI Spatial transcriptomics (ST) technology has enabled geographical gene expression profiling in tumors. However each tumor ST spot contains diverse immune and malignant cells with cell densities that vary significantly across tissue regions. Therefore the cell type decomposition in tumor ST data remains a challenge that existing methods for bulk tumors and general ST data cannot resolve. We developed Spatial Cellular Estimator (SpaCE) to infer cell identities and intercellular interactions from tumor ST data. SpaCE first estimates cancer cell clonal abundance through modeling segmental copy number variations. A constrained regression model then calibrates local cell densities and determines immune and stromal cell lineage fractions. SpaCE provides higher accuracy than existing methods based on simulated samples of known composition and human tumors with double-blind pathology annotations on hematoxylin and eosin images. Moreover coupling cell fraction results with ligand-receptor spatial expression SpaCE reveals how intercellular interactions at the tumor-immune interface promote cancer progression. 512397 +Cancer; Genetics; Immunotherapy Address;Adoptive Cell Transfers;Anti-Inflammatory Agents;Atlases;BMP6 gene;CD8-Positive T-Lymphocytes;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Communicable Diseases;Computer Models;Cytokine Signaling;Data;Databases;Disease;Functional disorder;Gene Expression Profile;Genes;Genetic Transcription;Goals;Growth Factor;Health;Human;IL8 gene;Immune;Inflammation;Inflammatory;Investigation;Knock-out;Malignant Neoplasms;Mediating;Modeling;Mus;Pathway interactions;Pattern;Population;Proliferating;Role;Sampling;Signal Transduction;Solid Neoplasm;T cell therapy;T-Lymphocyte;TNFSF10 gene;Transforming Growth Factor beta;cancer immunotherapy;chemokine;cohort;computer framework;cytokine;intercellular communication;predictive modeling;resilience;response;screening;severe COVID-19;therapeutic candidate;therapeutic target;transcriptome;transcriptomics;tumor;tumor microenvironment Data-driven inference of regulators for cytokine-mediated tumor killing n/a NCI 10702732 1ZIABC011889-04 1 ZIA BC 11889 4 16162128 "JIANG, PENG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 512397 NCI Project 1 Summary: Cytokines are critical for intercellular communication in human health and disease but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges we developed the Cytokine Signaling Analyzer (CytoSig https://cytosig.ccr.cancer.gov) providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20591 transcriptome profiles for human cytokine chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct immune cell populations in infectious diseases chronic inflammation and cancer using bulk and single-cell data. CytoSig revealed previously unidentified roles of many cytokines such as BMP6 as an anti-inflammatory factor and identified candidate therapeutic targets in human inflammatory diseases such as CXCL8 for severe COVID-19. Project 2 Summary: Despite recent breakthroughs in cancer immunotherapy T-cell therapies achieve limited efficacy in solid tumors. Identifying regulators in T-cell dysfunction remains challenging due to limitations of current screening platforms. Using single-cell transcriptomic data from tumors as input we developed a computational model to identify regulators of T-cell resilience defined as the ability of T cells to proliferate under immune-suppressive signals such as TGF-beta and TRAIL. Integrating 14 single-cell transcriptomic cohorts from seven tumor types we identified FIBP and TMEM222 as top regulators of T-cell resilience. Knocking out these genes especially FIBP in murine and human donor T cells significantly enhanced the efficacy of T-cell mediated cancer killing and adoptive cell therapy. We show that FIBP knockout in CD8 lymphocytes alleviates T-cell dysfunction by limiting cholesterol metabolisms and high cholesterol level is known to inhibit T-cell activity. Together our T-cell resilience model revealed FIBP as a candidate target to potentiate cancer immunotherapy. 512397 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Immunotherapy; Orphan Drug; Pancreatic Cancer; Rare Diseases Clinical Research;Clinical Trials;Combined Modality Therapy;Cytotoxin;Drug Kinetics;Drug resistance;Elements;Extramural Activities;Future;Growth;Human;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotoxins;Integrin alphaVbeta3;Malignant Neoplasms;Malignant neoplasm of pancreas;Mus;Patients;Pharmaceutical Preparations;Phase;Pre-Clinical Model;Protein Engineering;Safety;Solid Neoplasm;Stromal Cells;Supporting Cell;Testing;Therapeutic;United States National Institutes of Health;anticancer activity;clinical center;first-in-human;improved;mesothelin;mouse model;novel;pancreatic cancer cells;pancreatic cancer model;pancreatic ductal adenocarcinoma model;rational design;safety testing;tumor First in Human Trials of ProAgio a Cytotoxin n/a NCI 10702730 1ZIABC011886-04 1 ZIA BC 11886 4 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 520441 NCI AIM1 (ongoing): To test safety tolerability and pharmacokinetics (PK) of ProAgio in patients. We have initiated a Phase I clinical study at the NIH Clinical Center in previously treated patients with advanced solid tumor malignancies to gain information about safety tolerability and pharmacokinetics of single agent ProAgio. Accrual is in progress. AIM 2 (ongoing): To test the effect of ProAgio in combination with immunotherapeutics using pre-clinical models of PDAC. We are using novel syngeneic and autochthonous mouse models of pancreatic cancer to test whether ProAgio can improve delivery and anti-tumor efficacy of mesothelin-targeted immunotoxins immune checkpoint inhibitors and the combination. These studies could provide rationale for a future clinical trial of ProAgio combination therapy. 520441 +Cancer; Cancer Genomics; Genetics; Human Genome 3-Dimensional;Address;Biological Assay;Biological Process;Cells;Cellular Assay;Chromatin;Chromatin Structure;DNA;DNA analysis;DNA biosynthesis;Detection;Genetic Transcription;Goals;Histones;Human;Lead;Pattern;Population;Regulation;Role;Signal Transduction;Superhelical DNA;Topoisomerase;Transcriptional Regulation;Variant;cohesin;design;experimental study;genome-wide The dynamics of chromatin topology in human cells n/a NCI 10702729 1ZIABC011884-04 1 ZIA BC 11884 4 16162122 "CHEN, CHONGYI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1272834 NCI In FY 2022 we quantitatively characterized genome-wide DNA supercoiling patterns in human cells with carefully designed control experiments to correct for the offset due to the readout of other factors. We then analyzed DNA supercoiling patterns in correlation with the 3D chromatin structure and histone marks studied the potential players in establishing and maintaining such supercoiling patterns by perturbation experiments probing transcription cohesin and topoisomerase activities. The final goal is to elucidate the regulation mechanism and the biological function of DNA supercoiling in human cells. On the other hand the fast dynamics of DNA supercoiling in living cells lead to a significant cell-to-cell variation averaging out a significant portion of the meaningful signal. To address this challenge we are synchronizing cell populations by a variety of approaches to allow better and more sensitive detection. We are also developing single-cell assays for DNA supercoiling utilizing the principle of linear amplification derived from my previously developed LIANTI assay. 1272834 +Biotechnology; Cancer; Gene Therapy; Genetics; Immunotherapy; Orphan Drug; Precision Medicine; Rare Diseases Affinity;Antibodies;Antigens;Chromosomal translocation;Clinical Trials;Common Neoplasm;Engraftment;Epitopes;Goals;Human;Human Papilloma Virus-Related Malignant Neoplasm;Infusion procedures;Malignant Neoplasms;Mutate;Proto-Oncogenes;Safety;Signal Transduction;T cell therapy;T-Cell Development;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;T-Lymphocyte Epitopes;Therapeutic;Tumor Antigens;Viral Oncogene;base;cancer therapy;chimeric antigen receptor;conditioning;gene therapy;genetically modified cells;melanoma;personalized cancer therapy;synovial sarcoma;targeted treatment;therapeutic target;treatment strategy;tumor T-Cell Receptor Gene Therapy for Human Cancers-Cures n/a NCI 10702722 1ZIABC011871-04 1 ZIA BC 11871 4 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 973782 NCI T cell receptor (TCR) gene therapy is a personalized cancer treatment strategy that can precisely and potently target a wide variety of tumor antigens. It is based on the infusion of T cells that are genetically engineered ex vivo to express a TCR directed against a tumor antigen. This strategy enables tumor targeting with a large number of T cells that express a high affinity TCR. It also permits pretreatment host conditioning to enhance anti-tumor T cell engraftment and function. TCR gene therapy has shown encouraging results in melanoma synovial cell sarcoma and human papillomavirus-associated cancers. In contrast to antibody and chimeric antigen receptor (CAR) therapy TCR gene therapy can target intracellular antigens which is important because many of attractive oncological therapeutic targets (e.g. mutated protooncogenes viral oncogenes driver chromosomal translocations and cancer germline antigens) localize to the intracellular compartment. The goal of this NCI Moonshot Project is to catalyze the discovery and development of TCR gene therapy for a wide-array of cancers. 973782 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Genetics; Health Disparities; Human Genome; Immunotherapy; Liver Cancer; Liver Disease; Machine Learning and Artificial Intelligence; Minority Health; Networking and Information Technology R&D (NITRD); Orphan Drug; Precision Medicine; Prevention; Rare Diseases 3-Dimensional;Affect;Archives;Area;Artificial Intelligence;BAY 54-9085;Bioinformatics;Biological Markers;Biological Products;Biopsy Specimen;Blood;CCR;Carcinoma;Cells;Cholangiocarcinoma;Clinical;Clinical Data;Clinical Trials;Communities;DNA sequencing;Data;Development;Diagnosis;Early Diagnosis;Elements;Enrollment;Environment;Extramural Activities;Fellowship;Formalin;Foundations;Funding;Future;Genomics;Goals;Heterogeneity;Image Analysis;Immune checkpoint inhibitor;Immunophenotyping;Immunotherapy;Individual;Infrastructure;Institution;Intramural Research;Laboratories;Liver neoplasms;Machine Learning;Malignant Neoplasms;Malignant neoplasm of liver;Medical;Mission;Molecular;Molecular Profiling;Multimodal Imaging;Mutation;Optics;Outcome;Paraffin Embedding;Patient Care;Patient Monitoring;Patient-Focused Outcomes;Patients;Positioning Attribute;Prevention;Prevention approach;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Radiogenomics;Refractory;Relapse;Research;Research Activity;Research Personnel;Resistance development;Resources;Retrospective Studies;Role;Sampling;Site;Subgroup;Testing;Tissue Embedding;Training;Training and Education;Transcript;Translational Research;Treatment outcome;Tumor-infiltrating immune cells;United States National Institutes of Health;Universities;Urine;Variant;Vision;anticancer research;arm;base;biliary tract;cancer clinical trial;capecitabine;clinical center;clinical efficacy;effective therapy;exome sequencing;improved;insight;liver cancer patient;liver development;metabolomics;microbiome;microscopic imaging;molecular targeted therapies;multidisciplinary;multiplexed imaging;neoplastic cell;new therapeutic target;novel;novel therapeutics;optimism;oxaliplatin;patient response;patient subsets;pembrolizumab;phase 2 study;phase 3 study;precision medicine;predictive signature;prevent;programs;prospective;response;single cell sequencing;standard of care;statistical and machine learning;success;synergism;transcriptome sequencing;treatment responders;treatment response;tumor Liver Cancer Program n/a NCI 10702721 1ZIABC011870-04 1 ZIA BC 11870 4 16162108 "BUDHU, ANURADHA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1307380 NCI One of main reasons why survival for patients with primary liver cancer (PLC) including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) has not improved in the past twenty years is the lack of approved novel therapies with the exception of the limited success of sorafenib. Multiple phase III studies have failed to demonstrate any survival advantage for patients with liver cancer. We believe that this situation will change dramatically with the advent of immunotherapy and biologicals and by the implementation of precision cancer management strategy. Our optimism is supported by recent findings in the field of HCC. CCR is in a unique position to utilize its expertise in the area of immunotherapy and biologics to test these novel treatment options in patients with liver cancer. Molecular subgrouping and biomarker-guided molecularly-targeted therapies are promising approaches that will be implemented in our ongoing and future studies. One of the key elements of the NCI-LCP is to build an infrastructure which allows intramural investigators to expand on their research and not only collaborate with each other but also with extramural investigators. Our first effort is to build an NCI IRP-based collaborative translational science network of liver cancer clinical trial data accompanying biospecimens and correlative laboratory data to determine why immunotherapy is effective in certain patients but not in others. This goal is encompassed in our funded Liver Cancer Study (NCI-CLARITY). In this study we are building a national clinical network in liver cancer to 1) define at the molecular level which group of PLC patients respond to immunotherapy and which do not and why some patients develop resistance/tumor relapse and 2) to determine whether any similarities or differences in response to immunotherapy are observed in HCC versus CCA patients. This program is based on the creation of a unique and robust national information commons comprised of comprehensive clinical and molecular data which can be utilized by the cancer research community for future studies of PLC. To accomplish these aims the NCI IRP plans to serve as the leading and coordinating hub to leverage the ongoing immunotherapy-based clinical trials at major institutions treating PLC patients. We have partnered with clinical extramural collaborators across the U.S. to obtain biospecimens (biospy blood urine and fecal) and clinical data (medical chart data treatment outcome and survival) from PLC patients in their ongoing clinical trials and/or standard of care patients treated with immune checkpoint inhibitors. We aim to collect biospecimens and clinical data from 500 PLC patients over a 5-year period across study sites. Comprehensive correlative data will be performed at NCI and NCI Frederick National Laboratory along with our collaborators including molecular (DNA and RNA-Seq) single-cell sequencing metabolomics microbiome immunophenotyping by CODEX 3D-multiplex imaging (Optical Microscopy and Image Analysis Laboratory) and SNP/variant analysis. Radiogenomics pairing data mined from comprehensive multi-modality imaging with genomics by artificial intelligence/machine learning will also be used to screen and predict patient response to immunotherapy. Comprehensive statistical machine learning and bioinformatics analysis will be used to integrate correlative data and clinical data to molecularly characterize and define predictive signatures of treatment responders and nonresponders to immunotherapy in all cases or in the stratified analyses. In concert with this effort we also initiated a pilot retrospective study of archival biopsy specimens collected before and after immunotherapy treatment (IO) from liver cancer patients from the NIH Clinical Center and Georgetown University. Samples from 89 patients undergoing immunotherapy treatment were assessed by DNA and RNA sequencing to identify mutations transcripts and molecular signatures associated with patient outcome following IO treatment. A total of 230 primary HCC and CCA tumors and adjacent non-tumor tissues largely stored as formalin-fixed paraffin-embedded (FFPE) and attained before and following immunotherapy treatment using total RNA sequencing and whole exome sequencing were analyzed. We established a SOP and show feasibility to conduct molecular analytics to monitor patient response to immune therapy utilizing FFPE tissue. We identified four stable survival-related molecular subgroups defined by orthogonal axes of tumor aggressiveness and immune infiltration the latter associated with immunotherapy response. Furthermore although the underlying molecular status of tumors prior to immunotherapy treatment was largely maintained following treatment some molecular responses tracked with patient outcome. Thus outcome-related and intersecting molecular axes are apparent in FFPE liver tumors prior to immunotherapy treatment components of which could serve as indicators of treatment response. Additional samples from these and other collaborating sites will be incorporated and integrated with these analyses. The prospective arm of NCI-CLARITY is underway with 29 patients enrolled and 882 biospecimens collected. Other studies from this program include an assessment of genomic changes at the single-cell level at baseline and in response to therapy which have provided insight into tumor cell heterogeneity and the foundations of alterations which affect outcome in certain patient subgroups. We also conducted a phase II study of the combination of pembrolizumab with capecitabine and oxaliplatin (CAPOX) in patients with advanced biliary tract carcinoma (BTC) to assess response rate and clinical efficacy. We found that capecitabine and oxaliplatin in combination with pembrolizumab is tolerable and a potentially effective treatment for refractory advanced BTC. Overall we anticipate that these data will define specific subgroups of patients who are more likely to benefit from immune checkpoint inhibitor treatment. In addition biomarkers and novel druggable targets may be identified to better determine or affect treatment response. 1307380 +Biotechnology; Cancer; Clinical Research; Colo-Rectal Cancer; Digestive Diseases; Immunization; Liver Cancer; Liver Disease; Pancreatic Cancer; Rare Diseases; Women's Health Basic Science;Bile fluid;CA-19-9 Antigen;Cessation of life;Cholangiocarcinoma;Clinical;Disease;Epitopes;Evaluation;Excision;Goals;Innovative Therapy;Laboratory Research;Liver neoplasms;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mission;Operative Surgical Procedures;Patient Care;Patient-Focused Outcomes;Patients;Perioperative;Recurrence;Surgeon;Surgical Oncologist;Time;Translational Research;United States;human monoclonal antibodies;metastatic colorectal;neoplasm therapy;novel;pancreatic neoplasm;prevent;tumor Evaluating outcomes for patients with primary-metastatic gastrointestinal cancer n/a NCI 10702719 1ZIABC011861-04 1 ZIA BC 11861 4 15201727 "HERNANDEZ, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 25241 NCI As a surgical oncologist and hepatopancreatobiliary surgeon I specialize in the treatment of pancreatic tumors and tumors of the liver and bile ductsoal and I provide patients undergoing resection of localized tumor(s) with novel adjunctive therapies to prevent recurrence of their disease at a later time. The goal of this project is to bridge clinical and translational evaluation of GI cancers which often forms the basis of hypothesis-driven basic research. I opened a new trial this year NCT03801915 Perioperative MVT-5873 a Fully Human Monoclonal Antibody Against a CA19-9 Epitope for Operable CA 19-9 Producing Pancreatic Cancers Cholangiocarcinomas and Metastatic Colorectal Cancers. 25241 +Biotechnology; Breast Cancer; Cancer; Colo-Rectal Cancer; Digestive Diseases; Gene Therapy; Genetics; Immunotherapy; Lung; Lung Cancer; Neuroblastoma; Neurosciences; Orphan Drug; Rare Diseases; Transplantation; Women's Health Area;Automobile Driving;Blood Transfusion;Bone Marrow;Breast Carcinoma;CCR;Carcinoma;Cell Therapy;Cells;Cellular immunotherapy;Clinical;Collaborations;Colon Carcinoma;Development;Funding;Genes;Goals;Immunosuppression;Lung Adenocarcinoma;Malignant Neoplasms;Mesothelioma;Mission;Modern Medicine;Myeloid Cells;Neuroblastoma;Organ Transplantation;Patients;Pharmaceutical Preparations;Process;Property;Prostate carcinoma;Skin graft;Solid Neoplasm;Therapeutic;Work;cancer therapy;cancer type;cellular development;chimeric antigen receptor T cells;interest;lung Carcinoma;mesothelin;tumor;tumor microenvironment Center for Cell-based Therapy - Cures n/a NCI 10702717 1ZIABC011855-05 1 ZIA BC 11855 5 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 174423 NCI The mission of the Center for Cell-based Therapy is to facilitate the discovery and development of cellular immunotherapies for patients with cancer. Two important objectives of this work are: (1) developing approaches to successfully target solid tumors with cell-based immunotherapy and (2) facilitating collaborative cell-based therapy projects with strong clinical potential. Four areas currently in development for this project are: (1) developing CAR-T Cells targeting GPC2 as a treatment for Neuroblastoma in collaboration with Mitchell Ho Rosandra Kaplan and Carol Thiele; (2) creating CAR-T Cells targeting mesothelin as a therapy for mesothelioma and lung adenocarcinoma in collaboration with Mitchel Ho and Ira Pastan; (3) developing CAR-T cells to deliver genes of interest into the tumor micro-environment in collaboration with Mitchell Ho; and (4) identification of key genes driving immune suppression and tumor killing in myeloid cells in collaboration with Rosandra Kaplan. This could potentially facilitate the improvement of cell-based therapy strategies. 174423 +Behavioral and Social Science; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Services; Immunotherapy; Neurosciences; Orphan Drug; Patient Safety; Rare Diseases Address;Adult;Advocacy;Advocate;Agreement;Anxiety;Apple;Award;Awareness;Books;Brain;COVID-19;Cancer Survivor;Caregivers;Caring;Central Nervous System Diseases;Central Nervous System Neoplasms;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Communication;Communities;Comprehensive Cancer Center;Data;Data Analyses;Development;Diagnosis;Educational Activities;Educational workshop;Enrollment;Ependymoma;Event;Exhibits;Extramural Activities;Facebook;Fostering;Funding;Genetic Counseling;Genomic Data Commons;Glioblastoma;Glioma;Goals;Group Meetings;Growth;Guidelines;Health;Health Services Accessibility;Immune checkpoint inhibitor;Immunologic Monitoring;Immunologic Tests;Individual;Information Technology;Infrastructure;Institution;International;Journals;Laboratories;Language;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of central nervous system;Manuscripts;Medical;Methods;Molecular;Monitor;Multi-Institutional Clinical Trial;National Comprehensive Cancer Network;Natural History;Newsletter;Nivolumab;Observational Study;Oncology;Oral;Outcome;Paper;Participant;Pathology;Patient Monitoring;Patient advocacy;Patient-Focused Outcomes;Patients;Persons;Pharmaceutical Preparations;Physicians;Play;Primary Brain Neoplasms;Privatization;Professional Organizations;Professional counselor;Provider;Publishing;Quality of life;Recommendation;Recurrence;Reporting;Research;Research Personnel;Risk;SKIL gene;Science;Self Care;Self Management;Services;Site;Sleep;Specimen;Support Groups;Surveys;Symptoms;Telemedicine;Testing;Time;Translations;Twitter;United States;United States National Institutes of Health;Update;Vertebral column;Visit;Work;advocacy organizations;base;cancer care;cancer type;cohort;data repository;data sharing;first-in-human;genetic counselor;genetic testing;gliosarcoma;human study;impression;improved;improved outcome;medulloblastoma;meetings;member;multidisciplinary;mutant;neuro-oncology;novel therapeutics;oligodendroglioma;patient advocacy group;patient engagement;patient population;pre-clinical;programs;psychological distress;research clinical testing;sharing platform;survivorship;symposium;targeted therapy trials;tool;tumor;virtual;virtual reality environment;web site;webinar CONNECT: Comprehensive Oncology Network Evaluating Rare CNS Tumors - Cures n/a NCI 10702715 1ZIABC011853-05 1 ZIA BC 11853 5 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 358830 NCI Our NCI-CONNECT program includes a network of 33 institutions (Figure 1) across the nation that help us enroll patients for clinical trials and studies. Our network meets biannually to discuss program updates and new clinical trials for rare CNS tumors. Our consortium was instrumental to the launch of two first-of-their-kind multi-center clinical trials after a landmark agreement with Medical Science & Computing that provides unprecedented opportunity for intramural and extramural collaboration on clinical trials for the network. We have continued formal partnership under an NCI Memorandum of Understanding with patient advocacy groups to share educational content and raise awareness to improve outcomes for people with rare CNS tumors. We have nine advocacy partnerships (Table 1) with world-renowned national and international organizations that collaboratively host workshops meetings and virtual educational events to help us share the patient perspective. We have collaborated with our partners on seven events in the past three years including national and international conferences and educational webinars. Our network of investigators and advocacy partners helped us successfully host a Survivorship Care in Neuro-Oncology Symposium virtually in June 2021 with over 200 attendees marking our seventh scientific or clinical outcomes workshops for NCI-CONNECT since 2018. The scientific workshops bring together neuro-oncology experts and patient advocates worldwide to discuss the scientific progress and challenges of a selected specific rare CNS cancer type and find ways to collaborate to improve therapies and develop new clinical trials. We have published papers from these workshops - four proceedings papers in Neuro-Oncology Advances including our Survivorship Care in Neuro-Oncology Symposium manuscript which has been endorsed by professional and advocacy organizations who are working with us on the recommendations from the symposium to impact survivorship outcomes for people with rare CNS tumors and one supplement in Neuro-Oncology (Table 2) - and changed cancer care guidelines; notably in November 2020 the NCCN guidelines for medulloblastoma were updated due to our scientific workshop report. Our NCI-CONNECT website is a sought-after educational tool by patients caregivers and professionals especially during COVID-19 - from 2020 to 2021 it had a 98% growth rate in page views with a total of 941138 pages views and 539320 unique website visits from January to December 2021. In March 2020 we published a new Managing Self-Care section for people living with brain and spine tumors and their caregivers. The content was added to our Living with a Tumor section which had a 58 percent growth in page views in 2021. Our Spanish language version of the website which launched in March 2020 to reach a broader and underserved audience had a 7300 percent increase in monthly visitors in one year. Our monthly NCI-CONNECT e-newsletter is delivered to 8300 subscribers. Our private Facebook group NCI-CONNECT Community - the first ever for NCI - has 516 members; our YouTube Playlist in the NCI Channel has 35 videos accumulating 18728 views. Our Twitter account had 5729 followers and over 1 million impressions (number of times our tweets were seen) in 2021. All these platforms share educational and scientific information. We also developed a symptom-burden app called My STORI in 2021 which is available in the Apple Store and Google Play Store to facilitate patient symptom monitoring and tracking to impact quality of life. Our NCI-CONNECT Clinic is dedicated to bringing together patients with similar rare CNS tumor types for special services. We have seen 421 patients as part of NCI-CONNECT Clinics as of January 2022 which is 49 percent of our entire NOB patient population. These patients receive genetic testing and counseling a review of their diagnosis with advanced molecular testing and participate in a support group meeting called CARES with a dedicated Health and Wellness Counselor. During COVID-19 NCI-CONNECT has added partnerships with local physicians to provide study drug and telemedicine to expand access to care for our NCI-CONNECT Clinic patients. We currently have 10 active NCI-CONNECT clinical studies and trials that have accrued 585 subjects in four years. Progress for FY21 includes a positive interim analysis in the heavily pre-treated patient cohort for our basket trial testing the immune checkpoint inhibitor nivolumab for adults with rare CNS cancers (17C0102). The presentation on these results won an abstract Award for Excellence in Rare CNS Disease at the 2021 SNO Annual Meeting. Our research using data from our Natural History Study received an Abstract Award for Excellence in Survivorship and an Abstract Award. Based on study data from our natural history and specimen banking study for adults with rare central nervous system (CNS) cancers (16C0151) the 2021 WHO diagnosis book for ependymoma was updated. Our other trials include an online survey of outcomes and risk for patients with adult CNS cancers (17CN141); a rare CNS cancer tumor and data repository (P194734); and targeted treatment trials including first-in-human study of oral ONC206 in recurrent and rare primary CNS neoplasms (20C0069) (based on preclinical work done in Dr. Gilbert's laboratory program) nivolumab for patients with recurrent IDH mutant gliomas including oligodendrogliomas (19C0006); and immune monitoring for patients with gliosarcoma and glioblastoma (21C0015). In addition to address the needs of brain cancer survivors we launched a trial using immersive Virtual Reality (VR) at the time of clinical evaluation to improve psychological distress and anxiety (20C0065) in March 2021 a study on managing Cancer And Living Meaningfully (CALM) therapy in individuals diagnosed with a primary brain tumor (000293) and a sleep observation study in patients with brain cancer (000085) both in June 2021. The NCI-CONNECT consortium has allowed us to expand our research efforts across the United States and provides a network for patient referrals to our NCI-CONNECT Clinics for participation in our single-center studies. We have led educational activities for NCI-CONNECT members several times per year including virtual journal club sessions and live tumor board sessions that we videocast to NCI-CONNECT investigators in conjunction with our scientific workshops. In April 2020 we expanded our weekly multidisciplinary NIH Neuro-Oncology Tumor Board to include investigators and cases from participating NCI-CONNECT consortium sites including 16 Comprehensive Cancer Centers. These educational efforts have been well-attended and have successfully continued to engage the investigators across the NCI-CONNECT consortium as exhibited by our data: 28 providers have presented 41 cases at 24 meetings with 60 to 70 participants. Through intramural collaborations with the pathology team led by Dr. Kenneth Aldape NCI-CONNECT has submitted a request for its clinical trials data to the Genomic Data Commons to allow researchers access to important data for development of new research; with the information technology team led by Dr. Jason Levine NCI-CONNECT is analyzing data from its patient outcomes surveys to find ways to dynamically display it publicly online. NCI-CONNECT shares a genetic counselor with the Moonshot-funded program MyPART and meets with them to share patient engagement and communications strategies and discuss other initiative needs. Advo *TRUNCATED* 358830 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome DNA Methylation;DNA copy number;Data;Data Set;Epigenetic Process;Gene Expression;Genomics;Goals;Human;Malignant Neoplasms;MicroRNAs;Modeling;Pattern;The Cancer Genome Atlas;Tissue-Specific Gene Expression;Variant;cancer biomarkers;cancer subtypes;cancer type;genome wide methylation;genomic biomarker;genomic data Genomic Biomarkers of Cancer n/a NCI 10702713 1ZIABC011850-04 1 ZIA BC 11850 4 15687397 "ALDAPE, KENNETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1282387 NCI We will study existing genomic data sets from multi-platform analysis to find existing patterns and relationships between epigenetics and genomics. In particular we will study the relationship between changes in DNA methylation compared to changes in gene expression to account for the variation in gene expression among cancer types. In addition we will construct models that take into account epigenetics as well as changes in DNA copy number and microRNA expression that may account for differential gene expression in human cancer subtypes. We will utilize publicly available data sets such as TCGA for this purpose. 1282387 +Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Neurosciences; Precision Medicine; Radiation Oncology; Rare Diseases Adjuvant;Adjuvant Radiotherapy;Adjuvant Therapy;Behavior;Biological Markers;Cessation of life;Clinical;DNA;DNA Methylation;Data;Decision Making;Development;Excision;Genomics;Goals;Histology;Intracranial Neoplasms;Methylation;Molecular;Mutation;Nomograms;Operative Surgical Procedures;Patient Selection;Patients;Radiation;Recurrence;Subgroup;Therapeutic;Time;Validation;base;clinical predictors;clinically relevant;epigenome;experience;individual patient;meningioma;methylome;personalized decision;personalized medicine;prevent;standard of care;tumor;tumor progression Development and validation of a predictor of meningioma recurrence n/a NCI 10702711 1ZIABC011847-05 1 ZIA BC 11847 5 15687397 "ALDAPE, KENNETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1244669 NCI An important clinical problem in the management of patients with meningiomas is the difficulty in predicting recurrence at the individual patient level limiting appropriate selection of patients who would benefit from adjuvant therapy to delay recurrence. Grading of tumors is based entirely on histology without molecular considerations but recent data suggest the utility of DNA methylation profile as a clinically relevant biomarker. We therefore aimed to develop and validate a combined molecular and clinical predictor of meningioma recurrence in individual patients to help personalize decision making regarding adjuvant treatment. Results indicate that a molecular definition of meningioma may yield clinically relevant subtypes that can be used to optimize therapeutic decisions. 1244669 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Networking and Information Technology R&D (NITRD); Orphan Drug; Rare Diseases Brain;Brain Neoplasms;Cells;Computing Methodologies;DNA Methylation;DNA analysis;Data;Diagnosis;Goals;Heterogeneity;Histologic;Human;Immunotherapy;Individual;Malignant Neoplasms;Methods;Methylation;Modality;Pathologic;Pathologist;Sampling;Work;cell determination;cell type;information classification;neoplastic cell;new technology;novel therapeutics;single cell analysis;tumor;tumor microenvironment;virtual Single-cell DNA methylation analysis of human cancer n/a NCI 10702710 1ZIABC011846-05 1 ZIA BC 11846 5 15687397 "ALDAPE, KENNETH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1244669 NCI DNA methylation provides a signature to identify cell type. Previous data shows that DNA methylation signature of bulk tumors reveals important classification information that is not available using current standard pathological methods (histologic interpretation by a pathologist). In this project we will extend this concept by analyzing the DNA methylation signatures of individual cells within the tumor. The analysis of single-cell methylation will then enable a cell-by-cell determination of differentiation and heterogeneity within the tumor. It will also allow characterization of the tumor microenvironment which is emerging as a critically important component for new therapeutic modalities including immunotherapy. We have expanded this work to include deconvolution of bulk methylation data in tumors to continue the goals of this project. 1244669 +Biotechnology; Cancer; Lung; Lung Cancer; Orphan Drug; Rare Diseases; Women's Health 1-Phosphatidylinositol 3-Kinase;Apoptosis;Apoptotic;Bromodomain;Cancer Model;Cancer Patient;Cancer cell line;Cell Survival;Clinic;Clinical;Collaborations;Drug Combinations;Drug Synergism;Evaluation;FRAP1 gene;Goals;In Vitro;Malignant Neoplasms;National Center for Advancing Translational Sciences;PI3K/AKT;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Proto-Oncogene Proteins c-akt;Resistance;Signal Transduction;TSC2 gene;Therapeutic;Translating;Treatment Protocols;Up-Regulation;antitumor effect;effectiveness validation;high throughput analysis;high-throughput drug screening;in vivo;inhibitor;inhibitor therapy;lung small cell carcinoma;mTOR Inhibitor;mTOR inhibition;mouse model;novel;patient derived xenograft model;pre-clinical;resistance mechanism;screening;synergism;therapeutic target;transcriptome;tumor;upstream kinase Developing an Effective BET bromodomain inhibitor Drug Combo to Target SCLC n/a NCI 10702706 1ZIABC011839-05 1 ZIA BC 11839 5 15201759 "CHEN, HAOBIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 243898 NCI Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. BET inhibitors have shown promising preclinical activity in SCLC but their broad sensitivity spectrum limits their clinical prospects. To identify therapeutics potentiating BET inhibitors we performed high-throughput drug combination screens in SCLC cell lines. Inhibitors of the PI-3K-AKT-mTOR pathway were the top candidates from the screens. Among the therapeutics targeting this pathway mTOR inhibitors showed the highest degree of synergy with BET inhibitors. Furthermore the combination of mTOR and BET inhibitors showed superior antitumor efficacy and tolerability in vivo. Using both in vitro and in vivo SCLC models we demonstrate that BET inhibitors activate the intrinsic apoptotic cascade and mTOR inhibitors further enhance these apoptotic effects. Mechanistically BET inhibitors activate the TSC2-mTOR-p70S6K1 signaling cascade by upregulating RSK3 an upstream kinase of TSC2. Activation of p70S6K1 leads to BAD phosphorylation and cell survival. mTOR inhibition blocks this survival signaling and potentiates the antitumor effects of BET inhibitors. Our results demonstrate that RSK3 upregulation is a novel resistance mechanism of BET inhibitors in SCLC and mTOR inhibition overcomes this resistance and enhances apoptosis. These findings warrant further evaluation of the combination of mTOR and BET inhibitors in SCLC patients. Through independent low-throughput analysis we confirmed the findings of the high-throughput analysis. One combination mTOR inhibitor (mTORi) and BETi showed superior anti-tumor efficacy in SCLC cell lines. Furthermore the mTORi and BETi combination demonstrate superior tumor control and tolerability in several SCLC PDX models. Mechanistically BETi induces apoptosis but its anti-tumor effect is counteracted by a concomitant transcriptome change that promotes cell survival. mTORi effectively blocks this survival cascade and enhances BETi-induced apoptosis in SCLC. 243898 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Neurosciences; Prevention; Rare Diseases Adult;Brain Neoplasms;Cells;Central Nervous System Neoplasms;Characteristics;Clinical;Data Reporting;Disease;Early Diagnosis;Environmental Risk Factor;Exposure to;Genes;Genomics;Glioma;Health Status;Incidence;Knowledge;Malignant Neoplasms;Malignant neoplasm of central nervous system;Mutation;Outcome;Participant;Patient Self-Report;Persons;Physicians;Population;Predisposition;Primary Prevention;Process;Quality of life;Reporting;Risk;Risk Factors;Scientist;Symptoms;clinical predictors;cohort;functional status;rare cancer;tumor Outcomes and Risk of Rare Tumors n/a NCI 10702704 1ZIABC011837-05 1 ZIA BC 11837 5 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 497931 NCI Rare cancers are defined as those with 40000 cases per year. There are over 130 separate types of primary CNS tumors all of which meet the definition of a rare cancer. However some CNS cancers have incidences of less than 1000 cases per year. Because of its relative rarity limited reports of the presentation and clinical course have been completed. An additional consequence of the relative rarity of these CNS tumors studies to evaluate risk factors for the occurrence of these rare CNS tumors or predicting the clinical course of these rare CNS tumors are also limited. Rare CNS tumors like other cancers occur when there are changes to genes that control the way cells grow and divide often as a result of exposure to other environmental risk factors. Therefore exploring genetic changes in persons with rare CNS tumors will allow us to begin to understand what changes are associated specifically with these tumors. To date these participants are often included as part of larger cohorts which include other types of brain tumors. We now understand that even among gliomas the risk factors differ]. Therefore identifying the risk factors specifically associated with rare CNS tumors is critical for primary prevention and early detection. This knowledge would allow scientists and physicians to eventually screen for these changes or target the genes or the processes they control for treatment purposes. 497931 +Biotechnology; Cancer; Genetics; Hematology; Human Genome; Lymphatic Research; Lymphoma; Rare Diseases Acute;Allografting;Amplifiers;Cells;DNA Sequence Alteration;Dependence;Development;Financial compensation;Future;Gene Dosage;Genetic Models;Genetic Predisposition to Disease;Genetic Recombination;Genetic Transcription;Genome;Genomics;Genotype;Germ-Line Mutation;Growth;Hemangiosarcoma;Hypersensitivity;Immunohistochemistry;Knockout Mice;Li-Fraumeni Syndrome;LoxP-flanked allele;MYC Family Protein;MYC gene;Malignant Neoplasms;Modeling;Monitor;Mus;Neoplasms;Oncogenic;Outcome;Pathologic;Pathway interactions;Patients;Pharmaceutical Preparations;Physiological;RNA;Recovery;Reporter;Role;Siblings;Spectral Karyotyping;TP53 gene;Tamoxifen;Testing;Therapeutic;Thymic Lymphoma;Time;Tumor Promoters;c-myc Genes;cancer cell;cell type;design;dosage;effective therapy;genetic testing;mouse genetics;mutant;programs;therapeutic target;tumor;tumor growth;tumor progression;tumorigenesis;tumorigenic Minimal Myc functional threshold for tumorigenesis n/a NCI 10702703 1ZIABC011835-05 1 ZIA BC 11835 5 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 181329 NCI "We have designed a genetic test of the hypothesis that a minimum level of Myc function is required to ""amplify"" the transcriptional programs necessary for promoting and sustaining tumor formation. We employed the mouse p53 null mutant (p53 KO) as a robust tumor model to test for Myc-dependency by introducing modest changes in the endogenous c-Myc level (c-Myc+/-). Tumor-free survival times were compared in genetically similar p53 KO sibling mice that were either c-Myc+/+ (Myc WT; p53 KO) or c-Myc+/- (Myc-Het; p53 KO). Median tumor-free survival times doubled in the Myc-Het; p53 KO relative to Myc-WT (significant at P 0.0001). This difference was independent of the tumor type with hemangiosarcoma and thymic lymphoma being the most common (83%) tumor types in both groups. Analyses of c-Myc genomic alterations and expression levels in p53 KO tumors using Spectral Karyotyping (SKY) FISH and quantitative RNA ISH and immunohistochemistry revealed that compensation for the initially reduced endogenous c-Myc dosage had occurred in tumors arising in Myc-Het;p53 KO mice. Notably in hemangiosarcomas genome amplification achieved by several rounds of genome tetraploidization was consistently higher in the Myc-Het;p53 KO than in the Myc-WT;p53 KO tumors. Although thymic lymphomas of either genotype showed no genomic amplification expression of Myc RNA and Myc protein were nevertheless comparably elevated in both the Myc-WT and Myc-Het tumors suggesting that compensation for reduced Myc gene dosage had occurred at the transcriptional level. These results indicate that reduced endogenous c-Myc dosage substantially delays tumor development in mice that are genetically predisposed to neoplasia and that in order for Myc-Het;p53 KO mice to develop tumors a compensatory increase in expression of Myc which can occur by multiple mechanisms is required. We have also used allografts using of thymic lymphomas from p53 KO mice carrying conditional c-Myc-floxed and tamoxifen-dependent Cre allelesand a dual-fluorescent reporter to monitor recombination efficacy in order to test whether reducing c-Myc will adversely impact established tumors (i.e. growth progression) and found that after recovery from recombination induced apopstosis tumor growth rate is substantially slowed when endogenous Myc dosage is acutely reduced. Our results strongly suggest that a modest reduction in Myc can curtail cancer growth and has important implications particularly for extending tumor-free survival in patients with Li-Fraumeni syndrome (germline mutations in p53) as well as sporadic cancers. This study provides a framework and model for future analyses of c-Myc role in tumorigenesis and tumor progression and can be readily extended to other tumor types using analogous strategies and other tumor promoters such as oncogenic Ras. We are also exploring whether p53 tumors can arise at all in the context of severely reduced c-Myc expression levels." 181329 +Cancer; Genetics Biosensor;CDK2 gene;CDK4 gene;CRISPR screen;Cell Cycle;Cell Cycle Regulation;Cells;DNA Damage;Data;Decision Making;Event;G1 Phase;G1/S Transition;G2 Phase;Genes;Goals;Image;MEKs;Mediating;Molecular;Play;Reporter;Role;Stimulus;Time;genome-wide;imaging capabilities;inhibitor;neoplastic cell;response;senescence Study cell cycle regulation in dormant tumor cells n/a NCI 10702702 1ZIABC011832-05 1 ZIA BC 11832 5 15687383 "CAPPELL, STEVEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 604582 NCI The overall goal of this project is to investigate mechanisms underlying irreversible cell cycle exit. We recently uncovered the molecular mechanism underlying APC/C inactivation at the G1/S transition and showed how this molecular switch controls irreversible cell cycle entry. However several studies have recently shown that APC/C re-activation in G2 phase after DNA damage also plays a critical role in the decision to undergo senescence which is defined as an irreversible cell cycle exit. The molecular mechanism underlying this APC/C re-activation is not currently known. Using our APC/C and CDK2 biosensors our data shows that APC/C only re-activates in response to DNA damage when CDK2 activity is suppressed to lower levels than is needed in G1 phase to inactivate APC/C. This critical observation indicates APC/C re-activation demonstrates hysteresis a key feature in irreversible fate transitions and could therefore be the critical event underlying senescence entry. We are currently investigating the mechanism underlying Emi1 suppression in response to DNA damage. In addition we are investigating additional mechanisms that may maintain senescence. Using our time-lapse imaging capabilities we can induce senescence with a combination of MEK and CDK4/6 inhibitors and follow cells as they undergo senescence. By removing the initiating stimulus at various points we will identify the point of irreversibility in senescence. We also identify additional genes necessary to mediate this irreversibility in an unbiased manner using our suite of live-cell reporters and a genome-wide CRISPR screen. 604582 +Cancer Algorithms;Behavior;Biosensor;CDK2 gene;Cell Cycle;Cell Cycle Regulation;Cells;Cyclin D1;DNA Damage;Decision Making;Future;G1 Phase;Generations;Genotoxic Stress;Goals;Microscopy;Molecular;Signal Pathway;Signal Transduction;Sister;Source;Stress;prevent;time use Control of cell cycle commitment by APC-C-Cdh1 n/a NCI 10702700 1ZIABC011830-05 1 ZIA BC 11830 5 15687383 "CAPPELL, STEVEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 604582 NCI The overall goal of this project is to investigate how stress signaling pathways induce a return to quiescence during G1 phase of the cell cycle and to investigate the source of single-cell variability in this fate choice. It has been proposed that the decision to enter the cell cycle is made at a discreet point during G1 phase called the restriction point. However we recently showed that if cells encounter genotoxic stress even after they have passed the restriction point they can still exit the cell cycle and return to quiescence indicating cells have not yet committed to the cell cycle at the restriction point. Furthermore there is considerable single-cell variability with the majority of cells failing to trigger the G1/S checkpoint and exiting to quiescence after DNA damage is induced. These results call into question the concept that cells make the decision to divide at a single point in the cell cycle and also demonstrate that the DNA damage-regulated G1/S checkpoint is highly ineffective. To investigate the mechanisms underlying cell cycle de-commitment we are using using time-lapse microscopy and fluorescent biosensors for CDK2 and APC/C activity that we developed as well as automated single-cell tracking algorithms to follow single-cells as they enter and exit the cell cycle. We are currently dissecting the effects of DNA damage signaling on key cell cycle regulators including Cyclin D and p21 to understand why some cells are sensitive to DNA damage while others are not. Furthermore we are analyzing the behavior of genetically-identical sister cells to identify deterministic factors that can predict what fate a cell will choose. In addition we are tracking cells over multiple generations to understand the consequences of failing to return to quiescence after DNA damage is induced. 604582 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Pancreatic Cancer; Rare Diseases Combined Modality Therapy;DNA Damage;DNA Single Strand Break;Islet Cell Tumor;Lutetium;Malignant Neoplasms;Names;Neuroendocrine Tumors;Phase;Phase I/II Clinical Trial;Radioisotopes;inhibitor;repaired;stem Phase 1-2 study of Lu177-DOTATATE and olaparib in neuroendocrine tumors n/a NCI 10702698 1ZIABC011827-05 1 ZIA BC 11827 5 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 85931 NCI The rationale behind using combination therapies in cancer stems from the potential of synergistic mechanisms of action of the involved agents. Olaparib is a PARP-inhibitor which blocks the repair of single-stranded DNA breaks and is especially effective when combined with other agents which induces DNA damage. We are proposing a Phase I/II clinical trial to look at the combination of olaparib with the targeted radionuclide agent Lutetium-177-DOTATATE (trade name: Lutathera Novartis/Advanced Accelerator Appliations) in inoperable gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). 85931 +Cancer; Clinical Research; Dental/Oral and Craniofacial Disease Affect;Clinical Trials;Collaborations;Dental;FOLH1 gene;Future;Goals;Human;Institutes;Methods;Pre-Clinical Model;Rodent;Salivary Glands;Translating;Update;pre-clinical;radioligand;tumor;uptake Protection of Salivary Gland in PSMA-targeted radioligand therapy n/a NCI 10702697 1ZIABC011826-05 1 ZIA BC 11826 5 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 343726 NCI The goal of this project is to see if salivary gland uptake of PSMA injected systemically can be blocked selectively blocked by using local blocking methods at the salivary gland level. The desired end point would be blocking salivary gland uptake of PSMA without affected the tumor update. This is a collaboration with Dr. Blake Warner of the Dental Institute and involves the use of rodents as the pre-clinical model. If the pre-clinical approach is successful the approach will be translated to humans in a future clinical trial. 343726 +Cancer; Clinical Research; Immunization; Orphan Drug; Rare Diseases; Women's Health Agreement;Antibodies;Biodistribution;Biological Markers;Chelating Agents;Clinical Data;DNA Damage;Data;Disease;Dose;Drug Kinetics;Injections;Interruption;Label;Longterm Follow-up;Malignant - descriptor;Malignant neoplasm of ovary;Maximum Tolerated Dose;Mesothelioma;Molecular Profiling;Multicenter Studies;Patients;Pharmaceutical Preparations;Research Personnel;Safety;Serous;Testing;Thorium;Time;Visit;antibody conjugate;biomarker signature;cohort;first-in-human;follow-up;human study;immunogenicity;mesothelin;open label;participant enrollment;response biomarker;screening;tumor Th227-mesothelin and Zr89-mesothelin antibody conjugate in mesothelin tumors n/a NCI 10702696 1ZIABC011825-05 1 ZIA BC 11825 5 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 85931 NCI This is a first-in-human open-label multi-center study. The study is composed of the following periods: - Screening - Treatment - Follow-up (mandatory safety follow-up and whenever applicable efficacy follow-up visits) - Long-term follow-up. The thorium-227 dose escalation will be carried out in a step-wise fashion using two antibody doses 10 and 30 mg which will proceed independently for each dose of thorium-227. Enrollment of patients in the 10 mg and 30 mg cohorts will be allocated according to a pre-defined cohort management plan agreed between the sponsor and investigators and the decision to escalate to the next thorium-227 level will be taken independently for each cohort. No intra-subject dose escalation will be allowed. At any time point of the dose escalation testing of one of the two doses may be interrupted on the basis of emerging clinical data and/or substituted by testing of a different antibody dose within the range of 10-50 mg after discussion and agreement between the sponsor and the investigators. 85931 +Antimicrobial Resistance; Biodefense; Cancer; Emerging Infectious Diseases; Genetics; Infectious Diseases; Patient Safety Antibiotic Resistance;Antibiotics;Cessation of life;Clinical;Evolution;Fluoroquinolones;Future;Genes;Genetic Determinism;Goals;Health;Lead;Libraries;Metabolism;Methicillin;Multi-Drug Resistance;Mutation;Pathway interactions;Play;Population;Proteins;Resistance;Role;Staphylococcus aureus;Testing;Transcriptional Regulation;United States;antimicrobial;healthcare-associated infections;methicillin resistant Staphylococcus aureus;novel;novel therapeutics Evolution of antibiotic resistance n/a NCI 10702694 1ZIABC011821-05 1 ZIA BC 11821 5 15687374 "KHARE, ANUPAMA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 202523 NCI We have evolved several independent populations of methicillin-sensitive as well as methicillin-resistant S. aureus (MRSA) to multiple fluoroquinolones and identified the adaptive trajectories leading to antibiotic resistance. Apart from mutations in previously implicated as well as uncharacterized regions of target proteins we also found mutations in novel genes involved in metabolism transcriptional regulation and efflux. Several of these mutations arose early during the evolution before those in target proteins. We are characterizing how these mutations lead to resistance. In the future we will test the importance of the identified mutations in clinical antibiotic resistance. We will also utilize transposon libraries to identify additional genes that play a role in antibiotic resistance and persistence. 202523 +Cancer; Cystic Fibrosis; Infectious Diseases; Lung; Rare Diseases Bacteria;Cells;Clinical;Communities;Cystic Fibrosis;Data;Disease;Escherichia coli;Exposure to;Genes;Genetic Screening;Health;Human;Infection;Lead;Lung infections;Modeling;Molecular;Mutation;Oxidation-Reduction;Pathway interactions;Patients;Phenazines;Population;Pseudomonas aeruginosa;Pulmonary Cystic Fibrosis;Pyocyanine;Quinolones;Reporter;Research;Resistance;Signal Pathway;Signal Transduction;Signaling Molecule;Staphylococcus aureus;System;Testing;Wound Infection;antimicrobial;bacterial fitness;chronic wound;co-infection;emerging adult;fitness;genome-wide;interest;lung pathogen;microbial;microbiome;microorganism;novel;promoter;response;small molecule;transcriptome sequencing Mechanisms of multi-species bacterial interactions n/a NCI 10702693 1ZIABC011819-05 1 ZIA BC 11819 5 15687374 "KHARE, ANUPAMA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 810090 NCI Our research over the last year had two main directions as described below. I) Sensing of S. aureus by P. aeruginosa. Sensing of neighboring microbial species and a tailored response are critical for bacterial fitness in multispecies communities. Therefore we hypothesize that P. aeruginosa can sense the presence of foreign species and respond appropriately. In a two-species system consisting of P. aeruginosa and S. aureus we observed that P. aeruginosa could sense exoproducts secreted by S. aureus. Our specific aims of this project are thus to identify the signal molecules produced by S. aureus the sensing signaling pathway in P. aeruginosa as well as the response. We used RNAseq to identify the genes and pathways that are differentially regulated in P. aeruginosa upon exposure to S. aureus. Further using these data we identified several promoters that could serve as reporters in P. aeruginosa for the sensing of the S. aureus signal. We have recently constructed a fluorescent reporter system and are now working on using LC-MS on S. aureus exoproducts in combination with the reporter system to identify the S. aureus signal molecules. We are also using a genetic screen to identify the S. aureus signal molecules. II) Identify and characterize molecules involved in interactions between S. aureus and P. aeruginosa. P. aeruginosa produces multiple molecules with antimicrobial activity against several other species but their mode of action and the pathways by which other bacteria can adapt to them are not well-defined. We are interested in delineating the effect these molecules have on S. aureus cells and identifying the adaptive trajectories of S. aureus in their presence. We have evolved multiple populations of S. aureus against the P. aeruginosa redox-active phenazine molecule pyocyanin and have identified mutations in several genes that have not been previously implicated in pyocyanin resistance. We aim to characterize how these mutations confer pyocyanin resistance test their relevance in clinical isolates and better describe the cellular effects of pyocyanin on S. aureus. We will similarly study other P. aeruginosa antimicrobial molecules such as the quinolones. 810090 +Cancer; Genetics; Neurosciences; Rare Diseases; Stem Cell Research; Stem Cell Research - Embryonic - Non-Human Address;Adult;Affect;Anatomy;Anxiety;Architecture;Biological Models;Biology;Bone marrow failure;Brain;Cells;Central Nervous System;Child;Clinical;Clinical Research;Cutaneous;DNA Damage;Development;Disease;Dyskeratosis Congenita;Functional disorder;Genes;Genetic Diseases;Genetic Models;Growth;Health;Hereditary Disease;Human;Immunologic Deficiency Syndromes;Impairment;Intellectual functioning disability;Knock-out;Learning;Length;Lesion;Leukoplakia;Longevity;Malignant Neoplasms;Memory Loss;Mitotic;Molecular;Molecular Biology;Mus;Mutation;Nail plate;Neurons;Nonhomologous DNA End Joining;Pathway interactions;Phase;Play;Process;Psychoses;Role;Seizures;Syndrome;System;TP53 gene;Telomere Maintenance;Testing;Work;chromosome fusion;cognitive capacity;conditional knockout;dentate gyrus;embryonic stem cell;experimental study;genetic approach;granule cell;insight;mouse genetics;mouse model;nestin protein;neurogenesis;neuron loss;novel;progenitor;response;telomere Determine how telomere dysfunction impacts neuronal function n/a NCI 10702692 1ZIABC011816-05 1 ZIA BC 11816 5 10105415 "LAZZERINI DENCHI, EROS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 646908 NCI Here we will: i) define why telomere dysfunction selectively affects neurogenesis in the dentate gyrus (DG) and ii) we will define the mechanism of neuronal loss upon telomere dysfunction in the DG. To define why telomere dysfunction selectively affects neurogenesis in the dentate gyrus we will test the hypothesis that telomere dysfunction selectively affects adult-born granule cells GCs due to their prolonged maturation phase. To this end we generated conditional knockout TRF2 mouse embryonic stem cells that can be differentiated into neuronal cells. This system will allow us to test the hypothesis that the timing of differentiation plays a major role in response to telomere dysfunction. In parallel we will employ mouse genetics models with alteration in the process of DG differentiation. To define the mechanism of neuronal loss upon telomere dysfunction in the DG we will assess the role of the DNA damage activation and onset of end-to-end chromosome fusions taking advantage of our previous work aimed at dissecting the cellular response to TRF2 depletion. In this system activation of the DNA damage response can be abolished by depletion of ATM and to a lesser extent by depletion of p53. Suppression of the NHEJ-pathway completely abolishes the onset of end-to-end chromosome fusions. Collectively these experiments will provide a better understanding of the role of telomeres in the CNS as well as a deeper understanding of the molecular mechanism that leads to neuronal loss upon DNA damage activation in neurons. 646908 +Cancer; Genetics Address;Alleles;Animals;Binding;Cell Death;Cells;Cohort Analysis;Complex;Data;Data Analyses;Future;Genes;Germ Cells;Growth;Guide RNA;Homeostasis;Individual;Knockout Mice;Laboratories;Length;Play;Population;Process;Proteins;Research Institute;Role;TERF1 gene;Time;Work;Zinc Fingers;base;cancer cell;experimental study;genome-wide;in vivo;insight;next generation sequencing;novel;stem cells;telomere;telomere loss Investigate the mechanism of action of the novel telomere length regulator TZAP n/a NCI 10702691 1ZIABC011815-05 1 ZIA BC 11815 5 10105415 "LAZZERINI DENCHI, EROS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 646908 NCI Having started my laboratory at NCI in late May 2018 I have been mainly involved in setting up my laboratory. My future work at NCI will be to validate and characterize positive hits identified in the genome-wide gRNA screen described above. These experiments are expected to provide us with mechanistic insights into the role of TZAP and telomere trimming in telomere length homeostasis. In addition we will analysis of cohorts of TZAP null mice will allow us to establish whether TZAP depletion in vivo leads to progressive telomere elongation and the consequences of critically long telomeres in vivo. I am currently waiting for the transfer of animals to start this project here at NCI. 646908 +Autoimmune Disease; Bioengineering; Cancer; Cancer Genomics; Genetics; Human Genome; Lupus; Machine Learning and Artificial Intelligence; Rare Diseases; Women's Health Antibodies;Antigens;Biological;Biological Process;Blood;Blood Vessels;Bone Marrow;Boston;Cell Differentiation process;Cell Proliferation;Cells;Chronic;Clinical;Clinical Trials;Coin;Collaborations;Communication;Custom;Cytokine Signaling;Data;Data Analyses;Defect;Disease;Epitopes;Epstein-Barr Virus Infections;Equilibrium;Experimental Designs;Explosion;Foundations;Frequencies;Functional disorder;Funding;Genomics;Goals;Grant;Homeostasis;Hospitals;Immune;Immunologic Deficiency Syndromes;Immunologics;Immunologist;Immunology;Immunophenotyping;Inflammation;Interferons;Label;Leukocytes;Link;Machine Learning;Magnesium;Measurement;Measures;Methodology;Methods;Modeling;Mus;National Institute of Allergy and Infectious Disease;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Neoplasms;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Physics;Physiologic pulse;Population;Process;Regulation;Research;Research Project Grants;Resolution;Sampling;Seeds;Signal Pathway;Site;Systemic Lupus Erythematosus;T-Lymphocyte;Time;United States National Institutes of Health;Universities;Uracil;Validation;Variant;Whole Blood;Work;autoimmune lymphoproliferative syndrome;base;bioinformatics pipeline;cell type;clinical application;computational pipelines;congenital immunodeficiency;cytokine;density;design verification;granulocyte;high dimensionality;immunoregulation;machine learning pipeline;monocyte;neutrophil;response;single-cell RNA sequencing;tool;tumor;vector Immunophenotyping by CyTOF and machine learning n/a NCI 10702685 1ZIABC011807-05 1 ZIA BC 11807 5 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 556937 NCI "Our application of high-dimensional immune-phenotyping using CyTOF finds natural applications in clinical settings. There has been an explosion of experimental methodologies for measurement multiplexing in immunology (e.g. cytokine arrays by SomaLogic single-cell RNAseq) and we are focusing on CyTOF for its close connection to biological function in immunological problem. Our main project has been to develop new machine-learning derived tools to automatically analyze CyTOF data (collaboration with Pankaj Mehta's theoretical physics group at Boston University). This collaboration (funded in part by a seed grant from the Moore foundation) synergizes Pankaj Mehta's expertise in machine learning and the Altan-Bonnet lab's expertise in quantitative immunology to optimize new methods in CyTOF data analysis. We emphasize interpretability of immunological classifier to allow immunologists to leverage the results of our machine learning pipeline into testable hypotheses and experimental validation. We are collaborating with clinical labs at the NIH to apply our experimental/theoretical pipeline to analyze clinical samples from ongoing clinical trials. Our collaboration with Mike Lenardo's group at NIAID led to the design and validation of a CyTOF panel that provides general immunophenotyping for peripheral blood mononuclear cell (PBMC) samples for the clinical genomics group at NIAID. This 35-label panel covers all the main leukocyte cell types of the blood and leaves open channels for augmentation with antibodies against disease-specific epitopes. We are profiling the PBMC of patients afflicted with XMEN (""X-linked immunodeficiency with magnesium defect EBV infection and neoplasia"") and ALPS (""Autoimmune lymphoproliferative syndrome"") under study within the Lenardo lab. Preliminary measurements demonstrate how the large number of available samples within the clinical genomics branch at NIH can be leveraged with our high-dimensional phenotyping to generate immunological classifier that best correlates with disease status. We will apply support-vector classifiers to identify the leukocyte populations whose variation in frequency and/or change in differentiation status best correlates with clinical scores. Moving forward we will further this collaboration to build a custom-designed experimental and computational pipeline that robustly classifies patients from multiple primary immunological deficiencies. Hence our goal is to fine-tune our machine learning tools to clinical applications while probing the global disruption of immunological homeostasis (as studied in project I) with access to rare samples of patients with primary immunodeficiencies. Similar collaborative work is ongoing with Mariana Kaplan's lab within NIAMS. This collaboration aims at deepening our understanding of the dysregulation of neutrophils in Systemic Lupus Erythematosus (SLE) patients. The Kaplan lab has identified a new population of low-density granulocytes that trigger enhanced formation of neutrophil entrapment traps (""NETosis"") IFN secretion and vascular damage. Our working hypothesis for this collaboration is that such neutrophilic dysfunction in SLE globally displaces homeostasis by maintaining chronic inflammation. Here we expanded our general immune-phenotyping CyTOF panel with antibodies specific to neutrophils. Analysis of neutrophils requires the processing of fresh whole blood and the Kaplan lab receive fresh samples biweekly from patients at the NIH hospital. For this reason our CyTOF-based immune-phenotyping pipeline is particularly well suited to identify large-scale disruption of immune homeostasis in the blood of SLE patients as we have validated the robustness of the pipeline when fresh samples are being accrued processed and analyzed over a large period of time (1 month). Hence we will accrue samples (n100) with varied clinical presentations in order to focus our understanding of altered homeostasis in the blood of SLE patients. As in the collaboration with the Lenardo lab we are taking the opportunity of collaborating with the Kaplan lab to fine-tune our CyTOF pipeline in clinical settings as well as to further probe how global immunological disruption can be set in the context of chronic inflammation." 556937 +Bioengineering; Biomedical Imaging; Cancer; Digestive Diseases; Health Disparities; Immunotherapy; Liver Cancer; Liver Disease; Minority Health; Orphan Drug; Radiation Oncology; Rare Diseases Ablation;Biological;Cessation of life;Death Rate;Detection;Development;Diagnosis;Disease;Engineering;Excision;Goals;Image;Immunotherapy;Incidence;Intravenous;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Modality;Molecular;Patients;Phase;Positron-Emission Tomography;Primary carcinoma of the liver cells;Radiation therapy;Radioembolization;Survival Rate;Transplantation;United States;X-Ray Computed Tomography;cancer type;falls;high risk;imaging agent;improved;intrahepatic;novel;palliative;screening;treatment planning;tumor Engineering HCC-selective PET agent n/a NCI 10702679 1ZIABC011800-05 1 ZIA BC 11800 5 15687349 "ESCORCIA, FREDDY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1707995 NCI Liver cancer is ranked second in cancer-related deaths worldwide. Unlike many other cancer types the incidence and death rate of liver cancers is rising in the United States with a 5-year survival of 18% (all stages). Treatment of hepatocellular carcinoma the most common type of liver cancer transplant and resection offer curative potential and have 5 year overall survival (OS) rates of 70% and 40% respectively. For palliative local treatments 5 year OS rates fall to 20-35%. Classic imaging of HCC includes Tri-phasic CT scan and MRI however these modalities provide little biological information of the tumors especially after local ablative therapies compromising our ability to discern active from treated disease. Our goal is to engineer HCC-selective PET agents that will allow us to define the extent of disease to facilitate screening of in patients at high risk of HCC development aide in treatment planning once HCC has been diagnosed and help in selecting patients who may benefit from tumor-selective therapies (e.g. immunotherapy molecular radiotherapy). 1707995 +Cancer; Cancer Genomics; Diabetes; Digestive Diseases; Genetics; Health Disparities; Human Genome; Minority Health; Pancreatic Cancer; Rare Diseases Cell Lineage;Cells;Chromatin;DNA;DNA Sequence;Development;Diabetes Mellitus;Elements;Enhancers;Exocrine pancreas;Gene Expression;Genomics;Goals;Islets of Langerhans;Link;Logic;Malignant neoplasm of pancreas;Maps;Pancreas;Pancreatic Diseases;Regenerative Medicine;Regulatory Element;Research;Technology;Work;body system;cell type;diabetes risk;interest;programs;reference genome;risk variant Identification of genomic regulatory elements in pancreas cells n/a NCI 10702678 1ZIABC011798-05 1 ZIA BC 11798 5 15687347 "ARDA, HATICE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1511352 NCI Using cutting-edge genomic technologies we have mapped and categorized thousands of genomic elements that might be putative regulators of pancreas cell lineages. We identified chromatin regions that are associated with cell type-specific gene expression. Our work has revealed an enhancer logic that suggests a mechanism for the diversification of pancreas cell lineages during development. Our results also revealed previously unrecognized links between endocrine and exocrine pancreas in diabetes risk. 1511352 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Neurosciences; Rare Diseases Goals;Literature;Metastatic Pheochromocytoma;National Institute of Child Health and Human Development;Paraganglioma;Patients;Progression-Free Survivals;Safety;early phase clinical trial;improved;phase 2 study;rare cancer Phase 2 study of Lu-177-DOTATATE in inoperable paraganglioma - pheochromocytoa n/a NCI 10702675 1ZIABC011789-06 1 ZIA BC 11789 6 15201761 "LIN, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 171864 NCI The goal of this project it to assess the safety and to evaluate the ability of Lu-177-DOTATATE to improve upon progression-free survival (PFS) at 6 months in patients with inoperable SSTR positive PHEO/PGL by comparing PFS of patients treated with Lu-177-DOTATATE to historical controls from existing literature. This will be an early phase clinical trial of 90 patients which will seek to determine whether Lu-177-DOTATATE can be used to improved the PFS in the rare tumor metastatic pheochromocytoma and paraganglioma. This is a collaborative project with Dr. Karel Pacak of NICHD. 171864 +Cancer; Genetics; Lung; Lung Cancer; Orphan Drug; Precision Medicine; Rare Diseases; Women's Health BETA2 protein;BRD2 gene;Binding Proteins;Biological Markers;Bromodomain;Cancer cell line;ChIP-seq;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;Dissociation;Drug Targeting;FDA approved;Family;Gene Expression Profile;Genes;Growth;Immune checkpoint inhibitor;In Vitro;Knock-out;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane Proteins;Neoplasm Metastasis;Pharmacotherapy;Play;Protein Family;Proteins;Reporting;Resistance development;Role;Tertiary Protein Structure;Transactivation;Transcription Coactivator;cancer genome;cancer therapy;chemotherapy;clinical application;in vivo;inhibitor;interest;lung small cell carcinoma;mouse model;novel therapeutics;patient derived xenograft model;patient subsets;preclinical study;predicting response;predictive marker;response;transcription factor Predictive biomarker of BET bromodomain inhibitor in Small cell lung cancer n/a NCI 10702674 1ZIABC011787-06 1 ZIA BC 11787 6 15201759 "CHEN, HAOBIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 243898 NCI We hypothesized that BET bromodomain proteins are essential for the function of master transcription factors in SCLC and blocking these proteins could provide an alternative approach to target these master transcription factors. We have identified that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Blocking BET bromodomain proteins by inhibitors led to broad suppression of the NEUROD1-target genes especially those associated with superenhancers resulting in inhibition of SCLC growth in vitro and in vivo. LSAMP a membrane protein in the IgLON family was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether our study reveals an essential role of BET bromodomain proteins in regulating NEUROD1 transactivation and could be a target to block the master transcription factors in SCLC. 243898 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Clinical Research; Data Science; Genetics; Human Genome; Networking and Information Technology R&D (NITRD); Neurosciences; Orphan Drug; Precision Medicine; Rare Diseases Acceleration;Amino Acid Sequence;Animals;Area;Belief;Big Data;Biochemical Pathway;Bioinformatics;Biological;Biological Markers;Biological Process;Biology;Biomedical Research;Blood specimen;Brain Neoplasms;Cancer Genome Anatomy Project;Cancer Research Project;Cell Line;Cells;Central Nervous System Neoplasms;Chordoma;Classification;Clinical Data;Clinical Trials;Collaborations;Collection;Complex;Computer Analysis;DNA;DNA Sequence;DNA biosynthesis;Data;Data Analyses;Databases;Decision Making;Development;Disease;Enrollment;Evolution;Formalin;Freezing;Functional disorder;Funding;Gene Expression Profile;Gene Expression Profiling;Gene Proteins;Generations;Genes;Genetic Translation;Genomic Data Commons;Genomics;Glioma;Human;Human Genome Project;Hybrids;Impact evaluation;In Vitro;Information Storage;Laboratories;Link;Mainstreaming;Malignant Neoplasms;Malignant neoplasm of central nervous system;Maps;MicroRNAs;Microarray Analysis;Mining;Modality;Molecular;Molecular Analysis;Molecular Genetics;Monitor;Morphology;Natural History;Nature;Nucleic Acids;Paraffin Embedding;Patients;Pattern;Pharmacotherapy;Phenotype;Process;Proteins;Proteomics;RNA;RNA chemical synthesis;Research;Research Personnel;Resolution;Resources;Sampling;Science;Signal Transduction Pathway;Source;System;Techniques;Technology;The Cancer Genome Atlas;Therapeutic;Time;Tissue Sample;Tissues;Translating;Treatment Efficacy;Tumor Biology;Tumor Tissue;Variant;Work;analytical tool;base;bioinformatics tool;cDNA Arrays;cell behavior;clinical care;clinical practice;companion diagnostics;data acquisition;data streams;data warehouse;design;differential expression;driving force;drug development;genome wide methylation;genome-wide;histone methylation;improved;in vivo;laboratory experiment;metabolomics;methylation pattern;molecular diagnostics;molecular targeted therapies;neuro-oncology;novel;novel therapeutics;older patient;patient prognosis;patient stratification;peripheral blood;precision medicine;programs;prospective;protein distribution;protein metabolite;sample collection;small molecule;stem cells;therapeutic target;three dimensional structure;transcriptomics;treatment response;user-friendly;whole genome Bioinformatics: Characterizing Brain Tumor Data n/a NCI 10702672 1ZIABC011784-06 1 ZIA BC 11784 6 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 885997 NCI As a hybrid science that links biological data with techniques for information storage distribution and analysis to support multiple areas of scientific research including biomedicine Bioinformatics has been driven by the great acceleration in data-generation processes in biology. The NOB for the past years has enrolled over 1000 patients on the Natural History study which mandates the collection of tumor tissue as well as peripheral blood samples for germline DNA. This includes an unprecedented number of patients with rare CNS cancers. Moreover the sample collection is accompanied by careful and prospective clinical data acquisition allowing an unprecedented wealth of matched molecular and clinical data permitting a wide variety of analyses. Advances in the molecular analysis of genes proteins and metabolites have greatly improved our understanding of biological processes and disease and have increased our ability to monitor treatment response and stratify patients to improve treatment efficacy. Precision medicine facilitated by companion diagnostics is one of the driving forces accelerating the drug development process and improving therapeutic management. Launched in 2016 the NCI Genomic Data Commons (GDC) provides a single source for data from NCI initiatives and cancer research projects including TCGA and TARGET and the analytical tools needed to mine them. The new initiated NOB Bioinformatics has extended our bioinformatics and computational analyses efforts to utilize the GDC databases. For example using the TCGA data effectively doubles the number of GBMs we must work with and affords us the advantage of formulating computationally derived hypothesis based on one database with the ability to validate those hypotheses on a totally different database. For example a significant amount of time has been spent by NOB Bioinformatics on the databases to try and understand the biologically basis for the more aggressive phenotype and thus shorter survival of GBMs from older patients compared to those of younger GBMs. To date we have found a very interesting set of differentially expressed genes and miRNAs as well as specific genome wide methylation patterns and specific chromosomal number variants that differentiate older versus younger GBMs. We are in the process of using some of these findings to perform wet lab experiments to better annotate the significance of these findings. Furthermore in collaborated with NCI COMPASS program we analyzed and created genomic profiling data from the rare CNS tumors such as chordomas and dissected signal transduction pathways and aided in the design of novel therapeutics. In addition to characterizing the samples from patients enrolled the NOB Bioinformatics has generated genomic-scale analyses of the many human glioma initiating cells/glioma stem cells (GIC/GSC) lines produced in laboratory. This characterization is both at the primary cell level (including evolution through passages) as well as evaluation of the impact of different treatments (differentiation animal passages drug treatment etc) on the biological behavior of the cells. 885997 +Biotechnology; Cancer; Genetics; Precision Medicine; Prostate Cancer; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Urologic Diseases 3-Dimensional;Address;Adenocarcinoma;Antibody-drug conjugates;Apoptosis;Area Under Curve;Automobile Driving;Biological Assay;Biological Markers;Biology;Biopsy;Biopsy Specimen;Bypass;CCR;CD276 gene;CHD1 gene;Cell Count;Cell Cycle;Cell Line;Cell surface;Cells;Characteristics;Chronic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Complementary therapies;Coupled;Development;Disease;Dose;Double Strand Break Repair;Dropout;Drug Targeting;Drug resistance;Epithelial;Evolution;Future;Generations;Genes;Genomics;Genotype;Glucuronides;Goals;Growth;Histologic;In Vitro;Interferons;Libraries;Malignant neoplasm of prostate;Manuscripts;Metastatic Prostate Cancer;Methodology;Modeling;Molecular;Mutagens;Neoplasm Metastasis;Neurosecretory Systems;Normal tissue morphology;Organoids;Pathogenesis;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Physiological;Population;Pre-Clinical Model;Principal Component Analysis;Procedures;Proliferating;Proteins;Publications;RB1 gene;Recurrence;Refractory;Regimen;Reporting;Research;Resistance;Resolution;Sampling;Signal Transduction;Site;Solid;Solid Neoplasm;System;TP53 gene;Testing;Therapeutic;Tissues;Transforming Growth Factor beta;Translations;Treatment Efficacy;Tumor Antigens;Tumor Biology;Tumor Escape;Work;antibody conjugate;anticancer research;aurora kinase A;base;biomarker discovery;bone;cancer stem cell;cohort;comparative;coronavirus disease;disease heterogeneity;docetaxel;genotoxicity;high throughput screening;high-throughput drug screening;immunoregulation;improved;in vitro Model;in vivo;inhibitor;loss of function;matrigel;molecular phenotype;neuroendocrine phenotype;novel;patient derived xenograft model;patient population;patient prognosis;patient stratification;preclinical trial;predictive marker;progenitor;programs;prostate cancer model;protein expression;pyrrolobenzodiazepine;replication stress;resistance mechanism;responders and non-responders;response;response biomarker;screening;specific biomarkers;stem;stem cell population;stem cells;subcutaneous;success;targeted treatment;therapeutic target;transcription factor;transcriptomics;treatment response;tumor;tumor growth;tumor xenograft Mechanisms of pathogenesis in patient derived organoid models of prostate cancer n/a NCI 10702671 1ZIABC011782-06 1 ZIA BC 11782 6 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1401521 NCI I. A cancer stem cell population underlies a multi-lineage phenotype and drug resistance in prostate cancer: We have performed an in-depth analysis on an organoid culture established from a CCR patient biopsy sample exemplifying a resistance mechanism that bypasses an AR requirement via lineage plasticity resulting in the emergence of phenotypes spanning luminal epithelial and neuroendocrine phenotypes (NEPC). This work addresses the molecular phenotypes and lineage relationships as well as the therapeutic sensitivity of cells within a mixed lineage mPC tumor population. Some key accomplishments include: 1) The definition of multiple states of differentiation and their developmental hierarchy originating from bipotential and clonal stem/progenitor subpopulations. 2) A determination that the program driving the multi-lineage phenotype of the organoids included concurrently active luminal epithelial NE and stem cell-determining transcription factors. 3) The identification of specific molecular vulnerabilities in the stem/progenitor subpopulations to block tumor growth. The AURKA inhibitor alisertib caused a selective depletion of the stem/progenitors and combined inhibition of AURKA and AR blocked the growth of xenograft tumors. This work contributes significantly to our understanding of treatment-induced lineage plasticity in mPC by illuminating underlying cellular and molecular drivers of the phenomenon in near patient models. Importantly it demonstrates a potential treatment for certain types of CRPC. This work has been submitted for publication. II. A genotoxic antibody drug conjugate targeting CD276/B7H3 demonstrates efficacy across multiple biomarker defined classes of treatment refractory metastatic prostate cancer: We have analyzed the therapeutic response by our extensive organoid/PDX library of models to an antibody-drug conjugate that targets a tumor-specific antigen B7H3. B7H3 is a cell surface immunomodulatory protein often correlated with higher tumor grade and poor patient prognosis in several solid tumors. It is an attractive therapeutic target due to its frequent upregulated protein expression relative to normal tissue. We interrogated response to an anti-B7H3 targeted antibody conjugated to the pyrrolobenzodiazepine (PBD) genotoxic agent and identified predictive biomarkers of response. This analysis exemplifies the utility of comprehensively evaluating a large heterogeneous cohort. In addition to demonstrating broad efficacy for treatment-resistant forms of mPC we have identified multiple partially-overlapping specific biomarker classes of responsiveness which contribute to both a mechanistic understanding and also provide in-depth information for patient stratification. RB1-deficiency/ replication stress SLFN11 expression and chronic tumor intrinsic interferon (IFN) signaling are partially-overlapping significant predictors of B7H3-PBD response independent of tumor lineage. In addition models compromised in specific aspects of double-stranded break repair CHD1 and ATR loss of function were responsive even in the absence of the other biomarkers. We performed preclinical trials using four PDX models based on their RB1 SLFN11 and IFN signature status. B7H3-PBD eradicated large established subcutaneous tumors and metastasis and improved long-term overall survival in RB1-deficient tumors with or without SLFN11 expression but showed no response in an RB1+/SLFN11NEG tumor model. Collectively these findings support the potential of B7H3-PBD-targeted therapeutics for mPC. Of note at least one of the multiple above biomarkers is expressed in about 70% of CRPC clinical samples suggesting broad potential for mechanistically complementary treatment of tumors escaping current regimens. This work has been submitted for publication. III. High throughput drug screening: Because mPC/CRPC is a highly phenotypically and genotypically heterogenous disease our hypothesis has been that the effective translation of novel treatments requires a representative cohort of models in order to discover rational response classes and to effectively predict efficacy in treatment-resistant mPC patient populations. We have implemented a high throughput screening (HTS) approach in order to efficiently uniformly and comparatively assay a large number of drugs encompassing various mechanisms of action. Several conclusions from the HTS are summarized below. Unfortunately in vivo confirmatory studies were delayed due to COVID which has postponed the submission of a manuscript. High-throughput drug screening on a cohort of 30 patient-derived organoid models covering 5 histological phenotypes and 6 sites of metastasis has been completed (Fig. 1). Full transcriptomic sequencing of generation 1 organoids was conducted on the entire model cohort to aid in future biomarker discovery based on baseline transcriptomics shown in a principal component analysis plot (PCA) in Fig. 2. Adenocarcinoma (ARPC) models cluster together and with their matched recurrence ARPC models that were previously experimentally castrated (designated EXP-CR). Neuroendocrine models (NE) cluster together; amphicrine models (AMP) expressing both ARPC and NE markers reside in the space between ARPC and NE clusters and the single double negative (DNPC) model shows no overlap with any other histological phenotype. An important feature of this HTS was the screening in 3D solid Matrigel which enables a closer resemblance to physiological tumor biology. Each of the 80 compounds was tested at 10 doses resulting in the ability to generate entire drug response curves and enabling the use of Area Under Curve (AUC) as a continuous variable of response in organoid-drug pairs which maximized resolution in assigning responder and non-responder categorizations accurately. The drug response patterns demonstrated that the majority of compounds tested showed either single model-specific responses or a general lack of efficacy. However roughly 20 compounds demonstrated a range of responses providing opportunity for further analysis into characteristics governing resistance and sensitivity. Docetaxel (DTX) is a relatively widely used and proven efficacious drug for mPC and provided the largest observed range in AUC responses. Strikingly for a proportion of drugs including DTX we observed significant correlations between and among particular drugs targeting cell cycle apoptosis and cell replication pathways. This cluster of therapeutics demonstrated common response and nonresponse patterns across multiple models suggesting a similarity in the biology governing resistance and sensitivity among these correlated response patterns. Importantly removing RB1/TP53 null models largely conserved this cluster of co-efficacious compounds suggesting this observation holds true for ADPC and is not driven by replication stress or RB1-loss-dependent lineage/phenotypic differences. Because DTX responses overlapped with the majority of correlated compounds in the cluster of co-efficacious compounds it was used as the basis for building transcriptomic contrasts from sensitive versus resistant models in order to investigate the underlying mechanisms of vulnerability. Overrepresentation of differential gene analysis between responsive and nonresponsive RB1/TP53- intact models revealed strong enrichment in nonresponsive models for glucuronidation and HNF1A transcription factor driven activity. Responsive models demonstrated an enrichment of cell-cycle YAP/TAZ TGFbeta *TRUNCATED* 1401521 +Cancer; Hematology Animals;Antibodies;Autoimmune;Biological Phenomena;Blood;Bone Marrow;Bromodeoxyuridine;Cancer Burden;Cell Differentiation process;Cell Proliferation;Cells;Choristoma;Collaborations;Cytometry;Cytotoxic T-Lymphocytes;DNA biosynthesis;Detection;Development;Disease;Erythrocytes;Experimental Models;Genetic;Goals;Heavy Metals;Hematopoiesis;Homeostasis;Human;Immune;Immune system;Immunologics;Immunology;Inflammatory;Kinetics;Lymphoid Cell;Mathematics;Metals;Methodology;Mus;Myeloid Cells;Noise;Nucleotides;Organ;Organism;Physiologic pulse;Proliferating;Resolution;Rest;Signal Transduction;Source;System;T-Lymphocyte;Thymus Gland;Tissues;United States National Institutes of Health;Vascular blood supply;experimental study;flexibility;hematopoietic differentiation;instrument;interest;lymphoid organ;mathematical model;monocyte;stem;tool;tumor;tumor immunology;tumorigenesis Dynamics of hematopoietic differentiation n/a NCI 10702670 1ZIABC011781-06 1 ZIA BC 11781 6 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 445550 NCI "We have introduced a new methodology using a combination of CyTOF immune profiling IdU pulse-chasing and mathematical modeling to derive a systemic understanding of immune homeostasis. CyTOF is a recently-acquired instrument (within the NIH-wide Center for Human Immunology) that performs mass cytometry: it is similar to the classical flow cytometer except that its detection capacity relies on the mass-cytometric resolution of heavy metals tagging antibodies. We have implemented CyTOF within NIH and demonstrated its capacity to achieve immune profiling with a 40+ panel of antibodies (e.g. targeted against key markers of hematopoietic differentiation). We have also implemented IdU Pulse-chasing to mark proliferating cells (by incorporation of the metal-tagged nucleotide during DNA replication) and to detect its dilution by cell proliferation or differentiation (by relying on the mass-cytometric capacity of CyTOF): IdU pulse-chasing combines the non-perturbative high-signal noise of BrdU pulse-chasing with the deep immunological profiling of CyTOF. Finally we developed a mathematical framework to model the experimental results obtained from CyTOF IdU pulse-chasing: our quantitative analysis enables us to ""animate"" our network of immune cells and to quantitate the rates at which cells differentiate We have applied our methodology to delineate the differentiation of NK T cells in the thymus (in collaboration with Dr. Hyun Park from EIB-NCI) of monocytes (in collaboration with Dr. Frederic Geissmann from Memorial Sloan-Kettering) and other systems are under consideration. We are demonstrating the flexibility and resolution power of our new methodology to better analyze the systemic perturbation of hematopoiesis occurring during tumor development (in collaboration with Dr. Romina Goldzmid from CIP-NCI). One major finding so far has been that monocytes of the mouse immune system do not differentiate only in the blood of these animals but follow a parallel dynamic of differentiation in the bone marrow and in the lymphoid organs. This implies that the main source of blood monocytes may not reside in the blood itself but rather come from the bone marrow. Such result (obtained without perturbation at homeostasis) challenges the common understanding of blood monocyte differentiation as obtained from genetic perturbations. A second finding was that NKT2 cells (i.e. Type 2 natural-killer T cells) do not derive from NKT1 cells but rather have a direct (yet inefficient) path of differentiation from immature NK T cells. Again our kinetic analysis of pulse-chase experiments revealed an alternative path of differentiation that was partially uncovered by genetic perturbation. All in all this project offers new tools to dissect the dynamics of differentiation and homeostasis in the immune system." 445550 +Biotechnology; Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Address;Affect;Amino Acids;Amphipathic Alpha Helix;Antiviral Therapy;Binding;Categories;Cell fusion;Cell membrane;Cell-Matrix Junction;Cells;Cellular Membrane;Cholesterol;Development;Evolution;Exhibits;Glean;Glycoproteins;Goals;HIV-1;Human;IFITM1 gene;Infection;Influenza A virus;Integral Membrane Protein;Interferons;Journals;Measures;Mediating;Membrane;Membrane Fusion;Molecular Biology;Murine leukemia virus;Mutation;Oncogenic;Pathogenicity;Physiological;Play;Process;Protein Family;Proteins;Publishing;RNA Viruses;Reporting;Retroviridae;Role;Route;Signal Transduction;System;Therapeutic Intervention;Viral Proteins;Virion;Virus;Work;Zika Virus;base;biophysical properties;cell type;experimental study;gene therapy;insight;mutant;novel;preservation;scaffold;therapeutic target;transmission process;tumorigenic Mechanisms of Virus Entry into Cells and Antiviral Barriers Limiting Entry n/a NCI 10702668 1ZIABC011779-06 1 ZIA BC 11779 6 15201721 "COMPTON, ALEX " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 671484 NCI We published two articles pertaining to this project in 2020 (Ahi et al. mBio 2020; Rahman et al. eLife 2020) and one article in 2022 (Rahman et al. Journal of Molecular Biology 2022). Our work provides extensive insight into the function of IFITM proteins as well as the extended CD225 protein family to which they belong and will provide leverage for the development of new antiviral therapies. Notably we identified an amphipathic alpha helix that is required for the antiviral activity of IFITM3 against multiple viruses including HIV-1 Zika virus and Influenza A virus (Chesarino Compton et al. EMBO Reports 2017). Subsequently we showed that the amphipathic helix is required for the ability of IFITM3 to alter the biophysical properties of cellular membranes (membrane rigidity and curvature) (Rahman et al. eLife 2020). Most recently we demonstrated that the amphipathic helix exhibits direct cholesterol binding activity providing a possible explanation for its impacts on membranes and a plausible mechanism for how IFITM3 restricts membrane fusion pore formation (Rahman et al. Journal of Molecular Biology 2022). We now plan to directly measure cholesterol binding by IFITM3 contributes to its effect on membrane rigidity a feature that is functionally tied to its capacity to inhibit virus entry. Furthermore we plan to assess the functional role played by the amphipathic helix in the oncogenic functions of IFITM3 including its ability to act as a scaffold for PI3K signaling at the plasma membrane. Our findings will provide insight into the poorly characterized tumorigenic roles played by this family of proteins and provide therapeutic targets for inactivation. 671484 +Biotechnology; Breast Cancer; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Digestive Diseases; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Health Disparities; Immunotherapy; Lung; Lung Cancer; Minority Health; Orphan Drug; Ovarian Cancer; Pancreatic Cancer; Rare Diseases; Uterine Cancer; Women's Health Antibodies;Antigen Targeting;Antigens;Antineoplastic Agents;Autologous;Breast;CAR T cell therapy;CEA Family Protein;Cancer Patient;Cancer Vaccines;Carcinomatosis;Cells;Cellular immunotherapy;Cervical;Chemical Models;Clinic;Clinical;Clinical Research;Clinical Trials;Colorectal Cancer;Combined Modality Therapy;Disease Resistance;Endometrial;Endometrial Carcinoma;Engineering;Generations;Genes;Genetic;Goals;Greater sac of peritoneum;HLA Antigens;Half-Life;Head and Neck Cancer;Hour;Human;Immune;Immune response;Immune system;Immunize;Immunohistochemistry;Immunologic Surveillance;Immunotherapeutic agent;In Vitro;Interferon Type II;Interferon-alpha;Interferons;Intravenous;Location;Longevity;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Membrane Glycoproteins;Membrane Proteins;Mesothelioma;Messenger RNA;Methods;Modification;Monoclonal Antibodies;Mucinous;Natural Immunity;Natural Killer Cells;Normal Cell;Ovarian Serous Adenocarcinoma;Pancreatic Adenocarcinoma;Pathology;Pathway interactions;Patients;Peritoneal;Peritoneal Fluid;Phase;Phase I Clinical Trials;Play;Preparation;Process;Prognosis;Property;Proteins;Recombinants;Relapse;Risk;Role;Route;Safety;Sampling;Series;Serous;Signal Transduction;Site;Solid Neoplasm;Specimen;Stains;T-Lymphocyte;TNF gene;TNFSF10 gene;Testing;Therapeutic;Therapeutic antibodies;Time;Tissue Microarray;Tissue Sample;Tissues;Tumor Antigens;Tumor Cell Line;Viral;Woman;adaptive immunity;antigen binding;base;cancer cell;cancer initiation;cancer type;cell growth;chimeric antigen receptor T cells;cytokine;design;extracellular;fighting;human tissue;immune activation;improved;innovation;intraperitoneal;malignant breast neoplasm;member;mesothelin;monocyte;mouse model;neoantigens;neoplastic cell;novel;pembrolizumab;peripheral blood;phase I trial;preclinical study;receptor;safety testing;side effect;synergism;triple-negative invasive breast carcinoma;tumor Immune cell control of ovarian cancer n/a NCI 10702667 1ZIABC011775-06 1 ZIA BC 11775 6 9692487 "ANNUNZIATA, CHRISTINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 605550 NCI Goal 1: Monocytes It has been shown in mouse models of chemically induced cancer that Interferons (IFNs) are important in the immune-surveillance and immune-editing of tumors. While IFNs alpha (IFNa) and gamma (IFNg) have been shown to have potent anti-neoplastic and anti-proliferative properties in vitro they have shown little efficacy in the clinic. Our observations that IFNs play an important role in killing tumor cells in the presence of monocytes suggests that combination therapy of monocytes and IFNs may have a more potent effect than IFNs alone. We and others have shown that IFNs are more potent anti-cancer agents when used in combination with monocytes isolated from the peripheral blood. Based on these studies we have completed a Phase 1 clinical trial of immune cell therapy using autologous transfer of ex vivo monocytes stimulated with IFNs into the peritoneal cavity of patients who have resistant disease. We are now in the process of defining the mechanism of IFN-induced monocyte killing of ovarian cancer cells. we found that IFNs induce a unique set of genes regulated in monocytes that occurs only with the combination of IFNa and IFNg and this signature may be driven by the TNF/TRAIL pathway. I have the ability to examine tissue and peritoneal fluid samples from women on our phase 1 trial receiving intraperitoneal autologous monocytes stimulated with IFNs providing another platform for defining dual-IFN induced mechanisms of monocyte activity in the context of the complete immune response. Goal 2: ADCC A monoclonal antibody was developed against a semi-purified human membrane protein preparation derived from cancer tissues. The protein preparation was used in previous clinical trials for use as a cancer vaccine where it was demonstrated to be safe and efficacious. The antibody NEO201 was shown to react with the immunizing antigen preparation as well as several human tumor cell lines and tissues from colorectal pancreas lung and ovarian cancer patients. NEO201did not cross-react significantly with normal human tissues thus representing a potential therapeutic product. The target of NEO201was studied and shown to be related to CEACAM-5/6 a member of the carcinoembryonic antigen family of proteins which has been shown to be associated with several cancer types. Endometrial breast and ovarian cancer have specifically been found to have increased expression in human tumor samples. In endometrial cancer 45/88 (51%) of tissue samples show reactivity through immunohistochemistry 38/72 (53%) of breast and although 16/129 (12%) of ovarian cancer specimens stain positive in this series two subtypes mucinous 15/22 (68%)and signet cell 2/2 (100%) ovarian cancers shows significant reactivity (50%) in an IHC of ovarian cancer tissue arrays representing over 600 samples. Our phase 1 clinical trial is completed demonstrating safety and preliminary activity of the NEO201 in patients with solid tumors likely to express the target. The phase 2A expansion is ongoing testing NEO201 in combination with pembrolizumab in cervical endometrial lung and head/neck cancers. Goal 3: T cells Mesothelin (MESO) is a 41-kD cell surface glycoprotein that is highly expressed in many human cancers including high grade serous adenocarcinoma of the ovary (75%) pancreatic adenocarcinoma (85%) triple negative breast cancer (66%) epitheliod mesothelioma (95%) of patients with MESO-expressing malignancies. While the function of MESO on normal cells is non-essential the expression of MESO on cancer cells may contribute to the pathology of cancer with higher expression associated with poorer prognosis increased metastatic spread and activation of cell growth pathways. A tremendously innovative immunotherapeutic approach is the use of chimeric antigen receptor-modified T cells (CAR). CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that allows the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When expressed in T cells CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. The most widely used method for T-cell modification is viral transduction integration and expression of a genetic construct that expresses the chimeric receptor. Another approach to the generation of CAR T-cell therapies that may provide potent anti-tumor activity and improve safety and product preparation involves the use of mRNA to modify T-cells. Using mRNA to re-engineer a patient's T-cells to express a tumor-antigen targeted CAR T-cell can be accomplished in a few hours allowing on-site preparation and deployment to multiple treatment locations. mRNA CAR T-cells have the safety factor of a limited lifespan with half-life times similar to antibody therapeutics and lack of rapid immune activation and proliferation limiting the risk for severe cytokine release side effects. Meso-targeted CAR T-cells using mRNA have demonstrated significant promise in preclinical studies and clinical studies by intratumoral intraperitoneal and intravenous of routes of administration. We completed a phase 1 clinical trial testing the safety of intraperitoneal administration of the CARMA MCY-M11 in women with ovarian cancer and peritoneal carcinomatosis. 605550 +Biotechnology; Cancer; Clinical Research; Genetics; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases; Urologic Diseases Adult;Cells;Childhood;Childhood Solid Neoplasm;Clinic;Clinical;Clinical Research;Collaborations;DNA Damage;DNA Repair;Data;Development;Developmental Therapeutics Program;Disease;Enzymes;Ewings sarcoma;Extramural Activities;Genetic Screening;Goals;Heat-Shock Proteins 90;Hematologic Neoplasms;Lead;Malignant Childhood Neoplasm;Metabolic;Metabolism;Modeling;Molecular;National Center for Advancing Translational Sciences;New Agents;Oncogenes;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Population;Pre-Clinical Model;Process;Research Personnel;Rhabdomyosarcoma;Role;Screening procedure;Site;Testing;Topoisomerase;Translating;Translations;Urologic Oncology;Work;base;cancer cell;chemotherapy;childhood sarcoma;cohort;combinatorial;experience;first-in-human;human study;in vivo;inhibitor;interest;lactate dehydrogenase A;metabolic abnormality assessment;neoplastic cell;nicotinamide phosphoribosyltransferase;novel;novel therapeutics;patient population;phase 1 testing;pre-clinical;preclinical study;resistance mechanism;sarcoma;standard of care;targeted treatment;tumor metabolism Development and translation of novel therapies for pediatric sarcoma n/a NCI 10702666 1ZIABC011774-06 1 ZIA BC 11774 6 15201715 "HESKE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1274610 NCI Tumor Metabolism Studies: Our lab is interested in identifying specific metabolic vulnerabilities in pediatric sarcomas. We have previously identified lactate dehydrogenase A (LDHA) as an oncogene-driven vulnerability in Ewing sarcoma as well as PHGDH as an additional metabolic vulnerability in Ewing sarcoma. Our group has continued to study the mechanisms behind NAD metabolism in cancer cells. Specifically we are using inhibitors of the rate-limiting enzyme in the NAD salvage pathway nicotinamide phosphoribosyltransferase (NAMPT) in preclinical models of pediatric solid tumors. We initially identified the exquisite sensitivity of Ewing sarcoma cells to these inhibitors as part of a collaboration with The National Center for Advancing Translational Science (NCATS). Based on this work we have continued our preclinical studies to better understand role of NAD and NAMPT in Ewing sarcoma and in other pediatric solid tumors. We have formed a collaboration with investigators in the Urologic Oncology Branch who also have an interest in targeting this pathway. To date there have been no clinical studies of NAMPT inhibitors in any pediatric cancers. We are in the process of developing a pediatric trial for this patient population using OT-82 a clinical NAMPT inhibitor currently undergoing phase 1 evaluation in an extramural first-in-human study for hematologic malignancies. DNA Damage and Repair Studies: Project 1. In FY2021 the first-in-human trial of PEN-866 a novel HSP90 inhibitor-SN38 drug conjugate which acts as to inhibit topoisomerase 1 and cause prolonged DNA damage in tumor cells accrued additional patients. The rationale for this study for which NCI was a lead site was based in part on preclinical work done in our lab demonstrating superior activity and durability of PEN-866 as compared to other standard of care chemotherapy in models of pediatric sarcoma. The study was conducted in collaboration with the Developmental Therapeutics Branch at NCI to target an adult population for the first-in-human experience. Based on our preclinical data in sarcoma and the available phase 1 data generated by the study we have developed a combination study using PEN-866 with chemotherapy which is we expect will be open shortly. This study incorporates disease-specific expansion cohorts for rhabdomyosarcoma and Ewing sarcoma. In the lab we have continued to study PEN-866 in Ewing sarcoma and rhabdomyosarcoma with a focus on identifying and overcoming potential mechanisms of resistance as part of a collaboration with the Developmental Therapeutics Branch and the Urologic Oncology Branch. Project 2. Related to our work with the topoisomerase 1 inhibitor PEN-866 we are evaluating several novel topoisomerase 1 inhibitors (the indenoisoquinolines) in our pediatric sarcoma models against the current standard of care topoisomerase agents for these diseases. This project is part of a collaboration with the Molecular Pharmacology Group in the Developmental Therapeutics Branch. Project 3. Our group has identified several potential new agents and combinations of agents that impact the DNA-repair machinery of cancer cells and are particularly effective in preclinical models of Ewing sarcoma. We are in the process of conducting in vivo studies to further describe the effects of these inhibitors. 1274610 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Neurosciences; Rare Diseases Central Nervous System Neoplasms;Clinical;Disease;Future;Genetic;Malignant neoplasm of central nervous system;Natural History;Patients;Phase;Protocols documentation;Specimen;Syndrome;design;high risk;interest;neuro-oncology;tumor Natural History and Specimen Banking for Patients with CNS Tumors n/a NCI 10702663 1ZIABC011768-06 1 ZIA BC 11768 6 15201740 "ARMSTRONG, TERRI S." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 746895 NCI This protocol is designed to meet an unmet need in neuro-oncology by evaluating patients with CNS tumors throughout their disease course. The protocol will evaluate patients with tumors of the central nervous system (CNS) who appear to be probable candidates for future protocol entry have disease manifestations that are of unique scientific interest importance and/or educational value or who have understudied tumors with unknown or unclear natural history. Patients with known genetic syndromes at high risk of developing CNS cancers will also be evaluated. 746895 +Biotechnology; Cancer; Genetics AKT1 gene;Animals;Body fat;Brain;Cancer Biology;Cell physiology;Cessation of life;Cholesterol;DNA Binding;Data;Gene Expression;Genes;Genetic Transcription;Goals;HSF1;Heat-Shock Response;Hepatomegaly;Human;Investigation;Laboratories;Lipids;Liver;Malignant Neoplasms;Mediating;Megalencephaly;Membrane;Messenger RNA;Metabolic;Modeling;Modification;Molecular;Mus;Oncogenic;Outcome;PI3K/AKT;PTEN gene;Phosphorylation;Physiological;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Renal carcinoma;Research;Research Project Grants;Role;SHH gene;STK11 gene;Sampling;Signal Transduction;Small Interfering RNA;Stress;Tissues;Tumor Suppressor Proteins;Xenograft procedure;amyloidogenesis;base;cancer addiction;cancer cell;cancer therapy;experimental study;in vivo;inhibitor;knock-down;lipid biosynthesis;lipid metabolism;malignant breast neoplasm;melanoma;novel;novel therapeutic intervention;postnatal;preservation;promoter;protein complex;proteostasis;proteotoxicity;sensor;smoothened signaling pathway;steroid hormone;transcription factor;tumor Preservation of Proteomic Stability and Promotion of Protein Lipidation by HSF1 n/a NCI 10702662 1ZIABC011767-06 1 ZIA BC 11767 6 15201738 "DAI, CHENGKAI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1263691 NCI Aim1: To examine the role of HSF1 in sustaining tissue overgrowth driven by oncogenic PI3K/AKT signaling. Our preliminary results show that the PI3K/AKT signaling cascade is required for activation of the HSR/PSR by heat shock (HS) in MEFs and for constitutive HSF1 activation in malignant cells. Importantly AKT physically interacts with HSF1. Furthermore AKT phosphorylates HSF1 at Ser230 and expression of the constitutively active AKT1 or loss of the tumor suppressor PTEN is sufficient to activate HSF1. By contrast AKT inhibitors block HSF1 Ser230 phosphorylation and its DNA binding to HSP gene promoters. Furthermore constitutively active PI3K/AKT signaling causes overgrowth or enlargement of both brains and livers in mice conditions similar to megalencephaly and hepatomegaly in humans respectively leading to rapid postnatal death. Importantly simultaneous deletion of Hsf1 in both tissues impedes overgrowth and prolongs animal survival. Moreover Hsf1 deletion also markedly impedes the liver overgrowth in mice deficient for Pten a tumor suppressor negatively regulating PI3K activity prolonging their survival. Our results further show that constitutively active PI3K/AKT disrupts proteostasis and induces proteotoxic stress which is markedly heightened by Hsf1 deficiency. Based on these preliminary results we plan to interrogate: 1) whether HSF1 is a new physiological substrate for AKT; 2) whether and how HSF1 suppresses proteotoxic stress induced by constitutive activation of PI3K/AKT signaling and thereby promotes tissue overgrowth in vivo; and 3) the molecular mechanisms underlying disrupted proteostasis in overgrown tissues. Aim 2: To examine the role of HSF1 in promoting lipid metabolism and protein lipidation. Our previous studies revealed that HSF1 is a physiological substrate for AMPK a key cellular metabolic sensor and that the AMPK-mediated Ser121 phosphorylation negatively regulates HSF1 activation. Now our preliminary results using HSF1 deletion constructs deficient for transcriptional activity show that just like the wild-type HSF1 they interact with AMPK and suppress AMPK Thr172 phosphorylation a modification key to its activation indicating a transcription-independent mechanism of action of HSF1. Conversely Hsf1 deficiency causes AMPK activation which is blocked by the AMPK inhibitor. Interestingly our results show that HSF1 can be co-precipitated with both AMPK and LKB1 revealing a LKB1-AMPK-HSF1 protein complex. Furthermore in human kidney and breast cancer samples higher HSF1 mRNA levels are inversely correlated with AMPK Thr172 phosphorylation congruent with the results of our mechanistic studies. Our preliminary data show that Hsf1 deficiency and enhanced HSF1 expression result in diminished and heightened cellular lipid content respectively suggesting that HSF1 promotes lipogenesis to support malignancy. Strikingly Hsf1-deficient mice display markedly reduced whole-body fat mass. Importantly these effects of HSF1 on cellular lipid content and body fat mass can be markedly rescued by either AMPK inhibitors or siRNA-mediated AMPK knockdown suggesting that the lipogenic effect of HSF1 is largely mediated via AMPK suppression. At the molecular level HSF1 deficiency causes inactivation of SREBP1c a key transcription factor controlling lipogenic gene expression in addition to inactivation of ACC. Cholesterol is an important lipid implicated in many key cellular processes including membrane composition signaling transduction and synthesis of steroid hormones. Congruent with diminished cellular lipid content our results reveal a markedly reduced cellular cholesterol level caused by HSF1 deficiency which is rescued by AMPK inhibition. Based on these preliminary results we plan to investigate: 1) the molecular mechanisms underlying AMPK suppression by HSF1; 2) whether HSF1 promotes cholesteroylation of sonic hedgehog (SHH) proteins and supports SHH signaling; and 3) whether HSF1 promotes lipid metabolism and SHH cholesteroylation in xenografted human melanoma models. 1263691 +Cancer; Cancer Genomics; Genetics; Human Genome Acute;Bacteria;Binding;Biogenesis;Cancer cell line;Cell Fate Control;Cell Proliferation;Cells;Chemistry;Chronic;Comparative Study;Development;Dioxygenases;Disease;Energy Metabolism;Environment;Enzymes;Family;Follow-Up Studies;Fumarates;Gene Expression;Genome;Goals;Growth;Health;Homeostasis;Human;Isocitrate Dehydrogenase;Malignant Neoplasms;Maps;Measures;Metabolic;Metabolism;Methods;Modification;Molecular;Mutate;Pathway interactions;Phenotype;Play;Positioning Attribute;Protocols documentation;RNA;RNA methylation;Regulation;Regulator Genes;Role;Succinate Dehydrogenase;Succinates;Surveys;Tissues;Transfer RNA;Translations;alpha ketoglutarate;cancer cell;cancer type;cellular engineering;epigenome;experimental study;improved;inducible gene expression Regulation of RNA biogenesis and function by RNA modifications n/a NCI 10702661 1ZIABC011766-06 1 ZIA BC 11766 6 15201736 "DE OLIVEIRA RODRIGUES BATISTA, PEDRO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1080635 NCI Uncontrolled cell proliferation is a hallmark of cancer and is often accompanied by reprogramming of energy metabolism. In addition to providing the building blocks required for uncontrolled proliferation metabolic reprograming interferes with gene expression enabling cancer cells to evade mechanisms that maintain tissue homeostasis. Imbalances in the metabolite pool driven by metabolic rewiring create an environment that inhibits activity of regulators of gene expression such as the alpha ketoglutarate (aKG)-dependent dioxygenase family. This family of enzymes includes the RNA demethylases FTO ALKBH1 and ALKBH5 important regulators of RNA methylation. Recent studies have demonstrated that RNA methylation plays an important role in cell identity and is implicated in cancer establishment and progression. Fumarate Succinate and (R)-2-hydroxyglutarate known to accumulate in multiple types of cancer are examples of metabolites known to inhibit 2-oxoglutarate (2OG)-dependent dioxygenase enzymes. To understand how energy reprograming remodels gene expression through modulation of RNA methylation dependent pathways we are performing comparative studies between established cancer cell lines (with chronic accumulation of these metabolites) with cells engineered to allow for acute inactivation of Fumarate Hydrogenase (FH) and Succinate Dehydrogenase (SDH) or inducible expression of mutated isocitrate dehydrogenase 1 (IDH1). This approach will allow us to understand how accumulation of fumarate (loss of FH) succinate (loss of SHD) or 2-HG (expression of mutated IDH1) contribute to the establishment and progression of cancer phenotype. Metabolite analysis shows similar metabolite accumulation in both groups of cells. Preliminary experiments suggest that changes in gene expression induced by chronic or acute accumulation of oncometabolites are distinct. For follow up studies we have established protocols to measure and map multiple types of RNA methylation including m6A m6Am 5mC m1A and Am. Modifications in tRNAs are critical to maintain fidelity in translation. The modification 4SU at position 8 of prokaryotic tRNA has been shown to respond to change in growth rate. In order to understand how the 4SU modification is regulated and determine if a similar modification is present in eukaryotic RNAs we develop a method that relies on orthogonal chemistry to capture 4SU modified tRNAs. With this method we are able to identify 4SU modified tRNAs at a genome level and easily survey multiple growth conditions greatly improving our ability to study this modification. Moving forward we will use this method to identify 4SU modified tRNAs in bacteria with a negative impact on human health. 1080635 +Autoimmune Disease; Cancer; Genetics Autoimmune;Autoimmune Diseases;Autoimmune Responses;Autoimmunity;CD4 Positive T Lymphocytes;Cell Differentiation process;Cells;Cessation of life;Clinical;Combined Modality Therapy;Cytokine Receptors;Development;Disease;EGR2 gene;FOXP3 gene;Family;Future;Gene Expression Profiling;Genes;Genetic Transcription;Goals;Immune;Infection;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-17;Lead;Mediating;Multiple Sclerosis;Mus;Organ;Pathogenesis;Pathogenicity;Pathway interactions;Peripheral;Pharmaceutical Preparations;Pharmacology;Psoriasis;Resolution;Rheumatoid Arthritis;Role;T-Lymphocyte;Testing;Therapeutic;Transcriptional Regulation;Treatment Efficacy;cytokine;genetic signature;immunoregulation;improved;novel;overexpression;premature;programs;transcription factor Transcriptional regulation of inflammatory and autoimmune responses n/a NCI 10702660 1ZIABC011765-06 1 ZIA BC 11765 6 11592667 "LAZAREVIC, VANJA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1052527 NCI TH17 cells have been implicated in the pathogenesis of most common autoimmune and inflammatory diseases. However not all TH17 cells are pathogenic. The goal of this project is to identify novel transcriptional regulators that regulate differentiation of TH17 cells with immunoregulatory versus pathogenic effector functions. We have focused on the role of Egr family of transcription factors in TH17 differentiation because high resolution transcriptional profiling predicted that Egr1 and Egr2 could function as positive regulators of TH17 differentiation program. Our studies have shown that the transcription factor Egr2 but not Egr1 is a positive regulator of TH17 cell differentiation. Egr2 augmented the expression of the TH17 lineage-signature genes: Rorc Il17a Il17f and Il22. Interestingly over-expression of Egr2 in non-pathogenic TH17 cells induced the expression of pathogenicity-associated genes (e.g. Il22 Tbx21 Ccl3) and augmented the expression of immunoregulatory genes (e.g. Foxp3 Il9 Il10). To determine whether Egr2 was required for the development of immunoregulatory or pathogenic TH17 cells we have generated mice with peripheral T cell-specific deletion of Egr2 (Egr2f/f hCD2-Cre+). In our future studies we investigate the effects of T cell-specific Egr2-deficiency on the differentiation and effector function CD4+ T cells in the context of infections and autoimmunity. 1052527 +Cancer; Cancer Genomics; Genetics; Human Genome; Prostate Cancer; Urologic Diseases Affinity;Anoikis;Apoptosis;Binding;Biological Assay;Code;Cyclic AMP-Dependent Protein Kinases;DNA Sequence Alteration;Data Set;Development;Event;Family member;Frequencies;G Protein-Coupled Receptor Signaling;G-Protein-Coupled Receptors;Gene Amplification;In Vitro;Investigation;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Molecular;Neoplasm Metastasis;Oncogenic;PKA inhibitor;Pathway interactions;Phenotype;Phosphotransferases;Physiological;Proteins;Research;Resistance;Role;Sampling;Signal Transduction;Skin;Supporting Cell;The Cancer Genome Atlas;Therapeutic Intervention;Time;advanced prostate cancer;cancer cell;cancer initiation;cell motility;new therapeutic target;overexpression;prostate cancer cell line;prostate cancer progression;therapeutic development;tumor;tumor growth G-protein-coupled receptor signaling in cancer development and treatment n/a NCI 10702659 1ZIABC011764-06 1 ZIA BC 11764 6 15201732 "IGLESIAS-BARTOLOME, RAMIRO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 283744 NCI The PKA inhibitor (PKI) family members PKIalpha PKIbeta and PKIgamma bind with high affinity to PKA and block its kinase activity modulating the extent and duration of PKA mediated signaling events. While PKA is a well known regulator of physiological and oncogenic events the role of PKI proteins in these pathways has remained elusive. I have demonstrated that overexpression of the PKA binding domain of PKIalpha (PKIalpha1 24) in the skin is sufficient to induce BCC formation. My results suggested that expression levels of endogenous PKIs could have a role in mediating tumor formation or suppression by modulating PKA activity. Indeed analysis of PKI genomic alterations in the TCGA dataset indicated that amplification of the gene coding for PKIalpha (PKIA) is common in various cancers with the greatest frequency in prostate cancer samples. Further analyzing PKIA gene amplifications indicated a correlation with a significant reduction in time to prostate cancer progression. Furthermore in vitro metastasis assays using prostate cancer cell lines revealed that PKIA supports cell migration and confers resistance to detachment-induced apoptosis (anoikis). Taken together we hypothesize that PKIA potentiates prostate cancer progression and metastasis. Our ongoing investigations are focused on identifying the molecular mechanisms involved in these prostate cancer phenotypes to better clarify the role of PKIA in potentiating metastasis and tumor growth; potentially revealing novel therapeutic targets in advanced prostate cancer. 283744 +Cancer; Genetics; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human Basal Cell;Basal cell carcinoma;Cell Maintenance;Cell Nucleus;Cell surface;Cells;Coupled;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Disease;Dominant-Negative Mutation;Drug Targeting;Epithelial Cells;Erinaceidae;Family;G-Protein-Coupled Receptors;GTP-Binding Proteins;Genetic Transcription;Goals;Growth;Heterotrimeric GTP-Binding Proteins;Homeostasis;Human;Intervention;Libraries;Malignant Neoplasms;Mediating;Mus;NF-kappa B;Nuclear;Oncogenic;Pathologic;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Physiological Processes;Play;Pre-Clinical Model;Production;Proteins;RNA Interference;Regulation;Repression;Research;Role;STAT3 gene;Second Messenger Systems;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Small Interfering RNA;Therapeutic;Tissues;cancer cell;drug development;efficacy study;epithelial stem cell;inhibitor;keratinocyte;knock-down;migration;mouse model;paralogous gene;protein function;receptor;stem cell differentiation;stem cell fate;stem cell model;stem cells;tissue regeneration;transcription factor;transcriptome sequencing;tumor Signaling pathways regulating stem cell fate decisions n/a NCI 10702658 1ZIABC011763-06 1 ZIA BC 11763 6 15201732 "IGLESIAS-BARTOLOME, RAMIRO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 662069 NCI This project focuses on generating a mechanistic signaling framework for the regulation of epithelial cells by GPCRs the heterotrimeric G proteins Galphas and Galphai and their downstream pathways. Galphas- and Galphai-coupled GPCRs either stimulate (Galphas) or inhibit (Galphai) production of the intracellular second-messenger cyclic AMP (cAMP). Utilizing basal-skin keratinocytes as a stem cell model we have demonstrated that regulation of cAMP and PKA by Galphas and Galphai is essential for epithelial stem cell differentiation. More recently to study the receptors that might modulate epithelial stem cell fate upstream of heterotrimeric G-proteins we performed RNA sequencing (RNAseq) analysis in primary human keratinocytes (HEK). We identified 53 GPCRs expressed at significant levels. Using a pooled interference RNA (siRNA) library we found that knockdown of specific GPCRs that couple to Galphai leads to reduced proliferation in keratinocytes. We are currently elucidating the downstream signaling mechanisms responsible for the effect of these GPCRs in keratinocyte proliferation and migration. Since GPCRs are attractive targets for drug development identifying the role of specific receptors in epithelial cell fate will allow us to identify potential GPCRs that can be targeted to regulate stem cell activity. Downstream of GPCR activity we have found that Galphas and Galphai signaling in the skin are central regulators of YAP1 translocation to the nucleus and activation of downstream targets. YAP1 and its paralog TAZ (WWTR1) are co-transcriptional regulators downstream of the Hippo pathway essential for skin homeostasis and epithelial stem cell maintenance. YAP1 and TAZ are also implicated in skin cancer formation and this axis has been listed as one of the top 10 signaling pathways altered in human cancer. Interaction with TEAD transcription factors is the primary way YAP1 and TAZ execute their regulatory and oncogenic functions. As such efforts are underway to develop YAP1/TAZ-TEAD interaction inhibitors to treat hyperproliferative diseases. However the lack of preclinical models to characterize the consequences of TEAD inhibition is a significant challenge in studying the efficacy of this approach. To circumvent some of the limitations to study TEAD inhibition in cells and tissues our group developed TEADi. This genetically encoded fluorescently traceable dominant-negative protein blocks the nuclear interaction of TEAD with YAP1 and TAZ. TEADi rapidly inhibits TEAD transcription and concomitantly blocks both YAP1 and TAZ without altering the structural or cytoplasmic functions of these proteins. Ultimately unveiling YAP1/TAZ-TEAD dependent and independent effects could provide additional clues to suppress YAP1/TAZ activity in tumors. After validating the usefulness of TEADi to study TEAD transcription specifically we utilized TEADi in a mouse model of skin Basal Cell Carcinoma (BCC) to analyze the transcriptional and cell fate consequences of TEAD blockage in cancer. Both TEAD inhibitor and YAP1/TAZ knockdown reduced proliferation and increased differentiation of mouse BCC driven by oncogenic hedgehog-smoothened (SmoM2) activity. Although TEAD-transcriptional networks were essential to inactivate differentiation this inactivation was indirect and potentially mediated through KLF4 repression by SNAI2. By comparing the transcriptional effects of TEAD inhibition with those caused by YAP1/TAZ depletion we determined YAP1/TAZ TEAD independent effects in cancer cells that impact STAT3 and NF-KB. Overall our results indicate that repression of KLF4 transcriptional networks by YAP1/TAZ TEAD is essential for maintaining basal cell identity and block differentiation in BCC downstream of oncogenic hedgehog-smoothened activity. 662069 +Biotechnology; Cancer; Clinical Research; Digestive Diseases; Digestive Diseases - (Gallbladder); Genetics; Health Disparities; Liver Cancer; Liver Disease; Minority Health; Rare Diseases 1-Phosphatidylinositol 3-Kinase;3-Dimensional;Adjuvant;Amino Acids;Back;Binding;Biological Models;Biology;Cell Line;Cells;Cholangiocarcinoma;Cooperative Research and Development Agreement;Custom;DNA Binding;Data;Development;Distant;Drug Evaluation;Excision;Exportins;Gene Expression;Genes;Genetic Screening;Genetic Transcription;Human;Immune;Immune system;KRASG12D;Literature;Liver;Malignant Neoplasms;Mediating;Mediator of activation protein;Mesothelium;Metastatic Neoplasm to the Liver;Modeling;Molecular;Morphology;Mus;Mutation;Neoplasm Metastasis;Nuclear Export;Nutrient;Oncogenic;Oncology;Operative Surgical Procedures;Organ;Outcome;Pathway interactions;Patients;Pattern;Perfusion;Pharmaceutical Preparations;Phase I/II Trial;Phase II Clinical Trials;Phase III Clinical Trials;Phosphotransferases;Process;Protein Export Pathway;Proto-Oncogene Proteins c-akt;Rare Diseases;Recurrence;Resected;Sampling;Secure;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Specificity;Structure;System;Techniques;Therapeutic;Time;Transplantation;Tumor Biology;Xenograft procedure;aminoacid biosynthesis;animation;base;cancer care;cancer imaging;cell killing;clinical efficacy;clinical predictors;cytokine;drug mechanism;ex vivo perfusion;imaging modality;in vivo;inhibitor;insight;kinase inhibitor;knock-down;mortality;neoplastic cell;next generation sequencing;novel;patient response;patient subsets;programs;promoter;quadruplex DNA;response;sensor;stem;targeted agent;transcription factor;transcriptomics;tumor;tumor microenvironment;tumorigenesis Interrogating the molecular underpinnings of metastatic colonization n/a NCI 10702656 1ZIABC011759-06 1 ZIA BC 11759 6 15201727 "HERNANDEZ, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2498874 NCI Sub-Project 1. I used 318 patient samples to demonstrate specific cytoplasmic accumulation of XPO7 within tumor cells in a subset of patients with CCA and further verified this localization pattern in a panel of CCA cell lines. I then used the cells lines to show that XPO7 binds to and stabilizes Ste20-like kinase (SLK) which in turn activates downstream oncogenic signaling pathways including the PI 3-Kinase-AKT pathway and subsequently reverted back to tumor samples to verify this relationship. Given the absence of specific SLK inhibitors we next profiled the kinome-specificity of 250 inhibitors to identify those with activity against SLK. Based on that data I selected one of those agents tivozanib for further study. Using murine xenografts and CCA tumor from a patient in the SMART system (see Project #3) I demonstrated that tivozanib treatment resulted in tumor shrinkage/tumor cell killing and substantial morphologic alterations similar to those observed with XPO7 or SLK knockdown. Based upon these results I have successful secured tivozanib from Aveo Oncology through a CRADA mechanism and have opened a Phase I/II trial (NCT 04645160) for patients with CCA. Sub-Project 2. Genetic screening identified the amino acid sensor GCN1 as a driver of metastatic outgrowth in the liver by activating a dual translational and a transcriptional gene expression program. While the translational program activates genes involved in nutrient acquisition and intrinsic amino acid biosynthesis in an ATF4-dependent manner the transcriptional function sustains oncogenic drive by interacting with DNA binding transcription factor HNRNPK which activates the expression of KRASG12D through DNA quadruplex (G4) unwinding in its promoter. Intriguingly the GCN1-dependent translational and transcriptional program is negatively regulated by IMPACT which binds and inhibits GCN1 function. The expression of IMPACT is lost in highly aggressive and metastatic cell lines and inversely correlates with GCN1 pathway activation. Our data suggest that GCN1 signaling is indispensable for in vivo liver metastasis and agents targeting GCN1 and downstream signaling pathway may have clinical efficacy in the adjuvant setting. Sub-Project 3. I utilized tumor-bearing mesothelium and created an oxygenated perfusion circuit termed the SMART System (Surgically-resected Mesothelium ContAining UnalteRed Tumor Microenvironment) which I demonstrated maintains tumor with minimal alterations in structure cellular composition and transcriptomics. Importantly cells remain functional and respond to cytokines and drugs. The SMART System is the subject of an EIR. I developed hardware to perform live imaging of the tumor repurposing our advanced confocal and multiphoton scopes. This technique gives unprecedented insight into tumor biology dynamics. To compliment the SMART system I conceived and implemented ex vivo perfusion of tumor-bearing liver segments. We initially sought to repurpose commercially available transplant machines but these lacked real-time adjustment capabilities required for prolonged ex-vivo animation. To circumvent the limitations I have assembled a team and built a custom liver perfusion system. 2498874 +Biotechnology; Cancer; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; Gene Therapy; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health 2019-nCoV;Address;Anti-Inflammatory Agents;Autophagocytosis;Benefits and Risks;Biogenesis;CCI-779;Cell Line;Cell Survival;Cells;Cellular Metabolic Process;Clinical;Endocytosis;Endosomes;Epithelial Cells;FRAP1 gene;Gene-Modified;Goals;Growth;Hamsters;Human;Immune response;Immunosuppressive Agents;Infection;Influenza A virus;Innate Immune Response;Lead;Lentivirus Vector;Link;Lysosomes;Malignant Neoplasms;Manuscripts;Mediating;Metabolic;Metabolic Pathway;Multivesicular Body;Mus;Oncogenic;Pathway interactions;Patients;Peer Review;Pharmaceutical Preparations;Predisposition;Property;Proteins;Publications;Publishing;Regimen;SARS-CoV-2 infection;Signal Transduction;Sirolimus;TSG101 gene;Therapeutic;Tissues;Ubiquitination;Virus;Virus Diseases;Work;antiviral immunity;cell growth;cellular targeting;gene therapy;improved;in vivo;inhibitor;mTOR inhibition;member;mutant;scaffold;severe COVID-19;therapeutic gene;trafficking;transcription factor;tumorigenesis;vacuolar H+-ATPase An Intrinsic Link between the Metabolic and Antiviral States of the Cell n/a NCI 10702654 1ZIABC011756-06 1 ZIA BC 11756 6 15201721 "COMPTON, ALEX " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 657496 NCI Since work on this project began in February 2017 we have made a number of key advancements. Our initial work using rapamycin on transformed epithelial cell lines revealed that mTOR inhibition confers a 4- to 20-fold enhancement of infection by lentiviral vectors and by Influenza A virus. Furthermore we found that the rapamycin-dependent enhancement of infection is reversed by inhibitors of endosomal acidification (v-ATPase) revealing that the enhancement requires active degradation of cellular factors via the lysosomal pathway. Through a number of approaches we show that mTOR inhibition by multiple drugs leads to lysosomal degradation of IFITM3 in an autophagy-independent manner. Instead endocytic trafficking through multivesicular bodies is necessary to delivery of IFITM3 to lysosomes as confirmed by a functional requirement of ESCRT member TSG101 and by inhibition of multivesicular body formation by the compound U18666A. By studying mutant IFITM3 constructs we found that mTOR inhibition leads to clearance of IFITM2 and IFITM3 from endosomes in a manner that is dependent on endocytosis ubiquitination and lysosomal acidification. This work is the first instance to describe an interrelationship between mTOR cell-intrinsic antiviral immunity and virus entry into cells. These results have been published in 2018 (Shi et al. PNAS 115: E10069 2018). More recently we have compared the ability of rapamycin analogs (rapalogs) to downmodulate IFITM proteins and to enhance other virus infections including SARS-CoV-2. Rapamycin is currently being investigated as a therapeutic anti-inflammatory compound to treat severe COVID-19. We found that some rapalogs downmodulate IFITM proteins and enhance SARS-CoV-2 infection while others do not laying the groundwork for a mechanistic understanding of the cellular pathways involved. Speficially we found that some rapalogs promote IFITM downmodulate by activating TFEB a transcription factor controlling lysosome biogenesis and function. TFEB is also required for the SARS-CoV-2 infection-enhancing effects of rapalogs and together with our previous publication we found TFEB triggers IFITM degradation and SARS-CoV-2 enhancement through microautophagy an endosomal remodeling pathway. We also showed that rapalog administration in hamsters and mice increases susceptibility to experimental SARS-CoV-2 infection and viral disease in vivo. These results have been posted as a preprint in 2021 (Shi et al. bioRxiv) and the manuscript is now in revision following peer review. We now plan to study how rapalogs which are already used clinically to inhibit cancer growth influence the oncogenic functions of IFITM3. IFITM3 is commonly upregulated in a variety of cancers and may act as a scaffold for PI3K/Akt/mTOR signaling to favor cell survival and growth. Thus this project has provided an opportunity for my lab to explore new avenues with relevance to the basic and clinical understanding of tumorigenesis. 657496 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Pediatric; Pediatric Cancer; Rare Diseases Alveolar Rhabdomyosarcoma;Antibodies;Antibody Therapy;Biologic Development;Biological;Bypass;Childhood;Clinic;Clinical;Clinical Data;Clinical Trials;Combined Modality Therapy;Dasatinib;Dose;Embryonal Rhabdomyosarcoma;IGF1 gene;Insulin-Like-Growth Factor I Receptor;Investigation;Manuscripts;Pathway interactions;Patients;Phase;Phase I/II Clinical Trial;Play;Pre-Clinical Model;Process;Refractory;Relapse;Resistance;Rhabdomyosarcoma;Role;Testing;Work;base;cell growth;efficacy evaluation;industry partner;inhibitor;neoplastic cell;novel;pre-clinical;preclinical study;receptor;response;src-Family Kinases;stability testing Development of biologic based therapies for rhabdomyosarcoma n/a NCI 10702650 1ZIABC011745-06 1 ZIA BC 11745 6 15201715 "HESKE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 224931 NCI In FY2021 our phase I/II clinical trial testing the combination of the IGF-1R antibody ganitumab with dasatinib a multi-kinase inhibitor targeting the SRC-family kinase YES in patients with relapsed and refractory rhabdomyosarcoma continued to accrue patients. This study was developed based upon preclinical work in our lab that identified YES activation as a bypass pathway for resistance to IGF-1R inhibition. Dual blockade of YES and IGF-1R demonstrated enhanced tumor cell growth inhibition in a number of preclinical models of both embryonal and alveolar rhabdomyosarcoma. We accrued 13 patients onto the phase 1 part of this study which is now complete. We are in the process of preparing the manuscript describing the findings. We accrued 1 additional patient onto the phase 2 part of this trial but due to a decision by our industry partner to discontinue stability testing and restrict our access to the investigational product ganitumab we were forced to close to accrual in late 2021. This trial has several aims including identification of the highest safe dose for this combination (complete) evaluation of efficacy of this combination in patients with relapsed and refractory rhabdomyosarcoma (incomplete) and correlative biologic studies of response and resistance (currently ongoing). 224931 +Biotechnology; Cancer; Genetics; Lung; Lung Cancer; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human 3-Dimensional;Adoption;Affect;Alveolar;Alveolar Cell;Biology;Cancer cell line;Carcinoma;Cell Culture Techniques;Cell Survival;Cell model;Cells;Development;Dissection;Epithelial;Epithelial Cells;Exhibits;Gene Expression;Goals;Growth;Human;In Vitro;KRAS2 gene;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Methods;Microscope;Modeling;Molecular Genetics;Mus;Oncogenes;Oncogenic;Organoids;Outcome;Phenotype;Signal Transduction;Surface;System;Xenograft procedure;cancer cell;cell behavior;cell growth;cost;in vitro Model;in vivo;lung cancer cell;metaplastic cell transformation;monolayer;mutant;neoplastic cell;scale up;stem cells;stemness;targeted treatment;transplant model;tumor;tumor behavior Organoid models of KRAS mutant cancer n/a NCI 10702642 1ZIABC011733-07 1 ZIA BC 11733 7 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 473481 NCI BACKGROUND. Traditional cell culture method of growing epithelial cancer cells as a 2D monolayer on a stiff adherent surface fails to capture the transformed phenotype of these cells. Indeed a key hallmark that distinguishes cancer from normal epithelial cells is their ability to grow under anchorage-independent conditions. Alternatively cancer cells that can be cultured under 3D anchorage-independent conditions and under such conditions they often form a spheroid that mimic a microscope tumor. Such tumor spheroid culture has been difficult to scale up in the past thus limiting their utility. A method to grow tumor spheroids on a larger scale with lower cost will enable the wider adoption of this model for in vitro studies. Recent development in organoid culture has made it possible to grow primary epithelial cells and maintain their lineage identify in vitro. In the lung evidence suggests that alveolar type 2 (AT2) cells which are the resident stem cells of the alveolar space are also the cell of origin for lung adenocarcinoma. A scalable murine lung organoid model of normal and KRAS mutant AT2 cells will provide better resemblance of lung cancer cell in vivo. These advanced cell models will be valuable for dissecting the function of the KRAS oncogene in the context of anchorage-independent cell growth. OBJECTIVES. 1) Develop a scalable tumor spheroid culture method for human cancer cells and elucidate the function of the KRAS oncogene in anchorage-independent cell growth and survival; 2) Develop a scalable murine lung organoid model of KRAS mutant cells and investigate the function of the KRAS oncogene in the oncogenic transformation of lung epithelial cells; and 3) Use mouse xenograft and orthotopic transplant models to validate discoveries from organoid models. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Elucidating KRAS oncogene function under anchorage-independent conditions. We have developed a tumor spheroid culture method that can be applied to many epithelial KRAS mutant cancer cell lines. Importantly this culture method is scalable and it is amenable to molecular and genetic dissection of cellular phenotypes. Using this system we have identified features of KRAS oncogene signaling that is distinct from those in 2D cell culture. We are investigating the functional impact of these 3D-specific signaling from the KRAS oncogene and dissecting how they contribute to cellular transformation. 2) Using murine AT2 organoid to model lung adenocarcinoma in vitro. We have established organoid culture of KRAS mutant murine AT2 cells to study the biology of KRAS mutant lung adenocarcinoma. These organoids stably maintain their AT2 lineage markers exhibit features of transformation and are addicted to the KRAS oncogene for their growth. We are using this system to understand how mutant KRAS impact signaling gene expression and stemness in AT2 cells. We are developing organoid culture of normal AT2 cells to understand how targeted therapies affect their viability. 473481 +Cancer; Genetics Anchorage-Independent Growth;Attention;CRISPR/Cas technology;Cancer Patient;Cancer cell line;Cells;Clinical Trials;Colorectal;Colorectal Cancer;Combined Modality Therapy;Dependence;Development;Drug Combinations;Drug Targeting;Drug resistance;Drug toxicity;Epithelial Cells;Genes;Genetic;Genetic Screening;Genetic Transcription;Goals;KRAS2 gene;Lead;Libraries;Lung;MAP Kinase Gene;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Modality;Modeling;Multiple Myeloma;Mus;Oncogenes;Oncogenic;Outcome;Pancreas;Pathway interactions;Patients;Pharmacology;Pre-Clinical Model;Resistance;Signal Transduction;Stress;Therapeutic;Xenograft procedure;cancer cell;driver mutation;functional genomics;high-throughput drug screening;improved;in vivo;inhibitor;kinase inhibitor;loss of function;mutant;new therapeutic target;novel drug combination;novel therapeutics;oncogene addiction;prevent;ras Oncogene;resistance mechanism;response;small molecule inhibitor;targeted treatment;tool;treatment response;tumor Target discovery and combination therapy in KRAS mutant cancer n/a NCI 10702641 1ZIABC011732-07 1 ZIA BC 11732 7 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 473481 NCI BACKGROUND. The KRAS oncogene is a driver mutation in a significant fraction of lung pancreatic and colorectal cancers. Recently breakthroughs with inhibitors targeting the KRAS-G12C mutant is the first Ras targeted therapies in decades. For other KRAS mutant tumors there are no effective targeted therapies. Resistance to KRAS inhibitors develop rapidly in cancer patients and drug combination that can prevent or delay drug resistant are needed to extend the durability of response in patients. In addition to Ras kinases inhibitors against Ras effector pathways have been developed to target the MAPK and PI3K pathways. However these agents have not demonstrated efficacy in clinical trials against KRAS mutant tumors. Thus far targeted therapies have primarily focused on blocking OA and less attention have been devoted to blocking NOA in KRAS mutant cells. Co-targeting NOA and OA together could lead to better drug combinations with orthogonal therapeutic modalities improved therapeutic window and more durable response in KRAS mutant tumors. OBJECTIVES. 1) Using functional genomic screens to identify genetic dependencies resulting from oncogene addiction (OA) and non-oncogene addiction (NOA) in KRAS mutant cancer cells; 2) Evaluating the mechanism selectivity of targeted therapies in KRAS mutant cells and the mechanisms leading to drug resistance; and 3) Identify drug combinations that orthogonally target distinct aspects of OA and NOA in KRAS mutant cells to achieve better therapeutic window. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Genetic screens to identify functional vulnerabilities in KRAS mutant cancer cells. Using pooled CRISPR/Cas9 gene KO libraries we have carried out loss-of-function screens in KRAS mutant cancer cells under different culture conditions. We have identified a candidate druggable gene that is critical for the anchorage-independent growth of KRAS mutant cells and we are currently investigating the mechanism of this genetic dependency and exploring small molecule inhibitors of this target. 2) Mechanisms of drug resistant to Ras pathway inhibitors. Using different KRAS mutant cancer cell lines including colorectal pancreatic lung and multiple myeloma cells we have evaluated genetic and post-transcriptional mechanisms that contribute to resistance to KRAS inhibitors and MEK inhibitors. We are currently elucidating how these resistance mechanisms can be reversed to improve therapeutic response in pre-clinical models. 3) Identification of novel drug combinations for KRAS mutant cancer. Using high-throughput drug screen and hypothesis-driven approach we are evaluating drug combinations that involve inhibitors targeting Ras OA to block oncogenic Ras signaling and inhibitors targeting NOA pathways to exacerbate oncogenic stress in KRAS mutant cancer cells. We contrast the toxicity of drug combinations in KRAS mutant cancer cells against that in normal epithelial cells to assess the therapeutic window and we use mouse xenograft and autochthonous tumor models to evaluate the drug combination's efficacy against KRAS-driven tumors in vivo. 473481 +Cancer Address;Antigens;Antitumor Response;Autoantigens;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cell Communication;Cell model;Cells;Cessation of life;Collaborations;Cues;Development;Feedback;Frequencies;Goals;Heterogeneity;Immune response;Immunity;Individual;Interleukin-2;Laws;Leukocytes;Microfluidics;Output;Pathway interactions;Population;Predisposition;Production;Property;Reaction;Recovery;Signal Transduction;Stimulus;T cell response;T-Cell Activation;T-Lymphocyte;Time;Tissues;Translating;Tumor Antigens;Work;Yang;analog;anti-tumor immune response;antigen-specific T cells;cytokine;design;exhaustion;immunoreaction;macrophage;neoplastic cell;paracrine;quantum;response;self organization;tool;tumor Cytokine coordination of collective immune responses against tumors n/a NCI 10702640 1ZIABC011728-07 1 ZIA BC 11728 7 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 556937 NCI We developed quantitative models of the cell-to-cell communications via cytokines amongst population of T lymphocytes. Our goal is to understand how leukocytes self-organize to decide their cell fate (e.g. between quiescence -tolerance- and death/proliferation -responses). At a fundamental level we developed theoretical tools to analyze the heterogeneity and synchronicity of T cell responses in dense tissues. In the context of responses to tumor we found that a critical mass of T cells existed to drive tumor rejection. Additional work is being carried out to dissect quantitatively how T cell decide collectively between tumor rejection and tumor tolerance. We also made progress in the development of a microfluidic platform (collaboration with Don DeVoe within the NI/UMD partnership) to address spatial aspects of cell-to-cell communications. This platform allows the assembly of micro-immune reactions with tumor cells T cell and macrophages and the observation of the ensued immune responses. The platform is also designed to allow cell recovery towards off-chip analysis (e.g. scRNAseq and FACS). 556937 +Bioengineering; Cancer; Clinical Research; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD) Address;Antibodies;Antigens;Artificial Intelligence;B-Lymphocytes;Biochemical;Biological;Biology;Bone Marrow;Bypass;CCR;CD8B1 gene;Cell model;Cells;Clinical;Clinical Investigator;Collaborations;Communication;Computer Models;Custom;Cytokine Signaling;Cytometry;Data;Differential Equation;Discrimination;Distal;Down-Regulation;Feedback;Flow Cytometry;Fluorescence;Goals;Heterogeneity;Human;IL7 gene;Immune;Immune response;Immune system;Immunological Models;Individual;Interleukin-2;Kinetics;Lead;Leukocytes;Ligands;Lupus;Lymphocyte;MEKs;Malignant Neoplasms;Maps;Measurement;Memory;Methodology;Methods;Modeling;Monitor;Mus;Names;Nature;Outcome;PTPN6 gene;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiologic pulse;Population;Preparation;Proliferating;Proteins;Provider;Reagent;Regulation;Robotics;Sampling;Science;Sensitivity and Specificity;Signal Transduction;Sorting;Specificity;Speed;System;T-Cell Activation;T-Lymphocyte;Testing;Theoretical model;Therapeutic;Time;Transgenic Mice;United States National Institutes of Health;Vaccines;Validation;antagonist;base;biochemical model;chimeric antigen receptor T cells;combinatorial;computer program;cytokine;digital;disease classification;inhibitor;machine learning method;melanoma;neutrophil;phenomenological models;pre-clinical;profiles in patients;receptor;response;single cell analysis;small molecule inhibitor;tissue culture;tool;transcription factor;tumor Phenotypic variability within isogenic population of lymphocytes n/a NCI 10702639 1ZIABC011726-07 1 ZIA BC 11726 7 15201697 "ALTAN-BONNET, GREGOIRE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 445550 NCI "We found that phenotypic variability can be driven by the heterogenous expression of key components within signal transduction cascade. Such variability has practical importance when modeling how cells vary in their drug response. In particular we found that the topology of signal transduction cascades explain why small-drug inhibitors of proximal signaling components (e.g. Src) acted digitally (i.e. in an all-or-none manner) while inhibitors against distal signaling components (e.g. Mek) acted analogously (i.e. in a continuous manner) We expanded our findings on the phenotypic variability of cell signaling with a new methodology (termed ""cell-to-cell variability analysis): such method relies on single-cell phospho-profiling of primary cells in preclinical and clinical settings to identify which biological components (receptor kinase phosphatase transcription factor) is quantitatively limiting in terms of functional consequences. We illustrated the strength of this approach by showing how response to IL-2 and IL-7 are mutually exclusive within individual primary T cells. A computational model based on biochemical modeling and Bayesian optimization was introduced to test how sequestration of a shared but limited receptor chain could generate such flip-flop in cytokine signaling. This study provided a mechanistic explanation for the transition between effector and memory cells within an isogenic population of T cells (Cotari et al. Science Signaling 2013). Concomitantly we introduced and distributed a computer program (named ScatterSlice) that enables experimenters to analyze the cell-to-cell variability in their Flow Cytometry data (Cotari et al. Science Signaling 2013). Such methodology has found applications in many clinical settings (Palomba et al. PLoS One 2014; Kitano et al. Cancer Immunol Res 2014). In parallel we have been implementing mass cytometry (so-called CyTOF) at the NIH. CyTOF enables the multiplexing of large sets of antibodies (typically 40 at once) while bypassing issues of spectral overlap of classical fluorescence-based cytometry. We validated and optimized multiple antibody panels to profile multiple immunological systems: general profile of bone marrow in mouse and human deepvprofile of T cell populations in mouse and human human neutrophils and human B cells. We collaborated with clinical investigators at the NIH to profile patients' samples in the context of XMEN ALPS Lupus (PBMC) and melanoma (TIL). Moreover we developed a method to pulse-chase IdU (a reagent that gets picked up and inserted in proliferating cells) and monitor the kinetics of differentiation of leukocytes in mice. We have expanded our robotic platform with higher multiplexing of sample preparation of measurements (bulk cytokine and single-cell measurements) and used our well calibrated in mouse transgenic T cell model in order to map out the phenotypic diversity of human TILs and CAR-T cells (collaboration with Naomie Taylor and Nirali Shah in the CCR-POB). Finally we introduced a machine-learning-based method to automatically identify clusters of differentiation amongst leukocytes under consideration: this method was applied to define a new T cell population whose phenotype correlates with positive clinical outcomes. We are pursuing our goal to better characterize the cellular complexity of immune responses towards better classification of disease and therapeutic states and better modeling. Finally we are developing a platform to address leukocyte diversity (its origins and its functional significance). We built a custom-made robotic tissue culture system to systematically assemble immune responses ex vivo (using primary samples from mouse or human) and to monitor its time dynamics. Our system generates typically 500 conditions (as a convolution of cell contents activation conditions drug perturbations and time points) that get characterized for their soluble content (cytokine secretion) and cell composition (single-cell profiling by CyTOF and FACS). We then apply tools from the field of artificial intelligence to deconvolve the combinatorial complexity of these immune responses. Our goal is to identify new immune signatures & features that best classify immune responses then to validate these signatures in models of immune responses (against vaccines and/or tumors)." 445550 +Cancer; HIV/AIDS; Health Disparities; Minority Health Biology;Cell Line;Cells;Cellular biology;Complex;Crystallization;Cytoplasmic Tail;Data;Defect;Development;Elements;Future;Glycoproteins;Goals;HIV;HIV-1;Hela Cells;Human;Integration Host Factors;Lentivirus;Maryland;Mediating;Modification;Molecular;Monkeys;Mutation;NMR Spectroscopy;Natural Immunity;Nature;Pathway interactions;Peripheral Blood Mononuclear Cell;Play;Point Mutation;Primates;Process;Proteins;RNA Interference;Research;Retroviridae;Rhesus;Role;SIV;Signal Transduction;Structure;Surface Plasmon Resonance;T-Lymphocyte;Tail;Terminator Codon;Titrations;Universities;Viral;Virion;Virus;Virus Replication;Work;antagonist;antiretroviral therapy;cell type;experimental study;inhibitor;insight;interest;mutant;novel;overexpression;particle;recruit;trafficking;ubiquitin-protein ligase Envelope Glycoprotein Incorporation and Function n/a NCI 10702637 1ZIABC011721-07 1 ZIA BC 11721 7 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 823711 NCI We have been actively engaged in defining the molecular mechanism by which retroviral Env glycoproteins are incorporated into virus particles during the assembly process. A complete understanding of this process has been stymied by a lack of structural information about the matrix domain of Gag (MA) and the cytoplasmic tail (CT) of gp41 in virions cell-type-specific differences in the requirement for the gp41 CT in Env incorporation clear differences in the roles of the gp41 CT between HIV-1 and the SIVmac strain of simian immunodeficiency virus in human vs. monkey cells and the plethora of trafficking and signaling motifs present in the CTs of retroviral Env proteins. Recently we have made significant progress in understanding the structural requirements for Env incorporation from the perspective of MA and will build on these advances to elucidate the role of the gp41 CT in Env incorporation. ___Several lines of evidence suggest that HIV 1 Env glycoproteins are recruited into virions via direct interactions between Env and MA; for example mutations in both MA and the gp41 CT can block HIV 1 Env incorporation. Our recent findings strongly support the hypothesis that trimerization of the MA domain plays an important role in Env recruitment: a mutation at the putative MA trimer interface is able to rescue the Env-incorporation defect imposed by a large panel of MA mutations and a small deletion in the gp41 CT and mutations that disrupt MA trimer formation block Env incorporation. In this project we aim to further elucidate the structural requirements for Env incorporation focusing first on HIV-1 and then extending our analysis to other lentiviruses and more broadly other retroviruses. ___We showed a number of years ago that HIV-1 Env is likely to interact in a cell-type-dependent manner with host cell factors that promote Env incorporation. More recent studies suggested that Env incorporation is mediated by interactions between MA and the host factor tail-interacting protein of 47 kDa (TIP47). As part of our ongoing efforts to understand the host cell machinery required for HIV-1 Env incorporation we reevaluated the role of TIP47 in this process. A direct interaction between MA and TIP47 was confirmed by NMR spectroscopy titration experiments and surface plasmon resonance [performed in the labs of our collaborators Drs. Michael Summers (University of Maryland) and Simon Cocklin (Drexel University)]. However in HeLa cells TIP47 overexpression or RNAi-mediated depletion had no significant effect on HIV-1 Env incorporation virus release or particle infectivity. Similarly depletion of TIP47 in the Jurkat T-cell line did not impair HIV-1 Env incorporation virus release infectivity or replication. Our results thus do not support a role for TIP47 in HIV-1 Env incorporation or virion infectivity. ___More recently the Spearman lab demonstrated that another host protein Rab11-FIP1c plays an important role in Env trafficking and incorporation into virions. The retromer complex was also suggested to function in Env trafficking. An intriguing aspect of the cell-type-specific nature of lentiviral Env incorporation is that while in most relevant human cell types truncation of the gp41 CT blocks HIV-1 replication SIVmac acquires gp41 CT stop codons when propagated in human cells. These stop codons revert to the wild-type sequence when the mutant viruses are propagated in monkey cells (e.g. rhesus PBMCs). Thus the HIV-1 gp41 CT plays a positive role in virus replication whereas the SIVmac gp41 CT plays a negative role in human cells but a positive role in monkey cells. Understanding the basis for these observations is likely to provide novel insights into the role of gp41 in lentiviral biology. We will evaluate the role of host factors in primate lentiviral Env glycoprotein incorporation and the determinants in MA and gp41 required for Env incorporation. ___Although a trimeric MA crystal structure has been available since 1996 evidence for functional MA trimers has been elusive. The mechanism of HIV-1 Env recruitment into virions likewise has been unclear. We identified a point mutation in MA (62QR) that rescues the Env-incorporation defects imposed by an extensive panel of MA and Env mutations. Mapping the mutations onto the putative MA trimer reveals that the incorporation-defective mutations cluster at the tips of the trimer at the perimeter of a putative gap in the MA lattice into which the gp41 CT could insert. By contrast the rescue mutation is located at the trimer interface suggesting that it confers rescue of Env incorporation via modification of MA trimer interactions. These data strongly support the existence of MA trimers in the immature Gag lattice and demonstrate that rescue of Env-incorporation defects is mediated by modified interactions at the MA trimer interface. The importance of the trimer interface in rescuing HIV-1 Env incorporation suggests that the trimeric arrangement of MA plays a critical role in permitting incorporation of Env into the Gag lattice. Inhibitors could be developed to block HIV-1 Env incorporation by disrupting this essential structural element in MA trimerization. Future work could also yield strategies to block HIV-1 Env incorporation by disrupting the function of host factors or the interactions between host factors and either Env or Gag. We have also demonstrated that the cellular E3 ubiquitin ligase MARCH8 restricts a number of viral envelope glycoproteins including that of HIV-1. Our findings indicate that MARCH8-mediated antagonism of HIV-1 Env does not require the cytoplasmic tail of gp41. 823711 +Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Binding;Binding Proteins;Biochemistry;Capsid Proteins;Cell membrane;Cell surface;Cells;Cellular biology;Collaborations;Complex;Destinations;Development;Family;Glycoproteins;Goals;HIV;HIV-1;HIV-2;Imaging Techniques;Immunoglobulins;Inositol;Integration Host Factors;Interferons;Membrane;Molecular;Mucins;Natural Immunity;Ohio;P-selectin ligand protein;Pathway interactions;Phosphatidylinositols;Phosphatidylserines;Play;Production;Protein Family;Proteins;Reporting;Research;Role;SIV;Site;Sphingomyelinase;T-Lymphocyte;Universities;Viral;Virion;Virus;Virus Assembly;Work;antiretroviral therapy;env Gene Products;gene product;inhibitor;insight;interest;nef Protein;novel;particle;polyanion;protein function;trafficking;virology;vpu Protein Gag Trafficking Assembly and Release n/a NCI 10702636 1ZIABC011720-07 1 ZIA BC 11720 7 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 823711 NCI While it is clear that HIV-1 assembly occurs predominantly on the plasma membrane (PM) the itinerary that the HIV-1 Gag precursor follows to reach this destination remains ill defined. Likewise the host cell machinery that promotes Gag trafficking to the PM is incompletely understood. We and others have demonstrated that the matrix (MA) domain of Gag regulates targeting to the site of virus assembly and we discovered that the phosphoinositide PI(45)P2 is a key player in directing Gag to the PM. We hypothesize that host factors in addition to PI(45)P2 play a vital role in the trafficking of Gag to the PM. In this project we are defining the role of host cell machinery in Gag trafficking to the PM and in subsequent steps of particle assembly and release. This effort combines virology biochemistry cell biology and imaging techniques. Our overarching goal is to establish a unified view of the mechanism and pathway(s) involved in the late stages of the HIV-1 replication cycle and to develop inhibitors of HIV-1 Gag trafficking assembly and release. ___ Most of our efforts and those of our colleagues with regard to late-acting host factors have focused on factors that promote HIV-1 particle assembly and release. However we have become increasingly interested in cellular factors that interfere with the late stages of HIV-1 replication. The best-characterized example of a late-acting negative factor is tetherin (BST-2) an interferon-stimulated gene product that restricts viral particle release at the cell surface. Tetherin is counteracted by the HIV-1 Vpu protein and the Nef or Env proteins of certain strains of HIV-2 and simian immunodeficiency virus. Apart from tetherin however little is known about the host cell factors that interfere with HIV 1 assembly or release. We are engaged in studying these host proteins with an initial focus on the T-cell immunoglobulin and mucin domain (TIM) family of phosphatidylserine-binding proteins. We recently reported in collaboration with Dr. Shan-Lu Liu's lab (Ohio State University) that the TIM-family proteins strongly inhibit HIV-1 release by retaining HIV-1 particles on the cell surface through binding to phosphatidylserine on the viral membrane. We will further characterize the mechanism of action by which such host factors restrict HIV-1 particle production resulting in diminished viral production and replication. We have been involved with studies examining the effect of the host factor PSGL-1 on the binding of virus particles to target cells and the incorporation of viral envelope glycoproteins into virions. We are also examining the role of neutral sphingomyelinase 2 on HIV assembly release and maturation. Finally we have several major projects focused on the role of the small cellular polyanion inositol hexkisphosphate (IP6) in HIV-1 assembly and maturation. 823711 +Cancer; Immunotherapy; Rare Diseases; Transplantation Acute Graft Versus Host Disease;Adhesions;Affect;Affinity;Antigens;Autoimmune Diseases;Binding;Blood;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Calcineurin;Cell Adhesion;Cell Proliferation;Cells;Co-Immunoprecipitations;Complex;Confocal Microscopy;Cyclosporine;Defect;Disease;Disease Progression;Distal;Event;FK506;Family;Follow-Up Studies;Graft Rejection;Hepatocyte;ICAM1 gene;Image;Immunity;Immunosuppression;Immunosuppressive Agents;Intercellular adhesion molecule 1;LCP2 gene;Ligands;Lymphocyte-Specific p56LCK Tyrosine Protein Kinase;MAP Kinase Gene;MAP Kinase Modules;Mediating;Molecular;Mus;Peptides;Phosphorylation;Phosphotransferases;Physiologic pulse;Process;Production;Protein Dephosphorylation;Protein Tyrosine Kinase;Proteins;Receptor Signaling;Reporting;Series;Signal Transduction;Signaling Molecule;Small Interfering RNA;Stress;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Tissues;Treatment Efficacy;Tumor-infiltrating immune cells;Uncertainty;Work;ZAP-70 Gene;adaptive immune response;calcineurin phosphatase;cytokine;in vivo;knock-down;lymph nodes;member;mimetics;mutant;novel;nuclear factors of activated T-cells;p38 Mitogen Activated Protein Kinase;perforin;recruit;response;standard care;transcription factor;transplantation therapy;two-photon T cell receptor proximal signaling n/a NCI 10702634 1ZIABC011715-07 1 ZIA BC 11715 7 9692263 "ASHWELL, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 423767 NCI Cyclosporin A (CsA) and FK506 are widely used immunosuppressive drugs that inhibit the Ca2+-activated phosphatase calcineurin. Calcineurin's major activity in T cells is thought to be dephosphorylation (and thus activation) of the NFAT family of transcription factors which are important for cytokine production and cell proliferation. It inhibition of this process that is thought to underlie the therapeutic efficacy of CsA in the treatment of transplant rejection and autoimmune diseases. It has been reported that CsA also inhibits the classic MAP kinase cascade and therefore the stress-induced activation of p38. Signaling via the TCR results in the activation of the MAP kinase p38 by a MAPK cascade-independent mechanism: phosphorylation of p38 Y323 by ZAP-70. Therefore we were surprised to observe that CsA also inhibited p38 activation downstream of TCR signaling. This led us to explore the molecular mechanism for this inhibition and we have made the following observations: 1. Remarkably CsA and FK506 inhibited a number of key events in proximal T cell signaling. These include phosphorylation of ZAP-70 on Y493 LAT and SLP76 whereas phosphorylation of ZAP-70 Y319 PLCgamma1 and ERK were intact. 2. Calcineurin itself is recruited to the TCR signalosome within two minutes of activation and then slowly dissociates over the next 30-60 minutes. This was confirmed both by co-immunoprecipitation studies as well as imaging of TCR micro clusters by confocal microscopy. 3. Calcineurin recruitment requires Lck signaling and ZAP-70 but not ZAP-70 signaling. Therefore we believe that it is binding phosphorylated ZAP-70. 4. siRNA-mediated knockdown of calcineurin recapitulates inhibition of ZAP-70 493 and introduction of ZAP-70 Y493R (which cannot be phosphorylated on residue 493) results in signaling defects similar to those described above (point 1). 5. The calcineurin target in the TCR signalosome is Lck S59 whose phosphorylation has been reported to inhibit TCR signaling. Consistent with this introduction of Lck mutants (Lck S59A which can not be phosphorylated and Lck S59E a phospho-mimetic) resulted in enhanced and inhibited signaling respectively. 6. To determine if inhibition of proximal TCR signaling could be a novel mechanism for it's immunosuppressive effects we looked for important NFAT-independent events downstream of TCR signaling. LFA-1-dependent adhesion to ICAM-1 is a very rapid and essential step in T cell activation and egress from the blood to tissue. We found that CsA inhibited conversion of LFA-1 from the inactive to the active state and blocked cell adhesion to ICAM-1-coated wells. Studies with T cells expressing the Lck-mutants confirmed that the phosphorylation status of S59 was responsible. Followup studies have shown that the addition of CsA to T cells already activated and bound to ICAM-1-coated plates or antigen-pulsed APC results in rapid (minutes) reversal of adhesion. These results have shown that unexpectedly calcineurin is an integral member of the TCR signaling complex. We have performed in vivo studies to assess the affect of cyclosporin A on T cell activation. We have B6 mice in which LckS59A (unable to be phosphorylated and thus not a calcineurin target) has been knocked into the WT locus. We used these mice to study acute graft-vs-host disease (aGVHD) in which H-2b T cells are injected into irradiated (H-2b X H-2a)F1 mice. CsA is a standard treatment for this disease and it is accepted that it works by inhibiting NF-AT-dependent cytokine production. By comparing the effect of CsA on disease caused by WT or LckS59A T cells we can determine if NF-AT TCR signaling or a combination of the two is responsible for CsA efficacy. We found that despite effective inhibition of NFAT-dependent cytokine production aGVHD progression was largely unaffected by CsA when LckS59A T cells were the transferred effectors. There was less CD8 T cell infiltration in the liver and the cells that were there expressed very little of the cytolytic protein perforin. Moreover 2-photon imaging of antigen-specific T:DC interactions in lymph nodes in WT or LckS59A mice treated with CsA found that the former but not the latter had markedly decreased T:DC interations and fewer T cell clusters consistent with the effect of CsA on LFA-1/ICAM1 binding. These results demonstrate that the current paradigm that CsA ameliorates aGVHD by inhibiting NFAT activation is incorrect. Rather it does so by inhibiting TCR signaling that otherwise increases inLFA-1-affinity andp erforin expression and no doubt other not-yet-characterized responses. In addition to these we have found that siRNA-mediated knockdown of calcineuring alpha and beta results in a more profound loss of TCR signaling than inhibition of calcineurin enzymatic activity. We have generated CRISPR/Cas9 KO of the calcineurin alpha and beta forms of the A chain in Jurkat T cells and are using confocal microscopy to characterize the ability of these cells to form signaling TCR microclusters and propogate downstream events. 423767 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Immunotherapy; Neurosciences; Orphan Drug; Rare Diseases Adjuvant;Adrenal Cortex Hormones;Adult;Basic Science;Biology;Blood;Blood - brain barrier anatomy;Blood specimen;Brain Neoplasms;Cell Hypoxia;Clinical Trials;Complex;Enrollment;Epigenetic Process;Exhibits;Face;Foundations;Functional disorder;Future;Glioblastoma;Goals;Heat shock proteins;Hematologic Neoplasms;Iatrogenesis;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Monitoring;Immunologics;Immunology;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;Laboratories;Lymphocyte;Lymphocyte Function;Lymphopenia;Malignant Neoplasms;Malignant neoplasm of central nervous system;Metabolic;Molecular;Multi-Institutional Clinical Trial;Natural Immunity;Newly Diagnosed;Nivolumab;Oncology;Patients;Peptides;Persons;Play;Primary Brain Neoplasms;Process;Proteins;Randomized;Randomized Clinical Trials;Regimen;Regulatory T-Lymphocyte;Role;Running;Sampling;Seminal;Silent Mutation;Solid;T-Lymphocyte;Tissues;Toxic effect;Translational Research;Tumor-associated macrophages;United States National Institutes of Health;Vaccines;base;brain based;cancer immunotherapy;cancer therapy;checkpoint inhibition;clinical center;collaborative trial;design;efficacy evaluation;fighting;gliosarcoma;immune function;improved;improved outcome;in vivo;interest;ipilimumab;neoantigens;neoplastic cell;novel;pembrolizumab;peripheral blood;phase II trial;prevent;programmed cell death ligand 1;programmed cell death protein 1;programs;response;trafficking;treatment response;tumor;tumor microenvironment Translational Immunology n/a NCI 10702633 1ZIABC011714-07 1 ZIA BC 11714 7 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 516832 NCI Although there have been advances in ways of how to overcome tumor related immunosuppression many factors such as T cell lymphopenia T cell dysfunction disproportionately high numbers of circulating suppressive regulatory T-lymphocytes tumor cell expression of PD-L1 and a suppressive tumor-associated macrophage (TAM) orientation as well as impaired immune effector trafficking across the BBB present challenges for effective immunotherapy in glioblastoma. Our basic and translational research focuses on the immunologic interactions between brain tumors the local tissue microenvironment and the systemic immune response. We aim to enhancing immune therapies by 1) improving lymphocyte function and 2) making the tumor more susceptible to immune attack. We are interrogating components of the tumor microenvironment such as immune modulating cells hypoxia and metabolic factors for their impact on immune function. We are also examining the mechanisms of immune depletion induced by corticosteroids and anti-cancer therapies. Finally we are examining the epigenetic and molecular mechanisms employed by tumor cells to evade immune attack. The Immunology Program has two major components: Immunologic monitoring for immune-based brain tumor clinical trials and elucidating the mechanisms of immunosuppression in brain tumor patients focusing on iatrogenic causes such as corticosteroid use lack of neoantigens and the impact of the tumor microenvironment. The immunologic monitoring will be performed as correlative biology for seminal brain tumor clinical trials whereas the modulation of the immunosuppression in brain tumors will serve as the foundation for future hypothesis-based clinical trials. In collaborate with NOB PTRF and Clinical Center we are further investigating the experimental immunotherapeutics in vivo. Two clinical trials are then open recently (17C0102 Immune Checkpoint Inhibitor Nivolumab in People with Select Rare CNS Cancers; 21C0015 Phase II Trial Evaluating the Association of Peripheral Blood Immunologic Response to Therapeutic Response to Adjuvant Treatment with Immune Checkpoint Inhibition (ICI) in Patients with Newly Diagnosed Glioblastoma or Gliosarcoma). 516832 +Bioengineering; Brain Cancer; Brain Disorders; Cancer; Rare Diseases Biological;Brain Neoplasms;Cell Line;Cells;Databases;Exposure to;Goals;Incubators;Maps;Metabolism;Methods;Noise;Nuclear;Pharmaceutical Preparations;Pharmacotherapy;Raman Spectrum Analysis;Signal Transduction;Slide;Tissues;improved;in vivo;instrument;new technology;tumor Develop RAMAN imaging to visualize metabolism in cell lines and tissue n/a NCI 10702632 1ZIABC011711-07 1 ZIA BC 11711 7 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 394129 NCI We have developed conditions to record RAMAN spectra with high signal/noise ratio while maintaining the cells alive. We have recorded cells after exposure to different treatments and are satisfied with the results of the instrument. Our result pinpoint to certain classes of metabolites that are altered upon drug treatment and we will use these to further investigate via mass spec. We can also map the nuclear or cytosolic localization of different drugs. In addition the method can establish a line between the normal and tumor in tissue slides. 394129 +Cancer Brain;Clinical;Disease Progression;Glucose;Glutamine;Image;In Vitro;Injections;Label;Laboratories;Magnetic Resonance Imaging;Measures;Metabolic;Mus;Normal Cell;Pathway interactions;Protocols documentation;Source;cohort;experimental study;in vivo;mouse model;pre-clinical;tumor In vivo and in vitro metabolic flux analysis in preclinical mouse models n/a NCI 10702631 1ZIABC011710-07 1 ZIA BC 11710 7 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 262752 NCI Our mice protocol has been approved for the next 3 years. We plan to use a cohort of mice for the metabolic flux analysis and correlate with in in vitro studies. We are in the initial stages of this project and therefore do not have significant result yet. Mice that developed mature tumors will be transported from building 37 to building 10 MIF initially for different field imaging using 1H-MRS and 13C-MRS then to Dr. Murali Cherukuri's laboratory where the injection of precursors will take place right before the hyperpolarized MRI experiment. In between experiments we will keep the mice in the allocated cage in building 10. We will inject the mice with the 13C precursors in order to probe different pathways then immediately start the imaging experiment. 262752 +Cancer; Neurosciences Animal Model;Biological Markers;Blood;Cerebrospinal Fluid;Data;Diagnosis;Disease remission;Future;Human;Hydrophobicity;Measures;Metabolic;Metabolism;Methods;Modeling;Mus;Mutate;Patient Monitoring;Patients;Prognosis;Reporting;Sampling;Serum;Statistical Data Interpretation;Time;Tissues;Urine;Xenograft procedure;hydrophilicity;mutant;treatment response;tumor Metabolite profiling of patients blood urine cerebrospinal fluid and tissue n/a NCI 10702630 1ZIABC011709-07 1 ZIA BC 11709 7 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 131377 NCI We have developed methods to separate and quantify D-2HG from IDH-mutant patients. We have robust methods to extract and manipulate hydrophobic and hydrophilic metabolites from urine serum cerebrospinal fluid and tissue. In order to provide significance to our animal models in the future we plan to correlate these studies with the mice xenografts. This will help establish whether mice metabolism is similar enough to human to constitute viable future models. In addition the extraction of metabolites from biofluids is easy and represents a non-invasive approach to the identification of metabolic signatures specific to IDH1-mutated tumors. 131377 +Biotechnology; Cancer DNA sequencing;Defect;Goals;Human;Lead;Mass Spectrum Analysis;Metabolic;Metabolism;Mus;Mutate;Mutation;NMR Spectroscopy;Pathway interactions;Running;Time;Tissue Sample;Xenograft procedure;cohort;established cell line;experimental study;metabolomics;novel;targeted treatment;tumor Targeted and untargeted metabolomics in IDH1 mutated xenografts in mice n/a NCI 10702629 1ZIABC011708-07 1 ZIA BC 11708 7 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 262752 NCI We have been approved to start the studies in mice for the next 3 years. Our pilot experiments has provided with a time frame for mice developing tumors and their survival. We have confirmed the presence of IDH1 mutation via WB and DNA sequencing. Our next goal is to start a larger cohort of mice and to use them for global metabolic profiling. We will use NMR spectroscopy and mass spectrometry to profile metabolites. This study will uncover novel pathways altered by IDH mutations which can be targeted for therapies. 262752 +Brain Cancer; Brain Disorders; Cancer; Genetics; Nutrition; Rare Diseases Animal Model;Biological Assay;Biological Models;Cell Culture Techniques;Cell Death;Cell Line;Cells;Cessation of life;DNA Methylation;Diet;Drug Combinations;Future;Glioma;Goals;In Vitro;Investigation;Mass Spectrum Analysis;Metabolic;Methods;Modeling;Mus;Mutate;Mutation;Pharmaceutical Preparations;Phenotype;Production;Research;Testing;Therapeutic;Therapeutic Effect;Western Blotting;established cell line;histone methylation;in vivo;mouse model;protein expression;response;tumor The effect of therapeutics on mutated IDH1 cell lines and mice tumor models n/a NCI 10702628 1ZIABC011707-07 1 ZIA BC 11707 7 14732003 "LARION, MIOARA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 262752 NCI Using the methods described above we have identified 2 IDH-mutated cell lines that are producing the expected phenotype and will be used for further investigations. The cells behave as expected in terms of D-2HG production and the response to different therapeutics will be determined in the future. We are evaluating different metabolic drugs as well as diets. The goal is to establish a combination of drugs or drug/diets that causes cellular death. once we understand the mechanism of cell death we plan to test these in animal models. 262752 +Cancer; Cancer Genomics; Genetics; Human Genome; Pediatric; Pediatric Cancer; Rare Diseases Address;Affinity;Alternative Splicing;Anabolism;Apoptosis;Binding;Biochemical;Biogenesis;Biological Assay;Biological Models;Bone Tissue;CCR;Cancer Biology;Carbon;Carcinoma;Cell Line;Cell Survival;Cell physiology;Cells;Chimeric Proteins;Chromosomal Rearrangement;Chromosome 11;Chromosome 22;Chromosomes;DNA;DNA Damage;Data;Dependence;Detection;Development;Disease;Dissociation;Distant;Dreams;EWSR1 gene;Enzymes;Evaluation;Event;Ewings sarcoma;Exclusion;Exhibits;Exons;Exposure to;FLI1 Transcription Factor;FLI1 gene;Follow-Up Studies;Fusion Oncogene Proteins;G-Quartets;GTP-Binding Protein alpha Subunits Gs;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Glutamine;Glycine;Growth;Guanine;Individual;Interferometry;Introns;Investigational Drugs;Laboratories;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Messenger RNA;Meta-Analysis;Molecular;Molecular Carcinogenesis;Molecular Conformation;Molecular Target;Mutation;National Center for Advancing Translational Sciences;Neoplasms;Nucleic Acids;Nutrient;Oncogene Deregulation;Oncogenes;Oncogenic;Oncoproteins;Oxidation-Reduction;Pathology;Pathway interactions;Pediatric Oncology;Pharmacotherapy;Post-Transcriptional Regulation;Post-Translational Regulation;Primary Neoplasm;Process;Proteins;Publishing;RNA;RNA Binding;RNA Interference;RNA Splicing;RNA interference screen;Reactive Oxygen Species;Regulation;Reporter;Reporting;Research;Research Personnel;Reverse Transcription;Series;Serine;Signal Transduction;Site;Small RNA;Source;Spliceosomes;Stimulus;Structure;Technology;Therapeutic;Tissues;Transcript;Transcriptional Regulation;Translations;Translocation Breakpoint;Tumor Cell Invasion;United States National Institutes of Health;Work;base;cancer cell;cancer therapy;combinatorial;design;functional genomics;fusion gene;gene discovery;genome-wide;genome-wide analysis;insight;leukemia;loss of function;mRNA Precursor;migration;neoplastic cell;new therapeutic target;nucleic acid binding protein;protein complex;protein expression;protein function;proteostasis;recruit;response;soft tissue;transcription factor;transcriptome;treatment strategy;tumor;tumorigenesis;uptake Discovery of genes required for expression or activity of fusion oncogenes n/a NCI 10702627 1ZIABC011704-07 1 ZIA BC 11704 7 9692277 "CAPLEN, NATASHA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1767955 NCI We began our work to discover genes required for the expression or function of fusion oncogenes by using the results of a genome-wide RNAi screen designed to identify genes needed for the activity of the fusion oncoprotein EWSR1::FLI1. The development of this RNAi screen was a collaborative effort involving the Caplen laboratory and researchers from CCR's Pediatric Oncology Branch and the trans-NIH RNAi screening facility at the National Center for Advancing Translational Sciences (NCATS). EWSR::FLI1 is an oncogenic transcription factor that results from a chromosomal rearrangement involving chromosomes 11 and 22. Chromosome 11:22 translocation is the most frequent primary genetic event observed in Ewing sarcoma (EWS) a cancer of the bone and soft tissues. The genome-wide RNAi screen revealed that EWSR1::FLI1 fusion transcript expression is sensitive to inhibiting the activity of specific splicing factors. We identified that expression of the EWSR1::FLI1 transcripts expressed in EWS cells harboring translocations where the breakpoint in chromosome 22 occurs within a region of DNA (intron 8 of the EWSR1 gene) requires the splicing factor HNRNPH1 to generate an in-frame mRNA (Grohar Kim ... Caplen Cell Reports 2016). The depletion of HNRNPH1 in EWS cells that harbor a chromosome 22 breakpoint in EWSR1-intron 8 disrupts the expression and the activity of the EWSR::FLI1 protein and reduces cell survival. A follow-up study (Neckles ... Caplen RNA 2019) demonstrated that guanine-rich sequences within EWSR1-exon 8 that can fold into RNA G-quadruplex structures influence the recruitment of HNRNPH1. Critically we showed that EWSR1-exon 8 fusion-positive cell lines are more sensitive to treatment with the pan-quadruplex binding molecule pyridostatin (PDS) than EWSR1-exon 8 fusion-negative lines. Also the treatment of EWSR1-exon 8 fusion-positive cells with PDS decreases EWSR::FLI1 transcriptional activity and reverses the transcriptional deregulation driven by EWSR1::FLI1. Most recently (Vo et al. Nucleic Acids Research 2022) we performed a meta-analysis of studies reporting Chr. 22 breakpoints and determined that about 35% of EWSR::FLI1-positive Ewing sarcomas harbor EWSR1-intron 8 breakpoints. Using long-read sequencing we have determined that the exclusion of EWSR1-exon 8 is the dominant HNRNPH1-dependent event observed in the processing of EWSR1::FLI1 in EWS cell lines harboring EWSR1-intron 8 breakpoints. Though the HNRNPH1/H2 and F proteins are highly homologous (90 and 70% respectively) minigenes focused on EWSR1-exon 8 confirmed our previous findings that only HNRNPH1 is responsible for excluding EWSR1-exon 8. Furthermore a series of minigenes in which we included G-A substitutions to disrupt G-tracts to which HNRNHP1 could bind demonstrated a shift in splicing from detection of both exon inclusion and exclusion events to only exon inclusion. Analysis of HNRNPH1's binding of RNA oligomers corresponding to G-rich regions of the EWSR1-exon 8 3' end using Bio-layer Interferometry demonstrated its binding of these G-rich sequences. HNRNPH1 binds these G-rich sequences with low nM affinities irrespective of structural state - unfolded or folded as parallel G4 structures but exhibits faster association and dissociation rates when these RNAs are in a folded state. Critically using spectroscopic assays we showed that the binding of HNRNPH1 to EWSR1-exon 8 G-rich sequences in a folded state results in a concentration-dependent change in RNA structure to that of one that more resembles an unfolded state. Our results indicate that HNRNPH1's binding of G-rich sequences can destabilize rG4 structures in a non-catalytic fashion. In summary our results provide the first evidence that HNRNPH1's binding of G-rich sequences in a quadruplex state can alter this structural conformation provides insights into the function of HNRNPH1 as a regulator of alternative splicing and suggest means for inhibiting EWSR1::FLI1 expression through disruption of EWSR1::FLI1 mRNA biogenesis. Our current research aims are as follows (1) Determination of cis-regulatory sequences defining EWSR1-exon 8 exclusion in the context of the EWSR1::FLI1 transcript as the basis of a strategy for inhibition of fusion oncoprotein expression in a subset of Ewing sarcomas. (2) Exploration of the adaption of mechanisms that regulate the processing of the pre-mRNAs expressed by EWSR1 or its partner genes to express the translatable product of a fusion gene. (3) The evaluation of splicing regulation by HNRNPH1 to define its functions further and inform the study of disease states associated with mutations in HNRNPF/H genes or sequences they bind Our follow-up studies of the genome-wide RNAi screen of EWSR1::FLI1 activity also identified SF3B1 the catalytic component of the spliceosome a protein complex required for splicing as a protein that EWS cells are dependent upon for cell survival. We discovered that the biogenesis of the EWSR1::FLI1 mRNA is sensitive to disruption of spliceosome function and that canonical splicing is a potential vulnerability in EWS. In 2020 we published an opinion piece that discussed the rationale for studying the biology of cancer-associated fusion transcripts in further detail which included discussion of several other fusion driven cancers including subtypes of leukemia lung and prostate cancer and NUT-midline carcinoma (Neckles Sundara Rajan Caplen Wiley Interdiscip Rev RNA 2020). We have also initiated studies that use multi-dimensional assays to identify additional proteins that regulate the expression or activity of the fusion oncoprotein EWSR1::FLI1. We are using EWS reporter cell lines to evaluate the following hypotheses: (1) A combination of transcriptional post-transcriptional and post-translational mechanisms regulate EWSR1::FLI1 protein homeostasis at levels that support tumorigenesis. (2) One or more regulators of EWSR1::FLI1 protein expression are targetable. Our research also involves evaluating the hypothesis that mechanisms contributing to and resulting from the EWSR1-fusion oncoprotein's deregulation of gene expression represent potential tumor-specific dependencies with therapeutic potential. We are investigating how gene expression regulatory mechanisms contribute to the pathology of an EWSR1-fusion driven cancer with an initial focus on EWSR1 and the study of pathways EWSR1::FLI1 deregulates. For example we demonstrated recently that EWSR1::FLI1 positively regulates the expression of proteins required for serine-glycine biosynthesis and uptake of the alternative nutrient source glutamine (Sen .. Caplen Molecular Carcinogenesis 2018). Specifically we show that EWSR1::FLI1 can alter the expression of PHGDH PSAT1 PSPH and SHMT2 genes encoding enzymes required for serine-glycine biosynthesis. Using cell-based studies we also established that EWS cells are dependent on glutamine for cell survival and that EWSR1::FLI1 positively regulates the expression of the glutamine transporter SLC1A5 and two enzymes involved in the one-carbon cycle MTHFD2 and MTHFD1L. Inhibition of serine-glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species DNA damage and apoptosis. Importantly analysis of EWS primary tumor transcriptome data confirmed that most of the genes identified by our cell-based studies also exhibit increased expression compared with non-diseased tissues including PHGDH and SHMT2. Current studies aim to examine other cellular *TRUNCATED* 1767955 +Antimicrobial Resistance; Biotechnology; Cancer; Cancer Genomics; Genetics; HIV/AIDS; Health Disparities; Human Genome; Infectious Diseases; Minority Health; Pediatric; Pediatric AIDS; Women's Health AIDS clinical trial group;Acquired Immunodeficiency Syndrome;Acute;Adherence;Affect;Anti-Retroviral Agents;Antiretroviral resistance;Biological Assay;Cells;Clinical;Collaborations;Data Set;Drug resistance;Enrollment;Evolution;Failure;Far East;Frequencies;Genes;Genetic;Genetic Recombination;Genome;Genotype;Goals;HIV;HIV Envelope Protein gp120;HIV Genome;HIV Infections;HIV drug resistance;Hawaii;In Vitro;Individual;Infection;Integrase;Interruption;Length;Libraries;Link;Medical;Methods;Minority;Multi-Drug Resistance;Mutation;Participant;Pharmaceutical Preparations;Phylogenetic Analysis;Plasma;Population;Population Dynamics;Proviruses;Recombinants;Red Cross;Regimen;Reporting;Research;Research Institute;Resistance;Rest;Retrovirology;Role;Sampling;Science;Techniques;Technology;Thailand;Variant;Viral;Viral Genome;Viremia;Virion;Virus;acute infection;antiretroviral therapy;bioinformatics pipeline;cost;design;env Genes;experimental study;genome analysis;genome sequencing;high risk population;improved;in vivo;insight;integration site;nanopore;next generation;next generation sequencing;off-target mutation;pre-exposure prophylaxis;pressure;prevent;programs;rare variant;resistance mutation;response;transmission process;virtual Ultrasensitive Single-Genome Sequencing to Study HIV Transmission and Evolution n/a NCI 10702626 1ZIABC011699-07 1 ZIA BC 11699 7 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 954783 NCI "BACKGROUND: In this project we developed a new method for NGS library construction of viral genomes that reduces PCR bias and error eliminates PCR recombinants from the final datasets and generates thousands of single-genome HIV sequences of the same quality as standard sequencing but with 100-fold more variants (Boltz et al. Retrovirology 13:87 2016). This new ultrasensitive SGS (uSGS) assay has been used not only for detecting linkage of rare alleles including drug-resistance mutations (Boltz et al. JCI Insight 2021) but also for in-depth phylogenetic analyses of viral populations. Although it is generally believed that most HIV infections are initiated with a single virion this conclusion rests on experiments in which the number of viral genomes analyzed was relatively small (about 10-100 HIV genomes). We will utilize our uSGS method to perform a deep-dive study of HIV genetics in acute infection. The underlying question is whether in some of the individuals that appear to have been infected with a single virus there were also minority variants that were missed due to shallow sampling. We were able to obtain plasma samples from 15 donors enrolled in the RV254/South East Asia Research Collaboration with Hawaii 010 Trial (101). The trial was conducted by the Thai Red Cross AIDS Research Centre and the Department of Retrovirology U.S. Army Medical Component Armed Forces Research Institute of Medical Sciences. The study was designed to identify acute HIV infection in high-risk populations in Thailand and offer immediate initiation of ART. Fifteen samples were collected from participants during acute HIV infection. Ten of the donors were previously reported to have a single founder virus in acute infection by standard SGS and five donors were shown to have two to five founders using the same approach. In our study we will investigate the presence of a single founder virus verses transmission of multiple founders in acute HIV infection. In total we aim to obtain 10000 HIV genomes from each donor sample constituting the deepest look into the genetics of acute HIV infection. Results from this aim will inform studies using bNAbs in acute infection to target founder viruses and will contribute to our understanding of HIV transmission evolution and population dynamics. In addition to our goals of applying uSGS to studies of transmission and evolution we will also develop the next generation of uSGS using Oxford Nanopore Technologies (ONT). We have begun these studies by demonstrating that ONT can be used to generate accurate near full-length HIV sequencing (Wright et al. Cells 2021) and by developing a pipeline to annotate the sequences generated (Wright et al. Retrovirology 2021). Moving forward we will improve our current ONT assays and pipeline to capture the HIV integration sites as well as the full-length HIV sequences in samples collected from donors on ART. This advancement will contribute significantly to our understanding of HIV persistence. Dr. Freed recently reported that HIV can develop drug resistance in vitro to multiple classes of antiretroviral drugs by acquiring Env mutations. However it is not known if these mutations confer multidrug resistance in vivo as they do in vitro. To investigate the possible contribution of Env mutations to drug resistance in vivo we obtained plasma samples from five donors failing INSTI [raltegravir (RAL)]-containing regimens without mutations in the integrase gene by standard HIV genotyping and with plasma drug levels confirming adherence. Using samples obtained from the ACTG study A5273 we are currently performing uSGS on donor samples from pre-ART early RAL failure and during late RAL failure. Sequences obtained thus far were analyzed for known drug resistance mutations in IN and for newly emergent Env mutations. Several Env mutations emerged upon drug failure in the highly conserved gp120/gp41 interface similar to those confirmed to confer drug resistance in vitro (Hikichi et al. mBio 2021). These preliminary findings suggest that Env mutations might contribute to HIV drug resistance in vivo. If Env mutations are demonstrated to confer resistance to ART we will initiate evolutionary studies to determine the origin and selection pressures on the newly identified drug resistance mutations (e.g. if they existed prior to ART and if so at what frequencies if they are found in donors failing other ART regimens and if they are selected in donors without ART). Understanding the role of Env in ART resistance will have significant clinical impact if mutations are found to confer drug resistance alone or to be a ""stepping stone"" toward virologic failure. ____ACCOMPLISHMENTS: ___Using our SGS assays we demonstrated that pre-exposure prophylaxis can fail to prevent HIV transmission when drug-resistance mutations are present in the donor population of viral variants (Spinelli et al. Clin. Infect. Dis. 72:2025-2028 2021). ___In collaboration with the lab of Dr. Eric Freed (HIV Dynamics and Replication Program) we investigated the role of off-target mutations in the failure of ART to control HIV replication in vivo. We identified several mutations in the gp120-gp41 interface of the HIV env gene that are capable of conferring low- to medium-level resistance to multiple ARVs (Hikichi et al. mBio12:e03134-20 2021). ___We developed new near full-length HIV single-genome sequencing assay using Oxford Nanopore Technologies and demonstrated it's accuracy to be equivalent to other approaches at a reduce cost and higher throughput. This assay will be used to characterize HIV proviruses that persist on ART (Wright et al. Cells. 10 2021). ___We developed a new bioinformatic pipeline to annotate near full-length HIV sequences and determine if they are intact and likely capable of fueling rebound viremia if ART is interrupted (Wright et al. Retrovirology. 18: 16 2021.)." 954783 +Cancer; Genetics; HIV/AIDS; Health Disparities; Immunotherapy; Infectious Diseases; Minority Health Adult;Aftercare;Biological Assay;Cell Fraction;Cell Proliferation;Cells;Child;Clonal Expansion;Clone Cells;Collaborations;Cytotoxic T-Lymphocytes;Data;Disease remission;Dose;Emodin;Ensure;Future;Genes;Genetic;Genetic Transcription;Genome;HIV;HIV Infections;HIV-1;Heterogeneity;Histone Deacetylase Inhibitor;Immune;Immune checkpoint inhibitor;Immune system;In Vitro;Individual;Infection;Infusion procedures;Intervention;Maintenance;Measures;Minor;Modification;National Institute of Allergy and Infectious Disease;Nature;North Carolina;Oncogenes;Opportunistic Infections;Participant;Patients;Peripheral Blood Mononuclear Cell;Population;Process;Production;Proviruses;RNA;Reporting;Research;Resistance;Retroviridae Infections;Sampling;Source;Structure;T memory cell;T-Lymphocyte;Technology;Tissues;Universities;Viral;Virus;Vorinostat;acute infection;anti-PD-1;antiretroviral therapy;cell killing;curative treatments;cytotoxicity;in vivo;inhibitor;insight;integration site;lymph nodes;neutralizing antibody;neutralizing monoclonal antibodies;new technology;peripheral blood;pressure;response;symposium Impact of Interventions on Clonally Expanded Proviruses and Their RNA Expression n/a NCI 10702625 1ZIABC011698-07 1 ZIA BC 11698 7 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 763826 NCI BACKGROUND: The persistence of HIV during antiretroviral therapy (ART) has been shown to be driven by the proliferation of cells that were infected prior to initiating treatment and not from ongoing cycles of HIV replication in the peripheral blood or in tissues such as lymph nodes or gut (McManus et al. J. Clin. Invest. 129:4629-4642 2019; Bozzi et al. Sci. Adv. 5:eaav5045 2019). However little is known about the drivers of cellular proliferation or about their selective maintenance during ART or during treatment with new interventions aimed at controlling HIV without ART. New interventions aimed at achieving HIV remission without ART include latency-reversing agents broadly neutralizing antibodies genetic modifications of HIV proviruses enhancement of immune recognition of infected cells and more. Our current studies are aimed at understanding the selection and persistence of cell clones during ART the drivers of clonal proliferation before and during ART and the effect of new interventions on clonal expansion of infected cells and on the expression of proviruses that persist during ART. Firstly we investigated the distribution of HIV integration sites in cell clones prior to ART and compared it to the distribution of cell clones after years on ART to identify the selection pressures that allow HIV to persist despite treatment (Coffin et al. JCI Insight 4:e128432 2019; Coffin et al. PLoS Pathog. 17:e1009141 2021; Bale Katusiime et al. mBio 12:e00568-21 2021). We found that HIV proviruses that persist on ART are more frequently integrated in regions of the host genome that are not highly expressed and that they are often integrated in the opposite orientation of the host gene. We also found that infected cell clones arise in acute infection and persist for at least 9 years on ART. We are now investigating the effect of the latency-reserving agents on the persistence and dynamics of infected cell clones and on the expression of HIV within infected cell clones. _____One proposed curative intervention for HIV has included treating with agents such as HDAC inhibitors that activate latent proviruses inducing expression of intracellular RNA in the hopes that such expression will result in viral production and killing of infected cells by viral cytotoxicity or targeted cytotoxic T-lymphocyte (CTL) response. However previous studies in which we collaborated with Dr. David Margolis (University of North Carolina) showed only a limited effect on reservoir reduction in participants treated with single or multiple doses of the HDAC inhibitor vorinostat (Archin et al. Nature 487:482-485 2012; Archin et al. J. Infect. Dis. 210:728-735 2014) including a lack of increased viral production in vivo measured by the HIV single-copy assay (SCA). More promising data have been obtained from more potent inhibitors and from combinations of HDAC inhibitors in in vitro studies some of which were conducted by the University of Pittsburgh directed by Dr. John Mellors (Cillo et al. PNAS 111:7078-7083 2014; Wei et al. PLoS Pathog. 10:e1004071 2014). Although these potent inhibitors are believed to be more effective at inducing proviral expression it is not currently known what levels of proviral expression are necessary to induce cell killing. By comparing uninduced and induced PBMCs from the same individuals we will determine which inhibitors are capable of reactivating latent proviruses (those that are not expressing HIV RNA prior to induction) in expanded cell clones and which only increase expression of proviruses that were already expressing at low levels prior to the induction and the heterogeneity of these effects among proviruses. While conducting the in vitro studies on the HDAC inhibitors we also plan to assess the efficacy of curative interventions on expanded clones in vivo. We are using samples accessible through our collaboration with Dr. Eli Boritz at NIAID from before and after a single-dose infusion of anti-PD-1 to measure the effects on clonal proliferation of infected and uninfected cell clones. ____ACCOMPLISHMENTS: Our current research is focused on the effect of anti-PD-1 on the HIV reservoir in vivo. In collaboration with Dr. Boritz we obtained samples from HIV-1-infected patients who received anti-PD-1 infusions to determine the effect of this checkpoint inhibitor on levels of HIV-infected cells during ART (Perez-Rodrigo et al. Conference on Retroviruses and Opportunistic Infections 2021). Using our MDA-SGS assay (described in Project ZIA BC 011681) we are characterizing the sites of integration into the host genome and the proviral structure in infected cells obtained before and after treatment with anti-PD-1. Thus far we have demonstrated the expansion of infected cells with defective proviruses in response to anti-PD-1. We are currently evaluating the effect of anti-PD-1 on cells with intact proviruses. ____Because children have immune systems that are different from adults including a much higher fraction of naive T cells that have been reported to be more resistant to HIV infection we investigated the number of infected cells clones in children the timing of their emergence and their persistence on ART (Bale Katusiime et al. mBio 12:e00568-21 2021). We found that infected cell clones in children arise in early infection and persist for at least 9 years on ART. We also found that there is a selection for proviruses that are in the opposite orientation of the host gene and are in genes that are not highly expressed. We are currently investigating the levels of infected naive and memory T cells in children and the degree to which they form cell clones. To date we have found that 8/8 children studied carry populations of infected naive cells and that some infected naive cells can form cell clones. We are in the process of determining if these cell clones can differentiate and persist despite infection creating a renewable source of infected cells during ART. ____To investigate the drivers of clonal expansion of infected cells before and during ART we compared the integration site profile in ex vivo infected PBMCs to in vivo infected PBMCs collected from donors on short- and long-term ART (Coffin et al. PLoS Pathog. 17:e1009141 2021). We found that integration into oncogenes is only a minor driver of clonal expansion of infected cells suggesting that homeostatic and/or antigenic-driven clonal expansion are the main drivers for persistence of HIV during ART. ____We developed a new technology to investigate the dynamics of infected cell clones before and during ART with higher accuracy and sensitivity than the integration sites assay (Brandt et al. Viruses 13:1235 2021). Using this technology we showed that clones with intact or defective proviruses can increase or decrease in size during treatment. 763826 +Cancer; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health 5' Untranslated Regions;Address;Binding;Biological Assay;Blood;Case Study;Cell Fraction;Cell Proliferation;Cells;Clonal Expansion;Clone Cells;Code;CpG Islands;DNA;Data;EZH2 gene;Epigenetic Process;Frequencies;Future;Genes;Genetic Transcription;Genome;Guanine;HIV;HIV Infections;HIV-1;Histone H3;Immune;Immune response;In Vitro;Individual;Interruption;Intervention;Laboratories;Lysine;Manuscripts;Measures;Methods;Methylation;Multi-Drug Resistance;Natural Killer Cells;Nucleosomes;Opportunistic Infections;Patients;Peripheral Blood Mononuclear Cell;Persons;Plasma;Population;Proliferating;Proviruses;Publications;Publishing;RNA;RNA Splicing;Reporting;Repressor Proteins;Research;Rest;Retroviridae Infections;Reverse Transcription;Role;Sampling;Science;Site;Source;T memory cell;T-Lymphocyte;T-Lymphocyte Subsets;Technology;Testing;Time;Tissues;Transcription Initiation Site;Variant;Viremia;Virus;Virus Latency;animation;antiretroviral therapy;digital;env Genes;epigenetic silencing;follow-up;genome sequencing;in vivo;innovation;lymph nodes;member;prevent;promoter;recruit;resistance mutation;response;symposium;transcription factor;viral fitness Effects of Antiretroviral Therapy on Transcriptional Activity of HIV Proviruses n/a NCI 10702624 1ZIABC011697-07 1 ZIA BC 11697 7 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 763826 NCI BACKGROUND: We and others recently discovered that HIV infection can be maintained during antiretroviral therapy (ART) by the proliferation of cells that were infected prior to initiating ART. However it was not known how commonly such clones express HIV RNA during ART. The findings that expanded clones can be the source of persistent viremia (Maldarelli et al. Science 345:179-183 2014; Simonetti et al. PNAS 113:1883-1888 2016) indicated that at least some members of clonal populations can express unspliced RNA during ART and may therefore result in rebound viremia if ART is interrupted. We hypothesized that the majority of infected cells that persist in individuals on ART have undergone clonal expansion and are composed of members that express HIV RNA. To test this hypothesis we examined HIV expression levels in single cells in both treated and untreated individuals using our single-cell HIV cell-associated RNA and DNA single-genome sequencing (CARD-SGS) method (Wiegand et al. PNAS 114:E3659-E3668 2017). We determined the fraction of HIV-1 proviruses within infected cell clones that express unspliced HIV-1 cell-associated RNA during ART (Musick et al. Front. Microbiol. 10:2204 2019). In total 34 different clones carrying either intact or defective proviruses were assessed. We found that about 3% of cells within clones contained unspliced HIV-1 RNA. Highest levels of HIV-1 RNA were found in the effector memory T-cell subset. The fraction of cells within clones that contained HIV-1 RNA was not different in clones with intact (median 2.3%) vs. defective (median 3.5%) proviruses (p=0.2). However higher fractions and levels of RNA were found in cells with proviruses containing multiple drug resistance mutations including those contributing to rebound viremia. These findings show that the vast majority of HIV-1 proviruses within expanded T-cell clones including intact proviruses may be transcriptionally silent at any given time implying that infected T cells may be able to be activated to proliferate without inducing the expression of the integrated provirus or alternatively may be able to proliferate without cellular activation. ____ACCOMPLISHMENTS: We previously reported a replication-competent HIV-1 variant that is produced by a highly expanded cell clone and persists in the plasma of an HIV-infected donor treated with ART (Simonetti et al. PNAS 113:1883-1888 2016). In 2020 we expanded this case study to 5 additional donors with their viremia suppressed on ART and demonstrated that clones carrying and expressing replication-competent HIV are common among donors (Halvas et al. J. Clin. Invest. 130:5847-5857 2020). To follow up on the hypothesis that cells may differentiate and proliferate without inducing the expression of the integrated provirus we sorted PBMCs collected from patients with viremia fully suppressed on ART into resting (DR-) and activated (DR+) subsets. We isolated single infected cells from the subsets and measured the fraction that have HIV RNA and the levels of HIV RNA in each of the single cells. Our data show that the fraction and levels of HIV RNA are not different in the resting and activated cells indicating that infected cells that persist on ART are able to maintain proviral latency despite proliferation and activation (Groebner et al. Conference on Retroviruses and Opportunistic Infections 2021). The results of this study are currently being assembled into a manuscript. _____Because our previous studies showed that only a small fraction of infected cells that persist on ART have proviruses that are transcriptionally active we hypothesized that the HIV promotor in the 5' untranslated region may contain CpG islands that are DNA methylated. Such methylation may prevent the expression of the HIV provirus by inhibiting the binding of the HIV transcription factors. To test this hypothesis we isolated single HIV proviruses that were previously shown to be transcriptionally silent in vivo treated them with bisulfate to deaminate unmethylated CpG islands and quantified the number of guanines that retained their animation (indicating that they were methylated). Although we found CpG islands within HIV coding regions that were methylated we rarely identified methylated guanines within the HIV promotor of transcriptionally silent proviruses. Our findings show that methylation of the HIV promotor is not a mechanism for HIV persistence. We published these findings in Viruses in 2021 (Boltz et al. Viruses 13:799. 2021). ___Since methylation of the HIV promoter was not found to be a mechanism for HIV latency in donors on ART we investigated the expression of an antisense gene (Ast) encoded within the HIV env gene (Sklutuis et al. Conference on Retroviruses and Opportunistic Infections 2022). In vitro studies showed that HIV encodes an antisense gene that recruits and retains EZH2 a component of the polychrome repressor complex-2 (PRC2) to the HIV-1 5'LTR. EZH2 catalyzes the trimethylation of lysine 27 on histone H3 a suppressive epigenetic mark that promotes nucleosome assembly and suppresses of HIV-1 transcription. This mechanism suggests that Ast acts as a lncRNA in promoting epigenetic silencing of the HIV-1 5'LTR to induce and maintain viral latency in HIV infected cells. To address these findings our laboratory recently explored the expression levels of Ast in single infected cells isolated from donors with viremia suppressed on ART using digital reverse transcription PCR. We found that a median of 26% of infected PBMCs were detected to express HIV Ast at a given point in time. This finding confirmed the presence of detectable Ast levels in donors with their viremia suppressed on ART and suggests its potential role as a regulatory RNA. The results of our Ast study are being prepared for publication. ____ In the absence of ART levels of plasma viremia vary in people living with HIV (PLWH). What determines levels of plasma viremia within individuals is not fully understood but is likely associated with levels of proviral expression immune-control and viral fitness. More than 90% of PLWH have limited natural control of HIV-1 replication without ART (non-controllers); however a small fraction of PLWH (5%) naturally control levels of HIV-1 replication which is reflected by lower levels of plasma viremia (controllers). However using the CARD-SGS assay (described above) our preliminary data reveal that there is not a higher fraction of infected cells with transcriptionally active proviruses in non-controllers compared to viremic controllers (determined by measuring levels of unspliced HIV-1 RNA in single infected cells). Rather there are fewer total infected cells in viremic controllers. These findings suggest that natural control of HIV replication is not due to a higher fraction of latently infected cells in these individuals but is due to more potent immune responses (i.e. NK cell and/or CTL responses) that efficiently recognize and kill infected cells that express HIV RNA. Our future studies will characterize the immune responses in HIV controllers and non-controllers. 763826 +Biomedical Imaging; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Adult;Adult Glioma;Affect;American;Apoptosis;Area;Astrocytoma;Basic Science;Biopsy;Brain Neoplasms;CCR;Cancer Center;Canis familiaris;Catalogs;Cell Line;Central Nervous System;Characteristics;Childhood Glioma;Classification;Classification Scheme;Clinical;Clinical Trials;Collaborations;Companions;Comparative Pathology;Consensus;Data;Data Commons;Development;Diagnosis;Discipline;Disease;Early Diagnosis;Enrollment;Event;Excision;Expression Profiling;Extramural Activities;Face;Freezing;Funding;Future;Genomics;Glass;Glioma;Goals;Grant;Group Structure;Hematoxylin and Eosin Staining Method;Histologic;Histology;Histopathology;Human;Illinois;Image;Immunotherapeutic agent;Incidence;Income;Informatics;Infrastructure;Institution;Internal Medicine;Joints;Journals;Knowledge;Link;Magnetic Resonance Imaging;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Manuscripts;Medicine;Methylation;Minnesota;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;National Center for Advancing Translational Sciences;National Heart Lung and Blood Institute;Nature;Neurologist;Neurology;Oncology;Operative Surgical Procedures;Outcome;PAC1 phosphatase;Paper;Pathologic;Pathology;Patient Care;Patients;Pharmacology;Physicians;Pituitary Neoplasms;Play;Positron-Emission Tomography;Pre-Clinical Model;Prevention;Procedures;Process;Publications;Publishing;Radiology Specialty;Reporting;Research;Research Personnel;Role;Slide;Specialist;Stains;Surveys;TP53 gene;Texas;The Jackson Laboratory;Time;Tissues;Training;United States National Institutes of Health;Universities;Update;Veterinarians;Veterinary Medicine;base;cancer cell;cancer clinical trial;college;comparative;disease natural history;drug development;drug discovery;exome;exome sequencing;experience;glioma cell line;high-throughput drug screening;human disease;human model;imaging agent;improved;improved outcome;interest;irradiation;meetings;member;meningioma;neuro-oncology;neuropathology;novel;oligodendroglioma;oncology program;pathology imaging;prospective;ranpirnase;small molecule;statistics;stem cells;transcriptome sequencing;tumor;ultrasound;working group Comparative Brain Tumor Consortium n/a NCI 10702623 1ZIABC011696-07 1 ZIA BC 11696 7 14280471 "LEBLANC, AMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 108586 NCI The COP has made significant progress on the inaugural comparative pathology effort for this new initiative in 2018 with a publication currently in review at the Journal of Neuropathology and Experimental Neurology. The pathology board consisting of a joint veterinary/physician neuropathology commission of 14 members developed an updated grading and classification scheme for canine gliomas to promote uniformity in diagnosis across institutions and improve making comparisons with human adult and childhood gliomas. A retrospective pathologic assessment of approximately 200 hematoxylin and eosin stained glass slides + a panel of 5 IHC markers treatment-naive canine gliomas of all subtypes and grades has been conducted. The CBTC membership has also proposed genomic analyses and expression profiling of a minimum of 50 canine high-grade gliomas meeting these newly revised classification criteria to allow for comparison with human adult and childhood gliomas and to generate potential pharmacologic targets for canine patients. This project will be both retrospective and prospective in nature. For the retrospective portion snap-frozen tissue from institutions with paired banked FFPE tissue from histopathology-confirmed glial tumors that have been confirmed within the newly proposed grading and classification scheme will be subjected to whole-exome sequencing and RNA-seq. For the prospective portion CBTC members (Texas A&M University/MD Anderson Cancer Center University of Minnesota and University of Califnornia @ Davis) have partnered with Roel Verhaak at the Jackson laboratory. Dr Verhaak is working with these CBTC members whom have received NCI funding through a P30 CC supplemental mechanism to generate molecular profiles from an overlapping set of canine gliomas which will include WGS/WES/RNAseq and methylation profiling data. Sequence information was subjected to informatics processed and shared publicly through the NCI Integrated Canine Data Commons (ICDC) and published in Cancer Cell. We have also initiated several other projects in this area which are listed here: 1. Whole-exome and RNA sequencing of n = 100 canine meningiomas (in collaboration with Peter Dickinson at UC-Davis M. Renee Chambers at UAB and Greg Tawa/NIH/NCATS 2. Survey instrument to veterinary neurologists in the US to capture the clinical landscape of canine brain tumor management 3. High-throughput drug screening of P53 w/t canine and childhood glioma cell lines 4. A clinical trial of a novel capsize-3 activating small molecule (PAC-1) in dogs with meningioma which is linked to assessment of a novel apoptosis-reporting PET imaging agent (in collaboration with NHLBI/IPDC NCI/CCR/MIP and University of Illinois. 5. MRI consensus statement on harmonization of imaging parameters for dogs enrolled in brain tumor clinical trials (manuscript published in Veterinary Radiology and Ultrasound). New projects proposed for 2018- beyond include: a companion comparative histologic and molecular characterization project in canine meningioma; extension of the HTS project with NCATS to include 5 new canine glioma stem cell lines generated at Univ of CA-Davis and a bi-monthly WebEx to offer continuing exchange of ideas and projects among interested CBTC members. 108586 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Address;Adjuvant;Adolescent;Adult;Adverse event;Age;Agonist;Aliquot;Amputation;Animal Testing;Antineoplastic Agents;Area;Back;Biological;Biological Assay;Biological Markers;Biological Models;Biological Specimen Banks;Biology;Brain Neoplasms;Cancer Biology;Cancer Model;Cancer Patient;Canis familiaris;Carboplatin;Cell Line;Characteristics;Child;Childhood;Childhood Osteosarcoma;Clinical;Clinical Data;Clinical Trials;Collaborations;Collection;Companions;Complex;Conduct Clinical Trials;Custom;DNA;DNA Resequencing;DNA Sequence Alteration;DNA copy number;DNA sequencing;Data;Databases;Development;Disease;Drug Combinations;Drug Targeting;Early treatment;Engraftment;Event;Extramural Activities;Formalin;Freezing;Future;Gene Expression;Genes;Genome;Genomics;Goals;Growth;Health;Human;Human Cell Line;In Vitro;Infrastructure;Inherited;Investigation;Knowledge;Laboratories;Libraries;Link;Malignant Bone Neoplasm;Malignant Neoplasms;Metastatic Neoplasm to the Lung;Mission;Modeling;Molecular;Multi-Institutional Clinical Trial;Mus;National Center for Advancing Translational Sciences;Natural History;Neoplasm Metastasis;Normal tissue morphology;Oncogenes;Outcome;Pathologist;Pathology;Pathway interactions;Patients;Pediatric Neoplasm;Pharmaceutical Preparations;Phase;Physicians;Positioning Attribute;Pre-Clinical Model;Preclinical Drug Development;Preclinical Testing;Primary Neoplasm;Process;Progression-Free Survivals;Proteomics;Publishing;Puma;RNA;Rapid screening;Reagent;Research Design;Resource Development;SNP array;Sampling;Single Nucleotide Polymorphism;Sirolimus;Specimen;Techniques;Testing;Time;Tissue Preservation;Toxicogenomics;Translating;Treatment Failure;Treatment Protocols;Tumor stage;Work;Xenograft procedure;anticancer research;arm;assay development;base;cancer clinical trial;cancer type;central database;chemotherapy;clinical application;cohort;comparative;comparative genomic hybridization;demographics;design;dog genome;drug development;exome;exome sequencing;experimental study;genome-wide;improved;improved outcome;in vivo;in vivo Model;inhibitor;innovation;laboratory experiment;mouse model;neglect;new therapeutic target;novel therapeutic intervention;novel therapeutics;oncology program;osteosarcoma;pre-clinical;programs;repository;sarcoma;screening;standard of care;success;transcriptome sequencing;translation to humans;treatment response;tumor Comparative Oncology Program Laboratory n/a NCI 10702622 1ZIABC011692-07 1 ZIA BC 11692 7 14280471 "LEBLANC, AMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1954544 NCI Laboratory activities and projects carried out by the COP laboratory have the specific goal of improving the understanding of the impact of anti-cancer agents on comparative aspects of metastasis biology by virtue of parallel study of murine canine and human cell lines in a variety of in vitro ex vivo/in vivo (Pulmonary Metastasis Assay or PuMA) model systems. Data generated in this manner improves understanding of naturally-occurring canine osteosarcoma (OS) models and could be employed to answer unique in vivo questions regarding the anti-metastatic potential of agents via the COTC clinical trial mechanism. To extend our investigations into the comparative aspects of naturally-occurring OS in dogs to humans we have recently initiated the DOG2 project: Decoding the Osteosarcoma Genome of the Dog. The DOG2 project fulfills the main mission of the NCI-COP which is to strategically position the canine cancer patient in studies of cancer biology and drug development in order to improve outcome for both dogs and humans. The COP has a longstanding focus in osteosarcoma (OS) biology and clinical trials. OS is an aggressive pediatric/AYA malignancy and the most common malignant bone tumor in children and adolescents. OS is also a common naturally-occurring canine cancer with strikingly similar clinical presentation and natural history; preliminary studies suggest a shared molecular landscape. While dogs largely develop OS in adulthood the similar genomic features and clinical disease characteristics underscore the notion that age does not distinguish canine OS from the disease in children. We recognize that osteosarcoma is a complex disease and success is unlikely with a single approach. Therefore to expand this work it is necessary to identify additional targets and drugs. Collectively this work is designed to address the following strategic priorities: 1. Improved knowledge of comparative OS cancer biology to enhance dog to human translation 2. Discovery of new targets and companion biomarkers in support of drug development 3. Assessment and prioritization of new therapeutic strategies in preclinical models 4. Harmonization of comparative canine and human oncology clinical trials to advance new therapeutic concepts Biospecimens. We will utilize an existing high-quality clinically-annotated biospecimen repository of 400 canine OS patient sample sets unique to the NCI gathered from ongoing and completed canine OS clinical trials. This repository contains multiple aliquots of both tumor and matched normal tissues preserved as frozen RNAlater and formalin-fixed specimens. Samples have been derived from treatment-naive dogs that all underwent the same treatment protocol (amputation + 4 cycles of carboplatin chemotherapy). We have full clinical data on every patient including demographics treatment details/adverse events and event-free and overall survival. We propose beginning with a subset of n = 100 patient samples selected from the ends of a Kaplan-Meier curve that represent early treatment failures (progression-free survival less than 90 days) vs. elite responders (progression-free survival greater than 360 days). We will also query n = 25 matched pairs of tumors with their metastases that developed despite therapy. We have not attempted to perform viability testing for PDX engraftment in NSG mice due to the technical challenges and low rate of metastasis associated with PDXs; rather we use 4 unique canine OS cell lines developed in our lab for dog-in-mouse preclinical testing and are in the process of creating and curating a collection of over 25 additional canine OS cell lines from extramural collaborators. All specimens will be subjected to pathology review by an expert board of veterinary and physician sarcoma pathologists to verify adequate sample quality for further genomic study. For genomic profiling we will employ the following platforms to execute a combination of experiments to understand relationships between genomic complexity and integrity (CGH and WES to identify structural rearrangements single nucleotide variants copy number gain/loss) and gene expression (through RNAseq). The specific breed of dog will be verified through use of a germline SNP array recently made available through MARS/Wisdom Health. Samples for genomic profiling will be sent to our collaborator at NCSU (Matthew Breen) for DNA and RNA isolation library prep CGH for genome-wide DNA copy number profiling (Agilent CGH array) and for DNA whole exome sequencing (150b paired end reads at 100x for tumors/30x for normal NovaSeq6000 platform with Roche dog exome kit) methyl-DNA resequencing as well as RNA sequencing (125b paired end reads Illumina HiSeq2500 platform). Computational approach. This project is an extension of an existing collaboration with NCSU and the NCATS Division or Preclinical Innovation (DPI) and Therapy for Rare and Neglected Diseases (TRND) program. Through experiments we have already conducted in n = 12 canine OS sample sets similar to those described above as a discovery cohort the TRND bioinformaticians have developed a strategy that identifies distinct gene co-expression models between and specific to a set of 5 selected canine cancer types of which OS is one from which they derive cancer-specific gene panels. A similar analysis is performed on existing RNAseq data publicly available from human tumor samples from the same tumor types to produce cancer-specific human gene panels. These cancer-specific shared gene panels are compared and genes common to both are retained to facilitate dog-to-human translation of genomic alterations. The RNAseq data after alignment to reference is then compared back to CGH and whole-exome DNA sequencing carried out in the same tumor sample to identify genomic changes (CNV SNV) that are linked to expression changes and that may represent new druggable targets. These oncogenes or other drug targets in given pathway(s) were used to identify inhibitors suppressors or agonists utilizing Pharos which interfaces to a central database containing information about the targets collected by the Illuminating the Druggable Genome (IDG) program and the Comparative Toxicogenomic Database (CTD). This combined experimental/computational approach has already been tested using both proteomic and RNAseq data generated from the first n = 12 OS tumor/normal pairs. The data has been analyzed at NCATS to match changes in gene expression to drugs known to modulate the pathways associated with the associated genes. Canine OS cell line screening is already underway through NCATS to determine the in vitro impact of 40 drugs including 30 synergistic combinations based on the respective drugs' pathway modulation profile. These data serve as a proving ground for additional work carried out in a larger outcome-linked collection of tumor samples proposed herein. Single agents or combinations of drugs identified in Phase I will be tested in our existing panel of human and canine OS cell lines and screened rapidly through available xenograft human-in-mouse and canine-in-mouse models within the COP laboratory. This preclinical animal testing is critical to ranking and advancing appropriate candidates for further study and to understand the comparative features of how drugs behave in our in vivo models. We have expertise in both primary tumor and metastasis modelling to evaluate drug impact at several stages of tumor development and progression. These results will be the basis (go/no go decisi *TRUNCATED* 1954544 +Biotechnology; Cancer; Digestive Diseases; Lung; Lung Cancer; Orphan Drug; Rare Diseases; Women's Health Antibodies;Antibody-drug conjugates;Bioinformatics;Colorectal Cancer;Critical Pathways;Dependence;Development;Drug Targeting;Enzymes;Genetic;Genomic approach;Goals;Head Cancer;Head and Neck Cancer;KRAS2 gene;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of ovary;Modality;Molecular;Neck Cancer;Oncogenic;Phosphotransferases;Play;Role;Small Interfering RNA;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;Structural Models;Therapeutic Intervention;anticancer research;functional genomics;genome editing;inhibitor;lung tumorigenesis;malignant breast neoplasm;mutant;novel;novel therapeutics;precision drugs;screening;targeted treatment;tumorigenesis Oncogenic Kinases in Cancer n/a NCI 10702621 1ZIABC011691-07 1 ZIA BC 11691 7 14731989 "BROGNARD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2017257 NCI The lab utilizes a multitude of strategies to identify critical pathways required to promote tumorigenesis. These include high-throughput bioinformatics and structural modelling siRNA screening and precision genome editing to establish various functional genomic approaches to identify novel drivers. Utilizing bioinformatics we identify novel kinases enriched for copy number alterations to hone in on activated enzymes that can serve as drug targets. We are focused on novel drivers of the 3q amplicon that play a critical role in promoting tumorigenesis in lung squamous cell carcinoma head and neck cancer and ovarian cancer (Torres-Ayuso et. al. Cancer Discovery Edwards et al. Cancer Research). These novel drivers can serve as targets of therapeutic intervention and an intense effort will be focused on the mechanisms by which these amplified kinases promote tumorigenesis. In addition we are studying a novel kinase target that represent a genetic dependency in KRAS mutant lung adenocarcinomas (Hoang et al. JBC). Lastly we are developing novel antibody-precision drug conjugates (APDCs) to co-target multiple kinase drivers in head and neck Breast Esophageal and colorectal cancer. 2017257 +Biotechnology; Cancer; Genetics Alleles;BRAF gene;Biochemical;Bioinformatics;Biological Assay;Communities;Critical Pathways;Cultured Cells;Dependence;Development;Genetic;Genomic approach;Goals;Human;Knowledge;Lead;Malignant Neoplasms;Molecular;Monitor;Mutation;Oncogenic;Pathway interactions;Patients;Phenotype;Phosphotransferases;Process;Research;Screening for cancer;Small Interfering RNA;Somatic Mutation;Structural Models;cancer genomics;driver mutation;drug development;functional genomics;functional restoration;genome editing;in vivo;loss of function;loss of function mutation;mutant;novel;response;screening;targeted treatment;tumor;tumorigenesis Novel Tumor Suppressing Kinases in Cancer n/a NCI 10702620 1ZIABC011690-07 1 ZIA BC 11690 7 14731989 "BROGNARD, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 106172 NCI Cancer genomic sequencing has significantly impacted our understanding of the temporal and spatial genetic alterations that lead to tumorigenesis. This information enables the development of targeted therapies that result in durable and less toxic responses in patients. In regard to kinases the biomedical community has focused research efforts on approximately 200 kinases among the 538 kinases present in the human kinome yet siRNA screens and cancer genomic studies indicate that the vast majority of these unexplored kinases (approximately 300) are implicated in cancer and harbour putative driver mutations. The major focus of my research will be to elucidate novel cancer-associated kinases in the unexplored kinome guided by bioinformatics and functional genomic approaches with an overarching aim of understanding the molecular mechanisms utilized by these kinases to promote tumorigenesis. The lab utilities a multitude of strategies to identify critical pathways required to promote tumorigeneis. These include high-throughput bioinformatics and structural modeling siRNA screening and precision genome editing to establish various functional genomic approaches to identify novel drivers. A completed focus for this project was to perform a motif driven pan-cancer analysis to elucidate the tumour suppressing kinome. This strategy utilities our knowledge of kinases and the requirement for certain kinase motifs to maintain activity (DFG HRD APE for example) and our screen has identified several novel kinases enriched for functional mutations. We will take these kinases further such as MYO3A to assess if this is a novel tumor suppressing kinase. We will study the kinases identified in these screens as follows: general strategy - to determine the functional consequences of somatic mutations in candidate cancer-associated kinases we will carry out a focused logical and stepwise process. We will begin with biochemical kinase assays and functional analysis by expression of WT (wild type) and mutant kinases in cultured cells progressing to utilize genome editing to correct mutant alleles and monitoring phenotypic impacts of restoring function of a tumor suppressing kinase moving on to in vivo tumorigenesis studies and finally investigating the mechanisms of action. Analysis of somatic mutations in a given kinase will only be continued if promising results are observed at each step. When this is not the case we will terminate studies on that kinase and proceed to the next top-tier kinase from our bioinformatic analysis. 106172 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health; Pediatric; Pediatric AIDS; Women's Health Address;Anatomy;Area;BACH2 gene;Biological Assay;CD4 Positive T Lymphocytes;Cells;Cellular biology;Child;Chromosome inversion;Clonal Expansion;Clone Cells;Collaborations;Data;Databases;Event;Frequencies;Genes;Genetic;Genetic Recombination;Genetic Structures;Genome;HIV;HIV Genome;HIV Infections;Individual;Interruption;Investigation;Lead;Length;Location;Malignant Neoplasms;Manuscripts;Measures;Memory;Meta-Analysis;Methods;Mutation;Patients;Population;Process;Proto-Oncogenes;Proviruses;Research;Research Personnel;Retrovirology;STAT5B gene;Sampling;Science;Site;Source;Structure;T memory cell;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Tissues;Universities;Update;Variant;Viral;Viremia;Virion;Virus;Virus Replication;antiretroviral therapy;base;bioinformatics pipeline;cell type;experimental study;genetic information;genome sequencing;homologous recombination;improved;indexing;integration site;lymph nodes;nanopore;next generation sequencing;novel;pressure;prevent;programs;public database;self-renewal;virtual;web page;web-accessible Dynamics and Genetics of HIV Proviruses before and during Antiretroviral Therapy n/a NCI 10702615 1ZIABC011681-07 1 ZIA BC 11681 7 14731978 "KEARNEY, MARY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1145739 NCI BACKGROUND: We and others showed that HIV-infected cells can clonally expand and persist despite ART and that the proviral integration site may influence this phenomenon (Maldarelli et al. Science 345:179-183 2014; Wagner et al. Science 345:570-573 2014). A major focus of this project is to determine how commonly such clonally expanded infected cells that persist during ART carry replication-competent proviruses and in which tissues and cell types they persist. To answer this question we developed a novel method called the multiple-displacement amplification single-genome sequencing (MDA-SGS) assay which allows us to analyze the proviruses in highly expanded clones (Patro et al. PNAS 116:25891-25899 2019). The MDA-SGS assay will determine if HIV proviruses in expanding clones that persist during ART have intact sequences or contain lethal mutations or deletions. We will further determine if when activated such clones are capable of producing infectious virions. If we show that latent intact proviruses in infected cells commonly undergo clonal expansion it will mean that strategies intended to cure patients will have to not only block viral replication but also cope with the proliferation of these latently infected cells. ____ACCOMPLISHMENTS: Last year to investigate the HIV reservoir in children we conducted studies to determine if expanded infected cell clones were present in children born with HIV infection and if these cell clones persisted during ART (Bale Katsuimme et al. mBio 12:e00568-21 2021). We found that infected T cell clones arose early in children (less than 2 months old) and that they persisted for at least 9 years during treatment. These findings demonstrated that the HIV reservoir in children is maintained by clonal expansion of cells that were infected prior to initiating treatment. This year we expanded these studies to address two additional questions pertaining to children born with HIV. First we investigated the proviral structures in the largest infected T cell clones in children on ART for more than 6 years and found all of them to contain only solo LTRs. These findings are important because they suggest that homologous recombination of the HIV LTRs after integration may lead to the deletion of HIV genes leaving only a single LTR. If correct then it is reasonable to assume that some intact HIV genomes will be deleted over time through this mechanism and that this mechanism may be able to be exploited towards a cure for HIV. The results of this study are currently being assembled into a manuscript. Our second accomplishment in this area is a finding that infected naive cells can be identified in virtually all children born with HIV and that at least in some clones of infected naive cells are found. These findings change our understanding of T cell biology and of HIV persistence since the proliferation of infected naive cells can lead to a self-renewing pool of infected central and effector memory T cells. We are currently in the process of defining the proviral structures in the clones of infected naive cells in children. ____We previously established two new public database to store and annotate HIV proviral sequences and their integration sites into the host genome especially those that persist in donors on ART. These databases (PSD; https://psd.cancer.gov and RID; https://rid.ncifcrf.gov/index.php ) are available for meta-analyses of proviruses that persist on ART to better understand the HIV reservoir and to inform strategies towards a cure. This year we grew the PSD to 4870 full-length HIV proviruses collected from donors on ART. The PSD is accessed about 25 times daily by investigators worldwide. We grew the RID to 6300189 HIV integration sites. The RID is accessed about 45 times daily from investigators worldwide. ____We developed two new bioinformatic pipelines to annotate and detect intact HIV proviruses that persist during ART (Wright et al. Retrovirology 18:16 2021) (Wright et al. Cells 10 2021). Our pipelines are unique because they can be incorporated into existing pipelines to extract and align HIV sequence reads from next-generation sequencing experiments (Illumina and Oxford Nanopore). This year we also improved the pipelines to detect sequence inversions in some HIV proviruses that persist during treatment. ____In collaboration with John Mellors (University of Pittsburgh) we investigated the genetic structure of proviruses that persist on ART using a new integration sites assay that captures HIV LTR gag env and nef sequences. This assay is an improvement on the previous HIV integration sites assay which is not capable of capturing HIV genetic information. We found that a high fraction of HIV proviruses that persist on treatment have asymmetric LTRs possibly preventing recombination of the LTRs and allowing these proviruses to persist for years on treatment (Joseph et al. J. Virol. e0012222 2022). ____ To build on our collaboration with John Mellors we developed a qPCR-based assay that measures the size of HIV infected cell clones in donors on ART and can be used to investigate the dynamics of these cell clones over the course of treatment (Brandt et al. Viruses. 13 2021). We found that most infected cell clones are highly stable over the course of treatment including those with intact HIV proviruses. However a few infected T cell clones with intact HIV proviruses grew larger over time and a few diminished in size over longitudinal samples. ____ In collaboration with John Coffin (Tufts University) and Steve Hughes (HIV Dynamics and Replication Program NCI) we conducted the most thorough investigation to date of selection pressures for and against HIV proviruses that persist in individuals on long-term ART (Coffin et al. PLoS Pathog. 17: e1009141 2021). We found that integration events into 6 different genes can results in selection for persistence of HIV proviruses. Integration events into these genes which are proto-oncogenes such as BACH2 and STAT5B enhance the proliferation of the T cells or promote their survival. This finding demonstrates that there is a self-renewing pool of HIV infected cells during treatment and show that halting viral replication alone will not be sufficient to cure HIV infection. 1145739 +Cancer; Immunotherapy; Infectious Diseases; Microbiome; Nutrition Address;Affect;Animals;Anorexia;Antibiotics;Antitumor Response;Autoimmunity;Blood;Bone Marrow;Cell Differentiation process;Cell physiology;Cells;Characteristics;Chronic;Cues;Dendritic Cells;Development;Diet;Distant;Embryonic Development;Epithelial;Experimental Neoplasms;Germ-Free;Goals;Homeostasis;Immune;Immune Evasion;Immune response;Immunity;Immunotherapy;Individual;Infection;Inflammation;Inflammatory;Invaded;Lead;Lymphoid;Lymphoid Tissue;Maintenance;Malignant Neoplasms;Mammals;Metabolic;Metabolism;Modeling;Molecular;Mononuclear;Mus;Myelogenous;Myeloid Cells;Natural Immunity;Nature;Neoplasm Metastasis;Neutrophilic Infiltrate;Obesity;Outcome;Pathologic;Pathway interactions;Peripheral;Phagocytes;Phenotype;Play;Population;Population Control;Predisposition;Regulation;Resistance;Resolution;Role;Science;Signal Transduction;Surface;System;T-Lymphocyte;Tissues;Transcriptional Regulation;Tumor Immunity;Virus Diseases;adaptive immune response;adaptive immunity;angiogenesis;anti-cancer;cancer cachexia;cancer therapy;chemotherapy;commensal bacteria;commensal microbes;comorbidity;dietary manipulation;gut microbiota;improved;macrophage;microbiota;monocyte;neutrophil;novel;novel therapeutic intervention;pathogen;response;subcutaneous;systemic inflammatory response;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression Role of the microbiota in regulating the mononuclear phagocyte system n/a NCI 10702612 1ZIABC011670-08 1 ZIA BC 11670 8 78355387 "GOLDSZMID, ROMINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1277572 NCI Mononuclear phagocytes MPs play crucial roles in the initiation of innate and adaptive immune responses and in the maintenance of tissue homeostasis. Although MPs share several phenotypic and functional characteristics it has recently become clear that dendritic cells (DC) macrophages (Mac) and monocytes (Mo) are not homogeneous populations and instead they represent developmentally and functionally distinct populations that differentially regulate T cell function. MPs are major components of the tumor microenvironment where they play a dual role inducing adaptive anti-tumor responses but also sustaining immune evasion tumor progression and metastasis formation. Despite major advances in the identification of the MPs developmental pathways and their transcriptional regulation the individual contribution of these distinct cell subsets to the induction and resolution of immunity against invading pathogens or to anti-tumor responses or immune evasion as well as the environmental signals involved in their regulation remain unclear. In this project we will use murine experimental tumor models to investigate the mechanisms regulating MP differentiation and function with particular emphasis on the role of the commensal microbiota. Local and systemic inflammation modulates cancer susceptibility (e.g. in obesity) cancer progression response to therapy and co-morbidity (e.g. cancer cachexia/anorexia). The microbiota influences both immune and metabolic function beyond the gut including peripheral innate cell responses autoimmunity and response to viral infections. In recent studies we have shown that gut commensals control the response of subcutaneous tumors to immunotherapy and chemotherapy by modulating tumor infiltrating MP function (Science 2013 342:967-970). This study demonstrates the novel finding that and intact gut microbiota is needed for optimal response to cancer therapy and underscores the potential to improve cancer treatment by manipulating the gut microbiota. However the exact molecular mechanisms by which commensal bacteria modulate systemic inflammation are still unknown. We use several approaches to address this question performing parallel studies in cancer and infection models. We utilize the germ-free (GF) facility at NCI-Frederick to compare conventionally reared GF animals or animals treated with different antibiotics or given different diets to modulate the microbiota composition either under steady state or different inflammatory settings. We have characterized the innate myeloid and lymphoid infiltrate in several tumor models in the presence or absence of intact microbiota. Our results showed that in the absence of an intact microbiota there is a skewing of myeloid cell differentiation towards a pro-tumoral phenotype. We have shown that these changes occur specifically in the tumor and are not observed in the bone marrow blood or peripheral lymphoid tissues. Importantly we have identified the cellular and molecular pathways involved and we have shown that dietary manipulation of the microbiota can trigger the same pathways to improve anti-cancer immunity. We are currently extending these studies to interrogate the role of microbiota in metastasis formation. In parallel studies we are dissecting the role that individual myeloid cell population play in response to cancer therapy. We demonstrated that neutrophils are required for the optimal response to chemotherapy showed that tumor-infiltrating neutrophils are highly heterogeneous and phenotypically and functionally distinct from circulating neutrophils. We have also shown that microbiota-derived signals regulate neutrophil dynamics in the TME. In a different set of studies we are addressing the role of different myeloid cell populations in tumor progression. In particular we are studying the dynamics of the monocyte/macrophage compartment during chronic inflammatory conditions and how their impact on tumor growth. 1277572 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics; Hematology; Immunotherapy; Lymphatic Research; Lymphoma; Orphan Drug; Rare Diseases Antigens;CAR T cell therapy;CD28 gene;Cell Culture Techniques;Chimeric Proteins;Clinical;Clinical Protocols;Clinical Trials;Development;Generations;Goals;Hodgkin Disease;Human;Immune response;In Vitro;Ki-1 Large-Cell Lymphoma;Lead;Lentivirus Vector;Lymphoma;Manuscripts;Methods;Modeling;Mus;Patients;Phase I Clinical Trials;Proteins;Reporting;Risk;Series;T-Cell Activation;T-Lymphocyte;TNFRSF8 gene;Testing;Toxic effect;Transmembrane Domain;Work;chimeric antigen receptor;chimeric antigen receptor T cells;design;human tissue;improved;large cell Diffuse non-Hodgkin's lymphoma;novel therapeutics;pre-clinical;receptor;response;tumor Development of fully-human anti-CD30 chimeric antigen receptors n/a NCI 10702609 1ZIABC011660-08 1 ZIA BC 11660 8 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 138759 NCI We designed 4 different single chain Fv molecules as antigen-recognition domains for anti-CD30 CARs and compared CARs with these different scFvs in vitro. We selected the optimal scFv and tested it in different CAR designs in vitro and in mouse tumor models. We have identified an optimal scFv and CAR design for further development. This work led to 2 CARs that are both highly effective in mice. We have selected one of these CARs for a phase I clinical trial. Simultaneous work has been completed that has led to generation of a clinical-grade lentiviral vector encoding this CAR. We completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR. We have completed preclinical work to improve anti-CD30 CAR design and T-cell culture methods with an emphasis on comparing different hinge and transmembrane domains as well as comparing CD28 versus 4-1BB costimulatory domains . A clinical trial of T cells expressing an anti-CD30 CAR has opened and we have treated 21 patients on this trial. Unfortunately the longest objective duration of response in these patients has been only 3 months. We have ended this clinical trial of anti-CD30 CAR T cells due to toxicity plus lack of efficacy and now we are preparing a manuscript to report the results. 138759 +Cancer; Clinical Research; Health Disparities; Hematology; Minority Health; Prevention; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Transplantation Acute Graft Versus Host Disease;Allogeneic Bone Marrow Transplantation;Antigens;Bone Marrow Transplantation;Cell Therapy;Clinical;Clinical Research;Clinical Trials;Cyclophosphamide;Dose;Engineering;Engraftment;Enrollment;Ensure;Funding;Goals;HLA Antigens;Hematologic Neoplasms;Hematology;Hematopoietic;Human;Immune;Immunologics;Institutional Review Boards;Laboratories;Laboratory Research;Major Histocompatibility Complex;Mixed Lymphocyte Culture Test;Modeling;Modification;Mus;Non-Malignant;Outcome;Patient-Focused Outcomes;Patients;Phase;Prevention;Protocols documentation;Recovery of Function;Relapse;Risk;Siblings;Study models;T-Lymphocyte;Toxic effect;Translating;Translations;Transplant-Related Disorder;Transplantation;Work;clinical efficacy;clinical translation;cohort;conditioning;graft vs host disease;improved;improved outcome;mouse model;novel strategies;pharmacokinetic model;post-transplant;prevent;stem;transplant model Deciphering the efficacy of posttransplant cyclophosphamide in BMT n/a NCI 10702608 1ZIABC011659-08 1 ZIA BC 11659 8 14280085 "KANAKRY, CHRISTOPHER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1845452 NCI Over the past several years we have been using our murine transplant models to dissect the mechanisms underlying the efficacy of PTCy and have found that these diverge widely from the prior dogma in the field. We are actively working across several projects to better define a new mechanistic model which will inform rational translation of new approaches or modifications to improve outcomes for patients. Indeed in the course of these studies we have determined that the optimal dose of PTCy is an intermediate dose rather than a very high dose. We have now completed enrollment of the primary cohort of a phase I/II study that has shown that reduced dosing PTCy allows for excellent prevention of acute GVHD while allowing lower early transplant-associated toxicity and better hematopoietic and immune recovery and function. Pharmacokinetic modeling studies by Jeannine McCune accompanying this trial are funded by an R01. We have three other clinical trials that are accruing or will begin accruing soon that are stemming from the work performed in the laboratory. Our goals with these clinical studies and ongoing laboratory research are to use our developing understanding as a basis to explore how to refine this BMT approach clinically towards the clinical goals of further reducing graft-versus-host disease ensuring reliable engraftment with minimal conditioning and serving as a platform for other therapies to reduce relapse. We also are exploring the impact of PTCy on human T cells in mixed lymphocyte cultures with the goal of improving our understanding of the immunologic impact of PTCy in order to improve clinical outcomes. Lastly we have been working over the past 5 years on a way of integrating engineered antigen-specific cellular therapies safely and effectively with haplo BMT using PTCy in our murine models. We are now developing a protocol to clinically translate this approach and expect within the next 12-18 months to have this clinical study open. 1845452 +Bioengineering; Biotechnology; Cancer; Gene Therapy; Genetics; Lung; Lung Cancer; Nanotechnology; Orphan Drug; Rare Diseases; Women's Health 3-Dimensional;Antineoplastic Agents;Apoptosis;Bioinformatics;Biology;Biopsy;Cell model;Cells;Characteristics;Chemicals;Chemistry;Chest;Clinical;Collaborations;Complex;Databases;Development;Diagnosis;Drug Targeting;Epigenetic Process;Evaluation;Feedback;Film;Future;Genes;Genomics;Goals;Human;Hydrogels;In Vitro;Interdisciplinary Study;Investigation;KRAS2 gene;Legal patent;Malignant Neoplasms;Malignant Pleural Mesothelioma;Malignant neoplasm of thorax;Membrane;Mesothelial Cell;Mesothelioma;Methods;MicroRNAs;Modeling;Molecular;Non-Small-Cell Lung Carcinoma;Organ;Outcome;Pathogenicity;Pathway interactions;Patients;Peptides;Performance;Pharmaceutical Preparations;Phenotype;Pleura;Pleural;Prognosis;Regimen;Reporting;Research;Research Project Grants;Surface;Surveys;System;Systems Biology;TP53 gene;Techniques;Testing;Therapeutic;Thinness;Thymus Epithelial Neoplasm;Time;Tissues;Translating;Translational Research;Untranslated RNA;Xenograft procedure;anti-cancer;base;biomarker discovery;bioprinting;cancer cell;cancer type;cell type;combinatorial;human tissue;in vivo;innovation;insight;interest;knowledge base;manufacturing scale-up;materials science;method development;nanoparticle;nanoscale;neoplastic cell;next generation;novel;novel drug class;preclinical development;preclinical study;response;small molecule;therapeutic candidate;therapeutic miRNA;transcription factor;tumor;tumor initiation;tumorigenesis microRNA-based and novel molecular therapeutics in thoracic cancers n/a NCI 10702607 1ZIABC011657-08 1 ZIA BC 11657 8 14280083 "HOANG, CHUONG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2105365 NCI "This project continues to be developed. We are performing bioinformatic analyses to survey genomic databases of mesothelioma to infer microRNA and transcription factors regulatory pairings (in a feedback loop circuit or other relevant motif) of high significance. We are systematically testing the functional relevance of such circuits in vitro and validating phenotypic consequences in vivo. Several candidate microRNA associated with and biologically active in mesothelioma have been reported from our lab with several more in the pipeline. To translate this body of work we have developed a clinical delivery platform based on peptide nanoparticle-hydrogel composite material that can effectively deliver microRNA to tumor cells (in vivo mesothelioma models). Refinements are being made to optimize efficacy and performance characteristics (e.g. scale-up manufacturing) of this hydrogel-based system. New groundwork is established to create the next generation mesothelial cell model for mesothelioma oncogenesis investigation using 3D bioprinting techniques. In this new model construct we are using multiple cell types derived from human tissues to reconstruct the equivalent of ex-vivo pleural membrane ""organs""." 2105365 +Cancer; Clinical Research; Digestive Diseases; Immunotherapy; Orphan Drug; Pancreatic Cancer; Rare Diseases Abdominal Cavity;Address;Antibodies;Antibody Formation;Apoptosis;Bacterial Toxins;Binding;Biological Models;Blood;Blood Vessels;CTLA4 gene;Cancer Patient;Cancer Vaccines;Cancer cell line;Cell surface;Cells;Cholangiocarcinoma;Clinical;Clinical Trials;Collaborations;Combination immunotherapy;Combined Modality Therapy;Cytosol;Data;Deposition;Development;Disease;Engineering;Enzymes;Goals;Heart;Human;Immune;Immune checkpoint inhibitor;Immune system;Immunotoxins;Impairment;Institutional Review Boards;Journals;Lung;MSLN gene;Malignant neoplasm of pancreas;Manuscripts;Modeling;Molecular;Mouse Strains;Mus;Neoplasm Metastasis;Normal Cell;Oncolytic viruses;Paclitaxel;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Participant;Pathway interactions;Patients;Peritoneal;Persons;Pharmaceutical Preparations;Phase;Phenotype;Pre-Clinical Model;Preparation;Protein Biosynthesis;Protein Precursors;Proteins;Pseudomonas aeruginosa toxA protein;Publications;Publishing;Recombinants;Reporting;Research;Role;Safety;Signal Pathway;Signal Transduction;Solid Neoplasm;Surface Antigens;System;Testing;Therapeutic;Toxin;Tumor Antigens;Variant;advanced disease;anti-CTLA-4 therapy;anti-PD-1;anti-tumor immune response;anticancer research;arm;base;cancer cell;cell killing;cell type;design;effective therapy;efficacy evaluation;experimental study;genomic locus;immune activation;improved;inhibitor;mesothelin;neoplastic cell;next generation;novel;novel therapeutics;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;pancreatic neoplasm;peer;phase 1 study;preclinical study;targeted treatment;translational oncology;tumor;tumor microenvironment;tumor-immune system interactions;tumorigenic Mesothelin-targeted immunotoxins in Pancreatic Cancer n/a NCI 10702606 1ZIABC011652-08 1 ZIA BC 11652 8 14280079 "ALEWINE, CHRISTINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 507430 NCI "GOAL #1 LMB-100 Combinations. LMB-100 is a next generation recombinant immunotoxin developed by the Pastan Lab (NCI/ LMB) in collaboration with Roche. This RIT binds to the cancer antigen MSLN and delivers a potent bacterial toxin to the cell cytosol. The toxin a molecularly engineered variant of Pseudomonas exotoxin A kills cells by irreversibly modifying a critical enzyme in the protein synthesis pathway resulting in a halt in the cell's ability to produce new proteins. This insult triggers apoptosis in many cell types. AIM 1 (completed): Evaluate efficacy of MSLN-targeted RITs in pancreatic cancer patients. At least 70% of pancreatic adenocarcinomas express the surface antigen MSLN making these tumors good targets for MSLN-targeted therapies. Based on our previous results we initiated ""A Phase Ib/II Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with Nab-Paclitaxel in Participants with Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma"" (PI Alewine) to determine the safety tolerability and efficacy of the LMB-100 + NAB-paclitaxel combination. This trial received IRB approval in 6/2016 and formally opened for accrual 8/2016. The trial has completed accrual. We described the results for Arm A of the study in our 2020 publication in Clinical Cancer Research. We found that the development of anti-drug antibodies against LMB-100 limits effective treatment to 2 cycles. A second manuscript describing results of Arm B and the immune effects of LMB-100 treatment is currently undergoing review. Subsequently we opened a new clinical trial testing combination of LMB-100 with the JAK inhibitor tofacitinib (""A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination with Tofacitinib in Persons with Previously Treated Pancreatic Adenocarcinoma Cholangiocarcinoma and other Mesothelin Expressing Solid Tumors"" PI Alewine). Tofacitinib has been shown by our collaborators (Fitzgerald Pastan Onda) to delay anti-drug antibody formation and also to change the immune composition of tumors resulting in increased efficacy of immunotoxin drugs. This trial was closed to accrual 1/2021 and a mansucript is in preparation. AIM 2 (ongoing): Determine whether LMB-100 or other mesothelin-targeted RITs can boost the effect of immune activating drugs. Pancreatic adenocarcinoma produces an immunosuppressive microenvironment. Killing tumor cells with oncolytic viruses or administering anti-tumor vaccines can cause immune activation. Combining these treatments with immune checkpoint inhibitors (ICIs) has been demonstrated to produce anti-tumor immune responses in pre-clinical models of pancreatic cancer. We hypothesize that since LMB-100 uses a bacterial toxin to kill tumor cells it may also induce immune activation within the pancreatic cancer microenvironment that could be leveraged to induce an anti-tumor immune response in combination with ICIs. Because our immunotoxins bind only to human (hMSLN) and not to native mouse MSLN (mMSLN) completing this project required development of a syngeneic mouse pancreatic cancer cell line expressing hMSLN and a humanized MSLN mouse strain that would not reject these cells. We have developed such a model in collaboration with the CAPR group at Frederick (Serguei Kozlov Leidos). Experiments using anti-PD1 and anti-CTLA4 therapies in combination with immunotoxin were negative for efficacy in our new pancreas cancer model; these data have been published. We are currently exploring other novel immunotherapy combinations. GOAL #2 Understanding MSLN Signaling. MSLN is the target of many therapeutics being tested in clinical trials. It has previously been shown to increase the aggressiveness of pancreatic cancer. It is unknown whether current anti-MSLN therapies inhibit the pro-tumorigenic signaling by MSLN or whether they are just addressing toxic payloads to tumor cells. AIM 1 (ongoing): Determine a phenotype of MSLN loss in pancreatic cancer cells. We found that loss of MSLN impairs ability to pancreatic cancer cells to establish peritoneal metastasis deposits. MSLN loss impaired the establishment of blood vessels to the new tumor deposits. This data was published in the journal Molecular Cancer Research in 2020. A review examining peritoneal metastasis in pancreas cancer was published in Cancer and Metastasis Reviews. We are continuing to characterize the signaling pathways responsible and are investigating the role of the immune system in MSLN pro-tumorigenic activity. Recently we incidentally discovered that furin is not required for the processing of mesothelin pre-cursor protein and reported this result in Biochimica et Biophysica Acta- Molecular Cell Research. AIM 2 (completed): Determine why MSLN can be detected in the blood of some but not all patients with tumors that make MSLN. We found that elevated concentrations of the two proteins expressed from the MSLN gene locus MSLN and MPF are not found in the blood of pancreas cancer patients (with L. Cao). We identified a model system in mice to determine what happens to MSLN shed from PDAC. Modeling (by C. Peer) of MSLN transit in this system suggests that shed MSLN is trapped within PDAC tumors. These data were published in Translational Oncology in 2022." 507430 +Aging; Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Women's Health African American;Age;Blood coagulation;Breast Cancer Patient;Characteristics;Classification;Clinical;Clinical Trials;DNA;Data;Databases;Development;Diagnosis;ERBB2 gene;Enrollment;Estrogen receptor negative;Genomics;Germ Lines;Mammary Neoplasms;Metaplastic carcinoma of the breast;Multivariate Analysis;Mutation;Nature;Outcome;Patients;Prognosis;Proteomics;Research;Research Institute;Sampling;The Cancer Genome Atlas;Tissue Banks;Woman;base;biobank;cohort;exome sequencing;high risk;malignant breast neoplasm;older women;patient population;public database;transcriptome sequencing;tumor;young woman Genomic characterization of breast cancer in high risk subsets of breast cancer n/a NCI 10702604 1ZIABC011650-08 1 ZIA BC 11650 8 14821366 "LIPKOWITZ, STANLEY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 185117 NCI Women under the age of 40 account for approximately 5% percent of breast cancer patients but numerous studies have shown that they have a worse prognosis and poorer outcome than women diagnosed at older ages. Breast tumors from young women are often ER-negative from African-American patients and have other indicators of high risk: yet multivariate analyses demonstrated that young age in and of itself is an independent predictor of poor outcome. At least partially due to the unique nature of the patient population served by DOD a disproportionate number of breast cancer cases in young women are seen at WRNMMC. Thus CBCP has enrolled a good number of invasive breast cancer patients under 40 making it possible for us to propose this study. The CBCP Tissue Bank hosted at the Windber Research Institute has 40 tumors in OCT with germ line DNA available from blood clots for these sample. Thus there are sufficient numbers to get meaningful data. The tumors from young patients will be directly compared to those in the biobank from older women using the same platforms. The tumors will undergo whole exome sequencing RNAseq and proteomic analysis. These analyses will allow us to determine the spectrum of mutations seen in tumors from young women. All of these samples are clinically annotated into groups based on the clinical classification of the tumors (Luminal A Luminal B HER2+ and triple negative). For patients enrolled from the WRNMMC most of the cases have outcome data and more outcome data is being collected. These analyses will be compared to the publicly available databases for breast cancer (e.g. TCGA) in order to validate differences between the younger and older cohort in our data. Despite the poor prognosis of young women with breast cancer little research and no clinical specific clinical trials are available. This project and its further development could represent a major advance in the field. 185117 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Neurosciences; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human 10q;11p;11q;12q13;13q;14q13;19q;1p34;1q32;20p;20q;22q;3q26;8q24;Animals;Apoptosis;Area;Astrocytoma;Automobile Driving;Binding Proteins;Bioinformatics;Biological Assay;Biology;Biotechnology;Brain;Brain Neoplasms;CDKN2A gene;Cancer Genome Anatomy Project;Candidate Disease Gene;Cell Line;Cellular biology;Central Nervous System Neoplasms;Chromatin;Chromosome abnormality;Classification;Clinical;Collaborations;Complex;DNA;DNase I hypersensitive sites sequencing;Data;Data Analyses;Decarboxylation;Deoxyribonuclease I;Development;Dioxygenases;Disease;Enzymes;Epidermal Growth Factor Receptor;Epigenetic Process;Exhibits;Gene Chips;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Gene Expression Regulation;Gene Silencing;Genes;Genetic;Genetic Transcription;Genome;Genomics;Glioblastoma;Glioma;Gliomagenesis;Goals;Heterogeneity;Human;Human Genome Project;Hypersensitivity;In Vitro;Isocitrate Dehydrogenase;Isocitrates;Laboratories;Learning;Link;Location;Loss of Heterozygosity;Malignant - descriptor;Methods;Methylation;Microarray Analysis;Molecular;Molecular Target;Morphology;Mutation;Neuroglia;Neurons;Nuclear;Nucleic Acid Regulatory Sequences;Oncogenes;Operative Surgical Procedures;PTEN gene;Pathologic;Patients;Process;Protocols documentation;Receptor Biology and Gene Expression;Recurrence;Role;SNP array;Sampling;Signal Transduction Pathway;Site;Specimen;Structure;TP53 gene;Testing;Therapeutic Intervention;Tissues;Transplantation;Tumor Biology;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;Work;Xenograft procedure;alpha ketoglutarate;base;cDNA Arrays;chromosome 5q loss;enzyme activity;experimental study;expression vector;falls;gene cloning;gene discovery;genome-wide;immunosuppressed;in vivo;insight;malignant phenotype;new technology;new therapeutic target;next generation sequencing;novel;self-renewal;stem cells;transcription factor;transcriptome;tumor;tumorigenesis;tumorigenic Identifying New Glioma-Associated Tumor Suppressors and Oncogenes n/a NCI 10702602 1ZIABC011647-08 1 ZIA BC 11647 8 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 516832 NCI "Previously we have initiated a large cDNA microarray effort in collaboration with the Human Genome Project and the Cancer Genome Anatomy Project (CGAP) to develop a comprehensive and novel molecular classification schema for human gliomas based on a gene expression profile using cDNA microarray technology. We have constructed our own cDNA microarray ""chips"" which will be enhanced for new and selective genes thought to be important in glioma biology. This project will include hundreds of tumor specimens and offer an unprecedented opportunity for gene discovery dissecting signal transduction pathways and learning this exciting new technology. Glioma stem cell is a tumor subpopulation that can self-renew in culture perpetuate a tumor in orthotopic transplant in vivo and generate diversified neuron-like and glia-like postmitotic progeny in vivo and in vitro. Recently conventional and array-based CGH (aCGH) profiling of human gliomas have shown a significant number of copy number alterations (CNAs) including gain/amplification (1p34-36 1q32 3q26-28 5q 7q31 8q24 11q 12q13 13q 15p15 17q22- 2519q 20p and 20q) and deletion/loss (3q25-26 4q 6q26-27 9p10p 10q 11p 12q22 13q 14q13 14q23-31 15q13-21 17p11-13 18q22-23 19q and 22q) (Kotliarov et al. 2006; Nigro et al. 2005; Phillips et al. 2006). The large number of chromosomal aberrations and the large number of genes contained therein have to date made it impossible to identify which genes are in part responsible for driving the biology of these tumors. We have analyzed a large number glioma samples for genetic characterization of recurring CNAs using Affymetrix 100K single-nucleotide polymorphism (SNP) array chips and Genechip HumanGenome U133 Plus 2.0 Expression array (Kotliarov et al. 2006). Based on our bioinformatics data from these array and gene expression profiling experiments we have found novel genes frequently altered in gliomas. Furthermore we have explored the new biotechnology such as next generation sequencing for this project. We have generated sequence-verified gene Gateway entry clones of these genes and cloned them into pLenti/UbC/V5 expression vectors for transduction of various target cell lines. With our candidate gene constructs we will identify whether candidate genes change the biology of these cells in such a way that may be consistent with a role in tumorigenesis (i.e. clonogenecity proliferation apoptosis tumorigenic potential in immunosuppressed animals). The NOB Laboratory recently began collaborating with Dr. Gordon Hager and the Laboratory of Receptor Biology and Gene Expression. Dr. Hager's work has focused on the reorganization of the nuclear chromatin and the impact of these changes on gene regulation. In the context of brain tumor biology there are a variety of primary central nervous system tumors that despite a malignant phenotype have few mutations. Therefore it is possible that alterations in the transcriptional profile may help explain this apparent disparity. The NOB laboratory is using the DHS-seq method to profile genome-wide transcriptional changes in glioma patient samples. As described above the DHS-seq will reveal dynamic changes in the chromatin which are important in the development and progression of brain tumors and allow us to identify novel molecular targets to treat this disease. We have tested the DHS-seq protocol on two glioma stem cell lines (827P12 and 923P9) and corresponding xenograft tissues. Preliminary analyses of these data suggest that in combination with gene expression and copy number data we will obtain novel insights into the genomics underlying brain tumor biology. To this end the NOB laboratory has begun testing this method on patient samples using tumor tissues and adjacent normal brain directly from surgical specimens. The plan is to continue processing additional patient samples as they become available with the ultimate goal of incorporating the ""transcriptome"" analysis into the comprehensive genomic analysis that is being planned as a component of the molecular tumor board described in the Clinical Project." 516832 +Biotechnology; Cancer; Cancer Genomics; Colo-Rectal Cancer; Digestive Diseases; Genetics; Human Genome; Women's Health Attention;Biology;CRISPR/Cas technology;Cell Cycle Arrest;Cell Line;Cell Survival;Cell physiology;Colorectal;Colorectal Cancer;DNA Damage;Gene Expression;Gene Expression Profiling;Genes;Genetic Transcription;Genetic Translation;Genome;Goals;Human;Investigation;Laboratories;Malignant Neoplasms;Mediating;Messenger RNA;MicroRNAs;Modeling;Mus;Mutate;Pathogenesis;Pathway interactions;Phenotype;Play;Post-Transcriptional Regulation;RNA Binding;RNA Splicing;RNA-Binding Proteins;Research;Role;Sampling;Signal Transduction;TP53 gene;Untranslated RNA;colon cancer patients;epigenetic regulation;experimental study;human disease;mRNA Stability;novel;protein function;response;transcription factor;transcriptome;translational potential Role of long non-coding RNAs and RNA-binding proteins in p53 signaling n/a NCI 10702601 1ZIABC011646-08 1 ZIA BC 11646 8 11142391 "LAL, ASHISH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1654468 NCI Our research is focused on investigating the function and mechanism of novel lncRNAs and RNA-binding proteins (RBPs) in p53 signaling using colorectal cancer as a model. We hypothesize that in response to DNA damage select p53-regulated lncRNAs and RBPs play a critical role in regulating a subset of the p53-regulated transcriptome to control cell survival and/or cell cycle arrest. As a first step towards achieving our goal we have identified novel lncRNAs transactivated by p53 in multiple p53-proficient colorectal cell lines. To examine their function we use CRISPR/Cas9 to abolish their expression and for phenotypic studies. To determine their role in regulating the transcriptome we employ gene expression profiling from candidate lncRNA-proficient and lncRNA-deficient isogenic cell lines in the presence or absence of DNA damage. In parallel we perform lncRNA pulldowns to identify the factors bound by the candidate lncRNA. To examine the role of these lncRNAs in cancer pathogenesis we conduct experiments in colorectal cancer patient samples and in mice. These investigations will further our understanding of the function and mechanism of action of novel p53-regulated lncRNAs in the DNA damage response and their involvement in colorectal cancer. In addition to lncRNAs we are also investigating the roles of RBPs in the p53 pathway. Our recent study on ZMAT3 a p53-induced RBP has uncovered a function of ZMAT3 in regulating mRNA splicing. Currently we are investigating how other p53-induced RBPs function in mediating the effects of p53. 1654468 +Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Immunotherapy; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Precision Medicine; Rare Diseases Adult;Advocacy;Agreement;Anxiety;Astrocytoma;BRAF gene;Brain Neoplasms;Calendar;Caregivers;Central Nervous System Neoplasms;Central Nervous System Sarcoma;Choroid Plexus Neoplasms;Classification;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Consensus;DNA sequencing;Data Management Resources;Disease;Education and Outreach;Ependymoma;Evaluation;Funding;Gene Mutation;Genomic DNA;Genomics;Glioblastoma;Glioma;Gliomatosis cerebri;Histones;Imaging technology;Immune checkpoint inhibitor;Immunologic Monitoring;Immunotherapy;Incidence;Infrastructure;International;Investigation;Joints;Laboratories;Leadership;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of central nervous system;Molecular;Molecular Analysis;Monitor;Monograph;Mutate;Mutation;National Cancer Institute;Natural History;Neoplasms;Nivolumab;Normal tissue morphology;Pathogenesis;Patient Monitoring;Patient Outcomes Assessments;Patient Participation;Patients;Pediatric Oncology;Persons;Pineal Region Tumor;Preclinical Testing;Primary Brain Neoplasms;Primary Neoplasm;Procedures;Proteomics;Publishing;Rare Diseases;Recruitment Activity;Regimen;Research;Research Personnel;Resources;Rhabdoid Tumor;Sleep Wake Cycle;Testing;Therapeutic;Tissue Banks;Translating;Tumor Biology;Tumor Tissue;United States;United States National Institutes of Health;Visit;accurate diagnosis;base;exome;first-in-human;gliosarcoma;human study;imaging biomarker;immunotherapy trials;improved;interest;medulloblastoma;meningioma;metabolomics;methylation testing;novel;oligodendroglioma;outreach;participant enrollment;patient advocacy group;patient engagement;patient population;pineoblastoma;precision medicine;predicting response;predictive marker;prognostic;programs;rare cancer;routine imaging;transcriptome sequencing;treatment response;tumor;virtual assessment;virtual reality headset;web site Rare Central Nervous System Cancers Initiative n/a NCI 10702600 1ZIABC011643-08 1 ZIA BC 11643 8 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 516832 NCI The NIH is uniquely suited to create a rare CNS cancer initiative. This effort utilizes the following specific resources of the NIH. This has required developing a clinical trial infrastructure including data management system to oversee the disease specific therapeutic and natural history studies. Collaborations with experts in imaging technologies to create imaging biomarkers and routine imaging for monitoring response to therapies are planned. A tissue repository has been established to store both tumor and normal tissue for molecular analyses including genomics metabolomics and proteomics with the intent of advancing the understanding of tumor biology and pathogenesis leading to better prognostic information sub-classification and ultimately markers predictive of response to specific treatments. Additionally specific testing capabilities have been developed such as methylation testing for accurate diagnosis whole exome DNA and RNA sequencing to look for novel mutations and gene alterations such as fusions. A variety of clinical studies have been developed for this population of patients with rare cancers. For example an immunotherapy trial is underway and actively recruiting. This study includes immunologic monitoring that are being performed in Dr. Gilbert's laboratory. NIH-based outreach efforts will be utilized to interact with patient advocacy groups to enhance patient participation in these efforts and provide a venue for educational programs to improve patient and caregiver understanding of their uncommon disease. Finally an important component of the rare CNS Tumor program is outreach and education. Formal Memorandum of Understanding Agreements has been signed with 9 advocacy groups and the NCI-CONNECT website has been highly successful with over 500000 unique visits and over 900000 page views in calendar year 2021. Additionally the website content has been translated into Spanish and this is garnering over 20000 visits per month. 516832 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Neurosciences; Orphan Drug; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human Bioinformatics;Biological Models;Biology;Brain Neoplasms;Cancer cell line;Cell Culture Techniques;Cell Line;Cells;Cellular biology;Characteristics;Ciliary Neurotrophic Factor;Clinic;Clinical;Collaborations;Computer Analysis;Cytostatics;Data;Database Management Systems;Embryo;Equilibrium;Gene Expression;Gene Expression Profiling;Genes;Genetic;Genomics;Genotype;Glioblastoma;Glioma;Homeostasis;Human;In Vitro;Laboratories;Messenger RNA;Metabolic;Modeling;Molecular;Mus;Mutate;Normal tissue morphology;Oncogenes;Pathway interactions;Patients;Phenotype;Primary Neoplasm;Research;Resources;Serum;Signal Pathway;Signal Transduction;Study models;System;Technical Expertise;Therapeutic;Therapeutic Agents;Tretinoin;Tumor Stem Cells;Tumor Suppressor Proteins;Tumor-Derived;Ursidae Family;base;exome sequencing;experimental study;gene function;genome-wide;glioma cell line;immunoreaction;improved;in vivo;material transfer agreement;methylome;miRNA expression profiling;neoplastic cell;nerve stem cell;new therapeutic target;novel therapeutics;personalized medicine;pre-clinical;preclinical study;screening;stem cell biology;stem cell differentiation;stem cell self renewal;stem cells;tool;transcriptome;transcriptome sequencing;translational study;tumor;tumor xenograft;tumorigenesis Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas n/a NCI 10702599 1ZIABC011640-08 1 ZIA BC 11640 8 14280069 "GILBERT, MARK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 369166 NCI We have performed experiments to improve our understanding of the molecular mechanisms of deregulated differentiation pathways in TSCs: The delicate balance between stem cell self-renewal and differentiation is controlled by various cell intrinsic and extrinsic factors that are critical for normal tissue homeostasis. Despite extensive phenotypic and functional similarities between GSCs and normal stem cells the differentiation potentials of GSCs are not entirely normal. Elucidation of the differentiation pathways that are operative in both normal stem cells and GSCs will be critical for fully understanding tumorigenesis and will likely lead to novel therapeutic targets. We have also identified a set of deregulated differentiation pathways in GSCs derived from human primary GBM. Elucidation of underlying molecular mechanism will provide important clues for predicting sensitivity of differentiation therapeutic approach. Characterization of TSCs in aspect of differentiation-inducing agents further revealed the limitations of traditional glioma cell lines grown in serum. For example retinoic acid treatment and CNTF exposure potently induce differentiation in most GBM tumor initiate cells (TICs) but not of traditional cell lines. This prompted us to question whether many of potential tumor suppressors and/or cytostatic genes previously studied in cell lines were not recognized. Given the ever-increasing number of potential GSGs and oncogenes in glioblastoma TSCs identified from bioinformatics approaches and technical expertise of stem cell culture accumulated in the laboratories we have set up screening systems to study the function of these genes in stem cell cultures. In addition we have made significant progress on one of keystone projects that is to understand the genomic and molecular signaling similarities and differences between our glioma TSCs and normal neural stem cells (NSC). We have performed a very large scale study of 7 different GBM-derived TSCs and normal embryonic NSC lines under both proliferative and differentiating conditions and derived high-throughput mRNA and microRNAs profiling. Since November of 2014 when Dr Gilbert initiated the new glioma stem cell translational study project we have created 6 more glioma-derived TSCs introduced 3 IDH- mutated TSCs and subsequently performed the computational analyses for characterization of the genetics and signaling pathways in these GSCs enabling these cell lines to be used to explore the therapeutic potential of glioma stem cell biology such as metabolic changes and immunological reactions. Additionally we have through collaborations and Material Transfer Agreements obtained important cell lines that provide an outstanding resource for the laboratory. In total there are now 62 human tumor lines in the NOB Laboratory. As part of this project each of these cell lines has been extensively molecularly characterized including whole exome sequencing analysis of the methylome and RNA sequencing. These data are being uploaded into a database system (CellMinerDB) to enable analysis and selection of optimal model systems for preclinical studies for all of the research groups in the NOB. 369166 +Cancer; Cancer Genomics; Genetics; Human Genome; Regenerative Medicine Bone Marrow;Cell Lineage;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Defect;Development;Epithelial Cells;Gene Expression Profiling;Genetic Transcription;Growth;Hematopoietic;Immune;Immunity;Infection;Influenza;Laboratories;Lymphocyte;Lymphoid Cell;Maintenance;Malignant Neoplasms;Modeling;Mutagenesis;Natural regeneration;Organ;Role;Signal Transduction;System;T cell response;T-Cell Development;T-Lymphocyte;Technology;Thymic epithelial cell;Thymus Gland;Tissues;Work;age related;cell type;epigenomics;fetal;insight;mouse model;notch protein;progenitor;programs;single-cell RNA sequencing;thymic regeneration;transcription factor T cell Development and Regeneration n/a NCI 10702598 1ZIABC011633-08 1 ZIA BC 11633 8 14280065 "BHANDOOLA, AVINASH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2065246 NCI There are two major ongoing projects in our laboratory: 1. The development and function of innate lymphoid cells. Innate lymphoid cells have transcriptional programs that appear to mirror those of T cells. The comparison of innate lymphocyte cell development with T cell development provides an opportunity to understand the factors that underlie the shared as well as the unique features and functions of these apparently closely related cell lineages. We have identified the earliest known precursors committed to innate cell lineages and are characterizing the functions of transcription factors expressed in these early innate lymphocyte precursors. 2. Transcription factors in thymic epithelial cells. Distinct transcription factors are expressed in fetal thymic epithelial cells and in different subtypes of thymic epithelial cells. We are combining models of CRISPR mutagenesis to generate appropriate mouse models with single-cell RNA sequencing and single-cell epigenomics. These technologies will provide unprecedented insight into the mechanisms that support the development and maintenance of adaptive and innate immune lymphocytes. 2065246 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunotherapy; Kidney Disease; Minority Health; Rare Diseases; Urologic Diseases Adverse event;Angiogenesis Inhibitors;Anorexia;Avidity;Binding;Bladder Adenocarcinoma;Blood;Body Weight decreased;CCR;CD8-Positive T-Lymphocytes;Cancer Patient;Cancer cell line;Carboplatin;Carcinoid Tumor;Cell surface;Cells;Cisplatin;Clear cell renal cell carcinoma;Clinical;Clinical Treatment;Data;Data Pooling;Databases;Dehydration;Diarrhea;Dose;Dose-Limiting;ENG gene;Endoglin;Endometrial Carcinoma;Enzymes;Equilibrium;Evaluable Disease;Fatigue;Flow Cytometry;Functional disorder;Goals;HGF gene;Human;Immune;Immune checkpoint inhibitor;Immunotherapeutic agent;Innate Immune Response;International;Journals;KDR gene;Literature;Liver;MAP Kinase Gene;Malignant neoplasm of penis;Malignant neoplasm of urinary bladder;Manuscripts;Mediating;Medicine;Metastatic Renal Cell Cancer;Monoclonal Antibodies;Mononuclear;Mucositis;Myelogenous;Myeloid-derived suppressor cells;Nausea and Vomiting;Neuroendocrine Tumors;New England;Nivolumab;Non-Small-Cell Lung Carcinoma;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Phase;Phase II Clinical Trials;Placebos;Platinum;Population;Primary carcinoma of the liver cells;Progressive Disease;Property;Protein Tyrosine Kinase;Proteins;Randomized;Receptor Protein-Tyrosine Kinases;Recurrence;Regulatory T-Lymphocyte;Renal Cell Carcinoma;Reporting;Risk;Running;Safety;Sarcomatoid Features;Sarcomatoid Renal Cell Carcinoma;Series;Signal Pathway;Signal Transduction;Squamous cell carcinoma;T-Lymphocyte;Testing;Therapeutic;Therapeutic Trials;Thyroid Gland;Toxic effect;Transitional Cell Carcinoma;Triplet Multiple Birth;Unresectable;Urine;Urothelium;Uterine Corpus Carcinosarcoma;adaptive immunity;advanced disease;angiogenesis;base;bevacizumab;checkpoint inhibition;chemotherapy;cohort;effector T cell;exhaust;gemcitabine;granulocyte;immunoregulation;improved;ipilimumab;lenalidomide;melanoma;monocyte;mortality risk;neoplastic cell;neuroendocrine differentiation;peripheral blood;phase 1 study;phase 2 study;phase 3 study;phase III trial;programmed cell death protein 1;rare cancer;response;small molecule inhibitor;standard care;symposium;targeted agent;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression Targeting the MET Pathway in Urothelial Carcinoma n/a NCI 10702596 1ZIABC011594-09 1 ZIA BC 11594 9 10687150 "APOLO, ANDREA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1189328 NCI Effect of cabozantinib on peripheral blood immune subsets in urothelial carcinoma and other GU tumors We conducted a study to assess the impact of cabozantinib on systemic innate and adaptive immune cells. TKIs against VEGFR and other receptor tyrosine kinases may have antitumor immune mediated mechanisms. MET is expressed in tumor cells and in immunosuppressive myeloid cells including human monocytes and granulocytic MDSCs. Signaling downstream of HGF MET interaction in monocytes may shift the Th1/Th2 balance and expand MDSCs and Tregs. We hypothesized that cabozantinib can modify the tumor microenvironment by modulating immunosuppressive Tregs and MDSCs. We assessed peripheral blood mononuclear cell (PBMC) immune subsets including effector T cells exhausted T cells Tregs MDSCs and the functional markers PD 1 and TIM 3 using flow cytometry in metastatic urothelial carcinoma patients undergoing treatment with cabozantinib at baseline and after 2 cycles of continuous cabozantinib treatment and correlated our findings with clinical response to therapy PFS and OS. In summary our study showed that cabozantinib has innate and adaptive immunomodulatory properties that provide a rationale for combining cabozantinib with immunotherapeutic strategies. Cabozantinib modulated peripheral blood myeloid populations including decreasing classical monocytes increasing non classical monocytes and decreasing MDSCs. Cabozantinib also favorably impacted CD4 polarization to decrease Tregs increase the ratio of CD8 T cells to Tregs and upregulate PD 1 expression on Tregs. We plan to validate these findings in 155 patients treated with CaboNivo or CaboNivoIpi with a larger immune subset panel and additional functional markers with the goal to further understand the immune response of innate mononuclear cells that may serve as a targetable nexus for therapeutic engagement of adaptive immunity. Combining cabozantinib with checkpoint inhibition with nivolumab and ipilimumab Based on the immunomodulation seen with cabozantinib I initiated a multicenter phase 1 study where I combined CaboNivo or CaboNivoIpi. The study included a phase 1 study with 8 dose levels (n = 54) and 7 expansion cohorts including urothelial carcinoma renal cell carcinoma urothelial carcinoma patients previously treated with checkpoint inhibitors adenocarcinoma of the bladder/urachal penile cancer squamous cell carcinoma and other rare tumors (n = 155). The phase 1 portion is complete but we are still running the expansion cohorts. Safety of the combination of CaboNivo and CaboNivoIpi: In a phase 1 study I assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) with or without ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma and other GU malignances. Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase 2 dose (RP2D). Overlapping toxicities with the use of TKIs and checkpoint inhibitors included thyroid dysfunction diarrhea and elevated liver enzymes. Cabozantinib 60 mg/day led to higher rates of clinical treatment related adverse events of all grades including fatigue diarrhea anorexia weight loss nausea vomiting mucositis and dehydration. Although the study did not have any dose limiting toxicities the RP2D was cabozantinib 40 mg/day plus nivolumab 3 mg/kg for the doublet and cabozantinib 40 mg/day nivolumab 3 mg/kg and ipilimumab 1 mg/kg for the triplet based on better clinical tolerability and similar efficacy of cabozantinib at 40 mg/day vs. 60 mg/day. These data established the safety of the combinations and the RP2D for larger trials. Activity of CaboNivo and CaboNivoIpi: In the phase 1 study of CaboNivo and CaboNivoIpi (n = 54) we reported an ORR of 30.6% for all patients and 38.5% for urothelial carcinoma patients.23 Median duration of response was 21.0 months for all patients and not reached for metastatic urothelial carcinoma patients. Median PFS was 5.1 months for all patients and 12.8 months for urothelial carcinoma patients. Median OS was 12.6 months for all patients and 25.4 months for metastatic urothelial carcinoma patients. Based on the initial efficacy seen in the phase 1 patients additional expansion cohorts were added to the study. Expansion cohorts of CaboNivo and CaboNivoIpi in patients naive to checkpoint inhibition: The pooled data from the phase 1 and expansion cohorts in patients naive to immune checkpoint inhibition (n = 120) are currently being analyzed. For all currently evaluable patients (n = 109) the ORR = 37.6% CR = 9.2% PR = 28.4% and SD = 43.1%. The urothelial carcinoma expansion cohort included 24 patients treated with CaboNivo (n = 12) and CaboNivoIpi (n = 12). Similar to the phase 1 study where the ORR was 38.5% in the urothelial carcinoma expansion cohort the ORR = 42.9% for the 24 urothelial carcinoma patients and for the phase 1+ expansion cohort (n = 40) the ORR = 41.2% CR = 20.6% PR = 20.6% SD = 38.2% and progressive disease = 23.5%. The clear cell renal cell carcinoma (RCC) patients included patients with sarcomatoid features. In phase 1 all 3 RCC patients had a PR the RCC expansion cohort included 12 patients treated with CaboNivo (n = 6) and CaboNivoIpi (n = 6) and an additional RCC sarcomatoid patient from the rare tumor cohort. The phase 1 + RCC expansion cohort (n = 16) had an ORR = 62.5% CR = 12.5% PR = 50% SD = 37.5% and progressive disease = 0%. The promising activity seen in this phase 1 study has led to additional expansion cohorts within this study including cohorts for urothelial carcinoma RCC and other rare GU tumors with no standard treatment options and has also led to larger trials in GU tumors including CheckMate 9ER a randomized phase 3 trial of CaboNivo vs. sunitinib in the first line treatment of mRCC PDIGREE an adaptive phase 3 trial of CaboNivoIpi in untreated mRCC COSMIC 313 a phase 3 trial of CaboNivoIpi vs. NivoIpi plus placebo in mRCC and the Alliance ICONIC study of CaboNivoIpi for rare GU tumors. Several other trials are testing CaboNivo in non clear cell RCC carcinoid tumors metastatic triple negative breast cancer locally advanced hepatocellular carcinoma advanced endometrial cancer recurrent uterine carcinosarcoma poorly differentiated neuroendocrine tumors and non small cell lung cancer. A study of CaboNivoIpi in unresectable advanced melanoma is also underway. I am on the steering committee for CheckMate 9ER. The first results from the randomized phase 3 study n = 651 were presented in the presidential symposium at ESMO 2020 showing first line CaboNivo vs. sunitinib improves PFS 16.6 vs. 8.3 months OS 40% decrease in risk of death and ORR 55.7 vs. 27.1% with benefit in all International Metastatic RCC Database Consortium risk groups. CaboNivo has potential as first line therapy for metastatic RCC patients. I am an author of the manuscript which was submitted to the New England Journal of Medicine. I am currently working on a subset analysis for patients with sarcomatoid RCC within the 9ER study. For bladder cancer patients I am working on developing a phase 3 study for the second line treatment of patients post platinum based therapy. 1189328 +Breast Cancer; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Ovarian Cancer; Rare Diseases; Women's Health Apoptosis;BAY 54-9085;BRCA mutations;Blood;Clinic;Clinical Data;Clinical Trials;Collaborations;Dasatinib;Development;Enrollment;Goals;Growth Factor;Hereditary Breast and Ovarian Cancer Syndrome;Institutional Review Boards;International;Investigation;Karyotype;Li-Fraumeni Syndrome;Malignant Neoplasms;Malignant neoplasm of ovary;Metabolic;Metformin;Patients;Peritoneal;Phase;Pleural;Pregnant Women;Process;Protein Family;Protocols documentation;Research Personnel;Source;Specimen;Testing;Therapeutic;Woman;angiogenesis;bevacizumab;drug testing;effusion;fetal;inhibitor-of-apoptosis protein;phase 1 study;prevent Clinical trials in womens cancers n/a NCI 10702594 1ZIABC011584-09 1 ZIA BC 11584 9 9692487 "ANNUNZIATA, CHRISTINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 403700 NCI We are currently in the process of analyzing specimens and data from clinical trials 07C0058 - Bevacizumab and Sorafenib phase 2 in ovarian cancer; and 09-C-0019 phase 1 study of bevacizumab and dasatinib. As a Branch we opened 19-C-0025 to collect blood and effusions (pleural and peritoneal) from patients with cancer enrolled on other protocols at the NCI. Additional clinical trials are under development at the concept stage or are under review by IRB. Within the WMB I collaborate with Jung-min Lee and Stan Lipkowitz as Associate Investigator on several other clinical trials. I also collaborate with Diana Bianchi on a clinical trial to investigate the source of abnormal cfDNA in pregnant women with normal fetal karyotype. Another collaboration tested the metabolic effects of metformin in patients with Li Fraumeni Syndrome and a larger international clinical trial is under development to test this drug as a strategy to prevent cancer in LFS patients. 403700 +Biotechnology; Cancer; Complementary and Integrative Health; Immunotherapy; Orphan Drug; Rare Diseases 2019-nCoV;Advanced Development;Alkaloids;Amino Acids;Biochemical;Biochemistry;Biological;Biological Assay;Biology;CCR;Cancer Biology;Cell physiology;Cellular biology;Chemicals;Chemistry;Chimeric Proteins;Collaborations;Collection;Complement;Computational Science;Computer Models;Cyclic AMP-Dependent Protein Kinases;DNA;DNA Single Strand Break;Data Analyses;Development;Disease;Enzymes;Evaluation;Exhibits;Extramural Activities;FOXO1A gene;Fibrolamellar Hepatocellular Carcinoma;Fingerprint;Fractionation;Gene Fusion;Generations;Genetic;Genetic Transcription;Goals;HIV;Immune checkpoint inhibitor;Immunology;Immunotherapeutic agent;Individual;Industrialization;Intervention;Investigation;Lead;Libraries;Malignant Neoplasms;Malignant neoplasm of prostate;Merkel cell carcinoma;Methodology;Microbe;Modification;Molecular;Molecular Biology;Molecular Conformation;Molecular Probes;Molecular Target;Names;Natural Products;Natural Products Chemistry;Neurosecretory Systems;New Agents;Nuclear Pore Complex;Octadecenoic Acids;Oncogenic;Organic Synthesis;PAX3 gene;PRKACA gene;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Pharmacology;Plakortis;Plants;Play;Porifera;Positioning Attribute;Process;Protein Chemistry;RNA Viruses;Reporting;Research;Resources;Role;Scientist;Series;Skin Cancer;Source;Specificity;Structure;Structure-Activity Relationship;Synthesis Chemistry;Techniques;Technology;Topoisomerase;United States National Institutes of Health;Urochordata;Xenograft procedure;alternative treatment;analog;anti-cancer;assay development;base;bioactive natural products;cancer cell;dimer;enantiomer;experience;fungus;high throughput screening;improved;insight;interdisciplinary approach;marine organism;novel;pembrolizumab;preclinical development;programs;protein kinase A kinase;proto-oncogene protein c-cbl;response;scaffold;screening;skills;structural biology;therapeutic target;transcription factor;ubiquitin ligase Natural Products Discovery and Characterization Through Network Collaborations n/a NCI 10702593 1ZIABC011568-09 1 ZIA BC 11568 9 78355366 "DU, LIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1244726 NCI We utilized high throughput screening technologies to help identify compounds and extracts that can specifically interact with or modulate the function of selected biochemical targets or processes. Bioassay-guided chemical fractionation of natural products extracts is employed to isolate and purify the individual bioactive compounds. Identification and structural characterization of these compounds provides new structural classes or molecular scaffolds for the development of potential drug leads or biological probes that can interact with the desired molecular target. In addition to extensive NMR and mass spectroscopic analyses our efforts include rigorous evaluation of a new compound's potency molecular target specificity and mode of action. In FY 2022 we have been continuing our research campaign to identify bioactive natural products that interact with a wide variety of molecular targets including the oncogenic transcription factor PAX3-FOXO1 the ubiquitin ligase Cbl-b the Merkel cell carcinoma the PKA kinase fusion protein and the topoisomerase-3b. (1) PAX3-FOXO1: Chemical investigation of the marine hydroid Dentitheca habereri led to the identification of eight new diacylated zoanthoxanthin alkaloids named dentithecamides A-H along with three previously reported analogues zoamides B-D. These compounds are the first zoanthoxanthin alkaloids to be reported from a hydroid. Dentithecamides A and B along with zoamides B-D which all share a conformationally mobile cycloheptadiene core inhibited PAX3-FOXO1 regulated transcriptional activity with IC50 values in the range of 1167 uM. (2) Cbl-b: The E3 ubiquitin-protein ligase Cbl-b represents an attractive target for immunotherapeutic intervention in cancer. Bioassay-guided fractionation of the active fractions of a marine sponge Plakortis sp. afforded an unprecedented dimeric alkaloid plakoramine A. Chiral separation of the racemic plakoramine A led to the purified enantiomers (+)-plakoramine A and (-)-plakoramine A which inhibited the Cbl-b activities with IC50 values at 7.5 and 9.7 uM respectively. (3) Merkel cell carcinoma: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer. The treatment of advanced MCC often utilizes immune checkpoint inhibitors such as avelumab or pembrolizumab. Despite relatively high response rates to these agents less than half of patients achieve durable benefit; thus alternative treatments are urgently needed. A new 11 amino acid linear peptide named roseabol A and the known compound 13-oxo-trans-910-epoxy-11(E)-octadecenoic acid were isolated from the fungus Clonostachys rosea. 13-oxo-trans-910-epoxy-11(E)-octadecenoic acid showed inhibitory activity against Merkel cell carcinoma with an IC50 value of 16.5 uM. (4) The PKA kinase fusion protein (PKADJ): The DNAJB1-PRKACA (PKADJ) oncogenic gene fusion has been identified as an attractive antitumor target against the rare fibrolamellar hepatocellular carcinoma. A high-throughput assay was developed to identify selective modulators of the PKADJ catalytic activity by screening the prefractionated natural product library recently created by the NCI Program for Natural Product Discovery (NPNPD). In 2022 the NPCS has been engaged in the bioassay-guided fractionations of 35 PKADJ-active extracts. Totally 9 active compounds have been identified from these projects so far. Bioassay-guided fractionation of the extract of a marine tunicate Aplidium sp. led to the discovery of two novel alkaloids aplithianines A and B. Aplithianine A showed potent inhibition against both PKADJ and wide-type PKA with an IC50 value of 1.1 uM. (5) Topoisomerase-3b: Topoisomerase-3b (TOP3B) is an enzyme that alters DNA topology during transcription by catalyzing transient single strand DNA breaks and passage of the intact strand through this break. TOP3B was proposed as an attractive potential therapeutic target following studies showing that it is required for the efficient replication of positive-sense RNA viruses including SARS-CoV-2 in hosts. In this new high-throughput screening campaign the NPCS has been engaged in the bioassay-guided fractionations of 18 TOP3B-active extracts. We are in the process of isolation and identification of active natural products from these projects. (6) Discorhabdins: We have undertaken a structure-activity relationship study of discorhabdin L a natural product that showed promising preliminary prostate cancer xenograft results. In FY22 a series of new discorhabdin natural products were isolated and discorhabdin L was used as a scaffold for the generation of semi-synthetic derivatives probing the structure activity relationship of the lead compound. We will continue to improve the efficiency of our HTS-based bioassay-guided fractionation platform by optimizing the analytical-fingerprint-based dereplication and project selection pipelines. We will also incorporate new computational modeling and organic synthesis techniques/methodologies to establish our expertise in structure modification target identification and activity optimization. The long-term focus of this project is to exploit the vast spectrum of chemical diversity within the NPR for potential anticancer and anti-HIV applications. It relies on close integration with the MTP Assay Development and Screening Section Chemical Diversity Development Section and the Protein Chemistry and Molecular Biology Section for extract screening data analysis bioassay support and functional analysis of isolated compounds. Our CCR collaborators who study aspects of cancer biology genetics and immunology provide expertise for target selection and subsequent compound evaluation. We have assembled a broad consortium of intramural and extramural partners with expertise in organic synthesis chemical biology molecular pharmacology computational sciences and spectroscopic analysis to help characterize and advance our natural product discoveries. The Natural Products Chemistry Section is uniquely positioned within the NCI to combine molecular target-based discovery with natural products chemistry. Natural products are a source of structural complexity and biological activity that can provide insight on the function of new targets pathways or cellular processes. They play an important role in dissecting and understanding the intricacies of cancer development and progression so continued natural products discovery efforts can complement the goals of the CCR and NCI. 1244726 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Biochemical;Biogenesis;Biological;Biological Process;Cell Nucleus;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;DNA Polymerase II;DNA Polymerase III;Data Analyses;Databases;Development;Disease;Enzymes;Focus Groups;Foundations;Future;Genes;Genetic;Genetic Screening;Goals;Health;Hemostatic function;Hour;Malignant Neoplasms;Mammals;Methods;MicroRNAs;Modification;Monitor;Nucleotides;Pathway interactions;Physiology;Plasmids;Play;Proteins;RNA Interference;Regulation;Role;Safety;Small Interfering RNA;Specificity;System;Tail;Testing;The Cancer Genome Atlas;Therapeutic;Transcript;Untranslated RNA;Variant;base;cancer cell;cancer therapy;design;gene therapy;genome-wide;improved;in vivo;insight;knock-down;next generation sequencing;novel;novel strategies;overexpression;small hairpin RNA;tool;tumor progression;tumorigenesis Mechanism Regulation and Application of miRNA pathway in cancer n/a NCI 10702592 1ZIABC011566-09 1 ZIA BC 11566 9 12448167 "GU, SHUO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1864683 NCI "We focus on the first step of miRNA biogenesis where most of the regulations take place. Drosha initiates miRNA biogenesis by chopping hairpin-shaped miRNA precursors (pre-miRNA) off the primary transcripts (pri-miRNA) in the nucleus. Reduced enzymatic activity of Drosha has been described in various malignancies. We have created a powerful genome-wide genetic screen approach based on CRISPR. Applying this method in addition to data-analysis of the TCGA database we plan to identify novel cellular regulators of Drosha activity and investigate why and how these are regulated in physiology and in cancer. Their impacts on the efficiency and accuracy of miRNA biogenesis will then be tested by in the corresponding KO cells. DNA-directed RNAi (shRNA expressed from plasmids) is more desirable than traditional synthetic siRNAs in setting of gene therapy. However unsatisfactory knockdown efficacy and off-target effects hamper its applications often due to inefficient low fidelity of processing. Our previous finding on Dicer processing has established a ""loop-counting"" rule which laid the groundwork in designing Pol III-driven pre-miRNA-like shRNAs free of the off-target effects resulting from heterogeneous processing. We are currently working on transferring such a design into the Pol II system in which more complicated manipulation of shRNA function is possible. In particular we are developing conditionally activated shRNAs whose function can be specifically turned on in cancer cells. This approach will dramatically increase shRNA specificity and safety. Given the long half-lives of mature miRNAs (ranging from hours to days) biogenesis control by itself is inadequate in situations that require rapid changes in miRNA function. Post-maturation regulation is an important component of how miRNAs function. Thus in alignment with our goal of understanding miRNA regulation we study the biogenesis and function of 3' isomiRs which are miRNA variants generated by post-maturation tailing (adding nucleotides) and/or trimming (removing nucleotides). Interestingly the alteration in isomiR profile rather than in overall miRNA abundance correlates with cancer progression which suggests a unique role of isomiRs in tumorigenesis. These observations highlight the importance of isomiR study. To investigate the function of 3' isomiR we checked the status of 3' sequence modifications during miRNA overexpression and decay. We found that isomiR profiles are not random but rather tightly regulated. This suggests that the 3' end modification is not merely a consequence of miRNA overexpression but rather plays an active role in maintaining the miRNA hemostasis. To establish a causative relation we are working on identifying the enzymes that are responsible for producing certain isomeric forms. We also aim to develop novel strategies to monitor the function specific to certain isomiRs. Overall these studies seek to significantly advance our basic understanding of isomiRs and provide a foundation for future mechanistic study of their functions in cancer." 1864683 +Biomedical Imaging; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Minority Health; Prostate Cancer; Radiation Oncology; Urologic Diseases Biochemical;Biological;Biological Markers;Biopsy;Cancer Patient;Cancer Therapy Evaluation Program;Characteristics;Chemotherapy and/or radiation;Clinical;Clinical Trials;Data;Enrollment;Evolution;Failure;Genetic;Goals;In Vitro;Laboratories;Laboratory Study;Localized Malignant Neoplasm;MEK inhibition;MEKs;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular;Neoadjuvant Therapy;Outcome;Pathway interactions;Patients;Phase I Clinical Trials;Prostate;Protocols documentation;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Radiosensitization;Rectal Cancer;Recurrence;Recurrent disease;Research;Resistance;Risk Factors;Therapeutic;Time;Tissues;Tumor Tissue;Work;chemoradiation;chemotherapy;clinical translation;imaging modality;in vivo;inhibitor;irradiation;novel;phase I trial;prospective;radiation resistance;radiation response;radiological imaging;resistance factors;targeted radiotherapeutic;tumor;tumor specificity Targeting mechanisms of radiation resistance n/a NCI 10702589 1ZIABC011552-09 1 ZIA BC 11552 9 9414510 "CITRIN, DEBORAH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1846567 NCI An example of this approach is my laboratory's work with AZD6244 a MEK inhibitor. My laboratory demonstrated the therapeutic potential of MEK inhibition as a radiation sensitizer in several cancers both in vitro and in vivo(12) evaluated the impact of concurrent chemotherapy on the radiosensitizing effect of MEK inhibition(13) identified biomarkers that may predict efficacy of this approach and highlighted the mechanisms of radiation sensitization when this pathway is targeted.(12-14) This work culminated in the initiation of a CTEP sponsored Phase I trial at the NCI investigating MEK inhibition combined with the current standard chemoradiotherapy in the neoadjuvant setting in patients with locally advanced rectal cancer. There are currently three open and two completed Phase I clinical trials evaluating MEK inhibition combined with radiation and chemotherapy for the treatment of localized cancers. We have recently identified additional compounds that show preliminary efficacy in vitro as radiation sensitizers. The approach we have used in the past to select agents for study has been effective in identifying radiation sensitizers. This approach is evolving as we collect tumor tissue and clinical outcomes data from prostate cancer patients on my protocol 13-C-0119. This clinical trial will allow us to evaluate multiple biologic clinical and radiographic predictors of local failure in patients treated with radiotherapy for localized prostate cancer. Patients enrolled in this study undergo a pretreatment multiparametric MRI and MRI-guided research biopsy of all tumors within their prostate. Following radiation therapy patients with a rising PSA who meet biochemical failure criteria undergo repeat multiparametric MRI of the prostate and repeat MRI-guided research biopsy of persistent tumor. The molecular characteristics of tumor are analyzed to evaluate for predictors of failure and to study tumor evolution after radiation. Data from the tissue studies described above will be mined to generate a list of candidate pathway responsible for radiation resistance in prostate cancer. These data will inform laboratory studies aimed at determining the importance of these pathways in radiation response. 1846567 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Genetics; Immunotherapy; Orphan Drug; Ovarian Cancer; Rare Diseases; Women's Health AKT inhibition;American Association of Cancer Research;Angiogenesis Inhibition;Angiogenesis Inhibitors;Angiogenesis Pathway;Attenuated;BRCA1 gene;BRCA2 gene;Biological Markers;Biopsy;Biopsy Specimen;Blood specimen;Breast Cancer Risk Factor;CCNE1 gene;CCR;CHEK1 gene;Canada;Cancer Patient;Cancer Therapy Evaluation Program;Cancer cell line;Cell Cycle;Cell Cycle Arrest;Cell Cycle Checkpoint;Cell Cycle Progression;Cells;Characteristics;Chronic Inflammatory Demyelinating Polyradiculoneuropathy;Clinical;Clinical Investigator;Clinical Trials;Clinical Trials Design;Cohort Analysis;Combined Modality Therapy;Complement;Core Biopsy;Correlative Study;DNA;DNA Damage;DNA Repair;DNA Repair Gene;DNA Repair Inhibition;DNA Repair Pathway;Data;Defect;Development;Disease;Dissection;Drug Combinations;Enrollment;Evaluable Disease;Fresh Tissue;Functional disorder;Genes;Genomic Instability;Genomics;Gynecologic Oncology Group;Immune checkpoint inhibitor;Immune response;Immunotherapy;In Vitro;In complete remission;Investigation;Japan;KDR gene;Laboratories;Letters;M cell;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Manuscripts;Measures;Mediating;Mediator of activation protein;Modality;Molecular;Molecular Target;Mutate;Mutation;National Center for Advancing Translational Sciences;Oncogenes;Oncology;Outcome;PI3K/AKT;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phenotype;Physicians;Platinum;Poly(ADP-ribose) Polymerases;Population;Program Development;Progression-Free Survivals;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Publications;Publishing;RNA Helicase;Randomized;Recurrence;Reporting;Research Personnel;Resistance;Role;Scientist;Serous;Signal Transduction;South Korea;Stable Disease;TP53 gene;Testing;Therapeutic;Therapeutic Studies;Tissue Sample;Translational Research;United States;United States National Institutes of Health;Validation;Vascular Endothelial Growth Factors;Woman;Work;angiogenesis;base;cancer cell;checkpoint inhibition;chemotherapy;cohort;cytotoxic;exceptional responders;high risk;homologous recombination;immune checkpoint blockade;immunoregulation;improved;in vivo Model;inhibitor;mutant;next generation;novel;novel therapeutic intervention;novel therapeutics;partial response;phase 2 study;phase II trial;pre-clinical;predicting response;programs;randomized trial;recombinational repair;recruit;replication stress;resistance mechanism;response;standard care;synergism;tenure track;therapeutic target;therapeutically effective;translational approach;translational research program;tumor;tumor DNA;tumor-immune system interactions Leveraging DNA damage repair pathways as therapeutic targets in womens cancers n/a NCI 10702587 1ZIABC011525-10 1 ZIA BC 11525 10 12032154 "LEE, JUNG-MIN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1301281 NCI 1) Project 1: Therapeutic modulation of cell cycle checkpoint pathways in women's cancer (1) Cell cycle checkpoints e.g. ATR and CHK1 are the major regulators of cell cycle and DNA repair pathways. CHK1 functions as a primary mediator of G2/M cell cycle arrest in tumors with TP53 mutation and consequent G1/S cell cycle dysregulation such as HGSOC. I previously opened the first investigator-initiated phase II trial of the CHK1 inhibitor (CHK1i) prexasertib for HGSOC (14-C-0156) to test the hypothesis that inhibition of ATR/CHK1 signaling would result in clinical activity in HGSOC. Early clinical activity of prexasertib was observed in heavily pretreated BRCA wild-type (BRCAwt) HGSOC patients (33% response rate [RR] with a median progression free survival [PFS] of over 7 months). This was the first demonstration of CHK1i clinical activity in ovarian cancer and published in Lancet Oncology in 2018. Based on this promising activity Acrivon Therapeutics is launching a multi-center late-stage phase II study of prexasertib (ACR-368) in platinum-resistant recurrent HGSOC. I am the Study Chair of this study (GOG-3082) and actively participated in the clinical trial design and collaborated with Acrivon Therapeutics for the validation of their proteomics-based biomarker of CHK1i response. In addition my analysis of the cohorts of BRCAwt platinum-resistant HGSOC patients (biopsy cohort and non-biopsy cohort of 14-C-0156) confirmed similar clinical activity of prexasertib in this hard-to-treat population (31% [12/39] RR and 59% [23/39] clinical benefit rate [complete response [CR]+ partial response [PR]+ stable disease [SD] lasting longer than 6 months]) (AACR 2022). We collected baseline fresh tissue samples from 15 patients of biopsy cohort and approximately 30 blood samples from both cohorts and are currently analyzing biomarkers to identify mechanisms of sensitivity or resistance to CHK1i. In BRCA mutant HGSOC patients of 14-C-0156 study we observed modest clinical activity of CHK1i treatment. Two of 18 (11%) evaluable patients achieved PR. All patients except one exceptional responder (PR 41 months of PFS) had prior PARP inhibitor (PARPi). To study possible cross-resistance between PARPi and CHK1i we conducted genomic analyses and other molecular investigations using fresh core biopsies and blood samples. BRCA reversion mutations a well-known mechanism of cross-resistance between PARPi and platinum drugs were not associated with lack of response to CHK1i. But we found high levels of replication stress measured by high BLM expression and CCNE1 expression or amplification were associated with a response to CHK1i. The manuscript detailing correlative study findings is currently under review. Also my lab generated preclinical data for an ATR inhibitor (ATRi) another important cell cycle regulator upstream of CHK1 -based combination therapy using PARPi-resistant HGSOC in vitro and in vivo models. The letter of intent (LOI) of phase I/Ib study of ATRi and AKTi has been approved by CTEP/NCI for a multi-center ETCTN study anticipated study opening in 1/2Q2023. (2) In the laboratory I am studying the molecular characteristics that predict the response to ATR/CHK1 signaling blockade and potential mechanisms of resistance of cell cycle inhibitors or PARPi. For this my lab has developed PARPi-resistant HGSOC cell lines to recapitulate the PARPi-resistant patients (in revision Oncogene). Using PARPi-resistant HGSOC cells I collaborated with NCATS/NIH for a high-throughput drug combination screen for the development of better therapeutic combinations for PARPi-resistant population. In the screen several inhibitors of PI3K/AKT signaling induced synergistic cytotoxic activity with ATRi or CHK1i. I have extended this work to further understand the mechanisms of underlying synergy and to develop the next generation clinical trials. Mechanistically we found a novel function of AKT in R-loop mediated replication stress. Specifically AKT inhibition augments ATRi-induced replication stress by inhibiting the expression of DNA/RNA helicase DHX9 and its recruitment on R-loops causing significant R-loop-mediated replication stress in PARPi resistant cells. The manuscript detailing mechanistic findings is now under review. 2) Project 2: Therapeutic strategies to complement immune checkpoint blockade (ICB) in HGSOC (1) Immunotherapy has emerged as a major therapeutic modality in oncology yet most patients with ovarian cancer do not derive benefit from ICB monotherapy highlighting the need to develop and test rational combination strategies. Data suggest inhibition of DNA repair and angiogenesis pathways may modulate immune response by increasing DNA damage and by attenuating immunosuppressive microenvironment. I previously opened a phase I/II investigator-initiated study (15-C-0145) which tests the hypothesis that DNA damage induced by PARPi olaparib and modulation of immune-suppressive milieu by a VEGFR inhibitor cediranib may improve clinical activity of ICB (anti-PD-L) durvalumab monotherapy which has yielded early activity signal in recurrent ovarian cancer patients (JCO 2017 CCR 2020). (2) Based on my clinical findings from ovarian cancer cohort of 15-C-0145 study the concept of randomized Phase II study of triple therapy (durvalumab plus olaparib and cediranib) vs. standard care chemotherapy in platinum-resistant ovarian cancer was approved by CTEP/NCI and NRG Oncology. This randomized multi-center Phase II trial is now open and accruing patients (Study Chair: JM Lee a target accrual of 164 patients NRG-GY023 [NCI000484]). (3) This 15-C-0145 clinical trial has been expanded to bring these therapeutic opportunities and translational research approaches to other tumor types such as prostate and lung cancers. Phase II findings of D and O in prostate and lung cancer cohorts yielded multiple publications and suggest preliminary clinical activity in subsets of heavily pretreated patients. 3) Project 3: Therapeutic targeting the key proteins of DNA repair and angiogenesis pathways in recurrent HGSOC (1) Angiogenesis and DNA damage repair pathways are active and interactive therapeutic targets in recurrent HGSOC. I hypothesized optimal targeting of PARP and VEGF/VEGFR pathways would improve clinical outcome in recurrent HGSOC. The promising activity of olaparib and cediranib combination led to the development of the NRG Oncology multi-center Phase II/III randomized trial of olaparib and cediranib for platinum-resistant ovarian cancer for which I am the Study Chair (NRG GY005 [16-C-0088]). NRG GY005 study has enrolled a target accrual of 208 patients for a phase II part and a phase III part completed the accrual of total 540 patients in the U.S. Canada Japan and South Korea with anticipated data maturation and report in 2Q2023. Collectively this focused clinical and translational approach will make our branch/CCR a recognized center focusing on the treatment of women with genetically high-risk breast and/or ovarian cancer or those with tumor DNA repair deficient phenotypes with a strong translational research program. 1301281 +Cancer 3-Dimensional;Abnormal Cell;Aneuploidy;Animals;Architecture;Biogenesis;Biological Process;C-terminal;Cell Cycle;Cell Cycle Progression;Cell division;Cell physiology;Cells;Cellular biology;Centrioles;Centrosome;Chromosome Segregation;Client;Complex;Data;Defect;Development;Disease;Ensure;Etiology;Eukaryotic Cell;Event;Exhibits;Fluorescence Recovery After Photobleaching;Future;Goals;Human;In Vitro;Life;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Microtubule-Organizing Center;Mitotic spindle;Molecular;Molecular Sieve Chromatography;Names;Nanoscopy;Organelles;Organism;PLK1 gene;Phase;Play;Polo-Box Domain;Procentriole;Process;Property;Proteins;Research;Role;Scaffolding Protein;Site;Structure;Subcellular structure;Ultracentrifugation;Work;X-Ray Crystallography;biophysical techniques;density;genome integrity;human disease;in vivo;macromolecular assembly;mutant;nanoscale;novel;scaffold;sedimentation equilibrium;self assembly;self organization;single molecule Molecular basis of centriole duplication n/a NCI 10702585 1ZIABC011518-10 1 ZIA BC 11518 10 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1289799 NCI "The centrosome a unique membrane-less multiprotein organelle that serves as the main microtubule-organizing center in animal cells plays a pivotal role in the orderly progression of the cell cycle. Since faulty assembly and duplication of the centrosome results in abnormal cell division which then leads to various human disorders elucidating the molecular mechanisms underlying centrosome assembly and function is likely a key step to understanding the etiology of centrosome-associated human diseases. By combining cell biology with biophysical methods and X-ray crystallography we demonstrated that two pericentriolar scaffolds Cep152 and Cep63 possess intrinsic activity of co-phase-separating into condensates and form a heterotetrameric complex that serves as a building block for generating a nanoscale cylindrical self-assembly around a centriole. Remarkably two short uncharacterized regions named Self-Assembly Motifs (one each from Cep63 and Cep152) cooperatively conferred physicochemical properties that allowed them to undergo density transition and self-assemble into a cylindrical architecture. Interestingly the Cep152-Cep63 condensates exhibited a rapid turnover underwent fusion with other assemblies and carried out a significant degree of internal rearrangement within a condensate. A Cep152-Cep63 cylindrical architecture that self-assembled on a flat substrate displayed a decreased but still detectable level of dynamic turnover. Interestingly Polo-like kinase 4 (Plk4) a key regulator of centriole biogenesis also dynamically phase-separated from a Cep152-bound state around a centriole (i.e. ring state) into a dot-like low-nanoscale spherical condensate (i.e. dot state) upon autophosphorylating its C-terminal cryptic polo-box domain. Additional in vitro and in vivo data suggest that the Plk4 condensate serves as an assembling body at the future procentriole assembly site by amassing downstream procentriole assembly components such as STIL and Sas6 and facilitating Plk4-mediated centriole biogenesis. Thus the formation of biomolecular condensates appears to be a fundamental step that not only promotes the self-assembly of a pericentriolar architecture but also triggers the process of centriole duplication. Along with this progress we have been focusing on examining the mechanism underlying pericentriolar material (PCM) organization self-assembling activity of pericentriolar scaffold proteins molecular basis of building higher-order PCM architectures. To this end we performed size-exclusion chromatography sedimentation equilibrium ultracentrifugation and interferometric scattering mass spectrometry and showed that the heterotetrameric building block generates octameric and hexadecameric complexes in a concentration-dependent manner suggesting that the cylindrical self-assembly is formed through stepwise processes. By using MINFLUX nanoscopy which offers low-nanometer-scale localization precision in a three-dimensional space we further showed that mutants defective in forming the Cep63-Cep152 heterotetramer exhibited crippled pericentriolar Cep152 organization consequently failing to promote polo-like kinase 4 (Plk4)'s dynamic relocalization from around the centriole to the future procentriole assembly site as well as Plk4-mediated centriole duplication. Remarkably the entire self-assembly process could be driven by two short uncharacterized regions (which we named ""self-assembly modules"") in Cep63 and Cep152 capable of cophase-separating and generating cylindrical self-assemblies in vitro. Fluorescence recovery after photobleaching revealed that the self-assembled architecture is highly dynamic undergoing internal rearrangement within the assembly while exchanging its components with those in the surroundings. Dynamic turnover of pericentriolar Cep63 and Cep152 has also been observed in human centrosomes. Taken together given the evolutionarily conserved organization of PCM this work could serve as a paradigm for investigating the structure and function of centrosomal scaffolds in other organisms while offering a new direction for probing organizational defects in PCM-related human diseases." 1289799 +Bioengineering; Biomedical Imaging; Cancer; Digestive Diseases; Esophageal Cancer; Nanotechnology; Orphan Drug; Rare Diseases Antibodies;Appearance;Area;Cancer Center;Cell Death;Cell membrane;Cell surface;Cells;Clinical Trials;Collaborations;Development;Diagnosis;ERBB2 gene;Epidermal Growth Factor Receptor;Exposure to;FOLH1 gene;GPC3 gene;Goals;Head and neck structure;IL2RA gene;Image;Light;Liposomes;Malignant Neoplasms;Membrane;Mucin 1 protein;Names;Necrosis;Normal Cell;Photosensitizing Agents;Process;Production;Proteins;Reagent;Sensitivity and Specificity;Singapore;Site;Surgeon;Therapeutic Effect;Tissues;cancer cell;cancer therapy;cell injury;cell killing;cell type;chemotherapy;effective therapy;esophageal squamous cell cancer;hydrophilicity;imaging modality;imaging probe;improved;mesothelin;nanoparticle delivery;nanosized;non-invasive imaging;novel;photoimmunotherapy;scale up;targeted cancer therapy;tumor Cancer-cell specific therapy: photo-immunotherapy n/a NCI 10702584 1ZIABC011513-10 1 ZIA BC 11513 10 12032143 "KOBAYASHI, HISATAKA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1387661 NCI Photoimmunotherapy has been established as a potential and highly selective cancer therapy against EGFR HER2 PSMA and CD25 postive tumors. All targeted cells are killed by necrotic cell death after irreversible damage to the cell membrane immediately after exposure to near infrared light at 690 nm. We are currently investigating precise mechanisms of membrane damage. We are also expanding the repertoire of potential target molecules to include MUC1 CEA laminine GPC3 mesothelin etc. by obtaining new antibodies for covering wider varieties of cancer. Additionally we are also establishing novel non-invasive imaging methods to diagnose the therapeutic effects of PIT because necrotic cell killing induced by PIT is a very rapid process and cells die well in advance of changes of physical appearance on conventional images. We have recently discovered that PIT dramatically increases (20-fold) the delivery of nanoparticle sized therapies (e.g. liposomal chemotherapy) to PIT-treated cancer tissue. Therefore the combination of PIT with nano-sized cancer reagents holds potential for even more effective therapy. Finally we are now preparing clinical trials in head and neck and esophageal squamous cell cancer at NCI/Hopkins National Cancer Center Singapore and Netherland/Groningen Univ in collaboration with surgeons at these sites. We are working with the Image Probe Development Center (IPDC) to scale up production of IR700 and antibody-IR700 conjugates for eventual use in these trials. 1387661 +Bioengineering; Biomedical Imaging; Cancer Angiography;Antibodies;Binding;Biodistribution;Biological;Cells;Clinical;Contrast Media;Detection;Diagnostic;Disease;Electron Transport;Fluorescence;Fluorescence Resonance Energy Transfer;Gadolinium;Gamma-glutamyl transferase;Homo;Indocyanine Green;Iodine;Label;Lesion;Magnetic Resonance Imaging;Malignant Neoplasms;Molecular;Operative Surgical Procedures;Optics;Pharmacology;Photons;Procedures;Property;Published Comment;Radioisotopes;Radionuclide Imaging;Sensitivity and Specificity;Signal Transduction;Specificity;Testing;Tissues;X-Ray Computed Tomography;base;cancer imaging;clinical application;design;dimer;flexibility;fluorescence imaging;imaging modality;imaging probe;in vivo;molecular imaging;rational design Activatable molecular cancer imaging probe n/a NCI 10702583 1ZIABC011512-10 1 ZIA BC 11512 10 12032143 "KOBAYASHI, HISATAKA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 154185 NCI We have been investigating the rational design and in vivo applications of target-cell specific activatable probes. Designing these probes based on their photo-chemical (e.g. activation strategy) pharmacological (e.g. biodistribution) and biological (e.g. target specificity) properties has recently allowed the rational design and synthesis of target-cell specific activatable fluorescence imaging probes which can be conjugated to a wide variety of targeting molecules. Several different photo-chemical mechanisms have been utilized each of which offers a unique capability for probe design. These include: self-quenching homo- and hetero-fluorescence resonance energy transfer (FRET) H-dimer formation and photon-induced electron transfer (PeT). In addition the repertoire is further expanded by the option for reversibility or irreversibility of the signal emitted using the aforementioned mechanisms. Given the wide range of photochemical mechanisms and properties target-cell specific activatable probes possess considerable flexibility and can be adapted to specific diagnostic needs. From a translational viewpoint including considerations of both the clinical value and regulatory approval requirements several clinically applicable candidates including indocyanine green labeled antibodies or a small molecular gamma-glutamyltransferase activatable probe which are designed to be used during surgical or endoscopic procedures have been tested. 154185 +Breast Cancer; Cancer; Genetics; Pediatric; Pediatric Cancer; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Women's Health Autophagocytosis;Breast;Breast Cancer Cell;CBFB gene;Cancer Etiology;Cell Line;Cell Survival;Cells;Cessation of life;Clinical;Defect;Etiology;Event;FDA approved;Future;Gene Expression;Gene Expression Regulation;Genetic Transcription;Genomics;Goals;Human;Malignant Neoplasms;Mammary Neoplasms;Mediating;Mesenchymal Stem Cells;Metabolic;Modeling;Molecular;Mutate;Oncogenes;Pathway interactions;Ramp;Regulation;Reporting;Research;Role;Signal Transduction;TP53 gene;Translational Regulation;Translations;base;malignant breast neoplasm;mortality;novel;novel therapeutic intervention;osteoblast differentiation;osteosarcoma;pediatric patients;programs;sarcoma;targeted treatment;transcription factor;tumor Vulnerabilities in osteosarcoma and breast cancer n/a NCI 10702581 1ZIABC011504-10 1 ZIA BC 11504 10 10270570 "HUANG, JING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1698012 NCI Osteosarcoma (OS) is a leading cause of cancer-related death in pediatric patients. Mortality rates for this cancer have not changed substantially during the last three decades partly due to the lack of an FDA-approved targeted therapy. Understanding the etiology of OS is a critical need for developing new treatment options. Genomic sequencing studies did not find any dominant actionable targets. Our strategy is to identify OS cells' survival signals related to the p53 pathway. In addition to human OS cell lines we have been using mesenchymal stem cells (MSCs) as a model since they are the putative cell-of-origin of OS cells. During this review period we have made several critical advances. First we showed that p53 represses RUNX2 expression in MSCs and p53 loss predisposes these cells to osteoblast differentiation providing an explanation for the clinical observation that OS is tightly associated with p53 loss. Second we identified the CBFB/RUNX2 axis as a survival signal in OS cells. Third we uncovered that in the context of p53 loss oncogenes determine the types of sarcomas originating from MSCs. For example the cFos-Sox9 axis promotes chondroblastic OS from p53 null MSCs. Future studies are focused on further investigating the pro-survival function of RUNX2 in OS. We hope that we will find vulnerabilities of OS in RUNX2-regulation gene expression that can be exploited for developing a novel treatment of OS. We have recently ramped up our efforts to study translation dysregulation in breast cancer based on our discovery of a new function for CBFB in the translational regulation of breast cancer. The CBFB gene is mutated in about 5 percent of breast tumors; however its function in breast cancer had not been known. We were the first to report that CBFB has a tumor-suppressive role in breast cancer. The underlying molecular mechanism was completely unexpected. In contrast to the well-accepted view that CBFB is a transcription factor we found that cytoplasmic CBFB directly regulates translation in breast cancer cells. Because transcriptional events are difficult to target translation represents a vital step in gene expression for identifying cancer vulnerabilities. Indeed our preliminary studies suggested that downstream events caused by deregulation of CBFB-mediated translation could be further exploited to identify vulnerabilities in breast cancer. Therefore understanding CBFB-regulated translation in breast cancer has become a major focus of my research program. Ongoing efforts are concentrated on investigating the metabolic shift and autophagy dysregulation caused by the CBFB defect in breast cells. 1698012 +Bioengineering; Cancer; Nanotechnology; Patient Safety; Radiation Oncology Blood Vessels;CCR;Cells;Cessation of life;Clinical;Clinical Protocols;Disease;Disseminated Malignant Neoplasm;Elements;Goals;Immune;Immune response;Immunosuppression;Laboratories;Laboratory Research;Malignant Neoplasms;Medical Oncology;Patient Care;Patient Monitoring;Patients;Protocols documentation;Quality of life;Radiation;Radiation Oncologist;Radiation Oncology;Radiation therapy;Research;Role;Sampling;Stromal Cells;Stromal Neoplasm;Study Section;Surgical Oncology;System;Translational Research;Tumor Markers;United States National Institutes of Health;Unresectable;Work;base;clinical practice;cohesion;curative treatments;design;extracellular vesicles;immune activation;improved;improved outcome;irradiation;liquid biopsy;nanobiology;neoplastic cell;particle;patient population;phosphatidylserine receptor;response to injury;tissue injury;tool;translational goal;translational research program;treatment response;tumor;tumor progression Discovery of Tumor Treatment Response and Systems-based EVP Signatures n/a NCI 10702580 1ZIABC011503-10 1 ZIA BC 11503 10 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 767629 NCI As a practicing radiation oncologist seeking to integrate my laboratory and clinical efforts into a cohesive translational research program I have focused my clinical practice on the care of patients with metastatic cancers for whom radiation may be beneficial. In the past year I created the Treatment of Extra-cranial Advanced Malignancies (TEAM) group in the NCI Radiation Oncology Branch and we are developing protocols designed to improve the assessment and treatment of patients with advanced malignancies. A major focus of my work with the TEAM group is liquid biopsies and a major research aim currently is to determine what liquid biopsy or biofluid EVP profiles correlate with responses to treatment. The translational research efforts of this project are following a two-pronged approach: 1) collaborating with medical and surgical oncology colleagues at NIH to investigate EVPs as biomarkers for tumor status as part of those collaborators' existing protocols and 2) developing new clinical protocols to capture information and samples from this patient population in a more cohesive and informative manner. Both of these approaches are supported by and provide support to the CCR's clinical translational mission and the basic scientific work ongoing in the Translational Nanobiology Section for the study of EVP repertoires. 767629 +Bioengineering; Cancer; HIV/AIDS; Immunization; Nanotechnology; Prevention; Vaccine Related; Vaccine Related (AIDS) Area;Biological;Biology;Biomedical Research;Biophysics;Blood Tests;Blood Vessels;CCR;Cancer Patient;Clinical;Collaborations;Communities;Computer software;Detection;Disease;Foundations;Future;Goals;Immune;Immune Evasion;Immune response;Immunobiology;Investigation;Knowledge;Malignant Neoplasms;Measures;Medicine;Methods;Mission;Molecular;Monitor;Neoplasm Circulating Cells;Nucleic Acids;Patient Care;Protocols documentation;Radiation;Reproducibility;Research;Resolution;System;Tumor Biology;Vision;Work;anticancer research;base;biological systems;biophysical properties;exosome;extracellular vesicles;frontier;improved;interest;liquid biopsy;macromolecular assembly;microvesicles;multiple omics;nano;nanobiology;nanoparticle;nanoscale;neglect;neoplastic cell;novel;particle;programs;submicron;tool;treatment response;treatment strategy;tumor;tumor progression Biophysical Characterization of EVPs and other Macromolecular Nanoparticles n/a NCI 10702579 1ZIABC011502-10 1 ZIA BC 11502 10 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 686103 RMOD Liquid biopsies are part of this emerging frontier in biomedical research. This frontier is of interest to all areas of biology and medicine and is of particular interest to the cancer research community. Circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) are two types of liquid biopsies where clear progress has been made in the past decade towards understanding these CTC and cfNA tumor-related and systems-based biological information. Systematic accurate and reproducible studies of sub-micron extracellular vesicles (EVs) and other nanoscale macromolecular assemblies (collectively referred to hereafter as extracellular vesicles and particles or EVPs) are difficult to perform due to a lack of robust and reliable tools for correctly measuring these submicron and nanoscale materials. CCR's mission is to improve the lives of all cancer patients by solving important challenging and neglected problems in cancer research and patient care. The Translational Nanobiology Section's particular expertise perspective collaborations and vision within CCR is building bridges to span the existing gaps between basic biophysical and metrological first principles advanced molecular multi-omics strategies and clinical translational investigation in order to develop systematic robust and accurate ways to study EVPs tumor- immune- and stromal-/vascular- EVP compositions as they relate to tumor progression and treatment response in our cancer patients. Although the specific focus of my lab pertains most immediately to cancer and cancer-related immunobiology we intend for our work to be a general asset to the biomedical research community. As such my Section is committed to sharing our tools for general research use so that they can accelerate studies in other diseases as well. The ultimate goal of my program is to leverage the information content in EVPs to interrogate biological systems in a systematic manner that is by identification and characterization of specific sub-sets of EVPs to 'read' the status of compartments represented by those sub-sets. The purpose of Projects 1 and 2 in the Translational Nanobiology Lab is to develop and demonstrate the use of new tools for the field to use that will enable us to monitor tumor immune and vascular/stromal systems in a manner that we hope will enable us to perform blood tests to detect relevant changes in those systems early in the course of radiation or other therapies and we hope that this will more broadly serve as a foundation for enabling selectively (system-specific) adaptive treatment strategies in the future. Project 1 is focused on spanning the gap in available tools and knowledge to accurately characterize the liquid biopsy components EVPs and their cargo for Project 2. 72000 +Bioengineering; Cancer; HIV/AIDS; Immunization; Nanotechnology; Prevention; Vaccine Related; Vaccine Related (AIDS) Area;Biological;Biology;Biomedical Research;Biophysics;Blood Tests;Blood Vessels;CCR;Cancer Patient;Clinical;Collaborations;Communities;Computer software;Detection;Disease;Foundations;Future;Goals;Immune;Immune Evasion;Immune response;Immunobiology;Investigation;Knowledge;Malignant Neoplasms;Measures;Medicine;Methods;Mission;Molecular;Monitor;Neoplasm Circulating Cells;Nucleic Acids;Patient Care;Protocols documentation;Radiation;Reproducibility;Research;Resolution;System;Tumor Biology;Vision;Work;anticancer research;base;biological systems;biophysical properties;exosome;extracellular vesicles;frontier;improved;interest;liquid biopsy;macromolecular assembly;microvesicles;multiple omics;nano;nanobiology;nanoparticle;nanoscale;neglect;neoplastic cell;novel;particle;programs;submicron;tool;treatment response;treatment strategy;tumor;tumor progression Biophysical Characterization of EVPs and other Macromolecular Nanoparticles n/a NCI 10702579 1ZIABC011502-10 1 ZIA BC 11502 10 12032135 "JONES, JENNIFER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 686103 NCI Liquid biopsies are part of this emerging frontier in biomedical research. This frontier is of interest to all areas of biology and medicine and is of particular interest to the cancer research community. Circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) are two types of liquid biopsies where clear progress has been made in the past decade towards understanding these CTC and cfNA tumor-related and systems-based biological information. Systematic accurate and reproducible studies of sub-micron extracellular vesicles (EVs) and other nanoscale macromolecular assemblies (collectively referred to hereafter as extracellular vesicles and particles or EVPs) are difficult to perform due to a lack of robust and reliable tools for correctly measuring these submicron and nanoscale materials. CCR's mission is to improve the lives of all cancer patients by solving important challenging and neglected problems in cancer research and patient care. The Translational Nanobiology Section's particular expertise perspective collaborations and vision within CCR is building bridges to span the existing gaps between basic biophysical and metrological first principles advanced molecular multi-omics strategies and clinical translational investigation in order to develop systematic robust and accurate ways to study EVPs tumor- immune- and stromal-/vascular- EVP compositions as they relate to tumor progression and treatment response in our cancer patients. Although the specific focus of my lab pertains most immediately to cancer and cancer-related immunobiology we intend for our work to be a general asset to the biomedical research community. As such my Section is committed to sharing our tools for general research use so that they can accelerate studies in other diseases as well. The ultimate goal of my program is to leverage the information content in EVPs to interrogate biological systems in a systematic manner that is by identification and characterization of specific sub-sets of EVPs to 'read' the status of compartments represented by those sub-sets. The purpose of Projects 1 and 2 in the Translational Nanobiology Lab is to develop and demonstrate the use of new tools for the field to use that will enable us to monitor tumor immune and vascular/stromal systems in a manner that we hope will enable us to perform blood tests to detect relevant changes in those systems early in the course of radiation or other therapies and we hope that this will more broadly serve as a foundation for enabling selectively (system-specific) adaptive treatment strategies in the future. Project 1 is focused on spanning the gap in available tools and knowledge to accurately characterize the liquid biopsy components EVPs and their cargo for Project 2. 614103 +Aging; Cancer; Colo-Rectal Cancer; Digestive Diseases; Genetics; Neurosciences; Stem Cell Research; Stem Cell Research - Embryonic - Human; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human Aging;Alzheimer's Disease;Apoptosis;Astrocytes;Attenuated;Benign;CD8-Positive T-Lymphocytes;Cancer Survivor;Cell Aging;Cell Cycle;Cell Cycle Arrest;Cells;Characteristics;Chromosomal Instability;Coculture Techniques;Colon Carcinoma;DNA Damage;DNA Repair;DNA Repair Gene;Data;Defect;Disease;Dominant Genes;Dominant-Negative Mutation;Double Strand Break Repair;Ensure;Epithelial;Epithelial Cells;Etiology;Fibroblasts;Gene Expression;Generations;Genes;Human;Immune;Impaired cognition;In Vitro;Insulin-Like Growth Factor I;Interleukin-6;Knock-out;Laboratory Study;Longevity;Malignant Neoplasms;Mediating;Mesenchymal;MicroRNAs;Molecular;Mutation;Nerve Degeneration;Neurons;Neurosciences;Nuclear;Oxidative Stress;Pathologic;Patients;Phenotype;Pluripotent Stem Cells;Progeria;Prognosis;Property;Protein Isoforms;Publishing;Radiation;Radiation therapy;Regulation;Regulatory T-Lymphocyte;Reporting;Repression;Role;Signal Pathway;Stress;Syndrome;T-Lymphocyte;TP53 gene;Teratoma;Testing;Therapeutic;brain tissue;cancer cell;carcinogenesis;cell injury;colon cancer patients;exhaustion;exosome;gain of function;human embryonic stem cell;in vivo;induced pluripotent stem cell;irradiation;knock-down;macrophage;monocyte;mutant;neurotoxic;neurotoxicity;neurotrophic factor;non-oncogenic;overexpression;premature;prevent;recruit;senescence;tau Proteins;therapeutic target;tumor;tumor microenvironment;tumorigenesis p53 Aging and Cancer n/a NCI 10702577 1ZIABC011496-10 1 ZIA BC 11496 10 9692183 "HARRIS, CURTIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1873482 NCI Cellular senescence is induced by DNA damage oxidative and other stresses and is characterized by cell cycle arrest and the senescence-associated secretory phenotype (SASP). p53 protein regulates multiple aspects of signaling pathways leading to cellular senescence. delta133p53alpha and p53beta isoforms regulate cellular senescence in human epithelial cells astrocytes macrophages and CD8+ T cells (Joruiz SM. et al. Cancers (Basel). 12: 2020). The delta133p53alpha mediated cellular reprogramming is our therapeutic strategy for senescence-associated disorders (Beck J. et al. Carcinogenesis. 41: 1017-1029 2020) including radiation-induced neurodegeneration (Turnquist C. et al. Neuro Oncol. 21: 474-485 2019) Alzheimer's disease (Ungerleider K. et al. Cell Cycle. 20: 752-764 2021) and Hutchinson-Gilford progeria syndrome (HGPS). Tumor Microenvironment regulation: delta133p53alpha and tumor exosome-secreted microRNAs are critical regulators of macrophages and CAR-M in the tumor microenvironment (TME). We showed that macrophages are regulated non-cell-autonomously by mutant p53 protein in cancer cells. Colon cancer cells with gain-of-function (GOF) mutant p53 (e.g. R248W and R273H) secrete exosomes enriched for miR-1246 which are taken up by macrophages and reprogram them to an immune-suppressive cancer-promoting TAM state. These in vitro findings recapitulate the in vivo TME in colon cancer patients where cancer mutant p53 and exosomal miR-1246 are associated with immune-suppressive signatures recruitment of immune-suppressive Treg epithelial-mesenchymal transition and poor prognosis. We have found that the endogenous expression of delta133p53alpha is downregulated during monocyte-to-macrophage differentiation especially in M2 macrophages. Therapeutics: delta133p53alpha inhibits astrocytic SASP-mediated neurotoxicity which is triggered and amplified by synergistic and non-overlapping activities of A-beta and tau. We have found that brain tissues from cancer survivors with radiotherapy-associated cognitive impairment like those from AD patients have increased numbers of senescent cells mainly astrocytes. Irradiation of primary human astrocytes in vitro induced them to become senescent with diminished expression of delta133p53alpha accumulation of DNA damage induction of neurotoxic SASP (e.g. IL-6) and repression of neurotrophic factors (e.g. IGF-1). We have shown that overexpression of delta133p53alpha in astrocytes attenuated DNA damage upon irradiation repressed IL-6 and restored IGF-1 leading to abrogation of neurotoxicity in neuron-astrocyte co-culture. These data suggest a key role for astrocytic delta133p53alpha in the etiology and potential therapy of radiation-induced cognitive impairment.(Ungerleider Kyra et al. Neuroscience. 498:190-202 2022) delta133p53alpha is a therapeutic target that can be enhanced to mitigate progeria-associated pathological changes. We have revealed that endogenous delta133p53alpha expression is diminished upon premature induction of senescence in HGPS-derived fibroblasts and consistently overexpressed delta133p53alpha abrogates such premature senescence through inhibiting senescence-inducing p53 targets p21WAF1 and miR-34a. Our data also show that delta133p53alpha overexpression does not correct the progerin-induced nuclear defect but prevents oxidative stress-associated DNA damage and proinflammatory SASP which are cellular downstream defects characteristic of HGPS. We have shown that the dominant-negative activity of delta133p53alpha preferentially inhibits p53-mediated cellular senescence. In contrast p53 target genes involved in DNA repair and apoptosis are not or are minimally inhibited by delta133p53alpha which would ensure prompt repair of DNA damage and elimination of severely damaged cells to prevent oncogenesis. Consistently we have also shown that overexpression of delta133p53alpha is non-mutagenic and non-oncogenic in human induced pluripotent stem cells highlighting a contrast to total knockout or knockdown of all p53 activities. The senescence-selective dominant-negative non-mutagenic and non-oncogenic properties of delta133p53alpha all support its safe application in therapeutic approaches. 1873482 +Cancer; Cancer Genomics; Clinical Research; Digestive Diseases; Emerging Infectious Diseases; Genetics; Human Genome; Immunotherapy; Infectious Diseases; Liver Cancer; Liver Disease; Lung; Lung Cancer; Microbiome; Pancreatic Cancer; Precision Medicine; Prevention; Rare Diseases; Women's Health Acids;Adenocarcinoma Cell;African;Annual Reports;Anus;Bacteria;Bacterial Infections;Bioinformatics;Biological Assay;Biological Factors;Biological Markers;CA-19-9 Antigen;CD8B1 gene;COVID-19 pandemic;Cancer Patient;Cancer Prognosis;Cells;Cholestanes;Clinical;Collaborations;Contracts;Creatine;DNA Methylation;Data;Development;Diagnosis;Diagnostic;Disease;Environmental Exposure;Escherichia coli;Evaluation;Exposure to;Fluorescence-Activated Cell Sorting;Foundations;Frequencies;Genets;Glucuronides;Health Disparities Research;Human;Human Resources;Hydrocortisone;Immune;Immunotherapy;Infection;Infiltration;Inflammatory;Inflammatory Response;Intrahepatic Cholangiocarcinoma;Investigation;Ions;KPC model;Laboratories;Leukocytes;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Measures;Mediating;Medical;Messenger RNA;MicroRNAs;Mitochondria;Molecular;Molecular Analysis;Mus;Mutation;N-Acetylneuraminic Acid;Natural Immunity;Neutrophil Infiltration;Neutrophilic Infiltrate;PTPRC gene;Pathway interactions;Phenotype;Plasma;Play;Population;Prognosis;Property;Proteome;Recurrence;Reporting;Research;Resources;Role;Serum;Signal Transduction;Smoking;Squamous cell carcinoma;Statistical Data Interpretation;Sterility;Sulfate;T-Lymphocyte;TP53 gene;Taxonomy;Therapeutic;Time;Tissue-Specific Gene Expression;Tissues;Tumor Burden;Urine;adaptive immunity;base;bench to bedside;cancer biomarkers;cancer cell;cancer diagnosis;cancer initiation;cancer risk;cancer therapy;cancer type;cohort;cytokine;diagnostic value;genome wide association study;health disparity;high risk;improved;individual patient;liquid biopsy;lung carcinogenesis;lung lesion;lung microbiome;lung tumorigenesis;metabolome;microbiome;microbiota;mouse model;neutrophil;novel;pathogenic Escherichia coli;patient subsets;personalized diagnostics;precision medicine;precision oncology;prognostic;programmed cell death ligand 1;programs;riboside;screening;therapeutic target;therapy outcome;transcriptome sequencing;treatment response;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenic;urea cycle;urinary; T cells Precision Medicine of Cancer n/a NCI 10702576 1ZIABC011492-10 1 ZIA BC 11492 10 9692183 "HARRIS, CURTIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2810223 NCI Precision medicine in cancer is multifaceted and our research following the bench to bedside approach has led to significant discoveries that will advance the diagnostic and prognostic utilization of biomarkers and elucidate the role and mechanism the microbiome plays in lung carcinogenesis. In addition researching health disparity remains a focus (Graff M. et al. Am J Hum Genet. 108: 564-582 2021; Jiang M. et al. Lung Cancer 152: 58-65 2021) that build on the laboratory's legacy of having been the first to conduct GWAS in the US population of African heritage (Zanetti KA. et al. Lung Cancer 98: 33-42 2016). Cancer Microbiome: A recent study of microbiota composition revealed an abundance of bacteria in several cancer types once thought to be sterile (Greathouse KL. et al. Cancer Cell 38: 158-160 2020). We have discovered Acidovorax spp associated with TP53 mutations and smoking in both adenocarcinoma and squamous cell carcinoma. Using a mouse model of lung cancer we show Acidovorax spp is a contributor not a passenger of lung carcinogenesis via activation of proinflammatory lung neutrophils. Our data showed that mice exposed to A. temperans (Acidovorax temperans) had significantly larger tumor burden and more abundant lung lesions compared to PBS-instilled (sham) control mice. A. temperans instillation is deleterious to survival and repeated exposure accelerates lung tumor development in tumor-bearing mice thus A. temperans has a functional role in lung cancer development. Whole tissue RNA sequencing (RNAseq) comparing differential gene expression in A. temperans-instilled mice and sham controls showed a strong inflammatory response to A. temperans through MyD88-dependent signaling a pathway essential to launch innate and adaptive immunity and contributes to cancer progression. In collaboration with Romina Goldszmid we investigated the changes in the tumor immune microenvironment upon instillations with A. temperans. Our fluorescence activated cell sorting (FACS) analysis results showed an increase of CD45+ve immune populations in the lungs of A. temperans-instilled mice driven by neutrophils CD4+ve CD8+ve double negative (DN) T-cells as well as an increase in gamma-delta T cells. Overall our results indicate that A. temperans increases infiltration of proinflammatory cells which sustained over time promote lung adenocarcinoma development. Neutrophil recruitment is exacerbated in the lungs of KPC mice upon challenge with A. temperans. The phenotype of the infiltrated neutrophils in A. temperans -instilled mice have increased frequency of CD44lowICAM1highSiglecF+PDL1+ neutrophils previously characterized as long-lived mature pro-tumorigenic tumor-associated neutrophils important for lung tumor progression in KPC mice. RNAseq showed higher signature scores for activated and mature neutrophils in A. temperans-challenged mice. Bacterial exposure is likely the reason for neutrophil maturation so we compared scores for a previously reported neutrophil signature of pathogenic Escherichia coli (E. coli) infection and found that A. temperans-instilled mice had higher signature scores for neutrophil maturation due to bacterial infection. Neutrophils are the dominant immune cell population in the tumor microenvironment of lung cancer patients and evidence shows that an increased ratio of circulating neutrophils to leukocytes is associated with poor prognosis and worse response to therapy including immunotherapy. Next is to develop a therapeutic mouse model and to validate the role of neutrophils in mediating A. temperans-induced lung tumorigenesis. Cancer Metabolome: Correlation of identified metabolites with specific cancers created biomarker profiles that can be utilized for non-invasion diagnostic and prognostic evaluation of many types of human cancer. Liquid biopsy of urine serum and plasma are used to measure four biomarkers (creatine riboside (CR) N-acetylneuminic acid (NANA) cortisol sulfate (CS) and 27alpha-nor-5beta-cholestane-3aplpha 7alpha 12alpha 24alpha 25alpha Pentol glucuronide (NCPG) of lung cancer by mass spectrometry (Haznadar M. et al. Cancer Epidemiol. Biomarker Prev. 25:978-86 2016). CR paired with other identified urinary metabolite biomarkers such as (NANA) improve diagnostic capability and reliability. We have shown that creatine riboside (CR) is a cancer cell-derived metabolite that at high levels is associated with mitochondrial urea cycle dysregulation and it an indicator of poor prognosis for cancer patients(Parker A. et al. JNCI 132(14)2022). These foundational studies validated the use of urinary metabolite screening leading to further investigation into biomarker association with human cancer. (Patel DP. et al. J Pharm Biomed Anal. 191: 113596 2020) And as mentioned in the 2020 and 2021 annual report urinary metabolite biomarker profiling could offer diagnostic and prognostic evaluation of intrahepatic cholangiocarcinoma (ICC). Employing UPLC-MS/MS four metabolites for the quantitation of metabolites CR N-acetylneuraminic acid (NANA) cortisol sulfate and a glucuronide fragmented ion designated as 561+ are significantly increased in HCC and ICC and are robust at classifying ICC in combination with a clinically utilized marker CA19-9. NCI-MD cohort were studied and observations verified by the TIGER-LC cohort. We determined properties that are significant for a biomarker to its use in CLIA based assays of biomarkers in liquid biopsy. 2810223 +Cancer; Genetics; Human Genome Affect;Aneuploidy;Binding;Biochemical;Cell Cycle Progression;Cell division;Cells;Centromere;Chemicals;Chromatin;Chromatin Structure;Chromosome Segregation;Chromosomes;Complex;Defect;Detection;Ensure;Enzymes;Event;Genome;Genomic Instability;Geometry;Histones;Human;In Vitro;Kinetochores;Lead;Maintenance;Microtubules;Mitosis;Mitotic;Poison;Post-Translational Protein Processing;Process;Proteins;Research;Role;Signal Pathway;Signal Transduction;Sister Chromatid;Somatic Cell;System;Work;Xenopus;aurora B kinase;blastomere structure;cancer cell;chromatin modification;daughter cell;egg;histone modification;interdisciplinary approach;interest;prevent;reconstitution;repaired;response;scaffold;technique development Role of kinetochore proteins in chromosome segregation n/a NCI 10702575 1ZIABC011491-10 1 ZIA BC 11491 10 12032122 "KELLY, ALEXANDER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1557765 NCI The faithful segregation of chromosomes is the key event of mitosis and its dysregulation can lead to aneuploidy and genomic instability both hallmarks of cancer cells. A fundamental component in genome distribution during cell division is the centromere. Proteinaceous complexes known as kinetochores that form on centromeric chromatin generate a dynamic interface with spindle microtubules to segregate chromosomes to each daughter cell. Signalling pathways emanating from centromeric chromatin detect and correct errors in the geometry of chromosome-spindle microtubule attachments and prevent cell cycle progression until all chromosomes are properly connected. A key player in this process is the kinase Aurora B which is part of the Chromosomal Passenger Complex (CPC) and resides at the centromeric chromatin between two joined sister chromatids. Histone modification and chromatin structure control the localization abundance and activity of Aurora B at the centromere. Aurora B phosphorylates targets that regulate kinetochore-microtubule attachment to release erroneous geometries. However Aurora B also controls kinetochore assembly and we are interested in understanding the interplay between Aurora B's roles in assembly and error sensing. The proposed work will focus on defining the mechanisms by which centromeric chromatin functions as a scaffold to coordinate kinetochore assembly microtubule attachment and the detection and repair of erroneous attachments. The impact of mitotic histone modifications on chromatin structure and their roles in centromeric identity will be analyzed through in vitro reconstitution with purified proteins and in Xenopus egg extracts. The mechanism of chromatin binding by the CPC and its role in Aurora B kinase activation at the centromere will also be analyzed using a combination of structural and biochemical approaches. The mechanism by which the CPC responds to and senses tension applied by spindle microtubules to kinetochores will be examined in the Xenopus extract system and genetically defined human cells and elucidated with the development of techniques to globally define Aurora B substrates in response to microtubule poisons. 1557765 +Bioengineering; Brain Cancer; Brain Disorders; Breast Cancer; Cancer; HIV/AIDS; Kidney Disease; Neurofibromatosis; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases; Women's Health Actins;Address;African;Algorithms;Allografting;Animal Model;Antineoplastic Agents;Benzene;Bioinformatics;Biological Assay;Biological Testing;Breast Cancer cell line;Cancer Cell Growth;Cancer cell line;Cell Line;Cells;Cellular Assay;Central Nervous System;Central Nervous System Neoplasms;Child;Collaborations;Collection;Cytoskeleton;Data;Defect;Deoxyglucose;Dependence;Development;Esters;Euphorbiaceae;Ewings sarcoma;F-Actin;Formulation;Foundations;Fractionation;Glioblastoma;Glucose;Glycolates;Grant;HSF1;Investigation;Iowa;Isomerism;Link;Location;Macaranga;Malignant Neoplasms;Miniature Swine;Modeling;Molecular Target;Natural Products;Nature;Neoplasm Metastasis;Neurofibromatosis 1;Optical Rotation;Pathway interactions;Pattern Recognition;Peripheral Nerve Sheath Neoplasm;Pharmacologic Substance;Pharmacotherapy;Phyllanthus;Plant Roots;Plants;Play;Province;Renal Cell Carcinoma;Renal carcinoma;Reporting;Role;Sampling;Series;Sesquiterpenes;Small Interfering RNA;Source;Structure;Synthesis Chemistry;Tanzania;Testing;Toxic effect;Trees;Tumor Cell Line;Universities;Variant;Xenograft Model;addiction;analog;anti-cancer therapeutic;anticancer activity;base;cell growth;cellular imaging;cerivastatin;drug candidate;enantiomer;in vitro activity;in vivo Model;inhibitor;methyl group;novel;osteosarcoma;pi bond;preclinical development;renal toxin;schweinfurthin A;stem;tumor Development of Natural Product Leads as Anticancer Therapeutics n/a NCI 10702569 1ZIABC011470-11 1 ZIA BC 11470 11 11592706 "BEUTLER, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 602680 NCI ENGLERINS: Englerin A was isolated based on the activity of the organic extract of the bark of Phyllanthus engleri Pax in the NCI 60 cell screen. The extract was identified in a retrospective bioinformatic analysis of testing data for 68000 extracts which sought to identify samples with the most selectivity against renal cancer cell lines. Bioassay guided fractionation of the extract led to isolation of the novel sesquiterpene diester englerin A. Englerin A was isolated in high yield (1-4 g/kg dry wt.) from stem bark and root bark of the Tanzanian tree Phyllanthus engleri Pax (Euphorbiaceae). Isolation required three purification steps. Other plant parts from the initial collection did not contain appreciable amounts of englerins and were devoid of anticancer activity. Three collections of bark collected from the original location in Iringa Province Tanzania have all yielded similar amounts of englerin A showing that natural collections are a viable source for preclinical development. The NCI currently possesses 6 g of pure englerin A which is available for development activities isolated from Tanzanian bark. I recently reported a series of chlorinated analogues derived from englerin A one of which has activity only 2.5-fold weaker than the natural product. Structure-activity studies have established several important points: a) Cell growth inhibition is not simply due to release of glycolate a well-known but low-potency renal toxin since a reverse ester analogue which cannot generate glycolate is active. b) The cinnamate moiety tolerates substantial variation without loss of activity. The cinnamate double bond plays a rigidifying role but its electronic contributions are not important. c) The isopropyl group plays an important role in activity since its simplification to ethyl and methyl groups rapidly decreases potency. d) The cinnamate benzene ring is not required to be aromatic. Our current hypothesis is that the net effect of englerin A is to simultaneously starve the cells of glucose while creating an addiction to glucose. We believe that the selectivity depends on cells expressing both PKC-theta and HSF1 and/or being highly glucose dependent. Sensitivity to englerin A also correlates directly with sensitivity to 2-deoxyglucose further highlighting the link between englerin A sensitivity glucose dependence and PKC-theta activation. Englerin A was shown to be active in two different xenograft models. Pharmaceutical formulation and other preclinical development is ongoing. Collaborations with three synthetic chemistry groups have resulted in a number of active analogues which are being evaluated in tandem with the natural product. In addition we have discovered that englerin A has excellent in vitro activity in a large panel of Ewing's sarcoma cell lines. SCHWEINFURTHINS: I isolated schweinfurthins A and B from the African plant Macaranga schweinfurthii Pax. The compounds displayed potent and selective activity against central nervous system renal and breast cancer cell lines in the NCI 60 cell assay with GI50 values for four sensitive CNS tumor cell lines in the 10-25 nM range. The spectrum of anticancer activity did not match that of any currently used agent indicating that these compounds might be acting at a previously unrecognized target or through a novel mechanism. Thus far a total of 11 schweinfurthins have been isolated from nature. Synthetic strategies have been developed by the Wiemer lab (University of Iowa) to provide a reliable source of natural schweinfurthins and synthetic analogues for further biological testing. In the case of schweinfurthin F total synthesis of the (RRR) and (SSS) enantiomers and comparisons of spectral data optical rotations and bioassay data with those reported for the natural product have resulted in assignment of the natural compounds as the (RRR) isomers. These synthetic efforts have continued and most of the naturally occurring schweinfurthins have now been obtained by total synthesis. Investigations into the mechanism of action of schweinfurthins have yet to identify a proximate molecular target; however in glioblastoma cell lines it appears that a defective neurofibromatosis type 1 (NF1) pathway confers sensitivity. With a grant from the Children's Tumor Foundation we are conducting a massive siRNA screen for potential targets at a CRO. My collaboration with the Lockett lab (FNLCR) focused on the clear effect of natural schweinfurthins on the cellular actin cytoskeleton in sensitive cell lines. Development of pattern recognition algorithms for cellular images has enabled quantitation of changes in F-actin distribution with drug treatment. A synthetic analogue of schweinfurthin A has shown activity in an allograft model of peripheral nerve sheath tumor driven by an NF1 defect. Pharmaceutical development is ongoing with planned studies in genetically altered mini-pigs to examine three promising compounds for efficacy and toxicity. 602680 +Cancer; Complementary and Integrative Health; Dietary Supplements; HIV/AIDS Actinobacteria class;Agreement;Biological Assay;Biotechnology;Boston;Cells;Chemicals;Collaborations;Collection;Custom;Data;Development;Funding;Future;Geographic state;Goals;Industrialization;Information Systems;Institutes;International;Kansas;Kazakhstan;Laboratories;Libraries;Methodology;Microbiology;Molecular Target;National Institute of General Medical Sciences;Natural Products;Online Systems;Pharmaceutical Chemistry;Phosphotransferases;Plant Extracts;Plants;Process;Research Personnel;Rome;Sampling;Science;Scientist;Series;Soil;Source;Specimen;Structure;System;Technology;Testing;Travel;Tube;Universities;analog;base;bioweapon;design;gang;improved;material transfer agreement;programs;repository;screening;screening program;virology Building Libraries with Chemical Diversity for Screening n/a NCI 10702568 1ZIABC011469-11 1 ZIA BC 11469 11 11592706 "BEUTLER, JOHN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 602680 NCI We established MTAs with three of the four NIGMS-funded Chemical Methodologies & Library Developments (CMLD) (Boston University University of Kansas and University of Pittsburgh). These three centers alone have provided over 15000 samples of known structure. Each CMLD has a distinct approach to library design thus there is negligible overlap between their libraries. The MTP has subsequently entered into numerous agreements with other academic and industrial partners to increase the breadth of our libraries. Notable collaborations with traditional medicinal chemistry groups are with Prof. Gang Liu of Tsinghua University and Prof. Roberto DiSanto of the University of Rome. Furthermore we have obtained a number of focused compound sets including LOPAC the Glaxo Smith Kline kinase library BioMol Natural Products ICCB Known Bioactives as well as a large series of synthetic compounds from DCTD NCI. As part of a US State Department-funded threat reduction program scientists at the former bioweapons (BW) facility in Stepnogorsk Kazakhstan have been encouraged to explore non-BW scientific horizons. The program is conducted under the umbrella of the International Science and Technology Center (ISTC) in Astana Kazakhstan. MTP staff traveled to Kazakhstan on five occasions to develop this collaboration. We have organized plant collections focused on the 800 species endemic to Kazakhstan. To date we have collected over 227 plant specimens; the plant extracts have been tested in the NCI 60 cell screen and prefractionated for testing in MTP screens. We have also collaborated with the Institute of Virology and Microbiology in Kazakhstan to screen 300 extracts of extremophilic actinomycetes from hypersaline and basic soils. Another library is a collection of 700 plant extracts from the Brazilian cerrado with Dr. Espindola of the University of Brasilia. Our ongoing collaboration with these laboratories has enabled us to receive a large collection of purified plant natural products as well. New samples have also been received from a collaboration with the University of Istanbul as well as hosting several Turkish scientists in the MTP. A new collaboration with the Moller lab in Copenhagen promises to add to our plant biotechnology based samples. . We recently began to add prefractionated samples from the DTP to our screening set replacing our in-house set. 326000 samples have been added so far with a similar number expected each year in the near future. Currently our storage system holds 91712 tubes and 1236 plates. Over the past 12 years the Chemical Diversity Development Section in the MTP has developed a customized web based assay and sample management system which allows our researchers to manage sample libraries design assay plates and store and analyze bioassay data. This system is currently under considerable renovation to improve its functionality and to add new capabilities. 602680 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Infectious Diseases; Minority Health Acquired Immunodeficiency Syndrome;Affect;Anti-Retroviral Agents;BACH2 gene;Biological Assay;Biopsy;Blood;Bronchoalveolar Lavage Fluid;CD4 Positive T Lymphocytes;Cells;Chronic;Clinical Protocols;Clonal Expansion;Collaborations;Colon;Colonoscopy;Complement;Data;Evaluation;Event;Evolution;Fluorescence-Activated Cell Sorting;Funding;Future;Gastrointestinal tract structure;Gene Expression;Genes;Genetic;Goals;HIV;HIV Drug Resistance Program;HIV-1;Immunologics;Individual;Infection;Interruption;Intestines;Investigation;Learning;Light;Location;Lymphocyte;Lymphoid Tissue;Measures;Memory;Methodology;Mutation;National Institute of Allergy and Infectious Disease;Natural History;Participant;Pathway interactions;Patients;Penetration;Peripheral Blood Mononuclear Cell;Persons;Pharmaceutical Preparations;Plasma;Population;Process;Proliferating;Protocols documentation;Proviruses;Reporting;Research Personnel;STAT5B gene;Sampling;Shapes;Site;Source;Structure;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Tonsil;United States National Institutes of Health;Universities;Viral;Viremia;Virus;antiretroviral therapy;clinical center;cohort;digital;driving force;follow-up;ileum;in vivo;integration site;lymph nodes;next generation sequencing;novel strategies;programs;tool;virus host interaction HIV Persistence During Suppressive Antiretroviral Therapy n/a NCI 10702567 1ZIABC011466-11 1 ZIA BC 11466 11 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1058789 NCI Combination antiretroviral therapy (ART) results in marked suppression of viremia in persons with HIV-1 infection. Therapy is not curative however and detectable viremia and replication-competent HIV-1 persist despite ART-induced suppression. The origin of persistent viremia on therapy is uncertain; potential sources include ongoing complete cycles of HIV-1 replication long-lived reservoirs of chronically infected cells sanctuary sites into which antiretrovirals have poor penetration or a combination of these possibilities. Understanding the source and mechanisms of viral persistence on ART has critical implications for future therapeutic approaches and strategies for virus eradication. We began our investigation of the source of persistent HIV by developing an assay for viremia (HIV RNA) with single-copy sensitivity and by developing clinical protocols to determine the effects of ART intensification. These studies and others revealed no decrease in persistent viremia after drug intensification suggesting that persistent viremia may be the product of long-lived reservoirs of chronically infected cells. Others however suggested ongoing replication of HIV is the source of persistent viremia. In the last year we conducted a critical test of the question of whether ongoing HIV replication persists in sanctuary locations by analyzing HIV populations in blood and tissues from individuals after prolonged cART (8-16 y). In untreated individuals HIV replication is rapid and error prone leading to the accumulation of genetic changes that are readily detectable in the proviruses. Here we found that infected cells persist and clonally expand but there was no detectable evidence of HIV evolution nor was there any evidence of compartmentalization of the HIV proviruses in blood or tissues in six individuals who were studied during effective combination ART for prolonged periods cumulatively totaling over 60 patient-years of follow-up. These studies did not reveal any evidence for ongoing replication as a mechanism for HIV persistence during ART. Instead we found that HIV is maintained during therapy through long-lived cells that persist and can undergo clonal expansion. We are now building on these studies to quantify and genetically characterize virus in plasma to investigate HIV reservoirs in cellular compartments and expanding the range of our analyses by applying new single-cell methodologies and isolating specific cell subsets in blood and tissue from infected individuals. We are investigating HIV in plasma PBMC and cells derived from ileum and colon in infected individuals taking combination ART with suppressed less than 50 copies who are undergoing colonoscopy at the NIH Clinical Center. We have performed these colonoscopies in collaboration with J. Kovacs (CCMD) in the protocol Virologic and Immunologic Evaluation of Lymph Node Tonsillar and Intestinal Biopsies and Bronchoalveolar Lavage Fluid and have used a new sampling strategy that will yield useful information regarding the distribution of HIV-infected cells in the gastrointestinal tract.___In collaboration with S. Hughes (HIV DRP) X. Wu (Leidos) J. Coffin (Tufts) M. Kearney (HIV DRP) and J. Mellors (University of Pittsburgh) we have investigated HIV integration sites in vivo in these individuals. We are expanding these analyses to investigate HIV-infected cells in CD4 cell subsets in individuals undergoing long-term combination ART (supported by Intramural AIDS Targeted Antiviral Program funding). It is critical to learn how clonal expansion shapes the overall population of HIV-infected cells. It is also important to understand how HIV proviruses are expressed in these subsets. We began these studies using blood-derived T cells but we also need to understand the dynamics of HIV-infected T cells as they traffic through lymphoid tissue where 98% of all lymphocytes are located. We also need to know whether clonal expansion of HIV-infected cells in blood and tissues reflects global T-cell expansion. We will therefore complement our studies of clonal expansions of HIV-infected cells by investigating the diversity and clonal expansion of the T-cell repertoire using next-generation sequencing to quantify the T-cell receptor diversity in these subsets (collaboration with E. Boritz and D. Douek). In this collaboration we will study HIV-infected individuals undergoing combination ART for prolonged periods in our natural history study. Drs. Boritz and Douek will obtain highly purified subsets of CD4 cells such as central and transitional naive and effector memory populations by fluorescence-activated cell sorting (FACS) of PBMC from these participants and will determine T-cell receptor diversity and quantify the extent of T-cell clonal expansion in these T-cell subsets. We will quantify the levels of HIV proviruses in these highly purified subsets as well as characterize the genetic composition of HIV populations. With Dr. Hughes we will determine the distribution of integration sites of the proviruses in these subsets and investigate the extent of clonal expansion. These studies will determine whether clonal expansion of HIV-infected cells reflects overall T-cell clonal expansion or represents a distinct process that takes place whether generalized T-cell clonal expansion occurs or not. In support of these studies we recently reported new droplet digital PCR techniques to accurately measure relative amounts of defective proviruses and found that defective proviruses are enriched over time in most patients undergoing ART. The enrichment was progressive and took place only after several years on therapy suggesting the enrichment was due either to selective elimination of intact proviruses or to increases in defective proviruses perhaps by clonal expansion. These new techniques will greatly assist the field in understanding the dynamics of HIV-infected cells during ART. We have also initiated several new studies of HIV persistence. Previously in collaboration with Dr. Hughes we identified relatively rare examples in which integration of a provirus in specific portions of particular genes (e.g. BACH2 MKL2 STAT5B) was implicated in persistence and clonal expansion. We suggested that the provirus affects the expression of these host genes making it important to determine the structure of these proviruses. Most (over 98%) proviruses are defective and it is not known whether the proviruses in these three genes are intact or highly defective. To resolve this issue we are determining the structure of proviruses integrated in BACH2 and MKL2. Preliminary data suggest that proviruses integrated in these genes have large deletions indicating that they are not infectious. By determining the structure of the proviruses we will better understand how they affect gene expression and drive replication and persistence. These studies will shed light on specific pathways necessary for HIV persistence and identify testable strategies to interrupt expansion and persistence driven by specific integration events. 1058789 +Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health Accounting;Acute;Affect;Amplifiers;Apoptosis;Binding;Binding Sites;Biochemical;Biology;CRISPR screen;Cells;Chromatin;Code;Complex;Coupled;DNA;DNA Damage;DNA-Directed RNA Polymerase;Equipment and supply inventories;Event;Gene Expression;Genes;Genetic;Genetic Processes;Genetic Transcription;Genome;Growth;Human;Immediate-Early Genes;In Vitro;Intercept;Investigation;Knock-in Mouse;Literature;Lymphocyte Activation;MYC gene;MYCN gene;Malignant Neoplasms;Maps;Mechanical Stress;Metabolism;Methods;Modeling;Molecular;Mutation;Normal Cell;Nuclear;Oncogenes;Oncogenic;Output;Pathologic;Pathway interactions;Physiologic pulse;Physiological;Proto-Oncogenes;RNA Polymerase II;Regulation;System;TOP1 gene;TOP2A gene;TP53 gene;Testing;Therapeutic;Tissues;Topoisomerase;Transact;Transcriptional Activation;Transfection;Variant;Work;ZIP protein;base;c-myc Genes;cancer cell;carcinogenesis;chromatin modification;design;embryonic stem cell;experimental study;genome integrity;genome-wide;genome-wide analysis;in vitro activity;in vivo;neoplastic cell;preservation;promoter;protein function;recruit;synthetic biology;theories;transcriptome;tumor c-Myc Function n/a NCI 10702566 1ZIABC011465-11 1 ZIA BC 11465 11 9692465 "LEVENS, DAVID L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 721527 NCI The c-Myc bHLH-ZIP protein has been implicated in physiological or pathological growth proliferation apoptosis metabolism and differentiation at the cellular tissue or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc?s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated the transcriptomes and the genome-wide distributions of Myc RNA polymerase II and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity but is a non-linear amplifier of expression acting universally at active genes except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. Current investigations are exploring the molecular mechanisms exploited by MYC to augment gene expression and to demonstrate how small changes in MYC levels or short pulses of MYC activity may modify the growth of normal and neoplastic cells. The theory that MYC is an amplifier was derived from genome-wide studies of MYC and RNA polymerase binding to chromatin in vivo and RNA expression. We are now testing this theory with an orthogonal set of methods and experiments based on transfections and synthetic biology that thus far fully confirm the predictions of the amplifier model. We are exploring a possible a biochemical mechanism that unifies MYC's diverse activities and that has therapeutic implications. We have recently found that MYC forms a complex with both top1 and top2 simultaneously and stimulates both of their activities in vitro and in vivo. Because DNA topology is an issue for all DNA transactions via topoisomerases MYC can contribute directly to all genetic processes. We have mapped the sites of binding and activity of this complex (the topoisome) across the genome and have determined that two related complexes form: one includes MYC TOP1 and TOP2A while the other includes MYCN TOP1 and TOP2B. We have found that excessive MYC topoisome activity leads to its replacement by a p53-assembled topoisome that acutely and effectively guards against too much MYC. We have also devised a CRISPR screen to identify the cellular components that contribute to MYC amplifier action and an in vitro transcription system responsive to MYC recruited factors. This screen is designed to be conducted in almost any cell system. 721527 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Coronaviruses; Emerging Infectious Diseases; HIV/AIDS; Health Disparities; Immunotherapy; Infectious Diseases; Minority Health; Prevention 2019-nCoV;Acquired Immunodeficiency Syndrome;Adverse effects;Affect;Anatomy;Antibiotics;Antigens;Antineoplastic Agents;Bacterial Translocation;Biopsy;CD4 Positive T Lymphocytes;COVID-19;COVID-19 impact;Cells;Central Nervous System;Characteristics;Clinical;Clinical Protocols;Clinical Research;Clonal Expansion;Collaborations;Conduct Clinical Trials;Defect;Disease;Event;Goals;HIV;HIV Infections;HIV therapy;HIV/AIDS;Human;Immune response;Immune system;Immunologics;Immunomodulators;Immunosuppression;Individual;Infection;Inflammatory;Integration Host Factors;Interferon-alpha;Interferons;Interruption;Intervention;Intervention Studies;Location;Long-Term Effects;Lymphoid Tissue;Malignant Neoplasms;Modality;National Institute of Allergy and Infectious Disease;National Institute of Neurological Disorders and Stroke;Natural Immunity;PET/CT scan;Participant;Patients;Peripheral Blood Lymphocyte;Phylogenetic Analysis;Plasma;Population;Protocols documentation;Resistance;Retrovirology;Role;Sampling;Series;Source;Structure;Syndrome;Tissue Sample;Tissues;Tuberculosis;United States National Institutes of Health;Viral;Viremia;Virus Diseases;X-Ray Computed Tomography;antiretroviral therapy;cancer therapy;clinical center;clinical effect;co-infection;comorbidity;cytotoxic;design;driving force;experience;gastrointestinal;gut microbiome;immune activation;immune reconstitution;in vivo;interest;interferon therapy;long term consequences of COVID-19;microbiome;neoplastic;protocol development;research clinical testing;response;rifaximin Clinical Interventional Studies of HIV Reservoirs n/a NCI 10702565 1ZIABC011464-11 1 ZIA BC 11464 11 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 635273 NCI Fundamental gaps in our understanding of HIV reservoirs preclude a precisely targeted approach to eradication. HIV is neither eliminated nor often controlled by the human immune system and the immunologic defect(s) responsible for this lack of control are unknown. We are conducting several studies to investigate the effects of clinical events on HIV reservoirs. We have established useful collaborations to investigate the effects of clinical interventions on HIV reservoirs. We are collaborating with R. Yarchoan (HIV and AIDS Malignancy Branch NCI) to study individuals with HIV infection and comorbid cancer treated at the NIH Clinical Center. These study patients receive antineoplastic cytotoxic and immune modulator therapy to treat cancers treatment modalities that may also have significant effects on HIV-infected cells and we are studying the effects of these therapies on HIV reservoirs. In collaboration with I. Sereti (NIAID) we are studying patients with advanced HIV/AIDS who initiate antiretroviral therapy (ART) and experience immune reconstitution inflammatory syndrome (IRIS) in response to coinfections such as tuberculosis. IRIS results in a vigorous immune response to the comorbid infection with significant increases in CD4 T cells; as such IRIS may have profound effects on HIV reservoirs. We have been studying individuals with IRIS and TB and found that HIV-infected cells are part of the robust immune response that occurs during IRIS. In fact HIV-infected cells can specifically respond to TB antigens. We have also found that IRIS has long-term effects on the structure of HIV populations during therapy suggesting IRIS may alter HIV reservoirs. These studies indicate that specific events may have profound effects on HIV reservoirs and our ability to eradicate HIV. We are now developing a new protocol to investigate the effects of the SARS-CoV-2 virus infection on HIV reservoirs. We are especially interested in the effects of COVID-19 on HIV infection for a number of reasons. COVID-19 may have particularly devastating effects on individuals with immunosuppression and it is not known what the clinical effects of COVID-19 are in HIV-infected individuals. Participants in the new study will have detailed clinical evaluations and sample acquisition. We are collaborating closely with colleagues in NINDS (A. Nath) in the development of this protocol so that we can evaluate the specific and long-term effects of COVID-19 on the central nervous system. We are also conducting clinical trials of targeted interventions to characterize HIV reservoirs in individuals suppressed on ART. We are also initiating new analytic treatment interruption studies to determine the sources of rebound viremia when HIV therapy is interrupted. We are completing a clinical study (NIH protocol 13-I-0062) investigating generalized immune activation in the gastrointestinal-associated lymphoid tissue (GALT) on persistent HIV in individuals undergoing ART. We have been studying the effects of the nonabsorbable antibiotic rifaximin to specifically alter the gut microbiome and affect translocation of bacterial cell products and the consequent levels of generalized immune activation and low-level HIV viremia. Although we identified changes in the gut microbiome these changes did not result in downstream effects on levels of HIV viremia or levels of immune activation. These studies will further our understanding of the role of modifying the microbiome in immune activation. We are also investigating the role of innate immunity in HIV persistence by studying the effects of the innate immune modulator interferon alpha 2b. We have characterized the effects of exogenous interferon therapy in a series of HIV-infected individuals undergoing ART (NIH protocol 11-I-0057). We found no effect of interferon on levels of HIV in plasma or in peripheral blood lymphocytes and are now characterizing interferon effects on the phylogenetic structure of the HIV populations. Our studies of HIV reservoirs indicate a critical role of anatomic locations particularly lymphoid tissues in HIV persistence. We are developing a new protocol to evaluate the role of tissue sanctuaries of HIV reservoirs using detailed PET/CT imaging combined with targeted biopsy to obtain tissue samples prior to and following analytic treatment interruption. We will analyze virologic and immunologic characteristics prior to and following interruption of HIV therapy to determine the forces that contribute to the emergence of rebound viremia. 635273 +Cancer; Coronaviruses; Emerging Infectious Diseases; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health 2019-nCoV;ACE2;Affect;Alleles;Binding;C Type Lectin Receptors;C-Type Lectins;CD209 gene;Cells;Coculture Techniques;Endothelial Cells;HIV-1;Infection;Lentivirus Vector;Lung;Pathway interactions;Predisposition;Proteins;Receptor Activation;SARS-CoV-2 infection;SARS-CoV-2 spike protein;SARS-CoV-2 variant;Serine Protease;System;TMPRSS2 gene;Tissues;alveolar type II cell;cell transformation;neutralizing antibody;receptor;respiratory;virus envelope SARS-CoV-2 and HIV-1 Interactions with C-Type Lectins n/a NCI 10702564 1ZIABC011461-11 1 ZIA BC 11461 11 8123034 "KEWALRAMANI, VINEET N" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 395790 NCI Using lentiviral vectors pseudotyped with SARS-CoV-2 Spike protein we are examining different SARS-CoV-2 variants for their ability to interact with CLEC4M and whether this interaction facilitates direct infection of cells or efficient transfer and infection of cells expressing canonical SARS-CoV-2 entry and activation receptors. Different allelic forms of CLEC4M appear to support the direct infection of cells expressing the C-type lectin by the pseudoviruses in a manner that is dependent on Spike interaction with CLEC4M. We are (1) studying the domains of CLEC4M that bind the Spike protein (2) the efficiency of transfer to target cells (3) susceptibility to neutralizing antibodies and (4) whether CLEC4M affects the neutralization of Spike variants of SARS-CoV-2 is effected in a coculture system. 395790 +Biotechnology; Brain Disorders; Cancer; Clinical Research; Emerging Infectious Diseases; Immunization; Infectious Diseases; Kidney Disease; Prevention; Vaccine Related Acquired Immunodeficiency Syndrome;Acute;Adult;Animal Model;Antibodies;Antibody Response;Antigens;BK Virus;Brain Diseases;Capsid Proteins;Chronic;Clinical;Colorectal Cancer;Development;Disease;Genotype;Goals;Human;Human Papillomavirus;Humoral Immunities;Immunocompromised Host;Immunosuppressive Agents;India;Individual;Industry;Infection;Injection product;JC Virus;Kidney Diseases;Kidney Transplantation;Legal patent;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Mediating;Mus;Oral;Pathology;Patients;Phase I/II Clinical Trial;Play;Polyomavirus;Polyomavirus Infections;Preventive vaccine;Progressive Multifocal Leukoencephalopathy;Resistance;Risk;Role;Route;Serotyping;Serum;Symptoms;System;Therapeutic immunosuppression;Transplant Recipients;Urinary tract;Urine;Vaccination;Vaccines;Variant;Viral;Virion;Virus;Virus-like particle;Viviparous-1 protein;Work;base;human monoclonal antibodies;industry partner;invention;neutralizing antibody;novel;pressure;prevent;recombinant virus;renal damage;tool;vaccine development;virus development BKV and JCV vaccine development n/a NCI 10702563 1ZIABC011460-11 1 ZIA BC 11460 11 9692553 "BUCK, CHRISTOPHER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 661981 NCI "Two distinct polyomaviruses called BKV and JCV chronically infect the human urinary tract. Most healthy adults are stably infected with both viruses and occasionally shed infectious virions in the urine. Although BKV and JCV aren't known to cause overt symptoms in healthy individuals each of the two viruses can cause severe pathology in immunocompromised individuals. Most notably BKV causes acute kidney damage in up to 10% of kidney transplant recipients. In AIDS patients and patients taking certain immunosuppressive drugs JCV can cause a fatal brain disease called progressive multifocal leukoencephalopathy (PML). A further concern is that a controversial body of evidence has linked both BKV and JCV to various forms of cancer including prostate and colorectal cancer respectively. Our goal for this project is to develop preventive vaccines that might protect at-risk patients against BKV associated nephropathy (BKVN) or PML. The vaccines would draw on the same approach that led to the current highly successful vaccines against human papillomaviruses - specifically the BKV or JCV vaccine would be composed of recombinant virus-like particles (VLPs) composed solely of the viral major capsid protein VP1. The VLP vaccine would be aimed at eliciting antibody responses capable of neutralizing the infectivity of BKV or JCV virions. To be successful viruses must avoid being recognized by neutralizing antibodies elicited by previous infections. This evolutionary pressure drives the development of distinct viral ""serotypes"" that are not cross-recognized by serum antibodies. For example it is well established that BKVs are not generally recognized by antibodies elicited during JCV infection. Although it has long been recognized that different BKV isolates are genetically distinct no prior work has investigated the possibility that some BKV genotypes are resistant to neutralization by antibodies elicited by other other BKV genotypes. In other words it is unclear whether distinct serotypes exist within the viral species BKV. This question is also unresolved for JCV. Our lab's work in FY2011 revealed that BKV genotype I (BKV-I) and BKV-IV are distinct serotypes that are reciprocally resistant to antibody-mediated cross-neutralization. Work in FY2012 has revealed that BKV genotypes can be divided into as many as five distinct serotypes. Encouragingly administration of a multivalent VLP-based vaccine to mice elicits highly potent neutralizing antibody responses capable of neutralizing all five BKV serotypes. This suggests that a multivalent BKV VLP vaccine might be effective for protecting kidney transplant recipients against BKVN. We have recently begun extending our BKV findings to JCV. Specifically we hypothesize that JCV VP1 variants found in PML lesions may allow the virus to escape from antibody-mediated neutralization. If this hypothesis is true it would suggest that administering patients a VLP-based vaccine containing PML-variant VP1 might protect patients who are candidates for immunosuppressive therapy against PML. This work is the subject of an NCI patent application submitted in FY12. In FY15 we have began building industry partnerships to develop BKV and JCV vaccines. In FY16 we have developed industry and academic partnerships to investigate BKV- and JCV-neutralizing human monoclonal antibodies. Such antibodies could be of clinical utility for patients and would also provide a practical demonstration that the humoral immunity we seek to stimulate through vaccination will be effective. During FY20 these discoveries were licensed to an industry partner in India. We have been supporting the partner's development of VLP immunogens. During FY22 we began a new project exploring the possibility that vaccination can be achieved by non-injection routes (for example oral or intranasal delivery). We anticipate development of a Phase 1/2 clinical trial for the original injection product in FY23." 661981 +Cancer; Rare Diseases Affect;Animals;Architecture;Biochemistry;Biogenesis;Biological Models;Biology;Cell Cycle;Cell Proliferation;Cell division;Cell physiology;Cells;Centrioles;Centrosome;Cilia;Continuous Positive Airway Pressure;Defect;Development;Diagnostic;Disease;Electron Microscopy;Ensure;Event;Genetic;Genetic Diseases;Goals;Homeostasis;Human;Image;Individual;Knowledge;Malignant Neoplasms;Manuscripts;Membrane;Microcephaly;Microscopy;Microtubules;Mitotic spindle;Molecular;Molecular Biology;Multiprotein Complexes;Mutation;Organelles;Phosphotransferases;Process;Proteins;Protocols documentation;Publications;Publishing;Reporting;Research;Resolution;Seckel syndrome;Sensory;Signal Transduction;Site;Structure;Therapeutic;Tissues;Transmission Electron Microscopy;base;cell motility;ciliopathy;cilium motility;imaging approach;light microscopy;mutant;tumor;tumorigenesis Control of centrosome biogenesis n/a NCI 10702562 1ZIABC011459-11 1 ZIA BC 11459 11 11592694 "LONCAREK, JADRANKA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1554729 NCI Centrosomes are minute multifunctional membrane-less organelles present in only two copies in a typical cycling animal cell. In the core of a centrosome is a nine-fold symmetrical cylindrical microtubule-based structure called a centriole. The centriole organizes the second major part of the centrosome called pericentriolar material which is a large and dynamic multiprotein complex and the site of most centrosomal functions. Centrosomes perform vital cellular functions such as microtubule nucleation organization of the bipolar mitotic spindle pole during cell division cellular signaling and they influence tissue architecture and cell motility. Centrioles also organize sensory and motile cilia which are critically important for development and tissue homeostasis. Supernumerary and/or structurally aberrant centrioles and centrosomes can initiate tumorigenesis promote tumor invasiveness and are present in almost all types of tumors. Centriolar or ciliary defects are in addition an underlying cause of genetic disorders known as ciliopathies. Therefore we continue to direct our research efforts toward understanding the molecular mechanisms that regulate centriole and centrosome number their architecture. Specifically we elucidated the localization and the dynamics of a centrosomal protein CPAP (also known as CENPJ) in human cells. CPAP is critical for centriole and centrosome assembly and its mutations have been found in genetic diseases such as microcephaly and Seckel syndrome. Therefore understanding how CPAP is regulated and how it affects centrosome and cilia formation is of paramount importance. We have generated a model system in which we can inducibly replace endogenous version of CPAP protein with various disease-associated CPAP mutants and study their effects on centrosome and cilia assembly cell division and cell proliferation. We have identified and are now characterizing CPAP mutants involved in centriole elongation maturation and aberrant centriole reduplication. In addition we have characterized centriolar defects that occur under suboptimal levels of CPAP protein which include the lack of complete centriole walls structural instability and breakage. We have also demonstrated that CPAP is a highly dynamic within the centriole but that it may not directly participate in the formation of mitotic spindles and cell division as previously suggested. In another line of research we have explored how various cell cycle kinases (Plk1 Cdk2 Plk4) which are frequently upregulated in cancer regulate centriole and centrosome number and ensure centriole and centrosome homeostasis and how their dysregulation leads to centrosome amplification and reduplication. Manuscripts reporting new findings are being prepared for publication. In addition we studied the basic principles of centriole elongation in human cells. Proper centriole structuring is a prerequisite for the subsequent proper centrosome and cilia functioning. However strikingly little is still known about the mechanisms that regulate centriole assembly. Partially this is because centrioles are small sub-resolutional structures which are difficult to study using conventional microscopy. So in 2022 we have invested in development of super resolution protocols that would allow us to further increase imaging resolution providing us with in-depth view of centrosomal architecture and localization of its components during centriole assembly. The current resolution that we can achieve using a combination expansion microscopy and STED is nearing 10 nm which is unprecedented. Some of the results using this imaging approach have been published. We are currently using this approach to dissect the process of centriole elongation. Specifically we are exploring how individual cell cycle regulators affect centriole elongation during specific parts of the cell cycle. The final goal of this study is to understand how healthy cells maintain relatively uniform centriole and centrosome size and to identify how structurally defective centrioles and centrosomes occur in tumors. 1554729 +Biotechnology; Cancer; Clinical Research; Gene Therapy; Genetics; Health Disparities; Hematology; Immunotherapy; Minority Health; Rare Diseases Antigen Targeting;Antigens;Apoptosis;Area;B-Lymphocytes;Binding;Blood;CAR T cell therapy;CASP9 gene;Cell Line;Cell Maturation;Cells;Clinical Trials;Development;Dimerization;Disease remission;Enrollment;Family member;Genetic Engineering;Goals;Human;Immunohistochemistry;In Vitro;Industry;Journals;Laboratories;Malignant - descriptor;Malignant Neoplasms;Measurable;Medicine;Multicenter Trials;Multiple Myeloma;Mus;New England;Normal tissue morphology;Organ;Paper;Patients;Pattern;Phase;Phenotype;Plasma Cells;Publications;Publishing;Research;Research Personnel;SLAM protein;Site;T-Lymphocyte;Testing;Time;Work;cancer cell;chimeric antigen receptor;chimeric antigen receptor T cells;design;design and construction;dimer;human tissue;immunogenic;improved;novel;phase I trial;preclinical development;response;suicide gene;tumor Development of Chimeric Antigen Receptors Targeting Multiple Myeloma n/a NCI 10702561 1ZIABC011439-11 1 ZIA BC 11439 11 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1387598 NCI An important focus of my work is development of chimeric antigen receptor T cell therapies for multiple myeloma which is a usually incurable malignancy of plasma cells. My group was the first to design and construct CARs that specifically recognize B-cell maturation antigen (BCMA). BCMA has a very restricted expression pattern in normal tissues but BCMA is expressed on the malignant plasma cells of multiple myeloma. The BCMA specific CARs that we have constructed specifically recognize multiple myeloma cell lines and primary myeloma cells in vitro and eradicate myeloma tumors in mice. An extensive analysis of BCMA expression in normal human tissues by immunohistochemistry and quantitative PCR has been conducted. Except for expression by normal plasma cells BCMA expression was not detected in nomal human organs by immunohistochemistry. The first clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma was opened for enrollment in September 2014. James Kochenderfer was Principle Investigator of this trial. Twenty -six patients were treated on this trial. There have been impressive responses on this trial which were the first demonstrated examples of elimination of measurable multiple myeloma by CAR T cells. This work led to a publication in the journal Blood in 2016. In conjunction with Bluebird Bio Inc. We have developed a new anti-BCMA CAR that Bluebird licensed from the NCI. This new CAR was developed in my laboratory and modified by bluebird bio. This new CAR is being tested in a world-wide phase I and II multicenter trials conducted by Celgene Inc. I am a site PI of the phase I trial of this CAR. The longest ongoing complete remission from this trial is 3 years in duration. Results from his trial were published in the New England Journal of Medicine in May 2019; James Kochenderfer was senior author of this paper. Another general area of research on CAR T-cell therapies for multiple myeloma is improving the design of CARs. We have designed novel CARs with fully-human heavy-chain-only antigen-recognition domains and a clinical trial testing one of these CARs designated FHVH33-CD8BBZ is underway. We hypothesize that fully-human heavy-chain-only anti-BCMA CAR T cells will be less immunogenic than traditional CARs with single-chain variable fragment antigen-recognition domains. 25 patients have been treated on this clinical trial and 92% of patients have had objective responses. We are also designing CARs against antigens other than BCMA because multiple myeloma is a phenotypically heterogeneous malignancy in many cases so targeting more than one antigen might be necessary to effectively induce long progression-free intervals of multiple myeloma. We have designed CAR constructs containing a CAR targeting signaling lymphocyte activation molecule family member 7 (SLAMF7). We have completed preclinical development of a construct that encodes an anti-SLAMF7 CAR and a suicide gene. The suicide gene allows on-demand elimination of the CAR-expressing T cells. The suicide gene is activated by a dimerizer agent called Rimiducid. After dimerization caspase 9 is activated which leads to apoptosis of the CAR-expressing T cells. The anti-SLAMF7 p;lus suicide gene construct is designated IC9-Luc90-CD828Z. We have initiated a clinical trial of IC9-Luc90-CD828Z T cells. The clinical trial of SLAMF7 CAR T cells did not yield any responses. We are focused on finding new anti-SLAMF7 CAR strategies. 1387598 +Autoimmune Disease; Brain Disorders; Cancer; Genetics; Health Disparities; Minority Health; Multiple Sclerosis; Neurodegenerative; Neurosciences Affect;Animal Model;Autoimmune Diseases;CD4 Positive T Lymphocytes;CNS autoimmune disease;Candidate Disease Gene;Cell Differentiation process;Cells;Central Nervous System;Central Nervous System Diseases;Complex;Demyelinations;Development;Disease;Disease remission;Encephalomyelitis;Etiology;Exhibits;Experimental Autoimmune Encephalomyelitis;Genes;Genetic;Genetic Predisposition to Disease;Goals;Immune;Immunity;Immunologics;Impairment;Individual;Inflammatory;Intervention;Investigation;Laboratories;Lead;Mediating;Modeling;Multiple Sclerosis;Nature;Nervous System Trauma;Neurologic Deficit;Pathogenesis;Pathogenicity;Pathologic;Patients;Primary Progressive Multiple Sclerosis;Process;Progressive Disease;Relapse;Research;Role;Secondary Progressive Multiple Sclerosis;Signal Transduction;Th1 Cells;axon injury;environmental agent;gene product;genome-wide;interleukin-23;multiple sclerosis patient;multiple sclerosis treatment;neuroinflammation;new therapeutic target;novel therapeutics;programs;response;transcription factor;treatment strategy Role of T-bet in the pathogenesis of experimental autoimmune encephalomyelitis n/a NCI 10702558 1ZIABC011431-11 1 ZIA BC 11431 11 11592667 "LAZAREVIC, VANJA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1052527 NCI Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) of uncertain etiology. It is a complex disease in which one or more environmental agents predispose genetically susceptible individuals to develop immunologically mediated CNS demyelination and axonal injury. In 80-90% of cases MS starts with a relapsing-remitting course (RR-MS) but most patients develop progressive neurological deficits (i.e. secondary progressive MS; SP-MS). In 10-20% of cases MS patients exhibit a more progressive disease without remission namely primary progressive MS (PP-MS). Despite intense investigation into the pathological changes of MS many questions regarding the nature of immunological dysregulation that lead to the development of MS remain unanswered. Most of our understanding of the pathogenesis of multiple sclerosis comes from investigations using experimental autoimmune encephalomyelitis animal model. In this model both CD4+ T helper type 1 (TH1) and T helper type 17 (TH17) cells contribute to the pathogenesis of the disease. The transcription factor T-bet (encoded by the Tbx21 gene) drives the development of TH1 cells and inhibits the differentiation of TH17 cells. Interestingly despite its role as a negative regulator of TH17 differentiation program in naive CD4+ T cells T-bet is critical for the function of mature TH17 cells. T-bet is re-expressed in TH17 cells in response to IL-23 which drives the pathogenesis of several autoimmune diseases. T-bet deficient TH17 cells treated with IL-23 are not pathogenic in the setting of neuroinflammation. This observation raised important questions: (a) What makes TH17 cells pathogenic? (b) Is it the genetic program regulated by T-bet in response to IL-23 signaling? To answer these questions we have performed genome-wide profiling of wild-type and T-bet deficient TH17 cells. In the process an intriguing panel of candidate genes has been uncovered. Identifying the T-bet target genes in CD4+ T cells responsible for conferring pathogenicity and understanding how these gene products lead to CNS damage will lead to novel therapeutic targets. Treatment strategies directed at a specific subset of T-bet target genes rather than T-bet itself will provide selective intervention without causing global impairment of Type 1 immunity. Ultimately the goal of this research is to lead to the development of new therapies for multiple sclerosis. 1052527 +Cancer; Genetics; HIV/AIDS; Health Disparities; Hematology; Infectious Diseases; Lymphatic Research; Lymphoma; Minority Health; Orphan Drug; Rare Diseases Active Sites;Acute;Animal Model;Animals;Anti-HIV Agents;Anti-Retroviral Agents;Antigens;Antiviral Agents;Antiviral Therapy;Behavior;Biological Assay;Blood;Cancer Etiology;Cell Fraction;Cells;Chemistry;Clonal Expansion;Collaborations;Complex;Cultured Cells;DNA;DNA Integration;Data;Development;Drug Kinetics;Drug resistance;Enzymes;FDA approved;Genes;Genome;Goals;Growth;HIV;HIV Infections;HIV-1;HIV-1 integrase;HIV/AIDS;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immunologic Deficiency Syndromes;In Vitro;Individual;Infection;Integrase;Integrase Inhibitors;Integration Host Factors;Introns;Laboratories;Life Cycle Stages;Macaca;Malignant Neoplasms;Modification;Mutation;Nucleotides;Oncogene LCK;Oncogenes;Oncogenic Viruses;Patients;Peripheral Blood Mononuclear Cell;Persons;Pharmaceutical Preparations;Play;Process;Proliferating;Proteins;Provirus Integration;Proviruses;Reaction;Research;Resistance;Resolution;Retroviridae;Risk;Role;STAT3 gene;Site;Structure;T-Cell Development;T-Cell Lymphoma;T-Lymphocyte;Testing;Time;Toxic effect;United States National Institutes of Health;Variant;Viral;Virion;Virus;Work;antiretroviral therapy;cancer risk;cell transformation;cytokine;experimental study;in vivo;inhibitor;integration site;mutant;nanomolar;prevent;resistant strain;side effect;structural biology;treatment strategy;viral DNA;virology HIV-1 Integrase n/a NCI 10702556 1ZIABC011426-11 1 ZIA BC 11426 11 8122993 "HUGHES, STEPHEN H" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1373844 NCI INSTI development: The development of new broadly effective anti-HIV drugs that have little or no toxicity is a high-priority NIH goal for HIV/AIDS research. Because integration is an essential step in the virus life cycle IN is an important target for antiretroviral drugs. The HIV-1 integration reaction proceeds in two steps both of which are carried out by IN. In the first step (3' processing or 3'P) IN removes two nucleotides from the 3' ends of the linear viral DNA. In the second step IN inserts the trimmed 3' ends of the viral DNA into host DNA; this reaction is called strand transfer or ST. IN has only one active site which carries out both the 3'P and ST reactions. The four approved anti-IN drugs (raltegravir elvitegratir dolutegravir and bictegravir) all target the ST reaction and are for this reason called integrase strand transfer inhibitors or INSTIs. Despite their relatively recent development INSTIs are potent drugs with few side effects that are becoming increasingly important in antiretroviral therapies (ART). Cabotegravir has been formulated with rilpivirine and this combination has shown promise in long-term treatment strategies. However as is the case with all anti-HIV drugs INSTIs select for resistant strains of HIV. We are developing new INSTIs that are broadly effective against the known drug-resistant mutants. We have made excellent progress in developing IN inhibitors that have low nanomolar potency against the WT virus in a one-round inhibition assay retain potency against a broad panel of resistant mutants and show little or no toxicity in cultured cells. Our collaborator Dmitry Lyumkis has solved high resolution structures of HIV-1 IN (both WT and drug resistant) in complexes with both FDA approved INSTIs and with the most promising of the compounds developed and synthesized in the laboratory of another collaborator Dr. Terry Burke. Although we continue to make and test new INSTIs we have made sufficient progress that with help from the NCI pharmacokinetic testing is being done in macaques on the best of our compounds. Integration site analysis: There are millions of retroviral integration sites in the host cell genome but for many retroviruses including HIV integration is far from random. We have been studying the distribution of HIV proviruses (integration sites) in both cultured cells and patients. HIV integration is known to favor the bodies of highly expressed genes. In work that was done in cultured cells we were part of a collaboration that showed that the host protein HRP2 could replace LEDGF in directing HIV-1 integration to the bodies of highly expressed genes. We also showed that the host factor CPSF6 plays a key role in guiding the preintegration complex to regions of the genome that are gene rich and contain numerous highly expressed genes. We and others have used integration site analysis to show that there is extensive clonal expansion of HIV-infected cells in patients on ART. We also showed in HIV-infected individuals on long-term ART that more than 40% of the infected T cells are in clones and that in some cases proviruses integrated into six oncogenes can contribute to clonal expansion of infected T cells. Some of these highly expanded clones carry infectious proviruses and a small fraction of the cells in the clones can release infectious virions into the blood. Thus expanded clones of HIV infected T cells that carry intact infectious proviruses represent a large fraction of the infected cells that comprise the reservoir that has made it impossible to cure HIV infections with the available anti-viral therapies. The reservoir which arises early in infection persists on ART and can rekindle an active infection if ART is discontinued. Because the number of possible sites of HIV DNA integration is very large each infected cell and all of its descendants can be identified by the site where the provirus is integrated. Surprisingly we found that the distribution of HIV proviruses even after years of complete virological suppression in which the majority of the infected surviving cells are removed from the originally infected cells by many divisions closely resembles the distribution of the proviruses at the time the cells were initially infected. In our experiments the initial distribution was represented by the distribution of the proviruses in PBMC acutely infected in vitro. In addition to a modest modification to the initial distribution by a positive selection for proviruses integrated in six known oncogenes the distribution of proviruses is also modified by selection against cells with proviruses integrated in highly expressed genes. Thus although proviruses in oncogenes can cause the extensive in a small fraction of the clones of infected cells our data imply that most important factors causing clonal expansion of HIV infected T cells are antigen and/or cytokine stimulation. Our data also strongly support the idea that the integration site of a provirus has little if any effect on the expression of the integrated provirus. Retroviruses can cause cancers in animals by integrating in or near oncogenes. Although HIV-1 infection increases the risk of cancer most of the risk is associated with HIV induced immunodeficiency which allows oncogenic viruses to proliferate (EBV KSHV HPV). As was described in the previous paragraph HIV-1 proviruses integrated in six oncogenes can cause clonal expansion of infected T cells in vivo; however the infected cells are not transformed. Until very recently it was generally believed that HIV-1 does not cause cancer directly. However we recently showed that HIV-1 proviruses integrated in the first introns of STAT3 and LCK can play an important role in the development of T cell lymphomas. The development of these cancers appears to be a multi-step process involving additional non-viral mutations which could help explain why T cell lymphomas are rare in people living with HIV-1 infections. 1373844 +Cancer; Cancer Genomics; Genetics; Human Fetal Tissue; Human Genome; Pediatric; Pediatric Cancer; Rare Diseases Address;Biological Models;Biology;Body Regions;Categories;Cells;Child;Childhood;Chromatin;Clinical;Cre lox recombination system;DNA;DNA Methylation;DNA analysis;Data;Development;Engineering;Epigenetic Process;Etiology;Evaluable Disease;Event;FOXO1A gene;Family;Frequencies;Gene Fusion;Genes;Genetic Transcription;Genomic DNA;Goals;Heterogeneity;Human;Hypermethylation;Institutes;Malignant Neoplasms;Methylation;Molecular;Mus;Mutation;Nucleic Acid Regulatory Sequences;Oncogenic;Other Genetics;Outcome;PAX3 gene;PAX7 gene;Pattern;Point Mutation;Principal Component Analysis;Promoter Regions;Recurrence;Regulatory Element;Rhabdomyosarcoma;Sampling;Series;Skeletal Muscle;Soft Tissue Neoplasms;Supervision;Tissue-Specific Gene Expression;Tissues;Tumor-Derived;base;bead chip;cancer therapy;density;driver mutation;genome wide methylation;genome-wide;methylation pattern;mouse model;promoter;sarcoma;soft tissue;therapy development;tumor;tumor DNA Epigenetic studies in rhabdomyosarcoma n/a NCI 10702555 1ZIABC011423-11 1 ZIA BC 11423 11 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 566564 NCI In our previous studies of human rhabdomyosarcoma (RMS) we detected numerous DNA methylation differences between fusion-negative (FN) and fusion-positive (FP) RMS tumors. Furthermore two methylation-defined subsets were detected in the FN RMS category and two subsets were detected in the FP RMS category; these subsets were associated with differences in the frequency of mutations that are commonly found in these categories. When considering the heterogeneity within the RMS family of tumors we postulate that there are differences in the underlying cell of origin (lineage) as well as the genetic changes (driver mutations) that occur in these cells. Though it would be difficult to dissect the contribution of lineage and driver mutations to DNA methylation patterns in human RMS tumors the availability of engineered mouse models of RMS provides a strategic direction to address these questions. In particular my collaborator Dr. Charles Keller (Children's Cancer Therapy Development Institute) has used the Cre-LoxP system to generate a series of mouse models in which one or more driver mutations (Pax3-Foxo1 [P3F] fusion and deletions of Tp53 Rb1 or Ptch) is introduced into one of four myogenic lineages (as defined by activity of the Pax3 Pax7 Myf5 or Myf6 expression regulatory elements). Mice with an engineered Tp53 deletion +/- other driver mutations frequently developed soft tissue tumors resembling RMS or related sarcomas. After identifying tumors corresponding to a variety of lineages and driver mutations DNA was subsequently isolated from these tumors for DNA methylation analysis on the Infinium Mouse Methylation BeadChip (Illumina). Unsupervised analysis of the DNA methylation data identified two main clusters of mouse tumors one cluster in which P3F is expressed in Pax3 Myf5 or Myf6-associated lineages and a second cluster in which P3F is expressed in a Pax7-associated lineage or other driver mutations (without P3F) were expressed in any of the four lineages. Previous studies revealed very low P3F expression when P3F is directed to the Pax7 lineage (but not in the other three lineages) so that the two main clusters can be defined by high P3F expression vs low/no P3F expression. This finding provides evidence supporting a major contribution of the driver mutation P3F to the DNA methylation pattern. In addition to this finding the cluster with low/no P3F expression consists of two distinct subclusters. Although both of the subclusters contain tumors in which a non-P3F driver mutation is expressed in the Pax3 or Myf6 lineage one subcluster contains all tumors in which a driver mutation is expressed in the Pax7 lineage and the other subcluster contains all tumors in which a non-P3F driver mutation is expressed in the Myf5 lineage. It is particularly interesting to note that one subcluster contains all evaluable cases with Ptch1 and Tp53 deletions in the Myf5 lineage whereas the other subcluster contains all evaluable cases with Ptch1 and Tp53 deletions in the Pax7 lineage. This finding thus provides support that the lineage also makes a major contribution to the DNA methylation pattern in these tumors. Based on these findings the DNA methylation pattern in these tumors appears to be influenced by both the driver mutations and the underlying lineage. Additional unsupervised studies to compare human and murine RMS tumors revealed substantial differences in DNA methylation pattern such that all human RMS tumors were more similar to each other and all mouse were more similar to each other than the FP RMS tumors or the FN RMS tumors in the two species. Subsequent supervised studies to determine genes that were differentially methylated between FP and FN RMS tumors in each species identified only a small number of genes that were differentially methylated in both species. In particular for genes in which there was differential methylation of the 5' regulatory regions between FP and FN tumors only 2% showed differential methylation in both human and mouse tumors. Similarly for genes in which there was differential methylation of the gene body regions between FP and FN tumors only 4% showed differential methylation in both species. Therefore despite the significance of DNA methylation changes in RMS the specific genes involved appear to differ between human RMS tumors and the tumors developing in these engineered mouse model systems. This difference may reflect an intrinsic difference between human and mouse biology or may point to issues that are just not well recapitulated in these specific mouse models. 566564 +Autoimmune Disease; Cancer; Digestive Diseases; Esophageal Cancer; Infectious Diseases; Rare Diseases Antifungal Agents;Autoimmune Diseases;B-Cell Development;B-Lymphocytes;CD4 Positive T Lymphocytes;Cells;Chronic;Development;Epidermal Growth Factor Receptor;Esophageal Squamous Cell Carcinoma;Fostering;Human;IKK alpha;Immunity;Impairment;Infection;Inflammation;Knock-in Mouse;Link;Modeling;Mycoses;NF-kappa B;Pathway interactions;Patients;Phenotype;Phosphotransferases;Polyglandular Autoimmune Syndrome Type I;Role;Spleen;T-Cell Depletion;T-Lymphocyte;Thymic epithelial cell;autoreactive T cell;autoreactivity;carcinogenesis;cell type;central tolerance;epithelial injury;lymphoid organ;oral fungal;organ growth;tissue injury Role of IKK alpha in lymphoid organ development n/a NCI 10702554 1ZIABC011422-11 1 ZIA BC 11422 11 10270679 "HU, YINLING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 355421 NCI Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) a T cell-driven autoimmune disease caused by impaired central tolerance are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikka knockin mice develop APECED-like phenotypes including impaired central tolerance autoreactive T cells chronic fungal infection and ESCCs expressing specific human ESCC markers. Using this model we investigated the link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or autoreactive CD4 T cell depletion rescues whereas oral fungal administration promotes ESCC development. Inhibition of inflammation or EGFR activity decreases fungal burden. Fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore autoreactive T cells and chronic fungal infection fostered by inflammation and epithelial injury promote ESCC development. 355421 +Bioengineering; Biotechnology; Cancer; Nanotechnology 3-Dimensional;ADP-Ribosylation Factors;Binding;Biophysics;Collaborations;Complex;Data;Development;Environment;Family;GTP-Binding Proteins;GTPase-Activating Proteins;Head;Investigation;Isotope Labeling;Lipids;Membrane;Methodology;Methods;Molecular;Molecular Conformation;Multiprotein Complexes;Mutation;NMR Spectroscopy;Neutrons;PH Domain;Pathway interactions;Phosphatidylinositol 45-Diphosphate;Process;Protein Family;Proteins;Publications;Publishing;Roentgen Rays;Role;Science;Signal Transduction;Structural Models;Structure;Surface;System;Uveal Melanoma;Variant;Work;base;cofactor;collaborative approach;insight;interest;member;mimetics;molecular dynamics;multidisciplinary;nanodisk;nanomembrane;novel;spectroscopic survey;stable isotope;structural biology;tool Structural Biology of GTPase Activating Proteins n/a NCI 10702553 1ZIABC011419-12 1 ZIA BC 11419 12 15201459 "BYRD, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 801829 NCI In collaboration with Dr. Paul Randazzo we are studying the structure and interactions between Arf proteins and a member of the ASAP family of Arf-GAP proteins. We have produced a variety of stable-isotope variants of these proteins and established conditions for NMR spectroscopic studies. Studies are underway to provide resonance assignments structure confirmation based on existing known structures and to determine structures which are unknown binding studies of cofactors and to examine the assembly of larger multi-domain and multi-component systems. New findings emerged on the role of the PH domain within ASAP1 and an integrated multi-disciplinary study was published in Science Advances this year. We have developed methods to examine these proteins in a membrane environment. We will also combine the use of Neutron Reflectometry (NR) data with novel NMR and EPR methods to develop three-dimensional structural models of these complexes. We have utilized unique methodology in the NMR spectroscopy structure calculation and isotopic labeling to obtain new structural information about ASAP1. These data are combined with binding information to activating lipids and membrane mimetics to pursue functional understanding of these important proteins. Previous developments include structural elucidation by X-ray and NMR of the PH domain from ASAP1 interacting with PIP2 lipid head groups. Our current work demonstrates binding to nano disk membrane mimetics the equivalence of the mimetic and large unilamellar membrane standards and we have described a unique cooperative binding mechanism of the ASAP1 PH domain with membrane surfaces. We have demonstrated that we can assemble functional and isotopic labeled (for NMR) myristoylated-Arf1 into membrane nano disks. This systems shows functional complexation with ASAP1 functional domains at the membrane surface. Current work in submission for publication describes the distribution of and conformational selection process involved in Arf1 recognition of ASAP1. Understanding the mechanism of interaction between Arf1 and ASAP1-PZA is progressing extremely well with publications and molecular insight. 801829 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Health Disparities; Hematology; Immunotherapy; Lymphatic Research; Lymphoma; Minority Health; Orphan Drug; Rare Diseases Adoptive Transfer;Adrenal Cortex Hormones;Antigens;B cell therapy;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Biological;CD19 gene;Chronic Lymphocytic Leukemia;Clinical Trials;Clone Cells;DNA Sequence;Effectiveness;Enrollment;Event;FDA approved;Gammaretrovirus;Gene Transduction Agent;Human;Infusion procedures;Lymphoma;MS4A1 gene;Patients;Principal Investigator;Role;T-Lymphocyte;Testing;Time;Toxic effect;anti-CD20;cell bank;chimeric antigen receptor;chimeric antigen receptor T cells;chronic T-cell leukemia;curative treatments;cytokine;design;experimental study;genetically modified cells;improved;large cell Diffuse non-Hodgkin's lymphoma;leukemia/lymphoma;novel therapeutics;pre-clinical;vector Improved Chimeric Antigen Receptor Therapies B-cell Malignancies n/a NCI 10702551 1ZIABC011417-12 1 ZIA BC 11417 12 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1110078 NCI In the past year we have designed and selected an optimal bicistronic CAR construct that targets both CD19 and CD20. The bicistronic construct encodes 2 CARs one of the CARs is the previously -described Hu19-CD828Z CAR. The second CAR is an anti-CD20 CAR designated Hu20-CD8BBZ. The entire bicistronic construct is designated Hu19-CD828-Hu20BB and the construct is encoded by a gammaretroviral vector. We plan to start a clinical trial with bicistronic CAR designs targeting CD19 and CD20 in late 2022. We have spent extensive time optimizing the DNA sequence of the bicistronic vector to eliminate deletion events driven by homologous DNA sequences. We have an optimized gene therapy vector that has been produced under GMP conditions. An IND will be submitted to the FDA very soon. We have also prepared a producer cell clone that generates a gamma-retrovirus encoding the Hu19-CD828Z anti-CD19 CAR. GMP-grade vector has been produced from this master cell bank. We plan to use this vector in a clinical trial that will enroll CLL patients. Substantial time and effort has been expended in the past year to prepare required regulatory documents for the two upcoming clinical trials. We have also carried out experiments to examine the impact of cytokines on CAR toxicity including the role of corticosteroids which are used to treat CAR T-cell toxicity on CAR T cells. 1110078 +Biotechnology; Cancer; Childhood Leukemia; Clinical Research; Gene Therapy; Genetics; Hematology; Immunotherapy; Lymphatic Research; Lymphoma; Pediatric; Pediatric Cancer; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Acute Lymphocytic Leukemia;Allogenic;B lymphoid malignancy;B-Cell Leukemia;Blood;CD19 gene;Cell Transplantation;Cells;Clinical Oncology;Clinical Trials;Collaborations;Disease remission;Donor person;Enrollment;Goals;Hematopoietic stem cells;Homologous Transplantation;Immunology;Infusion procedures;Journals;Learning;Lymphoma;Malignant Neoplasms;Manuscripts;Paper;Partial Remission;Patients;Preparation;Process;Proliferating;Proteins;Publishing;Relapse;Reporting;Research Personnel;Stem cell transplant;T cell differentiation;T cell therapy;T memory cell;T-Lymphocyte;Testing;Toxic effect;Work;cellular transduction;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;experimental study;genetically modified cells;leukemia/lymphoma;recruit;stem Allogeneic T cells Transduced with an Anti-CD19 Chimeric Antigen Receptor n/a NCI 10702550 1ZIABC011415-12 1 ZIA BC 11415 12 11142408 "KOCHENDERFER, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 138759 NCI This trial is one of few CAR trials exclusively focused on applying anti-CD19 CAR T cells to the allogeneic transplantation setting. This trial is significant because unlike most trials of anti-CD19 chimeric antigen receptors it does not include chemotherapy so it gives a pure assessment of the activity of the anti-CD19 CAR T cells. We continue recruit more patients for this trial. We have obtained important information on toxicity and predictors of successful therapy with each patient. A paper covering this trial (Brudno et al.) was published in the Journal of Clinical Oncology in 2016. The project is now focused on testing less-differentiated T cells called stem memory T cells (Ttscm) transduced with an anti-CD19 CAR. In this effort we are currently collaborating with another Investigator Luca Gattinoni in developing a process for administering allogeneic anti-CD19 CAR stem memory T cells. We have treated 11 patients with anti-CD19 CAR Tscm cells on this clinical trial. A patient with acute lymphoid leukemia obtained a complete remission after infusion of Tscm anti-CD19 CAR T cells that is ongoing. Another patient with lymphoma obtained a partial remission. This trial has now ended enrollment and a manuscript reporting the results is in preparation. Many correlative immunology experiments are in progress. 138759 +Cancer; Health Disparities; Lung; Lung Cancer; Minority Health; Rare Diseases; Women's Health Adenocarcinoma;Adenocarcinoma Cell;Affect;Attenuated;Bone Marrow;CCL22 gene;CD4 Positive T Lymphocytes;CSF1 gene;Cancer Etiology;Cells;Cessation of life;Code;Development;Disease;Epidermal Growth Factor Receptor;Epithelial Cells;Generations;Genetic Transcription;Human;IKK alpha;Immunity;Impairment;Inflammation;KRAS2 gene;KRASG12D;Link;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Mus;Mutant Strains Mice;NFKB Signaling Pathway;Pathway interactions;Patients;Phosphotransferases;Prevention;Regulatory T-Lymphocyte;Reporting;Role;Signal Transduction;Smoker;Squamous Cell Lung Carcinoma;TNF gene;TNFRSF1B gene;TP53 gene;United States;cancer cell;carcinogenesis;cytokine;lung tumorigenesis;macrophage;monocyte;mouse model;recruit;targeted cancer therapy;therapeutic target;tumor;tumor microenvironment;tumorigenic Role of IKK alpha in lung cancer development n/a NCI 10702546 1ZIABC011391-12 1 ZIA BC 11391 12 10270679 "HU, YINLING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 710843 NCI The tumor microenvironment (TME) provides potential targets for cancer therapy. However how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus coding for IkB kinase alpha (IKKa) correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice but it is unknown how reduced IKKa expression affects the TME. Here we report that low IKKa expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cells (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1 CCL22 TNF and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation these cytokines promote lung ADC progression. Depletion of TNFR2 c-Rel or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion reduced cancer cell IKKa activity enhances formation of a pro-tumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC. This study reveals that impaired IKKa expression or activity in lung cancer enhances differentiation of pro-tumorigenic Treg cells through a TNF/TNFR2/NF-kB signaling pathway in both human and mouse lung ADC. Depletion of one of the molecules that are required for Treg cell induction represses lung ADC development. Thus the components that interfere with this particular Treg differentiation provide new targets for the generation of TME-modifying therapies. 710843 +Cancer; Genetics; Pediatric; Pediatric Cancer; Rare Diseases Animals;Biological Assay;CRISPR/Cas technology;Candidate Disease Gene;Categories;Cell Culture System;Cell Culture Techniques;Cell Line;Cells;Childhood;Chimeric Proteins;Collaborations;Cultured Cells;Development;Doxycycline;Event;Excision;FOXO1A gene;Family;Feedback;Gene Fusion;Genes;Genetic Transcription;Genetic study;Goals;Heterogeneity;Human;In Vitro;Knock-out;Laboratory mice;MYC Family Protein;MYCN gene;Maintenance;Malignant Neoplasms;Modeling;Molecular;Myoblasts;Neoplasm Metastasis;Oncogenes;Oncogenic;Oncoproteins;PAX3 gene;Pathogenicity;Pathway interactions;Patients;Pharmacology Study;Phenotype;Point Mutation;Population;Primary Neoplasm;Proliferating;Proteins;Recurrence;Recurrent tumor;Rhabdomyosarcoma;Role;System;Testing;Time;Tumor-Derived;base;cDNA Expression;cell transformation;experimental study;genetic analysis;genome-wide;in vivo;neoplastic cell;novel;protein expression;resistance mechanism;soft tissue;targeted treatment;transcription factor;tumor;tumor progression;tumorigenesis;tumorigenic Studies of gene fusions in rhabdomyosarcoma n/a NCI 10702545 1ZIABC011387-12 1 ZIA BC 11387 12 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 604334 NCI We investigated the molecular collaborating events that are needed for P3F to exert its oncogenic activity during tumorigenesis. In our past studies with the human myoblast system we showed that the combination of high level MYCN and P3F expression supports a high level of transformation and induces rapid tumorigenesis (3-4 weeks). In contrast in the setting of P3F expression without exogenous expression of a Myc family protein there is no detectable transformation and tumorigenesis only occurs after a significant lag (8-9 weeks). Of note when cells from the P3F-only tumors are cultured and retested in oncogenic assays these tumor-derived cells show a high level of transformation and rapid tumorigenesis (3-4 weeks) similar to the activity found in cultured cells derived from P3F/MYCN tumors. We hypothesize that whereas most P3F/MYCN-expressing myoblasts are transformed and tumorigenic only rare myoblasts expressing P3F alone are transformed and tumorigenic and thus additional time is needed for these rare cells to proliferate sufficiently to form a grossly detectable tumor mass. To examine the molecular events occurring in these rare transformed P3F-only myoblasts we assayed RNA and protein expression of P3F MYC and MYCN in the parental and tumor-derived cells from both P3F-only and P3F/MYCN myoblasts. P3F expression is relatively comparable in parental and tumor-derived cells from both groups of myoblasts. The MYCN expression level in parental P3F-only myoblasts is near the lower limits of detectability whereas the expression level in the parental P3F/MYCN myoblasts is several orders of magnitude higher. Furthermore the MYCN expression level in the P3F/MYCN tumor-derived cells is comparable to the P3F/MYCN parental cells whereas the MYCN expression level in the P3F-only tumors is substantially higher than the corresponding parental cells though still lower than the level in the P3F/MYCN parental and tumor-derived cells. In contrast MYC expression is higher in P3F-only parental cells than in P3F/MYCN parental cells. Furthermore MYC expression appears to be higher in P3F-only tumor-derived cells than parental cells (particularly at the protein level) whereas there is no difference in MYC expression between P3F/MYCN parental and tumor-derived cells. These findings are compatible with the presence of a feedback mechanism by which the high level of exogenous MYCN expression in the P3F/MYCN cells results in a lower level of MYC expression in these cells compared to the P3F-only cells. Furthermore though there is no difference in MYCN or MYC expression between P3F/MYCN parental and tumor-derived cells there appears to be a selection for cells expressing higher MYCN and MYC levels in the P3F-only tumor-derived cells compared to the parental cells. We hypothesize that the rare transformed cells in the P3F-only population are those with higher Myc family expression and thus selection for the transformed phenotype effectively selects for higher MYCN and MYC expression. In a final set of experiments we assessed the functional significance of MYCN and MYC in the tumor-derived cells by using a CRISPR/Cas9 targeting strategy to inactivate MYCN or MYC expression. In the P3F/MYCN tumor-derived cells MYCN but not MYC is required for transforming activity (as defined by the focus formation assay). In contrast MYCN knockout partially reduces transforming activity in the P3F-only tumor-derived cells but MYC knockout almost completely abrogates transforming activity. Based on these knockout experiments we conclude that the P3F/MYCN cells are primarily dependent on MYCN for their oncogenic activity whereas P3F-only cells are primarily dependent on MYC. These two systems provide models to examine the molecular basis and functional significance of heterogeneity within the FP RMS category. 604334 +Biotechnology; Cancer; Cancer Genomics; Childhood Leukemia; Clinical Research; Genetics; Hematology; Human Genome; Pediatric; Pediatric Cancer; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Women's Health Acute;Acute Myelocytic Leukemia;Area;Behavior;Biophysics;Blood;Cells;Cellular biology;Clinical;Clonal Hematopoietic Stem Cell;Complement;Computer Analysis;Computer Models;Coupled;Coupling;DNA-Directed RNA Polymerase;Development;Disease;Disease Progression;Dysmyelopoietic Syndromes;Dysplasia;Eukaryotic Cell;Fluorescent Probes;Gene Expression;Gene Expression Alteration;Gene Expression Process;Gene Expression Profiling;Gene Expression Regulation;Genes;Genetic Transcription;Genomic approach;Goals;Health;Hematopoiesis;Heterogeneity;Human;In Vitro;Individual;Ineffective Hematopoiesis;Laboratories;Malignant - descriptor;Marrow;Methods;Microscopy;Modeling;Molecular;Molecular Machines;Mutation;Myeloproliferative disease;Nuclear Structure;Nucleotides;Patients;Play;Population;Process;Prognosis;Proteins;RNA;RNA Splicing;Regulation;Research;Resolution;Ribosomes;Role;Sampling;Site;Spliceosome Assembly Pathway;Spliceosomes;Sum;Time;Tissues;Translations;Variant;Visualization;Work;base;bench to bedside;cytopenia;hematopoietic stem cell differentiation;live cell imaging;macromolecule;peripheral blood;programs;reconstitution;single molecule;stem cells;structural biology;transcriptome sequencing Transcription and Splicing Dynamics in Single Cells n/a NCI 10702544 1ZIABC011383-12 1 ZIA BC 11383 12 11142375 "LARSON, DANIEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2494706 NCI "Gene Expression in Single Cells: Gene expression refers to the sum of processes that enable cells to control their complement of RNA and protein. Megadalton molecular machines such as RNA polymerase the spliceosome and the ribosome carry out the synthesis processing and translation of RNA. Advances in structural biology have revealed the atomic details of these machines and the revolution in sequencing has engendered an understanding of their respective enzymatic activities with nucleotide resolution. A central challenge in cell biology is to understand how these processes are coupled and regulated in time and space in single living cells. In recent years through parallel advances in microscopy fluorescent probe development computational modeling and gene editing it is now possible to directly observe the processes of gene expression (transcription splicing translation) in living cells. The Larson lab has played an essential role in this development for example by being the first lab to visualize transcription and splicing of single human genes in real time. The view that has emerged from these studies is that gene regulation is an extremely dynamic process where the random behavior of individual molecules plays an important role in determining how a cell controls expression. Coupling live-cell imaging with RNA-sequencing based methods is an exciting approach for understanding gene expression in health and disease. Gene Expression in Myeloid Malignancy: The differentiation of hematopoietic stem cells into committed lineages in the blood is the result of concerted regulation between transcription splicing and translation and a goal of the laboratory is to understand the dynamic interplay between these processes in single cells. Moreover mutations in the gene expression machinery drive the development of clonal stem cell disorders termed 'myeloid malignancies.' Specifically the Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are a heterogeneous group of malignant clonal hematopoietic stem cell disorders with poor prognosis and few treatment options. MDS is characterized by ineffective hematopoiesis marrow dysplasia peripheral blood cytopenia and a high propensity for transformation into AML which is an acute proliferative disease. Simply stated MDS is a disease of differentiation while AML is a disease of differentiation plus proliferation. Over 60% of MDS patients carry a mutation in the spliceosome and the Larson lab has proposed a non-canonical role for the splicing machinery in disease progression. Overall gene regulation in this tissue is exceptionally dependent on post-transcriptional mechanisms opening new avenues of research for understanding hematopoiesis. Analysis of primary human samples and close coupling with the newly-established Myeloid Malignancies clinical program - ""bench-to-bedside-to-bench"" - makes this area a vibrant and impactful area of study where basic concepts in gene regulation can be immediately applied to human health. Thus the projects in the laboratory are loosely divided into several areas: 1) Visualizing spliceosome assembly and splice site selection 2) Deciphering the role of nuclear structure in modulating gene expression 3) Determining the causes and consequences of transcriptional heterogeneity 4) Developing in vitro reconstituted models for examining the coupling between transcription splicing translation 5) Computational analysis of gene expression 6) Understanding gene expression alteration in myeloid malignancy." 2494706 +Cancer; Genetics Active Sites;Affinity;Binding;Cancerous;Collaborations;Complex;Computer Models;Crystallization;Cyclic Amino Acids;Cyclic Peptides;DNA Damage;Deuterium;Development;Enzymes;Family;Generations;Genetic Transcription;Goals;Homologous Gene;Laboratories;Lead;Mass Spectrum Analysis;Molecular Conformation;Mutagenesis;National Institute of Diabetes and Digestive and Kidney Diseases;PPP2CA gene;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphotransferases;Process;Protein Serine/Threonine Phosphatase;Proteins;Pyrroles;Role;Series;Structural Models;Structure;Substrate Specificity;Synthesis Chemistry;TP53 gene;Testing;Work;X-Ray Crystallography;ataxia telangiectasia mutated protein;base;cell growth;cell growth regulation;cell transformation;design;experimental study;inhibitor;magnesium ion;member;p38 Mitogen Activated Protein Kinase;protein phosphatase 2C;scaffold;small molecule;small molecule inhibitor;virtual screening Inhibitor Development Against the Wip1 Phosphatase n/a NCI 10702542 1ZIABC011379-12 1 ZIA BC 11379 12 9692529 "DURELL, STEWART " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 106039 NCI This project is part of a long-standing collaboration with the laboratory of Dr. Ettore Appella (LCB/NCI) in which the Wip1 protein was discovered. Initial characterization resulted in determining two classes of phosphorylated substrates involving many proteins involved in cell growth regulation. The first has a diphosphorylated sequence motif (pT-X-pY) such as in p38 MAP Kinase while the second has a mono-phosphorylated sequence motif (p(S/T)Q) such as in the p53 Chk1/2 and ATM proteins. By development of an atomic-scale computer model of the extended active site of Wip1 and a series of mutagenesis experiments we were able to reveal the structural basis for the range of substrate specificity. This lead to the development of a cyclic peptide molecule that competitively inhibits Wip1 the first inhibitor of any kind for this family of enzymes. We then pursued development of a more drug-like small molecule inhibitor in collaboration with Dr. Daniel Appella (LBC/NIDDK) who specializes in synthetic chemistry. The resultant small molecule is based on a pyrrole ring scaffold with 5 different emanating sidechains to mimic the amino acids of the cyclic peptide. While successful the final inhibition constant was still only in the low micromolar range. To further this effort we returned to optimizing the cyclic peptide inhibitor. By multiple iterations of design and testing we were able to drastically increase the binding affinity resulting in an inhibition constant of 110 nM. The structural modeling involved in this process revealed both important new interactions in the extended active site and the role of the proximal B-loop in binding substrate and regulating activity. Since the B-loop is unique to the Wip1 member of the PP2C family its role was previously unknown. We are now applying these lessons to designing a new generation of pyrrole-based inhibitors. We are also pursuing generating sufficient Wip1 protein to determine the structure by X-ray crystallography which will greatly aid in inhibitor optimization. Recently we have verified the requirement of binding a 3rd magnesium ion for activity of Wip1 and the related PP2Ca homologue and used deuterium exchange mass spectroscopy to study the functional conformational changes. We are currently determining the crystal and NMR structures of PP2Ca/cyclic peptide inhibitor complexes. Recently we used Deuterium Exchange Mass Spectroscopy to study the functional structural changes of Wip1 and the PP2Ca homologue. We have also determine the crystal structure of PP2Ca with a bound substrate. We are using our recently determined crystal structure of Wip1 with the elusive B-loop to perform virtual screening to identify inhibitor leads. 106039 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Pediatric; Pediatric Cancer; Rare Diseases 12q13;13q14;1p36;Address;Behavior;Binding;Biological;Biological Assay;CRISPR/Cas technology;Candidate Disease Gene;Cell Culture System;Cell Death;Cell Line;Cells;Characteristics;Chemicals;Childhood;Clustered Regularly Interspaced Short Palindromic Repeats;Complement;Complementary DNA;Data;Doxycycline;Event;FOXO1A gene;Gene Amplification;Gene Chips;Genes;Genetic Heterogeneity;Genomics;Goals;Growth;Guide RNA;Human;Immunohistochemistry;Investigation;MYC Family Protein;MYCN gene;Malignant Neoplasms;Mediating;MicroRNAs;Modeling;Molecular;Mus;Myoblasts;Oncogenic;Oncoproteins;PAX3 gene;PAX7 gene;Pathogenesis;Pathway interactions;Performance;Phenotype;Population;Porifera;Process;Proteins;Publishing;RNA Interference;Reagent;Recurrence;Rhabdomyosarcoma;Role;System;Therapeutic Intervention;Tissue Microarray;Untranslated RNA;Western Blotting;base;directed attention;experimental study;fusion gene;genome-wide;inducible gene expression;loss of function;overexpression;pri-miRNA;protein expression;research study;soft tissue;targeted treatment;therapeutic target;transcriptome sequencing;tumor;tumorigenesis Studies of amplification in rhabdomyosarcoma n/a NCI 10702541 1ZIABC011378-12 1 ZIA BC 11378 12 11142369 "BARR, FREDERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 566564 NCI "In recent studies we commenced an investigation of the inter-relatedness of the PAX3-FOXO1 (P3F) fusion with several key genes that are overexpressed by the different amplicons in FP RMS. In particular we noted that MYCN is overexpressed as a result of the 2p24 amplicon and MIR17HG is overexpressed as a result of the 13q31 amplicon. In our previous studies we gathered evidence that MYCN expression is upregulated by P3F and other previous published data revealed that MIR17HG is upregulated by Myc family proteins such as MYCN. Based on these previous findings we wanted to confirm the relationship of P3F MYCN and MIR17HG in FP RMS cells and develop a system for extending studies of this relationship. Our goal was to set up a dynamic FP RMS cell system in which P3F expression could be inducibly turned off. In particular we transduced the Rh30 FP RMS line with a construct constitutively expressing guide RNA's corresponding to PAX3 cDNA sequences 5' of the P3F fusion point as well as a construct with the components for doxycycline inducible expression of Cas9. To optimize the performance characteristics of this system we screened multiple subclones for cells in which doxycycline induces substantial loss of P3F protein expression. Using this system we then investigated the consequences of inducible loss of P3F expression and found a corresponding loss of MYCN and MIR17HG expression. In addition to decreased expression of the MIR17HG pri-miRNA there is decreased expression of the six mature miRNA's (miR-17 miR-18 miR-19a miR-19b miR-20 and miR-92) processed from the MIR17HG pri-miRNA. Although a subset of the cells in this population show decreased proliferation along with differentiation or cell death a subpopulation can be recovered that still demonstrates decreased P3F MYCN and MIR17HG expression. To examine the forward effects of P3F or MYCN action in these cells we established lentiviral constructs constitutively expressing P3F or MYCN. Transduction of the P3F construct into these cells resulted in increased P3F levels and a corresponding increase in expression of MYCN the MIR17HG pri-miRNA and the six mature miRNA's. In addition transduction of the MYCN construct into these cells resulted in increased MYCN levels and a corresponding increase in expression of the MIR17HG pri-miRNA and the six mature miRNA's; however there is no change in P3F expression. These findings are consistent with a model in which P3F induces MYCN expression and MYCN in turn induces MIR17HG expression in FP RMS cells. Therefore we propose that an important downstream target of both P3F and MYCN in FP RMS is MIR17HG and the associated miRNA's and also postulate that MIR17HG overexpression may recapitulate certain functional aspects of MYCN and P3F overexpression in FP RMS. To address these issues we will next compare the phenotypic effects of P3F MYCN and MIR17HG expression in RMS cells as well as in our human myoblast cell culture system. For this purpose we have developed a lentiviral construct constitutively expressing MIR17HG which when transduced into the human myoblasts results in increased expression of the MIR17HG pri-miRNA as well as the six resulting mature miRNA's. For loss of function studies in addition to the CRSIPR-Cas9 system for inactivating P3F expression we have also identified guide RNA's corresponding to sequences in MYCN cDNA that mediate effective inactivation of MYCN expression. For loss of function studies involving the miRNA's of the MIR17HG the number and small size of these effector molecules complicates use of a standard CRISPR-Cas9 system. For this reason we are developing ""sponge"" constructs that will bind up specific miRNAs as well as alternative CRISPR systems for inactivating MIR17HG expression." 566564 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunotherapy; Minority Health; Orphan Drug; Rare Diseases; Urologic Diseases Adjuvant Study;Area;Cancer Etiology;Cessation of life;Clinical;Cystectomy;Disease;High Prevalence;Human;IgG1;Immune checkpoint inhibitor;Immunotherapy;Ligands;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Modality;Muscle;PD-1/PD-L1;Pathway interactions;Patients;Phase III Clinical Trials;Principal Investigator;Randomized;Reporting;Research;Somatic Mutation;Testing;Transitional Cell Carcinoma;Treatment outcome;Tumor-Infiltrating Lymphocytes;United States;United States Food and Drug Administration;Urothelium;Woman;anti-PD-L1;bladder transitional cell carcinoma;first-in-human;high risk;improved;improved outcome;inhibiting antibody;men;novel therapeutics;pembrolizumab;programmed cell death ligand 1;programmed cell death protein 1;programs;response;targeted agent;treatment choice;tumor;tumor microenvironment Bladder Cancer Program n/a NCI 10702537 1ZIABC011351-13 1 ZIA BC 11351 13 10687150 "APOLO, ANDREA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1057180 NCI Immunotherapy with immune checkpoint inhibitors particularly agents targeting the axis of programmed cell death protein 1 and its ligand (PD-1/PD-L1) has improved treatment outcomes in many tumor types. The rationale for assessing immune checkpoint inhibitors in advanced urothelial cancer is supported by a high prevalence of tumor somatic mutations and the presence of PD-L1 expression on tumors and tumor-infiltrating lymphocytes in the tumor microenvironment. Avelumab is a fully human anti-PD-L1 IgG1 antibody that inhibits PD-1/PD-L1 interactions but leaves the PD-1/PD-L2 pathway intact. The first-in-human trial of avelumab was led at the intramural NCI and I led the clinical effort for avelumab in advanced/metastatic urothelial carcinoma which showed clinical benefit leading to approval by the U.S. Food and Drug Administration (FDA) for this indication. Given the activity of several immune checkpoint inhibitors in this setting I was eager to test these agents in an earlier disease setting in patients with high-risk muscle-invasive disease. I initiated a phase 3 clinical trial of adjuvant pembrolizumab post-cystectomy in patients with high-risk muscle-invasive urothelial carcinoma of the bladder and upper tract. I am the principal investigator on this Alliance/NCI-sponsored study. The trial is accrued with 702 patients randomized. If positive would provide a treatment choice for patients with urothelial carcinoma in this setting. 1057180 +Autoimmune Disease; Cancer; Cancer Genomics; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Digestive Diseases - (Gallbladder); Genetics; Human Genome; Immunotherapy; Inflammatory Bowel Disease; Liver Cancer; Liver Disease; Microbiome; Orphan Drug; Rare Diseases Affect;Bacteria;CXCL1 gene;Cells;Cholangiocarcinoma;Chronic;Cirrhosis;Colitis;Development;Environment;Gastrointestinal Diseases;Genetic;Germ-Free;Hepatic;Hepatocyte;IL8RB gene;Immunologic Surveillance;Immunosuppressive Agents;Infection;Inflammation;Lipopolysaccharides;Liver;Liver diseases;Malignant Neoplasms;Malignant neoplasm of liver;Mus;Myelogenous;Neomycin;Patients;Risk Factors;Sampling;TLR4 gene;Tumor Immunity;fatty liver disease;fecal transplantation;gut dysbiosis;gut microbiome;microbiome;primary sclerosing cholangitis;tumor;tumor growth Analysis of cancer-related immune suppressor mechanisms in mice n/a NCI 10702536 1ZIABC011345-13 1 ZIA BC 11345 13 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1913193 NCI Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders however its effect on anti-tumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects anti-tumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis two known risk factors for cholangiocarcinoma which promote tumor development in mice caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived immunosuppressive cells (PMN-MDSC) in the liver. A decrease in gut barrier function observed in mice with PSC and colitis allowed gut derived bacteria and lipopolysaccharide (LPS) to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSC. On the contrary neomycin treatment blocked CXCL1 expression PMN-MDSC accumulation and inhibited tumor growth in the liver even in the absence of liver disease and or colitis. Fecal transplant studies demonstrated that fecal samples derived from patients with cirrhosis induced hepatic PMN-MDSC accumulation in germ free mice compared to healthy controls. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSC to promote liver cancer. 1913193 +Autoimmune Disease; Cancer; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Digestive Diseases - (Gallbladder); Inflammatory Bowel Disease; Liver Cancer; Liver Disease; Microbiome; Rare Diseases Affect;Bacteria;CXCL1 gene;Cells;Cholangiocarcinoma;Chronic;Cirrhosis;Colitis;Development;Environment;Gastrointestinal Diseases;Germ-Free;Goals;Hepatic;Hepatocyte;IL8RB gene;Immune;Lipopolysaccharides;Liver;Liver diseases;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Mus;Myelogenous;Neomycin;Patient-Focused Outcomes;Patients;Primary Neoplasm;Risk Factors;Sampling;TLR4 gene;Tumor Immunity;base;fecal transplantation;gut dysbiosis;gut microbiome;novel;primary sclerosing cholangitis;therapy outcome;tumor;tumor growth;tumor microenvironment Immune suppressor mechanisms in patients with GI cancer n/a NCI 10702535 1ZIABC011344-13 1 ZIA BC 11344 13 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 127546 NCI Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders however its effect on anti-tumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects anti-tumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis two known risk factors for cholangiocarcinoma which promote tumor development in mice caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived immunosuppressive cells (PMN-MDSC) in the liver. A decrease in gut barrier function observed in mice with PSC and colitis allowed gut derived bacteria and lipopolysaccharide (LPS) to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSC. On the contrary neomycin treatment blocked CXCL1 expression PMN-MDSC accumulation and inhibited tumor growth in the liver even in the absence of liver disease and or colitis. Fecal transplant studies demonstrated that fecal samples derived from patients with cirrhosis induced hepatic PMN-MDSC accumulation in germ free mice compared to healthy controls. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSC to promote liver cancer. 127546 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Health Disparities; Immunotherapy; Liver Cancer; Liver Disease; Minority Health; Orphan Drug; Pancreatic Cancer; Patient Safety; Radiation Oncology; Rare Diseases; Women's Health Autophagocytosis;CAR T cell therapy;Carcinoma;Cessation of life;Chemoembolization;Chemotherapy and/or radiation;Clinical Protocols;Colorectal Cancer;Combined Modality Therapy;Conduct Clinical Trials;Enrollment;GPC3 gene;Gastrointestinal Neoplasms;Hydroxychloroquine;Immunotherapy;Indium-111;KRAS2 gene;Liver;MEKs;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mutation;Nivolumab;Oncolytic viruses;Operative Surgical Procedures;Oral;Patient-Focused Outcomes;Patients;Phase;Pilot Projects;Primary carcinoma of the liver cells;Protocols documentation;Radiation therapy;Refractory;Treatment Protocols;United States;Vancomycin;anti-PD-1;base;bevacizumab;biliary tract;checkpoint inhibition;experience;hepatobiliary cancer;improved;improved outcome;inhibitor;metastatic colorectal;molecular targeted therapies;phase 1 study;phase 2 study;phase II trial;tadalafil;treatment strategy;tumor Clinical protocols for the treatment of gastrointestinal cancer n/a NCI 10702534 1ZIABC011343-13 1 ZIA BC 11343 13 10712484 "GRETEN, TIM " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 510185 NCI Gastrointestinal cancer represents one of the major reasons for tumor related death in the United States. Current treatment options are limited to surgery chemotherapy radiation therapy and molecular targeted therapy and new treatment options are urgently needed. We have been enrolling patients on the following protocols:NCI-20-C-0022: Phase II trial of VB-111 in Combination with Nivolumab in Patients with Metastatic Colorectal Cancer (mCRC). NCI-19-C-0033:Phase II Study of Nivolumab (anti-PD1) Tadalafil and Oral Vancomycin in Patients with Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer from Colorectal or Pancreatic Cancers; NCI-17-C-0092: A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination with Immune Checkpoint Inhibition in Refractory Colorectal Cancer; NCI-16-C-0135: A Pilot Study of Combined Immune Checkpoint Inhibition in combination with ablative therapies in Subjects with Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC) ;.19C0094 A: A Phase II Study of Combined Treatment of Durvalumab Bevacizumab Tremelimumab and Transarterial Chemoembolization (TACE) in Subjects with Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinoma (BTC).NCI-21-C-0030: Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC); NCI-20-C-0152: Phase II Study of combination of Trametinib (MEK inhibitor) and Hydroxychloroquine (HCQ) (autophagy inhibitor) in Patients with KRAS Mutation Refractory Bile Tract Carcinoma (BTC). 510185 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Immunotherapy; Orphan Drug; Pediatric; Pediatric Cancer; Precision Medicine; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human Adjuvant;Adjuvant Therapy;Adult;Aging;Area;Biological;Biological Assay;Biological Markers;Biological Models;Blood;Blood Vessels;Bone Marrow;Bone Marrow Neoplasms;CD8-Positive T-Lymphocytes;CSF1R gene;Cell Communication;Cell Line;Cell Lineage;Cell Therapy;Cells;Chemotherapy and/or radiation;Childhood;Chronic Disease;Clinical;Clinical Trials;Collaborations;Colony-Stimulating Factors;Cytometry;Cytotoxic T-Lymphocytes;Data;Development;Disease;Disseminated Malignant Neoplasm;Distant;Effectiveness;Endothelial Cells;Endothelium;Engineering;Enrollment;Epigenetic Process;Ewings sarcoma;Excision;Extracellular Matrix;FLT3 gene;Fibrinogen;Fibroblasts;Flow Cytometry;Gene Expression Profile;Genetic;Genetic Engineering;Genetic Transcription;Giant Cell Tumors;Growth;Growth and Development function;Heart Diseases;Hematopoietic;Hematopoietic stem cells;High-Risk Cancer;Human;Image;Immune;Immune Targeting;Immune response;Immune system;Immunofluorescence Immunologic;Immunology;Immunosuppression;Immunotherapy;Individual;Inflammatory;Institutes;Institutional Review Boards;Investigation;Laboratories;Lead;Li-Fraumeni Syndrome;Longevity;Longitudinal Studies;Luciferases;Macrophage Colony-Stimulating Factor;Malignant Neoplasms;Measures;Mediating;Mediator of activation protein;Mesenchymal;Metabolic;Modeling;Molecular;Monitor;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Neuroblastoma;Normal tissue morphology;Organ Transplantation;Outcome;Patients;Pericytes;Phase;Play;Population;Pre-Clinical Model;Primary Neoplasm;Process;RNA;Recurrence;Relapse;Rhabdomyosarcoma;Risk;Role;Sampling;Shapes;Signal Transduction;Site;Stromal Cells;Supporting Cell;Syndrome;System;T-Lymphocyte;TP53 gene;Testing;Therapeutic;Tissues;Translational Research;Transplant-Related Disorder;Treatment Efficacy;Tumor Cell Line;Tumor Immunity;Tumor Markers;Vascular Diseases;Work;Wound healing therapy;base;bone circulation;cancer predisposition;cell behavior;cell type;childhood sarcoma;chimeric antigen receptor T cells;clinical investigation;conventional therapy;cytotoxicity;delivery vehicle;endothelial stem cell;experimental study;fighting;hematopoietic stem cell niche;high risk;immune phagocytosis;improved;in vitro Model;in vivo;individualized medicine;inhibitor;inhibitor therapy;insight;macrophage;microvesicles;monocyte;myeloid cell development;neoplastic cell;non-genetic;novel;osteosarcoma;pediatric patients;pre-clinical;preclinical study;predictive tools;progenitor;prognostic tool;programs;rare cancer;receptor;recruit;repository;response;single cell sequencing;specific biomarkers;standard care;stem cells;targeted treatment;therapeutic target;therapy design;therapy development;tissue regeneration;transcriptomics;tumor;tumor microenvironment;tumor progression;tumor xenograft;tumorigenesis Biomarkers and Therapeutic Targets in Tumor Microenvironment and Metastasis n/a NCI 10702532 1ZIABC011334-13 1 ZIA BC 11334 13 10712506 "KAPLAN, ROSANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1116420 NCI As one of the crucial steps in metastatic progression requires tumor to successfully interact with its local microenvironment it follows that targeting this cross-talk may be an attractive adjuvant to standard treatment approaches. We are focused on developing therapies that can target and modulate the associated tumor recruited host immune and stromal cells. We have an IRB approved biological repository study to obtain blood bone marrow tumor and adjacent normal tissue when available from patients with malignancy and healthy donors. In addition to on-going studies of measuring and characterizing the circulating bone marrow-derived progenitor immune endothelial and mesenchymal cells that may be altered in the setting of cancer and other chronic diseases we have more recently been developing functional assays for human circulating monocytes. Utilizing both quantification and functional assays including flow cytometry and immune suppression and phagocytosis assays we are assessing the circulating bone marrow-derived myeloid cell populations in pediatric and adult patients with malignancies. We have broadened our investigations to better understand the changes in the hematopoietic stem cell niche that results in alterations in immune milieu in response to a growing primary tumor. These studies now include in addition to monitoring hematopoietic and endothelial progenitor cells but also CD4 and CD8 T cells and myeloid cells including MDSCs and M1 and M2 macrophages and stromal cell populations. Furthermore we measure circulating microvesicles released by tumor cells and tumor associated myeloid and stromal cells that may impact important cell behavior and are known to be critical to cell-cell communication. We have on-going investigations as to which cells make which microvesicles and their particular content and determining which would be most useful as a biomarker for metastatic risk. Our recent studies have determined host cell plasticity and cell state determine the microvesicles released from these cells and this plasticity in perivascular cells play key roles in regulating metastasis. We are currently investigating markers of this perivascular cell plasticity as a predictor of metastasis and response to conventional therapies and immune based therapies. We continue our collaboration with Dr. Sharon Savage to examine circulating bone marrow-derived cell populations in patients with Li Fraumeni syndrome which is a high-risk cancer predisposition syndrome related to loss of tumor suppressor p53. We have also developed assays to examine biological functional of specific cells and correlates that can be measured in stored RNA samples in order to correlate outcome data with these biomarkers for metastatic risk. We have established a pre-clinical model system for testing microenvironment-targeting therapy in pediatric sarcomas. Utilizing a Ewings sarcoma (EWS) xenograft tumor cell line and two syngeneic models- rhabdomyosarcoma (RMS) cell line and an osteosarcoma (OS) cell line we have performed flow cytometry and immunofluorescence to demonstrate the influx of myeloid cells and alterations in stromal cell populations in the tumor and pre-metastatic tissues. We also monitor metastatic progression in a resection model using luciferase imaging. In this fashion pre-metastatic metastatic colonization and progression to visible metastasis can be followed and compared in treated and untreated groups without requiring multiple terminal end points. We are conducting pre-clinical investigations utilizing inhibitors targeting stromal cell plasticity specifically to assess impact on metastatic progression. We also now have a marker of tumor associated fibroblast activation and stromal cell lineage tracing mice in order to monitor activation of these cells in this process. We have performed serial in vivo mouse experiments examining targeting of myeloid cells and stromal cells to determine their impact on metastatic progression. We are using different investigational agents to determine their specific impact on each microenvironmental cell. These pre-clinical studies will answer whether this approach to treatment may likely be a good window for targeting the recruitment of these microenvironment tumor-associated cells that support tumor progression. Our studies using a colony stimulating factor -one receptor (csf1-R) inhibitor revealed that these models of RMS and Ewings sarcoma secrete a good deal of CSF-1 and lead to the recruitment of CSF-1R expressing cells. These cells are found in early metastatic sites and are immune suppressive and can protect disseminated tumor cells from cytotoxic T cell activity. We are working on developing approaches to promoting myeloid based anti-tumor immunity and performing studies to determine the critical effectors of this cytotoxicity. We have also established a good in vitro model to understand the role of tumor-secreted factors on myeloid cell development and stromal cell plasticity and function and investigating different approaches to targeting this process. These studies allow for investigating function of potential therapeutic inhibitors of the myeloid skewing and polarization process and the activation and expansion of specific perivascular cell populations that promote metastasis. We completed the Phase I portion of Pexidartinib which inihibits FLT3 Kit and CSF1R. We are now planning enrollment on the expanded Phase I in pediatric patients with tenosynovial giant cell tumor for open access approval for this agent for pediatric patients as it is approved for this tumor in adults. We are also actively planning two new trials to target immune suppressive myeloid cells. We have developed a new cell therapy based on genetically engineering myeloid cells (GEMys) that can be novel delivery vehicles given their propensity to accumulate in tumor and metastatic sites. These cells can be engineered to deliver Il12 into the tumor milieu and reprogram multiple cell types change gene transcriptional signatures and reverse immune suppression and enhance anti-tumor immunity. We have developed humanized murine systems to examine human cell therapy with advanced human tumors. On going work to bring this to clinical setting is on-going and harnessing myeloid cells for introduction of signaling in microenvironments. These investigations also include stromal cells and extracellular matrix remodeling. Single cell sequencing can provide exquisite detail of individual cell cluster transcriptional programs. Our laboratory has begun performing single cell sequencing of rare tumors to investigate tumor and microenvironmental interactions. Such studies can be invaluable for tumor and microenvironment genetic and non genetic interactions that provide insights to targeting cross talk and unique aspects of both tumor and associated microenvironment. We have recently leveraged the data we have generated from our first clinical trial of chimeric antigen receptor T cells targeting GD2 in patients with osteosarcoma and neuroblastoma. This collaboration with Dr. Lynn Hedrick and team at La Jolla Institute of immunology and Dr. Mackall and team at Stanford has allowed deep transcriptomic mass cytometry and epigenetic investigations into immune response in patients on CART trial. We found that myeloid cells are kep regulators of the CART cells. These investigations are shaping a new understanding of key markers of CAR expansion and may ultimately impact efficacy and serve as a path to combine myeloid and T cell *TRUNCATED* 1116420 +Biotechnology; Breast Cancer; Cancer; Clinical Research; Health Disparities; Hematology; Minority Health; Pediatric; Pediatric Cancer; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Women's Health Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Adhesions;Adjuvant;Adrenocortical carcinoma;Adult;Area;Blood Circulation;Blood Vessels;Bone Marrow;Breast Carcinoma;CSF1R gene;Cell Compartmentation;Cell Line;Cell Survival;Cell Therapy;Cells;Cellular Assay;Cessation of life;Characteristics;Childhood;Childhood Lymphoma;Childhood Rhabdomyosarcoma;Clinic;Clinical;Colon Carcinoma;Cyclophosphamide;Data;Disease;Distant;Dose;Dysmyelopoietic Syndromes;Endothelial Cells;Environment;Event;Ewings sarcoma;Extracellular Matrix;FLT3 gene;Fibroblasts;Gene Proteins;Genes;Genetic Engineering;Glioma;Goals;Growth;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;High-Risk Cancer;Human;ITGAM gene;Immune;Immune Evasion;Immunosuppression;In Vitro;Individual;Inflammation;Interleukin-12;Investigation;Lead;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Mediating;Mesenchymal;Metalloproteases;Metastatic Neoplasm to the Bone;Modeling;Molecular;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Nerve;Neuroblastoma;Organ;Pathway interactions;Patients;Pediatric Neoplasm;Pericytes;Pharmaceutical Preparations;Phase;Phenotype;Physiological;Play;Population;Pre-Clinical Model;Primary Neoplasm;Proteins;Recurrence;Refractory;Reproducibility;Rhabdomyosarcoma;Role;Sampling;Seeds;Signal Transduction;Site;Soil;Stromal Cells;Supporting Cell;T cell response;T-Lymphocyte;Tissues;Translating;Tumor-Derived;Vascular Endothelial Growth Factor Receptor-1;Vascular Endothelial Growth Factors;Work;Wound Repair Pathway;adolescent patient;angiogenesis;anticancer research;arginase;bone;bone scaffold;cancer therapy;cancer type;cellular engineering;design;exosome;fludarabine;genetic manipulation;hematopoietic stem cell niche;human tissue;in vivo;lung Carcinoma;malignant breast neoplasm;melanoma;metastatic process;mouse model;neoplastic cell;neurofibroma;novel;novel strategies;novel therapeutic intervention;osteosarcoma;pediatric patients;pre-clinical;prevent;programs;recruit;response;sarcoma;small molecular inhibitor;stem cell biology;stem cell niche;stem cells;therapy design;therapy development;transcription factor;translational study;tumor;tumor growth;tumor microenvironment;tumor progression Tumor Microenvironment in Cancer Progression n/a NCI 10702530 1ZIABC011332-13 1 ZIA BC 11332 13 10712506 "KAPLAN, ROSANDRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1116420 NCI We have established that during primary tumor growth there is a formation of a niche environment in distant tissue sites during metastatic initiation. This pre-metastatic tissue has an influx of bone marrow-derived cells including populations of myeloid hematopoietic cells which provide factors such as matrix metalloproteases to remodel extracellular matrix and pro-growth and survival signals such as VEGF and arginase to support the colonizing disseminated tumor cells. These sites are created as a systemic response to tumor progression and may be organ specific damage response programs in specific microenvironments. Using syngeneic cells lines that have a high spontaneous metastatic rate we have identified unique changes within the bone marrow microenvironment that lead to mobilization of bone marrow-derived hematopoietic stem and progenitor cells that are recruited to the pre-metastatic niche in multiple tumor models including E0771 breast carcinoma F4 osteosarcoma 76-9 and M3-9M pediatric rhabdomyosarcomas and B16 melanoma. Previously we have shown that CD11b myeloid cells expressed VEGFR1 in the pre-metastatic tissue. We have now discovered these cells are hematopoietic progenitor cells that become an immune suppressive myeloid population that alter the local immune environment favoring immune evasion similar to sanctuary sites in stem cell niches (Giles et al Cancer Research 2016). We have also identified the central role of immune suppression in creation of pre-metastatic and early metastatic niche and the means of reprogramming this immune suppression to limit metastasis (Kaczanowska et al Cell 2021). These cells are immune suppressive myeloid cells derived from mobilized bone marrow-derived hematopoietic stem and progenitor cells we demonstrated play an integral role in regulating tumor specific T cells and T cell responses (Giles et al Cancer Research 2016; Kaczanowska et al Cell 2021). We have also been able to manipulate metastatic progression by altering these unique bone marrow-derived cell enriched areas. We have new data demonstrating that the pre-metastatic niche has similar features to physiological stem cell niches in order to promote distant tumor cell survival. We have found that the localized tumor prior to established metastasis is activating the hematopoietic stem cell niche within the bone marrow and inducing proliferation of hematopoietic stem cells and mobilization of these cells into the circulation. We have found that there are changes that occur in the bone marrow microenvironment in response to tumor secreted factors that induce the myeloid skewing and expansion of hematopoietic progenitor cells that we have seen during tumor progression (Giles et al Cancer Research 2016). Targeting the skewing to prevent the expansion in hematopoietic progenitor cells and myeloid cells may be a way to reset this maladaptive response to a growing tumor and prevent metastatic progression. We have on-going investigations examining the small molecular inhibitor PLX3397 that targets CSF1R found on myeloid cells cKit and FLT3-ITD which we have determined that when the drug is given in the adjuvant setting can limit metastatic progression in tumor bearing hosts. We have initiated and completed the Phase I dose escalation of PLX3397 in pediatric and adolescent patients with recurrent or refractory tumors (Boal et al Clinical Cancer Research). We have also developed a new cell therapy approach platform to reprogram these recruited immune suppressive myeloid cells by introducing genetically engineered myeloid cells (GEMys) that express IL12. These IL12 GEMys can reverse the immune suppression program in the pre-metastatic niche and lead to inhibition of metastatic progression and significantly prolong overall survival in highly metastatic murine models (Kaczanowska et al Cell 2021). IL12 GEMys when given following fludarabine and cyclophosphamide tumor bearing hosts lead to long term cures in these metastatic pre-clinical models (Kaczanowska et al Cell 2021). In addition to investigations into the recruited hematopoietic progenitor bone marrow derived cell populations that become immune suppressive cells in pre-metastatic sites we continue to investigate the essential changes in stromal cells including pericytes vascular cells and fibroblasts as well as the extracellular matrix in the pre-metastatic and metastatic niche. We have established several lineage tracing models to better track and characterize these stromal cell populations as well as genetically manipulate key genes within specific cell populations. Using these models we can interrogate the function of specific proteins to these cells and their role in the metastatic process. A specific transcription factor KLF4 we have discovered is critical to mediating this stromal cell plasticity. These stromal cells that become activated create a distinct extracellular matrix that support disseminated tumor cell survival. We are currently investigating the role of tumor conditioned media and tumor derived exosomes in making local changes in the stromal cell compartment and matrix that provides the scaffolding for bone marrow-derived cells and are essential component of the pre-metastatic niche (Murgai et al Nat Med 2017). We have identified two critical cellular pathways in pre-metastatic niche formation related to inflammation and stem cell biology including myeloid cells and stromal cell populations. Understanding the activation of these stem cell niche/wound repair pathways and inflammation- related pathways in the metastatic process are an active area of investigation. In addition to our existing stromal models we have developed a new lineage tracing model to track mesenchymal cells that support nerves. These models are robust and show a new phenotype of mesenchymal nerve support cells that are found in bone and other sites and we have preliminary data to suggest a function in the pre-metastatic niche in bone during bone metastasis. Our current investigations reveal important components of the dysregulated microenvironments that occur during metastatic progression. Our novel cell therapy approach can provide a platform locally rebalance these altered microenvironments and a potential new therapeutic approach to limit metastatic progression in pediatric and adult patients at high risk for cancer progression. We are developing multiple approaches to translate this new cell therapy platform into the clinic setting. We are also actively exploring which cargo are most effective to rebalance dysregulated microenvironments that occur during metastasis. As many cancers have a dense extracellular matrix and we determined that extracellular matrix remodeling is occurring in an enhanced fashion from stromal cell expansion. We are investigating modulation of extracellular matrix through cell therapy delivery of extracellular matrix remodeling proteins. More dense matrix is associated with malignant tissue. We aim to explore the impact of matrix remodeling on metastatic progression. We have developed robust cell engineering strategies culture conditions and reproducible assays for cell therapy development. We continue to develop functional studies that help demonstrate human genetically engineered myeloid cell therapy (GEMys) can effectively deliver the cargo and that the cargo has the anticipated response in vitro and in preclinical in vivo studies. We are preforming extensive IND enabling studies. We are also developing correlative markers to explore response and *TRUNCATED* 1116420 +Biotechnology; Cancer; Genetics; Neurosciences Address;Anatomy;Apoptotic;Behavior;Cardiac;Cell Death;Cell Proliferation;Cells;Chronic Kidney Failure;Cis-Acting Sequence;Connective Tissue;Data;Defect;Dermis;Development;Differentiated Gene;Disease;Dorsal;Embryo;Embryonic Development;Family member;Fibroblast Growth Factor;Future;GBX1 gene;Gene Expression;Gene Expression Profiling;Gene Family;Gene Targeting;Genes;Genetic;Goals;Growth Factor Gene;Human;Interneurons;Knowledge;Label;Malignant Neoplasms;Mantle Zone;Mesoderm;Messenger RNA;Modeling;Molecular;Motor Neurons;Muscle;Mutant Strains Mice;Pathology;Pathway interactions;Periodicity;Play;Reaction;Regulation;Regulatory Element;Role;Segmentation Clock Pathway;Signal Pathway;Signal Transduction;Somites;Spinal Cord;Trans-Activators;Transcription Repressor;Vertebral column;Work;angiogenesis;base;bone;cell behavior;combinatorial;insight;member;migration;mutant;neurogenesis;notch protein;novel;prevent;somitogenesis;spine bone structure;synergism;transcription factor Identification and characterization of FGF target genes n/a NCI 10702527 1ZIABC011321-13 1 ZIA BC 11321 13 8123123 "LEWANDOSKI, MARK B" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 314856 NCI To address the deficiency in our knowledge of what genes respond to FGF signaling we have an ongoing project to molecularly define FGF targets genes as well as their function and regulation. In past work we and others have identified the transcription factors encoded by Gbx1 and Gbx2 as FGF targets. Recently we investigated the functional relationship between Gbx family members in the developing spinal cord using combinatorial Gbx mouse mutants. We showed that each Gbx gene is upregulated if the other is absent. Additionally Gbx genes regulate development of a subset of PAX2+ dorsal inhibitory interneurons. Also expansion of proliferative cells into the anatomically defined mantle zone occurs in Gbx mutants. Lastly our data shows a marked increase in apoptotic cell death in the ventral spinal cord of Gbx mutants during mid-embryonic stages. While our studies reveal that both members of the Gbx gene family are involved in development of subsets of PAX2+ dorsal interneurons and survival of ventral motor neurons Gbx1 and Gbx2 are not sufficient to genetically compensate for the loss of one another. Thus our studies provide novel insight to the relationship harbored between Gbx1 and Gbx2 in spinal cord development (J Dev Biol. 2020. PMID: 32244588). In current work we demonstrate that the Hes7 transcriptional repressor may be a direct target of Fgf4 signaling. During vertebrate development the presomitic mesoderm (PSM) is periodically segmented into somites which will form the segmented vertebral column and associated muscle connective tissue and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. We examined mouse mutants lacking only Fgf4 or Fgf8 which we previously demonstrated act redundantly to prevent PSM differentiation. Fgf8 is not required for somitogenesis but Fgf4 mutants display a range of vertebral defects. Analyzing gene expression with spatial model-based quantification of mRNAs fluorescently labeled by hybridization chain reaction we show that FGF4 controls Notch pathway oscillations through the transcriptional repressor HES7. We support this hypothesis by demonstrating a genetic synergy between Hes7 and Fgf4 but not with Fgf8. Thus we establish Fgf4 as an essential Notch oscillation regulator and potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. (eLife 2020 Nov 19;9:e55608. doi: 10.7554/eLife.55608.) Future work will focus on what regulatory elements within the Hes7 gene are responsive to Fgf4 signals. 314856 +Biotechnology; Cancer; Congenital Structural Anomalies; Genetics; Pediatric Alleles;Alternative Splicing;Apical Ectodermal Ridge;Apoptosis;Biological;CCR;Cell Aging;Cell Death;Cell Survival;Cell division;Cell physiology;Cells;Cessation of life;Clinic;Collaborations;Colorectal Cancer;Complex;Cre driver;Development;Developmental Biology;Digit structure;Drosophila genus;Elements;Embryo;Ensure;FBP interacting repressor;Factor Analysis;Feedback;Fibroblast Growth Factor;Fingers;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomics;Goals;Growth;Homologous Gene;Human;Intercept;Joints;Lead;Learning;Length;Light;Limb Bud;Limb Development;Limb structure;Link;LoxP-flanked allele;Malignant Neoplasms;Mesoderm;Mission;Modeling;Moon;Morphogenesis;Mus;Neoplasm Metastasis;Neoplasms;Normal tissue morphology;Organ;Organogenesis;Pathologic;Pathology;Pathway interactions;Pattern;Phalanx;Phenotype;Physiological Processes;Play;Process;Proteomics;Regulation;Research;Role;SHH gene;Shapes;Signal Transduction;Skeleton;Structure;Study models;System;Systems Biology;Testing;Thumb structure;Tissues;Tumor Biology;Tumor Suppressor Proteins;Vertebrates;WNT Signaling Pathway;Wing;base;beta catenin;c-myc Genes;cancer therapy;cell behavior;cell motility;cellular targeting;conditional mutant;design;gene function;implantation;in vivo;insight;mutant;neoplastic cell;null mutation;programs;protein protein interaction;skeletal;smoothened signaling pathway;transcription factor;tumorigenesis Role of FIR in limb morphogenesis n/a NCI 10702526 1ZIABC011319-13 1 ZIA BC 11319 13 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 181329 NCI The developing limb is a well-studied model for morphogenesis in which many of the regulatory components governing skeletal pattern and growth have been elucidated providing a strong biological framework for interpreting gene function based on mutant phenotypes. FIR (FBP interacting repressor) is a highly evolutionarily conserved negative regulator of myc transcription present in both vertebrates and Drosophila. The Drosophila homolog (half pint) controls the zone of non-proliferation in the developing embryonic wing disc. The human homolog has been implicated in colorectal cancer; alternatively spliced dominant-interfering forms of FIR are associated with these cancers. Elucidation of the normal function of FIR in mammalian tissues has been hampered by the very early embryonic lethal (prior to implantation) of FIR null mutant embryos limiting the ability to assess the role of this gene in normal tissue morphogenesis. In collaboration with Dr. Levens (CCR NCI) who has generated a conditional (floxed) allele of mouse FIR we are using several Cre drivers to selectively remove FIR from the early limb bud. We want to test whether FIR plays a role in regulating limb outgrowth and if it does learn how it acts to regulate growth. In preliminary results we have found that surprisingly loss of FIR function in early limb bud mesoderm results in considerable apoptosis leading to truncations of the limb skeleton. In Drosophila half pint is a target of Wg (wingless Wnt) pathway. Interestingly loss of the Wnt signaling effector beta-catenin from limb bud mesoderm also causes limb truncation phenotypes in mouse embryos related to abnormalities in formation of an early Fgf signaling center in the limb bud (AER apical ectodermal ridge) that is necessary for limb outgrowth. We are analyzing components of the Wnt pathway to determine whether they are altered in the FIR mutant limbs along with other analyses of factors and signaling centers critical for cell survival in the early limb. Surprisingly we have found that the requirement of FIR for cell survival appears to be context dependent rather than universal and is dispensable in some cells where Sonic hedgehog signaling is active in the limb. We are also collaborating with Dr. Anne Moon (Geisinger Clinics) who has identified CAPER as a factor regulating cell division and senescence in the limb and has discovered a CAPER-FIR protein-protein interaction. We are studying how these interactions regulate cell survival in a selective fashion using the limb as a model to understand how hedgehog signaling alters requirements for FIR function. These studies will shed new light on the varied roles of FIR in regulating growth and will have implications for developing cancer therapies that may target the function of this Myc-regulator. 181329 +Biotechnology; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health CRISPR library;CRISPR/Cas technology;Cancer Model;Cells;Collection;Complex;Dependence;Development;Gene Expression;Gene Mutation;Genes;Genetic;Genetic Screening;Genotype;Guide RNA;Human;Libraries;Mammalian Cell;Mammalian Genetics;Methods;Modeling;Mus;Mutation;Outcome;Pattern;Proteins;Publishing;RNA Interference;Reagent;Small Interfering RNA;Somatic Mutation;Technology;Work;anticancer research;cancer cell;cancer genome;cell behavior;combinatorial;flexibility;genetic analysis;genetic manipulation;genetic testing;genome editing;genome-wide;genomic locus;knock-down;knockout gene;neoplastic cell;paralogous gene;preclinical study;tool;tumor Methods for mammalian genetic analysis n/a NCI 10702520 1ZIABC011304-13 1 ZIA BC 11304 13 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 157827 NCI BACKGROUND. Cancer research requires our ability to accurately model the pattern of gene mutation and gene expression observed in human tumors. Gene expression can be downregulated with RNAi. More recently CRISPR/Cas9 has become a major genome-editing tool for introducing mutations and for altering gene expression in mammalian cells. A major challenge in modeling the cancer genome is that we can currently recapitulate only a fraction of the complex changes observed in a tumor cell. Thus developing methods that enable genome editing on a more complex scale will be critical for the modeling of cancer cell behavior in pre-clinical studies. OBJECTIVES. 1.) To develop combinatorial RNAi method and reagents for downregulating the expression of multiple genes simultaneously in human and mouse cells; 2) To develop combinatorial CRISPR/Cas9 gene knockout method and reagent for deleting multiple genes simultaneously in human and mouse cells; and 3) to develop method and reagent for gene editing in human and mouse cells to introduce mutations and to regulate gene expression. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1). Multiplexed RNAi for combinatorial gene knockdown. We have developed a multiplexed gene knockdown method using high potency siRNAs. This method enables the simultaneous knockdown of up to 7 genes in the same cell. This level of complexity allows us to interrogate gene paralog redundancy and the function interaction of multiple genetic nodes in human cancer cells. This work was published. 2). Multiplexed CRISPR/Cas9 for combinatorial gene knockout. We have developed a multiplexed CIRSPR/Cas9 gene knockout method using pre-validated synthetic guide RNAs. This method enables the simultaneous knockdown of up to 3 genes in human cancer cells. This approach enables rapid genome editing at multiple gene loci. This work was published. 3). Development of modular CRISPR libraries for genetic screens. We have developed a curated collection of pooled sgRNAs library modules. Genes in each module were curated by their functional annotation. This enables the construction of sub-genome scale focused CRISPR libraries of flexible size for specialized genetic screen purposes. 157827 +Cancer; Genetics Antineoplastic Agents;Autophagocytosis;Biological Models;CHD1 gene;Cancer Biology;Categories;Cells;Chromosomal Stability;DNA Damage;Dependence;Development;Drug Targeting;Equilibrium;Evolution;Genes;Genetic;Genetic Screening;Goals;Growth;Immunologic Surveillance;Inflammatory;KRAS oncogenesis;KRAS2 gene;Knowledge;Ligase;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic stress;Mitotic;Molecular;Mutate;Neoplasm Metastasis;Normal Cell;Oncogenes;Oncogenic;Outcome;Pathway interactions;Phenotype;Play;Pre-Clinical Model;Proteins;Publishing;RAF1 gene;RNA Interference;RNA Splicing;RNA interference screen;Role;Signal Transduction;Spliceosomes;Stress;Sumoylation Pathway;Therapeutic;Work;base;biological adaptation to stress;cancer cell;cancer genome;cancer therapy;combinatorial;effective therapy;experience;inhibitor;malignant state;mutant;novel therapeutics;oncogene addiction;proteotoxicity;small molecule;targeted treatment;tumor Non-oncogene addiction in cancer cells n/a NCI 10702519 1ZIABC011303-13 1 ZIA BC 11303 13 10712486 "LUO, JI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 473481 NCI BACKGROUND. We define NOA as increased dependency of cancer cells on stress-response pathways for survival. The malignant state of the cancer cell is associated with a unique set of oncogenic stress phenotypes involving DNA damage metabolic stress proteotoxic stress inflammatory microenvironment and immune surveillance. Oncogenic stress renders cancer cells more dependent on stress-response pathways for survival and consequently more sensitive to the disruption of these stress-response pathways. In contrast normal cells in the body do no experience oncogenic stress therefore normal cells are much less sensitive to the perturbation of stress-response pathways. This fundamental difference in cancer vs. normal cell's dependency on stress-response pathways forms the theoretical basis of NOA. NOA is distinct from oncogene dependency because stress response pathway genes are rarely mutated in the cancer genome. NOA represents a broad category of synthetic lethal and collateral dependency mechanisms in cancer cells and targeting NOA could offer orthogonal therapeutic approaches to current targeted treatment of tumors. OBJECTIVES: The objectives of this project are 1.) Identify NOA genes and genetic pathways in cancer cells using genetic screen and hypothesis-based approaches; 2) Investigate the molecular mechanism that underly a NOA phenomenon and understand its essentiality to the oncogenic state; and 3) Explore the therapeutic implication of NOA as potential cancer drug targets. We will carry out these objectives primarily using cancer cells harboring the KRAS oncogene as our model system as KRAS mutant tumors have generally lacked effective therapies. MAJOR ACTIVITIES SIGNIFICANT RESULTS AND KEY OUTCOMES. 1.) NOA of KRAS mutant cells to the RNA splicing factor ERH. Through a synthetic lethal RNAi screen in KRAS mutant cells we have identified the ERH gene as a synthetic lethal partner in KRAS mutant cells. ERH is an evolutionarily conserved protein with poorly understood function. Using mass-spectrometry we identified ERH associates with the spliceosome protein SNRPD3 and is therefore a component of the RNA splicing machinery. We showed that ERH is required for the proper splicing and expression of a subset of mitotic genes including CENPE that are critical for maintaining chromosomal stability in KRAS mutant cells. This work defined a new function for the ERH protein uncovered a previously unknown NOA in KRAS mutant cells to the RNA splicing machinery. This work suggests that selective perturbation of RNA splicing to disrupt the balance of mitotic proteins could be a potential approach to target KRAS mutant cancer cells. This work has been completed and published. 2.) NOA of KRAS mutant cells to the SUMO pathway for transformed growth. Through a synthetic lethal RNAi screen in KRAS mutant cells we have identified the SUMO pathway particularly the SUMO E2 ligase UBE2 to play an important role in supporting the viability and transformation growth of KRAS mutant cancer cells. Using mass-spectrometry we identified multiple proteins whose SUMOylation are disrupted in a KRAS-dependent manner. Using gene rescue approaches we showed that several SUMO target proteins including KAP1 CHD1 and EIF3L are critical for the viability of KRAS mutant cells under anchorage independent conditions. This work identifies a new role of the SUMO pathway in KRAS-driven oncogenesis and suggests the SUMO pathway as a potential drug target for KRAS mutant tumors. This work has been published. We are currently exploring the effect of small-molecule SUMO inhibitors in preclinical models of KRAS mutant cancer. 3) NOA of KRAS mutant cells to autophagy. Through a combinatorial RNAi analysis of the gene dependency landscape in KRAS mutant cells we identified critical OA and NOA that components in the Ras signaling network and in stress-response pathways respectively. We found CRAF/RAF1 as the major onco-effector of mutant KRAS and the autophagy E1 ligase ATG7 as a major NOA. This work identifies the autophagy pathway as a co-target with CRAF as a rational combination for KRAS mutant cells. This work has been published. We are currently investigating the mechanism by which autophagy contributes to the growth and survival of KRAS mutant tumors. 473481 +Biotechnology; Cancer; Genetics; Infectious Diseases Ablation;Affect;Affinity;Alloantigen;Animals;Antibodies;Antigens;Autoantigens;Autoimmune Responses;Avidity;Biological;Biological Assay;Biosensor;CD3 Antigens;Cell physiology;Cells;Cessation of life;Chimeric Proteins;Chromatin;Clinical;Corticosterone;Cytochrome P450;Deoxycorticosterone;Detection;Detergents;Ensure;Environment;Enzymes;Epithelial;Event;Exposure to;Fixatives;Generations;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gonadal Steroid Hormones;Hormones;Immune response;Immunization;Immunosuppressive Agents;In Vitro;Infection;Knock-in Mouse;Knock-out;Knockout Mice;Laboratories;Life;Ligands;LoxP-flanked allele;Lymphocytic choriomeningitis virus;Major Histocompatibility Complex;Mature T-Lymphocyte;Membrane;Mitogens;Mixed Function Oxygenases;Mus;Names;Nuclear Receptors;Pathologic;Pathway interactions;Peptides;Play;Production;Progestins;Proliferating;Receptor Signaling;Regenerative pathway;Role;Series;Shapes;Specificity;Steroids;T cell response;T-Cell Antigen Receptor Specificity;T-Cell Development;T-Cell Receptor;T-Lymphocyte;T-cell receptor repertoire;Techniques;Testing;Thymic epithelial cell;Thymocyte Development;Thymus Gland;Time;Tissues;Transcriptional Regulation;Transgenes;Transgenic Organisms;Virus;Work;alpha-beta T-Cell Receptor;anti-tumor immune response;cross reactivity;crosslink;deep sequencing;in vivo;mouse model;neoplastic;neoplastic cell;paracrine;pathogen;receptor;receptor expression;response;thymocyte;transcription factor;tumor;tumor growth Glucocorticoids and T cell development and function n/a NCI 10702515 1ZIABC011264-13 1 ZIA BC 11264 13 9692263 "ASHWELL, JONATHAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 847535 NCI "We have previously generated conditional glucocorticoid receptor (GR) knockout mice which were crossed with lck-Cre animals to produce mice that lack GR expression in thymocytes and T cells (GRlck-Cre). These mice have a modest reduction (about 40%) in the number of double positive (DP) and single positive (SP) thymocytes. Introduction of a transgenic T cell receptor (TCR) that has differing affinities for different MHC-encoded class II molecules revealed that the higher the avidity for self the greater the reduction in thymocyte number in the GR KO mice indicating that the thymocytes are undergoing increased negative selection in the absence of GR signaling. If the TCR repertoire the range of receptors expressed after selection is indeed affected by glucocorticoids there should be changes in the specificity of immune responses. We have found that mature T cells from the conditional GR-null mice proliferate normally to mitogens or to TCR cross-linking but poorly to alloantigen. Moreover immunization with peptide antigens results in a poor T cell recall response. Strikingly if the TCR repertoire is ""fixed"" by introducing alpha/beta TCR transgenes the proliferative response of GRlci-Cre T cells to antigen in normal in vitro and in vivo. Deep sequencing of TCRbeta CD3 regions which have the largest contribution to TCR specificity found that there was a significant difference between but not within groups of wild type and GRlci-Cre naive T cells. These results demonstrate that exposure to glucocorticoids in the thymus is a critical event in shaping the T cell repertoire and thus the ability to respond to foreign pathogens. We have also made mice in which the enzyme responsible for corticosterone production Cyp11b1 encoding steroid 11beta-hydroxylase is floxed. We have crossed these mice onto Cre-expressing animals to knockout glucocorticoid production in thymic epithelial cells (TEC) allowing us to test the hypothesis that local glucocorticoid production is important for thymocyte development. We have found that the T cell response to alloantigen is blunted just as it is in the GRlck-Cre mice. Furthermore the response to infection with the virus LCMV show changes in the fine-specificity of the TCRs used. In another series of studies we found that if one uses a cell fixative plus a detergent (to permeabilize the membrane) glucocorticoid receptors that are ligand bound and chromatin-associated will be cross linked to adjacent chromatin. As a result the GR (and other nuclear receptors) can be used as biosensors that can quantitate ambient ligand concentration. Use this ""perm-fix"" technique we have been able to identify for the first time the effects of paracrine hormone production in the thymus. We have found that DP thymocytes that have been triggered by self antigen are in a high glucocorticoid environment (approximately threefold higher than other thymocytes) due to corticosterone production by thymic epithelial cells. This assay allows the detection and quantification of hormone exposure in tissues at the single cell level. Because antibodies against Cyp11b1 are highly cross-reactive with other P450 enzymes involved in steroid synthesis we have created a ""knockin"" mouse that expresses a fluorescent Cyp11b1 fusion protein. We have found that Cyp11b1 is exclusively made by medullary thymic epithelial cells under the control of the transcription factor Aire. In fact we identified Aire-regulated production of sex steroids and progestins by medullary thymic epithelial cells. This represents the first example of Aire controlling expression of entire enzymatic pathways that result in the production of non-protein (in this case steroid) biologically active products. In another facet of our studies we have found that some neoplastic tumor cells produce glucocorticoids by a regeneration pathway in which the enzyme 11b-HSD1 (gene name 11HSD1b1) produces deoxycorticosterone from the inactive metabolite dehydrocorticosterone. Genetic ablation of 11HSDb1 in the tumors enhances the anti-tumor immune response and reduces tumor growth. Current studies are aimed at understanding the biological mechanism." 847535 +Breast Cancer; Cancer; Cancer Genomics; Genetics; Human Genome; Precision Medicine; Prevention; Women's Health Adjuvant Chemotherapy;American;Bioinformatics;Biological Models;Biology;Breast cancer metastasis;Cancer Etiology;Cell physiology;Cessation of life;Clinical;Copy Number Polymorphism;Critical Pathways;Data;Data Set;Diagnosis;Discipline;Disease;Distant;Environment;Etiology;Experimental Models;Future;Genes;Genetic;Genetic Transcription;Genetic study;Genomic Instability;Genotype;Goals;Human;Human Genetics;Inherited;Intervention;Investigation;Localized Disease;Malignant Neoplasms;Mammary Neoplasms;Mechanics;Mediating;Metastatic to;Modeling;Molecular;Morbidity - disease rate;Mouse Mammary Tumor Virus;Multiprotein Complexes;Mutate;Mutation;Neoplasm Metastasis;Nuclear Pore;Patients;Penetrance;Point Mutation;Pore Proteins;Predisposition;Primary Lesion;Primary Neoplasm;Proteomics;Public Health;Publishing;Recurrence;Relapse;Role;Sampling;Single Nucleotide Polymorphism;Somatic Mutation;Survival Rate;Susceptibility Gene;System;Therapeutic;United States;Variant;Woman;advanced breast cancer;anticancer research;burden of illness;design;driver mutation;epigenomics;extracellular;genetic approach;genome-wide;malignant breast neoplasm;mechanical signal;mechanotransduction;metastatic process;migration;mortality;mouse genetics;mouse model;multidisciplinary;precision medicine;prevent;promoter;response;transcriptome sequencing;tumor;tumor progression Genetic Modifiers of Initiation and Progression of Mammary Cancer n/a NCI 10702514 1ZIABC011255-13 1 ZIA BC 11255 13 1867359 "HUNTER, KENT WILLIAM" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2699964 NCI Breast cancer remains the most commonly diagnosed malignancy and is the second leading cause of cancer-related death in American women. It is estimated that there were more than 266000 new cases of breast cancer in the United States in 2018 with 41000 patients succumbing to the disease. Although the 5-year survival approaches 100% for those patients diagnosed with localized disease the 5-year survival rate for patients diagnosed with distant metastatic disease in only 27% highlighting the critical importance of the metastatic process in patient mortality. For those patients diagnosed with localized disease the widespread application of adjuvant chemotherapy has reduced late relapse and long-term mortality by an estimated 19%. However despite these efforts 25% of patients receiving adjuvant chemotherapy still progress to metastatic disease. Despite changes in therapeutic strategies little improvement in the survival of these patients has been observed . At present it is estimated that 155000 women are currently living with metastatic disease in the United States highlighting the significant public health burden of this disease. It is therefore critically important to obtain a comprehensive understanding of the etiology and biology of metastases to develop more effective clinical interventions to further reduce the morbidity and mortality of advanced breast cancer. In FY22 we have performed two parallel strategies for further investigations into the etiology of breast cancer metastasis. The first strategy investigated the acquisition of somatic mutations and copy number variations that might function as driver mutations for metastatic progression. Extending our previous analysis in the MMTV-PyMT mouse model we have added additional primary-metastasis pairs to our data set as well as analyzing three additional models of metastatic mammary cancer MMTV-Myc MMTV-Her2 and C3(1)-TAg. Surprisingly unlike the in primary tumor transformation activation mutations enriched in metastases induced by single nucleotide variants (SNVs) were relatively rare suggesting that point mutations are not a major driver of tumor progression. In contrast recurrent copy number variations (CNVs) were frequently enriched metastases compared to primary tumors in a genotype-specific manner suggesting that genomic instability may be the primary somatic driver of metastatic disease. Despite these recurrent CNVs however RNAseq revealed little transcriptional variation between matched primary and metastatic lesions. These data imply that transient interactions and cellular responses may be more important in metastatic progression than the stable differences and that genomic instability may be required to enable cellular plasticity during the multiple cellular insults and challenges faced during the metastatic cascade. The second strategy pursued is the continuation of our genetic studies into the etiology of metastasis susceptibility. In FY2022 we published the results of a study of the role of the nuclear pore protein NUP210 in metastatic progression. These studies demonstrated that NUP210 mediates mechanical signaling from the extracellular environment to poised promoters of migration and invasion genes inducing tumor dissemination from the primary tumor mass. Intriguingly proteomics analysis has revealed that additional previously identified metastasis susceptibility genes also participate in this mechanical response mechanism. The convergence of these independently identified metastasis-associated factors on a single multiprotein complex suggests that our genetic strategy is interrogating a critical component of the metastatic cascade. Importantly these genes are not frequently mutated in either experimental model systems of metastasis nor in human clinical samples. Thus our gene susceptibility screen appears to be highlighting important cellular and molecular mechanisms that would be difficult to access by conventional cancer research strategies. Current efforts are focused on more detailed analysis of the mechanisms and potential integration of additional metastasis susceptibility genes that may contribute to the tumor dissemination mechanotransduction response. 2699964 +Cancer; Chronic Pain; Health Disparities; Immunotherapy; Interstitial Cystitis; Minority Health; Pain Research; Urologic Diseases; Women's Health Amino Acids;Anabolism;Annual Reports;Baltimore;Binding;Binding Proteins;Biological Assay;Bladder;Bladder Diseases;Bladder Neoplasm;Cancer cell line;Cells;Characteristics;Chemicals;Chronic Disease;Collaborations;DTR gene;Data;Data Analyses;Disaccharides;Down-Regulation;Drug Design;Epidermal Growth Factor;Epithelial;Epithelial Cells;Fluorine;Frizzled Domain;Glycobiology;Glycopeptides;Goals;Growth Factor;Heparin Binding;Increased frequency of micturition;Interstitial Cystitis;Investigational Drugs;Journals;Lead;Location;Manuscripts;Maps;Maryland;Methods;Modeling;Molecular Conformation;Morphology;National Institute of Dental and Craniofacial Research;Natural Products;Pain;Paper;Pathologic;Patients;Peptides;Permeability;Pharmaceutical Preparations;Play;Protein Fragment;Proteins;Publishing;Receptor Signaling;Reporting;Role;Seminal;Series;Stretching;Structural Models;Structure;Therapeutic Agents;Thinness;Tight Junctions;Translating;Transmembrane Domain;Tumor Cell Line;Tumor-Associated Carbohydrate Antigens;Ulcer;Universities;Urine;Vaccine Design;WNT Signaling Pathway;Work;alanylproline;analog;anti-cancer;anticancer activity;antiproliferative agents;base;biophysical techniques;cancer cell;cancer immunotherapy;carbohydrate analog;cell transformation;design;glycosyltransferase;hydroxyl group;information model;inhibitor;micturition urgency;molecular modeling;nanomolar;neoplastic cell;novel;novel anticancer drug;receptor;scaffold;sugar A Glycopeptide from Interstitial Cystitis Patients as a Novel Anticancer Lead n/a NCI 10702513 1ZIABC011232-14 1 ZIA BC 11232 14 8777873 "BARCHI, JOSEPH JOHN" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 302756 NCI Interstitial cystitis/painful bladder disease (IC/PBS) is a chronic disease of the bladder characterized by thinning and ulceration of the bladder epithelial layer causing severe pain urinary frequency and urgency. Seminal work at the University of Maryland Baltimore showed that a specific factor was responsible for many of the characteristic pathological changes that occur in IC/PBS. This factor called APF was shown to have antiproliferative activity toward bladder epithelial cells at sub-nanomolar concentrations. APF caused an increase in paracellular permeability the down regulation of several proteins involved in tight junctions formation and reduced the levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF). In addition APF was also a potent antiproliferative agent against bladder tumor cells at equally low concentrations and has subsequently been shown to inhibit proliferation of other tumor cell lines. The peptide portion of APF has 100% sequence identity to a stretch of amino acids in the 6th trans-membrane domain of Frizzled 8 a Wnt signaling receptor. Whereas the sugar portion Neu5Ac(alpha)2-3Gal(beta)1-3GalNAc(alpha)-O-Thr is the sialylated form of the well-known Thomsen Friedenreich disaccharide a tumor associated carbohydrate antigen used in vaccine design and in the immunotherapy of cancer. In 2006 synthesis began on a series of analogues of the asialo derivative of APF (as-APF equipotent to the natural sialylated compound) to define the structure-activity profile of the natural glycopeptide. In the last annual report we outlined the extensive structure-activity studies we had done with this molecule and reported in the minimal requirements for full activity of the molecule as an antiproliferative agent. We published this year on the two inhibitors we identified and the normalization of IC/PBS-like bladder cells when treated with these drugs. They are being developed as therapeutic agents for IC/PBS. We are continuing with the SAR work by preparing carbohydrate analogues where specific hydroxyl groups are removed or replaced with isosteres like fluorine to map the important interactions of the sugar. Several of these have been prepared and two have been incorporated into the peptide. Our work with the CKAP protein was stalled since the construct we prepared as unstable and aggregated very rapidly under standard conditions. Thus we were not able to develop and assay for all our analogues. This is being revised and modified protein fragments will be explored. We have made a lot of progress on the structural front with our collaborators at the University of Maryland. By NMR and molecular modeling methods we have identified specific motifs in various analogues that are important for dictating the conformational bias of those structures. These data have helped in elucidation the manner in which the sugar portion of the glycopeptides interacts with the peptide portion: this could be highly relevant to its interactions with specific cellular receptors and thus aid in actual drug design of particular analogues that may have selective anticancer activity. A manuscript on this work was published in the Journal of Chemical Information and Modeling. We are also working with collaborators now at the National Institute of Dental and Craniofacial Research to determine the specific glycosyltransferases that are involved in the biosynthesis of APF and to explore whether or not the sugar portion is relevant to binding with specific receptors on cancer cells. The major accomplishments were: 1) Analysis of data on all 8-mer analogues as well as 4 of the most important 9-mer analogues by NMR and modeling defined the important interactions of the molecule with itself and now expanding to protein binding; 2) Anticancer activity of two of the analogues in 11 different cancer cell lines with our collaborators and publishing a full paper in Investigational New Drugs; and 3) Exploration of the two inhibitor molecules on APF-transformed cells; and 4) Synthesis of the carbohydrate analogues and compilation of all these data for another manuscript. We have now prepared several synthetically challenging fluorinated carbohydrate analogues of APF and found that one of them is almost as active as the natural material. A fruitful collaboration with Dr. Alex Mackerell of the University of Maryland has yielded a structural model of APF where we can now perform pharmacaphore searches and try to design a non-peptidic APF anlogue that is as active as the natural product. We can also attempt to design analogues that will selectively target cancer cells. 302756 +Autoimmune Disease; Cancer; Cancer Genomics; Genetics; Human Genome; Rare Diseases American;Attenuated;Autoimmune Diseases;CD4 Positive T Lymphocytes;Carcinogens;Cells;Chemicals;Cutaneous;Databases;Development;Disease;Endocrine;Environment;Event;Genes;Genetic;Genomic Instability;Genomics;Homeostasis;Human;IKK alpha;Induced Mutation;Infiltration;Inflammasome;Inflammation;Inflammatory;Investigation;Knock-in Mouse;Lesion;Malignant Neoplasms;Mediating;Molecular;Mus;Mutation;Myeloid Cells;Organ;Pathogenesis;Patients;Phenotype;Phosphotransferases;Polyglandular Autoimmune Syndrome Type I;Reporting;Role;Skin;Skin Carcinogenesis;The Cancer Genome Atlas;Time;Tumor Suppressor Proteins;Tumor-infiltrating immune cells;Ultraviolet B Radiation;Uric Acid;autoinflammation;autoinflammatory;autoreactive T cell;autoreactivity;carcinogenesis;central tolerance;early onset;inhibitor;macrophage;microorganism;neutrophil;new therapeutic target;prevent;skin disorder;skin squamous cell carcinoma;tumor;tumorigenesis Functions of IKK alpha in Skin Homeostasis and Skin Tumorigenesis n/a NCI 10702509 1ZIABC011212-14 1 ZIA BC 11212 14 10270679 "HU, YINLING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 710843 NCI Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) show diverse endocrine and non-endocrine manifestations initiated by self-reactive T cells due to AIRE mutation-induced defective central tolerance. A large number of American APECED patients suffer from early-onset cutaneous inflammatory lesions accompanied by an infiltration of T cells and myeloid cells. The role of myeloid cells in this setting remains to be fully investigated. In this study we characterize the autoinflammatory phenotypes in the skin of both APECED-like kinase-dead Ikka knockin (KA/KA) mice and APECED patients. We found a marked infiltration of autoreactive CD4 T cells macrophages and neutrophils; elevated uric acid; and increased NLRP3 a major inflammasome component. Depleting autoreactive CD4 T cells or ablating Ccl2/Cxcr2 genes significantly attenuated the inflammasome activity inflammation and skin phenotypes in KA/KA mice. Importantly treatment with an NLRP3 inhibitor reduced skin phenotypes and decreased infiltration of CD4 T cells macrophages and neutrophils. These results suggest that increased myeloid cell infiltration contributes to autoreactive CD4 T cell-mediated skin autoinflammation. Thus our findings reveal that the combined infiltration of macrophages and neutrophils is required for autoreactive CD4 T cell-mediated skin disease pathogenesis and that the NLRP3-dependent inflammasome is a novel therapeutic target for the cutaneous manifestations of autoimmune diseases. 710843 +Cancer; Cancer Genomics; Genetics; Human Genome Address;Binding Proteins;Biochemical;Biological Models;Cell Cycle;Cells;Centromere;Chromatin;Chromatin Structure;Collaborations;Complex;Computer Models;Cryoelectron Microscopy;Data;Epigenetic Process;Funding;Genome;Goals;Human;Kinetochores;Manuscripts;Mitotic;Modification;Molecular Chaperones;Nucleosomes;Paper;Postdoctoral Fellow;Proteins;Publishing;Structure;Technology;Untranslated RNA;Work;centromere protein A;centromere protein C;complex data;daughter cell;graduate student;in vivo;nuclear division;protein complex;segregation;unpublished works Formation of Centromeres in vivo n/a NCI 10702507 1ZIABC011209-14 1 ZIA BC 11209 14 8630576 "DALAL, YAMINI P" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 411467 NCI Our goal is to dissect the mechanism by which kinetochore proteins binds the centromeric chromatin in the genome and creates the basis for a functional centromere. We have published a few papers on this work and have 2 more manuscripts that detail more cenRNAs involved in centromere function. We also have unpublished work with EM and biochemical data demonstrating how CENP-A nucleosomes can be altered in the presence or absence of various proteins. These data demonstrate how various epigenetic factors namely lncRNAs and kinetochore proteins can modulate CENP-A structure to uniquely define how functional centromere domains are formed and maintained. 411467 +Cancer; Cancer Genomics; Genetics; Human Genome Acetylation;Amino Acids;Antineoplastic Agents;Binding;Binding Proteins;Biochemical;Biological Assay;Cancer Biology;Cell physiology;Centromere;Chromatin;Chromatin Modeling;Chromatin Remodeling Factor;Chromatin Structure;Chromosome Segregation;Chromosome Structures;Complex;Coupled;Cullin Proteins;DNA;DNA Binding;DNA Damage;DNA biosynthesis;Defect;Development;Elements;Enzymes;Epigenetic Process;Euchromatin;Eukaryota;Eukaryotic Cell;Event;Family;Fission Yeast;Gene Expression Profile;Gene Expression Regulation;Gene Silencing;Genes;Genetic Screening;Genetic Transcription;Genome;Heterochromatin;Higher Order Chromatin Structure;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone Deacetylation;Histone H3;Histones;Human;Link;Lysine;Maintenance;Malignant Neoplasms;Measures;Mediating;Methylation;Modification;Molecular;Mutagens;Nucleosomes;Pathway interactions;Pattern;Phosphorylation;Positioning Attribute;Post-Translational Protein Processing;Process;Proteins;RNA Interference;RNA Polymerase I;RNA Polymerase II;Repression;Research;Retrotransposon;Role;Sister Chromatid;Site;Structure;Tail;Transcript;Transposase;Variant;Work;cancer therapy;cell type;centromere autoantigen 80K;centromere protein A;chromatin remodeling;cohesin;cohesion;genome integrity;histone methyltransferase;histone modification;human disease;insight;malignant breast neoplasm;methylation pattern;mutant;novel;prevent;promoter;recruit;scaffold;therapeutically effective;ubiquitin ligase Roles of Chromatin-modifying Factors in Epigenetic Control of the Genome n/a NCI 10702506 1ZIABC011208-14 1 ZIA BC 11208 14 8777973 "GREWAL, SHIVINDER S" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1870043 NCI The involvement of histone modifications in higher-order chromatin assembly has been highlighted by our studies in S. pombe showing that several factors identified in genetic screen for mutants defective in heterochromatic silencing (such as Clr3 Clr4 and Clr6) are involved in modification of histone tails. Among these Clr4 belongs to a highly conserved Suv39 family of histone methyltransferases which specifically methylate histone H3 at lysine 9 (H3-K9) across heterochromatic domains associated with repetitive DNA elements. Biochemical analysis has shown that Clr4 is a component of multisubunit complex containing a cullin family protein Cul4 that serves as scaffold to assemble ubiquitin ligases and a WD protein Rik1 which mediates recruitment of Clr4 activity to the target repeat loci via a RNA polymerase II transcription coupled process. Clr3 and Clr6 are histone decaetylases with strong homologies to class II and class I HDACs from humans. We have shown that Clr6 exists in at least two distinct core complexes. One of these complexes (Clr6-C1) predominantly targets gene promoters and is responsible for regulation of gene expression through local deacetylation of histones. The second Clr6 complex (Clr6-CII) that targets transcribed chromosomal regions and centromeric loci is responsible for global deacetylation of histones. Our analyses suggest that defects in Clr6-CII abrogate global protective functions of chromatin such as suppression of antisense transcripts strand-specific repression of heterochromatic repeats and protection of DNA from damage by genotoxic agents. We have also performed biochemical characterization of Clr3. Clr3 exists in a multienzyme effector complex termed SHREC that in addition to histone decaetylase activity associated with Clr3 contains a Snf2 family chromatin remodeling factor Mit1. We have shown that SHREC is targeted across all major heterochromatic domains and its activities are essential for proper positioning of nucleosomes to assemble higher-order chromatin structures critical for heterochromatin functions. We are continuing to investigate the functions of these and other histone modifying activities. Given that histone modifiers are conserved among species and control fundamental chromosomal processes including stable maintenance of gene expression patterns during development and maintenance of genomic integrity their deeper understanding is important for the development of effective therapeutic measures for treatment of cancer and other human diseases. Heterochromatin nucleated at specific sites spread in a manner that depends upon the activities of histone decaetylases heterochromatin proteins and the ability of Clr4 to both methylate H3-K9 as well as bind to methylated H3 tail via its chromodomain. Moreover methylation of H3-K9 is essential for recruitment of HP1 proteins such as Swi6 Chp2 and Chp1. Our research has unraveled a new theme wherein HP1 proteins bound to methylated H3-K9 provide a dynamic platform for factors involved in many cellular processes including proteins involved in cell-type switching and proper segregation of chromosomes. Chp1 a component of the RITS complex tethers RNAi machinery to heterochromatic loci facilitating post-transcriptional silencing of repeats in cis. However the exact functions of Chp2 and Swi6 in heterochromatin assembly and their associations with other factors were poorly understood. We recently showed that Swi6 and Chp2 associate with Clr6 and SHREC histone deacetylase complexes which are critical for transcriptional silencing of the heterochromatic centromeric repeats. This work further revealed that Swi6 and Chp2 proteins and their associated HDAC complexes have overlapping functions in limiting RNA polymerase II occupancy across pericentromeric heterochromatin domains. Interestingly purified Swi6 fraction also contains factors involved in a variety of chromosomal processes such as chromatin remodeling and DNA replication. In addition Swi6 co-purifies a cohesin loading factor essential for sister chromatid cohesion and with centromere-specific histone H3 variant CENP-A which is incorporated into chromatin in a heterochromatin-dependent manner. These analyses suggest that HP1 proteins associate with a variety of factors including histone-modifying factors essential for the assembly of repressive chromatin. Identification of HP1 associated factors and their role in chromatin assembly may help us understand the causes of breast cancer associated with altered HP1 expression. Although HP1 proteins are critical for the preferential recruitment of histone deacetylases to repeat elements within heterochromatin domains alternative mechanisms exist to target these activities to repeats dispersed across the genome. Specifically we have uncovered a novel genome surveillance mechanism for retrotransposons by a family of transposase-derived CENP-B homologs. We found that CENP-Bs localize at and recruit histone deacetylases to silence retrotransposons. This mechanism also represses retrotransposon relics scattered throughout the S. pombe genome. CENP-B-mediated surveillance is proactive capable of preventing an extinct retrotransposon from reentering the host genome. These results reveal a likely ancient retrotransposon surveillance pathway and suggest that eukaryotic cells have a toolkit of repressor activities that are either targeted across large domains via HP1 proteins or in a site-specific manner by CENP-B and other DNA binding factors. We also gained insight into the significance of the role of HDAC in regulating histone turnover. By using a newly developed assay we were able to detect differential turnover rates at heterochromatin and euchromatin domains. Interestingly we found that defects in RNAi machinery which is required to establish the H3K9me mark for HP1 recruitment cause increased histone turnover. Similarly we found that defects in HP1 or the associated histone deacetylase (HDAC) activity also cause increased histone turnover. This work has yielded a novel insight into the role of HDACs which are recruited by HP1 or other factors in precluding histone turnover to promote silencing and inheritance of heterochromatin. These findings have implications for our understanding of heterochromatin assembly in higher eukaryotes as the machinery and activities that operate in fission yeast are often conserved. 1870043 +Aging; Bioengineering; Cancer; Cancer Genomics; Genetics; Human Genome Address;Aging;Biology;Biomechanics;Biophysics;Cells;Centromere;Chromatin;Chromosomes;Crowding;Disease;Epigenetic Process;Genome;Genomics;Goals;Histones;Malignant Neoplasms;Mitosis;Normal Cell;Nuclear;Oncogenic;Paper;Phenotype;Polymers;Process;Property;Publishing;Seminal;Stress;Stretching;Variant;Work;cancer cell;daughter cell;epigenome;field study;mechanical properties;response Biomechanical properties of chromatin in cancer and normal cells n/a NCI 10702505 1ZIABC011207-14 1 ZIA BC 11207 14 8630576 "DALAL, YAMINI P" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 822934 NCI In 2019 we published a seminal paper showing that mechanical properties of chromatin are encoded in the histone variants which epigenetically and structurally mark specialized loci like centromeres. Since that work several papers have also been published in the field studying this phenomenon on a global genomic scale. Our current work attempts to bring together biophysical questions to the cancer and aging epigenome to understand whether changes in stretching crowding or other properties of chromatin are altered with disease and if so which factors underlie these changes. We then anticipate asking whether reversal of such factors might restore integrity to the chromatin meshwork thereby suppressing oncogenic or aging related phenotypes in the nuclear response to strain/stress. 822934 +Aging; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Machine Learning and Artificial Intelligence; Rare Diseases Address;Adult Glioblastoma;Aging;Area;Automobile Driving;Chromatin;Chromosomal Instability;Chromosomal translocation;Collaborations;Computer Models;Coupled;Epigenetic Process;Failure;Genes;Genome;Glioblastoma;Histones;Human;Lead;Location;Machine Learning;Malignant Neoplasms;Manuscripts;Maps;Microscopy;Mus;Organ;Organoids;Outcome;Pathway interactions;Patients;Property;Publications;Publishing;Research Personnel;Resolution;Role;Sampling;Solid;Solid Neoplasm;Specificity;Time;Tissues;Untranslated RNA;Variant;Work;cancer cell;centromere protein A;follow-up;genome-wide;new technology;repaired;small molecule inhibitor;tumor;tumorigenesis;virtual Role of histone variants in aging and cancer n/a NCI 10702504 1ZIABC011206-14 1 ZIA BC 11206 14 8630576 "DALAL, YAMINI P" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 822934 NCI We are currently focused on analysis of chromosome translocations and mechanisms involved in the breaks and repair machinery involved in the translocations. Using high resolution microscopy coupled to machine learning we are currently finding new ways to automatically score patient samples for translocations involving the CENP-A domain we mapped in previous publications and using small molecule inhibitors that can disrupt these pathways. These translocations and amplifications occur in virtually every time of solid tumor we have examined. We have expanded our work significantly to include adult glioblastomas and aging tissues derived from human patients. In collaboration with NIA we also contributed to a study examining chromatin dynamics in aging mice. 822934 +Cancer; Genetics ATP phosphohydrolase;ATP-Dependent Proteases;ATPase Domain;Adaptor Signaling Protein;Affect;Bacteria;Bacteria sigma factor KatF protein;Biochemical;Biological;Cell division;Cells;Codon Nucleotides;Collaborations;Complex;Cues;DNA Damage;DNA-Directed RNA Polymerase;Defect;Dissection;Ensure;Escherichia coli;Feedback;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic;Growth;Hyperactivity;In Vitro;Magnesium;Mutation;Mutation Analysis;N-terminal;Names;National Institute of Diabetes and Digestive and Kidney Diseases;Organism;Peptide Hydrolases;Play;Polyamines;Polymerase;Polysaccharides;Process;Protease Domain;Proteins;Proteolysis;Quality Control;Recovery;Regulation;Resistance;Ribosomes;Role;Sigma Factor;Signal Transduction;Small RNA;Starvation;Stress;Structure;System;Translations;Universities;Work;base;biological adaptation to stress;cell growth;endopeptidase Clp;environmental change;extreme temperature;falls;feeding;flexibility;in vivo;inhibitor;inorganic phosphate;insight;misfolded protein;multicatalytic endopeptidase complex;mutant;novel;programs;promoter;protein degradation;reconstitution;response;small molecule;summer student;virtual Proteolysis and Regulation of Bacterial Cell Growth Control n/a NCI 10702502 1ZIABC011203-14 1 ZIA BC 11203 14 2402881 "GOTTESMAN, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 782977 NCI For many years our lab has investigated the role of energy-dependent proteolysis in regulation of gene expression in bacteria. The ATP-dependent cytoplasmic proteases akin to the eukaryotic proteasome contain ATPase domains or subunits that recognize substrates and unfold them feeding them to the proteolytic domains. Bacteria contain multiple ATP-dependent proteases; five of them have been characterized in E. coli. Abnormal or misfolded proteins are degraded by these proteases. In addition to this quality control role the proteases degrade proteins that are naturally unstable; for these proteins degradation is likely to play an important biological role. Such protease substrates fall into two general classes: proteins that are always degraded so that regulation of their abundance depends primarily on changes in synthesis and proteins that show regulated proteolysis. In all cases identifying how the substrate is recognized by the protease and how recognition is affected by growth conditions is important in understanding how and when regulation is carried out. Our lab showed that the Lon ATP-dependent protease regulated capsular polysaccharide synthesis and cell division by degrading the RcsA and SulA proteins discovered and characterized the two-component Clp proteases ClpAP and ClpXP and investigated the roles of these proteases in vivo and in vitro. In recent years our focus has been on the regulated degradation of the RpoS sigma factor a subunit of RNA polymerase that directs the polymerase to specific promoters. RpoS is important for cells to switch to a stationary or stress response gene expression program; the expressed genes provide resistance to starvation temperature extremes and other stresses. However RpoS and its expressed genes are detrimental when the bacteria is under optimal growth conditions. The cell regulates RpoS accumulation in a variety of ways including at the level of translation via small RNA activators of translation and by regulated proteolysis. We have been studying this proteolysis one of the best examples of regulated protein turnover in E. coli. RpoS is rapidly degraded during active growth in a process that requires the energy-dependent ClpXP protease and the adaptor protein RssB a phosphorylatable protein that presents RpoS to the protease. RpoS becomes stable after various stress or starvation treatments; the mode of stabilization was a mystery until work from our lab led to discovery of a small previously uncharacterized protein now named IraP (inhibitor of RssB activity after phosphate starvation). Mutants of iraP abolish the stabilization of RpoS after phosphate starvation. IraP blocks RpoS turnover in a purified in vitro system and directly interacts with RssB. In E. coli phosphate starvation leads to IraP induction due to an increase in the levels of the small molecule alarmone ppGpp; the iraP promoter has become the best example of how ppGpp positively regulates promoters. Two other small proteins also stabilize RpoS in a purified in vitro system IraM and IraD. These proteins are not similar in predicted structure to IraP. IraM is made in response to magnesium starvation dependent on the PhoP and PhoQ regulators; IraD is important after DNA damage. The anti-adaptors define a new level of regulatory control interacting with the RssB adaptor protein and blocking its ability to act; environmental signals regulate RpoS turnover by regulating expression of different anti-adaptors. In continuing collaborative studies with Sue Wickner (NCI) on the structure and function of RssB and its anti-adaptors we use in vivo genetics and in vitro reconstitution to understand how the antiadaptors and adaptor protein work. A collaboration with A. Deaconescu (Brown University) has led to a structure of an IraD/RssB complex providing valuable new insight into how IraD inactivates RssB and fully supporting our earlier genetic and biochemical studies. We are further defining how RssB interacts with ClpX the ATPase subunit of the ClpXP protease. The N-terminal domain of ClpX known to interact with some other adaptors and substrates interacts with the RssB C-terminus. Continued dissection of this system is providing insight into how this process is balanced in the cell. Other anti-adaptors are likely to exist based on a variety of results. A long-standing question has been how the cell recovers from stress in particular from the antiadaptors. We have investigated this process for recovery from phosphate starvation. During this starvation IraP is induced and stabilizes RpoS. We find that degradation of RpoS is restored rapidly after phosphate is returned to cells and that this rapid recovery implying active inactivation of IraP is dependent on a feedback loop in which RpoS increases the synthesis of RssB. Another regulator of RpoS Crl plays a critical and unexpected role in the recovery from starvation. Crl promotes the association of RpoS with the core RNA polymerase thus favoring expression of RpoS-dependent promoters including the promoter for the rssB gene encoding the adaptor. Mutational analysis of IraP demonstrates that the C-terminus of this anti-adaptor is critically necessary for rapid recovery suggesting that it modulates the interaction of IraP with RssB. In vitro and in vivo IraP mutant for the C-terminus is hyperactive. Therefore the C-terminus acts as a critical negative regulator of IraP ensuring that it is active only when required. A virtual summer student project identified a number of other likely regulators of RpoS that will be the subject of future analysis. In another aspect of RpoS regulation H. Tabor's lab (NIDDK; deceased in 2020) had observed that cells devoid of polyamines have very low levels of RpoS. In a collaboration with them we have confirmed and extended this work. We find that the lack of polyamines allows rapid co-translational degradation of RpoS. Ribosomal mutations that increase translational proofreading have a similar if not as drastic effect. In both cases changing codon usage within the rpoS gene is sufficient to overcome much of the defect. These results suggest that previously unrecognized aspects of codon usage poise some genes including rpoS to be particularly sensitive to translational stress. Overall our proteolysis studies continue to provide novel insights into regulatory mechanisms used by bacteria. 782977 +Cancer; Genetics; Immunotherapy; Lung; Lung Cancer; Neuroblastoma; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases; Women's Health Binding;Biochemical;Biological Assay;Biological Availability;Biophysics;Blood Cells;CD8B1 gene;Catalytic Domain;Cell Proliferation;Cells;Characteristics;Chemicals;Collaborations;Crystallization;DNA Damage;Detection;Deuterium;Development;Dose;Drug Kinetics;Family;Family member;Fluorescence;France;Genetic;Genetic Transcription;Goals;Growth;Human;Hydrogen;Immune;Immune system;Immunotherapy;Infiltration;Investigation;Ionizing radiation;Ions;Lead;Lewis lung carcinoma cell;Libraries;Ligands;Lymphocyte;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Measures;Metals;Methods;Modeling;Molecular Conformation;Mus;Mutate;Myelogenous;Myeloid Cells;National Center for Advancing Translational Sciences;Neuroblastoma;Normal Cell;Outcome;Ovarian Clear Cell Tumor;PPM1D gene;Pancreatic Adenocarcinoma;Peptides;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Prevalence;Property;Protein Serine/Threonine Phosphatase;Proteins;Radiation therapy;Recombinants;Regulation;Research;Resistance;Resolution;Role;Solid Neoplasm;Specificity;Stress;Structure;TP53 gene;Tumor Immunity;Tumor Suppressor Proteins;Ultraviolet Rays;Universities;Work;X-Ray Crystallography;anti-cancer;base;cancer cell;cancer immunotherapy;cancer therapy;checkpoint therapy;chemotherapy;cytotoxic;follow-up;granulocyte;high throughput screening;improved;inhibitor;malignant breast neoplasm;malignant stomach neoplasm;medulloblastoma;melanoma;member;neoplastic cell;neutrophil;novel;overexpression;p38 Mitogen Activated Protein Kinase;phosphatase inhibitor;precision medicine;protein phosphatase 2C;response;scaffold;screening;small molecule libraries;therapeutic development;tumor;tumor progression;tumorigenesis Regulation and Function of WIP1 Phosphatase and its Role in Tumor Cells n/a NCI 10702501 1ZIABC011197-14 1 ZIA BC 11197 14 6568841 "APPELLA, ETTORE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 721121 NCI The wild-type p53-induced phosphatase Wip1 (PP2Cdelta or PPM1D) is a member of the serine/threonine protein phosphatase 2C (PP2C) family. Although Wip1 is expressed at low levels in most normal cells its transcription is induced by p53 after exposure of cells to DNA damage-inducing agents such as ionizing radiation (IR) or ultraviolet (UV) light. The Wip1 protein is frequently overexpressed or the PPM1D gene is amplified in several human cancers and this increased expression is associated with worse outcomes. Studies on human cells have shown that overexpression of Wip1 compromises tumor suppressor functions and studies of mice that lack Wip1 show that they are resistant to tumorigenesis. The current research on Wip1 is focused on understanding its regulation and functions identifying its functional targets and performing high-throughput screens (HTS) of small molecule libraries to identify specific modulators of Wip1 phosphatase activity. Recently we characterized the effects of the binding of the labile metal ion and the phospho-peptide substrate on the conformation of human PPM1A a family member of Wip1 by both hydrogen/deuterium exchange mass spectrometry and x-ray crystallography. These structural studies have allowed us to better understand substrate binding in this family of phosphatases and to characterize the labile third metal ion that is essential for catalytic activity both critical aspects that could be abrogated by the binding of a specific inhibitor. In collaboration with Dr. Oleg Demidov (University of Burgundy Dijon France) we have used syngeneic tumor models to investigate the effects of ablating Wip1 in the immune system on tumor progression. We observed that overexpression of Ppm1d in the blood cells of mice accelerated the growth of solid tumors. We found that myeloid-specific deletion of Wip1 delayed the growth of both B10 melanoma tumors and LLC1 lung cancer tumors confirming an important role of Wip1-deficient innate immune cells in anti-tumor immunity. The loss of Wip1 expression significantly increased the infiltration of solid tumors by myeloid granulocytes and by the presence of neutrophils. Genetic depletion of Ppm1d in neutrophils transformed them into efficient activators of CD8 + cytotoxic lymphocytes in part through p53-dependent induction of lymphocyte costimulating ligands 4-1BBL and OX-40L. Moreover the depletion of Ppm1d in myeloid cells potentiated both anticancer chemotherapy and immunotherapy. Therefore combining immune checkpoint therapy with genetic or chemical inhibition of Wip1 could be a valuable strategy to increase the efficiency of current anticancer immunotherapies. These findings demonstrate that Wip1 is a promising target for increasing the efficiency of anti-cancer immunotherapy. Determination of a high-resolution structure of the Wip1 catalytic domain that includes the conformation of the B-loop would greatly aid further development of specific inhibitors of Wip1 phosphatase activity. Additionally high-resolution structural information for the Wip1 catalytic site would be useful for further optimization of known inhibitors and activators and to guide structure-activity investigations. To that end we have continued optimizing the expression of recombinant Wip1 and screening for crystallization conditions. We anticipate that these systematic efforts will provide the first structure of Wip1 to help better understand the specificity and potential for inhibition and activation. As Wip1 is amplified or overexpressed in numerous human cancers including breast cancer ovarian clear cell carcinoma gastric cancer pancreatic adenocarcinoma medulloblastoma and neuroblastoma. Developing inhibitors of Wip1 activity may be beneficial in the treatment of several human cancers. Wip1 can function as a tumor suppressor in cancer cells bearing inactive mutated p53. Therefore developing activators of Wip1 is as important as characterizing inhibitors of this phosphatase. We have developed and validated two orthogonal plate-based Wip1 activity assays for high-throughput screens (HTS). The two assays have high sensitivity and broad dynamic range enabled by either fluorescence detection or mass spectrometry and are suitable for screening compound libraries for modulators of Wip1 activity. In collaboration with the National Center for Advancing Translational Sciences (NCATS) we have used the above-mentioned HTS method to screen more than 100000 compounds from the NCATS Genesis library using physiologically relevant substrates to identify Wip1 modulators. This library comprises novel chemotypes with a combination of diverse chemical scaffolds as well as well-characterized and targeted compounds possessing new properties for further therapeutic development. Several hundred compounds were considered active after the primary screen and plated in dose response format in order to refine the selection. We implemented orthogonal readouts to reduce the prevalence of interference compounds and follow-up counter assays eliminated those with non-specific activity. The most promising compounds were assessed to confirm their biophysical interaction with Wip1. Using a cell-based assay we optimized to determine Wip1 activity by measuring gammaH2AX phosphorylation following ionizing radiation we assessed the bioavailability of the lead molecules. Our biophysical biochemical and cell-based studies of confirmed hits revealed two inhibitors one competitive and one uncompetitive and one activator. These new scaffolds are prime candidates for further optimization studies. We hope that the new Wip1 inhibitor scaffolds might be amenable to optimization for better pharmacokinetic properties. Also very little work has been done on the activation of Wip1 in p53-negative tumors and no activator of this phosphatase has been described. Characterizing new Wip1 inhibitor and activator scaffolds represents a means to control the phosphatase activity using a precision medicine approach for cancer treatment. 721121 +Brain Cancer; Brain Disorders; Breast Cancer; Cancer; Genetics; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Women's Health ABCG2 gene;Anaplasia;BRAF gene;Breast;C-terminal;CD44 gene;Cancer Patient;Cells;Clinical;Development;Diagnosis;Disease;Endocrine Gland Neoplasms;Evaluation;Follicular thyroid carcinoma;Gene Expression;Genes;Genetic Transcription;Glioma;Growth and Development function;Human;Hyperactivity;Hypermethylation;In Vitro;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thyroid;Mediating;Mesenchymal Stem Cells;Metabolic;MicroRNAs;Molecular;Mus;Mutate;Mutation;Normal tissue morphology;Oncogenes;Operative Surgical Procedures;Outcome;Papillary thyroid carcinoma;Patients;Phase II Clinical Trials;Pituitary Neoplasms;Population Sizes;Primary carcinoma of the liver cells;Promoter Regions;Renal Cell Carcinoma;Renal carcinoma;Reporting;Resistance;Signal Transduction;Solid;THRB gene;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Thyroid Function Tests;Thyroid Gland;Thyroid Hormone Receptor Beta;Tumor Suppressor Proteins;Tumor stage;Tyrosine Kinase Inhibitor;United States Food and Drug Administration;Variant;aldehyde dehydrogenases;anaplastic thyroid cancer;beta catenin;c-myc Genes;cancer stem cell;chemotherapy;clinically significant;improved;in vivo;inhibitor;malignant breast neoplasm;molecular targeted therapies;mouse model;novel;pre-clinical;radioiodine therapy;recruit;self-renewal;stem cell population;stem cells;therapy resistant;transcription factor;transcriptome;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor initiation;tumor microenvironment;tumor progression Preclinical Mouse Models of Thyroid Cancer n/a NCI 10702500 1ZIABC011191-14 1 ZIA BC 11191 14 6569140 "CHENG, SHEUE-YANN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 880039 NCI Our present study provides compelling evidence to show that TRbeta acts as a tumor suppressor by regulating CSC activity. TRbeta functions as a potent inhibitor of CSC activity by blocking tumor-sphere formation in vitro and by reducing CSCs and their self-renewal capacity in vivo to block tumor initiation and progression. The inhibition of CSC activity by TRbeta is mediated by suppressing key stem-cell regulators including ALDHs KLF2 ABCG2 SOX2 beta-catenin and CD44. T3 in particular potentiates the CSC-suppressing activity of TRbeta suggesting that TRbeta directly regulates transcription of CSC-related genes. Remarkably our single-cell transcriptomic analysis of tumors induced by ATC patient-derived cells showed that TRbeta significantly reduces total CSC population size blocks recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment and ultimately shifts the cell landscape toward a tumor-free milieu through re-differentiation. This CSC-suppressing action of TRbeta has clinical significance. Our integrative transcriptome analysis of The Cancer Genome Atlas (TCGA) reveals inverse relationships of the THRB gene with many essential CSC-related genes in diverse human cancers including thyroid breast glioma kidney and lung cancer. These observations provide additional evidence to support our findings that TRbeta can function to suppress CSC activity. Furthermore the THRB gene expression was suppressed in these cancers but not in normal tissues supporting the premise that TRbeta is a tumor suppressor. In breast cancer the expression of the THRB gene is downregulated during progression to triple-negative breast cancer (TNBC) as occurs in anaplastic changes in ATC. Further the low THRB expression significantly contributes to poor clinical outcomes including advanced tumor stage and shorter disease-free/overall survival of the patients through cMYC signaling activation and transcriptional/metabolic hyperactivity which are hallmarks of CSCs. Our studies have shown that TRbeta could be tested as a potential molecular target for therapeutic intervention of ATC. 880039 +Cancer; Genetics; Rare Diseases Affect;Animal Model;Apoptosis;Apoptotic;Area;Behavior Disorders;Biological;Biology;Cell Cycle;Cell Death;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell membrane;Cell physiology;Cells;Cellular Structures;Ceramides;Cessation of life;Coupling;Diabetes Mellitus;Disease;Drosophila genus;Drug resistance;Embryo;Endocrine;Endocytosis;Enzymes;Essential Genes;Exocytosis;Genes;Genetic Screening;Glucosylceramides;Heart Abnormalities;Human;Impairment;Inborn Errors of Metabolism;Individual;Lipids;Mammals;Membrane;Metabolic;Metabolism;Mitochondria;Movement;Mus;Mutant Strains Mice;Neoplasm Metastasis;Niemann-Pick Diseases;Organogenesis;Pathway interactions;Phagocytosis;Phenotype;Phospholipids;Play;Process;Proteins;Research;Research Personnel;Response to stimulus physiology;Role;Second Messenger Systems;Signal Transduction;Sphingolipids;clinically relevant;fly;gastrointestinal system;heart function;human disease;mouse development;mutant;tumor Sphingolipid Signaling in Mammals n/a NCI 10702498 1ZIABC011187-14 1 ZIA BC 11187 14 6802050 "ACHARYA, JAIRAJ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 877705 NCI We have also extended to study the role of CERT protein in mammalian biology. CERT is an essential gene for mouse development and embryonic survival and quite strikingly is critical for mitochondrial integrity. CERT mutant embryos accumulate ceramide in the ER but also mislocalize ceramide to the mitochondria compromising their function. Cells in mutant embryos show abnormal dilation of the ER and degenerating mitochondria. These subcellular changes manifest as heart defects and cause severely compromised cardiac function and embryonic death around embryonic day 11.5. In spite of ceramide accumulation CERT mutant mice do not die as a result of enhanced apoptosis. Instead cell proliferation is impaired and expression levels of cell cycle-associated proteins are altered. Individual cells survive perhaps because cell survival mechanisms are activated. Thus global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways. PL and SL at the plasma membrane play an important role in stimulus-response coupling cell differentiation movement and exo- and endocytosis. They are asymmetrically distributed in biological membranes and different proteins catalyzing uni- and bi-directional movements of lipids perpetuate asymmetry. Our current efforts focus on scramblase a protein proposed to be involved in bi-directional transbilayer movement of phospholipids. We have recently completed two genetic screens and obtained Drosophila flies lacking two of the identified scramblase proteins. We have also generated flies lacking both genes (double mutants). Phenotypic analysis of the double mutants indicates that surprisingly scramblases do not have a determining role in the scrambling of phospholipids that accompany apoptosis phagocytosis and fusion. Instead scramblases play a regulatory role in regulated exocytosis. This has implications for a wide range of cellular processes involving digestive system and endocrine and exocrine secretions with clinical relevance for a wide range of diseases such as diabetes behavior disorders and even tumor metastasis. 877705 +Cancer; Digestive Diseases; Genetics; Pancreatic Cancer; Rare Diseases Ablation;Antibodies;Biological Process;Biological Response Modifiers;Biology;CCL2 gene;CCR;Cause of Death;Clinical Trials;Collaborations;Complex;DNA;Data;Data Set;Development;Diagnosis;Disease;Division of Cancer Epidemiology and Genetics;E-Cadherin;Elements;Endothelium;Excision;Free Radicals;Generations;Genes;Genetic;Genetically Engineered Mouse;Goals;Growth;Host Defense;Human;Human Characteristics;Immune;Immune signaling;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Innate Immune Response;Investigation;KPC model;Knockout Mice;Lesion;Ligands;Literature;Liver;Lymphomagenesis;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Mediator of activation protein;Messenger RNA;Microsatellite Repeats;Migration Inhibitory Factor;Molecular;Mus;Mutation;N-Cadherin;NOS2A gene;NOS3 gene;Nature;Neoplasm Metastasis;Nitric Oxide;Nitric Oxide Synthase;Nitrogen;Operative Surgical Procedures;Organoids;Oxygen;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic duct;Patients;Pharmaceutical Preparations;Pharmacology;Physiological Processes;Play;Pre-Clinical Model;Primary Neoplasm;Production;Prognosis;Prognostic Marker;Properdin;Proteins;Quantitative Reverse Transcriptase PCR;Refractory;Regression Analysis;Regulation;Reporting;Research;Resected;Role;Severities;Signal Pathway;Signal Transduction;Stains;TP53 gene;Testing;Therapeutic;Therapeutic Effect;Tumor-Derived;United States;Vasodilation;Vimentin;attenuation;base;cancer statistics;cancer type;chemokine;chronic inflammatory disease;clinical center;clinically relevant;cohort;cytokine;gemcitabine;genetic approach;hazard;human disease;immunoregulation;in vivo;inducible gene expression;inhibitor;macrophage;mouse model;neoplastic cell;neurotransmission;novel;pancreatic cancer model;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;pancreatic tumorigenesis;pre-clinical;preclinical study;promoter;protein expression;small molecule;standard of care;therapeutic candidate;therapeutic target;therapy resistant;tumor;tumor progression;tumor xenograft Role of Immune and Inflammation Mediators in Progression of Pancreatic Cancer n/a NCI 10702497 1ZIABC011185-14 1 ZIA BC 11185 14 15201469 "HUSSAIN, SYED PERWEZ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1071845 NCI We reported that a higher expression of MIF in tumors is associated with poorer survival in PDAC patients. Furthermore we validated these findings in 3 additional cohorts including in publicly available data sets. We hypothesized that MIF is a potential therapeutic target in PDAC. To test this hypothesis we used a genetic strategy by deleting MIF gene in LSL-KrasG12D/+;LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice a genetically engineered mouse model of PDAC which mirrors the development progression and molecular and histopathological characteristics of human disease. Kaplan-Meier analysis showed that MIF-deficient KPC (MKPC) mice survived significantly longer than that of KPC mice with wild-type MIF (P 0.0001). Additionally MKPC mice showed a significant reduction in metastatic burden (P 0.01). Most of the metastasis occurred in liver of both KPC and MKPC mice. Furthermore primary tumor cells isolated from MKPC mice showed an enhanced expression of E-cadherin and reduced expression of vimentin zeb1 and N-cadherin at both the protein and mRNA levels as compared with primary tumor cells from KPC mice suggesting an attenuation of EMT in MKPC tumors. These findings provided in vivo proof-of-concept that MIF is a potential therapeutic target in PDAC. We are currently using pharmacological MIF inhibitors and anti-MIF antibodies to examine the effect of MIF inhibition on pancreatic cancer growth progression and survival using several pre-clinical models including KPC mice PDTX and human pancreatic cancer organoids. Additionally we assessed the clinical relevance of NOS2/NO signaling in the patients with PDAC and examined the NOS2 expression by qRT-PCR in tumors from 107 early stage resected cases. Patients were then divided into NOS2-high and NOS2-low groups based on the median value of NOS2 expression. Patients with the tumor NOS2 expression above the median value were defined as NOS2-high group and the patients with the NOS2 expression lower than the median value constituted NOS2-low group. Kaplan-Meier analysis showed that patients with a higher NOS2 had significantly poorer survival as compared to the patients with lower NOS2 expression in resected tumors (Log-rank test p=0.012). Furthermore a higher NOS2 in tumors predicted poor prognosis by both univariable (hazard ratio=1.73 95 percent CI=1.09-2.75 p=0.020) and multivariable (hazard ratio=1.75 95 percent CI=1.10-2.79 p=0.018) Cox-regression analyses. Additionally immunohistochemical staining showed a significantly higher NOS2 protein expression in tumors as compared to nontumor pancreatic ducts. These findings showed that NOS2 is a candidate prognostic marker in early stage PDAC patients undergoing surgical resection and NOS2/NO signaling may play a role in pancreatic cancer progression. To examine the role of NOS2/NO signaling in pancreatic cancer progression we used a genetic strategy by deleting the NOS2 gene in KPC mouse model of PDAC and generating NOS2-deficient NKPC mice. Pancreatic tumors in KPC mice expressed a high level of NOS2 protein which as expected was undetectable in tumors from NKPC mice. Kaplan-Meier analysis showed that NKPC mice survived significantly longer than KPC mice (Log Rank test p 0.01). Compared to tumors in KPC mice NKPC tumors showed significantly reduced macrophages infiltration as determined by immunohistochemical analysis of F4/80 a murine macrophage marker and a marked decrease in the expression of chemokine ligand 2 (CCL2) also known as monocyte chemoattractant protein-1 (MCP1). Furthermore qRT/PCR analysis revealed a significant decrease in the expression of mir-21 in NKPC tumors as compared to tumors from KPC mice. These findings using a genetic strategy provided in vivo proof-of-concept that targeting NOS2 may have potential therapeutic benefits. Furthermore NOS2/NO signaling may enhance inflammation and miR-21 expression in PDAC. We are currently pursuing pharmacological inhibition of NOS2 using a small molecule NOS2-specific inhibitor in multiple preclinical models of PDAC to assess the therapeutic effect of NOS2 inhibition on PDAC. Furthermore based on our observation of a lower expression of miR-21 in pancreatic tumors from NOS2-deficient mice we are extending our investigation on the mechanistic role of NOS2 signaling by investigating the interactive role of NO and miR-21 in pancreatic cancer progression and disease aggressiveness. Our ongoing research builds upon our current findings on the role of MIF and NO in pancreatic cancer. As described we have recently shown that a higher ( median) expression of MIF and NOS2 are associated with poor survival in pancreatic cancer. Furthermore genetic ablation of either MIF or NOS2 in a genetically engineered mouse model of PDAC prolonged survival. We hypothesize that MIF and NOS2 are candidate therapeutic targets in PDAC. Based on the genetic proof-of-concept as described above that MIF and NOS2 may be potential targets for PDAC we are pursuing several preclinical studies using KPC mice patient-derived tumor xenografts and patient organoids. These preclinical studies involve pharmacological inhibition of MIF and NOS2 as single agents or in combination of the standard of care drug gemcitabine to evaluate their effects on the pancreatic cancer growth progression and survival. Our major goal is to establish strong preclinical evidence providing key support to initiate a clinical trial at CCR/NCI clinical center. Furthermore we have extended our investigation on the regulation of MIF- and NO-mediated signaling pathways in pancreatic cancer progression which includes the interactive role of NO and miR-21 in pancreatic cancer progression and genetic regulation of MIF activity in disease aggressiveness in PDAC patients. These investigations are being pursued by the generation of NOS2 and mir-21 double knockout mice in the background of pancreas specific p53 and Kras mutation. To examine the genetic regulation of MIF we have focused on the presence of a higher number of CATT microsatellite repeat in MIF promoter. A higher than 5 CATT repeat enhances the MIF production and severity of several inflammatory diseases. We are testing the hypothesis that a higher than 5 CATT repeats in MIF promoter is associated with poorer survival in pancreatic cancer patients. To test this hypothesis DNA of patients from PLCO cohorts have been examined in collaboration with the DCEG NCI. 1071845 +Biotechnology; Cancer; Cancer Genomics; Digestive Diseases; Genetics; Health Disparities; Human Genome; Minority Health; Pancreatic Cancer; Precision Medicine; Rare Diseases 3' Untranslated Regions;Automobile Driving;Baltimore;Biochemical;Biological;Biological Markers;Biology;Cell Line;Cell physiology;Characteristics;Clinical;Code;Collaborations;Critical Pathways;Development;Diagnosis;Disease;Disease Outcome;Disease Progression;Endothelium;Evaluation;Event;Excision;Future;Gene Expression;Gene Expression Profiling;Genes;Genetically Engineered Mouse;Genomics;Growth;Human;Immune signaling;Impairment;Inflammation;Inflammatory;Investigation;Kynurenine;Link;Lipase;Maintenance;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Maryland;Medical;Metabolic;Metabolic Pathway;MicroRNAs;Mineralocorticoid Receptor;Molecular;Molecular Profiling;Molecular Target;NOS3 gene;Nitric Oxide;Nonesterified Fatty Acids;Nuclear Receptors;Operative Surgical Procedures;Outcome;Pancreatic Ductal Adenocarcinoma;Pathogenesis;Pathologic;Pathway interactions;Patients;Play;Precision Medicine Initiative;Precision therapeutics;Prevention therapy;Primary Neoplasm;Production;Prognosis;Protocols documentation;RUNX3 gene;Receptor Gene;Regulation;Regulatory Pathway;Reporting;Resected;Role;Sampling;Signal Pathway;Signal Transduction;Subgroup;Surveys;System;Testing;Therapeutic;Therapeutic Intervention;Tumor Suppressor Proteins;United States;Universities;Untranslated RNA;Validation;base;cohort;design;differential expression;gene network;improved;inhibitor;insight;malignant breast neoplasm;member;metabolic profile;metabolome;metabolomics;molecular subtypes;novel;novel strategies;pancreatic cancer patients;pancreatic neoplasm;patient subsets;profiles in patients;screening;targeted treatment;therapeutic candidate;therapeutic target;therapy resistant;transcriptomics;translational potential;treatment response;treatment strategy;tumor;tumor growth;tumor progression Integrative Molecular Profiling of Human Pancreatic Cancer n/a NCI 10702490 1ZIABC011162-14 1 ZIA BC 11162 14 15201469 "HUSSAIN, SYED PERWEZ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1071845 NCI This project utilizes a combination of omics-based and targeted strategies for investigating the underlying mechanisms of pancreatic cancer progression and disease aggressiveness to identify candidate therapeutic targets. During the course of our investigation several cross-talks have developed with the first project described earlier. In one of our studies we tried to attain a comprehensive molecular insight into tumors with high- and low-MIF expression and to identify key MIF-signaling pathways that drive tumor progression we analyzed the expression of coding and non-coding genes in high (above median) and low (below medianmedian) MIF-expressing tumors in multiple cohorts of PDAC patients. The identified key genes and pathways were linked to patients' survival and were mechanistically functionally and clinically characterized using cell lines genetically engineered mouse model and PDAC patient cohorts. We reported mechanistic functional and clinical evidence of a novel MIF-driven signaling pathway that inhibits a previously undescribed potential tumor suppressor nuclear-receptor-subfamily-3 group-C member-2 (NR3C2) leading to enhanced disease aggressiveness and poorer survival in PDAC. Mechanistically MIF upregulated miR-301b which then targeted and suppressed NR3C2 expression. Tumors with a higher MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally patients with a lower NR3C2 expression in tumors showed poorer survival in multiple independent cohorts of PDAC patients. These findings discovered a key MIF-induced signaling pathway which enhances tumor progression and disease aggressiveness in PDAC. This study also identified NR3C2 a mineralocorticoid receptor gene as a putative inhibitor of disease progression. We are currently investigating the mechanistic role of NR3C2 in PDAC which involves it potential function in regulating the metabolic pathway genes. Furthermore in our initial effort to characterize tumors from early stage resected PDAC patients with markedly different survival we compared gene expression profiles in tumors from early stage PDAC cases with extremely poor survival (6 months) and those surviving 2 years or more following surgical resection. Inflammatory gene network dominated among 1820 differentially expressed genes between the two groups. A lower expression of NOSTRIN was associated with significantly poor survival indicating its potential tumor inhibitory role in disease progression. NOSTRIN inactivated endothelial NOS (eNOS/NOS3) and inhibited the production of nitric oxide (NO). Furthermore miR-221 bound to the 3'UTR of NOSTRIN and suppressed its expression and an increased miR-221 expression associated with poor survival in PDAC. Our findings are consistent with the hypothesis that NOSTRIN is a potential negative regulator of disease aggressiveness which may be targeted for designing improved treatment strategy in PDAC. We are investigating the NO-dependent and NO-independent mechanistic role of NOSTRIN in PDAC. By using a similar strategy to characterize the patients tumor with markedly different survival as described above we conducted an untargeted micro-RNA profiling and identified a novel miR-331-3p/ADAMTSL3 axis which enhances disease aggressiveness in resected pancreatic cancer patients As mentioned earlier molecular subgroups of pancreatic ductal adenocarcinoma have been reported based on the differences in genomic transcriptomics and metabolic profiling however specific molecular targets with therapeutic significance in these subgroups are yet to be clearly defined. Our ongoing study is investigating a highly aggressive subgroup to define key mechanisms driving tumor progression and disease aggressiveness that may be targeted with potential therapeutic significance. In our metabolomic studies we have shown that impairment in a lipolytic pathway involving lipases and a unique set of free fatty acids may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention. We are currently investigating the role of inflammatory signaling pathways in the regulation of metabolic reprogramming in pancreatic cancer. Our effort also includes the investigation of an interactive role of MIF-miR-301b-NR3C2 signaling axis in the regulation of metabolic reprogramming in pancreatic cancer. Additionally we have defined a novel NO/RUNX3/kynurenine metabolic signaling pathway which enhances disease aggressiveness in human pancreatic cancer and may have potential translational significance in improving disease outcome. Furthermore we are conducting and in-depth analysis of the most aggressive molecular subtype to get an insight into the disease aggressiveness and identify potential therapeutic target. 1071845 +Cancer; Cancer Genomics; Genetics; Human Genome; Rare Diseases; Stem Cell Research; Stem Cell Research - Embryonic - Non-Human Apoptosis;Binding;Biological Models;CHARGE syndrome;CRISPR/Cas technology;Cell Differentiation process;Cells;ChIP-seq;Code;DNA;DNA Damage;DNA Sequence Alteration;Data Set;Development;Down-Regulation;Embryo;Embryonic Development;Enhancers;Feedback;Foundations;Gene Expression Profile;Genes;Genetic Transcription;Genome;Genome Stability;Glioblastoma;Goals;Human;Hypersensitivity;Inherited;Inner Cell Mass;Knock-out;Malignant Neoplasms;Mammary Neoplasms;Mandibulofacial Dysostosis;Maps;Mediating;Metabolism;Modeling;Molecular;Mus;Mutate;Mutation;Normal Cell;Nuclear;Organism;Outcome;Peptides;Play;Prognosis;Proliferating;Prostatic Neoplasms;Proteins;RNA;Regulation;Role;Signal Transduction;Stress;Syndrome;TP53 gene;Technology;Testing;Transcript;base;biological adaptation to stress;blastocyst;cancer genome;cell motility;cell type;clinical practice;daughter cell;embryonic stem cell;genetic signature;genome-wide;in vivo;insight;interest;knock-down;mutational status;neoplastic cell;novel;programs;receptor;response;stem;stem cell differentiation;tissue regeneration;transcriptome sequencing;tumor;tumor progression;tumorigenesis;tumorigenic Stress responses in embryonic stem cells n/a NCI 10702489 1ZIABC011158-14 1 ZIA BC 11158 14 10270570 "HUANG, JING " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 89369 NCI Compared to differentiated cells ES cells are hypersensitive to DNA damage-induced apoptosis. It is thought that this hypersensitivity to DNA damage-induced apoptosis contributes to the low mutation burden of ES cells because ES cells with mutated DNA caused by DNA damage are removed by apoptosis. We have hypothesized that ES cell-specific factors contribute to this ES cell-specific hypersensitivity to DNA damage-induced apoptosis. During fiscal year (FY) of 2015 we have made significant progress of identifying these ES cell-specific factors that could potentially regulate the hypersensitivity of mES cells to DNA damage. We have previously mapped a global p53 signaling in ES cells (Li M et al. Molecular Cell 2012). Based on the datasets generated by this earlier study we have identified ES cell-enriched factors that may be involved in p53 signaling in ES cells. We have decided to focus on one transcript called Apela for further study because Apela is repressed by p53 and encodes a putative secretory peptide Apela. Apela peptide binds to its receptor Aplnr to regulate cell movement in differentiated cells. We found that Apela positive regulates p53-regulated apoptosis in mouse ES cells as knockdown of Apela compromised p53-mediated apoptosis in the cells. Surprisingly the coding ability of Apela is dispensable for its role in p53-mediated apoptosis. Instead Apela binds and antagonizes the function of heterogeneous nuclear ribonuclear protein L (hnRNPL). hnRNPL interacts with p53 and inhibits p53 activation. Therefore we have discovered an Apela RNA-mediated negative feedback loop in mouse ES cells that regulates apoptosis. Given that Apela is specifically expressed in ES cells our findings provide an explanation to the hypersensitivity of ES cells to DNA damage. Our study on Apela also establishes foundations for investigating two aspects of the regulation of p53 signaling in ES cells. First under unstressed condition p53 activity needs to be controlled to allow ES cells to proliferate. However the factor(s) inhibits p53 activity under unstressed condition is(are) unknown. Here we identified hnRNPL as one of such inhibitory factors that control p53 activities in ES cells. Interestingly hnRNPL knockout embryos die at the blastocyst stage. We plan to test whether hnRNPL is the inhibitory factor for p53 activity in vivo. A second aspect of the regulation of p53 signaling concerns about the mechanisms underlying the enhancer interference by activated p53. We have previously found that p53 represses ES cell-specific genes such as Nanog Oct4 and Sox2 by interfering with their enhancer activities. However the mechanisms of enhancer interference are unclear. We were not able to use Nanog Oct4 or Sox2 as our model genes to study the mechanisms because prolonged down-regulation of either of these genes will lead to ES cell differentiation. Apela down-regulation however does not cause ES cell differentiation. Therefore Apela serves as a good model gene to study enhancer interference. We plan to use Apela and CRISPR technology to investigate the molecular mechanism of p53-directed enhancer interference in ES cells. In the next several years our main interest is to study the role of p53 in metabolism regulation in ESCs. 89369 +Cancer; Diabetes; Genetics; Pediatric; Women's Health Address;Affect;Aging;Alpha Cell;Architecture;Beta Cell;Binding;Binding Proteins;Biological;Biological Models;Biological Process;Biology;Birth;Blood;Carcinogens;Cell Nucleus;Cell model;Cell physiology;Cell secretion;Cell-Free System;Cells;Cellular Structures;Chromatin;Chromatin Fiber;Chromatin Remodeling Factor;Chromatin Structure;Chromosome 21;Code;Communities;Congenital Abnormality;DNA;DNA Methylation;DNA Repair;Defect;Development;Developmental Process;Disease;Down Syndrome;Drug Targeting;Embryo;Embryonic Development;Endocrine;Etiology;Eukaryota;Event;Experimental Models;Gene Expression;Gene Expression Profile;Generations;Genes;Genetic Diseases;Genetic Transcription;Germ Cells;Glucagon;Glucose;Goals;HMGN Proteins;HMGN1 gene;HMGN2 gene;HMGN3 gene;High Mobility Group Proteins;Histone H1;Human;Immunity;Impairment;Insulin;Islets of Langerhans;Knock-out;Knockout Mice;Laboratories;Lead;Link;Literature;Maintenance;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of prostate;Mental Retardation;Mesoderm;Molecular;Molecular Target;Mus;Muscle;Myocardium;Neoplasm Metastasis;Newborn Infant;Nuclear Protein;Nucleosome Core Particle;Organism;Pharmaceutical Preparations;Phenotype;Physiological Processes;Placenta;Play;Property;Protein Family;Proteins;Protocols documentation;Reporting;Research;Role;Structural Protein;Structure;Structure of beta Cell of islet;System;Testing;Therapeutic;Transgenic Mice;Variant;biological systems;blastocyst;blood glucose regulation;cancer therapy;carcinogenesis;cell motility;diabetic;embryo tissue;gamma irradiation;histone modification;implantation;insight;insulin secretion;lead-binding proteins;link protein;liver development;malignant breast neoplasm;member;migration;overexpression;practical application;promoter;protein expression;protein function;repaired;tissue culture;tissue repair;tissue/cell culture;tool;transcription factor;trophoblast;tumorigenesis;tumorigenic Biological Functions of Chromosomal Proteins n/a NCI 10702488 1ZIABC011154-14 1 ZIA BC 11154 14 6568847 "BUSTIN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 927598 NCI Chromatin regulates gene expression and therefore plays a key role in developmental processes and in the etiology of various diseases including cancer. Nuclear protein such as histone H1 and HMGs have been shown to bind to and alter the properties of the chromatin fiber. Changes in the expression of these architectural proteins are linked to various developmental defects and to various diseases including cancer. It is significant that in higher eukaryotes every cell contains H1 and HMGs. The ubiquitous presence of these proteins in numerous cells and their relative conserved structure is a strong argument that their biological function is important for the generation or maintenance of the cellular phenotype. However in spite of numerous studies the mechanism of action and the exact cellular function of these proteins remains one of the most perplexing aspects of chromatin biology. Towards understanding the biological function and mechanism of action of HMGNs and other chromosomal proteins we have generated genetically modified mice that either lack or overexpress all the HMGN protein variants. An early and very important general finding of these studies is the realization that previous observations with cell free systems or even with cells grown in tissue culture do not fully explain the possible biological functions of the various proteins in the context of the entire organism. HMGN5/NSBPB1 a new member of the HMG protein family which we discovered is highly expressed in preimplantation embryos but after implantation it is not expressed in embryonic tissues but it is highly expressed in the placenta and in trophoblast cells. At later developmental stages the protein is re-expressed in most cells albeit at low levels. The migration of trophoblast cells during and after implantation has been used as a model for cell migration during metastasis. The high expression of HMGN5 in trophoblast cells together with recent reports in the literature that the levels of HMGN5 are elevated in prostate and breast cancer implicate the protein in tumorigenesis. Using transgenic mice in which we specifically targeted HMGN5 expression to embryonic tissues we found that aberrant expression of HMGN5 affects the viability and phenotype of the born mice. A significant number of newborn mice are either very small or die immediately after birth. Further analysis revealed abnormalities in the heart muscles. The muscle contained numerous abnormal nuclei in which the chromatin structure seems significantly perturbed. These studies demonstrate the biological consequences of structural alterations in the chromatin fiber. We have elicited conditional HMGN5-/- knock out mouse and are studying its phenotype. We found that HMGN3 a member of the HMGN protein family is highly and specifically expressed in all the endocrine cells of Langernas pancreatic islets. Knock-out mice lacking HMGN3 protein are diabetic. In the blood of these mice the glucose levels are elevated and both glucagon and insulin levels are lower than those of normal mice. Detailed studies on alpha cells indicated that HMGN3 does not affect the synthesis or secretion of glucagon from alpha cells. On the other hand HMGN3 has significant effect of the transcription profile of the insulin-secreting beta cells. but both their We elucidated the molecular mechanism leading to this phenotype and demonstrated that in pancreatic beta cells HMGN3 enhances the binding of the transcription factor PDX1 to the promoter of the Glut2 transporter. Loss of HMGN3 decreases the levels of Glut2 thereby impairing glucose import into beta cells insulin secretion from these cells and glucose homeostasis of the mice. These studies demonstrate directly that the interaction of HMGN protein with chromatin has significant biological consequences. Our previous studies suggest that loss of HMGN1 protein may affect the tumorigenic potential of mice. HMGN1-/- mice cannot properly repair the damage induced in their DNA either by UV or by gamma irradiation. The impaired DNA repair of these mice can be linked directly to the interaction of HMGN1 protein with chromatin and to the effect of HMGN protein on the properties of the chromatin fiber. To address directly whether loss of HMGN could affect carcinogenesis we have initiated a study in which we treat wild type and HMGN1-/- mice with N-nitrosodiehylamine a potent carcinogen leading to liver cancer. We are using standard protocols developed and extensively used by other laboratories at NCI to test whether loss of HMGN1 affects the development of liver cancer. The gene coding for human HMGN1 is located in located on chromosome 21 in a region that contains only 33 genes which are known to be critical for the development of Downs syndrome one of the most prevalent genetic disease. We have generated a transgenic mice overexpressing HMGN1 at levels similar to those found in humans containing 3 copies of chromosome 21. Using these mice and also mice lacking HMGN1 we find that HMGN1 modulates the expression of genes known to lead to significant mental retardation and to other biological abnormalities. Potentially these studies may provide new insights into molecular mechanisms underlying the generation of the Downs syndrome phenotype. Studies with a conditional HMGN2 knock-out moue which we have recently generated reveal that proper expression of this protein during development is crucial for embryonic survival. Loss of the protein leads to embryonic lethality at E8.5 just before full mesoderm induction. The results suggest that HMGN2 may play a crucial role in the induction of this germ cell layer. These studies also serve as a classical example that studies with tissue culture cells may not always help elucidate the true biological function of a protein. Tissue culture cells lacking HMGN2 do survive but mouse embryos do not. Studies with these mice will lead to an understanding of the mechanisms whereby HMGN regulate the orderly progression of gene expression that is needed for proper development and differentiation. Cell migration is essential for various physiological processes such as embryonic development immunity and tissue repair. The metastasis of tumor cells involves gain of migration capabilities. Thus elucidating the fundamental mechanisms regulating cell migration has important implication to the understanding of a wide range of biological processes and may have practical applications to the development of better cancer therapies. We have discovered that cell migration involves and is contingent on major reorganization in the structure of the chromatin fiber. This pioneering study which is the first to report that cell migration involves changes in the structure chromatin fiber points out to an additional cellular structure that can be targeted by drugs aimed at interfering with cell migration. In summary we have developed new model systems for studies on the role of chromatin and chromosomal-binding proteins in various biological processes. These experimental systems provide necessary tools and experimental models for detailed studies on the role of chromatin and chromatin modifiers in a wide range of biological systems. We intend to share these mice with the entire scientific community thereby expanding the scope of our research efforts and contribute to the understanding of the molecular mechanisms whereby events occurring in chromatin ultimately impact the entire organism.An important resent finding is that HMGN1 plays a major r *TRUNCATED* 927598 +Autoimmune Disease; Cancer; Colo-Rectal Cancer; Digestive Diseases; Inflammatory Bowel Disease; Women's Health Bacteria;Cells;Cessation of life;Chronic;Colon;Colon Carcinoma;Color;Disease;Engineering;Experimental Models;Food;Goals;Human;IL17 gene;IL7 gene;Immune;Immune response;Immunologics;Immunosuppression;Inflammation;Inflammation Process;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-17;Intestines;Knock-in;Lactococcus lactis;Lymphocyte;Malignant Neoplasms;Mus;Oral;Organoids;Process;Reporter;T-Lymphocyte;Therapeutic;Tissues;carcinogenesis;cytokine;design;gut inflammation;insight;interleukin-22;macrophage Chronic Inflammation and Carcinogenesis n/a NCI 10702485 1ZIABC011150-14 1 ZIA BC 11150 14 6569217 "DURUM, SCOTT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 355790 NCI We have two projects in colon cancer that emerged from our previous focus on IL-7. One project involves IL-17A IL-17 F and IL-22. These are cytokines that are produced by cells that strongly promote the intestinal inflammation that leads to colon cancer. It had not been determined where IL-17 or IL-22 is produced during this inflammatory response. We developed knockin reporter mice for the two IL-17 genes using two colors and for IL-22. This enabled us to visualize T cells and innate lymphocytes producing these critical inflammatory cytokines during bowel inflammation leading to colon cancer. These reporter mice have been sent to numerous labs around the world and are in use for investigating many immunological processes. A second project aims to inhibit the bowel inflammation leading to colon cancer. IL-27 is a suppressive cytokines that we have cloned into the food bacterium Lactococcus lactis. These engineered bacteria were given orally to mice with three different models of experimentally-induced inflammatory bowel disease. IL-27 rescued all mice from disease and death and therefore is an extremely promising therapeutic. To investigate the mechanism of IL-27 therapy we have also developed murine organoids derived from colon. Using cultures of organoids and inflammatory cells we find that IL-27 acts on inflammatory macrophages suppressing their ability to damage colon tissues. Currently we are characterizing a new L.lactis-IL-27 construct that is designed for human therapy. 355790 +Bioengineering; Biotechnology; Cancer Annual Reports;Area;Binding;Binding Proteins;Biophysics;Complex;Data;Deer;Development;Disease;Dissection;Engineering;Equilibrium;Event;Isotope Labeling;Label;Lipids;Measurement;Measures;Membrane;Membrane Proteins;Methods;Molecular Conformation;Molecular Structure;Monitor;Multidimensional NMR Techniques;NMR Spectroscopy;Neutrons;Physiologic pulse;Protein Engineering;Proteins;Publishing;Relaxation;Reporting;Roentgen Rays;Sampling;Scheme;Speed;Structure;Surface;System;Techniques;Work;biophysical techniques;data acquisition;experimental study;improved;in vivo;intermolecular interaction;macromolecule;method development;mimetics;molecular dynamics;nanodisk;novel;novel strategies;protein complex;protein protein interaction;small molecule inhibitor;structural biology;tool Methods Development n/a NCI 10702484 1ZIABC011132-15 1 ZIA BC 11132 15 15201459 "BYRD, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 400914 NCI We devote our efforts in this project to the development of improved NMR techniques and hardware and to new approaches to protein engineering and isotopic labeling. We are continuing and expanding our efforts to develop new approaches to tagging macromolecules with paramagnetic centers and obtaining unique structural information about intermolecular interactions and structures of multi-component complexes. In addition new approaches are developed when traditional methods require augmentation with new experiments or data. These methods include novel isotopic labeling schemes pulse sequence development automated methods and novel methods in relaxation NMR of proteins. This effort is continuing as a subset of the various structural biology projects described in other parts of the annual report. Specific developments have included the use of non-uniform sampling to speed up data acquisition of multi-dimensional NMR data tagging with a range of molecules to facilitate both paramagnetic relaxation enhancement and the anticipated use of pulsed EPR (DEER) to measure long-range distances in multi-component complexes. We have reported new and optimized approaches to engineering systems for deuteration segmental labeling lipidation and construction of multi-domain systems that include intrinsically disordered regions. These tools enable the strength of NMR spectroscopy to be applied to more complex systems much more similar to in vivo settings. Ongoing work in membrane mimetics is expected to impact both major projects in the lab in the coming year and beyond. New approaches to characterizing nano disk membrane mimetics have been developed and will be published in this year. Our recent work includes the development of new methods for examining fast conformational dynamics in proteins and the application of this to E2:E3 interactions. 400914 +Cancer Affinity;Binding;Binding Sites;Biological;Biology;Biophysics;CCR;Cells;Collaborations;Complex;Data;Development;Disease;Endoplasmic Reticulum;Engineering;Enzymes;Family;Human;Intervention;Investigation;Label;Laboratories;Link;Malignant Neoplasms;Membrane;Methods;Molecular;Molecular Biology;Molecular Conformation;Motion;Neoplasm Metastasis;Pathway interactions;Positioning Attribute;Process;Proteins;Publications;Publishing;Reaction;Regulation;Reporting;Research;Ring Finger Domain;Roentgen Rays;Role;Series;Specificity;Structure;Substrate Specificity;Surface;System;Therapeutic;UBE2G2 gene;Ubiquitin;Ubiquitin-Conjugating Enzymes;Ubiquitination;Work;insight;interest;member;method development;mimetics;molecular dynamics;multidisciplinary;protein complex;protein degradation;protein protein interaction;receptor;sarcoma;structural biology;tumor;ubiquitin-protein ligase Investigation of Protein-Protein Interactions in the ERAD Ubiquitylation Pathway n/a NCI 10702483 1ZIABC011131-15 1 ZIA BC 11131 15 15201459 "BYRD, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 801829 NCI Our studies of the ubiquitin-ligase E3 called gp78 are conducted in collaboration with Dr. Allan Weissman CCR. The gp78 protein has a role in sarcoma metastasis and it is an excellent target for a combined structural and molecular biological investigation of mechanism and intervention. We have reported major findings from this project in a series of publications. The effort is an interdisciplinary effort involving molecular biology in the Weissman lab NMR structural biology and biophysics in the Byrd lab and X-ray crystallograpny in the Ji lab. These studies uncovered a new aspect of the E2:E3 interaction wherein the action of a newly identified E2-binding site in gp78 results in an allosteric effect on the E2 Ube2g2 increasing the affinity for the gp78-RING finger domain by 50-fold. We also showed that the effect of the binding region (G2BR) is effective for other RING finger containing E3s (Mol. Cell). The generalization of this phenomenon is leading to a broader understanding of ubiquitination and shifting in the paradigm for the molecular mechanism of ubiquitin transfer. These studies have been extended in both the Weissman and Byrd labs. We published structural information on the ternary complex of the gp78-RING:Ube2g2:G2BR system from both NMR and crystallographic studies (EMBO J) and a related approach was undertaken for a different E2:E3 pair and published in Molecular Cell. We have examined the solution structure of the CUE domain which is a distinct functional domain within gp78 and its interactions with ubiquitin and di-ubiquitin. These results were published in Structure. We are continuing our examination of the detailed interactions and mechanism of ubiquitin transfer. Another aspect of this system is the role of dynamics in determining chain linking specificity. We are employing NMR methods to directly correlate molecular motions/dynamics of regions of the Ube2g2 enzyme with the pertinent interactions to domains of gp78. These data will be critical to developing an overview of the reaction cycle for ubiquitin loading transfer and chain specificity. We have added the use of small-angle X-ray scattering (SAXS) conducted on protein complexes in solution to enable us to examine larger constructs of the ubiquitination machinery. We have also developed a membrane mimetic which will enable the extension of these studies to the membrane surface. These efforts will continue for the next year. Current efforts also involve understanding the role of conformational dynamics via both experimental NMR and computational (molecular dynamics) methods to provide molecular insight to the allosteric mechanisms (published in Structure 2017 and methods developments in 2016-2020). We are also investigating the positioning and dynamics of the ligated ubiquitin in the context of E2Ub and E3:E2Ub complexes. Our efforts are expanding to include the use of NMR-derived conformational dynamics to understand allosteric mechanisms. Current developments are enabling us to examine the complete gp78C system in complex with the E2 Ube2g2 using our developed segmental engineering and labeling approaches. We are also examining further specificity identified in the Weissman laboratory regarding E2 recognition by complimentary E3 proteins. This year (2021) an extension of the concepts found in this work have led to a publication in PLoS Biology that illustrates a related allosteric binding partner for E2 enzymes. This new protein AUP1 provides the means to dissect the allosteric selection and activation of E2:E3 pairs and will lead to further understanding of recognition and specificity in ERAD. 801829 +Biotechnology; Cancer; Genetics; HIV/AIDS; Health Disparities; Immunization; Infectious Diseases; Minority Health; Prevention; Vaccine Related; Vaccine Related (AIDS) AIDS prevention;Acquired Immunodeficiency Syndrome;Address;Adjuvant;Affect;Age;Animal Model;Animals;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Blood;CD14 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Canarypox Vectors;Cells;Chinese;Collaborations;Combined Vaccines;Communities;DNA;Data;Dependence;Development;Epigenetic Process;FCGR3B gene;Female;Frequencies;Futility;Future;Genes;Genetic Transcription;HIV;HIV Envelope Protein gp120;HIV Vaccine Trials Network;HIV vaccine;Homing;Human;Hypoxia;IL8 gene;Immune;Immune response;Immune system;Immunity;Immunize;Immunoglobulin G;Infection;Infection prevention;Infectious Agent;Inflammasome;Insulin-Like Growth Factor I;Integrin Binding;Interleukin-10;Interleukin-6;Intervention;Intramuscular;Joints;Knowledge;Legal patent;Life;Liposomes;Logistics;Lung;Lymphoid Cell;MF59;Macaca;Macaca mulatta;Malignant Neoplasms;Mediating;Memory;Metabolic;MicroRNAs;Modality;Modeling;Monoclonal Antibodies;Mucositis;Mucous Membrane;Myeloid Cells;National Institute of Allergy and Infectious Disease;Natural Immunity;Pathway interactions;Peripheral Blood Mononuclear Cell;Phase;Plasma;Political Factor;Population Genetics;Preventive;Proteins;Recombinant Vaccines;Regimen;Research;Research Personnel;Risk;Role;SIV;SIV Vaccines;STAT3 gene;South Africa;Specificity;T cell response;T-Lymphocyte;Testing;Th2 Cells;Thailand;Training;Uncertainty;United States National Institutes of Health;Universities;Vaccinated;Vaccines;Viral;Virus;Virus Diseases;Work;adaptive immune response;age related;aluminum sulfate;animal facility;animal model development;antiretroviral therapy;arm;base;cytotoxic CD8 T cells;design;efficacy testing;exosome;expectation;extracellular vesicles;gender difference;immunogenic;immunogenicity;insight;lymph nodes;macrophage;male;microbiome research;monocyte;natural killer cell protein 44-kDa;neonate;neutralizing antibody;neutrophil;next generation;novel;novel vaccines;nutrition;pathogen;predictive modeling;rational design;rectal;response;risk minimization;sex;simian human immunodeficiency virus;simian immunodeficiency virus gp120;vaccine candidate;vaccine efficacy;vaccine evaluation;vaccine platform;vaccine strategy;vaccine trial;volunteer Development of rationally designed HIV vaccines n/a NCI 10702482 1ZIABC011126-15 1 ZIA BC 11126 15 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 4253554 NCI "Accomplishments 1: Assess which macaque model better predicts or recapitulates the efficacy of HIV vaccine candidates in humans. The SIVmac251 model has predicted and recapitulated RV144: In 2005 a collaborative study in neonates predicted the results of RV144. More recently we recapitulated the efficacy of the RV144 vaccine regimen in young (2-3 years) male and female macaques. The latter study has provided more value than just the evaluation of vaccine efficacy. Our integrated study of RNA expression in PBMCs and exosomes together with comprehensive analyses of innate and adaptive immune responses in blood lymph nodes and mucosa uncovered unexpected correlates of risk of virus acquisition such as mucosal innate lymphoid cells (ILCs) and the expression of 12 genes ten of which are part of the RAS pathway. The usefulness of this model was validated by similar observations in another protective vaccine regimen that I developed in collaboration with Dr. Strbo and the late Dr. Eckhart Podack of Miami University. This approach was the subject of a joint patent. We have also performed a confirmatory study entirely supported by the Division of AIDS NIAID in other animal facilities wherein we compared the immunogenicity and efficacy of the ALVAC and NYVAC SIV-based vaccine regimens. The ALVAC-SIV based vaccine was also protective in Chinese macaques whereas the ""more immunogenic"" NYVAC-based SIV recombinant vaccine was not. Of note the NYVAC-based vaccine did not induce an early burst of IL-1B as was the case in the non-protective Ad26 prime regimen. Will the SIVmac251 model predict the results of HVTN-702? We tested the efficacy of the ALVAC-based SIV vaccines in the SIVmac251 model using the alum in parallel with the MF59 adjuvant in the gp120 boost. To our surprise the MF59 based regimen in the SIV model was not efficacious despite its higher immunogenicity. While this observation stirred debate in the scientific community our findings did not influence the decision by the P5 Partnership to use MF59 as an adjuvant in the HVTN-702 study in South Africa. Instead logistical and political factors likely influenced the decision to proceed as originally planned. Given the current uncertainty of how accurately the SIVmac251 animal model will predict human results our study will provide crucial information to define the model's utility since we observed no efficacy in macaques. The preliminary analysis of futility in HVTN-702 will be made public in 2018 and will address this issue. SHIV-clade C Tier 1 in female Chinese rhesus macaques: In another study supported mostly by NIAID macaques were immunized with the identical ALVAC-HIV-based vaccines used in HVTN702 combined with either the MF59 or the alum (Novartis) in the gp120 boost and challenged with a SHIV clade C Tier 1 virus. The MF59 based regimen was protective whereas the alumN was not. Protection was associated with neutralizing antibodies to the SHIV clade C Tier 1 virus. In its current state I don't believe that this SHIV model will predict the results of HVTN-702 because only 1% of HIV clade C viruses in South Africa are sensitive to neutralization. However the interim analysis of HVTN-702 for futility will further our knowledge of animal model predictability and will guide the choice and refinement of faithful animal models for the development of fully effective vaccines for HIV. 2. HIV vaccine candidate activation of hypoxia and inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition. This study demonstrated that CD14+ and CD16+ monocytes have a role in the risk of SIVmac251 acquisition and has contributed to the mechanistic insight on the role of IL-1B and IL-10 in the DNA/ALVAC/alum vaccine platform. We compared ALVAC-SIV DNA-SIV and Ad26-SIV prime modalities in combination with two ALVAC-SIV + gp120 protein boosts in young male macaques. We used the intramuscular DNA-SIV prime with the intent of increasing CD4+ T cells and antibody responses since we demonstrated in prior work that the CD4+ T cells elicited by the DNA prime influence the anti-envelope titers. The Ad26-SIV prime was chosen with the intent of increasing mucosal antibodies to Env and CD8+ T cell responses. The DNA prime protected against infection in the DNA prime regimen and VE correlated with hypoxia and inflammasome activation in classical CD14+ CD16negative monocytes that in turn directly correlated with the gut-homing CCR5negative Th2 cell responses and with mucosal NKp44+ cells and IgG to V2. In the same group the frequency of differentiated CD16+ monocytes correlated with reduced vaccine efficacy via STAT3 activation. The Ad26 prime regimen did not protect against SIV acquisition despite its higher immunogenicity and it was associated with a decrease in total CD14+ DR+ monocytes in blood accumulation of de novo differentiated CX3CR1+ CD163+ macrophages in lymph nodes mucosal inflammation and skewing of CD4+ T cells toward Th17 cells in the rectal mucosa and lungs. Th17 cells are preferentially infected by HIV/SIV and negatively regulate NKp44+ cells. It is possible that vaccine-generated target cells for virus infection may have decreased the efficacy of the Ad26 prime regimen as was observed in other vaccine studies in macaques and humans. 3. A simplified vaccine regimen based on DNA/ALVAC-SIV / ALVAC-SIV + gp120 / alum affords 69% vaccine efficacy. With the intent of confirming the importance of monocyte-mediated innate immunity and investigating whether the DNA/ALVAC/gp120/alum approach was also effective in female macaques we designed a study in young and old females. We tested a simplified version of the DNA prime ALVAC/gp120/alum vaccine approach using two intramuscular DNA primes (weeks 0 and 4) one ALVAC-SIV boost (week 8) and a single final boost with the combination ALVAC-SIV and gp120 in alum at week 13. Challenge exposure was started at week 17 and continued for 11 weeks. We found that this vaccine had 69% VE in young female macaques (average age 2.7 years) but failed to protect old female macaques (average age 7.5 years). Protection in young females correlated with the frequency of CD14+ classical monocytes confirming the results of the previous study in young males. In old vaccinated females however we observed a correlation with the plasma level of IL-6 and IL-8 and increased virus acquisition. These data further support a role for monocytes in protection of both female and male macaques and uncovered an age-dependent factor. No difference in SIVmac251 acquisition was observed in young or old naive controls (data not shown). Current Research and Future Plans 1. Define the epigenetic signatures of CD14+ monocytes neutrophils and Th2 CCR5negative T cells and study the miRNA signatures in extracellular vesicles (EV) that track with protective immunity. 2. Define the specificity and mechanistic intersection between protective vaccine-induced V2-targeted humoral responses and innate immunity 3. Development of the next generation of ALVAC based HIV vaccine candidate leveraging innate immunity to elicit durable protective immune profiles 4. Investigate whether monoclonal antibodies to V2 that inhibit a4B7 integrin binding protect against SIVmac251 acquisition alone or in combination with innate monocyte memory immunity 5. Durability 6. Investigate the basis for the age bias vaccine efficacy and test adjuvants that may overcome it such as IGF-1 and an alum-based liposome ALFA adjuvant with respect to innate immunit *TRUNCATED*" 4253554 +Biotechnology; Cancer; Cancer Genomics; Congenital Structural Anomalies; Genetics; Human Genome; Pediatric; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Adult;Apoptotic;Binding Proteins;Biochemical Genetics;Biotin;Cell Adhesion;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Chick;Complex;Data;Development;Developmental Biology;Digit structure;Elements;Ensure;Equilibrium;Erinaceidae;Event;Feedback;Fibroblast Growth Factor;Fingers;Foundations;GLI gene;GLI3 gene;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Diseases;Genetic Transcription;Genetic study;Genomics;Goals;Growth;HOX protein;Homeobox Genes;Homeostasis;Human;Intercept;Internet;Joints;Label;Lead;Learning;Length;Light;Limb Bud;Limb Development;Limb structure;Link;Malignant Neoplasms;Mammals;Mass Spectrum Analysis;Mission;Modeling;Modification;Molecular;Molecular Genetics;Morphogenesis;Morphology;Mus;Mutant Strains Mice;Mutate;Neoplasm Metastasis;Neoplasms;Organ;Organogenesis;Pathogenesis;Pathologic;Pathology;Pathway interactions;Pattern;Phalanx;Physical condensation;Physiological Processes;Process;Proteins;Proteomics;Regulation;Research;Role;SHH gene;Secondary to;Shapes;Signal Pathway;Signal Transduction;Skeleton;Skin;Sonic Hedgehog Pathway;Structure;Study models;System;Systems Biology;Thumb structure;Tissues;To specify;Tumor Biology;Vertebrates;Work;beta catenin;cell behavior;cell motility;cellular targeting;chromatin immunoprecipitation;design;genetic approach;genome-wide;insight;integrated circuit;morphogens;mutant;neoplastic cell;osteoprogenitor cell;progenitor;programs;protein protein interaction;regeneration potential;response;self-renewal;single-cell RNA sequencing;smoothened signaling pathway;stem cells;three dimensional structure;transcription factor;transcriptome;transcriptome sequencing;tumorigenesis Genome-wide target analysis of Shh-activated transcription network in limb bud n/a NCI 10702481 1ZIABC011120-15 1 ZIA BC 11120 15 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 362659 NCI Our long term goal is to unravel the steps linking early patterns of gene regulation and expression with the ultimate realization of structure to serve as a paradigm for how signaling networks orchestrate the formation of a complex tissue. To accomplish this we are using combined genetic genomic and proteomic approaches to study transcription factors and regulatory cascades operating during limb development with the ultimate aim of elucidating the regulatory hierarchy between early induction of antero-posterior pattern (thumb to pinky) and the final morphogenesis of distinct digits. Learning how this 3-dimensional structure forms will be generally relevant for understanding how organogenesis is achieved and insights on how growth and morphogenesis are orchestrated will advance our understanding of how to treat genetic diseases and cancers that arise when such regulatory components are either mutated or expressed abnormally. 1) Early events downstream of Shh: Our analyses of temporal requirements for Shh signals in mutant mouse limb buds suggests that Shh acts at early stages to specify digits through an indirect signal relay rather than acting as a classical morphogen and more likely acts to divide the limb field into discrete domains with differing potential to respond to secondary downstream signals than to specify 'final' distinct digit identities. To determine the initial differences established during early signaling we will perform single cell transcriptome analysis from normal limb buds at and shortly after Shh activation to identify expression signatures and characterize immediate-early response zones. This will provide a foundation for subsequent studies using mouse mutants in which early Shh activity is altered. Furthermore our genetic studies indicate that there are 2 classes of Shh responsive target genes with very different regulatory features: those that respond to a transient signal and become stably expressed and those that require continuous signaling to maintain their expression. From our analysis the former class would include targets critical for organizing a basic pattern of limb elements that can form and the latter would include regulators of growth and survival necessary for the later expansion and morphogenesis of these elements. We are comparing the transcriptomes of control Shh mutant and rescued Shh mutant limb buds (enforced cell survival substituting for late function) to begin to characterize the genes in these two distinct target classes and determine the basis of their differential regulation. Understanding the proliferative and anti-apoptotic roles of Shh in the context of these differentially regulated target classes will provide a reference for deciphering and intercepting Shh roles in cancer as well as normal development. 2) Feedback circuits between Shh and Fgf signaling: Reciprocal positive and negative feedback loops between the mesodermal Shh-expressing and ectodermal Fibroblast growth factor (Fgf)-expressing signaling centers in the limb bud act to both maintain and restrict each other's activity in regulating digit pattern and outgrowth and eventually to terminate activity when limb organogenesis is complete. We are using genetic strategies to manipulate Shh and Fgf levels at different limb bud stages to begin to unravel the positive and negative regulatory inputs controlling their expression. These results will be incorporated into the analysis of the regulatory networks operating at different stages of limb morphogenesis to arrive at a more complete model of how these circuits are integrated. 3) Gli3-Hox interactions and regulation of morphogenesis: Gli3-Hox protein-protein interactions govern multiple processes in limb morphogenesis including the rate of proliferation and timing of cell adhesion during formation of progenitor skeletal condensations and the control of distinct final digit morphologies by late signals from interdigital tissues (webbing) adjacent to each of the digit primordia. We previously identified a highly conserved domain in Gli3 that interacts with Hox factors and also several other key developmental regulators (Smad1 beta-catenin). We will use mass spectrometry (with BioID-biotin tag proximity labeling to capture and enrich interaction partners) to elucidate the range of partners that can modulate Gli3 activity in the limb and may also compete Hox protein binding which will be validated using other biochemical and genetic strategies. In parallel to gain insight into the mechanisms by which Gli3 and Hoxd proteins act antagonistically we are comparing the normal limb transcriptome with 5'Hoxd Gli3 and compound mutants to identify expression changes in potential gene targets. Our results will be compared with known direct transcriptional targets of Hoxd13 and of Gli3 (from available ChIPseq data) and supplemented with ChIPseq in our lab for later limb stages if needed. Identifying late-stage Hoxd and Gli3 targets will provide insight into co-regulated genes and Gli3-Hoxd roles as well as illuminating late effectors of Hoxd genes in limb morphogenesis. The transcriptional network regulated by Hoxd and Gli3 in the limb will also be analyzed in relation to Shh-pathway targets that form two distinct classes requiring either transient or sustained signaling for their stable activation. Finally single cell expression profiling will be used to characterize the digit progenitor regions (digit tips) that are instructed to form phalangeal segments and joints by the interdigit signaling network that is controlled by Gli3-Hox balance. This region behaves as a stem cell pool for the digit skeleton and has some limited regenerative potential even in mammals. Using this combination of approaches we hope to uncover the regulatory cascade leading to formation of defined digit morphologies with distinct numbers of segments and joints. Gli3 and Hox genes are also aberrantly co-expressed in some cancers and may contribute to their pathogenesis and these studies will also shed light on their possible roles in these contexts. 4) Insights on regulatory network from adaptive limb modifications: The basic regulatory network instructing formation of the limb skeleton is largely conserved throughout vertebrates. Uncovering regulatory changes that underlie evolutionary adaptations can illuminate critical network parameters and basis for robustness. Previous work in chick and in mouse from our lab have shown that digit morphology (identity) is regulated at late stages by interdigit signals. Our genetic evidence indicates that 5'Hoxd and Gli3 are part of an interdigit signaling center that regulates final digit identity. Elucidating signaling pathway differences between different interdigits will provide new insights on how digit identity is regulated at late stages and potential mechanisms by which Hoxd and Gli3 genes act. 362659 +Cancer; Congenital Structural Anomalies; Genetics; Pediatric Adult;Ambystoma;Amphibia;Anterior;Appearance;Cartilage;Cell Adhesion;Cell Aggregation;Cell Death;Cell physiology;Cessation of life;Chromatin Remodeling Factor;Complex;Congenital Abnormality;Development;Developmental Biology;Digit structure;Disease;Distal;Elements;Ensure;Equilibrium;Erinaceidae;Evolution;Excision;Failure;Feedback;Fibroblast Growth Factor;Finger joint structure;Fingers;GLI3 gene;Gene Dosage;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomics;Goals;Growth;Homeobox;Homeostasis;Human;Intercept;Joints;Lead;Learning;Length;Limb Bud;Limb Development;Limb structure;Link;Maintenance;Malignant Neoplasms;Mammals;Mesenchyme;Mission;Morphogenesis;Morphology;Mus;Natural regeneration;Neoplasm Metastasis;Neoplasms;Organ;Output;Pathologic;Pathology;Pathway interactions;Pattern;Periodicity;Phalanx;Phalanx of hand;Phase;Physical condensation;Physiological Processes;Play;Positioning Attribute;Process;Proteins;Proteomics;Radial;Regenerative capacity;Regulation;Replication Licensing;Research;Role;Running;SHH gene;Shapes;Signal Transduction;Site;Skeleton;Skin;Structure;Study models;System;Systems Biology;Thumb structure;Tissues;Tumor Biology;Vertebrates;Work;austin;base;beta catenin;cell behavior;cell motility;cellular targeting;design;gastrointestinal epithelium;genetic approach;insight;joint formation;mutant;neoplastic;neoplastic cell;progenitor;programs;regeneration potential;selective expression;skeletal;skeletal regeneration;smoothened signaling pathway;transcription factor;tumorigenesis;ulna Hoxd and Gli3-Hoxd interaction roles in Hedgehog regulated digit morphogenesis n/a NCI 10702480 1ZIABC011119-15 1 ZIA BC 11119 15 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 543989 NCI 5'Hoxd genes play many roles during limb development and may control the effectors of morphogenesis at late stages. How Hoxd genes guide digit morphogenesis and their downstream targets remain enigmatic. Using genetic approaches in mice we find that in addition to a role in initiating Sonic hedgehog (Shh) expression 5'Hoxd genes determine the polarity of the primary limb axis early and regulate digit pattern and morphogenesis at late stages after digit condensations have already formed including joint formation and positioning; a major mechanism by which Hoxd genes regulate digit identity. We previously discovered genetic and physical interactions between 5Hoxd and Gli3 that modify Gli3 repressor (Gli3R) function (and hence Shh output) antagonizing Gli3R and potentially converting it to an activator. We find that Gli3-Hox interactions both modulate the polarity of limb axis formation and regulate the pacing of cartilage vs joint formation in digits which may have relevance for skeletal homeostasis and disease as well as skeletal birth defects. ....................................................................................................................................................................................................................................................................................................................Role Role of 5'Hoxd genes and Hoxd-Gli3 interaction in determining polarity of primary limb axis formation: In most vertebrates the primary limb axis runs through the posterior limb with the ulna/digit4 (d4) condensing first. In urodele amphibians such as axolotl which retain the ability to regenerate limbs as adults the anterior limb axis is dominant (radius/d2 appear first). Based on altered expression patterns it has been proposed that the axis shift in Urodeles results from a failure to expand 5'Hoxd gene expression in the late distal limb. We have analyzed limb axis formation in the 5'Hoxd mutant (Hoxd11-13 deleted) and found that the anterior axis forms first as in urodeles. Furthermore we find that in compound 5'Hoxd;Gli3 mutants posterior axial dominance is restored. The 5'Hoxd homeobox transcription factors play roles in replication licensing and cell adhesion. Gli3R expressed anteriorly also regulates proliferation and condensation and antagonizes 5'Hoxd function. We are analyzing how changes in the relative timing and rate of proliferation and of cell aggregation/condensation in different zones of the limb bud are altered in these mutants and if they correlate with anterior vs posterior axial dominance. We propose that the balance between antagonistic 5'Hoxd-Gli3 functions governs the polarity of primary limb axis formation and are investigating the potential relation between altered axis polarity and regenerative capacity. ....................................................................................................................................................................................................................................................................................................................Role of Hoxd genes and Hoxd-Gli3 interaction in cartilage differentiation and joint formation to determine distinct digit identities: Digit identity remains plastic even after the formation of the digit primordial chondrogenic condensations and is regulated by interdigit zones which are also late sites of 5'Hoxd and Gli3 expression. We found that genetic removal of several Hoxd genes (d11-d13) results in abnormal joint formation both loss of digit joints and/or abnormal joint position as well as short biphalangeal digits. Collaborating with Marian Ros (Univ. Cantabria) we are also examining the role of Hoxa13 in digit formation. Hoxa13 acts upstream of and induces the late phase of Hoxd13 expression and plays a distinct role in regulating the formation of a normal thumb acting hierarchically upstream of and together with Hoxd13. The canonical Wnt pathway plays an essential role in joint formation and we find that activated beta-catenin restores normal joint formation in the 5'Hoxd mutant digits. But surprisingly selective activation of stabilized beta-catenin in the interdigital tissues is required for rescue indicating that at least some aspects of beta-catenin and 5'Hoxd function in joint formation occur indirectly via interdigit signaling. Gli3 (the transcriptional effector of Shh and Hoxd protein interactor) also has striking effects on cartilage differentiation and joint formation in digits. During joint formation in digit precursors Gli3 mutants form abnormal segments with excessive joint formation extending into the cartilage elements. Genetically the balance between total 5'Hoxd and Gli3 gene dosage regulates the periodic formation of normal joints and the normal 3 bony segments typical of mammalian digits. Our genetic evidence indicates that the Hoxd-Gli3 balance acts indirectly from interdigital mesenchyme to modulate Bmp activity and thereby regulate the periodic appearance of digit elements (phalanges) and joints from a digit tip progenitor pool. We are extending our analysis to determine: 1) targets regulated by Gli3-Hoxd interaction and 2) other signaling inputs that regulate the digit tip progenitor pool to determine phalanx number and size including signals induced by beta-catenin activation in interdigits. Collaborating with Steve Vokes (UT-Austin) we will examine the role of the chromatin modifier Prmt5 which is selectively expressed in the digit tip progenitors in maintaining this progenitor pool. Even in mammals distal digit tips retain a limited capacity for regeneration and understanding the regulation of this distal digit progenitor pool and it's maintenance will provide new insights relevant to skeletal regeneration potential. 543989 +Cancer; Congenital Structural Anomalies; Genetics; Pediatric; Rare Diseases Adult;Affect;Anterior;Apoptosis;Apoptotic;Basal Cell Nevus Syndrome;Biological Assay;Brain;Cell Death;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cessation of life;Child;Communities;Complement component C5;Complex;Development;Developmental Biology;Digit structure;ERG gene;Elements;Embryo;Ensure;Enterobacteria phage P1 Cre recombinase;Family member;Feedback;Fibroblast Growth Factor;Fingers;Gene Deletion;Gene Expression Profile;Gene Expression Regulation;Genes;Genetic;Genetic Diseases;Genomics;Goals;Growth;Holoprosencephaly;Hour;Human;Infant;Intercept;Joints;Lead;Learning;Length;Limb Bud;Limb Development;Limb structure;Link;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mesoderm;Mission;Mitogens;Modeling;Morbidity - disease rate;Morphogenesis;Mus;Mutant Strains Mice;Mutate;Mutation;Neoplasm Metastasis;Neoplasms;Neural Crest;Normal tissue morphology;Organ;Pancreas;Pathologic;Pathology;Pathway interactions;Pattern;Phalanx;Phase;Physiological Processes;Play;Process;Prostate;Proteomics;Regulation;Research;Role;SHH gene;Shapes;Signal Pathway;Signal Transduction;Skeleton;Skin;Sonic Hedgehog Pathway;Specific qualifier value;Stomach;Structure;Study models;System;Systems Biology;Tamoxifen;Testing;Thumb structure;Time;Tissues;To specify;Tumor Biology;body system;cancer type;cell behavior;cell motility;cellular targeting;design;developmental genetics;morphogens;mortality;mutant;neoplastic cell;novel;progenitor;programs;response;selective expression;smoothened signaling pathway;stem cell population;tissue regeneration;tool;transcription factor;transcriptome;tumorigenesis Role of Shh in developmental patterning and growth of digit skeleton n/a NCI 10702479 1ZIABC011118-15 1 ZIA BC 11118 15 9692609 "MACKEM, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 543989 NCI Sonic hedgehog (Shh) acts as a mitogen and cell survival factor in many adult processes during normal tissue renewal and in many types of cancer but acts as a morphogen in several developmental contexts. How the mitogenic role of Shh is integrated with the morphogenetic role in developmental contexts is still poorly understood. In the limb Shh regulates both digit number and identity of different digits (A-to-Pthumb to pinky). Shh is thought to act as a morphogen forming a gradient along the limb AP axis with higher concentrations specifying more posterior digit types. We have determined the time-requirements for Shh function in limb (using a tamoxifen-regulated Cre to remove Shh at different times in mice). To perform this analysis we generated and characterized a novel conditional Cre recombinase line selectively expressed in early limb mesoderm neural crest gut and tailbud. This line provides an excellent tool available to the scientific community to illuminate different temporal roles of key developmental regulators in several important developmental models using mouse mutants as well as for genetic lineage tracing studies in mice. Our results deleting Shh function at different time points are most consistent with a model in which Shh activity is required only very transiently (several hours) to specify the complete complement of 5 different digit types but is required for a prolonged time (about 2 days) to maintain cell survival and proliferation enabling 5 normal digits to form. To further test this model for Shh function we have assessed whether restoring cell survival can rescue normal digit formation in mutant embryos after a transient period of Shh activity that is terminated by Shh gene deletion. To rescue cell survival the compound mutant for the pro-apoptotic Bcl2 family members Bax/Bak (which play roles in normal interdigital apoptosis) has been introduced to inactivate the intrinsic death pathway. Our results indicate that both normal digit number and pattern (morphogenesis) can be rescued by simply restoring cell survival and proliferation in Shh mutant embryos. In addition genetic lineage tracing of cells in the limb that have responded to Shh signals at different time points indicates that Shh only signals directly to the very posterior part of the limb bud at the time when all 5 digit progenitors have been specified. This result indicates that Shh acts indirectly in the early limb bud via a system of relay signals to specify digits. We developed a genetic assay to test for relay signaling by artificially enforcing Shh-response in the posterior limb bud in embryos lacking all Shh function (Shh KO). This partly rescues anterior digit formation and strongly suggests the presence of relay signals acting downstream of Shh. Our results are incompatible with Shh acting as a classic morphogen in the limb and suggest that Shh acts as a trigger to activate a relay mechanism. Furthermore our results indicate that there are 2 classes of Shh responsive target genes those that respond to a transient signal and become stably expressed and those that require continuous signaling to maintain expression. We are comparing the transcriptomes of Shh mutant and rescued limb buds to characterize the types of genes in these two differentially regulated target classes. In parallel single cell transcriptome analysis from normal limb buds will be performed to identify expression signatures in the transient Shh signaling phase and characterize immediate-early response genes. Understanding the proliferative and anti-apoptotic actions of Shh in the context of these differentially regulated target classes will provide a reference for deciphering and intercepting Shh roles in cancer. 543989 +Biotechnology; Cancer; Clinical Research; Emerging Infectious Diseases; Infectious Diseases; Urologic Diseases Adenoviruses;Affect;Animals;Arachnida;BK Virus;Basic Science;Bioinformatics;Collaborations;DNA Viruses;Data Set;Deposition;Distant;Division of Cancer Epidemiology and Genetics;Exanthema;Family;Goals;Human;Human Biology;Immunity;Individual;Investigation;JC Virus;Light;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mission;Molecular Biology;Names;Papillomavirus;Parvovirus;Peer Review;Perception;Play;Polyomavirus;Process;Proteins;Pruritus;Recombinants;Recording of previous events;Retroviridae;Risk;Role;Testing;United States National Institutes of Health;Virion;Virus;Work;clinical center;deep sequencing;immunosuppressed;neutralizing monoclonal antibodies;organ transplant recipient;precursor cell;prevent;public database;receptor;tumor;vaccine development;vaccine-induced antibodies Molecular biology of human polyomaviruses n/a NCI 10702468 1ZIABC011090-15 1 ZIA BC 11090 15 9692553 "BUCK, CHRISTOPHER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 661981 NCI "During FY22 we developed bioinformatics approaches to discovering divergent new families of viruses in our deep sequencing datasets. The work led to the deposit of several thousand highly diverse previously virus species into public databases. In a parallel set of studies we discovered several previously unrecognized families of animal viruses. We have suggested the names adomavirus adintovirus and ahomavirus. The names denote the distant relationships of the new families to known families including adenoviruses parvoviruses and retroviruses. These lines of investigation are presently in press or under peer review. A related study involving the molecular biology of the virion proteins of a new group of arachnid-associated polyomaviruses we discovered promises to draw further evolutionary ties between multiple families of non-enveloped animal DNA viruses. We have been collaborating with NIH Clinical Center colleagues to investigate cases of human polyomavirus 7 (HPyV7) associated pruritic rashes. The project led to the discovery of a previously unknown HPyV7 protein that we dub ""Agnoprotein."" We are testing the hypothesis that Agnoprotein is involved in assembly of the HPyV7 and we are exploring the possibility that the protein directly triggers receptors involved in itch perception. A related project seeks to develop recombinant HPyV7-neutralizing monoclonal antibodies that could be used for treatment of HPyV7 pruritis. In collaboration with colleagues at NCI DCEG we have performed deep sequencing of bladder cancers affecting organ transplant recipients who are known to be at increased risk of developing bladder cancer. The work shows that bladder cancers from immunosuppressed individuals often harbor polyomaviruses or papillomaviruses. The results suggest a possible causal role for these viruses and raise the possibility that the vaccine we are developing against BK and JC polyomaviruses might prevent bladder cancer." 661981 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Immunotherapy; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Biological Assay;Biopsy;CCR;Clinical Trials;Collaborations;Combination immunotherapy;DNA Damage;DNA Double Strand Break;Development;Developmental Therapeutics Program;Division of Cancer Treatment and Diagnosis;Enzyme-Linked Immunosorbent Assay;Gamma-H2AX;Goals;Immunofluorescence Immunologic;MEKs;Molecular;New Agents;Pediatric Oncology;Pharmacodynamics;Pharmacology;Phase;Phase 0/1 Clinical Trial;Poly(ADP-ribose) Polymerases;Protein Isoforms;Proto-Oncogene Proteins c-akt;Series;System;Therapeutic Agents;Tumor Tissue;Type I DNA Topoisomerases;United States National Institutes of Health;clinical center;clinical development;detector;first-in-human;inhibitor;insight;novel;novel anticancer drug;novel therapeutics;rapid diagnosis;rare cancer Phase 0-1 Clinical Trials n/a NCI 10702466 1ZIABC011078-15 1 ZIA BC 11078 15 9692531 "DOROSHOW, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 621311 NCI The collaboration between the DTB and DCTD has been responsible for the development of several new pharmacodynamic assays including an ultrasensitive immunofluorescence assay for gamma H2AX (DNA double strand break detector) in tumor tissue biopsies and ELISAs for topoisomerase I and poly ADP-ribose polymerase (PARP) as well as assays for other DNA damage markers (pNBS1) all of the isoforms of MEK ERK and AKT DNMTs as well as a series of immuno-PD markers. These assays have been essential for first in human clinical trials of novel non-camptothecin topoismerase I inhibitors DNMT1 inibitors and immunotherapy combinations that have been activated in the NIH Clinical Center. In addition collaborations with the Pediatric Oncology Branch have facilitated the development of new agents used for rare tumors. Additional collaborations have developed around our use of the NCI 60 for systems pharmacology. 621311 +Autoimmune Disease; Cancer; Childhood Leukemia; Emerging Infectious Diseases; HIV/AIDS; Hematology; Hodgkin's Disease; Infectious Diseases; Lymphatic Research; Lymphoma; Pediatric; Pediatric Cancer; Rare Diseases Adopted;Adult;Area;Autoimmune Diseases;B-Cell Lymphomas;B-Lymphocytes;Basic Science;CCND1 gene;Cell Differentiation process;Cell physiology;Childhood;Childhood Leukemia;Classification;Clinical;Clinical Protocols;Clinical Research;Communities;Consultations;Development;Diagnosis;Diagnostic;Diagnostic Services;Disease;Education;Extranodal;Genes;Goals;Growth;Hematologic Neoplasms;Hematopathology;Hodgkin Disease;Human Herpesvirus 4;Human Herpesvirus 8;Hyperplasia;Immunohistochemistry;Immunologic Deficiency Syndromes;In Situ Hybridization;Institutes;Institution;International;Knowledge;Laboratories;Lesion;Lymphoblastic Leukemia;Lymphocyte Function;Lymphoid;Lymphoid Cell;Lymphoma;Lymphomatoid Granulomatosis;Lymphoproliferative Disorders;Malignant lymphoid neoplasm;Mission;Molecular;Multicentric Angiofollicular Lymphoid Hyperplasia;National Heart Lung and Blood Institute;National Human Genome Research Institute;National Institute of Allergy and Infectious Disease;Neoplasms;Nodal;Non-Hodgkin's Lymphoma;Pathogenesis;Pathologist;Pathology;Patients;Physicians;Physiology;Publications;Rare Diseases;Reproducibility;Research;Second Opinions;Services;Standardization;T-Cell Lymphoma;T-Cell and NK-Cell Neoplasm;Training;Uncertainty;United States National Institutes of Health;Work;age group;autoimmune lymphoproliferative syndrome;base;clinical diagnosis;clinical practice;disease classification;education research;histiocyte;in vivo;leukemia/lymphoma;lymphoid neoplasm;molecular diagnostics;neoplastic;novel;post-transplant;promoter;symposium;tool;translational study Hematopathology Diagnosis n/a NCI 10702465 1ZIABC011070-15 1 ZIA BC 11070 15 9692515 "JAFFE, ELAINE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1051929 NCI "Dr. Pittaluga and I aid in the diagnosis and classification of reactive and neoplastic lymphoproliferative disorders immunodeficiency states and diverse hematological malignancies. We provide consultative and collaborative services to physicians in the NCI as well as to physicians studying patients with hematolymphoid disorders in other institutes in particular NIAID NHLBI NHGRI and NIAMSD. We regularly present at conferences sponsored by clinical branches in the NCI and other Institutes (NIAID NHLBI and NHGRI.) We receive more than 2000 cases in consultation each year. We try to restrict consultations to difficult or challenging cases and do not accept cases for ""routine second opinions"". A significant proportion (approximately 20%) of the cases are submitted by other academic institutions based on diagnostic uncertainty or because of differences of opinion among several institutions. We are often the final arbiter on challenging diagnostic problems. Additionally we have made novel observations based on our clinical practice and a number of publications have emanated from case material originally reviewed in consultation. Our clinical consultation practice also synergizes with other NIH clinical groups enhancing referral to NIH clinical protocols. Our work has led to improvement in the diagnosis and classification of several rare diseases including multicentric Castleman disease KSHV- and EBV-associated proliferations and aggressive B-cell lymphomas including double-hit and triple-hit lymphomas with CCND1 translocation. We have helped to define the differences between lymphomas occurring in adults from those in the pediatric age group. We have studied the difference between nodal and extranodal lymphomas. This work has advanced our knowledge regarding the classification of lymphoid and histiocytic neoplasms." 1051929 +Biotechnology; Cancer; Immunization; Immunotherapy; Prevention; Vaccine Related; Women's Health Antibodies;Antibody Response;Antigens;Area;Binding;Biological Assay;Biological Markers;Cancer Vaccines;Carbohydrates;Collaborations;Detection;Disease;Forssman Antigen;GVAX Cancer Vaccine;Goals;Human;Immune response;Immunoglobulin M;Malignant Neoplasms;Measures;Monitor;Pancreas;Patients;Play;Polysaccharides;Prognosis;Prostate Cancer Vaccine;Proteins;Research;Role;SARS-CoV-2 infection;Serum;Technology;Trisaccharides;Vaccination;Vaccines;Whole Cell Vaccine;blood group;cancer biomarkers;cancer diagnosis;cancer therapy;improved;response;treatment response Serum Antibody Profiling with a Carbohydrate Microarray n/a NCI 10702462 1ZIABC011055-15 1 ZIA BC 11055 15 15201322 "GILDERSLEEVE, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 157851 NCI Biomarkers play a critical role in cancer diagnosis and treatment. Serum antibodies represent an important class of biomarkers with many advantageous features such as good stability accessibility in biofluids and easy detection. There has been extensive research on identifying changes in antibody levels to protein antigens; however analysis of antibodies that binding carbohydrate antigens have been largely underutilized. Our carbohydrate microarray is well-suited to monitor the repertoire of anti-glycan antibodies in human serum and to study changes in their levels in response to disease or treatment of disease. The high-throughput approach can be used to identify new single biomarkers or to identify combinations of changes or profiles that are useful as biomarkers. Over the last few years we have developed and validated a carbohydrate microarray assay for measuring antibody levels in human serum. We are now applying this technology in a variety of areas. In collaboration with Dr. Schlom and colleagues we have been using the array to evaluate immune responses to the PSA-TRICOM prostate cancer vaccine (PROSTVAC-VF). We have found the pre-vaccination IgM antibody levels to blood group A trisaccharide correlate with survival on PROSTVAC-VF. In addition we have found that antibody response to the Forssman antigen correlate with overall survival. Both correlations are consistent in two independent patient groups encompassing over 100 patients. These are promising new biomarkers for determining which patients should receive PROSTVAC-VF and which patients on PROSTVAC-VF are having a favorable immune response. Finally in collaboration with Elizabeth Jaffee we have profiled immune responses induced by GVAX Pancreas whole cell vaccine. We also began studying antibody responses to carbohydrate antigens induced by SARS-CoV-2 infection. 157851 +Cancer; Genetics; Ovarian Cancer; Rare Diseases; Women's Health Adhesions;Affect;Aggressive behavior;Apoptosis;Biological;Biological Markers;Biology;Bypass;CASP8 gene;Cancer cell line;Cell Nucleus;Cell physiology;Cells;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinic;Clinical;Clinical Trials;Complex;Databases;Dependence;Diagnosis;Disease;Drug Screening;Family;Gene Expression;Gene Expression Profile;Genes;Goals;Growth;Heterogeneity;Histone Deacetylase Inhibitor;IKKepsilon;Immunofluorescence Immunologic;In Vitro;Laboratories;Libraries;Lymphoid;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Mammary Neoplasms;Mediating;Molecular Structure;Multiple Myeloma;Mutation;NF-kappa B;Neoplasm Metastasis;Nuclear;Outcome;Output;Pathogenesis;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacology;Phase II Clinical Trials;Phenotype;Phosphorylation;Phosphotransferases;Population;Process;Property;Proteins;Refractory;Relapse;Research;Resistance;Role;Signal Pathway;Signal Transduction;Solid Neoplasm;Specificity;TNFRSF5 gene;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Woman;Work;base;cancer cell;cancer survival;chemotherapy;cytokine;design;development of lymphoid malignancy;effective therapy;extracellular;genetic manipulation;genetic signature;improved;inhibitor;insight;malignant breast neoplasm;mimetics;mouse model;multicatalytic endopeptidase complex;neoplastic cell;novel;ovarian neoplasm;overexpression;p65;preclinical development;prevent;prognostic;prostate cancer cell;response;small hairpin RNA;synergism;taxane;therapeutic target;transcription factor;translational approach;tumor Nuclear Factor-kappaB in Ovarian Cancer n/a NCI 10702461 1ZIABC011054-15 1 ZIA BC 11054 15 9692487 "ANNUNZIATA, CHRISTINA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1009250 NCI The NF-kB pathway promotes survival of cancer cells. My research in ovarian cancer began with characterizing the activation state and biological relevance of NF-kB in this disease. The NF-kB family of transcription factors is ubiquitously expressed. NF-kB signaling has been implicated in ovarian cancer but the significance and mechanism of NF-kB signaling in ovarian cancer is unknown. There is precedent to propose that NF-kB is a critical signaling mechanism in cancer. I initially hypothesized that the NF-kB pathway is over-activated in ovarian cancers with more aggressive behavior. The NF-kB pathway was implicated in ovarian cancer proliferation and cytokine secretion in vitro and contributed to chemoresistance of ovarian cancer cell lines. I therefore sought to determine the expression patterns and prognostic associations of NF-kB pathway proteins in primary ovarian cancer tissues. I demonstrated that overexpression of the NF-kB subunit p50 at diagnosis conveyed poor outcome in these patients. The biological relevance of NF-kB in ovarian cancer was established in my laboratory. Having demonstrated the coordinate presence of NF-kB machinery in ovarian cancers I sought to modulate its activity. Inhibitors of NF-kB (IkBs) are tagged for degradation through the proteasome upon specific inducible phosphorylation by IkB kinases (IKKs). Therefore targeted inhibition of IKKs could isolate NF-kB as a mechanism for ovarian cancer pathogenesis. A subset of ovarian cancer cell lines was affected by inhibition of IKKb in properties of growth adhesion invasion and cytokine secretion. I developed a gene expression signature of IKKb signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKKb. This signature gave insight into the results of NF-kB in ovarian cancer based on known functions of the ovarian cancer-specific target genes and allowed me to probe established ovarian cancer databases in order to estimate the relative impact of NF-kB signaling on the survival of women with ovarian cancer. Higher NF-kB activity conveyed a worse outcome suggesting that modulation of IKKb might benefit patients whose tumors showed elevated target gene expression. A key discovery from this work was the tissue specificity of NF-kB signaling. The 9-gene signature experimentally defined in ovarian cancer was completely different from the 11 genes I previously identified in multiple myeloma. The overall goal of this project is to dissect the molecular structure of NF-kB signaling in ovarian cancer with the intent to develop biomarkers of dependence on NF-kB and novel points of therapeutic intervention. We completed two shRNA library screens one in combination with an inhibitor of IKKbeta and another in combination with shRNA against IKKepsilon. These studies identified novel interactions between the NF-kB pathway in ovarian cancer. In combination with IKKbeta we found caspase 8 to be cooperative in protecting the cells from necroptosis. This work continues with designing a translational strategy for improving clinical outcome of women with caspase 8-deficient cancers. We plan to target the necroptosis pathway therapeutically to bypass the defective apoptosis that mediates resistance to standard chemotherapy regimens. In a related avenue we continue to study NF-kB signaling in ovarian cancer tumor-initiating cells. We observed by immunofluorescence that classical NF-kB appeared to be active in only a sub-population of the cultures at any given time based on the presence of NF-kB p65 in the nucleus. Elevated classical NF-kB signaling has been observed in tumor-initiating cells (TICs) of prostate breast and ovarian tumors but there are limited studies examining alternative NF-kB signaling. Both classical and alternative signaling cascades are required for maintenance and promotion of breast cancer TICs. The classical and alternative NF-kB pathways can regulate each other and integrate with other signaling pathways for fine-tuning functional outputs. Thus the diverse and complex roles of NF-kB suggest this transcription factor family regulates cellular functions in a context dependent manner and may be a key factor in maintaining heterogeneity. We are currently testing the hypothesis that classical and alternative NF-kB pathways support distinct subpopulations of ovarian cancer tumor-initiating spheroids that collaborate to populate secondary tumors following chemotherapy. Our recent results suggest that NF-kB supports the TIC phenotype and functional outputs of NF-kB are responsible for proliferation chemoresistance differentiation multipotency. A better understanding of the biology underlying NF-kB signaling in TIC and non-TIC populations of tumor cells will guide the design of more effective therapies to overcome chemoresistance prevent relapse and improve survival of women with ovarian cancer. From a therapeutic standpoint we previously completed a phase 2 clinical trial using the SMAC mimetic birinapant - that can target NF-kB signaling via inhibition of IAP proteins - in women with relapsed and refractory ovarian cancer. There were no clinical responses. Therefore we completed a matrix drug screen testing 2000 compounds in combination with birinapant in order to identify synergistic combinations to move to the clinic. We identified drug classes that met the criteria for synergy and are in the process of testing these in mouse models. Ongoing work is testing the combination of SMAC mimetic with either HDAC inhibitor or Taxane chemotherapy in vitro and in mouse models. Three clinical trials are currently under development from this preclinical work. 1009250 +Biotechnology; Cancer; Genetics; Prostate Cancer; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Urologic Diseases Adenocarcinoma;Androgen Receptor;Androgens;Antibodies;Bacterial Artificial Chromosomes;Basal Cell;Binding Sites;Biological Assay;Biological Models;Bioluminescence;Brain;Bypass;Castration;Cell Line;Cells;Chromatin;Chromosomal Rearrangement;Chromosomal translocation;Clinical;DNA Damage;Data;Dependence;Development;Doxycycline;Epithelial;Epithelial Cells;Exons;Fusion Protein Expression;Gene Mutation;Generations;Genetic;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth;Histologic;Hormonal;Human;Human Cell Line;In Vitro;Investigation;KRAS oncogenesis;LNCaP;Length;Lesion;Malignant - descriptor;Malignant neoplasm of prostate;Measures;Metastatic Neoplasm to the Bone;Modeling;Molecular Analysis;Monitor;Monoclonal Antibodies;Morphology;Mus;Mutation;Neoplasm Metastasis;Nucleic Acid Regulatory Sequences;Nude Mice;Null Lymphocytes;Oncogenes;Oncogenic;Organoids;PTEN gene;Pathway interactions;Pattern;Preparation;Process;Property;Prostate;Prostate Adenocarcinoma;Prostatic Neoplasms;Protein Analysis;Proteins;RNA;RNA Splicing;Recombinants;Regulation;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Serial Passage;Severities;Signal Pathway;Site;Stains;TACSTD1 gene;TMPRSS2 gene;TP53 gene;Techniques;Technology;Tetanus Helper Peptide;Time;Tissues;Transcript;Transfection;Transgenic Animals;Transgenic Mice;Transgenic Organisms;Translations;Tumor Suppression;Western Blotting;advanced prostate cancer;cell type;cytokine;differential expression;genetically modified cells;in vivo;mutant;novel;preneoplastic cell;progenitor;prognostic value;promoter;receptor binding;response;self-renewal;senescence;soft tissue;synergism;transcriptome sequencing;tumor growth;tumorigenesis;tumorigenic;virtual TMPRSS2-ERG chromosomal translocations and prostate cancer n/a NCI 10702460 1ZIABC011053-15 1 ZIA BC 11053 15 9692485 "KELLY, KATHLEEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 116794 NCI The generation of the TMPRSS2:ERG recombinant bacterial artificial chromosome (BAC) using recombineering has been completed. Transgenic animals were generated in the FVB and C57/BL6 backgrounds and one line from each background A5 and H7 respectively was selected for further investigation. RT-PCR analysis of prostate-derived RNA utilizing primer pairs that span TMPRSS2 and ERG exons showed specific expression of the fusion transcripts in transgenic animals. Sequencing revealed appropriately spliced transcripts and transient transfection produced the expected-sized translation products. Transcripts with and without the 72 bp exon 11 were observed similar to endogenous transcripts described in human cell lines and clinical samples. Western blot analysis of protein lysates from prostate epithelial organoids using monoclonal antibody 2805 (Epitomics Burlingame CA) directed to the COOH-terminus of ERG revealed a protein migrating slightly slower and therefore distinct from endogenous ERG. ERG fusion protein expression was 2-4 fold greater than endogenous ERG. The regulation of the TMPRSS2-ERG fusion by androgen in primary prostate epithelial cells has not been investigated. To establish the regulatory potential of the integrated TMPRSS2-ERG BAC we analyzed the androgen receptor (AR) binding sites that previously have been identified for the TMPRSS2 promoter in LnCaP. Using ChIP analysis performed on total prostates we confirmed that AR bound to sites in the transgenic human TMPRSS2 promoter. Importantly these data suggest that appropriate chromatin organization leading to AR association was established in the BAC transgenic prostates. Regulation of the fusion transcript by androgen was analyzed in vivo and in vitro and no induction of fusion RNA or protein was observed despite induction of the AR-regulated FKBP5 RNA. In addition castration of transgenic animals confirmed partial androgen dependence for the fusion construct and endogenous mouse Tmprss2. The TMPRSS2 promoter has been shown to be androgen inducible in human cell lines derived from advanced prostate cancers and it has been commonly assumed that androgen regulation of TMPRSS2-ERG is an important feature of transformation. Our data challenge this concept and suggest that TMPRSS2 regulation be investigated in additional cellular and genetic contexts to define the full spectrum of TMPRSS2 control by androgen. To establish the pattern of ERG expression in the prostate tissue sections from wild type and transgenic fusion mice were stained with monoclonal antibodies which recognize mouse and human ERG. ERG antibody staining verified epithelial-specific increased expression of the fusion construct and demonstrated expression in the majority of luminal cells and in a fraction of basal cells. Interestingly it has been shown that the majority of prostate progenitor activity fractionates with basal cells expressing high Sca-1 and we asked whether the expression of full-length ERG in this fraction was associated with changes in progenitor activity. Sphere-forming activity was assayed in prostate cells fractionated using Lin Sca-1 and EpCam markers and virtually all of the sphere-forming units (SFU) from wt and fusion transgenics were found in the Sca-1+/EpCam+ fraction. A comparison of sphere-forming activity in dissociated whole prostates revealed on average a 2-3 fold increase in the relative number of spheres in fusion mice preparations showing the existence of an increased pool of primary prostate cells capable of self-renewal. Furthermore the ability to form spheres upon serial passage in vitro a measure of intrinsic self-renewal was 2-3 fold higher in fusion compared to wt as measured by sphere or colony formation. TMPRSS2-ERG translocations often occur in combination with decreased PTEN expression in human prostate cancer. The effect of Pten loss upon TMPRSS2-driven ERG expression has not been evaluated directly. Histologically fusion A5 mice containing a heterozygous deletion of Pten showed at 28 weeks increased total numbers and severity of mPIN lesions compared to Pten+/-. Further studies using models such as the one described here in conjunction with clinical samples will aid in defining the mechanism and prognostic value of mutations occurring in conjunction with TMPRSS2-ERG translocations. We have used a technique developed by Tan Ince to grow luminal cell lines from primary prostate samples of TMPRSS2-ERG transgenic mice some in combination with other relevant alterations. These cell lines have allowed the direct analysis of ERG-dependent properties which we have shown include invasion and clonogenic growth propagation. We have been able to show using TMPRSS2-ERG and wild type lines that mutant Ras synergizes with ERG to produce adenocarcinoma which does not occur with mutant Ras or transgenic ERG alone. We have observed that ERG expressing lines display reduced senescence in response to Ras induction. Following inducible KrasG12V expression or Pten depletion TMPRSS2-ERG suppressed oncogene-induced senescence as determined by growth morphological and select cytokine secretion criteria. TP53 was not induced following KrasG12V expression in wt or TMPRSS2-ERG cells and Tp53 null cell lines underwent vigorous senescence in response to oncogenic RAS. In addition neither the Rb pathway nor DNA damage response was substantially altered preceding KrasG12V induced senescence showing that ERG blocks senescence initiated by non-classical RB- and TP53- independent mechanisms. Confirming the relationship of senescence suppression to transformation oncogenic Kras-expressing TMPRSS2-ERG but not wt cell lines were tumorigenic and metastatic. In summary the studies described here reveal a previously unappreciated function of ERG whereby preneoplastic cells possess a survival advantage resulting from a suppression of oncogene-induced senescence following the accumulation of additional gene mutations. To investigate the mechanism(s) responsible for the synergy we established multiple luminal prostate epithelial cell lines. By orthotopically or intracardially injecting genetically engineered cell lines into nude mice and monitoring tumor growth by bioluminescence we demonstrated the synergy between TMPRSS2-ERG and one of the gene mutations in prostate tumor development and metastasis to bone brain and other soft tissues. Subsequently tet-on inducible target gene mutation cell lines were established in WT and TMPRSS-ERG cells and analyzed. Multiple assays showed that TMPRSS2-ERG suppressed an important process that is normally a barrier for cells to progress to become malignant upon a gene mutation. To investigate which signaling pathway(s) TMPRSS2-ERG targets to bypass this tumor suppression process to promote tumorigenesis and metastasis we have extensively assessed the classic pathways involved in this process. We found that the process in our model system is atypical. To distinguish the transcriptional differences between WT and TMPRSS2-ERG upon doxycycline induced expression of the target mutation at different time points we performed RNAseq on tet-on inducible cell lines. Molecular analyses suggest that ERG-dependent MYC expression modulates senescence induction to allow continued anabolic functions such as protein translation and transcription which are otherwise inhibited in senescent cells. 116794 +Cancer; Clinical Research; Genetics; Kidney Disease; Orphan Drug; Rare Diseases Affect;American;Animal Model;Animals;Area;Binding;Binding Proteins;Cancer Etiology;Cancer cell line;Cell Surface Receptors;Cells;Clear Cell;Clear cell renal cell carcinoma;Clinical;Code;Cutaneous;Cyst;Cystic kidney;Cytoplasm;Development;Disease;Evaluation;Family;Folliculin;Foundations;Frameshift Mutation;Genes;Germ-Line Mutation;Growth Factor;HGF gene;Hereditary Neoplastic Syndromes;Hereditary Papillary Renal Carcinoma;Histology;Human;Hybrids;Hyperplasia;In Vitro;Inherited;Kidney;Kidney Neoplasms;Knockout Mice;Lead;Loss of Heterozygosity;Lung;MET Gene Mutation;MET Oncogene;MET gene;Modeling;Molecular;Mus;Mutation;New Agents;Nonsense Mutation;Oncogenes;Papillary;Pathway interactions;Patients;Phenotype;Phosphorylation;Proteins;Renal Cell Carcinoma;Renal carcinoma;Risk;Role;Sampling;Sirolimus;Somatic Mutation;Specimen;Syndrome;Testing;Therapeutic;Tissues;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tyrosine Kinase Domain;VHL gene;Work;cancer type;in vitro Model;in vivo;kindred;loss of function;novel;patient subsets;receptor;targeted agent;targeted treatment;tumor Molecular Therapeutics of Kidney Cancer: MET Gene and BHD Gene n/a NCI 10702459 1ZIABC011043-15 1 ZIA BC 11043 15 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 952264 NCI Molecular Therapeutics of Kidney Cancer-MET Gene and BHD Gene: Understanding the genes that cause kidney cancer provides the opportunity to develop approaches for molecular therapeutics for this disease. We have identified 3 genes that cause cancer of the kidney: the VHL gene (clear cell renal cell carcinoma); the c-Met gene (papillary type 1 renal carcinoma); and the BHD gene (chromophobe renal carcinoma). Targeting the MET Gene - Type 1 Papillary Kidney Cancer: We have found activating mutations of the MET gene in the germline of patients with Hereditary Papillary Renal Cell Carcinoma (HPRC) as well as in a subset of tumors from patients with sporadic type 1 papillary kidney cnacer Studies are underway to target the c-Met type 1 papillary kidney cancer gene pathway in papillary kidney cancer. The Met gene codes for a cell surface receptor for a systemically circulating growth factor hepatocyte growth factor (HGF). The germline mutations identified in the HPRC kindreds and somatic mutations of the c-Met oncogene in sporadic type 1 papillary renal carcinoma are located in the tyrosine kinase domain of the MET gene and are predicted to activate this receptor. In-vitro and in-vivo studies are underway to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of type 1 papillary renal carcinoma. Targeting the BHD Gene - Chromophobe Kidney Cancer: The BHD gene is the gene for the inherited form of chromophobe kidney cancer associated with Birt-Hogg-Dub syndrome. When we found the BHD gene it was a novel gene with no known function. Studies are currently underway to determine what type cancer gene the BHD gene how it functions normally and how damage to this gene leads to chromophobe renal carcinoma. We have identified mutations of the BHD gene in 94% of the BHD families tested. In order to determine what type of gene the BHD gene is we searched for mutation of the second copy of the gene in kidney tumor specimens from BHD patients. We found mutation (or loss of heterozygosity) of the second copy (the wild type copy) of the BHD gene in 70% of the tumor samples evaluated. These findings provided the evidence that the BHD gene is a loss of function tumor suppressor gene. When we found the BHD gene it was a novel gene with unknown function. In order to determine what the function of the BHD gene is we performed studies to determine which proteins bind to the BHD protein (called folliculin). We found that folliculin binds to a novel protein called FNIP1 (folliculin interacting protein) that FNIP1 binds to AMPK which is the cells main energy sensing protein. AMPK phosphorylates both FNIP1 and AMPK and FNIP phosphorylate folliculin. AMPK inhibits the function of MTOR through the TS pathway. We found that MTOR phosphorylates folliculin and that this phosphorylation is inhibited in-vitro by treatment with rapamycin. We have subsequently found that folliculin binds to a second protein FNIP2 which also binds AMPK and which is also phosphorylated by AMPK and that AMPK/FNIP2 phosphorylate folliculin. Folliculin and FNIP1 and FNIP2 co-localize in the cytoplasm and the binding of folliculin to FNIP1 and FNIP2 is in the carboxy terminus of the protein. The finding that the germline BHD mutations are predominantly mutations that are predicted to truncate the protein (frameshift or nonsense mutations) suggests that folliculin binding to FNIP1/FNIP2 is critical to folliculins tumor suppressor function. In order to develop a BHD animal model to further understand the effect of mutation of the BHD gene and to provide a model for evaluation of targeted therapeutics we developed a kidney specific BHD knockout mouse. In this model BHD -/- mice developed large cystic kidneys with areas of hyperplastic tissues. These animals develop renal insufficience and survive for only 30 days. In order to evaluate the effect of a targeted therapeutic approach for the BHD gene pathway the BHD -/- animals were treated with rapamycin. The rapamycin treated animals had a significant diminution in the kidney phenotype and their survival was doubled. We have developed a unique in-vitro model of a human kidney cancer cell line from a BHD patient and are evaluating multiple agents with target the BHD pathway in our in-vivo and in-vitro models. These studies provide the basis for the development of a targeted therapeutic approach for BHD-associated kidney cancer and for a subset of patients with sporadic non-inherited chromophobe kidney cancer. 952264 +Cancer; Clinical Research; Coronaviruses; Coronaviruses Therapeutics and Interventions; Emerging Infectious Diseases; Genetics; Health Disparities; Infectious Diseases; Kidney Disease; Minority Health; Orphan Drug; Rare Diseases 2019-nCoV;Affect;American;Binding;COVID-19 treatment;Cancer Etiology;Cancer Model;Catalytic Domain;Cell Culture Techniques;Cell Line;Citric Acid Cycle;Clear Cell;Clear cell renal cell carcinoma;Clinical;Clinical Trials;Complex;Conventional (Clear Cell) Renal Cell Carcinoma;Cryoelectron Microscopy;Cutaneous Leiomyoma;Development;Disease;Enzymes;Family;Foundations;Fumarate Hydratase;Fumarates;Geldanamycin Analogue;Genes;Genetic Transcription;Genome;Goals;Growth;Heat-Shock Proteins 90;Hereditary Leiomyomatosis and Renal Cell Cancer;Hereditary Neoplastic Syndromes;Histology;Human;Hypoxia;Hypoxia Inducible Factor;In Vitro;Individual;Inherited;Iron;Kidney Neoplasms;Lead;Loss of Heterozygosity;MET gene;Malignant Neoplasms;Mediating;Metal Binding Site;Metals;Modeling;Molecular;Mutate;Mutation;New Agents;Oncogenes;Papillary;Pathway interactions;Patients;Platelet-Derived Growth Factor;Process;Procollagen-Proline Dioxygenase;Proteins;RNA-Directed RNA Polymerase;Renal Cell Carcinoma;Renal carcinoma;Risk;Role;SARS-CoV-2 antiviral;SARS-CoV-2 inhibitor;Scientist;Site;Small Interfering RNA;Stains;Structure;Sulfur;System;Therapeutic;Transforming Growth Factor alpha;Translations;Tumor Tissue;Ubiquitin;Urologic Oncology;Uterine Fibroids;VHL gene;VHL protein;Vascular Endothelial Growth Factors;Viral;Von Hippel-Lindau Syndrome;Work;Zinc;base;beta catenin;cancer type;cofactor;elongin B;elongin C;helicase;in vitro Model;in vivo;novel;oxidation;prevent;protein complex;receptor;targeted agent;targeted treatment;tempol;transcription factor;tumor Molecular Therapeutics of Kidney Cancer: VHL Gene and Fumarate Hydratase Gene n/a NCI 10702458 1ZIABC011038-15 1 ZIA BC 11038 15 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2856790 NCI Molecular Therapeutics of Kidney Cancer-VHL Gene and Fumarate Hydratase Gene: Understanding the genes that cause kidney cancer provides the opportunity to develop approaches for molecular therapeutics for this disease. We have identified 3 genes that cause cancer of the kidney: the VHL gene (clear cell renal cell carcinoma); the c-Met gene (papillary type 1 renal carcinoma); and the BHD gene (chromophobe renal carcinoma). Targeting the VHL Clear Cell Kidney Cancer Gene Pathway: Urologic Oncology Branch scientists are studying intensively how damage (mutation) to the VHL gene leads to the manifestations in VHL and sporadic renal carcinoma patients. Recently it is has been shown that the VHL protein forms a complex with other proteins including elongin C and B and the CUL-2 protein and this complex targets the alpha subunit of hypoxia inducible factors (HIF1-alpha and HIF2-alpha) for ubiquitin-mediated degradation. This is a hypoxia-mediated process normally i.e. under hypoxic conditions HIF is not degraded by the VHL complex. HIF is a transcription factor that regulates the transcription of a number of downstream genes important for cancer such as VEGF Glut 1 TGF-alpha and PDGF. When the VHL gene is mutated in the germline of VHL patients or in tumor tissue from patients with clear cell renal carcinoma the HIFs cannot be degraded and the result is the over-transcription of VEGF Glut1 TGF-alpha and PDGF. One approach to evaluating the role of agents targeting the VHL pathway in VHL and clear cell renal carcinoma is to determine the activity of agents which block the VEGF and TGF-alpha/EGFr pathways in-vitro and in-vivo. Another approach for molecular therapeutics of clear cell RCC is by use of agents such as geldanamycin analogues which disrupt the binding of HIF to HSP-90. In-vitro studies have shown that the 17AAG geldanamycin analogues can degrade HIF even in VHL -/- cell lines. In-vitro and in-vivo studies are underway in kidney cancer models that we have developed from human material to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of clear cell kidney cancer. Clinical trials evaluating the role of geldanamycin analogues as well as agents which target the VEGF/EGFr receptors and other parts of the VHL pathway are currently in progress. Targeting the Fumarate Hydratase Gene - Type 2 Papillary Kidney Cancer: The Krebs cycle enzyme fumarate hydratase (FH) is the gene for Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). HLRCC patients are at risk for the development of cutaneous and uterine leiomyomas as well as a very aggressive form of type 2 papillary kidney cancer. We have found mutations of the FH gene in the germline of 95% of our HLRCC families and loss of heterozygosity of the FH gene in HLRCC-associated kidney cancer. In order to understand how mutation of a Krebs cycle enzyme could cause kidney cancer we stained HLRCC-associated kidney tumors for the presence of hypoxia induced factor 1-alpha (HIF1-alpha) and hypoxia induced factor 2-alpha (HIF2-alpha). We found both HIF1-alpha and HIF2-alpha to be elevated in the HLRCC kidney tumors. We are developing novel in-vitro models from human tumors and evaluating growth in in-vitro and in-vivo systems. In in-vitro models we found that when fumarate hydratase was inactivated (with SiRNA) fumarate increased and the increase in fumarate inhibited prolyl hydroxylase. The inhibition of prolyl hydroxylase prevented normoxic VHL-mediated HIF degradation providing a VHL-independent mechanism for dysregulation of HIF degradation in HLRCC kidney cancer. These studies provided the rationale for the development of a targeted therapeutic approach for the treatment of HLRCC-associated kidney cancer. In-vitro and in-vivo studies are underway to evaluate the role of agents which block this cancer gene pathway as a potential approach for the treatment of HLRCC-associated as well as sporadic type 2 papillary kidney cancer. Based on our work targeting iron sulfur clusters in order to inhibit HIF2 translation in VHL-deficient renal cell carcinoma we began to examine Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase with T. Rouault. SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp nsp12 ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly potently inhibited the RdRp and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19. We have shown that tempol will be an excellent anti-viral for SARS-CoV-2. 2856790 +Cancer; Clinical Research; Genetics; Kidney Disease; Orphan Drug; Rare Diseases Adrenal Gland Neoplasms;Adrenal Glands;Affect;American;Bilateral;Blood Tests;Brain;Brain Neoplasms;Chromosome 17;Chromosome 3;Chromosome 7;Chromosome Arm;Chromosome Mapping;Clear Cell;Clinical;Clinical Management;Clinical Research;Clinical Trials;Complex;Conventional (Clear Cell) Renal Cell Carcinoma;Cytogenetics;Defect;Detection;Development;Diagnosis;Disease;Ear Neoplasms;Event;Eye;Family;Family Study;Foundations;Fumarate Hydratase;Gene Mutation;Genes;Genetic;Genetic study;Genomics;Genotype;Germ-Line Mutation;Hereditary Leiomyomatosis and Renal Cell Cancer;Hereditary Papillary Renal Carcinoma;Histology;Hybrids;Iceland;Individual;Inherited;Institutes;Kidney;Kidney Neoplasms;Laboratories;Labyrinth;Leiomyomatosis;MET gene;Malignant Neoplasms;Methods;Methylation;Molecular Genetics;Mutation;New Agents;Oncogenes;Pancreas;Papillary;Pathology;Pathway interactions;Patients;Pattern;Phenotype;Pheochromocytoma;Proto-Oncogenes;Renal carcinoma;Reporting;Research Personnel;Risk;Running;Series;Somatic Mutation;Surgical Management;Syndrome;Tumor Suppressor Genes;Tyrosine Kinase Domain;United States National Institutes of Health;VHL gene;VHL mutation;Vertebral column;Von Hippel-Lindau Syndrome;Work;base;cancer type;clinical diagnosis;design;genetic linkage analysis;genetic testing;improved;kindred;member;minimally invasive;new therapeutic target;novel;pancreatic neoplasm;preclinical study;targeted treatment;tumor;working group Clinical Studies of the Molecular Genetic Basis of Kidney Cancer n/a NCI 10702455 1ZIABC011028-15 1 ZIA BC 11028 15 2093160 "LINEHAN, WILLIAM MARSTON" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1904526 NCI Our work has shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer each with a different histology a different clinical course responding differently to therapy and each caused by a different gene. Our approach has been to identify the genes that cause kidney cancer in order to provide the foundation targeted therapeutic approaches to this disease. In order to identify the genes that cause kidney cancer we have studied the inherited forms of cancer of the kidney. Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are a number of different types of inherited kidney cancer including: 1) von Hippel Lindau (VHL) the inherited form of clear cell renal carcinoma; 2) Hereditary Papillary Renal Carcinoma (HPRC) hereditary Type 1 kidney cancer 3) Birt Hogg Dub (BHD) the inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC) type 2 papillary renal carcinoma. In order to develop new methods for treatment of patients with sporadic as well as familial kidney cancer we established an NIH kidney cancer working group involving clinicians and investigators from 29 different laboratories and branch from 9 different NIH Institutes. Individuals affected with von Hippel Lindau (VHL) are at risk for the development of bilateral multifocal clear cell kidney cancer as well as tumors in the brain spine eyes pancreas adrenal gland and inner ear. By studying VHL families we were able to perform genetic linkage analysis to localize and subsequently identify the VHL gene on chromosome 3. We have identified the VHL gene mutation in the germline of 246/246 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating novel minimally invasive forms of therapy for kidney and adrenal tumors in VHL. We have described the surgical management of VHL kidney cancers as well as VHL pheochromocytoma pancreas tumors ear tumors and brain and spine tumors. We currently have two clinical trials in progress targeting the VHL gene pathway in patients affected with VHL. We have shown that the VHL gene is also the gene for the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). In a series of studies we have identified mutation/methylation of the VHL gene in up to 92% of tumors from patients with sporadic (non-inherited) clear cell kidney cancer. Study of the VHL gene pathway has provided the foundation for the development of targeted therapeutics for patients with both clear cell kidney cancer as well as von Hippel-Lindau. We currently are conducting a clinical trial of an agent which targets the VHL pathway in patients with advanced clear cell kidney cancer. In 1994 we described a novel form of inherited kidney cancer Hereditary Papillary Renal Carcinoma (HPRC). HPRC is an inherited cancer syndrome in which affected individuals are at risk for the formation of multifocal bilateral type 1 papillary kidney cancer. In order to identify the gene for HPRC we studied families with this rare inherited cancer syndrome to determine which individuals had the kidney cancers and which did not. Linkage analysis performed in the families to localized the gene to the long arm of chromosome 7. The proto-oncogene MET was subsequently identified as the HPRC gene. We have identified activating mutations in the tyrosine kinase domain of the MET gene in the germline of the HPRC families as well as in a subset of tumors from patients with sporadic non-inherited type 1 papillary kidney cancer. These findings provided the foundation for the development of a targeted therapeutic approach to the treatment of patients affected with HPRC as well as for patients with sporadic non-hereditary papillary kidney cancer. We are currently conducting a clinical trial with an agent which targets the MET gene pathway in patients with Hereditary Papillary Renal Carcinoma and sporadic papillary kidney cancer. We also described another novel type of inherited kidney cancer associated with Birt Hogg Dub (BHD). Birt-Hogg-Dub patients are at risk for the development of bilateral multifocal chromophobe and hybrid/oncocytic kidney cancer. By studying BHD families and we were able to localize and subsequently identify the BHD gene on chromosome 17. We have detected BHD gene mutations in over 95% of BHD families and are now able to 1) make the clinical diagnose of BHD with a blood test as well as determine which at-risk members of BHD families are affected with BHD. We have defined the kidney cancer phenotype of BHD and have described the surgical management of BHD-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the BHD pathway in patients with BHD-associated kidney cancer. In addition we have described another inherited form of papillary kidney cancer which is now called Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). Affected individuals in HLRCC families are at risk for the development of a very aggressive form of type 2 papillary renal carcinoma. We have reported the identification of germline mutations of the fumarate hydratase gene (FH) in the germline of over 90% of North American HLRCC kindreds. We have described the HLRCC kidney cancer phenotype and the method of clinical management of HLRCC-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the FH pathway in patients with HLRCC-associated kidney cancer. Kidney Cancer Genetic Testing The identification of germline VHL c-Met BHD and FH mutations makes possible pre-symptomatic genetic testing for at-risk individuals in VHL HPRC BHD and HLRCC families and paves the way for additional studies to understand the pathology of these diseases and for the design of effective new therapies targeted to the specific defects brought about by mutation of the these disease genes. We have recently demonstrated improved detection of germline mutations in the von Hippel Lindau disease tumor suppressor gene. We can now detect mutations in nearly 100% of families. We have additionally detected a new phenotype associated with complete deletion of the VHL gene. We are intensively studying the somatic events (genomic cytogenetic) associated with the development of tumors in patients with different types of germline mutations. The ability to detect germline as well as somatic mutations of the VHL Met BHD and FH gene may provide substantial opportunity for improvements in the diagnosis of both hereditary as well as sporadic forms of kidney cancer. Finally we are studying the genetic basis of Familial Renal Carcinoma (FRC). FRC is a term that describes the kidney that runs in families that are not part of previously described hereditary kidney cancer syndromes. Studies in Iceland have suggested that nearly 60% of kidney cancer may be genetic. We suspect that there is a complex genetic pattern to FRC and we are currently evaluating FRC kindreds in order to 1) describe this clinical syndrome and 2) to identify its genetic basis. 1904526 +Cancer; Cancer Genomics; Genetics; Human Genome Binding;Biological;Biological Models;Cells;Chemicals;Chromatin Structure;Coupling;DNA;DNA Structure;DNA-Directed RNA Polymerase;Drug Targeting;Elements;Enhancers;Enterobacteria phage P1 Cre recombinase;Enzymes;Episome;Excision;Exposure to;Fiber;Gene Expression;Gene Expression Regulation;Generations;Genes;Genetic;Genetic Processes;Genetic Transcription;Genome;Genomics;Hand;Human Herpesvirus 4;In Vitro;Knowledge;Left;Light;Link;Literature;Malignant Neoplasms;Maps;Measures;Mechanics;Medical;Metallothionein;Methods;Molecular Conformation;Molecular Machines;Monitor;Nucleic Acid Binding;Oncogenes;Output;Oxides;Pathologic;Pathologic Processes;Physics;Physiologic pulse;Physiological;Physiological Processes;Potassium Permanganate;Process;Psoralens;Pyrimidines;RNA Binding;Regulator Genes;Regulatory Element;Replication Origin;Resolution;Role;SS DNA BP;Site;Solvents;Specificity;Stress;Structure;Superhelical DNA;Testing;Topoisomerase;Topoisomerase II;Topoisomerase Inhibitors;Torque;Torsion;Transact;Transcription Initiation Site;Transcriptional Regulation;Ultraviolet Rays;Variant;Work;Z-Form DNA;Zinc;base;c-myc Genes;chemotherapeutic agent;crosslink;density;endonuclease;enzyme activity;experimental study;genome-wide;improved;in vivo;nanopore;novel;permanganate;preference;preservation;promoter;recruit;transcription factor;virtual;whole genome The genome-wide function of supercoiling and alternative DNA conformations n/a NCI 10702454 1ZIABC011011-15 1 ZIA BC 11011 15 9692465 "LEVENS, DAVID L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1082291 NCI First to establish that our hypothesis that transcriptionally generated DNA supercoiling regulates the activity of particular elements we prepared a model system comprised of an EBV-based episome where the FUSE element was sandwiched between divergent metallothionein promoters. By adding zinc to defined levels we could adjust the level of ongoing transcription and control the forces propagated onto FUSE. Upon exceeding a key threshold the FUSE element would become single-stranded recruit the specific single stranded DNA binding protein FBP and reprogram the output of the metallothionein promoters. Using Cre-recombinase to excise precisely defined DNA circles allowed us to monitor directly the accompanying changes in DNA topology validating this novel mechanism as potentially general principle to confer precise control on activated promoters. We are now developing experimental and analytical approaches to map the level and distribution of supercoiling forces on a genome-wide basis. to accomplish this we are exploiting the known preference for psoralen to intercalate into negatively supercoiled DNA. Because psoralen readily penetrates living cells and can be cross-linked to DNA by a pulse of UV light by comparing the relative hybridization of cross-linked to uncross-linked DNA to high density genomic tiling arrays we can map the genome-wide distribution of psoralen. By including proper controls to account for ongoing transcription chromatin structure and by eliminating the influence of replication (by using properly synchronized cells) we can infer the distribution of supercoils. Because high levels of supercoiling promotes the formation of non-B DNA structures we have also devised a method to map the distribution of non-B DNA across the genome. Virtually any of the non-B DNA structures formed in vitro result in the exposure of DNA bases to the local solvent (at least the the junctions between B and non-B DNA) potassium permanganate can be used as a chemical probe of unpaired bases. Because permanganate rapidly permeates cells following a short exposure to this chemical when DNA is extracted the permanganate oxidized pyrimidines in stabilize foci of non-B DNA and preserve sensitivity to cleavage by single strand specific endonucleases. Following cleavage with such endonucleases these ends can be marked and recovered and analyzed by sequencing. Application of this approach reveals enrichment for permanganate sensitive sites in sequences computationally predicted to 1)be sensitive to supercoil induced duplex destabilization (SIDD); 2) to be Z-DNA (left handed double helix; or 3) to form G-quadraplex structures. Application of the methods that we have developed reveals the genome to be extraordinarily dynamic with changes in structure associated with particular gene sets and particular physiological and pathological processes. The same methods will allow us to associate topoisomerase activity with changes in DNA structure and gene activity. We exploring variations on this method that should improve its efficiency and approach the examination of DNA structure and topology at the single cell level. We are currently developing a high-resolution method that concurrently interrogates DNA structure and topology across a whole genome to illustrate the interplay between genetic transactions and DNA physics.These studies will likely shed new light on how chemotherapeutic agents that alter DNA conformation and topology may be improved to increase efficacy and improve specificity. Topoisomerases are enzymes that control the distribution and level of supercoiling and torsional stress in DNA fibers. We have recently commenced the combination of Oxford Nanopore long read sequencing with the in vivo use of permanganate and other agents that react with non-B DNAs to map alternative structures on chromosomal DNA strands without the need for strand fragmentation or PCR. These results will allow us to study the linkage of non-B DNA structure with associating promoters and enhancers or replication origins to get a better perspective on the mechanics of genomic processes. We have begun to analyze where type I and type II topoisomerase act across the genome to assess their relationship to gene activity and DNA structure. We are using ChIP to map sites of topoisomerase 1 binding across the genome to overlay the sites of top 1 binding on top maps of supercoiling and alternative DNA structures. We have discovered that there is tight coupling between RNA polymerase recruitment and topoisomerase action at the promoters of active genes. Moreover topoisomerase 1 is used as a component of the transcription machinery independently of its enzymatic activity. In fact topoisomerase 1 activity is held in check until the topoisomerase is recruited beyond 1 kilobase downstream of the transcription start site. Now we are exploring the ability of other specific or general transcription factors to activate or inhibit topoisomerase activity. Because MYC activity serves to sustain the expression of all genes but especially those that are highly expressed the best MYC targets are also those most dependent on topoisomerase. Because of this MYC was tested to see if it interacted with and/or activates topoisomerases. Focusing on top 1 we found that MYC both binds and activates top 1. Current experiments are determining which features of each molecule support this interaction and how top 1 activity is augmented. Additional studies are testing the hypothesis that FUBP1 has intrinsic or augments other toposiomerase activities. Because the FUBP's bind nucleic acids through KH-motifs that are often associated with RNA-binding we are exploring whether the FUBPs influence the generation or removal of R-loops and if so the relationship between R-loops and gene expression at FUBP targets. 1082291 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Pediatric; Pediatric Cancer; Rare Diseases Age;Bioinformatics;Biological;Biology;Cancer Biology;Cells;Clinical;Complex;DNA;DNA copy number;Genes;Genetic Transcription;Genome;Genomics;Goals;Individual;Investigation;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Messenger RNA;MicroRNAs;Modeling;Morbidity - disease rate;Mutation;Outcome;Pathway interactions;Patients;Phenotype;Proteins;Proteome;Proteomics;Systems Biology;Transcriptional Regulation;biological systems;cancer cell;cell growth;dynamic system;epigenetic profiling;genome wide methylation;genome-wide;high risk;improved;mathematical model;methylation pattern;protein expression Bioinformatics: Systems Biology of Cancers n/a NCI 10702450 1ZIABC011002-15 1 ZIA BC 11002 15 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 854306 NCI It has become increasingly clear that individual genes do not act in isolation within a cell but acts in concert with other genes within pathways. In addition many genes within a pathway are redundant such that many genes can perform a particular function and conversely a single gene can have many functions depending on its cellular context. High throughput genome wide approaches allow the investigation of the complexity of cell as a whole. The integration of genomics and proteomics with functional analysis will be referred to as systems biology. My lab has utilized these systematic approaches to understand more clearly the biology of high-risk pediatric cancers. Systems biology seeks to integrate high-throughput biological studies to understand how the whole biological systems function. By studying the relationships and interactions between various parts of the biological system (NB in our case) including DNA copy number methylation patterns mRNA miRNA and protein levels cell growth clinical parameters (age stage and outcome (survival)) it is hoped that eventually this will enable a more complete understanding of NB which will lead to improved survival of patients with minimal long term morbidity. The genome and proteome of a cell is a complex interrelated dynamic system. DNA copy number can impact the mRNA and miRNA expression. mRNA is transcribed into proteins and can contain miRNA sequences and proteins control transcription by its action on DNA mRNA and miRNA. In addition miRNAs control protein and mRNA levels. These global interactions thus control the phenotype of a cancer cell which determines the outcome. 854306 +Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Clinical Research; Congenital Structural Anomalies; Genetics; Human Genome; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases; Women's Health Age;Alveolar;Amino Acids;Antibodies;Antibody-drug conjugates;Apert-Crouzon syndrome;Biology;Cancer Biology;Childhood Soft Tissue Sarcoma;Chromosomal translocation;Chromosome 13;Clinical Trials Design;Code;Colon Carcinoma;Development;Diagnosis;Disease;Embryonal Rhabdomyosarcoma;Endometrial Carcinoma;Epigenetic Process;Event;FGFR1 gene;FGFR2 gene;FGFR3 gene;FGFR4 gene;FOXO1A gene;Fibroblast Growth Factor Receptor Family Gene;Fibroblast Growth Factor Receptors;Gene Expression Profiling;Gene Family;Genes;Genetic Polymorphism;Genome;Genomics;Germ-Line Mutation;Glioblastoma;Goals;Growth;Growth Factor Receptor Genes;Histologic;Human;Lead;Loss of Heterozygosity;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Molecular;Monoclonal Antibodies;Mutate;Mutation;Natural Products;Oncogenes;Oncogenic;Outcome;PAX3 gene;Pathway interactions;Patients;Pattern;Pfeiffer Syndrome;Phenotype;Process;Prognosis;Proteins;Publishing;Reagent;Receptor Protein-Tyrosine Kinases;Reporting;Rhabdomyosarcoma;Site;Somatic Mutation;Testing;Tumor Biology;angiogenesis;cell motility;chimeric antigen receptor;diagnostic biomarker;efficacy testing;epigenome;fusion gene;hypochondroplasia;improved;in vivo;inhibiting antibody;inhibitor;insight;interest;mRNA Expression;malignant breast neoplasm;member;mouse model;neoplastic cell;new therapeutic target;novel strategies;older patient;paralogous gene;sarcoma;small molecule inhibitor;targeted treatment;tumor;tumor progression Targeting FGFR4 RAS and PAX3-FOXO1 gene in Rhabdomyosarcoma n/a NCI 10702449 1ZIABC010999-15 1 ZIA BC 10999 15 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1025166 NCI Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma typically classified as either alveolar (ARMS) or embryonal histological subtypes. ARMS is observed in older patients and is associated with a chromosomal translocation creating a fusion gene involving FOXO1A on chromosome 13 and members of the PAX gene family. Embryonal RMS is characterized by a younger age at diagnosis loss of heterozygosity and altered patterns of genomic imprinting1. An important determinant of poor long term survival for all RMS histological subtypes is the presence of metastatic disease. Factors contributing to tumor progression and metastatic disease are not well understood. Analysis of gene expression patterns have led to improved accuracy of tumor identification and advances in sarcoma biology particularly new insights into possible mechanisms of metastatic regulators. We and others have previously reported that FGFR4 a receptor tyrosine kinase (RTK) member of the fibroblast growth factor receptor (FGFR) gene family is highly expressed in RMS and mRNA expression correlates with protein levels. These observations suggest that FGFR4 could be a tumor specific diagnostic marker and/or a determinant of tumor biology. In other human cancers the presence of a common polymorphism in the coding region (FGFR4 G388R) is associated with increased tumor cell motility and prognosis in patients with sarcomas colon or breast cancer. The FGFR genes are of great interest in cancer biology because they regulate essential processes including cellular survival motility development and angiogenesis. Comparison of the FGFR coding regions indicates segments of high amino acid conservation in FGFR1 FGFR2 FGFR3 and FGFR4. Germline mutations in these paralogs have been described for several rare highly penetrant Medelian disorders including Crouzon syndrome Pfeiffer syndrome and hypochondroplasia. Somatic mutations at the same sites of paralologs have been observed within the FGFR TK domains in glioblastoma multiforme breast cancer lung cancer and endometrial carcinoma. These observations lead us to hypothesize that FGFR4 activation perhaps by somatic mutational events could be critical to the oncogenic process in RMS sarcomas or other cancers. Furthermore FGFR4 over activity could be associated with advanced stage disease and poor outcome. We have now published a manuscript that confirms that activating FGFR4 mutations occur in 7.5% or RMS and that over expression is associated with a more aggressive phenotype. Our group has also recently performed a comprehensive genomic analysis of the rhabdomyosarcoma genome and found that RAS pathway genes are mutated in 50% of fusion negative rhabdomyosarcoma. Finally we are dedicating considerable efforts in characterizing the molecular epigentic and functional effects of the PAX3/7- FOXO1 fusion oncogene and developing novel strategies to target the epigenome of fusion positive rhabdomyosarcoma including a natural product screen. We are therefore developing new therapies targeting FGFR4 RAS and the fusion gene in rhabdomyosarcoma. 1025166 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome; Immunotherapy; Neuroblastoma; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Archives;Area;Bioinformatics;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Development;Drug resistance;Equipment;Gene-Modified;Genes;Genome;Genomics;Germ Lines;Goals;Human;Human Genome;Human Genome Project;Immunotherapy;Malignant Childhood Neoplasm;Malignant Neoplasms;Massive Parallel Sequencing;Mutate;Mutation;Neuroblastoma;Oligonucleotides;Patients;Pharmacotherapy;Rhabdomyosarcoma;Sampling;Techniques;Validation;cancer genome;design;druggable target;exome;genome-wide;high risk;next generation;next generation sequencing;novel;novel therapeutics;resistance mechanism;single molecule;targeted treatment;transcriptome;tumor;whole genome Novel Mutations and Therapy Resistance Mechanisms in Pediatric Cancers n/a NCI 10702448 1ZIABC010998-15 1 ZIA BC 10998 15 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 512584 NCI The human genome project has identified categorized and sequenced most of the 30000 or so human genes. Recently the ability to perform massively parallel sequencing of the whole genome has increased with the development of next generation and single molecule sequencers. It is speculated that within the next 2-5yrs it will be possible to sequence whole human genomes for under $1000. Through collaborative networks my lab has archived over 600 clinically annotated neuroblastoma and over 100 rhabdomyosarcoma tumor samples. By bioinformatic techniques we are identifying all know targets in neuroblastoma and rhabdomyosarcoma. We are using microarray and next generation sequencing of the pediatric cancer genome. Our goal is to identify activating mutations that can be targeted for therapy in patients with high risk neuroblastoma rhabdomyosarcoma and other pediatric cancers for which there is no currently available therapy. Another goal is to utilize gene modification studies such as genome wide CRISPR studies and genomics to identify mechanism of resistance and synergistic combinations to drugs or immune therapy. 512584 +Cancer; Hematology; Orphan Drug; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Transplantation Address;Allogenic;Angiogenesis Inhibitors;Apoptosis Inhibitor;Azacitidine;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Cell Line;Cell Therapy;Cells;Collaborations;Cooperative Research and Development Agreement;Cytosine;Cytotoxic Chemotherapy;DNA;DNA Methyltransferase Inhibitor;Data;Decitabine;Disease;Disease remission;Division of Cancer Treatment and Diagnosis;Donor Lymphocyte Infusion;Dose;Dysmyelopoietic Syndromes;Funding;Generations;Genome;Graft-Versus-Tumor Induction;Hematology;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Histocompatibility;Histone Deacetylase Inhibitor;Hypermethylation;Immune;Industry;Institution;Ionizing radiation;Licensing;MCL1 gene;Manuscripts;Mediating;Methylation;Minor;Minor Histocompatibility Loci;Modeling;Mouse Cell Line;Mus;NUP98 gene;Patients;Peripheral;Pharmacologic Substance;Phase I Clinical Trials;Pre-Clinical Model;Preparation;Proteins;Publishing;Relapse;Research Personnel;Role;Saline;Sampling;T-Lymphocyte;T-Lymphocyte Subsets;Time;Transgenes;Transgenic Mice;Transgenic Organisms;Transplantation;Xenograft Model;chemoradiation;conditioning;cytopenia;cytotoxic;effective therapy;experimental study;graft vs leukemia effect;human disease;inhibitor;meetings;mouse model;novel;novel therapeutics;peripheral blood;post-transplant;pre-clinical;preclinical study;predicting response;small molecule;treatment response Pre-clinical Studies of Therapy for Myelodysplastic Syndrome n/a NCI 10702445 1ZIABC010983-15 1 ZIA BC 10983 15 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 599222 NCI Our initial studies used the DNA-methyltransferase inhibitor 5-azacytidine; some of these results have been published (Genome Res. 4:580-91 2014).However since our initial studies used transgenic mice effective treatment with 5-azacytidine could not replace the MDS bone marrow with completely normal (ie wildtype or WT) bone marrow since all of the bone marrow was transgenic. Therefore in order to distinguish improvement in peripheral blood cytopenia due to differentiation of the MDS clone from elimination of the MDS clone we have repeated the experiments using chimeric mice that have both WT and NHD13 bone marrow. These repeat experiments have been performed using Decitabine (DAC) a related DNA methyltransferase inhibitor. Mice treated with DAC showed hematologic improvement and a survival advantage compared with saline-treated control mice; this experiment has now been repeated three times. Sorted BM cells from treated mice show clear differences in global cytosine methylation between the NHD13 and WT samples and partial reversal of this hypermethylation with DAC treatment (collaboration with Dr. J.P. Issa). A manuscript describing these findings is in preparation. Drs. Difillipantonio Doroshow and colleagues from the Division of Cancer Treatment and Diagnosis (DCTD) have developed two novel DNMT1 inhibitors both of which are in phase I clinical trials. In collaboration with Dr. Difillipantonio and colleagues we are now treating chimeric NHD13/WT mice with these compounds to assess efficacy in treatment of MDS. A manuscript describing the generation of chimeric mice with MDS was published in FY2019 (PMID: 30346380). Preliminary results show a survival benefit as well as improvement in hematopoiesis in mice receiving one of these DNMT1 inhibitors designated T-dCyd. Portions of this data were presented at the 2018 ASH meeting and a manuscript describing these findings is in preparation. Similar experiments investigating therapy with a related small molecule Aza-TdCyd are now in progress. Finally we have refined our model to enable transplant of NHD13 MDS hematopoietic cells without using ionizing radiation as a conditioning agent. We have successfully engrafted WT mice with NHD13 BM by pre-treating the recipient mice with the Cdc42 inhibitor CASIN which leads to egress of the WT hematopoietic stem cells. The only curative option for patients with MDS remains allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT has two essential components high-dose cytotoxic chemo-radiotherapy and an immune-mediated graft versus host (GVH) or graft versus leukemia (GVL) effect. However the relative contributions of high dose cytotoxic therapy and GVL are not well established in MDS patients. We propose to use transplantation of the NHD13 mice as a means to investigate this question. 1000 CGy induced a remission of 26-38 weeks defined by normalization of peripheral blood counts and less than 2% circulating host cells. However despite this period of prolonged remission and prolonged survival compared to non-transplanted mice all mice ultimately relapsed indicating that this myeloablative therapy was not curative. To address the question of a GVL effect we crossed C57bl6 mice with C3h.SW mice. C3H.SW mice are identical to C57Bl6 mice at the major histocompatibility loci but have numerous mismatches at minor histocompatibility loci. For this reason transplantation of C3H.SW donor cells into C57Bl6 host mice has been used to study GVH and GVL. We transplanted BM from C57Bl6/C3HSW mice into C57Bl6 NHD13 recipients. The mice developed little GVH or GVL under these conditions. Subsequent experiments using higher doses of BM or 5 x 10E06 peripheral T cells showed severe GVH. A third trial using a higher dose of bone marrow cells (10E07)has led to survival 52 weeks post-transplant (PMID: 28953912). These results demonstrate a survival benefit for bone marrow transplant; ongoing experiments are aimed at determining whether donor lymphocyte infusion or co-transplantation of specific T cell subsets will lead to yet greater survival. In addition to the experiments outlined above we have transferred NHD13 mice to colleagues at many academic institutions and have licensed NHD13 mice to industry for pre-clinical studies. These colleagues have treated NHD13 mice with a variety of agents including histone deacetylase inhibitors apoptosis inhibitors and angiogenesis inhibitors. One of these compounds (ACE-536 or luspatercept) was recently approved for treatment of anemic MDS patients by the FDA. We y executed a CRADA with Tolero Pharmaceuticals who have provided us with funding to study the effects of alvocidib (a Cdk9/Mcl1 inhibitor) and DNMTi on NHD13 mice and cell lines. These studies are now underway. 599222 +Biotechnology; Cancer; Childhood Leukemia; Genetics; Hematology; Lymphatic Research; Lymphoma; Pediatric; Pediatric Cancer; Rare Diseases 3' Untranslated Regions;ABL1 gene;Acute Myelocytic Leukemia;Acute leukemia;Age-Months;Alleles;Animal Model;Apoptosis;B cell differentiation;B lymphoid malignancy;B-Cell Acute Lymphoblastic Leukemia;B-Cell Leukemia;B-Lymphocytes;Blood;Bone Marrow;Bone Marrow Cells;CD8B1 gene;Candidate Disease Gene;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complex;DNA;DNA biosynthesis;DNA replication fork;DNMT3a;Development;Epigenetic Process;Erythroid;Gene Expression Profile;Generations;Genes;Genetic;Genetically Engineered Mouse;Genets;Genomic DNA;Growth;Hematopoietic stem cells;Human;Hunger;Immunophenotyping;Impairment;In Vitro;Insertional Mutagenesis;Knock-in;Lead;Length;Leukemic Cell;Licensing Factor;Ligands;Loss of Heterozygosity;Lymphoblastic Leukemia;Lymphoma;Maintenance;Malignant - descriptor;Malignant Neoplasms;Manuscripts;Methylation;Modeling;Molecular;Mouse Strains;Mus;Mutant Strains Mice;Mutate;Mutation;Myelogenous;Myeloid Cells;NOTCH1 gene;NU/NU Mouse;NUP214 gene;NUP98 gene;Nature;PTPN1 gene;Pathway interactions;Patients;Pattern;Phenotype;Phosphotransferases;Proteins;Publishing;Recurrence;Reporting;Sampling;Site;T-Cell Leukemia;T-Lymphocyte;TAL1 gene;TCF3 gene;TOP1 gene;Thymocyte Development;Thymus Gland;Transgenes;Transgenic Mice;Transplantation;Tumor Suppressor Genes;V(D)J Recombination;acute T-cell lymphoblastic leukemia cell;acute myeloid leukemia cell;cancer cell;cell type;exome sequencing;experimental study;fusion gene;helicase;human disease;in vivo;inhibitor;leukemia;leukemia initiating cell;leukemia/lymphoma;leukemic transformation;mutant;novel strategies;offspring;precursor cell;progenitor;replication stress;retroviral transduction;small hairpin RNA;stem cell self renewal;theories;thymocyte;tumor;whole genome Collaborative Pathways that Lead to Leukemia n/a NCI 10702444 1ZIABC010982-15 1 ZIA BC 10982 15 9692357 "APLAN, PETER " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 599222 NCI "Using NP23 micewe identified frequent acquired mutations in progenitor B1 cell ALL in the Bcor and Jak1/2 genes. Subsequently we used CRISPR to introduce Bcor mutations in primary WT and NP23 BM cells; these cells were transplanted into recipient mice and verified collaboration between NP23 and Bcor in vivo. The leukemias also acquired Jak pathway mutations suggesting that NP23 Bcor and Jak collaborated to produce pro-B1 ALL. These results were published in FY2020 (PMID: 30992267). We previously demonstrated that spontaneous mutations of IDH2 occur in NHD13 leukemias. These mutations occur at R140Q; homologous residues are mutated in human leukemia. We crossed IDH2 R140Q transgenic mice with NHD13 mice; the offspring develop a form of early T cell precursor (ETP) leukemia that resembles the human disease in terms of clinical presentation immunophenotype gene expression profile and collaborative mutations. In terms of molecular mechanism the IDH2R140Q mutant mice produce the oncometabolite 2HG; consistent with overproduction of 2HG the leukemic cells show aberrant methylation of genes required for normal thymocyte development. Finally a specific inhibitor of mutant IDH2 (AG-221) inhibits the growth of these ETP cells in vitro. A manuscript describing these findings was published in FY2021 (PMID: 34321240). Both NP23 and NHD13 mice develop a wide variety of leukemia at 9-14 months of age. Surprisingly 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within 3 months. The leukemias were characterized by extraordinarily high WBC and replacement of the thymus with AML cells; the percent of malignant myeloid cells in the thymus was often higher than the bone marrow (BM). These findings led to the intriguing hypothesis that the AML in NP23-NHD13 mice arose in the thymus as opposed to the BM. To investigate this possibility we transplanted CD4-/CD8- double negative (DN) thymocytes from the thymus of a NP23-NHD13 mouse. All mice developed AML within 26 days indicating that the AML was aggressive and transplantable and could be transmitted by DN thymocytes. Fractionating DN thymocytes into DN1-DN4 sub-populations revealed that AML initiating cells were found in the DN1 and DN2 compartments. Taken together these results demonstrate that NP23-NHD13 thymic progenitors retain myeloid and erythroid potential and are potently leukemogenic leading to the intriguing hypothesis that some human AML might originate in the thymus. A manuscript describing these findings was published in FY2020 (PMID: 31748606). Ongoing experiments are focused on assessing the leukemic potential of combining Bahcc1 mice (see project 1) with NHD13 transgenic mice. Mini-chromosome maintenance component 2 (Mcm2) is a DNA replication licensing factor that is part of the Mcm2-7 complex which functions as a DNA helicase unwinding genomic DNA at the replication fork. Not surprisingly homozygous deletion of Mcm2 is lethal. However insertion of a cre cassette into the 3' UTR of Mcm2 leads to 50% reduction in Mcm2 protein and cells with two copies of the cre knock-in allele express only 20-30% as much Mcm2 protein compared to wild-type cells. Despite the diminished Mcm2 protein levels mice with two copies of the Mcm2cre allele are born at normal Mendellian ratios are not growth-retarded and are indistinguishable from wild-type littermates at two months of age. Beginning at 2-3 months of age the mice become ill and invariably die from pre-T lymphoblastic leukemia/lymphoma (pre-T LBL). Copy number alteration (CNA) analysis reveals a pattern of gains and losses predominantly losses 10-1000 kb in length. Notably there is a recurrent constellation of losses including biallelic deletions of Pten Tcf3 (E2a) and Dnmt3a and mono-allelic deletions of the amino-terminus of Notch1. This constellation of cooperative deletions fits a model (supported by published experiments with Pten Tcf3 Dnmt3a) in which Dnmt3a deletion leads to increased stem cell self-renewal Tcf3 deletion blocks thymocyte differentiation Pten deletion leads to hyperproliferation and deletion of the amino terminus of Notch1 leads to ligand independent growth. All of these genes except TCF3 are frequently mutated in human T-ALL; NOTCH1 being the single gene most commonly mutated in human T-ALL. Although TCF3 is not frequently deleted in human T-ALL TCF3 is functionally inactivated by inappropriate expression of TAL1/SCL and LMO1/2 proteins (EMBO J 16:2408-19; Nature Immunol 1:138-44) in 25-50% of human T-ALL patients (Cancer Cell 1:75-87) underscoring the relevance of TCF3 inactivation in human T-ALL. Mice that express a NUP98-HOXD13 (NHD13) transgene develop myeloid T-cell and B-cell leukemia. Crossing the NHD13 transgene onto an Mcm2cre/cre background led to B-cell precursor (BCP) ALL in a subset of Mcm2cre/creNHD13+ mice. CNA analysis of these BCP-ALL revealed consistent deletions in Pax5 gains of a region bounded by Nup214 and Abl1 and bi-allelic loss of Ptpn1. The gains of Nup214 and Abl1 led to generation of a Nup214-Abl1 fusion gene similar to that seen in some human T-ALL and BCP-ALL patients. PTPN1 deletions have not been reported in human BCP-ALL however deletions of the closely related PTPN2 co-occur with NUP214-ABL1 fusions and PTPN2 was identified as a negative regulator of the NUP214-ABL1 kinase (Nat Genet 42:530-5 2010). This constellation of cooperative losses and gains fits a model in which the NHD13 transgene leads to increased stem cell self-renewal the Pax5 deletion leads to a block in B cell differentiation the Nup214-Abl1 fusion leads to hyperproliferation and the Ptpn1 deletion enforces hyperproliferation. Similar to the findings for T-ALL these genes and pathways have been highlighted as being important for human BCP-ALL (see review by Mullighan and Hunger Blood 125:3977-87). Sequencing of 323 independent junctions from 91 tumors revealed that mononucleotide repeats were enriched near the breakpoint junctions consistent with recent observations that increased replicative stress is associated with DNA DSB at sites of mononucleotide repeats (Cell 174:1127-42 2018). Overall this Mcm2 deficiency leads to a unique mutator phenotype characterized by copy number gains/losses of 50-1000 kb. A manuscript describing these findings was published in FY2020 (PMID: 31622281). In theory this mutator phenotype could be used to identify constellations of mutations in other forms of cancer if they lived for 3 months. if Mcm2cre/cre mice could be protected from the highly penetrant pre-T LBL we might uncover additional malignancies triggered by the Mcm2 deficiency. Therefore we crossed Mcm2cre/cre mice onto a nu/nu background and demonstrated that these mice are indeed protected from development of pre-T LBL living a median of 8 months as opposed to 3 months. However the vast majority of Mcm2cre/cre:nu/nu mice develop B cell ALL beginning at approximately 9 months of age. We are now crossing the Mcm2cre/cre mice onto scid/scid and RAG2 KO backgrounds to determine if mice that lack VDJ recombination will be ""protected"" from both T and B cell malignancies." 599222 +Breast Cancer; Cancer; Women's Health Biochemical;Breast Cancer Model;CBL Protein;CBLB gene;Carcinoma;Cells;Collaborations;Complex;Down-Regulation;ERBB2 gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Human;In Vitro;Laboratories;Malignant Neoplasms;Mammalian Cell;Mediating;Molecular Target;Mus;Mutation;Natural Killer Cells;Outcome;PIK3CA gene;Pathogenesis;Pathway interactions;Protein Family;Protein Tyrosine Kinase;Proteins;Receptor Protein-Tyrosine Kinases;Regulation;Research Personnel;Ring Finger Domain;Role;Signal Pathway;Signal Transduction;Solid Neoplasm;Structure;T-Lymphocyte;Tumor Immunity;Ubiquitin-Conjugating Enzymes;Ubiquitination;Work;cancer cell;cell killing;in vivo;inhibitor;malignant breast neoplasm;member;mutant;overexpression;patient subsets;programs;trafficking;tumor;ubiquitin-protein ligase Cbl Proteins as Regulators of Tyrosine Kinase Signaling n/a NCI 10702443 1ZIABC010977-15 1 ZIA BC 10977 15 14821366 "LIPKOWITZ, STANLEY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 647907 NCI RTKs such as EGFR HER2 MET and RET are often inappropriately active (due to mutation or overexpression) in a wide array of epithelial malignancies. My laboratory cloned two of the three members of the mammalian Cbl protein family and demonstrated that they are negative regulators of the EGFR in mammalian cells. We have shown that Cbl proteins are RING finger E3s and that all mammalian Cbl proteins mediate ubiquitination of the activated EGFR resulting in the degradation of the activated EGFR signaling complex. Work in my lab in collaborations with other laboratories and by other investigators has shown the Cbl proteins regulate many RTKs and signaling pathways. In addition my lab has contributed to the structure function analysis of the Cbl proteins. More recently my laboratory has identified and characterized proteins which interact with and modify the function of Cblc the least well characterized Cbl protein identified and are characterizing E2 proteins that interact with the Cbl proteins and identified mutant forms of Cbl proteins in human and mouse epithelial tumors. Ongoing work: 1) investigates the spectrum of ubiquitin conjugating enzymes (E2s) that function with Cbl proteins. 2) investigates the proteins that collaborate with Cbl proteins to mediate RTK downregulation by identifying proteins in the active complex by mass spec analysis. 3) studies mutations of Cbl proteins found in murine and human solid tumors. 4) a screen to identify Cblb E3 inhibitors In a translational project we have found that EGFR is amplified in 2% of breast cancer tumors and that this protends a poor outcome. Further we have found that the EGFR amplified tumors frequently have activating mutations in the PI3K pathway (40-70%). Ongoing work is 1) characterizing the ability of EGFR inhibitors +/- PIK3CA inhibitors to kill cells with mutations in these pathways in vitro and in vivo; and 2) evaluating the effects of these inhibitors on tumor initiating cells. 647907 +Biotechnology; Cancer; Immunization; Immunotherapy; Prevention; Radiation Oncology; Vaccine Related; Women's Health Abscopal effect;Antigens;Antitumor Response;Brachytherapy;CD8-Positive T-Lymphocytes;Cancer Vaccines;Carcinoembryonic Antigen;Chelating Agents;Clinical;Colorectal Cancer;Combined Modality Therapy;Coupling;Cytolysis;Distal;Environment;External Beam Radiation Therapy;Gamma Rays;Goals;Human;Immune system;Immunotherapy;In Vitro;Label;Laboratory Finding;Low Dose Radiation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mediating;Modality;Modeling;Monoclonal Antibodies;Neoplasm Metastasis;Patients;Phenotype;Poxviridae;Primary Neoplasm;Process;Prostate Cancer therapy;Radiation;Radiation therapy;Radio;Radioisotopes;Radiolabeled;Regimen;Role;Site;Source;System;Systemic disease;T cell response;T-Lymphocyte;Therapeutic;Transcend;Transgenic Mice;Translating;Tumor Antigens;Vaccination;Vaccine Antigen;Vaccine Therapy;Vaccines;base;bone;cancer cell;cancer therapy;cancer vaccination;cell killing;immunoregulation;improved;interest;neoplastic cell;preclinical study;prevent;radiation effect;radio frequency;subcutaneous;synergism;thermal stress;tumor;tumor growth;tumor microenvironment;vaccine response Vaccine and radiation for the therapy of human cancers n/a NCI 10702442 1ZIABC010975-15 1 ZIA BC 10975 15 9692343 "HODGE, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 697290 NCI Radiation is a primary modality in cancer treatment. Radiation can also reduce tumor growth outside the treatment field often referred to as the abscopal effect. The mechanisms and therapeutic potential of the abscopal effect have not been fully elucidated. Here we evaluated the role of vaccination directed against a tumor-associated antigen (TAA) in the induction and amplification of radiation induced abscopal effects. Active-specific immunotherapy with a TAA- specific vaccine regimen was used to induce and potentiate T-cell responses against carcinoembryonic antigen (CEA) in combination with local radiation of subcutaneous tumors. We examined the potential synergy of a poxvirus-based CEA vaccine regimen in CEA-transgenic (Tg) mice in combination with either external beam radiation or brachytherapy of local tumors. The induction of CD8+ T-cells specific for multiple TAAs not encoded by the vaccine were observed after the combination therapy. In two tumor models the antigen cascade responses induced by vaccine and local radiation mediated the regression of antigen negative metastases at distal subcutaneous or pulmonary sites. Clinically local control of the primary tumor is necessary and can sometimes prevent metastases radiation generally fails to control pre-existing metastases. By The studies here suggest that by coupling tumor radiation with immunotherapy the abscopal effect can transcend from anecdotal observation to a defined mechanism that can be exploited for the treatment of systemic disease. As our understanding of the immunomodulatory effects of radiation has improved interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further more robust immune system activation. We have now focused preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy including external beam radiation radiolabeled monoclonal antibodies bone-seeking radionuclides and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination. 697290 +Autoimmune Disease; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Hematology; Immunotherapy; Infectious Diseases; Lung; Lupus; Minority Health; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Adult;Autologous;Bronchiolitis Obliterans;Clinical;Clinical Trials;Disease remission;Failure;Frequencies;Graft Rejection;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Immune system;Interferons;Joints;Laboratory Finding;Logistic Regressions;Modeling;Musculoskeletal;Nature;Patients;Phase;Publishing;Refractory;Relapse;Serology;Symptoms;Syndrome;Systemic Lupus Erythematosus;barrier to care;base;chronic graft versus host disease;cohort;genetic signature;graft vs host disease;hematopoietic cell transplantation;montelukast;reconstitution;tumor ETIB Clinical Trials n/a NCI 10702441 1ZIABC010960-15 1 ZIA BC 10960 15 9692325 "GRESS, RONALD " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 3334786 NCI This year we published our phase II results that suggest montelukast may safely halt the progression of bronchiolitis obliterans syndrome which is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation. In a collaborative study we found a high frequency of musculoskeletal symptoms in a cohort of adult patients with cGVHD. The multivariable logistic regression models showed that a joint set of factors were moderately well associated with musculoskeletal symptoms in this study. In addition we found durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory systemic lupus erythematosus (SLE) following lymphodepleting autologous haematopoietic cell transplantation (AHSCT). 3334786 +Cancer; Congenital Structural Anomalies; Neurosciences; Pediatric Adhesions;Affect;Apical;Binding;Biochemical;Biological Models;Breast;Cancer cell line;Cell Adhesion;Cell Fate Control;Cell Line;Cell Lineage;Cell membrane;Cell physiology;Cell-Cell Adhesion;Cells;Cephalic;Colon;Complex;Contact Inhibition;Data;Defect;Development;Developmental Process;Disease;Disseminated Malignant Neoplasm;Distal;E-Cadherin;Embryo;Embryonic Development;Endosomes;Environment;Eph Family Receptors;Ephrins;Epithelial Cells;Event;Family;Family member;GTPase-Activating Proteins;Histologic;Human;Intercellular Junctions;Investigation;Laboratories;Ligands;Locomotion;Lung;Malignant Neoplasms;Maps;Mediating;Membrane;Metalloproteases;Morphogenesis;Morphology;Movement;Neoplasm Metastasis;Neural Crest;Neural Crest Cell;Neural Tube Closure;Neural tube;Neuroblastoma;Ovarian;Pathway interactions;Play;Predisposition;Process;Prosencephalon;Prostate;Proteins;Rana;Receptor Protein-Tyrosine Kinases;Recycling;Research;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;System;Telencephalon;Tissues;Tyrosine;Visual Fields;Xenopus;Xenopus oocyte;angiogenesis;autism spectrum disorder;cancer cell;cell motility;experimental study;flotillin;gene product;improved;insight;interest;loss of function;melanoma;member;migration;mutant;neoplastic;novel;planar cell polarity;protein complex;rab11 protein;receptor;retinal progenitor cell;scaffold;tumorigenesis Signaling Mechanisms of EphrinB1 in Cell Adhesion Migration and Invasion n/a NCI 10702439 1ZIABC010958-15 1 ZIA BC 10958 15 9692315 "DAAR, IRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 832771 NCI Our current research interests are aimed toward examining the mechanism by which Eph receptor tyrosine kinases and their ephrin ligands signal events affecting cell-cell adhesion and morphogenetic movements. From the elucidation of these signal transduction pathways we may improve our understanding of oncogenesis. The cell-cell adhesion system plays a major role in normal development and morphogenesis. Inactivation of this adhesion system is thought to play a critical role in cancer invasion and metastasis. The Xenopus embryo is well suited for investigations of these processes because the frog has a well characterized and invariant cell fate map and cell lineage can be easily traced during experiments. Mutant receptors ligands and other proteins can be ectopically expressed in embryos. Thus their effects on signal transduction motility and differentiation can be assessed morphologically and histologically as well as biochemically in a developing vertebrate. Our laboratory is currently investigating the role of the Xenopus Eph receptor tyrosine kinases and ephrinB transmembrane ligands in cell signaling and function using the Xenopus oocyte and embryo systems as well as human cultured cell lines. At present our emphasis is placed upon the mechanism by which these Eph family members send signals affecting morphogenetic movements. Members of the Eph family have been implicated in regulating numerous developmental processes and have been found to be deregulated in metastatic cancers for example prostate ovarian breast colon neuroblastoma lung and melanoma. Our laboratory has continued these studies examining proximal and distal signaling from ephrinB1 that controls cell adhesion and cell movement. We found evidence that ephrinB1 signals via its intracellular domain to control retinal progenitor movement into the eye field by interacting with Dishevelled (dsh) and co-opting the Wnt/planar cell polarity (PCP) pathway. Using biochemical analysis and gain or loss of function experiments our data suggest that dsh associates with ephrinB1 and mediates ephrinB1 signaling via downstream members of the PCP pathway during eye field formation. Thus we have used the eye field as a model system for understanding how ephrinB1 controls cell movement. Recently we have examined the mechanisms by which ephrinB1 affects cell-cell junctions. A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells and the formation of cell and tissue boundaries. These processes are dependent on the cell cell adhesion system which plays a crucial role in normal morphogenetic processes during development as well as in invasion and metastasis. Although ephrinB ligands are bi- directional signaling molecules the precise mechanism by which ephrinB1 signals through its intracellular domain to regulate cell-cell adhesion in epithelial cells remains unclear. We also have shown that a decrease in a highly related Eph ligand ephrinB2 protein causes neural tube closure defects during Xenopus embryogenesis. Such a decrease in ephrinB2 protein levels is observed on the loss of flotillin-1scaffold protein a newly identified ephrinB2-binding partner. This dramatic decline in ephrinB2 protein levels on the absence of flotillin-1 expression is specific and is partly the result of an increased susceptibility to cleavage by the metalloprotease ADAM10. These findings indicate that flotillin-1 regulates ephrinB2 protein levels through ADAM10 and is required for appropriate neural tube morphogenesis in the Xenopus embryo. Although Eph-ephrin signaling has been implicated in the migration of cranial neural crest (CNC) cells it is still unclear how ephrinB transduces signals affecting this event. We provide evidence that TBC1d24 a putative Rab35-GTPase activating protein (Rab35 GAP) complexes with ephrinB2 via the scaffold Dishevelled (Dsh) and mediates a signal affecting contact inhibition of locomotion (CIL) in CNC cells. Moreover we found that in migrating CNC ephrinB2 interacts with TBC1d24 which in turn negatively regulates E-Cadherin recycling in these cells via Rab35. Upon engagement of the cognate Eph receptor ephrinB2 is tyrosine phosphorylated which disrupts the ephrinB2/Dsh/TBC1d24 complex. The dissolution of this complex leads to increasing E-Cadherin levels at the plasma membrane resulting in loss of CIL and inhibition of CNC migration. Our results indicate that TBC1d24 is a critical player in ephrinB2 control of CNC cell migration via CIL. We have also completed a study that pertains to our previous focus on mechanisms that regulate ephrinB protein levels and the resulting effects on development. Rab11Fip5 is a target of the non-canonical Wnt/PCP signaling pathway and regulates recycling of proteins to the membrane through its interaction with Rab11. Rab11 and its role in neural tube closure has been shown to be under the control of PCP signaling which is required for the apical accumulation of the recycling Rab11-associated endosomes. We were able to determine that Rab11Fip5 plays a critical role in cycling ephrinB1 to the membrane in the developing forebrain. Moreover the interaction between ephrinB1 and Rab11Fip5 is mediated by Rab11 protein and is key to maintaining ephrinB1 at the membrane and maintaining the proliferative capacity of these telencephalic cells. These results provide a novel mechanistic connection between the candidate autism spectrum disorder gene product Rab11fip5 and ephrinB1 and indicate that proper recycling of ephrinB1 through the Rab11/Rab11fip5 complex controls proper telencephalon formation. 832771 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Health Disparities; Immunization; Immunotherapy; Lung; Lung Cancer; Minority Health; Orphan Drug; Prevention; Prostate Cancer; Rare Diseases; Urologic Diseases; Vaccine Related; Women's Health Biopsy;Bladder;Brachyury protein;Breast;CCR;CTLA4 blockade;Cancer Vaccines;Cells;Clinical;Clinical Data;Clinical Trials;Colorectal;Combined Modality Therapy;Combined Vaccines;Cooperative Research and Development Agreement;Correlative Study;Data;Disease;Dose;Effector Cell;Enrollment;Epithelial;FDA approved;Genes;Goals;Human;Human Papilloma Virus-Related Malignant Neoplasm;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immune response;Immunotherapeutic agent;Immunotherapy;Interleukin-15;International;Lead;Lung;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measurable Disease;Merkel cell carcinoma;Mesothelioma;Modality;Nomograms;Non-Small-Cell Lung Carcinoma;Outcome;PD-L1 blockade;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase;Prostate;Publications;Publishing;Radiation;Randomized;Recombinants;Renal Cell Carcinoma;Reporting;Safety;T-Lymphocyte;Testing;Therapeutic;Thymus Gland;Transforming Growth Factor beta;United States National Institutes of Health;Vaccines;Viral Vector;Work;anti-CTLA4 antibodies;anti-PD-L1;anti-PD-L1 antibodies;anti-cancer;anti-tumor immune response;antibody-dependent cell cytotoxicity;base;cancer therapy;checkpoint inhibition;chemotherapy;clinical center;cytokine;design;first-in-human;immune activation;immune checkpoint;immune-related adverse events;interest;ipilimumab;neoplastic cell;novel therapeutics;patient subsets;phase 1 study;preclinical study;programmed cell death ligand 1;programmed cell death protein 1;response;small molecule inhibitor;survival prediction;synergism;therapeutic vaccine;tumor;tumor microenvironment;vaccine development Clinical trials employing cancer vaccine combination therapies n/a NCI 10702437 1ZIABC010945-15 1 ZIA BC 10945 15 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 715531 NCI Much of the focus of new therapies for cancer has shifted in the last decade to include immunotherapy. This is in part due to the rapid profound and durable responses seen with immune checkpoint inhibitors. However these important clinical results are only seen in a subset of patients ones with and underlying immune recognition of the tumor. Data from Dr. Gulley's clinical trials has suggested that therapeutic vaccines can efficiently generate immune recognition and activation against targets present in the vaccine and found in tumor cells (multiple publications). In addition there is an increased infiltrate following vaccine (JITC 2020). However this anti-tumor immune response may not be sufficient to generate an improvement in clinical outcome for the patient without providing for adequate effector functionality within the tumor microenvironment. There are multiple immune checkpoints that are engaged on immune activation. CCR preclinical studies suggested synergy of vaccine with CTLA4 blockade. Dr. Gulley was the PI of one of the first studies combining a CCR developed vaccine (PSA-TRICOM) along with ipilimumab an anti-CTLA4 antibody. Up to 10 mg/kg of ipilimumab was safely administered with PSA-TRICOM. Immune-related adverse events were similar in proportion and grade to those previously reported with ipilimumab alone. Furthermore while the median predicted survival was about 18 months based on a validated nomogram actual median OS exceeded 34 months in this phase I study. This also compares favorably to OS data of ipilimumab alone however a randomized study would be required to validate these hypothesis generating findings. Recent clinical data on PD1 or PDL1 inhibition have accelerated interest in the field of immunotherapy. Dr. Gulley served as the coordinating PI of a phase I dose-escalation study of the only anti-PDL1 antibody designed to not only antagonize PDL1 but to initiate antibody mediated cellular cytotoxicity (ADCC). This first-in-human international study of this agent sponsored by our CRADA partner EMD-Serono enrolled 130 patients at the NIH Clinical Center and has demonstrated dramatic prolonged responses seen in a variety of cancers including lung cancer thymic epithelial malignancies mesothelioma bladder cancer and ovarian cancer. Our data also demonstrated no impact of ADCC on immune cells which can also express PDL1 (albeit often at lower levels than tumor cells). Based on this clinical data the FDA approved avelumab for use in patients with bladder cancer. This data was also used in part to approve avelumab for Merkel Cell Carcinoma and subsequently for 2 more indications (in Renal Cell Carcinoma in combination with axitinib and in 2020 the approval in the switch maintenance setting in bladder cancer). However immune checkpoint inhibition requires an underlying anti-tumor immune response that it can unleash. In prostate cancer the level of activated immune cells within the prostate is limited. Thus combining vaccine with PDL1 blockade is a rational immunotherapeutic approach. We now have multiple ongoing studies in the CCR looking at vaccine with immune checkpoint inhibition. One study combining vaccine with immune checkpoint inhibitor has shown evidence of sustained 90% PSA declines in 2 of 12 patients associated with objective responses (2 CRs) with one patient remaining on study for over 3 years and the other in ongoing CR for about 4 years. Thus it is likely that generating an immune recognition / response by specific therapeutics such as a vaccine is necessary but perhaps not sufficient for tumors like prostate cancer where there is little or no evidence of immune recognition. We also have recently opened a first-in-human first-in-class anti-PDL1/TGF Beta Trap agent (M7824) with initial data published in 2019 demonstrating safety and preliminary evidence of activity (including PRs and a CR in the first 19 patients tested). The activity appears to be increased in HPV associated cancers (about 30% ORR) and in non-small cell lung cancer (about 28% ORR) compared to PD-1 or PDL-1 inhibition alone (JITC 2021). This study has opened the door for multiple combination therapy studies utilizing M7824 to block two important negative regulatory mechanisms that dampen an effective anti-cancer immune response. These ongoing studies will also have built in biopsies and other correlative studies to analyze the impact of the combined therapy on the tumor microenvironment. Dr. Gulley and team also have multiple studies combining modalities to initiate an immune response (vaccine or tumor targeted cytokine) along with immune checkpoint inhibition and / or TGB-beta inhibition cytokine IDO inhibition or small molecule inhibitors (JITC 2018 ESMO 2020). Preliminary data suggests that a combination of vaccine (pox viral vectors encoding genes for 3 T-cell costimulatory molecules and brachyury) IL-15 (N-803) and bintrafusp alfa (an anti-PDL1 antibody that sequesters TGF-beta also known as M7824) have led to sustained deep PSA declines in 6 of 13 patients tested to date with objective responses by RECIST in the 2 of 6 patients with PSA responses who had disease measurable by RECIST. This could not be explained by microsattelite status in these patients and is a confirmation that approaches that generate sufficient numbers of highly functional immune cells (with vaccine and IL15) and allow them to work in the tumor micro-environment (M7824) may lead to traditionally immune unresponsive cancers being able to respond. Additional enrollment is ongoing to further characterize the clinical activity and mechanism of this activity. Additional studies with multiple experimental IO agents are ongoing in a variety of diseases. 715531 +Biotechnology; Breast Cancer; Cancer; Digestive Diseases; Gene Therapy; Genetics; Immunization; Immunotherapy; Liver Cancer; Liver Disease; Lung; Lung Cancer; Neuroblastoma; Neurosciences; Orphan Drug; Pancreatic Cancer; Pediatric; Pediatric Cancer; Rare Diseases; Women's Health Albumins;American;Animal Model;Antibodies;Antibody Therapy;Antigen Targeting;Antigens;Bacteriophages;Binding;Bispecific Antibodies;CAR T cell therapy;CCR;CD276 gene;Cancer Biology;Cancer Family;Canis familiaris;Cell Surface Proteins;Cell Therapy;Cell membrane;Cell physiology;Cell surface;Cells;Childhood Extracranial Solid Tumor;Chimeric Proteins;Clinical;Clinical Research;Clinical Trials;Communities;Data;Development;Disease;Down-Regulation;Epitopes;Event;Fusion Toxin;GPC3 gene;GPI Membrane Anchors;Glypican;Half-Life;Hematologic Neoplasms;Heparan Sulfate Proteoglycan;Human;Immunization;Immunosuppression;Immunotherapeutic agent;Immunotoxins;Infiltration;Journals;Laboratories;Libraries;Liver neoplasms;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of liver;Malignant neoplasm of pancreas;Mediator of activation protein;Membrane;Mesothelioma;Methodology;Methods;Molecular;Molecular Biology;Monoclonal Antibodies;Muromonab-CD3;Mus;National Cancer Institute;Neoplasm Metastasis;Neuroblastoma;Oncolytic;Patients;Pediatric Neoplasm;Phage Display;Primary carcinoma of the liver cells;Production;Protein Biosynthesis;Protein Inhibition;Proteoglycan;Protocols documentation;Pseudomonas aeruginosa toxA protein;Publishing;Research;Role;Serum;Shark;Signal Transduction;Signal Transduction Pathway;Site;Solid Neoplasm;T-Lymphocyte;Technology;Therapeutic;Therapeutic antibodies;Tumor Antigens;United States National Institutes of Health;WNT Signaling Pathway;Work;Xenograft Model;antibody engineering;base;beta catenin;cancer cell;cancer therapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;cross reactivity;exhaustion;extracellular;immunogenic;improved;inducible gene expression;inhibiting antibody;irinotecan;malignant breast neoplasm;mesothelin;nanobodies;neoplastic cell;new technology;novel;novel strategies;overexpression;pancreatic neoplasm;preclinical development;preclinical study;programmed cell death ligand 1;programs;screening;small molecule;syndecan;targeted treatment;treatment strategy;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Development of new antibody-based cancer therapies n/a NCI 10702433 1ZIABC010891-15 1 ZIA BC 10891 15 9692203 "HO, MITCHELL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1629751 NCI "Heparan sulfate proteoglycans (HSPGs) regulate numerous cell surface signaling events. They are extracellular modulators of signal transduction pathways during development and diseases such as cancer. HSPGs are cell-surface proteins that mainly consist of glycosylphosphatidylinositol (GPI)-anchored glypicans and transmembrane syndecans. In the last over 14 years Dr Mitchell Ho's laboratory at the National Cancer Institute (NCI) has studied GPC3 and other glypicans as a new family of cancer targets and developed novel antibody and cell-based immunotherapeutic technologies for treating solid tumors including liver cancer pediatric cancers and other solid tumors. In FY2022 we created novel immunotoxins targeting GPC1 in pancreatic cancer and showed immunotoxins inhibited pancreatic cancer in mice and published our preclinical studies in Molecular Cancer Therapeutics [Pan et al. Molecular Cancer Therapeutics 2022]. GPC1 is a cell surface proteoglycan that is upregulated in multiple types of human cancers including pancreatic cancer. We investigated whether GPC1 could be a target of antibody-toxin fusion proteins (i.e. immunotoxins) for treating pancreatic cancer. We constructed a panel of GPC1-targeted immunotoxins derived from a functional domain of Pseudomonas exotoxin A. An albumin-binding domain was also introduced into the anti-GPC1 immunotoxin to improve serum half-life. Small-molecule screening was performed to identify irinotecan that shows synergistic efficacy with the immunotoxin. We showed that GPC1 was internalized upon antibody binding. Anti-GPC1 immunotoxins alone inhibited tumor growth in a pancreatic cancer xenograft model. The immunotoxin treatment reduced active beta-catenin expression in tumor cells. Furthermore immunotoxins containing an albumin-binding domain in combination with irinotecan caused pancreatic tumor regression. GPC1 expression was reduced by the immunotoxin treatment due to the degradation of the internalized GPC1 and its short cellular turnover rate. Our data indicate that the GPC1-targeted immunotoxin inhibits pancreatic tumor growth via degradation of internalized GPC1 downregulation of Wnt signaling and inhibition of protein synthesis. The anti-GPC1 immunotoxin in combination with irinotecan thus provides a potential new treatment strategy for patients with pancreatic tumors. We also summarized our work in studying GPC1 as an immunotherapeutic target in pancreatic cancer in a review article published in the American Journal of Physiology Cell Physiology [Pan and Ho Am J Physiol Cell Physiol. 2021]. In FY2022 we also developed novel PD-L1 targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer [Li et al. Molecular Therapy Oncolytics 2022]. Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies but it remains challenging to treat solid tumors mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule programmed death-ligand 1 (PD-L1) is widely overexpressed in multiple tumor types and the programmed death-ligand 1 (PD-1)/PD-L1 interaction is a crucial mediator of immunosuppression in the TME. In this new study we constructed a semi-synthetic shark VNAR phage library and isolated anti-PD-L1 single-domain antibodies. Among these VNARs B2 showed cross-reactivity to human mouse and canine PD-L1 and it partially blocked the interaction of human PD-1 with PD-L1. CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1 and hindered tumor metastasis. Combination of PD-L1 CAR (B2) T cells with CAR T cells targeted by GPC3 (a liver cancer-specific antigen) regresses liver tumors in mice. We concluded that PD-L1-targeted shark VNAR single-domain-based CAR-T therapy is a novel strategy to treat breast and liver cancer. This study provides a rationale for potential use of PD-L1 CAR-T cells as a monotherapy or in combination with a tumor-specific therapy in clinical studies. Besides cell-based therapy we also developed bispecific antibody hYP7-OKT3-hFc targeting GPC3 and showed its potent activity in mice [Chen et al. Mol Cancer Ther 2022]. We also published three protocols regarding the construction and production of CAR-T cells and immunotoxins for cancer therapy in STAR Protocols (Cell Press) and Methods in Molecular Biology [Li et al. STAR Protocols 2021; Li and Ho Methods in Molecular Biology 2022; Fleming and Ho Methods in Molecular Biology 2022]. We shared our protocols and methodologies in the scientific community to help advance the CAR-T field quickly. To develop CAR-T for treating other solid tumors we collaborated with Dr. Ira Pastan's lab and Dr. Raffit Hassan's lab to develop novel CAR-T cell therapies targeting mesothelin [Tomar et al. Mol Cancer Ther 2022; Liu et al. PNAS 2022] and with Javed Khan's lab and Brad St Croix's lab to develop novel bicistronic CAR against GPC2 or CD276 in neuroblastoma [Tian et al. J Clin Invest. 2022]. We developed hYP218 (against membrane-proximal epitope) CAR T cells [Tomar et al. Mol Cancer Ther 2022]. Our results show that hYP218 CAR T cells targeting mesothelin epitope close to cell membrane are very effective against mesothelin-positive tumors and are associated with increased persistence and tumor infiltration. These results support its clinical development to treat patients with mesothelin-expressing cancers. In another study led by Dr. Pastan's lab and our lab we have identified shed mesothelin as a major obstacle to successful antibody therapies and prepared a monoclonal antibody that inhibits shedding and makes very active CAR T cells whose activity is not blocked by shed mesothelin and merits further preclinical development [Liu et al. PNAS 2022]. CAR-T cell therapies targeting single antigens perform poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs) limited T-cell persistence and exhaustion. A project led by Dr. Khan's lab Dr. St Croix's lab and our lab aimed to identify optimal CARs against GPC2 or CD276 (B7-H3) which were highly but heterogeneously expressed in neuroblastoma (NB) a lethal extracranial solid tumor of childhood. We made a bicistronic ""OR"" CAR (BiCisCAR). BiCisCAR T-cells effectively eliminated tumor cells expressing GPC2 or CD276. For clinical development we have developed GPC3 (hYP7) GPC2 (CT3) and mesothelin (hYP218) CAR T cells for the clinical trials at the NIH for treating liver cancer mesothelioma and neuroblastoma as supported by the Cancer Moonshot program and the NCI CCR." 1629751 +Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Breast Cancer; Cancer; Cancer Genomics; Clinical Research; Diabetes; Genetics; Health Disparities; Human Genome; Mental Health; Minority Health; Nutrition; Obesity; Precision Medicine; Prevention; Social Determinants of Health; Women's Health ATAC-seq;Affect;African;African American;African ancestry;Age;Alcohol dehydrogenase;American;Architecture;Autopsy;Award;Bile Acids;Biological;Biology;Blood specimen;Body mass index;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;CCR;Cancer Biology;Cancer Research Project;Cancerous;Cell Nucleus;Cell Proliferation;Cells;Characteristics;Chromatin;Clinical Research;Collaborations;Consent;Contracts;DNA Damage;DNA Methylation;DNA Repair;DNA Repair Disorder;Data;Data Set;Dental crowns;Development;Diabetes Mellitus;Diagnosis;Disease;Disease Outcome;Disease Progression;Division of Cancer Epidemiology and Genetics;Environment;Environmental Exposure;Estrogen receptor negative;Ethnic Origin;European;Excess Mortality;Exposure to;Follow-Up Studies;Food;Freezing;Gene Expression;Gene Proteins;Glutamine;Heterogeneity;Hormonal;Human;Hyperglycemia;Immune;Immunologics;Inflammation;Insulin-Dependent Diabetes Mellitus;Investigation;Iron;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Mammary Gland Parenchyma;Mammary Neoplasms;Marker Discovery;Maryland;Measures;Medical Records;Mesenchymal Stem Cells;Messenger RNA;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Mutation;Neighborhoods;Neoplasm Metastasis;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncoproteins;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Pathology;Pathway interactions;Patient Self-Report;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Pilot Projects;Population;Population Group;Premenopause;Process;Proteins;Proteome;Publishing;Race;Reactive Oxygen Species;Reproductive History;Research;Research Personnel;Resources;Risk Factors;Role;Schedule;Signal Transduction;Small Nuclear RNA;Social Environment;Social isolation;Stress;Stressful Event;Structure;Surveys;System;Technology;Tissue Banks;Tissue Sample;Tissues;Transcript;Tumor Biology;Tumor Markers;Validation;Woman;Women's Group;base;biomarker discovery;breast cancer diagnosis;breast cancer progression;breast density;c-myc Genes;cancer surgery;clinically significant;cohort;comorbidity;deprivation;design;digital;digital pathology;epigenome;exome sequencing;experience;genome-wide;health disparity;improved;indexing;inflammatory marker;inhibitor;insight;interest;malignant breast neoplasm;metabolome;metabolomics;methylation pattern;microbiome;neoplastic cell;novel marker;patient biomarkers;perceived stress;prognosis biomarker;response;stem-like cell;survival outcome;targeted treatment;transcriptome;transcriptome sequencing;transcriptomics;tumor;tumor xenograft;tumor-immune system interactions Novel Markers for Disease Outcome in Breast Cancer n/a NCI 10702431 1ZIABC010887-15 1 ZIA BC 10887 15 9692197 "AMBS, STEFAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 913469 NCI Project 1: We continued to comprehensively examine the metabolome proteome and transcriptome of breast tumors from African American and European-American patients for biomarker discovery. The promise of this approach is the discovery of markers for prognosis and of mechanisms that may drive the aggressiveness of breast cancer in African American women. We characterized the metabolomic profile of breast tumors and adjacent non-cancerous tissue from 67 patients and described the differential abundance of more than 200 metabolites. One of them was 2-hydroxyglutarate which was elevated up to 100-fold in tumors that were primarily estrogen receptor-negative. This accumulation of 2-hydroxyglutarate was closely associated with the co-occurrence of a c-Myc signaling signature in the tumors (PMID: 24316975). In a follow up study we could show that breast tumors predominately accumulate D-2-hydroxyglutarate and describe the D-2-hydroxyglutarate-producing alcohol dehydrogenase iron-containing protein 1 (ADHFE1) as a breast cancer oncoprotein that is associated with disease survival. Our data show that ADHFE1 promotes a reductive glutamine metabolism with increased D-2-hydroxyglutarate and mitochondrial reactive oxygen species formation (PMID: 29202474). In an extension to these metabolome studies we analyzed breast tumors for presence of bile acids and how their accumulation may relate to breast cancer biology. This exploratory analysis revealed that a subset of breast tumors accumulates bile acids and show a distinct tumor biology. Tumors with a high bile acid content showed a decreased proliferation rate and associated with improved survival (PMID: 31296531). In a different study focusing on the breast cancer proteome we performed an integrated proteotranscriptomic characterization of breast tumors. We measured global proteome and transcriptome expression in 118 human breast tumors and adjacent non-cancerous tissues. Comparing proteome with transcriptome data we found that the proteome describes differences between cancerous and non-cancerous tissue that are not captured by the transcriptome. Moreover the proteome and transcriptome highlighted partially different tumor biologies. When we applied an integrated analysis of both technologies the approach revealed a global increase in protein-mRNA concordance in tumors. Highly correlated protein-gene pairs were enriched in protein processing and disease metabolic pathways and occurred more commonly in tumors of African American patients. The increased concordance between transcript and protein levels was further associated with aggressive disease including basal-like/triple-negative tumors and decreased patient survival. Our study indicates that an integrated analysis of the proteome and transcriptome in cancer can uncover disease characteristics beyond the ability of a single technology. These data have been published in 2018 (PMID: 30501643). Project 2: Environmental exposures and obesity can modify DNA methylation patterns and alter the tumor epigenome as shown for prostate and breast cancer. Our current research investigates genome-wide DNA methylation in human breast tissues in association with age body mass index tissue inflammation population group and neighborhood deprivation measures. Here we are combining the resources from the NCI-Maryland contract resource with a complementary resource acquired by the Gierach laboratory (DCEG/NCI) from the Komen tissue bank. This partnership will encompass genome-wide DNA methylation data from about one thousand women. It is the unique aspect of the NCI-Maryland cohort that we can link DNA methylation pattern to the neighborhood deprivation index breast cancer and the diagnosis of diabetes in this population. The Komen tissue bank cohort consists of African American and European American age-matched pre-menopausal donors without breast cancer. These women provided non-cancerous breast tissue from breast reduction surgery. We will study DNA methylation and tissue inflammation markers in these tissues additional breast reduction tissues from the NCI-Maryland cohort and in normal breast tissues obtained from autopsy cases. This study will be supplemented with DNA methylation data from breast tumor-adjacent non-cancerous tissue pairs from African American and European American patients. It is the main aim of this collaboration to evaluate patterns of genome-wide DNA methylation in association with tissue inflammation markers like crown-like structures and other risk factors differences between African American and European-American women the impact of diabetes and neighborhood deprivation measures on DNA methylation and to study differences between cancerous and non-cancerous tissues in African American and European-American women. The DNA methylation data can also be integrated with existing gene expression data sets for many of these tissues. Project 3: This project evaluates the role of environmentally induced stress signaling and co-morbidities in breast cancer progression. We started projects studying the impact of stressful life events and diabetes on tumor biology. In a clinical study we will give breast cancer patients who are scheduled for breast cancer surgery a short survey evaluating their perceived stress and social isolation. We will also collect frozen tumor and adjacent normal breast tissue and blood samples from these patients and evaluate whether the breast tissue or the blood samples have a biological signature related to their perceived stress and social isolation status. We hypothesize that patients with a high perceived stress exposure have a biological signature consistent with a more aggressive disease and poorer survival. The pilot study is designed to collect 100 tumor/normal pairs from consented patients with a completed survey. In a second study we are evaluating the relationship between self-reported diabetes and tumor biology and breast cancer aggressiveness. Here a patient's diabetes status based on survey and medical record data will be correlated with global gene expression metabolite patterns and mutational signatures in their tumors to identify cancer-related pathway that are impacted by diabetes. This study is ongoing and will assess whether type 1 and 2 diabetes induce changes to tumor biology that enhance the odds of disease progression. We are particularly interested in changes to metabolic pathways and how they can be targeted to decrease the negative impact that a diabetes diagnosis may have on breast cancer outcomes. More specifically we are investigating the influence of diabetes on breast cancer biology using a three-pronged approach that includes analysis of orthotopic human tumor xenografts patient tumors and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. Current findings are as follows: Diabetes did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. It also promoted oxyradical formation and both transcriptome and mutational signatures of DNA repair deficiency. Moreover food- and microbiome-derived metabolites tended to accumulate in breast tumors in presence of diabetes potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations diabetes-associated breast tumors may show an increased drug response to DN *TRUNCATED* 913469 +Cancer; Clinical Research; Health Disparities; Hematology; Immunotherapy; Infectious Diseases; Minority Health; Orphan Drug; Patient Safety; Pediatric; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation Acute;Adolescence;Allogenic;B-Lymphocytes;Biological;Chimerism;Clinical;Clinical Protocols;Disease;Disease-Free Survival;Dysmyelopoietic Syndromes;Engraftment;Flow Cytometry;Hematology;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Immunologic Deficiency Syndromes;Incidence;Individual;Infection;Kinetics;Leukocytes;Mutation;Mycobacterium avium Complex;Natural Killer Cells;Opportunistic Infections;Patients;Pattern;Phenotype;Population;Recording of previous events;Residual state;Safety;Syndrome;T cell reconstitution;T-Lymphocyte;Therapeutic;Time;Toxic effect;Transplantation;chronic graft versus host disease;curative treatments;emerging adult;immune reconstitution;leukemia;monocyte;patient population;peripheral blood;primary endpoint;reconstitution Hematopoietic Stem Cell Transplant for GATA2 Deficiency n/a NCI 10702426 1ZIABC010870-15 1 ZIA BC 10870 15 9692167 "HICKSTEIN, DENNIS " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1152822 NCI The primary aim of this clinical protocol is to evaluate whether allogeneic hematopoietic stem cell transplant (HSCT) reverses the hematological abnormalities in a recently described syndrome known as MonoMAC which is characterized by: 1) onset in late adolescence or early adulthood; 2) clinical history of opportunistic infection frequently with mycobacterium avium complex (MAC); 3) a distinct peripheral blood leukocyte subset pattern with the presence of T-lymphocytes but a severe deficiency of B-lymphocytes natural killer (NK) cells and the lack of monocytes; 4) dominant inheritance; and 5) frequent progression to myelodysplastic syndrome (MDS). We propose to evaluate whether allogeneic hematopoietic stem cell transplantation (HSCT) can reconstitute normal hematopoiesis in MonoMAC and reverse the hematological abnormalities in myelodysplastic syndrome (MDS) if MDS is present at the time of transplant. While allogeneic HSCT is the conventional curative treatment for immunodeficiency and MDS patients with MonoMAC because of an intact T-cell population and co-existing infection represent a profile not generally encountered in the setting of allogeneic HSCT. The biological questions with MonoMAC center around whether the individual leukocyte compartments that are lost in MonoMAC (B-lymphocytes natural killer cells and monocytes) will be constituted with HSCT and whether the residual recipient T-lymphocytes will represent an impediment to engraftment. We will also evaluate whether we achieve sufficient donor chimerism to reverse the myelodysplastic syndrome. Our specific aims are: 1) To determine whether allogeneic HSCT reconstitutes normal hematopoiesis and reverses the MonoMAC flow cytometry phenotype in patients with MonoMAC by day +100; 2) To determine whether HSCT demonstrates potential as a pre-emptive anti-leukemia strategy in this patient population; 3) To characterize the engraftment kinetics of specific leukocyte subsets (monocytes B-lymphocytes and natural killer cells) deficient in MonoMAC as well as reconstitution of T-cells that are depleted in the course of therapy and the kinetics and extent of reversal of the abnormalities in MDS; 4) To determine the safety of this therapeutic HSCT approach including transplant-related toxicity the incidence of acute and chronic graft-versus-host disease (GVHD) immune reconstitution overall survival and disease-free survival. The primary end-points are to determine whether allogeneic HSCT reconstitutes normal hematopoiesis and reverses the MonoMAC flow cytometry phenotype in patients with MonoMAC by day +100 and to determine whether HSCT demonstrates potential as a pre-emptive anti-leukemia strategy in this patient population. We have now transplanted 15 patients with this syndrome with excellent results. 1152822 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Minority Health; Physical Injury - Accidents and Adverse Effects; Prevention; Radiation Oncology Acute;Animals;Biological Markers;Cell Culture Techniques;Clinic;Clinical Trials;Collection;Complex;Development;Dose;Environment;Extensive Radiation;Goals;Immobilization;Injury;Intervention;Intestines;Knowledge;Laboratories;Lung;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of prostate;Methods;Normal tissue morphology;Organ;Pathway interactions;Patients;Peripheral;Phenotype;Play;Process;Program Evaluation;Protocols documentation;Radiation Dose Unit;Radiation Injuries;Radiation Protection;Radiation Toxicity;Radiation exposure;Radiation therapy;Radiobiology;Radiodermatitis;Role;Sampling;Skin;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Translating;Work;candidate marker;design;experience;experimental study;in vivo Model;interest;irradiation;malignant breast neoplasm;prevent;radiation delivery;radiation mitigator;senescence;targeted agent;tissue injury;tissue stem cells Mechanisms of Normal Tissue Toxicity From Irradiation n/a NCI 10702425 1ZIABC010850-16 1 ZIA BC 10850 16 9414510 "CITRIN, DEBORAH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1846567 NCI In order to evaluate mechanisms of normal tissue injury adequate in vivo models must be developed. Cell culture does not provide the complex environment that is found in tissues thought to be responsible for the initiation of radiation injury. In addition experiments assessing late toxicity often require 6 months to determine if the expected injury has occurred. The delivery of radiation with these experiments must be precisely localized to the tissue of interest to prevent possible peripheral effects to confound results. Our laboratory has established a program for evaluation of late normal tissue toxicity through initiation of a number of animal protocols designed to develop and further study acute and late toxicity in the skin lung and intestine. This has involved the development of specialized radiation treatment immobilizers and shields to deliver the intended dose accurately. Animals have been treated with doses of radiation that we found could reproducibly result in toxicity and samples have been collected for additional high-throughput and hypothesis-driven work to determine the temporal activation of known and yet undescribed pathways in the process of radiation toxicity. In addition two clinical trials were conducted NCI 07-C-0111 and NCI 09-C-0120 that included the collection of various biospecimens in patients receiving radiotherapy for gastrointestinal malignancies breast cancer and prostate cancer. A number of candidate biomarkers of radiation toxicity are being tested in the context of this clinical trial. An additional trial was completed testing a topical nitroxide as a possible method to reduce radiation dermatitis. This nitroxide has been studied extensively by the radiation biology branch who is collaborating in this trial. The major goal of this project is to describe pathways associated with radiation injury target them and translate these findings to the clinic. Several pathways important in radiation injury have already been identified in this project and agents targeting these pathways have been shown to be effective radiation mitigators. We hope to translate these findings into the clinic. 1846567 +Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Genetics; Human Genome; Orphan Drug; Ovarian Cancer; Rare Diseases; Women's Health 3-Dimensional;ABCB1 gene;ABCC1 gene;ABCG2 gene;ATAC-seq;Affect;Antineoplastic Agents;Binding;Bioreactors;Blood capillaries;Breast Cancer Cell;CRISPR screen;Cancer Cell Growth;Cataloging;Cell Death;Cell Line;Cell physiology;Cell surface;Cells;Ceramides;Childhood Rhabdomyosarcoma;Chiroptera;Cisplatin;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Collaborations;Complex;Cultured Cells;Cutaneous;Cytoplasm;Cytotoxic agent;DNA Repair;Development;Diffusion;Disease;Drug resistance;Evolution;Exposure to;FDA approved;Gene Expression;Gene Expression Profile;Genes;Genomics;Goals;Growth;Guide RNA;HDAC3 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;Hydrogels;In Vitro;KB Cells;Knock-out;Length;MAP Kinase Gene;MCF7 cell;Malignant Neoplasms;Malignant neoplasm of ovary;Metabolism;Methylation;Methyltransferase;Microtubules;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Molecular;Multi-Drug Resistance;Multidrug Resistance-Associated Proteins;Mutation;Oxygen;Patients;Pattern;Peripheral;Pharmaceutical Preparations;Phenotype;Physiological;Platinum Compounds;Play;Polymers;Probability;Protein Isoforms;Proteins;Resistance;Rhabdomyosarcoma;Role;Sampling;Serous;Signal Pathway;Silicon;Solid Neoplasm;Specificity;Specimen;Sulfhydryl Compounds;Suspensions;System;T-Cell Lymphoma;Technology;Tubulin;Validation;Verapamil;Vorinostat;Zinc;base;cancer cell;cancer drug resistance;clinically relevant;drug development;efficacy evaluation;efflux pump;glycosylation;in vivo;inhibitor;lung small cell carcinoma;mutant;overexpression;oxaliplatin;paralogous gene;patient derived xenograft model;polymerization;pre-clinical research;prevent;receptor;resistance mechanism;scale up;transcriptome sequencing;tumor;uptake Mechanisms of non-classical multidrug resistance in cancer n/a NCI 10702418 1ZIABC010830-16 1 ZIA BC 10830 16 9414470 "GOTTESMAN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1215034 NCI Three major approaches have been taken to define non-classical multidrug resistance in cancer. In the first we isolate KB cells and ovarian cancer cells resistant to increasing levels of cisplatin (CP-r) and demonstrate multidrug resistance to many other cytotoxic agents. In some cases this cross-resistance pattern is due to reduced uptake of each of these agents because their receptors have been relocalized from the cell surface into the cytoplasm of the cell. We have undertaken a complete genomic analysis using RNA-seq ATAC-seq and Pro-seq technologies to define the alterations in gene expression that accompany the development of drug resistance in cisplatin-selected cell lines and one cataloguing alterations in cisplatin-resistant cells that contribute to drug resistance. These changes have been compared to gene expression changes in clinical samples of serous ovarian cancer and small cell lung cancers for which the primary treatment involves cisplatin as a cytotoxic agent. Preliminary results indicate that a number of genes in addition to those involved in DNA damage repair are associated with the evolution of cisplatin resistance in ovarian cancer cells. Comparing gene expression in cisplatin-sensitive 1A9 ovarian cancer cells cisplatin-resistant 1A9CP80 cells and partially revertant 1A9CP80R cells we noted increased expression of TPPP3 (tubulin polymerization promoting protein 3) in the resistant cells with lower levels in the revertant cells and no expression observed in the parental line. Additionally we noted that cisplatin treatment destabilizes microtubule ends and reduces microtubule length and hypothesized that TPPP3 might mitigate these effects. Interestingly the ability of TPPP3 to counteract the effects of cisplatin treatment were most effective in tubulin purified from 1A9CP80 cells and least effective in 1A9 cells and appeared to correlate with changes in expression of tubulin isoforms in the cell lines. Deletion of TPPP3 via CRISPR knockout partially resensitized the 1A9CP80 cells to cisplatin. High expression of TPPP3 in tumors from patients treated with cisplatin correlated with worse survival probability suggesting a possible clinical role for this protein. Mechanisms of resistance to oxaliplatin differ somewhat from those conferring resistance to cisplatin. Although most cisplatin-resistant cells are partially cross-resistant to oxaliplatin selection for oxaliplatin resistance appears to yield different mechanisms of resistance. One such alteration occurs in ceramide metabolism manifested as increased ceramide glycosylation in some oxaliplatin-resistant cells. To understand more about non-classical mechanisms of multidrug resistance in cancer we are undertaking positive CRISPR screens in cells exposed to various drugs including cisplatin and oxaliplatin. These screens involve using gRNAs in combination with CRISPR-cas constructs that can activate inhibit or knock out target genes. Cells exposed to platinum compounds or other drugs undergo cell death and surviving cells overexpress gRNAs which turn on genes which can independently confer resistance or underexpress genes whose expression is needed for sensitivity to cisplatin. We are currently cataloguing genes whose over- or under-expression affects drug resistance with the goal of defining clinically relevant molecular changes. Histone deacetylase inhibitors (HDIs) are used clinically to treat cutaneous and peripheral T-cell lymphomas diseases for which 3 HDIs have been FDA approved as single-agent therapies. In the case of solid tumors the HDIs have not been effective suggesting intrinsic resistance mechanisms to these drugs. Based on earlier findings in collaboration with Dr. Susan Bates demonstrating that activation of signaling pathways can potentiate resistance to the HDI romidepsin we found that synergistic killing can be achieved with HDIs and inhibitors of the MAPK and PI3K signaling pathways in cells that harbor Ras mutations. We also found that a dual ERK/PI3K inhibitor could take the place of separate MAPK and PI3K inhibitors when combined with an HDI. Further studies have shown that the dual BRD4/PI3K inhibitor SF2523 is synergistically toxic to Ras mutant cells when combined with an HDI. In collaboration with Dr. Mari Yohe we demonstrated that SF2523 alone is particularly effective in childhood rhabdomyosarcoma cell line models and its efficacy can be increased by the addition of the HDI romidepsin. The Center for Advanced Preclinical Research (CAPR) has agreed to examine the efficacy of the SF2523/romidepsin combination in patient-derived xenograft models of rhabdomyosarcoma. Resistance to HDI's such as romidepsin can occur in cultured cells owing to overexpression of P-glycoprotein but in clinical cancers resistance does not appear to be due to this mechanism and studies are in progress to identify other mechanisms of resistance to HDI's. To identify non-P-gp mechanisms of resistance we selected MCF-7 breast cancer cells with romidepsin and verapamil to yield the MCF-7 DpVp300 line which is about 200-fold more resistant to romidepsin than the parental cells. Interestingly the cells appeared to be uniquely resistant to romidepsin as the resistant line was only 3- to 5-fold more resistant to other HDIs such as vorinostat belinostat or panobinostat. RNA Seq analysis comparing the parental and resistant line identified the gene METTL7A which codes for a poorly-described methyltranferase as a potential resistance mechanism. METTL7B a paralog of METTL7A was recently determined to be an alkly thiol methyltransferase that is capable of methylating thiol groups. As the active form of romidepsin has a thiol in its active form and as methylation of the thiol group would prevent coordination of the molecule with zinc in the HDAC binding pocket we hypothesized that METTL7A might be able to inactivate romidepsin or other HDIs with a thiol as the zinc-binding group. In support of this hypothesis knockout of METTL7A from DpVp300 cells resensitized the cells to romidepsin as well as other thiol-based HDIs such as KD5170 and largazole. Interestingly HEK293 cells transfected with METTL7A were resistant to all of the thiol-based HDIs but METTL7B overexpression conferred less resistance to largazole and KD5170 than METTL7A and no resistance to romidepsin. METTL7A and METTL7B thus appear to be methyltransferases with somewhat different specificity that confer resistance to thiol-based HDIs by inactivating these drugs. Validation of these results indicating that MDR is complex and multifactorial in clinical cancers will require the development of reliable in vitro culture models. Towards this goal we have developed a bioreactor that mimics capillary delivery (through silicon hydrogels and the polymer PTMS) of oxygen to cells grown in 3D suspension. We have demonstrated physiological oxygen gradients and altered growth of cancer cells more closely approximating in vivo phenotypes. Evidence that oxygen gradients substantially change gene expression patterns has been obtained by detailed RNAseq analysis. Delivery of physiological concentrations of 3% oxygen directly to cells via artificial capillaries mimics the gene expression patterns of 20% oxygen delivered via diffusion. The bioreactor can be scaled up for growth of multiple cultures of primary cancer cells or cultured cancer cells to determine whether growth conditions and mode of oxygen delivery play a primary role in affecting patterns of drug resistance. 1215034 +Cancer; Cancer Genomics; Genetics; Human Genome; Prevention Acetylation;Address;Affect;Amyloid Beta Precursor Protein-Binding Protein 2;Aneuploidy;Area;Basic Science;Biochemical;Biological Assay;Cell Cycle Regulation;Cell Line;Cell model;Cells;Cellular biology;Centromere;Chromatin;Chromosomal Instability;Chromosomal Stability;Chromosome Segregation;Chromosomes;Clinic;Clinical Trials;Complement;DAXX gene;DNA;DNA Sequence;Defect;Diagnosis;Diploidy;Dose;Drosophila polo protein;Ensure;Euchromatin;Excision;F-Box Proteins;Future;Gene Dosage;Genes;Genetic;Genetic Screening;Genome;Hela Cells;Heterogeneity;Histone Acetylation;Histone Deacetylase Inhibitor;Histone H3;Histone H4;Histones;Human;In Vitro;Incidence;Kinetochores;Length;Link;Lysine;Malignant Neoplasms;Mediating;Methylation;Microtubules;Mitosis;Mitotic;Molecular;Molecular Chaperones;Mus;Nucleosomes;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Post Translational Modification Analysis;Post-Translational Protein Processing;Process;Prognosis;Proteins;Proteolysis;Regulation;Reporting;Research;Role;Saccharomyces cerevisiae;Saccharomycetales;Sister Chromatid;Site;Solid Neoplasm;Sumoylation Pathway;Topoisomerase II;Translating;Ubiquitin-mediated Proteolysis Pathway;Ubiquitination;Variant;Xenograft procedure;Yeast Model System;Yeasts;anticancer research;base;cancer cell;cancer therapy;centromere protein A;chromosome loss;chromosome missegregation;cohesin;cohesion;daughter cell;dosage;established cell line;fly;genome wide screen;genome-wide;in vivo;inducible gene expression;insight;interdisciplinary approach;mouse model;multidisciplinary;mutant;novel;overexpression;prevent;segregation;stoichiometry;targeted treatment;tool;transmission process;tumorigenesis Molecular Determinants of Chromosome Transmission and Cell Cycle Regulation n/a NCI 10702417 1ZIABC010822-16 1 ZIA BC 10822 16 9414472 "BASRAI, MUNIRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2319415 NCI We use multi-organismal (yeast mouse and human cells) and multi-disciplinary (genetic cell biology biochemical and genome-wide) approaches to study faithful chromosome segregation a fundamental process of every living cell. Genetic screens served as a starting point and in-depth mechanistic studies have provided evidence for new roles for kinetochore genes and the identification of new kinetochore genes. We have identified and defined roles for post-translational modifications (acetylation methylation phosphorylation sumoylation and ubiquitination) of Cse4 in chromosome segregation. Our research is focused on understanding the role of Cse4-associated proteins in chromosome segregation and defining pathways that prevent mislocalization of Cse4 to non-centromeric regions. In the first project we defined roles for Scm3 Pat1 Cdc5 and Sgo1 for the assembly of centromeric chromatin and characterized role of post-translational modifications of centromeric histones in faithful chromosome segregation. We determined that imbalanced stoichiometry of a Cse4 chaperone Scm3 (HJURP in humans) leads to chromosome mis-segregation in both human and yeast cells thereby providing a link between HJURP overexpression and mitotic defects in cancers (Mishra et al. 2011). Scm3 interacts with Pat1 (Protein associated with topoisomerase II) and Pat1 regulates the topology of centromeric chromatin (Mishra et al. 2013). We used a pat1 deletion strain to define the number of Cse4 molecules at the yeast kinetochore (Hasse Mishra 2013 Mishra et al. 2015) and provided evidence for a structural role for Pat1 in the structural integrity of centromeric chromatin and localization of Cse4 for faithful chromosome segregation. In addition to kinetochore proteins association of cohesins with centromeres and along the length of the chromosomes ensures faithful segregation of sister chromatids during mitosis. We reported that evolutionarily conserved polo kinase Cdc5 associates with centromeric chromatin to facilitate the removal of centromeric cohesins (Mishra et al. 2016) and Cdc5-mediated phosphorylation of Cse4 regulates faithful chromosome segregation (Mishra et al. 2019). Furthermore evolutionarily conserved Sgo1 which protects centromeric cohesion interacts with Cse4 and this is required for faithful chromosome segregation (Mishra et al. 2018). We recently reported that evolutionarily conserved Hpr1 prevents the accumulation of R-loops at centromeric chromatin affects the assembly of kinetochore and leads to chromosomal instability (Mishra et al. 2021). We have done a comprehensive analysis of Post-translational modifications (PTMs) of Cse4 and identified conserved sites for acetylation methylation and phosphorylation (Boeckmann et al. 2013). We determined that evolutionarily conserved Aurora B/Ipl1 kinase phosphorylates Cse4 in vivo and in vitro for faithful chromosome segregation (Boeckmann et al. 2013). Using budding yeast with a single nucleosome we provided the first evidence that yeast centromeres contain hypoacetylated histone H4 and that increased acetylation of histone H4 on lysine 16 (H4K16) leads to chromosome mis-segregation (Choy et al. 2011). Even though HDAC inhibitors (HDACi) are used in clinical trials we do not fully understand their mode of action. A genome-wide screen with an HDACi was used to identify pathways that are vulnerable to altered histone acetylation. Our results showed that chromosome segregation mutants are more sensitive to HDACi (Choy et al. 2015). Future studies will allow us to understand the molecular role of PTMs of Cse4 in chromosome segregation and determine if these PTMs are conserved in human CENP-A. In the second project we have focused on the identification of pathways that prevent mislocalization of Cse4 and CIN. We showed previously that S. cerevisiae spt4 mutants show mislocalization of Cse4 and chromosome segregation defects that are complemented by human SPT4 (Basrai et al 1996 and Crotti and Basrai 2004). We established the cause and effect of Cse4 mislocalization by showing that altered histone dosage and mislocalization of Cse4 to non-centromeric chromatin correlate with chromosome loss (Au et al. 2008). We identified a novel role for the N terminus of Cse4 in ubiquitin (Ub)-mediated proteolysis for faithful chromosome segregation (Au et al. 2013) and showed that Cse4 is sumoylated and ubiquitination of sumoylated Cse4 by Slx5 regulates its proteolysis to prevent mislocalization to euchromatin (Ohkuni et al. 2016 2018 2020). Genome-wide approaches have been used to identify regulators that prevent mislocalization of Cse4 to euchromatin and these studies revealed a role for histone chaperones (Ciftci-Yilmaz et al. 2018). F-box proteins Cdc4 and Met30 in Cse4 proteolysis (Au et al. 2020) Dbf4 dependent kinase (DDK) (Eisenstatt et al. 2020) and Cdc48 (Ohkuni et al. 2022). Furthermore reduced dosage of histone H4 prevents mislocalization of Cse4 (Eisenstatt et al. 2021). In the third project we have focused on causes and consequences of mislocalization of CENP-A in human cells and xenograft mouse model. Mislocalization of CENP-A has been observed in many cancers and this correlates with poor prognosis. Hence it is critical to understand how CENP-A overexpression contributes to tumorigenesis and whether CENP-A expression can be exploited for prognosis diagnosis and targeted treatment of CENP-A overexpressing cancers. We established cell lines and optimized cell biology-based assays to address a long-standing question of whether mislocalization of overexpressed CENP-A contributes to CIN. We determined that constitutive or inducible expression of CENP-A in HeLa and stable diploid RPE1 cells results in mislocalization of CENP-A to non-centromeric regions. Comprehensive analysis for mitotic effects showed a dose-dependent effect of CENP-A overexpression on chromosome segregation defects and higher incidence of micronuclei. Altered localization of kinetochore proteins contributes to a weakening of the native kinetochore in CENP-A overexpressing cells. Depletion of the histone chaperone DAXX prevents CENP-A mislocalization and rescues the CIN phenotype in CENP-A overexpressing cells. These results show that mislocalization of CENP-A is one of the major contributors for CIN in CENP-A overexpressing cells. Our studies provide the first evidence for how mislocalization of CENP-A to non-centromeric chromatin contributes to CIN in human cells and provide mechanistic insights into how CENP-A overexpression may contribute to aneuploidy in CENP-A overexpressing cancers (Shrestha et al. 2017). We recently reported that mislocalization of overexpressed CENP-A in pseudodiploid DLD1 cell line and xenograft mouse model contribute to CIN aneuploidy with karyotypic heterogeneity (Shrestha et al. 2021). We are pursuing studies with human homologs of the yeast genes identified in genome wide screens and using genome-wide approaches to identify and characterize pathways that prevent mislocalization of CENP-A and CIN. In summary our studies using multi-organismal and multi-disciplinary approaches have provided mechanistic insights for how defects in kinetochore function contribute to aneuploidy in human cancers. We are optimistic that our studies will help translate basic science research to the clinic and aid in the diagnosis prognosis and treatment of cancers that show overexpression of CENP-A. 2319415 +Antimicrobial Resistance; Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Acute;Africa South of the Sahara;Algorithms;Award;Bioinformatics;Cells;Chronic;Clinic;Collaborations;Data;Drug resistance;Enrollment;Epidemic;Genetic;Genetic Polymorphism;Genetic Population Study;Genetic Recombination;Genetic Variation;Genotype;Goals;HIV;HIV Drug Resistance Program;HIV Infections;HIV drug resistance;HIV risk;HIV-1;High Prevalence;Individual;Infection;Integrase Inhibitors;Israel;Lamivudine;Light;Link;Mediating;Molds;Mutation;Nature;Patients;Peripheral;Plasma;Population;Population Dynamics;Population Genetics;Population Heterogeneity;Population Sizes;Positioning Attribute;Procedures;Protocols documentation;Public Health;Reporting;Research;Resistance;Resistance development;Role;Sampling;Source;Structure;Technology;United States National Institutes of Health;Variant;Viremia;Virus;Washington;Zidovudine;abacavir;algorithm development;antiretroviral therapy;assay development;base;bench to bedside;cathinone;genetic analysis;genetic approach;genome sequencing;in vivo;inhibitor;insight;intravenous drug user;invention;next generation sequencing;non-nucleoside reverse transcriptase inhibitors;population based;resistance mutation;technique development HIV-1 Genetic Variation in Infected Individuals n/a NCI 10702416 1ZIABC010819-16 1 ZIA BC 10819 16 1928666 "MALDARELLI, FRANK " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 423515 NCI HIV replication in vivo is rapid and error prone and results in large and genetically diverse populations of HIV-infected cells. We are using population-based sequencing as well as the single-genome sequencing (SGS) technology we developed previously. In addition with M. Kearney's group (HIV DRP) we have investigated the use of next-generation sequencing (NGS) approaches (Illumina sequencing) to study HIV population genetics. We have utilized these approaches to analyze and understand the accumulation of genetic variation in gag/pol and env. We have made significant advances in additional assay development and have extended studies to a number of different patient groups including chronically infected patients both naive and on therapy as well as in primary and early HIV infection. As a result we are obtaining a more comprehensive picture of HIV genetic variation in vivo in the presence or absence of drug resistance. _____We have previously reported that replicating population size is substantial prior to initiating antiretroviral therapy (ART). We have applied NGS approaches to refine the estimates of HIV and found that 1X107 infected cells may be replicating in infected individuals daily. In our new studies we have been able to investigate rates of recombination in vivo and found that recombination occurs at a high rate in vivo such that there are very few linked polymorphisms in any virus population and that recombination represents a potentially important mechanism for spread of HIV mutations. As resistance to integrase inhibitors increases and NIH clinics are enrolling more such patients we are studying the development of resistance to this important class of HIV inhibitors. ____We have recently reported the emergence of high-level resistance to dolutegravir with the addition of a single secondary mutation at position T97A. We have now completed a detailed analysis of the emergence of resistance and found that the T97A variant emerged from a limited number (3-4) of variants that arose rapidly by replication and as predicted by our population genetics studies through recombination. The development of these techniques has led to new insights in HIV population dynamics in understanding the effects of ART the nature of replication in natural suppression of HIV and population dynamics of non-subtype B HIV populations. ____The dynamics of HIV-1 populations in patients undergoing ART remain uncertain and we are conducting an extensive genetic analysis of HIV-1 before and after initiation of ART (completed Protocol 97-I-0082 new Protocol 08-I-0221). These results will yield new information regarding the nature and timing of genetic bottlenecks occurring during ART. Analysis of HIV-1 sequences at relatively low viremia has been limited by technical issues in amplifying the relatively few HIV-1 sequences present in plasma during therapy. We have successfully adapted the SGS procedure to obtain acceptable numbers of sequences from patients suppressed on ART. In collaboration with M. Polis and D. Persaud (NIH Bench to Bedside Award 2006) we are analyzing genetic variation in patients enrolled in Protocol 97-I-0082 (now 08-I-0221; F. Maldarelli PI) who have been suppressed on ART for prolonged (greater than 8 y) periods. Initial analyses demonstrate that HIV does not undergo a genetic bottleneck upon initiation of ART; despite a 100- to 10000-fold decline in levels of peripheral viremia no significant decreases in genetic diversity were detected in the first 1-2 y of therapy. These data indicate a common source of virus infecting short-lived cells (responsible for greater than 90-99% of virus produced prior to therapy) and longer-lived cells (responsible for virus produced 1-2 years after therapy is initiated). After prolonged therapy emergence of predominant clones (as previously noted by Bailey et al.) was detected in the majority (7/8) patients. We are also applying population genetics approaches to quantify the emergence of drug-resistance mutations in rebound viremia in patients undergoing ART. We are specifically investigating the relative roles of mutation and selection in development of resistance to AZT and NNRTI as well as quantifying the role of APOBEC-mediated mutations in the emergence of the M184I mutation conferring resistance to 3TC FTC and to a degree abacavir. ____We are using these approaches to investigate the spread of HIV in the US and in selected populations in the world. We have demonstrated clear evidence of early spread of drug-resistant HIV in the HIV epidemic in Washington DC which has the highest prevalence of HIV in the US. We are now investigating the spread of HIV in DC using samples stored early in the epidemic. We have demonstrated that subtype C HIV the most common subtype in the world was present a number of years earlier than previously thought and prior to the rapid expansion of this subtype in sub-Saharan Africa. These studies have yielded information and new sequences that are critical to understanding the current spread of HIV in DC and will inform public health strategies to eliminate the spread of HIV in DC. In addition we recently reported analysis of a mini-epidemic spread of a specific subtype A HIV variant among intravenous drug users (IVDU) associated with cathinone abuse in Israel. Despite public health efforts to halt the spread we found this variant was continuing to spread in IVDU and could also be detected in other HIV risk groups. Understanding the expansion of genetic diversity following infection from a genetically limited to a highly diverse population has useful implications for applicability in understanding the HIV epidemic. Based on our understanding of genetic variation in acute and chronically infected individuals we developed a new bioinformatics algorithm to discriminate between recently and chronically infected individuals based exclusively on population-based commercial genotyping data. Development of this algorithm has yielded the invention report EIR #238-2009. This approach has been used in a variety of settings and we have used it to investigate spread of HIV in DC and more recently in analysis of the subtype A mini-epidemic in Tel Aviv Israel. ____These studies have shed new light on the spread of HIV in populations and inform the public health efforts to eradicate HIV worldwide. 423515 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Gene Therapy; Gene Therapy Clinical Trials; Genetics; Health Disparities; Immunotherapy; Lung; Lung Cancer; Minority Health; Orphan Drug; Prevention; Rare Diseases; Women's Health Adoptive Cell Transfers;Affinity;Animal Model;Antibodies;Ascites;Bacterial Toxins;Biopsy;C-terminal;CAR T cell therapy;CTLA4 gene;Cancer Patient;Categories;Cell Line;Cell surface;Cells;Characteristics;Clinic;Clinical;Clinical Trials;Complex;Conduct Clinical Trials;DNA Repair Gene;Development;Differentiation Antigens;Distal;Drug Targeting;Enrollment;Epidermal Growth Factor Receptor;Epitopes;Follow-Up Studies;Genetic;Germ-Line Mutation;Goals;Human;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunotherapeutic agent;Immunotherapy;Immunotoxins;In Vitro;Infiltration;Inflammation;Injections;KRAS2 gene;Laboratories;Laboratory Research;Laboratory Study;Lead;Link;Liquid substance;Longterm Follow-up;Lung Adenocarcinoma;Malignant Neoplasms;Malignant mesothelioma;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of thorax;Maximum Tolerated Dose;Membrane;Mesothelial Cell;Mesothelioma;Modeling;Monoclonal Antibodies;Morphology;Mus;Mutation;Non-Small-Cell Lung Carcinoma;Oryctolagus cuniculus;Outcome;Pancreatic Adenocarcinoma;Pathway interactions;Patient Recruitments;Patients;Peripheral Blood Mononuclear Cell;Peritoneum;Pharmaceutical Preparations;Phase I Clinical Trials;Phase I/II Clinical Trial;Platinum;Pleura;Pleural;Pleural Mesothelioma;Prior Therapy;Prognosis;Pseudomonas aeruginosa toxA protein;Publishing;Regulation;Research;Role;Safety;Screening for cancer;Surface;T cell therapy;T-Cell Activation;T-Cell Receptor;Therapeutic Agents;Translational Research;Tumor Cell Line;Tumor-Derived;Vaccines;Work;anti-PD-L1 antibodies;anti-PD1 antibodies;antitumor effect;cancer prevention;cancer therapy;cell killing;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;cytotoxicity test;de-immunization;differential expression;drug sensitivity;effective therapy;falls;graft vs host disease;human model;humanized mouse;immune checkpoint;immunotherapy clinical trials;improved;in vivo;in vivo Model;ipilimumab;mesothelin;mouse model;mutant;neoplastic cell;novel;novel strategies;novel therapeutics;pembrolizumab;pericardial sac;phase 2 study;phase I trial;phase II trial;preclinical study;programmed cell death ligand 1;programs;systemic inflammatory response;targeted agent;translational medicine;tumor;tumor xenograft;tumor-immune system interactions;vector Immunotherapy for Malignant Mesothelioma and Lung Cancer n/a NCI 10702415 1ZIABC010816-16 1 ZIA BC 10816 16 6189074 "HASSAN, RAFFIT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2018756 NCI 1. Exploiting mesothelin for mesothelioma therapy and related translational research Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin which is expressed on normal mesothelial cells lining the pleura pericardium and peritoneum but is highly expressed in several human tumors especially mesothelioma ovarian cancer lung cancer and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. These include anti mesothelin immunotoxin (LMB-100) an anti-mesothelin drug conjugate (BAY 94-9343) mesothelin vaccine (CRS-207) and adoptive T-cell therapy (TC-210). We are currently developing mesothelin-targeting adoptive cellular therapy using chimeric antigen receptor (CAR)-T cells. Majority of the anti-mesothelin antibodies in clinical development target the membrane distal region of mesothelin that could partly account for the lack of activity of anti-mesothelin CAR-T cell therapy in the clinic. To improve CAR-T cell anti-tumor activity we propose a new approach i.e. developing anti-mesothelin CAR-T cells that target an epitope close to the surface of tumor cells. My collaborator Dr. Mitchell Ho has identified a high affinity rabbit monoclonal antibody (YP218) specific for region III which is located at the C-terminal end of mesothelin close to the tumor cell surface. We have tested the cytotoxicity of the hYP218 CAR-T construct on several mesothelin expressing cell lines and anti-tumor effect in animal models. The pre-clinical studies have shown increased tumor killing (1). This construct is now under clinical development. Parallelly we are conducting a clinical trial of a T-cell receptor fusion construct (TRuCs). Unlike other constructs TRuCs are naturally incorporated into the native TCR complex thus exploiting the full potential of TCR-driven T cell activation effector function and regulation. LMB-100 is an immunotoxin consisting of the anti-mesothelin Fv linked to a truncated form of the potent bacterial toxin Pseudomonas exotoxin A which has been de-immunized to decrease its antigenicity. We have recently completed the phase I trial of LMB-100 and established its safety and maximum tolerated dose (MTD) published in Cancer (2). Currently we are evaluating the results of a recently concluded a phase II study of LMB-100 in patients with mesothelioma in combination with immune checkpoint inhibitor Pembrolizumab. Since LMB-100 causes systemic inflammation and increase in immune cell infiltration in patient tumors we hypothesized that intra- tumoral injection of LMB-100 would lead to increased inflammation and immune cell infiltration. Administering checkpoint inhibitors would further increase tumor-cell killing. We are presently conducting a phase 1 clinical trial in patients with mesothelioma where they are intratumorally administered LMB-100 on days 1 and 4 followed by CTLA-4 checkpoint inhibitor ipilimumab given i.v. on day 2 of a 21 day cycle. Patients will receive 2 cycles of LMB-100 plus ipilimumab followed by 2 cycles of ipilimumab alone. Tumor biopsies will be performed prior to each administration of LMB-100 to evaluate changes in the tumor immune microenvironment. The trial is recruiting patients. We have previously shown that germline mutations in DNA repair genes increases sensitivity to platinum therapy and improves overall survival in patients with pleural mesothelioma (3). Currently my laboratory is studying germline mutations in DNA repair genes that could predispose to mesothelioma and influence clinical outcome. We are enrolling patients and their relatives harboring such mutations for a long term follow up study for early cancer detection and prevention. In the laboratory we have focused on developing in-vitro and in-vivo models of human mesothelioma. We have established several early passage tumor cell lines from ascites and pleural fluid of patients. We have evaluated the morphological and genetic characteristics of these cell lines and are using them to study in-vitro drug sensitivity. Additionally we have established a humanized mesothelioma xenograft tumor model with patient derived tumor cells and human PBMCs from healthy donor for in-vivo studies. As the development of Graft Versus Host Disease (GVHD) in the PBMC-humanized mouse model limits assessment of duration of anti-tumor efficacy we have developed a syngeneic immunocompetent mouse model. Because the immunotoxin LMB-100 can target human mesothelin specifically we established a human mesothelin expressing immunocompetent syngeneic mouse tumor model by transfecting PD-L1 positive mouse lung adenocarcinoma cell line with a hMSLN expressing vector encoding the membrane bound fragment of hMSLN. These cell lines were used to develop tumor. We have studied the effect of LMB-100 in combination with anti-PD1 antibody in both the models and have seen tumor regression. We have published our findings in Science Translational Medicine (4). These models are essential to evaluate novel therapeutic agents for mesothelioma and for the mechanistic studies of anti-tumor efficacy. Other ongoing laboratory studies are focused on understanding the mesothelioma tumor immune micro-environment and changes following treatment with anti-mesothelin targeted agents. 2. Immunotherapy to treat lung cancers. We are currently conducting clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C in patients with lung adenocarcinoma who have failed prior therapies. Our laboratory has recently shown that about 25% of patients with metastatic lung adenocarcinoma highly express mesothelin. Mesothelin expression in these tumors is highly associated with KRAS mutations and wild type EGFR status and is independently associated with poor prognosis. Our hypothesis is that patients with K-RAS mutant lung cancer can benefit from mesothelin directed therapies. Clinical trials of mesothelin directed therapies for treating lung cancer are about to open. Our laboratory is also studying the role of immune checkpoints in malignant mesothelioma so that drugs targeting this pathway can be exploited for treating mesothelioma. We are currently conducting a Phase II trial of NSCLC patients treated with LMB-100 in combination with pembrolizumab. 2018756 +Cancer; Cancer Genomics; Genetics; HIV/AIDS; Health Disparities; Human Genome; Infectious Diseases; Minority Health Adopted;Affect;Binding;Biochemical;Biogenesis;Biological Assay;Bypass;Carrier Proteins;Cell Nucleus;Cell membrane;Cells;Characteristics;Collaborations;Complex;Cytoplasm;Deltastab;Dimerization;Elements;Epidemic;Equilibrium;Evolution;Exhibits;Gatekeeping;Gene Expression;Genetic Transcription;Genome;Goals;Guanosine;HIV;HIV-1;HIV-2;Image;Individual;Integration Host Factors;Knowledge;Length;Location;Mediation;Molecular Cloning;Nuclear Export;Nuclear RNA;Nucleotides;Pathway interactions;Primate Lentiviruses;RNA;RNA Binding;RNA Folding;RNA Transport;RNA-Binding Proteins;Regulation;Replication Origin;Role;SIV;Site;Structure;Time;Transcription Initiation Site;Translating;Translations;Travel;Treatment Protocols;Untranslated RNA;Vaccines;Viral Genome;Viral Proteins;Virion;Virus;Virus Replication;base;cell growth regulation;dimer;experimental study;exportin 1 protein;insight;mutant;particle;pathogen;pol Gene Products;progenitor;rev Protein;rev-Responsive Elements;viral RNA Elucidating the Regulation of HIV RNA Functions: Translation Genome Packaging n/a NCI 10702414 1ZIABC010814-16 1 ZIA BC 10814 16 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 951445 NCI Retroviral full-length RNA serves two important roles in viral replication: the template for Gag/Gag-Pol translation and the genome in the virion. Our previous results showed that most HIV-1 particles have two copies of viral RNA genome indicating that the packaging is tightly regulated. We have performed studies and showed that HIV-1 packaging is not regulated by RNA mass but by recognizing a dimeric RNA. We have now defined the sequences necessary and sufficient for packaging RNA into HIV-1 virions. Additionally we have determined the role of several highly structured RNA elements in HIV-1 replication. We are also examining the translation of the full-length RNA and delineating the host factors that affect HIV-1 RNA nuclear export and the dynamics of HIV-1 RNA export from the nucleus to the cytoplasm. These experiments seek to gain insights into how HIV-1 RNA serves its functions. ___BACKGROUND: The full-length HIV-1 RNA (hereafter referred to as HIV-1 RNA) serves as a template for Gag/Gag-Pol translation and as the virion genome. HIV-1 RNA needs to negotiate through the complex cellular regulation of the host to be exported from the nucleus to the cytoplasm. Once exported HIV-1 RNA can be translated and/or packaged and needs to strike a balance between these two functions. In this project we seek to gain a better understanding of how HIV-1 RNA serves its roles. ___As an unspliced RNA HIV-1 RNA needs to bypass the cellular gatekeepers to be exported from the nucleus and reach the cytoplasm. HIV-1 RNA contains an RNA structure the Rev responsive element (RRE). The viral protein Rev binds to the RRE and interacts with the host protein CRM1 to allow for the export of HIV-1 RNA. Recent studies revealed that the regulation of RNA export may be more complex than previously envisioned and may involve multiple host factors other than CRM1 and RanGTP. We are studying how export pathways affect cytoplasmic HIV-1 RNA transport and proteins associated with the RNA. ___It was recently shown that HIV-1 uses heterogenous transcriptional start sites and the usage of the sites can affect RNA function. We have established a collaboration with Dr. Karin Musier-Forsyth to examine the impact of HIV-1 transcription start site usage on RNA structures and functions. Additionally we are collaborating with Dr. Brandon Keele to study the conservation of the usage of transcription start sites to control RNA functions. ___ACCOMPLISHMENTS: To gain a better understanding of HIV-1 gene expression we tracked translation of individual HIV-1 RNAs in living cells. We found that on average half of the cytoplasmic HIV-1 RNAs are being actively translated at a given time. Furthermore translating and nontranslating RNAs are well mixed in the cytoplasm; thus Gag biogenesis occurs throughout the cytoplasm without being constrained to particular subcellular locations. Because Gag is an RNA-binding protein and packages HIV-1 RNA a long-standing question regarding HIV-1 gene expression is whether Gag modulates its own translation. We observed that despite its RNA-binding ability Gag expression does not alter the proportion of translating HIV-1 RNA. Although both translating and nontranslating RNAs can travel to the plasma membrane the major HIV-1 assembly site Gag selectively packages nontranslating RNA into the assembly complex. These studies illustrate that although HIV-1 RNA serves two functions as a translation template and as a viral genome individual RNA molecules carry out only one function at a time. ____ HIV-1 transcription initiates from multiple neighboring sites generating RNA species that only differ by a few nucleotides at the 5' end including those with one (1G) or three (3G) 5' guanosines. Strikingly 1G RNA is preferentially packaged into virions over 3G RNA. We used biochemical and virological assays to investigate how HIV-1 distinguishes between these two nearly identical HIV-1 RNAs. We found that 1G RNA but not 3G RNA mainly folds into structures that expose elements important for RNA:RNA and RNA:Gag interactions. Additionally we have identified mutants in which 1G and 3G RNAs fold into similar structures resulting in efficient packaging of 3G RNA. Thus HIV-1 selects its viral genome based on its capacity to adopt structures that facilitate RNA dimerization and Gag binding. Unspliced HIV-1 RNA serves two important roles during viral replication: as the virion genome and as the template for translation of Gag/Gag-Pol. Previous studies of two HIV-1 molecular clones have concluded that the TSS usage affects unspliced HIV-1 RNA structures and functions. To investigate the evolutionary origin of this replication strategy we determined transcription start sites (TSS) of HIV-1 RNA in infected cells and virions for 15 primate lentiviruses. All the HIV-1 isolates examined including several transmitted founder viruses utilized multiple TSS and selected a particular RNA species for packaging. Furthermore these features were observed in SIVs related to the progenitors of HIV-1 suggesting that these characteristics originated from the ancestral viruses. HIV-2 SIVs related to HIV-2 and other SIVs also exhibited multiple TSS and preferential packaging of specific unspliced RNA species. These findings indicate that multiple TSS usage and selective packaging of a particular unspliced RNA species predate the emergence of HIV-1. 951445 +Cancer; Genetics; Health Disparities; Minority Health Binding;Chromatin;Chromatin Structure;Cryoelectron Microscopy;DNA;DNA Binding Domain;DNA Sequence;Eukaryota;GATA4 gene;Genome;High Mobility Group Proteins;Histones;Kinetochores;Molecular Chaperones;Nucleosomes;Play;Proteins;Role;Structural Models;Structure;TAF1 gene;Time;chromatin remodeling;gene function;insight;interest;residence;transcription factor Chromatin structure and dynamics n/a NCI 10702413 1ZIABC010808-16 1 ZIA BC 10808 16 8778148 "BAI, YAWEN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2145329 NCI For FY21/22 we used cryo-EM to determine the structures of the nucleosomes containing native-DNA sequences bound to various pioneer transcription factors including OCT4 Pu.1 FoxA1/GATA4 and Ascl1. Our studies provide structural insights into the hypothesis of pioneer transcription factors (PTF) by showing: (i) PTFs help evict H1 by direct blocking and by an allosteric effect; (ii) the DNA binding domain can serve as a wedge to unwrap the nucleosomal DNA; (iii) multiple PTFs can bind to the nucleosome which may increase the overall residence time. In addition we found surprisingly that PTFs may use non-canonical motifs instead of canonical motif to recognize the nucleosome. We also established a structural model of H1 bound to its chaperone TAF1-beta using NMR. We showed that TAF1-beta binds to the linker histone and functions as a chaperone by blocking H1 interactions with DNA. 2145329 +Biotechnology; Cancer; Cancer Genomics; Gene Therapy; Genetics; Human Genome; Immunotherapy; Neuroblastoma; Neurosciences; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases ALK gene;Affinity;Amino Acids;Animal Model;Antigens;Apoptosis;Automobile Driving;Biological Assay;Biological Products;Biology;Bromodomain;Burkitt Lymphoma;CD8B1 gene;CMV promoter;CRISPR screen;CRISPR/Cas technology;Cell Count;Cell Death;Cell Line;Cell Survival;Cell surface;Cells;Cetuximab;Childhood;Childhood Solid Neoplasm;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complement;DNA;Data;Detection;Development;Down-Regulation;Drug Compounding;Drug Screening;Enhancers;Enzyme-Linked Immunosorbent Assay;Epidermal Growth Factor Receptor;Epigenetic Process;Extracellular Domain;FDA approved;FGFR4 gene;FOXO1A gene;Family member;Firefly Luciferases;Freezing;Gene Expression;Generations;Genes;Genetic Transcription;Goals;Green Fluorescent Proteins;Growth;Guide RNA;Human;Immune Targeting;Immunohistochemistry;Immunotherapeutic agent;Immunotherapy;Injury;Investigational Drugs;Knock-in;Laboratories;Lead;Libraries;Luciferases;Malignant Childhood Neoplasm;Measurement;Mediating;Methods;Molecular Target;Monitor;Monoclonal Antibodies;Mus;Mutate;Mutation;Myoblasts;National Center for Advancing Translational Sciences;Neuroblastoma;Normal tissue morphology;Nucleotides;Oncogenes;Organ;PAX3 gene;PAX7 gene;Patients;Peptides;Pharmaceutical Preparations;Pharmacology;Phase;Plasmids;Post-Translational Protein Processing;Principal Component Analysis;Prognostic Marker;Property;Protein Biosynthesis;Proteins;RNA Interference;Receptor Protein-Tyrosine Kinases;Renilla Luciferases;Reporter;Reporting;Rhabdomyosarcoma;Signal Transduction;Site-Directed Mutagenesis;System;T-Lymphocyte;Technology;Tertiary Protein Structure;Testing;Tissue Microarray;Toxic effect;Translating;Transmembrane Domain;Work;Xenograft procedure;cancer therapy;cell growth;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;design;diagnostic biomarker;differential expression;drug mechanism;experimental study;fusion gene;gene repression;genome-wide;genomic locus;high risk;high throughput screening;in vivo;inhibitor;kinase inhibitor;knockout gene;luminescence;muscle regeneration;nano;novel;novel therapeutics;overexpression;patient derived xenograft model;peripheral blood;preclinical development;protein protein interaction;proteostasis;receptor;response;skeletal muscle differentiation;small hairpin RNA;small molecule;stoichiometry;synergism;targeted treatment;therapeutic target;trafficking;transcriptome;transcriptome sequencing Developing Novel Therapies for High Risk Pediatric Cancers n/a NCI 10702412 1ZIABC010806-16 1 ZIA BC 10806 16 9692453 "KHAN, JAVED " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 854306 NCI "Among other assays we will use the Incutyte and ACEA systems to monitor cell growth. For the CRISPR screens we are performing genome wide and epigenetic focused libraries. For the drug screen we will use single agent and combination responses of a panel of 2000 drugs (Mechanism Interrogation Plate (Libraries) developed by NCATS. The content of this library include FDA approved compounds several of which are approved for cancer therapy those in clinical trials (phase 1 2 or 3) several kinase inhibitors. For all these compounds the target or mechanism of action is known. The most promising targets will be further evaluated in patient derived xenograft animal models. In a complementary effort with NCATs we have teamed up the Molecular Targets Laboratory to identify inhibitors of the PAX3-FOXO1 fusion gene. To do this we will utilize the PAX3-FOXO1 activity reporter cell line developed by our laboratory using the super-enhancer region within the ALK gene which was cloned upstream of a minimal CMV promoter driving a Green Fluorescent Protein (GFP)-Luciferase reporters. We confirmed that RH41 cells (FP-RMS) appeared green with the stably transduced reporter construct whereas RD cells (FN-RMS) containing the reporter construct were negative. We also confirmed that the ALK enhancer luciferase activity in the RH41 cell line was suppressed rapidly upon induction of the shRNA against PAX3-FOXO1. Of note decrease in luciferase activity preceded reduction of cell number. This property allows for the cell line to be utilized in drug screening experiments. This is currently being performed in large scale. For epigenetic studies our group has recently showed that PAX3-FOXO1 reprograms the cis-regulatory epigenetic landscape by inducing de novo super enhancers in collaboration with the bromodomain and extra-terminal domain protein family member BRD4 freezing FP-RMS cells in a myoblast-like state. These studies proved the feasibility of using unbiased high-throughput screening approaches to identify small molecules that disrupt the PAX3-FOXO1 core regulatory circuitry. In particular we demonstrated that PAX3-FOXO1 transcriptional activity depends on its physical interaction with BRD4. The BRD4 inhibitor JQ1 ablated this interaction resulting in decreased PAX3-FOXO1 protein levels that correlated with suppression of FP-RMS xenograft growth in mice. In addition to protein-protein interactions protein homeostasis (encompassing protein synthesis folding trafficking and degradation) is influenced by many other factors including post-translational modifications. Therefore selectively targeting modifications that will result in decreased stability or activity of PAX3-FOXO1 is an attractive approach toward development of novel therapies for FP-RMS. Our previous screens used indirect approaches as they assessed PAX3-FOXO1-driven target gene expression or FP-RMS cell viability with PAX3-FOXO1 protein levels being characterized post-hoc. Assay readouts of tagged endogenous proteins obviate the limitations associated with exogenous reporters where overexpression may disrupt the natural stoichiometry of interacting proteins or result in aggregation or mislocalization. Further it is critical that the functional activity of the protein not be impeded by the addition of the tag and thus smaller tags are desirable because of their presumably reduced impact. For these reasons we chose to fuse the pro-luminescent HiBiT peptide to endogenous PAX3-FOXO1 using CRISPR/Cas9-mediated knockin. HiBiT is a small 11-amino acid peptide capable of producing a luminescence signal that is about 100-fold brighter than firefly or Renilla luciferases through high affinity complementation with LgBiT an 18 kDa subunit derived from the NanoLuc luciferase thereby allowing detection at high sensitivity. Plasmids encoding Cas9 and single guide RNAs targeting the carboxy terminus of FOXO1 together with a DNA construct for homology-directed HiBiT addition were transfected into two FP-RMS cell lines RH4 and SCMC. The DNA homology construct encoding HiBiT was followed by a P2A ""self-cleaving"" peptide for coexpression of an mCherry fluorescent protein as a FACS-selectable marker. Single mCherry-positive clones were sorted into 96-well plates and expanded. Six clones were obtained for each cell line in which the HiBiT tag was demonstrated to be successfully appended to the carboxy terminus of PAX3-FOXO1 using the Nano-Glo HiBiT Blotting System. Nucleotide sequencing of clones RH4.P3F-HmC 1A9 (RH4.PAX3-FOXO1-HiBiT-P2A-mCherry clone 1A9) and SCMC.P3F-HmC 3C4 (SCMC.P3F-HiBiT-PAX3-FOXO1-P2A-mCherry clone 3C4) confirmed accurate in-frame addition of the HiBiT tag to PAX3-FOXO1. Principal component analysis of RNA-seq data showed that the edited clones faithfully recapitulated the transcriptome landscape of the parental FP-RMS cell lines. HiBiT signal was readily detectable and HiBiT-tagged PAX3-FOXO1 was reduced at the protein level upon treatment with JQ1 and the clinical BRD4 inhibitor CPI-0610. RH4.P3F-HmC 1A9 and SCMC.P3F-HmC 3C4 are being subjected to quantitative high-throughput screening using single agent and combination responses of a panel of 4500 FDA-approved and advanced investigational drugs toward the identification and preclinical and clinical development of new treatment options for FP-RMS. For Rhabdomyosarcoma (RMS) FGFR4 is a rational target given that it is a key regulator of myogenic differentiation and muscle regeneration after injury; it is expressed in myoblasts but not in differentiated skeletal muscle. We and others have found that FGFR4 is highly expressed in all RMS and high expression is a diagnostic and prognostic biomarker. It is a direct target and strongly induced by PAX3-FOXO1 PAX3 and PAX7 and we reported that PAX3-FOXO1 established a super-enhancer at the gene's locus. We have reported that approximately 10% of FN-RMS have activating mutations in FGFR4 and that cells harboring FGFR4 mutations are oncogene addicted and sensitive to pharmacological inhibition by small molecules. Therefore FGFR4 is a key cell surface tyrosine kinase receptor for RMS biology growth and survival. We are developing monoclonal antibodies and human scFv binders. The majority detect the human FGFR4 protein by both ELISA and by FACS analysis . To mitigate for potential organ toxicity we are examining FGFR4 expression levels in normal human organs. We are currently performing extensive RNAseq and immunohistochemistry (IHC) analysis of normal organ and rhabdomyosarcoma tissue arrays. We are testing our scFv binders as potential FGFR4 chimeric antigen receptors (CARs) to generate a second-generation CAR receptor lentiviral construct that contains the CD8 transmembrane region 41BB and CD3zeta intracellular domains and a human EGFR extracellular domain. This design was chosen because of its efficacy in clinical trials and CAR T cell persistence in patient's peripheral blood for several months after therapy. The truncated EGFR in the CAR construct allows for the measurement of transduced T cells as well as therapeutic targeting of CAR T cells with Cetuximab in clinical trials in case of uncontrolled toxicity. Anti-FGFR4 CART cells could lyse RH30 but not RAJI a FGFR4 negative Burkitt's lymphoma cell line (data not shown). Work is currently underway to validate FGFR4 CAR T cells in-vivo. We are also developing novel TCRs as therapies for pediatric solid tumors. If successful we anticipate the development of potent immunotherapeutic biologics and cell-ba *TRUNCATED*" 854306 +Biotechnology; Breast Cancer; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health; Women's Health Alternative Splicing;Area;Bacillus subtilis;Bacteria;Base Pairing;Biochemical;Biochemical Genetics;Biochemistry;Bioinformatics;Biological;Biological Assay;Biological Models;Breast Cancer Cell;Breast Cancer cell line;Cells;Clinical;Codon Nucleotides;Collaborations;Communication;Coupled;Coupling;Cues;DNA;DNA Polymerase II;DNA Repair;DNA lesion;DNA sequencing;DNA-Directed RNA Polymerase;Data;Disease;Distal;ERBB2 gene;Elongation Factor;Energy-Generating Resources;Environment;Epigenetic Process;Escherichia coli;Estrogen receptor negative;Eukaryota;Eukaryotic Cell;Evaluation;Event;Failure;Foundations;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomic Instability;Goals;Growth;Human;Hypoxia;In Vitro;Intervention;Laboratories;Malignant Neoplasms;Manuscripts;Metabolic;Methodology;Methods;Modeling;Modernization;Molecular;Molecular Biology;Nature;Neoplasm Metastasis;Nonsense Mutation;Nucleosomes;Organism;Outcome;Oxidative Phosphorylation;Paper;Pathway interactions;Play;Preparation;Progesterone Receptors;Prognosis;Prokaryotic Cells;Protein Isoforms;Proteins;Publishing;RNA;RNA Caps;RNA Processing;RNA Splicing;Reaction;Regulation;Reporter Genes;Research;Resolution;Ribonucleases;Role;Saccharomyces cerevisiae;Signal Transduction;Site;Solid;Solid Neoplasm;Stress;Structure;Targeted Research;Techniques;Technology;Testing;Transcript;Transcriptional Elongation Factors;Transcriptional Regulation;Translations;Woman;Work;Yeasts;attenuation;base;biological adaptation to stress;cancer cell;cancer type;cleavage factor;court;environmental change;genetic approach;genetic manipulation;genome-wide;hormone therapy;in vivo;knock-down;knockout gene;malignant breast neoplasm;mutant;next generation sequencing;novel;promoter;response;rho;termination factor;transcription factor;transcription factor S-II;transcription termination;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor progression;tumorigenesis Mechanisms of transcription pausing and fidelity in prokaryotes and eukaryotes n/a NCI 10702411 1ZIABC010795-16 1 ZIA BC 10795 16 6802163 "KASHLEV, MIKHAIL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1743689 NCI In this project my lab published 2 research papers (PNAS and Nature Communications) and a review article in Critical Reviews in Biochemistry and Molecular Biology. We also have one collaborative manuscript published in 2021 in eLife that describes the role of elongation factor NusG in transcription termination in B. subtilis. We completed developed a new powerful NGS method involving a combination of ribonuclease-coupled NET-seq (RNET-seq) and DNA-seq that allows genome-wide mapping of pause sites for E. coli B. subtilis and human RNA polymerase II (Pol II) with a single base pair resolution. This methodology allowed us to determine translocation register of RNA polymerase at each pause site and identify the underlying causes of pausing. This method enabled direct examination of the role of ALL general and specialized transcription elongation and termination factors NusA NusG NusB Rho RfaH SuhB RpoD (sigma70) GreA GreB mfd and UvrD in pausing and promoter escape in vivo. This goal was achieved by applying RNET-seq/DNA-seq to the genetically modified bacterial strains carrying the systematic gene knockouts and conditional knockdowns (using inducible dCas9 transcription roadblocks) of the corresponding target gene followed by biochemical evaluation of the mechanism of pausing at the representative pause sites in vitro. By using RNET-seq we were first to demonstrate the crucial role of sigma70 subunit and Gre transcript cleavage factors in regulation of promoter escape at a striking large number of E. coli promoters primarily involved in regulation of stress response and cellular responses to changing environmental cues (Nature Communications). We also elucidated the role of elongation factors NusA and NusG in regulation of transcription pausing and termination in E. coli and B. subtilis (PNAS eLife and manuscript in preparation). Transcription fidelity: In our approach to study transcription fidelity we combine the efficiency and high-sensitivity of the novel cre/lox-based genetic assay developed for the yeast and E. coli cells in our group as a team effort with three other RBL groups with the power and precision of biochemical analysis of RNAP mutants transcription factors and reaction conditions promoting transcription errors in these organisms. We also study in vitro the mechanisms of transcription fidelity in higher eukaryotes. For genetic assay we create site-directed chromosomal mutants and gene constructs using advanced high-precision methods of gene manipulations based on recombineering developed in collaboration with Don Court's group. Application of the modern NGS RNA sequencing techniques brings our analysis of transcription errors to a genome-wide scale. The use of four biological models namely E. coli B. subtilis S. cerevisiae and human triple negative breast cancer (TNBC) cells under normal and stress conditions allows us to do the cross-species and cross-kingdom study of transcription fidelity helping to unravel conserved and unique features of strategies that various organisms implement to control transcription fidelity. We believe that the experimental strategy and techniques that we use in the current work lay a solid foundation for our future studies on transcription fidelity. In 2020-21 my lab continued active intervention to the new area of transcription research targeting the role of pausing of human Pol II in transcription-coupled events of 5' RNA capping co-transcriptional splicing and transcription termination in triple negative breast cancer cells (TNBCs). This study will help us in identifying the novel splicing isoforms genome-wide which are deregulated in TNBC cells. Since hypoxic stress is an emerging hallmark of TNBCs we aim to determine how the RNA capping co-transcriptional splicing and transcription termination downstream from polyA sites are deregulated during hypoxic stress. Our preliminary data strongly indicate that co-transcriptional splicing and transcription termination downstream from the polyA sites are significantly altered in TNBC cells compared to their non-TNBC counterparts including these events in hypoxia-induced genes. 1743689 +Biotechnology; Cancer; Clinical Research; Genetics; HIV/AIDS; Immunization; Prevention; Vaccine Related; Women's Health Affect;Africa;African American population;African ancestry;Agreement;Alleles;American;Amino Acid Sequence;Antibodies;Antigens;Autoimmune Diseases;Binding;Biology;Black race;Cell surface;Characteristics;Code;Collaborations;Communicable Diseases;Complex;Data;Data Set;Disease;Disease Outcome;Disease Progression;Effector Cell;Endoplasmic Reticulum;Enzyme-Linked Immunosorbent Assay;European;Exhibits;Failure;Genes;Genetic;Genetic Polymorphism;Genetic Population Study;Genome;Genotype;Goals;HIV;HIV Antigens;HLA Class I Genes;HLA-B Antigens;Heterozygote;Human;IgG1;IgG2;IgG3;Immune;Immune Response Genes;Immune response;Immunoglobulin G;Individual;Inflammatory;Investigation;KLRD1 gene;Laboratories;Laboratory Study;Ligands;Measures;Messenger RNA;Methods;Modeling;Molecular;Molecular Genetics;Mosaicism;Natural History;Natural Killer Cells;Pathogenesis;Pathogenicity;Peptide Signal Sequences;Peptides;Phase II Clinical Trials;Population;Population Group;Predisposition;Regulation;Resistance;Serology;South African;T-Lymphocyte;Vaccination;Vaccine Antigen;Vaccines;Variant;Viral Load result;Work;base;causal variant;cohort;env Gene Products;experimental study;gene product;human disease;inter-individual variation;interest;member;novel;preference;receptor;response;tapasin;trait;vaccine trial Molecular genetics and population studies of the KIR and HLA gene complexes n/a NCI 10702409 1ZIABC010792-16 1 ZIA BC 10792 16 9414396 "CARRINGTON, MARY N." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 624706 NCI "Human immunoglobulin G (IgG) molecules IgG1 IgG2 and IgG3 exhibit substantial inter-individual variation in their constant heavy chain regions as discovered by serological methods. This polymorphism is encoded by the IGHG1 IGHG2 and IGHG3 genes and may influence antibody function. We sequenced the coding fragments of these genes in 95 European Americans 94 African Americans and 94 Black South Africans. Striking differences were observed between the population groups including extremely low amino acid sequence variation in IGHG1 among South Africans and higher IGHG2 and IGHG3 diversity in individuals of African descent compared to individuals of European descent. Molecular definition of the loci illustrates a greater level of allelic polymorphism than previously described including the presence of common IGHG2 and IGHG3 variants that were indistinguishable serologically. Comparison of our data with the 1000 Genome Project sequences indicates overall agreement between the datasets although some inaccuracies in the1000 Genomes Project are likely. These data represent the most comprehensive analysis of IGHG polymorphisms across major populations which can now be applied to deciphering their functional impact. HLA-E presents VL9 nonomers derived from signal peptides (SP) of classical HLA-I molecules and serves as a ligand for the inhibitory CD94/NKG2A and activating CD94/NKG2C receptors expressed on NK and T cells. We are investigating how HLA-I SP polymorphism can influence HLA-E peptide loading and interaction with their receptors. Of 16 common HLA-I SP variants only six can be loaded on HLA-E and facilitate receptor recognition. We plan to expand our experiments to comprehensively characterize the impact of SP polymorphism on HLA-E function in regulating effector cell activity. We also found that SP polymorphism can influence cell surface expression levels of classical HLA-I a regulatory mechanism in addition to the HLA allele-specific mRNA regulation previously characterized by our lab. Investigation of SP polymorphism influence on HLA-I function will serve as a basis for developing models to predict immune responses in human diseases based on HLA genotypes alone. A number of HLA class I (HLA-I) alleles especially HLA-B alleles are strongly associated with protection from or susceptibility to HIV disease progression. We considered that HLA genotype might influence the immune response against HIV antigens after vaccination against HIV. The Janssen vaccine phase 2 clinical trial studied the immune response to a mosaic antigen vaccine. Although there was no significant correlation of HLA alleles with overall response to all antigens combined as measured by either ELISA or ELISpot there was a significant correlation of HLA-I alleles with differential ELISpot response to gag vs. env antigens that reflect the impact of the same alleles on control of HIV viral load in natural history cohorts. The Imbokodo vaccine trial in Africa was deemed a failure but we hope to determine (again in collaboration with Janssen) whether the trial was actually successful in subjects carrying these protective HLA alleles. The products of the highly polymorphic HLA-I genes initiate the immune response by presenting antigenic peptides to T cells. Individuals heterozygous at HLA loci are able to present a greater repertoire of peptides potentially allowing a more productive immune response against a greater variety of pathogenic threats. We have developed a metric to quantitate the similarity between pairs of HLA-I alleles based on the set of peptides they present which we term ""functional distance"". We propose that functional distance between pairs of HLA alleles will provide greater sensitivity in distinguishing the breadth of peptides any given individual can present to T cells than a simple binary division of homozygosity vs. heterozygosity. Those individuals carrying HLA-I genotypes with greater functional distance may be particulary resistant to infectious diseases but perhaps more susceptible to inflammatory/autoimmune disease a hypothesis that we would like to pursue." 624706 +Cancer; Clinical Research; Emerging Infectious Diseases; Genetics; HIV/AIDS; Immunotherapy; Infectious Diseases; Orphan Drug; Precision Medicine; Rare Diseases; Women's Health Accounting;Acute;Advanced Malignant Neoplasm;Affect;Age;Algorithms;Alleles;Alternative Therapies;Autoimmune Diseases;Binding;Biological;Biological Process;Case Study;Cell surface;Cells;Cellular Immunity;Centers for Disease Control and Prevention (U.S.);Characteristics;Clinical;Communicable Diseases;Complex;Convalescence;Data;Data Set;Databases;Democratic Republic of the Congo;Dependence;Disease;Disease Outbreaks;Disease Outcome;Drug Side Effects;Ebola;Ebola Hemorrhagic Fever;Ebola virus;Enrollment;Eye;Frequencies;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Guinea;HIV-1;HLA-A gene;HLA-B Antigens;HLA-C Antigens;Homozygote;Immune;Immune Response Genes;Immune response;Immunogenetics;Immunoglobulins;Immunologic Receptors;Immunologics;Individual;Innate Immune Response;Killer Cells;Knowledge;Leukocytes;Liberia;Ligands;Liver;Malaria;Malignant Neoplasms;Measures;Molecular;Outcome;Pathogenesis;Patients;Peptides;Play;Polymerase Chain Reaction;Population;Predisposition;Property;Research Personnel;Resistance;Resources;Reverse Transcription;Risk Factors;Role;Seminal fluid;Serum;Severity of illness;Shapes;Signal Pathway;Single Nucleotide Polymorphism;Site;Survivors;Symptoms;T-Lymphocyte;Test Result;Testing;Time;Transplantation;Variant;Viral;cancer immunotherapy;cancer therapy;checkpoint inhibition;cohort;differential expression;experience;genetic association;human disease;improved;interest;lens;mRNA Expression;male;novel;patient stratification;peptide I;predictive marker;receptor;response;tapasin;tool;tumor;viral RNA Effects of genetic polymorphism in MHC KIR and related loci on human disease n/a NCI 10702408 1ZIABC010791-16 1 ZIA BC 10791 16 9414396 "CARRINGTON, MARY N." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 780882 NCI "Immune checkpoint inhibition therapy (ICI) is now first-line therapy for certain cancers but response rates rarely exceed 40% and side effects of these drugs can be debilitating and even lethal. There is a critical need for improved predictive biomarkers to facilitate better patient stratification and management algorithms. We measured the effect of HLA variation on survival in patients with advanced cancer treated with various ICI vs. alternative therapies and found that HLA-A*03 was associated with shorter survival in each tumor type evaluated in these analyses. Overall responses to ICI were absent or rare in HLA-A 03 homozygotes. Thus HLA-A 03 is a predictive biomarker of poor response to ICI and should be considered in decisions regarding cancer therapy. We are interested in determining the basis for the deleterious effect of HLA-A 03 in patients treated with ICI and identifying additional immunogenetic risk factors (or beneficial variants) in cancer and cancer immunotherapy. HLA-I allotypes vary widely in their dependence on tapasin (TAPBP) an integral component of the peptide loading complex to present peptides on the cell surface. We have determined tapasin dependence (TD) values for common HLA-I allotypes across worldwide populations (N = 250) which show a continuum of values for HLA-A HLA-B and HLA-C. This variation is functionally relevant as tapasin-independent allotypes were shown to present a broader array of peptides than tapasin-dependent allotypes and tapasin independence conferred protection in HIV-1 disease. Given the role of tapasin in shaping the HLA-I peptide repertoire and its impact on disease outcome we hypothesized that natural variation in its expression level could also affect disease pathogenesis and susceptibility. We identified two single nucleotide polymorphisms (SNPs) that control TAPBP mRNA expression and those that confer higher TAPBP expression associate with protection against malaria outcomes specifically amongst individuals with tapasin-dependent HLA allotypes. Tapasin expression had no effect on tapasin-independent allotypes. These data highlight the importance of cellular immunity against malaria at the liver stage of disease. Long-term persistence of Ebola virus (EBOV) in immunologically privileged sites has been implicated in recent outbreaks of Ebola virus disease (EVD) in Guinea and the Democratic Republic of Congo. We collaborated on a study with investigators at the CDC to try to understand how the acute course of EVD convalescence and host immune and genetic factors may play a role in prolonged viral persistence in semen. A cohort of 131 male EVD survivors in Liberia were enrolled in a case-case study. ""Early clearers"" were defined as those with 2 consecutive negative EBOV semen test results by real-time reverse-transcription polymerase chain reaction (rRT-PCR) greater than or equal to weeks apart within 1 year after discharge from the Ebola treatment unit or acute EVD. ""Late clearers"" had detectable EBOV RNA by rRT-PCR greater than 1 year after discharge from the Ebola treatment unit or acute EVD. Compared with early clearers late clearers were older (median 42.5 years) and experienced fewer severe clinical symptoms. Late clearers had more lens opacifications after accounting for age higher total serum immunoglobulin G3 (IgG3) titers and increased frequency of HLA-C 0304. Overall older age decreased illness severity elevated total serum IgG3 and HLA-C 0304 allele expression may be risk factors for the persistence of EBOV in the semen of EVD survivors. EBOV persistence in semen may also be associated with its persistence in other immunologically protected sites such as the eye." 780882 +Autoimmune Disease; Cancer; Digestive Diseases; Immunotherapy; Infectious Diseases; Inflammatory Bowel Disease; Liver Cancer; Liver Disease; Rare Diseases Achievement;Acquired Immunodeficiency Syndrome;Acute;Affect;Animal Cancer Model;Anti-Tumor Necrosis Factor Therapy;Antigen-Antibody Complex;Antigens;Antineoplastic Agents;Apoptosis;Apoptotic;Arthritis;Autoimmune;Autoimmune Diseases;Biological;Blood Vessels;COVID-19;Cell Proliferation;Chronic;Crohn's disease;Development;Disease;Dose;Exhibits;Genes;Glucocorticoids;Growth;Helicobacter Infections;Hepatitis C;Immature Monocyte;Immune;In Vitro;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Innate Immune System;Integrins;Interferons;Interleukin-1;Interleukin-10;Interleukin-13;Interleukin-4;Knock-out;Laboratories;Lead;Lipopolysaccharides;Lymphangiogenesis;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Mediator of activation protein;Metalloproteases;Modeling;Molecular;Multiple Sclerosis;Mus;NF-kappa B;Necrosis;Neoplasm Metastasis;Nitric Oxide;Parasites;Participant;Pathogenesis;Pathologic;Pathway interactions;Peripheral;Phenotype;Play;Primary carcinoma of the liver cells;Process;Production;Proteins;Receptor Signaling;Regulation;Research;Rheumatoid Arthritis;Role;SARS-CoV-2 infection;Septic Shock;Signal Pathway;Signal Transduction;Site;Skin;T-Lymphocyte;TLR3 gene;TLR4 gene;TNF gene;TNFR1 Signaling Pathway;TNFRSF1A gene;TRADD gene;Testing;Therapeutic;Tissue Differentiation;Tissues;Toll-like receptors;Transforming Growth Factors;Tumor Cell Invasion;Tumor-associated macrophages;Virus Diseases;Whole Organism;activating transcription factor;adaptive immune response;angiogenesis;antagonist;arginase;cancer therapy;cancer type;chronic inflammatory disease;colon carcinogenesis;cytokine;cytotoxicity;extracellular;leukemia/lymphoma;macrophage;malignant breast neoplasm;malignant stomach neoplasm;monocyte;mouse model;neoplastic cell;neutralizing antibody;pathogen;response;transcription factor;tumor;tumor growth;tumor initiation;tumorigenesis Inflammation Macrophage Differentiation and Cancer n/a NCI 10702405 1ZIABC010783-16 1 ZIA BC 10783 16 9417013 "LIU, ZHENG-GANG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 651310 NCI Inflammation plays a critical role in tumorigenesis and it is known that many cancers are associated with sites of chronic inflammation. For instance colon carcinogenesis is associated with inflammatory bowel diseases (IBD) Helicobacter pylori infection is the cause of stomach cancer and hepatitis C viral infection correlates with liver carcinoma. Opposing effects of TNF on cancer have been described: high dose of TNF (acute inflammation) has antineoplastic effects such as direct cytotoxicity on certain types of cancer while endogenous low-dose of TNF (chronic inflammation) promotes cancer development. As a potent inducer of NF-kB activation the tumor promoting effect of TNF is believed to be through activating this transcription factor. The constitutive activation of NF-kB is associated with many autoimmune inflammatory diseases such as rheumatoid arthritis multiple sclerosis and inflammatory bowel disease as well as certain cancers such as leukemia and lymphomas breast cancer and gastrointestinal cancers. NF-kB promotes tumorigenesis both by enhancing cell proliferation and by induction of anti-apoptotic genes. Inhibition of NF-kB is a potential anti-cancer therapy. However one of the caveats in inhibiting NF-kB systemically is that NF-kB is indispensable for both innate and adaptive immune responses. Tissue-specific knock-out models allow to study the effects of selective targeting of the NF-kB pathway on tumorigenesis without affecting NF-kB in the whole organism. Due to the tumor promoting effect of TNF TNF antagonists have been suggested as potential cancer treatment agents. Alternatively targeting various molecules involved in TNFR1 signaling pathway upstream of NF-kB is another possible therapeutic strategy against cancer-promoting inflammatory responses. Using TRADD-deficient mice we have shown that TRADD plays an important role in mediating TNF signaling. In addition TRADD is involved in TLR3 and TLR4 signaling as well. It is known that Toll-like receptors (TLRs) play an essential role in the development of innate and adaptive immune responses and that TLR signaling triggers inflammation through the activation of NF-kB and other transcription factors. Moreover recent studies suggest that one of the mechanisms by which tumors evade immune attack is through expressing TLRs. TLR signaling promotes tumor cell proliferation and reduces apoptosis. It enhances tumor invasion by regulating metalloproteinases and integrins and induces the synthesis of pro-inflammatory cytokines. Since deletion of TRADD will affect several signaling pathways including TNFR1 and TLR3/4 TRADD is a potential target for blocking tumor-promoting inflammatory responses. Therefore we have started to investigate the importance of TRADD-mediated inflammatory responses in tumor development with tissue-specific TRADD deletion in the mouse models of skin tumorigenesis. Macrophages are chief participants in host inflammatory responses of the innate immune system. Deregulation of macrophage differentiation and function may lead to diseases including cancer Following antigen stimulation immature monocytes emigrate from blood vessels into peripheral tissues where they differentiate into mature macrophages. Macrophages are considered classically activated (M1) when stimulated by interferon (IFN) or lipopolysaccharide (LPS) to release nitric oxide (NO) important for killing intracellular pathogens and alternatively activated (M2) when stimulated by interleukin (IL)-4 or IL-13 (M2a) to produce IL-10 transforming growth factor (TGF) and arginase-1 (Arg1) important for killing extracellular parasites. M2 can be further subdivided to those induced by immune complexes (ICs) and LPS or IL-1 (M2b) or those induced by IL-10 TGF or glucocorticoids (GC) (M2c) (51). The molecular processes that occur during monocyte/macrophage differentiation and polarization particularly in the differentiation of M2 type macrophage are not completely understood. The capability of macrophages to express distinct functional phenotypes is typically manifested in pathological conditions including cancer. Tumor-associated macrophages (TAMs) which represent the major inflammatory component of the stroma of many tumors are critical mediators of tumor initiation progression and metastasis. In contrast with normal macrophages TAMs exhibit pro-tumoral functions including the growth survival invasion and metastasis of tumor cells as well as angiogenesis and lymphangiogenesis in tumors. TAMs have been shown to display an alternative M2 like activation phenotype and play a detrimental pro-tumoral role. Blocking TAMs functions has been shown to have great inhibitory effect on tumorigenesis. We also study the regulation of monocyte/macrophage differentiation. Particularly how tumor cells regulates macrophages to become tumor associated macrophages. Recently we found that tumor necrosis/necroptosis-induced inflammation is critical for tumorigenesis. tumor cells secret certain proteins to mediate the differentiation of TAMs which in turn promote tumor growth. we are evaluating the roles of these proteins on TAMs function in animal cancer models. Eventually we will test if using neutralizing antibodies against these proteins will help to control tumor metastasis. We also collaborated with others to study the inflammation-promoting effect on tumor development. We are currently using mouse macrophages to study macrophage-mediated response to SARS-Cov-2 infection in vitro. 651310 +Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Adverse effects;Anti-Retroviral Agents;Antiviral Agents;Betulinic Acid;Binding;Biochemical;Capsid;Cells;Clinical Trials;Collaborations;Conduct Clinical Trials;Development;Generations;Genetic Polymorphism;Goals;HIV-1;Link;Maps;Molecular;Mutation;Pathway interactions;Patients;Peptide Hydrolases;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phytic Acid;Play;Polyproteins;Preclinical Testing;Property;Research;Resistance;Role;SP1 gene;Site;Structural Biologist;Structure;Structure-Activity Relationship;Techniques;Time;Toxic effect;Viral;Viral Load result;Virus;Work;analog;antiretroviral therapy;gag Gene Products;inhibitor;insight;multidisciplinary;mutant;novel;resistance mutation;response;structural biology;viral resistance HIV-1 Maturation n/a NCI 10702403 1ZIABC010778-16 1 ZIA BC 10778 16 9698291 "FREED, ERIC " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 851167 NCI "While currently available antiretroviral therapies are highly effective in suppressing HIV-1 replication in treated patients these drugs are not curative. Patients are thus required to remain on continuous lifelong therapy which has been associated with a variety of toxicities and adverse effects. Also over time viral resistance is likely to pose an increasingly serious problem for patients on therapy. The development of novel classes of inhibitors that block steps in the replication cycle distinct from those targeted by currently available drugs is therefore a high priority. We have played a leading role in the development of one such novel class of HIV-1 antiviral drugs the maturation inhibitors (MIs). _____In the HIV-1 replication cycle Gag proteins are synthesized as a polyprotein precursor (Pr55Gag) that is cleaved by the viral protease (PR) during virus release from the infected cell. Completion of the Gag processing cascade is essential for virus maturation and infectivity. In collaboration with Panacos Pharmaceuticals we found that 3-0-(3'-3'-dimethylsuccinyl) betulinic acid (PA-457 now known primarily as bevirimat or BVM) potently inhibits HIV-1 maturation by specifically blocking a late step in the Gag-processing pathway the conversion of the capsid-spacer peptide 1 (CA-SP1) region of HIV-1 Gag to mature CA. Clinical trials conducted with BVM produced mixed results; in some patients significant reductions in viral loads were achieved whereas in other patients no benefit of BVM therapy was observed. We and others demonstrated that this lack of response was linked to polymorphisms in SP1. We have also studied in detail the target mechanism of action and resistance pathways of a second structurally distinct MI discovered by Pfizer (PF-46396 or PF96). We found that resistance to PF96 was conferred by mutations not only in the vicinity of the CA-SP1 cleavage site [where resistance to BVM maps] but also upstream in the CA major homology region (MHR). Notably the MHR mutants that arose during selection for PF96 resistance were markedly PF96 dependent. The MHR mutants which on their own are highly deficient in assembly and replication could also revert by acquiring a second-site mutation in SP1 residue 8 (T8I). The study of the PF96-dependent MHR mutants and the T8I compensatory mutant is providing a wealth of information about the role of CA and SP1 in assembly and maturation and will advance our understanding of the structural properties of SP1. Our research on BVM and PF96 has provided novel insights into the structure-function relationship between CA and SP1 as well as a framework for increased structural understanding of HIV-1 MI activity. _____We have now forged a multidisciplinary collaborative effort together with chemists at DFH Pharmaceuticals to develop ""second-generation"" BVM analogs that are significantly more potent and broadly active against polymorphic isolates of HIV-1 than BVM or PF96. The best of these analogs are undergoing preclinical testing in anticipation of clinical trials. More long term we hypothesize that defining the structure of the MI-binding pocket in HIV-1 Gag will greatly facilitate the development of novel and more potent inhibitors; to this end we are collaborating with several structural biology labs to define the structure of the CA-SP1 region in the immature Gag lattice in both the presence and the absence of bound inhibitor. Our working hypothesis is that MIs block CA-SP1 processing by stabilizing a six-helix bundle that extends from the C-terminus of CA into SP1. Resistance mutations confer escape by stabilizing this helical bundle. We are collaborating with structural biologists to define the structure of MI-bound Gag by NMR techniques. We are also studying the effect of inositol hexakisphosphate (IP6) on MI activity. We believe that our work in this project will be transformative both in understanding the structure and function of the CA-SP1 region of Gag which plays critical roles in HIV-1 assembly and maturation and in developing MIs as a novel class of antiretroviral agents." 851167 +Biotechnology; Cancer; Neuroblastoma; Neurosciences; Rare Diseases Agonist;Antibodies;Basic Science;Binding;Carbohydrates;Child;Clinical;Databases;Diagnostic;Disease;Disease Progression;Engineering;Evaluation;FDA approved;Goals;Lectin;Malignant Neoplasms;Mammals;Microarray Analysis;Monoclonal Antibodies;Neuroblastoma;Play;Polysaccharides;Protein-Carbohydrate Interaction;Proteins;Reagent;Research;Role;Therapeutic Agents;antagonist;cancer cell;carbohydrate binding protein;carbohydrate database;design;high throughput technology;interest;tool;tumor;tumor progression Carbohydrate Microarray Profiling of Glycan-Binding Antibodies and Lectins n/a NCI 10702399 1ZIABC010740-17 1 ZIA BC 10740 17 15201322 "GILDERSLEEVE, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1104956 NCI Carbohydrate-binding antibodies are used extensively for basic research and are useful as diagnostic and therapeutic agents. They are especially useful in the field of cancer. Cancer cells undergo dramatic changes in carbohydrate expression during the onset and progression of disease. As a result there has been considerable interest in understanding why these changes occur how they contribute to the disease and exploiting these changes for clinical use. For example Unituxin (dinituximab) is an FDA approved monoclonal antibody that targets the tumor associated carbohydrate GD2 and is used to treat children with neuroblastoma. Unfortunately there are very few good monoclonal antibodies to carbohydrates. The lack of high quality antibodies is a major barrier for the field. We are taking a multi-pronged approach to help alleviate this problem. First we use our glycan microarray to evaluate the selectivities of existing antibodies to carbohydrates. This information is crucial for selecting the right antibody for a particular application and interpreting results. Second we have developed a database of antibodies to carbohydrates (Database of Anti-Glycan Reagents; DAGR) that can be used to find antibodies and information about those antibodies. Third we are studying the mechanisms by which antibodies to carbohydrates are produced in mammals. Fourth we are using our glycan microarray to discover and engineer new antibodies to carbohydrates 1104956 +Cancer Abnormal Cell;Accounting;Antimitotic Agents;Biological Assay;Biological Availability;Catalytic Domain;Cause of Death;Cell Cycle;Cell Cycle Regulation;Cell Proliferation;Cell division;Cell physiology;Cells;Cessation of life;Characteristics;Chemicals;Collaborations;Crystallization;Cyclic AMP-Dependent Protein Kinases;Cyclin-Dependent Kinases;Development;Docking;Dose-Limiting;Enzyme-Linked Immunosorbent Assay;Epithelial Cells;Exhibits;Generations;Goals;Human;In Vitro;International;Investigation;Laboratories;Lead;Legal patent;Ligand Binding Domain;Lymphocyte;Malignant Neoplasms;Mediating;Microtubules;Mission;Mitosis;Mitotic;Modeling;Mus;National Center for Advancing Translational Sciences;National Institute of Diabetes and Digestive and Kidney Diseases;Normal Cell;PLK1 gene;Paper;Parents;Permeability;Pharmaceutical Preparations;Phosphotransferases;Play;Polo-Box Domain;Process;Prodrugs;Protein Kinase;Proteins;Role;Series;Specificity;Structural Models;Structure;Structure-Activity Relationship;Therapeutic Agents;Toxic effect;Treaty;United States National Institutes of Health;Vinca Alkaloids;Work;anti-cancer therapeutic;base;cancer addiction;cancer cell;cancer therapy;cell type;cross reactivity;drug discovery;high throughput screening;improved;in silico;in vitro Assay;inhibitor;intestinal epithelium;lead optimization;molecular modeling;novel;novel strategies;overexpression;screening;small molecule;targeted agent;taxane;therapeutic target;tumor;tumorigenesis Development of inhibitors targeting Plk1 polo-box domain n/a NCI 10702393 1ZIABC010681-18 1 ZIA BC 10681 18 10202830 "LEE, KYUNG " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 276385 NCI Anti-mitotic drugs such as taxanes and vinca alkaloids that are directed at inhibiting the dynamic function of microtubules (MTs) have proved to be effective in the treatment of cancer. However the use of these conventional MT-targeting agents is severely constrained by their dose-limiting toxicities due to the wide-spread functions of MTs in mediating both mitotic and non-mitotic cellular processes in many cell types notably intestinal epithelia cells and lymphocytes. Therefore developing a new class of anti-cancer therapeutics by targeting mitosis-specific proteins critical for cancer cell proliferation is an important line of investigation. Polo-like kinase 1 (Plk1) is one of the most attractive targets for anti-cancer therapy. Efforts to generate Plk1-specific inhibitors by targeting the catalytic activity of Plk1 have proven to be difficult due to similarities with the catalytic domains of other structurally related kinases. Here we propose to develop a new class of mono-specific Plk1 inhibitors by employing a novel approach of targeting the non-catalytic but functionally essential PBD of Plk1. To this end we have carried out a high throughput screen in collaboration with NCATS Bethesda MD. From this screen we have identified 3000 compounds from a primary screen which were narrowed down to the final 2 compounds (1S and B7) through secondary medium throughput and tertiary cell-based assays. Through systematic molecular modeling/docking of these parent compounds we obtained six significantly improved compounds which showed Plk1 PBD inhibition activity at levels similar to that of one of the previously characterized PBD-binding ligands PLHSpT (Kd = 450 nM) in an in vitro ELISA. Since the original HTS leads may belong to a class known as pan-assay interference compounds or PAINS we will further incorporate many drug-like characteristics during the hit-to-lead optimization in order to obtain a high-impact chemical probe that ultimately exhibits the desired efficacy against the Plk1 PBD in proof-of-concept mouse tumor models. As the first step of drug discovery we generated the co-crystal structure of Plk1 PBD with one of the lead compounds. This structural model will be used to carry out structure-activity relationship studies and further optimization of the compounds. As a result of this effort we obtained several initial hits which have been subjected to several rounds of in silico derivatization and ELISA-based Plk1 PBD inhibition analysis. These efforts led to the discovery of seven compounds (NC21 to NC27) with distinct chemotypes. In vitro FP and ELISA assays with purified compounds confirmed their anti-PBD specificity with Kd values in the range of 100-200 nM. For the past two years we have carried out hit-to-lead optimizations (in collaboration with Dr. Ken Jacobson NIDDK NIH) and developed 20 inhibitors that appear to potently inhibit Plk1 PBD inhibitors in vitro assays. However the efficacy and bioavailability of these inhibitors exhibit less than expected. Now the effort is being focused on improving both the potency and permeability. This work has resulted in a paper (Alverez CN et al. J. Med. Chem. 2020) that describes several novel triazoloquinazoline-derived small-molecule prodrugs specific against Plk1 PBD. A second paper describing subsequent structural optimization and characterization of several advanced anti-Plk1 PBD prodrugs is under way. In addition a provisional patent was filed on September 24 2020 (patent application number 63/082813) and the international patent cooperation treaty was applied on September 24 2021. 276385 +Biotechnology; Cancer; Colo-Rectal Cancer; Digestive Diseases; Women's Health Angiogenesis Inhibitors;Cancer Cell Growth;Cell Cycle;Cell Proliferation;Colon Carcinoma;Colorectal Cancer;Down-Regulation;Drug Targeting;EGF gene;Epithelial;Flavoproteins;Future;G1/S Transition;Genes;Goals;Growth;Growth Factor;HT29 Cells;Human;Induction of Apoptosis;Inflammatory;Knock-out;Laboratories;Ligand Binding;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Membrane;Modification;NADP;NADPH Oxidase;NADPH Oxidase 1;Oxidants;Oxidases;Oxidation-Reduction;Oxidative Stress;Oxygen;Pathogenesis;Pharmaceutical Preparations;Platelet-Derived Growth Factor;Play;Production;Protein Isoforms;Protein Kinase;Protein Tyrosine Phosphatase;Proteins;Reactive Inhibition;Reactive Oxygen Species;Receptor Protein-Tyrosine Kinases;Regulation;Role;Series;Serine;Signal Transduction;Signal Transduction Pathway;Superoxides;Therapeutic;Therapeutic Agents;Threonine;Vascular Endothelial Growth Factors;Xenograft Model;Xenograft procedure;angiogenesis;base;cell growth;colon cancer cell line;cytokine;in vivo;inhibitor;interest;member;neoplastic cell;novel;novel therapeutic intervention;receptor;small hairpin RNA;targeted cancer therapy NADPH Oxidases as Novel Targets for Cancer Therapy n/a NCI 10702392 1ZIABC010677-18 1 ZIA BC 10677 18 9692531 "DOROSHOW, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1153863 NCI Epithelial NADPH oxidases are flavoproteins that catalyze the NADPH-dependent reduction of oxygen to superoxide following binding of ligands for receptor tyrosine kinases (including EGF PDGF VEGF). Current evidence suggests that NADPH-dependent reactive oxygen species play a critical role in growth factor-mediated signal transduction and that the NADPH oxidase 1 isoform is abundantly expressed in human colon cancers. Because inhibition of constitutive oxidant production and cell growth of human colon cancer cell lines as well as induction of apoptosis and blockade of the G1/S transition and induction of p27 occurred over the same concentration range for a series of iodonium-based flavoprotein inhibitors Dr. Doroshows studies suggest that the therapeutic potential of iodonium NADPH oxidase inhibitors may be related to modification of redox-related signal transduction pathways essential for colorectal cancer cell growth. Iodonium derivatives have also been found to be active in two human colon cancer xenograft models. In future studies Dr. Doroshow plans to develop additional novel members of the iodonium drug class as potential therapeutic agents. Dr. Doroshow has also employed stable shRNA constructs developed in his laboratory (that are capable of downregulating NADPH oxidase 1 expression by >80%) to specifically investigate the role of this protein in colorectal cancer cell proliferation. These recent studies demonstrate that downregulation of NADPH Oxidase 1 leads to a significant decrease in reactive oxygen production in HT-29 cells a G1 cell cycle block down regulation of a large number of antiangiogenic genes and inhibition of reactive oxygen-mediated signaling through several receptor protein kinases. In addition we have found that the activity of several serine threonine and tyrosine phosphatases are increased when NADPH oxidase is knocked out. In vivo downregulation of NADPH oxidase 1 dramatically decreases the growth of HT-29 xenografts in part due to diminished angiogenesis. We have also found that pro-inflammatory cytokines involved in the pathogenesis of colon cancer strongly upregulate NADPH Oxidase 1. These studies strongly suggest that NADPH oxidase 1 is an important potential drug target in colon cancer. 1153863 +Biotechnology; Cancer Adhesions;Antibodies;Antigens;Avidity;Basic Science;Binding;Binding Sites;Biological Assay;Biological Process;Bovine Serum Albumin;Carbohydrates;Carrier Proteins;Cells;Complex;Development;Diagnostic;Enzyme-Linked Immunosorbent Assay;Epoxy Compounds;Glycopeptides;Glycoproteins;Immobilization;Inflammation;Lectin;Libraries;Ligands;Methodology;Methods;Microarray Analysis;Microscope;Neoglycoproteins;Neoplasm Metastasis;Play;Polysaccharides;Protein-Carbohydrate Interaction;Proteins;Reagent;Robotics;Role;Slide;Solid;Translational Research;Tumor Antigens;Vaccines;Viral;Virus;carbohydrate binding protein;high throughput analysis;improved;inhibitor;interest;macromolecule;miniaturize;novel;tool Development of a Carbohydrate Microarray n/a NCI 10702391 1ZIABC010675-18 1 ZIA BC 10675 18 15201322 "GILDERSLEEVE, JEFFREY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 315701 NCI Carbohydrate-protein interactions are essential for a wide range of biological processes such as inflammation bacterial and viral adhesion and metastasis. As a result there has been significant interest in identifying carbohydrate binding proteins and developing ligands to modulate their activity. Analysis of carbohydrate-protein interactions is complicated by a number of factors. First carbohydrates are extremely difficult to isolate or synthesize. Therefore only small amounts can be obtained in many cases. Second traditional methods for studying binding are not high-throughput and require large amounts of material. Third monovalent interactions between carbohydrates and proteins are notoriously weak. To achieve a high avidity carbohydrate-binding proteins contain multiple binding sites and form multivalent complexes. As a result carbohydrates must be presented in a multivalent fashion and the spacing and orientation of the carbohydrates play a critical role in recognition. Carbohydrate microarrays or glycan arrays contain many different carbohydrates or glycans immobilized on a solid support in a spatially-defined arrangement. Using an array one can evaluate binding of a lectin antibody cell or virus to all the carbohydrates on the array simultaneously. The array provides a multivalent presentation of carbohydrates and the miniaturized format requires only picogram amounts of each carbohydrate for an assay. We have developed a novel glycan array format utilizing neoglycoproteins. Neoglycoproteins are multivalent conjugates wherein carbohydrates are covalently attached to a carrier protein such as bovine serum albumin. These neoglycoproteins as well as natural glycoproteins are printed onto epoxide coated microscope slides using a robotic microarrayer to produce microarrays. Neoglycoproteins can be used as multivalent reagents for other assays such as ELISAs as multivalent inhibitors and as multivalent immunogens. We currently have one of the largest and most unique glycan arrays in the world. Recently we have focused on expanding and improving the carbohydrate microarray. One objective is to increase the number of glycans on the array. We have been developing improved synthetic methods for preparing glycopeptides. The methodology will be used to prepare a large library of glycopeptides for addition to the array. in addition we are optimizing methods to conjugate carbohydrates to proteins to produce neoglycoproteins. 315701 +Biotechnology; Cancer; Cancer Genomics; Digestive Diseases; Genetics; Human Genome; Immunization; Immunotherapy; Infectious Diseases; Vaccine Related Address;Affect;Affinity;Aging;Agonist;Amino Acids;Antibodies;Antigen Receptors;Antigen Targeting;Antigens;Area;B-Lymphocytes;BTB/POZ Domain;Binding;Binding Sites;Biochemical;Biochemical Genetics;Bone Marrow Transplantation;CD4 Antigens;CD4 Positive T Lymphocytes;CD8 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;CRISPR/Cas technology;Cancer Patient;Cause of Death;Cell physiology;Cells;Cessation of life;Chromatin;Colitis;Complex;Computer Analysis;DNA-Binding Proteins;Deacetylase;Development;Experimental Models;Experimental Neoplasms;Gene Expression;Gene Expression Profiling;Generations;Genes;Genetic;Genetic Transcription;HIV;Hematopoietic;Homing;Immune response;Immune system;Immunity;Immunization;Immunologic Deficiency Syndromes;Immunology;In Vitro;Infection;Inflammation;Inflammatory;Integrins;Interferon Type II;Intestines;Laboratories;Laboratory Research;Laboratory Study;Leukocytes;Life;Ligands;Major Histocompatibility Complex;Mass Spectrum Analysis;Mediating;Membrane Glycoproteins;Memory;Modeling;Molecular;Morbidity - disease rate;Mutant Strains Mice;Myeloablative Chemotherapy;Nucleosomes;Pattern;Peptides;Phase;Prevention;Process;Proliferating;Property;Protein Analysis;Proteins;Puberty;RUNX3 gene;Regulatory Element;Regulatory T-Lymphocyte;Reporting;Repression;Research;Shapes;Small Intestines;Specificity;Surface;T cell differentiation;T cell response;T-Cell Depletion;T-Cell Development;T-Lymphocyte;T-Lymphocyte Subsets;Thymus Gland;Transcriptional Regulation;Tumor Antigens;Vaccine Antigen;Virus;Virus Diseases;Work;XCL1 gene;Zinc Fingers;cell mediated immune response;chromatin immunoprecipitation;chronic infection;cofactor;gene regulatory network;genetic analysis;genetic approach;genome editing;genome-wide;high throughput analysis;in vivo;insight;interest;intestinal epithelium;intestinal homeostasis;memory CD4 T lymphocyte;migration;mortality;novel;pathogen;programs;protein function;recruit;recurrent infection;response;single cell analysis;thymocyte;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;tumor;vaccination strategy Genetic Analysis of T-cell Differentiation n/a NCI 10702390 1ZIABC010671-18 1 ZIA BC 10671 18 8778182 "BOSSELUT, REMY " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2424498 NCI "We study T cell development and function. T cells are essential for immune responses. Most recognize peptide antigens presented by class I (MHC-I) or class II (MHC-II) classical Major Histocompatibility Complex molecules and express either of two surface glycoproteins that contribute to antigen recognition: CD4 which binds MHC-II or CD8 which binds MHC-I. Consistent with such binding properties MHC I-specific T cells generally are CD4-CD8+ (CD8 T cells) whereas MHC II-specific T cells generally are CD4+CD8- (CD4 T cells). CD4 T cells are essential for life: CD4 T cell deficiency whether innate or acquired leads to recurrent or chronic infections and death. CD4 T cell responses have remained an essential area of focus for the laboratory. After infection or immunization (e.g. vaccine) antigen-specific CD4 T cells proliferate and depending on the local inflammatory context differentiate into effector subtypes endowed with specific functions. Infections by intra-cellular pathogens (e.g. viruses) result in the generation of Th1 CD4 T cells producing interferon (IFN)-gamma and of follicular helper CD4 T cells (Tfh) which provide help to B cells for antibody maturation. Additionally long-lived memory CD4 T cells persisting after pathogen clearance contribute to durable immunity together with the B cell response. Accordingly efficient differentiation of Tfh and memory CD4 T cells are key objectives of vaccination strategies. To gain insight into T cell development and function we implemented single cell (sc) analyses of gene expression by RNA sequencing (scRNAseq). We used this approach to study T cell responses to viral infection and tumor antigens (Ciucci et al. 2019; Vacchio et al. 2019; Magen et al. 2019; Jaiswal et al. 2021). We recently extended these studies to chromatin accessibility (ATAC sequencing scATACseq) which provides a broader view of the cell functional potential than analyses of actual gene expression. In the current report year we combined scRNAseq and scATACseq to demonstrate that virus-specific memory and Tfh CD4 T cells develop through distinct transcriptional mechanisms suggesting that these two fates represent distinct lineages that separate in the early phases of the immune response to infection (Ciucci et al. 2022). We also continued our studies or T cell development in the thymus focusing on the main T cell subset defined by expression of an antigen receptor (TCR) made of an alpha and a beta chain (ab T cells). A recent study from the laboratory (Chopp et al. 2020) combined scRNAseq and scATACseq to identify developmental trajectories during the intrathymic differentiation of ab T cell precursors notably those carrying antigen receptors with high affinity for self ligand (called ""agonist-selected"") including regulatory T cells. In the current year we reported analyses of thymic precursors of an intriguing ab T cell subset homing to the intestinal epithelium and expressing the CD8alpha subunits of the CD8 molecule (Nie et al 2022). Using scRNAseq we identified immature and mature thymic precursors and showed that differentiation of the mature component depends on the zinc finger transcription factor LRF (encoded by Zbtb7a). Furthermore we showed that LRF is necessary for the migration of these precursors to the small intestine and for their contribution to intestinal homeostasis and prevention of inflammation in an experimental model of colitis. Using genetic biochemical (chromatin immunoprecipitation) and computational approaches we found that LRF is necessary for expression of the intestine-homing integrin beta7 and that LRF molecules bind the gene encoding this protein. We are currently expanding these studies leveraging single cell analyses of transcriptome and chromatin status aiming to (i) identify relevant transcriptomic patterns and cis-regulatory elements (from scRNAseq and scATACseq respectively) involved in thymocyte differentiation (ii) infer gene regulatory networks controlling these processes and (iii) leverage this information to identify using genetic approaches factors needed for CD4 T cell development. The long term objective of these studies is to build in vitro strategies for the differentiation of CD4 T cells. Among the factors needed for CD4 T cell development in the thymus is the zinc finger transcription factor Thpok encoded by Zbtb7b. Understanding Thpok functions has been a key objective or the laboratory research over the past 5-10 years. We recently reported the genome-wide distribution of Thpok binding sites in CD4 T cells and differentiating CD4-lineage thymocytes (Ciucci et al. 2019; Chopp et al. 2020). In the current report year we completed studies investigating how Thpok affects the expression of its target genes (including those encoding CD4 CD8 and molecules critical for CD4 T cell functions). Combining mass spectrometry biochemical and genetic analyses we identified the nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We showed that three amino-acid residues located within the amino-terminal region of Thpok (the BTB domain) are required for both NuRD binding and Thpok functions. We further showed that conversely NuRD recruitment recapitulates the functions of the Thpok BTB domain. We found that NuRD binding mediates Thpok repression of CD8+-lineage genes including the transcription factor Runx3 that controls CD8 T cell differentiation but is dispensable for Cd4 expression. Last we showed that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6 which fails to bind NuRD. This indicates that cofactor binding critically contributes to the functional specificity of BTB-zinc finger factors which control the differentiation of most hematopoietic subsets." 2424498 +Biomedical Imaging; Cancer; Genetics; Immunotherapy; Prostate Cancer; Radiation Oncology; Urologic Diseases Abscopal effect;Advisory Committees;Biological;Biological Markers;COVID-19 pandemic;Caring;Cells;Clinical;Code;Collaborations;Combined Modality Therapy;Complex;DU145;Data;Development;Diagnosis;Disaster Planning;Dose;Dose Fractionation;Drug Design;Drug usage;Educational workshop;Endothelial Cells;Epigenetic Process;Event;Extramural Activities;Genes;Genetic Transcription;Health;Healthcare;Human;Immune;Immune response;Immunotherapy;Intensity-Modulated Radiotherapy;LNCaP;Laboratories;Low Dose Radiation;Lung diseases;Magnetic Resonance Imaging;Malignant Neoplasms;Medical;Medical center;Messenger RNA;MicroRNAs;Miniature Swine;Modeling;Molecular;Molecular Target;Mus;National Institute of Allergy and Infectious Disease;Normal tissue morphology;Nuclear;Nuclear Radiology;Ontology;PC3 cell line;Pathway interactions;Pattern;Pharmaceutical Preparations;Phenotype;Policies;Proteins;Proteomics;Publishing;Radiation;Radiation Accidents;Radiation Dose Unit;Radiation Injuries;Radiation Oncology;Radiation therapy;Radiology Specialty;Readiness;Research;Resources;Role;Science;Services;Systems Analysis;Techniques;Technology;Terrorism;Testing;Thinking;Time;Treatment Efficacy;Triage;United States National Institutes of Health;Untranslated RNA;Update;Work;biodosimetry;biological adaptation to stress;cancer care;cell killing;chemoradiation;citrin;coronavirus disease;drug-sensitive;experience;fractionated radiation;image guided radiation therapy;immunoregulation;in vivo;interest;mass casualty;medical countermeasure;metabolic abnormality assessment;metabolomics;molecular targeted therapies;novel;point-of-care diagnostics;programs;resilience;response;targeted agent;targeted treatment;tissue injury;tumor Radiation-induced molecular targets n/a NCI 10702389 1ZIABC010670-18 1 ZIA BC 10670 18 15686950 "COLEMAN, NORMAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1135907 NCI "The long-standing focus of our laboratory program involves the radiation and microenvironmental stress response. We are now focusing on ""radiation inducible targets"" that is exploring the use of multi-fractionated (MF) radiation as well as higher single doses (SD) to induce a cellular phenotype that makes the cell susceptible for molecular targeted therapy and immunotherapy. In essence radiation would set up the tumor for enhanced drug killing and enhanced immune response. This project has now demonstrated that different dose sizes of radiation- MF and SD - (10 Gy x1 2 Gy x5 1 Gy x10 and down to 0.5 Gy x 10) produce different phenotypes. We have demonstrated and published that the cells post-radiation are more drug sensitive for at least 1 drug in the short term and 1 drug 90 days later indicating cellular adaptation. This is now published. The novel observation of an inducible target has broad implications for cancer adaptation to treatment for both molecular-targeted therapy and immunotherapy. We are now studying combination therapy of targets and ""synthetic lethality"" We have made significant progress in studying the inducible mRNA miRNA proteins and metabolomics changes. Projects now in progress include studying metabolomic changes in vivo SD and MF for PC3 DU145 and LNCaP cells and epigenetic changes. We are now working with experts in complex systems analysis to identify pathways to target and working on timing of radiation and drug(s). With the major interest in immune modulation our work has significant bearing on the dose and fractionation of radiation that can be exploited for immune enhancement for tumor control including direct and abscopal effects. With a recently successful laboratory review we are expanding collaborations by which we can possibly detect the adaptive changes working with Jim Mitchell of RBB and Deb Citrin or ROB and Murali Cherukuri of RBB who has hyperpolarized MRI techniques to study metabolic adaptation Closely related to this work are efforts being done on identifying biomarkers of radiation injury. This relates to cancer and also to work I do in the Office of the Assistant Secretary for Preparedness and Response in Health and Human Services (HHS). I am heading a group developing civilian medical response planning for radiological and nuclear terrorism and other events. This involves planning policy and normal tissue injury-related science. Medical countermeasures are being developed through NIAID support in the Centers for Medical Countermeasures Against Radiation (CMCR). This overall program has major impact to U.S. preparedness and also has a spin-off for normal tissue injury from radiation and the potential for post-exposure mitigators and treatments. We are working with other agencies (NIAID and Dept of Defense) on the potential of bringing these mitigators into cancer care. The critical importance of the NCI- HHS linkage is bringing up-to-date scientfic thinking to medical countermeasure development and diagnosis - A more direct linkage between the NIH and DHHS programs is our work on biomarkers for biodosimetry supported by NIAID. This is looking at coding and non-coding RNA expression at various times after a range of whole body doses currently using mouse minipig and NHP models. The importance of having an accurate point-of-care diagnostic with which to triage potential radiation casualties cannot be over estimated given the potential size of a nuclear/radiological disaster. The biomarker work is supported by NIAID and BARDA (of ASPR). The COVID disruption has impacted everyone. From my experience in disaster planning and response I am involved with the scarce resources/crisis standards of care issues for the COVID19 pandemic including working with the Healthcare Resilience Task Force and PPE. From my role in the extramural Radiation Research Program we conducted a workshop on the potential use of Low Dose Radiation Therapy (LDRT) to treat COVID lung disease. The jury is still ""out"" on the efficacy of this treatment." 1135907 +Bioengineering; Biomedical Imaging; Cancer Animals;Area;Basic Science;Biodistribution;Charge;Chemicals;Clinical Trials;Code;Computer software;Coupled;Crystallization;Custom;Data Analyses;Development;Devices;Disease;Electronics;Evaluation;Event;Future;Gamma Cameras;Goals;Growth;Human;Image;Imaging Device;Imaging technology;Label;Laboratory Animals;Light;Magnetic Resonance Imaging;Measurement;Mind;Mission;Mus;Names;National Cancer Institute;National Cancer Program;Nuclear;Pathway interactions;Photons;Positioning Attribute;Positron-Emission Tomography;Radioisotopes;Radionuclide Imaging;Research;Research Personnel;Scanning;Scientist;Side;Speed;Structure;Support Groups;System;Systems Development;Technology;Testing;Time;Tube;United States National Institutes of Health;Validation;Work;animal imaging;base;cancer therapy;clinical diagnostics;computerized data processing;cost;design;detector;drug development;flexibility;human subject;imaging program;imaging system;improved;instrumentation;magnetic field;microPET;microSPECT;molecular imaging;news;novel;nuclear imaging;optical imaging;photomultiplier;portability;programs;simulation software;single photon emission computed tomography;thallium-doped sodium iodide;tomography Instrumentation for microSPECT and microPET imaging n/a NCI 10702388 1ZIABC010668-18 1 ZIA BC 10668 18 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 415848 NCI In 2008 as a first step towards a novel flat panel microPET device the Nuclear Camera Team produced a new dual flat panel projection imaging device for mouse imaging. It consists of two flat panel detectors side-by-side with the ability to rapidly obtain projection image in mice on a portable device. This system is now operational and plans are being put in place to further develop devices that allow tomorgraphic imaging. In 2010 work began on leveraging the first device code named MONICA for Mobile Nuclear Imaging Camera into a low cost projection microPET employing two parallel detectors (rather than side by side). The design incorporates coincidence scanning between the two plates but also the capability for depth of interaction (DOI) measurement allowing some tomographic abilities. Also in 2010 work began on adapting this device to a projection microPET MR compatible device. Testing is ongoing to determine the ability of new crystals to withstand the effects of a strong magnetic field. Development work carried out by the nucelar camera group and its (essential) collaborators is based on the notion of directed exploration where technological opportunities are examined at the research level but with a particular systems level goal in mind (A): Research areas in imaging system development: (B): current focused systems level development project: dual gamma camera planar projection imaging system for single photon high-speed dynamic whole body bio-distribution studies in mice. To illustrate this parallelism work is now underway in each of the areas shown in LaBr3 slab and NaI(Tl) pixelated detector modules and support electronics development (CIT-NIH/RIG); evaluation of a new modular DAQ system (Thomas Jefferson National Accelerator Facility (JLAB) Newport News VA/RIG); creation of a high speed data processing interface using both centroid event positioning and advanced Maximum Likelihood (ML) positioning (RIG/CIT); and evaluation of a commercial system (Nuclear Mac) for image display and analysis (RIG/CIT). Each of these sub-system projects are evaluated in light of the current systems level goal of creating a dual planar gamma camera device for imaging mice while at the same time providing information in each technical area for potential use in our next systems level development project. For example one of the detector modules will be comprised of a rectangular pixelated NaI(Tl) array coupled to two side-by-side Hamamatsu H8500 position-sensitive photomultiplier tubes Initial imaging results obtained with this combination required full use of the JLAB DAQ CIT developed electronics and RIG-developed data processing software for acquisition and analysis of these data. Thus considerable progress is being made in the development of novel microSPECT and microPET cameras that could result in much less costly imaging cameras in the future. Moreover because of their larger coverage the sensitivity for such devices might be considerably higher leading to the possibility of detecting disease with ever greater sensitivity. Clearly improved camera design could have a significant impact on molecular imaging research in the future. We plan to continue this exploratory work with the goal of turning over the completed dual gamma camera system to MIP scientists followed by a review of accrued technical findings and designation of the next systems level project. 415848 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunization; Immunotherapy; Infectious Diseases; Minority Health; Orphan Drug; Patient Safety; Prevention; Prostate Cancer; Radiation Oncology; Rare Diseases; Urologic Diseases; Vaccine Related Advisory Committees;Antibodies;Antigen Targeting;Area;Biliary Tract Cancer;Brachyury protein;CCR;Cancer Patient;Cancer Vaccines;Cell physiology;Cells;Clinic;Clinical;Clinical Trials;Cohort Studies;Collaborations;Combination immunotherapy;Combined Modality Therapy;Combined Vaccines;Conduct Clinical Trials;Data;Disease;Enrollment;Epithelial;European;FDA approved;Genitourinary system;Goals;Head;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;IL8 gene;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologics;Immunotherapy;Industry Collaboration;Inflammation;Interleukin-12;International;Intervention;Intravenous;Laboratories;Laboratory Finding;Logistics;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measures;Mediating;Medicine;Merkel cell carcinoma;Modality;Mucin 1 protein;Natural Killer Cells;Neoadjuvant Study;Orphan Drugs;Pathologist;Pathway interactions;Patients;Phase;Phase III Clinical Trials;Play;Process;Prostate Cancer Vaccine;Proteins;Radiation Oncologist;Randomized;Recombinant Vaccines;Recombinants;Renal Cell Carcinoma;Research;Research Personnel;Role;Route;Safety;Scientist;Signal Transduction;Surgeon;T cell response;T-Lymphocyte;T-cell inflamed;Testing;Therapy Clinical Trials;Tissues;Transforming Growth Factor beta;Tumor Antigens;Tumor-infiltrating immune cells;Vaccines;Viral;Yeasts;advanced disease;anti-PD-L1;anti-PD-L1 antibodies;antibody-dependent cell cytotoxicity;base;cancer cell;cancer therapy;castration resistant prostate cancer;clinical development;clinical translation;cohort;design;first-in-human;immune checkpoint;immunogenic;improved;innovation;interest;novel;objective response rate;peripheral blood;phase 2 study;phase 3 study;phase II trial;programmed cell death ligand 1;programmed cell death protein 1;radiologist;research clinical testing;response;safety study;side effect;subcutaneous;targeted agent;therapy design;trend;trial design;tumor;tumor microenvironment;vaccine strategy;vaccine trial Cancer Therapy Clinical Trials Using Novel Recombinant Vaccines n/a NCI 10702387 1ZIABC010666-18 1 ZIA BC 10666 18 8778166 "GULLEY, JAMES L." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 429318 NCI Dr. Gulley is interested in immunotherapy for epithelial malignancies with a focus on prostate cancer. As head of the Immunotherapy Section of the Genitourinary Malignancies Branch he designs and conducts clinical trials based on promising laboratory findings. These innovative investigator-initiated studies involve the use of cancer vaccines and other immunostimulatory agents to modulate the immune response in cancer patients and the addition of other strategies to enhance vaccine-mediated tumor killing. Dr. Gulley played a pivotal role in the clinical development of the prostate cancer vaccine Prostvac. Working with scientists in the laboratory he developed the data needed to bring this logistically simple but immunologically sophisticated vaccine strategy developed within the CCR into phase I (first-in-human safety studies) and phase II (first test for clinical activity) clinical trials in prostate cancer. A multicenter randomized phase II trial designed in collaboration with Dr. Gulley provided evidence of enhanced median overall survival (OS) (P = 0.0061) in patients with metastatic castration-resistant prostate cancer. A concurrent study ran by Dr. Gulley at the CCR demonstrated that patients with greater PSA-specific T-cell responses showed a trend (P = 0.055) toward enhanced survival. Median OS was 26.6 months with a greater apparent treatment benefit in patients with less aggressive or less advanced disease. Dr. Gulley and colleagues then met with the FDA and designed a phase III clinical trial that he subsequently shepherded through the process of gaining approvals from the Recombinant Advisory Committee the FDA and European Medicines Agency. This randomized controlled phase III study which he led enrolled 1297 patients and disappointingly showed no improvement in overall survival. A neoadjuvant study of this vaccine demonstrated that not only could vaccine specific immune cells be generated in the peripheral blood but that increase infiltrates following vaccine could be seen in or around the tumors of these patients compared with pre-vaccine (Sater JITC 2020). This has led to combination immunotherapy efforts described in detail in Dr. Gulley's other project. Other vaccines that Dr. Gulley has helped bring into the clinic in phase I or II studies include pox-viral platforms targeting CEA MUC-1 and Brachyury; yeast platforms targeting CEA and Brachyury and adenoviral vaccines targeting CEA MUC-1 PSA and Brachyury. He has also been involved in the clinical translation of several vaccines targeting HPV specific targets which are more immunogenic than most off the shelf tumor associated antigen targets. Dr. Gulley has also been involved in the clinical evaluation of different routes of administration of vaccines (intradermal subcutaneous intratumoral and intravenous). Immunotherapy remains the most active area of research in cancer based in part on the rapid profound and durable responses seen with immune checkpoint inhibitors targeting PD-1 or PD-L1 proteins. (Immune checkpoints are molecules that modulate immune system signals. Many cancers use them to evade immune attack.) Dr. Gulley served as the coordinating PI of an international trial of avelumab an anti-PD-L1 antibody. This trial is a CCR collaboration with EMD Serono (who also partnered with Pfizer). Early data suggest robust activity for avelumab with a side-effect profile similar to other agents. However unlike other anti-PDL1 agents avelumab is also capable of antibody-dependent cellular cytotoxicity (ADCC). Thus this antibody in addition to directly enhancing the activity of T cells can mediate ADCC which involves Natural Killer Cell-mediated killing of the tumors and immune cells that block T-cell function. Recent findings suggest that anti-PD-L1 agents that can mediate ADCC have improved activity over agents that cannot do so. Dr. Gulley's study has now enrolled over 1700 patients (about 130 at the CCR) providing the initial safety and efficacy data that have led to six ongoing phase III clinical trials of avelumab with more in the planning stages. In 2017 the FDA approved avelumab for 2nd line bladder cancer and Merkel Cell cancer and in 2019 for Renal Cell Carcinoma and in 2020 for an expansion indication in bladder cancer. While the clinical response with immune checkpoint modulators has been profound it is limited to patients who have an underlying T-cell inflamed tumor. The importance of determining the immune relevant cells and pathways operational within the tumor microenvironment is thus crucial to selecting patients who may benefit from immune checkpoint modulating therapies alone but more importantly the impact of therapies designed to generate a T-cell inflamed tumor and to guide rationale for potential combination studies. To further explore this we have established multiple strong collaborations with several groups (including surgeons radiation oncologists interventional radiologists pathologists and various industry collaborations) who can assist us with obtaining and analyzing tissue before and after immunotherapy in various different disease settings. Furthermore we are investigating a range of different modalities to induce T-cell inflammation which are in active clinical trials including vaccines immunocytokines (e.g. NHL-IL12) and planned clinical trials (NK cells). As an extension of the importance of overcoming negative immune regulatory influences within the tumor microenvironment we also have brought into the clinic a first-in-class agent (M7824 or bintrafusp alfa) that targets both cell intrinsic (PDL-1) and cell extrinsic (TGF-beta) pathways and have seen that this is well tolerated and has preliminary evidence of activity. This initial study performed at the NCI now has multiple expansion cohorts with promising levels of activity seen in a number of different tumors including biliary tract cancer (for which it received FDA orphan drug designation) lung cancer (objective response rate 28%) and HPV associated malignancies (objective response rate 30% Strauss et al. JITC 2021). This has led to a number of phase 2 studies. Internationally over 700 patients have been treated with M7824. We have multiple ongoing studies combining vaccines with agents designed to augment the clinical activity of the vaccine activated immune response. Dr. Gulley is also leading efforts to bring in other novel agents such a agents targeting IL8 (Humax) Lair-1 (NC-410) and tumor targeted IL-12 (NHS-IL12) with the goal to bring these from first-in-human studies into combination clinical trials. 429318 +Cancer; Genetics; Immunization; Immunotherapy; Lung; Lung Cancer; Orphan Drug; Ovarian Cancer; Rare Diseases; Vaccine Related; Women's Health ABCB1 gene;Aftercare;Apoptosis;Apoptotic;BCL2 gene;CXCL5 gene;Cell Death;Cell Line;Cell Maturation;Cell surface;Cells;Cisplatin;Clinical;Colorectal Cancer;Combination Drug Therapy;Combined Vaccines;Complex;Cytolysis;Cytostatics;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Dose;Exposure to;Gene Expression Profile;Genes;Goals;Granzyme;Growth;HMGB1 gene;Human;Human Biology;IL8 gene;Immune response;Immunotherapy;In Vitro;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mediating;Membrane;Modeling;Molecular;Molecular Profiling;Mucin 1 protein;Non-Small-Cell Lung Carcinoma;Peptides;Pharmaceutical Preparations;Phenotype;Platinum;Pre-Clinical Model;Prostate Cancer therapy;Protein Secretion;Regimen;Resistance;Signal Transduction;T cell response;T-Lymphocyte;TNF gene;Transcript;Transforming Growth Factor beta;Tumor Cell Line;Vaccines;Vinorelbine;anti-tumor immune response;antigen processing;calreticulin;cancer cell;chemokine;chemotherapeutic agent;chemotherapy;cytokine;cytotoxic CD8 T cells;cytotoxicity;docetaxel;exposed human population;genetic signature;immunogenic;immunogenic cell death;knock-down;lung Carcinoma;neoplastic cell;perforin;predicting response;response;small molecule inhibitor;standard of care;tumor;vector Vaccine and Drug Combination Therapy for Human Cancers n/a NCI 10702386 1ZIABC010661-18 1 ZIA BC 10661 18 9692343 "HODGE, JAMES " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 697290 NCI "Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast several chemotherapeutic drugs modulate antitumor immune responses despite not inducing classic ICD. In addition in many cases tumor cells do not die after treatment. Here using docetaxel one of the most widely used cancer chemotherapeutic agents as a model we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion or cell death. However calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA MUC-1 or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery and mediated largely by calreticulin membrane translocation as determined by functional knockdown of calreticulin PERK or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+ CD133+) by continuous exposure to docetaxel. These cells while resistant to direct cytostatic effects of docetaxel were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. We provided an operational definition of ""immunogenic modulation"" where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy. Chemotherapy with platinum doublets including cisplatin plus vinorelbine is standard of care for non-small cell lung cancer (NSCLC). Sublethal exposure to certain chemotherapeutic agents has been demonstrated to alter the phenotype or biology of human tumor cells rendering them more susceptible to cytotoxic T lymphocyte (CTL)-mediated lysis. However the effects of cisplatin/vinorelbine on tumor sensitivity to T-cell cytotoxicity and its molecular mechanisms have not been fully elucidated. Here we examined the effect of this chemotherapy on growth cell-surface phenotype and CTL-mediated lysis of five distinct human lung carcinoma cell lines in vitro and examined the molecular mechanisms associated with enhanced CTL sensitivity. These studies demonstrate that sublethal exposure of human lung tumor cells to the platinum doublet modulates tumor cell phenotype and increases sensitivity to MHC-restricted perforin/granzyme-mediated CTL killing. These studies also demonstrate that exposure to chemotherapy markedly decreased the protein secretion ratio of TGF-beta/IL-8. We examined the gene expression profile of two lung tumor cell lines in order to identify a shared gene signature in response to sublethal cisplatin/vinorelbine and found coordinate expression of only 16 transcripts including those for cytokine/chemokine expression and apoptosis such as TNF-alpha IL8 CXCL5 and BCL-2 like genes. Overall these results suggest that sublethal exposure to cisplatin/vinorelbine increases sensitivity to perforin/granzyme-mediated CTL killing by modulation of a) tumor phenotype b) cytokine/chemokine milieu and c) the pro-apoptotic/anti-apoptotic gene ratio. The data presented here propose a complex mechanism that is distinct from and complementary to that of immunogenic cell death. This molecular signature may be useful in predicting responses to immunotherapy as well as provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine regimens." 697290 +Bioengineering; Biomedical Imaging; Biotechnology; Cancer; Digestive Diseases; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Women's Health Affect;Affinity;Albumins;Antibodies;Area;BODIPY;Binding;Biomaterials Research;Biomedical Engineering;Biotechnology;Bone Marrow Transplantation;Cell Therapy;Cell membrane;Cell surface;Cells;Cetuximab;Chemistry;Clinical;Clinical Research;Collaborations;Color;Colorectal Cancer;Cytoplasm;Data;Dendritic Cells;Development;Dose;Dyes;Elements;Endocytosis;FDA approved;Fiber;Fluorescence;Future;Galactose;Gastrointestinal tract structure;Goals;Human;Image;In Situ;Indocyanine Green;Injections;Kinetics;Label;Lead;Lesion;Ligands;Light;Magnetic Resonance Imaging;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Methods;Molecular;Molecular Probes;Monitor;Multimodal Imaging;Mus;Nanotechnology;Natural Killer Cells;Normal Cell;Normal tissue morphology;Optics;Oxyquinoline;Positron-Emission Tomography;Primates;Radioisotopes;Reporter Genes;Reporting;Research;Resolution;Rhodamine;Route;Series;Site;Synthesis Chemistry;Techniques;Testing;Therapeutic Agents;Time;Tokyo;Toxic effect;Translating;Trastuzumab;Universities;Vertebral column;Work;adult stem cell;base;biomaterial compatibility;cancer cell;cancer cell differentiation;cancer site;cell killing;cell type;cellular engineering;clinical application;design;dimer;fluorophore;galactose receptor;imaging agent;improved;in vivo;in vivo imaging;malignant stomach neoplasm;method development;molecular imaging;nanocrystal;near infrared dye;neoplastic cell;optical imaging;photoimmunotherapy;receptor;single photon emission computed tomography;stem cells;success;targeted imaging;theories;tumor Cellular In vivo Imaging n/a NCI 10702385 1ZIABC010657-18 1 ZIA BC 10657 18 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1247547 NCI Cell tracking studies are vital to the development of new cell based therapies. For instance we are using PET labeled adult stem cells to track the intrabone injection of cells for possible bone marrow transplants. Similarly we exploring the kinetics of NK cell injections by PET labeling these cells and injecting them. We are conducting studies to see whether dendritic cells can be induced to traffic to tumors to which they are sensitized. In vivo molecular imaging agents specifically target the cell surface or microenvironment. However most of the highly specific changes of cancer cells that differentiate cancers cells from normal cells occur intracellularly. The challenge therefore is to develop agents that report intracytoplasmic changes yet still are capable of being imaged in vivo. The first step in achieving this goal is to target the imaging agent to the cell surface which requires affinity for a cell surface marker. The ligand must then be internalized by endocytosis and then bind to the appropriate site whereupon it activates. Endocytosis can also be used without specific cell surface binding but internal binding. These requirements place large demands on synthetic chemistry since the molecular construct must have multiple functionalities. We are developing activatable optical constructs which only fluoresce when they are internalized to the cytoplasm. Using a series of commercially available dyes that are bound to targeting compounds and then modified to fluoresce under specific intracellular conditions such as lower pH and in the presence of specific enzymatic activity we are making progress toward the goal of intracellular in vivo imaging. This work is being performed in collaboration with Prof. Urano from the University of Tokyo Chemistry Department. We have made considerable advances in this area by proving that it is possible to create highly activatable optical imaging agents based on the BODIPY and Rhodamine backbones. We are also pioneering efforts to create multimodal imaging agents; agents that can be seen on both optical cameras as well as PET MR or radionuclide cameras. The agents being designed are highly biocompatible and elements have already been used in humans. For instance the agent Galactosylserum Albumin (GSA) which we have labeled with Rhodamine Green (GSA-RhG) is internalized rapidly within cancer cells and may be viable as an agent for human use. We are developing activated fluorescent molecular imaging agents and have a number of successes over the year. However we continue to pursue a solution that will activate only within cancer cells and not within other normal cells. In addition to GSA as a targeting ligand we are employing commercially available antibodies such as trastuzumab and cetuximab that will enable targeting binding and internalization. Specifically we have used trastuzumab in combination with a self quenched indocyanine green ICG an FDA approved Near InfraRed (NIR) dye to target in situ tumors. When the antibody binds its cognate receptor it is internalized releasing the ICG which then begins to fluoresce. Both components of this construct are FDA-approved so in theory this technique could be translated clinically fairly easily. The ability to image multiple targets simulanteously led us to explore multiexcitation and multiemission cameras. We had hoped that a single excitation light would be able to activate multiple fluorophores at differing wavelengths but this proved to be unrealistic. Instead we use multiple wavelength excitation light using a new Maestro camera. This has allowed us to simultaneously image up to 4 targets in the near infrared and is very promising for clinical application. Additionally we are developing fiberoptic scopes with fluorescence receptors to allow very small areas to be examined percutaneously using small fiber-based scopes. Recently we have demonstrated that is possible to image live unanesthetized mice by using a highly tuned real time camera. It may be possible in the near future to develop multi-targeted multi color imaging to better characterize tumors. Most recently we have developed highly specific activatable probes based on H dimer formation. For instance Rhodamine dimerizes when bound to the Fc portion of an antibody leading to a quenching of fluorescence. pH activatable probes have been developed as well as upconverting nanocrystals that are excited at higher wavelengths than they emit at. Finally uniquely targeted near infrared probes have been developed that appear to have specific cell membrane toxicity suitable for photoimmunotherapy therapy that is highly targeted. Relevant cancer sites: Ovarian Cancer Stomach Cancer Colorectal Cancer Gastrointestinal Tract Pancreatic Cancer. Relevant Research Areas: Bioengineering Nanotechnology Biomaterials Research Biotechnology Clinical Research. More recently MIP has been developing new methods of tracking cells using Zr89 oxine labeling. Hematopoetic cells of all types have been labeled and tracked. We intend to try tracking cells in vivo using PET imaging and have demonstrated feasibility in a variety of cell types and conditions both in mice and primates as preliminary data prior to human testing. Reporter gene strategies are being developed to monitor cells over longer duration. Cellular engineering that combines therapies and cell tracking is also currently undergoing study. 1247547 +Biomedical Imaging; Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Immunotherapy; Orphan Drug; Radiation Oncology; Rare Diseases; Women's Health Animal Model;Antibodies;Antibody-drug conjugates;Binding;Biodistribution;CCR;CXCR4 gene;Cell Proliferation;Cell surface;Cells;Client;Clinical;Clinical Research;Clinical Trials;Diagnosis;Dyes;ERBB2 gene;Epidermal Growth Factor Receptor;Exposure to;Goals;Growth;Growth Factor;Growth Factor Receptors;Head and Neck Cancer;Human;IL2RA gene;Image;Immune response;Immunity;Immunoconjugates;Isotopes;Japan;Light;Long-Term Survivors;Malignant Neoplasms;Mediating;Membrane;Microscopic;Monitor;Multiple Myeloma;Neoadjuvant Therapy;Operative Surgical Procedures;Patient Selection;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phase III Clinical Trials;Photons;Photosensitizing Agents;Positron-Emission Tomography;Prior Therapy;Protocols documentation;Radioimmunoconjugate;Radioimmunotherapy;Radiolabeled;Recurrence;Regulatory T-Lymphocyte;Research;Resources;Role;Site;T memory cell;T-Lymphocyte;Therapeutic;Time;Tissue Sample;Trastuzumab;United States National Institutes of Health;Work;Writing;antibody conjugate;base;cancer cell;cancer immunotherapy;cancer therapy;cell killing;clinical center;imaging agent;imaging program;immunogenic;immunoreaction;implantation;invention;mesothelin;molecular imaging;mouse model;neoplastic cell;novel therapeutics;objective response rate;phase 2 study;phase 3 testing;photoimmunotherapy;preclinical study;prevent;programs;receptor;receptor expression;response;small molecule;targeted agent;targeted imaging;treatment effect;tumor;tumor microenvironment;tumor progression Growth Factor Imaging and Photoimmunotherapy n/a NCI 10702384 1ZIABC010656-18 1 ZIA BC 10656 18 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2495095 NCI This project spans many parts of the molecular imaging program. We have been and continue to be focused on developing membrane receptor targeted agents in order to diagnose stage and select patients for therapy. One class of imaging agents is based on antibodies. We have developed multiple radiolabeled antibodies and have completed several clinical trials involving them. In addition we have developed a novel therapy called photoimmunotherapy (PIT) that conjugates a specific photon absorbing dye IR700 to an antibody. This antibody photon absorber conjugate (APC) is then injected and binds to the cognate receptor on the tumor cell surface. Exposure to near infrared light (NIR) produces a rapid and selective cancer cell killing. PIT was discovered by our team in 2010 and multiple animal models were undertaken. By 2013 the invention was licensed to Aspyrian which is now Rakuten. Over the past several years Phase 1 and Phase II studies in head and neck cancers have been performed with a 44% objective response rate in recurrent head and neck cancers. Several long term survivors have been seen. PIT is now in global Phase 3 testing and was approved in Japan in late 2020. Meanwhile we are developing PIT that targets immunosuppressive cells in the hopes of promoting an even stronger immune response than is evoked by PIT of the tumor. When for instance Treg PIT is combined with anti tumor PIT in mouse models strong immunogenic responses are seen with induction of memory T cells preventing further implantation of the tumor. We are studying this phenomenon in mouse models at the microscopic level to better understand how removing T reg cells from the tumor microenvironment specifically causes T cell mediated cell killing. At the same time we continue as a program to develop targeted small molecule and antibody conjugates for PET imaging. In one project we are radiolabeling Elotuzumab an antibody against the receptor SLAMF7 which is upregulated on multiple myeoma cells. If successful this agent should be able to identify sites of myeloma throughout the body a long sought-after goal. We are also developing agents against CXCR4 a commonly found receptor on hematopoetic cells and some cancers. We have also worked with various companies to help develop antibody drug conjugates based on PET biodistribution profiles. We are initiating a clinical trial in the CC NIH to use PIT as a neoadjuvant therapy prior to surgery in patients with operable head and neck cancers. A CD25 antibody for killing Treg cells has been developed and is currently being manufactured for use in human trials. This agent when combined with a tumor targeted PIT will cause a substantial increase in the immune response to PIT leading to more profound treatment effects. 2495095 +Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Prostate Cancer; Radiation Oncology; Urologic Diseases Ablation;Acetates;Adenocarcinoma;Affect;Aftercare;Age;Algorithms;American;Amino Acids;Androgen Antagonists;Animal Model;Antigen Targeting;Arachidonic Acids;Area;Artificial Intelligence;Basic Science;Biological Markers;Biopsy;Biopsy Specimen;Bombesin;CXCR4 gene;Cancer Etiology;Canis familiaris;Cessation of life;Circumscribed Lesion;Clinical Trials;Cognitive;Computer-Assisted Diagnosis;Cooperative Research and Development Agreement;Coupled;Custom;DNA Sequence Alteration;Data;Devices;Diagnosis;Diagnostic;Disease;FOLH1 gene;Focused Ultrasound Therapy;Generations;Genes;Genomics;Gleason Grade for Prostate Cancer;Glutamine;Goals;Grant;Human;Image;Image Guided Biopsy;Immunoglobulin Fragments;Implant;Intervention;J591 Monoclonal Antibody;Joints;Lamivudine;Lasers;Lutetium;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Medical;Medical center;Metabolism;Metastatic Neoplasm to the Bone;Methods;Military Personnel;Molds;Molecular;Molecular Weight;Morbidity - disease rate;Names;Natural History;Neoplasm Metastasis;Operative Surgical Procedures;PSA level;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Physicians;Positron-Emission Tomography;Prior Therapy;Procedures;Prostate;Prostatectomy;Pyruvate;Quality of life;Quality-Adjusted Life Years;RB1 gene;Radiation;Radiation therapy;Recurrence;Regulation;Research;Resolution;Role;Sales;Salivary;Salivary Glands;Salivary duct structure;Screening Result;Screening for Prostate Cancer;Sensitivity and Specificity;Serum;Skin Cancer;Sodium Fluoride;Specificity;Specimen;Staging;System;Systemic Therapy;TP53 gene;Techniques;Testing;Time;Tracer;Treatment Side Effects;Ultrasonography;Urologic Oncology;analytical tool;androgen sensitive;artificial intelligence algorithm;base;blind;bone imaging;cancer cell;cancer imaging;cancer recurrence;castration resistant prostate cancer;clinically significant;computer generated;design;digital;digital pathology;high risk;histological specimens;imaging agent;imaging modality;improved;male;men;metabolic abnormality assessment;minimally invasive;non-invasive monitor;novel;overtreatment;photoimmunotherapy;preclinical study;preservation;prognostic;programs;prostate biopsy;prostate cancer model;prostate lesions;radiologist;screening;serum PSA;small molecule;standard care;standard of care;success;targeted agent;targeted imaging;tumor;ultrasound;uptake Prostate Cancer Imaging n/a NCI 10702383 1ZIABC010655-18 1 ZIA BC 10655 18 8778172 "CHOYKE, PETER L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 4158492 NCI Prostate cancer is the 2nd leading cause of cancer death in males. As a result of screening with serum prostate specific antigen (PSA) there has been a dramatic increase in the number of men diagnosed with prostate cancer. The diagnosis is being made at a younger age yet the morbidity of the standard treatment such as surgery and radiation---remain unchanged. Thus men with the diagnosis of prostate cancer are often overtreated for their disease and will live with the consequences of this treatment for many years greatly affecting the Quality of Life Years (QALY). The ultimate answer to this dilemma is serum biomarkers that identify lethal cancers but not incidental cancers but this is unlikely to occur soon. In the meantime methods of localizing prostate cancer and treating them with minimally invasive therapy would dramatically lessen the morbidity associated with widespread screening and the overdiagnosis/overtreatment of prostate cancer. A variety of imaging methods have been developed and we are exploring their role in localizing early prostate cancer. The MIP has partnered with the Urologic Oncology Branch to develop new imaging methods to be coupled with minimally invasive treatment methods which include RF/laser ablation targeted radiation and photoimmunotherapy. The MIP is engaged in a number of pre-clinical studies in prostate cancer. We have been investigating a variety of targeted imaging agents. Initially we have evaluated several antibodies and antibody fragments against PSMA (3TC J591) in animal models of prostate cancer. Recently we began using PSMA PET based on small molecules that target PSMA. We are seeking to understand at a molecular level what controls the expression of PSMA in a cancer cell. Metabolic studies of prostate cancer may have implications for therapy. We are investigating PET in animal models of prostate cancer to detect differences in metabolism between the androgen-sensitive and insensitive state. Moreover we are launching a program in C13 hyperpolarization of pyruvate which will enable non invasive monitoring of metabolism Clinical Trials The MIP has been studying prostate cancer imaging in humans since its inception. We have developed analytic tools in conjunction with a CRADA with Philips Medical Systems. We have demonstrated that a multiparametric approach improves the specificity of 3T MRI for prostate cancer. However there remain significant limitations in the sensitivity and specificity of 3T MRI. After patients undergo prostatectomy and their specimens are available for review it is clear that less than 40% would be amenable for focal therapy based on being single well circumscribed lesions that are visible on MRI. We have designed a customized prostate mold which is in use in all patients undergoing surgery at NCI. It enables the imaging to be directly correlated with the pathologic specimen. Therefore working with Philips Medical Systems we have designed an US-MR fusion system that takes the data from the 3T MRI and fuses it to the real time ultrasound image. This product was released for sale in 2013 under the name UroNav. Biopsy and interventional procedures can then be performed under MR guidance using the ultrasound. This device has been used successfully in over 2000 patients at NCI. A dog study showed the accuracy was about 3-4mm but was much better than cognitive biopsies. We are currently using a similar platform to direct focal laser ablation (FLA) of suitable prostate lesions (i.e. ones that are well demarcated low Gleason score and could otherwise be watched. We are also testing HIFU in animal models. Computer aided diagnosis and machine learning are new areas of research for the MIP. Significant progress has been made in designing new AI algorithms to help radiologists identify cancers and characterize them. We have extended these AI algorithms to encompass pathologic analysis of biopsy specimens in the hopes of better predicting high risk patients. We are developing novel PET agents that might be more specific for prostate cancer especially in detecting metastases. For instance we completed a PET study using 11C-Acetate and 18F-ACBC an agent associated with amino acid transport which has shown success in localizing recurrent prostate cancer. Ultimately we wish to combine PET-MR studies and conduct minimally invasive therapies after US fusion. We completed a trial of the agent F18-DCFBC which is a first generation low molecular weight tracer directed at PSMA. We are performing PET studies with a PSMA targeted PET agent. We are conducting trials using F18 DCFPyl a second generation agent directed at PSMA. This agent has already shown great potential to characterize the disease status even when post treatment PSA levels are quite low. We are hoping to use cold PSMA injected retrograde in the salivary ducts to block uptake in the salivary glands. This will be useful in preserving salivary function when PSMA-directed therapies such as lutetium 177 PSMA are used to treat metastatic castrate resistant prostate cancer. We are also generating computer aided diagnosis (CAD) devices and algorithms that could automate the diagnosis of prostate cancer. As part of a FLEX grant we have tested numerous other PET agents including F-DHT arachidonic acid CXCR4 FDG and F Glutamine and F Bombesin in order to select better agents for imaging prostate cancer. Moreover since PSMA is so important we have begun basic research to evaluate the expression of PSMA and what controls it. For instance we found PSMA is one a small group of genes that is regulated by numerous co-factors. We have improved the understanding of FOLH1 regulation which is responsible for PSMA expression. Also we have demonstrated alterations in metabolism related to specific genetic mutations (RB1 TP53) in adenocarcinomas. ADT slow release implants are also introduced into tumors to reduce need for systemic ADT especially during radiation therapy. Artificial intelligence methods are being used to improve diagnostics with imaging and digital pathology. A major project is underway with the Joint Pathology Center at Walter Reed Military Medical Center to evaluate 30 years of digital pathologic specimens of prostatectomy specimens using AI. 4158492 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Genetic Testing; Genetics; Health Disparities; Human Genome; Minority Health; Orphan Drug; Patient Safety; Precision Medicine; Rare Diseases; Women's Health 3' Untranslated Regions;ABCB1 gene;ABCG2 gene;Affect;African;African American;African American population;Alleles;Anaplastic astrocytoma;Anti-Retroviral Agents;Antiepileptic Agents;Antimetabolites;Antineoplastic Agents;Azathioprine;Biological;CYP1A2 gene;CYP1B1 gene;CYP2C19 gene;CYP2D6 gene;CYP3A4 gene;CYP3A5 gene;Candidate Disease Gene;Carboplatin;Case Study;Chemotherapy-Oncologic Procedure;Clinical;Clinical Trials;Code;Colon Carcinoma;Colorectal;Data;Development;Differentiation Antigens;Disease;Dose;Drug Kinetics;Drug Targeting;Drug Transport;Enzymes;Etiology;Fluorouracil;Future;Gender;Gene Frequency;Genes;Genetic;Genetic Determinism;Genetic Markers;Genetic Polymorphism;Genetic Variation;Genotype;Glioblastoma;Goals;HLA Antigens;Hypophosphatemia;Immunoglobulins;Immunosuppressive Agents;Inherited;Investigation;Killer Cells;Knowledge;Laboratories;Link;Malignant Neoplasms;Mediating;Membrane;Metabolism;Minor;Molecular;Movement;Mutation;Nucleotides;Oncology;Organ;Outcome;Paclitaxel;Pancytopenia;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacogenetics;Pharmacogenomics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Phase I Clinical Trials;Phenotype;Physiology;Plasma;Platinum;Plicamycin;Population;Prior Therapy;Process;Publishing;Recurrence;Refractory;Research;Research Design;Scanning;Statistical Data Interpretation;Therapeutic;Therapeutic Index;Tissues;Topoisomerase Inhibitors;Toxic effect;Transitional Cell Carcinoma;UGT1A1 gene;United States National Institutes of Health;Update;Variant;Vascular Endothelial Growth Factors;Work;Xenobiotics;abiraterone;antiangiogenesis therapy;base;bevacizumab;cancer therapy;chemotherapy;clinical center;clinical effect;cohort;comorbidity;docetaxel;drug development;drug disposition;drug metabolism;experience;experimental study;fluoropyrimidine;genetic association;genetic variant;genotyped patients;improved;inter-individual variation;interest;lenalidomide;metabolic rate;novel;patient response;patient stratification;pharmacodynamic biomarker;phase 1 study;phase II trial;precision medicine;predicting response;programs;racial population;receptor;response;side effect;success;temozolomide;therapeutic protein;therapy outcome;treatment response Clinical Pharmacogenetics n/a NCI 10702382 1ZIABC010627-19 1 ZIA BC 10627 19 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 878724 NCI Our laboratory has a strong interest in clinical pharmacogenetics. We have integrated pharmacogenetics and pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism pharmacokinetics (PK) response and toxicity as well as to understand the contribution of inter-individual variation in clinical outcomes in therapies with an already narrow therapeutic window. Given the importance of pharmacogenomics in precision medicine we are actively involved with implementing the pharmacogenomics program at the NIH Clinical Center. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein MDR1) ABCG2 (BCRP) SLCO1B3 (OATP1B3 OATP8) CYP3A4 CYP3A5 CYP1B1 CYP2C19 CYP2D6 UGT1A1 UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such they are involved in physiology development of disease drug PK and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable inter-individual variation in physiology and pharmacotherapy. Thus we are interested in studying how inherited variants in transporters are associated with disease etiology disease state and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. While many studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. In the past we have genotyped patients with the Drug Metabolizing Enzymes and Transporters (DMET) platform (which ascertains 1931 genotypes in 235 genes) to explore potential links between these genes and outcomes from several cancer therapies. In the current fiscal year we have transitioned over to the updated Pharmacoscan platform which interrogates 4627 variants in 1191 ADME genes. It also detects 4389 ancestry informative markers 239 gender markers 7116 human leukocyte antigen markers and 1484 killer cell immunoglobulin-like receptor markers. We have studied the PG assessments of many anticancer agents including recently mithramycin belinostat docetaxel/lenalidomide/bevacizumab combination olaparib/carboplatin combination carfilzomib azathioprine abiraterone and paclitaxel. In a phase II trial of cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma we found that VEGF genotypes (1498CT and. 634CG) were associated with hypophosphatemia - one of the common grade 3-4 toxicities of cabozantinib in the study. We recently conducted a pharmacogenetic analysis in patients on a recent phase I clinical trial to investigate zotiraciclib combined with temozolomide in recurrent glioblastoma and anaplastic astrocytoma. Zotiraciclib is metabolized by CYP1A2 and CYP3A4; from the pharmacoscan results we identified a single-nucleotide change in gene coding CYP1A2 (CYP1A2 5347TC; rs2470890). This SNP is also associated with a significant difference in zotiraciclib pharmacokinetics (higher AUCinf value) in a cohort of 13 patients. This PK/PG analysis identified a polymorphism that potentially alters the PK of zotiraciclib suggesting further investigations are warranted for a genotype-guided dosing to reduce the toxicities. Cancers of the colon are commonly treated with fluoropyrimidines which often cause severe toxicities in patients with certain variants in DPYD. Moderate to strong evidence indicates that ten genetic variants in DPYD are associated with a reduction in the rate of fluoropyrimidine metabolism and at least 17 other DPYD genotypes may reduce DPYD function. Several of these variants are observed in specific racial populations and understanding of genetic variability in specific racial populations will be crucial for future reductions in fluoropyrimidine toxicity. We present a case report of an African-American patient who underwent FOLFOX therapy for a colorectal malignancy who developed profound pancytopenia during treatment. Pharmacoscan analysis identified the patient with the DPYD Y186C variant (rs115232898) an uncommon allele (minor allele frequency (MAF) = 0.032 in African-Americans) that causes a 46% decrease in the DPYD-mediated fluoropyrimidine metabolic rate. The patient was also heterozygous for a SNP in the 3' untranslated region of DPYD (rs12132152) an uncommon variant (MAF = 0.0061 in African-Americans) that has also been associated with fluorouracil toxicity. The severe pancytopenia and high fluorouracil plasma concentration this patient experienced is likely a function of uncommon genetic variants that affect DPYD metabolism. The present data adds to emerging evidence that the Y186C variant is important in patients with African origins who are receiving 5-FU and future studies should evaluate the consequences of rs12132152 on interindividual variation of DPYD function and its clinical effects on fluoropyrimidine therapy. While over ten-thousand phase I studies are published in oncology fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84) evaluating toxicity (n = 42) response or PFS (n = 32) and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors antimetabolites and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities prior therapies racial backgrounds and other factors that confound statistical analysis of pharmacogenetics. Taken together phase I studies analyzed herein treated small numbers of patients (median 95% CI = 28 24-31) evaluated few variants that are known to change phenotype and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions. 878724 +Aging; Cancer; Cancer Genomics; Clinical Research; Emerging Infectious Diseases; Genetics; Health Disparities; Human Genome; Immunotherapy; Infectious Diseases; Minority Health; Prevention; Prostate Cancer; Social Determinants of Health; Urologic Diseases ATAC-seq;Address;Affect;African;African American;African American population;African ancestry;Alleles;American;Amphotericin B;Anti-Inflammatory Agents;Antigen Presentation;Arachidonic Acids;Area;Aspirin;Award;Biological Assay;Blood Platelets;Blood specimen;Cancer Patient;Case/Control Studies;Chemotaxis;Chemotherapy and/or radiation;Chromatin;Chromatin Structure;Chromosomes;Clinical;Cohort Studies;Collaborations;Communities;DNA;DNA Damage;DNA Methylation;Data;Data Set;Development;Disease;Disease Progression;Eicosanoids;Endogenous Retroviruses;Environment;Epigenetic Process;Ethnic Origin;Ethnic group;European;Fatty Acids;Future;Gene Expression;Genes;Genetic;Genotype;Ghana;Goals;Herpesviridae;High-Throughput Nucleotide Sequencing;Human;Human Herpesvirus 8;Immune;Immune response;Immunobiology;Immunomodulators;Immunosuppression;Immunotherapy;Incidence;Infection;Inflammation;Inflammatory;Integration Host Factors;Interferons;Knowledge;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Maryland;Measures;Medical History;Mesenchymal;Metastatic Prostate Cancer;Mission;Modeling;Molecular Profiling;Mutation;Neighborhoods;Neoplasm Metastasis;Nigeria;PTGS1 gene;Participant;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Platelet aggregation;Pollution;Population;Prevention;Prostatic Neoplasms;Publishing;Quantitative Trait Loci;Race;Recording of previous events;Recurrence;Reduce health disparities;Research;Resected;Resistance;Resources;Risk;Risk Factors;Role;Seroprevalences;Serum;Sex Behavior;Signal Pathway;Signal Transduction;Socioeconomic Status;Surveys;Technology;Testing;Therapeutic;Thromboxane A2;Tobago;Transposase;Tumor Biology;Tumor Immunity;Tumor Suppression;Tumor-Derived;Up-Regulation;Variant;Viral;Virus;Virus Diseases;West Indies;Work;anticancer research;cancer cell;cancer health disparity;chemokine;cohort;cooking;cytokine;deprivation;disease disparity;environmental agent;exome sequencing;genetic signature;genome wide association study;genome-wide;high risk population;indexing;inflammatory marker;lifestyle factors;malignant breast neoplasm;men;men's group;metastatic process;mimicry;mortality;neoantigens;new technology;novel;pathogen;precision medicine;predictive signature;prevent;programs;prostate cancer progression;prostate cancer risk;protein metabolite;proteomic signature;recruit;research study;response;systemic inflammatory response;tumor;tumor microenvironment;urinary The Molecular Profile of Prostate Tumors in African-American Men n/a NCI 10702381 1ZIABC010624-19 1 ZIA BC 10624 19 9692197 "AMBS, STEFAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 685102 NCI "Previously we generated gene expression profiles of primary prostate tumors resected from African American and European American men. Analyzing the resulting dataset we identified gene expression differences between African American and European American patients that portray the existence of a distinct tumor microenvironment for these two patient groups. Many of the differently expressed genes were immune-regulatory and pro-inflammatory. Unexpected was the presence of an interferon signature in many of the African American tumors. This signature is related to an ""interferon-related DNA damage resistance signature (IRDS)"" that predicts resistance to chemotherapy and radiation in breast cancer. IRDS has also been linked to the pro-metastatic mesenchymal transition of cancer cells. Thus IRDS may promote the metastatic process and is as we found associated with early disease recurrence in prostate cancer (PMID:30012562). Furthermore we observed that aspirin use significantly reduces the risk of aggressive prostate cancer in African American men (PMID: 2829292333293340) suggesting inflammation as a driver of disease progression. Because of these findings we will test if the tumor biology of prostate cancer patients who are regular aspirin users is different from patients who do not take aspirin showing less inflammation. In addition we examined and continue to examine whether the development of the IRDS signature and systemic inflammation could be functionally linked to a germline variation that frequently occurs in men of African ancestry but is rather uncommon in men of European ancestry and encodes a novel interferon termed interferon lambda 4 (IFNL4 rs368234815-dG). Patients with the dG allele which is significantly more common in African than European populations have an increased occurrence of IRDS. This finding has been published in Clinical Cancer Research (PMID: 30012562). The presence of an interferon gene signature in prostate tumors further suggested a possible involvement of either a viral infection in disease pathology or the reactivation of endogenous retroviruses in the tumor microenvironment. This hypothesis was supported by data showing that the interferon signature in prostate tumors coincides with a gene signature of retroviral activation. Moreover men with IFNL4-dG may have an increased risk of a herpesvirus 8 (HHV-8) infection and HHV-8-associated prostate cancer as we showed (PMID: 35468990). Because viral infection-related host factors are associated with prostate cancer in African American men as we showed we begun to study the relationship between viral infection history and the disease using a novel technology termed VirScan (PMID: 32526205). VirScan can detect an infection history of all human viruses analyzing blood samples. We will examine the viral infection history in men of African descent and how it relates to prostate cancer analyzing men from the NCI-Maryland and NCI-Ghana studies and a cohort from Tobago West Indies. We will also further investigate the relationship between the IFNL4 dG genotype and viral infections and whether there is an interaction between them in prostate cancer development and progression. A completed study linking sexual activity to prostate cancer supports the hypothesis that a viral infection may contribute to the risk of prostate cancer among carriers of the IFNL4 dG genotype (PMID:30456312). An alternative pathway that may lead to an interferon signature in prostate tumors is the aberrant expression of tumor-derived neo-antigens which can elicit an immune response. For example it was shown that therapy-induced alterations in DNA methylation can cause the expression of otherwise silenced endogenous retroviral sequences resulting in an interferon response in tumors and enhanced sensitivity to immune therapy. The observation supports the hypothesis that changes in DNA accessibility can lead to increased neo-antigen presentation linking DNA accessibility to neo-antigen expression and an immune response. DNA accessibility is largely controlled by the chromatin structure (e.g. open vs. condensed). We hypothesize that distinct chromatin accessibility signatures could be the underlying cause for the increased expression of endogenous retroviral sequences in tumors of African American men and the common occurrence of an interferon signature in them. To test this hypothesis we will use the Assay for Transposase Accessible Chromatin with high throughput sequencing termed ATAC-seq which is a technology for fast and sensitive profiling of chromatin accessibility. Lastly we are completing work in support of the DoD Impact award W81XWH1810588 (PI Ambs Yates Cook) ""A Precision Medicine Study of How Inflammation May Underlie the Excessive Burden of Prostate Cancer in Men of African Ancestry"". Here 82 immune-inflammation marker and the fatty acid profile (n=24) of blood samples will be analyzed in NCI-Maryland (see ZIA BC 010499) and NCI-Ghana study participants and will be linked to GWAS and survey data. The aim is to examine associations of these proteins and metabolites with lethal prostate cancer African ancestry lifestyle factors socioeconomic status and neighborhood deprivation index and medical history. Lastly we will link these data to tumor biology by studying gene expression profiles and the mutational spectrum (whole exome sequencing) of prostate tumors from the NCI-Maryland study and a cohort from Nigeria (PI Yates). Data from this ongoing project show that circulating chemokines and cytokines related to immune suppression and chemotaxis are generally higher in men of African ancestry (African American and Ghanaian men). When we link the markers to survival up-regulation of markers that comprise the ""suppression of tumor immunity"" pathway associated with lethal prostate cancer in fully adjusted models (PMID:35365620). The preventative benefits of aspirin in the development of lethal prostate cancer have been attributed to inhibition of the arachidonic acid signaling pathway. Thromboxane A2 (TXA2) an eicosanoid produced primarily via COX1 in activated platelets orchestrates platelet aggregation. TXA2 elevated during inflammation contributes to metastasis. Hence we assessed the role of TXA2 levels in the development of lethal prostate cancer. Measuring levels of urinary 11-dehydrothromboxane B2 (TXB2) a stable metabolite and marker for TXA2 we observed a distinct elevation of urinary TXB2 in African American men and an inverse association between TXB2 levels and aspirin use. Moreover high TXB2 was positively associated with metastatic prostate cancer. High TXB2 was also associated with all-cause and prostate cancer-specific mortality in African American men. The data are consistent with our previous findings of a prevalent immune-inflammation signature and an inverse association of aspirin use with lethal prostate cancer in these patients. Our study highlights the potential benefit of aspirin for prevention of lethal prostate cancer in this high-risk group of men through inhibition of TXA2 synthesis (PMID: 34264335)." 685102 +Biotechnology; Cancer; Cervical Cancer; HPV and/or Cervical Cancer Vaccines; Health Disparities; Immunization; Immunotherapy; Infectious Diseases; Prevention; Sexually Transmitted Infections; Vaccine Related; Women's Health Animal Model;Animals;Antibodies;Antigen Targeting;B-Lymphocytes;Basement membrane;Benign;Binding;Biological Assay;Biology;Blocking Antibodies;C-terminal;CD8-Positive T-Lymphocytes;Capsid;Carrageenan;Cell Culture Techniques;Cervical;Clinical Trials;Communicable Diseases;Controlled Clinical Trials;Cosmetics;Costa Rica;Data;Development;Disease;Dose;Epithelial;Epithelial Cells;Epitopes;Exposure to;FDA approved;Female genitalia;Food;Gel;Genes;Genital;Genital Human Papilloma Virus Infection;Genitalia;Goals;Gold;HIV Infections;Hour;Human;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immune;Immune response;In Vitro;Infection;Intervention;Legal patent;Lesion;Life Cycle Stages;Lubricants;Macaca mulatta;Malignant - descriptor;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular Conformation;Mucous Membrane;Mus;Nonoxynol 9;Oropharyngeal;Papillomavirus;Papillomavirus Infections;Persons;Pharmaceutical Preparations;Plasmids;Polysaccharides;Prevention;Process;Proteins;Regimen;Research;Serum;Simplexvirus;Site;Stains;Surface;T-Lymphocyte;Technology;Testing;Therapeutic Agents;Translational Research;Vaccination;Vaccine Clinical Trial;Vaccines;Vagina;Virion;Virus;Virus Diseases;Virus-like particle;Woman;base;cervicovaginal;chronic infection;efficacy testing;gene transfer vector;genetic vaccine;immunogenicity;improved;in vivo;intraepithelial;keratinocyte;microbicide;mouse model;neutralizing antibody;particle;prevent;reproductive tract;response;technology development;therapeutic effectiveness;therapeutic vaccine;vaccination strategy;vaccine development;vaccine evaluation;vector;young woman Papillomavirus Virion Proteins and Vaccines n/a NCI 10702377 1ZIABC010579-19 1 ZIA BC 10579 19 2093670 "LOWY, DOUGLAS R." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 673565 NCI Papillomaviruses (PVs) infect the epithelia of animals and humans where they generally induce benign proliferations at sites of infection. In addition persistent infection by some human papillomaviruses (HPV) especially HPV16 can induce malignant progression of human genital and oropharynx lesions. Our research is mainly concerned with the biology of papillomavirus infection elucidation of the PV life cycle and development of vaccines and other strategies to inhibit HPV infection. We previously developed a simple and efficient strategy for generating high titers of infectious papillomavirus particles that transduce encapsidated marker plasmids i.e. pseudovirions. We have exploited this technology in our basic virologic and translational research efforts leading to developing a mouse cervicovaginal challenge model for HPVs. Using this model we determined that transient disruption of epithelial integrity is required for HPV infection that the first step in the virus life cycle involves binding of the virus to the basement membrane and that the virus transfers to target epithelial cells only after the L2 protein in the capsid has undergone an enzymatic cleavage while the virus is on the basement membrane. The cleavage of L2 is associated with a conformational change in the capsid leading to exposure of highly conserved L2 cross-neutralization epitopes that lie C-terminal to the cleavage site. In a process that takes several hours the virions transfer from the basement membrane to the surface of keratinocytes that are re-epithelializing the exposed basement membrane and the virions are then internalized. The mouse model also enabled us to determine that antibodies induced by L1 VLP (virus-like particle) vaccines and L2 vaccines block in vivo infection by distinct mechanisms. At high concentrations L1 VLP-induced antibodies block virion binding to the basement membrane while at low concentrations they permit basement membrane binding but prevent binding to target keratinocytes. Since the L2 cross-neutralization epitopes are cryptic and are not exposed until after the virions have been bound to the basement membrane L2 antibodies that broadly cross-neutralize HPV types do not interfere with initial basement membrane binding. Once the L2 epitopes are exposed however while the virions remain on the basement membrane the L2 antibodies can bind to the virions and abrogate the infectious process by preventing transfer of the virions to target keratinocytes. Both in the mouse model and in an analogous model developed for the rhesus macaque infection is prevented by local application of carrageenan which is an algal polysaccharide widely used in processed food and cosmetics and is the main gelling agent in some over-the-counter lubricants. Based on our data clinical trials of carrageenan as a microbicide to prevent genital HPV infection in young women are underway. Using HPV pseudoviruses we previously developed a high throughput in vitro HPV neutralization assay that has become the gold standard for the field. Based on the improved understanding of the in vivo infectious process and the mechanism by which L2 vaccines confer protection we developed an alternative in vitro neutralization assay that is approximately three orders of magnitude more sensitive than the standard assay in detecting L2 neutralizing antibodies. The alternative assay has considerable potential for determining the immunogenicity of candidate L2 vaccines and for clinical trials of L2 vaccines. Our development of a method to induce efficient HPV pseudovirus infection of the female genital tract after transient epithelial disruption with nonoxynol-9 (N-9) proved to be the key to our development of an effective intravaginal vaccination strategy. In patent pending studies we found that intravaginal pseudovirus vaccination of N-9-treated mice induces strong systemic and mucosal T and B cell responses to target antigens transduced by the pseudovirions. Systemic responses rival those induced by previously optimized Ad5 vectors. Intravaginal responses are remarkably strong with up to 80% of intravaginal CD8 T cells staining tetramer positive for the targeted antigen. Most of the induced T cells appear to be intraepithelial and are maintained in the vaginal tract at least 100 days after vaccination. Intravaginal pseudovirus vaccination is a promising approach for focusing immune responses to the female genital tract that may increase the effectiveness of therapeutic vaccines directed at herpes simplex virus infection HIV infection and HPV infection. We have also organized and participated in NCI human clinical trials of the virus-like particle vaccines following our earlier development of the technology that underlies the commercial HPV vaccines. We initially tested the bivalent HPV vaccine (manufactured by GlaxoSmithKline) in Costa Rica where post-hoc analyses of women who received fewer than the standard 3 dose regimen indicated they were as protected during 7 years of study against infection by the HPV types targeted by the vaccine (HPV16/18) as the women who received all 3 doses. In addition the women who received only one dose had stable serum HPV16/18 antibody levels between years 1 and 7 suggesting the strong protection may be durable. This surprising result raised the possibility that a single vaccine dose might confer long-term protection. A rigorously controlled clinical trial that tests the efficacy of one vaccine dose vs. two doses with two FDA-approved vaccines has now started in Costa Rica. 673565 +Bioengineering; Biomedical Imaging; Biotechnology; Cancer; Clinical Research; Health Disparities; Minority Health; Nanotechnology; Precision Medicine; Prostate Cancer; Urologic Diseases Adult;Algorithms;Androgen Receptor;Androgens;Animal Testing;Behavior;Biological Assay;Biological Markers;Biology;CCR;Camptothecin;Cell Proliferation;Classification;Clinic;Clinical;Clinical Pharmacology;Collaborations;Complex;Contrast Media;Cystitis;Development;Diagnosis;Disease;Disease Progression;Dose;Drug Design;Drug Kinetics;Drug Screening;Evaluable Disease;Evaluation;FDA approved;Failure;Gadolinium;Gene Expression;Gene Targeting;Goals;Growth;Haplotypes;Hypoxia;Hypoxia Inducible Factor;Image;Imaging Techniques;Immunohistochemistry;In Vitro;Injections;Intravenous infusion procedures;Laboratories;Lead;Lesion;Liver;Localized Malignant Neoplasm;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Metastatic to;Modeling;Molecular;Monitor;Myelosuppression;Neoplasm Metastasis;Oral;Pathway interactions;Patients;Pharmacogenomics;Pharmacology and Toxicology;Phase;Physicians;Pilot Projects;Population;Pre-Clinical Model;Process;Prognostic Marker;Provenge;Regimen;Research;Resistance;Role;Solid Neoplasm;Subgroup;System;Testing;Time;Tissues;Treatment outcome;Tumor Volume;Up-Regulation;VCaP;Validation;Work;Xenograft Model;Xenograft procedure;advanced prostate cancer;androgen biosynthesis;angiogenesis;arm;base;bench to bedside;cancer therapy;castration resistant prostate cancer;chemotherapy;clinical development;clinical efficacy;contrast enhanced;contrast imaging;docetaxel;drug candidate;drug development;drug discovery;effective therapy;efficacy evaluation;enzalutamide;experience;hormone therapy;improved;in vivo;inhibitor;inter-individual variation;interest;men;metastatic process;molecular imaging;nanoparticle;nanoparticle drug;neoplastic cell;next generation;non-invasive imaging;novel;novel therapeutics;open label;phase 2 study;potential biomarker;pre-clinical;precision medicine;preclinical development;prognostic significance;prostate cancer metastasis;prostate cancer model;research clinical testing;resistance mechanism;risk stratification;standard of care;subcutaneous;targeted treatment;therapy resistant;tool;treatment response;trend;tumor;tumor growth;tumor hypoxia;uptake Drug Development for Prostate Cancer and other Metastatic Processes n/a NCI 10702375 1ZIABC010547-20 1 ZIA BC 10547 20 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 973508 NCI Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of novel therapeutics with efforts on characterizing their molecular and clinical pharmacology as well as evaluating for potential biomarkers of treatment response and resistance. The use of non-invasive imaging techniques to increase our understanding of prostate cancer development progression and to aid physicians in risk stratification is a rapidly expanding field. Gadoxetate disodium is an FDA-approved gadolinium-based hepatoselective MRI contrast agent that has a proven role in improving the diagnosis and classification of liver lesions. Gadoxetate disodium is a substrate of OATP1B3 and its uptake has been shown to correlate with OATP1B3 expression in other cancers. OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. In collaboration with Drs. Peter Choyke and Baris Turkbey (Molecular Imaging Branch CCR NCI) we conducted a single center open-label non-randomized pilot study of men with (1) localized and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3 NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20- 40- and 60-min timepoints (p0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group but no retention over time. OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype with N130D and V174A substitutions impacted enhancement at 40-60 min (p0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance gadoxetate disodium has potential as a biomarker in prostate cancer. We are also interested in understanding the mechanisms of resistance of prostate cancer regimens. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Effective treatments for patients with mCRPC following disease progression on enzalutamide are currently an unmet clinical need. We previously demonstrated that simultaneous inhibition of the HIF-1and androgen receptor (AR) pathways can overcome enzalutamide resistance in vitro. Combination treatment with NLG207 a nanoparticle-drug conjugate of camptothecin and inhibitor of HIF-1a and enzalutamide was evaluated in preclinical prostate cancer models of enzalutamide resistance. The effect of NLG207 and enzalutamide on average tumor volume and tumor re-growth after 3 weeks of treatment was evaluated in vivo using the subcutaneous 22Rv1 xenograft and castrated subcutaneous VCaP xenograft models. Correlative assessments of antitumor activity were evaluated in vitro using cell proliferation and qPCR assays. NLG207 8 mg/kg alone and in combination with enzalutamide reduced average tumor volume by 93% after 3 weeks of treatment (P 0.05) in comparison with vehicle control in the subcutaneous 22Rv1 xenograft model. Notably the addition of NLG207 also enhanced the efficacy of enzalutamide alone in the castrated subcutaneous VCaP xenograft model decreasing the median rate of tumor growth by 51% (P = 0.0001) in comparison with enzalutamide alone. In vitro assessments of cell proliferation and gene expression further demonstrated antitumor activity via AR-HIF-1a crosstalk inhibition. Combination treatment with NLG207 and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. Furthermore we conducted a population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors. We sought to characterize the complex PK of NLG207 and better describe CPT release from nanoparticles using a semi-mechanistic population PK (popPK) model. The semi-mechanistic popPK model confirmed nanoparticle behavior of bound CPT and mechanistically characterized CPT release from NLG207. Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207 in combination with enzalutamide in patients with mCRPC following progression on enzalutamide. This was a single-arm optimal two-stage phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide (NCT03531827). A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily. Between March 2019 and June 2021 four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients. NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy. 973508 +Biotechnology; Cancer; Hematology; Immunotherapy; Lymphatic Research; Lymphoma; Orphan Drug; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Affect;Aging;Allogenic;Biology;CAR T cell therapy;CCR9 gene;CD3 Antigens;CD4 Positive T Lymphocytes;Cells;Chronic Lymphocytic Leukemia;Down-Regulation;Goals;Hematopoietic Stem Cell Transplantation;Homeostasis;IL7 gene;Immune;Immunotherapy;Malignant Neoplasms;Natural Killer Cells;Peripheral;Role;T cell reconstitution;T-Lymphocyte;Tissues;cancer therapy;cell regeneration;cytokine;immune reconstitution;improved;in vivo;novel;senescence;sialic acid binding Ig-like lectin Immune Reconstitution n/a NCI 10702373 1ZIABC010525-20 1 ZIA BC 10525 20 9692325 "GRESS, RONALD " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1896251 NCI This year we have: 1) identified a novel CAR-T cell therapy for chronic lymphocytic leukemia (CLL) and establish Siglec-6 as a possible target for immunotherapy; 2) shown that the NK-CAR framework improves the activity of CARs in NK cells and that CD5 would be a better target than CD3 for T-cell malignancies as dynamic downregulation of target expression may affect in vivo efficacy; 3) revealed a previously unappreciated role for CCR9 in the tissue homeostasis and effector function of CD4 T cells in the gut; and 4) demonstrated that the abundance of IL-7 and not IL-15 limits the size of the peripheral iNKT cell pool. These results redefine the cytokine requirement for iNKT cells and indicate competition for IL-7 between iNKT and conventional alpha-beta T cells. 1896251 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Affect;Antisense RNA;Biochemical;Cell Cycle;Cell physiology;Cells;Chromatin;Chromatin Modeling;Chromosome Structures;Complex;Coupled;Cues;Development;Double-Stranded RNA;Elements;Ensure;Epigenetic Process;Eukaryota;Fission Yeast;Foundations;Gametogenesis;Gene Expression Profile;Gene Silencing;Genes;Genetic;Genetic Recombination;Genetic Transcription;Genome;Heterochromatin;Histone H2A;Histone H3;Introns;Investigation;Large-Scale Sequencing;Light;Link;Location;Lysine;Maintenance;Maps;Measures;Mediating;Messenger RNA;Modeling;Modification;Pathway interactions;Play;Polyadenylation;Polycomb;Process;Proteins;RNA;RNA Degradation;RNA Interference;RNA Polymerase II;RNA Splicing;Regulation;Resolution;Role;S phase;Signal Transduction;Site;Small Interfering RNA;Small RNA;Structure;Transcript;Variant;Work;cancer therapy;exosome;genome integrity;genome-wide;human disease;insight;novel;preservation;prevent;protein complex;recruit;response;therapeutically effective RNAi and Epigenetic Control of Higher-Order Chromatin Assembly n/a NCI 10702371 1ZIABC010523-20 1 ZIA BC 10523 20 8777973 "GREWAL, SHIVINDER S" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1870043 NCI The dynamic regulation of higher-order chromosome structure governs diverse cellular processes ranging from stable inheritance of gene expression patterns to other aspects of global chromosome structure essential for preserving genomic integrity. Our earlier studies revealed that RNA interference (RNAi) whereby double-stranded RNAs silence cognate genes plays a critical role in targeting of heterochromatin a specialized form of chromatin that can inhibit transcription and recombination across large chromosomal domains to specific locations in the fission yeast Schizosaccharomyces pombe genome. Subsequent genetic and biochemical investigations identified the RNAi-induced transcriptional gene silencing (RITS) complex that provides a direct link between small RNAs and heterochromatin formation. These studies also uncovered surprising interdependency between heterochromatin and RNAi mechanism and led to the discovery of an elegant self-reinforcing RNAi loop mechanism that ensures both transcriptional and post-transcriptional silencing in cis. In this loop mechanism RNAi machinery operates as a stable component of the heterochromatic domains via tethering of RNAi complexes (such as RITS) to heterochromatin marks (including histone H3 methylated at lysine 9) to destroy repeat transcripts that escape heterochromatin-mediated transcriptional silencing. The processing of transcripts by RNAi machinery generates small interfering RNAs (siRNAs) that are utilized for further targeting of heterochromatin complexes so the mechanism continues. We have extended these analyses to gain insights into the full spectrum of target sequences affected by the RNAi and heterochromatin machineries. In a comprehensive study we developed a high-resolution map of heterochromatin distribution across the entire S. pombe genome. These analyses together with mapping of RNAi components and large scale sequencing of siRNAs associated with an RNAi effector RITS complex involved in heterochromatic silencing have yielded novel insights into the epigenetic profile of this model eukaryotic genome. In an interesting new development our recent work suggests that heterochromatic structures are dynamically regulated during the cell cycle. In particular heterochromatic repeat elements are transcribed during a brief window during the S-phase. Importantly we have discovered that the transcription of repeats by RNA polymerase II is coupled to the recruitment of heterochromatin complexes supporting a prominent role for transcriptional machinery in determining the epigenetic makeup of the genome. In another surprising finding we have discovered that low levels of heterochromatin factors localize broadly across euchromatic regions containing genes and cooperate with RNAi machinery to regulate expression of RNA polymerase II transcripts across large portions of the genome. In particular we have found that heterochromatin/RNAi factors prevent accumulation of potentially deleterious antisense RNAs. Heterochromatin and RNAi factors are partially redundant in this regard with a histone H2A variant H2A.Z. Loss of Clr4/Suv39h-containing heterochromatin silencing complex or an Argonaute protein alone has little effect on antisense transcript levels but cells lacking either of these factors and H2A.Z show markedly increased levels of antisense RNAs that are normally degraded by the exosome. These analyses suggest that in addition to performing other functions heterochromatin and RNAi factors cooperate with H2A.Z to suppress antisense transcripts which has important implications for diverse chromosomal processes. In another important finding we have discovered a novel heterochromatin assembly pathway that relies on transcription and RNAs but does not require RNAi machinery. We have discovered that facultative heterochromatin is established at genes required for gametogenesis (which are repressed in vegetative cells) and that its formation is dependent on conserved RNA degradation factors including a protein complex involved in polyadenylation of transcripts and the exosome that degrade gene transcripts. Importantly heterochromatin formation by this pathway is modulated in response to signals that induce gametogenesis. Most recently we have investigated how the cell distinguishes different types of RNA molecules and links their processing to heterochromatin establishment. We discovered core machinery that associates with different factors (including splicing factors) to mediate targeting of mRNA ncRNA and introns to assemble heterochromatin domains at specific sites throughout the genome. These groundbreaking studies have paved the way for understanding the more complex regulatory networks at work in higher eukaryotes including that involve polycomb silencing and has provided a foundation for understanding the large scale reprogramming of the genome in response to developmental and environmental cues that occur through modifications of heterochromatin. 1870043 +Cancer; Congenital Structural Anomalies; Genetics; Pediatric; Women's Health Address;Adult;Affect;Apoptosis;Behavior;Biology;Bone Morphogenetic Proteins;Cell Death;Cells;Cellular biology;Data;Development;Disease;Distal;Down-Regulation;Effector Cell;Elements;Embryo;Embryonic Development;Family;Fibroblast Growth Factor;Gastrointestinal Neoplasms;Gene Expression;Gene Silencing;Generations;Genetic;Goals;Growth;Heart;Hindlimb;Imagery;Limb Bud;Limb Development;Limb structure;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mesenchyme;Metastatic Neoplasm to the Bone;Modeling;Molecular;Mus;Normal Cell;Pathway interactions;Pattern;Pelvis;Phocomelia;Protein Family;Role;Signal Transduction;Signaling Molecule;Signaling Protein;Surface Ectoderm;Testing;Work;bone morphogenetic protein receptors;breast cancer progression;homeodomain;insight;novel;premature;transcription factor;tumor Role of BMP and FGF signaling during limb development n/a NCI 10702370 1ZIABC010518-20 1 ZIA BC 10518 20 8123123 "LEWANDOSKI, MARK B" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 377827 NCI In previous work we produced genetic evidence for a novel model in which the surface ectoderm must receive a BMP signal resulting in down regulation of Fgfs which in turn induces apoptosis of the underlying mesenchyme. Thus we demonstrated that BMPs control programmed cell death indirectly by regulating FGF signaling. However it is important to emphasize that this insight does not exclude a direct role for BMP signaling in controlling cell death in the developing limb. Therefore we extended these studies by studying the role of BMP and FGF signaling in various aspects of limb development using mouse lines that express Cre in specific region of the developing limb. For example the only way to test the hypothesis that BMPs act as direct effectors of cell death is to inactivate BMPs receptors only in the lineage that undergoes cells death without affecting FGF expression in nearby cells. We have achieved this using new Cre lines that allow Cre-mediated gene inactivation in these lineages. With these lines we have determined that BMPs are direct effectors of cell death (Dev Biol. 411: 266-76). In current work we showed that a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal FGF signals. Elimination of Meis results in premature limb distalization and proximalization of PD segmental borders and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning (Sci Adv 2020 PMID: 32537491) . In ongoing work we are defining the role of distal FGF signals in generating the pattern and differentiation of the pelvis in the hindlimb. We had previously demonstrated that these FGF signals are downstream of the BMP receptor 1a (Development 2007 PMID: 17537800) . We are now using sophisticated genetics and cutting edge imagery of gene expression to define which FGFs are responsible for forming this most proximal element and initiating limb formation. 377827 +Cancer; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health 5' Untranslated Regions;Address;Affect;Binding;Binding Sites;Biological Assay;Cell Nucleus;Cell membrane;Cells;Chemicals;Cytoplasm;Defect;Diffuse;Diffusion;Ensure;Epidemic;Event;Evolution;Family;Fluorescence Microscopy;Frequencies;Future;Gene Expression;Genome;Goals;Guanosine;HIV;HIV Genome;HIV-1;HIV-2;Human;Infection;Kinetics;Knowledge;Lead;Length;Location;Mediating;Monitor;Movement;Mutate;Mutation;Nucleocapsid;Parents;Play;Process;Production;Property;Proteins;Proviruses;RNA;RNA Binding;RNA Recognition Motif;Regulation;Reporting;Research;Retroviridae;Role;Shapes;Signal Transduction;Site;Structure;T-Lymphocyte;Testing;Time;Travel;Treatment Protocols;Vaccines;Viral;Viral Genome;Viral Packaging;Viral Proteins;Virion;Virus;Virus Assembly;Virus Replication;complement system;dimer;gag Gene Products;genetic information;in vitro Assay;in vivo;insight;live cell imaging;macromolecule;mutant;particle;pathogen;protein complex;single molecule;stem;trafficking;viral RNA;virological synapse;virus genetics Defining Mechanisms of HIV-1 Gag:RNA Interactions and Virus Assembly n/a NCI 10702366 1ZIABC010506-20 1 ZIA BC 10506 20 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 951445 NCI We are studying the trafficking of HIV-1 macromolecules and assembly. Once it has exited the nucleus HIV-1 RNA needs to travel to various subcellular locations to carry out its functions including dimerizing with another viral RNA and assembling into a viral particle. Our current and future studies are focused on exploring the initiation of Gag:RNA interaction in the cells examining RNA trafficking in T cells and defining the role of the viral RNA genome in particle assembly. We will also determine the kinetics of virus maturation by live-cell imaging and determine the factors that shape RNA structures in the virions. ___BACKGROUND: To generate infectious particles HIV-1 RNA and proteins traffic to the plasma membrane the major virus assembly site. The Gag protein drives HIV-1 assembly and interacts with viral RNA and proteins to ensure the packaging of the viral genome and replication machinery. Additionally Gag interacts with host proteins for virus egress. It has often been suggested that the interactions of HIV-1 RNA and Gag leading to assembly are initiated in the cytoplasm. To better understand the regulation of virus assembly we are examining cytoplasmic HIV-1 Gag:RNA and RNA:RNA interactions. We are also studying HIV-1 RNA trafficking in T cells and exploring the role of the RNA genome in HIV assembly. ___The studies in this project sought to address several unanswered questions on the trafficking of HIV-1 macromolecules and virus assembly which are essential processes in viral replication. We visualized HIV-1 RNA and monitored its movement in the cytoplasm by using single-molecule tracking and determined that most of the HIV-1 RNA molecules have diffusive movement. Additionally we showed that in the presence of Gag HIV-1 RNA is transported by diffusion with mobility similar to that of RNAs unable to express functional Gag. These studies have defined a major mechanism important to HIV-1 gene expression. Polarized T cells not only constitute a majority of HIV-1 target cells in vivo but also play a critical role in the spread of HIV-1 via cell-to-cell infection. To determine the distribution of HIV-1 RNA in polarized T cells we visualized the RNA and found that HIV-1 RNAs were enriched near the uropod plasma membrane in a Gag-dependent manner. These results indicated that HIV-1 RNA is enriched during the process of virus assembly. As the Gag-enriched uropod is more likely to form a virological synapse such targeting facilitates cell-mediated infection and virus spread in vivo. : We have examined the dynamics of viral RNA and Gag-RNA interactions near the plasma membrane by total internal reflection fluorescence (TIRF) microscopy. We found that in the absence of Gag most of the HIV-1 RNAs stayed near the plasma membrane transiently. The presence of Gag significantly increased the time RNAs stay near the plasma membrane. We observed that the frequency of HIV-1 RNA packaging was dependent on the Gag expression level. Our results showed that only a small proportion of the HIV-1 RNAs (approximately one tenth to one third) that reached the plasma membrane was incorporated into viral protein complexes. These studies determined the dynamics of HIV-1 RNA on the plasma membrane and obtained the temporal information of RNA-Gag interactions that lead to RNA encapsidation. ___We have studied the role of HIV-1 RNA during virus assembly. We hypothesize that HIV-1 full-length RNA facilitates the formation of viral particles. To test our hypothesis we examined the efficiencies of particle formation with and without RNA containing HIV-1 packaging signal. We found that although viral particles can be generated without the presence of RNA genome the HIV-1 RNA genome facilitates the production of HIV-1 particles. Furthermore the effects of the RNA genome are dependent on the level of Gag expressed in the cells. These observations are consistent with our hypothesis that packaging a dimeric RNA is the nucleation process of HIV-1 assembly. ACCOMPLISHMENT: Although several nucleocapsid (NC)-binding sites have been identified in the 5' UTR of HIV-1 RNA whether these sites direct HIV-1 RNA genome packaging has not been fully investigated. It has been shown that HIV-1 NC binds exposed guanosines. Thus we introduced G-to-A substitution on exposed guanosines in the NC-binding sites and examined the ability of these mutant RNAs to compete for packaging with wild-type RNA. We observed that multiple NC-binding sites affect RNA packaging; of the sites tested those located at stem-loop 1 of the 5' UTR had the most significant effects. These sites were previously reported as the primary NC-binding sites using a chemical probing reverse-footprinting assay and the major Gag binding sites using an in vitro assay. We found that substituting 3 to 4 guanosines resulted in less than twofold defects in packaging. However when mutations were combined severe defects were observed. Furthermore combining mutations had synergistic effects on RNA packaging defects suggesting redundancy in Gag:RNA interactions and a requirement for multiple Gag proteins to bind RNA to encapsidate the HIV-1 genome. Additionally we examined whether exposed guanosines in the 5' untranslated region are important for HIV-2 genome packaging. We found that mutating as few as three guanosines significantly reduce RNA packaging efficiency. However not all guanosines examined have the same effect; instead a hierarchical order exists wherein a primary site a secondary site and three tertiary sites are identified. Furthermore there are functional overlaps in these sites and mutations of more than one site can act synergistically to cause genome packaging defects. HIV-1 Gag:RNA interactions mediate genome packaging but the mechanism remains unclear. We posited that besides RNA binding other properties of Gag contribute to genome packaging. To examine features of Gag that are important for genome packaging we established complementation systems that separate the particle-assembling and RNA-binding functions of Gag: we used a set of Gag proteins to drive particle assembly and an RNA-binding Gag to package HIV-1 RNA. We have developed two types of RNA-binding Gag in which packaging is mediated by the authentic nucleocapsid (NC) domain or by a nonviral RNA-binding domain. We found that in both cases mutations that affect the multimerization or plasma membrane anchoring properties of Gag reduce or abolish RNA packaging. These mutant Gag can coassemble into particles but cannot package the RNA genome efficiently. Our findings indicate that HIV-1 RNA packaging occurs at the plasma membrane and RNA-binding Gag needs to multimerize on RNA to encapsidate the viral genome. 951445 +Antimicrobial Resistance; Biotechnology; Cancer; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health 3-Dimensional;Address;Capsid;Capsid Proteins;Cell Nucleus;Cell division;Cells;Chromosomes;Complex;DNA;Epidemic;Event;Evolution;Family;Generations;Genetic Recombination;Genetic Transcription;Genome;Genomic DNA;Goals;HIV;HIV Drug Resistance Program;HIV Genome;HIV-1;Infection;Innate Immune Response;Integration Host Factors;Knowledge;Location;Nuclear;Nuclear Envelope;Nuclear Import;Nuclear Pore;Parents;Positioning Attribute;Process;Proviruses;RNA;Research;Retroviridae;Reverse Transcription;Role;Rupture;Sampling;Site;Time;Treatment Protocols;Vaccines;Viral;Virus Diseases;Virus Replication;bioinformatics pipeline;chromosomal location;clinical sequencing;dimer;genetic information;insight;integration site;particle;pathogen;preservation;transcriptional coactivator p75;viral DNA;viral RNA;virus genetics Understanding Retroviral Reverse Transcription Recombination and Replication n/a NCI 10702365 1ZIABC010504-20 1 ZIA BC 10504 20 1882058 "HU, WEI-SHAU " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 249188 NCI During replication HIV-1 converts its packaged dimeric RNA genomes into DNA and generates one provirus in an infection event. In this process HIV-1 needs to preserve its genetic information while the host innate immune response attempts to abolish the generation of proviruses capable of producing infectious progeny. HIV-1 must protect its genome during virus infection while navigating through the host cell. Dr. Vinay Pathak (HIV DRP) and colleague has shown that HIV-1 cores that retained 94% of their capsid (CA) protein entered the nucleus and disassembled (uncoated) near their integration site 1.5 h before integration. However whether the nuclear capsids lost their integrity by rupturing or a small loss of CA before capsid disassembly was unclear. We have assisted Dr. Pathak's section to address this question. Using a GFP content marker we found that nuclear capsids retained their integrity until shortly before integration and lost their GFP content marker on average of 1 to 3 min before loss of capsid-associated host factor (mRuby-CPSF6). These observations imply that intact HIV-1 capsids are imported through nuclear pores; that reverse transcription occurs in an intact capsid; and that interactions between the preintegration complex and LEDGF/p75 and possibly other host factors that facilitate integration must occur during the short time period between loss of capsid integrity and integration. HIV-1 integrates its genomic DNA into the chromosomes of the infected cell but how it selects the site of integration and the impact of their location in the 3-dimensional nuclear space is not well understood. Additionally we have assisted Dr. Pathak's section to investigate the intranuclear positions of transcriptionally active HIV-1 proviruses. We found that integration sites are first located near the nuclear envelope but become randomly distributed throughout the nucleus after a few cell divisions indicating that the locations of the chromosomal sites of proviral integration are dynamic. Additionally we observed that HIV-1 cores were localized to nuclear speckles shortly after nuclear import but transcriptionally active proviruses were located adjacent to nuclear speckles. Overall these studies provide insights into HIV-1 integration site selection and their effect on transcription activities. We have also assisted Dr. Mary Kearney's group (HIV DRP) to establish a bioinformatic pipeline to define the intactness of HIV-1 proviral genomes identified in sequencing of clinical samples. 249188 +Behavioral and Social Science; Cancer; Clinical Research; Genetics; Health Disparities; Minority Health; Prevention; Prostate Cancer; Social Determinants of Health; Tobacco; Tobacco Smoke and Health; Urologic Diseases Affect;African;African American;African American population;African ancestry;Age;American;Amphotericin B;Area;Aspirin;Award;Baltimore;Biological;Blood;Cancer Etiology;Cancer Patient;Case/Control Studies;Cell Line;Cessation of life;Chemotaxis;Child;Chronic;Cities;Cohort Studies;Collaborations;Collection;Colon Carcinoma;Communities;Control Groups;DNA Methylation;Data;Databases;Development;Diabetes Mellitus;Diagnosis;Diet;Dietary Factors;Disease;Disease Marker;Disease Outcome;Disease Progression;Enrollment;Environmental Risk Factor;European;Female;Freezing;Frequencies;Gene Expression;Genotype;Ghana;Gleason Grade for Prostate Cancer;Goals;Guidelines;Hereditary Malignant Neoplasm;Hospitals;Household;Human;Immune;Immune response;Individual;Infection;Inflammation;Investigation;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Maryland;Measures;Medical;Medical History;Medical Records;Medical center;Metastatic Prostate Cancer;Minor;Molecular;Molecular Profiling;Motor Vehicles;Mutation Spectra;National Comprehensive Cancer Network;Native American Ancestry;Neighborhoods;Nigerian;Occupational;Operative Surgical Procedures;Outcome;PSA level;Paraffin Embedding;Participant;Pathologic;Pathology;Pathway interactions;Patients;Pattern;Penetrance;Pharmaceutical Preparations;Phase;Pilot Projects;Poverty;Procedures;Prospective Studies;Prostatectomy;Prostatic Neoplasms;Proteins;Protocols documentation;Public Assistance;Race;Recording of previous events;Records;Recurrence;Reporting;Research;Risk;Risk Factors;Risk Reduction;Role;Secure;Sexually Transmitted Diseases;Smoker;Socioeconomic Status;Specimen;Study Subject;Surveys;Susceptibility Gene;TNM;Time;Tissue Sample;Tissues;Tobacco use;Tumor Biology;Tumor Immunity;Tumor Markers;Tumor Suppression;Unemployment;United States Department of Veterans Affairs;Universities;Update;Urine;Virus Diseases;Work;advanced disease;base;bead chip;cancer diagnosis;cancer health disparity;case control;cigarette smoking;cohort;cooking;database of Genotypes and Phenotypes;deprivation;design;disease diagnosis;disorder risk;ethnic difference;follow-up;gene environment interaction;genetic risk factor;genetic signature;genetic variant;high risk;indexing;inflammatory marker;male;men;metabolome;mortality;mouse model;population based;precision medicine;prostate cancer risk;protective effect;recruit;risk sharing;smoking exposure;survival disparity;systemic inflammatory response;tumor Maryland Prostate Cancer Case-Control Study n/a NCI 10702364 1ZIABC010499-20 1 ZIA BC 10499 20 9692197 "AMBS, STEFAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 685102 NCI Our study was implemented in two phases. The first phase which started in April of 2005 constituted a pilot study to evaluate recruitment procedures. This phase was successful and the full study was initiated with minor changes to the protocol in April of 2006. The full study was completed in 2015 [976 cases (489 African American and 487 European American) and 1034 population-based controls (486 African American and 548 European American)]. We collected blood and urine from all individuals and paraffin-embedded and fresh-frozen tissue specimens form 135 prostatectomy surgeries. Cases are from two Baltimore hospitals the Veterans Affairs Medical Center and the University of Maryland Medical Center. Cases have pathologically confirmed prostate cancer. They had a disease diagnosis within the last two years prior to recruitment and presented with prostate cancer at all stages of the disease. One-hundred and thirty-eight cases had advanced stage disease (n = 79 with T3 and n = 59 with T4 disease). Cases were also assigned to National Comprehensive Cancer Network risk groups based on the patients' TNM stage Gleason score Gleason pattern and PSA level at diagnosis according to the guidelines for prostate cancer version 2.2021. They were classified into low intermediate high and very high risk based on the likelihood of their disease to progress to lethal prostate cancer. Lastly we have secured current information on overall and disease-specific survival from National Death Index records for the cases. The most recent update brought the number to 247 deaths from all causes with 66 of them being reported as a prostate cancer-specific mortality. The median survival follow-up time for the cohort is now 8.4 years. We will continue to collect this information for both cases and controls. More recently we were able to determine PSA values at recruitment for 888 men from the control group. Sixteen of them had PSA 4 at time of recruitment ( 2%). Furthermore we defined 823 patients as incident cases (422 African American 401 European American) when they were recruited into the study within one year after the disease diagnosis having an average interval between diagnosis and enrollment into our study of 4.8 months (4.4 months for African American and 5.2 months for European-American men). The population-based controls were identified through the Maryland Department of Motor Vehicles database and were frequency-matched by age and race to cases. The study involved the administration of a survey and collection of blood and urine from all study subjects. Tumor specimens were obtained from cancer patients if they were available after prostatectomy. Our survey evaluates tobacco use medication use occupational history diet medical and sexual history familial cancer history and socioeconomic status. Current activities in this study include the collection of additional data from pathology and medical records to have clinicopathology for all cases and information on disease recurrence as available. We continue to characterize the study participants and performed ancestry-typing in collaboration with the Kittles laboratory (City of Hope). Participants were evaluated for their West African European and Native American ancestry using 105 ancestry informative markers. The genotyping data showed that self-identified African American participants have an average West African ancestry of 75.5% among cases and 72.1% among controls whereas the European ancestry in the self-identified European American participants ranged from an average 85.8% among cases to 89.9% among the controls. For a subset (83%) of the cases and controls we obtained additional West African ancestry estimates using the Infinium HumanOmni5-Quad BeadChip array (genotyping data for 706 cases and 744 controls were submitted to dbGaP). West African ancestry estimates using the two approaches were highly similar (r=0.98). In 2021 we completed a multi-year effort to link neighborhood measures of poverty to participants in our studies. A neighborhood deprivation index was generated following the guidelines by Messer at al. Our index contains the following variables: percent (%) households in poverty % female headed households with dependent children % households on public assistance % households earning under $30000/year % households with no car and % males and females unemployed. Our study is aimed at identifying differences in risk factor exposure and tumor biology between African American and European American men. Molecular work will be used to examine race/ethnic differences in tumor biology. Our research is also aimed at identifying environmental and inherited factors (e.g. infections and immune response smoking exposure ancestry-related factors low penetrance susceptibility loci) that promote the development of an aggressive disease and specifically contribute to the survival disparity between African American and European American men. A major research focus is the role of tumor and systemic inflammation in disease progression because of our previous observation that tumors of African American patients contain a prominent immune-inflammation gene signature. Additionally we have been examining the role of cigarette smoking in the development of metastatic prostate cancer with the analysis of human tumors and the use of cell lines and a mouse model of metastatic prostate cancer. Data from this project suggest that the underlying molecular mechanism - a tumor-associated immune-inflammation gene signature - could be a shared risk factor among smokers and men of African descent and promotes disease progression (PMID: 26719530). We also investigated the link between regular use of aspirin and prostate cancer. Aspirin use has been shown to protect against several cancers but most effectively against colon cancer. Investigations of mainly European or European-American men observed that aspirin use decreases the risk of prostate cancer development and progression; however the findings across studies were heterogeneous and the risk reduction by aspirin was generally modest. In contrast our study shows that aspirin use significantly reduces the risk of aggressive prostate cancer in African American men (PMID: 28292923). Moreover regular aspirin use reduced disease recurrence in these men. We did not find the same strong protective effects of aspirin among the European American men. Thus regular aspirin use before and after a prostate cancer diagnosis may reduce the development of an aggressive disease in African American men who are at high risk of a lethal malignancy. This finding has been corroborated with an analysis of the Southern Community Cohort Study (SCCS) a large prospective study to investigate the causes of cancer health disparities. Here we found that regular aspirin use at baseline protects against a prostate cancer mortality on follow-up among the African American men in SCCS (PMID:33293340). We think these are significant observations indicating that regular aspirin use protects against lethal prostate cancer. More recently we studied if men of African descent harbor a unique systemic immune-oncological signature and measured 82 circulating proteins in almost 3000 Ghanaian African American and European American men from the NCI-Maryland and NCI-Ghana studies. Protein signatures for suppression of tumor immunity and chemotaxis were elevated in men of West African ancestry. Importantly the suppression of tumor immunity protein signa *TRUNCATED* 685102 +Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Affect;Affinity;Antiviral Agents;Attenuated;Binding;Binding Proteins;C-terminal;Caliber;Cell Line;Cell Nucleus;Cell membrane;Cells;Complex;Cyclosporine;Cytoplasm;Dependence;Diffusion;Dipeptides;Docking;Exhibits;Filament;Genes;Genome;Glycine;HIV-1;Hela Cells;Host Factor 1 Protein;Human;Human Cell Line;Human immunodeficiency virus test;Impairment;Infection;Integration Host Factors;Interphase Cell;Jurkat Cells;Karyopherins;Mediating;Membrane Fusion;Modeling;Mutation;N-terminal;Night Monkey;Nuclear;Nuclear Envelope;Nuclear Import;Nuclear Pore;Nuclear Pore Complex;Nuclear Pore Complex Proteins;Nucleoplasm;Pathway interactions;Phenotype;Play;Pore Proteins;Process;Proline;Property;Proteins;RNA;Reporter;Resistance;Retroviridae;Reverse Transcription;Role;Route;Series;Side;Site;Small Interfering RNA;TRIM5 gene;Testing;Variant;Vesicular stomatitis Indiana virus;Viral;Virus;Virus Replication;cell type;experimental study;genome wide screen;heterokaryon;inhibitor;knock-down;macromolecule;molecular mass;mutant;nucleocytoplasmic transport;particle;prevent;receptor;trafficking HIV-1 passage through the nuclear pore complex n/a NCI 10702363 1ZIABC010488-20 1 ZIA BC 10488 20 8123034 "KEWALRAMANI, VINEET N" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 395790 NCI In the mature viral particle two plus sense copies of the HIV-1 RNA genome and viral enzymatic proteins are enclosed in a conical core which is composed of a lattice of CA hexamers and pentamers. After the HIV-1 Envelope fuses with the target-cell membrane the viral core is released into the cytoplasm. Although previous models suggested that the core immediately disassembled after membrane fusion the persisting integrity of the core in the cytoplasm and the presence of CA at the NPC indicate that CA is not an immediate castaway during early steps of replication and is instead functionally associated with the PIC facilitating critical steps in infection. HIV-1 infects dividing and nondividing cells equally well due to efficient utilization of NPCs . NPCs are transport channels that span the nuclear envelope and regulate bidirectional transport of macromolecules between the nucleus and cytoplasm. With an estimated molecular mass of more than 100 MDa NPCs are composed of multiple copies of 30 different proteins called nucleoporins (Nups); including transmembrane Nups (Poms) structural Nups and FG (phenyalanine-glycine) Nups. FG Nups are essential components of the nuclear diffusion barrier and provide docking sites for transport receptors. NPCs allow the passive diffusion of molecules with a diameter of up to 9 nm and active translocation of large cargoes with a diameter of up to 39 nm. Structural analysis suggests that the NPC can dilate up to 50 nm in diameter. How the PIC traverses the NPC has been a subject of great inquiry. Early experiments with HIV-1/MLV chimeric viruses revealed that replacement of HIV-1 CA with MLV CA impairs the ability of HIV-1 to infect nondividing cells. These findings were supported by studies showing specific mutations in CA also prevented HIV-1 infection of nondividing cells. Studies with host factors that regulate nuclear transport solidified a role for CA in this process. Genome-wide screens for HIV-1 host factors exhibited significant overlap in identifying karyopherins as well as nuclear pore protein components. In particular transportin-3 (TNPO3 or TRN-SR2) Nup358 (also known as RNABP2) and Nup153 emerged as potent regulators of HIV-1 infection. Nup358 the largest FG Nup is the main component of NPC filaments that extend towards the cytoplasmic side of the pore and plays an essential role in regulating cargo trafficking by forming a physical meshwork of FG repeats. Another FG Nup Nup153 is anchored in the nuclear side of the NPC and its FG enriched filaments extend into the nucleoplasm. Depletion of Nup358 or Nup153 impairs HIV-1 infection and reduces 2-LTR circle formation but does not affect reverse transcription. Parallel studies from our group on CPSF6 had revealed that mutation forms of the protein blocked HIV-1 nuclear entry. Notably we selected for a virus resistant to this nuclear entry block and obtained N74D HIV-1 again implicating a role of CA in regulating HIV-1 nuclear entry. However unlike previous HIV-1 CA mutants that were impaired for nuclear entry the N74D mutant virus efficiently infected nondividing cells. We exploited this property to test if N74D HIV-1 had different nuclear pore requirements relative to WT HIV-1. Indeed we soon discovered that TNPO3 Nup358 and Nup153 depletion impaired WT HIV-1 but not N74D HIV-1 infection. WT HIV-1 and N74D HIV-1 do overlap in utilization of some Nups and N74D HIV-1 appears to be more dependent on Nup85 and Nup155 relative to WT HIV-1. With this finding we and others more carefully investigated the relationship between CA and NPC components. Nup358 and Nup153 are thought to have distinct interactions with CA. One group has shown that Nup358 interacts with CA through a CypA-homology domain in C-terminal domain of Nup358 while other studies have found that three FG repeats in the N-terminal domain are sufficient to support HIV-1 infection. In contrast Nup153 has been shown to bind to a conserved pocket in CA also targeted by CPSF6 and the antiviral compounds PF-74 and BI-2. Interestingly both Nup153 and CPSF6 possess 'FG' dipeptides that are necessary for binding CA. Notably HIV-1 with CA mutations that prevent CypA-interaction also appeared to exhibit reduced sensitivity to Nup153 depletion. CypA is a highly abundant cellular protein and binds to the HIV-1 CA residues glycine 89 and proline 90 on the proline-rich loop between helices 4 and 5. Disruption of this interaction by CA mutation (such as G89V or P90A) by cyclosporine A (CsA a competitive inhibitor of CypA) by CypA knockdown or by homozygous deletion of the CypA gene impairs HIV-1 replication in most human cells. Although CypA is incorporated into HIV-1 particles CypA-CA interaction in the target cell rather than in the producer cell is necessary to enhance viral replication. CypA can also have deleterious effects on HIV-1 replication. Passage of HIV-1 in a CD4+ HeLa cells in the presence of CsA selected two mutants (A92E and G94D) in the CypA-binding loop of CA although neither mutation affected the affinity of CA for CypA. Viruses bearing either A92E or G94D show attenuated HIV-1 infectivity in some human cell lines such as HeLa and H9 cells; however reducing the CypA-CA interaction by CsA treatment or by introducing an additional mutation at proline 90 rescued HIV-1 infectivity in these cells. In contrast the A92E and G94D mutants are able to replicate in the presence or absence of CsA in other cell lines such as Jurkat cells. How these CA mutants behave very differently following CsA treatment in different target cells is still a puzzle. One possible explanation for these phenotypes is that differential effects of CypA mutants on HIV-1 replication in different cell types might be due to variations in CypA expression levels. In support of this idea some studies have shown that there is correlation between different CypA expression levels and CsA effects in different cell lines. Another possibility to explain the CsA-dependency of these mutants in some cell types is a CypA-dependent restriction factor activity. In owl monkey cells TRIMCyp blocked HIV-1 infection but restriction was released by CA mutants that disrupt the interaction with CypA and by CsA treatment. Since A92E HIV-1 infection was also rescued by CA mutants or CsA it was hypothesized that a CypA-dependent restriction factor was inhibiting A92E replication in these cells. Use of heterokaryons has shown that CsA-dependent infection by A92E and G94D mutants is due to a dominant cellular restriction factor but the restriction is not by retrovirus restriction factor TRIM5alpha. Because A92E HIV-1 and G94D HIV-1 are impaired at the level of nuclear entry in nonpersmissive cell types we sought to understand whether CypA interaction with the WT HIV-1 PIC also had the potential to restrict nuclear transport - but HIV-1 had adapted in use of the NPC to overcome the impediment. To investigate the role of nuclear pore subcomplexes in HIV-1 infection we systematically depleted all thirty-two human nuclear pore proteins in HeLa cells with siRNA and then infected with VSV-G pseudotyped reporter viruses. In this effort we have identified HIV-1 dependency on nucleoporins that are regulated by CA interactions with CypA. Strikingly CypA dictates the nuclear import route utilized by HIV-1 favoring an FG-receptor mediated pathway. We hypothesize that CypA regulates access the N74 pocket of HIV-1 CA and facilitates subsequent interaction with FG-nucleoporins. 395790 +Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Affect;Antiviral Therapy;C-terminal;Cell Nucleus;Cells;Chromatin;Companions;Complex;Cytoplasm;Data;Dependence;Equine Infectious Anemia Virus;Feline Immunodeficiency Virus;Genetic;Genetic Transcription;HIV;HIV-1;HIV-2;Infection;Integration Host Factors;Karyopherins;Mutation;Nuclear;Nuclear Pore;Pore Proteins;Role;Route;SIV;Virus;experimental study;trafficking;viral resistance The role of CPSF6 in HIV-1 infection n/a NCI 10702362 1ZIABC010487-20 1 ZIA BC 10487 20 8123034 "KEWALRAMANI, VINEET N" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 791581 NCI We have previously described a C-terminally truncated form of CPSF6 (CPSF6-358) that has potent antiviral activity against different HIV-1 HIV-2 and SIV isolates but no activity against EIAV FIV or MLV. CPSF6-358 interferes with the nuclear entry of HIV-1. We selected for HIV-1 replication in cells expressing CPSF6-358 and identified a mutation of N74D of CA as sufficient to confer viral resistance. We examined the nuclear pore dependencies for wild-type (WT) and N74D HIV-1 and found that the isolates require some of the same pore proteins but differ in requirements for others. In particular N74D HIV-1 was less sensitive to depletion of TNPO3 (a karyopherin) NUP153 and NUP358/RanBP2 than WT HIV-1. These experiments established a genetic interaction between HIV-1 CA and the nuclear pore. We are now attempting to define the route that HIV-1 takes to the nucleus: the cell factors it interacts with and how it interacts with these factors. Our data suggest a direct interaction of WT CPSF6 with CA. We have also discovered that TNPO3 regulates CPSF6 nuclear localization. We are examining whether CPSF6 normally interacts with HIV-1 CA in the cytoplasm and whether this interaction is important for nuclear entry of the virus. Within the nucleus we find that the HIV-1 pre-integration complex interacts with CPSF6 and this interaction regulates HIV-1 integration in the host cell chromatin. Notably we find that by interacting with CPSF6 HIV-1 is first directed to speckles after entering the nucleus and prior to integration. Nuclear speckles colocalize with regions of chromatin that HIV-1 preferentially integrates. Thus we hypothesize that HIV-1 co-opted CPSF6 to access regions of chromatin that are broadly transcriptionally active due to their proximity to nuclear speckles. A companion effort has identified cytoplasmic and nuclear host factors that affect CPSF6-trafficking of the HIV-1 to nuclear speckles. 791581 +Cancer; Genetics; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Active Sites;Affect;Anti-HIV Agents;Antiviral Therapy;Behavior;Binding;Cells;Chemicals;Clinical;Combined Modality Therapy;Complex;DNA;DNA biosynthesis;DNA-Directed DNA Polymerase;Development;Drug Targeting;Drug resistance;Drug usage;Enzymes;Genome;Goals;HIV;HIV Genome;HIV Infections;HIV-1;Hybrids;Hydrophobicity;Infection;Integrase;Lamivudine;Life Cycle Stages;Minor;Mitochondria;Mutation;Nuclear;Pancreatic ribonuclease;Patients;Pharmaceutical Preparations;Pharmacotherapy;Polymerase;Positioning Attribute;Predisposition;RNA;RNA-Directed DNA Polymerase;Research Priority;Resistance;Resistance development;Retroviridae;Reverse Transcriptase Inhibitors;Ribonuclease H;Structure;Subgroup;Tenofovir;Threonine;Toxic effect;United States;United States National Institutes of Health;Viral;Virus;Virus Replication;Work;Zidovudine;abacavir;base;design;ds-DNA;genomic RNA;inhibitor;mutant;non-nucleoside reverse transcriptase inhibitors;novel;nucleoside analog;polymerization;pre-exposure prophylaxis;prophylactic;resistance mutation;therapy development;viral DNA;viral RNA;viral genomics HIV-1 Reverse Transcriptase n/a NCI 10702360 1ZIABC010481-20 1 ZIA BC 10481 20 8122993 "HUGHES, STEPHEN H" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 343461 NCI The life cycle of retroviruses is characterized by two steps that are carried out by two essential virally encoded enzymes reverse transcriptase (RT) and integrase (IN). In the first of these steps RT converts the single-stranded genomic viral RNA into a linear double-stranded DNA that is longer than the genomic RNA from which it is derived. In the second step IN inserts this linear viral DNA into the host genome. Both steps are essential for the retroviral life cycle; both RT and IN are key anti-HIV drug targets. The development of new broadly effective low-toxicity anti-HIV drugs is one of the high-priority research goals of the NIH in part because of problems with emerging drug resistance in both the developed and the developing world. The conversion by RT of retroviral genomic RNA into DNA involves the two enzymatic activities: a polymerase that can copy either RNA or DNA and a ribonuclease H (RNase H) that cleaves RNA if it is part of an RNA/DNA hybrid. There are two clinically important classes of anti-RT drugs: nucleoside analogs (NRTIs) and nonnucleoside RT inhibitors (NNRTIs) both of which target the polymerase. Although the RNase H of RT is essential for viral replication there are no anti-HIV drugs that target RNase H. The NRTIs that are currently used to treat HIV-1 infections lack the 3'-OH found on normal deoxynucleosides. If an NRTI is incorporated into viral DNA by RT polymerization is blocked. NNRTIs bind to a hydrophobic pocket that is near the polymerase active site. Because NRTIs can also be incorporated into the mitochondrial and nuclear DNA of host cells these drugs can be toxic to patients particularly because HIV drug therapies are usually lifelong. A bound NNRTI distorts the structure around the active site blocking the chemical step of DNA synthesis. However NNRTIs do not affect host DNA polymerases and as a consequence are relatively nontoxic. A major focus of our work has been to understand the mechanism(s) of RT inhibitor resistance to NRTIs and NNRTIs. There is at this point a reasonably good understanding of the mechanism(s) of NNRTI resistance and considerable progress has been made in understanding NRTI resistance. Although NNRTIs are as a group relatively nontoxic they are more susceptible to the development of resistance than NRTIs. We have worked to develop NNRTIs that are more broadly effective against the known drug-resistant mutants of HIV-1 and on understanding NRTI resistance. Most of the analysis that has been done on the susceptibility of HIV to various drugs has been done with subgroup B viruses. Subgroup B viruses are common in the United States but B is not the major subgroup worldwide. Subgroup C is much more prevalent worldwide and it is important to know if therapies developed based on subgroup B viruses will be equally effective against subgroup C. In particular we wanted to know if complex group of resistance mutations behaved similarly in subgroups B and C RTs. We identified a complex drug resistant RT mutant in a subgroup C RT and asked if various combinations of these mutations had similar effects in subgroup B and subgroup C RTs. The subgroup C virus was obtained from a donor who was on combination therapy with abacavir AZT and 3TC. An RT was sequenced that had mutations at positions 67 70 184 219 and a threonine insertion after position 69. We found that these mutations affected the ability of NRTIs to inhibit DNA synthesis by both the subgroup B and C RTs. Although there were minor differences in the behavior of the RTs it appears that these mutations behave similarly in both B and C subgroup RTs which suggests that similar therapies can be used successfully with both subgroups. However the presence of the inserted threonine reduced the susceptibility of both the subgroup B and subgroup C mutant RTs to inhibition by tenofovir which is a potential problem given the importance of that drug in anti-viral therapies. 343461 +Bioengineering; Biomedical Imaging; Cancer Aftercare;Biochemical;Biochemical Pathway;CD3 Antigens;Carbohydrates;Cell Nucleus;Chemicals;Clinical Trials;Colorectal;Complex;Contrast Media;Copper;Dependence;Detection;Deuterium;Development;Devices;Diffusion Magnetic Resonance Imaging;Dimethyl Sulfoxide;Future;Guidelines;HT29 Cells;Human;Hydration status;Image;In Situ;Investigation;Iridium;Label;Ligation;Lipids;Liquid substance;Magnetic Resonance Imaging;Magnetism;Malignant Neoplasms;Measures;Metabolic;Metabolism;Methodology;Methods;Molecular;Molecular Probes;Monitor;NMR Spectroscopy;Nature;Nitrogen;Normal tissue morphology;Nuclear;Nuclear Magnetic Resonance;Nucleic Acids;Pancreas;Physiology;Proteins;Protons;Pyruvate;Reaction;Relaxation;Reporting;Residual state;Sampling;Signal Transduction;Sodium;Source;Structure;Techniques;Temperature;Time;Tissues;Tracer;Water;Xenograft procedure;aerobic glycolysis;alanine aminopeptidase;base;cancer imaging;catalyst;clinically relevant;cold temperature;comparative;cost;density;design;detection sensitivity;enzyme activity;imaging approach;imaging biomarker;in vivo;iron oxide;magnetic field;metabolic imaging;molecular imaging;mouse model;novel;pressure;real-time images;response;treatment effect;treatment response;tumor;tumor growth Overhauser Enhanced Magnetic Resonance Imaging (OMRI) n/a NCI 10702359 1ZIABC010477-20 1 ZIA BC 10477 20 15686910 "KRISHNA, MURALI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1133624 NCI Rational Probe Design: Dynamic nuclear polarization (DNP) is a cutting-edge technique that markedly enhances the detection sensitivity of molecules using nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI). This methodology enables real-time imaging of dynamic metabolic status in vivo using MRI. To expand the targetable metabolic reactions there is a demand for developing exogenous i.e. artificially designed DNP-NMR molecular probes; however complying with the requirements of practical DNP-NMR molecular probes is challenging because of the lack of established design guidelines. Here we report Ala-[1-(13)C]Gly-d2-NMe2 as a DNP-NMR molecular probe for in vivo detection of aminopeptidase N activity. We developed this probe rationally through precise structural investigation calculation biochemical assessment and advanced molecular design to achieve rapid and detectable responses to enzyme activity in vivo. With the fabricated probe we successfully detected enzymatic activity in vivo. This report presents a comprehensive approach for the development of artificially derived practical DNP-NMR molecular probes through structure-guided molecular design. Low cost hyperpolarizer: Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) is investigated to achieve rapid hyperpolarization of (13) C1 spins of [1-(13) C]pyruvate using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co-ligation of DMSO and H2 O. Order-unity (13) C (50 %) polarization of catalyst-bound [1-(13) C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1-(13) C]pyruvate at lower temperatures. On the catalyst bound pyruvate 39 % polarization is measured using a 1.4 T NMR spectrometer and extrapolated to 50 % at the end of build-up in situ. The highest measured polarization of a 30-mM pyruvate sample including free and bound pyruvate is 13 % when using 20 mM DMSO and 0.5 M water in CD3 OD. Efficient (13) C polarization is also enabled by favorable relaxation dynamics in sub-microtesla magnetic fields as indicated by fast polarization buildup rates compared to the T1 spin-relaxation rates (e. g. approximately 0.2 s(-1) versus approximately 0.1 s(-1) respectively for a 6 mM catalyst-[1-(13) C]pyruvate sample). Finally the catalyst-bound hyperpolarized [1-(13) C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water paving the way to future biomedical applications of hyperpolarized [1-(13) C]pyruvate produced via comparatively fast and simple SABRE-SHEATH-based approaches. Parahydrogen generator: We report on a robust and low-cost parahydrogen generator design employing liquid nitrogen as a coolant. The core of the generator consists of catalyst-filled spiral copper tubing which can be pressurized to 35 atm. Parahydrogen fraction 48% was obtained at 77 K with three nearly identical generators using paramagnetic hydrated iron oxide catalysts. Parahydrogen quantification was performed on the fly via benchtop NMR spectroscopy to monitor the signal from residual orthohydrogen-parahydrogen is NMR silent. This real-time quantification approach was also used to evaluate catalyst activation at up to 1.0 standard liter per minute flow rate. The reported inexpensive device can be employed for a wide range of studies employing parahydrogen as a source of nuclear spin hyperpolarization. To this end we demonstrate the utility of this parahydrogen generator for hyperpolarization of concentrated sodium [1-(13)C]pyruvate a metabolic contrast agent under investigation in numerous clinical trials. The reported pilot optimization of SABRE-SHEATH (signal amplification by reversible exchange-shield enables alignment transfer to heteronuclei) hyperpolarization yielded (13)C signal enhancement of over 14000-fold at a clinically relevant magnetic field of 1 T corresponding to approximately 1.2% (13)C polarization-if near 100% parahydrogen would have been employed the reported value would be tripled to (13)C polarization of 3.5%. Imaging markers from MRI using D2O: Purpose: Water is a substrate in many biochemical pathways. Systemic administration of deuterated water (D2O) results in deuterium incorporation into nucleic acids carbohydrates proteins and lipids. Given their relatively high rates of proliferation and resultant deuterium enrichment we hypothesized that tumors would be more easily discerned from healthy tissues via deuterium MRI. Methods: We initiated D2O administration in two xenograft mouse models harboring either human colorectal HT-29 or pancreatic MiaPaca2 cancers. Results: After 14 days of in vivo tumor growth and 7 days of systemic labeling with D2O a clear dMRI contrast was demonstrated between the xenografts and normal tissue. Conclusions: Our novel clinically relevant labeling-imaging approach enables non-radioactive sensitive tumor detection and supports the use of deuterium in cancer imaging. 1133624 +Biomedical Imaging; Cancer; Digestive Diseases; Orphan Drug; Pancreatic Cancer; Radiation Oncology; Rare Diseases 3-Dimensional;Aftercare;Agreement;Biochemical;Cell Line;Cell Nucleus;Characteristics;Chemicals;Chemoresistance;Chemotherapy and/or radiation;Chemotherapy-Oncologic Procedure;Clinical;Combined Modality Therapy;DNA Repair;DNA lesion;Dependence;Effectiveness;Electron Spin Resonance Spectroscopy;Hypoxia;Image;In Vitro;Kidney;Label;Magnetic Resonance Imaging;Magnetism;Maps;Measures;Metabolic;Metabolism;Methods;Monitor;Mus;Nature;Nude Mice;Organ;Oxidation-Reduction;Oxygen;Oxygen saturation measurement;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Penetration;Pharmaceutical Preparations;Physiology;Pimonidazole;Process;Prodrugs;Protons;Pyruvate;Radiation;Radiation therapy;Research;Residual Tumors;Signal Transduction;Solid;Stains;Techniques;Testing;Time;Tissues;Toxic effect;Tracer;Tumor Oxygenation;Water;Width;Work;Xenograft Model;Xenograft procedure;aerobic glycolysis;anticancer treatment;base;cell killing;chemotherapy;cytotoxic;density;ds-DNA;gemcitabine;homologous recombination;improved;improved outcome;in vivo;kidney imaging;metabolic imaging;molecular imaging;pre-clinical;radioresistant;repaired;response;stem;synergism;treatment effect;treatment response;tumor;tumor hypoxia;tumor microenvironment Time Domian Electron Paramagnetic Resonance Imaging n/a NCI 10702358 1ZIABC010476-20 1 ZIA BC 10476 20 15686910 "KRISHNA, MURALI " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1133624 NCI Dynamic range extension of pO2 imaging: In the preceding research we examined and confirmed the utility of spin probe Ox071 deuterated version of Ox063 for both R1 and R2* based EPR oximetry. Due to the narrow line width and slower signal decay it was expected that pO2 estimation using Ox071 is suitable not only in hypoxic tissue but also in less hypoxic tissue such as solid organs. In this work we present our first 3D in vivo EPR oximetry study using Ox071 in comparison with Ox063 oximetry. The R2* change with [Ox071] and pO2 was calibrated using standard phantom solutions at 12510 mM and 0 2 5 10 21% respectively. In vivo EPR imaging of a mouse bearing MIA Paca-2 tumor was performed on successive days by using either Ox071 or Ox063. The spin density pO2 maps and pO2 histograms in the tumor regions marked by co-registration with MRI were similar between Ox063 and Ox071. Healthy kidney imaging was also performed on athymic mice using both Ox071 and Ox063. Ox071 oximetry showed more homogeneous pO2 profile in kidney compared with Ox063 suggesting that Ox071 is suitable for oximetry in tissue at higher pO2 range. Tumor microenvironment determinants in evofosfamide efficacy: Pancreatic ductal adenocarcinomas (PDACs) form hypovascular and hypoxic tumors which are difficult to treat with current chemotherapy regimens. Gemcitabine (GEM) is often used as a first line treatment for PDACs but has issues with chemoresistance and penetration in the interior of the tumor. Evofosfamide a hypoxia activated prodrug has been shown to be effective in combination with GEM although the mechanism of each drug on the other has not been established. We used two mouse xenografts from two cell lines (MIA Paca-2 and SU 86.86) with different tumor microenvironmetal characteristics to probe the action of each drug on the other. GEM treatment enhanced survival times in mice with SU.86.86 xenografts (HR =0.35 95% CI=0.13 to 0.90 p=0.03) but had no effect on MIA Paca-2 mice (HR =0.91 95% CI=0.37 to 2.25 p=0.84). Conversely evofosfamide had no effect on SU86.86 mice and did not improve survival times to a statistically significant degree (HR=0.57 95% CI=0.23 to 1.42 p=0.22). In MIA Paca-2 tumors which were initially poorly perfused electron paramagnetic resonance (EPR) imaging showed that oxygenation worsened when treated with GEM providing a direct mechanism for the activation of evofosfamide by GEM and the effectiveness of evofosfamide and GEM combinations. Sublethal amounts of either treatment enhanced the toxicity of other treatment in vitro in Su86.86 but not in MIAPaca-2. Repair of double stranded DNA lesions was enhanced in the combination treatment in Su86.86 but not MIA Paca-2. A possible mechanism for the synergy between evofosfamide and GEM has been proposed. The synergy between GEM and evofosfamide appears to stem from the dual action of GEM's effect on tumor vasculature and the GEM inhibition of the homologous recombination DNA repair process. The relative importance of each pathway is dependent on the tumor microenvironment and merits further study. The hypoxia activated prodrug Evofosfamide improves tumor oxygenation. Tumors have regions with low. Levels of oxygen called hypoxic zones These regions are resistant to radiation therapy and chemotherapy. Hypoxia activated prodrugs such as Evofosfamide are developed to specifically kill cells in hypoxic regions. In hypoxic tumor microenvironments the strongly reducing redox state converts evofosfamide (TH-302) to a reduced form and releases a cytotoxic bromo-isophosphoramide (Br-IPM) moiety. This drug therefore preferentially attacks hypoxic regions in tumors where other standard anti-cancer treatments such as chemotherapy and radiation therapy are often ineffective. Various combination therapies with evofosfamide have been proposed and tested in preclinical and clinical settings. However the treatment effect of evofosfamide monotherapy on tumor hypoxia has not been fully understood partly due to the lack of quantitative methods to assess tumor pO2 in vivo. Here we use quantitative pO2 imaging by EPR to evaluate the change in tumor hypoxia in response to evofosfamide treatment using two pancreatic ductal adenocarcinoma xenograft models; MIA Paca-2 tumors responding to evofosfamide and Su.86.86 tumors which do not respond. EPR imaging showed oxygenation improved globally after evofosfamide treatment in hypoxic MIA Paca-2 tumors in agreement with the ex vivo results obtained from hypoxia staining by pimonidazole and in apparent contrast to the decrease in Ktrans observed in DCE MRI. The observation that evofosfamide not only kills the hypoxic region of the tumor but also improves oxygenation in the residual tumor regions provides a rationale for combination therapies using radiation and anti-proliferatives post evofosfamide for improved outcomes. 1133624 +Aging; Biotechnology; Cancer; Cancer Genomics; Genetic Testing; Genetics; Health Disparities; Human Genome; Minority Health; Obesity; Precision Medicine; Prevention; Prostate Cancer; Urologic Diseases 3' Untranslated Regions;Affect;Androgens;Asian;Automobile Driving;Benign;Binding;Biological;Biological Assay;Biology;Black race;Body mass index;Cancer Biology;Candidate Disease Gene;Cells;Chemopreventive Agent;Clinical;Collaborations;Complex;DNA Sequence Alteration;Data;Development;Diffusion;Disease;Disease Management;Finasteride;Frequencies;Future;Genes;Genetic;Genetic Polymorphism;Genetic Predisposition to Disease;Genetic Transcription;Genetic Variation;Genomics;Germ-Line Mutation;Goals;Gonadal Steroid Hormones;Haplotypes;Hereditary Malignant Neoplasm;Heritability;Hormones;Hyperplasia;IGFBP2 gene;Impairment;In Vitro;Incidence;Individual;Institution;Insulin;Insulin-Like Growth Factor I;Insulin-Like Growth-Factor-Binding Proteins;Investigation;Kinetics;Knowledge;Laboratories;Link;Logistic Regressions;Luciferases;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;MicroRNAs;Molecular;Molecular Biology;Molecular Genetics;Mutation;Nested Case-Control Study;Obesity;Odds Ratio;Organic Anion Transporters;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacogenetics;Pharmacogenomics;Prevention strategy;Prostate Cancer Prevention Trial;Race;Regulator Genes;Regulatory Element;Reporter;Research;Research Personnel;Resistance;Resistance development;Risk;Risk Assessment;Role;Sample Size;Sampling;Screening for cancer;Serum;Serum Markers;Single Nucleotide Polymorphism;Specimen;Steroids;Testing;Testosterone;The Cancer Genome Atlas;Therapeutic;Time;Tissues;Transcript;Translational Research;Update;Variant;Xenograft Model;abiraterone;advanced prostate cancer;ancestry analysis;androgen deprivation therapy;biomarker discovery;black men;cancer genomics;cancer risk;castration resistant prostate cancer;clinically relevant;cohort;differential expression;drug development;health disparity;improved;in vivo Model;interest;men;miRNA expression profiling;microRNA biomarkers;mortality;nano-string;new therapeutic target;novel;overexpression;precision medicine;precision oncology;predictive marker;promoter;prostate biopsy;prostate cancer prevention;prostate cancer risk;racial difference;randomized placebo controlled trial;resistance mechanism;steroid hormone;targeted treatment;therapy resistant;tool;transcription factor;treatment response;trend;tumor;uptake Genetics and Molecular Mechanisms of Prostate Cancer n/a NCI 10702357 1ZIABC010453-21 1 ZIA BC 10453 21 9979589 "FIGG, WILLIAM DOUGLAS" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 730131 NCI We have conducted translational research to understand the genetic and molecular mechanism that govern prostate cancer development and progression to identify novel pathways for drug development and investigate mechanisms of resistance to treatment paradigms. Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer and germline testing is increasingly important in cancer screening risk assessment and the overall treatment and management of the disease. We are interested in understanding germline variants associated with inherited predisposition prostate cancer risk and outcomes. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. We have a longstanding collaboration with the Prostate Cancer Prevention Trial (PCPT) investigators to elucidate the molecular and genetic mechanisms that may help explain the trial outcomes of the PCPT. The overall goals of this project are: a) to better understand associations between important androgen regulatory gene polymorphisms and PCa risk; and b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for PCa. Studies are ongoing examining the effects of obesity-related serum markers on modulating the association of obesity with prostate cancer risk. Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor 1 (IGF1) pathways. We investigated the association of circulating serum markers (e.g. androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case-control study are from the Prostate Cancer Prevention Trial a randomized placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF1 axis analytes. Logistic regression estimated odds ratio and 95% CIs for risk of overall low-grade (Gleason 2-6) and high-grade (Gleason 7-10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF1 axis was significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI only the IGF1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments. As the era of cancer genomics expands disproportionate rates of prostate cancer incidence and mortality by race have demonstrated increasing relevance in clinical settings. While Black men are most particularly affected as data has historically shown the opposite is observed for Asian men thus creating a basis for exploring genomic pathways potentially involved in mediating these opposing trends. Studies on racial differences are limited by sample size but recent expanding collaborations between research institutions may improve these imbalances to enhance investigations on health disparities from the genomics front. In this study we performed a race genomics analysis using GENIE v11 the most recent data update released in January 2022 to investigate mutation and copy number frequencies of select genes in both primary and metastatic patient tumor samples. Further we investigate the TCGA race cohort to conduct an ancestry analysis and to identify differentially expressed genes highly upregulated in one race and subsequently downregulated in another. Our findings highlight pathway-oriented genetic mutation frequencies characterized by race and further we identify candidate gene transcripts that have differential expression between Black and Asian men. We are also interested in understanding the molecular genetics of androgen transport. The organic anion transporter OATP1B3 encoded by SLCO1B3 is involved in the transport of steroid hormones. We have shown that prostate cancer overexpresses OATP1B3 compared to normal or benign hyperplastic tissue and the common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with CaP. We found that a polymorphism in this transporter increases testosterone import is associated with a shorter time to androgen independence in patients with CaP who are treated with ADT. Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. We recently conducted studies to ascertain the androgen uptake kinetics functional and clinical relevance of de novo expression of OATP1B3. We found that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Studies are ongoing to characterize the molecular mechanisms of SLCO1B3 transcription including transcription factor complexes that assemble at distinct regulatory elements in the SLCO1B3 promoter for driving tissue-specific expression of OATP1B3 in prostate cancer. We discovered that abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3'-untranslated region (3'UTR) of the SLCO1B3. Using dual luciferase reporter assays we verified that hsa-miR-579-3p indeed binds to the SLCO1B3 3'UTR and significantly inhibited SLCO1B3 reporter activity. Treatment with abiraterone significantly downregulated hsa-miR-579-3p indicating its potential role in upregulating SLCO1B3 expression. In this study we demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will also assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics. 730131 +Bioengineering; Biotechnology; Cancer; Immunization; Nanotechnology; Vaccine Related Acetates;Adaptor Signaling Protein;Adhesives;Affinity;Amines;Amino Acids;Anabolism;Animals;Annual Reports;Antibodies;Antigens;Apoptotic;Area;Attenuated;B-Cell Activation;B-Lymphocyte Epitopes;B-Lymphocytes;Binding;Biological Assay;Buffers;CCR;Cancer Vaccines;Carbohydrates;Cell Line;Cell Surface Proteins;Cell surface;Cells;Chemicals;Chemistry;Collaborations;Colloids;Complement 3;Complement 3d;Complement 3d Receptors;Conflict (Psychology);Cytokine Gene;Data;Detection;Development;Diagnostic Imaging;Disaccharides;Drug Delivery Systems;Enzymes;Epitopes;Evaluation;Event;Extramural Activities;Galectin 3;Gene Expression;Glycopeptides;Glycosides;Gold;Hybrids;Immune response;Implant;Inflammatory;Journals;Keyhole Limpet Hemocyanin;Knock-out;Ligands;Magnetism;Malignant Neoplasms;Manuscripts;Mediating;Medical Research;Metals;Methods;Monoclonal Antibodies;Mucins;Mus;N-terminal;Nanosphere;Neoplasm Metastasis;North Carolina;Organic Synthesis;Paper;Particle Size;Pathway interactions;Peptides;Pharmaceutical Preparations;Phenotype;Play;Polysaccharides;Preparation;Procedures;Process;Production;Proteins;Publishing;Quantum Dots;Reagent;Reporting;Reproducibility;Research;Research Personnel;Role;Sampling;Science;Serine;Signal Transduction;Stains;Surface;System;TNF gene;Testing;Therapeutic Agents;Thompson-Friedenreich Antigen;Threonine;Time;Tissues;Toll-like receptors;Toxic effect;Tumor Cell Line;Tumor Tissue;Tumor-Associated Carbohydrate Antigens;Universities;Vaccinated;Work;analog;animal imaging;biophysical techniques;cancer cell;cell motility;cell type;cytokine;cytotoxic;cytotoxicity;design;experimental study;fascinate;gag Gene Products;imaging program;in vivo;interest;macromolecule;macrophage;mimetics;monomer;mutant;nano;nanoGold;nanoparticle;neoplastic cell;novel;novel therapeutics;novel vaccines;particle;physical property;polyclonal antibody;professor;receptor;response;sugar;tumor;tumorigenesis Carbohydrate Antigen-bearing Nanoparticles for Antitumor Therapy n/a NCI 10702356 1ZIABC010451-21 1 ZIA BC 10451 21 8777873 "BARCHI, JOSEPH JOHN" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 706429 NCI An established hallmark of tumorigenesis is the biosynthesis of aberrant glycan chains due to changes in the expression of glycoprocessing enzymes in tumor tissue. These aberrations become more marked as the tumor acquires a more aggressive phenotype. Tumor cell-surface carbohydrates play important roles in the motility and metastasis of many different cancer cells. In addition many of these aberrant glycans are tumor-associated carbohydrate antigens (TACA) and have been used in the development of tumor vaccines. Since most of the cellular interactions with TACAs are not well understood there is an urgent need to better characterize the specific molecular interactions that occur during these events. One feature of carbohydrate binding to macromolecules that is well understood is the concept of multivalency: Monomer carbohydrates bind to proteins very weakly while clustering of a monomer raises this affinity as much as a million-fold. We have prepared the important Thomsen-Friedenreich (Tf) antigen (Gal(beta)1-3GalNAc(alpha)-O-Ser/Thr) on very specific templates to take advantage of this so-called cluster glycoside effect. As mentioned in the last report we have prepared gold self-assembled nanospheres and quantum dots containing sugar derivative and reported preliminary details on their function. The in vivo experiments with our gold nanospheres in mice were conflicting so we retreated to basics and performed more rigorous characterization and explored a host of new syntheses that allowed for production of more uniform particles. We proceeded to systematically study the optimum procedure from several related methods that offered the highest quality particles with regards to stability and uniformity. We have now a new optimized and reproducible synthesis for gold nanoparticles bearing the TF antigen attached to both eth threonine and serine amino acid residues with a capping acetate at the N-terminal amine group. Examination of these particles in various tumor cell lines for cytotoxicity has been performed and compared against each construct. These cells were chose to be either positive or negative for expression of the anti-apoptotic protein Galectin-3 an in vivo receptor for the TF antigen. Cells that are negative for Gal-3 do not respond to our particles which suggest that cytotoxicity does go through a Gal-3 mediated pathway. We put a heavy emphasis on preparing particles that encompassed what we consider the best antigen a glycopeptide from tumor associated cell-surface mucins and combined that with various concentrations of linker and B-cell epitopes to construct particles that may act as novel immunogens. We prepared at least seven separate particles with various placements of the disaccharide on the peptide and along with linker and a 28-residue portion of C3d a domain of complement component 3 and a ligand of CD21 a B-cell surface protein that when engaged lowers the threshold of B-cell activation.. These particles were injected into mice and the sera were analyzed for immune responses. A statistically significant immune response was observed in at least two test groups and animals we boosted a second time with fresh particles. Tumors were implanted and survival was followed. Although one specific antigen group did better than the others they did not do better than the group that received only PBS. There are several parameters that could have led to a lower than desired response and we are looking into these now. A full paper in Bioconjugate Chemistry was recently published on this work and the antitumor activity of some of these constructs has been evaluated by several methods and this paper is written with Kate Rittenhouse-Olson and close to submission. Further work in this area for this research cycle has been to take the aforementioned best construct called MUC4-5TF and prepare polyclonal antibody sera. This construct as prepared by us was conjugated to KLH and mice were vaccinated by Precision Antibodies Inc. Titers against our specific glycopeptides antigen are in the tens-of-thousand range and the sera were given to Professor Pinku Mukherjee at the University of North Carolina at Charlotte. This sera did not stain any of the tissue that was available but we are looking at more appropriate tumor samples with distinct expression of aberrant MUC4. However in this cycle we tested the polyclonal sera for binding to our glycopeptide constructs that we put on a glycopeptide array developed by our collaborator Jeff Gildersleeve. This sera stained ONLY the glycopeptides we printed and not to the TF antigen in ANY OTHER CONTEXT (there are about 30 on Jeff's array). Thus we have a company preparing a monoclonal antibody for us that we feel will be an extremely useful reagent for detection of aberrant MUC4 on tumor cells. The new study started in collaboration with Howard Young mentioned in the last annual report continues to explore the modulation in cytokine profiles that is elicited by particles with varying antigens in different chemical guises. Initial data showed that levels of several cytokines from activated murine macrophages are either potentiated or attenuated with particles containing different surface chemistries. This was reexamined and refined to show that specifically TNF-alpha expression was turned on much more with very specific glycopeptide constructs than others. We have prepared three new sets of particles of various sizes coated with our important antigens. These were examined in the macrophage system and showed a dramatic increase in cytokine expression with particle size. Thus particles from sizes of 3 16 25 and 40 nm have dramatically different effects on cytokine gene expression which is also dependent on the ligand for activity. In addition we tested al the constructs in a mutant MyD88 knockout macrophage cell line. MyD88 is an adapter protein involved in the signal transduction cascade for the expression of toll-like receptor proteins. The cytokine expression induced by the nanoparticles was greatly reduced in the knockout cell line suggesting that toll-like receptors are involved in the process of cytokine gene expression by the nanoparticles. To complete this study we are focusing on the MUC4-5TF construct (vide supra) to hone in on the actual chemical requirements for eliciting gene expression of inflammatory cytokines. The manuscript mentioned in the last report on the evaluation of the optimum precursors for the preparation gold nanoparticles with a variety of ligands was published in the Journal of Colloid and Interface Science this year. We have shown that some of the particles are cytotoxic through an apoptotic mechanism and we now want to define why the multivalent platforms work in cells but not on simple proteins. This is probably due to the aggregation state of gal-3 being very different in cells and in while in a simple buffer solution and we are designing experiments to help unravel this mystery. We are looking at various cell types that either express or do not express Gal-3 with Chand Khann of the CCR as well as performing antimetastaic studies in vivo in collaboration with the Small Animal Imaging Program of Leidos Biomedical. We have found that nano-constructs where the TF antigen is displayed on a threonine residue are are active than those where it is attached to a serine residue. This was a fascinating result and we are now trying to reproduce this in mice with a variety of different nanoparticles. A new mouse study using a statistica *TRUNCATED* 706429 +Biotechnology; Cancer; Chronic Obstructive Pulmonary Disease; Genetics; Lung; Women's Health 1 year old;2 year old;Adenocarcinoma;Age;Aging;Alveolar;Anti-Inflammatory Agents;Asthma;Binding;Biological Process;Birth;CASP4 gene;Caspase;Cell Culture Techniques;Cell Death;Cell Surface Receptors;Cells;Characteristics;Chronic Obstructive Pulmonary Disease;Complex;Development;Disease;Elastic Fiber;Embryo;Endocytosis;Event;Family member;Genes;Genotype;Goals;Growth Factor;Heparan Sulfate Proteoglycan;Histologic;Homeostasis;Homo;Human;Immune;Immune system;Immunity;In Vitro;Inflammasome;Inflammation;Inflammatory;Intercept;Knock-out;Knockout Mice;Lacrimal gland structure;Lipopolysaccharides;Lung;Lung diseases;Lymphocyte;Lymphoma;Maintenance;Malignant neoplasm of lung;Malpighian corpuscles;Messenger RNA;Molecular Weight;Mus;Organ Culture Techniques;Pathway interactions;Pharmaceutical Preparations;Physiology;Pregnancy;Premature Infant;Process;Prostate;Protein Family;Proteins;Pulmonary Emphysema;Pulmonary Fibrosis;Pulmonary Surfactant-Associated Protein A;Pulmonary Surfactant-Associated Protein B;Pulmonary Surfactant-Associated Protein C;Pulmonary Surfactant-Associated Protein D;Recombinants;Research Project Grants;Risk;Role;Salivary Glands;Serum;Site;Spleen;Stains;Surface;Uterus;Wild Type Mouse;age related;airway epithelium;anticancer activity;cancer cell;cytokine;diagnostic biomarker;immunoregulation;indexing;lipopolysaccharide-binding protein;macrophage;member;mouse model;novel;postnatal period;pulmonary function;receptor;surfactant;syndecan;transcriptome sequencing;tumor Role of Novel Cytokine-like Molecule Secretoglobin (SCGB) 3A2 in Lung n/a NCI 10702355 1ZIABC010449-21 1 ZIA BC 10449 21 6568943 "KIMURA, SHIOKO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 720526 NCI In aim to identify additional role for SCGB3A2 we focused on aging process using Scgb3a2-knockout (KO) and wild-type (WT) littermate mice. Lungs of both genotyped mice from birth to 8 weeks (postnatal period) and from 8 weeks to 2 years (aging period) were subjected to histological analysis Victoria blue staining to evaluate elastic fibers and lung morphometric analysis as a parameter for assessing lung function. The analyses demonstrated that the alveolar space of KO mice continuously expanded between 0.5 and 2 years of age accompanied by increases of the mean linear intercept and destructive index a sign of emphysema. Further KO mouse lungs displayed inflammation associated with lymphocyte aggregate starting at 1 year of age and the inflammation was worse than that of WT mouse lungs. A high number of lymphoma-like cells were presented in 2-year-old KO mouse lungs. Since spleen is the site of lymphocyte maturation their spleens were histologically examined. The analysis demonstrated white pulp fusions present in both WT and KO mice older than 0.5 years and the fusion was more severe in KO mice than in WT mice. It is to note that SCGB3A2 is not normally expressed in the spleen. Further lymphocytes and macrophages mature in the spleen and migrate throughout the body including the lung. In fact we detected SCGB3A2 in serum. Therefore it seems that numerous lymphocyte aggregation sites in the lungs of aging KO mice may have been caused by splenic abnormalities. However the exact mechanism on how the lack of SCGB3A2 expression in lung relates to the development of splenic abnormalities remains to be understood. The expression of surfactant protein (SP)-A SP-B SP-C and SP-D mRNAs in KO mouse lungs decreased with age and after 1 year of age the expression of most SPs was significantly lower in KO mice than in WT mice. SPs are known to participate in the homeostatic maintenance and immunity of lungs. Our findings suggest that SCGB3A2 deficiency accompanied by age-related decreases of SP levels increases the risk of emphysema in aging mice. RNAseq analysis carried out using KO vs WT mouse lungs demonstrated that KO mouse lungs have more severe inflammation and the expression of immune system-related genes was highly altered in KO mouse lungs. All these results suggest that SCGB3A2 may be required for maintaining homeostasis and immune activity in the lungs during aging and SCGB3A2 deficiency might increase the risk of emphysema of the lung. 720526 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome 3-Dimensional;Affect;Aging;Aneuploidy;Antibodies;Antineoplastic Agents;Artificial Human Chromosomes;Binding;Biogenesis;Biological Assay;Biotechnology;Candidate Disease Gene;Catalogs;Cell Cycle Progression;Cell Line;Cells;Centromere;Chemicals;Chromatin;Chromatin Remodeling Factor;Chromosomal Instability;Chromosome 22;Chromosome Segregation;Chromosomes;Clinical Trials;Cloning;Collection;Complex;DNA;Development;Dicentric chromosome;Disease;Distal;Engineering;Epigenetic Process;Event;Evolution;Functional disorder;Gastrointestinal Stromal Tumors;Gene Dosage;Gene Duplication;Generations;Genes;Genetic Recombination;Genetic study;Genome;Genomics;Goals;Human;Human Chromosomes;Human Genome;Immune;Integrase;Interphase Cell;Japan;Kinetochores;Knowledge;Lead;Maintenance;Malignant Neoplasms;Methods;Mitosis;Molecular;Molecular Chaperones;Mutation;National Center for Advancing Translational Sciences;Nucleolar Organizer Region;Ontology;Pharmacotherapy;Phenotype;Play;Polyploidy;Process;Proteins;RNA;RNA Folding;Repressor Proteins;Research;Ribosomal DNA;Ribosomal Proteins;Ribosomal RNA;Ribosomes;Role;Site;Small Interfering RNA;Solid Neoplasm;Structure;Tandem Repeat Sequences;Telomerase;Telomerase Inhibitor;Tetanus Helper Peptide;Therapeutic;Transfection;Transgenes;Variant;Work;Yeasts;anticancer research;arm;base;biological adaptation to stress;cancer cell;cancer therapy;centromere autoantigen 80K;chromosome number abnormality;drug candidate;experimental study;functional genomics;gene therapy;genetic variant;genomic locus;high throughput screening;improved;inhibitor;knock-down;novel;novel therapeutic intervention;response;screening;synthetic biology;targeted treatment;telomere;transmission process;tumor;tumor growth;tumor progression;vector Human Artificial Chromosomes for Cancer Research and Functional Genomics n/a NCI 10702349 1ZIABC010413-22 1 ZIA BC 10413 22 6808478 "LARIONOV, VLADIMIR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2019980 NCI Human Artificial Chromosomes (HACs) assembled from alphoid DNA arrays represent novel vectors that have a great potential for the study and maintenance of human kinetochore as well as for gene therapy screening of anticancer drugs and biotechnology. As known HACs are generated after transfection of alphoid DNA arrays into human cells. Efficiency of HAC formation is quite low that requires analysis of a large number of the transfectants. In our recent collaborative work we have performed the first systematic study of structural requirements of the alphoid DNA arrays for efficient HAC formation. We demonstrated that combination of CENP-B box positive and negative synthetic alpha satellite repeats greatly improves de novo HAC formation. Previously we constructed a synthetic HAC (tetO-HAC) allowing tethering of the HAC kinetochore by different chromatin modifies fused with the Tet repressor protein. The tetO-HAC whose centromere contains tetO repeats has been extensively used to investigate protein interactions within the kinetochore and to define the epigenetic signature of centromeric chromatin. In our recent study we developed a novel synthetic HAC containing two alphoid DNA arrays with different targeting sequences tetO and lacO i.e. a lacO/tetO-HAC. This new HAC can be used for detailed epigenetic engineering studies and to study a mechanism of centromere repositioning and inactivation in dicentric chromosomes. The tetO-HAC has an advantage over other HAC vectors because it can be easily eliminated from cells by inactivation of the HAC kinetochore via binding of chromatin modifiers such as the tTS to its centromeric tetO sequences. In separate experiments a platform with multi-integrase recombination sites has been inserted into the tetO-HAC for assembly of large genetic loci in the HAC. Our work is in progress to assemble a synthetic nucleolar organizer region (NOR) in the HAC to clarify a molecular mechanism of NORs association with nucleoli. For this purpose 45 kb rDNA units and flanking proximal junction (PJ) and distal junction (DJ) sequences were isolated from human chromosomes 21 and 22 by a transformation-associated recombination (TAR) cloning method developed in our lab. It is worth noting that analysis of the rDNA units revealed an unexpectedly high number of sequence variants in the 45S RNA region. Some variants in 18S and 28S rRNA regions may affect either ribosome RNA folding or interaction with ribosomal proteins. An entire rDNA array along with the flanking PJ and DJ regions isolated from chromosome 22 provides a platform for assembly of a synthetic NOR region. This can enable a detailed study of the sequence requirements and the mechanism of nucleolar formation in human cells including the role of PJ and DJ in this process. To characterize the sequence requirements for nucleolar formation in human cells we inserted different fragments of a NOR from chromosome 22 corresponding to a complete 45 kb rDNA unit DJ and PJ regions into a gene loading site of the tetO-HAC propagated in human HT1080. To determine the nucleoli association status of the HACs carrying different TAR constructs in interphase cells we applied 3D immune-FISH. The HACs were visualized with the PNA probe for the tetO-alphoid array. Nucleoli were visualized using an antibody against Nop52. The nucleoli association was observed for the HAC carrying the 45 kb entire rDNA repeat and the 58 kb DJ region. In contrary the percentage of nucleoli association of the HAC carrying the 53 kb PJ fragment did not differ from the control HAC carrying the GFP transgene. Collectively our analysis of the HACs carrying different regions of a NOR from chromosome 22 revealed that a single rDNA repeat and a 58 kb of the DJ DNA fragment are sufficient to drive nucleolar association of these HACs. Work is in progress to clarify a molecular mechanism of NORs association with nucleoli using a HAC vector carrying different fragments of the rDNA unit and DJ region. An abnormal chromosome number is a feature of most solid tumors and is often accompanied by an elevated rate of chromosome instability (CIN). Gain or loss of entire chromosomes leads to large-scale changes in gene copy number and expression levels. Mutations in CIN genes are thought to be an early event in tumor development. At present approximately 400 human genes that control proper chromosome transmission have been annotated with gene ontology terms while systematic CIN gene screens in yeast have revealed more than 900 genes. Therefore it may be supposed that many human CIN genes remain unidentified. In our previous work we developed a high-throughput assay for identification of new human CIN genes using the tetO-HAC expressing a degron-destabilized EGFP. In the current study we are using an available at NCATS Ambion collection of 19000 siRNAs covering the whole human genome for screening new CIN genes. As a result 250 new CIN candidate genes were identified. The experiments on reconfirmation of 250 CIN candidate genes are in progress. The first step is the genes knock-down using newly developed siRNAs. Identification of new CIN genes should create opportunities for the development of new therapeutic strategies to target the CIN phenotype of cancer cells. Telomerase/telomere targeting therapy is a potentially promising approach for cancer treatment because even transient telomere dysfunction can induce chromosomal instability (CIN) and may be a barrier to tumor growth. However till now only a limited number of chemical compounds that target telomerase or telomeres have been identified and only a few are in clinical trials. Three years ago we developed a dual HAC assay that enables identification and ranking of compounds that induce CIN as a result of telomere dysfunction. This assay is based on the use of two isogenic cell lines one carrying a linear HAC (containing telomeres) and the other carrying a circular HAC (lacking telomeres). Disruption of telomeres in response to drug treatment results in specific destabilization of the linear HAC. In recent work we used a dual HAC assay for analysis of five Hsp90 molecular chaperone inhibitors 17-AAG TAS-116 XL888 SNX-2112 and STA-9090 some of which are in clinical trials. It was previously demonstrated that human Hsp90 is associated with a functional telomerase complex. Unexpectedly all five chaperone inhibitors induce a very high loss of a linear HAC with no effect on stability of a circular HAC. Additional experiments demonstrated a shortage of telomeric repeats in the treated cells. It means that the analyzed compounds are very specific inhibitors of telomerase and are promising drug candidates for treatment of cancer. One of them TAS-116 has been recently approved for treatment of gastrointestinal stromal tumors (GIST) in Japan. 2019980 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Address;Affect;Anaphase;Back;Binding;Biochemical;Bioinformatics;Cell Cycle;Cell Proliferation;Cell division;Cells;Chromatin;Chromosome abnormality;Chromosomes;Clinical;Complex;Consensus;DNA;DNA Damage;DNA Repair Pathway;DNA Sequence;DNA biosynthesis;DNA replication fork;DNA-Protein Interaction;Development;Developmental Therapeutics Program;Distal;Elements;Energy Metabolism;Ensure;Epigenetic Process;Event;Exhibits;Exposure to;Fiber;Future;Genetic;Genome;Genome Stability;Genomic Instability;Health;Human;Image;Lead;Learning;Link;Location;Malignant Neoplasms;Mammalian Cell;Maps;Mediating;Metabolic;Metaphase;Mitosis;Molecular;Molecular Machines;Nature;Oncogenes;Pathway interactions;Phosphotransferases;Play;Property;Protein Family;Proteins;Recruitment Activity;Regulation;Replication Initiation;Replication Origin;Replication-Associated Process;Research Personnel;Role;SIRT1 gene;Set protein;Signal Pathway;Signal Transduction;Site;Specificity;TOPBP1 Gene;Techniques;Testing;Therapeutic Studies;Transact;Translating;Work;anti-cancer therapeutic;base;biochemical tools;cancer cell;cancer therapy;cell growth;cell type;chemotherapeutic agent;chromatin modification;chromosome replication;cis acting element;computerized tools;genome integrity;genome-wide;histone modification;inhibitor;insight;member;novel;prevent;programs;protein complex;protein protein interaction;recruit;replication stress;response;segregation;tool;translational potential;treatment response;tumorigenesis;ubiquitin ligase;whole genome Initiation of DNA Replication in Mammalian Cells n/a NCI 10702348 1ZIABC010411-23 1 ZIA BC 10411 23 8314239 "ALADJEM, MIRIT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1770526 NCI "Our studies focus on cellular signaling pathways that regulate the location timing and progression of DNA synthesis. We have identified cis-acting elements that facilitate the initiation of DNA replication generated whole-genome-scale maps of replication initiation sites in human cells and detected novel protein-DNA interactions at replication initiation sites (replication origins). These discoveries were enabled by novel bioinformatics and biochemical approaches that we developed and implemented. Mapping replication origin activity and characterizing replication fork progression have demonstrated strong links between replication histone modifications and chromatin packaging. The observed highly orchestrated order of the DNA replication program however contrasts with the low sequence-specificity exhibited by the molecular machines that catalyze DNA synthesis and the absence of a ""consensus"" DNA sequence that identifies all replication origins. We address this challenge by proposing and testing the hypothesis that genome duplication is guided by nuanced selective protein-DNA interactions at discrete groups of replication origins that share distinct features. In the recent review period we used a combination of genetic biochemical bioinformatics imaging and functional analyses to study DNA-protein interactions and chromatin transactions that govern the initiation of DNA replication. We identified protein complexes that selectively assemble on groups of replication origins and modify their initiation capacity providing the first example of site-specific interactions that modulate the initiation of DNA replication. The approach exemplified in our studies can pave a path towards a complete understanding of the interactions that spatially and temporally orchestrate chromosome duplication. Our current studies focus on two sets of protein-DNA interactions at replication origins. First we found that the RepID protein a member of the DDB1-Cul4-associated-factor (DCAF) protein family preferentially interacts with replication origins. We have shown that RepID is required for initiation of DNA replication at the origins that bind it. We have further shown that RepID controls the replication program by recruiting the ubiquitin ligase complex CRL4 to chromatin. In turn RepID-recruited CRL4 prevents aberrant chromosome re-replication ensuring that genome duplication occurs only once per cell division. We also discovered another function of RepID and CRL4 in regulating the metaphase-anaphase transition during mitosis. These observations have provided new insights into the mechanisms by which the fidelity of chromosome duplication and segregation can be compromised in cancer cells. Our current studies probe into the question of how cells orchestrate the activity of RepID and CRL4 with other ubiquitin ligases on chromatin to regulate cell proliferation and characterize in detail the consequences of dysregulation of CRL4 chromatin recruitment and activity at replication origins. Given the mounting evidence that chromosomal re-replication and mis-segregation can be triggered by oncogenes at the onset of tumorigenesis and the recent development of CRL4 inhibitors (e.g. NEDDylation inhibitors) as anti-cancer therapeutics these studies have potential translational implications. Second we identified an interaction between replication origins and the NAD+-dependent protein deacylase SIRT1. Unlike RepID SIRT1 is not required for DNA replication but instead restricts the initiation of DNA replication to a particular group of origins (""baseline"" origins) while preventing replication from initiating at other (""dormant"") origins. This observation points to a mechanistic link between cellular energy metabolism epigenetic marks and the regulation of replication origin activation which play critical roles in maintaining genome integrity. Using SIRT1 activity as a molecular switch to turn dormant origins on and off we have begun to characterize origin dormancy in detail mapping the locations of dormant origins and identifying chromatin modifications that distinguish dormant from baseline origins. This work led us to identify components of a signaling network involving the ATR kinase and the replication accessory protein TOPBP1 that relieves SIRT1-mediated origin dormancy when the baseline origins are stalled as it occurs when cells are under replication stress. Pointing to the critical role in SIRT1 in maintaining origin dormancy and genome stability cells with activated dormant origins harbor extrachromosomal elements and exhibit DNA breaks. Our current studies are focused on proteins that associate with dormant origins the mechanism(s) by which SIRT1 suppresses initiation. We also study molecular pathways including the abovementioned ATR pathway that counter SIRT1-mediated suppression to activate dormant origins in cells exposed to stressful conditions. Because ATR inhibitors are explored at the DTB and elsewhere as promising therapy agents these analyses also have a translational potential. The responses of the replication machinery to perturbations are pertinent to human health and the specific cell-cycle regulatory deficiencies in distinct cancer cell types are likely to provide clues to their sensitivity to therapy. Our studies demonstrate that deregulation of the early stages of DNA replication leads to excess replication and subsequent genomic instability through two distinct paths: one that involves activation of dormant origins and another involving over-activation of baseline origins. We are currently characterizing genetic and epigenetic properties of the replication origins activated by each pathway as well as protein-DNA interactions modulated by each pathway. Using a combination of single-fiber analyses and sequencing-based techniques we analyze replication dynamics following exposure to chemotherapeutic agents and chromatin modulators. These studies are expected to identify chromatin targets that are normally involved in preventing excess replication and uncover signaling pathways that convey metabolic status to chromatin. As we learn more about local and distal interactions that promote DNA replication we will explore pathways that signal back from chromatin to the cell cycle machinery to affect the replication landscape and the cellular responses to anticancer therapy. Our studies rely on tools we have developed to map replication initiation sites throughout the genome and compare replication initiation sites with distinct chromatin features. We are also collaborating with other investigators within and outside NCI to characterize genetic and epigenetic features of cancer cells and participate in collaborative efforts that link genetic and epigenetic signatures with responses to therapy. In future studies we plan to further dissect the molecular interactions that regulate chromosome duplication. Specifically using a combination of single-fiber analyses biochemical and computational tools we will systematically characterize protein-DNA and protein-protein interactions that mediate the effects of RepID SIRT1 and DNA damage signaling pathways on the chromosome replication program." 1770526 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Coronaviruses; Coronaviruses Vaccines; Emerging Infectious Diseases; Genetics; HIV/AIDS; Health Disparities; Immunization; Infectious Diseases; Minority Health; Prevention; Vaccine Related; Vaccine Related (AIDS) 2019-nCoV;AIDS prevention;Adjuvant;Adverse effects;Anatomy;Animals;Antibodies;Antibody titer measurement;Antigens;B-Lymphocytes;Binding;Biology;COVID-19;Cells;Codon Nucleotides;Combined Vaccines;DNA;DNA Vaccines;DNA delivery;Data;Development;Disease;Electroporation;Epitopes;FCGR3A gene;Gene Expression;Genes;HIV;HIV Antigens;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Immune;Immune response;Immunity;Immunization;Immunologics;Infection;Infection prevention;Interleukin-12;Intramuscular;Longevity;Lower respiratory tract structure;Macaca;Maintenance;Mediating;Messenger RNA;Methodology;Methods;Modality;Modeling;Molecular;Mucosal Immune Responses;Nucleic Acid Amplification Tests;Nucleic Acid Vaccines;Nucleic Acids;Play;Production;Proteins;Protocols documentation;RNA;Regimen;Relative Risks;Reporting;Research;Risk;Role;SARS-CoV-2 infection;SIV;Site;Structure of mucous membrane of nose;T cell response;Testing;Translating;Vaccinated;Vaccination;Vaccines;Viral reservoir;Virus;antibody-dependent cell cytotoxicity;antibody-dependent cellular phagocytosis;base;cytokine;design;draining lymph node;efficacy testing;env Gene Products;experience;expression vector;immunogenicity;improved;in vivo;mRNA Expression;mucosal site;neutralizing antibody;novel;plasmid DNA;recombinant viral vector;rectal;response;scaffold;simian human immunodeficiency virus;transmission process;treatment strategy;vaccine delivery;vaccine development;vaccine efficacy;vaccine platform;vaccine-induced immunity;vaginal mucosa;vector;vector vaccine Development testing of nucleic acid-based vaccine for HIV other indications n/a NCI 10702343 1ZIABC010350-23 1 ZIA BC 10350 23 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 845848 NCI The development of a safe and effective vaccine and to improve treatment strategies aiming to reduce/eliminate the virus reservoir are currently at the forefront of our research. Based on our recognition of the fundamental mechanisms of mRNA expression exemplified by the regulated expression of HIV we developed the key methodology to express HIV antigens at high level from RNA/codon-optimized genes which allows efficient antigen production when expressed from simple DNA plasmids or as part of recombinant viral vectors (Schwartz J. Virol. 66: 150-159 1992; Schwartz J. Virol. 66: 7176-7182 1992; Nasioulas J. Virol. 68: 2986-2993 1994; Schneider J. Virol. 71: 4892-4903 1997). Attractive features of the nucleic acid (DNA mRNA) platform lie in its simplicity versatility stability with repeated administration without vector immunity being a non-replicating vaccine and not association with adverse effects. Immunogenicity is augmented in the presence of cytokines i.e. IL-12 DNA co-administration. We optimized DNA delivery with the result of achieving systemic and mucosal immune responses. Importantly we reported the dissemination of the DNA vaccine induced T cell responses to mucosal sites including rectal and vaginal mucosa the portal of entry of HIV. We also found that DNA induced immune responses show extraordinary longevity in vaccinated macaques detectable for several years after the last vaccination. Using DNA+Protein combination vaccines the magnitude breadth and longevity of the immune responses increased resulting in significant improved protection from infection in the SIV/SHIV NHP model (Patel PNAS 110: 2975 2013; Jalah PLoS One 9: e91550 2014 Felber Cell Reports 31:107624 2020). The vaccine platform combines the delivery of both vaccine components into the same anatomical site targeting the same draining lymph node. We recently reported that co-administration in the same site showed a 67% reduction in per exposure acquisition risk relative to the controls whereas neither animals vaccinated with DNA and protein in separate sites nor the controls were protected from an intravaginal SHIV CH505 virus challenge (Felber Cell Reports 31:107624 2020). Non-neutralizing Env antibodies antibodies mediating cellular cytotoxicity (ADCC) and antibodies with high binding to Fc-gamma RIIIa were associated with decreased transmission risk. These data suggest that simultaneous recognition processing and presentation of DNA + Env protein in the same draining lymph nodes play a critical role in the development of protective immunity. These data have important implications for other vaccine modalities because combination vaccines are typically administered in separate anatomical sites. We hypothesize that optimization of immunogens to better target the rare B cell precursor combined with the co-administration of vaccine vector and protein in same draining lymph nodes could provide an immunological advantage over current protocols resulting in significantly improved protection and we are exploring this mechanism in the macaque model. Our aim has been to design and test a vaccine regimen focusing the immune response to targets associated with infection prevention i.e. the V2 domain of the HIV gp120 Env. In the VR144 trial non-neutralizing antibodies targeting V2 were found to correlate with reduced risk of HIV infection suggesting this region as a target for vaccine development. To favor induction of V2-specific Ab we developed novel molecules to direct and focus humoral immune responses to V2 domain of the HIV gp120 Env. We showed that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region in the absence of immune interference by other epitopes. We reported that priming with this DNA altered the hierarchy of humoral immune responses to V2 region epitopes providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection (Devasundaram J Virol 95:e01193 2020). We are testing the hypothesis whether these responses translate to better protection in the macaque model. We applied our experience in developing HIV vaccines towards SARS-CoV-2 (Rosati PLoS Pathog 17:e1009701; 2021). The different Spike DNA-based vaccine regimens induced robust antibody and T cell responses able to effectively mediate protection and to control SARS-CoV-2 infection in macaques. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly a vaccine regimen comprising simultaneous co-immunization of DNA and protein at the same anatomical site showed was more effective than DNA alone in inducing protective immune responses and controlling SARS-CoV-2 infection. We are now exploring novel nucleic acid-based vaccines and delivery methods to achieve better immunity of DNA-only vaccine to simplify the vaccine platform. 845848 +Cancer; Congenital Structural Anomalies; Genetics; Pediatric; Women's Health Affect;Alleles;Behavior;Biological;Biology;CD3E gene;Cell Death;Cell Lineage;Cell Maintenance;Cells;Central Nervous System;Collaborations;Communities;Complex;Computer Models;Congenital Abnormality;Defect;Dermis;Development;Disease;Embryo;Embryonic Development;FGF17 gene;Family;Fibroblast Growth Factor;Fibrosis;Gene Expression;Gene Silencing;Genes;Genetic;Genetic Models;Genetic study;Genets;Goals;Growth Factor Gene;Hair follicle structure;Health;Hindlimb;Homeostasis;Human;Intermediate Mesoderm;Kidney;Knowledge;Ligands;Limb Bud;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Mesoderm;Messenger RNA;Modeling;Molecular;Morphogenesis;Mus;Muscle;Neural Tube Closure;Organogenesis;Palate;Paper;Pathogenicity;Pathway interactions;Play;Positioning Attribute;Problem Solving;Process;Publications;Publishing;Role;Signal Transduction;Skeleton;Somites;Spinal Dysraphism;Technology;Testicular Neoplasms;Time;Tissues;Undifferentiated;WNT Signaling Pathway;Work;allantois;bone;cancer therapy;cancer type;cell behavior;external genitalia;fibroblast growth factor 18;genetic analysis;innovation;insight;male;malignant breast neoplasm;migration;mouse genetics;mutant;nephrogenesis;notch protein;novel;postnatal;reproductive tract;somitogenesis;spine bone structure;stem cells;tool;tumorigenesis;vertebra body;vertebrate embryos The Role of Fgf Signaling in Vertebrate Development n/a NCI 10702340 1ZIABC010338-23 1 ZIA BC 10338 23 8123123 "LEWANDOSKI, MARK B" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 566741 NCI The long term goal of this project is to understand how an important family of signaling ligands called Fibroblast Growth Factors (FGFs) control a wide spectrum of cell biological behaviors such as proliferation cell death migration stem cell maintenance and gene expression. In particular we use complex mouse genetics to understand the role of FGF signaling in mesodermal lineages with a special emphasis on extension of the body axis and formation of somites (segmented mesodermal segments that are the building blocks of vertebrate muscle dermis and vertebral bodies). Our work has made clear that genetic redundancy is an important aspect of this biology; therefore all work in this project emerges from an effort to comprehensively characterize the genetic redundancy of FGF signaling in the mesodermal lineage. Such work is relevant to many cases of cancer where more than one FGF gene may be damaged. To achieve this we have generated and characterized important Cre mouse lines which are tools that allow the control of gene expression in the early embryo. These include TCre (expressed in the early emerging nascent mesoderm; see Development. 132: 3859-71. ) TCreERT2 (active in emerging nascent mesoderm at all embryonic stages; see PLoS ONE. 8: e62479) and Tbx4-Cre (expressed in a posterior mesodermal domain that includes the allantois hindlimb and external genitalia; see Dev Dyn. 240: 2290-300. doi: 10.1002/dvdy.22731). TCre in particular has had a major impact on the field being essential in over 50 publications. For example both TCre and TCreERT2 have important in a collaborative effort to demonstrate that Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension (Hum Mol Genet. 2014 Jul 31. pii: ddu397). Besides providing the mouse genetics community with valuable mouse lines this project has yielded papers that document our major insights regarding FGF signaling in the early embryo. We published that Fgf8 not required for somitogenesis although a body of high profile work had placed it in a central position in current models. However in collaboration with NCI colleague Alan Perantoni we demonstrated that Fgf8 was essential for development of the kidney and male reproductive tract (Development. 132: 3859-71 Development. 138: 5369-78). We showed that Fgf8 together with Fgf4 are required for essential aspects of somitogenesis: expression of oscillating gene domains WNT pathway genes and markers of undifferentiated presomitic mesoderm (Proc Natl Acad Sci U S A. 108: 4018-23). By examining FGF mutants in which we genetically restored WNT signaling we demonstrated that FGF signaling operates independently of WNT signaling in this process. The functional redundancy that we uncovered has implications for cancer as both FGFs have been found to be aberrantly active in testicular tumors. This past year we have delved deeper into this work and have shown that Fgf4 mutants (but not Fgf8 mutants) display a range of vertebral defects that model a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations. An key innovation in this work is our adaption of computational modeling to generate embryonic volumetric subsets of the embryo. We then quantify mRNA levels of key target genes affected by the loss of Fgf4 signaling within these volumes (eLife 2020;9:e55608. DOI: https://doi.org/10.7554/eLife.55608). In another recent publication we demonstrated that the Fgf8 subfamily (Fgf8 Fgf17 and Fgf18) are required for closing the ventral body wall in the vertebrate embryo. Defects in this process are a major class of human birth defect and a significant health burden (Development (2020) 147 dev189506. doi:10.1242/dev.189506). We are continuing to study genetic redundancy in FGF signaling in several aspects of embryonic development. For example we recently showed that Fgf3 signaling is important in neural tube closure an important study that concerns one of the most common birth defects spina bifida (PLoS Genet. 12(5):e1006018; Genesis 54:91-8). We are investigating the role of Fgf4 and Fgf8 in the differentiation of the somite into its derivative lineages (muscle and bone). In the past year we generated and characterized a new mouse line that carries an FGF18 allele that allows conditional gene inactivation and that allows the precise identification of cells and their lineage that express Fgf18 (Dev Dyn. 2019 Sep;248(9):882-893. doi: 10.1002/dvdy.85). Fgf18 functions in the development of several tissues including the lung limb bud palate skeleton central nervous system and hair follicle. Fgf18 functions in the development of several tissues including the lung limb bud palate skeleton central nervous system and hair follicle. Postnatally FGF18 is being evaluated for pathogenic roles in fibrosis and several types of cancer. Therefore these mice will be useful to investigate FGF18 function during organogenesis and tissue homeostasis and to target specific cell lineages at embryonic and postnatal time points. 566741 +Bioengineering; Biotechnology; Cancer; Clinical Research; Emerging Infectious Diseases; Genetics; HIV/AIDS; Health Disparities; Immunization; Immunotherapy; Infectious Diseases; Minority Health; Nanotechnology; Prevention; Vaccine Related 2019-nCoV;AIDS clinical trial group;Achievement;Address;Adjuvant;Antibody Response;Antigens;COVID-19;Chronic;Clinic;Clinical Trials;Collaborations;Cytotoxic T-Lymphocytes;DNA;DNA Vaccines;DNA delivery;Data;Data Analyses;Development;Disease remission;Electroporation;Elements;Epitopes;Formulation;Genes;Goals;HIV;HIV Infections;HIV Vaccine Trials Network;HIV vaccine;HIV-1;Highly Active Antiretroviral Therapy;Homologous Gene;Human;Immune checkpoint inhibitor;Immune response;Immunization;Immunologics;Immunotherapeutic agent;Immunotherapy;Infection;Interleukin-12;Lead;Length;Macaca;Memory;Messenger RNA;Methodology;Methods;Modality;Modeling;Molecular;Mus;National Institute of Allergy and Infectious Disease;Nucleic Acid Vaccines;Pathway interactions;Persons;Phase;Preventive vaccine;Proteins;Proteome;RNA vaccine;Regimen;Research;SIV;Secondary Immunization;T cell response;T-Lymphocyte;Testing;Translating;Translations;Vaccination;Vaccines;Variant;Viral;Viral reservoir;Virus;Virus Diseases;clinical development;cohort;combinatorial;cytokine;expression vector;frontier;human disease;in vivo;insight;lipid nanoparticle;novel;novel strategies;novel vaccines;prevent;response;therapeutic vaccine;tool;treatment strategy;vaccin protein;vaccine development;vaccine evaluation;vaccine platform;vaccine strategy;vaccine trial Conserved Element DNA Vaccine n/a NCI 10702339 1ZIABC010334-23 1 ZIA BC 10334 23 6802097 "FELBER, BARBARA K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 563898 NCI "An ideal HIV vaccine should provide protection against all HIV-1 variants. Thus an important aspect of HIV vaccine development is the selection of immunogens which has to take into consideration the diversity of the different HIV clades and the identification of the critical epitopes able to induce relevant immune responses avoiding potential immunodominant ""decoy"" epitopes. Considering the diversity of the different HIV clades we are focusing on highly conserved regions of HIV to induce immune responses to nearly invariable proteome segments essential for the function of the virus while excluding responses to variable and potentially immunodominant ""decoy"" epitopes (Kulkarni PLoS One 9: e86254 2014; Kulkarni PLoS One 9: e111085 2014; Hu Hum. Vaccin. Immunother. 14: 2163 2018). In proof-of-concept studies in mice and macaques we demonstrated that immunization with Gag CE DNA elicits robust cellular and humoral immune responses including robust cytotoxic T cell responses targeting subdominant epitopes against CE which cannot be achieved by vaccination with the full-length p55gag DNA and induces Priming with CE DNA and boosting with CE+gag DNA maximizes both magnitude and breadth (Kulkarni PLoS One 9: e86254. 2014; Kulkarni PLoS One 9: e111085 2014; Hu J. Immunol. 197: 3999 2016). This DNA vaccine regimen induces potent memory responses that can be rapidly recalled 2 years later by CE DNA booster vaccinations (Hu Hum. Gene Ther. 29: 1029-1043 2018. Thus we identified a novel and effective strategy to maximize responses against Gag and provide a novel strategy to shift the immunodominance hierarchy and to induce robust immune responses to subdominant epitopes effectively targeting the Achilles' heel of the virus. We are currently expanding this concept to SARS-Co-V2. We further developed an SIV homolog of the CE and demonstrated that priming with CE DNA followed by CE+gag DNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth (Hu J. Immunol. 197: 3999 2016). These data mirror our findings from the HIV p24CE vaccine and provide us with a tool to explore the functional applications of the Gag CE DNA vaccine in the macaque model. SIV Gag CE-specific T cells are able to reduce viral infection (Hu Hum. Vaccin. Immunother. 14: 2163-2177 2018) and application of this CE DNA vaccine is expanded to our on-going therapeutic vaccine trials in the macaque model. We have translated the HIV CE DNA vaccine concept to the clinic in the HIV Vaccine Trial Network (HVTN)/DAIDS/NIAID-supported clinical trial (HVTN 119; NCT03181789) with the aim to test whether our p24CE DNA vaccine concept elicits superior breath and magnitude of Gag responses compared to the optimized immunogen comprising the complete p55Gag protein. This vaccine includes Profectus' GENEVAX IL-12 DNA as molecular adjuvant and in vivo electroporation as DNA delivery method two vaccine components our research had shown to be of importance to induce potent T cell responses in macaques. HVTN 119 combines several of milestones (DNA expression vectors adjuvants and delivery) we have achieved over many years in vaccine development. This trial is now closed and we are finalizing data analysis. In another on-going study we have translated the Gag CE DNA vaccine in a phase I/IIb trial (ACTG A5369; NCT03560258) supported by the AIDS Clinical Trial Group to be tested in HIV-infected persons under HAART. This trial is now closed and we are finalizing data analysis. Together HVTN119 and A5369 will allow us to explore the translation of our data from mice and macaques to humans and initial data analysis supports our achievement of this goal. These two trials offer another unique opportunity to directly compare the same vaccines in two different cohorts naive and HIV-infected on ART using the same methodology and will provide novel insight in the development in immune responses comparing the two cohorts. The CE DNA vaccine regimen is being tested in a third trial NCT04357821 supported by amfAR and UCSF as part of a combinatorial therapy to induce an HIV remission. Our goal is to develop and test immunotherapeutic methods that can lead to virus reservoir reduction or elimination. We have further expanded the CE vaccine regimen in collaboration with CureVac Inc. as an mRNA/lipid nanoparticle (LNP) formulation in the macaque model (Valentin Frontiers Immunol 2022). The mRNA/LNP formulation induced robust durable antibody responses but low adaptive T-cell responses a feature also shared with the current COVID-19 mRNA vaccine. On the other hand the mRNA/LNP vaccine was able to strongly boost pre-existing cellular response suggesting that it could be useful in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases. Our studies have provided useful information about different nucleic acid vaccine platforms and guide further clinical development." 563898 +Cancer Active Biological Transport;Aging;Anabolism;Antineoplastic Agents;Apoptosis;Biochemical;Cell Death;Cell membrane;Cell physiology;Cells;Ceramidase;Ceramides;Cessation of life;Chemotherapy-Oncologic Procedure;Clinical;Complex;Deterioration;Development;Disease;Drosophila genus;Drosophila inturned protein;Drug resistance;Endocytosis;Endoplasmic Reticulum;Environment;Enzymes;Epinephrine;Etiology;Failure;G-Protein-Coupled Receptors;Generations;Genetic;Golgi Apparatus;Growth Factor;Homologous Gene;Inhibition of Apoptosis;Investigation;Lead;Link;Lipid Peroxides;Lipids;Longevity;Malignant Neoplasms;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Molecular;Multi-Drug Resistance;Oxides;Pathway interactions;Phospholipid Metabolism;Phospholipids;Photoreceptors;Physiological;Physiology;Process;Production;Property;Protein Secretion;Proteins;Reactive Oxygen Species;Receptor Protein-Tyrosine Kinases;Regulation;Research;Research Personnel;Rhodopsin;Role;Second Messenger Systems;Signal Transduction;Sphingolipids;Sphingomyelins;Sphingosine;Structure;Thrombin;Transgenic Organisms;base;cancer cell;cancer therapy;cell growth;ceramide 1-phosphate;chemotherapy;drug development;experimental study;fly;in vivo;mutant;oxidative damage;phosphoethanolamine;response;sphingosine 1-phosphate;success;therapeutically effective;vector Phospholipid and Sphingolipid Signaling in Drosophila n/a NCI 10702338 1ZIABC010331-23 1 ZIA BC 10331 23 6802050 "ACHARYA, JAIRAJ " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 877705 NCI Intermediates of sphingolipid (SL) and phospholipid (PL) metabolism serve as second messengers for a number of signaling cascades including activation of G-protein-coupled receptors such as adrenaline thrombin etc. as well as receptor tyrosine kinases by growth factors. These intermediates mediate a number of processes ranging from protein secretion to activation of apoptosis. We have initiated studies to understand different aspects of lipid signaling in Drosophila. Sphingomyelin (or phosphorylethanolamine ceramide CPE in Drosophila) could serve as a reservoir for several lipid messengers such as ceramide ceramide 1-phosphate sphingosine and sphingosine 1-phosphate. We have initiated studies to delineate the in vivo role of some of the enzymes of the putative 'Sphingomyelin Cycle'. We have begun by identifying homologous genes in Drosophila. We are using transgenic and mutagenic studies to analyze the importance of such a pathway in Drosophila. We have recently demonstrated that modulation of the sphingolipid biosynthetic pathway such as targeted expression of ceramidase rescues degeneration in certain photoreceptor mutants. We have also demonstrated that ceramidase facilitates membrane turnover and rhodopsin endocytosis in Drosophila photoreceptors. Sphingolipids are synthesized vectorially. While the steps that lead up to the generation of ceramide occur in the endoplasmic reticulum (ER) the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids occurs mostly outside of the ER either in the Golgi complex or in the plasma membrane. This necessitates the active transport of ceramide from ER to the Golgi complex. This transport is mediated by a protein called ceramide transfer protein (CERT). We have now demonstrated that CERT-mediated transfer of ceramide is critical for the biosynthesis of sphingomyelin (or CPE in Drosophila) and complex sphingolipids. Lack of CERT in Drosophila leads to decreased CPE and complex sphingolipids and plasma membranes with altered physical and physiological properties. These changes render them susceptible to normal loads of reactive oxygen species encountered by the cell. The ensuing oxidative damage to the plasma membrane leads to production of lipid peroxides that will further oxidize the membrane and cellular constituents leading to a rapid deterioration in the metabolic function of the cell. All these changes manifest as accelerated aging in Drosophila and thus result in a very short life span for these flies. We anticipate that a combination of genetic molecular and biochemical approaches in Drosophila will define the important players involved in PL SL signaling in their normal cellular environment. 877705 +Cancer; Genetics; HIV/AIDS; Infectious Diseases 4-Aminobenzoic Acid;Acquired Immunodeficiency Syndrome;Anti-Bacterial Agents;Anti-HIV Agents;Basic Science;Binding;Biochemical;Biogenesis;Biological;Biological Assay;Biological Models;Biophysics;Catalysis;Cell division;Closure by clamp;Complex;Couples;Crystallization;DNA Damage;DNA-Directed RNA Polymerase;Data;Dimerization;Double-Stranded RNA;Drug Design;Elements;Endoribonucleases;Enzymes;Evolution;Exhibits;Family;Folic Acid;Goals;Guanine;Guanine Nucleotides;Guanosine Triphosphate Phosphohydrolases;Hydrolysis;Ions;Legal patent;Link;Magnesium;Malignant Neoplasms;Mammals;Maps;Measures;Modeling;Molecular Conformation;N-terminal;Nitric Oxide;Nucleotides;Orthologous Gene;Play;Prodrugs;Proteins;Pterins;Purines;RNA;RNA Binding;RNA Interference;RNA Processing;RNA metabolism;Reaction;Research;Resolution;Ribonuclease III;Ribonucleases;Role;Side;Site;Site-Directed Mutagenesis;Specificity;Structure;System;Virus Diseases;Yeasts;anti-cancer;antimicrobial;antimicrobial drug;base;cancer cell;cell growth;design;drug development;drug discovery;endonuclease III;enzyme mechanism;enzyme pathway;helicase;improved;inhibitor;macromolecule;magnesium ion;member;microorganism;novel;novel anticancer drug;phosphodiester;repaired;structural biology;targeted agent;therapeutic development;transcription factor Biomolecular Structure and Mechanism Structure-Based Drug Design n/a NCI 10702336 1ZIABC010326-23 1 ZIA BC 10326 23 6801952 "JI, XINHUA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1982040 NCI Our goal of structural analysis is to map the reaction trajectory or functional cycle of selected biological macromolecules and our goal of drug discovery is to design synthesize and characterize novel anticancer and antimicrobial agents. To date we have characterized the reaction trajectory and/or functional cycle of HPPK (a folate pathway enzyme essential for microorganisms but absent in mammals) Era (an essential GTPase that couples cell growth with cell division) RapA (a Swi2/Snf2 protein that recycles RNA polymerase) two members of the RNase III family (a family of dsRNA-specific endoribonucleases) and DDX3X (a DEAD-box helicase that unwinds short RNA duplexes). Among these biomolecules HPPK is a target for novel antibacterial agents and DDX3X is a target of novel anticancer and anti-HIV agents. Structure-based drug development is in progress. Representative members of the RNase III family include prokaryotic RNase III and eukaryotic Rnt1p Drosha and Dicer. They play important roles in RNA processing and maturation post-transcriptional gene silencing and defense against viral infection. For mechanistic studies bacterial enzyme is a valuable model system for the entire family. We have shown how the dimerization of the RNase III endonuclease domain (RIIID) creates a catalytic valley where two cleavage sites are located how the catalytic valley accommodates a dsRNA in a manner such that each of the two RNA strands is aligned with one of the two cleavage sites how the hydrolysis of each strand involves both RIIIDs and how RNase III uses the two cleavage sites to create the 2-nucleotide (2-nt) 3' overhangs in its products. We have also shown how magnesium is essential for the formation of a catalytically competent protein-RNA complex how the use of two magnesium ions can drive the hydrolysis of each phosphodiester bond and how conformational changes in both the substrate and the protein are critical elements for assembling the catalytic complex. Moreover we have provided a stepwise trajectory by which RNase III executes the phosphoryl transfer reaction. As informative as the bacterial enzyme for the mechanism of RNase III action yeast Rnt1p is a valuable model system for eukaryotic RNase III enzymes. Unlike bacterial enzymes that use four catalytic side chains eukaryotic RNase IIIs use six. It is also distinguished from bacterial enzymes that every eukaryotic RNase III has an N-terminal extension. What is more Rnt1p exhibits a strict guanine nucleotide specificity which is unique among RNase III enzymes. We have shown how the substrate-binding mode of Rnt1p is distinct from that of bacterial RNase III how all six catalytic side chains are engaged in the cleavage site how a new RNA-binding motif of Rnt1p functions as a guanine-specific clamp and how the dsRNA-binding domain and N-terminal domain of Rnt1p function as two rulers measuring the distances between the guanine nucleotide to the two cleavage sites. This unusual mechanism of substrate selectivity represents an example of the evolution of substrate selectivity. All members of the RNase III family propel RNA hydrolysis by two-Mg2+-ion catalysis. We have also provided a stepwise trajectory by which Rnt1p executes the phosphoryl transfer reaction. The structural basis for the reaction trajectory of two-Mg2+-ion catalysis is provided by the crystal structure of a postcleavage complex determined at a stage immediately after the cleavage of the phosphodiester bond for which we have determined high-resolution structures for both bacterial RNase III and yeast Rnt1p. These postcleavage structures reveal distinct features of two-Mg2+-ion catalysis by prokaryotic and eukaryotic RNase III enzymes including Drosha and Dicer for which the available structures fail to provide the basis of two-Mg2+-ion catalysis. DDX3X belongs to the family of DEAD-box helicases that regulate RNA processing and metabolism by unwinding short RNA duplexes. Sharing a helicase core composed of two RecA-like domains (D1D2) DDXs function in an ATP-dependent non-processive manner. As an attractive target for cancer and AIDS treatment DDX3X and its orthologs are extensively studied yielding a wealth of biochemical and biophysical data including structures of apo-D1D2 and post-unwound D1D2:ssRNA complex. However the structure of a pre-unwound D1D2:dsRNA complex was not available until we have recently determined the crystal structure of a D1D2 core in complex with a 2-turn RNA duplex at the pre-unwound state showing that two DDXs recognize the RNA duplex. Each DDX mainly recognizes a single strand and conformational changes induced by ATP binding unwinds the RNA duplex in a cooperative manner. Our new structure has significantly altered a previous model of three-molecule cooperativity. To validate our new model we are currently elucidating the functional cycle of DDX3X using site-directed mutagenesis RNA-unwinding assay ATP-hydrolyzing assay Hill cooperativity analysis and structural studies. We have also started to develop DDX3X inhibitors based on available structural and mechanistic information. We carry out structure-based drug development primarily as a continuation of our basic research on the structure and mechanism of biomolecular systems with anticancer and antimicrobial significance. Previously we designed PABA/NO an enzymatically activated anticancer prodrug that kills cancer cells from within by releasing nitric oxide. We also made significant progress toward novel antibacterial agents targeting HPPK by the design and synthesis of linked purine pterin inhibitors and the determination of their crystal structures in complex with the enzyme. Recently we have further developed both the PABA/NO and HPPK inhibitors. The PABA/NO derivative contains a PARP inhibitor and so it not only generates nitric oxide but also release a PARP inhibitor simultaneously in the same compartment which damage DNA and inhibit its repair (PMID: 24521039; US Patent Number: 9168266). The improved HPPK inhibitors mimic closely the transition state of the catalytic complex and thereby have much higher potency (PMID: 33199204; US Patent Number: 11091509). 1982040 +Biomedical Imaging; Biotechnology; Cancer; Cancer Genomics; Endocrine Disruptors; Estrogen; Genetics; Human Genome; Women's Health Address;Adrenal Cortex Hormones;Antiinflammatory Effect;Binding;Biochemical;Biological Assay;Cells;Characteristics;Chromatin;DNA;DNA Binding;Data;Dimerization;Endocrine Disruptors;Endocrine system;Environment;Exposure to;Genes;Genomics;Glucocorticoid Receptor;Health;Higher Order Chromatin Structure;Human;Mammalian Cell;Metabolic Pathway;Methods;Modeling;Nuclear;Nuclear Receptors;Physiological;Population;Privatization;Public Health;Receptor Activation;Recovery;Response Elements;Risk;Risk Management;Rivers;Role;Sampling;Seasons;Signal Transduction;Site;Solid;Source;Steroid Receptors;Steroids;Thyroid Gland;United States;Water;Water Supply;androgenic;aryl hydrocarbons;base;dimer;estrogenic;genome-wide analysis;health data;in vivo imaging;live cell imaging;mutant;novel;receptor binding;receptor function;response;screening;water sampling In vivo Imaging Analysis of Steroid-Nuclear Receptor Function n/a NCI 10702332 1ZIABC010308-24 1 ZIA BC 10308 24 8777551 "HAGER, GORDON L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 510670 NCI 1. In the United States and globally contaminant exposure in unregulated water sources is a recognized public-health data gap and an obstacle to both risk-management. To address the lack of data on broad contaminant exposures in hydrologically-vulnerable aquifers rivers and tap water samples were collected from multiple sources. We assessed EDCs activity (aryl hydrocarbon [AhR] androgenic [AR] thyroid [Ty] estrogenic [ER] corticosteroid [CS]) with novel mammalian cell-based assays that express nuclear steroid receptors. We quantified receptor activation relative to negative controls and compared activity by season and utility/sample characteristics. Results demonstrate that AR and AhR activities are commonly detected in water supplies and that bioactivity varies by season and utility/sample characteristics. Screening EDCs with bioassays holds promise for characterizing population exposure to diverse EDCs mixtures. Continued assessment of unmonitored and unregulated private supply TW is needed to model contaminant exposures and human-health risks. 2. A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant allegedly incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric genomic studies on the basis of recovery of enriched half-site response elements suggest monomeric engagement on DNA. We performed genome-wide studies on GRdim and a constitutively monomeric mutant. Results show that GR must form dimers to bind even pre-accessible chromatin and that earlier characterizations of half-response elements do not constitute solid evidence of monomeric action. Results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repres 510670 +Cancer; Clinical Research; Health Disparities; Hematology; Immunotherapy; Minority Health; Orphan Drug; Rare Diseases Acute;Affinity;American Society of Clinical Oncology;Anti-CD22;Aspirate substance;B lymphoid malignancy;B-Lymphocytes;BCL2 gene;BL22 immunotoxin;BRAF gene;Behavior;Biological Assay;Biology;Blood;Bone Marrow;CD22 Immunotoxin;CD22 gene;COVID-19 pandemic;COVID-19 patient;Capillary Leak Syndrome;Cells;Characteristics;Chemoresistance;Cladribine;Clinical;Combination Drug Therapy;Data;Development;Disease;Disease remission;Dose;Enrollment;Evaluable Disease;Exotoxins;FDA approved;Flow Cytometry;Genes;Hairy Cell Leukemia;Hairy Cell Leukemia Variant;Hematologic Neoplasms;Hemolytic-Uremic Syndrome;Histology;Immune;Immune system;Immunoglobulins;Immunotoxins;Kidney Failure;Laboratory Research;Light;MEK inhibition;MEKs;Measures;Molecular;Mutation;Newly Diagnosed;Nodal;Normal Cell;Ohio;Pathogenesis;Pathway interactions;Patients;Pentostatin;Persons;Pharmaceutical Preparations;Phase;Prognosis;Progression-Free Survivals;Protocols documentation;Pseudomonas;Publishing;RNA;Randomized;Recombinants;Refractory;Regimen;Relapse;Reporting;Residual Neoplasm;Retreatment;Running;Sampling;Symptoms;TP53 gene;Testing;Thrombocytopenia;Time;Toxic effect;Toxicity due to chemotherapy;Toxin;Treatment Efficacy;Treatment-related toxicity;Tumor Markers;United States National Institutes of Health;Universities;Vaccination;Variant;Work;anaplastic thyroid cancer;clinical development;cohort;coronavirus disease;cytotoxicity;deep sequencing;design;exome sequencing;follow-up;genetic profiling;hairy cell leukemia cell;immunogenicity;improved;inhibitor;novel therapeutic intervention;novel therapeutics;optimal treatments;phase I trial;primary endpoint;prospective;purine analog;randomized trial;response;rituximab;small molecule;standard of care;targeted agent;targeted treatment;transcriptome Development of Recombinant Toxins to Treat Hematologic Malignancies n/a NCI 10702329 1ZIABC010301-25 1 ZIA BC 10301 25 6212020 "KREITMAN, ROBERT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1340622 NCI Overview. We focus on targeted therapy for hematologic malignancies particularly hairy cell leukemia (HCL) and other new therapies for HCL. Moxetumomab pasudotox (Moxe) contains truncated Pseudomonas exotoxin (PE) fused to an anti-CD22 Fv fragment. Previously called HA22 or CAT-8015 it is an affinity-matured form of a previous molecule BL22 for targeting hematologic malignancies particularly HCL. We test combinations of chemotherapy and rituximab to help determine the optimal therapy of newly diagnosed and multiply relapsed HCL and to better understand the behavior of HCL in immunotoxin-treated patients. We also test small molecules as targeted therapy for HCL and poor-prognosis variants like HCLv. In the lab we use clinical samples from patients to investigate treatment efficacy and toxicity and to better understand the biology and pathogenesis of HCL/HCLv. Development of anti-CD22 recombinant immunotoxins for CD22+ B-cell malignancies. We reported multicenter phase 1 and 3 results for Moxe. Of 49 patients enrolled on the phase I trial 33 received the highest dose level 50 ug/Kg x3 and in this group the complete remission (CR) rate was 64% with overall response rate (ORR) 88%. We published that most of the evaluable CRs (11 of 20) were without minimal residual disease (MRD) using the highest sensitivity standard assay bone marrow aspirate (BMA) flow cytometry. For the first time in HCL we reported that eradication of MRD was associated with a significantly longer CR duration. A worldwide pivotal trial in 80 patients including 26 at NIH met its primary endpoint with a durable CR rate of 36%. The most important toxicities reported earlier with BL22 included reversible capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS) the latter a combination of transient thrombocytopenia and renal insufficiency resolving without treatment. On 9/13/18 the FDA approved Moxe for patients with relapsed/refractory HCL the first time in decades that a new treatment was approved for HCL and the first FDA approval for a recombinant immunotoxin. To improve efficacy in HCL we began a trial at NIH testing Moxe with rituximab the latter to decrease immunogenicity and to help kill HCL cells and to hasten MRD-free CR. We presented the first 9 patients at ASCO 2021 reporting an MRD-free CR rate of 78%. Development of MAb-chemotherapy combinations for early and relapsed/refractory HCL. For the past 30-35 years cladribine alone or less commonly pentostatin alone was the standard 1st and 2nd line treatment of HCL but without cure in most patients. To determine the value of rituximab added to cladribine newly diagnosed or once-relapsed HCL patients were randomized to cladribine with either immediate or 6-month delayed rituximab and MRD at 6 months and other time points measured. As published in 2020 for 68 purine-analog naive HCL patients randomized 1:1 1st line concurrent cladribine-rituximab (CDAR) eradicates MRD in 97% vs 32% of patients with cladribine alone (CDA) (p0.0001). In this protocol delayed rituximab was given when MRD was detected in blood and eradicates MRD in 2/3 of patients with most MRD-free CRs persisting at a median follow-up of 6.5 years. Patients could get up to 2 courses of 8 weekly doses of Rituximab. Of 68 patients treated with either approach only 1 progressed to the point of needing next treatment vs 28% of 90 historical patients treated with CDA alone and followed until retreatment was needed for relapse (p0.0001). Thus while CDAR is superior with respect to long-term MRD-free CR CDA alone with delayed rituximab is also established as a new standard of care for treatment of newly diagnosed HCL. Once-relapsed HCL patients are continuing to be randomized on the trial. In the poor prognosis HCL variant (HCLv) concurrent rituximab + cladribine was highly effective establishing CDAR as a new standard of care for early HCLv. We recently published long-term data from the 20 patient-cohort of HCLv showing a 95% CR rate and 80% MRD-free CR rate. Eradication of MRD improved progression free survival (PFS) and overall survival (OS) and TP53 mutations in HCLv decreased PFS and OS. To study pentostatin-rituximab and bendamustine-rituximab (BR) combinations in HCL prospectively a randomized trial showed both regimens as a highly effective combination particularly in eradicating MRD albeit with chemotherapy toxicities. Targeted therapy for HCL. Although the BRAF V600E mutation is thought to be present in 100% of classic HCL we showed that up to 20% lack V600E (wild-type WT) particularly those with unmutated IGHV4-34 immunoglobulin rearrangement which characterizes a variant first described by our group in 2009. For the first time in HCL we began treating BRAF V600E+ HCL patients by inhibiting both BRAF with Dabrafenib and its downstream pathway MEK with Trametinib. This trial is part of a Novartis-sponsored multicenter registration trial in many different BRAF V600E+ histologies which completed accrual. As part of this trial we treated several patients with anaplastic thyroid cancer (ATC) a rapidly fatal disease also expressing BRAF V600E leading to the approval of Dabrafenib and Trametinib by the FDA for the treatment of ATC. To continue development of BRAF/MEK inhibition for HCL we initiated a trial of BRAF inhibitor Encorafenib and MEK inhibitor Binimetinib in HCL. For HCLv which is BRAF WT and those more aggressive HCL cases which are also BRAF WT we have initiated a trial of Binimetinib alone. As part of this trial we are determining if response to Binimetinib depends on the presence of MEK mutations which we have reported in about half of BRAF WT HCL/HCLv. Finally we treated 20 of the 37 patients enrolled on the multicenter BTK inhibitor Ibrutinib study run by Ohio State University and the report published. While agents targeting BRAF MEK and BTK generally do not eliminate MRD they can achieve regression of nodal disease and may be useful as a bridge to Moxe or Moxe-R which can then eliminate MRD. Laboratory research with other therapies for hematologic malignancies. To better target HCL/HCLv new potential drugs are also being tested in cytotoxicity assays including BRAF MEK BTK and BCL-2 inhibitors. Using clinical samples from HCL/HCLv patients we are sequencing immunoglobulin rearrangements (IgH) unique to each HCL patient to study HCL biology and to design patient-specific PCR assays for MRD. The RQ-PCR test can detect 1 HCL cell in 1 million normal cells and we are testing deep sequencing (MiSeq) for determining MRD as well. We are performing whole exome sequencing and RNA transcriptome analysis for HCLv and BRAF WT HCL samples to determine what causes disease in these variant cells. We have found genes which are characteristic of patients with HCL and/or HCLv including Myf6 which as we published is the most common gene expressed in HCL compared to HCLv and is expressed in 100% of HCL patients. Our work with this and other genes may shed light on pathogenesis of HCL/HCLv and possible new treatments for these disorders. We began several projects related to the COVID-19 pandemic. The first project started very early in the COVID pandemic was to study the humoral immune symptom via its immunoglobulin repertoire in otherwise healthy people acutely infected with COVID. The 2nd project was to study the humoral immune system in HCL patients infected with COVID with respect to time since their most recent treatment and with respect to their normal B-cell *TRUNCATED* 1340622 +Antimicrobial Resistance; Arthritis; Bioengineering; Breast Cancer; Cancer; Infectious Diseases; Nanotechnology; Orphan Drug; Rare Diseases; Women's Health ABCB1 gene;ABCG2 gene;ATP Hydrolysis;ATP phosphohydrolase;ATP-Binding Cassette Transporters;ATP-binding cassette transport;Actinic keratosis;Address;Adenine;Adenosine A3 Receptor;Affect;Affinity;Agonist;Alanine;Antibodies;Antineoplastic Agents;Area;Binding;Biochemical;Biological Assay;Biological Availability;Biophysics;Brazil;Breast Cancer Cell;CCR;Cancer Patient;Carrier Proteins;Cells;Chemicals;Chemoresistance;Chemotherapy-Oncologic Procedure;Chronic Disease;Clinic;Clinical;Collaborations;Complement;Cryoelectron Microscopy;Curcumin;Data;Derivation procedure;Development;Disease;Docking;Dose;Drug Interactions;Drug Kinetics;Drug Transport;Drug resistance;Enzyme Inhibitor Drugs;Esters;Exhibits;FDA approved;Formulation;Goals;Head and Neck Cancer;Hydrophobicity;Intestines;Japan;Knowledge;Label;Learning;Libraries;Ligands;Light;Link;Lipids;Malignant Neoplasms;Maryland;Mediating;Molecular;Molecular Conformation;Monoclonal Antibodies;Multi-Drug Resistance;Mutation;Natural Products;Non-Small-Cell Lung Carcinoma;Nucleosides;Optics;Orthovanadate;PUVA Photochemotherapy;Paclitaxel;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phosphotransferases;Photochemistry;Photosensitizing Agents;Play;Primary carcinoma of the liver cells;Property;Proteins;Psoriatic Arthritis;Pump;Purinergic P1 Receptors;Reactive Oxygen Species;Regulation;Resistance;Resolution;Rheumatoid Arthritis;Role;Series;Singlet Oxygen;Site;Structure;Structure-Activity Relationship;Substrate Specificity;Taiwan;Testing;Time;Transmembrane Domain;Tyrosine Kinase Inhibitor;Ubiquitin-Activating Enzymes;Universities;Variant;Western Blotting;Work;absorption;analog;antagonist;base;cancer imaging;cancer type;chronic pain;crosslink;design;dimer;drug repurposing;fluorescence imaging;gel electrophoresis;improved;in silico;inhibitor;inhibitor therapy;inorganic phosphate;insight;interdisciplinary approach;medical schools;member;molecular dynamics;molecular modeling;multi drug transporter;multidrug resistant cancer;mutant;nanodisk;nanomedicine;novel strategies;novel therapeutic intervention;nucleobase;particle;programs;reconstitution;refractory cancer;screening;small molecule;tool;triple-negative invasive breast carcinoma Biochemical Analysis of Multidrug Resistance-linked Transport Proteins n/a NCI 10702323 1ZIABC010030-27 1 ZIA BC 10030 27 6569320 "AMBUDKAR, SURESH " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1503264 NCI We have designed a coordinated strategy using multidisciplinary approaches to understand the molecular basis of the polyspecificity exhibited by the ATP-binding cassette (ABC) drug transporter P-glycoprotein (P-gp) and the mechanism of P-gp-mediated drug transport. Our approaches include several biochemical and biophysical assays cell-based transport assays purification and reconstitution in lipid nanodiscs for structural studies using cryo-EM medicinal chemistry to synthesize a large number of compounds to assess structure-activity relationships in silico molecular modeling and MD simulations to extend our understanding of the mechanistic aspects and structure-function relationships. In addition we are employing a novel approach of substituting multiple conserved residues with alanine in homologous transmembrane helices (TMHs) to elucidate the transport mechanism of P-gp. Furthermore we are devoting considerable effort to the screening and development of tyrosine kinase inhibitors (TKIs) and small molecule modulators of both P-gp and ABCG2 that are used in the clinic for treatment of various types of cancers. 1. Elucidation of the catalytic cycle of ATP hydrolysis and transport pathway of P-gp: We continue to study the catalytic cycle of P-gp specifically correlating the structural conformations with the various steps that occur during ATP hydrolysis. Cryo-EM single particle studies have revealed two major conformations one being the inward-open (IO) conformation in which the NBDs are separated and the drug-binding cavity is accessible for interaction with substrates or inhibitors. The second conformation inward-closed (IC) is observed in the ATP-bound E556Q/E1201Q (EQ) mutant in which the NBDs are dimerized (closed) and the drug-binding cavity is collapsed. Orthovanadate is a transition-state analog of inorganic phosphate that inhibits the ATPase activity of P-gp and other ABC transporters. We tested several polyoxyvanadate compounds for their effect on the drug transport and ATPase activity of P-gp. Interestingly we found that decavanadate inhibits both the drug transport and ATPase activity of P-gp with the same potency as orthovanadate. Molecular docking studies indicate that decavanadate does not appear to bind to the drug-binding pocket suggesting that most likely it interacts with the ATP sites. Moreover decavanadate binding to P-gp is conformation-sensitive. We plan to exploit this property of decavanadate to learn more about conformational changes associated with the catalytic cycle. 2. Reversal of the direction of transport mediated by P-gp: We used a novel approach of introducing multiple mutations in homologous transmembrane helices biochemical and cell-based transport assays and molecular modeling to investigate the mechanism of drug transport by P-gp. A variant of P-gp termed 14A having 14 mutations in TMH 6 and TMH 12 which line the central cavity of the drug-binding pocket lost the ability to export most of the substrates tested but gained the ability to import four substrates including Rhodamine123 and Flutax-1 (a Taxol derivative). By generating several variants with substitution of residues in both TMH 6 and 12 we found that the switch that controls the direction of transport resides in the center region. Further characterization of a series of mutants indicated that three residues (V334 F336 and F336) from TMH 6 and six residues (F978 S979 V981 V982 F983 and M986) from TMH 12 contribute to maximal accumulation of four substrates. Interestingly residues F978 S979 V981 V982 and F983 are critical for modulation of the direction of drug transport. To assess the role of residues in TMH 4 and TMH 10 we generated a TM410-14A mutant in which seven residues from TMH 4 and seven from TMH 10 were substituted with Ala. This mutant P-gp did not mediate accumulation of any tested substrate and also failed to efflux all tested substrates. These data demonstrate that the residues in TMH 4 and 10 are critical for the transport function of P-gp. 3. Mechanism of photodynamic regulation of P-gp and ABCG2: We have begun to elucidate the molecular mechanism of photo dynamic therapy (PDT)-mediated regulation of ABC drug transporters. PDT is a photochemistry-based tool that involves light activation of photosensitizers to generate reactive oxygen species. In the clinic PDT has been used to treat various diseases such as actinic keratosis non-small cell lung cancer and head and neck cancer. ATPase activity and in silico molecular docking analyses show that the photosensitizer benzoporphyrin derivative (BPD) binds to ABCB1 and ABCG2 with micromolar half-maximal inhibitory concentrations in the absence of light. Light activation of BPD generates singlet oxygen to further reduce the ATPase activity of ABCB1 and ABCG2 by up to 12-fold in an optical dose-dependent manner. Gel electrophoresis and Western blotting revealed that light-activated BPD induces aggregation of these transporters by covalent crosslinking. Thus PDT affects the function of ABCB1 and ABCG2 by modulating the ATPase activity and protein integrity of these transporters. Insights gained from this study concerning the photodynamic manipulation of ABC drug transporters could aid in the development and application of new optical tools to overcome the multidrug resistance that often develops after cancer chemotherapy. To improve the efficiency of PDT for drug-resistant cancer we devised a photoimmunoconjugate formulation combining hydrophobic BPD photosensitizers and a conformation-sensitive UIC2 monoclonal antibody to identify P-gp expression on triple negative breast cancer (TNBC) cells. We found that a UIC2-BPD conjugate can be used to fluorescently label P-gp in live TNBC cells indicating its potential use for fluorescence imaging of tumors expressing this multidrug transporter. These studies were carried out in collaboration with Huang-Chiao (Joe) Huang as a part of partnership program between CCR NCI and the University of Maryland. 4. Development of non-toxic natural product and small molecule modulators to overcome resistance mediated by P-gp and ABCG2: We continue to characterize recently developed TKIs including SKLB610 ensartinib and OTS964 repurposed drugs small molecules (phenylfurocoumarin derivative and ubiquitin-activating enzyme inhibitor TAK-243) and natural products for their effect on the function of P-gp and ABCG2. These studies were carried out in collaboration with Drs. Glaucio Valdameri (Federal University of Parana Brazil) Chung-Pu Wu (Chang Gung University Taiwan) Zhe-Sheng Chen (St. John's University NY) and Shinobu Ohnuma (Tohoku University Graduate School of Medicine Japan). A3 adenosine receptor agonists have been developed for the treatment of chronic diseases such as rheumatoid arthritis psoriasis chronic pain and hepatocellular carcinoma. Previously we demonstrated that various agonists and antagonists of adenosine receptor modulate the function of P-gp. We expanded these studies to test whether A3 adenosine receptor ligands both adenine nucleoside and nucleobase derivatives interact with ABCG2 modulating the absorption of drugs in the intestine. We synthesized 63 compounds and tested them for their effect on the ATPase activity of ABCG2. Of these compound 60 a 7-deaza-5'-ester derivative with low adenosine receptor affinity was identified as a high-affinity ligand for ABCG2 (in collaboration with Kenneth Jacobson). We found that A3 adenosine receptor ligands can exhibit *TRUNCATED* 1503264 +Biotechnology; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Minority Health Architecture;Cell Nucleus;Chromatin;Chromatin Loop;Complex;Enhancers;Exhibits;Gene Expression Regulation;Gene Structure;Genes;Genome Mappings;Genomics;Glucocorticoid Receptor;Glucocorticoids;Interphase;Mass Spectrum Analysis;Mediating;Methods;Mutation;Nuclear;Patients;Play;Role;Site;Steroid Receptors;Time;Transcriptional Regulation;acute myeloid leukemia cell;cancer initiation;cohesin;experimental study;interest;response;single molecule;transcription factor Function of Steroid Receptors in Subcellular Compartments n/a NCI 10702322 1ZIABC010027-28 1 ZIA BC 10027 28 8777551 "HAGER, GORDON L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 510670 NCI The cohesin complex is central to chromatin looping but mechanisms by which these long-range chromatin interactions are formed and persist remain unclear. We discovered that interactions between a transcription factor (TF) and the cohesin loader NIPBL regulate enhancer dependent gene activity. Using mass-spectrometry genome mapping and single-molecule tracking methods we demonstrated that the glucocorticoid receptor interacts with NIPBL and the cohesin complex at the chromatin level promoting loop extrusion and long-range gene regulation. Real time single molecule experiments showed that cohesin-mediated loops entrap TFs molecules at specific nuclear confinement sites increasing TF local concentration and promoting gene regulation. Finally patient-derived acute myeloid leukemia cells harboring cohesin mutations exhibit a reduced response to glucocorticoids (GCs) suggesting that the GR-NIPBL-cohesin interaction is defective in these patients resulting in poor response to GC treatment. 510670 +Cancer; Coronaviruses; Emerging Infectious Diseases; Immunization; Infectious Diseases; Prevention; Vaccine Related 2019-nCoV;Animals;Anti-Bacterial Agents;Antibiotics;Antigens;Bacterial Infections;Bacteriophage T7;Bacteriophage lambda;Bacteriophages;Biotechnology;COVID-19 vaccine;Caring;Communicable Diseases;Data Analyses;Diagnosis;Disease;Drug resistance;Engineering;Future;Genes;Glioblastoma;Goals;Infection;Investigation;Klebsiella;Libraries;Link;Malaria;Malignant Neoplasms;Mutation;Peptide Antibiotics;Peptides;Phage Display;Process;Production;Prophages;Proteins;Publishing;Resistance;SARS-CoV-2 immunity;SARS-CoV-2 spike protein;Tail;Technology;Testing;Time;Vaccines;base;delta protein;developmental genetics;epidermal growth factor receptor VIII;experimental study;human disease;leukemia;mouse model;mutant;prevent;protein expression;screening Use of Bacteriophages to Prevent Diagnose and Treat Diseases n/a NCI 10702319 1ZIABC010017-27 1 ZIA BC 10017 27 6129912 "ADHYA, SANKAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1079030 NCI Part A. Three lines of investigations are being pursued currently. 1. Use of bacteriophages in treating human diseases because of bacterial infections. We are currently dealing with infections caused by Klebsiella. We have succeeded in defining bacteriophage cocktails that take care of bacteriophage resistance that arises during infection processes. 2. We have succeeded in engineering Klebsiella phages to have multiple tails to increase the host range of a phage to be capable of infecting and killing multiple hosts species. 3. We have succeeded to construct a T7 bacteriophage derivative in which we cloned a peptide antibiotic gene (AMP) which when infects a given host also produces vast amount of the antibiotic. This enables the phage to kill by the action of AMP any mutant bacterial host which becomes resistant to phage. However the expression of AMP has been poor which does not kill phage resistant hosts. But when the AMP expression is covalently linked to a soluble protein the expression was reasonable. Currently we have made a library of phage carrying random mutations in the peptide anti biotic and screening them for one with more effective anti-bacterial activity. These findings encourage us to pursue the process further. Part B. We are using our previously developed phage display technology using bacteriophage Lambda to make vaccines against infectious diseases as well as against cancer. We already constructed displaying potential antigenic peptides and proteins of CLL leukemia malaria and Covid 19 virus. We invested a lot of time in engineering purifying validating and testing the authenticity of multiple phage constructs that could potentially be developed as a phage-based vaccine for COVID-19 CLL and malaria. Currently we are performing several experiments and analyzing data on testing phage-based vaccines in a mouse model to generate immunity against COVID-19 and glioblastoma. We are currently working in the future experimental plan to demonstrate the efficacy of phage-based COVID-19 vaccine. The goal is the same in both cases: to prepare purified engineered lambda for animal immunogenecity study. In the first branch of the project we engineered a phage with the EGFRvIII antigen present in glioblastoma and attached to the D protein of the lambda phage. The other branch of the project involved the same process but the antigen was a fragment of the covid-19 spike protein. These constructions were made as prophages. The prophages were then induced phage production and phages purified and concentrated. The respective phages are now being tested for immunogenecity in animals. 1079030 +Cancer; Genetics; Stem Cell Research; Stem Cell Research - Nonembryonic - Human Alleles;Base Pairing;Binding Sites;Bone Marrow Transplantation;CRISPR/Cas technology;Cell Communication;Cell physiology;Cell-Mediated Cytolysis;Cells;Clinical;Collaborations;Complex;Data;Development;Distal;Education;Elements;Family;Frequencies;Future;Genes;Genetic Polymorphism;Genetic Variation;Goals;HLA-A gene;HLA-B Antigens;HLA-C Antigens;Hematopoietic stem cells;Human;Immune;Individual;Inflammation;Investigation;Ligands;Major Histocompatibility Complex;Malignant Neoplasms;Messenger RNA;Minnesota;Molecular;Mus;Mutation;Natural Killer Cells;Nature;Oncogenic Viruses;Outcome;Pattern;Peripheral Blood Lymphocyte;Population;Process;Program Research Project Grants;RNA Splicing;Receptor Cell;Regulation;Regulatory Element;Research;Role;System;T-Cell Receptor;Tissues;Transcriptional Regulation;Universities;Variant;Work;donor stem cell;interest;man;novel;programs;promoter;receptor;receptor expression;stem cells;transcription factor;trophoblast Molecular Studies of Cellular Cytotoxicity n/a NCI 10702316 1ZIABC010013-27 1 ZIA BC 10013 27 6569288 "ANDERSON, STEPHEN K" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1204631 NCI "Our group has been studying the regulation of class I major histocompatibility complex (MHC) receptors in mouse (Ly49) and man (KIR) for many years and we are pioneers in the identification of molecular mechanisms underlying the variegated expression of these receptors by NK cells. We have discovered many instances of genetic variation in KIR and Ly49 genes that can change the responsiveness of NK cells to MHC on target cells. However our long-standing collaboration with the Carrington lab in the Cancer and Inflammation Program (CIP) has stimulated our interest in studying the expression of the KIR ligands and the HLA-C gene in particular. Dr. Carrington's lab has demonstrated significant allelic variation in HLA-C expression suggesting that both the receptors and ligands are involved in an evolutionary ""tuning"" process to produce optimal NK:target cell interactions. We have therefore conducted an extensive characterization of polymorphisms in HLA-C regulatory elements. In the past year significant progress has been made in the investigation of the transcriptional control of HLA-C expression -a major ligand for the KIR family of human class I MHC receptors expressed by natural killer (NK) cells. We have identified and characterized a novel distal NK cell-specific HLA-C promoter. This discovery has important implications for the study of NK cell education by self MHC molecules. NK cell education has been a major focus in the field and recent data has suggested a role for MHC expression by the NK cell itself in this process. Our work has defined a novel paradigm for cell-intrinsic regulation of NK cells by HLA-C and we have discovered a complex system of tissue-specific alternative mRNA splicing that controls HLA-C expression by NK cells in different tissues. Furthermore we have identified specific HLA-C alleles that have a single base pair polymorphism that inactivates the NK-specific promoter resulting in reduced HLA-C expression by NK cells. We have found that this polymorphism has a significant effect on NK cell activity and we are in the process of determining if hematopoietic stem cells donors that have low HLA-C expression on NK cells are associated with a distinct clinical outcome. This study is a component of our participation in a program project grant led by Dr. Jeffery Miller at the University of Minnesota. In addition we have conducted a thorough analysis of allelic variation of transcription factor binding sites in the HLA-C gene and identified multiple polymorphisms that account for the variation of HLA-C expression levels in peripheral blood lymphocytes that has been observed by the Carrington lab. Our detailed study of HLA-C has also revealed the presence of trophoblast-specific elements in the HLA-C gene that are not present in HLA-A or HLA-B genes providing an explanation for the specific expression of HLA-C by trophoblasts. Future plans include: investigating the mechanism of NK cell-intrinsic tuning by HLA-C; using CRISPR technology to confirm functional role of the multiple KIR and HLA-C elements identified; studying clinical correlations of polymorphisms in the KIR and HLA genes. Preliminary data obtained from the study of bidirectional promoters in lineage-defining transcription factors has indicated that the bidirectional elements in these genes can act as switches transcribing in only one direction in an individual cell leading to variegated expression patterns. Future studies in this project will investigate the effect of mutations in these elements on the frequency of specific immune cell subsets generated from progenitor cells." 1204631 +Cancer; Eye Disease and Disorders of Vision; Lung; Neurosciences; Pediatric; Pediatric Cancer; Stem Cell Research; Stem Cell Research - Embryonic - Non-Human Actins;Adhesions;Affect;Apical;Axon;Benign;Biological Models;Body Regions;Breast;Cancer cell line;Cell Adhesion;Cell Cycle Progression;Cell Maturation;Cell physiology;Cell-Cell Adhesion;Cell-Matrix Junction;Cells;Centrioles;Cilia;Colon;Complex;Congenital Abnormality;Cytoplasmic Tail;Development;Developmental Process;Docking;Down Syndrome;Dsh protein;Embryo;Embryonic Development;Enzymes;Eph Family Receptors;Ephrins;Epithelial Cells;Event;Fibroblast Growth Factor;Fibroblast Growth Factor Receptors;Frequencies;GTPBP1 gene;Glean;Human;Knowledge;Laboratories;Licensing;Ligands;Link;Male Infertility;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Membrane;Modification;Morphogenesis;Movement;Neoplasm Metastasis;Neural Crest Cell;Neuroblastoma;PLK1 gene;Pathway interactions;Patients;Pattern;Phenotype;Phosphotransferases;Play;Positioning Attribute;Process;Prostate;Proteins;Receptor Protein-Tyrosine Kinases;Reporting;Research;Respiratory Disease;Retina;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Signaling Molecule;Specificity;Stem Cell Development;System;Therapeutic;Tissues;Tumor Angiogenesis;Tumor Cell Invasion;Tumor Stem Cells;Tyrosine Phosphorylation;Vertebrates;Visual Fields;WNT Signaling Pathway;Xenopus;Xenopus laevis;angiogenesis;apical membrane;cell motility;ciliopathy;cilium biogenesis;embryonic stem cell;epithelial to mesenchymal transition;hindbrain;human disease;in vivo;insight;kinetosome;link protein;lung small cell carcinoma;melanoma;member;migration;neoplastic cell;overexpression;pluripotency;recruit;retinal progenitor cell;scaffold;separase;skeletal;stem cell fate specification;stem cells;tumor;tumorigenesis Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways n/a NCI 10702314 1ZIABC010006-27 1 ZIA BC 10006 27 9692315 "DAAR, IRA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 832771 NCI During normal development progenitor cells of many tissues undergo progressive restriction of pluripotency epithelial-to- mesenchymal transition proliferation migration and differentiation. Most if not all of these events involve modifications of cell-cell and cell-matrix adhesion and abnormal modifications of these adhesion systems are often associated with the formation of tumors. The Eph family of receptor tyrosine kinases and their ligands the ephrins are frequently over-expressed in a wide variety of cancers including breast small-cell lung and gastrointestinal cancers melanomas and neuroblastomas. Using the Xenopus embryonic system we have demonstrated that signaling mediated by the intracellular domain of ephrinB affects cell-cell adhesion and that this activity can be modulated by interaction with an activated FGF receptor. The transmembrane ephrinB1 protein is a bi-directional signaling molecule that signals through its cytoplasmic domain to promote cellular movements into the eye field whereas activation of the fibroblast growth factor receptor (FGFR) represses these movements and retinal fate. In Xenopus embryos ephrinB plays a role in retinal progenitor cell movement into the eye field through an interaction with the scaffold protein Dishevelled (Dsh). We recently identified Drg1 (Developmentally regulated GTP binding protein 1) as a new but requisite interactor and regulator of Dishevelled (Dvl) for proper ciliogenesis. Dvl is a central scaffold that mediates both canonical and non-canonical Wnt signaling and can decisively orchestrate various developmental and cellular processes. One of these processes is ciliogenesis and while Dvl is known to be critical for apical docking and planar polarization of basal bodies in ciliated epithelial cells little mechanistic insight into the players and their roles have been gleaned since this original discovery. We previously reported the identification of Drg1 a little studied GTP-binding protein 1 that interacts with Dvl and localizes it to the basal body region and we provided critical in vivo evidence that a Drg1/Dvl interaction plays a critical role in ciliogenesis. We now show that Ccdc108 a protein linked to male infertility has an evolutionarily conserved requirement in motile multiciliation. Using Xenopus laevis embryos Ccdc108 is shown to be required for the migration and docking of basal bodies to the apical membrane in epidermal multiciliated cells (MCCs). We demonstrate that Ccdc108 interacts with the IFTB complex and governs the centriolar recruitment of IFT while IFT licenses the targeting of Ccdc108 to the cilium. Moreover Ccdc108 is required for the centriolar recruitment of Drg1 and activated RhoA factors that help establish the apical actin network in MCCs. Finally we show that CEP97 which is known as a negative regulator of primary cilia formation interacts with dual specificity tyrosine phosphorylation regulated kinase 1A (Dyrk1a) to modulate multiciliogenesis. We show that Dyrk1a phosphorylates CEP97 which in turn promotes the recruitment of Polo-like kinase 1 (Plk1) which is a critical regulator of MCC maturation that functions to enhance centriole disengagement in cooperation with the enzyme Separase.Thus our study reveals that Dyrk1a and CEP97 coordinate with Plk1 to promote Separase function to properly form multicilia in vertebrate MCCs. Our findings on the collaborative role of CEP97 and Dyrk1a in multiciliation may add to our existing knowledge regarding patients with trisomy 21 and therapeutic approaches for the respiratory diseases in patients with ciliopathy and Down syndrome. 832771 +Cancer; Genetics; Hematology; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Ablation;Acute Myelocytic Leukemia;Aging;Binding;Binding Proteins;Bioinformatics;Blood Cells;Cell Count;Cell Cycle;Cell Lineage;Cells;Chronic stress;Clonal Expansion;DNA;Development;Developmental Process;Differentiation Inhibitor;Down-Regulation;Enzymes;Erythroid Cells;Event;Family member;Flow Cytometry;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Genomic Instability;Goals;Growth;Helix-Turn-Helix Motifs;Hematopoiesis;Hematopoietic Neoplasms;Hematopoietic Stem Cell Specification;Hematopoietic stem cells;Histones;Hypoxia;Hypoxia Inducible Factor;ID2 gene;Immunohistochemistry;In Vitro;Incidence;Inflammatory;Laboratories;Lead;Lymphoid;Mediating;Mediator of activation protein;Membrane;Modeling;Molecular;Mus;Mutate;Mutation;Myelogenous;Myeloid Cells;Oxidative Phosphorylation;Pathway interactions;Patients;Phase;Process;Proteins;Publishing;RNA;Relapse;Reporter;Reverse Transcriptase Polymerase Chain Reaction;Role;Signal Transduction;Stains;Stress;Testing;Time;Transgenic Organisms;Ubiquitination;VHL protein;cell growth regulation;differential expression;exhaustion;genotoxicity;hematopoietic stem cell quiescence;in vivo;leukemia;leukemia/lymphoma;mouse model;myeloid cell development;programs;protein expression;recruit;response;self-renewal;single-cell RNA sequencing;stem cell biology;stem cells;therapeutic target;transcription factor;transcriptome;transcriptome sequencing Molecular-Cellular Regulation of Hematopoietic Stem Cells n/a NCI 10702313 1ZIABC010001-27 1 ZIA BC 10001 27 6569266 "KELLER, JONATHAN R" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1091585 NCI During the last year we continued to define the molecular events that regulate hematopoietic stem and progenitor cell (HSPC) quiescence survival self-renewal and myeloid cell lineage commitment and differentiation. We have found that the helix loop helix (HLH) transcription factor inhibitor of differentiation 1 (Id1) is induced during the early stages of myeloid development and can instruct hematopoietic stem cells toward a myeloid versus lymphoid/erythroid cell fates suggesting that this gene and other family members Id2 and Id3 may regulate cell specification of HSPC. In this regard we found that HSCs express ID2 using an Id2 reporter mouse model (Id2-EYFP/+ mice) developed in our laboratory which directly correlates with Id2 RNA expression by Q-RT-PCR analysis. To test if ID2 functions in HSC we developed an Id2 conditional (Id2F/F) mouse model and bred these to transgenic Mx1-Cre+ mice to delete Id2 in vivo. The number of HSCs and ST-HSCs were significantly reduced in Id2-/- mice compared to controls and mice that lack Id2 show reduced survival over time demonstrating that Id2 is essential to maintain HSCs numbers during steady state hematopoiesis. To identify the molecular mechanism(s) that mediate HSC exhaustion in Id2-/- mice we examined the transcriptome of purified Id2-/- and Id2+/+ HSCs by single cell RNA-seq and RNA-seq. Bioinformatic analysis of differentially expressed genes revealed that Id2-/- HSCs show increased gene expression in pathways that promote growth/proliferation and oxidative phosphorylation and decreased expression of hypoxia response pathway genes compared to Id2+/+ HSCs. These results suggest that loss of Id2 may lead to HSC activation/proliferation and decreased quiescence via down regulation of hypoxia inducible factor (HIF) and downstream targets. We confirmed that Id2-/- HSCs show significantly reduced levels of HIF-1a protein expression by flow cytometry and immunohistochemistry (IHC) while Hif-1a RNA levels were not changed. HIF-1a promotes HSC quiescence and is required to maintain steady state numbers of HSCs. We found that Id2-/- HSCs show increased cycling 2 weeks after Id2 ablation in vivo by Ki-67 staining and flow cytometry. We determined that ID2 binds to the VHL protein which interferes with the ubiquitination and degradation of HIF-1a. Furthermore we demonstrated that stabilization of HIF-1a rescues the exhaustion of Id2-/- HSCs in vitro and in vivo. These studies were published this year in JCI. In other studies we discovered that mice that lack Id1 show increased quiescence during BMT and are protected from exhaustion during serial BMT and in other models of chronic stress including genotoxic and inflammatory stress and aging. These studies laid the foundation for our current and future goals to determine if Id1 promotes clonal hematopoiesis a preleukemic phase that proceeds leukemia and if reducing Id1 expression can reduce hematopoietic stem and progenitor (HSPC) cell cycling and clonal expansion and reduce the incidence of hematopoietic malignancies. We found that Id gene expression is increased in HSPC progenitor cells from Tet2-/- mice a murine model of clonal hematopoiesis. Furthermore we have determined that reducing Id1 levels in Tet2-/- mice rescues enhanced donor repopulation during BMT reduces HSPC expansion and myeloid skewing of Tet2-/- HSPCs. These results suggest we are reducing clonal expansion in Tet2-/- mice. We have shown that reducing Id1 levels in Tet2-/- mice delays the onset of leukemia. Future studies are aimed at demonstrating that reducing Id1 gene expression reduces the mutational load and genomic instability that is observed in Tet2-/- in HSPCs in vivo. We are also pursuing studies to determine if Id1 promotes relapse of acute myeloid leukemia and evaluating the role of ID2 in maintaining AML LSCs in vitro and in vivo. 1091585 +Ataxia Telangiectasia; Biotechnology; Cancer; Genetics; Hematology; Human Genome; Lymphatic Research; Lymphoma; Neurodegenerative; Rare Diseases ATM deficient;Affect;Age;Aggressive Clinical Course;Aplastic Anemia;B lymphoid malignancy;B-Cell Activation;B-Cell Development;B-Cell Lymphomas;B-Lymphocytes;B-Lymphoma Development;BCL10 gene;Biology;Breeding;Buffers;CD3E gene;CRISPR/Cas technology;Cell Aging;Cell Lineage;Cell Proliferation;Cell Survival;Cell division;Cells;Chromosomal Instability;Chromosome 18;Chromosome Structures;Clinical;Collaborations;Complex;Defect;Dependence;Development;Disease;Disease model;Down-Regulation;Dyskeratosis Congenita;Enzymes;Epigenetic Process;Excision;Exhibits;Family;Fibroblasts;Frequencies;Gene Expression;Gene Expression Profiling;Generations;Genes;Genetic Engineering;Genetic study;Histologic;Human;Immunoglobulin M;Immunologic Surveillance;In Vitro;Incidence;Knock-out;Knockout Mice;Laboratories;Length;Link;Lymphocyte;Lymphoma;Lymphomagenesis;Malignant - descriptor;Malignant Neoplasms;Malignant lymphoid neoplasm;Mediating;Modeling;Mucosa- associated lymphoid tissue lymphoma translocation protein-1;Mus;Mutation;NF-kappa B;National Heart Lung and Blood Institute;Oncogenic;Outcome Study;PTEN gene;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Play;Predisposition;Proto-Oncogene Proteins c-akt;Pulmonary Fibrosis;RNA-Directed DNA Polymerase;Recurrence;Regulation;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Ribonucleoproteins;Role;Signal Pathway;Signal Transduction;Skin;Somatic Cell;Stress;Study models;T-Cell Lymphoma;T-Cell Receptor Genes;T-Cell Transformation;T-Lymphocyte;TP53 gene;Telomerase;Telomerase RNA Component;Telomere Length Maintenance;Telomere Maintenance;Telomere Shortening;Testing;Therapeutic Intervention;Thymic Lymphoma;Thymus Gland;Time;Transcriptase;Translations;Up-Regulation;ataxia telangiectasia mutated protein;cancer cell;early onset;embryonic stem cell;gene product;genome integrity;human model;in vivo;inhibitor;insight;knock-down;large cell Diffuse non-Hodgkin's lymphoma;lymphocyte proliferation;mouse model;neoplastic cell;non-genetic;offspring;overexpression;prevent;recombinase;senescence;small hairpin RNA;telomere;tumor;tumorigenesis Regulation of Lymphocyte Proliferation and Replicative Capacity n/a NCI 10702312 1ZIABC009405-28 1 ZIA BC 9405 28 2405210 "HODES, RICHARD J." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 33791 NCI Telomeres are unique terminal chromosomal structures that shorten with cell division in vitro and with increased age in vivo in human somatic cells. Telomerase a ribonucleoprotein enzyme that is capable of synthesizing telomeric repeats is expressed in germline and malignant cells and is absent in most normal human somatic cells.We demonstrated that telomerase is in fact highly regulated during development and activation of mouse and human lymphocytes. Expression of the two genes encoding the necessary and sufficient components of telomerase RNA template (TR) and reverse transcriptase catalytic component (TERT) was found to be regulated during lymphocyte development and activation. Our studies of genetically engineered knockout mice have demonstrated that in addition to the defect in telomere length maintenance observed in complete homozygous knockouts for either of the telomerase components there is a deficiency in telomere maintenance in mice that are heterozygous for inactivation of one copy of either telomerase component. This phenomenon termed haplo-insufficiency has recently been observed in an increasing number of clinical entities including dyskeratosis congenita aplastic anemia and pulmonary fibrosis resulting from mutation and inactivation of telomerase components or related genes. In collaboration with the laboratory of Dr. Neal Young (NHLBI) we have assessed the impact of parental haplo-insufficiency for telomere maintenance on the telomere length and function of genetically normal or abnormal offspring in these affected families. The outcome of studies in mice and humans demonstrated that inheritance of telomere length is not determined by species-specific homeostatic mechanisms but by stochastic factors. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells but its role in somatic cells remains to be understood. In recent studies we have identified an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed Tert heterozygous knockout mice (mTert +/-) for 26 generations during which time there was progressive shortening of telomeres and obtained primary skin fibroblasts from mTert +/+ and mTert -/- progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations both mTert +/+ and mTert -/- fibroblasts showed comparable and extremely short telomere length. However mTert -/- cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than mTert +/+ cells. Furthermore an evident upregulation of TERT expression was detected in mTert +/+ cells at the pre-senescence stage. Moreover removal or downregulation of TERT expression in mTert +/+ and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated mTert -/- phenotypes of accelerated senescence and transformation and overexpression of TERT in mTert -/- cells rescued these phenotypes. Together this study suggests that TERT has a previously under-appreciated protective role in buffering senescence stresses due to short dysfunctional telomeres and preventing malignant transformation. Cell survival and proliferation are also regulated by the p53 tumor suppressor molecule. Ataxia-telangiectasia mutated (ATM) is a kinase that plays a central role in maintaining genomic integrity. In both humans and mice ATM deficiency is associated with an increased incidence of lymphoid cancers. We asked if ATM plays a more general role in preventing non-T cell malignancies by breeding mice that were both ATM-and T cell-deficient. This model removes T cells as targets for lymphomagenesis as well as eliminating T cell-dependent immune surveillance. These mice exclusively develop early onset IgM+ B cell lymphomas that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B cell lymphomas (DLBCL). Tumors express clonal as well as emerging IghV hypermutation and express AID but B lymphoma development is independent of AID occurring at equal frequency in AID knockout mice. These ATM-deficient lymphomas show considerable chromosomal instability with a recurrent amplification of a 4.48Mb region on chromosome 18 (MMU18) orthologous to a region amplified in some cases of human ABC-DLBCL and containing Malt1 in the region of highest amplification. Importantly these lymphomas also depend on NF-kB MALT1 and BCR signaling for survival. Gene expression analysis revealed strong similarities between these mouse lymphomas and human ABC-DLBCL. This study reveals that ATM is required to prevent the development of B cell lymphomas that model human ABC-DLBCL and identifies an unappreciated role of T cells in preventing the emergence of these tumors. Studies now in progress are characterizing the pathways that mediate transformation of the T cell thymic lymphomas in ATM-deficient mice. We had previously reported that thymic T cell lymphomas develop in mice that are deficient in RAG-1 or RAG-2 recombinase in addition to ATM deficiency. These findings contrast to the absence of T cell lymphomas in mice double deficient in ATM and CD3e. This suggests the possibility that CD3e-containing complex independent of rearranged TCR gene products is required for lymphomagenesis. Additional studies now in progress are testing the requirement for components of the prototypic TCR/pre-TCR signal pathways such as LAT in development of lymphomas. The requirements for survival and proliferation of ATM-deficient T cell lymphomas have in fact not been fully elucidated. We have therefore initiated studies of the genetic and epigenetic changes in these lymphomas and their dependence on defined signaling pathways. Initial findings have included a universal defect in the phosphatase PTEN through genetic/non-genetic mechanisms that vary from tumor to tumor. Consistent with loss of PTEN activity we have observed activation of the AKT pathway and concomitant susceptibility of lymphomas to inhibitors of AKT activity. These findings will inform the underlying biology of T cell transformation with potential relevance to clinical approaches to human T cell malignancies. Lentiviral shRNA knockdown of targets including CD3e and LAT are in progress to test the requirements for TCR signaling pathways in survival of ATM-deficient T cell lymphomas. Initial results have demonstrated that thymic lymphomas which develop in ATM-deficient mice comprise two distinct subsets which differ in expression of TCR/pre-TCR components in gene expression assessed by RT-PCR and in susceptibility to in vitro survival by inhibition and shRNA knockdown of CD3e. These findings provide a basis for translation to categorization and treatment of subsets of human T cell lymphomas. 33791 +Autoimmune Disease; Biotechnology; Cancer; Hematology; Immunization; Immunotherapy; Infectious Diseases; Orphan Drug; Rare Diseases; Sepsis; Transplantation Asthma;Autoimmune Diseases;Autoimmunity;CCR;Cell Transplantation;Cell division;Cells;Childhood;Clinical;Clinical Trials;Code;Dermatitis;Diabetes Mellitus;Disease;Drug Combinations;Genetic Polymorphism;Goals;Health;Human;Hydrogels;IL7 gene;IgG1;Immune;Immune system;Immunologic Deficiency Syndromes;Immunotherapy;In Vitro;Interleukin 7 Receptor;Leukemic Cell;Lymphoblastic Leukemia;Lymphocyte Count;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Methods;Monoclonal Antibodies;Multiple Sclerosis;Mus;Mutate;Neoplasms;Pathway interactions;Patients;Pharmaceutical Preparations;Receptor Signaling;Reporting;Sepsis;Signal Transduction;Stem cell transplant;T-Cell Development;Texas;Therapeutic;Therapeutic Monoclonal Antibodies;antagonist;antibody-dependent cell cytotoxicity;chemotherapy;cytokine;improved;leukemia;mortality;mutant;receptor;relapse patients;secondary infection;septic patients Cytokines and T Cell Development n/a NCI 10702308 1ZIABC009287-38 1 ZIA BC 9287 38 6569217 "DURUM, SCOTT " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1423160 NCI The IL-7 pathway is critical for regulating the number of lymphocytes as has been shown in humans as well as in mice. We and our collaborators recently showed that the IL-7 receptor is mutated in pediatric lymphocytic leukemia and the mutant receptors drive cell division. We developed a panel of monoclonal antibodies against mutant receptors all of which also react with normal receptors. These mouse monoclonals have been chimerized with human IgG1 to optimize antibody-dependent cell-mediated cytotoxicity. These monoclonals are effective as single agents in treating human leukemia cells transplanted into mice. A clinical trial is being developed together with the Fannin Group and Baylor Medical Center in Houston Texas and will also involve CCR. Pediatric lymphocytic leukemia patients that relapsed following chemotherapy will be treated with our monoclonal antibodies. This clinical trial is expected to begin within one year. In addition to leukemias the IL-7 pathway has also been implicated in other neoplasias including lung cancer and we aim to explore treatment of these other cancers with our monoclonal antibodies. Using a different approach we recently reported that drugs which block signaling from the IL-7 receptor combined with drugs that block the Ras pathway are effective in killing leukemia cells in vitro and in mice. These drug combinations will be evaluated for treating patients. The same monoclonal antibodies and drugs will also be evaluated in autoimmune diseases. It was previously found by others that a polymorphism in the coding region of IL-7 receptor predisposes to autoimmune diseases. We recently found that this polymorphism regulates the strength of signal by the receptor offering promise for inhibiting these signals in autoimmunity. Therefore antagonists of the IL-7 pathway may be effective in autoimmunity and we are exploring this possibility. While blocking the IL-7 pathway has promise in autoimmunity and cancer IL-7 itself has therapeutic potential in clinical settings that could benefit from its potent activities in stimulating the immune system. Together with collaborators we recently reported results of a small clinical trial in sepsis patients showing that IL-7 effectively rescues immune cells that are severely suppressed. A larger trial in sepsis patients is planned. There is a great need for improved treatment of these patients who suffer high mortality from secondary infections. In another project together with collaborators at NCI we developed a new method for delivering IL-7 that is incorporated in a slow-release hydrogel. We are evaluating this material for improving immunotherapy because it greatly improves transfer of immune cells. 1423160 +Autoimmune Disease; Brain Disorders; Cancer; Immunotherapy; Multiple Sclerosis; Neurodegenerative; Neurosciences Affect;Affinity;Antibody Affinity;Antibody Formation;Antibody Response;Antigen-Presenting Cells;Antigens;Appearance;Autoimmune Diseases;Autoimmunity;B-Cell Activation;B-Lymphocytes;Binding Sites;CD28 gene;CD4 Positive T Lymphocytes;CD8B1 gene;CRISPR/Cas technology;Cell Communication;Cell surface;Cells;Critical Pathways;Cytoplasmic Tail;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Dependence;Development;Disease;Disease model;Event;Experimental Autoimmune Encephalomyelitis;General Population;Generations;Genetic Models;Helper-Inducer T-Lymphocyte;Human;Humoral Immunities;Immune Sera;Immunoglobulin Class Switching;Intervention;Ligands;Lymphoid Cell;Mediating;Modeling;Molecular;Mouse Strains;Mucous Membrane;Multiple Sclerosis;Mus;Myeloid Cells;Pathogenesis;Pathogenicity;Pathway interactions;Peripheral;Phase;Play;Population;Predisposition;Process;Recombinants;Regulation;Reporting;Role;Severities;Signal Transduction;Specificity;Structure of germinal center of lymph node;T memory cell;T-Cell Activation;T-Cell Development;T-Cell Proliferation;T-Lymphocyte;TNFRSF5 gene;TNFSF5 gene;TP53 gene;Thymic epithelial cell;Thymus Gland;antigen-specific T cells;conditional knockout;cytokine;draining lymph node;experimental study;human model;in vivo;insight;mouse genetics;mouse model;mutant;novel;receptor;response;thymocyte;vaccine response Receptor Mediated T and B Cell Activation n/a NCI 10702306 1ZIABC009281-36 1 ZIA BC 9281 36 2405210 "HODES, RICHARD J." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 540649 NCI We investigated the function of tumor suppressor p53 in regulating proliferation and function of T lymphocytes. These studies elucidate a critical role of p53 as a negative regulator of T cell proliferation. It is the termination of p53 elevation by TCR signaling that allows proliferative responses to occur enforcing antigen specificity. Preliminary studies of p53 effect on antigen-inexperienced and memory T cell repertoire have strongly suggested that p53 affects the threshold of TCR signaling required for activation of unprimed T cells by specific antigen and their subsequent differentiation into memory T cells. p53 thus appears to be an important regulator of antigen-specific T cell activation and in vivo response proliferation and differentiation. T cell-dependent germinal center (GC) responses require coordinated interactions of T cells with two distinct antigen-presenting cell populations (APCs) B cells and dendritic cells (DCs) in the presence of B7- and CD40-dependent costimulatory pathways. Conventional models describe the expression of both of these costimulatory molecules on the same APC both for T cell presentation and for cross-regulation of B7 and CD40 expression. Here we report that contrary to the conventional paradigm cellular requirements for B7 and CD40 expression were distinct for GC TFH GC B cell and high affinity antibody responses. B7 expression was required on DCs but not on B cells while CD40 was required on B cells but not DCs; and there was in fact no requirement for co-expression of B7 and CD40 on the same cell for GC responses. Our findings thus identify a much revised model for costimulatory function in the GC response with crucial and distinct contributions of B7- and CD40-dependent pathways expressed by distinct APC populations. T cell-dependent germinal center (GC) responses require coordinated interactions of T cells with two distinct antigen-presenting cell populations (APCs)-B cells and dendritic cells (DCs)-in the presence of B7- and CD40-dependent costimulatory pathways. T-APC interactions with both populations are generally considered to depend on similar molecular mechanisms including the involvement of these two costimulatory receptor-ligand pairs but direct assessment of the role of each pathway in germinal center-dependent adaptive responses has not been conducted. Here we have utilized models that enable the selective elimination of CD28-B7 and CD40-CD40L signaling during T-DC vs. T-B antigen-driven interactions to probe this issue. In contrast to prevailing views that both pathways are critical for productive T-dependent humoral immunity at both the early (T-DC) and late (T-B) phases of the response we found that the cellular requirements for B7 and CD40 expression were distinct. B7 expression was required on DCs but not on B cells while CD40 was required on B cells but not DCs. These data emphasize the emerging evidence that distinct molecular rules apply to CD4+ T cell-myeloid cell and CD4+ T cell-lymphoid cell interactions with important implications for understanding how to optimize or inhibit these events to promote vaccine responses or limit autoimmunity To further elucidate the role of CD40-CD40L interactions in multiple T cell-developmental and functional events we have generated unique mouse genetic models. To analyze the role of signaling through CD40 on diverse cell populations we have produced by CRISPR-Cas9 a set of CD40 cytoplasmic domain mutants that disrupt putative binding sites for TRAFs 23 and 6 and have generated initial data indicating differential dependence of these cytoplasmic domains for diverse functions including B cell germinal center responses Ig class switching and affinity maturation; susceptibility to experimental autoimmune encephalomyelitis (EAE); in vivo T cell cytokine responses; and iNKT cell selection. Costimulatory CD40 plays an essential role in autoimmune disease models including EAE a murine model of human multiple sclerosis (MS). However the mechanism underlying CD40 function are not well defined in these processes. Conditional knockout of CD40 on either dendritic cells (DCs) or B cells led to profoundly reduced severity of EAE induced by recombinant human MOG (rhMOG). CD40 expression on DCs but not on B cells was required for priming of pathogenic T helper (Th) cells in peripheral draining lymph nodes and for appearance of these pathogenic T cells in the CNS. In marked contrast CD40 on B cells but not on DCs was essential for class-switched MOG-specific antibody production. The distinct function of CD40 on B cells and DC was confirmed by the ability of transferred MOG-immune serum to restore sensitivity to EAE in mice lacking CD40 on B cells but not in mice lacking CD40 on DC. Thus CD40 expressed on B cells and on DC provides distinct and complementary pathways essential for EAE pathogenesis providing multiple targets for intervention in EAE and potentially for MS and other autoimmune diseases. Our studies of EAE have identified requirements for CD40 expression by B cells and DC for distinct functions in disease induction. They have further identified requirements for distinct cytoplasmic domains of CD40 in EAE. To determine CD40L function we are in the process of generating mutants that express only cell surface or only secreted forms of CD40L. Invariant natural killer T (iNKT) cells develop in the thymus where iNKT cell development depends on TCR recognition of CD1d ligand on CD4/CD8 double positive thymocytes. We previously reported that B7-CD28 co-stimulation is required for thymic iNKT cell development while underlying cellular and molecular mechanisms are largely not understood. Here we report the unexpected finding that CD28 expression on CD1d expressing antigen presenting T cells is required for thymic iNKT cell development. Mechanistically antigen-presenting T cells provide costimulation through a novel mechanism acquiring B7 molecule via CD28-dependent trogocytosis from B7-expressing thymic epithelial cell DC and B cells and providing critical B7 co-stimulation to developing iNKT cells. Thus these studies demonstrate a previously unappreciated mechanism of B7 co-stimulation in thymic T cell development by antigen-presenting T cells. We have most recently identified an additional mechanism of iNKT regulation demonstrating a role for p53 selectively in generation of the iNKT17 subset. We have in addition initiated studies of generation of mucosal-associated invariant (MAIT) cells another non-conventional T cell population with semi-invariant TCR expression. Initial findings include a functional role of B7 costimulation in thymic MAIT cell generation. 540649 +Autoimmune Disease; Cancer Address;Affect;Algorithms;Amino Acids;Antigen-Presenting Cells;Antigens;Autoantigens;Autoimmunity;B-Lymphocytes;CD28 gene;CD40 Ligand;CD80 gene;CD86 gene;CD8B1 gene;Cell physiology;Cells;Characteristics;Clonal Deletion;Dangerousness;Defect;Dendritic Cells;Development;Epithelial Cells;Generations;High-Throughput Nucleotide Sequencing;Immunity;Knockout Mice;Machine Learning;Maintenance;Mature Thymocyte;Mediating;Mediator of activation protein;Methods;Molecular;Mouse Strains;Mus;Organogenesis;Pathway interactions;Peptide/MHC Complex;Peripheral;Play;Population;Prevention;Process;Property;Regulatory T-Lymphocyte;Repression;Role;Self Tolerance;Shapes;Signal Transduction;Specificity;T cell regulation;T cell response;T-Lymphocyte;TNFRSF5 gene;TNFSF5 gene;Testing;Thymic epithelial cell;Thymus Gland;Time;Tissues;Transgenic Mice;antigen-specific T cells;autoreactive T cell;autoreactivity;base;cancer cell;cell type;central tolerance;conditional knockout;cytokine;differential expression;machine learning algorithm;novel;pathogen;receptor;response;thymocyte;transcriptome sequencing Analysis of the T Cell Repertoire n/a NCI 10702304 1ZIABC009265-40 1 ZIA BC 9265 40 2405210 "HODES, RICHARD J." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 101371 NCI "Mice with genetically altered expression of costimulatory molecules CD80 (B7-1) CD86 (B7-2) and CD40 or of the costimulatory receptors CD28 and CD154 (CD40 ligand) have been analyzed for thymic development and T cell repertoire. Our findings identify a previously unappreciated role of redundant costimulatory pathways mediating an essential function in thymic development. The effect of these costimulatory pathways on selection of the T cell repertoire was studied in parallel. Two pathways of negative selection have been identified. One pathway is CD40L-dependent and acts at a relatively early stage in intra-thymic development and is mediated by a non-cell-autonomous mechanism. The second is CD40L-independent and occurs later in intra-thymic or post-thymic development. Interestingly we have observed that when negative selection is abrogated by inactivation of the CD40L pathway functional self tolerance is maintained by a non-deletional mechanism. This non-deletional tolerance is mediated by a CD28-dependent pathway. Thus redundant pathways exist to protect against self reactivity in the thymus and disruption of both C40L (deletional) and CD28 (non-deletional) mechanisms of self tolerance results in a population of highly self-reactive thymic T cells. We have analyzed the signals that mediate T cell-epithelial cell cross-talk during thymic development. We have observed that CD28 costimulation is essential for optimal induction of TNFab in single-positive (SP) thymocytes and that combined defects in CD40-CD40L and TNFab pathways result in defects in medullary thymic eipthelial cell (mTEC) development that are similar to those in combined CD40-CD40L and CD28-B7 disruption and are in fact as profound as those seen in complete absence of mature SP TCRab thymocytes. These findings indicate a novel role for CD28-B7 in addition to other mediators of T cell-TEC cross-talk and demonstrate that any and all signals provided by mature thymocytes for mTEC development are provided by activation of RelB-dependent alternative NFkB signaling. Generation of the T cell repertoire requires positive selection of cells expressing TCR capable of recognizing foreign antigens but negatively selected to eliminate cells with potentially dangerous specificity against normal self antigens. The function of costimulatory CD28-B7 and CD40-CD40L pathways in this repertoire selection has not been fully elucidated. We have initiated studies using peptide-MHC tetramers to identify antigen-specific T cells and have generated the first conditional knockouts for B7 and CD40 to analyze cell type-specific function of these costimulatory pathways in repertoire selection. Generation of the T cell repertoire requires positive selection of cells expressing TCR capable of recognizing foreign antigens but negatively selected to eliminate cells with potentially dangerous specificity against normal self antigens. The function of costimulatory CD28-B7 and CD40-CD40L pathways in this repertoire selection has not been fully elucidated. We have used peptide-MHC tetramers to identify antigen-specific T cells and have generated the first conditional knockouts for B7 and CD40 to analyze cell type-specific function of these costimulatory pathways in repertoire selection.Thymic central tolerance is critical for the prevention of autoimmunity. However the underlying molecular and cellular mechanisms mediating this tolerance are not fully understood. We have analyzed the requirements for B7-CD28 co-stimulation and for B7 expression by specific antigen-presenting cell (APC) types for thymic clonal deletion and Treg cell generation of endogenous tissue-restricted-antigen (TRA)-specific thymocytes. We have employed p-MHC tetramers to identify and track T cells with specificity for specific endogenous tissue-restricted antigens and our recently generated conditional B7 knockout mouse strains to identify APC requirements for Treg generation and for clonal deletion of TRA-reactive cells. Our findings determined that: 1) both clonal deletion and Treg cell generation of TRA-specific thymocytes are B7-CD28-dependent; 2) clonal deletion and Treg cell generation differ in their CD28 signaling domain requirements ; and 3) the role of B7-expressing dendritic cells (DC) B cells and thymic epithelial cells (TEC) can differ in B7-dependent clonal deletion versus Treg cell generation. In the absence of B7-CD28 co-stimulation mature TRA-specific Tconv cells populated the periphery in increased numbers and were capable of mediating destructive autoimmunity. Our findings reveal a previously unappreciated role of B7-CD28 co-stimulation in shaping the T cell repertoire through thymic clonal deletion and Treg cell generation with distinct requirements of CD28 signaling and B7-expressing APC. The ability to generate a rapid and sustained T cell response to external pathogens and transformed cancer cells is essential for protection of the host. At the same time deletion of autoreactive T cells during development and repression of excessive or autoreactive responses in peripheral tissues is essential to proper T cell protective function. This duality in regulation of T cell function is accomplished by two types of T cells: conventional T cells (Tconv) that provide ""helper"" (CD4+) and ""killer"" (CD8+) functions and regulatory T cells (Treg) that control Tconv T cell-dependent responses. Treg cells have been assigned to two subsets based on the origin of their generation: thymic (or natural) Treg (tTreg) that develop in the thymus and peripheral Treg (pTreg) generated in periphery from Tconv cells under specific conditions. The development of tTreg appears to require both TCR and other factors such as costimulatory receptors and cytokines but the precise mechanisms of tTreg generation have not been fully elucidated. We addressed the role of TCR sequence in determining whether T cells develop into tTreg or Tconv lineages. We carried out a comprehensive comparison of both TCRa and TCRb sequences of thymic tTreg and Tconv cells using a UMI based 5' smart switch method. This comparison revealed that although many sequences were unique to either Treg or Tconv a substantial proportion of TCaR (14-20%) and TCRb (8-22%) sequences from tTreg were also found in Tconv cells of two normal mouse strains. TCRa analysis of a TCRb transgenic mouse line revealed an even higher proportion (71%) of sequences found in tTreg that were also found in Tconv cells. Interestingly these shared TCRa clonotypes that were common to tTreg and Tconv cells were significantly more abundant than non-shared TCRa sequences of tTreg and Tconv cells. Finally we used machine learning to develop an algorithm that was capable of distinguishing non-shared TCRa and TCRb sequences expressed by tTreg from those of Tconv cells and in addition found that specific amino acid trimers were differentially expressed in either tTreg or Tconv cells. Taken together our findings identify TCR sequence characteristics that bias to tTreg or Tconv fate in addition to factors that can drive cells with identical TCR sequence into either Tconv or tTreg lineages. These findings identify two populations of tTreg one in which Treg fate is determined by unique properties of the TCR and another with TCR properties characteristic of Tconv cells with tTreg determined by TCR-independent factors. Ongoing studies combining single cell TCR expression and RNAseq will characterize in detail the effect of costimulation on repertoire selection." 101371 +Cancer; Genetics Affect;Alleles;Amino Acid Motifs;Anchorage-Independent Growth;Attenuated;Binding;Binding Sites;Biological;Biological Process;CDK5 gene;Cells;Code;DLC1 gene;DLEC1 gene;Data;EZH2 gene;Epigenetic Process;Focal Adhesion Kinase 1;Gene Deletion;Gene Expression;Genes;Goals;Growth;Guanosine Triphosphate;Half-Life;Histone H3;In Vitro;Intervention;Lesion;Ligands;Lipids;Malignant Neoplasms;Methylation;Missense Mutation;Molecular Biology;Molecular Conformation;Mutate;N-terminal;Neoplasms;Nuclear Protein;Oncogenes;Pathogenesis;Phosphorylation;Phosphotransferases;Physiological;Point Mutation;Post-Translational Protein Processing;Process;Protein Methyltransferases;Proteins;Proto-Oncogene Proteins c-akt;Receptor Protein-Tyrosine Kinases;Regulation;Research;Role;Serine;Signaling Molecule;Talin;The Cancer Genome Atlas;Therapeutic;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tyrosine;antitumor effect;attenuation;cancer type;caveolin 1;cell motility;experimental analysis;in vivo;inhibitor;kinase inhibitor;mRNA Expression;multicatalytic endopeptidase complex;mutant;non-genetic;overexpression;rho;rho GTPase-activating protein;src-Family Kinases;tensin;tumor;tumor xenograft Tumor gene expression in vitro and in vivo n/a NCI 10702302 1ZIABC008905-41 1 ZIA BC 8905 41 2093670 "LOWY, DOUGLAS R." Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1250906 NCI Our growth regulation research has been concerned with oncogenes as positive regulators and tumor suppressor genes as negative regulators of normal and neoplastic growth. The main current project is focused on the molecular biology of the tumor suppressor gene DLC1 including the targets that regulate it and the targets that it regulates. DLC1 is inactivated frequently in a wide range of tumors but many aspects of its mechanism of action remain incompletely understood. DLC1 negatively regulates Rho via its Rho-GAP activity and also encodes other activities. A major hypothesis is that DLC1 is frequently inactivated in cancer because it encodes a biologically important multifunctional protein. In support of this possibility we have previously determined that DLC1 interacts with: 1) the tensin proteins via an N-terminal region of DLC1 for which no function had been previously identified; 2) focal adhesion kinase (FAK) and talin via a shared 8 amino acid motif; and 3) caveolin-1 (CAV-1) via the StAR-related lipid transfer (START) domain near the C-terminus of DLC1. DLC1 mutant analysis indicated that the binding sites for each of these interactions contributed to the growth suppressor function of DLC1 but that reduced binding seen with the mutants did not affect in vivo Rho-GAP activity of DLC1. These studies validate the hypothesis that DLC1 is a multifunctional protein whose biological activity depends both on its Rho-GAP activity and its ability to bind a variety of signaling molecules. We have also evaluated 12 cancer types in TCGA for the presence of point mutations in DLC1 and 9 other Rho-GAPs. The results indicate that DLC1 is the Rho-GAP that is mutated most frequently with 5-8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore 20-26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated seven of nine mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Point mutations in DLC1 were scattered throughout the coding sequences of the gene implying that important biological functions are present throughout the protein. These results indicate that point mutation in DLC1 is an important mechanism for its decreased function in cancer in addition to gene deletion and epigenetic or other non-genetic changes. We have characterized how post-translational modifications of DLC1 especially phosphorylations may affect its activity. We first identified CDK5 a cytoplasmic kinase whose physiologic role promotes differentiation as a major activator of DLC1 which occurs via CDK5 phosphorylation of 4 serines in DLC1. When these serines which are located N-terminal to the RHO-GAP domain of DLC1 are not phosphorylated the N-terminus binds to the Rho-GAP domain which places DLC1 in a closed inactive conformation. When the serines are phosphorylated it decreases the interaction of the N-terminus with the Rho-GAP domain which places DLC1 in an open active conformation. AKT is another kinase that directly phosphorylates DLC1 on 3 serines located N-terminal to the Rho-GAP domain. The effects of AKT antagonize those of CDK5 in that the AKT phosphorylations attenuate the Rho-GAP and tumor suppressor activities of DLC1 by changing DLC1 from an open active configuration to a closed inactive configuration. AKT lies downstream from receptor tyrosine kinases (RTKs) and our data indicate that increased Rho-GTP following stimulation of cells with RTK ligands is attributable to the activation of AKT and its attenuation of DLC1. We also identified SRC family kinases (SFKs) as direct targets for phosphorylating DLC1 on two tyrosines which attenuate the RHO-GAP and tumor suppressor activities of DLC1. One tyrosine is located in the RHO-GAP domain and its phosphorylation by SFKs reduces the RHO-GAP function of DLC1. The other tyrosine is located near the sequence required for binding tensin and its phosphorylation reduces tensin binding. The findings with AKT and SFKs may have therapeutic potential as treatment of tumor xenografts with AKT and/or SFK inhibitors has much greater antitumor activity against tumors that express DLC1 compared with isogenic tumors that do not express DLC1. The high antitumor activity from AKT and/or SFK inhibition is associated with loss of phosphorylation of the DLC1 by AKT and/or SFK together with reactivation of the RHO-GAP and tumor suppressor activities of DLC1. We have identified methylation of DLC1 as yet another biologically important post-translational modification. The methylation is attributable to cytoplasmic EZH2 a protein methylase that is overexpressed in many cancers and known mainly as a nuclear protein that regulates mRNA expression because it methylates Histone-H3. DLC1 methylation enables ubiquitnation of the methylated residue and proteasome-dependent degradation of DLC1. This multistep process means DLC1 has a shortened half-life in many tumors and is even absent in some. This process is reversible and inhibition of EZH2 ubiqutination or the proteasome can stabilize the protein. For EZH2 this is conceptually distinct from using its inhibition to change mRNA expression. By itself increasing DLC1 protein levels does not have a major effect on growth regulation but adding an AKT inhibitor and/or SRC inhibitor strongly reduces growth. This effect depends on DLC1 protein and is more than a correlation as disrupting the DLC1 alleles abolishes most of the antitumor effect. 1250906 +Biotechnology; Cancer Antibodies;Antibody Specificity;Antibody-drug conjugates;Antineoplastic Agents;Apoptosis;Apoptotic;BCL-2 Protein;Bacteria;Bacterial Toxins;Binding;Cancer Model;Cells;Cessation of life;Cholera Toxin;Clinic;Complement;Cytosol;Cytotoxic agent;Data;Drug Screening;Drug resistance;Effectiveness;Enzymes;Epidermal Growth Factor Receptor;Eukaryotic Cell;Exhibits;Exotoxins;Genes;Goals;Human;Immunoglobulin Fragments;Immunotoxins;Inflammatory;Investigation;KDR gene;Link;Malignant Neoplasms;Mammalian Cell;Monoclonal Antibodies;Nature;Normal Cell;Pathway interactions;Peptide Elongation Factor 2;Pharmaceutical Preparations;Population;Protein Biosynthesis;Proteins;Pseudomonas;RNA Interference;Recombinants;Reporting;Resistance;Toxin;Vibrio cholerae;Xenograft Model;base;cancer cell;cancer therapy;cell growth;cell killing;chemotherapy;colon cancer cell line;density;design;experimental study;gene product;in vivo;inhibitor;mimetics;mutant;neutralizing antibody;pre-clinical;preclinical development;programs;receptor;response;screening;targeted agent;targeted treatment;therapy development;tissue culture;toxin V;whole genome Bio-Therapies for the Treatment of Cancer n/a NCI 10702301 1ZIABC008757-35 1 ZIA BC 8757 35 6569148 "FITZGERALD, DAVID " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1559704 NCI We use bacterial toxins as killing agents to eliminate cancer cells. To accomplish this we modify the toxin so it no longer binds via its own cell-binding domain and substitute in place of the binding domain a monoclonal antibody. The antibody is chosen to bind cancer cells preferentially over normal cells. These toxin-antibody molecules are called immunotoxins. Immunotoxins are promising but imperfect anticancer agents. Our goal is to understand the interaction of various toxins with eukaryotic cells and use this information to design better agents for treating cancer. To study interactions we add toxins to mammalian cells and study the pathway of death. In tracking the killing of cancer cells by immunotoxins we made the observation that cells grown to high density are resistant to killing. We wish to understand this phenomenon and determine its relevance for cancer therapy in general. A convenient and potentially useful way to study cell-killing pathways is to use RNA interference to identify pathways that participate in toxin delivery to the cytosol - where it acts. Recently we initiated studies with a newly described toxin from V cholera called Vibrio Cholera Exotoxin (CET). This toxin is related to the exotoxin from Pseudomonas exhibiting about 50% identity in selected domains (domains II and III). However antibodies that neutralize the exotoxin from Pseudomonas do not neutralize CET despite the close similarity. Truncated versions of Pseudomonas Exotoxin (PE) have been fused with antibody fragments to produce potent cytotoxic agents termed recombinant immunotoxins. These agents are targeted to kill cancer cells based on the binding specificity of the antibody fragment. Potency is derived from the enzymatic nature of the toxin as it translocates to the cytosol ADP-ribosylates elongation factor 2 and terminates the synthesis of new cellular protein. Most prior investigations reported that PE and PE-immunotoxins kill cells via apoptosis. Here we report that PE and PE immunotoxin inhibit protein synthesis and cell growth of colon cancer cell lines but do not provoke an apoptotic response. However the addition of the BH3-only mimetic ABT-737 in combination with the immunotoxin produces a profound apoptotic response in these cells that neither agent alone can achieve. Tissue culture data for ABT-737 activity has now been confirmed in xenograft models confirming this approach as a viable approach for overcoming resistance to immunotoxin action. We are conducting whole genome screens using RNAi agents to silence all human genes. Immunotoxin is then added to RNAi-treated cells with the goal of identifying genes that inhibit immunotoxin action. These inhibitory genes are identified because when silenced cells display greater sensitivity to immunotoxin action. Likewise we conduct large scale drug screens: again to identify and inhibit gene products that reduce the effectiveness of immunotoxin action. These are likely to include gene products that interfere with cell killing and might also be useful in reversing some forms of drug resistance to chemotherapy. Our overarching goal is to make our immunotoxin program more effective by eliminating the cellular barriers to targeted therapy. Recently we have investigated the utility of using JAK/STAT inhibitors to enhance immunotoxin activity in vivo. The use of tofacitinib has produced promising results with several immunotoxins and an antibody-drug conjugate. The mechanism of enhancement is currently linked to changes in the population of inflammatory cells. We have also identified VEGFR inhibitors as agents that routinely enhance immunotoxin killing in several cancer models. Here the mechanism is less clear but we continue to study the problem with a view to establishing optimal combinations for enhancing immunotoxin activity. We produced seven monoclonal antibodies to EGFR. One of these has proved particularly useful and is now being used to generate antibody drug conjugates. 1559704 +Cancer; Digestive Diseases; Genetics; Health Disparities; Minority Health Adult;Anemia;Attention deficit hyperactivity disorder;Attenuated;Binding;Biological Assay;Bone Development;Calmodulin;Caveolae;Cell Differentiation process;Clinical;Collagen;Colon;Communication;Complex;Constipation;Defect;Development;Disease;Electrolytes;Epithelial;Erythroid;Erythropoiesis;Exhibits;Feces;Gap Junctions;Gene Expression;Gene Expression Regulation;Genes;Genomics;Goals;Growth;Growth and Development function;Health;Histologic;Homeostasis;Human;Impairment;Interstitial Cell of Cajal;Intestines;Lamina Propria;Lead;Liquid substance;Maintenance;Mediating;Metabolic;Modeling;Molecular;Mus;Muscle Cells;Muscle Fibers;Muscularis Mucosa;Mutation;Myosin Light Chain Kinase;Myosin Light Chains;Nuclear;Nuclear Hormone Receptors;Pathologic;Patients;Protein Isoforms;Proto-Oncogene Protein c-kit;Rectum;Regulation;Reporting;Repression;Research;Resistance;Role;Serum;Signal Transduction;Smooth Muscle;Structure of fontanel of skull;Submucosa;Surgical sutures;Symptoms;THRA gene;THRB gene;Thyroid Hormone Receptor;Thyroid Hormone Receptor Gene;Thyroid Hormones;Thyrotropin;Time;Tissues;Transcriptional Regulation;Transmission Electron Microscopy;Villus;Water;bone;bone age;cranium;fluorescence imaging;genetic corepressor;hearing impairment;hormone response element;human disease;insight;lucifer yellow;molecular targeted therapies;mouse model;mutant;postnatal;recruit;rectal;small molecule;stem cell proliferation Thyroid Hormone Nuclear Receptors in Health and Disease n/a NCI 10702298 1ZIABC008752-42 1 ZIA BC 8752 42 6569140 "CHENG, SHEUE-YANN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 880039 NCI Using a mouse model of RTHalpha (Thra1PV/+ mice) we aimed to understand the molecular basis underlying the severe constipation observed in patients. We used histopathological analysis confocal fluorescence imaging transmission electron microscopy (TEM) and gene expression profiles to comprehensively analyze the colonic abnormalities of Thra1PV/+ mouse. We found a significant increase in colonic transit time and decrease stool water content in Thra1PV/+ mouse mimicking constipation as found in patients. Histopathological analysis showed expanded lamina propria filled with interstitium fluid between crypt columns enlarged muscularis mucosa and increased content of collagen in expanded submucosa. TEM analysis revealed shorter muscle fibers with wider gap junctions between muscle cells fewer caveolae and hypoplastic interstitial cells of Cajal (ICC) in the rectal smooth muscles of Thra1PV/+ mice. These abnormal histological manifestations suggested defective intercellular transfer of small molecules electrolytes and signals for communication among muscles cells validated by Lucifer Yellow transferring assays. Expression of key smooth muscle contractility regulators such as calmodulin myosin light-chain kinase and phosphorylated myosin light chain was markedly lower and c-KIT signaling in ICC was attenuated resulting in decreased contractility of the rectal smooth muscles of Thra1PV/+ mice. Collectively these abnormal histopathological alterations and diminished contractility regulators led to the constipation exhibited in patients. This is the first demonstration that TRalpha mutants could act to cause abnormal rectum smooth muscle organization defects in intercellular exchange of small molecules and decreased expression of contractility regulators to weaken the contractility of rectal smooth muscles. These findings provide new insights into the molecular basis underlying constipation found in RTHalpha patients. 880039 +Biotechnology; Cancer; Genetics 3-Dimensional;Activation Analysis;Affect;Affinity;Animal Model;Architecture;Bacterial Chromosomes;Bacterial Physiology;Bacteriophage lambda;Bacteriophages;Base Pairing;Binding;Biochemical;Biological Models;Biology;Bundling;Cell Cycle;Cells;Chromatin Loop;Chromosome Structures;Chromosomes;Color;Complex;Computer Models;Cruciform DNA;DNA;DNA Binding;DNA Structure;DNA-Directed RNA Polymerase;Data;Development;Dissociation;Electrostatics;Environment;Escherichia coli;Eubacterium;Exhibits;Fluorescence Microscopy;Future;Gene Activation;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genetic;Genetic Transcription;Goals;Grain;HU Protein;Histones;Homeostasis;Image;In Vitro;Investigation;Ionic Strengths;K-18 conjugate;Kinetics;Label;Laboratories;Lysine;Lytic;Maintenance;Manuscripts;Maps;Measurement;Mediating;Microscopy;Molecular;Molecular Biology;Mutate;Mutation;Operon;Pattern;Physiological;Physiological Processes;Play;Positioning Attribute;Proline;Property;Prophages;Proteins;Regulation;Repression;Research;Role;Site;Structure;Superhelical DNA;Surface;System;Systems Analysis;Systems Biology;Techniques;Therapeutic;Transcriptional Regulation;Work;X-Ray Tomography;antimicrobial;antimicrobial drug;base;biophysical techniques;cancer cell;cell growth;design;developmental genetics;environmental adaptation;experimental study;fluidity;gene repression;inhibitor;inorganic phosphate;ionic bond;kinked DNA;mathematical methods;microbial;mutant;novel;pathogen;prevent;promoter;response;single molecule;small molecule;three dimensional structure;transcriptome;viscoelasticity Regulation of Gene Transcription n/a NCI 10702297 1ZIABC008751-42 1 ZIA BC 8751 42 6129912 "ADHYA, SANKAR " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1079030 NCI "Part A. Chromosome structure and function. From our studies of mechanisms of gene regulation we have previously proposed that the bacterial chromosome (nucleoid) has a condition dependent defined structure that dictates gene expression. HU is the most conserved nucleoid-associated protein in eubacteria but how it impacts global chromosome organization and gene expression is poorly understood. (i) Using single-molecule tracking we demonstrate that HU exhibits nonspecific weak and transitory interactions with the chromosomal DNA. These interactions are largely mediated by three conserved surface-exposed lysine residues (triK) which were previously shown to be responsible for nonspecific binding to DNA. The loss of these weak transitory interactions in a HUa(triKA) mutant results in an over-condensed and mis-segregated nucleoid. Mutating a conserved proline residue (P63A) in the HUa subunit deleting the HUb subunit or deleting nucleoid-associated naRNAs each previously implicated in HU's high-affinity binding to kinked or cruciform DNA leads to less dramatically altered interacting dynamics of HU compared to the HUa(triKA) mutant but highly expanded nucleoids. Our results suggest HU plays a dual role in maintaining proper nucleoid volume through its differential interactions with chromosomal DNA. On the one hand HU compacts the nucleoid through specific DNA structure-binding interactions. On the other hand it decondenses the nucleoid through many nonspecific weak and transitory interactions with the bulk chromosome. Such dynamic interactions may contribute to the viscoelastic properties and fluidity of the bacterial nucleoid to facilitate proper chromosome functions. (ii) By imaging of near-native unlabeled E. coli cells by soft X-ray tomography we showed that HU remodels nucleoids by promoting the formation of a dense condensed core surrounded by less condensed isolated domains. Nucleoid remodeling during cell growth and environmental adaptation correlate with pH and ionic strength controlled molecular switch that regulated HUaa dependent intermolecular DNA bundling. Through crystallographic and solution-based studies we show that these effects mechanistically rely on HUaa promiscuity in forming multiple electrostatically driven multimerization interfaces. Changes in DNA bundling consequently affects gene expression globally likely by constrained DNA supercoiling. Taken together our findings unveil a critical function of HU-DNA interaction in nucleoid remodeling that may serve as a general microbial mechanism for transcriptional regulation to synchronize genetic responses during the cell cycle and adapt to changing environments. (iii) We strived to elucidate how the chromosome's three-dimensional architecture is organized and maintained in bacterial cells. Using fluorescence microscopy techniques we are probing the organization of the E. coli chromosome by directly visualizing the positions of specifically labeled DNA sites within living cells. Using two orthogonal ParB - parS systems we were able to simultaneously label two DNA sites in two colors in the same E. coli strain. Our labeling strategy had a fixed locus as a control point in all strains and additionally had a 'moving' locus that maps the entire chromosome in coarse-grain. Data from our experiments preliminarily suggested that there is a correlation between the linear (genetic) distance separation between DNA sites and their spatial separation. Eventually with the help of computational modeling we hope to simulate the three-dimensional organization of the chromosome from a wealth of carefully conducted distance measurements between different DNA loci in living cells. (iv) We have additionally demonstrated separate physiological roles of specific and non-specific DNA binding of the histone-like protein HU in E. coli. A manuscript is being prepared. in bacterial physiology from maintenance of chromosome structure to regulation of gene transcription. HU is essential in many pathogens making it an attractive target for developing anti-microbial therapeutics. A mechanistic understanding of HU DNA binding and its regulation of physiological processes will aid in the design and development of small molecule HU inhibitors. We have used Escherichia coli as a model organism to investigate how HU interacts with chromosomal DNA and regulates various physiological processes. In E. coli HU binds to DNA in two ways: (i) with low affinity to any DNA (non-specific) through three surface-exposed lysine residues (K3 K18 and K83) that make ionic bonds with DNA phosphates; (ii) with high affinity to contorted DNA of given structures containing a pair of kinks (structure-specific) through conserved proline residues (P63) that mediate specific binding by inducing and/or stabilizing the kinks. We recently demonstrated that HU interacts with chromosomal DNA with rapid association/dissociation kinetics largely through its non-specific binding mediated by the lysine residues. This provides evidence that the overall association of HU to the chromosome is through non-specific binding. Incidentally HU is essential in many pathogens making it a target for developing anti-microbial drugs. A mechanistic understanding of HU DNA binding will aid in the design and development of HU inhibitors. Part B. Gene regulation in Bacteriophage Lambda and Gal operon: The current year we have made more progress in our work with phage Lambda. Investigation of RNA Polymerase & CI repressor Interactions . One of the best understood systems in genetic regulatory biology is the so called ""genetic switch"". This determines the choice the phage-encoded CI repressor makes by binding cooperatively to two tripartite operators OL (OL1 OL2 & OL3) and OR (OR1 OR2 & OR3) in a defined pattern. Transcription at two lytic promoters PL and PR is blocked while transcription at lysogenic promoter PRM is activated and repressed at low CI and high CI concentrations respectively. The autoregulation of PRM is dependent on the interaction of RNA polymerase (RNAP) binding to the PRM promoter and CI binding to OR2. By using a purified in vitro transcription system we analyzed the activation complex between RNAP at PRM and CI at OR2 by DNA and protein mutations. We inserted 5-bp or deleted 1-bp DNA between OR2 & OR3 to change the angular orientation and distance between RNAP and CI. We also mutated E34K of CI which interacts with RNAP during the activation of PRM. We obtained unexpected findings. First a 1-bp DNA deletion of -34A of PRM resulted in the repression of PRM at the same CI concentration for the repression of PL and PR. This repression is depending on DNA looping and the binding of CI to OR2. Second a 5-bp DNA insertion between the PRM promoter site and OR2 site resulted in the repression of PRM at the same CI concentration for the repression of PL and PR. Third mutating E34K of CI which is involved in the activation complex resulted in the repression of PRM at the same CI concentration for the repression of PL and PR. Finally DNA looping enhances PRM activation and repression. Conclusion: Disruption of the activation complex between RNAP at PRM and CI at OR2 by mutating CI or inserting or deleting base pair to change the angular orientation and distance between RNAP and CI led to the repression of PRM. These unexpected results suggest that maybe RNAP is creating negative contacts with CI at OR2 preventing RNAP from escaping and repressing PRM. Future studies are being conducted to *TRUNCATED*" 1079030 +Cancer; Genetics 3' Untranslated Regions;5' Untranslated Regions;Acetates;Aerobic;Affect;Alleles;Anaerobic Bacteria;Antibiotics;Area;Bacteria;Bacteria sigma factor KatF protein;Behavior;Binding;Binding Sites;Biological Assay;C-terminal;Carbon;Catabolism;Cell Communication;Cells;Collaborations;Complex;Conflict (Psychology);Development;Dissection;Distal;Equilibrium;Escherichia coli;Eukaryotic Cell;Face;Family;Genes;Genetic Transcription;Genetic Translation;Goals;Growth;In Vitro;Investigation;Klebsiella;Laboratories;Libraries;Mediating;Membrane;Messenger RNA;Metabolism;Mismatch Repair;Molecular Chaperones;Mutagenesis;Mutation;National Center for Advancing Translational Sciences;National Institute of Child Health and Human Development;Nickel;Nutrient;Operon;Organism;Pathway interactions;Phase;Physiological;Plasmids;Play;Polyribonucleotide Nucleotidyltransferase;Porifera;Process;Protein Family;Proteins;RNA;RNA Binding;RNA Degradation;RNA Splicing;RNA Stability;Regulation;Regulatory Pathway;Reporter;Repression;Resistance;Ribose;Role;Running;Series;Sigma Factor;Signal Transduction;Signaling Molecule;Site;Small RNA;Stress;System;Translation Initiation;Translational Activation;Translations;Untranslated RNA;Virulence Factors;Work;acetyl phosphate;base;biological adaptation to stress;capsule;cell behavior;cell growth;endonuclease;falls;genetic regulatory protein;in vivo;insight;interest;member;mutant;novel;overexpression;pathogenic bacteria;response;screening;small molecule;symbiont;tool;transcription factor;transcriptome sequencing Bacterial Functions Involved in Cell Growth Control n/a NCI 10702296 1ZIABC008714-45 1 ZIA BC 8714 45 2402881 "GOTTESMAN, SUSAN " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1174466 NCI "Complex and rapidly adaptable regulatory networks allow bacteria such as E. coli to change metabolism to optimize growth and survival both aerobically and anaerobically in mammalian hosts and outside of the host and in response to a variety of stresses. In the last twenty years the important roles of small non-coding RNAs in regulation in all organisms have been recognized. Our laboratory in collaboration with others undertook two global searches for non-coding RNAs in E. coli contributing significantly to the 100-200 regulatory RNAs that are now known. A large number of these small RNAs (sRNAs) bind tightly to the RNA chaperone Hfq. We and others have shown that sRNAs that bind tightly to Hfq act by pairing with multiple target mRNAs regulating stability and translation of the mRNA either positively or negatively although some of these sRNAs also have additional roles. Our lab has studied many of these sRNAs in detail. Each sRNA is regulated by different stress conditions suggesting that the sRNA plays an important role in adapting to stress. We have also examined the mechanism by which Hfq operates to allow sRNAs to act. The lab continues to investigate the in vivo roles of small RNAs identifying the regulatory networks they participate in and their roles in those networks. Using our previously developed approaches for screening targets of interest and the sRNAs regulating them we continue to investigate regulatory pathways for sRNAs. mutS encoding a component of the mismatch repair system was found to be regulated by a small RNA ArcZ and somewhat surprisingly directly by Hfq in the absence of sRNAs dependent upon sites in the mutS 5'UTR. Hfq repression of MutS translation in stationary phase cells allows mutagenesis considered to be a form of bet-hedging as cells run out of nutrients. We are investigating whether Hfq regulates other genes in this sRNA-independent fashion using global RNA seq results in a set of Hfq mutants to find changes independent of the sRNA-binding face of Hfq. In another project a small RNA processed from the 3' UTR of an operon encoding TCA proteins was found to regulate levels of the signaling molecule acetyl phosphate and change flux through the ""acetate switch"". This work demonstrates the importance of previously unappreciated sRNAs made from 3' UTRs. The action of these small RNAs depends on the RNA chaperone Hfq a protein with homology to the Lsm and Sm families of eukaryotic proteins involved in RNA splicing and other functions. Hfq binds both to sRNAs and to mRNAs and stimulates pairing but exactly how it does this has not been clear. In a series of studies in collaboration with G. Storz (NICHD) and with S. Woodson (JHU) we have carried out an in vivo dissection of Hfq that has changed our understanding of how this protein acts with sRNAs. We have found that the Hfq-dependent sRNAs fall into two classes defined by their behavior in different Hfq mutants. All of these sRNAs depend on the known sRNA binding site on the proximal face of Hfq for in vivo stability. Class I sRNAs are rapidly degraded when used most likely dependent upon pairing; their targets bind to the distal face. Class II sRNAs are generally more stable than Class I sRNAs and their targets bind to rim sites in Hfq. These results help to explain previously observed competition between sRNAs and differential effects of different hfq alleles on different sRNA:mRNA pairs. The C-terminus of E. coli Hfq (CTD) is unstructured and its role has been unclear. In collaboration with S. Woodson we defined in vivo and in vitro roles for the CTD in stabilization and release of Class II sRNAs. In recent work in our lab in collaboration with the lab of G. Storz we have examined the global effect of deleting the CTD of Hfq and find only subtle effects on RNA accumulation. However in combination with mutations on the RNA binding faces of Hfq loss of the CTD can have synergistic effects. Our results define two independent roles for the CTD one involved in reinforcing the distal face RNA binding activity of Hfq and the second defined by mutations at the C-terminal tip of Hfq. These different roles help to explain why previous studies came to conflicting conclusions about the role of the CTD. We identify genetic changes (mutations or overexpression) that perturb expression of the RpoS general stress factor and use those to investigate regulatory pathways. In a screen of a plasmid library for negative regulation of RpoS we identified two novel regulators both of which appear to act by blocking the ability of sRNAs to activate RpoS translation. In the first case the mRNA for a gene of the ribose catabolism operon was found to act as a small RNA decoy; this mRNA is expressed at high levels whenever the cell encounters ribose. Thus RpoS is down-regulated when ribose is present. A poorly characterized transcription factor was also found to counteract translational activation of RpoS likely indirectly. Using a newly developed bi-functional fluorescent reporter we have identified novel regulators of sRNA stability and function including a new RNA sponge and two previously uncharacterized proteins. One of the new proteins the founding member of a family of proteins highly conserved in bacteria specifically targets a subset of sRNAs for degradation. It requires polynucleotide phosphorylase (PNPase) to do this suggesting that it may work in a complex with the PNPase. Work by others demonstrated a novel endonuclease activity for this family of proteins. The other new protein has global effects on sRNA-based regulation when overproduced. This is likely due to its direct interaction with the distal face of Hfq. Unexpectedly this protein a member of the broad transacetylase family is needed under anaerobic conditions for resistance to high levels of Nickel. Our results suggest multiple important activities for this protein. Each of these opens up previously unknown levels of regulation of sRNA function. Overall we have developed highly efficient in vivo tools for studying sRNAs and the networks they reside in. Our focus is increasingly on the role of the sRNAs in complex bacterial behavior investigations into the mechanism of sRNA function and dissecting of novel mechanisms for regulating translation initiation. We have also returned to our interest in the regulatory cascade affecting capsule synthesis in a collaboration with S. Buchanan and NCATs. The proteins in this cascade also regulate aspects of the bacterial response to membrane stress are needed for in vivo establishment of commensal growth and are important virulence factors in Klebsiella. Studies on the Interactions of the components of the regulatory cascade have changed our understanding of signal transduction through this system demonstrating that a critical negative regulator of signaling acts by interaction with a phosphorelay protein leading to a major revision in our understanding of signaling in this system and providing new insight into the general principles affecting related and widespread signaling systems. Recent work has demonstrated that signaling to this cascade can also take place independently of the best-characterized pathway. We have developed an efficient assay for screening for small molecules that activate or inactivate the cascade and have found evidence for effects of a variety of antibiotics in inducing the system. The long-term goal of this is to investigate the development of novel antibiotics that act by perturb *TRUNCATED*" 1174466 +Cancer; HIV/AIDS; Health Disparities; Infectious Diseases; Minority Health Acquired Immunodeficiency Syndrome;Adenosine;Anti-HIV Agents;Binding;Biological Assay;Cell Culture Techniques;Clinical;Collaborations;Complex;Cryoelectron Microscopy;DNA;Data;Drug resistance;Drug resistance pathway;Enzymes;Exhibits;FDA approved;Future;Generations;Geometry;Goals;HIV;HIV Integrase;HIV therapy;HIV-1;HIV-1 integrase;Hydration status;In Vitro;Individual;Infection;Institutes;Integrase;Integrase Inhibitors;Laboratories;Metals;Molecular Conformation;Mutate;Mutation;Naphthyridines;National Institute of Diabetes and Digestive and Kidney Diseases;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Play;Positioning Attribute;Process;Proteins;Reaction;Resistance;Reverse Transcriptase Inhibitors;Role;Salvage Therapy;Side;Structural Biologist;Structure;Variant;Viral;Virus;Water;Work;anti-viral efficacy;base;clinically relevant;cofactor;design;improved;inhibitor;mutant;next generation;novel;novel therapeutics;nucleoside analog;preclinical evaluation;resistance mechanism;response;treatment response;viral DNA Design and Synthesis of HIV Integrase as Potential Anti-AIDS Drugs n/a NCI 10702293 1ZIABC007363-28 1 ZIA BC 7363 28 6569096 "BURKE, TERRENCE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1362849 NCI "FDA-approved HIV-1 IN inhibitors belong to a class of drugs called ""integrase strand transfer inhibitors"" (INSTIs) due to their ability to preferentially block the enzymes strand transfer (ST) reaction as related to the enzymes 3-processing (3-P) reaction. The current recommended front-line therapy for HIV-1 infected patients is an INSTI either Dolutegravir (DTG) or Bictegravir (BIC) in combination with two nucleoside analog reverse transcriptase inhibitors. Both DTG and BIC potently inhibit most of the first generation INSTI-resistant IN mutants. Although little resistance has been selected by either BIC or DTG in treatment-naive patients patients who have preexisting first-generation INSTI-resistant mutants and have switched to a salvage therapy featuring DTG respond poorly emphasizing the importance of developing new and improved IN inhibitors. This adds impetus to a continuing need to develop next-generation agents that can retain high antiviral efficacy against emerging strains of INSTI-resistant virus. Utilizing my laboratorys design and synthetic capabilities we have teamed with pharmacologists (Dr. Yves Pommier NCI) and virologists (Drs. Hughes and Eric Freed NCI) to develop a new genre of INSTIs. We have examined our best inhibitors side by side with the clinically relevant INSTIs using a single round infection assay against panel of new IN-resistant mutants that were selected in vitro with DTG BIC and CAB. Of these three INSTIs BIC and our compounds had the broadest efficacy and were superior to DTG. In further collaborations with structural biologists (Dr. Robert Craigie NIDDK Dr. Dmitry Lyumkis the Salk Institute Dr. Cherepanov the Francis Crick Institute UK) we have performed studies to better understand the interactions of INSTIs with intasomes (multimeric integrase with DNA substrate and metal cofactor) and to clarify the roles that mutations play in downregulating these interactions. Cryo-electron microscopy (Cryo-EM) has played a key role in these efforts. Cryo-EM structures of our best INSTIs bound to HIV-1 intasomes revealed a complex and dynamic network of water molecules surrounding bound INSTIs with many of these waters appearing to be conserved and occupying similar positions in the unliganded and INSTI-bound structures. However some waters are displaced or shifted as a consequence of binding of our INSTI; others are found only when INSTIs are bound suggesting that the conformational changes induced by the binding stabilize their position. We concluded that within the ""substrate envelope"" (the region defined by the binding of host and viral DNA) differences in geometry of the catalytic pockets their overall volume the nearby patterns of hydration among other features all matter for understanding INSTI interactions. Most recently we have partnered with Dr. Lyumkis to employ cryo-EM to determine how INSTIs interact with INSTI-resistant intasome mutants and elucidate the mechanisms by which resistance to these drugs emerges. The focus of these efforts is to provide a mechanistic understanding of both why and how select viral resistant variants that arise in response to the clinically used DTG as well as our best in-house compound which is currently under pre-clinical evaluation by the NCI. This collaboration is identifying and analyzing novel mechanisms and pathways of drug resistance that arise in response to treatment with 2nd generation drugs highlighting both primary and compensatory mutations and providing strategies to predict future variants. Our work will elucidate the structural basis for mechanisms underlying the superior potency of novel compounds against resistant mutant forms of IN. There are four primary pathways through which IN resistance occurs in response to therapy with the potent INSTI DTG which involve these changes: Q148H/K/R N155H G118R and R263K. Substitutions at one of these positions usually arise first both in patients and in cell culture and can cause a major loss of INSTI potency. There are 20 additional positions where a residue can be mutated to give rise to more complex IN mutants. This collectively amounts to hundreds of possible combinations. The Hughes laboratory has determined antiviral EC50 values against viral constructs having the triple mutant E138K/G140A/Q148K and found that our INSTI 4d (XZ426) has an EC50 that is 20-fold lower than that of DTG. To understand the basis of this increased potency Dr. Craigie has prepared HIV intasomes bearing these three triple mutations. Dr. Lyumkis has determined structures of Dr. Craigies triple mutant intasomes bound to either to DTG or to our current best INSTI. Although the binding modes of both INSTIs and the configuration of individual protein residues are similar the terminal adenosine of vDNA exhibits a stacked configuration in the context of our INSTI but an unstacked configuration in the context of DTG. These data suggest that adenosine stacking is a real phenomenon that specifically enhances the binding of our naphthyridine-based INSTIs which may contribute to the improved ability of our INSTI to retain antiviral efficacy against this (and perhaps other) mutant(s)." 1362849 +Cancer Advanced Development;Affinity;Aldehydes;Amines;Amino Acid Sequence;Antineoplastic Agents;Area;Benzoic Acids;Binding;Biochemical;C-terminal;Catalytic Domain;Cell division;Clinical Trials;Collaborations;Complex;Crystallization;DNA;DNA Repair Enzymes;Development;Docking;Drug resistance;Elements;Exhibits;Goals;Hot Spot;Hydrolysis;Imidazole;Label;Laboratories;Legal patent;Libraries;Ligand Binding;Ligand Binding Domain;Ligands;Link;Malignant Neoplasms;Mediating;Molecular;Molecular Target;N-terminal;Nitrogen;Oximes;PLK1 gene;Parents;Peptides;Pharmaceutical Preparations;Pharmacology;Phosphopeptides;Phosphoserine;Phosphothreonine;Phosphotransferases;Phthalic Acids;Physiological;Play;Polo-Box Domain;Process;Prognosis;Proteins;Reaction;Reagent;Reporting;Roentgen Rays;Role;Serine;Signal Transduction;Skeleton;Structure;Substrate Interaction;TOP1 gene;Technology;Threonine;Time;Type I DNA Topoisomerases;Tyrosine;Tyrosine Kinase Inhibitor;Up-Regulation;Variant;Work;analog;antagonist;anti-cancer;anti-cancer therapeutic;base;cancer therapy;chemical stability;cytotoxicity;design;improved;inhibitor;inorganic phosphate;nanomolar;overexpression;peptide structure;phosphodiester;polo-like kinase kinase 1;protein kinase inhibitor;protein protein interaction;repaired;small molecule;therapeutic development;therapy development;tool;tyrosyl-DNA phosphodiesterase Inhibitors of Tyrosine Kinase-Dependent Signaling as Anti-Cancer Agents n/a NCI 10702292 1ZIABC006198-33 1 ZIA BC 6198 33 6569096 "BURKE, TERRENCE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 454284 NCI "defined as a molecular target for anti-cancer therapy development. The Plk1 plays a central role in cell division and upregulation of Plk1 activity appears to be closely associated with aggressiveness and poor prognosis of several cancers. This protein is overexpressed in many cancers and its inhibition can result in antiproliferative effects. Plk1 requires the coordinated actions of both an N-terminal kinase domain (KD) which executes its catalytic function and a C-terminal polo-box domain (PBD) which engages in protein - protein interactions (PPIs) with phosphoserine (pS) and phosphothreonine (pT)-containing sequences. Although Plk1 KD-directed agents are currently in clinical trials for the treatment of cancers issues related to cytotoxicity have arisen that may result from off-target effects. Targeting protein - protein interactions (PPIs) has emerged as an important area for anticancer therapeutic development. In the case of phospho-dependent PPIs such as the Plk1 PBD a phosphorylated protein residue can provide high-affinity recognition and bind to target protein hot spots. Starting from the 5-mer phosphopeptide ""PLHSpT"" and in collaboration with the NCI laboratory of Dr. Kyung Lee and the MIT laboratory of Dr. Michael Yaffe we initially identified inhibitory peptides that showed from 1000- to more than 10000-fold improved PBD-binding affinity. X-ray co-crystal structures of these peptides bound to Plk1 PBD indicated unanticipated modes of binding which take advantage of a ""cryptic"" binding channel that is not present in the non-liganded PBD or engaged by the parent pentamer phosphopeptide. The cryptic pocket is accessed by means of a phenylalkyl moiety attached to the N(pi) nitrogen of the His imidazole ring. Multivalency can be a powerful means to achieve highly potent and selective ligand-protein interactions. The selectivity and affinity of protein kinase (PK) inhibitors can be greatly increased by linking an element that binds within the ATP-binding cleft together with a component that binds exterior to the cleft. When the secondary component accesses ancillary regulatory domains the resulting ligand may be described as being intramolecular ""bivalent."" We have undertaken work to develop bivalent ligands designed to simultaneously engage both KD and PBD regions of Plk1. This has resulted in bivalent constructs exhibiting more than 100-fold Plk1 affinity enhancement relative monovalent PBD-binding ligands which had until this time exhibited among the highest PBD-binding affinities yet reported. Startlingly and in contradiction to widely accepted notions of KD-PBD interactions we have found that extremely high affinities can be retained even with minimal linkers between KD and PBD-binding components. In addition to significantly advancing the development of PBD-binding ligands our findings may cause a rethinking of the structure-function of Plk1 and potential implications for the physiological roles played by this kinase. Objective Two: Tyrosyl-DNA phosphodiesterase 1 (TDP1) it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. It achieves this by promoting the hydrolysis of the phosphodiester bond between the Y723 residue of TOP1 and the -phosphate of its DNA substrate. Blocking TDP1 function would be an attractive means of enhancing the efficacy of TOP1 inhibitors and overcoming drug resistance. TDP1 inhibitors would represent a new and potentially promising class of anticancer agents that could be used with TOP1 inhibitors in anticancer therapy. Although there have been reports of TDP1 inhibitors there is a pressing need for the discovery of effective and specific TDP1 inhibitors for which there is validated binding and a defined mechanism of actions. In collaboration with the NCI laboratories of Dr. David Waugh and Dr. Yves Pommier used an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. Yet the majority of these compounds showed limited (millimolar) TDP1 inhibitory potencies. More recently in collaboration with the NCI laboratory of Dr. Jay Schneekloth we performed a TDP1 small molecule microarray screen of over 21000 drug-like molecules in a small molecules microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified 109 hits from 21000 compounds (0.5% hit rate) and arrived at a preferred TDP1-binding motif. Among the hits were structurally similar N2-diphenylimidazo[12-a]pyrazin-3-amines which we demonstrated functioned as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke-Blackburn-Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structures of a subset of compounds showed their binding at the TDP1 catalytic site while mimicking substrate interactions. We are currently elaborating the structure of the parent SMM-derived platform by adding functionality that extends into the peptide and DNA substrate binding regions. We are using a ""click""-based oxime diversification strategy that we have used successfully in several applications to optimize the binding interactions of parent ligands. A key to this approach is its ability to take a single synthetic parent construct and easily diversity it using a library of readily obtainable aldehyde reagents. In this work we are modifying our SMM-derived platforms by adding aminooxy handles. This yielded two parent aminooxy-containing constructs. The benzoic acid moieties of these constructs are intended to bind within the catalytic site phosphoryl-binding pocket while the aminooxy groups are situated so that the resulting oxime derivatives would access the DNA or peptide substrate-binding channels. In this way we were able to rapidly interrogate the structures of approximately 500 oxime derivatives. The most promising compounds (low micromolar IC50 values) were further derivatized to increase the chemical stability of the parent oxime linkages. Through this process we have been able to achieve TDP1 inhibitors with nanomolar potencies. We have recently received the crystal structure of oxime-derived inhibitors bound to the TDP1 catalytic site and it appears that they bind in a fashion that is similar to what was predicted by our molecular docking studies. Going forward our goal is to derive validated inhibitors with defined binding interactions. These inhibitors will provide pharmacological tools for studying the biochemical effects of competitively inhibiting TDP1 function in cellular settings. Our work should advance the general field of TDP1 inhibitor development. A PCT patent application has recently been filed covering aspects of this technology." 454284 +Breast Cancer; Cancer; Clinical Research; Digestive Diseases; Prevention; Women's Health Abdominal Pain;Anogenital venereal warts;Anthracycline;Antimitotic Agents;Antineoplastic Agents;Bile Acids;Bile fluid;Biological Markers;Breast;Breast Cancer Patient;CYP2C19 gene;CYP2C9 gene;CYP3A4 gene;CYP3A5 gene;Cancer Etiology;Carcinogens;Cervical Tuberculous Lymphadenitis;Cessation of life;Characteristics;Chemicals;Chemotherapy-Oncologic Procedure;Clinical;Coughing;Coupled;Cyclophosphamide;Diarrhea;Disease;Dose;Doxorubicin;Drug resistance;ERBB2 gene;Effectiveness;Electrospray Ionization;Enzymes;Epithelial Cells;Estrogen receptor positive;Etoposide;Evaluation;Event;FDA approved;Feces;Gastrointestinal tract structure;Generations;Glucuronides;Goals;Gonorrhea;Growth;Hepatic;Hepatotoxicity;Herb;Hour;Human;Human Papillomavirus;Image;In Vitro;In complete remission;Individual;Ingestion;Intestines;Lipids;Liquid Chromatography;Liver Microsomes;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;Mixed Function Oxygenases;Mus;NADP;Oral Administration;Overdose;Oxidative Stress;Parents;Pathologic;Patient-derived xenograft models of breast cancer;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacometabolomics;Phase;Podophyllotoxin;Podophyllum;Podophyllum peltatum;Poison;Poisoning;Polyamines;Production;Prognosis;Publications;Publishing;Recombinants;Recurrence;Resistance;Safety;Sampling;Slice;Spermidine/Spermine N1-Acetyltransferase;Stable Isotope Labeling;Structure;Symptoms;Syphilis;System;Techniques;Teniposide;Therapeutic;Tissues;Topoisomerase II;Topoisomerase-II Inhibitor;Toxic effect;Tracer;Treatment Effectiveness;Treatment Failure;Tumor Volume;Urine;Vomiting;Woman;Xenobiotic Metabolism;base;cancer biomarkers;cancer chemoprevention;cancer recurrence;cancer subtypes;cell injury;chemotherapy;clinical application;clinical biomarkers;clinical development;condyloma;disease diagnosis;dosage;drug clearance;drug metabolism;follow-up;human subject;in vivo;inhibitor;lipidomics;malignant breast neoplasm;metabolomics;mortality;neoplastic cell;nervous system disorder;programs;response;side effect;skills;targeted treatment;taxane;time of flight mass spectrometry;toxicant;treatment response;triple-negative invasive breast carcinoma;tumor;urinary Xenobiotic metabolism cancer chemoprevention and cancer biomarkers n/a NCI 10702287 1ZIABC005708-31 1 ZIA BC 5708 31 6568962 "GONZALEZ, FRANK J" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 854326 NCI Project 1 Podophyllotoxin and hepatotoxicity: Introduction. Since the early 19th century extracts of Podophyllum peltatum Podophyllum emodi also known as podophyllin were used to treat a variety of diseases and conditions such as scrofula syphilis gonorrhea and coughing. Podophyllotoxin (POD) was first isolated from this herb and the planar structure and configuration of POD was established and its synthesis achieved in the 1960s. POD can inhibit the growth of epithelial cells infected with human papilloma virus (HPV) and thus it was initially used to treat genital warts. As the primary compound POD was then revealed to have antimitotic and antitumor activities and showed more potency than podophyllin extracts. However clinical development of POD was impeded due to its severe side effects. Because of its poor selectivity against tumor cells and narrow therapeutic window POD has been implicated in many poisoning cases as a result of either overdose or accidental ingestion of herbs containing POD. Major toxicities induced by POD include clinical symptoms in the gastrointestinal tract such as vomiting diarrhea abdominal pain and abnormal hepatic functions and sometimes even neurological disorders. Etoposide and teniposide two semi-synthetic derivatives of POD and DNA topoisomerase-II inhibitors were approved by the FDA and are presently used as anticancer agents. POD is mainly used as a first-line treatment for condyloma acuminate as an externally applied agent. Drug metabolism an important contributor to the clearance of drugs and determination of safe and effective dosage can detoxify toxic compounds or activate drugs to chemically reactive electrophilic derivatives that may be potentially toxic or produce oxidative stress. Drug-induced toxicity is one of the main reasons limiting the clinical use of many drugs. Whether the toxicity of POD is due to the parent compound or its metabolites is still not clear. A previous study showed that POD possesses strong inhibitory effects on CYP2C9 and CYP3A4 in a concentration-dependent manner. However there are no comprehensive studies on POD metabolism and the metabolic enzymes involved in its metabolism which is a prerequisite for a better understanding of the mechanism of POD-induced toxicity. Results. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo. Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in vitro incubation mixtures and bile samples from mice treated with POD were analyzed with ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 38 metabolites including six phase-I metabolites and 32 phase-II metabolites of POD were identified from bile and feces samples after oral administration and their structures were elucidated through interpreting MS/MS fragmentation patterns. Nine metabolites including two phase-I metabolites five glucuronide conjugates and two GSH conjugates were detected in both human and mouse liver microsome incubation systems and the generation of all metabolites were NADPH-dependent. The main phase-I enzymes involved in metabolism of POD in vitro include CYP2C9 CYP2C19 CYP3A4 and CYP3A5.POD administration to mice caused hepatic and intestinal toxicity and the cellular damage was exacerbated when 1-aminobenzotriazole a broad-spectrum inhibitor of CYPs was administered with POD indicating that POD but not its metabolites induced hepatic and intestinal toxicities.This study elucidated the metabolic map and provides important reference basis for the safety evaluation and rational for the clinical application of POD. Project 2 Urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer: Introduction. Women have a 1-in-8 chance of developing breast cancer which is the second leading cause of cancer-related death. Triple negative breast cancer (TNBC) accounts for 10-20% of breast cancers. In the absence of targets to exploit with therapy TNBC patients are treated with aggressive chemotherapy as the primary systemic treatment. TNBC chemotherapy regimens typically contain a combination of taxanes cyclophosphamide and anthracyclines such as doxorubicin to maximize therapeutic response. Only 30-40% of patients with TNBC who receive taxane- and anthracycline-based therapy will achieve a pathological complete response. TNBC has the worst prognosis of all breast cancer subtypes with the highest 5-year mortality across all disease stages. Recurrence is frequent in TNBC patients with most events occurring within 3 years of the disease diagnosis. Current techniques for detecting TNBC recurrence rely on imaging and are limited by many factors including tumor size individual breast characteristics skill of the examiner and follow-up to minimize false negatives. Consequently a recurrence can only be detected months after primary therapy. Therefore identification of clinical biomarkers that can be used to evaluate drug response during treatment would be beneficial to patients with TNBC. Metabolomics was sed to identify diacetylspermine as cancer biomarker Results. TNBC patients receive chemotherapy treatment including doxorubicin due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore there is a need to identify biomarkers that determine effective drug response. A pharmacometabolomics study was performed using doxorubicin sensitive and resistant TNBC patient-derived xenograft (PDX) models to detect urinary metabolic biomarkers of treatment effectiveness. Evaluation of metabolite production was assessed by directly studying tumor levels in TNBC-PDX mice and human subjects. Metabolic flux leading to biomarker production was determined using stable isotope labelled tracers in TNBC-PDX ex vivo tissue slices. Findings were validated in 12-hour urine samples from control (n=200) ER+/PR+(n=200) ER+/PR+/HER2+ (n=36) HER2+ (n=81) and TNBC (n=200) subjects. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment which persisted after the final dose. Urine diacetylspermine was produced by the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N1-acetyltransferase 1 expression and activity which was corroborated by elevated polyamine flux. In breast cancer patients tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. Urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC. 854326 +Cancer; Genetics; Hematology; Infectious Diseases; Lung; Rare Diseases Aborigine;Affect;Alveolar;Animal Model;Animal Testing;Animals;Anti-Inflammatory Agents;Australia;Autophagocytosis;B-Lymphocytes;Biopsy;Blood;Body Weight decreased;Bronchiectasis;CD4 Positive T Lymphocytes;CD8B1 gene;Caring;Cell Line;Cell physiology;Cells;Cerebrospinal Fluid;Cessation of life;Clonality;Coculture Techniques;Collaborations;Communities;Complementary DNA;Coupled;Cytarabine;Data;Disease;Exons;Foundations;Future;Genetic Polymorphism;HTLV-1 Infection;High-Throughput Nucleotide Sequencing;Hospitals;Human;Human Genome;Human T-lymphotropic virus 1;IL2RA gene;IL8 gene;Immune;Immunocompetent;In Vitro;Indigenous;Individual;Infection;Infiltration;Inflammasome;Inflammatory;Initiator Codon;Interleukin-6;Irrigation;Knock-out;Knowledge;Lentivirus;Link;Lung;MHC Class I Genes;Macaca;Maps;Measures;Melanesia;Messenger RNA;Methods;Microbial Biofilms;Modeling;Molecular Cloning;Mus;Nanotubes;Natural Killer Cells;Northern Territory;Open Reading Frames;Organ;Pathway interactions;Peripheral Blood Mononuclear Cell;Persons;Pharmacotherapy;Physicians;Plasma;Population;Primary Infection;Proteins;Protocols documentation;Pulmonary Inflammation;RNA Splicing;Reagent;Research;Research Personnel;Resistance;Role;Sampling;Seroprevalences;Signal Transduction;Spleen;T-Cell Proliferation;T-Lymphocyte;Taxes;Testing;Tokyo;United States National Institutes of Health;Vertebral column;Viral;Viral Load result;Virus;Virus Integration;animal data;chemokine;chronic infection;cytokine;cytotoxic;human data;humanized mouse;in vivo;inflammatory lung disease;integration site;leukemia;lymph nodes;macrophage;monocyte;mortality;mutant;nonhuman primate;nucleoside analog;pathogen;response;viral DNA;viral transmission;virological synapse;virtual Role of the HTLV-1A and HTLV1-C inflammatory profile in disease n/a NCI 10702286 1ZIABC005645-33 1 ZIA BC 5645 33 9692619 "FRANCHINI, GENOVEFFA " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 411634 NCI Accomplishments 1. By performing integrated studies on orf-I sequence in 160 HTLV-1A infected individuals and animal testing on the infectivity of molecular clones carrying polymorphism that result in preferential expression of p8 or p12 we established that efficient HTLV-1A persistence and spread in vivo requires the combined functions of the orf-I proteins. We also found that p8 is essential for productive infection of monocytes and that the expression of both proteins renders infected cells completely resistant to the MHC-class I restricted cytotoxic CD8 killing. 2. Cell-associated HTLV-1 can be transmitted by at least three different mechanisms: virological synapse cellular conduits including Tunneling Nano Tubes and biofilm. However the contribution of each of these mechanisms to viral transmission remains unknown. We have demonstrated that the HTLV-1 p8 increases viral transmission by increasing both cellular conduits and Tunneling Nano Tubes. More recently we found that inhibition of p8-medaited TNT formations by the nucleoside analog cytarabine (cytosine arabinoside AraC) decreases viral transmission by 30% thereby providing a treatment to partly curb the spread of HTLV-1 in vivo. Current Research & Future Plans 1. Functional studies with HTLV-1A and HTLV-1A/C viruses and orf-I cDNAs. We have synthesized the cDNAs derived from the doubly spliced rex-orf-I mRNAs of HTLV-1C that juxtapose the first exon of Rex in frame with orf-I and demonstrated that it produces p16 a protein that increases autophagy. We constructed a chimeric virus by swapping the Cla-1-Sal-1 fragment which contains both the entire orf-I and most of the orf-II of HTLV-1A with that of HTLV-1C. The resultant molecular clone is a replicating virus designated as HTLV-1A/CDF. We plan to create a second HTLV-1A/C by substituting the entire 3' end (HTLV-1A/C) and generating mutants of both chimeric viruses to inhibit the splicing of the rex-orf-I mRNA (HTLV-1A/CDFd16 and HTLV-1A/CDFd16) as a control. The viral DNA clones will be transduced in the 729 B cell line that supports HTLV-1 replication and will be used to infect primary CD4+ T cells. We plan to perform functional studies on monocytes with lentiviruses that express p8 or p16 on primary monocytes and are infected by HTLV-1A WT and the orf-I knockout mutant the chimeric HTLV-1A/CDF WT or rex-orf-I knock-out virus (HTLV-1A/CDFd16). We will assess inflammasome activation autophagy and the level and type of inflammatory cytokines and chemokines produced by primary monocytes and T cells in vitro. 2. HTLV-1A and HTLV-1A/C infection of humanized mice. We have preliminary data that demonstrate that our HTLV-1A molecular clone can be transmitted to humanized NOD/SCID-yc-/- mice using infected irradiated CD4+ T cells. We observed proliferation of human CD25+ CD4+ T cells engrafted in the humanized mice that causes extensive infiltration of these CD4+ T cells in vital organs such as the spleen high viral burden weight loss and death. To explore HTLV-1 clonality in hu-Mice we applied an optimized high-throughput sequencing (HTS) method to map viral integration sites in the human genome and simultaneously measure the abundance of the corresponding clones. The CD4+ T cell proliferation is polyclonal as expected. We do not anticipate differences in the ability of HTLV-1A and HTLV-1A/C to cause this proliferative disease in mice since the Tax is virtually identical in the two viruses. However these studies will be prerequisite to demonstrate viral infectivity of the chimeric HTLV-1A/C in vivo before they can be used in studies in non-human primates. In addition this small animal model may be foundational in testing the extent of inhibition of viral transmission by cytarabine in vivo. 3. Study the inflammatory profile of HTLV-1A and HTLV-1A/C infected macaques and humans. We have demonstrated that HTLV-1A WT and the HTLV-1 orf-I knockout viruses infect monocytes in vitro and macaques in vivo but the HTLV-1 orf-I knockout does not appear to persist. We obtained PBMCs infected with HTLV-1A WT or the HTLV-1A orf-I knockout virus cultured them for 3 days and measured the ability of adherent cells (macrophages) to produce cytokines. The blood was collected at a timepoint when both animals were positive for viral DNA in PBMCs (weeks 8-10). We found higher levels of IL-1B IL-6 and IL-8 in the animal infected with the HTLV-1A orf-I knockout than that with the HTLV-1A WT demonstrating that the absence of orf-I results in a qualitatively different inflammatory profile in vivo as also demonstrated in vitro. We plan to extend this study by infecting 4 macaques with HTLV-1A and 4 with HTLV-1A orf-I knockout viruses to follow the inflammatory profiles caused by the two viruses in detail. We also plan to infect additional macaques with the HTLV-1A/CCS and the HTLV-1A/CCSd16 if warranted by the data. In all the animal studies we will collect lung biopsies bronchial alveolar lavage blood lymph nodes gut biopsies and spinal fluid to quantitate viral burden and differences in systemic inflammatory profiles. To compare the inflammatory profiles of ex vivo monocytes from macaques and humans infected by HTLV-1A and HTLV-1C we have established collaborative efforts with Australian physicians at the Alice Springs Hospital that care for HTLV-1C infected Aborigines and with the IMSUT Hospital in Tokyo and Steve Jacobson at the NIH who both care for HTLV-1A infected people to study their inflammatory profiles directly in plasma or by short term cultures of PBMCs. Our collaboration with Australian researchers is a large pan-Australian consortium to share PBMCs culture protocol Luminex data and reagents for the comparison of human and animal data. 411634 +Cancer; Genetics; Rare Diseases Acetylation;Adenocarcinoma Cell;Affect;Amyloidosis;Apoptosis;Apoptotic;Attenuated;Binding;Biochemical;Biological;Biotin;C-terminal;CRISPR interference;CRISPR-mediated transcriptional activation;Cancer cell line;Catalytic Domain;Cell Cycle Arrest;Cell Line;Cells;Chemicals;Collaborations;Colon Carcinoma;Critical Pathways;DNA;DNA Damage;DNA Repair;Deubiquitinating Enzyme;EP300 gene;Esophageal Adenocarcinoma;Etoposide;Exhibits;Family;Genetic;Genetic Transcription;Goals;Growth;Heat-Shock Response;Homo;Hot Spot;Human;Hydroxylation;Hypoxia;Image;Lysine;MCF7 cell;Malignant neoplasm of ovary;Mass Spectrum Analysis;Metabolism;Methods;Methylation;Modeling;Modification;Molecular Conformation;Mutation;N-terminal;Nuclear Extract;Nuclear Proteins;Oncogenic;Outcome;Pathway interactions;Peptides;Pharmacology;Phosphorylation;Play;Point Mutation;Post-Translational Protein Processing;Proteins;Regulation;Reporting;Research;Role;Site;Small Interfering RNA;Stress;Sumoylation Pathway;TP53 gene;Transactivation;Transcription Coactivator;Transcriptional Activation;Tumor Suppressor Proteins;Ubiquitin;Ubiquitination;anticancer treatment;base;cancer stem cell;cofactor;druggable target;endoplasmic reticulum stress;experimental study;gain of function;high throughput screening;improved;in vivo;inhibitor;member;mutant;neuroblastoma cell;novel;peptidomimetics;preference;prevent;response;senescence;small molecule;transcription factor;tumor;tumor growth;tumorigenic;ultraviolet damage Tumor Suppressor Protein p53 n/a NCI 10702285 1ZIABC005599-32 1 ZIA BC 5599 32 6568841 "APPELLA, ETTORE " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 480747 NCI "The p53 tumor suppressor protein is a key component of the cellular response to stress. It is a homo-tetrameric sequence-specific transcription factor activated by DNA damage hypoxia heat shock and other types of stress and regulates DNA repair cell cycle arrest senescence metabolism and apoptosis. It is maintained at low levels in unstressed cells but becomes stabilized and activated following DNA damage through extensive post-translational modification (PTM). Our research has focused on identifying and exploring the biological roles of p53 PTMs to better understand how they modulate p53 functions. The tandem N-terminal transactivation domains (TADs) of p53 are crucial for p53 activity as a transcription factor. The two subdomains TAD1 (residues 1-40) and TAD2 (residues 35-59) interact with several domains of the transcriptional coactivator p300. However the two subdomains can function independently of one another suggesting the participation of distinguishing transcriptional cofactors in transcriptional activation by TAD1 and TAD2 in which interactions may be differentially regulated by p53 phosphorylation. To identify distinct interacting partners for TAD1 and TAD2 peptides comprising TAD1 (residues 9-33) or TAD2 (residues 35-59) with and without phosphorylation at Thr 18 or Ser 46 respectively were synthesized and covalently attached to biotin at the N-termini. We used these peptides as a bait for pulldown of interacting proteins from nuclear extracts prepared from MCF7 cells treated with etoposide; mass spectrometry analysis was used to identify and quantitatively compare the interactors to discriminate between those preferentially interacting with the TAD1 or TAD2 subdomains. Our experiments using biological triplicate pulldowns have identified a list of potential interactors that show a preference for either unmodified or modified p53 in untreated cells or following etoposide treatment. In addition to known binding partners of p53 TAD1 and TAD2 we identified several new interactors. We have validated a few of the new interactors identified and are performing functional experiments to investigate the consequences of these interactions on p53 activity and stability. We have also expanded the experiments to determine whether these interactions also occur under other stress conditions known to activate p53 including ER stress and UV damage. Understanding the effects of these new interactors on p53 regulation will open new methods to increase p53 activity in tumors. The C-terminus of p53 exhibits a diverse array of PTMs including phosphorylation methylation acetylation ubiquitination sumoylation neddylation and hydroxylation that are primarily localized to the terminal thirty residues of the protein. We have shown that p53 can be both mono- and dimethylated on Lys382 with the former modification repressing p53 transcriptional activity and the latter promoting DNA repair in addition to demonstrated acetylation and ubiquitination of the same site. SETD8 monomethylates p53 on lysine 382 attenuating p53 pro-apoptotic and growth arrest functions. Using a high-content imaging siRNA screen and a chemical screen in a collaboration with Drs. Veschi and Thiele we identified SETD8 as a suppressor of p53 activity in neuroblastoma cell lines. Genetic or pharmacological inhibition of SETD8 activity resulted in activation of the p53 wild-type pathway by decreasing p53K382me1. We have initiated a collaboration with Drs. Veschi and Stassi and recently showed that SETD8 is highly expressed in colon cancer stem cells (CSCs) with commensurate increased levels of p53K382me1. These two effects may play a synergistic role in the tumorigenic and metastatic capabilities of CSCs. We are currently using a high-throughput assay to identify novel inhibitors of SETD8 with an improved activity and tolerability in vivo. p53 point mutations have been reported to occur in approximately half of all human tumors with marked over-representation of specific ""hot-spot"" residues. These mutations abolish the ability of p53 to function as a transcription factor and tumor suppressor. Moreover many mutant forms of p53 have acquired novel oncogenic activities through gain-of-function mechanisms. p53 mutations generally either affect DNA contact or cause structural instability with partial unfolding and aggregate formation similar to that seen in amyloid diseases. We are examining a small molecule NSC59984 in esophageal adenocarcinoma cells and investigating its mechanism of action and effects on the oncometabolic profile. The findings will help elucidate pathways critical for preventing tumor growth by inhibiting gain-of-function mutant p53 activities and restoring wild-type p53 activity. A second means to target mutant p53 was reported by Padmanabhan et al. (Nat Commun. 9(1):1270 (2018)) showing that an inhibitor targeting deubiquitinase USP15 specifically results in p53-R175H degradation by disrupting the USP15-p53-R175H interaction. This leads to increased p53-R175H ubiquitination and degradation of the mutant protein. Based on these findings we have chosen to explore other members of the deubiquitinating enzyme (DUB) family as potential modulators of mutant p53 protein stability. Using CRISPR-interference and CRISPR-activation screens with DUB-targeting sgRNAs in ovarian cancer cell lines of varying p53 status we are identifying DUBs that contribute to mutant p53 stability. These lines encompass several p53 expression models p53-null wild-type and mutant p53-R175H commonly seen in ovarian cancer. The DUBs that are identified will be further analyzed as druggable targets. The ability to selectively target DUBs will be crucial since they take on several roles in the ubiquitin pathway particularly by focusing on the N-terminal domains adjacent to the catalytic domain which vary significantly among USPs. The goal is to develop small molecules and/or peptidomimetic compounds that disrupt the accumulation of mutant p53 and/or rescue p53 wildtype tumor suppressive function." 480747 +Cancer; Genetics; Precision Medicine; Women's Health ABCB1 gene;ABCC1 gene;ABCG2 gene;ATP Hydrolysis;ATP-Binding Cassette Transporters;Amino Acids;Binding;Binding Sites;Biological Models;Blood - brain barrier anatomy;Cell Line;Cells;Chemicals;Clinical;Collaborations;Cryoelectron Microscopy;Crystallography;Cytotoxic agent;Doxorubicin;Drug Efflux;Drug resistance;Failure;Family;Genes;Goals;Histone Deacetylase Inhibitor;Human;Laboratories;Malignant Neoplasms;Modeling;Molecular;Molecular Conformation;Molecular Profiling;Multi-Drug Resistance;Multidrug Resistance Gene;Mus;Natural Product Drug;Natural Products;Paclitaxel;Patients;Pattern;Pharmaceutical Preparations;Pharmacopoeias;Phenotype;Physiological;Population;Process;Property;Proteins;Refractory;Research Personnel;Resistance;Rhodamine;Role;Sampling;Site;Solubility;Specificity;Structure;Structure-Activity Relationship;System;Thiosemicarbazones;Transmembrane Domain;Vinca Alkaloids;Work;analog;cancer cell;chemotherapeutic agent;chemotherapy;genetic analysis;high throughput screening;human tissue;improved;inhibitor;insight;kinase inhibitor;member;multi drug transporter;multidrug resistant cancer;neoplastic cell;novel strategies;personalized approach;predictive signature;resistance mechanism;therapy resistant;tool;treatment response;uptake Genetic Analysis of the Multidrug Resistance Phenotype in Tumor Cells n/a NCI 10702284 1ZIABC005598-33 1 ZIA BC 5598 33 9414470 "GOTTESMAN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 607518 NCI Resistance to chemotherapy occurs in cancer cells because of intrinsic or acquired changes in expression of specific proteins. We have studied resistance to natural product chemotherapeutic agents such as doxorubicin Vinca alkaloids and taxol and more recently histone deacetylase inhibitors and targeted kinase inhibitors. In most cases cells become simultaneously resistant to multiple drugs because of reductions in intracellular drug concentrations. For the natural product drugs this cross-resistance is frequently due to expression of an energy-dependent drug efflux system (ABC transporter) known as P-glycoprotein (P-gp) the product of the MDR1 or ABCB1 gene or to other members of the ABC transporter family including ABCG2 and ABCB5. Work from our laboratory and others has revealed that some drugs are more toxic to P-gp-expressing cells than to non-expressors suggesting a novel approach to treatment of MDR cancers. Several different chemical classes with this property including thiosemicarbazones (e.g. NSC73306) have been identified. A quantitative structure activity analysis of NSC73306 analogs a further correlation analysis in the NCI-60 cell lines and a high-throughput screen for compounds in the U.S. Pharmacopeia that kill P-gp-expressing cells have yielded many additional compounds with improved ability to kill selectively P-gp-expressing cells but also with improved solubility properties. To understand how the structure of P-gp determines its polyspecificity and how specificity is altered with changes in folding we have collaborated with other senior investigators in the LCB including Di Xia Suresh Ambudkar and Sriram Subramaniam. Cryo-EM studies have demonstrated that apo P-gp has a dynamic structure in which the two ATP-binding sites are either separated or close together. Binding of ATP fixes the conformation of P-gp in the latter state and ATP hydrolysis results in separation of the ATP sites. Crystallography studies using mouse P-gp as a model show that the separation between the ATP sites determines the pitch of the transmembrane (TM) helices where substrates bind suggesting the hypothesis that as the ATP sites move together and apart the TM helices expose different residues that enable binding to many different substrates. Studies on mouse-human chimeric P-gps have revealed similar structure-function relationships for these two evolutionarily related transporters. In collaboration with the group of Suresh Ambudkar we have examined the basis of directional transport of compounds out of cells by P-glycoprotein. These studies have revealed a set of amino acid residues in the transmembrane regions of P-glycoprotein which can be altered to change the direction of transport of certain rhodamine compounds from out of the cell to into the cell. This process is concentration- and ATP-dependent and gives important insight into how directionality of transport is determined in P-glycoprotein. We have used AML as one model system to determine the clinical role of ABC transporters in drug resistance. In one study samples from the same patients before and after chemotherapy were analyzed. In this case resistance in each case shows a different pattern of expression of ABC genes and other MDR genes suggesting that individualized approaches to resistance to therapy will be needed. A more detailed analysis of a large population of primary refractory AMLs has shown that there are 3 molecular signatures that predict poor response to therapy. One of these is associated with increased expression of ABCG2. These results argue that clinical samples must be stratified to facilitate effective targeting of inhibitors of ABC transporters to circumvent drug resistance. 607518 +Cancer; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Endocrine Disruptors; Hepatitis; Liver Disease; Nutrition; Obesity; Women's Health Ablation;Acetaminophen;Adipose tissue;Affect;Agonist;Benzene;Biological;Biological Assay;Blood;Brown Fat;C57BL/6N Mouse;CYP2E1 gene;Carbon Tetrachloride;Carcinogenesis Mechanism;Catabolism;Cholesterol;Cirrhosis;Clinic;Colon Carcinoma;Correlative Study;Cytochrome P450;Diabetes Mellitus;Diagnosis;Diet;Dietary Fats;Diethyldithiocarbamate;Disease;Dyslipidemias;Endocrine;Energy Intake;Energy Metabolism;Enterocytes;Enzymes;Ethanol;Excretory function;Extrahepatic;FGF21 gene;Fasting;Fatty Acid-Binding Protein 1;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Fibrates;Fructose;Genes;Genetic;Genomics;Goals;Hepatic;Hepatocyte;High Fat Diet;Homeostasis;Human;Hydrophobicity;Insulin Resistance;Intestines;Knock-out;Knockout Mice;Ligands;Lipids;Liver;Luciferases;Lysophosphatidylcholines;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Molecular;Molecular Analysis;Molecular Weight;Monoglycerides;Mus;Nonesterified Fatty Acids;Nuclear Receptors;Obesity;Organoids;PPAR alpha;Pathologic Processes;Pharmaceutical Preparations;Pharmacology;Phenocopy;Phenotype;Play;Polyunsaturated Fatty Acids;Primary carcinoma of the liver cells;Publications;Regulation;Reporter;Reporting;Risk;Rodent Model;Role;Sampling;Signal Transduction;Specimen;Thermogenesis;Tissues;Triglycerides;Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;antagonist;chromatin immunoprecipitation;chronic liver disease;diet-induced obesity;dietary;drug discovery;end stage liver disease;fatty acid transport;fatty liver disease;fibroblast growth factor 21;humanized mouse;improved;inhibitor;intestinal fatty acid binding protein;member;metabolomics;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;programs;receptor;targeted treatment;transcription factor;transcriptome;uptake Xenobiotic receptors n/a NCI 10702283 1ZIABC005562-35 1 ZIA BC 5562 35 6568962 "GONZALEZ, FRANK J" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1993428 NCI Project 1 PPARalpha and CYP2E1: : Introduction Obesity and the associated metabolic disorders are increasing at an alarming rate globally. An imbalance between energy intake and expenditure results in obesity and adipose browning induction is one attractive strategy in rodent models for enhancing non-shivering thermogenesis and thus countering the excess energy intake. Nuclear receptors have become drug targets for the treatment of metabolic diseases although less is known about their roles in the modulation of adipose browning. Cytochrome P450 (CYP) 2E1 expression was suggested to be closely related to the pathological process of metabolic diseases. CYP2E1 activity is significantly increased in both humans and experimental rodent models under conditions of diabetes fasting obesity and high-fat diet (HFD) treatment. Cyp2e1-null mice are protected from HFD-induced obesity and nonalcoholic steatohepatitis. Peroxisome proliferator-activated receptor alpha (PPARalpha) plays an essential role in lipid homeostasis and energy regulation and the expression and excretion of hepatic fibroblast growth factor (FGF)21 a major PPARalpha target gene in liver could act as an endocrinal beige stimulator to alleviate the obesity. However the mechanism by which CYP2E1 affects metabolic diseases has not been explored. CYP2E1 a member of the CYP superfamily was initially identified as an ethanol-inducible enzyme involved in the metabolism of various low-molecular weight xenobiotics including ethanol benzene carbon tetrachloride and acetaminophen. Notably beyond these xenobiotics CYP2E1 also metabolizes endogenous substrates including fatty acids while various endogenous ligands also including fatty acids were reported to activate PPARalpha. Thus it is possible that some of the endogenous substrates of CYP2E1 also serve as PPARalpha agonists. However how the shared substrates and ligands of CYP2E1 and PPARalpha could act as signaling-transducing molecules in modulating the metabolic diseases are largely unknown. To explore the potential crosstalk between CYP2E1 and PPARalpha global genomics metabolomics in combination with Cyp2e1-null mice and liver-specific Ppara-null mice as well as the CYP2E1 inhibitor diethyldithiocarbamate were employed to uncover whether and how CYP2E1 deficiency decreased obesity by modulating white adipose browning through the CYP2E-PPARalpha crosstalk with shared substrates as signaling-transducing molecules. Results. Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) target genes including fibroblast growth factor (FGF)21 that upon release from the liver enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics among which four compounds lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARalpha agonists thus explaining how CYP2E1 deficiency causes hepatic PPARalpha activation through increasing cellular levels of endogenous PPARalpha agonists. Translationally a CYP2E1 inhibitor was found to activate the PPARalpha-FGF21-beige adipose axis and decrease obesity in wild-type mice but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARalpha and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism. Project 2 PPARalpha and FABP1: Introduction. Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver diseases. Persistent NAFLD could progress to nonalcoholic steatohepatitis (NASH) and increase the risk of the end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. To date no drug has been approved for the treatment of NASH and thus pharmacological therapies for NASH treatment are warranted. PPARalpha agonists such as fibrates are widely prescribed for the treatment of dyslipidemias as lipid-lowering drugs in clinic however their use in human NASH treatment has not been approved. Global PPARalpha knockout in mice markedly enhances NASH but protects against insulin resistance. suggesting the pleiotropic roles of PPARalpha. Hepatocyte-specific PPARalpha knockout was found to only partially phenocopy the phenotype of global PPARalpha knockout in NAFLD and fasting-induced hepatic steatosis. Understanding the tissue-specific role of extrahepatic PPARalpha may guide drug discovery from PPARalpha modulators. Dietary fat is absorbed by the enterocytes in the form of free fatty acids and 2-monoacylglycerols that are produced from dietary triglycerides (TG) while the absorbed fatty acids and monoacylglycerols are re-esterified into TG and exported to the blood. Fatty acid-binding protein 1 (FABP1) is known to facilitate transport of fatty acids and other hydrophobic molecules in the liver while the role of intestinal FABP1 in modulating dietary fat absorption and NASH is still unknown. Results. The role of intestine PPARalpha-FABP1 signaling in modulating the NASH progression was studied using intestine-specific PPARalpha or FABP1 knockout mice intestine-specific PPARalpha/FABP1 double knockout mice PPARA-humanized mice PPRE-Luc mice primary intestinal organoids and PPARalpha-specific antagonist GW6471 in combination with global transcriptome and molecular biological analyses. Correlative studies on PPARalpha/FABP1 signaling with obesity were carried out on human intestine samples. Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates fatty acid transport and catabolism in liver. However the role of intestinal PPARalpha in lipid homeostasis is largely unknown. Here intestinal PPARalpha was examined for its modulation of obesity and nonalcoholic steatohepatitis (NASH). Intestinal PPARalpha was activated and FABP1 upregulated in obese humans and high-fat diet-fed mice by using human intestine specimens or high-fat diet (HFD) or high-fat high-cholesterol high-fructose diet (HFCFD)-fed C57BL/6N mice or PPARA-humanized PPRE-Luciferase mice. Intestine-specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity-associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin-immunoprecipitation assays in combination with fatty acid uptake assay in primary intestinal organoids revealed that intestinal PPARalpha targeted FABP1 that mediated the effects of intestinal PPARalpha in modulating fatty acid uptake. The PPARalpha antagonist GW6471 improved obesity and NASH dependent on intestinal PPARalpha or FABP1. PPARalpha and FABP1 double-knockout mice revealed that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally GW6471 reduced human PPARA-driven intestinal fatty acid uptake and improved obesity-related metabolic dysfunctions in PPARA-humanized but not Ppara-null mice. This study revealed t *TRUNCATED* 1993428 +Cancer; Genetics; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Acute;Address;Adult;Amitrole;Area;Bioinformatics;Cartilage;Cell Culture Techniques;Cell Line;Cell surface;Cells;Characteristics;Death Rate;Development;Diet;Differentiation Antigens;Epithelial;Felis catus;Gene Mutation;Genes;Genotype;Goals;Goitrogens;Growth;Growth Factor;Herbicides;Human;Individual;Injury;Laboratory mice;Light;Malignant Neoplasms;Malignant neoplasm of thyroid;Messenger RNA;Modeling;Mus;Muscle;Names;Natural regeneration;Nature;Neoplasm Metastasis;Pattern;Play;Process;Recurrence;Role;Signal Transduction;Signaling Molecule;Source;Thinness;Thyroid Adenoma;Thyroid Diseases;Thyroid Function Tests;Thyroid Gland;Thyroid Hormones;Thyroidectomy;Thyrotropin Receptor;Tissues;Triazoles;Wild Type Mouse;adenoma;anaplastic thyroid cancer;cancer drug resistance;cancer stem cell;carcinogenesis;experimental study;genome sequencing;laser capture microdissection;mortality;nano-string;progenitor;receptor;stem;stem cells;thyroid neoplasm;transcription factor;transcriptome sequencing;whole genome Thyroid regeneration and carcinogenesis n/a NCI 10702282 1ZIABC005522-35 1 ZIA BC 5522 35 6568943 "KIMURA, SHIOKO " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 720526 NCI Tshr (TSH receptor)-null and littermate wild-type mice were subjected to partial thyroidectomy (acute thyroid injury model) that activates thyroid regeneration. A cluster of thin and elongated shaped cells were found near the tracheal cartilage and muscle in both Tshr-null and wild-type mouse thyroids that were positive for NKX2-1 with some cells also positive for Pax8. NXK2-1 and PAX8 are the transcription factors critical for development differentiation and function of the thyroid and are considered thyroid differentiation markers. The thin and elongated cells were clearly different from matured NKX2-1-positive round-shaped thyroid follicular cells. The results suggested that a cluster of thin elongated cells may be a precursor to thyroid follicular cells. In fact we found a cluster of NKX2-1 positive thin elongated cells that are connected to a follicle consisting of mature NKX2-1-positive thyroid follicular cells. These clusters of thin elongated cells were present in both genotyped mouse thyroids which may become more visible after partial thyroidectomy particularly in wild-type thyroids. Changes in expression patterns of mRNAs for various thyroid-specific genes growth factors their receptors and related signaling molecules before and after partial thyroidectomy were similar between thyroids of Tshr-null and wild-type mice. These results suggested that a cluster of thin elongated cells present near the tracheal cartilage and muscle are a source of newly formed follicles and at least this type of thyroid regeneration does not require TSH signaling. This is critical in terms of possible restoring thyroid functions in humans after thyroidectomy due to various thyroid diseases including cancer. Whether the thin elongated cells can be considered as thyroid stem/progenitor cells and what are the origin of these cells remain to be understood. In order to address these questions and to better understand the nature of these thin elongated thyroid stem/progenitor-like cells we carried out Nanostring GeoMX analysis where cells from the area of a cluster of thin elongated cells the surrounding tissues and normal thyroid tissues are captured by laser microdissection followed by RNAseq analysis of each area of cells. Bioinformatic analysis and further confirmatory experiments are currently under way. We also study mouse thyroid adenoma-derived cells to understand what genes mutations might be responsible for thyroid cells becoming adenomas and whether and/or how these genes mutations relate to cancer stem cells. To this end mouse thyroid adenoma-derived cell lines were established in our laboratory from mice that were fed a diet containing amitrole (3-amino-124-triazole) a non-food herbicide. Amitrole is a known goitrogen inducing thyroid tumors by inhibiting thyroid hormone synthesis. Mice fed amitrole developed adenoma within 6-12 months. Adenomas from individual mouse were collected pooled and subjected to cell culture. Five cell lines were established and named CAT (cells from amitrole treated thyroids). Two CAT cell lines CAT458 and 459 out of five established showed epithelial characteristics with one line clearly expressing NKX2-1 indicating that CAT458 and CAT459 are derived from thyroid follicular cells. They were subjected to whole genome sequencing and the analysis is on the way to identify and understand what genes might be contributing to adenoma development and possibly to understand if there is any correlation to cancer stem cells of the thyroid. 720526 +Cancer; Genetics; Women's Health Affect;Affinity;Behavior;Binding;Biological Models;Cell Nucleus;Chromatin;Chromatin Structure;Complex;Crowding;Disease;Environment;Epigenetic Process;Gene Activation;Gene Expression;Gene Expression Regulation;Genetic Transcription;Heterogeneity;Kinetics;Laws;Ligands;Modeling;Modification;Motion;Nuclear;Nuclear Receptors;Photobleaching;Process;Property;Proteins;Repression;Response Elements;Space Explorations;Spacer DNA;Time;Work;base;chromatin modification;genome-wide;in vivo;interest;kinetic theory;recruit;single molecule Chromatin Structure and Gene Expression n/a NCI 10702281 1ZIABC005450-39 1 ZIA BC 5450 39 8777551 "HAGER, GORDON L" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2383132 NCI Single Molecule Tracking (SMT) allows the study of TF dynamics in the nucleus giving important information regarding the search and binding behavior of these proteins with chromatin in vivo. However how TFs navigate within the intricate nuclear environment to find and bind their response elements on chromatin recruit the transcription machinery and ultimately regulate gene expression remains largely unknown. By the implementation of proper photobleaching kinetics theory-based models and an unbiased model selection approach we revealed a new model of TF dynamics where TFs binding times are power-law distributed. Previous models suggested that TFs bound either non-specifically or specifically with each mode of binding having their own distribution that was largely discrete from the other. The power-law model on the other hand indicates that TFs bind not discretely in these two modes but with a continuous distribution from fast to very slow kinetics. These results are aligned with the theoretical underpinnings of TF motions in the crowded nuclear space and exploration of a complex DNA space To fully understand the broad distribution of TFs binding affinities we explored how the nuclear microenvironment affects the binding of TFs to chromatin. We found that TFs present two types of binding: local confinement (also designated State 2) and direct binding to chromatin (also designated as State 1). We showed that the power law distribution of binding times is due to TFs confinement and heterogeneity in binding affinity to chromatin. 2383132 +Biotechnology; Cancer; Genetics Biochemical;Biological Models;Biological Process;Chromosome Structures;Chromosomes;Complex;Congenital Abnormality;Cruciform DNA;DNA Damage;DNA Double Strand Break;DNA Repair;Development;Double Strand Break Repair;Ensure;Event;Failure;Genetic;Genetic Recombination;Genome;Growth;High-Throughput Nucleotide Sequencing;Homologous Gene;Human;Infertility;Lead;Location;Malignant Neoplasms;Meiosis;Meiotic Recombination;Methods;Mitosis;Mitotic Cell Cycle;Molecular;Molecular Chaperones;Mosaicism;Pathway interactions;Population;Process;Proteins;Recombinants;Regulation;Research;Saccharomyces cerevisiae;Saccharomycetales;Sister Chromatid;Somatic Cell;Testing;Topoisomerase;Work;Yeasts;base;helicase;homologous recombination;insight;member;migration;novel;prevent;recruit;repaired;tool;topoisomerase IIIalpha;transmission process Mechanism of Meiotic Recombination n/a NCI 10702279 1ZIABC005268-35 1 ZIA BC 5268 35 2068571 "LICHTEN, MICHAEL J" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 1299951 NCI Meiotic double-strand DNA break (DSB) repair by homologous recombination occurs via multiple processes defined by distinct decisions points. One important decision involves partner choice between recombining with the sister chromatid (the dominant repair partner during mitosis) or with the homolog (the homologous chromosome of different parental origin the preferred partner during meiosis). Another important decision involves recombination pathway choice between producing crossovers where flanking chromosome sequences are exchanged or noncrossovers. A signature contribution of our group was the demonstration that crossover and noncrossover recombination proceed via different mechanisms that diverge after initial stages of strand invasion and that feature different biochemical activities and genetic requirements. Work during previous review periods had shown that the conserved Sgs1-Top3-Rmi1 helicase-topoisomerase complex (STR) is responsible for partitioning early recombination events between noncrossover and crossover pathways. Sgs1-Top3-Rmi1 is the yeast homolog of the mammalian BLM helicase-Top3alpha-BLAP75 complex implicated in cancer avoidance and recombination control in humans. We showed that all three members of the yeast complex are essential for normal recombination partner choice and for population of regulated meiotic crossover and noncrossover recombination pathways. Based on these findings we hypothesized that STR by promoting frequent disassembly of early strand invasion intermediates acts as a chaperone for early recombination intermediates. We hypothesized that these repeated cycles of strand invasion and disassembly would result in template switching which in turn would lead to recombinants with mosaic parental strand contributions. This hypothesis has now been confirmed by high-throughput sequencing of recombinants that occur in a highly polymorphic test interval; more than 2/3 of recombinants display clear evidence for template switching multiple strand invasions or both. In addition we uncovered evidence for activities specific to the crossover pathway including branch migration (2/3 of crossovers) and exonucleolytic gap-formation (1/3 of crossovers). Current work is aimed at determining the proteins responsible for these activities. Other work is aimed at confirming branch migration by mapping the location of Holliday junctions in recombination using a novel method we have developed to specifically purify Holliday junction-containing intermediates. Finally we are studying how chromosome structure specifically the meiotic chromosome axis contributes to the regulation of recombination. A meiosis-specific subset of chromosome axis components the Hop1 and Red1 proteins are important for meiotic DSB formation and partner choice and are enriched in some regions of the genome relative to others. Using a novel method to recruit axis proteins to regions that are normally depleted of these proteins we have shown that high concentrations of the Hop1 protein are necessary and sufficient for meiotic DSB formation but the recombination events initiated by these DSBs do not follow canonical meiotic recombination pathways. We are currently determining the mechanism by which Hop1 promotes DSB formation and what additional factors are needed for Hop1-dependent DSBs to be repaired by canonical meiotic recombination mechanisms. 1299951 +Cancer; Climate-Related Exposures and Conditions; Clinical Research; Congenital Structural Anomalies; Eye Disease and Disorders of Vision; Genetics; Pediatric; Pediatric Cancer; Prevention; Rare Diseases; Women's Health 20 year old;Adult;Affect;Age;Alleles;Aminoglycosides;Autopsy;B-Lymphocytes;BRAF gene;Big Data;Biological Assay;Cataract;Cell Line;Cells;Cessation of life;Child;Clinical;Cockayne Syndrome;Collaborations;Collection;Communities;DNA;DNA Damage;DNA Repair;DNA Repair Gene;Databases;Defect;Development;Disease;ERCC1 gene;ERCC3 gene;Enrollment;Epidemiologist;Eye;Eye Abnormalities;Family;Family member;Fetal Development;Follow-Up Studies;Frequencies;Functional disorder;Gene-Modified;General Population;Genes;Genetic Diseases;Genetic Transcription;Goals;Growth;Gynecologist;Head;Health;Hematologic Neoplasms;Heterogeneity;Heterozygote;Histologic;Human;Human Development;Hypersensitivity;Individual;Infant;International;Investigation;Italy;Laboratories;Lead;Link;Longterm Follow-up;Malignant Neoplasms;Messenger RNA;Methods;Molecular;Mothers;Mutation;Natural History;Necrosis;Nerve Degeneration;Nevi and Melanomas;Nonsense Codon;Nucleotide Excision Repair;Operative Surgical Procedures;Ophthalmologist;PTEN gene;Patients;Peripheral Nervous System Diseases;Phenotype;Point Mutation;Polymerase;Postoperative Complications;Preclinical Testing;Predisposition;Pregnancy;Pregnancy Complications;Premature Menopause;Process;Proteins;Protocols documentation;Publishing;RNA Splicing;Rare Diseases;Reporting;Research Personnel;Risk;Role;Series;Site;Skin Cancer;Skin Carcinoma;Sun Exposure;System;Testing;Thyroid Nodule;Trichothiodystrophy;Tumor Suppressor Genes;Ultraviolet Rays;United States National Institutes of Health;Variant;Walking;Woman;XPA gene;Xeroderma Pigmentosum;brain size;cancer prevention;cancer risk;cell bank;cohort;exome sequencing;gene repair;hearing impairment;improved;infancy;insight;melanoma;offspring;radiologist;rare genetic disorder;systemic toxicity;targeted treatment;ultraviolet damage DNA Repair in Human Cancer-Prone Genetic Diseases n/a NCI 10702278 1ZIABC004517-46 1 ZIA BC 4517 46 6568851 "KRAEMER, KENNETH H" Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 2095301 NCI 1. XERODERMA PIGMENTOSUM We have been examining XP patients at NIH since 1971. We performed long term follow-up studies of cancer hearing lossof eye abnormalities and gynecological health in XP patients. We found that the XP patients under age 20 years had a 10000-fold increased risk of non-melanoma skin cancer (NMSK) and a 2000-fold increased risk of melanoma. In our natural history protocol we ascertained and intensively examined more than 100 XP or Cockayne Syndrome (CS) patients and more than 200 family members at NIH and are collaborating with international researchers to study additional patients. We published detailed autopsy reports of 4 XP patients - including the first autopsy of an XP-D patient. The XP-A and XP-D patients were adults with severe neurological degeneration and were found to have infant sized brains. We found that peripheral neuropathy types differed between the XP-A and XP-D patients. We have now identified mutations in all of the 9 currently known DNA nucleotide excision repair (NER) genes (XPA XPB XPC XPD XPE XPF XPG ERCC1 and TTDA) in the error-prone polymerase pol eta and in TTDN1 in nearly 200 XP or TTD patients. We have established several hundred carefully documented cell lines and contributed them to cell banks for use of the general scientific community. We are using targeted and whole exome sequencing to look for mutations in other genes in cells from XP and TTD patients who do not have mutations in these genes. Our laboratory is the major center in the US for basic clinical and translational expertise concerning DNA repair related disorders. We are actively seeking and have developed the expertise to recognize unusual patients who have unique disease features that provide insights into the functioning of DNA repair genes. These studies have enabled us to identify some remarkable XP patients and better characterize different mechanisms of DNA repair. For example we found XPC patients with splice lariat branch point mutations who had 3 to 5% of XPC mRNA but mild disease indicating that only a small amount of XPC is sufficient for some cancer protection. We found that NER proteins accumulate and persist at sites of DNA damage in XP-B cells. In contrast these NER proteins rapidly accumulate but fail to persist in UV damaged XP-E cells. We found that the melanomas and nevi in the XP patients were different from those in the general population both clinically and histologically. They had a high proportion of mutations in the PTEN tumor suppressor gene (90% UV type) a lower frequency of mutations in BRAF NRAS or KIT and rarely had the BRAF V600E mutation found in the general population. About 12% of genetic diseases involve premature stop codons (PTC). We developed sensitive assay systems to detect readthrough of premature stop codons using cells from our collection with PTC in the XPC DNA repair gene. We found the aminoglycoside gentamycin can improve DNA repair in selected patients permitting precise targeting of therapy to responsive individual cell lines. We are plan to perform pre-clinical tests to determine if topical aminoglycosides can increase DNA repair without systemic toxicity. We are collaborating with NCI epidemiologists to study clinically normal family members of XP patients to determine if XP heterozygotes who are much more frequent than XP patients have increased cancer risk. We have more than 250 XP patients and family members in 54 families enrolled in this protocol. Our investigation of Big Data in the gnomAD database of more than 200000 alleles revealed an unexpectedly high frequency of 2 XP causing missense variants suggesting that there may be thousands of patients who are homozygous for these XP causing mutations in the US. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population. It is possible that variants in other genes modify the phenotype so that the usual features of XP are not apparent. We found that many of the women with mutations in the XPC gene have premature menopause. We found hematologic malignancies in 4 young (18 to 36 years) XP patients with mutations in the XPC gene. XP patients have increased frequency of thyroid nodules at a early age. 2. TRICHOTHIODYSTROPHY In contrast to the profound environmental influence of sun exposure on XP TTD is a disease of altered development. In our current natural history protocol we have ascertained and intensively examined more than 50 TTD or XP/TTD patients and more than110 TTD family members. This is the largest cohort of patients with this rare disorder in the world. We found that TTD patients with mutations in the TTDN1 gene had a distinct phenotype. In collaboration with gynecologists and epidemiologists we published 3 studies on pregnancy abnormalities in TTD. There was a high frequency of gestational abnormalities in pregnancies resulting in TTD affected offspring compared to pregnancies resulting in unaffected offspring from the same mothers or to the general population. These pregnancy complications were present only in pregnancies that had XP-D mutations that resulted in TTD offspring but not in XP-D mutations resulting in XP offspring. These observations provide important insights into the role of DNA repair genes in human pregnancy and fetal development. In collaboration with the ophthalmologists we published a detailed report of the eye findings of 32 TTD patients we studied from 2001 to 2010. Infantile cataracts were present in more than half of these patients. We documented the severe growth retardation in children with TTD. Several young children with TTD have lost the ability to walk due to aseptic necrosis of the femoral head. Unfortunately surgical treatment was followed by a series of post-operative complications leading to death. We are collaborating with radiologists to attempt to determine early signs of this problem and guide management. We have also found patients with features of more than one disease. Thus we identified 12 XP/TTD patients who have features of both XP and TTD and increased cancer risk. We are attempting to further define this entity by use of laboratory testing of DNA repair. In collaboration with colleagues in Italy we identified mutations in a transcription associated gene (GTF2E2) as causing TTD in two patients. This closely links TTD to transcription defects rather than DNA repair defects. 2095301 +Cancer; Genetics; Human Genome ATM activation;Ablation;Acetylation;Affect;Aging;Architecture;Binding;Binding Proteins;Biochemical;Bioinformatics;Biological Process;Biology;Bypass;C-terminal;Cell physiology;Cells;Chondrocytes;Chromatin;Chromatin Fiber;Chromatin Structure;Collaborations;Congenital Abnormality;Cytology;DNA;DNA Damage;DNA Double Strand Break;DNA Methylation;DNA Repair;Defect;Development;Developmental Process;Diagnosis;Disease;Down-Regulation;Epithelial;Etiology;Euchromatin;Event;Family;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genomic Instability;Genomic Segment;Global Change;Goals;HDAC4 gene;HMGN Proteins;HMGN1 gene;Hair;Hepatocarcinogenesis;Higher Order Chromatin Structure;Histone Deacetylase Inhibitor;Histone H1;Histone H3;Histones;Hypersensitivity;Image;Impairment;In Vitro;Investigation;Kinetics;Link;Malignant Neoplasms;Mediating;Mediator of activation protein;Molecular;Molecular Target;Mus;Names;Nuclear Protein;Nuclear Proteins;Nucleic Acid Regulatory Sequences;Nucleosome Core Particle;Nucleosomes;Nucleotide Excision Repair;Organism;Pathway interactions;Pharmaceutical Preparations;Phenotype;Photobleaching;Play;Post-Translational Protein Processing;Property;Proteins;Research;Role;SOX9 protein;Site;Stratum Basale;Stress;Structural Protein;Structure of beta Cell of islet;System;TP53 gene;Therapeutic;Up-Regulation;ataxia telangiectasia mutated protein;blastomere structure;cancer therapy;corneal epithelium;ds-DNA;epigenetic marker;epigenetic regulation;gamma irradiation;genome-wide;histone modification;insight;interdisciplinary approach;lead-binding proteins;link protein;novel;protein expression;protein function;reconstitution;repaired;targeted treatment;tissue culture;tumorigenesis;tumorigenic;ultraviolet irradiation Chromosomal Proteins and Chromosomal Functions n/a NCI 10702276 1ZIABC004496-45 1 ZIA BC 4496 45 6568847 "BUSTIN, MICHAEL " Not Applicable n/a Unavailable DIVISION OF BASIC SCIENCES - NCI Other Domestic Non-Profits UNITED STATES N Intramural Research 2022 927598 NCI Chromatin regulates gene expression and therefore plays a key role in developmental processes and in the etiology of various diseases including cancer. Nuclear protein such as histone H1 and HMGs have been shown to bind to and alter the properties of the chromatin fiber. Changes in the expression of these architectural proteins are linked to various developmental defects and to various diseases including cancer. However in spite of numerous studies the mechanism of action and the exact cellular function of these proteins remains one of the most perplexing aspects of chromatin biology. We are using a multidisciplinary approach including analyses of genetically modified mice to gain a comprehensive understanding of the biological function and mechanism of action of the HMGN proteins the only nuclear proteins that bind specifically to the nucleosome core particle the building block of the chromatin fiber. Biochemical and cytological approaches were used to demonstrate that the binding of these proteins to chromatin alters the higher-order chromatin structure and affect the cellular transcription profile. Using immunochemical analysis and fluorescent photobleaching imaging of living cells we demonstrated that the binding of HMGNs and H1 to chromatin is dynamic rather than static a finding that led to new insights into the kinetics of the intranuclear organization of most nuclear proteins. By microinjecting proteins into living cells expressing tagged proteins we demonstrated that H1 and HMGs form a network of competitive interactions on nucleosomes a novel concept that is relevant to understanding functional redundancy among related proteins and cellular homeostatic mechanisms. We have discovered a new chromatin binding protein named HMGN5/NSBP1 which we show that it binds specifically to euchromatin the genomic region containing transcriptionally active genes. We observed that this protein changes the global structure of chromatin and demonstrated that the C-terminal region of HMGN5 specifically interacts with the C-terminal region of H1. These studies provide fundamental insights into the molecular mechanisms governing chromatin dynamics. By analyzing Hmgn1-/- cells and by studying in vitro nucleosome reconstitution systems we found that H1 and HMGNs affect the levels of histone posttranslational modifications thereby identifying an additional mechanism that regulates the levels of these epigenetic markers. Indeed mice and cells lacking HMGN1 are more susceptible to various stresses such as heat ahock and DNA damage. The hypersensitivity to stress can be directly related to HMGN-dependent changes in histone modifications. Alterations in the levels of posttranslational modifications of histones have been linked to multiple biological processes including genetic instability and cancer. Our analyses of genetically modified mice and cells derived from these mice indicate that HMGN proteins play a role in the repair of damaged DNA and in the etiology of certain cancers. We find that loss of HMGN1 impairs the repair of both single stranded and double stranded DNA damage. The repair of the single stranded damage is impaired because the nucleotide excision repair (NER) cannot effectively access the damage sites. The repair of double stranded DNA breaks (DSB) is largely dependent on the action of the nuclear protein kinase ataxia-telangiectasia mutated (ATM). ATM regulates the activity of key molecules that affect tumorigenesis including p53. We found that loss of HMGN1 or ablation of its ability to bind to chromatin reduces the levels of DSB-induced ATM autophosphorylation and the activation of several ATM targets. HMGN1 alters the interaction of ATM with chromatin both prior to and following the induction of DNA damage and also enhances the DSB-induced acetylation of Lys14 of histone H3 (H3K14). Treatment of cells with a histone deacetylase inhibitor bypasses the HMGN1 requirement for ATM activation. Thus HMGN1 mediate the efficient activation of ATM by optimizing its chromatin interactions both prior to and after DSBs formation. Our studies identify a new mediator of ATM activation and demonstrate a direct link between the steady-state intranuclear organization of ATM and the kinetics of its activation following DNA damage. As chromatin binding proteins HMGNs affect developmental processes. We found that the expression of HMGN proteins is developmentally regulated and that during development the expression of these proteins is severely down regulated. Loss of HMGN1 affects the in vitro differentiation of chondrocytes. This effect is due to misexpression of Sox-9 a key regulator of chondrocyte differentiation. HMGNs bind to the chromatin of Sox 9 gene and affect its expression. Likewise we find that HMGN1 is expressed in the hair bulge region and loss of HMGN1 protein alters the hair cycle. We also found that HMGN1 is highly expressed in the basal layer of the epithelium including the corneal epithelium. Loss of HMGN1 affects the organization of the corneal epithelium. In mouse embryonic cells misexpression of HMGN affects several differentiation pathways. The results suggest that HMGNs regulate transcription levels of specific genes. Indeed our recent unpublished studies indicate that either down regulation or upregulation of HMGN in cells alters the cellular transcription profile. Towards further understanding the molecular mechanisms whereby HMGNs affect the cellular transcription profile we have initiated several collaborations aimed at elucidating the genome wide global organization of HMGNs. The results indicate that genome-wide HMGNs are associated with chromatin regulatory regions.A major new finding is that redundant and compensatory binding of HMGN proteins to nucleosomes maintain DNaseI hypersensitive regions in chromatin. This finding suggests that HMGN proteins maintain or establish regulatory sites in chromatin. Taken together our findings with genetically engineered mice and cells and our previous biochemical findings indicate that HMGNs are fine tuners of chromatin function and that proper differentiation and proper cellular function requires regulated expression of HMGN. 927598 +No NIH Category available Address;Affinity;Agonist;Alleles;Amino Acids;Antigen-Presenting Cells;Binding;Biomechanics;Cancerous;Cell surface;Cells;Clone Cells;Complex;Dangerousness;Data;Disease;Encapsulated;Engineering;Hour;Immune response;Immunologic Surveillance;Immunotherapy;In Vitro;Malignant Neoplasms;Methods;Microfluidics;Patients;Peptide Receptor;Peptide Vaccines;Peptides;Physiological;Play;Proteins;Qualifying;Recombinants;Role;Sensitivity and Specificity;Sorting;Surface;T cell response;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;TCR Activation;Techniques;Technology;Testing;Training;Transfusion;Tumor Antigens;Work;antigen-specific T cells;cancer immunotherapy;cancer therapy;cost;cytotoxic;engineered T cells;fighting;improved;in vivo;invention;microfluidic technology;neoantigens;new technology;next generation sequencing;novel;receptor binding;screening;side effect;tool Using microfluidics to realize patient-specific anti-cancer immunotherapies Project NarrativeT cells recognize diseased cells via molecular interactions between T cell receptors (TCRs) andpeptides presented by MHC molecules (pMHCs) and an improved ability to predict whichpMHC/TCR pairs drive strong T cell responses could improve our ability to engineerpersonalized anti-cancer therapies without dangerous side effects. T cell crawling duringimmunosurveillance applies biomechanical forces to pMHC/TCR complexes that are crucial forsensitive and specific recognition with activating pMHC/TCR pairs forming catch bonds thatstrengthen under force but current screening methods test pMHC/TCR binding in the absenceof force and thus fail to predict potent agonists in vivo. Here I will develop new microfluidictechnologies that make it possible to systematically interrogate 10000s of pMHC/TCRcomplexes for their ability to form catch bonds and drive potent T cell activation generatingcritical new tools and quantitative training data in the fight against cancer. NCI 10702214 9/19/23 0:00 RFA-RM-22-018 1DP1CA290563-01 1 DP1 CA 290563 1 "JOHNSON, ERIC MICHAEL" 9/19/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-MBBC-N(70)R] 8945082 "FORDYCE, POLLY MORRELL" Not Applicable 16 GENETICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 1080800 OD 700000 380800 Project SummaryT cells play a central role in the immune response detecting antigenic peptides cradled within MHC molecules(pMHCs) displayed on the surface of diseased cells via specific interactions with cell-surface T cell receptors(TCRs). This recognition triggers downstream T cell activation and cytotoxic killing. In vivo T cells areexquisitely sensitive and specific able to be activated by a single antigenic peptide displayed by a diseasedcell. Immunotherapies attempt to harness this sensitivity and specificity to eliminate cancerous cells by eithertransfusing patients with T cells engineered to display TCRs specific for tumor-associated antigens(neoantigens) or injecting peptide vaccines to stimulate expansion of neoantigen-specific T cell clones.Predicting which neoantigen/TCR combinations will activate a potent T cell response in a patient remains aformidable challenge. There are a vast number of potential pMHC/TCR complexes: MHC molecules areencoded by 23000 HLA alleles each MHC displays a ~9 amino acid peptide (209 possibilities) and eachpatient can express >1020 possible TCRs. While many techniques leverage next-generation sequencing toscreen millions of pMHC/TCR combinations for high-affinity binders these screens can test only a smallfraction of possible combinations.Moreover the strength of pMHC/TCR binding does not predict activation:many high-affinity peptides do not activate T cells and many potent agonists bind with only moderate affinities.T cells generate pN to nN forces on pMHC/TCR complexes as they crawl over antigen-presenting cells andemerging evidence has established that these biomechanical forces are essential for sensitive and specificTCR-pMHC recognition: pMHC/TCR complexes that drive potent activation form catch bonds that strengthenunder force while those that do not form slip bonds more likely to break. Thus developing improvedimmunotherapies requires new technologies capable of testing large numbers of candidate pMHC/TCRinteractions for their ability to form catch bonds and activate T cells under physiological forces.My lab is uniquely qualified to address this critical need. In prior work we developed a microfluidic platform thatenables recombinant cell-free expression purification and quantitative in vitro characterization of >1500proteins in hours and at low cost. Here we will apply this powerful technology to systematically investigatewhich pMHC/TCR combinations form catch bonds that predict activation (Platform 1) and which neoantigensare efficiently displayed by 1000s of different MHC sequences encoded by variable HLA alleles (Platform 2).To further test candidate pMHC/TCR combinations in their cellular context we will apply a novel droplet-basedtechnology we invented to co-encapsulate 10s of millions of T cell/APC pairs and sort them based on activation(Platform 3). 1080800 +No NIH Category available Alternative Splicing;Astrocytes;Brain;Breast Cancer Cell;Breast Cancer Model;Breast cancer metastasis;Cancer Biology;Cell Line;Cessation of life;Clinical;Data;Distant;ERBB2 gene;Exons;Family;Fatty acid glycerol esters;GLI gene;Genes;Goals;Hand;Human;In Vitro;Injections;Laboratories;Malignant Neoplasms;Mediating;Mediator of activation protein;Metastatic Neoplasm to Lymph Nodes;Metastatic malignant neoplasm to brain;MicroRNAs;Modeling;Molecular;Mouse Mammary Tumor Virus;Mus;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;Pathway interactions;Patients;Pattern;Play;Prognosis;Protein Isoforms;Proteins;Role;Route;SHH gene;Sampling;Sampling Studies;Signal Transduction;Stains;TP53 gene;Testing;Transcription Repressor;Transgenic Mice;Transgenic Organisms;Up-Regulation;Validation;Xenograft procedure;Zinc Fingers;angiogenesis;autocrine;base;brain cell;cancer cell;cytokine;exosome;gain of function;implantation;in vivo;insight;knock-down;malignant breast neoplasm;malignant phenotype;mammary;migration;monomer;mouse model;neoplastic cell;neurotropic;novel;nucleocytoplasmic transport;overexpression;paracrine;patient derived xenograft model;transcription factor;tumor;tumor growth Roles of tGLI1 and microRNA Network in Breast Cancer Brain Metastasis The goal of this project is to gain a better molecular understanding of breast cancer brain metastasis a majorcause of breast cancer death. This goal will be reached through using relevant models of breast cancerincluding cell line-derived xenograft mouse models PDXs and newly generated transgenic mouse models. Ifsuccessful our project will provide major advances in breast cancer biology. NCI 10702139 10/29/22 0:00 PA-21-268 7R01CA228137-04 7 R01 CA 228137 4 "SNYDERWINE, ELIZABETH G" 4/1/20 0:00 3/31/25 0:00 Tumor Progression and Metastasis Study Section[TPM] 7510037 "LO, HUI-WEN " "WATABE, KOUNOSUKE " 18 NEUROSURGERY 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF MEDICINE 770305400 UNITED STATES N 10/1/22 0:00 3/31/23 0:00 396 Non-SBIR/STTR 2022 414041 NCI 265411 148630 The goal of this proposal is to determine the role of tGLI1 (truncated glioma-associated oncogene homolog 1)in breast cancer brain metastasis (BCBM). Our laboratory discovered tGLI1 as an alternatively spliced GLI1 thatlacks entire exon 3 and part of exon 4 but retains the ability to undergo nuclear transport and respond to sonichedgehog-smoothened signaling. In addition to activating known GLI1 target genes tGLI1 gains the ability toactivate genes not regulated by GLI1 leading to increased migration invasion and angiogenesis. Whether tGLI1plays any role in metastasis of any tumor type is unknown. Our mouse studies indicated that tGLI1 promotesbreast cancer preferential metastasis to the brain and conversely tGLI1 knockdown selectively suppressedBCBM. tGLI1 protein is overexpressed in lymph node metastases and BCBM samples. In elucidating how tGLI1promotes BCBM we found that exosomes secreted from tGLI1-high cancer cells strongly activated astrocytesthe most abundant brain cells known to promote tumor growth when activated and that tGLI1-high cancer cellshad an increased ability to interact with and activate astrocytes in vitro and in vivo. Since microRNAs can beloaded into exosomes and circulating tumor exosomal miRNAs can prime distant organs for organ-specificmetastasis we conducted an exosomal miRNA microarray followed by validations and found that tGLI1-highcancer cells secreted high levels of exosomal miR-1290 and miR-1246 in vitro and in vivo. Whether miR-1290and miR-1246 play any role in brain metastasis of any cancer or astrocytes is unknown. We observed thatmiR-1290/1246 inhibited expression of two transcription repressors (FOXA2 and SOX9) which leads to secretionof ciliary neurotropic factor (CNTF) to activate astrocytes and stimulate cancer cells. We hypothesize thattumoral tGLI1 promotes brain metastasis by priming astrocytes in the metastatic niche and activated astrocytesin turn facilitate BCBM through secreting CNTF. We further hypothesize that tGLI1-high breast cancer cellsprime astrocytes via the novel signaling axis: tumoral tGLI1exosomal miR-1290/1246astrocyte FOXA2/SOX9astrocyte CNTFastrocyte activation. In Aim 1 we will determine the extent to which tGLI1 promotesBCBM using three mouse models (cell line-derived xenograft PDX and transgenic mice) overexpression andknockdown approaches two inoculation routes (intracardiac and mammary fat pad injections) and humanpatient samples. In Aim 2 we will examine whether and how tumoral tGLI1 upregulates exosomal miR-1290/1246 to activate astrocytes in the metastatic niche and clarify how miR-1290/1246 suppress FOXA2 andSOX9 expression within astrocytes how FOXA2 and SOX9 repress CNTF expression and the role of CNTF inastrocyte activation and BCBM progression. In Aim 3 we will examine if miR-1290 and miR-1246 play essentialroles in tGLI1-mediated BCBM identify their downstream targets and elucidate the roles of intracellular miR-1290/1246 in BCBM. The project could define tGLI1 miR-1290/1246 and CNTF as novel mediators of BCBMand regulators of astrocytes in the metastatic niche thus providing novel mechanistic insights into BCBM. 414041 +No NIH Category available Address;American Indians;Anxiety;Area;Cancer Burden;Cancer Care Facilities;Cancer Death Rates;Cancer Patient;Caregivers;Caring;Censuses;Cheyenne;Collaborations;Communities;Community Health Aides;Development;Education;Emergency department visit;Enrollment;Family;Family member;Future;General Hospitals;Goals;Great Plains;Health;Health Personnel;Healthcare;Healthcare Systems;Home;Hospitalization;Hospitals;Inpatients;Intervention;Interview;Knowledge;Leadership;Malignant Neoplasms;Massachusetts;Methods;Modeling;Montana;North Dakota;Outcome;Outcome Assessment;Outcome Measure;Pain;Palliative Care;Patients;Phase;Population;Population Intervention;Preparation;Protocols documentation;Provider;Quality of Care;Quality of life;Research;Rivers;Rural;Rural Health;Rural Population;School Nursing;Service delivery model;Services;Social Conditions;South Dakota;State Government;Symptoms;Testing;Teton Sioux Indian;Time;Translating;Transportation;Tribes;United States;United States Indian Health Service;Universities;Walking;Work;base;cancer care;care coordination;care delivery;care outcomes;care systems;design;effectiveness evaluation;end of life;experience;healing;health care service utilization;improved;improved outcome;innovation;member;mortality;multidisciplinary;northern plains;novel;novel strategies;palliative;patient engagement;programs;rural area;rural dwellers;rural healthcare;rural setting;rural underserved;satisfaction;socioeconomics;tribal health;tribal healthcare;tribal lands;tribal leader;urban area Advancing Palliative Care in Northern Plains American Indians American Indians in the Northern Plains experience high rates of cancer mortality inadequateaccess to cancer care and adverse social conditions making the development of an innovativeand culturally appropriate model of palliative care delivery a priority for tribes providers andhealth care systems in Western South Dakota. In this application we propose a two-phasestudy that will develop and evaluate a novel culturally appropriate approach to the delivery ofpalliative care services that builds upon existing work in the Northern Plains and advances inpalliative delivery in other settings. This proposal leverages a collaboration across 8organizations committed to improving the health of American Indians in Western South Dakotaan extraordinary opportunity to address a key aspect of the quality of cancer care in one of themost underserved rural populations in the US. NCI 10702121 9/20/22 0:00 PA-21-268 3R01CA240080-04S1 3 R01 CA 240080 4 S1 "WEAVER, SALLIE JAYNE" 7/1/22 0:00 8/31/24 0:00 ZCA1-SRB-2(M1)R 2087173 "ARMSTRONG, KATRINA " "PETEREIT, DANIEL G" 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 7/1/22 0:00 8/31/23 0:00 397 Non-SBIR/STTR 2022 393765 OD 352951 40814 C6 The quality of cancer care in the rural United States (US) is inadequate. The Northern Plains is one of the mostrural areas of the US including three states with the highest proportion of rural residents in the 2010 census(South Dakota North Dakota and Montana). In the Northern Plains the burden of cancer is not distributedequally with substantially higher cancer mortality among American Indians (AI) than Whites. Annual cancerdeath rates in this region are 338 per 100000 for American Indians compared to 223 for Whites. One of the greatest areas of need in cancer care for AIs in the Northern Plains is palliative care.Defined as the services needed to live well with serious illness access to palliative care by this population isalmost non-existent particularly in areas like western South Dakota where many tribal lands are located.Because of distance to the nearest cancer care facility inadequate transportation and lack of community-based palliative care support most AIs with cancer living on tribal lands are separated from their familiesduring inpatient cancer care and die either alone in a hospital or at home suffering unnecessarily fromsymptoms such as pain and anxiety. This situation is particularly unacceptable given the the US governmentalresponsibility for tribal health care the adverse socioeconomic conditions experienced by the tribes and theimportance the tribes place on spiritual preparation and community support at the end of life. This proposal arises from a collaboration of 8 programs dedicated to improving cancer care among AIsin Western South Dakota: the Walking Forward program of Avera Health the Oglala Sicangu and CheyenneRiver Lakota tribes the Great Plains Tribal Chairmen's Health Board the School of Nursing at South DakotaState University the Indian Health Service Great Plains Region and the Rural Health and Palliative Careprograms at Massachusetts General Hospital (MGH). These groups have come together to propose a two-phase study that will lead to a sustainable culturally tailored and effective palliative care program for AI cancerpatients in Western South Dakota. In Phase 1 we will build upon formative work understanding palliative careneeds barriers and opportunities in American Indians in this area palliative care educational programsdeveloped at MGH/Harvard and innovations in care delivery and patient engagement ongoing at MGH andelsewhere to create a culturally appropriate intervention for this population focusing on two key componentsprioritized by stakeholders: (1) multidisciplinary provider education and (2) in-home support and carecoordination through a palliative care focused community health worker program. In Phase 2 we will evaluatethese components using an innovative quasi-experimental factorial design examining the combined andindependent impact of the interventions on patient and caregiver outcomes as well as provider knowledge andcomfort. All phases of the project will be guided by a community advisory board composed of tribal healthleaders and representative enrolled members from the three tribes. 393765 +No NIH Category available Accountability;Area;Attitude;Behavior;Biomedical Research;Collaborations;Common Data Element;Communication;Communities;Complex;Data;Data Collection;Data Sources;Ecosystem;Elements;Ensure;Equity;Evaluation;Evidence based practice;Faculty;Failure;Feedback;Focus Groups;Fostering;Goals;Individual;Infrastructure;Institution;Intervention;Interview;Knowledge;Leadership;Maps;Measures;Mentors;Methods;Modeling;Monitor;Outcome;Participant;Pathway Analysis;Perception;Policies;Process;Program Evaluation;Progress Reports;Reporting;Reproducibility;Research;Research Personnel;Schools;Social Network;Source;Structure;Surveys;System;Teacher Professional Development;Testing;Time;United States National Institutes of Health;Universities;Work;career;cohort;cultural values;design;efficacy evaluation;empowerment;equity diversity and inclusion;faculty community;formative assessment;implementation determinants;improved;interoperability;knowledge translation;member;operation;organizational climate;primary outcome;programs;recruit;research faculty;skills;success;timeline Evaluation Core n/a NCI 10701949 9/11/23 0:00 RFA-RM-21-025 5U54CA272163-02 5 U54 CA 272163 2 9/9/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-X] 8474 12074246 "HOLMES, KRISTI " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 224889 141311 83578 EVALUATION COREABSTRACTThe Evaluation Core (EvalCore) for NURTURE: Northwestern University Recruitment to Transform Under-Representation and achieve Equity will evaluate and continuously improve our proposed ecosystem aimed attransformation to inclusive excellence. The EvalCore will use a systems approach that is equitable participatoryand continuously improving. It will monitor and track the progress of the program and participants; assessinterventions; map interactions and networks; monitor timelines; deeply examine knowledge skills attitudesand behaviors; and report progress toward the stated overall aims. These activities have been designed to bothlimit any evaluation burden on program participants and ensure that the NURTURE leadership investigatorsand advisors have a deep view into the complex and layered structure and operations of NURTURE and cantherefore refine improve and empower its activities. Program evaluation will be accomplished through thefollowing Specific Aims. Aim 1: Coordinate with other FIRST programs. The EvalCore will collaborate with theFIRST CEC and the FIRST awardee institutions to develop and coordinate evaluation activities reporting andcross-institution research metrics and approaches. Aim 2: Develop the evaluation framework and operationsneeded to assess the primary outcomes. EvalCore will use well-established strategy metrics workflows andquantitative and qualitative data measures and sources for evaluation in a systems approach to evaluation andresearch. Our approach is based on participatory and utilization-focused assessments that integrate evaluationdata reflection and feedback from across the system to advance the goal of NURTURE to create inclusiveexcellence. This evaluation framework will help NURTURE test the hypothesis that a cohort model of facultyhiring within a sustaining culture valuing inclusive excellence will achieve significant improvements in metrics ofinstitutional culture and scientific workforce diversity among biomedical research faculty. Aim 3: Implementexisting formative evaluations and develop new ones as needed for continuous improvement. The EvalCorein collaboration with the other cores of NURTURE will employ mixed methods to evaluate the efficacy of theNURTURE program elements. By exploring how each program element impacts the members of the NURTUREcohort and the broader Northwestern community we will adapt program elements as needed to achieve success.Aim 4: Communicate results for maximum impact. The EvalCore will establish a robust disseminationinfrastructure to drive accountability and transformative impact at Northwestern and beyond. It will provide andleverage FAIR (Findable Accessible Interoperable and Reproducible) dissemination channels to supportequitable knowledge translation and capacity building for the NURTURE program and its recruited cohort. Thesechannels will be used to communicate the results of NURTURE and the broader FIRST program. +No NIH Category available Address;Advanced Malignant Neoplasm;African American;African American population;Alabama;Attitude;Awareness;Behavior;Belief;Biomedical Research;Cancer Patient;Cancer health equity;Catchment Area;Clinical;Clinical Research;Clinical Trials;Communities;Community Health;Comprehensive Cancer Center;Disease;Early Diagnosis;Education;Environment;Equity;Evaluation;Genetic;Genomics;Goals;Institution;Joints;Knowledge;Latinx;Latinx population;Logic;Malignant Neoplasms;Medicine;Minority Participation;Modeling;Morehouse School of Medicine;National Cancer Institute;Outcome;Outcome Measure;Participant;Population;Population Heterogeneity;Prevention;Privacy;Research;Research Project Grants;Resources;Rural Community;Safety;Scientific Advances and Accomplishments;Services;Standardization;Surveys;Tablets;Technology;Therapeutic Clinical Trial;Training;Trust;Underserved Population;United States National Institutes of Health;Universities;Urban Community;anticancer research;cancer clinical trial;cancer genomics;cancer health disparity;cancer prevention;cancer risk;cancer therapy;clinical trial enrollment;design;education resources;evidence base;health disparity populations;interest;outreach;patient navigation;precision oncology;preference;programs;recruit;research study;theories Outreach Core n/a NCI 10701942 8/16/23 0:00 PAR-18-767 5U54CA118623-18 5 U54 CA 118623 18 9/28/05 0:00 8/31/26 0:00 ZCA1-SRB-2 8469 10345513 "CARTER, VIVIAN L" Not Applicable 3 Unavailable 128214178 U9JCYEXFEEU4 128214178 U9JCYEXFEEU4 US 32.428345 -85.709321 8439801 TUSKEGEE UNIVERSITY TUSKEGEE INSTITUTE AL Domestic Higher Education 360883606 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 194586 132367 62219 PROJECT SUMMARY: OUTREACH (This core is identical to all three partnering institutions)The overall goal of the Outreach Core is to implement and evaluate an evidence-based theory-informed multi-level clinical trial and cancer genomics education program (CTC-GEP) that addresses the determinants forAfrican American (AA) and Latinx participation in clinical trials and cancer genomics studies. The CTC-GEP isinformed by the Increasing Minority Participation in Clinical Trials (IMPaCT) program an efficacious clinical trialsnavigator program implemented at the University of Alabama at Birmingham ONeal Comprehensive CancerCenter. We will build on the findings of this program and extend application of the patient navigation model toparticipation in clinical trials and genomic cancer research. A cadre of lay community navigator professionalswill be trained and serve as clinical trials navigators (CCN) to deliver two unique types of toolkits comprised ofevidence-based educational resources on research participation (low-tech) and culturally tailored educationaland multiple media content via mobile tablet technology (high-tech). The CCNs will deliver these toolkits andprovide logistical support to participants interested in participating in cancer research in rural and urbancommunity health and academic research centers within the Partnership catchment areas. The CTC-GEP willalso address AA and Latinx beliefs values attitudes concerns and preferences related to participation inresearch such as privacy trust and safety. An evaluation plan based on a logic model will be applied throughoutthe project. Outcome measures will be assessed through pre- and post- surveys. The outcomes of the CTC-GEP include a) intentions to participate in research b) awareness and knowledge about research and c)genomic research and clinical trial enrollment. Additionally having a Joint Clinical and Biomedical ResearchAdvisory Roundtable (JCAR) guided clinical community navigation and education program will lead to increasedawareness opportunity and participation in genomic research and clinical trials among a diverse population ofAAs and Latinx. The rationale for this Core intended to facilitate research and not conduct research is to identifyeffective strategies to facilitate research participation among AA and Latinx populations. Thus the activitiesoutlined in this proposal are congruent with the strategies in the Comprehensive Partnerships to Advance CancerHealth Equity (CPACHE) RFA listed for the Outreach Core. +No NIH Category available Abdomen;Address;Binding;Cancer Etiology;Cancer Patient;Cause of Death;Cells;Cessation of life;Clinical Trials;Collagen;Colorectal Cancer;Data;Diffuse;Disease;Extracellular Domain;Extracellular Matrix;Extracellular Matrix Proteins;FDA approved;Fibroblasts;Fibronectins;Goals;Human;Imaging Device;In Vitro;Injections;Intestines;Knockout Mice;Knowledge;Ligands;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mediating;Mesothelial Cell;Mesothelium;Metalloproteases;Mus;Neoplasm Metastasis;Omentum;Organ;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Phase I Clinical Trials;Phosphotransferases;Play;Proliferating;Protein Secretion;Proteins;Publishing;Receptor Protein-Tyrosine Kinases;Recurrent Malignant Neoplasm;Recurrent tumor;Risk;Role;Serous;Small Interfering RNA;Stromal Cells;Testing;Tumor Cell Invasion;Tumor Promotion;Tyrosine Kinase Inhibitor;Wild Type Mouse;Woman;Work;cancer recurrence;cancer type;chemotherapy;discoidin domain receptor 2;fluorescence imaging;imaging platform;improved;in vivo;inhibitor;intraperitoneal;malignant stomach neoplasm;mouse model;neoplastic cell;novel;novel marker;novel therapeutics;ovarian neoplasm;overexpression;patient derived xenograft model;preclinical study;prevent;response;small molecule;statistics;targeted treatment;treatment response;tumor;tumor microenvironment Role of the microenvironment in ovarian cancer metastasis PROJECT NARRATIVEIn women ovarian cancer is the 11th most common cancer and the 5th most common cause of cancer-associated death. This proposal addresses an important cause of death for these women metastasis byuncovering mechanisms that contribute to disease spread and testing a novel drug that may help prevent it. Inthe long term this work may lead to Phase I clinical trials of DDR2 inhibitors in women at risk for ovarian cancerrecurrence. NCI 10701874 8/21/23 0:00 PA-18-484 5R01CA234553-05 5 R01 CA 234553 5 "AULT, GRACE S" 9/19/19 0:00 8/31/24 0:00 Tumor Microenvironment Study Section[TME] 11896219 "FUH, KATHERINE CYNTHIA" Not Applicable 11 OBSTETRICS & GYNECOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 361740 NCI 306269 55471 PROJECT SUMMARY / ABSTRACTHalf of all ovarian cancer patients die within five years. This is largely because their tumors recur afterchemotherapy and metastasize within the intraperitoneal cavity eventually blocking function of organs such asthe bowel. Additionally no FDA-approved drugs block the steps of intraperitoneal metastasis. Thus newstrategies are needed to prevent ovarian cancer metastasis. This proposal focuses on the receptor tyrosinekinase Discoidin Domain Receptor 2 (DDR2) as a candidate target to prevent ovarian cancer metastasis for thefollowing reasons. First DDR2 is overexpressed in 74% of advanced-stage high-grade serous human ovariantumors and 100% of metastases. Second patients whose tumors had higher levels of DDR2 had shorter survivalthan those with lower levels of DDR2. Third preliminary data shows that after tumor cell injection tumors formedin syngeneic DDR2 knockout mice were smaller and contained less collagen (the ligand for DDR2) than thosein DDR2 wild-type mice. Fourth promising small molecule DDR2 inhibitors have been developed that unlike allother receptor tyrosine kinase inhibitors bind and allosterically inhibit the extracellular domain of DDR2. Thisproposal will test the central hypothesis that DDR2 in stromal cells promotes steps of metastasis by actingthrough its ligand collagen to alter the microenvironment. Aim 1 will build on strong preliminary data showing thatDDR2 in the stroma promotes metastasis by identifying the particular stromal cells (fibroblasts and mesothelialcells) and steps in which DDR2 contributes to metastasis. This aim will make use of a large bank of humanprimary omental stromal cells and ovarian tumor cells. Aim 2 will test the hypothesis that DDR2 in the mesothelialcells fibroblasts or both is activated by collagen I leading to increased matrix metalloprotease 2 activity andfibronectin cleavage. Additionally this aim will test the hypothesis that DDR2 regulates collagen amount andorganization in the microenvironment and will identify proteins secreted by DDR2-expressing fibroblasts thatpromote ovarian tumor cell invasion. Aim 3 will assess the ability of a novel DDR2 inhibitor to enhance responseto chemotherapy and identify tumor microenvironment components that correlate with response. In addition totesting a novel DDR2 inhibitor in mouse syngeneic and patient-derived xenograft models of ovarian cancer thisaim will use a novel multi-parameter fluorescent imaging tool to define tumor/stromal cell expression patternsand extracellular matrix signatures that correlate with treatment response in mouse and human tumors.Completion of these aims will uncover novel mechanisms by which the tumor microenvironment contributes tointraperitoneal metastasis and reveal new potential targets for therapy. 361740 +No NIH Category available 3-Dimensional;AIDS-Related Diffuse Large B-cell Lymphoma;AIDS-Related Lymphoma;Acquired Immunodeficiency Syndrome;Address;Affect;B cell differentiation;B lymphocyte immortalization;B-Cell Development;B-Cell Lymphomas;B-Lymphocytes;BCL6 gene;Biology;Burkitt Lymphoma;Cell Compartmentation;Cells;Cellular biology;Central Nervous System Lymphoma;ChIP-seq;Chromatin;Classification;Clustered Regularly Interspaced Short Palindromic Repeats;Cues;Cytometry;Cytosine;DNA;DNA Modification Methylases;DNMT3B gene;Development;Down-Regulation;Enzymes;Epigenetic Process;Epstein Barr Virus B cell lymphoma;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Lymphoma;Epstein-Barr Virus-Related Malignant Neoplasm;Event;Exhibits;Family;Foundations;Frequencies;Future;Gene Silencing;Genes;Genetic;Genetic Transcription;Genome;Grant;HIV;Herpesviridae;Heterogeneity;Histologic;Histone H1;Histones;Hodgkin Disease;Human;Human Herpesvirus 4;Image;Immune;Immunocompetent;Immunologics;Infection;Integration Host Factors;Intrinsic factor;Knowledge;LMP1;Large-Cell Immunoblastic Lymphoma;Lead;Learning;Link;Lymphoma;Lymphomagenesis;Lymphoproliferative Disorders;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mediating;Memory;Methylation;Methyltransferase;Mexico;Modeling;Molecular;Mutate;Mutation;Mutation Analysis;Oncogenic;Oncogenic Viruses;Oncoproteins;PRC1 Protein;Patients;Pattern;Persons;Protein Isoforms;Proteomics;Recurrence;Regulation;Role;STAT3 gene;Sampling;Signal Transduction;Site;Structure of germinal center of lymph node;T-Cell Immunodeficiency;Tumor-Derived;Ubiquitination;Untranslated RNA;Variant;Viral;Viral Genome;Viral Proteins;Virus;Virus Latency;Work;antiretroviral therapy;cDNA Expression;cancer genome;chemical genetics;co-infection;cohort;cytokine;derepression;driver mutation;epigenome;genetic analysis;genetic manipulation;high risk;histone methyltransferase;infected B cell;interleukin-21;large cell Diffuse non-Hodgkin's lymphoma;latent gene expression;loss of function mutation;lytic gene expression;multiple omics;neoplastic cell;novel therapeutic intervention;post-transplant;pressure;primary effusion lymphoma;programs;promoter;recruit;superinfection;tumor;viral DNA;viral genomics;virology B cell determinants of EBV latency NarrativePeople living with HIV are at a much higher risk for developing B cell lymphomas and these are frequentlycaused by the Epstein Barr virus. This grant investigates how the biology of B cells determines what viralproteins are expressed how the virus affects B cell biology and how these events lead to lymphomadevelopment. NCI 10701826 7/27/23 0:00 PAR-21-348 5U01CA275301-02 5 U01 CA 275301 2 "DASCHNER, PHILLIP J" 9/9/22 0:00 8/31/27 0:00 ZCA1-SRB-P(M2) 1883862 "CESARMAN, ETHEL " "GEWURZ, BENJAMIN ELISON; ROTH, LISA GIULINO" 12 PATHOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 827799 NCI 631671 196128 Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with multiple cancers including Burkittlymphoma Hodgkin lymphoma primary central nervous system lymphoma and post-transplant lymphomas.EBV-associated B-cell lymphomas occur at significantly higher frequency in the setting of HIV co-infectioneven with the use of antiretroviral therapy. AIDS-related lymphomas (ARLs) are most commonly diffuse large Bcell lymphomas (DLBCLs) followed by Burkitt lymphoma and classical Hodgkin lymphoma (cHL) all frequentlyassociated with EBV infection. Each of these cancers is linked to a viral latency program that is used as EBV-infected B-cells navigate the B-cell compartment to colonize memory cells the reservoir for lifelong infection.Yet much remains to be learned about epigenetic mechanism that control viral oncoprotein expression andhow this can ultimately be exploited in novel therapeutic approaches. We therefore recently performedCRISPR and chemical genetic analysis to identify host factors that tightly regulate the expression of EBVoncoproteins in B-cells. These analyses highlighted host DNA and histone methyltransferases with key roles inregulation of EBV latency and lytic gene expression. Characterization of top screen hits revealed multiplelayers of EBV oncoprotein control yet how DNA and histone methyltransferases target specific EBV genomicpromoter sites remains largely unknown. In parallel we integrated these studies with tumor genome mutationanalysis to identify host genes that are mutated at high frequency in EBV-infected and EBV-uninfected B-celllymphomas. These analyses recently identified that linker H1 histone genes which are highly recurrent in Bcell lymphomas are genetic driver mutations in lymphomagenesis. They also demonstrated that histone H1mutation drives malignant transformation via three-dimensional genome reorganization resulting in epigeneticreprogramming and de-repression of developmentally silenced genes. Notably our proteomic analysisidentified that EBV strongly downmodulates expression of multiple linker histone 1 isoforms though it remainsunknown how this H1 subversion alters the viral and host genome landscape in EBV-associated lymphomas.We hypothesize that germinal center microenvironment cues orchestrate B-cell epigenetic programsthat together with EBV oncoprotein effects on linker histone expression dictate tumor latencyprograms. While immunological selective pressures also contribute to latency we propose that T-follicularhelper signals and cell intrinsic factors control EBV latency patterns. Our specific aims are therefore to: 1)Identify how key germinal center cytokines affect epigenetic writers to alter the EBV epigenome and dictatelatency program selection. 2) Identify dynamic histone H1 roles in EBV epigenome and latency programregulation. 3) Define the relationship between B-cell differentiation state epigenetic profile and EBV latencypattern in HIV+ DLBCL. Collectively these studies address long-standing question in the EBV tumor virologyfield and lay the foundation for novel therapeutic approaches to EBV-driven human malignancies. 827799 +No NIH Category available Antibodies;Antineoplastic Agents;Attenuated;Cancer Etiology;Cancer Patient;Cessation of life;Characteristics;Clinical;Collagen;Combined Modality Therapy;Culture Media;Data;Deposition;Desmoplastic;Developing Countries;Diameter;Distal;Dose;Drug Delivery Systems;Encapsulated;Engineering;Enzymes;Epithelium;Extracellular Matrix;Extracellular Matrix Degradation;Frequencies;Goals;Hyaluronan;Hyaluronic Acid;Hyaluronidase;Immune;Immunotherapy;Incidence;Infiltration;Investigational Drugs;Legal patent;Malignant Neoplasms;Malignant neoplasm of pancreas;Manuals;Measures;Mesenchymal;Methods;Myofibroblast;National Cancer Institute;Neoplasm Metastasis;Pancreatic Ductal Adenocarcinoma;Patients;Penetration;Perfusion;Permeability;Pharmaceutical Preparations;Plasmids;Play;Primary Neoplasm;Production;Public Health;Publishing;Recombinants;Regenerative capacity;Regimen;Research;Role;Salmonella;Salmonella typhimurium;Serious Adverse Event;Solid;Solid Neoplasm;Surface;Survival Rate;Testing;Therapeutic;Therapeutic Effect;Tissues;Treatment Efficacy;Tumor Burden;Tumor Promotion;Tumor Tissue;Tumor-infiltrating immune cells;Vascularization;Work;advanced disease;cancer therapy;candidate identification;chemotherapy;clinical translation;clinically relevant;collagenase;comparative efficacy;conventional therapy;cost;density;design and construction;experience;immune cell infiltrate;immune checkpoint blockade;improved;innovation;interstitial;macromolecule;manufacture;microbial;mortality;mouse model;novel;novel strategies;pancreatic ductal adenocarcinoma model;pressure;prevent;promoter;protein expression;remediation;side effect;smoothened signaling pathway;standard of care;systemic toxicity;therapy resistant;tumor;tumor growth;vector Microbial- based targeting of major extracellular matrix components for improved therapy of pancreatic cancer PROJECT NARRATIVEPancreatic cancer has a mortality rate approximately equal to its incidence and will soon become the second-leading cause of all cancer-related deaths. High mortality is primarily the result of treatment resistance andtherefore the current proposal seeks to develop microbial-based tumor-targeted approaches to diminish theabundance of extracellular matrix components that significantly reduce delivery and efficacy of therapy inpancreatic cancer. Our research is relevant to public health because it is expected to generate approachesthat will safely promote tumor permeability and drug perfusion ultimately enabling anticancer agents to achievetheir greatest therapeutic effects in cancer patients. NCI 10701792 8/28/23 0:00 PAR-19-193 5R01CA266472-02 5 R01 CA 266472 2 "RASOOLY, AVRAHAM" 9/9/22 0:00 8/31/27 0:00 Developmental Therapeutics Study Section[DT] 10890689 "MANUEL, EDWIN " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 357896 NCI 203350 154546 PROJECT SUMMARYTherapeutic resistance is a major contributor to high lethality in pancreatic ductal adenocarcinoma (PDAC). Aprominent feature of PDAC is desmoplasia the formation of fibrous tissue that not only plays a critical role inreducing drug perfusion but also in limiting anti-tumor immune cell infiltration and function. The fibrous tissue isprimarily composed of the extracellular matrix (ECM) components hyaluronan (HA) and collagen (CN). Previousmethods to target these major ECM components have caused severe systemic side effects in patients and thusfinding a safe effective approach to disrupt the PDAC ECM and improve drug delivery remains a critical unmetneed. Our long-term goal is to develop tumor-specific microbial-based agents that express functional ECM-degrading enzymes. This novel strategy will remediate tumor desmoplasia minimize systemic toxicity andmaximize the penetration and efficacy of therapeutics against primary PDAC tumors as well as distalmetastases. The objective of this proposal is to determine the utility of attenuated Salmonella typhimurium(ST)-based agents engineered to express the ECM-degrading enzymes hyaluronidase (ST-HAse) andcollagenase (ST-CNase) in triggering collapse of dense tumor stroma and in enhancing therapeutic efficacy inclinically-relevant models of PDAC. The rationale underlying this proposal is that successful completion of thesestudies will identify a feasible tumor-targeting approach to ameliorate desmoplasia in PDAC which will enableanticancer agents to achieve their greatest therapeutic effects.Our central hypothesis is that degrading both HA and CN in PDAC using tumor-specific ST vectors will inducethe greatest stromal collapse ultimately leading to enhanced penetration and efficacy of therapeutic treatment.This central hypothesis will be tested in relevant models of PDAC by pursuing three specific aims: (1) Determinethe effect of dual ST-HAse/CNase treatment on the antitumor efficacy of standard-of-care chemotherapy; (2)Determine the impact of dual ST-HAse/CNase treatment on efficacy of immune checkpoint blockade therapy;and (3) Develop and characterize recombinant STs expressing HAse and CNase under tumor-induciblepromoters.The use of tumor-colonizing ST and tumor-inducible bacterial promoters to express ECM-degrading enzymes isan innovative strategy to limit the effects of stromal degradation to tumor tissues. Furthermore simultaneouslydegrading HA and CN will result in greater tumor permeability than targeting either component alone. The resultsof this work will have a significant impact for PDAC patients because it is predicted to yield an agent(s) thatcan in the short-term be optimized for manufacturing and Investigational New Drug (IND)-enabling studies andin the long-term become a first-in-class microbial-based agent used to significantly improve drug permeabilityof desmoplastic primary and metastatic tumors that are inaccessible to conventional therapy. 357896 +No NIH Category available Abstinence;Acceleration;Address;Adherence;Adoption;Affect;Appalachian Region;Area;Biochemical;Chronic Disease;Clinical;Code;Combined Modality Therapy;Communities;Community Pharmacy;Compensation;Counseling;Diabetes Mellitus;Documentation;Effectiveness;Face;Focus Groups;Future;Health;Health Promotion;Hypertension;Insurance Carriers;Intervention;Maintenance;Malignant Neoplasms;Medication Management;Methods;Modeling;National Cancer Institute;Outcome;Participant;Patients;Pharmaceutical Preparations;Pharmacists;Pharmacy facility;Policies;Population;Prevalence;Primary Care;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Research;Resources;Risk Factors;Rural;Rural Appalachia;Rural Population;Services;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Statutes and Laws;Surveys;Time;Tobacco;Tobacco Use Cessation;Tobacco use;Tobacco-Related Carcinoma;Update;acceptability and feasibility;cigarette smoking;cost;effectiveness evaluation;evidence base;experimental study;follow-up;high risk;implementation evaluation;implementation fidelity;improved;incremental cost;medically underserved;medication compliance;nicotine gum;nicotine replacement;parity;post implementation;primary care setting;primary outcome;programs;quitline;recruit;relative cost;rural area;smoking cessation;smoking-related cancer;text messaging intervention;underserved area;underserved rural area;urban area Leveraging Community Pharmacists to Optimize Smoking Cessation Services for Rural Smokers in Appalachia While there are publicly available smoking cessation resources (e.g. state quitlines text-basedinterventions nicotine replacement therapy [NRT]) these programs are under-utilized by ruralAppalachian smokers. Community pharmacists may be ideally situated to identify recruit andrefer these hard-to-reach smokers in rural areas to resources using an ask-advise-connectmodel and provide medication therapy management support for smoking cessation to enhanceboth the reach and effectiveness of existing tobacco cessation resources for smokers. Thecurrent proposal will accelerate scientific discovery and dissemination of widely availablesmoking cessation strategies by integrating treatment into community pharmacies inunderserved rural areas of Appalachia thus leading to significant improvement in smoking-related cancer health outcomes among high-risk rural smokers. NCI 10701777 8/31/23 0:00 RFA-CA-20-051 5R01CA267963-02 5 R01 CA 267963 2 "BLAKE, KELLY D" 9/8/22 0:00 8/31/27 0:00 ZCA1-RPRB-L(A1)R 11325974 "LITTLE, MELISSA ASHLEY" Not Applicable 5 PUBLIC HEALTH & PREV MEDICINE 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 997074 NCI 617383 379691 Rural Appalachian populations have the highest rates of cigarette smoking in the U.S. and aredisproportionately affected by tobacco-related cancers. Publicly available smoking cessation resources (e.g.state quitlines text-based interventions nicotine replacement therapy [NRT]) are under-utilized by ruralAppalachian smokers. Furthermore rural Appalachia is medically underserved; thus smoking cessationservices within primary care settings face additional barriers. Community pharmacists with theircentralized placement in local communities and clinical expertise are ideally situated to build capacityin underserved areas such as rural Appalachia to enhance existing smoking cessation resources forsmokers. Research on pharmacist-delivered smoking cessation interventions is limited and does not providefor documentation and billing to compensate pharmacists for their time spent counseling patients. MedicationTherapy Management (MTM) a pharmacist-delivered medication adherence approach that allows pharmaciststo receive compensation for providing medication expertise could be leveraged to promote smoking cessation.To address this gap we developed an MTM intervention QuitAid to increase smoking cessation among ruralsmokers. QuitAid was based on a medication adherence intervention shown to be efficacious in a quitlinesetting. The purpose of the proposed study is to use a pragmatic approach guided by the ReachEffectiveness Adoption Implementation and Maintenance (RE-AIM) framework to identify the essentialcomponents of an effective smoking cessation program that can easily integrate within community pharmaciesin underserved rural areas. Smokers (n=768) recruited through 14 community pharmacies in rural Appalachiawill be randomized in a 25 full factorial experiment to the following five treatments: (1) QuitAid (Yes vs. No) (2)tobacco quitline (Yes vs. No) (3) SmokefreeTXT (Yes vs. No) (4) Combination NRT Gum + NRT Patch (vs.NRT patch alone) and/or (5) 8 weeks of NRT (vs. standard 4 weeks). The primary outcome is biochemically-confirmed point prevalence abstinence at the 6-month follow-up. We will also assess implementation includingrelative cost as well as facilitators and barriers of reach adoption and maintenance of QuitAid and standardevidence-based tobacco treatments through an ask-advise-connect method in community pharmacies. Ourmain hypothesis is that a smoking cessation MTM will increase smoking cessation and enhance reach andadherence to publicly available smoking cessation resources in medically underserved rural areas. Theproposed study will: (1) provide foundational evidence for leveraging community pharmacists in underservedand rural areas to promote utilization of existing evidence-based tobacco cessation resources throughenhanced MTM support (2) inform updated national guidance on treating rural smokers and (3) aid statelegislation efforts related to pharmacy smoking cessation programs and policies. Ultimately this research willinform strategies for smoking cessation in rural areas such that cancer rates achieve parity with urban areas. 997074 +No NIH Category available Age;Anatomy;Astrocytoma;Biological Markers;Blood Volume;Brain;Brain Neoplasms;Carbon;Cell Respiration;Cerebrum;Clinical;Clinical Management;Clinical Research;Cognition;Creatine;Data;Decision Making;Diagnosis;Diffusion;Edema;Evaluation;Excision;Functional Magnetic Resonance Imaging;Glioma;Gliosis;Glutamates;Glycolysis;Grant;Image;Impaired cognition;Impairment;Infrastructure;Injury;Intervention;Lesion;Location;Magnetic Resonance Imaging;Measures;Metabolic;Metabolism;Modeling;Monitor;Mutation;N-acetylaspartate;Neurocognitive;Neurocognitive Deficit;Neurons;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Perfusion;Physiological;Positioning Attribute;Productivity;Protocols documentation;Protons;Publications;Pyruvate;Quality of life;Radiation therapy;Recording of previous events;Recurrence;Recurrent tumor;Reproducibility;Research;Research Design;Rest;Risk;Scanning;Schedule;Scientist;Severities;Technology;Testing;Time;Tissue Sample;Tissues;Treatment Protocols;Tumor Biology;Tumor Burden;Tumor Volume;United States National Institutes of Health;Work;brain abnormalities;clinical examination;cognitive function;early detection biomarkers;effective therapy;experience;first-in-human;image guided;imaging study;improved;interest;metabolic imaging;multimodal neuroimaging;multimodality;neoplastic cell;novel;pre-clinical;real-time images;regional difference;response;spectroscopic imaging;survival outcome;survival prediction;temozolomide;treatment effect;treatment response;treatment strategy;tumor;tumor growth;volunteer;white matter Multimodality Neuroimaging Evaluation of Cognitive Functioning in Lower Grade Astrocytoma PROJECT NARRATIVEDespite patients with lower grade glioma benefit from better survival injury from tumor growth andconsequence of treatment such as radiation therapy often leads to impaired cognition and quality of life. Theproposed study will investigate patients with lower grade astrocytoma using a multimodality MR protocol toassess the tumor burden cognitive functioning and quality of life. The results of the proposed study will becritical for developing effective treatment strategies to improve quality of life in lower grade astrocytoma. NCI 10701775 8/18/23 0:00 PA-20-185 5R01CA273028-02 5 R01 CA 273028 2 "TANDON, PUSHPA" 9/9/22 0:00 8/31/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 11594290 "LI, YAN " "GORDON, JEREMY WILLIAM; VILLANUEVA-MEYER, JAVIER " 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 653911 NCI 404898 249013 PROJECT SUMMARYSurvival outcomes for patients with lower grade gliomas continue to improve as diagnosis and treatmentevolve. However damage caused by tumor growth and by the consequences of treatment often leads tosignificantly impaired cognitive function. Our previous work has demonstrated that radiation therapy reducedratios of N-acetyl-aspartate (a neuronal biomarker) levels to creatine derive from proton-1 MR spectroscopicimaging within the normal-appearing white matter. This steady state metabolic imaging also provides othermetabolic parameters to differentiate tumor cells from normal brain detect the presentence of IDH mutationand predict survival in lower grade glioma. In addition stable and treatment-free lower grade glioma hadimpaired cognition and quality of life with the severity associated with the history of treatment and the volumeof T2 lesions. These results suggest that the use of multiparametric MRI could improve tumor delineationidentify patients at risk for specific deficits and provide an opportunity for intervention. The objective of thistranslational proposal is to utilize a novel multimodality MR protocol which integrates dynamic and steadystate MR metabolic imaging with diffusion perfusion and resting-state functional MRI to provide quantitativemetrics on dynamic and steady-state metabolism white matter integrity blood volume and functionalnetworks to evaluate cognitive functioning and quality of life in patients with lower grade astrocytoma. We willtake advantage of our unique experience in proton-1 MR spectroscopic imaging which has been implementedinto routine clinical examinations and hyperpolarized carbon-13 pyruvate imaging where we performed thefirst-in-human [2-13C]pyruvate study to image real-time glycolysis and oxidative metabolism simultaneously toassess tumor burden cognitive functioning and quality of life. Once the multimodality MR protocol has beenestablished in Aim 1 we will evaluate the normal and abnormal brain changes during radiation therapy andthen correlate these changes to impairments in cognitive functioning and quality of life in Aim 2. Aim 3 willexamine signatures associated with recurrent tumors and evaluate the impact of tumor burden on cognitionand quality of life. The results of the proposed study will be critical for assessing response to treatmentdeveloping effective treatment strategies and improving quality of life. Ultimately it will provide effectiveclinical management of patients and aid neuro-oncologists in making timely decisions. 653911 +No NIH Category available Address;Collaborations;Communication;Communities;Coordination and Collaboration;Data;Data Reporting;Elements;Evaluation;Faculty;Feedback;Florida;Focus Groups;Fostering;Funding;Goals;Growth;Hawaii;Health Sciences;Human Resources;Individual;Infrastructure;Institution;Interview;Knowledge;Laboratories;Leadership;Learning;Logic;Mentors;Methods;Modeling;Monitor;Outcome;Outcome and Process Assessment;Participant;Process;Productivity;Program Evaluation;Recommendation;Records;Reporting;Research;Resources;Science;System;Systems Theory;Teacher Professional Development;Techniques;Training;Universities;archived data;career;career development;cohort;diversity and inclusion;effectiveness evaluation;equity diversity and inclusion;implementation evaluation;improved;innovation;meetings;member;model design;programs;recruit;research and development;timeline Fostering Institutional Resources for Science Transformation: The FLORIDA-FIRST Health-science Brigade n/a NCI 10701774 8/31/23 0:00 RFA-RM-20-022 5U54CA267730-03 5 U54 CA 267730 3 9/24/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 5979 10133944 "BARILE, JOHN PAUL" Not Applicable 2 Unavailable 790877419 JF2BLNN4PJC3 790877419 EXTRKMMCVKS7; JF2BLNN4PJC3; WEUJG9RND395 US 30.441455 -84.297889 513804 FLORIDA STATE UNIVERSITY TALLAHASSEE FL Domestic Higher Education 323064166 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 262872 262872 0 PROJECT SUMMARY We will apply a systems-theory approach that leverages participatory techniques archival data andsustainable infrastructure to establish monitor and report on The FLORIDA-FIRST BRIGADE. Traditionalsystem-theory approaches with cutting-edge participatory approaches and common element themes in concertwith the Coordination and Evaluation Center (CEC) to collect data that benefits the participants in TheFLORIDA-FIRST BRIGADE informs the FSU community and leads to a more diverse and productive scientificcommunity. The purpose of the evaluation will be to carry out an innovative formative (process) and summative(outcome) approaches to monitoring and reporting on the FLORIDA-FIRST BRIGADE. Recent research on theevaluation of collaborative health-science centers finds that for (1) an evaluation to be successful allstakeholders must have significant engagement participation and commitment to the evaluation; (2) include acomprehensive logic model; and (3) include participation of the evaluator in leadership and core meetings tofacilitate continuous feedback. The Evaluation Core will meet these recommendations and be responsible formonitoring inputs resources and activities; identifying implementation difficulties; and assessing theeffectiveness of function activities in attaining the specific aims of the FLORIDA-FIRST BRIGADE. Theevaluation will focus on assessing the implementation of short- and long-term goals while providing quarterlyrapid cycle evaluations to maximize growth opportunities during the funding period. The evaluation willdocument program integrity monitor progress and provide feedback to The FLORIDA-FIRST BRIGADEleadership and the CEC. The Overall Administrative and Faculty Cores each have specific aims and statedtimelines to meet these aims. The evaluation will continuously evaluate progress towards meeting these aimsand provide program leadership with timely assessments to support quality improvement and programmaticchange. The Evaluation Core will focus on assessing three specific aims: Aim 1. Assess the quality and impact of changes to the tenure and promotion process for 6 UMR faculty(FIRST Cohort) in research centers and/or laboratories instead of traditional academic departments. Aim 2. Assess the level or coordination and collaboration among the Office of Human Resources and theOffice of Faculty Development and Advancement associated with addressing diversity equity inclusion andretention for The FIRST Cohort. Aim 3. Assess the process and outcomes associated with the integrated individual research and careerdevelopment and mentoring plans for The FIRST Cohort. +No NIH Category available Address;Biological Markers;CD44 gene;Cancer Patient;Cell Survival;Cells;Critical Pathways;Development;Disease;Disease Progression;Disease remission;Drug resistance;Engraftment;Gene Expression;Genes;Genetic Transcription;Goals;IL2RA gene;Impairment;Knowledge;Leukemic Cell;Link;Malignant Neoplasms;Methylation;Modeling;Modification;Molecular;Mus;Outcome;Pathway interactions;Patients;Positioning Attribute;Process;Proliferating;Protein Tyrosine Kinase;Proto-Oncogene Protein c-kit;RNA;Recurrent disease;Refractory;Regimen;Regulation;Research;Resistance;Resistance development;Role;Signal Transduction;Source;Testing;Therapeutic;Translational Research;Treatment Efficacy;Treatment Failure;Tyrosine Kinase Inhibitor;Untranslated RNA;Up-Regulation;Work;advanced disease;cancer drug resistance;cancer stem cell;cell growth;clinical biomarkers;clinical translation;demethylation;design;differential expression;drug maintenance;drug sensitivity;epitranscriptomics;experience;fat mass and obesity-associated protein;gain of function;gene repression;improved;inhibitor;inhibitor therapy;innovation;knock-down;leukemia;leukemia treatment;leukemic stem cell;loss of function;methylome;molecular targeted therapies;mouse model;new therapeutic target;novel;novel strategies;patient response;pharmacologic;pre-clinical;refractory cancer;response;self-renewal;stem cell biomarkers;stem cell fate;stem cell function;stem cell self renewal;stemness;targeted treatment;treatment strategy;tumor progression Role of an Aberrant N6-Methyladenosine-LncRNA Axis in the Development and Maintenance of Drug Resistance through Regulating the Leukemia Stem Cell Despite the initial responses to molecular-targeted therapies many cancer patients experience diseaserecurrence because cancer stem cells (CSCs) are refractory to these treatments with largely unknownmechanisms. This project will identify new genes/pathways (i.e. FTO-m6A-lncRNAs) regulating CSCpersistence and test novel strategies (i.e. inhibiting FTO-m6A-lncRNAs to restore drug sensitivity) to eliminateCSCs. The findings will propel the design of new treatment options to achieve treatment-free remissionimproving cure rates and survival. NCI 10701762 8/31/23 0:00 PA-20-185 5R01CA266256-02 5 R01 CA 266256 2 "O'HAYRE, MORGAN" 9/12/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-OTC1-M(80)S] 9226287 "LIU, SHUJUN " "HUANG, GANG ; TSE, WILLIAM W" 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 591097 NCI 435258 155839 Tyrosine kinase targeted (TKI) therapies have revolutionized leukemia treatment but TKIs are not able to killleukemia stem cells (LSCs) which are responsible for propagating and disease recurrence and believed to bethe source of treatment failure. Our long-term goals are to further address how LSC persistence is regulatedand to develop new LSC-eliminating treatment strategies to improve cure rates and survival. The short-termgoals of this research are to determine whether a N6-methyladenosine (m6A)--long non-coding RNA (lncRNA)axis regulates LSC stemness and persistence during TKI selection process and to explore the therapeuticpotential of targeting the m6A-lncRNA axis for eradicating TKI resistant LSCs and also decipher the underlyingmolecular mechanisms. The m6A methylation is the most common epitranscriptomic modification on RNAs (i.e.lncRNAs) and crucially regulates lncRNA-initiated gene expression. lncRNA abnormalities frequently associatewith cancer disease progression and drug resistance. The preliminary evidence linking an m6A-lncRNA axis toresistant LSCs is from our proof of principle studies demonstrating that i) a dynamic and reversible m6Amethylome determined by fat mass and obesity-associated protein (FTO) helps leukemia cells avoid TKI killingleading to TKI resistance; ii) there are many lncRNAs (annotated) that are differentially expressed in resistantversus sensitive cells. About 50% of these lncRNAs bear m6A motifs and have the changed m6A amounts inresistant cells collectively suggesting a unique lncRNA signature that is specific to TKI resistance and isregulated by m6A methylation; iii) upregulation of these m6A-associated lncRNAs in patients who do not respondto TKIs is predicative of worse outcomes and knockdown of them impairs resistant cell growth and rendersresistant cells sensitive to TKIs; iv) compared to sensitive ones TKI-resistant cells highly express LSC markers(CD117 CD44 CD25 CD133) whose upregulation is associated with m6A reduction. Our hypothesis is that theFTO-m6A-lncRNA cascade may be a critical pathway to control LSC persistence to TKIs and a new druggabletarget to eradicate persistent LSCs improving TKI cure rates. We will test our hypothesis through three aims: 1)Determine how the FTO-m6A axis regulates lncRNA aberrations in TKI resistance; 2) Determine whether andhow a dynamic m6A methylome regulates LSC persistence to TKIs; 3) Determine whether and howpharmacological targeting of the FTO-m6A-lncRNA cascade kills persistent LSCs using preclinical leukemiamodels. The proposed studies are conceptually innovative because it targets a new pathway (the FTO-m6A-lncRNA cascade) in understanding LSC persistence to TKIs and in developing new regimens to eliminate TKIresistant LSCs. The proposed research is significant because the findings will a) identify new pathways (i.e.FTO-m6A-lncRNA cascade) that regulate LSC persistence deepening the molecular understanding of LSCs andlncRNA functions; b) develop new approaches (targeting the FTO-m6A-lncRNA cascade) to eliminate persistentLSCs improving the management of patients with refractory leukemia. 591097 +No NIH Category available Activated Natural Killer Cell;Antigens;B-Lymphocytes;Cell Maturation;Cell physiology;Cell-Mediated Cytolysis;Cells;Cellular biology;Complex;Computer Models;Data;Data Set;Development;Disease;Effector Cell;Engineering;Equilibrium;Flow Cytometry;Host Defense;Human;Immune;Immunotherapy;Kinetics;Knowledge;Libraries;Ligands;Link;Machine Learning;Mass Spectrum Analysis;Mathematics;Measures;Mediating;Membrane;Methods;Modeling;Molecular;Multiple Myeloma;NK Cell Activation;Natural Killer Cell Immunotherapy;Natural Killer Cells;Outcome;Pathway interactions;Phosphorylation;Play;Protein Engineering;Receptor Cell;Receptor Signaling;Research;Role;Signal Pathway;Signal Transduction;Signaling Protein;Site;Source;Structure;Systems Biology;T-Lymphocyte;Testing;Time;Tumor Antigens;Western Blotting;Work;cancer cell;cancer immunotherapy;cell killing;cell type;chimeric antigen receptor;cytokine;cytotoxic;cytotoxicity;data-driven model;design;engineered T cells;experience;immune function;in vitro testing;in vivo;insight;interest;mathematical model;mouse model;novel;phosphoproteomics;predictive modeling;receptor;receptor-mediated signaling;response;success;tool;tumor Modeling based design of chimeric antigen receptors for Natural Killer cell-based immunotherapy NARRATIVENatural killer (NK) cells are innate immune effector cells that may be engineered for cancer immunotherapy byexpression of chimeric antigen receptors (CARs) engineered proteins that direct NK cells to kill cancer cells.Our proposed studies will generate a fundamental understanding of intracellular signaling mediated by NK-CARsto enable efficient design of optimal CARs for multiple myeloma. This research has the potential to unlock thetransformative power of NK-CAR cells for cancer immunotherapy. NCI 10701754 8/14/23 0:00 PAR-19-287 5U01CA275808-02 5 U01 CA 275808 2 "ZAMISCH, MONICA" 9/9/22 0:00 8/31/27 0:00 ZCA1-RTRB-R(M2) 10296807 "FINLEY, STACEY DELERIA" "GRAHAM, NICHOLAS ALEXANDER" 37 BIOMEDICAL ENGINEERING 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA BIOMED ENGR/COL ENGR/ENGR STA 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 513835 NCI 378777 135058 PROJECT SUMMARY/ABSTRACT Natural killer (NK) cells are innate immune effector cells that play an immediate role in host defense. Theactivation of NK cells is mediated by receptor-ligand interactions and downstream intracellular signaling path-ways. One type of immunotherapy that has achieved great success in recent years is based on chimeric antigenreceptors (CARs). These are engineered receptors composed of both target recognition and cell activation func-tions that can direct immune cells to mediate killing of cancer cells. Although T cells are the predominant immunecell type used for CAR-based immunotherapy NK cells provide significant advantages over CAR-engineered Tcells because they can be derived from non-autologous sources. However most studies testing CAR-NK cellshave used CAR constructs based on T cell signaling pathways that are not optimized for NK cell signaling. Inaddition the development of CAR constructs is largely achieved using a trial-and-error experimental approachand there is no systematic understanding of how altering the CAR signaling domains influences cell activation. The main objective of this proposal is to identify effective NK based-CAR designs using systems biologytools. Our approach combines computational modeling and quantitative phospho-proteomics to generate a de-tailed understanding of CAR-mediated NK cell signaling and cytotoxicity. The outcome of our work will be a setof validated NK CARs that target and kill BCMA-positive multiple myeloma (MM) cancer cells. We will also testthe optimized CARs against CS1-expressing MM cells. The approach builds on our teams extensive experiencein modeling and characterizing cell signaling and studying NK cell biology. Guided by strong preliminary datawe propose to pursue three Specific Aims: (1) Characterize intracellular and cellular-level responses of CAR-expressing NK cells; (2) Develop computational models to predict the dynamic responses of CAR-expressingNK cells; (3) Identify novel CAR constructs that effectively activate NK cells. Collectively our proposed research will generate a quantitative understanding of how CAR signaling encodesNK cell-mediated cytotoxicity and how NK-CAR constructs can be optimized for cancer immunotherapy. Ourresearch will broadly impact the field of cancer immunotherapy by providing insight into how intracellular NK cellsignaling and CAR structure influence NK cell activation. Ultimately this research will expand our knowledge ofNK cell signaling and the design criteria for NK-CAR-based immunotherapy for other tumor types and cancerantigens. Our work has the potential to unlock the transformative power of NK-CAR cells for cancer immuno-therapy. 513835 +No NIH Category available Accounting;Affect;Age;Aneuploidy;Biological Markers;Biological Specimen Banks;Blinded;Blood;Blood Tests;Blood specimen;CA-125 Antigen;CA-19-9 Antigen;Cancer Detection;Cancer Etiology;Case/Control Studies;Cessation of life;Characteristics;Clinical Trials;Cyst Fluid;Data;Databases;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic Sensitivity;Diagnostic Specificity;Diagnostic tests;Drops;Early Diagnosis;Evaluation Studies;Family;Future;Genes;Genetic;Genotype;Guidelines;High grade dysplasia;Icterus;Image;Incidence;Individual;Juice;Lead;Magnetic Resonance;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Malignant neoplasm of pancreas;Metabolic;Metabolic syndrome;Methods;Multicenter Studies;Outcome;Pancreas;Pancreatic Cyst;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Performance;Plasma;Predisposition;Prevalence;Recording of previous events;Reference Values;Research Personnel;Resectable;Resolution;Resources;SEER Program;Sampling;Screening for cancer;Serum;Site;Specificity;Specimen;Subgroup;Testing;Time;Tissue Banks;Tissues;Training;Tumor Markers;Variant;X-Ray Computed Tomography;advanced disease;artificial intelligence method;cancer diagnosis;cancer imaging;clinical diagnosis;cohort;deep learning;design verification;diagnostic panel;disorder control;early detection biomarkers;genetic testing;genetic variant;glycosylation;high risk;high risk population;improved;improved outcome;microbiome;novel marker;pancreas imaging;pancreatic cancer patients;pancreatic juice;pancreatic neoplasm;patient subsets;pre-clinical;programs;prospective;sample collection;screening;surveillance imaging Using markers to improve pancreatic cancer screening and surveillance: a multi-center study Project NarrativePancreatic cancer is the deadliest of the common cancers and one of commonest causes ofcancer death. Detecting pancreatic cancer at an early stage greatly improves survival frompancreatic cancer. We propose to evaluate a tumor marker gene blood test for pancreaticcancer early detection in a clinical trial and to evaluate other promising tests aimed at improvingthe early detection of pancreatic cancer in patients with an increased susceptibility undergoingpancreatic surveillance. NCI 10701743 8/15/23 0:00 PAR-21-334 5U01CA210170-07 5 U01 CA 210170 7 "YOUNG, MATTHEW R" 7/18/16 0:00 8/31/27 0:00 ZCA1-RPRB-8(M)2 7060159 "GOGGINS, MICHAEL G." Not Applicable 7 PATHOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 544589 NCI 488038 204759 AbstractPatients diagnosed with Stage I pancreatic cancer have a much better outcome than mostpatients who present with advanced disease. The Cancer of the Pancreas Screening (CAPS) studycurrently follows a familial/genetic high-risk cohort of ~1500 patients undergo regular pancreaticsurveillance. Recent results from the CAPS program indicate that most patients who maintain regularsurveillance are down-staged many are diagnosed with Stage I pancreatic cancer and achievelong-term survival. Circulating tumor marker tests are not currently used for pancreas surveillancebut we propose to evaluate blood tests for patients undergoing pancreatic surveillance. Wewill evaluate the use of tumor marker gene tests to better define an individuals tumor marker normalreference range. We will evaluate the use of plasma MR spectroscopy as a diagnostic test thatutilizes artificial-intelligence methods to detect subtle circulating metabolic changes associated withhaving pancreatic cancer. We will also determine if blood biomarker changes occur before thediagnosis of pancreatic cancer in our cohort. The addition of annual blood tests to pancreaticsurveillance is expected to improve the detection of early-stage pancreatic cancer. We will continueto evaluate the long-term outcomes of patients in our cohort and bank biospecimens for futurebiomarker studies. 544589 +No NIH Category available Adult;Advisory Committees;Affect;American;Animal Model;Biology;Cell Adhesion;Cell Line;Cell physiology;Cell-Mediated Cytolysis;Cells;Characteristics;Clinical;Clinical Sciences;Clinical Trials;Committee Members;Complement;Comprehensive Cancer Center;Cyclic AMP-Responsive DNA-Binding Protein;Data;Deubiquitinating Enzyme;Deubiquitination;Development Plans;Diagnosis;Dialysis procedure;Disease;Doctor of Philosophy;Elderly;Eligibility Determination;Gene Expression;Genetic;Genomics;Goals;Grant;Growth;Health Care Costs;Hematology;Hospital Costs;Human;Immune;Immune Evasion;Immune response;Immune system;In Vitro;Internal Medicine;Knowledge;Leadership;Learning Skill;Length of Stay;MEKs;Malignant Neoplasms;Mediating;Mentors;Minority;Modeling;Molecular Abnormality;Morbidity - disease rate;Multiple Myeloma;Mus;NCAM1 gene;Names;Natural Killer Cells;Neurons;Ohio;Outcome;Oxidative Regulation;Oxidative Stress;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Physicians;Productivity;Prognosis;Proteins;Quality of life;Recurrence;Recycling;Rehabilitation therapy;Reporting;Research;Resistance;Role;Science;Scientist;Signal Induction;Signal Transduction;Surface;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Translational Research;Tumor Escape;Universities;Writing;career;career development;cell growth;cell type;cytotoxicity;design;drug development;experience;genomic data;high risk;improved;improved outcome;in vivo Model;individualized medicine;loss of function;overexpression;predictive marker;professor;programs;protein degradation;response biomarker;skills;therapeutically effective;transcription factor;treatment response;tumor;tumor immunology;tumor microenvironment;ubiquitin C-terminal hydrolase;ubiquitin isopeptidase Investigating CD56 signaling in multiple myeloma growth and immune escape PROJECT NARRATIVEMultiple Myeloma (MM) is an incurable disease that affects vulnerable elderly adults and minorities causingmorbidity and poor quality of life. We identified the protein CD56 as a key player able to support MM growth andescape from the immune system. We propose to study how CD56 induces signaling changes and affectsresponses to therapies and block its activity to benefit patients with this deadly disease. NCI 10701702 8/23/23 0:00 PA-20-203 5K08CA263476-02 5 K08 CA 263476 2 "BIAN, YANSONG" 9/9/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 77848662 "COTTINI, FRANCESCA " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 253208 NCI 234452 18756 PROJECT SUMMARY/ABSTRACT Francesca Cottini MD is a Tenure-eligible Assistant Professor in the Division of HematologyDepartment of Internal Medicine (70% research 30% clinical) at The Ohio State University ComprehensiveCancer Center. Dr. Cottinis career goal is to become an independent and productive physician scientist whoseresearch will combine aspects of multiple myeloma (MM) pathogenesis and tumor immunology to developtailored therapies for MM patients. MM is an incurable disease that affects vulnerable adults causing high healthcare costs and poor qualityof life. No tailored therapies exist to treat patients with MM despite major differences in terms of geneticabnormalities gene expression profiles or immune signatures. To fill this gap Dr. Cottini has identified a surfacemarker named CD56 which is present in 70 percent of patients and is associated with poor prognosis. Thusfar Dr. Cottini has demonstrated the feasibility of her project with strong preliminary data showing that CD56promotes MM growth and tumor escape from the immune system. The main objective of Dr. Cottinis K08proposal is to characterize the mechanisms associated with CD56 protumoral phenotype in terms of: 1. MMgrowth; 2. resistance to anti-MM therapies; 3. regulation of oxidative stress; and 4. escape from natural killer(NK) cell-mediated cytotoxicity. The final step of Dr. Cottinis proposal is to find strategies to promote CD56degradation in MM and induce tumor regression. This knowledge will lead to science-driven clinical trials andimprove outcomes in high-risk CD56 positive MM patients. To support her pathway to independence Dr. Cottini has established a mentoring committee consistingof: Drs. Don Benson MD PhD (Primary Mentor: expertise in MM biology tumor immunology and translationaland clinical science) Yiping Yang MD PhD (co-Mentor: expertise in tumor immunology grant writing andleadership skills) Bei Liu PhD (Advisory Committee Member: expertise in MM murine animal models) andNatarajan Muthusamy DVM PhD (Advisory Committee Member: expertise in signaling and translationalscience). She will also take advantages of two additional collaborators with experience in genomics (Dr. PearllyYan) and drug development (Dr. Gerard Hilinski). She formulated a career development plan with objectives of(1) learning skills in tumor immunology drug development and animal models; (2) developing knowledge in theanalysis and interpretation of genomic data and design of correlatives for clinical trials; (3) improving expertisein leadership grant writing and team management. These objectives will complement Dr. Cottinis currentknowledge to help achieving independence as a physician scientist in the field of MM. To conclude Dr. Cottinisstudies have the potential to identify therapeutic options based on disease characteristics and hence improveoutcomes and reduce toxicities in patients. 253208 +No NIH Category available Biological Assay;Biological Sciences;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cell Communication;Cell Separation;Cells;Collaborations;Complex;Comprehensive Cancer Center;Consultations;Core Facility;Cytometry;Education;Ensure;Equipment;Experimental Designs;Faculty;Flow Cytometry;Growth;Hour;Image;Immune;Industry;Institution;Methodology;Microscope;Modeling;Process;Proteomics;Publications;Reporting;Research;Research Personnel;Services;Source;Standardization;Suspensions;Technical Expertise;Technology;Testing;Tissues;Training;University of Texas M D Anderson Cancer Center;anticancer research;cancer genomics;cellular imaging;flexibility;imaging facilities;imaging system;instrumentation;liquid crystal polymer;member;neoplastic cell;new technology;novel;programs;single cell technology;spectrograph;stem;success;tool Single Cell Spatial Analysis in Tissue Project NarrativeFlow Cytometry Cell Sorting Imaging and Mass Cytometry are essential tools for a wide range of methodologiesaimed at understanding complex single cell proteomic and genomic cancer research. Dr. Jared K. Burks the co-Director of the Flow Cytometry and Cellular Imaging Facility North Campus at MD Anderson Cancer Centeridentifies acquires and develops cutting-edge single cell technologies in support of the cancer researchperformed at MD Anderson. Technologies including Akoya Biosciences Vectra Polaris featuring Phenotics 2.0Fluidigm Helios Suspension Mass Cytometer and Hyperion Imaging Mass Cytometer (IMC) are being assessedrefined standardized and expanded for use at MD Anderson and for researchers worldwide. NCI 10701699 9/7/23 0:00 PAR-19-290 5R50CA243707-04 5 R50 CA 243707 4 "AMIN, ANOWARUL" 9/9/20 0:00 8/31/25 0:00 ZCA1-SRB-1(M2)S 10726569 "BURKS, JARED KYLE" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 258385 NCI 159497 98888 Project Summary/AbstractFlow Cytometry Mass Cytometry Cell Sorting and Imaging are essential tools for a wide range of methodologiesaimed at understanding complex single cell proteomic and genomic cancer research. The instrumentationinvolved is large complex and can be difficult to maintain and operate. As such a targeted core facility is criticalfor a Comprehensive Cancer Center such as MD Anderson. The FCCIF est. 1982 provides these services.Since the last CCSG renewal (2012) 404 cancer center members from all 16 cancer center programs have usedthe facility and produced 604 publications. Many of the hot topics in cancer biology currently stem from immunecell interaction with the tumor cell; immunephenotyping is an in demand field of research that requiring a uniquehigh plex assay. This requires a specialized imaging or cytometry approach and the FCCIF has specificallyacquired two different platforms because of their diversity and flexibility. These platforms are the VectraMultispectral imaging system and the CyTOF (suspension and imaging) Mass Cytometers. The FCCIF providesa common source of state-of-the-art expertise and technical skills to support the varied research efforts of MDAnderson investigators. The FCCIF provides a comprehensive service to all of the institutional investigatorsregardless of prior expertise. Dr. Jared K. Burks (author of this R50 co-Director of the FCCIF-NC) providescritical services including: 1) education 2) consultation on needed technological approach 3) training onequipment use analytics and proper experimental design. I identify and acquire novel technologies for use byMDACC investigators and I provide support in a manner to ensure success and mitigate pitfalls. I am expectedto develop new strategies and technologies to meet the research needs of our faculty. A few examples of whatI have currently been working on is the Vectra Polaris Multispectral Microscope Helios and Hyperion Suspensionand Imaging CyTOFs. The Polaris has operated on average 13.5 hours per day for the last year. The CyTOFsare reporting 5090% growth since the last CCSG renewal. These results stem from mitigating the pitfalls makingthe technologies approachable and affordable and supporting the researchers throughout the process all theway to publication. Collaborations both academic and industry have resulted to develop or test novelapplications. The models we have created to support these technologies have and will continue to be sharedwith others operating the technologies. We are highly involved with both developing and standardizing newtechnologies for use at MD Anderson and with our facilities and researchers implementing them worldwide. 258385 +No NIH Category available Adult;Afferent Neurons;Blood;Catecholamines;Chemotherapy-Oncologic Procedure;Chemotherapy-induced peripheral neuropathy;Chronic;Chronic stress;Clinical;Clinical Research;Development;Drug usage;Exposure to;Future;Gene Expression;Glucocorticoids;Grant;Harvest;Knowledge;Mediator;Medical;Neuronal Plasticity;Neurosecretory Systems;Nociceptors;Opioid Analgesics;Patients;Peripheral Nervous System;Peripheral Nervous System Diseases;Platinum;Play;Predisposition;Rattus;Research Project Grants;Resistance;Risk Factors;Role;Spinal Ganglia;Stress;allodynia;biomarker development;chemotherapy;comorbidity;early life stress;experimental study;genomic biomarker;new therapeutic target;oxaliplatin;pre-clinical;prevent;receptor;resilience;stressor;taxane Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress n/a NCI 10701692 8/22/23 0:00 5R01CA250017-05 5 R01 CA 250017 5 "ALTSHULER, RACHEL DINA" 9/9/19 0:00 8/31/24 0:00 ZCA1-RPRB-J(J1) 1891649 "LEVINE, JON DAVID" Not Applicable 11 DENTISTRY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF DENTISTRY/ORAL HYGN 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 648263 NCI 401401 246862 The premise of this research project is that nociceptor neuroplasticity is an important mechanism underlying chronic chemotherapy-induced peripheral neuropathy (CIPN) and that stress plays a key role in the induction of this neuroplasticity. In this grant we will evaluate the role of nociceptor neuroplasticity in chronic CIPN induced by two clinically important classes of cancer chemotherapy (CTX) i.e. platinum and taxane compounds. Experiments will evaluate the role of diverse stressors (i.e. CTX administration early life stress adult chronic stress prior to during or after CTX) drugs used to treat co-morbid medical conditions that also act on stress axis mediator receptors (i.e. glucocorticoid and catecholamine) as well as resilience (i.e. resistance to stress) on the development of chronic CIPN. In addition we will study neuroplasticity and stress in two other clinically important features of chronic CIPN that remain poorly understood: 1) platinum-induced cold allodynia and 2) coasting (i.e. worsening of CIPN after stopping CTX). Finally we will harvest dorsal root ganglia (DRG) as well as blood from rats exposed to CTX and stress to evaluate changes in gene expression in blood and the peripheral nervous system. These analyses will allow us to better identify risk factors for and potential mechanisms of chronic CIPN and could be used to help interpret future clinical studies to identify patients susceptibility for development of CIPN. The results of the proposed preclinical experiments have important clinical implications including: 1) increased knowledge of the role of mechanisms of neuroplasticity underlying chronic CIPN that could identify new therapeutic targets to prevent and treat chronic CIPN; 2) increased understanding of how neuroendocrine stress axis mediators acting at their cognate receptors on sensory neurons contribute to chronic CIPN; 3) understanding mechanisms responsible for loss of efficacy of opioid analgesics in CIPN and its relationship to induction of nociceptor neuroplasticity; 4) understanding the mechanism of oxaliplatin-induced cold allodynia; 5) determining if tapering instead of stopping CTX mitigates coasting; and 6) elucidate genomic biomarkers for the development of chronic CIPN. 648263 +No NIH Category available Adult;Affect;Attitude;California;Cancer Burden;Cancer Patient;Cancer-Predisposing Gene;Caring;Clinical;Communication;Communication Tools;Communities;Complex;Conflict (Psychology);Counseling;Decision Making;Diagnosis;Early Diagnosis;Education;Eligibility Determination;Enrollment;Evaluation;Family;Family member;Future;Genetic;Genetic Counseling;Genetic Risk;Guidelines;Health;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Human;Incentives;Intervention Trial;Malignant Neoplasms;Medical;Outcome;Pathogenicity;Patients;Population;Positioning Attribute;Prevention;Prevention strategy;Price;Professional counselor;Randomized;Relative Risks;Reporting;Resources;Risk Reduction;Sampling;Screening for cancer;Second Degree Relative;Services;Specialist;Subgroup;Technology;Test Result;Testing;Variant;cancer diagnosis;cancer prevention;cancer risk;clinically actionable;clinically relevant;clinically significant;cohort;contextual factors;cost;cost effective;data infrastructure;design;evaluation/testing;family genetics;genetic panel test;genetic testing;health care disparity;high risk;improved;individualized prevention;interest;neoplasm registry;novel strategies;population based;practical application;precision genetics;precision oncology;primary outcome;programs;randomized trial;social factors;therapy design;tool;variant detection;virtual;virtual platform;virulence gene A population-based virtual solution to reduce gaps in genetic risk evaluation and management in families at high risk for hereditary cancer syndromes: The Georgia-California GeneLINK Trial Project Narrative: There is pressing need to develop and evaluate novel approaches to close the enourmousgap in cascade genetic risk evaluation (GRE) in families with hereditary cancer syndromes. We propose arandomized trial of 900 cancer patients diagnosed in 2018-2019 in Georgia and California with a clinicallysignificant pathogenic variant detected by genetic testing that will offer initial GRE and testing to relatives toevaluate the effects of the level of personalized genetic risk navigation support and the price offered to therelative for the genetic test on receipt of initial GRE and patients and relatives appraisal of communication andengagement. The findings of this study have the potential to transform prevention precision oncology in thecommunity with broad applications in practice. NCI 10701690 9/8/23 0:00 RFA-CA-20-006 5U01CA254822-04 5 U01 CA 254822 4 "NELSON, WENDY" 9/15/20 0:00 8/31/25 0:00 ZCA1-TCRB-T(A1) 1972398 "KATZ, STEVEN J." "AN, LAWRENCE CHIN-I; KURIAN, ALLISON W." 6 INTERNAL MEDICINE/MEDICINE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 742946 NCI 596435 146511 Project Abstract: There is growing evidence that targeting genetic risk evaluation (GRE) in families where acancer susceptibility gene pathogenic variant (PV) has been identified may be the most cost-effectiveapproach to reduce the population burden of cancer through prevention. However there are enormouschallenges to implementing successful cascade genetic risk evaluation in families with hereditary cancersyndromes. The clinical context of GRE after cancer diagnosis is increasingly complex: As MGP testing hasbecome the norm guideline organizations have converged on a list of >40 cancer susceptibility genes in whichPVs are clinically actionable with wide variability in cancer threat and a myriad of strategies for prevention andearly detection. A daunting challenge is that the cancer patient is responsible for communication andengagement of relatives for GRE. Despite the shared health threat among at risk relatives (ARRs) the socialand contextual factors that affect family communication are complex. Furthermore ARRs are dispersed world-wide and receive care in disparate health care practices. Importantly there is little incentive and limitedresources for clinicians to engage cancer patients relatives and genetic counseling services are increasinglystrained. Given the lack of guidance for families it is not surprising that most ARRs of cancer patients with PVsdo not undergo GRE. We are uniquely positioned to develop and optimize a direct-to-family virtual genetic riskevaluation and testing solution offered to all at risk relatives of a population-based sample of adults recentlydiagnosed with cancer in Georgia and California who tested positive for a clinically relevant PV. We will use aunique data infrastructure we pioneered to identify and invite a diverse cohort of cancer patients with clinicallyrelevant PVs and their families to participate in our study. We propose a 2 x 3 factorial randomized trial of 900patients diagnosed in 2018-2019 in the two states who had a clinically significant PV detected by genetictesting that will offer genetic risk evaluation and testing to all 1st and 2nd degree relatives. We will evaluate theeffects of two intervention design features on patient- and relative-centered outcomes: 1) the level ofpersonalized family genetic risk support (a technology assisted personally tailored patient and family membereducation and communication tool called the Family Genetic Health Program FGHP) vs. the FGHP plus directassistance from a human FGHP Navigator); and 2) the price offered to the relatives for the genetic test(standard $200 vs. $100 vs. $50 per test). We will determine the independent effects of the two designfeatures on 1) the cancer patients appraisal of communication and their engagement with relatives abouthereditary cancer and GRE; 2) the invited relatives appraisal of decision-making and receipt of genetic testing;and 3) on the enrolled relatives completion of formal GRE. We will also explore the effect of the features onthe outcomes across patient SES subgroups. The findings of this study have enormous potential to improvecancer prevention and early detection in families at high risk of hereditary cancer syndromes in the US. 742946 +Bioengineering; Cancer; Data Science; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Pediatric; Pediatric Cancer; Rare Diseases; Social Determinants of Health Address;Adolescent and Young Adult;Adult;Agreement;Algorithmic Software;Algorithms;Applied Research;Architecture;Artificial Intelligence;Basic Science;Biomedical Research;Cancer Burden;Cancer Diagnostics;Cancer Patient;Cancer Survivor;Catchment Area;Categories;Cessation of life;Characteristics;Clinical;Clinical Trials;Collaborations;Communities;Complex;Computational Science;Computing Methodologies;Data;Data Analytics;Data Linkages;Data Science;Data Set;Data Sources;Databases;Department of Energy;Development;Diagnostic;Documentation;Effectiveness;Engineering;Enrollment;Evaluation;Face;Funding;Future;General Population;Goals;Graph;Guidelines;Health;Health Sciences;Healthcare;High Performance Computing;Infrastructure;Joints;Knowledge;Laboratories;Late Effects;Leadership;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical;Mission;Modality;National Cancer Institute;Patients;Pediatric Oncology;Pediatric Oncology Group;Pharmacy facility;Population;Positioning Attribute;Private Sector;Radiation Oncology;Recording of previous events;Records;Recurrence;Recurrent disease;Registries;Research;Research Personnel;SEER Program;Science;Secure;Social Environment;Source;Structure;Surveillance Program;Survivors;System;Technical Expertise;Technology;Text;United States Centers for Medicare and Medicaid Services;United States Department of Veterans Affairs;United States National Institutes of Health;Visualization;Work;anticancer research;base;cancer diagnosis;cancer genomics;cancer therapy;childhood cancer survivor;computerized tools;data fusion;data infrastructure;data registry;data sharing;deep learning model;design;follow-up;health data;indexing;interest;knowledge graph;large scale data;multiple data sources;neoplasm registry;predictive modeling;research and development;social health determinants;symposium;tool;tumor;virtual Childhood Cancer Data Initiative National Childhood Cancer Registry Development and Refinement of Algorithm Tools n/a NCI 10701645 APC20005001-1-0-1 Y01 77897325 "LAKE, JOE " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 1500000 NCI The Childhood Cancer Data Initiative (CCDI) 2019 symposium hosted by the National Cancer Institute (NCI) identified a critical need to collect analyze and share data to address the burden of cancer in children adolescents and young adults. Currently cancer registries in the U.S. hold structured information on every cancer case including pediatric cancers within their respective catchment areas. For childhood cancer patients and survivors issues of late effects recurrence subsequent malignant neoplasms (SMN) and follow-up are critically important to consider and further study. It is also important to address survivors life trajectories which often include moving to different states and away from where their data was initially collected. The aim of the National Childhood Cancer Registry (NCCR) is to build a connected data infrastructure that includes longitudinal data from multiple sources and enables secure sharing of childhood cancer data with vetted research investigators. These efforts will support childhood cancer research and provide a population-level dataset on all childhood cancer patients. As a base for the infrastructure data currently collected at targeted cancer registries including those in the Surveillance Epidemiology & End Results (SEER) program will be used to aggregate key information on childhood cancer patients and survivors. In addition to registry data NCCR aims to incorporate unique data sources including the National Death Index (NDI) State vital records LexisNexis (residential history and social determinants of health data) and Virtual Pooled Registry (VPR) data on subsequent primaries as well as pharmacy and radiation oncology data. Additional categories of information that may be integrated into the database include detailed diagnostic characterization of the tumor treatment information indicators of tumor recurrence identification of multiple primary cancers and genomic characterization of initial and potentially recurrent disease. The Department of Energy (DOE)/Oak Ridge National Laboratory (ORNL) is the largest multipurpose science laboratory in the DOE national laboratory system. The mission of ORNL is to deliver scientific discoveries and technical breakthroughs that will accelerate the development and deployment of solutions to meet pressing global challenges aligned with the DOEs goals. This science-to-solutions mission depends on the integration and application of distinctive capabilities in basic and applied research which include leadership positions and capabilities in high-performance computing (HPC) advanced visualization and data fusion and computational science and systems engineering and integration. ORNL is recognized as a leader in the research and development of health and data sciences. In the DOE national laboratory system ORNL has a highly capable and proven data and computing enclave certified to host and analyze protected health information (PHI). ORNLs capabilities certified systems that accommodate PHI HPC capabilities and facilities and the technical expertise that has proven successful in a recent multi-year project with the Centers for Medicare and Medicaid Services (CMS) Department of Veterans Affairs (VA) and its broader engagement with the National Institutes of Health (NIH) are unmatched in the domestic private sector making ORNL uniquely qualified to perform the work required for this effort. With growing complexity of cancer diagnosis and treatment the national cancer surveillance program faces increasing challenges in capturing essential information needed to better understand the effectiveness of cancer treatments in the context of our complex medical and social environment. The capacity to collect automatically and comprehensively information about cancer patients would enhance the ability of cancer registry data to support a broad variety of cancer research and would provide an infrastructure that would permit evaluation of the generalizability of cancer diagnostics and therapies outside the clinical trials setting to the 97% of the general population not covered by clinical trials. These advances will be important in future healthcare applications beyond cancer and the knowledge gained will be directly related to technology for future HPC architectures and for making HPC more available to biomedical research.The Current DOE collaboration with NIH/NCI known as the Joint Design of Advanced Computing Solutions for Cancer has produced several useful tools and documentation which have been utilized by the cancer surveillance community for adult cancer populations. In particular ORNL has developed deep learning models and modalities of data analytics that are of particular interest to the NCCR. Their expertise and development of various tools using information from multiple data sources can be used to support various data queries provide assessment of feasibility of developing trials and enabling comparisons of key characteristics among the entire population of childhood cancer patients at a population level to compare to patients enrolled in clinical trials (e.g. Childrens Oncology Group [COG]). Furthermore their expertise and computing capabilities will enable NCI to refine and develop scaling mechanisms of existing data extraction algorithms to obtain data from text documentation in pediatric cancer abstracts that would otherwise be difficult to obtain. This infrastructure will serve as the central data index and warehouse for childhood cancer data through large-scale data identification and linkages and has the potential to provide real-world evidence to support data-driven clinical guidelines. These developed tools combined with this data infrastructure will also support a broad range of research questions. Through the shared follow-up information across registries and other data linkage sources annual follow-up data will be greatly enhanced for childhood cancer survivors and pediatric oncology research.The purpose of this agreement is to provide funding to 1) support the development and refinement of advanced computational tools (e.g. artificial intelligence knowledge graph graph analytics text extraction algorithms predictive modeling and other advanced computational methodologies) using key data from the NCCR infrastructure and various other external data sources and 2) utilize NCCR to further refine existing tools developed by DOE/ORNL. 1500000 +No NIH Category available Area;Benign;Biological Assay;Biological Markers;Biopsy;Blinded;Blood;Blood Tests;Blood specimen;Breast;Breast Cancer Early Detection;Breast Diseases;Breast biopsy;CLIA certified;Characteristics;Clinical;Clinical Chemistry;Collaborations;Collection;Complement;Development;Digestion;ERBB2 gene;Early Detection Research Network;Early Diagnosis;Environment;Enzyme-Linked Immunosorbent Assay;Evaluation;Evaluation Studies;Flow Cytometry;Goals;Guidelines;Human;Laboratories;Malignant Neoplasms;Mammary Neoplasms;Mammographic screening;Mammography;Mass Spectrum Analysis;Medicine;Methods;Mus;Pathologic;Patient Selection;Patient-derived xenograft models of breast cancer;Patients;Phase;Plasma;Plasma Proteins;Preparation;Procedures;Proteins;Qualifying;Quality Control;Reagent;Regulation;Reproducibility;Research Design;Sampling;Selection Bias;Services;Specificity;Target Populations;Technology;Testing;Thyroglobulin;Translating;United States;Validation;Variant;Woman;biobank;biomarker discovery;biomarker validation;cancer biomarkers;cancer invasiveness;candidate marker;case control;early detection biomarkers;experience;follow-up;high risk;improved;instrumentation;malignant breast neoplasm;manufacturing run;multiple reaction monitoring;multiplex assay;next generation sequencing;novel;novel marker;pre-clinical;prospective;protein biomarkers;quality assurance;repository;sample collection;support network;validation studies Core - Biomarker Reference Laboratory n/a NCI 10701483 6/5/23 0:00 RFA-CA-22-040 1U2CCA271873-01A1 1 U2C CA 271873 1 A1 6/5/23 0:00 5/31/28 0:00 ZCA1-SRB-P(J2) 8385 2110147 "HOOFNAGLE, ANDREW N" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 Other Research-Related 2023 40021 22739 17282 Project Summary/Abstract (Biomarker Reference Laboratory (BRL) RFA-CA-22-040) We propose to develop a blood-based test whose indicated use is to complement mammography in the earlydetection of breast cancers. Although mammography saves lives through early detection it is imperfect.Approximately one in seven breast cancers goes undetected despite screening mammography and intervalcancers that manifest within a year of a normal mammogram remain a vexing problem especially (although notexclusively) for the >27 million women in the United States with heterogeneously or extremely dense breasts athigh risk for interval cancers. We propose to develop a blood test that could be used as an adjunct tomammography to improve early detection by improving sensitivity and/or specificity of mammography. Using a novel biomarker discovery approach leveraging human-in-mouse breast cancer patient-derivedxenograft models and state-of-the-art mass spectrometry methods we prioritized a subset of 162 candidatebreast cancer protein biomarkers (verified in human plasma from breast cancer cases vs. controls) for follow upEDRN phase 2 validation studies in this proposed BCC. Our project will clinically validate and deploy (in our CLIA laboratories) a novel multiplex immuno-multiplereaction monitoring mass spectrometry (immuno-MRM-MS) assay to perform EDRN phase 2 biomarkervalidation studies using strongly unbiased sets of plasma samples obtained from existing biorepositories. The Biomarker Reference Laboratory will contribute to the proposed EDRN phase 2 biomarker validationstudies by: (i) validating a CLIA-compliant standard operating procedure for an immuno-MRM assay to quantifyup to 162 candidate plasma protein biomarkers of early-stage breast cancer that will serve as the basis for ourbiomarker validation studies (ii) performing a phase 2 case-control biomarker validation study using stronglyunbiased plasma collections collected using EDRN PRoBE study design and (iii) providing reference laboratorysupport for the EDRN network including high-throughput targeted mass spectrometric analyses flow cytometrynext-gen sequencing and 96-well plate ELISA assays as needed. +Cancer Program Evaluation;meetings MEETING SUPPORT FOR THE NCORP PROGRAM EVALUATION. n/a NCI 10701382 91020A00191022F00003-0-0-1 N02 8/31/22 0:00 8/30/23 0:00 78844072 "EWING, AMY " Not Applicable 8 Unavailable 175358027 ENKBUQ4WXUW7 175358027 ENKBUQ4WXUW7 US 38.99818 -77.025807 2473201 NOVA RESEARCH COMPANY BETHESDA MD Domestic For-Profits 208146900 UNITED STATES N R and D Contracts 2022 124620 NCI MEETING SUPPORT FOR THE NCORP PROGRAM EVALUATION. 124620 +No NIH Category available Address;Bioinformatics;Biological Assay;Biological Markers;Biometry;Biopsy;Cancer Diagnostics;Certification;Classification;Clinical;Clinical Chemistry;Clinical Investigator;Clinical Research;Clinical Treatment;Collaborations;Detection;Development;Diagnostic;Diagnostic Procedure;Disease;Early Detection Research Network;Enrollment;FDA approved;Funding;Genomics;Goals;Guidelines;Health;Industrialization;Industry;Institution;International;Knowledge;Laboratories;Leadership;Licensing;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Medical;Mission;Morbidity - disease rate;Numerical value;Ovarian;Pathology;Patient Monitoring;Patient Triage;Performance;Physicians;Population Surveillance;Principal Investigator;Procedures;Productivity;Prostate;Proteomics;Publications;Quality Control;ROC Curve;Research;Research Design;Resources;Scientist;Screening for cancer;Serum;Specificity;Surveillance Program;Technology;Testing;Translating;Translations;Treatment outcome;Universities;Urine;Urology;Validation;Work;assay development;biomarker discovery;biomarker evaluation;biomarker identification;biomarker panel;biomarker performance;biomarker validation;cancer biomarkers;cancer diagnosis;cancer therapy;cancer type;clinical assay development;clinical epidemiology;clinical practice;clinically significant;computerized tools;design;diagnostic assay;experience;follow-up;improved;in-vitro diagnostics;indexing;innovation;mortality;multidisciplinary;non-invasive monitor;overtreatment;patient population;potential biomarker;predictive modeling;product development;progression risk;quality assurance;research study;success;technology development;tissue biomarkers;tumor;validation studies Biomarker Reference Laboratory n/a NCI 10701248 7/19/23 0:00 RFA-CA-22-040 1U2CCA271895-01A1 1 U2C CA 271895 1 A1 7/20/23 0:00 6/30/28 0:00 ZCA1-SRB-P(J2) 8347 6265412 "CHAN, DANIEL WANYUI" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Other Research-Related 2023 237151 144825 92326 Our proposed EDRN BRL which is located within the Clinical Chemistry Division (CCD) of the Johns HopkinsMedical Institutions will be an integral part of the BCC. The BRL will continue to serve as a network resource forclinical and laboratory validation of biomarkers which includes technological development and assay refinementas well as knowledge of quality management and regulatory requirements. Our laboratory is certified by CAPand regulated by CLIA (certificates provided). We follow stringent GLP guidelines for quality control and qualityassurance. The proposed product developmental project of the BCC will be conducted at the JHU Center forBiomarker Discovery and Translation (CBDT). The project goal is to validate prostate cancer biomarkersdiscovered by our BDL & BRL during the current funding period de novo discoveries from the BDL componentof the new BCC and/or other potential biomarkers from within and outside EDRN using cutting edge technologiesin proteomics bioinformatics and clinical assay development. The proposed diagnostic products are in vitrodiagnostic multivariate index assays (IVDMIAs) consisting of a panel of biomarkers 1) to assist in thepreoperative assessment of PCa aggressiveness and decision for enrollment into active surveillance (AS); and2) non-invasive biomarkers for the detection of rising risk of progression during AS to triage patients for additionalworkup procedures for possible disease reclassification. We have assembled a strong team of research andclinical scientists with many years of experience with cancer biomarkers and in technology development studydesign bioinformatics validation and translation. Dr. Chan the contact PI and the BRL PI is the Director ofboth CCD and CBDT. He has >30 years of experience in clinical chemistry and has conducted many (>75)research studies funded by industry on cancer diagnostics leading to FDA approval for clinical use. Furthermoreseveral leading scientists from the diagnostics industry will serve as collaborators to provide expertise andfacilitate product development and validation. Our BRL has been extremely productive. Since the inception ofthe EDRN in 2000 eight EDRN developed assays have been approved by the FDA for clinical use and of theseeight our BRL led the development of the OVA1 and Overa serum IVDMIAs for ovarian cancer led the serumproPSA validation study and served as the reference lab for the urine PCA3 validation trial. In addition Dr. Chanwas involved in the development of the MiCheck Prostate cancer test by Minomic International Ltd. This test waslicensed to a CLIA certified lab. In this application we plan to continue our commitment to the EDRN missionthrough network collaborations with BCCs CVCs and the DMCC. With this multi-disciplinary team of scientistsand clinicians the BRL at JHU offers the best opportunity for the success of cancer biomarker validation andtranslation. If the over-treatment under-treatment and decrease in unnecessary biopsies in prostate cancer canbe successfully addressed the morbidities associated with prostate cancer diagnosis and treatment can besignificantly decreased while enhancing the detection and treatment of clinically significant prostate cancer. +No NIH Category available Adherence;Biological Markers;Clinical;Collaborations;Communication;Diagnostic;Early Detection Research Network;Ensure;Fostering;Goals;Industry;Laboratories;Leadership;Malignant neoplasm of prostate;Research Personnel;Resources;Structure;Teleconferences;Translations;Work;base;biomarker validation;clinical practice;experience;insight;meetings;member;operation;programs;public-private partnership;success;timeline Admin Core n/a NCI 10701246 7/19/23 0:00 RFA-CA-22-040 1U2CCA271895-01A1 1 U2C CA 271895 1 A1 7/20/23 0:00 6/30/28 0:00 ZCA1-SRB-P(J2) 8345 6265412 "CHAN, DANIEL WANYUI" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Other Research-Related 2023 63687 38893 24794 SummaryThe primary goal of the Administrative Core is to provide logistical organizational and managerial support forthis Biomarker Characterization Center (BCC) and foster the interaction of the BCC with the other EDRN teammembers and Centers including BCCs CVCs the DMCC and the NCI. As current BDL and BRL grantees fromJHU we will build on the effective communication and coordination strategies in place to form an integrated BCCthat works effectively with all EDRN Centers and aligned with NCI goals and priorities. We will have a strongbase of support from the experienced investigators and an internal framework to ensure integrated operationsof the BDL and BRL components adherence to project and network milestones and timelines and overall projectsuccess. We will work to ensure the success of the entire EDRN program and will participate in the EDRNSteering Committee and EDRN meetings and teleconferences. The Administrative Core will collaborateinteract and ensure bidirectional exchange of findings and insights with the other EDRN BCC CVC and DMCCteam members. We will also provide resources and support for the validation of biomarkers developed by theEDRN and ensure participation in collaborative projects with other laboratories and centers. In summary wewill leverage the robust leadership structure and collaborative-team work experience of the proposed BCC tofacilitate realization of the overall goals of the EDRN and ensure the success of the BDL and BRL. +No NIH Category available Address;Adoption;Biological Assay;Biological Markers;Biopsy;CLIA certified;Cancer Patient;Certification;Classification;Clinical;Clinical Research;Clinical Treatment;Communities;Computer Models;Detection;Development;Diagnostic;Disease;Early Detection Research Network;Enrollment;FDA approved;GDF15 gene;Glycoproteins;Goals;Health;Immunoassay;Industry;Laboratories;Lasers;Malignant neoplasm of prostate;Mass Spectrum Analysis;Methods;Modeling;Monitor;Morbidity - disease rate;Numerical value;Patient Triage;Patients;Performance;Population Surveillance;Post-Translational Protein Processing;Predictive Value;Principal Investigator;Procedures;Prostate;Prostate Cancer therapy;Protein Glycosylation;Proteins;Proteomics;Reaction;Receptor Protein-Tyrosine Kinases;Resources;Risk;Serum;Specificity;Specimen;Surveillance Program;TIE-2 Receptor;Target Populations;Technology;Time;Tissues;Translating;Translations;Universities;Urine;Validation;Work;assay development;biomarker development;biomarker discovery;biomarker panel;biomarker validation;cancer biomarkers;cancer diagnosis;cancer therapy;cancer type;candidate marker;clinical development;clinical diagnostics;clinically significant;cost;disorder risk;experience;follow-up;glycoproteomics;growth differentiation factor 1;high risk;improved;in-vitro diagnostics;indexing;industry partner;innovation;interest;laboratory development;laser capture microdissection;men;mortality;multidisciplinary;multimodality;novel;overtreatment;predictive marker;progression risk;prostate cancer cell;prostate cancer risk;research clinical testing;single cell analysis;syndecan;technology platform;tissue biomarkers;verification and validation BCC for Prostate Cancer: Discovery and Translation of Biomarkers for Clinical Unmet Needs Our EDRN BCC proposal aims to address the critical clinical unmet needs of over-treatment and under-treatmentin prostate cancer. We plan to develop in vitro diagnostic multivariate index assays (IVDMIA) that combine apanel of biomarkers into a single-valued numerical index for the conservative treatment of prostate cancerpatients through the Active Surveillance (AS) approach. The discovery validation and translation of prostatecancer biomarkers into clinical diagnostics as well as the development of clinical-grade assays will beaccomplished through partnerships with EDRN BCC CVC and DMCC components and the diagnosticsindustry. NCI 10701245 7/19/23 0:00 RFA-CA-22-040 1U2CCA271895-01A1 1 U2C CA 271895 1 A1 "KOHAAR, INDU" 7/20/23 0:00 6/30/28 0:00 ZCA1-SRB-P(J2) 6265412 "CHAN, DANIEL WANYUI" "ZHANG, HUI " 7 PATHOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 7/20/23 0:00 6/30/24 0:00 394 Other Research-Related 2023 679564 NCI 415001 264563 Active surveillance (AS) is the preferred management option for low risk prostate cancer (PCa) patients whowould benefit from conservative treatment. However due to the lack of reliable methods in the initial clinicalevaluation to identify true low-risk PCa patients for AS enrollment and during AS monitoring to detect a risingrisk of progression patients who could benefit from conservative management through AS are often over-treatedyet at the same time patients initially chosen for AS with a missed high-risk disease are under-treated. The goalof the proposed EDRN Biomarker Characterization Center (BCC) is to develop and validate in vitro diagnosticmultivariate index assays (IVDMIA) that combine a panel of biomarkers into a single-valued numerical index withthe intended use for the clinical unmet needs for 1) assisting in the preoperative assessment of PCaaggressiveness and decision for enrollment into AS; and 2) detecting a rising risk of progression during AS totriage patients for additional and possibly more invasive procedures for needed disease reclassification. Theobjective for the IVDMIA development is to improve specificity while maintaining a high negative predictive valuein order to safely enroll more patients with true low-risk PCa into AS and reduce the number of unnecessarybiopsies and or costly workup procedures for patients in AS. To achieve this goal we propose an integratedBCC at the JHU consisting of a multi-disciplinary team including PIs from current EDRN BDL (Dr. Hui Zhang)and BRL (Dr. Daniel W. Chan) and a previous CVC (Dr. Alan Partin). The targeted population is JHU AS patientswith >20 years of enrollment and clinical follow-up. Our team has many years of experience in biomarkerdiscovery verification validation and translation into clinical diagnostics and the development of IVDMIA e.g.OVA1 the 1st proteomics IVDMIA cleared by the FDA (2009). We plan to take advantage of the serumbiomarkers already discovered for aggressive PCa from our current BDL and BRL and begin the verification andvalidation in the targeted AS population by our BRL. In parallel our BDL will focus on the discovery of newcandidate serum urine and tissue biomarkers by applying cutting edge technologies to the AS population suchas mass spectrometry based high throughput proteomics protein modifications and single cell analysis of laser-capture-microdissected tissues. We plan to combine these biomarkers into IVDMIAs. Finally we will work withour industry partners to translate these IVDMIAs into CLIA certified and/or FDA cleared/approved clinicaldiagnostics. We believe with these innovative yet practical approaches our BCC offers the best opportunity tomake significant contributions to the EDRN network and address the critical clinical unmet needs for PCapatients. If the over-treatment under-treatment decrease in unnecessary biopsies and increase in biopsyaccuracy can be successfully addressed the morbidities associated with PCa diagnosis and treatment can besignificantly decreased while enhancing the detection and treatment of clinically significant PCa. In addition ourBRL a CLIA and CAP certified clinical laboratory at JHU will serve as a resource center for the EDRN network. 679564 +Cancer; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Liver Disease; Prostate Cancer; Urologic Diseases Determinants of Liver Metastasis PROGRAM NARRATIVETumor metastasis to the liver is a leading cause of cancer death in the United States and it is known to beassociated with the increasing prevalence of obesity and non-alcoholic fatty liver disease. This Programrepresents the only coordinated multi-investigator effort nationwide to focus on the causes of and approachesto address liver metastasis from cancers of the prostate pancreas and colon. Successful completion of theProgram will lead to new targets for treatments for patients with liver metastasis. NCI 10701208 9/8/22 11:54 PAR-18-290 3P01CA233452-03S1 3 P01 CA 233452 3 S1 "WATSON, JOANNA M" 1/1/22 0:00 12/31/24 0:00 ZCA1-RPRB-F(O1) 8338 1895258 "LU, SHELLY CHI-LOO" "BHOWMICK, NEIL A." 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 1/1/22 0:00 12/31/22 0:00 Non-SBIR/STTR 2022 123849 74161 49688 PROGRAM TITLE: Determinants of Liver MetastasisPROGRAM ABSTRACTLiver metastasis indicates a terminal illness for many cancers and is a leading cause of cancer death in theUnited States. There is currently no integrated research program devoted to mechanisms of liver metastasis.While common in certain cancer types (such as pancreas and colon) metastasis is less common but highlymalignant in other cancer types (such as prostate cancer). The long-term goal of our Program is tounderstand and address the shared and unique drivers of liver metastasis in colon pancreas andprostate primary tumor types. Published work and preliminary data from the four integrated projects point tokey roles for four critical molecular signaling axes in mediating liver metastasis through mechanisms likelycommon across many primary tumor types. To complement this mechanistic expertise this Program assemblesclinical expertise across different tumor types and liver microenvironment models.Together this collaborative Program investigates the hypothesis that normal liver tissue is inherently suppressiveof metastatic tumor expansion unless alterations in the liver microenvironment result in the loss of metastaticsuppressors. Project 1 explores the acquisition of features that enable metastasis from circulating saturated fatand subsequent endoglin signaling in hepatocytes and cancer epithelia. The pro-metastatic impact of hepaticstellate cell (HSC)-derived hyaluronic acids in non-alcoholic fatty liver disease is examined in Project 2. Thoughtto activate pro-cancer phenotypes of HSCs and macrophages Project 3 investigates the regulation andcontribution of yes-associated protein (YAP) and downstream signaling pathways to create a pro-metastatic livermicroenvironment. Project 4 investigates the roles of methionine adenosyltransferase (MAT) proteins in livermetastasis from the loss of protective MAT1A to the pro-cancer elevated expression of MAT2A and MAT2B. Byexamining these four intersecting signaling pathways and comparing findings across models this Program willaugment current understanding of factors in the liver microenvironment and tumor that permit the developmentof liver metastases.This Program unites essential expertise in the fields of liver and cancer pathobiology to represent the first multi-investigator effort focused on common mechanisms involved in liver metastasis from disparate tumor models(prostate colon and pancreas). The Program adopts a unique approach investigating the role of the normalliver microenvironment and leveraging each project teams substantial expertise along with essential resourcesincluding pharmacologic means of addressing the signaling axes partnerships with healthcare providers tovalidate the findings in animal models through human tissue specimens and innovative technology to isolateand analyze metastatic factors including circulating tumor cells and extracellular vesicles. Successful completionof the Program will establish new paradigms in liver metastasis and test novel therapeutic strategies. +Biomedical Imaging; Brain Cancer; Brain Disorders; Cancer; Clinical Research; Health Services; Neurosciences; Patient Safety; Precision Medicine; Rare Diseases Adverse event;Biological Markers;Cancer Center;Clinical;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Services;Collaborations;Communication;Complex;Consent;Correlative Study;Data;Databases;Disease;Effectiveness;Enrollment;Ensure;Evaluation;Funding;Glioma;Goals;Grant;Human Resources;Image;Individual;Informed Consent;Infrastructure;Institutional Review Boards;Laboratories;Leadership;Manuscripts;Metabolic;Molecular;Monitor;Neurosurgeon;Nursing Research;Oncologist;Patient Rights;Patient imaging;Patients;Pharmaceutical Preparations;Preparation;Procedures;Progress Reports;Protocols documentation;Reporting;Research;Research Assistant;Research Personnel;Research Project Grants;Research Subjects;Research Support;Safety;Scientist;Specific qualifier value;Subgroup;Therapeutic Human Experimentation;Time;Tissues;Toxic effect;United States National Institutes of Health;design;experience;follow-up;improved;individual patient;meetings;member;molecular subtypes;multiparametric imaging;neuro-oncology;operation;programs;radiologist;research study;success Administrative and Clinical Services Core The proposed P01 consists of four highly integrated projects focused on identifying metabolic signatures associated with molecular subgroups of glioma and combining them with multi-parametric imaging strategies to evaluate spatial and temporal changes in individual patients during the course of their disease. This Core will provide administrative and fiscal oversight for all four projects and clinical services for the two projects that will be performing patient studies. NCI 10701120 9/8/22 8:46 PAR-18-290 3P01CA118816-14S1 3 P01 CA 118816 14 S1 "WANG, YISONG" 7/1/07 0:00 7/31/24 0:00 ZCA1-RPRB-6(M1) 8347 7690446 "CHANG, SUSAN M" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Non-SBIR/STTR 2022 85963 56605 29358 The Director of the Administrative and Clinical Services (ACS) Core will be Dr. Susan Chang and the Associate Director will be Dr. Jennifer Clarke. The Administrative component will be led by Dr. Chang and the Clinical component will be led by Dr. Clarke. Dr. Sarah Nelson and Dr. Daniel Vigneron will serve as co-investigators in order to provide oversight of the technical aspects of the Projects planned. Dr. Chang is the Director of the Division of Neuro-Oncology and is the overall PI of the PI and was as well as the director of the Administrative Core of the prior PPG. She is experienced in the coordination of multiple projects and cores and has effectively provided the leadership for the successful activities of the previous cycle. She has demonstrated clear commitment to providing oversight of the PPG. The specific aims of the ACS Core are to provide Administrative and Clinical services to all our Projects to accomplish their Specific Aims and Research Plans. Administrative support will include fiscal grants management and clerical support for annual progress reports and manuscript preparation and organization for meetings between the key personnel from the projects and cores as well as for meetings with the External Advisory Board. Two of the Projects will involve patient research studies and the clinical component will provide the infrastructure and personnel to allow the conduct of non-therapeutic and therapeutic research studies. This will include clinical scientists neurosurgeons research nurses and clinical research assistants as well as clinical space to obtain informed consent treat and follow patients enrolled in clinical studies within all the Projects. The overall goal of the ACS Core will be to facilitate the interactions of the members of this P01 provide clinical research support for the Projects and administratively coordinate activities of the P01investigators. The following table depicts the distribution of effort provided to the four Projects by the two components of the ACS Core. +Behavioral and Social Science; Cancer; Cardiovascular; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Heart Disease; Hematology; Lymphatic Research; Lymphoma; Minority Health; Physical Activity; Physical Rehabilitation; Prevention; Rare Diseases; Rehabilitation Activities of Daily Living;Address;Adherence;Aerobic;Animals;Anthracycline;Attenuated;Cancer Center;Cancer Patient;Cancer Survivor;Cardiac Output;Cardiac rehabilitation;Cardiopulmonary;Cardiotoxicity;Cardiovascular Physiology;Cardiovascular system;Clinical Trials;Cognitive;Communities;Comprehensive Cancer Center;Data;Data Analyses;Enrollment;Event;Exercise;Exercise Tolerance;Fatigue;Feedback;Focus Groups;Fostering;Functional disorder;Funding;Goals;Heart failure;Home;Hospitalization;Human;Immunocompromised Host;Impaired cognition;Individual;Instruction;Intervention;Interview;Knowledge;Lead;Left Ventricular Dysfunction;Left Ventricular Function;Life Style;Lymphoma;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Methods;Morbidity - disease rate;Myocardial dysfunction;Non-Hodgkin's Lymphoma;North America;Outcome;Oxygen;Participant;Patients;Peripheral;Phase;Physical Exercise;Physical Performance;Physical activity;Physiological;Prognosis;Property;Quality of life;Randomized;Randomized Clinical Trials;Rehabilitation Centers;Research Personnel;Structure;Survivors;Testing;Time;Translating;Travel;Treadmill Tests;Treatment-Related Cancer;United States National Institutes of Health;Walking;adverse outcome;arm;base;cancer therapy;cardiovascular risk factor;chemotherapy;clinical practice;cognitive function;design;exercise capacity;exercise intervention;exercise intolerance;exercise program;exercise training;experience;functional decline;health related quality of life;heart function;improved;insight;mortality;non-Hodgkin's lymphoma patients;novel;participant enrollment;physical inactivity;preservation;primary outcome;programs;screening;secondary outcome;sedentary lifestyle;treadmill;trend Improving Exercise Capacity with a Tailored Physical Activity Intervention in Lymphoma Patients Undergoing Treatment PROJECT NARRATIVELymphoma survivors are increasingly experiencing morbidity and mortality due to cardiovascular events thatoften result from the anthracycline-based chemotherapy used to treat their cancer. Our team of experiencedinvestigators will test the utility of a patient-centric individually tailored physical activity interventionimplemented throughout chemotherapy to attenuate physical inactivity reduce fatigue and preserve exercisecapacity cardiac and cognitive function strength and health-related quality of life: all metrics that associatewith or reduce cardiovascular risk. By fostering a lifestyle that maintains or increases physical activity andexercise capacity this project seeks to reduce overall cardiovascular morbidity and mortality of lymphomasurvivors and thereby improve their overall survival and quality of life. NCI 10701107 9/15/22 0:00 PAR-18-307 4R33CA226960-03 4 R33 CA 226960 3 "DIMOND, EILEEN" 12/1/18 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-RPHB-W(55)R] 6855679 "HUNDLEY, WILLIAM GREGORY" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2022 386994 NCI 321599 65395 Cardiovascular (CV) events related to the receipt of potentially cardiotoxic anthracycline-based chemotherapy(Anth-bC) are emerging as leading causes of morbidity and mortality for survivors of lymphoma (the 5thmost common cancer in North America). The objective of our proposal is to reduce this cancer treatmentrelated CV morbidity by developing enabling and testing a physical activity intervention that commences andcontinues throughout receipt of Anth-bC for the purpose of attenuating physical inactivity preserving exercisecapacity CV & cognitive function strength and health-related quality of life (HRQOL) for those with lymphoma.The need for and the design of this program is based in part on feedback from lymphoma survivor focusgroups treated in our NIH funded Comprehensive Cancer Center - preliminary pilot data (Section 3.C.1).Several novel features of this proposal include:1) Performance of physical activity during receipt of cancer treatment where exercise intolerance originates.2) Creation of patient communities that enable cancer patients to support one another during treatment.3) Administration of aerobic & strength activities suited to one's individual lifestyle in the home guided by instruction provided from 4 close to home cardiac rehabilitation facilities experienced in exercising immunocompromised individuals and those with other pre-existing activity limitations due to cancer.4) Utilization of newly developed magnetic resonance cardiopulmonary exercise treadmill testing methods to measure the two components (cardiac function and peripheral factors) that contribute to peak VO2 (a measure of maximal exercise capacity). This new information will provide mechanistic insight into how physical activity helps preserve exercise capacity and reduce fatigue.5) Assessment of the relationships between cognitive function activity and exercise capacity thereby helping to unravel the association between physical activity HRQOL and cognitive function in cancer patients.In this application we propose to refine the physical activity intervention during the R21 Phase in patients whoparticipate in the intervention for 6 months. If suitable milestones are achieved we will conduct a randomizedclinical trial in the R33 Phase to test the utility of the integrated physical activity intervention for sustaining peakV02 6-min walk distance cardiac and cognitive function strength activity and HRQOL.If we achieve our study goals this proposed intervention could reduce CV mortality and heart failure relatedhospital admissions translate into clinical practice via extension through cardiac rehabilitation centers (oftenlocated close to cancer centers) increase health-related quality of life reduce fatigue to perform activities ofdaily living and attenuate cognitive function decline in lymphoma survivors. The results of this study could helpto change existing sedentary behavior paradigms during receipt of chemotherapy and ultimately lead toimproved long term outcomes for those with lymphoma and potentially other forms of cancer. 386994 +No NIH Category available Advisory Committees;Ancillary Study;Award;Back;Cancer Burden;Clinical;Clinical Oncology;Clinical Research;Colorado;Communication;Correlative Study;Disease;Doctor of Philosophy;Ensure;Environment;Faculty;Fostering;Foundations;Funding;Future;Grant;Individual;Interdisciplinary Study;Knowledge;Lead;Learning;Malignant Neoplasms;Medical;Mentors;Mentorship;Oncology;Outcome;Peer Review;Program Development;Publications;Qualifying;Research;Research Design;Research Personnel;Research Project Grants;Running;Science;Scientist;The University of Colorado Cancer Center;Training;Training Programs;United States National Institutes of Health;Universities;Virginia;bench-to-bedside translation;cancer clinical trial;career;clinical training;cohort;design;experience;flexibility;innovation;meetings;member;multidisciplinary;novel;personalized cancer therapy;professor;programs;role model;skills;success Paul Calabresi Award in Clinical Oncology Research Project NarrativeThe Paul Calabresi Award for Clinical Oncology Research trains the future leaders of translationalclinical and basic cancer research who can work together to combine molecular methods with clinicalinformation to personalize cancer clinical trials to improve the outcome for cancer patients with lesstoxicity. NCI 10701084 8/30/23 0:00 PAR-18-292 5K12CA086913-22 5 K12 CA 86913 22 "DAMICO, MARK W" 9/18/00 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 8612929 "BORGES, VIRGINIA F." "SLANSKY, JILL E" 6 INTERNAL MEDICINE/MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 474136 NCI 737906 56952 Project Summary/AbstractThe rationale of this Paul Calabresi Award in Clinical Oncology Research (PCACOR) competitive renewalapplication is to continue to prepare highly qualified cancer clinical researchers called Scholars who willbecome independent leaders. These clinical research leaders will meet the ongoing need for highly trainedacademicians running pivotal cancer clinical trials and/or the critical clinical correlative studies that will informongoing translation from bench to bedside. Through this unique training program and the expertise of ourmentors the Scholars will succeed in learning to communicate and coordinate multidisciplinary teams ofscientists and apply the ever growing amount of scientific knowledge to personalize cancer treatment. Specificobjectives are to: 1) Design a flexible Individual Development Program for each Scholar selected by theMultidisciplinary Advisory Committee from applicants who may be oncology trained MDs PhD clinicianswith completed clinical training or PhD level basic scientists committed to an academic cancer career withheavy clinical focus; 2) Foster interdisciplinary training communication and interaction through intentionalteam mentoring and regular Scholar-centered meetings creating completed PCACOR Scholars successfullytransitioned to independence; 3) Create a diverse cohort of highly trained clinical research leaders thatwill run novel innovative multidisciplinary research agendas to move the translational of our current science toreduce the burden of cancer. Also these highly trained thought leaders will become part of the ongoingmentorship cycle back to new trainees. The PCACOR design incorporates our exceptional faculty asstrong mentors who will provide exceptional training and role models in the very richly supported environmentof the University of Colorado Cancer Center. Experienced Program Leaders are Madeleine A. Kane MD PhDand Virginia F. Borges MD MMSc both Professors with extensive relevant experience. The tailored TrainingPeriod lasts from two to five years and includes Core Requirements of a selection of Scholar tailored didacticcoursework a Scholar designed major research project of at least one cancer clinical trial or ancillary study.The Training Period will focus on the specific individual training needs of each Scholar for which mastery ofthese needed skills through the mentored environment will ensure transition to independence. As an outcomesmetric all Scholars submit an NIH or equivalent grant by the third year. The ultimate success isdemonstrated by our track record. A total of twenty-two junior faculty have trained as PCACOR Scholarsseven during the current funding period (out of 24 applications). Eighteen Scholars are faculty members atUniversity of Colorado Denver Anschutz Medical Campus (UCD-AMC); fourteen have been promoted all havemultiple peer-reviewed publications. Eighteen have obtained peer-reviewed funding from NIH DOD ACSand/or disease-based foundations. All have designed at least one cancer clinical trial and several lead nationalcancer clinical trials. Our PCACOR successfully produces the translational cancer clinical researchers ofnow and the future. 474136 +No NIH Category available Abstinence;Address;Adoption;Adult;Algorithms;Area;Biochemical;Cancer Control;Cancer Prevention Intervention;Caring;Cigarette;Clinical;Clinical assessments;Clinical effectiveness;Code;Commuting;Consolidated Framework for Implementation Research;Counseling;Data;Data Collection;Disparity;Effectiveness;Electronic Health Record;Evidence based intervention;Evidence based treatment;FDA approved;Face;Familiarity;Future;Goals;Guidelines;Health Services Accessibility;Healthcare;Healthcare Systems;Hybrids;Incidence;Individual;Intervention;Intervention Studies;Interview;Knowledge;Malignant Neoplasms;Methods;Modeling;Motivation;Outcome;Participant;Patient Recruitments;Patients;Penetration;Pharmaceutical Preparations;Pilot Projects;Practice Guidelines;Prevalence;Primary Cancer Prevention;Primary Care;Proctor framework;Provider;Qualifying;Randomized;Reporting;Research Personnel;Research Project Grants;Resources;Risk;Risk Factors;Rural;Rural Population;Site;Smoker;Smoking;Smoking Cessation Intervention;Smoking History;Smoking Status;Source;South Carolina;Testing;Time;Tobacco;Tobacco use;United States;United States Centers for Medicare and Medicaid Services;United States Public Health Service;cancer health disparity;cancer prevention;cigarette smoke;dissemination strategy;eVisit;effectiveness evaluation;effectiveness outcome;effectiveness trial;effectiveness/implementation trial;electronic health record system;evidence base;follow-up;implementation barriers;implementation cost;implementation evaluation;implementation facilitators;implementation outcomes;improved;informant;information gathering;modifiable risk;patient-level barriers;pilot trial;primary care clinic;primary care practice;primary care provider;primary care setting;provider-level barriers;psychosocial;randomized clinical trials;relative effectiveness;remote delivery;remote therapy;rural area;rural dwellers;rural healthcare;smoking cessation;tool;treatment as usual;urban disparity Addressing Rural Cancer Disparities via Proactive Smoking Cessation Treatment within Primary Care: A Hybrid Type 1 Effectiveness-Implementation Trial of a Scalable Smoking Cessation Electronic Visit PROJECT NARRATIVEPrimary care providers are the gateway to reaching rural smokers but need resources to deliver evidence-basedcessation treatment uniformly to all. The widespread adoption of Electronic Health Record (EHR) systems withcoded smoking status data offers a ripe opportunity to proactively provide treatment. The present researchproject will test the clinical effectiveness and evaluate implementation of an asynchronous smoking cessationelectronic visit that will be delivered proactively via the EHR to all rural smokers. NCI 10701074 8/28/23 0:00 RFA-CA-20-051 5R01CA268023-02 5 R01 CA 268023 2 "D'ANGELO, HEATHER" 9/8/22 0:00 8/31/27 0:00 ZCA1-RPRB-L(A1)R 10973126 "DAHNE, JENNIFER RENEE" Not Applicable 6 PSYCHIATRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 909034 NCI 624654 284380 ABSTRACTRural residents are both more likely to smoke cigarettes and less likely to quit than their urban counterparts.Consequently individuals in rural areas have a 7% higher incidence of tobacco-associated cancers.Comprehensive smoking cessation treatment dissemination strategies are needed to increase utilization ofevidence-based treatment improve cessation outcomes and ultimately decrease cancer incidence among ruralsmokers. Primary care providers (PCPs) see 70% of smokers annually and rural residents are more likely thanurban residents to have a usual source of health care. As such primary care offers a ripe opportunity to delivercessation treatment to rural smokers. All primary care practices that qualify for Centers for Medicare andMedicaid Services reimbursement are required to maintain electronic health records (EHRs) with coded smokingstatus data for adult patients. These data can be utilized to proactively identify smokers and deliver remotetreatment. Our team recently completed a pilot study to develop refine and preliminarily evaluate a proactiveasynchronous smoking cessation electronic visit (e-visit) delivered via the EHR. The goal of the e-visit is toautomate best practice guidelines for cessation treatment via primary care to ensure that all smokers receive anevidence-based intervention. An initial baseline e-visit gathers information about smoking history and motivationto quit followed by an algorithm to determine the best FDA-approved cessation medication to prescribe. A one-month follow-up e-visit assesses progress toward cessation. Clinical outcomes of our pilot (N=51 followed forthree months) were promising. Among rural participants who received the e-visit (n=6) 17% reported 7-day pointprevalence abstinence (PPA) 67% reduced their cigarettes per day (CPD) by >50% and 50% used a cessationmedication. E-visit participants relative to treatment as usual (TAU) were 4.2 times more likely to report 7-dayPPA 4.1 times more likely to have reduced their CPD by >50% and 4.7 times more likely to have used acessation medication. Acceptability outcomes were strong with 100% of rural e-visit participants reporting thatthey would use an e-visit again in the future. These data suggest that the e-visit may be a feasible efficaciousapproach to extend the reach of evidence-based cessation treatment via rural primary care. We now propose aHybrid Type I effectiveness-implementation trial to comprehensively assess e-visit effectiveness relative to TAUwhile simultaneously evaluating implementation when delivered across rural primary care settings. Effectivenessoutcomes will be assessed through 6-months of follow-up and include: 1) biochemically verified 7-day PPA 2)reduction in CPD and 3) evidence-based cessation treatment utilization. Implementation outcomes will beassessed at patient provider and organizational levels. This trial has the potential to expand cessation treatmentaccess in a manner scalable across rural healthcare systems and ultimately reduce rural cancer disparities. 909034 +No NIH Category available Academia;Address;Cell Culture Techniques;Clinical;Clinical Trials;Development;Disease;Drug Industry;Drug Targeting;Drug usage;FDA approved;Future;Genomics;Malignant neoplasm of prostate;Modality;Multiple Myeloma;Nuclear Hormone Receptors;Oncogenic;Oncology;Oncoproteins;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Play;Proteasome Inhibitor;Proteins;Proteolysis;Refractory;Relapse;Research;Small Interfering RNA;Technology;Translating;Validation;Work;bench to bedside;drug candidate;drug development;first-in-human;in vivo;innovation;knock-down;malignant breast neoplasm;novel;novel anticancer drug;novel drug class;novel therapeutics;protein degradation;proteostasis;recruit;small molecule;success;translational cancer research;tumor;ubiquitin-protein ligase;wasting Inducing Proximity: An Emerging Paradigm for New Therapeutic Modalities The function of many rogue disease-causing proteins cannot not be easily blocked using a smallmolecule drug approach hence they are undruggable. To address this we propose to simply eliminateor inactivate these unwanted proteins from the body instead of trying to use drugs to block their function.Here we describe the development of a new classes of drugs that target undruggable proteins fordestruction or inactivation and propose to implement these new pharmaceutical strategies againstproblem proteins that play key roles in oncology. NCI 10701073 8/3/23 0:00 PAR-21-333 5R35CA197589-09 5 R35 CA 197589 9 "FU, YALI" 9/9/15 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 7093779 "CREWS, CRAIG M" Not Applicable 3 BIOCHEMISTRY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF ARTS AND SCIENCES 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 898724 NCI 588000 317737 The pharmaceutical industry is in a crisis; unfortunately the post-genomic era has not significantly changedthe number of proteins pursued by drug companies. This dearth of new cancer drug targets has resultedin too many me too drugs and wasted effort. To address this need my lab has focused on developingthe new field of Controlled Proteostasis. Our initial efforts focused on inhibiting protein turnover; wedeveloped a novel proteasome inhibitor YU101 which served as the basis of a new oncology-basedbiopharma Proteolix Inc. from my lab. Ultimately YU101 became carfilzomib/Kyprolis which wasapproved by the FDA in 2012 for relapsed/refractory multiple myeloma. More recently my lab has beenfocused on the flipside of protein turnover i.e. developing a small molecule analogy to siRNA to induceprotein knockdown. We have shown that this strategy known as Proteolysis Targeting Chimerae(PROTACs) can effectively recruit targeted oncoproteins to E3 ubiquitin ligases for induced degradationboth in cell culture and in vivo. Over the past six years of the current R35 I have worked closely withanother biopharma that I founded Arvinas Inc. to apply this approach to nuclear hormone receptors inoncology. Arvinas two PROTAC-based drug candidates (targeting AR and ER for prostate and breastcancers respectively) have been shown to decrease their target proteins in first-in-human clinical trialsthus validating our PROTAC technology. In the next R35 phase I propose to develop this technologyfurther through the identification of key degradable oncogenic driver proteins and through the developmentof tumor-selective PROTACs. Moreover the clinical validation of PROTACs supports the development ofadditional novel therapeutic modalities based on heterobifunctional compounds that co-opt variousintracellular machineries. These innovative approaches have the potential to be new drug developmentparadigms that could have a significant impact by dramatically expanding the protein classes one cantarget pharmaceutically. Finally for the past 26 years I have focused on translating research from my labinto both new oncology-focused ventures and a FDA-approved drug thus demonstrating truly bench-to-bedside research that is not common in academia today. This track record of innovation and executionwithin translational cancer research are strong predictors of continued future success. 898724 +No NIH Category available Acute;Address;Australia;Binding;Biological Sciences;Blood;Brain;Breast;Cancer Etiology;Cancer Patient;Cancerous;Caring;Cathepsins;Cause of Death;Cessation of life;Chronic;Clinic;Clinical;Clinical Trials;Collaborations;Colorectal;Colorectal Cancer;Diagnosis;Disease;Dose;Double-Blind Method;Drug Kinetics;Enrollment;Ensure;Equipment;Event;Excision;Family;Formulation;Freeze Drying;Goals;Good Manufacturing Process;Head and neck structure;Histologic;Histopathology;Human Volunteers;Image;Image-Guided Surgery;Intravenous;Iowa;Label;Left;Lesion;Light;Location;Lung;Lung Neoplasms;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measures;Modality;Molecular Target;Near-infrared optical imaging;Nodule;Operating Rooms;Operative Surgical Procedures;Ovarian;Palpation;Patient Care;Patient Schedules;Patient Selection;Patient-Focused Outcomes;Patients;Pennsylvania;Peptide Hydrolases;Persons;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Phase;Phase II Clinical Trials;Placebo Control;Postoperative Period;Predictive Value;Process;Prognosis;Radiation therapy;Randomized;Recovery;Recurrence;Recurrent tumor;Respiratory Insufficiency;Risk;Risk Reduction;Safety;Site;Solid Neoplasm;Specific qualifier value;Specificity;Specimen;Stomach;Surgeon;Surgical Oncology;Survival Rate;Tactile;Techniques;Testing;Time;Tissues;Training;Translating;Tumor Tissue;United States;Universities;University Hospitals;Vial device;Visual;Visualization;arm;cancer diagnosis;cancer surgery;cancer type;clinically significant;curative treatments;falls;fluorescence imaging;high risk;imaging agent;imaging system;improved;malignant breast neoplasm;manufacture;medical schools;molecular imaging;novel;open label;optical imaging;overexpression;phase 3 study;phase I trial;phase II trial;preclinical safety;standard of care;surgery outcome;tumor Improving lung cancer surgery with an intraoperative tumor-targeted activatable fluorescent imaging agent PROJECT NARRATIVELung cancer is the second leading cause of death in the United States killing more people than colorectalbreast and prostate cancers combined. Despite the many advances in surgical care and preoperative imagingsurgeons must often rely only on their visual and tactile abilities to distinguish tumor tissue from healthy tissueduring surgical resection which may result in positive tumor margins and higher risks of recurrence. A targetedmolecular imaging agent VGT-309 will be used in a Phase 2 clinical trial to illuminate lung tumor tissue duringsurgery and facilitate the precise identification of tumor margins ensuring all cancerous tissue is removed andproviding lung cancer patients with an urgently needed intraoperative imaging solution. NCI 10701056 6/5/23 0:00 PA-21-260 5R44CA277890-02 5 R44 CA 277890 2 "POND, MONIQUE ADRIANNE" 9/8/22 0:00 5/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Z(10)B] 9942005 "BENSEN, ERIC SCOTT" "SINGHAL, SUNIL " 3 Unavailable 81216261 H6N2Y333JHS5 81216261 H6N2Y333JHS5 US 44.962792 -93.284945 10051275 "VERGENT BIOSCIENCE, INC." MINNEAPOLIS MN Domestic For-Profits 55439 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 SBIR/STTR 2023 874253 NCI 752439 64620 PROJECT SUMMARY/ABSTRACTMore than 228000 people in the United States will receive a lung cancer diagnosis this year. Only 14%-49% ofearly-stage patients survive at least 5 years after their diagnosis and the survival rates fall below 5% forpatients with advanced-stage IIIB or IV. Tumor recurrence after resection is a critical factor influencing thesepoor prognoses. If any cancerous tissue is left behind during surgery the risk of an aggressive tumorrecurrence increases dramatically. These recurrent tumors rapidly spread and negatively impact a patientsclinical outlook. Therefore accurately identifying tumor tissue during surgical resection is crucial. Despite thisneed translating preoperative images into the surgical suite for real-time precise visualization remains achallenge; in an intraoperative setting for lung cancer tissues are often displaced lungs are deflated andblood can obscure the surgical field. Vergent Bioscience Inc. developed a molecular imaging agent VGT-309to meet this urgent need for improved intraoperative visualization of tumors. This agent is administered as asingle intravenous dose prior to surgery after which it will bind to upregulated cathepsins in the canceroustissue become activated and fluoresce. Commercially available near-infrared (NIR) imaging systems can thenbe used during surgery to illuminate the tumor and enable surgeons to precisely identify and remove tumormargins ensuring no cancerous tissue is left behind. VGT-309 has a wide post-dose imaging window and canbe seamlessly integrated into existing surgical workflows without requiring additional training or equipment.Extensive preclinical safety efficacy and dosing studies have validated the use of VGT-309 to facilitate theresection of a variety of solid tumor types. A Phase 1 randomized double-blind placebo-controlled singleascending dose study in healthy subjects was completed in early 2021 to evaluate the safety tolerability andpharmacokinetics of VGT-309. All four doses were safe and well-tolerated during this trial so a starting dose of0.05mg/kg was selected for patients with lung cancer who are currently enrolled in an ongoing Phase 2 clinicaltrial in Australia to determine optimal VGT-309 dose and timing. During the present Direct to Phase IIapplication Vergent will 1) manufacture VGT-309 drug product following Current Good ManufacturingPractices and 2) collaborate with the Hospital of the University of Pennsylvania to evaluate this agent in aPhase 2 open-label study to assess its safety tolerability and efficacy in 35 patients scheduled to undergostandard of care surgical resection for suspected or proven lung cancer. Once successfully validated in ourPhase 2 clinical trial VGT-309 will be evaluated in larger multi-site Phase 2b and Phase 3 studies. Ultimatelywe plan to expand the use of this fluorescent activatable molecular imaging agent to other solid tumors suchas colorectal head and neck ovarian brain gastric and breast. This agent has the potential to transform thesurgical oncology space and optimize clinical outcomes for patients undergoing resection of tumors. 874253 +No NIH Category available Acute;Address;Animal Model;Antitumor Response;Bioinformatics;Biology;Blood;Blood specimen;CD34 gene;Cancer Biology;Cancer Model;Cancer Patient;Cancer cell line;Cell Death;Cells;Chromosome abnormality;Clinical;Clinical Trials;Cytoplasm;DNA;DNA Damage;DNA Repair;DNA Repair Inhibition;DNA biosynthesis;DNA replication fork;Data;Data Science Core;Extensive Stage;Gene Activation;Genetic;Genetically Engineered Mouse;Genomic Instability;Goals;Human;Immune;Immune checkpoint inhibitor;Immune system;Immunocompetent;Immunotherapy;Impairment;In Vitro;Innate Immune Response;Innate Immune System;Laboratories;Lead;MYC-Family Oncogene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mitotic;Modeling;Molecular;Molecular Profiling;Mus;Mutation;Natural Immunity;Neoplasm Circulating Cells;Non-Small-Cell Lung Carcinoma;Oncogene Activation;Oncogenes;Oncogenic;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Productivity;RB1 gene;RBL2 gene;Refractory;Relapse;Research Personnel;Resistance;Series;Specimen;Stimulator of Interferon Genes;TP53 gene;Telomerase;Testing;Therapeutic;Thioguanine;Umbilical cord structure;Xenograft procedure;anti-PD-1;anti-PD-L1;anticancer research;aurora kinase;aurora kinase A;biological adaptation to stress;biomarker driven;biomarker identification;cancer cell;cancer therapy;candidate marker;chemotherapy;clinical development;cytotoxicity;effective therapy;efficacy evaluation;experience;experimental study;genetic approach;immune checkpoint;immune checkpoint blockade;improved;in vivo;inhibitor;kinase inhibitor;lung cancer cell;mouse model;mutant;neoplastic cell;novel;overexpression;patient derived xenograft model;pembrolizumab;personalized medicine;pharmacologic;pre-clinical;preclinical study;predicting response;predictive marker;programmed cell death ligand 1;protein expression;reconstitution;replication stress;response;safety assessment;small cell lung carcinoma;targeted agent;targeted cancer therapy;targeted treatment;telomere;therapeutic target;tumor;tumor-immune system interactions;tumorigenesis Project 4: Therapeutic Targeting of Replication Stress Vulnerabilities in Small Cell Lung Cancer Project 4 Project NarrativeProgress is slow in treating advanced small cell lung cancers (SCLC) and there remains an urgent need toprovide patients with long-term durable responses. Approaches to develop SCLC targeted therapy improveresponses to immunotherapy and to more effectively treat primary chemotherapy relapsed and refractory SCLCare acutely needed. Our Project addresses all of these aspects by testing targeted therapy induced replicationstress (RS) as a potential SCLC therapeutic vulnerability which also would increase innate immune responsesagainst SCLC and lead to improved responses against immune checkpoint blockade immunotherapy. This newSCLC RS vulnerability is studied through a series of preclinical translational experiments and an investigator-initiated Phase 2 clinical trial. NCI 10701038 8/21/23 0:00 PAR-18-313 5P50CA070907-24 5 P50 CA 70907 24 9/5/97 0:00 8/31/25 0:00 ZCA1-RPRB-J 8317 10415175 "BYERS, LAUREN AVERETT" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 423659 378417 46293 Project 4 Project Summary/AbstractThe goal of this project is to develop novel synthetic lethal replication stress related approaches for SCLCpatients based on their tumors molecular profiles. There are two major unmet needs for SCLC therapy: firstthe majority of patients will experience primary or acquired resistance to clinically available chemotherapy andimmunotherapy; and second despite new data supporting molecularly and biologically distinct subsets of SCLCthere are no established approaches for biomarker-driven personalized treatments (such as is standard fortargetable oncogenic drivers in NSCLC). Many of the currently undruggable oncogenic changes that arecommon in SCLC promote tumorigenesis through replication stress (RS) and genomic instability. Thesehallmarks of cancer lead to high tumor mutational burden and chromosomal aberrations. SCLCs have acontinuous high degree of RS due to the universal loss of p53 and RB1 function and frequent activation ofoncogenes such as MYC. In the presence of RS cancer cells depend on RS responses (RSR) which are abranch of DNA damage repair responses (DDR) to resolve DNA damage and stalled replication forks. SeveralRSR inhibitors are in clinical development and we have preliminary findings in preclinical models indicating thatSCLC lines xenografts and genetically engineered mouse models (GEMMs) are sensitive to agents that targetRSR or that increase RS or genomic instability beyond tolerable levels. The latter group includes aurora kinaseinhibitors (which induce mitotic catastrophe in the setting of high RS levels as well as directly inhibiting DNArepair and decreasing replication fork stability) and 6-thio-dG (distinct from the well-known drug 6 thioguanine)which is incorporated by telomerase positive cells leading to telomere disruption and increased RS.Furthermore we have recently found that therapeutic targeting of RS (e.g. by inhibitors of Chk1 or PARP)increases cytoplasmic DNA resulting in activation of the innate immune response (via the Stimulator of InterferonGenes [STING] pathway) immune-mediated cytotoxicity and enhanced response to immune checkpointblockade. We hypothesize that: 1. RS targeting (through Aurora Kinase inhibition or telomere disruption) willlead to synthetic lethality in molecularly-defined subsets of SCLC (Aim 1); and 2. that RS targeting will enhanceresponse to immune checkpoint blockade in immunotherapy-refractory subsets of SCLC via activation of theinnate immune system (Aims 2 and 3). Specifically we expect that RS-targeted therapies will lead to replicationcatastrophe and cell death in oncogene-driven lung cancers and enhance responses to immune checkpointblockade (e.g. anti-PD-L1). We will test our hypotheses in an extensive panel of molecularly characterizedSPORE lung cancer cell lines patient derived xenografts (PDXs tumor and circulating tumor cell (CTC)-derived)GEM-derived animal models (Aims 1 and 2) and in clinical specimens from an investigator-initiated Phase 2clinical trial (Aim 3) of Aurora Kinase inhibition combined with checkpoint inhibitor immunotherapy in extensive-stage SCLC. +No NIH Category available Area;Baltimore;Biomedical Research;Cancer Biology;Communicable Diseases;County;Engineering;Faculty;Immunology;Institution;Joints;Maryland;Medicine;Microbiology;Modeling;Neurosciences;Scholars Program;Science;Teacher Professional Development;Technology;Training;Underrepresented Populations;United States National Institutes of Health;Universities;career;medical schools;member;programs;recruit;undergraduate student University of Maryland First Program The University of Maryland School of Medicine (UMSOM) and the University of MarylandBaltimore County (UMBC) are submitting a joint application to the NIH Faculty InstitutionalRecruitment for Sustainable Transformation (FIRST) program to recruit new faculty membersfrom groups traditionally underrepresented (UR) in biomedical research. This consortium willuse a model for faculty development and promotion that is based on the UMBC MeyerhoffScholars Program which has been highly in training undergraduates from UR groups who havegone on to careers in STEM (Science Technology Engineering Medicine). The model willfeature cluster hires of 10 new faculty in the areas of cancer biology neuroscience andmicrobiology/immunology/infectious diseases in which there is great institutional strength. NCI 10701032 9/11/23 0:00 RFA-RM-21-025 5U54CA272205-02 5 U54 CA 272205 2 9/9/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-R] 8315 8737978 "BROWN, JESSICA " Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 159639 144424 15215 A lack of diversity in STEM continues to be a persistent problem limiting our capacity to address pressing problems facing individuals institutions communities and our society as a whole. Although many initiatives exist on our campuses to promote diversity and include underrepresented populations at the student level diversity in the STEM professoriate remains low. For lasting change to occur and to truly include URM faculty in our institutions of higher learning we need to identify approaches that can be implemented by universities to transform hiring faculty engagement and tenure and promotion processes. Modeled on the Meyerhoff Scholars Program the UM FIRST initiative will work toward effecting institutional departmental and faculty-level changes to foster inclusive excellence at both the University of Maryland School of Medicine (UMSOM) and the University of Maryland Baltimore County (UMBC). The goals of the Evaluation Core team are to work collaboratively across UMSOM and UMBC as well as with the NIH FIRST Coordination and Evaluation Center (CEC) to assess monitor and track program activities. Using a mixed methods approach the Evaluation Core will assess the impact of the UM FIRST Initiative in addition to providing ongoing feedback throughout the project to inform modifications in the UM FIRST activities. The evaluation will examine several primary and intermediate outcomes of UM FIRST. The primary outcomes of interest include: examining the change in percent of new faculty hires representing URM groups at the institution and department level; examining the change in percent of URM faculty retained at the institution and department level and; examining the impact of the UM FIRST initiative on academic productivity of UM FIRST cluster hires. The intermediate outcomes of interest include: an increase in URM representation among new faculty applicant pools at the institution and department level; the successful hiring of UM FIRST faculty cluster hires across UMBC and UMSOM; documented change in written institution hiring policies; documented change in written APT policies; a significant increase in institution DEI culture and climate; an increase in institutional commitment to DEI among leadership STEM faculty and their departments and among UM FIRST faculty cluster hires and their mentors and; the successful implementation of UM FIRST Faculty Development Core activities. +No NIH Category available Accounting;Biological;CD8B1 gene;Cancer Patient;Cells;Clinic;Clinical;Collaborations;Combination Drug Therapy;DNA Sequence Alteration;Dependence;Disease;Epidermal Growth Factor Receptor;Equilibrium;Genetic;Genomics;Glutaminase;Glutamine;Goals;Human;Immune;Immune Targeting;Immunogenomics;Immunologics;Immunosuppression;Immunotherapy;KRAS2 gene;Label;Laboratories;Lung Adenocarcinoma;Macrophage;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Metabolic;Metabolism;Molecular;Mutation;Non-Small-Cell Lung Carcinoma;Nucleotides;PD-1/PD-L1;Pathway interactions;Patients;Phenotype;Population;Pre-Clinical Model;Production;Proteins;Publications;Reporting;Resected;Resistance;Resources;STK11 gene;Specimen;Stress;Subgroup;Systemic Therapy;T-Lymphocyte Subsets;Testing;Therapeutic;Therapeutic Agents;Translating;Tumor Immunity;Tumor Suppressor Proteins;Tumor-infiltrating immune cells;Validation;chemotherapy;cohort;driver mutation;effector T cell;gemcitabine;immune checkpoint blockade;immunosuppressed;improved;inhibitor;knock-down;metabolic phenotype;mouse model;mutant;neoplastic cell;novel therapeutic intervention;nucleoside analog;patient population;pharmacologic;pre-clinical;programmed cell death ligand 1;replication stress;response;single-cell RNA sequencing;targeted agent;therapeutically effective;therapy resistant;tumor;tumor growth;tumor-immune system interactions Project 2: Targeting Immune Vulnerabilities in Lung Cancer Project 2 Project NarrativeAlthough PD-1/PD-L1 immune checkpoint blockade (PCB) therapy has transformed the treatment of non-smallcell lung cancer (NSCLC) patients the majority still do not have an objective response to PCB and the moleculardeterminants of therapeutic resistance are not well understood. We have found that STK11/LKB1 mutant NSCLCis one the largest genomic subgroups associated with a cold immune phenotype accounting for ~40% of theprimary resistance to checkpoint blockade therapy and we hypothesize that there are distinct biological featuresof these tumors that may contribute their immunologically inert phenotype and that represent therapeuticvulnerabilities. In this proposal will leverage unique preclinical and clinical resources to comprehensivelyinvestigate the immune landscape of STK11/LKB1 mutant lung adenocarcinoma and test whether targeting twopotential therapeutic vulnerabilities- lactate metabolism and replication stress- can enhance antitumor immunityin these tumors. NCI 10701031 8/21/23 0:00 PAR-18-313 5P50CA070907-24 5 P50 CA 70907 24 9/5/97 0:00 8/31/25 0:00 ZCA1-RPRB-J 8314 1894553 "HEYMACH, JOHN V." Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 321285 276043 46293 Project 2 Summary/AbstractImmunotherapy with PD-1/PD-L1 checkpoint blockade (PCB) given alone or with chemotherapy now representsthe standard first-line treatment for NSCLC patients with wild-type (wt) EGFR and ALK. This is a major advancebut the majority of NSCLC patients do not have an objective response to PCB. The molecular determinants ofPCB resistance are incompletely understood although low tumor mutation burden and PD-L1 levels predictsome cases. Recently we reported that LKB1 deficient (LD) tumors resulting from mutations or deletions in theSTK11/LKB1 gene are associated with an inert or cold immune phenotype and represent the largestgenomically-define subgroup with primary resistance to PCB accounting for more than 30% of PCB resistancein lung adenocarcinoma. The LKB1 protein is a master regulator of metabolism energetic balance andnucleotide stores. Recent publications from our group and others indicate that LD tumors have a distinctmetabolic phenotype that includes enhanced lactate production vulnerability to targeting intracellular nucleotidepathways and increased replicative stress (RS). These features may contribute to the cold immune phenotype.The primary goals of Project 2 (P2) are to investigate new therapeutic approaches for targeting LD NSCLC andenhancing antitumor immunity with a focus on targeting the lactate pathway and RS. This focus integrates theimmunotherapy focus of Project 2 with studies in the other SPORE Projects and provides multiple HumanEndpoints for the SPORE Projects. We hypothesize that: 1) Enhanced lactate production or secretioncontributes to the cold immune phenotype in LD NSCLC; 2) LD NSCLC will be preferentially vulnerable totargeting RS; and 3) targeting RS and/or lactate pathways may enhance antitumor immunity and response toPCB. To test these hypotheses in SA1 we will comprehensively characterize the immune phenotypes of LDNSCLC using two sets of resected tumors: the MD Anderson ICON cohort and a validation cohort from UTSWwhich have undergone metabolic labeling in P1. We will also examine immune cells in greater detail using singlecell RNA sequencing. In SA2 we will test whether targeting the lactate pathway using inhibitors of MCT4 andLDHA can reverse LD-associated immunosuppression and enhance PCB efficacy. In SA3 we will target RSusing inhibitors of ATM ATR and the nucleoside analog 6-thio-dG in collaboration with P4 alone or incombination with PCB. Significance: LD NSCLC tumors have a cold immune phenotype and frequent primaryresistance to PCB or PCB/chemotherapy. This patient population is larger than EGFR-mutant NSCLC andcomparably sized to metastatic pancreatic cancer. P2 aims to leverage our unique set of clinical and preclinicalresources to develop more effective therapeutic approaches for LD NSCLC patients which can then translatedby our group and others into the clinic. P2 also provides the opportunity to spearhead a new paradigm ofgenomically-guided tailored immunotherapy for PCB-resistant tumors. +No NIH Category available Accounting;Address;Affect;Area;CD147 antigen;CRISPR/Cas technology;Cancer Patient;Carrier Proteins;Cell Communication;Cells;Cellular Metabolic Process;Clinical;Clinical Data;Clinical Research;Clinical Trials;Data;Data Set;Dependence;Disease Progression;Dissection;Genetic;Glucose;Goals;Growth;Heterogeneity;Histologic;Histopathology;Human;Image;Immune;Immune checkpoint inhibitor;Immunotherapy;Impairment;Infusion procedures;Intrinsic factor;Label;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methods;Modeling;Molecular;Molecular Profiling;Mus;Needle biopsy procedure;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Nutrient;Oncogenic;Outcome;Patients;Pattern;Phenotype;Population;Positioning Attribute;Pre-Clinical Model;Predisposition;Progression-Free Survivals;Proteins;Recording of previous events;Reporting;Source;Squamous Cell Lung Carcinoma;Structure of parenchyma of lung;System;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Time;Tissues;Translating;Work;anti-tumor immune response;biological heterogeneity;cancer cell;cell type;clinically relevant;cohort;design;exome sequencing;follow-up;human subject;immune checkpoint blockade;in vivo;inhibitor;innovation;interest;metabolic phenotype;metabolomics;mouse model;multidisciplinary;multiparametric imaging;new therapeutic target;novel;patient derived xenograft model;pharmacologic;pre-clinical;predict clinical outcome;predictive marker;somatic cell gene editing;therapeutic target;transcriptome sequencing;treatment response;tumor;tumor growth;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumor progression;tumor xenograft;tumor-immune system interactions;uptake Project 1: Targeting Metabolic Vulnerabilities in Lung Cancer Project 1 Project NarrativeThe goal of SPORE Project #1 Targeting Metabolic Vulnerabilities in Lung Cancer is to identify previouslyunknown acquired vulnerabilities related to tumor cell metabolism in lung cancer and in preclinical models testthe effect of targeting these vulnerabilities alone and with clinically available therapies. This proposal will identifyspecific metabolic activities that predict disease progression in humans and will thoroughly study the effect oftherapeutically inhibiting one such activity lactate transport on tumor growth and metastasis in preclinicalmodels in mice. In addition this project will provide some of the first data on how lung cancer metabolism affectsits tumor microenvironment (and vice versa) particularly related to anti-tumor immune responses which will beof value to all of the other SPORE Projects. NCI 10701028 8/21/23 0:00 PAR-18-313 5P50CA070907-24 5 P50 CA 70907 24 9/5/97 0:00 8/31/25 0:00 ZCA1-RPRB-J 5952 1900629 "DEBERARDINIS, RALPH J" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 269497 224255 46293 Project 1 Project Summary/AbstractHuman lung tumors are metabolically distinct from adjacent lung tissue. It is unknown whether thesereprogrammed activities predict clinical outcomes or represent meaningful therapeutic liabilities. The majorbottleneck in understanding the clinical relevance of cancer metabolism has been a lack of data about humantumor metabolism in vivo. For the first time we have overcome this limitation and used intra-operative infusionswith 13C-glucose to define metabolic phenotypes in human non-small cell lung cancer (NSCLC). We reportedthat one NSCLC subset displays prominent import of lactate while another subset produces lactate fromglucose. Our observation that lactate uptake via monocarboxylate transport protein-1 (MCT1) correlates withrapid disease progression in lung adenocarcinoma is the first and to date only metabolic flux phenotypedemonstrated to predict clinical outcomes in any human cancer. In this Project we will expand the scope ofmetabolic analysis in human NSCLC performing 13C infusions in more than 100 patients assessing hundredsof metabolites in each tumor and following clinical histories to identify new activities correlating with outcomes.In Specific Aim 1 tumors infused with 13C will be analyzed by imaging quantitative histopathology RNAsequencing and whole exome sequencing to understand relationships between these features and cancermetabolism. We will focus on identifying metabolic features that correlate with reduced progression-free survivalunder the rationale that such activities are attractive therapeutic targets to test in preclinical models. We willestablish patient-derived xenografts (PDXs) from these tumors to test the importance of predictive metabolicactivities for tumor growth and metastasis. While our open-ended metabolomics approach is designed to uncovernovel therapeutic targets based on our earlier work we will specifically test whether inhibiting MCT1 reducestumor growth and metastasis in mice. In Specific Aim 2 we will follow up on our observation that lung squamouscell carcinomas require lactate export for maximal growth. We will test whether genetic or pharmacologicalinhibition of novel molecular components of MCT4-mediated lactate export suppresses tumor growth in mousemodels and PDXs. Specific Aim 3 will examine metabolic crosstalk among cancer cells and several importantimmune cell populations in the tumor microenvironment in mice and humans. We will test the hypothesis thatlactate metabolism impacts these metabolic exchanges and that blocking lactate transport enhances the efficacyof immune checkpoint blockade therapy. Overall these efforts will produce the most detailed and clinically-relevant view of NSCLC metabolism to date. The ability to combine our ongoing study assessing metabolic fluxin human NSCLC with large legacy clinical datasets ideally positions us to understand the relationship betweentumor metabolism and cancer progression and to advance high-priority therapeutic targets into clinical trials.The immediate Human Endpoint of this project is the direct detailed examination of tumor metabolism andtumor microenvironment patients with lung cancer following 13C-glucose infusions while later Human Endpointswill involve therapeutic interventions targeting MCT1 and MCT4. +No NIH Category available Affect;Area;Baltimore;Biomedical Research;Cancer Biology;Collaborations;Communicable Diseases;County;Engineering;Ensure;Environment;Evaluation;Faculty;Faculty Recruitment;Federal Government;Funding;Future;Goals;Immunology;Individual;Infrastructure;Institution;Institutional Policy;Joints;Leadership;Learning;Legal Rights;Maryland;Medical;Medicine;Microbiology;Modeling;Monitor;Neurosciences;Pathway interactions;Philosophy;Positioning Attribute;Postbaccalaureate;Procedures;Process;Racial Equity;Recording of previous events;Research Personnel;Resources;Role;Scholars Program;Science;Series;Social Justice;State Government;State Interests;Statutes and Laws;System;Talents;Teacher Professional Development;Technology;Textiles;Thinking;Training;Translating;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Universities;Vision;biomedical scientist;career;career development;cohort;diversity and inclusion;equity diversity and inclusion;evidence base;expectation;experience;faculty mentor;faculty support;high school;junior high school;medical schools;member;novel;outreach;process improvement;professor;programs;recruit;sound;success;tenure track;tool;undergraduate student Administrative Core-UM First The University of Maryland School of Medicine (UMSOM) and the University of MarylandBaltimore County (UMBC) are submitting a joint application to the NIH Faculty InstitutionalRecruitment for Sustainable Transformation (FIRST) program to recruit new faculty membersfrom groups traditionally underrepresented (UR) in biomedical research. This consortium willuse a model for faculty development and promotion that is based on the UMBC MeyerhoffScholars Program which has been highly in training undergraduates from UR groups who havegone on to careers in STEM (Science Technology Engineering Medicine). The model willfeature cluster hires of 10 new faculty in the areas of cancer biology neuroscience andmicrobiology/immunology/infectious diseases in which there is great institutional strength. NCI 10701025 9/11/23 0:00 RFA-RM-21-025 5U54CA272205-02 5 U54 CA 272205 2 9/9/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-R] 8311 1877813 "KAPER, JAMES B" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 3766351 3165211 601140 PROJECT SUMMARYThe goal of the proposed UM FIRST program is to catalyze institutional change through therecruitment of URM faculty with a stated interest in diversity equity and inclusion. Acollaboration between the University of Maryland School of Medicine (UMSOM) and theUniversity of Maryland Baltimore County (UMBC) will capitalize on the strengths of eachinstitution in developing and maintaining inclusive programs to encourage diversity in thebiomedical research workforce and developing NIH-funded faculty from junior investigatorsrespectively. The role of the Administrative Core is to ensure the program activities are effectiveand well-integrated across both institutions through collaboration with the Faculty Developmentand Evaluation Cores oversee sound fiscal management through a team-based plan that willensure strategic deployment of resources recruit a diverse cohort of new faculty by capitalizingon a series of novel activities that will transform search and recruitment practices at bothinstitutions and implement new institutional policies and procedures that codify the importanceof a diverse faculty and provide an embracing infrastructure that leads to sustainableinstitutional change.The Administrative Core will span both institutions and will be directed by the PIs and Co-CoreLeaders Drs. Kaper and LaCourse and Co-Directors Dr. Prasad and Ms. Johnson. Additionaloversight and guidance will be provided by the Program Steering Committee and the FiscalOversight Committee as well as the Internal and External Advisory Boards. +No NIH Category available Academy;Affect;Appointment;Area;Baltimore;Biomedical Research;Cancer Biology;Climate;Communicable Diseases;Communities;County;Dedications;Development;Educational process of instructing;Engineering;Ensure;Environment;Evaluation;Faculty;Fostering;Funding;Future Generations;Goals;Immunology;Individual;Infrastructure;Institution;Institutional Policy;Joints;Link;Maryland;Medicine;Mentors;Microbiology;Modeling;Monitor;Neurosciences;Postdoctoral Fellow;Procedures;Process;Productivity;Qualifying;Readiness;Research;Research Personnel;Resources;Scholars Program;Schools;Science;Series;Services;Teacher Professional Development;Technology;Textiles;Training;Training Programs;Underrepresented Minority;Underrepresented Populations;Underrepresented Students;United States National Institutes of Health;Universities;Vision;Work;career;cohort;design;experience;faculty mentor;medical schools;member;professor;programs;recruit;role model;skills;suburb;success;tenure track;undergraduate student University of Maryland FIRST Program The University of Maryland School of Medicine (UMSOM) and the University of MarylandBaltimore County (UMBC) are submitting a joint application to the NIH Faculty InstitutionalRecruitment for Sustainable Transformation (FIRST) program to recruit new faculty membersfrom groups traditionally underrepresented (UR) in biomedical research. This consortium willuse a model for faculty development and promotion that is based on the UMBC MeyerhoffScholars Program which has been highly in training undergraduates from UR groups who havegone on to careers in STEM (Science Technology Engineering Medicine). The model willfeature cluster hires of 10 new faculty in the areas of cancer biology neuroscience andmicrobiology/immunology/infectious diseases in which there is great institutional strength. NCI 10701024 9/11/23 0:00 RFA-RM-21-025 5U54CA272205-02 5 U54 CA 272205 2 "CALZOLA, JESSICA MARIE" 9/9/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-R(70)R] 1877813 "KAPER, JAMES B" "LACOURSE, WILLIAM RICHARD" 7 MICROBIOLOGY/IMMUN/VIROLOGY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 4101345 OD 3444525 656820 Modified Project Summary/Abstract Section The overarching goal of the University of Maryland FIRST program is to create a comprehensive model that is dedicated to ensuring a diverse scholarly environment and encouraging outstanding individuals to enter the academic profession through a commitment to inclusive excellence. This proposal represents a Partnership between the University of Maryland School of Medicine (UMSOM) and the University of Maryland Baltimore County (UMBC). As defined by the FIRST RFA the UMSOM is a Highly Resourced Institution (HRI) with an average of $140 million in NIH funding over the last three years and UMBC is a Limited-Resourced Institution (LRI) with an average of $7.5 million in NIH funding over the last three years. The UMSOM is one of six professional schools on the University of Maryland Baltimore (UMB) campus located in downtown Baltimore. UMBC is located in the Baltimore suburbs just 8 miles away from UMB. UMB and UMBC have been closely linked ever since the 1966 founding of UMBC through a variety of interactions and relationships as described in the proposal. We will build upon UMBCs rich reputation as a public research university for producing highly capable and competitive undergraduate and graduate scholars in a diverse setting. We will combine our experience in hiring a diverse faculty through effective post-doctoral and pre-professoriate programs with the stellar reputation of UMB-SOM in producing highly successful biomedical researchers. This new model will seek to hire three cohorts of underrepresented scholars who are committed to diversity in the academy and to prepare those scholars for successful possible tenure track appointments at UMBC. In addition the program will serve to encourage and support departments and programs in their efforts to enrich their intellectual communities through the increased representation of diverse perspectives in research teaching and service. Cohorts will be recruited into broadly themed areas of cancer biology neuroscience and microbiology/infectious diseases which are all areas of significant strength at both institutions. Ten new faculty members from underrepresented groups will be recruited with six recruits being primarily affiliated with the UMSOM and four recruits primarily affiliated with UMBC. All recruits will have secondary appointments in the other institution and will undergo faculty development and other program activities as a cohort. The general approach proposed in this initiative is to combine the experiences and strengths of our two institutions through leveraging existing programs and new initiatives to infuse the unbiased hiring and mentoring of faculty especially underrepresented minorities into the fabric of departmental culture and thereby affect institutional change. Of primary importance are institutional policies and procedures that codify the importance of a diverse professoriate and provide a sustainable infrastructure for it to establish and grow. 4101345 +No NIH Category available B-Lymphocytes;Basic Science;Belief;Blood Banks;Blood Cells;Blood specimen;Cancer Patient;Cancer cell line;Catalogs;Cell Line;Cells;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Collection;Confidentiality of Patient Information;Consent;DNA;Data;Data Science Core;Deposition;Development;Drug or chemical Tissue Distribution;Ensure;Epithelial Cells;Extramural Activities;Fostering;Funding;Genomics;Goals;Grant;Guidelines;Histologic;Human;Immune;Immunogenomics;Immunotherapy;Informed Consent;Institution;Institutional Review Boards;Investigation;Lung;Lung Neoplasms;Malignant - descriptor;Malignant neoplasm of lung;Measures;Methodology;Methods;Molecular;Molecular Analysis;Neoadjuvant Study;Neoplasm Circulating Cells;Non-Malignant;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Pathogenesis;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Peer Review;Play;Positioning Attribute;Process;Proteins;Protocols documentation;Publications;RNA;Reagent;Research;Research Activity;Research Personnel;Research Project Grants;Resectable;Resource Sharing;Resources;Role;Sampling;Selection for Treatments;Services;Site;Specimen;Testing;Tissue Banks;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translational Research;Tumor Cell Line;United States National Institutes of Health;University of Texas M D Anderson Cancer Center;Xenograft procedure;biobank;career;cell bank;clinical translation;data sharing;high standard;immune checkpoint blockade;immunopathology;individual patient;innovation;liquid biopsy;lung cancer cell;molecular pathology;novel;personalized medicine;programs;small cell lung carcinoma;success;synergism;tissue resource;translational applications;translational cancer research;tumor;tumor xenograft;tumor-immune system interactions Molecular Pathology and Tissue Resource Pathology Core (Core B) Project NarrativeThe Molecular Pathology and Tissue Resources Core will provide routine and innovative tissue resourcesand materials essential for achieving the aims of the SPORE projects Developmental and CareerEnhancement Programs using IRB approved protocols informed consent and protection of patientconfidentiality. This Core will play a crucial role on promoting collaboration among our own SPOREinvestigators and investigators at other Lung Cancer SPORE sites and other intra and extra-muralcollaborations by coordinating the proper procurement storage and use of tissues providing access tospecimens and cell lines and performing molecular and immuno-pathology methodologies. An importantfeature of the materials collected and analyzed by this Core is their clinical histopathologicimmunohistochemical immune microenvironment and molecular annotation which provides clinical translationand synergism between available data and other studies performed on these samples. NCI 10701012 8/21/23 0:00 PAR-18-313 5P50CA070907-24 5 P50 CA 70907 24 9/5/97 0:00 8/31/25 0:00 ZCA1-RPRB-J 5950 10624693 "BISHOP, JUSTIN A." Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 199396 154153 46294 Pathology Core (Core B) Project Summary/AbstractThe Molecular Pathology and Tissue Resources Core will provide routine and innovative tissue resources andmaterials essential for achieving the aims of the SPORE projects. Routine materials include tumors non-malignant lung specimens tumor cell lines and clinical annotation all of which have been obtained with informedconsent and measures to ensure patient confidentiality. Over 6000 tumors including tumors on clinicallyannotated tissue microarrays (TMAs) 300 lung cancer cell lines of all histologic types and over 180 lung tumorpatient-derived and circulating tumor cell-derived xenografts (PDXs/CDXs) are available to investigators. Manyof these samples have been distributed to our SPORE investigators as well as other investigators at our ownand outside institutions (including other SPOREs). These partnerships have fueled multiple lung cancertranslational research collaborations and have generated over 380 publications in the last ten years. In additionto important clinical and histologic annotation the genomic molecular and immune microenvironment profilingof these samples provide important Human Endpoints for correlative data and synergy both within the UT LungSPORE and as components of other lung cancer translational research. Given the increasing importance ofimmunotherapy for lung cancer the Pathology Core has developed methods to provide state of the art immuneprofiling annotation. Additionally the Core has participated in collection of patient samples from the MDACCImmunogenomiC prOfiling of NSCLC (ICON) and NEOadjuvant STudy of induction checkpoint blockade forResectable stage I-IIIA NSCLC (NEOSTAR) clinical trials. Our Aim 1 is to collect process store catalog anddistribute tissues cell lines and blood specimens both malignant and non- malignant tumor xenografts andrelevant clinico-pathologic and molecular data as requested by the various component projects of the SPOREprogram; we will use IRB-approved protocols informed consent and measures to protect subject confidentiality.Aim 2 is to develop and utilize innovative and routine tissue and cell line resources that will aid in the successfulcompletion of the SPORE program aims; these include development of new tumor cell lines additional lungcancer TMA resources molecular analysis of tumors and liquid biopsy and comprehensive immune profiling oftissues. Aim 3 is to perform interpret analyze and deposit tissue-based molecular and immune analysismethodologies in close collaboration with the component Projects DRP CEP and Data Sciences Core of theSPORE program to achieve their approved aims. Within these aims the Pathology Core will play a crucial rolein promoting vertical and horizontal collaborations among our own SPORE investigators investigators at otherLung Cancer SPORE sites and other investigators at our own and other institutions. All of our SPORE projectswill use Core B materials and services. Heavy utilization of our routine and innovative materials as well as closeinteractions with the SPORE investigators will greatly aid the successful completion of the aims of our SPOREproposal. +No NIH Category available Address;Affect;Alcohol consumption;Alcohols;American Cancer Society;Arizona;Behavior;Behavior Therapy;Behavioral;Belief;Cancer Center;Cancer Control;Cancer Prevention Intervention;Clinic;Colorado;Communication;Communities;Comprehensive Cancer Center;Data Analytics;Eating;Employment;Enrollment;Ethnic Origin;Facebook;Family;Food;Geography;Gills;Goals;Guidelines;Health;Healthcare;Healthy Eating;Heavy Drinking;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Individual;Information Dissemination;Instruction;Internet;Intervention;Intervention Studies;Knowledge;Life;Literature;Malignant Neoplasms;Marketing;Measures;Media Campaign;Media Intervention;Mediating;Misinformation;New Mexico;Nicotine;Participant;Pattern;Physical activity;Population;Population Heterogeneity;Prevalence;Prevention program;Preventive healthcare;Privatization;Process;Protocols documentation;Randomized;Randomized Controlled Trials;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Factors;Rural;Rural Community;Rural Population;School Enrollments;Schools;Social support;Sunburn;Surveys;Testing;UV Radiation Exposure;Unhealthy Diet;United States;United States National Institutes of Health;Utah;Vaccines;Voice;Workplace;aged;biological sex;cancer prevention;cancer risk;cohort;cost;design;digital;digital media;effectiveness evaluation;emerging adult;experience;flexibility;health care service utilization;improved;innovation;literacy;literate;moderate-to-vigorous physical activity;modifiable risk;pragmatic randomized trial;prevent;prospective;prospective test;public trust;randomized trial;recruit;response;rural area;rural counties;rural underserved;sedentary lifestyle;skills;social interventions;social media;socioeconomics;sun protection;theories;tobacco advertising;trend;underserved area;uptake;vaccine acceptance;young adult #4Corners4Health: A Social Media Cancer Prevention Program for Rural Emerging Adults Young adults aged 18-26 engage in a number of behaviors that increase their risk of developing cancer later inlife including sedentary lifestyles unhealthy eating nicotine produce us heavy drinking of alcohol increasedUV exposure and incomplete uptake of HPV vaccination. A multi-risk factor campaign will be developed toreduce these cancer risk behaviors and delivered to young adults over social media a popular channel that canreach nearly all young adults. The campaign will be evaluated for effectiveness in a rigorous randomized trialwith measures of moderate to vigorous physical activity healthy eating patterns nicotine product use alcoholintake sunburn prevalence and HPV vaccination uptake. NCI 10700996 8/31/23 0:00 RFA-CA-20-051 5R01CA268037-02 5 R01 CA 268037 2 "CHOU, WEN-YING" 9/8/22 0:00 8/31/27 0:00 ZCA1-RPRB-L(A1)R 1872473 "BULLER, DAVID B" "SUSSMAN, ANDREW LOUIS" 7 Unavailable 117936042 NWQ2AMLQTLN6 117936042 NWQ2AMLQTLN6 US 39.74171 -105.155318 4368501 "KLEIN BUENDEL, INC." GOLDEN CO Domestic For-Profits 804013313 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1024466 NCI 811188 213278 Several risk factors are prevalent during early adulthood that can lead to cancer later in life. Emerging adults(EAs) aged 18-26 residing in rural areas of the United States engage in many cancer risk behaviors especiallysedentary lifestyles poor eating patterns nicotine product use excess alcohol intake infrequent sunprotection and inadequate uptake of the HPV vaccine. This application responds to RFA-CA-20-051 Socialand Behavioral Intervention Research to Address Modifiable Risk Factors for Cancer in Rural Populations.The goal is to improve cancer risk behavioral factors among diverse EAs aged 18-26 living in rural counties inthe Four Corners states a unique underserved region using a social media campaign designed withcommunity advisors. EAs including in rural communities are heavy consumers of online content especiallyover social media and social media provide responsive engaging and low-cost platforms for distributingcancer prevention information with high dissemination potential. But social media also circulate inaccuratemisleading and harmful information. The specific aims of this research are to: 1) Develop a social mediaintervention for diverse EAs in rural communities via a community-engaged process that combines expertadvice user-generated content and online instruction to communicate about behavioral cancer risks cancermisinformation counter marketing digital and media literacy and family communication; 2) evaluate theeffect of a theory-based social media intervention on moderate to vigorous physical activity (MVPA) healthyeating patterns nicotine product use alcohol intake sunburn prevalence and HPV vaccination with thediverse population of EAs aged 18-26 in rural counties in AZ CO NM and UT (Four Corners states) recruitedfrom Qualtrics' survey panel and enrolled in a pragmatic randomized trial using a stepped-wedge design inwhich individual EAs will be randomized to 1 of 4 cohorts and receive the social media feed for varyingdurations in separate Facebook private groups; 3) test if improvements in EAs' cancer risk knowledge andbeliefs digital and media literacy skills accurate cancer prevention information and family communicationmediate impact of the social media campaign; and 4) explore whether the impact of the social media campaigndiffers according to: a) level of EAs' engagement with campaign b) cancer risk factors and c) biological sex ofthe participants (as required by NIH). The research is innovative because it tests a theory-based multi-riskfactor approach to cancer prevention with diverse EAs in rural counties an under-studied population in a verypopular new media. Social media may reach EAs more than interventions through other community channels(e.g. clinics schools and workplaces) and for lower cost in the geographically-dispersed underserved ruralcommunities in the Mountain West. The overall impact is extremely high because it will aid rural EAs inmaking informed decisions that reduce cancer risk factors and prevent cancer later in life and help EAscritically evaluate and resist misinformation and marketing that promote cancer risk behaviors. 1024466 +No NIH Category available Areca catechu;Authorization documentation;Cancer Center;Cancer health equity;Data;Data Collection;Development;Ethnic Population;Funding;Guam;Hawaii;Health Disparities Research;Incidence;Infrastructure;Interview;Joints;Malignant Neoplasms;Malignant neoplasm of liver;Mastication;Medical Records;Nuts;Pacific Islands;Patients;Pilot Projects;Play;Publications;Registries;Reporting;Research;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Secure;Territoriality;Training;Universities;anticancer research;authority;cancer health disparity;data sharing;male;mortality;multi-ethnic;neoplasm registry;outreach;surveillance data;synergism;tumor registry Shared Resources - 003: Registry n/a NCI 10700969 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T 8294 11831643 "LEON GUERRERO, RACHAEL T" Not Applicable 98 Unavailable 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU Domestic Higher Education 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 10230 7255 2975 PROJECT SUMMARY/ABSTRACTThe Cancer Registry Shared Resource Core (CRSRC) will serve a key role in identifying and characterizingcancer disparities in the multiethnic populations of Guam and Hawaii. The overall objective of the CRSR is toprovide key infrastructure support for cancer research and outreach activities of the Pacific Island Partnershipfor Cancer Health Equity (PIPCHE). The CRSRC meets the requirements of PIPCHE shared resources toenhance the ability to conduct cancer disparities research.The CRSRC represents a partnership between the Guam Cancer Registry (GCR) and the Hawaii TumorRegistry (HTR) the central cancer registries of the Territory of Guam and the State of Hawaii respectively.This partnership has been critical to the development of the GCR as a fully functioning registry throughtechnical support and training provided by the HTR and through the establishment of statutory authority forcancer reporting and securing territorial funding. The CRSRC subsequently played a critical role in thedevelopment of the Pacific Regional Central Cancer Registry covering the US Affiliated Pacific Islands.The CRSRC serves as a critical resource for PIPCHE research and outreach. The CRSRC generates high-quality cancer surveillance data through which cancer disparities can be identified and characterized. Thisinformation is key to establishing PIPCHE research and outreach priorities. The CRSR also provides keysupport for research and outreach activities.The CRSRC will continue to serve as an important Core of the PIPCHE.Specific Aim 1. Provide cancer data and related support for PIPCHE research projects (full andpilot) and outreach activities.Specific Aim 2. Build capacity for cancer surveillance and health disparities research at theUniversity of Guam (UOG) and the University of Hawaii Cancer Center (UHCC). This alignment willallow for a synergy and sharing of data that would not be possible otherwise. +No NIH Category available Cancer Center;Cancer health equity;Collaborations;Communication;Communications Media;Communities;Community Outreach;Consultations;Database Management Systems;Funding;Goals;Guam;Hawaii;Health Personnel;Industry;Informatics;Information Technology;Infrastructure;Institution;Maintenance;Malignant Neoplasms;Pacific Islands;Play;Research;Resource Sharing;Site;Universities;Videoconferencing;Work;education research;experience;outreach;social media;student training;training opportunity;web site Shared Resources - 002: Information Technology n/a NCI 10700967 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T 8293 12589994 "HECHANOVA, MANUEL " Not Applicable 98 Unavailable 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU Domestic Higher Education 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 65998 46807 19191 PROJECT ABSTRACTThe Information Technology Shared Resource Core (ITSRC) plays a key role in facilitating the important workof the Pacific Island Partnership for Cancer Health Equity (PIPCHE) by providing infrastructure support for itsresearch research education and outreach activities. The overall goal of the ITSRC is to provide essentialcommunication infrastructure support to the Partnership in to the order to overcome the nearly 4000 miledistance between the partnering institutions. The ITSRC is led by industry professionals experienced in onlineinfrastructure multi-platform communication collaborations and social media. The ITSRC will satisfy thecommunication and information technology needs of all U54 projects by providing communications support(e.g. videoconferencing synchronous file sharing whiteboard discussions) between sites technical assistancefor informatics (e.g. database management) and maintenance of the Partnership websites and othercommunication and social media platforms to inform the community about the Partnership and to disseminateresearch findings. +No NIH Category available Acute;Adipose tissue;Adrenergic Agents;Adrenergic Receptor;Animals;Anorexia;Atrophic;Attenuated;Behavior;Behavioral;Body Weight decreased;Cachexia;Cancer Patient;Cardiac;Cardiovascular system;Catabolism;Chronic;Chronic Disease;Chronic stress;Clinical Trials Design;Collaborations;Corticosterone;Corticotropin-Releasing Hormone;Data;Dedications;Disease;Energy Metabolism;Evolution;Exhibits;Fatigue;Functional disorder;Genetic;Glucocorticoids;Goals;Human;Hypothalamic structure;Impairment;Inflammatory;Intervention;Laboratories;Lethargies;Life;Malignant Neoplasms;Metabolic;Metabolic dysfunction;Metabolic syndrome;Metabolism;Modeling;Morbidity - disease rate;Motivation;Mus;Muscle;Muscular Atrophy;Nerve;Neuroendocrinology;Neurons;Neurosecretory Systems;Neurotransmitters;Norepinephrine;Observational Study;Organ;Organism;Output;Pancreatic Ductal Adenocarcinoma;Pathologic;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Pharmacologic Substance;Phase II Clinical Trials;Phenotype;Physical Function;Physiological;Plasma;Pre-Clinical Model;Prevention;Quality of life;Reagent;Research;Role;Sick Role;Signal Transduction;Skeletal Muscle;Stress;Sympathetic Nervous System;Systemic disease;Testing;Therapeutic;Therapeutic Intervention;Tissues;acute stress;behavioral phenotyping;behavioral response;biological adaptation to stress;cancer cachexia;cancer type;clinical translation;defined contribution;density;design;exercise intolerance;experience;functional decline;hypothalamic-pituitary-adrenal axis;metabolic phenotype;mortality risk;mouse model;neuroinflammation;new therapeutic target;novel;novel therapeutics;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pharmacologic;prospective;response;synergism;systemic inflammatory response;therapeutically effective;tumor;tumor growth;wasting PQ6: Therapeutic approaches for autonomic and neuroendocrine dysfunction in cancer cachexia Project NarrativeInvoluntary weight loss anorexia fatigue and exercise intolerance are common in patients with cancer. Newresearch demonstrates that these problems limit quality of life for many patients and also are a significantcontributor to risk of death. Our studies are designed to investigate the ways in which cancer leads to thesedisabling changes in behavior and metabolism to better understand how this might be treated. NCI 10700965 8/1/23 0:00 RFA-CA-20-004 5R01CA264133-03 5 R01 CA 264133 3 "WATSON, JOANNA M" 9/10/21 0:00 8/31/26 0:00 ZCA1-SRB-F(M2)R 9605952 "GROSSBERG, AARON " Not Applicable 1 PEDIATRICS 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 424120 NCI 275403 148717 Project Summary:Illness behaviors metabolic disturbances and cardiovascular compromise are common in patients withchronic systemic diseases and contribute substantially to quality of life and ultimate survival. Other illness-induced morbidities including anorexia and lethargy also compromise the ability of patients to recover from life-saving or extending interventions and diminish the motivational drive to aggressively battle the underlyingcondition. Although cachexia in cancer patients was described more than two thousand years ago the centralmechanisms underlying this disorder are poorly understood. Furthermore there is currently no effectivepharmaceutical treatment. Cardiovascular impairment is common in all chronic diseases and can be apresenting complaint in cancer patients even prior to initiation of therapy. Our laboratory is dedicated tounraveling the basic mechanisms whereby cancer triggers neuroinflammation and subsequent chronicactivation of systemic stress responses in patients with cancer. In this proposal we will focus on understandingthe scope and mechanism by which systemic illness induces chronic activation and alteration in thesympathetic nervous system. The significance of this proposal resides in its unique combination of ourhistorical focus on neuroendocrinology and neuroinflammation with new collaborations and efforts directed atunderstanding the extent and mechanisms of cardiovascular impairment and sympathetic nervous systemplasticity in patients with cancer. The long-term goal of our research is to gain mechanistic understanding ofthe acute illness response and how it is transitioned into chronic neuroinflammation in all cancer types in orderto develop more effective therapeutic interventions. 424120 +No NIH Category available Advisory Committees;Biometry;Biostatistics Shared Resource;Cancer Center;Cancer health equity;Collaborations;Consultations;Data;Data Analyses;Exposure to;Guam;Hawaii;Health Disparities Research;Incidence;Information Technology;Mentors;Methods;Monitor;Pacific Islands;Pilot Projects;Population;Prevalence;Research;Research Design;Research Infrastructure;Research Project Grants;Resource Sharing;Respondent;Risk Factors;Role;Sampling;Scheme;Students;Universities;anticancer research;cancer health disparity;cancer risk;data curation;data management;data resource;experience;faculty mentor;health disparity;member;novel strategies;outreach;protective factors;sound;statistics Shared Resources - 001: Bio Statistics n/a NCI 10700964 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T 8292 11375855 "BADOWSKI, GRAZYNA " Not Applicable 98 Unavailable 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU Domestic Higher Education 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 92868 65865 27003 PROJECT SUMMARY/ABSTRACTThe Biostatistics Shared Resource Core (BSRC) serves a critical role in enhancing the U54 researchinfrastructure. The BSRC is led by biostatisticians who have the expertise and experience to contributesubstantially to successful cancer research in Pacific Island populations. The BSRC adds to the scientific rigorof U54 research through sound statistical advice and inclusion of novel approaches such as RespondentDriven Sampling and an interim analysis scheme in current projects. The BSRC provides support for allquantitative aspects of research endeavors including study design data management statisticalprogramming data analysis and interpretation and presentation of results. A primary biostatistician is assignedto each U54 research project in order to provide consultation throughout the study. The BSRC Leaders serveas non-voting members of the U54 Internal Advisory Committee and provide statistical review of and input tonew research concepts. The Shared Resource builds capacity for health disparities research at University ofGuam and the University of Hawai`i Cancer Center through mentoring of faculty and students on quantitativemethods thus building research capacity and through formal seminars. Additionally the BSRC will facilitateresearch through curation of information on cancer risks and prevalence of cancer risk and protective factors inGuam and Hawai`i to be used to inform research projects and through creation with the InformationTechnology Shared Resource of a platform for storage and sharing of current and past U54 project data anddocuments. +No NIH Category available Address;Applications Grants;Asian Pacific Islander;Asian population;Cancer Burden;Cancer Center;Cancer Control;Cancer Research Center of Hawaii;Cancer health equity;Caucasians;Collaborations;Communities;Degree program;Development Plans;Distant;Economics;Education;Educational Curriculum;Educational workshop;Enrollment;Epidemiology;Ethnic Origin;Faculty;Funding;Future;Geographic Locations;Geography;Goals;Graduate Degree;Grant;Guam;Hawaii;Health;Incidence;Individual;Institution;Intervention;Island;Journals;Location;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Manuscripts;Master of Science;Mentors;Micronesia;Output;Pacific Islander;Pacific Islands;Pathway interactions;Peer Review;Population;Positioning Attribute;Postdoctoral Fellow;Publications;Publishing;Race;Research;Research Assistant;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Scholarship;Series;Students;Supervision;Time;Training;Training Activity;Travel;Underserved Population;Universities;Writing;anticancer research;cancer health disparity;cancer prevention;career;career development;community based research;curriculum enhancement;doctoral student;education research;ethnic disparity;ethnic diversity;experience;follow-up;graduate student;health disparity;improved;interest;meetings;member;minority health disparity;mortality;novel;online course;programs;psychosocial;skills;success Research Education Core n/a NCI 10700948 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T 8286 15107558 "AMES, TODD " Not Applicable 98 Unavailable 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU Domestic Higher Education 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 150746 106912 43834 PROJECT SUMMARYThe setting of this training activity within the Pacific Island Partnership for Cancer Health Equity (PIPCHE)between the University of Guam (UOG) and the University of Hawaii Cancer Center (UHCC) is unique in itsethnic diversity and its distant location. Pacific Islanders are extremely underrepresented in the nationsbiomedical workforce which limits progress in research and prevention of cancer health disparities. PIPCHEaddresses training Pacific Islander cancer researchers in the context of the vast diversity and geography of theregion. The impact of the two previous cycles is remarkable. Without a cancer center in Guam youngresearchers and students had no opportunity to be involved in cancer research despite the high incidence ofmany cancers. During the past 10 years an infrastructure for research training in Guam and Micronesia hasbeen built; many UOG faculty members are collaborating in cancer research with UHCC. Since the initiation ofPIPCHE two previous trainees moved into faculty positions at UOG two graduates supported in cycle one arenow in faculty positions on the US mainland and one trainee is now employed at the National Institute ofMinority Health Disparities. To date ten trainees have entered doctoral programs in different locations. Of the45 PIPCHE research assistants at least nine went on graduate and professional degree programs. ThisResearch Education Core (REC) will continue the successful path with three specific aims: 1) Provideguidance support and opportunities to acquire research skills and experience to Pacific Islander studentspursuing a masters degree with a focus on cancer-related health disparities in the Pacific Island region.Students will be supported at UOG or at UHCC in programs not offered at UOG and mentored in a researchproject under the supervision of one or more PIPCHE faculty. An expanded curriculum consisting of an onlinecourse and a journal club will address critical current topics in cancer research. 2) Provide guidance supportand opportunities to acquire research skills and experience for students interested in cancer healthdisparities in the Pacific who are enrolled in a graduate degree program (masters or doctoral). Students willparticipate in biomedical epidemiologic psychosocial and community-based research projects led by UHCCfaculty. 3) Support guide and develop Early Stage Investigators (ESIs) to become independent investigators incancer health disparities with the help of a mentoring committee an annual manuscript and grant writingworkshop attendance at scientific meetings and course releases. Important enhancements are incorporatedinto the proposed program: increasing support from four to six UOG masters students per year due to highdemand; novel online modules related to health disparities in the Pacific; extension of UHCC funding fromdoctoral to masters students; travel scholarships for trainees to attend scientific meetings; an annual intensivewriting workshop at UOG to improve output in published manuscripts and grant applications; implementation ofmentoring committees and funds to provide ESIs with protected time for grant and manuscript writing. +No NIH Category available Acceleration;Animal Model;Atypical lymphocyte;Calibration;Cancer Etiology;Cancer Patient;Cessation of life;Clinical;Clinical Research;Clinical Trials;Development;Diagnosis;Digital Imaging and Communications in Medicine;Future;Genetically Engineered Mouse;Glean;Goals;IL8RB gene;Image;Immune checkpoint inhibitor;Immunotherapy;Industry Standard;Infiltration;Informatics;Link;Lung Adenocarcinoma;Malignant - descriptor;Malignant neoplasm of lung;Medical Imaging;Metadata;Methods;Modeling;Mus;Non-Small-Cell Lung Carcinoma;Oncology;Outcome;PD-1/PD-L1;PET/CT scan;Phase;Positron-Emission Tomography;Protocols documentation;Resources;Site;Squamous Cell Lung Carcinoma;Structure;Testing;Therapeutic;Work;animal imaging;antagonist;anti-PD-1;anti-PD-L1 therapy;cancer imaging;cancer therapy;checkpoint therapy;clinical imaging;co-clinical trial;data sharing;digital;early detection biomarkers;human disease;imaging informatics;imaging modality;improved;improved outcome;innovation;member;monocyte;mouse model;neutrophil;novel;oncology trial;open data;open source;pre-clinical;preclinical imaging;preclinical study;programs;quantitative imaging;recruit;response;success;tumor;tumor microenvironment;web-accessible A Quantitative PET/CT Research Resource for Co-Clinical Imaging of Lung Cancer Therapies Project NarrativeThe use of small animal models and clinical trials using medical imaging have led to improved diagnosis andtreatment of human disease. The goal of this work is develop methods and resources for co-clinical trials usingPET imaging and to implement them in a co-clinical trial evaluating immunotherapy treatment for lung cancer.The methods and resources developed to improve the utility of early-phase oncology trials using co-clinicalstudies with PET imaging will be distributed to accelerate the development of needed effective cancertherapies. NCI 10700944 8/11/23 0:00 PAR-18-841 5U24CA264044-03 5 U24 CA 264044 3 "ZHANG, HUIMING" 9/15/21 0:00 8/31/26 0:00 ZCA1-SRB-X(M1) 1972615 "KINAHAN, PAUL E." "HOUGHTON, A MCGARRY" 7 RADIATION-DIAGNOSTIC/ONCOLOGY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 389775 NCI 500371 123416 Project AbstractThe specific goal of this proposal is to develop and optimize methods for quantitative pre-clinical PET imagingfor immune checkpoint inhibitor (ICI) therapies in non-small cell lung cancer (NSCLC). We will leverage anexisting co-clinical trial using our genetically-engineered mouse model (GEMM) of lung adenocarcinoma todevelop test and implement the methods and populate a web-accessible research resource. This web-accessible research resource will in turn leverage recent developments in quantitative cancer imaginginformatics using the industry-standard DICOM format. In response to PAR-18-841 there are four componentsto our proposal: (1) appropriate models (2) a co-clinical trial including a therapeutic goal (3) quantitativepreclinical and clinical PET imaging and (4) an innovative quantitative cancer imaging informatics platform.Our longer term goal is to improve outcomes for NSCLC patients as lung cancer is still the leading cause ofcancer deaths worldwide. Although ICI therapy has been a tremendous clinical benefit for some NSCLCpatients only ~20% of NSCLC patients respond to anti-PD1/PDL1 therapy. Using PET co-clinical imaging toimprove ICI therapies for NSCLC is challenged by a lack of suitable informatics methods to capture and tracknecessary meta-information appropriate response criteria for preclinical imaging which in turn is aconsequence in part of the lack of quantitative preclinical PET imaging methods that are linked to quantitativeclinical PET imaging methods. We will address these challenges with three Specific Aims:1 Develop and optimize quantitative preclinical quantitative imaging methods and protocols. These methodswill involve novel long-lived phantoms that can cross-calibrate multiple preclinical and clinical PET scanners.This will be tested with partner members of the Co-Clinical Imaging Research Resources Program.2. Implement the optimized methods in our co-clinical trial of ICI treatment of NSCLC with a GEMM lungadenocarcinoma model and a GEMM model lung squamous cell carcinoma. From this we will evaluate how theinformation gleaned from the pre-clinical and clinical studies can be used to inform future pre-clinical studies interms of optimized mouse imaging protocols and response criteria.3. Share data and resources on co-clinical trials using quantitative PET imaging using a web-accessible openscience approach (open source + open data) by extending the DICOM standard for pre-clinical small animalimaging with DICOM-compliant structures that provide necessary quantitative meta-data.These methods and resources developed during this project will be distributed to accelerate the developmentof needed effective cancer therapies by improving the utility of early-phase oncology trials using co-clinicalstudies with PET imaging. In addition we will determine and potentially improve the utility of PET imaging asa biomarker for early assessment of response in co-clinical immunotherapy studies by using an appropriatemouse model. 389775 +No NIH Category available Apoptosis;Biological;Biometry;Cancer Burden;Cell Proliferation;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Community Clinical Oncology Program;Complement;Data Reporting;Databases;Development;Division of Cancer Prevention;Dose;Event;Goals;Growth Factor;Immune response;Informatics;Information Technology;Intervention;Leadership;Leg;Malignant Neoplasms;Methodology;Molecular Target;Morbidity - disease rate;National Cancer Institute;Oncogenes;Pattern;Phase;Preclinical Drug Development;Prevention trial;Preventive;Process;Program Development;Research;Resources;Risk Reduction;Role;Site;Toxicology;Training and Education;cancer prevention;carcinogenesis;clinical development;cost effective;data management;design;early phase clinical trial;early phase trial;effective intervention;innovation;insight;mortality;novel;oncology trial;operation;phase III trial;pre-clinical;prevention clinical trial;programs;protocol development;recruit;response;safety assessment;trend;virtual CP-CTNet Coordinating Center Project NarrativeCancer is the leading cause of morbidity and mortality in the US and in the world. The overall goal of theCancer Prevention Clinical Trials Network (CP-CTNet) is to perform early phase cancer prevention clinicaltrials to identify safe and effective preventive agents and interventions that can advance to late phases ofclinical development to ultimately reduce the risk and burden of cancer. Working with the National CancerInstitute's Division of Cancer Prevention and the CP-CTNet Sites the CP-CTNet Data Management Auditingand Coordinating Center will coordinate trans-network activities and support these early phase trials byproviding expertise and resources in 1) centralized data management and reporting 2) clinical trials auditingand 3) administrative and logistical coordination including expertise in clinical trials methodology andbiostatistics across CP-CTNet. NCI 10700942 8/2/23 0:00 RFA-CA-18-030 5U24CA242637-05 5 U24 CA 242637 5 "JOHNSEY, DONALD" 9/20/19 0:00 7/31/24 0:00 ZCA1-TCRB-O(M1) 1965840 "KIM, KYUNGMANN " Not Applicable 2 BIOSTATISTICS & OTHER MATH SCI 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Other Research-Related 2023 2361057 NCI 2178932 182125 Project Summary/AbstractCancer is the leading cause of morbidity and mortality in the US and in the world. One approach to reducingthe risk and burden of cancer is to use preventive agents and interventions that are effective and safe.According to the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI) this requires thesystematic development of cancer preventive agents and interventions with three critical components; i)preclinical/toxicology studies for identification of agents ii) early phase trials of identified agents and otherpromising interventions and iii) late phase III trials of preventive agents and interventions that havesuccessfully passed through early phase trials in a three-legged approach.The goal of the Cancer Prevention Clinical Trials Network (CP-CTNet) is to identify safe and effectivepreventive agents and interventions in order to advance their further clinical development for cancerprevention. Further clinical development is to be undertaken in late phase III trials conducted by the third legi.e. the National Community Oncology Research Program (NCORP) supported by the DCP's CommunityOncology and Prevention Trials Research Group to ultimately reduce the risk and burden of cancer. As thesecond leg of this three-legged approach the CP-CTNet will conduct early phase trials to assess the safetytolerability and cancer preventive potential of agents and interventions of varying classes identified by the firstleg i.e. the DCP's Cancer Preclinical Drug Development Program (PREVENT) support of preclinical/toxicologystudies many of which target molecules or processes known to be important during carcinogenesis. The CP-CTNet Sites will perform these early phase trials supported by the DCP and the CP-CTNet Data ManagementAuditing and Coordinating Center (DMACC). These trials include phase 0 (micro-dosing) phase I (dose-finding) and phase II (preliminary efficacy) clinical trials.To support these early phase trials which will be conducted by the CP-CTNet sites alone or as cross-Networktrials the CP-CTNet DMACC will coordinate trans-Network activities and provide expertise and resources in 1)centralized data management and reporting 2) clinical trials auditing and 3) administrative and logisticalcoordination including expertise in clinical trials methodology and biostatistics across CP-CTNet. In additionthe CP-CTNet DMACC will provide an advisory role in early phase caner prevention trial development for allCP-CTNet trials and the primary statistical role for cross-Network trials. 2361057 +No NIH Category available Advisory Committees;Cancer Center;Cancer health equity;Charge;Collaborations;Communities;Community Outreach;Data;Development;Disparity;Education and Outreach;Ensure;Evaluation;Faculty;Feedback;Funding;Funding Opportunities;Future;Goals;Grant;Guam;Hawaii;International;Leadership;Malignant Neoplasms;Monitor;Outcome;Pacific Islander;Pacific Islands;Persons;Pilot Projects;Population;Process;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Site;Specialist;Strategic Planning;Universities;anticancer research;cancer health disparity;education research;improved;inter-institutional;meetings;member;programs;response;success Planning and Evaluation Core n/a NCI 10700940 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T 8282 11831643 "LEON GUERRERO, RACHAEL T" Not Applicable 98 Unavailable 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU Domestic Higher Education 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 586714 416109 170605 PROJECT SUMMARYThe Planning and Evaluation Core (PEC) is responsible for monitoring the progress of Partnership componentsand of the Pacific Island Partnership for Cancer Health Equity (PIPCHE) as a whole and providing guidanceand input to ensure success. The PEC also supports the continuous progress of PIPCHE by providing for thedevelopment review and funding of new research projects as well as evaluation of existing projects andcores and PIPCHE overall. +No NIH Category available Advisory Committees;Cancer Center;Cancer health equity;Collaborations;Communication;Communities;Development;Educational workshop;Effectiveness;Environment;Evaluation;Goals;Guam;Hawaii;Indigenous;Infrastructure;Institution;Leadership;Malignant Neoplasms;Mission;NCI-Designated Cancer Center;Office of Administrative Management;Pacific Islander;Pacific Islands;Population;Preparation;Progress Reports;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Resource Allocation;Resource Sharing;Science;Services;Universities;Vision;anticancer research;career development;design;meetings;programs;recruit Administrative Core n/a NCI 10700934 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T 8279 11831643 "LEON GUERRERO, RACHAEL T" Not Applicable 98 Unavailable 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU Domestic Higher Education 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 271810 192772 79038 PROJECT SUMMARYThe Administrative Core is responsible for the implementation of the Pacific Island Partnership for CancerHealth Equity (PIPCHE). This is achieved through continued leadership coordination integration and alongstanding infrastructure designed to facilitate administrative management communication and rigorousteam science; promote integration; and oversee research progress to achieve PIPCHEs overarching goal: topromote cancer health equity and mitigate the impact of cancer on Pacific Island Populations (PIP) throughincreasing cancer research leadership and capacity in Hawaii Guam and the USAPI. The AdministrativeCore (AC) will implement all aspects of the Partnership including coordinating and planning all meetings andworkshops including monthly PIPCHE Team meetings and Executive Committee (EC) meetings Internal TeamMeetings as needed quarterly Internal Advisory Committee (IAC) meetings yearly Program SteeringCommittee (PSC) meetings and Scientific and Planning Workshops; biennial Retreats semiannual CommunityAdvisory Board meetings comprehensive PIPCHE evaluation through the Planning and Evaluation Corepreparation of the annual progress reports for the PSC and the annual noncompetitive application for the NCIand working with institutional leadership regarding recruitment fiscal management and resource allocation. Inaddition the Administrative Core functions as the primary liaison to the NCI PSC and IAC and is responsiblefor communicating and advancing their recommendations. By serving these functions the Core will allowinvestigators to focus on conducting and disseminating regionally-relevant and culturally appropriate researchsupported by PIPCHE. +No NIH Category available Address;Adolescence;Adolescent and Young Adult;Adverse effects;Age;Age Months;Anxiety Disorders;Attention deficit hyperactivity disorder;Behavioral;California;Cannabinoids;Cannabis;Cannabis policy;Characteristics;Chronic;Cigarette;Community Health;Data;Data Sources;Dedications;Dependence;Development;Devices;Disease;Drug abuse;Drug usage;Electronics;Emotional;Expectancy;Flavoring;Friends;Future;Health;High School Student;Impulsivity;Inhalation;Intervention;JUUL;Left;Link;Malignant Neoplasms;Marijuana Smoking;Measures;Mediating;Modeling;Mood Disorders;Nicotine;Oils;Outcome;Participant;Pharmaceutical Preparations;Plants;Play;Policies;Policy Maker;Population;Prevention;Prevention strategy;Problem behavior;Proliferating;Public Health;Research;Rewards;Risk;Risk Factors;Role;Sampling;Schools;Science;Scientist;Self Administration;Smoking;Students;Surveys;THC concentration;Technology;Testing;Tobacco;Tobacco use;Tobacco-Related Carcinoma;Uncertainty;Variant;Waxes;Youth;adverse outcome;aged;biopsychosocial;catalyst;cigarette smoking;cohort;combustible tobacco;design;deviant;digital;distress tolerance;electronic cigarette use;emerging adult;experience;experimental study;flexibility;follow-up;habituation;heated tobacco products;high risk;high school;high-risk adolescents;marijuana use;marijuana vaping;multiple drug use;nicotine exposure;nicotine use;ninth grade;novel;prevent;programs;progression risk;public health priorities;public policy on tobacco;recruit;risk prediction;smoking initiation;social;stem;tobacco products;trait;uptake;vaping;vaping nicotine;young adult Vaping Nicotine and Cannabis Across Adolescence and Young Adulthood !PROJECT NARRATIVEVapingthe inhalation of vaporized substances from electronic deviceshas increased in adolescents andyoung adults (AYAs) including vaping of flavors only nicotine and cannabis products. This study will providenew essential information about whether low-risk AYAs begin nicotine and cannabis use via vaping and whethervaping may lead to adverse consequences including cigarette and cannabis smoking. This study will providepublic health officials with data regarding the potential adverse public health impact of AYA vaping and cleartargets for intervention to reduce AYA vaping and the health consequences that may follow. NCI 10700931 9/8/23 0:00 PA-18-484 5R01CA229617-05 5 R01 CA 229617 5 "RODITIS, MARIA LEIA" 9/20/19 0:00 8/31/25 0:00 Addiction Risks and Mechanisms Study Section[ARM] 9227137 "LEVENTHAL, ADAM MATTHEW" "BARRINGTON-TRIMIS, JESSICA LOUISE" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 741796 NCI 374204 220592 !PROJECT SUMMARYIn 2015 evidence that e-cigarette use (vaping) in adolescents and young adults (AYAs) had increased andwas associated with increased risk of cigarette smoking initiation generated concern in the public health community. Subsequent research has left the field with several critical questions including: (1) whether vaping trulyhas a causal effect on smoking or merely reflects a common liability toward deviancy among high-risk AYAswith emotional or behavioral problems (2) whether an emerging wave of new vaping products including newnicotine products such as JUUL and an increasingly diverse class of products dedicated to vaping cannabisplant oils and waxes may increase the appeal and addictive potential of vaping and (3) whether there existparticular characteristics of vaping products and biopsychosocial mechanisms that underlie the risk of AYA vaping initiation progression and transition to other forms of drug use that could be targeted in prevention efforts.The uncertainties regarding the impact of AYA vaping have left policy officials with little evidence to determine ifAYA vaping should be prioritized in public health programs and if so the most effective strategies for prevention.To address the evidence needs and provide a flexible framework for future study of the impact of various vapingproducts on the AYA tobacco product and cannabis use burden we will test a novel catalyst model of AYAvaping. The catalyst model proposes two steps which we will evaluate in Aims 1 and 2 of this proposal. Step 1(AIM 1). To determine whether (a) AYAs with fewer emotional-behavioral risk factors who have been previouslydeterred from drug use in traditional (non-vaporized) forms are at risk of vaping initiation (b) the unique qualitiesand product features of vaping (e.g. concealability flavors appealing technology social acceptability low perceived harm) increase risk of AYA vaping and (c) features of vaping products disproportionately increase therisk of vaping initiation for low-risk AYAs. Step 2 (AIM 2). To determine whether (a) vaping increases the risk ofcross-product transitions involving initiation of other vaping products or combustible nicotine or cannabis aswell as increases risk of progression to problematic drug use outcomes including dependence poly-drug useand chronic drug use through early adulthood (b) rewarding effects from exposure to nicotine cannabinoidsand other product components (e.g. flavorings) increases risk of cross-product transitions and problematic druguse outcomes and (c) product characteristics modify this association. To test the model we will leverage datacollected from participants from age 14-19 (2013-2018) from our existing cohort and follow participants into earlyadulthood (20-23 from 2019-2023; N~2000). We will also recruit a new cohort of 9th grade students at age 14(N=2500) at the same schools as part of a cohort-sequential design that will apply causal inference analyticapproaches to determine whether observed associations are likely causal. Collectively this project will providecritical information regarding the priority and potential targets of public health efforts aimed at reducing the potential adverse public health effects resulting from AYA vaping including tobacco-related cancer. 594796 +No NIH Category available Address;Adolescence;Adolescent and Young Adult;Adverse effects;Age;Age Months;Anxiety Disorders;Attention deficit hyperactivity disorder;Behavioral;California;Cannabinoids;Cannabis;Cannabis policy;Characteristics;Chronic;Cigarette;Community Health;Data;Data Sources;Dedications;Dependence;Development;Devices;Disease;Drug abuse;Drug usage;Electronics;Emotional;Expectancy;Flavoring;Friends;Future;Health;High School Student;Impulsivity;Inhalation;Intervention;JUUL;Left;Link;Malignant Neoplasms;Marijuana Smoking;Measures;Mediating;Modeling;Mood Disorders;Nicotine;Oils;Outcome;Participant;Pharmaceutical Preparations;Plants;Play;Policies;Policy Maker;Population;Prevention;Prevention strategy;Problem behavior;Proliferating;Public Health;Research;Rewards;Risk;Risk Factors;Role;Sampling;Schools;Science;Scientist;Self Administration;Smoking;Students;Surveys;THC concentration;Technology;Testing;Tobacco;Tobacco use;Tobacco-Related Carcinoma;Uncertainty;Variant;Waxes;Youth;adverse outcome;aged;biopsychosocial;catalyst;cigarette smoking;cohort;combustible tobacco;design;deviant;digital;distress tolerance;electronic cigarette use;emerging adult;experience;experimental study;flexibility;follow-up;habituation;heated tobacco products;high risk;high school;high-risk adolescents;marijuana use;marijuana vaping;multiple drug use;nicotine exposure;nicotine use;ninth grade;novel;prevent;programs;progression risk;public health priorities;public policy on tobacco;recruit;risk prediction;smoking initiation;social;stem;tobacco products;trait;uptake;vaping;vaping nicotine;young adult Vaping Nicotine and Cannabis Across Adolescence and Young Adulthood !PROJECT NARRATIVEVapingthe inhalation of vaporized substances from electronic deviceshas increased in adolescents andyoung adults (AYAs) including vaping of flavors only nicotine and cannabis products. This study will providenew essential information about whether low-risk AYAs begin nicotine and cannabis use via vaping and whethervaping may lead to adverse consequences including cigarette and cannabis smoking. This study will providepublic health officials with data regarding the potential adverse public health impact of AYA vaping and cleartargets for intervention to reduce AYA vaping and the health consequences that may follow. NCI 10700931 9/8/23 0:00 PA-18-484 5R01CA229617-05 5 R01 CA 229617 5 "RODITIS, MARIA LEIA" 9/20/19 0:00 8/31/25 0:00 Addiction Risks and Mechanisms Study Section[ARM] 9227137 "LEVENTHAL, ADAM MATTHEW" "BARRINGTON-TRIMIS, JESSICA LOUISE" 37 PUBLIC HEALTH & PREV MEDICINE 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 741796 NIDA 92483 54517 !PROJECT SUMMARYIn 2015 evidence that e-cigarette use (vaping) in adolescents and young adults (AYAs) had increased andwas associated with increased risk of cigarette smoking initiation generated concern in the public health community. Subsequent research has left the field with several critical questions including: (1) whether vaping trulyhas a causal effect on smoking or merely reflects a common liability toward deviancy among high-risk AYAswith emotional or behavioral problems (2) whether an emerging wave of new vaping products including newnicotine products such as JUUL and an increasingly diverse class of products dedicated to vaping cannabisplant oils and waxes may increase the appeal and addictive potential of vaping and (3) whether there existparticular characteristics of vaping products and biopsychosocial mechanisms that underlie the risk of AYA vaping initiation progression and transition to other forms of drug use that could be targeted in prevention efforts.The uncertainties regarding the impact of AYA vaping have left policy officials with little evidence to determine ifAYA vaping should be prioritized in public health programs and if so the most effective strategies for prevention.To address the evidence needs and provide a flexible framework for future study of the impact of various vapingproducts on the AYA tobacco product and cannabis use burden we will test a novel catalyst model of AYAvaping. The catalyst model proposes two steps which we will evaluate in Aims 1 and 2 of this proposal. Step 1(AIM 1). To determine whether (a) AYAs with fewer emotional-behavioral risk factors who have been previouslydeterred from drug use in traditional (non-vaporized) forms are at risk of vaping initiation (b) the unique qualitiesand product features of vaping (e.g. concealability flavors appealing technology social acceptability low perceived harm) increase risk of AYA vaping and (c) features of vaping products disproportionately increase therisk of vaping initiation for low-risk AYAs. Step 2 (AIM 2). To determine whether (a) vaping increases the risk ofcross-product transitions involving initiation of other vaping products or combustible nicotine or cannabis aswell as increases risk of progression to problematic drug use outcomes including dependence poly-drug useand chronic drug use through early adulthood (b) rewarding effects from exposure to nicotine cannabinoidsand other product components (e.g. flavorings) increases risk of cross-product transitions and problematic druguse outcomes and (c) product characteristics modify this association. To test the model we will leverage datacollected from participants from age 14-19 (2013-2018) from our existing cohort and follow participants into earlyadulthood (20-23 from 2019-2023; N~2000). We will also recruit a new cohort of 9th grade students at age 14(N=2500) at the same schools as part of a cohort-sequential design that will apply causal inference analyticapproaches to determine whether observed associations are likely causal. Collectively this project will providecritical information regarding the priority and potential targets of public health efforts aimed at reducing the potential adverse public health effects resulting from AYA vaping including tobacco-related cancer. 147000 +No NIH Category available Acceleration;Accreditation;Address;Advanced Malignant Neoplasm;Affect;American;Area;Areca;Asian;Awareness;Behavioral;Biological;Biology;Biometry;Cancer Burden;Cancer Center;Cancer Control;Cancer Etiology;Cancer Research Infrastructure;Cancer Research Project;Cancer Science;Cancer health equity;Clinical;Clinical Trials;Collaborations;Communities;Community Health;Community Outreach;Complex;Country;Dedications;Disparity;Distant;Economics;Education;Enrollment;Environment;Epidemiology;Equity;Ethnic Origin;Evaluation;Extramural Activities;Faculty;Funding;Goals;Guam;Hawaii;Health;Health Educators;Health Personnel;Health Sciences;Health system;Incidence;Individual;Information Technology;Infrastructure;Institution;Investments;Island;Knowledge;Leadership;Learning;Life Style;Location;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Marshall Islands;Mastication;Mentors;Minority;Minority-Serving Institution;Modeling;NCI-Designated Cancer Center;National Cancer Institute;Nuts;Obesity;Outcome;Pacific Island Americans;Pacific Islander;Pacific Islands;Pilot Projects;Policies;Population;Positioning Attribute;Poverty;Prevention;Process;Race;Research;Research Personnel;Research Project Grants;Research Training;Resource Sharing;Resources;Risk Factors;Screening for cancer;Series;Site;Socioeconomic Status;Students;Surveys;Survival Rate;Training;Translational Research;Underserved Population;United States;Universities;Work;Workforce Development;adolescent smoking;anticancer research;cancer education;cancer health disparity;cancer prevention;cancer risk;community organizations;community partnership;cultural competence;education research;evidence base;expectation;geographic population;health care availability;health determinants;health equity;health literacy;higher education;improved;insight;malignant mouth neoplasm;member;mortality;neoplasm registry;outreach;population health;programs;psychosocial;public health intervention;recruit;social (2/2) Pacific Island Partnership for Cancer Health Equity (PIPCHE) PROJECT NARRATIVE: OVERALLThe Pacific Island Partnership for Cancer Health Equity (PIPCHE) represents the next step in augmenting aHawaii-Guam-USAPI cancer research infrastructure by investing in Pacific Island Populations leaders EarlyStage Investigators community partners and community-informed disparities research. As a result of the 17-year commitment PIPCHE is also well positioned to increase the diversity of the biomedical cancer scienceworkforce and research leadership that better reflects the Hawaii-Guam-USAPI larger racial/ethnicrepresentation and to stimulate new areas of disparities and translational research. PIPCHE has assembleddedicated academic and community partnerships needed to synergistically accelerate disparities research intoa sustainable forum that pursues cultural and environmental appropriate solutions. NCI 10700918 8/15/23 0:00 PAR-18-767 5U54CA143728-14 5 U54 CA 143728 14 "GHOSH, SANGEETA AHUJA" 9/1/09 0:00 8/31/25 0:00 ZCA1-SRB-T(A1) 11831643 "LEON GUERRERO, RACHAEL T" "HATTORI, MARGARET P; PALAFOX, NEAL A." 98 NONE 779908151 YL62T9FVJXG3 779908151 YL62T9FVJXG3 US 13.461978 144.794011 3087201 UNIVERSITY OF GUAM MANGILAO GU UNIVERSITY-WIDE 969131800 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1329430 NCI 942858 386572 PROJECT SUMMARY: OVERALLThe Pacific Island Partnership for Cancer Health Equity (PIPCHE) is a 17-year collaboration between theUniversity of Guam (UOG) and the University of Hawaii Cancer Center (UHCC) that continues to advancecancer health equity increase the cancer research and education capacity and decrease significant cancerdisparities in Pacific Islands Populations. Americans of Pacific Islander ancestry are a highly underserved andvulnerable minority with a disparate cancer burden including significant underrepresentation among cancerand biomedical researchers and healthcare providers which further exacerbates the disparities. Theoverarching goal and long-term objective are to promote cancer health equity and mitigate the impact of canceron Pacific Island Populations through increasing cancer research leadership and capacity in Hawaii Guamand the United States Affiliated Pacific Islands which comprise the Pacific Island Populations addressed bythis project. As the only National Cancer Institute-funded Partnership serving the underrepresented PacificIsland region PIPCHE will accomplish its goals through the following specific aims: (1) Continue to develop adiverse portfolio of Pacific Island Population-focused cancer research projects that include clinical basic andpopulation health sciences (2) Collaborate with local and regional Pacific Island community organizations thatwork with underrepresented Pacific Island Populations to promote cancer health equity and enhanceopportunities for research training and workforce development (3) Sustain strengthen and continuouslyevaluate of all the Partnerships research core activities and research education programs (4) Enhance andimplement evidence-based relevant cancer-related public health interventions and cancer prevention andcontrol strategies with and within underrepresented communities and (5) Expand the scientific collaborationamong PIPCHE members and other faculty within the two institutions with an emphasis on recruiting EarlyStage Investigators of Pacific Island ancestry. PIPCHE will carry out these aims by continued investment infour Cores (Cancer Outreach Research Education Planning and Evaluation and Administration) whichprovide the infrastructure and governance of the Partnership. The proposed Shared Resources (BiostatisticsEpidemiology Information Technology and Cancer Registry) will provide essential technical and scientificsupport to the PIPCHE student scholars trainees and the proposed full research projects and pilot projectsthat specifically address the cancer disparities of the Pacific Island Populations. Using its arc of cancer equityPIPCHE has identified 10 major domains (education/health literacy policy environment lifestyleculture/community biology treatment healthcare access psycho-social and socio-economic status) thatinfluence Pacific Islander cancer health disparities/equity. Each of the research projects cores andinfrastructure affects one or more of the domains and therefore knowledge about the action of PIPCHEs workis value added and helpful as individuals as a team while working towards Pacific cancer health equity. 1329430 +No NIH Category available Administrator;Advocate;Agreement;Collaborations;Country;Development;Documentation;Ensure;Evaluation;Evaluation Research;Fred Hutchinson Cancer Research Center;Funding;Goals;Grant;IACUC;Individual;Infrastructure;Institution;Institutional Review Boards;Joints;Leadership;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Monitor;NCI-Designated Cancer Center;Occupational activity of managing finances;Patients;Productivity;Program Appropriateness;Progress Reports;Research;Research Personnel;Research Support;Resource Allocation;Structure;Time;Universities;Washington;career;meetings;programs;translational impact Administrative Core Project Narrative Administrative CoreThe Administrative Core of the Fred Hutch Lung SPORE will provide the necessary infrastructure organization coordination and fiscal management necessary to successfully complete the tasks proposed within this application. The overall function of the Administrative Core is to coordinate a collaborative effort between Fred Hutch Lung SPORE investigators and leadership through leaders of our Center who compose the Internal Advisory Board and scientific experts assembled to serve on the External Advisory Board. The Administrative Core will ensure that the collective plans agreed upon by SPORE leadership are efficiently executed and that appropriate documents are filed fiscal responsibilities are adequately met and the Developmental Research and Career Enhancement Programs are appropriately managed. NCI 10700915 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N 8267 6786529 "HOUGHTON, A MCGARRY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 128071 81352 46719 Project Summary/Abstract Administrative CoreThe Administrative Core of the Fred Hutch Lung SPORE will provide the necessary infrastructure organization coordination and fiscal management necessary to successfully complete the tasks proposed within this application. Ultimately the responsibility for the successful completion of all SPORE related activities belongs to Dr. Houghton the SPORE PI. Dr. Martins will assist him in this endeavor. Additionally the Lung SPORE Administrator Jessica Paulishen will carry out all administrative responsibilities. Collectively the Fred Hutch Lung SPORE leadership will coordinate all SPORE related activities. Advice received from advisory boards will be implemented into the program through the administrative core. Specific tasks of the Administrative Core will include: 1) to provide coordination and oversight to all Lung SPORE activities to meet the scientific and administrative needs of the individual projects and cores 2) to provide fiscal management of grant funds for projects and cores 3) to prepare and file regulatory documents and progress reports 4) to administer the Developmental Research Program and Career Enhancement Program 5) to coordinate SPORE interaction with the Fred Hutch/UW Cancer Consortium 6) to arranged the monthly Lung SPORE Research Meeting and the annual Lung SPORE Retreat and 7) to provide oversight for all necessary regulatory requirements and documentation. +No NIH Category available Address;Arizona;Bioinformatics;Biometry;Cancer Center;Cancer Research Project;Collaborations;Communication;Communities;Development;Educational workshop;Ensure;Evaluation;Extramural Activities;Faculty;Feedback;Funding;Funding Opportunities;Goals;Grant;Health Disparities Research;Institution;Leadership;Learning;Manuscripts;Measures;Mentors;Methodology;Native Americans;Participant;Play;Population;Positioning Attribute;Preparation;Process;Publications;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Services;Study Section;System;Technology;Time Management;Training;Universities;Writing;anticancer research;cancer health disparity;cancer prevention;career;community engagement;design;education research;experience;inter-institutional;next generation;outreach;research and development;skills;success;tool Shared Resource Core - GUIDeS n/a NCI 10700914 8/15/23 0:00 PAR-18-767 5U54CA143925-15 5 U54 CA 143925 15 9/29/09 0:00 8/31/24 0:00 ZCA1-SRB-2 8266 8324555 "INGRAM, JANI CHERI" Not Applicable 2 Unavailable 806345542 MXHAS3AKPRN1 806345542 MXHAS3AKPRN1 US 35.192568 -111.656765 482601 NORTHERN ARIZONA UNIVERSITY FLAGSTAFF AZ Domestic Higher Education 860114130 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 56088 36900 19188 PROJECT SUMMARY/ABSTRACT: GUIDeS SHARED RESOURCEGoals of the Partnership for Native American Cancer Prevention (NACP) include expanding the number of NativeAmerican investigators working in cancer research and increasing the total number of investigators focused oncancer health disparities within the Native American communities of Arizona. This fifteen-year partnershipbetween Northern Arizona University (NAU) and the University of Arizona Cancer Center (UACC) has madesignificant progress toward these goals with increasing numbers of successful early stage investigators (ESIs)and junior investigators (JIs) engaged in cancer research and cancer health disparities research within the NativeAmerican population. Numerous ESIs and JIs from the earlier years of the partnership have now establishedindependent research careers with successful academic rank promotions. This success has primarily beenachieved through intentional and collaborative research and career mentoring. In fact some of the earlier NACP-associated ESIs and JIs including Native Americans now hold leadership positions within the NACP and areplaying a critical role in training the next generation of NACP investigators.The NACP leadership team for this renewal application proposes to build and expand on the success learningexperiences and participant feedback from current and prior project periods by implementing a new-sharedresource called GUIDeS or Guiding U54 Investigator Development to Sustainability. This shared resource willorganize and facilitate a range of new services and career enhancement opportunities primarily targeted forESIs and JIs. The GUIDeS Shared Resource has been strategically designed to interface with the other NACPcomponents Outreach Research Education Planning and Evaluation Administrative and NACP-sponsoredresearch projects to ensure services and expertise across NACP are available to ESIs and JIs and that ESIsand JIs are fully integrated into the full range of NACP activities and research collaborations between NAUUACC and the Native American communities it serves.Specifically GUIDeS will: 1) assist ESIs and JIs through the process of developing a rigorously designed cancerresearch project and identifying potential funding opportunities; 2) pair them with senior NACP faculty researchermentors and other inter-institutional collaborators for the development of their projects and resulting grants andpublications; 3) navigate them through the university system in developing the regulatory financial andinstitutional requirements for conducting and submitting research to extramural agencies; 4) afford opportunitiesto participate in grant development workshops and mock study sections as well as access to grant writing andproposal development services; 5) provide biostatistics and bioinformatics support services as well asstreamlined access to experts in Native American-based community engagement specifically regardingresearch (Outreach Core); and 6) support their development of effective organizational time management andresearch communication skills e.g. seminar presentation and manuscript preparation. +No NIH Category available Accounting;Address;Antibody Therapy;Antigens;Atypical lymphocyte;Biopsy Specimen;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cancer Patient;Cell Lineage;Cells;Cessation of life;Clinical;Clinical Trials;Consent;Core Biopsy;Correlative Study;Data;Data Set;Development;Failure;Fred Hutchinson Cancer Research Center;Gene Expression Profile;Genetic;Genetically Engineered Mouse;Goals;Human;IL8RA gene;IL8RB gene;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunohistochemistry;Immunotherapeutic agent;Immunotherapy;Infiltration;Interferon Type II;Lung;Lung Adenocarcinoma;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Mus;Mutant Strains Mice;Mutation;Myelogenous;Myeloid Cells;Nivolumab;Non-Small-Cell Lung Carcinoma;Outcome;PD-1/PD-L1;Patients;Phase II Clinical Trials;Phenotype;Population;Pre-Clinical Model;Prospective cohort;Retrospective cohort;Safety;Single Nucleotide Polymorphism;Slide;Smoke;Solid Neoplasm;Specimen;Testing;Therapeutic;Tissues;Treatment Efficacy;Treatment Failure;Work;antagonist;anti-PD-1;anti-PD-L1 antibodies;anti-PD-L1 therapy;anti-PD1 antibodies;anti-PD1 therapy;cancer type;cell type;checkpoint therapy;cigarette smoke;cigarette smoking;co-clinical trial;cohort;design;diagnostic strategy;exhaust;exhaustion;immune checkpoint;immune checkpoint blockade;improved;mortality;mouse model;nano-string;neutrophil;novel;novel diagnostics;novel therapeutics;prevent;prospective;response;small molecule;success;synergism;treatment response;tumor;tumor microenvironment Project 1: Targeting the Neutrophil Lineage To Enhance Immune Checkpoint Inhibitor Efficacy in NSCLC Project Narrative Project 1Lung cancer is the leading cause of cancer deaths worldwide accounting for ~160000 lives in the US alone; although emerging immune therapies for lung cancer patients have shown initial promise response rates are just ~20%. The major goals of this project are to show that neutrophil lineage cells prevent tumor reactive lymphocytes from accessing the malignant portions of tumor and that depleting neutrophils from the tumor microenvironment will improve anti-PD1 response rates. The development of a novel mouse model that is suitable for the study of immunotherapies is an additional goal of the proposal. NCI 10700909 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N 8263 6786529 "HOUGHTON, A MCGARRY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 193285 117832 75453 Project Summary/Abstract Project 1Although immune checkpoint inhibitor (ICI) therapy has been a tremendous clinical success just ~20% of non-small cell lung cancer (NSCLC) patients respond to anti-PD1/PDL1 therapy. In efforts to improve upon this figure the field has launched over 800 clinical trials (across all cancer types) testing novel therapeutics in conjunction with immune checkpoint blockade. Effectively none of these trials adequately address the neutrophil lineage as a substantial contributor to ICI treatment failure. We provide preliminary data that neutrophils are the most prevalent immune cell type in NSCLC inversely correlate with CD8 cellular content and preclude the presence of the IFN signature previously shown to correlate with favorable ICI treatment response. We will perform multiplex-immunohistochemistry on a dataset of FFPE slides obtained from patients treated with anti-PD1/PDL1 therapy to show that neutrophils associate with poor outcomes. We utilize a novel mouse model in which the tumor harbors hundreds of mutations to identify the mechanistic determinants of ICI treatment response and test a novel CXCR1/CXCR2 antagonist to synergize with anti-PDL1 treatment. Lastly we will perform a Phase 2 clinical trial testing the combination of the novel CXCR1/CXCR2 antagonist (SX-682 Syntrix Biosystems Inc.) and nivolumab in advanced stage NSCLC patients who have previously failed anti-PD1/PDL1 therapy. +No NIH Category available ASCL1 gene;Biological Models;CREBBP gene;Cancer Model;Cancer Patient;Candidate Disease Gene;Cell Survival;Cessation of life;ChIP-seq;Chemoresistance;Chromatin;Clinical;Clinical Data;Clinical Trials;Collecting Cell;Copy Number Polymorphism;DNA;DNA Resequencing;DNA Sequence Alteration;Data;EP300 gene;Enzymes;Exhibits;Fred Hutchinson Cancer Research Center;Gene Amplification;Gene Deletion;Genes;Genetic study;Genetically Engineered Mouse;Genotype;Immunocompetent;KDM1A gene;Link;Lung;Lysine;MLL2 gene;Magnetic Resonance Imaging;Modeling;Mutate;Mutation;NOTCH1 gene;Neoplasm Circulating Cells;Oncogenes;Pathway interactions;Patients;Phase II Clinical Trials;Research Personnel;Resistance;Role;TP53 gene;Testing;Tissues;Work;arm;cancer therapy;chromatin modification;differential expression;efficacy evaluation;efficacy testing;in vivo;inhibitor;lung cancer cell;mouse model;mutant;neuroendocrine differentiation;novel;novel strategies;patient derived xenograft model;patient subsets;potential biomarker;predict responsiveness;response;response biomarker;screening;small cell lung carcinoma;targeted treatment;therapeutic target;transcription factor;transcriptome sequencing;trial design;tumor;tumor xenograft Project 3: Identifying Determinants of Sensitivity to LSD1 Inhibition in SCLC Project Narrative Project 3The LSD1 demethylase is a potential therapeutic target in small cell lung cancer (SCLC) a recalcitrant tumor type in great need for new treatments. We use patient derived xenograft and genetically engineered mouse models to identify and understand genetically defined subsets of SCLC with strong responses to LSD1inhibition. We will also conduct an Investigator Initiated clinical trial to test the efficacy of an LSD1 inhibitor inSCLC patients and to link tumor mutations to clinical responses. NCI 10700906 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N 8260 9856130 "MACPHERSON, DAVID " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 189539 120540 68999 Project Summary/Abstract Project 3Small cell lung cancer (SCLC) leads to >30000 deaths in the USA each year and therapies resulting indurable responses are greatly needed. This proposal is focused on a potent and selective LSD1 inhibitor ORY1001. In preliminary data we found efficacy of ORY1001 as monotherapy in a subset of patient derivedxenograft (PDX) models of SCLC. PDX models differed greatly in sensitivity to ORY1001 with one model exhibiting complete and durable regression upon ORY1001 treatment. We found that strong tumor regression was linked to robust NOTCH pathway activation which led to suppression of ASCL1 a transcription factor critical for SCLC. We hypothesize that robust activation of NOTCH and suppression of ASCL1 drives strong response to LSD1 inhibition in a subset of SCLC models. We also hypothesize that mutation in chromatin regulating genes may contribute to robust NOTCH pathway activation and increased sensitivity to LSD1 inhibition in SCLC. Specific Aim 1: To use genetically engineered mouse and PDX models to test the efficacyof ORY1001 in SCLC. We will expand our PDX studies to identify additional strongly responding models andwill include models with mutations in chromatin regulating genes such as CREBBP and KMT2D that we hypothesize may contribute to strong responses. This aim will also test a novel Crebbp-deficient genetically engineered mouse model of SCLC that we generated to clearly determine whether inactivation of Crebbpincreases response to LSD1 inhibition in SCLC. Specific Aim 2: To understand roles for LSD1-NOTCH-ASCL1 axis in control of SCLC cell viability. We will use tumors from PDX and GEM models treated in vivo and PDX tumors treated ex vivo with ORY1001 to interrogate roles for a NOTCH-ASCL1 axis in conferring strong responses to ORY1001 in SCLC. We will also perform studies in PDX models of SCLC studied ex vivo to identify and better understand differences between strongly responding and non-responsive models. This Aim will include RNAseq and ChIPseq studies that will identify key differences between these groups. Specific Aim 3. Perform an Investigator Initiated clinical trial to test ORY1001 in SCLC patients. Here we will study circulating tumor cells (CTCs) for biomarkers of response to LSD1 inhibition in a clinical trial. The design of this trial may be modified based on work performed in SCLC model systems as we identify potential biomarkers that may predict responsiveness. This work aims to direct LSD1 inhibition to SCLC patients most likely tobenefit. +No NIH Category available Age;Age Years;Antibodies;Antigens;Area;Autoantibodies;Benign;Biological Markers;Biopsy;Cancer Etiology;Cancerous;Cessation of life;Chest imaging;Classification;Clinical;Colorado;Complex;Detection;Diagnosis;Diagnostic;Evaluation;Fred Hutchinson Cancer Research Center;Goals;Guidelines;Image;Lung;Lung nodule;Malignant - descriptor;Malignant neoplasm of lung;Measures;Methods;Military Personnel;Modeling;Nodule;Patient Care;Patients;Plasma;Procedures;Proteomics;Quality of life;ROC Curve;Sampling;Semantics;Smoker;Smoking;Testing;Texture;Universities;Validation;X-Ray Computed Tomography;aged;biomarker panel;care costs;clinical biomarkers;cohort;cost;high risk population;imaging biomarker;improved;low dose computed tomography;lung cancer screening;machine learning algorithm;mortality;novel;novel strategies;radiologist;radiomics;risk stratification;screening;shape analysis;standard care Project 4: Risk stratification for pulmonary nodules detected by CT imaging using plasma and imaging biomarkers Project Narrative Project 4Management of patients with lung cancer nodules found by screening or incidental Computed Tomography (CT) imaging is an important but challenging problem. Nodule detection and treatment can save lives but at considerable financial and quality of life costs and making the right choice between benign or cancerous status is a critical part of the choice to treat or observe. We propose to combine plasma radiomic semantic and clinical biomarkers to improve the determination of whether pulmonary nodules are cancerous or benign to reduce lung cancer mortality and patient care costs. NCI 10700904 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N 8259 3168785 "LAMPE, PAUL D." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 296265 227924 68341 Project Summary/Abstract Project 4Lung cancer is the leading cause of cancer deaths worldwide with >159000 deaths annually in the US alone. The National Lung Screening Trial (NLST) employed low-dose Computed Tomography (CT) imaging of the chest to screen for lung cancer in a high-risk population (smokers aged 55-74). This study demonstrated a 20% reduction in mortality in the group receiving CTs when compared to standard care and has led to generalized acceptance of lung cancer screening in heavy smokers. Unfortunately pulmonary nodules are a relatively common finding with 25-56% of smokers >50 years of age having CT identifiable pulmonary nodules but less than 2.5% of these actually were cancerous. For diagnosis of incidentally detected pulmonary nodules current guidelines call for additional imaging and/or invasive biopsy procedures. For both of these scenarios we propose to combine two novel approaches to improve risk stratification for subjects with pulmonary modules. The first involves an antibody array platform for proteomic glycomic and autoantibody-antigen complex interrogation that has yielded a four-marker panel with an area under the ROC curve (AUC) of 0.82 in prediagnostic samples and 0.83 in a validation diagnostic set of malignant and benign nodules. The second novel component is the analysis of quantitative nodule features extracted from CT images using the methods of 'radiomics'. We have developed a validated radiomics pipeline that used machine learning algorithms for image texture features that when combined with radiologist-described shape or semantic features yielded anAUC of 0.82 using the same diagnostic sample set described above. We have created a rule that combinesclinical factors (age smoking etc.) plasma biomarkers radiomic CT image semantic and texture features for classification of CT-detected nodules as malignant or benign. The addition of both radiomic and biomarkers to the rule significantly increase the AUC (p<0.005) over clinical and semantic CT measures alone. This rule will be tested first in a Vanderbilt CVC incidental/diagnostic cohort then fixed and tested in the Detection of Early lung Cancer Among Military Personnel Study 1 (DECAMP-1) cohort (Aim 1) with the goal of improving nodule evaluation. We will also test the rule in the NLST screening cohort (Aim 2) to create a final rule that models lung cancer early detection. In Aim 3 we will test the fixed rules from aims 1 and 2 in University of Colorado diagnostic and DECAMP-2 (prediagnostic) cohorts respectively. +No NIH Category available Area;Award;Communication;Core Facility;Development;Ensure;Fred Hutchinson Cancer Research Center;Funding;Funding Mechanisms;Future;Goals;Grant;Institution;Leadership;Lung;Malignant neoplasm of lung;Monitor;Phase;Pilot Projects;Process;Publications;Research;Research Personnel;Research Project Grants;Resources;Role;Talents;anticancer research;follow-up;innovation;meetings;outreach;programs;success;translational impact Developmental Research Program Project Narrative Developmental Research ProgramThe Fred Hutch Lung SPORE Developmental Research Program (CEP) will identify and fund pilot project proposals from talented investigators engaged in highly innovative and potentially impactful research; this will be accomplished by assembling a DRP Committee composed of a broad area of research expertise that is strategically located throughout our greater institution to ensure optimal outreach efforts with respect to solicitation. In conjunction with administrative resources the DRP Committee will solicit applications conduct a rigorous and fair review process select superior applicants to receive financial and other SPORE support and ensure adequate collaborative opportunities and follow-up in the post-award phase. Continued support and development of promising research projects will be focus of the SPORE to ensure that mature projects capable of becoming new projects in the future or replacing current SPORE renewals are continuously available. NCI 10700903 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N 8258 6786529 "HOUGHTON, A MCGARRY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 206084 27837 178247 Project Summary/Abstract Developmental Research ProgramThe availability of mature projects of potentially high translational impact forms the cornerstone of any successful SPORE. The Developmental Research Program (DRP) of the Fred Hutch Lung SPORE will ensure that such projects are always available for inclusion in future iterations of the SPORE or as replacements for faltering projects. To accomplish this we have assembled a DRP Committee that includes a broad array of research expertise as pertains to lung cancer. Dr. Houghton and Dr. Lampe both SPORE project PIs will serve as the Chair and Co-Chair respectively. Both Dr. Houghton and Dr. Lampe serve on the Executive Committee as well which will ensure effective communication with SPORE leadership as the development of new projects is such an essential requirement for programmatic success. In conjunction with appropriate administrative support the DRP Committee will solicit applications and select the most highly meritorious proposals for funding. Each DRP Awardee will be integrated into the Lung SPORE and gain access to all SPORE core facilities. Importantly SPORE investigators will ensure that all DRP Awardees identify necessary collaborators for the successful completion of the project and for guidance to reach putative translational endpoints. +No NIH Category available Award;Clinical;Ensure;Environment;Faculty;Fred Hutchinson Cancer Research Center;Funding;Future;Goals;Institution;Lead;Lung;Malignant neoplasm of lung;Mentors;Mentorship;Monitor;Outcome;Performance;Persons;Phase;Postdoctoral Fellow;Process;Productivity;Program Development;Program Effectiveness;Research;Research Personnel;Research Project Grants;Resources;Self Assessment;Talents;Training;Translational Research;Vocational Guidance;anticancer research;career;career development;ethnic diversity;experience;follow-up;gender diversity;interest;programs;research faculty;senior faculty;translational cancer research;translational research program Career Enhancement Program Project Narrative Career Enhancement ProgramThe Fred Hutch Lung SPORE Career Enhancement Program (CEP) will aspire to identify and nurture the careers of promising junior investigators and senior faculty interested in re-focusing their programs on lungcancer translational research; this will be accomplished by assembling a CEP Committee comprised of senior faculty with extensive mentoring and career development experience. In conjunction with administrative resources the CEP Committee will solicit applications conduct a rigorous and fair review process select superior applicants to receive financial and other SPORE support and ensure adequate mentorship and follow-up in the post-award phase. Enhancing the gender and ethnic diversity of research faculty is a Center-wide initiative at our institution; accordingly we have leveraged these efforts to benefit the Lung SPORE program. NCI 10700902 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N 8257 11468710 "MARTINS, RENATO " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 45662 27837 17825 Project Summary/Abstract Career Enhancement ProgramThe development of talented junior faculty into future leaders in their respective fields is a key goal of essential all successful research organizations. The Fred Hutch Lung SPORE Career Enhancement Program (CEP) will aspire to identify and nurture the careers of promising junior investigators and senior faculty interested in re-focusing their programs on lung cancer translational research. This will be accomplished through a calculated solicitation process to identify all talented junior investigators at the post-doctoral fellow level (must be in last year of training) and junior faculty level. We will also solicit applications from senior investigators who wish to re-focus their research programs on translational lung cancer research. A thorough review process will be performed by a highly accomplished panel of senior leaders at our Center who comprise the CEP Committee. In conjunction with the Executive Committee (EC) final award decisions will be made. The CEP Committee will closely monitor the progress of CEP Awardees throughout the duration of the award. The EC and CEP Committee will ensure that the awardees become immersed within the Lung SPORE and benefit the research expertise and available core resources. Self-assessments will be made by the Committee such that the effectiveness of the program can be carefully monitored and necessary adjustments made. Ongoing efforts at our Center will be leveraged to promote an environment of inclusion in which gender and ethnic diversity is promoted within the Lung SPORE. +No NIH Category available Address;Antigens;Atypical lymphocyte;Autologous;Benign;Bioinformatics;Biological Markers;Biometry;CREBBP gene;Cancer Etiology;Cancer Patient;Cell Lineage;Cessation of life;Chromatin;Clinical;Colorado;Data Set;Development;Diagnosis;Diagnostic;Evaluation;Fred Hutchinson Cancer Research Center;Genes;Genetic Determinism;Genotype;Goals;Histopathology;Hybrids;Image Analysis;Immune checkpoint inhibitor;Immune response;Immunotherapy;Infiltration;Infrastructure;KDM1A gene;Lung;Lung CAT Scan;Lung nodule;Lymphocyte;Malignant - descriptor;Malignant neoplasm of lung;Medical;Methodology;Modeling;Mutation;Neoplasm Circulating Cells;Nivolumab;Non-Small-Cell Lung Carcinoma;Oncogenes;Operative Surgical Procedures;Patient-Focused Outcomes;Patients;Performance;Phase I Clinical Trials;Phase II Clinical Trials;Plasma;Prognosis;Proteins;Research;Research Design;Research Personnel;Research Project Grants;Resources;Specimen;Survival Rate;T cell therapy;T-Lymphocyte;Testing;Therapeutic;Time;Translational Research;Vaccines;X-Ray Computed Tomography;antagonist;bench to bedside;cancer cell;cancer immunotherapy;career;checkpoint therapy;clinical care;cohort;early screening;effective therapy;human tissue;imaging biomarker;improved;industry partner;inhibitor;innovation;lung cancer screening;mouse model;neoantigens;neutrophil;novel;patient derived xenograft model;programs;radiological imaging;radiomics;receptor;response;risk prediction model;risk stratification;screening;small cell lung carcinoma;success;therapeutic target;translational cancer research;treatment response;tumor;tumor microenvironment Fred Hutchinson Cancer Research Center Lung SPORE Project Narrative OverallThe Fred Hutch Lung SPORE consists of four innovative translational research projects three supportivecores and the required Developmental Research Program and Career Enhancement Program. We haveleveraged the strengths of the investigators and our Center to tackle three critical barriers precludingmeaningful improvements in lung cancer survival rates: facilitation of pulmonary nodule evaluation for lungcancer early detection and screening lack of effective therapies for small cell lung cancer (SCLC) and thesub-optimal response rates of non-small cell lung cancer (NSCLC) patients to novel immune-based therapies. NCI 10700901 6/26/23 0:00 PAR-18-313 5P50CA228944-06 5 P50 CA 228944 6 "UJHAZY, PETER" 8/1/19 0:00 5/31/24 0:00 ZCA1-RPRB-N(J1) 6786529 "HOUGHTON, A MCGARRY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 2447085 NCI 1493094 953991 Project Summary/Abstract OverallThe Fred Hutch Lung SPORE consists of four innovative projects three supportive cores and the requiredDevelopmental Research Program and Career Enhancement Program. We have leveraged the strengths ofthe investigators and our Center to tackle three critical barriers precluding meaningful improvements in lungcancer survival rates: facilitation of pulmonary nodule evaluation for lung cancer early detection andscreening lack of effective therapies for small cell lung cancer (SCLC) and the sub-optimal response rates ofnon-small cell lung cancer (NSCLC) patients to novel immune-based therapies. To overcome these barrierswe propose the following four projects: 1) Targeting the Neutrophil Lineage to Enhance Immune CheckpointInhibitor Efficacy in NSCLC 2) Targeting Neoantigens for Lung Cancer Immunotherapy 3) IdentifyingDeterminants of Sensitivity to LSD1 Inhibition in SCLC and 4) Risk Stratification for Pulmonary NodulesDetected by CT Imaging Using Plasma and Imaging Biomarkers. These projects will be supported by anAdministrative Core a Biostatistics and Bioinformatics Core (BBC) and a Histopathology and BiospecimenCore (HBC). 2447085 +No NIH Category available Acceleration;Active Learning;Address;Arizona;Award;Cancer Center;Collaborations;Communities;Complement;Critical Thinking;Degree Completion;Degree program;Disparity;Drops;Education;Educational Curriculum;Enrollment;Ensure;Ethnic Population;Evaluation;Funding;Goals;Graduation Rates;Grant;Health Sciences;Institution;Internet;Joints;Laboratory Research;Malignant Neoplasms;Mentors;Modeling;Native Americans;Navajo;Outcome;Paper;Peer Review;Positioning Attribute;Postdoctoral Fellow;Process;Publications;Reporting;Research;Research Personnel;Research Training;Resource Sharing;Resources;Science;Scientist;Services;Students;Training;United States National Institutes of Health;Universities;Work;Writing;cancer education;cancer health disparity;cancer prevention;education research;experience;faculty mentor;graduate student;mid-career faculty;outreach;programs;racial population;recruit;responsible research conduct;socioeconomics;student participation;success;tribal Nation;tribal community;undergraduate student Research Education Core n/a NCI 10700899 8/15/23 0:00 PAR-18-767 5U54CA143925-15 5 U54 CA 143925 15 9/29/09 0:00 8/31/24 0:00 ZCA1-SRB-2 8256 11942350 "DE HEER, HENDRIK DIRK" Not Applicable 2 Unavailable 806345542 MXHAS3AKPRN1 806345542 MXHAS3AKPRN1 US 35.192568 -111.656765 482601 NORTHERN ARIZONA UNIVERSITY FLAGSTAFF AZ Domestic Higher Education 860114130 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 172368 113400 58968 PROJECT SUMMARY/ABSTRACT: RESEARCH EDUCATION COREThe Research Education Core will engage students from the undergraduate to the doctoral level andcomplement other federally-supported mechanisms at NAU and the UACC. The NACP will continue one-on-one student research experiences with NACP-associated faculty and expand curricular offerings acrossinstitutions. The Research Education Core will promote guided grant writing experiences in collaboration withthe GUIDeS Shared Resource to increase the number of Native American scholars entering the CUREpipeline. Finally the Core will continue its strong partnership with the Planning and Evaluation and OutreachCores to provide validated outcomes and cancer education to students' communities. The specific aims are to:Aim 1. Develop a new undergraduate cancer disparities course as a joint effort between NAU andUACC. The course will include NACP-associated faculty from both institutions and fill gaps in existing curricula.Coursework will cover cancer disparities research with tribal communities scientific writing critical thinkingand Responsible Conduct of Research training. The course will enroll 20-30 students per year.Aim 2. Provide research experiences to further grow the Native American biomedical workforce. NACP-associated faculty will continue to offer hands-on experiential learning opportunities within researchlaboratories focused on cancer and/or Native American cancer health disparities. The goal is to mentor andtrain at least 18 Native American undergraduate students per year and assist in the transition of at least 35Native American students into advanced biomedical degree programs with a continued focus in cancer.Aim 3. Create programming and support services to promote CURE pipeline applications from NativeAmerican graduate students and postdoctoral trainees. Activities will entail: 1) recruiting NACP scholarswho want to become independent cancer researchers; 2) guiding scholars to NACP institutional and nationalresources for developing competitive CURE pipeline proposals; and 3) mentoring faculty to work with theirscholars to obtain competitive CURE funding and begin developing a publication track record. The aim is todevelop six CURE submissions and ensure every scholar co-authors one paper.Expected Impact: The expected impact after five years is that the Research Education Core will haveprovided cancer disparities curriculum to >100 undergraduates engaged 18 students a year in researchexperiences mentored 35 Native American students into advanced degree programs and developed 10CURE applications with NACP mentors. +No NIH Category available Address;Advisory Committees;Alaska Native;American Indians;Americas;Arizona;Award;Cancer Burden;Cancer Center;Cancer health equity;Categories;Charge;Collaborations;Communication;Communities;Comprehensive Cancer Center;Data;Development;Documentation;Ensure;Evaluation;Exhibits;Faculty;Funding;Goals;Health Disparities Research;Indigenous;Individual;Institution;Investments;Lead;Leadership;Location;Medical;Mentors;Modeling;Names;National Cancer Institute;Native Americans;Native Hawaiian;Navajo;Occupational activity of managing finances;Office of Administrative Management;Persons;Population;Principal Investigator;Process;Race;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Services;Strategic Planning;Terminology;Tribes;Underrepresented Students;United States National Institutes of Health;Universities;anticancer research;cancer education;cancer health disparity;cancer prevention;career development;community engagement;education research;experience;health definition;health disparity populations;inter-institutional;outreach;programs;recruit;success;tribal community Administrative Core n/a NCI 10700894 8/15/23 0:00 PAR-18-767 5U54CA143925-15 5 U54 CA 143925 15 9/29/09 0:00 8/31/24 0:00 ZCA1-SRB-2 8254 8324555 "INGRAM, JANI CHERI" Not Applicable 2 Unavailable 806345542 MXHAS3AKPRN1 806345542 MXHAS3AKPRN1 US 35.192568 -111.656765 482601 NORTHERN ARIZONA UNIVERSITY FLAGSTAFF AZ Domestic Higher Education 860114130 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 291904 192042 99862 SUMMARY/ABSTRACT: ADMINISTRATIVE CORE The Partnership for Native American Cancer Prevention (NACP) is a 16-year collaboration betweenNorthern Arizona University (NAU an institution serving underserved heath disparity populations andunderrepresented students (ISUPS)) and the University of Arizona Cancer Center (UACC a National CancerInstitute-designated comprehensive cancer center). The overarching goals of the NACP are to reduce thecancer burden within the Native American population through research and community engagement; expandthe number of Native American investigators working in cancer research; and increase the total number ofinvestigators focused on cancer health disparities within the Native American communities of Arizona. The NACP Administrative Core is the organizational component that brings together the inter-institutional leadership to coordinate goals and aims of the Partnership. Additionally the Core ensures thateach of the other components of NACP (Cores Shared Resource and research projects) have aims andactivities that align with these goals. The Administrative Core provides essential administrative servicesacross these components to guarantee effective and efficient coordination financial management anddocumentation of all activities as well as facilitates the interactions with the three NACP advisory committees Internal Advisory Committee Program Steering Committee and the Community Advisory Committee. Giventhe 255-mile distance separating the two institutions and the dispersed locations of many of the advisors theAdministrative Core's fundamental roles must include promoting effective communications as well. TheAdministrative Core will also initiate recruitment of Early Stage Investigators focused on cancer healthdisparity research that will serve tribal communities. To ensure the success of NACP's goals and strategic plan outlined throughout this application theAdministrative Core is charged with the following aims: Aim 1. Engage a Partnership leadership team that integrates all Research Projects Cores and SharedResource activities in support of NACP goals. Aim 2. Provide administrative management for the entire partnership including facilitating communicationbetween Cores and Projects and fiscal management of all components. Aim 3. Coordinate the participation of the Internal Advisory Committee Program Steering Committeeand Community Advisory Committee within NACP's planning and evaluation activities. Aim 4. Initiate the recruitment process of Early Stage Investigators to enable their successful careerdevelopment and to increase the number of Native American investigators at both institutions. +No NIH Category available Address;Age;Applications Grants;Arizona;Basic Science;Biological;Biomedical Research;Cancer Burden;Cancer Center;Cancer Death Rates;Cancer health equity;Cause of Death;Collaborations;Communities;Comprehensive Cancer Center;Degree program;Development;Disparity;Disparity population;Education;Educational Activities;Educational Curriculum;Ethnic Population;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Health Disparities Research;Inequity;Institution;Intervention;Joints;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;NCI Center for Cancer Research;National Cancer Institute;Native Americans;Navajo;Outcome;Pilot Projects;Population;Positioning Attribute;Publications;Research;Research Personnel;Research Project Grants;Research Support;Research Training;Resource Sharing;Screening for cancer;Services;Students;Techniques;Training;Translating;Tribes;Trust;Underrepresented Populations;Underrepresented Students;United States;United States National Institutes of Health;Universities;Workforce Development;Writing;anticancer research;biomedical scientist;cancer education;cancer health disparity;cancer prevention;cancer survival;cancer therapy;career development;clinical practice;community engaged research;community engagement;community partnership;cultural competence;design;education research;expectation;experience;forging;graduate student;health disparity;health disparity populations;health inequalities;improved;insight;malignant stomach neoplasm;outreach;programs;racial population;recruit;screening;socioeconomics;success;tribal Nation;tribal community;undergraduate student 1/2 The Partnership for Native American Cancer Prevention NARRATIVEThe Partnership for Native American Cancer Prevention (NACP) is well-situated to impact cancer healthdisparities for Native Americans in the Southwest. The goals of the NACP are to further increase: the cancerresearch at Northern Arizona University the cancer health disparities research at the University of ArizonaCancer Center cancer research education capacity for Native American researchers and the number ofNative American students and investigators in the cancer disparities workforce. We strive to make NACP thenationally-recognized leader in cancer disparities research education and outreach activities focused on theneeds and concerns of tribal communities. NCI 10700893 8/15/23 0:00 PAR-18-767 5U54CA143925-15 5 U54 CA 143925 15 "REVILLEZA, MARIA" 9/29/09 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 8324555 "INGRAM, JANI CHERI" "WILDER, JASON A" 2 CHEMISTRY 806345542 MXHAS3AKPRN1 806345542 MXHAS3AKPRN1 US 35.192568 -111.656765 482601 NORTHERN ARIZONA UNIVERSITY FLAGSTAFF AZ SCHOOLS OF ARTS AND SCIENCES 860114130 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1340640 NCI 882000 458640 PROJECT SUMMARY/ABSTRCT: OVERALLThe Partnership for Native American Cancer Prevention (NACP) is uniquely positioned to address cancerhealth inequities in Native American communities. Cancer is the second leading cause of death for NativeAmericans over the age of 45 years. Despite improvements in cancer screening techniques and majordevelopments in cancer treatment in past decades tribal communities have not benefited equally from theseadvances. Further the NIH recognizes that Native Americans have the lowest representation of allunderrepresented groups in the biomedical research workforce which contributes to the overall cancer healthinequities for this population. NACP began in 2002 as a partnership between Northern Arizona University(NAU) as the institution serving underserved health disparity populations and underrepresented students andthe University of Arizona Cancer Center (UACC) as the Comprehensive Cancer Center. The overarchinggoals of NACP are to increase NAU's cancer research and UACC's cancer health disparities capacities byhonoring existing and establishing new Native American community partnerships. To meet these goals thefollowing aims are proposed: Aim 1. Conduct Pilot Research Projects and Full Research Projects whichaddress Native American cancer disparities and reflect community concerns; Aim 2. Recruit and supportNative American faculty focused on cancer research; Aim 3. Create a new shared resource called GuidingU54 Investigator Development to Sustainability (GUIDeS) with the goal to facilitate the transition of NACP-affiliated Early Stage Investigators/Junior Investigators to research independence; Aim 4. Expand andimplement cancer disparities research education with a focus on Native American students across NAU/UAundergraduate and graduate programs; Aim 5. Integrate community engagement principles into all NACPactivities facilitating dissemination of the Partnership's research findings and the National Outreach Network'sinitiatives to Native American communities. To achieve these Aims two Full and one Pilot project areproposed; two have Native American co-leaders. One of the Full projects and the Pilot project combine basicscience and community engaged research to address gastric and cervical cancer; death rates for thesecancers are higher in Native American populations. We propose Administrative Planning and EvaluationResearch Education Outreach and GUIDeS Cores to support the research projects and integrate activitiesacross the Partnership. NAU and UACC commit institutional funds to support new projects and NativeAmerican investigators. New priorities in this proposal are community engaged research that will impact cancerscreening rates recruitment and mentoring of Native American early stage investigators grant writing activitiesto sustain Native American-focused cancer disparities research and initiatives and joint research educationcurricula to develop a stronger Native American biomedical workforce. By the end of the proposed fundingperiod NACP will move Native Americans in Arizona closer to cancer health equity. 1340640 +No NIH Category available Agonist;Animal Model;Attenuated;Behavior;Behavioral;Blocking Antibodies;Cancer Pain Management;Cancer Patient;Cations;Cell Line;Chronic;Clinical Trials;Cultured Cells;Data;Dose;Endothelin;Endothelin-1;Foundations;Future;Genes;Genomics;Goals;Growth;Human;Hypersensitivity;Immunohistochemistry;In Vitro;Incidence;Individual;Invaded;Malignant Neoplasms;Measurable;Measures;Mechanics;Mediator;Modeling;Mus;Nature;Neoplasm Metastasis;Nerve Endings;Nerve Growth Factors;Neurons;Nitroquinolines;Nociception;Nociceptors;Non-Malignant;Oncogenes;Oncogenic;Opioid;Oral;Oxides;Pain;Pathway interactions;Patients;Phenotype;Protein Family;Proteins;Quality of life;Questionnaires;Reporting;Research;Role;Sampling;Specimen;Structure of trigeminal ganglion;TRPV1 gene;Testing;Work;Xenograft procedure;attenuation;autocrine;cancer pain;cancer therapy;carcinogenesis;combinatorial;effective therapy;experience;glial cell-line derived neurotrophic factor;improved;individualized medicine;innovation;malignant mouth neoplasm;member;mouse model;neural;neutralizing antibody;novel strategies;oral pain;oral tissue;overexpression;paracrine;precision medicine;receptor;side effect;spinal nerve posterior root;synergism;transcriptome;treatment response;tumor microenvironment;tumorigenesis Artemin overexpression in oral cancer pain and carcinogenesis Project NarrativePatients with oral cavity cancers may experience extreme pain which is induced by mediators from thecancers acting on local nerve endings. The proposed studies investigate the potential of a geneartemin that is highly expressed in the cancers to both promote cancer and induce pain. A role forartemin in oral cancer and oral cancer pain has not been appreciated previously and a betterunderstanding of its contribution to oral cancer and pain offers the possibility of developing newapproaches to treating cancer and alleviating cancer pain through blocking function of artemin. NCI 10700882 8/25/23 0:00 PA-18-484 5R01CA228525-05 5 R01 CA 228525 5 "ALTSHULER, RACHEL DINA" 9/1/19 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-IFCN-B(03)M] 1964334 "ALBERTSON, DONNA G" "SCHMIDT, BRIAN L" 10 DENTISTRY 41968306 NX9PXMKW5KW8 41968306 NX9PXMKW5KW8 US 40.729659 -73.997018 5998301 NEW YORK UNIVERSITY NEW YORK NY SCHOOLS OF DENTISTRY/ORAL HYGN 100122300 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 202375 NCI 335402 196210 Oral cancer patients suffer severe chronic and mechanically-induced pain. Opioids are initiallyeffective but dose escalation is required and side effects reduce quality of life. The long-termgoal is to improve management of oral cancer and oral cancer pain. Oral cancer pain is initiatedand maintained in the cancer microenvironment. Some overexpressed cancer genesoncogenes can function in an autocrine manner to promote cancer and in a paracrine manneras cancer pain mediators. The ensemble of altered genes/pathways in a cancer dictatesresponse to treatment which motivates the use of combinatorial therapies tailored to theindividual (precision medicine) to both treat the cancer and pain. The overall objectives of thisapplication are to determine (a) whether artemin (ARTN) a gene overexpressed in oral canceris an oral cancer oncogene (b) whether ARTN is an oral cancer pain mediator and (c) whetherantagonizing ARTN stops oral cancer and alleviates oral cancer pain. The central hypothesis isthat there are oral cancer oncogenes that promote cancer and induce oral cancer pain. Therationale for this project is that proalgesic oncogenes could be targeted to treat cancer and pain.The central hypothesis will be tested by pursuing three specific aims: (1) Determine if ARTN is aproalgesic oncogene in human cancer; (2) Determine whether ARTN is an oncogene and anociceptive mediator; and (3) Determine the potential to stop oral cancer and alleviate oralcancer pain by antagonizing proalgesic oncogenes. In the first aim expression of ARTN will beassessed by immunohistochemistry in archival specimens from patients who completed theUCSF Oral Cancer Pain Questionnaire (UCSFOCPQ) to determine if expression is correlatedwith pain. The second aim will evaluate the function of ARTN as an oncogene by manipulatingexpression in cultured cells in vitro and in human xenograft mouse models. Whether ARTN is apain mediator will be assessed by measuring nociception induced by manipulating expression ofARTN in animal models in the absence of cancer growth. For the third aim the potential ofantagonizing ARTN to stop cancer and cancer pain will be evaluated by anti-ARTN treatment ofmouse xenograft and carcinogenesis models. The proposed research is innovative in theapplicants' opinion because it uses information gained from genomic analysis of oral cancers toidentify putative oral cancer proalgesic oncogenes. The research is significant because it isexpected to lay the foundation for future clinical trials assessing the utility of targeting ARTN forcancer treatment and attenuation of cancer pain. The work will motivate identification ofadditional proalgesic oncogenes to improve precision cancer pain management. 202375 +No NIH Category available Acute;Address;Adverse effects;Affect;Allogenic;Anxiety;Area;Award;Behavior Therapy;Behavioral;Biometry;Buffers;Cardiac;Clinical;Clinical Trials;Clinical Trials Design;Data;Dedications;Dissemination and Implementation;Distress;Doctor of Philosophy;Effectiveness;Event;Feedback;Funding;Goals;Health;Health Care Costs;Health behavior;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Homologous Transplantation;Hospitalization;Individual;Intervention;Intervention Studies;Intervention Trial;Interview;Letters;Life;Malignant Neoplasms;Medical;Mental Depression;Mental Health;Mental health promotion;Mentors;Mentorship;Methods;Modeling;Moods;Motivation;Nature;Oncology;Outcome;Participant;Patients;Personal Satisfaction;Phase;Physical Function;Physical activity;Population;Principal Investigator;Process;Psychiatry;Psychology;Quality of life;Randomized;Randomized Controlled Trials;Recovery;Reporting;Research;Research Personnel;Research Project Grants;Review Literature;Stem cell transplant;Structure;Supportive care;Survivors;Symptoms;Telephone;Testing;Training;Transplant Recipients;Transplantation;United States;United States National Institutes of Health;Well in self;Work;Writing;arm;behavioral outcome;career;clinical practice;clinical training;coping;curative treatments;emotional experience;evidence base;exercise intervention;experience;feasibility testing;functional outcomes;gratitude;implementation barriers;implementation facilitators;implementation science;improved;intervention refinement;long term recovery;medical complication;medication compliance;novel;optimism;phase 1 study;phase 2 study;physical symptom;pilot trial;positive emotional state;post-transplant;primary outcome;programs;prospective;psychologic;psychological distress;psychological outcomes;psychosocial;sociodemographic variables;symposium;theories;therapy development;transplant survivor;treatment as usual A Positive Psychology Intervention for Allogeneic Stem Cell Transplant Patients. PROJECT NARRATIVEPatients with hematologic malignancies who are recipients of allogeneic stem cell transplantation have a highburden of psychological distress that undermines their psychological well-being coping health behaviorsquality of life (QOL) and overall recovery. This proposed research project aims to develop and test a novel 9-week positive psychological intervention for allogeneic transplant patients (PATH) that specifically targetspsychological behavioral and QOL outcomes during the post-transplantation recovery period. The PATHintervention has the potential to greatly impact health outcomes and recovery in this vulnerable cancerpopulation. NCI 10700872 8/24/23 0:00 PAR-18-336 5K08CA251654-04 5 K08 CA 251654 4 "RODRIGUEZ, LARITZA MARIA" 9/3/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 14980430 "AMONOO, HERMIONI L." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 257900 NCI 238796 19104 PROJECT SUMMARY/ABSTRACTAllogeneic stem cell transplantation is a potentially curative treatment for some hematologic malignancies andit often requires a 3-4-week hospitalization. Notwithstanding the promising nature the transplantation processand recovery is intensive and fraught with potential life-threatening complications during acute and long-termrecovery. Hence allogeneic transplant recipients have a high burden of psychological distress and quality of life(QOL) deficits are common. Most efforts to achieve optimal psychological well-being in this population havetargeted the reduction of distress symptoms (e.g. depression and anxiety). However positive psychologicalwell-being (e.g. optimism positive affect) can buffer against this distress and has been prospectively associatedwith improved QOL physical functioning and survival in allogeneic transplant patients. Positive psychologicalinterventions (PPIs) which utilize systematic activities (e.g. recalling positive life events using personalstrengths) to promote psychological well-being have consistently and durably enhanced psychological healthand QOL in medical settings but have never been used in allogeneic transplant patients. Given the need fornew programs to promote well-being and recovery after allogeneic transplantation the proposed project willdevelop and test a novel PPI in allogeneic transplant recipients PATH (Positive psychology for AllogeneicTransplantation of Hematopoietic stem cells) to fill this unmet need. Principal Investigator Dr. Amonoo willdevelop the PATH intervention via a review of the literature and application of a theoretical framework and testits acceptability (via quantitative participant ratings and qualitative feedback at exit interviews) in a one-arm proof-of-concept trial (N=10; Aim 1). Next Dr. Amonoo will test the feasibility (primary outcome) and preliminaryefficacy of the PATH intervention (refined using Aim 1) on psychological functional and behavioral outcomes ina pilot randomized controlled trial with 70 allogeneic transplant recipients (Aim 2). Finally in Aim 3 Dr. Amonoowill use individual semi-structured interviews with Aim 2 pilot trial participants and 20 oncology clinicians toexplore the facilitators and barriers to implementing PATH in clinical settings. This project will facilitate trainingessential to Dr. Amonoos research career goals: intervention development clinical trial design and executionadvanced biostatistics and implementation science. Dr. Amonoo has assembled dedicated mentors who arerenowned researchers with complementary expertise: PPI trials in medical populations (primary mentor: JeffHuffman MD) supportive oncology interventions (co-mentor: Areej El-Jawahri MD) quantitative methods (co-mentor: William Pirl MD) implementation science (co-mentor: Elyse Park PhD MPH) and biostatistics(research advisor: Brian Healy PhD). Dr. Amonoos mentorship will be supplemented by structured courseworkseminars and conferences. In sum this K08 award will prepare Dr. Amonoo to become an independent R01-funded investigator and leader who develops novel evidence-based supportive care interventions to improvehealth outcomes for allogeneic transplant patients and other vulnerable cancer populations. 257900 +No NIH Category available Academia;Acute Lung Injury;Age;American;Animals;Area;Buffers;Cessation of life;Characteristics;Cigar;Communities;Comprehensive Cancer Center;County;Data;Decision Making;Disparity;Educational workshop;Electronic Nicotine Delivery Systems;Electronic cigarette;Environment;Exposure to;Florida;Focus Groups;Friends;Funding;Geographic Information Systems;Goals;High School Student;Interruption;Laws;Legal;Licensing;Link;Location;Malignant Neoplasms;Marketing;Measures;Mentored Research Scientist Development Award;Mentorship;Methodology;Methods;Middle School Student;Natural experiment;Neighborhoods;Nicotine;Pattern;Policies;Policy Analysis;Proxy;Quasi-experiment;Race;Regulation;Reporting;Research;Sales;Schools;Scientist;Series;Source;Students;Surveys;Time;Tobacco;Tobacco smoking behavior;Tobacco use;Training;Translations;United States;Universities;Youth;black women;cancer health disparity;career;career development;cigarette smoking;comparative;density;econometrics;electronic cigarette use;electronic hookah;ethnic segregation;evidence base;experience;foot;health equity;medical schools;meetings;neighborhood disadvantage;participatory mapping;programs;public policy on tobacco;relative effectiveness;segregation;skills;smokeless tobacco use;social;social epidemiology;sociodemographics;substance use;theories;tobacco exposure;tobacco products;tobacco regulation;twelfth grade;vape pens;vaping Electronic Nicotine Delivery Systems (ENDS) Use and Access in Florida's Tobacco Regulatory Environment PROJECT NARRATIVEThe recent vaping-related acute lung injuries and deaths as well as the first animal studies linking vaping tocancer have highlighted the need to respond to e-cigarette use among youth. This study will assess therelationship between e-cigarette retailer access and youth e-cigarette use access and exposure to marketingin Florida explore where how why and from whom youth access e-cigarettes and whether combined tobaccoregulations will reduce youth e-cigarette use and marketing exposure. It will also lay the groundwork for a tobaccoregulation-oriented research program that blends multiple methods of policy analysis to guide the translation ofdisparities-focused research to evidence-based policy. NCI 10700865 9/5/23 0:00 PAR-18-364 5K01CA255417-03 5 K01 CA 255417 3 "VAHEDI, SHAHROOZ" 9/1/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 10848825 "BAILEY, ZINZI DIANA" Not Applicable 27 RADIATION-DIAGNOSTIC/ONCOLOGY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 176872 NCI 163770 13102 PROJECT ABSTRACTWhile cigarette smoking and smokeless tobacco use has declined among American youth over time use ofelectronic cigarettes or vaping among youth has increased tremendously. The recent vaping-related acutelung injuries and deaths as well as the first animal studies linking vaping to cancer have highlighted the need torespond to e-cigarette use among youth.In Aim 1 the project will assess the relationship between spatial density and proximity of tobacco/e-cigaretteretailers around schools and county-level youth e-cigarette use and marketing exposure in Florida overall andby county-level sociodemographic characteristics and racial/ethnic segregation. In Aim 2 it will qualitativelyexplore where how why and from whom youth access e-cigarettes interactions with tobacco/e-cigaretteretailers exposure to e-cigarette marketing and combined substance use as well as whether these factors differacross neighborhood sociodemographic characteristics using participatory mapping and focus groups. Finallyin Aim 3 I will leverage a natural experiment in tobacco regulation across three Florida counties to assesswhether T21+TRL is more effective in reducing youth ENDS use and marketing exposure than T21 alone usingquasi-experimental methods comparative interrupted time series and difference-in-differences analysis.Dr. Zinzi Bailey is an Assistant Scientist in the Jay Weiss Institute for Health Equity at the SylvesterComprehensive Cancer Center at the University of Miami Miller School of Medicine. As a Black woman inacademia where Black women are underrepresented Dr. Bailey seeks a K01 Mentored Research ScientistDevelopment Award to Promote Diversity to gain the skills experience and preliminary data needed for anindependent policy-focused research program in translational cancer disparities research. Dr. Bailey willintegrate her background in social epidemiology and tobacco smoking behavior with methods and theories thatcapture the socio-ecological complexity of tobacco regulation and its potential impact across communities.To achieve this goal Dr. Bailey proposes to gain the training and experience in policy analysis using quasi-experimental designs geographic information systems and participatory research through mentorshipcoursework workshops/seminars and scientific meetings. Her career development objectives include (1)obtaining training in quasi-experimental designs for policy analysis (2) advancing my expertise in assessinglocal state and federal tobacco policies and regulations (3) receiving formal policy-relevant training ingeographic information systems (GIS) and spatial econometrics and (4) developing methodological training onqualitative participatory methods.This study will lay the groundwork for a tobacco regulation-oriented research program that blends multiplemethods of policy analysis to guide the translation of disparities-focused research to evidence-based policy. 176872 +No NIH Category available Address;Adolescent;Affect;Age;Attention;Behavioral;Brain;Code;Color;Complement;Development;Electronic cigarette;Exposure to;Focus Groups;Future;Goals;Grant;Guidelines;Image;Industry;Informal Social Control;JUUL;Language;Marketing;Measures;Methodology;Methods;Modified Risk Tobacco Product;Monitor;Nicotine;Patient Self-Report;Pattern;Perception;Persons;Poison;Printing;Reaction;Regulation;Research;Research Design;Research Personnel;Risk;Sales;Scientist;Smoker;Smoking;Source;Surveys;Technology;Testing;Text;Time;Tobacco Industry;Tobacco use;Training;Update;Work;Youth;addiction;career;cigarette advertising;combustible cigarette;combustible tobacco;e-cigarette aerosols;electronic cigarette use;electronic cigarette user;experimental study;gaze;interest;nicotine exposure;novel;prevent;response;tobacco products;tobacco regulatory science;trend;uptake;vaping;vaping nicotine;visual tracking;warning label The Impact of E-cigarette Marketing Features on Youths' E-cigarette Perceptions and Use Intentions PROJECT NARRATIVEE-cigarette use among youth is common and leads to numerous risks including the potential to initiatecombustible tobacco use. In order to prevent youth uptake of e-cigarettes the effects of branded e-cigarettemarketing must be thoroughly understood for effective regulation. The proposed research will monitor andassess the impact of branded e-cigarette marketing features on youth e-cigarette perceptions and useintentions using a triangulation of methods. NCI 10700863 9/11/23 0:00 RFA-OD-18-005 5K01CA242591-05 5 K01 CA 242591 5 "RADAEV, SERGEY" 9/1/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-RPHB-R(57)R] 15100459 "JEONG, MICHELLE " Not Applicable 10 PUBLIC HEALTH & PREV MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 77 Other Research-Related 2023 189606 OD 175561 14045 PROJECT SUMMARY/ABSTRACT E-cigarettes are the most commonly used tobacco product among youth and can pose various risks amongyouth. Exposure to branded e-cigarette marketing and marketing features such as the use of color use ofpeople in images and language specifically targeting smokers likely contributes to youths e-cigarette-relatedperceptions and use intentions. A better understanding of how these features work and how they interact withthe required nicotine warning on e-cigarette marketing material will help to inform future regulatory effortspertaining to marketing and may also serve as guidelines for industry self-regulation. In addition the field is inneed of new study designs that will complement existing methods to accurately assess the impact of e-cigarette marketing. Thus the overarching goal of my proposed research is to determine the impact ofbranded e-cigarette marketing features on youths e-cigarette perceptions and use intentions relyingon a triangulation of methods. In Aim 1 I will conduct a longitudinal content analysis of e-cigarette printonline and point-of-sale marketing material to monitor the potential for youth exposure to e-cigarettemarketing and to detect changing trends in e-cigarette marketing over time. In Aim 2 I will assess the impact ofdifferent branded e-cigarette marketing features on youths e-cigarette perceptions and use intentions via twoactivities. First I will conduct four online focus groups with youth (13-17) non-current users of e-cigarettes toqualitatively understand their perceptions about e-cigarettes and branded e-cigarette marketing. Findings willinform the development of a survey instrument for the next activity in which I will conduct a 2x2x2 onlinesurvey experiment with 600 youth (13-17) non-current users of e-cigarettes to quantitatively test the effects ofuse of color use of people in images and smoker-targeting language on e-cigarette perceptions and useintentions. In Aim 3 I will supplement the findings from Aim 2 with objective measures of attention assessedwith eye tracking technology. In this pilot eye tracking study with 60 youth (13-17) non-current users of e-cigarettes I will examine dwell time and gaze patterns to explore the effects of use of people in images andsmoker-targeting language as well as whether these features undermine attention paid to the nicotinewarning. This research addresses FDA CTPs priority scientific interest in understanding marketinginfluences particularly on youth initiation in the context of industry marketing of novel and/or potentialmodified risk tobacco products. In addition this K01 will allow me to achieve my long-term career goal ofbecoming a leading behavioral scientist in tobacco regulatory science by providing training in a new contentarea i.e. industry marketing and new methodologies i.e. focus groups content analyses and eye trackingand supporting my transition to becoming an independent researcher. The proposed research will allow me towork towards an R01 grant that will examine potential regulatory solutions to mitigate the impact of tobaccoindustry marketing of potential modified risk tobacco products on youth. 189606 +No NIH Category available Advisory Committees;Area;Cancer Center;Collaborations;Data;Development;Discipline;Emerging Technologies;Extramural Activities;Fostering;Funding;Future;Goals;Grant;Institution;K-Series Research Career Programs;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mission;Neoplasms;Pilot Projects;Procedures;Publications;Reproduction spores;Research;Research Personnel;Rewards;System;Tennessee;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Translational Research;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Universities;Woman;advanced disease;anticancer research;career;design;gastrointestinal;high risk;innovation;medical schools;member;minority investigator;new technology;novel;programs Developmental Research Program "PROJECT NARRATIVE: Developmental Research ProgramThe Developmental Research Program (DRP) is designed to broaden the translational research efforts of theVanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer (hereafter VICC GI SPORE) byfunding ""pilot projects"" or early stage short term ( 2 years) projects with limited preliminary data but have thepotential to lead to significant advances that: 1) produce high impact publications; 2) attract new extramuralfunding and enhance or replace existing VICC GI SPORE projects; and 3) form the basis of a new project infuture VICC GI SPORE applications. The DRP will be used to encourage new ideas novel technologies andcollaborative projects as well as to attract new investigators into the area of GI cancer research. A high prioritywill be placed on attracting young investigators women and underrepresented minorities to apply for DRPfunding and mechanisms are in place to achieve this goal." NCI 10700860 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7 8251 1898854 "BEAUCHAMP, ROBERT DANIEL" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 93628 63032 32550 PROJECT SUMMARY/ABSTRACT: Developmental Research ProgramThe overall objective of the Developmental Research Program (DRP) within the Vanderbilt-Ingram CancerCenter SPORE in Gastrointestinal (GI) Cancer (hereafter VICC GI SPORE) is to encourage innovativetranslational research in GI neoplasia. The DRP will be led by a Director (R. Daniel Beauchamp MD) and willbe supported by the Developmental Research Advisory Committee (DRAC) made up of senior investigators atVanderbilt and Meharry Medical College (MMC). The DRP leadership has significant crossover with the CareerEnhancement Program (CEP) leadership to encourage CEP recipients to apply for DRP funding and to identifypromising investigators from DRP for the CEP. The VICC GI SPORE DRP will use an established and highlyeffective procedure to solicit applications from investigators at Vanderbilt MMC and Tennessee StateUniversity. The Director and the DRAC will also actively solicit applications from targeted investigators (womenand underrepresented minorities) within the three institutions. Internal and external researchers includingmembers of the GI SPORE External Advisory Board will review applications using the NIH 9-point scoringsystem. Reviewers will evaluate scientific merit and the likelihood of the project to support current GI SPOREactivities lead to extramural funding and/or lead to future GI SPORE projects. Special emphasis will be placedon attracting young investigators into GI cancer research high risk/high gain projects and projects thatincorporate emerging technologies and apply them to GI cancer research. Thus the VICC GI SPORE DRP willoffer the opportunity for new directions of study that may be of higher risk but also have a significant chance forreward including independent funding and additional projects that may form the basis of the next competingrenewal. +No NIH Category available APC mutation;Acute;Affinity;Animals;Antineoplastic Agents;Attenuated;Binding;Binding Proteins;Biochemistry;Biological;Biological Markers;Biological Models;Cancer Center;Cancer Model;Cells;Characteristics;Chromatin;Clinical;Clinical Trials;Colorectal Cancer;Dose;Drug Combinations;Drug Design;Drug Kinetics;Drug or chemical Tissue Distribution;Effectiveness;Functional disorder;Funding;Genes;Genetic;Genome;Genomic approach;Goals;Human;Hydrophobicity;In Vitro;Investigational Drugs;KRAS2 gene;Lead;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Maximum Tolerated Dose;Modeling;Molecular;Molecular Analysis;Monitor;Mus;Mutation;Oncogenic;Oncoproteins;Outcome;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Play;Property;Recurrence;Reproduction spores;Resources;Role;Safety;Scaffolding Protein;Series;Site;Structure;Surface;Time;Toxicokinetics;Tumor Promotion;Variant;cancer cell;cancer type;candidate marker;candidate validation;clinical candidate;cofactor;colon cancer cell line;colon cancer patients;colon tumorigenesis;colorectal cancer prevention;colorectal cancer treatment;drug discovery;drug metabolism;drug-like compound;efficacy testing;efficacy validation;improved;in vivo;in vivo evaluation;inhibitor;innovation;mouse model;nanomolar;overexpression;patient derived xenograft model;pharmacodynamic biomarker;pharmacologic;pre-clinical;preclinical safety;prevent;programs;research clinical testing;response;safety assessment;small molecule;structural biology;tool;transcription factor;translational goal;tumor;tumorigenic Project 3: Targeting MYC in CRC PROJECT NARRATIVE: P3. Targeting MYCMYC is an oncoprotein and transcription factor that plays a critical pro-tumorigenic role in many cancersincluding colorectal cancer (CRC). Although MYC is generally considered undruggable we have identified anew strategy to target MYC in cancer cells by disrupting interaction with the essential MYC co-factor WDR5.Completion of this project will generate first-in-class MYC WDR5 inhibitors that are validated for efficacy inCRC and ready to proceed to Investigational New Drug (IND)-enabling studies. NCI 10700857 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7 8250 1898854 "BEAUCHAMP, ROBERT DANIEL" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 308057 307864 9738 PROJECT SUMMARY/ABSTRACT: P3. Targeting MYCRecurring genetic perturbations in colorectal cancer (CRC) activate MYC an oncogenic transcription factorthat features prominently in human cancer. Despite the pervasive involvement of MYC in CRC and a wealth ofstudies demonstrating that genetic inhibition of MYC promotes frank tumor regression in mouse modelsystems MYC is generally considered undruggable. Indeed there are currently no drug-like moleculescapable of directly blocking MYC function in cancer cells. Recently however we presented a new paradigm fortarget gene recognition by MYC that also created a new opportunity to discover drugs that block MYC function.We found that the stable association of MYC with chromatin depends on its direct interaction with thechromatin scaffolding protein WDR5 which co-localizes broadly with MYC across the genome and facilitatesMYC binding to target genes. Structural analysis revealed that MYC binds WDR5 by engaging a shallowhydrophobic cleft on the surface of WDR5 that is well-suited for drug discovery. The goal of this project is totarget the MYCWDR5 interface to discover a drug that will disable MYC function in CRC by preventing thestable association of MYC with target gene chromatin. This project combines drug discovery structural biologymedicinal chemistry biochemistry and cutting-edge genomic approaches along with powerful model systemsto identify refine and validate drug-like molecules that disrupt the MYC-WDR5 interaction and to explore theireffectiveness as anti-cancer agents against CRC. Within the five year funding period we intend to producefirst-in-class MYCWDR5 inhibitors that will be fully validated for their utility in treating CRC and ready toproceed to Investigational New Drug (IND)-enabling studies. Successful completion of this project will addressa clear unmet clinical need for targeted anti-MYC therapies which are expected to have broad efficacy againstCRCs for which there are only limited treatment options. Drugs discovered in this program will likely also haveutility against a wide spectrum of cancer types. +No NIH Category available Address;Anabolism;Avidity;Biological Assay;Biological Markers;Biological Sciences;Cancer Cell Growth;Cancer Center;Cancer Etiology;Carbon;Cell Proliferation;Cessation of life;Cetuximab;Citric Acid Cycle;Classification;Clinical;Clinical Trials;Colorectal Cancer;Combined Modality Therapy;Complex;Data;Development;Disease;Enzymes;Epidermal Growth Factor Receptor;Exhibits;Future;Glucose;Glutamates;Glutaminase;Glutamine;Goals;Growth;In Vitro;Investigation;Laboratory Study;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Metabolic;Metabolism;Mitochondria;Mitogen-Activated Protein Kinases;Molecular;Monoclonal Antibodies;Monoclonal Antibody Therapy;Nitrogen;Nutrient;Pathogenesis;Pathway interactions;Patients;Pharmacodynamics;Phase I Clinical Trials;Phase II Clinical Trials;Play;Positron-Emission Tomography;Prediction of Response to Therapy;Production;Proliferating;Reactive Oxygen Species;Refractory;Regimen;Resistance;Role;Signal Transduction;Solid Neoplasm;Source;System;Therapeutic;Tracer;Translations;cancer cell;cell growth;chemotherapy;colon cancer patients;combinatorial;cytotoxic;efficacy evaluation;genetic signature;improved;in vivo;inhibitor;member;metastatic colorectal;mouse model;neutralizing monoclonal antibodies;novel;novel therapeutic intervention;novel therapeutics;panitumumab;participant enrollment;patient derived xenograft model;pharmacologic;precision medicine;preclinical study;predict responsiveness;predicting response;predictive marker;proteogenomics;receptor-mediated signaling;refractory cancer;response;statistics;targeted treatment;transcriptome sequencing;translational approach;translational goal;tumor;tumor metabolism Project 2: Targeting Glutamine Metabolism to Enhance EGFR Blockade in Wild-Type RAS CRC PROJECT NARRATIVE: P2. Targeting Glutamine Metabolism to Enhance EGFR Blockade in WT RASCRCEpidermal growth factor receptor (EGFR) neutralizing monoclonal antibodies are approved for treatment ofadvanced wild-type (WT) RAS colorectal cancer (CRC) and commonly used as targeted therapies for late-stagemetastatic CRC. However durable responses to anti-EGFR monotherapy occur in only 1217% of patients andresistance to monoclonal antibody (mAb) therapy commonly occurs. Prioritizing glutamine metabolism as anactionable vulnerability in WT RAS CRC we propose a two-pronged translational approach to optimize EGFRtherapy that includes a novel way to prioritize patients for EGFR-targeted therapy novel positron emissiontomography (PET) imaging as a predictive marker and a novel therapeutic combination. NCI 10700852 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7 8248 3054726 "BERLIN, JORDAN D" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 392038 241829 157706 PROJECT SUMMARY/ABSTRACT: P2. Targeting Glutamine Metabolism to Enhance EGFR Blockade inWT RAS CRCColorectal cancer (CRC) is the second leading cause of cancer-related death in the US. A wealth ofproteogenomic information has provided a deep understanding of the molecular pathogenesis of CRC and hasled to improved classification systems of the disease. However matching a CRC patient to the optimumtherapeutic regimen remains a major challenge. Epidermal growth factor receptor (EGFR) neutralizingmonoclonal antibodies (mAbs; e.g. panitumumab) are approved for patients with advanced wild-type (WT)RAS CRC. However in late-line therapy only 1217% of patients exhibit durable responses to EGFR mAbmonotherapy and addition of EGFR mAbs to standard chemotherapy has limited clinical benefit. Clearlytherapeutic strategies that enhance efficacy of EGFR mAb and/or overcome resistance are needed along withnovel ways to prioritize patients for such therapy. The metabolic requirements of proliferating cells link signaltransduction with nutrient accumulation resulting in a direct link between proliferation and metabolism.Glutamine (Gln) is a key anaplerotic substrate used by cancer cells providing energy carbon and nitrogen tomeet the demands of rapid and sustained growth. Gln replenishes the supply of tricarboxylic acid (TCA) cycleintermediates used to fuel biosynthesis and also plays a critical role in depleting cytotoxic reactive oxygenspecies (ROS). In many cancers EGFR and Gln cooperate to provide both `signals' and `fuel' which arerequired for mitogen activated protein kinase (MAPK)-dependent growth and proliferation. The ScientificPremise of this project is that Gln provides a `fuel' source to support EGFR-mediated proliferation; blockingGln metabolism will deplete a critical metabolic `fuel' required for cell growth and proliferation. The OverallHypothesis is that inhibition of Gln metabolism will enhance EGFR mAb therapy for a select group of patientswith CRC who have failed prior EGFR mAb-containing regimens. We propose to evaluate non-invasive PETimaging as a biomarker of Gln avidity from which we will develop a Gln PET-derived gene signature. A genesignature of Gln avidity will allow this information to be utilized in lieu of complex PET imaging. Our project hasthree Specific Aims. Aim 1. Conduct a phase II clinical trial evaluating the efficacy of combined CB-839 andpanitumumab in patients with WT RAS CRC who progressed on prior anti-EGFR mAb therapy. Aim 2.Evaluate quantitative Gln PET in EGFR mAb-naive and EGFR mAb-refractory patients to predict response totherapy. Aim 3. Develop a PET imaging-derived gene signature of Gln avidity to predict responsiveness toinhibitors of Gln metabolism. Spanning laboratory studies and clinical trials deliverables of this project includea new therapeutic combination to improve response and overcome resistance to anti-EGFR mAb therapy inWT RAS CRC as well as a new way to identify patients likely to benefit from inhibitors of Gln metabolism. +No NIH Category available Ablation;Affect;Aftercare;Alleles;Architecture;Behavior;Cancer Center;Cancer Model;Cancer Prognosis;Cells;Cellular biology;Characteristics;Classification;Clinical Trials;Colon;Colon Carcinoma;Colonoscopy;Colorectal Cancer;Dependence;Distal;EGF gene;Epidermal Growth Factor Receptor;Fluorouracil;Goals;Homeostasis;Human;Immunofluorescence Immunologic;Individual;LGR5 gene;Maintenance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Maps;Modeling;Monitor;Monoclonal Antibodies;Mus;Optics;Organoids;Pathway interactions;Patients;Play;Population;Primary Neoplasm;Property;Recurrent Malignant Neoplasm;Recurrent tumor;Reporter Genes;Role;Sampling;Signal Transduction;Site;System;Testing;Therapeutic;Therapeutic Intervention;Time;Tissue Microarray;Tissues;Translating;Treatment Efficacy;Work;cancer cell;cancer recurrence;cancer stem cell;cancer therapy;cell behavior;chemotherapy;combinatorial;conventional therapy;design;in vivo;irinotecan;molecular marker;novel;patient response;predicting response;predictive modeling;prognostic;prospective;repository;response;single cell technology;single-cell RNA sequencing;stem;stem cell population;stem cells;therapy resistant;tool;transcriptomics;translational goal;treatment response;tumor;tumor growth;tumor initiation;tumorigenic Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC PROJECT NARRATIVE: P1. Interrogating Distinct Tumor-Initiating CellsCancer stem cells designated tumor-initiating cells (TICs) in this application are thought to have thepropensity to resist therapy and induce tumor recurrence. We will use single-cell technologies to interrogatedistinct populations of colorectal cancer TICs in response to therapies. Our goal is to understand how theseTICs behave in order to design strategies to inhibit their function(s). NCI 10700848 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7 8246 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 381249 261889 127480 PROJECT SUMMARY/ABSTRACT: P1. Interrogating Distinct Tumor-Initiating CellsA major therapeutic barrier in advanced colorectal cancer (CRC) is tumor recurrence after treatment. Thecancer stem cell hypothesis posits that rare populations of cancer cells with stem cell characteristics alsoknown as tumor-initiating cells (TICs) fuel tumor growth resist therapy and repopulate the tumor at distalsites. In the normal colon multiple stem cell populations exist in a reserve-to-active continuum. Wehypothesize that distinct TIC populations exist in CRC and these distinct populations of TICs have differentclonogenic properties and tumor-repopulating potential. Using TICs marked by Lrig1 and Lgr5 to representreserve and active TICs respectively we will use novel single-cell approaches to investigate the behaviors ofthese populations in the context of therapeutic intervention. First we will determine whether there is a defineddirectional hierarchy where reserve TICs give rise to active TICs versus mutual interconversion. Second wewill determine whether TICs with malignant characteristics pre-exist in the primary tumor or if TICs acquirethese characteristics de novo as a result of treatment. Third we will determine whether a signature derivedfrom TIC behaviors provides prognostic and/or predictive information for individuals with CRC. Ourtranslational goal is to apply a systems approach to predict likelihood of tumor recurrence based on propertiesof TIC populations with the long-term goal of using combinatorial pathway alterations to target TIC behaviors. +No NIH Category available Animals;Bioinformatics;Biological;Biometry;Cancer Center;Clinical Research;Colorectal Cancer;Coupled;Cyclic GMP;Data;Data Analyses;Development;Digital X-Ray;Equipment;Feasibility Studies;Functional Imaging;Future;Genomic approach;Human;Human Resources;Image;Individual;Infrastructure;Institution;Magnetic Resonance Imaging;Malignant neoplasm of gastrointestinal tract;Measures;Mission;Molecular;Molecular Probes;Mus;Optics;Pathology;Phenotype;Pilot Projects;Play;Positron-Emission Tomography;Quality Control;Radiochemistry;Reproduction spores;Research;Research Personnel;Resource Development;Resources;Role;Specimen;Tissues;Translational Research;Work;X-Ray Computed Tomography;anatomic imaging;data de-identification;gastrointestinal;human imaging;imaging biomarker;imaging facilities;imaging modality;liquid biopsy;molecular imaging;novel;pre-clinical;pre-clinical research;research study;single photon emission computed tomography;translational goal;tumor Core 2: Mouse and Human Molecular Imaging PROJECT NARRATIVE: Mouse and Human Molecular Imaging CoreThe Mouse and Human Molecular Imaging (MHMI) Core will play a central role in the translational researchmission of the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer providingstate-of-the-art imaging resources for three projects future pilot and feasibility studies and developmentalresearch. The MHMI Core will leverage existing institutionally-supported equipment and infrastructure to offera full range of small animal and human functional molecular and anatomical imaging resources includingmagnetic resonance imaging (MRI) computed tomography (CT) digital X-ray optical single photon emissioncomputed tomography (SPECT) and positron emission tomography (PET). A unique feature of this core theVICC GI SPORE investigators will also have access to novel probe development resources that leverage thecapabilities of the Vanderbilt Center for Molecular Probes (CMP) including high-throughput diversity-orientedsynthesis capabilities suitable for developing novel imaging compounds as well as world-class preclinical andcGMP resources of the CMP radiochemistry facility. NCI 10700844 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7 8243 8028499 "MANNING, HENRY CHARLES" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 237623 149310 92943 PROJECT SUMMARY/ABSTRACT: Mouse and Human Molecular Imaging CoreThe Mouse and Human Molecular Imaging (MHMI) Core will play a central role in the translational researchmission of the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer providingstate-of-the-art imaging resources for three projects future pilot and feasibility studies and developmentalresearch. The MHMI Core will leverage existing institutionally-supported equipment and infrastructure to offera full range of small animal and human functional molecular and anatomical imaging resources includingmagnetic resonance imaging (MRI) computed tomography (CT) digital X-ray optical single photon emissioncomputed tomography (SPECT) and positron emission tomography (PET). A unique feature of this core VICCGI SPORE investigators will also have access to novel probe development resources that leverage thecapabilities of the Vanderbilt Center for Molecular Probes (CMP) including high-throughput diversity-orientedsynthesis capabilities suitable for developing novel imaging compounds as well as world-class preclinical andcGMP resources of the CMP radiochemistry facility. The MHMI has three Specific Aims: Aim 1. To developoptimize and provide quantitative surrogate molecular imaging biomarkers of colorectal cancer (CRC) forsupport of preclinical and clinical research; Aim 2. To provide support for imaging data analysis customized toproject-specific applications including co-registration and integration of multiple imaging modalities along withquality control metrics to be performed as part of all preclinical and clinical research studies; Aim 3. To workwith both the Tissue Pathology and Cellular Analysis (TPCA) Core and the Biostatistics and Bioinformatics(BBC) Core to establish strategies for networking of requests specimen tracking extraction of de-identifieddata relating to imaging biospecimens and other research data. Translational goal: Molecular imaging holdsgreat promise to illuminate the cellular and molecular underpinnings of individual tumors. Complementary togenomic approaches molecular imaging provides a quantitative functional measure of tumor `phenotype' andwhen coupled with other tissue-based or newer `liquid' biopsy approaches can provide a wealth of biologicalinformation about individual tumors. The MHMI Core will provide VICC GI SPORE investigators a mechanismand the expert personnel required for advancing cutting-edge translational research in CRC through the use ofnon-invasive molecular imaging in mice and humans. +No NIH Category available Academic Medical Centers;Advocate;Basic Science;Biological Sciences;Biology;Cancer Center;Clinical Research;Clinical and Translational Science Awards;Collaborations;Colorectal Cancer;Communication;Communities;Development;Digestive System Disorders;Education;Ensure;Epithelium;Evaluation;Fostering;Institution;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Monitor;Mucositis;National Cancer Institute;Occupational activity of managing finances;Patient advocacy;Patients;Pharmacologic Substance;Regulation;Report (document);Reporting;Reproduction spores;Research;Research Personnel;Research Project Grants;Resources;Schedule;Series;Tennessee;Translational Research;Universities;career;gastrointestinal;improved;malignant breast neoplasm;medical schools;meetings;outreach;programs Administrative Core PROJECT NARRATIVE: Administrative CoreThe Administrative Core will be responsible for the organizational administrative and scientific management(both basic and clinical research) of the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI)Cancer program which focuses on translational research that will substantially improve the management ofcolorectal cancer. This management and support will be accomplished through a series of oversightcommittees and organized administrative and scientific meetings of GI SPORE investigators institutionalrepresentatives and external advisors. NCI 10700838 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7 8241 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 184629 117557 70717 PROJECT SUMMARY/ABSTRACT: Administrative CoreThe Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer Administrative Core will supportall GI SPORE cancer-related research projects and investigators by managing SPORE resourcescommunication and outreach and by fostering interactions among investigators collaborators other VICCSPOREs other GI SPOREs the patient and advocate community and the National Cancer Institute. Thismanagement and support will be accomplished by administrative and scientific meetings of GI SPOREinvestigators with oversight provided by the Internal and External Advisory Boards. +No NIH Category available Administrator;Advocate;Bioinformatics;Biometry;Cancer Center;Cancer Etiology;Cells;Cessation of life;Clinical Investigator;Collaborations;Colorectal Cancer;Consultations;Development;Environment;Epidermal Growth Factor Receptor;Funding;Glutamine;Human;Institution;International;Malignant neoplasm of gastrointestinal tract;Metabolism;Mus;National Cancer Institute;Pathology;Patient advocacy;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Process;Productivity;Reproduction spores;Research;Research Personnel;Resources;Scientist;Seasons;Talents;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Tissues;United States;animal imaging;cancer stem cell;career;drug discovery;drug resource;human imaging;molecular imaging;new technology;recruit;success;therapeutic target;translational research program;tumor initiation Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer PROJECT NARRATIVE: OverallThis application is a new submission of the Vanderbilt-Ingram Cancer Center GI SPORE which will focus oncolorectal cancer the second leading cause of cancer-related deaths in the United States. Building upon ourpast success and leveraging institutional resources and support as well as a newly formed patient advocacycouncil we propose three projects. Using novel technologies supported by three cores we will (1) examinewhether cancer stem cells represent a tractable therapeutic target (2) optimize EGFR blockade by targetingglutamine metabolism (3) develop a drug to inhibit MYC (thought to be an undruggable target). NCI 10700836 7/26/23 0:00 PAR-18-313 5P50CA236733-05 5 P50 CA 236733 5 "NOTHWEHR, STEVEN F" 7/9/19 0:00 5/31/24 0:00 ZCA1-RPRB-7(J1) 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 2278912 NCI 1614818 714162 PROJECT SUMMARY/ABSTRACT: OverallThis application is a new submission of the Vanderbilt-Ingram Cancer Center GI SPORE which will focus oncolorectal cancer the second leading cause of cancer-related deaths in the United States. Our potential forsuccess is high based on 1) productivity during the last cycle of our prior GI SPORE 2) exceedingly stronginstitutional support 3) recruitment of talented investigators to the field of GI cancer through career enhancementand developmental research funding 4) access to unparalleled resources for drug discovery and small animalimaging 5) a blend of young and seasoned clinical investigators and basic scientists working together in a highlycollegial environment 6) a committed group of patient advocates now organized into a patient advocacy counciland 7) multiple inter-SPORE pharmaceutical national and international horizontal and vertical collaborations.We propose three projects and three supporting cores.Projects Cores1: Interrogating Distinct Tumor-Initiating Cells in CRC 1: Tissue Pathology and Cellular Analysis2: Targeting Glutamine Metabolism to Enhance EGFR 2: Mouse and Human Molecular Imaging Blockade in Wild-Type RAS CRC3: Targeting MYC in CRC 3: Biostatistics and Bioinformatics 2278912 +No NIH Category available Algorithms;Antigens;Arizona;Autoantibodies;Benign;Biological Assay;Biological Markers;Blood;Blood Tests;CA-125 Antigen;CTAG1 gene;Cancer Center;Cancer Detection;Clinical;Collaborations;Combination Drug Therapy;Complement;Complex;Computer Models;Diagnosis;Disease;Early Detection Research Network;Early Diagnosis;Endometrial Carcinoma;Epithelial ovarian cancer;Evaluation;FOLR1 gene;General Hospitals;Goals;Grant;IL8 gene;Image;Individual;Lead;Lesion;Link;Malignant neoplasm of ovary;Massachusetts;Measurement;Measures;Operative Surgical Procedures;Ovarian;Ovary;Patients;Peer Review;Pelvis;Plasma;Postmenopause;Predictive Value;Published Comment;Publishing;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Reporting;Research Personnel;Risk;Sampling;Screening for Ovarian Cancer;Second Look Surgery;Serum;Site;Specificity;Specimen;TP53 gene;Technology;Testing;Time;Tissue Sample;Tissues;Tumor Debulking;Ultrasonography;United Kingdom;United States;Universities;Vagina;Validation;WFDC2 gene;Woman;advanced disease;biomarker identification;cancer recurrence;chemotherapy;collaborative trial;disease heterogeneity;early detection biomarkers;improved;mortality;novel marker;operation;osteopontin;preservation;rapid test;routine screening;screening;ultrasound MD Anderson Cancer Center EDRN- Clinical Validation Center for Early Detection of Ovarian Cancer with a multiple marker algorithm NARRATIVEWhen ovarian cancer is diagnosed at an early stage combination surgery and chemotherapy can cure 90% ofwomen with disease contained in the ovary (stage I) and 70% with disease limited to the pelvis (stage II) butwhen disease has spread further cure slips to 20% or less. Our group has shown that annual measurement ofCA125 followed by ultrasound and surgery if indicated can detect early stage (I II) disease in 71% of patientswith no more than two-three operations for each case detected but a multi-marker algorithm is likely to berequired to impact mortality. Our Clinical Validation Center will continue to collaborate and to providespecimens to EDRN BCCs and test whether annual measurement of four blood tests detects early stage casesin >70% of cases with an acceptable number of benign ovarian lesions. NCI 10700583 6/30/23 0:00 RFA-CA-22-039 2U01CA200462-06A1 2 U01 CA 200462 6 A1 "PATRIOTIS, CHRISTOS F" 5/5/16 0:00 5/31/28 0:00 ZCA1-SRB-P(J2) 2717823 "BAST, ROBERT C" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 6/30/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 1014275 NCI 702316 311959 ABSTRACT: Advances in cytoreductive surgery and combination chemotherapy have improved 5-year survivalin patients with epithelial ovarian cancer but the rate of cure remains essentially unchanged over the last twodecades. Computer models suggest that detection of ovarian cancer in early stage (I-II) could improve rates ofcure by 10-30%. In two major trials a two-stage strategy where rising values of CA125 analyzed with a BayesianRisk of Ovarian Cancer Algorithm (ROCA) prompted transvaginal sonography and abnormal imaging promptedsurgery proved sufficiently specific to exceed a positive predictive value (PPV) of 10%. With support of the EDRN7869 apparently healthy women have participated in the Normal Risk Ovarian Cancer Screening Study(NROSS) at 11 different sites in the United States with 46008 CA125 determinations over the last 21 years.Twenty-nine patients have been referred for operations detecting 17 ovarian cancers with 12 (71%) in early stageI or II. In addition 4 cases of early stage endometrial cancer were detected yielding a PPV for detecting cancerof 72%. No more than 2-3 operations will be required to detect each case of ovarian cancer. As CA125 isexpressed by only 80% of epithelial ovarian cancers better sensitivity is likely to be achieved with multiplebiomarkers. During this grant cycle we have reported that HE4 HE4 antigen-autoantibody complexes andosteopontin significantly enhance the sensitivity of CA125 for detecting early stage (I-II) disease and havedeveloped a ROCA2 that includes all 4 biomarkers and detects advanced disease 1.4 to 4.8 years earlier thanROCA. We have found elevated levels of anti-TP53 autoantibodies (AA) in 20-25% of patients with ovariancancer. Titers of anti-TP53 rise 12 months prior to CA125 and 22 months prior to diagnosis in patients whereCA125 does not increase. In an EDRN consortium with investigators from Fred Hutchinson Cancer CenterArizona State University and the Massachusetts General Hospital we have compared 5 anti-TP53 autoantibodyassays and found the RAPID assay most sensitive. Some 28 different AA have been assayed in a standardpanel of 952 sera to identify three - TP53 CTAG1 and IL-8 that can be detected in early stage disease andcomplement CA125. Over the last two decades we have collected and preserved 922 blood and 774 tissuesamples at the time of initial surgery in patients with ovarian cancers. During the last 6.5 years we have banked18754 new serum and plasma samples from the NROSS and provided serum/plasma samples for 11investigators to test biomarkers for early stage ovarian cancer. We have published 23 peer reviewed articlesreviews and commentaries. A team of 36 investigators and staff will pursue 3 Specific Aims: 1) to conduct theNROSS2 trial to determine the specificity and PPV of a two-stage ovarian cancer screening strategy using a 4biomarker ROCA2 and a panel of 3 autoantibodies; 2) to evaluate multiple biomarkers for early detection ofrecurrence or persistence of disease at positive second look operations; and 3) to maintain and share a serumand plasma bank to facilitate evaluation of novel biomarkers for early detection of ovarian cancer. 1014275 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;B-Lymphocytes;CD4 Positive T Lymphocytes;Cancer Burden;Cell Line;Cells;DNA Sequence Alteration;DNA Transposable Elements;Data;Data Set;Development;Elements;Endogenous Retroviruses;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Lymphoma;Evolution;Family;Freezing;Genes;Genetic Transcription;Genome;Goals;HIV;HIV Infections;Hematologic Neoplasms;Herpesviridae;Highly Active Antiretroviral Therapy;Human;Human Genome;Human Herpesvirus 4;Human Herpesvirus 8;Immune;Immunity;Immunocompetent;Immunosuppression;In Vitro;Infection;Integration Host Factors;Kaposi Sarcoma;Lentivirus Vector;Literature;Lymphoma;Lymphoma cell;Lymphomagenesis;Malignant - descriptor;Malignant Neoplasms;Mediating;Membrane;Modeling;Molecular;Non-Hodgkin's Lymphoma;Nuclear;Oncogenes;Oncogenic;Oncogenic Viruses;Oncoproteins;Pathogenicity;Patients;Persons;Play;Population;Process;Proteins;Renal Cell Carcinoma;Research;Retroelements;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tissues;Transactivation;Transcript;Tumor Tissue;Variant;Viral;Virus;Virus Diseases;Virus Latency;Work;antiretroviral therapy;carcinogenesis;checkpoint inhibition;co-infection;cohort;differential expression;enhancing factor;extracellular;gene product;genetic element;genomic locus;high risk;in vitro Model;in vivo;infected B cell;knock-down;large cell Diffuse non-Hodgkin's lymphoma;mortality;multiple omics;novel;overexpression;premalignant;protein expression;single cell sequencing;targeted treatment;tool;transcriptome sequencing;transcriptomics;translational impact;tumor microenvironment;tumorigenesis;tumorigenic;virus related cancer Identifying Endogenous Retroviral Factors in Viral Lymphomagenesis PROJECT NARRATIVEVirus-associated malignancies may account for an estimated 15 percent of all human cancers worldwide whichrepresents a significant component of the global cancer burden. Both HIV and EBV have documentedassociations with a number of malignancies and people living with HIV are at a higher risk of developing cancerdespite antiretroviral treatments. This study aims to identify and characterize novel interactions betweenexogenous viral factors and endogenous retroviral oncogenes that play an essential role in virus-associatedcancers. NCI 10700554 5/4/23 0:00 PA-21-049 1F30CA278653-01A1 1 F30 CA 278653 1 A1 "PURI, ANU" 5/4/23 0:00 5/3/27 0:00 Special Emphasis Panel[ZRG1-F17A-M(20)L] 15611044 "MARSTON, JEZ LIM" Not Applicable 12 BIOCHEMISTRY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 5/4/23 0:00 5/3/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTMalignancy is the leading cause of mortality amongst people living with HIV (PLWH). Of these malignanciesNon-Hodgkin lymphoma (NHL) is the most common hematological neoplasm affecting PLWH. Despite theintroduction of highly active antiretroviral therapy (ART) PLWH are 10-20 times more likely to develop NHL thanthose without HIV. Epstein Barr Virus (EBV) is an oncogenic virus that is associated with the lymphomas mostcommonly observed in PLWH. Active HIV infection can lead to Acquired Immunodeficiency Syndrome (AIDS) inuntreated people and it is known that AIDS promotes the development of EBV+ lymphomas termed AIDS-defining cancers (ADCs) the effect of host factors including endogenous retroviruses on lymphomagenesis inimmunocompetent PLWH treated with ART remains to be explored. Work in the Cesarman and Nixon labs hasshown that EBV and HIV each hijack host cell signaling pathways upon infection to induce the expression ofendogenous retroelements including as human endogenous retroviruses (HERV). To determine thecontributions of these viruses on lymphomagenesis we will generate data from in vitro lymphoma models to testthe effect of EBV and HIV proteins on the expression of endogenous retroviral oncoproteins. Additionally we willperform bulk and single-cell sequencing of Diffuse Large B Cell Lymphoma (DLBCL) from PLWH to determinethe changes in cell populations of the tumor microenvironment (TME). We hypothesize that there will be uniquepopulations of EBV infected B cells with pre-malignant transcriptomic signatures that correlate with dysregulatedHERV expression including expression of the HERVK(HML2) Np9 oncogene.In Aim 1 we will determine the impact of EBV latency III LMP2A and extracellular HIV p17 variants on theexpression of the Np9 oncogene. We will perform stepwise molecular and cellular studies to determine thetranslational impact of exogenous viral infection on the expression of this endogenous retroviral oncogene. Wewill additionally perform multi-omic analysis to identify viral and host factors relevant to the transcriptionalmachinery of virus-mediated Np9 oncogene expression.In Aim 2 we will use our novel established single cell pipeline to determine locus-specific endogenous retroviraltranscription of DLBCL samples from PLWH. Preliminary data from our work in the Nixon lab strongly suggeststhat we will be able to use the pipeline that we have developed to identify and quantify these HERV transcriptsfrom RNA-sequencing data. We will assess the relative cell populations of samples that are EBV+ to those thatare EBV- and determine the differences in host gene retroviral and viral transcripts. Additionally we intend tovalidate these single cell findings with bulk RNA-sequencing from a larger cohort of EBV+/- fresh frozen tissueof DLBCL from PLWH. 52694 +No NIH Category available 3-nitrotyrosine;AIDS-Related Lymphoma;Acquired Immunodeficiency Syndrome;Aftercare;Angiolymphoid hyperplasia;Architecture;B-Lymphocytes;Biological Assay;Cell Proliferation;Cell Survival;Cell model;Cells;Chromatin;Chromosomes;Complex;DAXX gene;DNA;DNA Binding;DNA biosynthesis;Data;Disease;Epigenetic Process;Episome;Frequencies;Gene Expression;Gene Expression Profile;Genetic Recombination;Genetic Transcription;Genome;Genome Stability;Goals;HIV/AIDS;Herpesviridae;Herpesviridae Infections;Higher Order Chromatin Structure;Histone H3.3;Human;Human Herpesvirus 4;Human Herpesvirus 8;Immune Evasion;Immune System Diseases;Inflammatory;Investigation;Kaposi Sarcoma;Knowledge;Life Cycle Stages;Liquid substance;Lymphatic Endothelium;Lymphoma;Lymphoma cell;Lytic;Maintenance;Malignant Neoplasms;Mesenchymal Stem Cells;Metabolic;Metabolic Pathway;Metabolic stress;Mitochondria;NOS2A gene;Nuclear;Nuclear Antigens;Oxidative Phosphorylation;Pathogenesis;Pathway interactions;Phase;Pleural effusion disorder;Process;Receptor Protein-Tyrosine Kinases;Regulation;Role;Structure;Syndrome;Terminal Repeat Sequences;Therapeutic Intervention;Tumor Suppressor Proteins;Tyrosine;Viral;Viral Genome;cell growth;chronic infection;cohesin;cytokine;drug sensitivity;endothelial stem cell;epigenetic regulation;epigenome;epigenomics;genome integrity;histone modification;inhibitor;latent gene expression;latent infection;mouse model;novel;programs;recombinase;targeted treatment;transcriptomics;tumor;tumorigenesis;viral DNA;virus episome maintenance Epigenomic Control of KSHV Latency Narrative:The long-term goal of this R01 is to further advance our knowledge of the AIDS-defining malignancies causedby Kaposis Sarcoma-Associated Herpesvirus (KSHV). Investigation of the mechanisms regulating KSHVlatency episome persistence and oncogenesis through a deeper understanding of KSHV LANA will providenovel viral-specific targets for therapeutic intervention in KSHV-associated cancers and related disorders. NCI 10700329 5/8/23 0:00 PA-20-185 2R01CA117830-16A1 2 R01 CA 117830 16 A1 "READ-CONNOLE, ELIZABETH LEE" 4/1/06 0:00 6/30/28 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 1869983 "LIEBERMAN, PAUL M" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 410175 NCI 225000 185175 Abstract:Kaposis Sarcoma (KS)-Associated Herpesvirus (KSHV) is a human g-herpesvirus responsible for KS pleuraleffusion lymphoma (PEL) multlicentric Castlemans disease (MCD) and KSHV inflammatory cytokine syndrome(KICS). KS and PEL are HIV-AIDS-defining malignancies that occur at high frequency during AIDS but alsoafter treatment with ART especially in endemic regions. KSHV oncogenesis is driven by the complex life cycleof KSHV involving long-term latent infection of B-lymphocytes reactivation and persistent infection of lymphaticendothelial and mesenchymal stem cells and immune evasion. KSHV encoded nuclear antigen LANA isexpressed in all KSHV-associated tumors and is essential for maintenance of the viral episome during latentinfection in proliferating cells. KSHV LANA is also thought to contribute directly to viral oncogenesis andpathogenesis through interactions with tumor suppressor proteins and rewiring of host gene expressionprograms. We have previously shown that LANA contributes to the viral DNA replication epigenetic regulationand higher-order structure of KSHV episomes. We have also identified chromatin organizing factors such asCTCF and cohesins as key regulatory factors in the control of latent gene expression and restriction of lyticreactivation. More recently we have explored KS tumor transcriptomics and drug sensitivity assays to identifymetabolic pathways implicated in the regulation of LANA and KSHV-infected cell survival. We now propose toadvance each of these findings and continue our long-term effort to understand the role of LANA in episomemaintenance latency regulation and oncogenesis. Specifically we will investigate (1) the role of LANA inregulating latency-associated DNA replication and genome integrity through a potential intrinsic tyrosinerecombinase activity that regulates replication termination and genome decatenation at the viral terminal repeats(2) the role of LANA and cellular chromatin organizing factors DAXX CTCF and cohesin in forming higher-ordernuclear bodies that protect and organize the viral episome to maintain stable genomes and gene expressionpatterns in latently infected cells and (3) how onco-metabolic stress disrupts LANA function and KSHV latencyto drive tumorigenesis. Together these studies provide an integrated framework to further advance ourknowledge of KSHV infection and latency and provide new opportunities for therapeutic intervention in KSHV-associated disease. 410175 +No NIH Category available Address;Area;Autoantibodies;Benign;Biological Markers;Blinded;CA-19-9 Antigen;Cancer Center;Cancer Detection;Clinical;Collaborations;Collection;Cyst;Diabetes Mellitus;Diagnosis;Diagnostic;Disease;Early Detection Research Network;Early Diagnosis;Endocrine Gland Neoplasms;Environment;Family;Foundations;Funding;Gastroenterology;General Population;Germ-Line Mutation;Goals;Health;Health system;Hospitals;Hyperglycemia;Image;Individual;Institution;Joints;Leadership;Letters;Malignant - descriptor;Malignant neoplasm of pancreas;Mucinous;Operative Surgical Procedures;Pancreas;Pancreatic Cyst;Pancreatic Diseases;Pancreatic Ductal Adenocarcinoma;Pancreatic cystic neoplasia;Parents;Pathology;Patients;Phase;Population;Prospective cohort;Proteins;Public Health;Publications;Publishing;Recording of previous events;Research;Research Activity;Research Design;Research Personnel;Risk;Sampling;Sensitivity and Specificity;Site;Specificity;Tissue Inhibitor of Metalloproteinase-1;Translating;Tumor Antigens;Underrepresented Minority;United States;Unresectable;Validation;biomarker panel;biomarker validation;chronic pancreatitis;circulating biomarkers;cohort;disparity gap;ethnic minority;gulf coast;high risk;improved;improved outcome;industry partner;patient prognosis;patient subsets;phase 3 study;phase 4 study;prospective;protein biomarkers;racial minority;recruit;screening;validation studies Clinical Validation Center for Early Detection of Pancreatic Cancer Pancreatic cancer is a disease of near uniform lethality and early diagnosis preferably at an asymptomatic stagerepresents the best chance of improving long term prognosis of patients. The objective of this Gulf Coast-GreatLakes EDRN Clinical Validation Center (GCGLEC) is to collect the highest quality annotated biospecimensincluding from populations typically underrepresented in biomarker studies in order to facilitate biomarkervalidation in early stage pancreatic cancer as well as in at-risk and pre-diagnostic cohorts. As an EDRN fundedvalidation center collaborative endeavors within the network will be an integral component of the GCGLEC. NCI 10700171 9/6/23 0:00 RFA-CA-21-033 5U01CA200468-07 5 U01 CA 200468 7 "YOUNG, MATTHEW R" 5/4/16 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 7626839 "MAITRA, ANIRBAN " Not Applicable 9 PATHOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 996338 NCI 768590 227748 AbstractEarly detection of pancreatic ductal adenocarcinoma (PDAC) is an area of highest priority and an unmet needfor advancing public health in the United States. Certain sub-groups of patients such as those with germlinemutations mucinous pancreatic cysts and new-onset diabetes (NOD) are at higher than average risk for PDAC.In the immediate prior cycle our EDRN Clinical Validation Center (CVC) at MD Anderson Cancer Center(MDACC): (a) facilitated the conduct of the first ever multi-institutional blinded biomarker bakeoff in PDAC byproviding annotated biospecimens (b) completed one of the first EDRN-defined Phase 3 biomarker studies inPDAC using pre-diagnostic samples (Fahrmann et al Gastroenterology 2021) and (c) served as a conduit forthe implementation of additional EDRN collaborative research initiatives including a pre-diagnostic PDACimaging consortium. Our renewal application represents a Gulf Coast-Great Lakes EDRN Clinical ValidationCenter (GCGLEC) in Pancreatic Cancer is comprised of UTMDACC/Lyndon B Johnson Hospital (Harris HealthTX) Henry Ford Health System (HFHS Detroit MI) and Ochsner Health System (OHS New Orleans LA) andhas three major objectives: First to implement a multi-institutional framework for collecting the highest qualitybiospecimens from patients with a variety of well-defined pancreatic pathologies (including early stage PDACpancreatic cystic lesions and other benign pancreatic diseases such as chronic pancreatitis benign cysts andendocrine tumors of low malignant potential) in order to conduct biomarker validation studies for early detectionof PDAC that conform to EDRN-defined Phase 2 and Phase 3 study design. Current PDAC biomarker studiestypically have sparse representation from racial and ethnic minorities and therefore a major impetus of theGCGLEC will be to address the disparity gap in biomarker research by obtaining biospecimens fromunderrepresented minorities. Second the GCGLEC will build upon our published Phase 3 study utilizing theanchor panel of CA19-9 LRG1 and TIMP-1 by conducting four additional PRoBE-compliant studies thatincorporate autoantibodies metabolites and additional protein biomarkers for improving the sensitivity ofdiagnosing asymptomatic PDAC without compromising the 99% or greater specificity threshold. These EDRN-defined Phase 3 studies will be conducted in pre-diagnostic cases and controls obtained from existing cohortsincluding the PLCO WHI and the so-called Harvard cohorts (NHS PHS WHS and HPFS) as well as ongoingprospective cohorts undergoing accrual such as the NCI-funded New Onset Hyperglcyemia and Diabetes (NOD)cohort and the Early detection Initiation (EDI) in PDAC a collaboration between PanCAN and the NCI. Thirdthe GCGLEC will serve as a hub for collaborative activities within and outside the EDRN includingcollaborations with investigators funded by the Pancreatic Cancer Detection Consortium (PCDC) and laying thefoundations for conducting an EDRN-approved multi-institutional clinical utility (Phase 4 study) for PDAC earlydetection within a CAP/CLIA environment. 996338 +No NIH Category available Address;Affect;Antibodies;Autopsy;Award;Benign;Biological;Biological Markers;Biology;Blood;Blood specimen;Cancer Detection;Characteristics;Clinical;Clinical Data;Collection;Cystic Lesion;Diabetes Mellitus;Diagnostic;Disease;Disease Progression;Doctor of Philosophy;Early Detection Research Network;Early Diagnosis;Enrollment;Etiology;Evaluation;Female;Foundations;Freezing;Frequencies;Future;Germ-Line Mutation;Glycoproteins;Grant;Human;Immunohistochemistry;Inherited;Intuition;Laboratories;Laboratory Research;Lesion;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Medical Oncologist;Methods;Mucins;Mutation;Neoplasm Metastasis;Operative Surgical Procedures;Organoids;Pancreas;Pancreatic cystic neoplasia;Patient Recruitments;Patients;Performance;Phase;Plasma;Principal Investigator;Procedures;Proteins;Research;Research Personnel;Resources;Risk;Sampling;Screening for cancer;Sensitivity and Specificity;Serum;Specimen;Target Populations;Time;Tissue Banks;Tissue Sample;Tissues;Validation;anticancer research;biomarker development;biomarker discovery;biomarker validation;cancer biomarkers;cancer diagnosis;cancer risk;chronic pancreatitis;circulating biomarkers;clinical application;clinical diagnosis;cohort;early detection biomarkers;exosome;human tissue;imaging biomarker;imaging modality;improved;individual patient;interest;male;medical schools;member;mouse model;novel;novel marker;pancreatic cancer model;patient population;premalignant;professor;prospective;sample collection;tissue resource;translational cancer research;tumor microenvironment;tumor progression Pancreatic Cancer Detection Consortium Project NarrativeThis proposal to continue in the Pancreatic Cancer Detection Consortium will further build and enhance ourbiospecimen resource that collects longitudinal blood samples on patients at risk of developing pancreatic cancerand unique tissue resources that include rare pancreatic premalignant lesions. We also propose to enhance ourdiscovery and validation of blood-based and imaging-based biomarkers that have the potential to detect anddifferentiate at the earliest possible stages pancreatic lesions that are likely to progress to cancer. NCI 10700159 9/1/23 0:00 PAR-21-334 5U01CA210240-07 5 U01 CA 210240 7 "YOUNG, MATTHEW R" 5/1/17 0:00 8/31/27 0:00 ZCA1-RPRB-8(M)2 1891494 "HOLLINGSWORTH, MICHAEL A." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 801505 NCI 649196 152309 AbstractThis proposal to continue in the Pancreatic Cancer Detection Consortium will further build and enhance ourbiospecimen resource that collects longitudinal blood samples on patients at risk of developing pancreatic cancerand unique tissue resources that include rare pancreatic premalignant lesions. We propose to continue andenhance our discovery and validation of blood-based and imaging-based biomarkers that have the potential todetect and differentiate the earliest possible stages of pancreatic lesions that are likely to progress to cancer.This proposal proceeds from an ongoing effort that was initiated 3.5 years ago in which we have enrolledapproximately 469 patients with known germline mutations or with significant inherited risk of unknown etiology(more than 2 affected with no defined mutations) for pancreatic cancer. We prospectively collect biologicalspecimens (100 mL blood) and detailed clinical data every six months from an at-risk cohort that represents thetarget population envisioned for clinical application of biomarkers with potential to detect pancreatic cancer. Inaddition to patients with inherited risk we will continue to collect longitudinal samples on groups of patients withincreased risk of pancreatic cancer: those with pancreatic cystic neoplasms or chronic pancreatitis and newonset diabetes (NOD). We also propose three biomarker research specific aims that have grown out of progressduring the previous grant award. One aim will build upon our previous results with mucin type biomarkers andrelated glycoproteins by examining the potential of a set of additional biomarkers to improve detection cancerprior to clinical diagnosis in the earliest stages of disease progression. A second aim will examine the capacityof newly identified antibodies to CEACAM6 to identify earliest lesions in the pancreas by immunohistochemistryand state of the art imaging modalities. A third aim will determine the performance characteristics of a panel ofexosome-based biomarkers detecting early pancreatic cancer and differentiating benign cystic lesions fromthose that progress to cancer. 801505 +No NIH Category available Acceleration;Acquired Immunodeficiency Syndrome;Address;Adoption;Adult;Africa;African;Aftercare;California;Cancer Control;Cancer Etiology;Caring;Cervical Cancer Screening;Cessation of life;Clinical effectiveness;Communities;Country;Data;Diagnosis;Emergency Situation;Epidemic;Exploration Preparation Implementation and Sustainment;Female;General Population;Goals;HIV;HIV Infections;Health;Health Personnel;Health care facility;Healthcare;Hybrids;Implementation readiness;Improve Access;Individual;Infrastructure;Intervention;Life Expectancy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Methods;Nigeria;Outcome;Persons;Population;Prevalence;Protocols documentation;Randomized;Recommendation;Reporting;Research;Resource-limited setting;Resources;Risk;Services;System;Universities;Woman;World Health Organization;anticancer research;antiretroviral therapy;arm;cancer care;comparative effectiveness;effectiveness outcome;evidence base;implementation evaluation;implementation outcomes;implementation science;implementation strategy;improved;low and middle-income countries;meetings;mortality;programs;scale up;screening;service delivery;treatment center;treatment program;treatment site;trial design;uptake ACCESS: Accelerating Cervical Cancer Elimination through the integration of Screen-and-treat Services PROJECT NARRATIVEWhile there has been a significant increase in the uptake of antiretroviral therapy among women living withHIV (WLHIV) in many low- and-middle income countries (LMICs) the coverage of cervical cancer screeningand treatment among WLHIV remains low. In this study we aim to leverage the available infrastructure for HIVcare and treatment programs in Nigeria to integrate cervical cancer screening and treatment and conduct acluster randomized hybrid type III trial design to assess the comparative effectiveness of a Core set ofimplementation strategies versus a Core+ (enhanced) set of implementation strategies to implement cervicalcancer screening onsite treatment referral and referral completion treatment and retention in careamong WLHIV. The overarching goal is to improve the health and life expectancy of WLHIV with co-occurringcervical cancer. NCI 10700152 8/21/23 0:00 RFA-CA-21-056 5U01CA275118-02 5 U01 CA 275118 2 "VEDHAM, VIDYA" 9/7/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M2) 2792918 "AARONS, GREGORY " "EZEANOLUE, ECHEZONA EDOZIE" 50 PSYCHIATRY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 639958 NCI 555744 84214 Program SummaryNigeria has one of the largest HIV epidemics in the world with 1.8 million people living with HIV infection. Withan estimated female population of 102 million and HIV prevalence of 1.6% among adult females Nigeria has thelargest population of women and the 4th largest number of women living with HIV (WLHIV) in Africa. Althoughaccess to antiretroviral therapy (ART) among WLHIV in Nigeria has increased over the years with over 98% ofthe 960000 WLHIV on ART AIDS-related mortality remains high. In 2020 16000 WLHIV died from AIDS-related illnesses including cervical cancer. A pilot implementation program in Nigeria demonstrated thatleveraging the U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR) supported HIV programs for theprovision of evidence-based cervical cancer screen-and-treat interventions in WLWH is feasible. The pilotprogram demonstrated however that tailored implementation strategies will be needed to address specificmultilevel barriers along the cancer control continuum in order to address adoption reach and sustainability thatare necessary for successful scale-up. However in many African countries with a high burden of both HIV andcervical cancer there is a paucity of evidence-based implementation strategies to inform effective integration ofHIV and cervical cancer services delivery. Objectives of this proposal are to: 1) Refine strategies to integratecervical cancer screening treatment and management within existing comprehensive HIV treatment programsand determine implementation readiness; 2) Determine the comparative effectiveness of a Core set ofimplementation strategies versus Core+ enhanced implementation strategies; and 3) assess sustainment of theintegration of cervical cancer screening treatment and management intervention into HIV programs. We haveassembled a strong team from University of California San Diego; University of Nigeria Nsukka and JohnHopkins University with expertise in implementation science HIV care and research and cancer care andresearch. Our proposal is responsive to the NCI RFA and consistent with the World Health Organization globalplan of elimination of cervical cancer by 2030. If effective the proposed project will result in a set of feasibleculturally adaptable and sustainable implementation strategies to integrate evidence-based cervical cancerscreening and treatment into HIV programs in order to improve the health and life expectancy of WLHIV. 639958 +No NIH Category available Automobile Driving;BRAF gene;Buffers;CRISPR/Cas technology;Cardiolipins;Cell Proliferation;Cell Survival;Cells;Clinical;Combined Modality Therapy;Coupled;Data;Dependence;Development;Diglycerides;Disease;Disease model;Endothelin;Endothelin-1;Engineering;Environment;Enzymes;Exposure to;Eye;Family member;Feedback;G-Protein-Coupled Receptors;GNAQ gene;Gene Mutation;Genes;Genetic Engineering;Goals;Immune checkpoint inhibitor;In Vitro;Knock-in Mouse;Knock-out;Knockout Mice;Ligands;Lipid Synthesis Pathway;Lipids;Liver;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Melanoma Cell;Metastatic Neoplasm to the Liver;Metastatic to;Methods;Mitogen-Activated Protein Kinases;Mutation;NF1 gene;Nature;Neoplasm Metastasis;Oncogenic;Pathway interactions;Patients;Phenotype;Phosphatidylinositols;Phospholipase C;Phosphorylation;Protein Kinase C;Protein Kinase C Inhibitor;Regimen;Regulation;Resistance;Role;Second Messenger Systems;Signal Pathway;Signal Transduction;Somatic Mutation;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;United States;Up-Regulation;Uveal Melanoma;Work;Xenograft Model;Xenograft procedure;clinical efficacy;clinically relevant;effective therapy;experimental study;genome-wide;immune checkpoint blockade;improved;in vivo;inhibitor;loss of function;melanocyte;melanoma;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;overexpression;phosphatidate;phosphatidylcholine-specific phospholipase C;phosphoproteomics;receptor;resistance mechanism;subcutaneous;success;targeted treatment;therapeutic target;therapeutically effective;transcriptional reprogramming;transcriptome sequencing;tumor Targeting Gq pathway in uveal melanoma NarrativeUveal melanoma (UM) is the most common eye malignancy with high mortality once itmetastasizes to the liver. No effective treatments exist for metastatic patients. Ourproposed studies aim to identify new therapeutic strategies and validate them usingclinically relevant in vivo disease models with the overall goal to develop new treatmentapproach for UM patients. NCI 10700134 8/30/23 0:00 PA-20-185 5R01CA273020-02 5 R01 CA 273020 2 "COVELL, DAVID G" 9/7/22 0:00 8/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 12677359 "CHEN, XU " Not Applicable 11 DERMATOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 445160 NCI 275641 169519 Project summary: Uveal melanoma (UM) is the most common intraocular cancer in the United States and accounts for about5% of all kinds of melanomas. Approximate 50% of UM patients develop metastases predominantly to the liverwith 100% mortality. UM lacks mutations in BRAF NRAS NF1 and KIT common to other melanoma types.Instead over 90% harbor somatic activating mutations in the Gaq family members GNAQ or GNA11 with theremainder carrying mutations of genes also acting in the Gaq signaling pathway such as CYSLTR2 a Gaq-coupled GPCR phospholipases C b4 (PLCb4) a direct effector of Gaq. Therefore UM is genetically defined byactivating mutations of the Gaq pathway. Despite dramatic successes in other melanoma subtypes immunecheckpoint inhibitors and targeted therapies have failed to demonstrate clinical benefits in UM leading to anurgent need to develop novel and effective therapeutic regimens. The CYSLTR2->Gaq->PLCb-> protein kinaseC (PKC) module is a linear signaling cascade that drives the essential MAP-kinase (MAPK) signaling for UM cellproliferation making Gaq pathway the prime target for targeted therapy for this devasting disease. Although bothGNAQ/11 and PKC inhibitors are very effective to suppress UM cell proliferation/survival in vitro targeting eitherGNAQ/11 or PKC alone has shown limited efficacy in UM liver metastasis. Understanding the resistance to theGaq pathway inhibition is of paramount importance to develop new strategies that work in the specific signalingcontext of a constitutively activated Gaq pathway. Our preliminary data show either GNAQ/11 inhibition or PKCinhibition yields strong upregulation of the Gaq-coupled receptor EDNRB which when encountering its ligandEDN1 from the liver environment can lead to reactivation of MAPK thus driving resistance to Gaq pathwayinhibition in UM. In this proposal we will evaluate that blocking endothelin signaling will increase the therapeuticefficacy of targeting oncogenic Gaq signaling directly or downstream using newly developed geneticallyengineered and xenograft models of UM metastatic to the liver. While the role of endothelin signaling inmelanocyte development and melanoma progression is well documented the nature of the feedback thatupregulates EDNRB expression/signaling is not understood. We will utilize a combination of candidateapproaches RNAseq and phospho-proteomics to dissect the underlying mechanisms in UM cells and inmelanocytes. Our preliminary data also show that secondary mutations in GNA11 can confer resistance to theGaq inhibition. In this proposal we will expand the emerging landscape of the mechanism underlying theadaptive and acquired resistance to Gaq pathway inhibition and identify rational therapy combinations to improvethe therapeutic efficacy for metastatic UM. Using a combined genome-wide CRISPR/Cas9 synthetic lethalityscreen and phospho-proteomic screen we identified a lipid synthesis pathway that is essential for the survival ofcells with Gaq mutation which we will explore as entirely novel therapeutic target for UM. 445160 +No NIH Category available Adult;Affect;Antibodies;Astrocytoma;Blindness;Blood;Brain;Brain Neoplasms;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Cell Growth;Carboplatin;Cell physiology;Cells;Child;Childhood;Childhood Malignant Brain Tumor;Common Neoplasm;Data;Dependence;Development;Etiology;Evolution;Experimental Designs;Flow Cytometry;Future;Gene Mutation;Genetic Transcription;Glioma;Goals;Growth;Growth Factor;Heterozygote;Human;Immune;Immune system;Immunohistochemistry;In Vitro;Individual;Laboratories;Lymphocyte;MEKs;Macrophage;Malignant - descriptor;Malignant Glioma;Malignant neoplasm of brain;Mediating;Medical;Meninges;Microglia;Molecular;Molecular Target;Morbidity - disease rate;Mouse Strains;Mus;Mutant Strains Mice;Mutation;NF1 gene;NF1 mutation;Neoplasms;Neurofibromatosis 1;Neurons;Optic Nerve;Optic Nerve Glioma;Optics;Pathway interactions;Patients;Persons;Population;Population Dynamics;Production;Property;Regulation;Role;Series;Solid Neoplasm;Syndrome;T cell regulation;T-Cell Activation;T-Cell Depletion;T-Lymphocyte;Testing;Tumor-Associated Process;Vincristine;cancer cell;cancer predisposition;cell type;conventional therapy;cytokine;design;experimental study;genotoxicity;immune modulating agents;in vivo;inhibitor;midkine;monocyte;mouse model;mutant;neuronal excitability;neurotoxicity;recruit;single-cell RNA sequencing;tumor T Cell Regulation of Low-Grade Glioma NarrativeThe goal of this proposal is to employ the Neurofibromatosis type 1 (NF1) childhood brain cancer predispositionsyndrome as an experimental platform to mechanistically define the selective role of CD8+ T cells as centralcellular integrators of neuron-mediated and immune system modulation of glioma formation and growth.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page 1 Continuation Format Page NCI 10700099 8/7/23 0:00 PAR-19-353 5R01CA261939-02 5 R01 CA 261939 2 "JHAPPAN, CHAMELLI" 9/9/22 0:00 8/31/27 0:00 Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] 1862603 "GUTMANN, DAVID H" Not Applicable 1 NEUROLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 483265 NCI 310781 172484 Project SummaryGliomas are the most common brain cancer. Whereas malignant gliomas predominate in adults low-gradegliomas (LGGs) comprise the majority of brain tumors in the pediatric population. While LGGs are not typicallyfatal young children with these neoplasms commonly have long-term medical morbidities from either the tumoritself or the neurotoxicity associated with conventional therapies. This is particularly true for individuals with theNeurofibromatosis type 1 (NF1) cancer predisposition syndrome where nearly 20% of children will developLGGs involving the optic pathway (optic pathway gliomas; OPGs) that can lead to vision loss. Currently therapiesfor NF1-LGGs are focused on arresting the growth of the cancer cells using either genotoxic (e.g.carboplatin/vincristine) or molecularly targeted (e.g. MEK inhibitors) treatments with variable durable effects.Importantly 30-50% of the cells in human NF1-LGGs are non-neoplastic cells such as neurons lymphocytes(T cells) and monocytic cells (macrophages and microglia) which our laboratory has shown are required for bothtumor formation and growth in experimental murine models of Nf1-OPG. Using these Nf1-OPG mouse strainswe have previously defined a neuron-immune-cancer cell circuit in which Nf1-mutant neurons activate T cellsto produce cytokines that stimulate microglia to support LGG formation and continued growth. Specifically wedemonstrated that NF1-mutant human and murine neurons produce midkine which activates T cells in vitro andin vivo to secrete Ccl4 which then acts on microglia to induce Ccl5 expression an essential growth factor forNf1-OPG formation and growth. Surprisingly we found that CD8+ T cells predominate in both human and mouseNF1-LGG where high CD8 but not CD4 levels correlate with reduced overall survival in people with LGG.Moreover studies in our laboratory revealed that antibody-mediated CD8+ T cell depletion reduces mouse Nf1-OPG growth in vivo. Based on these findings we hypothesize that CD8+ T cells function in a neuron-immune-cancer cell circuit as obligate modulators of LGG development and progression. To test thishypothesis we have designed a series of experiments we have designed a series of experiments that aim to (a)define the immune composition of Nf1 optic gliomas in mice (b) determine why CD8+ T cells are selectivelyrecruited in these murine brain tumors and (c) elucidate how NF1 mutation in neurons modifies T cell-microgliainteractions. Collectively these studies aim to mechanistically dissect the role of CD8+ T cells in neuron-immune-cancer cell axis regulation of LGG formation and growth relevant to the development of futureimmunomodulatory therapeutic strategies.OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page 1 Continuation Format Page 483265 +No NIH Category available Address;Adoption;Africa;Africa South of the Sahara;African;Cancer Control;Caring;Cervical;Cervical Cancer Education;Cervical Cancer Screening;Cessation of life;Clinic;Clinic Visits;Clinical;Collaborations;Collection;Communication;Community Health Aides;Competence;Counseling;Country;Cytology;DNA;Data;Diagnostic;Diagnostic tests;Early Diagnosis;Early treatment;Face;Female;Funding;HIV;HIV Infections;HIV Seronegativity;HIV/AIDS;HPV-High Risk;Health system;Home;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immune Evasion;Immunosuppression;Incidence;Income;Infection;Infrastructure;Knowledge;Laboratories;Learning;Maintenance;Mali;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Muslim population group;Needs Assessment;Nigeria;Oncogene Activation;Patients;Persons;Prevalence;Prevention strategy;Process;Recommendation;Religion;Reporting;Research;Resources;Risk;Risk Assessment;Sampling;Secure;Sexually Transmitted Diseases;Site;Specimen;Surveys;Swab;Target Populations;Temperature;Test Result;Testing;Training;Transportation;United States National Institutes of Health;Vagina;Woman;Women's Health;acceptability and feasibility;care systems;cervical cancer prevention;cervical carcinogenesis;cervicovaginal;co-infection;collaborative approach;cost;cost effective;dashboard;effectiveness evaluation;evidence base;experience;health care settings;high risk;hospital laboratories;human papilloma virus oncogene;implementation fidelity;implementation framework;implementation strategy;improved;low and middle-income countries;novel;programs;sample collection;scale up;screening;social;social culture;social stigma;success;webinar West Africa Self-Sampling HPV Based Cervical Cancer Control Program (WA-SS-HCCP) for WLWHA: Barriers challenges and needs NARRATIVEThis proposed research is responding to RFA-CA-21-056 and aims to leverage our decade-long extensiveand successful training partnership and research collaborations in Mali and Nigeria to implement a novel WestAfrican Self-Sampling Human Papillomavirus (HPV)-Based Cervical Cancer Control Program in these twocountries. The project capitalizes on existing strengths and resources including the HIV systems of care withCommunity Health Workers who have established relationships with women living with HIV/AIDS and canprovide HPV and cervical cancer education/counseling guidance for Self-Sampling by women rapid collectionand transport of vaginal swab specimens to hospital laboratories personalized delivery of test results directlyto the women and facilitation of clinic referrals for those with high-Risk HPV infection for advanced diagnosticsand treatment. The study will conduct an in-depth assessment of barriers challenges and needs to implementcontextually adapt and evaluate the effectiveness of the proposed program. NCI 10700092 8/14/23 0:00 RFA-CA-21-056 5U01CA275129-02 5 U01 CA 275129 2 "VEDHAM, VIDYA" 9/7/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M2) 9243845 "HOU, LIFANG " "HOLL, JANE LOUISE; MAIGA, MAMOUDOU " 5 PUBLIC HEALTH & PREV MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 625679 NCI 554670 71009 PROJECT SUMMARY/ABSTRACTWorldwide 70% of new HIV infections every year occur in Sub-Saharan Africa (SSA) home to 74% of peopleliving with HIV/AIDS (PLWHA) of whom over 50% are women. Furthermore the highest rates of cervicalcancer (CC) incidence and related death also occur in SSA where approximately 60% of all CC cases are inwomen living with HIV/AIDS (WLWHA). Human Papillomavirus (HPV) amajor cause of CC is the mostcommon sexually transmitted infection in SSA and nearly all WLWHA worldwide who develop CC are co-infected with HPV. CC is largely preventable by HPV vaccination and cervical screening for early detection andtreatment. In high income countries (HICs) these strategies have led to a steep decline in CC; however theyremain largely inaccessible to women in low- and middle-income countries (LMICs). Self-sampling-based HPV(SS-HPV) tests have been shown to be a cost-effective and feasible approach to identifying women infectedwith high-risk HPV strains (hr-HPV) who need more advanced diagnostic tests and treatment. However SS-HPV testing has not been widely implemented in most LMICs including SSA despite high HIV prevalence.Leveraging our decade-long extensive and successful training partnership and research collaborations in Maliand Nigeria we propose to implement a novel West African Self-Sampling HPV-Based Cervical CancerControl Program (WA-SS-HCCP). The project capitalizes on existing strengths and resources including theHIV systems of care with Community Health Workers (CHWs) who have established relationships withWLWHA and can provide HPV and CC education/counseling and SS specimen collection guidance rapidtransportation of specimens to hospital laboratories personalized delivery of test results directly to the womenand facilitation of clinic referrals for women with hr-HPV for advanced diagnostics and treatment. The study willconduct in-depth assessment of barriers challenges and needs to contextually adapt implement andevaluate the effectiveness and success of WA-SS-HCCP. The specific aims are to (1) Assess barriers andneeds for contextual adaptations of WA-SS-HCCP among WLWHA in Mali and Nigeria using qualitative riskassessment and observation methods; (2) Contextually adapt using a learning collaborative approach (e.g.monthly webinars rapid-cycle small tests of change) and an implementation framework (e.g. training tocompetency of CHWs data coordination across settings implementation dashboard) to optimize the WA-SS-HCCP across all four sites; and (3) Conduct a dual evaluation of the effectiveness (e.g. % WLWHA fullyscreened and % change in) and implementation (e.g. reach adoption implementation fidelity andmaintenance or sustainability) and develop a WA-SS-HCCP Scale-Up Toolkit for wide dissemination of thisdetect-to-treat program that can be expanded to HIV- women and across LMICs. 625679 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;Africa South of the Sahara;Age;Biopsy;Cancer Control;Cancer Etiology;Capital;Caring;Centers for Disease Control and Prevention (U.S.);Cervical;Cervical Cancer Screening;Cervical Intraepithelial Neoplasia;Cessation of life;Cities;Clinic;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Clinical Trials Network;Cold Therapy;Colposcopy;Communicable Diseases;Communities;Conduct Clinical Trials;Country;County;Cytology;Data;Disease;Education;Eligibility Determination;Emergency Situation;Enrollment;Excision;Feasibility Studies;Funding;Government;Guidelines;HIV;HIV Infections;Health;Health Services Accessibility;High Prevalence;Histology;Hospitals;Human Papillomavirus;Human papilloma virus infection;Incidence;Infrastructure;Intervention;Intervention Studies;Kenya;Laboratories;Lead;Leadership;Lesion;Location;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;National Cancer Institute;Participant;Patient Recruitments;Persons;Plasma;Prevalence;Prevention Research;Procedures;Randomized;Recommendation;Recurrence;Reporting;Research;Site;Testing;Triage;Viral Load result;Woman;World Health Organization;anticancer research;antiretroviral therapy;barrier to care;base;burden of illness;cancer clinical trial;cancer prevention;cancer therapy;cervical cancer prevention;clinical research site;clinical trial implementation;clinically significant;experience;follow-up;high risk;improved;insight;loop electrosurgical excision procedure;low and middle-income countries;meetings;mortality;premalignant;programs;protocol development;randomized clinical trials;recruit;response;screening;screening services;synergism;treatment center;treatment services;uptake HIV/cervical cancer cOntrol and Prevention clinical sitE in Kenya (HOPE-Kenya) NARRATIVEBecause many women living with HIV (WLWH) are also infected with human papillomavirus (HPV) the causeof cervical cancer they have a very high likelihood of developing cervical cancer over their lifetime. In thisproject we propose to implement a clinical site in Nairobi Kenya at a high-volume HIV treatment clinic calledthe Coptic Hope Center for Infectious Diseases where clinical trials can be conducted and test interventions toimprove cervical cancer screening and treatment for WLWH. At our site we have the experience and expertiseto study methods that can potentially increase the number of women getting screened improve how womenwho test positive are managed and better treat any disease that is detected. NCI 10700090 7/10/23 0:00 RFA-CA-21-047 5UG1CA275400-02 5 UG1 CA 275400 2 "FRECH, MARIA SILVINA" 9/8/22 0:00 5/31/27 0:00 ZCA1-SRB-F(M2)R 8223125 "CHUNG, MICHAEL HOONBAE" "SAKR, SAMAH RAFIE" 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 399 Other Research-Related 2023 234007 NCI 209270 24737 ABSTRACTCervical cancer (CC) is a highly preventable disease and yet hundreds of thousands of women die each yearfrom CC with the large majority of deaths occurring in low- and middle-income countries (LMICs). LMICs in sub-Saharan Africa (SSA) are particularly affected because of the dual burden of human papillomavirus (HPV) andHIV infection which interact with deadly synergism. Women living with HIV (WLWH) have accessed antiretroviraltherapy (ART) across SSA but have yet to fully benefit from integrated CC screening and treatment services.The challenges lie not in any particular barrier to care but in the many gaps that occur in the cascade of CCprevention from screening uptake to management of positive cases to treatment access and application. Clinicalresearch sites are needed worldwide to implement clinical trials that examine potential interventions and one ofthe most ideal locations may be found at the Coptic Hope Center for Infectious Diseases in Nairobi Kenya. Co-founded by Dr. Michael Chung (MPI) and Dr. Samah Sakr (MPI) at the Coptic Hospital in 2004 the Hope Centeris one of the largest single-site ART treatment centers in Kenya having enrolled over 20000 people living withHIV (PLWH) with over 6000 WLWH currently in care. The Hope Center has been screening WLWH for cervicalcancer since 2005 and has been the site for HIV CC research and many clinical trials conducted by TreatmentResearch and Expert Education (TREE) which Dr. Chung leads as Executive Director. Based at the HopeCenter TREE has a powerful physical administrative and laboratory infrastructure that has been implementingHIV clinical trials at the site for over a decade including a study that screened over 6000 WLWH withPapanicolaou (Pap) smear and colposcopy-directed biopsy randomized 400 to cryotherapy and loopelectrosurgical excision procedure (LEEP) and examined recurrence of cervical intraepithelial neoplasia (CIN)cervical shedding of HIV and clearance of HPV over 2-year follow-up. In this proposal Dr. Chung and Dr. Sakrwill co-lead the implementation of a clinical site at the Hope Center in Nairobi by Coptic Hospital and TREE thatwith assistance from Drs. Mary Nderitu (co-I) and Evans Nyongesa-Malav (co-I) will study interventions thatwill: 1) increase screening uptake among WLWH; 2) improve management of women who screen positive; and3) optimize precancer treatment for WLWH. They will achieve this by providing: 1) a pluripotent infrastructure foraccruing participants to network clinical trials from the Hope Center and a network of four Coptic HIV Clinicsthroughout the country that are overseen by Dr. Andrew Nagy (co-I) for a total of 6533 CC screen eligibleWLWH between the ages of 25 and 49; 2) insights and input on clinical significance and study feasibility duringconcept and protocol development through the participation of Dr. Chung and Dr. Sakr; and 3) and on-siteoperational leadership for the successful conduct of network clinical trials by TREE and its staff led by Dr. RoseKosgei (co-I). 234007 +No NIH Category available Acute Myelocytic Leukemia;Adult;Age;Aging;Bar Codes;Blood;Bone Marrow;Cell Nucleus;Cells;Chromatin;Clonal Evolution;Clonal Expansion;Clone Cells;DNA;Development;Elderly;Enhancers;Environment;Epigenetic Process;Evolution;Exhibits;FLT3 gene;Foundations;Gene Expression Regulation;Gene Mutation;Genes;Genetic;Genomics;Hematopoiesis;Hematopoietic Neoplasms;Hematopoietic stem cells;Heterogeneity;Individual;Inflammation;Joints;Malignant - descriptor;Malignant Neoplasms;Mediating;Molecular Profiling;Mus;Mutation;Pathway interactions;Phenotype;Population;Predisposition;Process;Proliferating;Risk Factors;Somatic Mutation;Stress;Supporting Cell;Therapeutic;Time;Transplantation;age related;aged;bisulfite sequencing;bone aging;cancer initiation;epigenetic regulation;epigenomics;fitness;forging;high risk;human old age (65+);insight;leukemia;leukemic transformation;leukemogenesis;methylome;mutant;novel therapeutic intervention;permissiveness;prevent;preventive intervention;promoter;resilience;response;self-renewal;single-cell RNA sequencing;stem cell biology;stem cell function;stem cell proliferation;transcriptome;transcriptomics;tumor heterogeneity Impact of aging and clonal hematopoiesis on epigenetic heterogeneity evolvability and leukemogenesis PROJECT NARRATIVEAcute myeloid leukemia (AML) is a deadly blood cancer that occurs mostly in adults over 65 and is associatedwith the abnormal overproliferation of blood stem cells a common age-related condition called 'clonalhematopoiesis' (CH). Although we know that aging and specific gene mutations in the blood stem cells contributeto the development of CH and its progression to AML we do not understand how old age and CH interact topromote the evolution of AML. Here we will elucidate how aging and CH influence the propensity of blood stemcells to adapt to altered environments (evolvability) which could not only forge a new paradigm for ourunderstanding of leukemia onset but also provide candidate pathways for the development of preventativeinterventions. NCI 10700071 8/11/23 0:00 RFA-CA-20-040 5U01CA271830-03 5 U01 CA 271830 3 "KLAUZINSKA, MALGORZATA" 9/23/21 0:00 8/31/26 0:00 ZCA1-SRB-T(O1)R 12243946 "LI, SHENG " "DEGREGORI, JAMES V" 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 372507 NCI 298001 74506 PROJECT SUMMARYAcute myeloid leukemia (AML) occurs mostly in adults 65 years and older and is associated with age-relatedclonal hematopoiesis (CH). This condition that results from the clonal expansion of mutationally-markedhematopoietic stem and progenitor cells (HSPC). These HSPC expansions often feature somatic mutations inleukemia-associated genes such as the epigenetic regulator TET2. TET2-mutant CH is a risk factor for AMLand CH progression to AML is promoted by acquiring cooperating mutations such as constitutively active FLT3ITD.Yet it is unclear how aging and TET2 mutation interact to drive the evolution of CH to leukemia. We seek toreveal the epigenetic mechanisms for how CH evolves to leukemia in an aging microenvironment laying thefoundation for therapeutic strategies to block this evolution and prevent leukemia in the aging US population. Tothis end we will leverage our team's complementary expertise in intra-tumor heterogeneity and computationalepigenomics; aging cancer evolution and leukemogenesis; inflammation and hematopoietic stem cell (HSC)biology; and mouse HSC proliferation and functional heterogeneity. Our preliminary results in mice show thatHSPC epigenetic heterogeneity increases in old age. This process occurs in an aged bone marrow (BM)microenvironment characterized by inflammation and altered HSPC support. The rise of epigenetic andtranscriptomic heterogeneity in HSC with Tet2 mutation (Tet2MT) and Flt3ITD precedes leukemic transformation.We hypothesize that aging and TET2 mutation cooperatively enhance epigenetic heterogeneity and evolvabilityof HSPC thus contributing to clonal expansion and leukemogenesis. In Aim 1 we will determine the combinedimpact of aging and Tet2MT on epigenetic heterogeneity and gene regulation in HSPC by examining the somaticepigenomic landscape of Tet2MT HSPC from young (2-3 months) and old (22 months) mice including single-cell(sc) transcriptomes by scRNA-seq open-chromatin profiles by snATAC-seq and DNA methylomes by RRBS.We expect to define epigenetic configurations in old Tet2MT HSPC associated with genes in self-renewalquiescence and responses to inflammation and stress. In Aim 2 we will define epigenetic configurations ofTet2MT HSPC that are adaptive in the aged context. We will transplant genetically barcoded HSPC into young orold mice and assess subclone expansion/contraction to determine if an age-dependent selection is for all Tet2MTHSPC or only a subset. We will use scRNA-seq and snATAC-seq to define molecular signatures and epigeneticheterogeneity of barcoded HSPC that are positively selected in the aged context. In Aim 3 we will define theepigenetic configurations of Tet2MT HSPC that are permissive to Flt3ITD-induced transformation in the agedcontext. We will transduce the Flt3ITD gene into young or aged Tet2MT or wild-type HSC and then transplant thesegenetically barcoded cells into young or old host mice. We will assess the epigenetic profiles of the selectedHSPC by scRNA-seq and scATAC-seq of their identified progeny. We expect our findings will shift the paradigmfor how epigenetic plasticity promotes somatic evolution and leads to cancer initiation in aging individuals. 372507 +No NIH Category available Abdomen;Accelerometer;Adherence;Adult;Anthropometry;Asian;Behavior assessment;Behavioral;Biological;Biological Markers;Blood;Body Weight;Body Weight decreased;Body fat;Body mass index;Breast Cancer Risk Factor;Central obesity;Clinical;Cohort Studies;Conduct Clinical Trials;Consultations;DASH diet;Data;Diet;Diet Monitoring;Dietary Intervention;Dietary Practices;Dietary intake;Dietitian;Disparity;Dual-Energy X-Ray Absorptiometry;East Asian;Eating;Effectiveness;Ethnic Origin;Ethnic Population;Etiology;Expectancy;Fatty acid glycerol esters;Food;Frequencies;Future;General Population;Hawaii;Health;Heart;Hip region structure;IGFBP3 gene;Insulin;Insulin-Like Growth Factor I;Intervention;Interview;Intra-abdominal;Leptin;Liver;Longevity;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Measurement;Measures;Mediator;Mediterranean Diet;Metabolic;Metagenomics;Modification;Native Hawaiian or Other Pacific Islander;Obesity;Obesity associated cancer;Outcome;Pacific Islander;Participant;Phenotype;Physical activity;Play;Population;Population Heterogeneity;Problem Solving;Production;Protocols documentation;Psychological reinforcement;Questionnaires;Randomized;Recommendation;Reporting;Research;Risk;Risk Factors;Role;SHBG gene;Safety;Self Efficacy;Social support;Stimulus;Structure;Telephone;Testing;Time;Translational Research;Visceral;Visceral fat;Woman;Work;abdominal fat;actigraphy;active comparator;adiponectin;behavior prediction;blood-based biomarker;cancer risk;cohort;dietary restriction;dissemination research;ethnic difference;ethnic disparity;ethnic diversity;good diet;group intervention;gut microbiome;gut microbiota;healthy lifestyle;healthy weight;improved;lipid metabolism;malignant breast neoplasm;microbial;microbiome composition;middle age;multi-ethnic;new technology;non-alcoholic fatty liver disease;obesity risk;post intervention;psychosocial;racial difference;racial disparity;racial population;randomized trial;recruit;safety and feasibility;systemic inflammatory response Effects of Intermittent Energy Restriction on Intra-Abdominal Fat and the Gut Microbiome: A Randomized Trial PROJECT NARRATIVEIn past work we demonstrated striking ethnic/racial disparities regarding propensity to accumulate fat intra-abdominally and in the strength of the association between obesity and cancer risk among the five racial/ethnicgroups of the Multiethnic Cohort Study. We also demonstrated the feasibility of an intermittent energy restriction(IER) dietary intervention in a diverse population of Hawaii and the short-term effectiveness of IER in reducingintra-abdominal fat and modifying gut microbiome composition. We now propose an expanded 24-weekrandomized trial to compare IER to daily ER in reducing intra-abdominal fat and total body fat and in improvingcancer-related biomarkers and gut microbiome functions as well as to better understand behavioral predictorsof adherence to IER. NCI 10700063 9/1/23 0:00 RFA-CA-20-004 5R01CA258179-03 5 R01 CA 258179 3 "RISCUTA, GABRIELA" 9/22/21 0:00 8/31/26 0:00 ZCA1-SRB-E(M1)R 1898900 "LE MARCHAND, LOIC " "BOUSHEY, CAROL J" 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1110521 NCI 809903 300618 PROJECT SUMMARY/ABSTRACTIntermittent energy restriction (IER) has been suggested to have important advantages over daily ER (DER) inproducing sustained weight loss and reducing cancer risk. While IER is already being promoted in the generalpopulation to improve health and longevity supportive evidence is urgently needed from rigorously conductedrandomized trials. We propose a six-month randomized trial to demonstrate the superiority of IER over DER inreducing ectopic fat and total fat mass and in improving cancer-related biomarkers and gut microbiomefunctions. Our previous work strongly suggests that ectopic fat independently of total adiposity plays animportant role in the etiology of and in the racial/ethnic disparities in obesity-related cancers. We reportedstriking racial/ethnic differences in the strength of the association between body mass index (BMI) and risk ofobesity-related cancers in the Multiethnic Cohort (MEC). We observed corresponding disparities in thepropensity to accumulate visceral and liver fat among the same five ethnic groups in a recent MRI-based studyand demonstrated an independent association of a robust biomarker-based visceral fat score with incident breastcancer in MEC. Additionally we adapted an IER protocol combined with a Mediterranean dietary pattern(IER+MED) and demonstrated its feasibility safety and greater efficacy over an active comparator (a heart-healthy DER approach) in reducing total and ectopic adiposity and improving beneficial gut microbiome functionsin a 12-week randomized trial among 60 middle-aged adults of various Asian ethnicities with visceral obesity.We now propose the Healthy Diet and Lifestyle Study II a 24-week randomized trial of IER+MED vs. MED/DERamong 260 middle-aged Oahu adults of East-Asian Pacific Islander or white ethnicity with VAT greater than thepopulation median. The intervention will be delivered through 16 focused and customized consultations withresearch dietitians and will consist of an IER+MED (IER is 70% energy restriction on two consecutive days anda euenergetic MED diet for the other five days of the week) or the MED with a 20% daily energy restriction(MED/DER). Dietitians will monitor dietary compliance using the mobile food record (mFR) and compliance to acommon physical activity recommendation using interviews and actigraphy throughout the intervention. We willcompare IER+MED vs. MED/DER for reduction in MRI-measured visceral and liver fat and DXA-measured totaladiposity (Aim 1) and for improvement in cancer-related biomarkers (IGF-1 IGFBP3 insulin HOMA-IR leptinadiponectin S HBG hsCRP) and fecal metagenomic markers of microbial metabolite production (Aim 2). Wewill also investigate behavioral predictors of adherence to the prescribed IER including psychosocial measuresof self-efficacy and outcome expectancies and dietary patterns based on timing and frequency of eatingepisodes (Aim 3). This study will provide robust effectiveness data for IER on lowering cancer related risk factorsand inform future translational and dissemination research to reduce cancer risk in various US populations. 1110521 +No NIH Category available ADAR1;Affect;Animals;Antiviral Response;Autoimmune Diseases;Autoimmunity;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biological Process;Caenorhabditis elegans;Candidate Disease Gene;Cell Death;Cell Line;Cells;Chemicals;Communicable Diseases;Complement;Conflict (Psychology);Deamination;Detection;Disease;Double-Stranded RNA;Engineering;Enzymes;Epitopes;Evaluation;Evolution;Experimental Models;Family;Future;Genes;Genetic;Genome;Goals;Hand;Homologous Gene;Immune;Immune response;Immunity;Immunoprecipitation;Immunotherapy;In Vitro;Innate Immune Response;Interferons;Intervention;Invaded;Invertebrates;Knowledge;Logic;Malignant Neoplasms;Mammalian Cell;Mammals;Masks;Mediating;Medical;Molecular;Molecular Biology;Monitor;Mus;Orthologous Gene;Outcome;Pathway interactions;Pattern;Phosphoric Monoester Hydrolases;Phosphorylation;Phylogenetic Analysis;Population;Proteins;RNA;RNA Interference;RNA-Directed RNA Polymerase;Recording of previous events;Reporting;Role;Sampling;Scientist;Signal Transduction;Source;Specificity;Substrate Specificity;Testing;Vertebrates;Viral;Virus;Work;arm;checkpoint modulation;comparative;design;ds RNA-Binding Proteins;dsRNA adenosine deaminase;experimental study;immune function;innate immune checkpoint;innate immune pathways;innovation;insight;member;model organism;prevent;programs;response;sensor;theories;therapy outcome;tripolyphosphate;tumor;tumorigenesis;viral RNA Unlocking evolutionarily latent immune functions for treating disease Project NarrativeHarnessing immune pathways to attack a diseased state or immunotherapy is a proven and powerful way totreat disease such as cancer. Yet there are many natural checkpoints in place to prevent an aberrant immuneresponse. Proposed studies are designed to identify and modulate innate immune checkpoints to revealpreviously unsuspected ways to exploit innate immune pathways to treat disease. NCI 10700046 8/1/23 0:00 RFA-RM-19-007 5R01CA260414-04 5 R01 CA 260414 4 "KUO, LILLIAN S" 9/1/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-BCMB-A(51)] 1863234 "BASS, BRENDA L." "ELDE, NELS C.; JACKMAN, JANE ELIZABETH; STETSON, DANIEL B" 1 BIOCHEMISTRY 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 1165317 OD 972117 193200 Project Summary/AbstractAll animals possess a robust innate immune response that depends on their ability to recognize viral double-stranded RNA (dsRNA) as foreign. Yet animal cells also encode and express dsRNA and this cellular dsRNAmust be distinguished as self to prevent an aberrant immune response. Adenosine deaminases that act onRNA or ADARs deaminate dsRNA to mark it as self and prevent an aberrant immune response. In this capacityADARs serve as an Innate Immune Checkpoint (IIC) and recent studies reveal that a decrease in ADAR activityin tumors releases this IIC eliciting an immune response that leads to cell death. ADARs are the only IIC knownto date and proposed studies are designed to fill this gap in knowledge towards the goal of newimmunotherapies. Comparative phylogenetic analyses will be complemented with molecular biology andbiochemistry experiments to identify mitigators such as ADARs that prevent inappropriate deployment ofantiviral defense and ancient incompatibilities such as invertebrate proteins that may activate an antiviralresponse when introduced into vertebrates. Experiments in mammalian cells and mice and the invertebratemodel organism C. elegans will provide a wide phylogenetic sampling to identify test and compare new IICs.Engineered mice and cell lines are in hand and established assays are in place to monitor effects on the immunepathway of both animals. Known dsRNA binding proteins as well as those identified by immunoprecipitationstrategies will be prioritized by phylogenetic assays for testing as IICs. In vitro biochemistry experiments andstructural analyses will guide subsequent rounds of phylogenetic comparisons. Mammalian ADAR1 p150prevents an interferon response by modulating the MDA5 arm of the vertebrate innate immune pathway andIICs for the RIG-I arm have not been reported. Strategies to identify IICs for the RIG-I arm will focus on enzymesknown to modify the 5' terminus of RNA a known epitope for RIG-I recognition. The culmination of proposedstudies will be the evaluation of candidate IICs in experimental models of tumorigenesis. 1165317 +No NIH Category available Academic Medical Centers;Animals;Bioinformatics;Biological Assay;Biometry;Blood;Bone Marrow Transplantation;Cell Therapy;Cells;Cities;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Data Monitoring Committees;Clinical Trials Design;Collaborations;Computer Systems;Consult;Consultations;Data;Data Analyses;Data Collection;Data Storage and Retrieval;Development;Elderly;Ensure;Faculty;Funding;Grant;Health;Hospitals;Human Resources;Immunologic Monitoring;Institutional Review Boards;International;Intervention;Journals;Laboratories;Marrow;Massive Parallel Sequencing;Medical;Medical Research;Methods;Mission;Monitor;Multi-Institutional Clinical Trial;Multicenter Trials;NCI Center for Cancer Research;Patients;Phase;Physicians;Policies;Preparation;Procedures;Production;Program Research Project Grants;Publications;Randomized;Reporting;Research;Research Activity;Research Assistant;Research Personnel;Schedule;Scientist;Services;Shapes;Statistical Data Interpretation;Systems Development;T cell receptor repertoire sequencing;Technology;Thinking;Training;Translational Research;Transplantation;Universities;Work;bench-to-bedside translation;data access;data integrity;data management;design;experience;hematopoietic cell transplantation;improved;leukemia/lymphoma;meetings;member;method development;next generation;pre-clinical;preclinical study;programs;protocol development;sound;transplant database;treatment planning;trial planning Core B: Biostatistics and Data Management Core Core B (Biostatistics and Data Management Core): Project Narrative Core B supports the clinical and pre-clinical projects and Core C in the proposal by leveraging the depth of expertise in analytics at Stanford University to assist project investigators in all aspects of their studies. Core B has been successfully carrying out this mission for >25 years and has helped the PPG investigators shape the field of Hematopoietic Cell Transplantation. NCI 10700022 9/8/23 0:00 PAR-18-290 5P01CA049605-33 5 P01 CA 49605 33 5/1/97 0:00 8/31/24 0:00 ZCA1-RTRB-R 8184 6404175 "LU, YING " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 291778 183100 108678 Core B (Biostatistics and Data Management Core): Project Summary/Abstract Core B which has supported the PPG for >25 years consists of a Core Leader (Lavori) a Core Physician leader (Lowsky) two Biostatisticians (Narasimhan and Tamaresis) and a Clinical Research Coordinator (Elder) who (in addition to her PPG work) supervises six Clinical Research Assistants who are supported by Stanford University Medical Center and other grants which provide services as needed to support the PPG aims. The leader of Core B and the two biostatisticians have decades of experience in medical research and in particular clinical trial design and data management work (organization planning management monitoring and analysis) in collaboration with medical investigators including many years of collective experience working with the BMT investigators. The Core B physician leader Dr. Lowsky has extensive experience in the development conduct data collection and analysis study completion and monitoring of single center and multi-center clinical trials. The Core supports the clinical and preclinical projects and Core C in the proposal by leveraging the depth of expertise in analytics at Stanford University to assist project investigators in all aspects of their studies. Core B meets weekly to review and plan work often joined by other key PPG personnel. The Core staff meet on a monthly basis with all clinical research assistants the program project PI and the other clinical investigators to resolve difficulties and problems for example in data collection data flow definitions forms design and protocol development. Frequent ad hoc meetings between investigators and Core B members are scheduled as needed. Each of the 5 new projects in the program project (on the basis of past experience and preparation of plans for the coming years to be supported through this program) will use about the same fraction of Core B effort (15% each) and the remainder is split between Core C (25%). The Core has 5 specific aims: 1) provide biostatistics consultation to the PPG project investigators for animal studies and clinical trials 2) develop analytics for the TCR sequencing and immune monitoring assays generated by the massively parallel sequencing technologies deployed by Core C 3) maintain the integrity of the data generated by the projects 4) analyze data for scientific reports and annual IND and DSMC submissions and 5) maintain the extensive BMT database. Core B is committed to active and continued participation in the PPG to help ensure that project Aims are fulfilled in the most scientifically meaningful manner. +No NIH Category available Address;Adoptive Transfer;Allogenic;Antigen Targeting;Antigens;Autologous;Autologous Stem Cell Transplantation;B lymphoid malignancy;B-Cell Acute Lymphoblastic Leukemia;Bar Codes;Biological;Blood Component Removal;Bone Marrow Transplantation;CAR T cell therapy;CD19 Antigens;CD19 gene;CD22 gene;Cancer Personalized Profiling by Deep Sequencing;Cell Therapy;Cell surface;Cells;Clinic;Clinical;Clonal Evolution;Consolidation Therapy;Data;Disease;Disease remission;Dose;Engineering;Epitopes;Failure;Generations;Goals;Graft-Versus-Tumor Induction;Immune;Immunotherapy;Impairment;In complete remission;Infusion procedures;Laboratories;Lymphoma;Maintenance;Malignant Neoplasms;Maps;Measures;Mediating;Modality;Monitor;Mutation;Outcome;Patients;Program Research Project Grants;Recurrence;Refractory;Relapse;Reproducibility;Research;Residual Neoplasm;Resistance;Role;Seminal;Specificity;Stem cell transplant;Stratification;T cell receptor repertoire sequencing;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Time;Translating;Transplantation Conditioning;Tumor Escape;Tumor Immunity;Variant;Work;alpha-beta T-Cell Receptor;anti-cancer;anti-tumor immune response;antitumor effect;burden of illness;cancer therapy;cell free DNA;cell mediated immune response;chimeric antigen receptor;chimeric antigen receptor T cells;design;disorder control;efficacy testing;exhaustion;experience;genetic signature;genetically modified cells;graft vs leukemia effect;high dimensionality;improved;large cell Diffuse non-Hodgkin's lymphoma;leukemia/lymphoma;novel;novel marker;outcome prediction;patient subsets;predict clinical outcome;predictive marker;prognostic;regenerative;relapse risk;resistance mechanism;response;stem cells;success;transcriptome sequencing;tumor;tumor DNA Project 4: Enhancing the Efficacy of Chimeric Antigen Receptor Therapy for B-ALL and DLBCL Project 4: Project NarrativeResponse rates following CD19-CAR for DLBCL plateau at approximately 50% across numerous studies andmost patients with DLBCL and B-ALL who experience a complete response following CD19-CAR therapyultimately relapse. This project seeks to enhance the efficacy of CAR therapeutics for B cell malignancies byaddressing the competing problems of limiting antigen expression and limiting CAR T cell expansion/persistence.We will also test whether monitoring circulating tumor DNA post-CAR therapy in DLBCL can provide prognosticinformation as a first step toward determining which patients will require post-CAR consolidation. NCI 10700010 9/8/23 0:00 PAR-18-290 5P01CA049605-33 5 P01 CA 49605 33 5/1/97 0:00 8/31/24 0:00 ZCA1-RTRB-R 8176 14354500 "MACKALL, CRYSTAL " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 316522 198628 117894 Project 4: Project Summary/AbstractBone marrow transplantation provided the first irrefutable evidence that cell therapy can mediate potent andlong-lasting anti-cancer effects. Based upon these seminal observations the field has worked diligently tounderstand and enhance cell mediated graft-versus-tumor (GVT) effects in the context of allogeneic andautologous stem cell transplantation. Despite these efforts clinical benefit from GVT in B cell malignanciesremains largely limited to patients with low burden disease who undergo dose intensive transplant conditioningfollowing by infusion of autologous or allogeneic stem cell rescue. Since the first observation in 2011 it hasbecome increasingly clear that T cells genetically engineered to express chimeric antigen receptors (CARs) canmediate potent and durable effects against B cell malignancies establishing cell therapy for cancer as a viabletherapeutic modality even for patients with chemorefractory high burden disease. Thus emergence of CAR-Tcell therapies is a natural extension of the efforts to harness cell based anti-tumor immunity that has longdominated research in the context of stem cell transplantation. Very simply this Project seeks to improve short-and long-term benefit of CAR based therapies for B cell malignancies. Experience in B-ALL has identified twomajor mechanisms of CAR resistance which appear to be largely mutually exclusive: tumor escape due to lossor diminished expression of the targeted antigen (which typically occurs in the presence of persistent CAR-Tcells) and T cell failure (which typically occurs with continued expression of the targeted antigen). Aim 1 will testthe hypothesis that antigen level is an important factor impacting response and relapse following CD19-CAR andCD22-CAR for DLBCL and will test the efficacy of the first bispecific CAR to enter the clinic with the goal ofdiminishing the risk of relapse due to antigen neg/lo variants in both B-ALL and DLBCL. Aim 2 tests thehypothesis that T cell exhaustion is the major cause of relapse associated with T cell failure. We will seek toidentify predictive biomarkers that can distinguish patients whose CAR T cells are predisposed to exhaustionand undertake state-of-the-art single cell TCR/RNA sequencing to fate map persistent CAR T cells as a firststep toward a long-term goal of engineering grafts for exhaustion resistance. Aim 3 begins to address a majorpractical challenge facing clinicians treating patients with CD19-CAR T cells for DLBCL namely which patientsshould undergo post-CAR consolidation with autologous or allogeneic HSCT?. Building upon previoussuccesses in this Program Project Grant in demonstrating the utility of circulating tumor DNA (ctDNA) inpredicting clinical outcomes for B cell malignancies we will test whether ctDNA can predict outcomes followingCD19-CAR therapy for DLBCL as a first step toward personalized stratification of post-CAR consolidationtherapy. +No NIH Category available Acute Graft Versus Host Disease;Acute Myelocytic Leukemia;Acute leukemia;Antibodies;Antigens;Antithymoglobulin;B-Cell Antigen Receptor;B-Cell Lymphomas;B-Cell Neoplasm;Bone Marrow Transplantation;CD34 gene;CD8B1 gene;Cell Therapy;Cells;Chimera organism;Chimerism;Clinical;Clinical Protocols;Clinical Research;Clone Cells;Cytomegalovirus;DNA Sequence;Disease-Free Survival;Donor Lymphocyte Infusion;Dose;Dysmyelopoietic Syndromes;FBXL2 gene;Graft-Versus-Tumor Induction;Histocompatibility;Human;Human Herpesvirus 4;Immunization;Immunize;Immunoglobulin Idiotypes;Immunotherapy;Incidence;Infection;Infusion procedures;Laboratories;Lymphoma;Mediating;Memory;Minor;Monitor;Mus;Myeloid Leukemia;Myeloproliferative disease;Patients;Peptides;Phenotype;Population;Protocols documentation;Recurrent disease;Regimen;Relapse;Residual Neoplasm;Risk;Risk Reduction;Secondary Immunization;Sorting;Staging;T cell therapy;T memory cell;T-Cell Depletion;T-Cell Receptor Genes;T-Lymphocyte;Technology;Testing;Transplant Recipients;Transplantation;Tumor Antigens;Tumor Expansion;Tumor Immunity;Vaccinated;Vaccination;Viral;allotransplant;arm;cell type;complementarity-determining region 3;conditioning;design;graft vs host disease;hematopoietic cell transplantation;immune reconstitution;improved;innovation;leukemia;leukemia/lymphoma;lymphoid irradiation;migration;mortality;mouse model;neoplastic cell;overexpression;post-transplant;pre-clinical;preclinical study;prevent;primary endpoint;standard of care;thymocyte;transcriptome sequencing;tumor Project 3: Tumor Antigen Reactive Donor T Cell Immunotherapy Project 3: Project NarrativeWe have developed strategies to reduce GVHD by use of the TLI and ATG conditioning regimen and the use ofCD8+ memory T cells for DLI treatment of HCT recipients. This approach will be combined with immunization ofdonors and recipients against tumor antigens to increase GVT activity without increasing GVHD. NCI 10700007 9/8/23 0:00 PAR-18-290 5P01CA049605-33 5 P01 CA 49605 33 5/1/97 0:00 8/31/24 0:00 ZCA1-RTRB-R 8175 8718040 "LOWSKY, ROBERT " Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 334901 210161 124740 Project 3: Project Summary/AbstractThe object of the proposed studies is to determine whether tumor antigen vaccination of donors of MHC matchedhematopoietic cell transplants (HCT) can increase graft-versus-tumor (GVT) activity without increasing graft-versus-host disease (GVHD) in both pre-clinical and clinical studies. In the case of B cell lymphomas we willuse vaccination with idiotype peptides derived from the B-cell receptor (BCR) CDR3 region to immunize againstthe tumors. In the case of myeloid leukemia we will use vaccination with the WT-1 peptide that is anoverexpressed leukemia tumor antigen. Mouse and human recipients with B cell lymphoma will be conditionedwith total lymphoid irradiation and anti-thymocyte antibodies (an acute GVHD protective regimen) and mixedchimeras will receive phenotypic CD8+ memory T (TM) cell donor lymphocyte infusions (DLI) that mediate GVTwithout GVHD from idiotype immunized donors. Sorted CD8+ TM cells express the CD8+CD44hi phenotype inmice and CD8+CD45R0+CD45RA- phenotype in humans. It is also expected that the DLI will induce conversionfrom mixed to complete chimerism and that the tumor antigen immunized TM cell DLI will mediate potent GVTactivity as compared to the nonimmunized TM cell DLI. Booster vaccinations of recipients is expected to increaseanti-tumor activity even further. GVHD will be minimized in myeloid leukemia transplant recipients givenmyeloablative conditioning by using T cell depleted (TCD) CD34+ selected grafts combined with donor CD8+ TMcells. The infusion of the latter cells is expected to improve immune reconstitution and GVT activity as comparedto TCD CD34+ selected grafts alone. In summary we will use strategies developed in our laboratory to preventGVHD and tumor antigen immunization to increase GVT activity such that overall and event-free survival isincreased in the proposed preclinical and clinical studies. +No NIH Category available 19q;3-Dimensional;Adoption;Adult;Anatomy;Automation;Back;Biological Markers;Body part;Brain Neoplasms;Calibration;Choline;Chromosomal Loss;Clinical;Clinical Research;Communities;Computer software;Cystathionine;Data;Data Analyses;Data Set;Exhibits;Glioma;Isocitrate Dehydrogenase;Judgment;Lesion;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Malignant neoplasm of brain;Measurement;Measures;Metabolic;Methods;Molecular;Monitor;Morphologic artifacts;Multi-Institutional Clinical Trial;Mutation;Normal tissue morphology;Pathologic;Patient Care;Patients;Performance;Phenotype;Phospholipid Metabolism;Physiologic pulse;Positioning Attribute;Procedures;Research;Research Personnel;Research Project Grants;Scanning;Site;Source;Spectrum Analysis;System;Technical Expertise;Techniques;Time;Training;Vendor;Water;anticancer research;arm;automated analysis;body system;cancer therapy;clinical practice;clinical research site;data acquisition;deep neural network;heuristics;image guided;improved;informatics tool;interest;novel;open source;open source tool;prevent;skills;tool;translational barrier;transmission process;treatment response;tumor;tumor progression Developing informatics tools for optimized MRS for brain cancer research PROJECT NARRATIVEMagnetic resonance spectroscopy (MRS) can provide metabolic information noninvasively for assessment oftumor type and treatment response in any body part. The clinical impact of MRS has been limited by thetechnical expertise required to make these measurements. This research project will develop and evaluateautomated tools to make MRS measurements easier and more robust for both research and clinical uses. NCI 10700005 9/8/23 0:00 RFA-CA-21-014 5U01CA269110-02 5 U01 CA 269110 2 "KIM, BOKLYE" 9/7/22 0:00 8/31/25 0:00 ZCA1-SRB-X(J1)R 8547821 "MARJANSKA, MALGORZATA " Not Applicable 5 RADIATION-DIAGNOSTIC/ONCOLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 377601 NCI 243614 133987 PROJECT SUMMARY/ABSTRACTThis project proposes to develop methods for automated real-time single-voxel magnetic resonancespectroscopy (MRS) in brain tumors integrate these methods with a clinical MRI system evaluate theirperformance and distribute them as open-source tools to the research community. MRS can provide metabolicinformation noninvasively for assessment of tumor phenotype and therapeutic response. Single-voxel MRSmethods provide the best quality and most reliable data but require the scanner operator to have a high skilllevel and expertise to produce good quality results. The need for this expert involvement in both acquisitionand processing remains a critical barrier to the translation of MRS methods to clinical research sites withoutspectroscopy experts and to clinical practice. The first part of this project is to develop a method for 3D voxelplacement using image guidance integrate this method with a clinical MR system and evaluate itsperformance. In the second part we will automate our advanced MRS methods. In the third part we will createreal-time automatic quantification tool specific to the obtained MRS data that will provide clinically interpretableresults. We identified collaborators the brain cancer researchers and clinicians who will be early adopters andbeta-testers of our tools. Successful completion of this project will improve data robustness and qualityeliminating the need for the expert interaction at the time of the scan and enabling adoption of MRS in multi-site clinical trials and clinical practice. 377601 +No NIH Category available Acceleration;Address;Adult;Antineoplastic Agents;Bioinformatics;Biological Models;Cancer Model;Cancer Patient;Child;Childhood;Clinical;Clinical Trials;Collaborations;Communication;Communities;Complement;Data;Data Analyses;Data Security;Database Management Systems;Databases;Decision Making;Development;Engineering;Ensure;Equity;FDA approved;Foundations;Generations;Genomics;Goals;Institution;International;Laboratories;Leadership;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Molecular Target;New Agents;Online Systems;Pediatric Oncology;Performance;Pharmacologic Substance;Pharmacology;Preclinical Testing;Process;Productivity;Program Evaluation;Property;Protocols documentation;Publications;Recording of previous events;Research;Research Personnel;Resource Development;Resource Informatics;Resources;Secure;Site;Standardization;Statutes and Laws;System;Systems Analysis;Testing;The Jackson Laboratory;Therapeutic Agents;Time;Vision;cancer genomics;cancer therapy;cloud based;data integrity;data management;data portal;data sharing;efficacy evaluation;experience;genomics cloud;human cancer mouse model;improved outcome;in vivo;in vivo Model;in vivo evaluation;member;metadata standards;model development;new therapeutic target;novel therapeutics;patient derived xenograft model;pediatric patients;precision medicine;preclinical study;programs;public-private partnership;software systems;success;targeted cancer therapy;targeted treatment;technical report;user-friendly;web page Pediatric Oncology In Vivo Testing Program Coordinating Center PROJECT NARRATIVEPediatric oncology lags behind adult cancers with respect to the availability of targeted therapies. Expandingand accelerating treatment options for pediatric cancers to improve outcomes and to satisfy the requirementsof the Research to Accelerate Cures and Equity (RACE) for Children Act is a central goal for NCI's Pediatric InVivo Testing Program (Ped-In Vivo-TP). We will establish the Pediatric In Vivo Testing Coordinating Center(PIVOT CC) to manage a comprehensive and cohesive testing program to advance precision medicine inpediatric oncology through effective public-private partnerships among pharmaceutical companies regulatoryagencies funders and research organizations. NCI 10700004 6/13/23 0:00 RFA-CA-20-041 5U24CA263963-03 5 U24 CA 263963 3 "SMITH, MALCOLM M" 8/25/21 0:00 6/30/26 0:00 ZCA1-GRB-I(M1) 6093730 "BULT, CAROL J" "CHUANG, JEFFREY HSU-MIN" 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Other Research-Related 2023 847161 NCI 498330 348831 PROJECT SUMMARYThe overarching goal of NCI's Pediatric In Vivo Testing Program (Ped-In Vivo-TP) is to improve outcomes ofpediatric cancer patients and to satisfy the requirements of the Research to Accelerate Cures and Equity(RACE) for Children Act to assess the efficacy of targeted anti-cancer agents developed for adults in pediatriccontexts. To coordinate the activities of the new Ped-In Vivo-TP initiative we have assembled a team ofinvestigators from The Jackson Laboratory (JAX) and Seven Bridges Genomics (SB) with unique combinedexpertise and experience with in vivo cancer models scalable cloud-based data management and analysissystems informatics resource development and multi-site project coordination. Combining the complementarystrengths of JAX and SB provides the ideal foundation for a coordinating center to maximize the short- andlong-term impacts of the Pediatric In Vivo Testing Program for advancing the application of precision medicinein pediatric oncology. We will manage a comprehensive and cohesive testing program to advance precisionmedicine in pediatric oncology through effective public-private partnerships among pharmaceutical companiesregulatory agencies funders and research organizations. We will achieve this goal through the following aims:Aim 1: Establish and maintain the Pediatric In Vivo Testing Coordinating Center (PIVOT CC) to provideadministrative and logistical support for diverse stakeholders in the Pediatric in Vivo Testing Programconsortium. We will draw on our team's combined decades of experience with multi-site programmanagement cancer model development standardized testing of in vivo cancer models data managementand analysis and informatics resource development to ensure timely decision making conformance tostandard protocols resource tracking and effective communications within the Ped-In Vivo-TP. Aim 2:Provide data management statistical and bioinformatics support to ensure data security and integrity.We will leverage existing protocols and software systems at JAX and SB to identify relevant in vivo cancermodels and to collect analyze and securely manage data generated from testing centers within theconsortium. We will perform statistical and bioinformatic analyses on consortium data to reliably inform theevaluation of the efficacy of novel therapeutic agents in a pediatric oncology setting. We will develop a public-facing data portal for sharing of data and methods with the broader scientific community. Aim 3: Providescientific coordination to maintain an efficient and effective preclinical testing pipeline. We will drawfrom the extensive experience of our team with in vivo pharmacology and coordination of similar consortia tomanage and coordinate the testing of agents by the Ped-In Vivo-TP centers at all stages of the process fromthe identification of relevant in vivo models to the generation of final technical reports and publication of results.We will develop record and track performance metrics for the consortium to inform the evaluation of theprogram's success and impact. 847161 +No NIH Category available Academic Medical Centers;Biological;Biological Markers;Biostatistical Methods;Body mass index;Branched-Chain Amino Acids;C-Peptide;C-reactive protein;Cancer Etiology;Cessation of life;Characteristics;Chronic Disease;Clinical;Clinical Nutrition;Colorectal Cancer;Consumption;Coupled;Dana-Farber Cancer Institute;Data;Development;Diet;Dietary Factors;Dietary Intervention;Dietary Practices;Dimensions;Doctor of Philosophy;Elasticity;Environment;Epidemiologic Methods;Epidemiologist;Epidemiology;FRAP1 gene;Follow-Up Studies;Food;Frequencies;General Hospitals;Genetic;Goals;Health;Health Professional;Health Sciences;Human;Incidence;Inflammation;Inflammatory;Insulin Resistance;Interleukin-6;Intervention;Knowledge;Link;Malignant Neoplasms;Massachusetts;Mediating;Mediation;Mediator;Medicine;Mentors;Mentorship;Metabolic;Metabolic Pathway;Methods;Modeling;Nurses' Health Study;Obesity;Oncologist;Oxidative Stress;Pathogenesis;Pathway interactions;Pattern;Physical activity;Physicians;Plasma;Population Sciences;Principal Component Analysis;Processed Meats;Proliferating;Prospective Studies;Public Health Schools;Questionnaires;Receptors Tumor Necrosis Factor Type II;Research;Research Personnel;Risk Factors;Role;Sampling;Signal Pathway;Statistical Methods;Students;TNF gene;TNFRSF1B gene;Testing;Training;Tumor Necrosis Factor Receptor;Tumor Promoters;Unhealthy Diet;Variant;Woman;adipokines;adiponectin;cancer epidemiology;career;clinical epidemiology;clinical training;cohort;colorectal cancer prevention;colorectal cancer risk;data integration;design;dietary;early onset colorectal cancer;energy balance;experience;gastrointestinal;high body mass index;lifestyle factors;lifestyle intervention;medical schools;meetings;member;men;metabolomics;mid-career faculty;modifiable risk;mortality;neoplastic;novel;novel marker;novel strategies;nutrition;physical inactivity;population health;pre-doctoral;professor;programs;risk prediction;screening;symposium;tumor;waist circumference Metabolomic signatures of inflammation and metabolic health in relation to colorectal cancer risk Project NarrativeDespite advances in screening and identification of modifiable risk factors the incidence and mortality ofcolorectal cancer (CRC) remains high as does the incidence of obesity which is a well-established risk factorfor CRC. Lack of understanding of the biological pathways linking obesity and associated risk factors to CRC isa major limiting factor in the development of new strategies for CRC prevention. If successful our project willidentify novel pathways for CRC prevention and will establish methods for integrating metabolomic and otherbiomarker data and dimension-reduction approaches to identify pathways underlying risk factors for cancerand other chronic diseases. NCI 10699979 8/15/23 0:00 PA-21-049 5F30CA265012-02 5 F30 CA 265012 2 "PURI, ANU" 9/30/22 0:00 9/29/26 0:00 Special Emphasis Panel[ZRG1-F18-A(20)L] 16315030 "BEVER, ALAINA " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/30/23 0:00 9/29/24 0:00 398 "Training, Individual" 2023 39877 NCI 39877 0 Project Summary/AbstractColorectal cancer (CRC) is the third most common cancer in both men and women. The role of inflammationand metabolic disturbance in the pathogenesis of CRC is well-established. However the biologicalmechanisms underlying these pathways and how they may mediate the diet-CRC link are poorly understood.In this application we propose to derive metabolomic signatures that characterize inflammation and metabolichealth in three large cohorts: the Nurses Health Study I and II and Health Professionals Follow-up Study. Wewill use reduced rank regression a novel statistical method that combines the data-driven approach ofprincipal components analysis with prior knowledge of intermediate factors to identify patterns of metabolitesdescribing maximal variation in biomarkers and lifestyle factors that characterize 1) inflammation (TNF receptorsuperfamily member 1B interleukin 6 C-reactive protein and adiponectin) and 2) metabolic health (body massindex waist circumference C-peptide physical activity and adiponectin). We will then use elastic netregression to select the most important metabolites contributing to the two factors derived using reduced rankregression and test the association between these metabolomic signatures and CRC risk independently andas a mediator of processed meat consumption. The goal of this project is to elucidate the biologicalmechanisms relating inflammation and metabolic health to CRC and in the long-term to generate strategies tooptimize dietary and lifestyle interventions for CRC prevention. Ms. Bever (PI) will conduct this research underthe mentorship of Dr. Meir Stampfer Professor of Epidemiology and Nutrition at Harvard T.H. Chan School ofPublic Health (HSPH); Dr. Mingyang Song Assistant Professor of Clinical Epidemiology and Nutrition atHSPH; Dr. Jeffrey Meyerhardt a practicing gastrointestinal oncologist and researcher at the Dana-FarberCancer Institute and Professor of Medicine at Harvard Medical School (HMS); Dr. Liming Liang AssociateProfessor of Statistical Genetics at HSPH; Dr. Edward Giovannucci Professor of Epidemiology and Nutrition atHSPH; Dr. Andrew Chan a practicing gastrointestinal oncologist and Director of Cancer Epidemiology atMassachusetts General Hospital; and Dr. Wei Zheng Professor of Medicine and Associate Director forPopulation Sciences Research at Vanderbilt University Medical Center. Ms. Bever is a rising fourth-yearstudent in the Harvard/MIT MD-PhD Program about to begin her second year of the Population HealthSciences PhD program at HSPH. Her training plan includes coursework in advanced biostatistics andepidemiologic methods local seminars and national conferences and weekly meetings with mentors. Thetraining plan has been designed to support Ms. Bevers long-term goal of becoming a physician-epidemiologistwith expertise in risk factors for cancer. The plan includes integration of clinical activities during Ms. Beverspre-doctoral training and continued opportunities for research during her last two years of medical school. 39877 +No NIH Category available Accounting;African American population;Asian population;Bayesian Modeling;Biological Factors;Boston;Cancer Patient;Cations;Caucasians;Cause of Death;Censuses;Cessation of life;Clinical;Compensation;Complex;Computer software;Country;DNA;DNA Sequence Alteration;Dana-Farber Cancer Institute;Data Set;Databases;Detection;Diagnosis;Disparity;Equilibrium;Equity;Ethnic Origin;Fostering;General Hospitals;Genetic;Goals;Health;Health Disparities Research;Inequity;International;Knowledge;Leukocytes;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Massachusetts;Mayo Clinic Cancer Center;Methods;Mutation;Observational Study;Oncogenic;Outcome;Pathology;Patients;Population;Population Characteristics;Procedures;Process;Property;Race;Research;Research Design;Research Personnel;Sample Size;Serum;Smoking;Stage at Diagnosis;Structural Racism;Target Populations;Tumor Tissue;Uncertainty;United States National Institutes of Health;Weight;cancer health disparity;cancer survival;cohort;data structure;density;design;dietary;ethnic disparity;flexibility;health care availability;high dimensionality;improved;innovation;interest;minority patient;multiple omics;mutational status;novel;open source;racial disparity;racial minority;racial minority population;racial population;screening;social;social determinants;social disparities Detecting racial disparities in cancer survival by integrating multiple high-dimensional observational studies PROJECT NARRATIVELeveraging the Boston Lung Cancer Survival Cohort (BLCSC) one of the largest lung cancercohorts globally we develop methods with a common goal of effectively identifying racialdisparities in cancer outcomes by integrating high dimensional observational studies with multipleracial groups. Our methods facilitate integrative unconfounded detection of racial disparities incancer outcomes and generalization to a realistic and inclusive larger population. NCI 10699968 8/16/23 0:00 PA-20-185 5R01CA269398-02 5 R01 CA 269398 2 "HOWLADER, NADIA" 9/7/22 0:00 8/31/26 0:00 Biostatistical Methods and Research Design Study Section[BMRD] 6880153 "LI, YI " "GUHA, SUBHARUP " 6 BIOSTATISTICS & OTHER MATH SCI 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF PUBLIC HEALTH 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 325483 NCI 276105 49378 PROJECT SUMMARY/ABSTRACTDespite overall improvements ethnic or racial disparities continue to increase suggestingdeficiencies in research designs for understanding disparities. For example compared to the2017 US Census most observational cancer studies were found to over represent Caucasiansand underrepresent African Americans and Asians. How to utilize these studies to detect andunderstand racial disparities remains challenging.This proposal is motivated by the Boston Lung Cancer Survival Cohort (BLCSC) one of thelargest lung cancer cohorts globally which consists of lung cancer cases registered since 1992at the Dana-Farber Cancer Institute (DFCI) and the Massachusetts General Hospital (MGH) andhas expanded to the MD Anderson Cancer Center (MDACC) and Mayo Clinic. This rich databaseprovides a unique opportunity for studying racial disparities in cancer outcomes as well aspresents a challenge with unbalanced covariates across racial groups. We also have access tothe International Lung and Cancer Consortium (ILCCO) an international cohort established in2004 with a data structure similar to BLCSC.Leveraging these cancer cohorts we develop methods with a common goal of effectivelyidentifying racial disparities in cancer outcomes by integrating high dimensional observationalstudies with multiple racial groups. Rich datasets like BLCSC and ILLCO are ideal for integrativeunconfounded detection of racial disparities in cancer outcomes and for generating statisticalfindings generalizable to a realistic and inclusive larger population. 325483 +Bioengineering; Cancer; Cervical Cancer; Nanotechnology; Women's Health Cancer Etiology;Case Report Form;Cervix Neoplasms;Cessation of life;Clinical;Clinical Trials;Collaborations;Contracts;Country;Goals;Health Personnel;Healthcare;High Prevalence;Infrastructure;Institutional Review Boards;Letters;Logistics;Malignant neoplasm of cervix uteri;Pharmaceutical Preparations;Phase;Phase I/II Clinical Trial;Preparation;Prevention;Qualifying;Resource-limited setting;Resources;Site;Technology;Woman;analytical method;cancer therapy;cost effective treatment;design;effective therapy;electronic data capture system;interest;low and middle-income countries;nanoengineering;nanoparticle;novel therapeutics;success TOPIC TITLE: CANCER TREATMENT TECHNOLOGIES FOR LOW-RESOURCE SETTINGSPROJECT TITLE: PRV311: A STANDALONE SAFE EFFECTIVE AND AFFORDABLE TREATMENT FO n/a NCI 10699948 75N91022C00020-0-9999-1 N44 9/15/22 0:00 9/14/24 0:00 78846484 "GOLDBERG, MANIJEH " Not Applicable 6 Unavailable 963247924 E6ACGUBJMQC5 963247924 E6ACGUBJMQC5 US 42.368029 -71.091377 10027190 "PRIVO TECHNOLOGIES, LLC" PEABODY MA Domestic For-Profits 19603840 UNITED STATES N R and D Contracts 2022 2049944 NCI Cervical cancer (CC) has a high prevalence in low- and middle-income countries (LMICs) and remains the leading cause of cancer deaths among women despite the remarkable improvements in prevention seen in wealthier countries. Privo Technologies intends to bridge this healthcare gap with PRV311 a nanoengineered standalone and cost-effective treatment for localized delivery of chemo-loaded nanoparticles to cervical tumors. PRV311 does not require special infrastructure or expert clinicians making it viable in low resource area lacking said specialization. The goal of this project is to complete clinical trial preparation activities in order to validate the PRV311 technology in an LMIC clinical setting. This will require developing and qualifying analytical methods GMP manufacturing for clinical trial manufacturing optimization for LMICs design of electronic data capture systems and case report forms and other tasks. Given the success of the Phase I-like activities Privo predicts that PRV311 will be clinically validated as an effective treatment for CC. This contract will support preparation for a Phase 1/2 clinical trial which will subsequently support a pivotal Phase 3 and new drug application for PRV311. 2049944 +Bioengineering; Cancer; Genetics; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD); Patient Safety Apoptosis;Cause of Death;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical Treatment;Computing Methodologies;Development;Drug Targeting;Drug resistance;Genes;Genetic Variation;Growth;Health;Heart Diseases;Interview;Machine Learning;Malignant Neoplasms;Modeling;Molecular;Oncologist;Pathway interactions;Patients;Proteins;Research;Severities;Software Design;Systems Biology;Variant;Work;acquired drug resistance;base;cancer drug resistance;clinical decision-making;experience;genetic variant;hands-on learning;molecular dynamics;network models;prototype;shift work;simulation;software development;tumor TOPIC 438 - PREDICTION OF CANCER DRUG RESISTANCE TO AID IN CLINICAL DECISION MAKING n/a NCI 10699945 75N91022C00025-0-9999-1 N43 9/1/22 0:00 78846872 "ANDRABI, SUMAIRA " Not Applicable 8 Unavailable 6989629 MHRXDJYJAPU9 6989629 MHRXDJYJAPU9 US 10067020 PATHODYNAMICS LLC POTOMAC MD Domestic For-Profits 208541024 UNITED STATES N R and D Contracts 2022 399999 NCI Cancer is the second leading cause of death behind heart disease with ~600000 deaths annually according to the CDC. Approximately 90% of cancer deaths are attributed to drug resistance making it a major health problem. Both intrinsic and acquired drug resistance in cancers have been attributed to the presence of genetic variant in the genes involved in growth or apoptosis. However many of the variants found in patients tumor are of unknown significance. The proposed research develops a computational method that leverages machine learning applied to molecular dynamics simulations of wild-type and variant proteins that are drug targets to predict drug resistance and its severity. This quantitative information will be incorporated into protein network models describing cancer growth and apoptosis to predict how off-target variants can cause drug resistance through pathway interactions. This proposal brings together a collaborating team of experts in molecular simulation machine learning pathway modeling software design and development and systems biology accomplishing this paradigm shifting work. At the conclusion of the proposed work a prototype will be developed that can help oncologists and their team to understand and deliver information to patients about possible drug resistance in the patients tumor and to make clinical treatment decisions. 399999 +No NIH Category available Address;Adjuvant;Aftercare;Aminolevulinic Acid;Animals;Apoptosis;Area;Brain;Brain Neoplasms;Cell Death;Cells;Cessation of life;Clinical;Clinical Data;Clinical Trials;Combined Modality Therapy;Common Terminology Criteria for Adverse Events;Conduct Clinical Trials;Data;Devices;Diagnosis;Disease;Dose;Dose Limiting;Enrollment;Excision;Family;Focused Ultrasound;Future;Glioblastoma;Glioma;Grant;Human;Incidence;Infiltration;Intravenous;Laboratories;Left;Magnetic Resonance Imaging;Malignant Neoplasms;Maximum Tolerated Dose;Microscopic;Modeling;Nature;Necrosis Induction;Operative Surgical Procedures;PUVA Photochemotherapy;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase;Phase 0/1 Clinical Trial;Phase II Clinical Trials;Process;Prognosis;Radiation therapy;Reactive Oxygen Species;Recommendation;Recurrence;Recurrent tumor;Reporting;Safety;Schedule;Singlet Oxygen;Site;Small Business Innovation Research Grant;Surgically-Created Resection Cavity;Survival Rate;Temperature;Therapy Clinical Trials;Toxic effect;Translating;Translations;Treatment Protocols;Treatment-related toxicity;Ultrasonic Therapy;cellular targeting;clinical center;cohort;design;effective therapy;efficacy evaluation;first-in-human;improved;improved outcome;meetings;neoplastic cell;neuro-oncology;objective response rate;phase II trial;pre-Investigational New Drug meeting;preclinical study;protoporphyrin IX;radiological imaging;response;side effect;standard of care;temozolomide;tumor;ultrasound Sonodynamic therapy using MRI-guided focused ultrasound in combination with 5-aminolevulinic acid to treat recurrent glioblastoma multiforme PROJECT NARRATIVERecurrent glioblastoma (rGBM) is a rare aggressive cancer with no effective therapy and extremely poorprognosis. Preclinical studies have shown that non-invasive sonodynamic therapy (MRI-Guided FocusedUltrasound to activate Protoporphyrin IX a metabolite of 5-aminolevulinic acid) selectively and rapidly killsgliomas and greatly extends survival in animal glioma models. Recent data from a first-in-man clinical trial inrGBM demonstrated that sonodynamic therapy is well-tolerated in humans with no off-target side effects andsupports a Phase 2 clinical trial in rGBM that will establish dosing safety and preliminary efficacy to informfuture clinical trials to improve patient outcomes and survival. NCI 10699858 3/21/23 0:00 PA-22-177 1R44CA275508-01A1 1 R44 CA 275508 1 A1 "REGMI, SAROJ GOPAL" 4/1/23 0:00 3/31/26 0:00 Special Emphasis Panel[ZRG1-OTC-R(12)B] 16154397 "MARCUS, STUART " Not Applicable 12 Unavailable 116975949 LC3GHFGF2KK1 116975949 LC3GHFGF2KK1 US 37.858697 -122.29041 10056236 SONALASENSE INC Oakland CA Domestic For-Profits 94607 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 394 SBIR/STTR 2023 694814 NCI 575683 73676 PROJECT SUMMARYGlioblastoma multiforme (GBM) is a rare and deadly cancer. First line treatment for GBM includes maximalsurgical resection with radiotherapy administered post-surgery and concomitant administration of adjuvanttemozolomide. Tumor recurrence is nearly inevitable due to the microscopic infiltrating cells that are foundcentimeters from the margin of visible tumor mass. There is currently no effective standard of care for recurrent(rGBM) and this highly aggressive disease leads to death within 15 months after diagnosis and has a 5-yearsurvival rate of <10%. Therefore there is a clear and significant clinical need for better therapies for rGBM. Toaddress this unmet need SonALAsense is developing sonodynamic therapy (SDT) a non-invasive drug-devicecombination to treat rGBM. SDT uses an MRI-Guided Focused Ultrasound (MRgFUS) device in combinationwith a drug called 5-aminolevulinic acid (ALA). Three independent laboratories have demonstrated the safetyand efficacy of ALA SDT in animal glioma models where the animals were dosed first with ALA and then treatedwith MRgFUS at energies that do not raise brain temperature. MRgFUS activated Protoporphyrin IX (PpIX) ametabolite of ALA created singlet oxygen that induced necrosis and apoptosis in the glioma in a process similarto photodynamic therapy. Activation of PpIX non-invasively caused regression of the gliomas and extendedsurvival. A first-in-human Phase 0/1 clinical trial in rGBM showed that ALA SDT was well-tolerated and notassociated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen speciesformation and targeted tumor cell death in rGBM only 4 days after treatment. These Phase 0/1 data obtained todate may be interpreted as the successful translation of ALA SDT-treated animal glioma model effects to humanrGBM patients. Due to its non-invasive nature ALA SDT has the unique opportunity to be used multiple timesto extend survival. Therefore a Phase 2 clinical trial will be conducted at 6 clinical trial sites to determinethe optimal Phase 2 dosing and schedule to comprehensively evaluate efficacy. This Direct to Phase II projectwill focus on one clinical trial site at the Ivy Brain Tumor Center. This will be accomplished through theexecution of 3 Aims. In Aim 1 we will enroll single patient cohorts to determine maximum tolerated dose andenergy for a single dose schedule. In Aim 2 we will determine the recommended schedule by escalating thedosing schedule to 2 then 3 treatments. In Aim 3 we will use the dosing and treatment schedule identifiedin Aims 1 and 2 to evaluate preliminary efficacy and follow patients weekly in month 1 biweekly in month 2and monthly thereafter. Completion of this clinical trial will address FDA guidance in our pre-IND meeting andthe safety and clinical data from this Phase 2 trial will provide the basis for an end of Phase 2 meeting with theFDA to establish criteria for the approval of ALA SDT as an effective treatment for rGBM. UltimatelySonALAsenses ALA SDT combination therapy has great potential to positively impact rGBM patients and theirfamilies by improving outcomes. 694814 +No NIH Category available 4T1;Abscopal effect;Adjuvant;Adverse effects;Affect;Alginates;Antibodies;Autoimmune;Biocompatible Materials;Biological Sciences;Biomedical Engineering;Biopsy;Breast Cancer Model;CAR T cell therapy;Canis familiaris;Caring;Cells;Certification;Cessation of life;Clinical Trials;Cytotoxic T-Lymphocytes;Data;Development;Devices;Distant;Distant Metastasis;Drug Kinetics;Early treatment;Endowment;Exons;Flow Cytometry;Formulation;Funding;Goals;Hematologic Neoplasms;Histology;Human;Immune;Immune system;Immunity;Immunologics;Immunotherapy;Implant;In Situ;Incubators;Infiltration;LoxP-flanked allele;Lymphocyte;Lymphoma;Malignant Neoplasms;Mechanics;Metastatic breast cancer;Modality;Mus;Myelogenous;Neoadjuvant Therapy;Neoplasm Metastasis;Operative Surgical Procedures;Outcome;Performance;Phase;Pilot Projects;Porifera;Rattus;Regulatory T-Lymphocyte;Secure;Site;Solid Neoplasm;T cell response;T-Cell Activation;T-Lymphocyte;Techniques;Testing;Time;Toxic effect;Transforming Growth Factor beta;Translating;Tumor Suppression;United States;Work;arm;biocompatible polymer;biodegradable polymer;cancer infiltrating T cells;chemotherapy;cytokine release syndrome;design;effector T cell;engineered T cells;exhaustion;experience;fighting;immunoregulation;improved;inhibitor;innovation;lymph nodes;malignant breast neoplasm;manufacturability;manufacture;melanoma;mouse model;neoplastic cell;novel therapeutics;particle;patient derived xenograft model;polyoma middle tumor antigen;pre-Investigational New Drug meeting;recruit;response;scaffold;side effect;standard of care;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor-immune system interactions Immunomodulatory biomaterial to enhancing T-cell responses to triple negative breast cancer Project NarrativeSolid tumors cause over 1500 deaths per day in the United States highlighting a profound unmetneed for new therapies. Our companys long-term goal is to produce an affordable chemo-/cell-free treatments that harness the immune system to fight solid tumors. NCI 10699815 4/19/23 0:00 PA-22-176 1R44CA281563-01 1 R44 CA 281563 1 "WEBER, PATRICIA A" 5/1/23 0:00 4/30/24 0:00 Special Emphasis Panel[ZRG1-OTC-R(12)B] 78325044 "MAJEDI, FATEMEH SADAT " Not Applicable 36 Unavailable 117955789 NUGCJMCBBHV1 117955789 NUGCJMCBBHV1 US 10066523 "SYMPHONY BIOSCIENCES, INC." SANTA MONICA CA Domestic For-Profits 904033209 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 SBIR/STTR 2023 399586 NCI 290599 85146 Project SummaryDeaths from solid tumors vastly outnumber deaths from hematopoietic cancers. Yet progress inimmunotherapies for solid tumors is well behind those for lymphoma. CAR-T cell therapies andengineered T cells have become revolutionary approaches for hematopoietic cancers but theirpotential for solid tumors is yet to be realized. Significant challenges hinder the potential ofimmune therapies in solid tumors including insufficient activation and eventual exhaustion ofeffector T cells; and suppression of T cell effector responses in the tumor microenvironment. Inthis proposal we consider these hurdles and offer a biomaterial solution that overcomes them.This proposal is significant in facilitating endogenous T cells to fight solid tumors. Surgery is amajor treatment modality for both invasive and in situ tumors but at this time there are no specificimmunotherapies initiated at the time of surgery; they all start days to weeks later. Our proposalis significant for offering a way to start treatments early right at the time of initial surgery. Hereour synthetic scaffold SymphNode can be injected at the time of biopsy or surgery not to onlyrecruit and active tumor-experienced local immune cells but also to suppress the inhibitory cellscreated by tumor cells. Our long-term goal is to develop this bioengineered locally injectedsynthetic lymph node into a therapy for human tumors. 399586 +No NIH Category available 3' Untranslated Regions;Acquired Immunodeficiency Syndrome;Address;B-Lymphocytes;Biochemical;Biogenesis;Biology;Cell model;Cells;DNA Virus Infections;DNA Viruses;Data;Defense Mechanisms;Development;Disease;Disease Progression;Endoribonucleases;Ensure;Etiology;Gammaherpesvirinae;Gene Expression;Genes;Genetic Transcription;Herpesviridae Infections;Human;Human Herpesvirus 8;Immune response;Kaposi Sarcoma;Knowledge;Life Cycle Stages;Link;Literature;Lymphoma cell;Lymphoproliferative Disorders;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Messenger RNA;Methodology;Molecular;Outcome;Pathway interactions;Plants;Positioning Attribute;Predisposition;Process;Proteins;Quality Control;RNA;RNA Decay;RNA Degradation;RNA Processing;RNA Viruses;Regulation;Reporting;Retroviridae;Ribosomes;Role;Series;Testing;Therapeutic;Transcript;Transcriptional Activation;Translations;Viral;Viral Genes;Viral Genome;Viral Proteins;Virus;Virus Replication;antagonist;antiviral immunity;experimental study;genome wide screen;genome-wide;in vivo;infected B cell;insight;lytic replication;mRNA Decay;member;novel therapeutic intervention;pathogen;primary effusion lymphoma;protein complex;recombinant virus;recruit;response;transcription factor;transcriptome;transcriptomics;viral RNA Restriction of KSHV by cellular RNA decay pathways Project NarrativeSubversion of cellular defense mechanisms is critical for robust Kaposi's sarcoma-associated herpesvirus(KSHV) gene expression replication and dissemination and its ability to cause disease. This proposalinvestigates how cellular RNA quality control mechanisms regulate KSHV gene expression and viral replicationas well as the mechanisms KSHV employs to disrupt these restrictive processes. Completion of this proposalwill provide fundamental knowledge regarding the interactions between KSHV and cellular gene expressionmachinery and provide a framework for further therapeutic exploration. NCI 10699800 3/8/23 0:00 PA-20-185 1R01CA278642-01A1 1 R01 CA 278642 1 A1 "READ-CONNOLE, ELIZABETH LEE" 4/1/23 0:00 3/31/28 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 12267108 "KARIJOLICH, JOHN " Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 400313 NCI 228750 171563 Project SummaryKaposis sarcoma-associated herpesvirus (KSHV) is a member of the subfamily gammaherpesvirinae and iscausally associated with the development of several malignancies including Kaposis sarcoma and primaryeffusion lymphoma (PEL). The virus ability to establish latency as well as reactivate are essential for thedevelopment of KSHV-associated disease. Despite these requirements for disease progression there aresignificant gaps in knowledge regarding cell-intrinsic mechanisms that restrict the KSHV lifecycle. While innaterestriction is typically thought of in the context of antiviral immune responses growing evidence suggests thatcellular RNA quality control pathways have an antiviral role. Nonsense-mediated RNA decay (NMD) is anevolutionarily conserved RNA decay pathway that facilitates degradation of RNAs on which ribosomes aredeemed to terminate translation aberrantly. Emerging evidence has pointed to a role for NMD in antiviralrestriction with a prominent role limiting replication of positive-stranded RNA viruses however a role for NMD inDNA virus restriction such as KSHV was unknown. We recently reported the discovery that NMD is a cell-intrinsic restriction mechanism for DNA viruses and demonstrated that it imposes a significant restriction on theKSHV lifecycle in PEL cells. Our data demonstrate that NMD-dependent restriction is linked both to the regulationof the unfolded protein response (UPR) as well as targeted degradation of the main KSHV transcription factorRTA. Building upon these observations our central hypothesis is that NMD restricts KSHV reactivation bytargeting key viral mRNAs as well as cellular transcripts in pathways important for viral gene expression and thatthe virus antagonizes NMD through viral-encoded mechanisms. To test this hypothesis we propose anintegrated series of experiments aimed at determining the interactions between NMD and KSHV. In Aim 1 wewill investigate how NMD-dependent regulation of the UPR pathway regulates the KSHV lifecycle. In Aim 2 wewill investigate a class of KSHV mRNAs that escape NMD despite harboring sequence features that shouldrender them NMD-susceptible. In Aim 3 we will determine the mechanism by which KSHV-encoded proteinsinhibit NMD. Completion of these studies is expected to determine how NMD restricts the KSHV lifecycle as wellas the mechanisms the virus employs to antagonize it. These will represent fundamental new insights into howDNA virus infection is regulated by cell-intrinsic mechanisms and can be harnessed for the development of newtherapeutic strategies. 400313 +No NIH Category available 3-Dimensional;Acute;Adverse event;Aftercare;Area;Calibration;Clinical;Clinical Research;Cohort Studies;Common Terminology Criteria for Adverse Events;Coupled;Custom;Cutaneous;Dermal;Digital Photography;Dimensions;Dose;Electrocardiogram;Eligibility Determination;Event;HIV;Heart Function Tests;Hemorrhage;Hour;Image;Incidence;Infection;Kaposi Sarcoma;Laboratories;Lasers;Lesion;Light;Local Therapy;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metastatic breast cancer;Monitor;Myelogenous;Normal tissue morphology;Operative Surgical Procedures;Outcome;PUVA Photochemotherapy;Pain;Participant;Patients;Pharmaceutical Preparations;Phase;Phase II/III Trial;Photosensitivity;Photosensitizing Agents;Phototherapy;Physicians;Population;Progression-Free Survivals;Pruritus;Psoriasis;Quality of life;Radiation therapy;Recovery;Recurrent tumor;Refractory;Relapse;Reporting;Research;Research Design;Research Personnel;Safety;Severities;Site;Source;Special Event;Specificity;Standardization;Sum;Symptoms;Systemic Therapy;Systemic disease;Testing;Therapeutic Effect;Therapy trial;Time;Tissues;Treatment Efficacy;Treatment-related toxicity;Ulcer;Visit;arm;associated symptom;design;dosage;efficacy evaluation;efficacy study;experimental study;follow-up;healing;improved;interest;light intensity;minimal risk;objective response rate;open label;phase III trial;response;safety study;side effect;standard of care;symptom treatment;treatment response;tumor An Open-Labeled Single Arm Phase 2 Efficacy and Safety Study of REM-001 Photodynamic Therapy (PDT) for Treatment of Cutaneous Metastatic Breast Cancer (CMBC) NARRATIVECutaneous metastatic breast cancer (CMBC) develops in up to 24% of patients with metastatic breast cancerand has limited treatment options due to the extent and recurrence of tumors and treatment toxicity.Photodynamic therapy (PDT) uses a photo-sensitive drug (REM-001) and directed light to treat tumors withminimal effects to surrounding tissue. This trial will test a reduced dose of PDT on patients with CMBC whocannot undergo surgery or radiation therapy to confirm that it produces therapeutic effects for their symptomaticlesions while minimizing the duration of post-treatment healing. NCI 10699535 6/29/23 0:00 PA-22-177 1R44CA281615-01 1 R44 CA 281615 1 "ZHAO, MING" 7/1/23 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-CTH-E(11)B] 11919399 "BROWN, DENNIS " Not Applicable 51 Unavailable KKRNN9JWJLA4 968808472 KKRNN9JWJLA4 US 37.47688 -122.197503 10034572 "KINTARA THERAPEUTICS, INC." San Diego CA Domestic For-Profits 921214396 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 SBIR/STTR 2023 1254180 NCI 1123983 48148 ABSTRACTCutaneous metastatic breast cancer (CMBC) develops in up to 24% of patients with metastatic breast cancer.Systemic therapy often has limited efficacy in such cases and surgery and radiotherapy offer only transient reliefand their use may be limited in the CMBC population due to the side-effects involved and the extent of cutaneouslesions. CMBC can cause infection bleeding malodor and disfigurement and can progress to occupy large areasof the body. Kintara proposes a photodynamic therapy (PDT) known as REM-001 Therapy wherein aphotosensitive drug is injected into the body to collect at tumor sites and is activated by a specially-designedlaser focused on the selected lesions. The activated drug destroys tumors with minimal effects to surroundingtissue. REM-001 has been proven to be effective for many conditions including CMBC. However previous trialsusing a higher-than-threshold dose also reported high rates of unwanted side effects and longer healing time. Inprevious trials symptoms such as eschar and ulceration increased recovery time and caused patients to leavestudies but was not associated with better lesion outcomes. This project will reduce the treatment dosage to thepreviously identified threshold level which demonstrated a 79% response rate in an initial study in an effortto reduce side effects while still treating lesions. Kintara will test the reduced dose on 15 patients withsymptomatic cutaneous lesions and stable systemic disease who are unable to receive surgery or radiotherapyat the time of treatment. These patients will be administered a single dose of REM-001 followed by light treatmentand will be monitored for efficacy (lesion shrinking or disappearing as well as pain and itch subsiding andimproved quality of life) and safety/tolerability (eschar and ulceration and bleeding and discharge from thelesions treatment related photosensitivity as well as standard clinical side-effect monitoring). Patients willcontinue on their existing standard of care systemic therapy and will receive it throughout the trial. If this trial issuccessful the treated lesions shrink or disappear with the reduced treatment dose Kintara will continue to amulti-site Phase III trial for CMBC and explore the use of REM-001 photodynamic therapy in other dermalindications. 1254180 +No NIH Category available Affinity;Animals;Anti-Inflammatory Agents;Antibodies;Autoimmunity;Biochemical;Biological Assay;Biological Response Modifiers;Biology;CD3 Antigens;CD8B1 gene;CT26;CTLA4 gene;Cell physiology;Cells;Chronic;Clinical;Data;Dendritic Cells;Development;Enzyme-Linked Immunosorbent Assay;Evaluation;Exhibits;Family;Generations;Genetic Engineering;Genetically Engineered Mouse;Grant;Head and Neck Cancer;Histologic;Human;Immune;Immune checkpoint inhibitor;Immunooncology;Immunosuppression;Immunotherapy;In Vitro;Inflammation;Knowledge;Lead;Lymphocyte;Macaca fascicularis;Macrophage;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Maximum Tolerated Dose;Medical;Modality;Modeling;Monoclonal Antibodies;Mus;Myeloid Cells;Natural Immunity;New Agents;Patients;Phase;Phospholipase;Phospholipase A2;Pilot Projects;Polyunsaturated Fatty Acids;Population;Proteins;Publishing;Resistance;Sampling;Series;Serum;Small Business Innovation Research Grant;T-Lymphocyte;Therapeutic;Therapeutic Monoclonal Antibodies;Toxic effect;Toxicokinetics;Transgenic Mice;Transgenic Organisms;Tumor Immunity;Tumor Promotion;anti-PD-1;anti-PD1 antibodies;antitumor effect;cancer immunotherapy;cancer therapy;candidate identification;clinical application;clinical development;cross reactivity;drug candidate;effector T cell;efficacy evaluation;experience;follow-up;gain of function;humanized mouse;immune checkpoint;in vivo;lipid mediator;malignant breast neoplasm;melanoma;member;neoplasm immunotherapy;novel;pembrolizumab;pre-clinical;programmed cell death ligand 1;programmed cell death protein 1;protein distribution;protein expression;restraint;success;therapeutic target;tumor;tumor growth PLA2G2D Antibodies for Cancer Immunotherapy PROJECT NARRATIVEThe clinical success of immune checkpoint inhibitors (ICIs) represents a transformative advancement in cancertherapy however >70% of patients fail to respond and new treatments promoting anti-tumor immunity are stillurgently needed. PLA2G2D a member of the secreted phospholipase A2 family has emerged as an importantnegative immune regulator and a novel checkpoint suppressing anti-tumor immunity. This project seeks toidentify the best anti-PLA2G2D monoclonal antibody drug candidate for development as a novelimmunotherapy to benefit patients resistant to current ICIs. NCI 10699504 6/9/23 0:00 PA-22-176 1R43CA278134-01A1 1 R43 CA 278134 1 A1 "FRANCA-KOH, JONATHAN C" 6/9/23 0:00 5/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-R(12)B] 7084851 "LEE, LI-FEN " Not Applicable 15 Unavailable 29694617 LQVBQAEB9L23 29694617 LQVBQAEB9L23 US 37.664293 -122.384512 10060967 APEXIMMUNE THERAPEUTICS INC. SOUTH SAN FRANCISCO CA Domestic For-Profits 940801913 UNITED STATES N 6/9/23 0:00 5/31/24 0:00 395 SBIR/STTR 2023 399618 NCI 311258 62252 PROJECT SUMMARY / ABSTRACTCurrently approved immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However mostpatients do not respond to these treatments because of primary or acquired resistance. Identifying new immuneregulators and developing therapeutics targeting such molecules is a current focus in immuno-oncology. Wehave found that the secreted phospholipase A2 PLA2G2D is highly expressed in various human tumors andpositively correlated with that of classic checkpoints such as CTLA-4 PD-1 and PD-L1. PLA2G2D potentlydiminishes dendritic cell function suppresses T cell activity and promotes macrophage M2 polarization.Accordingly studies using genetically-engineered loss- or gain-of-function mice demonstrate that PLA2G2Dstrongly enhances tumor growth indicating that PLA2G2D is a novel targetable checkpoint for tumorimmunotherapy. We have generated more than 700 anti-PLA2G2D monoclonal antibodies and using a seriesof in vitro biochemical and immune cell functional assays we have identified 39 leading function-blockingcandidates. This proposal seeks to evaluate the anti-tumor efficacy of the 5 most functionally potent drugcandidates (which do not cross-react with mouse PLA2G2D) alone and in combination with existing ICIs usingsyngeneic tumor models in transgenic PLA2G2D-humanized mice. We will also assess how anti-PLA2G2Dchanges the tumor immune profile and histologically evaluate PLA2G2D protein expression in various humantumors using our drug candidate (Aim 1). The best drug candidate identified in Aim 1 will then be subjected tonon-GLP maximum tolerated dose toxicity and toxicokinetic evaluation in cynomolgus monkeys (Aim 2).Collectively the successful execution of this proposal will enable us to nominate our final lead molecule andbegin IND-enabling studies as part of a follow-up phase II SBIR proposal. Ultimately an efficacious therapeuticanti-PLA2G2D antibody will comprise a new treatment for patients resistant to currently available ICIs. 399618 +Biomedical Imaging; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Immunotherapy; Lung; Lung Cancer; Precision Medicine Adoption;Aftercare;Antitumor Response;Biological;Biological Markers;Biopsy;Cancer Patient;Characteristics;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Computer Vision Systems;Computers;Development;Diagnosis;Disease Progression;Early identification;Early treatment;Eastern Cooperative Oncology Group;Environment;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunotherapeutic agent;Immunotherapy;Inflammatory;Institution;Letters;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Molecular;Monitor;Morphology;Mutation;Nature;Neoadjuvant Therapy;Nivolumab;Nodule;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Outcome;PD-1/PD-L1;Pathologic;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Phenotype;Predictive Value;Publishing;Radiology Specialty;Reporting;Resected;Scanning;Shapes;Site;Testing;Texture;Time;Tissues;Toxic effect;Training;Treatment outcome;Tumor Biology;Tumor-Infiltrating Lymphocytes;Validation;X-Ray Computed Tomography;anti-PD-1;anti-PD-1/PD-L1;anti-PD-L1 therapy;base;cost;imaging biomarker;immunotherapy clinical trials;immunotherapy trials;industry partner;inhibitor therapy;non-invasive imaging;novel;phase III trial;predicting response;predictive marker;primary endpoint;prognostic;prognostic of survival;prognostic value;programmed cell death ligand 1;prospective;radiological imaging;radiomics;responders and non-responders;response;success;survival outcome;survival prediction;tool;treatment response;tumor;tumor behavior;tumor heterogeneity Novel Radiomics for Predicting Response to Immunotherapy for Lung Cancer RELEVANCE: Only 1 in 5 lung cancer patients treated with immunotherapy (IO) has a favorable response.Additionally the cost of IO is extremely high >$200K/year per patient. The goal of this project is to develop novelcomputational radiomic tools which in conjunction with routine CT scans from IO clinical trials will allow for (1)identifying pre-IO therapy as to which non-small cell lung cancer patients could potentially benefit from immunecheckpoint inhibitors and (2) quantitatively monitor serial changes in tumor heterogeneity during IO treatment forearly identification of responders and non-responders. NCI 10699497 9/9/22 0:00 PA-21-268 7R01CA257612-02 7 R01 CA 257612 2 "HANCU, ILEANA" 4/2/21 0:00 3/31/26 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(03)M] 8352708 "MADABHUSHI, ANANT " "VELCHETI, VAMSIDHAR " 5 BIOMEDICAL ENGINEERING 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 7/15/22 0:00 3/31/23 0:00 394 Non-SBIR/STTR 2022 567039 NCI 406700 160339 ABSTRACT: In 2019 an estimated 228150 patients in the US are expected to be diagnosed with non-small celllung cancer (NSCLC). A recent landmark development has been the approval of the immune checkpointinhibitors (anti-PD-1 and anti-PD-L1) for the treatment of locally advanced and metastatic NSCLC. Theseimmunotherapy (IO) drugs have an excellent toxicity profile and have the potential to induce durable clinicallymeaningful responses. However only 1 in 5 NSCLC patients treated with IO will have a favorable response.Unfortunately the current tissue based biomarker approach to selecting patients for these treatments is sub-optimal due to the dynamic nature of the interaction of the immune system with the tumor. Given the prohibitivecosts associated with IO (>$200K/year per patient) there is a critical unmet need for predictive biomarkers toidentify which patients will not benefit from IO. Additionally the current clinical standard to evaluating tumorresponse (i.e. RECIST and irRC which evaluate change in tumor size and nodule disappearance) is sub-optimalin evaluating early clinical benefit from IO drugs. This is due at least in part to the fact that some patientsundergoing IO present apparent disease progression (pseudo-progression) on post-treatment CT scans. Unlike the standard canon of radiomics (computer extracted features from radiographic scans) thatassess textural or shape patterns our group has been developing novel computer vision strategies to capturepatterns of peri-tumoral heterogeneity (outside the tumor) and tumor vasculature from CT scans. In N>300patients our group has shown that (1) radiomics of vessel tortuosity on baseline pre-treatment CT for NSCLCpatients undergoing IO were significantly different between responders (less tortuous) and non-responders(more tortuous) (2) serial changes in these measurements were better predictors of early response to IOcompared to clinical response criteria such as RECIST and irRC and (3) these radiomic attributes wereassociated with PD-L1 expression and degree of tumor infiltrating lymphocytes on baseline biopsies. Criticallythese radiomic features predicted response for NSCLC patients treated with 3 different IO agents from 3 sites. In this project we will further develop vasculature peri- and intra-tumoral radiomic features for monitoringand predicting benefit and early response for NSCLC patients treated with IO. We will uniquely train our radiomicsusing a set of N>180 resected NSCLC patients treated with first line IO and for whom we will have majorpathologic response (MPR) as primary endpoint. In addition we will establish the biological underpinnings ofthese predictive radiomic signatures by evaluating their association with the morphology immune landscape(from biopsies) and molecular pathways of the tumor. In addition we have access to N>700 NSCLC patientstreated on completed clinical trials via our industry partners (Astrazeneca Bristol-Myers Squibb) for toolvalidation. Finally we will deploy LunIOTx within the ECOG-5163 (INSIGNA) trial (N>600) the first time thatradiomics will be evaluated within a prospective cooperative group clinical trial for IO. 567039 +No NIH Category available 90Y;Address;Beta Particle;Binding;Biodistribution;Blood Proteins;Cancer Etiology;Cancer Patient;Cessation of life;Clinical;Collagen;Combination Drug Therapy;Control Groups;Copper;Cyclic GMP;Cyclic Peptides;Data;Deposition;Derivation procedure;Detection;Dose;Drug Kinetics;Extracellular Matrix;Extravasation;Fibrin;Frequencies;Gastric Tissue;Histologic;Human;Image;Immunohistochemistry;Injections;Kinetics;Legal patent;Licensing;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Medical;Methods;Neoplasm Metastasis;Organ;Outcome;Patients;Peptides;Phase;Positron-Emission Tomography;Prevalence;Prognosis;Radiation therapy;Radiolabeled;Rattus;Rodent;Safety;Signal Transduction;Specificity;Stomach Neoplasms;Targeted Radiotherapy;Therapeutic Effect;Thrombus;Time;Tissue Microarray;Tissues;Toxic effect;Treatment Protocols;Treatment outcome;advanced disease;clinical translation;dosage;dosimetry;human model;image guided therapy;improved;malignant stomach neoplasm;mouse model;neoplastic cell;novel therapeutic intervention;patient derived xenograft model;patient prognosis;response biomarker;targeted treatment;theranostics;therapeutic target;tool;translational therapeutics;treatment optimization;treatment response;tumor;tumor growth;tumor microenvironment;uptake Theranostic for gastric cancer Project NarrativeGastric cancer (GCa) is the fifth most common cancer and the third leading cause of cancer-related deathworldwide. The prognosis of patients with advanced GCa is poor with a median survival of 12-14 months evenwith combination chemotherapy. To address this unmet clinical need Collagen Medical is developing an image-guided therapy tool targeting the fibrin in the extracellular matrix of gastric tumors. NCI 10699365 9/11/23 0:00 PA-22-176 1R44CA275590-01A1 1 R44 CA 275590 1 A1 "EVANS, GREGORY" 9/11/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-E(11)B] 11329405 "HUMBLET, VALERIE " Not Applicable 5 Unavailable 967097218 GJLBDQT8K757 967097218 GJLBDQT8K757 US 42.392805 -71.168546 10028861 "COLLAGEN MEDICAL, LLC" BELMONT MA Domestic For-Profits 24783006 UNITED STATES N 9/11/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 395933 NCI 294221 75810 Project SummaryThe overarching objective of this application is to develop an image-guided therapy paradigm forimproving the management of gastric cancer (GCa) by targeting fibrin in the tumormicroenvironment. GCa is the fifth most common cancer and the third leading cause of cancer-related deathworldwide. Despite progress in management of advanced GCa the prognosis remains poor with a mediansurvival of 12-14 months even with combination chemotherapy. Therefore novel therapeutic approaches are ofutmost need to improve clinical outcomes in patients with advanced disease.The central hypothesis is that high energy beta particle radiotherapy targeted to the fibrin in tumormicroenvironment improves the treatment outcome of GCa. Primary and metastatic gastric tumors haveleaky vasculature which results in extravasation of blood proteins and abundant deposition of fibrin in theextracellular matrix (ECM). Given that fibrin is only present in the tumors and thrombi but not in healthytissues we posit that fibrin could be used as a therapeutic target representing a large depot in the ECM for ahigh energy beta particle to kill surrounding tumor cells. Collagen Medical has developed and licensed patentedfibrin-specific short cyclic peptides and derivatized them for imaging and therapy. We have shown that fibrin-targeted positron emission tomography (PET) can detect thrombi in patients using a copper-64 modified peptideyet provides minimal background PET signal in tissues where GCa metastasizes.Our preliminary data shows that the fibrin-specific probe 64Cu-CM500 detects fibrin in a mouse modelof GCa. We have also modified the peptide to incorporate the high energy beta emitter yttrium-90 for targetedtherapy. Building upon this preliminary data in this FastTrack project we propose to establisha theranostic approach to treating GCa by using 64Cu-CM500 PET to identify patients with fibrin-rich gastrictumors and then treating them with fibrin-targeted 90Y-CM600 beta emitting radiotherapy. In Phase 1 wewill evaluate the extent of fibrin deposition in a wide range of human GCa tissue arrays to estimatethe prevalence of fibrin in GCa. We will also demonstrate the specificity of our compounds for both detectingtumor fibrin and for targeting fibrin for radiotherapy. In Phase 2 we will evaluate the kinetics of 64Cu-CM500PET in tumors in GCa patients and estimate how long the probe remains bound to the tumor. We will alsodemonstrate the efficacy of 90Y-CM600 radiotherapy in multiple mouse models of GCa and optimize thetreatment regimen.Lastly to enable clinical translation of this therapeutic we will synthesize the CM600 precursor under cGMPconditions validate the 90Y radiolabeling method and perform IND enabling GLP toxicity biodistribution anddosimetry studies in rodents. 395933 +No NIH Category available Ablation;Acoustics;Address;Adult;Affect;Algorithms;Anatomy;Animals;Arteries;Atrial Fibrillation;Breast;Cardiac ablation;Childhood;Cryosurgery;Data;Databases;Detection;Development;Devices;Disease;Epilepsy;Family suidae;Feedback;Focused Ultrasound Therapy;Goals;Incidence;Intervention;Kidney;Left;Liver;Liver neoplasms;Location;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Marketing;Methods;Modeling;Needles;Neurologic;Newly Diagnosed;Operative Surgical Procedures;Patient risk;Patients;Performance;Perfusion;Phase;Physics;Pilot Projects;Population;Positioning Attribute;Procedures;Property;Recurrent tumor;Regulatory Pathway;Resolution;Screening for Hepatocellular Cancer;Shapes;Site;Small Business Innovation Research Grant;Solid Neoplasm;Structure;Surgeon;Survival Rate;Techniques;Technology;Testing;Thermal Ablation Therapy;Time;Tissues;Training;Transducers;Treatment Efficacy;Ultrasonic Transducer;United States;Work;algorithm training;cancer diagnosis;cancer imaging;cancer therapy;commercialization;cost;curative treatments;deep learning;detection method;effective therapy;image processing;imaging system;improved;in vivo;in vivo Model;in vivo evaluation;innovation;microwave electromagnetic radiation;minimally invasive;porcine model;real time monitoring;real-time images;sensor;simulation;targeted delivery;tool;tumor;ultrasound In vivo feasibility of a smart needle ablation treatment for liver cancer Project NarrativeLiver cancer is a deadly disease with 43000 new diagnoses every year in the United States and a five year survival rate of only 18% (SEER database 2020). Although we can detect liver cancer at an early stage more than 35% of these patients are ineligible for effective treatments such as surgery or traditional ablation due to the tumor's proximity to critical anatomy. The proposed device will expand the use of ablation to allow for early-stage precise interventions not only for currently untreatable liver tumors (affecting more than 6600 in the United States annually) but also for a broad range of cancers such as those in the kidney lung and breast-regardless of proximity to critical structures-and could also improve neurological and cardiac ablation treatments for conditions such as epilepsy and atrial fibrillation in both adult and pediatric populations (affecting more than 8 million patients in the United States annually). NCI 10699190 3/28/23 0:00 PA-22-176 1R43CA277895-01A1 1 R43 CA 277895 1 A1 "ZHAO, MING" 4/1/23 0:00 3/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 77984281 "MASHAL, ALIREZA " Not Applicable 98 Unavailable 117551103 MEJ2GKMPHHJ1 117551103 MEJ2GKMPHHJ1 US 38.940217 -77.018157 10062153 CURRENT SURGICAL INC. WASHINGTON DC Domestic For-Profits 200115943 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 394 SBIR/STTR 2023 400000 NCI 277555 98376 Project SummaryA significant number (~30-50%) of liver cancers have no curative treatments due to their proximity to criticalanatomy. Minimally invasive thermal ablation is a promising treatment for these untreatable solid tumors. Ifdelivered precisely ablations offer the treatment efficacy of traditional surgery with lower patient riskclinician time and overall cost. Existing ablation technology however does not offer the necessary precision.Ablation tools do not provide feedback on (1) whether or not the probe has been accurately placed within thetumor (2) if the tumor has been completely destroyed or (3) if surrounding healthy tissue has been leftintact. Because of this lack of precision and feedback ablation cannot currently be used to treat tumors nearcritical anatomy.A proposed solution to these currently untreatable cancers is an ultraprecise ablation needle embedded withhigh-resolution ultrasound sensors at its tip. These sensors will provide multiple benefits: aiding the clinicianin placing the device correctly by imaging the tumor relative to the needle delivering the treatment energy toa precise location through focusing and providing real-time monitoring of the procedure by detecting thethermal changes in tissue-all without the need for a large imaging system. This innovation will allowsurgeons to complete an ablation with the required precision to treat even the most difficult-to-reach cancers.This Phase 1 SBIR proposal will demonstrate the capabilities of small-scale ultrasound transducers toprecisely control ablations near critical anatomical structures (e.g. arteries) in an in vivo porcine modelthrough three specific aims: (1) optimization of previously developed ultrasound-based ablation zoneestimation in ex vivo liver tissue using deep learning and physics-based simulations (2) ablation zoneestimation in an in vivo porcine liver model and (3) demonstration of in vivo closed-loop ablation zonecontrol near critical anatomy (artery in liver). Completion of this phase will demonstrate the key technologyin a pilot animal study where Phase 2 work would address critical development milestones tocommercialization for an anticipated Class 2 device (approval via de nova regulatory pathway). 400000 +No NIH Category available 3-Dimensional;Acute Myelocytic Leukemia;Artificial Intelligence;Artificial Intelligence platform;Biological Assay;Biological Markers;Blinded;Categories;Cell Nucleus;Chromosome Structures;Chromosome abnormality;Chromosomes;Clinical;Collection;Complex;Computer software;Cytogenetic Analysis;Cytogenetics;DNA;DNA Sequence Alteration;Data;Data Aggregation;Data Set;Decision Making;Development;Diagnostic;Diagnostic Reagent Kits;Disease;Disparate;Foundations;Frequencies;Genetic Epistasis;Genome;Hematology;Hi-C;Individual;Karyotype;Karyotype determination procedure;Length;Ligation;Link;Machine Learning;Malignant Neoplasms;Methods;Modeling;Mutation;Neoplasms;Oncology;Outcome;Patient risk;Patient-Focused Outcomes;Patients;Pattern;Phenotype;Recurrence;Research;Resolution;Risk;Sampling;Sensitivity and Specificity;Severity of illness;System;Testing;Training;Translating;Unbalanced Translocation;Variant;Work;cloud based;falls;genome-wide;homologous recombination;improved;information gathering;insight;leukemia;machine learning model;next generation;next generation sequencing;novel;patient population;patient stratification;physical property;predictive test;prognostic;prognostic value;risk prediction;risk stratification;tool;tumor AI-based AML risk stratification using next generation cytogenomics NARRATIVEChromosomal aberrations are essential biomarkers used to guide treatment decisions for acute myeloidleukemia patients. In this proposal we describe the use of a comprehensive method to assay chromosomeaberrations at high resolution and use this information to more accurately predict the severity of disease. Thisinformation will potentially be helpful guiding decision making when making treatment decisions for patientspoorly stratified by current methods. NCI 10699150 6/8/23 0:00 PA-22-176 1R44CA278140-01A1 1 R44 CA 278140 1 A1 "FRANCA-KOH, JONATHAN C" 7/1/23 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OTC-V(13)B] 8860440 "EACKER, STEPHEN MATTHEW" Not Applicable 7 Unavailable 79752735 TQ67ST6YELX5 79752735 TQ67ST6YELX5 US 47.67118 -122.285148 10038678 "PHASE GENOMICS, INC." SEATTLE WA Domestic For-Profits 981052218 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 SBIR/STTR 2023 1000000 NCI 749978 184601 ABSTRACT Chromosome aberrations are a hallmark of acute myeloid leukemia and offer mechanistic andprognostic insights into disease. As such a combination of cytogenetic assays are routinely applied as a partof the AML diagnostic workflow. While offering invaluable information on disease severity most chromosomeaberrations fall into the cytogenetic abnormalities not classified or complex karyotype categories. A rangeof studies have shown that while ambiguous these variants have prognostic value suggesting the existenceof cryptic variants of significance or complex epistases that drive the AML phenotype. However there iscurrently no system for translating genome-wide chromosomal aberration information into patient risk. To improve the predictive potential of chromosome aberration profiles we propose the development ofa risk-prediction metric that will add new prognostic value to AML studies. Specifically we will produce amethod which will establish a patient risk metric that can help guide treatment decisions for patientstraditionally judged as of intermediate risk. This development will employ our scalable cytogenomic tools andnovel machine learning analytics to generate a large collection of cytogenomic datasets and analyze them toidentify patterns linked to AML phenotypes. Once completed we will have a combined kit and softwaresolution that will not only improve upon existing cytogenetic applications in AML but will offer new prognosticinsights beyond what is possible with current tools. This product will deliver high-resolution view of thechromosome aberration landscape in AML and an offer a data-driven interpretation of how variants will impactdisease severity. 1000000 +No NIH Category available Acceleration;Address;Adoptive Cell Transfers;Aliquot;Antibodies;Bar Codes;Biological Assay;Biological Markers;Cancer Patient;Cancer Vaccines;Cell Separation;Cell physiology;Cell surface;Cells;Chemicals;Chronic;Collaborations;Contractor;Data;Detection;Development;Enzyme-Linked Immunosorbent Assay;Exhibits;Flow Cytometry;Fostering;Goals;Hour;Human;Immune;Immunologics;Immunooncology;Immunotherapy;Individual;Interferon Type II;Interleukin-10;Interleukin-2;Kinetics;Lasers;Malignant Neoplasms;Marketing;Measurement;Measures;Methods;Monitor;Patients;Performance;Peripheral Blood Mononuclear Cell;Phase;Phenotype;Prediction of Response to Therapy;Process;Production;Protocols documentation;Quality Control;Reporting;Research;Research Personnel;Resistance;Resolution;Sampling;Scientist;Small Business Innovation Research Grant;Specificity;Standardization;Stimulus;T cell response;T-Lymphocyte;TNF gene;Technology;Time;Treatment Protocols;Treatment outcome;Validation;cancer cell;cancer immunotherapy;cellular imaging;commercialization;cytokine;exhaustion;immune checkpoint blockade;improved;in vitro Assay;individualized medicine;innovation;instrumentation;laboratory development;novel;particle;phenotypic biomarker;programmed cell death protein 1;research and development;response;systemic toxicity;vaccine development Time-lapse Flow Cytometry for Kinetic Profiling of T-Cell Function NarrativeThis project aims to foster fundamental discoveries and innovative research for the improvementof immunotherapies to treat cancer by harnessing the patients own immune cells. A majortechnological limitation is the lack of methods to characterize immune cells over time at high-throughput. The proposed research to develop novel time-lapse flow cytometry addresses thislimitation accelerating immunology and immune-oncology research and development. NCI 10699148 9/5/23 0:00 PA-22-176 1R44CA281529-01 1 R44 CA 281529 1 "LOU, XING-JIAN" 9/5/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-MCST-G(15)B] 12673473 "KWOK, SHELDON J.J." Not Applicable 7 Unavailable 81480108 LQDAZMN14NM7 81480108 LQDAZMN14NM7 US 42.364534 -71.081074 10057920 LASE INNOVATION INC. CAMBRIDGE MA Domestic For-Profits 21424201 UNITED STATES N 9/5/23 0:00 8/31/24 0:00 396 SBIR/STTR 2023 1002340 NCI 671000 268400 AbstractDespite progress in immunotherapies there are significant challenges to overcome to make themmore broadly applicable to different cancers and more effective for patients. However currentefforts to improve adoptive cell therapies and immune checkpoint blockade as well as cancervaccines are hampered by the lack of a method to characterize the functional and phenotypicalchanges of different subpopulations of T cells over time at high throughput. The goal of this SBIRPhase II project is to develop a novel flow-cytometry method that can solve this technologicalbottleneck. The time-lapse flow cytometry uses laser particle (LP) barcodes to track each cellacross flow measurements taken at different time points. Built on demonstrated proof-of-conceptdata this project is focused on establishing a set of novel assays for characterizing T cells inresponse to different stimuli in a time-resolved manner. The first specific aim is to demonstrateshort-term time-lapse assays to profile cytokine secretion (t-SEC). Secretion of TNF IFN andIL10 from millions of the same cells in response to different types of stimulation are measured atmultiple timepoints over 24 hours. The second specific aim is to demonstrate long-term time-lapseassay to monitor phenotype (t-PHENO) including T-cell exhaustion over 10 days. The thirdspecific aim is to validate the t-SEC and t-PHENO assays with patient samples. The time-resolved high-throughput high-parameter assays are expected to accelerate the development ofmore effective and durable immunotherapies for cancer (>$100 B global market). Beyondimmunotherapy time-lapse flow cytometry is also expected to be useful in fundamentalimmunological research and vaccine development. 1002340 +No NIH Category available Abdomen;Adjuvant Therapy;Advanced Development;Apoptosis;Area Under Curve;Biological Availability;Cell Death;Chemotherapy and/or radiation;Clinic;Clinical;Clinical Trials;Collaborations;Data;Defense Mechanisms;Desmoplastic Small Round Cell Tumor;Development;Dose;Drug Kinetics;Foundations;Funding;Future;Goals;Growth;Half-Life;High Prevalence;Human;Light;MDM2 gene;Malignant Neoplasms;Modeling;Molecular;Monkeys;Mutate;Newly Diagnosed;Normal tissue morphology;Operative Surgical Procedures;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Positioning Attribute;Pre-Clinical Model;Primary Neoplasm;Proteins;Rattus;Recommendation;Recurrence;Refractory;Safety;Small Business Innovation Research Grant;Soft tissue sarcoma;Solid Neoplasm;TP53 gene;Testing;Therapeutic;Thrombocytopenia;Toxic effect;Toxicology;Treatment Protocols;Tumor Suppressor Proteins;United States;Work;arm;burden of illness;cancer therapy;cancer type;cell growth;clinical development;cohort;drug metabolism;early phase trial;efficacy study;experience;first-in-human;in vivo;inhibitor;innovation;liposarcoma;manufacture;morphogens;neoplastic cell;novel;novel therapeutics;phase I trial;prevent;programs;rare cancer;sarcoma;screening;small molecule;therapy resistant;tumor;tumor growth;tumor initiation Development of a novel small molecule MDM2 inhibitor for innovative sarcoma treatment Project narrativeSarcomas account for 13000 new diagnoses per year in the United States. They are treated with majorsurgery toxic chemotherapy and/or radiation but many fail therapy. More effective and less toxic therapiesare needed. We propose development of a new drug that activates an intrinsic defense mechanism (p53). Thetarget of our novel therapy is MDM2 which inactivates p53 thereby increasing treatment resistance. Othercancers have a similar mechanism for p53 inactivation thus an effective new drug for relatively rare sarcomasmay impact treatment paradigms for many other cancers as well. NCI 10699023 8/7/23 0:00 PA-22-177 1R44CA281622-01 1 R44 CA 281622 1 "BOZZA, WILLIAM PATRICK" 8/7/23 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 11952184 "HANNA, GABI " Not Applicable 4 Unavailable UW1XNBTQ7EA5 UW1XNBTQ7EA5 US 10070974 LAMASSU BIO INC DURHAM NC Domestic For-Profits 277056468 UNITED STATES N 8/7/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 1304141 NCI 1162841 71300 Project summary/abstractThis proposal advances the development of a novel therapeutic for p53 wild type sarcomas. Our team hasidentified a novel MDM2 inhibitor SA53 with best-in-class potency bioavailability and in vivo efficacy across abroad range of preclinical models. It has also undergone extensive safety and pharmacokinetic testing suitablefor support of an IND submission with an identified starting dose in humans. SA53 has the potential tofacilitate apoptosis in p53 wild-type cancers and to spare normal tissue. To drive proof of concept we willconduct a first in human trial to 1) identify a safe dose for future clinical trials 2) establish the pharmacokineticprofile and appropriate safety endpoints 3) in an expansion cohort establish feasibility and early indication ofefficacy in treating p53 wild type soft tissue sarcoma. Our primary objective is to rapidly and efficiently advanceSA53 through clinical trials to implement a novel and innovative treatment for p53 wild type soft tissuesarcoma. Our approach is first establishing the recommended phase 2 dose in a trial for p53 wild typerefractory solid tumors then to apply this novel therapy in an expansion cohort targeting a pre-surgical windowin soft tissue sarcoma patients. To achieve these goals we will complete the following specific aims:Aim 1: We will complete GMP manufacturing of the drug and formulated clinical product suitable to complete aphase 1 clinical trial.Aim 2: We will conduct a phase 1 clinical trial to establish the recommended dose for phase 2 and earlyindication of feasibility and efficacy in soft tissue sarcoma patients.At the completion of this proposal we will have completed a phase 1 trial to have established safety andpreliminary efficacy which will serve as the foundation for registration directed studies. In light of ourexceptional in vivo efficacy data we further believe that this can be a breakthrough paradigm-changing therapyfor cancer treatment. 1304141 +No NIH Category available Address;Adherence;Affect;Age;Algorithms;American;Anxiety;Area;Back;Behavior;Cancer Etiology;Caring;Charge;Child;Communication;Complex;DNA Sequence Alteration;Data;Development;Diagnosis;Effectiveness;Emotional;Face;Family;Family Caregiver;Family health status;Family member;Fatigue;Feedback;Foundations;Future;Gene Mutation;General Population;Genes;Genetic Predisposition to Disease;Germ-Line Mutation;Goals;Health;Health Personnel;Health Promotion;Hearing;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Individual;Inherited;Intervention;Knowledge;Learning;Life;Malignant Neoplasms;Meaning and purpose;Measures;Mental Depression;Mental Health;Metaphor;Mutation;Operative Surgical Procedures;Organ;Outcome;Parents;Participant;Persons;Phase;Population;Process;Program Acceptability;Public Health;Quality of life;Recommendation;Recording of previous events;Research;Resistance;Resources;Risk;Risk Reduction;Scanning;Science;Screening Result;Screening for cancer;Specific qualifier value;Stress;Technology;Testing;Text Messaging;Thinking;Time;Uncertainty;behavior change;cancer diagnosis;cancer risk;cancer type;coping;cost effective;design;digital;epidemiological model;evidence base;experience;genetic testing;improved;innovation;intervention program;lifetime risk;next generation;pilot test;programs;promote resilience;prophylactic;protective behavior;prototype;provider communication;recruit;resilience;resilience scale;skills;social;stressor;tailored text messaging;tool Previvors Recharge: A Resilience Program for Cancer Previvors 8. Project NarrativeFor the estimated one out of every 300 Americans who have a Hereditary CancerSyndrome but have not yet been diagnosed with cancer (Previvor) adversity oftencomes disguised as a multitude of cancer screenings a year and the uncertainty of thehealth of family members. The proposed research will develop and evaluate a prototypeof PREcharge an interactive program designed to increase resilience among Previvorsby administering brief assessments and using multivariate algorithms and provenapproaches to behavior change tailoring to provide timely individually tailored textmessages to promote a positive mindset strong social connections and a deep sense ofmeaning and purpose while also proactively addressing scanxiety through online tools.This program has the potential to improve the psychological health of a growingpopulation of individuals navigating the uncertainty and emotional toll of HereditaryCancer Syndromes. NCI 10698965 4/25/23 0:00 PA-22-177 1R43CA275673-01A1 1 R43 CA 275673 1 A1 "WEBER, PATRICIA A" 5/1/23 0:00 4/30/25 0:00 Special Emphasis Panel[ZRG1-CCHI-J(10)B] 8270372 "EVERS, KERRY " Not Applicable 2 Unavailable 36861821 KX8KMKQNGM97 36861821 KX8KMKQNGM97 US 41.451027 -71.497523 3933401 "PRO-CHANGE BEHAVIOR SYSTEMS, INC." Narragansett RI Domestic For-Profits 2882 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 SBIR/STTR 2023 265253 NCI 163092 84808 It is estimated that approximately 5-10% of all diagnosed cancers are caused by Hereditary CancerSyndromes (HCS) that are associated with germline mutations (inherited genetic mutations passed directlyfrom a parent to a child that create a genetic predisposition to certain types of cancer). Recent epidemiologicmodels indicate that 1 in 279 people may be carriers of one of the most common HCS and advances in genetictesting continue to identify new inherited mutations. Individuals with an HCS (Previvors) have up to an 80%lifetime risk of developing cancer and are at an increased risk of developing multiple primary cancers duringtheir lifetime often with onset at an early age. Previvors face multiple forms of adversity including a multitudeof annual cancer screenings and the uncertainty of not only their own health but the health of affected familymembers. Previvors also regularly experience scanxiety while anticipating undergoing and awaiting theresults of screenings. While interventions to promote resilience among Previvors would address an importantunmet public health need existing solutions have a number of gaps that limit effectiveness widespreaddissemination and applicability to Previvors. The proposed research will employ a participatory design approach to create and examine theacceptability and preliminary effects of PREcharge a resilience-boosting solution specifically designed forPrevivors and delivered primarily via bi-directional text messaging. PREcharge will use proven approaches tobehavior change tailoring to increase resilience by promoting a positive mindset strong social connections anda deep sense of meaning and purpose while also proactively addressing scanxiety. The design and developmentof PREcharge will be informed by extensive and ongoing end-user input from 10 Previvor advisors as well as 6experts in this area. One hundred and twenty-nine Previvors will be recruited for a 30-day pilot test. Phase Imilestones will include: 1) acceptability of the program as evidenced by overall mean ratings of at least 4 out of5 on a widely used acceptability measure and obtaining 75% endorsement that users would recommend theprogram to a fellow Previvor; (2) engagement as evidenced by continued receipt of text messages and one ormore interactions with the online tools by at least 70% of participants; and (3) benefit from the programevidenced by statistically significant pre-post improvement on the Connor Davidson Resilience Scale. Pilotparticipants who fail to sustain engagement will be asked to provide feedback on how PREcharge could beimproved. The data from this pilot test will lay the foundation for the further development of tailored text-messaging solutions to improve resilience outcomes among the expanding population of Previvors. This type ofeasily disseminable potentially cost-effective and highly tailored solution would overcome the limitations ofexisting interventions and provide a framework for messaging on other key behaviors (e.g. health careprovider communication) in the future. 265253 +No NIH Category available 3-Dimensional;Acceleration;Acute;Animal Model;Attention;Clinic;Clinical;Complex;Computer software;Development;Electron Spin Resonance Spectroscopy;Environment;Evaluation;Fast Electron;Frequencies;Future;Goals;Hour;Human;Hypoxia;Image;Imaging Device;Inbred C3H Mice;Individual;Injury;Leg;Letters;Licensing;Machine Learning;Malignant Neoplasms;Maps;Measurement;Measures;Methods;Modeling;Myocardial Infarction;National Cancer Institute;Organ Transplantation;Oxygen;Pathway interactions;Performance;Perfusion;Periodicity;Phase;Physiologic pulse;Process;Radiation Dose Unit;Radiation therapy;Reporting;Resolution;Scientist;Speed;Stroke;System;Techniques;Technology;Testing;Time;Tissues;Tumor Biology;United States National Institutes of Health;Width;absorption;cancer imaging;cancer therapy;computerized data processing;deep learning;design;drug development;fibrosarcoma;image reconstruction;imager;imaging modality;imaging software;improved;in vivo;in vivo imaging;instrument;learning network;mouse model;pre-clinical;pressure;reconstruction;response;success;technology platform;therapy resistant;tool;tumor;tumor hypoxia Methods for Fast and Efficient Oxygen Imaging NarrativeCyclic hypoxia with frequencies between a few cycles per minute to hours is receiving increased attentionbecause of its influence on tumor malignancy and treatment resistance. Fast tumor oxygen imaging methods areneeded for the measurement of acute hypoxia. This project will apply advanced hardware and deep learningtechnologies to single point imaging a pulse electron paramagnetic resonance oxygen imaging method toacquire fast oxygen maps in tumors. NCI 10698818 9/6/23 0:00 PA-22-176 1R43CA275537-01A1 1 R43 CA 275537 1 A1 "EVANS, GREGORY" 9/6/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 14979628 "KOTECHA, MRIGNAYANI " Not Applicable 7 Unavailable 80562602 RLM1GHQF3MM6 80562602 RLM1GHQF3MM6 US 41.874027 -87.683141 10045963 "O2M TECHNOLOGIES, LLC" CHICAGO IL Domestic For-Profits 606123738 UNITED STATES N 9/6/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 400000 NCI 267023 106809 AbstractIntermittent or acute/cyclic hypoxia in tumors with frequencies between a few cycles per minute to hours isreceiving increased attention because this type of hypoxia has been reported to have an influence on tumormalignancy as well as treatment resistance via increased expression of pro-survival pathways. Fast oxygenimaging methods are needed for the measurement of acute tumor hypoxia. Pulse electron paramagneticresonance imaging (pEPRI) is a promising tool to provide three-dimensional partial oxygen pressure (pO2) mapsin live tissues and tumors to assist with advanced studies of tumor biology perfusion drug development andradiation treatment. Single point imaging (SPI) an acquisition technique developed at National Cancer Institute(NCI) is a subset of pEPRI methods that can be used for oxygen image acquisition. It provides high-resolutionhigh-fidelity images but is slow due to the need for acquiring each k-space point individually. In the currentproject our goal is to improve the image acquisition speed of SPI by utilizing a combination of advancedhardware and deep learning. This will improve the imaging speed by many folds without compromising theimage quality. These advances will be tested in a mouse model of fibrosarcoma tumor. This project will bring anNIH-developed technology to the commercial level. Our long-term goal is to imply the advanced hardware andsoftware technologies of oxygen imaging to clinics to assist with oxygen-guided tumor treatments. 400000 +No NIH Category available Address;Adoption;Affinity;Allogenic;Animals;Antigen Targeting;Antigens;Autologous;B lymphoid malignancy;B-Cell Activation;B-Lymphocytes;Benefits and Risks;Binding;Biological Assay;CAR T cell therapy;CD19 gene;Cell Line;Cell Therapy;Cells;Cellular biology;Chemistry;Clinical;Coculture Techniques;Complex;DNA;DNA Transposons;Data;Development;Documentation;Dose;Drug Kinetics;Engineering;Evaluation;Family;Generations;Genetic;Genetic Engineering;Human;Immunocompromised Host;Immunotherapeutic agent;Immunotherapy;In Vitro;Interleukin 4 Receptor;Life;Ligands;Longevity;MS4A1 gene;Malignant - descriptor;Malignant Neoplasms;Mantle Cell Lymphoma;Mature B-Lymphocyte;Memory;Messenger RNA;Methods;Mus;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Population;Positioning Attribute;Process;Production;Property;Protocols documentation;Qualifying;Quality Control;Recommendation;Recurrent disease;Relapse;Reproducibility;Residual state;Running;Safety;Signal Transduction;Source;Specific qualifier value;System;T cell therapy;T-Lymphocyte;Technology Transfer;Testing;Therapeutic Intervention;Time;Toxic effect;Toxicity Tests;Tumor Antigens;Validation;Viral;Work;Xenograft procedure;cancer cell;cell killing;chimeric antigen receptor;chimeric antigen receptor T cells;commercialization;cost;cost effective;cytotoxic;cytotoxicity;design;efficacy evaluation;engineered T cells;experience;good laboratory practice;graft vs host disease;improved;improved outcome;in vivo;in vivo evaluation;innovation;manufacture;manufacturing process;mouse model;neoplastic;novel;novel therapeutics;patient subsets;pre-clinical;preclinical evaluation;preservation;prevent;product development;receptor;receptor expression;response;safety study;safety testing;targeted treatment;therapeutic development;timeline;tumor;tumor xenograft; T cells Allogeneic BAFF Ligand Based CAR T Cells as a Novel Therapy for B Cell Malignancies PROJECT NARRATIVEThis proposal describes a novel allogeneic chimeric antigen receptor (CAR) T cell therapy that aims to improveoutcomes for patients with mantle cell lymphoma. Our approach improves upon current immunotherapies byengineering T cells in a unique way to express a novel CAR against multiple underexplored targets in an allogenicplatform. We expect immunotherapeutic delivery of these modified T cells will reduce disease recurrence bypreventing antigen escape improving persistence and decreasing manufacturing burden. NCI 10698759 6/30/23 0:00 PA-22-176 1R44CA278021-01A1 1 R44 CA 278021 1 A1 "BOZZA, WILLIAM PATRICK" 7/1/23 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1-OTC-V(13)B] 11510946 "DUNMIRE, SAMANTHA " "GIBBONS, HUNTER RAMSDELL" 5 Unavailable 117107790 MNKBAEZHWJS1 117107790 MNKBAEZHWJS1 US 44.928994 -93.319207 10056556 "LUMINARY THERAPEUTICS, INC." MINNEAPOLIS MN Domestic For-Profits 55415 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 SBIR/STTR 2023 397934 NCI 267580 104356 ABSTRACTSince the first FDA approval of chimeric antigen receptor (CAR) T cell therapy in 2017 the use of engineered Tcells expressing specific CARs to treat cancer has generated durable cures for many patients. Nevertheless asignificant subset of patients with B cell malignancies relapse following treatment due to lack of CAR T cellpersistence and the ability of cancer cells to change with time and evade therapeutic interventions. AutologousT cell therapies also carry significant timeline and cost burdens making widespread adoption difficult. In thisapplication we propose a novel allogeneic CAR T cell therapy aimed at improving outcomes for patients withmantle cell lymphoma (MCL) by overcoming deficiencies present in current generation CD19 targetedtherapeutics. B cell activating factor (BAFF) provides critical survival signals to both normal and neoplastic Bcells through a family of receptors (BAFF receptor TACI and BCMA) thus mitigating potential for antigen escape.BAFF and its receptors have remained underexplored in the context of B cell malignancies where strategieshave relied overwhelmingly on pan B cell antigens such as CD19 and CD20. Since BAFF binds its receptorswith moderate affinity we believe this will increase the ability of these cells to form memory populations andengage in serial killing. We will leverage this ligand-based CAR design in an allogeneic gamma delta () T cellplatform as T cells have been shown to have high replicative properties in vitro and do not mediate graftversus host disease in new hosts. We have produced preliminary data that confirms our ability to use the non-viral TcBuster DNA transposon system to generate T cells with BAFF-CAR expression. The overall objective ofthis proposal is to further develop and evaluate our BAFF-CAR T cell therapy for the treatment of MCL in INDenabling studies. In doing so our allogeneic BAFF-CAR T cell therapy supports an urgently needed shift intherapeutic development toward new tumor antigens that protect against antigen escape while reducing themanufacturing burden associated with cellular therapies through use of a readily available cell source. 397934 +No NIH Category available Address;Adoption;Affect;Aminolevulinic Acid;Applications Grants;Automatic Data Processing;Biomedical Engineering;Blood;Brain Neoplasms;Breast-Conserving Surgery;Carcinoma;Caring;Clinical;Collaborations;Community Clinical Oncology Program;Contrast Media;Custom;Data;Detection;Development;Devices;Equipment;Excision;Fluorescence;Frequencies;Funding;Glioma;Human;Image;Imaging Device;Intuition;Judgment;Light;Lighting;Manufacturer;Marketing;Measurement;Medical;Medical Device;Medical Imaging;Microscope;Mission;Morbidity - disease rate;Noise;Normal tissue morphology;Oncology;Operating Rooms;Operative Surgical Procedures;Patients;Perception;Performance;Phase;Phase III Clinical Trials;Physiologic pulse;Pilot Projects;Price;Property;Quality of life;Research;Residual Cancers;Residual Neoplasm;Sampling;Scheme;Side;Signal Transduction;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Source;Speed;Structure;Surface;Surgeon;Surgical Instruments;Surgical Oncology;System;Techniques;Technology;Time;Tissues;Translating;Tumor Tissue;United States National Institutes of Health;Validation;Visual;Visualization;Work;analog;brain tumor resection;clinical practice;commercialization;computerized data processing;cost;data acquisition;detection sensitivity;digital;fluorescence lifetime imaging;fluorescence-guided surgery;fluorophore;imaging agent;imaging system;improved;in vivo;instrumentation;intraoperative optical imaging;member;nanosecond;neoplastic cell;neurosurgery;operation;processing speed;protoporphyrin IX;ratiometric;tumor Fluorescence lifetime imaging device for 5-ALA-guided neurosurgery PROJECT NARRATIVE5-ALA-induced PpIX fluorescence guided surgery (FGS) enables real-time visualization of residual tumor tissueduring resection of brain tumors improving overall survival. Currently surgeons visually appreciate thefluorescence intensity using modified microscopes under low-light conditions. This approach is qualitative anddisrupts the surgical workflow. We have demonstrated using research instrumentation that fluorescence lifetimeimaging (FLIm) enables highly sensitive and quantitative detection of PpIX during surgery. In this grantapplication we will develop a FLIm data acquisition and processing approach using a low-cost and high-performance ADC with FPGA data processing that will lead to a 4-fold reduction in instrumentation costs andthus facilitate the commercialization and broad adoption of FLIm FGS technology. NCI 10698741 6/1/23 0:00 PA-22-178 1R41CA281543-01 1 R41 CA 281543 1 "DJEMIL, SARRA" 6/1/23 0:00 5/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 15586125 "BEC, JULIEN " Not Applicable 4 Unavailable ZZK2B8UXTFJ3 ZZK2B8UXTFJ3 US 10070915 "HILIGHT SURGICAL, INC." DAVIS CA Domestic For-Profits 956161734 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 SBIR/STTR 2023 239040 NCI 180797 42608 PROJECT SUMMARY5-ALA-induced PpIX fluorescence-guided surgery (FGS) enables real-time visualization of residual cancer tissueduring resection of brain tumors. This addresses a critical need in surgical oncology as the ability to identifyresidual tumor leads to improvements in overall survival whereas the sparing of normal tissue benefits thepatients quality of life. Currently surgeons visually appreciate the PpIX fluorescence intensity under low-lightconditions using modified microscopes. This approach is qualitative as the perception of PpIX fluorescenceintensity is influenced by many factors including: 1) the type of light source used for illumination 2) themicroscopes working distance 3) the presence of endogenous absorbers such as blood and 4) non-uniformillumination of the surgical field which is especially critical as residual tumor present on the sides of the surgicalcavity may be missed due to insufficient fluorescence excitation. Additionally operation under low-lightconditions disrupts the surgical workflow. Our research group at UC Davis has developed a fluorescence lifetime (FLIm) based FGS approach that ishighly sensitive quantitative and insensitive to room light addressing the challenges of the existing 5-ALA FGSinstrumentation. The performances of this system were evaluated in a recent pilot study demonstrating 5-ALA-induced PpIX fluorescence detection in human high- and low-grade glioma patients in vivo (patients duringsurgery). Building on these results HiLight Surgical was established by team members from UC Davis with the missionto support surgeons by developing and commercializing easy-to-use imaging systems that provide accuratequantitative information about fluorophore accumulation at a price point suitable for broad adoption by thesurgical oncology community. We plan to develop and validate a low-cost high performance FLIm FGS systemin this phase I proposal by: SA1: Implementing FLIm data acquisition and processing using a low-cost high-speed analog-to-digital converter (ADC) and an FPGA. This will enable a ~4-fold cost reduction of the system as well as reduceits footprint. SA2: Characterize the performance of this alternative data acquisition and processingimplementation compared to the reference research-grade instrumentation. At the conclusion of this work we will have determined whether the performance achieved with thisalternative low-cost data acquisition and processing is suitable to proceed with the development of a commercialFLIm device well-tailored for the requirements of 5-ALA fluorescence-guided surgery. 239040 +No NIH Category available 3-Dimensional;Artificial Intelligence;Basal cell carcinoma;Benchmarking;Biopsy;Cancerous;Clinical;Collaborations;Computer software;Consumption;Devices;Diagnosis;Diagnostic;Engineering;Ensure;Equipment;Evaluation;Excision;Failure;Fluorescence;Freezing;Fresh Tissue;Frozen Sections;Funding;Glass;Goals;Head;Health system;Hematoma;Hemorrhage;Histopathology;Hour;Image;Imaging Techniques;Infection;Infectious Skin Diseases;Laboratories;Lateral;Legal patent;Light;Malignant Epithelial Cell;Malignant Neoplasms;Maps;Marketing;Medical Electronics;Methods;Microscope;Microscopic;Modernization;Mohs Surgery;Morphologic artifacts;Noise;Nuclear;Operative Surgical Procedures;Optics;Pain;Pathologic;Pathologist;Pathology;Pathway interactions;Patients;Performance;Perioperative complication;Persons;Phase;Postoperative Complications;Procedures;Process;Reading;Reagent;Reproducibility;Resected;Resolution;Risk;Sampling;Scanning;Screening Result;Sensitivity and Specificity;Signal Transduction;Skin Cancer;Skin Carcinoma;Slice;Slide;Specific qualifier value;Specimen;Specimen Handling;Speed;Squamous cell carcinoma;Staging;Stains;Surface;Surgeon;Surgical Pathology;Surgical complication;System;Technology;Thick;Time;Tissue Preservation;Tissue Sample;Tissues;Training;Tumor stage;United States National Institutes of Health;Validation;Visual;Work;analog;cancer diagnosis;cancer invasiveness;cancer subtypes;cancer surgery;care burden;care costs;commercial prototype;contrast imaging;cost;cost effective;design;digital;digital imaging;digital pathology;disease diagnosis;healing;imaging system;improved;infection rate;meter;miniaturize;miniaturized device;necrotic tissue;novel;pathology imaging;phase 2 study;point of care;prototype;screening;standard of care;success;tissue processing;treatment choice;tumor;validation studies;verification and validation;wound;wound healing Advanced Surgical Pathology Device NarrativeSurgery is currently the best option for treating invasive cancers but successful surgery is constrained by thelimits of modern pathology methods specifically rate-limited by histopathology a time-consuming process thatintroduces artifacts that limit accurate interpretation destroys tissue specimens and causes pain and increasedrate of infections and other surgical complications. SurgiVance is developing the Surgical Pathology System(SPS) a compact durable confocal-based product that produces high-resolution 3D digital pathology imagesat a patients bedside within seconds. This laboratory-in-a-box is designed to replace outdated slow andexpensive tissue specimen processing and imaging procedures in pathology and enable AI-driven analysis. NCI 10698697 4/25/23 0:00 PA-22-176 2R44CA235915-02 2 R44 CA 235915 2 "EVANS, GREGORY" 8/1/19 0:00 4/30/25 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 14272381 "HAWKES, JASON EZRA" "GAREAU, DANIEL SUMMER" 12 Unavailable 80990952 JH4EDZ5CQZD5 80990952 JH4EDZ5CQZD5 US 40.76109 -73.957919 10049768 "SURGIVANCE, INC." NEW YORK NY Domestic For-Profits 100657954 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 393 SBIR/STTR 2023 1020044 NCI 824312 129000 AbstractDiagnosing diseases relies heavily on pathologically analyzing tissue samples from patients. For cancers aloneover 30 million people undergo tissue biopsies annually in the US. While surgery currently represents the beststandard of care treatment to cure invasive cancers its success depends on timely excision of the tumor beforeit can spread. This is especially true for the removal of skin cancers more common in the populace than all othermalignancies combined with Mohs surgery deemed the best treatment of choice for its high skin cancer curerates. However this procedure requires the repeated histopathological evaluation of patient tissue samples toconfirmation of cancerous or non-cancerous tissue. This time-consuming step requires freezing slicing andpreserving the tissue between microscope slides to take an image adding 2-3 hours to surgical times. Itincreases operative times and the risk of postoperative complications including skin infections bleeding orhematoma wound dehiscence (disruption of recently repaired wounds) tissue necrosis and pain. The processis also expensive requiring ~$70k of equipment to set up and pricy reagents and highly trained staff to maintain.There is an unmet need in the market for a cost-effective digital pathology solution to rapidly produce high-qualityimages. SurgiVance is developing a confocal-based Surgical Pathology System (SPS) to non-invasively andrapidly image intact specimens with high resolution. The SPS system uses a novel patented line-scanningstage-scanning confocal microscope. The NIH Phase 1 funded prototype successfully images standard sizedspecimens (5 mm x 10 mm) in only 17 seconds at 1.2 m lateral resolution and 8.6 m optical section thickness.In this Phase II project SurgiVance has 3 specific aims: 1) Recreate the prototype SPS device in a partnerfacility which will perform design and engineering work to miniaturize the device reduce its complexity andincrease its durability for market use 2) develop AI-based software to rapidly scan and map the surfaces of freshsamples resected directly from patients and 3) clinically validate the superior performance of SPS created 3Ddigital images of fresh tissue samples in comparison to the standard-of-care histopathology in Mohs patients inbenchmarks established by the SurgiVance FDA Q-Sub Class II 510(k) pathway to meet beachhead marketneeds. This Phase II study will enable SurgiVance to shift the paradigm towards instant digital 3D pathologythat when integrated with SurgiVances AI-based diagnostics could enable robust reproducible and rapidautomated diagnoses. 1020044 +No NIH Category available Aftercare;Anatomy;Animal Model;Animals;Benign Prostatic Hypertrophy;Biochemical;Brachytherapy Seeds;Canis familiaris;Cervical;Clinical;Clinical Data;Clinical Trials;Data;Devices;Dimensions;Dose;Effectiveness;Environment;Evaluation;Formulation;Foundations;Gases;Grant;Head and Neck Cancer;Head and neck structure;Health;Human;Hypoxia;Image;Immunotherapy;Innovation Corps;Interview;Lead;Literature;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Measurement;Measures;Methods;Modeling;Monitor;Mus;Nature;Oncology;Outcome;Oxygen;PC3 cell line;Patient-Focused Outcomes;Patients;Performance;Phase;Physiological;Pilot Projects;Polymers;Prostate;Radiation Dose Unit;Radiation therapy;Resistance;Resolution;Rodent Model;Science;Silicones;Site;Small Business Innovation Research Grant;Testing;Tissues;Trauma;Validation;Visual;Work;arm;biomaterial compatibility;chemotherapy;design;good laboratory practice;implantation;improved outcome;in vivo;malignant breast neoplasm;mechanical properties;migration;minimally invasive;mortality;personalized cancer care;personalized medicine;preclinical evaluation;programs;prostate cancer model;prostate enlargement;sensor;targeted treatment;technology validation;treatment planning;trend;tumor;tumor hypoxia Minimally invasive quantitative tissue oxygen sensors to personalize cancer care Project NarrativeLow oxygen tumors are more resistant to treatment and lead to poorer outcomes for patients.Boosting radiation dose to the low oxygen regions of the tumor offers an opportunity to overcomethis resistance but has been limited due to the lack of a suitable clinical oxygen sensor. Theproposed oxygen sensor would overcome the limitations of existing alternatives and offer theopportunity for personalized treatment approaches. NCI 10698650 9/14/23 0:00 PA-22-176 1R43CA281444-01 1 R43 CA 281444 1 "DJEMIL, SARRA" 9/14/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-S(11)B] 16144747 "EKCHIAN, GREGORY " Not Applicable 5 Unavailable 117111977 U88TTMK6HUM4 117111977 U88TTMK6HUM4 US 42.366294 -71.103353 10055925 "STRATAGEN BIO, INC." CAMBRIDGE MA Domestic For-Profits 21392402 UNITED STATES N 9/14/23 0:00 8/31/24 0:00 393 SBIR/STTR 2023 399888 NCI 287482 86245 Project Summary and AbstractHypoxic (oxygen depleted) tumors are more resistant to treatments including radiation therapy. This trend hasbeen seen across a wide range of cancers including prostate head and neck and cervical. Radiobiologicalstudies have shown that elevated radiation doses can be used to overcome hypoxia-induced resistance andachieve the same level of effectiveness as lower doses in more well-oxygenated environments. The majorimpediment to implementing this (and other) hypoxia targeting therapies is the lack of a suitable oxygen sensor.Actionable oxygen sensors should be quantitative workflow compatible and provide spatial context for eachmeasurement. Current and past alternatives for oxygen sensing are either qualitative too invasive or both. Theproposed oxygen sensor will offer a workflow-compatible method to obtain quantitative tumor oxygen data. Thesensor is measured non-invasively using MRI which provides a spatial/anatomical context for eachmeasurement. The sensor is made completely of silicone inserted with minimally invasive methods equilibratesquickly with the surrounding tissue and is fully reversible. The polymeric nature of the material allows it to remainat the site of insertion indefinitely to enable long-term monitoring. The proposed work focuses on selection of alead formulation (Aim 1) evaluation in a small animal tumor model (Aim 2) and evaluation in a large animalmodel to mimic the tissue volumes expected during human use (Aim 3). The sensor produced as part of thisproposal will be translatable to additional applications in oncology but also to non-oncology applicationsincluding tissue health and trauma. 399888 +No NIH Category available Acceleration;Acute;Amino Acids;Animal Model;Biological Products;Businesses;C57BL/6 Mouse;Cancer Patient;Cattle;Cell Line;Cells;Cicatrix;Classification;Clinical;Clinical Treatment;Connexin 43;Connexins;Consumption;Data;Disease;Dose;Drug Delivery Systems;Dyspepsia;Encapsulated;Expectancy;Food;Formulation;Future;Gastrointestinal Injury;Gastrointestinal tract structure;Glioblastoma;Healthcare Systems;Heart Diseases;Histologic;Human;In Vitro;Industrialization;Injury;Journals;Juice;Legal patent;Lethal Dose 50;Licensing;Link;Long-Term Effects;Malabsorption Syndromes;Malignant Neoplasms;Medical;Medical Technology;Methods;MicroRNAs;Military Personnel;Milk;Miniature Swine;Modality;Modeling;Mucous Membrane;Mus;Myocardial Ischemia;Nausea;Nutrient;Oral;Oral Administration;Pain;Pathology;Patients;Penetration;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Phase III Clinical Trials;Prevention;Production;Quality of life;Radiation;Radiation Protection;Radiation exposure;Radiation induced damage;Radiation therapy;Radiation-Protective Agents;Rattus;Recurrent Malignant Neoplasm;Regimen;Regulation;Reporting;Research;Route;Skin;Small Business Technology Transfer Research;Technology;Testing;Therapeutic;Tissues;Topical application;Toxic effect;Virginia;Vomiting;Weight;Whole-Body Irradiation;Work;animal rule;cancer radiation therapy;cancer recurrence;commercialization;compliance behavior;efficacy evaluation;exosome;experimental study;extracellular vesicles;gastrointestinal;gastrointestinal epithelium;in vivo;in vivo evaluation;insight;interest;irradiation;medical countermeasure;mimetics;mouse model;nanotheranostics;novel;novel therapeutics;peptide drug;porcine model;prevent;prophylactic;radiation burn;radiation effect;radioprotected;side effect;technology platform;treatment strategy;uptake Novel Drug Delivery Platform as Medical Countermeasure for treatment of Gastrointestinal Radiation Damage PROJECT NARRATIVETiny Cargo has developed a novel drug delivery system combining non-immunogenic bovinemilk derived EVs (mEVs) with highly potent peptide therapeutics for treatment ofgastrointestinal radiation damage following Radiation Therapy. The successfulcommercialization of this technology will allow for more intensive radiation therapy regimensand a reduction in cancer recurrence thus increasing quality of life and lifetime expectancy forthose afflicted with cancer; additionally this research will provide an effective medicalcountermeasure to the US military to protect against radiation exposure in the field a key focusof BARDA. Most importantly this research will establish mEVs loaded with peptide therapeuticsas a novel drug delivery platform capable of treating a wide range of diseases via a patientcompliance oral uptake route advancing clinical treatment of diseases from glioblastomamultiforme to ischemic cardiac disease representing a new modality in treatment. NCI 10698637 9/22/23 0:00 PA-22-178 1R41CA272078-01A1 1 R41 CA 272078 1 A1 "BOZZA, WILLIAM PATRICK" 9/22/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-BBBT-F(10)B] 78348963 "MARSH, SPENCER REID" Not Applicable 6 Unavailable 103379362 V4VBSJU5L458 103379362 V4VBSJU5L458 US 10066358 "TINY CARGO COMPANY, THE" ROANOKE VA Domestic For-Profits 240141823 UNITED STATES N 9/22/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 400000 NCI 267023 106809 Project Summary/AbstractThe Tiny Cargo Company offers a unique orally administered medical countermeasure for treatment andprevention of the gastrointestinal (GI) side effects of cancer radiation therapy (RT). Our therapeutic iscomprised of milk-derived extracellular vesicles (mEVs) loaded with a safe and highly effectiveradioprotective drug a formulation that we call Milactatm. RT complications include nausea vomitingpain and dyspepsia mucosal barrier breakdown and nutrient malabsorption - with long-term effects thatcan also include cumulative and irreversible scarring of the gut. Presently there are no treatments toprevent or mitigate these side-effects of RT. Our world-wide exclusive license from Virginia Tech includespending patents for the composition and method of drug loading into mEVs of our radioprotective drugas well as methods for industrially scalable production and isolation of pharmaceutical-grade mEVs frombovine milk. mEVs are subject to minimal regulation by the FDA and our radioprotective drug is a novelshort 9 amino acid peptide (RPRPDDLEI) mimicking the C-Terminus of the human gap junction proteinConnexin 43. Our technical premise is that encapsulation of RPRPRDDLEI in mEVs will enable oraldelivery and protection of our fragile peptide therapeutic in digestive juices prior to uptake in GI-tractcells. Our preliminary data indicates an optimized mEV-drug loading approach demonstration of uptakeof mEVs by gut cells/tissues following oral administration and in vitro data that our RPRPDDLEI-mEVformulation provides potent levels of radioprotection to cultures of the rat GI-tract derived primary cellline IEC-6 comparable to Phase III Clinical Trial therapeutic CT1. In two aims we will: 1) Undertaketesting in vivo of the prophylactic efficacy of our mEV-RPRPDDLEI formulation (i.e. Milacta) in a mousemodel of whole-body irradiation and; 2) Determine the optimal dosing regimens (i.e. prophylactic post-irradiation dual-treatment) for maximized radioprotection. Tiny Cargos technology meets an urgentclinical need that could increase patient uptake and compliance with highly effective radiation-basedcancer mitigation strategies as well as providing a medical technology that is likely to be of high strategicinterest to the US and our military. Moreover our mEV-based and drug loading method represents aplatform technology that in the future could be adapted for other difficult-to-drug biologics includingmicroRNAs and other therapeutic peptides thereby providing new licensing and commercialcollaborative opportunities for Tiny Cargo as it develops its business plan and pipeline beyond mitigationof the effects of radiation therapy in cancer patients. 400000 +Cancer Age;Censuses;County;Population;Race;sex ANNUAL POPULATION ESTIMATES FOR COUNTIES AND CENSUS TRACTS BY SEX AGE AND RACE n/a NCI 10698546 75N91022P00514-0-0-1 N02 5/26/22 0:00 11/25/22 0:00 78692045 "HOLDRICH, MARTIN " Not Applicable Unavailable 126551290 WMDKRKNECL24 126551290 WMDKRKNECL24 US 38.922689 -77.042478 -354856 WOODS & POOLE ECONOMICS I WASHINGTON DC Other Domestic Non-Profits 200092808 UNITED STATES N R and D Contracts 2022 34000 NCI ANNUAL POPULATION ESTIMATES FOR COUNTIES AND CENSUS TRACTS BY SEX AGE AND RACE 34000 +Cancer Data;Educational workshop;Logistics;Malignant Neoplasms;Training;cancer registrars;web site SEER TRAINING WEBSITE AND CANCER PATHCHART TECHNICAL AND LOGISTICAL SUPPORT n/a NCI 10698544 75N91022P00406-0-0-1 N02 6/1/22 0:00 5/31/23 0:00 78704016 "ALLEN, NANCY " Not Applicable 8 Unavailable 175355734 V89HKGKH55G8 175355734 V89HKGKH55G8 US 38.815352 -77.052065 3641001 NATIONAL CANCER REGISTRAR'S ASSOCIATION ALEXANDRIA VA Other Domestic Non-Profits 223141693 UNITED STATES N R and D Contracts 2022 136838 NCI SEER TRAINING WEBSITE NEW DATA ITEM FEASIBILITY ADVANCED TOPICS FOR CANCER REGISTRARS WORKSHOP AND CANCER PATHCHART TECHNICAL AND LOGISTICAL SUPPORT 136838 +No NIH Category available Animal Model;Award;Biochemical;Biodistribution;COVID-19 vaccine;Cancer Model;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Colon Carcinoma;Colonic Neoplasms;Colorectal;Colorectal Cancer;DNA;Data;Disease;Disease model;Dose;Drug Combinations;Drug Kinetics;FDA approved;Fluorouracil;Formulation;Foundations;Generations;Genetic;Human;Immunotherapy;Laboratories;Leucovorin;Lung;Malignant neoplasm of gastrointestinal tract;Metabolism;Metastatic Neoplasm to the Liver;Modeling;Mus;Nucleic Acids;Outcome;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacology Study;Pharmacology and Toxicology;Phase;Physiological;Physiology;Polymers;Preclinical Drug Development;Preclinical Testing;Property;Rattus;Refractory;Regimen;Research;Rodent;Rodent Model;Safety;Saline;Schedule;Small Business Technology Transfer Research;Sterility;Testing;Therapeutic;Toxic effect;Toxicity Tests;Toxicology;Translating;anticancer activity;cancer cell;chemotherapy;clinical candidate;clinical development;colon cancer patients;colorectal cancer treatment;commercialization;design;efficacy testing;fluoropyrimidine;forest;improved;innovation;lipid nanoparticle;medical schools;metastatic colorectal;mortality;mouse model;nonhuman primate;novel strategies;oxaliplatin;pharmacokinetic model;pharmacologic;phase 2 study;preclinical study;standard of care;systemic toxicity;targeted treatment;therapy resistant;tumor Improved Treatment of Colorectal Cancer with CF10 PROJECT NARRATIVEThis Phase 2 STTR proposal will develop CF10 the first DNA-based fluoropyrimidine (FP) polymer as a newtreatment for metastatic colorectal cancer (mCRC). The best available treatments for mCRC use 5-fluorouracil(5-FU)-based regimens and were optimized over decades but result in <15% 5 year survival with <50% of mCRCpatients treated with chemotherapy surviving 1 year. Through Phase 1 STTR support we demonstratedimproved anti-cancer activity for CF10 in rodent colon cancer models and an improved toxicity profile relative to5-FU. To advance CF10 into clinical trials we will test for improved survival relative to current therapy in a rodentmodel of pre-treated mCRC. We also develop a lipid nanoparticle (LNP) formulation to improve CF10pharmacokinetics. Safety Pharmacology testing of CF10 with LNP formulation will be performed in rodents andnon-human primates (NHPs). Our studies will provide a foundation for regulatory approval to initiate clinicalstudies. Ultimately CF10 will improve long-term survival for patients with mCRC. NCI 10698394 5/1/23 0:00 PA-22-178 2R42CA254834-02A1 2 R42 CA 254834 2 A1 "POND, MONIQUE ADRIANNE" 5/1/23 0:00 4/30/25 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 1862406 "GMEINER, WILLIAM H" Not Applicable 5 Unavailable 117358393 K3KKUWLAKDE3 117358393 K3KKUWLAKDE3 US 36.122459 -80.582902 10058093 "DEEP CREEK PHARMA, LLC" YADKINVILLE NC Domestic For-Profits 270555624 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 SBIR/STTR 2023 964465 NCI 910282 33580 PROJECT SUMMARYDecades of modulating the anti-cancer activity of fluoropyrimidine drugs (FPs) thru schedule optimizationbiochemical modulation and drug combinations have provided a significant but limited survival advantage fortreating colorectal cancer (CRC) patients with locally advanced or metastatic disease (mCRC). Howeveroutcomes remain poor for patients with mCRC and since targeted therapies and immunotherapies provide onlya limited benefit to a sub-set of CRC patients new approaches are urgently needed. Deep Creek Pharmatogether academic partner Wake Forest School of Medicine (WFSM) is developing CF10 the first DNA-basedFP polymer as an improved treatment for CRC. In pre-clinical studies through Phase 1 STTR support we havedemonstrated that CF10 is much more potent than 5-FU to CRC cells and demonstrated improved survivalrelative to 5-FU in multiple colon tumor models in rodents. Further CF10 displayed reduced systemic toxicitiesrelative to 5-FU making it a strong candidate for clinical development. We have also established CF10 displaysdistinct pharmacological and mechanistic properties relative to conventional FP drugs. Based on these findingsDeepCreek Pharma and WFSM/Gmeiner Lab propose to jointly investigate CF10 as a candidate for clinicaldevelopment.A major unmet need is treatment of mCRC that is refractory to FOLFOX (5-FU Leucovorin (LV) oxaliplatin) andother front-line therapies for mCRC. The proposed research in phase II will therefore focus on (Aim 1) DevelopingCF10 lipid nanoparticles (LNPs) and testing for improved activity including in a therapy-resistant CRC livermetastasis model. LNP formulation has proven to be a robust delivery strategy for multiple nucleic acid drugsand identifying a preferred LNP formulation will promote CF10 clinical development. In Aim 2 of the Phase IIstudies we will perform safety pharmacology studies of CF10 and CF10:LNPs in rodents while in Aim 3 we willevaluate pharmacokinetics (PK) and biodistribution in non-human primates (NHPs). Studies in NHPs accuratelyreflect human physiology and metabolism and are particularly important for regulatory apprval. Collectively ourPhase II STTR studies will provide critical data for to advance CF10 into clinical trials and ultimately itscommercialization. 964465 +No NIH Category available Ablation;Address;Algorithms;Area Under Curve;Artificial Intelligence;Biomedical Engineering;Biopsy;Biopsy Specimen;Brain Neoplasms;Bronchoscopy;Cancer Detection;Cancer Patient;Cells;Certification;Cessation of life;Classification;Clinical;DNA Sequence Alteration;Data Set;Detection;Development;Devices;Diagnosis;Diagnostic;Disease;Epidermal Growth Factor Receptor;Evaluation;Forcep;Future;Grant;Hilar;Histology;Image;Image Analysis;Institution;KRAS2 gene;Location;Lung;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Mediastinal;Medical Device;Medicine;Modality;Molecular;Molecular Diagnosis;Molecular Profiling;Multicenter Studies;Mutation;Nature;Needles;Outcome;Pathologic;Pathologist;Pathology;Patients;Performance;Peripheral;Pharmacologic Substance;Procedures;ROC Curve;Research Design;Sampling;Science;Site;Specificity;System;Testing;Time;Tissues;Training;Translating;Validation;aspirate;cost;deep learning;deep learning algorithm;low dose computed tomography;lung imaging;lung lesion;lymph nodes;meetings;microscopic imaging;molecular marker;next generation sequencing;participant enrollment;prognostic;programmed cell death ligand 1;screening program;standard of care;tool;treatment planning A multicenter study in bronchoscopy combining Stimulated Raman Histology with Artificial intelligence for rapid lung cancer detection - The ON-SITE study Project NarrativeLung cancer accounts for about 25% of all cancer deaths in the US since it is often caught atan advanced stage when treatment options are limited. This has led to the institution ofscreening programs with low-dose CT resulting in ~1.6 million pulmonary nodules detectedevery year most of them (~80%) in the periphery of the lung. We propose the development ofan FDA-cleared medical device that allows microscopic imaging of fresh unprocessed tissuebiopsies in the treatment room and that would provide accurate near real-time diagnosis basedon deep learning to identify tissue biopsies that are of diagnostic quality. NCI 10698382 3/1/23 0:00 PA-22-176 1R44CA281581-01 1 R44 CA 281581 1 "EVANS, GREGORY" 3/1/23 0:00 2/28/25 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 10889383 "FREUDIGER, CHRISTIAN " "BURKS, ALLEN COLE; HUSTA, BRYAN CHRISTOPHER; OST, DAVID EDWARD" 17 Unavailable 967799516 N8ADGJWND191 967799516 N8ADGJWND191 US 37.478721 -122.140531 10030586 INVENIO IMAGING INC. SANTA CLARA CA Domestic For-Profits 950511301 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 394 SBIR/STTR 2023 945279 NCI 750901 133852 Project Summary & AbstractLung cancer accounts for about 25% of all cancer deaths in the US as it is often caught at anadvanced stage when treatment options are limited. This has led to the institution of screeningprograms with low-dose CT resulting in ~1.6 million pulmonary nodules detected every yearmost of them (~80%) in the periphery of the lung.Tissue biopsy is the standard of care for establishing a definitive diagnosis for treatmentplanning. Rapid on-site evaluation (ROSE) of tissue biopsies in the procedure room bycytopathologists or cytotechnicians can be used to establish that: 1. Diagnostic quality tissue has been procured; identifying malignancy by ROSE has been shown to reduce the number of biopsy tools and repeat procedures 2. An adequate number of cells have been obtained to allow molecular profiling by next- generation sequencing and molecular testing 3. The absence of metastatic disease in the lymph nodes justifies the more-invasive peripheral biopsy.Nevertheless ROSE is not the standard of care despite its advantages because its quality ishighly variable across sites it can increase procedure times and its costs are unlikely to be fullyreimbursed. We propose the development of an FDA-cleared medical device that allowsmicroscopic imaging of fresh unprocessed tissue biopsies in the treatment room and providesaccurate near real-time diagnosis based on deep learning.Specifically the proposed system uses Stimulated Raman Histology (SRH) which waspioneered by the PI translated for intraoperative diagnosis in brain tumors shown to be suitablefor automated diagnosis via deep learning with a performance that is non-inferior topathologists and resulted in the first CE-certified device for identification of brain tumor marginsby the company. Here we address an urgent clinical need in lung cancer giving doctorsconfidence in their intraoperative decisions and reducing unnecessary biopsies/procedures forpatients and payers.Further we will investigate the potential to provide accurate intraoperative diagnosis ofmolecular markers that could enable local delivery of pharmaceuticals ablation and othertherapies in the biopsy procedure. 945279 +Behavioral and Social Science; Cancer; Health Disparities; Sexual and Gender Minorities (SGM/LGBT*) Adherence;Administrative Efficiency;Area;Awareness;Basic Science;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Community Outreach;Computer software;Data;Data Collection;Data Management Resources;Development;Documentation;Education;Ensure;Faculty Recruitment;Foundations;Funding;Gender Identity;Goals;Guidelines;Infrastructure;Institution;Investments;Leadership;Marketing;Mission;NCI Center for Cancer Research;NCI-Designated Cancer Center;Operations Research;Patient Care;Plan B;Policies;Population Sciences;Process;Productivity;Reporting;Research;Research Personnel;Resource Sharing;Resources;Role;Services;Sex Orientation;Strategic Planning;Structure;System;Time;Training;Training Support;Training and Education;Universities;Update;Work;administrative database;anticancer research;career;data management;digital;implementation strategy;improved;member;operation;outreach;programs;social media Cancer Center Administration n/a NCI 10698310 9/7/22 0:00 PA-20-272 3P30CA056036-23S2 3 P30 CA 56036 23 S2 "PTAK, KRZYSZTOF" 6/22/95 0:00 5/31/23 0:00 ZCA1 8040 12630208 "HUESSER, MATTHEW HOWARD" Not Applicable 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 6/1/22 0:00 5/31/23 0:00 Research Centers 2022 150000 96154 53846 PROJECT SUMMARYThe Administration unit of the Sidney Kimmel Cancer Center (SKCC) provides comprehensive programmaticdirection and administrative support to all aspects of the Center. Under the direction of Dr. Knudsen and there-aligned leadership structure an entirely new Administration mission and focus was implemented alignedwith the strategic plan (IMPACT). Administration strives to complete this mission by providing comprehensiveoversight in the follow seven areas: 1) Facilitating the strategic planning processes and continuedimplementation of IMPACT; 2) Prioritizing catchment-related issues pertaining to programmatic developmentand community outreach; 3) Documentation organization and communication related to SKCC-organizedactivities; 4) Oversight of the CCSG application fiscal management of funds adherence to NCI guidelines andCCSG reporting; 5) Operational oversight of space and Shared Resources; 6) Administration of SKCC facultyrecruitment and retention efforts; 7) Oversight of pilot fund processes and clinical research operations; 8)Governance of membership processes and consortium relations and/or partner institutions; 9) Facilitatescancer research career enhancement related-initiatives. Through these mechanisms Administration providesa strong foundational platform to support the Center Director Senior Leaders Programs Shared ResourcesTIPS mechanism and key leadership committees. Furthermore Administration is integrated into the SKCCExecutive Committee which is now the governing body of the Center. This committee meets weekly andincludes major responsibilities outlining: strategy resource deployment policy strategic alliances high-levelmanagement of SKCC clinical operations research education assessment of catchment area needs andoutreach activities.SKCC Administration is comprised of a well-trained comprehensive staff that are aligned to support the 159members of SKCC as well as Senior Leaders the Clinical Research Organization and Shared Resourceoperations. Although SKCC Administration is comprised of more than 15 members in various diverse rolessupport for only 2 FTE equivalents is requested during this CCSG project period. In the next funding cycleAdministration endeavors to: 1) Refine mechanisms to support the expanding SKCC research missionincluding basic clinical and population science related to catchment area needs; 2) Enhance communicationefforts that promote the goals of the strategic plan awareness and outreach through the facilitation oftransdisciplinary research; 3) Tighten administrative efficiencies to reduce the burden on investigators anddevelop new capabilities for administrative oversight. +No NIH Category available Acetonitriles;Achievement;Address;Aliquot;Automation;Biological Assay;Businesses;Cancer Patient;Clinic;Color;Contrast Media;Data Analyses;Deoxyglucose;Development;Devices;Endotoxins;Ensure;Equipment;Ethanol;Freezing;Half-Life;Health;Industry;Injections;Malignant Neoplasms;Manuals;Manufacturer;Measurement;Methods;Molds;Molecular;Oncology;Optics;Patients;Performance;Pharmaceutical Preparations;Phase;Positioning Attribute;Positron-Emission Tomography;Problem Solving;Procedures;Process;Production;Quality Control;Radioactive;Radioactivity;Reader;Records;Recurrence;Reporting;Risk;Sampling;Site;System;Technology;Testing;Tracer;Validation;Visual;Work;base;cancer type;clinical imaging;comparative;cost;design;drug quality;high risk;imaging modality;industrial production;innovation;manufacture;manufacturing process;manufacturing scale-up;manufacturing technology;new technology;operation;patient population;scale up;skills;standard of care;tool;tumor;validation studies Establishing industrial production of components that enable expanding accessibility of PET imaging to cancer patient population. Achievement of the project aims will put Trace-Ability in position to support all manufacturers of cancer PET drugs intheir full capacity with a fully-automated QC solution. The impact in the field of Oncology will be manifested in increasedavailability of FDG and other cancer PET scans and facilitation of new tracer development. Such availability is currentlylimited by throughput and compliance issues in PET drug QC which Tracer-QC has proven to address successfully butneeds scalable kit production to offer the enabling benefits to the entire industry. NCI 10698218 4/20/23 0:00 PAR-20-128 2SB1CA192499-04 2 SB1 CA 192499 4 "EVANS, GREGORY" 5/1/23 0:00 4/30/25 0:00 Special Emphasis Panel[ZRG1-MCST-K(19)B] 12217587 "ELIZAROV, ARKADIJ " Not Applicable 29 Unavailable 79094557 S11KA2DGF4J6 79094557 S11KA2DGF4J6 US 34.014578 -118.465765 10036116 "TRACE-ABILITY, INC." VAN NUYS CA Domestic For-Profits 914064844 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 394 SBIR/STTR 2023 156157 NCI 115197 30758 CRP Technical assistance is intended to accomplish the following for Tracer-QC product under development.It will establish industrial production methods (specifically high-precision injection molding) necessary to ensure consistentand controlled scale-up manufacturing of Tracer-QC analysis plates that are currently manufactured by non-salable variableand costly machining process. CRP Problem. Trace-Ability is focusing a lot of current effort on scaling up Tracer-QC kit production to the levelsthat can supply the entire PET industry with high-quality kits. However there is one aspect where the current manufacturingtechnology is not scalable and carries quality risks. It needs to be replaced by a completely new technology in order tosupport the PET industry. Specifically it is the manufacturing of the core Tracer-QC analysis plate in which all QCassessments take place. Current plates are made by cutting standard 384-well plates. Such process is not scalable. It hasinherent plate-to-plate variability and a high risk of debris contaminating the wells required for precise optical analysis. CRP Solution. Trace-Ability has developed a proposal together with Agilent Technologies Inc. to manufactureanalysis plates by injection molding. This project is designed to establish scalable production of analysis plates and re-validate all existing Tracer-QC assays in these plates. Specific Aim 1: Scalable injection molding process for manufacturing high-quality analysis plates. The high-qualityacceptance criteria are (a) well absorbance <0.065 AU in the range of 400-700 nm with a standard deviation (b) <0.003 AUin empty wells and (c) <1% in filled wells at 500 nm. Development will be performed by Agilent. Milestones: (a) Moldedplates meet all acceptance criteria. (b) Finalized molding process is suitable for over 200000 plates per year. Specific Aim 2: Tracer-QC tests validated successfully in molded plates. Before the new plates can be included inTracer-QC kits that can be used for release testing of FDG and other PET drugs 8 assays that rely on the wells of the platewill require testing and validation: color clarity pH Endotoxin Kryptofix acetonitrile ethanol and radioactivityconcentration. Proposed work will be carried out at Trace-Ability. Milestone: Validation results meet all ICH Q2 (R1)acceptance criteria for all assays. This proposal is for technical assistance associated with manufacturing including industrial production equipment andmethods necessary to ensure consistent and controlled scale-up manufacturing according to recognized quality standards.Achievement of the above aims will put Trace-Ability in position to support all manufacturers of cancer PET drugs in theirfull capacity with a fully-automated QC solution. This will maximize the commercial potential of the Tracer-QC businessthat relies on recurring kit revenues from the growing install base. The impact in the field of Oncology will be manifestedin increased availability of FDG and other cancer PET scans and facilitation of new tracer development. Such availabilityis currently limited by throughput and compliance issues in PET drug QC which Tracer-QC has proven to addresssuccessfully but needs scalable kit production to offer the enabling benefits to the entire industry. 156157 +No NIH Category available Address;Affect;Behavior;Biological Assay;CRISPR interference;Cell model;Cells;Data;Educational process of instructing;Etiology;Event;Funding;Generations;Genes;Genetic;Genetic Transcription;Genome;Goals;Human;Individual;Intervention;Learning;Logic;Malignant - descriptor;Malignant Neoplasms;Mammalian Cell;Mediating;Molecular;Molecular Profiling;Mutation;Nature;Normal Cell;Organ;Pharmaceutical Preparations;Physiological;Population;Process;Proteins;Proteome;Reagent;Regulation;Research;Series;Signal Transduction;Signaling Protein;Statistical Models;Technology;Time;cancer cell;cell behavior;curative treatments;expectation;forging;genetic regulatory protein;knock-down;learning network;network models;novel;pharmacologic;predictive modeling;programs;quantum;response;single-cell RNA sequencing;small molecule;synergism;transcriptome sequencing;transdifferentiation;tumor;tumor microenvironment;virtual Predicting Cancer Cell Response to Endogenous and Exogenous Perturbations at the Single Cell Level Once the regulatory and signaling logic of the cell is irreversibly dysregulated by mutations cells are no longerconstrained to well-defined physiologic states but rather transition to a novel dysregulated and highly plasticlandscape where de-differentiation and trans-differentiation events become common and novel synergies withother non-transformed cell populations are forged leading to the emergence of bona fide neomorphic organs.We propose that identifying vulnerabilities that are more universal and less likely to be defeated by the cancercells remarkable adaptive nature will require a quantum leap in our ability to dissect and interrogate intra- andinter-cellular network models that are predictive of the dynamic behavior of cancer as a bona fide neomorphicorgan. For this purpose we will leverage breakthrough technology allowing silencing of thousands of genes inmillions of individual cells followed by RNA-seq profiling thus creating the first generation of genome- andproteome-wide network models that can effectively predict the probabilistic time-dependent response ofmammalian cells to small molecule and genetic perturbations as well as their ability to plastically reprogramacross the relatively small number of molecularly distinct states detected in virtually all human malignancies. NCI 10698176 8/10/23 0:00 PAR-21-333 5R35CA197745-09 5 R35 CA 197745 9 "DUECK, HANNAH RUTH" 8/14/15 0:00 7/31/29 0:00 ZCA1-GRB-I(M1) 7827402 "CALIFANO, ANDREA " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 957321 NCI 588000 379260 The study of cancer has been predicated on the discovery of individual events mechanisms and processes thatare implicated in the malignant transformation of normal cells. The expectation has been that learning howtumors arise would teach us how to defeat them by providing pharmacologically actionable targets.Unfortunately while the etiology of many cancers has been elucidated in painstaking detail curative therapiesfor the more aggressive subtypes remain elusive. Indeed once their regulatory and signaling logic isdysregulated by events leading to transformation cells are no longer constrained to well-defined physiologicstates but rather transition to a novel dysregulated and highly plastic landscape where de-differentiation andtrans-differentiation events become common and novel synergies with other non-transformed cell populationsare forged leading to the emergence of bona fide neomorphic organs. Thus to study cancer we must generatecellular network models that are fully capable of recapitulating dynamic cell behavior and response to drugperturbations mutations and interactions with cells in the tumor microenvironment (TME). Our prior researchsuggests that identifying vulnerabilities that are more universal and less likely to be defeated by the cancer cellsremarkable adaptive nature will require a quantum leap in our ability to dissect and interrogate intra- and inter-cellular network models that are predictive of the dynamic behavior of cancer as a bona fide neomorphic organ.To address this challenge we will create the first generation of genome- and proteome-wide network modelsthat can effectively predict the probabilistic time-dependent response of mammalian cells to small molecule andgenetic perturbations as well as their ability to plastically reprogram across the relatively small number ofmolecularly distinct states detected in virtually all human malignancies. To achieve these goals we will leveragea repertoire of state-of-the-art experimental and computational advances developed over the last six years withR35 funding for the creation of systematic large-scale Transcriptional Regulator Knock-down (TREK) single cellprofiles at multiple time points following CRISPRi-mediated silencing of regulatory proteins. Owing to theirnovelty and value these reagents have already been distributed by Addgene to >270 labs. TREK datacomprising hundreds of thousands to millions of individual molecular profiles and billions of individual molecularreadouts will be used for causal network learning with intervention allowing the assembly of probabilistic modelsof cell regulation that effectively recapitulate the dynamic behavior of both normal and cancer-related cells aswell as their interactions within the TME. By the end of the R35 funding cycle we expect to be able to infer thetime-dependent activity of most regulatory and signaling proteins following arbitrary genetic or pharmacologicperturbations and to infer which proteins were affected by a perturbation based on generation of a small (n 6)longitudinal series of scRNA-seq profiles. These new cellular network models will also allow rapid systematicelucidation of mechanisms that have been traditionally studied via low-throughput hypothesis-driven assays. 957321 +No NIH Category available Address;Adolescence;Adolescent;African;Age;Cancer Burden;Cancer Etiology;Cessation of life;Child;Clinic;Clinical;Communities;Country;Development;Dose;Education;Educational workshop;Elements;Ethnography;Evidence based intervention;Exclusion;Exposure to;Feedback;Friends;HIV;HIV-infected adolescents;Health;Health Services;Household;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papilloma virus infection;Hybrids;Inequity;Infrastructure;Institution;Intention;Intervention;Interview;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Methods;Misinformation;Modeling;Orphan;Outcome;Persons;Politics;Population;Prevalence;Process;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Research;Resources;Risk;Rural;Schedule;Schools;Services;Sex Behavior;Site;Source;Southern Africa;Strategic Planning;System;Technical Expertise;Testing;Thinking;Translating;Trust;Vaccination;Vaccines;Vulnerable Populations;Woman;Zambia;acceptability and feasibility;cancer prevention;cancer risk;cervical cancer prevention;clinical care;clinical infrastructure;contextual factors;design;effectiveness/implementation trial;evidence base;experience;girls;high risk;high risk population;implementation design;implementation evaluation;implementation outcomes;implementation research;implementation science;implementation strategy;informant;low and middle-income countries;novel;peri-urban;prevent;routine care;scale up;social stigma;success;supply chain;tool;vaccine acceptance;vaccine access;vulnerable adolescent Leveraging HIV infrastructure to implement cervical cancer prevention: A study to integrate HPV vaccination in adolescent HIV clinics in Zambia PROJECT NARRATIVECervical cancer is the leading cause of cancer death in women in Zambia a country in southern Africa whereHIV has heightened the risk of developing and dying from cervical cancer. The HPV vaccination is anevidence-based intervention that when delivered in adolescence can prevent most HPV infectionthe causeof cervical cancerand adolescents living with HIV who are at greater risk may especially benefit fromeffective processes to deliver the vaccination to them. Our project builds on a successful stakeholder-engagedsystems thinking approach to design and implement strategies to reduce cervical cancer in low- and middle-income countriesan approach we will use to integrate HPV vaccination services into HIV clinical care aneeded step to reduce global inequities in cervical cancer. NCI 10698170 8/22/23 0:00 RFA-CA-21-056 5U01CA275033-02 5 U01 CA 275033 2 "VEDHAM, VIDYA" 9/6/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M2) 11386883 "HUNLETH, JEAN MARIE" "SILVER, MICHELLE " 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 653874 NCI 520777 133097 ABSTRACT/SUMMARYCervical cancer is the leading cause of cancer death in Zambia where HIV prevalence is also high (11.3%).HIV heightens the risk of developing and dying from cervical cancer. The human papillomavirus (HPV) vaccineis a WHO-endorsed evidence-based tool that can prevent 90% of cervical cancers and is recommended forgirls ages 9-14. However HPV vaccine coverage is low (16%) in low- and middle- income countries (LMICs)and our team's on-the-ground experience suggests HPV vaccination is even lower in Zambia particularlyamong girls with HIV who are most at risk of poor cancer outcomes. Currently HPV vaccination isdelivered via school-based campaigns which are viewed as efficient for broad coverage but also exclude themost vulnerable childrenthose out-of-school or who irregularly attend (e.g. orphans poor). Adolescentsliving with HIV (ALHIV) are more likely to have these additional vulnerabilities. In addition WHO recommendsALHIV receive a 3rd dose of the HPV vaccine which is not given in traditional 2-dose school-based campaigns.To ensure that ALHIV have access to the WHO-recommended 3-doses we propose to integrate HPVvaccination into routine care in adolescent HIV clinics. Adolescent HIV clinics in Zambia have regularcontact with ALHIV and are trusted sources of health information for the community. Given the knownchallenges of providing cervical cancer prevention in LMICs including Zambia (e.g. stigma misinformationstaffing supply chain) integrating HPV vaccination requires a multilevel approach stakeholderengagement and diversified implementation strategies. To achieve success we will co-design a packageof implementation strategies using a previously successful implementation research approach developed forcervical cancer prevention in LMICs: the Integrative Systems Praxis for Implementation Research (INSPIRE).INSPIRE is a novel formal and comprehensive framework to develop implement and evaluateimplementation science efforts. Following key elements of INSPIRE our specific aims are to: 1) Identify theunique multilevel contextual factors (barriers and facilitators) across HIV settings (rural urban peri-urban) thatinfluence HPV vaccine uptake; 2) Use Implementation Mapping to translate stakeholder feedback and findingsfrom Aim 1 into a package of implementation strategies to integrate HPV vaccine into HIV clinics; 3) Conduct aHybrid Type 3 effectiveness-implementation trial to evaluate the package of multilevel implementationstrategies for integrating HPV vaccine into HIV clinics. Our research team has significant expertise in HIVHPV cancer prevention implementation science and LMIC research. Wehave strong institutional backingincluding$325000 over the course of the study;strong support technical expertise and resources (e.g.vaccines) from the Zambian Ministry of Health; and political will for scale-up. If successful thisstakeholder-based implementation model could be transported to HIV clinics across Zambia and serve as amodel to address cancer prevention priorities for those with HIV in other LMICs. 653874 +No NIH Category available Acute;Adenocarcinoma;Architecture;Attention;Benign;Carcinoma;Cell Nucleus;Cells;Chromatin;Chronic;Coupled;DNA;DNA Methylation;DNA Sequence Alteration;Data;Development;Engineering;Epigenetic Process;Epithelial Cells;Equilibrium;Frozen Sections;Future;GSTP1 gene;Gene Activation;Gene Expression;Genes;Genetic;Genomics;Growth;Human;Hypermethylation;Immune;Immune response;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Infiltrate;Interleukin-1 beta;Knock-out;Lesion;Lymphoid Cell;Macrophage;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Metastatic Prostate Cancer;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Neoplasms;PTGS2 gene;Pattern;Phase;Positron-Emission Tomography;Prostate;Prostate Adenocarcinoma;Prostatic;Publishing;RNA Interference;Regulatory T-Lymphocyte;Sampling;Signal Transduction;Stimulator of Interferon Genes;Stress;Testing;Tissues;Up-Regulation;Variant;XCL1 gene;biological adaptation to stress;cancer initiation;cell injury;epigenetic silencing;epigenomics;genome sequencing;imaging agent;immune activation;inhibitor;laser capture microdissection;mouse model;multimodality;neoplastic;neoplastic cell;novel;overexpression;pharmacologic;promoter;recruit;single nucleus RNA-sequencing;synergism;transcriptome sequencing;whole genome Elucidating and testing causal drivers of inflammation triggered prostatic early lesions n/a NCI 10698123 9/1/23 0:00 RFA-CA-21-054 5U54CA274370-02 5 U54 CA 274370 2 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-2 7978 2146873 "DE MARZO, ANGELO MICHAEL" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 287979 223043 64936 "Project Summary/Abstract:We have proposed that inflammatory infiltrates in human PIA reflect an anti-prostatic pro-inflammatory immuneresponse that serves as a hotbed for cancer initiation. Interestingly the acute and chronic inflammatory cellinfiltrates common in PIA are generally not seen in most prostate cancers. These observations have promptedour proving ground hypothesis which suggests that in order for prostate cancer to develop past theseinitiated steps in PIA to bona fide pre-neoplastic precursor (PIN) and to invasive carcinoma this immuneresponse must be abrogated. We observed upregulation of stress-response and inflammatory genes in humanPIA luminal epithelial cells. These same genes (examples: GSTP1 PTGS2 and LTF ) are epigenetically silencedin PIN and early and metastatic invasive adenocarcinoma of the prostate. This led to a potential molecularmechanism in which a set of genes whose expression is highly induced in PIA undergo silencing to allow cells toemerge as PIN and invasive carcinoma. We show here that the major inflammatory mediator Stimulator ofInterferon Genes (STING) is absent in normal prostate luminal cells is highly induced in intermediate luminalcells in PIA and is not expressed in the vast majority of human PIN and adenocarcinomas. We hypothesizeSTING expression in PIA luminal cells is required for inflammation cell injury and the prostate cancer initiation.Second we hypothesize that in a subset of PIA cells epigenetic silencing of STING (or of its downstreamsignaling activity) results in dampening of the immune response imparting a growth advantage by allowing themto emerge as neoplastic cells. We will test these hypotheses in as follows. In Specific Aim 1 we will geneticallyand pharmacologically test the STING activation hypothesis for developing acute and chronic inflammation PIAand PIN in the mouse prostate using our unique mouse model of IL1-beta induced prostatic inflammation andPIA progressing to PIN (IMPI mice). In Specific Aim 2 we will test the epigenetic silencing of induced geneshypothesis in human samples by performing a comprehensive characterization of DNA-methylation basedepigenomic changes in mouse and human epithelial cells in the transitions from prostatic inflammatory lesions toneoplasia. Mechanistically we hypothesize that STING (along with many other stress and inflammation inducedgenes) is epigenetically silenced at the transition stage of PIA to high grade PIN. In Specific Aim 3 wehypothesize that in ""graduating"" from the proving ground neoplastic cells leave behind the pro-inflammatorymicroenvironment in PIA and sculpt a microenvironment with reduced adaptive immune cells throughrecruitment of immune suppressive myeloid and lymphoid cells (e.g. MDSCs M2 macrophages and Tregs) thathelp quell the cancer immune response. We will define the cellular composition and spatial architecture ofmicroenvironment in mouse and human early precursor prostatic inflammatory lesions." +No NIH Category available Accounting;Acute;Adjuvant Chemotherapy;Adjuvant Radiotherapy;Adjuvant Therapy;Affect;Asian Americans;Biological Assay;Breast;Breast Cancer Patient;Cancer Center;Cancer Patient;Cell Nucleus;Chemotherapy and/or radiation;Clinical;Clinical Trials;Collaborations;Computer Vision Systems;Data Set;Diagnosis;Diagnostic tests;Early identification;Estrogen receptor positive;Gene Expression;Gene Expression Profiling;Genomics;Head and Neck Cancer;Health Services Accessibility;Hematoxylin and Eosin Staining Method;Image;Image Analysis;In complete remission;India;Individual;Malignant Neoplasms;Malignant Squamous Cell Neoplasm;Malignant neoplasm of lung;Malignant neoplasm of prostate;Molecular;Morphology;Neoadjuvant Therapy;Nomograms;Oral cavity;Outcome;Pathologic;Patient-Focused Outcomes;Patients;Pattern;Pattern Recognition;Pelvis;Performance;Physical shape;Population;Postoperative Period;Prevalence;Price;Prognosis;Prostate;Radiation;Radiation Therapy Oncology Group;Radiation therapy;Recurrence;Recurrent disease;Resources;Risk;Role;Shapes;Slide;South Asian;Southwest Oncology Group;Stains;Testing;Therapeutic;Tissue Stains;Tissues;Universities;Validation;Visual;Woman;behavioral outcome;cancer diagnosis;caucasian American;companion diagnostics;cost comparison;digital;digital imaging;digital pathology;high risk;high risk population;improved;innovation;low and middle-income countries;malignant breast neoplasm;malignant mouth neoplasm;men;mouth squamous cell carcinoma;oncotype;outcome prediction;overtreatment;precision medicine;predictive modeling;predictive test;predictive tools;prognostic;prognostic assays;prognostic model;prognostic tool;prognostication;prospective;prostate cancer risk;response;side effect;success;tool;treatment response;trial comparing;triple-negative invasive breast carcinoma;tumor behavior An AI-enabled Digital Pathology Platform for Multi-Cancer Diagnosis Prognosis and Prediction of Therapeutic Benefit PROJECT RELEVANCE: We propose to optimize and validate an AI-enabled Digital Pathology Platform(ADAPT) for multi-cancer diagnosis prognosis and prediction of therapeutic benefit. By integrating the AI-pathomic tools within PathPresenter a widely used digital pathology image analysis platform ADAPT will havea global footprint for the prognostic and predictive tools. ADAPT will be validated in the context of estrogenreceptor positive (ER+) and triple negative (TN) breast cancer oral cavity squamous cell carcinoma (OC-SCC)and prostate cancer for (1) prognosticating recurrence (2) predicting pathologic complete response toneoadjuvant chemotherapy (3) predicting benefit of adjuvant chemotherapy and radiotherapy as well as for (4)identifying individuals in whom radiation therapy can be de-intensified respectively. NCI 10698122 8/21/23 0:00 RFA-CA-21-030 5U01CA269181-02 5 U01 CA 269181 2 "DIVI, RAO L" 9/5/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q(J2) 8352708 "MADABHUSHI, ANANT " "PARMAR, VANI " 5 BIOMEDICAL ENGINEERING 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 553532 NCI 412722 140810 SUMMARY: Recognizing that over-diagnosis of many cancers is leading to over-treatment with adjuvantchemotherapy or with radiation therapy boost there is a growing appreciation for the need for prognostic andpredictive assays to identify those cancer patients who can benefit from therapy de-intensification. While multi-gene-expression based tests such as Oncotype DX and Decipher exist for identifying early-stage breast andprostate cancer patients who could avoid adjuvant therapies and hence mitigate side-effects and complicationsthe price of these tests ($3K-4K/patient) puts them beyond the reach of most patients in low- and middle-incomecountries (LMICs). Ironically the need for these prognostic and predictive tests is even more acute in LMICs likeIndia where access to treatment resources like radiation and chemotherapy are limited and hence need to beadministered judiciously to those patients who stand to receive the most benefit from them. Sophisticated digital pathomic analysis with computer vision and pattern recognition tools has beenshown to unlock sub-visual attributes about tumor behavior and patient outcomes from hematoxylin & eosin(H&E)-stained slides alone. The Madabhushi team at Case Western Reserve University (CWRU) has extensivelyshown the potential for these approaches for predicting outcome and therapeutic response for breast head andneck lung and prostate cancer. The Madabhushi team working with collaborators Dr. Parmar and Dr. Desai atthe Tata Memorial Center (TMC) the largest cancer center in India has shown that advanced pathomic analysisis able to identify unique prognostic morphologic signatures of breast cancer that are different between SouthAsian (SA) and Caucasian American (CA) women 1. In addition the CWRU group has shown that digital pathomicbased image classifiers can significantly improve and even outperform the prognostic and predictiveperformance of expensive gene-expression assays for breast (Oncotype Dx) and prostate cancer (Decipher) 2. Building on the strong extant collaboration between CWRU and TMC 3 and a strong track record in digitalimage based prognostic and predictive based assays we propose to optimize and validate an AI-enabled DigitalPathology Platform (ADAPT) for Multi-Cancer Diagnosis Prognosis and Prediction of Therapeutic Benefit.ADAPT will involve optimizing the previously developed image assays by the CWRU group in the context of SAcancer patients. Furthermore by integrating the AI-pathomic tools with PathPresenter a widely used digitalpathology image analysis platform ADAPT will have a global footprint for the prognostic and predictive tools.Specifically ADAPT will be validated for predicting outcome and benefit of adjuvant chemo- and radiation therapyin the context of estrogen receptor positive (ER+) breast cancer (BC) and triple negative breast cancer (TNBC)oral cavity squamous cell carcinoma (OC-SCC) and prostate cancer at TMC via a number of clinical trial datasetsin the US (SWOG S8814 RTOG 0920 0521) and at TMC (AREST POP-RT). Successful project completionwill establish ADAPT as an Affordable Precision Medicine (APM) solution for Indian cancer patients. 553532 +No NIH Category available Address;Atlases;Basic Science;Collaborations;Communication;Communities;DNA Methylation;Data Analyses;Data Collection;Data Coordinating Center;Development;Discipline;Electronic Mail;Evaluation;Evolution;Fostering;Funding;GSTP1 gene;Genomics;Grant;Human Resources;Individual;Indolent;Inflammation;Inflammatory;Infrastructure;Institution;Joints;Knowledge;Leadership;Lesion;Malignant Neoplasms;Malignant neoplasm of prostate;Mentors;Mission;Modality;Molecular and Cellular Biology;Neoplasms;Peer Review;Postdoctoral Fellow;Procedures;Progress Reports;Prostate;Prostatic;Publications;Research;Research Activity;Research Personnel;Research Project Grants;Role;Site Visit;Students;Summary Reports;Teleconferences;Telephone;Work;anticancer research;carcinogenesis;diverse data;graduate student;interdisciplinary approach;meetings;molecular pathology;mouse model;pre-clinical;programs;support network;synergism;transcriptome sequencing;translational approach;tumor microenvironment;virtual;working group TBEL Administrative Core n/a NCI 10698120 9/1/23 0:00 RFA-CA-21-054 5U54CA274370-02 5 U54 CA 274370 2 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-2 7977 2146873 "DE MARZO, ANGELO MICHAEL" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 380980 236255 144725 Project Summary/Abstract:The mission of the Administration Core is to ensure that the individual Research Projects and the Research Corecombine with synergy beyond their individual parts to contribute to the TBEL Program creating strength beyondthe individual Centers to integrate with the NCI and the cancer research community. The Administrative Coreprovides the infrastructure essential for this mission. The Core will supervise a multi-component research programencompassing two basic science and one translational projects and utilizing diverse data collection and analysismodalities. To foster synergy the Core will be the primary contact for internal activities including logistical andorganizational activities scientific and administrative activities and collaborative project solicitation reviewfunding and evaluation. To embed our proposed Center within the TBEL Program and the broader cancer researchcommunity this Core will also be the primary contact for external interactions with the NCI other TBEL Centersthe Coordinating and Data Management Center (CDMC) and external cancer researchers. The Core LeadersDrs. De Marzo and Yegnasubramanian have been active collaborators for 19 years have joint funding on the NCISPORE grant as well as the NCI MCL grant for the past 6 years and are co-authors on 50 peer-reviewed primarypublications and 16 review articles. Drs. De Marzo and Yegnasubramanian are also embedded in internal andexternal research networks that support their roles. In addition they have co-mentored several graduate studentsand post-doctoral fellows often serving on their fellow graduate student's thesis committees. They have workedtogether extensively on the molecular pathology and genomics of prostate cancer over the last 10 years includingleading all the RNAseq and whole genomic sequencing efforts for JHU the NCI MCL-U01 projects including thepre-clinical atlas pilot. Also together they have worked extensively on the molecular and cellular biology of prostateprecursor lesions together finding partial DNA methylation of GSTP1 in high grade PIN lesions and PIA; a findingdirectly relevant to the current proposal. Finally they have worked together extensively with Dr. Bieberich on themolecular pathology and genomics of mouse models of prostatic inflammation driven neoplasia and of aggressiveversus indolent prostate cancer and with Dr. Pienta in all administrative aspects and tumor microenvironmentstudies related to the NCI MCL-U01 Program. +No NIH Category available Acute;Address;Aging;Animal Model;Atrophic;Basic Science;Cancer Etiology;Cancer Model;Carcinoma;Cell Death;Cell Proliferation;Cells;Characteristics;Chronic;Clinical;DNA Sequence Alteration;Development;Disease;Disease Outcome;Disease Progression;Environmental Risk Factor;Epidemiology;Epigenetic Process;FDA approved;FOLH1 gene;Fibroblasts;Genes;Genetic;Genome;Genomics;Gleason Grade for Prostate Cancer;Growth;Heterogeneity;Image;Imaging technology;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Surveillance;Immunotherapy;Inflammation;Inflammatory;Innate Immune Response;Intercept;Lesion;Life Style;Link;Localized Disease;Longitudinal Studies;Macrophage;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Metastatic Neoplasm to Lymph Nodes;Metastatic Prostate Cancer;Molecular;Mus;Mutation;Myeloid-derived suppressor cells;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;Outcome;PET/CT scan;PTEN gene;Pathologic;Phase;Population;Positron-Emission Tomography;Process;Prostate;Prostate carcinoma;Prostatectomy;Prostatic;Research;Research Project Grants;Resource Sharing;Risk;Role;Signal Transduction;TP53 gene;Testing;Therapeutic;Tissue Sample;Tissues;United States;Up-Regulation;Visualization;X-Ray Computed Tomography;adaptive immune response;adaptive immunity;anti-cancer;cancer cell;cancer diagnosis;cancer initiation;carcinogenesis;carcinogenicity;cell injury;disorder control;epigenetic silencing;epigenomics;fibroblast-activating factor;high risk men;human tissue;imaging agent;immune cell infiltrate;immunoreaction;improved;innovation;men;microbial;molecular imaging;mortality;mouse model;neoplastic;neoplastic cell;preneoplastic cell;prevent;programmed cell death ligand 1;prospective;prostate cancer cell;prostate cancer progression;prostate carcinogenesis;recruit;response;stem;synergism;translational study;tumor;tumor microenvironment Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer NARRATIVEProstate cancer is the most common serious cancer diagnosed in men in the United States and a leadingcause of cancer mortality. This proposal is focused on understanding whether prostate cancer emerges frominflamed regions of the prostate and in the process gains the ability to evade the immune system. Throughthis research we will identify new ways to prevent and intercept the development of aggressive prostatecancer. NCI 10698119 9/1/23 0:00 RFA-CA-21-054 5U54CA274370-02 5 U54 CA 274370 2 "GHOSH-JANJIGIAN, SHARMISTHA" 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 2146873 "DE MARZO, ANGELO MICHAEL" "YEGNASUBRAMANIAN, SRINIVASAN " 7 PATHOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1485601 NCI 996593 489008 Project Summary: Epidemiological and pathological studies have implicated lifestyle microbial andenvironmental factors in prostate cancer etiology/risk. A potential link between these factors and prostatecarcinogenesis is the presence of chronic inflammation associated with atrophy (PIA) in prostates of agingmen. Yet there is a paradox surrounding the role of the immune response in prostate cancer: theinflammation paradox. On one hand inflammation may be a driver of carcinogenesis. On the other theimmune system is known to seek and destroy cancer cells. The majority prostate cancer lesions are immunedeserts and ICIs are ineffective in most cases. Why is there an evidently strong immune reaction in non-neoplastic regions in PIA but a lack of a robust immune response in most prostate cancers? We hypothesizethat chronic inflammation in PIA represents evidence of an innate immune response that drivescarcinogenesis. However in this inflammatory proving ground only cells that can epigeneticallyswitch off this response can emerge to become aggressive neoplastic precursors. We hypothesize thatthe paucity of immune infiltrates and lack of PD-L1 is evidence that prostate cancer cells develop a number ofdifferent mechanisms that evade anti-tumor adaptive immunity. We postulate that additional cell non-autonomous immune suppressive mechanisms enable disease progression. We propose 3 synergisticResearch Projects (2 basic1 translational) to mechanistically test key questions stemming from our provingground hypothesis. In Proj 1 (Basic Science) we hypothesize that the STING induction in PIA drives acuteand chronic inflammation leading to cell injury/cell death and proliferation. Second in a subset of PIA cellsepigenetic silencing of STING dampens of the immune response allowing them to emerge as overt pre-neoplastic cells. We will test this in animal models and in translational studies employing annotated andmolecularly characterized prostatectomies. The combination of PTEN loss and MYC copy number gain is anindependent predictor of poor outcome in prostate cancer. We hypothesize that the combination of MYC andPTEN stimulates a cell non-autonomous immune evasion mechanism induced by the recruitment of immuno-suppressive myeloid cells and fibroblast activation protein (FAP)-positive fibroblasts. Proj 2 (Basic Science)will test these hypotheses in animal models and in human tissues. Recently introduced imaging technologieshave raised the hypothesis that PET/CT imaging results may be able to predict molecular and tumoral micro-environmental characteristics of aggressive prostate cancer. PET imaging for PSMA using PyL PET/CT hasbeen FDA approved for imaging high risk men prior to prostatectomy. In Proj 3 (Translational) we employPET/CT scanning for PSMA and combine this with mpMRI to address these hypotheses. Also in Proj 3 we willapply newly developed/developing PET imaging agents to non-invasively and longitudinally study the extent ofM2 macrophages and cancer associated fibroblasts in our mouse prostate progression cancer models. 1485601 +No NIH Category available Address;Admixture;Adoption;Affect;Awareness;Biological Assay;Bone Marrow;Cell physiology;Cell surface;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Chromatin;Chronic Lymphocytic Leukemia;Clonal Evolution;Clonal Expansion;Development;Disease Resistance;Epigenetic Process;Evolution;Frequencies;Genes;Genetic;Genetic Heterogeneity;Genetic Transcription;Genomics;Genotype;Goals;Growth;Hematopoiesis;Heterogeneity;Human;Human body;Immune system;Individual;Knowledge;Lead;Link;Malignant - descriptor;Malignant Neoplasms;Minority;Molecular;Mosaicism;Mutate;Mutation;Myeloproliferative disease;Nature;Normal Range;Normal tissue morphology;Output;Phenotype;Population;Proteins;RNA Splicing;Resistance;Resolution;Risk;Sampling;Signal Transduction;Slide;Somatic Mutation;Spatial Distribution;Technology;Time;Transcript;Variant;analytical method;cancer diagnosis;cancer genomics;cancer therapy;cell behavior;cell type;clinical diagnosis;driver mutation;epigenomics;experience;fitness;hematopoietic differentiation;human tissue;methylome;multiple omics;mutant;novel;phenotypic biomarker;protein expression;single cell sequencing;single cell technology;single-cell RNA sequencing;targeted treatment;therapy development;therapy resistant;transcription factor;transcriptome;transcriptomics Expanding the GoT toolkit to link single-cell clonal genotypes with protein transcriptomic epigenomic and spatial phenotypes Project NarrativeCancer mutations drive the outgrowth of small populations of cells in normal tissue years before clinicaldiagnosis of cancer or the outgrowth of cells resistant to therapy. However how such mutations change cellularbehavior to provide them with a competitive growth advantage over adjacent cells remains poorly understood.To address this gap in knowledge we propose to apply and develop novel single-cell sequencing technologiesto study the mechanisms underlying growth advantage in cancer. NCI 10698112 7/12/23 0:00 RFA-CA-21-004 5R33CA267219-02 5 R33 CA 267219 2 "LI, JERRY" 9/7/22 0:00 8/31/25 0:00 ZCA1-TCRB-D(M1) 10910623 "LANDAU, DAN " Not Applicable 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 410790 NCI 244018 166772 AbstractClonal outgrowths are observed across a wide range of normal human tissues. They also appear during thecourse of cancer evolution leading to clonal heterogeneity that fuels the development of treatment-resistantdisease. Clones harbor somatic mutations in known cancer driver genes and show evidence of positiveselection. Nevertheless how these driver mutations alter the cellular states of cells to allow clones tooutcompete wildtype counterparts remains poorly understood. To date efforts to chart clonal outgrowths innormal or malignant human tissues have been largely limited to genotyping. This is due to the fact that theseclones often affect a minority of cells in a sample without distinguishing cell-surface markers.To address this challenge we developed an array of multi-omic single-cell technologies that are capable ofcapturing multiple layers of information (e.g. genotypes transcriptomes methylomes protein expression) fromthe same single cells. Moreover we addressed the specific challenge of genotyping in scRNA-seq in singlecells at high throughput by developing Genotyping of Targeted loci (GoT). Importantly GoT turns the admixtureof mutant and wildtype hematopoiesis from a limitation to an advantage enabling the direct comparison ofmutant (winner) and wildtype (loser) cells within the same individual.Given the increasing adoption of our GoT platform we now aim to extend the multi-omics single-cell toolkit tostudy how somatic mutations lead to clonal growth advantage. We will integrate GoT with Cellular Indexing ofTranscriptomes and Epitopes by sequencing (CITE-seq) to yield GoT-CITE which will add the critical layer ofcell surface marker phenotyping to single-cell whole transcriptomes. As mutations in splicing factors arespecifically associated with greater risk of malignant transformation we will develop and implement GoT-Splice where long-read sequencing will be used to define splicing variation as a function of cell identity. Giventhe high frequency of epigenetic mutations in cancer we will also develop and apply targeted single-cellgenotyping in the context of chromatin accessibility (GoT-ChA). Finally as clone growth will also bedetermined by its interaction with the microenvironment to define clonal driver genotypes in its spatial contextwe will adapt spatial transcriptomics (ST) to add the critical feature of genotyping (GoT-ST).Our overarching goal is to invoke multi-omic comparisons at the single-cell level between wildtype and mutantcells to comprehensively identify the underpinnings of fitness advantage in clonal outgrowth. The proposedcomprehensive GoT toolkit will enable the linking at high throughout single-cell genotypes with transcriptionalprotein epigenetic and spatial phenotypes. We anticipate that these advances will transform the study of clonalmosaicism as a harbinger of cancer as well as resistance to cancer therapies. 410790 +No NIH Category available Address;Adenocarcinoma;Adherence;Adult;African American population;Age;Archives;Biological Markers;Blood;Clinic;Clinical;Clinical Data;Collaborations;Colon;Colon Carcinoma;Colonoscopy;Colorectal;Colorectal Cancer;Colorectal Neoplasms;DNA;Development;Diagnostic;Early Detection Research Network;Early Diagnosis;Enrollment;Feces;Future;High grade dysplasia;Incidence;Individual;Industrialization;Institution;Link;Low income;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Methods;Morbidity - disease rate;Neoplasms;New England;Participant;Patients;Performance;Phase;Plasma;Population;Prevalence;Procedures;Proteins;Research;Research Personnel;Risk Assessment;Sampling;Serum;Specimen;Testing;Tissues;Tubulovillous Adenoma;Underserved Population;Urine;Validation;Villous Adenoma;adenoma;biomarker discovery;biomarker panel;biomarker validation;blood-based biomarker;candidate marker;circulating biomarkers;colorectal cancer screening;cost;early detection biomarkers;early onset colorectal cancer;follow-up;high risk;mortality;point of care;predictive marker;preservation;prospective;response;sample collection;screening;sex;stool sample;underserved community Great Lakes New England Clinical Validation Center NARRATIVEThe Great Lakes New England Clinical Validation Center (GLNE CVC) a Clinical ValidationConsortium component of the Early Detection Research Network (EDRN) is a highlycollaborative group of investigators whose aim is to validate biomarkers for the early detectionand risk assessment of cancers of the gastrointestinal tract. NCI 10698103 9/8/23 0:00 RFA-CA-21-033 5U01CA086400-22 5 U01 CA 86400 22 "YOUNG, MATTHEW R" 5/15/00 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 1891491 "BRESALIER, ROBERT S" "SYNGAL, SAPNA " 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1016923 NCI 735706 281217 The Great Lakes New England Clinical Validation Center (GLNE CVC) a Clinical Validation Consortiumcomponent of the Early Detection Research Network (EDRN) is a highly collaborative group of investigatorswhose aims to validate biomarkers for the early detection and risk assessment of cancers of the gastrointestinaltract. In this fifth competitive application the GLNE continues to test the overall hypothesis that a panel ofcirculating and stool based biomarkers will increase the adherence to colorectal screening and in doing so reducemortality caused by colorectal cancers. Based on the rising incidence of colorectal cancer (CRC) among adultsage <50 in the US and the low compliance and high mortality in underserved populations increased emphasisis placed on these populations. The GLNE also proposes to continue its ongoing support of EDRN discoverypriorities. We propose to address the following aims: (1) Primary Aim To expand and renew the archive ofappropriately preserved stool serum plasma urine tissue and DNA biospecimens to be used by EDRNinvestigators for current and future validation and biomarker discovery research with expanded inclusion ofsubjects with early-onset CRC and underserved populations. This will allow assessment of the utility of individualstool-based and serum-based biomarkers and biomarker panels for discriminating between individuals withoutneoplasia (subjects both at average and higher risk for developing colon cancer) and those with colon canceror screen-relevant neoplasia (cancer plus advanced adenoma) and construction of panels of markers todiscriminate between these groups. (2) To perform validation trials of promising biomarkers discovered by EDRNinvestigators external collaborating institutions and collaborating EDRN industrial partners for the early detectionof colorectal neoplasia. In this context we propose to (a) to clinically validate (via a methods comparison study)the performance of a point-of-care blood- based biomarker panel with the testing of serum/plasma samplesobtained in clinics serving low-income and underserved communities and (b) to clinically validate an established4-plex stool protein panel for early diagnosis of CRC. (3) To follow prospectively subjects enrolled in anestablished prospective Phase 2 validation trial to identify pre-diagnostic specimens which may be used todevelop predictive markers. 1016923 +No NIH Category available Area;Award;Bioinformatics;Biometry;Cancer Research Network;Cells;Classification;Clinical;Collaborations;Communication;Data;Data Commons;Data Element;Databases;Development;Ensure;Equity;Evaluation;FAIR principles;Feedback;Future;Genome;Genomics;Goals;Infrastructure;Institution;Knowledge;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medical center;Mentorship;Metadata;Methodology;Mission;Modeling;Molecular;Monitor;Morbidity - disease rate;New York;Pathology;Productivity;Reproducibility;Research;Research Personnel;Research Project Grants;Resolution;Resource Sharing;Resources;Risk;Scientist;Secure;Standardization;Structure;Technology;Time;Training;Training Programs;Training Support;Universities;Vision;Work;cloud based;collaborative approach;data harmonization;data portal;data sharing;experience;gastroesophageal cancer;in vitro Model;in vivo;meetings;mortality;multidisciplinary;next generation;organizational structure;prevent;programs;success;symposium;synergism;tumor initiation;web-accessible;working group Coordinating Center for the Program on the Origins of Gastroesophageal Cancers The overarching mission of the NCIs Program on the Origins of Gastroesophageal Cancers and the sixtransdisciplinary R01 projects is to extend recent findings regarding molecular classifications and genomics ofgastroesophageal cancers and examine and define how these cancers initially evolve at the cellular level. TheColumbia Coordinating Center (CCC) will provide the necessary leadership infrastructure and oversight tosupport this consortium and optimize programmatic productivity. Training and mentorship of junior investigatorsbuilding collaborations and networks and FAIR data sharing will be an emphasis. NCI 10698096 9/8/23 0:00 RFA-CA-21-027 5U24CA272897-02 5 U24 CA 272897 2 "YASSIN, RIHAB R" 9/6/22 0:00 8/31/27 0:00 ZCA1-RPRB-6(M)2 7040249 "HUR, CHIN " "GENKINGER, JEANINE M.; HU, JIANHUA ; ZODY, MICHAEL C" 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 830961 NCI 592321 238640 The Columbia Coordinating Center (CCC) will provide the necessary leadership infrastructure and oversight tosupport and fulfill the overarching goals of NCIs Program on the Origins of Gastroesophageal Cancers (PGEC)and the six transdisciplinary R01 projects. The mission of the PGEC is to extend recent findings regardingmolecular classifications and genomics of gastroesophageal cancers examine and define how these cancersinitially evolve at the cellular level and compare and contrast the contributions and underlying mechanisms oftumor-initiating cells to risk and progression. Inadequate coordination communication and access will createsignificant barriers to program success.The CCC will provide the leadership and organizational structure to facilitate and strengthen cross collaborationthrough trainings meetings and working groups. The CCC will develop standardization and harmonization ofdata elements (e.g. track the cell of origin correctly) across research projects enable the resolution of technicalchallenges share models and resources and advance the use of cutting-edge technologies. The CCC willfacilitate equitable and FAIR (employing principles of findability accessibility interoperability and reusability)access to in vivo and in vitro models provide real time feedback on research objectives and allow for assessmentof rigor and reproducibly. The CCC will provide training and support for early-stage investigators to conduct pilotwork and engage in transdisciplinary research to build the next generation of scientists.Our CCC and the assembled Scientific Advisory Board brings together multidisciplinary scientists with necessaryand diverse research clinical database and consortia experience to support these aims. This research team inconjunction with the many institutional resources at Columbia University Irving Medical Center (CUIMC) andNew York Genome Center (NYGC) will be pivotal assets to program success.Specific Aim 1: Provide strong vision and scientific leadership to ensure the PGEC meets itsprogrammatic goals. Sub-Aim 1A- training and development of junior investigators; and Sub-Aim 1B-monitoring research progress and to provide real time feedback that are actionable.Specific Aim 2: Provide administrative oversight and structure for the PGEC.Specific Aim 3: Coordinate and organize meetings and conferences.Specific Aim 4: Build and maintain a data commons and portal for the program.Impact: The CCC will provide strong leadership with an experienced and multidisciplinary team and anorganizational structure for all PGEC activities to facilitate resource sharing that will expedite productivitycollaboration and ultimately impact to better understand and prevent GE cancer morbidity and mortality. Furtherintegration with other long-standing resources and training programs are additional important deliverables. 830961 +No NIH Category available AML/MDS;ATAC-seq;Acute Myelocytic Leukemia;Adult;Age;Architecture;Biogenesis;ChIP-seq;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Complex;Core-Binding Factor;Coupled;DNA Binding;Data;Data Set;Disease remission;Dysmyelopoietic Syndromes;Enrollment;Epigenetic Process;Familial Platelet Disorder;Gene Expression;Gene Expression Profile;Genetic;Germ-Line Mutation;Guide RNA;Harvest;Hematopoiesis;Homologous Transplantation;Impairment;In Vitro;Lesion;Libraries;MCL1 gene;Malignant - descriptor;Maps;Mediating;Messenger RNA;Molecular;Mus;Mutation;Myeloproliferative disease;Network-based;Newly Diagnosed;Outcome;Patients;Phase Ib/II Clinical Trial;Phase Ib/II Trial;Prognosis;Progression-Free Survivals;Protein Inhibition;Proteins;RUNX1 gene;Recurrent disease;Refractory;Relapse;Repression;Research;Resistance;Ribosomes;Risk;Safety;Science;Tertiary Protein Structure;Translations;Treatment Protocols;Xenograft Model;Xenograft procedure;acute myeloid leukemia cell;analog;attenuation;autosome;c-myc Genes;chemotherapy;co-clinical trial;graft vs host disease;high risk;homoharringtonine;improved;in vivo;in vivo Model;inhibitor;knock-down;loss of function mutation;mutant;new therapeutic target;next generation sequencing;novel;participant enrollment;preclinical efficacy;response;small hairpin RNA;targeted agent;targeted treatment;transcription factor;transcriptome sequencing Novel combination therapy for AML expressing mutant RUNX1 Following current treatment regimens clinical outcome in patients with high-riskMyelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) with mutant RUNX1remains poor. Research proposed here will conduct a clinical trial of a novel combination ofomacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies aswell as develop additional novel and rational OM-based combinations for therapy of MDS orAML with mutant RUNX1. NCI 10698087 8/18/23 0:00 PAR-18-560 5R01CA262636-03 5 R01 CA 262636 3 "HENDERSON, LORI A" 9/1/21 0:00 8/31/25 0:00 Clinical Oncology Study Section[CONC] 10599643 "DINARDO, COURTNEY " "BHALLA, KAPIL ; TAKAHASHI, KOICHI " 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 523503 NCI 323150 200353 With current treatment regimens long-term remission rates for adult patients with high riskMyelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) are 15-25%. RUNX1 is the DNA-binding subunit of the core-binding factor (CBF) complex and a master-regulator transcription factorinvolved in hematopoiesis. Majority of mutant (mt) RUNX1 are missense large deletions or truncation-mutations behaving mostly as loss of function (LOF) mutations. Presence of mtRUNX1 confers relativetherapy-resistance and poorer survival in patients with MDS/AML. The germline mutations and deletionsin RUNX1 cause the highly penetrant (~40%) Familial Platelet Disorder with a propensity to evolve intoMDS or AML. Lack of specific targeted therapy coupled with resistance to standard therapy may accountfor poorer prognosis and outcome in MDS/AML expressing somatic or germline mtRUNX1. Thereforethere is an unmet need to develop novel targeted therapies for MDS/AML expressing mtRUNX1. Ourpreliminary studies demonstrate that knockdown of RUNX1 induces significantly more in vitro lethality inAML blasts expressing mtRUNX1 versus wild type (wt) RUNX1. Utilizing RNA-Seq signature of RUNX1knockdown and querying the LINCS1000-CMap (Connectivity-Mapping) datasets we identifiedhomoharringtonine (HHT) among the top expression mimickers (EMs). Consistent with observations thatpresence of mtRUNX1 impairs ribosomal biogenesis (RiBi) treatment with HHT or its semisyntheticanalog omacetaxine mepesuccinate (OM) which inhibit protein translation preferentially exerted morelethality in vitro and efficacy in vivo in models of AML expressing mtRUNX1. This was associated withrepression of RUNX1 and its targets as well as attenuation of short-lived proteins including c-Myc andMCL-1. Notably co-treatment with OM and venetoclax (Ven) induced synergistic lethality and superior invivo efficacy in xenograft models of AML expressing mtRUNX1. Therefore our Overarching hypothesismotivating studies proposed is that targeted combination of OM and Ven will yield high remission ratesand improved survival correlating with specific genetic and gene-expression signatures in patients withhigh-risk MDS/AML expressing mtRUNX1. Specific aims of studies proposed are: AIM 1: To conduct aPhase Ib/II clinical trial of co-treatment with OM and Ven in patients with high risk MDS or AML expressingmtRUNX1. AIM 2: To determine correlates of efficacy/resistance to co-treatment with OM and Venincluding genetic-lesions architecture (via NextGen and scDNA sequencing) epigenetic and gene-expression signature (via RNA-Seq RPPA and CyTOF analyses) and impaired RiBi features in MDS/AMLcells of patients enrolled on the Phase Ib/II trial. AIM 3: To determine pre-clinical efficacy of additionalOM-based combinations with BET or CDK9 inhibitor as well as with novel targeted agents directedagainst druggable hits nominated through an in vitro protein domain-specific CRISPR-gRNA screen. 523503 +No NIH Category available 3-Dimensional;Acceleration;Adopted;Adoption;Aging;Antibodies;Aorta;Area;Atlases;Automation;Bar Codes;Biomedical Engineering;Cardiac;Cardiovascular system;Cells;Communities;Computer Analysis;DNA;Data;Data Set;Databases;Democracy;Development;Devices;Discrimination;Disease;Embryo;Environment;Extracellular Matrix;Extracellular Matrix Proteins;Fluorescent in Situ Hybridization;Formalin;Freezing;Generations;Genes;Genomic approach;Glass;Head;Health;Heart;Histology;Human;Human BioMolecular Atlas Program;Human body;Image;In Situ;Individual;Injections;Kidney;Longevity;Manuals;Maps;Measurement;Messenger RNA;Methods;Microfluidics;Molecular;Morphology;Motivation;Mus;Nature;Organ;Organogenesis;Paraffin Embedding;Permeability;Phase;Physiology;Preparation;Procedures;Process;Proteins;Proteome;Protocols documentation;Public Health;RNA;Research;Research Personnel;Resolution;Role;Sampling;Skin;Slide;Solid;Specimen;Spottings;Surgeon;System;Technology;Tissue Embedding;Tissue Sample;Tissue atlas;Tissue imaging;Tissues;Validation;Variant;cost;extracellular;genome-wide;high throughput technology;human data;human tissue;improved;interest;molecular imaging;monolayer;mosaic;multiple omics;next generation sequencing;novel;novel strategies;paraform;process optimization;rheumatologist;scale up;self assembly;single molecule;single-cell RNA sequencing;synergism;tissue mapping;transcriptome;transcriptome sequencing;transcriptomic profiling;transcriptomics High-spatial-resolution ECM-inclusive multi-omics sequencing of human PFA and FFPE tissue slides PROJECT NARRATIVEThis project aims to develop a transformative technology for high-throughput high-spatial-resolution and high-content co-mapping of transcriptome and proteome in human PFA or FFPE tissue samples prepared usingstandard tissue histology process. It can be applied to a wide range of human tissues to generate the referencebiomolecular atlas of human tissues and organs rapidly and cost-effectively. It will improve our understanding ofaging or disease development throughput the life span and the health-disease continuum in the areas ofsignificant public health interest. NCI 10698076 8/18/23 0:00 RFA-RM-20-001 5UH3CA257393-04 5 UH3 CA 257393 4 "SRINIVAS, POTHUR R" 9/10/20 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-IMST-M(50)R] 9372328 "FAN, RONG " Not Applicable 3 ENGINEERING (ALL TYPES) 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT BIOMED ENGR/COL ENGR/ENGR STA 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 598119 OD 358209 241791 SUMMARYThis project focuses on the accelerated development of a high-spatial-resolution sequencing technology for theco-mapping of transcriptomes and proteomes (hsrTP-seq) via deterministic barcoding in tissue which will bevalidated with paraformaldehyde(PFA)-fixed and formalin-fixed paraffin-embedded (FFPE) human tissuespecimens. This is a fundamentally new approach as compared to any existing spatial omics technologies. Thecore idea is to molecularly barcode RNAs proteins or other biomolecular information in tissues using a novelmicrofluidic in situ barcoding method. The tissue slide after barcoding remains morphologically intact butconsists of a mosaic of tissue pixels each of which has a distinct DNA barcode. The size of the pixels is assmall as ~5-10m which is close to the size of individual cells. It is built upon the power of Illuminas NextGeneration Sequencing (NGS) systems to achieve significantly higher sample high-throughput lower cost andthe elimination of laborious procedures for repeated single-molecule imaging as in seqFISH. It will demonstratehigh-spatial-resolution (~5-10m pixel size) high-throughput (up to 100 tissue samples flow barcoded per dayper operator) and high-content (genome-wide mRNAs proteins and non-cellular environment). Using a panelof DNA-tagged antibodies against extracellular matrix (ECM) proteins this approach further allows for spatialomics sequencing to include the mapping of non-cellular components which are completely missing in scRNA-seq or current spatial transcriptomics technologies. It is uniquely suited for mapping human collagenoustissues including heart aorta skin and kidney to improve our understanding of the role of ECM in normalphysiology disease and aging. We will pursue the following specific aims. In the UG3 phase we will develop aset of new devices to significantly increase the tissue mapping area (4mmx4mm) develop a proteome-scale(~500 proteins co-analyzed) and ECM-inclusive spatial sequencing and develop a novel tissue optimizationprotocol performed on the same tissue slide for hsrTP-seq and generate a set of 3D spatial transcriptome-proteome atlas data from human heart or aorta. In the UH3 phase we will further develop a multi-pin injectionhead to increase sample throughput (up to 100 samples per day) and the mapping area (1.2cmx1.2cm) forfurther scale up and automation develop a new in-tissue template switching method to retain intact tissuesection after hsrTP-seq for conducting other measurements on the same tissue slide and constructing 3Dtissue atlas and finally develop an optimized PFA and FFPE tissue protocol to generate the 3D multi-omicstissue atlas data (>20 tissue sections per sample) from the human heart aorta skin and kidney. 598119 +No NIH Category available Address;Affect;Archives;Bioinformatics;Biological Assay;Biological Markers;Cancer Etiology;Cells;Chemical Agents;Chemoprevention;Chemopreventive Agent;Chronic;Cirrhosis;Clinical;Clinical Chemoprevention;Clinical Trials;Clinical assessments;Collection;Detection;Development;Diet;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Etiology;FDA approved;Future;Genes;Goals;Hepatic Stellate Cell;Hepatocyte;Human;Kupffer Cells;Libraries;Liver;Liver Fibrosis;Macrophage;Malignant Neoplasms;Malignant neoplasm of liver;Modeling;Molecular;Monitor;Organ;Pathway interactions;Patients;Pharmaceutical Preparations;Population;Prevention strategy;Prevention therapy;Process;Proteins;Rattus;Reverse engineering;Risk;Sampling;Screening for Hepatocellular Cancer;Serum;Serum Proteins;Specimen;System;Testing;Tissues;Toxic effect;cancer chemoprevention;cancer initiation;cancer risk;cancer type;candidate identification;candidate validation;carcinogenicity;cell type;clinical application;clinical biomarkers;clinical translation;clinically relevant;cohort;cost effective;detection assay;diagnostic platform;follow-up;genetic signature;immune cell infiltrate;improved;in vivo;inhibitor;injured;innovation;liver cancer prevention;loss of function;lysophosphatidic acid;member;multidisciplinary;nano-string;nonalcoholic steatohepatitis;novel;patient prognosis;precision cancer prevention;prevent;prevention clinical trial;research clinical testing;risk prediction;screening;transcriptome;transcriptomic profiling;transcriptomics Reverse-engineering precision liver cancer chemoprevention Liver cancer chemoprevention will substantially improve the dismal patient prognosis althoughstill impossible. We have developed Precision Liver Cancer Prevention Consortium and willemploy an innovative multidisciplinary reverse-engineering approach to simultaneously identifyliver cancer chemoprevention biomarkers targets and drugs ready for subsequent clinicalassessment and deployment with special focus on non-alcoholic steatohepatitis the fastestrising etiology of liver cancer globally. NCI 10698060 9/8/23 0:00 PA-18-484 5R01CA233794-05 5 R01 CA 233794 5 "PERLOFF, MARJORIE" 9/23/19 0:00 8/31/24 0:00 Chemo/Dietary Prevention Study Section[CDP] 9925976 "HOSHIDA, YUJIN " Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 613866 NCI 447649 166217 Identification of clinically relevant cancer chemoprevention targets has been challenging. Our multidisciplinaryteam (Precision Liver Cancer Prevention Consortium) will employ an innovative reverse-engineering approachstarting from transcriptome analysis of archived clinical specimens with long-term clinical follow-up thenmoving to multifold experimental verification of only clinically well-validated targets to elucidatechemoprevention targets with the highest likelihood of successful clinical application. With this approach wecould successfully identify liver cancer risk signatures and chemoprevention dugs leading to a clinical trial(NCT02273362). To achieve our long-term goal of establishing clinically applicable chemoprevention strategieshere we aim to elucidate molecular dysregulation underlying carcinogenic milieu in livers affected with non-alcoholic steatohepatitis (NASH) the fastest rising liver cancer etiology as clues to refined chemopreventiontargets drugs and biomarker assays which are expected to enable personalized patient management andmore cost-effective liver cancer chemoprevention clinical trials and lead to revolutionary improvement ofpatient prognosis and establishment of a new paradigm reverse-engineering precision cancer prevention.Aim 1. Computationally-targeted screening of liver cancer chemoprevention agents. Candidate livercancer chemopreventive compounds will be computationally prioritized and screened together with LPApathway inhibitor library in liver cancer risk signature-inducible cell system for the gene signature reversal. Forselected compounds in the screen mechanisms of action will be interrogated by gain- or loss-of-functionassessment in the cell system.Aim 2. Functional validation of candidate liver cancer chemoprevention agents. In vivo liver cancerchemopreventive effect of the candidate agents will be validated in a diet-induced fibrotic/carcinogenic ratmodel mimicking global human cirrhosis transcriptome. Human relevance of the agents will be evaluated inorganotypic ex vivo culture of clinical fibrotic liver tissues (n=30). To determine target cell type(s) andmechanisms of action for the agents major hepatic cell types will be isolated from the rats and transcriptomeprofiling will be performed to assess liver cancer risk signature member genes the inferred target genes for thecompounds and related molecular pathways. Human fibrotic/cirrhotic NASH livers will be similarly profiled forcell type-specific transcriptomic dysregulation to verify that the modulated genes are relevant in human.Aim 3. Development of tissue- and serum-based liver cancer risk biomarker assays. Liver tissue-basedcancer risk signatures will be implemented in clinically applicable tissue- (NanoString) and serum- (Luminex)based assays and evaluated for technical validity and capability to predict future cancer risk in a cohort of 200NASH patients with paired serum and liver tissue specimens as well as completed long-term clinicalobservation for cancer development. 613866 +No NIH Category available Age;Aging;Behavior;Biological;Black Populations;Black race;Bone Marrow;Chronology;Data;Development;Disease;Early Diagnosis;Environment;Family history of;Fracture;Goals;Hematologic Neoplasms;Hospitalization;Immune;Individual;Inflammation;Kidney Failure;Lead;Link;MALDI-TOF Mass Spectrometry;Molecular;Monoclonal Gammapathies;Monoclonal gammopathy of uncertain significance;Morbidity - disease rate;Multiple Myeloma;Organ;Participant;Populations at Risk;Prevalence;Prevention;Process;Proteins;Race;Recording of previous events;Research;Risk;Risk Factors;Symptoms;Testing;Therapeutic Intervention;Tissues;anticancer research;cancer prevention;carcinogenicity;ethnic diversity;frontier;genomic signature;improved;paragon;prevent;randomized trial;risk prediction;screening;trait Molecular Prediction of Myeloma Initiation Molecular Prediction of Myeloma Initiation NARRATIVEThe next frontier in cancer research is early detection and prevention and my overarching goal is to apply thisto myeloma by defining the first steps of disease development and treating it early before symptoms occur. Wewill redefine the risk factors of race and chronological age based on underlying biological traits. We will identifyancestry risk scores and genomic signatures that increase the risk of developing myeloma in Black individualsand dissect the molecular mechanisms of effective age of the tissue of origin (bone marrow). NCI 10698026 8/11/23 0:00 PAR-21-333 5R35CA263817-02 5 R35 CA 263817 2 "HOWCROFT, THOMAS K" 9/6/22 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 8436435 "GHOBRIAL, IRENE M." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1019592 NCI 637392 382200 SUMMARYMultiple Myeloma (MM) is the second most common hematologic malignancy and is almost always preceded bymonoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Recentrandomized trials have shown that early therapeutic intervention at the stage of SMM can improve progression-free and overall survival. This indicates that early detection and therapeutic intervention before symptomatic MMoccurs may lead to improved survival and decreased morbidity from other complications such as bone fracturesrenal failure and hospitalizations related to end-organ damage from myeloma. Early detection requires acomprehensive screening of the population at risk for developing MM. Known risk factors for developing MMinclude aging race (Blacks) and familial history of hematologic malignancies. Our preliminary data of screening~7500 ethnically diverse individuals at risk of developing MM using a sensitive quantitative MALDI-TOF massspectrometry has shown a prevalence rate of monoclonal protein in 45% in individuals of age >50y and havingan early immune dysregulation that we termed Monoclonal Gammopathy of Indeterminate Potential (MGIP).MGUS was significantly more prevalent in Black participants and participants with familial hematologicmalignancy (HM) history than in White participants with no family history of HM. To begin to delineatemechanisms by which these early MGIP clones progress to MGUS and further lead to MM we plan to explorethe host intrinsic (age race germline risk factors) and acquired (inflammation antigenic activation) risk factorson the expanding clone and its environment that influence its behavior. We believe the next frontier in MMresearch is to understand how one develops myeloma and treat it early before end-organ damage.Identifying and preventing the development of the earliest stages of MM will lead to transformative approachesto treatment and serve as a paragon of cancer prevention. We hypothesize that defining risk as ancestryscores and genomic signatures instead of defining risk by self-identified race can improve riskprediction for MM. Similarly instead of using chronological age as a risk factor for MM we will test thehypothesis that the effective age of the bone marrow niche confers biological risk of developing MM.Together we believe that these studies will help define the mechanistic underpinnings of the carcinogenicprocess linked to MM. This approach will allow the field to transition from a purely demographic definition of riskto a biological one. 1019592 +No NIH Category available Adult;Biology;CRISPR/Cas technology;Cells;Clinical;Code;Combined Modality Therapy;Complex;Data;Development;Diagnosis;Distant;FAT gene;Foundations;Funding Agency;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Screening;Genetically Engineered Mouse;Genomics;Goals;Grant;High-Throughput RNA Sequencing;Human;Immunohistochemistry;In Vitro;K22 Award;Knock-out;Knowledge;Lung;Malignant Fibrous Histiocytoma;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mesenchymal Cell Neoplasm;Metastatic Neoplasm to the Lung;Methods;Modeling;Modification;Mus;Muscle;Mutate;Mutation;Neoplasm Metastasis;Oncogenes;Oncogenic;Organ;Pathway interactions;Patients;Play;Population;Prognosis;Protein Splicing;Proteins;RNA;RNA Splicing;Research;Resistance;Role;Signal Pathway;Soft tissue sarcoma;Spliced Genes;Survival Rate;Testing;Therapeutic;Tissue Microarray;Translating;Tumor Suppressor Proteins;Untranslated RNA;Up-Regulation;Wild Type Mouse;chemotherapy;design;genome-wide;human data;improved;improved outcome;in vivo;in vivo Model;inhibitor;insight;mouse model;novel;novel therapeutic intervention;overexpression;pharmacologic;preclinical trial;programs;sarcoma;targeted treatment;therapeutically effective;transcriptome sequencing;treatment strategy;tumor;tumor growth DISSECTING THE ROLES OF FAT1 AND NEAT1 IN SOFT TISSUE SARCOMA DEVELOPMENT AND METASTASIS USING NOVEL IN VIVO SARCOMA MODELS This K22 award will allow me to build my own research platform to further characterize the criticalsignaling pathways and target genes in sarcoma development and metastasis using these unique in vivosarcoma models. In Specific Aim 1 we will dissect the mechanism by which the Hippo pathways andtheir effectors Yap1/Taz drive sarcomas through the mutation of Fat1. In addition we will use my novelin vivo sarcoma models to test and optimize the best combination treatment strategies that suppresssarcoma tumor growth. In Specific Aim 2 we will determine the mechanisms by which lncRNA Neat1drives sarcoma metastasis. My preliminary results suggest that RNA splicing regulating genes such asKhsrp interact with Neat1 and promote sarcoma metastasis. We will use my unique in vivo sarcomamodels to dissect the mechanisms governing sarcoma metastasis and the implications of these genes fortargeted therapies in treating metastatic sarcoma patients. In conclusion completion of this proposalwill determine the functional consequences of expression of the coding gene Fat1 and the non-codinggene Neat1 in sarcoma development and metastasis and provide novel candidate pathways and genesfor designing effective targeted therapies to improve outcomes for sarcoma patients. NCI 10697997 8/15/23 0:00 PAR-18-467 5K22CA248849-02 5 K22 CA 248849 2 "JAKOWLEW, SONIA B" 9/7/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI(B)-I] 12684024 "HUANG, JIANGUO " Not Applicable 9 Unavailable 79611840 H3R1MLL2VLT7 79611840 H3R1MLL2VLT7 US 45.533688 -122.617301 10061009 PROVIDENCE HEALTH & SERVICES - OREGON Renton WA Other Domestic Non-Profits 980543368 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 162000 NCI 150000 12000 Soft tissue sarcomas (STSs) are rare heterogeneous mesenchymal tumors that have more than 75 subtypes. STSs areunderstudied tumors for which there are few established research models and a lack of funding sources. Over decadesthere has been little improvement in the therapeutic strategies for STSs which are often resistant to current therapiesand can be frequently fatal as 50% of patients develop metastasis in distant organs. To solve this unmet clinical problemin vivo models that accurately recapitulate this spectrum of cancers provide a unique and effective platform for studyingsarcoma biology and preclinical trials before novel therapeutic strategies translate to limited population of sarcomapatients. However there are very few in vivo sarcoma models available because the tumor suppressor and oncogenicdrivers for sarcoma development and metastasis remain unknown. Therefore I performed genome-wide in vitro geneticscreens and direct in vivo CRISPR/Cas9 knockout screens in wild type mice to identify driver genes whose mutation isrequired for sarcoma initiation. From these screens I generate a novel in vivo sarcoma model driven by the mutation ofFat1 which is frequently mutated in human STSs. This is a de novo in vivo model that recapitulates a subset of humanSTSs and to our knowledge the first determination that Fat1 is a potent tumor suppressor in human STSs. Furthermoreusing in vivo sarcoma models and high throughput RNA sequencing I also identified the long non-coding RNA (lncRNA)Neat1 as an oncogenic driver for sarcoma metastasis. This K22 award will allow me to build my own research platform tofurther characterize the critical signaling pathways and target genes in sarcoma development and metastasis using theseunique in vivo sarcoma models. In Specific Aim 1 we will dissect the mechanism by which the Hippo pathways and theireffectors Yap1/Taz drive sarcomas through the mutation of Fat1. In addition we will use my novel in vivo sarcomamodels to test and optimize the best combination treatment strategies that suppress sarcoma tumor growth. In SpecificAim 2 we will determine the mechanisms by which lncRNA Neat1 drives sarcoma metastasis. My preliminary resultssuggest that RNA splicing regulating genes such as Khsrp interact with Neat1 and promote sarcoma metastasis. We willuse my unique in vivo sarcoma models to dissect the mechanisms governing sarcoma metastasis and the implications ofthese genes for targeted therapies in treating metastatic sarcoma patients. In conclusion completion of this proposalwill determine the functional consequences of expression of the coding gene Fat1 and the non-coding gene Neat1 insarcoma development and metastasis and provide novel candidate pathways and genes for designing effective targetedtherapies to improve outcomes for sarcoma patients. 162000 +No NIH Category available Address;Aliquot;Amines;Animals;Area;Automation;Biological Assay;Blood capillaries;Calibration;Capillary Electrophoresis;Cells;Charge;Chemicals;Clinical;Complex;Consumption;Detection;Development;Devices;Diagnostic Imaging;Dose;Ensure;Equipment;FOLH1 gene;Formulation;Geometry;Gold;Head;High Pressure Liquid Chromatography;Human;Human Resources;Infrastructure;Isotopes;Label;Laboratories;Measurement;Measures;Medicine;Methods;Microchip Electrophoresis;Microfluidics;Miniaturization;Molecular;Monitor;Nature;Optics;Outcome;Patients;Performance;Phase;Play;Positron-Emission Tomography;Process;Production;Publishing;Quality Control;Radiation;Radio;Radiochemistry;Radioisotopes;Radiopharmaceuticals;Reagent;Reporting;Research;Resolution;Role;Safety;Sampling;Silicon Dioxide;Source;Specificity;System;Technetium 99m;Techniques;Technology;Testing;Therapeutic;Time;Tracer;Validation;Work;clinical care;commercial prototype;cost;detection sensitivity;detector;drug development;imaging agent;improved;in vivo;instrument;instrumentation;manufacture;operation;patient safety;pre-clinical;radiochemical;radiotracer;skills;tool Microchip electrophoresis as basis for fully integrated fully automated low-cost radiopharmaceutical QC platform RELEVANCEShort-lived radiopharmaceuticals play a critical role in medicine as diagnostic imaging agents and therapeuticsbut the complex facilities and processes needed for their manufacture combined with the relatively small sizeof each batch produced (i.e. just a few patient doses up to at most a few dozen) result in high costs. Oneaspect is that every batch must be analyzed via a comprehensive set of quality control (QC) tests to ensuresafety for the patient which requires a suite of expensive equipment and skilled personnel to maintaincalibrate and clean the equipment as well as perform and document the tests. This project leveragesmicrofluidics to integrate QC tests into a compact benchtop device for fully-automated QC testing ofradiopharmaceuticals. NCI 10697506 6/21/23 0:00 PA-22-176 1R43CA278090-01A1 1 R43 CA 278090 1 A1 "REGMI, SAROJ GOPAL" 9/1/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-Z(10)B] 14212109 "JONES, JASON " Not Applicable 32 Unavailable 118626333 ZJ7YCLEP1DB4 118626333 ZJ7YCLEP1DB4 US 10069706 DROPLETPHARM INC. SHERMAN OAKS CA Domestic For-Profits 914034303 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 275766 NCI 211648 46077 PROJECT SUMMARYPositron emission tomography (PET) is an indispensable tool in research drug development and clinical caredue to its very high sensitivity and quantitative nature. The complexity and high cost of producing PET tracerslimits their use in research and their development and validation into quantitative in vivo biological assays. Forexample thousands of different PET tracers have been reported but very few have been validated for use inanimals or humans and only a tiny fraction are approved for routine use in patients.New methods being developed for PET tracer manufacturing especially microfluidics have demonstratedpotential for vastly reduced tracer production cost and complexity through (i) reduction of expensive reagents(ii) efficient production at preclinical and clinical scales and (iii) compact instrumentation that can be operatedwith minimal infrastructure. As the quality control (QC) tests necessary to ensure radiopharmaceutical safetymust be performed after every synthesis there have been some efforts to apply microfluidics in this area aswell. DropletPharm Inc. seeks to leverage microfluidic developments to create a tabletop radiopharmacyplatform to eliminate the typical costly radiopharmacy infrastructure (i.e. hot cell radiosynthesizer stackmonitoring system QC equipment) and replace it with a self-shielded benchtop device that performs bothsynthesis and analysis. In the current project we seek to develop a microfluidics-based QC platform toautomatically perform all necessary radiopharmaceutical QC tests reducing costs and increasing throughput.While many QC tests can be implemented as simple optical and radiation measurements (of aliquotspre-mixed with indicators) the (radio)chemical identity and purity tests are more challenging and requirechemical separations. Recently numerous research groups have used capillary electrophoresis for rapidseparation and analysis of radiopharmaceuticals labeled with various isotopes (incl. Tc-99m and F-18). Thevan Dam lab used [18F]FLT samples to demonstrate high-resolution and sensitivity can be achieved usingmicrochip electrophoresis (MCE) where advantages of vastly reduced size lower cost and short analysis timemakes this technique highly attractive as a replacement for the gold standard techniques of radio-HPLC orradio-TLC for assessing radiochemical identity and purity as well as chemical purity and molar activity. Toassess the technical feasibility to use this technology at the core of DropletPharms QC testing platform thisproposal aims to address two limitations of the method published to date and compare the analysisperformance head-to-head with radio-HPLC or radio-TLC. Aim 1 will explore strategies to improve radiationdetection sensitivity to enable the analysis of a wider range of clinical batches (i.e. those that are more dilute).Aim 2 will explore radio-MCE separation of example radiotracers including [18F]FLT and [68Ga]Ga-PSMA-11and compare performance with the gold standard (radio-HPLC and radio-TLC). Successful completion of themilestones will indicate that Phase II commercial development into a full QC-testing module is warranted. 275766 +No NIH Category available Animals;Area;Bioinformatics;Biological Sciences;Biometry;Cancer Biology;Cells;Cellular biology;Clinical Research;Collaborations;Colon;Communication;Data Analyses;Dedications;Ensure;Epithelium;Experimental Designs;Funding;Genomics;Goals;Grant;Human;Human Resources;Immune;Individual;Institution;Joints;Laboratories;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Methods;Modeling;Multiomic Data;Proteomics;Publications;Qi;Quality Control;Recording of previous events;Research Design;Research Project Grants;Science;Services;Shapes;Signal Transduction;Systems Biology;Technology;Trust;Work;adenoma;data integration;epigenomics;exome sequencing;experience;malignant breast neoplasm;meetings;member;microbiota;multidimensional data;multiple omics;novel;premalignant;programs;skills;transcriptome sequencing;transcriptomics Quantitative Bioscience Core n/a NCI 10697377 9/8/23 0:00 RFA-CA-21-054 5U54CA274367-02 5 U54 CA 274367 2 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-2 7930 11408346 "LIU, QI " Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 146529 83731 62798 PROJECT SUMMARY/ABSTRACTCore 1: Quantitative Bioscience CoreThe main goal of the Quantitative Bioscience Core is to provide a centralized service for biostatistics andbioinformatics needs of the program. The core will work closely with all three projects and the HPM Core toprovide experimental design and multi-level omics data analysis to enable in-depth understanding ofmicroenvironment alterations associated with adenoma progression and malignant transformation. The core willprovide quality control for all animal and clinical studies cutting edge pipelines and methods for multi-omics dataanalysis and develop and evaluate novel methods for integrative single-cell and spatial transcriptomics analysis. +No NIH Category available Algorithms;Atlases;Big Bang Cosmology;Biological Assay;Biological Models;CRISPR/Cas technology;Cancer Biology;Cell Communication;Cells;Chromosome Mapping;Clinical;Clonal Expansion;Coculture Techniques;Colon;Colorectal Cancer;Communication;Complex;Computer Models;Cytotoxic T-Lymphocytes;DNA sequencing;Data;Development;Dysplasia;Ecosystem;Elements;Environment;Epithelium;Event;Evolution;Exhibits;Genetic;Genomics;Human;Hyperactivity;Immune;Immune Evasion;Immune system;Immunosuppression;Immunotherapy;In Vitro;Individual;Intervention;Knowledge;Malignant - descriptor;Malignant Neoplasms;Maps;Modeling;Molecular;Monitor;Morphology;Mutation;Myelogenous;Neighborhoods;Organoids;Pathologic;Pathologist;Pathway interactions;Patients;Phylogeny;Polyps;Prevention;Sampling;Shapes;Somatic Mutation;Specimen;System;Systems Analysis;T cell clonality;Technology;Testing;Therapeutic Intervention;Tumor stage;Work;adaptive immunity;arms race;cell community;colon tumorigenesis;cytotoxic;cytotoxicity;exome sequencing;genetic evolution;immunogenic;immunoregulation;laser capture microdissection;microbiota;multiple omics;multiplexed imaging;neoantigens;neoplastic cell;new technology;patient prognosis;patient response;predictive modeling;premalignant;pressure;reconstruction;response;scaffold;single cell sequencing;single-cell RNA sequencing;stem;stem cells;stemness;transcriptomics;transfer learning;tumor;tumor heterogeneity;tumor progression;tumor-immune system interactions;tumorigenesis Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression n/a NCI 10697376 9/8/23 0:00 RFA-CA-21-054 5U54CA274367-02 5 U54 CA 274367 2 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-2 7929 10925153 "LAU, KEN S" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 303650 293550 10100 PROJECT SUMMARY/ABSTRACTProject 3: Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping AdaptiveCytotoxicity and Myeloid-Derived SuppressionThe pre-cancer-to-cancer transition is a critical juncture in colorectal cancer (CRC) biology that has clinical valuein prevention and surveillance. This transition is characterized by an evolutionary arms race where the bodysimmune system seeks to eliminate the tumor while the tumor cells evolve mechanisms to suppress and evadethe immune system. The small number of human pre-precancers that transition into cancer precludes effectivepredictive modeling of critical genetic and microenvironmental factors that drive these alterations. Herein we willleverage regional intratumoral heterogeneity due to asynchronicity of evolution with spatially resolved profilingtechnologies on human tumor specimens to build trajectories of pre-cancer transition into malignancy. We willmodel two pathways of pre-cancer transitions the conventional pathway driven by mutations in the WNTpathway and the serrated pathway characterized by an immunogenic microenvironment. Our previous pre-cancer atlas describes a dichotomy between stemness in tumor cells and cytotoxic T cells in themicroenvironment between these two pathways. Thus we hypothesize that pre-cancers gain stemness to enableepithelial mechanisms to suppress a cytotoxic immune environment resulting in malignant evolution. In Aim 1we will use spatially resolved DNA sequencing to map genetic evolution of pre-cancer cells with selectivepressures conferred by neoantigen-specific adaptive immunity. In Aim 2 we will use integrative spatial multi-omics to interrogate tumor mechanisms to modulate immune cell communication networks during progression.By combining novel technologies with data-driven systems modeling we will shed light on the complex interplaybetween human tumors and their microenvironment that shape their transition trajectories into malignancy. +No NIH Category available Attention;Behavior;Binding;Biological Assay;Biological Markers;Biological Process;Cell Line;Cells;Cellular biology;Characteristics;Coculture Techniques;Colon;Colonic Adenoma;Colorectal Adenoma;Colorectal Cancer;Communication;Confocal Microscopy;Data;Dipeptidases;Dipeptides;Electrical Resistance;Enzyme-Linked Immunosorbent Assay;Epithelium;Exposure to;Extracellular Matrix;Flow Cytometry;Future;Human;Immune;Immunofluorescence Immunologic;In Vitro;Invaded;Knock-out;Knowledge;Lesion;Leukocyte Elastase;Malignant Neoplasms;Malignant neoplasm of pancreas;Manuscripts;Mediating;Monitor;Mus;Nature;Neoplasm Metastasis;Neutrophil Infiltration;Organoids;Patients;Polyps;Population;Proliferating;Property;Proteins;Reporter;Reporting;Role;Sampling;Selection Criteria;Shapes;Signal Transduction;Source;Specimen;Stains;System;Techniques;Testing;Tissue Microarray;Tissues;Tumor Suppressor Proteins;Western Blotting;adenoma;cancer biomarkers;cancer cell;colon cancer cell line;elastase inhibitor;exosome;extracellular vesicles;healthy volunteer;immunoreactivity;in vivo;interest;microbiota;mouse model;neutrophil;premalignant;protein biomarkers;repository;single-cell RNA sequencing;spatial relationship;stem cells;timeline;transcriptome sequencing;tumor;tumor microenvironment;tumor progression Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression n/a NCI 10697369 9/8/23 0:00 RFA-CA-21-054 5U54CA274367-02 5 U54 CA 274367 2 9/15/22 0:00 8/31/27 0:00 ZCA1-SRB-2 9302 1901947 "COFFEY, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 379488 226077 153411 PROJECT SUMMARY/ABSTRACTProject 1: Shaping the Microenvironment by DPEP1 Facilitates Adenoma ProgressionProject 1 aims to examine how shaping the microenvironment by DPEP1 facilitates adenoma progression. Thiswill be a basic project. We propose that dipeptidase-1 (DPEP1) marks those adenomas with the potential toprogress to colorectal cancer (CRC) through an active bi-directional communication with neutrophils. DPEP1has two functions: dipeptidase activity and recently identified neutrophil-binding activity. Our hypothesis is thatDPEP1 largely through its neutrophil-binding activity marks adenomas with a predilection for progression. Wehave found that DPEP1 immunoreactivity is detected in 27% of colorectal adenomas but this increases to 72%of CRCs consistent with DPEP1 marking the small subset of adenomas that progress to CRC. Utilizing humanspecimens a unique Transwell co-culture system of adenoma organoids and freshly isolated neutrophils isolatedfrom healthy volunteers and an informative mouse model we will test if DPEP1-expressing adenomas moreeffectively communicate with neutrophils and create a neutrophil-enriched microenvironment increasing thelikelihood that these adenomas will progress. Exosomes have attracted a great deal of recent attention as a richsource of cargo that may serve as cancer biomarkers. We have found that DPEP1 is released in exosomes fromCRC cell lines and that it highly enriched in a subset of exosomes that contain known CRC biomarkers CEAand EPCAM. Of interest neutrophils also release small extracellular vesicles (sEVs) that contain neutrophilelastase in a form that cannot be inhibited by elastase inhibitors and thus it is especially potent in degrading theextracellular matrix a key step in cancer invasion. We will also use a unique neutrophil reporter mouse to monitoronset and perdurance of neutrophil infiltration along with the properties of these neutrophils in an induciblestem cell-driven mouse model of colonic adenomas.. +No NIH Category available Acetylation;Actins;Adjuvant Chemotherapy;Affect;Animal Model;Antineoplastic Agents;Behavior;Biomedical Engineering;Blood Circulation;Blood capillaries;Breast Cancer Cell;Breast Cancer Treatment;Breast Epithelial Cells;CRISPR/Cas technology;Calcium Signaling;Cancer Etiology;Cancer Patient;Cell membrane;Cells;Cessation of life;Chemicals;Clinical Treatment;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Desmosomes;Digitoxin;Disease;Distant;Epithelium;Equilibrium;Extracellular Matrix;FDA approved;Foundations;Genes;Genetic;Growth;Hour;Image;In Vitro;Invaded;Lung;Lymphatic;MCAM gene;Mediating;Metastatic breast cancer;Metastatic/Recurrent;Methods;Microfluidics;Microscopy;Microtubule Stabilization;Microtubules;Modeling;Molecular;Mus;Neoadjuvant Therapy;Neoplasm Circulating Cells;Neoplasm Metastasis;Operative Surgical Procedures;Organ;Ouabain;Outcome;Paclitaxel;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphotransferases;Post-Translational Protein Processing;Prognosis;Proteins;Regulation;Risk;Role;Surface;System;Techniques;Testing;Therapeutic;Tissues;Translating;Tubulin;Tumor Promotion;Xenograft procedure;Zebrafish;cancer therapy;cell growth;cell motility;drug development;drug discovery;improved;in vivo;inhibitor;innovation;mechanical properties;mechanotransduction;neoplastic cell;novel therapeutics;patient derived xenograft model;precision medicine;pressure;response;side effect;standard of care;targeted cancer therapy;therapeutic target;treatment strategy;triple-negative invasive breast carcinoma;tumor;whole animal imaging Tubulin microtentacles in detached mammary epithelial cells This project will test the role of actin cortical contraction in microtentacle formation and theclustering of circulating breast tumor cells. The PIs lab has established the counterbalancebetween MT extension and actin cortical contraction and identified specific molecularmechanisms to alter this balance. Innovative bioengineering approaches animal models PDXand live patient CTCs will be used to test these mechanisms of targeting the actin cortex to reducemicrotentacles. NCI 10697349 9/1/23 0:00 PA-20-185 5R01CA124704-13 5 R01 CA 124704 13 "AULT, GRACE S" 6/1/07 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 6948120 "MARTIN, STUART S" Not Applicable 7 PHARMACOLOGY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 424018 NCI 283816 140202 Tubulin microtentacles in detached mammary epithelial cells. Breast tumor cells metastasize to distant organs through non-adherent microenvironments such as thebloodstream or lymphatics. However very little is known about the dynamic behavior and drug responses ofnon-adherent tumor cells due to the challenges of imaging non-adherent cells without blurring from cell drift. The PIs lab discovered unique microtentacles (McTNs) on the surface of non-adherent tumor cells thatpromote the aggregation and retention of circulating tumor cells (CTCs) in the lung capillaries of living mice. This project will test the hypothesis that actin cortical contraction regulates molecular mechanisms underlyingMcTNs and can be targeted through independent pathways to reduce the clustering and reattachment of CTCsduring metastasis. Predictions of this hypothesis will be tested in the following specific aims.Specific Aim 1: Inhibit kinases regulating actin cortical contraction to impact McTNs.A) Define impact of pathway inhibitors on microtentacles and supporting molecular mechanisms.B) Analyze inhibitor impacts on tumor cell mechanical properties (Brillouin microscopy AFM).C) Test prioritized drugs in zebrafish (CTC reattachment) mice (orthotopic PDX) and live patient tumor cells.Specific Aim 2: Test role of X-ROS mechanotransduction on McTN mechanisms and function.A) Chemically inhibit TRPM8 and calcium signaling to influence McTN mechanisms.B) Gauge effects of pathway inhibitors on MCAM and genetically regulating MCAM or TRPM8 (CRISPR).C) Test prioritized mechanotransduction genes and drugs in zebrafish mice and patient tumor cells.Specific Aim 3: Target mechanisms of McTN-mediated tumor clustering.A) Define McTN mechanisms that inhibit homotypic/heterotypic clustering with Digitoxin or Ouabain.B) Downregulate desmosomal protein DSG3 to reduce McTN-mediated tumor cell clustering.C) Test prioritized anti-clustering mechanisms in zebrafish mice and live patient tumor cells.This project will use innovative bioengineering techniques (TetherChip Brillouin microscopy) and examinehighly-conserved mechanotransduction principles (X-ROS) recently identified by the PIs lab in epithelial tumorcells. Inclusion of FDA-approved therapies and drugs in current clinical trials will increase the potential to rapidlytranslate the outcomes of this project to impact the clinical treatment of metastatic breast cancer. 424018 +No NIH Category available Address;Advanced Malignant Neoplasm;Adverse event;Area;Assertiveness;Award;Behavior;Behavior Therapy;Behavioral;Cancer Center;Cancer Pain Management;Caregivers;Caring;Cessation of life;Characteristics;Client satisfaction;Clinical Practice Guideline;Communication;Communities;Conduct Clinical Trials;Coping Skills;Data;Dedications;Development;Disparity;Elements;Enrollment;Feedback;Foundations;Fright;Future;Health;Health behavior;Impairment;Intervention;Intervention Trial;Label;Link;Literature;Malignant Neoplasms;Mentors;Mentorship;Methodology;Mission;Not Hispanic or Latino;Oncology;Opioid;Opioid Analgesics;Outcome;Outcome Assessment;Overdose;Pain;Pain management;Pain quality;Participant;Patients;Personal Satisfaction;Persons;Preparation;Principal Investigator;Process;Publishing;Qualitative Research;Quality of life;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research;Research Methodology;Research Personnel;Resources;Social isolation;Stereotyping;Stress and Coping;Surveys;Symptoms;Testing;Training;Underserved Population;United States;Woman;acceptability and feasibility;addiction;adherence rate;adverse outcome;cancer pain;cancer therapy;career;career development;concept mapping;design;efficacy testing;efficacy trial;emotional distress;experience;health related quality of life;high risk;improved;innovation;internalized stigma;multidisciplinary;novel;opioid epidemic;opioid policy;opioid use;palliative;patient engagement;patient-clinician communication;people of color;pilot test;pilot trial;post intervention;prescription opioid;primary outcome;randomized trial;rural area;skills;social;social cognitive theory;social stigma;theories;therapy development;tool;treatment as usual;underserved community Development and piloting of an intervention to reduce the impact of opioid stigma in cancer pain PROJECT NARRATIVE Effective pain management is a core element of advanced cancer treatment as under-treated pain is associated with adverse health consequences and suboptimal quality of life. Cancer-related pain is commonly managed with prescription opioids; however patients with advanced cancer experience unique challenges associated with this strategy due to the opioid crisis including stigma surrounding prescription opioid use (opioid stigma). The project described in this NCI K08 application will develop and pilot test an intervention to address opioid stigma in patients with advanced cancer which can then be tested in a randomized controlled trial. NCI 10697340 8/16/23 0:00 PA-20-202 5K08CA263317-02 5 K08 CA 263317 2 "RADAEV, SERGEY" 9/7/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 12262707 "BULLS, HAILEY WADDELL" Not Applicable 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 145537 NCI 134975 10562 ABSTRACT Moderate-to-severe cancer pain is common in patients with advanced cancer and is often effectively treated with prescription opioids. Effective pain management is crucial for optimal quality of life and health outcomes in these patients. However the emergence of the opioid crisis in the United States has sparked widespread fears about the use of opioid pain medications given the potential for negative outcomes such as addiction and overdose. Despite being exempted from restrictive opioid policies patients with cancer experience adverse consequences of efforts to address the opioid crisis including stigma associated with prescription opioid use (opioid stigma). Based on our recently published Opioid Stigma Framework we anticipate that opioid stigma results in several proximal (e.g. impaired patient-provider communication suboptimal health behaviors emotional distress maladaptive coping skills) and long-term health consequences (e.g. less effective pain management reduced health-related quality of life). Emerging evidence indicates that opioid stigma is common pervasive and has the potential to seriously impact patient well-being. However there are no known interventions to mitigate opioid stigma in patients with advanced cancer. Additionally perspectives from underserved communities at high risk for pain undertreatment people of color people in rural areas and women are lacking and understanding these experiences is critical to build a robust inclusive opioid stigma intervention Thus the proposed project will develop and test a novel behavioral intervention for opioid stigma in an effort to fill this unmet need. Together with her mentors Principal Investigator Dr. Bulls will explore opioid stigma experiences and treatment priorities reported by a diverse group of 75 patients with advanced painful cancer using rigorous concept mapping methodology (Aim 1). Next Dr. Bulls will design a theory-based intervention to reduce negative proximal impacts of opioid stigma in patients with advanced cancer soliciting feedback from patients and community-engaged resources prior to piloting (Aim 2). Finally Dr. Bulls will conduct a pilot trial of the intervention with 45 patients with advanced cancer pain to evaluate feasibility and acceptability in preparation for a full-scale randomized controlled trial (Aim 3). This project will facilitate training crucial to Dr. Bulls' career development: advanced skills in participatory and stakeholder-engaged research methods in-depth training in behavioral intervention development and expertise in conducting clinical trials. Dr. Bulls has convened a dedicated multidisciplinary26 mentorship team with expertise in essential content and methodological areas including palliative oncology27 opioid pain management health-related stigma concept mapping behavioral intervention development and28 testing and research in underserved groups among others. This proposal represents a comprehensive training29 mentoring and research plan to support Dr. Bulls' transition into a successful independent investigator. At the30 end of the award period Dr. Bulls will contribute substantially to the field as a leader in behavioral approaches to31 improve opioid stigma in patients with advanced cancer.3233 145537 +No NIH Category available AIDS related cancer;Address;Adoption;Appointments and Schedules;Area;Behavior;Botswana;Cancer Control;Cancer Control Research;Caring;Cervical Cancer Screening;Cessation of life;Clinic;Clinical;Communication;Complement;Complex;Consolidated Framework for Implementation Research;Country;Data;Developing Countries;Diagnosis;Diagnostic Procedure;Disparity;Early Diagnosis;Effectiveness;Ensure;Evaluation;Evidence based practice;Evidence based treatment;Failure;Female;Goals;HIV;HIV diagnosis;Health Services Accessibility;High Prevalence;Hybrids;Incidence;Income;Individual;Intervention;Interview;Knowledge;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Modeling;Motivation;National Cancer Institute;Newly Diagnosed;Outcome;Pathology;Patients;Persons;Prevention;Preventive;Public Health;Publishing;Randomized;Recommendation;Research;Resource-limited setting;Sequential Multiple Assignment Randomized Trial;Shapes;Surveys;System;Testing;Theoretical model;Touch sensation;Translating;Visit;arm;behavioral economics;cancer care;cancer diagnosis;cancer therapy;care coordination;clinical care;cohort;comparative;contextual factors;design;effectiveness evaluation;effectiveness testing;evidence base;implementation cost;implementation outcomes;implementation strategy;implementation trial;improved;innovation;low and middle-income countries;mortality;outreach;outreach clinics;patient navigation;patient outreach;response;screening;success;system-level barriers;trial design Thibang Diphatlha: Testing adaptive strategies to close the gap from cervical cancer diagnosis to treatment in Botswana PROJECT NARRATIVEDelays and missed opportunities for timely treatment contribute significantly to global disparities in cervical cancer in low- and middle-income countries {LMICs) compared to high-income countries yet little is known about how best to increase adoption of evidence-based cancer care in LMICs. This project will help to fill this critical research gap by testing the effectiveness of patient- and system-level strategies on timeliness of care among females diagnosed with cervical cancer in Botswana. The results of this project will yield fundamental knowledge about how to improve and sustain timely cancer care in Botswana and if successful identify strategies that can be easily translated to address other areas of cancer control across LMICs. NCI 10697331 8/14/23 0:00 RFA-CA-21-056 5U01CA275032-02 5 U01 CA 275032 2 "VEDHAM, VIDYA" 9/6/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M2) 12105432 "GROVER, SURBHI " "RENDLE, KATHARINE " 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 694021 NCI 499797 194224 PROJECT SUMMARYDelays and missed opportunities for timely treatment contribute significantly to disparities in cervical cancer mortality in low- and middle-income countries (LMICs) compared to high-income countries (HICs). Cervical cancer is one of the most common female cancers globally with approximately 90% of cases and deaths occurring in LMICs particularly those with high rates of HIV. This global disparity is partly driven by successful efforts in HICs to implement evidence-based practices focused on early detection and timeliness of care. In Botswana a LMIC with an extremely high prevalence of HIV and cervical cancer we identified substantial delays in cancer care from diagnosis to treatment driven by a myriad of individual- and system-level barriers. To date most of the implementation and cancer control research in Botswana and other LMICs has focused on prevention and screening with limited focus on treatment following diagnosis of HIV-associated malignancies. As such there is a critical need to identify effective strategies to ensure timely care and to understand contextual factors that shape the response to strategies. Without this fundamental knowledge cervical cancer will remain a public health crisis in Botswana and other LMICs. To help fill this critical gap this study will test the effectiveness of adaptive strategies on timely treatment adoption using a Sequential Multiple Assignment Randomized Trial (SMART) design and evaluate contextual mechanisms contributing to the success or failure of each adaptive strategy using qualitative comparative analysis. The adaptive strategies are designed to target individual- and system-level determinants identified in our preliminary data including delayed communication of results individual and structural barriers to accessing treatment and suboptimal care coordination between referring and cancer treatment clinics and are supported by systematic evidence of the effectiveness of nudge strategies in clinical care. The primary implementation outcome will be adoption defined as the initiation of treatment within 90 days. Secondary implementation outcomes include fidelity (i.e. completion of recommended treatment) reach acceptability implementation costs and cancer and HIV-related clinical outcomes. The rationale for the study is that enhancing coordination communication and navigation through centralized outreach will both increase timely treatment adoption and be scalable and sustainable after the project is completed. This innovative study responds directly to the call by the National Cancer Institute to develop and test implementation strategies in cancer control in LMICs. Furthermore the highly efficient design enables the comparison of different adaptive strategies within one study helping to advance an understanding of the minimum level of intervention needed to improve and sustain cancer control in lower resource settings. If successful these strategies can be easily translated to address other areas of cancer control. The long-term goal of this project is to decrease cervical cancer mortality in LMICs by developing and implementing effective and sustainable strategies. 694021 +No NIH Category available Acute;Acute Lymphocytic Leukemia;Base Sequence;Bioinformatics;Cancer Biology;Chromatin Structure;Complement Factor B;Complex;Computational Biology;Computer Analysis;DNA Polymerase II;Data;Data Analyses;Defect;Development;Dimensions;Genes;Goals;MLL gene;Machine Learning;Malignant Neoplasms;Methods;Myelogenous;Oncogenic;RNA;Reproducibility;Research;Research Design;Research Personnel;Signal Transduction;Speed;Techniques;Therapeutic;Transcription Elongation;high standard;insight;large datasets;next generation;next generation sequencing;novel;skills;transcription factor;tumorigenesis Computational Approaches for Studying Transcription Elongation Control in Cancer Project NarrativeNext-generation sequence-based techniques can provide an unmatched insight into developmental mechanismsand the defects that lead to or sustain cancer but the handling and analysis of these large data sets requiresmethods and approaches not typically part of the skillset of an experimental biologist. The goal of this R50proposal is to support Dr. Iwanaszkos efforts in bioinformatics and computational biology which are focused onunderstanding oncogenic alterations in chromatin structure and transcription elongation and to evaluate novelcancer therapeutics. NCI 10697319 8/30/23 0:00 PAR-21-285 5R50CA265372-02 5 R50 CA 265372 2 "JOHNSON, ERIC MICHAEL" 9/5/22 0:00 8/31/27 0:00 ZCA1-SRB-1(M1) 14158281 "IWANASZKO, MARTA " Not Applicable 5 BIOCHEMISTRY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 144392 NCI 90245 54147 Project SummaryThe goal of this proposal is to provide bioinformatics support to advance research into the misregulation oftranscription elongation in oncogenesis. For example translocation of the mixed lineage leukemia (MLL) genewith a variety of genes expressing regulators of transcription elongation result in acute myeloid or acute lymphoidleukemia. Many of these factors are subunits of the Super Elongation Complex (SEC) which can enhancetranscription elongation by two submodules: the positive regulator of transcription factor b (P-TEFb) whichsignals for the release of paused Pol II and the RNA processivity factor ELL. A common denominator of theseprojects is the need for meticulous biologically relevant computational analysis which ultimately have severalfunctions: decoding next generation sequencing data into a useful set of findings combining data from multipleexperimental platforms for a multi-dimensional perspective and integrating machine learning approaches toextract data-specific signatures. These functions serve the goal of helping researchers beginning with studydesign data analysis and further hypothesis building to advance our understanding of cancer biology and tohelp evaluate cancer therapeutics. Dr. Iwanaszko will be responsible for implementing these approaches andproviding expertise in both bioinformatics and computational biology to support cancer biologists in extractingmore information from their data speeding up the analysis and to maintain a high standard of scientific rigorand reproducibility. 144392 +No NIH Category available Address;Affect;Alleles;Area;BRCA2 gene;Breast;Cell Death;Cells;Cisplatin;Constitution;Constitutional;DNA Damage;DNA Repair;DNA Sequence Rearrangement;DNA biosynthesis;Defect;Epithelium;Frequencies;Genes;Genome;Genome Stability;Genomic Instability;Germ-Line Mutation;Goals;Heterozygote;Homeostasis;Homologous Protein;Individual;Lesion;Loss of Heterozygosity;Malignant neoplasm of ovary;Mammalian Oviducts;Molecular Analysis;Mutation;Ovary;Pathway interactions;Poly(ADP-ribose) Polymerase Inhibitor;Predisposition;Proteins;Research;Resistance;Serous;Tissues;Tumor Suppressor Proteins;cancer therapy;chromosome loss;crosslink;homologous recombination;interest;malignant breast neoplasm;mutant;paralogous gene;protein function;repair function;repaired;targeted treatment;therapy resistant;treatment response;tumor;tumor initiation Homology-directed repair: BRCA2 and RAD51 paralogs PROJECT NARRATIVELesions that arise in the genome compromise its integrity and need to be properly repaired since loss of repairor misrepair leads to chromosome loss and genomic rearrangements which are associated with many tumortypes in particular of the breast and ovary. Defects in repair also sensitize tumors to particular therapies. Thisproject addresses fundamental questions about the tumor suppressors BRCA2 and RAD51 paralogs whichare involved in homology-direct repair and addresses underexplored areas of research including how cellslose the intact copy of genes how mutant genes revert and DNA repair in the fallopian tube. NCI 10697318 8/1/23 0:00 PAR-19-349 5R35CA253174-04 5 R35 CA 253174 4 "WITKIN, KEREN L" 8/1/20 0:00 7/31/27 0:00 ZCA1-GRB-S(M1) 1880290 "JASIN, MARIA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 999388 NCI 564626 434762 Project Summary/AbstractHomologous recombination i.e. homology-directed repair (HDR) is a major repair pathway for double-strandbreaks (DSBs) including lesions arising during DNA replication. HDR mutants are characterized by genomicinstability and sensitivity to DNA damaging agents such as interstrand cross-linking agents like cisplatin andpoly(ADP-ribose) polymerase inhibitors both of which are used in cancer treatment. Several proteins central tothe HDR pathway are tumor suppressors notably the breast and ovarian cancer suppressor BRCA2 whichpromotes the function of RAD51 the critical protein for homologous strand exchange. RAD51 paralogs arealso key HDR proteins and have also been identified both as tumor suppressors and as proteins that affecttherapy response. These HDR proteins are essential. Individuals with germline mutations are constitutionallyheterozygous but tumors typically have somatic undergone loss of heterozygosity (LOH) losing the wild-typeallele presumably as an early step in tumor initiation. This proposal has an overarching goal of integrating our understanding how HDR proteins act tomaintain genomic stability and cell and tissue homeostasis how they come to be lost in cells and how theirfunction can be restored. Thus this broad goal impacts tumor initiation therapy response and therapyresistance. It incorporates molecular analysis of HDR protein function with a particular focus on BRCA2 anddelineates how cells respond to HDR protein loss including how they escape cell death to allow tumorformation. Within this goal is understanding tumor initiation from the standpoint of determining mechanisms ofLOH that lead to HDR protein loss as well as uncovering factors that affect LOH frequencies. While HDRprotein loss sensitizes tumors to targeted therapies HDR function is often restored by secondary mutationsleading to therapy resistance. Understanding which mutations are susceptible to reversion and how therapyimpacts reversion is of major interest. Finally HDR within tissues is also part of this integrated goal inparticular within the fallopian tube epithelium which is considered the tissue of origin of high-grade serousovarian cancers. 999388 +No NIH Category available Abstinence;Address;Adult;Appalachian Region;Area;Attention;Carbon Monoxide;Chronic Disease;Clinic;Clinical Services;Code;Communication;Communities;Complex;County;Data;Electronics;Emergency medical service;Employee Engagement;Equilibrium;Ethnic Origin;Funding;Future;Geography;Goals;Human Resources;Hybrids;Individual;Institution;Internal Medicine;Intervention;Knowledge;Monitor;North Carolina;Odds Ratio;Participant;Pathway Analysis;Pathway interactions;Patients;Personnel Staffing;Persons;Prevalence;Preventive Medicine;Process;Protocols documentation;Publishing;Randomized;Recommendation;Recording of previous events;Reporting;Research;Role;Rural;Rural Community;Rural Health;Rural Population;Sampling;Science;Self Efficacy;Services;Smoke;Smokeless Tobacco;Smoker;Smoking;Smoking Behavior;Technology;Testing;Thinking;Time;Tobacco use;Training;Urban Population;Variant;Vulnerable Populations;Work;budget impact;cancer prevention;comparison group;cost;design;digital;effectiveness outcome;effectiveness research;effectiveness trial;evidence base;experience;health care delivery;high reward;high risk;implementation cost;implementation evaluation;implementation fidelity;implementation outcomes;implementation research;implementation strategy;implementation trial;innovation;mHealth;nicotine cessation;nicotine replacement;novel;patient engagement;patient level intervention;patient navigation;patient navigator;population health;programs;routine practice;rural area;rural counties;skills;smoking cessation;smoking prevalence;success;tobacco control;vaping Using Rural Community Paramedicine to Engage Lower-Motivated Smokers: Spreading an Effective mHealth-Assisted Intervention to Motivate Cessation 8. Project NarrativeWe propose a multi-level trial to test 1) novel implementation programs in rural counties designed to increaseaccess to 2) recent advances in tobacco control services for people who are not-yet-ready-to-quit smoking. Inthis field most trials have focused only on those already ready-to-quit. Thus the proposed trial addresses animportant knowledge gap critical to advance tobacco control in rural areas. NCI 10697314 8/29/23 0:00 RFA-CA-20-051 5R01CA268041-02 5 R01 CA 268041 2 "D'ANGELO, HEATHER" 9/5/22 0:00 8/31/27 0:00 ZCA1-RPRB-L(A1)R 6983464 "HOUSTON, THOMAS K" "SADASIVAM, RAJANI " 5 SURGERY 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 741061 NCI 548476 192585 7. Project Summary/Abstract We will conduct a multi-level hybrid type 2 study (i.e.: implementation and effectiveness outcomes) to test1) a novel implementation program in rural counties and 2) a mHealth (mobile health)-assisted brief abstinenceexperience (Take a Break TAB) for rural adults who smoke and are not-yet-ready to quit. In our network of ruralcounties the implementation trial will use a novel multi-strategy implementation program centered on countyemployees engaged in community paramedicine. Emergency Medical Services personnel (EMS) are evolvinginto this more expansive role (e.g.: non-emergent healthcare delivery monitoring of chronic disease andpreventive medicine). To test the implementation we will randomize rural counties with EMS servinggeographically complex and ethnically varied areas (the mountainous region of Appalachia and plains of easternNorth Carolina). These counties have some of the highest smoking rates in the U.S. We will compare a well-tested (standard) implementation program versus a novel enhanced program. The standard program usesevidence-based external facilitation providing training and technical support to EMS services to support theintegration of enhanced tobacco control practices (including recommending and referring people who smoke andnot-yet-ready-to-quit to the mHealth-assisted population health intervention. The novel enhancedimplementation program will include the standard program an EMS Champion program. EMS who currentlysmoke will be offered participation in TAB themselves. Those who participate Champions will then use theirTAB experience to support implementation as internal facilitators. They will encourage other EMS to experienceTAB longitudinally encourage use of the tobacco control practices in routine workflow for all EMS and will beable to use their personal experience with TAB to engage in a richer dialog with patients who smoke. Using thesestrategies we seek to engage individuals living in harder-to-reach rural areas with less access to clinical services.Engaging these individuals is possible with brief low intensity palatable interventions that target self-efficacyand facilitate skills building to support future abstinence. The TAB intervention addresses the challenge ofengaging lower motivated individuals using a novel format a brief abstinence game supported using mHealthand building upon 10 years of research. We recently published the first TAB effectiveness trial in JAMA InternalMedicine. This preliminary data supports the current application and does not include a large number ofindividuals living in rural areas. In this project we will randomize to TAB versus an active comparison designedto isolate the effect of TAB and balance the participant contact across the two groups. In addition to evaluatingimplementation success and effectiveness outcomes we will study pathways to cessation. To informsustainment and dissemination we will collect data on implementation fidelity county-level adaptationsvariations in referrals and patient-level engagement across the counties and at the EMS and patient-level. Toevaluate budget impact we will track the cost of the implementation strategies and the intervention. 741061 +No NIH Category available Accounting;Adjuvant Therapy;African American;Androgen Suppression;Architecture;Biochemical;Biological Assay;Biological Markers;Biopsy;Biopsy Specimen;Cancer Patient;Cell Nucleus;Cessation of life;Clinic;Clinical;Clinical Trials;Collagen;Collagen Fiber;Complement;Computer software;Computers;Country;Cues;Data;Dedications;Ethnic Population;Exhibits;Genomics;Gland;Gleason Grade for Prostate Cancer;Goals;Guidelines;Habitats;Image;Image-Guided Surgery;Malignant Neoplasms;Malignant neoplasm of prostate;Medical Oncology;Modeling;Molecular;Morbidity - disease rate;Morphology;National Comprehensive Cancer Network;Neoplasm Metastasis;Nomograms;Nuclear;Oncology;Operative Surgical Procedures;Organ;Outcome;Paper;Pathologic;Pathology;Patients;Pattern;Pennsylvania;Performance;Phenotype;Population;Prognosis;Prostate Cancer therapy;Publishing;Radiation;Radiation Therapy Oncology Group;Radiation therapy;Radical Prostatectomy;Recurrence;Recurrent Malignant Neoplasm;Risk;Risk Reduction;Secure;Site;Slide;Specimen;Testing;Time;Tissue imaging;Tissues;Translating;Tumor Tissue;Universities;Validation;Visual;advanced disease;androgen deprivation therapy;cancer recurrence;caucasian American;chemotherapy;companion diagnostics;computerized;cost;diagnostic assay;digital;digital imaging;digital pathology;disorder risk;effective therapy;follow-up;genetic testing;hazard;head-to-head comparison;high risk;high risk population;improved;indexing;innovation;men;mortality risk;precision medicine;precision oncology;predictive test;prognostic;prognostic assays;prostate cancer model;prostate cancer risk;prototype;randomized clinical trials;risk minimization;success;tool;treatment guidelines;tumor Prognostic and Predictive Digital Tissue Image Assay for Prostate Cancer RELEVANCE: The goal of this project is to develop and validate an integrated risk score (IRiS) predictor usinghistomorphometric features derived from digital images of surgically excised tissue specimens and biopsiedtissue that is both prognostic of prostate cancer (PCa) outcome and predictive of added benefit of adjuvanttherapy following definitive therapy (surgery OR radiation therapy). IRiS will help to identify which of the over160000 men with high-risk prostate cancer in the US and who annually undergo definitive therapy have higherrisk disease and hence may receive added benefit from additional chemotherapy following definitive therapy. NCI 10697304 8/28/23 0:00 PA-20-185 5R01CA268287-02 5 R01 CA 268287 2 "MCKEE, TAWNYA C" 9/5/22 0:00 8/31/27 0:00 Clinical Translational Imaging Science Study Section[CTIS] 8352708 "MADABHUSHI, ANANT " "GUPTA, SHILPA ; LAL, PRITI " 5 BIOMEDICAL ENGINEERING 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 627645 NCI 463988 163657 "PROJECT SUMMARY: There were >34000 PCa-related deaths in 2020 in the US alone. Definitive treatmentincludes Radical prostatectomy (RP) or radiotherapy (RT) with long term androgen-suppression therapy (ADT).These have been shown to be effective treatments for organ-confined PCa and have been demonstrated toreduce the risk of death from PCa. In 38-52% of cases however advanced disease with potentially poorprognosis is found on tissue pathology. A number of recent clinical trials have shown the benefit of adjuvanttherapy in select PCa patients post-RP or RT. However it is critical to identify those PCa patients who followingdefinitive therapy (surgery or radiation) are at high-risk for recurrence or metastasis and thus will benefit fromadjuvant therapy versus patients who will not and hence may be spared the morbidity and cost of therapy. Recognizing the significance of this unmet clinical need in 2018 the NCCN guidelines for PCa weremodified to include the Decipher Score a prognostic molecular gene-based test to identify the likelihood ofmetastasis following surgery. We have developed our own ""Integrated Risk Score"" (IRiS) image classifier that(npj Precison Onc In Press14) combines computer extracted morphologic glandular features from H&E tissueslides of the tumor. IRiS stratified PCa patients (N>900 6 sites) based on their time to biochemical recurrence(BCR) into low- and high-risk groups (p<0.001; HR=2.44). Further IRiS when combined with pre-op PSA andGleason grade outperformed Decipher in predicting BCR in N=173 patients (p<0.001; HR=3.23 vs HR=2.76). In this R01 we will validate IRiS as (1) prognostic of BCR and risk of metastasis as well as (2)predictive of the added benefit of additional chemotherapy following definitive therapy (surgery or radiation) inPCa. In a recent paper in Clin Cancer Res we identified IRiS specific prognostic features for African American(AA) men with PCa. We will build on these findings to develop population specific IRiS models for PCa. We willalso further optimize IRiS by including (1) features of stromal and cribriform morphology (2) develop populationspecific IRiS models for different ethnic groups and (3) complement IRiS with clinico-pathological features. Tovalidate IRiS as predictive of benefit of adjuvant therapy we need access to randomized clinical trial tissue slideimages involving PCa patients treated with definitive therapy alone (surgery or ADT+radiation) and definitivetherapy+ adj. chemo. The STAMPEDE and RTOG-0521 trials fit these criteria; we have secured approval toaccess tissue slide images from these trials. To make the tool widely available IRiS will be integrated intoPathPresenter a digital pathology viewer and management platform currently in use in 178 countries. Thispartnership will combine expertise in (a) computational pathology of the Madabhushi group (2) clinicalpathological and biomarker expertise of PCa from the University of Pennsylvania (Drs. Priti Lal) and (3) GUmedical oncology expertise from the Cleveland Clinic (Dr Shilpa Gupta) to translate IRiS as the first tissue non-destructive prognostic and predictive Affordable Precision Medicine (APM) solution for PCa." 627645 +No NIH Category available Abdomen;Acute;Address;Adjuvant Therapy;Adopted;Adoption;Affect;Animals;Characteristics;Chemotherapy and/or radiation;Chicago;Cities;Clinical;Clinical Services;Clinical Trials;Collaborations;Colorado;Data;Development;Devices;Diagnosis;Disease;Drug Delivery Systems;Effectiveness;Electronics;Elements;Eligibility Determination;Ensure;Environment;FDA approved;Family suidae;Fat necrosis;Feasibility Studies;Feedback;Fiber Optics;Frequencies;Future;Geometry;Goals;Heating;Human;Human Resources;Hyperthermia;Illinois;Implant;Kansas;Kidney;Liver;Liver neoplasms;Location;Longitudinal Studies;Magnetic Resonance;Magnetic Resonance Imaging;Malignant neoplasm of pancreas;Marketing;Maryland;Measurement;Measures;Mediating;Medical Device;Medical center;Modeling;Modification;Monitor;Newly Diagnosed;Oncology;Oncopig;Operative Surgical Procedures;Organ;Pancreas;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Performance;Phase;Primary carcinoma of the liver cells;Radiation;Radiation therapy;Radiation-Sensitizing Agents;Reporting;Research Personnel;Resolution;Safety;Series;Services;Skin;Small Business Innovation Research Grant;Solid Neoplasm;Spleen;Structure;Survival Rate;System;Techniques;Technology;Temperature;Testing;Thermometers;Thermometry;Time;Tissues;Transgenic Organisms;Translations;United States;Universities;Work;biomaterial compatibility;cost;curative treatments;design;dielectric property;experimental study;first-in-human;improved;in silico;innovation;invention;microwave electromagnetic radiation;novel;operation;optical fiber;pancreatic cancer model;pancreatic cancer patients;perfusion imaging;porcine model;preclinical study;prototype;radiofrequency hyperthermia;risk mitigation;sensor;skin burn;standard of care;success;tool;tumor;ultrasound Integration of non-invasive deep tissue microwave thermometry in the VectRx hyperthermia device in a transgenic liver tumor pig model Project NarrativeClinical trials show that hyperthermia sensitizes tumors to standard chemotherapy and radiation treatments andimproves patient outcomes but adoption in the US has lagged due to inadequate devices and the inability tomeasure tissue temperature to ensure safety and effectiveness. In this proposal NTO and the University ofColorado-Boulder will co-develop and validate in a pig model a microwave thermometer customized for operationwith VectRx a device NeoTherma Oncology (NTO) has developed to safely heat deep solid tumors. Successin this study will provide NTO with a practical low-cost non-invasive pathway to measure temperature in deeptissue with microwave thermometers. NCI 10697183 7/20/23 0:00 PA-22-176 1R43CA278168-01A1 1 R43 CA 278168 1 A1 "ZHAO, MING" 8/1/23 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-ISB-S(11)B] 15338769 "FLORIANO, PIERRE " Not Applicable 4 Unavailable 80356714 ZXNHUFMN6254 80356714 ZXNHUFMN6254 US 37.722441 -97.371492 10048554 "NEOTHERMA ONCOLOGY, INC." WICHITA KS Domestic For-Profits 672032000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 SBIR/STTR 2023 399999 NCI 399999 0 Project Summary/AbstractNeoTherma Oncology (NTO/www.neothermaoncology.com) has developed a novel non-invasive medical devicethat delivers mild hyperthermia (HT) loco-regionally as adjuvant therapy to standard of care treatment ofabdominal deep-seated tumors. The VectRx device designated Breakthrough by the FDA hasdemonstrated its ability to safely heat abdominal organs (pancreas liver kidney spleen) in pre-clinical studiesin healthy swine. FDA approved an investigational device exemption for VectRx on the basis of these data andthe lack of a validated large animal tumor model for pancreatic cancer. NTO has initiated a First in Human earlyfeasibility study (EFS) study at the University of Maryland Medical Center to collect initial safety and performancedata in pancreatic cancer patients.In parallel to the EFS NTO will collaborate with University of Colorado-Boulder researchers who have developeda microwave thermometer (MT) that could be utilized to non-invasively measure temperatures in deep tissue.This development is based on the ability to detect the black body radiation proportional to temperature that isemitted at different tissue depths from skin to deep organ. Successful integration of the MTs will effectivelyimprove the clinical utility of VectRx. This will address challenges posed by the limited availability access highcost logistical concerns and reliance on specialized personnel as is the case with magnetic resonancethermometry. A series of MTs and a radiometer will be designed fabricated and integrated into VectRx withpotential VectRx coil adjustments to 1) achieve compatible designs of active and passive MTs with operationwithin VectRx (on and off); 2) manage any potential heating of the MTs coil detuning E-field and H-field patternintegrity during VectRx operation. Following co-development and optimization the MTss performance will beestablished in a hepatocellular carcinoma (HCC) Oncopig model with an accuracy goal of 1.5C. HCC is adisease with low survival rates and only a small fraction (15%) of newly diagnosed patients are eligible forcurative treatments due to late diagnosis. The model is relevant to NTOs indication pipeline of deep-seatedabdominal tumors and NTO has previously completed installation of the VectRx device and performedpreliminary work in 3 HCC Oncopigs with the veterinary team at the University of Illinois to optimize ultrasound-guided surgical placement of fiberoptic probes that will be used to correlate temperatures measured by the MTs.Despite the known benefits of mild HT it has not been widely adopted in the US because of the technicallimitations of current technologies to address deep hard to heat tumors and the lack of thermometry. In thisPhase I project we will demonstrate that these critical deficiencies can be overcome through integration of novelmicrowave-based temperature techniques with VectRx providing an innovative demonstration of advancedtemperature monitoring of HT in deep tissue in a large animal tumor model. 399999 +Cancer; Prevention Area;Cancer Patient;Cause of Death;Consent;Data;Dose;Guidelines;Health Personnel;Hospitals;Individual;Laws;Life;Malignant Neoplasms;Medical;National Cancer Institute;Oncologist;Oncology;Patients;Physicians' Offices;Provider;Recurrence;Reporting;SEER Program;Series;Source;System;Systemic Therapy;cancer care;care delivery;data registry;demographics;follow-up;interest;neoplasm registry;surveillance data ELECTRONIC CAPTURE OF CANCER CLAIMS DATA FOR THE SEER PROGRAM n/a NCI 10697121 75N91021P00809-P00001-0-1 N02 9/7/21 0:00 9/6/23 0:00 78346133 "GOCKERMAN, BRIAN " Not Applicable Unavailable 57900426 T669R8JHHBG7 57900426 T669R8JHHBG7 US -472194 CINCINNATI OH Other Domestic Non-Profits 452361670 UNITED STATES N R and D Contracts 2022 306000 NCI Healthcare providers in all 50 states are required by law to report new cases of cancer to their states cancer registries. The National Cancer Institutes (NCIs) Surveillance Epidemiology and End Results (SEER) Program collects data on eachand every cancer patient in SEER covered areas. This data includes demographics a description of their cancer limited initial treatment information and patient follow-up including cause of death for deceased patients. In the past the main source of registry data came from Hospitals. With the increasing complexity of cancer care and delivery systems patients are being increasingly treated exclusively at physicians offices. Thus for SEER to continue capturing all cancer casesand their treatment information SEER is interested in obtaining other sources of data such as claims data from oncology practices. Oncology practice claims has proven to be a rich source of information on detailed systemic therapy includingagents doses administration dates etc. 306000 +Burden of Illness; Cancer; Networking and Information Technology R&D (NITRD); Prevention Agreement;Architecture;Behavioral;Caliber;Cancer Burden;Cancer Survivor;Cessation of life;Congresses;Contractor;Contracts;Country;Data;Data Analyses;Databases;Decision Making;Development;Diagnosis;Division of Cancer Control and Population Sciences;Epidemiology;Evaluation;Extramural Activities;Fostering;Funding;Grant;Incidence;Informatics;Information Systems;Information Technology;Instruction;Maintenance;Malignant Neoplasms;Monitor;National Cancer Institute;Population;Prevention;Process;Quality of life;Research;Research Priority;Research Project Grants;Risk;Services;Statutes and Laws;Strategic Planning;Systems Development;Training;United States;United States Dept. of Health and Human Services;United States National Institutes of Health;anticancer research;cancer genetics;cancer therapy;design;effective intervention;operation;programs;social;trend Department of the Interior: Calibre Database Support Information Technology Services and Support (ITSS) n/a NCI 10697120 APC20006001-1-0-1 Y01 77897581 "COUNTS, ANDREW " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 2118584 NCI The National Cancer Institute (NCI) is part of the National Institutes of Health (NIH) and is an operating division within the Department of Health and Human Services (DHHS). The creation of the National Cancer Institute (NCI) was authorized by the U.S. Congress in the National Cancer Act of 1937. In this landmark legislation NCI was given a mandate to engage in certain fundamental activities: conducting and fostering cancer research; reviewing and approving grant-in-aid applications to support promising research projects on the causes prevention diagnosis and treatment of cancer; collecting analyzing and disseminating the results of cancer research conducted in the United States and in other countries; and providing training and instruction in the diagnosis and treatment of cancer. NCI is the world's pre-eminent cancer research organization.The Division of Cancer Control and Population Sciences (DCCPS) of the National Cancer Institute (NCI) National Institutes of Health (NIH) aim to reduce the risk incidence and deaths from cancer as well as to enhance the quality of life for cancer survivors. The Division conducts and supports an integrated program of the highest quality cancer genetic epidemiological behavioral social and surveillance research. The major objective of DCCPS is to fund extramural research. Extramural research is funded via grants contracts and interagency agreements. Under the direction of the Office of the Director the Information Technology Services Group (ITSG) provides Information Technology (IT) services and information systems for tracking and disseminating information relevant to the DCCPS Research Portfolio (grants contracts IAAs). DCCPS information systems provide data for analysis and decision-making that aids in evaluating what has been learned identifying new research priorities and strategies and effectively applying research discoveries to reduce the cancer burden. DCCPS is designed to:understand the causes and distribution of cancer in populationssupport the development and implementation of effective interventions andmonitor and explain cancer trends in all segments of the population.Central to these activities is the process of synthesis and decision-making that aids in:evaluating what has been learnedidentifying new priorities and strategies andeffectively applying research discoveries to reduce the cancer burden.Under the direction of the DCCPS Office of the Director the Information Technology Services Group (ITSG) provides Information Technology (IT) services and information systems for tracking and disseminating information relevant to the DCCPS Research Portfolio. Data and information from the systems are used by management and program staff to aide in analysis evaluation and decision-making regarding the existing research portfolio and to identify new research priorities and strategies that will effectively apply research discoveries to reduce the cancer burden. 2118584 +No NIH Category available Address;Aerosols;Blood Volume;Bypass;Cancer Etiology;Cancer Patient;Cells;Characteristics;Circulation;Clinical;Clinical Research;Combination Drug Therapy;Data;Deposition;Dose;Drug Delivery Systems;Dryness;Effectiveness;Electroencephalography;Elements;Equipment Contamination;Excipients;Formulation;Growth;Histologic;Human;Immunotherapy;In Vitro;Inhalation;Inhalation Toxicology;Inhalators;Intravenous;Investigational Drugs;Investigational New Drug Application;Lead;Leucine;Lung;Lung Neoplasms;Malignant neoplasm of lung;Maximum Tolerated Dose;Medical;Medical Staff;Medicine;Metabolism;Methods;National Heart Lung and Blood Institute;Nebulizer;Non-Small-Cell Lung Carcinoma;Oncology;Operative Surgical Procedures;Oral cavity;Outcome;Pathway interactions;Patients;Penetration;Performance;Peripheral;Pharmaceutical Preparations;Pharmacotherapy;Pharyngeal structure;Phase;Powder dose form;Production;Research;Risk;Rodent;Rodent Model;Route;Safety;Small Business Innovation Research Grant;Sodium Chloride;Survival Rate;Techniques;Technology;Testing;Therapeutic;Toxicokinetics;Toxicology;Translations;Treatment outcome;Tumor Burden;Tumor Tissue;United States Food and Drug Administration;United States National Institutes of Health;Universities;Virginia;Wettability;Work;chemotherapy;commercialization;drug development;efficacy study;first-in-human;gemcitabine;good laboratory practice;improved;in vivo;innovation;manufacture;meter;mortality;novel;particle;pre-clinical;preclinical study;scale up;side effect;standard of care;systemic toxicity;targeted delivery;translational potential;tumor Treating non-small cell lung tumors with a novel inhaled dry powder chemotherapeutic formulation Project Narrative Lung cancer is the leading cause of cancer mortality with a 5-year survival rate of less than 20% followingstandard of care treatment. There is strong evidence that targeted delivery of inhaled chemotherapy medicationto the lung at a fraction of the current dose will have a major impact on increasing survival and reducing lungtumor burden in lung cancer patients with far less side effects than those associated with current systemicintravenous chemotherapy. Based on preliminary data we will develop a novel inhaled chemotherapy treatmentin order to directly target pulmonary tumors in order to improve survival in lung cancer patients. NCI 10696996 3/30/23 0:00 PA-22-176 1R44CA277898-01A1 1 R44 CA 277898 1 A1 "POND, MONIQUE ADRIANNE" 4/1/23 0:00 3/31/25 0:00 Special Emphasis Panel[ZRG1-BBBT-F(10)B] 15202598 "BEVERLIN II, BRYCE " Not Applicable 4 Unavailable 80748920 JVLSL7GNVK25 80748920 JVLSL7GNVK25 US 44.954198 -93.200735 10047178 "QUENCH MEDICAL, INC." SAINT PAUL MN Domestic For-Profits 551160000 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 395 SBIR/STTR 2023 1127538 NCI 824650 232395 Project Summary / AbstractSignificanceLung cancer is the leading cause of cancer mortality with a 5-year survival rate of less than 20% followingstandard of care therapy.ProblemDespite the use of aggressive surgery combination chemotherapy and immunotherapy a major limitation in thecontrol of primary and metastatic non-small cell pulmonary tumors with the use of the systemic administration ofdrugs is the low drug concentration in the lungs due to blood volume dilution and metabolism. There is a criticalunmet medical need to develop new strategies to improve patient treatment outcomes.InnovationIn contrast to systemic delivery of chemotherapy inhalation delivers a chemotherapeutic drug directly to tumortissues in the lung thereby enhancing its efficacy and safety due to increased local drug concentration in thelung decreased systemic drug levels in the circulation and decreased systemic toxicity.GapPreliminary pre-clinical in-vivo studies using nebulized chemotherapy drugs has demonstrated efficacy andestablished the feasibility of delivery via aerosol but nebulization of toxic drugs has major drawbacks. Thesedrawbacks include a lack of efficient peripheral airway penetration high mouth-throat deposition contaminationof equipment and collateral aerosol risk to medical staff.Project ObjectiveTo address these drawbacks we are developing a new method of delivering a chemotherapeutic drug viainhalation to reach pulmonary tumors directly in order to maximize the effectiveness and safety of the aerosoltreatment with a fraction of the standard dose. We will create a novel dry powder chemotherapeutic formulationcontaining an FDA approved chemotherapy medication for the treatment of non-small cell lung cancer.AimsAims of this proposal will be 1) scale-up the lead Quench EEG formulation and conduct characterization stabilityand performance studies and 2) conduct IND-enabling toxicology studies in an established inhalation toxicologyrodent model for regulatory submission.Commercial PotentialTranslation of this technology into a clinically beneficial inhalable chemotherapy product has the potential tosignificantly improve the treatment of pulmonary tumors in lung cancer patients by delivering targeted lowerdoses of medicine directly to the lung while minimizing systemic toxicity. 1127538 +No NIH Category available Address;Advisory Committees;Affect;Apoptosis;Award;Bass;Biochemical;Biological Assay;Biology;Cell Cycle Arrest;Cell Survival;Cells;Cellular Assay;ChIP-seq;Clinical;Collaborations;Colon Carcinoma;Coupled;Cyclic GMP;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;DNA Structure;DNA replication fork;Dana-Farber Cancer Institute;Data;Deletion Mutation;Dependence;Development;Dinucleoside Phosphates;Dinucleotide Repeats;Drug Design;Drug usage;Endometrial Carcinoma;Essential Genes;Funding;Genetic;Genetic Transcription;Genomics;Goals;Immunotherapy;Impairment;Inflammatory Response;Innate Immune Response;Interferons;Knock-out;Laboratory Study;Length;Lysine;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Medical Oncologist;Mentors;Microsatellite Instability;Microsatellite Repeats;Mismatch Repair;Modeling;Molecular Biology;Mus;Mutate;Nuclear;Pathway interactions;Patients;Phosphorylation;Phosphotransferases;Physicians;Play;Positioning Attribute;Post-Translational Protein Processing;Repetitive Sequence;Reporter;Research Personnel;Research Proposals;Resistance;Role;Scientist;Serine;Signal Transduction;Stimulator of Interferon Genes;Structure;Structure-Activity Relationship;TNF gene;Techniques;Testing;Therapeutic;Threonine;Toxic effect;Training;Translations;Tyrosine;WRN gene;antitumor effect;cancer cell;cancer type;career;career development;drug discovery;functional genomics;helicase;immune checkpoint blockade;in vivo Model;inhibitor;malignant stomach neoplasm;new combination therapies;novel;novel therapeutics;prevent;programmed cell death protein 1;programs;rational design;replication stress;response;skills Advancing WRN as a synthetic lethal target for microsatellite unstable cancers Project NarrativeWe have identified WRN as a synthetic lethal target for MSI cancers. This research proposalseeks to investigate why WRN is required in MSI cancers inform rational drug design andinvestigate the relationship between the innate immune response and the DNA-damageresponse following WRN depletion in cancers with MSI. The overarching goal of this project is toenable the translation of our discovery into a clinically-meaningful therapeutic. NCI 10696950 8/8/23 0:00 PA-19-117 5K08CA256173-03 5 K08 CA 256173 3 "BIAN, YANSONG" 9/1/22 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 15120039 "CHAN, EDMOND " Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 238634 NCI 220957 17677 Project SummaryMicrosatellite instablility (MSI) a class of genetic hypermutability arising from impaired DNAmismatch repair contributes to development to types of cancers. While immune checkpointblockade (ICB) is effective for some patients 45-60% of patients do not response to ICB and theuse of these agents can be limited by their toxicity and/or acquired resistance. The pressing needfor further therapies against this large class of cancers inspired our efforts identifying the RecQhelicase WRN as a synthetic lethal target for MSI cancers. This discovery raises fundamentalquestions about how WRN functions to protect the MSI cancers from DNA double strand breaksand what is the best strategy to implement WRN inhibition to treat MSI cancers. This project seeksto address these questions by first testing our hypothesis that WRN is required to unwindsecondary DNA structures that are specifically enriched in MSI cells (Aim 1). Furthermore we willexplore the structure/function relationship of WRN in the context of MSI with a goal of identifyingessential regions to inform drug discovery efforts (Aim 2). Our preliminary data also demonstratedthat WRN inhibition induces a TNF transcriptional response in MSI cells. These results inspiredour hypothesis that the DNA damage following WRN depletion triggers an innate immuneresponse in MSI cancers (Aim 3). By integrating functional genomics biochemical techniquesDNA repair biology and in vivo modeling we seek to define the mechanism underlying thedependence upon WRN in MSI cells for survival facilitate rational design of WRN inhibitors andpromote development of new combination therapies for MSI cancers.I am a medical oncologist with a background in functional genomics and DNA repair biology. Mylong-term goal as a physician-scientist is to lead a basic/translational laboratory studying howcancers tolerate impaired DNA repair pathways and the vulnerabilities that arise in this context. Iwill be primarily mentored by Dr. Adam Bass at the Broad Institute and Dana-Farber CancerInstitute. Furthermore my scientific advisory committee composed of Drs. Alan DAndreaRaymond Monnat Matthew Meyerson and David Barbie will help guide my scientific and careerdevelopment. Coupled with collaborations with Drs. Andre Nussenzweig and Tyler Jacks afocused training and career developmental plan the proposed training plan will help me build themomentum to launch my career as an independent investigator. 238634 +No NIH Category available Alternative Splicing;Area;Award;Bioinformatics;Biological Assay;Biological Markers;Cancer Center;Cells;Chromatin Structure;Collaborations;Comprehensive Cancer Center;DNA Methylation;Data;Data Analyses;Development;Epigenetic Process;Future;Gene Expression;Genomics;Immunologic Markers;Informatics;Lead;Malignant Neoplasms;Measurement;Methods;Multiomic Data;Play;Postdoctoral Fellow;Regulation;Research;Research Activity;Research Personnel;Role;Services;Software Tools;T cell receptor repertoire sequencing;T-Lymphocyte;Techniques;Technology;The Cancer Genome Atlas;Training;Tumor Biology;Universities;Work;analysis pipeline;anticancer research;biomarker discovery;cancer immunotherapy;cancer type;data integration;density;genomic data;innovation;member;predicting response;tumor Comprehensive Analysis and Multi-Omics Data Integration for Cancer-Related Studies Project NarrativeComprehensive bioinformatics analysis and multi-omics data integration is an essentialpart of a wide variety of cancer-related studies such as biomarker discovery for cancerimmunotherapy or the role of epigenetics in cancer-specific regulation. This applicationis aimed to support the development of state of the art bioinformatics analysis pipelinesthrough my role as Research Associate and Bioinformatics Manager of TheExperimental and Computational Genomics Core in the Sidney Kimmel ComprehensiveCancer Center. The support of the R50 award will enable broader access ofcomprehensive bioinformatics expertise provided by the Experimental andComputational Genomics Core for diverse cancer-related studies by members of boththe Sidney Kimmel Comprehensive Cancer Center and the Bloomberg~Kimmel Institutefor Cancer Immunotherapy at Johns Hopkins. NCI 10696940 9/7/23 0:00 PAR-18-887 5R50CA243627-05 5 R50 CA 243627 5 "JOHNSON, ERIC MICHAEL" 9/11/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 10210486 "DANILOVA, LUDMILA " Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 101004 NCI 61682 39322 Project Summary/AbstractI am a Research Associate and Bioinformatics Manager of The Experimental andComputational Genomics Core in the Sidney Kimmel Comprehensive Cancer Center(ECGC) at Johns Hopkins University. This Core offers comprehensive bioinformaticssupport to members of both the Cancer Center and the Bloomberg~Kimmel Institute forCancer Immunotherapy (BKI) including both standard informatics and innovativeanalysis pipeline development. To this work I bring expertise in genomics data analysismethods through my role leading the DNA methylation analysis in several tumor typesfor The Cancer Genome Atlas (TCGA). In my role as Bioinformatics Manager of ECGCI oversee day-to-day bioinformatics services and supports the bioinformatics needs ofinvestigators in areas of data integration annotation and high-throughput data analysis.In this capacity I develop bioinformatics software tools to support many cancerresearch activities. I collaborate with a number of investigators across both the cancercenter and BKI. I highlight three key collaborations in this application as illustrative ofmy research portfolio. For example (1) I played a key role in the comprehensiveanalysis of T-cell receptor sequencing data for the FEST (Functional Expansion ofSpecific T cells http://www.stat-apps.onc.jhmi.edu/FEST/) assay. (2) I performintegrative analysis of multiplex data to find better biomarkers to predict response tocancer immunotherapy using both expression of immune markers in addition to densityand a spatial correlation of cells expressing those makers. (3) I am lead analyses forbasic tumor biology to determine how chromatin structure is associated with geneexpression and alternative splicing. With the support of this R50 award I will extend mycurrent pipeline development to state of the art single cell measurement technologiesand data integration techniques and train future bioinformatics analysts to benefitvarious cancer-related studies throughout the cancer center and BKI. 101004 +No NIH Category available Adoptive Cell Transfers;Allogenic;Antibodies;Antigen Targeting;Antigens;Autologous;Autologous Tumor-Infiltrating Lymphocyte;Back;Biopsy;CD3 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Center;Cell Line;Cells;Clinical;Clone Cells;Data;Diameter;Effectiveness;Endotoxins;Enrollment;Escherichia coli;Frequencies;Generations;Guidelines;Harvest;Human;IL17 gene;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Individual;Infiltration;Interleukin-2;Letters;Link;Lymphocyte;Lymphocyte Activation;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Memory;Metastatic Melanoma;Monoclonal Antibodies;Mus;Operative Surgical Procedures;Pancreas;Pathway interactions;Patients;Phase I Clinical Trials;Phenotype;Population;Portugal;Privatization;Process;Production;Protocols documentation;Recombinants;Recurrence;Regulatory T-Lymphocyte;Relapse;Reporting;Resectable;Resected;Site;Solid Neoplasm;Source;Specimen;Sterility;T cell response;T memory cell;T-Lymphocyte;T-cell receptor repertoire;Therapeutic;Time;Tissues;Transfection;Tumor Antigens;Tumor Immunity;Tumor Promotion;Tumor Tissue;Tumor-Infiltrating Lymphocytes;Work;anti-CTLA4;anti-PD-1;anti-PD-L1;antigen-specific T cells;cancer therapy;cancer type;clinically significant;cytokine;effector T cell;efficacy validation;exhaust;experience;falls;fitness;improved;in vivo;innovation;lymphocyte product;manufacture;manufacturing process;neoantigens;objective response rate;pancreatic cancer patients;pancreatic neoplasm;protein purification;response;scale up;stem;stem cells;success;treatment optimization;tumor;tumor progression Optimization of TIL Cell Manufacturing for Cancer Treatment NARRATIVE We will improve cell-based cancer therapy by optimizing the ex vivo therapeutics and protocol to robustlyand rapidly generate tumor antigen-specific infiltrating lymphocytes with younger phenotypes from small tumorbiopsies or surgically resected tumors obtained from patients with pancreatic cancer. NCI 10696746 2/17/23 0:00 PA-22-176 1R43CA275458-01A1 1 R43 CA 275458 1 A1 "BOZZA, WILLIAM PATRICK" 3/1/23 0:00 2/28/25 0:00 Special Emphasis Panel[ZRG1-OTC-R(12)B] 12596346 "JEONG, SOON SEOG " Not Applicable 11 Unavailable 36640349 F4N9XZWABV33 36640349 F4N9XZWABV33 US 41.774867 -88.195101 10038151 HUMAN CELL CO NAPERVILLE IL Domestic For-Profits 605406685 UNITED STATES N 3/1/23 0:00 2/28/25 0:00 396 SBIR/STTR 2023 400000 NCI 267023 106809 ABSTRACTAdoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has demonstratedtremendous potential for treatment of advanced solid tumors. Objective response rates ranging from 34 to 72%have been reported in patients with metastatic melanoma with durable complete tumor regression observed inup to 20% of treated patients. However the current process for isolating identifying and expanding therapeuticTIL cells was established more than 30 years ago. TILs are stimulated with a murine anti-CD3 monoclonalantibody (OKT-3) high concentration of recombinant IL-2 produced from E. coli and irradiated allogeneic orautologous feeder cells. Shortcomings of this process include the need for a surgically resectable tumor as asource of TIL cells inability to grow TILs for a significant portion of patients significant presence of regulatory Tcells and long production time. Moreover TILs are predominantly differentiated into old effector T cells in vitrowith a terminal phenotype thereby reducing their long-term survival and antitumor effectiveness in vivo. Youngerphenotype T cells including stem cell memory and central memory T cells provide superior persistence andantitumor immunity compared with effector memory T cells and effector T cells. This is consistent with recentclinical findings by Dr. Rosenberg and his group that the response of TILs against human cancer is primarilymediated by neoantigen-specific and stem-like CD8+ T cells (CD39-CD69-).Moreover there is a high unmetneed for rapidly progressing cancer types where the window of treatment is limited and where the time for TILThese shortcomings can be surmounted by improving theantibodies and cytokines used ex vivo and optimizing the combination and manufacturing process to robustlyand rapidly produce TIL cells thus enabling TIL treatment for a broad spectrum of solid tumor patients withhigher response rate and curative potential.production becomes of paramount importance.We have been using stably transfected HEK293 cells to produce proprietary antibodies and cytokines. Theseancillary materials are critical in TIL manufacturing but are not intended to be part of the final cell product.Ourinnovative products for TIL cell production as ex vivo therapeutics have demonstrated striking advantages overcurrent commercial products for TIL production by improving the culture success rate absolute expansionnumber fitness and critically shortening the duration of TIL manufacturing while minimizing regulatory T cells.We have formed a strategic partnership to rigorously evaluate the products and optimize the manufacturingprocess of TILs. CurrentlyTILs have been successfully cultured from small tissues of 60 pancreatic and 20 non-pancreatic tumors andscaled up using the Cocoon Platform (Lonza) for pancreatic tumors the most difficultTILs to grow so far. Critically the TILs manufactured in clinical scale has a high frequency of CD8+CD39-CD69- T cells and the reactivities of TILs against neo-antigens were robustly detected by IFN release. The dataobtained thus far show a focused yet diverse TCR repertoire. In addition to a more general TCR analysis in TILwe were able to link individual TCR clonotypes to individual private target antigens and to trace these back tothe TIL product and to the corresponding harvested tumor tissue respectively. Specific Aim. To determine whether anti-CD137HC and/or IL-12HC enriches antigen-specific T cells and anti-TGFHC anti-IL-6HC and/or anti-IL-23HC blunts Th17 differentiation and IL-17 release; select top Expi293 cellclones and complete pilot scale production of proprietary antibodies and cytokines critical for TIL manufacturing. The strategic collaborator will validate the efficacy and consistency of our products and pursue regulatoryclearance for clinical manufacturing of TILs from pancreatic patients. Importantly a Phase 1 clinical trial formetastatic or recurrent pancreatic cancer patients has been planned the first patient is anticipated to be enrolledas soon as 2023. 400000 +No NIH Category available Affinity;Amino Acids;Antibodies;Antibody-drug conjugates;Antigen Targeting;Automobile Driving;Binding;Binding Proteins;Biological Assay;Blood Chemical Analysis;Cancer Etiology;Cell Line;Cells;Cessation of life;Chimeric Proteins;Clinical Research;Colon Carcinoma;Colorectal;Colorectal Cancer;Cytotoxic agent;DNA Damage;Development;Digit structure;Dose;Drug Delivery Systems;Drug resistance;Drug usage;Duocarmycin;Endocytosis;Fc domain;Funding;GPR4 gene;Gene Expression;Gene Fusion;Genetic Models;Goals;Growth;Half-Life;Heterogeneity;Histopathology;Human;IgG1;Immune System Diseases;Immune checkpoint inhibitor;Immunoglobulin G;Immunotherapeutic agent;In Vitro;LGR5 gene;Leucine-Rich Repeat;Ligands;Link;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Microtubules;Modality;Monoclonal Antibodies;Mus;Mutate;Neoplasm Metastasis;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Phase;Play;Pre-Clinical Model;Property;Protein Secretion;Proteins;Recurrence;Relapse;Role;Series;Signal Transduction;Solubility;Specificity;System;Testing;Therapeutic;Therapeutic Index;Time;Tissues;Toxic effect;Toxicology;Tumor Promotion;Up-Regulation;WNT Signaling Pathway;Work;Xenograft Model;Xenograft procedure;analytical method;antagonist;anticancer treatment;antitumor effect;cancer cell;cancer stem cell;cell growth;cell killing;checkpoint therapy;clinical development;colon cancer cell line;colon cancer patients;colorectal cancer treatment;cytotoxic;dimer;drug candidate;drug development;in vitro Model;in vivo;inhibitor;mouse genetics;mutant;neoplastic cell;novel;novel strategies;overexpression;patient derived xenograft model;patient subsets;pharmacologic;public health relevance;pyrrolobenzodiazepine;receptor;targeted agent;therapeutically effective;tumor;tumor eradication;tumor growth;tumor heterogeneity;tumor initiation;tumor xenograft;ubiquitin-protein ligase Development of drug conjugates of R-spondin peptibodies for the treatment of colorectal cancer Public Health Relevance Statement:Project title: Development of drug conjugates of R-spondin peptibodies for the treatment ofcolorectal cancer.Contact P.I. Jie CuiStatement: Colorectal cancer remains a major cause of cancer-related death in the world. Theproposed study aims to establish proof-of-principle in preclinical models for the use of drug conjugatesof R-spondin peptibodies against a group of related receptors that are highly upregulated in colorectalcancer. The work may lead to the discovery and development of a novel class of therapeutics for thetreatment of colorectal cancer patients. NCI 10696733 4/19/23 0:00 PA-22-178 1R41CA281553-01 1 R41 CA 281553 1 "WEBER, PATRICIA A" 5/1/23 0:00 4/30/24 0:00 Special Emphasis Panel[ZRG1-OTC-R(12)B] 12643737 "CUI, JIE " "LIU, QINGYUN " 18 Unavailable 79729258 HE6LHLBVCLY5 79729258 HE6LHLBVCLY5 US 30.190477 -95.562143 10038495 "WNTRIX, INC." Houston TX Domestic For-Profits 77021 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 SBIR/STTR 2023 400000 NCI 400000 0 PROJECT SUMMARYColorectal cancer is still a major cause of cancer-related death in the world and only a small subset ofpatients benefits from therapy by immune checkpoint inhibitors. Antibodydrug conjugates (ADCs) aremonoclonal antibodies (mAbs) that are covalently linked to cell-killing drugs and have emerged as amajor modality in anti-cancer treatment. This approach combines high specificity of mAbs against theirantigen targets with highly potent cytotoxic drugs resulting in armed mAbs that deliver the payload(drug) to tumor cells with enriched levels of the antibody target. The approach has become a majormodality of cancer therapeutics with several ADCs approved in the last few years. Leucine-rich repeatcontaining G protein-coupled receptor 4 5 and 6 (LGR4-6) are three related receptors that are highlyupregulated in colorectal cancers. They bind R-spondins (RSPOs) a group of secreted proteins withhigh affinity and potentiate Wnt signaling. Aberrant RSPO-LGR signaling plays critical roles in tumorformation progression and drug resistance. In particular LGR5 is enriched in cancer stem cells ofcolon cancer and LGR5-positive cells drive tumor growth and metastasis. However LGR5-positive and-negative cells can interconvert and ADCs targeting LGR5 inhibited tumor growth but failed tocompletely eradicate tumors due to cancer cell plasticity. Remarkably LGR5-negative cells stillexpress LGR4 or LGR6 or both. We reasoned that simultaneous targeting LGR4-6 may overcomecancer cell plasticity and drug resistance. Recently we demonstrated that a mutated form of RSPOcan bind to LGR4-6 with high affinity without potentiating Wnt signaling. Drug conjugates of RSPOmutant fused to IgG1-Fc domain was able to inhibit tumor cell growth in vitro and in vivo. We havenow generated a pyrrolobenzodiazepine dimer (PBD)-based drug conjugate of an RSPO2 mutant thatshowed potent anti-tumor effect in colon cancer models in vitro and in vivo. In this proposal we willevaluate the drug conjugate in a series of colon cancer models in vitro and in vivo and determine itstolerability in mice. These results and conclusions may for the first time validate PBD-conjugatedRSPO-Fc protein as a novel approach for simultaneous targeting of LGR4-6 for colorectal cancertreatment and identify drug candidates for further development. 400000 +No NIH Category available Acceleration;Achievement;Address;Advanced Malignant Neoplasm;Area;Award;Awareness;Cancer Survivor;Cancer Survivorship;Cancer health equity;Chicago;Cities;Clinical;Clinical Trials;Collaborations;Communities;Community Health;Community Networks;Community Outreach;Comprehensive Cancer Center;Continuity of Patient Care;Development;Disabled Persons;Disparity;Dissemination and Implementation;Early Diagnosis;Education;Education and Outreach;Educational Activities;Evaluation;Event;Evidence based practice;Faculty;Fostering;Funding;Geographic Locations;Grant;Health;Health Educators;Health Fairs;Human;Illinois;Immersion;Incidence;Individual;Inequity;Institution;Interview;Lead;Leadership;Learning;Linguistics;Localized Malignant Neoplasm;Low income;Malignant Neoplasms;Maps;Needs Assessment;Neighborhoods;Outreach Research;Penetrance;Persons;Phase;Population;Positioning Attribute;Prevention;Productivity;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Secure;Services;Sexual and Gender Minorities;Students;Surveys;Underserved Population;Universities;Vulnerable Populations;Work;anticancer research;cancer care;cancer education;cancer health disparity;cancer prevention;cancer therapy;citizen science;community center;community engagement;community organizations;community partnership;disability;education research;ethnic minority;evidence base;experience;forging;gender minority community;health disparity populations;health equity;improved;innovation;literacy;member;men of color;minority communities;mortality;neoplasm registry;outreach;peer;peer coaching;process evaluation;programs;racial minority;response;screening;survivorship;symposium;tool;underserved community Outreach Core n/a NCI 10696253 9/1/23 0:00 PAR-18-767 5U54CA202995-09 5 U54 CA 202995 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7867 10468666 "LUEDKE, TRACY J" Not Applicable 5 Unavailable 879331445 MR73WF5SHRW4 879331445 MR73WF5SHRW4 US 41.982453 -87.716237 215501 NORTHEASTERN ILLINOIS UNIVERSITY CHICAGO IL Domestic Higher Education 606254699 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 196476 147318 49158 OUTREACH CORE ABSTRACTCancer incidence and mortality rates for racial and ethnic minorities and other underserved and vulnerablepopulations are substantially higher in Chicago than the national average for most cancers (Illinois State CancerRegistry). Addressing these disparities demands culturally and linguistically relevant community-drivenapproaches. In 2015 a consortium comprised of community members and three major academic institutions inChicago University of Illinois at Chicago (UIC) Northeastern Illinois University (NEIU) and the Robert H. LurieComprehensive Cancer Center of Northwestern University (NU-LCC) secured NCI U54 funding to establish theChicago Cancer Health Equity Collaborative (ChicagoCHEC) which aims to foster rigorous and meaningfulresearch education training and community outreach/engagement to advance health equity. Through theoriginal U54 award the Outreach Core identified community needs and provided leadership and programmaticsupport for community-based cancer education engagement and outreach activities. In this renewal theproposed activities of the ChicagoCHEC Outreach Core will build upon the existing strengths prior and ongoingwork accomplishments and lessons learned from the first U54 award to elevate ChicagoCHECs collectiveimpact on reducing cancer inequities. A major area of the Outreach Cores focus for the next five years will beto develop targeted cancer support efforts for underserved and vulnerable populations. These include thefollowing non-mutually exclusive groups: people with disabilities sexual and gender minorities men of color andlow-income cancer survivors. Proposed community engagement approaches span the cancer continuumencompassing prevention screening and early detection community-based education and cancer treatmentand survivorship. Specific aims of the Outreach Core are to: (1) Foster community partnerships and conductongoing needs assessment to identify new and innovative areas of opportunity including outreach research forcommunity-engaged activities that will reach individuals from health disparities populations; (2) Implementoutreach and education activities across the cancer continuum; (3) Foster opportunities for building cancer healthequity research capacity among community partners faculty and students; (4) Plan implement and evaluateNCI National Outreach Network activities locally; and (5) Rigorously evaluate achievement and progress of theOutreach Cores stated aims using a comprehensive evaluation strategy. A highly effective and diverse tri-institutional leadership team with complementary expertise will lead these activities supported by experiencedCommunity Health Educators with strong clinical and community networks. A Community Steering Committeewill guide the development and implementation of the proposed outreach and engagement activities. TheOutreach Core will leverage each ChicagoCHEC partner academic institutions numerous ties to Chicagosdiverse neighborhoods and community organizations in its activities collectively aimed at advancing cancerhealth equity. +No NIH Category available Accounting;Adult;Advanced Malignant Neoplasm;Affect;Africa South of the Sahara;Age;Anus;Awareness;Botswana;Breast;Breast Cancer Cell;Breast Cancer Early Detection;Cancer Burden;Cancer Detection;Cancer Patient;Caring;Cause of Death;Cervix Uteri;Cessation of life;Clinic;Communities;Complex;Counseling;Country;Diagnosis;Diagnostic;Disease;Early Diagnosis;Education;Effectiveness;Family;Geography;HIV;HIV diagnosis;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Health system;Healthcare;Incidence;Income;Individual;International;Intervention;Knowledge;Limited Stage;Malignant Neoplasms;Medical;Mentors;Modeling;Nurses;Oncology;Pathology;Pathway interactions;Patient advocacy;Patients;Persons;Phase;Physicians;Population;Prevalence;Primary Care;Printed Media;Probability;Provider;Qualitative Research;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Records;Research;Resource-limited setting;Resources;Rural Community;Schedule;Screening for cancer;Self Efficacy;Social Workers;Speed;Symptoms;Syndrome;Time;Transportation;Vagina;Viral;Vital Status;Vulva;aged;cancer care;cancer diagnosis;cancer initiation;cancer risk;cancer survival;cancer therapy;care seeking;cohort;common symptom;curative treatments;effectiveness evaluation;effectiveness testing;effectiveness/implementation trial;family support;implementation evaluation;implementation intervention;improved;innovation;low and middle-income countries;medical care fees;mortality;multidisciplinary;pandemic disease;patient engagement;patient navigation;penis;pilot trial;programs;response;rural dwellers;self help;theories A multilevel intervention (Potlako+) to improve timely cancer detection and treatment initiation NarrativeDelayed cancer symptom recognition diagnosis and treatment are primary contributors to cancer mortalityglobally. People living in resource-constrained environments and persons living with HIV who are at increasedrisk of cancer are disproportionally affected. We will examine whether interventions to improve awareness ofsymptoms of common cancers and support to expedite diagnosis and treatment will increase number of peopletreated earlier for their cancer. Understanding the impact of these interventions will inform strategies of carefor populations at increasing risk of cancer death and contribute to developing models of primary care inresource-constrained environments. NCI 10696252 8/25/23 0:00 PAR-18-559 5R01CA236546-05 5 R01 CA 236546 5 "SAHASRABUDDHE, VIKRANT V" 9/19/19 0:00 8/31/24 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 10343338 "DRYDEN-PETERSON, SCOTT " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 469486 NCI 449407 20079 Project Summary/AbstractThe HIV pandemic has intensified the growing burden of cancer in low- and middle-income countries (LMICs)where nearly three-quarters of all cancer deaths occur. The majority of patients in LMICs have advanced cancerstage and limited opportunity for survival. Meaningful improvements in cancer mortality in LMICs will requireprompt diagnosis and efficient linkage to care however research identifying effective strategies has not beenconducted. Botswana has key resources in place free-of-charge medical care including comprehensive cancercare accessible primary clinics and an internationally-emulated ART program yet large gaps in timelycancer care and thus provides a key opportunity to innovate strategies to detect cancer earlier and engagepatients in care. The Potlako pilot trial (ORBIT phase IIa) evaluating an intervention targeting diagnostic andpre-treatment intervals in a single district (27 communities) in Botswana has successfully increased thenumber of patients entering cancer care and number treated with curative intent compared to historicalcontrols. As a next step the Potlako+ trial a community-randomized (26 geographically diverse ruralcommunities 1:1) pragmatic ORBIT phase IIb type 1 hybrid effectiveness-implementation trial will assess acomplex theory-informed intervention to promote earlier clinic presentation with symptoms suggestive ofcancer enable efficient diagnosis and facilitate prompt initiation of oncologic treatment. The Potlako+ trialtargets high burden cancers accounting for 60% of cancer deaths (breast cervix anus penis vulva and headand neck) which are typically curable with early detection of symptoms. We utilize cancer stage at time oftreatment initiation incidence of curative intent treatment and the duration of Models of Pathways toTreatment intervals as primary effectiveness endpoints. Implementation will be evaluated using the RE-AIMframework. The project will achieve three aims: 1) Assess the effectiveness of cancer symptom awarenessintervention with rural residents (persons living with HIV and HIV-uninfected) aged 30 years and older indecreasing time to presentation with moderate and high probability cancer syndromes 2) Assess impact of acomprehensive cancer patient navigation platform on reducing time to diagnosis and initiation of cancertreatment (diagnostic and pre-treatment intervals) and 3) Evaluate whether the combined multilevelintervention improves early stage treatment and cumulative incidence of curative intent treatment.Understanding the impact and implementation of these interventions will inform strategies of care for LMICpopulations at increasing risk of cancer death and contribute to developing models of primary care in resource-constrained environments. 469486 +No NIH Category available Achievement;Architecture;Bioinformatics;Cancer cell line;Code;Communities;Computer software;Data;Databases;Development;Education and Outreach;Educational Activities;Encyclopedias;Funding;Gene set enrichment analysis;Genes;Genomics;Leadership;Malignant Neoplasms;Maps;Methods;Molecular Profiling;Pathway interactions;Reproducibility;Research;Research Activity;Research Personnel;Resources;Scientist;Software Tools;Specialist;The Cancer Genome Atlas;Visualization;anticancer research;bioinformatics tool;cancer genomics;design;distributed data;genomic data;interoperability;online resource;open data;open source;tool;treatment response Platform and portal development for accessible reproducible cancer genomics research Project NarrativeThis project will develop new public open source bioinformatic software resources for the analysis andvisualization of cancer data. Special emphasis in design will be placed on accessibility to nonprogrammingscientists reproducibility of analysis results and interoperability between diverse tools and resources. NCI 10696249 9/5/23 0:00 PAR-18-888 5R50CA243876-05 5 R50 CA 243876 5 "JOHNSON, ERIC MICHAEL" 9/12/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 15770872 "LIEFELD, JOHN THEODORE" Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 211104 NCI 133610 77494 AbstractTed Liefeld is an accomplished software architect and bioinformatics programmer at UCSD who contributes tomany cancer research activities in the lab of Unit Director Jill Mesirov. Over the past 20 years he has developedbioinformatics software tools for reproducible cancer research and open science as well as numerous canceranalysis and visualization portals and online resources. He has provided architectural and project leadership on:(1) GenePattern a genomic analysis platform enabling access to hundreds of genomic analysis tools for usersat all levels of computational sophistication from nonprogramming investigators to accomplished codingbioinformatic scientists; (2) Gene Set Enrichment Analysis/Molecular Signatures Database (GSEA/MSigDB)used for identifying coordinately regulated sets of genes and activated pathways in genomic data; (3) the designof numerous cancer portals for distributing data from cancer projects including the Cancer Cell LineEncyclopedia Cancer Therapeutics Response Portal Project Achilles Portal Differentiation Map Portal andTCGA Tumorscape.Mr. Liefeld will use the provided funds for (1) designing and developing new software architectures promotinginteroperability of diverse bioinformatics tools and enabling reproducible research; (2) making advancedcompute-intensive cancer bioinformatics methods available to researchers in the worldwide oncogenomicscommunity; (3) developing accessible portals for NCI-funded cancer projects; (4) supporting the cancer researchcommunity through outreach and educational activities and initiatives. Based on his past achievements in cancerbioinformatics open science and reproducible research we believe Mr. Liefeld will continue to make essentialcontributions as an NCI Cancer Research Specialist. 211104 +No NIH Category available Address;African American;Area;Attention;Cancer Science;Cancer health equity;Chicago;Cities;Communities;Complement;Comprehensive Cancer Center;Development;Disparity;Diverse Workforce;Dryness;Education;Educational Activities;Educational Curriculum;Educational Status;Ensure;Ethnic Origin;Evaluation;Faculty;Fostering;Foundations;Funding;Gender;Goals;Grant;Health Disparities Research;Healthcare;Hispanic;Illinois;Immersion;Influentials;Institution;Internships;Laboratory Research;Link;Malignant Neoplasms;Medical Students;Medicine;Mentors;Minority;Not Hispanic or Latino;Postdoctoral Fellow;Program Evaluation;Race;Readiness;Recording of previous events;Research;Research Personnel;Research Project Grants;Science;Science Technology Engineering and Mathematics Education;Social Network;Structure;Student recruitment;Students;Underrepresented Populations;Underrepresented Students;Universities;Work;anticancer research;cancer health disparity;career;career development;career preparation;college;community college;community engagement;curriculum development;design;disability;diversity and equity;education research;experience;fortification;health disparity;high school;improved;interest;laboratory experience;life-long learning;lower income families;member;minority student;peer;programs;research faculty;science education;skills;social culture;success;summer program;summer research;undergraduate student;university student Research Education Core n/a NCI 10696248 9/1/23 0:00 PAR-18-767 5U54CA202995-09 5 U54 CA 202995 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7866 15576777 "KAHOUADJI, NABIL " Not Applicable 5 Unavailable 879331445 MR73WF5SHRW4 879331445 MR73WF5SHRW4 US 41.982453 -87.716237 215501 NORTHEASTERN ILLINOIS UNIVERSITY CHICAGO IL Domestic Higher Education 606254699 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 153367 119190 34177 RESEARCH EDUCATION CORE ABSTRACTThe overall objective of the Chicago Cancer Health Equity Collaborative (ChicagoCHEC) Research EducationCore (REC) is to increase the number of students from underrepresented populations engaged in cancerresearch by fostering meaningful research education and community engaged experiences which link facultyand students of the University of Illinois at Chicago (UIC) Northeastern Illinois University (NEIU) and the RobertH. Lurie Comprehensive Cancer Center of Northwestern University (NU-LCC). For this Core we define studentsas high school through postdoctoral fellows. Between 2016 2019 the REC launched research educationexperiences bringing together diverse students across the Chicagoland area developed curricula introducingstudents to the science of cancer disparities and built robust networks with high school and local communitycollege students to encourage their entry into REC programs. In that period the REC provided structuredsummer research education experiences through the ChicagoCHEC Research Fellows (CHEC Fellows)Program to 65 students from minority and underrepresented backgrounds. The CHEC Fellows Program is anintensive 8-week summer program that introduces students to a breadth of cancer health disparities researchtopics and to the work of leading cancer researchers provides hands-on engagement with community partnersand builds professional skills as a foundation for lifelong learning. In this renewal we seek to sustain thesuccesses of the CHEC Fellows Program and add programming to further student entry into cancer researchtrajectories and further meet the needs of students within ChicagoCHEC sponsored Projects. Thus the CHECFellows Program will be complemented by development of new career readiness and career developmentsupports and an expansion of ChicagoCHEC Laboratory Experiences and Programs (LEaP) which matchesstudents including graduates of the CHEC Fellows Program to intensive one-on-one mentored immersionexperiences in cancer research laboratories. A diverse and exceptional tri-institutional team of cancer researchfaculty has been assembled to lead the REC in achieving its specific aims which are to: (1) develop curriculumand support professional development opportunities to increase Chicago area undergraduate interest andreadiness in entering the cancer research career pipeline; (2) refine and sustain the CHEC Fellows and LEaPPrograms for diverse undergraduate students recruited from NEIU UIC NU and City Colleges of Chicago; (3)link underrepresented students (undergraduates graduate/medical students and postdoctoral fellows) tomentored cancer research experiences within ChicagoCHEC Projects and provide career development support;and (4) implement continuous tracking and program evaluation. Initiatives of the ChicagoCHEC REC will directlyintroduce students to cancer research and enhance their capacity to seek out opportunities that will enable themto pursue meaningful highly effective careers in this field. +No NIH Category available Acculturation;Address;Advisory Committees;Area;Attitude;Belief;Biological;California;Cancer Etiology;Cause of Death;Cessation of life;Client satisfaction;Colorectal Cancer;Communication;Communities;Community Health Aides;Conflict (Psychology);Consent;County;Cross-Sectional Studies;Data;Data Analyses;Disparity;Education;Educational Assessment;Enrollment;Evaluation;Evolution;Exhibits;Feedback;Focus Groups;Fostering;Foundations;Genomics;Hispanic;Hospitals;Informed Consent;Interviewer;Investigation;Knowledge;Language;Latino;Latino Population;Los Angeles;Malignant Neoplasms;Medical center;Molecular;Newly Diagnosed;Oncologist;Participant;Patient Recruitments;Patient-Focused Outcomes;Patients;Population;Process;Provider;Quality of Care;Research;Research Personnel;Role;Surveys;Survival Rate;Survivors;Testing;United States;Woman;cancer genomics;clinical trial participant;cohort;colon cancer patients;colorectal cancer treatment;empowerment;evidence base;experimental study;follow-up;genetic counselor;health literacy;improved;literacy;low socioeconomic status;mathematical ability;meetings;men;metastatic colorectal;patient engagement;primary outcome;process optimization;psychological distress;randomized trial;recruit;secondary outcome;study population;tool;treatment response;tumor;virtual Engagement Optimization Unit n/a NCI 10696246 9/18/23 0:00 RFA-CA-19-045 5U2CCA252971-03 5 U2C CA 252971 3 9/22/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7865 1910369 "BAEZCONDE-GARBANATI, LOURDES A." Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 361105 249527 111578 ABSTRACT: ENGAGEMENT OPTIMIZATION UNIT (EOU)With advances in molecular genomics we have an improved understanding of the drivers of tumor evolution andtherapy response yet inclusion of Hispanic/Latino CRC patients in these studies has been minimal. Moreoverthere are virtually no empirical data to inform best practices for educating consenting enrolling and retainingH/L patients in cancer genomics investigations nor are there culturally language literacy and numeracyappropriate tools to utilize to reach these patients or to facilitate interpretation of data they receive. A betterunderstanding of how H/Ls understand value and communicate genomics-related information is the essentialfoundation for rigorous research to optimize patient engagement and outcomes. The Engagement OptimizationUnit (EOU) will fill these gaps by conducting rigorous research to generate evidence-based best practices andby validating culturally specific tools for optimizing Hispanic/Latino patient engagement and empowerment. Thiswill be accomplished via an iterative process of experimentation evaluation implementation and re-evaluationin a study population at LAC+USC and Norris of 275 H/L participants with metastatic CRC as well as a separatecohort of 500 H/L participants with CRC (both newly diagnosed and survivors) who will be engaged in genomicsequencing and follow up. The Specific Aims are: (1) to assess the educational and communication needs ofH/L CRC patients related to participation in cancer genomics research; and evaluate the role of languageacculturation numeracy and health literacy; (2) to develop best practices for engagement of H/L CRC patientsin informed consent for genomic characterization; (3) to determine the most efficacious strategies tocommunicate genomic results to H/L CRC patients; and (4) to develop and test a comprehensive tool kit (TheHispanic/Latino Genomic Engagement through Narrative Empowerment Tool Kit (H/L G.E.N.E.)) for use bypromotores de salud (community health workers) and other providers with the purpose of optimizing H/Lengagement enhancing recruitment and strengthening retention of H/L patients into cancer genomics research. +No NIH Category available Achievement;Advisory Committees;Award;Benchmarking;Cancer Research Project;Cancer health equity;Chicago;Clinical Sciences;Communication;Communities;Consultations;Counseling;Data;Data Analyses;Decision Making;Development;Educational workshop;Ensure;Evaluation;Faculty;Foundations;Funding;Funding Mechanisms;Goals;Grant;Health;Incubators;Infrastructure;Institution;Intervention Studies;Knowledge;Leadership;Learning;Logic;Mentors;Mentorship;Mission;Modeling;Monitor;Outcome;Performance;Pilot Projects;Process;Program Development;Progress Reports;Quasi-experiment;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Running;Statistical Data Interpretation;Structure;Surveys;Time;Translational Research;Universities;Work;analytical tool;anticancer research;cancer health disparity;career;career development;catalyst;data tools;early-career faculty;experience;faculty mentor;health disparity;improved;innovation;mathematical model;member;novel;process improvement;programs;skills Planning and Evaluation Core n/a NCI 10696245 9/1/23 0:00 PAR-18-767 5U54CA202995-09 5 U54 CA 202995 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7864 14722531 "HIBDON, JOSEPH EDWARD" Not Applicable 5 Unavailable 879331445 MR73WF5SHRW4 879331445 MR73WF5SHRW4 US 41.982453 -87.716237 215501 NORTHEASTERN ILLINOIS UNIVERSITY CHICAGO IL Domestic Higher Education 606254699 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 206042 194113 11929 PLANNING AND EVALUATION CORE ABSTRACTOur Chicago Cancer Health Equity Collaborative (ChicagoCHEC) Planning and Evaluation Core (PEC) iscomprised of an exceptional team with complementary expertise and responsibility to lead the cores monitoringand evaluation activities. PEC members include: Drs. Kristi Holmes and Brian Hitsman from NU-LCC; RaymondFuller and Dr. Wamucii Njogu from NEIU; and Drs. Timothy Johnson and Lisa Sanchez-Johnsen from UIC. ThisRenewal application for the ChicagoCHEC PEC proposes to build on the infrastructure created programprogress and lessons learned from our first U54 award and continue to improve our integrated and responsivefoundation to support planning monitoring and evaluation. The PEC will continue to monitor progress throughongoing evaluation processes maximize resources identify novel directions for the Partnership in ongoingconsultation with the Administrative Core and report progress to institutional leaders and the NCI on a continualbasis. The PEC team will work closely with the Internal Advisory Committee (IAC) and the Program SteeringCommittee (PSC) and is composed of two teams: The Evaluation Action Team (EvAT) and the Mentoring andProject Team. The decisions made by the PEC will be guided by data systematically collected and organized bythe EvAT while the PECs Mentoring and Project Team will monitor the provision of support and mentorship ofChicagoCHECs early career faculty in addition to working closely with the Administrative Core to seedcollaborative tri-institutional cancer research projects and developmental pilots over the next five-year grantperiod. The overall specific aims of the PEC are to: (1) Conduct ongoing tracking and evaluation of all Partnershipactivities to inform planning improve processes maximize resources and communicate impact to stakeholdersover the duration of the ChicagoCHEC Partnership with support of the IAC PSC and NCI; (2) Create andsustain an ongoing Incubator and Catalyst Research Grant Program encouraging tri-institutional partnershipand a focus on cancer health equity; and (3) Bolster a pipeline of faculty focused on cancer research bycoordinating and monitoring career enhancement mentoring and professional development activities for earlycareer faculty. +No NIH Category available Address;Area;Automation;Behavioral Sciences;Bioinformatics;California;Cancer Biology;Clinical;Clinical Data;Collaborations;Collection;Colorectal Cancer;Communication;Communities;Complement;Copy Number Polymorphism;DNA Integration;DNA Methylation;DNA analysis;DNA methylation profiling;Data;Data Set;Dedications;Detection;Development;Diagnosis;Emerging Technologies;Ensure;Epidemiology;Event;Feedback;Foundations;Funding Opportunities;Gene Mutation;Generations;Genes;Genetic Counseling;Genome;Genomic Data Commons;Genomics;Goals;Guidelines;Hispanic;Knowledge;Latino;Lead;Leadership;Malignant Neoplasms;Measurement;Mission;Molecular;Office of Administrative Management;Oncology;Patient Recruitments;Patients;Performance;Population;Predictive Value;Process;Program Evaluation;Psyche structure;Publications;Quality Control;Reporting;Reproducibility;Research;Research Institute;Resources;Scanning;Scientist;Services;Specimen;Strategic Planning;Structure;Supervision;Transcript;Universities;Untranslated RNA;Validation;Variant;Vision;Work;cancer genome;cancer genomics;clinical sequencing;clinically relevant;colon cancer patients;data communication;data sharing;exome sequencing;experience;flexibility;genome sequencing;genome-wide;implementation strategy;improved;mRNA sequencing;medical schools;member;next generation sequencing;novel;patient engagement;patient population;prognostic value;research clinical testing;transcriptome sequencing;translational genomics;tumor;tumor DNA;tumor exome;variant detection;whole genome Genome Characterization Unit n/a NCI 10696242 9/18/23 0:00 RFA-CA-19-045 5U2CCA252971-03 5 U2C CA 252971 3 9/22/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7863 8146152 "CRAIG, DAVID W" Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 542171 374645 167526 ABSTRACT: ADMINISTRATIVE CORE (AC)The mission of the University of Southern California (USC) Center for Optimization of Participant Engagementfor Cancer Characterization (USC COPECC) is to provide both the biomedical and patient communities withoptimized best practices for Participant Engagement in genomic research specifically in the context of Hispanicpatients diagnosed with Colorectal Cancer (CRC). USC COPECC will operate as an NCI U2C ParticipantEngagement in Cancer Genome Sequencing (PE-CGS) Center and will participate as a member of the NCI PE-CGS Network. COPECC will be locally managed by the Administrative Core (AC) which will serve as the hub ofthe Center's activities including the management coordination supervision and promotion of the Centeractivities. USC COPECC builds on the strong foundation of a significantly diverse and Hispanic enriched patientpopulation established standard processes for Participant Engagement and recruitment into genomic studieshighly experienced genome scientists with vast experience in clinical cancer genomics and strong leadership inthe areas of oncology genetic counseling epidemiology and behavioral science. The administrative leadershipwill be primarily responsible for the Center's strategic planning including: defining and upholding its mission andobjectives conducting environmental scanning for strategy development directing and managing strategyimplementation and ensuring adjustments are made for continuous quality improvement (CQI) based onprogram evaluation. +No NIH Category available Accounting;Acculturation;Address;Advocate;Age;Age Years;Benchmarking;Biological;Blood specimen;California;Cancer Burden;Cancer Patient;Caribbean Hispanic;Caring;Cessation of life;Clinical;Clinical Data;Clinical Trials;Collection;Colorectal Cancer;Communication;Consent;Country;Data;Development;Diagnosis;Disparity;Distant;Education;Ethnic Population;Family;Formalin;Genetic;Genetic Counseling;Genetic Research;Genomics;Health Services Accessibility;High Prevalence;Hispanic;Hispanic Populations;Immigration;Incidence;Individual;Informed Consent;Knowledge;Latino;Malignant Neoplasms;Mexican;Minority Groups;Modeling;Molecular;Molecular Profiling;Mutation;Oncogenes;Paraffin Embedding;Participant;Patients;Pattern;Play;Population;Population Heterogeneity;Process;Provider;Quality of Care;Race;Recording of previous events;Rectal Cancer;Recurrence;Reporting;Research;Research Personnel;Resources;Risk;Role;Subgroup;Testing;The Cancer Genome Atlas;Therapeutic;Trust;Tumor Tissue;Underserved Population;Use Effectiveness;Whole Blood;Woman;advanced disease;cancer genomics;cancer type;clinically relevant;colon cancer patients;data registry;driver mutation;early onset colorectal cancer;effectiveness evaluation;epidemiologic data;ethnic minority population;exome;follow-up;genome sequencing;genome-wide;improved;improved outcome;interest;men;metastatic colorectal;mortality;neoplasm registry;novel;patient engagement;patient population;personalized approach;population stratification;precision medicine;preference;recruit;research study;sociodemographics;therapeutic target;transcriptome sequencing;tumor;tumor diagnosis;whole genome Participant Engagement Unit n/a NCI 10696241 9/18/23 0:00 RFA-CA-19-045 5U2CCA252971-03 5 U2C CA 252971 3 9/22/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7862 6545166 "LENZ, HEINZ JOSEF " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 293510 202817 90693 ABSTRACT: PARTICIPANT ENGAGEMENT UNIT (PEU)H/L tend to be diagnosed at a younger age and with higher stage and we have previously reported that MexicanH/L in California have the greatest proportion of young (<50 years of age) diagnoses compared to other H/Lsubgroups. Moreover Mexican H/L showed higher prevalence of rectal cancer cases compared to other H/L andNHW. Our most current analyses using the California Cancer Registry data (unpublished results) including datafor 52557 H/L diagnosed between 1995-2017 show that ~43% of US H/L are diagnosed before 62 years old(median age of diagnosis across NHW and H/L). Moreover they show a greater proportion of distant tumordiagnoses compared to NHW and greater proportion of metastatic CRC. Overall in spite of the variousdisparities observed among H/L that contribute to their cancer burden there are scarce studies that have focusedon this minority population contributing to further disparities in this group. Therefore there is an urgent need toincrease resources that will contribute much needed data about the tumor landscape of US H/L taking intoaccount genetic ancestry. Therefore to address the lack of knowledge about the CRC tumor landscape amongH/L and increase engagement and participation of H/L in genetic research we propose to develop effective andculturally tailored participant engagement approaches tailored to H/L through the following specific aims 1) toaddress the knowledge gap in H/L CRC participation using a culturally appropriate direct cancer participantengagement platform for recruiting consenting and communicating genomic risk based on cancer genomicsequencing; 2) to deploy current best practices for collection and quality assessment of biospecimens andrelevant clinical and epidemiological data among H/L participants; 3) To develop and assess the effectivenessof using culturally sensitive strategies for communication in clinical settings that consider participant preferencesin receiving results from genomic analyses and return of their clinical and epidemiological data; and 4) Tocontinuously improve participant engagement by assessing benchmarks and working with the EngagementOptimization Unit to identify strategies to optimize informed consent communication of results and follow-uptaking into account the patients and providers perspectives. The results of these aims will be integrated acrossan engagement optimization framework to create a robust and validated model for engaging H/L cancer patientsinto cancer genomic research studies. +No NIH Category available Address;Administrator;Area;Behavior;Behavioral Sciences;Benchmarking;Budgets;California;Cancer Patient;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Comprehensive Cancer Center;Conflict (Psychology);Consent;Data;Data Set;Development;Diagnosis;Enrollment;Ensure;Epidemiology;Evaluation;Foundations;Genetic Counseling;Genetic study;Genome;Genomics;Goals;Hispanic;Human Resources;International;Latino;Latino Population;Lead;Leadership;Link;Malignant Neoplasms;Mission;Modeling;Molecular;Monitor;National Cancer Institute;Office of Administrative Management;Oncology;Online Systems;Outcome;Patient Recruitments;Patients;Policies;Population;Principal Investigator;Procedures;Process;Program Evaluation;Publications;Research;Research Personnel;Scanning;Scientist;Strategic Planning;Structure;Supervision;System;Testing;Universities;cancer genome;cancer genomics;cancer health disparity;colon cancer patients;experience;genome sciences;genome sequencing;implementation strategy;improved;member;patient engagement;patient population;programs;success Administrative Core n/a NCI 10696239 9/18/23 0:00 RFA-CA-19-045 5U2CCA252971-03 5 U2C CA 252971 3 9/22/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7861 6367572 "CARPTEN, JOHN D." Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 189300 130808 58492 ABSTRACT: ADMINISTRATIVE CORE (AC)The mission of the University of Southern California (USC) Center for Optimization of Participant Engagementfor Cancer Characterization (USC COPECC) is to provide both the biomedical and patient communities withoptimized best practices for Participant Engagement in genomic research specifically in the context of Hispanicpatients diagnosed with Colorectal Cancer (CRC). USC COPECC will operate as an NCI U2C ParticipantEngagement in Cancer Genome Sequencing (PE-CGS) Center and will participate as a member of the NCI PE-CGS Network. COPECC will be locally managed by the Administrative Core (AC) which will serve as the hub ofthe Center's activities including the management coordination supervision and promotion of the Centeractivities. USC COPECC builds on the strong foundation of a significantly diverse and Hispanic enriched patientpopulation established standard processes for Participant Engagement and recruitment into genomic studieshighly experienced genome scientists with vast experience in clinical cancer genomics and strong leadership inthe areas of oncology genetic counseling epidemiology and behavioral science. The administrative leadershipwill be primarily responsible for the Center's strategic planning including: defining and upholding its mission andobjectives conducting environmental scanning for strategy development directing and managing strategyimplementation and ensuring adjustments are made for continuous quality improvement (CQI) based onprogram evaluation. +No NIH Category available Address;Advocate;African American population;Age;Age Years;Area;Behavioral;Behavioral Sciences;Biology;Biomedical Research;California;Cancer Etiology;Cause of Death;Cessation of life;Characteristics;Clinic;Clinical;Clinical Data;Collaborations;Colorectal Cancer;Communication;Communities;Community Healthcare;Community Outreach;Consent;Data Analyses;Diagnosis;Disease;Ethnic Population;Etiology;Fasting;Fostering;Genome;Genomics;Goals;Health Services Accessibility;High Prevalence;Hispanic;Hispanic Populations;Incidence;Knowledge;Laboratories;Latino;Latino Population;Malignant Neoplasms;Medical;Mexican;Molecular;Not Hispanic or Latino;Outcome;Patient Preferences;Patient-Focused Outcomes;Patients;Positioning Attribute;Process;Rectal Cancer;Reporting;Research;Risk;Scientist;Subgroup;Taxonomy;Techniques;Technology;Testing;The Cancer Genome Atlas;Time;Treatment Factor;Underrepresented Minority;Underserved Population;cancer care;cancer genome;cancer genomics;caucasian American;clinical translation;colon cancer patients;community engagement;demographics;design;early onset colorectal cancer;genome sequencing;genomic data;health care settings;improved;member;minority patient;novel;novel strategies;participant enrollment;patient engagement;patient population;research study;socioeconomics;translational cancer research;translational genomics USC PE-GCS: Optimizing Engagement of Hispanic Colorectal Cancer Patients in Cancer Genomic Characterization Studies PROJECT NARRATIVE: OVERALLWe propose the creation of the USC Center for Optimization of Participant Engagement in CancerCharacterization (COPECC) with a focus on optimizing the engagement of Hispanic/Latinos in colorectal cancer(CRC) Genomic Characterization research studies as part of the NCI U2C Participant Engagement and CancerGenome Sequencing national network. The overall goal of USC COPECC is to generate results on participantengagement optimization and translational CRC genomic research that will be shared with the broadercommunity to promote best practices for engaging Hispanic/Latino and improving overall outcomes for CRC inthis underserved population. NCI 10696237 9/18/23 0:00 RFA-CA-19-045 5U2CCA252971-03 5 U2C CA 252971 3 "GILLANDERS, ELIZABETH" 9/22/21 0:00 8/31/27 0:00 ZCA1-TCRB-O(M1) 6367572 "CARPTEN, JOHN D." "LENZ, HEINZ JOSEF " 37 UROLOGY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 1386086 NCI 957797 428289 ABSTRACTColorectal Cancer (CRC) is the second leading cause of cancer death in the US. Hispanic/Latinos are the largestand fasting growing ethnic group in the US and cancer is the leading cause of death among H/L in the US.Therefore we need to fully understand the full complexity of the molecular etiology of cancer in this ethnic group.For instance although incidence rates of CRC are lower among Latinos as compared to Whites or AfricanAmericans Hispanics with metastatic disease have shorter overall survival when adjusted for health care settingdemographics disease characteristics and treatment factors. H/L also tend to be diagnosed at a younger ageand with higher stage and we have previously reported that Mexican H/L in California have the greatestproportion of young (<50 years of age) diagnoses compared to other H/L subgroups. Moreover Mexican H/Lshowed higher prevalence of rectal cancer cases compared to other H/L and NHW. Although socio-economicsand access to care might influence these differences we need to take a complete look at the biology of diseasein this ethnic group to determine once and for all if these clinical differences are related to differences in molecularetiology. The Cancer Genome Atlas has provided a deep overview of the molecular taxonomy of CRC in 594cases however less than 1% of the cases (n=5) were H/L. Therefore it is imperative for us to take more detailedassessment of the molecular genomic landscape of CRC in H/L. One of the major issues likely limiting our abilityto perform these large genomic initiatives in minority patients is that Patient or Participant Engagement practicesmay not been investigated to identify best practices for accruing and consenting patients into clinical translationalbiomedical research studies. This concept of Participant Engagement is critically important for both the patientsand the translational cancer research community. Optimizing and improving our approaches for directlyengaging patients at initial contact throughout the course of a translational genomic study and during the timeof return of results is likely to lead to stronger relationships between the medical community and patients butcould also lead to significant improvement in outcomes for patients and for the cancer care community as awhole. As such we propose the creation of the USC Center for Optimization of Participant Engagement inCancer Characterization (COPECC) with a focus on optimizing the engagement of Latinos in CRC GenomicCharacterization research studies. USC COPECC would serve as a member of the NCI U2C ParticipantEngagement and Cancer Genome Sequencing (PE-CGS) Network. Our investigative team includes experts inall relevant areas of research for genomic characterization participant engagement and engagementoptimization. We have an established platform for consenting patients into cancer genomics studies that willserve as a standard process. The overall goal of USC COPECC is to generate results on participant engagementoptimization and CRC genomic research that will be shared with the broader community to distribute bestpractices for engaging Latinos in hopes of improving overall outcomes for CRC in this underserved population. 1386086 +No NIH Category available Adherence;Advanced Malignant Neoplasm;Advisory Committees;Award;Budgets;Cancer health equity;Chicago;Clinical;Collaborations;Communication;Communities;Comprehensive Cancer Center;Decision Making;Education;Ensure;Equity;Evaluation;Faculty;Foundations;Goals;Guidelines;Illinois;Individual;Infrastructure;Institution;Institutional Policy;Lead;Leadership;Logic;Malignant Neoplasms;Manuals;Mentors;Minority;Minority-Serving Institution;Modeling;Process;Protocols documentation;Reporting;Research;Resources;Solid;Stream;Structure;Student recruitment;Students;Talents;Time;Universities;Work;anticancer research;cancer health disparity;career;career development;conflict resolution;early-career faculty;experience;improved;interest;meetings;member;operation;outreach;programs;recruit;research facility;success;tool Administrative Core n/a NCI 10696236 9/1/23 0:00 PAR-18-767 5U54CA202995-09 5 U54 CA 202995 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7860 10468677 "CIECIERSKI, CHRISTINA " Not Applicable 5 Unavailable 879331445 MR73WF5SHRW4 879331445 MR73WF5SHRW4 US 41.982453 -87.716237 215501 NORTHEASTERN ILLINOIS UNIVERSITY CHICAGO IL Domestic Higher Education 606254699 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 442836 329889 112947 ADMINISTRATIVE CORE ABSTRACTThe Chicago Cancer Health Equity Collaborative (ChicagoCHEC) Administrative Core (AC) leverages a sharedgovernance model in order to fulfill its responsibilities to establish mechanisms and infrastructure that promoteplanning communication interaction integration and evaluation that support the broad spectrum of researcheducation and outreach activities to advance cancer health equity. ChicagoCHEC builds on the solid foundationof a 10-year collaborative track record that includes our first NCI U54 Comprehensive Partnership to AdvanceCancer Health Equity (CPACHE) award. The AC led by a tri-institutional MPI team capitalizes on the strengthsof each institution and leverages those strengths to build cancer research capacity at two minority servinginstitutions University of Illinois at Chicago (UIC) and Northeastern Illinois University (NEIU) and to expandcancer disparities research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University(NU-LCC). AC leadership is instrumental in guiding our Partnership identifying resources building collaborativeties capacity building and helping facilitate faculty and students advancement in cancer research educationand outreach within the framework of institutional policies. The AC team from UIC NEIU and NU-LCC haveworked together in varying capacities for the past 10 years and are a well-integrated team laying the groundworkfor a strong collaboration upon which to launch and sustain ChicagoCHECs next chapter. To guide operationsand ensure best practices and the realization of targeted milestones in all Partnership activities we will leverageour established standard operating protocol a full operations manual and detailed logic models that guidePartnership activities and evaluation processes. Our AC is guided by an Internal Advisory Committee (IAC) anda Program Steering Committee (PSC). We now plan to further advance the foundation built through our initialU54 award to fulfill the following Specific Aims: (1) Provide overall support for ChicagoCHEC activities ensuringintegration coordination collaboration and fiscal administration across the Projects and Cores; (2) Refine andmaintain communication processes and structures to enhance the overall visibility of the ChicagoCHECPartnership; (3) Facilitate mechanisms to optimize integration with and efficient utilization of institutionalresources within the partnering institutions NU-LCC UIC and NEIU; (4) Organize and maintain a robust pipelinefor continuous recruitment of students and faculty from minority and underrepresented backgrounds into thisPartnership; and (5) Drive iterative and robust evaluation of all ChicagoCHEC Partnership activities. +No NIH Category available Acceleration;Advanced Malignant Neoplasm;African American;Applications Grants;Award;Cancer Research Infrastructure;Cancer Research Project;Cancer health equity;Chicago;Circadian Rhythms;Cities;Clinical;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;DNA Double Strand Break;Decision Making;Dedications;Double Strand Break Repair;Education;Education and Outreach;Evaluation;Extramural Activities;Faculty;Funding;Funding Mechanisms;Generations;Goals;Grant;Health Disparities Research;Hematopoietic Stem Cell Transplantation;Hispanic-serving Institution;Illinois;Infrastructure;Institution;Lead;Leadership;Long-Term Effects;Malignant Neoplasms;Mentors;Midwestern United States;Minority;Mission;Peer Review;Pilot Projects;Positioning Attribute;Prevention;Productivity;Publications;Records;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Science;Scientist;Students;Survivors;Training;Translational Research;Transplant Recipients;Underrepresented Populations;Underrepresented Students;Underserved Population;Universities;Variant;anticancer research;cancer health disparity;career;community engagement;disability;early-career faculty;education research;empowerment;experience;forging;fortification;gut microbiome;health disparity populations;health inequalities;high risk;improved;innovation;lung cancer screening;mHealth self-management;men;minority student;next generation;oral microbiome;outreach;outreach program;programs;rapid growth;recruit;social;survivorship;tool;underserved community 2/3: The Chicago Cancer Health Equity Collaborative (ChicagoCHEC) OVERALL PROJECT NARRATIVEThe presence of major cancer health inequities in Chicago is well-documented. The Chicago Cancer HealthEquity Collaborative (ChicagoCHEC) a comprehensive cancer research partnership between the Robert H.Lurie Comprehensive Cancer Center of Northwestern University the University of Illinois at Chicago andNortheastern Illinois University builds upon its productive first U54 award to continue strengthening collaborativeinfrastructure and implementing innovative cancer research education and outreach programs aimed ateliminating Chicagos deeply-engrained cancer disparities. NCI 10696235 9/1/23 0:00 PAR-18-767 5U54CA202995-09 5 U54 CA 202995 9 "SAN MIGUEL-MAJORS, SANDRA L" 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T(A1) 10468677 "CIECIERSKI, CHRISTINA " "FEINGLASS, JOSEPH M; FILUS, LIDIA ; FITZGIBBON, MARIAN L.; JIMBO, MASAHITO ; SIMON, MELISSA A." 5 MISCELLANEOUS 879331445 MR73WF5SHRW4 879331445 MR73WF5SHRW4 US 41.982453 -87.716237 215501 NORTHEASTERN ILLINOIS UNIVERSITY CHICAGO IL SCHOOLS OF ARTS AND SCIENCES 606254699 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 998721 NCI 790510 208211 OVERALL ABSTRACTThe Chicago Cancer Health Equity Collaborative (ChicagoCHEC) is a comprehensive partnership to advancecancer health equity bringing together the synergistic strengths of two federally designated Hispanic ServingInstitutions the University of Illinois at Chicago (UIC) and Northeastern Illinois University (NEIU) with a worldclass NCI-designated comprehensive cancer center the Robert H. Lurie Comprehensive Cancer Center ofNorthwestern University (NU-LCC). ChicagoCHEC combines the attributes of these three exceptionalinstitutions each with robust capacity to interact with their urban-shared setting. Launched in 2015ChicagoCHEC is dedicated to advancing cancer health equity through rigorous and innovative scienceeducation and outreach and engagement of Chicagos underserved communities. This is reflected in thefollowing goals: Aim 1. To strengthen a transformational alliance between UIC NEIU and the NU-LCC in pursuitof cancer health equity in Chicago; Aim 2. To initiate conduct and support innovative bench translationalclinical and prevention and control focused cancer research with emphasis on cancer health disparities; Aim3. To develop and implement cancer-related education and outreach activities generated with the engagementof underserved communities across Chicago; Aim 4. To coordinate research education and mentoringopportunities to recruit retain and advance a pipeline of underrepresented students in cancer research careersand to develop early career faculty who will forge independent cancer research careers; and Aim 5. To conductongoing rigorous evaluation of ChicagoCHEC activities. These goals are accomplished by a nurturing hub offour Cores (Administrative Planning and Evaluation Research Education and Outreach) and a research projectfunding program. Since the launch of ChicagoCHEC in 2015 there has been rapid growth in collaborativeinfrastructure built across the three partnering institutions; enhanced cancer research engagement capacityand education; extensive community outreach and engagement; and encouraging advancement ofChicagoCHEC faculty and students. ChicagoCHEC projects and programs provided research experiences to155 students provided cancer research and leadership opportunities for 57 faculty (21 have beenpromoted/received tenure) and directly resulted in 94 peer-reviewed publications 47 extramural grantssubmitted and 24 grants awarded. ChicagoCHEC will leverage the momentum forged by the initial U54 awardto drive innovative cancer research research education and community outreach and engagement that cutsacross disciplinary and institutional boundaries. ChicagoCHEC will leverage its diverse team of faculty studentsand partners connectivity to Chicagos underserved communities and guidance of internal and external advisorybodies. The next chapter will include two initial full cancer research projects and two initial pilot projectscontinued support from four tri-institutional ChicagoCHEC Cores and strong institutional commitment. 998721 +No NIH Category available Antibodies;Area;Base Pairing;Binding;Binding Proteins;Binding Sites;Biochemical;Biological Assay;Cells;Chromatin Loop;Collaborations;Complex;Comprehensive Cancer Center;Cryoelectron Microscopy;DNA;DNA replication fork;DNA-Directed RNA Polymerase;Electron Microscopy;Funding;Gelshift Analysis;Gene Expression;Genetic Recombination;Genetic Transcription;Genomic DNA;Gold;Grant;Herpesviridae;Herpesvirus 1;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Hybrids;Image;Immunology procedure;Immunoprecipitation;In Vitro;Individual;Laboratories;Location;Maps;Measures;Metals;Methods;Microtomy;Modeling;Molecular Weight;Nature;Negative Staining;North Carolina;Photometry;Preparation;Productivity;Program Research Project Grants;Proteins;RNA;Research Project Grants;Sampling;Side;Specificity;Techniques;Technology;Terminal Repeat Sequences;Transcript;Transmission Electron Microscopy;Viral;Virus;Virus Replication;Visualization;Work;density;detection assay;dimer;exosome;experimental study;extracellular vesicles;member;monomer;nano;novel;novel strategies;oncology program;particle;performance site;programs;protein complex;recombinase;single molecule;structural biology;tumorigenesis;viral DNA Structural Core Core C: EM and Mass Photometry Structural CoreProject NarrativeCore C Electron Microscopy and Mass Photometry provides support for all projects in the area of structuralbiology including EM cryoEM Mass Photometry and immuno-EM. Both routine analysis and long-range in-depth studies are conducted with members of the program project. NCI 10696229 6/1/23 0:00 PAR-20-077 5P01CA019014-43 5 P01 CA 19014 43 5/1/97 0:00 6/30/27 0:00 ZCA1-RPRB-L 7859 1876826 "GRIFFITH, JACK D" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 177270 114000 63270 Core C: EM and Mass Photometry Structural CoreProject Summary AbstractThis is a renewal application of a long-standing P01 grant. Core C provides support for structural studiesincluding routine and advanced transmission electron microscopy cryo-EM cryo-shadowing (a technology notavailable anywhere else) and the novel transformative technology of Mass Photometry. Members of the programproject have direct access to this support through routine day to day analysis of samples and also in-depthresearch projects carried out between members of the core and members of the program project groups. Theexpertise of the Griffith laboratory in herpesvirus studies augments core C studies. +No NIH Category available 2019-nCoV;Bioinformatics;Biological Assay;Biology;Biometry;Biopsy;Biostatistics Core;Cell Line;Cell Lineage;Cells;ChIP-seq;Clinical;Comprehensive Cancer Center;Cytomegalovirus;DNA;Data Security;Dedications;Ensure;Evolution;FAIRE sequencing;Formalin;Funding;Generations;Genetic Transcription;Genome;Grant;Guidelines;Herpesviridae;Herpesvirus 1;Hour;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Hybridization Array;Infrastructure;Ions;Lead;Lesion;Life Cycle Stages;Linux;Location;Malignant Neoplasms;Maps;Messenger RNA;MicroRNAs;Molecular Biology;Molecular Virology;North Carolina;Oncogenic Viruses;Open Reading Frames;Plasma;Policies;Program Research Project Grants;RNA;RNA Splicing;Research Personnel;Resources;Saliva;Sampling;Services;System;Technology;Time;Tumor-Derived;United States National Institutes of Health;Untranslated RNA;Viral;Viral Pathogenesis;Virus;bioinformatics infrastructure;data sharing;distinguished professor;exome sequencing;extracellular vesicles;innovation;instrument;mRNA sequencing;member;nanopore;next generation;next generation sequencing;novel;performance site;sequencing platform;single cell analysis;single cell sequencing;statistics;technology validation;tissue fixing;transcriptome sequencing;tumor;tumorigenesis;viral genomics;virology;whole genome Vironomics and Biostatistics Core Core B: Vironomics and Biostatistics CoreProject NarrativeCore B Vironomics and Biostatistics provides bioinformatics support for all projects and specializes in systemsand high-throughput biology. Both analysis and wet-lab sequence generation are combined in one unit tomaximize efficiency. NCI 10696228 6/1/23 0:00 PAR-20-077 5P01CA019014-43 5 P01 CA 19014 43 5/1/97 0:00 6/30/27 0:00 ZCA1-RPRB-L 7858 6691168 "DITTMER, DIRK P" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 225347 152000 73347 Core B: Vironomics and Biostatistics CoreProject Summary AbstractThis is a renewal application of a long-standing P01 grant. Core B provides Next Generation Sequencingbioinformatic and biostatistics capabilities that are specific to viral genomics and that are unique among USinvestigators. It is used by all projects. Core B houses both physical instrument and specialized expertise suchas dedicated Oxford Nanopore and Ion Torrent sequencers (S5 and Genexus) a BD Rhapsody single-cellsequencing instrument a project specific high-compute server and full-time programmer. This will ensure thatthis long-standing VPP remains at the cutting edge in terms of technical innovation in tumor virology. +No NIH Category available Adherence;Budgets;Communication;Data;Ensure;Expenditure;Fostering;Funding;Goals;Grant;Leadership;Manuscripts;Measures;Monitor;Preparation;Productivity;Reagent;Regulation;Reporting;Research;Resource Sharing;Scientist;Series;Structure;United States National Institutes of Health;Viral;Visit;data sharing;meetings;member;oncology program;programs;success;tumorigenesis;virology Administrative Core A Core A: Administrative CoreProject NarrativeThe Administrative Core (Core A) will provide the structure for the overall program and will facilitateinteractions between the four Projects and the two other Cores. It will provide scientific leadership facilitatescientific exchange between all components in the program and provide fiscal support for all projects andcores. In summary Core A will promote programmatic interactions and foster the exchange of information andreagents to ensure all aspects of a successful and productive program project. NCI 10696226 6/1/23 0:00 PAR-20-077 5P01CA019014-43 5 P01 CA 19014 43 5/1/97 0:00 6/30/27 0:00 ZCA1-RPRB-L 7857 6931559 "DAMANIA, BLOSSOM A" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 145686 93689 51997 Core A: Administrative CoreProject Summary AbstractThe Administrative Core (Core A) will provide the structure for the overall program and will facilitateinteractions between the four Projects and the two other Cores. It will provide the scientific leadership for thewhole program and will guide the scientific exchange between all the components in the program. Core A willalso provide fiscal support for all projects and cores and organizational support for the regular scientificmeetings of the project and core leaders as well as host the external advisory board member visits. Insummary Core A will promote programmatic interactions and foster the exchange of information and reagentsto ensure all aspects of a successful and productive program project. +No NIH Category available Abstinence;Acquired Immunodeficiency Syndrome;Address;Adult;Agonist;Algorithms;Behavior Therapy;Behavioral;Biological Markers;CD4 Lymphocyte Count;Carbon Monoxide;Cardiovascular Diseases;Caring;Cause of Death;Chronic;Clinic;Clinical Pathways;Clinical Pharmacists;Clinical Trials;Clinical Trials Design;Conduct Clinical Trials;Data;Data Analyses;Enrollment;Evaluation;Exhalation;General Population;Goals;HIV;Health;Health system;Healthcare Systems;Incentives;Individual;Intervention;Leadership;Life Expectancy;Lung diseases;Malignant Neoplasms;Measures;Medical;Medication Management;Mental Depression;Meta-Analysis;Morbidity - disease rate;New York;Nicotinic Receptors;Outcome;Pain;Participant;Patient Care;Patient Self-Report;Patients;Persons;Pharmaceutical Preparations;Pharmacists;Prize;Promoting Action on Research Implementation in Health Services framework;Publishing;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Regimen;Relapse;Reproducibility;Research;Research Design;Rewards;Role;Sample Size;Sampling;Sequential Multiple Assignment Randomized Trial;Site;Smoke;Smoker;Smoking;Smoking treatment;Specific qualifier value;Testing;Time;Tobacco;Tobacco Use Disorder;Tobacco use;Training;Treatment Protocols;United States Health Resources and Services Administration;United States National Institutes of Health;Viral;Viral Load result;addiction;antiretroviral therapy;arm;behavior change;cigarette smoke;cigarette smoking;clinically relevant;cohort;comparative effectiveness;contingency management;design;effectiveness study;effectiveness/implementation hybrid;evidence base;future implementation;implementation science;improved;indexing;information gathering;innovation;mortality;mortality risk;multidisciplinary;neglect;nicotine replacement;non-smoking;novel;optimal treatments;pharmacologic;primary outcome;process evaluation;randomized trial;responders and non-responders;response;smoking abstinence;smoking cessation;smoking intervention;smoking prevalence;tobacco cessation intervention;treatment response;treatment strategy;trial design;varenicline;years of life lost A SMART Approach to Treating Tobacco Use Disorder in Persons Living with HIV NARRATIVEMany people living with HIV (PLWH) smoke. Smoking in these individuals is often undertreated. We plan to study theability of various clinical pathways involving tobacco treatment medications and contingency management (payingsmokers for not smoking) to improve smoking cessation in a group of PLWH. NCI 10696223 7/25/23 0:00 RFA-CA-18-027 5R01CA243910-05 5 R01 CA 243910 5 "KAUFMAN, ANNETTE R" 9/19/19 0:00 8/31/25 0:00 ZCA1-RTRB-U(A1) 11801519 "EDELMAN, E. JENNIFER" "BERNSTEIN, STEVEN L" 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 666020 NCI 515558 150462 ABSTRACTSmoking is the leading threat to health of patients living with HIV (PLWH). Unfortunately the evidence-base fortobacco use disorder treatment in PLWH lags behind that of HIV itself. A 2016 Cochrane meta-analysis of data from12 clinical trials involving 2087 participants receiving both medications and behavioral support found modestevidence of improved abstinence in the short term (<6 months) but not long-term. A short-coming of these studies isthat treatment algorithms did not include plans for non-response or relapse to smoking. A newer clinical trial designthe Sequential Multiple Assignment Randomized Trial (SMART) includes a dynamic treatment strategy in which pre-specified decision rules guide the ongoing treatment of both responders and non-responders. This approach allowsSMART designs to better mirror the management of chronic relapsing conditions such as tobacco use disorder. Wetherefore propose a two-arm two-stage randomized trial of 622 adult PLWH who smoke cigarettes and receive carein one of three health systems. At inception participants will be randomized to either combination nicotinereplacement therapy (NRT) (patch and gum or lozenge) or combination NRT+contingency management (CM). At 12weeks responders (non-smoking participants confirmed by exhaled carbon monoxide [eCO]) in both arms willreceive 12 more weeks of the same treatment. Non-responders (participants with continued smoking by self-reportand/or eCO) in both the NRT and NRT+CM arms will be re-randomized to 12 weeks of treatment either withvarenicline (VAR) or varenicline+CM (VAR+CM). The intervention will be delivered by trained clinical pharmacists.The primary outcome will be eCO-confirmed abstinence at 24 weeks post-enrollment. The specific aims of theproposed study are to: (1) study the effectiveness of a dynamic treatment approach to reduce the prevalence ofsmoking in a cohort of PLWH and to identify the optimal approach; (2) study the effectiveness of various dynamicregimens on CD4 count HIV viral suppression and VACS index (validated measure of morbidity and mortality risk);and (3) grounded in implementation science and using a Hybrid Effectiveness-Implementation Type I design identifybarriers and facilitators to delivering our intervention to inform future implementation. The study team includesindividuals with expertise in tobacco use disorder treatment HIV and addiction in PLWH clinical trials CMimplementation science and SMART designs. Study components are readily scalable and all interventions are richlyevidence-based. This proposal offers innovation as the first use of the following in a smoking intervention targetingPLWH: (1) a SMART design with first-line tobacco treatment medications; (2) clinical pharmacists as keyinterventionists; (3) VACS Index 2.0 as an outcome among a general sample of PLWH who smoke; and (4)implementation-focused process evaluation of tobacco intervention including pharmacists and CM in HIV clinics. Thisstudy holds exceptional promise to transform tobacco use disorder treatment in HIV treatment settings nationally. 666020 +No NIH Category available Adaptor Signaling Protein;Advisory Committees;Alleles;Binding;Biological;Biology;Bone Marrow;CBL Protein;CBL gene;CRISPR screen;CRISPR/Cas technology;Cell Line;Cell Proliferation;Cell Survival;Cells;Chronic Myelomonocytic Leukemia;Clinical;Collaborations;Combined Modality Therapy;Communities;Dana-Farber Cancer Institute;Dasatinib;Data;Development;Development Plans;Disease;Disease Resistance;Drug resistance;Educational process of instructing;Environment;FDA approved;FRAP1 gene;Genetic;Hematologic Neoplasms;Hematopoietic;Hematopoietic Neoplasms;In Vitro;Individual;Knock-out;LYN gene;Laboratories;Malignant Neoplasms;Measures;Mediating;Mentors;Mentorship;Mus;Mutate;Mutation;Myelogenous;Neoplasms;Oncogenic;PI3K/AKT;Pathologist;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Phosphotransferases;Physicians;Principal Investigator;Prognosis;Proliferating;Regimen;Research;Research Personnel;Research Proposals;Resistance;Role;SYK gene;Sampling;Scientist;Selection for Treatments;Series;Signal Transduction;Therapeutic;Time;Training;Translational Research;Treatment Efficacy;Tyrosine Kinase Inhibitor;Work;Writing;acquired drug resistance;career;career development;clinical practice;clinical translation;design;drug resistance development;effective therapy;efficacy testing;experimental study;genome-wide;improved;in vivo;inhibitor;innovation;loss of function;mouse model;mutant;myeloid leukemia cell;new therapeutic target;novel therapeutics;overexpression;patient derived xenograft model;pharmacologic;prevent;resistance mechanism;src-Family Kinases;transfusion medicine;translational potential;ubiquitin-protein ligase Novel targeted therapies for chronic myelomonocytic leukemia PROJECT NARRATIVEChronic myelomonocytic leukemia (CMML) is a highly aggressive blood cancer with no effective drug therapies.Mutations in the CBL gene which occur in approximately 15% of CMML patients are associated with anespecially poor prognosis. This project will employ cutting-edge genetic and pharmacologic approaches toidentify new targeted therapies for patients with CBL-mutant CMML. NCI 10696221 8/22/23 0:00 PAR-21-300 5K08CA258803-02 5 K08 CA 258803 2 "RODRIGUEZ, LARITZA MARIA" 9/2/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 10602161 "BELIZAIRE, ROGER VINCENT" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 269244 NCI 249300 19944 PROJECT SUMMARYChronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy with extremely poorsurvival and no effective pharmacologic therapies. The CBL gene which encodes an E3 ubiquitin ligase andsignaling adaptor protein is frequently mutated in CMML patients. We identified hyperactivation of the SRCfamily kinase LYN as a key oncogenic driver in CBL-mutant cells. Consistent with this finding we have alsodemonstrated the in vitro and in vivo anti-proliferative effects of LYN inhibition by dasatinib in CBL-mutant celllines and patient-derived CMML samples providing rationale to explore the therapeutic potential of dasatinib inpatients with CBL-mutant CMML. The development of drug resistance represents a possible challenge to theefficacy of dasatinib in CMML patients. Thus an understanding of dasatinib-resistance mechanisms is essentialfor the design of durable therapeutic approaches in CBL-mutant CMML. Moreover discovery of other targetablepathways in CBL-mutant disease will guide the selection of combination therapies that prevent the emergenceof drug resistance. Indeed we have observed that an inhibitor of SYK fostamatinib also has anti-proliferativeactivity against CBL-mutant cell lines presenting an opportunity to test the efficacy of combined LYN/SYKinhibition. In Aim 1 of this proposal I will assess dasatinib resistance and intracellular signaling in CBL-mutantcells expressing a series of LYN and SYK alleles including wild-type kinase-dead and drug-binding mutants. Iwill also define genetic mechanisms of dasatinib resistance via a genome-wide CRISPR-Cas9 knockout screenin dasatinib- or vehicle-treated cells. In Aim 2 I will assess the biological effects of combined treatment withdasatinib and a panel of FDA-approved inhibitors of SYK in vitro and test the efficacy of dasatinib plusfostamatinib in patient-derived xenograft murine models of CBL-mutant CMML. Altogether the experimentsproposed here will build significantly on our previous work and lead to further progress in the discovery ofeffective treatments for CMML patients. The applicant Dr. Roger Belizaire is a clinical pathologist andlaboratory-based investigator in the Department of Oncologic Pathology at the Dana-Farber Cancer Institute(DFCI). He spends 80% of his time in translational research and 20% in clinical practice as a transfusion medicinephysician. He has proposed a five-year career development plan to enable the development of his independentlaboratory at the DFCI. Dr. Belizaire has assembled an Advisory Committee of world-renowned experts toprovide scientific and career mentorship. He has established collaborations with experts in myeloid neoplasiaoncogenic signaling and targeted cancer therapeutics to provide experimental guidance and specific training inthe field. Dr. Belizaire will conduct this research under the mentorship of Dr. Benjamin Ebert at the DFCI andleverage the exceptional research and teaching environment at the DFCI. The DFCI which comprises anoutstanding research community with an extensive track-record of successfully mentoring physician-scientistsis an ideal environment for completion of these experimental and career development aims. 269244 +No NIH Category available ATP phosphohydrolase;Adenosine;Adenosine Triphosphate;Apyrase;Automobile Driving;B-Cell Lymphomas;B-Lymphocytes;Biology;Cancer Burden;Cell Proliferation;Cells;Cellular biology;Cervix carcinoma;Code;DNA Tumor Viruses;DNA Viruses;Development;EBV reactivation from latency;Endothelium;Epithelium;Epstein-Barr Virus-Related Lymphoma;Epstein-Barr pathogenesis;Equilibrium;Future;Generations;Growth;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immune;Immune response;Immune signaling;Immunity;Inflammatory;Inflammatory Response;Kaposi Sarcoma;Life Cycle Stages;Lymphoma;Lymphomagenesis;Lymphoproliferative Disorders;Lytic;Malignant Neoplasms;Mediating;Mitochondrial RNA;Nasopharynx Carcinoma;Oncogenic;Oncogenic Viruses;Oxidative Phosphorylation;Pathway interactions;Proteins;Purines;RNA;Reporting;Role;Satellite Viruses;Signal Pathway;Signal Transduction;Stimulus;Transforming Growth Factor beta;Tumorigenicity;Viral;Viral Pathogenesis;Virus;Virus Diseases;cancer cell;co-infection;dsRNA adenosine deaminase;ecto-nucleotidase;extracellular;gammaherpesvirus;immune activation;in vivo;infected B cell;malignant oropharynx neoplasm;malignant stomach neoplasm;primary effusion lymphoma;reactivation from latency;tumorigenesis;virus related cancer Gammaherpesviral interactions with the host cell Project 3Project NarrativeIn this application we propose to explore how the oncogenic gammaherpesviruses KSHV and EBV modulatehost immune pathways and contribute to oncogenesis. Investigating the various mechanisms involved inmodulation of host immunity and oncogenesis by these tumor viruses will inform our understanding of thebiology and pathogenesis of these viruses. Our findings will also pave the way for future therapies to treatvirus-associated cancers. NCI 10696209 6/1/23 0:00 PAR-20-077 5P01CA019014-43 5 P01 CA 19014 43 5/1/97 0:00 6/30/27 0:00 ZCA1-RPRB-L 7851 6931559 "DAMANIA, BLOSSOM A" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 347154 223250 123904 Project 3Project Summary AbstractGlobally oncogenic DNA viruses cause a significant cancer burden. These viruses establish life-longpersistence in the human host and are associated with the development of epithelial endothelial and B cellcancers. The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated virus(KSHV) are associated with B cell lymphomas Kaposis sarcoma gastric cancer and nasopharyngealcarcinoma (NPC). Moreover human papillomavirus (HPV) is associated with oropharyngeal and cervicalcarcinoma.In this application we propose to explore how the oncogenic gammaherpesviruses KSHV and EBV modulatecellular pathways including adenosine-related signaling pathways and how they contribute to oncogenesis.Investigating the various mechanisms involved in modulation of host immunity and oncogenesis by thesetumor viruses will inform our understanding of the biology and pathogenesis of these viruses. Our findings willalso pave the way for future therapies to treat virus-associated cancers. +No NIH Category available Adult;Affect;Africa South of the Sahara;Antineoplastic Agents;Biological Assay;Biology;Blood Vessels;Burkitt Lymphoma;CD81 gene;Cells;Child;Childhood;Circulation;Clinical;Complement;Cryoelectron Microscopy;Cytotoxic Chemotherapy;Data;Doxorubicin;Drug Delivery Systems;Endothelium;Epstein-Barr Virus Infections;Exposure to;Foundations;Funding;Future;Grant;High Dose Chemotherapy;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papilloma Virus Vaccination;Image;Individual;Infection;Infrastructure;Kaposi Sarcoma;LMP1;Liposomal Doxorubicin;Lymphoma;Lymphomagenesis;Lytic;Malignant Childhood Neoplasm;Malignant Neoplasms;MicroRNAs;Molecular;Paclitaxel;Pathogenesis;Persons;Phase I Clinical Trials;Plasma;Population;Process;Puberty;Publishing;Role;Structure;Testing;Time;Vaccines;Viral;Viral Cancer;Viral Genome;Virion;Virus;Visualization;analytical tool;cancer therapy;chemotherapy;clinical infrastructure;clinically significant;curative treatments;delivery vehicle;epidemiologic data;exosome;extracellular vesicles;gammaherpesvirus;in vivo;lymph nodes;lymphatic vessel;novel;novel marker;particle;programs;standard of care;superresolution microscopy;therapeutic evaluation;tumor;tumor microenvironment;tumorigenesis;vaccine delivery;viral carcinogenesis Modulation of tumorigenesis by viral exosomes Project 1Project NarrativeProject 1 continues to explore the biology of gammaherpesviruses and will probe the role of extracellularvesicles or exosomes in viral carcinogenesis. We will look at single extracellular vesicles by super resolutionmicroscopy and cryo EM and explore novel treatment approaches. NCI 10696202 6/1/23 0:00 PAR-20-077 5P01CA019014-43 5 P01 CA 19014 43 5/1/97 0:00 6/30/27 0:00 ZCA1-RPRB-L 7849 6691168 "DITTMER, DIRK P" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 347154 223250 123904 Project 1Project Summary AbstractThis is a renewal application of a long-standing P01 grant. Our central hypothesis is that ExtracellularVesicles(EVs) or exosomes reprogram the tumor microenvironment of Kaposi Sarcoma (KS) and thatthese processes also affect neighboring EBV infected cells in the lymph nodes. In Sub-Saharan Africawhere both KSHV and EBV are endemic approximately 40% of KSHV shedders also shed EBV. Hencewe expect that even asymptomatic persons will have viral derived EVs in their circulation. About 1011 /mlEVs circulate in human plasma as compared to ~104 infectious KSHV particles during systemic KS. Theendothelial lining of blood and lymphatic vessels are continuously exposed to systemically circulating EVsand these are the lineage of origin for KS. All KSHV-derived EVs carry all KSHV microRNAs. If only one ina million plasma EVs are derived from a latent or lytic KSHV-infected cell more KSHV miRNAs aretransferred by EVs than viral genomes by virions. New this funding period we will probe the interaction ofKSHV EVs on EBV pathogenesis image single EV particles and explore novel ways to repurpose naturalEVs for targeted KS therapy. +No NIH Category available Animal Model;Applications Grants;Awareness;Biochemical;Bioinformatics;Biological;Biological Assay;Biology;Biometry;Biostatistics Core;Cancer Etiology;Cell Culture Techniques;Cell physiology;Cells;ChIP-seq;Cryoelectron Microscopy;DNA Tumor Viruses;Development;Electron Microscopy;Environment;Epigenetic Process;Epstein-Barr Virus Infections;Experimental Models;Fostering;Gene Expression;Genes;Genomics;Goals;Herpesviridae;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Immune Evasion;Immune response;Immune signaling;Immunity;In Vitro;Individual;Integration Host Factors;Investigation;Knowledge;Laboratories;Life Cycle Stages;Link;Malignant Neoplasms;Mediating;Messenger RNA;Methodology;MicroRNAs;Molecular;Neoplasm Metastasis;Oncogenic;Oncogenic Viruses;Pathway interactions;Photometry;Population;Postdoctoral Fellow;Process;Program Research Project Grants;Property;RNA;Research;Research Personnel;Role;Shapes;Signal Pathway;Signal Transduction;Structure;System;Technology;Testing;Therapeutic;Therapeutic Intervention;Training;Untranslated RNA;Viral;Viral Genes;Viral Pathogenesis;Viral Proteins;Virus;carcinogenesis;cell growth;co-infection;equity diversity and inclusion;exosome;extracellular vesicles;gammaherpesvirus;genetic approach;graduate student;human disease;in vivo Model;innovation;neoplastic cell;new therapeutic target;next generation sequencing;novel;novel therapeutics;oncology program;primary effusion lymphoma;programs;single-cell RNA sequencing;therapeutic target;tumor;tumor microenvironment;tumorigenesis;virus related cancer Viral Oncogenesis Latency and Replication OVERALLProject NarrativeThis program project grant application focuses on the DNA tumor viruses Epstein-Barr Virus (EBV) KaposiSarcoma-associated Herpesvirus (KSHV) and human papillomavirus (HPV) to identify the critical mechanismsby which these agents induce human cancer and deregulate cell growth. The projects will investigate howthese viruses modulate cellular processes including cell signaling pathways epigenetic networks and immuneevasion and will explore potential therapeutics to treat virus-associated cancers. NCI 10696201 6/1/23 0:00 PAR-20-077 5P01CA019014-43 5 P01 CA 19014 43 "DASCHNER, PHILLIP J" 5/1/97 0:00 6/30/27 0:00 ZCA1-RPRB-L(M1)S 6931559 "DAMANIA, BLOSSOM A" "RAAB-TRAUB, NANCY JOAN" 4 MICROBIOLOGY/IMMUN/VIROLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 1936921 NCI 1252691 684230 OVERALLProject Summary AbstractThis program project grant application focuses on three DNA tumor viruses namely humanpapillomavirus (HPV) Epstein-Barr Virus (EBV) and Kaposi Sarcoma-associated Herpesvirus(KSHV) to identify the critical mechanisms by which these agents induce cancer and deregulatecell growth. EBV HPV and KSHV are linked to multiple cancers in the human population. Thisproposal will study how these viruses promote carcinogenesis and investigate overarchingbiological principles. To identify the mechanisms responsible for the oncogenic properties ofthese viruses the projects will characterize the basic molecular properties of these viruses aswell as viral genes and proteins. They will investigate how these viruses modulate cellularprocesses including cell signaling pathways epigenetic networks and immune evasion.Furthermore the potential therapeutic benefits of targeting these viruses will be tested in cellculture assays and animal models.This application consists of four projects and three cores. Project 1 will investigate themodulation of tumorigenesis by extracellular vesicles secreted from tumor virus-infected cells.Project 2 will investigate the role of long non-coding RNAs and R-loops in the lifecycle ofoncogenic viruses. Project 3 will investigate how gammaherpesviruses evade host immunesignaling pathways and the impact of host factors on viral lifecycles. Project 4 will examine thefunction of EBV-encoded lncRNAs and how EBV infection impacts tumorigenesis. Core Aprovides administrative support for the overall program. Core B provides state-of-the-artgenomics and viral and cellular gene profiling as well as biostatistics support for all the projectsin this application and Core C provides electron microscopy and mass photometry for structurestudies. 1936921 +No NIH Category available Bioinformatics;Biological Products;Biometry;Bortezomib;Cancer Therapy Evaluation Program;Caring;Cells;Clinical Trials;Combined Modality Therapy;Correlative Study;Coupled;DNA;Data;Development;Dose;Drug Targeting;Eligibility Determination;Enrollment;Etoposide;Future;Genes;Glioblastoma;Glioma;Goals;Growth;Heterogeneity;Homeostasis;Link;Malignant Glioma;Malignant Neoplasms;Maximum Tolerated Dose;Microdialysis;Modeling;Molecular;Molecular Profiling;Mutate;Outcome;PTEN gene;Participant;Pathway interactions;Patient Recruitments;Patient-Focused Outcomes;Patients;Penetration;Performance;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phenotype;Play;Pre-Clinical Model;Proteasome Inhibitor;Proteins;Recommendation;Recurrence;Research Project Grants;Resected;Role;Safety;Sampling;Signal Transduction;Specificity;Stream;System;TOP2A gene;Teniposide;Testing;Toxic effect;Ubiquitin;Up-Regulation;Work;Xenograft Model;Xenograft procedure;candidate identification;data sharing;design;drug development;drug discovery;exome;exome sequencing;genomic signature;improved;in vitro Model;in vivo;inhibitor;molecular subtypes;multicatalytic endopeptidase complex;participant enrollment;patient derived xenograft model;phase 1 study;precision medicine;predicting response;protein degradation;response;small molecule;small molecule inhibitor;synergism;targeted agent;therapeutic target;timeline;transcriptome sequencing;tumor Signature-guided treatment of GBM with neddylation inhibitor pevonedistat n/a NCI 10696195 9/12/23 0:00 RFA-CA-20-047 5U19CA264512-03 5 U19 CA 264512 3 9/13/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7845 1881103 "BERENS, MICHAEL E." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 196205 189253 6952 PROJECT SUMMARY PROJECT 3The ubiquitin/proteasome system maintains intracellular homeostasis via degradation of unwanted proteins.Neddylation is a specific pathway within the ubiquitin/proteasome system that is overactive in glioblastoma(GBM) and whose upregulation has been associated with glioma progression and worse survival. Pevonedistatis a first-in-class small-molecule neddylation inhibitor shown to impact protein degradation and inhibit growth ofGBM cells in culture and orthotopic xenografts. Pevonedistat is in clinical trials and available through NCIsCancer Therapy Evaluation Program (CTEP). Because the molecular heterogeneity within and across GBMpatients obscures therapeutic targets and obfuscates signals of efficacy in clinical trials we propose the use ofmolecular signatures of vulnerability to targeted agents in subsets of models and to use these signatures toguide patient enrollment in early-stage clinical trials. Our preliminary data revealed molecular determinants ofsynergy against PTEN-deleted (PTENdel) and PTEN-mutated (PTENmt) GBM from combining pevonedistat witha TOP2A inhibitor etoposide. We hypothesize that a specific synergy signature can be used to identify patientslikely to respond to pevonedistat + etoposide and propose a signature-guided clinical trial to achieve synergy inpatients with recurrent GBM (rGBM). We propose the following Aims: Aim 1. Discover and validate themechanism underlying the antitumor synergy of pevonedistat + TOP2Ais in GBM. We will use GBMpatient-derived xenograft (PDX) explant cultures and orthotopic tumors to pursue this aim and will validate thepredictive performance of the synergy signature in patient tumor samples from the proposed clinical trial inAim 3. Aim 2. Validate a signature of vulnerability to pevonedistat alone in GBM. We will use GBM PDXcultures and orthotopic models to refine and test the predictive accuracy of a signature of vulnerability topevonedistat for future clinical trials. Aim 3. Determine the safety of pevonedistat + etoposide in synergysignature rGBM patients in a phase I clinical trial. We will enroll patients with synergy signature GBM to aphase I study of pevonedistat + etoposide to determine the maximum tolerated dose/recommended phase IIdose of the combination therapy; obtain preliminary response data; define the neuropharmacokinetic (nPK) ofpevonedistat using intracerebral microdialysis; and evaluate the neuropharmacodynamics (nPD) ofpevonedistat using a window of opportunity design in subsets of study participants. This project relies on supportfrom Core A for nPK analysis Core B for exome and RNA Seq and bioinformatics and the Admin Core forcoordination and integration with Projects 1 and 2 for data sharing and comparison of signatures of vulnerabilityto OV-CD47-G1 and tasquinimod. If successful our project will advance drug development in the setting of aheretofore recalcitrant tumor by linking molecular subsets of GBM with both drug discovery/development andpatient recruitment for highest likelihood of conveying precision medicine into the care stream. +No NIH Category available Accreditation;Adoption;Aftercare;Alleles;Aneuploidy;Anti-CD47;Antibodies;Beds;Bioinformatics;Biological Products;CLIA certified;Catheters;Cell Nucleus;Cells;Certification;Characteristics;Cities;Clinic;Clinical;Clinical Data;Clinical Trials;Collaborations;Consultations;DNA sequencing;Data;Data Analytics;Data Reporting;Data Set;Decision Making;Development;Effectiveness;Eligibility Determination;Engineering;Enrollment;Ensure;Etoposide;Evolution;Excision;Fostering;Future;Gene Expression Profiling;Genes;Genomics;Glioblastoma;Glioma;Goals;Harvest;Herpesviridae;Herpesviridae Infections;Individual;Infection;Infiltration;Infrastructure;Intervention;Laboratories;Lead;Liquid substance;Loss of Heterozygosity;Lymphocyte;Machine Learning;Manuscripts;Methods;Microdialysis;Mission;Modeling;Molecular;Molecular Profiling;Mus;Mutation;Normal tissue morphology;Oncolytic;Oncolytic viruses;Operative Surgical Procedures;PTEN gene;Patient Care;Patients;Phenotype;Population;Pre-Clinical Model;Predisposition;Process;RNA;Research;Research Personnel;Research Project Grants;Resistance;Resources;Running;Sampling;Secure;Services;Simplexvirus;Single Nucleotide Polymorphism;Specimen;Surgically-Created Resection Cavity;TOP2A gene;Techniques;Technology;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Tissue-Specific Gene Expression;Tissues;Transcript;Tumor Tissue;Variant;Work;Writing;bioinformatics pipeline;bioinformatics tool;biomedical informatics;design;exome;exome sequencing;experimental study;feature selection;genomic data;genomic profiles;immune cell infiltrate;immunological status;immunopharmacology;improved;improved outcome;inhibitor;insight;novel;participant enrollment;patient derived xenograft model;pre-clinical;preclinical study;programs;response;small molecule inhibitor;synergism;transcriptome;transcriptome sequencing;transcriptomics;tumor;tumor heterogeneity;tumor-immune system interactions Molecular Profiling and Bioinformatics n/a NCI 10696184 9/12/23 0:00 RFA-CA-20-047 5U19CA264512-03 5 U19 CA 264512 3 9/13/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7839 1881103 "BERENS, MICHAEL E." Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 175243 165188 10055 PROJECT SUMMARY CORE BThe U19 Molecular Profiling and Bioinformatics Core (Core B) will provide state-of-the-art genomics andbioinformatics technology and expertise to advance each of the projects in the City of Hope U19 program. Inanticipation of delivering on the larger mission of the Glioblastoma Translational Network (GTN) Core B willprovide CAP-certified CLIA-approved exome and transcriptome sequencing that returns data for patient caredecision-making. Core B bridges bench discovery of molecular determinants of glioblastoma vulnerability to thethree novel agents in this U19 and the clinical setting in which precision use of these treatments may have thehighest likelihood of benefiting patients. Core B will achieve this by: A) Providing comprehensive CLIA-certifiedgenomic profiling for patients enrolled on our U19 clinical trials as well as genomic sequencing of preclinicalmodels and offering single cell/nuclei transcriptomic analyses of harvested cell infiltrates collected from thetumor bed following resection or dispersed tissue. These studies will provide granular insight into tumorheterogeneity tumor sensitivity or resistance and tumor evolution. B) Identifying signatures of vulnerability tothe agents being evaluated. For Project 1 GBM exome and transcriptomic data will be analyzed to identifyfeatures that modify susceptibility to oncolytic herpes virus infection the impact of alleles of genes that play arole in HSV replication and deconvolution of patient tumors to depict the host cell infiltrate comprising thepretreatment microenvironment immune status of syngeneic models and glioma patients enrolled in the oncolyticvirus/anti CD-47 clinical trial. For Project 2 exome and transcriptome data from tumors of patients enrolled inthe clinical trial evaluating tasquinimod will be deconvoluted to discern populations of immune cell infiltrates tocompare with post-treatment single cell transcriptomic analysis of resection cavity fluid collected from surgicallyplaced catheters. Tumors from syngeneic glioma models receiving different treatments will analyzed by singlenuclei transcriptomics for cell deconvolution. For Project 3 we will further develop a synergy signature indicativeof GBM vulnerability to the combination of pevonedistat + etoposide leading to a patient-enrichment strategy forfuture clinical trials. Preliminary data indicates that PTEN status (copy number mutation expression levels)serves as a determinant for likelihood of response to the neddylation inhibitor pevonedistat as well as thesynergistic activity of etoposide (TOP2A inhibitor) with pevonedistat. C). Deliver state-of-the-art biomedicalinformatics and data analytics expertise and services. Core B will provide state-of-the-art bioinformatics methodsincluding machine learning techniques to derive highest value from the preclinical and clinical data in eachproject. Core B will also foster data and information exchange and collaboration with individual Projects/Coresacross the GTN. The long term goal of Core B is to participate in the design development and adoption of anadaptive signature-guided umbrella clinical trial supporting all new treatments emerging from the GTN. +No NIH Category available Adverse reactions;Antibodies;Atlases;Autoimmune Diseases;Biological Markers;Cells;Collaborations;Cutaneous;Data Analyses;Detection;Development;Disease;Doctor of Philosophy;Environment;Funding;Grant;Human;Image;Immune;Immunofluorescence Immunologic;In Situ Hybridization;Inflammation;Laboratories;Malignant Neoplasms;Manuscripts;Methods;Mus;Oligonucleotides;Pathology;Periodicity;Pharmacology;Pharmacotherapy;Process;Reagent;Reporting;Research;Research Personnel;Resolution;Sampling;Scientist;Senior Scientist;Skin;Specialist;Stains;Supervision;System;Technology;Tissue imaging;Tissues;United States National Institutes of Health;Work;Writing;career development;cellular imaging;digital pathology;high dimensionality;medical schools;melanoma;member;multiplexed imaging;premalignant;programs;skin organogenesis;treatment response;tumor;tumor microenvironment High dimensional digital pathology to investigate the tumor micro environment and its impact on response to therapy Project NarrativeGrant: Research Specialist (PAR-19-291)Title: High dimensional digital pathology to investigate the tumor microenvironment and its impact onresponse to therapyThis project involves developing a digital pathology platform for highly-multiplexed tissue imaging anddata analysis to support NCI-funded grants including the construction of a melanoma precancer atlasfor the Cancer Moonshot Human Tumor Atlas Network. This proposal will also support originalresearch to characterize the cutaneous immune landscape in cancer autoimmune disease andadverse reactions to drug therapy. Finally this grant will promote my career development as aresearch specialist and increase my independence as a scientist in the Laboratory of SystemsPharmacology at Harvard Medical School. NCI 10696177 8/21/23 0:00 PAR-19-291 5R50CA252138-04 5 R50 CA 252138 4 "OSSANDON, MIGUEL" 9/1/20 0:00 8/31/25 0:00 ZCA1-SRB-1(M1)S 14089646 "MALIGA, ZOLTAN " Not Applicable 7 BIOLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 201041 NCI 118608 82433 SummaryGrant: Research Specialist (PAR-19-291)Under the supervision of senior scientist Zoltan Maliga PhD investigators and staff at the HarvardMedical School Laboratory of Systems Pharmacology (LSP) will contribute to cell and tissue imagingand analysis for U2C and U54 program grantsLSP-based investigators will perform the tissue-based cyclic immunofluorescence (t-CyCIF) methoddeveloped at HMS on FFPE human and mouse skin samples provided by investigators and will worktogether to define and validate antibodies to stain biomarkers of skin development inflammationmelanoma progression and tumor microenvironment and will share technologies under developmentto further advance the t-CyCIF method (e.g. switch to six-channel imaging use of oligo-modifiedantibodies as detection reagents combination of in situ hybridization or sequencing methods). TheLSP will process t-CyCIF images provide quantitative cell and tissue-level analysis and helpdistribute high-resolution multiplexed images as part of a disease pathology atlas.Maliga will work with PIs Lian Murphy LeBoeuf Haigis Aster to prepare manuscripts write reportsfor the NIH and collaborate with other members of the project teams as required the by PAR-19-291. 201041 +No NIH Category available Address;Applications Grants;Biomedical Research;Career Mobility;Climate;Clinical;Communities;Development;Development Plans;Discrimination;Educational workshop;Ethnic Population;Evaluation;Extramural Activities;Faculty;Funding;Goals;Grant;Health system;Individual;Institution;Knowledge;Manuscripts;Medicine;Mentors;Mentorship;Modeling;Personal Satisfaction;Population;Preparation;Productivity;Publications;Research;Research Support;Resources;STEM field;STEM research;Scholars Program;Science;Secure;Series;Social support;Teacher Professional Development;Testing;Training;Training Programs;Underrepresented Populations;United States National Institutes of Health;Work;Writing;anti-racism;career;career development;career life balance;cohort;community building;cultural competence;curriculum enhancement;design;early-career faculty;experience;faculty research;faculty support;improved;medical schools;member;parity;peer coaching;programs;racial population;racism;satisfaction;skill acquisition;skills;success;unconscious bias Faculty Development Core n/a NCI 10696176 9/11/23 0:00 RFA-RM-20-022 5U54CA267776-03 5 U54 CA 267776 3 9/24/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 7835 7310301 "CHEN, BENJAMIN K" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 216339 128426 88615 SUMMARYEfforts to diversify the trainee population in STEM and biomedical research in the US have achieved somesuccess. Nevertheless diversifying the faculties of research institutions has lagged behind and remains asignificant challenge. This disturbing lack of parity is attributed to numerous factors including disproportionatelyhigh rates of attrition from underrepresented racial and ethnic groups during the transition from training intofaculty-level research careers lack of adequate mentorship bias and racism and challenges associated withsecuring extramural funding. The overarching goal of the Faculty Development Core (FDC) is to support facultydevelopment mentoring sponsorship and promotion for the FIRST Cohort. We will implement a program ofprofessional development and career advancement tailored for a cohort/cluster model and intended to supportthe research success of the individual members of the cohort and of the cohort as a whole. Our program willcombine mentoring/sponsorship a curriculum of enhanced research skills development with support forproducing strong grant applications social supports to help FIRST Cohort faculty navigate the specificchallenges and obstacles often faced by early-career faculty from underrepresented groups in science andmedicine and opportunities for networking at all levels across our institution within the local community and inthe broader scientific community. The FDC will work closely with the Evaluation Core to track and assess metricsof success. Activities will include 1) required mentor/sponsor training centered on bias reduction anti-racismand mentoring for research success; 2) creation of individual development plans (IDPs); 3) mentor/sponsorcommittees; 4) a focused and FIRST Cohort program to support the development of knowledge and skills aroundbuilding a successful research program and preparation of competitive grant applications. To reduce isolationbuild community and promote well-being we will implement an integrated program to enhance professionaldevelopment incorporating: 1) a cohort Coaching Team focused on work-life balance and well-being and on thespecific barriers faced by underrepresented groups in academic medicine; 2) a Professional DevelopmentWorkshop series to equip early-career faculty with strategies to improve their productivity and overall sense ofsatisfaction; and 3) a program of individualized coaching; and; 4) peer mentoring. To create opportunities fornetworking and increasing the visibility of FIRST Cohort faculty within our institution and beyond we will identifyformal and informal networking opportunities that will begin immediately upon hire and which will evolve over theperiod of the grant incorporating opportunities to network and engage with 1) faculty at all levels; 2) institutionalleaders; 3) the larger scientific community; and 4) local communities. The proposed FIRST Cohort program willcreate a cohesive program of faculty development integrating various resources currently siloed at our institution.The program can potentially serve as a model for other research-focused institutions committed to inclusiveexcellence and dissemination of best practices will be coordinated through the Center for Scientific Diversity. +No NIH Category available Award;Biomedical Research;Brain;Budgets;Collaborations;Communicable Diseases;Communication;Data;Dedications;Development;Ensure;Equity;Evaluation;Faculty;Feedback;Fostering;Funding;Goals;Human Resources;Institution;Leadership;Link;Malignant Neoplasms;Microbiology;Mission;Monitor;National Cancer Institute;Process;Productivity;Reporting;Research;Research Personnel;Research Support;Resource Sharing;Resources;Scientist;Strategic Planning;Surveys;Teacher Professional Development;U-Series Cooperative Agreements;Underrepresented Populations;United States National Institutes of Health;career development;climate data;cohort;community building;design;diversity and inclusion;emerging pathogen;empowerment;evidence base;executive function;global health;health equity;innovation;medical schools;meetings;organizational climate;programs;recruit;research and development;success;web site Administrative Core n/a NCI 10696175 9/11/23 0:00 RFA-RM-20-022 5U54CA267776-03 5 U54 CA 267776 3 9/24/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 7834 9550274 "BENN, EMMA KATHERINE TARA" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 5036991 2990133 2063191 SUMMARYThe FIRST Cohort program is housed within the Center for Scientific Diversity (CSD) at the Icahn School ofMedicine at Mount Sinai (ISMMS) in collaboration with Institutes and Departments across ISMMS and with thesupport of institutional leadership. The mission of the CSD is to foster develop and assess empiricallysupported practices that promote and enhance scientific innovation diversity and equitable advancement withinthe biomedical investigator workforce. This Administrative Core will serve as the conduit among and betweenFIRST Cohort program stakeholders across the institution to advance our overarching goal to develop andsustain a culture of inclusive excellence. The Administrative Core will assist in all aspects of the administrationcommunication and overall conduct of the FIRST Cohort program. It will act to advance the FIRST Cohortprogram goals which are to 1) integrate and modify existing and evolving strategic plans to achieve systemicand sustainable culture change; 2) recruit a FIRST cohort of four clusters of three scientists each fromunderrepresented groups in biomedical research (URM) and/or who have a demonstrated commitment topromoting diversity and inclusive excellence to be embedded within and across The Friedman Brain Institute(FBI) The Institute for Health Equity Research (I-HER) the Tisch Cancer Institute (TCI) and the Global Health and Emerging Pathogens Institute/Microbiology and Infectious Disease;and 3) develop strategies to support the research and career development of FIRST cohort faculty includingplans to reduce isolation and build community. The Administrative Core will provide support for personnelinvolved in the administrative scientific communication and budgetary oversight functions associated with theproposed FIRST Cohort program. Our aims are designed to advance the goals for this application at the IcahnSchool of Medicine at Mount Sinai while developing evidence-based best practices for inclusive excellence morebroadly for the national biomedical research enterprise. To that end the aims of the Administrative Core areleadership administration communications integration across Cores recruitment of a diverse cohort andoversight of advancement/promotion and retention activities and tracking and evaluation. We will coordinate withthe Faculty Development Core to provide metrics of success. The AC is responsible for oversight of all activitiesand initiatives associated with the FIRST Cohort Program to create and sustain a culture of inclusive excellence.We will coordinate with the NIH under the terms of the Cooperative Agreement Award and participate in NIHFirst Executive Steering Committee meetings. +No NIH Category available Acceleration;Address;Advisory Committees;Appointment;Award;Biomedical Research;Black race;Career Mobility;Climate;Collaborations;Committee Members;Communities;Data;Development;Development Plans;Discrimination;Educational workshop;Ensure;Equity;Evaluation;Extramural Activities;Faculty;Financial compensation;Fostering;Funding;Goals;Grant;Health system;Individual;Institution;Intervention;Interview;Investments;Job Application;Latinx;Leadership;Life;Medicine;Mentors;Modeling;Personal Satisfaction;Policies;Positioning Attribute;Process;Program Development;Program Evaluation;Protocols documentation;Research;Research Support;Secure;Standardization;Strategic Planning;Surveys;Teacher Professional Development;Training;Underrepresented Populations;United States National Institutes of Health;Work;anti-racism;career;career development;climate change;cohort;community building;design;diversity and inclusion;early-career faculty;expectation;experience;faculty support;gender equity;health equity;interest;marginalization;medical schools;member;novel;outreach;peer coaching;primary outcome;professor;programs;racism;recruit;skill acquisition;statistics;success;tenure track;unconscious bias NIH FIRST Cohort Cluster Hiring Initiative at Icahn School of Medicine at Mount Sinai NARRATIVEThe FIRST Cohort Program at the Icahn School of Medicine at Mount Sinai (ISMMS) will integrate developmentof a Roadmap for Inclusive Excellence strategic plan a Cohort/cluster model of recruitment of a diverse cohortof early-career faculty committed to diversity and inclusive excellence and a robust program of facultydevelopment. The programs goals are to effect sustainable culture change at our institution and to support theFIRST Cohort faculty hires in obtaining extramural funding. NCI 10696174 9/11/23 0:00 RFA-RM-20-022 5U54CA267776-03 5 U54 CA 267776 3 "CALZOLA, JESSICA MARIE" 9/24/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 9550274 "BENN, EMMA KATHERINE TARA" "CAMPBELL, KIRK N; NESTLER, ERIC J.; RICHARDSON, LYNNE D." 13 EMERGENCY MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5481503 OD 3254010 2245267 SUMMARYThe barriers to research and career success for underrepresented groups in academic medicine have beenwidely documentedan inhospitable climate discriminatory policies lower financial compensation lack ofleadership opportunities a sense of marginalization and racism among others. Strategies to eliminate thesebarriers have been largely unsuccessful as evidenced by the persistent representation gap. Research suggeststhat while strategies focused on individuals are useful an integrated approach will be necessary to effectsystemic change. Efforts toward inclusive excellence are underway at the Icahn School of Medicine at MountSinai (ISMMS) with such transformative initiatives as the Mount Sinai Health System (MSHS) Task Force toAddress Racism; a novel recruitment program to attract junior and senior Black/AA and Latinx faculty (TheBiomedical Laureates Program); creation of the Office for Gender Equity; establishment of the Institute for HealthEquity Research; and launch of The Center for Scientific Diversity. The purpose of the proposed FIRST Cohortprogram is to accelerate inclusive excellence at our institution and by extension contribute to acceleratinginclusive excellence more broadly in the national biomedical research enterprise. Building on current initiativesour goals are to (1) foster sustainable culture/climate change; (2) promote inclusive excellence by hiring a diversecohort of new early-career faculty; and (3) support faculty development mentoring sponsorship and promotion.Our primary outcome is for FIRST Cohort faculty hires to secure an NIH R-award by the conclusion of the grantperiod. We will pursue three related aims. First we will modify the MSHS Task Force To Address RacismRoadmap for Change with key strategies as the basis for an ISMMS Roadmap for Inclusive Excellence to include(1) development of a process to collect accurate comprehensive demographic faculty data and to make thisdata accessible; (2) engagement of the faculty in regular climate surveys and the sharing of results with facultyand institutional leaders; (3) departmental/Institute level review of advancement & promotion practices policiesand processes; among other key strategies. Second we will recruit a diverse Cohort comprised of 4 clusters of3 faculty per cluster to be embedded within our interdisciplinary Institutes. We will develop a new recruitmentprotocol to ensure fairness and equity in the hiring process require bias reduction training for search committeemembers and establish standardized interview processes. Next we will provide an integrated program of facultydevelopment to include both career advancement and professional development activities (e.g. individualdevelopment plans mentor/sponsor committees Grants-in-Progress workshops individual coaching aroundsuch issues as work-life integration peer mentoring etc.) Cluster Sponsors will lead the way in identifyingopportunities for formal and informal networking across the ISMMS and in the larger scientific community. Withthe support of an institutional investment all FIRST Cohort faculty will be retained at the conclusion of the awardperiod. We will conduct a rigorous evaluation of the program and collaborate closely with NIH CEC as required. 5481503 +No NIH Category available Academic advising;Acceleration;Applied Research;Area;Award;Basic Science;Biochemistry;Bioethics;Bioinformatics;Biology;Biometry;Cellular biology;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Dedications;Development;Dreams;Education;Educational process of instructing;Epidemiologist;Epidemiology;Epigenetic Process;Evaluation;Faculty;Fellowship Program;Fostering;Foundations;Funding;Future;Generations;Genetic;Genomics;Goals;Individual;Institution;International;Investigation;Knowledge;Laboratories;Laboratory Research;Leadership;Malignant Neoplasms;Manuscripts;Mentors;Mentorship;Methods;Minority;Molecular;Molecular Biology;Participant;Pathologist;Physicians;Positioning Attribute;Postdoctoral Fellow;Productivity;Proteomics;Qualifying;Records;Research;Research Personnel;Research Project Grants;Resources;Science;Scientist;Structure;Systems Biology;Talents;Technical Expertise;Time;Training;Translational Research;Woman;Writing;anticancer research;biobank;career;career development;clinical translation;design;drug development;epigenetic therapy;experience;innovation;interest;member;novel;novel therapeutic intervention;pharmacokinetics and pharmacodynamics;programs;recruit;skills;success;translational potential;translational scientist;translational study Career Enhancement Program PROJECT NARRATIVE (Career Enhancement Program)The Career Enhancement Program fosters the scientific development of investigators who intend to focus theircareers on translational studies of cancer epigenetic therapies. This is achieved by recruiting innovative entry-level scientists to enhance the SPOREs overall translational research capability helping these individualsdevelop intellectual and technical skills required to be productive investigators and teaching these individualsbasic principles of translational research. NCI 10696173 7/12/23 0:00 PAR-18-313 5P50CA254897-03 5 P50 CA 254897 3 8/16/21 0:00 6/30/26 0:00 ZCA1-RPRB-7 7833 1888492 "ISSA, JEAN-PIERRE J." Not Applicable 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 82536 46499 36037 PROJECT SUMMARY (Career Enhancement Program)The goal of the Career Enhancement Program (CEP) is to provide training and guidance for academic physician-scientists clinician-investigators and laboratory-based scientists who wish to dedicate their career and researchefforts to translational cancer epigenetics research. To achieve this goal the CEP will pursue the followingspecific aims: 1. Recruit train and mentor physicians scientists and senior postdoctoral fellows to become excellent investigators focused on cancer epigenetics translational research. 2. Educate awardees in all the basic principles of cancer epigenetics biology including molecular cellular and systems biology drug development pharmacokinetic and pharmacodynamics studies and basic principles of biostatistics and bioinformatics. 3. Provide a firm foundation for awardees in the specific area of cancer epigenetics translational and early clinical research.These objectives will be achieved through strong mentorship in which awardees will be instructed in the principlesof clinical basic and translational cancer epigenetics research. Specific areas of education may include scientificand clinical methods biomedical ethics statistical design and analysis bioinformatics biology biochemistrygenetics epidemiology and other areas relevant to individual projects. Mentorship will include laboratory-basedinvestigators clinical-translational investigators biostatisticians bioinformaticians and epidemiologists. Mentorsfrom within the Epigenetic Therapy SPORE the Van Andel Institute-Stand Up To Cancer Epigenetics DreamTeam Coriell Institute the Van Andel Institute and institutions of PIs and members of the IAB and EAB willprovide the expertise required for the development of strong productive translational research skills. +No NIH Category available American Association of Cancer Research;Award;Cancer Patient;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Development;Dreams;Eligibility Determination;Ensure;Epigenetic Process;Fostering;Funding;Goals;Grant;Hematologic Neoplasms;Institution;Investments;Laboratory Research;Leadership;Letters;Mainstreaming;Malignant Neoplasms;Mission;Modeling;Monitor;Nature;Peer Review;Pilot Projects;Process;Quality of life;Recording of previous events;Research;Research Peer Review;Research Personnel;Research Project Grants;Scientist;Selection Criteria;Solid Neoplasm;Source;Structure;Therapeutic Studies;Translating;Translational Research;University of Texas M D Anderson Cancer Center;cancer therapy;clinically relevant;epigenetic therapy;flexibility;high reward;high risk;improved;innovation;leukemia;novel;novel therapeutic intervention;pre-clinical;programs;research study;success;translational potential Developmental Research Program PROJECT NARRATIVE (Developmental Research Program)The Developmental Research Program aims to support and develop research projects involving cancerepigenetics therapies with translational potential that will ultimately improve the survival and the quality of life ofcancer patients. NCI 10696172 7/12/23 0:00 PAR-18-313 5P50CA254897-03 5 P50 CA 254897 3 8/16/21 0:00 6/30/26 0:00 ZCA1-RPRB-7 7832 1888492 "ISSA, JEAN-PIERRE J." Not Applicable 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 82536 46499 36037 PROJECT SUMMARY (Developmental Research Program)The specific objectives of the Developmental Research Program are to:1. Publicize the availability of funds for pilot translational research studies in the field of Epigenetic Therapy for cancers.2. Identify through this mechanism innovative projects with significant potential for developing and improving Epigenetic Therapies for cancers.3. Encourage collaborations of projects with scientists within the SPORE and outside the SPORE specifically the Van Andel Institute-Stand Up To Cancer Epigenetics Dream Team (VAI-SU2C).4. Enhance the communication between the SPORE leaders and VAI-SU2C Investigators to encourage the development of innovative epigenetics therapies for cancer.5. Ensure program flexibility so that developmental projects that show promise can be: 1) funded for a second year; 2) encouraged to apply for peer-reviewed funding (i.e. R01); or 3) expanded to become full SPORE projects.The structure and processes of this program are modeled after a long-standing and successful DevelopmentalResearch Program within the MDACC Leukemia SPORE and on the success of the VAI-SU2C EpigeneticsDream Team in soliciting reviewing awarding and monitoring developmental research project proposals. Toachieve our aims we will establish 1) specific criteria for selection and funding through a peer review mechanismand 2) mechanisms for close monitoring of and collaboration between the SPORE leaders and programawardees to enhance the quality of the translational research goals. +No NIH Category available Apoptosis;Apoptotic;C-terminal;Cancer Patient;Cancer cell line;Cell Line;Cells;Cessation of life;Clinic;Cytotoxic agent;Data;Data Set;Defect;Development;Early Diagnosis;Event;Excision;Glean;Goals;In Vitro;Induction of Apoptosis;Investigation;Knock-in;Knowledge;Laboratories;MAPK8 gene;MCL1 gene;Malignant Female Reproductive System Neoplasm;Malignant neoplasm of ovary;Mediating;Mediator;Minor;Molecular;N-terminal;Neurons;Outcome;Patients;Phosphorylation;Phosphotransferases;Platinum;Play;Probability;Protein Kinase;Proteins;Recurrence;Recurrent Malignant Neoplasm;Resistance;Role;SKOV3 cells;Serous;Signal Pathway;Signal Transduction;Site;Small Interfering RNA;Surgical Management;TP53 gene;Testing;The Cancer Genome Atlas;Therapeutic;Tyrosine;Ubiquitination;Work;aptamer;cancer cell;cancer recurrence;chemotherapy;data mining;drug repurposing;efficacy evaluation;improved;in vivo Model;inhibitor;insight;knock-down;mortality;novel;p53 Signaling Pathway;patient derived xenograft model;prevent;public database;screening;success;therapeutic target Novel protein kinase signaling associated with platinum resistance in ovarian cancer PROJECT NARRATIVEPlatinum resistance is probably the most important factor contributing to ovarian cancer recurrence andmortality. This application aims to understand the molecular mechanism responsible for platinum resistance ofovarian cancer. This application also aims to develop an effective strategy to overcome platinum resistance byblocking the function of SRMS a key regulator of platinum resistance in ovarian cancer. NCI 10696169 9/8/23 0:00 PA-20-185 5R01CA256482-03 5 R01 CA 256482 3 "O'HAYRE, MORGAN" 9/1/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 1971797 "HUANG, SHUANG " "JIN, LINGTAO " 3 ANATOMY/CELL BIOLOGY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 434151 NCI 284689 149462 PROJECT SUMMARYDevelopment of platinum resistance is one of the most important factors contributing to ovarian cancerrecurrence and mortality. In our effort to decipher molecular mechanisms underlying platinum resistance weperformed a kinome-wide screening on platinum-resistant SK-OV3 ovarian cancer cell line and identified Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS) as a topplatinum resistance regulator. Further analysis of TCGA ovarian cancer dataset revealed that patients with highSRMS expression responded poorly to platinum-based therapy and had worse overall survival. Since knockdownof SRMS markedly sensitized p53-deficient ovarian cancer cell lines to platinum while only displayed minor effecton p53-competent cell lines we reason that SRMS plays a critical role in platinum resistance of p53-deficientovarian cancer. To glean the mechanistic insight into the role of SRMS in platinum resistance we showed thatSRMS prevents JNK activation possibly by directly phosphorylating JNKs. JNK signaling pathway is wellestablished as an essential mediator for apoptosis triggered by cytotoxic agents; our observation that SRMS isspecifically involved in platinum resistance in p53-deficient cells suggests that 1) platinum induces apoptosis inp53-deficient ovarian cancer cells in a JNK signaling pathway-dependent manner because of the defect in p53signaling pathway-mediated apoptosis; and 2) SRMS-led inhibition of JNK signaling alleviates platinum-inducedapoptosis and thereby promotes platinum resistance in p53-deficient cells. p53 is uniformly deficient in highgrade serous ovarian cancer (HGSOC). The discovery of SRMS prominent role in platinum resistance of p53-deficient cells indicates that SRMS can be an ideal therapeutic target against platinum resistance in HGSOC. Inour drug repurposing screening we found that PLX4720 a selective inhibitor of B-RafV600E can potentlyinhibit SRMS activity. In this application we propose 3 specific aims: 1) Characterize molecular mechanismsunderlying SRMS-conferred platinum resistance; 2) Define platinum resistance-relevant events that aregoverned by SRMS-JNK signaling; and 3) Investigate the potential of targeting SRMS to augment efficacy ofplatinum therapy. The success of this application will uncover molecular mechanism underlying SRMS role inplatinum resistance of ovarian cancer. Importantly we will evaluate SRMS-targeted strategy to overcomeplatinum resistance in ovarian cancer. 434151 +No NIH Category available AML/MDS;ATAC-seq;Achievement;Address;Affect;Antigen Presentation;Applications Grants;CDC2 gene;CDK4 gene;CDK5 gene;Cancer Model;Cell Cycle;Cells;Cellular Assay;ChIP-seq;Clinic;Clinical;Clinical Drug Development;Clinical Trials;Cyclin-Dependent Kinase Inhibitor;Cyclin-Dependent Kinase Inhibitor 2A;Cyclin-Dependent Kinases;DNA Modification Methylases;DNA methyltransferase inhibition;Data;Dendritic Cells;Development;Dominant-Negative Mutation;Dose;Double-Stranded RNA;Drug Screening;Drug Targeting;Engineering;Enzymes;Epigenetic Process;Gene Activation;Gene Expression;Gene Silencing;Genetic Transcription;Heart;Heterochromatin;Immune checkpoint inhibitor;Immune response;Immune system;Immunotherapy;Interferon Type II;Interferons;Malignant Neoplasms;Modeling;Myeloid Leukemia;Oncogenes;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phosphorylation;Proteins;Regulation;Reporter;Repression;Resistance;Signal Transduction;System;T cell infiltration;T cell response;Testing;Therapeutic Effect;Toxicology;Tumor Immunity;Tumor Suppressor Proteins;Up-Regulation;antitumor effect;cancer cell;cancer therapy;checkpoint inhibition;design;efficacy study;epigenetic drug;epigenetic profiling;epigenetic silencing;epigenetic therapy;epigenome;expectation;falls;immunoregulation;improved;inhibitor;interest;leukemia;malignant breast neoplasm;mouse model;neoplastic cell;novel strategies;novel therapeutic intervention;novel therapeutics;pre-clinical;preclinical study;programs;promoter;response;targeted treatment;transcriptome sequencing;trial comparing;tumor;tumorigenesis Cyclin Dependent Kinases as Epigenetic Therapy Targets NARRATIVEEpigenetic Therapy aims to treat cancer by blocking enzymes that control regulation of abnormal cellular identityin cancer. In doing so these therapies also make immunotherapies more effective. This SPORE project seeksto improve on current epigenetic therapies by exploring a new target CDK9 and testing a new drug in pre-clinical (and eventual clinical) combination studies. NCI 10696168 7/12/23 0:00 PAR-18-313 5P50CA254897-03 5 P50 CA 254897 3 8/16/21 0:00 6/30/26 0:00 ZCA1-RPRB-7 7829 1888492 "ISSA, JEAN-PIERRE J." Not Applicable 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 498235 347201 151034 PROJECT SUMMARYEpigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. To dateDNA methyltransferase (DNMT) inhibition (DNMTi) is the most effective form of epigenetic therapy beingparticularly active in myeloid leukemias. Using a live cell assay to screen for drugs that achieve the same degreeof epigenetic reprogramming as DNMTi we discovered a new class of epigenetic drugs that activate silencedexpression through inhibition of CDK9. Cyclin Dependent Kinases (CDKs) are of considerable clinical interest incancer therapy and fall into two classes cell cycle regulatory (e.g. CDK1246 etc.) and transcriptionalregulators (e.g. CDK7912 etc.). Our new data place CDK9 at the heart of a node that regulates both genesilencing and activation. Targeting CDK9 has pleotropic effects on gene expression that appear ideal from ananti-tumor perspective: One observes simultaneous gene activation (of tumor suppressors) repression (ofoncogenes) and induction of an interferon immune signature which may be immunosensitizing for cancertherapy. This latter effect is of particular interest given the phenomenal recent development of immune basedtherapies and our preliminary data suggest that CDK9 targeting may be a useful new approach toimmunosensitization. Interestingly CDK9 may not be the only CDK involved in immune regulation. Inhibition ofCDK4/6 and of CDK5 have been shown to induce an IFN response and/or to be immunosensitizing in cancertherapy. Moreover other transcriptional CDKs (e.g. CDK7) share phosphorylation targets with CDK9 raising thepossibility that they also similarly affect gene silencing. Given that drugs that target CDK4 and/or 6 are in clinicaluse in breast cancer and drugs targeting CDK7 and/or 9 are in clinical trials it becomes important to knowwhether other CDKs are also immunosensitizing epigenetic regulators. Epigenetic effects may lead to differentstrategies for clinical development of these drugs (e.g. low doses rather than MTD expectation of slow responsesthat take multiple cycles to occur etc.) and for the design of combination strategies (combined epigenetictherapy combinations with immune checkpoint inhibitors etc.). This project therefore aims to test the hypothesisthat targeting CDKs leads to immunosensitizing epigenetic effects. We will confirm this hypothesis and testmechanisms and clinical/translational implications for cancer therapy in three aims: (i) Immunosensitization byCDK9 inhibition in which we will study mechanisms and potential ways to enhance the effects; (ii) Epigeneticeffects of CDKs in which we will ask whether targeting CDK456 and 7 has similar epigenetic andimmunosensitizing effects as targeting CDK9; and (iii) Preclinical studies and a clinical trial of combined CDK9inhibition DNMT inhibition and Immune checkpoint inhibition in AML and MDS in which we will complete thenecessary studies to bring CDK targeting as epigenetic therapy into the clinic in combination with DNMTtargeting and immune checkpoint inhibition. Successful achievement of these aims will introduce a new form ofepigenetic therapy for cancer and leukemias. +No NIH Category available Address;Age;Algorithms;Biological Assay;Biological Markers;Biological Specimen Banks;Biometry;Blinded;Blood;Blood Proteins;Blood specimen;CA-19-9 Antigen;Cancer Detection;Cancer Etiology;Cancer-Predisposing Gene;Centers of Research Excellence;Cessation of life;Characteristics;Clinic;Collection;Cyst Fluid;DNA Markers;DNA Methylation;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic;Discrimination;Disease;Early Diagnosis;Early identification;Eligibility Determination;Epidemiology;Evaluation;Familial pancreatic cancer;Family;Family history of;Gastroenterology;General Population;Genetic;Genetic Predisposition to Disease;Germ-Line Mutation;Goals;Grant;Guidelines;Incidence;Individual;Infrastructure;Knowledge;Leadership;Longitudinal cohort;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Measurable;Methodology;Methods;Non-Malignant;Pancreas;Pancreatic Cyst;Pancreatic Diseases;Pancreatic Ductal Adenocarcinoma;Participant;Patients;Pennsylvania;Performance;Phase;Plasma;Population;Procedures;Proteins;Protocols documentation;Race;Recommendation;Recording of previous events;Resources;Risk;Risk Factors;Sampling;Screening for cancer;Smoking;Standardization;Survival Rate;Symptoms;THBS2 gene;Testing;Time trend;Tissues;United States;Universities;Validation;biobank;biomarker development;biomarker panel;biomarker validation;blood product;clinical effect;clinical translation;cohort;design;diagnostic accuracy;disorder control;early detection biomarkers;early onset;experience;high risk;high risk population;improved;individual patient;innovation;kindred;member;multidisciplinary;mutational status;new technology;novel;novel marker;novel strategies;pancreatic ductal adenocarcinoma model;patient variability;phase 2 designs;phase 2 study;phase 2 testing;phase 3 study;phase 3 testing;prospective;protein biomarkers;recruit;sample collection;screening;sex;stem cell model;tool Mayo Clinic Prospective Resource for Biomarker Validation and Early Detection of Pancreatic Cancer PROJECT NARRATIVEDetection of PDAC at an early stage positively impacts survival and screening in eligible high-risk individuals(HRIs) defined by family history and mutation status is considered best practice. The overall goal of thisproposal is to use our accumulated knowledge to considerably enhance use of new blood protein andmethylated DNA (MDM) biomarkers for early detection of PDAC. We will leverage our extensive biospecimenresources to test whether a combination of proteins MDMs and CA19-9 will accurately identify early stagePDAC in HRIs. NCI 10696167 8/11/23 0:00 PAR-21-334 5U01CA210138-07 5 U01 CA 210138 7 "YOUNG, MATTHEW R" 7/15/16 0:00 8/31/27 0:00 ZCA1-RPRB-8(M)2 15726305 "MAJUMDER, SHOUNAK " "ZARET, KENNETH " 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 781677 NCI 589715 191962 Pancreatic ductal adenocarcinoma (PDAC) is typically detected at late stage due to absence of a cancerscreening strategy with concomitant poor survival rates. Detection of PDAC at an early stage positively impactssurvival and currently screening in eligible high-risk individuals (HRIs) defined by family history and germlinemutation status is considered best practice. The overall goal of this proposal is to use knowledge gained duringthe last grant period to considerably enhance our ability to develop and validate the diagnostic performance ofnew blood protein and methylated DNA (MDM) biomarkers for early detection of PDAC using prospectivespecimen collection and retrospective blinded evaluation (PRoBE) compliant methods. We hypothesize that acombination of proteins MDMs and CA19-9 will accurately identify early stage PDAC in HRIs. We will assessthe performance characteristics of our approaches in early stage and pre-diagnostic phase of PDAC and identifyapproaches that are optimized for clinical translation as an early detection tool using HRIs. For over two decadesMayo Clinics prospective biospecimen resources have accrued using standardized high-quality procedureswell-annotated biospecimens from thousands of PDAC patients including those with germline mutations inpancreas cancer susceptibility genes high risk members in familial pancreatic cancer kindreds patients withhigh-risk pancreatic conditions and healthy controls. We have also launched the PCDC Signature Protocols atour center. Among those at risk with biospecimens who we have followed longitudinally over two decadesincident PDAC cases have developed enabling us to utilize novel approaches to address the challenges andbetter design PRoBE phase 3 studies. Based on our findings in the last grant period we now focus on tailoringsamples for PRoBE phase 2 studies and characterizing performance to improve phase 3 studies. Our approachwill allow us to assess for example variability in biomarker expression for intended use HRI settings andtemporality of biomarker expression to improve the ability to detect early onset PDAC. Our Specific Aims are to:1) Accrue formal biospecimen sets from blood sample products and pancreatic cyst fluid suitable for PCDCbiomarker studies; 2) Leverage our past knowledge and experience to develop new biomarker panels usingtailored phase 2 designs and incorporating covariates to refine detection (age sex race smoking personalhistory of diabetes mellitus symptoms at diagnosis) to optimize detection; and 3) Evaluate needed performanceparameters that will inform the design of a successful phase 3 study for PDAC in a surveillance setting of HRIs.Our multidisciplinary team is committed to continue its leadership and contribution to the PCDC organization toadvance the early detection of pancreatic cancer. Our project leverages existing infrastructures and biospecimenbanks of pancreatic cancer and other pancreatic diseases at Mayo Clinic and University of Pennsylvania and itwill extend new prospective collections of blood and pancreatic cyst fluid from patients contributing to PCDCSignature Protocol cohorts and a PCDC central biorepository. 781677 +No NIH Category available Bioinformatics;CDK4 gene;CDK9 Protein Kinase;Cells;Cessation of life;ChIP-seq;Chromatin;Clinical;Clinical Research;Clinical Trials;Collection;Complex;Cyclin-Dependent Kinases;DNA Integration;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Modification Methylases;DNA Sequence Alteration;DNA methyltransferase inhibition;Data;Data Analyses;EZH2 gene;Endogenous Retroviruses;Epigenetic Process;Equipment;Gene Expression;Gene Mutation;Genetic Transcription;Genomics;Goals;Human Resources;Immune;Immune checkpoint inhibitor;Immunologic Sensitization;Immunotherapy;Inflammasome;Intervention;Methylation;Mutation Detection;Pathology;Polycomb;Population;Pre-Clinical Model;Principal Investigator;Quality Control;Repetitive Sequence;Research Project Grants;Resources;Sampling;Signal Transduction;Solid Neoplasm;Sorting;Statistical Data Interpretation;T-Lymphocyte;Therapeutic;Tissues;Translational Research;Tumor Tissue;biobank;cancer cell;cancer therapy;data acquisition;data management;data sharing;design;epigenetic therapy;epigenomics;exhaustion;exome sequencing;experimental study;genome-wide;high dimensionality;high throughput analysis;inhibitor;innovation;machine learning algorithm;novel therapeutic intervention;preclinical study;predicting response;prospective;single-cell RNA sequencing;synergism;targeted treatment;transcriptome sequencing;transcriptomics;translational study;tumor Genomics Core NARRATIVEThe Genomics Epigenomics and Bioinformatics Core will provide personnel equipment and expertise tosupport all projects of Epigenetic Therapy SPORE. The Core will be a resource for design and execution ofgenomic and epigenomic experiments data acquisition quality control bioinformatic analysis datamanagement sharing and distribution. The Core will support translational research and clinical trials inepigenetic therapy of cancer. NCI 10696164 7/12/23 0:00 PAR-18-313 5P50CA254897-03 5 P50 CA 254897 3 8/16/21 0:00 6/30/26 0:00 ZCA1-RPRB-7 7827 8604395 "JELINEK, JAROSLAV " Not Applicable 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 231106 130200 100906 Abstract - Genomics Epigenomics and Bioinformatics CoreThe Genomics Epigenomics and Bioinformatics Core will provide personnel equipment and expertise tosupport all projects of the Epigenetic Therapy SPORE. The Core will be a resource for design and execution ofgenomic and epigenomic experiments data acquisition quality control bioinformatic analysis datamanagement sharing and distribution. It will closely cooperate with all SPORE Projects and thePathology/Biospecimen Core. Project 1 studies immune-sensitization by inhibition of cyclin-dependent kinaseCDK9. It will discover whether clinically targetable CDKs are also epigenetic regulators and conduct pre-clinicaland clinical studies of combined epigenetic therapy and immunotherapy using CDK inhibitors DNAmethyltransferase (DNMT) inhibitors and immune checkpoint inhibitors. The Core will analyze (i) geneexpression and chromatin accessibility in tumor and immune cells in preclinical models of tumors treated withCDK9 inhibitors (ii) genome-wide effects of CDK4 6 and 7 inhibition on DNA methylation and geneexpression and (iii) support preclinical studies and a clinical trial combining CDK9 DNMT and immunecheckpoints inhibitors by the analysis of collected samples for transcriptomic and epigenetic parameters (geneexpression and expression of endogenous retroviruses and repetitive elements by RNA-seq DNA methylationby RRBS) and immune cell parameters (gene expression and markers of exhaustion in sorted T cells). TheCore will also perform whole exome sequencing (WES) to determine whether baseline DNA mutation and DNAmethylation profiles predict response. Project 2 is focused on epigenetic synergy between inhibitors of DNMTand Polycomb repressive complex subunits EZH1/2 for therapy in solid tumors. The Core will analyze andintegrate DNA methylation ChIP-seq RNA-seq and WES data to assess the combinatory effects of DNMT andEZH1/2 inhibitors and perform single-cell RNA-seq analysis of the tumor tissue to delineate tumor-associatedimmune populations. Project 3 combines induction of inflammasome signaling by hypomethylating agents withinhibitors of polyADP-ribosylation to induce death of cancer cells. The Core will assess genome-wide andLINE-1 repeat methylation. RNA-seq data will be analyzed for expression of ERVs and other repetitiveelements in tumors and sorted immune cells. +No NIH Category available Address;Administrator;Advocate;Award;Cancer Prognosis;Clinic;Clinical;Clinical Trials;Collaborations;Communication;Complex;Consultations;Data;Decision Making;Development;Electronic Mail;Eligibility Determination;Ensure;Genomics;Grant;Infrastructure;Institution;Interdisciplinary Study;Laboratories;Leadership;Malignant Neoplasms;Medical Research;Minority;Monitor;National Cancer Institute;Outcome;Pathology;Patients;Policies;Preparation;Progress Reports;Protocols documentation;Publications;Quality Control;Regulation;Reporting;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Strategic Planning;Supervision;Therapeutic Studies;Translational Research;United States National Institutes of Health;Woman;Work;cancer care;cancer therapy;career;clinical research site;data sharing;design;epigenetic therapy;experience;improved;interdisciplinary collaboration;lectures;meetings;novel;novel therapeutic intervention;programs;quality assurance;recruit;screening;success;symposium;web site Admin Core PROJECT NARRATIVEThe Administrative Core will provide the support and infrastructure for research and financial oversight; clearand open communications among all SPORE investigators patient advocates and developmental awardees;and regulatory monitoring to optimize the successful outcome of the translational research in epigenetictherapy for cancer. NCI 10696162 7/12/23 0:00 PAR-18-313 5P50CA254897-03 5 P50 CA 254897 3 8/16/21 0:00 6/30/26 0:00 ZCA1-RPRB-7 7826 1888492 "ISSA, JEAN-PIERRE J." Not Applicable 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 400151 225437 174714 PROJECT SUMMARYThe Administrative Core will provide essential support to the Coriell Institute for Medical Research (Coriell) andVan Andel Institute (VAI) Epigenetic Therapy SPORE PIs and investigators to maximize success. It will be co-directed by Drs. Jean-Pierre Issa Stephen Baylin and Peter Jones who co-chair the Executive Committee andprovide overall supervision of three Projects two additional Cores Developmental Research (DRP) and CareerEnhancement (CEP) Programs and scientific direction of the SPORE. The Core Co-Directors will rely on theextensive broad-based scientific research and SPORE experience of the Internal and External Advisory Boardsin critical decision making. An oversight committee consisting of the SPORE PIs and three clinical experts fromthe VAI-SU2C team (Drs. Rudin El-Khoueiry and OConnell) will ensure prioritization of SPORE trials within theVAI-SU2C team and at clinical sites. Success of the complex interdisciplinary research in the SPORE dependson integration of diverse epigenetic therapy research approaches. The Core will overcome barriers tointerdisciplinary collaboration and data sharing and will ensure a unified translational research effort. The SPOREwill be founded on planning integration and translational research efforts supported by this Core. Its leadershipand staff will be responsible for monitoring/planning scientific activities; providing scientific direction; ensuringemphasis on translational research; ensuring interdisciplinary and inter-SPORE integration with major epigenetictherapy programs within/outside Coriell and VAI and other broad translational research activities; and providingoptimal administrative and fiscal management. Specific responsibilities of the Core are: oversee and monitor allSPORE activities; promote integration and communication among the SPORE-related clinical programs; monitorthe scientific integrity of all projects and grant awards; assure compliance with institutional governmental andNational Cancer Institute regulations; oversee the fiscal and budgetary activities of the SPORE; coordinate datacontrol quality assurance issues; coordinate activities associated with clinical trials including design of protocolsapproval by regulatory bodies implementation and eligibility screening and assignment of patients to differentstudies; provide oversight and support for the shared Resources Cores; coordinate and manage meetings of theSPORE Oversight Committee Executive Committee Internal and External Advisory Boards investigatormeetings research meetings lectures and symposia; administer the DRP and the CEP; coordinateinterdisciplinary and inter-SPORE interactions and exchanges/meetings with other Epigenetic Therapy SPOREprograms and investigators and other SPORE programs; administer the activities of the Patient Advocates;comply with and improve policies addressing recruitment and retention of women and minorities; and maintaina Epigenetic Therapy SPORE website focused on issues in epigenetic therapy translational research in cancers. +No NIH Category available Address;Biochemical;Biological Markers;Cancer Patient;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Cultured Cells;Cyclin-Dependent Kinases;DNA Damage;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Modification Methylases;DNA methyltransferase inhibition;Development;Dreams;Drug Combinations;EZH2 gene;Ensure;Enzymes;Epigenetic Process;Funding;Gene Expression;Gene Expression Profile;Generations;Genetic Transcription;Genomics;Goals;Hematologic Neoplasms;Histone Deacetylase;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunologic Monitoring;Immunotherapy;Inflammasome;Interferons;Isocitrate Dehydrogenase;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Mentors;Modification;Molecular;Mus;Nature;Pathology;Patients;Pattern;Pharmaceutical Preparations;Phase I Clinical Trials;Phase I/II Trial;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Regulation;Repetitive Sequence;Repression;Research;Research Personnel;Research Project Grants;Resistance;Running;Science;Signal Transduction;Solid Neoplasm;Testing;Therapeutic;Therapeutic Effect;Therapy Clinical Trials;Tissues;Translational Research;Work;analysis pipeline;cancer cell;cancer therapy;cancer type;career;chemotherapy;chromatin remodeling;clinical application;design;drug action;drug testing;epigenetic drug;epigenetic regulation;epigenetic silencing;epigenetic therapy;immune modulating agents;improved;inhibitor;inhibitor therapy;malignant breast neoplasm;next generation;novel;novel therapeutic intervention;pharmacodynamic biomarker;preclinical study;programs;repaired;response;response biomarker;synergism;targeted treatment;therapy resistant;translational pipeline;translational study;tumor;tumor growth Epigenetic Therapies - New Approaches NARRATIVE (Overall)Epigenetic Therapy aims to treat cancer by blocking enzymes that control regulation of abnormal cellular identityin cancer. In doing so these therapies also make immunotherapies more effective. This SPORE proposal seeksto improve on current epigenetic therapies by exploring new targets new ways of combining epigenetic therapywith other cancer therapies and by designing and running clinical trials of these new strategies. NCI 10696160 7/12/23 0:00 PAR-18-313 5P50CA254897-03 5 P50 CA 254897 3 "UJHAZY, PETER" 8/16/21 0:00 6/30/26 0:00 ZCA1-RPRB-7(M1)P 1888492 "ISSA, JEAN-PIERRE J." "BAYLIN, STEPHEN B.; JONES, PETER A" 1 Unavailable 69894707 XQJNZNQZAFP3 69894707 XQJNZNQZAFP3 US 39.919573 -75.078043 7603801 CORIELL INSTITUTE FOR MEDICAL RESEARCH CAMDEN NJ Research Institutes 81031505 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 2345381 NCI 1840686 504695 ABSTRACT (Overall)Epigenetics refers to stable gene expression patterns mediated by DNA methylation and/or chromatinremodeling and is involved in cellular identity and repression of spurious transcription including from repetitiveelements. Over the past 20 years in work led in part by investigators in this application epigenetic changes wererecognized as important drivers of cancer formation progression and resistance to therapy. This recognitionalong with the reversible nature of the biochemical modifications required for epigenetics led to the field ofEpigenetic Therapy which aims to reprogram gene expression to achieve a therapeutic effect. This field whichstarted with DNA methyltransferase (DNMT) inhibitors has grown to a dozen epigenetic targets and over 30drugs in clinical trials. Four targets have made it to US-FDA approval (DNMTs Histone Deacetylases (HDACs)EZH2 and Isocitrate Dehydrogenases) and tens of thousands of cancer patients benefit from this every year.With the identification of new targets and the recognition that epigenetics is involved in sensitivity and resistanceto chemotherapy and immunotherapy the clinical potential of epigenetic therapy has begun to be explored inearnest. There remain fundamental challenges from the lack of robust biomarkers of activity to the emergenceof resistance and to the unexplained divide in responses between hematologic malignancies and solid tumors.This SPORE application will address all of these challenges. The SPORE team consists of investigators who arepioneers in the fields of cancer epigenetics and epigenetic therapy and explores new epigenetic targets andcombination strategies along with a robust biomarker analysis pipeline to identify patients likely to respond andpharmacodynamic markers of response. The team leverages a strong clinical and translational pipeline builtthrough the Van Andel Institute Stand Up To Cancer Epigenetics Dream Team which has conducted 14epigenetic therapy clinical trials in the past few years and is fully committed to the clinical trials proposed in thisapplication. This Epigenetic Therapy SPORE encompasses four major themes: (i) Develop and test drugsagainst new epigenetic targets (Projects 1 2) (ii) Mechanistic and translational studies of immunosensitizationby epigenetic therapy (projects 1-3) (iii) Studies of drug combinations that enhance the efficacy of knownepigenetic drugs (projects 1-3); and (iv) Biomarker studies to define sensitivity and resistance to epigenetictherapy in the clinic (all Projects). These themes will be addressed through 3 projects: (i) Cyclin DependentKinases as Epigenetic Therapy Targets; (ii) Epigenetic synergy between DNMT and EZH1/2 inhibitors; (iii)Linking epigenetic-therapy induction of inflammasome signaling to generation of a BRCAness phenotype. Theseprojects will be supported by three cores (administrative pathology genomics) and a key goal will also be tomentor the next generation of Epigenetic Therapy investigators and support cutting-edge science through theCareer Enhancement and Developmental Research Programs. 2345381 +No NIH Category available Alternative Splicing;B-Cell Activation;B-Cell Development;B-Cell NonHodgkins Lymphoma;B-Lymphocyte Subsets;B-Lymphocytes;Blood;Bodily secretions;C-terminal;Cell Cycle;Cell Maturation;Cell physiology;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Cysteine;DNA Damage;Data;Defect;Development;Disease;Disease Progression;Evolution;Frameshift Mutation;Future;Genes;Genetic;Genetic Transcription;Goals;Lead;Length;Lymphoid;Lymphoma;Lymphoma cell;Lymphomagenesis;Malignant Neoplasms;Mantle Cell Lymphoma;Mantle Zone;Messenger RNA;Modeling;Molecular;Mus;Mutant Strains Mice;Mutate;Mutation;Non-Hodgkin's Lymphoma;Nonsense Codon;Pathogenesis;Pathway interactions;Patients;Phenotype;Plasma Cells;Population;Proliferating;Protein Splicing;Proteins;Proteomics;Publishing;RNA Splicing;Role;Sampling;Signal Transduction;Spleen;Spliceosomes;Structure of germinal center of lymph node;Survival Rate;System;Technology;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Ubiquitin;Up-Regulation;cohort;conditional mutant;drug discovery;effective therapy;functional disability;insight;knock-down;lymph nodes;migration;mouse model;multicatalytic endopeptidase complex;mutant;new therapeutic target;next generation sequencing;novel;overexpression;protein degradation;protein expression;scaffold;therapeutic target;tool;tumor;ubiquitin-protein ligase Dissecting the Role Ubiquitin E3 Ligase UBR5 in Lymphomagenesis NarrativeThe ubiquitin E3 ligase UBR5 is one of the most commonly mutated genes (~18%) in mantle cell lymphoma(MCL) with the majority of mutations identified in UBR5 were frame shift mutations found within the HECTdomain. Here we will study the molecular function of ubiquitin E3 ligase UBR5 mutations in lymphomagensis.Deciphering the role of the UBR5 and pathways dysregulated by mutations in mantle cell lymphoma willprovide clues to lymphoma transformation with the goal of identifying targets for future therapeutics. NCI 10696146 7/31/23 0:00 PA-20-185 5R37CA262635-03 5 R37 CA 262635 3 "JHAPPAN, CHAMELLI" 8/1/21 0:00 7/31/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10974463 "BUCKLEY, SHANNON " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 400180 NCI 275321 124859 ABSTRACTMantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkins lymphoma. Unfortunately limitedtherapies for MCL are currently available suggesting a need to further unravel molecular mechanismsregulating transformation and progression of the disease. The majority of MCL patients have a t(11;14)translocation leading to overexpression of CyclinD1 resulting in extensive proliferation and block indifferentiation originating in the mantle zone of the lymph node however additional mutations are necessary fortransformation. Next generation sequencing has identified a number of novel mutations in MCL patientsincluding the ubiquitin E3 ligase UBR5. E3 ubiquitin ligases serve as the substrate-recognizing component forprotein degradation by the ubiquitin proteasome system. In a cohort of 196 MCL patients UBR5 was the 3rdmost frequently mutated gene and ~60% of the mutations were found within the HECT domain of UBR5 whichcan accept and transfer ubiquitin molecules to the substrate. In order to understand the role of UBR5 HECTdomain in B-lymphoid development we generated a conditional mouse using novel CRISPR/Cas 9 technology.Loss of the HECT domain leads to a block in pre-germinal center B cells in the spleen with a reduction of bothB1 and marginal B cell subsets. In addition follicular B cells in the spleen are phenotypically abnormal and failto terminally differentiate to anti-body secreting plasma cells. Proteomic studies reveal up-regulation of proteinsassociated with mRNA splicing via the spliceosome in B cells lacking the HECT domain of UBR5. Thesestudies suggest that 1) cooperation of UBR5 mutations along with expression of cyclinD1 may led to diseaseprogression of mantle cell lymphoma (Aim 1) 2) understanding molecular mechanism of UBR5 mutationscould provide potential therapeutic targets in MCL (Aim 2) and 3) aberrant expression of U5 spliceosomeproteins block B cell maturation and promote lymphomagenesis (Aim 3). In this application we propose studiesto understand the role of UBR5 and its interacting proteins in B-cell lymphomagenesis and define molecularpathways regulated by UBR5 in B-cells. Our goal of the proposed studies is to provide insights to mantle celllymphoma transformation progression and potential future therapeutics targets. 400180 +No NIH Category available APC Vaccine;Adhesions;Adjuvant;Affect;Animal Testing;Antibodies;Antigen Presentation;Antigen-Presenting Cells;Antigens;Area;Autoantigens;Autologous;Back;Binding;Biological;Blood;Breast Cancer Patient;CD28 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cell Adhesion Molecules;Cell Size;Cell membrane;Cells;Complex;Consumption;Cytoskeleton;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Emulsions;Engineering;Engraftment;Evaluation;Formulation;Goals;Grant;Hydrogels;Immune system;Immunologic Memory;In Vitro;Incubated;Individual;Influenza;Integral Membrane Protein;Integrins;Interferon Type II;Ligands;Lipid Bilayers;Malignant Neoplasms;Mechanics;Membrane;Methods;Microfluidic Microchips;Microfluidics;Modeling;Molecular;Mus;Patients;Peripheral Blood Mononuclear Cell;Process;Production;Proliferating;Proteins;Specificity;Synapses;T cell response;T cell therapy;T-Cell Activation;T-Lymphocyte;TNF gene;Testing;Time;Tumor Antigens;Tumor Expansion;Vaccination;antigen-specific T cells;cancer immunotherapy;cell preparation;cytotoxic CD8 T cells;efficacy evaluation;fighting;immunological synapse;in vivo;in vivo evaluation;malignant breast neoplasm;manufacturing scale-up;mechanical properties;melanoma;neoplastic cell;response;scale up;tumor;tumor eradication;tumor microenvironment;tumor progression;unilamellar vesicle Microfluidic Precision Engineered Artificial Antigen Presenting Cells for Cancer Immunotherapy PROJECT NARRATIVEImmunotherapy of cancer using cells is an expensive and cumbersome process. The present project aims atdeveloping artificial cells that can be produced inexpensively via microfluidic engineering based methods. Theseartificial cells will be developed to activate T cells in vivo to boost its capability to fight cancer. NCI 10696138 7/24/23 0:00 RFA-CA-21-004 5R33CA267258-02 5 R33 CA 267258 2 "MCKEE, TAWNYA C" 9/2/22 0:00 8/31/25 0:00 ZCA1-TCRB-D(M1) 7745390 "LEE, ABRAHAM P." "AGRAWAL, ANSHU " 47 ENGINEERING (ALL TYPES) 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA BIOMED ENGR/COL ENGR/ENGR STA 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 373718 NCI 244022 129696 AbstractThe goal of cancer immunotherapy is to build long-lasting tumor-specific immunologic memory in patients thatenables the lifelong rejection of tumors. The two prominent types of antigen-specific cancer immunotherapyadoptive T cell therapy and APC-based vaccination both require expansion of anti-tumor T cells via APCs.However for the purpose of effective adoptive T cell therapy the critical question is how to generate within ashort period of time large numbers of antitumor T cells. Furthermore in vitro-expanded T cells must also possessthe capacity to engraft proliferate and persist in vivo with sufficient antitumor function to induce sustainedantitumor activity. Autologous antigen-presenting cells (APCs) such as DCs also have several serious limitations.The necessity to access large amounts of cancer patients blood to prepare autologous APC from each patientin a timely manner is cumbersome. To overcome these problems we developed the microfluidic process togenerate cell-sized unilamellar vesicles (CUVs) and decorated them with antigen presenting ligands for artificialAPCs (or aAPCs). Preliminary results show that aAPCs are able to bind and interact with T cells and cause theirexpansion. The objective of the present proposal is to further optimize the aAPCs preparation and test itscapacity to induce tumor specific responses in vitro and in vivo. The hypothesis is that the optimized aAPCfunctionalization will result in enhanced expansion of cytotoxic CD8 T cells and a reduction in tumor progressionover the present one (original). The Specific Aims are- 1) Bioinspired optimization of artificial antigen presentingcell (aAPC) production via microfluidic engineering. We will insert the antigen presenting ligands in themembrane to mimic cells. The aAPCs will also be produced with hydrogel cytoskeletons to optimize itsmechanical properties for maximum T cell expansion. 2) Evaluation of the capacity of aAPCs to induce tumorspecific T cell responses in vitro. Using PBMCs from healthy donors and breast cancer patients we will evaluatethe capacity of aAPCs to induce cytotoxic T cells. 3) Evaluation of the capacity of aAPCs to induce T cellresponses and tumor killing with an in vivo mice tumor model. Methods to scale up the production of aAPCs forin vivo use will be developed. The capacity of aAPCs to kill tumor in vivo in mice will also be determined using amelanoma model. The goal is to produce an aAPC preparation that mimics cells is stable easy to produce inlarge quantities and capable of expanding tumor specific CD8 T cells for immunotherapy of cancer. 373718 +No NIH Category available Award;Brain Neoplasms;Cancer Center;Communication;Data;Development;Funding;Future;Glioma;Goals;Infrastructure;Institution;Measures;Monitor;Outcome;Patients;Pilot Projects;Process;Program Research Project Grants;Progress Reports;Request for Proposals;Research;Research Project Grants;Scientist;experience;innovation;programs;synergism;targeted treatment;translational potential Dev-Res-Prog-001 The Developmental Research Program supports innovative pilot studies that will generate feasibility data andthat have the potential to emerge as full SPORE projects with possible future benefit for brain tumor patients. NCI 10696110 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7823 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 92136 52318 41332 The objective of the Glioma SPORE Developmental Research Program (DRP) is to identify innovative pilotresearch projects in glioma that have translational potential. The DRP utilizes a solicitation and review processto select meritorious pilot projects for funding. The solicitation process capitalizes on an established extensiveDana-Farber/Harvard Cancer Center (DF/HCC) communications infrastructure to widely disseminate an annualRequest for Proposals (RFP). The review process utilizes an experienced panel of DF/HCC glioma scientists.The DRP provides limited-duration funding for innovative projects that have ultimate translational potential andcould synergize with existing SPORE projects and cores. DF/HCC institutions match DRP funding from thisSPORE to expand the pool of DRP awardees. The DRP applications are judged for their potential as pilot orcollaborative studies that will generate feasibility data and for their ultimate potential to emerge as full projectsin future years of the SPORE program. The DRP employs a monitoring process to measure progress andoutcomes of DRP projects including the possible elevation of successful DRP awards to full projects. Theprogram is closely monitored through clearly established metrics and oversight by the DRP AwardsCommittee. DRP awardees are required to present biannual progress reports. +No NIH Category available Award;Dana-Farber Cancer Institute;Faculty;Funding;Glioma;Grant;Institution;Measures;Mentored Clinical Scientist Development Program;Mentors;Minority;Monitor;Outcome;Patients;Phase;Process;Program Development;Research;Research Personnel;Research Support;Resources;Source;System;Talents;Teacher Professional Development;Training;Training Programs;Woman;career;cohort;experience;faculty mentor;interest;member;multidisciplinary;neuro-oncology;programs;success;targeted treatment;translational scientist Career-Enh-Prog-001 The Career Enhancement Program provides research support for junior or new investigators in the field ofglioma research. Through support mentoring and monitoring the program enables awardees to embark onsuccessful careers in glioma research that will ultimately benefit patients. NCI 10696109 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7822 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 92136 52318 41332 The primary objective of the Glioma SPORE Career Enhancement Program (CEP) is to attract talented newinvestigators to translational glioma research. Potential CEP awardees include junior faculty beginning theircareers or established faculty members in other fields who wish to redirect their interests and efforts to gliomaresearch. We will maintain a comprehensive system-wide process for solicitation of CEP applications and anexpert-based review process to select the most meritorious applicants. The CEP program faculty consists of amultidisciplinary cohort of experienced senior mentors for CEP awardees. The CEP provides limited-durationfunding for promising junior translational investigators who are focused on glioma research. The program willprovide support mentoring and monitoring for CEP awardees. We will maintain a monitoring process tomeasure progress and outcomes of CEP awardees and the CEP program. We carefully monitor the progressof CEP awardees through clearly enumerated metrics on a biannual basis. The overall Career EnhancementProgram is assessed on an annual basis by the internal and external advisory boards. The CEP leveragesinstitutional resources to support and enhance the success of the program. +No NIH Category available Adult Glioma;Agar;BRAF gene;Biological Markers;Biological Specimen Banks;Blood;CDK4 gene;Cancer Center;Cell Communication;Cell Line;Cells;Childhood Glioma;Clinical;Clinical Data;Clinical Trials;Collection;Consent;Cytometry;Data;Development;Engineering;Ensure;Evaluation;Expression Profiling;Fingerprint;Genetic Transcription;Genetically Engineered Mouse;Genomics;Glioblastoma;Glioma;Goals;Human;Image;Imaging Techniques;Immune;Immunohistochemistry;Immunotherapy;In Situ;Institution;Methods;Modeling;Mus;Mutation;Neoplasm Circulating Cells;Outcome;PD-1 inhibitors;Pathology;Patients;Pharmaceutical Preparations;Pilot Projects;Play;Proteins;RB1 gene;Reproducibility;Research Personnel;Research Project Grants;Resistance;Resources;Role;SNP array;Sampling;Services;Slide;Specimen;Technology;Testing;Tissue Sample;Tissues;Translational Research;Xenograft Model;Xenograft procedure;biobank;blood-brain barrier penetration;co-clinical trial;comparative genomic hybridization;drug distribution;examination questions;glioma cell line;human tissue;improved;inhibitor;innovation;innovative technologies;insight;liquid biopsy;mass spectrometric imaging;molecular targeted therapies;multiplexed imaging;mutant;neoplastic cell;neuropathology;new therapeutic target;next generation sequencing;patient derived xenograft model;peripheral blood;preclinical trial;programs;protein expression;response;response biomarker;single-cell RNA sequencing;success;targeted treatment;tissue resource;transcriptome sequencing;tumor Pathology - Core A The goal of the Pathology Core is to provide expert services and support to the Projects of the SPORE. TheCore will collect tissue samples and clinical data from patients with gliomas and distribute these to theinvestigators in the program. The Core will create cell lines and mouse tumor models from tumors for use inthe research of the Projects. The Core will perform sequencing of gliomas as well as perform innovativeservices to look at drug distribution and circulating tumor cells in the blood of patients to see if they respond totargeted therapies. NCI 10696107 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7821 6885500 "LIGON, KEITH LLOYD" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 309147 249836 66540 The overall goal of this SPORE application is to develop more effective targeted molecular therapies andbiomarkers for glioblastoma. The four proposed projects of the SPORE focus on 1) targeted therapeutics totreat BRAF-mutant pediatric gliomas; 2) development of improved targeted therapies for IDH-mutant gliomas;3) combining targeted CDK4/6 inhibitors with immunotherapies to treat glioblastoma; and 4) evaluation ofNlgn3 as a novel therapeutic target in gliomas. The Pathology Core will support the goals of these SPOREProjects by providing expert neuropathologic review specimen banking genomic analysis and clinical trialsupport. In addition the Pathology Core will be a centralized resource for validated patient derived cell linesand xenografts of gliomas. The Core will also offer innovative CyTOF on a slide multiplex imaging (MIBI) massspectrometry imaging of drug distribution within tissue sections and liquid biopsy of circulating tumor cells(CTC) to determine responses to targeted therapies in clinical trials. By centralizing these activities thePathology Core will ensure the reproducibility of data and effective use of finite glioma tissue resourcesessential to the collaborative translational research of the SPORE program. +No NIH Category available Animals;Area;Bioinformatics;Biological Markers;Biometry;Clinical;Clinical Protocols;Clinical Trials;Code;Collaborations;Computational Biology;Computing Methodologies;Consult;Consultations;Data;Data Analyses;Data Collection;Data Science;Data Set;Databases;Dedications;Development;Event;Extramural Activities;Fostering;Funding;Futility;Genomics;Glioma;Grant;Guidelines;Health protection;Human;Image;Investigation;Laboratories;Laboratory Study;Leadership;Manuscripts;Measurement;Medical;Methodology;Methods;Mission;Modeling;Molecular;Monitor;Outcome;Pathology;Patients;Pre-Clinical Model;Preparation;Process;Proteomics;Reporting;Reproducibility;Research;Research Personnel;Resources;Role;Safety;Security;Statistical Data Interpretation;Statistical Methods;Statistical Models;Techniques;Time;Tissues;Translating;United States National Institutes of Health;Variant;Work;anticancer research;clinical translation;clinical trial analysis;complex data;cost;data exchange;data management;data resource;design;experimental study;high standard;indexing;laboratory experiment;metabolomics;novel;pre-clinical;programs;research study;scientific hub;symposium;targeted treatment;translational study Biostatistics and Computational Biology Core - Core B The Biostatistics and Computational Biology Core will provide statistical and computational biologyexpertise to the glioma SPORE research program in the areas of planning design conduct analysis andreporting of laboratory experiments clinical trials and translational studies. NCI 10696106 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7820 8219484 "LONDON, WENDY BETH" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 156285 132299 27814 This Glioma SPORE will require statistical and bioinformatics collaboration on a wide variety of researchranging from pre-clinical models to human studies. The mission of the Biostatistics and ComputationalBiology Core of this glioma SPORE is to foster rigor and reproducibility. Towards this end the core will workwith project leaders to insure statistical integrity in the design of their experiments and interpretation of theirdata. The Biostatistics and Computational Biology Core will function as a scientific hub to facilitate interandintra- SPORE collaborations between all Projects and with the Pathology Core. The core will advise on allissues related to data collection analysis and interpretation. The core will provide 1) ready and dedicatedresources for database and computing requirements 2) consultation and expertise on the development andimplementation of plans for data collection particularly the coding convention and variable format required forstatistical analysis 3) advice on the data management plan including form design and database requirementsduring development of the SPORE-related clinical trials 4) expertise and resources for data transfer mergingsharing and security while maintaining the confidentiality of all patient-related protected health information 5)statistical expertise for the design planning and conduct of preclinical experiments clinical trials andcorrelative tissue and biomarker studies 6) analysis of the clinical trials and interim monitoring and analysis ifnecessary including the stopping rules for safety and futility 7) statistical and bioinformatics expertise forinference and interpretation of research studies including manuscript preparation. +No NIH Category available Academic Medical Centers;Administrator;Adult;Adult Glioma;Age Years;Cancer Center;Cancer Etiology;Cessation of life;Childhood Glioma;Clinical;Clinical Trials;Collaborations;Communication;Communication Programs;Electronics;Female;Foundations;Funding;Gender;Glioma;Grant;Human Resources;Image;Infrastructure;Institution;Leadership;Malignant Neoplasms;Minority;Monitor;Persons;Positioning Attribute;Preparation;Primary Brain Neoplasms;Protocols documentation;Research;Research Design;Research Personnel;Role;Series;Specialized Program of Research Excellence;Structure;Translational Research;Underrepresented Minority;Woman;Work;clinical imaging;design;experience;imaging scientist;imaging study;improved;meetings;member;multidisciplinary;patient population;pediatric patients;programs;standard of care;success;targeted treatment Administration - Core C "Primary brain tumors including high-grade gliomas are the third leading cause of cancer-related death amongall persons 15-39 years of age (http://www.CBTRUS.org). In the fullness of time the work that we propose withtargeted therapies could change the standard of care and improve adult and pediatric patients with gliomas.The Administration Core serves as the ""hub"" for the governance of this SPORE research program." NCI 10696105 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7819 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 333279 216882 122673 This Specialized Program of Research Excellence (SPORE) grant is intended to support multi-projectinterdisciplinary and multi-institutional translational research in glioma. The governance structure of this Dana-Farber/Harvard Cancer Center (DF/HCC) SPORE grant provides the foundation for the implementationexecution and ultimate success of all projects and cores. The Administration Core serves as the hub for thisgovernance structure and aims to achieve a number of specific objectives as defined below. We will execute aplan that provides experienced centralized program leadership and administration. The Glioma SPOREDirector and Co-Director are senior administrators institutional leaders and researchers who have workedtogether on the current funding period for this SPORE and on prior DF/HCC initiatives and consequentlyprovide consistent strong complementary leadership for the grant. The trans-institutional administrative teamconsists of senior personnel at DF/HCC institutions who have worked together effectively in the current fundingperiod of this grant. We will expand our management to an external funded component (Project Four) of theSPORE at Stanford University Medical Center and to both adult and pediatric patient populations. Wemaintain two senior clinical and imaging scientists in the Administration Core to supervise Glioma SPOREspecificclinical trials and Glioma SPORE-specific imaging studies respectively and to enable this GliomaSPORE to capitalize on existing DF/HCC P30 Cores to support these types of studies. We have establishedand utilized an effective internal and external committee structure to provide multidisciplinary expertise adviceand oversight of the program. Each of the committees consists of collaborative complementary members whohave worked together in the current funding period of this SPORE or on prior projects. A series of regularGlioma SPORE meetings involving both administrative and scientific SPORE personnel will continue tofacilitate close collaboration troubleshooting and monitoring of the SPORE program. We will continue andexpand an effective internal and external communications program which includes a Glioma SPORE-specificcomponent. An established and extensive DF/HCC communications infrastructure is utilized to promote openregular trans-institutional communication regarding SPORE opportunities and activities. We will reinforce anactive SPORE program to enhance participation by underrepresented minorities and women. +No NIH Category available 3-Dimensional;Address;Aftercare;Age;Anabolism;Autophagocytosis;Basic Science;Biological Markers;Biological Models;Blood - brain barrier anatomy;Brain Glioblastoma;Brain Neoplasms;Cancer Therapy Evaluation Program;Categories;Cell Survival;Cells;Chemotherapy and/or radiation;Clinical;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Collection;Complement;Consumption;Critical Pathways;DNA;DNA Repair;Data;Dependence;Development;Dihydroorotate Dehydrogenase Inhibitor;Dihydroorotate dehydrogenase;Dioxygenases;Drug Targeting;Ensure;Enzymes;Epigenetic Process;Excision;Family;Funding;Genes;Genetic;Genomics;Glioblastoma;Glioma;Glutamates;Glutaminase;Goals;Hypersensitivity;Hypoxia;Image;Imaging Techniques;Imaging technology;Isocitrate Dehydrogenase;Magnetic Resonance Spectroscopy;Malignant - descriptor;Malignant Neoplasms;Maps;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methodology;Mission;Mixed Function Oxygenases;Modeling;Molecular;Monitor;Mutation;Oncogenes;Oncogenic;Oncoproteins;Operative Surgical Procedures;Outcome;PARP inhibition;Pathogenesis;Patient Monitoring;Patients;Pharmacodynamics;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Pre-Clinical Model;Procollagen-Proline Dioxygenase;Production;Protocols documentation;Public Health;Pyrimidine;Pyrimidine Nucleotides;Radiation therapy;Radiosensitization;Recurrence;Ribose;Role;Safety;Scanning;Screening Result;Signal Transduction;Techniques;Testing;Therapeutic;Tumor Burden;United States National Institutes of Health;Variant;Work;alpha ketoglutarate;brain tissue;cancer cell;cytotoxicity;design;detection method;enzyme pathway;epigenome;histone demethylase;homologous recombination;imaging biomarker;improved;in vivo;inhibitor;insight;leukemia;magnetic resonance spectroscopic imaging;member;mutant;mutational status;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;participant enrollment;patient response;pharmacologic;pre-clinical;programs;response;satisfaction;screening;small molecule;small molecule libraries;spectroscopic imaging;targeted treatment;therapeutically effective;treatment response;tumor;tumor growth Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin) Genomic sequencing studies carried out over the past decade have revealed that the vast majority of lowgradeglioma and secondary glioblastoma brain tumors share a single common mutation in the metabolicenzyme IDH1 that causes aberrant accumulation of a small molecule metabolite termed 2HG. We seek toleverage this new insight by developing imaging technology to directly measure 2HG content in brain tissueand identifying new effective therapeutic strategies that exploit vulnerabilities unique to IDH1 mutant gliomas.These tumors are more common in patients younger than age 45 and therefore the work is highly relevant tothe NCI mission and public health. NCI 10696101 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7816 1902302 "CAHILL, DANIEL P." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 283553 292004 0 Discovery of a recurrent hotspot IDH1 mutation in the vast majority of low-grade gliomasand secondary glioblastomas has revolutionized our understanding of the molecular pathogenesis of thesemalignancies. The canonical glioma-associated IDH1 mutation encodes a mutant isocitrate dehydrogenaseenzyme IDH1 R132H that gains the neomorphic ability to convert 2-oxoglutarate (2-OG) to theoncometabolite R-2-hydroxyglutarate (2-HG). Consequently 2-HG accumulates to millimolar levels in IDH1mutant gliomas representing a 100- to 1000-fold increase relative to normal brain tissue. The structuralsimilarity between 2-HG and 2-OG enables 2-HG to competitively modulate the activity of many 2-OGdependentdioxygenases including JmjC family histone demethylases TET family DNA hydroxylases and thehypoxia-responsive prolyl hydroxylase EglN1. Studies from our group and others demonstrate fundamentalroles for epigenetic rewiring and HIF1alpha suppression in the oncogenic program induced by IDH1 mutationsin glioma. Although our understanding of the function of the IDH1 R132H oncoprotein has expandedtremendously successful exploitation of the inherent difference in 2-HG content between normal andmalignant brain tissue to improve clinical outcomes has not yet been realized. Our proposal seeks to addressthis impediment to progress in two ways.First we aim to use 2-HG as a biomarker of IDH mutational status and optimize methodology toquantify this metabolite non-invasively through magnetic resonance spectroscopy (MRS) imaging. Wehypothesize that MRS-generated 3D maps of 2HG concentration could be used as a complement to traditionalT2/FLAIR imaging to enable more precise delineation of tumor boundaries and yield improvements in theefficiency of surgical resection and the quantification of therapeutic responses in glioma patients. Furthermore2HG 3D MRS imaging represents an ideal approach to assess pharmacodynamic responses in patientsenrolled in ongoing clinical trials of IDH targeting therapeutics.Second we aim to develop novel therapeutic strategies designed to preferentially eradicate IDH1mutant glioma cells by targeting vulnerabilities engendered by high 2-HG accumulation. Pharmacologicalinhibitors of mutant IDH enzymes have shown remarkable activity in IDH mutant leukemia but early clinicaldata suggest that such inhibitors will be considerably less active in IDH mutant gliomas. An alternativeapproach to directly targeting mutant IDH enzymes entails the exploitation of synthetic lethality with the IDH1-R132H oncogene. We have undertaken orthogonal hypothesis-driven and screening-based approaches toidentify NAD+ metabolism and de novo pyrimidine synthesis as targetable vulnerabilities in IDH1 mutant gliomacells. We propose to evaluate the safety and efficacy of targeting these metabolic pathways in preclinicalmodels of IDH1 mutant glioma to establish rationale for clinical studies of these novel therapeutic strategies. +No NIH Category available Adult;Animals;Astrocytoma;BRAF gene;Biological Assay;Biomedical Engineering;Brain;Brain Neoplasms;CDKN2A gene;Cell Culture Techniques;Child;Childhood;Childhood Malignant Brain Tumor;Chimeric Proteins;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Daphne plant;Development;Disease Progression;Doctor of Medicine;Doctor of Philosophy;Drug Targeting;Excision;Funding;Fusion Oncogene Proteins;Ganglioglioma;Generations;Genetic;Genetically Engineered Mouse;Glioma;Grant;Hydrogels;Imatinib;In Vitro;Juvenile Pilocytic Astrocytomas;KRAS2 gene;MAP Kinase Gene;MEKs;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Medicine;Minor;Mitogen-Activated Protein Kinases;Monitor;Morbidity - disease rate;Mus;Mutate;Mutation;Oncogenes;Oncogenic;Oncology;Oncoproteins;Operative Surgical Procedures;Organoids;PTEN gene;Pathology;Pathway interactions;Patients;Pediatric Neoplasm;Pediatric cohort;Penetrance;Penetration;Peripheral Blood Lymphocyte;Pharmaceutical Preparations;Phase;Phospho-Specific Antibodies;Phosphorylation;Phosphotransferases;Point Mutation;Primary Neoplasm;Protein Kinase;Proteins;Protocols documentation;RAS inhibition;Ras/Raf;Recurrence;Research;Research Personnel;Resected;Scientist;Series;Signal Transduction;Signal Transduction Inhibitor;Solid Neoplasm;Specimen;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;System;Testing;Transformed Cell Line;Trastuzumab;Tube;Tumor Tissue;Variant;Visualization;Work;antagonist;chemotherapy;clinical material;counterscreen;drug development;experience;inhibitor;innovation;kinase inhibitor;melanoma;member;mutant;neoplastic cell;nerve stem cell;neuro-oncology;novel;pharmacokinetics and pharmacodynamics;precision medicine;protein purification;reconstitution;response;small molecule;spectroscopic imaging;standard of care;structural biology;targeted treatment;tumor;virtual Project 1--Targeted therapies for pediatric low-grade astrocytoma (Eck/Wright/Haas) Low-grade astrocytomas are the most common brain tumor in children. Current standard of care (surgery andchemotherapy) has limited efficacy and treatment-related morbidity is significant. The broad objective of thisresearch is to develop potent brain-penetrant targeted therapies (a.k.a. smart drugs) for children with thesetumors. NCI 10696099 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J 7815 2793446 "ECK, MICHAEL J" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 308692 308424 9194 Project Summary/Abstract Low-grade astrocytomas are the most common brain tumor in children.Standard of care therapies have limited efficacy and treatment-related morbidity is significant. The broadobjective of our study plan is to develop potent brain-penetrant targeted therapeutics for pediatric low-gradeastrocytoma (PLGA). Towards this end mutated constitutively active forms of the BRAF protein kinase areexpressed in ~75% of all PLGAs and are attractive targets for drug development. A minor cohort of PLGAsexpress V600E BRAF - a point mutation oncoprotein that is a frequent driver of malignant melanoma in adultpatients. More commonly PLGAs express a truncation/fusion oncoprotein known as KIAA1549:BRAF. Smallmolecule type 1 RAF inhibitors developed for adult melanoma have poor brain penetrance and are moreoverineffective antagonists of KIAA1549:BRAF. Against this backdrop we have three specific aims:Aim 1 is to examine the clinical activity of TAK-580 in progressive BRAF-mutant PLGAs. Underauspices of this SPORE we showed that TAK-580 (a clinical stage type 2 RAF inhibitor) has good brainpenetrance and targets both forms of the BRAF oncoprotein. A phase 0/I/II trial of TAK-580 in children withBRAF mutant low-grade gliomas tumors has been initiated. Using clinical materials from the phase I and IIcomponents of the trial we will establish the pharmacokinetics and pharmacodynamics of TAK-580 in childrenrelative to adult patients where the drug has been previously evaluated. In the Phase 0 component of this trialwe will directly measure drug penetration into tumors.Aim 2 is to define the impact of cellular and genetic modifiers on response of PLGAs to TAK-580. Aninconvenient truth in precision medicine is that target expression does not guarantee responsiveness to atargeted therapeutic. For example type 1 RAF antagonists are effective inhibitors of V600E BRAF inmelanoma but are ineffective on the same oncoprotein in colon cancers. Accordingly as the TAK-580 clinicaltrial goes forward we will conduct a series of in vitro avatar trials on primary patient tumor cells grown in asynthetic hydrogel system developed in collaboration with a bioengineering group at MIT. This system issimilar to organoid systems developed for other solid tumors.Aim 3 is to develop second generation brain-penetrant drugs for BRAF-mutant PLGA with enhancedselectivity for KIAA1549:BRAF. TAK-580 targets both forms of the BRAF oncoprotein but WT BRAF is alsoinhibited by the drug. Thus TAK-580 is a signal transduction inhibitor but not a true targeted therapeutic.Although signal transduction inhibitors can be highly efficacious cancer medicines (e.g. imatinib ortrastuzumab) a drug that is truly mutant-specific would be preferable for growing children. By far the mostcommon form of BRAF oncoproteins in PLGA is a truncation/fusion protein known as KIAA1549:BRAF. In thisaim we take a mechanism-based approach to development of a drug that selectively targets KIAA1549:BRAF. +No NIH Category available 3-Dimensional;Address;Adjuvant;Adult;Adult Glioblastoma;Adult Glioma;Age;Agreement;Astrocytoma;Award;BRAF gene;Basic Science;Biology;Biometry;Boston;Brain;Brain-Derived Neurotrophic Factor;CDK4 gene;Cancer Center;Cancer Etiology;Cell Cycle Arrest;Cell Cycle Progression;Cells;Cessation of life;Child;Child Care;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Clinical;Clinical Trials;Collaborations;Complement;Computational Biology;Cyclin D1;Dana-Farber Cancer Institute;Daphne plant;Development;Diagnosis;Doctor of Medicine;Doctor of Philosophy;Enzymes;Excision;Fostering;Funding;General Hospitals;Genetic;Genetically Engineered Mouse;Glioblastoma;Glioma;Growth;Hospitals;Human;Image;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotherapy;Independent Living;International;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Massachusetts;Metabolic;Methods;Modality;Molecular;Mutation;Nature;Neurons;Neurosurgeon;Oncologist;Operative Surgical Procedures;Pathology;Patient-Focused Outcomes;Patients;Pediatric Hospitals;Persons;Pharmaceutical Preparations;Pharmacology;Phosphorylation;Primary Brain Neoplasms;Protein Isoforms;Protein Kinase;Protein-Serine-Threonine Kinases;Quality of life;Recurrence;Reproducibility;Research Personnel;Research Project Grants;Resected;Science;Scientist;Signal Transduction;Structural Biologist;Survivors;Talents;Teaching Hospitals;Testing;Therapeutic;Time;Tumor Immunity;Tumor Tissue;Universities;Variant;Woman;Work;alpha ketoglutarate;antagonist;brain tissue;career;cell type;childhood cancer mortality;clinical imaging;efficacy study;flexibility;humanized mouse;imaging study;improved;in vivo;inhibitor;innovation;leukemia;medical schools;melanoma;mouse model;mutant;neuro-oncology;neuroligin 3;novel;novel strategies;novel therapeutics;professor;programmed cell death protein 1;programs;response;single cell sequencing;skills;small molecule;standard of care;targeted treatment;tool;translational scientist;tumor;tumor growth;tumor microenvironment;young adult SPORE: Targeted Therapies for Glioma NarrativePrimary cancers of the brain have surpassed leukemias as the number one cause of cancer-related death inchildren and low-grade astrocytomas are the most common brain tumor of childhood. Pediatric low-gradeastrocytomas (PLGAs) are survivable with current standard of care. However the quality of life for long-termPLGA survivors and their capacity for independent living is compromised to a significant degree. Targetedtherapeutics for PLGA are urgently needed. The work proposed for Project One has the potential to deliverbrain-penetrant targeted therapies for these tumors. Primary brain tumors including high-grade gliomas arethe third most common cause of cancer-related death in persons ages 15-39 years (http://www.CBTRUS.org).In the fullness of time the work proposed for Projects Two and Three could change the standard of care andimprove patient outcomes for these tumors via highly selective synthetic lethal therapeutic modalities(Project Two) or small molecule adjuvants to immunotherapy (Project Three). Project Four addresses aunique feature in the biology of high-grade gliomas. These tumors occur within the context of the brainmicroenvironment. Preliminary studies have shown that neuronal activity within the glioma microenvironmentsecrete a factor (NLGN3) that promotes the growth of these tumors in adults and also in children. The studyplan for this project will explore a novel therapeutic opportunity embedded within the NLGN3 requirement. NCI 10696098 8/21/23 0:00 PAR-18-313 5P50CA165962-10 5 P50 CA 165962 10 "HUBBARD, LEAH" 9/19/13 0:00 8/31/24 0:00 ZCA1-RPRB-J(M1) 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2207927 NCI 1866038 395890 This is the competing renewal of a SPORE initiative on glioma at Dana-Farber/Harvard Cancer Center. Ourobjective is to improve the standard of care for children young adults and adults with these tumors throughthe use of targeted therapies. Towards this end basic scientists from Harvard Medical School and the BroadInstitute join with clinical/translational investigators from Boston Childrens Hospital Brigham and WomensHospital Dana-Farber Cancer Institute and Massachusetts General Hospital. There are four projects: Project One targets pediatric low-grade astrocytomas (PLGAs). Nearly 75% of PLGAs are driven byactivating mutations in the BRAF protein kinase. Clinician/scientists Daphne Haas-Kogan M.D. and KarenWright M.D. together with structural biologist Michael Eck M.D. Ph.D. will develop and test brain-penetranttargeted therapeutics for BRAF-mutant PLGAs. Project Two targets IDH-mutant gliomas which presenttypically in young adults. IDH-mutant gliomas produce extraordinarily high levels of the oncometabolite R-2-hydroxyglutarate (2-HG). However therapeutic exploitation of the differential 2-HG content between normaland malignant brain tissue has yet to be realized. Neurosurgeon Daniel Cahill M.D. Ph.D. and cancerbiologist William Kaelin M.D. will address this therapeutic lacuna. Project Three targets adult gliomas.Recent studies by basic scientist Jean Zhao Ph.D. show that in addition to suppressing cell cycle progressionCDK4/6 antagonists promote anti-tumor immunity and synergistically enhance the response to checkpointinhibitors. Going forward Dr. Zhao together with neuro-oncologist Patrick Wen M.D. will test the hypothesisthat brain penetrant CDK4/6 inhibitors can augment immunotherapeutic approaches to GBM. Project Fourtargets the neuronal microenvironment of adult and pediatric gliomas. Neuro-oncologist and developmentalneurobiologist Michelle Monje M.D. Ph.D. has shown that neurons promote glioma growth through activity-regulated secretion of neuroligin-3 (NLGN3) into the tumor microenvironment. Basic scientist Mario SuvaM.D Ph.D. has refined methods for single cell sequencing of the multiple cell types within themicroenvironment of freshly resected human gliomas. Working together Monje and Suva will define themolecular mechanisms whereby microenvironmental NLGN3 modulates formation and progression of gliomasand explore a novel therapeutic opportunity embedded within the NLGN3 requirement. Rigor and reproducibility of work conducted in the four projects will be fostered by cores for Pathologyand for Biostatistics and Computational Biology. An Administration core will enable and manage themultiple consortium agreements and collaborative interactions between Harvard Medical School the fourparticipating Harvard teaching hospitals and facilitate clinical trials and imaging studies. Intellectual vigorwithin the program is sustained and refreshed by annual Career Enhancement Awards to young investigatorsand by annual Developmental Project Awards. 2207927 +No NIH Category available Adoption;Age;Algorithms;American;Autopsy;BRCA2 gene;Behavior;Benchmarking;Biochemical;Biological Assay;Biological Markers;Biopsy;Cancer Etiology;Cessation of life;Classification;Clinical;Clinical Management;DNA Repair;Data;Data Analyses;Data Set;Defect;Detection;Diagnosis;Disease;Distant;Early Detection Research Network;Early Diagnosis;Early identification;Ecosystem;Exhibits;Fostering;Gene Expression;Genetic;Germ-Line Mutation;Incidence;Indolent;Institution;Laboratories;Lesion;Life;Liquid substance;Local Therapy;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Medical Care Costs;MicroRNAs;Modernization;Molecular;Molecular Profiling;Monitor;Morbidity - disease rate;Neoplasm Metastasis;Newly Diagnosed;Nomograms;Outcome;Pathogenicity;Pathologic;Patients;Performance;Population;Prostate;Prostatic Neoplasms;Proteins;Proteomics;Protocols documentation;Publishing;Quality of life;Radiology Specialty;Research Personnel;Risk;Site;Skin Cancer;Stratification;Talents;Tissues;Tumor Tissue;United States;Urine;Variant;Virginia;aging population;biomarker development;biomarker panel;biomarker validation;cancer diagnosis;candidate marker;cohort;cost;diagnostic biomarker;disorder risk;efficacy testing;gene repair;genetic testing;improved;innovation;laboratory development;lifetime risk;male health;men;mutant;new growth;novel;patient subsets;predictive marker;premature;protein biomarkers;proteogenomics;risk stratification;serum PSA;standard of care;synergism;tool;tumor;urinary;validation studies;variant of unknown significance Core-Biomarker Development Laboratory n/a NCI 10696075 8/21/23 0:00 RFA-CA-21-035 5U2CCA271894-02 5 U2C CA 271894 2 9/2/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 7813 10312406 "BOUTROS, PAUL CHRISTOPHER" Not Applicable 3 Unavailable 58625146 CTLVX9M7AMR4 58625146 CTLVX9M7AMR4 US 36.855732 -76.295467 471501 EASTERN VIRGINIA MEDICAL SCHOOL NORFOLK VA Domestic Higher Education 235011980 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 384479 384479 0 Project SummaryThe critical challenge in the clinical management of newly-diagnosed localized prostate cancer remainsdistinguishing indolent from aggressive and life-threatening cancers. Biomarkers are urgently needed toidentify those patients who harbor aggressive disease and will derive benefit from definitive treatment. Wetherefore propose to apply complimentary proteogenomic-based discovery approaches to identify and thenvalidate molecular features in prostate proximal fluids and tumor tissues that will be utilized in accurate earlydetection of aggressive forms of prostate cancer and improve disease risk stratification. The intended use ofthese biomarkers will be the early identification of men at risk for grade progression and improved risk-stratification for them.We have three biomarker development laboratory aims: 1) Validate our existing urine-based biomarkers forgrade progression in a ProBE-compliant study selected from our own cohorts and the EDRN GU upgradingstudy. 2) Develop and validate urine and tissue-based biomarkers for the risk-stratification of MRI invisiblehigh-grade lesions. 3) Develop and validate biomarkers to sub-stratify risk associated with deleteriousgermline BRCA2 variants.Our biomarker reference laboratory will develop and validate targeted clinically robust assays for multi-proteinbiomarkers panels. We will also develop decision algorithms that are cross-referenced for statistical rigor andbenchmarked for optimal clinical performance. In addition to these BCC activities we will develop robustPRM-MS assays and statistically rigorous decision tools for other EDRN BCCs and CVCs.Taken together our EDRN biomarker characterization center will be a core part of the the EDRN ecosystem.We will continue to actively participate in trans-Network activities and to share patient cohorts protocolsdatasets and analysis approaches and expertise. We will supplement these activities by focusing onpromoting the growth of new and diverse talent in biomarker development through fostering junior investigatorinvolvement across the full spectrum of biomarker development. +No NIH Category available Advisory Committees;Architecture;Brain Neoplasms;Brain Stem;CAR T cell therapy;CSF1R gene;Cancer Etiology;Cell Therapy;Cell surface;Cells;Child;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Clinical Trials;DNA;Dedications;Development;Diffuse intrinsic pontine glioma;Dose;Environment;Evaluation;FDA approved;Faculty;Five-Year Plans;Flow Cytometry;Fostering;Foundations;Goals;Grant;Human;Human Cell Line;Immune;Immune system;Immunocompetent;Immunogenomics;Immunohistochemistry;Immunologics;Immunotherapeutic agent;Immunotherapy;In Vitro;Inflammation;Inflammatory;Infusion procedures;International;K-Series Research Career Programs;Laboratories;Location;Malignant Childhood Neoplasm;Mentors;Mentorship;Messenger RNA;Microglia;Modeling;Molecular;Mus;Neuroblastoma;Neurologic;Neurons;Normal tissue morphology;Nucleosides;PDGFA gene;Patients;Pediatric Hospitals;Pennsylvania;Pharmaceutical Preparations;Philadelphia;Physicians;Pontine structure;Preclinical Testing;Research;Resources;Role;Safety;Scientist;Signal Transduction;Swelling;T-Lymphocyte;TP53 gene;Technical Expertise;Techniques;Technology;Testing;Therapeutic;Therapeutic Index;Tissues;Titrations;Toxic effect;Training;Transgenic Organisms;Translating;Translations;Treatment-related toxicity;Universities;Viral;Work;Xenograft Model;Xenograft procedure;blood-brain barrier crossing;career;childhood cancer mortality;chimeric antigen receptor;chimeric antigen receptor T cells;combinatorial;comparative efficacy;cytotoxicity;empowerment;experience;glioma cell line;high dimensionality;immunosuppressed;improved;in vivo Model;inhibitor;manufacture;member;mouse model;neoplastic cell;nestin protein;neural;neuroinflammation;novel;overexpression;pre-clinical;preclinical evaluation;safety testing;sialogangliosides;single-cell RNA sequencing;stem cells;tool;translational physician;translational research program;translational study;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Defining a therapeutic platform for DIPG with mRNA CAR T cells and microglia inhibition PROJECT NARRATIVEDiffuse intrinsic pontine glioma is a devastating pediatric brain tumor that despite decades of clinical trialsremains fatal with a median survival of less than a year. This proposal focuses on the development of safe andeffective immune-based therapies for these tumors using chimeric antigen receptor T cell therapy. Throughthese studies we hope to improve our understanding of the tumor growth within the immune microenvironmentand translate effective immunotherapies to patients. NCI 10696064 8/8/23 0:00 PA-20-203 5K08CA263179-03 5 K08 CA 263179 3 "BIAN, YANSONG" 9/9/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 14226552 "FOSTER, JESSICA B" Not Applicable 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Other Research-Related 2023 181291 NCI 167862 13429 PROJECT SUMMARY/ABSTRACTDr. Jessica Foster's career goal is to become a translational physician-scientist focused on immunotherapy forpediatric brain tumors. This proposal describes a five-year plan to facilitate her transition to independencethrough the acquisition of critical technical skills and scientific training in brain tumor modeling and evaluationof the tumor microenvironment with single cell RNA sequencing integrated with comprehensive mentoringfrom a diverse team of faculty members. She will conduct the proposed studies under the proven mentorship ofDr. John Maris an international leader in translational neuroblastoma research and immunogenomics.Additionally her dedicated Advisory Committee is comprised of highly regarded physician-scientists withdiverse expertise in immunotherapy and pediatric brain tumors. Finally the collaborative research environmentwith unparalleled resources at the University of Pennsylvania and the Children's Hospital of Philadelphiaprovides an ideal setting to conduct these translational studies.Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor that remains incurable despitedecades of clinical trials with a median survival of 11 months. This proposal seeks to use chimeric antigenreceptor (CAR) T cell therapy a form of immunotherapy to target DIPG. Recently GD2 was identified as animmunotherapeutic target for DIPG and lentiviral GD2-directed CAR T cells were able to successfully treatmurine models of DIPG. However a significant number of mice treated with CAR T cells died due toinflammation and herniation prompting concerns for potential toxicity from this therapy in particular in thepons. This proposal is building upon the applicant's experience utilizing mRNA for the creation of CAR T cellsthat are transient and can be titrated to effect to avoid toxicity here using repeated local delivery of GD2-directed mRNA CAR T cells to effectively treat DIPG while still maintaining safety. Aim 1 will determine theeffect of GD2-directed mRNA CAR T cells on tumor microenvironment and normal tissue using bothimmunocompetent and xenograft models of DIPG. Aim 2 will use single cell RNA sequencing to investigate therole of microglia in DIPG development and test mRNA CAR T cells in combination with inhibition of microglia.Dr. Foster's ultimate goal is to create a clinical trial for patients with DIPG using mRNA CAR T cells directedagainst GD2 as well as generating a new treatment platform for all pediatric brain tumors. These efforts willprovide an outstanding foundation for her career as a physician-scientist and the development of anindependent translational research program. 181291 +No NIH Category available Award;Chicago;Comprehensive Cancer Center;Credentialing;Department chair;Electronic Mail;Ensure;Epidemiologist;Extramural Activities;Faculty;Funding;Future;Grant;Health system;Individual;Institution;Leadership;Length;Letters;Malignant neoplasm of prostate;Medical Oncologist;Mentors;Minority;Molecular;Monitor;Pilot Projects;Process;Research Personnel;Research Project Grants;Science;Secure;Source;Structure;System;Talents;Underrepresented Populations;Universities;Urologist;Woman;Work;anticancer research;biomedical scientist;career;experience;flexibility;interest;meetings;member;programs;recruit;success;translational cancer research;web site Career Enhancement Program CAREER ENHANCEMENT PROGRAM (CEP): PROJECT NARRATIVEThe Career Enhancement Program is a critical component of the SPORE in Prostate Cancer in that it ensuresthat there will be a continuous influx of talented investigators devoted to prostate cancer research. NCI 10696058 7/28/23 0:00 PAR-18-313 5P50CA180995-08 5 P50 CA 180995 8 8/18/15 0:00 7/31/26 0:00 ZCA1-RPRB-6 7805 8790794 "CATALONA, WILLIAM J" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 96225 60704 35521 CAREER ENHANCEMENT PROGRAM (CEP): ABSTRACTThe Career Enhancement Program provides a highly structured mechanism to select and mentor juniorinvestigators interested in careers in prostate cancer research. The Career Enhancement Program (CEP)uses several mechanisms to recruit these investigators including emails letters to department chairs and website announcements. In addition the Directors of the Robert H. Lurie Comprehensive Cancer Center and theUniversity of Chicago Comprehensive Cancer Center advertise the CEP when recruiting junior investigatorsto their respective Institutions. CEP investigators are selected after careful review of their credentials theirproposed projects and their potential to develop an independent career in prostate cancer research. CareerEnhancement investigators are clinicians or basic scientists from biomedical science departments atNorthwestern University University of Chicago and NorthShore University HealthSystem. The fact that theawardees come from a variety of departments provides a source of diversity and scientific expertise tomembers of the SPORE Program.The Career Enhancement Program has flexibility in terms of offering awards and the length of the award.However there is a consistent and highly-structured process for solicitation and selection of CEP investigatorsand a good tracking system for monitoring their progress. The specific aims of the Career EnhancementProgram are:1. To solicit and select career enhancement investigators through a highly structured process2. To mentor and continuously evaluate career enhancement investigators through individual meetings with mentors and bi-annual presentations at SPORE investigator meetings3. To cultivate new faculty to embark on careers in prostate cancer research to ensure a future source of talented diverse investigators committed to prostate cancer research.4. To maintain the administrative structure for the Career Enhancement Program +No NIH Category available Area;Chicago;Clinic;Development;Developmental Process;Funding;Goals;Health system;Leadership;Malignant neoplasm of prostate;Mission;Monitor;Peer Review;Pilot Projects;Process;Progress Reports;Prostate;Request for Applications;Research;Research Personnel;Review Committee;Secure;Structure;System;Translating;United States National Institutes of Health;Universities;Woman;Writing;advanced prostate cancer;anticancer research;flexibility;innovation;insight;interest;medical schools;meetings;member;minority investigator;programs;recruit;translational potential;web site Developmental Research Program DEVELOPMENTAL RESEARCH PROGRAM (DRP): NARRATIVEThe SPORE Developmental Research Program provides yearly funding to 4-6 projects that have promisingtranslational potential. It is anticipated that investigators who develop their pilots sufficiently may replace mainprojects that are not progressing or will secure independent funding in prostate cancer research. NCI 10696057 7/28/23 0:00 PAR-18-313 5P50CA180995-08 5 P50 CA 180995 8 8/18/15 0:00 7/31/26 0:00 ZCA1-RPRB-6 7804 2564393 "ABDULKADIR, SARKI A." Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 241341 150838 90503 DEVELOPMENTAL RESEARCH PROGRAM (DRP): ABSTRACTThe Developmental Research Program (DRP) is an essential component of the Prostate SPORE providingyearly funding to 4-6 projects that are peer reviewed and deemed to have promising translational potential.Funding is flexible supporting projects for a period of two years or less. It is expected that DRP investigatorswill develop and advance their pilots sufficiently to either replace main projects that are not progressing or willsecure independent funding in prostate cancer research. Of note all three projects presented in the renewalhave emanated from pilot projects and propose translating discoveries made in the investigators labs to theclinic. The DRP follows a highly structured process to solicit projects from investigators who are interested indeveloping projects in the area of prostate cancer to review projects according to NIH review criteria and tomonitor projects for scientific progress. The DRP is maintained throughout the entire period of SPORE funding.The specific aims of the Developmental Research Program are: Specific Aim 1: To solicit review and select innovative and translational pilot projects through the highly structured process. A request for applications (RFA) is sent out to investigators at the Northwestern University (NU) University of Chicago and its affiliated NorthShore University HealthSystems. The Scientific Review Committee reviews pilot projects based on the quality and importance to the overall SPORE mission. Specific Aim 2: To monitor progress of pilot projects within the context of the overall SPORE goals. Pilot project investigators are required to present their results twice per year at SPORE investigators meeting. They also meet twice per year with the Directors of the DRP to obtain translational insight and to ensure that scientific milestones are being achieved. DRP investigators are required to submit a written progress report that is rigorously evaluated by the SPORE PI and members of the Executive Committee. Specific Aim 3: To encourage and recruit additional investigators to pursue research in prostate cancer through a SPORE web site and by widely distributing the RFA announcing the availability of funds. Women and minority investigators are strongly encouraged to submit pilot projects. Specific Aim 4: To maintain the administrative process for the Developmental Research Program throughout the SPORE funding period. +No NIH Category available Address;Animal Model;Antiandrogen Therapy;Apoptosis;Binding;Biological Assay;CWR22Rv1;Castration;Cells;Chemicals;Chromatin;Clinical;Complex;Coupled;Data;Disease;Drug Kinetics;Gene Amplification;Gene Expression;Genetic Transcription;Goals;Heterodimerization;Human;Impairment;In Vitro;Lead;Link;MYC Family Protein;Malignant Neoplasms;Malignant neoplasm of prostate;Maximum Tolerated Dose;Mediating;Modeling;Mus;Neuroendocrine Prostate Cancer;Oncogenes;Oncoproteins;Pathway interactions;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase I Clinical Trials;Phosphorylation;Play;Pre-Clinical Model;Proliferating;Prostate Cancer therapy;RNA Splicing;Recurrence;Regulation;Resistance;Role;Safety;Series;Specificity;Therapeutic;Threonine;Toxicology;Tumor Tissue;Tumorigenicity;Ubiquitin;Up-Regulation;c-myc Genes;castration resistant prostate cancer;circulating DNA;clinical application;cohort;cytotoxicity;enzalutamide;genetic approach;in silico;in vivo;in vivo Model;inhibitor;leukemia;mouse model;multicatalytic endopeptidase complex;novel;novel therapeutics;overexpression;pharmacodynamic biomarker;pharmacophore;phase I trial;pre-Investigational New Drug meeting;pre-clinical;preclinical study;prostate cancer cell;prostate cancer cell line;prostate cancer model;protein expression;research clinical testing;scaffold;small molecule;small molecule inhibitor;small molecule libraries;therapy resistant;tumor;tumor growth Project 1: Targeting the MYC Pathway in Prostate Cancer PROJECT 1: NARRATIVEThe oncoprotein MYC (c-MYC N-MYC and L-MYC) is implicated in the majority of human cancer includingprostate cancer. We have generated first-in-class small molecule inhibitors of MYC with in vivo efficacy andtolerability that we plan to develop for the treatment of castration-resistant prostate cancer. NCI 10696052 7/28/23 0:00 PAR-18-313 5P50CA180995-08 5 P50 CA 180995 8 8/18/15 0:00 7/31/26 0:00 ZCA1-RPRB-6 7801 2564393 "ABDULKADIR, SARKI A." Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 376099 235062 141037 PROJECT 1: ABSTRACTMYC oncoproteins (including c-MYC L-MYC and N-MYC) have been implicated in up to 70% of all humancancers. In prostate cancer elevated levels of MYC protein expression are observed across all grades. Incastration-resistant prostate cancer (CRPC) there is evidence of further upregulation of c-MYC levels with geneamplification occurring in 45% of cases. In late-stage therapy-resistant neuroendocrine prostate cancer (NEPC)N-MYC is overexpressed in 40% of cases. In preclinical studies inhibition of MYC can effectively kill CRPC andNEPC cells. A viable therapeutic strategy to inhibit MYC is therefore likely to have a significant impact on thisdisease and to fulfill the ongoing need for novel impactful therapies spanning the spectrum of castration resistantprostate cancer. Despite its recognition as an attractive cancer target MYC has proved difficult to target andthere are currently no clinically viable small molecule MYC inhibitors (MYCi) available. By employing apharmacophore-based in silico screen of a large chemical library (32 million compounds) coupled to a rapid invivo screen in mice we identified a series of novel small molecule inhibitors. These MYC inhibitors are highlydrug-like and have shown excellent pharmacokinetic toxicological and anti-tumor activity profiles in MYC-drivenmodels of prostate cancer and leukemia. The compounds engage MYC inside cells as shown by the cellularthermal shift assay (CETSA); disrupt MYC/MAX complex formation which is required for MYC activity; and inhibitMYC-driven target gene expression. Furthermore the MYCi compounds enhance phosphorylation of MYC onthreonine-58 (T58P) which promotes MYC degradation via a well-characterized ubiquitin-proteasome pathway.Consequently treatment with MYCi impaired tumorigenicity in vitro and in vivo. The goals of this project are todevelop the lead MYC inhibitor MYCi975 for clinical application in the treatment of prostate cancer and tocharacterize the mechanisms of MYCi-induced degradation of c-MYC and N-MYC oncoproteins. We willimplement the following Specific Aims: Aim 1 is to investigate the mechanisms of MYCi975 regulation of c-MYC and N-MYC phosphorylation and stability and the potential of MYC pT58 as a pharmacodynamic marker.Aim 2 will assess MYCi anti-tumor efficacy and impact on pharmacodynamic biomarkers in preclinical modelsof c-MYC and N-MYC driven prostate cancer. Aim 3 will seek to develop MYCi975 for use in patients byconducting formal IND-enabling toxicology studies and initiate a phase 1 trial in mCRPC patients.Impact: Successful completion of these studies could lead to first-in-class therapies for lethal prostate cancersdependent on c-MYC/N-MYC activity. This benefit can extend to other human cancers as well because of thepervasive role MYC proteins play in cancers of all types. +No NIH Category available Address;Adherence;Affinity;Binding;Bioinformatics;Biological;Biometry;Cell physiology;Cells;ChIP-seq;Chicago;Clinical;Clinical Data;Clinical Trials;Code;Collaborations;Complement;Comprehensive Cancer Center;Computer Systems;Computer software;Consultations;Custom;Data;Data Analyses;Data Analytics;Data Science;Data Set;Databases;Dedications;Development;Dose;Ensure;Environment;Evaluation;Experimental Designs;Faculty;Fostering;Funding;Gene set enrichment analysis;Genes;Health system;High Performance Computing;High-Throughput Nucleotide Sequencing;Individual;Investigation;Link;Maintenance;Malignant neoplasm of prostate;Maps;Modification;Molecular;Monitor;Monitoring Clinical Trials;Ontology;Output;Pathway interactions;Patients;Phase I Clinical Trials;Prostate;Protocols documentation;Registries;Reporting;Reproducibility;Research;Research Design;Research Personnel;Safety;Secure;Site;Statistical Data Interpretation;Techniques;Time;Tissue Sample;Tissues;Universities;Visualization;bioinformatics pipeline;clinical database;clinical trial participant;cohort;data integration;data management;data registry;data resource;data standards;differential expression;experimental study;genetic manipulation;genome browser;high dimensionality;improved;innovation;medical schools;member;pre-clinical;preclinical study;programs;reference genome;repository;single-cell RNA sequencing;synergism;transcriptome sequencing Biostatistics and Bioinformatics Core CORE B: NARRATIVEThe Biostatistics and Bioinformatics Core (Core B) has three primary responsibilities: 1) developmentmaintenance and enhancement of preclinical and clinical database functionality to support all Prostate SPOREProjects; 2) application of state-of-the art bioinformatics pipelines for pre-processing and analysis of high-dimensional omics data; and 3) biostatistical contribution to study design data analysis and interpretation ofresults for all preclinical and clinical Prostate SPORE Projects to ensure that all reported programaccomplishments undergo rigorous evaluation. NCI 10696047 7/28/23 0:00 PAR-18-313 5P50CA180995-08 5 P50 CA 180995 8 8/18/15 0:00 7/31/26 0:00 ZCA1-RPRB-6 7799 8559840 "KOCHERGINSKY, MASHA " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 164505 102816 61689 CORE B: ABSTRACTThe Biostatistics and Bioinformatics Core (Core B) is a central component of the Prostate SPORE providingstate-of-the-art integrated data science support to all Prostate SPORE projects. Database development andmaintenance will provide a centralized resource for data tracking for preclinical studies ensuring efficientreporting and statistical analysis of all experiments. In addition clinical databases will be enhanced anddeveloped in conjunction with all project teams to complement existing clinical trial data registries atNorthwestern and ensure custom data capture in a highly secure environment. Bioinformatics activities of CoreB are central to discovery and will help define new and significant research directions. The large omics datasets that will be generated in the Prostate SPORE Projects require specialized expertise for preprocessinganalysis and interpretation of molecular and biological consequences of genetic manipulations and treatments.Bioinformatics functionality provided by Core B will provide this crucial assistance for all proposed ProstateSPORE Projects. Biostatistical activities of Core B are central to the concerns of rigor and reproducibility: byproviding study design guidance data management statistical analysis and consultation for interpretation ofresults the core will see that reported results have been rigorously controlled and will be reproducible by others.All functions of the Core B will be conducted in association with the following Specific Aims: AIM 1: Maintain andenhance the pre-clinical clinical and tissue databases of the Prostate SPORE; AIM 2: Provide state-of-the-artbioinformatics expertise to the Prostate SPORE projects; AIM 3: Provide experimental design guidance andbiostatistics collaboration and analysis support for all preclinical studies and clinical trials Through these activitiesCore B will serve as a key contributor to all individual projects and will ensure that project output is accuratereliable and of the highest quality. +No NIH Category available Activities of Daily Living;Address;Adoptive Cell Transfers;Antibodies;Antigen Presentation;Antigen Targeting;Antigens;Autoimmune Diseases;Autologous;Bar Codes;Binding;Biological Models;CRISPR/Cas technology;Cancer cell line;Cell Line;Cell Lineage;Cell surface;Cells;Clinical;Clone Cells;DNA;DNA Library;Development;Dimensions;Engineering;Gene Expression;Generations;Genomics;Human;Immune System Diseases;In Vitro;Infection;Libraries;Link;Major Histocompatibility Complex;Malignant Neoplasms;Membrane Proteins;Methods;Organoids;Patients;Peptides;Peripheral Blood Mononuclear Cell;Population;Primary Neoplasm;Process;Reporter;Reporting;Research;Surface;System;T cell therapy;T-Cell Antigen Receptor Specificity;T-Cell Receptor;T-Lymphocyte;Technology;Testing;Therapeutic;Time;Tumor Antigens;Tumor-Infiltrating Lymphocytes;Validation;antigen test;antigen-specific T cells;cancer cell;cancer immunotherapy;cancer type;clinical practice;cytotoxicity;in vivo;neoantigens;neoplastic cell;patient derived xenograft model;prevent;protein biomarkers;rapid technique;screening;sensor;success;technology development;tumor A streamlined high-throughput platform for validation of cancer antigen presentation and isolation of cancer antigen reactive T cells NarrativeT cell based therapies either infusing expanded patient autologous tumor-specific T cells or infusing cancer-specific TCR engineered autologous T cells have revolutionized cancer immunotherapy. However identifyingcancer antigens are presented on cancer cell surface and quickly identify a large number of clones of antigen-specific T cells are two major challenges that prevent the wide use of T cell based therapies. The proposedtechnology addresses these challenges and offer a streamlined process for antigen-specific T cell based cancerimmunotherapy. This technology development will transform both cancer immunotherapy research and clinicalpractice. NCI 10696045 8/11/23 0:00 RFA-CA-20-018 5R33CA256086-03 5 R33 CA 256086 3 "AGRAWAL, LOKESH" 9/23/21 0:00 8/31/24 0:00 ZCA1-TCRB-J(M1) 9884345 "JIANG, NING JENNY" "BROCK, AMY " 3 BIOMEDICAL ENGINEERING 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA BIOMED ENGR/COL ENGR/ENGR STA 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 370830 NCI 287842 82988 AbstractT cell receptor (TCR) based cancer immunotherapies either infusing expanded patient autologous tumor-specific T cells or infusing cancer-specific TCR engineered autologous T cells have shown great clinical benefitin several types of cancer. However two challenges have prevented the broad application of these therapies tomany types of cancer. First there lacks a quick and sensitive method to detect patient-specific presentation ofcancer antigen peptides on the surface of tumor cells. Second there lacks a rapid method for the isolation ofantigen-specific T cells that can be propagated quickly in vitro to meet the real-time needs of adoptive cell transfertherapy. These challenges have become road blocks for the application of TCR based cancer immunotherapyto many types of cancer and have prevented the exploration of other classes of cancer-antigens in addition toneo-antigens (NeoAs) that also have therapeutic potential such as cancer germline antigens (CGA).In this study we propose the development of AbTR (Antigen sensing-based T cell Recall) technology to addressthese two critical challenges in large scale. The AbTR technology will provide a quick and streamlined path toidentify cancer antigens presented on tumor cell from hundreds of possible targets and isolate many antigen-specific T cell clones that are functionally capable of killing tumor cells and are ready to be used in adoptive celltransfer therapy. The success of the project address two urgent needs in cancer immunotherapy. This technologynot only can be applied to all types of cancer but may also be relevant for the study of other immunologicaldiseases such as infection and autoimmune diseases. 370830 +No NIH Category available Advanced Malignant Neoplasm;Advocacy;Cancer Center;Cancer health equity;Chicago;Collaborations;Communities;Comprehensive Cancer Center;Dedications;Department of Defense;Development;Diagnosis;Education;Ensure;Evaluation;Foundations;Funding;Health system;Intervention;Laboratory Scientists;Lead;Leadership;Malignant neoplasm of prostate;Medical Oncologist;Pathologist;Patient-Focused Outcomes;Patients;Productivity;Research;Research Personnel;Research Project Grants;Structure;Testing;Training;Translational Research;United States National Institutes of Health;Universities;Urologist;anticancer research;career;improved outcome;innovation;leadership development;multidisciplinary;next generation;organizational structure;programs Administrative Leadership Development and Advocacy Core CORE A: NARRATIVEThe SPORE Administrative Leadership Development and Advocacy (Admin) Core provides integration andstrong leadership and coordinates oversight of projects and cores to ensure that scientific objectives areaccomplished such that the SPORE can have the greatest impact on patients with prostate cancer. NCI 10696044 7/28/23 0:00 PAR-18-313 5P50CA180995-08 5 P50 CA 180995 8 8/18/15 0:00 7/31/26 0:00 ZCA1-RPRB-6 7797 2564393 "ABDULKADIR, SARKI A." Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 325863 216188 109675 CORE A: ABSTRACTThe SPORE in Prostate Cancer brings together a highly motivated multidisciplinary team of investigators fromNorthwestern University and the University of Chicago with contributions from NorthShore UniversityHealthSystem (UC affiliate). The team includes laboratory scientists urologists medical oncologistspathologists biostatisticians and bioinformaticians all of whom are dedicated to conducting state-of-the-arttranslational research to develop and test interventions that improve the outcome of patients diagnosed withprostate cancer.The Administrative Leadership Development and Advocacy Core has the following Specific Aims:Specific Aim 1: To provide integration within the SPORE and with the Robert H. Lurie Comprehensive CancerCenter and the University of Chicago Comprehensive Cancer CenterSpecific Aim 2: To provide strong oversight of research projects and cores as well as financial oversight throughplanning and evaluation activitiesSpecific Aim 3: To oversee the Developmental Research (DRP) and Career Enhancement (CEP) Programs ofthe SPORE to encourage investigators to conduct translational prostate cancer researchSpecific Aim 4: To lead an advocacy group and diversity education initiatives in the communitySpecific Aim 5: To train the next generation of leaders in prostate cancer researchSpecific Aim 6: To facilitate collaborations and integration with NIH and other nationally funded programs suchas the U54 CA203000 (The Chicago Collaborative to Promote and Advance Cancer Health Equity) Departmentof Defense and Prostate Cancer Foundation. +No NIH Category available Activated B-Lymphocyte;Address;Affect;Age;Aging;Angiogenic Factor;Anti-Inflammatory Agents;Antibodies;Antigens;Archives;Asian;Asian Americans;Asian population;Aspirin;B cell differentiation;B-Cell Activation;B-Lymphocytes;Benign;Biological Assay;Biological Markers;Black American;Black Populations;Black race;Body mass index;CXCL10 gene;CXCL13 gene;CXCR3 gene;Cell secretion;Chlamydia trachomatis;Chronic;Cohort Studies;Collaborations;Communities;Data;Development;Diabetes Mellitus;Disparity;Epidemiology;Ethnic Origin;Ethnic Population;Exercise;Family;Female;Goals;Growth;Growth Factor;Helicobacter pylori;Hematologic Neoplasms;Hepatitis B Virus;Hepatitis C virus;Hispanic;Hispanic Populations;Human Papillomavirus;IL17 gene;IL6 gene;IL6ST gene;Immune;Immune response;Immunologic Markers;Immunologic Stimulation;Incidence;Individual;Infection;Infectious Agent;Inflammation;Interleukin-10;Knowledge;Laboratories;Latino;Life Style;Logistic Regressions;Malignant Neoplasms;Measures;Medical Records;Memory;Metformin;Monoclonal gammopathy of uncertain significance;Multiple Myeloma;Nested Case-Control Study;Not Hispanic or Latino;Obesity;Outcome Assessment;Participant;Pharmaceutical Preparations;Physical activity;Plasma Cells;Population;Positioning Attribute;Prevalence;Prevention;Preventive;Proteins;Race;Relative Risks;Reporting;Research;Research Personnel;Risk;Risk Factors;Role;Sampling;Serum;Signal Transduction;Specimen;Stromal Cell-Derived Factor 1;System;Techniques;Toxoplasma gondii;Treponema pallidum;Variant;Virus;Women's Health;adiponectin;angiogenesis;black women;cancer epidemiology;cancer health disparity;caucasian American;cell growth;chemokine;chronic infection;cohort;cytokine;epidemiology study;ethnic difference;ethnic disparity;ethnic diversity;experience;lifestyle factors;male;microbial;multi-ethnic;multidisciplinary;neoplasm registry;progression risk;racial determinant;racial difference;racial disparity;racial diversity;racial population;response;screening;sex Determinants of the racial/ethnic disparity in MGUS risk: An epidemiologic study in 4 cohorts We seek to understand whether the observed racial disparities in monoclonal gammopathy of undeterminedsignificance (MGUS) the precursor to multiple myeloma may be explained by differences in underlying immunealterations and B-cell activation as well as lifestyle factors such as obesity diabetes and use of anti-inflammatorymedications between racial/ethnic groups. To address these research questions we will conduct anepidemiologic study among four racially/ethnically diverse cohorts with available archived serum specimens forexposure and outcome assessment. Findings from this study will provide critical information on the determinantsof the racial/ethnic disparity in MGUS. NCI 10696042 8/24/23 0:00 PAR-19-279 5R01CA260615-03 5 R01 CA 260615 3 "STARKS, VAURICE" 9/20/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-B(55)R] 1865233 "COZEN, WENDY " "BERTRAND, KIMBERLY A; DESAI, PINKAL " 47 INTERNAL MEDICINE/MEDICINE 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 885812 NCI 829061 56751 Multiple myeloma (MM) is the second most common hematological malignancy and is largely incurable. BlackAmericans experience an unexplained 2-fold excess risk compared to White Americans while Asian Americansexperience a lower risk. MM is preceded by a precursor state characterized by an accumulation of benignmonoclonal plasma cells that secrete a monoclonal protein (monoclonal gammopathy of undeterminedsignificance MGUS) which occurs with the same racial/ethnic disparity as seen in MM. Thus explaining thecauses of the disparity in MGUS will shed light on the causes of the disparity in MM. We (MPIs Cozen Desaiand Bertrand) are submitting this proposal in response to PAR 19-279 MMDPQ1: What risk factors singularlyor in cooperation explain the variation in MGUS incidence among different races? Our central hypothesis isthat racial and ethnic differences in plasma cell growth/angiogenic factors microbial translocation chronicantigenic stimulation due to previous infection and lifestyle factors can explain the observed MGUS incidencedisparity. By screening participants in 4 multiethnic NCI epidemiology cohorts (Black Women's Health StudyWomen's Health Initiative Multiethnic Cohort Southern Community Cohort Study) we will identify 844 Blacks844 Non-Latino Whites 146 Latino and 146 Asians with laboratory validated MGUS and an equal number ofage- sex- race/ethnicity- matched controls without MGUS by the same laboratory screening. We will measurelevels of 18 biomarkers reflecting plasma cell growth angiogenesis inflammation and microbial translocation(IL6 IL17 XCL13 IL6-R BAFF APRIL gp130 HGF CCL-8 Angioprotein-2 LBP sCD14 adiponectin BCMAIP-10 IL10 MIP1-a CXCL12) (Aim 1). We will also examine exposures associated with B-cell activationincluding lifetime cumulative infection from chronic immune stimulating agents by measuring antibodiessimultaneously in a multiplex system to Hepatitis B and C viruses H. pylori T. gondii T. pallidum C. trachomatisHPV and all 8 Herpes family viruses (Aim 2) and lifestyle factors obesity physical activity diabetes and use ofanti-inflammatory medications metformin statins and aspirin known to affect B-cell response (Aim 3). Todetermine whether a given putative risk factor can (at least partly) explain the racial disparities in MGUS we will(1) determine whether the factor is consistently related to MGUS within all four ethnic groups and if so then; (2)estimate the strength of the relationship in a combined analysis and; (3) determine whether the prevalence of anMGUS-associated factor differs by race in a direction consistent with the known racial differences in MGUS risk.We will use logistic regression techniques that relate either continuous or binary factors (body mass indexdiabetes individual infections) to the log odds of MGUS. With our multidisciplinary team of co-investigators andcollaboration of 4 racially/ethnically diverse cancer epidemiology cohorts we are uniquely positioned to be ableto identify causes of the MGUS disparity about which there is little known. This study will provide criticalinformation on the knowledge gap that exists in the causes of racial/ethnic disparity for MGUS. 885812 +No NIH Category available Advocacy;Advocate;Aggressive course;American;Antibody Therapy;Antitumor Response;Basic Science;Bioinformatics;Biology;Biometry;Biopsy Specimen;Blood specimen;Cancer Etiology;Cancer Patient;Catchment Area;Chicago;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Combined Modality Therapy;Comprehensive Cancer Center;Core Facility;DNA Damage;Dedications;Development;Diagnosis;Disease;FDA approved;Family member;Focus Groups;Friends;Funding;Genetic Transcription;Health;Health system;Human;Immune system;Immunotherapy;Infrastructure;Innovative Therapy;Institution;Leadership;MHC Class I Genes;Malignant neoplasm of prostate;Measurable;Measures;Mediating;Metastatic Prostate Cancer;Myelogenous;National Cancer Institute;Oncogenic;PIK3CG gene;PTEN gene;Pathologist;Pathway interactions;Patient Care;Patient-Focused Outcomes;Patients;Pharmacologic Substance;Phase I Clinical Trials;Phosphorylation;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Prostate specific antigen measurement;Qualifying;Quality of life;Regulation;Rejuvenation;Research;Research Personnel;Research Project Grants;Resistance;STING agonists;Scientist;Signal Transduction;Source;T cell infiltration;T-Cell Activation Pathway;Talents;Testing;Therapeutic;Tissues;Translating;Translational Research;Translations;Treatment Efficacy;Universities;Visceral;Work;anticancer research;bone;c-myc Genes;cancer genetics;career;castration resistant prostate cancer;cohort;design;efficacy evaluation;experience;experimental study;humanized monoclonal antibodies;immune checkpoint blockade;improved;improved outcome;inhibitor;innovation;investigator-initiated trial;member;men;mortality;mouse model;new technology;novel;novel strategies;novel therapeutics;patient population;pre-Investigational New Drug meeting;preclinical study;programmed cell death protein 1;programs;prostate cancer model;recruit;safety study;success;targeted treatment;tumor;tumor microenvironment;tumor-immune system interactions SPORE in Prostate Cancer OVERALL: PROJECT NARRATIVEThe SPORE in Prostate Cancer brings together basic scientists clinicians pathologists biostatisticiansbioinformaticists and advocates who together will work to improve the outcome of patients with prostate cancerthrough experiments to understand the basic biology and through the design and conduct of innovativeparadigm-shifting clinical trials. NCI 10696035 7/28/23 0:00 PAR-18-313 5P50CA180995-08 5 P50 CA 180995 8 "SCROGGINS, BRADLEY TODD" 8/18/15 0:00 7/31/26 0:00 ZCA1-RPRB-6(O1)P 2564393 "ABDULKADIR, SARKI A." "HUSSAIN, MAHA H" 5 UROLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 1758412 NCI 1119030 639382 OVERALL: ABSTRACTThis application is a request for renewal funding of the SPORE in Prostate Cancer P50 CA180995 at the RobertH. Lurie Comprehensive Cancer Center of Northwestern University in collaboration with the University of ChicagoComprehensive Cancer Center and NorthShore University HealthSystem an affiliate of the University ofChicago. The SPORE first received support from the National Cancer Institute in 2001; a renewal applicationwas funded in 2009. In 2015 we were the recipients of a new SPORE and we are now requesting continuedfunding for this program. Our SPORE unites basic scientists clinicians pathologists biostatisticiansbioinformaticists and advocates from our academic institutions all of whom are dedicated to advancingtranslational prostate cancer research. In this application we propose three highly translational and innovativeresearch projects that have both basic science and clinical science co-leadership: Project 1: Targeting the MYCPathway in Prostate Cancer (Abdulkadir Hussain); Project 2: Re-directing the sensitivity of metastaticcastration-resistant prostate cancer to immunotherapy (Wu Sosman Morgans); Project 3: STING Activation toOvercome Resistance to Immune Checkpoint Blockade in PTEN-deficient Prostate Cancer (Patnaik GajewskiStadler). Three core facilities support the proposed research projects: Administrative Leadership and Advocacy(Abdulkadir Hussain Stadler); Biostatistics/Bioinformatics (Kocherginsky Zhao) and Biospecimen (Yang).Internal and External Advisory Boards provide a source of scientific input to members of the SPORE team on abiannual and yearly basis respectively. Our Advocacy Group are well established in the SPORE arena andmake a valued contribution to our success. The SPORE includes Developmental Research and CareerEnhancement Programs both of which provide a source of innovation and new discoveries. All together weanticipate that the results obtained from our research endeavors will have a significant impact on the health ofpatients diagnosed with prostate cancer. 1758412 +No NIH Category available Address;Adult;Advocate;Area;Behavioral Research;Cancer Center;Cancer Patient;Cholangiocarcinoma;Collaborations;Communication;Communities;Community Outreach;Consent;Data Collection;Decision Aid;Decision Making;Development;Diagnosis;Diffusion;Disclosure;Education;Education and Outreach;Ensure;Ethical Issues;Ethicists;Ethics;Evaluation;Feedback;Future;Genome;Genomic medicine;Genomics;Goals;Guidelines;Intervention;Interview;Lead;Malignant Neoplasms;Methodology;Minority;Minority Groups;Mission;Multiple Myeloma;Online Systems;Outcomes Research;Participant;Patient Education;Patient Preferences;Patients;Prevention;Process;Randomized;Randomized Controlled Trials;Recommendation;Research;Research Ethics;Rural;Rural Population;Sampling;Testing;Underrepresented Populations;Underserved Population;Universities;Vision;Washington;Work;cancer education;cancer genomics;cancer health disparity;cancer prevention;community engagement;early onset colorectal cancer;ethical legal and social implication;experience;follow-up;formative assessment;genetic testing;high risk;implementation framework;implementation measures;implementation science;implementation strategy;improved;innovation;patient engagement;patient outreach;preference;programs;randomized trial;rare cancer;recruit;trial comparing;tumor;understudied cancer;web based decision aid Engagement Optimization Unit n/a NCI 10696019 9/7/23 0:00 RFA-CA-19-045 5U2CCA252981-03 5 U2C CA 252981 3 9/1/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7787 8953837 "DRAKE, BETTINA F." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 414397 456794 251413 Project Summary: Engagement Optimization UnitThe overall goal of the Engagement Optimization Unit (EOU) of the Washington University ParticipantEngagement and Cancer Genomic Sequencing Center (WU-PE-CGS) is to conduct ongoing and iterativeresearch to integrate optimal approaches to participant engagement in the recruitment consent follow-up andcommunication of genomic characterization results. The EOU will optimize the engagement process for genomiccharacterization of patients diagnosed with three rare of understudied cancers including those that significantlyimpact minority and rural populations (cholangiocarcinoma multiple myeloma and early onset colorectalcancer). The outcomes of research conducted within the EOU will be fully integrated with the ParticipantEngagement Unit and the Genome Characterization Unit to optimize participant experiences throughout thegenomic research process. The EOU will support the overall mission of WU-PE-CGS through the following aims:(1) conduct ongoing evaluation of participant engagement and ELSI concerns related to genomic testing amongunderserved populations with rare cancers; (2) conduct a randomized controlled trial to optimize the return ofresults process; (3) utilize an embedded ethics approach to synthesize and address ELSI issues arising acrossall units and the Patient Engagement Advisory Board to optimize participant engagement. The EOU will use animplementation science framework for the main research objectives. Aim 1 will interview a random sample ofparticipants at various stages in their study participation (decliners post-consent post disclosure). Aim 2 willexpand and test a web-based decision aid to elicit participants' values and preferences for receiving results fromcancer genomic sequencing. Participants will be randomized to intervention (Genomics ADvISOR decision aid)or control (standard discussion). In Aim 3 will use embedded ethics to explore ELSI concerns that arise whengenetic testing is offered to minority and rural-residing adults with rare cancer. This approach will ensure thatethical issues arising within components (PEU EOU and GCU) will be identified and communicated across theentire center. The innovation of this project brings rigorous implementation science to the otherwise slowdiffusion of guideline driven genetic testing and return of results to cancer patients. We will focus our engagementoptimization research on rural and high-risk minority populations that are under-represented in cancer genomicanalyses and have often been omitted from implementation science directed studies in the area of genomicmedicine. +No NIH Category available Address;African American population;Amendment;Biocompatible Materials;Biological Assay;Board Certification;CLIA certified;CLIA certified sequencing;Cancer Biology;Categories;Cholangiocarcinoma;Clinical;Clinical Data;Collection;Colorectal Cancer;Communities;Computers;DNA;Data;Data Commons;Data Storage and Retrieval;Databases;Detection;Diagnostic;Disease Progression;Eligibility Determination;Ensure;Event;Evolution;Friends;Gene Fusion;Genes;Genome;Genomic Data Commons;Genomics;Germ-Line Mutation;Goals;Guidelines;Health Insurance Portability and Accountability Act;Human Resources;Incidence;Individual;Industry Standard;Inherited;Libraries;Methodology;Methods;Molecular;Monitor;Multiple Myeloma;Mutation;Normal tissue morphology;Nucleic Acids;Participant;Pathogenicity;Pathologist;Patients;Peptides;Physicians;Practice Management;Preparation;Procedures;Process;Prognosis;Proteomics;Published Comment;Publishing;RNA;Recommendation;Reporting;Research;Running;Sampling;Schedule;Secure;Single Nucleotide Polymorphism;Somatic Mutation;Specimen;Surveys;System;Testing;Time;Tumor Tissue;Universities;Washington;archive data;bioinformatics tool;cancer genomics;cancer type;candidate selection;cell free DNA;cellular imaging;clinically actionable;clinically relevant;data acquisition;deep sequencing;early onset;exome sequencing;follow-up;genomic data;health disparity;imaging study;immunogenic;indexing;insertion/deletion mutation;mortality;neoplastic cell;patient engagement;preference;programs;prospective;research study;single-cell RNA sequencing;statistics;targeted sequencing;timeline;transcriptome sequencing;tumor;tumor diagnostic;tumor-immune system interactions;web portal Genome Characterization Unit n/a NCI 10696013 9/7/23 0:00 RFA-CA-19-045 5U2CCA252981-03 5 U2C CA 252981 3 9/1/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7785 9766169 "DING, LI " Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 1898469 1399062 793218 Project Summary - Genome Characterization Unit (GCU)The GCU will provide comprehensive end-to-end CLIA-compliant genomic testing and cutting-edge research-level analysis of patients with MM CRC and CHOL who are engaged by the PEU. This testing will beconducted on diagnostic tumor samples and matched normal tissue from 300 patients for each of the threecancer types during the WU PE-CGS research program. Additional follow-up samples from 150 of thesepatients will also be analyzed during disease progression. Sample processing by the GCU will include nucleicacid extraction and QC. Diagnostic samples will be analyzed using 250X tumor/normal exome sequencing(WES) with both somatic and germline analysis for gene-level single nucleotide variants (SNV andinsertion/deletions (indels). Tumor-only WGS (60X) will be performed to detect tumor-associated structuralmutations and tumor RNA-seq will support confirm and extend findings from the DNA-based assays. Tumortissue and/or cell-free DNA will also be analyzed with targeted deep sequencing (>10000X) using uniquemolecular indexes (UMI) for sensitive detection and monitoring of tumor-associated mutations. All of theseassays will be performed using CLIA-compliant procedures with integrated quality management practices. TheGCU will also conduct research-level scRNA-Seq proteomics and cellular imaging studies on selectedsamples to enhance our understanding of these tumor types. Genomic assays will proceed according to aplanned schedule for year-by-year combinations of diagnostic specimens and follow-up collections with smallnumbers of candidates selected for research studies. Results from these assays will be returned to participantsusing a tiered reporting system that will depend on participant preference. Tier 1 results will highlight findingswith established clinical relevance obtained from CLIA sequencing of individual participants includingpathogenic tumor-associated somatic drivers and inherited mutations that are clinically actionable according topublished guidelines and that will be reported using established categorization for somatic drivers andpathogenic germline variants their clinical implications and possible actions. Participants can also elect toreceive Tier 2 results which will be comprised of additional mutations from the same CLIA-compliant data thatare identified with advanced methods and are predicted to be clinically relevant via functional annotation aswell as results from targeted sequencing of follow-up samples for monitoring tumor evolution over time.Research-level Tier 3 molecular studies may also be provided to participants as aggregate deidentified reportsthat can be used to enhance and extend interpretations of their individualized CLIA results. These results willalso be securely uploaded to the NCI Genomic Data Commons (GDC) for use by the cancer biologycommunity. All GCU activities will be coordinated with the PEU and EOU to ensure clarity and consistencyacross the WU PE-CGS program. +No NIH Category available Address;Adherence;Advanced Malignant Neoplasm;African American population;Age;Archives;Area;Biopsy;Cholangiocarcinoma;Clinical;Clinical Trials Database;Colorectal Cancer;Communication;Consent;Data;Databases;Enrollment;Ensure;Evaluation;Excision;Foundations;Future;Genome;Genomics;Goals;Informatics;Institution;Investigation;Knowledge;Malignant Neoplasms;Metadata;Methodology;Methods;Minority;Minority Groups;Mission;Multiple Myeloma;Participant;Pathologist;Patients;Physicians;Process;Prospective Studies;Protocols documentation;Recommendation;Reporting;Research;Research Personnel;Sampling;Specimen;Techniques;Therapeutic;Time;Underserved Population;Universities;Update;Vision;Washington;Work;cancer care;cancer genomics;cancer health disparity;cancer type;design;experience;fighting;improved;individual patient;innovation;interest;novel;participant enrollment;participant retention;patient advocacy group;patient engagement;programs;prospective;recruit;success;tumor;understudied cancer Participant Engagement Unit n/a NCI 10696011 9/7/23 0:00 RFA-CA-19-045 5U2CCA252981-03 5 U2C CA 252981 3 9/1/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7784 8182718 "FIELDS, RYAN C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 388967 440648 242130 PROJECT SUMMARY PARTICIPANT ENGAGEMENT UNIT (PEU)The PEU will be responsible for direct participant engagement to enroll patients into the Washington University(WU) PE-CGS program. Under the direction of PIs Fields and Drake we will leverage investigator andinstitutional expertise to directly address the Cancer Moonshot Blue Ribbon Panel recommendation to establisha network for direct patient engagement. We will prioritize 8 areas that are directly tied to the PEU SpecificAims: (1) identify; (2) contact; and (3) consent participants; (4) obtain tumor/normal samples and clinical/metadata; (5) create and prospectively maintain patient specimen and ongoing treatment data; (6) report researchfindings directly to study participants using cutting-edge innovative informatics-driven methodologies thatleverage unique partnerships; (7) guide patients through the flow of the WU-PE-CGS program providingoversight of program-wide integration; and (8) bi-directionally interact with the other WU-PE-CGS Units forongoing iterative refinement of program-wide protocols based on prospective study of participants.To achieve success in these seven areas that is in-line with the Cancer Moonshot mission we need novelparadigms for engagement. The WU-PE-CGS has developed several innovative approaches following ouroverall mission to develop implement evaluate and modify. First we have partnered with three world-classpatient advocacy groups (PAGs) that have significant experience in working directly with patient-partners (PPs)in advancing cancer care: The Cholangiocarcinoma Foundation (CCF) Fight Colorectal Cancer (FCRC) andThe Multiple Myeloma Research Foundation (MMRF). Second we will leverage our institutional strengths todirectly address this RFA's stated knowledge gaps of genomically characterizing and engaging patients withunderstudied tumor types (cholangiocarcinoma [CHOL]) and cancers that are understudied in minoritypopulations (colorectal cancer in African Americans under the age of 50 [CRC-AA<50] and multiple myeloma inAfrican Americans [MM-AA]). Third we will employ bi-directional real-time informatics-driven methods tointeract with the EOU to evaluate and iteratively refine our program to ensure that the WU-PE-CGS optimallyidentifies enrolls evaluates and interacts with the participants.The innovative and impactful aims of the PEU directly address the Cancer Moonshot goals of enlisting directpatient engagementto facilitate participation in research and ensure patients are respected and have accessto the research enterprise with a high priority to reach minority and underserved populations. Our partnershipswith PAGs and PPs leveraging of investigator and institutional expertise adherence to PCORI rubrics andongoing methodological refinement will result in impactful research across a broad group of cancer types. +No NIH Category available Affect;Antiviral Response;Cancer Patient;Cells;Communities;Correlative Study;Disease;Disease Resistance;Disease remission;Dose;Family;Fostering;Funding;Generations;Goals;Health;Hematopoietic Neoplasms;Histone Deacetylase Inhibitor;In Vitro;Infection;Isotopes;Laboratories;Leflunomide;Malignant Neoplasms;Mission;Multiple Myeloma;National Cancer Institute;Oncornaviruses;Oral;Patients;Persons;Pharmaceutical Preparations;Phosphotransferases;Proteasome Inhibitor;Protein-Serine-Threonine Kinases;Proto-Oncogene Proteins c-myc;Public Health;Qualifying;Radioimmunotherapy;Regimen;Research;Rheumatoid Arthritis;Scientist;Serine;Specialist;Surface;Therapeutic;Therapeutic Uses;Tumor Burden;United States;United States National Institutes of Health;Work;adhesion receptor;anticancer research;cancer cell;chimeric antigen receptor T cells;clinical effect;combinatorial;experience;immune modulating agents;immunoregulation;improved;improved outcome;lenalidomide;negative affect;new therapeutic target;novel therapeutic intervention;novel therapeutics;receptor;relapse risk;resistance mechanism;side effect Improving Outcomes for Multiple Myeloma Patients through Novel Therapeutic Interventions PROJECT NARRATIVEThe contributions of the Research Scientist are relevant to public health because the identification of effectivecombinatorial therapeutic regimens for multiple myeloma with correlative studies leading to the discovery of newdrug targets is expected to lead to novel therapies for this currently incurable malignancy. Thus the goals arerelevant to the part of the NIH's mission that pertains to fostering discoveries as a basis of improving health. NCI 10696008 8/29/23 0:00 PAR-20-288 5R50CA252135-03 5 R50 CA 252135 3 "HENDERSON, LORI A" 9/21/21 0:00 8/31/26 0:00 ZCA1-SRB-1(A1) 10291581 "CASERTA, ENRICO " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 112893 NCI 64144 48749 PROJECT SUMMARYMultiple myeloma (MM) is an incurable blood cancer affecting approximately 83000 people in the United States.Although treatments for MM have improved significantly in recent years the vast majority of patients experiencemultiple relapses and ultimately succumb to complications of the disease. For the last 12 years I the ResearchSpecialist have devoted my work toward contributing to improving outcomes for cancer patients. Since 2014 Ihave worked in the laboratory of Unit Director Flavia Pichiorri where we exclusively specialize in MM. I am nowinvolved with three National Cancer Institutefunded studies. 1) Radioimmunotherapy/CAR T cells: The useof therapeutic isotopes such as the beta emitter 177Lu or the alpha emitter 225Ac have increased the specific killingof cancer cells but side effects are clinical concerns. Although CAR T cells may reduce tumor burden patientsremain at risk of relapse. We predict that the use of CD38-directed radioimmunotherapy and CS1-directed CART cells will result in more durable remissions while lowering the dose for each agent with decreased side effectsand enhanced immunomodulation. 2) Reolysin: Reolysin an oncovirus shows only modest activity in MMpatients likely because of resistance mechanisms to oncoviruses. We observed that carflizomib a secondgeneration proteasome inhibitor showed synergic killing of MM cells in vitro when combined with Reolysin. Wefound that carfilzomib facilitates Reolysin infection through modulation of the antiviral response of themicroenvironment. We also discovered that HDAC inhibitors can reduce the surface expression of an importantadhesion receptor and upregulate the expression of an oncovirus receptor. 3) Overcoming IMiD research inmyeloma: To overcome disease resistance to immunomodulatory drugs (IMiDs) such as lenalidomide (Len)combinatorial therapies may be necessary. I have investigated the safe orally available drug leflunomide (Lef)which has been used for rheumatoid arthritis for the last 20 years. We demonstrated that Lef directly inhibitsseveral kinases including the PIM family of serine/threonine kinases in MM cells negatively affecting c-Mycprotein levels which are commonly upregulated in MM. With this information we reasoned that a suitable drugto use in combination is the immunomodulatory drug lenalidomide (Len). The completion of the projects goalswill rely in large part on my qualifications and the results thus far point to my value as a Research Specialist inthe cancer research community. 112893 +No NIH Category available Accountability;Advocate;Cancer Control;Cancer Control Research;Cholangiocarcinoma;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Creativeness;Discipline;Effectiveness;Elements;Environment;Evaluation;Feedback;Fostering;Foundations;Funding;Future;Genomics;Goals;Guidelines;Individual;Infrastructure;Knowledge;Leadership;Logic;Logistics;Maintenance;Malignant Neoplasms;Minority;Mission;Modeling;Monitor;Multiple Myeloma;Patients;Population;Positioning Attribute;Process;Productivity;Public Health;Recording of previous events;Records;Research;Research Personnel;Scholarship;Science;Scientific Evaluation;Scientist;Series;Structure;Time;Training;Translating;United States National Institutes of Health;Universities;Washington;cancer genomics;cancer health disparity;career;fighting;genome sequencing;innovation;meetings;member;operation;outreach;patient advocacy group;patient engagement;programs;rare cancer;response;synergism;timeline;understudied cancer Administrative Core n/a NCI 10696007 9/7/23 0:00 RFA-CA-19-045 5U2CCA252981-03 5 U2C CA 252981 3 9/1/21 0:00 8/31/27 0:00 ZCA1-TCRB-O 7783 2110411 "COLDITZ, GRAHAM A." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 407513 452424 248900 Project Summary: Administrative CoreThe Administrative Core will support an environment of research excellence scientific innovation andtransdisciplinary scholarship within the Washington University Participant Engagement and Cancer GenomicSequencing (WU-PE-CGS) Center and among other members of the NCI PE-CGS network of researchcenters and the coordinating center. The Administrative Core will implement a matrix-style administrativestructure to foster excellence in management and communication. Leaders and co-leaders of the three workingunits in the Center will form the Leadership Committee which (together with patient advocates) will use acollaborative process to engage and maintain the creativity and leadership of the significant individual andteam expertise involved in the Center. The goal of the Administrative Core is to provide the structure foreffective and efficient operation and maintenance of the WU-PE-CGS center in compliance with NIH andUniversity guidelines while leveraging innovative opportunities to advance the field of participant engagementand cancer genomics. The Core will support the overall mission of the WU-PE-CGS through the followingaims: (1) Organize the operational structure and scientific leadership for all WU-PE-CGS components andprovide oversight to maximize efficiency effectiveness and accountability; (2) Build participant engagement forunderserved/understudied populations to engage in network-driven collaborative studies via outreach amongother Centers in the network and collaboration with patient advocacy groups; (3) Provide scientific leadershipin minority and underserved participant engagement and in genome sequencing among other scientists in thenetwork; (4) Evaluate all WU-PE-CGS activities and provide feedback to refine ongoing activities; (5) Establisha timeline and milestones to monitor progress and coordinate efforts. The administrative core will position theWU-PE-CGS to optimize the innovation pace and impact of participant engagement research andgenomic characterization of rare understudied cancers. The WU-PE-CGS investigators have substantialexpertise and proven track records in conducting collaborative transdisciplinary science including researchand programs in cancer control genome sequencing dissemination of findings to other stakeholders andtranslating results for practitioners working in multiple settings. We are uniquely situated to provide scientificleadership to connect and expand a network of cancer-focused participant engagement researchers; supportinnovation; and enhance capacity for genome sequencing of rare and understudied cancers and directlyinteract with patient advocacy groups and patients for return of results and ongoing participant engagement.The Administrative Core is a critical element of the overall scientific program and infrastructure for the Centerand provides a strong foundation for scholarly excellence research synergy and efficiency and clinical andcommunity impact of the Center during and beyond the five-year initial funding period +No NIH Category available Administrator;Communication;Equity;Goals;Grant;Laboratories;Malignant Neoplasms;Manuscripts;Mission;National Cancer Institute;Operations Research;Pennsylvania;Radiation Oncology;Regulation;Research Personnel;Resources;Role;Running;Travel;United States National Institutes of Health;Universities;Visit;Work;biological adaptation to stress;meetings;member;programs;symposium Core A: Administrative Core n/a NCI 10696000 8/21/23 0:00 PAR-18-290 5P01CA165997-10 5 P01 CA 165997 10 9/18/13 0:00 8/31/24 0:00 ZCA1-RPRB-F 7779 2090001 "KOUMENIS, CONSTANTINOS " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 48693 30246 18447 ABSTRACT (Core A)The Administrative Core (Core A) will provide support and effort coordination for each of theprojects in this P01 as well as the two scientific cores. The aims of the Administrative Core areto ensure that the resources within the P01 are distributed equitably to the investigators and thatall rules and regulations of the National Cancer Institute and the National Institutes of Health arefollowed. The Administrative Core will coordinate meetings of the investigators and theirlaboratories and facilitate communication between our investigators with the External AdvisoryBoard. The finances of the P01 will be organized by Ms. Jenine Iannaccone Grants Administratorin the Department of Radiation Oncology who will meet monthly with the P01 PrincipleInvestigator and quarterly with each Project and Core Leader. Ms. Andrea Rycroft AdministrativeCoordinator will coordinate travel arrangements for the members of the P01 as well as theadvisors who will visit the University of Pennsylvania. She will also provide administrative supportfor each of the P01 investigators for efforts related to the Program. It is anticipated that throughthe combined efforts of the Core Director Ms. Rycroft and Ms. Iannaccone the researchoperations and communications of the P01 will run with optimum efficiency +No NIH Category available Acceleration;Address;Advocacy;Aftercare;Age;CLIA certified;Cancer Patient;Cancer Survivor;Capital;Characteristics;Cholangiocarcinoma;Colorectal Cancer;Communication;Communities;Complex;Creativeness;Development;Disadvantaged;Discipline;Disparity;Ensure;Environment;Evaluation;Family;Fostering;Genomics;Goals;Health Benefit;Health system;Investments;Knowledge;Leadership;Malignant Neoplasms;Methodology;Multiple Myeloma;Participant;Patient advocacy;Patients;Persons;Population;Positioning Attribute;Provider;Research;Research Personnel;Resources;Rural Population;Science;Technology;Testing;Underserved Population;Universities;Vision;Washington;anticancer research;cancer genomics;cancer health disparity;career;evidence base;follow-up;genome sequencing;improved;innovation;interdisciplinary collaboration;member;outreach;patient engagement;patient oriented;patient population;rare cancer;recruit;success;synergism;tumor;understudied cancer Washington University Participant Engagement and Cancer Genomic Sequencing Center (WU-PE-CGS) PROJECT NARRATIVEThe goal of the WU-PE-CGS is to build a rigorous scientific evidence base for approaches direct engagementof cancer patients and post-treatment cancer survivors from rural and underserved populations as participantsin cancer research. Our Center will provide a significant return on the scientific investment resulting ininnovations to advance participant engagement outreach and communication in genomic characterizationstudies. NCI 10695997 9/7/23 0:00 RFA-CA-19-045 5U2CCA252981-03 5 U2C CA 252981 3 "MECHANIC, LEAH E" 9/1/21 0:00 8/31/27 0:00 ZCA1-TCRB-O(M1) 2110411 "COLDITZ, GRAHAM A." "DING, LI ; DRAKE, BETTINA F.; FIELDS, RYAN C" 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 3109346 NCI 2748928 1535661 PROJECT SUMMARYVision. Participant engagement and sequencing research from the Washington University ParticipantEngagement and Cancer Genomic Sequencing Center (WU-PE-CGS) will fill critical gaps in knowledgemethodology and characterization of understudied cancer populations leading to optimal approaches toparticipant engagement outreach and communication in genomic characterization studies.Goal. The overall goal of the WU-PE-CGS is to build a rigorous scientific evidence base for approaches directengagement of cancer patients and post-treatment cancer survivors as participants in cancer research. Ourfocus is on rare and understudied cancer populations with significant disparities including cholangiocarcinomamultiple myeloma and colorectal cancer under age 50. Participant engagement strategies are most effectivewhen they are adapted and implemented in real-world settings in partnership with community and patientadvocacy stakeholders.Setting. Our Center will be housed in an exceptional environment that fosters transdisciplinary collaborationcatalyzes new ideas in patient engagement and ensures support for patient engagement and genomesequencing that finds solutions for complex recruitment and engagement challenges in real-world settings withunderrepresented patient populations. Significant matching contributions from Washington University will allowus to quickly and strategically invest in ideas.Aims. The specific aims of the Center are to: (1) Advance the field of participant engagement to study cancerdisparities and rare cancers by conducting innovative and impactful direct stakeholder engagement withcontinuous evaluation and research; (2) Expand an exceptional diverse team of investigators patients andadvocacy stakeholders; (3) Address cancer disparities by understanding barriers to and improving the abilityfor disadvantaged and understudied populations to encounter use and benefit from genomic sequencing andanalysis; (4) Organize and integrate Center units to facilitate transdisciplinary team science within our Centerand across the PE-CGS Network.Innovations and impact. The WU-PE-CGS builds on a long and outstanding record of leadership in both cancerdisparities and genomic research across the cancer continuum. We will be particularly innovative and allow fora significant return on the scientific investment in several ways. First our Center has distinctive features thatinclude a combined focus on cancer disparities the application of strategies to increase participantengagement in research success in biospecimen acquisition and exceptional genomic sequencing expertise.Second we have assembled a diverse world class team with strong linkages to multiple rare and understudiedcancers. Third we engage investigators from different disciplines and invest in the development of earlycareer scholars. Fourth we will strategically and creatively disseminate products in ways that will benefitresearchers practitioners and community members. Fifth we will partner with exceptional patient-centeredand wide-reaching advocacy groups to engage patients optimize recruitment and seamlessly return results.Input from these groups patients and their families is a key strength that will leverage our track record ofstakeholder-engaged research. And finally we have developed a focused strategy for collective integration ofour units. These synergies will allow our Center to become a national resource for optimal approaches toparticipant engagement outreach and communication in genomic characterization studies and other studiesas technologies advance that will accelerate progress for both the scientific community patients and theircommunities. In summary we are uniquely situated to advance a network of participant engagement and sequencingresearchers integrate research with patients and their stakeholders build intellectual capital and significantlyenhance the capacity for participant engagement and genomic characterization studies. This Center willultimately benefit health systems providers and people with rare cancers and lead to a reduction in cancerdisparities. 3109346 +No NIH Category available ARNTL gene;Adoptive Transfer;Affect;Affinity;Attenuated;Benign;Bypass;Cell Proliferation;Cells;Cessation of life;Complement;Cytokine Receptors;Cytotoxic T-Lymphocytes;Data;Development;Down-Regulation;Funding;Generations;Genes;Genetic;IFNAR1 gene;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Surveillance;Immunotherapy;Interferon Type I;Interferon alpha;Interferons;Interleukin-2;Knowledge;Ligands;Lymphocyte;Malignant - descriptor;Malignant Neoplasms;Mediating;MicroRNAs;Mus;Pathway interactions;Play;Protein Biosynthesis;Protein Kinase;Recombinant Interferon;Resistance;Role;Signal Transduction;Stabilizing Agents;Stress;Stress Response Signaling;T cell therapy;Testing;Translational Repression;Tumor Escape;Tumor Immunity;Work;anti-cancer;biological adaptation to stress;cancer cell;cancer therapy;chimeric antigen receptor T cells;cytokine;cytotoxic;experimental study;feasibility testing;improved;improved outcome;in vivo;innovation;mRNA Translation;metabolomics;mouse model;neoplastic cell;novel;response;restoration;therapy outcome;tumor;tumor growth;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Project 3- Integrated Stress and Interferon Responses NARRATIVETumors escape from the anti-tumor immune defenses through a number of mechanisms including the integratedstress response-mediated inactivation of effects of Type 1 interferon cytokines (IFN1). Our recent findingssuggest that inactivation of IFN1 receptor (IFNAR1) on the intratumoral cytotoxic T lymphocytes is central toundermining their ability to confront malignant cells. Here we propose to determine how the integrated stressresponses inactivate IFNAR1 inside the tumors and whether targeting these mechanisms can improve the anti-tumor immunity and the efficacy of immune therapies against cancer. NCI 10695996 8/21/23 0:00 PAR-18-290 5P01CA165997-10 5 P01 CA 165997 10 9/18/13 0:00 8/31/24 0:00 ZCA1-RPRB-F 7777 1966250 "FUCHS, SERGE Y" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 294512 182934 111578 ABSTRACTDevelopment and progression of cancer occurs in spite of anti-tumorigenic effects of Type 1 interferon cytokines(IFN1 including IFN and IFN). IFN1 counteract tumor development and progression directly (by suppressionof malignant cells) and indirectly (by stimulation of anti-tumor immunity). Our work in the past funding periodrevealed that the integrated stress response (ISR) induced in the tumor microenvironment help malignant andbenign tumor cells to evade the anti-tumorigenic effects of IFN1. We found that ISR-driven inactivation of IFN1receptor IFNAR1 deprives tumor cells from ability to respond to IFN1 and plays an important role in tumor growthand progression. Furthermore our work revealed an important role of IFNAR1 inactivation in the ISR-induceddeath of activated intra-tumoral cytotoxic T lymphocytes and accordingly in generation of the immune privilegedniche that helps to overcome anti-tumor immunity. Our new pilot experiments also suggested that inactivation ofIFNAR1 decreases the tumoricidal activity of cytotoxic T lymphocytes and undermines the efficacy of adoptivetransfer of chimeric antigen receptor T cells and of inhibitors of immune checkpoints.New preliminary studies from our group and our collaborators (Projects 1-2) also revealed that additionalinnovative mechanisms promoting tumorigenesis depend on inactivation of the IFNAR1 pathway in a mannerthat involve ATF4 and its regulated miRNAs (e.g. miR-211 and miR-217) and include the suppression oftranslation of the mRNAs for IFNAR1 and the IFN-stimulated genes (IGSs). In our current proposal we aim todefine these mechanisms and target them to augment anti-cancer therapies. We will test an integratedhypothesis that in the tumor microenvironment the ISR-driven inactivation of the IFNAR1 pathway in thecytotoxic T lymphocytes plays a pivotal role in tumor growth and progression. Furthermore efforts to restoreIFNAR1 signaling can stimulate anti-cancer immune responses and improve the outcome of therapeuticapproaches. To test this hypothesis we propose to delineate the mechanisms underlying ISR-induced IFNAR1-dependent and independent inactivation of the IFN1 pathway and its role in the loss of viability of intratumoralcytotoxic lymphocytes and the generation of the immune privileged niches (Aim 1). We will also delineate themechanisms underlying ISR-driven inactivation of the tumoricidal activities of cytotoxic T lymphocytes anddetermine whether targeting these mechanisms can augment anti-cancer immunity (Aim 2).Completion of these studies should improve our knowledge on the role of ISR in generating the immuneprivileged niches that provide safe harbor for malignant cells and drive tumor growth and progression.Furthermore identification and characterization of the mechanisms leading to IFNAR1 pathway inactivation willenable us to identify specific targets for improving the efficacy of anti-cancer immune therapies. +No NIH Category available 3-Dimensional;ARNTL gene;Ablation;Acceleration;Acute;Allografting;Amino Acids;Apoptosis;Attenuated;Autophagocytosis;B-Cell Lymphomas;Binding;Bioenergetics;Cells;ChIP-seq;Collaborations;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Cytotoxic T-Lymphocytes;Development;Down-Regulation;EIF-2alpha;Endoplasmic Reticulum;Enzymes;FRAP1 gene;Face;Funding;Genes;Genetic;Genetic Engineering;Genetic Transcription;Glucose Transporter;Glycolysis;Glycolysis Inhibition;Hematopoietic stem cells;Homeostasis;Immunologic Surveillance;In Vitro;Induction of Apoptosis;Infiltration;Interferon Type I;Investigation;Knock-out;Large Intestine Carcinoma;Lymphoma;Lymphoma cell;Lymphomagenesis;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolism;Modeling;Molecular;Mus;Nutrient availability;Oncogene Activation;Oncogenic;Organoids;Oxygen;Pathway interactions;Patients;Phosphorylation;Play;Process;Proliferating;Prostate carcinoma;Prostatic Neoplasms;Protein Biosynthesis;Proteins;Regulation;Role;SLC2A1 gene;Signal Transduction;Stress;Testing;Text;Therapeutic Intervention;Transcriptional Activation;Transfer RNA;Transgenic Model;Translational Regulation;Translations;Transplantation;Up-Regulation;Work;Xenograft procedure;arm;biological adaptation to stress;c-myc Genes;cell growth;cell transformation;colon carcinogenesis;conditional knockout;endoplasmic reticulum stress;experimental study;glucose uptake;glycosylation;in vivo;inhibitor;knock-down;neoplastic cell;new therapeutic target;novel;pharmacologic;programs;promoter;prostate cancer cell;response;sensor;transplant model;tumor;tumor growth;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Project 2- The ISR effector ATF4 in metabolic reprogramming and survival during Myc-induced tumorigenesis PROJECT NARRATIVE (Project 2)Tumor cells face extrinsic stresses in the tumor microenvironment as well as from intrinsic stress imposed byoncogenic genes activated during malignancy which metabolic demands on these cells thereby activatingadaptive processes to survive and proliferate. We will study the of such an adaptive process termedIntegrated Stress Response in malignant progression of lymphoma colorectal and prostate cancer. Bydefining the essential nodes in reprogramming metabolism by this pathway we should uncover potential newtargets for therapeutic intervention. NCI 10695993 8/21/23 0:00 PAR-18-290 5P01CA165997-10 5 P01 CA 165997 10 9/18/13 0:00 8/31/24 0:00 ZCA1-RPRB-F 7775 2090001 "KOUMENIS, CONSTANTINOS " Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 287854 230785 57069 ABSTRACT/SUMMARY (Project 2) Tumor cell intrinsic stress including oncogene activation as well as extrinsic stresses such as lowoxygen/nutrient availability elicit perturbations in the endoplasmic reticulum (ER). Moreover oncogenicallytransformed cells face increased burden placed by augmented biosynthetic pathways and rewired metabolismto meet the demands imposed by rapid proliferation. Adaptation to the ensuing stress and re-establishmentof cellular homeostasis is achieved via activation of a coordinated signal transduction program termed theIntegrated Stress Response (ISR). During the previous funded period we demonstrated that increased ratesof protein synthesis elicited by oncogenic MYC activate the PERK/GCN2eIF2 arm of the ISR therebysupporting MYC-induced cell transformation. In preliminary unpublished studies we have accumulated strongevidence supporting an essential role for the ISR effector and target of eIF2 ATF4 in transformation andtumorigenesis particularly in tumors with activated MYC. However how ATF4 elicits differential responsesto various stresses in the context of MYC-dependent transformation is a critical question that remainsunanswered. We will test the hypothesis that activation of ATF4 by the ISR plays a critical role in MYC-induced transformation and tumor progression by promoting metabolic and translational adaptationin coordination with MYC by focusing on three specific Aims. In Aim 1 we will identify critical nodes incellular metabolism and translational regulation which are coordinately regulated by both ATF4 and c-MYC.Specifically we will delineate the mechanism of Glut-1 and eIF4E transcriptional activation by ATF4 anddetermine functional requirements of GLUT1 and eIF4E in regulating glycolysis translation and survival duringMYC-dependent transformation in vitro and in vivo. Under Aim 2 we will delineate the mechanism of co-regulation of transcriptional targets between ATF4 and MYC by ChIP-seq analysis in lymphoma colorectal(CRC) and prostate (PCa) cancer cells expressing inducible forms of MYC and analyze coordinately regulatedgenes. We will then determine the effects of knockout/knockdown of the identified co-regulated genes andnewly identified targets in MYC-dependent proliferation apoptosis and tumor growth. Finally under Aim 3we will determine the role of ATF4 in MYC-dependent transformation and tumorigenesis in PCa and CRCtumors using a conditional knockout ATF4 model crossed with PTENfl/fl:MycTg and mouse CRC models(orthotopic syngeneic and spontaneous) as well as 3D CRC organoids. We will also work with Project 1 toanalyze the regulation of ATF4-dependent downregulation of BMAL1 and Clock genes and their role intranslation and lymphomagenesis. Finally with Project 3 we will analyze the effects of ATF4 ablation ontype I interferon pathway and viability/effector functions of tumor-infiltrating cytotoxic T lymphocytes.Completion of these aims will provide a better understanding of the critical role of ATF4 in MYC-dependentpro-tumorigenic processes and may uncover new targets for therapeutic intervention in these malignancies. +No NIH Category available ARNTL gene;Address;Apoptosis;Apoptotic;B-Cell Lymphomas;Blood Vessels;Cell Cycle Inhibition;Cell Cycle Progression;Cell Death;Cell Fate Control;Cell Survival;Cell division;Cells;Circadian gene expression;Collaborations;Data;Defect;Development;EZH2 gene;Endoplasmic Reticulum;Foundations;Funding;Gene Expression;Genetic Transcription;Glucose;Growth;Growth Factor;Homeostasis;Human;IFNAR1 gene;Induction of Apoptosis;Lymphoma;Lymphomagenesis;Malignant Neoplasms;Mediator;Messenger RNA;Metabolic;MicroRNAs;Modeling;Molecular;Molecular Chaperones;Normal Cell;Nutrient;Nutrient availability;Organism;Oxygen;Pathway interactions;Proliferating;Property;Protein Biosynthesis;Proteins;Regulation;Repression;Role;Signal Transduction;T-Lymphocyte;Testing;Tissues;Translational Regulation;Translational Repression;Translations;Tumor Promotion;Tumor Volume;Work;anti-cancer;biological adaptation to stress;cancer cell;cancer therapy;cell growth;circadian;circadian pacemaker;cyclin G1;defined contribution;deprivation;design;endoplasmic reticulum stress;experimental study;glucose metabolism;mRNA Translation;misfolded protein;neoplastic cell;novel;prevent;protein metabolism;response;small molecule inhibitor;stem;transcription factor;tumor;tumor metabolism;tumor progression;tumorigenesis Project 1- Micro-RNA-dependent signaling by the UPR NarrativeRecent work has revealed that inactivation of PERK can promote tumor progression providing support forthe development of small molecule inhibitors of PERK for cancer treatment. However the mechanisms forthis activity remain poorly defined limiting our understanding of PERK regulation of cell fate. The workdescribed in this Project will delineate molecular mechanisms of both pro-tumor properties of PERK. NCI 10695990 8/21/23 0:00 PAR-18-290 5P01CA165997-10 5 P01 CA 165997 10 9/18/13 0:00 8/31/24 0:00 ZCA1-RPRB-F 7774 6730667 "DIEHL, JOHN ALAN" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 292907 292907 0 AbstractRapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such asglucose oxygen and growth factors become limiting as tumor volume expands beyond the establishedvascularity of the tissue. In normal cells limits in nutrient availability trigger growth arrest and/or apoptosisthereby preventing cellular expansion under such conditions. Our scientific premise is that the pro-survivalactivities of PERK reflect the combined impact of PERK-dependent differential control of protein synthesisand gene expression. In the previous funding cycle we identified miR-211 and miR-216b as a PERK-ATF4regulated micro-RNAs that regulate cell survival. We identified three critically important miR-211 targets.The first is the pro-apoptotic transcription factor Chop. The second target is the Bmal1-Clock heterodimerictranscription factor that functions as the primary driver of circadian gene expression and thus circadianoscillation. Both Bmal1 and Clock are direct targets of miR-211 and are repressed by miR-211 during aUPR. Through analysis of PERK-miR-211 regulation of Bmal1 and the circadian clock we discovered that1) circadian gene expression is disrupted by the UPR 2) Bmal1 loss contributes to PERK-dependentregulation of mRNA translation. We propose a hypothesis wherein the UPR inducible micro-RNAs (miR-211 miR-217) regulate cell fate by silencing key targets such as Bmal1 which thereby contributes to PERK-dependent translational regulation and cell survival. To address this hypothesis we propose three specificaims. Aim 1 will defined the critical targets of PERK-miR211-Bmal1 regulation and their contribution to cellsurvival. Aim 2 will define the role of miR-217 in antagonizing miR-211 regulation of its transcriptionaltargets. Aim 3 will define the role of miR-211-dependent regulation of Bmal1 to the development andprogression of B-cell lymphoma. There are obvious points of cross-talk between this proposal and Project 2which focuses on how the UPR antagonizes myc induced apoptosis and ATF4-dependent regulation oftumor cell metabolism. Through collaboration with Project 2 we will assess the role of miR-211 and Bmal1as a mediator of tumor cell metabolism and survival. Through collaboration with Project 3 we willdetermine how miR-211 miR-217 and Bmal1 regulate IFNAR1 signaling and regulation in cytotic T-lymphocytes. The findings steming from work proposed herein will provide a foundation for the design ofnovel anti-cancer therpeutics. +No NIH Category available Agreement;Awareness;Biometry;Blood;Bone Marrow Transplantation;Cancer Center;Cancer Center Support Grant;Cancer Control;Clinical Research;Clinical Trials;Committee Members;Communities;Consent;Consultations;Disease;Electronics;Ensure;Epidemiology;Goals;Grant;Hematology;Hour;Indiana;Industry;Knowledge;Leadership;Monitor;NCI Center for Cancer Research;Patients;Pediatrics;Pharmacology;Population;Process;Protocols documentation;Published Comment;Research Personnel;Research Priority;Resources;Rest;Review Committee;Solid Neoplasm;System;Time;Universities;cancer prevention;cancer research center director;design;experience;interest;investigator-initiated trial;meetings Protocol Review and Monitoring System n/a NCI 10695987 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7772 15058561 "DURM, GREG " Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 56134 35416 20718 ABSTRACT Protocol Review and Monitoring System (PRMS)The Scientific Review Committee (SRC) and Protocol Progress Committee (PPC) comprise the Protocol Reviewand Monitoring System (PRMS) for the Indiana University Melvin and Bren Simon Cancer Center (IUSCC). TheSRC and PPC focus on the following three specific aims:Aim 1: To ensure the IUSCC prioritizes and conducts impactful trials with high scientific merit.The IUSCC prioritizes Investigator Initiated Trials (IITs) > national cooperative group > industry-sponsored trials.Initial responsibility for prioritization rests with the disease-oriented teams (DOTs). DOTs review proposed trialsin the context of their programmatic goals and their current trial portfolio. In addition DOTs analyze patientvolumes and accrual to current/recent trials to ensure the accrual goals are reasonable and adequate. Once aDOT has agreed to support a trial the full protocol consent and all supporting documents along with thefeasibility checklist and prioritization scorecard are submitted to the SRC for review. SRC review focuses onscientific merit but also ensures that the DOTs have appropriately prioritized trials and managed any conflicts.Trials submitted to the SRC by an investigator or DOT that has had a trial closed for low accrual within theprevious three years require additional justification of the accrual estimates.Aim2: To facilitate rapid activation by conducting efficient and timely review of new protocols.The goal of the PRMS is to conduct reviews in an efficient and timely manner to support rapid activation of highpriority trials. To enhance efficiency beginning in January 2018 the SRC meets twice a month. The SRC usese-PRMS a paperless committee management system which is housed within OnCore. The online submissionand review console offers immediate access to electronic protocol documents eliminating the need to trackcopy and collate multiple binders for reviewers. Reviewers submit comments at least 48 hours prior to themeeting which are forwarded to the PI who can respond prior to the meeting if possible. Concurrent scientificand feasibility review facilitates rapid activation while minimizing resource utilization until feasibility is assured.Aim 3: To maximize the use of resources by monitoring protocol accrual and progress.Once approved the PPC monitors protocol progress and accrual. Protocols not reaching the minimum accrualtarget are subject to closure by the PPC. High priority IITs and trials in rare populations are granted additionaltime to meet accrual goals but still must make progress to avoid closure. The PPC is a subcommittee of theSRC and meets concurrently with the SRC increasing reviewers' awareness of the resources lost to low accruingtrials. +No NIH Category available Address;Administrator;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Research Protocols;Clinical Sciences;Clinical Trials;Collaborations;Collection;Community Outreach;Conduct Clinical Trials;Consent;Data Element;Development;Disease;Doctor of Medicine;Documentation;Electronics;Eligibility Determination;Employee;Ensure;Funding;Future;Generations;Growth;Indiana;Infrastructure;Laboratories;Leadership;Multicenter Trials;Nurses;Nursing Research;Occupational activity of managing finances;Office Management;Oncology;Population Study;Positioning Attribute;Principal Investigator;Qualifying;Reporting;Research Personnel;Research Subjects;School Nursing;Services;Specialist;Therapeutic Intervention;Time;Training;Training and Education;Translational Research;Underserved Population;Universities;anticancer research;community engagement;cost effective;data integrity;data management;improved;member;operation;programs;protocol development;success;tool Clinical Protocol and Data Management n/a NCI 10695985 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7771 9848398 "LAUTENSCHLAEGER, TIM " Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 431740 272391 159349 ABSTRACT Clinical Protocol and Data Management (CPDM)The CTO is critical to the success of all clinical trials conducted through the IUSCC. In 2017 the CTOmanaged 367 active trials 101 of which were Investigator Initiated (IITs). The CTO is led by Associate Directorfor Clinical Research Kathy Miller M.D. (EDT) and Administrator Mario Contreraz MBA MSN RN CCRCwho provide leadership and oversight of the day-to-day operations to ensure comprehensive high-qualityservices and to streamline efforts to open trials and increase accrual.The Indiana University Melvin and Bren Simon Cancer Center (IUSCC) Clinical Trials Office (CTO) supports andenhances IUSCC members' ability to conduct clinical cancer research. The CTO provides comprehensiveservices to assist investigators in developing activating and completing scientifically meritorious clinical trials ina high quality cost-effective efficient manner. At the same time the CTO ensures the validity and integrity ofdata in order to fulfill all NCI federal and local regulatory requirements. The CTO does so through the followingSpecific Aims: Aim 1: To facilitate the efficient development conduct and reporting of clinical trials across therange of therapeutic interventional correlative and population-based studies by maintaining a centralizedinfrastructure and educated workforce; Aim 2: To ensure continued and expanded access to clinical trialsparticularly for the underserved populations within our catchment area and beyond.; and Aim 3: To supportclinical trial accrual through the implementation and coordination of disease-oriented teams (DOTs).Over the past funding cycle we have created new positions to better support the increasing clinical trialcomplexity driven by the increase in IITs and IUSCC-led multicenter trials. For example we hired multicentercoordinators (MCRC) to support continued growth of our investigator-initiated multi-center trials and a secondprotocol development specialist to assist with IITs. The CTO has also created positions for Clinical ResearchProtocol Specialists (CRPS) who aid in the conduct and management of non-interventional correlative trialsincluding subject consent verification of eligibility collection and submission of key clinical and laboratory dataelements. +No NIH Category available Advisory Committees;Age;Basic Science;Bioinformatics;Biology;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Network;Catchment Area;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communities;Community Outreach;Development;Developmental Therapeutics Program;Disease;Early Diagnosis;Education;Evaluation;Extramural Activities;Faculty;Feedback;Funding;Genomics;Goals;Grant;Health;Heart Diseases;Hematologic Neoplasms;Hematopoiesis;Human Papilloma Virus Vaccination;Immunology;Incidence;Indiana;Indiana University Cancer Center;Infant Mortality;Infrastructure;Intervention;Investigational Therapies;Kenya;Knowledge;Leadership;Liquid substance;Lung;Malignant Neoplasms;Medicine;Mission;Molds;Multiple Myeloma;NCI-Designated Cancer Center;Names;Neoplasm Metastasis;Patient Care;Patient Education;Phase;Precision Health;Prevention;Process;Prospective cohort study;Proteomics;Public Health;Research;Research Personnel;Resource Sharing;Risk Behaviors;Rural Population;Science;Shapes;State Government;Strategic Planning;Students;Talents;Teenagers;Tobacco;Touch sensation;Translational Research;Underrepresented Minority;Underserved Population;Universities;Update;Work;anticancer research;cancer prevention;carcinogenesis;career;childhood sarcoma;community engagement;health care disparity;health goals;high risk behavior;improved outcome;innovation;malignant breast neoplasm;medical schools;member;mortality;next generation;outreach;population health;precision medicine;programs;recruit;survivorship;symptom science;teacher;translational research program;triple-negative invasive breast carcinoma;tumor;tumor immunology;tumor microenvironment Leadership Planning and Evaluation n/a NCI 10695982 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7769 6895846 "LEE, KELVIN P." Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 501296 316275 185021 ABSTRACT Leadership Planning and Evaluation The Indiana University Melvin and Bren Simon Cancer Center (IUSCC) has established an effective process for Leadership Planning and Evaluation that receives input from its Senior Leaders Program Leaders and Membership as well as internal and external advisory committees. Based on this input the IUSCC leadership has molded its strategic plan implemented this plan and regularly evaluates its impact on its four Research Programs and multiple Shared Resources (Cores) advancing our mission to serve the citizens of Indiana and beyond. The IUSCC Strategic Plan which was updated in 2018 has four major research pillars: Biology to Bedside Translational Research Precision Medicine Population Health (with an emphasis on Prevention Early Detection and Health Care Disparities) and Survivorship and Symptom Science. Following this strategic plan and with feedback from our advisors the Senior Leadership implemented a number of actions during the last funding period including: 1) dissolving the Breast Cancer Program and integrated its members into the remaining basic and translational research programs; 2) appointing an Associate Dean of Translational Research; 3) installing new leadership in the Cancer Prevention and Control (CPC) and the Experimental and Developmental Therapeutics (EDT) Programs; 4) renaming Hematopoiesis Hematologic Malignancies and Immunology (HMI) Program to Hematopoiesis and Hematologic Malignancies (HHM) to emphasize its focus on liquid tumors and recognizing that cancer immunology cuts across all programs; 5) creating the Office of Community Outreach and Engagement to drive our activities throughout the state; 6) formally establishing the Tumor Microenvironment and Metastasis (TMM) and HHM programs as basic research programs; 7) developed new Cancer Bioinformatics and Translational Research cores; and 8) integrated the IUSM's Proteomics and Genomics Cores with the IUSCC. These changes informed by the thematic pillars of our strategic plan drive the IUSCC's mission to impact research patient care and education both locally and globally by bolstering team science amplifying community outreach and engagement activities and expanding our educational footprint to inspire the next generation of cancer researchers. +No NIH Category available Acceleration;Address;Antineoplastic Agents;Applications Grants;Area;Award;Behavior Control;Biological Assay;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Patient;Cancer Research Project;Clinical;Collaborations;Development;Diagnosis;Evaluation;Evolution;Funding;Future;Goals;Grant;Incidence;Indiana;Intellectual Property;Investments;Leadership;Legal patent;Licensing;Malignant Neoplasms;Mentors;Molecular Target;Monitor;Patients;Phase I Clinical Trials;Pilot Projects;Prevention;Process;Progress Reports;Publications;Quality of life;Research;Research Personnel;Research Project Grants;Research Training;Resource Development;Resource Sharing;Review Committee;Scientist;Testing;Translating;Translational Research;Universities;Validation;Writing;anticancer research;drug candidate;drug development;innovation;meetings;member;mortality;novel;novel marker;operation;pharmacodynamic biomarker;predictive marker;programs;protocol development;recruit;success Developmental Funds n/a NCI 10695979 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7768 1899304 "KELLEY, MARK R." Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 322578 203519 119059 ABSTRACT Developmental FundsDevelopmental funds are a critical component of the budget used to invest in new innovations valuable sharedresources and key areas of research. In the coming project period the IUSCC will use developmental funds toaddress the following aims: 1: To identify the most promising and innovative pilot projects in cancerresearch. Cultivate and catalyze new research collaborations and teams around the strengths of our centerthrough continued investment in our pilot funding program. Priority is given to the most innovative projects thatcould lead to future NCI-sponsored research that leads to reduced incidence and mortality rates or increasedquality of life for cancer patients in Indiana and beyond; 2: To facilitate collaborative research projects andhow they are conducted to maximize their success. All award recipients are mentored and monitored throughthe novel IUSCC Translational Research Acceleration Collaboration (ITRAC) Project Management Process.Special emphasis is made to optimize use of IUSCC Cores and to encourage collaborations towards multi-PIgrant proposals; 3: To conduct rigorous monitoring and evaluation of all projects. Once approved forfunding all projects are monitored and evaluated using the ITRAC process of IUSCC. This process has beenused for monitoring and evaluating all IUSCC Pilot Funded Projects since 2006. Written progress reports aresubmitted to the IUSCC leadership council (LC) and executive committee (EC) for review of progress. In additionthe EAB and IAB reviews the progress at their annual meetings; and 4: To develop the Translational ResearchCore (TRC). The TRC has been developed to assist investigators both clinical and basic scientists withdeveloping and performing in-house drug development of Phase I clinical trials. The TRC also performscorrelative biological assays needed to validate mechanism(s) of action of candidate drugs/therapies and todevelop and test new hypotheses. +No NIH Category available Advisory Committees;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer health equity;Catchment Area;Cities;Clinical Trials;Communities;Community Outreach;County;Development;Disparity;Education and Outreach;Ethnic Origin;Funding;Future;Geography;Health Disparities Research;Health Policy;Health Promotion;Incidence;Indiana;Malignant Neoplasms;Monitor;Outcome;Play;Population Density;Population Sciences;Prevention;Prevention strategy;Race;Research;Research Personnel;Role;Rural Community;Specialist;Strategic Planning;Structure;Targeted Research;Underserved Population;United States National Institutes of Health;Universities;Urban Community;arm;cancer education;cancer research center director;clinical care;community engagement;evidence base;health disparity;improved;mortality;operation;outreach;outreach program;programs;screening;socioeconomics;survivorship;tobacco control Community Outreach and Engagement n/a NCI 10695976 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7767 1864817 "CHAMPION, VICTORIA LEE" Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 230990 145735 85255 ABSTRACT Community Outreach and EngagementThe Office of Community Outreach and Engagement (OCOE) supports the integration of research clinical careand dissemination of research findings to our catchment area which we have defined as the state of Indiana.Although the incidence of cancer in Indiana is equivalent to national averages mortality is significantly higher(181.0 vs 163.5 per 100000) and our underserved populations suffer the greatest cancer burden; thus they arethe primary focus of our collaborative efforts. The OCOE is led by the AD of Community Outreach and PopulationScience Research Dr. Champion who has 34 years of NIH funded research in the community and has playedcritical roles in the development and dissemination of cancer control science within the IUSCC. The OCOEincludes two interactive arms: 1) Research and 2) Outreach and Engagement. Building on the strategic plan ofIUSCC the OCOE acts as the primary structure to integrate IUSCC researchers and community partners todevelop implement and disseminate research targeting our catchment area and beyond to improve canceroutcomes and enhance cancer health equity. The following four aims are the focus of our community outreachand engagement activities: Specific Aim 1: To define understand and monitor the cancer incidence mortalitydeterminants and disparities in Indiana; Specific Aim 2: To conduct and implement impactful research(prevention screening treatment and survivorship) that targets issues relevant to catchment area; Specific Aim3: To develop and disseminate evidence-based strategies for prevention screening treatment and survivorshipin our catchment area and beyond; and Specific Aim 4: To promote health policy that will decrease the cancerburden in Indiana. The Research arm of the office is led by Dr. Susan Rawl Co-Leader of the CPC programand focuses on Aims 1 & 2 from the COE. The Outreach and Engagement arm is led by Drs. Clint Cary (CPC)and Sarah Wiehe who oversee the collective efforts that pertain to the development and dissemination ofevidence-based strategies and to the promotion of cogent health policy particularly tobacco control (Aims 3 &4). This arm also coordinates urban and rural community outreach activities and thus includes the managers fortobacco control and Community Operations clinical trial specialists and a statewide cancer liaison that leveragescancer education and outreach with all community outreach programs within the iCTSI. The Health DisparitiesAdvisory Board (HDAB) meets semiannually to advise the AD of Community Outreach and Population ScienceResearch on relevance of and future directions for research and dissemination that focuses on underservedpopulations in our state. +No NIH Category available Address;Applications Grants;Biochemical;Biology;Body Weight decreased;Budgets;CCKBR gene;CRISPR/Cas technology;Cells;Cholecystokinin;Cholecystokinin B Receptor;Cholecystokinin Receptor;Choline Deficiency;Cirrhosis;Collagen;Development;Development Plans;Diet;Dietary Fats;Engineering;Epidemic;Epigenetic Process;Ethionine;Fibroblasts;Fibrosis;Functional disorder;G-Protein-Coupled Receptors;Gastrins;Gastrointestinal tract structure;Goals;Growth;Hepatic;Hepatic Stellate Cell;Hepatocarcinogenesis;Hepatology;Histologic;Histology;Human;Immunologist;Immunology;In Vitro;Inflammation;Inflammatory;Knock-out;Knockout Mice;Ligands;Liver;Liver Fibrosis;Liver Stem Cell;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Manuscripts;Mediating;Mediator;Mentors;Methodology;MicroRNAs;Modeling;Mus;Neoplasm Metastasis;Organoids;Pathway interactions;Patients;Penetration;Peptic Ulcer;Pharmaceutical Preparations;Physiological;Preparation;Prevention;Primary carcinoma of the liver cells;Proglumide;Proliferating;Proteins;Publications;RNA;Receptor Activation;Research;Research Personnel;Risk;Role;Scientist;System;Testing;Therapeutic Agents;Tissue Microarray;Tissues;Training;Transgenic Mice;Transgenic Organisms;United States;Vitamin E;Work;antagonist;cancer cell;cancer risk;carcinogenesis;career;career development;chemokine receptor;cytokine;dietary;effective therapy;epigenetic regulation;epigenomics;experience;gastrointestinal;graduate student;human tissue;in vitro testing;in vivo;innovation;liver inflammation;liver injury;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;nutrition;overexpression;prevent;protein expression;receptor;receptor expression;response;saturated fat;stellate cell;stem cell population;stem cells;subcutaneous;symposium;timeline;transcriptome;transcriptome sequencing;tumor;tumor growth;undergraduate student Role of cholecystokinin receptor in hepatocellular cancer Project NarrativeThe overall purpose of this project is to understand the mechanism by which the cholecystokinin (CCK) B-receptor is activated in liver injury and NASH and how this activation increases the risk for hepatocellularcancer (HCC). Epigenetic regulation of the CCK receptor will be studied and cross-talk with chemokinereceptors. Several murine models of liver injury and a transgenic CCK-BR-knockout mouse model will be usedto investigate whether stem cells or liver progenitor cells express the CCK-BR and if a CCK-receptorantagonist can decrease the risk of HCC. NCI 10695975 8/2/23 0:00 PAR-18-364 5K01CA255572-03 5 K01 CA 255572 3 "VAHEDI, SHAHROOZ" 9/1/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 15181457 "GAY, MARTHA " Not Applicable 98 INTERNAL MEDICINE/MEDICINE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 162969 NCI 150897 12072 Project Summary/ AbstractBackground: The cholecystokinin (CCK) receptor is a G-protein coupled receptor that regulates physiologicgastrointestinal digestive functions and growth of the gastrointestinal tract. CCK receptors becomeoverexpressed in gastrointestinal cancers where receptor activation by the ligands CCK on or gastrinstimulate cancer growth and metastases. CCK receptors have also been described as fibroblasts. Whenactivated these cells produce collagen-associated proteins that lead to fibrosis associated with malignanciesand are thought to impede the penetration of therapeutic agents.Innovation: We recently showed that a diet high in saturated fat induces the expression of hepatic CCK- Breceptors in a murine model of nonalcoholic steatohepatitis. The CCK receptor antagonist proglumidereversed inflammation fibrosis and steatosis prevented the development of hepatocellular carcinoma in themurine NASH model.Long-term objectives: In this proposal I plan to investigate the mechanisms of how CCK receptors mediatehepatic inflammation and fibrosis and the role of CCK receptors in hepatocellular cancer.Research Aims: In vitro studies will be performed to analyze the potential of cross-talk between CCKreceptors and chemokine receptors. The role of CCK receptors in regulating hepatic fibrosis in stellate cells willbe carried out in vitro using CRISPR technology to selectively knockout cancer cell CCK receptors and in vivowith transgenic mice engineered to be null in the CCK-B receptor. Lastly we will examine the novel idea ofwhether liver injury and NASH induce proliferation of hepatic stem cells that express CCK-B receptors andthese stem cells are responsible for HCC.Candidate's Goals: Are to understand the pathophysiology of CCK receptors in liver cancer development andprogression. This proposal will be completed under the guidance of an experienced mentor team that includesaccomplished tumor biologists immunologists and hepatology cancer researchers. To accomplish thesegoals the candidate will work with her mentors and constantly review research objectives for publication toaddress candidates publication record and the Professional Development Office to follow a careerdevelopment plan by incorporating diverse methodologies for advancement which includes manuscriptpreparation project management adhering to timelines effectively managing a budget attending andpresenting at national conferences and departmental seminars mentoring graduate and undergraduatestudents and preparing application materials. 162969 +No NIH Category available Acute;Address;Allogenic;Animal Model;Animals;Appointment;Area;Autologous;Basic Science;Biological Markers;Biology;Blood Cells;Bone Marrow;Cancer Center Support Grant;Cell Communication;Cell Culture Techniques;Cell physiology;Cells;Clinical;Clinical Investigator;Core Facility;Direct Costs;Disease;Disease Progression;Endocrinology;Engraftment;Event;Funding;Goals;Grant;Health Benefit;Hematologic Neoplasms;Hematological Disease;Hematology;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homing;Human;Human Activities;Immune system;In Vitro;Indiana;Informatics;Institution;International;Intervention;Journals;Knowledge;Laboratories;Learning;Life;Malignant - descriptor;Malignant Neoplasms;Mediating;Medicine;Mentors;Mole the mammal;Multiple Myeloma;Mus;Neonatal;Paper;Pediatrics;Peer Review;Perinatal;Postdoctoral Fellow;Preleukemia;Process;Proliferating;Publications;Publishing;Radiation Oncology;Recording of previous events;Regulation;Research;Research Personnel;Science;Scientist;Series;Siblings;Signal Transduction;Site Visit;Training;Translating;Translations;Umbilical Cord Blood;United States National Institutes of Health;Universities;Work;bone;bone cell;cancer cell;cancer stem cell;cell type;chemokine;chronic graft versus host disease;clinical efficacy;clinical translation;cytokine;doctoral student;graft vs host disease;graft vs leukemia effect;hematopoietic cell transplantation;hematopoietic engraftment;improved;in vivo;insight;knowledge translation;leukemia;leukemic stem cell;medical schools;meetings;member;next generation;novel marker;peripheral blood;population health;pre-clinical;pre-doctoral;progenitor;programs;self-renewal;stem;stem cells;tumor;tumor progression Hematopoiesis and Hematological Malignancies Program n/a NCI 10695967 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7763 2095806 "KAPUR, REUBEN " Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 32123 20267 11856 ABSTRACT Hematopoiesis and Hematologic Malignancies Program (HHM)Based on the robust basic mechanistic studies performed by our members that resulted in consecutiveoutstanding scores for the last four NCI site visits HHM is now a basic science Program whose ultimate goal isto advance treatment of hematologic malignancies and disorders through rigorous basic scientific laboratoryefforts. Our goal is to gain mechanistic insight into malignant cell processes how they differ from normalprocesses through interactions with the TMM Program and to provide this information with our guidance to theEDT and CPC programs for translation for clinical utility and health benefit to modulate and slow diseaseprogression with the ultimate goal of curing malignant diseases. Our Program has two areas of focus:Hematopoiesis (H) and Hematologic Malignancy (HM) themes. The H-theme includes: characterization ofhuman and mouse hematopoietic stem (HSC) and progenitor (HPC) cells and their mechanistic regulationunderstanding the biology of cytokine/chemokine actions including cells of the hematopoietic microenvironmentand the immune systems and their interactions that regulate HSC and HPC functions; this includes proliferationsurvival self-renewal differentiation mobilization and engraftment for hematopoietic cell transplantation (HCT)and biomarker/biomolecule assessment for predicting and modulating graft vs host disease after HCT withoutadversely modulating graft vs. leukemia/tumor effects. The HM-theme is focused on understanding andmodifying the biology of leukemia/myeloma (including leukemia stem cells) and bone cell interactions (especiallyfor multiple myeloma) including intracellular events mediating the function and interactions of these cells. TheProgram has two highly interactive co-leaders: Broxmeyer and Roodman both with national and internationalreputations and who have a deep and long history of research in hematopoiesis and hematologic malignancies.HHM has a total of 17 Full and 7 Associate interactive members from 6 different Departments of the IU Schoolof Medicine. Our Program members have published 304 papers during the past CCSG funding period of which25% are intra-programmatic 17% are inter-programmatic and 65% are multi-institutional with 32% of thesepublications in journals with an impact factor ranging from 9 to greater than 40. The total (direct cost) of externalpeer-reviewed funding and NCI funding are respectively $7.6M and $1.17M with the current funding per Fullmember currently at $448K. The Program also has three NIH T32 Training grants (DK007519 HL007910 andAI060519) at $733.3K and a U54 Cooperative Center of Excellence in Hematology (DK106846). Our Programhas greatly benefited from IUSCC through: pilot-funding core facilities sponsored seminar series cancer grandrounds and with numerous formal and informal intra- and inter-programmatic meetings. Collectively these haveenhanced our capacity for continuing to perform outstanding cutting-edge science through interactions with theTMM EDT and CPC Programs and for the translation of this knowledge for health benefits. +No NIH Category available Address;Age;Baptist Church;Board Certification;Cancer Control;Clinic;Clinical;Clinical Informatics;Collaborations;Collection;Communities;Community Clinical Oncology Program;Comprehensive Cancer Center;Electronic Health Record;Ensure;Ethnic Origin;Evaluation;Fostering;Geographic Locations;Geography;Goals;Group Practice;Health;Healthcare;Hospitals;Individual;Informatics;Infrastructure;Institution;Laboratories;Laboratory Research;Leadership;Link;Massachusetts;Medical;Methods;Monitor;North Carolina;Nurses;Oncology;Operations Research;Patients;Physician Executives;Population;Primary Care;Primary Care Physician;Process;Productivity;Race;Research;Research Personnel;Resources;Role;Rural;Site;Socioeconomic Status;Solo Practices;Structure;Technology;Testing;Time;United States;Universities;Veterans Health Administration;Work;base;cancer prevention;clinical data warehouse;clinical infrastructure;clinical research site;data management;eHealth;ethnic diversity;experience;forest;implementation process;implementation science;innovation;member;patient population;programs;research study;socioeconomics;success;urban area;virtual iDAPT: Implementation and Informatics - Developing Adaptable Processes and Technologies for Cancer Control n/a NCI 10695963 8/16/23 0:00 RFA-CA-19-005 5P50CA244693-05 5 P50 CA 244693 5 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7762 6983464 "HOUSTON, THOMAS K" Not Applicable 5 Unavailable 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC Domestic Higher Education 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 117590 93416 24174 PROJECT SUMMARY iDAPTs Implementation Laboratory will support the emerging theme to use technology to support rapid cycle and real time deployment and testing of implementation processes and adaptations in cancer control. The Laboratory will do so via three distinct yet interrelated Aims. First iDAPTs Developing Center will existing relationships with primary care and oncology clinics representing diversity in terms of geographic locations clinic structure and patient populations utilizing a Hub and Spokes framework. The Lab will start in Hubs geographically co-located clinics at our two hubs in North Carolina (Wake Forest Baptist Health Network and Wake Forest Baptist Comprehensive Cancer Center) and Massachusetts (UMass Memorial Health UMass- Baystate and Reliant Medical Group). The Lab will grow in collaboration with our Spokes: existing virtual networks including community-based oncology clinics affiliated with the Wake Forest National Community Oncology Research Program (NCORP) Research Base (over 900 total clinics) and the Veterans Health Administration clinics affiliated with the VA eHealth Quality Enhancement Research Initiative (eQUERI - a national implementation science initiative led by UMMS/VA dual investigators). Second the Implementation Laboratory will provide critical infrastructure to facilitate the rapid initiation and successful conduct of cancer prevention and control implementation and methods studies concordant with Lab Member priorities and iDAPTs emerging theme. Third the Implementation Laboratory will maintain a Data Management Unit and Practice Surveillance Unit to ensure scientific rigor identify best practices and inform the refinement of Center resources to maintain and sustain the Lab. iDAPTs Implementation Laboratory builds upon an existing robust infrastructure for clinical innovations and support for evaluation. Lab infrastructure will emphasize shared governance with co-PIs located at Wake Forest and UMass with complementary expertise and experiences in the Hub and Spoke sites state-of-the-art data management and purposeful programmatic surveillance. The Implementation Laboratory will work closely with the Administrative Core and the Research Program to ensure the success of the iDAPT Developing Center. +No NIH Category available ARNTL gene;Address;Amino Acids;Animal Model;Autophagocytosis;Award;Back;Behavior;Bioenergetics;Bioinformatics;Biology;Biometry;Biostatistics Core;Blood Vessels;Carbon;Cell Survival;Cells;Cellular biology;Clinical;Collaborations;Colonic Neoplasms;Colorectal Adenocarcinoma;Colorectal Cancer;Communication;Complement;Cytoplasm;Development;EIF-2alpha;Endoplasmic Reticulum;Event;Experimental Designs;Foundations;Gene Expression Profiling;Generations;Genetic Transcription;Genomics;Glucose;Glycolysis;Goals;Growth Factor;Hypoxia;IFNAR1 gene;Immune;Interferons;International;Investigation;Journals;Lymphocyte;Lymphoma;MYC gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Manuscripts;Mass Spectrum Analysis;Mediating;Medicine;Messenger RNA;Metabolic;Metabolism;MicroRNAs;Molecular;Nature;New Territories;Normal Cell;Normal tissue morphology;Nutrient;Oncogene Activation;Oncogenes;Ontology;Outcome;Oxygen;PERK kinase;Pathway interactions;Phosphotransferases;Play;Process;Proliferating;Prostate;Protein Biosynthesis;Proteins;Publishing;Reagent;Receptor Signaling;Reporting;Repression;Research Design;Role;SLC2A1 gene;Sampling;Science;Signal Pathway;Signal Transduction;Stress;Stress Response Signaling;Testing;Text;Time;Tissues;Translations;Tumor Immunity;Tumor Volume;Tumor-Infiltrating Lymphocytes;Untranslated RNA;Work;anti-cancer;arm;biological adaptation to stress;c-myc Genes;cancer cell;cell growth;cell transformation;circadian;combat;cost effective;cytotoxic;data visualization;endoplasmic reticulum stress;experimental study;immune function;meetings;metabolomics;neoplastic cell;nutrient deprivation;power analysis;programs;response;sensor;tumor;tumor microenvironment;tumor progression;tumorigenesis The Role of the Integrated Stress Response in Cancer PROJECT NARRATIVEThe Integrated Stress Response (ISR) coordinates multiple cellular responses to tumormicroenvironment stress and endogenous stress caused by activation of oncogenes.These processes help the cells adapt to these stresses and to continue to proliferate.The assembled team of ISR experts will delineate molecular mechanisms by which theISR regulates these adaptive processes and thereby contribute to the development ofmore effective approaches to combat cancer. NCI 10695961 8/21/23 0:00 PAR-18-290 5P01CA165997-10 5 P01 CA 165997 10 "SALNIKOW, KONSTANTIN" 9/18/13 0:00 8/31/24 0:00 ZCA1-RPRB-F(M1) 2090001 "KOUMENIS, CONSTANTINOS " Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1072828 NCI 829337 243491 ABSTRACT/SUMMARY (Overall)The overall goal of this Program is to investigate the role of the Integrated Stress Response (ISR)signaling pathway in tumor cell fate and tumor progression. Rapidly proliferating cancer cellsmust thrive in a microenvironment wherein metabolic nutrients such as glucose oxygen andgrowth factors become limiting as tumor volume expands beyond the established vascularity ofthe tissue. The ISR integrates signals from sensors (such as the endoplasmic reticulum kinasePERK and cytoplasmic kinase GCN2) of cellular nutrients to homeostatic processes includingtranslational control carbon and oxygen metabolism and receptor signaling. The ISR has alsobeen shown to facilitate oncogene-mediated tumor progression suggesting that it may alsorespond to bioenergetic challenges triggered by aberrant oncogene-dependent signaling. Theoverall hypothesis to be tested in the proposed studies is that the Integrated Stress Responseplays a pivotal role in mediating MYC-dependent and hypoxia-dependent tumorprogression through its capacity to engage and regulate key pathways involved incircadian translational metabolic and immune functions thereby facilitating tumor cellsurvival and growth. The above hypothesis will be tested by three highly integrated projects:Project 1 will define miRNAs subject to ISR control whose function is to fine-tune proteinsynthesis during an ISR/UPR response. Two key microRNAs miR-211 and miR-217 are thefocus; collectively they function as regulators of Bmal1 during ER stress and their contribution toBmal1 repression to lymphoma progression is critical for tumorigenesis. Project 2 will identifycritical nodes in metabolism and translation control which are coordinately regulated by both ATF4and c-MYC and delineate the mechanism of co-regulation of common transcriptional targets. Itwill also functionally test the role of ATF4 in MYC-dependent transformation and tumorigenesis.Project 3 will delineate the mechanisms underlying ISR-induced IFNAR1-dependent andindependent inactivation of the IFN1 pathway its role in the loss of viability of intratumoralcytotoxic lymphocytes and the generation of the immune privileged niches. It will also determinewhether targeting these mechanisms can augment anti-cancer immunity. All three projects willmake extensive use of Core A (Administrative) and scientific Cores B (Metabolomics/Genomics)and C (Biostatistics) and have already established a working highly collaborative relationship.Collectively our three integrated and synergistic Projects will provide a molecular framework thataddresses the potential efficacy of targeting the ISR to antagonize malignancy in three highlyprevalent and lethal types of tumors. 1072828 +No NIH Category available Acceleration;American;Automation;Cancer Control;Caring;Clinic;Clinical;Collaborations;Communication;Computers;Development;Dissemination and Implementation;Doctor of Philosophy;Electronics;Evaluation;Extramural Activities;Faculty;Feedback;Funding;Grant;Informatics;Institution;Intelligence;Knowledge;Laboratories;Lead;Leadership;Malignant Neoplasms;Manuals;Measurement;Medical Informatics;Mentors;Methods;Monitor;Natural Language Processing;Oncology;Patients;Pattern;Pilot Projects;Postdoctoral Fellow;Process;Public Health Informatics;Publishing;Reference Standards;Research;Research Personnel;Research Project Summaries;Research Proposals;Role;Running;Science;Scientist;Secure;Series;Smoking Cessation Intervention;Students;System;Technology;Testing;Time;Training;Underrepresented Populations;United States National Institutes of Health;Visit;Work;design;eHealth;experience;feasibility testing;implementation evaluation;implementation facilitation;implementation process;implementation research;implementation science;implementation study;improved;innovation;medical schools;member;population health;professor;programs;prototype;response;shared decision making;skills;sound;survivorship iDAPT: Implementation and Informatics - Developing Adaptable Processes and Technologies for Cancer Control n/a NCI 10695960 8/16/23 0:00 RFA-CA-19-005 5P50CA244693-05 5 P50 CA 244693 5 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7760 8842460 "DRESSLER, EMILY VAN METER" Not Applicable 5 Unavailable 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC Domestic Higher Education 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 495129 440148 54981 PROJECT SUMMARYThe Research Program will use three strategies to inform iDAPTs emerging theme to use technologies thatsupport rapid cycle and real time deployment and testing of implementation processes and adaptations withincancer control. First the Research Program will advance the science of technology-supported implementationscience in cancer control through a series of proposed pilot projects conducted in the Implementation Lab.Second it will advance the methods and measurement for implementation science using technology via methodspilot projects and support of the Implementation Studies Unit. Third the Research Program will identify andnurture nascent ideas for new cancer-focused Implementation Science proposals with high potential forextramural funding with an emphasis on assisting students junior faculty and underrepresented populations.The Research Program will lead with two pilot studies aligned with our emerging theme of technology-facilitatedimplementation science. The first is a highly innovative implementation pilot study that will address a gap insurvivorship care. Using a stepped-wedge design in 10 oncology clinics we will test an electronic referralmechanism and computer-tailored communication and intelligent automation to facilitate shared decision makingand survivorship care planning in-between clinical visits. The methods study will advance the field ofimplementation science in cancer control by testing the feasibility of using an automated communication patternmonitoring and feedback system to facilitate implementation programs designed to improve communicationbetween clinical teams and between clinical teams and patient. This study will create manually annotatedreference standard for natural language processing (NLP) train and validate the NLP system test the systemamong patients undergoing smoking cessation treatment and then build and test a prototype system to monitorcommunication extracted from secure messages over time. Both of these iDAPT vanguard pilot studies are ledby junior faculty. The Research Program will seek additional pilot research through a defined process forsoliciting reviewing and selecting promising studies using a validated approach for evaluating implementationresearch proposals for a total of 8-10 pilot studies. The Research Program depends upon a high degree ofcollaboration across the cores to ensure that the selection of pilot studies reflects laboratory member needs(Administrative Core Evaluation Unit) that laboratory members are engaged and have knowledge and skills toserve as equal partners in the research process (Implementation laboratory) and that the knowledge gainedfrom the pilot studies builds the field of implementation science in cancer control aligned with iDAPTs emergingtheme of technology-facilitated implementation science (Administrative Core Network Unit). The ResearchProgram is led by Dr. Thomas Houston (MPI) who is Professor and Chief Health Informatics and ImplementationScience Division at UMMS and is an elected fellow in the American College of Medical Informatics. +No NIH Category available Active Learning;Baptist Church;Cancer Control;Clinic;Communication;Comprehensive Cancer Center;Data;Department chair;Development;Educational workshop;Ensure;Evaluation;Faculty;Failure;Fostering;Hybrids;Informatics;Intervention;Knowledge;Laboratories;Lead;Leadership;Learning;Measures;Methodology;Methods;Mission;Modeling;Monitor;Oncology;Outcome;Pilot Projects;Primary Care;Process;Progress Reports;Research;Research Personnel;Research Priority;Resources;Science;Strategic Planning;Structure;Students;Technology;Testing;Time;Training;Underrepresented Populations;United States National Institutes of Health;Work;acceptability and feasibility;cancer prevention;experience;forest;implementation process;implementation science;implementation strategy;improved;medical schools;meetings;member;organizational structure;outreach;pragmatic trial;professor;programs;remediation;success;tool iDAPT: Implementation and Informatics - Developing Adaptable Processes and Technologies for Cancer Control n/a NCI 10695955 8/16/23 0:00 RFA-CA-19-005 5P50CA244693-05 5 P50 CA 244693 5 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7757 7892228 "FOLEY, KRISTIE L" Not Applicable 5 Unavailable 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC Domestic Higher Education 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 148154 95583 52571 PROJECT SUMMARYiDAPTs Administrative Core is responsible for the overall mission leadership and management of iDAPT:Implementation and Informatics - Developing Adaptable Processes and Technologies for Cancer Control. TheAims of the Administrative Core are to: (1) Create an organizational structure that fosters the successfulintegration of the Research Program and Implementation Laboratory to advance implementation science incancer control with an emerging thematic focus on technology-supported interventions and implementationprocesses; (2) Build the capacity of iDAPT laboratory partners to conduct implementation science researchaligned with iDAPTs emerging theme; (3) Foster a culture of shared learning by bringing discoveries to theImplementation Science Centers in Cancer Control (ISCCCs) while also sharing what is learned from the ISCCCswith iDAPTs research and laboratory partners; (4) Ensure iDAPT is achieving milestones outlined within theResearch Program and Implementation Laboratory utilizing a robust and iterative evaluation and strategicplanning process. Core functions of the center include timely and bi-directional communication engagementwith iDAPTs Research Program and Implementation Laboratory partners measuring knowledge and practicegaps that could be remediated by technology-supported interventions and strategies in primary care andoncology clinics reciprocal learning with the ISCCC network and a stage-based mixed methods implementationmonitoring plan. The Evaluation Unit will generate and analyze process-oriented data to assess progress andimprove practices of iDAPT and engage in a strategic planning initiative to understand more broadly the factorsthat influence Center development and successes. +No NIH Category available Address;Appalachian Region;Baptist Church;Behavioral Sciences;Biometry;Breast Cancer survivor;Cancer Control;Caring;Clinic;Clinical;Clinical Informatics;Collaborations;Communication;Communities;Community Clinical Oncology Program;Comprehensive Cancer Center;Computers;Consultations;Development;Doctor of Philosophy;Electronic Mail;Engineering;Ensure;Epidemiology;Evaluation;Faculty;Family;Fostering;Geographic Locations;Grant;Health;Health Services Research;Informatics;Infrastructure;Intervention;Laboratories;Lead;Leadership;Malignant Neoplasms;Massachusetts;Measures;Medical;Mentors;Methods;Mission;Monitor;Natural Language Processing;North Carolina;Office of Administrative Management;Oncology;Outcome;Patients;Pattern;Pilot Projects;Population;Population Sciences;Primary Care;Process;Public Health Informatics;Qualitative Methods;Research;Research Personnel;Science;Scientist;Site;Structure;Technology;Testing;Time;Training;Underrepresented Minority;Underrepresented Populations;United States;United States Department of Veterans Affairs;Universities;Work;base;cancer health disparity;cancer prevention;computer science;data management;design;experience;feasibility testing;forest;implementation fidelity;implementation process;implementation science;implementation study;improved;innovation;medical schools;member;multidisciplinary;patient population;peer learning;professor;programs;research study;shared decision making;socioeconomic disparity;support network;survivorship;synergism iDAPT: Implementation and Informatics - Developing Adaptable Processes and Technologies for Cancer Control PROJECT NARRATIVEiDAPT is a developing center that will use technologies to support rapid cycle and real time deployment andtesting of implementation processes and adaptations within cancer control. Our team focuses on buildingcapacity among primary care and oncology partners to engage in implementation science in cancer control andto conduct pilot studies aligned with iDAPTs theme. We have an extensive network of partners concentrated inan the urban northeast and southern Appalachia as well community-based primary care and oncology clinicsthroughout the United States. We are committed to the inclusion of junior faculty and under-represented personsin all aspects of iDAPTs developing center. NCI 10695954 8/16/23 0:00 RFA-CA-19-005 5P50CA244693-05 5 P50 CA 244693 5 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(A1) 7892228 "FOLEY, KRISTIE L" "CUTRONA, SARAH LELEIKO; HOUSTON, THOMAS K" 5 PUBLIC HEALTH & PREV MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 760873 NCI 629147 131726 PROJECT SUMMARYiDAPT Implementation and Informatics - Developing Adaptable Processes and Technologies for CancerControl is a developing center with an emerging theme on the use of technologies to support rapid cycle andreal time deployment and testing of implementation processes and adaptations within cancer control. TheAdministrative Core will manage the Center ensure that iDAPT is engaged with real world clinical partnerspatients and families is well-networked with the Implementation Science Centers in Cancer Controlconsortium and engage in a comprehensive evaluation of Center activities and milestones. The ResearchProgram will include an Implementation Studies Unit with an initial 2-year pilot study using adaptabletechnology to enhance shared decision-making in survivorship care planning for survivors of breast cancer.The Research Program also includes a Methods Unit with an initial innovation pilot study to test the feasibilityof natural language processing to measure communication patterns pre-implementation and to monitorimplementation fidelity of programs designed to enhance within-team and clinical team-to-patient electroniccommunication. The Research Program is expected to complete 8 to 10 pilot studies. In order to fosterresearch aligned with iDAPTs theme we will build and sustain iDAPTs Implementation Laboratory whichincorporates capacity building and infrastructure for testing the use of technologies to support rapid cycle andreal time deployment of implementation processes and adaptations within cancer control. The laboratoryincludes primary care and oncology clinics in our local Hubs in southern Appalachia (North Carolina) and thenortheast (Massachusetts) and Spokes including over 900 community-based oncology clinics in the NCIsNational Community Oncology Research Program and nationwide Veterans Administration clinics. iDAPTsleadership is a multi-disciplinary team of experts with extensive experience in cancer-focused implementationscience behavioral science computer engineering and computer science clinical informatics formativequalitative methods epidemiology and biostatistics. The iDAPT Developing Center will be consideredsuccessful if we achieve the following outcomes: (1) a robust collaborative Implementation Laboratory withpartners who are knowledgeable and experienced with implementation science in cancer control; (2)completion of 8 to 10 pilot projects related to iDAPTs emerging theme; (3) pilot grantees and lab partners areprepared to lead investigator initiated studies as a result of capacity building and pilot grant experiences; (4)junior faculty and underrepresented persons are engaged in all Center activities; (5) The field ofimplementation science in cancer control is advanced aligned within iDAPTs emerging theme; and (6) iDAPTis part of a new network of ISCCCs who collectively build the field of implementation science in cancer control. 760873 +No NIH Category available 16S ribosomal RNA sequencing;ATAC-seq;Advanced Malignant Neoplasm;Advisory Committees;Age;Alleles;Alternative Splicing;Bioinformatics;Biological Assay;Biology;Biomedical Research;CRISPR screen;Cancer Center;Cancer Center Support Grant;Cells;ChIP-seq;Chromium;Client;Committee Members;Complex;Computational Biology;DNA sequencing;Detection;Development;Disease;Education;Elements;Epigenetic Process;Exons;Gene Expression;Genes;Genomics;Genotype;High School Student;Human;Indiana;Ions;Lead;Libraries;Malignant Neoplasms;Measures;Medical center;Metagenomics;Methods;MicroRNAs;Microarray Analysis;Mission;Play;Preparation;Prevention approach;Price;Protocols documentation;Protons;RNA;Reporter;Research;Research Personnel;Running;SNP genotyping;Sampling;Science;Scientist;Services;Shotgun Sequencing;Site;Surveys;System;Technology;Testing;Training Activity;Universities;Variant;Vendor;Virus;anticancer research;base;bisulfite sequencing;cancer therapy;college;course introduction;course module;crosslinking and immunoprecipitation sequencing;design;epigenomics;equipment acquisition;exome sequencing;experience;experimental study;functional genomics;genomic tools;human genome sequencing;individualized medicine;laser capture microdissection;mRNA sequencing;medical schools;member;model organism;new technology;next generation sequencing;novel;response;single-cell RNA sequencing;technology development;training opportunity;transcriptome;transcriptome sequencing;whole genome Center for Medical Genomics n/a NCI 10695949 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7754 8636465 "LIU, YUNLONG " Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 119951 75679 44272 ABSTRACT Genomics Core (GC)With the sequencing of the human genome biomedical sciences have entered the age of functional genomics.New technologies offer the promise of vastly increased understanding of biology and through that of betterapproaches to the prevention and treatment of complex disease including cancer. Next-generation sequencing(NGS) of DNA and RNA has become a powerful tool for genomics study. It allows detection and identification ofknown as well as novel variations at base level. It measures gene expression allele-specific expressionepigenomic changes and alternative splicing of whole transcriptome. Microarray technology is also powerful forexperiments involving known gene elements. SNP genotyping allows confirmation of variations discovered inNGS. These state-of-the-art technologies provide comprehensive approaches for functional genomics in cancerresearch. Studies based on these genomic tools both in humans and in model organisms will lead cancertreatment into an era of more individualized treatments.The Genomics Core (GC) at Indiana University School of Medicine (IUSM) provides state-of-the-art genomicsservices to investigators at Indiana University Simon Cancer Center (IUSCC) including next generationsequencing single-cell analytics microarray and high-throughput genotyping. With decades of experience andstrong track record in supporting cancer research significant subsidization from IUSM and IUSCC and strongties with the Center for Computational Biology and Bioinformatics (CCBB) the GC strives to provide IUSCCmembers high-quality genomic services with fast-turnaround times at affordable prices. +No NIH Category available AML/MDS;Address;Affect;Algorithms;Allogenic;Antigen Targeting;Antigens;Applications Grants;Binding;Cell Line;Cell physiology;Cells;Characteristics;Clinical;Collaborations;Combined Modality Therapy;DNA analysis;DNA sequencing;Data;Data Analyses;Detection;Genomics;Genotype;Goals;Hematopoiesis;Hematopoietic;Immune;Immune response;Immunogenomics;Immunologics;Individual;Laboratories;Leukemic Cell;Malignant Neoplasms;Minor Histocompatibility Antigens;Non-Malignant;Outcome;Pathway interactions;Patients;Peptides;Phenotype;Population;RNA analysis;Resistance;Sampling;Single Nucleotide Polymorphism;Somatic Mutation;Specimen;Stem cell transplant;T cell clonality;T cell response;T-Cell Immunologic Specificity;T-Cell Receptor;T-Lymphocyte;T-cell receptor repertoire;TCR Activation;Testing;Therapeutic;Transplantation;Variant;alpha-beta T-Cell Receptor;beta Chain Antigen T Cell Receptor;candidate identification;computerized tools;exome sequencing;graft vs leukemia effect;immune cell infiltrate;immune reconstitution;immunogenic;immunogenicity;immunoregulation;insertion/deletion mutation;insight;leukemia;neoantigens;novel;novel vaccines;predicting response;rational design;response;single cell sequencing;stem cell population;targeted treatment;tool;transcriptome;transcriptome sequencing;treatment response;vaccine strategy Single Cell and Immunogenomics NarrativeTo support the Projects of this application we will implement experimental workflows for bulk and single-celltranscriptome analysis of AML/MDS and non-malignant immune cell populations including determination of Tcell receptor repertoires and apply advanced computational tools to perform genomic analyses of leukemia DNAand RNA sequencing data. Application of our advanced immunogenomic approaches will enable the Projects toidentify predictors of response and resistance to stem cell transplantation and to discover the influence of CHIPon response to HCT. Furthermore we will aid the Projects to identify candidate immunogenic antigens that aretargeted by transplant-related immune responses and which can be targeted therapeutically through a novelvaccine strategy. NCI 10695941 8/1/23 0:00 PAR-18-290 5P01CA229092-05 5 P01 CA 229092 5 8/14/19 0:00 7/31/24 0:00 ZCA1-RTRB-R 7751 15142698 "LIVAK, KENNETH JAMES" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 280535 235014 45521 Project SummaryThe projects proposed for this grant application seek to test novel transplant (HCT)-based immunomodulatorycombination treatments for AML and MDS to dissect how leukemia cells and their surrounding immune cellpopulations co-evolve in relationship to allo-HCT course (with the aim of gaining essential insights into therational design of effective combination therapy for AML and MDS) and to understand how donor clonalhematopoiesis (CHIP) in the stem cell population impacts the reconstitution of immune cell subpopulations. Core3 will support the single cell- and immunogenomics-related goals of these projects by focusing on applying thelatest computational and experimental tools to these studies. Core 3 will analyze whole exome sequencing datafrom leukemia and normal samples to identify cancer-specific somatic mutations and polymorphic differencesbetween donor and recipient and use matched RNA sequencing data to determine which of these variants areexpressed. Recently developed sophisticated algorithms will be implemented to use this information to predictpersonal HLA-binding peptides that compose personal leukemia neoantigens and hematopoietic-lineagerestricted minor histocompatibility antigens (Aim 1). In order to determine the immune response to HCT single-cell transcriptome sequencing of non-tumor immune cell populations will be used to identify pathways related toimmune cell functions (Aim 2). Targeted RNA analysis will be used to determine how these discoveredphenotypes relate to the genotype of individual cells and will be used to define how CHIP affects response toHCT. Response of T cells to HCT will be further characterized by TCR repertoire analysis using targeted bulkand single-cell sequencing to assess T cell clonality (Aim 3). The paired alpha/beta TCR chain single-cellsequence information will be used to reconstruct cell lines expressing individual enriched TCRs (Aim 4) in orderto functionally determine exactly which TCR interacts with which antigen. This analysis will directly assess ifneoantigen- or mHAg-directed T cell responses contribute to clinical responses to therapy. +No NIH Category available Allogenic;Biometry;Blinded;Blood;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Data;Data Analyses;Data Element;Databases;Donor Lymphocyte Infusion;Goals;Graft vs Tumor Effect;Hematopoiesis;Hematopoietic Stem Cell Transplantation;Immune;Immune system;Immunologics;Immunotherapy;Laboratories;Laboratory Research;Laboratory Study;Leukemic Cell;Maintenance;Malignant Neoplasms;Manuscripts;Mediating;Minor Histocompatibility Antigens;Outcome;Patient-Focused Outcomes;Patients;Procedures;Protocols documentation;Quality Control;Regulatory T-Lymphocyte;Relapse;Research Design;Research Personnel;Research Project Grants;Services;T cell response;Therapeutic;Transplantation;Tumor Immunity;Vaccination;Writing;clinical translation;data management;design;donor stem cell;graft vs leukemia effect;high risk;immune checkpoint blockade;immunoregulation;improved;inhibitor;neoantigens;novel;novel strategies;operation;post-transplant;programs;relapse patients;research study Biostatistics and Data Management Project NarrativeThis core will be responsible for providing biostatistical collaboration on all aspects of study design definition ofendpoints analysis and interpretation of results and presentation of results from translational clinical andlaboratory studies of this Program Project. The core will also provide the centralized mechanisms to assure thetimely and complete clinical data management support and regulatory binder support for clinical trials.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page NCI 10695932 8/1/23 0:00 PAR-18-290 5P01CA229092-05 5 P01 CA 229092 5 8/14/19 0:00 7/31/24 0:00 ZCA1-RTRB-R 7747 7699835 "KIM, HAESOOK T" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 280533 157381 123152 Project SummaryAllogeneic hematopoietic stem cell transplantation (HSCT) is a long-established therapy for blood malignancies.The therapeutic benefit and potential cure achieved by HSCT is mediated by the graft-vs-tumor (GVT) effect thatis derived from donor immune system. The overarching objective of the research projects in this Program Projectapplication is thus to enhance this GVL effect for high risk patients for relapse by administering subsequentimmunomodulation with the goal of developing novel strategies for selectively enhancing tumor immunity andimproving patient outcomes. Specifically Project 1 will focus on clinical trials for novel immunotherapies that aredesigned to enhance post-transplant immune reactivity pre-emptively using whole leukemia cell vaccinationneoantigen/minor histocompatibility antigens (mHAgs) vaccination or check point blockade inhibitor or to treatrelapse using Treg depleted donor lymphocyte infusion plus check point blockade inhibitor. Project 2 willinvestigate the underlying mechanisms of GVL and the specific T cell responses to neoantigen/mHAgsvaccination generated in clinical trials carried out in Project 1. Project 3 will focus on the impact of clonalhematopoiesis (CHIP) in the donor stem cell product on clinical and immunologic outcomes after transplant. Theprimary objective of the Biostatistics and Data Management Core (Core 1) is to provide statistical collaborationfor all investigators involved in this Program Project. This includes collaboration with project investigators in thedesign of clinical trials in Project 1 and laboratory studies in Projects 2 and 3 analysis of clinical and laboratorydata and to establish correlations of clinical outcomes with laboratory results in Projects 1-3 and participate inmanuscript writing in all Projects. Core 1 will also provide centralized mechanisms to assure the timely andcomplete capture of all clinical data in this Program Project. This includes collection and maintenance ofnecessary clinical information data management support quality control for clinical data and oversight of clinicaltrial operations to ensure that all data elements required by each protocol are collected in timely fashion; andwhere necessary design of research procedures and databases to allow blinded laboratory assessments andlater integration with patient-level data for analysis.PHS 398/2590 (Rev. 11/07) Page Continuation Format Page +No NIH Category available Acceleration;Area;Award;Budgets;Cancer Center;Cancer Center Support Grant;Capital;Center for Translational Science Activities;Clinical Research;Clinical Trials;Collaborations;Communication;Contracts;Databases;Development;Equipment;Evaluation;Faculty;Foundations;Funding;Grant;Group Meetings;Human Resources;Indiana;Information Technology;Infrastructure;Leadership;Maintenance;Occupational activity of managing finances;Organization administrative structures;Pilot Projects;Process;Research;Research Support;Resource Sharing;Schools;Series;Strategic Planning;Universities;Work;equipment acquisition;medical schools;member;programs;recruit;web page;working group Cancer Center Administration n/a NCI 10695930 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 7745 6895846 "LEE, KELVIN P." Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 199087 125607 73480 ABSTRACT AdministrationThe Indiana University Melvin and Bren Simon Cancer Center (IUSCC) is a distinct organizational unit within theIU School of Medicine. IUSCC administration works closely with the various units of the school includingFinance Human Resources Information Technology Strategic Communication Research Administration andthe Office of Clinical Research. Administration provides infrastructure support including finance pre- and post-award of grants and contracts financial management of shared resources capital equipment procurementmaintenance of common equipment in IUSCC space internal and external communication and support of theIUSCC pilot project program. The major functions of the IUSCC Administration are: to coordinate strategicplanning; to stimulate and support transdisciplinary Research Programs; and to provide administrative andfinancial oversight for the Shared Resource facilities including the Clinical Trials Office (CTO). In additionIUSCC Administration is responsible for providing support in the following key areas: pre- and post-awardmanagement for grants and contracts; financial management of university and foundation accounts;development and maintenance of the IUSCC webpages and databases; coordination of communication toIUSCC members; information technology support for members staff and shared resources; and human resourcemanagement of IUSCC staff. Administration supports Research Programs through coordination of monthlyseminars and working group meetings yearly retreats pilot project announcements administration of the IUSCCTranslational Research Acceleration Collaboration (ITRAC) process dissemination of external fundingannouncements and coordination of the IUSCC Seminar Series. The IUSCC budget in FY 2018 was $27.7Mincluding $2.18M from the CCSG (8%). IUSCC supports 142 programmatically aligned members fromnine schools and 42 Departments. +No NIH Category available Address;Affect;Africa South of the Sahara;African American;American Cancer Society;Area;Asian;Automobile Driving;Basic Science;Behavioral;Bioinformatics;Biological;Biology;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Etiology;Carcinogenesis Mechanism;Catchment Area;Censuses;Cessation of life;Characteristics;Clinical;Clinical Data;Clinical Research;Clinical Trials;Colorectal;Colorectal Cancer;Communities;Community Outreach;Country;County;Dedications;Developmental Therapeutics Program;Direct Costs;Disease;Drug resistance;Early Diagnosis;Education;Educational Activities;Environment;Funding;Geography;Goals;Grant;Health Policy;Health Professional;Hematologic Neoplasms;Hematopoiesis;Hispanic Populations;Home;Human Papilloma Virus Vaccination;Incidence;Indiana;Institution;Interdisciplinary Study;Investigational Therapies;Latino Population;Link;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Medical Informatics;Minority Groups;Mission;Modeling;Morbidity - disease rate;NCI-Designated Cancer Center;Neoplasm Metastasis;North America;Oncology;Pancreas;Pathway interactions;Patient Care;Patient-Centered Care;Patients;Pediatric Neoplasm;Persons;Population;Prevention;Race;Research;Research Personnel;Resource Sharing;Risk Behaviors;Risk Factors;Rural Population;Science;Smoking;Strategic Planning;Teenagers;Therapeutic;Tobacco;Training;Training and Education;Translational Research;Underrepresented Minority;Underserved Population;Universities;Urban Population;Vision;Work;anticancer research;cancer health disparity;cancer prevention;clinical care;clinical development;community engagement;fundamental research;gastrointestinal;genomic data;health care disparity;innovation;malignant breast neoplasm;mortality;mortality disparity;novel;novel strategies;population health;precision medicine;programs;screening;socioeconomics;survivorship;symptom science;training opportunity;translational research program;tumor microenvironment;working group Indiana University Melvin and Bren Simon Cancer Center Support Grant NARRATIVE Overview and Essential CharacteristicsThe Indiana University Melvin and Bren Simon Cancer Center is an NCI-designated Cancer Center whosemission is to conduct outstanding translational research to provide excellence in education and to deliver highquality patient centered care with the goal to eliminate cancer's burden in Indiana and beyond. NCI 10695929 9/5/23 0:00 PAR-17-095 5P30CA082709-24 5 P30 CA 82709 24 "HE, MIN" 9/22/99 0:00 8/31/24 0:00 Cancer Centers Study Section (A)[NCI-A] 6895846 "LEE, KELVIN P." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2746580 NCI 1732858 1013722 "ABSTRACT Overview and Essential CharacteristicsThe IU Simon Cancer Center is an NCI-designated Cancer Center that is dedicated to cancer researcheducation and patient care for the citizens of Indiana and beyond. Since our last review the IUSCC hassubstantially increased the depth and breadth of our science and cancer relevant research as evidenced by overa 38% increase in NCI funding (Direct Costs) a 176% increase in our multi-PI grants while attracting over 30new investigators in cancer research to our institution. We are the home to the country's first pathway-drivenSPORE that focuses on pediatric tumors and the birthplace to three active cancer consortia including one thatlinks researchers from North America and sub-Saharan Africa. The IUSCC is composed of two basic programsHematopoiesis and Hematologic Malignancies (HHM) and Tumor Microenvironment and Metastasis (TMM) andtwo translational programs Experimental and Developmental Therapeutics (EDT) and Cancer Prevention andControl (CPC). We define our catchment area as the entire state of Indiana as patients come from each of the92 counties and 89% of the counties have at least one patient entered on clinical trials.Our community outreach and engagement activities have focused on the urban and rural populations of Indianawith the diseases with the highest mortality in the state (i.e. lung breast and gastrointestinal cancers) as wellas behavioral risk factors which adversely impact screening and prevention (e.g. tobacco and HPVvaccinations). We focus on developing novel approaches for screening treatment and symptom science using""precision medicine"" and expanding work in bioinformatics and medical informatics to address the increasingcomplexity of understanding the genomic and clinical data. We embrace the vision of increasing the researchworkforce in Indiana and globally through education from ""Teens-to-Tenure"" and the integration of clinical andtranslational research in our strategic plan. This strategic plan which has its underpinnings with education andimpact to our catchment area is composed of four pillars that are foundational to the IUSCC. These pillarsinclude: 1) Biology to Bedside Research; 2); Precision Medicine; 3) Prevention Early Detection and PopulationHealth: Local-Global Approaches; and 4) Health Care Disparities Survivorship and Symptom Science." 2746580 +No NIH Category available Age;Age Years;Allogenic;Archives;Bar Codes;Biological;Biology;Cardiovascular system;Cells;Characteristics;Clinical;Clonal Evolution;Clone Cells;Cytokine Signaling;Data;Development;Donor Selection;Donor person;Effector Cell;Engraftment;Epigenetic Process;Frequencies;Functional disorder;Genetic;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homologous Transplantation;Human;Immune;Immune System Diseases;Impairment;Infection;Inferior;Inflammatory;Laboratories;Leukemic Cell;Link;Measures;Mediating;Modality;Modeling;Morbidity - disease rate;Mutation;Mutation Detection;Myeloproliferative disease;Non-Malignant;Outcome;Pathology;Patients;Production;Property;Recovery;Recurrent disease;Relapse;Reporting;Risk;Safety;Sampling;Technology;Testing;Time;Transplant Recipients;Transplantation;Universities;Validation;Work;age related;chronic graft versus host disease;clinically significant;cohort;curative treatments;cytokine;cytopenia;donor stem cell;fitness;genetic approach;genetic evolution;graft dysfunction;graft function;graft vs host disease;high risk;immune function;immune reconstitution;immunoregulation;improved;improved outcome;innovation;insight;mortality;next generation sequencing;novel strategies;post-transplant;sequencing platform;stem cell engraftment;stem cells;success;tool;transcriptome;transcriptomics Defining the scope and clinical impact of donor CHIP after allogeneic HCT PROJECT NARRATIVEAllogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many high-riskblood cancers but is associated with significant morbidity and mortality. This project will use state-of-the-arttools to identify and characterize the relationship between genetic changes in normal donor stem cells anddevelopment of post-HSCT complications in patients. Understanding this fundamental relationship and theirfunctional impact on donor immune cells could lead to novel approaches to HSCT and improved outcomes. NCI 10695927 8/1/23 0:00 PAR-18-290 5P01CA229092-05 5 P01 CA 229092 5 8/14/19 0:00 7/31/24 0:00 ZCA1-RTRB-R 7744 10995642 "LINDSLEY, ROBERT COLEMAN" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 568893 319381 249512 PROJECT SUMMARYAllogeneic hematopoietic stem cell transplantation (HSCT) involves the transfer of healthy donor hematopoieticcells including hematopoietic stem cells and mature immune effector cells to recipients with high-riskhematologic malignancies. The success of HSCT is fundamentally dependent on engraftment of normal donor-derived hematopoiesis. Inadequate graft function can cause a range of complications that impact recipientoutcomes including disease relapse graft versus host disease and infection. In preliminary studies weidentified healthy stem cell donors with clonally restricted hematopoiesis marked by mutations in canonicalgenetic drivers of myeloid malignancies where the aberrant clone engrafted in a transplant recipient underwentselective expansion and was associated with abnormal hematopoietic function. While rare patients developeddonor cell leukemia after long latency our data suggest that non-malignant outcomes of donor-engrafted clonalhematopoiesis such as hematopoietic dysfunction or graft versus host disease may be more common and maymanifest earlier after transplantation thereby contributing significantly to transplant-related morbidity. Wehypothesize that the presence of clonal hematopoiesis of indeterminate potential (CHIP) is an age-independentpredictor of donor hematopoietic fitness that negatively impacts recipient outcome by causing impaired graftfunction. This proposal combines complementary genetic functional and transcriptomic approaches in a largecohort of stem cell donor-recipient pairs to define the impact of donor CHIP on allo HSCT outcomes. In SpecificAim 1 we will determine the frequency and clinical significance of CHIP in a 1911 allogeneic stem cell donors40 years of age and older (discovery cohortn=1189; external validation cohort n=722). To complete this aimwe have developed and validated a highly sensitive sequencing platform for identification of CHIP in donorsamples with >50-fold greater sensitivity than standard next generation sequencing modalities. This work willbe closely linked to Specific Aim 2 where we will focus on the subset of donors with clonal mutations to definethe efficiency and lineage potential of clonal stem cell engraftment and the genetic evolution of clones over time.Finally in Specific Aim 3 we will dissect the functional impact of donor CHIP on immune function in transplantrecipients testing the hypothesis that stem cell clones can perturb inflammatory cytokine production and properrecovery of immune activity via their clonal contribution to mature immune cell subsets. Together the proposedstudies may define a new paradigm of donor-attributable risk in allogeneic HSCT and provide insights intobiological mechanisms of clonal dominance and the influence of microenvironmental context on clonal evolution. +No NIH Category available Acute Myelocytic Leukemia;Advisory Committees;Affect;Allogenic;Area;Biologic Characteristic;Biological Assay;Biological Process;Biology;Biometry;Bone Marrow;Cardiovascular Diseases;Caring;Cells;Characteristics;Clinical;Clonal Evolution;Clonal Expansion;Collaborations;Communities;Cyclophosphamide;DNMT3a;DNMT3a mutation;Dana-Farber Cancer Institute;Data;Data Science;Development Plans;Disease;Disease remission;Donor Selection;Donor person;Engraftment;Environment;Genes;Genomics;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Histologic;Immune;Immune Evasion;Immune system;Immunologic Surveillance;Immunologics;Immunology;Immunophenotyping;Impairment;Individual;Inflammatory;Intervention;Investigation;Leukocytes;Mediating;Mentorship;Modality;Mutate;Mutation;Myeloid Cells;Outcome;Output;Pathogenicity;Pathway interactions;Patients;Pattern;Physicians;Population;Recurrent disease;Relapse;Research;Research Personnel;Residual state;Risk;Sampling;Scientist;Shapes;Signal Transduction;Somatic Mutation;Stem cell transplant;T-Cell Development;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Testing;Time;Toxic effect;Training;Transplant Recipients;Transplantation;Transplantation Immunology;Work;adverse outcome;age related;cancer cell;career;career development;cell type;curative treatments;cytokine;cytopenia;disorder risk;exhaustion;experimental study;graft failure;graft function;graft vs leukemia effect;hematopoietic cell transplantation;improved;improved outcome;insight;leukemia relapse;mutant;novel;novel strategies;novel therapeutic intervention;post-transplant;pressure;relapse risk;single cell technology;success The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients PROJECT NARRATIVEHematopoietic stem cell transplantation is an important but imperfect modality for the treatment of patients withhematologic malignancies. This project builds on a novel observation that transplant recipients of donors whohave acquired mutations in the gene DNMT3A in their hematopoietic cells have improved outcomes aftertransplant and assesses how donor clonal hematopoietic DNMT3A mutations affect both the bone marrow andT cells of recipients. Understanding these factors will lead to new insights in transplant immunology and newapproaches to the care of transplant patients. NCI 10695926 8/18/23 0:00 PA-20-203 5K08CA263555-03 5 K08 CA 263555 3 "LIM, SUSAN E" 9/1/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 12331468 "GIBSON, CHRISTOPHER JAMES" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 219904 NCI 203615 16289 PROJECT SUMMARY/ABSTRACTHematopoietic cell transplant (HCT) is an important treatment modality for patients with hematologic malignancy(HM). Its success depends on the ability of donor hematopoietic cells to establish long-term hematopoiesis andimmunologically mediated elimination of residual malignant cells. Clonal hematopoiesis (CH) is an age-relatedcondition in which detectable somatic mutations alter the biologic function and inflammatory output ofhematopoietic cells and in non-transplant populations is uniformly associated with adverse outcomes. Bystudying 1727 HCT donor-recipient pairs I found that CH in donors is common and that inactivating mutationsin the gene DNMT3A are the most frequent alterations. My preliminary data shows that donor DNMT3A-CH isassociated with improved global recipient outcomes mediated by a reduced risk of HM relapse but alsoincreases the risk of graft failure in a subset of recipients. Based on these data and the known function ofDNMT3A in hematopoietic cells I hypothesize that the effects of donor DNMT3A-CH I observe in HCT recipientsare due to engraftment of DNMT3A-mutated long-term hematopoietic stem cells and subsequent altered functionin mature DNMT3A-mutant leukocyte subsets particularly T cells. To test this hypothesis I propose the followingtwo aims: (1) Determine the effect of DNMT3A-CH on normal and impaired hematopoiesis following HCT. I willuse genomic immunophenotypic and single-cell technologies to define the characteristics including cellularcompartment of donor DNMT3A mutations that engraft in recipients. I will then focus on elucidating the biologyof graft failure developing in recipients of donor DNMT3A-CH. (2) Define the effect of DNMT3A-CH in donor-engrafted T-cells after transplantation. I will use genomic immunophenotypic and single-cell techniques todetermine the effect of donor DNMT3A mutations on T-cell composition and function in recipients aftertransplantation focusing specifically on how DNMT3A mutations modulate the development of T-cell exhaustion.I will then specifically assess how donor DNMT3A mutations in T cells affect the pathways of immune evasionutilized by relapsing cases of acute myeloid leukemia. The information gained from these studies will providenew insights into the biology of post-transplant hematopoiesis and immune surveillance that could have profoundimplications for donor selection and strategies to augment the graft-versus-leukemia effect. In concert with theproposed experiments I have outlined a five-year career development plan aimed at the goal of becoming anindependent investigator in translational transplant research. I have assembled an advisory committee of globallyrecognized experts in hematopoiesis transplant immunology and biostatistics to provide experimental inputand specific training in these fields. Dana-Farber Cancer Institute which harbors an outstanding researchcommunity and has a long track record for successful mentorship of independent physician scientists is an idealenvironment for completion of these experiments and realization of my short and long-term career goals. 219904 +No NIH Category available 3-Dimensional;ATAC-seq;Acetylation;Acetyltransferase;Amino Acid Motifs;Bacterial Infections;Binding;Biochemical;Biological;Biological Assay;Biophysics;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;Cadherins;Cell Aging;Cell Nucleus;Cessation of life;ChIP-seq;Chromatin;Chromatin Structure;Clinical;Complex;Cytoplasm;DNA;Data;Deacetylase;Deacetylation;Development;Disease;Enzymes;Epithelial Cells;Exhibits;Female;Gene Expression;Gene Silencing;Genes;Genetic;Genetic Transcription;Genomic DNA;Genomics;HDAC7 histone deacetylase;Histones;Human;Immune;Immune Evasion;Immune mediated destruction;Immune system;In Vitro;Informatics;Injections;Innate Immune Response;Knock-in;Malignant Neoplasms;Malignant neoplasm of lung;Mammary Neoplasms;Mediating;Metastatic breast cancer;Metastatic to;Mitochondrial DNA;Molecular;Natural Immunity;Neoplasm Metastasis;Nuclear;Nuclear Import;Nuclear Localization Signal;Outcome;Pathway interactions;Peptides;Phenotype;Play;Post-Transcriptional Regulation;Primary Neoplasm;Prognostic Marker;Proteomics;Reader;Recurrent Malignant Neoplasm;Regulation;Role;Sampling;Signal Transduction;Specimen;Stimulator of Interferon Genes;Tail;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Tissue Microarray;Tissues;Veins;Viral;Virus Diseases;Woman;Xenograft procedure;cancer recurrence;cell motility;cell type;clinical prognosis;cohort;epithelial to mesenchymal transition;genetic approach;genetic regulatory protein;genome-wide;histone methylation;immune resistance;in vivo;insight;lymph nodes;mRNA Expression;malignant breast neoplasm;migration;mortality;mouse model;novel;novel therapeutics;pathogen;prevent;sensor;therapeutic development;therapeutically effective;transcriptome;transcriptome sequencing;tumor-immune system interactions;tumorigenesis Elucidating novel functions of cGAS in breast cancer Metastatic breast cancer is a deadly disease with no effective cure to date. This proposal aims to elucidate anovel function for nuclear cGAS in suppressing metastatic gene expression independent of its canonicalfunction in innate immunity. We will also examine whether cGAS acetylation is a critical regulation to promotecGAS nuclear enrichment and whether inhibiting the major cGAS deacetylase could be used as a new avenueof therapeutic intervention for metastatic breast cancer. NCI 10695903 6/23/23 0:00 PA-19-056 5R01CA244825-04 5 R01 CA 244825 4 "AULT, GRACE S" 7/7/20 0:00 6/30/25 0:00 Tumor Progression and Metastasis Study Section[TPM] 10959055 "LIU, PENGDA " Not Applicable 4 BIOCHEMISTRY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 348592 NCI 224175 124417 The human immune system exhibits both specific and non-specific immunity (innate immunity) to defendagainst pathogens. The cGAS/STING pathway plays an essential role in innate immunity by sensingcytoplasmic DNA derived from viral or bacterial infection and damaged genomic or mitochondrial DNA.Evading immune destruction is a hallmark of cancer and loss of STING in certain cancers promotes immune-resistance. Interestingly cGAS has been found to promote cellular senescence and low cGAS expressioncorrelates with poor outcome in lung cancer. However whether and how cGAS inactivation is critical fortumorigenesis and whether cGAS exerts any innate immunity-independent functions in cancer remain elusive.Breast cancer constitutes 25% of all cancers in women making it the most common malignancy in females.Metastatic disease rather than primary tumors causes most death in breast cancer patients and there iscurrently no effective therapeutic options available for this deadly disease. Understanding the molecularmechanisms governing breast cancer metastasis may lead to development of therapeutic interventions totarget an Achilles heel this disease. Here we provide several lines of evidence to indicate that nuclear cGAS exerts a novel function which isindependent of its canonical function in innate immunity in suppressing breast cancer metastasis. First weobserved levels of nuclear cGAS decreased in metastatic compared with primary breast cancer. Second wefound that acetylation of cGAS in its NLS (nuclear localization signal) promoted cGAS nuclear enrichment andthat loss of nuclear cGAS promoted breast cancer metastasis. Third we identified cGAS as a novel H4K8me1reader which functions to suppress metastatic gene expression. As a result deficiency in H4K8me1 bindingsignificantly facilitated breast cancer metastasis. Given that our informatics analyses in TCGA breast cancerpatients indicated that total cGAS expression did not correlate with metastasis nor disease stage we willfurther determine whether reduced cGAS acetylation (that correlates with reduced nuclear cGAS levels) can beused as a prognostic marker for metastatic breast cancer using a cohort of primary and metastatic breastcancer patient samples readily available. In addition we will examine the molecular mechanisms and biologicalconsequences underlying the metastasis suppressive function of cGAS using both xenograft and geneticmurine models along with the initial exploration of therapeutic vulnerabilities associated with this dysregulatedpathway. Overall our studies have significant implications for metastatic breast cancer along with newpotential insights relative to breast cancer recurrence. We are hopeful that our studies will facilitate thedevelopment of new therapeutic options for breast cancer patients with potential relevance to a subset of lungcancer as well. 348592 +No NIH Category available Acceleration;Animals;Anogenital cancer;Antigens;Antiviral Agents;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cell Count;Cell Membrane Permeability;Cells;Cellular Immunity;Cervical;Cervical Intraepithelial Neoplasia;Clinical Data;Clinical Trials;DNA;DNA Vaccines;Development;Devices;Disease;Disease Outcome;Dose;Electroporation;Exhibits;Genotype;Goals;HIV;HPV-High Risk;Head and neck structure;Heat shock proteins;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Humoral Immunities;Immune response;Immunocompromised Host;Incidence;Individual;Infection;Infection Control;Injections;Intramuscular;Intramuscular Injections;L2 viral capsid protein;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mediating;Methodology;Methods;Needles;Patients;Physiologic pulse;Population;Pre-Clinical Model;Prevalence;Preventative vaccination;Prevention;Preventive;Preventive vaccine;Proteins;Recurrence;Resolution;Safety;Site;Squamous intraepithelial lesion;System;T cell response;Testing;Therapeutic;Tissues;Toxic effect;Tumor Antigens;Vaccinated;Vaccination;Vagina;Viral Load result;Woman;calreticulin;cancer prevention;cancer risk;cell mediated immune response;cellular transduction;co-infection;gene gun;immunogenicity;in vivo;malignant oropharynx neoplasm;neutralizing antibody;organ transplant recipient;pathogen;plasmid DNA;pre-clinical;preclinical study;premalignant;prevent;protective effect;response;therapeutic candidate;tumor;tumor progression;uptake;vaccine development;vector Electroporation delivery of pNGVL4aCRTE6E7L2 DNA for treatment of HPV16+ CIN2/3 patients ProjectNarrative Humanpapillomavirus(HPV)type16infectioncauses50-60%ofallcervicalcancers(and~90%ofotherHPV- associatedanogenitalandoropharyngealcancers)andHIVco-infectionincreasesriskforcancerprogression. HereweproposetotestacandidatetherapeuticandpreventiveHPVvaccineinHIVandHIV+womeninwhom bothHPV16andtheprecursorlesionofcervicalcancer(CIN2/3)havebeendetected. NCI 10695858 9/8/23 0:00 PAR-18-313 5P50CA098252-20 5 P50 CA 98252 20 9/30/03 0:00 8/31/24 0:00 ZCA1-RPRB-7 5055 14371823 "LEVINSON, KIMBERLY " Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 267351 217156 51757 Project Summary/Abstract: HPV-associated cancer incidence is significantly elevated in cervical and at othersitesinHIV+patients.HIV+patientsacquiremorefrequentmulti-typeinfectionsincludingmanygenotypes infrequentlyseeninhealthyindividualsandnottargetedbythecurrentHPVpreventivevaccines.Wepreviously developedacandidatetherapeuticandpreventiveHPVvaccinepNGVL4a-CRTE6E7L2(CRTE6E7L2)which comprisesaDNAvectorencodingtheheatshockproteincalreticulinfusedgeneticallywithHPV16E6andE7 (that are obligately expressed in HPV malignancies) as well as the L2 capsid protein (a broadly protective antigen). We showed that fusion with calreticulin (CRT) profoundly enhances the potency of DNA vaccines in generating HPV antigen-specific CD8+ T cell mediated immune responses even in CD4-depleted animals. In addition vaccination with the CRTE6E7L2 DNA vaccine induces both L2-specific neutralizing antibodies and protectionfromexperimentalvaginalchallenge.ThesefeaturesmaketheCRTE6E7L2DNAvaccineparticularly promisingforuseinHIV+patientsachallenginggrouptotreatandtopreventmultipletypesofHPVinfections. Although DNA vaccines are relatively safe and well suited for multiple administrations they generally exhibit suboptimal immunogenicity when administered by conventional intramuscular needle injection likely reflect inefficienthostcelltransduction.WehavepreviouslyshownthatelectroporationisamuchmoreeffectiveDNA vaccine administration method to generate HPV-specific CD8+ T cell immune responses as compared to conventionalintramuscularinjectionorepidermaldeliveryviagenegun.Thusthegoalofthisproposalistouse the Ichor TriGrid Delivery System Electroporation Device which has been used in multiple clinical trials for intramuscularadministrationoftheCRTE6E7L2DNAvaccineatescalatingdosesinbothHIVandHIV+patients with HPV16-associated high-grade cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3) and to examine thesafetyvirologicanddiseaseoutcomes.TheSpecificAimsofthisstudyareto(1)evaluatethesafetyand toxicity of CRTE6E7L2 administered via electroporation in HIV and HIV+ patients with HPV16+ CIN2/3; (2) characterizetheHPV16E6/E7-specificcell-mediatedandhumoralimmuneresponsesinHIVandHIV+patients with HPV16+ CIN2/3 vaccinated with CRTE6E7L2 via electroporation; (3) characterize L2-specific humoral immune responses in HIV and HIV+ patients with HPV16-associated CIN2/3 upon vaccination with CRTE6E7L2DNAvaccineviaelectroporation;and(4)determinetheHPVloadandhistopathologicalchanges inthelesionanditsmicroenvironmentinHIVandHIV+patientswithHPV16-associatedCIN2/3upontreatment withCRTE6E7L2DNAvaccineviaelectroporation.Thesuccessfulimplementationofourproposalwillprovide a new methodology for the treatment of HPV-associated high-grade squamous intraepithelial lesions in HIV andHIV+patients. +No NIH Category available Address;Adjuvant;African American;Aluminum Hydroxide;Animals;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Award;B-Lymphocyte Epitopes;Baculoviruses;Baltimore;Biological Assay;Cells;Cervical Cancer Screening;Chimeric Proteins;Clinical;Clinical Research;Cold Chains;Country;Data;Developing Countries;Disparity;Dose;Dysplasia;Economic Development;Electron Microscope;Enzyme-Linked Immunosorbent Assay;Epitopes;Female;Formulation;Freeze Drying;Funding;Gardasil;Geographic Locations;Glass;Goals;Hispanic Populations;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Human papillomavirus 18;Human papillomavirus 6;Ice;Immune Sera;Immune response;In Vitro;Income;Insecta;L2 viral capsid protein;Legal patent;Licensing;Location;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Medical Care Costs;Minor;Monoclonal Antibodies;Mucous Membrane;Mus;Oncogenic;Oryctolagus cuniculus;Patients;Phylogenetic Analysis;Pilot Projects;Population;Positioning Attribute;Powder dose form;Preventative vaccination;Primary Prevention;Process;Property;Proteins;Protocols documentation;Race;Recombinant Proteins;Recombinants;Research Design;Risk;Safety;Serum;Shipping;Spodoptera frugiperda;Surface;Technology;Temperature;Testing;Toxicology;Transition Temperature;Vaccinated;Vaccination;Vaccine Antigen;Vaccines;Vagina;Virus-like particle;Woman;aluminum sulfate;arm;carcinogenicity;cervical cancer prevention;head-to-head comparison;high risk;immunogenic;immunogenicity;improved;in vivo;innovation;mouse model;neutralizing antibody;paragon;particle;phase 1 study;phase I trial;pre-Investigational New Drug meeting;pre-clinical;prevent;programs;protective efficacy;response;scaffold;screening;self assembly;thermostability;transmission process;vaccine development;virtual;volunteer Thermostable RG1-VLPs a candidate broadly protective HPV vaccine for the prevention of cervical cancer ProjectNarrative Oncogenichumanpapillomavirus(HPV)infectionisanecessarycauseof10%ofallcancersofwomenglobally including99%ofcervicalcancers.Tohelpovercomedisparitiesinprimarypreventionofcervicalcancerhere weseektodevelopanaffordableHPVvaccinethatbothextendsthebreadthofprotectiontocoverallcancer- associatedHPVtypesandisstableatambienttemperature. NCI 10695857 9/8/23 0:00 PAR-18-313 5P50CA098252-20 5 P50 CA 98252 20 9/30/03 0:00 8/31/24 0:00 ZCA1-RPRB-7 5053 8528539 "HUH, WARNER KING" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 377621 325530 54432 ProjectSummary/Abstract:HPVisanecessarycauseof10%ofallcancersofwomengloballyincluding 99% of cervical cancers. Rates of cervical cancer vary markedly by geographic region and level of economic developmentwith>85%occurringindevelopingcountries.SuccessfulprophylacticvaccinationagainsthrHPV typescanpreventdysplasiaandthuscervicalcancer.GlobalestimatesofHPVvaccinationdeliveryandcervical screeningbyregionandincomelevelshowvirtuallynosignificantdeliverytomanypoorerpopulationsofwomen worldwide.Thereare13hrHPVtypesplusagroupof11possiblycarcinogenictypes.LicensedHPVvaccines alltargetHPV16andHPV18andonealsotargetsthenextfivemostcommontypesincervicalcancer.Since theydonottargetallcancer-associatedHPVtypesscreeningmustbemaintainedeveninvaccinatedwomen adding to medical costs. In addition the stringent cold-chain requirements of HPV vaccines provide a serious impedimenttotheirdeliveryindevelopingcountries.OuroverallgoalistodevelopanaffordableHPVvaccine that both extends the breadth of protection to all cancer-associated HPV types and is stable at ambient temperature.Hereweaddressthisgoalwithtwoinnovations:1)displayinganL2-basedprotectiveepitope(RG1) thatisconservedforHPVsinauniquepositiononthesurfaceofHPV16L1VLPsproducingasingleantigen broadlyprotectiveHPVvaccinetechnologyRG1-VLPand2)theRG1-VLPvaccineisformulatedonalumand embeddedinglassyorganicmatricesformedbyadjustinglyophilizationandformulationparametersinorderto control ice crystal nucleation rates glass transition temperatures and other material properties and thereby protectagainstdegradationduringprocessingshippingandstorage. HYPOTHESIS1:ColdchainstoragepropertiesareasignificantbarriertothedistributionofcurrentHPVvaccines andthedevelopmentofapowderedRG1-VLPvaccineincludingadjuvantthatisthermostablewilladdressthis need. Specific Aim 1: Develop a GLP freeze-dry protocol for a powder formulation of RG1-VLPs in alum and study its in vitro temperature stability and in murine models its immunogenicity and protective efficacy in comparisontoGardasil9. HYPOTHESIS2:RG1-VLPvaccinationissafeandwelltolerated.SpecificAim2:ToperformaDoseEscalation PhaseITrialoftheSafetyandImmunogenicityofthermostableRG1-VLPin36healthyfemalevolunteerswith theinclusionofacontrolGardasil9arminthestudy. HYPOTHESIS3:RG1-VLPvaccinationofhealthywomeninducesbroadlyprotectiveserumantibody.Specific Aim3:ToanalyzethelevelsofprotectiveantibodiesintheserumofpatientsfromthephaseIstudyinducedby RG1-VLPvaccinationorGardasil9.Wewillutilizethepassivetransferassaytomeasureprotectiveresponses as well as L2 and L1 VLP ELISA and in vitro neutralization assays to quantify antigen-specific neutralizing antibodytitersinserum. +No NIH Category available Alabama;Antigens;Bioinformatics;Biological;Biological Assay;Biometry;Blinded;Blood;Blood Banks;Blood specimen;Carcinoma;Clinical;Clinical Protocols;Clinical Trials;Colorado;Consultations;Country;Data Set;Databases;Development;Disasters;Disease;Doctor of Medicine;Doctor of Philosophy;Dysplasia;Enrollment;Ensure;Epidemiology;Funding;Generations;Genotype;Goals;Guidelines;Gynecologic;Gynecology;Harvest;Histologic;Human;Human Papilloma Virus Vaccine;Human Papillomavirus;Human Resources;Image Analysis;Immune response;Immunologics;Immunology;In Situ;Institution;Lesion;Liquid substance;Malignant neoplasm of cervix uteri;Microdissection;Microscopic;Molecular;Molecular Analysis;National Cancer Institute;National Research Council;Normal tissue morphology;Online Systems;Pathologic;Pathologist;Pathology;Patient Care;Peripheral Blood Mononuclear Cell;Photography;Practice Guidelines;Process;Protocols documentation;Recommendation;Recovery;Reproducibility;Research;Research Design;Research Personnel;Resource Sharing;Resources;Sampling;Serology test;Serum;Site;Specimen;System;T-Lymphocyte;Tissue Banks;Tissue Microarray;Tissue Sample;Tissue Stains;Tissues;Translational Research;Universities;Vaccination;Validation;Work;World Health Organization;biobank;career;clinically relevant;data integrity;data management;digital;digital imaging;encryption;human tissue;image processing;laser capture microdissection;member;neoplastic;participant enrollment;preservation;programs;recruit;success;tissue preparation;tumor;web platform Tissue and Pathology/Immunology Core ProjectNarrative The Tissue/Pathology/Immunology Core (Core C) will acquire process preserve and distribute clinically- annotatedhigh-qualityhumanbiospecimensharvestedfromstudiesrelatedtocervicalcancerandHPVdisease and provide pathologic interpretation and immunologic expertise support for tissue-based molecular analyses forinvestigatorsintheCervicalCancerSPOREattheJohnsHopkinsUniversitytheUniversityofAlabamaat BirminghamandtheUniversityofColoradoatBoulderaswellasexternalcollaborators. NCI 10695856 9/8/23 0:00 PAR-18-313 5P50CA098252-20 5 P50 CA 98252 20 9/30/03 0:00 8/31/24 0:00 ZCA1-RPRB-7 5052 11899394 "AREND, REBECCA C" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 175016 135959 40036 ProjectSummary/Abstract TheoverallgoalofthisTissue/Pathology/ImmunologyCore(CoreC)istoacquirepreserveanddistribute clinically-annotated high-quality human biospecimens related to cervical cancer and HPV disease and to provide pathologic and immunologic expertise support and in situ analyses for tissue-based analyses for investigators in the Cervical Cancer SPORE at the Johns Hopkins University the University of Alabama at BirminghamandtheUniversityofColoradoatBoulderaswellasexternalcollaborators.CoreChasbeenin existence since 1998 and has expanded with the support of the Cervical Cancer SPORE. To date we have bankedbloodcytologicandtissuesamplesfrom4299subjectsandsupported6clinicaltrials.Allhumantissues and biologic fluids are harvested and banked in accordance with the National Cancer Institutes Best Practice Guidelines for Biorepositories. Core C personnel have been expanded to strengthen expert pathologic and immunologic consultation to investigators including guidance for quantitative digital image analyses of multiparameter molecular studies of tissues microdissection preparation of tissue microrarrays HPV genotypingHPVseroepidemiologyandHPVAntigenFunctionalExpansionofSpecificTcells(FEST)viaTCR Vclonotypesequencingandquantitation.Collectionoftissuecytologicandbloodspecimensissupervisedby gynecologicpathologistsandclinicalcolleaguesingynecology.Clinicalinformationforsubjectsenrolledinour clinical protocols is entered into a password-protected web-based tracking system. This internal web-based system follows the recommendations of the National Research Council and includes user authentication encryptionaudittrailsanddisasterrecovery.Areviewmechanismisinplaceforprioritizationofdistributionof requested resources to investigators within and external to the Johns Hopkins Cervical Cancer SPORE. Biosamples have been shared with collaborators at academic institutions across the country. This shared resourceispivotaltothesuccessofallfourHPVvaccine-basedSPOREprojectsandwillsupportallfourHPV vaccine-based SPORE projects external collaborators as well as the Developmental Research Program (DEP)andCareerEnhancementProgram(CEP)awardeesandexternalcollaborators.CoreCisledbyDrs. AnnaYemelyanovaM.D.(UAB)LawrenceLambPh.D.(UAB)RaphaelViscidiM.D.(JHU)andRussellVang M.D. (JHU). Co-Investigators that support Core C include Drs. Kellie Smith Ph.D. (JHU) Sailesh Pillai Ph.D. (UAB)DeyinXingM.D.Ph.D.(JHU)andRobertAndersM.D.Ph.D.(JHU). +Behavioral and Social Science; Cancer; Clinical Research; Coronaviruses; Emerging Infectious Diseases; Health Services; Infectious Diseases; Prevention; Tobacco; Tobacco Smoke and Health Admission activity;Adoption;Behavioral;Biological Markers;COVID-19;COVID-19 complications;COVID-19 patient;Cancer Burden;Cancer Center;Cancer Control;Cessation of life;Collaborations;Communication;Communities;Creativeness;Custom;Data;Data Element;Development;Diagnosis;Division of Cancer Control and Population Sciences;Drug Prescriptions;Effectiveness;Ensure;Foundations;Funding;Goals;Government Agencies;Health system;Hospitalization;Information Technology;Infrastructure;Institution;International;Internet;Intervention;Intubation;Knowledge;Knowledge Management;Lead;Logistics;Monitor;National Cancer Institute;Occupational activity of managing finances;Outcome;Patients;Privatization;Professional Organizations;Research;SARS-CoV-2 positive;Services;Severity of illness;Site;Smoking Status;Test Result;Tobacco Use Cessation;Training Programs;Training Support;Translations;United States National Institutes of Health;Universities;Wisconsin;Work;cancer prevention;comorbidity;demographics;design;discrete data;experience;innovation;mHealth;meetings;mortality;outreach;practical application;programs;smoking cessation CRDF Coordinating Center: Logistics Support Under CRDF Global n/a NCI 10695844 APC21003001-1-0-1 Y01 78408917 "HOWERTON, SAMUEL " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 850000 NCI As part of its long-standing support for international research programs of the National Institutes of Health (NIH) CRDF Global will provide project coordination financial management and logistical support services for the National Cancer Institute's (NCI) Division of Cancer Control and Population Science (DCCPS). 850000 +Cancer; Cervical Cancer; Clinical Research; Clinical Trials and Supportive Activities; HPV and/or Cervical Cancer Vaccines; Immunization; Infectious Diseases; Orphan Drug; Prevention; Rare Diseases; Sexually Transmitted Infections; Vaccine Related; Women's Health Area;Cervical;Costa Rica;Dose;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human papilloma virus infection;Human papillomavirus 16;Immunization;Lesion;Logistics;Malignant neoplasm of cervix uteri;Participant;Phase;Regimen;Risk;Running;Safety;Schedule;Vaccinated;cervical cancer prevention;cost;follow-up;girls;mortality;premalignant;prevent;prophylactic;vaccine acceptance;vaccine evaluation;vaccine trial Follow-up and Extended Follow-up of Participants - Option 1 n/a NCI 10695839 261201700012I-P00007-26100002-1 N01 4/6/18 0:00 9/15/23 0:00 15726313 "GONZALEZ-MAYA, PAULA " Not Applicable n/a Unavailable 853088008 KDL2VERNRKA5 853088008 KDL2VERNRKA5 CS 9.93333 -84.08333 10011285 FUNDACION INCIENSA SAN JOSE Unavailable 10108 COSTA RICA N R and D Contracts 2022 566352 NCI This SOW describes activities related to NCIs Human Papillomavirus (HPV) vaccine evaluation efforts required for the next phase of these studies and will cover the follow-up of participants in both the existing trial of the bivalent HPV vaccine (Costa Rica Vaccine Trial or CVT) and the new trial aimed at evaluating the non-inferiority of 1 versus 2 doses of the HPV vaccines. Human papillomavirus (HPV) vaccination successfully prevents targeted HPV infections related precancerous lesions and ultimately has the potential to substantially reduce cervical and other HPV-related cancers. Despite the established efficacy and safety of the HPV vaccine most girls living in areas with the greatest risk for cervical cancer are not being vaccinated. The cost and logistical difficulties of the recommended multiple-dose schedule has been a significant impediment to vaccination uptake and the prevention of cervical cancer and its associated mortality. Task A and Task B will run concurrently. 566352 +No NIH Category available ABCB1 gene;ABCG2 gene;Ames Assay;Animal Model;Animals;BIRC4 gene;Biological Assay;Blood Circulation;Bypass;CYP1A2 gene;Caco-2 Cells;Camptothecin;Cancer Etiology;Canis familiaris;Cardiotoxicity;Cessation of life;Chemical Structure;Chemistry;Circulation;Clinical;Clinical Research;Clinical Trials;Cytochrome P450;DNA Repair;Data;Development;Drug Kinetics;Drug Packaging;Drug Targeting;Drug resistance;ERCC1 gene;ERCC6 gene;Erythrocytes;Formulation;Future;Goals;Grant;Guidelines;Hepatocyte;Human;In Vitro;Intravenous;Investigational Drugs;Investigational New Drug Application;Lead;Light;Liver;Liver Microsomes;Lymphoma;MCL1 gene;Malignant Neoplasms;Maximum Tolerated Dose;Mus;Mutagenicity Tests;Names;Neoplasm Metastasis;Oncogenic;Oncoproteins;Oral;Pancreatic Ductal Adenocarcinoma;Patients;Permeability;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Plasma;Play;Proteins;Publications;Qualifying;Quality of life;Rattus;Recommendation;Resistance;Role;Route;Small Business Innovation Research Grant;Survival Rate;Testing;Topotecan;Toxic effect;Toxicokinetics;Toxicology;Water;Whole Blood;Work;Writing;advanced disease;advanced pancreatic cancer;analog;c-myc Genes;cancer invasiveness;cancer stem cell;canine model;chemical stability;disorder control;effective therapy;enantiomer;feasibility testing;first-in-human;good laboratory practice;high throughput screening;improved;in vivo;innovation;irinotecan;manufacture;novel anticancer drug;novel therapeutics;pancreatic cancer patients;patient derived xenograft model;pre-Investigational New Drug meeting;preclinical study;prevent;stem cell biomarkers;survivin;therapy resistant;tumor;tumor xenograft Perform non-GLP and GLP TOX/TK studies and file a novel drug IND with the FDA for advanced pancreatic cancer patient clinical trials NarrativeA novel anticancer drug named FL118 has high efficacy to eliminate pancreatic ductal adenocarcinoma (PDAC)tumors which is an extremely difficult-to-treat cancer with an overall 5-year survival rate of ~11% and is 3%for advanced PDAC in the US. Completion of this project will qualify FL118 for its first-in-human clinical trial withadvanced PDAC patients. NCI 10695608 9/12/23 0:00 PA-22-176 1R43CA275410-01A1 1 R43 CA 275410 1 A1 "LOU, XING-JIAN" 9/12/23 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-CTH-T(10)B] 9871876 "LING, XIANG " "LI, FENGZHI " 26 Unavailable 78470121 TJ1JCE59GKX3 78470121 TJ1JCE59GKX3 US 42.98321 -78.750483 10031914 "CANGET BIOTEKPHARMA, LLC" BUFFALO NY Domestic For-Profits 142214548 UNITED STATES N 9/12/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 400000 NCI 303008 75752 Abstract/SummaryThe goals of this SBIR Phase I grant are: (1) to use the clinically compatible FL118 product to perform the non-good laboratory practice (GLP) and GLP toxicology (TOX) and toxicokinetics (TK) studies; and (2) to author andfile the FL118 Investigational New Drug (IND) application with the FDA for first-in-human FL118 phase 1 clinicaltrials in patients with advanced pancreatic ductal adenocarcinoma (PDAC). The reason to use PDAC as FL118sfirst indication in clinical trials is that (i) FL118 targets the oncoprotein DDX5 and shows high efficacy to eliminatePDAC with low toxicity; (ii) PDAC is a difficult-to-treat cancer with a 5-year survival rate of ~11% and is 3% inadvanced PDAC patients; (iii) PDAC is expected to become the second greatest cause of cancer death by 2030;and (iv) currently there is no effective treatment. Therefore there is an unmet clinical need for PDAC patients.We discovered FL118 via high throughput screening followed by in vitro-&-in vivo hit-to-lead analyses. FL118 iswater-insoluble which has prevented its development. Together with our partners we have now resolved theFL118 water-insoluble issues. FL118 has a unique chemical structure of 1011-methylenedioxy and possessesdistinct mechanisms of action (MOA) from camptothecin (CPT) and its clinically used analogues (e.g. irinotecanand topotecan). Our studies indicated that FL118 inhibits multiple oncogenic proteins (e.g. survivin Mcl-1 XIAPcIAP2 MdmX c-Myc) and key DNA damage repair regulators (e.g. ERCC6) by directly targeting the upstreammaster oncogenic regulator DDX5. Unlike clinically used CPTs FL118 is not a substrate of multi-efflux proteinsABCG2/BCRP and MDR1/Pgp and can bypass their drug resistance. Furthermore cancer stem cells (CSC) areknown to play a critical role in treatment resistance. Accordingly FL118 inhibits both CSC markers (ABCG2ALDH1A1 Oct4) and invasive CSC spread. FL118 has demonstrated the capability to eliminate PDAC patient-derived xenograft (PDX) tumors and inhibit PDAC metastasis while showing low toxicity in murine and canineanimal models. FL118 is orally available highly stable chemically accumulates and resides in tumors and israpidly cleared from the bloodstream circulation (favorable pharmacokinetics - PK).Canget along with its partner Roswell Park successfully held the first pre-IND meeting (No: PIND 133477) withthe FDA in 2017. Following the IND guideline and the pre-IND outline recommended by the FDA we havecompleted the major components of IND-Enabling Studies and CMC (Chemistry Manufacturing and Control)work. FL118 has passed numerous hurdles and the results obtained to date from the IND-Enabling Studies andother preclinical studies strongly support FL118 first-in-human clinical trials with PDAC patients.The Specific Aim of this SBIR Phase I project is to file the FL118 IND with the FDA after performing the non-GLP TOX/MTD and GLP TOX/TK studies using the clinically compatible FL118 product. Test of Feasibility:FDA accepts our IND application and allows for FL118 clinical trials to commence. Upon completion of thisproject we will have the FL118 IND in place for qualifying FL118 first-in-human clinical trials. 400000 +No NIH Category available ATP phosphohydrolase;Affinity;Biochemistry;Biology;Cell Survival;Cells;Chemicals;Complex;DNA;Development;Disease;Docking;Drug Industry;Exhibits;Goals;Human;Libraries;Ligands;Ligase;Link;Lysine;Methods;Nucleosome Core Particle;Pattern;Peptides;Play;Proteins;Proteome;Recovery;Resistance development;Technology;Ubiquitin;Variant;antagonist;base;cancer cell;expectation;improved;innovation;insight;multicatalytic endopeptidase complex;novel;particle;protein degradation;protein protein interaction;receptor;recruit;screening;small molecule;ubiquitin-protein ligase Development of Ubiquitin-Independent Degraders Project NarrativeThis project will develop a new class of Ubiquitin-independent protein-degrading small molecules that functionby recruiting target proteins directly to the proteasome. This approach is quite novel and differs from any existingdegrader strategy and will greatly simplify the development of degraders. Critical to this effort will be thediscovery of high-quality ligands for the 19S Regulatory Particle of the proteasome which will be accomplishedby a novel DNA-encoded library screening strategy. NCI 10695284 8/28/23 0:00 RFA-RM-22-020 1R01CA290247-01 1 R01 CA 290247 1 "AMIN, ANOWARUL" 9/1/23 0:00 8/31/28 0:00 Special Emphasis Panel[ZRG1-BBBT-J(70)R] 1883003 "KODADEK, THOMAS J." Not Applicable 3 BIOCHEMISTRY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 826413 OD 427750 398663 Project SummaryDegraders are chemical dimerizers that recruit a target protein (TP) to an E3 Ubiquitin(Ub) ligase. In favorable cases this results in TP poly-Ubiquitylation and subsequentdestruction by the proteasome. Degraders are difficult to develop because of therequirement that the degrader promote significant protein-protein interactions betweenthe TP and E3 Ub ligase in such a way that a TP lysine residue is placed appropriately toattack the activated Ub molecule. Here we propose to develop a new class of degradersthat will recruit TP directly to the proteasome. We anticipate that this mechanism ofaction will result in potent TP destruction without the need for Ubiquitylation which inturn will make the development of these degraders far more straightforward. 826413 +No NIH Category available 3-Dimensional;Active Sites;Amino Acids;Area;Binding Sites;Biological;Cancer Center;Cancer Center Support Grant;Cancer Science;Core Facility;Crystallization;DNA Binding;Data;Data Collection;Disease;Education;Ensure;Enzymes;Fee-for-Service Plans;Funding;Growth;Image;Individual;Isotope Labeling;Knowledge;Laboratories;Ligand Binding;Macromolecular Complexes;Malignant Neoplasms;Methods;Modification;Molecular;Molecular Conformation;Nebraska;Nuclear Magnetic Resonance;Postdoctoral Fellow;Process;Protein Chemistry;Proteins;Protocols documentation;Recombinant Proteins;Research;Research Personnel;Resource Sharing;Robotics;Roentgen Rays;Role;Sampling;Services;Side;Signaling Molecule;Structure;Students;Techniques;Training;Visualization;Work;X-Ray Crystallography;experience;experimental study;instrument;instrumentation;macromolecule;member;novel therapeutics;protein expression;protein protein interaction;protein purification;screening;shared decision making;side effect;structural biology;transcription factor Structural Biology Shared Resource n/a NCI 10695260 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7714 6626753 "BORGSTAHL, GLORIA EO" Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 128045 83417 44628 PROJECT SUMMARY: STRUCTURAL BIOLOGY SHARED RESOURCEAtomic images of the arrangement of amino acid side chains in three dimensions give the atomic detail neededto visualize the active sites of enzymes see the DNA-binding sites of transcription factors and view theprotein-protein interactions of signaling molecules. Function can be understood through the determination ofatomic structures by X-ray crystallography. Modification of the function of macromolecules is key to developingspecific therapies without side effects. In the absence of crystals the molecular envelopes of macromolecularcomplexes individual proteins and their gross conformational changes upon ligand binding can be determinedusing small-angle X-ray scattering (SAXS). The SBF (Structural Biology Facility) was initiated many years agothrough funding from the Nebraska Research Initiative (NRI) and the UNMC Vice Chancellor for Research(VCR). Its expanding use by Cancer Center members and its important role in supporting the science of theCancer Center led to its designation as a Cancer Center core facility beginning in 2008. In the years 2013through 2015 $1741452 was obtained from the NRI and VCR for upgrades. The SBF has four mainlaboratory services:1. Protein expression and purification (PrEP).2. Crystal screening and growth (CSG).3. X-ray (Small-angle X-ray scattering (SAXS) and single crystal diffraction).5. Nuclear magnetic resonance (NMR) data collection.The PrEP laboratory provides high-quality purified recombinant protein samples that can be isotopically labeledfor NMR data collection ready for crystallization or other experiments. The CSG laboratory includes state-of-the-art robotic crystallization instruments with microscale capabilities. SAXS single-crystal X-raycrystallography and NMR are used for structure determination. The SBF has two co-directors (one withexpertise in protein chemistry and X-ray methods and the other with expertise in NMR) who share the decisionmaking and have experience in structure determination. Two managers a technician and one postdoc areemployed to develop protein purification and crystallization protocols maintain the high-tech instrumentationensure that the best data is collected/processed and train users/students. +No NIH Category available Abdomen;Academic Medical Centers;Antibodies;Antigens;Automation;Autopsy;Basic Science;Benign;Biological Assay;Blood;Cancer Center;Cancer Center Support Grant;Cell Culture Techniques;Cell Survival;Chest;Client;Collaborations;Consultations;Core Facility;Custom;DNA;Database Management Systems;Detection;Directories;Disease;Education;Educational workshop;Effectiveness;Enzymes;Equipment;Faculty;Fishes;Formalin;Fostering;Freezing;Frozen Sections;Genes;Hematologic Neoplasms;Histology;Human Resources;Image;Image Analysis;Immunohistochemistry;In Situ Hybridization;Individual;Institutional Review Boards;Interdisciplinary Study;Laboratories;Laboratory Scientists;Liquid substance;Malignant - descriptor;Malignant neoplasm of pancreas;Management Information Systems;Measures;Mentors;Messenger RNA;Methodology;Modernization;Morphology;Neoplasm Metastasis;Neoplastic Processes;Nitrogen;Occupations;Online Systems;Organ;Organ Harvestings;Organoids;Pancreas;Paraffin;Paraffin Embedding;Paraffin Tissue;Pathologic;Pathology;Pathology processes;Patients;Primary Neoplasm;Process;Prospective Studies;Proteins;Protocols documentation;Quality Control;RNA;Registries;Reproducibility;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Retrospective Studies;Review Committee;Sampling;Science;Services;Slide;Stains;Standardization;Suspensions;Testing;Tissue Banks;Tissue Embedding;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Training;Translational Research;Urine;Viscera;biobank;cost effective;design;digital imaging;digital pathology;equipment training;human biological material;human tissue;improved;innovation;instrumentation;interdisciplinary collaboration;laboratory experience;member;neoplastic;novel;preservation;process improvement;quality assurance;tissue processing;tissue resource;tool;whole slide imaging Pathology Shared Resource n/a NCI 10695258 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7712 14605060 "FOSTER, KIRK W" Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 158008 102937 55071 PROJECT SUMMARY: PATHOLOGY SHARED RESOURCETogether the Tissue Sciences Facility (TSF) and Tissue Procurement Shared Resource (TPSR) make up thePathology Core Facility which was created to provide comprehensive tissue banking histology imaging andrelated instrumentation and expertise to members of the Fred and Pamela Buffett Cancer Center (BCC)investigators. The Tissue Sciences Facility (TSF) was created to provide comprehensive histology and imagingapplications to Fred and Pamela Buffett Cancer Center (BCC) investigators. The Tissue Procurement SharedResource (TPSR) also part of the Pathology Core Facility was created to provide frozen and rapid autopsysamples to members of the Buffett Cancer Center. The availability of expert advice and services to both newand established investigators including routine histology paraffin and frozen sectioning histochemicalstaining routine and multiplex immunohistochemistry in situ hybridization digital imaging projectcustomization and pathology consultation are emphasized in the facility. These services provided by highlytrained laboratory scientists offer comprehensive pathology support for basic science and translationalresearch. Collaboration and pathological consultation are available to BCC investigators at all points in theresearch process by Pathology faculty. +No NIH Category available Biological;Biological Assay;Budgets;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cells;Chemicals;Communication;Communities;Computer software;Consultations;DNA sequencing;Data;Dideoxy Chain Termination DNA Sequencing;Educational workshop;Effectiveness;Equipment;Experimental Designs;Faculty;Gene Expression Profiling;Genes;Genomics;Human Resources;Image;Infrastructure;Laboratories;Lead;Learning;Malignant neoplasm of gastrointestinal tract;Mentors;Metagenomics;Methods;Mission;Molecular;Molecular Biology;Molecular Biology Shared Resource;Organism;Performance;Population;Postdoctoral Fellow;Procedures;Process;RNA;Reagent;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Ribosomes;Services;Small Interfering RNA;Students;Techniques;Technology;Tissues;Training;Update;Validation;assay development;cellular imaging;cost;design;exome;functional genomics;genome sequencing;genome-wide;graduate student;high throughput screening;instrumentation;lectures;mRNA sequencing;meetings;member;miRNA expression profiling;nano-string;next generation;next generation sequencing;operation;programs;screening;skills training;small molecule;symposium;targeted sequencing;transcriptome sequencing;virtual;whole genome Molecular Biology Shared Resource n/a NCI 10695257 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7711 9819322 "EUDY, JAMES " Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 129688 84487 45201 PROJECT SUMMARY: MOLECULAR BIOLOGY SHARED RESOURCEThe Molecular Biology Shared Resource (MBSR) was created in 2009 to bring together into one consolidatedoperation the Genomics Facility and the Molecular Biology/High-Throughput Screening (MB/HTS) Facility. Themerger enhanced the communication between the cores maximized the utilization of staff expertise andraised the quality of services used by representatives of all Cancer Center programs. The MBSR offers: 1)next-generation sequencing (Illumina) single-cell genomics (10xGenomics) NanoString targeted geneexpression assays and Sanger sequencing; 2) genome-wide siRNA and small-molecule chemical (>100K)HTS screening 3) high-content imaging and analysis and 4) multi-analyte profiling using Luminex xMAPtechnologies. The resource provides free consultation to every researcher regarding experimental designbudget estimates results and data assessment and is a significant resource for molecular biological reagentsinformation and training in molecular biological techniques and analysis software. The MBSR is under thedirection and oversight of two Co-Directors who manage the day-to-day activities of the Facility. In this regardDr. David Kelly oversees the MB/HTS Facility located in the BCC and Dr. James Eudy oversees the GenomicsFacility located in the Durham Research Center II both on the UNMC campus. Six technical staff members areemployed in the MBSR with personnel extensively cross-trained to perform virtually all services and to operatevirtually all instrumentation and equipment. The MBSR is one of the most widely used BCC Shared Resourcesupporting over 184 biomedical laboratories in the UNMC research community of which approximately 53%are laboratories led by BCC investigators in the BCC research programs (Targets Probes and DeliveryCancer Biology Program and Gastrointestinal Cancer Program). To meet the rapidly changing needs of and toinform BCC investigators the MBSR personnel conduct workshops speak at local seminars attend CancerCenter program meetings and multi-investigator project meetings and present at laboratory meetings.Moreover they attend national and regional technology conferences to learn the latest technologiestechniques and methods. +No NIH Category available Adopted;Affect;Area;Award;Big Data;Bioinformatics;Bioinformatics Shared Resource;Biological;Biological Process;CLC Gene;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Cells;ChIP-seq;Cloud Computing;Collaborations;Collection;Communities;Computer software;Consultations;Custom;DNA methylation profiling;DNA sequencing;Data;Data Analyses;Data Set;Data Storage and Retrieval;Databases;Dedications;Development;Diagnostic;Discipline;Emerging Technologies;Environment;Epigenetic Process;Experimental Designs;Funding;Gene Expression;Genes;Genetic;Genomics;Goals;Grant;High Performance Computing;Homology Modeling;Human Resources;Individual;Infrastructure;Institution;Internet;Investments;Laboratory Research;Licensing;Machine Learning;Malignant Neoplasms;Maps;Metagenomics;Methods;Methylation;Micro Array Data;Molecular;Multiomic Data;Nature;Neoplasm Circulating Cells;Output;Pathway Analysis;Pathway interactions;Performance;Policies;Procedures;Proteins;Proteomics;Protocols documentation;Public Domains;Quality Control;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Running;Services;Software Tools;Source;Systems Biology;Technical Expertise;Technology;Testing;The Cancer Genome Atlas;Training;Training Programs;Training Support;Trust;United States National Institutes of Health;Visualization software;anticancer research;bioinformatics resource;bioinformatics tool;cancer genomics;cell free DNA;cluster computing;college;comparative genomic hybridization;computer infrastructure;computer program;computer science;data analysis pipeline;data pipeline;deep learning;drug discovery;exome sequencing;experimental analysis;experimental group;falls;gene product;genomic data;high dimensionality;improved;infrastructure development;learning strategy;member;metabolomics;neoplasm resource;next generation sequencing;novel;open source;open source tool;precision medicine;prognostic;programs;software development;statistics;student mentoring;supercomputer;tool;transcriptome sequencing;transcriptomics;volcano;whole genome Bioinformatics Shared Resource n/a NCI 10695254 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7708 8278309 "GUDA, CHITTIBABU " Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 82884 53996 28888 PROJECT SUMMARY: BIOINFORMATICS SHARED RESOURCEBioinformatics has become an essential part of cancer research due to the high-throughput nature of multi-omics data (such as genetic genomic epigenetic transcriptomic proteomic and metabolomic) that are beinggenerated from cancer research projects. Thus a tremendous need exists for developing computationalinfrastructure for the collection processing storage analysis and facilitation of the use of such data by thecancer research community. The main goals of the Bioinformatics and Systems Biology (BSB) SharedResource are to facilitate access to bioinformatics resources that include hardware software and personnelexpertise; train researchers in the use of such resources; and provide custom support for research projectsincluding the development of cutting-edge tools and protocols to match the rapidly changing technologies inthe realm of cancer research. BSB Shared Resource is equipped with locally installed bioinformatics tools anddatabases related to cancer research backed by state-of-the-art computational and storage infrastructure. Inaddition to an extensive collection of trusted open-source tools the Shared Resource will also provide accessto several licensed bioinformatic software tools such as Ingenuity Pathway Analysis CLC GenomicsWorkbench Partek Flow Schrodinger Molecular Drug Discovery suite and BioCyc Database Collection.Similarly the computational infrastructure includes dedicated servers for data storage high-performancecomputing database and web development and optional cloud computing. The Shared Resource offers a widerange of bioinformatics services that fall into five thematic areas including (i) analysis of next-generationsequencing (NGS)-based genomics data; (ii) analysis of array-based and systems biology data; (iii) machine-learning big-data analysis and precision medicine research; (iv) development of software and databaseapplications for bioinformatics projects; and (v) support for experimental design and grant consultation. In thepast funding cycle the Shared Resource has supported several hundred distinct research projects with over athird of the Shared Resource users hailing from the Fred and Pamela Buffett Cancer Center (BCC). TheShared Resource Director is assisted by four well-trained support staff with diverse training backgrounds incomputer programming statistics cancer genomics and systems biology. An advisory board that consists ofmembers representing different colleges at UNMC oversees the Shared Resource policies and procedures andmakes recommendations. The Shared Resource Director also leads a research program in cancer genomicsand bioinformatics mentors students in the Cancer Biology Training Program and collaborates with a numberof BCC investigators to facilitate the development of customized data analysis protocols that meet the evolvingneeds of cancer researchers. +No NIH Category available Cancer Center;Cancer Center Support Grant;Cells;Communities;Consultations;Core Facility;Coupled;Data;Dedications;Development;Fees;Goals;Image;Image Analysis;Imaging Techniques;Laser Scanning Confocal Microscopy;Lighting;Maintenance;Medical center;Microscope;Microscopic;Microscopy;Modeling;Nebraska;Optics;Photobleaching;Publishing;Research;Research Personnel;Resolution;Resource Sharing;Services;Structure;Techniques;Technology;Three-Dimensional Imaging;Tissues;Training;Universities;cell fixing;design;experimental study;image processing;innovation;light microscopy;live cell imaging;member;microscopic imaging;molecular imaging;notch protein;reconstruction;single molecule;superresolution microscopy;ultra high resolution Advanced Microscopy Shared Resource n/a NCI 10695253 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7707 7924925 "CAPLAN, STEVEN H" Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 37219 24247 12972 PROJECT SUMMARY: ADVANCED MICROSCOPY SHARED RESOURCEThe UNMC Advanced Microscopy Core Facility (UAMCF) at the University of Nebraska Medical Center isdedicated to providing top-notch microscopy and imaging services for competitive fees. The UAMCF waslaunched in August 2014 to replace the previous campus microscopy core facility (Confocal Laser ScanningMicroscopy Facility: CLSMF) with the goal of acquiring super-resolution microscopy capabilities on campus.UAMCF currently provides users with access to a dual-platform super-resolution microscope with capabilitiesfor super-resolution Structured Illumination Microscopy (sr-SIM) and single molecule PhotoactivatibleLocalization Microscopy/direct Stochastic Optical Reconstruction Microscopy. Sr-SIM capabilities include up to100 nm resolution in the x/y axis and ~300 nm axial resolution. PALM/dSTORM capabilities include singlemolecule imaging and precision of ~5 nm coupled with ~10 nm Nyquiste Resolution. In addition two recent-model Zeiss confocal microscopes fully equipped for live image analysis and complete with adjacentworkstations are also available. The Zeiss LSM 800 confocal microscope also has an Airyscan unit forenhanced resolution that approaches that of sr-SIM imaging. The facility provides outstanding service includingconsultations by active researchers with expertise who have published studies using advanced microscopytechniques. In addition a Zeiss Cell Discoverer 7 microscope is available for a variety of automated studies.Finally the facility also boasts a complete Imaris workstation for advanced 3D imaging processing andquantification. Overall the UAMCF provides outstanding support for Cancer Center members and otherresearchers on and off campus. +No NIH Category available Basic Science;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Communication;Ensure;Equipment;Feedback;Flow Cytometry;Funding;Funding Agency;Future;Goals;Grant;Human Resources;Institution;Leadership;Malignant Neoplasms;Microscopy;Molecular Biology;Monitor;Pathology;Policies;Process;Productivity;Publications;Quality Control;Reporting;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Services;Suggestion;Surveys;Technology;cost effectiveness;functional status;improved;meetings;member;operation;preclinical imaging;programs;satisfaction;structural biology Shared Resource Management n/a NCI 10695252 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7706 1891494 "HOLLINGSWORTH, MICHAEL A." Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 77504 50491 27013 PROJECT SUMMARY: SHARED RESOURCE MANAGEMENTWe propose to manage and provide support (space funds personnel) to eight Cancer Center Support Grant(CCSG)-supported Shared Resources (Flow Cytometry Advanced Microscopy Structural Biology MolecularBiology Pathology Preclinical Imaging Bioinformatics and Biostatistics) that are necessary and highly utilizedby Cancer Center members. Shared Resources supported by the CCSG are configured and managed to provideaccess to specialized state-of-the-art technologies services and expertise that enhance scientific interactionand productivity in the Fred and Pamela Buffett Cancer Center (BCC) in a manner that ensures stability reliabilitycost-effectiveness and quality control of these services. The Director of the BCC Dr. Cowan makes finaldecisions regarding the allocation of CCSG resources (space funds personnel) to Shared Resources. Dr.Cowan is assisted by the Associate Director for Basic Research Dr. Michael A. (Tony) Hollingsworth whomanages policies and practices to ensure an effective and fair process for setting scientific and other prioritiesregarding CCSG Shared Resource support and usage and assuring accessibility to members across campuses.Fiscal management and day-to-day administrative support for the Shared Resources is provided by Mr. MatthewWinfrey the Associate Director for Administration and External Affairs. Shared Resources supported by theBCC are a subset of many Shared Resources available at UNMC and all Shared Resources supported by theBCC are also supported in part by the Institution (UNMC) which allows us to leverage CCSG funds withinstitutional assets and support. Our management plan for all resources is cooperative and collaborative with theinstitutional oversight of UNMC-wide resources which is housed in the Office of the Vice Chancellor for Research(VCR) Dr. Jennifer Larsen. To ensure that supported shared resources are most effectively meeting theresearch services needs of its members the Buffett Cancer Center employs regular user satisfaction surveys toevaluate quality timeliness upcoming needs and comprehensiveness of shared resource service. Alsocommunication from users regarding Shared Resource functionality is encouraged on an ongoing as-neededbasis for problems that arise in the daily operations of the resource. Dr. Hollingsworth and Mr. Winfrey conductan annual review of Shared Resources with each Manager (and associated personnel that conduct cancerrelated activities). On an annual basis subsequent to receiving results of the UNMC-wide and Cancer Centerspecific surveys reports of internal advisory boards notes from presentations and direct feedback from usersDr. Hollingsworth and Mr. Winfrey meet with the leaders of each Shared Resource to review usage ongoingand completed cancer related research projects publications grant support quality and user satisfaction. Wealso solicit input from each user and resource leader regarding the need for improvement in equipmentpersonnel or resources in order to maintain the state-of-the-art functional status for each facility. As part of thesurveys of users and managers Cancer Center members are asked to identify current and anticipated needswith respect to capabilities within the shared resources. Suggestions for new or enhanced resources arereviewed and prioritized by leadership in the Cancer Center including Program Leaders Associate Directorsand the Director. Funding plans (using Institutional or funds from sources other than the CCSG) for high priorityresources are developed and when possible enacted. +No NIH Category available Amendment;Authorization documentation;Biometry;Cancer Center;Cancer Center Support Grant;Caring;Charge;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Collection;Committee Members;Data;Detection;Development;Diagnosis;Discipline of Nursing;Disease;Enrollment;Ensure;Faculty;Feasibility Studies;Feedback;Hematologic Neoplasms;Institution;Institutional Review Boards;Intervention Trial;Lead;Logistics;Longterm Follow-up;Malignant Neoplasms;Medical Oncology;Medical center;Modification;Monitor;Nebraska;Oncology;Pathology;Patient Outcomes Assessments;Patients;Pediatric Oncology;Peer Review;Pharmacology;Population;Population Sciences;Prevention;Principal Investigator;Process;Protocols documentation;Qualifying;Quality of life;Radiation Oncology;Recommendation;Regulation;Research;Research Activity;Research Personnel;Review Committee;Safety;Site;Solid Neoplasm;Students;Suggestion;Supportive care;Surgical Oncology;System;Universities;authority;behavioral study;cancer prevention;cancer therapy;expedited review;falls;human subject;innovation;member;multidisciplinary;patient safety;screening;sound;survivorship;symptom management Protocol Review and Monitoring System n/a NCI 10695250 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7704 9658016 "GANTI, APAR KISHOR " Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 115865 75482 40383 PROJECT SUMMARY: PROTOCOL REVIEW AND MONITORING SYSTEMThe Buffett Cancer Center (BCC) has established a process by which proposed BCC clinical and populationscience research protocols undergo internal peer review for scientific merit and prioritization prior to Universityof Nebraska Medical Center (UNMC) Institutional Review Board approval. The BCC SRC is a multidisciplinarycommittee charged with overseeing the scientific aspects of cancer-related research involving human subjectsconducted by members of the UNMC faculty and students and BCC Members. Cancer prevention studiesscreening trials behavioral studies quality of life / survivorship studies and interventional trials that rely oncollection of patient-reported outcomes are reviewed by the SRC. The BCC SRC has the authority to approverequire modifications or disapprove research activities that fall within its jurisdiction. The SRC confirms thescientific validity of the proposed study and assesses the feasibility of the study relative to the availability ofhuman subjects and ongoing protocols based on enrollments from that same or patient and/or subjectpopulation. The BCC SRC review also assures that the data and safety monitoring plan for the proposedclinical trial is appropriate and in accordance with regulations and provides feedback and recommendations tothe investigator to enhance the scientific merit and/or the logistics of the planned study. Initial review includestwo stages beginning with preliminary review and approval by the Disease Focused Teams (DFTs) followedby the SRC review. National Externally Peer Reviewed and Multi-Institutional studies with an approved NCIDesignated or Comprehensive Center as the lead site received expedited review which focuses on priorityand feasibility. The BCC SRC members are selected to represent the broad spectrum of oncology research.The BCC SRC has broad expertise with representation from Medical Surgical Pediatric and RadiationOncology Pharmacology Pathology Nursing and Biostatistics. The Committee also has broad expertise inhematological malignancies and solid tumors as well as in clinical research in supportive care and symptommanagement. Any Cancer Center member with expertise specific to a particular protocol may also be asked toserve as an at-large or ad-hoc reviewer based on their unique qualifications or when expertise is not availablefrom SRC members. +No NIH Category available Adherence;Amendment;Area;Awareness;Cancer Center;Cancer Center Support Grant;Caring;Case Report Form;Catchment Area;Child;Clinical;Clinical Data;Clinical Protocols;Clinical Research;Clinical Trials;Data;Data Reporting;Development;Disease;Education;Electronics;Enrollment;Ensure;Frequencies;Guidelines;Industry;Institution;Malignant Neoplasms;Minority Groups;Mission;Monitor;Monitoring Clinical Trials;National Clinical Trials Network;Nebraska;Office Management;Pediatric Oncology Group;Phase;Population;Population Sciences;Procedures;Protocols documentation;Recommendation;Regulation;Reporting;Research;Research Personnel;Research Support;Resources;Review Committee;Rural Population;Safety;Serious Adverse Event;Site;System;Training and Education;Underserved Population;Woman;anticancer research;cancer care;cancer clinical trial;cancer therapy;clinical trial implementation;data management;electronic data;investigator-initiated trial;member;metropolitan;participant safety;process improvement;programs;protocol development;quality assurance;recruit;research study;screening Clinical Protocol and Data Management n/a NCI 10695249 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7703 9658016 "GANTI, APAR KISHOR " Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 133938 87256 46682 PROJECT SUMMARY: CLINICAL PROTOCOL AND DATA MANAGEMENTThe Fred & Pamela Buffett (BCC) Clinical Trials Office (CTO) previously referred to as the CentralizedProtocol Data Management Unit (CPDMU) is the centralized office which supports clinical cancer research inthe Cancer Center. The BCC CTO provides centralized support for investigator-initiated trials (IIT) NCI NationalClinical Trials Network and cooperative group trials (Main Member of Alliance Children's Oncology Group NRG)multi-institutional consortium trials (BIG10 Cancer Consortium ACCRU) and industry-sponsored studies. Themission of the BCC CTO is to assist with the planning development conduct quality assurance monitoring andcompliance of with regulatory agency requirements for clinical trials involving cancer treatments and care andto provide regulatory support for cancer-related population science studies as well. The BCC CTO assures thehighest quality of research and adherence to relevant regulations by primary upfront coordination of the studyand ongoing review of research compliance. The BCC CTO is the resource within the Cancer Center whichprovides support to investigators for all cancer clinical research. It is organized by disease-focused teams (DFT's)that coordinate study management activities including screening subjects; coordination of treatment and care;and collecting and recording study data; as well as the regulatory management teams responsible for submittingand maintaining all regulatory documents and applications. The BCC CTO provides BCC investigators supportfor protocol development data management monitoring for cooperative group studies and liaison with federaland industry sponsors and regulatory bodies. The BCC CTO also provides support to the BCC ScientificReview Committee (SRC) the Data Safety Monitoring Committee (DSMC) and the Audit Committee (AC).The BCC CTO manages the clinical trials management system (OnCore) which houses protocol data necessaryfor planning reporting and internal oversight as well as the development of electronic case report forms (eCRF)and study data reporting in Forte EDC (Electronic Data Capture). The BCC CTO has been active in NCI initiativesregarding Clinical Trial Reporting Program (CTRP). +No NIH Category available Authorization documentation;Cancer Biology;Cancer Center;Cancer Center Support Grant;Collaborations;Dentistry;Department chair;Development;Discipline of Nursing;Ensure;Evaluation;Faculty;Faculty Recruitment;Financial Support;Funding;Goals;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medicine;NCI Center for Cancer Research;Peer Review;Pharmacy facility;Public Health;Research;Research Personnel;Strategic Planning;anticancer research;authority;base;college;cost;interdisciplinary collaboration;member;programs;recruit;success Developmental Funds n/a NCI 10695248 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7702 2401856 "COWAN, KENNETH H." Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 383750 250000 133750 PROJECT SUMMARY: DEVELOPMENTAL FUNDSCCSG Developmental Funds provide an essential base of support for strategic recruitment initiatives of the Fred& Pamela Buffett Cancer Center (BCC) consistent with its strategic goals to enhance cancer research andpromote transdisciplinary research collaborations. Strategic initiatives including faculty recruitment andenhancements to shared facilities are incorporated into the BCC strategic plan and reviewed by BCC AdvisoryBoards to ensure that goals are fully evaluated and ultimately achieved. During the current periodDevelopmental Funds were utilized to assist in the recruitment of 24 faculty members with each of the BCCResearch Programs benefitting from strategic recruitment (8 in Cancer Biology Program (CBP); 8 in TargetsModulators and Delivery Program (TMDP); 8 in GI Cancer Program (GICP)). In addition to providing financialsupport to these 24 recruits 17 members were allocated BCC research space by the Director. Of the 24 BCCrecruits who received Developmental Funds 23 are peer-reviewed funded investigators 14 funded by the NCI.BCC recruits who received Developmental Funds have been successful in receiving peer-reviewed funding withtotal direct cancer relevant research costs amounting to over $22 million. Addition of new BCC faculty during thenext funding period will be facilitated through recruitment in the Eppley Institute (under the direct authority of theDirector) as well as in collaboration with deans and department chairs in the Colleges of Medicine DentistryNursing Pharmacy and Public Health. With senior BCC Leaders serving as Department Chairs in the Collegeof Medicine the BCC has a very strong and collegial team working together to ensure the success of strategicrecruitment initiatives of the Buffet Cancer Center. Over the next project period the BCC is requestingDevelopmental Funds to support 20-30 new cancer research faculty recruits. +No NIH Category available Address;Advisory Committees;Area;Authorization documentation;Basic Science;Cancer Burden;Cancer Care Facilities;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Consultations;Development;Disparity;Ensure;Evaluation;Faculty;Feedback;Foundations;Funding;Future;Goals;Growth;Healthcare;Hospitals;Institution;Leadership;Malignant Neoplasms;Medicine;Mission;NCI-Designated Cancer Center;Nebraska;Nursing Faculty;Outcome;Periodicals;Physicians;Positioning Attribute;Process;Reporting;Research;Research Infrastructure;Research Priority;Resource Sharing;Resources;Scientific Advances and Accomplishments;Services;Strategic Planning;Students;Surveys;Teacher Professional Development;Technology;Training and Education;Translational Research;Universities;Vision;Work;anticancer research;authority;cancer care;cancer education;cancer health disparity;cancer research center director;clinical care;community engagement;improved;innovation;interdisciplinary collaboration;member;patient oriented;programs;recruit;research faculty;translational cancer research Leadership Planning and Evaluation n/a NCI 10695247 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7701 2401856 "COWAN, KENNETH H." Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 474946 309411 165535 PROJECT SUMMARY: LEADERSHIP PLANNING AND EVALUATIONThe Fred & Pamela Buffett Cancer Center (BCC) will continue to leverage strong leadership and effectiveplanning processes internal and external advisors university and hospital leaders and community partnersto strengthen and advance innovative scientific and clinical research promote transdisciplinary collaborationsintegrated with cancer care strengthen and expand cancer training and educational programs for trainees andfaculty and expand community outreach and engagement with diverse community partners across the state.Important accomplishments since the last review include the opening of the new BCC ($350 M 615000 sq ft)Integrated Cancer Research and Cancer Care Facility which resulted in expansion and consolidation ofresearch space. The BCC Director now has authority over 400000 sq ft space for research which representsa 67% increase since the last review and 3.3-fold increase since 1999. During this funding period the BCCorganization was strengthened with the Director now reporting directly to both the UNMC Chancellor and theNebraska Medicine CEO and serving as the BCC Physician-in-Chief ensuring oversight over cancer researchand clinical programs across the university and the healthcare network. Since the last review the BCC hasrecruited Ray Bergan as BCC Deputy Director and added a new position as Associate Director for CommunityOutreach and Engagement. In addition three new leaders were appointed since 2015 including the AssociateDirector Basic Research Associate Director Translational Research and Associate Director Training andEducation. To continue to achieve advances envisioned by the leadership the BCC will: 1) expand support forrecruitment and development of key priority areas of scientific focus; 2) increase research that addresses thecancer burden and disparities in our catchment area (Nebraska); 3) develop an organization committed tointerdisciplinary collaborative translational research; and 4) expand training and education and externallyfunded programs with an emphasis on diversity. Evaluation is a priority and is used to ensure that resourcesare aligned with priorities. Progress is reviewed throughout the year with a comprehensive review annually thelatter in particular serving as a foundation to assess progress and revise strategies. This includes evaluationsby Members of all Shared Resources and key activities such as those managed through the Clinical TrialOffice. Progress in Community Outreach and Engagement is reviewed with the COE Community AdvisoryBoard and Internal Advisory Board quarterly. The BCC will continue to receive input from its External AdvisoryBoard annually and throughout the year as needed. The BCC will leverage institutional leadership andresources and will engage key stakeholders in support of its aims to: 1) develop a strong senior leadership forestablishing the BCC vision and goals; 2) advance effective strategies to achieve BCC objectives; and 3)implement processes to evaluate progress and refine strategies to achieve BCC objectives. +No NIH Category available Address;African American population;Area;Autopsy;Award;Basic Science;Biological Markers;Black race;Cancer Care Facilities;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Cycle Regulation;Cell Proliferation;Cessation of life;Chemoresistance;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Colorectal Cancer;Colorectal Neoplasms;Death Rate;Detection;Development;Direct Costs;Disease;Disease Management;Disparity population;Doctor of Philosophy;Environment;Evaluation;Faculty;Foundations;Functional disorder;Funding;Future;Goals;Grant;Growth;High School Student;Human;In Vitro;Incidence;International;Invaded;Investments;Journals;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Manuscripts;Medical Oncologist;Medical center;Medicine;Mentors;Middle School Student;Minority Groups;Mission;NCI Center for Cancer Research;Nature;Nebraska;Neoplasm Metastasis;Nursing Faculty;Organoids;Pancreas;Pathogenesis;Pathologist;Patients;Peer Review;Phase;Pilot Projects;Play;Pre-Clinical Model;Prognosis;Prognostic Marker;Publications;Publishing;Radiation Oncologist;Radiation Oncology;Radiation Protection;Radiosensitization;Research;Research Personnel;Research Support;Research Training;Resistance;Resource Sharing;Role;Scientist;Series;Signal Transduction;Surgical Oncologist;Testing;Therapeutic Trials;Tissue Banks;Tissue Microarray;Training Activity;Training and Education;Translating;Translational Research;Translations;Universities;anticancer research;biomarker development;biomarker discovery;biomarker validation;cancer cell;clinical translation;college;colorectal cancer screening;diagnostic biomarker;diagnostic tool;in vivo;inter-institutional;interest;meetings;member;mortality;new therapeutic target;next generation;novel;novel diagnostics;novel marker;novel strategies;novel therapeutic intervention;novel therapeutics;oncology trial;pancreatic cancer model;pancreatic cancer patients;pancreatic neoplasm;porcine model;pre-clinical;prognostic tool;programs;radiation resistance;radioprotected;recruit;risk stratification;success;treatment response;tumorigenesis;working group Gastrointestinal Cancer Program n/a NCI 10695244 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7698 1966553 "BLACK, JENNIFER D." Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 63650 41466 22184 Project Summary/Abstract: Gastrointestinal Cancer Program (GICP)Established in 2013 the Gastrointestinal Cancer Program (GICP) is the newest Program in the Fred & PamelaBuffet Cancer Center (BCC). The research and clinical efforts of the GICP focus on pancreatic and colorectalcancer two cancers that are highly relevant to our state of Nebraska catchment area. The mission of the GICPis to better understand the pathogenesis and pathophysiology of pancreatic and colorectal cancers identify andvalidate new diagnostic and prognostic tools for these diseases and develop new therapeutic options for patientswith these malignancies. To address these goals the GICP has been organized into three interacting themeseach of which integrates basic and translational science: 1) Mechanisms of GI Tumorigenesis 2) Biomarkersand 3) Novel Treatment Approaches. The establishment of the GICP reflects the success of a longstandingWorking Group in Pancreatic Cancer the foundation of which includes an internationally recognized RapidAutopsy Program for comprehensive collection of tissues from pancreatic cancer patients. Additional support forresearch initiatives in pancreatic cancer comes from several multi-investigator grants focusing on targetidentification biomarker discovery and validation and novel treatment approaches which highlight theinteractive nature of the GICP membership. Accomplishments in pancreatic cancer have recently been extendedto colorectal cancer with the recruitment of several investigators with expertise in colorectal cancer researchserving to enhance this focus area since the last review. The Program is co-led by a clinician scientist Chi LinMD PhD and a basic scientist Jennifer Black PhD with complementary expertise in radiation oncology andclinical trials and signal transduction mechanisms in colorectal and pancreatic cancer respectively. The Programhas 27 members 14 basic scientists and 13 clinician scientists. The Co-Directors leverage their expertise toenhance intra- and inter-programmatic collaboration through the development of new shared resources theevaluation and funding of pilot projects supporting the GICP mission the attraction of high profile speakers forGrand Rounds and regular seminar series the organization of regular programmatic meetings and theidentification of opportunities for clinical advancement of research findings. These activities have promoted astrongly collaborative group as demonstrated by inter- and intra-programmatic publications and grants. Clinicalinvestigators have facilitated the translation of recent preclinical findings into new investigator-initiatedtherapeutic trials. Cancer relevant peer-reviewed funding (annual direct costs) for the program is currently$5.59M; of which ~82% is from the NCI. 406 manuscripts were published by GICP investigators during thecurrent funding period of which 50% are intra-programmatic 48% are inter-programmatic and 34% are inter-institutional. Future plans include development of novel models for pancreatic and colorectal cancer researchexpansion of biomarker validation and development efforts growth of the colorectal cancer research focusrecruitment of additional clinical faculty and continued strengthening of the GICP clinical trial portfolio. +No NIH Category available Acute leukemia;Adult;Antineoplastic Agents;Award;Basic Science;Cancer Biology;Cancer Center;Cancer Center Support Grant;Chemicals;Childhood;Clinic;Clinical Trials;Collaborations;Computer Analysis;Detection;Development;Direct Costs;Docking;Evaluation;Faculty;Foundations;Funding;Future;Gene Expression;Genetic;Goals;Hematologist;Hyaluronic Acid;Intellectual Property;Investigation;Investments;Journals;Lymphoma;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Methods;Mission;Molecular;Molecular Target;Multiple Myeloma;NCI Center for Cancer Research;Nanodelivery;Nebraska;Oncogenes;Oncologist;Oncology;Pediatric Hematologist;Pediatric Oncologist;Peer Review;Pharmaceutical Chemistry;Pharmacology;Physicians;Population;Protac;Publications;RNA Interference;Radiation Oncologist;Radiosurgery;Regulation;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Signal Transduction;Structure;Surgical Oncologist;Synthesis Chemistry;Technology;Technology Transfer;Testing;Therapeutic;Training and Education;Translational Research;Translations;Validation;bench to bedside;cancer cell;cancer imaging;cancer therapy;clinical translation;commercialization;computational chemistry;copolymer;delivery vehicle;drug development;in silico;inter-institutional;interest;malignant breast neoplasm;medulloblastoma;member;nanomaterials;neoplastic cell;new technology;next generation;novel;novel strategies;preclinical study;programs;prospective;small molecule;tool;translational research program;translational study;tumor Targets Modulators and Delivery Program n/a NCI 10695242 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7696 9765464 "HOLSTEIN, SARAH A" Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 95175 62003 33172 Project Summary/Abstract: Targets Modulators and Delivery Program (TMDP)The mission of the Targets Modulators and Delivery Program (TMDP; formerly known as the Cancer Genesand Molecular Regulation Program) is to validate targets develop small molecules that modulate cancer targetsand develop methods for efficient delivery of modulators to tumor cells. The TMDP is organized to promotecollaboration and catalyze the translation of scientific discoveries from Fred & Pamela Buffett Cancer Center(BCC) basic research program members while providing BCC translational research programs access tovalidated targets small molecule modulators and delivery methods for clinical translation. The TMDP integratesthe efforts of 18 physician-scientists (including adult and pediatric hematologist/oncologists radiation oncologistsand surgical oncologists) with expertise in clinical trial development and 23 investigators with expertise in cancertarget development medicinal chemistry pharmacology and nanodelivery. Together the program membersdevelop tools and technology to facilitate translation of basic science discoveries by the bench-to-bedsidecontinuum within BCC research programs. Resources developed by the TMDP to support novel chemical entity(NCE) discovery/development within the TMDP and the BCC include the Synthetic and Medicinal ChemistryResource PROteolysis Targeting Chimera (PROTAC) synthesis and Computational Chemistry Resource. Thetranslational research efforts of the TMDP faculty extend across the full range of malignancies that are of criticalimportance to the population of Nebraska including lung cancer ovarian cancer multiple myeloma lymphomaacute leukemia breast cancer pancreatic cancer and medulloblastoma. The research interests of TMDP facultyare organized around three interactive themes Target Validation Small Molecule Modulators Delivery Methods that contribute to the overarching goal of bench-to-bedside research translation through intra- and inter-programmatic collaboration. These themes exemplify the specific aims of the TMDP to 1) develop conceptualand technical approaches to validate cancer targets; 2) identify and characterize target- and mechanism-specificsmall molecules directed at validated cancer targets; and 3) explore novel technologies for efficient delivery ofsmall molecules or RNAi against validated cancer targets. Physician scientists within the TMDP with clinicaltrials expertise facilitate the translation of putative targets chemical modulators and delivery methods withtherapeutic potential. The interactions between TMDP members their interactions with other BCC Programsand their inter-institutional collaborations promote impactful and translational studies. These interactions haveresulted in $4.25M (direct) of cancer-relevant peer-reviewed funding to TMDP investigators with 3.17M from theNCI. During the funding period the TMDP investigators reported 647 cancer-relevant publications (averagejournal impact factor = 7) with 37% intra-programmatic 28% inter-programmatic 18% both intra- and inter-programmatic and 41% inter-institutional publications. +No NIH Category available Advanced Malignant Neoplasm;Alcohols;Animal Cancer Model;Animals;Area;Atomic Force Microscopy;Biochemical;Biological Markers;Biology;Cachexia;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Fatigue;Cancer Model;Cancer Patient;Catchment Area;Cell model;Cells;Cessation of life;Collaborations;Communication;Crystallography;DNA Damage;DNA Repair;DNA Sequence Alteration;DNA metabolism;Development;Direct Costs;Education;Employment;Ensure;Epigenetic Process;Etiology;Evaluation;Faculty Recruitment;Fatigue;Foundations;Functional disorder;Funding;Genetic;Genetic Models;Genome;Genome Stability;Genomic Instability;Goals;Grant;Inherited;International;Intervention;Maintenance;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mammalian Cell;Mammalian Genetics;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Mission;Molecular;Molecular Target;Morbidity - disease rate;Neoplasm Metastasis;Oncogenes;Organ;Oxidation-Reduction;Pathway interactions;Patients;Peer Review;Phenotype;Physiology;Pilot Projects;Prevention;Process;Publications;Receptor Signaling;Reporting;Research;Research Personnel;Resource Sharing;Role;Signal Pathway;Signal Transduction;Symptoms;System;Therapeutic;Translations;Tumor Burden;Ubiquitin;Universities;Validation;Vision;body system;cancer cachexia;cancer care;cancer cell;cancer diagnosis;cancer genome;cancer initiation;cancer risk;chemotherapy;clinical translation;design;epigenome;female fertility;fertility preservation;genetic approach;genome-wide;improved outcome;inhibitor;insight;inter-institutional;interest;meetings;member;metabolic abnormality assessment;metabolomics;mortality;multicatalytic endopeptidase complex;multidisciplinary;neoplastic cell;next generation;next generation sequencing;novel;posttranscriptional;programs;receptor;repaired;response;trafficking;transcriptomics;translational study;tumor;tumor metabolism;tumor microenvironment;tumor progression;tumorigenesis;working group;yeast genetics Cancer Biology Program n/a NCI 10695239 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7694 1883967 "BAND, HAMID " Not Applicable 2 Unavailable 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE Domestic Higher Education 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 63650 41466 22184 Project Summary/Abstract: Cancer Biology Program (CBP) The overall goal of research in the Cancer Biology Program (CBP) previously the Molecular and BiochemicalEtiology Program is to understand mechanisms that underlie cancer initiation and progression that could leadto new biomarkers and interventional strategies to positively impact cancer diagnosis prevention andtherapeutic strategies across cancers prevalent in the BCC catchment area. To clearly delineate our missionand themes we strategically reorganized the program to focus on basic cancer mechanisms with translationalefforts pursued in collaboration with the Targets Modulators and Delivery (TMDP) and GI Cancer (GICP)programs. To this end we retained 14 prior members and added 24 new investigators with a basic cancer biologyfocus. The major goals of the CBP are to define the molecular mechanisms that maintain genome stability andtheir alterations in cancer dissect intracellular signaling mechanisms and tumor cell-microenvironmentinteractions and elucidate and harness metabolic and other mechanisms that lead to host systemic organdysfunction and contribute to cancer patient morbidity and mortality. The 38 CBP members come from eightdepartments across the University with multidisciplinary interests in DNA damage/repair processes signalingmechanisms metabolomics redox biology and cell- and animal-based cancer models. The research interestsof program members are organized around three Themes. Theme 1. Genome Instability and Cancer. Membersfocus on studies of genome replication DNA damage responses and repair and identification of new genomicalterations that drive hereditary or sporadic cancer. Theme 2. Signaling Mechanisms in Cancer. Members focuson elucidating intra- and inter-cellular signaling mechanisms that drive tumorigenesis and metastasis. Theme 3.Metabolic Alterations and Systemic Dysfunction in Cancer. Members focus on cancer cell metabolism and redoxbiology and the impact of tumor burden on organ systems with a particular focus on cancer cachexia andfatigue. There is extensive cross-talk between Themes and basic mechanisms and pathways elucidated underCBP provide a rich basis for inter-programmatic collaborations with TMDP and GICP towards further translationinto potential target validation and inhibitor design and translational studies. The Co-Leaders leverage theircomplementary expertise to enhance inter- and intra-programmatic collaborations through the development andemployment of new and existing shared resources evaluation and funding of pilot projects supporting the CBPmission involvement in faculty recruitment and organization of regular programmatic meetings. These activitieshave led to a strong collaborative group as demonstrated by impactful inter- and intra-programmatic cancer-focused publications and grants and an increased focus on basic biology with the potential for clinical translation.Cancer-relevant peer-reviewed CBP funding is $6.87M (direct) of which $1.9M is from the NCI. During theprevious funding period CBP members reported 304 cancer-relevant publications with 43% intra-programmatic45% inter-programmatic 28% both intra- and inter-programmatic and 38% inter-institutional publications. +No NIH Category available Acceleration;Address;Adjuvant;Adoptive Cell Transfers;Adoptive Transfer;Affect;Aftercare;Agonist;Allogenic;Antitumor Response;Autologous;Biological;Biological Assay;Biopsy;Blood Component Removal;Bone Marrow;Cancer Model;Cancer Patient;Canis familiaris;Caring;Cell secretion;Cells;Child;Childhood Osteosarcoma;Client;Clinic;Clinical;Clinical Protocols;Clinical Trials;Cytotoxic Chemotherapy;Cytotoxic T-Lymphocytes;Data;Disease;Disease-Free Survival;Dose;Effectiveness;Engineering;Engraftment;Exhibits;Flow Cytometry;Gene Expression Profiling;Generations;Genes;Genetic Engineering;Glioma;Glycolipids;Graft-Versus-Tumor Induction;Granzyme;Hematologic Neoplasms;Hematopoietic Neoplasms;Histopathology;Homing;Human;Immunocompetent;Incidence;Infusion procedures;Maximum Tolerated Dose;Mediating;Metastatic Osteosarcoma;Mus;Oncology;Patient-Focused Outcomes;Patients;Peripheral Blood Mononuclear Cell;Phenotype;Publishing;Random Allocation;Refractory;Regimen;Relapse;Safety;Solid;Solid Neoplasm;Specificity;Supporting Cell;T cell therapy;T-Lymphocyte;Therapeutic Effect;Tissues;Toxic effect;Treatment Efficacy;Tropism;Tumor Immunity;Tumor-associated macrophages;Whole-Body Irradiation;Work;advanced disease;antileukemic activity;antitumor effect;cancer cell;cell bank;chemokine;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinically relevant;comparative;cross reactivity;cytokine;cytotoxic;design;genetically modified cells;graft versus host disease induction;graft vs host disease;immunoregulation;insight;irradiation;limb amputation;mouse model;nano-string;novel;novel strategies;osteosarcoma;perforin;pre-clinical assessment;preclinical study;preconditioning;prevent;rare cancer;response;safety assessment;transcriptomics;trial design;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;tumorigenic Advancing allogeneic CAR-iNKT for the treatment of solid tumors through comparative oncology Project narrativePatient T cells genetically engineered with chimeric antigen receptors (CAR-T) have shown unprecedented anti-tumor activity in hematological malignancies however this approach is patient specific and has limited activityin solid tumors. In this proposal we will investigate the use of genetically engineered iNKT cells as an off-the-shelf cellular platform with intrinsic tumor homing and microenvironment modulating effects to increase therapyavailability and effectiveness in solid tumors. Allogeneic CAR-iNKT cells will be evaluated in pet dogs withspontaneous osteosarcoma to determine optimal preconditioning regimens safety and tolerability of cell doseand effects of different iNKT cell profiles on their persistence survival tumor homing and immunomodulatorycapacity that aims to increase anti-tumor activity and prolong disease free survival paving the way to advancingthis approach in human cancer patients. NCI 10695238 8/24/23 0:00 RFA-CA-21-050 5U01CA272270-02 5 U01 CA 272270 2 "HU, ZHANG-ZHI" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-C(M1) 6809415 "MASON, NICOLA J" Not Applicable 3 VETERINARY SCIENCES 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF VETERINARY MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 575647 NCI 354244 221403 Chimeric antigen receptor T (CAR-T) cells have produced unprecedented results in blood cancers but clinical responses in solid tumors are rare due to the detrimental effects of the hostile immunosuppressive tumor microenvironment (TME) and the use of patient derived dysfunctional T cells adversely affected by advanced disease state and previous chemotherapy. Invariant Natural Killer T cells (iNKTs) are a distinct lineage of CD1d-restricted T lymphocytes with natural tissue (and tumor) tropism direct cytolytic effect on CD1d+ cancer cells and tumor associated macrophages and adjuvant effects on endogenous anti-tumor immunity. Unlike conventional T cells allogeneic iNKTs mediate a robust graft-versus tumor effect without inducing graft-versus-host disease thus eliminating the need for gene editing to maintain tolerance. Moreover preclinical studies in mouse models suggest that CAR-enhanced iNKTs can eradicate solid and solid-like hematological tumors where CAR-T cells fail. We hypothesize that allogeneic CAR-engineered iNKTs will overcome the barriers to successful CAR-therapy and provide a powerful off-the-shelf universal platform with curative potential for solid tumors. Yet unsolved questions related to allo CAR-iNKT safety optimal preconditioning regimens to promote persistence cell dose and therapeutic efficacy in solid tumors remain. Furthermore while healthy human donors for allogeneic iNKT clinical trials are randomly selected cells generated from different donors have different immunomodulatory capacities that may affect their engraftment and survival and it is currently unknown which products are best for adoptive cell therapy (ACT). These questions cannot be adequately addressed in mice due to the dissimilarity between murine and human iNKT cells. In contrast our preliminary studies demonstrate that canine and human iNKT cells share remarkable phenotypic and functional similarities and can be CAR engineered and expanded to clinical scale for trial use. Here we will use immunocompetent pet dogs with spontaneous osteosarcoma (OSA) which is remarkably similar to pediatric OSA to advance allogeneic IL-13R2-targeting CAR-iNKT cells into the human clinic. We will first characterize CAR-iNKT cells from different donor dogs and generate a master cell bank of canine alloCAR-iNKT products with different immunomodulatory capacities. Next we will address the safety and effects of 3 strategically designed pre-conditioning regimens including a combination of cytotoxic chemotherapies low dose total body irradiation and a clinical grade iNKT glycolipid agonist RGI-2001 on allo-CAR-iNKT engraftment and persistence in dogs with metastatic OSA. Finally we will determine the maximum tolerated dose of alloCAR-iNKT cells using an accelerated dose escalation trial design and evaluate their effects on the TME systemic immunome and disease free interval in dogs with appendicular OSA. This work addresses pivotal questions for the advancement of allogeneic-CAR-iNKT cells in a clinically relevant canine cancer model to accelerate clinical use of this promising off the shelf approach in human patients with solid tumors. 575647 +No NIH Category available Address;Award;Basic Science;Biological Markers;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Communities;Community Outreach;Development;Direct Costs;Early Diagnosis;Education;Environment;Fostering;Funding;Health care facility;Healthcare;Intervention;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medical center;Medicine;Mission;Modeling;NCI-Designated Cancer Center;Names;Nebraska;Organoids;Patients;Pharmaceutical Chemistry;Physicians;Population Sciences;Positioning Attribute;Prevention;Prognosis;Reporting;Research;Research Infrastructure;Research Peer Review;Research Support;Resource Sharing;Resources;Risk;Role;Scientific Advances and Accomplishments;Synthesis Chemistry;Teacher Professional Development;Tissue Microarray;Training and Education;Translational Research;Universities;anticancer research;cancer care;cancer education;cancer health disparity;cancer initiation;clinical care;community engagement;computational chemistry;health disparity;innovation;interdisciplinary collaboration;member;metabolomics;multidisciplinary;novel therapeutic intervention;outreach;patient oriented;preclinical imaging;programs;recruit;research facility;translational cancer research;tumor progression;underserved community Buffett Cancer Center Support Grant PROJECT NARRATIVEThe Fred & Pamela Buffett Cancer Center (BCC) the only NCI-designated cancer center in Nebraska is a matrixcancer center at the University of Nebraska Medical Center and our affiliated healthcare network NebraskaMedicine. The Mission of the BCC is to promote innovative translational cancer research excellence in cancereducation and training and outstanding patient-centered cancer care and to reduce the burden of cancer andcancer health disparities across Nebraska and beyond. NCI 10695234 9/11/23 0:00 PAR-20-043 5P30CA036727-37 5 P30 CA 36727 37 "BELIN, PRECILLA L" 9/5/97 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 2401856 "COWAN, KENNETH H." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2401911 NCI 1564763 837148 PROJECT SUMMARYThe Fred & Pamela Buffett Cancer Center (Buffett Cancer Center or BCC) an NCI-designated Cancer Centersince 1984 is committed to basic translational clinical and population science research comprehensiveeducational programs and outreach to underserved communities in our catchment area (Nebraska). The newBCC integrated cancer research and care facility increased Cancer Center-controlled research space 1.7-fold(total 400000 sq ft) creating an environment which fosters scientific innovation and transdisciplinarycollaborations. The Cancer Center is fully integrated into the university and its affiliated healthcare networkNebraska Medicine (NM) with the Director reporting directly to the UNMC Chancellor and CEO NM andappointed BCC Physician-in-Chief. Two Cancer Center leadership positions were established since the lastreview Deputy Director and Associate Director for Community Outreach and Engagement (COE) with the latterleading efforts to reduce cancer burden and disparities in diverse communities across Nebraska. The BCC alsoappointed four new senior leaders and eliminated dual leadership roles to promote clinical and translationalresearch. The centralization expansion and reorganization of the BCC Clinical Trials Office was completed anda new CTMS (OnCore) installed culminating in a 1.8-fold increase in accrual to interventional clinical trials.Research infrastructure was enhanced by the addition of a new Preclinical Imaging Shared Resource as well asseveral new resources (e.g. Metabolomics Organoids Patient-Derived Models Tissue Microarrays Syntheticand Medicinal Chemistry and Computational Chemistry). The BCC has three Research Programs: CancerBiology Program (CBP); Targets Modulators and Delivery Program (TMDP); and GI Cancer Program (GICP).Two programs CBP and TMDP changed names reflecting the strategic realignment of their missions themesand memberships. With 28 Members recruited during the current funding period the BCC has a robust trackrecord of clinical and translational research supported by 14 multidisciplinary awards (P01 P50 P20s U awards;6 from NCI) and 16 new MPI awards (11 from NCI). Cancer-relevant peer-reviewed research funding in the BCCincreased 1.4-fold to $25.3M (Annual Direct Costs) and NCI funding increased 1.3-fold to $12.5 M (Annual DirectCosts) since our last review. 2401911 +No NIH Category available Acceleration;Advisory Committees;Area;Bioinformatics;Biological Markers;Biometry;Canis familiaris;Clinic;Clinical;Clinical Management;Clinical Research;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Collaborations;Combined Modality Therapy;Communication;Community Clinical Oncology Program;Consultations;Correlative Study;Data;Data Analyses;Data Collection;Data Commons;Data Element;Data Management Resources;Data Set;Databases;Deposition;Development;Enrollment;Ensure;Fostering;Funding;Future;General Population;Goals;Home;Human;Immune response;Immunologic Monitoring;Immunologist;Immunology procedure;Immunooncology;Immunotherapeutic agent;Immunotherapy;Infrastructure;Laboratories;Leadership;Malignant Neoplasms;Medical;Methods;Mission;Monitor;Oncology;Patients;Pennsylvania;Performance;Procedures;Process;Production;Productivity;Quality Control;Reagent;Registries;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Scientist;Secure;Services;Site;Specimen;Technology;Translational Research;Translations;Universities;Work;biomarker identification;cancer clinical trial;cancer immunotherapy;cloud based;comparative;data curation;data management;data quality;data sharing;design;experience;immune modulating agents;immunotherapy clinical trials;immunotherapy trials;innovation;insight;meetings;member;next generation;novel;oncology program;operation;outreach;participant enrollment;research study;skills;sound;tool;translational applications;translational study;treatment response;trial design;virtual;web site;working group Advancing the Coordinating Center for the Canine Cancer Immunotherapy Network The primary mission of the coordinating center of the Pre-medical Cancer Immunotherapy Network forCanine Trials (PRECINCT) is to provide infrastructure and oversight to a highly collaborative and interactivenetwork of researchers and clinician scientists working to investigate immunotherapeutic strategies in dogswith cancer identify correlates of immunological and therapeutic responses and determine the value of dogswith spontaneous cancers in informing human clinical trial design. Leveraging the renowned expertise of theUniversity of Pennsylvania in human and canine immunotherapy trials PRECINCT's coordinating center willprovide expert services in project management and research technology data management and sharing andbiostatistical and bioinformatics support to U01 awardees and network members. This work will advancediscovery promote collaborative research and accelerate the translation of safe and effective immunotherapiesinto the human cancer clinics. NCI 10695232 9/7/23 0:00 RFA-CA-21-051 5U24CA272267-02 5 U24 CA 272267 2 "SOMMERS, CONNIE L" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-C(M1) 6809415 "MASON, NICOLA J" "LONG, QI " 3 VETERINARY SCIENCES 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF VETERINARY MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Other Research-Related 2023 464244 NCI 250635 213609 The primary mission of the coordinating center (CC) at the University of Pennsylvania is to facilitate theperformance of immunotherapy clinical trials in dogs with cancer within the K9CIN (previously known as the Pre-medical Cancer Immunotherapy Network for Canine Trials (PRECINCT)) and to determine the suitability of dogswith spontaneous cancer to study immunomodulatory agents and combination therapies to inform human clinicaltrials. The CC will achieve these goals by supporting a highly coordinated clinical trials network of participatingU01 sites and will work in consultation with U01 investigators the network's Steering Committee representativesfrom the Comparative Oncology Program (COP) at NCI and an External Advisory Committee to provide expertservices in project management and research technology data management and biostatistical and bioinformaticsupport. Specifically PRECINCT's CC will provide comprehensive project oversight supervise all projectmanagement and regulatory compliance activities and coordinate site management for all aspects of trialprojects. Through the CC U01 investigators will have ready access to research services and standard operatingprocedures (SOPs) for clinical and immunological monitoring and collection of data reagents and biospecimensthat will facilitate the performance of clinical research across the network. Patient accrual will be tracked andwhere necessary cross-site accrual will be coordinated within the network to expedite enrollment. The CC willassist in designating supplemental funds to U01 awardees to support intra-network collaborative projectsidentified by a chosen scientific review panel for funding. We will continue to build infrastructure and expand the network and associate memberships will beencouraged to achieve the critical mass necessary to build working groups to advance PRECINCT's missionand build inter-network collaborations with IOTN PI-DDN and PACMEN. We will extend PRECINCT's DataManagement System to collect store and share all clinical and correlative data amongst the U01 sites and withthe COP directors and Steering Committee through the development of a cloud-based workspace that willfacilitate intra-network collaborative projects and we will perform data quality control and re-formatting requiredto enable ready upload to the Integrated Canine Data Commons (ICDC). We will build a specimen and reagentregistry that will facilitate sharing and tracking of resources and serve to ensure their most efficient use withinthe network. This together with development of a cloud-based workspace will foster collaborations between U01researchers. We will provide biostatistical and bioinformatic support for study design and data analysisto ensure that clinical trials performed within the network are strategically designed and appropriately poweredto achieve meaningful clinical and laboratory data results in the most expedite way. Together the activities andexpertise provided by the CC will ensure that reliable and reproducible datasets emerge from these studieswhich aim to provide essential insight for future translational application to human patients. 464244 +No NIH Category available Adult;Adult Glioblastoma;Aftercare;Animals;Biological;Biological Markers;Biology;Blood - brain barrier anatomy;Brain Neoplasms;Cell Death;Cells;Clinical Trials;Collaborations;Cyclic GMP;DNA Damage;Data;Deoxyguanosine;Dependence;Euthanasia;Evaluation;Event;Evolution;Failure;Gamma-H2AX;Genes;Glioblastoma;Gliomagenesis;Goals;Harvest;Human;Immune;Immune response;Immune signaling;Immunity;Immunosuppression;Immunotherapy;Implant;Induced Mutation;Infrastructure;Interferons;Malignant Neoplasms;Measures;Mediating;Methods;Modality;Modeling;Molecular;Monitor;Mus;Mutation;Mutation Detection;Newly Diagnosed;Operative Surgical Procedures;Patients;Pattern;Pharmacodynamics;Phase;Phase 0 Clinical Trial;Phase 0 Study;Phase 0 Trial;Pre-Clinical Model;Prodrugs;Radiation;Recurrence;Relapse;Resistance;Role;Seminal;Signal Transduction;Subgroup;Telomerase;Testing;Therapeutic;Time;Tissues;Toxic effect;Tumor Tissue;Tumor-infiltrating immune cells;Up-Regulation;Work;anti-tumor immune response;checkpoint inhibition;cohort;cytotoxicity;design;early phase clinical trial;efficacy evaluation;experience;experimental study;immune activation;immunogenic;improved;in vivo;innate immune sensing;mutant;neoplasm immunotherapy;novel;novel therapeutics;patient derived xenograft model;patient population;pharmacodynamic biomarker;pre-clinical;preclinical development;preclinical study;predictive marker;pressure;primary endpoint;promoter;purine analog;response;response biomarker;standard of care;targeted agent;telomere;temozolomide;transcriptome sequencing;treatment response;tumor;tumor heterogeneity 6-thio-2'-deoxyguanosine in GBM: Evaluation of Pharmaco-dynamics Effects of Prior Standard of Care and A Human Phase 0 Study n/a NCI 10695229 9/1/23 0:00 RFA-CA-20-047 5U19CA264385-03 5 U19 CA 264385 3 9/13/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7691 16283798 "KHASRAW, MUSTAFA " Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 134044 134908 47707 PROJECT SUMMARY Project 2Glioblastoma (GBM) remains uniformly lethal with an overall survival of <21 months despite standard of caretherapies. Immunotherapy has remarkable efficacy in many cancers but has been less successful in GBM duein part to the tumors immunosuppressive effects and high levels of intratumoral heterogeneity. The Duke/UTSouthwestern Glioblastoma Therapeutics Network (GTN) team will complete pre-clinical development of a noveltreatment for patients with glioblastoma (GBM) and investigate the biologic activity of this agent in an early-phaseclinical trial. Project 2 will contribute to this goal by investigating biomarkers of response to the telomerase-targeted agent 6-thio-dG in pre-clinical models and by conducting a Phase 0 clinical trial to examine thesebiomarkers in humans. 6-thio-dG is a blood brain barrier (BBB)-penetrant purine analog pro-drug that ispreferentially incorporated into newly synthesized telomeres under the control of telomerase. Incorporation of 6-thio-dG into telomeres induces DNA damage and activates innate immune signaling resulting in cell death.Because roughly 90% of GBM express telomerase resulting from early and highly clonal TERT-promotermutations 6-thio-dG represents an exciting mechanism to overcome tumor heterogeneity and activate anti-tumorimmune responses. Although we have shown that treatment with 6-thio-dG induces telomeric DNA damage andelicits immune-mediated cytotoxicity in telomerase-positive cells the optimal time-point for measuring 6-thio-dG-induced DNA damage and innate immune activation as pharmacodynamic (PD) endpoints is unknown and willbe rigorously determined using patient-derived xenograft models (Aim 1). Additionally most GBM patientsreceive first-line treatment with temozolomide (TMZ) which can induce hypermutation and loss of telomeraseactivity at recurrence. We will therefore evaluate the efficacy of 6-thio-dG following prior TMZ treatment andidentify mechanisms of therapy resistance in vivo (Aim 1). Based on experiments conducted in Aim 1 and inProject 1 we will establish preliminary biomarkers of sensitivity and response to 6-thio-dG treatment in a Phase0 window-of-opportunity trial in adults with newly diagnosed telomerase-positive GBM (Aim 2). Following a 2-day pre-surgical course of 6-thio-dG we will examine GBM tissues for detectable increases in DNA damage(primary endpoint) and activation of immune responses. These studies will enable the design and conduct of aPhase 0 trial of 6-thio-dG identify patient populations likeliest to benefit from therapy and assess biomarkers ofsensitivity and response to 6-thio-dG among newly diagnosed patients with telomerase-positive GBM. The GBMclinical trials infrastructures of Duke and UTSW which treat a diverse patient population representing ~10% ofall U.S. patients with GBM is an excellent setting for this trial. Project 2 thus contributes to this GTN U19s overallgoal and to the NCIs goal to develop novel therapies to improve treatment for adults with GBM. +No NIH Category available Adult;Biological Assay;Biological Markers;Cell Death;Cell Line;Cell division;Cells;Cessation of life;Chromosomes;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Collaborations;Colon;Colon Carcinoma;Complex;DNA;DNA Damage;Data;Deoxyguanosine;Dose;Dose Limiting;Enrollment;Enzymes;Excision;Flow Cytometry;Functional disorder;Genes;Glioblastoma;Glioma;Goals;Guanine;Human;Immunocompetent;Inflammatory;Inflammatory Response;Innate Immune Response;Lung;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Mediating;Modeling;Mutation;Natural Immunity;Normal Cell;Normal tissue morphology;Operative Surgical Procedures;Organoids;Pathologic;Patients;Pre-Clinical Model;Prodrugs;Publishing;RNA-Directed DNA Polymerase;Radiation;Resources;Series;Signal Pathway;Slice;Specificity;Stimulator of Interferon Genes;Telomerase;Telomerase inhibition;Telomere Maintenance;Telomere Shortening;Testing;Therapeutic;Tissues;Toxic effect;Tumor Immunity;United States;Work;Xenograft procedure;adaptive immune response;aggressive therapy;base;biomarker identification;blood-brain barrier crossing;blood-brain barrier penetration;cancer cell;cell killing;clinical application;cytokine;cytotoxic;deoxyguanosine triphosphate;efficacy testing;immune checkpoint blockade;immunogenic;lung Carcinoma;melanoma;molecular marker;mouse model;mutational status;novel;pharmacodynamic biomarker;pre-clinical;preclinical efficacy;preclinical evaluation;prevent;promoter;purine analog;response biomarker;small molecule;targeted treatment;telomere;temozolomide;therapy resistant;transcriptomics;tumor;tumor microenvironment 6-thio-2'-deoxyguanosine in GBM: Pre-clinical Evaluation of Mechanism of action Efficacy and Biomarker identification n/a NCI 10695227 9/1/23 0:00 RFA-CA-20-047 5U19CA264385-03 5 U19 CA 264385 3 9/13/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7690 15321972 "ASHLEY, DAVID M." Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 328761 430350 53351 PROJECT SUMMARY Project 1Gliomas are the most common primary malignant brain tumor in adults and account for over 14000 deathsannually in the United States. The most common type of glioma glioblastoma (GBM) has a median overallsurvival of less than 21 months in spite of aggressive therapy. GBMs like other human cancers have activatedan enzyme called telomerase that rebuilds the ends of the chromosomes regions known as telomeres toenable the cells replicative immortality. Indeed roughly 90% of GBM cases harbor genetic alterations in theTERT gene that activate telomerase. Unfortunately efforts to directly target telomerase activity to date havebeen hindered by lack of effective small molecules that cross the blood-brain-barrier demonstrate on-targeteffects and show efficacy and specificity in GBMs. Therefore there is a critical need to develop safe andefficacious telomerase-targeted therapies for patients with GBM whose tumors harbor telomerase activatinggenetic alterations. We previously used the purine analog pro-drug 6-thio-2-deoxyguanosine (6-thio-dG) which was used inhuman clinical trials in the 1970s to develop a strategy for rapidly inducing telomerase-mediated cytotoxic DNAdamage at telomeres. Rather than inhibiting telomerase and allowing telomeres to get progressively shorter 6-thio-dG is taken up by cancer cells and converted into 6-thio-dGTP which is then incorporated into newlysynthesized telomeric repeats. Once these modified segments accumulate in the telomeres telomeric DNAdamage rapidly results ultimately leading to cell death. In pre-clinical models of lung colon and melanomatreatment with 6-thio-dG led to rapid killing of the cancer cells with little toxicity to normal cells and tissues.Importantly telomeric DNA damage induced by 6-thio-dG also enhanced anti-tumor innate immunity. Buildingon these data we have extended our pre-clinical analysis to GBMs and obtained evidence that 6-thio-dG crossesthe blood-brain-barrier. The overall objective for Project 1 is to advance 6-thio-dG toward a clinical trial to beconducted by Project 2. We propose the following Specific Aims: 1) Characterize the pre-clinical efficacy andpharmacodynamic biomarkers of 6-thio-dG treatment alone or in combination with Temozolomide (TMZ) in anextended panel of patient-derived cell lines PDX and organoid models; 2) Test the anti-tumor efficacy andinflammatory potential of 6-thio-dG alone and in combination with TMZ or immune checkpoint blockade (ICB)therapies in immune competent murine models of GBM; and 3) Define cell toxicity and innate inflammatorypotential of 6-thio-dG in an ex vivo glioma tissue framework and patient-derived organoids. These studies willdetermine the pre-clinical efficacy of 6-thio-dG in GBM and confirm biomarkers of efficacy that will guide thedesign of clinical trials including enrollment criteria. This Project will work closely with the proposed AdministrativeCore Molecular Biomarker Core Resource and Project 2 to achieve our shared goal of advancing 6-thio-dGtoward clinical application in GBM. +No NIH Category available Accounting;Address;Adult Glioblastoma;Bioinformatics;Biological;Biological Markers;Budgets;Clinical Trials;Collaborations;Communication;Data;Data Provenance;Deoxyguanosine;Drug Targeting;Ensure;Evaluation;Expenditure;Fostering;Funding;Future;Glioblastoma;Goals;Guidelines;Infrastructure;Institution;Manuscripts;Mediating;Monitor;Occupational activity of managing finances;Office of Administrative Management;Patients;Pilot Projects;Policies;Preparation;Process;Productivity;Program Evaluation;Publications;Regulation;Reporting;Research;Research Personnel;Research Subjects;Resource Sharing;Resources;Schedule;Science;Site;Specimen;Structure;Telomerase;Therapeutic;United States National Institutes of Health;Universities;Visit;biobank;conflict resolution;data integrity;data management;early phase clinical trial;immunogenic;innovation;meetings;novel;novel strategies;operation;patient population;preclinical development;professor;quality assurance;telomere Administrative Core n/a NCI 10695223 9/1/23 0:00 RFA-CA-20-047 5U19CA264385-03 5 U19 CA 264385 3 9/13/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7688 15321972 "ASHLEY, DAVID M." Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 89827 78781 39410 PROJECT SUMMARY Administrative CoreThis Duke/UT Southwestern Glioblastoma Therapeutics Network (GTN) team will complete pre-clinicaldevelopment of a novel treatment for patients with glioblastoma (GBM) and investigate the biologic activity ofthis agent in an early-phase clinical trial. In support of this goal this Administrative Core is responsible foroverseeing integrating coordinating and supporting Projects 1 and 2 and the shared Biomarker Bioinformaticsand Biorepository Core. The Administrative Core will oversee the organizational infrastructure integration of allcomponents and carry out day-to-day administrative activities; serve as the liaison with all internal and externalconstituencies; provide support for preparation of reports manuscripts and regulatory documents; and fosterteam science by facilitating collaboration and smooth communication through regular meetings seminars andother interactions. It will also provide fiscal management to ensure timely financial accounting and reportingaccording to university and NIH policies; provide regulatory support to ensure compliance with institutional stateand federal research guidelines; oversee data operations to ensure use of best practices for data provenanceand integrity (e.g. monitoring standards such as SOPs GCP); provide scientific management by monitoringresearch progress/productivity and enable effective use of shared resource cores relative to scientific milestonesand budget milestones; conduct ongoing rigorous Program evaluations with guidance and direction provided bya Steering Committee and an Internal Advisory Board; resolve conflict; and delineate specific publication anddata distribution policies. Critically this Core will also oversee interactions with other funded GTN U19 sitescommunication with Network Coordination Center and the use of yearly trans-U19 Pilot Project Funds. ThisCore is structured to reduce administrative burden allowing investigators to focus on developing a novelapproach for treating adult GBM using an innovative telomerase-mediated telomere-targeting drug 6-thio-2-deoxyguanosine (6-thio-dG) through high-quality rigorous and efficient research. +No NIH Category available Address;Adult;Adult Glioblastoma;Animals;Basic Science;Bioinformatics;Biological;Biological Markers;Biological Models;Biotechnology;Brain;Brain Neoplasms;CD8-Positive T-Lymphocytes;Cancer Etiology;Clinical;Clinical Data;Clinical Research;Clinical Treatment;Clinical Trials;Collaborations;Communication;Cross-Priming;DNA;DNA Damage;Data;Decision Making;Dendritic Cells;Deoxyguanosine;Development;Diagnosis;Doctor of Philosophy;Drug Targeting;Eligibility Determination;Ensure;Excision;Experimental Designs;Future;Glioblastoma;Human;Immune;Immunologic Adjuvants;Immunotherapeutic agent;Infrastructure;Innate Immune Response;Institution;Interferons;Leadership;Letters;Link;Malignant - descriptor;Mediating;Medical center;Modeling;Monitor;Office of Administrative Management;Operative Surgical Procedures;Organoids;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase 0 Clinical Trial;Pilot Projects;Population Heterogeneity;Primary Brain Neoplasms;Publishing;Reporting;Research;Resistance;Resources;Safety;Sampling;Scientist;Slice;Solid Neoplasm;Somatic Cell;Stratification;Telomerase;Texas;Therapeutic;Time;Tissues;Toxic effect;Translational Research;Tumor Escape;Universities;Work;adaptive immune response;anti-tumor immune response;biobank;blood-brain barrier penetration;chemotherapy;childhood cancer mortality;clinical translation;design;drug action;effectiveness study;fighting;immune checkpoint blockade;immunogenic;in vivo;innovation;mouse model;neuro-oncology;novel;novel strategies;operation;overexpression;patient population;pharmacodynamic biomarker;pre-clinical;preclinical development;preclinical efficacy;response;response biomarker;screening;success;synergism;telomere;temozolomide;translational physician;translational scientist;tumor;young adult 6-thio-2'-deoxyguanosine: A Novel Immunogenic Telomerase-Mediated Therapy in Glioblastoma - A Duke and UTSW Collaboration PROJECT NARRATIVE OverallGlioblastoma (GBM) is one of the most frequent cause of cancer death in children and young adults and is themost common malignant primary brain tumor in adults. Moreover current therapy is incapacitating and is limitedby non-specific toxicity to systemic tissue or surrounding brain. Focused on development of a novelimmunotherapeutic against GBM called 6-thio-dG the research proposed will investigate and integrate themechanisms behind the action of this drug and takes basic science to the next level of clinical translation in anearly human trial. NCI 10695222 9/1/23 0:00 RFA-CA-20-047 5U19CA264385-03 5 U19 CA 264385 3 "ESPEY, MICHAEL G" 9/13/21 0:00 8/31/26 0:00 ZCA1-TCRB-D(A1) 15321972 "ASHLEY, DAVID M." "SHAY, JERRY WILLIAM" 4 NEUROSURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 586523 NCI 678069 152581 PROJECT SUMMARY OverallGlioblastoma (GBM) is one of the most frequent causes of cancer death in children and young adults and is alsothe most common malignant primary brain tumor in adults. Moreover current therapy is incapacitating and islimited by non-specific toxicity. Despite hundreds of clinical trials few agents have been approved for clinicaluse and the tumors addressed in this application remain uniformly lethal. This Glioblastoma Trials Network(GTN) application will address this problem through a collaborative group of translational physician-scientists atDuke University and the University of Texas Southwestern Medical Center proposing a novel approach fortreatment of GBM using a telomere-targeting drug 6-thio-2-deoxyguanosine (6-thio-dG). Telomerase is an attractive target for anti-GBM therapy as it is over-expressed in the vast majority ofGBM. Additionally our pre-clinical data shows that treatment of tumor bearing animals with 6-thio-dG leads totumor regression through the dual activity of both DNA damage and innate and adaptive immune responses.Most recently through our collaborative effort we have already commenced studies in GBM with a developmentalplan ideally suited to the GTN. Project 1 will use a variety of model systems to characterize how 6-thio-dG leadsto tumor regression in GBM examining both DNA damage and innate and adaptive immune responses and willinform the design of the 0 trial proposed in Project 2. Project 2 will examine mechanisms of tumor escape to 6-thio-dG treatment in mouse models of GBM conduct a phase 0 clinical trial of 6-thio-dG treatment in GBM andinformed by Project 1 and the Biomarker Bioinformatics and Biorepository Core utilize a number ofscreening stratification and pharmacodynamic biomarkers to guide decision-making. The proposed BiomarkerBioinformatics and Biorepository Core will support accurate and robust diagnoses and pharmaco-dynamic(PD) assessments of 6-thio-dG therapy. It will also provide a number of utilities including sample acquisition anddistribution statistical leadership and expertise in the design conduct analysis and reporting of biomarkerstudies. The Core will acquire high-quality primary human samples linked with clinical data in Project 2 anddevelop and validate innovative analytical and immune profiling strategies to ensure rigorous experimentaldesign and conduct is consistent across the Projects. The Administrative Core will provide organizationalleadership fiscal management administrative support and will monitor research progress oversee dataoperations ensure compliance and quality and facilitate communication and collaboration for both Projects. ThisGTN proposal benefits from strong leadership an established collaboration and the large and diverse populationof patients with glioblastoma who are seen at Duke and UTSW. The proposed work successfully completedwould lead to initial studies of effectiveness in patients with GBM potentially adding an important new approachto fight GBM. 586523 +No NIH Category available 3-Dimensional;Acceleration;Address;Affect;Algorithms;Artificial Intelligence;Biology;Brain;Breast Cancer Cell;Breast Cancer Model;Breast Cancer cell line;Cancer Biology;Cell Culture Techniques;Cell Line;Cells;Cellular biology;Classification;Computer software;Consumption;Cytometry;Data;Development;Discriminant Analysis;Disease;Disseminated Malignant Neoplasm;Genomics;Heterogeneity;Human;Image;In Vitro;Individual;Informatics;Location;Lung;MDA MB 231;Machine Learning;Malignant Neoplasms;Measures;Metastatic breast cancer;Methodology;Methods;Morphology;Neoplasm Metastasis;Neural Network Simulation;Organ;Organelles;Patients;Performance;Phenotype;Population;Primary Neoplasm;Productivity;Proteomics;Research Personnel;Sampling;Spatial Distribution;System;Time;Tissues;Visual;analysis pipeline;anticancer research;artificial intelligence algorithm;cancer cell;cancer classification;cancer site;cancer type;classification algorithm;commercialization;convolutional neural network;deep learning;deep learning algorithm;deep learning model;diagnostic value;feature extraction;innovation;learning network;learning strategy;machine learning algorithm;machine learning model;machine learning pipeline;malignant breast neoplasm;microscopic imaging;multiplexed imaging;neoplastic cell;novel;prognostic value;protein biomarkers;random forest;success;supervised learning;tool;transcriptomics;tumor;tumor xenograft Artificial intelligence enhanced cancer cell classification based organelle morphology and topology NARRATIVEThe identification of tumor cell populations involved in metastatic progression using genomics andproteomics approaches has been difficult. Recently organelle morphology and function has beenused as a direct readout of the functional phenotypic state of an individual cancer cell. We proposeto use the spatial context of organelles specifically their subcellular location and inter-organellerelationships (topology) to classify novel and distinct cancer cell subpopulations. Artificialintelligence algorithms will be developed to measure organelle topology as a novel imaging- andcomputational-based approach to identify subpopulations of metastatic cells withinheterogeneous primary tumors with potential diagnostic and prognostic value. NCI 10695218 8/31/23 0:00 RFA-CA-21-013 5R21CA274622-02 5 R21 CA 274622 2 "MILLER, DAVID J" 9/1/22 0:00 8/31/24 0:00 ZCA1-TCRB-Q(M1) 1973884 "BARROSO, MARGARIDA " "KRUGER, UWE " 20 PHYSIOLOGY 190592162 G6VVMPNK4Y48 190592162 G6VVMPNK4Y48 US 42.652632 -73.77526 8455007 ALBANY MEDICAL COLLEGE ALBANY NY SCHOOLS OF MEDICINE 122083479 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 188212 NCI 144917 43295 ABSTRACTBreast cancer is a highly heterogenous disease both phenotypically and genetically. The quantity andsubcellular location of cancer protein biomarkers are used to classify breast cancer types. Transcriptomicsmultiplexed imaging or mass cytometry have been used to classify breast tumor cell heterogeneity with varyingsuccess. Although genomics and proteomics have been successful in the identification of tumor cell populationsinvolved in metastatic progression the ability to determine whether patient tumors contain metastaticsubpopulations is still lacking. Recently organelle morphology and function has been used as a direct readoutof the functional phenotypic state of an individual cancer cell. We propose to use the spatial context of organellesspecifically their subcellular location and inter-organelle relationships (topology) to classify novel and distinctmetastatic cancer cell subpopulations. We developed an Organelle Topology-based Cell Classification Pipeline(OTCCP) to quantify for the first time the topological features of subcellular organelles defined as the distancebetween each organelle object and all its neighbors within a cell. Under RFA-CA-21-013 (Development ofInnovative Informatics Methods and Algorithms for Cancer Research and Management) we will adapt or developMachine learning and Deep Learning methodologies to accelerate and automate OTCCP-based organelle-based topology cancer cell classification to identify subpopulations of metastatic cells within heterogeneousprimary tumors with potential diagnostic and prognostic value. This approach will also have major impact as adiscovery tool to advance our understanding of cancer cell biology on a subcellular level. 188212 +No NIH Category available Accounting;Affect;African;African American;African American population;African ancestry;Alternative Splicing;Awareness;Biological;Biology;Blood Cells;Bone Marrow;Cancer Control;Cancer Research Project;Cessation of life;Clinical;Clonal Expansion;Complement;Creativeness;Data;Development;Diagnosis;Disparity;Environmental Exposure;Epidemiology;Ethnic Origin;Etiology;European;European ancestry;Event;Frequencies;Future;Gene Expression;Genes;Genetic;Genetic Determinism;Genetic Predisposition to Disease;Genetic Research;Genetic Variation;Genetic study;Genomics;Goals;Health;Hematologic Neoplasms;Hematology;Immune;Incidence;Individual;Inherited;Investigation;Leukocytes;Malignant Neoplasms;Maps;Mendelian randomization;Methods;Multiomic Data;Multiple Myeloma;Mutation;Outcome;Participant;Pathway interactions;Patients;Phenotype;Plasma Cells;Play;Population;Positioning Attribute;Precision Health;Predisposition;Process;Quantitative Trait Loci;Race;Research;Risk;Role;Spliced Genes;Survival Rate;Testing;Training;Underrepresented Populations;United States;Variant;White Blood Cell Count procedure;Work;anticancer research;biobank;cancer epidemiology;cancer health disparity;career;causal variant;comparative;design;ethnic disparity;experience;genetic architecture;genetic epidemiology;genetic predictors;genetic variant;genome wide association study;genome-wide;health equity;high risk;improved;innovation;insight;novel;polygenic risk score;predictive modeling;programs;racial disparity;risk stratification;risk variant;skills;trait;transcriptome;transcriptomics;tumor;tumor heterogeneity Comprehensive Investigation of Multiple Myeloma Genetic Susceptibility in African Americans PROJECT NARRATIVEMultiple myeloma (MM) is the most common hematological cancer in African Americans who experienceincidence rates 2-3 times higher than whites for reasons that remain unclear. The goal of this project is toinvestigate the role of inherited genetic variation involved in regulating gene expression and variation of whiteblood cell traits in modulating susceptibility to MM in African Americans. Leveraging integrative and innovativemethods for incorporating gene expression genetic ancestry and somatic tumor features will provide insight intothe biology of MM and its racial/ethnic disparity which may inform new avenues for risk-stratification. NCI 10695192 9/8/23 0:00 RFA-CA-19-029 5R00CA246076-04 5 R00 CA 246076 4 "HOWCROFT, THOMAS K" 5/1/20 0:00 8/31/25 0:00 ZCA1-TCRB-T(O2) 15587188 "KACHURI, MIRLINDA " Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 248999 NCI 158195 90804 PROJECT SUMMARYMultiple myeloma (MM) is an incurable plasma cell malignancy with a 50% survival rate. MM is the leadinghematological cancer in African Americans who are diagnosed 2-3 times more commonly than whites. Thefactors contributing to this disparity remain unclear but genetics and immune dysregulation are believed to playa key role. The scientific goals of this proposal are: (1) to apply integrative and innovative methods that leveragegenetic and transcriptomic data to elucidate biological pathways contributing to this disparity and (2) to contributeevidence to inform future precision health efforts in this population. The first objective will be to identify putative causal genes associated with MM susceptibility by conductinga transcriptome-wide association study (TWAS) using genetic prediction models of gene expression developedspecifically in African Americans. TWAS will be performed by imputing gene expression profiles in 1813 casesfrom the African American Multiple Myeloma Study (AAMMS) and 8871 controls the largest genome-wideassociation study of MM in African Americans. The next objective will focus on white blood cell (WBC) traitswhich are important intermediate phenotypes for hematologic and immune-related cancers. The distribution andgenetic architecture of WBC traits varies substantially across ethnicities and may contribute importantinformation for deciphering MM risk in African Americans. The shared genetic basis of WBC variation and MMsusceptibility will be examined by conducting: (1) genome-wide genetic correlation analyses and (2) developinggenetic scores for predicting an individuals inherited predisposition to a specific WBC profile. Genetic scoreswill be applied to AAMMS data to test their association with MM and comparative analyses of WBC-predictorsfrom African and European ancestry populations will be conducted. The last research component will aim toelucidate genetic factors that are associated with specific features of MM tumors. Analyses will focus onexamining the contribution of local genetic ancestry to somatic events such as translocations and amplificationsthat are more commonly observed in African American patients. The role of genetic mechanisms involved ingene expression or alternative splicing will also be investigated to test the hypothesis that some tumor featuresseen in African Americans are due to germline genetic effects on these processes. This research plan is complemented by a training plan that builds on the applicants strengths in cancerand genetic epidemiology to develop new expertise in integrative and ancestry-aware genomic analyseshematological cancer and cancer disparities. Novel insights into MM etiology in African Americans will beimportant for improving health outcomes in this population that is disproportionately affected by MM yet under-represented in genetics studies. The research and training plan will prepare the applicant for a successfulindependent career in cancer research with an interdisciplinary focus on risk stratification and cancer control. 248999 +No NIH Category available ATR gene;Adopted;Androgen Receptor;Automobile Driving;Basal Cell;CRISPR/Cas technology;Cancer Patient;Carboplatin;Castration;Cells;Characteristics;Clinical;Clinical Trials;Combined Modality Therapy;DNA Damage;DNA Repair;DNA Repair Inhibition;DNA Repair Pathway;Data;Dependence;Disease;Double Strand Break Repair;EZH2 gene;Early identification;Enhancers;Epigenetic Process;Frequencies;Gene set enrichment analysis;Genes;Genetic;Homologous Gene;Hypersensitivity;Immunotherapy;KRP protein;Knowledge;Malignant neoplasm of prostate;Mediating;Metastatic Prostate Cancer;Mitotic Checkpoint;Modeling;Molecular;Multi-Institutional Clinical Trial;Mus;Neurosecretory Systems;Nonhomologous DNA End Joining;Outcome;Pathway interactions;Patients;Phenotype;Phosphotransferases;Pre-Clinical Model;Predisposition;Proliferating;Prostate;Protein Inhibition;Protein-Serine-Threonine Kinases;Quality of life;RB1 gene;Receptor Signaling;Research Personnel;Resistance;Sampling;Signal Transduction;TP53 gene;Testing;Therapeutic;Update;Validation;Work;androgen deprivation therapy;antagonist;checkpoint therapy;docetaxel;ds-DNA;enzalutamide;functional genomics;genome-wide;immune checkpoint blockade;immunogenicity;inhibitor;innate immune pathways;innovation;loss of function;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;pre-clinical;prostate cancer cell;prostate cancer cell line;receptor expression;repaired;resistance mechanism;resistance mutation;response;stem cells;synergism;therapeutic target;therapy resistant;treatment strategy;tumor ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer PROJECT NARRATIVEDue to inevitable therapeutic resistance driven by RB deficiency prostate cancer remains a lethal disease so iscritical to delineate mechanisms underlying RB deficient driven therapeutic resistance to implement noveltreatments that will extend patient survival and quality of life. We hypothesize that RB deficient prostate canceracquires dependence on ATR kinase activity. We will test this hypothesis and determine novel treatment strategiesfor RB deficient prostate cancers by targeting ATR and validate the potential of ATR inhibition as monotherapyand in combination with carboplatin EZH2 inhibition and check-point immunotherapy. NCI 10695179 5/23/23 0:00 PA-19-056 5R01CA252468-05 5 R01 CA 252468 5 "VENKATACHALAM, SUNDARESAN" 6/8/20 0:00 5/31/26 0:00 Developmental Therapeutics Study Section[DT] 10264854 "ELLIS, LEIGH " Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 354150 NCI 212066 142084 PROJECT SUMMARY Metastatic prostate cancer (mPCa) is incurable and responsible for the majority of PC associated mortality.Therefore there is a critical need to identify drivers of mPCa to enable early identification and interceptivetherapeutic strategies to provide durable responses in patients. Androgen deprivation therapy (ADT) is theprimary line of treatment for mPCa. ADT initially extends survival but is not curative as the patients tumoracquires castration resistance (mCRPC). A majority of mCRPC remain dependent on the function of the androgenreceptor (AR) though due to the inclusion of more potent AR antagonist (eg: enzalutamide) has led to theemergence in a subset of cases (approximately 20%) of resistance mechanisms independent of AR activity(CRPC-AI). CRPC-AI adapt to ADT via lineage plasticity rather than a result of resistant mutations adopting aphenotype no longer reliant on AR expression and signaling. These tumors may display neuroendocrine featuresa stem or basal cell-like phenotype altered kinase signaling and characteristic epigenetic alterations. Recentlywe and others have characterized the molecular landscape of CRPC-AI and have identified and validated newtherapeutic targets and drivers including loss of Retinoblastoma-1 (RB) and TP53 and induction of specificepigenetic/reprogramming factors such as (Enhancer of Zeste Homolog 2) EZH2 and SOX2. Additionally our work validated the importance of EZH2 reprogramming downstream of RB1 loss drivinglineage plasticity and resistance to ADT. Moreover inhibition of EZH2 enabled lineage reversal and re-sensitizedRB loss prostate cancer to ADT. Importantly recent data from patients with mCRPC identified RB geneticaberrations as the strongest predictor of poor outcome. These data implicate RB as a dominant molecularmechanism driving lethal prostate cancer. Currently there is no therapeutic option to provide durableresponse in patients with RB loss-of-function (LOF). Therefore there is a critical need to delineatedownstream effectors of RB LOF so that therapeutic targets can be identified and validated in clinicaltrials. Specific to this application our functional genomic screen has identified dependence on DNA damagerepair kinases specifically ATR. This proposed work is innovative because it will provide deeper mechanisticknowledge of drivers of RB deficient prostate cancer and therapeutic options towards a currently untreatablephenotype. Through this work we will validate the ability of DDR kinase targeting to exacerbate DDR deficiencyand to generate hypersensitivity in RB-deficient prostate models (Aim 1) determine the correlation between RBfunction HR proficiency and response to M6620+carboplatin and docetaxel+carboplatin in preclinical modelsand clinical samples (Aim 2) and evaluate synergy of ATR kinase inhibition EZH2 inhibition and immunecheckpoint blockade therapy in pre-clinical RB-deficient prostate mouse models (Aim 3). Ultimately thisinformation will enable us to gather sufficient preliminary evidence to make a compelling case to commenceinvestigator-initiated multi-center clinical trials. 354150 +No NIH Category available Address;Advisory Committees;Age;Behavior;Benefits and Risks;Biological Assay;Biological Markers;Biology;CLIA certified;Cancer and Leukemia Group B;Cessation of life;Cetuximab;Characteristics;Classification;Clinic;Clinical;Clinical Chemistry;Clinical Trials;Collaborations;Colon Adenocarcinoma;Colon Carcinoma;Colorectal Cancer;Consensus;DNA;Data;Development;Discrimination;Disease;Enrollment;Ensure;Formalin;Freezing;Future;Gene Expression;Gene Expression Profile;Generations;Genetic Transcription;Goals;Grant;Individual;Institution;International;Knowledge;Laboratories;Measures;Mesenchymal;Metabolic;Methods;Modeling;Molecular;Mutation;National Surgical Adjuvant Breast and Bowel Project;Outcome;Paraffin Embedding;Pathologic;Patients;Pattern;Performance;Prevalence;Primary Neoplasm;Procedures;Prognosis;Prognostic Marker;Prospective Studies;Publishing;Quality Control;RNA;Randomized;Randomized Controlled Clinical Trials;Reproducibility;Research;Research Personnel;Risk;Risk Factors;Sampling;Series;Southwest Oncology Group;Specimen;Subgroup;System;Testing;Therapeutic;Tissue Embedding;Transforming Growth Factor beta;Tumor Biology;Validation;assay development;bevacizumab;cancer classification;chemotherapy;clinical biomarkers;clinical prognostic;cohort;colon cancer patients;drug development;genetic signature;hazard;high risk;immune cell infiltrate;improved;innovation;insight;irinotecan;molecular subtypes;mutation assay;nano-string;novel;novel therapeutics;oncotype;oxaliplatin;patient prognosis;phase 3 study;predicting response;prognostic;prognostic assays;prognostic signature;prognostic value;prognostication;standard of care;support vector machine;tool;tumor;tumor behavior Colorectal Cancer Molecular Subtype Assay Development and Validation NARRATIVEThe molecular characteristics of colon cancer can be described by RNA-based expression and a consensusclassification method has been developed. Establishment of an analytically validated clinical assay will allowconfirmation of the prognostic ability of the assay in clinical trials. NCI 10695149 8/10/23 0:00 PAR-15-095 5UH3CA207101-05 5 UH3 CA 207101 5 "DEY, SUMANA MUKHERJEE" 9/21/18 0:00 8/31/24 0:00 ZCA1-TCRB-T(O1) 8783318 "MARU, DIPEN M." "KOPETZ, SCOTT ; LUTHRA, RAJYALAKSHMI ; MORRIS, JEFFREY S" 9 PATHOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 149772 NCI 213117 127870 ABSTRACTStage III colorectal cancer (CRC) demonstrates substantial variability in tumor biology and clinical outcomes andthere is a need to understand prognosis for patients in order to gauge risk benefit for chemotherapy and intensityof chemotherapy administration. These features are not well recapitulated by the current biomarkers in use inthe clinic majority of them are DNA based mutation assays. RNA expression patterns have been described byvarious investigators and may more fully recapitulate tumor biology. The clinical utility of these findings havebeen limited by the apparent conflicting subgrouping efforts and lack of a validated gene expression signatureas a clinical grade assay applicable on formalin fixed paraffin embedded (FFPE) tissue. In our internationalcollaboration with several academic leaders who have previously published in this field we have identified arobust consensus subgroup classification based on clustering approaches independent of clinicaloutcomes. Remarkably this classification system termed consensus molecular subtypes (CMS) identified 4subgroups that provide novel insights into the classification of CRC. One subgroup with mesenchymal TGF-and angiogenic features (CMS4) is associated with a hazard ratio for death of 2.26 (95% CI of 1.41 to 3.61P=.001) significantly higher than other subgroups in a multivariate model inclusive of current clinical andpathologic risk factors and genetic signature (Oncotype Dx). We hypothesize that a gene expressionsignature classifier can be developed and validated for determining the CMS in FFPE tissues and thatthis classifier can be implemented to improve prognostication of stage III CRC by classifying them inCMS 4 vs. other subtypes. We have developed a support-vector-machine classifier with very high accuracy forclassification based on an Affymetrix array from fresh frozen specimens. We have demonstrated goodclassification accuracy (>90%) using customized Nanostring codesets on FFPE tumor samples of 85patients with stage III CRC. We have also demonstrated good technical reproducibility in six of those 85samples. In this application we will transfer the assay using the Nanostring Codeset to fresh frozen (FF) andFFPE using a set of paired samples while maintaining classifier performance. We will then pursue technical andanalytic validation of the assay including precision in repeatability reproducibility between sample types inter-lab reproducibility and impact of RNA quality/quantity. In the UH3 portion of the grant we will clinically validatethe prognostic utility of the gene expression signature assay in single-institution cohort and then in a completedprospective study of FOLFOX chemotherapy (NRG/NSABPC-08) in a CLIA certified laboratory. Additional datawill be used in predicting response to various standard of care therapeutics which represents a series of futurepotential applications of the assay. By utilizing an assay developed to classify CRC by its tumor biologywe anticipate development of an enduring tool that will be of greater use than traditional fit-for-purposetests. 149772 +No NIH Category available Address;Adenocarcinoma;Area;Biological Markers;Biology;Biopsy;Blood;Blood flow;CDKN2A gene;Cells;Clinical;Clinical Trials;Collecting Cell;Collection;Combined Modality Therapy;Continuous Infusion;DNA analysis;DNA sequencing;Data;Diagnosis;Disease;Disease Management;Disease Progression;Dose;Drug Screening;Enrollment;Evaluation;Evolution;Excision;FGFR2 gene;Floxuridine;Foundations;Gene Mutation;Genes;Genomics;Geography;Goals;Hepatic;Hepatic artery;Heterogeneity;Image;Incidence;Infusion procedures;Institution;Intrahepatic Cholangiocarcinoma;KRAS2 gene;Laparoscopy;Liver;Local Therapy;Malignant Neoplasms;Methods;Modality;Modeling;Molecular;Molecular Analysis;Morbidity - disease rate;Mutation;Oncology;Operative Surgical Procedures;Organoids;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Pattern;Peripheral;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Platinum Compounds;Positive Lymph Node;Prediction of Response to Therapy;Primary Neoplasm;Prognosis;Progression-Free Survivals;Pump;Radiogenomics;Randomized;Recurrence;Regimen;Regional Chemotherapy;Reporting;Research;Research Project Grants;Resistance;Risk Factors;Sampling;Site;Solid Neoplasm;Source;Specimen;Staging;Systemic Therapy;TP53 gene;Techniques;Testing;Time;Tissue Banks;Toxic effect;Treatment Failure;Treatment Protocols;Treatment outcome;Unresectable;Vascular blood supply;Work;X-Ray Computed Tomography;arm;biliary tract;cell free DNA;chemotherapeutic agent;chemotherapy;cohort;contrast enhanced computed tomography;drug sensitivity;effective therapy;gemcitabine;genetic predictors;genetic signature;genomic data;improved;improved outcome;intrahepatic;mortality;multimodality;neoplastic cell;novel;oxaliplatin;patient population;patient stratification;patient subsets;peripheral blood;phase 2 study;precision medicine;predictive marker;primary endpoint;prognostic;prospective;protein expression;quantitative imaging;radiological imaging;radiomics;response;risk stratification;standard care;subclonal heterogeneity;targeted exome sequencing;targeted sequencing;targeted treatment;therapeutic target;therapy resistant;treatment response;treatment strategy;tumor;tumor DNA;tumor heterogeneity Improving Outcome in Patients with Advanced Intrahepatic Cholangiocarcinoma: A Randomized Phase II Study of Gemcitabine and Oxaliplatin With or Without Regional Floxuridine (FUDR) NARRATIVEIntrahepatic cholangiocarcinoma (IHC) is a devastating largely incurable cancer with a rising worldwideincidence and few effective treatment options. The goals of this research project are to 1) establish the efficacyof hepatic arterial infusion of floxuridine (FUDR) combined with systemic chemotherapy for the treatment ofunresectable IHC and 2) to use the unique collection of tissue blood and radiographic samples from trial patientsto uncover biomarkers of clinical response. NCI 10695133 8/1/23 0:00 PAR-18-560 5U01CA238444-04 5 U01 CA 238444 4 "UNDALE, ANITA H" 9/10/20 0:00 8/31/25 0:00 Clinical Oncology Study Section[CONC] 1935333 "JARNAGIN, WILLIAM ROBERT" "CERCEK, ANDREA ; IACOBUZIO-DONAHUE, CHRISTINE A" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 642310 NCI 430591 211719 SUMMARYIntrahepatic cholangiocarcinoma (IHC) is a subtype of biliary tract adenocarcinoma with a poor prognosis andrising incidence. SEER data recently documented an average 4.4% rise over the past decade. Similarly ananalysis spanning 18 years reported a 7% annual increase in incidence the highest of any biliary tract subtype.Both studies highlight the abysmal survival of patients with IHC the latter reporting a median of approximately 6months. Most patients with IHC have unresectable disease at diagnosis and even those few fortunate enoughto undergo resection recur commonly. For these patients treatment options are limited with systemicchemotherapy representing the standard and in most cases the only approach. Combination therapy withgemcitabine (GEM) and a platinum agent is the current gold standard but its benefit is limited offering a medianoverall survival of approximately 12 months. Recently our group completed a phase II single-arm study ofregional chemotherapy using continuous infusion hepatic arterial (HAI) floxuridine (FUDR) combined with GEMand oxaliplatin (OX). The median overall survival was 25 months with four patients responding sufficiently toundergo resection. Based on these promising results the primary goal of this proposal is to establish the efficacyof HAI FUDR added to the most active systemic regimen (GEM/OX) for the treatment of unresectable IHC in amulti-center randomized phase II study with the primary endpoint of progression-free survival.Further improvements in the management of IHC have been hindered in large part by a poor understanding ofthe biology of the disease. IHC is among the most genomically heterogeneous solid tumor resulting from thewide array of risk factors and multiple potential cells of origin. Significant heterogeneity has been shown not onlyfrom patient to patient but even within the same tumor. This feature has precluded precise characterization ofmolecular pathogenesis made it difficult to identify effective targeted therapies and results in inaccurateassessment of the mutational landscape when based on a single biopsy. The proposed clinical trial provides anideal opportunity to address these gaps. We will evaluate intratumoral heterogeneity (ITH) using targeted exomesequencing of multiple tumor biopsies and cell-free DNA (cfDNA) from a large cohort of patients and use thesefindings to stratify patients with respect to response and survival. For the subset of patients that progress whileenrolled in the trial we will obtain tumor biopsies and blood at the time of progression to elucidate mechanism(s)of treatment resistance by tumor DNA and cfDNA sequencing. Using these same samples we will establishpatient-derived organoid models for functional evaluation of genetic predictors of treatment response. Finallywe will use radiogenomics or the merger of quantitative imaging with molecular analyses to explore non-invasive stratification of patients based on mutational patterns and to quantify the degree of heterogeneity. Usingan integrated analysis approach these studies will provide a foundation for multimodal risk stratification for IHC. 642310 +No NIH Category available Areca catechu;Authorization documentation;Cancer Center;Cancer health equity;Data;Data Collection;Development;Ethnic Population;Funding;Guam;Hawaii;Health Disparities Research;Incidence;Infrastructure;Interview;Joints;Malignant Neoplasms;Malignant neoplasm of liver;Mastication;Medical Records;Nuts;Pacific Islands;Patients;Pilot Projects;Play;Publications;Registries;Reporting;Research;Research Project Grants;Research Support;Resource Sharing;Resources;Role;Secure;Territoriality;Training;Universities;anticancer research;authority;cancer health disparity;data sharing;male;mortality;multi-ethnic;neoplasm registry;outreach;surveillance data;synergism;tumor registry Core II: Cancer Registry Core n/a NCI 10695119 8/15/23 0:00 PAR-18-767 5U54CA143727-14 5 U54 CA 143727 14 9/28/09 0:00 8/31/25 0:00 ZCA1-SRB-T 7664 1890717 "HERNANDEZ, BRENDA Y" Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 85756 57775 33542 PROJECT SUMMARY/ABSTRACTThe Cancer Registry Shared Resource Core (CRSRC) will serve a key role in identifying and characterizingcancer disparities in the multiethnic populations of Guam and Hawaii. The overall objective of the CRSR is toprovide key infrastructure support for cancer research and outreach activities of the Pacific Island Partnershipfor Cancer Health Equity (PIPCHE). The CRSRC meets the requirements of PIPCHE shared resources toenhance the ability to conduct cancer disparities research.The CRSRC represents a partnership between the Guam Cancer Registry (GCR) and the Hawaii TumorRegistry (HTR) the central cancer registries of the Territory of Guam and the State of Hawaii respectively.This partnership has been critical to the development of the GCR as a fully functioning registry throughtechnical support and training provided by the HTR and through the establishment of statutory authority forcancer reporting and securing territorial funding. The CRSRC subsequently played a critical role in thedevelopment of the Pacific Regional Central Cancer Registry covering the US Affiliated Pacific Islands.The CRSRC serves as a critical resource for PIPCHE research and outreach. The CRSRC generates high-quality cancer surveillance data through which cancer disparities can be identified and characterized. Thisinformation is key to establishing PIPCHE research and outreach priorities. The CRSR also provides keysupport for research and outreach activities.The CRSRC will continue to serve as an important Core of the PIPCHE.Specific Aim 1. Provide cancer data and related support for PIPCHE research projects (full andpilot) and outreach activities.Specific Aim 2. Build capacity for cancer surveillance and health disparities research at theUniversity of Guam (UOG) and the University of Hawaii Cancer Center (UHCC). This alignment willallow for a synergy and sharing of data that would not be possible otherwise. +No NIH Category available Achievement;Address;Areca;Awareness;Behavior;Biological;Cancer Control;Cancer health equity;Cause of Death;Cervical Cancer Screening;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Community Outreach;Competence;Complex;Death Rate;Education;Equity;Ethnic Population;Failure;Filipino;Goals;Guam;Hawaii;Health;Health Educators;Health Personnel;Health Professional;Human Papilloma Virus Vaccination;Incidence;Knowledge;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of lung;Nuts;Outcome;Pacific Islander;Pacific Islands;Population;Population Group;Prevention;Program Sustainability;Provider;Research;Research Personnel;Research Project Grants;Research Training;Resource Development;Resources;Risk Reduction Behavior;Screening for cancer;Students;Surveys;Tobacco;Training;Work;anticancer research;cancer health disparity;cancer prevention;cancer risk;care providers;colorectal cancer screening;community organizations;design;evidence base;experience;high risk behavior;improved;malignant mouth neoplasm;men;mortality;outreach;parity;population based;recruit;social determinants;underserved minority;uptake Community Outreach Core PROJECT NARRATIVEPacific Islanders are one the fastest growing ethnic groups in the US found in every state. The work of thePacific Island Partnership for Cancer Health Equitys (PIPCHE) Community Outreach Core (COC) directlyaddresses the disproportionately high rates of cancer incidence and mortality found among Pacific IslandPopulations (PIP) in Hawaii and Guam. Using community-engaged approaches the Community OutreachCore will work to support enhance and disseminate the PIPCHEs research to better understand thedeterminants of cancer in this group. The COCs activities will also serve to reduce the burden of preventablecancers found in PIP living in Hawaii and Guam which may be applicable to groups found elsewhere in theUS. NCI 10695113 8/15/23 0:00 PAR-18-767 5U54CA143727-14 5 U54 CA 143727 14 9/28/09 0:00 8/31/25 0:00 ZCA1-SRB-T 7662 11794835 "CASSEL, KEVIN DARRYL" Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 281831 183062 104331 PROJECT SUMMARY/ABSTRACTIn Hawaii and Guam Pacific Island Populations represent a highly underserved minority withdisproportionately high rates of lung cervical colorectal liver and oral cancers compared to other ethnicpopulations in the US. Limited knowledge of cancer prevention low rates of cancer screening and unique highrisk behaviors such as tobacco and areca nut use contribute to the cancer health disparities found amongPacific Island Populations. Also Pacific Island Populations are highly underrepresented among cancerresearchers and cancer health care professionals. Culturally-grounded approaches to achieve parity in cancercontrol are sorely needed which is a focus of the Pacific Island Partnership for Cancer Health Equitys(PIPCHE) Community Outreach Core. The objectives of the Community Outreach Core are to include PacificIsland Populations community perspectives to assist and promote the research of the Partnership build thecompetencies of healthcare providers serving Pacific Island Populations and help train new cadres of cancerresearchers and care providers from Pacific Island Populations. The Aims of Community Outreach Core areto: 1) Provide an essential resource to PIPCHE research projects and to the Partnership overall 2) Implementevidence-based cancer prevention outreach resources and promotion of PIPCHE research and 3) Assessthe Partnerships capacity to design and implement culturally relevant research in Hawaii and Guam.Achievement of these Aims is expected to lead to sustainable programs that seek to better understandaddress and reduce cancer disparities and underrepresentation of cancer researchers in Hawaii and GuamsPacific Island Populations. The long-term goal of the Community Outreach Core is to reduce barriers leading tocancer disparities in Guam and Hawaii among Pacific Island Populations. +No NIH Category available Address;Algorithms;Automobile Driving;Bioinformatics;Biological;Biological Models;Cancer Biology;Cancer Model;Cancer Patient;Cancer cell line;Cause of Death;Cell Survival;Cell physiology;Cells;Cessation of life;Clinical;Communities;Computational Science;Computing Methodologies;DNA Sequence Alteration;Data;Data Set;Development;Environment;Genes;Genetic study;Genomics;Goals;Informatics;Lead;Malignant Neoplasms;Methods;Missense Mutation;Molecular;Mutation;National Cancer Institute;Oncogenic;Outcome;Pathway interactions;Performance;Pharmaceutical Preparations;Process;Program Development;Protein Analysis;Proteins;Proteome;Publications;Sampling;Suppressor Mutations;Systems Biology;Testing;Therapeutic;Time;Translating;Tumor Suppressor Proteins;analytical tool;cancer genome;cancer genomics;cancer type;clinically actionable;computerized tools;design;experience;genetic signature;genomic data;informatics tool;innovation;insight;mutant;novel;novel therapeutic intervention;personalized approach;personalized therapeutic;pharmacologic;precision medicine;programs;protein protein interaction;protein structure;response;screening;tool;tumor;tumorigenesis Predicting actionable cancer vulnerabilities enabled by mutant-directed protein-protein interactions Genomic alterations such as missense mutations lead to the acquisition of cancer hallmarks by rewiringnetworks of protein-protein interactions (PPI). Understanding of how such mutant-directed neomorph PPIs(neoPPIs) promote tumorigenesis is a challenge vital for the successful development of effective personalizedtherapeutic strategies in cancer. We propose to address this challenge by developing novel computationalmethods specially designed to determine the neoPPI-enabled therapeutically actionable vulnerabilities incancer patients. NCI 10695111 8/29/23 0:00 RFA-CA-21-013 5R21CA274620-02 5 R21 CA 274620 2 "MILLER, DAVID J" 9/1/22 0:00 8/31/24 0:00 ZCA1-TCRB-Q(M1) 10517954 "IVANOV, ANDREY " Not Applicable 5 PHARMACOLOGY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 215101 NCI 137445 77656 Cancer is the second leading cause of death worldwide causing more than 10 million deaths every year. Inresponse tremendous efforts have been made over the past decades to understand the molecular mechanismsof tumorigenesis and inform new therapeutic strategies in cancer. Unraveling the cancer genome and proteomelandscapes revealed that genomic alterations such as missense mutations promote tumorigenesis by rewiringnetworks of protein-protein interactions (PPI). However the understanding of how mutant-directed neomorphPPIs (neoPPI) lead to the acquisition of cancer hallmarks and the discovery of neoPPI-enabled cancervulnerabilities remain major challenges. We propose to address this challenge by developing novelcomputational methods termed Averon Notebook to discover actionable vulnerabilities enabled by rewiredoncogenic networks. To achieve this goal we will leverage our expertise in both cancer bioinformatics andexperimental cancer biology demonstrated in numerous publications and long-time participation in the CancerTarget Discovery and Development (CTD^2) Network of the National Cancer Institute. Over the past decade wehave established comprehensive bioinformatics workflows and novel analytical tools to collect processintegrate and analyze different types of cancer-related data. To integrate cancer genomics data with protein-protein interaction networks and clinical compounds we have developed the OncoPPi Portal which has alreadyenabled the discovery of multiple new molecular mechanisms of tumorigenesis. In this project we will capitalizeon our expertise in computational science and cancer biology to develop i) a new algorithm to determine theneoPPI-regulated biological programs and ii) methods to determine actionable vulnerabilities in neoPPI-regulated pathways. Ultimately this project will provide the first computational environment specially designedto rapidly identify actionable targets and pathways enabled by mutant-directed protein-protein interactions toinform target discovery in cancer. 215101 +No NIH Category available Address;Applications Grants;Asian Pacific Islander;Asian population;Cancer Burden;Cancer Center;Cancer Control;Cancer Research Center of Hawaii;Cancer health equity;Caucasians;Collaborations;Communities;Degree program;Development Plans;Distant;Economics;Education;Educational Curriculum;Educational workshop;Enrollment;Epidemiology;Ethnic Origin;Faculty;Funding;Future;Geographic Locations;Geography;Goals;Graduate Degree;Grant;Guam;Hawaii;Health;Incidence;Individual;Institution;Intervention;Island;Journals;Location;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Manuscripts;Master of Science;Mentors;Micronesia;Output;Pacific Islander;Pacific Islands;Pathway interactions;Peer Review;Population;Positioning Attribute;Postdoctoral Fellow;Publications;Publishing;Race;Research;Research Assistant;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Scholarship;Series;Students;Supervision;Time;Training;Training Activity;Travel;Underserved Population;Universities;Writing;anticancer research;cancer health disparity;cancer prevention;career;career development;community based research;curriculum enhancement;doctoral student;education research;ethnic disparity;ethnic diversity;experience;follow-up;graduate student;health disparity;improved;interest;meetings;member;minority health disparity;mortality;novel;online course;programs;psychosocial;skills;success Research Education Core n/a NCI 10695109 8/15/23 0:00 PAR-18-767 5U54CA143727-14 5 U54 CA 143727 14 9/28/09 0:00 8/31/25 0:00 ZCA1-SRB-T 7661 1903184 "MASKARINEC, GERTRAUD " Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 248734 161219 93077 PROJECT SUMMARYThe setting of this training activity within the Pacific Island Partnership for Cancer Health Equity (PIPCHE)between the University of Guam (UOG) and the University of Hawaii Cancer Center (UHCC) is unique in itsethnic diversity and its distant location. Pacific Islanders are extremely underrepresented in the nationsbiomedical workforce which limits progress in research and prevention of cancer health disparities. PIPCHEaddresses training Pacific Islander cancer researchers in the context of the vast diversity and geography of theregion. The impact of the two previous cycles is remarkable. Without a cancer center in Guam youngresearchers and students had no opportunity to be involved in cancer research despite the high incidence ofmany cancers. During the past 10 years an infrastructure for research training in Guam and Micronesia hasbeen built; many UOG faculty members are collaborating in cancer research with UHCC. Since the initiation ofPIPCHE two previous trainees moved into faculty positions at UOG two graduates supported in cycle one arenow in faculty positions on the US mainland and one trainee is now employed at the National Institute ofMinority Health Disparities. To date ten trainees have entered doctoral programs in different locations. Of the45 PIPCHE research assistants at least nine went on graduate and professional degree programs. ThisResearch Education Core (REC) will continue the successful path with three specific aims: 1) Provideguidance support and opportunities to acquire research skills and experience to Pacific Islander studentspursuing a masters degree with a focus on cancer-related health disparities in the Pacific Island region.Students will be supported at UOG or at UHCC in programs not offered at UOG and mentored in a researchproject under the supervision of one or more PIPCHE faculty. An expanded curriculum consisting of an onlinecourse and a journal club will address critical current topics in cancer research. 2) Provide guidance supportand opportunities to acquire research skills and experience for students interested in cancer healthdisparities in the Pacific who are enrolled in a graduate degree program (masters or doctoral). Students willparticipate in biomedical epidemiologic psychosocial and community-based research projects led by UHCCfaculty. 3) Support guide and develop Early Stage Investigators (ESIs) to become independent investigators incancer health disparities with the help of a mentoring committee an annual manuscript and grant writingworkshop attendance at scientific meetings and course releases. Important enhancements are incorporatedinto the proposed program: increasing support from four to six UOG masters students per year due to highdemand; novel online modules related to health disparities in the Pacific; extension of UHCC funding fromdoctoral to masters students; travel scholarships for trainees to attend scientific meetings; an annual intensivewriting workshop at UOG to improve output in published manuscripts and grant applications; implementation ofmentoring committees and funds to provide ESIs with protected time for grant and manuscript writing. +No NIH Category available 16S ribosomal RNA sequencing;Alcohols;Areca;Bacterial Genes;Biological Markers;Blood;Cancer health equity;Case/Control Studies;Chronic Hepatitis C;Circadian Rhythms;Collaborations;Data;Diabetes Mellitus;Disease;Early Intervention;Etiology;Fatty Liver;Fatty acid glycerol esters;Fibrosis;Genes;Glucose;Guam;Hepatitis C virus;High Prevalence;Incidence;Link;Lipids;Liver;Liver Cirrhosis;Liver Fibrosis;Liver diseases;Malignant neoplasm of liver;Mastication;Measures;Mediating;Metabolic;Metabolic Diseases;Native-Born;Nuts;Obesity;Oral;Oral cavity;Oral health;Pacific Islands;Pathogenicity;Patient Self-Report;Patients;Pattern;Periodontal Diseases;Population;Primary carcinoma of the liver cells;Questionnaires;Research;Risk;Risk Factors;Role;Sampling;Severities;Sleep;Sleep Apnea Syndromes;Sleep disturbances;Snoring;Stratification;United States;Viral hepatitis;cancer health disparity;chronic liver disease;circadian pacemaker;clinical examination;commensal bacteria;cryptochrome;dysbiosis;insulin signaling;mRNA Expression;microbial;mortality;non-alcoholic fatty liver disease;novel;novel strategies;oral microbiome;preventive intervention;secondary outcome;sleep abnormalities Full Project II: Novel Risk Factors and Disease Associations of Liver Cancer in Guam PROJECT NARRATIVEWe propose a case-control study of 300 liver fibrosis cases and 300 matched controls among Chamorros inGuam. Liver fibrosis a well-established precursor of liver cancer as well as liver steatosis as a secondaryoutcome will be measured by transient elastrography (Fibroscan). We hypothesize that oral dysbiosis andsleep/circadian rhythm disturbance contribute to liver fibrosis through glucose and lipid dysmetabolism and thepotential modifying effect of other exposures. NCI 10695107 8/15/23 0:00 PAR-18-767 5U54CA143727-14 5 U54 CA 143727 14 9/28/09 0:00 8/31/25 0:00 ZCA1-SRB-T 7660 1890717 "HERNANDEZ, BRENDA Y" Not Applicable 1 Unavailable 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI Domestic Higher Education 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 89874 65126 30310 PROJECT SUMMARY/ABSTRACTThe US territory of Guam has a staggeringly high burden of liver cancer with incidence and mortality more thantwice that of overall rates in the United States (US) where rates have nearly tripled over the past three decades.Excess risk is most prominent among CHamorus who are the native people of Guam comprising 42% of thepopulation. Hepatocellular carcinoma (HCC) the primary form of liver cancer develops entirely within the contextof progressive chronic liver disease (CLD) characterized by advancing levels of fibrosis. Thus there is an urgentneed to understand the etiology of progressive CLD in CHamorus and to identify novel strategies and targets forprevention and early intervention. Our proposed research will address whether oral dysbiosis and sleep/circadianrhythm disturbance contribute to liver fibrosis through glucose and lipid dysmetabolism and the potentialmodifying effect of other exposures. We propose a case-control study of 300 liver fibrosis cases and 300 matchedcontrols among CHamorus in Guam. Liver fibrosis a well-established precursor of liver cancer as well as liversteatosis as a secondary outcome will be measured by transient elastrography (Fibroscan).The Specific Aims of Full Project II are to:1) Evaluate the association of oral dysbiosis with liver fibrosis and steatosis. Oral dysbiosis will be defined asdeleterious patterns of the oral microbiome and/or the presence of periodontal disease. We will perform bacterial16S rRNA sequencing to measure oral bacterial diversity and composition. We will determine periodontaldisease by clinical examination and self-report. The association between oral dysbiosis and liver fibrosis with orwithout stratification by steatosis grades will be evaluated; the potential modifying effects of other exposures(e.g. betel nut chewing viral hepatitis alcohol) and the mediating effects of glucose and lipid dysmetabolismwill be assessed. We hypothesize that having moderate to severe liver fibrosis is associated with: 1a) reducedoral microbial diversity enriched pathogenic and depleted commensal bacteria and aberrations in insulin-signaling bacterial genes; 1b) the presence and severity of periodontal disease; and 1c) oral dysbiosis throughand independently of glucose/lipid dysmetabolism.2) Evaluate the associations of sleep (quantity and quality) and circulating Mrna expression levels of circadianclock genes with liver fibrosis and steatosis. We will determine sleep duration and quality using validatedquestionnaires and analyze the expression of the period (Per1 Per2 Per3) and cryptochrome (Cry2) genes inblood as a biomarker of circadian rhythm. We hypothesize that liver fibrosis is associated with: 2a) short sleepduration and sleep apnea; 2b) reduced expression of the clock genes; and 2c) sleep/circadian rhythmdisturbances through and independently of glucose/lipid dysmetabolism. +No NIH Category available Accountability;Address;Adoption;Award;Career Choice;Climate;Collaborations;Communities;Data Set;Discipline of Nursing;Ensure;Environment;Equity;Evaluation;Extramural Activities;Faculty;Feedback;Funding;Goals;Grant;Health Disparities Research;Health Occupations;Individual;Institution;International;Intervention Studies;Life;Logic;Measures;Mentors;Methods;Modeling;Outcome;Output;Policies;Population Sciences;Process;Productivity;Program Sustainability;Public Health Schools;Publications;Reporting;Research;Research Activity;Research Support;Scholarship;Scientific Evaluation;Scientist;Self Assessment;Social Justice;Social Values;Social isolation;Teacher Professional Development;Textiles;United States National Institutes of Health;Universities;Work;career;clinical practice;cohort;college;design;experience;health equity;improved;intersectionality;member;minority disparity;minority health;organizational climate;organizational readiness;pedagogy;programs;recruit;response;success;tool;underserved community Catalyzing Systemic Change at Drexel University to Support DiverseFaculty in Health Disparities Research n/a NCI 10695082 8/24/23 0:00 RFA-RM-20-022 5U54CA267735-03 5 U54 CA 267735 3 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 6020 12002737 "KAIMAL, GIRIJA " Not Applicable 3 Unavailable 2604817 XF3XM9642N96 2604817 XF3XM9642N96 US 39.954073 -75.186541 2205901 DREXEL UNIVERSITY PHILADELPHIA PA Domestic Higher Education 191043443 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 212100 140000 72100 PROJECT SUMMARYThe Evaluation Core (EC) for the Drexel FIRST Program has as its main goal to evaluate using mixedmethods and in coordination with the FIRST Coordination and Evaluation Center multi-level outcomes(individual mentors department institution) including an evaluation of scientific impact of the FIRST Facultyhires. The efforts of the EC are grounded in theoretical frameworks reflecting equity inclusivity andintersectionality and are guided by a logic model conceptualizing our change efforts the activities planned tocontribute to desired changes the immediate outputs and ultimate outcomes that will be tracked anddocumented. Specifically the EC will: (1) work closely with the designated FIRST Coordination and EvaluationCenter to help design and implement a uniform and systematic core data set across FIRST Programawardees; (2) develop and implement an evaluation strategy specific to Drexel FIRST Program activities; (3)provide formative evaluative reports to the Coordination and Evaluation Center and our Administrative andFaculty Development Cores to inform programmatic adjustments and improvements; and (4) evaluate impactsat multiple levels (individual FIRST faculty hire department college and institution) of Drexels FIRST Cohorthires on outcomes ranging from individual ratings of inclusivity and social isolation to organizational readinessand climate. Furthermore we will evaluate scientific impact of FIRST faculty in advancing the science of healthdisparities research using the National Institute of Minority Health and Disparities framework to identifydomains and levels addressed in their scholarship. Finally as our long-term goal is to sustain a researchculture of inclusive excellence the EC will establish an approach including tracking tools for continuousinstitutional self-assessment analysis and feedback assuring accountability and integration of the FIRSTProgram into the fabric of institutional life at Drexel during the life of the grant and thereafter. The specific aimsof the Evaluation Core are: (1) To characterize and track the various components that compose the FIRSTprogram at Drexel University; (2) To evaluate the impact of the FIRST program at Drexel on institutionaloutcomes including organizational research climate and implementation and adoption of FIRST strategiespolicies and processes to promote inclusive excellence; (3) To evaluate the impact of the FIRST program atDrexel on outcomes defined at the level of the hiring academic units and the new faculty hires themselvesincluding unit culture mentoring environment sponsorship other cohort experiences (social isolation support)and career progression opportunities including productivity as reflected in publications presentationscollaborative opportunities grant submissions and funding successes; and (4) To evaluate the impact of theFIRST Cohort on advancing the science of health disparities research. Importantly the EC will provide asummative evaluation as to whether we have achieved the goal of inclusive excellence of the Drexel FIRSTProgram and how it can be sustained beyond funding. +No NIH Category available Accountability;Address;Area;Communication;Development;Discipline of Nursing;Effectiveness;Ensure;Environment;Evaluation;Evidence based practice;Faculty;Funding;Goals;Growth;Health;Health Disparities Research;Health Occupations;Infrastructure;Institution;Intervention;Intervention Studies;Leadership;Medicine;Mentors;Modeling;Pennsylvania;Population Intervention;Population Sciences;Process;Program Sustainability;Public Health Schools;Research;Research Personnel;Role;Science;Scientist;Strategic Planning;Structure;Teacher Professional Development;Testing;United States National Institutes of Health;Universities;Update;Woman;Work;career;cohort;college;design;health disparity;health disparity populations;higher education;improved;medical schools;minority disparity;minority health;organizational structure;population health;programs;recruit;success Catalyzing Systemic Change at Drexel University to Support Diverse Faculty in Health Disparities Research n/a NCI 10695079 8/24/23 0:00 RFA-RM-20-022 5U54CA267735-03 5 U54 CA 267735 3 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 6018 7754784 "DIEZ-ROUX, ANA V" Not Applicable 3 Unavailable 2604817 XF3XM9642N96 2604817 XF3XM9642N96 US 39.954073 -75.186541 2205901 DREXEL UNIVERSITY PHILADELPHIA PA Domestic Higher Education 191043443 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 4114673 2715956 1398717 PROJECT SUMMARYThe Drexel University FIRST program will build a collaborative structure involving multi-level inputs fromUniversity leaders academic units and faculty to catalyze sustainable institutional change that supportsscientific and inclusive excellence in the conduct of health disparities research. The Administrative Core (AC)will (1) recruit and ensure the success of a diverse set of junior faculty and (2) support the transformation of theenvironment at Drexel University to facilitate the recruitment and success of other diverse NIH fundedresearchers and create a sustained culture of inclusive excellence across the University. We will leverage andexpand on Drexel University strengths including (1) Drexels historical commitment to inclusion and civicengagement; (2) the updated University strategic plan which prioritizes enhancing faculty diversity andsustaining a culture of inclusive excellence; (3) the recent exponential growth of externally fundedinterdisciplinary population health intervention science and health disparities research at Drexel; and (4)University supported interdisciplinary population health initiatives with a health disparity focus. We haveselected health disparities as our area of emphasis because of its importance to the health of the nation thecritical role of diverse faculty and the strong track record support and infrastructure for health disparitiesresearch at Drexel. The program will test the primary hypothesis that a cohort model of faculty hiringsponsorship continual mentoring and support for professional development embedded within an institutionimplementing evidence-based practices will create an academic culture of inclusive excellence demonstratedby significant improvements in metrics of institutional culture and scientific workforce diversity. We alsohypothesize that the cohort model will lead to impactful science in health disparities. The Administrative Corewill provide administrative and budgetary oversight organizational structure external input Universitypartnerships communications and accountability mechanisms necessary to test these hypotheses. TheSpecific Aims of the AC are: (1) To provide general administrative and budgetary oversight of the FIRSTCohort program including the creation and implementation of a governance structure that engages facultyacross the university is responsive to program needs in a timely manner. (2) To oversee faculty developmentand evaluation activities including coordination with other FIRST cohorts and with the +No NIH Category available Address;African American;Aging;Applications Grants;Appointment;Area;Biometry;Career Choice;Chronic Disease;Clinical Research;Collaborations;Color;Communities;Complex;Dedications;Discipline of Nursing;Disparity;Documentation;Effectiveness;Ensure;Equity;Ethnic Origin;Evaluation;Extramural Activities;Faculty;Funding;Gender;Goals;Health Disparities Research;Health Occupations;Individual;Inequity;Infrastructure;Institution;International;Intervention;Intervention Studies;Joints;Latino;Life Cycle Stages;Measures;Mentors;Mentorship;Methodology;Methods;Outcome;Policies;Population Sciences;Positioning Attribute;Procedures;Program Evaluation;Program Sustainability;Public Health Schools;Race;Records;Research;Research Personnel;Research Proposals;Research Support;Science;Scientist;Social Justice;Social Values;Structure;Teacher Professional Development;Translating;United States National Institutes of Health;Universities;career;career development;clinical practice;college;ethnic diversity;evidence base;experience;faculty support;health disparity;health equity;health inequalities;improved;intersectionality;learning community;multi-component intervention;multidisciplinary;novel;pedagogy;population health;programs;racial diversity;recruit;research and development;response;success;tenure track;theories;therapy development;underserved community Catalyzing Systemic Change at Drexel University to Support Diverse Faculty in Health Disparities Research PROJECT NARRATIVEThe Drexel FIRST initiative (Catalyzing Systemic Change at Drexel University to SupportDiverse Faculty in Health Disparities Research) will create a collaborative structure involvingUniversity leaders academic units and faculty to catalyze sustainable institutional change thatsupports scientific and inclusive excellence in the conduct of health disparities research. Wewill recruit 10 diverse early career scientists support their career development createsustainable institutional changes necessary to promote inclusive excellence broadly andevaluate the outcomes of the program at multiple levels including scientific impact. NCI 10695078 8/24/23 0:00 RFA-RM-20-022 5U54CA267735-03 5 U54 CA 267735 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 7754784 "DIEZ-ROUX, ANA V" "GITLIN, LAURA N." 3 NONE 2604817 XF3XM9642N96 2604817 XF3XM9642N96 US 39.954073 -75.186541 2205901 DREXEL UNIVERSITY PHILADELPHIA PA SCHOOLS OF PUBLIC HEALTH 191043443 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 4538873 OD 2995956 1542917 PROJECT SUMMARYIn response to the NIH U54 Faculty Institutional Recruitment for Sustainable Transformation (FIRST) Program(RFA-RM-20-022) Drexel University proposes to establish a robust transformative and sustainableprogram to support diverse early career scientists engaged in health disparities research spanningpopulation science to intervention research. This proposal a collaboration across Drexel University led byDrexels Dornsife School of Public Health and College of Nursing and Health Professions leverages ournationally and internationally recognized NIH and other extramurally supported research our community-basedclinical practices serving diverse underserved communities and our shared core values of social justice andhealth equity guiding our pedagogy research and hiring practices. Our proposal also strongly reflects DrexelUniversitys unwavering commitment and newly instituted strategic goals to promote inclusive excellence andensure diversity equity retention and promotion across for diverse faculty across their career pathways.Our proposed program will create a collaborative structure involving multi-level inputs from University leadersacademic units and faculty to catalyze sustainable institutional change that supports scientific and inclusiveexcellence in the conduct of health disparities research. With support from the FIRST program we will hireand mentor a diverse (gender race ethnicity) group of 10 early-stage faculty in three clusters who arecompetitive for tenure-track research positions with joint or secondary appointments across relevantdepartments programs or colleges Using evidence-based multi-level mentorship strategies at the individualdepartment college and university levels we will form a scientifically rigorous and supportive learningcommunity in which FIRST faculty will engage in individual and group activities leading to submissions ofcompetitive NIH R01 research proposals. FIRST faculty will be hired who are committed to diversity and whoseresearch addresses one of 3 pillars of health disparities research: detecting (defining/measuring healthdisparities) understanding (identifying determinants of disparities) and/or reducing (intervene evaluatetranslate scale policy) health inequities in cross-cutting thematic areas (aging chronic disease and/orenvironmental determinants). Developing and supporting a cadre of diverse researchers has been identified asan evidence-based strategy for advancing new methodologies measures and novel multi-level/multi-modalinterventions that address inequities and improve individual and population health outcomes. We will deploy amulti-level and multi-methods evaluative approach guided by critical and intersectionality theories to evaluatenuanced experiences of bias and structural discriminatory practices as well as program successes at theindividual department mentor college and University levels of achieving inclusive excellence. Our FIRSTProgram is co-led by nationally/internationally recognized leaders in population health intervention sciencementorship of racially/ethnically diverse faculty and evaluation of programs seeking inclusivity. 4538873 +No NIH Category available Acceleration;Active Sites;Address;Architecture;Binding;Biology;Buffers;Cells;Cellular biology;Communication;Complement;Complex;Coupled;Cryoelectron Microscopy;Crystallization;Crystallography;DNA;DNA Probes;DNA Repair;DNA Repair Gene;DNA Repair Pathway;DNA-dependent protein kinase;Data Analyses;Data Collection;Environment;Eukaryotic Cell;Exclusion;Fluorescence;Goals;Gold;Individual;Institution;Label;Laboratories;Ligands;Light;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Methods;Microscopy;Modality;Modeling;Molecular;Molecular Conformation;Mutation;New York;Nuclear;Optics;Patients;Phase Transition;Process;Proteins;Publications;RNA;Repair Complex;Research;Research Personnel;Resolution;Resources;Roentgen Rays;Scientist;Signal Transduction;Source;Structure;Synchrotrons;System;Technology;Testing;Variant;Visit;Visualization;Work;X-Ray Crystallography;X-Ray Tomography;beamline;crosslink;design;empowerment;flexibility;genome integrity;imaging modality;member;photonics;programs;protein purification;reconstitution;response;screening;sensor;single-molecule FRET;small molecule;structural biology;superresolution microscopy;ultra high resolution Core 2: Structural Cell Biology (SCB) Core NARRATIVE CORE 2: STRUCTURAL CELL BIOLOGY (SCB)Quantitative structural information can provide highly informative clues to how proteins work and in cases ofpatient mutations clues as to how they fail. The SCB Core provides empowering access to and expertise oncutting-edge structural biology technologies needed to probe DNA repair proteins and complexes and notavailable in individual research institutions. NCI 10695059 8/22/23 0:00 PAR-20-077 5P01CA092584-23 5 P01 CA 92584 23 9/27/01 0:00 8/31/26 0:00 ZCA1-SRB-K 7653 10291443 "HURA, GREGORY L" Not Applicable 12 Unavailable 78576738 ENBLDJUN4N73 78576738 ENBLDJUN4N73 US 37.868252 -122.258486 577512 UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB BERKELEY CA Other Domestic Non-Profits 947208118 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 746099 463531 282568 SUMMARY - CORE 2: STRUCTURAL CELL BIOLOGY (SCB)A major challenge for cancer structural biology in SBDR4 is to structurally define the DNA repair (DR) proteinsand assemblies that maintain genomic integrity. However. DR proteins and complexes have encoded flexibilityand function in spatially and temporally coordinated complexes that make their structural characterizations sochallenging. With SBDR investigators Core 2 the Structural Cell Biology (SCB) Core overcomes theseextreme challenges by providing access to and expertise on cutting-edge structural biology technologiesneeded to probe DR proteins and complexes and not available in individual research institutions.Aim 1. Determine structures conformations and assembly states. The SCB Core centered at a nationalsynchrotron facility will provide macromolecular crystallography (MX) and small angle X-ray scattering (SAXS)data collection and beamline scientist-level expertise for SBDR members. MX provides high resolution atomicstructures while SAXS can rapidly assess flexibility solution conformation(s) and assemblies. SCB SAXSincludes ligand or buffer screening and assessing DNA bending via GOLD-SAXS.Aim 2. Detect folds and conformations for integrative structural biology. Analysis of large complexes in theProjects by megadalton structural mass spectrometry (MS) and with SAXS-validated structure predictions willprovide testable hypotheses on their own or will accelerate CryoEM studies at individual institutes.Aim 3. Define molecular architectures in reconstituted systems and in the cell through synchrotron soft X-raytomography (SXT) of reconstituted phase transitions and cells and super-resolution fluorescencemeasurements for quantitative measurements of DR assemblies that would otherwise be problematic fortraditional structural methods.The SCB Core is centered at the Advanced Light Source (ALS) synchrotron where three beamlines (12.3.18.3.1 and National Center for X-ray Tomography/NCXT) will provide SAXS MX and SXT data collection toSBDR members. For enabling access to additional structural technologies and capabilities SCB has branchesat Calgary (MS) New York (super-resolution microscopy) Oxford (MX) and Scripps (MX).All four Projects will use the SCB Core regardless of structural expertise in member laboratories to optimallyand efficiently address Project structural and mechanistic Aims in ways that typical laboratories and beamlinevisits cannot or do not do. Together these SCB modalities allow SBDR-5 interrogation of dynamic DRmachines from atomic to cellular scales. The broad long range objective of the SCB Core is to support SBDRProjects to determine the impact of sequence variations the means to dissect multiple functions and themechanisms whereby flexible and dynamic DR machinery functions. +No NIH Category available Binding;Biochemical;Biochemistry;Biological;Biophysics;Cancer Etiology;Cell physiology;Cells;Cellular biology;Collaborations;Coupled;Cryoelectron Microscopy;DNA;DNA Damage;DNA Repair;DNA Structure;DNA biosynthesis;DNA replication fork;DNA-Binding Proteins;Dangerousness;Development;Digestion;Drug resistance;Ensure;Enzymes;Exonuclease;Genetic;Genome Stability;Genomic Instability;Genomics;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Methodology;Motor;Mutation;Pathway interactions;Poly(ADP-ribose) Polymerase Inhibitor;Post-Translational Protein Processing;Predisposition;Process;Proteins;Proteome;Reagent;Recording of previous events;Regulation;Research;Research Personnel;SMARCA3 gene;Stress;Structure;Testing;Therapeutic Intervention;Work;X-Ray Crystallography;biological adaptation to stress;cancer therapy;chemotherapeutic agent;driver mutation;endonuclease;genetic approach;interest;novel therapeutics;repaired;replication stress;response;shunt pathway;stress tolerance;structural biology;targeted treatment;translocase;tumor;tumorigenesis;ubiquitin ligase Project 4: Fork Repair: Mechanisms and consequences of stalled replication fork processing NARRATIVE - PROJECT 4: Fork Repair: Mechanisms and consequences of stalled replication forkprocessingThe vast majority of mutations including those that drive cancer are generated during DNA replication. Thisproject will discover the mechanisms that ATP-dependent motor proteins use to avoid error and complete DNAsynthesis. NCI 10695050 8/22/23 0:00 PAR-20-077 5P01CA092584-23 5 P01 CA 92584 23 9/27/01 0:00 8/31/26 0:00 ZCA1-SRB-K 7648 2436424 "CORTEZ, DAVID K" Not Applicable 12 Unavailable 78576738 ENBLDJUN4N73 78576738 ENBLDJUN4N73 US 37.868252 -122.258486 577512 UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB BERKELEY CA Other Domestic Non-Profits 947208118 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 380881 341965 38916 SUMMARY- PROJECT 4 - Fork Repair: Mechanisms and consequences of stalled replication forkprocessingDNA replication is central to cancer etiology and treatment since errors during replication generate most cancerdriver mutations and many cancer treatments including PARP inhibitors and chemotherapeutic agents targetDNA replication. We aim to discover the mechanisms of replication-coupled DNA repair and tolerance that areimportant for tumorigenesis and development of new therapeutics. The premise of this application is that ATP-dependent motor proteins act in pathways to control replication fork remodeling as a mechanism of replicationstress tolerance and error avoidance. In order to overcome challenge intermediates in these pathways areshunted towards alternative mechanisms including translesion synthesis and repriming. The mechanismdeployed may depend on the type of challenge its persistence and the inactivation of selected replication stressresponse and repair proteins that are common in cancer. While ensuring replication is completed the use oferror-prone mechanisms can generate the genetic alterations that drive tumor development and drug resistance.This genetic instability may also provide new opportunities for therapeutic intervention through synthetic lethalapproaches. This project will answer fundamental questions about these replication stress responsemechanisms using a combination of structural biochemical genetic and cell biology approaches. Specificallywe will determine how ATP-dependent fork reversal enzymes control replication fork dynamics identify themechanisms that regulate replication stress tolerance pathways and determine the consequences of damagetolerance and fork repair pathways for genome stability. These aims will be accomplished by the combined effortsof four investigators with expertise in cell biology genetics biochemistry biophysics and structural biology anda history of working in cooperation with each other and with the other project investigators and research cores. +No NIH Category available Address;Adjuvant Chemotherapy;Affect;Biological;Biological Assay;Biological Markers;Bone Marrow;Breast Cancer Patient;Breast Cancer therapy;Carboplatin;Cell Communication;Cells;Classification;Clinical;Cytotoxic Chemotherapy;Data;Dendritic Cells;Detection;Development;Diagnosis;Disease;Disease Resistance;Distant;Environment;Funding;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Genes;Goals;Heterogeneity;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Markers;Immunotherapy;In complete remission;Individual;Institution;Intervention;Macrophage Colony-Stimulating Factor Receptor;Malignant Bone Marrow Neoplasm;Methods;Molecular;Molecular Profiling;Neoadjuvant Therapy;Neoplasm Metastasis;Newly Diagnosed;Nivolumab;Paclitaxel;Pathologic;Pathway interactions;Patient Participation;Patients;Phase;Phenotype;Population;Primary Neoplasm;Randomized;Recurrence;Recurrent disease;Relapse;Residual Neoplasm;Residual state;Risk;Selection for Treatments;Specimen;T-Lymphocyte;Testing;Therapeutic Intervention;Therapeutic Trials;Tumor-infiltrating immune cells;Validation;antagonist;biobank;biomarker development;biomarker panel;checkpoint therapy;chemotherapy;cohort;combinatorial;cytotoxic;diagnostic assay;diagnostic tool;digital;gene panel;improved;insight;malignant breast neoplasm;metastatic process;molecular phenotype;mortality;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;participant enrollment;phase II trial;prevent;prognostic;prospective;response;risk stratification;single cell sequencing;standard of care;synergism;targeted treatment;therapy resistant;triple-negative invasive breast carcinoma;tumor;tumor-immune system interactions Synergized Immune and Tumor Cell Bone Marrow Biomarkers to Predict Recurrence in Triple Negative Breast Cancer Project NarrativeThe goals of this project are to understand the immune bone marrow environment anddisseminated tumor cells interactions which lead to metastases in triple negative breast cancer(TNBC) as well as develop biomarkers for therapy selection. We will accomplish this by 1:evaluating the ability of an 8-gene DTC gene panel to predict distant disease development inTNBC patients enrolled in a therapeutic trial of carboplatin/paclitaxel/nivolumab with or withoutcabiralizumab; Aim 2: understanding the extent of intra- and inter-patient molecular heterogeneityof BM DTCs in TNBC patients treated with conventional chemotherapy and ICI therapy and Aim3: Correlating alterations in specific T cell and conventional dendritic cells (cDCs) populations inthe BM with the presence of DTCs and to determine the impact of conventional and ICI therapy. NCI 10695048 8/29/23 0:00 PA-20-185 5R01CA262555-03 5 R01 CA 262555 3 "DEY, SUMANA MUKHERJEE" 9/21/21 0:00 8/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 1941675 "AFT, REBECCA L." "DENARDO, DAVID G; WATSON, MARK A." 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 640551 NCI 406699 233852 Project Summary/AbstractTriple negative breast cancer (TNBC) is aggressive and a large percentage of patients develop metastaticdisease. Disseminated tumor cells (DTCs) found in the bone marrow (BM) of TNBC patients may be theintermediaries of the metastatic process. Data from our lab as well as others suggest that the immune landscapeof BM may influence DTC latency treatment resistance and metastatic potential. We have already defined andvalidated an 8 gene expression-based biomarker panel that can detect DTCs in the BM of treatment nave TNBCpatients and that predicts development of distant metastatic disease. Our recent data indicate that TNBC patientswith DTC-positive BM have altered populations of immune cell precursors and this is associated with recurrentdisease development. Based on these findings we hypothesize that immune checkpoint inhibitors willfacilitate the elimination of BM DTCs in TNBC patients by altering the immune microenvironment inpatients with specific DTC and/or BM immune cell populations and that cell population-specific geneexpression signatures can predict which patients will benefit most from aggressive immunotherapy toprevent metastatic disease relapse. We will test this hypothesis using our extensive biorepository of BM specimens collected from TNBC patientswho received conventional chemotherapy as well as prospectively collected specimens from TNBC patientsparticipating in an independently funded institutional phase II immune checkpoint inhibitor (ICI) trial ofcarboplatin/paclitaxel/nivolumab with or without cabiralizumab. Our goals are: 1. To evaluate the ability of our 8-gene DTC gene panel to predict distant disease development in TNBC patients enrolled in our ICI therapeutictrial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab; 2. To understand the specificsubpopulations of BM DTCs in TNBC patients treated with conventional chemotherapy and ICI therapy whichare resistant to therapy and; 3. To understand alterations in specific T cell and conventional dendritic cell (cDC)populations in the BM when DTCs are present and how this is impacted by conventional and ICI therapy. Theresults of this proposal will lead to a greater understanding of immune escape and heterogeneity of BMmicrometastatic disease as well as biomarkers for improving conventional and ICI therapy in TNBC patients. 640551 +No NIH Category available BARD1 gene;BRCA1 gene;Biochemical;Cancer Model;Cancer Patient;Cell Cycle;Cell Survival;Cells;Cellular biology;Chemicals;Chemotherapy and/or radiation;Chromosomal Rearrangement;Clinic;Clinical Trials;Collaborations;Complex;Core Protein;Coupled;Cryoelectron Microscopy;DNA;DNA Double Strand Break;DNA Ligases;DNA Ligation;DNA Repair;DNA Repair Pathway;DNA biosynthesis;DNA replication fork;DNA-Directed DNA Polymerase;DNA-PKcs;DNA-dependent protein kinase;Development;Double Strand Break Repair;Environment;Enzymes;Excision;G2 Phase;G22P1 gene;Genetic;Genomic Instability;Human;In Vitro;Insecta;Interphase;Interphase Cell;Invaded;Ionizing radiation;Joints;Knowledge;LIG4 gene;Ligation;Link;Malignant Neoplasms;Mediating;Molecular;Mutation;Non-Malignant;Nonhomologous DNA End Joining;Normal Cell;Paint;Pathway interactions;Play;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Process;Productivity;Proteins;Publications;Rad51 recombinase;Radiation induced double strand break;Radiation therapy;Reagent;Regulation;Research Personnel;Resected;Resolution;Resort;Role;S phase;Single-Stranded DNA;Sister Chromatid;Structure;Synapses;Tail;Therapeutic;Tumor Suppressor Proteins;Work;XRCC1 gene;XRCC4 gene;artemis;biophysical techniques;cancer cell;cancer genome;cancer therapy;chemotherapy;cytotoxic;improved;inhibitor;insight;novel;novel strategies;novel therapeutic intervention;nuclease;patient response;pre-clinical;precision medicine;preservation;presynaptic;protein expression;radiation response;reconstruction;recruit;repaired;response;small molecule inhibitor;structural biology;student training;success;synergism;therapeutic target;tool;tumor Project 2: DSBR: Mechanisms of DNA double strand break repair and pathway selection NARRATIVE - Project 2: DSBR: Mechanisms of DNA double strand break repair and pathway selectionMost cancer patients are treated with DNA double strand break inducing radiation and chemotherapy. Project 2aims to understand how normal and cancer cells detect and repair DNA double strand breaks by integration ofthree major cellular pathways non-homologous end joining homology-directed repair and alternative endjoining leading to novel insights into mechanism and uncovering new approaches for therapeutic targeting. NCI 10695042 8/22/23 0:00 PAR-20-077 5P01CA092584-23 5 P01 CA 92584 23 9/27/01 0:00 8/31/26 0:00 ZCA1-SRB-K 7644 8680060 "LEES-MILLER, SUSAN " Not Applicable 12 Unavailable 78576738 ENBLDJUN4N73 78576738 ENBLDJUN4N73 US 37.868252 -122.258486 577512 UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB BERKELEY CA Other Domestic Non-Profits 947208118 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 470854 422745 48109 SUMMARY - Project 2: DSBR: Mechanisms of DNA double strand break repair and pathway selectionUnderstanding how cells detect and repair DNA double strand breaks (DSBs) is critical to improving patientresponses to radiation therapy and many forms of chemotherapy. The major pathway for repair of DSBs innormal cells is non-homologous end joining (NHEJ) which is active throughout interphase but error prone.However in S and G2 phases the more accurate homology directed repair (HDR) pathway is also active.Moreover cancer cells sometimes use highly error-prone mutagenic alternative-end joining (Alt-EJ) pathwaysfor DSB repair. While we know a significant amount about the proteins involved in each pathway there are wideknowledge gaps in understanding how these pathways intersect and how they are regulated in normal andcancer cells. Project 2 brings together leading investigators with expertise in NHEJ HDR and Alt-EJ to determinehow DNA end resection directs DSB repair pathway choice. In Aim 1 we will determine how NHEJ proteinstether broken DSB ends in synaptic complexes prior to processing to remove damaged end groups and howDNA ligase IV uniquely catalyzes rejoining of DSB ends. We will also determine how the nuclease Artemis andthe end-processing enzyme PNKP interact with synaptic complexes providing the first comprehensive view ofhow NHEJ complexes function at DSBs. In Aim 2 we will explore how Artemis interacts with the MRN complexto regulate the initial stages of resection how the short- and long-range resection machineries are coupled andhow the tumor suppressor BRCA1-BARD1 complex stimulates long range resection by DNA2/BLM. In Aim 3 wewill determine how XRCC1/DNA ligase III interacts with MRN and DNA polymerase to link DNA resectiongap-filling DNA synthesis and ligation during Alt-EJ and how DNA polymerase interacts with the key HDRprotein RAD51. Our studies will yield unprecedented molecular level insights into fundamentally important DNArepair pathways and will also paint a comprehensive picture of how DSB repair pathways act together as anintegrated network to repair radiation and chemotherapy-induced DSBs in cancer cells and non-malignant cells.The information generated by Project 2 will pave the way for novel approaches to better target tumors in theclinic. Indeed small molecule inhibitors of NHEJ protein DNA-PKcs are in clinical trials and inhibitors of ArtemisPNKP MRE11 and DNA ligases are being evaluated in pre-clinical cancer models Moreover novel Pol inhibitors with the potential to selectively target cancer cells that are dependent upon Alt-EJ will be identified inProject 2 by our structure-based approaches. EMB core expertise in protein expression and cutting-edgebiophysical approaches of the SCB core are critical for the success of our project which is fully synergistic withProject 4 on replication fork preservation Project 3 on the role of PARP1 and PARylation in DSB repair andProject 1 on the cellular responses induced by DSB-inducing chemotherapeutics. We will share and exchangeideas results and reagents with all the SBDR investigators contributing to a scientific environment conducivefor advancing mechanism- and structure-based cancer therapies and for the training of students and fellows. +No NIH Category available Address;Adult;Affect;American;Authorization documentation;Blood;Brain Neoplasms;Clinical;Clinical Trials;Collaborations;Collection;Communication;Communication Tools;Communities;Computer software;Constitution;Constitutional;Consumption;Data;Data Collection;Development;Diagnosis;Disease;Education;Eligibility Determination;Enrollment;Epidemiologic Methods;Epidemiology;Evolution;Excision;Funding;Generations;Genomics;Geography;Glioma;Goals;Individual;International;Knowledge;Learning;Medical Records;Methods;Molecular;Molecular Evolution;Movement;Netherlands;Online Systems;Operative Surgical Procedures;Outcome;Paraffin Embedding;Patient Recruitments;Patient advocacy;Patients;Personal Health Records;Persons;Population Heterogeneity;Portraits;Process;Protocols documentation;Rare Diseases;Recurrence;Recurrent disease;Registries;Research;Research Design;Research Personnel;Resources;Saliva;Secure;Societies;Specimen;Survival Rate;Test Result;Testing;Time;United States;Work;advocacy organizations;cloud based;cohort;cost;data communication;data sharing;digital;flexibility;improved;innovation;member;middle age;neural network;novel;participant enrollment;patient engagement;recruit;sample collection;satisfaction;scale up;social media;success;tool;tumor Participant Engagement Unit n/a NCI 10695029 9/11/23 0:00 RFA-CA-19-045 5U2CCA252979-03 5 U2C CA 252979 3 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-O 8529 1934123 "CLAUS, ELIZABETH B." Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 825525 1723246 408228 PROJECT SUMMARY: PARTICIPANT ENGAGEMENT UNIT (PEU)Traditional epidemiological methods used to recruit patients with rare diseases such as LGG who aregeographically widely spread into research cohorts is costly labor-intensive and time-consuming. Thus thereis a need for alternative methods that include 1) engagement with patient stakeholders 2) partnership withpatient organizations and 3) use of web-based collection methods and social media platforms. Using thesetools our group created the International Low Grade Glioma (LGG) Registry the overarching goal of which is toallow for focused study of LGG. In this Patient Engagement Unit and in collaboration with our EngagementOptimization Unit (EOU) we will learn from pilot data drawn from the LGG Registry to refine effective means toengage patients and other stakeholders in the development of messages materials and protocols forrecruitment enrollment and retention in the LGG Registry and use these means to 1) enroll 700 LGG patientswith recurrent disease into the International LGG Registry 2) collect epidemiological clinical and outcomedata as well as constitutional (blood/saliva) and paraffin-embedded tumor specimens for these 700 LGGpatients and 3) communicate overall study and individual level results (including those performed by theGenomic Characterization Unit) to the 700 LGG patients. +No NIH Category available Address;Administrator;Advisory Committees;Advocate;Authorization documentation;Behavioral Sciences;Bioethics;Bioethics Consultants;Bioinformatics;Brain Neoplasms;Caregivers;Caring;Client satisfaction;Clinical Management;Clinical Trials;Colorado;Communication;Communities;Data;Diagnosis;Disease;Doctor of Philosophy;Education;Epidemiology;Evolution;Excision;Facebook;Gays;Genetic;Genomic medicine;Genomics;Glioma;Goals;Grant;Health Personnel;Hospitals;Institutional Review Boards;International;Internet;Knowledge;Leadership;Location;Maintenance;Malignant neoplasm of brain;Medical Records;Medical center;Molecular Evolution;Movement;National Cancer Institute;Occupational activity of managing finances;Office of Administrative Management;Operative Surgical Procedures;Outcome;Patients;Personal Health Records;Persons;Postdoctoral Fellow;Process;Protocols documentation;Recurrence;Registries;Research;Research Assistant;Research Personnel;Resources;Secure;Site;Talents;Telephone;Time;Underserved Population;Universities;Woman;World Health Organization;cloud based;genetic counselor;implementation science;improved;innovation;interest;meetings;member;neurosurgery;organizational structure;patient engagement;repository;social media;software development;success;web site;young adult Administrative Core n/a NCI 10695028 9/11/23 0:00 RFA-CA-19-045 5U2CCA252979-03 5 U2C CA 252979 3 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-O 8528 1934123 "CLAUS, ELIZABETH B." Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 148929 162382 109608 PROJECT SUMMARYLower grade (World Health Organization (WHO) grade II/III) glioma (LGG) a malignant tumor of the brain is auniformly fatal disease of young adults. The optimal clinical management for LGG remains unknown. Acomprehensive genomic characterization of the evolution from primary LGG to recurrence is requiredto begin to address the LGG knowledge gap; optimizing the engagement of LGG patients in this effortis critical to the success of this process. Using our International Low Grade Glioma Registry as a startingpoint we will construct a community of 700 LGG patients who have undergone surgical resection at time ofdiagnosis and at time of recurrence and want to participate in research. We will use both hospital-based aswell as web- and social media-based patient engagement efforts and adapt pre-existing resources developedat Yale including HUGO PHR a secure cloud-based personal health record platform that allows secure andpermission-based movement of data bi-directionally between patients and researchers and ARCHETYP aYale-developed software that assists patients in the location of clinical trials. We hypothesize that LGGpatient engagement and satisfaction (and thus overall participation) in genomic characterizationstudies will be improved by 1) the ability to obtain and share medical record data with researchers 2)the availability of bi-directional communication between study and patients regarding study focusprogress outcomes as well as patient specific results 3) improved messaging and educationregarding study and patient goals with respect to genomic characterization of patient materials. Wealso propose that the knowledge gained in this application will provide a significant improvement inthe care of LGG patients. +No NIH Category available Address;Adopted;Affect;Age;Aneuploidy;Authorization documentation;Automobile Driving;Brain Neoplasms;CDKN2A gene;Cancer Etiology;Caring;Cells;Characteristics;Client satisfaction;Clinical;Clinical Management;Clinical Trials;Collaborations;Communication;Communities;Data;Diagnosis;Disease;Education;Enrollment;Ethics;European ancestry;Evolution;Excision;Genetic;Genome;Genomics;Glioma;Goals;Hospitals;Individual;International;Internet;Knowledge;Location;Longitudinal cohort;Malignant neoplasm of brain;Measures;Medical Records;Methods;Modeling;Molecular Evolution;Movement;Mutation;Operative Surgical Procedures;Outcome;Participant;Pathology Report;Patient-Focused Outcomes;Patients;Personal Health Records;Persons;Population;Process;Protocols documentation;Qualifying;Questionnaires;Radiation Tolerance;Radiation therapy;Recurrence;Registries;Reporting;Research;Research Personnel;Research Priority;Resistance;Resources;Sampling;Secure;Socioeconomic Status;Software Tools;Technology;Testing;The Cancer Genome Atlas;Time;Translating;Trust;World Health Organization;cloud based;cohort;data reduction;data sharing;design;dynamical evolution;effective therapy;follow-up;handheld mobile device;health data;improved;improved outcome;innovation;iterative design;longitudinal analysis;method development;optimal treatments;outreach;patient engagement;patient privacy;recruit;response;rural setting;social;social media;software development;success;temozolomide;theories;treatment response;tumor;willingness;young adult OPTimIzing engageMent in discovery of molecular evolution of low grade glioma (OPTIMUM) PROJECT NARRATIVE: OVERALLLower grade (World Health Organization (WHO) grade II/III) glioma (LGG) a malignant tumor of the brain is auniformly fatal disease of young adults for which the optimal clinical management remains unknown. Acomprehensive genomic characterization of the evolution from primary LGG to recurrence is required to beginto address the LGG knowledge gap. As optimizing the engagement of LGG patients in this effort is critical tothe success of this process we will use our International Low Grade Glioma Registry as a starting point todevelopment methods to engage and construct a community of 700 LGG patients who have undergonesurgical resection at time of diagnosis and at time of recurrence and want to participate in research. NCI 10695027 9/11/23 0:00 RFA-CA-19-045 5U2CCA252979-03 5 U2C CA 252979 3 "FILIPSKI, KELLY" 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-O(M1) 1934123 "CLAUS, ELIZABETH B." "KWAN, BETHANY MATTHEWS; VERHAAK, ROEL GW" 3 PUBLIC HEALTH & PREV MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 1447257 NCI 2401137 865804 PROJECT SUMMARYLower grade (World Health Organization (WHO) grade II/III) glioma (LGG) a malignant tumor of the brain is auniformly fatal disease of young adults. The optimal clinical management for LGG remains unknown. Acomprehensive genomic characterization of the evolution from primary LGG to recurrence is requiredto begin to address the LGG knowledge gap; optimizing the engagement of LGG patients in this effortis critical to the success of this process. Using our International Low Grade Glioma Registry as a startingpoint we will construct a community of 700 LGG patients who have undergone surgical resection at time ofdiagnosis and at time of recurrence and want to participate in research. We will use both hospital-based aswell as web- and social media-based patient engagement efforts and adapt pre-existing resources developedat Yale including HUGO PHR a secure cloud-based personal health record platform that allows secure andpermission-based movement of data bi-directionally between patients and researchers and ARCHETYP aYale-developed software that assists patients in the location of clinical trials. We hypothesize that LGGpatient engagement and satisfaction (and thus overall participation) in genomic characterizationstudies will be improved by 1) the ability to obtain and share medical record data with researchers 2)the availability of bi-directional communication between study and patients regarding study focusprogress outcomes as well as patient specific results 3) improved messaging and educationregarding study and patient goals with respect to genomic characterization of patient materials. Wealso propose that the knowledge gained in this application will provide a significant improvement inthe care of LGG patients. 1447257 +No NIH Category available Address;Adoption;Adult;African American;Alabama;American;Biochemical;Cancer Biology;Cancer Prognosis;Caregivers;Communication;Communities;Comprehension;Data Analyses;Diagnosis;Diffusion of Innovation;Disadvantaged;Disparity;Education;Educational Status;Educational workshop;Ethnic Population;Focus Groups;Funding;Genes;Genetic;Genomic medicine;Genomics;Geographic Locations;Goals;Group Interviews;Health Benefit;Health Sciences;Impairment;Incidence;Investments;Knowledge;Literature;Louisiana;Low Income Population;Low Literacy Population;Low income;Malignant neoplasm of prostate;Maryland;Mentors;Methods;Microarray Analysis;Minority;Mission;Mississippi;National Comprehensive Cancer Network;National Human Genome Research Institute;Neoplasm Metastasis;North Carolina;Nurses;Participant;Patient Care;Patients;Prognosis;Prostate Cancer therapy;Prostatectomy;Public Health;Race;Radiation;Recommendation;Recurrence;Research;Risk;Rural;Rural Population;South Carolina;Structure;Technology;Time;Tissues;Training;Treatment outcome;United States;United States National Institutes of Health;Virginia;cancer education;cancer health disparity;community engaged research;design;directed attention;efficacy evaluation;evidence based guidelines;genetic technology;genetic testing;genome sciences;health disparity;health literacy;improved;innovation;literacy;low health literacy;low socioeconomic status;mRNA Expression;mathematical ability;men;mortality;next generation sequencing;novel;novel strategies;oncotype;prognostic;prognostic value;programs;randomized controlled study;skills;theories;treatment planning Genetic Literacy and Patient-Caregiver Communication of Prognostic Genetic Technology for Localized Prostate Cancer Project NarrativeWith this greater certainty regarding prognosis men with localized prostate cancer are now equipped with tomake better treatment planning decisions. This project is designed to investigate the understanding ofprognostic genetic technology and patient-caregiver communication in African American and rural White menwith localized prostate cancer. NCI 10695019 8/31/23 0:00 PAR-18-365 5K01CA230193-04 5 K01 CA 230193 4 "VAHEDI, SHAHROOZ" 9/1/22 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 11049144 "COBRAN, EWAN KEMAR" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 168264 NCI 155800 12464 Project Summary/AbstractNovel genomic technology such as microarray analyses and next-generation sequencing have improved theunderstanding of prostate cancer biology and prognosis. The National Comprehensive Cancer Network(NCCN) in 2016 recommended that patients and clinicians consider tissue-based genetic tests for localizedprostate cancer. However while much enthusiasm currently exits for the rapidly increasing field of genomicmedicine the use of multi-gene mRNA expression panels raises the potential for further divergence in prostatecancer treatment outcomes by race and low socioeconomic status. We know that health disparities persist inlow income groups despite the existence of evidence-based guidelines and that adoption of state-of-the-artmethods often lag behind in these groups.The goals of this NCI K01 application are to (1) explore how men with localized prostate cancer and theircaregivers comprehend prognostic genetic technology and (2) examine how an educational video aboutgenetics impacts patient-caregiver communication of prognostic genetic technology. The study rationale is thatwithout direct attention to genomic comprehension the enthusiasm that exists in the rapidly increasing field ofprostate cancer genomic medicine may not translate into health benefits for men with localized prostatecancer. The central hypotheses are (1) men and caregivers with lower levels of education will demonstrate asevere lack of genomic comprehension of tissue-based genetic tests for localized prostate cancer; and (2)tailored prostate cancer education communication coaching and a genomic literacy educational video willsignificantly improve patient-caregiver communication in a low literacy population.The study approach is innovative because it applies a mixed-methods community-engagement researchframework to explore how African American and rural White men with localized prostate cancercomprehend and interpret data generated from genetic technology. The proposed research is significantbecause of its potential to improve public health by (1) improving the understanding of prognostic genetics inminority low income and rural populations and (2) engage and educate these diverse communities aboutgenomics. The proposed research in combination with a structured mentoring and training plan that includesdidactic course and workshops is designed to facilitate Dr. Ewan Cobrans long term goal of developing anindependently-funded research program in prostate cancer disparities consistent with the mission of theNCI. 168264 +No NIH Category available Address;Aftercare;Cancer Etiology;Cell Cycle Arrest;Cell Death;Cell Line;Cessation of life;Clinical;Clinical Trials;Combined Modality Therapy;DNA Sequence Alteration;Data;Dependence;Development;Disease;Drug Combinations;Drug Kinetics;Drug Targeting;Drug resistance;Esophagus;Exhibits;Exposure to;FRAP1 gene;Failure;Gene Mutation;Genes;Genomics;Growth;Head and Neck Squamous Cell Carcinoma;In Vitro;Incidence;Individual;Link;Lung;Malignant Neoplasms;Mediating;Molecular;Mutate;Mutation;NOTCH1 gene;PI3K/AKT;PIK3CA gene;PIK3CG gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phosphatidylinositols;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Recurrence;Regulation;Reporting;Research;Resistance;Signal Pathway;Signal Transduction;Skin;Squamous cell carcinoma;Survival Rate;Testing;The Cancer Genome Atlas;Therapeutic;Tumor Suppressor Proteins;Work;aurora B kinase;biomarker driven;cancer type;care outcomes;clinical care;clinically relevant;drug-sensitive;efficacy evaluation;experience;genomic data;improved;in vivo;inhibitor;insight;loss of function mutation;mTOR Inhibitor;molecular targeted therapies;mutant;neoplastic cell;new therapeutic target;personalized medicine;phosphoinositide-dependent kinase 1;potential biomarker;pre-clinical;preclinical study;prevent;prospective;response;synergism;targeted treatment;tumor Targeting Alterations of the NOTCH1 Pathway in Head & Neck Squamous Cell Carcinoma (HNSCC) PROJECT NARRATIVEThe identification of gene mutations in head and neck squamous cell carcinoma (HNSCC) has not resulted inany changes in clinical care or patient outcomes and the overall survival rate for this cancer has beenrelatively static for the past three decades. To address this problem we showed that HNSCC cell linesharboring mutations in a gene called NOTCH1 die when exposed to inhibitors of a cellular survival pathwaycalled PI3K/mTOR. In the proposed study we will: (1) conduct a clinical trial of NOTCH1-mutant HNSCCtreated with an inhibitor of PI3K/mTOR (2) determine the molecular mechanism that underlies tumor cell deathfollowing inhibition of PI3K/mTOR and (3) identify combinations of drugs that maximize killing and preventresistance in NOTCH1-mutant HNSCC. NCI 10694991 7/27/23 0:00 PAR-18-560 5R01CA235620-05 5 R01 CA 235620 5 "UNDALE, ANITA H" 9/18/19 0:00 8/31/24 0:00 Clinical Oncology Study Section[CONC] 1918982 "JOHNSON, FAYE " "FREDERICK, MITCHELL J" 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 637606 NCI 477657 159949 PROJECT SUMMARYHead and neck squamous cell carcinoma (HNSCC) is the seventh leading cause of cancer-related deathsworldwide and thus far the genomic alterations identified in this disease have not had an impact on clinicalcare. Our group was among the first to report frequent inactivating mutations of NOTCH1 in HNSCC. Morerecently the incidence of NOTCH1 mutations was found to be roughly 20% among over 500 patient HNSCCtumors sequenced as part of The Cancer Genome Atlas (TCGA) project placing NOTCH1 among the top fivemost frequently mutated genes in this cancer type. HNSCC cell lines harboring NOTCH1 mutations aresignificantly more sensitive to six different drugs targeting the PI3K/mTOR pathway than HNSCC cell lines withwild-type (wt) NOTCH1. Unlike HNSCC tumors with PIK3CA mutations which exhibited only growth arrestafter treatment with PI3K/mTOR inhibitors cell lines harboring NOTCH1 mutation also underwent cell death.Proteomic profiling of drug-sensitive HNSCC cell lines harboring NOTCH1 mutations and drug-resistantHNSCC lines with wt NOTCH1 before and after drug treatment revealed no differences in the modulation ofmany drug targets directly downstream of PI3K including AKT. However NOTCH1 mutants experiencedgreater drug-induced decreases in total expression of 3-phosphoinositide dependent kinase 1 (PDK1) andAurora kinase B. Collectively these data led to the hypothesis that HNSCC tumors with NOTCH1 mutationsare highly sensitive to PI3K inhibitors because the PI3K signaling pathway is uniquely tied to regulation of totalPDK1 protein levels impacting both phosphatidylinositol-dependent and -independent PDK1 function in thisgenomic subtype. Therefore drugs targeting PI3K/mTOR should be effective for treating HNSCC patients withNOTCH1-mutant tumors. We will address these hypotheses with a clinical trial (Aim 1) and conduct in vitromechanistic studies (Aim 2) and preclinical studies to identify ways to enhance killing of HNSCC tumorsharboring NOTCH1 mutations through combination therapy (Aim 3). The proposed research will have apositive impact because it will be the first to establish a therapeutic vulnerability of NOTCH1-mutant HNSCC toany class of drugs and may inform the development of the first biomarker-driven targeted therapy for HNSCC.Additionally we may define a previously unknown mechanism of PDK1 regulation and identify clinicallyrelevant targets that enhance the efficacy and durability of PI3K inhibition in NOTCH1-mutant HNSCC.Because NOTCH1 loss-of-function mutations are common in other squamous cell carcinomas including thoseof the skin esophagus and lung these findings will likely have implications beyond HNSCC. 637606 +No NIH Category available Adult;Alanine Transaminase;Alternative Splicing;Antineoplastic Agents;Astrocytoma;Automobile Driving;Binding;Binding Proteins;Bioinformatics;Biological Assay;Biology;Biophysics;Breast;Cancer Biology;Cell Line;Cell Proliferation;Cells;Cellular Stress;Chemistry;Childhood Glioma;Complex;Coupled;DNA Damage;Data;Disease;Dominant-Negative Mutation;Engineering;Event;Excision;Exons;Future;Generations;Genes;Genetically Engineered Mouse;Genome;Genotoxic Stress;Glioma;Goals;High-Throughput Nucleotide Sequencing;Human;In Vitro;Knowledge;Length;Lung;Lymphoma;MDM2 gene;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Mechanics;Mediating;Methodology;Methods;MicroRNAs;Modality;Modeling;Molecular;Mus;Mutation;Nuclear;Nuclear Protein;Nuclear RNA;Oligonucleotides;Oncogenic;Outcome;Ovary;Pathway interactions;Pharmacologic Substance;Phenotype;Play;Positioning Attribute;Primary Neoplasm;Property;Protein Isoforms;Proteins;Publishing;RNA;RNA Biochemistry;RNA Processing;RNA Sequences;RNA Splicing;RNA metabolism;RNA-Binding Proteins;Regulation;Regulatory Element;Repression;Research;Rhabdomyosarcoma;Role;Sampling;Stress;System;TP53 gene;Technology;Testing;Therapeutic;Therapeutic Intervention;Tumor Suppressor Proteins;Variant;Viral;Work;Xenograft procedure;cancer therapy;cancer type;cell growth;cell type;chemotherapeutic agent;combinatorial;design;drug discovery;exon skipping;genotoxicity;industry partner;liposarcoma;mRNA Precursor;mouse model;novel;novel therapeutic intervention;overexpression;prevent;response;therapy design;tumor;tumor progression;tumorigenesis;tumorigenic Mdm2 Alternative Splicing in DNA Damage and Cancer NARRATIVEMDM2 and its numerous isoforms are key regulators of the expression and function of the p53 gene a criticaltumor suppressor that prevents inappropriate cell growth and proliferation. The proposed research will study themolecular connection between DNA damage MDM2 isoform switching p53 and cancer. Unraveling thispathway could lead to the discovery of novel therapeutic intervention points and thus be a crucial stepping-stonefor cancer drug discovery. NCI 10694981 8/21/23 0:00 PA-20-185 5R01CA262873-03 5 R01 CA 262873 3 "MAAS, STEFAN" 9/1/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7767900 "CHANDLER, DAWN S" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 390286 NCI 268398 121888 ABSTRACTTumor suppressor p53 is the quintessential guardian of the genome whose function is inhibited in greater than50% of all human cancers. Though mutation and deletion of p53 are major contributors to p53 inactivationoverexpression of the negative regulators MDM2 and MDM4 (MDMX) are also known to inactivate p53 thusleading to the cancer phenotype. Our lab has shown that specific types of cell stress initiate the generation ofan alternatively spliced isoform of MDM2. The predominant MDM2 alternative isoform MDM2-ALT1 alsoknown as MDM2-B functions to primarily activate the p53 pathway by inhibiting MDM2 and MDM4 in adominant negative fashion. Paradoxically this isoform is upregulated in several human cancers such aspediatric high-grade gliomas astrocytomas rhabdomyosarcomas (RMS) and liposarcomas as well as adultcancers such as lymphomas and those of the breast. Thus MDM2-ALT1 plays opposing roles in cancerprogression dependent upon the context of its expression. In the proposed research we will study theunderpinnings of the control of the p53 pathway by MDM2-ALT1 to better understand 1) the specificmechanism by which that MDM2-ALT1 is generated in cancer and 2) the ability of the resultant isoforms to betargeted using splice-switching oligonucleotides. We hypothesize that the expression of oncogenic MDM2-ALT1 is modulated by alterations in protein and RNA nuclear factors during the progression to tumorigenesisand can be targeted to induce splicing changes. We will use assays that identify and measure splice regulationin conjunction with gene editing approaches to identify RNA sequences and their respective nuclear factor-binding partners necessary for regulation of MDM2 splicing. Furthermore we will use novel geneticallyengineered mouse models as well as established mouse xenograft assays and novel splice switchingoligonucleotides (SSOs) to modulate MDM2 isoform levels. Our work will broaden our knowledge ofcombinatorial regulation of RNA processing in response to stress and in cancer and interrogate the utility ofMDM2 isoforms modulation for rational control of the p53 pathway. 390286 +No NIH Category available Adherence;Adult;Age;Ambulatory Care;Cancer Patient;Caregivers;Caring;Child;Clinic;Clinic Visits;Clinical;Communication;Disease;Effectiveness;Electronic Health Record;Family;Fatigue;Feedback;Goals;Health;Healthcare;Individual;Influentials;Information Management;Information Technology;Institution;Intervention;Learning;Logistic Regressions;Longevity;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical Records;Modeling;Monitor;Notification;Outcome;Pamphlets;Parents;Patient Outcomes Assessments;Patient-Centered Care;Patients;Pediatric Oncology;Pediatric Oncology Group;Physicians;Pilot Projects;Positioning Attribute;Process;Provider;Quality of life;Randomized Controlled Trials;Reporting;Role;Schedule;Self Efficacy;Self Management;Severity of illness;Survivors;Symptoms;System;Time;Visit;Waiting Lists;burden of illness;cancer care;cancer therapy;care outcomes;clinical care;design;effectiveness evaluation;electronic health record system;experience;feasibility testing;handbook;health literacy;health related quality of life;improved;improved outcome;interest;medical specialist;patient engagement;patient oriented;patient portal;preference;programs;prototype;psychosocial;random forest;response;side effect;skills;survivorship;symptom management;treatment as usual;treatment planning;usability Using Information Technology to Improve Outcomes for Children Living with Cancer Project NarrativeThis study will evaluate the effectiveness of the Symptom Monitoring & Systematic Assessment and ReportingSystem in Young Survivors program (SyMon-SAYS) for children with cancer in decreasing patients symptomburden decreasing parent-perceived barriers in managing their childs symptoms increasing patients andparents self-efficacy and increasing patients quality of life. We will also examine influential variables impactingthe effectiveness of the SyMon-SAYS program. NCI 10694976 12/7/23 0:00 RFA-CA-19-033 5U01CA246612-05 5 U01 CA 246612 5 "MOLLICA, MICHELLE A" 9/20/19 0:00 12/31/24 0:00 ZCA1-RTRB-E(A1) 6136211 "LAI, JIN-SHEI " Not Applicable 5 PUBLIC HEALTH & PREV MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 1/1/24 0:00 12/31/24 0:00 393 Non-SBIR/STTR 2024 301745 NCI 411975 211552 This application plans to develop a program Symptom Monitoring & Systematic Assessment andReporting System in Young Survivors (SyMon-SAYS) to enable timely mitigation and management ofunrelieved symptoms for children with cancer. The SyMon-SAYS will administer score interpret and displaythe results of symptom assessments in real-time between clinic visits in cancer care ambulatory settingswhen patients are likely to be more symptomatic. We hypothesize that this system can facilitate promptidentification of problematic symptoms; consequently with the availability of graphical symptom reports overtime timely providers clinical care and an informative symptom management booklet patients will becomeinformed about their condition and take an active role in treatment which will further improve self-managementskills. Better self-management promotes adherence to treatment plans builds individual capacity improvesinteraction between patients and caregivers reduces the use of medical specialists and optimizes clinicaloutcomes across the lifespan throughout the treatment and disease continua. The proposed waitlist controlrandomized trial is based on our preliminary study testing the feasibility of the patient-centered SyMon-SAYS ina pediatric oncology clinic. Results showed that the SyMon-SAYS was acceptable to patients/parents and theywere willing to use it during their routine clinical care. Clinicians expressed interest in receiving reports yetpreferred to review them in the medical record. Based on what we learned from this pilot we now propose tointegrate the SyMon-SAYS system into the electronic health record (EHR) to streamline the alert notificationwith clinician workflow by using EHR (Epic) messaging and to include a broader range of symptoms. Patientsand parents will complete the weekly symptom assessment and review the symptom report by logging into theEpic MyChart patient portal. Instead of using a standalone SyMon-SAYS app we will align the SyMon-SAYSprogram with the Epic EHR. We plan to conduct a single institution modified waitlist control randomized trial of200 children (ages 8-17) with cancer over 16 weeks (Group A: 16-week SyMon-SAYS intervention; Group B:8-week usual care and then 8-week SyMon-SAYS intervention) to achieve the following specific aims: 1)evaluate effectiveness of SyMon-SAYS at week-8 and its maintenance effects at week-16. We hypothesizethat Group A (versus Group B) will report decreased parent-perceived barriers to managing their childrenssymptoms decreased patient symptom burden increased patient and parent self-efficacy and ultimatelyincreased patient HRQOL at week-8 and no significant differences between Groups A & B at week-16; 2)evaluate influential factors to Aim 1 including contextual patient and parent factors adherence to the SyMon-SAYS intervention and symptom communication; and 3) evaluate predictors of adherence to the SyMon-SAYSintervention and preference of SyMon-SAYS versus usual care. 301745 +No NIH Category available Address;Area;Biological Markers;Cancer Center;Cancer Center Support Grant;Cancer Science;Caring;Cities;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Health;Community Outreach;Consultations;Cultural Diversity;Development;Diagnosis;Education;Education and Outreach;Educational Materials;Engineering;Ensure;Face;Focus Groups;Foundations;Galanin;Genetic;Genetic Transcription;Genomics;Goals;Growth;Health Educators;Health Services Accessibility;Health Services Research;Home;Immunotherapy;Incidence;Interview;Language;Limited English Proficiency;Linguistics;Link;Literature;Malignant Neoplasms;Medical;Memorial Sloan-Kettering Cancer Center;Methodology;Modeling;Modernization;Multilingualism;Neighborhoods;Outcome;Outreach Research;Patients;Policies;Population Heterogeneity;Qualitative Research;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Risk;Risk Reduction;Schools;Services;Students;Surveys;Testing;Training;Translational Research;Translations;Work;anticancer research;bilingualism;cancer education;cancer health disparity;community engagement;community partnership;design;education research;genetic testing;improved;individualized prevention;informant;marginalization;member;outreach;personalized immunotherapy;personalized screening;precision medicine;programs;research study;screening;service delivery;shared decision making;skills;tool;translational cancer research Core 1: Linguistic and Cultural Responsiveness Shared Resource Core (LCRSR) n/a NCI 10694973 8/25/23 0:00 PAR-18-767 5U54CA137788-15 5 U54 CA 137788 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 7625 1988063 "GANY, FRANCESCA M" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 173368 96530 76838 Linguistic and Cultural Responsiveness Shared Resource CoreThe Linguistic and Cultural Responsiveness Shared Resource Core (LCRSR) builds upon the U54 foundationthat was developed to reach large at-risk communities who face linguistic and cultural barriers to cancereducation services and research participation. The LCRSR responds to the tremendous need for linguisticand cultural inclusiveness to reduce cancer disparities and to capitalize on the great strengths expertise andtools of the U54 partners in this area. Cancer disparities are fueled in part by barriers to cancer informationrisk reduction screening and care access and by the insufficient participation of diverse populations in cancerresearch. The goal of the LCRSR is to provide linguistically and culturally responsive support to the U54Partnership Cores (Developmental/Research Research Education Partnership Community Outreach-Research-Education (PCORE)) and build the capacity of U54-connected researchers and communitymembers to reduce cancer disparities by conducting community-engaged culturally and linguistically inclusivetranslational research outreach education and navigation. This crucial work leverages the strengths of theCCNY Department of Classical and Modern Languages and Literatures the CCNY Grove School ofEngineering and the MSK Language Initiatives Program to support the U54. The specific aims of the LCRSRare: 1) to provide research consultation support and training in the selection and/or design of specificlinguistically and culturally responsive quantitative survey tools research study materials educationalmaterials and practices for the U54 Developmental PCORE and Research Education cores; 2) to assistCCNY MSKCC and community U54 investigators in the design implementation and analysis of qualitativeresearch with diverse populations: to assist in the translation and transcreation of focus group and keyinformant and in-depth interview guides; to provide multilingual facilitation of focus groups and key informantand in-depth interviews; and to facilitate multilingual transcription and translation services for qualitativestudies; 3) to access the CCNY Grove School of Engineering expertise to enable U54-linked studies andprograms to utilize remote simultaneous medical interpreting (UN-style interpreting) to enable seamlesscommunication between limited English-proficient community members researchers and PCORE includingthose activities with a focus on precision medicine/precision prevention; and 4) to support the developmentand implementation of the CCNY Certificate in Medical Translation and Interpretation program to give bilingualCCNY students the skills to provide translation and interpretation services for cancer outreach educationservice delivery and research and to build the LCRSR Core capacity in those areas. The LCRSR will improvethe way that translational cancer research activities and services reflect the rich linguistic and cultural diversityof our surrounding communities our city and ultimately through model dissemination the nation. +No NIH Category available Address;American Cancer Society;Area;Behavior;Black race;Cancer Center Support Grant;Cardiovascular Diseases;Chinese;Chronic Disease;Clinical;Collaborations;Communities;Community Health;Community Health Education;Community Outreach;Diagnosis;Diet;Disparity;Doctor of Philosophy;Early Diagnosis;Education;Education and Outreach;Educational Activities;Face;Faculty;Funding;Health;Health Services Accessibility;Home;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Immigrant;Immigrant community;Incidence;Infrastructure;Latino;Lead;Life Style;Limited English Proficiency;Linguistics;Malignant Neoplasms;Medical;Memorial Sloan-Kettering Cancer Center;Methodology;Mexican;Minority;Modeling;Needs Assessment;New York City;Obesity;Occupational Groups;Occupations;Outcome;Outreach Research;Patients;Persons;Physical activity;Play;Policies;Population;Population Heterogeneity;Poverty;Prevention;Primary Prevention;Provider;Quality of Care;Recommendation;Research;Research Activity;Research Personnel;Resource Sharing;Risk;Risk Factors;Role;Screening for Prostate Cancer;Secondary Prevention;Services;Social Medicine;South Asian;Students;System;Tobacco;Translational Research;Translations;Underrepresented Minority;Work;anticancer research;cancer health disparity;cancer prevention;cancer risk;clinical trial enrollment;colorectal cancer screening;community engaged research;community engagement;community partnership;disparity reduction;economic determinant;education research;evidence base;health care availability;health determinants;health disparity;high school;improved;improved outcome;individualized prevention;medical schools;medically underserved;member;outcome disparities;outreach;personalized immunotherapy;physical conditioning;precision medicine;precision oncology;professor;program dissemination;programs;recruit;screening;socioeconomics;stem;underserved community;working group PCORE (Partnership Community Outreach Research and Education Core) n/a NCI 10694972 8/25/23 0:00 PAR-18-767 5U54CA137788-15 5 U54 CA 137788 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 7624 9573353 "LENG, JENNIFER CF" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 300343 167229 133114 One in three U.S. residents over 100 million people are minorities. Over 39 million are foreign-born. New YorkCity (NYC) is home to 3 million foreign-born. Among foreign-born New Yorkers 48.8% are limited Englishproficient (LEP) 27.8% did not graduate from high school and 19.8% are living in poverty. This large anddiverse population faces significant disparities in cancer incidence diagnosis treatment and outcomes. Thesedisparities are fueled by health information and systems access barriers and by an inadequate evidence-basewhich stems from insufficient representation in research and program implementation. These factors limit thebi-directional translation of discoveries between bench patient community and policy levels. Over the past 10years the PCORE (Partnership Community Outreach-Research-Education) Core has implemented trailblazingcommunity-engaged outreach and research and addressed socioeconomic determinants of health and gaps incancer outcomes and quality of care for large underserved communities including the CCNY community theHarlem community in which CCNY is embedded and the broader NYC community. Through partnerships andmodel program dissemination PCORE has also extended its activities across the U.S. and is a vital memberof several NCI and American Cancer Society Committees addressing the inclusion of diverse populations inresearch. Over the next 5 years PCORE will further grow the robust community-academic U54 partnershipand infrastructure for community-engaged outreach and translational research. PCORE has the following twoSpecific Aims: AIM 1. To build upon and strengthen PCORE's community-academic partnership assets tofurther develop implement systematically disseminate and sustain effective community-engaged cancerdisparities reduction outreach community and provider education service policy and research activities toaddress socioeconomic determinants (centering on health care access) of cancer outcomes and decreasedisparities in five priority areas (determined by community-engaged needs assessments and guided by the NCIBlue Ribbon Panel): a) Clinical trials enrollment including in precision medicine/precision prevention andimmunotherapy activities; b) Colorectal cancer screening and treatment access and completion; c) HPVprevention and screening for HPV-associated cancers; d) Prostate cancer screening treatment access andcompletion; and e) Cancer risk factors including tobacco obesity diet physical activity and occupation. AIM 2.To build the capacity of researchers and community members to engage the community in the conduct oftranslational research to reduce cancer disparities working in concert with the Linguistic and CulturalResponsiveness Shared Resource Core: a) To facilitate community engagement to further enhance andsustain community capacity building utilizing the extensive network developed by PCORE; b) To support theU54 Partnership Cores working groups and projects and to collaborate with the MSK P30 CCSG to engagelimited English proficient (LEP) and other diverse populations in their programs and studies. +No NIH Category available Academic advising;Area;Awareness;Basic Science;Behavioral;Behavioral Research;Biomedical Engineering;Biomedical Research;Cancer Biology;Career Choice;Clinical;Communities;Community Outreach;Data Analyses;Doctor of Philosophy;Education;Education and Outreach;Educational Curriculum;Educational workshop;Engineering;Enrollment;Ensure;Evaluation;Face;Faculty;Family;First Generation College Students;Funding;Future;Goals;Immersion;Immigrant family;Institution;Laboratories;Learning;Malignant Neoplasms;Manuscripts;Measures;Memorial Sloan-Kettering Cancer Center;Mentors;Mentorship;Monitor;Nanotechnology;Performance;Postdoctoral Fellow;Preparation;Procedures;Process;Research;Research Design;Research Personnel;Research Training;Resources;Series;Services;Socialization;Students;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underrepresented Minority;United States National Institutes of Health;Writing;anticancer research;cancer health disparity;career;career development;community partnership;design;education research;experience;graduate student;hands on research;improved;innovation;member;minority communities;prevent;programs;recruit;skills;socioeconomic disadvantage;student mentoring;student participation;success;training opportunity;translational cancer research;undergraduate research;undergraduate student;underrepresented minority student Research Education Core n/a NCI 10694970 8/25/23 0:00 PAR-18-767 5U54CA137788-15 5 U54 CA 137788 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 7623 1885130 "HRICAK, HEDVIG " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 70315 39151 31164 Research Education CoreSince the inception of the NIH-funded CCNY-MSK U54 in 2008 we have developed and implementedapproaches to engage and mentor students and early stage investigators in cancer research. We haveprovided undergraduate and graduate students with hands-on research experiences developed cancer-relatedcurricula and have provided professional socialization and mentorship for students appropriate to theiracademic level and career interests. Also we have monitored the progress of our early stage investigators andprovided individualized resources to ensure their success. To expand our transdisciplinary research focus wehave hired several faculty members for the Partnership that have been integrated into our training efforts. Inthis competitive renewal we plan to recruit additional faculty who will enhance our translational focus inresearch and training and will broaden opportunities for our students. The majority of students at CCNYespecially those from underrepresented minority communities come from socioeconomically disadvantagedfamilies. Many of our students are also first generation college students and/or from immigrant families. Ourprogram is designed to provide opportunities for them to successfully conduct biomedical and behavioralresearch at CCNY and MSK and to provide mentorship and guidance towards career decisions. Our overallgoals are to: 1) Increase the number of competitively trained underrepresented minority students whoenroll in MD PhD or MD/PhD programs and specifically 2) Increase the numbers of these studentswho pursue cancer-related research careers and 3) Increase the research competitiveness of U54early stage investigators (ESI) (postdoctoral scholars and junior faculty). We will accomplish these goals by:a) Providing experiential activities and opportunities support services and Partnership activities to improve andincrease students' engagement and performance in cancer research related areas and professions; b)Providing academic counseling advisement and mentoring to students to ensure that they are aware of theopportunities and prerequisites for careers in cancer research; c) Providing translational research experiences(basic sciences; engineering; behavioral; clinical; and community-based) for each student prior to graduation;d) Providing resources for the career development of early stage investigators as well as closely monitoringtheir progress; e) Implementing an evaluation plan to measure the results of all program activities and theutilization of all resources; g) Developing and submitting proposals with the goal of providing sustainability ofour educational and training initiatives such as through R25 and IRACDA mechanisms. +No NIH Category available Advisory Committees;Collaborations;Community Outreach;Data;Decision Making;Development;Education;Education and Outreach;Ensure;Evaluation;Faculty;Funding;Goals;Grant;Institution;Linguistics;Memorial Sloan-Kettering Cancer Center;Mission;Monitor;Pilot Projects;Publications;Reach Effectiveness Adoption Implementation and Maintenance;Research Personnel;Research Proposals;Resource Sharing;Strategic Planning;Students;anticancer research;outreach;programs Planning and Evaluation Core n/a NCI 10694969 8/25/23 0:00 PAR-18-767 5U54CA137788-15 5 U54 CA 137788 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 7622 8906241 "AHLES, TIM ALAN" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 583479 324877 258602 Planning and Evaluation CoreThe Planning and Evaluation Core is composed of the Partnership's Internal Advisory Committee ProgramSteering Committee Executive Committee and external evaluators to provide oversight of the overallPartnership activities and programs. It will be responsible for all aspects of planning monitoring evaluationand tracking of Partnership activities. In addition this core serves as a platform from which the Partnership'sPIs can discuss strategic plans that can move the U54 Partnership towards new initiatives that strengthen thegoals and mission of both institutions. The specific goals and objectives are: 1) The Partnership PIs (Drs.Ahles Gany Hubbard and Barabino) will collaborate with the Internal Advisory Committee and the ProgramSteering Committee to ensure ongoing planning monitoring evaluation and tracking of Partnership activitiesincluding: a. Coordination and management of the solicitation of new research proposals; b. Review andselection of full and pilot projects for funding monitoring of project progress and decision making regardingdiscontinuation of funding for projects not meeting goals; c. Development of new initiatives based onopportunities presented on a national level (e.g. Blue Ribbon priorities RFAs and PARs issued) or at eitherinstitution; and d. Identification of faculty searches that are potentially synergistic with Partnership goals. 2)The Partnership PIs will monitor and evaluate all aspects of Partnership functioning in collaboration with theexternal evaluator Dr. Bosch: a. track pertinent data that monitors and assesses the Partnership's goals andobjectives such as publications and grant submissions by investigators student tracking data and communityoutreach assessments; b. monitor and evaluate all aspects of the proposed educational programs; c. utilizethe RE-AIM framework to monitor and evaluate all aspects of the proposed outreach(PCORE) activities; and d.ensure that the Linguistic and Cultural Responsiveness Shared Resource Core meets target metrics. +No NIH Category available Awareness;Community Health Education;Community Outreach;Development;Diamond;Education and Outreach;Educational process of instructing;Ensure;Faculty;Funding;Goals;Institution;Laboratory Research;Language;Linguistics;Manuals;Memorial Sloan-Kettering Cancer Center;Procedures;Research Personnel;Resource Sharing;Resources;Students;Update;anticancer research;career;community based participatory research;community partnership;education research;faculty support;meetings;programs;project-based learning;recruit;research facility;service learning;synergism Administrative Core n/a NCI 10694967 8/25/23 0:00 PAR-18-767 5U54CA137788-15 5 U54 CA 137788 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 7621 8906241 "AHLES, TIM ALAN" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 298436 166167 132269 Administrative CoreThe Administrative Core includes the four PIs Drs. Ahles and Gany (MSKCC) and Drs. Hubbard andBarabino (CCNY) Research Education Core Leaders Dr. Hricak (MSKCC) with Dr. Hubbard PCORELeaders Dr. Leng (MSKCC) and Dr. Dorn (CCNY) Linguistic and Cultural Responsiveness Shared ResourceCore Leaders Drs. Gany and Diamond (MSKCC) and Drs. Uyar and Riob (CCNY) and the AdministrativeCore staff from both CCNY and MSKCC. The U54 Administrative Core coordinates all of the Partnershipactivities and ensures that the Partnership continues to function effectively and efficiently. Specifically theAdministrative Core will: 1) coordinate biweekly meetings of Partnership PIs quarterly meetings of theAdministrative Committee which includes the leaders of the Research Education Core and PartnershipCommunity Research and Education Core and quarterly IAC meetings as well as the Annual ProgramSteering Committee meeting; 2) meet with the Executive Committee on an annual basis to evaluate thepotential synergy between Partnership goals and new institutional initiatives including recruitment of newfaculty; 3) provide support for both institutions' research resources and facilities and to provide access to andawareness of these resources for Partnership investigators faculty and students; 4) coordinate with GMapRegion 4 (CDRN) to ensure that Partnership students have access to regional career resources; 5)coordinate student placements at either CCNY or MSKCC in research laboratories or service-based learningprojects and to provide administrative support for faculty that teach in Partnership courses; 6) provide fiscalplanning and management for all aspects of the Partnership including the distribution of developmentalfunds; and 7) maintain and update a manual of Standard Operating Procedures. +No NIH Category available Androgen Metabolism;Androgen Receptor;Androgens;Animal Model;Binding;Cancer Etiology;Carcinogens;Cell Cycle;Cell Nucleus;Cells;Ceramides;Cessation of life;Cholesterol Homeostasis;Clinical Trials;Data;Development;Diet;Disease;Enzymes;Equilibrium;Estrogen Receptor alpha;Estrogens;Etiology;Exhibits;Fatty Acids;Female;Gene Expression;Generations;Genes;Genetic Transcription;Hepatic;Hepatocarcinogenesis;Hepatocyte;High Fat Diet;Histologic;Histone Acetylation;Histone Deacetylase;Human;Incidence;Inflammation;Isoenzymes;Knock-out;Knockout Mice;Link;Lipids;Liver;Liver Mitochondria;Malignant neoplasm of liver;Mediating;Metabolic;Mitochondria;Modeling;Molecular;Mus;Nuclear;Obesity;Oncogenic;Organelles;Oxidative Stress;Pathway interactions;Patients;Physiological;Play;Predisposition;Primary carcinoma of the liver cells;Production;Prognosis;Proliferating;Publishing;Reactive Oxygen Species;Regulation;Reporting;Resistance;Respiration;Risk;Rodent;Role;Sex Differences;Signal Pathway;Signal Transduction;Signaling Protein;Sphingolipids;Structure;Techniques;Testing;Testosterone;Triglycerides;Water;Woman;c-myc Genes;gene repression;high risk;human disease;inhibitor;intrahepatic;liver cell proliferation;male;men;mitochondrial dysfunction;mortality;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;personalized medicine;premalignant;prohibitin;respiratory;sex;sexual dimorphism;sexual disparity;sphingosine 1-phosphate;sphingosine kinase;stem cells;sugar;transcriptomics;treatment strategy;tumor;tumor initiation;tumorigenesis Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma PROJECT NARRATIVE Hepatocellular carcinoma (HCC) has a high mortality rate and its incidence exhibits significant sexualdimorphism as males have a higher risk for developing HCC than females. This proposal will utilize a new modelthat we developed of diet-induced progression of NASH to HCC that recapitulates key changes observed in thehuman disease to examine previously unrecognized roles of sphingosine kinase 2 an enzyme that regulates thebalance of bioactive sphingolipid metabolites in sexual dimorphism of HCC. The proposed studies have strongmechanistic and translational significance. NCI 10694959 8/10/23 0:00 PA-20-185 5R01CA266124-02 5 R01 CA 266124 2 "XU, WANPING" 9/1/22 0:00 8/31/27 0:00 Tumor Cell Biology Study Section[TCB] 14387357 "GREEN, CHRISTOPHER D" "SPIEGEL, SARAH " 4 BIOCHEMISTRY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 382369 NCI 246292 136077 PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide and itsincidence is increasing due to endemic obesity. Sexual dimorphism exists in HCC incidence as women have asignificantly lower risk for developing HCC than men. However the molecular mechanisms of HCC sexualdimorphism remain unclear hindering development of better therapies for this disease. This proposal willutilize a new model that we developed of diet-induced progression of NASH to HCC that recapitulates keyphysiological metabolic histologic and transcriptomic changes observed in the human disease to examinepreviously unrecognized roles of sphingosine kinase 2 (SphK2) an enzyme that regulates the balance ofbioactive sphingolipid metabolites sphingosine-1-phosphate (S1P) and ceramide in sexual dimorphism ofHCC. Similar to humans we found that on this diet wild-type male mice but not females develop HCC.Strikingly SphK2 knockout male mice have reduced tumor incidence whereas in females liver cancerdeveloped only in SphK2 knockout mice. Thus we propose that SphK2 plays a critical role in sexualdimorphism of HCC. We will test the central hypothesis that SphK2 protects females from HCC whilepromoting it in males through several mutually non-exclusive mechanisms in distinct hepatic subcellularorganelles. Aim 1 will examine the role of liver SphK2 in key signaling pathways that promote HCC in malesand Aim 2 will define the role of SphK2 in nuclear and mitochondrial mechanisms mediating resistance offemales to HCC. Our proposal utilizes a unique animal model and state-of-the-art techniques to identify novelSphK2-regulated molecular mechanisms involved in sexual disparity in diet-induced progression of NASH toHCC and also has translational implications for the use of SphK2 inhibitors now in clinical trials. This study willlead to better understanding of sex differences in HCC important for personalized treatment strategies for thisdevastating disease. 382369 +No NIH Category available 16S ribosomal RNA sequencing;Address;American Cancer Society;Animals;Bacteria;Biological Assay;Biomass;Cancer Burden;Cancer Prevention Study II;Candidiasis;Clinical;Communities;Data;Development;Diagnosis;Dideoxy Chain Termination DNA Sequencing;Disease;Etiology;Exposure to;Flow Cytometry;General Population;Genes;Genetic;Genetic Diseases;Goals;Human;Immune;Immune response;Immunity;Immunohistochemistry;Infiltration;Intervention;Investigation;Joints;Knowledge;Location;Lymphoid Cell;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Metabolic;Microbe;Myeloid Cells;Natural Immunity;Nature;Nested Case-Control Study;Obesity;Oral;Oral cavity;Outcome;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Diseases;Pancreatitis;Patients;Persons;Phenotype;Prevention;Preventive measure;Process;Prospective Studies;Reporting;Research;Research Design;Risk;Risk Factors;Sampling;Screening for cancer;Smoking;Testing;Tissues;Tumor Immunity;Tumor Tissue;Validation;adaptive immunity;bacteriome;cancer prevention;cancer risk;clinical practice;cohort;density;design;disorder risk;experimental study;fungal microbiota;fungus;high risk;improved;individualized prevention;innovation;microbial;microbial host;microbiome;microbiota;multidisciplinary;mycobiome;novel;oral bacteria;oral diagnostics;oral fungal;oral microbial community;oral microbiome;pancreas development;pancreatic neoplasm;pancreatic tumorigenesis;polymicrobial biofilm;prevent;prophylactic;tool;tumor;tumor-immune system interactions The Oral Mycobiome and Risk of Pancreatic Cancer PROJECT NARRATIVEPancreatic cancer is a highly fatal malignancy. Our research is designed to identify oral fungi associated withrisk for this disease and to identify related fungal microbialhost tumor immune interrelationships in pancreatictissue. The study will expand our current limited knowledge on the causes of pancreatic cancer will help toidentify people at high risk for this disease and may lead to microbial-based prophylactic preventions forpancreatic cancer. NCI 10694952 7/26/23 0:00 PAR-18-913 5U01CA250186-03 5 U01 CA 250186 3 "ZHU, CLAIRE" 9/23/21 0:00 8/31/25 0:00 ZCA1-TCRB-T(M1) 9966643 "AHN, JIYOUNG " "HAYES, RICHARD BERNARD" 12 INTERNAL MEDICINE/MEDICINE 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 249426 NCI 370393 257423 ABSTRACTWe hypothesize that oral fungi potentiate pancreas carcinogenesis via the pancreas tumor immunemicroenvironment. The human oral cavity hosts a diverse microbiota including bacteria and fungi. Our team hasmade novel findings that human oral bacterial microbiome is related to risk of pancreas cancer development. Inthis proposal we focus on oral fungi (the mycobiome) a keystone component of the oral microbiome with thehighest biomass. Clinical candidiasis and carriage of a rare candidiasis-related genetic disorder increase risk forpancreas cancer. In our preliminary data we made novel finding that specific oral fungi are associated with atleast 2-fold differentials in pancreatic cancer risk and those fungi are found in pancreas tumor tissue. We recentlyreported that fungi experimentally promote pancreas cancer and tumoral immune response in animals. Takentogether these data strongly support our hypothesis.Our ultimate goal is to identify specific oral fungal microbiota in the general population that may be managed toprevent pancreatic cancer. Our specific aims are: 1) to test whether oral fungal microbiome is associated withsubsequent risk of pancreatic cancer in a nested case-control study and 2) to test the hypothesis thatmetabolically active fungi in the pancreas influence tumor immunity. Strengths of this study include a largeprospective study design with oral samples collected prior to cancer development and state-of-the-art fungaland immune phenotype assays that will accurately and comprehensively characterize fungal composition andimmune phenotypes. This is the first investigation of oral and pancreas fungal microbiome and pancreatic cancerrisk.Pancreatic cancer is highly lethal and little is known about ways to detect and prevent this disease. We expectto identify specific oral fungi associated with risk of pancreas cancer and to identify fungalhost pancreatictumor immune response. These outcomes will expand our current limited knowledge on the causes of pancreaticcancer will help to identify people at high risk for this disease and may lead to microbial-based prophylacticprevention for pancreatic cancer. Thus findings may help to rapidly advance our ability to reduce the burden ofthis highly fatal disease. 249426 +No NIH Category available Address;Affect;African American;Area;Award;Biomedical Engineering;Bone neoplasms;Breast Cancer Early Detection;Cancer Research Project;Cell Line;Cellular biology;Cities;Clinical;Collaborations;Communities;Community Health Aides;Community Networks;Community Outreach;Computers;Data;Deuterium Oxide;Development;Drug Delivery Systems;Education;Education and Outreach;Educational process of instructing;Elderly;Engineering;Environment;Ethnic Origin;Funding;Future;Genome Stability;Goals;Grant;Health Disparities Research;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Resources;Image;Immersion;Immunoglobulin Genes;Immunology;Institution;Institutional Policy;Intervention;Label;Latino;Limited English Proficiency;Linguistics;Low income;Malignant Neoplasms;Measures;Mechanics;Medical;Medical Imaging;Memorial Sloan-Kettering Cancer Center;Mentorship;Minority;Modeling;Multilingualism;New York;Obesity;Pilot Projects;Policies;Populations at Risk;Positioning Attribute;Raman Spectrum Analysis;Recording of previous events;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Risk Reduction;Role;Schools;Scientist;Series;Students;Testing;Training;Translational Research;Translations;Underrepresented Minority;United States Health Resources and Services Administration;Universities;Woman;anticancer research;cancer care;cancer cell;cancer clinical trial;cancer education;cancer health disparity;cancer risk;cancer subtypes;career;clinical care;college;colorectal cancer screening;community engaged research;computer science;disparity reduction;economic determinant;education research;experience;health disparity;high risk;improved;innovation;interest;low socioeconomic status;medical schools;medically underserved;molecular imaging;multiphoton microscopy;outreach;pedagogy;post-doctoral training;programs;screening;socioeconomics;student retention;success;translational cancer research;translational medicine;triple negative cancer;tumor;underrepresented minority student;underserved community;working group 2/2 CCNY-MSKCC Partnership for Cancer Research Education and Community Outreach NarrativeThis proposal describes our plans to continue and enhance the City College of New York - Memorial SloanKettering Cancer Center Partnership for Cancer Research Education and Community Outreach. The CCNY-MSKCC Partnership is a mutually beneficial cross-institutional collaboration that has promoted translationalresearch created an education pipeline for minority and low-income students to advance in cancer researchcareers and has established community networks and resources for conducting culturally-responsivecommunity engaged research among diverse at-risk populations in the New York area. NCI 10694950 8/25/23 0:00 PAR-18-767 5U54CA137788-15 5 U54 CA 137788 15 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 8906241 "AHLES, TIM ALAN" "GANY, FRANCESCA M; HUBBARD, KAREN ; VUONG, BAO Q" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1425941 NCI 793954 631987 The CCNY-MSKCC Partnership has successfully created a mutually beneficial cross-institutional collaborationthat has emphasized research across the translational continuum the creation of an education pipeline forattracting minority and low-income students to careers in cancer research and the establishment of communitynetworks and resources for conducting linguistically and culturally-responsive community engaged researchamong diverse at-risk populations. Over the last five years areas of particular strength have been developedincluding: 1) rich collaborations between engineers and computer scientists at CCNY and clinicians and imagingexperts at MSKCC to develop innovative solutions to improve cancer care and 2) sustainable translationalhealth disparities research and activities that directly benefit underserved communities in New York and serveas national models in terms of: a) screening / identification of cancer risk factors that disproportionately affectminorities; b) socioeconomic determinants of access to and successful completion of treatment; and c) policychange. Consistent with these areas of emphases we propose two full projects that focus on: 1) Tumorensemble models to predict tumor dormancy and reactivation and testing how these models perform acrossvarious ethnic cell lines e.g. triple negative tumors that disproportionately affect African American women and2) Characterizing the Role of ATM in Immunoglobulin Gene Diversification and Genome Stability. Two proposedpilot projects include: 1) Raman spectroscopy with heavy water labeling and multiphoton microscopy to allowearly detection of breast cancer subtypes including triple negative cancers and 2) Development of MechanicalInterventions to Enhance Drug Delivery to Bone Tumors. New innovative Partnership components include: 1)development of the Linguistic and Cultural Responsiveness Shared Resource Core; 2) formation of theEngineering Health Disparities working group; and 3) new educational programs including the Scholars for theFuture program and the Certificate for Medical Translation and Interpretation. The Partnership specific aims areto: 1) Continue to develop outstanding cancer research programs in health disparities biomedicalengineering computer science / medical imaging cancer cell biology and immunology along theTranslational Research Continuum; 2) collaborate with diverse communities to conduct and facilitate trailblazingcancer disparities research and outreach education risk reduction and navigation activities to define andaddress cancer disparities with the goal of improving cancer care in the large medically underserved local andnational communities; 3) continue to develop and expand educational opportunities in a robust translationalcancer research environment to attract and retain students interested in cancer research (particularly minorityand low income students); these opportunities will be enhanced by educational opportunities and increasedmentorship and support; and 4) expand and integrate the personnel resources and environment needed forscientific collaboration across institutions and influence institutional policies in support of this objective. 1425941 +No NIH Category available 3-Dimensional;Acceleration;Address;Adult;Affinity;Antibody Therapy;BRCA2 Mutation;BRCA2 gene;Benign;Binding;Biological Assay;Biological Availability;Biology;Body Weight;Cell model;Clinical;Coculture Techniques;Collagen;Data;Data Analyses;Desmoplastic;Development;Diabetes Mellitus;Diagnosis;Ductal Epithelial Cell;Early Diagnosis;Engineering;Environment;Epithelial Cells;Epitopes;Evolution;Exposure to;Extracellular Matrix;Familial pancreatic cancer;Family history of;Fibroblasts;Fox Chase Cancer Center;Genes;Genetic Predisposition to Disease;Germ-Line Mutation;Goals;Growth;Human;Immunologic Surveillance;In Vitro;Individual;Inherited;Intercept;Interruption;Intervention;Lead;Lesion;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Molecular Target;Monoclonal Antibodies;Mus;Mutagens;Nutrient;Nutritional Support;Organ;PALB2 gene;Pancreas;Pancreatic Intraepithelial Neoplasia;Pancreatic duct;Pancreatitis;Patients;Penetration;Phenocopy;Phenotype;Population;Premalignant Cell;Preventive;Primary Neoplasm;Property;Proprotein Convertase 2;Risk Factors;Safety;Series;Signal Transduction;Smoker;Stress;Syndrome;System;Testing;Tissues;Toxic effect;Tumor Promotion;Tumor Suppressor Proteins;Work;cancer predisposition;cancer prevention;cancer risk;cell growth;cell type;cellular engineering;chemokine;clinical candidate;effectiveness evaluation;efficacy testing;experimental study;genetic variant;high risk;improved;in vivo;inhibiting antibody;lead candidate;lifetime risk;liver function;loss of function;molecular marker;mouse model;mutation carrier;netrin-G1;neutralizing antibody;neutralizing monoclonal antibodies;novel;novel strategies;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;premalignant;programs;screening;targeted agent;tumor;tumor progression;tumor-immune system interactions;tumorigenesis;tumorigenic Neutralizing Stromal NetrinG1 to Intercept Pancreatic Cancer n/a NCI 10694941 8/17/23 0:00 RFA-CA-21-038 5U54CA272686-02 5 U54 CA 272686 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7609 7852640 "CUKIERMAN, EDNA " Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 411831 219059 192772 PROJECT SUMMARY - PROJECT 2Most patients with pancreatic cancer (PC) do not survive one year and less than 10% survive five years. This isunfortunate given the slow rate of growth of PC over many years and the large window of opportunity forpotential intervention prior to diagnosis. Patients with hereditary familial PC (~10% of PC cases) as well as thoseexposed to mutagens and presenting with predisposing clinical conditions like pancreatitis and new onset ofdiabetes are at high risk for PC and would benefit greatly from improved early detection cancer preventionand/or interception strategies. The proposed project addresses this unmet need by joining the FCCC CancerPrevention-Interception Targeted Agent Discovery Program (CAP-IT) at the Agent Identification and Screeningstage. The proposal is the first to our knowledge to employ a stroma-targeting strategy to intercept progressionof precancerous tissue to overt PC. This proposal exploits our work in studying desmoplasia a uniquemicroenvironment enriched in stromal fibroblasts and dense extracellular matrix (ECM) that characterizes PC.We have defined distinct subsets of tumor-promoting and tumor-suppressing fibroblasts (TPFs and TSFs) whichcan reversibly interconvert in phenotype. We have shown that TPFs arise in early precancerous tissue and arecharacterized by expression of Netrin G1 (NetG1). NetG1-dependent signaling is essential for premalignant cellsto thrive as tumors. Mechanistically we have shown that NetG1+ TPFs provide nutritional support topremalignant initiated epithelial cells (IECs) and tumors allowing them to survive in the nutrient-poordesmoplastic environment and escape immunosurveillance by inducing an immunosuppressivemicroenvironment. While some support is delivered via TPF secretion of nutrients and chemokines; additionalsupport is provided by the TPF-generated ECM. Critically we have shown that a commercial monoclonalantibody (mAb) that inhibits NetG1 reverts all of these tumor-promoting properties and intercepts the formationof PC. Although the commercial mAb is sufficient for proof-of-concept experiments it is not sufficiently potent asa clinical candidate. A large panel of mAbs targeting diverse NetG1 epitopes with higher binding affinities thanthe one above-mentioned has been generated. In Aim 1 we will determine which of the new mAbs functionallyreverts TPFs to TSFs based on the expression of molecular markers that distinguish between the two classes.In Aim 2 co-culture experiments will be used to identify mAbs that reduce the ability of TPFs to provide nutritionalsupport to IECs and assess whether the same mAbs decrease the ability of the ECM produced by TPFs toenhance IEC growth. New IEC models will be engineered that parallel the loss of function genetic variants seenin populations at high risk for PC. In Aim 3 the lead candidate mAbs that can intercept the transition fromprecancer to cancer in vitro will be evaluated for their toxicity profiles and ability to inhibit formation of PanINsthe precursor of PC in KC mice a model of PC. These studies are expected to yield novel agents that target thestroma for PC prevention and/or interception. +No NIH Category available Address;Adverse effects;Animals;Binding;Biochemical;Biophysics;Cancer cell line;Cell Line;Cellular Assay;Characteristics;Chemicals;DNA;DNA Binding;Defect;Disease;Drug Design;Event;Family;Female;Fox Chase Cancer Center;Germ-Line Mutation;Goals;Hereditary Disease;Heterozygote;Histologic;In Vitro;Individual;Intercept;Lesion;Li-Fraumeni Syndrome;Malignant Neoplasms;Maps;Mediating;Membrane Proteins;Missense Mutation;Modeling;Molecular Conformation;Mus;Mutate;Mutation;Null Lymphocytes;Oncogenic;Patients;Pattern;Pharmaceutical Preparations;Prevention;Primary Prevention;Property;Proteins;Safety;Series;Somatic Mutation;Squamous cell carcinoma;Structure;Structure-Activity Relationship;TP53 gene;Testing;Thermodynamics;Time;Tissues;Toxic effect;Transfection;Validation;Work;analog;cancer prevention;design;drug testing;early onset;efficacy testing;gain of function;high risk population;improved;in vivo;in vivo Model;loss of function;male;mouse model;mutant;novel;novel therapeutics;pharmacologic;premalignant;programs;safety testing;screening;targeted agent;transcription factor;tumor Refolding Mutant p53: A Strategy for Cancer Prevention in Li-Fraumeni Syndrome n/a NCI 10694936 8/17/23 0:00 RFA-CA-21-038 5U54CA272686-02 5 U54 CA 272686 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7607 8681137 "KARANICOLAS, JOHN " Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 406353 216145 190208 PROJECT SUMMARY - PROJECT 1 Li-Fraumeni syndrome (LFS) an inherited disorder arising in heterozygous carriers of germline mutationsin TP53 is associated with early-onset cancers in many different tissues of origin. Because TP53 has beenstudied so extensively a unique opportunity exists to intervene early prior to tumor formation in LFSindividuals. Whether germline or somatic most cancer-associated TP53 mutations are missense mutations thatdisrupt p53s ability to bind DNA. While some of these mutations map to residues in direct contact with DNAmany do not. Rather these mutations reduce p53s thermodynamic stability so that an insufficient amount of(mutant) p53 is correctly folded: this leads to loss of function (LOF). Many of these mutations also conferoncogenic gain of function (GOF) activities. Among Li-Fraumeni individuals evidence suggests that the earlieststages in the emergence of precancerous lesions and progression of these lesions to cancer derive from mutantp53s GOF activities. Ongoing work in the Karanicolas lab focuses on developing drugs that bind and stabilize the foldedconformation of mutant p53 to directly correct the missense defects that underlie the LOF and GOF activities.These refolder drugs are designed to bind a region on the protein surface that is separate from all of p53smost common mutations so that the same drug can be applied irrespective of the specific mutation. We havetested these drugs in diverse cancer cell lines harboring many different mutations in TP53. Through thesestudies we have confirmed that these refolder drugs both: 1) restore LOF from mutant p53 and 2) revert mutantp53s GOF activities. The objectives of our proposed project are three-fold. First we will define the set of mutationscharacteristic of LFS individuals that can be addressed by this new class of agents. Second we will optimize ourcurrent best agent to enhance its expected safety and efficacy in animal studies. Third we will test the safetyof the resulting agents in mice heterozygous for a TP53 mutation seen frequently in LFS individuals and efficacyin a mouse model of p53-mediated squamous carcinoma that provides clear milestones of the progression fromprecancer to cancer. Successful completion of these studies will serve as important proof-of-concept that thesep53 refolding agents hold the potential to become new drugs for prevention and early interception of cancer inLFS individuals. +No NIH Category available 19q;Adult Glioma;Affect;Alleles;Amino Acid Motifs;Amino Acid Sequence;Amino Acids;Antibody Response;Antigen Presentation;Antigenic Variation;Antigens;Area;BK Virus;Binding;Biological Assay;Cells;Clinical Data;Cytomegalovirus;Data;Detection;Development;Etiology;Foundations;Genes;Genetic;Genetic Polymorphism;Genetic Variation;Genome;Glioma;Gliomagenesis;HHV-6A;HLA Antigens;Haplotypes;Herpesviridae;Herpesvirus 1;Herpesvirus Type 3;Histocompatibility Antigens Class I;Human;Human Herpesvirus 4;Human Herpesvirus 7;Immune response;Immunogenomics;Individual;Infection;Infectious Agent;International;Intervention;Link;Malignant Neoplasms;Malignant neoplasm of brain;Manuscripts;Maps;Measurement;Measures;Mediating;Mediation;Meta-Analysis;Modeling;Mutate;Mutation;Nucleotides;Pathogenesis;Pathway interactions;Patients;Pattern;Peptides;Play;Polyomaviridae;Polyomavirus;Predisposition;Prevention;Prognosis;Proteins;Risk;Risk Assessment;Risk Factors;Role;Sampling;Serology;Serology test;Serum;Simian virus 40;Simplexvirus;Technology;Testing;Therapeutic;Time;Viral;Viral Antigens;Virus;Virus Diseases;case control;co-infection;epidemiologic data;epidemiology study;genetic architecture;improved outcome;innovation;interest;member;modifiable risk;nanopore;novel therapeutics;pathogen;predictive modeling;prognostic;response;survival outcome;synergism Discovering Infection-mediated Pathways of Glioma Etiology and Prognosis by Leveraging Multiplex Serology and Immunogenomics PROJECT NARRATIVEGlioma has been associated with a number of infections. We will examine antigen reactivity to all infectionspreviously linked with glioma to assess the risk and survival associated with each of these infections andgroups of co-infections. We will then sequence an area of the genome that controls immune response todetermine which genetic alterations interact with infections and how infections and genetics together alter riskand survival of glioma. NCI 10694932 8/21/23 0:00 PAR-20-062 5R01CA266676-02 5 R01 CA 266676 2 "STARKS, VAURICE" 9/1/22 0:00 8/31/26 0:00 Immunity and Host Defense Study Section[IHD] 10681590 "FRANCIS, STEPHEN STARKO" Not Applicable 11 NEUROSURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 646077 NCI 400047 246030 PROJECT SUMMARYGliomas account for 80% of all malignant brain tumors and have an extremely poor prognosis with a 5-yearsurvival of 5.1%. The etiology of glioma remains poorly understood with few established modifiable risk factors.Multiple studies have implicated infections in the development of glioma however the underlying mechanismsand putative causal pathogens remain unclear. In addition to risk there is also accumulating evidence fromstudies investigating novel therapeutics suggesting that immune response to infection may be prognostic inglioma patients. Previous epidemiologic studies have investigated a limited number of pathogens usingserological assays that only allowed detection. We seek to conduct a large serologic study measuring 41antigens from all 12 infections previously associated with glioma using assays that provide quantitative measuresof antibody response. Our study will include 1000 glioma case-control pairs with extensive clinical andepidemiologic data. In Aim 1 we will estimate the effect of each individual infection on glioma risk and survivaland also examine grouped patterns of co-infections. In Aim 2 we will employ innovative long read sequencingtechnology to detail all polymorphisms in human leukocyte antigen (HLA) class I and II genes in the same set ofsubjects. Genetic variation in the HLA region plays a pivotal role in regulating immune response to viral challengeand has been previously linked to glioma risk and progression. We will investigate a range of functional HLApolymorphisms including antigen-presenting classical alleles and amino acid residues with respect to gliomarisk and survival. In Aim 3 we will integrate serological and HLA sequencing data to delineate host geneticmechanisms of immune response to infection and subsequent effects on glioma endpoints. This will allow us todevelop comprehensive immunogenomic models for predicting glioma risk and survival. Taken together theproposed study will contribute new high-quality data that will significantly advance our understanding of gliomapathogenesis as well as inform avenues for prevention and improvement of outcomes in glioma patients. 646077 +No NIH Category available Attention;Biological;Collaborations;Communication;Communities;Consultations;Data;Educational workshop;Ensure;Evaluation;Fox Chase Cancer Center;Goals;Hereditary Neoplastic Syndromes;Informatics;Infrastructure;Interdisciplinary Study;Laboratory Research;Leadership;Malignant Neoplasms;Molecular Target;Monitor;Prevention;Productivity;Reproducibility;Research;Research Activity;Research Personnel;Research Project Grants;Resource Sharing;Resources;Technical Expertise;Validation;cancer prevention;conflict resolution;efficacy testing;in vivo;meetings;member;multidisciplinary;pre-clinical;precision cancer prevention;programs;screening;skills;success;targeted agent Administrative Core n/a NCI 10694929 8/17/23 0:00 RFA-CA-21-038 5U54CA272686-02 5 U54 CA 272686 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7604 1885626 "CLAPPER, MARGIE L." Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 252717 134424 118293 PROJECT SUMMARY - ADMINISTRATIVE COREThe Administrative Core will provide the infrastructure required to ensure efficient coordination integrationplanning and evaluation of all agent discovery activities associated with the proposed CAP-IT Center. The Coreprovides an integrated multidisciplinary framework for scientific collaboration among the participating membersand Shared Resources at FCCC. To facilitate productivity the Administrative Core will provide fiscalmanagement and clerical support as well as ensure scientific rigor data reproducibility attention to importantbiological variables transparency and consistent communication. Importantly the Administrative Core will serveas a liaison with the NCI and other Specialized CAP-IT Centers and leverage the support of the InformaticsCore to effectively engage with the Data and Resource Coordinating Center. Active participation of CAP-ITmembers in meetings workshops and activities of the CAP-IT Network will be coordinated through theAdministrative Core. These activities will be accomplished according to four specific aims to: 1) Maintain aneffective framework of well-integrated multidisciplinary research activities by applying strong communication andorganizational skills and frequently monitoring research progress; 2) Promote trans-Network collaborations bycoordinating and participating in CAP-IT Network meetings and organizing inter-programmatic seminars andworkshops; 3) Engage early-stage investigators in precision cancer prevention interception research anddisseminate findings and capabilities to the scientific community; and 4) Evaluate the progress of the proposedCAP-IT Center using standard deliverables and defined metrics and milestones of success. The LeadershipTeam comprised of accomplished investigators with expertise in hereditary cancer syndromes target validationagent screening in vivo efficacy testing and informatics will provide oversight of all aspects of the researchprojects and make informed decisions at critical junctures of the discovery pipeline. In close consultation withthe NCI the FCCC CAP-IT will leverage its unique resources and technical expertise to fuel the discovery ofagents for cancer prevention and interception within the CAP-IT Network and beyond. +No NIH Category available Acceleration;Address;Adult;African ancestry;Antibodies;Area;Atlases;Award;Barrett Esophagus;Bioinformatics;Biological Assay;Biometry;Cancer Biology;Cancer Burden;Cancer Center;Cell Line;Chronic;Collaborations;Colonic Polyps;Communication;Computational Biology;Contractor;Data;Development;Disease;Division of Cancer Prevention;Dose;Drug Design;Early Detection Research Network;Early identification;Early treatment;Engineering;Epithelial Cells;Event;Family;Fibroblasts;Fostering;Fox Chase Cancer Center;Future;Genetic Risk;Germ-Line Mutation;Goals;Growth;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Heritability;High-Risk Cancer;In Vitro;Individual;Informatics;Inherited;Intercept;Intervention;Knowledge;Laboratory Research;Lead;Leadership;Lesion;Li-Fraumeni Syndrome;Malignant Neoplasms;Malignant neoplasm of pancreas;Medical Genetics;Molecular;Molecular Abnormality;Molecular Profiling;Molecular Target;Mutation;Operative Surgical Procedures;Oral Leukoplakia;Organ;Pancreas;Pancreatic Intraepithelial Neoplasia;Pathway interactions;Phenotype;Population;Predisposition;Prevention strategy;Preventive;Productivity;Proteins;Regimen;Research;Research Personnel;Resource Sharing;Resources;Risk Assessment;Risk Reduction;TP53 gene;Technology;Toxic effect;Training;Tumor Promotion;Validation;biological specimen archives;cancer diagnosis;cancer prevention;cancer risk;clinical risk;clinically relevant;cohort;data management;data sharing;disorder risk;drug development;drug discovery;efficacious intervention;efficacy study;experience;genetic variant;high risk;improved;in vivo;in vivo evaluation;individualized prevention;innovation;insight;lifetime risk;member;molecular modeling;mouse model;multidisciplinary;mutant;mutation carrier;netrin-G1;neutralizing antibody;novel;overexpression;pre-clinical;precision cancer prevention;premalignant;prevent;preventive intervention;programs;prophylactic;public database;rational design;screening;targeted agent;therapy development;time use;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis Cancer Prevention-Interception Targeted Agent Discovery Program at Fox Chase Cancer Center PROJECT NARRATIVE - OVERALLAn urgent need exists to develop better strategies for the prevention of cancer in high-risk subjects and inparticular in those who have inherited a predisposition for the disease. In close collaboration with the NCI andother Centers Fox Chase Cancer Center (FCCC) proposes to utilize multidisciplinary expertise novelcutting-edge technology and biospecimens and data from mutation carriers in the FCCC Risk AssessmentProgram to identify agents that can effectively disrupt the earliest steps in tumor formation. Establishment ofFCCC as a member of a highly collaborative Cancer Prevention-Interception Targeted Agent Discovery Program(CAP-IT) is anticipated to accelerate the development of efficacious preventive agents and have a significantimpact on reducing the burden of cancer among those at highest risk of disease. NCI 10694928 8/17/23 0:00 RFA-CA-21-038 5U54CA272686-02 5 U54 CA 272686 2 "GUNASEKHARAN, VIGNESH KUMAR" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U(M1) 1885626 "CLAPPER, MARGIE L." Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 1207007 NCI 642025 564982 PROJECT SUMMARY - OVERALLHereditable cancer-predisposing mutations are estimated to be an underlying cause of more than 100000 adultcancers in the US each year. For many hereditary cancer syndromes the life-time risk of developing cancerapproaches 100%. Despite revolutionary advances in omics technologies our understanding of the molecularalterations required to support the establishment of precancerous lesions and promote early tumor developmentremains very limited thus hindering the development of efficacious interventions. A multidisciplinary team ofaccomplished investigators at Fox Chase Cancer Center (FCCC) with combined expertise in cancer preventionheritable cancer risk cancer biology molecular modeling and drug discovery has been assembled to addressthis unmet in an unprecedented way. The goal of the FCCC CAP-IT Center is to effectively coordinate thedevelopment of efficacious molecularly-targeted agents for precision cancer prevention and early interception inpopulations at high risk for cancer. All studies are facilitated by the unique resources of the FCCC RiskAssessment Program which includes over 12000 families at high risk for cancer and 2000 confirmed germlinemutation carriers. A comprehensive pipeline for the development of agents for cancer prevention and interceptionis proposed that consists of three well-developed research domains: target validation (Aim 1) agent identificationand screening (Aim 2) and pilot in vivo efficacy studies (Aim 3). Each domain will be led by a FCCC investigatorwho is a national leader in the respective field. Two highly innovative projects are proposed that illustrate therobustness of the CAP-IT framework. Project 1 (entering at Target Validation) focuses on the development of anewly-identified agent that refolds mutant p53. Its ability to target the TP53 mutations associated with Li-Fraumeni Syndrome and inhibit precancerous lesions in a setting of mutant p53 will be evaluated. Project 2(entering at Agent Identification and Screening) uniquely targets the initiated pancreatic stroma as a strategy forearly interception in the formation of pancreatic cancer. A neutralizing antibody against the stromal protein NetrinG1 that can revert fibroblasts to a tumor-suppressive phenotype has been discovered. Antibodies with improvedpotency will be identified and tested in vivo for their ability to intercept the progression of pancreatic intraepithelialneoplasia. All CAP-IT research and training will be strongly supported by the Leadership Team and coordinatingactivities of the Administrative Core led by Dr. Clapper. Expertise in biostatistics bioinformatics and datamanagement will be provided to CAP-IT investigators by an Informatics Core led by Dr. Ross. Collaborationsamong the NCI FCCC and other CAP-IT Centers as well as the sharing of data and resources through the Dataand Resource Coordination Center will foster productivity and integration across the CAP-IT Network (Aim 4).The long legacy of FCCC in clinical risk assessment and preclinical preventive agent development whencombined with extensive expertise in drug design and cancer biology makes this Center uniquely poised to beinstrumental in the discovery of molecularly-targeted agents to prevent or intercept early oncogenesis. 1207007 +No NIH Category available Area;Biology;Cancer Biology;Cancer Etiology;Cancer Model;Cancer cell line;Chromatin;Clinic;Communication;DNA;Development;Disease;Enhancers;Enzymes;Epigenetic Process;Funding Mechanisms;Future;Gene Expression;Gene Targeting;Genes;Genomics;Histones;Link;Malignant Neoplasms;Membrane;Metabolic;Metabolic Pathway;Metabolism;Normal Cell;Nuclear;Oncogenes;Oncogenic;Pathway interactions;Production;Proteomics;Publishing;Recording of previous events;Regulatory Element;Research;Role;TP53 gene;Tumor Suppressor Proteins;Work;cancer immunotherapy;cofactor;epigenetic regulation;fascinate;individual variation;infancy;inhibitor;insight;mouse model;multidisciplinary;mutant;novel;patient population;patient response;pharmacologic;programs;refractory cancer;small molecule therapeutics;targeted treatment;transcription factor;tumor Interaction between nuclear epigenetic and metabolic pathways in cancer NarrativeDespite impressive advancements in treatment cancer continues to be devastating. Prominent amongchanges that cause cancer are alterations to metabolic and epigenetic pathways and there is surprisingevidence that these pathways directly communicate to regulate gene expression. Tackling theseinterconnected pathways for new insights will guide future novel treatments and will benefit patient populations. NCI 10694898 7/14/23 0:00 PAR-21-333 5R35CA263922-02 5 R35 CA 263922 2 "JOHNSON, RONALD L" 9/1/22 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 1860700 "BERGER, SHELLEY L" Not Applicable 3 ANATOMY/CELL BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 955500 NCI 588000 367500 AbstractDespitecancer impressive strides in conventional small molecule therapeutics and novel cancer immunotherapiescontinues to be a devastating disease. Certain cancers are refractory to available therapies andpatients' responses show large individual variability. Cancer involves striking dysregulation of epigeneticpathways with pharmacological approaches targeting chromatin regulators in the clinic and underdevelopment. There is also profound involvement of metabolic pathways in cancer including fascinatingnuclear-localized metabolic enzymes. These paradigm-shifting pathways represent an entirely new avenue fortargeted therapies with the potential to directly and specifically modulate cancer-related gene expressionprograms. However our understanding of epigenetic mechanisms in cancer especially as they connectto nuclear metabolic pathways remains in its infancy. Our history of groundbreaking research revealingnew chromatin biology and uncovering genomics and proteomics of the transcription factor p53 both in its roleas a crucial tumor suppressor and as a ruinous oncogene underpins our proposed novel directions. Inaddition we have new findings of a chromatin-localized role of a cancer-linked metabolic enzyme directlyfueling a histone modifying enzyme. Utilizing this background in this revised proposal we propose toinvestigate novel epigenetic regulation and its intersection with nuclear metabolism using a variety of normaland cancer cell lines as well as translational mouse models of cancer. We will investigate pivotaldevelopmental- and disease-relevant DNA regulatory elements called enhancers which our published findingsexpose as crucial in p53 function but which remain understudied in both wildtype and mutant p53 function. Inaddition we have recently illuminated awithwillspeckleschromatinexpression.enzymewholly novel and unanticipated mechanism of wildtype p53 associating membrane-less bodies called nuclear speckles to traffic p53's gene targets for enhanced expression; wedive deeply into the underlying mechanisms for wildtype and oncogenic p53 and explore alterations ofin cancer. Other recent findings implicate a nuclear metabolic-epigenetic axis to coordinate directly at metabolic enzyme production of cofactors with chromatin enzyme function to activate geneWe will unravel mechanisms underlying this organization identify new examples of metaboliccoordination with epigenetic enzymes and determinewhether the nuclear metabolic-epigenetic axis iscritical to cancer. Crucially we have developed an inhibitor targeting ACSS2 a nuclear metabolic enzymewhich presages potential new advancement in therapy. Taken together our combined focus on roles andinteractions of epigenetics and metabolism related to cancer promises to delineate novel mechanismsinvolved in tumor formation. This paradigm-shifting multidisciplinary work will bridge separate butrelated areas of cancer biology and is thus ideal for this broad funding mechanism. Critically resultsfrom our research will guide much-needed future treatments and significantly benefit patient populations. 955500 +No NIH Category available Antigen Presentation;Antigen-Presenting Cells;Award;Basic Science;Bioinformatics;Biological Response Modifiers;Biostatistics Core;CD4 Positive T Lymphocytes;Cancer Center;Cells;Cessation of life;Clinical;Clinical Trials;Coculture Techniques;Critical Pathways;Cytoprotection;Data;Dedications;Dendritic Cells;Development;Dimensions;Doctor of Philosophy;Environment;Equine mule;Event;Faculty;Failure;Flow Cytometry;Foundations;Generations;Human;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immune response;Immunologic Surveillance;Immunology;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Infrastructure;Interferon Type II;Interferon alpha;Interferons;Janus kinase;Ligands;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mediating;Medical Oncologist;Melanoma Cell;Mentors;Mentorship;Messenger RNA;Methods;Modeling;Mus;Myeloid-derived suppressor cells;Nitrates;Nitric Oxide;Nivolumab;Oncologist;Pathway interactions;Patients;Pattern;Peripheral Blood Mononuclear Cell;Physicians;Population;Positioning Attribute;Proteins;Proteomics;Records;Regimen;Research;Research Personnel;Resistance;STAT protein;STAT1 gene;Scientist;Seasons;Series;Signal Transduction;Skin Cancer;Specimen;Suppressor-Effector T-Lymphocytes;T-Cell Receptor;T-Lymphocyte;Therapeutic;Therapeutic Intervention;Tissues;Toxic effect;Translational Research;Tumor Immunity;United States;Unresectable;Up-Regulation;Work;anti-CTLA-4 therapy;anti-PD-1;anti-PD1 therapy;career;cost;effective therapy;experience;experimental study;immune cell infiltrate;improved;interest;melanoma;member;nitration;nitroaspirin;novel therapeutic intervention;patient response;pembrolizumab;programmed cell death ligand 1;programmed cell death protein 1;release factor;resistance mechanism;response;success;therapeutic development;tool;transmission process;treatment response;tumor Nitric oxide immune dependent resistance mechanisms to anti-PD-1 therapy Project NarrativeThis project will investigate the nitric oxide dependent resistance mechanisms to anti-PD-1 therapy as a potentialavenue for therapeutic development and intervention given that only 40% of melanoma patients have objectiveresponses to anti-PD-1 therapy. In addition I will develop tools to predict which patients are likely to fail anti-PD-1 therapy allowing those patients to be treated with other potentially more effective therapies. These toolsmay be applicable to study resistance patterns to other immunotherapies in melanoma and other tumor types aswell. NCI 10694871 9/7/23 0:00 PA-20-203 5K08CA252164-03 5 K08 CA 252164 3 "BOULANGER-ESPEUT, CORINNE A" 9/1/21 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 6915436 "MARKOWITZ, JOSEPH " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 209852 NCI 194307 15545 Project Summary/AbstractI Joseph Markowitz MD PhD am a junior medical oncologist at Moffitt Cancer Center interested in developingimmune-based therapeutics for the benefit of melanoma patients. Moffitt is the ideal environment for me todevelop into an independent physician scientist given the dedicated Moffitts Melanoma and Skin Cancers Centerof Excellence superb flow cytometry core extensive clinical trial support infrastructure and highly supportivebioinformatics and biostatistics core. Immune-based therapy has had mounting successes in the past few yearswith the introduction of checkpoint inhibitors. However many patients do not respond to therapy and I intend todedicate my career into turning these failures into successes. I will have the mentorship to adapt and grow withthe project. My mentorship team (Drs. Mul Sondak Conejo-Garcia Tarhini and Berglund) was carefullyselected to include translational and clinical mentors to ensure that I can mature into a successful immuno-oncologist for therapeutic development in melanoma. Melanoma cells protect themselves from immune attackby releasing factors that stimulate development of immune suppressor cells. Immune suppressor cells such asmyeloid-derived suppressor cells (MDSCs) release large amounts of nitric oxide (NO) that inactivate proteinsthat normally help immune cells sense and respond to cancer. Hypothesis: Anti-PD-1 resistance in melanomaresults in part from reduction of DC antigen presentation to T cells via a NO dependent mechanism.Furthermore NO causes nitration of multiple proteins including STAT1 and NFB as well as MHC and T-cellreceptor (TCR) molecules expressed by immune cells such as dendritic cells (DC) making them less effectivefor transmitting signals crucial for antigen presentation and rejection of tumors. Therefore this proposal outlinesa series of experiments that will: 1) use murine and ex-vivo models to measure antigen presentation from DC toT cells to elucidate the operative mechanism(s) by which nitration of antigen presentation proteins such asSTAT1 results in immune tolerance to melanoma and resistance to anti-PD-1 therapy and to follow the levels ofMDSCs nitric oxide and nitric oxide producing MDSCs over the course of treatment using multidimensional flowcytometry and 2) access to well-annotated tissue specimens from melanoma patients receiving anti-PD-1treatment (unresectable stage III/IV) to quantify the effects of NO and correlate this with changes in immune cellresponses to interferon as well as mRNA and proteomics profiles. Work completed in this proposal willpotentially enable the development of new therapeutic strategies to overcome the inhibitory effects of nitric oxideand enhance patient immune responses to melanoma with anti-PD-1 therapy (and potentially other immune-based therapies). In addition this proposal may lead to new quantitative mass spectrometry and bioinformaticsmethods to predict who will respond to anti-PD-1 therapy and spare patients from unnecessary toxicity if theyare unlikely to respond. The work will also provide me with the necessary research and clinical foundation tobecome an independent investigator. 209852 +No NIH Category available Affinity;Binding;Biological Assay;Biological Markers;Categories;Cell surface;Cells;Clinic;Cytokine Signaling;DNA biosynthesis;Dose Limiting;ERBB2 gene;Effector Cell;Elements;Engineering;Epidermal Growth Factor Receptor;Escherichia coli;Extracellular Domain;Flow Cytometry;Goals;Human;Immune;Immune system;Immunologics;Immunotherapeutic agent;Immunotherapy;In Vitro;Interferometry;Interleukin Receptor;Interleukin-12;Interleukin-2;Interleukin-4;Interleukins;Label;Malignant Neoplasms;Measures;Mission;Modeling;Molecular Sieve Chromatography;Monitor;Mus;Oncogenes;Peptide Synthesis;Phosphorylation;Population;Proliferating;Property;Protein Engineering;Proteins;Public Health;Regenerative Medicine;Renal Cell Carcinoma;Research Proposals;Signal Transduction;Structure;Surface;T-Lymphocyte;Therapeutic;Toxic effect;Transactivation;Tumor Markers;United States National Institutes of Health;X-Ray Crystallography;Yeasts;anti-cancer;biophysical properties;cancer cell;cancer immunotherapy;cancer therapy;clinical application;combat;cytokine;deep sequencing;design;disability;extracellular;frontier;immunogenicity;improved;in vivo;innovation;interleukin-21;manufacturability;melanoma;mimetics;nanobodies;novel;programmed cell death ligand 1;receptor;reconstitution;tumor;tumor growth;tumor xenograft Design of de novo interleukin mimics for targeted immunotherapy PROJECT NARRATIVEThe proposed project is relevant to public health because it seeks to develop a new class of targeted non-toxiccancer therapeutics. Computational protein design will be used to generate novel protein immunotherapeuticsthat mimic the activity of natural cytokines but with enhanced therapeutic properties. Thus the proposedproject aligns with the NIHs mission to reduce illness and disability. NCI 10694869 8/24/23 0:00 PA-18-484 5R01CA240339-05 5 R01 CA 240339 5 "FU, YALI" 9/1/19 0:00 8/31/24 0:00 Macromolecular Structure and Function D Study Section[MSFD] 1955169 "BAKER, DAVID " Not Applicable 7 BIOCHEMISTRY 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 338953 NCI 251218 87735 PROJECT SUMMARYAlthough immunostimulatory cytokines can be used to combat cancer their poor stability and high off-targettoxicity has limited their application in the clinic. The long-term goal of this project is to produce targetedanti-cancer cytokine mimetics with reduced toxicity. The overall objective is to apply recent breakthroughs in denovo protein design to yield a new category of targeted non-toxic immunostimulatory proteins. The centralhypothesis is that the beneficial stimulatory effects of natural cytokines can be engineered into de novodesigned proteins which do not engage in off-target binding thereby circumventing the dose-limiting toxicitiesseen in clinical applications of natural/reengineered cytokines. The specific aims are to: (1) use de novo proteindesign to generate hyperstable bioactive mimetics of interleukin-2 -4 -12 -15 and -21 which function byengaging with (i.e. binding to) interleukin receptors in vivo; (2) to split these mimics into inactive parts whichcan regain activity by reassembling in vivo; and (3) to fuse each of these inactive parts to specific targetingdomains thereby yielding conditionally-active cytokine mimics that stimulate T-cells by reassembling only onthe surface of a targeted cells (i.e. cancer cells displaying two specific surface biomarkers). As proof ofprinciple the first such de novo designed cytokine mimetic has been produced split and shown to reducetumors in mice without accompanying toxicity or immunogenicity. This research proposal is innovative becauseit seeks to resolve a long-standing barrier to cancer immunotherapy (namely the off-target toxicity ofcytokine-based therapeutics) by designing from scratch a new class of non-toxic cytokine mimics. Theproposal is significant because it would be the first example of computational protein design yielding targetedbiosuperior cancer therapeutics. Ultimately such molecules have the potential to treat a wide range of cancersincluding malignant melanoma renal cell carcinoma and more. 338953 +No NIH Category available Ascorbic Acid;Award;Biological Markers;Biology;Cancer Biology;Chemotherapy and/or radiation;Clinical;Clinical Research;Clinical Trials;Core Facility;DNA Damage;Dose;Environment;Free Radicals;Funding;Glioblastoma;Grant;Hydrogen Peroxide;In Vitro;Intravenous;Ions;Iowa;Iron;Leadership;Lung;Malignant Neoplasms;Measures;Mediating;Medicine;Metabolic;Metabolism;Metals;Modeling;Natural Products Chemistry;Non-Small-Cell Lung Carcinoma;Normal Cell;Oxidation-Reduction;Oxidative Stress;Pharmacologic Ascorbate;Pharmacy facility;Postdoctoral Fellow;Program Research Project Grants;Qualifying;Radiation Oncology;Radiobiology;Radiosensitization;Research;Research Personnel;Research Project Grants;Scientist;Signal Pathway;Sulfhydryl Compounds;Testing;Toxic effect;Training;Translational Research;Universities;Wages;Work;ascorbate;cancer cell;cancer therapy;chemoradiation;drug repurposing;experience;genetic approach;improved;in vivo;iron metabolism;knowledge base;member;novel;oxidation;oxidative damage;pancreatic cancer cells;pharmacologic;preclinical study;programs;radiation response;response;theories;translational study;tumor metabolism Repurposing redox active agents for exploiting differences in cancer cell metabolism for improving cancer therapy Project NarrativeIntravenous dosing of pharmacological levels of ascorbate has recently remerged as a redox active agent thatenhances lung glioblastoma and pancreatic cancer cell responses to radiation and chemotherapy withoutincreasing toxicity to normal cells. As pharmacological ascorbate advances through clinical trials it is importantthat we thoroughly understand the mechanisms involving metabolic oxidative stress and redox active metalions that account for the selective sensitization of cancer cells to radio-chemo-therapy. Dr. Fath's research andexpertise will help build the knowledge base in an active NCI P01 grant in order to identify novel mechanismsthat can be exploited to capitalize on the use of pharmacological ascorbate in cancer therapy. NCI 10694861 8/31/23 0:00 PAR-18-888 5R50CA243693-05 5 R50 CA 243693 5 "XI, DAN" 9/17/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 8604807 "FATH, MELISSA ANN" Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF MEDICINE 522421320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 155127 NCI 100406 54721 AbstractDr. Melissa Fath is currently 100% supported by the program project grant entitled Exploiting RedoxMetabolism Using Pharmacological Ascorbate (P-AscH) for Cancer Therapy (P01 CA217797). The theme ofthis P01 is exploiting cancer cell redox metabolism using pharmacological ascorbate (P-AscH-; high doseintravenous vitamin C) for improving cancer therapy. The P01 is composed of 3 major research projects and 3core facilities. The proposal is highly integrated and focused on preclinical translational and clinical studiesrelevant to the use of P-AscH in cancer therapy and Dr. Fath's research will impact all three of the researchprojects and two of the cores. This R50 application proposes 100 % salary support for Dr. Fath to support allthe projects and two cores in the P01 research program as well as any new research initiatives funded by NCIthat may arise from that work. The Unit Director of the current proposal Dr. Douglas Spitz is part of the multi-PI leadership team as well as the principle investigator on Project 2 Exploiting Labile Iron Pools for ImprovingNSCLC Therapy Using Pharmacological Ascorbate. Specifically Project 2 in the P01 will test the hypothesisthat P-AscH selectively sensitizes non-small cell lung cancers to radiation and chemotherapy by selectivelyincreasing cancer cell steady-state levels of H2O2 as a result of specific disruptions in redox-active ironmetabolism mediated by endogenous levels of O2.-/H2O2 . The Free Radical and Radiation Biology Program(FRRBP) in the Department of Radiation Oncology at the University of Iowa is an ideal scientific environmentfor this proposed research because of its historic roots in radiation biology as well as the free radical theory ofcancer in association with a strong Radiation Oncology Department. Dr. Spitz is the division director of FRRBPand Dr. Fath is an associate research scientist that has been an active collaborative member for over 10 years.Dr. Fath has considerable expertise in testing the involvement of free radicals thiol oxidation redox sensitivesignaling pathways and oxidative damage end-points in many studies exploiting manipulations of redoxmetabolism to repurpose drugs for cancer therapy. Her background and training in Clinical PharmacyMedicinal & Natural Products Chemistry and Free Radical Cancer Biology make her ideally suited to work inthis highly collaborative and integrated group doing both in vitro and in vivo translational research as well assupporting clinical trials. Dr. Fath will focus on the redox biology of O2- and H2O2 as well as the involvement ofFe metabolism in the differential effects of that mediate P-AscH- induced radio-chemotherapy sensitization.She will quantify radio-chemo- sensitization measure steady-state H2O2 study and manipulate labile ironpools using both pharmacological and genetic approaches and assess oxidative stress and DNA damageendpoints in cancer treatment models. In addition Dr. Fath will be responsible for measuring biomarkers ofoxidative stress in the clinical trials and determining if they correlate to clinical responses. It is clear that Dr.Fath's experience and expertise is invaluable to P01 CA217797 and she is well-qualified as a candidate for theP50 award mechanism. 155127 +No NIH Category available Acute;Address;Adherence;Adult;American;Area;Cancer Survivor;Cancer-Predisposing Gene;Caring;Childhood Cancer Survivor Study;Clinical;Clinical Trials;Cohort Studies;Communities;Community Clinical Oncology Program;Community Practice;Consolidated Framework for Implementation Research;Cost Analysis;Counseling;DNA Sequence Alteration;Data;Distress;Enrollment;Evidence based practice;Family Cancer History;Future;Genetic;Genetic Carriers;Genetic Counseling;Genetic Models;Genetic Services;Geography;Germ-Line Mutation;Guidelines;Health;Healthcare Systems;Home;Hybrids;Individual;Inferior;Inherited;Intervention;Intervention Trial;Knowledge;Location;Malignant Neoplasms;Mammography;Mental Depression;Methods;Modeling;National Comprehensive Cancer Network;Outcome;Participant;Pathogenicity;Patient-Focused Outcomes;Patients;Pediatric Oncology Group;Population;Preventive measure;Provider;Publishing;Randomized;Recommendation;Reporting;Risk;Risk Reduction;Screening for cancer;Service delivery model;Services;Site;Specialist;Survivors;System;TP53 gene;Telephone;Testing;Travel;Videoconferencing;Woman;Work;arm;barrier to testing;biomedical referral center;brca gene;cancer diagnosis;cancer genetics;cancer predisposition;cancer therapy;childhood cancer survivor;cohort;effectiveness evaluation;effectiveness study;efficacy evaluation;evidence based guidelines;gaps in access;genetic testing;group intervention;high risk;implementation evaluation;implementation study;improved;incremental cost-effectiveness;innovation;intervention cost;malignant breast neoplasm;mutation carrier;patient population;precision medicine;primary care provider;prophylactic mastectomy;remote delivery;sarcoma;screening guidelines;sociodemographics;telegenetics;telephone delivery;three-arm study;treatment as usual;uptake;usual care arm;videoconference Improving Delivery of Genetic Services to High Risk Childhood Cancer Survivors: A Randomized Study of Remote Genetic Services Versus Usual Care PROJECT NARRATIVEIn this proposal we are proposing a randomized intervention trial to examine the efficacy of remote geneticservices (videoconferencing or phone) as compared to usual care to increase the uptake of genetic testingaccording to published guidelines in childhood cancer survivors in the North American cohort study theChildhood Cancer Survivor Study (U24 CA 55727). We plan to evaluate the effectiveness of remotevideoconferencing to provide greater knowledge as well as decrease in distress and depression with geneticservices as compared to telephone delivery as well as the moderators of patient outcomes and have plannedan incremental cost-effectiveness of the three study arms. We expect our findings will provide critical data toprovide the basis for further dissemination of these services among cancer survivors and other populations inneed of specialized genetic services. NCI 10694845 6/28/23 0:00 PAR-18-559 5R01CA237369-04 5 R01 CA 237369 4 "RANDHAWA, GURVANEET" 7/8/20 0:00 6/30/25 0:00 Psychosocial Risk and Disease Prevention Study Section[PRDP] 9188566 "HENDERSON, TARA OLIVE" "BRADBURY, ANGELA R." 1 PEDIATRICS 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 658129 NCI 584276 73853 PROJECT SUMMARYGermline cancer genetic testing has become a standard evidence-based practice with risk reduction andcancer screening guidelines for genetic carriers. Yet many at-risk patients do not have access to geneticservices leaving many genetic carriers unidentified. Given increasing precision medicine applications and alimited and geographically restricted workforce of genetic providers innovative delivery models for geneticservices that are responsive to the needs of geographically and sociodemographically diverse patientpopulations in their local health care systems are needed. Suboptimal access to genetic services is an acuteproblem for childhood cancer survivors who have high rates of subsequent malignant neoplasms (SMN).Studies indicate that >10% of survivors carry a pathogenic or likely pathogenic germline mutation in cancersusceptibility genes (eg. TP53 BRCA ). In order to identify high-risk survivors for early surveillance andintervention NCCN and Children's Oncology Group Guidelines recommend that survivors with a personaland/or family history of cancer be referred for genetic services. However <15% of these survivors have accessto genetic counseling services and both survivors and their Primary Care Providers (PCPs) are largelyunaware of their health risks and thus adherence to high-risk surveillance guidelines is low. Our studies inadult patients with a personal or family history of cancer suggest that remote telegenetic services (by phone orvideoconferencing) may increase access to genetic services and identification of genetic mutation carriers. Yetour current studies have examined these models partnering on-site with community oncology practices limitingscalability. This is of particular importance for childhood cancer survivors who are widely distributed nationallyand >85% are receiving their care with PCPs. Thus our premise is that our adapted in-home collaborativePCP model of remote telegenetic services can provide a scalable model that will result in increased uptake ofevidence-based recommendations for cancer genetic services in survivors. We propose a 3-arm randomizedHybrid 1 effectiveness and implementation study in the Childhood Cancer Survivor Study (CCSS) to evaluatethe effectiveness of our in-home collaborative PCP model of remote telegenetic services to increase uptakeof cancer genetic testing in childhood cancer survivors compared to usual care (Aim 1) to evaluate theeffectiveness of videoconferencing to provide greater increase in knowledge and decrease in distress anddepression as compared to remote phone services (Aim 2a) the moderators of patient outcomes (Aim 2b) anda cost evaluation of the three study arms (Aim 2c). Also we will conduct a multi-stakeholder mixed-methodsimplementation evaluation to understand patient provider and system factors associated with uptake of ourremote telegenetic services model facilitators and barriers to uptake and recommendations for futureadaptation and sustainability (Aim 3). We expect our findings will provide critical data for the basis for furtherdissemination of these services among cancer survivors and other populations in need of genetic services. 658129 +No NIH Category available ATAC-seq;Antigens;Autologous;B lymphoid malignancy;B-Cell Acute Lymphoblastic Leukemia;Base Excision Repairs;Biological;Biological Assay;CAR T cell therapy;CD19 gene;CD8-Positive T-Lymphocytes;Cancer Patient;Cell Differentiation process;Cell Extracts;Cell Therapy;Cell physiology;Cells;Cellular immunotherapy;ChIP-seq;Chromatin;Chromatin Structure;Clonal Expansion;DNA;DNA Methylation;DNA Modification Process;DNA Sequence Alteration;DNA biosynthesis;DNA methylation profiling;Dioxygenases;Disease;Enzymes;Epigenetic Process;Excision;Exhibits;Functional disorder;Gene Expression;Genes;Genetic Transcription;Genome;Health;Histones;Human;Immune;In Vitro;In complete remission;Individual;Knock-out;Laboratories;Link;Longevity;Malignant Neoplasms;Maps;Measures;Mediating;Memory;Nature;Outcome;Pathway interactions;Patients;Phenotype;Play;Post-Translational Protein Processing;Proliferating;Property;Proteins;Regulation;Relapse;Research;Resolution;Role;Scientific Advances and Accomplishments;Shapes;Site;T cell differentiation;T memory cell;T-Cell Proliferation;T-Lymphocyte;Treatment Failure;Tumor Immunity;Tumor-infiltrating immune cells;base;cancer cell;cell type;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;chromatin remodeling;cytotoxicity;demethylation;engineered T cells;epigenetic regulation;exhaustion;histone modification;improved;improved outcome;in vitro Assay;in vivo;leukemia;methylome;mouse model;mutant;oxidation;patient response;personalized cancer therapy;receptor;refractory cancer;response;restraint;senescence;stem cells;success;transcriptome;transcriptome sequencing;tumor Mechanisms of TET2-dependent control of CAR T cell fate determination and antitumor function PROJECT NARRATIVEChimeric antigen receptor (CAR) T cells have been a breakthrough in personalized cancer treatment; however this therapy is not effective for many patients. Preliminary findings suggest that the epigenetic modifier TET2 is involved in controlling T cell fate and function; thus I propose to investigate TET2 to identify strategies to improve CART cell efficacy in response to tumor challenge. By investigating the mechanisms and extent to which TET2 modulates antitumor T cell function this research has the potential to improve patient responses to CAR T cell therapy as well as illuminate more general mechanisms by which DNA modifying enzymes alter the epigenetic landscape to regulate gene expression. NCI 10694842 8/1/23 0:00 PA-21-051 5F31CA274961-02 5 F31 CA 274961 2 "PURI, ANU" 8/1/22 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16287219 "HOPKINS, CAITLIN ROSEMARY" Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 ABSTRACTRecent scientific advancements have made chimeric antigen receptor (CAR) T cell therapy a prom1s1ng treatment option for relapsed and refractory cancers. In this strategy T cells are extracted from the patient and reprogrammed and then reinfused into the subject to seek out and destroy cancer cells. However not all individuals respond to this treatment and therefore a better understanding of the mechanisms that underlie antitumor immune cell function is required to improve response rates. Successful therapy has been linked to increased CART expansion long-term persistence as well as early memory differentiation and approaches to augment these properties could greatly enhance CAR T cell potency. DNA modifying enzymes such as the methylcytosine dioxygenase TET2 may be involved in the control of T cell differentiation and function and TET2 disruption leads to increased T cell proliferation longevity and early memory differentiation. However the role of TET2 in regulating CAR T cell fate and function is not well understood. I hypothesize that TET2 catalytically and non-catalytically regulates CAR T cell differentiation and antitumor activity by direct alteration of DNA methylation status as well as through chromatin remodeling. The catalytic function of TET2 induces active DNA demethylation through successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) 5- formylcytosine (5fC) and 5-carboxylcytosine (5caC). Demethylation is then achieved through either passive dilution of 5hmC or active excision of 5fC and 5caC. The biological impact of these two active demethylation pathways in CART cells is not understood. In Aim 1 I propose to elucidate the role of TET2-catalyzed changes to the methylome in mediating CART cell differentiation and effector function. I postulate that the active excision commitment step converting 5hmC to 5fC is indispensable for TET2-mediated control of T cell differentiation and antitumor function. To evaluate this I will investigate the effect of halting oxidation at the 5hmC step on differentiation antitumor function and global as well as site-specific DNA methylation profiles in CAR T cells. Additionally TET2 impacts chromatin structure through both catalytic and non-catalytic mechanisms involving interactions between histone modification proteins. The role of TET2-induced changes to chromatin structure on T cell fate is also currently unknown. In Aim 2 I will determine how chromatin remodeling by TET2 impacts regulation of CAR T cell differentiation and function. I hypothesize that TET2 influences changes to local chromatin structure through catalytic and non-catalytic activities to regulate CAR T cell differentiation and antitumor function. Thus I will investigate the effect of eliminating TET2 catalytic function on the differentiation antitumor efficacy and the epigenetic landscape of CAR T cells compared to simultaneous knockout of both catalytic and non-catalytic activity and stalled catalytic function. Together these aims will improve our understanding of TET2 function in regulating T cell-mediated tumor control and inform strategies to safely modulate TET2 activity to improve outcomes with CART cell therapy. 47694 +No NIH Category available 3-methyladenine;Affinity;Animals;Binding;Biological Assay;Biology;Bioluminescence;Cell model;Cells;Chemicals;Companions;Complex;Coupling;Degradation Pathway;Dihydrofolate Reductase;Dose;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Engineering;Escherichia coli;Excretory function;Family member;Firefly Luciferases;Flow Cytometry;Genes;Genetic;Goals;Guanosine Triphosphate Phosphohydrolases;Homologous Gene;Hour;Human;Hydroxychloroquine;Image;Imaging Techniques;Immunotherapy;Interleukin-2;Investments;Kinetics;Knock-out;Lead;Length;Libraries;Ligands;Luciferases;Lymphocyte;Lymphocyte-Specific p56LCK Tyrosine Protein Kinase;Malignant neoplasm of ovary;Measures;Mediating;Metabolism;Modeling;Molecular;Mus;Output;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Positron-Emission Tomography;Process;Property;Protac;Proteins;Proteolysis;RNA Interference;Radiolabeled;Radiopharmaceuticals;Regulation;Reporter;Reporter Genes;Research;Research Personnel;Rodent Model;Series;Signal Transduction;Specificity;Synthesis Chemistry;System;Technology;Tertiary Protein Structure;Testing;Therapeutic;Tissue Model;Tissue imaging;Trimethoprim;Ubiquitination;Validation;Western Blotting;Work;absorption;analog;bioluminescence imaging;cancer cell;career;cell growth regulation;clinically relevant;design;drug-like compound;efficacy evaluation;enzyme substrate;epoxomicin;experimental study;first-in-human;imaging capabilities;imaging probe;imaging study;improved;in vitro Assay;in vitro activity;in vivo;in vivo monitoring;inhibitor;interest;kidney cell;knock-down;molecular imaging;multicatalytic endopeptidase complex;mutant;nanomolar;novel;nuclear imaging;pomalidomide;portability;protein degradation;protein expression;quantitative imaging;radiotracer;response;scaffold;skills;small molecule;small molecule inhibitor;technology development;tissue culture;tool;tool development;tumor xenograft;ubiquitin-protein ligase;uptake;virtual Developing a genetic tag for in vivo protein regulation using PROTACs with companion PET imaging Project NarrativeHere we focus our skills in tool development and molecular imaging to engineer a portable protein domain and complementary small molecules for ligand-mediated protein knockdown. We accomplish this by designing a protein handle derived from E. coli dihydrofolate reductase and complementary probes from inhibitor trimethoprim which have been retrofitted for both proteolysis targeted chimera (PROTAC) mediated knockdown and positron emission tomography (PET) reporter imaging. This strategy would give researchers the ability to modulate protein activity of virtually any desired gene and study the outputs of these changes in vivo. NCI 10694841 8/1/23 0:00 PA-21-051 5F31CA275040-02 5 F31 CA 275040 2 "BOULANGER-ESPEUT, CORINNE A" 8/1/22 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-F15-P(20)L] 16324967 "ETERSQUE, JEAN MARIE" Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 35250 NCI 35250 0 Project Summary/AbstractThe following proposal describes my aims to use a known protein-ligand pair as a scaffold to create a molecular tool kit composed of small molecule degraders for protein regulation and nuclear imaging probes. Specifically this molecular tool kit is comprised of a small protein domain E. coli dihydrofolate reductase (eDHFR) and its small molecule inhibitor trimethoprim (TMP). TMP can be modified to function as a proteolysis targeted chimeric (PROTAC) molecule capable of protein regulation in a dose-dependent and reversible fashion. Additionally our group has developed eDHFR as a positron emission tomography (PET) imaging reporter protein capable of imaging engineered cells in vivo. Taken together my approach would give researchers the ability to modulate protein activity of any desired gene and quantitatively study the phenotypic outputs of these changes in animals and potentially in human patients.PROTAC regulation is the leading ligand-mediated knockdown approach for controlling cellular protein activity. Ligand-mediated strategies allow researchers to tune knockdown intensity with temporal precision. I have demonstrated that the eDHFR-TMP PROTAC system can induce 95% degradation of eDHFR-tagged protein in OVCAR8 cells at nanomolar concentration within 24 hours. I have also demonstrated that this process is reversible and proceeds through a proteolysis-mediated degradation mechanism. We are expanding this technology to determine if we can regulate diverse proteins in multiple subcellular compartments.Ultimately this suite of molecular tools will provide a modular system for rapidly inducible and reversible knockdown of proteins of interest that can be analyzed quantitatively in clinically relevant models and potentially in human therapies. To advance these molecular tools for in vivo use I will establish the kinetics of target degradation of the eDHFR-TMP PROTAC in OVCAR8 xenograft tumor models in mice using bioluminescence imaging. I hypothesize that the protein level response of eDHFR-luciferase will lag behind target-occupancy of TMP PROTAC in vivo. Therefore simultaneous PROTAC administration and PET imaging of eDHFR with established [18F]fluoropropyl-trimethoprim ([18F]FPTMP) radiotracer in mice will accurately quantify PROTAC specificity and kinetic activity. Overall this work is a novel application of PROTAC and PET technology where together these tools can be used to probe expression in vivo modulate protein activity and potentially be incorporated into human immunotherapies to improve therapeutic outputs. 35250 +No NIH Category available Abnormal Myeloid Cell;Acute Myelocytic Leukemia;Adult;Agonist;Blast Cell;CRISPR/Cas technology;Cell Death;Cell Differentiation Induction;Cell Differentiation process;Cell Maturation;Cell physiology;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Cessation of life;Characteristics;Clinical;Clonal Expansion;DNMT3a;DNMT3a mutation;Data;Disease;Event;FLT3 gene;Genes;Genetic Transcription;Goals;Growth;Hematologic Neoplasms;Hematopoietic;Hematopoietic stem cells;Heterogeneity;Human;ITGAM gene;Immune;Immune response;Immune signaling;Immune system;Impairment;In Vitro;Inflammatory;Inflammatory Response;Innate Immune Response;Lead;Leukemic Cell;Macrophage;Maps;Mediating;Molecular;Mus;Mutant Strains Mice;Mutate;Mutation;Myelogenous;Myeloid Cells;Pathogenesis;Pathway interactions;Patients;Pattern;Phenotype;Phosphorylation;Population;Production;Prognosis;Proliferating;Publishing;Receptor Signaling;Role;Sampling;Signal Induction;Signal Pathway;Signal Transduction;Specimen;Surface;System;TLR2 gene;Testing;Therapeutic;Therapeutic Agents;Time;Toll-like receptors;Work;acute myeloid leukemia cell;cell type;cytokine;directed differentiation;immune activation;in vivo;leukemia;leukemia treatment;loss of function;monocyte;mouse model;mutant;neutrophil;novel;novel strategies;pathogen;progenitor;prospective;receptor;response;self-renewal;stem;stem-like cell;stemness;transcription factor;transcriptional reprogramming Interrogation of TLR2 Inflammatory Signaling in AML PROJECT NARRATIVEA major therapeutic goal in acute myeloid leukemia (AML) is to promote differentiation of immature blast cells toa more mature cell state that would cause AML cells to lose proliferative and self-renewal capacity and beeliminated. Preliminary data uncover a novel approach to induce differentiation of Dnmt3a/Flt3-mutant AML bothin vitro and in vivo. This proposed study will fully elucidate the phenotypic and signaling consequences of TLR2activation on DNMT3A-mutant AML and provide the first single cell map of innate immune signaling in AML cellswhich will reveal genes and/or pathways that can be leveraged therapeutically for AML treatment. NCI 10694840 8/30/23 0:00 PA-21-051 5F31CA268843-02 5 F31 CA 268843 2 "SCHMIDT, MICHAEL K" 9/1/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16453764 "LAWLER, MICHAEL " Not Applicable 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARY Acute myeloid leukemia (AML) is defined as a clonal expansion of abnormal myeloid blasts which areimpaired to differentiate into mature and functional myeloid cells. Toll-like receptors (TLRs) are pathogen-associated molecular pattern (PAMP) receptors that specialize in recognizing foreign pathogens and elicit aninnate immune response through promoting myeloid cell differentiation and inflammatory cytokine production.The role of TLR signaling in AML is poorly understood and the mechanisms involved in an innate immuneresponse through TLRs and whether this induces differentiation and/or cell death of AML blasts is unclear. Twoof the most commonly mutated genes in AML are FLT3 and DNMT3A where 20% of AML patients can be foundwith co-occurring mutations which results in a poor prognosis. Preliminary data indicate that TLRs are expressedon the surface of AML cells and stimulation of these receptors produces a proinflammatory response associatedwith AML blast differentiation. In sum I identify in DNMT3A-mutant AML a TLR signaling network that regulatesdifferentiation of AML and increases the survival of this common and clinically poor AML subtype which can leadto a prospectively new differentiating/therapeutic agent for AML treatment. 47694 +No NIH Category available Address;Adherence;Adolescent and Young Adult;Adolescent and young adult cancer patients;Adopted;Adoption;Age;Anxiety;Behavior Therapy;Behavioral;Cancer Burden;Cancer Patient;Caring;Cellular Phone;Childhood;Chronic Disease;Clinic;Clinical;Clinical Trials;Cognitive;Cognitive Therapy;Collaborations;Dedications;Dependence;Development;Development Plans;Distress;Dose;Education;Educational process of instructing;Elderly;Employment;Enrollment;Environment;Funding;Future;Gender;Goals;Health Personnel;Health Services Accessibility;Health behavior;Improve Access;Intervention;Interview;Knowledge;Learning;Linear Regressions;Long Term Survivorship;Malignant Neoplasms;Measures;Medical;Mental Depression;Mental Health;Mentors;Mentorship;Methodology;Methods;Modeling;Oncology;Outcome;Patients;Pattern;Persons;Population;Psychosocial Assessment and Care;Qualitative Methods;Qualitative Research;Quality of life;Race;Randomized;Recording of previous events;Research;Research Methodology;Research Personnel;Risk;Scientist;Secure;Service delivery model;Site;Social isolation;Statistical Methods;Stress;Structure;Technology;Testing;Time;Training;Unemployment;Waiting Lists;Well in self;Work;Youth;acceptability and feasibility;age related;career;career development;cohort;coping;cost;cost effectiveness;design;digital;digital technology;disability;effectiveness/implementation trial;evidence base;experience;follow-up;health related quality of life;high risk;implementation measures;implementation outcomes;implementation science;implementation strategy;improved;improved outcome;innovation;interest;mHealth;meetings;mindfulness;mindfulness intervention;multidisciplinary;novel;patient engagement;pilot trial;portability;post-traumatic stress;prevent;programs;promote resilience;psychosocial;randomized trial;research and development;resilience;response;retention rate;scale up;self help;skill acquisition;skills;stress management;theories;treatment as usual;treatment effect;usual care arm;young adult Pilot trial testing mobile health psychosocial intervention for Adolescentsand Young Adults with cancer PROJECT NARRATIVECancer among Adolescents and Young Adults (AYAs) is associated with poor psychosocial outcomes andquality of life and patients experience disproportionately high levels of anxiety depression and posttraumaticstress in relation to their younger pediatric and older adult counterparts. Findings from the proposed project willhelp address the unmet psychosocial needs of AYA cancer patients using a novel mobile health psychosocialcare delivery model with the advantages of appeal reach and cost-effectiveness. Ultimately this work may helpimprove patient health-related quality of life and emotional well-being and reduce the burden of cancer byexpanding access to evidence-based care. NCI 10694835 8/7/23 0:00 PA-20-202 5K08CA263474-02 5 K08 CA 263474 2 "RADAEV, SERGEY" 9/1/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 14656284 "LAU, NANCY " Not Applicable 7 Unavailable 48682157 SZ32VTCXM799 48682157 SZ32VTCXM799 US 47.66243 -122.282291 1531401 SEATTLE CHILDREN'S HOSPITAL SEATTLE WA Independent Hospitals 981053901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 203831 NCI 189103 14728 "PROJECT SUMMARY/ABSTRACTIn addition to coping with their medical illness Adolescents and Young Adults (AYAs) with cancer struggle withthe age-related developmental challenges of independence education employment relationships andidentity. AYAs with cancer are at high risk of poor short-term and long-term outcomes including poor mentalhealth social isolation risky health behaviors unemployment and poor quality of life. With the rapid rise indigital technologies skills-based psychosocial interventions are increasingly deployed via mobile health(mHealth) platforms. Such interventions show promising treatment effects help overcome barriers to traditionalin-person delivery models and are highly appealing to AYAs. However mHealth interventions focused onimproving quality of life and psychosocial outcomes have not yet been successfully evaluated or implementedamong AYA cancer patients. This application builds on my prior work with the ""Promoting Resilience in StressManagement"" (PRISM) intervention for AYAs with cancer. This novel brief evidence-based 1:1 interventionteaches stress management goal-setting meaning making cognitive-behavioral and mindfulness strategies. Iand my team have adapted this in-person intervention to a self-guided mHealth intervention mPRISM. Thismixed-methods proposal has the following 3 complementary aims: (Aim 1) To evaluate the feasibilityacceptability and exploratory efficacy of mPRISM for AYAs with cancer in a pilot randomized trial; (Aim 2) Toanalyze backend digital usage patterns in order to identify and target aspects of digital engagement associatedwith improvement in psychosocial outcomes; and (Aim 3) To assess barriers and facilitators to the adoption ofmHealth interventions in clinical settings via semi-structured exit interviews with patient and clinic stakeholders.This proposal has technological methodological and dissemination innovations in potential for scale-up ofinterventions to overcome structural barriers to psychosocial treatment access. This K08 will provideopportunities to acquire skills and knowledge in: advanced clinical trials research as PI; mHealth researchincluding intervention testing digital analytics and strategies to optimize engagement and adoption; andadvanced implementation science methods. The research and career development plan supported by a multi-disciplinary team of experts (in AYA oncology implementation science mHealth and mobile analytics clinicaltrials research advanced statistics and qualitative methods) and in a rich academic environment will supportthe PIs transition to an independent clinical-scientist who possesses the skills and expertise to use cutting-edge mobile health methods to promote the implementation of evidence-based care for AYA oncology patients.This proposal will inform the design of the PIs large-scale multi-site hybrid effectiveness-implementation trial ofmPRISM (R01 proposal). Aligned with the NCIs priorities this program of research will promote evidence-based behavioral interventions that improve quality of life the utilization of portable low-cost technologies toexpand access to care and implementation science initiatives to bridge the research-practice gap." 203831 +No NIH Category available Adjuvant Therapy;Adoption;Biological Markers;Chemotherapy and/or radiation;Cisplatin;Clinical Trials Design;Data;Discrimination;Disease;Distant;Gene Expression;Genes;Genetic;Goals;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Human Papillomavirus;Incidence;Knowledge;Longterm Follow-up;Metabolic;Modeling;Modernization;Molecular;Oncogenes;Operative Surgical Procedures;Oral;Oropharyngeal;Outcome;Papillomavirus Transforming Protein E6;Patients;Pattern;Prognosis;Prognostic Marker;Proteins;Radiation Dose Unit;Recurrence;Recurrent tumor;Risk;Robotics;Somatic Mutation;Specimen;Survivors;Testing;Time;Toxic effect;Treatment Failure;Treatment-related toxicity;Up-Regulation;Validation;Viral;Viral Genes;Viral Genome;case control;cohort;differential expression;disability;exome sequencing;follow-up;genetic variant;genome sequencing;high risk;improved;individual patient;molecular marker;novel;novel therapeutics;oral HPV-positive head and neck cancers;prevent;prospective;safe patient;side effect;tool;trait;transcriptomics;treatment optimization;treatment response;tumor Pursuing molecular biomarkers to guide adjuvant therapy for HPV+ head and neck cancers after transoral robotic surgery PROJECT NARRATIVEThis project will identify molecular features that distinguish HPV-related head and neck cancers at high vs. lowrisk of lethal recurrence after robotic surgery which has been increasingly used over the last decade to treatthis disease. Doing so may greatly aid in identifying easily curable patients would greatly benefit in reductionsin chemotherapy and radiation after surgery to prevent disabling long-term side effects of these adjuvanttreatments. At the same time defining molecular traits of the HPV-related head and neck cancers at high riskof treatment failure would facilitate testing of novel adjuvant therapies in order to prevent lethal relapses. NCI 10694795 7/26/23 0:00 PAR-20-292 5UH2CA267502-02 5 UH2 CA 267502 2 "BHARTI, SANITA" 9/1/22 0:00 7/31/24 0:00 ZCA1-SRB-P(O1)S 10079279 "BASU, DEVRAJ " Not Applicable 3 OTOLARYNGOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 148899 NCI 91630 57269 PROJECT SUMMARYThis proposal aims to optimize therapy for human papilloma virus-related (HPV+) squamous cell carcinomas ofthe head and neck (HNSCCs) which are rapidly increasing in incidence. The relatively favorable prognosis forthe HPV+ subtype of HNSCC has justified ongoing efforts to de-intensify their treatment with high doseradiation and cisplatin whose toxicities can leave lifelong disabilities in survivors. A recently popularizedapproach to therapy de-escalation is transoral robotic surgery (TORS) which has markedly altered practicepatterns for this disease and allowed for reduction in cisplatin use and radiation dosing relative to nonsurgicaltherapy. However poor ability to stratify recurrence risk after TORS is a key barrier to both safely de-escalatingadjuvant therapy for typical HPV+ HNSCCs and intensifying treatment for certain cases that are predisposed tolethal outcome. This proposal seeks to fill this knowledge gap by leveraging a unique set of archival HPV+HNSCC specimens from patients treated by TORS to pursue novel molecular biomarkers of treatmentresponse and prognosis. Our studies of older cohorts with widely variable treatment suggest worse outcomesfor HPV+ HNSCCs with high oxidative metabolic gene expression reduced E2F target gene upregulation andlower viral E6 oncogene expression. Thus our overall hypothesis is that genetic variants and expressionprofiles of both host and viral genes will allow prospective discrimination of HPV+ HNSCCs at risk of lethaloutcome after TORS-based therapy. To test this hypothesis Aim 1 will identify host and viral expressionprofiles distinguishing HPV+ HNSCCs that recur after TORS. Case-control analyses will be applied to a cohortof 634 TORS-treated HPV+ HNSCCs with uniquely long-term follow-up in order to identify viral and host genesdifferentially expressed in tumors that later recurred. Recurrent cases will be matched to nonrecurrent controlsbased on stage adjuvant therapy and follow-up. Transcriptomic analysis will be followed by protein levelvalidation for select differentially expressed genes. Aim 2 will define genetic traits of HPV+ HNSCCs that recurafter TORS and pursue a multi-marker stratifier of recurrence risk. Whole exome sequencing will be used toidentify somatic mutations and copy number alterations that distinguish tumors that recurred from nonrecurrentcontrols. In addition viral genome sequencing will be used to assess for viral subtypes sub-lineages andnonsynonymous SNPs that are over-represented in recurrence-prone tumors. Genetic traits associated withtreatment failure will be integrated with transcriptomic data to develop a multi-marker signature that stratifiesHPV+ HNSCCs for lethal recurrence risk. This assessment of molecular traits that distinguish tumors with highrecurrence risk after TORS-based therapy will create a discrete panel of molecular features that can be testedin large cohorts leading to creation of strong prognostic biomarkers under a modern treatment paradigm forHPV+ HNSCC. Such tools would dramatically enhance clinical trial design by identifying easily curable patientsfor safe reduction in adjuvant therapy and patients at high risk of treatment failure for testing of novel therapies. 148899 +No NIH Category available AIDS-Related Lymphoma;Acquired Immunodeficiency Syndrome;Apoptotic;B-Cell Antigen Receptor;B-Lymphocytes;BCL6 gene;Blood Cells;Burkitt Lymphoma;CD4 Positive T Lymphocytes;Cell Culture System;Cell Culture Techniques;Cell Line;Cells;Collaborations;EBNA2 protein;Epstein-Barr Virus Infections;Epstein-Barr Virus latency;Epstein-Barr Virus-Related Lymphoma;Gene Mutation;Growth;Growth Factor;HIV Infections;Hodgkin Disease;Human;Human Herpesvirus 4;Immunocompromised Host;In Vitro;Induction of Apoptosis;LMP1;Lymphocyte;Lymphoma;MYC gene;MicroRNAs;Modeling;Mus;Mutation;NF-kappa B;Oncogene Activation;Oncogenes;Oncogenic;PRDM1 gene;Pathway interactions;Patients;Pre-Clinical Model;Prevention;Proteins;Retroviridae;Role;STAT3 gene;Signal Transduction;Small Nuclear RNA;Structure of germinal center of lymph node;TNFRSF5 gene;TNFSF5 gene;Tumor Suppressor Genes;Tumor Suppressor Proteins;Umbilical Cord Blood;Viral;Viral Proteins;Virus;Virus Latency;cyclin D3;humanized mouse;immunogenic;in vitro Model;in vivo;in vivo Model;infected B cell;interleukin-21;large cell Diffuse non-Hodgkin's lymphoma;matrigel;mouse model;mutant;notch protein;novel;overexpression;plasma cell differentiation;public health relevance;small hairpin RNA;stable cell line;synergism;transcription factor;transforming virus;tumor;tumor microenvironment Stringent Latent Epstein-Barr Virus (EBV) Infection Collaborates with Cellular Gene Alterations to Induce EBV+ Lymphomas PUBLIC HEALTH RELEVANCEEpstein-Barr virus (EBV) is an important cause of human lymphomas including Hodgkin lymphomas (HLs)and Burkitt lymphomas (BLs) especially in immunosuppressed hosts such as AIDS patients. EBV-infectedHLs and BLs have stringent forms of viral latency (types I and II) that cannot transform B cells in vitro andthere are no in vivo models available to study how stringent EBV infection cooperates with activation ofoncogenes or inhibition of tumor suppressor genes (TSGs) to induce BLs and HLs in humans. In thisproposal we will use cord blood-humanized (and non-humanized) mouse models and a novel cell culturesystem to define mechanisms by which stringent latent EBV infection collaborates with activated oncogenesinhibited tumor suppressors and growth signals derived from the tumor microenvironment to drive BL and HLlymphomas. NCI 10694456 5/5/23 0:00 PA-20-185 1R01CA281379-01 1 R01 CA 281379 1 "DASCHNER, PHILLIP J" 7/1/23 0:00 6/30/28 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 1860327 "KENNEY, SHANNON CELESTE" Not Applicable 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 425960 NCI 255269 170691 PROJECT SUMMARY/ABSTRACTEpstein-Barr virus is an important cause of human Burkitt lymphomas (BLs) Hodgkin lymphomas (HLs) anddiffuse large B cell lymphomas (DLBCLs) particularly in AIDS patients. Although the EBV protein EBNA2 (whichmimics Notch signaling) is required for EBV-induced transformation of B cells in vitro cells that express EBNA2have the type III form of viral latency which is highly immunogenic. Thus most EBV-infected humanlymphomas including BLs HLs and DLBCLs do not express EBNA2 even in AIDS patients. There is currentlyno in vivo or in vitro model available to study how EBV infection causes lymphomas in the absence of EBNA2expression. BLs which are largely driven by MYC translocations have stringent type I latency (expressing onlya single EBV protein EBNA1) and currently the major role of EBV in BLs is thought to be prevention of MYC-induced apoptosis by the virally-encoded microRNAs. EBV+ HLs which have type II latency express only threeviral proteins (EBNA1 LMP1 and LMP2A) and are thought to be driven by the LMP1 (a CD40 mimic) and LMP2A(a BCR mimic) proteins in conjunction with cellular mutations that activate JAK/STAT signaling and a supportiveCD4+ T cell-rich microenvironment. Here we propose to use a novel in vitro cell culture model in combinationwith a cord blood-humanized (CBH) mouse model developed by our lab to examine whether an EBNA2-deletedEBV mutant recently constructed by our lab (EBNA2 EBV) can induce BL-like HL-like or DLBCL-likelymphomas in vitro or in vivo when specific oncogenic pathways known to be induced in each type of tumor areactivated or tumors suppressor genes (TSGs) associated with these tumors are inactivated. Our promisingpreliminary results already suggest that over-expressing the MYC oncogene in B cells infected with the EBNA2-deleted EBV allows cells to form BL-like tumors with type I latency in NSG mice. In Aim 1 we will determine ifEBNA2 EBV cooperates with MYC BCL6 and/or cyclin D3 over-expression to induce BL-like and/or germinalcenter (GC) type DLBCL-like lymphomas in NSG mice. In Aim 2 we will determine if EBNA2 EBV cooperateswith JAK/STAT activation or inhibition of plasma cell differentiation to cause HL-like lymphomas in NSG mice.In Aim 3 we will identify novel cellular gene mutations/alterations that cooperate with EBNA2 EBV to induceBL- and/or HL-like or DLBCL-like lymphomas in NSG mice and define the mechanism(s) for this synergy. Wehypothesize that EBNA2-deleted EBV will cooperate with cellular alterations commonly found in EBV+ BLsand/or HLs to induce BL-like and/or HL-like lymphomas in vivo (although the cellular mutations required to induceBL-like versus HL-like tumors will be different) and that our approach will also identify novel cellular genealterations that cooperate with stringent EBV latency to cause AIDS-related lymphomas in humans. 425960 +Bioengineering; Biomedical Imaging; Cancer; Health Disparities; Radiation Oncology; Rural Health; Social Determinants of Health Aftercare;Architecture;Communication;Development;Dimensions;Focused Ultrasound Therapy;Future;Home;Image;Medical center;Monitor;Nature;Patients;Phase;Resource-limited setting;Rural;Small Business Innovation Research Grant;Speed;System;Training;Travel;Ultrasonic Therapy;Ultrasonography;cancer therapy;cost;digital;effective therapy;metastatic colorectal;metropolitan;operation;portability;tumor SBIR Phase I - Topic 431 -A Fully Digital Volumetric Ultrasound Imaging and Therapy System for Low Resource Environments n/a NCI 10694439 75N91022C00017-0-9999-1 N43 9/15/22 0:00 9/14/23 0:00 78841389 "BARNES, STEPHEN " Not Applicable 1 Unavailable 80469008 GWAFA7AB81Z7 80469008 GWAFA7AB81Z7 US 34.053275 -118.534568 10055770 ACOUSTIIC INC. Bellevue WA Domestic For-Profits 980052019 UNITED STATES N R and D Contracts 2022 399846 NCI Acoustiic will revolutionize cancer treatment in low resource settings by development of the first fully digital (no moving parts) system to image target and non-invasively destroy tumors with Volumetric High Intensity Focused Ultrasound (HIFU). The system will enable treatment in low resource environments due to its ease of use low training requirements compact nature for portability relatively low cost compared to alternatives ongoing monitoring during and post treatment and the non-invasive aspect of the treatment. Moreover it can be controlled remotely to target and treat tumors such as metastatic colorectal carcinoma allowing patients who live in rural remote settings to get effective treatment at home without frequent traveling to urban/metropolitan medical center. 399846 +Behavioral and Social Science; Cancer; Health Disparities; Sexual and Gender Minorities (SGM/LGBT*); Women's Health Administrative Coordination;Administrative Supplement;Award;Basic Science;Biostatistics Shared Resource;Budgets;Businesses;COVID-19 pandemic;California;Cancer Center;Cancer Center Support Grant;Cancer Science;Catchment Area;Clinical Research;Clinical Trials;Collaborations;Communication;Communities;Community Outreach;Complement;Complex;Comprehensive Cancer Center;County;Data;Data Collection;Data Science;Doctor of Philosophy;Educational Activities;Electronic Mail;Ensure;Equipment;Evaluation;Event;Faculty;Faculty Recruitment;Fostering;Funding;Future;Gender Identity;Gifts;Goals;Grant;Guidelines;Human Resources;Informatics;Information Technology;Infrastructure;Investments;Last Name;Leadership;Los Angeles;Malignant Neoplasms;Mission;NCI Center for Cancer Research;Names;Office of Administrative Management;Outcome;Patients;Peer Review;Policies;Population Research;Positioning Attribute;Preparation;Process;Productivity;Publications;Ramp;Reporting;Research;Research Personnel;Resource Sharing;Science;Services;Sex Orientation;Shapes;Strategic Planning;Structure;System;Training;Training and Education;Translational Research;Universities;anticancer research;base;cancer research center director;clinical investigation;community engagement;drug development;improved;innovation;meetings;member;operation;pre-clinical;programs;ranpirnase;recruit;science education;social media;square foot;tool;web site Administrative Core n/a NCI 10694272 9/8/22 0:00 PA-20-272 3P30CA014089-46S2 3 P30 CA 14089 46 S2 "HE, MIN" 12/1/96 0:00 11/30/26 0:00 7499 1875698 "LERMAN, CARYN " Not Applicable 37 Unavailable 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA Domestic Higher Education 900894304 UNITED STATES N 5/10/22 0:00 11/30/22 0:00 Research Centers 2022 150000 90909 59091 PROJECT SUMMARY - NCCC Administration (NCCC-A)The University of Southern California (USC) Norris Comprehensive Cancer Center (NCCC) is a matrix cancercenter with a longstanding tradition of exceptional science across the spectrum of basic clinical translationaland population research. NCCC Administration (NCCC-A) provides the critical infrastructure to support theDirector Associate Directors Program Leaders Shared Resources (SRs) 187 members and NCCC officesand external stakeholders engaged in cancer research community outreach and engagement and training andeducation. Over this grant period NCCC-A has undergone a major transformation to completely reshapeadministrative support for NCCC in order to improve its impact value efficiency and alignment with CCSGguidelines. Under the strong leadership of new NCCC Director Caryn Lerman PhD and Associate Director forAdministration Christopher Loertscher MA NCCC-A achieved many accomplishments over this grant periodincluding to: 1) help develop and implement a new Strategic Plan; 2) coordinate a major reorganization of thefive NCCC Research Programs and the six SRs presented in this application; 3) reorganize and expand theadministrative staff structure with three new senior administrative managers to expand expertise in finance SRsmanagement grants administration research informatics and communications; 4) revamp NCCC membershipand space policies to enhance cancer focus; 5) implement new tools to improve reporting on grants publicationspilot awards and clinical trials; 6) provide support to recruit and onboard 40 new external faculty; and 7)coordinate ramp-down and resumption of NCCC activities during the COVID-19 pandemic. NCCC-A managesall finances pilot awards grants space and SRs including NCCC's annual operating budget of $37 million(FY2020). It supports all governance and programmatic meetings and retreats to propel the NCCC researchenterprise to greater collaboration and innovation. NCCC-A manages NCCC's 300000 sq. ft. of space acrossthe three NCCC-dedicated buildings under the control of the Director. In the next grant period NCCC-A willcontinue to execute the initiatives within the new NCCC 2020-2025 Strategic Plan by providing critical supportto: hasten the pace of cancer discovery; recruit new high impact collaborative faculty; increase the impact ofcommunity outreach and engagement as well as training and education; and foster new team science grantsthrough targeted RFAs and administrative activities that foster new collaborations. The efforts of NCCC-Acontributed to a 18% increase in total cancer research funding (11% increase in peer-reviewed fundingincluding a 22% increase in NCI funding) over this grant period. +No NIH Category available Adolescent;Adverse event;Australia;Biology;Canada;Cancer Center;Cancer Patient;Child Support;Childhood;Childhood Cancer Treatment;Clinical;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Clinical Trials Design;Collaborations;Collection;Communities;Companions;Country;Data;Diagnosis;Disease;Ensure;Family;Foundations;Generations;Goals;Industry;Infrastructure;Interdisciplinary Study;Knowledge;Laboratories;Leadership;Malignant Childhood Neoplasm;Methods;Molecular;Monitor;New Zealand;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Phase;Procedures;Process;Quality of life;Reporting;Research;Research Personnel;Science;Survivors;Time;Translational Research;United States;Universities;anticancer research;base;data centers;data management;design;functional outcomes;improved outcome;innovation;member;multidisciplinary;organizational structure;programs;research study;statistics;translational clinical trial;translational study COG SDMC - Data Management Core n/a NCI 10694249 9/3/22 0:00 RFA-CA-17-057 3U10CA180899-09S2 3 U10 CA 180899 9 S2 "MOONEY, MARGARET M" 4/15/14 0:00 2/28/25 0:00 ZCA1-GRB-S 7489 1857551 "ALONZO, TODD A" Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 565797 598773 112251 PROJECT SUMMARY / ABSTRACTThis is the Data Management Core to support the overall application for the Children's Oncology Group Statisticsand Data Management Center. +No NIH Category available Adolescent;Australia;Biology;Canada;Cancer Center;Cancer Patient;Caring;Child Support;Childhood;Childhood Cancer Treatment;Clinical;Clinical Research;Clinical Trials Design;Collaborations;Communities;Companions;Country;Data;Development;Diagnosis;Disease;Ensure;Foundations;Generations;Genomics;Goals;Interdisciplinary Study;Investigation;Knowledge;Laboratories;Leadership;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Molecular;Monitor;Morbidity - disease rate;New Zealand;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Population Research;Quality of life;Reporting;Research;Science;Statistical Data Interpretation;Survivors;Translational Research;United States;Universities;anticancer research;base;data centers;data management;density;design;functional outcomes;improved;improved outcome;innovation;member;mortality;multidisciplinary;novel;organizational structure;programs;research study;statistics;survivorship;translational clinical trial;translational scientist;translational study;trial design COG SDMC - Statistics Core n/a NCI 10694248 9/3/22 0:00 RFA-CA-17-057 3U10CA180899-09S2 3 U10 CA 180899 9 S2 "MOONEY, MARGARET M" 4/15/14 0:00 2/28/25 0:00 ZCA1-GRB-S 7488 1857551 "ALONZO, TODD A" Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 580850 676628 68332 PROJECT SUMMARY / ABSTRACTThis is the Statistics Core to support the overall application for the Children's Oncology Group Statistics andData Management Center. +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Coronaviruses; Pediatric; Pediatric Cancer; Rare Diseases Adolescent;Australia;Biology;Canada;Cancer Center;Cancer Patient;Child Support;Childhood;Childhood Cancer Treatment;Clinical;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Clinical Trials Design;Collaborations;Communities;Companions;Country;Data;Development;Diagnosis;Disease;Ensure;Family;Foundations;Generations;Genomics;Goals;Industry;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Leadership;Malignant Childhood Neoplasm;Medidata;Methods;Molecular;Monitor;New Zealand;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Performance;Policies;Population Research;Quality of life;Reporting;Research;Research Personnel;Science;Structure;Survivors;Time;Translational Research;United States;Universities;anticancer research;base;data centers;data management;data sharing;density;design;functional outcomes;improved;improved outcome;innovation;member;multidisciplinary;organizational structure;programs;research study;statistics;translational clinical trial;translational study COG SDMC - Administrative Core n/a NCI 10694247 9/3/22 0:00 RFA-CA-17-057 3U10CA180899-09S2 3 U10 CA 180899 9 S2 "MOONEY, MARGARET M" 4/15/14 0:00 2/28/25 0:00 ZCA1-GRB-S 7487 1857551 "ALONZO, TODD A" Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 254195 272804 47558 PROJECT SUMMARYThis is the Administrative Core to support the overall application for the Children's Oncology Group Statisticsand Data Management Center. +No NIH Category available 1 year old;Acute;Acute Myelocytic Leukemia;Adolescent;Advanced Development;Australia;Biology;Brain Stem Glioma;Canada;Cancer Center;Cancer Patient;Cancer Survivor;Caring;Cause of Death;Cell Therapy;Child;Child Support;Childhood;Childhood Cancer Treatment;Childhood Leukemia;Clinical;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Clinical Trials Design;Collaborations;Collection;Communities;Companions;Complication;Country;Data;Diagnosis;Disease;Ensure;Family;Foundations;Functional disorder;Generations;Genomics;Goals;Hormonal;Immunotherapy;Industry;Infrastructure;Institution;Interdisciplinary Study;Knowledge;Laboratories;Late Effects;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Neuroblastoma;New Zealand;Organ;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Pharmaceutical Preparations;Population Heterogeneity;Population Research;Prognosis;Quality of life;Rare Diseases;Reporting;Research;Research Personnel;Science;Second Primary Cancers;Survival Rate;Survivors;Time;Tissues;Translational Research;United States;Universities;Work;anticancer research;base;cancer therapy;chemotherapy;childhood cancer survivor;data centers;data management;data sharing;density;design;experience;functional outcomes;health related quality of life;high risk;improved;improved outcome;innovation;member;mortality;multidisciplinary;novel;novel therapeutic intervention;organizational structure;programs;reproductive;small molecule;statistics;survivorship;translational clinical trial;translational scientist;translational study;trial design Children's Oncology Group Statistics and Data Center PROJECT NARRATIVEThe Childrens Oncology Group (COG) is the worlds largest organization devoted exclusively to childhood andadolescent cancer research. Over 220 leading childrens hospitals universities and cancer centers across USCanada and other countries participate in COG research which is focused on developing better treatmentsthat can improve the cure rate and outcome for all children with cancer. NCI 10694246 9/3/22 0:00 RFA-CA-17-057 3U10CA180899-09S2 3 U10 CA 180899 9 S2 "MOONEY, MARGARET M" 3/1/22 0:00 2/28/23 0:00 ZCA1-GRB-S(O1) 1857551 "ALONZO, TODD A" Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 395 Other Research-Related 2022 1400842 NCI 1548205 228141 Reg-CV PROJECT SUMMARYSince the introduction of chemotherapy for the treatment of childhood leukemia more than 60 years ago theprognosis of childhood cancer has improved dramatically. The overall 5-year survival rate for childhood cancersmany of which were uniformly fatal in the pre-chemotherapy era is now 84%. Progress for a number of childhoodcancers however has been limited with approximately 50% of children with acute myelogenous leukemia 50%of children with high-risk neuroblastoma and more than 90% of children with brainstem glioma still succumbingto their disease. In the US cancer remains the leading cause of death from disease in children greater than oneyear of age. Moreover the late effects of cancer treatment including permanent organ and tissue damagehormonal and reproductive dysfunction and second cancers are of special concern with more than 40% of theestimated 360000 survivors of childhood cancer experiencing a significant health related quality of lifecomplication from childhood cancer and its treatment. Thus despite our advances development of newtherapeutic approaches must be a priority for childhood cancer basic translational and clinical researchers. TheChildrens Oncology Group (COG) the worlds largest organization devoted exclusively to childhood andadolescent cancer research was founded 17 years ago. The COGs multidisciplinary research team comprisedof more than 9000 members conducts research at more than 220 leading childrens hospitals universities andcancer centers. This proposal is for COG as part of the National Cancer Institutes (NCI) National Clinical TrialsNetwork (NCTN) to continue its collaborative research work that supports the mission of improving the outcomefor all children with cancer. The COG will design and conduct clinical-translational studies for children with cancerthat builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highestpotential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseaseswe will study novel therapeutic approaches including but not limited to targeted small molecule drugsimmunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trialsfocused on improving the quality of life children with cancer and survivors. As more than 90% of childrendiagnosed with cancer in the US are treated at COG member institutions the COG has the ability to offer adiverse population of children with cancer and their families the opportunity to participate in innovative research.This research effort includes allowing for collection and annotation of biospecimens from all children with cancerproviding the foundation for discovery and accelerating the most promising research efforts conducted inlaboratories around the world. The proposal is for support of the COG Network Statistics and Data ManagementCenter which collaborates with COG scientific leaders to design conduct analyze and report the results ofclinical-translational trials for the treatment of childhood cancers. 1400842 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Pediatric; Pediatric Cancer; Rare Diseases Adolescent;Adverse event;Australia;Biology;Canada;Cancer Center;Cancer Patient;Child Support;Childhood;Childhood Cancer Treatment;Clinical;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Clinical Trials Design;Collaborations;Collection;Communities;Companions;Country;Data;Diagnosis;Disease;Ensure;Family;Foundations;Generations;Goals;Industry;Infrastructure;Interdisciplinary Study;Knowledge;Laboratories;Leadership;Malignant Childhood Neoplasm;Methods;Molecular;Monitor;New Zealand;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Phase;Procedures;Process;Quality of life;Reporting;Research;Research Personnel;Science;Survivors;Time;Translational Research;United States;Universities;anticancer research;base;data centers;data management;design;functional outcomes;improved outcome;innovation;member;multidisciplinary;organizational structure;programs;research study;statistics;translational clinical trial;translational study COG SDMC - Data Management Core n/a NCI 10694245 9/2/22 0:00 PA-20-272 3U10CA180899-09S1 3 U10 CA 180899 9 S1 "MOONEY, MARGARET M" 3/1/22 0:00 2/28/23 0:00 7486 1857551 "ALONZO, TODD A" Not Applicable 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 202816 174541 28275 PROJECT SUMMARY / ABSTRACTThis is the Data Management Core to support the overall application for the Children's Oncology Group Statisticsand Data Management Center. +No NIH Category available Address;Awareness;Back;Behavioral;Black Populations;Cancer Burden;Cancer Institute of New Jersey;Clinical;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Development;Disparity population;Education;Education and Outreach;Educational Background;Elements;Ensure;Environment;Evaluation;Event;Faculty;Family;Funding;Goals;Healthcare;High School Faculty;Hispanic Populations;Individual;Inequity;Instruction;Interdisciplinary Study;Journals;Knowledge;Lead;Leadership;Malignant Neoplasms;Mentors;Middle School Student;New Jersey;Outcome;Parents;Participant;Peer Review;Population Group;Prevention strategy;Public Health;Publishing;Research;Research Support;Research Training;Resources;Schools;Science;Science Technology Engineering and Mathematics Education;Students;Teacher Professional Development;Touch sensation;Training;Underrepresented Populations;Underrepresented Students;Youth;anticancer research;cancer health disparity;cancer prevention;career;career development;cohort;community engagement;curriculum development;ethnic minority;experience;faculty mentor;hands on research;health inequalities;high school;innovation;interest;junior high school;member;next generation;novel;outreach;peer coaching;population based;prevent;programs;racial minority;recruit;research and development;school district;science education;science teacher;skills;socioeconomics;student training;symposium;synergism;teacher;training opportunity;undergraduate student;web site Rutgers Youth Enjoy Science (RUYES) program Project NarrativeThe Rutgers Youth Enjoy Science project is relevant to public health because it will develop a more diversebiomedical cancer research and healthcare workforce to reduce cancer health disparities in New Jersey andnationally. This project at the Rutgers Cancer Institute of New Jersey will train motivate and support studentsfrom underrepresented groups to pursue biomedical cancer research careers. High school and undergraduatestudents will engage in mentored hands-on research experience co-curricular and professional careerdevelopment activities and their science teachers will be provided with mentored research experience andcurriculum development support. Innovative outreach activities will connect program participants with schoolsand families in their communities to enhance awareness and appreciation of science education and researchcareers. NCI 10694219 11/24/23 0:00 PAR-17-059 5R25CA247785-04 5 R25 CA 247785 4 "LOPEZ, BELEM G" 9/1/20 0:00 11/30/25 0:00 ZCA1-RTRB-R(J2) 8936236 "CHAUDHARY, SUNITA " Not Applicable 10 SURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 Other Research-Related 2024 317832 NCI 295422 22410 Project Summary. In New Jersey there are significant cancer disparities across population groups that arealso underrepresented in the cancer research and healthcare workforce. To reduce cancer inequities there isa need to train youth from disparate population groups to pursue cancer research and healthcare careers. Thegoal of this program at the Rutgers Cancer Institute of New Jersey (RCINJ) is to increase the diversity of thebiomedical specifically cancer research workforce. To achieve this goal we will: 1) provide mentored cancerresearch experience and curriculum development support to high school teachers working with students fromunderrepresented backgrounds; 2) engage high school and undergraduate students from underrepresentedbackgrounds in mentored hands-on cancer research co-curricular and professional career developmentactivities; and 3) develop innovative cancer related outreach activities that connect program participants withschools and families in their communities. Cohorts of science teachers will engage in mentored cancerresearch for eight weeks each for two consecutive summers (sixteen weeks total). Experts in curriculumdevelopment will support teachers in developing novel instructional approaches that are related to theirresearch experience. Cohorts of students will have the opportunity to conduct mentored cancer research forten weeks each for two consecutive summers (twenty weeks total). Students will receive co-curricular andprofessional development support throughout their research experience. Participants will engage in researchand program related activities for 3 months per year for two years. We will recruit program participants from allover New Jersey with special emphasis on school districts with high percentages of students fromunderrepresented backgrounds. Faculty members with active well-funded research programs and extensivementoring experience will support participants. Experienced leadership team with track-record of developingimplementing and evaluating pipeline programs for students from underrepresented backgrounds will ensuresuccessful implementation of the program. Both formative and summative evaluation by an external evaluatorwill be integral parts of the proposed program. We will annually track the educational and professionalactivities of trainees for at least 15 years after completing research training. We will disseminate results fromthe comprehensive evaluation on the program web site. Additional dissemination will occur through articlespublished in peer-reviewed journals and through presentations at regional and national conferences byprogram staff as well as participants. Our program will leverage the multi-disciplinary research environmentrobust educational and outreach resources of RCINJ the states only NCI designated Comprehensive CancerCenter. Synergistic collaborations with similar initiatives across Rutgers will ensure that the program succeedsin training the next generation of a diverse cancer research and healthcare workforce. 317832 +No NIH Category available Address;Applications Grants;Area;Big Data;Bioinformatics;Biometry;Cancer Center;Cancer Research Project;Career Mobility;Collaborations;Communication;Comprehensive Cancer Center;Computers;Creativeness;Data;Data Analyses;Data Science;Dedications;Development;Dimensions;Education;Educational Activities;Educational workshop;Ensure;Epidemiologist;Epidemiology;Ethics;Etiology;Evaluation;Flow Cytometry;Funding;Future;Gene Expression;Genome;Genomics;Goals;Hispanic Populations;Infection;Infrastructure;Journals;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Methodology;Methods;Modeling;Modernization;National Cancer Institute;Participant;Peer Review;Pharmacogenomics;Phase;Pilot Projects;Postdoctoral Fellow;Procedures;Productivity;Proteomics;Publications;Puerto Rico;Quality Control;Reporting;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Science;Statistical Data Interpretation;Statistical Methods;Taxonomy;Techniques;Technology;Training;Translational Research;Universities;Work;anticancer research;cancer education;data management;database design;design;education research;epigenomics;experience;graduate student;health disparity;high throughput analysis;improved;innovation;laboratory experience;lipidomics;metabolomics;microbiome;microbiome research;minority investigator;next generation sequencing;outreach;programs;research and development;skills;success;transcriptomics;undergraduate student Data and Omics Sciences Core (DATAOmics) n/a NCI 10694200 8/8/23 0:00 PAR-18-767 5U54CA096300-20 5 U54 CA 96300 20 8/16/02 0:00 8/31/24 0:00 ZCA1-SRB-2 7468 8617368 "HUANG, XUELIN " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 92360 57725 34635 DATA AND OMICS SCIENCES CORE (DATAOmics)PROJECT SUMMARY/ABSTRACTThe primary objective of the Data and Omics Sciences Core (DATAOmics) is to assist the work of theInfection-Driven Malignancies Program for Advancing Careers and Translational Sciences (IMPACT) a cancerresearch partnership between the University of Puerto Rico (UPR) and the MD Anderson Cancer Center(MDACC) through an enhanced infrastructure to support IMPACT's research education and outreachactivities in quantitative analyses and scientific reporting. We propose to expand and strengthen therelationships between IMPACT and the UPR Comprehensive Cancer Center by establishing a formal unit tosupport their researchers and participants (undergraduate and graduate students) in areas such asbiostatistics epidemiology bioinformatics and Omics sciences. DATAOmics capabilities will be enhanced withrespect to the previous Biostatistics Epidemiology and Bioinformatics Core (BEBiC) in at least two ways: 1)the incorporation of a new investigator with experimental and analytical expertise in Omics sciencesparticularly in next generation sequencing and mass spectrometry and with wet lab experience a dimensionwhich is now of paramount importance in modern cancer research particularly for Full Project A and PilotProject A; and 2) by adding a small and fully dedicated computer server to DATAOmics which will enhanceour computational ability to undertake realistic bioinformatics and Omics problems and will enable participantsto be trained in bioinformatics analyses. The overall goal of DATAOmics is to enhance the productivity ofIMPACT's research projects through the provision of high-quality and timely biostatistics data sciencesbioinformatics and Omics advice and consultancy at all stages of research. The specific aims of DATAOmicsare: 1) Provide support and consulting on study design data gathering and management and statisticalanalysis to all research projects; 2) Increase cancer research capacity in design and statistical analyses inbiostatistics data sciences bioinformatics and Omics through educational activities for our researchers andparticipants; and 3) Develop and apply innovative biostatistics and bioinformatics methodologies to the cancerresearch projects initiated by our researchers. DATAOmics will include two components: 1) Biostatistics andData Science and 2) Bioinformatics and Omics Sciences. The Biostatistics and Data Science component atUPR will have two statisticians and one epidemiologist dedicated to the methodological and statistical aspectsof the research projects. MDACC will engage one senior biostatistician and one senior data analyst. TheBioinformatics and Omics Sciences components at UPR will have two bioinformaticians engaged in thebioinformatics facets of the projects in a broad sense (including: genomics transcriptomicspharmacogenomics proteomics epigenomics metabolomics lipidomics and microbiomics) and MDACC willallocate one senior bioinformatician. +No NIH Category available 15 year old;Acceleration;Adolescent;Adoption;Area;Awareness;Behavior;Cancer Center;Cancer Control;Cancer Etiology;Cancer Prevention Intervention;Cancer Science;Cervical Cancer Screening;Cessation of life;Chronic Hepatitis C;Clinical;Collaborations;Communities;Communities That Care;Community Healthcare;Community Outreach;Comprehensive Cancer Center;Data Analyses;Development;Disparity;Disparity population;Dissemination and Implementation;Dose;Education;Education and Outreach;Educational Intervention;Educational Materials;Ensure;Evaluation;Evidence based program;Funding;Future;Goals;Guidelines;Health Services Accessibility;Healthcare;Healthy People 2020;Hepatitis;Hepatitis B Virus;High Prevalence;Hispanic;Hispanic Populations;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human Resources;Incidence;Infection;Infectious Agent;Infrastructure;Intervention;Island;Malignant Neoplasms;Malignant Vaginal Neoplasm;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of liver;Malignant neoplasm of penis;Malignant neoplasm of vulva;Mexico;Minority Groups;Mission;Not Hispanic or Latino;Outcome;Pilot Projects;Prevention;Process;Protocols documentation;Puerto Rican;Puerto Rico;Recommendation;Rectal Cancer;Reporting;Research;Research Personnel;Research Project Grants;Risk;Rural Community;Scientist;Services;Students;Subgroup;Texas;Training;Translational Research;Underserved Population;University of Texas M D Anderson Cancer Center;Vaccination;Vision;Vulnerable Populations;Work;anticancer research;cancer health disparity;cancer prevention;community engagement;cultural competence;effective intervention;evidence base;experience;falls;high risk;implementation intervention;implementation science;improved;infection rate;infection related cancer;innovation;malignant oropharynx neoplasm;minority communities;mortality;outreach;prevent;programs;public health relevance;screening;therapy development;vaccine access;virus related cancer Community Cancer Control Outreach Core public health relevance in PR and TX. The Outreach Core will result in meaningful collaboration across a large network of partners in both PR and TX engaged in cancer control efforts. To ensure that activities and community impact are sustained beyond the funding period we will develop the infrastructure personnel and protocols for a permanent program of Cancer Control Outreach and Education integrated within the UPR Cancer Center. NCI 10694198 8/8/23 0:00 PAR-18-767 5U54CA096300-20 5 U54 CA 96300 20 8/16/02 0:00 8/31/24 0:00 ZCA1-SRB-2 7466 2401885 "FERNANDEZ, MARIA EULALIA" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 120453 118094 2359 COMMUNITY CANCER CONTROL OUTREACH CORE (CCCOC) PROJECT SUMMARY/ABSTRACT Despite lower overall cancer incidence and mortality among Hispanics compared with non-Hispanic whites rates of infection-related cancers are up to twice as high in Hispanics. For example both Puerto Rico (PR) and Texas (TX) Hispanics experience a substantial burden of hepatitis and human papillomavirus (HPV) -related cancers. There is an urgent need to intervene to reduce these cancers in both settings. As part of the UPR/MDACC Partnership for Excellence in Cancer Research the Community Cancer Control Outreach Core (CCCOC; Outreach Core) proposes an integrated community-based participatory approach to identify needs and priorities and to develop multilevel outreach and educational interventions targeting cancers caused by infectious agents. During the past decade the CCCOC has made significant contributions to increasing cancer control education behaviors and access to services to decrease cancer health disparities in Puerto Rico. These efforts have identified and produced innovative outreach strategies and educational materials to reach the most vulnerable and underserved populations on the island. This new funding period will represent extension of our previous research and community work. The Outreach Core will build on previous partnerships and networks to improve community engagement and outreach to disseminate research findings and interventions related to HPV vaccination and cervical cancer screening implemented in both PR and TX. DATAOmics will provide data analysis support for the evaluation of the adaptation and implementation of these interventions (Aim 1). The Outreach Core will also contribute to the Education Core mission and will build capacity among IMPACT's scientists and students in areas such as community engagement across the research translation continuum and implementation science (Aim 2). Doing so will ensure community engagement across activities of the IMPACT program to inform research questions interpretation of data and future studies. These efforts will also serve to accelerate and improve the adoption and implementation of research findings guidelines and interventions for cancer prevention and control in PR TX and nationally through our participation with the National Outreach Network (NON) (Aim 3). Following our initial focus on HPV we will expand our outreach and educational efforts to include a broader focus on infectious malignancies of +No NIH Category available Achievement;Address;Advisory Committees;Cancer Center;Cancer Center Support Grant;Career Mobility;Charge;Collaborations;Communication;Communities;Comprehensive Cancer Center;Development;Documentation;Economically Deprived Population;Education;Ensure;Evaluation;Faculty;Foundations;Goals;Government;Grant;Infection;Infrastructure;Institution;Laws;Leadership;Malignant Neoplasms;Mission;Monitor;Names;Office of Administrative Management;Outcome;Principal Investigator;Progress Reports;Publishing;Puerto Rico;Research;Research Project Grants;Resources;Services;Strategic Planning;Students;Texas;Translational Research;Universities;University of Texas M D Anderson Cancer Center;Vision;Work;anticancer research;cancer health disparity;design;editorial;health equity;meetings;operation;outreach;programs;socioeconomic disadvantage;sound;success;underserved community Administrative Core n/a NCI 10694191 8/8/23 0:00 PAR-18-767 5U54CA096300-20 5 U54 CA 96300 20 8/16/02 0:00 8/31/24 0:00 ZCA1-SRB-2 7462 7840802 "GIORDANO, SHARON HERMES" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 243675 152297 91378 ADMINISTRATIVE COREPROJECT SUMMARY/ABSTRACTThe Administrative Core (AC) over the previous cycles has been effective in establishing the foundation of thePartnership and providing critical support across all components of the project: research outreach educationinfrastructure and professional development. In this renewal the AC will continue to serve as a facilitativeresource to provide strategic leadership and oversight in the development implementation coordination andmanagement of all Partnership activities for the Partnership's Infection-Driven Malignancies Program forAdvancing Careers and Translational Sciences (IMPACT). This core which works collaboratively with thePlanning and Evaluation and DATAOmics Cores provides assistance with the daily activities of thePartnership including but not limited to grants management program management and meeting planningas well as to spearhead short-term and long-term strategic planning and prioritization for the successfulachievement of Partnership initiatives. At each institution the AC is composed of three principal investigatorsand one program director. Specific Aims for the AC include: 1) Provide leadership administrativemanagement and organizational infrastructure including leading overall strategic planning and oversightof program implementation assessment and evaluation; 2) Oversee the scientific research agenda to ensureprogram goals are clearly defined and aligned with the goals of the grant and that activities are thoughtfulwell-planned and scientifically sound; 3) Ensure core operations are efficient and integrated projectdeliverables are met regular communications among the cores and projects are in place and facilitated andprogram goals for progress monitoring outcomes documentation and deliverables are met; 4) Engagedevelop and maximize collaborations with other U54 Partnerships as well as other internal and externalentities to promote sustainability; 5) Support communications across the Partnership's projects and cores andwith the Internal Advisory Committee (IAC) Program Steering Committee (PSC) and NCI CPACHE programoffice; 6) Augment the cancer research capacity of the UPR and the UPRCCC through the development oftargeted hires and leveraged strategic collaborations; and 7) Establish a centralized ScientificCommunication Core (SciCom) to provide a wide range of educational editorial and publishing services freeof charge to UPR and UPRCCC faculty and students. This core will strengthen the overall cancer researchenterprise in infection driven malignancies in PR and TX and will support the implementation of UPRCCC'sroadmap leading to the submission of a CCSG (P30) for NCI designation as a Cancer Center. +No NIH Category available Address;Advanced Malignant Neoplasm;Advocate;Affect;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Hospital;Career Mobility;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Development;Diagnosis;Early Diagnosis;Economically Deprived Population;Education;Elements;Ensure;Evaluation;Faculty;Goals;Government;Grant;HIV;Hispanic;Hispanic Populations;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Immunization Programs;Infection;Infrastructure;Institution;Interdisciplinary Study;Intervention;Joints;Laboratories;Latino Population;Laws;Link;Malignant Neoplasms;Medicine;Mission;Names;National Cancer Institute;National Cancer Program;Outcome Measure;Physicians;Prevention;Prevention program;Puerto Rico;Readiness;Research;Research Personnel;Research Project Grants;Resource Sharing;Risk Factors;Role;Science;Scientist;Students;Texas;Training;Translational Research;Translational Research Working Group;Underrepresented Minority;Universities;University of Texas M D Anderson Cancer Center;Vaccination;Vision;Work;anticancer research;cancer health disparity;cancer prevention;career;career development;design;disparity reduction;experience;health disparity;health equity;infection burden;infection risk;malignant stomach neoplasm;minority communities;multidisciplinary;outreach;population based;programs;socioeconomic disadvantage;success;survivorship;synergism;tool development;underserved community UPR/MDACC: Partnership for Excellence in Cancer Research (1 of 2) NARRATIVE STATEMENTHispanics have an increased risk of infection-driven malignancies including gastric cancer and HIV- and HPV-related malignancies. To address the increased risk factors and burden of infection-driven cancers that existamong Hispanic populations in the US the Partnership for Excellence in Cancer Research strives to reducethese disparities through efforts in Cancer Research Education and Outreach. Partnership contributionsincluding the development of a pipeline of well-trained Hispanic cancer researchers will help build a strongernational cancer research and prevention program. NCI 10694189 8/8/23 0:00 PAR-18-767 5U54CA096300-20 5 U54 CA 96300 20 "SAN MIGUEL-MAJORS, SANDRA L" 8/16/02 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 7840802 "GIORDANO, SHARON HERMES" "SCHEET, PAUL A; TRAVIS, ELIZABETH L; WEINER, BRAD R" 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1091199 NCI 724810 366389 OVERALLPROJECT SUMMARY / ABSTRACTThis competitive renewal of the Partnership for Excellence in Cancer Research (Partnership) between theUniversity of Puerto Rico (UPR) and the University of Texas MD Anderson Cancer Center (MDACC) will: 1)solidify strengthen and expand the relationship between UPR and MDACC; and 2) leverage the breadth andstrengths of an experienced and integrated Partnership in transition of the UPR Comprehensive Cancer Center(UPRCCC) towards a long-term overall goal: recognition of UPRCCC as an NCI-designated cancer center. Toaddress some of the most profound cancer health disparities in Puerto Rico and Texas the Partnership willestablish an Infection-Driven Malignancies Program for Advancing Careers and Translational Sciences(IMPACT). This application represents a partnership in which both institutions profit from sharing distinctexpertise to mutually benefit in implementation of integrated team science outreach education and careerdevelopment initiatives. To facilitate UPRCCC's transition towards NCI-designation the UPR PIs led thedevelopment of the specific aims with support of the MDACC PIs. The Specific Aims for the renewal are: 1)Develop a multidisciplinary research portfolio focused on health disparities derived from infection-drivenmalignancies; 2) Increase the number of Hispanic students pursuing careers in laboratory and population-based cancer research to produce a critical mass of clinicians scientists and physician-scientists whospecialize in cancer research with emphasis on cancer health disparities in underrepresented minorities andunderserved communities; 3) Strengthen sustainable collaborations among all the stakeholders to develop andpromote key community outreach education and interventions aimed at reducing cancer rates andemphasizing vaccinations against malignancy linked infections among Hispanic/Latino populations in PR TXand elsewhere; 4) Leverage strategic collaborations with NCI-designated cancer centers to augment the cancerresearch capacity of the UPR and the UPRCCC; and 5) Provide professional support and development toolsthrough the a) Administration; b) Planning and Evaluation; and c) Shared Resources Cores designed to nurtureand optimize the Partnership's research education and outreach agendas in support of the long-term goal ofan NCI-designated Cancer Center. Key elements of this application to advance the Partnership include: 1)Multidisciplinary collaborative research projects focused on IMPACT that represent stages of the translationalresearch continuum; 2) A comprehensive cancer-focused training and career development core; 3) Thedevelopment of a dual MD/MPH degree to address specific cancers disproportionately affecting Hispanicpopulations; 4) Outreach efforts to build educate and advocate for broad HPV vaccination programs; and 5) aDATAOmics Core that builds infrastructure. This initiative will strengthen the overall cancer research enterprisein infection-driven malignancies in both PR and TX and will support the implementation of UPRCCC's roadmapto submission of a Cancer Center Support Grant (P30) for NCI designation. 1091199 +No NIH Category available Address;Adherence;Affect;African American;Attitude;Behavior;Breast Cancer survivor;Cancer Science;Cancer Survivor;Cancer Survivorship;Characteristics;Collaborations;Communities;Development;Disparity;Documentation;Environment;Etiology;Evaluation;Funding;Future;Grant;Health;Health Status;Healthcare;Individual;Inequity;Infrastructure;Institutionalization;Intervention;Life Experience;Link;Longitudinal Studies;Malignant Neoplasms;Mediating;Medical;Modeling;National Cancer Institute;Neighborhoods;Not Hispanic or Latino;Outcome;Participant;Pathway interactions;Perception;Race;Research;Research Personnel;Risk;Self Management;Social support;Specific qualifier value;Structural Racism;Survivors;Techniques;Testing;Theoretical model;Time;Translating;Variant;advanced analytics;cancer survival;community engagement;effective intervention;experience;health disparity;health related quality of life;improved;innovation;knowledge translation;longitudinal design;metropolitan;mortality;negative affect;outcome disparities;prostate cancer survivors;racial disparity;racial health disparity;racial population;recruit;residential segregation;resilience;skills;social;social influence;sociodemographics;socioeconomic adversity;stressor;success;survivorship;syndemic;theories;therapy development;translational model African American Resilience in Surviving Cancer Project NarrativeCommunity interpersonal and individual influences combine to negatively affect the health-related quality oflife (HRQOL) of African American (AfAm) cancer survivors and create racial health disparities between AfAmand Non-Hispanic White survivors. Using a social-ecological model that emphasizes the impact of socialinequities on health this study will examine community interpersonal and individual domains of influence thatmay lead to variability in AfAm survivors HRQOL over time. We expect findings from this study will help toidentify modifiable targets of change and inform the development of interventions to address causes of poorerHRQOL experienced by AfAm survivors. NCI 10694187 8/22/23 0:00 PA-18-484 5R01CA232514-05 5 R01 CA 232514 5 "MOLLICA, MICHELLE A" 9/12/19 0:00 8/31/24 0:00 Health Disparities and Equity Promotion Study Section[HDEP] 8269175 "HARPER, FELICITY " "THOMPSON, HAYLEY S." 13 INTERNAL MEDICINE/MEDICINE 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 611220 NCI 396896 214324 Project Summary/Abstract Substantial racial disparities exist in the health-related quality of life (HRQOL) and mortality of AfricanAmerican (AfAm) relative to Non-Hispanic White (NHW) cancer survivors. The premise of this study is thatcommunity interpersonal and individual influences combine to negatively affect the HRQOL of AfAmcancer survivors and are thus responsible for health disparities between AfAms and NHWs. Wepropose that the best way to understand these disparities is to move beyond simple documentation of them toan examination of domains that cause variation in HRQOL among AfAm survivors. This effort however shouldbe implemented with a collaboration between academic researchers and community stakeholders. To understand the root causes of variability in HRQOL among AfAm breast and prostate cancer survivorsthis study proposes to (1) identify significant domains of causal influence on HRQOL among AfAm survivors;(2) specify the paths from these domains to survivors HRQOL; (3) identify modifiable factors affecting thestrength of these paths; and (4) specify targets of change for future interventions. Our theoretical model drawsheavily on a social-ecological model of health and assumes that the domains of influence include significantstressors linked to racial group membership that result from interpersonal institutionalized and structuralracism and socioeconomic adversity in the U.S. We will test this model in a four-wave longitudinal studyrecruiting 600 participants from a National Cancer Institute-funded infrastructure grant of 5500 AfAm cancersurvivors living in metropolitan Detroit. The study will address the following Specific Aims: Aim 1. 1a. To use an academic-community collaboration to create a theoretically and community-groundedmodel of variability in HRQOL among AfAm cancer survivors. 1b. To evaluate the success of the collaborationwith a systematic evaluation of community stakeholders perceptions of and attitudes toward the collaborationexperience. Aim 2. To conduct a four-wave longitudinal study of 600 AfAm cancer survivors that empirically tests therelationships proposed in our social-ecological model. Aim 3. To collaborate with the community stakeholders in the dissemination of study findings to scientificand lay audiences and to translate study findings and inform future interventions. The paths through which race-related community interpersonal and individual domains of influence mayaffect the HRQOL of AfAm cancer survivors have not been comprehensively investigated with a longitudinaldesign. Nor has academic research on AfAm cancer survivors combined a theoretically-driven approach withstrong community engagement to develop and test a social-ecological model and disseminate study findings.We expect findings from this study will help to identify modifiable targets of change and risk profiles and informthe development of interventions to address causes of poor HRQOL experienced by AfAm survivors. 611220 +No NIH Category available Adult;Basic Science;Binding;Biochemical;Biological Assay;Brain;Clinical;Clinical Trials;Collaborations;Dana-Farber Cancer Institute;Dimerization;Disease;Dose;Dose Limiting;Drug Kinetics;EGF gene;EGFR gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Exhibits;Failure;Gastrointestinal tract structure;Generations;Genetic;Genetically Engineered Mouse;Genomics;Glioblastoma;Grant;Image;Industry;Knock-out;Learning;Letters;Ligands;Malignant neoplasm of lung;Maximum Tolerated Dose;Medicine;Molecular;Molecular Conformation;Mus;Mutate;Mutation;Neurosphere;Non-Small-Cell Lung Carcinoma;Oncogenes;Operative Surgical Procedures;Oral;Oral Administration;Patients;Penetrance;Pharmaceutical Chemistry;Pharmacodynamics;Pharmacologic Substance;Phase;Phosphotransferases;Plasma;Property;Receptor Inhibition;Receptor Signaling;Recurrence;Resistance;Safety;Signal Transduction;Skin;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Structure;Testing;Therapeutic;Tissues;Toxic effect;Tyrosine Kinase Domain;Tyrosine Kinase Inhibitor;Variant;Work;Xenograft Model;clinical development;clinical effect;clinical material;clinical translation;dimer;drug development;effective therapy;efficacy study;epidermal growth factor receptor VIII;experience;first-in-human;inhibitor;mass spectrometric imaging;monomer;mutant;new therapeutic target;novel;pharmacologic;pre-clinical;programs;receptor;single cell sequencing;small molecule;small molecule inhibitor;stem;tumor;tumor heterogeneity Small molecule inhibitors with a therapeutic window for EGFR signaling variants in glioblastoma n/a NCI 10694182 8/21/23 0:00 RFA-CA-20-047 5U19CA264504-03 5 U19 CA 264504 3 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7458 2793446 "ECK, MICHAEL J" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 186507 173560 12947 Project Summary The epidermal growth factor receptor (EGFR) gene is mutated or amplified in over half of GBMs and itsmutation and focal amplification correlate with a more aggressive disease course. However EGFR-directedtyrosine kinase inhibitors (TKIs) have failed to show efficacy in this disease and these failures cannot beattributed strictly to poor brain penetrance. We posit that the failure to date of EGFR TKIs for GBM reflects lackof a therapeutic window. A lesson learned from application of EGFR inhibitors in non-small cell lung cancer(NSCLC) is that mutant-selectivity is absolutely required. Without selectivity systemic inhibition of wild-type(WT) EGFR signaling is the dose-limiting toxicity. In NSCLC activating mutations in the tyrosine kinase domainconfer enhanced sensitivity to certain EGFR TKIs relative to WT EGFR allowing true mutant-selectiveinhibition. The EGFR genetic aberrations in glioblastoma (GBM) create constitutive ligand-independentsignaling via signal generating domains that are almost exclusively WT in structure. Our objective is to createEGFR TKIs with a therapeutic window for aberrant EGFR signaling in GBM. We have two specific aims. Aim 1 is to test the hypothesis that an EGFR TKI with an allosteric mechanism of action will selectivelyblock ligand-independent EGFR signaling in GBM while sparing ligand-activated EGFR systemically therebyproviding a therapeutic window that allows effective treatment of EGFR-driven GBMs. In preliminary studieswe have developed small-molecule allosteric inhibitors that potently inhibit WT EGFR (IC50 < 100 nM inbiochemical assays) and have a good oral mouse PK profile and are brain-penetrant. Guided by efficacystudies in patient-derived GBM neurosphere and xenograft models we expect to identify a compound suitablefor clinical development in the first grant year to enable clinical translation in the out years. Aim 2 exploits CM93 a novel third generation EGFR TKI that is highly brain-penetrant so much sothat it actually displays a positive brain/plasma ratio. We will test the hypothesis that CM93 can provide a defacto tissue-based therapeutic window allowing effective inhibition of EGFR in the tumor with relative sparingof the receptor systemically. Towards this end we will conduct a first-in-human phase 1 dose-escalation anddose-expansion study as well as a surgical window of opportunity study to determine the maximum tolerateddose evaluate the safety pharmacokinetics pharmacodynamics and clinical effects of orally administeredCM93 in subjects with recurrent glioblastoma characterized by EGFR mutation or amplification. Studies on clinical materials will be facilitated by our Pharmacological and Genomics Imaging Core(PGIC). The PGIC will allow us to quantify intra-tumoral accumulation of CM93 using MALDI massspectrometry imaging and to define the impact of CM93 treatment on tumor heterogeneity using single cellsequencing. Collectively these studies promise to yield new targeted therapeutics for EGFR-driven GBMs andprovide a molecular understanding of determinants of sensitivity and resistance to these agents. +No NIH Category available Address;Adolescent;Adult;Adult Glioma;Agar;Anabolism;Apoptosis;Astrocytoma;Basic Science;Biological Markers;Biology;Brain;Branched-Chain Amino Acids;Catabolism;Cells;Central Nervous System Neoplasms;Classification;Clinic;Clinical;Clinical Trials;Collection;Combined Modality Therapy;DNA Damage;DNA analysis;Defect;Dependence;Diffuse;Dihydroorotate Dehydrogenase Inhibitor;Dihydroorotate dehydrogenase;Disease;Drug Targeting;Eligibility Determination;Enzymes;Excision;FDA approved;Foundations;Future;Genes;Genomics;Glioblastoma;Glioma;Gliomagenesis;Glutamates;Glutaminase;Glutathione;Goals;Human;Image;Immunohistochemistry;In Vitro;Isocitrate Dehydrogenase;Knowledge;Magnetic Resonance Spectroscopy;Malignant - descriptor;Malignant Glioma;Malignant Neoplasms;Medical;Metabolic;Methods;Modeling;Molecular;Monitor;Mutation;Newly Diagnosed;Nucleotide Biosynthesis;Oncogenes;Oncoproteins;Operative Surgical Procedures;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phase;Process;Property;Pyrimidine;Pyrimidine Nucleotides;Radiation;Recurrence;Research;Research Personnel;Resected;Resistance;Safety;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Technology;Testing;Tissue Sample;Translating;Tumor-Derived;United States;Work;World Health Organization;clinical material;clinical translation;cohort;effective therapy;gain of function;human subject;inhibitor;liquid chromatography mass spectrometry;mass spectrometric imaging;mutant;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;nucleotide metabolism;participant enrollment;patient population;pharmacokinetics and pharmacodynamics;pharmacologic;phase 2 study;pre-clinical;programs;rational design;response;screening;single-cell RNA sequencing;standard care;stem-like cell;synthetic lethal interaction;targeted treatment;tumor Targeting metabolic vulnerabilities in Astrocytoma IDH-mutant Grade 4 n/a NCI 10694181 8/21/23 0:00 RFA-CA-20-047 5U19CA264504-03 5 U19 CA 264504 3 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7457 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 176218 152987 23231 PROJECT SUMMARYGliomas represent 80% of the 26000 newly diagnosed cases of malignant brain and central nervous systemtumors in the United States each year and are among the most lethal and treatment-resistant human cancers.Although there is a dire need for effective therapies for this disease the standard treatment for gliomas has notchanged since 2005 and no new medical therapies have been approved for adult gliomas in the last decade. Inresponse to this challenge we have devised a new way to treat gliomas that have a mutation in either of theIDH1 or IDH2 genes. Collectively IDH mutations are present in ~20% of adult diffuse gliomas indicating thatany treatment advance in this patient population would have broad impact. Based on our knowledge that IDHmutations cause profound metabolic reprogramming in glioma cells we used a novel pharmacologicalscreening platform to systematically identify vulnerabilities that result from this process. We discovered that aclass of drugs targeting nucleotide metabolism preferentially kill glioma cells with IDH mutations therebyrevealing an avenue for tumor-selective biomarker-guided therapy that is poised for rapid clinical translation.To build on this discovery and translate exploitation of this vulnerability to the clinic we propose to conduct aphase 0 surgical window clinical trial of a brain-penetrant nucleotide metabolism inhibitor in IDH-mutant grade4 glioma patients. We will characterize response to this agent by addressing three Specific Aims. Specific Aim#1 is to use matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) conventionalliquid chromatography-mass spectrometry and magnetic resonance spectroscopy to comprehensivelycharacterize the pharmacokinetic and pharmacodynamic properties of this targeted therapeutic in gliomapatients. Specific Aim #2 is to investigate how this inhibitor alters the biology of IDH-mutant grade 4 gliomas atthe molecular and cellular levels by analyzing resected primary tissue samples via single-cell RNA sequencingand immunohistochemistry. Finally Specific Aim #3 is to evaluate the safety and tolerability of this drug in afocused cohort of IDH-mutant grade 4 glioma patients. Taken together our work will outline and test a newtreatment strategy for glioma patients that could be expanded to a larger multi-center phase II study if our trialis successful. Furthermore our efforts to elucidate key components of the mechanism of action of thisnucleotide metabolism inhibitor are expected to inform the rational design of combination therapies centeredon this agent that can be explored in future studies. +No NIH Category available Administrator;Adult Glioblastoma;Cancer Center;Catchment Area;Clinical;Clinical Trials;Collaborations;Communication;Communication Programs;Community Outreach;Complex;Dana-Farber Cancer Institute;Doctor of Medicine;Doctor of Philosophy;Electronic Mail;Electronics;Faculty;Fostering;Funding;Funding Opportunities;General Hospitals;Genomics;Glioblastoma;Glioma;Goals;Grant;Hospitals;Human Resources;Image;Infrastructure;Institution;Leadership;Massachusetts;Medical;Mentored Clinical Scientist Development Program;Mentorship;Monitor;Parents;Patients;Pilot Projects;Principal Investigator;Research Personnel;Research Project Grants;Resources;Scientist;Series;Site;Specialist;Structure;Students;Therapeutic;Training;Universities;Woman;Work;career development;community engagement;diversity and inclusion;drug development;experience;industry partner;inter-institutional;meetings;multidisciplinary;new therapeutic target;pharmacologic;programs;recruit;research and development;response;translational scientist Administrative Core n/a NCI 10694177 8/21/23 0:00 RFA-CA-20-047 5U19CA264504-03 5 U19 CA 264504 3 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 7455 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 108157 65988 42169 In response to a Funding Opportunity Announcement for multi-institutional teams to form a Glioblastoma Therapeutics Network (GTN) basic scientists and clinical/translational investigators from three institutions in the Dana-Farber/Harvard Cancer Center have joined forces with their counterparts in the Stanford Cancer Center to create the Harvard/Stanford GTN. The GTN study plan features three Projects an Administrative Core a Pharmacological and Genomic Imaging Core and a proposed Network Coordinating Center (NCC). The Administrative Core will be based at Brigham and Womens Hospital the parent organization for the Harvard/Stanford GTN and will serve as the coordinating center and hub for the four institutions comprising the program and all interactions with existing P30-supported resources for clinical trials. The core will coordinate internal and external components of this complex structure to foster and support multi-project inter-disciplinary and inter-institutional drug development research in adult glioblastoma. Core personnel include one GTN Principal Investigator three Site Leads at the Harvard/Stanford GTN institutions two scientific co-administrators a program coordinator two grants specialists and an administrative assistant. There are five Specific Aims in the Administrative Core. In the First Aim the core will develop and engage a multidisciplinary Internal Advisory Board to provide critical oversight of the overall Harvard/Stanford GTN program. In the Second Aim the core will organize regular meetings of key stakeholders to foster collaboration troubleshooting and monitoring of progress. In the Third and Fourth Aims the core will maintain a trans-institutional program for regular internal and external electronic communication among Harvard/Stanford project and core co-leads clinical trialists the GTN Steering Committee the NCC NCI program officials and industry partners. In the Fifth Aim the core will engage with institutional leaders at Harvard and Stanford to promote diversity and inclusion throughout the Harvard/Stanford GTN program. The Administrative Core Leader Tracy Batchelor M.D. will serve as the overall Principal Investigator of the Harvard/Stanford GTN program with able assistance from Site Leads at Dana-Farber Cancer Institute (Patrick Wen M.D.) Massachusetts General Hospital (Isabel Arrillaga M.D. Ph.D.) and Stanford University (Michelle Monje M.D. Ph.D.). This trans-institutional administrative team at Dana-Farber/Harvard Cancer Center and Stanford Cancer Center have worked together effectively on other multi-center multi-project NCI-sponsoredglioma research projects. +No NIH Category available Address;Adult;Adult Glioblastoma;Agar;Age Years;Agreement;Anabolism;Anaplastic astrocytoma;Astrocytoma;Basic Science;Biometry;Brain;Cancer Center;Cancer Etiology;Cancer Patient;Cause of Death;Cells;Cessation of life;Clinical;Clinical Pharmacology;Clinical Sciences;Clinical Trials;Clinical Trials Design;Collaborations;Communication;Communities;Data;Dedications;Doctor of Medicine;Drug Monitoring;Enzymes;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Failure;Funding;Funding Opportunities;Generations;Genomics;Glioblastoma;Glioma;Glutamates;Goals;Image;Institution;Learning;Ligands;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Metabolic;Methodology;Modeling;Mutation;National Cancer Institute;Nervous System;Neurons;Neurosciences;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Penetrance;Pharmaceutical Chemistry;Pharmaceutical Preparations;Plasma;Population;Pre-Clinical Model;Principal Investigator;Prodrugs;Protocols documentation;Pyrimidine;Research Personnel;Research Project Grants;Resources;Role;Science;Scientist;Services;Signal Transduction;Specific qualifier value;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Sum;Synapses;Testing;Therapeutic;Tissues;Translational Research;Visualization;Wit;Woman;Work;antagonist;cancer genetics;cancer imaging;cell type;clinical efficacy;clinical material;cost effective;early phase clinical trial;experience;feeding;imaging facilities;improved;inhibitor;insight;lead optimization;mass spectrometric imaging;men;middle age;mutant;neoplastic cell;neuropathology;neurotransmission;new therapeutic target;novel;pharmacologic;preclinical development;programs;response;single-cell RNA sequencing;skills;small molecule;small molecule therapeutics;structural biology;translational scientist;tumor;tumor addiction;tumor growth Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma Glioblastomas and malignant astrocytomas are the third leading cause of cancer-related death among middleaged men and the fourth leading cause of death for women between 15-34 years of age. The National CancerInstitute has issued a request for multi-institutional teams to form a national glioblastoma therapeutics network(GTN). In response scientists and clinicians from three institutions in the Dana-Farber/Harvard CancerCenter have joined forces with their counterparts in the Stanford Cancer Center to create a bi-coastalHarvard/Stanford GTN. NCI 10694176 8/21/23 0:00 RFA-CA-20-047 5U19CA264504-03 5 U19 CA 264504 3 "HUBBARD, LEAH" 9/21/21 0:00 8/31/26 0:00 ZCA1-TCRB-D(A1) 6257805 "BATCHELOR, TRACY T" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 864597 NCI 766371 98226 We respond here to a Funding Opportunity Announcement (FOA) for multi-institutional teams to form aGlioblastoma Therapeutics Network (GTN). Basic scientists and clinical/translational investigators from threeinstitutions in the Dana-Farber/Harvard Cancer Center (DF/HCC) have joined forces with their counterparts inthe Stanford Cancer Center (SCC) to create the Harvard/Stanford GTN. UT Southwestern is alsorepresented in one key collaboration. Distinctive features of this bi-coastal GTN include (i) broad and deepexpertise in brain-penetrant small molecule therapeutics and (ii) a strong presence in the emerging field ofCancer Neuroscience a field that addresses the central role of the nervous system in glioblastomapathogenesis. Our objective is to improve the treatment of adult glioblastomas (GBMs) and Astrocytoma IDH-mutant grade 4 by taking novel effective brain-penetrant small molecule drugs through lead optimization topreclinical development and into early phase clinical trials. Our study plan features three projects: Project 1 targets metabolic reprogramming in Astrocytoma IDH mutant grade 4. Project 2 targets theconstitutive ligand-independent EGFR signaling observed in more than 50% of adult IDH wild-type GBM.Project 3 targets a recently appreciated forward-feeding gliomagenic loop between tumor cells and electricallyactive neurons in IDH wild-type adult glioblastomas. All three projects feature surgical window clinical trials ofbrain-penetrant drugs that are hitherto untested in GBM. In addition Project 2 will develop novel allostericinhibitors that promise to address a shortcoming of all current EGFR antagonists as GBM therapeutics to witlack of a therapeutic window. Insights from clinical trials will be enhanced by a Pharmacological andGenomic Imaging Core (PGIC). This core will allow our trialists to monitor drug impact on glioblastoma cellpopulations using specialized single cell RNAseq protocols. Drug penetrance within tumors and drug-inducedchanges in key metabolites will be visualized using matrix assisted laser desorption ionization massspectrometry imaging and non-invasive magnetic resonance spectroscopy methodologies.In addition to these clinical/translational research projects and the PGIC the Harvard/Stanford GTNoffers to host a Network Coordinating Center (NCC) for the broader GTN initiative (as described andspecified by the FOA). Our proposed NCC offers essential skill sets in neuropathology cancer geneticsclinical trials biostatistics and clinical trial design that will enable multiple GTN centers to work together inways that exceed the sum of their component parts. An Administrative Core will serve as the primary contactand communication resource for the Projects the PGIC an Internal Advisory Board the NCC the GTNSteering Committee and NCI program officials. The Harvard/Stanford GTN Principal Investigator is TracyBatchelor M.D. an experienced clinical trialist with much practical experience in leading large multi-investigator/multi-institutional initiatives. 864597 +No NIH Category available Address;African American;Area;Attention;Cancer Science;Cancer health equity;Chicago;Cities;Communities;Complement;Comprehensive Cancer Center;Development;Disparity;Diverse Workforce;Dryness;Education;Educational Activities;Educational Curriculum;Educational Status;Ensure;Ethnic Origin;Evaluation;Faculty;Fostering;Foundations;Funding;Gender;Goals;Grant;Health Disparities Research;Healthcare;Hispanic;Illinois;Immersion;Influentials;Institution;Internships;Laboratory Research;Link;Malignant Neoplasms;Medical Students;Medicine;Mentors;Minority;Not Hispanic or Latino;Postdoctoral Fellow;Program Evaluation;Race;Readiness;Recording of previous events;Research;Research Personnel;Research Project Grants;Science;Science Technology Engineering and Mathematics Education;Social Network;Structure;Student recruitment;Students;Underrepresented Populations;Underrepresented Students;Universities;Work;anticancer research;cancer health disparity;career;career development;career preparation;college;community college;community engagement;curriculum development;design;disability;diversity and equity;education research;experience;fortification;health disparity;high school;improved;interest;laboratory experience;life-long learning;lower income families;member;minority student;peer;programs;research faculty;science education;skills;social culture;success;summer program;summer research;undergraduate student;university student Research Education Core n/a NCI 10694140 9/4/23 0:00 PAR-18-767 5U54CA202997-09 5 U54 CA 202997 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7446 7372587 "GRIPPO, PAUL J" "KIM, SAGE J." 7 Unavailable 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL Domestic Higher Education 606124305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 169330 105898 63432 RESEARCH EDUCATION CORE ABSTRACT The overall objective of the Chicago Cancer Health Equity Collaborative (ChicagoCHEC) Research Education Core (REC) is to increase the number of students from underrepresented populations engaged in cancer research by fostering meaningful research education and community engaged experiences which link faculty and students of the University of Illinois at Chicago (UIC) Northeastern Illinois University (NEIU) and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (NU-LCC). For this Core we define students as high school through postdoctoral fellows. Between 2016 2019 the REC launched research education experiences bringing together diverse students across the Chicagoland area developed curricula introducing students to the science of cancer disparities and built robust networks with high school and local community college students to encourage their entry into REC programs. In that period the REC provided structured summer research education experiences through the ChicagoCHEC Research Fellows (CHEC Fellows) Program to 65 students from minority and underrepresented backgrounds. The CHEC Fellows Program is an intensive 8-week summer program that introduces students to a breadth of cancer health disparities research topics and to the work of leading cancer researchers provides hands-on engagement with community partners and builds professional skills as a foundation for lifelong learning. In this renewal we seek to sustain the successes of the CHEC Fellows Program and add programming to further student entry into cancer research trajectories and further meet the needs of students within ChicagoCHEC sponsored Projects. Thus the CHEC Fellows Program will be complemented by development of new career readiness and career development supports and an expansion of ChicagoCHEC Laboratory Experiences and Programs (LEaP) which matches students including graduates of the CHEC Fellows Program to intensive one-on-one mentored immersion experiences in cancer research laboratories. A diverse and exceptional tri-institutional team of cancer research faculty has been assembled to lead the REC in achieving its specific aims which are to: (1) develop curriculum and support professional development opportunities to increase Chicago area undergraduate interest and readiness in entering the cancer research career pipeline; (2) refine and sustain the CHEC Fellows and LEaP Programs for diverse undergraduate students recruited from NEIU UIC NU and City Colleges of Chicago; (3) link underrepresented students (undergraduates graduate/medical students and postdoctoral fellows) to mentored cancer research experiences within ChicagoCHEC Projects and provide career development support; and (4) implement continuous tracking and program evaluation. Initiatives of the ChicagoCHEC REC will directly introduce students to cancer research and enhance their capacity to seek out opportunities that will enable them to pursue meaningful highly effective careers in this field. +No NIH Category available American College of Radiology Imaging Network;Cancer Detection;Caring;Characteristics;Classification;Clinic;Cost Effectiveness Analysis;Data;Detection;Development;Diagnostic;Disease;Early Diagnosis;Effectiveness;Epidermal Growth Factor Receptor;Gene Mutation;Goals;Health;Human;Image;Interdisciplinary Study;KRAS2 gene;Lead;Lesion;Magnetic Resonance Spectroscopy;Malignant neoplasm of lung;Mass Spectrum Analysis;Measures;Metabolic;Methodology;Pathology;Patients;Populations at Risk;Prognostic Marker;Quality of life;Research;Sampling;Sensitivity and Specificity;Serum;Signal Transduction;Smoker;Specimen;Technology;Testing;Tissues;biobank;biomarker identification;cancer diagnosis;candidate identification;cost effective;cost effectiveness;diagnostic biomarker;efficacy evaluation;efficacy validation;high risk;imaging approach;imaging probe;lung basal segment;lung cancer screening;mass spectrometric imaging;meetings;metabolomics;minimally invasive;mutational status;novel;novel strategies;prognostic;programmed cell death protein 1;protocol development;repository Novel metabolomic contrast probes for human lung cancer characterization RelevanceBased on our preliminary results we propose to evaluate tissue-serum LuCa metabolomics anddevelop them into early-stage lung cancer contrast probes. The overarching goal is to develop anovel serum contrast probe able to reveal early lung cancer. NCI 10694139 8/22/23 0:00 PA-20-185 5R01CA273010-02 5 R01 CA 273010 2 "MARQUEZ, GUILLERMO" 9/1/22 0:00 8/31/27 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 1865385 "CHENG, LEO L" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 652061 NCI 452195 199866 Novel metabolomic contrast probes for human lung cancer characterizationWe identified preliminary proof-of-concept metabolomic markers for human LuCa from paired tissue and bloodserum samples from pre-symptomatic LuCA patients. The markers can be used as imaging probes for Lucacharacterization. To validate the efficacy of the markers for classifying LuCa we propose to evaluate andenhance their capability as probes for LuCa detection and ultimately advance LuCa early-detection usingserum metabolomic markers. The projects goal will be achieved through tasks in the following three specificaims: 1) To evaluate the efficacy of tissue-serum LuCa MRS metabolomic probes identified in a successfulpreliminary project by comparison with an additional 200 pairs of tissue and serum specimens and 200 serumsamples from matched healthy controls 2) To measure tissue-serum LuCa MRS metabolomic probes withmass spectrometry (MS) and MS imaging (MSI) to associate the probes with LuCa pathologies and identifyserum MS LuCa probes and 3) To test LuCa metabolomics probes using 200 serum samples collected beforeLuCa detection and evaluate LuCa metabolomic probe health- and cost-effectiveness as compared to existingadvanced tests. The projects goal is to identify a novel serum contrast probe able to contribute to LuCa earlydisease detection at asymptomatic stages to overcome persistent challenges currently faced in the LuCa clinic. 652061 +No NIH Category available Accelerometer;Adolescent;Adult;Age;Attitude;Blood Pressure;Cancer Survivor;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Child;Childhood;Childhood Cancer Survivor Study;Chronic Disease;Competence;Counseling;Decision Making;Development;Diabetes Mellitus;Diagnosis;Diet;Diet Habits;Dietary Factors;Dyslipidemias;Exposure to;Future;General Population;Goals;Health;Healthcare;Healthcare Systems;Healthy Eating;Heart failure;Home;Hypertension;Inflammation;Insulin Resistance;Intervention;Intervention Studies;Learning;Life Style;Lipids;Long-Term Survivors;Maintenance;Malignant Neoplasms;Mediator;Mobile Health Application;Morbidity - disease rate;Myocardial Ischemia;Neighborhoods;Outcome;Participant;Physical activity;Physiological;Play;Randomized;Randomized Controlled Trials;Remote session;Research;Research Design;Resources;Risk;Risk Factors;Role;Self Determination;Self Efficacy;Self Management;Sequential Multiple Assignment Randomized Trial;Survivors;Testing;Time;Training;Treatment Efficacy;Unhealthy Diet;Woman;active lifestyle;aged;arm;cancer therapy;cardiometabolism;cardiovascular health;cardiovascular risk factor;childhood cancer survivor;cohort;dietary;experience;follow-up;improved;indexing;innovation;intervention participants;lifestyle factors;lifestyle intervention;mHealth;malignant breast neoplasm;modifiable risk;mortality;patient engagement;peer support;pharmacologic;premature;prospective;recruit;remote delivery;response;secondary analysis;sedentary;sex;social media;survivorship;telehealth;theories;trial design;young adult SALSA - Study of Active Lifestyle Activation PROJECT NARRATIVEWith improved treatments the vast majority of children diagnosed with cancer are now cured. Howeverpremature cardiovascular disease has become the leading non-cancer cause of death among childhoodcancer survivors. Using an adaptive study design the proposed trial seeks to determine if various innovativeintervention strategies can help childhood cancer survivors improve their physical activity and dietary habits inorder to reduce their long-term risk of early cardiovascular disease. NCI 10694134 8/30/23 0:00 RFA-CA-20-027 5R01CA263144-04 5 R01 CA 263144 4 "AGURS-COLLINS, TANYA" 9/21/21 0:00 8/31/26 0:00 ZCA1-SRB-T(M1) 8441297 "CHOW, ERIC JESSEN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 704529 NCI 459894 244635 PROJECT SUMMARY / ABSTRACTChildren and adolescents diagnosed with cancer now have on average nearly 85% 5-year survival. Howeverpremature cardiovascular (CV) disease has become the leading non-cancer cause of late mortality amongchildhood cancer survivors. There is a robust body of evidence from the general population and increasinglyamong cancer survivors (even those exposed to cardiotoxic cancer therapies) that greater physical activity (PA)and improved diet quality can reduce future CV-related morbidity. However while many general population andcancer-specific intervention studies have focused on a single lifestyle factor (e.g. PA or diet alone) given theinterplay between PA and dietary factors in influencing CV health a multi-faceted approach may result in overallbetter long-term CV health profiles. Research on lifestyle interventions in cancer survivors also has beenpredominantly conducted in women with breast cancer and the evidence for survivors of childhood cancer islimited. To accomplish our aims we will use the largest prospectively followed childhood cancer survivor cohortin the world the Childhood Cancer Survivor Study (CCSS; n>24000) to recruit adult-aged participants atincreased risk of early CV disease (n=403) for a remotely conducted 12-month randomized controlled trial testinga multi-faceted approach at improving PA and diet quality. Specifically the study will use a sequential multipleassignment randomized trial (SMART) design where participants with low PA or poor diet will first be randomizedbetween intervention and control conditions. Intervention participants will be further randomized to receive eitherclinician-led telehealth sessions focused on risk factor self-management or weekly mobile health (mHealth)supported individualized PA and dietary goal-setting with social media peer support. The adaptive SMARTdesign will allow further tailoring of the intervention experience based on initial response which may increaseoverall intervention efficacy. Participants not initially responsive to their assigned intervention will be furtherrandomized to receive an alternate intervention. The study will use consumer-grade mHealth applications thattrack PA and diet thereby increasing future dissemination capacity. The studys primary analyses will determinethe overall intervention efficacy and whether specific intervention strategies and sequence of strategies areassociated with optimal outcomes. Secondary analyses will examine potential predictors mediators andmoderating factors associated with PA and dietary changes over time as well as changes in participantscardiometabolic profiles. In summary lifestyle change represents one of the few available strategies to mitigateCV risk in childhood cancer survivors. Significant barriers (e.g. time training resources) limit the ability ofhealthcare systems to facilitate such change. To fill this void remote-based personalized and easilydisseminated multi-faceted mHealth-supported interventions may play a transformative role. 704529 +No NIH Category available Address;Adolescent;Australia;CD4 Lymphocyte Count;Cancer Burden;Cancer Control;Cancer Intervention and Surveillance Modeling Network;Cervical;Cervical Cancer Screening;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Comparative Carcinogenesis;Cost Effectiveness Analysis;Country;Data;Decision Making;Development;Disease;Disease Outcome;Disparity;Effectiveness;Ensure;Equity;Evaluation;Guidelines;HIV;Health;Health Benefit;Health Policy;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Infection;Information Dissemination;Kenya;Knowledge;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Modeling;Netherlands;New Mexico;North Dakota;Outcome;Policies;Policy Maker;Population;Populations at Risk;Preventative vaccination;Prevention strategy;Process;Productivity;Public Health;Reporting;Research Personnel;Risk;Route;Series;South Africa;Technology;Testing;Time;Uganda;United States;Update;Vaccinated;Vaccination;Vaccines;Woman;base;cancer health disparity;cervical cancer prevention;cervical carcinogenesis;co-infection;cohort;comparative;comparative effectiveness;cost;cost effective;cost effectiveness;disparity reduction;effectiveness evaluation;evidence base;improved;innovation;low and middle-income countries;mathematical model;new technology;programs;scale up;screening;screening guidelines;sexually transmitted virus;tool;vaccination strategy;working group Comparative Modeling to Inform Cervical Cancer Control Policies Project NarrativeNew technologies including screening tests and vaccines against human papillomavirus (HPV) a sexually-transmitted virus known to cause cervical cancer are dramatically changing the landscape of cervical cancercontrol in the US and worldwide. In order to address important evidence gaps our CISNET-Cervical workinggroup consisting of five teams who have been at the forefront of modeling cervical cancer prevention overthe last decade will continue this comparative modeling collaboration to evaluate the harms benefits andcost-effectiveness of screening and vaccination strategies and disseminate findings to inform health policiesand decisions. NCI 10694132 8/28/23 0:00 RFA-CA-19-054 5U01CA253912-04 5 U01 CA 253912 4 "TATALOVICH, ZARIA" 9/8/20 0:00 8/31/25 0:00 ZCA1-SRB-T(M3) 8689652 "KIM, JANE JOOYUN" "BARNABAS, RUANNE VANESSA; CANFELL, KAREN ; DE KOK, INGE MCM; KULASINGAM, SHALINI L." 7 PUBLIC HEALTH & PREV MEDICINE 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1225767 NCI 1024714 201053 Project SummaryDespite successful cervical cancer screening in the United States (US) over 13000 women develop and 4000women die from cervical cancer each year. The discovery of human papillomavirus (HPV) as the necessarycause of cervical cancer precipitated a surge of new evidence and development of innovative HPV-basedtechnologies both screening and prophylactic vaccination that have allowed for significant changes in ourapproach to cervical cancer control over the past two decades. These new technologies represent tremendousopportunities for effective equitable and efficient cervical cancer programs in the US but also pose significantchallenges for decision-making. Given the limited availability of outcomes data for new screening andvaccination approaches from empirical studies policy-makers have become uniquely reliant on mathematicalmodeling to provide a synthesized evidence base for decision-making for cervical cancer control strategies.These models can be used to integrate the most up-to-date data extrapolate short-term findings into long-termoutcomes and evaluate what-if scenarios that would otherwise be impractical or infeasible to conduct inclinical studies. The proposed CISNET project will represent the continued productive collaboration of fiveindependent modeling groups from the US Australia and the Netherlands that will leverage a series of state-of-the-art mathematical models of HPV and cervical carcinogenesis for comparative modeling. We will pursueanalyses related to the impact of newly-revised screening and HPV vaccination guidelines the comparativeeffectiveness of forthcoming screening and HPV vaccination strategies and approaches the optimal routes forreducing cervical cancer disparities the potential for cervical cancer elimination in the US and optimalscreening and vaccination strategies in women living with HIV. Our efforts will also involve wide disseminationof findings to various stakeholders to increase transparency and confidence in model-based analyses. 1225767 +No NIH Category available Adherence;Age;Black race;COVID-19 pandemic;Cancer Center;Cancer Survivorship;Caring;Clinic;Collaborations;Common Terminology Criteria for Adverse Events;Communication;Communities;Confusion;Consensus;Diagnosis;Disparity;Dissemination and Implementation;Education;Electronic Health Record;Eligibility Determination;Enrollment;Ensure;Explosion;Goals;Guidelines;Health;Health Services;Institution;Insurance;Interactive Communication;Intervention;Interview;Knowledge;Late Effects;Latinx;Life;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Medical Records;Methods;Modeling;Monitoring for Recurrence;Oncologist;Outcome;Patient Care;Patient Education;Patient-Focused Outcomes;Patients;Persons;Physicians;Process;Quality of Care;Radiation;Randomized;Randomized Controlled Trials;Recommendation;Recurrent tumor;Resources;Rural;Sampling;Self Efficacy;Site;Structure;Subgroup;Surveys;Technology;Telephone;Testing;Text Messaging;Travel;Visit;Work;acceptability and feasibility;adherence rate;arm;cancer therapy;chemotherapy;childhood cancer survivor;comparison group;cost;direct patient care;disparity gap;follow-up;future implementation;health disparity;improved;individual patient;innovation;instrument;intervention participants;medical specialties;patient engagement;patient health information;patient portal;preference;primary care clinic;primary care provider;primary endpoint;primary outcome;programs;provider-level barriers;socioeconomic disadvantage;survivorship;telehealth BRidging Information Divides and Gaps to Ensure Survivorship: the BRIDGES Randomized Controlled Trial of a Multilevel Intervention to Improve Adherence to Childhood Cancer Survivorship Project NarrativeMore than 80% of childhood cancer survivors develop serious or life-threatening late effects after cancer therapybut <20% receive recommended survivorship care offered at cancer center survivorship clinics. In a shared caremodel we propose to investigate an innovative multi-level intervention consisting of: 1) patient survivorshipeducation via telehealth with the cancer center 2) ongoing patient-tailored education program within theelectronic health record patient portal 3) a structured interactive phone communication between the cancercenter and the primary care clinic and 4) an in-person visit with the primary care clinic for survivorship care withthe goal of achieving high rates of adherence to recommended surveillance for late effects as well as improvingpatient and physician knowledge and self-efficacy. If our scalable intervention demonstrates patient completionof recommended care comparable to cancer center survivorship clinics our innovative study has the enormouspotential to deliver recommended care to a larger proportion of childhood cancer survivors and reducesurvivorship care disparities while engaging patients and primary care providers to integrate survivorship careas part of overall lifelong health maintenance. NCI 10694125 8/28/23 0:00 RFA-CA-20-027 5R01CA261881-03 5 R01 CA 261881 3 "MOLLICA, MICHELLE A" 9/21/21 0:00 8/31/26 0:00 ZCA1-SRB-T(M1) 7753669 "KADAN-LOTTICK, NINA S" Not Applicable 98 NONE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC ORGANIZED RESEARCH UNITS 200570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 599483 NCI 502466 97017 PROJECT SUMMARYMore than 80% of childhood cancer survivors (CCS) develop serious or life-threatening late effects. Yet <20%of CCS receive recommended survivorship care despite the availability of consensus guidelines for lifelongsurveillance for late effects starting 2 years post-therapy. The gold standard cancer center-based survivorshipclinic provides high-quality care to CCS who attend but patients avoid reminders of their past cancer and lackknowledge and self-efficacy for survivorship care. Other barriers include travel distance inadequate insuranceand out-of-pocket coststhese structural issues contribute to health disparities. Partnering with communityprimary care provider (PCP) clinics in a shared model of care is a promising strategy to overcome these barriersbut PCPs lack knowledge self-efficacy and interactive communication with the cancer center and are confusedabout the division of care responsibilities. Our intervention is scalable and distance-based is informed directlyby patient and PCP barriers and preferences from previous studies and is boosted by a nationwide explosion intelehealth services precipitated by the COVID-19 crisis. The proposed randomized controlled trial will enroll 240CCS 2.0-4.0 years post-chemotherapy/radiation to investigate an innovative multi-level intervention (i.e.interpersonal and organizational levels) consisting of 1) patient survivorship education via telehealth with thecancer center 2) ongoing patient-tailored education program within the EHR's patient portal 3) a structuredinteractive phone communication between the cancer center and the PCP clinic (with 1-year follow-up call) and4) an in-person visit with the PCP clinic for survivorship care. The comparison group will be randomized to anin-person visit with their cancer center survivorship clinic. This study includes 4 centers with high proportions ofsubgroups vulnerable to survivorship care disparities (i.e. rural Black Latinx Spanish-speakingsocioeconomically disadvantaged). Both groups will be asked to begin recommended surveillance for late effectswithin 1-year post-randomization separate from tumor recurrence monitoring by the primary oncologist. OurSpecific Aims are to Aim 1- Demonstrate patient completion of guideline-recommended surveillance tests inintervention participants is not inferior i.e. within 10% to that in the comparison group; Aim 2- Achieve greater1) patient knowledge self-efficacy and activation and 2) PCP knowledge and self-efficacy with survivorship careamong intervention participants and their PCPs compared to the comparison group; and Aim 3- Ascertainprocess outcomes for the 1) patient and 2) PCP clinic. Outcomes will also be assessed among subgroups withsurvivorship care disparities. Transformative Impact: If our intervention demonstrates patient completion ofrecommended survivorship care comparable to cancer center survivorship clinic our study has the enormouspotential to deliver recommended lifelong care to a larger proportion of CCS and reduce survivorship caredisparities while engaging patients and PCPs to integrate survivorship care as part of overall lifelong healthmaintenance. 599483 +No NIH Category available Adherence;Advanced Malignant Neoplasm;Advisory Committees;Award;Budgets;Cancer health equity;Chicago;Clinical;Collaborations;Communication;Communities;Comprehensive Cancer Center;Decision Making;Education;Ensure;Equity;Evaluation;Faculty;Foundations;Goals;Guidelines;Illinois;Individual;Infrastructure;Institution;Institutional Policy;Lead;Leadership;Logic;Malignant Neoplasms;Manuals;Mentors;Minority;Minority-Serving Institution;Modeling;Process;Protocols documentation;Reporting;Research;Resources;Solid;Stream;Structure;Student recruitment;Students;Talents;Time;Universities;Work;anticancer research;cancer health disparity;career;career development;conflict resolution;early-career faculty;experience;improved;interest;meetings;member;operation;outreach;programs;recruit;research facility;success;tool Administrative Core n/a NCI 10694123 9/4/23 0:00 PAR-18-767 5U54CA202997-09 5 U54 CA 202997 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7440 1899365 "FITZGIBBON, MARIAN L." "JIMBO, MASAHITO " 7 Unavailable 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL Domestic Higher Education 606124305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 591749 372227 219522 ADMINISTRATIVE CORE ABSTRACT The Chicago Cancer Health Equity Collaborative (ChicagoCHEC) Administrative Core (AC) leverages a shared governance model in order to fulfill its responsibilities to establish mechanisms and infrastructure that promote planning communication interaction integration and evaluation that support the broad spectrum of research education and outreach activities to advance cancer health equity. ChicagoCHEC builds on the solid foundation of a 10-year collaborative track record that includes our first NCI U54 Comprehensive Partnership to Advance Cancer Health Equity (CPACHE) award. The AC led by a tri-institutional MPI team capitalizes on the strengths of each institution and leverages those strengths to build cancer research capacity at two minority serving institutions University of Illinois at Chicago (UIC) and Northeastern Illinois University (NEIU) and to expand cancer disparities research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (NU-LCC). AC leadership is instrumental in guiding our Partnership identifying resources building collaborative ties capacity building and helping facilitate faculty and students advancement in cancer research education and outreach within the framework of institutional policies. The AC team from UIC NEIU and NU-LCC have worked together in varying capacities for the past 10 years and are a well-integrated team laying the groundwork for a strong collaboration upon which to launch and sustain ChicagoCHECs next chapter. To guide operations and ensure best practices and the realization of targeted milestones in all Partnership activities we will leverage our established standard operating protocol a full operations manual and detailed logic models that guide Partnership activities and evaluation processes. Our AC is guided by an Internal Advisory Committee (IAC) and a Program Steering Committee (PSC). We now plan to further advance the foundation built through our initial U54 award to fulfill the following Specific Aims: (1) Provide overall support for ChicagoCHEC activities ensuring integration coordination collaboration and fiscal administration across the Projects and Cores; (2) Refine and maintain communication processes and structures to enhance the overall visibility of the ChicagoCHEC Partnership; (3) Facilitate mechanisms to optimize integration with and efficient utilization of institutional resources within the partnering institutions NU-LCC UIC and NEIU; (4) Organize and maintain a robust pipeline for continuous recruitment of students and faculty from minority and underrepresented backgrounds into this Partnership; and (5) Drive iterative and robust evaluation of all ChicagoCHEC Partnership activities. +No NIH Category available Address;Advocate;Applications Grants;Area;Award;Cancer Center;Capital;Catchment Area;Collaborations;Communities;Complex;Data;Development;Disadvantaged;Discipline;Disparity;Diverse Workforce;Education;Education and Outreach;Faculty;Foundations;Funding;Future;Goals;Grant;Health Disparities Research;Historically Black Colleges and Universities;Incidence;Infrastructure;Institution;Institutionalization;K-Series Research Career Programs;Knowledge;Lead;Localized Malignant Neoplasm;Malignant Neoplasms;Manuscripts;Mentors;Minority;Mission;NCI Center for Cancer Research;Pilot Projects;Policies;Research;Research Personnel;Research Project Grants;Research Training;Resources;Secure;Series;Solid;Students;Training;Training Programs;Training and Education;Translations;Underrepresented Minority;United States National Institutes of Health;Universities;Virginia;Work;Writing;anticancer research;cancer health disparity;career;community engaged research;community engagement;course sequence;design;education research;experience;health disparity;health inequalities;improved;innovation;interdisciplinary approach;interest;minority investigator;minority student;mortality;multidisciplinary;outreach;pilot test;programs;skills;summer research;training project;undergraduate student;university student SUCCEED Cancer Research Education Program (CREP) CANCER RESEARCH EDUCATION PROGRAM: NARRATIVEIt is fundamental to establish a sustainable infrastructure that will facilitate the training and inclusion of moreunderrepresented minority faculty researchers and students in cancer health disparities research. Virginia StateUniversity (VSU) and Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) have establisheda collaborative Cancer Research Education Program (VSU-MCC CREP) to maximize existing institutionalresources and to build an infrastructure that will increase the capacity of faculty and students to pursue andfacilitate cancer health disparities research and enhance VSUs ability to lead in education communityengagement and research in cancer health disparities in Virginia. NCI 10694121 9/20/23 0:00 PAR-18-911 5P20CA264068-03 5 P20 CA 264068 3 9/20/21 0:00 8/31/25 0:00 ZCA1-SRB-2 7439 1923259 "FAISON, MILTON O" Not Applicable 4 Unavailable 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA Domestic Higher Education 238032520 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 49928 41249 8679 CANCER RESEARCH EDUCATION PROGRAM: SUMMARYEffectively addressing cancer health disparities requires a comprehensive multidisciplinary diverse workforce toaddress multi-level and complex health inequities which are evident in the continuing disproportionate cancerincidence and mortality rates of underrepresented minorities. To fully understand and address the most criticalfactors effecting cancer health disparities it is necessary to continuously enhance the design approachimplementation dissemination and practice of cancer health disparities research. Likewise it is fundamental toestablish a sustainable infrastructure that will facilitate the didactic training and inclusion of moreunderrepresented minority (URM) investigators and students in cancer health disparities research. Virginia StateUniversity (VSU) and Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) have establisheda collaborative Cancer Research Education Program (VSU-MCC CREP) to maximize existing institutionalresources and to build an infrastructure that will increase the capacity of faculty and students to pursue andfacilitate cancer health disparities research and enhance VSUs ability to lead in education communityengagement and research in cancer health disparities in Virginia.The overall goal of the VSU-MCC CREP partnership is to pilot test cancer health disparities training andeducation programs and to use the preliminary data to not only advocate for the institutionalization of theseprograms but also to inform the development of a pipeline for VSU URM faculty to successfully compete for NIHfunding (K awards R01s). The long-term goal is to develop a sustainable education and training program thatwill improve the impact and scope of research discoveries and translation by increasing the number ofunderrepresented minority investigators and students who can significantly inform influence and conduct cancerhealth disparities research. Our approach is threefold: 1) develop the research capacity and capital of developingfaculty at VSU to conduct cancer disparities research; 2) increase the number of diverse students at bothinstitutions interested in cancer health disparities research and participating in cancer research educationexperiences; and 3) increase the number of investigators at both institutions conducting cancer research.The SUCCEED CREP will provide a set of unique and sustainable training experiences aimed at increasing thecapacity of a local historically black college to take the lead in education community engagement and researchin cancer-related health disparities. The organizing theme of the educational and training experiences for facultyand students is to build the knowledge skills partnerships and capacity for multidisciplinary approaches toidentify and reduce local cancer-related health disparities and their determinants. +No NIH Category available Award;Career Mobility;Doctor of Philosophy;Environment;Funding;Gene Silencing;Genes;Genetic Transcription;Goals;Grant;Hypoxia;Hypoxia Inducible Factor;In Vitro;Invaded;Laboratory Research;Malignant Neoplasms;Mentors;Methods;Mission;Molecular;Molecular Biology;Molecular Biology Techniques;Monitor;Neoplasm Metastasis;Pathology;Postdoctoral Fellow;Productivity;Renal carcinoma;Research;Research Personnel;Research Project Grants;Small Interfering RNA;Specialist;Talents;Training;Work;cancer imaging;hypoxia inducible factor 1;in vivo Cellular and Molecular Imaging Centers;medical schools;molecular imaging;nanoparticle delivery;pediatric department;post-doctoral training;programs;recruit;small hairpin RNA;theranostics;tumor;tumor microenvironment;tumor progression INTEGRATING MOLECULAR BIOLOGY WITH CANCER MOLECULAR IMAGING AND THERANOSTICS Y at ha A hu Vai ryoDr. Krishnamachary represents the ideal candidate for this Research Specialist award that will provide him withstability for the next five years. This award will allow him to use his exceptional expertise in molecular biologyto advance research related to the tumor micro and macroenvironment as well as theranostics. Dr.Krishnamachary also has an excellent track record in training and mentoring. NCI 10694119 8/23/23 0:00 PAR-20-288 5R50CA243562-03 5 R50 CA 243562 3 "LIN, CHARLES" 9/23/21 0:00 8/31/26 0:00 ZCA1-SRB-1(A1) 9437545 "KRISHNAMACHARY, BALAJI " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 93367 NCI 57018 36349 Y at ha A hu Vai ryoThe purpose of this R50 application is to provide 6 months effort for Dr. Balaji Krishnamachary as a ResearchSpecialist working with Dr. Bhujwalla as Unit Director. Dr. Krishnamachary was awarded his PhD in 1995following which he completed his postdoctoral training first in the Department of Pathology at ULCA from 1998-2000 and subsequently in the Department of Pediatrics at Johns Hopkins School of Medicine from 2000-2006.During his postdoctoral training in the Department of Pediatrics Dr. Krishnamachary worked with Dr. GreggSemenza on hypoxia and the hypoxia inducible factor (HIF)-1. He gained significant expertise in constructingboth siRNA and shRNA establishing a retroviral delivery method to silence the transcription factor hypoxiainducible factor-1 (HIF-1) in vitro in renal carcinoma and was trained in various molecular biology techniques tointerrogate the transcriptional activity of genes involved in the progression of cancer.Dr. Krishnamachary joined Dr. Bhujwallas Cancer Imaging Research Program in 2006 as a Research Associate.Dr. Krishnamachary is a laboratory research-oriented investigator with an outstanding track record in integratingmolecular biology with molecular imaging and theranostics. As an exceptionally talented molecular biologist whohas been actively pursuing research within Dr. Bhujwallas NCI funded molecular imaging and theranosticsresearch program this opportunity is particularly relevant for Dr. Krishnamachary. He has shown clear evidenceof productivity and research excellence in molecular biology applied to molecular imaging. Dr. Krishnamacharywill continue to integrate his molecular biology expertise within the cancer molecular imaging research programdirected by Dr. Bhujwalla with the goal of making significant contributions to cancer molecular imaging that isrelevant to the NCI mission.The Unit Director Dr. Bhujwalla has been funded continuously by the NCI since 1997. Dr. Krishnamachary wasrecruited by her in 2006 to provide molecular biology expertise to her molecular imaging research programfollowing the funding of an NCI P50 grant (JHU ICMIC Program) that she held from 2003-2017. Dr. Bhujwallacurrently holds an NCI R35 Outstanding Investigator Award on Molecular Imaging and Theranostics of Cancerthat is funded until 2024. Since the previous R50 submission Dr. Bhujwalla competitively renewed her R01 titledHostile Environments promote Invasion and Metastasis and was awarded a new R01 on The TumorMicroenvironment in Nanoparticle Delivery and Function. Dr. Krishnamacharys efforts are closely integratedand critical to the scientific research of these grants providing clear evidence that Dr. Bhujwalla is stronglycommitted to Dr. Krishnamachary and his research. She has worked closely with Dr. Krishnamachary since2006 and will continue to be responsible for the planning direction monitoring and execution of the NCI fundedresearch together with Dr. Krishnamachary. Dr. Bhujwallas purpose in supporting this application to the best ofher ability is to achieve a stable environment for Dr. Krishnamachary and to advance his career. 93367 +No NIH Category available Accounting;Address;African American;Attenuated;Attitude;Awareness;Behavior;Belief;Cancer Etiology;Caring;Cellular Phone;Cessation of life;Code;Colonoscopy;Colorectal Cancer;Communities;Consent;Data;Development;Disease;Early Diagnosis;Education;Enrollment;Ethnic Population;Friends;Fright;General Population;Goals;Guidelines;Health behavior;Incidence;Individual;Institution;Insurance;Intervention;Malignant Neoplasms;Medical;Methods;Modeling;National Cancer Advisory Board;Patient Self-Report;Pilot Projects;Planning Theory;Poverty;Prevention;Preventive;Preventive care;Preventive screening;Privatization;Public Health;Recommendation;Reporting;Research;Risk;Scanning;Self Direction;Social Network;Social support;Surveys;Survival Rate;Tablets;Technology;Testing;Text;Training Programs;Trust;black men;cancer health disparity;colorectal cancer screening;community setting;design;evidence base;expectation;experience;feasibility testing;follow-up;health belief;health care settings;improved;intervention delivery;mHealth;men;mortality;novel;outreach;perceived discrimination;post intervention;premalignant;programs;racial population;racism;response;screening;screening participation;screening program;tailored messaging;therapy design;tool;uptake SUCCEED Pilot Project 2 PILOT PROJECT 2: PROJECT NARRATIVEColorectal cancer (CRC) is one of few cancers for which precancerous and early stage disease can be identifiedand treated successfully through preventive screening. African American (AA)/Black men experience 24% higherCRC incidence 47% higher mortality and have the shortest CRC survival rates of all racial/ethnic groups.Despite CRC screening participation rates 10%-30% lower than other groups to date very few screeningprograms have been tailored to the needs of AA/Black men. The overall goal of this proposal is to collect in-depth information about AA/Black mens CRC screening beliefs attitudes and participation to inform thedevelopment of culturally tailored mHealth intervention to improve AA/Black mens participation and CRCscreening completion. NCI 10694116 9/20/23 0:00 PAR-18-911 5P20CA264068-03 5 P20 CA 264068 3 9/20/21 0:00 8/31/25 0:00 ZCA1-SRB-2 7437 12091372 "KEEN, LARRY D" Not Applicable 4 Unavailable 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA Domestic Higher Education 238032520 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 73125 50781 22344 PILOT PROJECT 2: PROJECT SUMMARYThe NCI Screen to Save (S2S) has successfully increased awareness about colorectal cancer (CRC) and theimportance of screening for prevention and early detection. Using S2S tools and methods through 2018-2020our team educated over 211 individuals but identified the need to more effectively reach African American(AA)/Black men who represented only 10% of those we enrolled. AA/Black men experience 24% higher CRCincidence 47% higher mortality and have the shortest CRC survival rates of all racial/ethnic groups. MoreoverCRC screening participation rates among AA/Black men are 10%-30% lower than other groups. Because CRCis one of few cancers for which precancerous and early stage disease can be identified and treated successfullythrough preventive screening tailored interventions that can successfully increase AA/Black mens CRCscreening participation are critical. The goal of this proposal is to collect in-depth information on AA/Black mensCRC screening beliefs attitudes and values to inform the development of culturally tailored mHealth interventiondesigned to improve CRC screening participation. Transforming the traditional S2S materials content anddelivery this study will develop and test enhanced mHealth delivered materials that address constructs thatimpede screening uptake specific to AA/Black men. Secondly we will test the feasibility of intervention deliveryusing a novel mHealth platform not previously used by CRC screening interventions. This study leverages anexisting educational strategy institutional commitment and expertise infused technology and tailored messagesto address an important public health issue. If successful S2S mHealth has potential for wide-spreaddissemination with the 39 NON-S2S network and beyond. Aim 1. Determine factors associated with self-reportedCRC screening behaviors among (n=175) AA/Black men in Petersburg VA. H1.1. Lack of social support highermedical mistrust and perceived discrimination will be negatively associated with self-reported screeningbehaviors (ever & up-to-date). H2.2. Higher engagement in preventive care behaviors and greater perceived riskwill be associated with higher completion of CRC screening. Subaim1a. Examine potential interactions betweenperceived discrimination medical mistrust and engagement in preventive care behaviors. H1.3. Increasedperceptions of discrimination and greater medical mistrust will attenuate the relationship between preventivecare and self-reported screening (ever & up-to-date). Aim 2. Develop tailored S2S content for AA/Black men tobe delivered using a combination of short video and text-based information optimized for delivery via QR codesfor smartphones. Aim 3. Evaluate the feasibility of delivering the enhanced S2S intervention for AA/Black men(n=30) delivered via local barbershops. H3.1. 50% of those who scan the QR code will consent to participateand 70% of those consented will complete follow-up surveys (weeks 12). H2.2. Most men (75%) will be satisfiedwith the content and mode of delivery of the S2S mHealth intervention. H3.3. Most men (60%) who completethe enhanced S2S will report screening completion at 12-weeks post intervention. +No NIH Category available Advisory Committees;Animals;Cancer Center;Communication;Data;Doctor of Philosophy;Education Projects;Educational workshop;Ensure;Environment;Evaluation;Expenditure;Funding;Future;Goals;Grant;Human Resources;Institution;Institutional Review Boards;Interruption;Leadership;Mission;Modeling;Monitor;Policies;Principal Investigator;Problem Solving;Progress Reports;Publications;Research;Research Project Grants;Resource Allocation;Resources;Safety;Strategic Planning;System;Training;Training Programs;Universities;Virginia;anticancer research;cancer health disparity;education research;human subject;meetings;member;pressure;programs;timeline;tumor progression SUCCEED Administrative Core n/a NCI 10694112 9/20/23 0:00 PAR-18-911 5P20CA264068-03 5 P20 CA 264068 3 9/20/21 0:00 8/31/25 0:00 ZCA1-SRB-2 7435 1923259 "FAISON, MILTON O" Not Applicable 4 Unavailable 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA Domestic Higher Education 238032520 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 98556 68442 30114 ADMINISTRATIVE CORE: PROJECT SUMMARYThe Administrative Core will provide scientific and programmatic leadership to ensure the unifying scientificmission of the Virginia State University (VSU)-Virginia Commonwealth University (VCU) Massey Cancer Center(MCC) PartnErship for CancEr Disparities Research and Training (SUCCEED) program and create anenvironment in which the scientific and educational projects can flourish without the pressures of routineadministrative tasks and interruption. This core will be the hub of SUCCEED. It will support the 2 researchprojects implement a system for reviewing proposed new pilots during the project funding period support theCancer Research Education Program (CREP) activities and will be responsible for regulatory oversight fiscalmanagement facilitating communication among the investigative teams and strategic planning. It will alsoprovide a unifying entity for internal and external communication for strategic planning and dissemination. TheAdministrative Core will be led by a team of multi-principal investigators (MPIs) along with the guidance of anInternal Advisory Committee. The MPI team includes Robert A. Winn MD (VCU MCC Contact MPI) VanessaSheppard PhD (VCU MCC) Omar Faison PhD (VSU Contact MPI) and Daniel Roberts EdD (VSU).The aimsof the core are to: Aim 1: Provide overall support via close interaction with VSU and MCC leadership the InternalAdvisory Committee and the NCI; Aim 2: Provide administrative budgetary and regulatory oversight forSUCCEED; and Aim 3: Organize coordinate and monitor progress toward overall SUCCEED goals. +No NIH Category available Adjuvant;Antibodies;Biological Markers;Cancer Etiology;Cessation of life;Chemoprevention;Clinical Data;Clinical Trials;Cyclooxygenase Inhibitors;Cyst;Cyst Fluid;Cystic Neoplasm;Data;Development;Diagnosis;Diagnostic;Disease;Disease Outcome;Double-Blind Method;Early Diagnosis;Eligibility Determination;Endoscopic Ultrasonography;Excision;Failure;Gelatinase B;General Hospitals;Gland;Goals;Heterogeneity;Human;Image;Image Analysis;Inflammation;Inflammation Mediators;Inflammatory;Institution;Interleukin-4;Laboratories;Lesion;Liquid substance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Massachusetts;Measurement;Measures;Modeling;Monitor;Mucinous Neoplasm;Pancreas;Pancreatectomy;Pancreatic Adenocarcinoma;Pancreatic cystic neoplasia;Papillary;Patient-Focused Outcomes;Patients;Pattern;Persons;Placebo Control;Placebos;Pre-Clinical Model;Prevention;Prevention trial;Probability;Process;Randomized;Recommendation;Research;Risk;Solid;Stage at Diagnosis;Sulindac;Systemic Therapy;Techniques;Testing;Therapeutic;United States;University Hospitals;Variant;X-Ray Computed Tomography;arm;aspirate;biomarker panel;cancer invasiveness;cancer therapy;effectiveness evaluation;first-in-human;high risk;improved;improved outcome;inflammatory marker;novel strategies;pancreas development;participant enrollment;phase II trial;prevent;primary endpoint;progression risk;quantitative imaging;radiological imaging;radiomics;secondary endpoint;treatment arm;treatment effect;tumor progression Preventing an Incurable Disease: The Prevention of Progression to Pancreatic Cancer Trial (The 3P-C Trial) PROJECT NARRATIVEPancreatic cancer is an incurable disease and is projected to be the second highest cause of cancer death inthe United States by 2020. The goal of this multi-institutional research effort is to perform the first clinical trialin humans aimed at preventing the development of pancreatic cancer in high-risk patients. The significance ofpreventing this incurable malignancy cannot be overstated: With regards to pancreatic cancer an ounce ofprevention is worth many pounds of cure! NCI 10694111 8/21/23 0:00 PAR-18-559 5R01CA235677-05 5 R01 CA 235677 5 "UMAR, ASAD" 9/20/19 0:00 8/31/24 0:00 Cancer Prevention Study Section[CPSS] 8876021 "ALLEN, PETER J" Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 541606 NCI 409258 132348 PROJECT SUMMARYPancreatic cancer will be diagnosed in approximately 55000 people in the U.S. in 2019. Nearly all of thesepatients will die from this disease because of the late stage at diagnosis and the ineffectiveness of currentsystemic therapies. The shortcomings of current diagnostic and therapeutic strategies is exemplified by the factthat even when patients are diagnosed prior to the development of identifiable metastatic disease (<15% ofpatients) and are treated with operative resection and adjuvant systemic therapy the probability of five-yearsurvival is approximately 10%. There is an urgent need for novel strategies to improve patient outcomes for thisdisease.Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are cystic tumors that represent the onlyradiographically identifiable precursor lesion of pancreatic cancer. IPMN is a whole-gland process and it isknown that patients who undergo partial pancreatectomy for IPMN have an increased risk of developing cancerin the pancreatic remnant. Because of this recommendations for patients who have undergone partialpancreatectomy for non-invasive IPMN is serial radiographic and/or endoscopic surveillance of their pancreaticremnant. Recent data from our group has shown that approximately 25% of patients will develop radiographicsigns of IPMN progression within three to four years of resection. Between our four centers (Duke UniversityHospital Johns Hopkins University Hospital Massachusetts General Hospital Memorial Sloan Kettering) we arecurrently following over 450 patients who have undergone resection for IPMN. These patients are ideally suitedfor a chemoprevention trial.The goal of this multi-institutional research effort is to perform the first-in-human chemoprevention trial forpancreatic adenocarcinoma. Patients who have undergone partial pancreatectomy and have been found tohave high-risk IPMN will be eligible for this randomized double-blind placebo controlled Phase II trial (100patients/arm). This trial will utilize the selective COX inhibitor sulindac which has been demonstrated to behighly effective in preventing progression to pancreatic cancer in pre-clinical models. Clinical data from ourgroup and others have demonstrated a strong association between inflammation and progression in patientswith IPMN and sulindac has been shown to decrease the size of IPMN in patients with these cystic precursorlesions. The primary endpoint will be the rate of radiographic progression after three years. Patients will beclosely monitored with alternating CT imaging and endoscopic ultrasound/fluid aspiration every six months.Secondary endpoints will include: (1) assessment of the effects of this treatment on cyst fluid inflammatorymarkers and a previously developed cyst fluid biomarker panel and (2) a novel approach to radiographicassessment (radiomics) for early detection of progression to malignancy. 541606 +No NIH Category available Academia;Address;Adolescent;Advocacy;Advocate;Behavioral Sciences;Childhood;Clinic;Clinical;Collaborations;Communication;Cost Effectiveness Analysis;Data;Data Collection;Discipline of Nursing;Educational Curriculum;Educational Intervention;Educational workshop;Effectiveness;Effectiveness of Interventions;Ensure;Environment;Evaluation;Evidence based intervention;Family;Family Practice;Feedback;Future;Goals;Health Policy;Health Resources;Healthcare Systems;Hour;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Instruction;Intervention;Malignant Neoplasms;Measures;Medical;Medicine;Monitor;Nurse Practitioners;Nurses;Parents;Patients;Pediatrics;Performance;Physician Assistants;Physicians;Policies;Population;Preparation;Preventive care;Primary Care;Procedures;Production;Provider;Public Health;Recommendation;Research;Research Project Grants;Safety;Social Sciences;Speed;Testing;Trainers Training;Training;Training Programs;Translations;Update;Vaccination;Work;Youth;cancer prevention;clinical practice;clinical research site;cost;cost effectiveness;data sharing;design;financial incentive;health economics;implementation barriers;implementation evaluation;implementation facilitation;implementation measures;implementation outcomes;improved;intervention delivery;meetings;multidisciplinary;primary care practice;primary care team;program dissemination;programs;randomized clinical trials;recruit;research to practice;rural area;social media;therapy development;tool;tool development;trend;vaccine acceptance;web site Intervention Core - Improving Provider Announcement Communication Training (IMPACT) NARRATIVE Intervention Core The Intervention Core will support the efforts of 4 research projects to conduct high-quality evaluations ofAnnouncement Approach Training interventions. We will accomplish this goal by coordinating clinical expertisepreparing training materials and facilitators harmonizing key measures and sharing study products. NCI 10694108 9/8/23 0:00 PAR-20-077 5P01CA250989-03 5 P01 CA 250989 3 9/23/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 7433 11512394 "GILKEY, MELISSA B" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 219018 159057 59961 ABSTRACT Intervention Core The Intervention Core will support the proposed Program Project Improving Provider AnnouncementCommunication Training (IMPACT) with the goal of improving HPV vaccination in healthcare systems. TheIntervention Core will synthesize project-specific findings regarding the implementation and effectiveness ofstanding orders support (Project 1) financial incentives (Project 2) and clinical champions (Project 3) into theAnnouncement Approach Training (AAT) Intervention Package. AAT is a brief communication workshop thathelps primary care teams improve the way they recommend HPV vaccine and address parents' concerns. In aprior randomized clinical trial AAT increased HPV vaccine coverage by 5 percentage points over the controlwithin just 3 months. The proposed Program Project seeks to amplify AAT's impact by combining it with theinterventions to be tested in Projects 1-3. The Program Project will then compare the population impact andcost-effectiveness of these interventions including in rural areas (Project 4). The Intervention Core will supportthe four research projects in the P01 to maximize the quality and comparability of AAT interventions deliveredand evaluated over the 5-year study period. Aim 1 is to convene a Clinical Advisory Board to provideprojects with multi-disciplinary implementation support. Our board includes leaders in pediatrics familymedicine nursing quality improvement and patient and family advocacy. Through quarterly meetings theboard will support the development of intervention materials the recruitment and retention of clinical sites andthe interpretation and dissemination of study findings. Aim 2 is to prepare AAT facilitators and trainingmaterials for intervention delivery. To achieve the highest-quality interventions we will centralize (1) thetraining of the facilitators who will deliver our AAT workshops to primary care teams and (2) the preparation ofintervention materials. Aim 3 is to harmonize assessment of implementation measures including cost.The Intervention Core will monitor the quality of implementation data collected in Projects 1-3 to ensuretimeliness completeness and accuracy. This quality monitoring will support the successful completion ofProject 4's cost-effectiveness analyses and other information for the AAT Intervention Package. Aim 4 is tofacilitate the national dissemination of study findings and intervention materials. Collaborating withProjects 1-4 the Intervention Core will disseminate study deliverables to audiences in academia clinicalpractice and public health. Most notably the Core will lead the production of the AAT InterventionPackage for improving HPV vaccination in healthcare systems. In sum the Intervention Core will beinstrumental to the Program Project's goals of improving primary care teams' communication increasing HPVvaccine uptake and ensuring that today's youth have the highest level of protection against future HPVcancers. The Intervention Core addresses the IMPACT Program Project theme by building capacity for HPVvaccine communication interventions among primary care teams in healthcare systems. +No NIH Category available Cancer Detection;Cancer Diagnostics;Cancer Patient;Caring;Characteristics;Clinical;Collaborations;Competence;Controlled Study;Data;Diagnosis;Diagnostic;Diagnostic tests;Discipline;Disparity;Equity;Evaluation;FOLH1 gene;Generations;Growth;Knowledge;Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Medical Informatics;Methodology;Modeling;Newly Diagnosed;Outcome;PET/CT scan;Patients;Performance;Phase;Policies;Positron-Emission Tomography;Principal Investigator;Process;Recommendation;Recurrence;Research;Screening for Prostate Cancer;Screening for cancer;Techniques;Technology;Testing;Uncertainty;Update;Work;black men;cost;health care service utilization;high risk population;improved;interest;knowledge integration;new technology;novel;novel diagnostics;performance tests;precision medicine;programs;screening;screening guidelines;skills;statistical learning;tool;uptake Modeling and analytics for cancer diagnostics: traversing the data-evidence divide PROJECT NARRATIVEWe are witnessing explosive growth in new tests that can help detect cancer predict whether it is likely to spreadand decide which treatments have the best chance of being effective. There are so many new tests that theycannot always be studied properly to make sure they actually improve patients lives. This research programaims to carefully combine all the available data to learn which new tests we should be recommending to thepublic. NCI 10694105 9/5/23 0:00 PAR-21-333 5R35CA274442-02 5 R35 CA 274442 2 "HOWLADER, NADIA" 9/1/22 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 1883893 "ETZIONI, RUTH D" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1034429 NCI 587744 446685 The field of cancer diagnostics is in a rapidly expanding growth phase that goes hand in glove with the precisionmedicine revolution. However the rapid pace at which new technologies are entering the marketplace makesrigorous evaluation via controlled studies infeasible for all but a relative few. This means that while we typicallyhave some data about diagnostic test performance we frequently lack evidence regarding the outcomes thatdrive clinical and policy decisions. The Research Program outlined in this application will tackle this data-evidence divide using the tools of modeling and analytics. Modeling is an increasingly accepted discipline forintegrating knowledge about the process by which diagnostic performance drives outcomes. Analytics is the useof statistical learning techniques to fill in the knowledge gaps and to propagate uncertainty from model inputs tooutcomes. The Principal Investigator has built a leading research program in modeling and analytics for evidencegeneration in cancer policy. Among many methodologic and substantive contributions her work has informedprostate cancer screening guidelines from national policy panels established best practices for estimation ofoverdiagnosis and produced specific directions for screening high-risk populations including Black men. TheResearch Program outlined in this application will harness the modeling and analytics skillset developed by thePrincipal Investigator over nearly three decades to build a framework and tools for evidence generation aroundcancer diagnostics. The application details a sequence of projects for two technologies that are generatingintense current interest with wide-ranging practice implications and serious evidence gaps: Multi-cancer earlydetection testing and PSMA-PET/CT for newly diagnosed and recurrent prostate cancer. The MCED work willdeepen our understanding of performance characteristics provide guidance regarding a defensible testconfirmation strategy project benefits and harms of different MCED strategies and offer new ideas forshortcutting the typically lengthy process of cancer screening trials. The PSMA-PET/CT work will develop anapproach for updating treatment benefit estimated derived from trials that included a mixture of patients withunknown PSMA status and will project lives saved of treatment reallocation on the basis of PSMA-PET.CT result.The tools and processes developed for modeling these technologies will be applicable to other new diagnosticsthat emerge during the lifetime of the Research Program. The modeling work will be accompanied by a sequenceof real-world analytics projects to assess dissemination of and disparities in uptake of novel diagnostics and theirconsequences for healthcare utilization and costs. This work will establish collaborations with new real-worlddata partners and materially expand the Principal Investigators skillset to encompass a greater competency inmedical informatics. The successful execution of the Research Program will improve our understanding of hownovel cancer diagnostics impact clinical and policy relevant outcomes so that these technologies can be usedwisely and equitably to improve care for all cancer patients. 1034429 +No NIH Category available Acceleration;Address;Collaborations;Communication;Communication Programs;Complex;Data;Development;Dissemination and Implementation;Elements;Ensure;Ethics;Fostering;Foundations;Funding;Goals;Grant;Healthcare Systems;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Individual;Infrastructure;Institution;Intervention;Investments;Lead;Leadership;Monitor;Phase;Pilot Projects;Primary Care;Principal Investigator;Process;Program Research Project Grants;Provider;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Research Training;Resource Sharing;Resources;Safety;Scientist;Testing;Training;Training Programs;Vaccination;Work;cancer prevention;improved;innovation;intervention program;meetings;multidisciplinary;operation;primary care team;programs;public health research;research study;response;synergism;training project;uptake;vaccine acceptance Administrative Core Improving Provider Announcement Communication Training (IMPACT) NARRATIVE Administrative CoreNot applicable. NCI 10694104 9/8/23 0:00 PAR-20-077 5P01CA250989-03 5 P01 CA 250989 3 9/23/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 7431 8226109 "BREWER, NOEL TODD" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 243018 156282 86736 ABSTRACT Administrative Core The Administrative Core will provide overall guidance administrative support and fiscal management forthe P01 Program Project Improving Provider Announcement Communication Training (IMPACT). Dr. NoelBrewer will be the Administrative Core Lead as well as the Principal Investigator for the Overall ProgramProject. The Administrative Core will have a central function in establishing linkages and integration betweenall program elements ensuring regular communication both within the program and with externalorganizations and overseeing the Program Project as a whole and the pilot grant program. The three specificaims of the Administrative Core are as follows. Aim 1. Foster effective collaboration across IMPACT'sresearch projects and cores to achieve integration of their research activities and products. TheAdministrative Core will establish an Integration Committee comprised of project and core leads; annuallyconvene the External Advisory Board comprised of stakeholders including vaccination providers andhealthcare system leaders; and coordinate our Annual Scientific Retreat. Aim 2. Manage IMPACT'soperations and progress toward milestones. The Administrative Core will provide organizational leadershipand infrastructure necessary for overseeing research projects and shared core resources; provideadministrative support to ensure regulatory compliance of research; oversee fiscal management and reporting;and monitor projects' and cores' progress toward milestones across all phases of research. Aim 3. Administerthe Rapid Response Pilot Grant Program. The Pilot Grant Program will fund new and timely pilot studies toaddress emerging ideas and the evolving needs of the field. Using a comprehensive approach theAdministrative Core will leverage our integrated research projects and cores collaborative relationshipsshared resources and investigators' expertise to establish capacity that individual research projects could notachieve on their own. The Administrative Core addresses the IMPACT Program Project theme by helping ourresearch projects to build capacity for HPV vaccine communication interventions among primary care teams inhealthcare systems. +No NIH Category available Acceleration;Advanced Malignant Neoplasm;African American;Applications Grants;Award;Cancer Research Infrastructure;Cancer Research Project;Cancer health equity;Chicago;Circadian Rhythms;Cities;Clinical;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;DNA Double Strand Break;Decision Making;Dedications;Double Strand Break Repair;Education;Education and Outreach;Evaluation;Extramural Activities;Faculty;Funding;Funding Mechanisms;Generations;Goals;Grant;Health Disparities Research;Hematopoietic Stem Cell Transplantation;Hispanic-serving Institution;Illinois;Infrastructure;Institution;Lead;Leadership;Long-Term Effects;Malignant Neoplasms;Mentors;Midwestern United States;Minority;Mission;Peer Review;Pilot Projects;Positioning Attribute;Prevention;Productivity;Publications;Records;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Science;Scientist;Students;Survivors;Training;Translational Research;Transplant Recipients;Underrepresented Populations;Underrepresented Students;Underserved Population;Universities;Variant;anticancer research;cancer health disparity;career;community engagement;disability;early-career faculty;education research;empowerment;experience;forging;fortification;gut microbiome;health disparity populations;health inequalities;high risk;improved;innovation;lung cancer screening;mHealth self-management;men;minority student;next generation;oral microbiome;outreach;outreach program;programs;rapid growth;recruit;social;survivorship;tool;underserved community 3/3: The Chicago Cancer HealthEquity Collaborative (ChicagoCHEC) OVERALL PROJECT NARRATIVEThe presence of major cancer health inequities in Chicago is well-documented. The Chicago Cancer HealthEquity Collaborative (ChicagoCHEC) a comprehensive cancer research partnership between the Robert H.Lurie Comprehensive Cancer Center of Northwestern University the University of Illinois at Chicago andNortheastern Illinois University builds upon its productive first U54 award to continue strengthening collaborativeinfrastructure and implementing innovative cancer research education and outreach programs aimed ateliminating Chicagos deeply-engrained cancer disparities. NCI 10694101 9/4/23 0:00 PAR-18-767 5U54CA202997-09 5 U54 CA 202997 9 "SAN MIGUEL-MAJORS, SANDRA L" 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T(A1) 1899365 "FITZGIBBON, MARIAN L." "CIECIERSKI, CHRISTINA ; FEINGLASS, JOSEPH M; FILUS, LIDIA ; JIMBO, MASAHITO ; SIMON, MELISSA A." 7 PEDIATRICS 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL SCHOOLS OF MEDICINE 606124305 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1279596 NCI 802401 477195 OVERALL ABSTRACTThe Chicago Cancer Health Equity Collaborative (ChicagoCHEC) is a comprehensive partnership to advancecancer health equity bringing together the synergistic strengths of two federally designated Hispanic ServingInstitutions the University of Illinois at Chicago (UIC) and Northeastern Illinois University (NEIU) with a worldclass NCI-designated comprehensive cancer center the Robert H. Lurie Comprehensive Cancer Center ofNorthwestern University (NU-LCC). ChicagoCHEC combines the attributes of these three exceptionalinstitutions each with robust capacity to interact with their urban-shared setting. Launched in 2015ChicagoCHEC is dedicated to advancing cancer health equity through rigorous and innovative scienceeducation and outreach and engagement of Chicagos underserved communities. This is reflected in thefollowing goals: Aim 1. To strengthen a transformational alliance between UIC NEIU and the NU-LCC in pursuitof cancer health equity in Chicago; Aim 2. To initiate conduct and support innovative bench translationalclinical and prevention and control focused cancer research with emphasis on cancer health disparities; Aim3. To develop and implement cancer-related education and outreach activities generated with the engagementof underserved communities across Chicago; Aim 4. To coordinate research education and mentoringopportunities to recruit retain and advance a pipeline of underrepresented students in cancer research careersand to develop early career faculty who will forge independent cancer research careers; and Aim 5. To conductongoing rigorous evaluation of ChicagoCHEC activities. These goals are accomplished by a nurturing hub offour Cores (Administrative Planning and Evaluation Research Education and Outreach) and a research projectfunding program. Since the launch of ChicagoCHEC in 2015 there has been rapid growth in collaborativeinfrastructure built across the three partnering institutions; enhanced cancer research engagement capacityand education; extensive community outreach and engagement; and encouraging advancement ofChicagoCHEC faculty and students. ChicagoCHEC projects and programs provided research experiences to155 students provided cancer research and leadership opportunities for 57 faculty (21 have beenpromoted/received tenure) and directly resulted in 94 peer-reviewed publications 47 extramural grantssubmitted and 24 grants awarded. ChicagoCHEC will leverage the momentum forged by the initial U54 awardto drive innovative cancer research research education and community outreach and engagement that cutsacross disciplinary and institutional boundaries. ChicagoCHEC will leverage its diverse team of faculty studentsand partners connectivity to Chicagos underserved communities and guidance of internal and external advisorybodies. The next chapter will include two initial full cancer research projects and two initial pilot projectscontinued support from four tri-institutional ChicagoCHEC Cores and strong institutional commitment. 1279596 +No NIH Category available Address;Adolescent;Age;Certification;Clinic;Clinical;Communication;Data;Dose;Educational Intervention;Educational workshop;Electronic Health Record;Family Physicians;Goals;Healthcare Systems;Hour;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Intervention;Interview;Knowledge;Modeling;Outcome;Participant;Physicians;Primary Care;Primary Care Physician;Program Research Project Grants;Protocols documentation;Provider;Qualitative Research;Randomized;Recommendation;Research;Rural;Series;Surveys;System;Testing;Training;Training Activity;Training Programs;West Virginia;Wisconsin;Work;arm;clinical training;communication behavior;comparative cost effectiveness;compare effectiveness;comparison intervention;cost;cost effectiveness;data sharing;follow-up;implementation measures;implementation outcomes;improved;innovation;intervention cost;intervention delivery;intervention program;novel strategies;pediatrician;preference;prevent;primary care team;primary outcome;programs;randomized clinical trials;rural area;rural dwellers;scale up;training project;uptake;vaccination outcome;vaccine acceptance IMPACT Project 3 Engaging clinical champions to improve HPV vaccine communication and uptake in healthcare systems NARRATIVE Project 3 The proposed trial will test a new way to help healthcare systems improve HPV vaccination. We will trainclinical champions to deliver HPV vaccine communication workshops to primary care teams in their ownsystems. We expect that this champion-delivered intervention will improve HPV vaccination and build capacityfor communication training in healthcare systems. NCI 10694100 9/8/23 0:00 PAR-20-077 5P01CA250989-03 5 P01 CA 250989 3 9/23/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 7429 11512394 "GILKEY, MELISSA B" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 432814 342923 89891 ABSTRACT Project 3 Widespread HPV vaccination could prevent most HPV cancers but uptake among US adolescentsremains far below national goals. To increase uptake we developed Announcement Approach Training (AAT).AAT is a 1-hour communication workshop in which our physician facilitators train primary care teams toaddress the most critical barrier to HPV vaccination: infrequent and ineffective recommendations. AAT iseffective for increasing HPV vaccine uptake among adolescents and is certified as an NCI Research-TestedIntervention Program. One of the most promising opportunities for scaling up AAT is to implement theintervention in healthcare systems where most US pediatricians and family physicians now work. Howevernew approaches to delivering AAT will be needed to bring the intervention to scale effectively in these settings.Thus as part of the P01 Program Project Improving Provider Announcement Communication Training(IMPACT) Project 3 will enhance AAT to train systems' own clinical champions to deliver AAT therebybuilding capacity for HPV vaccine communication training. In Aim 1 we will identify opportunities toengage clinical champions in delivering AAT within their own healthcare systems. Working with 6partnering healthcare systems we will interview 24 champions to understand: anticipated barriers andfacilitators to AAT delivery; opportunities to extend AAT activities to increase reach and sustainability; andpreferences for receiving training on how to deliver AAT. In Aim 2 we will compare the impact of ChampionAAT to Traditional AAT on HPV vaccine uptake and communication. Using Aim 1 findings we will adaptour existing intervention package to train champions to deliver AAT to clinics in their own systems. In a 2-armnon-inferiority trial we will randomize 40 clinics in our 6 systems to receive Champion AAT or Traditional AAT.We will compare interventions on the primary outcome of HPV vaccine initiation among adolescents ages 11-12 at 12-month follow-up. We hypothesize that Champion AAT will be non-inferior to (i.e. as effective as)Traditional AAT. We will also compare our interventions on intermediate outcomes including changes inworkshop participants' communication to identify mechanisms that may explain improvements in HPV vaccineuptake. In Aim 3 we will generate guidance to help healthcare systems compare and implementChampion AAT and Traditional AAT. We will compare our interventions on implementation measures tounderstand whether Champion AAT offers advantages such as higher reach to primary care professionalscompared to Traditional AAT. Lastly to integrate Project 3 with other IMPACT projects we will share data tosupport cost-effectiveness modeling in Project 4 and contribute the Champion AAT module to the P01-wideAAT Intervention Package. In this way we will prepare our highly scalable intervention for nationaldissemination. Project 3 addresses the IMPACT Program Project theme by engaging clinical champions tobuild capacity for HPV vaccine communication interventions among primary care teams in healthcare systems. +No NIH Category available Address;Affect;African American;Black Populations;Black race;Cancer Burden;Cancer Center;Cause of Death;Collaborations;Colorectal Cancer;Communities;Comprehensive Cancer Center;Data;Development;Diagnosis;Disease;Disparity;Economics;Education;Elements;Emotional;Evaluation;Faculty;Family;Fostering;Funding;Funding Agency;Goals;Growth;Health;Health Disparities Research;Historically Black Colleges and Universities;Individual;Infrastructure;Institution;Intervention;Journals;K-Series Research Career Programs;Knowledge;Lead;Liver;Localized Malignant Neoplasm;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Massey Cancer Center at the Virginia Commonwealth University;Mentors;Modeling;Nature;Outcome;Output;Pattern;Peer Review;Phase;Pilot Projects;Positioning Attribute;Prevention;Publications;Recording of previous events;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Social Well-Being;Students;Testing;Training;Training Activity;Training Programs;Training and Education;Underrepresented Minority;Universities;Virginia;Vision;Vital Statistics;anticancer research;cancer health disparity;career;career development;community partnership;design;experience;health disparity;health inequalities;malignant breast neoplasm;meetings;member;minority investigator;minority undergraduate;mortality;multidisciplinary;neoplasm registry;programs;research study;rural dwellers;science education;statistics;summer research;survivorship;undergraduate student 2/2 VSU-MCC Partnership for Cancer Disparities Research and Training program (SUCCEED) OVERALL: PROJECT NARRATIVEThe overarching goal of the Virginia State University (VSU)-Virginia Commonwealth University (VCU) MasseyCancer Center (MCC) PartnErship for CancEr Disparities Research and Training (SUCCEED) program is to leadin the transformation of cancer-related outcomes for Virginians and to serve as a model of transdisciplinarydisparities research. The institutions will jointly conduct pilot research projects addressing local cancer-relatedhealth disparities and will develop a training program for VSU faculty and undergraduate students designed toattract and prepare investigators for careers in cancer disparities. NCI 10694096 9/20/23 0:00 PAR-18-911 5P20CA264068-03 5 P20 CA 264068 3 "RODRIGUEZ, LARITZA MARIA" 9/20/21 0:00 8/31/25 0:00 ZCA1-SRB-2(M2) 1923259 "FAISON, MILTON O" "ROBERTS, DANIEL M." 4 BIOLOGY 74744624 VKZLFK6M5DD3 74744624 VKZLFK6M5DD3 US 37.21386 -77.45568 8969901 VIRGINIA STATE UNIVERSITY PETERSBURG VA SCHOOLS OF ARTS AND SCIENCES 238032520 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 263460 NCI 189534 73926 OVERALL: PROJECT SUMMARYInvestigators from Virginia State University (VSU) a Historically Black College/University and the NCI-designated Virginia Commonwealth University (VCU) Massey Cancer Center (MCC) recognized a need tocollaborate and leverage the expertise and resources of both institutions to educate and train promisingindividuals who will ultimately contribute to diminishing cancer disparities in Virginia. The outcome of thiscollaboration resulted in the formation of the VSU-MCC PartnErship for CancEr Disparities Research andTraining (SUCCEED) program. The overarching goal of SUCCEED is to lead in the transformation of cancer-related outcomes for Virginians and to serve as a model of transdisciplinary disparities research and education.Guided by the NCI framework our preliminary data and the expertise of our multidisciplinary team we willemploy a multilevel approach to develop a robust collaborative infrastructure that will build on the strengths ofthe partnering institutions to enhance their capacity to conduct cancer health inequities research that is drivenby local data and informed by the cancer-related needs of local communities. Specific aims are to: Aim 1:Establish a mutually beneficial collaborative partnership between VSU and MCC in cancer disparities researchand training; Aim 2: Conduct collaborative locally focused liver/gastrointestinal (GI) cancer pilot research studiesby investigators at MCC and VSU; Aim 3: Provide an integrated cancer research training and careerdevelopment experience to VSU faculty; Aim 4: Support underrepresented minority undergraduate studentsfrom VSU to pursue careers in disparities research; Aim 5: Conduct an ongoing evaluation that reflects theprogress of the collaborative partnership in meeting its goals and objectives. To our knowledge this is the firsttargeted effort of this nature to address cancer disparities in the state of Virginia. 263460 +No NIH Category available Address;Adolescent;Age;Area;Child;Clinic;Clinic Visits;Clinical;Communication;Complement;Cost Effectiveness Analysis;Data;Development;Educational Intervention;Educational process of instructing;Educational workshop;Healthcare;Healthcare Systems;Hour;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Immunization;Intervention;Interview;Language;Laws;Medical;Mississippi;Missouri;Motivation;Nurses;Outcome;Parents;Participant;Patients;Persuasive Communication;Program Research Project Grants;Provider;Publications;Randomized;Recommendation;Registered nurse;Research;Role;Rural;Sampling;Series;Slide;Specific qualifier value;Surveys;System;Testing;Texas;Training;Training Programs;Trust;Update;Vaccines;Work;arm;cancer prevention;cost;cost effectiveness;implementation determinants;implementation intervention;implementation outcomes;improved;informant;innovation;intervention program;meetings;member;patient population;pilot test;primary care clinic;primary care team;programs;randomized clinical trials;rural area;rural health clinic;rural patients;rurality;skills;support tools;training project;uptake;vaccine acceptance;vaccine delivery IMPACT Project 1 The impact of standing orders support on HPV vaccine communication and uptake NARRATIVE Project 1 Our proposed research will expand the role of all primary care team members and support the use ofstanding orders in HPV vaccination. The Program Project will disseminate findings via the AnnouncementApproach Training Intervention Package publications and hpvIQ.org. NCI 10694094 9/8/23 0:00 PAR-20-077 5P01CA250989-03 5 P01 CA 250989 3 9/23/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 7426 8226109 "BREWER, NOEL TODD" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 425167 296070 129097 ABSTRACT Project 1 An ongoing and pressing cancer prevention challenge in the US is low HPV vaccine coverage due in partto infrequent and low-quality provider recommendations. Our 1-hour Announcement Approach Training (AAT)teaches providers to use presumptive announcements that presume the child will receive vaccines and to usebest practices for respectfully addressing parent concerns when they arise. The AAT increases HPV vaccineinitiation and is an NCI-designated Research-Tested Intervention Program. To increase the impact of the AATwe propose to leverage the whole primary care team including registered nurses (RNs) and medical assistants(MAs) by supporting the implementation of existing standing orders. Standing orders are widely available butoften underused. As part of the P01 Program Project Improving Provider Announcement CommunicationTraining (IMPACT) Project 1 will focus on AAT enhanced with standing orders support to expand the wholeprimary care team's involvement in HPV vaccine recommendations. We will do this work in healthcare systemsserving rural and nonrural areas. Aim 1 is to characterize the role of RNs and MAs and standing orders inHPV vaccination. We will conduct formative interviews (n=20) and then a national primary care team survey(n=2500) with our P01's Data Core to better understand how to expand the role of RNs and MAs inrecommending HPV vaccine and to implement existing standing orders for HPV vaccine. Aim 2 is to evaluatethe impact of supporting the implementation of existing standing orders for the whole primary careteam on HPV vaccine communication and uptake in an RCT. The standing orders support will be a seriesof activation meetings that use persuasion and skills building with system leaders clinic leaders and clinic staff.We will conduct a trial in 40 primary care clinics in Mississippi Missouri and Texas that have HPV vaccinationstanding orders serve patients from rural and nonrural areas and are part of a healthcare system. Clinics willbe randomized to AAT or AAT enhanced with standing orders support. The primary trial outcome will be clinic-verified HPV vaccine initiation among children ages 11-12. We hypothesize that AAT with standing orderssupport increases HPV vaccine uptake by improving HPV vaccine communication. Aim 3 is to generateguidance for healthcare systems to support implementation of HPV vaccine standing orders to leveragethe whole primary care team. We will gather and share intervention data (cost impact and implementationdata) with Project 4 to support cost-effectiveness analyses and development of their decision support tool. Wewill examine intervention implementation determinants and outcomes with our P01's Intervention Core. Finallywe will contribute modules to the AAT Intervention Package that provides guidance to healthcare systems forimproving HPV vaccination. Project 1 addresses the IMPACT Program Project theme by building capacity forHPV vaccine communication interventions among primary care teams in healthcare systems. +No NIH Category available Acceleration;Address;Administrative Coordination;Adolescent;Adoption;Area;Behavioral;Cancer Control;Clinic;Clinical;Communication;Communities;Data;Data Collection;Decision Aid;Educational Intervention;Effectiveness;Evolution;Face;Goals;Healthcare Systems;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Intervention;Malignant Neoplasms;Medical;National Cancer Institute;Nurse's Role;Online Systems;Parents;Perception;Prevention;Primary Care;Program Research Project Grants;Provider;Recommendation;Research;Research Activity;Research Project Grants;Resources;Rural;Surveys;System;Testing;Training;Training Activity;Training Programs;Work;budget impact;cancer prevention;contextual factors;cost;cost effectiveness;data management;effective intervention;financial incentive;improved;insight;intervention program;models and simulation;novel;population health;prevent;primary care team;programs;randomized clinical trials;rural area;support tools;synergism;uptake;vaccine acceptance Program Project Improving Provider Announcement Communication Training (IMPACT) NARRATIVE Overall The Program Project's goal is to improve HPV vaccine communication and coverage in healthcaresystems a critically important opportunity for cancer prevention. We will create a package of interventionmodules to accelerate improvements in HPV vaccine communication and uptake in healthcare systems. NCI 10694093 9/8/23 0:00 PAR-20-077 5P01CA250989-03 5 P01 CA 250989 3 "KOBRIN, SARAH" 9/23/21 0:00 8/31/26 0:00 ZCA1-RPRB-L(M1)P 8226109 "BREWER, NOEL TODD" Not Applicable 4 NONE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 2307603 NCI 1598952 708651 ABSTRACT Overall Widespread HPV vaccination in the US could prevent 32100 cancers every year. Despite this tremendouspotential HPV vaccination coverage is far short of the nation's goal of 80%. Provider recommendations areuniquely powerful in increasing HPV vaccine uptake. However primary care teams and healthcare systemsface barriers to effective HPV vaccine communication and many questions remain unanswered about how toincrease the potency of provider recommendations. We propose the P01 Program Project Improving ProviderAnnouncement Communication Training (IMPACT). The goal of IMPACT is to improve HPV vaccinecommunication and uptake among adolescents. IMPACT's specific aims are to 1) Identify opportunities toimprove HPV vaccine communication; 2) Evaluate the impact and cost of HPV vaccine communicationinterventions in cluster randomized clinical trials; and 3) Support implementation of HPV vaccinecommunication interventions in healthcare systems. The IMPACT Program Project's shared theme isamplifying the impact of a Research-Tested Intervention Program to improve HPV vaccinecommunication in healthcare systems. The projects will work together to enhance the impact of theAnnouncement Approach Training (AAT) an HPV vaccine communication training for primary careprofessionals which received designation as a Research-Tested Intervention Program (RTIP) from theNational Cancer Institute. Project 1 will establish how to involve the whole primary care team in HPV vaccinerecommendations. The project will examine whether optimizing the use of standing orders support increasesHPV vaccine uptake in clinics receiving the AAT. Project 2 will examine what motivates providers torecommend HPV vaccination. The project will establish whether clinic-level financial incentives increasevaccine uptake in clinics receiving the AAT. Project 3 will examine who should facilitate the trainings. Theproject will establish whether engaging clinical champions in healthcare systems to implement the AAT withintheir own systems increases vaccine uptake. Project 4 will examine which interventions fit systems' resources.The project will examine the budget impact cost-effectiveness and population health impact of HPV vaccineinterventions in rural and nonrural communities and aid decision makers with a decision support tool tofacilitate the adoption of promising interventions. The research projects will receive support from 3 cores:Administrative Data and Intervention. IMPACT's activities will culminate with the creation of the AATIntervention Package to support improving HPV vaccine uptake in healthcare systems. Throughout theproposed Program Project the shared theme and AAT focus will create synergies among the projects andcores that generates significant and novel scientific insights into how to improve HPV vaccine communicationand uptake. Our approach will also accelerate the evolution of communication trainings for primary careprofessionals accomplishing in 5 years what might otherwise take two decades. 2307603 +No NIH Category available 3-Dimensional;Active Sites;Address;Antineoplastic Agents;Binding;Biological;Biological Assay;Biological Process;Biology;Cell Cycle;Cell Cycle Regulation;Cell Line;Cells;Cellular biology;Chemicals;Communities;DNA Damage;DNA biosynthesis;Data;Development;Diabetes Mellitus;Disadvantaged;Disease;Disease Progression;Drug Targeting;Environment;Etiology;FDA approved;Family;Family member;Foundations;Free Will;Funding;Generations;Genome;Health;Human;Individual;Inflammation;Inflammatory Bowel Diseases;Knock-out;Knowledge;Left;Link;Malignant Neoplasms;Measures;Medicine;Mission;Mitosis;Modality;Molecular;Nature;Neurons;Oncology;Output;Pathologic;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phosphotransferases;Physiological;Play;Process;Proliferating;Protein Family;Protein Kinase;Proteins;Proteome;RNA Splicing;Reagent;Reporter;Research;Research Personnel;Resources;Role;Scientist;Signal Pathway;Signal Transduction;System;Therapeutic;United States National Institutes of Health;Validation;Work;cancer therapy;cell motility;chronic inflammatory disease;ciliopathy;cilium biogenesis;design;drug development;drug discovery;drug quality;druggable target;holistic approach;inhibitor;insight;kinase inhibitor;knock-down;lead optimization;member;migration;new therapeutic target;programs;response;scaffold;small molecule;success;tool Identification and characterization of chemical probes for interrogation of the NEK family of kinases in cancer PROJECT NARRATIVEThe Never in mitosis A-related kinase (NEK) family of protein kinases is an important yet understudied kinasefamily that has recently been implicated in a variety of disorders including numerous cancers ciliopathieschronic inflammatory diseases and neuronal disorders. The lack of reliable tools to study NEK function hasmade it difficult to determine the specific role(s) that NEK family members play in the etiology and progressionof these diseases. In the proposed project we will use a generalizable family-based strategy to develop a suiteof tools including high quality chemical probes that will be made freely available to the biomedical researchercommunity and enable researchers to build a firm understanding of how these understudied kinases contributeto health and disease and validate new druggable targets for cancer drug discovery. NCI 10694068 8/24/23 0:00 PAR-20-271 5R01CA273095-02 5 R01 CA 273095 2 "FORRY, SUZANNE L" 9/1/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-Y(56)R] 14608541 "DREWRY, DAVID HAROLD" "BUROW, MATTHEW E.; NEWMAN, ROBERT HOWARD" 4 NONE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PHARMACY 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 614579 NCI 516519 98060 ABSTRACT / PROJECT SUMMARYKinases a class of proteins with more than 500 members in the human proteome are important regulators ofbiological processes in health and disease. Kinases have proven to be excellent drug targets with more than 70FDA approved medicines that target kinases. Despite this success most kinases are understudied and detailsof their functions are poorly understood. The NEK family of 11 kinases (NEK1 through NEK11) is a particularlyunderstudied set of kinases that play roles in key biological processes like the cell cycle ciliogenesis and theDNA damage response (DDR) all with relevance to cancer and human health. These kinases have emerginglinks to numerous cancers diabetes inflammatory bowel disease ciliopathies and ALS. In this project we willuse an efficient kinase systems-based approach to create an enabling suite of chemical probes assaysreagents and molecular tools to identify NEK family members that have key roles in cancer. These high-qualitycompounds and reagents we generate which we will freely share will allow scientists to build a deepunderstanding of the physiological and pathological roles members of the NEK family play. In Aim 1 we willcreate potent and selective inhibitors of each NEK using iterative medicinal chemistry and state of the art in celltarget engagement assays. In a complementary effort for this aim we will also create inducible NEK knockdowncell lines. In Aim 2 using compounds and the NEK knockdown lines we will evaluate the role and importance ofeach NEK in a suite of NEK and oncology-relevant cell health and cell biology signaling assays measuringeffects on proliferation migration the cell-cycle DNA replication and ciliogenesis. In Aim 3 we willexperimentally determine the substrates of each NEK locate the NEKs in broader kinase-dependent signalingpathways and develop genetically targetable kinase activity reporters for tracking NEK activity within theendogenous cellular environment. Output from this project will include potent and selective NEK inhibitors NEKfamily-wide assays details on the impact of NEK inhibition and knockdown on key cancer processes moleculartools and NEK substrate and pathway information. Successful completion will provide a framework and theresources needed to validate individual NEKs as high quality druggable targets for the treatment of cancer. 614579 +No NIH Category available Affect;Antibodies;Biochemical;Biology;Cell Line;Cells;Chromatin;Chromatin Structure;Chromatography;Communities;Computing Methodologies;Enhancement Technology;Enzymes;Epigenetic Process;Epitopes;Formalin;Gene Expression Profile;Gene Mutation;Genes;Goals;Histones;Human;In Vitro;Injections;Isotope Labeling;Isotopes;Malignant Neoplasms;Mammalian Cell;Mass Spectrum Analysis;Measurement;Methods;Modeling;Modification;Mutation;Oncogenic;Paraffin Embedding;Pennsylvania;Post Translational Modification Analysis;Post-Translational Modification Site;Post-Translational Protein Processing;Process;Program Research Project Grants;Protein Analysis;Protein Conformation;Proteins;Proteome;Proteomics;Research;Research Personnel;Resource Sharing;Role;Sampling;Signal Pathway;Signaling Protein;Structure;Techniques;Technology;Therapeutic;Time;Tissues;Tumor Tissue;Universities;Work;combinatorial;design;experimental study;histone modification;human disease;improved;in vivo;member;nano;new technology;next generation;non-histone protein;novel;oncohistone;polypeptide;programs;protein expression;protein protein interaction;sample archive;sortase;structural biology;technology development;tumor;tumorigenesis Shared Resources Core 2: Quantitative Proteomics Core Project NarrativeMutations to several epigenetic related genes have been discovered across several classes of human cancers.This research will help define altered chromatin and signaling pathways due to these gene mutations whichwill inform mechanisms and potential design of therapeutics for treatment of human cancers. NCI 10694065 8/31/23 0:00 PAR-18-290 5P01CA196539-09 5 P01 CA 196539 9 9/9/15 0:00 8/31/25 0:00 ZCA1-RPRB-L 7419 8612003 "GARCIA, BENJAMIN A" Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 255696 255696 0 Project SummaryThe Quantitative Proteomics core led by Dr. Benjamin Garcia will provide cutting-edge mass spectrometry(MS) based proteomics technologies to the P01 Project team members to help elucidate biochemicalmechanisms involved in histone and histone-like mutations in human cancers. These MS approaches willinclude quantitative experiments to understand protein expression and post-translational modifications (PTMs)on histone and non-histone proteins from both cultured and primary cell lines tissue/tumors and formalin fixedparaffin embedded (FFPE) archived samples. Although most researchers in the epigenetics and chromatinbiology fields utilize antibody based methods for histone modification characterization antibodies have manytechnical issues (such as epitope occlusion) which confound the analyses. Mass spectrometry thereforeprovides a more unbiased and complementary approach that is also more sensitive and accurate for proteinPTM analysis. The Garcia Lab has for over a decade now developed methods for histone PTM analyses. Herein this propose we plan to continue to expand our proteomics toolbox to allow P01 team members to be able tocharacterize 500 histone PTM sites in rapid fashion perform quantitative analyses of histone combinatorialmodifications and determine which oncogenic histone mutations affect chromatin structure. Additionally wewill explore the downstream protein signaling pathways that are altered in epigenetically driven humancancers as transcriptional profiles do not always provide the most accurate pictures of protein expression.! +No NIH Category available ATAC-seq;Antibodies;Bioinformatics;Biological Assay;Cells;ChIP-seq;Chromatin;Collaborations;Computing Methodologies;DNA;DNA Methylation;Data;Detection;Emerging Technologies;Epigenetic Process;Gene Expression;Generations;Genes;Genome;Genomic approach;Genomics;Histones;Human;Malignant Neoplasms;Maps;Mediating;Methods;Modernization;Modification;Molecular;Molecular Conformation;Mutation;Neoplastic Cell Transformation;Phenotype;Production;Publications;Quality Control;Quebec;RNA;Resource Sharing;Role;Side;Signal Transduction;Techniques;Technology;Transcription Initiation Site;Universities;Variant;Work;comparative;computerized data processing;computerized tools;epigenome;epigenomics;functional genomics;genome-wide;genomic data;genomic tools;histone modification;improved;insight;interest;member;nanopore;novel;secondary outcome;single-cell RNA sequencing;success;tool;transcriptome;transcriptome sequencing;tumor progression;tumorigenesis Shared Resources Core 1: Genomics/Epigenomics Core PROJECT NARRATIVE (MAJEWSKI)Cancer progression is associated with massive global aberrations of genome and epigenome organization.Modern genomics technologies have provided invaluable new insights into molecular mechanisms of cancersincluding the discovery by our team members of the histone mutations that are the subject of this proposal. Theestablishment of this Core will provide team members with state of the art genomic and computational tools tounravel the mechanisms of action of histone mutations. NCI 10694063 8/31/23 0:00 PAR-18-290 5P01CA196539-09 5 P01 CA 196539 9 9/9/15 0:00 8/31/25 0:00 ZCA1-RPRB-L 7418 12185399 "MAJEWSKI, JACEK " Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 169978 169978 0 PROJECT SUMMARY (MAJEWSKI)Mutations in histone and modifier genes in cancers have dramatic downstream effects on the landscape of theepigenome chromatin state and DNA methylation with eventual secondary outcomes manifested in geneexpression and cellular phenotypes. Modern functional genomics approaches provide invaluable tools to studythe effects of this epigenome-mediated cascade. In this Core activity we will establish and provide a set ofgenomics tools and computation methods to elucidate the mechanisms through which histone variants impactthe epigenome transcriptome and the cell identity during neoplastic transformation. +No NIH Category available Administrative Personnel;Administrator;Attention;Budgets;Collaborations;Communication;Communities;Ensure;General Population;Histones;Human;Institution;Laboratories;Location;Maintenance;Malignant Neoplasms;Mutation;Occupational activity of managing finances;Office of Administrative Management;Postdoctoral Fellow;Program Development;Progress Reports;Records;Reporting;Research;Research Personnel;Role;Safety Management;Schedule;Science;Scientist;Students;Universities;Update;Workplace;career development;data sharing;experience;meetings;programs;research and development;synergism;tumorigenesis;web site Administrative Core n/a NCI 10694060 8/31/23 0:00 PAR-18-290 5P01CA196539-09 5 P01 CA 196539 9 9/9/15 0:00 8/31/25 0:00 ZCA1-RPRB-L 7417 3210235 "ALLIS, CHARLES DAVID" Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 57629 34000 23629 SummaryThe main objective of the Administrative Core of this Program is to provide support andassistance to all scientists and administrative personnel participating in the fourProjects and two Scientific Cores of this Program Project. It is imperative that all teamsinvolved in this Program integrate seamlessly to establish a symbiotic unit particularlygiven the uniquely integral functions that each Project and Core Leader will provide tothe overall Program. Under the direction of Dr. Allis his laboratory's administratorMarisa Cerio will manage this core. Ms. Cerio has demonstrated experience in theintegration of many projects across institutions worldwide including a well-establishedand ongoing collaboration between all Project leaders outlined in this proposal! +No NIH Category available Affect;Animals;Astrocytoma;Binding;Biochemical;Biochemistry;Biological Assay;Bone neoplasms;Brain Stem Glioma;CRISPR/Cas technology;Cancer Biology;Cancer Model;Cell Differentiation process;Cell Proliferation;Cells;Chemistry;Chondroblastoma;Chromatin;Clinical;Complex;CpG Islands;DNA Methylation;Development;Diagnostic;Diffuse;EZH2 gene;Elements;Enhancers;Enzymes;Ependymoma;Epigenetic Process;Foundations;Frequencies;Gene Expression;Gene Silencing;Genes;Genetic Screening;Genomics;Giant cell tumor of bone;Glioma;Goals;Health;Histone H3;Histones;Human;In Vitro;Investigation;Kinetics;Lead;Malignant - descriptor;Malignant Neoplasms;Mediating;Methods;Methylation;Methyltransferase;Modeling;Molecular;Molecular Chaperones;Molecular Target;Mutation;PRC1 Protein;Pathogenicity;Pathway interactions;Patients;Phenotype;Polycomb;Positioning Attribute;Post-Translational Protein Processing;Post-Translational Regulation;Posterior Fossa;Proliferating;Regulation;Role;Sampling;Squamous cell carcinoma;Structure-Activity Relationship;Surface;System;Testing;Therapeutic;Therapeutic Intervention;Toxic effect;Transcript;Undifferentiated;Work;big gastrin;chromatin modification;derepression;design;diffuse midline glioma;disease diagnosis;effective therapy;gene repression;genome-wide;histone methylation;in vivo;innovation;insight;interdisciplinary approach;member;mutant;novel;oncohistone;prevent;programs;recruit;sarcoma;sensor;theories;therapeutic development;tumor;tumorigenesis;tumorigenic PROJECT 4: ELUCIDATING MECHANISMS OF HISTONE H3K36 DYSREGULATION BY ONCOHISTONES PROJECT NARRATIVE: In this project we aim to define how misregulation of histone H3K36 methylation by oncohistones promotes tumorigenesis. Specifically our study will provide new insights into the role of H3K36-directed methyltransferases and the H3.3 G34 and H3 K36M oncohistones in cancer biology. Results from our studies will provide new insights into molecular targets for disease diagnosis and advance therapeutic intervention. NCI 10694057 8/31/23 0:00 PAR-18-290 5P01CA196539-09 5 P01 CA 196539 9 9/9/15 0:00 8/31/25 0:00 ZCA1-RPRB-L 7416 9035743 "LEWIS, PETER W" Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 231684 231684 0 SUMMARY: The known histone H3K36-directed methyltransferases are essential for normal animal development and are frequently dysregulated in human cancers. We have found that high-frequency histone H3 mutations (oncohistones) exploit normal chromatin-based regulatory mechanisms including H3K36 methylation to drive tumorigenesis. Previously we found that H3.3 G34 oncohistones selectively block SETD2-mediated H3K36 methylation and affect the activity of gene enhancers that results in aberrant cellular differentiation and proliferation. Moreover we found that the H3 K36M oncohistone promotes genome-wide changes in histone and DNA methylation through competitive inhibition of NSD1/2 and SETD2 enzymes. We will leverage and extend our preliminary findings to define the mechanisms by H3.3 G34 and H3 K36M oncohistones achieve pro-tumorigenic gene expression programs through misregulation of H3K36 methylation. We will employ a multi-disciplinary approach that integrates biochemical genomic and molecular methods to enhance our understanding of K36M and G34 oncohistones and apply our understanding toward diagnostic and therapeutic applications. Specifically we will: i) identify the changes in chromatin landscape by histone mutations using cell-based systems and patient tumor samples; and ii) characterize misregulated developmental programs that help establish tumorigenesis. These studies will provide guidance for the development of therapeutic strategies designed to ameliorate the pathogenic effects of NSD1/2 and histone H3 mutations in human cancers. We will also extend our findings to elucidate the mechanisms by which NSD1 and H3 K36M mutations alter the chromatin landscape in squamous cell carcinomas (Aim 1). We will define the mechanisms of by which G34 mutations alter chromatin modifications and gene expression and we will define the role of H3.3 chaperone pathways in mediating G34 phenotypes (Aim 2). Additionally we have found that H3K36 methylation opposes PRC2 activity thus preventing Polycomb-mediated gene repression. We will now leverage these biochemical findings to determine the function of the EZH2 H3K36-binding pocket in different tumorigenesis models (Aim 3). Expected results from our study will lead us formulate novel theories and provide crucial mechanistic insights of these oncohistones which can be readily tested in in vivo cancer models (Project 12) and in vitro chemistry platforms (Project 3). To accomplish these aims Project 4 also requires close interactions with both Cores. +No NIH Category available ATAC-seq;Affect;Alleles;Allografting;Animal Model;Bar Codes;Biological Assay;Biology;Cancer Biology;Cancer cell line;Cell Differentiation process;Cell Fate Control;Cell Line;Cell physiology;Cells;Cellular Structures;ChIP-seq;Characteristics;Charge;Chemicals;Childhood Glioma;Chondroblastoma;Chromatin;Chromatin Structure;Collaborations;Complementary DNA;Cues;DNA;DNA Damage;DNA Modification Process;DNA Repair;DNA methylation profiling;Data;Defect;Development;Epigenetic Process;Frequencies;Gene Expression;Genetic;Genetic Screening;Genetic Transcription;Genome;Goals;Grant;Growth;Histone H3;Histones;Human;Knock-in;Laboratories;Lead;Libraries;Link;Lysine;Malignant Childhood Neoplasm;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Mediating;Mesenchymal Stem Cells;Methionine;Missense Mutation;Modeling;Modification;Molecular;Mus;Mutate;Mutation;N-terminal;Nucleosomes;Oncogenic;Pathologic;Pathway interactions;Patients;Phenotype;Play;Positioning Attribute;Post-Translational Protein Processing;Pre-Clinical Model;Process;Property;Proteins;Reader;Recurrence;Research;Research Personnel;Role;Site;Somatic Mutation;Tail;Technology;Testing;Therapeutic;Translating;Transplantation;Tumor Subtype;Undifferentiated;Variant;Work;Writing;Xenograft procedure;cancer cell;cancer type;cell type;cellular transduction;design;driver mutation;epigenome;gain of function;genome-wide;histone methyltransferase;histone modification;in vivo;inducible Cre;insight;interdisciplinary approach;mouse model;multidisciplinary;novel;oncohistone;pharmacologic;prevent;programs;response;sarcoma;self-renewal;small molecule;small molecule inhibitor;success;transcriptome sequencing;transcriptomics;translational approach;tumor;tumorigenesis;tumorigenic Project 2: Elucidating Mechanisms of Chromatin Dysregulation by Oncohistones PROJECT NARRATIVE (ALLIS)Genome-wide sequencing technologies have allowed an unprecedented discovery of somatic mutations inchromatin and epigenetic modifiers in human cancers including high-frequency mutations in histones theproteins charged with packaging our genome. The proposed research will determine how newly identifiedcancer-associated histone mutations disrupt epigenetic landscapes and lead to cancer. These findings areexpected to pave new avenues for the development of cancer therapeutics in tumors harboring histonemutations. NCI 10694047 8/31/23 0:00 PAR-18-290 5P01CA196539-09 5 P01 CA 196539 9 9/9/15 0:00 8/31/25 0:00 ZCA1-RPRB-L 7414 3210235 "ALLIS, CHARLES DAVID" Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 288179 170017 118162 PROJECT SUMMARY (ALLIS)Genome-wide sequencing technologies have allowed an unprecedented discovery of somatic mutations inchromatin and epigenetic modifiers in human cancers providing mechanistic links between cancer epigenomesand genetic alterations. The collective number of oncogenic mutations in epigenetic regulators has led to theemerging view of driver mutations underlying cancer epigenomes. Nowhere is this better illustrated than withthe now classical findings of high-frequency (50-95%) missense mutations in core histones such as histone H3lysine 27 to methionine (H3K27M) mutation in pediatric gliomas and H3 lysine 36 to methionine (H3K36M)mutations in chondroblastomas and undifferentiated sarcomas. During the prior grant period we have shownthat these mutations directly prevent the writing of some critical regulatory histone post-translationalmodifications (PTMs) to promote oncogenesis through altered chromatin organization transcription and in somecases cell fate and differentiation. More recently we have extended our understanding of the landscape ofhistone mutations in cancers. We characterized an unexpectedly broad landscape of novel oncohistonemutations that occur in roughly 4% of all cancers. These mutations are found not only in the H3 N-terminal tailwhich is the site of classical oncohistones but also in the globular domain and in all four core histones. Ourpreliminary data suggest that a least a subset of these mutations affect one or more properties of chromatin andchromatin-dependent processes including nucleosome stability histone PTMs and cellular differentiation. Wetherefore hypothesize that novel oncohistone mutations will impact the landscape of histone PTMs and chromatinorganization in a context dependent manner leading to dysregulation of gene expression and effects on cell fateand tumorigenesis. The goal of this work is to rigorously test these hypotheses for a comprehensive set ofcancer-associated histone mutations using a multidisciplinary approach that include genetics (barcodedoncohistone libraries mouse models barcoded-cell lines) epigenetics (ChIP-seq ATAC-seq DNA-methylationprofiling) transcriptomics (RNA-seq) and chemical biology (designer chromatin small molecule inhibitors).Specifically we will 1) define molecular mechanisms by which novel oncohistones act and their impact onchromatin and gene expression; 2) determine how these molecular changes translate into phenotypes usingcellular differentiation and tumor allograft models and explore pharmacologic strategies to rescue differentiationblockade; and 3) extend our studies into animal models and diverse cellular contexts to test the roles of noveloncohistones in tumorigenesis and development. Together these approaches will shed light on the function ofnewly discovered oncohistones and provide important insight into the role of histones and chromatin structure intumorigenesis. Our findings are expected to pave new avenues towards intervening pharmacologically theaberrant epigenetic pathways for cancer therapeutics. To facilitate the success of this proposal a world-classteam of investigators experts in cancer chromatin and chemical biology have been assembled. +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Adopted;Affect;Amino Acid Substitution;Animal Model;Biochemical;Bone neoplasms;CRISPR/Cas technology;Cell Culture Techniques;Cell Differentiation process;Cell Line;Childhood Glioma;Chromatin;Classification;Clinical;Codon Nucleotides;Collaborations;Communities;Complement;Coupled;DNA Sequence Alteration;Data;Development;Dimensions;Disease;EZH2 gene;Elements;Engineering;Ependymoma;Epigenetic Process;Exhibits;Funding;Genes;Genetically Engineered Mouse;Giant Cell Tumors;Glioma;Goals;H3 K27M mutation;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Histone H3;Histone H3.3;Histones;Human;Immune checkpoint inhibitor;Immune system;Immunocompetent;In Vitro;Innate Immune Response;Joints;Knock-in Mouse;Knowledge;Lead;Lymphocytic Infiltrate;Malignant Neoplasms;Mediating;Modeling;Molecular;Mus;Mutation;Nature;Oncogenic;Pathogenicity;Patients;Phase;Phenotype;Posterior Fossa;Pre-Clinical Model;Proteins;Regulation;Resources;Role;Sampling;Specificity;Subgroup;System;Tail;Testis;Therapeutic;Tissues;Tumor Cell Line;Validation;Variant;Viral;Xenograft procedure;base;big gastrin;cancer cell;cancer therapy;clinical diagnosis;design;efficacy testing;epigenetic drug;epigenome;epigenome editing;epigenomics;genome-wide;histone methyltransferase;human disease;immune cell infiltrate;immunogenicity;improved;inhibitor;insight;knowledge base;member;metabolomics;mimicry;mouse model;mutant;non-histone protein;novel;oncohistone;osteosarcoma;overexpression;programs;sarcoma;spatiotemporal;stem cells;success;synergism;tool;transcriptome;tumor;tumorigenesis Project 1: Decoding Modeling and Targeting Oncohistones and an Oncohistone-like Protein PROJECT NARRATIVEDiscovery of mutations in histone genes (oncohistones) in deadly cancers has uncovered a novel mechanism ofoncogenesis with deregulation of normal development at its core. We aim in this project to understand how theH3.3G34 mutations and the new oncohistone-mimic EZHIP act to promote oncogenesis identify targetsamenable to therapy provide relevant pre-clinical models and design strategies to optimally engage the immunesystem to improve survival and provide cure for patients with oncohistone-associated cancers. NCI 10694045 8/31/23 0:00 PAR-18-290 5P01CA196539-09 5 P01 CA 196539 9 9/9/15 0:00 8/31/25 0:00 ZCA1-RPRB-L 7413 12410584 "JABADO, NADA " Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 422216 422216 0 PROJECT SUMMARYWe were one of two groups to first identify amino acid substitutions on histone H3 variants (oncohistones) inhuman disease. In the past funding cycle we showed that beyond their initial identification in specific subtypesof high-grade gliomas and bone tumors these oncohistones also occur in subgroups of sarcomas head andneck squamous cell carcinomas and acute myeloid leukemias. Working with members of this Program Projectwe showed how H3K27M and H3K36M (K-to-M substitutions) lead to stalled development and blockeddifferentiation through epigenome rewiring as they promote aberrant spreading/redistribution of key chromatinmarks from their initial boundaries which in turn facilitate oncogenesis. Furthermore our collaboration withLewis/Garcia labs uncovered that EZHIP a testis-specific protein aberrantly expressed in posterior fossa groupA ependymomas biochemically mirrors H3K27M oncohistone. Our preliminary data indicate that EZHIP is alsoaberrantly activated in subgroups of osteosarcomas. In contrast to the growing information on K-to-M mutationshowever there is limited knowledge on the oncogenic function molecular mechanisms and tumor-specificvulnerabilities of the oncohistone-mimic EZHIP and mutations affect H3.3G34. In large part this is due to apaucity of resources and models that faithfully recapitulate the cellular effects mediated by these alterations.Therefore a major goal of this project is to develop and employ novel patient sample- cell culture- and animalmodel-based systems to model oncohistone-associated cancers and investigate the underlying pathogenicmechanisms. Nearly all G34 mutations affect histone variant H3.3 and while H3.3G34R/V are frequently foundin pediatric gliomas giant cell tumors are predominantly defined by H3.3G34W mutations. This dichotomy isreflected by the distinct phenotypes of the H3f3a G34W R or V knock-in mouse models we have developed. Weaim to delineate the mechanisms behind the codon-specific phenotypes resulting from H3.3G34 mutations therole of specific mutational partnership for G34R/V-driven tumorigenesis and the necessity of H3.3 variant inmediating G34-dependent phenotypes (Aim 1). We will investigate the role of EZHIP in development how itsaberrant expression is achieved and promotes oncogenesis in osteosarcomas and ependymomas - comparingand contrasting to H3K27M mutation (Aim 2). Lastly we will build on our findings of the viral mimicry induced byK-to-M mutations to assess the degree and nature of immune infiltration in these tumors at baseline and upontreatment of epigenetic drugs (Aim 3). Notably these studies are enabled by the unique syngeneic mousemodels and CRISPR/Cas9-edited isogenic patient-derived tumor cell lines we have generated for variousoncohistones and EZHIP. This project will synergize with other efforts of this Program Project to providemechanistic insights and relevant and reliable pre-clinical models to the community building a knowledge andresource base upon which targets amenable to therapy that can be conceived and validated. +No NIH Category available Address;Area;Award;Cancer Education Grant Program;Code;Collaborations;Communication;Communities;Community Actions;Computational Biology;Computer Analysis;Computing Methodologies;Data Set;Dedications;Development;E-learning;Education Projects;Educational Curriculum;Educational process of instructing;Eligibility Determination;Emotional;Ensure;Event;Faculty;Family;Fellowship;Fostering;Fred Hutchinson Cancer Research Center;Future;Goals;High School Student;Home;Institution;Internships;Investments;Knowledge;Malignant Neoplasms;Mentors;National Cancer Institute;Pathway interactions;Population;Recording of previous events;Research;Research Personnel;Role;STEM career;Schools;Science;Scientist;Site;Structure;Students;Testing;Underrepresented Populations;Underrepresented Students;United States National Institutes of Health;Washington;Work;Youth;anticancer research;broadening participation research;cancer health disparity;career;career awareness;computerized tools;design;disadvantaged student;economic disparity;experience;health inequalities;high school;high school program;holistic approach;innovation;interest;outreach;outreach program;pandemic disease;programs;response;science education;science teacher;social;student training;teacher;twelfth grade;undergraduate student;virtual;virtual internship Pathways to Cancer Research Renewal NARRATIVEPathways to Cancer Research Renewal attracts underrepresented and economicallydisadvantaged students to science inspires them to pursue research careers and supportsthem as they advance professionally. Increasing diversity among researchers brings newperspectives that stimulate innovation and that ensures future cancer researchers will representthe communities they serve including populations disproportionately impacted by cancer. Thisrenewal has a special emphasis on two areas of need identified by the NCI: the role ofcomputational biology in current and future research and the importance of working withcommunities to address health inequities. NCI 10694041 8/30/23 0:00 RFA-CA-21-020 5R25CA221770-08 5 R25 CA 221770 8 "LOPEZ, BELEM G" 9/19/17 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9193330 "CHOWNING, JEANNE TING" "VANNIER, DAVID M" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 432000 NCI 400000 32000 ABSTRACTPathways to Cancer Research Renewal (Pathways Renewal) is a renewal of the Pathwaysto Cancer Research grant R25 CA221770 awarded to Fred Hutchinson Cancer ResearchCenter (Fred Hutch) in Seattle Washington. It is designed to meet the goals of the NationalInstitutes of Health (NIH) and National Cancer Institute (NCI) to broaden participation ofunderrepresented populations in science and thereby increase the diversity of the scientificworkforce. This renewal places a strong emphasis on developing two major focus areas acrossour Pathways programs - computational biology and cancer health inequities. These areasof importance were identified by our students and are also priorities of NCI/NIH. We will build onthe prior investments NCI has made in our science education efforts through the YES R25mechanism introducing new and innovative components and strengthening our existingPathways programs for educators and underrepresented high school and undergraduatestudents. We will develop and offer two new virtual high school activities that were piloted in2021 in response to the pandemic: an outreach program that focuses on using computationaltools to analyze cancer datasets and a school-year academic research internship. Our aims forthis proposal are to: 1) Provide Hutch Teacher Fellowship mentored multi-year researchexperiences for secondary science teachers preparing them to develop curriculum materialsfocused on computational biology and cancer health inequities; 2) Expand our Explorers andCoding for Cancer introductory outreach programs aimed at increasing the pool of eligibleyouth interested in cancer research in general and computational biology and cancer healthinequities in particular; and 3) Thread opportunities for computational analysis and communityaction related to cancer health inequities throughout our Explorers Virtual School-YearInternship and Pathways Undergraduate Researchers mentored multi-year researchinternship experiences. Across our programs we place a strong emphasis on the developmentof scientific identity fostering a sense of belonging in science and preparing students tocommunicate science to their families and communities. Our integrated and holistic approachbuilds on the long-standing robust institutional support for science education at Fred Hutch oursuccessful history of engaging and supporting underrepresented students to pursue cancerresearch careers and the strength of our science education staff and scientific faculty. 432000 +No NIH Category available Agammaglobulinaemia tyrosine kinase;Award;B lymphoid malignancy;B-Cell NonHodgkins Lymphoma;B-Lymphocytes;Blood;Bone Marrow Involvement;Bone marrow biopsy;Cause of Death;Cell Proliferation;Cell Survival;Chronic;Clinical;Clinical Trials;Data;Diagnosis;Disease;Disease Progression;Dose;Drug Utilization;Equation;Exposure to;FDA approved;Genetic;Half-Life;I131 isotope;Immuno-Chemotherapy;Immunoglobulin M;In complete remission;Life;Liver;Longterm Follow-up;Lymphoma;Lymphoplasmacytoid Cell;Malignant Neoplasms;Measures;Medical;Membrane Microdomains;Modification;Monoclonal Antibody CD20;Normal Cell;Normal tissue morphology;Organ;Outcome Measure;Patient Outcomes Assessments;Patient Participation;Patients;Pharmaceutical Preparations;Phase;Phospholipid Ethers;Plasma Cells;Prevention;Progression-Free Survivals;Property;Proteasome Inhibitor;Radiation exposure;Radioactive;Radiolabeled;Recommendation;Refractory;Relapse;Research Design;Rodent Model;Safety;Series;Serum;Signal Pathway;Small Business Innovation Research Grant;Spleen;Surface;Symptoms;Targeted Radiotherapy;Therapeutic;Time;Treatment-related toxicity;Tumor Burden;Tumor Volume;Tyrosine Kinase Inhibitor;Visit;Waldenstrom Macroglobulinemia;analog;anti-CD20;cancer cell;cancer type;clinical development;clinical trial protocol;cohort;efficacy evaluation;efficacy study;gammopathy;improved;inhibitor;intravenous administration;lymph nodes;meetings;neoplastic cell;novel therapeutics;open label;partial response;patient population;primary endpoint;prognostic indicator;radiation delivery;response;rituximab;safety study;screening;secondary endpoint;single photon emission computed tomography;standard care;standard of care;symptom treatment;targeted agent;targeted delivery;targeted radiotherapeutic;treatment duration;tumor;tumor growth;uptake An Open-Label Multicenter Phase 2/3 Efficacy and Safety Study of a targeted radiotherapy in Patients with Relapsed or Refractory Waldenstroms Macroglobulinemia NARRATIVESince there are limited treatment options for patients who have relapsed and who are intolerant to or have asuboptimal response to ibrutinib or other BTK inhibitors there is a clear unmet need for novel therapeutics withunique mechanisms of action that can provide an enhanced safety profile optimal responses and durable effectsin patients with relapsed WM regardless of the genetic landscape of the disease. NCI 10694038 8/30/23 0:00 PA-20-262 5R44CA265558-03 5 R44 CA 265558 3 "REGMI, SAROJ GOPAL" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-R(11)B] 77792542 "LONGCOR, JARROD " "REILLY, LAURENCE " 11 Unavailable 172626413 GG83LBASEK99 172626413 GG83LBASEK99 US 43.050542 -89.289764 10005896 "CELLECTAR BIOSCIENCES, INC." Florham Park NJ Domestic For-Profits 7932 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 475806 NCI 387845 87961 ABSTRACTWaldenstroms Macroglobulinemia (WM) is an incurable and life-threatening malignant tumor. It is a rare andchronic form of B-cell non-Hodgkin lymphoma (NHL) characterized by small B lymphocytes plasmacytoidlymphocytes and plasma cells typically involving the bone marrow lymph nodes and organs such as spleenand liver. Patients also have detectable levels of monoclonal immunoglobulin (Ig) M gammopathy with bonemarrow involvement. The median survival of WM patients from the time of diagnosis is approximately 6 yearsdepending on prognostic indicators. The main causes of death include disease progression transformation tohigh-grade lymphoma or therapeutic complications. While many drugs are utilized there is no standard treatmentin first-line WM patients. Recommendations include using chemoimmunotherapy with rituximab (anti-CD20monoclonal antibodies) or the combination of rituximab with proteasome inhibitors as well as ibrutinib for somepatients. Because all patients disease eventually progresses and ibrutinib is the only approved second linetherapy there continues to be a significant unmet medical need in patients in the relapsed or refractory setting.We propose the clinical development of CLR 131 for the treatment of relapsed WM in patients who do notrespond to ibrutinib (or other Brutons tyrosine kinase inhibitors) or are intolerant to it. CLR 131 a tumor targetedradiotherapeutic with a phospholipid ether (PLE) core is expected to have an enhanced efficacy and safetyprofile and provide durable efficacy due to CLR 131 actually modifying the disease regardless of the underlyinggenetic landscape of WM. CLR 131 exploits the tumor-targeting properties of PLEs to provide a targeted deliveryof radiation to malignant tumor cells and minimizes radiation exposure to normal tissues. PLEs selectively insertinto lipid rafts which are enriched on the surface of tumor cells and use them as a gateway for cellular entry.The combined nonclinical data confirm that administration with CLR 131 results in inhibition of tumour growthand increased survival. More importantly preliminary data from 6 WM subjects participating in our Phase II open-label multi-center study of CLR 131 in patients with relapsed or refractory select types of B-cell malignanciesshowed an overall response rate of 100% with one patient with a complete response four patients with a partialresponse one patient with a minimal response showing a 45% reduction in IgM (50% reduction equates to apartial response). In this project. we will conduct a non-randomized open-label multi-center Phase II/III efficacyand safety study of intravenous administration of CLR 131 in at least 50 patients with WM who have failedstandard of care first line treatment and either failed or had a suboptimal response to any BTK inhibitors (i.e.ibrutinib zanubrutinib or acalabrutinib). This study will allow us to receive regulatory approval for CLR 131 in theexamined patient population. 475806 +No NIH Category available Aftercare;Agonist;Animal Model;Animals;Antigens;Automobile Driving;Biochemical;Biological Assay;Biological Markers;Bone Marrow;Chemotherapy and/or radiation;Circulation;Clinical;Clinical Research;Clinical Trials;Combined Modality Therapy;Conduct Clinical Trials;Correlative Study;Cross Presentation;Cytometry;Cytotoxic agent;Data;Dendritic Cells;Development;Exclusion;FLT3 gene;Functional disorder;Future;Human;Image;Immune;Immune checkpoint inhibitor;Immunity;Immunologic Tests;Immunologics;Immunosuppression;Immunotherapy;Impairment;Infiltration;Ligands;Limes;Malignant neoplasm of pancreas;Myeloid Cells;Nature;Pancreatic Ductal Adenocarcinoma;Patients;Phase I/II Clinical Trial;Positioning Attribute;Productivity;Prognosis;Radiation therapy;Reporting;Research;Research Personnel;Role;Safety;Signal Transduction;Stimulant;T cell infiltration;T cell response;T-Lymphocyte;TNFRSF5 gene;Testing;Therapeutic;Tissues;Translating;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Tumor-Derived;Work;antigen-specific T cells;cancer cell;cancer type;checkpoint therapy;chemotherapy;clinical translation;cohort;density;experimental study;immune checkpoint blockade;immunosuppressive macrophages;improved;member;mouse model;pancreatic ductal adenocarcinoma model;patient response;pre-clinical;response;restraint;single cell analysis;treatment strategy;trial design;tumor;tumor microenvironment Re-wiring PDAC Tumor Immunity Through Dendritic Cells PROJECT NARRATIVEThese studies seek to understand the impact of dendritic cells on therapeutic responsiveness to radiation therapy in pancreas cancer. NCI 10694023 8/22/23 0:00 PAR-18-560 5R01CA262506-03 5 R01 CA 262506 3 "BUCHSBAUM, JEFFREY" 9/22/21 0:00 8/31/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 8710339 "DENARDO, DAVID G" "DESELM, CARL " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 603069 NCI 416305 186764 PROJECT SUMMARY The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. This is likely due to thepresence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most PDAC. Our datasuggest immune priming by conventional dendritic cells (cDCs) may be a necessary barrier to overcome togenerate lasting immunity in PDAC patients. cDCs are central for generating tumor antigenspecific T cellresponses. Our new data show that cDCs are severely dysfunctional in patients with PDAC. This dysfunction isdriven by two mechanisms: 1) We recently reported that PDAC patients have impaired cDC development intheir bone marrow and this leads to functional depletion of circulation pre-DCs and poor response tocheckpoint inhibitors. 2) We recently showed that even when cDC development is not fully impaired cDC1sare physically/biochemically excluded from the PDAC TME. These mechanisms to the loss of stereotactic bodyradiation therapy (SBRT)-induced priming of tumor antigen-specific T cell responses and ultimately failedtumor control in animal models. We overcame both of these dysfunctional barriers by targeting cDC1s using acombination of systemic treatment with FMS-like tyrosine kinase 3 ligand (FLT3L) and CD40 agonists. Our pre-clinical data are exceptionally strong and have placed us in a unique position to translate these findings intoPDAC patients. Our central hypothesis is that targeting cDC can unlock responsiveness to RT bygenerating lasting anti-tumor immunity. We will expand test this hypothesis in three specific aims.Aim 1. Determine the safety and efficacy of the combination of CDX-301 plus CDX-1140 and SBRT inlocally advanced PDAC patientsAim 2. Determine the mechanisms by which FLT3L plus a CD40 agonist induce anti-tumor immunity.Aim 3. Determine if FLT3L plus CD40 agonists improves responsiveness to checkpointimmunotherapy.Impact. PDAC patient responses to conventional radiation therapy have been disappointing. Our data stronglysupport the use of FLT3L and CD40 agonist to enhance patient responsiveness to RT and generate long-termanti-tumor immunity. Our team is well-positioned to test our central hypothesis directly in clinical andexperimental studies. 603069 +No NIH Category available Acceleration;Affect;BRCA mutations;CRISPR screen;Cancer Patient;Cell Cycle Checkpoint;Cell Proliferation;Clinical Trials;DNA Damage;DNA Repair;Defect;Development;Genes;Genomic Instability;Goals;Immune Targeting;In Vitro;Knowledge;Mismatch Repair Deficiency;Mutation;Pathway interactions;Poly(ADP-ribose) Polymerase Inhibitor;Proliferating;Proteins;anticancer treatment;cancer immunotherapy;cancer therapy;design;gene repair;immune checkpoint;improved outcome;in vivo;inhibitor;novel therapeutics;response;success;targeted cancer therapy;treatment strategy;tumor;tumor microenvironment;tumorigenesis Exploring DNA damage response pathways as targets for cancer therapy Project Narrative:Defective DNA repair is a double-edged sword. It leads to increased genomic instability and accelerates tumordevelopment and progression but it also renders tumors more vulnerable to anti-cancer treatments includinginhibitors targeting immune checkpoints and cell cycle checkpoints. We propose to investigate essential DNAdamage repair genes and pathways both in vitro and in vivo with the goal of exploiting these pathways anddefects for cancer treatment. NCI 10694017 8/2/23 0:00 PAR-21-333 5R35CA274234-02 5 R35 CA 274234 2 "WITKIN, KEREN L" 9/1/22 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 1980054 "CHEN, JUNJIE " Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 952560 NCI 588000 364560 Project Summary:It is well established that defects in DNA damage response (DDR) pathways accelerate tumorigenesis.Significant efforts have been devoted to target defective DDR pathways to improve outcome for cancer patients.These efforts led to the FDAs approval of PARP inhibitors for the treatment of cancers carrying BRCA1/2mutations and also the approval of immunotherapy for cancers with mismatch repair deficiency. Moreover manyinhibitors targeting DNA repair and/or cell cycle checkpoints have also entered clinical trials. Thus there is anurgent need to understand how to effectively use these existing and new therapies for cancer treatment.We now know that targeting DDR pathways and/or DDR defects not only affect intrinsic tumor proliferation butalso change tumor-microenvironment interactions. Thus we are expanding our DDR studies from in vitro to invivo settings. In this project we will determine mechanistically how several essential DDR genes/proteins controlcell proliferation and DNA damage repair. We plan to establish separation of function mutations to furtherelucidate the key roles of these DDR genes and pathways both in vitro and in vivo. Additionally we willinvestigate DDR defects in cancer therapy in vivo. Our recent success with in vivo CRISPR screens provides usan opportunity to explore avenues to target DDR pathways and DDR defects for cancer treatment in vivo. Weanticipate that knowledge gained from these studies will help us design better treatment strategies for cancerpatients. 952560 +No NIH Category available Acceleration;Active Learning;Adverse event;American Association of Cancer Research;American Society of Clinical Oncology;Antineoplastic Agents;Awareness;Cancer Biology;Cessation of life;Classification;Clinical;Clinical Trials;Combination Drug Therapy;Communities;Data;Data Sources;Databases;Development;Dose;Dose Limiting;Drug Combinations;Drug Design;Drug Exposure;Drug Interactions;Drug Kinetics;Drug toxicity;Failure;Feedback;Grant;Informatics;Knowledge;Label;Literature;Machine Learning;Malignant Neoplasms;Methodology;Methods;Oncologist;Paper;Patients;Performance;Pharmaceutical Preparations;Pharmacoepidemiology;Pharmacologic Substance;Pharmacotherapy;Phase;Phase Ib Trial;Preparation;PubMed;Public Domains;Quality Control;Records;Reporting;Research;Research Personnel;Safety;Sampling;Source;Surveys;System;Toxic effect;anticancer research;cancer clinical trial;cancer therapy;cohort;combination cancer therapy;data curation;data integration;deep learning;deep learning algorithm;design;drug development;experience;improved;innovation;knowledge base;knowledgebase;learning strategy;medication safety;novel;pharmacometrics;phase 1 study;phase I trial;pre-clinical;research and development;screening;software development;symposium;translational engagement;translational impact;trial design;trial enrollment An informatics bridge over the valley of death for cancer Phase I trials of drug-combination therapies NarrativePhase I studies usually focus on drug toxicity and drug exposure which have the largest failure rate 58% ofcancer drug development i.e. valley of death. Because of complexity of cancer biology they usually requiremulti-drug therapies. In order to overcome the valley of death for multi-drug cancer therapies we propose aninformatics bridge i.e. a translational drug interaction knowledge base (TDCKB) that will integrate multi-drugexposure and toxicity data from various data sources. TDCKB will accelerate the translational cancer drugcombination development research to the next phase of clinical trials. NCI 10694008 8/24/23 0:00 RFA-CA-20-008 5U01CA248240-03 5 U01 CA 248240 3 "UNDALE, ANITA H" 9/24/21 0:00 8/31/24 0:00 ZCA1-RTRB-R(M3) 8050089 "LI, LANG " Not Applicable 3 MISCELLANEOUS 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 299535 NCI 243755 135591 An informatics bridge over the valley of death for Phase I trials of drug-combination cancer therapiesSummaryPhase I studies usually focus on drug toxicity and pharmacokinetics and most (58%) drugs intended as cancertherapies fail these initial trials. Thus Phase I studies represent the largest valley of death in the course of drugdevelopment. Unlike the design of a single-drug Phase I study the design of a drug-combination study requiresprior knowledge of whether either drug changes the others drug exposure the drugs share toxicities and eachdrug has an established maximum tolerable dose. Although abundant toxicity and PK data are available in publicdomain sources the data are not integrated and no single database integrates data regarding both toxicity andPK. In addition data regarding single-drug and drug-combination MTD and DLT are present in the literature butabsent from any database. We are confident that a bridge can be built across the Phase I valley of death forcancer multi-drug research and development utilizing an informatics and pharmacometrics approach to takeadvantage of the abundant toxicity and PK data available for single drugs. In this grant we propose atranslational drug-interaction knowledgebase (TDCKB) that integrates toxicity and PK data. Aim 1 will developnovel active-learning approaches to mine evidence of toxicity and PK regarding drug interactions from theliterature. The active learning methodology will employ several innovations including random negative samplingstratified active learning by prescreening based on PubMed query and deep learning with embedding. The finalactive-learning method is optimized by a thorough integration of these innovative components. Aim 2 will developa translational drug-interaction knowledgebase (TDCKB) for cancer research. The TDCKB will integrate toxicityand PK evidence for single drugs and drug combinations from various data sources. The evidence of DDI willbe classified as either toxicity or PK and the strength of the evidence will be annotated. Synthesized evidencessuch as overlapping toxicity and predicted drug interactions between two drugs will assist in Phase I drugcombination trial design. Quality control will be conducted carefully during both data curation and TDCKBsoftware development. Engagement of TDCKB users and the ITCR community is planned. 299535 +No NIH Category available Address;Age;Alleles;Base Sequence;Blood;Brain;Breast;Breast Sarcoma;Cancer Family;Cancer Survivor;Cancer-Predisposing Gene;Caring;Cells;Cessation of life;Characteristics;Clinical;Clinical Management;Clonal Evolution;Clonal Expansion;Collection;Constitution;Constitutional;Diagnostic tests;Disease;Elderly;Exclusion;Exposure to;Family;Financial cost;Frequencies;Gene Frequency;Genes;Genetic Variation;Genomics;Genotype;Germ-Line Mutation;Heart Diseases;Hematologic Neoplasms;Hematology;Hematopoiesis;Hematopoietic;Hereditary Neoplastic Syndromes;Heterogeneity;High-Risk Cancer;Histologic;Individual;Inherited;Laboratories;Li-Fraumeni Syndrome;Malignant - descriptor;Malignant Neoplasms;Marrow;Medical Care Costs;Modification;Molecular;Molecular Genetics;Mosaicism;Multiple Primary Neoplasms;Mutation;Myelogenous;Natural History;Neoplasms;Other Genetics;Pathogenicity;Patient Care;Patients;Penetrance;Persons;Phenotype;Population;Population-Based Registry;Positioning Attribute;Precision Medicine Initiative;Predisposition;Premalignant Cell;Prevalence;Recommendation;Registries;Research;Research Personnel;Risk;Risk Estimate;Role;Saliva;Site;Specimen;Statistical Models;Syndrome;TP53 gene;Testing;Tissues;Variant;Weight;cancer risk;chemotherapy;clinical care;clinically relevant;cohort;cost;exome;genetic disorder diagnosis;genetic panel test;genetic testing;genetic variant;genomic profiles;high risk;improved;insight;lifestyle factors;loss of function;malignant breast neoplasm;mosaic;mutation carrier;next generation;next generation sequencing;novel;offspring;patient oriented;personalized approach;polygenic risk score;population based;proband;prospective;psychologic;recruit;sarcoma;segregation;translational impact;tumor Precision approaches to refining TP53-associated cancer risk PROJECT NARRATIVETP53 testing is now being performed through next generation sequence-based multigene panel testing(MGPT) on large numbers of people who do not meet criteria for Li-Fraumeni Syndrome (LFS) which hasraised questions about the true spectrum of LFS and also about possible confounding of germline geneticdiagnosis due to aberrant clonal expansion (ACE) of somatic TP53 variants often related to clonalhematopoiesis. In this project we will partner with commercial testing laboratories a large population-basedclinical exome project and patient oriented registries to recruit all individuals with TP53 mutations and improveour ability to distinguish between true germline TP53 variants and those associated with ACE since the clinicalimplications differ substantially and better define the TP53-associated tumor spectrum and cancer risks. NCI 10693974 9/13/23 0:00 RFA-CA-18-019 5R01CA242218-05 5 R01 CA 242218 5 "ROTUNNO, MELISSA" 9/18/19 0:00 8/31/24 0:00 ZCA1-SRB-K(M1)R 1902433 "GRUBER, STEPHEN B" "AMOS, CHRISTOPHER I.; GARBER, JUDY E." 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1709326 NCI 1226026 483300 Pathogenic TP53 gene variants underlie 70% of Li-Fraumeni Syndrome (LFS) a hereditary cancer syndromeclassically associated with predisposition to multiple primary neoplasms particularly sarcoma brain breastadrenocortical and other malignancies at unusually early ages. Traditionally clinical TP53 testing was limited toindividuals and families who met specific criteria. With the introduction of NGS-based multi-gene panel testing(MGPT) TP53 testing is now being performed on large numbers of people who do not meet LFS criteria. BroaderMGPT testing for TP53 mutations has raised concerns about:1) a broader phenotypic spectrum for mutationcarriers; and 2) the clinical relevance of TP53 variants identified in blood or saliva with allele frequencies belowthe 50% expected frequency for a germline carrier. We demonstrated that aberrant clonal expansions (ACE) ofhematopoietic cells (clonal hematopoiesis CH) with an acquired pathogenic TP53 variant is responsible for manysuch cases. ACE/CH which is observed at increasing frequency with advancing age in healthy populations andafter exposure to chemotherapy in cancer survivors has been associated with increased risk of hematologicmalignancy. Clinically it is critical to discern true germline from somatic TP53 variants (ACE) since the clinicalimplications differ substantially. Carriers of true germline TP53 mutations may bear the psychological medicaland financial costs of striking personal and family cancer risks the burden of intensive surveillance the highrisks of cancer deaths at disproportionately young ages and the weight of possibly passing TP53 variants tooffspring. Those with ACE/CH may be followed for increased risk of hematologic malignancy or heart disease.More research is needed to better quantify TP53 associated risks to clarify optimal management. The investigators will partner with colleagues from the Li-Fraumeni Exploration Consortium (LiFE) and otherswith patients ascertained through broader more agnostic approaches to testing: commercial genetic testinglaboratories the Geisinger MyCode project the PROMPT study of individuals with germline mutations and theORIEN tumor/germline sequencing project to assemble the largest cohort of individuals with a TP53 mutationin blood or saliva and their relatives. Given the rarity of LFS acquiring this cohort through other means would becost prohibitive and impracticable. In aim 1 we will estimate the TP53-related site-specific cancer risks in familiesidentified through agnostic testing approaches and study tumor genomic characteristics in their collected tumorspecimens. In aim 2 we will investigate the roles of TP53 allelic heterogeneity and specific genetic variation asmodifiers of these cancer risks. ACE will be characterized separately as described in aim 3 and we will excludeprobands with ACE rather than germline TP53 mutations from Aim 1 and 2 analyses. These studies will improve our ability to distinguish between germline TP53 variants and those associatedwith ACE and the genotype-phenotype correlations elucidated will better define the TP53-associated tumorspectrum and cancer risks to help refine clinical management recommendations for both groups. 1709326 +No NIH Category available AIDS related cancer;Adherence;Administrator;Adoption;Aftercare;Age;Anti-Retroviral Agents;Attitude;Belief;Cancer Control;Cancer Intervention;Caring;Cervical;Cervical Cancer Screening;Characteristics;Clinic;Clinical;Communities;Consensus;Consolidated Framework for Implementation Research;Data;Decision Making;Diagnostic Reagent Kits;Disadvantaged;Education;Effectiveness;Eligibility Determination;Ensure;Evaluation;Female;Focus Groups;HIV;HIV Seronegativity;HIV Seropositivity;HIV/AIDS;HPV-High Risk;Health Status;High Prevalence;Highly Active Antiretroviral Therapy;Home;Human Papillomavirus;Human papilloma virus infection;Impact evaluation;Incidence;Individual;Infrastructure;Intervention;Interview;Lesion;Maintenance;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Mentors;Methodology;Methods;Modeling;Monitor;Mothers;Nigeria;Nigerian;Participant;Persons;Pharmaceutical Preparations;Phase;Policy Maker;Prevention;Prevention program;Process;Professional counselor;Published Comment;Reach Effectiveness Adoption Implementation and Maintenance;Records;Recurrence;Resources;Risk;Rural Community;Sampling;Shapes;Structure;Support Groups;System;Training;Vertical Disease Transmission;Viral;Viral Load result;Woman;cancer risk;evidence base;experience;follow-up;health service use;home test;implementation evaluation;implementation fidelity;implementation framework;implementation process;innovation;insight;low and middle-income countries;male;mortality;outreach;peer;peer support;post implementation;premalignant;primary health center;process evaluation;program costs;programs;routine practice;scale up;screening;screening program;screening services;social stigma;symposium;systematic review;treatment program The CHESS (Community Home-based Education Screening Services) Strategy to increase cervical cancer control access for HIV positive women in Nigeria Project NarrativeDespite the increased risk of cervical cancer for women living with HIV access to cervical cancer screening inNigeria is limited. We will leverage existing HIV treatment infrastructure in Nigeria to integrate cervical cancercontrol activities into the successful MoMent (MOther MENTor) peer-based HIV support program. Usingimplementation science frameworks we will implement and evaluate the sustainability of the adapted MoMentHIV + Homebased Cervical Cancer program to advance cervical cancer control in Nigerian women living withHIV. NCI 10693963 8/30/23 0:00 RFA-CA-21-056 5U01CA275113-02 5 U01 CA 275113 2 "VEDHAM, VIDYA" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M2) 1872503 "FLOWERS, LISA C." "AWOLUDE, OLUTOSIN ; EZECHI, OLIVER CHUKWUJEKWU; GAYDOS, LAURA M; OGUNSOLA, OLABANJO OKUNLOLA" 5 OBSTETRICS & GYNECOLOGY 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 561420 NCI 521707 39713 AbstractDespite the increased risk of cervical cancer (CC) for women living with HIV (WLWH) access to CC screeningin Nigeria is limited. Access to screening prevention programs and highly active antiretroviral therapy hascontributed to dramatic declines in the incidence of many AIDS-associated malignancies but have not loweredCC risk in WLWH. Therefore we seek to leverage the existing HIV treatment infrastructure in Nigeria tointegrate home-based CC (HCC) screening for WLWH and evaluate the implementation and sustainability ofthis model. We will weave HCC activities into the successful long-standing MoMent (MOther MENTor) peer-based HIV support program and evaluate the implementation of this adapted program for adoption integrationsustainability and potential for national scale-up. The Consolidated Framework for Implementation Research(CFIR) and Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) conceptualframeworks will guide our implementation and impact evaluation. In this project we will pursue three specificaims: 1) use a stakeholder deliberation conference methodology to adapt the successful MoMent program topromote home-based HPV CC screening and follow-up treatment for women who are HIV positive; 2)implement the MoMent HIV+HCC screening program and assess program reach effectiveness adoption andfidelity; and 3) conduct post-implementation process evaluation of barriers and enablers to programmaintenance and sustainability. Stakeholder input from WLWH peer counselors clinical managers andfederal/state policymakers will shape the adapted program and promote its successful implementation in asample of 1500 WLWH. We will be among the first to apply recent systematic review findings that thecharacteristics of systems construct of CFIR is particularly relevant in low/middle income countries. Weensure scalability by focusing on national and state policymaker perspectives in the pre-implementationimplementation and maintenance phases of the adapted program. In this project we will advance CC controlfor WLWH in Nigeria and generate data that can inform effective adaptation and implementation of evidence-based cancer control strategies for people living with HIV in low/middle income countries worldwide. 561420 +No NIH Category available ATAC-seq;Aberrant crypt foci;Ablation;Affect;Age;Antibiotic Therapy;Bacteria;Bacteroides fragilis;Biological;Biological Markers;Blood;Blood Cells;Blood Tests;Carcinogenesis Mechanism;Cells;Chromatin;Coculture Techniques;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Community Networks;DNA;DNA Methylation;DNMT3a;Data;Development;Disease susceptibility;Epigenetic Process;Epithelial Cells;Epithelium;Exclusion;Exposure to;Feces;Fusobacterium nucleatum;Gene Expression;Genes;Genetic;Germ-Free;Growth;Histopathology;Human;Hypermethylation;Hypoxia;Immune response;Immunity;Immunology;Immunology procedure;Individual;Inflammation;Intestines;Invaded;Lactobacillus acidophilus;Large Intestine;Leukocytes;Link;Malignant Neoplasms;Methylation;Methyltransferase Gene;Microbe;Mucous Membrane;Mus;Mutation;Oral;Oral cavity;Organoids;Pathogenicity;Patients;Pattern;Prevention strategy;Process;Regulator Genes;Reporting;Risk Factors;Signal Pathway;Specimen;T-Lymphocyte;Testing;Tissues;Tumor Immunity;Tumor Promotion;Weaning;bacterial community;beta catenin;biobank;bisulfite sequencing;colon bacteria;colon cancer patients;colon carcinogenesis;colorectal cancer risk;colorectal cancer treatment;demethylation;epigenome;fecal microbiota;gut colonization;human microbiota;humanized mouse;improved;indexing;intestinal epithelium;methylome;microbial colonization;microbial community;microbiome;microbiota;mortality;mouse model;neoplastic cell;oral bacteria;oral commensal;oral pathogen;pathogen;risk stratification;stem cells;suckling;therapy resistant;transcriptome;transcriptome sequencing;tumor;tumor growth Epigenetic mechanisms of carcinogenesis by Parvimonas micra an oral cavity commensal turned colon cancer pathogen Project NarrativeBased on our recent findings we propose that oral commensals methylate host cell DNA and in this processpromote tumor growth and compromise immune responses. We will test this with microbiota humanized mousemodels of colorectal cancer and patient specimens including tumor organoids. \. NCI 10693952 8/31/23 0:00 PAR-19-198 5R01CA264048-03 5 R01 CA 264048 3 "DASCHNER, PHILLIP J" 9/13/21 0:00 8/31/26 0:00 Cancer Prevention Study Section[CPSS] 6107726 "KHAZAIE, KHASHAYARSHA " "BOARDMAN, LISA ALLYN; GOUNARI, FOTINI ; STALEY, CHRISTOPHER " 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 593887 NCI 445322 148565 Project Summary AbstractColorectal cancer (CRC) is among the most common malignancy worldwide and has a high mortality rate. Inspite of advances in our understanding of the genetics and immunology of CRC it remains largely resistant totherapy. Colonization of the large intestine by oral microbes is common among healthy individuals. Many of thesecommensals have pathophysiological effects in CRC patients. However their mechanism of action is unclear.Our recent study identified Parvimonas micra as the most enriched oral bacteria in CRC patient stool and colonmucosa relative to healthy individuals. Networks of P. micra and other oral commensal in the stool of CRCpatients excluded protective commensals. Changes in DNA methylation of a set of cardinal genes in the colonmucosa and blood of the patients predicted CRC risk. Transfer of CRC stool to germ free mice that were treatedwith AOM resulted in DNA methylation of the host and formation of aberrant crypt foci over and above thatobserved with transfer of microbiota from healthy individuals. We provided preliminary data that P. micra candirectly methylate human colon tumor cells when co-cultured together under hypoxic conditions. On the basisof these findings we hypothesize that oral commensals exemplified by Parvimonas alter DNA methylationof host DNA to adapt to tumors and promote CRC. We will address this in two Specific Aims. 1. We will testthe hypothesis that in mouse models of spontaneous CRC P. micra alters DNA methylation and expression ofhost genes that affect CRC tumor growth and tumor associate immunity. Mice prone to spontaneous CRC willget healthy human microbiota with or without P. micra or L. acidophilus for comparison. Reduced representationbisulfite sequencing (RRBS) ATACseq RNAseq immune assays and histopathology will determine howchanges in DNA methylation impacts (1) the growth and invasion of CRC tumors (2) tumor associatedinflammation and immune response (3) microbial community composition of the tumor mucosa and stool. 2. Wewill test the hypothesis that P. micra and bacterial community networks regulate tumor growth and immuneresponse in CRC by altering DNA methylation of host cells. To test this we will (1) Identify clusters of fecal andtissue-adherent bacteria in CRC patients and relate these to the DNA hypermethylation of patient colon andblood across different CMS subclasses (2) determine how altered DNA methylation of tumor and blood relateto mutation load and immune response (3) distinguish pathogenic versus protective patterns of DNA methylationin colon epithelial organoids that result from exposure to P. micra versus L. acidophilus. 593887 +No NIH Category available 3-Dimensional;Acetylcysteine;Amides;Antineoplastic Agents;Bromelains;Carcinoma;Cell Death;Cell Survival;Cell membrane;Charge;Colorectal Cancer;Complex;Curative Surgery;Cytoprotection;Dose;Doxorubicin;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug Targeting;Dryness;Esters;Face;Formulation;Glycoproteins;Greater sac of peritoneum;Histologic;In Vitro;Institution;International;Intravenous;Laboratories;Malignant neoplasm of appendix;Malignant neoplasm of ovary;Mediating;Membrane;Mitochondria;Mitomycin C;Mucin-2 Staining Method;Mucinous;Mucinous Neoplasm;Mucolytics;Mucous Membrane;Mucous body substance;Nanotechnology;Neoplasm Metastasis;Oligosaccharides;Organoids;Outcome;Pathway interactions;Patients;Penetration;Peptide Hydrolases;Peptides;Peritoneal;Permeability;Pharmaceutical Preparations;Polyethylene Glycols;Polymers;Positioning Attribute;Reactive Oxygen Species;Recurrence;Research Proposals;Serum;Structure;Surface;Therapeutic;Time;Tissues;Trypsin;Trypsin Inhibitors;Unresectable;Weight;Xenograft Model;absorption;anti-cancer;antitumor effect;arm;biomaterial compatibility;biomedical referral center;cancer cell;chemotherapy;cytotoxicity;disulfide bond;endoplasmic reticulum stress;extracellular;improved;in vitro Model;in vivo;in vivo Model;intraperitoneal;intraperitoneal therapy;mitochondrial membrane;nanoparticle;novel therapeutic intervention;patient derived xenograft model;pharmacokinetics and pharmacodynamics;preclinical study;safety assessment;small molecule;systemic toxicity;therapeutic nanoparticles;three dimensional cell culture;tumor;zeta potential Application of mucus modulating multipurpose trypsin nanoparticles to overcome the mucus barrier and deliver mitochondria-targeted anticancer drugs in mucinous carcinoma peritonei PROJECT NARRATIVEMucinous carcinoma peritonei (MCP) arising from mucinous colorectal and appendiceal cancers is frequentlyunresectable responds poorly to standard intravenous chemotherapy and often recurs after curative surgerywith intraperitoneal (IP) chemotherapy. IP chemotherapy is hindered by abundant extracellular mucus andrapid absorption of small molecule drugs from the peritoneal cavity. We have synthesized mucus modulatingmultipurpose TRYP nanoparticles (MTN) capable of mucolysis and delivery of positively charged mitochondria-targeted drugs along a progressively higher negative charge-gradient from nanoparticle surface to mucus tomitochondrial membranes. NCI 10693942 8/2/23 0:00 PAR-20-292 5R21CA273630-02 5 R21 CA 273630 2 "AVULA, LEELA RANI" 9/1/22 0:00 8/31/24 0:00 ZCA1-PCRB-9(M1)S 12269818 "CHOUDRY, MOHAMMAD HAROON ASIF" Not Applicable 12 SURGERY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 218538 NCI 137445 81093 PROJECT ABSTRACTMucinous colorectal and appendiceal cancers (MCAC) are unique histologic subtypes that frequentlymetastasize to the peritoneal cavity (known as mucinous carcinoma peritonei [MCP]). MCP is frequentlyunresectable responds poorly to standard intravenous chemotherapy and often recurs after curative surgerywith intraperitoneal (IP) chemotherapy resulting in poor oncologic outcomes. Intraperitoneal chemotherapyfor MCP faces two major challenges. First MCP is characterized by abundant extracellular mucus that formsa protective barrier around cancer cells hindering IP chemotherapeutic drug delivery. We have previouslydemonstrated robust mucolysis in patient-derived in vitro and in vivo models of MCP using mucolytic drugs(e.g. bromelain [BRO] N-acetylcysteine [NAC] and trypsin [TRYP]). We also found that the baseline net negativecharge of mucus was significantly increased after mucolysis (-potential in our studies: undigested mucus -1.93mV; digested mucus -17.2 mV). Second commonly administered IP drugs for MCP (e.g. doxorubicin [DOX] andmitomycin C [MITO]) are rapidly absorbed across the peritoneal membrane resulting in short IP retention timelow intra-tumoral (IT) penetration and systemic toxicity. Therapeutic nanoparticle formulations have longer IPretention and IT penetration than free drugs because of enhanced permeability and retention effect and provideprotection from early degradation and pre-absorption. The aim of this proposal is to leverage nanotechnologyand the significant negative charge of mucus following mucolysis to enhance IP retention IT penetration anddelivery of positively charged anticancer drugs in MCP. To this end we have synthesized mucus modulatingmultipurpose TRYP nanoparticles (MTN) comprised of three components; (a) a core of negatively charged TRYPclusters consisting of 4 arms of polyethylene glycol (PEG) and TRYP for enzymatic mucolysis and drug delivery;(b) nanoparticle-conjugated NAC for mucus disruption and mucoadhesion; and (c) nanoparticle-loaded andpositively-charged mitochondria-targeted anticancer drugs (mitocans) specifically triphenyl phosphonium (TPP)-doxorubicin (TPP-DOX) and TPP-mitomycin C (TPP-MITO) for anti-cancer effect. We hypothesize that ourMTN will disrupt the structural integrity of mucus enhance IP/IT retention and penetration of loaded drugs anddeliver positively charged TPP-DOX or TPP-MITO across a progressively higher negative charge-gradient fromthe nanoparticle surface to digested mucus to mitochondria (-potential: digested mucus -17.2 mV; cellmembranes -30 to -60 mV; mitochondrial membranes -160 mV). Our research proposal provides a noveltherapeutic strategy to overcome the cytoprotective mucus barrier and improve drug delivery in MCP. It isexpected that the proposed MTN will provide a pharmacokinetic and pharmacodynamic advantage over non-nanocarrier formulations of the drugs. Notably the proposed MTN are synthesized from biocompatible andbiodegradable materials increasing their translatability; TRYP is a naturally synthesized mammalian proteasecapable of hydrolyzing peptide- amide- and ester-bonds and does not digest living tissue since both serumand viable cells contain TRYP inhibitors; and TPP-MITO/TPP-DOX targeted to negatively charged mucus andmitochondria are newly developed in our laboratory and significantly effective against MCP in our preliminarystudies. This approach is likely to be applicable for other mucinous tumors (e.g. mucinous ovarian cancer) thatsecrete abundant extracellular mucus. We are uniquely positioned to conduct the preclinical studies in thisproposal given that we have already developed in vitro 3D cultures and in vivo xenograft models of MCAC/MCPand our institution is one of the major international referral centers for the management of patients with MCP. 218538 +No NIH Category available Advanced Malignant Neoplasm;Advisory Committees;Basic Science;Cancer Biology;Career Choice;Climacteric;Clinical;Clinical Oncology;Clinical Sciences;Communities;Community Practice;Discipline;Disease;Educational workshop;Effectiveness;Elements;Enrollment;Environment;Evaluation;Event;Faculty;Feedback;Fertilization;Future;Goals;Health;Healthcare;Individual;Interdisciplinary Study;Knowledge;Language Development;Learning;Life;Location;Malignant Neoplasms;Medical;Medical Students;Medicine;Mentors;Mentorship;Modeling;Modernization;Modification;Nature;Oncologist;Oncology;Outcome;Participant;Pennsylvania;Population;Population Sciences;Procedures;Process;Public Health;Recording of previous events;Recruitment Activity;Research;Research Institute;Research Personnel;Research Training;Rewards;STEM field;STEM student;Scientist;Students;Talents;Techniques;Training;Training Support;Translating;Underrepresented Populations;Underrepresented Students;anticancer research;base;career;clinical care;clinical practice;cohort;college;design;experience;faculty research;holistic approach;improved;interest;member;next generation;peer;peer coaching;prevent;programs;recruit;role model;skills;student participation;success;summer research;undergraduate student;underserved students;university student Penn State Research training in Oncology and Medicine to Inspire Student Engagement (PROMISE) PROJECT NARRATIVEThe Penn State PROMISE program (Penn State Research training in Oncology and Medicine to Inspire StudentEngagement) is an holistic approach to inspire attract and retain the next generation of cancer researchers andoncologists. PROMISE will instill in participants a gestalt understanding of cancer as a disease (how it isprevented controlled and treated) while stimulating interest in oncology careers and providing the skills neededfor durable research careers. In the long-term PROMISE will promote a deep and life-long understanding of howcancer research impacts the lives of individuals in the 21st century which will drive the on-going discovery ofnew knowledge by retaining a diverse cohort of trainees in cancer research careers. NCI 10693934 7/28/23 0:00 PAR-21-279 5R25CA272184-02 5 R25 CA 272184 2 "ZAHIR, NASTARAN" 9/1/22 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1941653 "ECKERT, KRISTIN A" "MATTERS, GAIL L." 10 PATHOLOGY 129348186 TNKGNDAWB445 129348186 TNKGNDAWB445 US 40.264414 -76.674014 1524204 PENNSYLVANIA STATE UNIV HERSHEY MED CTR HERSHEY PA SCHOOLS OF MEDICINE 170332360 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 318317 NCI 294738 23579 PROJECT SUMMARY/ABSTRACTPenn State Cancer Institutes (PSCI) PROMISE program (Penn State Research training in Oncology andMedicine to Inspire Student Engagement) is a holistic approach to inspire attract and retain cancer researchersfor the 21st century biomedical workforce. The program engages STEM college undergraduates and medicalstudents in an immersive program that provides authentic individual and team research experiencesdemonstrating first-hand how new cancer research discoveries are translated into clinical and societal practice.Additional program workshops provide support training in both professional and personal skills needed forsustained research careers. PROMISE emphasizes the interdisciplinary nature of modern cancer research. Wewill recruit motivated and talented students from a variety of disciplines and create an environment in whichcancer research is approachable and accessible for all participants. The PROMISE design is built upon arelational pedagogical model with peers near-peers and faculty to promote participants sense of belonging inand contributing to the cancer research community. The long-term goals of PROMISE are to instill in participantsa comprehensive understanding of cancer as a disease (how it is prevented controlled and treated) whilestimulating interest in oncology careers and providing skills needed for durable research careers. To achievethese goals Specific Aim 1 will provide integrated training in basic clinical and populations science approachesthrough mentored research experiences. The PROMISE: Research for Life training focus will show students howinterdisciplinary research is conducted to solve current oncology problems and to save lives through effectivecancer management. Under the experienced mentorship of PSCI scientists and clinicians the cohort will learnthe language techniques strategies and concepts used every day by cancer researchers. Specific Aim 2 willenhance trainee effectiveness through intensive support activities and rigorous program outcomes evaluations.Workshop activities will provide the opportunity to experience peer acceptance identify role models andovercome potential roadblocks to a successful research career. Events with stakeholders highlight howadvances in clinical oncology and societal practice are driven by research discoveries. Specific Aim 3 will createa diverse coalition cohort from varied disciplines that includes underserved students and inspire them to pursueadvanced training in cancer research and/or clinical oncology. STEM students who do not traditionally enterbiomedical careers will learn basic cancer biology and realize they can contribute to advancing cancer healthoutcomes through collaborative research. Peer and near-peer mentors will support self-identification as a cancerresearcher and faculty will provide authentic role models for future career paths. Participation in PROMISE willbe life-changing for our cohort as students will have experienced the critical importance of modern cancerresearch to saving the lives of individuals a perspective that will inspire them to pursue cancer research careersand sustain them during their advanced training years. 318317 +No NIH Category available Address;Adrenal Glands;Aggressive course;Area;Behavior;Biological;Biological Models;Biology;CDK4 gene;Catecholamines;Cells;Clinical;Clinical Management;Clinical Trials;Data;Detection;Development;Diagnosis;Disease;Drug Screening;Early Diagnosis;Epithelium;Experimental Designs;Experimental Models;Future;Genetic;Human;Individual;Investigation;Knowledge;Low Prevalence;Malignant - descriptor;Malignant Neoplasms;Malignant Paraganglionic Neoplasm;Malignant Pheochromocytoma;Metastatic Pheochromocytoma;Methods;Modeling;Molecular;Morphologic artifacts;Neoplasm Metastasis;Nervous System;Neural Crest;Neuroendocrine Tumors;Organoids;Outcome;Paraganglia structure;Paraganglioma;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pheochromocytoma;Population;Primary Neoplasm;Property;Recurrence;Research;Resources;Survival Rate;Testing;Therapeutic;Tumor Biology;Tumor Markers;anticancer research;chemotherapy;clinical application;clinical heterogeneity;clinical predictors;design;drug candidate;drug sensitivity;effective therapy;high-throughput drug screening;improved;insight;molecular marker;neuroendocrine cancer;novel;novel therapeutics;pluripotency;predict clinical outcome;predictive marker;targeted agent;therapeutic evaluation;therapeutic target;transcriptome;tumor;tumor behavior;tumor initiation;tumor progression;whole genome Addressing biological and therapeutic gaps in rare neuroendocrine cancer with a novel organoid-based model To address PQ9: What methods can be developed to effectively study small or rare populations relevant tocancer research we will develop organoids of rare neuroendocrine tumors pheochromocytomas andparagangliomas (PPGL). Currently there are no markers of clinical behavior and malignant PPGLs can only berecognized after metastases develop for which there are few treatment options. PPGL organoids will enableinvestigation of tumor markers of outcome and drug screen to identify potential new therapies. NCI 10693929 7/27/23 0:00 RFA-CA-20-004 5R01CA264248-03 5 R01 CA 264248 3 "LI, JERRY" 9/8/21 0:00 8/31/26 0:00 ZCA1-RPRB-N(M2)R 8773354 "DAHIA, PATRICIA LEAL" "SORAGNI, ALICE " 20 INTERNAL MEDICINE/MEDICINE 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 483461 NCI 401961 81500 This proposal responds to the provocative question PQ9: What methods can be developed to effectivelystudy small or rare populations relevant to cancer research? We will address this question by generatingorganoid models of pheochromocytomas and paragangliomas (PPGL) to fill gaps in the mechanisms underlyingtumor behavior and in therapeutic opportunities. PPGLs are rare catecholamine-secreting neural crest-derivedtumors originating from adrenal or extra adrenal paraganglia respectively. Malignant PPGLs can only berecognized after detection of metastases implying a late diagnosis. Approximately 30-40% of paragangliomasand 10-15% of pheochromocytomas can develop metastases. In addition PPGLs are clinically heterogeneouscan be recurrent and invasive even without metastasis but predictors of clinical behavior are lacking. Treatmentoptions are currently limited with modest effects on survival and advances in this area are dampened by ascarcity of research models. Therefore there is a critical need for developing models to uncover biologicalmechanisms that facilitate clinical outcome prediction and reveal molecular vulnerabilities which can be exploredfor therapeutic purposes. Our preliminary data indicate that we can successfully generate PPGL organoids thatare amenable for drug screen. Our aims are: 1) to determine if PPGL organoids recapitulate features of theparental tumor; 2) to leverage PPGL organoids to investigate outstanding biological questions including theexistence of cell subtypes that may be related to tumor outcome and 3) to utilize PPGL organoids for high-throughput drug screening that uncover vulnerabilities for future therapeutic testing including novel leadssuggested in our preliminary data. The proposed project will serve as a useful resource for designing futurestudies to decode the cellular and molecular mechanisms underlying PPGL development and clinicalheterogeneity. Results from these studies may provide the groundwork for future testing of candidate drugs thatmight have immediate clinical application. 483461 +No NIH Category available Acute;Adenocarcinoma Cell;Biological Models;Cells;ChIP-seq;Clustered Regularly Interspaced Short Palindromic Repeats;Exhibits;Genes;Glean;Goals;Human;Immune;In Vitro;Libraries;Lung Adenocarcinoma;Lymphoma;MYC gene;Malignant Neoplasms;Methods;Modeling;Molecular;Oncogenes;Pathway interactions;Primary carcinoma of the liver cells;Productivity;RNA;Renal Cell Carcinoma;Reporter;Research;Research Personnel;Research Proposals;Role;Seminal;System;T-Lymphocyte;Tetracyclines;Transgenic Mice;Work;anticancer research;bcr-abl Fusion Proteins;cancer therapy;carcinogenesis;in vivo;innovation;insight;leukemia;lipid biosynthesis;metabolomics;mouse model;new technology;new therapeutic target;novel;novel therapeutics;nucleocytoplasmic transport;osteosarcoma;patient derived xenograft model;programs;transcriptome sequencing;tumor;tumorigenesis Targeting the MYC Pathway for the Treatment of Cancer Project NarrativeWe propose to determine how MYC initiates and maintains tumorigenesis. We have generated a library ofconditional transgenic mouse models for MYC-driven cancer and human PDX models that we will use to identifynovel vulnerabilities in MYC-driven cancers through RNAseq ChIPseq and DESI-MSI CRISPR synthetic lethalscreens and MYC function reporter systems. Our collaborative research proposal will identify novel therapeutictargets for MYC driven cancer. NCI 10693915 8/25/23 0:00 PAR-19-349 5R35CA253180-04 5 R35 CA 253180 4 "GHOSH-JANJIGIAN, SHARMISTHA" 9/8/20 0:00 8/31/27 0:00 ZCA1-GRB-S(M1) 1889454 "FELSHER, DEAN W" Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 945225 NCI 587999 357228 AbstractMYC is the most commonly activated oncogene in human cancer. However to date no existing therapiesdirectly target MYC or the MYC pathway. My goal is now to target the MYC oncogene pathway to treat humancancer. Over the last 20 years I have gained fundamental new insights into how the MYC oncogene initiatesand maintains tumorigenesis. My work has established the idea that MYC is a hallmark of cancer and that manycancers are MYC oncogene addicted. I have identified both tumor intrinsic and host-immune dependentmechanisms. Now I will use these insights from lab and novel methods to develop new therapies for cancer. Iwas one of the first investigators to use the Tetracycline regulatory system (Tet system) to generate conditionaltransgenic mouse models to demonstrate that MYC-induced cancer is reversible or oncogene addicted(Felsher and Bishop Molecular Cell 1999). Since then I have used the Tet system to make a library ofoncogene driven transgenic mouse models (MYC RAS BCR-ABL) of T-cell acute lymphoma (T-ALL) leukemia(AML) osteosarcoma (OS) hepatocellular carcinoma (HCC) lung adenocarcinoma (LAC) and renal celladenocarcinoma (RCC). I have used my conditional transgenic mouse model systems to not only understandhow MYC and other oncogenes initiate and maintain tumorigenesis but also develop innovative methods andnovel technologies to make seminal contributions in cancer research exhibiting sustained productivity. Myproposed future research is built on recent observations that have used combined RNA ChIP and metabolomicanalysis to identify that lipogenesis and CRISPR synthetic lethal screen to identify nuclear transport as examplesof otherwise not known to be MYC-regulated gene pathways that when targeted can block and reverse MYC-driven cancer. Now I propose to use my library of conditional transgenic mouse models and human PDX modelsto generally identify targetable genes and pathways in the MYC oncogene pathway. I will use threecomplimentary approaches: RNAseq ChIPseq and DESI-MSI to identify novel vulnerabilities in MYC-drivencancers; CRISPR in vitro and in vivo synthetic lethal screens combined with CyTOF and CODEX analysis toidentify targets in my MYC-driven tumor models and understand their mechanistic role in tumorigenesis; MYCfunction reporter systems to be able to screen for genes and therapies to target MYC-driven cancers. Myproposed research program has extensive support from an interdisciplinary team of colleagues. My proposedstudies will glean novel mechanistic insights for how MYC drives tumorigenesis and use these insights to developnew therapeutic targets. 945225 +No NIH Category available Address;Affect;Aliquot;Androgen Receptor;Antiemetics;Atlases;Biological Assay;Biological Factors;Biological Markers;Biopsy Specimen;Blood;Cancer Patient;Cell Count;Cellular Assay;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Data;Data Analyses;Detection;Diagnosis;Disease;Early Diagnosis;Evaluation;Fasting;Foundations;Frequencies;Funding;Gene Frequency;Goals;Institutional Review Boards;Knowledge;Malignant Neoplasms;Malignant neoplasm of prostate;Memorial Sloan-Kettering Cancer Center;Methods;Molecular;Molecular Profiling;Monitor;Mutation;Mutation Detection;Neoplasm Circulating Cells;Noise;Nuclear;Patients;Performance;Pilot Projects;Plasma;Point Mutation;Procedures;Prognosis;Protocols documentation;Receptor Signaling;Relapse;Reporting;Reproducibility;Research;Resistance;Sampling;Science;Signal Transduction;Specificity;Steroids;Temperature;Testing;Time;Tube;Variant;Work;abiraterone;blood-based biomarker;cancer cell;castration resistant prostate cancer;cell free DNA;chemotherapy;clinical implementation;clinical practice;cohort;contextual factors;design;detection limit;genetic variant;implementation facilitation;individual patient;inhibitor;innovation;liquid biopsy;member;practice setting;predictive marker;preservation;response;taxane;tumor Evaluation of the effect of patient-context factors and sample acquisition on the quality and analytical performance of cell-free DNA and circulating tumor cells profiling assays in prostate cancer pa NarrativeAnalytes such as cell-free DNA (cfDNA) and circulating tumor cells (CTC) exist in very low proportion in liquidbiopsy specimens and therefore analyses of these samples are potentially heavily influenced by pre-analyticalfactors associated with acquisition and processing. We propose to expand our foundation-funded pilot study toevaluate effects of sample processing protocols on cfDNA and CTC analysis to further investigate effect of thepatient-specific context. Results will inform the design of liquid biopsy-incorporated clinical trials by identifyingoptimal timing of blood collection to minimize effects of pre-analytical variables and will be used to facilitateimplementation of liquid biopsy testing in a clinical setting. NCI 10693910 9/6/23 0:00 PAR-18-947 5U01CA253217-04 5 U01 CA 253217 4 "AGRAWAL, LOKESH" 9/8/20 0:00 8/31/25 0:00 ZCA1-RPRB-8(M2) 10923897 "ARCILA, MARIA E" "SCHER, HOWARD I" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 396790 NCI 224175 172615 SummaryThe analysis of liquid biopsy (eg cell-free DNA [cfDNA]; circulating tumor cells [CTC]) in blood is increasinglyintegrated in clinical contexts including diagnosis disease monitoring understanding resistance and earlydetection of relapse. The key challenge of detecting these analytes is that they are present at a very lowproportion of the biospecimens and therefore are heavily influenced by pre-analytical factors associated withacquisition and processing. Understanding effects of these pre-analytical variables on the quality of datagenerated in downstream molecular CTC and cfDNA assays is critical for robust clinical implementation ofliquid biopsy tests. To date research efforts have focused on effects of preservation methods processing timestorage temp and shipment conditions on quality of CTC and cfDNA in blood plasma. There are no studiesreported on effects of patient-specific context such as fasting administration of anti-emetics or biospecimenacquisition procedures (eg order of blood collection aliquots time of day when blood is drawn etc.) There is alack of data on this type of pre-analytical variable that impacts design of clinical trials such as optimal timing forblood draw and interpretation of data to distinguish technical variables introduced by these pre-analyticalfactors from the biological signals being evaluated. We propose to address this gap by extending the workdone by our team members on evaluating effects of sample processing protocols on cfDNA and CTC analysisto further investigate effect of patient-specific context. Hypothesis: Pre-analytic variables may affect signal-to-noise ratio in cfDNA and CTC analysis and thus have a higher impact on quantification at levels close to theassay limit of detection. Aim 1: Determine the effect of patient-specific context on the quality of cell-free DNA(cfDNA) and circulating tumor cells (CTC) in prostate cancer patients. Aim 2: Evaluate the impact of thesevariables on the performance of downstream cfDNA and CTC molecular profiling assays. We will apply anadaptive design in which we perform initial analysis with 20 patients per cohort then adjust as needed. In afoundation-funded pilot study we focused on one cohort to study effect of draw order. Results confirm thevariability of biomarkers quantification as a result of pre-analytical variables.Significance: Results will elucidate effects of multiple pre-analytical variables specific to individual patientcontext on performance of blood-based biomarker analysis in cfDNA and CTC. These data will inform thedesign of liquid biopsy-incorporated clinical trials by identifying optimal timing of blood collection to minimizeeffects of pre-analytical variables. Innovation: This will be the first study to examine the effect of patient-specific context on quality of liquid biopsy data. We will collaborate closely with commercial liquid biopsy testdevelopers as part of the Blood Profiling Atlas in Cancer (BloodPAC) project with the goal of sharingknowledge across different sectors and working toward harmonization of pre-analytical procedures for liquidbiopsy testing. 396790 +No NIH Category available Address;Adherence;Adult;Behavior Therapy;Behavioral;Biological Markers;Cancer Control;Cancer Patient;Clinical Trials;Cytokine Gene;Data;Development Plans;Diagnosis;Education;Elderly;Exercise;Fatigue;Feedback;Gene Expression;Genes;Goals;Grant;Home;Individual;Inflammatory;Interleukin-1 beta;Interleukin-6;Interleukin-8;Interruption;Intervention;Intervention Studies;Interview;Malignant Neoplasms;Measures;Mentors;Methylation;Mobile Health Application;Moods;Myeloproliferative disease;Oncologist;Oncology;Outpatients;Pathway interactions;Patient Outcomes Assessments;Patients;Phase;Physical Capacity;Physical Function;Physical Performance;Physical activity;Placebos;Positioning Attribute;Printing;Quality of life;Randomized Controlled Trials;Research;Research Personnel;Research Priority;Scientist;Self Efficacy;Serum;Solid Neoplasm;Symptoms;TNF gene;TNFR-Fc fusion protein;TNFRSF1A gene;Training;Translational Research;Treatment Efficacy;Universities;Walking;affective disturbance;aged;arm;cancer therapy;career development;chemotherapy;clinical practice;comorbidity;cytokine;design;epigenetic regulation;exercise adherence;exercise intervention;exercise physiologist;exercise prescription;exercise program;experience;improved;intervention effect;mHealth;mobile application;novel;older patient;phase I trial;post intervention;prevent;promoter;protein expression;public health relevance;resistance exercise;skill acquisition;standard of care;symptomatic improvement;usability A novel mobile health exercise intervention for older patients with myeloid neoplasms PROJECT NARRATIVE (PUBLIC HEALTH RELEVANCE)Up to 98% of older patients with myeloid neoplasms experience physical function decline fatigue and mooddisturbances. Mobile health exercise interventions are promising strategy to prevent physical function declineand improve fatigue and mood disturbances but older patients with myeloid neoplasms receivinghypomethylating agents are understudied. The proposed studies will help to develop a novel mobile healthexercise intervention that is adapted to older patients with myeloid neoplasms receiving outpatienthypomethylating agents and to investigate whether and how exercise can prevent physical function declineimprove fatigue and mood disturbances and prevent worsening quality of life. NCI 10693908 9/13/23 0:00 PA-19-129 5R00CA237744-05 5 R00 CA 237744 5 "PERNA, FRANK" 9/16/19 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 15434101 "LOH, KAH POH " Not Applicable 25 INTERNAL MEDICINE/MEDICINE 41294109 F27KDXZMF9Y8 41294109 F27KDXZMF9Y8 US 43.131774 -77.63546 7047101 UNIVERSITY OF ROCHESTER ROCHESTER NY SCHOOL OF MEDICINE & DENTISTRY 146113847 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 161688 87312 PROJECT SUMMARYOverview: Over 60% of myeloid neoplasms (MN) are diagnosed in adults aged 60 years and up to 98% ofthese patients [including those receiving hypomethylating agents (HMA)] experience physical function declineand symptoms (e.g. fatigue mood disturbances) leading to poor quality of life (QoL). Exercise may preventphysical function decline and improve symptoms in older patients with MN. Older patients with MN canexercise safely but adherence may be a challenge. Mobile health (mHealth) application (app) may improveadherence by enhancing exercise self-efficacy and by helping to address barriers to exercise. Inflammatorydysregulation [specifically tumor necrosis factor (TNF) and related cytokines] is associated with physicalfunction decline fatigue and mood disturbances. In this K99/R00 we propose to develop adapt and evaluatea novel mHealth exercise intervention for preventing physical function decline improving symptoms andpreventing worsening QoL in older patients with MN receiving outpatient HMA and to explore the effect of theintervention on TNF and related cytokine gene promoter methylation and their gene and protein expression.Career Development Plan: Dr. Loh is an emerging geriatric oncologist and has begun to study mHealth andcancer control. To become an independent clinician scientist conducting mHealth behavioral interventionresearch for older patients with MN Dr. Loh needs training to (1) develop and adapt mHealth behavioralinterventions for older patients with cancer (2) acquire skills to become an independent investigator who candesign conduct and analyze clinical trials (3) develop expertise in biomarkers of physical function. Dr. Loh'smentoring team has expertise in geriatric and exercise oncology behavioral intervention research mHealthand translational science. The University of Rochester is world-class for geriatric oncology and cancer control.Research Plan: The proposed mHealth exercise intervention (GO-EXCAP Mobile App) integrates the contentof an established exercise program (EXCAP) with a mobile app delivery platform (TouchStream). EXCAP is ahome-based progressive walking and resistance exercise program. The TouchStream mobile app tracksexercise data symptoms and barriers to exercise adherence and the exercise physiologist can adjustexercise prescriptions and address barriers to exercise. In K99 we will first develop and adapt the GO-EXCAPMobile App by obtaining feedback from 10 patients with MN receiving HMA. Second we will conduct a single-arm phase 1 trial to optimize the GO-EXCAP Mobile App in 25 patients. In R00 (phase 2 randomized controlledtrial) we will assess the preliminary efficacy of the GO-EXCAP Mobile App versus a chemotherapy educationcontrol (behavioral placebo) on physical function and patient-reported outcomes (fatigue mood and QoL) in100 patients. We will also explore the effect of the intervention on TNF and related cytokine pathways.Impact: The combined training and research plan will position Dr. Loh to become one of the few geriatriconcology investigators studying mHealth interventions and to allow her to transition to independence. 249000 +No NIH Category available Achievement;Affect;Area;Award;Biodistribution;Biological Markers;Brain;Cachexia;Cancer Detection;Cell membrane;Clinical;Cytotoxic T-Lymphocytes;Development;Dextrans;Ensure;FDA approved;Fibroblasts;Focal Adhesion Kinase 1;Functional Imaging;Glycolates;Granulocyte-Macrophage Colony-Stimulating Factor;Healthcare;Heart;Human;Image;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunosuppression;Infrastructure;Intercellular Fluid;Invaded;Liver;Malignant Neoplasms;Metabolic;Morbidity - disease rate;Mus;Muscle;Near-infrared optical imaging;Neoplasm Metastasis;Oncologist;Organ;Pancreatic Ductal Adenocarcinoma;Pathologist;Pathway interactions;Patients;Positron-Emission Tomography;Research;Surgeon;Symptoms;Syndrome;T cell infiltration;Technology;Translational Research;Xenograft Model;antibody conjugate;biomaterial compatibility;cancer cachexia;cancer cell;cancer infiltrating T cells;cancer therapy;effector T cell;fibroblast activation protein alpha;imaging probe;improved outcome;inhibitor;mechanotransduction;molecular imaging;multimodality;nanoparticle;near infrared dye;personalized medicine;photoimmunotherapy;pre-clinical;radiologist;response;siRNA delivery;theranostics;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor xenograft Molecular Imaging and Theranostics of Cancer The purpose of this R35 application is to expand the understanding of cancer through the applications ofmolecular and functional imaging. The three interactive research areas of focus are the tumormicroenvironment the tumor macroenvironment and theranostics that capitalize on our strong infrastructure totake our achievements into new directions in these three focus areas. These new directions will addresscritical questions in cancer invasion and metastasis cancer-induced cachexia and the development oftheranostic agents for siRNA delivery photoimmunotherapy and the development of cancer cell membranecoated nanoparticles to increase effector T cell infiltration in tumors. NCI 10693873 8/14/23 0:00 PAR-16-411 5R35CA209960-07 5 R35 CA 209960 7 "WANG, YISONG" 9/4/17 0:00 8/31/24 0:00 ZCA1-GRB-I(M2) 1878950 "BHUJWALLA, ZAVER M." Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 962412 NCI 587733 374679 Achieving cancer cure or even control continues to be a major unanswered challenge in health care despitethe remarkable technological advances of the 21st century. Advances in multi-modal noninvasive molecularand functional imaging are providing unique opportunities to expand our understanding of cancer anunderstanding that is critical to developing effective and cancer specific treatments. In this resubmission Ihave chosen three interactive focus areas within the tumor microenvironment (TME) the tumormacroenvironment (TMacE) and Theranostics that will be pursued in triple negative breast cancer (TNBC)and pancreatic ductal adenocarcinoma (PDAC) human tumor xenografts and syngeneic tumors in immunecompetent mice. In the TME focus we will use imaging to expand our understanding of the focal adhesionkinase (FAK) mechanotransduction pathway in the metastatic cascade that will include developing PETimaging probes to detect FAK noninvasively. FAK also plays a role in tumor immune suppression. In theTMacE focus we will expand our efforts in understanding PDAC induced cachexia that results in a wide rangeof symptoms affecting the function of organs such as muscle liver brain and heart causing significantmorbidity. The tumor secretome holds the key to this syndrome by influencing the `macroenvironment'. Wewill focus on characterizing the tumor interstitial fluid (TIF) in preclinical PDAC xenograft models to developbiomarkers of cachexia and identify potential metabolic targets that will be pursued through the Theranosticfocus. In the Theranostic focus we will direct our efforts and expertise in imaging and NP technology toimprove the outcome of checkpoint inhibitors in TNBC and PDAC. Lack of effector T-cell tumor infiltration hasbeen identified as a major cause of the poor response to these inhibitors. We will use FDA approvedpoly(lactic-co-glycolic acid) PLGA to create cancer cell membrane (CCM) coated `immunosome' NPsembedded with granulocyte macrophage colony-stimulating factor (GM-CSF) to increase effector T cell tumorinfiltration and apply molecular imaging to detect the biodistribution of the NPs and the changes in T cellinfiltration. Ultimately we want to use the patients own cancer cells to synthesize the NPs for personalizedmedicine. Since FAP- expressing cancer associated fibroblasts (CAFs) are known to create an immunesuppressive TME we will use anti-FAP- antibody conjugated to the near infrared (NIR) dye IR700 to detectCAFS with NIR imaging and eliminate them selectively in the tumor with PIT. If PIT of FAP- expressing CAFsresults in increased cytotoxic T cells in tumors this may have significant applications in combination withcheckpoint inhibitor treatment. We will use siRNA delivery with dextran based biocompatible NPs todownregulate FAK and metabolic targets identified in the TMacE focus. I have built a strong network ofcollaborators that include clinical oncologists radiologists pathologists and surgeons that will ensure the rapidtranslation of the research conducted through the R35 award to benefit cancer detection and treatment. 962412 +No NIH Category available Accountability;Address;Age;Cancer Center;Cancer Control;Cancer Control Research;Cancer Survivor;Caring;Certification;Characteristics;Clinical;Collaborations;Colorado;Communication;Communities;Community Practice;Cost Analysis;Costs and Benefits;Data;Death Rate;Development;Diagnosis;Dissemination and Implementation;E-learning;Evidence based practice;Evidence based program;Family;Future;Guidelines;Health Status;Healthcare;Infrastructure;Intervention;Laboratories;Malignant Neoplasms;Measures;Mentors;Methods;Modeling;Outcome;Patients;Population;Practical Robust Implementation and Sustainability Model;Primary Care;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Reporting;Research;Research Personnel;Resources;Rural;Surveys;Testing;Translating;Translational Research;Work;cancer prevention;career;certificate program;community engagement;comorbidity;contextual factors;cost;design;dissemination science;flexibility;health care availability;health care service;implementation measures;implementation science;implementation study;innovation;interest;lung cancer screening;member;mortality;outreach;pilot test;practice-based research network;pragmatic implementation;preference;primary care practice;primary care setting;programs;psychological distress;rural area;shared decision making;skills;smoking cessation;urban area;user-friendly Pragmatic Implementation Science Approaches to Assess and Enhance Value of Cancer Prevention and Control in Rural Primary Care n/a NCI 10693851 8/24/23 0:00 RFA-CA-19-005 5P50CA244688-05 5 P50 CA 244688 5 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7389 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 138852 108481 30371 Summary/Abstract Implementation LaboratoryThe theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. +No NIH Category available Address;Affect;Area;Cancer Control;Cancer Control Research;Certification;Characteristics;Collaborations;Colorado;Communication;Cost Analysis;Costs and Benefits;Data;Development;Evidence based program;Failure;Feedback;Future;Goals;Health system;Healthcare;Human Papilloma Virus Vaccination;Infrastructure;Intervention;Laboratories;Learning;Maintenance;Measures;Mentors;Methods;Modeling;Outcome;Patients;Pilot Projects;Population;Practical Robust Implementation and Sustainability Model;Prevention program;Primary Care;Procedures;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Research;Research Personnel;Resources;Risk Factors;Rural;Sampling;Science;Smoking Cessation Intervention;Societies;Surveys;Testing;Time;Translations;Work;cancer prevention;cancer risk;career;certificate program;contextual factors;cost;design;human centered design;implementation science;implementation strategy;implementation study;innovation;lung cancer screening;outreach;patient oriented;pilot test;pragmatic implementation;preference;primary care practice;primary care setting;programs;research to practice;rural area;rural health clinic;screening program;shared decision making;smoking cessation Pragmatic Implementation Science Approaches to Assess and Enhance Value of Cancer Prevention and Control in Rural Primary Care n/a NCI 10693848 8/24/23 0:00 RFA-CA-19-005 5P50CA244688-05 5 P50 CA 244688 5 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7388 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 379900 260662 119238 Project Summary/Abstract Research ProgramThe theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. +No NIH Category available Adherence;Adult;Advisory Committees;Arizona;Budgets;Cancer Center;Cancer Control;Certification;Characteristics;Child;Clinical;Collaborations;Colorado;Communication;Communities;Competence;Cost Analysis;Data;Development;Educational workshop;Ensure;Environment;Evaluation;Evidence based program;Expenditure;Funding;Goals;Health;Human Resources;Infrastructure;Institutional Review Boards;Interruption;Intervention;Leadership;Measures;Mentors;Methods;Mission;Modeling;Monitor;NCI-Designated Cancer Center;New Mexico;Outcome;Outcomes Research;Patients;Policies;Population;Population Sciences;Practical Robust Implementation and Sustainability Model;Primary Care;Printing;Program Development;Progress Reports;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Research;Research Methodology;Research Personnel;Resources;Rural;Safety;Science;Series;Strategic Planning;Structure;Surveys;Testing;Universities;Utah;cancer prevention;career;certificate program;contextual factors;cost;expectation;human subject;implementation science;implementation study;innovation;interest;lung cancer screening;meetings;member;organizational structure;outreach;pilot test;pragmatic implementation;preference;pressure;primary care setting;programs;research and development;rural area;shared decision making;smoking cessation;success;timeline;underserved area Pragmatic Implementation Science Approaches to Assess and Enhance Value of Cancer Prevention and Control in Rural Primary Care n/a NCI 10693844 8/24/23 0:00 RFA-CA-19-005 5P50CA244688-05 5 P50 CA 244688 5 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7387 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 Unavailable 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO Domestic Higher Education 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 238700 162541 76159 Project Summary/Abstract Administrative CoreThe theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. +No NIH Category available Acute;Address;Affect;Cancer Center;Cancer Control;Certification;Characteristics;Clinical;Collaborations;Colorado;Communication;Communities;Competence;Cost Analysis;Costs and Benefits;Data;Development;Dissemination and Implementation;Evidence based program;Guidelines;Human Papilloma Virus Vaccination;Infrastructure;Intervention;Laboratories;Maintenance;Malignant Neoplasms;Measures;Mentors;Methods;Modeling;Outcome;Patients;Pilot Projects;Population;Practical Robust Implementation and Sustainability Model;Prevention program;Primary Care;Provider;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Research;Research Personnel;Resources;Risk Factors;Rural;Rural Community;Sampling;Site;Standardization;Surveys;Testing;Training;Translating;Update;Work;cancer prevention;cancer risk;cancer therapy;career;certificate program;contextual factors;cost;design;evidence base;implementation framework;implementation measures;implementation research;implementation science;implementation study;innovation;intervention program;lung cancer screening;outreach;patient oriented;pilot test;practical application;practice setting;pragmatic implementation;preference;primary care practice;primary care setting;programs;rural area;rural health clinic;rural setting;screening program;shared decision making;smoking cessation;tool Pragmatic Implementation Science Approaches to Assess and Enhance Value of Cancer Prevention and Control in Rural Primary Care Project Narrative - OverallWe propose an Implementation Science Center for Cancer Control with a focus of developing validating andsharing innovative pragmatic models and methods related to the costs benefits and value of translatingevidence-based cancer control programs and guidelines into rural primary care practice settings. Our theme is`Pragmatic implementation science approaches to assess and enhance the value of cancer prevention andcontrol in rural primary care.' These approaches will inform strategies to implement lung cancer screening andother cancer prevention and control interventions and advance implementation science by providing measuresreporting guides resources training and certification of competence. NCI 10693843 8/24/23 0:00 RFA-CA-19-005 5P50CA244688-05 5 P50 CA 244688 5 "VANDERPOOL, ROBIN CLINE" 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(A1) 1862445 "GLASGOW, RUSSELL E" Not Applicable 6 FAMILY MEDICINE 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 757452 NCI 531684 225768 Project Summary/Abstract OverallThe theme of our proposed Implementation Science Center is Pragmatic implementation science approachesto assess and enhance the value of cancer prevention and control in rural primary care. We will apply andadvance frameworks pragmatic methods and measures related to cost benefits and value that are rigorousbut also generalizable across rural primary care settings that are often struggling with low resources and ahigh need population. These models and methods will be used to guide selection and implementation ofevidence-based programs for cancer prevention and control (CPC). We will initially focus on lung cancerscreening in rural primary care settings first in Colorado and then nationally through collaboration with a well-established primary care network (i.e. National Research Network).Our overarching framework will be our enhanced RE-AIM/PRISM model which is an extension of the broadlyused Reach Effectiveness Adoption Implementation and Maintenance framework with the addition ofcontextual factors (e.g. Intervention characteristics implementation and sustainability infrastructure). It willserve as the basis to develop and test innovative assessments of costs benefits and value from theperspective of different stakeholders to understand and guide implementation. We will meaningfully engagewith and include the perspectives of patients providers and staff stakeholders in all our studies. Our pilotImplementation Study will adapt implement and evaluate strategies using stakeholder-engaged approachesto value to guide the implementation of shared decision-making and smoking cessation related to lung cancerscreening.Our Methods Unit will refine and evaluate our pragmatic cost assessment methods to determineimplementation/replication costs from the perspective(s) of patients providers and delivery staff and thendevelop and pilot test brief survey measures of preferences regarding the relative benefit of different RE-AIMoutcomes. We will then assess relationships among RE-AIM outcomes preferences and selection of differentCPC programs. Finally our Outreach and Network Unit will engage in a) outreach activities targeted at juniorand mid-career investigators and practitioners including online professional development (e.g. graduatecertificate program micro-certification) and tailored mentoring and technical assistance approaches; b)dissemination activities to support the packaging and communication of research findings; and c)collaboration activities to facilitate partnerships on CPC and implementation science using multiple channelsand including development of shared pragmatic D&I measures and data. 757452 +No NIH Category available Address;Adopted;Advertisements;Age;Area;Arousal;Attention;Award;Behavior;Behavioral;Characteristics;Cognitive;Communication;Comparative Study;Control Groups;Data;Decision Making;Desire for food;Development;Education;Electroencephalography;Electronic cigarette;Emotional;Enrollment;Frequencies;Future;Goals;Individual Differences;Intention;Lead;Learning;Market Research;Marketing;Measures;Mediating;Mentors;Mentorship;Methodology;Methods;Modeling;Neurocognitive;Neurosciences;Nicotine;Perception;Phase;Policy Maker;Policy Making;Predisposition;Price;Public Health;Randomized;Reaction;Regulation;Research;Research Design;Research Methodology;Sampling Studies;Science;Shapes;Technology;Tobacco;Tobacco Control Research;Tobacco use;Training;Vulnerable Populations;Work;Youth;behavior influence;biobehavior;career;cigarette advertising;cigarette smoking;combustible tobacco;comparative;design;electronic cigarette use;experimental study;gaze;group intervention;improved;innovation;multidisciplinary;prevent;research study;response;sample fixation;theories;tobacco advertising;tobacco control;tobacco products;tobacco regulatory science;tobacco user;toxicant;uptake;virtual;visual tracking;young adult Understanding the Influence of E-cigarette Advertisement Features Project NarrativeE-cigarette use produces toxicants is addictive and is associated with future use of combustible tobaccoamong young adults. This project will address significant gaps in our understanding of the influence of ecigarette advertisement features on young adults neuro-cognitive reactions as well as the perceptions and intentions of using e-cigarettes. It will also provide timely scientific evidence to inform tobacco regulatory decision-making in the areas of e-cigarette marketing influences and behavior. NCI 10693832 8/18/23 0:00 RFA-OD-18-008 5R00CA242589-04 5 R00 CA 242589 4 "BLAKE, KELLY D" 9/1/18 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-RPHB-N(58)R] 15655946 "CHEN-SANKEY, JULIA CEN" Not Applicable 10 PUBLIC HEALTH & PREV MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 77 Non-SBIR/STTR 2023 244641 OD 158599 90401 Modified Project Summary/Abstract SectionProject SummaryYoung adults initiation and use of e-cigarettes are on the rise in the U.S. E-cigarette use produces toxicants is addictive and is associated with future use of combustible tobacco products among young adults. The situation is compounded by aggressive e-cigarette marketing which often features flavors models marketing claims and price promotions. Evidence has shown the strong influence of tobacco marketing on the initiation and use of tobacco products among young adults especially young adults who are nave to tobacco. Thus a timely public health response comprising more regulation on e-cigarette marketing is needed to prevent and reduce e-cigarette uptake among this group. Although e-cigarette marketing has been pervasive and is rapidly growing studies to examine the influence of e-cigarette advertisement features on young adults reactions have been virtually nonexistent. The proposed project will examine the influence of four e-cigarette advertisement features (flavors models marketing claims and price promotions) among young adult non- tobacco users who are susceptible to e-cigarette use. This study will pursue three Specific Aims: (1) Identify key features of e-cigarette advertisements that lead to greater attention. (2) Examine the associations between key features of e-cigarette advertisements and positive neurocognitive responses. (3) Determine whether edited advertisements without key features lead to reduced positive e-cigarette perceptions and behavioral intentions compared to original advertisements. Study on Aim 1 (K99 Phase) will use eye-tracking technology with a between-subject design among 70 young adults. Study on Aim 2 (R00 Phase) will apply electroencephalogram (EEG) technology with a fractional factorial study design among 120 young adults. Study on Aim 3 (R00 Phase) will adopt a comparative randomized experiment among 900 nationally representative young adults enrolled in an online panel. Individual differences in neuro-cognitive reactions and e-cigarette related perceptions and behavioral intentions will also be assessed throughout the three studies. The proposed studies will innovatively use neuroscience technologies to objectively measure young adults neuro-cognitive reactions to e-cigarette advertisements. It will be guided by a new conceptual framework comprising the communication model of the Limited Capacity Model of Mediated Message Processing. This proposal will enable me to expand my training in tobacco control regulatory science neuroscience-based experiments and tobacco marketing and counter-marketing research under the mentorship of a multidisciplinary team of experts in tobacco control and provide critical preliminary data to launch my independent research career. This research is directly relevant to the development of FDAs policymaking and educational efforts to reduce the impact of e-cigarette advertisements on young adults potential uptake of e-cigarettes. 244641 +No NIH Category available Address;Anus;Cells;Cervical;Chest;Clinical;Cutaneous;Disease;Genetically Engineered Mouse;Goals;HIV;Head and Neck Cancer;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Individual;Laboratories;Learning;Malignant Neoplasms;Malignant neoplasm of anus;Modeling;Molecular;Mus;Mutation;Neoplasms;Papillomavirus;Pathogenesis;Patients;Population;Prevalence;Prevention;Preventive vaccine;Radiation;Reagent;Research;Risk;United States;cancer therapy;carcinogenesis;chemotherapeutic agent;high risk;insight;new therapeutic target;novel strategies;patient derived xenograft model;response;targeted treatment;tool;vaccine access Defining Drivers of HPV-associated Carcinogenesis NARRATIVEHuman papillomaviruses cause 5% of all human cancers. HIV-infected individuals are at increased risk ofdeveloping these cancers. Over the past 2+ decades we have developed laboratory models to study thesecancers. Using insights gained from those studies and recent advances in identifying genetic changes thatarise in these cancers we propose studies to identify new approaches to treat these cancers. NCI 10693827 7/17/23 0:00 PAR-16-411 5R35CA210807-07 5 R35 CA 210807 7 "READ-CONNOLE, ELIZABETH LEE" 8/1/17 0:00 7/31/24 0:00 ZCA1-GRB-I(M2) 1942923 "LAMBERT, PAUL F." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 908100 NCI 600000 318000 ABSTRACTHuman papillomavirus (HPV)-associated cancers represent 5% of all human cancers and are among the mostcommon malignancies arising in the HIV-infected population. While highly effective prophylactic vaccines areavailable their utilization in the United States remains low. Meanwhile HPV-associated cancers particularlyanal cancer are increasing in their prevalence here in the US especially among the HIV-infected population.Treatment of these cancers relies upon decades old approaches using radiation and traditionalchemotherapeutic agents. In many cases these treatments are not curative with limited options for effectivesecond or third line treatments. The goal of our research is to define the factors that drive HPV-associatedcarcinogenesis with the ultimate goal to define ways to better treat patients with these cancers. This isparticularly of concern to the HIV-infected population who are at increasing risk of developing these cancers.We have assembled a tool chest of unique model reagents with which to address this goal including geneticallyengineered mouse (GEM) models as well as patient derived xenografts (PDXs) and associated cell strainsfrom patients with anal cervical and head/neck cancers. We have expanded our experimental tool chest toinclude MmuPV1 a mouse papillomavirus that models high-risk cutaneous HPVs in both its pathogenesis andmolecular activities. Using these models we will explore new therapeutic targets for the prevention and/ortreatment of HPV-associated disease/cancers. Of particular relevance to HIV-associated neoplasia we willuse PDX models for anal cancer to compare responses to targeted therapies between cancers arising in HIV-infected versus uninfected patients to learn if there are differences of potential clinical importance. Theproposed studies build upon insights we have gained over the past 2+ decades studying our GEM and PDXmodels for HPV-associated cancers. 908100 +No NIH Category available Address;Adjuvant Therapy;Advanced Malignant Neoplasm;Affect;African American population;Caring;Cessation of life;Clinical;Clinical Trials Design;Continuity of Patient Care;Data;Development;Disease;Disparity;Division of Cancer Control and Population Sciences;Enrollment;Equity;Excess Mortality;Goals;Head and Neck Cancer;Head and Neck Surgery;Health system;Interpersonal Relations;Intervention;Intervention Studies;Interview;Knowledge;Lead;Measures;Mentors;Modeling;Operative Surgical Procedures;Outcome;Patients;Patterns of Care;Pilot Projects;Population;Positioning Attribute;Postoperative Period;Process;Provider;Qualitative Research;Racial Equity;Radiation;Radiation therapy;Randomized;Randomized Controlled Trials;Research;Scientist;Self Efficacy;Site;Surgeon;Testing;Training;Treatment-related toxicity;Work;acceptability and feasibility;arm;cancer care;cancer health disparity;cancer surgery;cancer type;care coordination;care delivery;caucasian American;chemotherapy;clinical care;disparity reduction;effective intervention;efficacy evaluation;head and neck cancer patient;health disparity;implementation research;improved;informant;mortality;mortality disparity;multimodality;novel;patient navigation;patient population;pilot test;prevent;primary outcome;programs;racial difference;racial disparity;satisfaction;screening;social health determinants;systems research;theories;therapeutic target;treatment as usual Improving the Timeliness and Equity of Adjuvant Therapy Following Surgery for Head and Neck Cancer PROJECT NARRATIVEHead and neck cancer is a disease with poor survival especially for African Americans despite intense treatmentincluding surgery radiation and chemotherapy. Delays between surgery and the start of postoperative radiationtherapy are common cause excess mortality and contribute to worse survival in African Americans. Ourresearch team has identified a promising approach to minimize delays starting radiation after head and neckcancer surgery that could provide the first effective intervention to improve timely equitable care in this patientpopulation thereby improving survival for patients with head and neck cancer decreasing racial disparities inmortality and developing new standards of clinical care.1 NCI 10693818 7/31/23 0:00 PA-19-116 5K08CA237858-05 5 K08 CA 237858 5 "RADAEV, SERGEY" 9/11/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 14865589 "GRABOYES, EVAN MICHAEL" Not Applicable 6 OTOLARYNGOLOGY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 266549 NCI 246805 19744 PROJECT SUMMARY/ABSTRACTThe goal of this K08 proposal is to provide the candidate with a framework to develop a comprehensive researchprogram as a surgeon scientist investigating multi-level theory-based interventions to improve the timelinessequity and quality of head and neck cancer (HNC) care delivery. HNC is a disease with poor survival despiteintense therapy with surgery radiation and chemotherapy. HNC is also a disease with significant racialdisparities in mortality; African Americans (AAs) have a 51% relative decrease in survival compared to whites.Delays starting postoperative radiation therapy (PORT) after HNC surgery are a key driver of high mortality andracial disparities in survival and thus an appealing therapeutic target to address both issues. Delayed non-guideline-adherent PORT initiation affects 56% of HNC patients is 31% more common in AAs associated withan 11% absolute decrease in 5-year survival and a key contributor to racial differences in mortality. Althoughdelivering timely PORT is of critical importance to prevent excess mortality and racial disparities in survivaleffective interventions to improve the rate of timely equitable PORT are lacking in part due to the gap in ourunderstanding of the relevant barriers in this population. In this proposal the candidate will develop pilot-testand evaluate the preliminary clinical impact of NDURE (Navigation for Disparities and Untimely RadiationthErapy) a novel theory-based PN intervention to improve timely equitable PORT in HNC patients. Theresearch objective is to evaluate the preliminary clinical impact of NDURE on delays and racial disparities startingPORT among HNC patients. The central hypothesis is that NDURE will decrease PORT delays and racialdisparities in delay by improving care coordination self-efficacy interpersonal support and knowledge. SpecificAim 1 will identify the multi-level barriers that contribute to delays starting PORT after HNC surgery through keyinformant interviews with HNC patients and providers. Specific Aim 2 will assess the feasibility and acceptabilityof NDURE in a single-arm pilot study. Specific Aim 3 will test NDURE in a pilot randomized controlled trial (RCT)to evaluate its preliminary clinical impact on delays starting PORT among white and AA HNC patients. Ultimatelythis research will have a large scientific impact by enhancing our conceptual understanding of timely equitablemultimodal HNC care delivery. It will have a significant clinical impact through the development of a scalable andpractical intervention to decrease delays and racial disparities starting PORT thereby improving survival for HNCpatients and decreasing racial disparities in mortality. The training objective is to address the candidatesscientific gaps in cancer health disparities qualitative research health systems and interventions research andclinical trial design and analysis through mentored scientific training integrated and aligned with his research.Completion of the research and scientific training will position the candidate well to lead research investigatingmulti-level theory-based interventions to improve the timeliness equity and quality of HNC care delivery. 266549 +No NIH Category available Ablation;Acute;Address;Adult;Aftercare;Alzheimer's Disease;Anaphylatoxins;Animals;Apoptotic;Astrocytes;Behavior assessment;Biopsy;Brain;Brain Injuries;Brain Neoplasms;C5a anaphylatoxin receptor;Cancer Survivor;Cells;Childhood;Chronic;Clinical;Clinical Management;Cognition;Cognitive;Cognitive deficits;Complement;Complement 1q;Complement 3a;Complement 5a;Complement Activation;Complex;Cranial Irradiation;Data Set;Development;Dose;Epilepsy;Foundations;Gene Expression;Genes;Genetic;Glioma;Gliosis;Hour;Human;Hypertrophy;Immune signaling;Immunocompetent;Impaired cognition;Impairment;Inflammation;Intervention;Link;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of central nervous system;Mediating;Mediator;Medical;Metastatic malignant neoplasm to brain;Microglia;Molecular;Mus;Nerve Degeneration;Neurobiology;Oral;Outcome Study;Oxidative Stress;Patients;Play;Production;Prognosis;Proteins;Quality of life;Radiation;Radiation therapy;Receptor Inhibition;Reporting;Rodent Model;Role;Signal Transduction;Synapses;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Tissues;Transgenic Organisms;antagonist;astrogliosis;blood-brain barrier permeabilization;brain dysfunction;cancer invasiveness;cancer therapy;clinically relevant;cognitive function;complement 1q receptor;complement system;cytokine;design;effectiveness testing;glial activation;improved;knock-down;link protein;mouse model;neurogenesis;neuroinflammation;neuroprotection;neurotransmission;novel;pharmacologic;receptor;response;restoration;standard of care;stem cell proliferation;synaptic pruning;temozolomide;therapy design;treatment response;tumor;tumorigenic Glial immune signaling in radiation-induced brain injury PROJECT NARRATIVERadiation therapy for the clinical management of brain tumors and metastases is linked with severe cognitivedecline and neuroinflammation in cancer survivors. We hypothesize that radiation-induced aberrant activation ofthe glial complement cascade play a causal role in development of cognitive impairments. This proposal willaddress glial complement activation mechanism and translationally feasible intervention to curtain this unmetmedical need. NCI 10693817 7/20/23 0:00 PAR-19-325 5R01CA251110-03 5 R01 CA 251110 3 "PRASANNA, PAT G" 9/1/21 0:00 8/31/26 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11925590 "ACHARYA, MUNJAL M" Not Applicable 47 RADIATION-DIAGNOSTIC/ONCOLOGY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 430193 NCI 275777 154416 ABSTRACT: Glial immune signaling in radiation-induced brain injury.Cranial radiation therapy (CRT) for the treatment of CNS cancers often leads to unintended anddebilitating cognitive impairments. CRT also remains the standard of care to counter brainmetastases for other invasive cancers. However the molecular and cellular mechanismsunderlying CRT-induced cognitive decline are multifaceted and have not been completelyresolved. Our past findings show that whole-brain acute CRT induces progressiveneurodegenerative changes including oxidative stress reduced neurogenesis and increasedneuroinflammation. Microglia and astrocytes form complex glial networks in the CNS by pruningand maintaining thousands of synapses that are actively involved in cognition. Yet we haveshown that CRT-induced cognitive disruption coincides with astrocytic hypertrophy elevatedexpression of astrogliosis genes and persistent microglial activation in rodent models. Thereforewe hypothesize that detrimental glial signaling significantly contributes to cognitive deficits. Thecomplement system is a potent mediator of the glial activation but it also has a range of non-immune functions in the CNS including synaptic pruning and clearance of apoptotic cells andcellular debris which is detrimental if dysregulated. Particularly global elevation in the expressionof complement C1q and C3 in the CNS has been reported in neurodegenerative conditions. Ourfindings indicate that acute whole-brain CRT-mediated chronic microglial activation and reactiveastrocytes elevated co-expression of complement proteins (C1q C3) and specific receptors(C5aR1 TLR4) coincided with cognitive impairments. Reactive gliosis has been shown toupregulate complement cascade proteins that are destructive to synapses and associated withneurodegeneration. We hypothesize that brain cancer therapy-induced aberrant activation in theglial complement cascade leads to cognitive deficits. Our hypothesis is supported by two keypreliminary data sets targeting complement signaling at the upstream (C1q) and the downstream(C5a) activation branch points. First exposure of conditional microglia-selective C1q (knockdown)mice to CRT did not exhibit impaired cognition and showed a lack of neuroinflammation ascompared to irradiated WT mice. Second treatment with an orally active BBB permeable C5areceptor (C5aR1) antagonist ameliorated acute CRT-induced cognitive deficits and alleviatedmicroglial activation in the irradiated brain. Our hypothesis will be addressed using a clinicallyrelevant fractionated focal cranial irradiation paradigm temozolomide transgenic and glioma-bearing syngeneic mouse models and pharmacologic approaches designed to test mechanismsand therapeutic interventions to restore cognitive function in the impaired animals. 430193 +No NIH Category available Academia;Advisory Committees;Award;Clinic;Clinical;Clinical Trials;Comprehensive Cancer Center;Doctor of Medicine;Doctor of Philosophy;Funding;Future;Hematology;Infrastructure;Institution;Instruction;Leadership;Lymphoma;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mayo Clinic Cancer Center;Mentors;Methods;National Cancer Institute;National Clinical Trials Network;Oncology;Positioning Attribute;Principal Investigator;Program Development;Publications;Records;Research;Research Personnel;Specialized Program of Research Excellence;System;Time;Training;Training Programs;Translational Research;Woman;Work;anticancer research;career;career development;cohort;experience;hepatobiliary cancer;improved;innovation;malignant breast neoplasm;multidisciplinary;neuro-oncology;next generation;novel therapeutics;patient oriented research;programs;translational cancer research Paul Calabresi Program in Clinical/Translational Research at Mayo Clinic The Mayo Clinic Cancer Center seeks to renew its well-established career development program entitled ThePaul Calabresi Program in Clinical/Translational Research at the Mayo Clinic requesting 5 positions to trainthe next generation of investigators who will learn to conduct patient-oriented cutting edge hypothesis-drivenpractice-changing cancer research. NCI 10693805 9/8/23 0:00 PAR-19-242 5K12CA090628-23 5 K12 CA 90628 23 "DAMICO, MARK W" 9/25/01 0:00 6/30/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1871209 "JATOI, AMINAH " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 674416 NCI 750000 60000 "The Mayo Clinic Cancer Center (MCCC) is poised to provide an exceptional career development experiencefor clinician investigators and other translational cancer researchers who seek to establish a career in patient-oriented research. The MCCC is a National Cancer Institute (NCI)-designated comprehensive cancer centerwith 45+ years of continuous funding; it sits at the epicenter of high-quality practice-changing research. Itsfunding portfolio has remained highly competitive with respect to the acquisition of R01 and R01-equivalentfunding over the past 10 years; includes 3 Specialized Programs of Research Excellence (""SPORE's"") incancer of hepatobiliary system breast cancer and lymphomas (the latter is a 2-institution shared SPORE);and remains an active contributor to the NCIs National Clinical Trials Networks (NCTNs) including theAlliance for Clinical Trials in Oncology. In this application the MCCC seeks to renew the ""Paul CalabresiProgram in Clinical/Translational Research at Mayo Clinic"" requesting 5 career development positions at anyone time for a dual track M.D. or Ph.D. career development program. The MCCC has been privileged to holdthis award since 2001. To date this cohort of 40+ scholars remains engaged in translational cancer research;includes many who hold leadership positions in academia and other venues; and over the years hascumulatively amassed 3000+ publications during and after their scholar tenure. In this application scholarsmust focus on 1 of 5 research tracks that align with translational MCCC Programs: GastrointestinalMalignancies Hematology Neuro-Oncology Novel Therapeutics or Women's Cancers. Multidisciplinarymentoring teams will work with each scholar as he/she embarks upon a tailored career development programof didactic instruction hands-on patient-oriented research and a path toward career independence.Administrative infrastructure consists of a principal investigator who has been committed to this trainingprogram since its inception and an internal advisory committee comprised of accomplished leaders/mentorswithin the MCCC and expertise in training a diverse academic work force in cancer research. Marking almost20 years of this programs existence this application now strives to examine ways to integrate innovativemethods to further improve on the successful track records of future scholars. In essence the MCCC seeks totrain the next generation of investigators who will conduct cutting edge hypothesis-driven practice-changingcancer research." 674416 +No NIH Category available 5' Untranslated Regions;Adenosine;Autophagocytosis;Biological Assay;Carbon;Catalytic Domain;Cell Adhesion;Cell Proliferation;Cell Survival;Chemicals;Complex;DHFR gene;DNA Methylation;Data;Deposition;Development;Enzymes;FRAP1 gene;Folic Acid;Folic Acid Antagonists;Genes;Glioma;Growth;Growth Factor;Initiator Codon;Knowledge;Link;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Messenger RNA;Metabolic;Metabolic Pathway;Metabolism;Methionine;Methylation;Modification;Nephroblastoma;Nucleotides;Oncogenes;Oncogenic;Oxidation-Reduction;Pathway interactions;Phosphorylation;Process;Proliferating;Proteins;Proteome;RNA;RNA Helicase;RNA Splicing;RNA methylation;RNA-Binding Proteins;RNA-targeting therapy;Regulation;Resolution;Ribosomes;S-Adenosylhomocysteine;S-Adenosylmethionine;Scanning;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Sodium Chloride;Structure;Technology;Transcript;Transferase;Translations;Tumor Suppressor Proteins;c-myc Genes;cancer biomarkers;cancer cell;cancer survival;cancer therapy;cell growth;differential expression;enzyme activity;epitranscriptome;intermolecular interaction;leukemia;mTOR Signaling Pathway;mTOR inhibition;mTOR protein;malignant breast neoplasm;metabolome;nucleotide metabolism;phosphoproteomics;protein expression;targeted agent;transcriptome;transcriptome sequencing;transcriptomics;tumor;tumor growth;tumor progression;tumorigenesis Elucidating the regulation of RNA methylation by mTOR signaling in cancer PROJECT NARRATIVETumors rewire chemical modifications on RNA (epitranscriptome) to promote cell proliferation and survival.This project will define how the growth factor and mTOR signaling modulates N6-adenosine methylation onmRNA in cancer. Successful completion of this proposal will provide a rationale for the characterization of newcancer biomarkers and therapeutics targeting RNA methylation downstream of oncogenic signaling pathways. NCI 10693796 8/8/23 0:00 PAR-18-467 5K22CA234399-02 5 K22 CA 234399 2 "JAKOWLEW, SONIA B" 9/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11673570 "LEE, GINA " Not Applicable 47 MICROBIOLOGY/IMMUN/VIROLOGY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 257826 NCI 238728 19098 PROJECT SUMMARY/ABSTRACTOver the past decade our knowledge of RNA chemical modifications such as N6-adenosine methylation (m6A)on mRNAs has increased due to the development of transcriptome-wide sequencing technologies and severalassays to detect RNA modifications. Emerging evidence shows that alteration of m6A modification on mRNAsencoding oncogenes and tumor suppressors is linked to cancer development and progression includingleukemia glioma breast and lung cancers. These RNA modifications are processed by several RNA bindingproteins such as RNA methyl transferases and demethylases. The expression and activities of these enzymesare likely to be modulated by upstream signaling pathways during tumorigenesis however our understandingof how signal transduction pathway controls these enzymes and the consequent RNA modifications is stillrudimentary. Through phosphoproteomic and transcriptomic analysis of the mTOR signaling pathway I haveidentified links between the mTOR signaling and enzymes that regulate m6A RNA methylation. My workinghypothesis which is supported by preliminary data is that mTOR pathway by regulating the expression andactivities of m6A methyl transferase complex controls mRNA metabolism. More importantly my data suggestthat this mTOR-m6A signaling regulates the expression of enzymes involved in one-carbon metabolism ametabolic pathway required for high proliferation rate and survival of cancer cells. The proposed experimentalstrategies will reveal how mTOR signaling controls expression of oncogenes and tumor suppressors throughRNA methylation and its connection to one-carbon metabolism in cancer. Successful completion of thisproposal will provide a rationale for the characterization of new cancer biomarkers and therapeutics targetingRNA methylation process downstream of oncogenic signaling pathways. 257826 +Cancer; Prevention Biological;Clinical;Clinical Chemoprevention;Clinical Research;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs CANCER PREVENTION AGENT DEVELOPMENT PROGRAM: EARLY PHASE CLINICAL RESEARCH n/a NCI 10693789 261201200035I-P00004-759101900130-1 N01 9/23/19 0:00 9/22/23 0:00 16187672 "KHAN, SEEMA " Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N R and D Contracts 2022 384492 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 384492 +Bioengineering; Cancer; Cancer Genomics; Data Science; Genetics; Human Genome; Networking and Information Technology R&D (NITRD); Precision Medicine Area;Awareness;Bioinformatics;Computer software;Data;Development Plans;Diagnosis;Elements;Feedback;Infrastructure;Malignant Neoplasms;Performance;Prevention;Production;Resources;Schedule;Secure;Security;Services;Small Business Innovation Research Grant;System;Systems Development;Testing;analytical tool;anticancer research;bioinformatics pipeline;bioinformatics tool;cloud based;cost;data access;data management;data resource;design;genomic platform;improved;outreach;precision oncology;prototype;tool;usability TOPIC 407 TITLE: CLOUD-BASED SOFTWARE FOR THE CANCER RESEARCH DATA COMMONSPROJECT TITLE: COLLABORATE IN THE CLOUD TO ENABLE PRECISION ONCOLOGY n/a NCI 10693651 75N91022C00052-0-9999-1 N44 9/15/22 0:00 9/14/24 0:00 78834681 "DAVE, UTPAL " Not Applicable 14 Unavailable 80170203 FVBLJMZQLB67 80170203 FVBLJMZQLB67 US 41.717711 -88.195674 10041448 "NAVIPOINT GENOMICS, LLC" NAPERVILLE IL Domestic For-Profits 605648473 UNITED STATES N R and D Contracts 2022 1679321 NCI Precision oncology offers great potential in improving cancer-related diagnosis and treatment. The Navipoint Platform provides state of the art tools pipelines and cloud-based resources which will be extended and integrated with CRDC data and resources in order to enable Collaborate in the Cloud capabilities to help realize this promise. The product of this SBIR will be a production-grade system enabling streamlined and secure integration between Navipoint and CRDC. The proposed approach includes the following: To develop leverage and disseminate analytical tools in the Navipoint bioinformatics analysis platform seamlessly integrate with and fully leverage CRDC resources leverage scalable cloud-based infrastructure and cost-aware scheduling in order to help drive new cancer discoveries for improved prevention diagnosis and treatment. And to perform a usability study with a cross-section of users to confirm and enhance system capabilities and to conduct outreach and support to maximize benefits of utilizing CRDC resources in concert with Navipoint Genomics platform capabilities. 1679321 +Bioengineering; Biotechnology; Cancer; Digestive Diseases; Esophageal Cancer; Orphan Drug; Rare Diseases Adenocarcinoma Cell;Animals;Cancerous;Catheters;Cause of Death;Chronic;Device Designs;Drug Delivery Systems;Drug Exposure;Drug toxicity;Drug usage;Elements;Eligibility Determination;Esophageal Tissue;Esophagus;Family suidae;Goals;Heating;Human;Intravenous;Irrigation;Malignant Neoplasms;Malignant neoplasm of esophagus;Patients;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Squamous cell carcinoma;Survival Rate;System;Testing;United States;biomaterial compatibility;comparative;cost;design;design verification;first-in-human;gastrointestinal;human study;metastatic esophageal;systemic toxicity;tumor PHASE I -TOPIC 431 - DRUG DELIVERY BY ENDOESOPHAGEAL LAVAGE (EEL) TO TREAT ESOPHAGEAL CANCER n/a NCI 10693518 75N91022C00018-0-9999-1 N43 9/15/22 0:00 9/14/23 0:00 78834669 "BRIAN, CRAIG " Not Applicable 5 Unavailable 116996412 M3QDM72NME75 116996412 M3QDM72NME75 US 44.922937 -93.318008 10054313 ISOLA THERAPUETICS MINNEAPOLIS MN Domestic For-Profits 55410 UNITED STATES N R and D Contracts 2022 400000 NCI Cancer is the second leading cause of death in the United States and esophageal cancer has the 6th lowest survival rate for all cancers. Systemic drug therapy is first-line therapy for widely metastatic esophageal cancer but is limited by systemic toxicity patient eligibility or cost. The proprietary Isola system consists of a drug delivery catheter tubing heating element and a drug lavage solution. A proof-of concept animal study demonstrated that Isola can deliver drug directly to esophageal tissue while minimizing drug in plasma by using balloons to isolate the esophagus from the gastrointestinal track when a drug solution is delivered in the lumen of the esophagus. The goal of is to treat cancerous tumors (adenocarcinoma and squamous cell carcinoma) in the esophagus while minimizing systemic drug exposure and toxicity. The objective of this proposal is to advance activities to eventually complete a first in human (FIH) study using the Isola drug delivery system by a) finalizing the drug delivery system design and selecting the ideal drug for delivery b) completing device design verification and biocompatibility testing to use drug delivery system in humans and c) conducting comparative chronic animal studies to compare Isola drug delivery to standard intravenous drug delivery. 400000 +No NIH Category available 3-Dimensional;Address;Anatomy;Architecture;Biological;Biological Markers;Breast;Clinical;Clinical Research;Code;Contrast Media;Crystallography;Dehydration;Disease;Disease Progression;Ensure;Environment;Evolution;Exhibits;Hour;Image;Imaging Device;Laboratories;Laboratory Research;Legal patent;Length;Malignant Bone Neoplasm;Malignant Neoplasms;Maps;Measurement;Measures;Methods;Molecular;Molecular Analysis;Molecular Structure;Morphology;Multimodal Imaging;PET/CT scan;Pathology;Pathway interactions;Performance;Play;Preparation;Property;Protocols documentation;Research Personnel;Resolution;Roentgen Rays;Role;Rotation;Sampling;Scanning;Source;Specificity;Specimen;Stains;Structure;Surface;Synchrotrons;System;Techniques;Technology;Testing;Thick;Three-Dimensional Imaging;Tissues;Work;X ray diffraction analysis;X-Ray Medical Imaging;anticancer research;bone;bone imaging;cancer biomarkers;cell type;design;high resolution imaging;imaging biomarker;imaging modality;imaging software;innovation;insight;malignant breast neoplasm;meter;microCT;millimeter;multimodality;performance tests;prototype;radiological imaging;reconstruction;single photon emission computed tomography;soft tissue;tissue preparation;tomography;tool;transmission process;tumor;user-friendly Multimodality X-ray transmission and diffraction scanner for molecular analysis of cancer specimens RELEVANCE This project will provide a first-of-its-kind X-ray transmission/diffraction scanner for non-destructive analysis of cancer biospecimens which could enable pathways for new clinical studies exploring the role of XRD in tissue abnormalities eventually leading to a better understanding of the genesis and evolution of cancer. NCI 10693406 4/20/23 0:00 RFA-CA-20-018 5R33CA256102-03 5 R33 CA 256102 3 "OSSANDON, MIGUEL" 5/1/21 0:00 4/30/24 0:00 ZCA1-TCRB-J(O1) 12261679 "GREENBERG, JOEL " Not Applicable 4 Unavailable 81178326 J8EKVLUY96J9 81178326 J8EKVLUY96J9 US 35.974737 -78.992606 10064644 "QUADRIDOX, INC." DURHAM NC Domestic For-Profits 277057322 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 394 Non-SBIR/STTR 2023 262875 NCI 223179 39696 ABSTRACT Cancer research using biospecimens requires the analysis of samples with a large range of sizes (sub-mm to cm) and molecular composition over a wide range of length scales. In many cases 3-dimensional spatial information about the specimen is critical to understanding and addressing the progression of the disease. X-ray imaging has been widely recognized to play a key role in tissue analysis and cancer assessment. While transmission X-ray imaging (radiography or CT) has been used successfully in some applications wherein sample morphology is highly correlated with the disease state it lacks molecular specificity which limits its general utility in specimen analysis. Many groups have demonstrated the utility of X-ray diffraction (XRD) in analyzing molecular structure in biospecimens; however none have successfully implemented a viable method of fast and accurate 3D XRD measurement in a laboratory environment. The key challenges associated with realizing such a system include the fact that high accuracy XRD measurements have typically required access to a synchrotron or another specialized source which is difficult for the average researcher to access. In contrast conventional laboratory diffraction methods are slow require destruction or alteration of the specimens and exhibit poor or no volumetric spatial information. To overcome these challenges we propose to develop a new radiographic imaging device that can scan the entire volume of a biospecimen and generate co-registered multi-modal X-ray transmission and XRD images. Such technology would allow researchers to study molecular properties of tissue specimens with high spatial resolution and high specificity using a tool that is compact robust and easily accessible in an average research laboratory. The samples would be analyzed without contrast agents and with little to no sample preparation required. Through previous work we have built tested and demonstrated the underlying technology required for combined transmission and diffraction imaging of biospecimens. We will now build a clinically accessible high-resolution prototype of the scanner test and validate its performance and demonstrate its utility in imaging bone and breast cancer biospecimens. This project will provide a first-of-its-kind X-ray transmission/diffraction scanner for non-destructive analysis of cancer biospecimens which could enable pathways for new clinical studies exploring the role of XRD in tissue abnormalities eventually leading to a better understanding of the genesis and evolution of cancer. 262875 +No NIH Category available Adult;Age;Aging;Alveolar;Alveolar Cell;Cancer Etiology;Cell Aging;Cell model;Cells;Cessation of life;Cholesterol;Chromatin;Colorectal Cancer;Data;Disease;Distal;Epigenetic Process;Epithelial Cells;Functional disorder;Gene Expression;Genes;Genetically Engineered Mouse;Growth;Homeostasis;Human;Image;Impairment;Intervention;Link;Lipids;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lung diseases;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Malignant neoplasm of prostate;Maps;Mass Spectrum Analysis;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methyltransferase;Modeling;Modification;Molecular;Mus;Natural regeneration;Organoids;Pathway interactions;Persons;Population;Predisposition;Process;Pulmonary alveolar structure;Regulation;Reporting;Resolution;Respiratory physiology;Risk Factors;Role;Smoking;Source;Steroids;Study models;System;Technology;Testing;age effect;aged;alveolar epithelium;alveolar type II cell;cancer initiation;cell age;experience;in vivo Model;injury and repair;insight;lung cancer cell;lung development;lung injury;malignant breast neoplasm;mass spectrometric imaging;metabolome;metabolomics;molecular modeling;mortality;mouse model;novel;prevent;progenitor;self renewing cell;single cell sequencing;stem cell biology;stem cell function;stem cells;synergism;tumor;tumor initiation;tumor metabolism;tumor progression;tumorigenesis Progenitor cell states contributing to aging and lung cancer Progenitor cell states contributing to aging and lung cancerNarrativeAging is a primary risk factor for lung cancer which accounts for the largest cause of cancer deaths. Cells inthe lung alveoli are the source of the most common lung cancers and slowly become less functional as they age.We will use new models to investigate how molecular changes in alveolar cells contribute to cancer initiationduring aging. NCI 10693386 8/4/23 0:00 RFA-CA-20-040 5U01CA267827-03 5 U01 CA 267827 3 "KLAUZINSKA, MALGORZATA" 9/24/21 0:00 8/31/26 0:00 ZCA1-SRB-T(O1) 9078088 "HAIGIS, MARCIA " "KIM, CARLA F." 7 ANATOMY/CELL BIOLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 388396 NCI 318515 69881 Progenitor cell states contributing to aging and lung cancerAbstractLung cancer is the single largest contributor to global cancer mortality. With the exception of smoking age is thesingle biggest risk factor for all major lung diseases including cancer highlighting the role of age-associatedchanges in the lung for mortality. Metabolic changes and epigenetic alterations are both hallmarks of aging butlittle is known about how aging specifically impacts the lung and in particular lung progenitor cells. Furthermorethe synergy between metabolism and epigenetic states is emerging as an exciting new field for which implicationsin disease including cancer are only beginning to be explored. Preliminary data we have collected suggest thatboth metabolic and epigenetic changes accompany aging in lung alveolar type II (AT2) cells the primary cell-of-origin of the most common form of lung cancer lung adenocarcinoma. Our study will test the hypothesis thatalterations in metabolic pathways driven by epigenetic changes in AT2 cells contribute to increased tumorinitiation during aging. Firstly we will map metabolic and epigenetic changes in aged AT2 cells using state of theart technologies that will enable resolution of these differences onto highly select populations and even singlecells. Furthermore we will create new models to study the effects of aging in cancer. New organoid models oflung cancer initiation will be developed to support rapid modeling of the cellular and molecular aspects of cancerin aged cells. Genetically engineered mouse models will be derived to model tumorigenesis in the aging lung.Finally we will probe the specific mechanism by which loss of epigenetic modifications mediated by themethyltransferase G9a during aging contributes to increased tumor initiation through dysregulation of metabolicgenes and the metabolome. These studies will combine the strengths of two experienced PIs with expertise inaging metabolism stem cell biology and cancer to generate new models of lung cancer and provide significantinsight into the synergy of two major hallmarks of aging in the most-deadly form of cancer. 388396 +No NIH Category available Abnormal Cell;Address;Animals;Antitumor Response;Bacterial Toxins;Binding;Brain;Canis familiaris;Catheters;Clinical Protocols;Complement;Convection;Cyclophosphamide;Cytotoxic agent;Cytotoxin;Development;Disease Management;Disease model;Dose;Dose Limiting;Drug Delivery Systems;Drug Monitoring;EPHA3 gene;Engineering;Environment;EphA2 Receptor;EphB2 Receptor;Ephrins;Excision;Glioblastoma;Glioma;Good Manufacturing Process;Grant;Growth;Heterogeneity;Human;IL13RA1 gene;IgG1;Immune response;Immune system;Immunologics;Infiltration;Infusion procedures;Interleukin-13;Interleukin-13 Overexpression;Investigational Drugs;Ligands;Magnetic Resonance Imaging;Medicine;Molecular;Molecular Target;Monitor;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase I Clinical Trials;Play;Primary Brain Neoplasms;Progression-Free Survivals;Property;Recurrence;Reflux;Research;Resistance;Role;Safety;Site;System;Testing;Therapeutic;Therapeutic Agents;Time;Toxic effect;Tumor-associated macrophages;Variant;assault;brain parenchyma;catalyst;cell killing;cell transformation;cytotoxic;design;drug action;drug candidate;drug distribution;exhaustion;first-in-human;good laboratory practice;human disease;human model;immunogenic cell death;improved;in situ vaccination;mutant;neoplastic cell;neovasculature;novel;overexpression;pre-Investigational New Drug meeting;pre-clinical;real time monitoring;receptor;response;safety and feasibility;scaffold;stem-like cell;therapy resistant;translational model;tumor;tumor heterogeneity;tumor microenvironment;tumor progression Multi-receptor Targeting of Glioblastoma NarrativeGlioblastoma (GBM) is an incurable primary brain tumor of high heterogeneity. This heterogeneity is one of themajor obstacles to GBM treatment. To this end we identified four molecular targets that are over-expressedcollectively in all patients with GBM but not normal brain. This is a unique development and we generatedcytotoxic drug conjugates targeting these receptors simultaneously with an increased access to tumors toproduce effective molecular resection with long-lasting anti-tumor response. In addition we will also inflamethese immunologically cold tumors with a targeted conjugate so they can mount more effective immuneresponses to complement the direct killing action of the cytotoxins. This approach has a great potential ofsignificantly improving the management of the disease. NCI 10693378 8/28/23 0:00 PAR-18-560 5R01CA256285-03 5 R01 CA 256285 3 "UNDALE, ANITA H" 9/15/21 0:00 8/31/26 0:00 Clinical Oncology Study Section[CONC] 1861015 "DEBINSKI, WALDEMAR " Not Applicable 5 BIOLOGY 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 615701 NCI 459467 156234 Treatment of glioblastoma (GBM) represents an unmet need in medicine. We have been pursuing atherapeutic approach of delivering potent targeted and specific cytotoxins using convection-enhanced delivery(CED). We and others found that patients with GBM over-express interleukin 13 receptor alpha 2 (IL-13RA2)EphA2 EphA3 and EphB2 receptors. These receptors are present in various pathophysiological compartmentsof GBM and all four are expressed in tumor cells of the core of tumor and in locally-infiltrating tumor cells whileEphA2 is also found in tumor neovasculature. Further IL-13RA2 EphA2 and EphA3 are associated with andplay crucial roles in the pathobiology of glioma stem-like cells (GSC). Finally the EphA3 receptor can bereadily detected in M2 tumor-associated macrophages (TMA). Thus collectively IL-13RA2 EphA2 EphA3and EphB2 are over-expressed in principal GBM compartments shown to be involved in tumor progressionand/or resistance to therapies. One of the Eph receptor ligands ephrinA5 (eA5) binds EphA2 EphA3 andEphB2 receptors. In the current project we will pursue the novel idea of targeting all four receptors with onepharmaceutical compound delivered using monitored and effective CED. We have already engineered anagent based on eA5 and IL-13 mutants targeting all four receptors using an IgG1 scaffold and conjugated it to amodified bacterial toxin to form QUAD 3.0-PE38QQR. The conjugate is safe and effective in GBM tumors. Wewill continue this exciting line of research through three Specific Aims. In Specific Aim 1 we will evaluateQUAD 3.0-PE38QQR distribution safety and anti-tumor activity in treating canine high-grade gliomas whichrepresents the closest model of human disease. In Specific Aim 2 we will develop QUAD 3.0-PE38QQR forfirst-in-human Phase I clinical trial in patients with recurrent GBM. We will make QUAD 3.0-PE38QQR underGood Manufacturing Practices (GMP) conditions. The QUAD-CTX will undergo pre-clinical animal studiesbased on pre-IND discussions with the FDA. Studies will be performed under Good Laboratory Practices (GLP)conditions in order to obtain an Investigational New Drug (IND). In the third Specific Aim we will performPhase I clinical trial with QUAD 3.0-PE38QQR in patients with recurrent GBM. The focus will be on obtainingoptimal volume of distribution of the CED-administered drug its safety initial efficacy and evidence of inducingimmune responses. Thus with one therapeutic agent and improved delivery system we will beeliminating tumor cells and abnormal cells of the tumor microenvironment promoting its growth. Thisapproach also addresses crucial issues of inter- and intra-tumoral heterogeneity and is also expected to evokean in situ vaccination or so called tumor inflaming effect. We envision that this all-out assault termed by usmolecular resection will result in a more effective management of GBM. 615701 +No NIH Category available Address;Area;Behavioral Sciences;Biometry;Breast;Breast Cancer Risk Factor;Cancer Center;Cancer Control;Clinical;Clinical Research;Clinical Trials;Collaborations;Collection;Communities;Community Developments;Conduct Clinical Trials;Continuity of Patient Care;Coupled;Data;Disease;Disparity;Early Diagnosis;Educational Materials;Eligibility Determination;Enrollment;Epidemiology;Equity;Etiology;Evaluation;Exclusion;Exclusion Criteria;Experimental Designs;Future;General Hospitals;Goals;Health;Healthcare;Incidence;Information Dissemination;Infrastructure;Institution;Intervention;Intervention Trial;Investigator-Initiated Research;Learning;Link;Logic;Longitudinal cohort;Lung;Malignant Neoplasms;Mentorship;Methods;Minority Access;Mission;Modeling;Observational Study;Oncology;Outcome;Palliative Care;Participant;Pathology;Patient Recruitments;Patient-Focused Outcomes;Patients;Population Research;Population Sciences;Prevention;Public Hospitals;Recording of previous events;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Risk;Risk Assessment;Risk Factors;Science;Screening for cancer;Self Management;Supportive care;Tennessee;Therapeutic Clinical Trial;Time;Training;Trust;Underserved Population;Universities;Woman;Work;anticancer research;base;behavioral health;cancer care;cancer diagnosis;cancer health disparity;cancer subtypes;cancer therapy;care delivery;clinical infrastructure;clinical training;cohort;community engaged research;community engagement;comorbidity;control trial;design;doctoral student;education research;ethnic minority;improved;inclusion criteria;lung cancer screening;malignant breast neoplasm;medical schools;metropolitan;mortality;neoplasm registry;outreach;patient population;population based;pre-doctoral;prospective;racial minority;recruit;research study;safety net;success;survivorship;tobacco control;trial design Core 1: PRACTICE Shared Resource Core n/a NCI 10693370 9/7/23 0:00 PAR-18-767 5U54CA163072-14 5 U54 CA 163072 14 9/21/11 0:00 8/31/26 0:00 ZCA1-SRB-2 7324 1891854 "FRIEDMAN, DEBRA L" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 340367 196744 143623 PROJECT SUMMARY: PRACTICE SHARED RESOURCE COREThe proposed Population Research And Clinical Trials In Cancer Equity (PRACTICE) Shared Resource Corewill build upon the infrastructure of the existing Clinical Trials Core (CTC) that has provided support to theMeharry/Vanderbilt-Ingram Cancer Center/Tennessee State Cancer Partnership (MVTCP) since itsinception. While the CTC has been instrumental in bringing clinical trials to the patient base at NashvilleGeneral Hospital (NGH) at Meharry Medical College (MMC) to more completely address cancer healthdisparities we must augment these efforts with studies in prevention early detection treatmentsurvivorship and palliative care in the Nashville Metropolitan Statistical Area (MSA) served by ourPartnership. We propose to establish the PRACTICE Shared Resource Core to further benefit the NGHpatient base promote investigator-initiated research and extend the Partnership's reach to the underservedin the Nashville MSA. The MVTCP has great strength in population sciences research that will enhance theexisting strength in clinical research. Examples include studies led by MMC Tennessee State Universityand Vanderbilt-Ingram Cancer Center (VICC) investigators working with statewide cancer registries to recruitfor etiologic studies of breast cancer lung cancer screening trials for early detection a tobacco control trial inthe underserved enhancing participant recruitment to cancer research and collection of biospecimens incollaboration with the Cancer Outreach Core and Translational Pathology Shared Resource Core. There is arich history of conducting therapeutic clinical trials with interactions between the Clinical Trials Office (CTO) atVICC and the CTO at NGH. The overarching mission of the PRACTICE Shared Resource Core is to enhanceaccrual to therapeutic clinical trials while expanding access for minority and underserved patients to researchstudies across the cancer care continuum. The PRACTICE Core worked extensively with Lucy Spalluto MDin the genesis of her proposed project examining the implementation of breast cancer risk assessment inunderserved women. We will assist with implementation of this study and dissemination of the results. Our Corewill also support other clinical and population-based science research across the cancer care continuumillustrated in three thematic domains focused on decreasing cancer health disparities: prevention and earlydetection; interventional trials and observational studies during and following treatment; implementation ofhealthcare interventions to improve cancer care delivery. The PRACTICE Core will address the following aims:1) expand the portfolio of therapeutic clinical trials and cancer control studies relevant to the patient base ofNGH at Meharry and the Nashville MSA; 2) develop a cancer cohort at NGH at Meharry to serve as a resourcefor future studies across the cancer care continuum; and 3) provide training and mentorship for clinical traineesin the conduct of clinical trials and in the recruitment and retention of underserved populations in research. +No NIH Category available African American;American;Biology;Cancer Biology;Cancer Center;Career Choice;Chemistry;Clinical;Cognitive;Communities;Community Developments;Community of Practice;Development;Disparity;Doctor of Philosophy;Educational workshop;Ensure;Environment;Evolution;Goals;Growth and Development function;High School Student;Institution;Laboratory Research;Latinx;Maintenance;Malignant Neoplasms;Master of Public Health;Medical Students;Mentors;Pathway interactions;Population;Population Heterogeneity;Population Sciences;Psychosocial Assessment and Care;Research;Research Personnel;Research Project Grants;Research Support;Resources;Schools;Science;Self Efficacy;Series;Students;Talents;Tennessee;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Underrepresented Minority;Underrepresented Students;Universities;anticancer research;cancer health disparity;career;career development;doctoral student;education research;experience;faculty mentor;graduate student;high school;innovation;interest;learning materials;medical schools;peer coaching;programs;psychosocial resources;recruit;social;student participation;success;theories;translational cancer research;undergraduate student;underrepresented minority student Research Education Core n/a NCI 10693367 9/7/23 0:00 PAR-18-767 5U54CA163072-14 5 U54 CA 163072 14 9/21/11 0:00 8/31/26 0:00 ZCA1-SRB-2 7321 6902955 "DAHLMAN, KIMBERLY BROWN" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 76655 44309 32346 PROJECT SUMMARY: RESEARCH EDUCATION COREThe goal of the Meharry Medical College/Vanderbilt-Ingram Cancer Center/Tennessee State Cancer Partnership(MVTCP) Research Education Program is to facilitate the growth and career development of a new populationof outstanding underrepresented minority (URM) cancer researchers. Our current Pathway to Discovery programbegins with cancer research education for high school students continues for undergraduate Biology/Chemistrymajors at Tennessee State University (TSU) and culminates with support for graduate students (PhD MSPHand MPH) at Meharry Medical College (MMC) and TSU. The program also includes research support for medicalstudents at MMC and Vanderbilt University (VU). This program has proven to be very successful in supportingthe progression of a diverse population of students into cancer research careers. We propose to enhance theefficacy of the Pathway to Discovery program by including psychosocial resources derived from social cognitivecareer theory (SCCT). Research experience will engage students in the development and evolution of self-efficacy (SE) as well as a sense of being part of the scientific research community [science identity (SI)]. SCCTresearch shows that strong SE and SI are especially crucial to URM students entering and completing thenecessary programs to pursue research careers including cancer research. We propose a program groundedin SCCT that provides psychosocial resources and research experiences needed to develop and sustain SE andSI. MVTCP is particularly suited to target African American and Latinx undergraduate students (at TSU)graduate (at TSU and MMC) and medical students (at MMC). High school students come from two local STEMmagnet schools with predominant URM student populations. To achieve our goals we propose the followingaims: 1) Provide psychosocial resources for high school (8 students 4 juniors and 4 seniors) and undergraduatestudents (12 students 3 at each level freshmen through seniors) engaged in continuous academic year andsummer cancer research experiences to ensure development of SI and SE by leveraging the cancer researchand support resources at our Partnership institutions. Development of SE and SI will be accomplished byproviding opportunities for laboratory research and communities of practice (CoP) and a series of workshopsbased in SCCT. 2) Recruit and support a diverse population of graduate students (2 MPH/3 PhD students eachyear) who will evolve strengthen and maintain a strong SI and SE as they engage in cancer research with theultimate goal of enhancing the diversity of the cancer research workforce. SCCT-based workshops andresources targeted at the evolution and maintenance of SE and SI in our graduate students will be implemented.3) Provide educational research opportunities workshops and CoP to medical students (4 students each yearat MMC/4 at VU) to ensure successful evolution strengthening and maintenance of their SI and SE and tosustain their interest in clinical population sciences and translational cancer research with a focus on disparities. +No NIH Category available Abraxane;Academic Medical Centers;Affect;African American;Animals;Antibody Therapy;Biocompatible Materials;Biological;C57BL/6 Mouse;Cancer Center;Cardiotoxicity;Cells;Clinical;Clinical Trials;Death Rate;Disease;Doctor of Philosophy;Dose;Dose Limiting;Drug Kinetics;Extramural Activities;Flow Cytometry;Formulation;Frequencies;Funding;Glycolates;Goals;Gynecologic Oncology;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunotherapeutic agent;Immunotherapy;Incidence;Individual;Intraperitoneal Injections;Kinetics;Laboratories;Lesion;Ligands;Luciferases;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Methods;Minority;Modeling;Molecular;Mus;Not Hispanic or Latino;Outcome;Paclitaxel;Patients;Peritoneal;Peritoneum;Pilot Projects;Polymers;Productivity;Research;Research Project Grants;Resected;Rodent;Rodent Model;System;Tennessee;Testing;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Therapeutic Agents;Tissue Stains;Tissues;Toxic effect;Treatment Protocols;Tumor Burden;Tumor Immunity;United States National Institutes of Health;Universities;Woman;Work;anti-PD-L1;anti-PD-L1 therapy;anti-cancer;anticancer research;bioluminescence imaging;cancer health disparity;cancer immunotherapy;cancer therapy;checkpoint therapy;clinical practice;compliance behavior;controlled release;design;efficacy testing;experience;fabrication;human disease;human model;immune checkpoint;immunotherapy clinical trials;improved;innovation;intraperitoneal;medical schools;mortality;mouse model;novel;objective response rate;particle;response;response biomarker;side effect;success;tool;tumor;tumor progression Project 1: Developing immune checkpoint controlled-release biomaterials for cancer immunotherapy n/a NCI 10693362 9/7/23 0:00 PAR-18-767 5U54CA163072-14 5 U54 CA 163072 14 9/21/11 0:00 8/31/26 0:00 ZCA1-SRB-2 7318 1869980 "GIORGIO, TODD D" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 50237 50237 0 PROJECT SUMMARY: PILOT RESEARCH PROJECTImmunotherapies can provide effective cancer therapy but only in a minority of patients. The clinical success ofimmune checkpoint inhibitors in some malignancies has not translated to ovarian cancer. Objective responserates for single-agent immune checkpoint inhibitor (CPI) immunotherapy clinical trials in ovarian cancer are 6-15%. Also treated patients experience the consequences of dysregulated immunity from systemic administrationof these agents. For cancers in which primary disease is accessible/resected or in metastatic disease in whichlesions are accessible controlled release immunotherapy delivered locally may provide powerful and systemic anti-cancer immunity. Most anti-cancer therapies including CPI immunotherapies possess dose-limitingtoxicities in non-target tissues that compromise outcomes. Restricting delivery of these therapeutic agents hasdemonstrated benefit with the reduction in cardiotoxicity and significant improvement in therapy throughformulation of paclitaxel into Abraxane as a clinically powerful example. We propose to develop the firstcontrolled release biomaterials to enable local delivery of high dose immunotherapies that would be intolerableif systemically administered. We aim to significantly improve the frequency and durability of response followingCPI immunotherapy. We hypothesize that lower intraperitoneal immune checkpoint inhibitor concentration inhumans relative to rodents contributes to the low efficacy observed for ovarian cancer immunotherapies inclinical trials. Our proposed controlled-release CPI will allow assessment in mice of the intraperitoneal dosingconcentrations relevant to humans using a novel core/shell delivery system for sustained and controlled release.The overarching objective of this pilot project is to test improved response to cancer immunotherapy throughsustained release of immune checkpoint ligands from biomaterials that are applied locally/regionally (notsystemically). Our multi-PI complementary team aims to test this hypothesis in a rodent model of human ovariancancer that aligns with the exploratory and feasibility objectives of this Pilot Research Project mechanism andappropriate to lead to a full competitive project within 3 years. Aim 1 will synthesize and characterize biomaterialsthat enable the sustained release of anti-PD-L1 and can be retained locally following intraperitoneal injection toimprove immunotherapy while minimizing undesirable side effects. Aim 2 will characterize ovarian cancerprogression immune responses toxicity and overall survival from the sustained release of anti-PD-L1 in theintraperitoneal cavity of rodent models that replicate aspects of human disease. +No NIH Category available 3-Dimensional;AKT Signaling Pathway;Ablation;Address;Affect;African American;American;Androgens;Attenuated;Biogenesis;Cancer Etiology;Cells;Cessation of life;Data;Death Rate;Disease;Disease Outcome;Doctor of Philosophy;Enterobacteria phage P1 Cre recombinase;Female;Freezing;Generations;Genes;Gleason Grade for Prostate Cancer;Glycoproteins;Growth;Human;Immunohistochemistry;In Vitro;Indolent;Invaded;Knock-out;Knockout Mice;LNCaP;Laboratories;Linear Regressions;Malignant neoplasm of prostate;Mediating;Messenger RNA;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Mutant Strains Mice;Neoplasm Metastasis;Null Lymphocytes;PIK3CG gene;PTEN gene;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Play;Process;Production;Prognosis;Prognostic Marker;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Proto-Oncogene Proteins c-akt;Puberty;Refractory;Regression Analysis;Research Personnel;Role;Serum;Signal Pathway;Signal Transduction;TLR4 gene;The Vanderbilt-Ingram Cancer Center at the Vanderbilt University;Tissues;Transfection;Tumor Volume;Western Blotting;Xenograft procedure;alpha-Fetoproteins;biomarker identification;calcification;cancer health disparity;cancer initiation;cancer prevention;castration resistant prostate cancer;caucasian American;cell growth;cell motility;exosome;experimental study;in vivo;mRNA Expression;male;men;mouse model;mutant;nano-string;overexpression;probasin;prostate cancer cell;prostate cancer cell line;prostate cancer model;prostate cancer progression;transmission process;tumor;tumor growth;tumor initiation;tumor progression;tumorigenic;uptake Project 2: Fetuin-A in Prostate Cancer n/a NCI 10693358 9/7/23 0:00 PAR-18-767 5U54CA163072-14 5 U54 CA 163072 14 9/21/11 0:00 8/31/26 0:00 ZCA1-SRB-2 7315 1886146 "MATUSIK, ROBERT J." Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 70820 40936 29884 PROJECT SUMMARY: FULL PROJECT 2Even though the growth of prostate cancer (PCa) is largely driven by androgens a subset usually develops thatis refractory to androgen ablation (also known as castration resistant PCa; CRPC) with potential for metastasis.Preliminary data from our laboratory has implicated fetuin-A also known as alpha 2-Heremans-Schmidglycoprotein (AHSG) in the growth of PCa cells and in the production of uptake-competent exosomes. Theobjective of the proposed studies is to define the role and significance of fetuin-A in prostate cancer progression.We hypothesize that PCa cells express ectopic fetuin-A which is secreted and taken up by the cells via TLR4 tomediate the biogenesis of `uptake-competent' exosomes that promote PCa growth via activation of pAKT/pERK;moreover we postulate that elevated fetuin-A expression serves as a prognostic biomarker for PCa. Threespecific aims are proposed: Aim 1. To determine if fetuin-A expression is higher in AA PCa tissues relativeto Caucasian American (CA) PCa tissues and whether high fetuin-A expression is associated with highGleason Scores (>6) and enhanced pAKT and pERK. We will analyze mRNA expression of fetuin-A usingNanoString as well as pAKT/pERK protein levels using immunohistochemistry (IHC) analysis of human PCatissues. Multivariable linear regression analysis will be used to determine the correlation between fetuin-A pAKTpERK and Gleason scores in PCa tissues of AA and CA patients as well as other progression parameters suchas positive margins and spread of PCa. It is expected that fetuin-A pAKT and pERK will be expressed at highlevels in PCa tissues of AA patients particularly those with high Gleason scores (>6). Aim 2. To determine therole of ectopic fetuin-A in exosome biogenesis promotion of 2-D and 3-D growth motility and invasivecapacity of PCa cells. In this aim we will overexpress and knockout fetuin-A in two PCa cell lines to determinewhether fetuin-A plays a causal role in the biogenesis of `uptake competent' exosomes that transmit growthsignals in recipient cells. We expect to demonstrate that exosomes from fetuin-A overexpressing cells willpromote 2-D 3-D growth and motility and invasion of PCa cells while exosomes from fetuin-A null cells will not.Aim 3. To investigate the efficacy of targeting fetuin-A mediated signaling on the suppression of prostatetumor initiation and growth in mice. In this aim we will utilize the Pten-null mouse model for PCa to determinewhether Pten loss requires intact fetuin-A gene to mediate its tumorigenic role and whether loss of fetuin-A inPten-/-/fetuin-A-/- double mutant mice attenuates the tumorigenic role of Pten-null. We expect reduced tumorgrowth in the double mutant mice compared to Pten-null fetuin-A+/+ mice. Significance: There is an urgent needto identify biomarkers that can differentiate CRPC from indolent PCa and this proposal addresses that need andevaluates the process by which fetuin-A enhances PCa tumor growth. +No NIH Category available Address;Algorithms;Atlases;Benchmarking;Biological Process;Cancer cell line;Case Study;Cell Line;Cells;ChIP-seq;Classification;Communication;Communities;Companions;Complex;Computer software;Data;Data Analyses;Development;Disease;Educational workshop;FAIR principles;FarGo;Frequencies;Gene Expression;Gene Expression Process;Gene Expression Profile;Generations;Genes;Goals;Human;Infrastructure;Laboratories;Malignant Neoplasms;Manuals;Metadata;Methods;Mining;Molecular;Molecular Evolution;Mutation;Names;Natural Language Processing;Normal tissue morphology;Online Systems;Organism;Pathogen detection;Pathogenicity;Performance;Pharmaceutical Preparations;Phenotype;Process;Publishing;Pythons;Quantitative Trait Loci;Readability;Research Personnel;Resources;Sampling;Services;Single Nucleotide Polymorphism;Source;Supervision;Technology;Tissues;Training;Transcript;Tumor Subtype;Tumor Tissue;Untranslated RNA;Update;Variant;Work;anticancer research;application programming interface;cell type;cloud based;computational pipelines;computerized data processing;cost;cost effective;crowdsourcing;data format;data integration;data mining;data portal;data repository;data reuse;data visualization;deep learning;experimental study;file format;gene function;genome analysis;graphical user interface;human RNA sequencing;improved;insertion/deletion mutation;interoperability;neoplastic cell;novel;open data;outreach;repository;single-cell RNA sequencing;small molecule;transcriptome sequencing;transcriptomics;tumor;virtual ARCHS4: Massive Mining of Publicly Available RNA Sequencing Data NARRATIVEThe project will develop algorithms and software that will enhance the reuse of publicly available RNA-seq data.The resource will enable cancer researchers to form more informed hypotheses about tumor molecular evolution;and this work will lead to the identification of key molecular drivers as potential novel targets for the treatment ofvarious complex human cancers. NCI 10693339 8/17/23 0:00 RFA-CA-21-015 5U24CA264250-02 5 U24 CA 264250 2 "LI, JERRY" 9/1/22 0:00 8/31/27 0:00 ZCA1-TCRB-Q(M1) 7869507 "MA'AYAN, AVI " Not Applicable 13 PHARMACOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 775102 NCI 458640 316462 SUMMARYMany cancer-related independent studies that employ bulk and single cell RNA-seq remain under reused due totheir lower findability accessibility interoperability and reusability. The data from these studies can be found inthe Gene Expression Omnibus (GEO) but it is provided mostly as raw FASTQ files with non-uniform metadataannotations. While some studies provide aligned reads files these are processed non-uniformly. Thisshortcoming makes it difficult to query and integrate this data across studies and with additional external data.To bridge the gap that currently exists between RNA-seq data generation and RNA-seq data processing andreuse we developed the resource All RNA-seq and ChIP-Seq Sample and Signature Search (ARCHS4).ARCHS4 provides processed RNA-seq data from GEO to support retrospective data analyses and reuse.ARCHS4 caters to users with different levels of computational expertise and has been already employed formany post-hoc analyses and projects. The goals go far beyond just providing cancer researchers with directaccess to RNA-seq data through a web-based user interface. We plan to transform other transcriptomics datainto RNA-seq-like profiles with Deep Learning identify pathogenic sequences in human RNA-seq samplesidentify short variants from RNA-seq reads predict gene function from co-expression data including ways tomodulate the expression of long non-coding RNAs with small molecules and most importantly using theARCHS4 cost-effective infrastructure continue to provide a free FASTQ alignment service to the community. 775102 +No NIH Category available 3-Dimensional;Applications Grants;Area;Award;Biochemistry;Biological Assay;Biology;Cancer Biology;Cancer Center;Cancer Research Project;Chemicals;Clinical Trials Design;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Comprehensive Cancer Center;Computer software;Core Facility;Development;Drug Screening;Educational workshop;Exposure to;Funding;Genetic;Genomic approach;Genomics;Goals;Image;Investigation;Knowledge;Lead;Libraries;Malignant Neoplasms;Manuscripts;Modeling;Molecular;Molecular Probes;Organoids;Paper;Pharmaceutical Preparations;Pharmacology;Play;Postdoctoral Fellow;Research;Research Personnel;Role;Scientist;Services;Small Interfering RNA;Technology;Therapeutic;Training;Work;anticancer research;cancer cell;career development;design;drug discovery;functional genomics;graduate student;high throughput screening;high-throughput drug screening;innovation;instrumentation;meetings;member;new therapeutic target;novel;pharmacologic;programs;screening;skills;stem;success;symposium Cancer Pharmacologist and HTS Scientist Narrative:Dr. Joshua Bauer's cancer-related projects within the Vanderbilt High-Throughput Screening (HTS) Facility arefocused on three areas: 1) compound library screening and other HTS drug screening 2) functional genomics(siRNA/CRISPR) library screening and 3) high-content screening (HCS) and analysis. His integral role andsuccess stems from his ability to collaborate design and perform screens and intellectually contribute toprojects grant proposals and manuscripts. The blend of his skills expertise and knowledge provide a uniqueindispensable role within the Vanderbilt cancer research program to mend cancer research chemical biologygenomics drug discovery and translational drug investigation. NCI 10693286 8/23/23 0:00 PAR-20-287 5R50CA211206-08 5 R50 CA 211206 8 "SHARMAN, ANU" 9/19/16 0:00 8/31/26 0:00 ZCA1-SRB-1(A2) 7311765 "BAUER, JOSHUA A." Not Applicable 5 BIOCHEMISTRY 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN SCHOOLS OF MEDICINE 372032408 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 218965 NCI 138148 80817 Project Summary:The Vanderbilt-Ingram Cancer Center (VICC) is an NCI-designated Comprehensive Cancer Center with over270 members focused on cancer-related research. The Vanderbilt Institute of Chemical Biology (VICB) High-Throughput Screening (HTS) core facility was established to provide screening-based services for investigatorsfor molecular probe and pharmacological discovery. Dr. Joshua Bauer plays an integral role in the interfacebetween the cancer research and chemical biology programs at Vanderbilt. He has a strong background incancer biology pharmacology and biochemistry. His main goal is to use chemical genomic approachesincluding functional genomics screening and high-content imaging to identify novel drug targets and to betterunderstand the molecular and genetic mechanisms that underlie how cancer cells respond to therapeutics. Toachieve this goal his cancer-related projects within the HTS facility are focused on three areas: 1) compound/druglibrary screening (i.e. HTS) 2) functional genomics (siRNA/CRISPR) library screening and 3) high-contentscreening (HCS) and analysis. To date Dr. Bauer has provided support and intellectual contributions to over 80HTS projects including collaborations with at least 41 Cancer Center members including 31 that are NCI funded.These continued collaborations have allowed him to develop innovative assays and novel screening projectsthat contribute to the success of the Vanderbilt HTS core and cancer research program. His vital role andsuccess stems from his ability to conceive collaborate design and perform screens and intellectually contributeto projects grant proposals and manuscripts. In addition through participation in conferences meetings andworkshops Dr. Bauer strives to bring state-of-the-art technologies and ideas to the Vanderbilt HTS facility. Theblend of his skills expertise and knowledge provide a unique role within Vanderbilt to mend cancer researchchemical biology genomics drug discovery and translational drug investigation. Through his previously fundedR50 award Dr. Bauer has already further advanced his areas of focus in HTS and his career development. Sofar on the award (2016-20) he has been co-authored on 11 papers has supported 38 cancer-related grantproposals supported and trained over 50 graduate students and postdocs on HTS instrumentation or softwarehas developed several novel functional genomics screens (CRISPR and ORFeome) and has pioneered severalhigh-throughput 3D organoid models for high-content drug screening. Dr. Bauer has become a member of theNCI- Chemical Biology Consortium where he has been exposed to world-class drug discovery experts. Finallythe results of Dr. Bauer's work and collaborations have influenced the design of clinical trials initiated sponsoredresearch and has led to lead molecules for further development. Therefore Dr. Bauer's continued role as aCancer Pharmacologist & HTS Scientist is completely indispensable to the cancer research program atVanderbilt. 218965 +No NIH Category available Advisory Committees;American;Award;Communication;Country;Data;Department chair;Doctor of Philosophy;Evaluation;Feedback;Funding;General Population;Government;Grant;Health;Health Policy;Health behavior;Institution;International;Lead;Leadership;Logistics;Longitudinal Studies;Manuscripts;Marketing;Measures;Medical;Monitor;National Institute of Drug Abuse;Nicotine;Peer Review;Pilot Projects;Policies;Policy Maker;Population Assessment of Tobacco and Health;Production;Progress Reports;Protocols documentation;Public Health;Public Opinion;Publications;Publishing;Reporting;Research;Research Personnel;Role;Services;South Carolina;System;Tobacco Control Research;United States National Institutes of Health;Universities;Work;evidence base;experience;health organization;international health organization;meetings;member;nicotine use;operation;programs;public policy on tobacco;recruit;skills;tobacco control;web site Administrative Core NARRATIVEThe purpose of the Administrative Core (AC) is to provide and integrate scientific leadership administrativesupport and fiscal management for the entire Program Project. The three primary functions of the AC include:1) project management; 2) scientific planning coordination of activities across projects and evaluation; and 3)dissemination of research findings. NCI 10693266 9/1/23 0:00 PAR-20-077 5P01CA200512-08 5 P01 CA 200512 8 4/19/16 0:00 8/31/26 0:00 ZCA1-RPRB-L 7305 2448495 "CUMMINGS, KENNETH MICHAEL" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 246021 234407 11614 SUMMARY/ABSTRACTThe purpose of the Administrative Core (AC) is to provide and integrate scientific leadership administrativesupport and fiscal management for the entire Program Project. The three primary functions of theAdministrative Core (AC) include:1. Project management including communications logistics fiscal oversight compliance monitoring and submission of progress reports to NIH2. Scientific planning coordination and evaluation which will involve regular meetings of project and core leaders to develop common definitions and measures to be applied across studies shared systems for recruiting subjects tracking policies and new and modified products supporting pilot studies as appropriate to advance study aims and soliciting and responding to feedback from an expert external advisory committee; and3. Facilitating the dissemination of research products by: 1) publishing presenting and tracking research products produced by the P01; 2) creating dissemination products showcasing the findings from the P01; 3) partnering with key stakeholder organizations and 4) maintaining the P01 website were study protocols research products and policy tracking is shared.The AC will be located at the Medical University of South Carolina (MUSC). The Director of the AC will be K.Michael Cummings PhD MPH who will also serve as MPI (along with Dr. Geoffrey Fong and Andrew Hyland)of the overall Program Project. Dr. Cummings will be responsible for overall project management of the P01.Dr. Hyland will be responsible for coordinating P01 internal and external scientific planning and evaluation. Dr.Fong will lead dissemination activities of this P01. Dr. Cummings has previously served as the PI and ACDirector of the AC for the current P01 and has decades of experience leading multi-institutional NIH grants(P50 CA111236 2004-2009 and P01 CA138389 2009-2015) thus he is very experienced in the operations ofthe ITC Project and organization and oversight of AC services. Cynthia Smalls will serve as the ProgramManager for the P01. She previously served as the Program Manager for MUSC's current P01 and its relatedsupplements and therefore is experienced in the operations of a P01. +No NIH Category available Address;Adult;Affect;Australia;Behavior;Canada;Cigarette;Complement;Complex;Country;Data;Economic Models;Economics;Effectiveness;England;Future;Goals;Government;Health;Individual;Industry;International;Japan;Korea;Laws;Marketing;Modeling;New Zealand;Nicotine;Oral Tobacco;Outcome;Pattern;Play;Policies;Population Projection;Price;Public Health;Reaction;Regulation;Research;Role;Smoker;Smoking;Smoking and Health Research;Source;Structure;Surveys;Taxes;Tobacco Industry;Tobacco use;Update;Work;Youth;attributable mortality;cigarette smoke;cigarette smoking;combustible cigarette;heated tobacco products;heuristics;innovation;interest;models and simulation;nicotine use;novel;population health;product development;public policy on tobacco;response;tobacco control;tobacco products;trend;uptake;vaping;vaping nicotine;young adult An Economic and Public Health Analysis of the Evolving Nicotine Marketplace PROJECT NARRATIVEThis goal of this project is to first develop an economic model of the cigarette vaping and heated tobaccoindustry which considers firm pricing marketing and innovation and distinguishes independent from cigarettefirms. This model is used to inform public health models that consider the impact of tobacco control policies onvaping heated tobacco product and cigarette use and deaths attributable to their use. NCI 10693263 9/1/23 0:00 PAR-20-077 5P01CA200512-08 5 P01 CA 200512 8 4/19/16 0:00 8/31/26 0:00 ZCA1-RPRB-L 7304 1868168 "LEVY, DAVID THEODORE" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 86219 79530 6689 SUMMARY/ABSTRACTPatterns of tobacco use have changed dramatically since product development and marketing has expandedinto nicotine vaping products (NVPs) and more recently heated tobacco products (HTPs). NVPs are beingused by many adult smokers who continue to smoke cigarettes and by those who have transitioned off ofcigarettes. NVPs are also increasingly being taken up by youth and young adults in ways that may encouragefuture cigarette smoking or displace smoking. The net impact of NVPs and other emerging nicotine productsand the policies that have been implemented by governments to regulate them and ultimately on populationhealth are difficult to predict which is why modelling potential downstream impacts is useful. The three aims ofthis project are: 1) to develop economic models of industry behavior to better understand the impact of industryreactions to tobacco control policies; 2) to develop a framework that not only incorporates cigarettes and NVPuse but other new and emerging products such as HTPs; and 3) to develop simulation models for sevencountries with different regulatory frameworks and product use patterns for NVP and emerging nicotineproducts. For Aim 1 we will develop economic models of industry reactions to tobacco control policies thatconsider the role of traditional cigarette companies versus non-cigarette companies to better understand theimpact of market structure product pricing and marketing and product development. For Aim 2 we will expandour existing model developed in the current P01 to forecast the impact of NVPs on smoking and healthoutcomes to now include other emerging nicotine products including HTPs. We will apply this framework tounderstand the impact of specific cigarette-oriented NVP-oriented and HTP-oriented policies individually andtheir combination. The framework will also address the interaction between industry behavior policies andhealth outcomes. For Aim 3 the previously developed US Canada and England models will be updated andextended to consider HTPs and a broader set of policies. New country specific models will also be developedfor Australia Japan Korea and New Zealand. Our overarching goal of the proposed research is to show thelikely population health impacts of new tobacco products and the effect of new supply-oriented productregulations and the more traditional tobacco control demand-reduction policies on tobacco use patterns.Extensive sensitivity analysis will be conducted to identify the parameters that need to be better understood inorder to forecast population health impacts and to evaluate the plausible range of outcomes associated withspecific policies and regulations. +No NIH Category available Address;Adult;Age;Canada;Cigarette;Cigarette Smoker;Country;Data;Dependence;Development;England;Environment;Generations;Goals;Grant;Health;Individual;Intention;International;Knowledge;Laboratories;Laboratory Finding;Legal;Marketing;Measures;Menthol;Methodology;Methods;Modeling;Nicotine;Outcome;Participant;Pattern;Policies;Policy Analysis;Price;Public Health;Race;Reaction;Regulation;Research;Risk;Role;Sampling;Severities;Smoking;Socioeconomic Status;Surveys;Tobacco;Tobacco use;abuse liability;age stratification;behavioral economics;cohort;combustible cigarette;experience;experimental study;health communication;heated tobacco products;improved;innovation;low nicotine content cigarette;nicotine replacement;nicotine use;non-cigarette tobacco product;novel;policy implication;population health;public policy on tobacco;response;sex;tobacco control;tobacco products;tobacco regulation;tobacco user;uptake;vaping nicotine;young adult The Experimental Tobacco Marketplace (ETM) NARRATIVEThe tobacco landscape has changed significantly in terms of products and policy response with the responseto those policies potentially engendering illegal tobacco purchases. This project will experimentally examinethe effects of tobacco marketplace expansion (e.g. novel tobacco/nicotine products) new potential policies(e.g. reduced nicotine content) that may result in illegal purchasing and strategies to decrease illegalpurchases (i.e.. health communications availability of nicotine replacement therapy and penalties) amongdiverse users across different countries. The ultimate goal of this project is to inform tobacco regulation reducetobacco-related harm and improve public health. NCI 10693260 9/1/23 0:00 PAR-20-077 5P01CA200512-08 5 P01 CA 200512 8 4/19/16 0:00 8/31/26 0:00 ZCA1-RPRB-L 7303 1860001 "BICKEL, WARREN K" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 143949 132204 11745 SUMMARY/ ABSTRACTProject 3's long-term objectives are to understand the substitutability between novel and more frequently usedtobacco products the factors promoting and mitigating illegal tobacco purchases and the generality of thesefindings in diverse non-laboratory samples in different types of users. Project 3's aims are 1) to compare thesubstitution between different tobacco/nicotine products as a function of tobacco-user type 2) to model policiesthat may promote and mitigate illegal tobacco purchases for different types of tobacco users and 3) toexamine the generality of laboratory-based findings and their moderators using diverse samples (US Englandand Canada) from the International Tobacco Control Policy Evaluation Project. Participants will be bothexclusive cigarette smokers and dual cigarette/nicotine vaping product users because these individuals aremost at risk for negative health outcomes associated with combusted tobacco. The methods will employ theExperimental Tobacco Marketplace (ETM) an online purchasing experience that places a mix of productsprices and specific regulations under experimental conditions that simulate real world circumstances. TheETM provides estimates of the effects of product changes and/or policy changes on tobacco purchasingpatterns including between-product substitution in different types of tobacco product users. Here the ETM willbe used to examine the effects of novel products such as heated tobacco and nicotine pouch products onpurchasing patterns and the uptake of different products (substitution). Further the Illegal ExperimentalTobacco Marketplace (iETM) a methodological extension of the ETM was developed to examine conditionsthat promote or mitigate against illegal purchases. Here the iETM will be used to examine the effects ofregulatory environments that tend to promote illegal purchases such as high cigarette prices and reducednicotine content cigarettes. Moreover this project will examine policy strategies that may mitigate illegalpurchases such as health communications availability of nicotine replacement therapy and penalties. Theultimate health impact of this project is to inform tobacco regulation reduce tobacco-related harm and improvepublic health. +No NIH Category available Adult;Age;Canada;Cigarette;Country;Cross-Sectional Studies;Data;Dedications;England;Environment;International;Legal;Marketing;Measures;Menthol;Methods;Natural experiment;Nicotine;North America;Oral;Outcome;Pattern;Persons;Play;Policies;Policy Analysis;Population;Positioning Attribute;Prevalence;Price;Process;Public Health;Role;Sampling;Schedule;Series;Smoker;Smoking;Smoking Behavior;Subgroup;Surveys;Taxation;Testing;Time;Tobacco;Tobacco use;Variant;Youth;age group;aged;cigarette smoking;critical period;design;experience;health warning;heated tobacco products;marijuana legalization;nicotine use;novel;public policy on tobacco;rapid growth;rate of change;response;smoking cessation;theories;trend;uptake;vaping;vaping nicotine;young adult Examining uptake and use patterns of cigarettes and other nicotine delivery products among youth in countries with different regulatory environments: ITC Nicotine Product Youth and Young Adult Survey PROJECT NARRATIVEYouth and young adults play a central role in the rapidly evolving tobacco and nicotine market. The currentstudy will examine tobacco use nicotine vaping products and heated-tobacco products among youth andyoung adults in three countries with very different policy environments: the US Canada and England. Thebetween-country design provides a unique framework for assessing the impact of specific policies as well asthe emergence of novel HTPs and oral nicotine products. Finally the study is well-positioned to examinebroader contextual differences across countries such as the legalization of cannabis with direct implicationsfor the vaping and smoking among young people. NCI 10693256 9/1/23 0:00 PAR-20-077 5P01CA200512-08 5 P01 CA 200512 8 4/19/16 0:00 8/31/26 0:00 ZCA1-RPRB-L 7301 10572555 "HAMMOND, DAVID " Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 358343 354378 3965 SUMMARY/ABSTRACTYouth and young adulthood are critical periods for tobacco use. For most of the past two decades smokinghas steadily declined among young people in the US and other Western countries including Canada (CA) andEngland (EN). In contrast nicotine vaping products (NVPs) have experienced rapid growth and are now themost prevalent nicotine product used by youth and young adults. The long-term public health impact of NVPuse among young people is widely debated including its impact on smoking behavior as either a `gateway' intosmoking or a means to `displace' cigarette use. The nicotine market is poised to diversify further with theemergence of heated tobacco products (HTPs) such as Marlboro Heatsticks in the US and novel oral nicotineproducts. The extent to which these novel products appeal to young people and follow a similar trajectory asNVPs represents a critical question. The policy environment is changing in response to the rapidly evolvingproduct market. A range of new nicotine and tobacco policies are in the process of being implemented in theUS CA and EN most of which are targeted at reducing use among young people. The different regulatoryapproaches across countries creates a series of `natural experiments' in nicotine and tobacco policy which canbe used to evaluate their impact on young people. The proposed study consists of repeated cross-sectionalsurveys conducted annually with national samples of youth and young adults (aged 16-29) in the US CA andEN. The same methods and measures are used in all three countries to provide directly comparable estimatesover time. The study would expand the current focus of the International Tobacco Control Policy EvaluationProject (ITC) Youth surveys to include young adults (20-29) and will build on the four annual surveys wavesconducted between 2017 and 2020. The study has three primary aims: 1) to examine international variations insmoking NVP and HTP use among young people; 2) to examine the impact of national-level policies onprevalence and patterns of smoking and vaping among young people; and 3) to examine the relative impact ofpolicies on youth versus adult smokers. Overall the proposed Project is uniquely positioned to examinechanges in tobacco and nicotine use among young people during a critical period in which both the productand policy landscape is rapidly evolving. The between-country design provides a unique framework forassessing the impact of specific policies as well as the emergence of novel HTPs and oral nicotine products.Finally Project 2 is well-positioned to examine broader contextual differences across countries such as thelegalization of cannabis. +No NIH Category available Address;Adult;Affect;Age;Alternative Nicotine Delivery Systems;Applications Grants;Articulation;Australia;COVID-19 pandemic;Canada;Cannabis;Characteristics;Cigarette;Cigarette Smoker;Cohort Studies;Consumption;Country;Data;Electronic cigarette;England;Environment;Environmental Risk Factor;Evaluation;Foundations;Funding;Funding Agency;Future;Gender;Government;Grant;Heart;Income;Industry;Integration Host Factors;International;Japan;Longitudinal Studies;Manufacturer;Marketing;Measures;Methods;Modeling;New Zealand;Nicotine;Nicotine Dependence;Pattern;Policies;Policy Analysis;Policy Maker;Population;Population Assessment of Tobacco and Health;Population Group;Public Health;Quasi-experiment;Relapse;Research;Research Project Grants;Sampling;Science;Smoker;Smoking;South Korea;Surveys;System;Taxes;Time;Tobacco Industry;Tobacco use;United States;Work;Youth;age group;aged;analytical method;cigarette smoking;cohort;design;electronic liquid;experience;former smoker;health warning;heated tobacco products;innovation;nicotine use;nicotine vapor;programs;public policy on tobacco;sex;smoking cessation;symposium;tobacco control;tobacco products;vaper;vaping;vaping nicotine;vector;young adult Examining transitions between cigarettes and other nicotine delivery products among adults in countries with different regulatory environments: the ITC Nicotine Product Adult Survey PROJECT NARRATIVEThe rise of alternative nicotine delivery products (ANDS) which include nicotine vaporized products (NVPs;also known as e-cigarettes) and heated tobacco products (HTPs) have led to intense debates regardingwhether these products might serve to displace cigarette smoking thus benefiting public health. The proposedITC Nicotine Product Adult Survey is a longitudinal study (n=18900) of adult cigarette smokers and ANDSusers in 7 countries (United States Canada England Australia New Zealand Japan and Republic of Korea(South Korea)) that differ substantially in the ANDS that are available and in the ways in which theirgovernments have regulated them. This five-year research projectan extension of our ongoing internationallongitudinal study of ANDSwill provide unique evidence to inform policymakers about the public healthimpact of these new products and of the policies designed to regulate them. NCI 10693253 9/1/23 0:00 PAR-20-077 5P01CA200512-08 5 P01 CA 200512 8 4/19/16 0:00 8/31/26 0:00 ZCA1-RPRB-L 7299 2403016 "FONG, GEOFFREY T" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 616677 609760 6917 SUMMARY/ABSTRACTThe current P01 grant supported the creation of the International Tobacco Control Policy Evaluation (ITC)Project Four Country Smoking and Vaping Survey the first international cohort study of smoking and nicotinevaping product (NVP) use which was conducted in three countries supported by the P01 grant (United States[US] Canada England plus Australia which was supported by other funding). Three waves were conductedan average of 19 months apart in 2016 2018 and 2020. In this renewal application we build on that work bymatching the extraordinary international expansion of the nicotine marketplace by adding a focus on heatedtobacco products (HTPs) in addition to cigarettes and NVPs. We propose to continue the adult cohort survey inUS (n=2150) Canada (n=2150) and England (n=2300) for 3 additional waves 19 months apart over thenext 5 years with a substantial expansion by adding adult cohort surveys from 4 other ITC countries which arebeing supported by funding sources outside this proposed grant: Japan (n=4500) and the Republic of Korea(n=4700) countries that are the epicenter of the tobacco industry's introduction of HTPs; New Zealand(n=1600) which has incorporated NVPs into their endgame strategy; and Australia which continues itsmore restrictive approach to these Alternative Nicotine Delivery Systems (ANDS) (n=1500; grant applicationpending). The resulting 7-country ITC Nicotine Product Adult (NPA) Survey (total n=18900) will representan innovative international evaluation system that will allow the research team to conduct a comprehensiveresearch program on the use of nicotine products and transitions between cigarettes and nicotine productsbuilding on the ITC Project's 18-year global experience in conducting rigorous evaluation of tobacco controlpolicies employing quasi-experimental analytic methods. The NPA Survey will provide important evidence toadvance the science and understanding of nicotine products and policies during the next five years which iscertain to be a period of dynamic change in the nicotine product marketplace. Similar studies in the US such asthe Population Assessment Tobacco and Health (PATH) are limited since they do not readily permit cross-country comparisons using harmonized measures as the NPA survey does. This innovative Project has threeSpecific Aims: 1) to describe patterns use of and transitions of use across different tobacco products amongsmokers and recent ex-smokers both over time and by key user characteristics within and between countries;2) to examine how differences in current and future policies (e.g. taxes flavor bans product standards healthwarnings) for cigarettes NVPs and HTPs are related to differences in patterns of use of these products overtime; and 3) to examine the relative impact of policies on adults and youth (a Specific Aim shared with Project2). Two exploratory aims will also be addressed given their likely impact on nicotine product use: (a) toexamine how the COVID-19 pandemic is affecting smoking and ANDS use in the 7 countries over time; and(b) to examine the interplay between cannabis and smoking vaping and HTP use over time. +No NIH Category available Absenteeism;Address;Adult;Advertisements;Advertising;Affect;American;Area;Articulation;Basic Science;Benchmarking;Body mass index;Body measure procedure;Boston;Budgets;Cancer Center;Cancer Research Project;Child;Clinical Sciences;Collaborations;Communities;Consultations;County;Dana-Farber Cancer Institute;Data;Data Analyses;Data Collection;Development;Discipline;Disease;Disparity;District of Columbia;Early Intervention;Eating;Education;Educational workshop;Ensure;Environment;Ethnic Origin;Expenditure;Experimental Designs;Exposure to;Faculty;Food;Funding;Generations;Income;Individual;Infrastructure;Institution;Intervention;Knowledge;Letters;Link;Location;Logic;Low Income Population;Low income;Malignant Neoplasms;Massachusetts;Measurable;Measurement;Measures;Mediating;Mentorship;Methodology;Methods;Minority Groups;Mission;Modeling;Obesity;Outcome;Pattern;Persons;Population;Population Analysis;Population Sciences;Postdoctoral Fellow;Process;Program Evaluation;Qualifying;Race;Recommendation;Research;Research Design;Research Methodology;Research Personnel;Resource Sharing;Restaurants;Sales;Sampling;Sampling Biases;Selection Bias;Series;Services;Statistical Methods;Students;Techniques;Testing;Training;Underrepresented Minority;Underserved Population;United States;United States National Institutes of Health;Universities;Weight Gain;analytical method;anticancer research;cancer health disparity;data acquisition;data management;design;disparity reduction;econometrics;education pathway;education research;ethnic minority;ethnic minority population;experience;fast food;food environment;health equity;high risk;improved;innovation;member;minority communities;minority investigator;minority trainee;multiple data sources;novel;obesity risk;outreach;prevent;programs;racial minority;racial minority population;recruit;research study;sound;statistics;success;synergism;training opportunity Shared Resource Core n/a NCI 10693252 8/29/23 0:00 PAR-18-767 5U54CA156732-13 5 U54 CA 156732 13 9/27/10 0:00 8/31/26 0:00 ZCA1-SRB-2 7298 8219484 "LONDON, WENDY BETH" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 209383 117631 91752 Summary. Obesity is associated with 13 cancers and up to 11% of cancer in the United States is associatedwith excess body mass index (BMI). Evidence suggests that the food environment is associated with obesityrisk which affects one third of adults. Restaurants are an important component of the food environment. One-third of Americans will eat at a fast food restaurant on a typical day. Restaurant sales have steadily increasedover the past 5 decades; in 2015 restaurants spent $6.3 trillion in advertising (more than 100 times the NIHbudget). Advertisements for unhealthy items are often targeted towards those at higher risk for obesity andunhealthy food retail outlets like fast food restaurants are more densely located in low-income and minoritycommunities. Therefore the restaurant environment may more negatively impact low-income and racialminority populations. To date research on the relationship between restaurant advertising and obesity risk haslargely focused on children. Available studies are limited by cross-sectional data (limiting identification ofcausal relationships). To address these knowledge gaps we will combine multiple data sources to create aunique objective measure of local per capita restaurant advertising (adapting an approach we previouslydeveloped). This will be derived from local-level quarterly restaurant advertising spending from Kantar Mediafor the 100 top revenue generating restaurants in the U.S. and the annual physical addresses for all locationsfrom each restaurant chain from AggData. We will test associations of restaurant advertising per capita withpopulation weight gain using objectively measured BMI data for 2.3 million people (in 217 counties across 40states and the District of Columbia including 9 of the 10 most populous U.S. counties) from athenahealth. Wewill test whether this relationship is mediated by advertising exposure using data from Neilson Ad Intel. Theoverall objective is to leverage national data and provide a much-needed understanding of how exposure tochanges in local restaurant advertising impacts adult weight gain and disparities. We propose two specificaims: 1) examine changes in chain restaurant advertising expenditures from 2012 to 2016 and test whetherthose changes vary by income and race/ethnicity and 2) estimate the associations between chain restaurantadvertising and weight gain among U.S. adults by race and SES and whether this relationship is mediated bythe level of exposure to advertising. We will use a set of econometric techniques to assess whether theserelationships are causal. We hypothesize that increases in restaurant advertising per capita were larger inareas with higher concentrations of racial/ethnic minority and low-income populations and that greaterexposure to restaurant advertising will be associated with higher weight gain particularly for low-income andracial/ethnic minority populations and those with higher advertising exposure. This research will make a highlysignificant contribution to our understanding of how restaurant advertising impacts weight gain and disparitiesamong adults with important implications for subsequent cancer outcomes and health equity. +No NIH Category available Address;Adolescent and Young Adult;Adult;Affect;Age Years;Australia;Behavior;Behavioral;Canada;Cigarette;Country;County;Cross-Sectional Studies;Data;Dissemination and Implementation;Doctor of Philosophy;Emerging Tobacco Products;England;Etiology;Funding Agency;Future;Goals;Health;Health Policy;Industry;International;Intervention;Japan;Marketing;Mediation;Methods;Modeling;Monitor;New Zealand;Nicotine;Perception;Policies;Policy Analysis;Policy Maker;Population;Population Projection;Price;Public Health;Public Policy;Research;Resource Sharing;Scanning;Science;Series;South Korea;Statistical Models;Structure;Surveys;Testing;Tobacco;Tobacco Industry;Tobacco smoke;Tobacco use;Translating;United States;Work;Youth;access restrictions;cigarette smoking;cohort;consumer behavior;data hub;data management;design;experience;heated tobacco products;innovation;marijuana legalization;method development;multidisciplinary;nicotine use;operation;population health;programs;public policy on tobacco;response;tobacco control;tobacco products;tobacco regulation;tobacco user;trend;uptake;vaping nicotine;vapor;young adult Predicting and Understanding the Use of Nicotine Products In a Rapidly Evolving Nicotine Marketplace: The International Nicotine Product Policy and Market (INPAM) Study OVERALL NARRATIVEThe goal of this P01 renewal application is to address the question What have different countries done toregulate tobacco products and how has this impacted tobacco use behaviors? To fulfill this goal we willconduct a series of integrated multi-disciplinary studies in counties with different tobacco use landscapes toassess public health policies industry behavior and the impact on these forces on the use of cigarettesnicotine vaping products and heated tobacco products for the purpose of informing United States public healthpolicies. NCI 10693248 9/1/23 0:00 PAR-20-077 5P01CA200512-08 5 P01 CA 200512 8 "MAYNE, RACHEL G" 4/19/16 0:00 8/31/26 0:00 ZCA1-RPRB-L(M1)P 2448495 "CUMMINGS, KENNETH MICHAEL" "FONG, GEOFFREY T; HYLAND, ANDREW " 6 PSYCHIATRY 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1965406 NCI 1898708 66698 OVERALL SUMMARY/ABSTRACTThe proposed renewal of this P01 builds upon the longstanding International Tobacco Control (ITC) PolicyEvaluation Project which has used cross-country comparisons and a common mediation model to evaluate thebehavioral impacts of national-level tobacco control policies. The current P01 has extensively researched anddocumented the transitions between cigarettes and nicotine vaping products and how policies impact their use.For the renewal period we are adding heated tobacco products thus extending our previous two-productmodel to three products but otherwise maintaining a similar team structure and research approach. The goalof this P01 renewal application is to address the question What have different countries done to regulatetobacco products and how has this impacted tobacco use behaviors? Our common integrated theoreticalframework enables us to examine how and why policies and industry actions exert effects as well as exploreunder what conditions products or policy interventions might translate into actual population-level impacts. Wefocus on the well-established 4 `P's' product price placement and promotion and how public health policyand industry actions impact consumer perceptions behavior and ultimately health endpoints. Comparing theexperiences of different countries with varying regulatory approaches is intended to inform United States publicpolicy based upon the best science available to maximize population health. To accomplish this we proposeto analyze policies and industry actions in different jurisdictions to answer the following three integratedquestions: 1) Does the policy/industry action have an impact? (causality); 2) Under what conditions is iteffective? (moderation); and 3) How is it effective? (mediation). The proposed studies assess direct andindirect or unintended effects that can affect the overall impact of a policy or action. We propose to conduct thiswork with four inter-related Projects an Administrative Core and two Shared Resource Cores whichcollectively will: 1) track cohorts of adult tobacco users in 7 countries; 2) conduct repeated cross sectionalsurveys of youth and young adults in 3 countries; 3) utilize the Experimental Tobacco Marketplace to evaluatethe effects of product availability policy actions and the illicit marketplace; and 4) perform statistical modelingusing input from the Projects to predict consumer response. The three P01 specific aims are to: 1) understandhow policies and industry actions impact consumer behavior; 2) develop scientific methods for assessingresponse to policies; and 3) forecast population impact of different policy approaches. 1965406 +No NIH Category available Acetates;American;Anatomy;Animal Experimentation;Animal Housing;Animals;Area;Award;Biodistribution;Budgets;Cancer Biology;Cancer Center Planning Grant;Cancer Center Support Grant;Chemicals;Choline;Clinic;Clinical Trials;Communication;Companions;Complement;Comprehensive Cancer Center;Consult;Consultations;Cyclotrons;Data;Development;Doctor of Philosophy;Drug Kinetics;Drug Targeting;Ensure;Equipment;Ethics;Evaluation;Functional disorder;Funding;Gastroenterology;Genetic Engineering;Goals;Grant;Image;Imaging Device;Imaging Techniques;Imaging technology;ImmunoPET;Immunooncology;Individual;Infrastructure;Intervention;Investigation;Isotopes;Journals;Label;Laboratories;Leadership;Link;Magnetic Resonance Imaging;Malignant Neoplasms;Medical center;Metabolism;Methods;Misonidazole;Multimodal Imaging;NCI Center for Cancer Research;National Cancer Institute;Nature;Neurosciences;Optics;PET/CT scan;Peer Review;Performance;Prognostic Marker;Publications;Publishing;Radiation;Radiochemistry;Radioisotopes;Radiolabeled;Reagent;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Series;Services;Small Animal Imaging Shared Resource;Societies;Technology;Testing;Therapeutic;Therapeutic antibodies;Tracer;Training;Translational Research;Translations;Ultrasonography;Visualization;Work;anatomic imaging;animal imaging;anticancer research;cellular imaging;clinical investigation;community center;cost;experience;fluorodeoxyglucose;germ free condition;image guided;imaging approach;imaging biomarker;imaging facilities;imaging modality;improved;in vivo;insight;instrument;instrumentation;irradiation;meetings;member;molecular imaging;novel;novel strategies;novel therapeutic intervention;novel therapeutics;nuclear imaging;optical imaging;optoacoustic tomography;outreach;pre-clinical;precision oncology;programs;receptor;single photon emission computed tomography;success;symposium;theranostics;tool;treatment response;tumor;tumor hypoxia;ultrasound Small Animal Imaging Shared Resource n/a NCI 10693246 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7295 1968482 "MASON, RALPH P." Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 94043 57343 36700 The Small Animal Imaging Shared Resource (SAISR) at Simmons Comprehensive Cancer Center (SCCC) is acomprehensive small animal multimodality imaging resource that facilitates advances in the understanding ofcancer biology and the development of novel therapeutics. The SAISR enables noninvasive assessment of tumordevelopment progression and response to therapy based on multiple imaging technologies including opticalultrasound photoacoustics MRI CT SPECT and PET/CT. In addition to anatomical visualization the SAISRprovides spatial and functional context for prognostic biomarkers and theranostic interventions. Under theleadership of Ralph P. Mason PhD the SAISR facilitates and integrates pathophysiology metabolism andreceptor target identification with anatomical imaging. The SAISR provides SCCC investigators with assistedand unassisted usage of imaging technologies consultations on optimal imaging approaches and hands-ontraining in the use of imaging modalities. Since the last renewal the SAISR has incorporated several newapproaches in order to stay at the leading edge of technology. Important enhancements in infrastructure andcapabilities include new photoacoustic tomography and access to short-lived isotopes generated by a newcyclotron that provides multiple tracers including 18F-MISO 11C-acetate and choline that can be observed witha new Mediso PET/CT scanner. There have also been substantial upgrades to the MRI facilities that significantlyexpand the new preclinical radiation services so that investigators can use MRI and image-guided irradiationinside a specific pathogen-free vivarium complementing the existing instruments in conventional animal housingareas. These capabilities of the SAISR were utilized by 41 investigators across four SCCC research programsin 2019 and provided key data and insights to support the success of more than 30 peer-reviewed fundedresearch project grants and 119 peer-reviewed publications since 2014 including work published in high-impactjournals such as Nature Nature Communications Nature Neurosciences Journal of Clinical InvestigationGastroenterology and the Journal of the American Chemical Society. In summary the SAISR advancessupports and provides important cancer research imaging modalities to the SCCC community enabling themto efficiently test new therapeutic strategies in vivo as well as facilitate companion studies in clinical trials. +No NIH Category available Address;American;Area;Behavioral Sciences;Black Populations;Boston;COVID-19 pandemic;Cancer Center;Color;Communication;Communities;Dana-Farber Cancer Institute;Development;Disabled Persons;Discipline;Discipline of Nursing;Disparity;Doctor of Philosophy;Education;Educational Status;Enrollment;Ethnic Population;Faculty;Fellowship;Fostering;Genomics;Graduate Degree;Grant;Group Affiliation;Growth;Health;Health Disparities Research;Healthcare;Individual;Infrastructure;Institutional Racism;Intervention;Investments;Knowledge;Latinx;Low Income Population;Malignant Neoplasms;Manuscripts;Massachusetts;Mentors;Methods;NCI Center for Cancer Research;Native Americans;Peer Review;Phase;Population;Population Heterogeneity;Postbaccalaureate;Postdoctoral Fellow;Preparation;Process;Productivity;Publications;Research;Research Design;Research Personnel;Research Project Grants;Science;Science Enrichment;Scientific Advances and Accomplishments;Scientist;Students;Training;Underrepresented Populations;Underrepresented Students;Universities;Work;behavioral and social science;cancer health disparity;career;career development;design;education research;evidence base;experience;graduate school;graduate student;health communication;health disparity;improved;innovation;interest;multidisciplinary;outreach;personalized cancer therapy;physical science;programs;racial population;research and development;research study;skills;success;undergraduate student Research Education Core n/a NCI 10693245 8/29/23 0:00 PAR-18-767 5U54CA156732-13 5 U54 CA 156732 13 9/27/10 0:00 8/31/26 0:00 ZCA1-SRB-2 7294 10463030 "BURNS WHITE, KAREN ANN" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 67496 37919 29577 PROJECT SUMMARYThe UMass Boston Dana-Farber/Harvard Cancer Center Partnerships Research Education Core (REC) aimsto bridge the divide that exists in the biomedical workforce by increasing the number of UMass Bostonstudents particularly those from underrepresented populations to pursue graduate degrees and cancer/cancerhealth disparities research careers. Utilizing evidence-based training that fosters the growth and persistence ofunderrepresented students in the sciences the REC provides trainees with science enrichment education andmentored research experiences which emphasize professional development inclusive support and teamscience across multiple disciplines. The framework of the REC focuses on three areas that are critical to thedevelopment of research scientists: (1) acquisition of scientific knowledge; (2) development of communicationskills; and (3) individualized career development. The Core will provide four research education programs:undergraduate post-baccalaureate graduate and post-doctoral. Over the course of the grant cycle the RECseeks to support 60 undergraduates (15-20 per year minimum one semester or summer 90% multi-semester) 30 graduate students (6-8 per year most multi-semester) 15 post-baccalaureate students (3 peryear for 1-2 years) and 2 nursing post-doctoral scientists (1 per two-year fellowship) in innovative researcheducation programming. Partnership faculty will mentor trainees and fellows at all levels. Recognizing that theneeds of individuals vary and that they change at each educational level the REC will provide individualizedand developmentally appropriate experiences aimed at preparing students/trainees for the next phase of theiracademic and research careers. The REC will continue to provide research opportunities for students at theintersection between the natural/physical sciences and social/behavioral sciences. Over the past 15 years theResearch Education Core (REC) has provided 347 trainees/fellows across the scientific preparation levels withmentored research experiences and scholarly scientific and professional development that prepares them topursue advanced degrees & fellowships and then to become cancer health disparities and/or biomedicalscience researchers. The REC will continue to use innovative methods to assess the extent to which thePartnership research education program is preparing trainees and fellows to successfully pursue a productivecancer/cancer health disparities research career. The REC will also advance scientific knowledge on effectiveresearch education programs through the submission of manuscripts to peer-reviewed publications regardingthe impact of Partnership activities on the diversity of the biomedical workforce and effective strategies fordeveloping research scientists from underrepresented backgrounds. +No NIH Category available Aging;Animals;Award;Binding;Biomedical Engineering;Biomedical Research;Cancer Center Support Grant;Cells;Cellular biology;Communication;Comprehensive Cancer Center;Computer software;Consult;Consultations;Custom;Data Analyses;Development;Doctor of Philosophy;Educational Background;Educational workshop;Experimental Designs;Fiji;Fluorescence;Funding;Goals;Image;Image Analysis;Imaging technology;Institution;Instruction;Journals;Laboratories;Lasers;Leadership;Licensing;Light;Light Microscope;Lighting;Malignant Neoplasms;Medical center;Microbiology;Microscope;Microscopy;NCI Center for Cancer Research;Nature;Optics;Photons;Principal Investigator;Publications;Research;Research Personnel;Resource Sharing;Sampling;Scanning;Science;Services;Site;Slice;Spectrum Analysis;Techniques;Technology;Thick;Tissue imaging;Tissues;Training;Translations;United States National Institutes of Health;Vendor;cancer cell;cellular imaging;digital imaging;experience;fluorescence microscope;histological stains;image processing;innovation;instrument;instrumentation;light microscopy;live cell imaging;member;microscopic imaging;new technology;operation;programs;superresolution imaging;three dimensional structure;tool;two-photon;ultra high resolution Live Cell Imaging Shared Resource n/a NCI 10693242 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7292 1879482 "LUBY-PHELPS, KATHERINE J" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 97862 59672 38190 The Live Cell Imaging Shared Resource (LCISR) of Simmons Comprehensive Cancer Center (SCCC) enablesSCCC members to leverage advanced light microscopy techniques in support of their cancer-focused research.The LCISRs capabilities include digital imaging of histologically stained samples workhorse confocalmicroscopes sophisticated two-photon microscopes for imaging in live animals and thick tissues total internalreflection fluorescence (TIRF) microscopes and multiple modes of super-resolution imaging as well as twoimage processing workstations with comprehensive image analysis software. Under the leadership of KateLuby-Phelps PhD LCISR staff members provide individualized training of users and consult on experimentaldesign and image analysis. The LCISR has been proactive in evaluating new instrumentation and in obtainingfunding for instrumentation purchase. Since 2015 the LCISR has replaced two aging laser scanning confocalmicroscopes and has expanded its capacity by adding a third confocal with funding from the NIH S10 program.This acquisition included a Zeiss Airyscan FAST attachment for super resolution imaging and a fluorescencecorrelation spectroscopy module for examining molecular interactions in solution and in living cells that is uniqueon the UT Southwestern Medical Center (UTSW) campus. The LCISR recently acquired an OMX SR multimodesuper-resolution microscope with 3D structured illumination microscopy localization microscopy(PALM/STORM) and Ring TIRF capabilities. To keep up with ongoing rapid developments in light microscopetechnology the LCISR recently initiated a partnership with the UTSW Microscope Innovation Laboratory (MIL)led by Kevin Dean PhD. The MIL is a newly established institutionally supported initiative intended to fast-trackthe translation of cutting-edge light microscope imaging instrumentation to researchers at UTSW. Plannedinstrumentation includes custom-built lightsheet microscopes for cleared tissue imaging and fast volumetricimaging and a three-photon microscope for deep tissue imaging. Instruments developed by the MIL will be madeavailable to SCCC members through the LCISR. Since 2014 the LCISR has been used by more than 140principal investigators across all five SCCC research programs resulting in more than 140 cancer-focusedpublications including publications in high-impact journals such as Cell Nature Science Cancer Cell NatureCommunications Dev Cell and Nature Microbiology. The annual number of SCCC member laboratories usingthe LCISR has expanded from 54 in 2015 to 80 in 2019. +No NIH Category available AR gene;Address;Affect;African American population;African ancestry;American;Androgen Receptor;Androgen Therapy;Androgens;Apoptotic;Basic Science;Biological;Boston;CAG repeat;Cancer Center;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Clinical;Combined Modality Therapy;Critical Pathways;DNA Damage;DNA Sequence Rearrangement;Dana-Farber Cancer Institute;Dependence;Development;Dose;European ancestry;Genetic;Genetic Polymorphism;Genetic Transcription;Genomics;Glutamine;Grant;High Prevalence;KDM1A gene;Lead;Length;Ligands;Malignant neoplasm of prostate;Massachusetts;Modeling;Molecular Target;Mutation;N-terminal;Nuclear;Outcome;Pathway interactions;Patients;Play;Population;Proteins;Receptor Signaling;Research;Risk Factors;Role;Testing;Therapeutic;Translational Research;Universities;cancer health disparity;cancer initiation;men;polyglutamine;programs;prostate cancer cell;prostate cancer cell line;prostate cancer model;racial disparity;repaired;response;targeted agent;targeted treatment;transcription factor;tumor progression Targeting androgen receptor signaling in prostate cancer in men with African ancestry n/a NCI 10693241 8/29/23 0:00 PAR-18-767 5U54CA156732-13 5 U54 CA 156732 13 9/27/10 0:00 8/31/26 0:00 ZCA1-SRB-2 7291 1863884 "BALK, STEVEN P." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 171500 171500 0 PROJECT SUMMARYProstate cancer (PCa) is the second leading cause of cancer-related death in American men. Although men withEuropean ancestry (EA) still represent the largest population of PCa patients men with African ancestry (AA)are disproportionately affected by PCa with higher prevalence and worse outcomes. Androgen receptor (AR) aligand-dependent nuclear transcription factor plays a pivotal role in PCa development and there are well-established genetic differences in the AR gene and associated pathways between EA versus AA men. Howeverit remains unclear how these genetic differences alter AR interaction with associated proteins and their potentialrole in PCa development and response to AR targeted therapies. In this study we hypothesize that differencesin AR signaling contribute to the biological differences between PCa in AA versus EA men and that PCa in AAmen may have distinct AR-dependencies and be vulnerable to therapies that combine AR-targeted therapieswith other targeted agents. To test these hypotheses Aim 1 will assess the effect of androgen stimulation onPCa cells from AA versus EA patients and in isogenic cells reflecting the genetic difference of AR. Aim 2 willidentify vulnerabilities generated in response to AR-targeted therapies in AA versus EA PCa models. +No NIH Category available Address;Adherence;Adult;American;Behavior;Behavioral Mechanisms;Biological;Black race;Blood;Blood Glucose;Blood Pressure;Boston;Breast Cancer Treatment;C-Peptide;C-reactive protein;Cancer Center;Cancer Patient;Cancer Survivorship;Cardiotoxicity;Cardiovascular Physiology;Collaborations;Colorectal Cancer;Communities;Control Groups;Dana-Farber Cancer Institute;Data;Disadvantaged minority;Disparity;Enrollment;Ethnic Origin;European;European Organization for Research and Treatment of Cancer;Exercise;Fasting;Fatigue;Funding Mechanisms;Funding Opportunities;Hispanic;Hispanic Populations;Home;Insulin;Intervention;Knowledge;Life Style;Malignant Neoplasms;Malignant neoplasm of prostate;Massachusetts;Measures;Minority;Minority Groups;Mission;Obesity;Outcome;Overweight;Patient Outcomes Assessments;Patient Self-Report;Patients;Physical Function;Physical Performance;Physiological;Pittsburgh Sleep Quality Index;Population;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Recurrent disease;Reporting;Research;Resources;Risk Factors;Sampling;Science;Sleep;Socioeconomic Status;Testing;Treatment outcome;Underserved Population;Universities;Vulnerable Populations;Walking;actigraphy;black patient;cancer clinical trial;cancer health disparity;cardiorespiratory fitness;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;chemotherapy;comorbidity;comparison control;conditioning;cost effective;design;disorder risk;energy balance;ethnic minority population;exercise intervention;exercise training;experience;health disparity;high risk;improved;innovation;invention;lifestyle intervention;minority patient;mortality;novel;peripheral blood;post intervention;primary endpoint;psychologic;racial diversity;racial minority population;randomized trial;recruit;sedentary;underserved minority Testing Homebased ExeRcise Strategies to Improve Exercise Participation and CardioVascular Health in UndersErved Minority Patients with Cancer Undergoing Chemotherapy the THRIVE Study n/a NCI 10693238 8/29/23 0:00 PAR-18-767 5U54CA156732-13 5 U54 CA 156732 13 9/27/10 0:00 8/31/26 0:00 ZCA1-SRB-2 6581 10366548 "DIELI-CONWRIGHT, CHRISTINA " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 177874 99929 77945 SUMMARY/ABSTRACTProfound disparities exist in comorbid disease risk and lifestyle behaviors during and following chemotherapyin Hispanic and Black cancer patients compared with European American counterparts. This includes declinesin cardiorespiratory fitness paired with cardiotoxic effects placing minority cancer patients at a higher risk forcardiovascular disease. Despite the beneficial effect of exercise training for cancer patients rates ofparticipation in clinical cancer trials are low among disadvantaged and racial/ethnic minority groups possiblydue to greater barriers and less access to exercise training. Therefore the need for novel accessible and cost-effective home-based exercise intervention aimed at the Hispanic and Black communities to better understandphysical activity interventions is crucial. We propose a pilot randomized trial to examine the effect of 16-weeksupervised and unsupervised exercise interventions in sedentary overweight or obese Hispanic and Blackcancer patients undergoing chemotherapy for the treatment of breast colorectal and prostate cancer. Thisproposal will address the following aims: 1) examine whether the inventions will increase daily minutes ofexercise performed per week; 2) assess the effect of the inventions on cardiovascular risk factors; 3) determinethe effect of the inventions on patient-reported outcomes and physical function. We hypothesize that bothexercise groups will experience a significant increase in minutes of daily exercise per week reductions incardiovascular disease risk improved quality of life and physical function when compared to Controls. Thisstudy is innovative because a) we will conduct the study in high-need understudied population b) this is thefirst study to employ a novel and achievable intervention for a minority population receiving chemotherapy c)integration of novel physiological variables for the intervention. Our proposal addresses the priority focus of thisfunding opportunity announcement through the design and implementation of an exercise intervention for anunderserved understudied vulnerable population- Hispanic and Black patients receiving chemotherapy. TheCo-PIs Drs. Dieli-Conwright (DFCI) and Yan (UMB) will bring together their expertise in exercise sciencecancer survivorship and cardiovascular physiology to successfully execute this project. This collaboration isuniquely made possible by the UMB-DF/HCC Partnership with the resources supported by the NCI CPACHE.Findings from this study will generate new knowledge about the effects of exercise intervention and provideguidance towards improving the quality and treatment tolerability in this population of underserved vulnerablepatients with cancer. +No NIH Category available Award;Basic Science;Biological Markers;Biometry;Biostatistics Shared Resource;Biotechnology;Cancer Center Support Grant;Cancer Research Project;Clinical;Clinical Oncology;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Complex;Comprehensive Cancer Center;Computer Hardware;Computer software;Consultations;Data;Data Analyses;Data Science;Databases;Development;Doctor of Philosophy;Education;Educational workshop;Electronic Health Record;Ensure;Epidemiology;Extramural Activities;Faculty;Funding;Genetic;Goals;Grant;Institution;International;Investigation;Journals;Malignant Neoplasms;Manuscripts;Medical center;Methodology;Methods;Monitor;NCI Center for Cancer Research;Nature;Oncology;Peer Review;Play;Population;Population Sciences;Population Study;Postdoctoral Fellow;Productivity;Protocols documentation;Publications;Publishing;Quality Control;Reproducibility;Research;Research Design;Research Personnel;Resource Sharing;Resources;Role;Safety;Screening for cancer;Services;Statistical Methods;Therapeutic Agents;Therapeutic procedure;Training and Education;Translational Research;Work;Writing;anticancer research;cancer clinical trial;data management;data quality;design;experimental study;innovation;insight;investigator-initiated trial;lectures;member;method development;multidimensional data;novel therapeutics;population based;pre-doctoral;programs;quality assurance;randomized trial;recruit;statistical service;success;tool;translational pipeline;trial design Biostatistics Shared Resource n/a NCI 10693232 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7286 8328345 "AHN, CHUL W" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 235038 143316 91722 The Biostatistics Shared Resource (BSR) is a centralized resource that provides state-of-the-art biostatisticalsupport for investigators conducting cancer research at Simmons Comprehensive Cancer Center (SCCC).Advances in biotechnologies and computing hardware/software have greatly increased the need forsophisticated statistical methodologies and biostatistics is an essential component in ensuring high-qualitycancer research particularly in clinical and translational research. BSR biostatisticians play important integratedroles in each of the SCCC Research Programs. The formats of these productive collaborations include pre-award project and clinical trial development as well as post-award project-oriented statistical services. SCCCresearch covers the full spectrum of the translational pipeline ranging from basic science experimentsbiomarker studies investigator-initiated clinical trials of novel therapeutic agents and procedures to population-based studies. The BSR faculty also offers workshops office consultations seminars and courses on studydesign analysis methods and software implementation to fellows research staff and faculty. The BSR is ledby Chul Ahn PhD a distinguished biostatistician with a national and international reputation for his statisticaldesigns and analyses of cancer research and cancer clinical trials. BSR biostatisticians are also key contributingmembers of SCCCs Protocol Review and Monitoring Committee (PRMC) and Data and Safety MonitoringCommittee (DSMC) providing valuable independent statistical input. The BSR currently consists of efforts fromfive faculty biostatisticians and three analysts providing all levels of biostatistics support. The services of theBSR were utilized by 178 members across five SCCC research programs from 2014-2019 and provided keydata and insights to support the success of 68 new cancer-related extramurally funded grants 96 cancer clinicaltrials and 267 peer-reviewed publications including work published in top tier journals such as JAMA Journalof Clinical Oncology JAMA Oncology Lancet Oncology Cancer Discovery Cancer Nature Genetics andNature. Goals for the next funding period include recruiting additional biostatisticians to strengthen expertise inadaptive trial design. +No NIH Category available Age;Area;Authorization documentation;Cancer Center Support Grant;Child;Clinical Research;Clinical Sciences;Committee Membership;Comprehensive Cancer Center;Data;Discipline;Disease;Doctor of Philosophy;Education;Electronics;Ensure;Ethnic Origin;Faculty;Frequencies;Gender;Health;Healthcare Systems;Hospitals;Industry;Institution;Institutional Review Boards;Leadership;Malignant Neoplasms;Medical center;Modification;Monitor;Oncology;Outcome Study;Participant;Peer Review;Policies;Population Sciences;Population Study;Procedures;Process;Protocols documentation;Race;Recommendation;Reporting;Research;Research Personnel;Research Priority;Review Committee;Role;Safety;System;anticancer research;authority;design;expedited review;human subject;improved;meetings;research study;response;sound;timeline Protocol Review and Monitoring System n/a NCI 10693230 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7284 9949936 "COURTNEY, KEVIN D" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 200703 122380 78323 The Simmons Comprehensive Cancer Center (SCCC) Protocol Review and Monitoring System (PRMS) provides independent peer review for scientific merit prioritization and monitoring for all cancer-related clinical and population science studies conducted at the UT Southwestern Medical Center (UTSW) and its affiliated healthcare systems Parkland Health and Hospital System and Childrens Medical Center. PRMS functions are accomplished by a rigorous review in a two-stage process conducted by: 1) SCCC Disease-Oriented Teams (DOTs) where initial assessment of value fit and prioritization within the existing portfolio of studies is performed as well as an assessment of each studys operational and accrual feasibility; and 2) the Protocol Review and Monitoring Committee (PRMC) which is the definitive independent authority for determining which studies proceed to activation. The PRMC ensures that all SCCC-aligned cancer research studies involving human subjects are (1) scientifically sound (2) effectively designed (3) appropriately prioritized within DOT research portfolios (4) aligned with SCCC institutional clinical research priorities (5) feasible for completion (6) inclusive of appropriate data and safety monitoring plans and (7) monitored regularly for accrual and scientific progress. Utilizing standard operating policies and procedures the PRMS is conducted by 13 DOTs and three PRMCs (two for clinical studies and one for population studies) under the leadership of Hans Hammers MD PhD (PRMC1) Robert Timmerman MD (PRMC2) and Simon Craddock Lee PhD MPH (Population Science PRMC). During the current project period the PRMS made substantial progress in key areas including implementing parallel review with the Institutional Review Board (IRB) while still requiring PRMC approval before IRB approval increasing PRMC meeting frequency expanding PRMC membership and transitioning to a fully electronic review process all of which have contributed to decreased review timelines while maintaining the highest scientific standards. In 2019 the SCCC DOTs vetted 197 studies for potential submission and forwarded 162 studies for PRMC review. Of these 50 had undergone an appropriate external scientific peer review and therefore received an expedited review by the PRMC Chair and/or Vice Chair. The remaining 112 studies primarily representing SCCC investigator-initiated and industry-sponsored trials were forwarded for full PRMC review. More than 70% of the studies reviewed by PRMC required modifications prior to being approved. No studies were disapproved. Ten underperforming studies were closed. In the next CCSG cycle the PRMS will focus on further reduction in review timelines and enhancing information provided to investigators during the review process. +No NIH Category available Acceleration;Acids;Address;Adenocarcinoma;Affect;Agonist;Area;Barrett Esophagus;Bile Acids;Cell Count;Cells;Cessation of life;Collaborations;Data;Deoxycholic Acid;Development;Distal;Dysplasia;Epithelial Attachment;Esophageal Adenocarcinoma;Esophagogastric Junction;Esophagus;Future;High Fat Diet;Human;Immune;Inflammasome;Inflammation;Inflammatory;Knock-out;Knowledge;LGR5 gene;Malignant Neoplasms;Modeling;Modification;Molecular;Mus;Myeloid Cells;Natural Killer Cells;Neoplasms;Nuclear;Organoids;Patients;Population;Precancerous Conditions;Production;Proliferating;Prospective Studies;Public Health;Regional Cancer;Risk Factors;Role;Sampling;Series;Stomach;Stromal Cells;Techniques;Translating;Validation;Work;antagonist;carcinogenesis;chemokine;clinically significant;cohort;epithelial stem cell;experimental study;gastroesophageal cancer;gut bacteria;gut microbiome;microbiome;microbiome composition;mortality;mouse model;multidisciplinary;neutrophil;new therapeutic target;novel;novel strategies;prevent;probiotic therapy;prototype;rational design;receptor;single-cell RNA sequencing;spatiotemporal;stem;stem cell fate;stem cells;stomach cardia The Role of Secondary Bile Acids in Gastro-Esophageal Neoplasia PROJECT NARRATIVEDeaths from cancers arising from the gastro-esophageal junction represent a major public health burden yet thefactors that drive early changes in this region remain poorly understood. We aim to gain a clearer understandingof the effects of secondary bile acids produced by bacteria in the gut on stem cells in gastro-esophageal region.This knowledge can in turn be translated to future efforts to target the gut microbiome to prevent gastro-esophageal cancer. NCI 10693227 8/16/23 0:00 RFA-CA-21-026 5R01CA272898-02 5 R01 CA 272898 2 "YASSIN, RIHAB R" 9/1/22 0:00 8/31/27 0:00 ZCA1-RPRB-6(M)2 9047196 "ABRAMS, JULIAN " "QUANTE, MICHAEL ; WANG, HARRIS H" 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 812396 NCI 588000 224396 PROJECT SUMMARYStem and progenitor cells at the gastroesophageal junction (GEJ) have been identified as crucial to thedevelopment of adenocarcinoma of the distal esophagus gastroesophageal junction and proximal stomach.Combined these cancers have over 20000 new cases per year in the U.S. are associated high mortality andrepresent a major public health burden. Our group has identified both gastric cardia as well as GEJ transitionalbasal stem cells as likely cells of origin for precancerous states in this region. However defining the mechanismsand effectors that drive GE junction stem cell fate and promote cancer development remains a critical gap inknowledge. Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) represent the prototype forneoplasia arising from GE junction stem cells. We have extensive preliminary data demonstrating that circulatingsecondary bile acids derived from gut bacteria directly promote the development of BE and EAC treating ourL2-IL1B mouse model of BE/EAC with deoxycholic acid (DCA) accelerates neoplasia and treatment withobeticholic acid an agonist of nuclear bile acid receptor FXR (farnesoid X receptor) decreases proliferationGEJ stem cell numbers and dysplasia. However the exact mechanisms by which secondary bile acids impactGEJ stem cells and the associated microenvironment have not been elucidated. We hypothesize that circulatingsecondary bile acids produced by gut bacteria promote early cancer development via direct effects on GEjunction stem cells through FXR antagonism and by inducing pro-inflammatory microenvironment alterations.Using highly novel techniques and approaches (including scRNA-Seq and CyTOF) we will perform a series ofexperiments using mouse models mouse and human organoids and with validation of findings in a prospectivestudy of patients to address the following specific aims: Aim 1. To determine the role of circulating secondarybile acids in GEJ epithelial stem cell fate and early cancer promotion; Aim 2. To assess the effects of circulatingsecondary bile acids on the GEJ epithelial stem cell microenvironment; Aim 3. To determine whether targetedmicrobiome modification that regulates the circulating bile acid pool modifies GEJ cancer development. Toachieve these aims we will use our unique L2-IL1B mouse model with FXR knockout in stem cells (L2-IL1B/Fxrfl/fl) allowing us to assess the effects of secondary bile acids on GEJ stem cells as well the L2-IL1B/Nlrpfl/flmodel to explore inflammasome activation in stem cells and assess for cross-talk with the microenvironment.Ultimately we will perform experiments treating with distinct consortia of highly characterized bacterial strainsto modulate the secondary bile acid producing capacity of the gut microbiome and determine the effects oncancers arising from GE junction stem cells. Elucidation of the specific mechanisms by which secondary bileacids interact with GEJ stem cells and modify the microenvironment to promote cancer development may leadto the identification of novel therapeutic targets including the potential for rationally designed probiotic therapywhich would have a major public health impact. 812396 +No NIH Category available Adult;Age;Attention;Awareness;Cancer Center Support Grant;Catchment Area;Child;Childhood;Clinical Cancer Center;Clinical Data;Clinical Oncology;Clinical Protocols;Clinical Research;Clinical Trials;Combination immunotherapy;Community Outreach;Comprehensive Cancer Center;Conduct Clinical Trials;County;Data;Dedications;Dependence;Diagnosis;Disease;Documentation;Elderly;Electronics;Eligibility Determination;Enrollment;Ensure;Equity;Faculty;Funding;Health;Healthcare Systems;Hospitals;Individual;Infrastructure;Institution;Intervention;Intervention Trial;Leadership;Libraries;Location;Longevity;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Medical center;Metabolic;Minority;Minority Groups;Minority Participation;Monitor;Multicenter Trials;National Cancer Institute;Operations Research;Pediatric Oncology;Pediatric Oncology Group;Persons;Physician Executives;Procedures;Process;Protocol Compliance;Protocols documentation;Provider;Publishing;Radiation therapy;Renal carcinoma;Reporting;Research;Research Activity;Research Personnel;Risk;Safety;Satellite Centers;Services;Site;Solid Neoplasm;Support Groups;System;Technology;Texas;Time;Training;Underrepresented Minority;Underrepresented Populations;Underserved Population;Woman;Work;adverse event monitoring;anticancer research;cancer clinical trial;clinical trial participant;data management;demographics;design;ethnic diversity;ethnic minority;expectation;improved;inhibitor;investigator-initiated trial;oncology program;process improvement;quality assurance;racial diversity;racial minority;repository;research study;safety net;systems research;timeline;treatment trial;trial design Clinical Protocol and Data Management n/a NCI 10693226 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7282 11962354 "BEG, MUHAMMAD " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 540954 329850 211104 The Simmons Comprehensive Cancer Center (SCCC) Clinical Protocol and Data Management (CPDM)section reports information related to the (1) Clinical Research Office (CRO) (2) Data and Safety MonitoringCommittee (3) Inclusion of Women and Minorities in Clinical Research and (4) Inclusion of IndividualsAcross the Lifespan in Clinical Research. These efforts along with the Protocol Review and MonitoringSystem (PRMS) are closely monitored by the SCCC Clinical Cancer Research Committee which is led byDavid E. Gerber MD (Associate Director of Clinical Research). The CRO under the leadership of M.Shaalan Beg MD (CRO Medical Director) and Erin Williams MBA (CRO Administrative Director) providescomprehensive centralized services for the implementation and management of all oncology clinicalresearch studies conducted at UT Southwestern Medical Center (UTSW) and its affiliated healthcaresystems Parkland Health and Hospital System and Childrens Medical Center. The CRO serves as thecentral repository for all cancer studies maintains real-time reporting on research activities and providestraining and a library of standard operating procedures (SOPs) for all clinical research personnel. The Dataand Safety Monitoring Committee (DSMC) led by Jonathan Dowell MD operates independently of thePRMS and CRO and conducts risk-based monitoring for adverse events and protocol compliance for allSCCC interventional trials. The DSMC is supported by a three-person Quality Assurance Unit that ensuresthe highest level of protocol compliance according to the SCCCs National Cancer Instituteapproved DSMPlan. SCCC also promotes and monitors the inclusion of women and underrepresented minorities inclinical research. Key to promoting underrepresented minority participation in clinical research isSCCCs provision and support for clinical trials within its affiliate Parkland Health and Hospital Systemthesafety-net provider for Dallas County. The CRO also partners with the SCCC Office of CommunityOutreach Engagement and Equity to implement tailored strategies to support enrollment ofunderrepresented minorities. Inclusion of individuals across the lifespan is demonstrated most poignantlyby the CROs activities at Childrens Medical Center the largest pediatric oncology program in NorthTexas as well as SCCCs special attention to minimizing age restrictions in all clinical trials. In the currentCancer Center Support Grant funding period SCCC has made notable clinical research progress.Highlights include (1) a 28% increase in interventional treatment accruals since 2014 (48% increase forSCCC-led investigator-initiated treatment trials) (2) a 17% reduction in time to study activation (3)consistent enrollment of racial/ethnic minorities to trials proportional to SCCC catchment demographics(currently 34% of interventional accrual) and (4) a commitment to enrollment across the lifespan with SCCCamong the top 7% in accrual for all NCI Childrens Oncology Groupsupported institutions. +No NIH Category available Absenteeism;Address;Advanced Malignant Neoplasm;Area;Biology;Boston;Cancer Center;Cancer Control;Cancer Science;Cancer health equity;Charge;Color;Communities;Community Networks;Community Outreach;Creativeness;Data;Data Set;Dedications;Discipline;Disparity;Education;Ethnic Origin;Experimental Designs;Faculty;Foundations;Funding;Genomics;Goals;Government;Grant;Health Disparities Research;Incidence;Infrastructure;Institution;Joints;Lasers;Leadership;Malignant Neoplasms;Massachusetts;Mentors;Methods;Modeling;Morbidity - disease rate;Phase;Population;Population Group;Population Heterogeneity;Population Sciences;Postdoctoral Fellow;Race;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Solid;Source;Students;Training;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;anticancer research;cancer health disparity;career;career development;community engagement;community organizations;dissemination science;education research;experience;experimental study;implementation science;innovation;member;mortality;outreach;outreach program;programs;research and development;research study;socioeconomic disparity;translational model;translational potential 2/2 The University of Massachusetts Boston - Dana-Farber/Harvard Cancer Center U54 Comprehensive Partnership for Cancer Disparities Research PROJECT NARRATIVEThe University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC)Partnership is committed to further developing a shared rigorous and collaborative transdisciplinary cancer anddisparities-related research program that is primed for Bridging the Divides: Innovations to Address Gaps inCancer Disparities Research Education Outreach and Infrastructure. Sophisticated research projects areproposed across several areas of basic biomedical and population sciences that will employ evidence andmethods to converge upon and impact cancer and cancer health disparities at multiple levels of analysis.These projects together with state-of-the-art Outreach and Research Education Cores and creative ResearchDesign and Analysis Core and Genomics Cores will serve to build research capacity and infrastructure atUMass Boston expand the cancer disparities platform and community outreach programs at DF/HCC; andmake at an elevated level significant advances to the science of cancer control. NCI 10693225 8/29/23 0:00 PAR-18-767 5U54CA156732-13 5 U54 CA 156732 13 "WALI, ANIL" 9/27/10 0:00 8/31/26 0:00 ZCA1-SRB-2(A1)S 10189971 "ABEL, GREGORY ALAN" "VISWANATH, KASISOMAYAJULA " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1730738 NCI 1087983 642755 SUMMARYThe University of Massachusetts Boston (UMass Boston) and Dana-Farber/Harvard Cancer Center (DF/HCC)Partnership is primed for Bridging the Divides: Innovations to Address Gaps in Cancer DisparitiesResearch Education Outreach and Infrastructure. Our goal is to pursue Partnership activities andresearch that will bridge the divides in cancer disparities science research education and outreach throughinnovative research training and practice serving as models for translation at the state and national level. ThePartnerships to Advance Cancer Health Equity (PACHE) program itself is a prime example of bridged divides:partnerships formed between institutions have enhanced the education of underrepresented population groupsand provided well-established cancer centers with the necessary resources and research infrastructure toaddress cancer disparities.The specific aims of the UMass BostonDF/HCC Partnership are to: 1) Advance Partnership transdisciplinarycancer and cancer health disparities research programs reflecting the theme Bridging the Divides; 2) Developeducational experiences for students and trainees from a diverse population typically underrepresented inbiomedical careers; 3) Promote hiring and retention of diverse scholars particularly those fromunderrepresented populations by leveraging institutional resources; 4) Bridge research-community dividesthrough innovative platforms: forming and engaging networks of community-based organizations to advanceoutreach drawing on state of the science from dissemination and implementation sciences (D&I); 5) Developcutting-edge approaches to address data-absenteeism the lack of representation of underserved groups inpopulation- community- and genomics-based cancer and cancer disparities datasets and projects; and 6)Promote sustainability of partnership activities by reinforcing institutional support and grant matching with NIH-mechanisms and other sources of government foundation and philanthropic support. 1730738 +No NIH Category available Accountability;Achievement;Area;Award;Cancer Burden;Cancer Center;Cancer Center Support Grant;Caring;Catchment Area;Charge;Clinical;Communities;Community Outreach;Comprehensive Cancer Center;Education;Education and Outreach;Evaluation;Feedback;Foundations;Goals;Intervention Trial;Investments;Leadership;Maps;Medical center;Mission;Modeling;National Cancer Institute;Patient Care;Phase;Play;Policies;Practice Management;Process;Recording of previous events;Research;Research Personnel;Resource Allocation;Resources;Role;Science;Strategic Planning;Texas;Training and Education;Translating;Translational Research;Vision;anticancer research;cancer health disparity;cancer prevention;clinical care;community engagement;experience;implementation strategy;meetings;novel;recruit;success;translational scientist Leadership Planning and Evaluation n/a NCI 10693224 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7281 1894038 "ARTEAGA, CARLOS L" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 562614 343057 219557 Simmons Comprehensive Cancer Centers (SCCC) vision is to become a preeminent leader in translatingscientific discovery into cancer prevention and world-class care with an emphasis on community engagementefforts to eradicate cancer disparities in Texas and beyond. This vision is realized though SCCCs mission toease the burden of cancer through ground-breaking discovery transdisciplinary research impactful communityengagement education and exceptional patient care. It is pursued through a multi-faceted dynamic planningand evaluation process that is guided by a comprehensive strategic plan as well as input from both internal andexternal advisory entities. Renowned translational researcher and Center Director Carlos L. Arteaga MD whoarrived from the Vanderbilt-Ingram Cancer Center in 2017 has been instrumental in leading efforts to recast areinvigorated mission vision and road map for SCCC. Arteagas highly experienced and engaged team of eightAssociate Directors form an Executive Committee (EC) which is responsible for advising him on theestablishment of policies and practices for the management of SCCC and prioritizing new opportunities andinvestments. More importantly the EC is responsible for the +No NIH Category available Area;Award;Basic Science;Budgets;Cancer Center Support Grant;Charge;Clinical Investigator;Clinical Sciences;Comprehensive Cancer Center;Development;Extramural Activities;Funding;Funding Mechanisms;Goals;Grant;Investments;Leadership;Link;Medical center;National Cancer Institute;National Clinical Trials Network;Pilot Projects;Population Sciences;Request for Applications;Research;Research Personnel;Research Project Grants;Research Support;Resources;Strategic Planning;Translational Research;anticancer research;clinical investigation;innovation;investigator-initiated trial Developmental Funds n/a NCI 10693222 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7280 1894038 "ARTEAGA, CARLOS L" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 470665 286991 183674 Simmons Comprehensive Cancer Center (SCCC) utilizes the Cancer Center Support Grant (CCSG)developmental funds to invest in specific efforts that support the research goals of the Centers overall strategicplan. During the current project period a total of $590000 of CCSG developmental funds was distributed forpilot funding in support of 23 research projects and to date these investments have already yielded a $16Mreturn on investment. More importantly the SCCC Senior Leadership leveraged the CCSG developmental fundswith other Center resources during the project period. In total SCCC invested $5.3M in pilot awards since 2014which can be directly linked to the successful award of $48.7M in extramural multi-year grant funding. This isover a nine-fold yield from the combined investment. In the next project period SCCC is requesting $410000annually in developmental funds representing 11% of the total CCSG budget request. SCCC Senior Leadershipwill continue to support pilot projects but in addition it also will be supporting up to 20% effort for one early-stageclinical investigator annually who will be charged with developing and launching an innovative investigator-initiated trial and maximizing SCCCs participation in the National Cancer Institutes National Clinical TrialsNetwork. +No NIH Category available Acrolein;Adult;Affect;Alcohol consumption;Alcoholic Beverages;Alcoholic beverage heavy drinker;Alcohols;Cancer Etiology;Carcinogens;Cells;Characteristics;Cigarette Smoker;Collecting Cell;DNA;DNA Adduction;DNA Adducts;DNA Damage;DNA Structure;DNA analysis;Data;Disease;Early Diagnosis;Electrospray Ionization;Genes;Goals;Growth;Head and Neck Squamous Cell Carcinoma;Heavy Drinking;Human;Human Papillomavirus;Incidence;Individual;Intervention;Larynx;Life Style;Light;Lipid Peroxidation;Malignant Neoplasms;Measurement;Methodology;Methods;Monitor;Mucous Membrane;Mutation;Names;Operative Surgical Procedures;Oral;Oral Examination;Oral cavity;Patients;Pattern;Persons;Pharyngeal structure;Predisposition;Prevention;Process;Research;Resolution;Risk;Sampling;Smoker;Smoking;Source;Surface;Testing;Time;Tissues;Tobacco;adduct;analytical method;carcinogenicity;cigarette smoke;cigarette smoking;comparison group;high risk;indexing;nano-liquid chromatography;non-smoker;prevent;problem drinker;recruit;smoking cessation;statistics;tandem mass spectrometry;toxicant;tumor High resolution mass spectrometric profile analysis of carcinogen-DNA adducts in oral cells of cigarette smokers and squamous cell carcinoma of the head and neck Squamous cell carcinoma of the head and neck (HNSCC) comprises malignancies arising mainly from themucosal surface of the oral cavity pharynx and larynx. It is a devastating frequently disfiguring and oftenfatal disease which is expected to affect more than 53000 people in the U.S. in 2020 and kill more than10000. This project will establish a profile analysis of DNA damage in oral cells of cigarette smokers andalcohol drinkers and relate this to the presence of HNSCC so that the profile can be used to identify thoseindividuals who are at high risk for this terrible disease. NCI 10693217 8/25/23 0:00 PA-20-185 5R01CA263084-03 5 R01 CA 263084 3 "WANG, WENDY" 9/21/21 0:00 8/31/26 0:00 Cancer Etiology Study Section[CE] 1865674 "HECHT, STEPHEN S" "KHARIWALA, SAMIR S" 5 PATHOLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 628566 NCI 405526 223040 Squamous cell carcinoma of the head and neck (HNSCC) is a devastating frequently disfiguring and oftenfatal disease expected to affect more than 53000 people in the U.S. in 2020 and kill more than 10000.Prevention of this terrible disease is critical. Cigarette smoking alcohol consumption and human papillomavirus (HPV) are well established major causes of HNSCC; only smoking and alcohol consumption areconsidered here. Cigarette smoking and alcoholic drinks are sources of multiple DNA adducts that are criticalin the carcinogenic process. This proposal will establish a liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry (LC-NSI-HRMS/MS) profile analysis of 12 oral cell DNA adductsthat are likely causes of HNSCC. This was inspired by our recent analysis of DNA adducts in oral cells inwhich we found levels more than 20 times higher in cigarette smokers than in non-smokers. These excitingresults encouraged us to propose a profile analysis of important carcinogen-derived DNA adducts in oral cellsaccording to the following specific aims:1. Develop an LC-NSI-HRMS/MS profile analysis method for quantitation of 12 important and representative carcinogen and toxicant DNA adducts in human oral cells and tissue. The adducts are derived from various carcinogens and DNA reactive compounds in cigarette smoke and alcoholic beverages.2. Apply the profile analysis to oral cells from currently healthy individuals: a) 100 non-smokers who are non- drinkers or light drinkers; b) 100 cigarette smokers who are non-drinkers or light drinkers; and c) 100 cigarette smokers who are moderate or heavy drinkers. Comparisons of adduct levels in groups a and b will identify adducts enhanced by cigarette smoking while comparisons of groups b and c will identify adducts that are enhanced by the combination of smoking and moderate or heavy drinking.3. Test the longitudinal stability of the oral cell DNA adduct profile analysis over a 6 month period in 50 smokers who are non-drinkers or light drinkers.4. A) Determine the DNA adduct profile in oral cells collected from 75 smokers with HNSCC and compare to that in 200 smokers without HNSCC recruited in Specific Aim 2 with the goal of identifying an adduct profile that is characteristic of HNSCC incidence. B) Compare the oral cell DNA adduct profile from part A of this aim to that in tissue both normal and tumor in a subset of 60 patients from part A who undergo surgery to determine whether oral cell DNA adduct patterns are consistent with those in tissue.Our results will potentially identify individuals who are susceptible to HNSCC but are unable to quit smoking.Once identified aggressive lifestyle and monitoring interventions in these subjects such as oral examinations2-4 times per year can be initiated for prevention or early detection of this disfiguring and often fatal cancer. 628566 +No NIH Category available Acidosis;Address;Adult;Antitumor Response;Area;Autoantibodies;Award;Back;Basic Science;Biological Markers;Biotechnology;Breast;Catchment Area;Cell Cycle Checkpoint;Cells;Chemical Modifier;Chemicals;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Correlative Study;DNA Repair;Development;Diagnostic;Disease;Drug Delivery Systems;Education;Epigenetic Process;Equity;Estrogen Receptors;Excision;Faculty;Feedback;Funding;Future;Genomics;Goals;Hematologic Neoplasms;Human;Image;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Markers;Immunologic Surveillance;Immunooncology;Immunotherapy;Infrastructure;Investigational Therapies;Investments;KRAS2 gene;Laboratories;Lead;Leadership;Libraries;Lung;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medical center;Metabolic;Metabolism;Molecular;Monitor;NCI Center for Cancer Research;Nanotechnology;Natural Immunity;Natural Products;Neoplasm Metastasis;Oncology;Operative Surgical Procedures;Organ;Organoids;Pathologic;Phase;Population Sciences;Positron-Emission Tomography;Pre-Clinical Model;Prediction of Response to Therapy;Program Sustainability;Radiation Oncology;Radiation therapy;Radiation-Sensitizing Agents;Renal carcinoma;Research;Research Personnel;Role;Science;Specimen;Testing;Therapeutic;Tracer;Translating;Translational Research;Tumor Antigens;Work;antagonist;biomarker discovery;cancer cell;cancer diagnosis;cancer immunotherapy;cancer therapy;cancer type;clinical development;clinical translation;clinically relevant;combat;design;drug development;early phase clinical trial;functional genomics;humanized mouse;imaging agent;imaging capabilities;immunogenic;improved;inhibitor;innate immune pathways;investigator-initiated trial;malignant breast neoplasm;member;molecular drug target;molecular marker;mutant;nanoparticle;neuro-oncology;new therapeutic target;novel;novel imaging technology;novel strategies;precision oncology;preclinical development;predicting response;predictive marker;programs;recruit;response;siRNA delivery;success;synergism;targeted cancer therapy;therapeutic biomarker;therapeutic development;therapeutic evaluation;therapy outcome;therapy resistant;translational impact;translational research program;translational scientist;translational study;translational therapeutics;tumor;tumor microenvironment;tumor progression Experimental Therapeutics Program n/a NCI 10693213 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7274 9068342 "HAMMERS, HANS " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 79273 48337 30936 The Experimental Therapeutics (ET) Program provides an organized integrated infrastructure that enables both clinical translation of basic and population science research from Simmons Comprehensive Cancer Center (SCCC) research programs and identification of clinically relevant hypotheses for testing by SCCC basic science programs. The four program specific aims focus on therapeutic development and biomarker discovery where members work collectively to: (1) develop molecular therapeutic sensitizers by focusing on the development of unique tumor-selective agents that enhance existing therapies (2) target tumor microenvironment with immunotherapy by modulating the role of immune cells in tumor progression (3) advance imaging and drug delivery by developing novel imaging and nanotechnology delivery platforms to enhance cancer diagnosis and therapy and (4) exploit cancer vulnerabilities by leveraging synthetic lethalities as new targeted therapy for cancer. The ET Program brings together 78 SCCC members from six basic science and 12 clinical departments comprising 44 NCI-funded projects including two SPOREs and 14 multi-PD/PI awards. In response to evaluative activities and strategic goals to facilitate collaborative translational research ET recruited new senior clinical researchers; expanded translational studies and investigator-initiated clinical trials (IITs) to include most cancer types and to address the needs of the catchment area; enhanced interactions with SCCC members; integrated radiation oncology faculty into the program; and improved the infrastructure and funding for IITs. ET members participate in and lead multicenter IITs and they collaborate with pharma/biotech which often leads to investigator-initiated trials and translational studies. Importantly the funded SPORE programs in kidney and lung cancers and new SPORE applications in prostate and liver cancers are actively supported by ET member expertise. The ET Program has expanded therapeutic pipelines in a majority of adult and pediatric cancers. Highlighted successes include the in-house development and clinical translation of therapeutic strategies for KRAS mutant cancers HIF2alpha-targeting for kidney cancer antagonists against mutant estrogen receptors in breast cancers strategies to activate the STING innate immune pathway and clinical trials capitalizing on synergy between stereotactic radiation therapy and immune checkpoint inhibitors. Future directions include investment in preclinical models (spheroid/organoid cultures humanized mice) precision oncology (customized panels SCCC molecular tumor boards recruitment of a translational leader in genomic oncology) immuno- oncology (immune profiling; novel PET tracers; systemic and organ-specific autoantibody biomarkers; expansion of the innate immunity program) disease-focused translational research programs (recruitment of leadership in breast GI lung GU neuro-oncology hematologic malignancies and Phase I programs); and expansion of interactions with the Office of Community Outreach Education & Equity in order to increase clinical trial accruals across our catchment area and among the underserved. +No NIH Category available Activated Lymphocyte;Active immunity;Biology;CD8-Positive T-Lymphocytes;Cancer Biology;Cell physiology;Cells;Cellular biology;Clinical Trials;Data;Dendritic Cells;Engineering;Ensure;Future;Genetic;Goals;Human;Immune;Immunity;Immunology;Immunooncology;Immunotherapy;Infection;Infiltration;Institution;Interleukins;Ligands;Lymphocyte;Lymphoid Cell;Malignant Neoplasms;Malignant neoplasm of pancreas;Modeling;Molecular;Morals;Mus;Nature;Neoplasm Metastasis;Oncology;Organoids;PD-1 blockade;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Proteins;Regulation;Reporting;Research Personnel;Sampling;Survivors;T-Cell Activation;T-Lymphocyte;Testing;Th2 Cells;Tissues;Transgenic Organisms;Tumor Immunity;Tumor Necrosis Factor-Beta;cell motility;chemokine;cytokine;density;experience;immune checkpoint;immunogenic;migration;mouse model;multidisciplinary;novel;programmed cell death protein 1;rare cancer;recruit;response;restraint;skills;stem cells;tertiary lymphoid organ;therapeutic target;tool;transcriptomics;translational potential;tumor Group 2 Innate Lymphoid Cell Regulation of Pancreatic Cancer Immunity PROJECT NARRATIVEAs current immunotherapies boost T cells to kill cancers they are ineffective in ~80% of tumors that containtoo few T cells (cold tumors). We have identified a new immunotherapy to activate a new immune cell calledgroup 2 innate lymphoid cells (ILC2s) which increase T cells to control pancreatic cancer a deadly cold tumor.We now propose to study how ILC2s increase T cells in pancreatic cancer so that we may identify better waysto activate ILC2s in immunotherapies. NCI 10693207 8/10/23 0:00 PA-20-185 5R01CA262516-02 5 R01 CA 262516 2 "KUO, LILLIAN S" 9/1/22 0:00 8/31/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 9594184 "BALACHANDRAN, VINOD P" "MERGHOUB, TAHA " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 548714 NCI 310008 238706 PROJECT SUMMARY/ABSTRACTImmunotherapies that boost anti-tumor T cells are landmark breakthroughs in oncology. Yet currentimmunotherapies directly activate T cells and are therefore ineffective in ~80% of tumors with few T cells (coldtumors). Thus a primary challenge in oncology is to develop effective immunotherapies for cold tumors.Pancreatic ductal adenocarcinoma (PDAC) is a prime example ~91% of tumors have few T cells and thusPDAC rarely responds to current immunotherapies (<2% response rate). Yet immunotherapy is the mostpromising option in PDAC as all other therapies have failed and only the rare (9%) patients with immunogenichot tumors (high density of intratumoral T cells) survive long-term. Thus new immunotherapies are urgentlyneeded for PDAC and the principles can be applied to other cold tumors.To discover new targets that active immunity in PDAC we contrasted immune cells in hot tumors from rare long-term PDAC survivors to those in more typical cold tumors from short-term survivors. Unexpectedly we foundthat hot tumors have ~3-fold higher densities of group 2 innate lymphoid cells (ILC2s) (Moral et al. Nature 2020).ILC2s are lymphocytes that amplify CD4+ Th2 cells in infection but paradoxically can activate CD8+ T cells intumors. Using mouse models we found that ILC2s recruit CD103+ dendritic cells to activate CD8+ T cells andsuppress primary PDACs. Through further studies we have now found that unlike currently presumed ILC2scan also migrate to suppress metastatic PDAC tumors express lymphotoxin (LT) a protein that induces tertiarylymphoid structures in tumors and express the immune checkpoint PD-1 that regulates their anti-tumor function.As we are the first group to report that ILC2s can activate immunity in PDAC the mechanisms by which ILC2ssuppress PDACs which can thus inform rational strategies to harness them in immunotherapies are unknown.Thus we now propose to study how ILC2s migrate to tumors activate CD8+ T cells and are functionallyregulated. Through integrated multi-disciplinary study of ILC2 phenotype and function in human PDAC patientspatient-derived organoids and functional studies in mouse models we will: 1) define the cytokines that mobilizeanti-tumor ILC2s; 2) investigate how anti-tumor ILC2s utilize LT to activate CD8+ T cells; and 3) demonstratehow PD-1 blockade enhances anti-tumor ILC2 function. To ensure a cross-disciplinary approach we will use anexperienced team of investigators with complementary skills in PDAC biology ILC2 immunologyimmunotherapy organoid models and computational oncology. We expect our proposal will lay the scientificframework to understand ILC2 cancer biology and guide efforts to harness ILC2s in new immunotherapies. 548714 +No NIH Category available Abnormal Cell;Acceleration;Basic Science;Bioenergetics;Biological Markers;Cancer Center Support Grant;Catchment Area;Cell Death Signaling Process;Cells;Cellular biology;Clinic;Clinical;Clinical Oncology;Collaborations;Complement;Comprehensive Cancer Center;DNA Sequence Alteration;Data;Development;Disease;Disease Progression;Doctor of Philosophy;Environment;Evolution;Faculty;Fostering;Funding;Gene Expression Regulation;Genetic;Goals;Growth;Guidelines;Homeostasis;Human;Immunobiology;Infrastructure;Intervention;Intervention Studies;Journals;Knowledge;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical center;Mentors;Metabolism;Molecular;Neoplasm Metastasis;Non-Malignant;Patients;Peer Review;Physicians;Physiology;Population;Population Research;Positioning Attribute;Prevention strategy;Primary Neoplasm;Process;Productivity;Publications;Renal carcinoma;Research;Research Personnel;Resistance;Resource Sharing;Role;Science;Scientist;Signal Transduction;Solid;Specimen;Structure;Therapeutic Intervention;Tissues;Translating;Translations;Tumor Cell Biology;Vision;Work;cancer initiation;cancer prevention;cancer therapy;cell behavior;collaborative environment;design;diagnostic technologies;epigenetic regulation;fundamental research;insight;inter-institutional;live cell imaging;member;mortality;neoplastic cell;novel strategies;prevent;programs;success;translational potential;treatment strategy;tumor;tumor microenvironment;tumor progression;tumorigenesis Cellular Networks in Cancer Program n/a NCI 10693205 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7271 1883055 "COBB, MELANIE H." Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 26953 16435 10518 The Cellular Networks in Cancer (CNC) Program is a scientifically rich collaborative and productive researchprogram co-led by Melanie Cobb PhD and Ralph DeBerardinis MD PhD. The vision of the CNC Program isto advance the fundamental knowledge of both intercellular and intracellular networks that contribute to cancerinitiation tumorigenesis and metastasis then to translate these findings into novel approaches to cancerprevention and therapy. CNCs overarching scientific goal is to promote discoveries in how perturbation in thesecellular networks contribute to altered tissue physiology and promote cancer. The CNC Program provides ahighly interactive research environment that capitalizes on the UT Southwestern Medical Centers (UTSW)longstanding tradition of basic science discoveries and fosters translation of these discoveries into thedevelopment of new biomarkers diagnostic technologies and therapeutic interventions in clinical oncology-especially malignancies relevant to the SCCC catchment area (e.g. cancer of the lung and kidney). Theprograms structure is purposefully designed to stimulate interdisciplinary intra- and interprogrammaticcollaborations with the objective of delivering transformative discoveries. To accomplish this the Co-Leadersestablished four vibrant and synergistic subprograms that deliberately align with the strengths of programmembers and specifically relate to states of perturbed tissue homeostasis in cancer: (1) Signaling and CellBiology (2) Epigenetics and Gene Regulation (3) Immunobiology and (4) Metabolism. Each subprogram isdirected by an investigator who is highly respected for his or her science mentoring and collaborative spirit. Thesubprogram structure and activities have directly contributed to exciting new collaborative projects such as theSPORE in Kidney Cancer. The CNC Program is composed of 59 basic computational and physician-scientistsfrom 19 departments and centers at UT Southwestern Medical Center. Seven members of the CNC are HowardHughes Medical Institute investigators. Annual direct peer-reviewed funding to the CNC Program was $19.3Min 2019. This represents an increase of $3.8M as compared with 2014 data which were adjusted to conform torevised NCI guidelines. NCI funding has likewise increased from $3M in 2014 to $3.9M in 2019. Programmembers have authored 750 publications since 2014: 14% represent intraprogrammatic work 34% areinterprogrammatic collaborations 32% are inter-institutional and 37% are in journals with an impact factor 10.CNC Program members are heavily reliant upon all six CCSG Shared Resourcesespecially Live Cell Imagingand Tissue Managementin furtherance of their scientific goals. The CNC Programs success is supported bySCCCs strong infrastructure and grounded in the programs solid interactions among CNC members and thesubprograms as well as with other SCCC Research Program members and external collaborators. +No NIH Category available Academic Medical Centers;Administrator;Budgets;Cancer Center;Cancer Center Support Grant;Charge;Clinical Data;Clinical Protocols;Collaborations;Communication;Comprehensive Cancer Center;Data;Decision Making;Dedications;Development;Documentation;Environment;Equipment;Evaluation;Faculty Recruitment;Funding;Funding Mechanisms;Goals;Grant;Human Resources;Individual;Information Systems;Information Technology;Institution;Leadership;Medical center;Mission;Monitor;Outcomes Research;Pilot Projects;Process;Progress Reports;Reporting;Research;Research Personnel;Resource Sharing;Resources;Services;Strategic Planning;Vision;data management;experience;faculty support;meetings;member;operation;programs;technology platform Cancer Center Administration Core n/a NCI 10693202 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 7269 1894038 "ARTEAGA, CARLOS L" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 437014 266472 170542 The overarching goal of the Simmons Comprehensive Cancer Center (SCCC) Administration is to provide anefficient and effective administrative environment that nurtures and supports the Center's mission and vision.Administration's specific goals are to deliver value-added support to Cancer Center members by providing stellaradministrative support and leadership in facilitating collaborative transdisciplinary and multi-investigatorresearch; decision-making data from its information technology platforms; strategic planning implementationand monitoring; and support for the other CCSG components essential to SCCC such as shared resourcesclinical protocol and data management developmental funds and planning and evaluation. Administration'sservices include: Management of the CCSG application progress reports and supplements Financial coordination and oversight including budgeting and management of philanthropic resources Management of the membership processes research and grants activities and SCCC space Coordination of pilot funding mechanisms Oversight and management of operational aspects of the shared resources Representation of SCCC among UTSW institutional entities and collaboration with their representatives Support for faculty recruitment retention promotion and tenure Coordination and documentation of Center meetings Human resource management for CCSG personnel +No NIH Category available Address;Authorization documentation;Award;Basic Science;Biometry;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Science;Caring;Catchment Area;Chemistry;Child;Clinic;Clinical;Clinical Investigator;Clinical Sciences;Clinical Trials;Collaborations;Communities;Community Health Education;Community Outreach;Comprehensive Cancer Center;County;Coupling;Data Science;Development;Diagnosis;Disparity;Education;Educational Activities;Ensure;Extramural Activities;Fostering;Funding;Generations;Growth;Health;Health Personnel;Health system;Hospitals;Improve Access;Infrastructure;Institution;Intervention;Investigational Therapies;Investments;Laboratories;Leadership;Malignant Neoplasms;Medical center;Mission;Movement;National Cancer Institute;Outcome;Outpatients;Patient Care;Patients;Physicians;Pilot Projects;Population Heterogeneity;Population Sciences;Population Study;Positioning Attribute;Prevention;Prevention approach;Prevention education;Qualifying;Renal carcinoma;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Scientist;Secure;Shoulder;Strategic Planning;System;Texas;Tissues;Training and Education;Translating;Translational Research;Vision;animal imaging;anticancer research;authority;cancer care;cancer education;cancer health disparity;cancer prevention;cancer therapy;clinical care;clinical investigation;community engagement;design;empowerment;high throughput screening;improved;innovation;international center;live cell imaging;member;multidisciplinary;next generation;novel strategies;operation;outreach;outreach program;programs;rapid growth;recruit;training opportunity;translational impact UT Southwestern Medical Center Simmons Comprehensive Cancer Center OVERALLPROJECT NARRATIVEThe NCI-designated Simmons Comprehensive Cancer Center integrates cancer research cancercare cancer control community outreach and education and training across UT SouthwesternMedical Center and its health system affiliates. The overriding mission of the Center is to leveragethese affiliations and the exceptional resources available to foster translational research and improvecancer outcomes in the Dallas-Fort Worth (DFW) region and the nation. NCI 10693201 7/12/23 0:00 PAR-20-043 5P30CA142543-13 5 P30 CA 142543 13 "BELIN, PRECILLA L" 9/1/10 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 1894038 "ARTEAGA, CARLOS L" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 4306073 NCI 2625654 1680419 The Harold C. Simmons Comprehensive Cancer Center (SCCC) is the National Cancer Institute (NCI)-designated cancer center of the UT Southwestern Medical Center (UTSW) and its health system affiliatesParkland Health & Hospital System and Childrens Medical Center of Dallas. SCCCs mission is to ease theburden of cancer through ground-breaking discovery transdisciplinary research impactful communityengagement education and exceptional patient care. Upon arrival as the new Director in 2017 Carlos L.Arteaga MD shouldered authority over UTSW cancer activities and recasted a vision for the Center that focuseson the translation of science into the forefront of UTSWs overall mission. To accomplish this the SCCC StrategicPlan 2020-2025 prioritizes an increase in cancer-focused funding and infrastructure support for clinical trialsexpansion of the clinical capacity for cancer treatment through further developed multidisciplinary cancer carea new > 300000 sf. Outpatient Cancer Care Tower and a renewed emphasis on community outreach andengagement. In addition SCCC will continue to create educational and training opportunities aimed atempowering a new generation of basic scientists physician-scientists clinical investigators and other healthcareproviders to make a difference in cancer discovery clinical investigation and care cancer control and communityoutreach. The Centers operations are optimized through a visionary and highly qualified Senior Leadership teamand a value-creating administrative infrastructure. Together leadership infrastructure and an engaged Centermembership of 227 scientists and clinical investigators are organized into five highly interactive researchprogramsCellular Networks in Cancer Development and Cancer Chemistry and Cancer ExperimentalTherapeutics and Population Science and Cancer Control. During the current six-year funding cycle SCCC hassecured several large collaborative multi-investigator awards including a new SPORE in kidney cancer six newU01s and two new U54s and maintains two NCI-funded T32s. As a result of strengthening the clinical trialsinfrastructure accruals to interventional clinical trials has more than doubled. The rapid pace of discovery andmovement toward effective translational research is supported by six shared resources: Biostatistics DataScience High Throughput Screening Live Cell Imaging Small Animal Imaging and Tissue Management. TodaySCCC has $25M in annual direct NCI funding. It has successfully leveraged Cancer Center Support Grant(CCSG) funding during the current period to continue the rapid growth of the Center as demonstrated by therecruitment of 97 new members. SCCC has invested $210M since 2014 (six years) and has secured another$232M in institutional commitment for the next five years to increase the range of available resources. Theseimpressive developments ensure that catchment area needs and concerns are addressed and SCCC scientistswill continue their exemplary track record in advancing understanding of cancer biology while coupling thesefindings with the development of novel approaches to cancer control diagnosis and treatment. 4306073 +No NIH Category available 3' Untranslated Regions;3q26;5' Untranslated Regions;Animals;Autocrine Communication;Binding;Biochemical;Bioinformatics;Biological Markers;Cancer Patient;Cell Nucleus;Cells;Cisplatin;Complex;Computing Methodologies;Copy Number Polymorphism;Data;Development;Encapsulated;Endothelial Cells;Epigenetic Process;Gene Expression;Genes;Genetic Transcription;Growth;Growth Factor;Immunoprecipitation;Importins;In Vitro;Individual;Initiator Codon;Interleukins;Intervention;KDR gene;Knowledge;Ligands;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mediating;Metastatic Malignant Neoplasm to the Ovary;MicroRNAs;Modeling;Molecular;Molecular Conformation;NOS2A gene;Neoplasm Metastasis;Oncogenes;Oncogenic;Outcome;Pathway interactions;Phosphorylation;Proteins;Proteomics;Publications;Publishing;RNA;RNA Polymerase II;Receptor Signaling;Reporting;Research;Role;Signal Induction;Signal Transduction;Site;Solid Neoplasm;Stat3 protein;Stat5 protein;Testing;Therapeutic;Transcription Factor 3;Transcription Initiation;Transcriptional Activation;Translating;Translations;Tumor Promotion;Untranslated RNA;VEGFA gene;Vascular Endothelial Growth Factors;addiction;angiogenesis;cancer cell;cytokine;design;experimental study;improved;in silico;in vivo;in vivo Model;indexing;inhibitor;mRNA Expression;mRNA Stability;malignant breast neoplasm;neoplastic cell;new therapeutic target;novel;novel marker;oncogene addiction;oncostatin M;overexpression;paracrine;pharmacologic;posttranscriptional;promoter;receptor;targeted agent;therapeutic candidate;therapeutic target;transcription factor;transmission process;tumor;tumor growth;tumor progression;tumorigenesis Role of RNA activation in Tumor Progression and Metastasis Our preliminary data demonstrates an unexpected role of microRNAs on transcriptional activation ofmaster regulator STAT3 oncogene in ovarian cancer. Using cellular molecular biochemical approaches(in vitro) animal studies bioinformatical and computational methods (in silico) we will elucidate individualand collective effect of microRNA-551b aberrations and RNA activation resulted due to the 3q26.2amplification and their potential role in the tumorigenesis and progression of ovarian cancer. Based on ourresults our study will result a paradigm shift in our understanding of the transcriptional andposttranscriptional effects of microRNAs and identify novel biomarkers and therapeutic targets to treatovarian cancer. NCI 10693200 8/22/23 0:00 PA-18-484 5R01CA229907-05 5 R01 CA 229907 5 "WATSON, JOANNA M" 9/10/19 0:00 8/31/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 11244508 "CHALUVALLY RAGHAVAN, PRADEEP " Not Applicable 4 OBSTETRICS & GYNECOLOGY 937639060 E8VWJXMMUQ67 937639060 E8VWJXMMUQ67 US 43.04575 -88.020374 46001 MEDICAL COLLEGE OF WISCONSIN MILWAUKEE WI SCHOOLS OF MEDICINE 532263548 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 334391 NCI 236844 97547 Our studies identified that microRNAs amplified in the 3q26.2 locus are critical players in the progression andmetastasis of ovarian cancer (Cancer Cell 2014 and Cell Reports 2016). Our data demonstrate thatmicroRNA miR551b is amplified and overexpressed as a consequence of 3q26.2 locus amplification and isan unexpected driver in ovarian cancer. miRNAs are thought to primarily downregulate mRNA expressionthrough decreasing mRNA stability and protein translation through binding complementary seed sequencesin the 3'UTR. However the mechanism by which miR551b contributes to the progression and metastasis ofovarian cancer and whether it represents a novel targetable avenue remains to be ascertained. Our studiesidentified an unexpected seed match of miR551b on the STAT3 NOS2 and STAT5 promoter in the 5'UTRupstream of the transcription initiation codon at a site of predicted binding for multiple transcription factors(TFs). Our data shows that miR551b directly interacts with the STAT3 promoter and activates STAT3transcription through a mechanism called RNA activation (RNAa). We identified that tumor cells employ theRNAa mechanism for rapid induction of oncogenes for the progression and metastasis. We furtherdemonstrate that RNAa mediated induction of STAT3 transcription factor upregulates STAT3-inducedcytokines including Oncostatin M (OSM) and Interleukin-31 as well as their receptors OSMR and IL31R.We hypothesize that the above receptor-ligand interactions launch a self-reinforcing feed-forward loop thatestablishes a targetable oncogene addiction pathway in tumor cells. While the respective growth factors likeOSM IL31 VEGFA and their receptors and VEGFR IL31R and OSMR activate autocrine signaling foroncogenic addictions in tumor cells; growth factors like OSM and VEGF induces paracrine effect in tumorendothelial cells for neo-angiogenesis a vehicle for tumor metastasis. Thus interfering the RNAa mechanisminduced by miR551b will provide an unprecedented opportunity to disrupt tumor progression and metastasis.To disrupt the signaling addiction mechanism; we propose to use anti-miR551b encapsulated innanoliposme for in vivo delivery to inhibit the progression and metastasis of ovarian cancer. In brief ourstudies on the role of miR551b in ovarian cancer are designed to increase our understanding on the roles ofmicroRNA amplifications in ovarian cancer. We expect that our studies on miR551b will help us to identifynovel mechanisms and therapeutic approaches for ovarian cancer. miR551b is highly amplified andoverexpressed in breast lung and cervical cancers. Therefore we expect that our results can be translatedbroadly into other cancers that encompass miR551b amplification. 334391 +No NIH Category available Acceleration;Basic Science;Biological Response Modifier Therapy;Biology;Cells;Chemicals;Code;DNA sequencing;Development;Future;Goals;Human;Human Genetics;Immune;Immunology;Immunooncology;Knowledge;Malignant Neoplasms;Maps;Medicine;Methods;Modernization;Molecular;Mutate;Natural Immunity;Oncogenes;Play;Proteins;Proteome;Proteomics;Research;Role;System;Technology;Therapeutic;Translating;Translational Research;Validation;activity-based protein profiling;adaptive immunity;anticancer research;biological systems;cancer cell;cancer therapy;gene discovery;genetic information;innovation;insight;novel therapeutics;pharmacologic;programs;protein degradation;small molecule;small molecule libraries;technological innovation;tumorigenesis;ubiquitin-protein ligase Chemical Proteomic Platforms for Radically Expanding Cancer Druggability Modern human genetics has provided remarkable insights into the molecular basis of cancer but manygenetically-defined cancer targets lack chemical probes and are even considered potentially undruggable. Thegoal of this research program is to leverage our labs pioneering chemical proteomic technologies to radicallyexpand the druggable content of human cancer cells for the creation of chemical probes and ultimatelytherapeutics for biologically compelling human cancer targets. NCI 10693197 8/9/23 0:00 PAR-17-494 5R35CA231991-06 5 R35 CA 231991 6 "FU, YALI" 9/1/18 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 2132494 "CRAVATT, BENJAMIN F" Not Applicable 50 Unavailable 781613492 PHZJFZ32NKH4 781613492 PHZJFZ32NKH4 US 32.903062 -117.243592 7375802 "SCRIPPS RESEARCH INSTITUTE, THE" LA JOLLA CA Other Domestic Non-Profits 920371000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1137779 NCI 587999 549780 Cancer research and treatment have greatly benefited from advances in DNA sequencing methods whichhave accelerated the discovery of genes that when mutated promote tumorigenesis. The protein products ofsome of these oncogenes have served as direct targets for groundbreaking new medicines. Many oncogeneshowever code for proteins that lack chemical probes and are even considered undruggable. In these casesour understanding of the molecular basis of cancer has not yet translated into effective new therapies. A similargap can be found in cancer-related immunology (or immuno-oncology) where human genetics is discoveringproteins that play fundamental roles in innate and adaptive immunity; yet again most of these proteins lackchemical probes. A critical challenge has thus emerged in cancer research how can the massive gains inunderstanding of cancer and immunology bequeathed by modern human genetics be translated into newtherapies for cancer? The goal of this research program is to leverage and extend our labs innovative activity-based protein profiling (ABPP) technology to radically expand the druggable content of the human proteomeand develop high-quality chemical probes for genetically-defined protein targets in cancer and immuno-oncology. We have recently introduced advanced ABPP platforms that evaluate small-molecule interactionsacross thousands of proteins in parallel directly in native biological systems. By combining proteome-widedruggability maps of human cancer and immune cells furnished by ABPP with human genetic information wehave identified several high-priority cancer targets poised for chemical probe development. Optimized chemicalprobes will be used by our lab and a set of expert biology collaborators to characterize the functional relevanceof protein targets in cancer and cancer-related immunology. We will also describe plans for continuedtechnology innovation to further enhance chemical probe and target discovery by ABPP including the followingobjectives i) identify newly druggable E3 ligase systems capable of supporting targeted protein degradationin cancer cells; ii) discover chemical probes that selectively engage modified states of protein targets in cancercells; and iii) generate advanced chemical libraries for ABPP to further increase the druggable fraction of thehuman cancer proteome. In summary our research program should deliver high-quality chemical probes forand pharmacological validation of biologically compelling human cancer targets providing critical knowledgeto direct the future development of transformative cancer therapeutics. More generally we envision that ourresearch program will inspire chemical and cancer biologists to embrace the potential druggability of anyhuman protein as well as provide an experimental roadmap to realize this goal for the benefit of both basicand translational research. 1137779 +No NIH Category available Acceleration;Accidents;Affect;Apoptosis;Attenuated;B-Cell Lymphomas;CASP2 gene;Cell Culture Techniques;Cell Death;Cell Differentiation process;Cell Line;Cell Proliferation;Cell Survival;Cells;Complex;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;DNA lesion;DNA replication fork;DNA-PKcs;DNA-dependent protein kinase;Death Domain;Development;Double Strand Break Repair;G22P1 gene;Genome;Holoenzymes;In Vitro;Incidence;Inflammation;Investigation;Ionizing radiation;Liver;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Mediator;Mus;Mutation;Nonhomologous DNA End Joining;Normal Cell;Oncogene Activation;Oncogenes;Pathway interactions;Phosphorylation;Phosphotransferases;Play;Primary carcinoma of the liver cells;Process;Proteins;Radiation Tolerance;Radiation exposure;Reagent;Recovery;Regulation;Reporting;Resistance;Role;Signal Pathway;Steatohepatitis;TP53 gene;Testing;Tissues;Ultraviolet Rays;Work;ataxia telangiectasia mutated protein;biological adaptation to stress;cancer cell;cancer prevention;carcinogenesis;genome integrity;in vivo;liver cancer model;male;mouse model;mutant;novel;preservation;prevent;recruit;regenerative;repaired;replication stress;response;senescence;tumorigenesis;ultraviolet irradiation DNA-PKcs and PIDD interaction in DNA damage response Project NarrativeDNA-PKcs is a critical DNA repair factor against DNA double strand break and accidental stalling of replicationfork. Cellular response to both types of DNA lesion is essential for cell proliferation and survival against radiationexposure. Investigation of DNA-PKcs activity during these DNA repair processes will clarify its coordination withother repair factors in preservation of genome integrity and prevention of cancer development. NCI 10693192 9/7/23 0:00 PA-18-484 5R01CA233594-05 5 R01 CA 233594 5 "WEINREICH, MICHAEL DALE" 9/1/19 0:00 8/31/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 6681770 "DAVIS, ANTHONY J" Not Applicable 30 RADIATION-DIAGNOSTIC/ONCOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 363164 NCI 224175 138989 Project Summary/AbstractThe DNA dependent protein kinase catalytic subunit (DNA-PKcs) is a key regulator of the canonical non-homologous end-joining (NHEJ) pathway for repair of DNA double strand breaks (DSBs) and resistance toionizing radiation (IR). DNA-PKcs is recruited by the Ku70/80 heterodimer to the DSB ends to form the DNA-PKholoenzyme to initiate NHEJ mechanism. DNA-PKcs also plays an important role in cellular resistance toreplication stress. It coordinates with and is rapidly phosphorylated by the ATR (ataxia telangiectasia mutatedand Rad3 related) kinase at stalled replication forks upon UV although the mechanism is not well understood.Our recent work has focused on identifying the player(s) required for the recruitment of DNA-PKcs to stalledreplication forks. We have identified that PIDD (p53-induced protein with a death domain) a known apoptosismediator for assembling the PIDDosome complex and Caspase-2 activation is required for DNA-PKcsrecruitment to stalled replication forks and its association with ATR. Disrupting the interaction between DNA-PKcs and PIDD not only compromised ATR dependent DNA-PKcs phosphorylation at the Thr2609 cluster butalso attenuated the ATR signaling pathway and intra-S checkpoint. To assist our investigation we have createdcell lines and a mouse model expressing a DNA-PKcsPL mutant protein unable to interact with PIDD. Our resultsshowed that DNA-PKcsPL cells were highly sensitive to both UV and IR. Based on these preliminary findings wehypothesize that PIDD but not the Ku70/80 heterodimer mediates DNA-PKcs recruitment to stalled replicationforks and promotes its association with the ATR pathway. We also hypothesize that PIDD facilitates DNA-PKcskinase activation and DSB repair. Finally we hypothesize that the interaction of DNA-PKcs with PIDD will affectcell death regulation and cancer development. In this project we will determine the coordination between DNA-PKcs PIDD and ATR in the cellular response to replication stress. Our specific aims are: 1) To test thehypothesis that PIDD modulates DNA-PKcs kinase activation at stalled replication forks and at IR-induced DNAlesions that are not bound by Ku70/80 2) To test the hypothesis that PIDD is required for DNA-PKcs to properlyfunction at stalled replication forks upon UV irradiation and 3) To test the hypothesis that the DNA-PKcs-PIDDassociation affects cell fate determination upon DNA damage and cancer development. 363164 +No NIH Category available Abdominal Pain;Accounting;Age;American;Artificial Intelligence;Biological;Biological Markers;Biopsy;Cancer Etiology;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical;Collection;Data;Data Set;Development;Diagnosis;Diagnostic;Diagnostic Imaging;Disease;Early Diagnosis;Early treatment;Emergency department visit;Enrollment;Epidemiology;Eye;Future;Gender;Goals;Head;Image;Image Analysis;Incidence;Individual;Laboratories;Low Prevalence;Machine Learning;Malignant Neoplasms;Malignant neoplasm of pancreas;Manuals;Medical center;Modeling;Morphology;Operative Surgical Procedures;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic duct;Patients;Reader;Resectable;Risk;Scanning;Screening procedure;Shapes;Statistical Data Interpretation;Survival Rate;Symptoms;Tail;Techniques;Testing;Texture;Time;Training;Training Technics;United States;Validation;Visit;Woman;X-Ray Computed Tomography;abdominal CT;artificial intelligence algorithm;automated segmentation;clinically significant;comorbidity;deep learning;experience;follow-up;high risk;high risk population;human error;imaging study;improved;large datasets;men;mortality;pancreas imaging;predictive modeling;premalignant;radiologist;radiomics;risk prediction;risk stratification;tumor Predicting Pancreatic Ductal Adenocarcinoma (PDAC) Through Artificial Intelligence Analysis of Pre-Diagnostic CT Images Pancreatic Ductal Adenocarcinoma (PDAC) a common type of pancreatic cancer is the fourthleading cause of cancer-related deaths in both men and women in the United States. The goalof the proposed project is to develop an artificial intelligence algorithm based on computed-tomography scans to identify individuals at high risk for PDAC which may allow early detectionand increase survival rate. NCI 10693185 8/21/23 0:00 PA-20-185 5R01CA260955-03 5 R01 CA 260955 3 "YOUNG, MATTHEW R" 9/1/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(03)M] 1862820 "LI, DEBIAO " "PANDOL, STEPHEN J; TIRKES, TEMEL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 934447 NCI 718728 215719 The objective of the proposed project is to develop a Pancreatic Ductal Adenocarcinoma (PDAC) predictionmodel to identify individuals who have high risk for PDAC in the next 3 years through Artificial Intelligence (AI)analysis of pre-diagnostic CT images and non-imaging factors. PDAC is the fourth leading cause of cancer-related deaths in both men and women in the United States despite its low incidence rate. The 5-year survivalrate for all stages of PDAC is 10% but can be as high as 50% with early-stage diagnosis. Thereforeidentification of individuals at high risk for PDAC has high clinical significance as follow-up imagingexaminations or biopsy may assist in early detection and allow surgical intervention while the tumors are stillresectable. However PDAC prediction is difficult due to the lack of reliable screening tools the absence ofsensitive and specific symptoms and biomarkers and low prevalence. Abdominal pain is the single most common reason that Americans visit the emergency room (ER) wherean abdominal Computed Tomography (CT) scan is usually performed. Even though most scans dont showany signs of cancer visible to the naked eyes of radiologists some subjects eventually develop PDAC in thenext few years. These pre-diagnostic CT images provide critical morphological information associated withbiological changes at the pre-cancer or early cancer stage which can be extracted using AI to predict PDACrisk. Therefore the objective of the proposed project is to uncover unique features in pre-diagnostic imagesusing AI and develop PDAC prediction model based on these features. Non-imaging factors such asdemographic epidemiologic and anthropometric factors clinical comorbidities and laboratory tests will beincluded in the model to improve the prediction accuracy. The primary hypotheses are a) AI allows extractionof unique image features in pre-diagnostic CT images associated with pre-cancer or early cancer biologicalchanges that are invisible to naked eyes and b) the combination of pre-diagnostic image features and non-imaging factors improves the accuracy of PDAC risk stratification and prediction over that using conventionalnon-imaging factors alone. To verify these hypotheses we will retrospectively evaluate CT pancreatic imagesobtained up to 3 years prior to PDAC diagnosis that were deemed non-cancerous by radiologists. A group ofsubjects who underwent similar imaging studies for non-gastrointestinal disorders and were age/gendermatched with pre-diagnostic imaging will serve as healthy controls. Accurately stratifying high risk individualsmay allow for early detection of PDAC in the future. A major challenge of the project is the scarcity of theappropriate imaging data because of the low prevalence of PDAC and stringent enrollment criteria. Eight majormedical centers will participate in collection of 1064 cases. The end point of this project is the developmenttraining and validation of an AI-based PDAC prediction model which will identify individuals who are at highrisk for developing PDAC within the next 3 years. 934447 +No NIH Category available Address;B-Cell Lymphomas;Bioinformatics;Biological Assay;Biological Markers;Biological Models;Breast Cancer cell line;Cancer Etiology;Cancer Model;Cancer cell line;Cell Line;Cell model;Cells;Characteristics;Clinical;Cytidine;Cytosine deaminase;Data;Deaminase;Detection;Dimensions;Disease;Engineering;Enzymes;Etiology;Evolution;Exposure to;Family;Gene Mutation;Genome;Goals;High Prevalence;Human;Immune;Individual;Knock-out;Link;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Measures;Metastatic Carcinoma;Modeling;Molecular;Monitor;Mus;Mutagenesis;Mutation;Mutation Analysis;Neoplasm Metastasis;Outcome;Patient Selection;Pattern;Physiological;Play;Polymerase;Process;RNA Viruses;Reagent;Regulation;Resistance;Retroelements;Rodent;Role;Sensitivity and Specificity;Single base substitution;Single-Stranded DNA;Site;Source;Surrogate Markers;System;Testing;Therapeutic;Transgenes;Treatment Efficacy;Tyrosine Kinase Inhibitor;Xenograft procedure;biomarker validation;cancer cell;cancer genome;cancer prevention;cancer therapy;cancer type;carcinogenesis;experimental study;genome sequencing;human disease;imprint;insight;lung cancer cell;malignant breast neoplasm;member;mutant;novel strategies;overexpression;paralogous gene;preference;prognostic;reconstitution;recruit;scaffold;targeted treatment;therapeutic target;therapy resistant;tumorigenesis;whole genome Molecular origins and impact of APOBEC3 mutagenesis in cancer PROJECT NARRATIVEThe endogenous APOBEC3 enzymes are proposed to cause a large number of mutations found in manydifferent cancer types. Using newly discovered human cancer cell line models we will determine the causesand consequences of APOBEC3 mutagenesis in cancer with the goals of determining if APOBEC3-mutagenesis represents a disease modifying process that can be therapeutically exploited at different stagesof cancer evolution and identifying specific enzymes as putative targets for therapeutic pursuit. NCI 10693177 7/27/23 0:00 PA-20-185 5R01CA270102-02 5 R01 CA 270102 2 "OKANO, PAUL" 9/1/22 0:00 8/31/27 0:00 Cancer Etiology Study Section[CE] 9072090 "MACIEJOWSKI, JOHN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 409420 NCI 291352 118068 PROJECT SUMMARYMutations arise as a result of exogenous and endogenous processes that leave characteristic imprints orsignatures upon the genome. Systematic analysis of these mutational signatures led to the identification of >50distinct types of single base substitutions (SBS) in human cancer genomes. Revealing the origins of individualsignatures is critical for understanding cancer etiology with potential implications for cancer prevention andtherapy. Two of the most prevalent mutational signatures in cancer termed SBS2 and SBS13 are present in>78% of cancer types and 56% of all cancer genomes with a particular prominence in breast bladder andlung cancers. SBS2 and SBS13 are proposed to be caused by the endogenous APOBEC3 (A3) enzymeswhich target ssDNA and RNA of viruses and retroelements as part of the innate immune defense. Correlationsbetween A3 expression driver gene mutations in A3-preferred contexts and clinical outcomes suggest that A3mutagenesis may play important roles in cancer etiology and evolution. Thus there is strong rationale tounderstand the mechanisms of A3 activity. However reliance on engineered model systems and correlativedata have caused links between A3 enzymes mutations in cancer and cancer etiology to be poorlyunderstood. We have identified human cancer cell lines with endogenous A3 mutagenesis and developed aworkflow that enables us to quantify contributions of individual A3 members to mutations. Here we propose toleverage this workflow to accomplish the following goals: 1) Identify A3 mutator enzymes in cancer types whereA3 mutagenesis is prevalent and find biomarkers of their activity; 2) Investigate mechanisms modulating A3mutagenesis; 3) Determine the functional relevance of A3 mutagenesis in therapy resistance and metastasis.Aim 1 will expand upon our characterization of human cancer cells with active A3 mutagenesis to identify A3mutators in breast bladder and lung cancers. In parallel we will directly assess the unknown specificity andsensitivity of assays to measure activities of individual A3 enzymes. These experiments may further confirmthe speculative A3-etiology of a large number of cancer mutations and quantify contributions of individual A3enzymes thus nominating them as putative targets for therapeutic pursuit. Aim 2 builds on our preliminary datato investigate proposed modulators of A3 mutagenesis. These experiments have the potential to broaden thescope of therapeutic opportunities focused on cancer cell evolution. Aim 3 will assess the links between A3enzymes therapy resistance and metastasis in breast bladder and lung cancer cell lines. These experimentswill test predictions from multi-dimensional associations that A3-mutagenesis is a disease-modifying processthat can be therapeutically exploited at various stages of cancer evolution. Taken together these studies willdefine the etiologies of highly prevalent mutational processes and identify strategies to elicit more durableclinical benefits to targeted therapies and curb metastasis. 409420 +No NIH Category available Ablation;American;Autophagocytosis;Autophagosome;Binding;Biological;Biology;Cancer Etiology;Cancer Patient;Cause of Death;Cessation of life;Data;Data Set;Disease;Future;Gene Expression;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth;Invaded;Investigation;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Mitochondria;Neoplasm Metastasis;Play;Process;Promoter Regions;Public Health;Regulation;Repression;Role;Testing;The Cancer Genome Atlas;Therapeutic;Tumor Suppressor Proteins;United States;World Health Organization;effective therapy;gene repression;improved;insight;migration;novel;novel therapeutic intervention;statistics;transcription factor;translational potential Investigation of a mitochondria-associated metastasis regulatory mechanism Lung cancer remains one of the deadliest malignancies in the United States. Metastasis is the main cause oflung cancer patient death. Our application focuses on a novel mechanism regulating lung cancer metastasisand the role for autophagy related gene in this process. Our studies are expected to not only improve ourunderstanding of the ways in which lung cancer metastasizes but also form the basis for future developingnovel therapeutic strategies for this deadly disease. NCI 10693170 8/31/23 0:00 PA-20-185 5R01CA247929-03 5 R01 CA 247929 3 "AULT, GRACE S" 9/1/21 0:00 8/31/26 0:00 Tumor Progression and Metastasis Study Section[TPM] 1864291 "MC NIVEN, MARK A." Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 356438 NCI 224175 132263 Lung cancer is the leading cause of cancer-related death in the United States and more than 150000Americans die of lung cancer each year. Despite our best treatment efforts to cure lung cancer have failed inmost cases partly due to an insufficient understanding of the biology of metastasis which almost inevitably leadsto lung cancer death. Therefore understanding better the mechanism regulating metastasis will allow us to gaindeeper insights into the disease basis on which novel therapeutic strategies for treating metastatic lung cancercan be developed and tested. On the basis of our preliminary studies we posit that an autophagy related geneplays a critical role in the regulation of lung cancer metastasis through a novel mitochondria associatedmechanism. The primary objectives of this proposal are to determine whether manipulating the expression of thisgene or its mitochondria associated function can inhibit the dissemination of lung cancer. As such our studiesnot only reveal a new basic mechanism for lung cancer but have translational potentials. Because there areabout 2 million new lung cancer cases each year globally (World Health Organization statistics) our studies mayhave a major impact on public health. 356438 +No NIH Category available Ambulatory Care Facilities;Animals;Antibodies;BRAF gene;Biocompatible Materials;Biological Specimen Banks;Biological Specimen database;Biology;Biopsy;Cell Line;Cells;Chromium;Clinical Data;Combined Modality Therapy;Computer software;Cryopreservation;Cytometry;Development;Ensure;Fine needle aspiration biopsy;Fluorescence;Generations;Health Insurance Portability and Accountability Act;High-Throughput Nucleotide Sequencing;Histology;Human;Human Resources;Immune;Immune checkpoint inhibitor;Immunofluorescence Immunologic;Immunohistochemistry;Immunotherapy;In Situ;Label;Laboratories;Location;MEKs;Melanoma Cell;Metastatic Melanoma;Minority;Molecular;Online Systems;Paraffin Embedding;Pathologic;Pathology;Patients;Performance;Phenotype;Preparation;Procedures;Process;Quality Control;Reagent;Research;Research Personnel;Resistance;Sampling;Scanning;Services;Slide;Stains;Standardization;Suspensions;System;T cell receptor repertoire sequencing;Techniques;Technology;Tissue Embedding;Tissues;Validation;Work;biobank;clinically relevant;combinatorial;digital;established cell line;high throughput analysis;histological image;improved;inhibitor;laser capture microdissection;melanoma;participant enrollment;prevent;prospective;rational design;repository;response;single cell analysis;single-cell RNA sequencing;success;targeted treatment;therapeutic evaluation;treatment response;tumor;tumor microenvironment Core B: Biospecimen Repository and Processing Core CORE B PROJECT NARRATIVEThe proposed projects of this PPG seek to understand the molecular and cellular basis for mechanisms andresistance to targeted therapy or checkpoint inhibitors to allow the rational design of combinatorialtherapies that treat and eventually prevent resistance. These studies rely heavily on patient-derived samplescollected both at UCLA and provided by outside collaborators through the Biospecimen Repository andProcessing Core (BRPC). Core B will serve for obtention generation and authentication of biomaterial (tissueand biofluid) from patient samples; as well as provide advanced expertise in melanoma biology cell linedevelopment pathologic interpretation and biorepository management for all proposed studies. NCI 10693147 6/30/23 0:00 PAR-18-290 5P01CA244118-04 5 P01 CA 244118 4 9/11/20 0:00 6/30/25 0:00 ZCA1-TCRB-Q 7258 10762691 "COMIN-ANDUIX, BEGONYA " Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 342571 219597 122974 CORE B ABSTRACTRecent advances in the treatment of metastatic melanoma with targeted therapies are highly successful initiallybut are ultimately limited by the development of tumor resistance. On the other hand checkpoint inhibitors areassociated with durable responses but only benefit a minority of patients. The aims of all of the projects in thisapplication are to understand the mechanisms and develop strategies to overcome resistance to both combinedtargeted therapies and checkpoint inhibitor immunotherapies in melanoma. The proposed studies require anefficient Biospecimen Core that can provide a variety of high quality biospecimens to the investigators. Thespecific aims of the Biospecimen Repository and Processing Core (BRPC - Core B) of the PPG are to: 1 )Centralize performance of specialized pathology services including biosample (tissue and biofluid) storagetracking distribution and analysis; 2) Provide well-characterized melanoma tissues cell lines and short-termcultures from patients enrolled on combination therapies and treated with BRAF/MEK inhibitors or checkpointinhibitors and prospectively develop additional cell lines; and 3) Develop techniques to better characterize cellsfrom within the tumor microenvironment for more sophisticated analysis in situ and at the single cell level. BRPCprovide the advanced expertise in melanoma biology cell line development pathologic interpretation andbiorepository management that is required by all proposed studies. +No NIH Category available Address;Bar Codes;Big Data;Biological Specimen Banks;Breast Cancer Cell;Calibration;Cancer Biology;Cell Count;Cell Line;Cell Survival;Cells;Chemoresistance;Clinical;Communities;Data;Developmental Therapeutics Program;Diagnosis;Dimensions;Disease Progression;Doxorubicin;Drug resistance;Experimental Models;Fluorouracil;Future;Gene Expression;Genomics;Goals;Growth;Heterogeneity;Human;Individual;Link;Malignant Neoplasms;Maps;Measurement;Measures;Methods;Modeling;Molecular;Paclitaxel;Patients;Phenotype;Play;Population;Prediction of Response to Therapy;Regimen;Resistance;Role;Sampling;Schedule;System;Systems Biology;Technology;Testing;Texas;Therapeutic;Therapeutic Agents;Time;Treatment Failure;Universities;Variant;austin;behavior prediction;cancer therapy;cell dimension;cell growth;chemotherapeutic agent;chemotherapy;clinically relevant;cost;epigenetic variation;experimental study;high dimensionality;improved;individualized medicine;mathematical model;medical schools;model development;multidimensional data;neoplastic cell;new technology;novel;predictive modeling;response;single-cell RNA sequencing;standard of care;therapy resistant;transcriptome;transcriptomics;translational potential;treatment response;triple-negative invasive breast carcinoma;tumor;tumor heterogeneity Systems Approaches to Understanding Subpopulation Heterogeneity in Therapeutic Resistance PROJECT NARRATIVETreatment of cancer is complicated by intratumor variation in which individual cells and groupsof cells within a single tumor respond differently to therapeutic agents. The high degree ofintratumor heterogeneity in triple-negative breast cancers confounds treatment efforts. Here wedevelop a linked set of experiment-computational workflows to measure track and predict thebehavior of heterogeneous triple-negative breast cancer cells. NCI 10693146 9/1/23 0:00 PAR-19-287 5U01CA253540-04 5 U01 CA 253540 4 "ZAMISCH, MONICA" 9/8/20 0:00 8/31/25 0:00 ZCA1-RTRB-U(M1) 10352775 "BROCK, AMY " "YANKEELOV, THOMAS E" 37 BIOMEDICAL ENGINEERING 170230239 V6AFQPN18437 170230239 V6AFQPN18437 US 30.291188 -97.737568 578403 UNIVERSITY OF TEXAS AT AUSTIN AUSTIN TX BIOMED ENGR/COL ENGR/ENGR STA 787121139 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 421433 NCI 273800 147633 PROJECT SUMMARYIn recent years improvements in diagnosis and treatment have extended the lives of many patients with triplenegative breast cancer but resistance to treatment remains a major clinical and scientific challenge. Whilestandard-of-care treatment and chemotherapy is effective in many TNBC patients approximately 40% ofpatients display resistance leading to poor overall survival. TNBC are characterized by significant intratumorheterogeneity which further complicates treatment. Mechanisms of chemoresistance in TNBC patientsremain poorly understood in part due to a lack of available methods and models to measure intratumorheterogeneity and track changes in heterogeneous tumor compositions over time. Here we propose to use anew technology to track individual cells and clones as they respond to different chemotherapeutic agents; thismore detailed information about the tumor cell population will be used to build mathematical models betterpredict and optimize therapeutic response. We first measure individual cell gene expression changes inresponse to treatment and then assemble these measurements into cell subpopulation trajectories takingadvantage of a barcoding technology developed in our lab to quantify clonally-resolved single celltranscriptomes. These Aim 1 studies will build a compendium of gene expression cell growth and survivaldata that describes how each of the heterogeneous cells in major experimental models of subtypes of triplenegative breast cancer responds to clinically-relevant therapeutic agents. The new ability to layer clonalidentifier information on single cell gene expression data reveals the detailed trajectories of individual cellsthat escape therapy. It also distinguishes subpopulations with pre-existing treatment resistance from thosein which a resistant state is induced. At a higher conceptual level this proposal seeks to also address a broadpractical challenge: the high-dimensional omics data collected in many large-scale efforts points often pointsto correlations in disease progression but not been informative for building mechanistic models to aid in thepredictive of tumor response. Often other types of data are more readily available-- lower dimensional datawith more frequent measurements. We therefore next ask: How can these distinct data types be integratedinto a useful framework to build predictive models of tumor cell response to therapy? This seems a fitting goalfor the systems biology of cancer community. We propose to tackle this challenge with our barcode trackingtechnology; relative fractions of sensitive and resistance phenotypes along with separate longitudinalmeasurements of cell number (low dimension data) become the inputs for a mechanistic model to predicttherapeutic response and resistance (Aim 2). In Aim 3 we will perform trajectory-mapping and model testingusing patient-derived triple negative breast cancer cells towards understanding the potential for translationalutility. By integrating different data types into a cohesive framework we aim to describe how sensitive andresistant subpopulations in TNBC grow die and transition in response to treatment. 421433 +No NIH Category available Antimetastatic Agent;Antineoplastic Agents;Bar Codes;Biochemical;Biological;Biological Assay;Breast Cancer Cell;Cell Line;Cells;Characteristics;Chemical Weapons;Chemicals;Collection;Colorectal Cancer;Coupled;Cyanobacterium;Cytotoxin;Data;Data Set;Development;Dimensions;Dolastatin 10;Drug resistance;Event;Florida;Funding;Future;G-Protein-Coupled Receptors;GSTP1 gene;Gene Cluster;Genes;Genetic;Growth;HCT116 Cells;Habitats;Hawaii;Histone Deacetylase Inhibitor;Investigation;Knowledge;Laboratories;Learning;Libraries;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Metagenomics;Microtubules;Modeling;Molecular;Molecular Analysis;Molecular Target;Morphology;Mus;Natural Product Drug;Natural Products;Neoplasm Metastasis;Nuclear;Organism;Pathway interactions;Pattern;Peptide Hydrolases;Pharmaceutical Chemistry;Phenotype;Phylogenetic Analysis;Planet Earth;Reporter Genes;Research;Ribosomal RNA;Sampling;Source;Structure;Synthesis Chemistry;Taxonomy;Translating;Validation;Vascular Endothelial Growth Factors;angiogenesis;apratoxin;cancer cell;cancer drug resistance;cancer prevention;cancer therapy;carcinogenesis;chemical synthesis;colon cancer cell line;cytotoxicity;drug discovery;efficacy study;experience;genetic information;hypoxia inducible factor 1;in vivo;inhibitor;innovation;malignant breast neoplasm;marine;milligram;novel;novel anticancer drug;novel therapeutics;preservation;programs;prostate cancer cell;rRNA Genes;screening;secondary metabolite;success;tool;transcription factor;tumor xenograft Novel Targeted Anticancer Agents from Marine Cyanobacteria PROJECT NARRATIVEMarine cyanobacteria produce selective anticancer agents with specific molecular targets. This research willlead to the discovery of new compounds that could become new drug leads for the treatment of cancer. NCI 10693140 9/1/23 0:00 PA-18-484 5R01CA172310-10 5 R01 CA 172310 10 "FU, YALI" 3/6/13 0:00 8/31/24 0:00 Synthetic and Biological Chemistry B Study Section[SBCB] 7016782 "LUESCH, HENDRIK " Not Applicable 3 PHARMACOLOGY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF PHARMACY 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 430347 NCI 316604 113743 PROJECT SUMMARYCyanobacteria are among the most ancient organisms on Earth and have evolved chemical weapons fordefensive purposes which we are exploiting for anticancer drug discovery. Our past research has exemplifiedthat marine cyanobacteria produce compounds with exceptionally potent activity and/or possess unusual or first-in-class inhibitors with novel mechanisms of action. We apply a broad yet focused screening platform tomaximize discovery rate of new anticancer agents. We also integrate a synthetic chemistry component into ourprogram in order to perform rigorous biological studies to rapidly add value to our discoveries and to help solvethe supply problem. Specifically we will carry out field collections of marine cyanobacteria and prepare fractionlibraries for screening in a set of innovative pathway-focused cell-based assays utilizing various isogeniccolorectal cancer cell lines and reporter gene assays as well as newly developed unbiased phenotypic assays.We will perform dereplication identify cyanobacteria through molecular analysis and establish phylogeneticrelationships among benthic cyanobacteria. Samples will be prioritized based on bioactivity profiles and geneticuniqueness for further processing. Prioritized samples will be subjected to bioassay-guided isolation of the activecompounds. Structures will be determined using NMR and mass spectrometry. Basic validation of bioactivityand secondary assays will be performed before prioritizing targets for further investigation. Selected compoundswith intriguing structure and promising validated bioactivity will be targeted for total synthesis so that a rigorousbiological characterization can be performed to pinpoint the molecular changes induced in the cancer cell and todetermine potential direct targets. For novel noncytotoxic compounds that show potential antimetastatic activitywe will apply an orthogonal target-based screening platform. 430347 +No NIH Category available Biological Markers;Cancer Etiology;Cells;Cessation of life;Characteristics;Classification;Clinical;Clinical Trials;Communication;DNA Sequence Alteration;DNA sequencing;Decision Trees;Detection;Diagnostic tests;Effectiveness;Evaluation;Exhibits;FDA approved;Genes;Genetic Engineering;Genetic Transcription;Goals;Image;Immune;Immune checkpoint inhibitor;Immunotherapy;Incidence;Individual;Induced Mutation;Learning;Ligands;Machine Learning;Malignant Neoplasms;Maps;Metabolic;Microsatellite Instability;Minority;Missense Mutation;Modeling;Molecular;Mutate;Mutation;Odds Ratio;Oncogenic;Outcome;Participant;Pathway interactions;Patient Selection;Patients;Performance;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Positron-Emission Tomography;Prediction of Response to Therapy;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Process;Proteins;Refractory;Reporting;Research;Resistance;Signal Pathway;Signal Transduction;Source;Testing;Transcription Coactivator;Transcriptional Activation;Treatment outcome;Tumor Escape;Tumor Markers;Tumor Subtype;United States;Woman;X-Ray Computed Tomography;advanced disease;anti-PD-1;antibody inhibitor;beta catenin;blood-based biomarker;cancer therapy;cell free DNA;checkpoint therapy;clinic ready;clinical diagnostics;clinical predictors;cohort;determinants of treatment resistance;diagnostic tool;fluorodeoxyglucose;fluorodeoxyglucose positron emission tomography;genomic biomarker;imaging agent;imaging biomarker;immune-related adverse events;improved;liquid biopsy;melanoma;men;metabolic phenotype;migration;molecular subtypes;mortality;mutational status;neoplastic cell;next generation sequencing;objective response rate;predictive marker;predictive tools;programmed cell death protein 1;programs;prospective;response;screening;targeted sequencing;tool;transcriptomics;treatment response;tumor;tumor DNA;tumor microenvironment;tumor progression;uptake Evaluation of treatment predictors reflecting beta-catenin activation in hepatocellular carcinoma PROJECT NARRATIVE While immune-checkpoint inhibitor antibodies are a major advance in cancer treatment only a minorityof patients with hepatocellular carcinoma (the most common form of primary liver cancer) will benefit from thisform of immunotherapy. This project comprises a phase 2 clinical trial to evaluate positron emission tomography/computed tomography (PET/CT) imaging and DNA sequencing based liquid biopsy as diagnostic tools forpredicting resistance to immunotherapy in hepatocellular carcinoma. The goal is to determine whether usingthese tests can potentially increase a patients chance of receiving a drug that will help them. NCI 10693135 8/4/23 0:00 PAR-19-363 5R01CA262460-03 5 R01 CA 262460 3 "LIN, CHARLES" 7/1/21 0:00 6/30/27 0:00 Clinical Translational Imaging Science Study Section[CTIS] 8575961 "KWEE, SANDI ALEXANDER" Not Applicable 1 Unavailable 54787481 YLMUFAJEZPP6 54787481 YLMUFAJEZPP6 US 21.307803 -157.853947 6813401 QUEEN'S MEDICAL CENTER HONOLULU HI Independent Hospitals 968132402 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 586680 NCI 402438 184242 PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide and its incidence isrising in both men and women in the United States. Anti-PD1 and anti-PD-L1 immune checkpoint inhibitor (ICI)antibodies are now FDA approved for advanced HCC however as few as 20% of patients receiving these agentswill show an objective response to therapy. Because immune-related adverse events are non-trivial predictivebiomarkers that can explain the variability in immunotherapy response are needed to optimize patient selection. Several lines of research have recently converged to associate oncogenic activation of the Wnt/beta-catenin signaling pathway with tumor immune-evasion and poor clinical response to ICI therapy in HCC. Inprevious research we found that HCC exhibiting high uptake of the positron emission tomography / computedtomography (PET/CT) imaging agent 18F- fluorocholine (FCH) often belonged to molecular tumor sub-typesassociated with beta-catenin activation and immune avoidance. Liquid biopsy based on targeted sequencing ofcell-free DNA (cfDNA) has also made it possible to identify patients who have tumors that harbor mutationsassociated with increased Wnt/beta-catenin signaling. This project comprises a phase 2 biomarker clinical trial to prospectively evaluate these specificembodiments of PET/CT and liquid biopsy as tools for detecting HCC recalcitrant to ICI therapy on the basis ofbeta-catenin activation. In addition to characterizing and comparing the predictive capabilities of FCH PET/CTand cfDNA mutation profiling based on phase 2 clinical endpoints this project will utilize decision tree basedmachine learning to estimate the predictive performance of an integrative imaging-genomic biomarker while alsofurther examining how tumor mutations are related to PET metabolic phenotype and immunotherapy response.Furthermore because tumor 18F-fluorodeoxyglucose (FDG) uptake is incongruent with FCH uptake in HCC athird aim will utilize the trial as a molecular screening process to create an enriched sub-cohort of patients withFDG-avid tumors. These patients will undergo serial FDG PET/CT to evaluate FDG as a source of predictivebiomarkers of ICI response for an orthogonal molecular sub-type of HCC. If these diagnostic tests are foundreliable at predicting tumor resistance/response they could significantly enhance the clinical precision andoverall benefit of immunotherapy for HCC and possibly other cancers. 586680 +No NIH Category available Active Biological Transport;Annexin A1;Antibodies;Antibody-drug conjugates;Antineoplastic Agents;Blood;Blood Circulation;Blood Vessels;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer therapy;Cause of Death;Caveolae;Chemistry;Circulation;Clinical;Data;Development;Diagnosis;Disease;Dose;Drug Delivery Systems;Drug Kinetics;Drug Targeting;ERBB2 gene;Endothelial Cells;Endothelium;Engraftment;Glutathione;Human;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Maximum Tolerated Dose;Medicine;Metastatic breast cancer;Modeling;Molecular;Nature;Neoplasm Metastasis;Neoplasms in Vascular Tissue;Organ;Pathway interactions;Patient-derived xenograft models of breast cancer;Patients;Penetration;Pharmaceutical Preparations;Phase;Production;Publishing;Pump;Rattus;Regimen;Rodent;Safety;Series;Site;Solid Neoplasm;Specificity;Speed;Surface;System;Systemic Therapy;Therapeutic;Therapeutic Agents;Therapeutic Studies;Time;Tissues;Toxic effect;Treatment Efficacy;Tumor Tissue;Validation;Vascular Endothelial Cell;Woman;cancer diagnosis;chemotherapy;clinical application;clinical translation;clinically relevant;efficacy evaluation;efficacy validation;experimental study;human model;humanized antibody;immunoreactivity;improved;intravenous administration;intravital microscopy;malignant breast neoplasm;neoplastic cell;novel;novel therapeutics;personalized medicine;screening;targeted treatment;therapeutic evaluation;therapeutically effective;translational framework;translational therapeutics;treatment response;treatment strategy;tumor;vascular endothelium permeability Tumor caveolae-targeted systemic therapy of breast cancer with antibody drug conjugates This project intends to establish more effective and safer therapy of breast cancer by targeting of novel activetransport system operating across tumor blood vessels to accumulate extremely potent anticancer drug withinbreast tumor tissue in all stages of the disease. Extensive evaluation of efficacy and toxicity in clinicallyrelevant models of breast cancer will help to establish path toward clinical translation of this therapy. NCI 10693126 9/8/23 0:00 PA-18-484 5R01CA237109-05 5 R01 CA 237109 5 "FU, YALI" 9/1/19 0:00 8/31/24 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 15086700 "CHRASTINA, ADRIAN " Not Applicable 50 Unavailable 830928037 EAZXZLPJYJZ2 830928037 EAZXZLPJYJZ2 US 32.90615 -117.227647 10024578 PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED LA JOLLA CA Research Institutes 920374614 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 414724 NCI 224175 190549 Breast cancer is the most commonly diagnosed cancer in women and is a second leading cause of deathamong woman. Despite the significant progress in molecular understanding and personalized therapies ofbreast cancer this disease in progressed metastatic stage remains incurable and treatment options availableto patients provide only modest survival benefit. Efficacy of existing systemic chemotherapy is limited indelivery access and penetration into solid tumors as well as by toxicity to patients. Thus to develop moreeffective and safer therapies of breast cancer it is necessary to implement an efficient targeted drug deliverysystem. Caveolae at the surface of tumor endothelial cells act as a transendothelial transport system thatactively pumps targeted antibodies from the blood circulation into the tumor tissue. Our findings support thattargeting caveolae provides a platform for rapid pumping of targeted antibodies with attached cargo specificallyinto breast tumors at concentrations greatly exceeding maximum levels in the blood. Using these recentfindings we intend to target antibody drug conjugates (ADC) of DM1 maytansinoid one of the most potentanticancer drugs to target truncated form of Annexin A1 in tumor endothelial caveolae in order to deliver thispowerful therapeutic effectively inside of breast tumors. We have demonstrated that AnnA1 is expressed in thevasculature and caveolae of human tumors. Recently we have generated humanized antibody against AnnA1(hAnnA1) and our preliminary experiments demonstrate strong therapeutic response of breast cancer tohAnnA1 conjugated to DM1 (hAnnA1-DM1 ADC). We hypothesize that by pumping targeted antibodies armedwith DM1 drug into breast tumors caveolae can rapidly and specifically accumulate this therapeutic agentinside tumors leading to tumor destruction with significantly reduced toxicity. We propose these Specific Aims:Aim 1. To generate and characterize ADCs. We will prepare series of conjugates with DM1 drug covalentlyattached to hAnnA1 antibody using non-cleavable and cleavable linkers. Based on the screening in Aim2 wewill generate THIOMAB hAnnA1 with select linker chemistry.Aim 2. Screening for optimal linker chemistry production validation and pharmacokinetic analysis oftumor vascular caveolae-targeted DM1 THIOMAB ADC in rodent tumor model of breast cancer. Thesestudies will enable implementing optimal linker chemistry to develop ADC with site-specific attachment of DM1.Aim 3. Evaluation of therapeutic efficacy of the tumor vascular caveolae-targeted DM1 ADCs inclinically-relevant models of breast cancer. Therapeutic studies in clinically-relevant orthotopic models ofbreast cancer including intravital microscopy model of human tumor spheroids engrafted into human breasttissue and patient-derived breast cancer xenografts including triple-negative and HER2+ models will provideplatform to evaluate novel hAnnA1-DM1 ADC therapy. The proposed project will help to establish frameworkfor clinical translation of tumor-caveolae targeted ADC for treatment of breast cancer. 414724 +No NIH Category available Address;Antitumor Response;Apoptosis;Automobile Driving;BRAF gene;Biological Models;Biometry;Buffers;CTLA4 gene;Caring;Cell Death;Cell Death Process;Cell Line;Cells;Classification;Clinical;Clinical Trials;Collaborations;Combined Modality Therapy;Complement;Data;Data Set;Drug Targeting;Epigenetic Process;Genetic Transcription;Genomics;Goals;Human;Immune checkpoint inhibitor;Immune system;Immunotherapy;Inflammation;Interferons;Iron;Knowledge;Link;Lipids;MAP3K1 gene;MEKs;Mediating;Melanins;Melanoma Cell;Metabolism;Metastatic Melanoma;Modality;Modeling;Modernization;Mutate;Neural Crest;Oxidation-Reduction;Oxidative Stress;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Pharmacogenomics;Phosphotransferases;Pre-Clinical Model;Process;Production;Proto-Oncogene Proteins B-raf;Publications;Publishing;Regulation;Relapse;Research Personnel;Resistance;Resistance development;Role;Route;Sampling;Signal Transduction;Stress;Structure;Testing;Therapeutic;Undifferentiated;Validation;Variant;anti-PD-1/PD-L1;cancer cell;cell dedifferentiation;cytokine;efficacy testing;experience;experimental study;genetic approach;immune checkpoint blockade;immunogenic;inhibitor;inhibitor therapy;insight;iron metabolism;kinase inhibitor;lipid metabolism;lipidomics;melanocyte;melanoma;metabolomics;mouse model;new therapeutic target;patient derived xenograft model;pharmacologic;pre-clinical;prevent;programs;resistance mechanism;standard of care;statistics;targeted treatment;therapy resistant;treatment strategy;tumor;two-dimensional Project 2: Targeting differentiation-linked redox sensitivity in melanoma PROJECT 2 PROJECT NARRATIVEImmunotherapy and targeted therapeutics are having major impact on melanoma treatment. Nonetheless inmany patients resistance arises as these treatments drive melanomas towards aggressive resistant subtypessuch as dedifferentiated variants. We have discovered a new Achilles heel for dedifferentiated melanomasrelated to their sensitivity to oxidative stress and are pursuing co-treatment therapies that would preventdedifferentiation-based resistance. NCI 10693123 6/30/23 0:00 PAR-18-290 5P01CA244118-04 5 P01 CA 244118 4 9/11/20 0:00 6/30/25 0:00 ZCA1-TCRB-Q 7247 2202900 "GRAEBER, THOMAS G" Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 507564 325361 182203 PROJECT 2 ABSTRACTMelanoma treatment has had instrumental advances in two modern modalities: immunotherapy and targetedkinase inhibitor treatments. Nevertheless there is a crucial clinical need to address dedifferentiation as aresistance mechanism to modern melanoma therapies. Notably dedifferentiation is a documented cross-resistance mechanism that impacts both of the new expanding standards of care: BRAF and MEK kinase inhibitortherapies and immunotherapies such as immune checkpoint blockade (e.g. anti-PD-1/PD-L1). Our discovery ofa new dedifferentiation-associated sensitivity to iron-dependent oxidative stress (ferroptosis) provides a newangle from which to complement current standard of care therapies for melanoma. In our studies sensitivity toferroptosis is an Achilles heel for dedifferentiated cells independent of whether they were dedifferentiated atbaseline or induced to dedifferentiate by BRAF and MEK inhibitor therapy or by immunotherapy associatedcytokines. Thus using preclinical models we will further pursue this orthogonal sensitivity to prevent thededifferentiation escape route.Our discovery and proposed experiments brings the programmed cell death process of ferroptosis into the fieldof melanoma and melanocytes. We will investigate how the redox stress protection mechanisms specific toredox-regulated melanin production in melanocytes interact with iron metabolism ferritinophagy and ferroptosisin melanoma cells. Studies in the melanoma and melanocyte context will help advance our knowledge of thisrelatively recently discovered cell death mechanism. We will test the efficacy of combining ferroptosis inductionwith either kinase inhibitor therapy or checkpoint inhibitor immunotherapy using preclinical models. We willinterrogate human samples from clinical trials to assess the immunotherapy contexts in which dedifferentiationpresents the highest clinical challenge and opportunity. Our discovery of dedifferentiation-linked ferroptosissensitivity was the result of an integrative genomics and pharmacogenomics approach. We will continue toexpand our framework of the regulation of melanoma dedifferentiation using integrative genomics to delineatetranscription and epigenetic regulatory programs. To expand upon the multiple links between metabolism redoxbuffering differentiation and ferroptosis we will incorporate metabolomics and lipidomics in our discovery andmechanistic delineation approaches. Our goal in these aims is to mechanistically understand and enhance thetherapeutic approach of targeting the melanoma dedifferentiation resistance escape route. +No NIH Category available Acceleration;Agonist;Antibodies;Biological Markers;Biology;CTLA4 gene;Cell Death;Cell Death Induction;Cell Line;Cells;Chromatin;Clinical;Clinical Research;Clinical Trials;Collaborations;Combined Modality Therapy;Correlative Study;Cytoplasm;DNA Repair;Data;Dermatology;Dose;Evolution;Exposure to;Generations;Genome;Human;Immunotherapy;Joints;Laboratories;Letters;Life;MAP Kinase Gene;MEKs;Measures;Melanoma Cell;Modeling;Monitor;Multiomic Data;Mutation;Natural Immunity;Nivolumab;Oncology;PD-1 inhibitors;Pathway interactions;Patients;Phase;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Proteome;Protocols documentation;Publications;Reagent;Refractory;Regimen;Resistance;Resistance development;Rotation;Safety;Sampling;Stimulator of Interferon Genes;Technical Expertise;Testing;Tissues;Translating;Withdrawal;addiction;anti-CTLA-4 therapy;anti-CTLA4;anti-PD-1;anti-PD1 antibodies;anticancer research;cancer therapy;clinically relevant;combinatorial;design;dimer;exome;human subject;immune checkpoint;immune checkpoint blockade;immune resistance;immunogenic cell death;improved;in vivo;inhibitor;insight;investigator-initiated trial;melanoma;methylome;multiple omics;neoplastic cell;next generation;participant enrollment;patient derived xenograft model;pharmacologic;phase 2 study;potential biomarker;preclinical study;preclinical trial;predictive marker;prevent;programmed cell death protein 1;research clinical testing;resistance mechanism;response;single-cell RNA sequencing;small molecular inhibitor;standard of care;synergism;targeted treatment;therapy resistant;transcriptome;tumor;tumor microenvironment Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma PROJECT 1 PROJECT NARRATIVETherapeutic resistance is the rule rather than the exception and strongly limits the clinical benefits of recentlyintroduced breakthrough treatments for advanced melanoma. Translating cancer research into patient survivaldepends on a deep understanding of resistance mechanisms to clinically active therapies. As RAF/MEK andPD-1/CTLA-4 therapies were first developed in patients with advanced melanoma overcoming resistance tothese therapies has wide-reaching implications for cancer treatments in general. NCI 10693113 6/30/23 0:00 PAR-18-290 5P01CA244118-04 5 P01 CA 244118 4 9/11/20 0:00 6/30/25 0:00 ZCA1-TCRB-Q 7243 1890098 "LO, ROGER S" Not Applicable 36 Unavailable 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA Domestic Higher Education 900952000 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 507563 325361 182202 PROJECT 1 ABSTRACTMutation-targeted small molecular inhibitors and immune checkpoint blockade or ICB (anti-PD-1 and -CTLA-4antibodies) have extended the quality and quantity of life for patients with advanced BRAFMUT melanoma. BeyondICB which is ineffective in up to 60% of patients patients with advanced NRASMUT melanoma have no standard-of-care options. Due to the rapid onset of resistance MEK inhibitor (MEKi) monotherapy has limited clinicalactivity against NRASMUT melanoma with the potential exception of those melanoma previously exposed to ICB(the NEMO trial). Here we propose to design MEKi-based combinatorial-sequential regimens against advancedNRASMUT melanoma. First we will test the concept of priming MEKi responsiveness via anti-PD-1/L1pretreatment (regardless of anti-PD-1/L1 sensitivity). We will test this concept as well as dissect the mechanismsof action and innate/acquired resistance in human subjects (by conducting a phase II investigator-initiated trial)and in syngeneic melanoma models. Second we will test the concept of combining a next-generation RAFinhibitor (RAFi) with a MEKi to overcome and to prevent MEKi resistance. These studies will be conducted inhuman melanoma cell lines patient-derived xenografts (PDXs) and syngeneic models. Third we will test theconcept of overcoming MEKi resistance by pharmacologically exploiting a hallmark vulnerability of resistanttumors: MEKi-addiction or tumor cell death induced by MEKi withdrawal. Specifically to induce the regressionof a diverse array of NRASMUT MEKi-resistant PDX models we will test one strategy involving sequencing froma MEKi to a poly-ADP ribose polymerase inhibitor (PARPi) or another strategy involving rotations between MEKiand PARPi. We will also test whether these sequencing/rotational strategies by inducing various extents ofimmunogenic cell death and/or innate immunity would sensitize NRASMUT melanoma to combined anti-PD-1/L1therapy. In these clinical and preclinical studies we will derive multi-omic data and evaluate candidate pathwaysto identify predictive biomarkers. In addition to bulk tumor-based multi-omic analysis (exome genometranscriptome methylome chromatin accessibility proteome TCR clonotypes) of longitudinal tumor sampleswe will also dissect the single-cell (scRNA-seq CyTOF) evolution of NRASMUT melanoma to identify additionalcombinatorial-sequential targets to overcome and then to prevent resistance. These studies require a closecollaboration with Projects 2 and 3 and Cores A-C at levels of shared technical expertise reagents/models andpreliminary data and this collaboration is grounded on a 10-year track record of joint publications that haveresulted in deep insights into clinically relevant melanoma biology multiple clinical trials and even approvedtherapies. The combination of oncology and dermatology expertise (Ribas and Lo) and laboratories withcomplementary approaches (Ribas Lo Graeber) promises to accelerate scientific concepts to clinical testing. +No NIH Category available Acute;Address;Adipose tissue;Affect;Algorithms;American;Apoptotic;Automobile Driving;Base Sequence;Biological Assay;Blocking Antibodies;Breast;Breast Cancer Cell;Breast Cancer Epidemiology;Breast Cancer Model;Breast Cancer Patient;Breast Oncology;Bromodomains and extra-terminal domain inhibitor;CD8B1 gene;Cancer Burden;Cancer Model;Cancer Patient;Cell model;Cells;Cellular Metabolic Process;Chemicals;Chronic;Cities;Clinical;Coculture Techniques;Complex;Computer Models;Dangerousness;Data;Development;Diabetes Mellitus;Disease;Endocrinology;Estrogen receptor negative;Genes;Goals;Hospitals;Hypertension;Immune;Immunology;Immunooncology;Immunophenotyping;Immunotherapy;Infiltration;Inflammation;Inflammatory;Knowledge;Malignant Neoplasms;Mammary Neoplasms;Mass Spectrum Analysis;Medical Oncology;Metabolic;Metabolic Diseases;Metabolism;Metformin;Micrometastasis;Modeling;Molecular;Neoplasm Metastasis;Newly Diagnosed;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organoids;Outcome;Pathway Analysis;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Population Sciences;Prediabetes syndrome;Prevalence;Primary Neoplasm;Process;Prognosis;Prospective Studies;Proteins;Proteome;Proteomics;Public Health;Publishing;Research Personnel;Resolution;Risk;Signal Transduction;Suggestion;Surgical Oncology;System;Systems Biology;T cell receptor repertoire sequencing;T-Lymphocyte;T-Lymphocyte Subsets;Talents;Testing;The Cancer Genome Atlas;Tumor Immunity;Tumor Promotion;Tumor-infiltrating immune cells;Woman;breast cancer progression;cancer subtypes;cell killing;checkpoint receptors;chronic inflammatory disease;clinically relevant;cohort;comorbidity;epidemiologic data;exhaust;exhaustion;experience;experimental study;immune cell infiltrate;immune checkpoint;improved;innovation;malignant breast neoplasm;mathematical model;metabolic profile;model building;mortality;multi-scale modeling;multidisciplinary;multiple omics;neoplasm immunotherapy;neoplastic cell;network models;non-diabetic;novel;patient population;phosphoproteomics;polarized cell;primary outcome;profiles in patients;programs;response;safety net;transcriptome;transcriptome sequencing;treatment response;triple-negative invasive breast carcinoma;tumor;tumor microenvironment;tumor progression Multiscale analysis of metabolic inflammation as a driver of breast cancer NARRATIVEThe prevalence of co-morbid disorders of metabolism is expanding rapidly among breast cancer patients in U.Scities particularly at safety net hospitals where the burden of obesity hypertension and diabetes can easilyaffect half of the patient population. Systems biology approaches have not yet been mobilized effectively tounderstand complex relationships among abnormal metabolism chronic inflammation and immune exhaustionin the tumor microenvironment of breast cancer in patients with co-morbid metabolic disease. Specifically thereis an acute public health need for tumor infiltrate nucleic acid sequence data to be annotated with metabolicinformation: integrated -omics immune exhaustion and metabolic profiles of these patients such as we willdevelop must inform models of breast cancer progression and mortality for these at-risk patients. NCI 10693107 8/17/23 0:00 PAR-19-287 5U01CA243004-04 5 U01 CA 243004 4 "ZAMISCH, MONICA" 9/9/20 0:00 8/31/25 0:00 ZCA1-RTRB-U(M1) 2083861 "DENIS, GERALD V" "EMILI, ANDREW ; MONTI, STEFANO " 7 INTERNAL MEDICINE/MEDICINE 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 549519 NCI 410556 138963 Women with breast cancer and co-morbid Type 2 diabetes (T2D) have up to 40% worse overall survivalcompared to non-diabetic women; this co-morbidity burden is disproportionately high among vulnerable cohortssuch as patients at safety net hospitals in the U.S. where it can affect half of the patient population. Yet currentmodels of breast tumor progression and immunotherapy are based on data from metabolically healthy cancerpatients ignoring metabolic /inflammatory components of T2D. Preliminary and published data support an overallhypothesis: specific metabolic and immune exhaustion networks in breast cancer patients with co-morbid T2Dpromote tumor aggressiveness. We propose an innovative multiscale modelling framework to identify thesenetworks by integrating metabolic inflammatory and immune signatures in multi-omics cancer modelsencompassing RNA-seq and phosphoproteomics data. We take a systems biology approach to combineinnovative computational clinical and patient-derived tumor organoid experiments to investigate interactionsamong putative driver genes T2D and immune exhaustion with tumor progression/aggressiveness as theprimary outcome variable in estrogen receptor-negative (ER-) breast cancer which has poor prognosis and ishighly prevalent among safety net hospital patients. We will model how T2D rewires signaling hubs nodes andedges in newly diagnosed breast cancer patients then test these networks in breast organoid models. We willdevelop a unified model through three Aims: Aim 1: Determine how T2D reprograms immune exhaustion andmetabolism in the tumor microenvironment of ER negative (ER-) breast cancer. We will apply RNAseq andscRNAseq to primary ER- breast cancer cells and tumor immune infiltrates to compare three groups of patients(T2D T2D+ metformin-medicated (T2D+M) non-diabetic (ND) controls) to construct a preliminary networksupplemented with TCGA data. Differential gene and pathway analyses will elucidate regulatory relationshipsand key hubs. We hypothesize that the connectivity of the ER- cluster in T2D will be altered and denser than inND or T2D+M. Aim 2: We will generate patient-derived organoids including organoid-primed T cells (OpT) totest the computational model for metabolism and immune checkpoints. We will evaluate mechanistic hypothesesthat T2D medications immune checkpoint-blocking antibodies and chemical inhibitors of BET bromodomainproteins (which regulate checkpoint expression) overcome immune exhaustion to improve OpT cell metabolismand tumor cell killing. TCR sequencing will reveal emergent OpT oligoclonality; deep immunophenotyping willreveal T2D-driven signaling networks. Aim 3: Determine abnormal signaling networks impacting cancer immunityin organoid and OpT models. We will perform deep phosphoproteomic profiling of primary tumors organoidscirculating T cells and OpT cells from the three metabolic groups then use pathway projection and networkanalyses to refine our integrated model. Together our unique systems biology approach will capture the complexinteractions among tumor immune infiltrates and metabolic genes to address the cancer burden of T2D. 549519 +No NIH Category available 26S proteasome;5'-AMP-activated protein kinase;Affinity;Antigens;Antineoplastic Agents;Apoptosis;Binding;Binding Proteins;Biological Assay;Biophysics;Bromodomain;Calorimetry;Cancer Patient;Cancerous;Cell Culture Techniques;Cell Death Induction;Cells;Complex;Computer software;Dependence;Development;Docking;Dose;Double Minutes;Drug resistance;Elements;Event;Exhibits;Flow Cytometry;Fluorescein;Fluorescence;Fluorescence Polarization;Future;Gene Expression;Gene Family;Gene Proteins;Genes;Germ Lines;Homologous Gene;Induction of Apoptosis;Lead;Libraries;Ligands;MAGEA3 gene;Malignant Neoplasms;Measures;Mediating;Mus;Oncogenic;Program Description;Protac;Protein Degradation Induction;Protein Family;Proteins;Reporter;Research;Resistance profile;Solubility;Structure;Structure-Activity Relationship;System;Technology;Testing;Therapeutic;Tissues;Tryptophan;Ubiquitination;Western Blotting;biophysical techniques;c-myc Genes;cancer cell;cancer/testis antigen;cytotoxicity;design;functional group;improved;in silico;in vivo;innovation;insight;interest;male;melanoma;member;mutant;neoplastic cell;novel;protein degradation;recruit;small molecule;tumor;tumor specificity;tumorigenesis;ubiquitin-protein ligase;vector Developing Tumor-specific PROTACs Developing tumor-specific therapies that exhibit improved drug resistance profiles is important for advancingtreatment options for cancer patients. The main objective in the research program described herein is to developa new type of anti-cancer drug that eliminates problem proteins in a tumor-specific manner. NCI 10693103 8/22/23 0:00 RFA-CA-18-019 5R01CA238570-05 5 R01 CA 238570 5 "FU, YALI" 9/5/19 0:00 8/31/24 0:00 ZCA1-RTRB-R(J2) 7093779 "CREWS, CRAIG M" Not Applicable 3 BIOCHEMISTRY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF ARTS AND SCIENCES 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 374545 NCI 224175 150370 Proteolysis Targeting Chimeras (PROTACs) are event-driven bifunctional small-molecules that simultaneouslyengage an E3 ubiquitin ligase and a protein of interest (POI). Ternary complex formation between POI-PROTAC-E3 ligase results in E3-ligase mediated POI ubiquitination and subsequent degradation of the POI by the 26Sproteasome. The next innovation for PROTAC technology is the induction of tumor-specific proteindegradation. PROTACs that induce degradation selectively in tumor cells would likely have improvedtherapeutic utility due to decreased off-target cytotoxicity. Currently the E3 ligases most commonly hijacked forPROTAC-mediated POI degradation von Hippel-Lindau Cereblon and Mouse double minute 2 homolog areexpressed in both cancerous and untransformed tissues. Therefore new E3 ligase recruiting elements (E3REs)that engage E3 ligases with tumor-specific expression must be developed to impart tumor-specificity. Type IMelanoma Antigen Gene (MAGE) family proteins are cancer testis antigens whose expression is restricted tothe male germ line but can be re-expressed in cancers. MAGE-A3 binds TRIM28 a ubiquitously expressedprotein with E3 ligase activity to form an oncogenic tumor-specific E3 ligase complex. A PROTAC harboring aMAGE-A3 E3RE may be able to recruit MAGE-A3/TRIM28 and induce protein degradation in a tumor-specificmanner. MAGE proteins bind their cognate E3 ligases and substrates via a conserved MAGE homology domain(MHD). Using Schrdinger Glide docking software we screened >60000 compounds against the recentlyresolved structure of the MAGE-A3 MHD to identify ligands in silico that are predicted to disrupt MAGE-A3-substrate binding. We have identified a subset of lead-like compounds using intrinsic tryptophan fluorescenceand are currently corroborating these findings via orthogonal biophysical assays such as isothermal calorimetryand various NMR-based strategies. A structure-activity relationship study on bona-fide MAGE-A3 binders willthen be performed to improve solubility increase affinity and identify (a) potential vector(s) for linker attachmentin subsequent PROTAC development. Once tight-binding MAGE-A3 ligands have been developed we willsynthesize MAGE-A3-based-HaloPROTACs and test their ability to degrade HaloTag7-GFP in a MAGE-A3-dependent manner. Subsequently we will further test the utility of recruiting MAGE-A3/TRIM28 E3 ligasecomplex by targeting Bromodomain-containing protein 4 (BRD4) for MAGE based-PROTAC mediateddegradation. Induction of tumor-specific degradation of BRD4 and induction of apoptosis in a tumor-specificmanner by our MAGE-A3 based-PROTACs will be evaluated. Overall this project will determine the MAGE-A3/TRIM28 E3 ligase complex induce tumor-specific protein degradation. Additionally development of a newE3RE will help spark excitement for identification of novel E3REs for other E3 ligases thereby greatly expandingthe number of E3 ligase amenable to the PROTAC technology. Moreover PROTACs created during this projectmay serve as the starting point for the future development of a tumor-specific therapy. 374545 +No NIH Category available Ablation;Amino Acids;Arginine;Binding Sites;Biological Assay;Cancer Control;Cell physiology;Cells;Complex;Data;Development;Drug resistance;Endoplasmic Reticulum;Flow Cytometry;Functional disorder;Genetic Transcription;Genotype;Goals;Granzyme;Human;ITGAM gene;Immune;Immune Evasion;Immunotherapy;Interferon Type II;Interleukin-13;Interleukin-4;Knockout Mice;Knowledge;Life;Maintenance;Malignant - descriptor;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Metabolic stress;Metastatic Malignant Neoplasm to the Ovary;Molecular;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Operative Surgical Procedures;Ovarian Carcinoma;Pathway interactions;Phenotype;Pre-Clinical Model;Process;Proliferating;Publishing;Recurrent Malignant Neoplasm;Refractory;Role;STAT6 gene;Signal Transduction;Stress;Survival Rate;T cell response;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;Transactivation;Transgenic Mice;Translations;Tumor Immunity;United States;Woman;XBP1 gene;adaptive immunity;anti-cancer;arginase;cancer immunotherapy;cancer infiltrating T cells;cancer recurrence;chemotherapy;conditional knockout;cytokine;cytotoxic;effective therapy;effector T cell;endoplasmic reticulum stress;genetic signature;granulocyte;immune cell infiltrate;immune function;immunoregulation;improved;misfolded protein;neutrophil;novel strategies;novel therapeutic intervention;ovarian neoplasm;personalized immunotherapy;pharmacologic;programs;promoter;protein folding;response;sensor;standard care;success;transcription factor;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor progression Immunosuppressive Programs Driven by IRE1 signaling in ovarian cancer Project NarrativeTo offset the clear and present gap between metastatic ovarian carcinomas and effective immune basedtherapies this project seeks to explore the functions of tumor associated myeloid cells and their influence onanti-cancer immunity. Upon completion this proposal will uncover how diverse stress signals in the tumor drivemyeloid subsets into immunosuppressive cells which ultimately inhibit the protective anti-tumor activity of T cells.This knowledge will pave the way for novel strategies to develop precision immunotherapies and more effectivelycontrol cancer progression and recurrence. NCI 10693090 9/1/23 0:00 PA-21-052 5F31CA257631-03 5 F31 CA 257631 3 "DIBELLO, ANTHONY THOMAS" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 12677420 "EMMANUELLI, ALEXANDER " Not Applicable 12 OBSTETRICS & GYNECOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARY/ABSTRACT:Ovarian Carcinomas (OvCa) are the most life-threatening gynecological malignancy in the United Statesclaiming the lives of 14000 women every year. The 5-year survival rate for metastatic OvCa is 27% andstandard treatments and therapies such as chemotherapy and surgical intervention are largely ineffectual andcan often promote drug resistance and recurrence of the cancer. The recent advent of cancer immunotherapyhas proven effective in treating other cancers but shown minimal efficacy in OvCa. Understanding themechanisms that enable OvCa to escape immune control is crtical to developing more effective treatments.Ovarian Tumors have evolved strategies that enable them to thrive under adverse conditions while suppressingthe protective function of immune cells. Recent studies demonstrate that these cancers provoke severemetabolic stress in myeloid cells to escape immune control but it remains unknown how myeloid cellsintegrate and interpret metabolic stress signals in the tumor milieu. Our group determined that adverseconditions in the tumor microenvironment disrupt the protein-folding capacity of the endoplasmic reticulum (ER)in infiltrating immune cells. This process causes ER stress and elicits persistent responses via the IRE1-XBP1pathway that alter key immunometabolic processes required for the initiation and maintenance of anti-tumorimmunity. Multiple studies have shown that myeloid derived suppressor cells (MDSCs) and neutrophils canregulate anti-tumor T cell functions by depleting key amino acids from the TME. Our preliminary findings indicatethat IRE1-XBP1 signaling is required to sustain the capacity of MDSCs to express Arginase 1 (Arg1) andsuppress T cell proliferation by an unknown mechanism. The main goal of this proposal is to identify andunderstand the transcriptional and functional consequences of ER stress in tumor associated myeloid cells.Therefore our central hypothesis is that maladaptive activation of ER stress sensors regulates the function ofmyeloid cell subsets in the tumor by altering their transcriptional programming to induce immunosuppressivephenotypes. Specifically we postulate that the IRE1-activated XBP1 transcription factor is a directtranscriptional inducer of Arg1. We also hypothesize that ER stress-driven gene signatures will delineate newtranscriptional programs controlled by IRE1-XBP1 in tumor associated neutrophils. Lastly we will define howIRE1-XBP1 ablation in tumor associated neutrophils modulates the cytotoxic activity of T cells and thedevelopment of protective anti-tumor immunity. Understanding the consequences of ER stress in tumorassociated myeloid cells will be crucial to comprehensively define T cell dysfunction in ovarian cancer and todevelop new therapeutic interventions that augment T cell effector capacity in a harsh tumor microenvironment.The proposed project is mechanistically and translationally relevant as it has the potential to uncover howstress signals govern the regulatory phenotypes of myeloid cells in the tumor. 47694 +No NIH Category available Adult;Affect;Anabolism;Antineoplastic Agents;Behavioral;Brain;Brain region;Cancer Survivor;Cell division;Cell physiology;Cisplatin;Clinical Trials;Coenzymes;Cognitive;Cognitive deficits;Confocal Microscopy;DNA Repair;Data;Dendrites;Dendritic Spines;Development;Enhancers;Ensure;Enzymes;Functional disorder;Gliosis;Glycolysis;Goals;Hippocampus;Impaired cognition;Impairment;Laboratories;Learning;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Medical;Memory;Memory impairment;Metabolic;Metabolic Pathway;Metabolism;Molecular;Morphology;Mus;Neuronal Dysfunction;Neurons;Niacinamide;Nicotinamide Mononucleotide;Nicotinamide adenine dinucleotide;Pathway interactions;Patients;Pharmaceutical Preparations;Platinum;Play;Process;Quality of life;Role;Safety;Supplementation;Testing;Therapeutic;Transferase;Translational Research;United States;Work;age related neurodegeneration;aged;behavior test;cancer therapy;chemobrain;chemotherapy;clinically relevant;cognitive function;cohort;comorbidity;drug development;effective therapy;enzyme activity;healthspan;improved;insight;mouse genetics;mouse model;myelination;neurogenesis;neurotoxicity;novel;novel therapeutic intervention;older patient;overexpression;patient derived xenograft model;pharmacologic;prevent;side effect;stem;therapeutic target;therapeutically effective PQ#12; Targeting Nampt-mediated NAD+ metabolism in chemobrain PROJECT NARRATIVE In the United States cognitive dysfunction stemming from chemotherapy is a major adverse conditionaffecting approximately 14 million cancer survivors. Unfortunately the underlying pathophysiologicalmechanisms remain unknown. The findings of this proposal are crucial towards elucidating a role for theNampt-mediated NAD+ metabolic pathway in improving neuronal and cognitive dysfunction resulting fromchemobrain. This understanding will provide insight into development of novel therapeutic interventions thattarget chemotherapy-induced cognitive dysfunction. NCI 10693068 7/17/23 0:00 RFA-CA-18-019 5R01CA242158-06 5 R01 CA 242158 6 "CHEN, WEIWEI" 8/8/19 0:00 7/31/24 0:00 ZCA1-SRB-2(M2)S 10001078 "JANG, MI-HYEON " Not Applicable 10 NEUROSURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 386340 NCI 246076 140264 PROJECT SUMMARY Chemotherapy-induced cognitive dysfunction (referred to as chemobrain) negatively impacts cancersurvivors and has emerged as a significant medical problem. To date no effective treatment exists due to thelimited understanding of the mechanisms that drive chemotherapy-induced cognitive impairments. To provideeffective therapeutic strategies for this emergent medical problem this application aims to answer ProvocativeQuestion #12: What are the molecular and cellular mechanisms that underlie the development of cancertherapy-induced severe adverse sequelae? While the underlying molecular pathways vulnerable tochemotherapy-induced neurotoxicity are not well understood recent results from our laboratory indicate theNampt-mediated NAD+ pathway is a promising therapeutic target for chemobrain. Using the platinum-basedchemotherapy compound cisplatin we demonstrate its efficacy in suppressing the nicotinamide phosphoribosyltransferase (Nampt)-mediated NAD+ metabolic pathway. Cisplatin-mediated suppression of Nampt-NAD+metabolism leads to neurogenic dysfunction of the adult mouse hippocampus and memory impairments.Remarkably we found that by increasing NAD+ levels via administration of the NAD+ precursor nicotinamidemononucleotide (NMN) we can effectively reverse cisplatin-induced deficits in neuronal dendrite morphologyand memory function thus emphasizing the therapeutic potential of NAD+ metabolism in amelioration ofchemobrain. Based on these observations our central hypothesis is that increasing Nampt or NAD+ levelsprevent cisplatin-induced impairments in neuronal and cognitive function. Our findings represent a noveltherapeutic strategy for chemobrain. To test this novel hypothesis Aim 1 will determine whether increasingNAD+ levels through NMN supplementation can improve cisplatin-induced deficits in neuronal and cognitivefunction in both young and aged mice. In addition our translational proposal will ensure the safety of NMN as wewill determine if NMN has a detrimental impact on anti-neoplastic activity of cisplatin using patient-derivedxenograft (PDX) mouse models. Subsequently Aim 2 will elucidate if genetically increasing Nampt levels canprevent impairments in neuronal morphology and cognitive function. We will also evaluate if P7C3 a Namptenzyme activity enhancer can improve cisplatin-induced chemobrain in young and aged mice. Our proposedwork will provide critical pathophysiological mechanisms and improve our understanding of the Nampt-mediatedNAD+ metabolic pathway in order to improve chemotherapy-induced cognitive dysfunction. Ultimately thefindings will provide a framework by which safe and effective therapeutic strategies may be utilized in patientsundergoing cancer treatment so as to minimize or reverse neuronal and memory dysfunction. 386340 +No NIH Category available Adult;Adverse event;Affect;Biological Markers;Biopsy;Cancer Etiology;Cell Proliferation;Cessation of life;Chemoprevention;Chemopreventive Agent;Cirrhosis;Clinical;Clinical Chemoprevention;Companions;Compensation;Complication;Conduct Clinical Trials;Data;Development;Disease Progression;Dose;Drug Kinetics;Etiology;Fibrosis;Future;Gene Expression;Hepatic;Hepatology;Human;Immunohistochemistry;Incidence;Infrastructure;International;Intervention;Invaded;Length;Liver;Liver Cirrhosis;Liver Fibrosis;Liver diseases;Malignant Neoplasms;Measures;Meta-Analysis;Metabolic;Molecular;Monitor;Observational Study;Oncogenic;Outcome;Participant;Pathway interactions;Patient Selection;Patients;Pattern;Persons;Pharmacodynamics;Phase;Phase II Clinical Trials;Placebo Control;Placebos;Positioning Attribute;Predisposing Factor;Prevention;Prevention therapy;Prevention trial;Primary carcinoma of the liver cells;Prognosis;Prognostic Marker;Public Health;Randomized;Randomized Controlled Trials;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Risk;Risk Reduction;Safety;Sample Size;Serious Adverse Event;Serum;Signal Pathway;Signal Transduction;Surrogate Markers;Survival Rate;Testing;Therapeutic;Time;Tissue Sample;Translating;Translational Research;Viral;arm;atorvastatin;base;cancer cell;cancer chemoprevention;cancer risk;circulating biomarkers;clinical center;clinical translation;cohort;design;double-blind placebo controlled trial;efficacy testing;efficacy trial;epidemiologic data;follow-up;genetic signature;hazard;high risk;improved;in vivo;innovation;intrahepatic;lipophilicity;liver biopsy;liver inflammation;liver transplantation;mortality;neoplastic;novel;novel strategies;patient population;pharmacodynamic biomarker;population based;pre-clinical;prevent;prevention clinical trial;primary endpoint;prognostic;prospective;randomized controlled design;randomized clinical trials;research clinical testing;risk prediction;screening;secondary endpoint;standard of care;trend;tumor;two-arm study Trial of Statins for Chemoprevention in Hepatocellular Carcinoma Project NarrativeThe efficacy of existing therapies for hepatocellular carcinoma (HCC) is highly limited. Therefore prevention ofHCC development in patients at risk i.e. liver cirrhosis is urgently needed. Based on prior supportive datagenerated by us and others we will evaluate atorvastatin in a placebo-controlled phase II clinical trial for itssafety and efficacy in modulating a high-risk HCC gene signature in patients with compensated cirrhosis. NCI 10692915 9/1/23 0:00 PAR-18-559 5R01CA255621-03 5 R01 CA 255621 3 "UMAR, ASAD" 9/1/21 0:00 8/31/27 0:00 Cancer Prevention Study Section[CPSS] 1936402 "CHUNG, RAYMOND T" "HOSHIDA, YUJIN " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1 NCI 1 0 PROJECT SUMMARYWorldwide hepatocellular carcinoma (HCC) represents the fifth most common cancer and the second-leadingcause of cancer-related mortality. In the U.S. both the HCC incidence and mortality are increasing at an alarmingpace. Despite these concerning trends treatment options for HCC remain limited and the prognosis is grim witha 5-year survival rate of just 15%. Thus identifying effective strategies to prevent the development of incidentHCC represents a critical public health need. A growing body of preclinical and population-based observationaldata now demonstrate that lipophilic statins and in particular atorvastatin reduces hepatic inflammation cellularproliferation and cancer cell invasion and reduces the incidence of HCC in part by acting on relevant pathwaysincluding the Hippo-YAP signaling pathway. However despite these promising data well-designed randomizedcontrolled trials (RCTs) of atorvastatin for HCC prevention have not yet been reported. Historically the feasibilityof an HCC prevention trial has been limited by large sample size and long lengths of follow-up required to assesstarget endpoints. Recently however our group has derived and validated a 186-gene expression PrognosticLiver Signature (PLS) that represents an accurate reproducible and highly reliable surrogate biomarker for HCCrisk in multiple international cohorts of all major viral and non-viral etiologies of cirrhosis. Further we havedemonstrated that therapeutic modulation of the PLS accurately recapitulates future risk of developing incidentHCC tumors both in vivo and in confirmatory human studies. Finally we and others have demonstrated in humanliver tissue samples that atorvastatin modulates the PLS in part by acting on the Hippo-YAP pathway. Thus thePLS represents a novel and highly tractable surrogate biomarker endpoint for an RCT of atorvastatin for thereduction of incident HCC risk.In this proposal we will conduct a phase II RCT in 60 patients with compensated cirrhosis designed to test theefficacy safety and tolerability of 48 weeks of atorvastatin for the reduction of HCC risk defined by our validatedPLS profile. All subjects will have a high-risk PLS defined at screening liver biopsy and subjects will be randomlyassigned to 1 of 2 study arms for the 48-week study period: atorvastatin 20mg/day or placebo with appropriatemonitoring for the 48-week period followed by a repeat biopsy at week 48 to assess for improvement in the PLSprofile. We will also confirm whether atorvastatin has adequately engaged its targets by evaluatingpharmacokinetics/pharmacodynamics pre/neoplastic markers and alteration in the Hippo-YAP pathway. Wehypothesize that PLS-based HCC risk level decreases in the atorvastatin arm at the end of 48-week treatment.If atorvastatin treatment is effective safe and well-tolerated it could become the first chemopreventive agentdesigned to prevent the development of HCC guided by PLS in the growing population of patients in the U.S.who are affected by cirrhosis and are at high risk for this devastating complication. 1 +No NIH Category available Ablation;Affect;Allografting;Benign;Binding;Bladder;Carcinogens;Cell Line;Chromatin;Clinical;Clonal Expansion;Communication;Complex;DNA;Data;EZH2 gene;Enhancers;Epigenetic Process;Event;Exclusion;Exhibits;Functional disorder;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Engineering;Genetic Transcription;Genetically Engineered Mouse;Genomic Segment;Histologic;Histology;Histone H3;Histones;Human;KRASG12D;Kidney;Lesion;Location;Lysine;MLL gene;Malignant Neoplasms;Malignant neoplasm of ureter;Malignant neoplasm of urinary bladder;Maps;Mediating;Messenger RNA;Methyltransferase;Mitogen-Activated Protein Kinase Kinases;Modeling;Molecular;Morbidity - disease rate;Morphology;Mus;Muscle;Mutation;Neoplasm Metastasis;Nitrosamines;Oncogene Activation;Oncogenes;Oncogenic;Organoids;Output;PIK3CG gene;Pathway interactions;Patients;Phosphotransferases;Predisposition;Proteins;RNA;Recurrence;Recurrent disease;Regulation;Risk;Role;Running;Sampling;Secondary to;Signal Transduction;Site;Techniques;Time;Transcriptional Regulation;Transitional Cell;Transitional Cell Carcinoma;Tumor Suppression;Up-Regulation;Ureter;Urethra;Urothelial Cell;Urothelium;allotransplant;bladder transitional cell carcinoma;cancer invasiveness;combinatorial;fitness;gene repression;genetic signature;histone demethylase;histone methylation;histone methyltransferase;immune cell infiltrate;kinase inhibitor;loss of function mutation;men;migration;mortality;mouse model;preclinical study;programs;promoter;protein complex;response;single-cell RNA sequencing;stemness;synergism;transcription factor;transcriptome;tumor;tumor initiation;tumorigenesis Defining the role of histone H3K4 mono-methyltransferase dysfunction in urothelial carcinoma Project NarrativeComponents of the epigenetic complex that regulate enhancer function and methylate histone H3 at lysine 4including KMT2C KMT2D and KDM6A are early oncogenic events in urothelial cancer of the bladder andureters and can be detected in normal appearing urothelium. We have generated genetic engineered mousemodels of urothelial cancers based on mutations of KMT2C and KMT2D. In this proposal we will characterizethe epigenetic mechanisms of tumor suppression. NCI 10692913 7/27/23 0:00 PAR-19-183 5R01CA265026-02 5 R01 CA 265026 2 "JOHNSON, RONALD L" 9/1/22 0:00 8/31/27 0:00 Molecular Oncogenesis Study Section[MONC] 8725597 "CHEN, YU " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 590257 NCI 333479 256778 Project Summary/AbstractUrothelial carcinoma (UC) involves the urothelial cells that line the bladder kidney and ureters and is a majorcause of morbidity and mortality in the US especially in men. Bladder UC can be clinically separated intononmuscle invasive (NMIBC) and muscle invasive (MIBC). MIBC accounts for the vast majority of metastasisand mortality having only a ~50% cure rate. Patients with treated NMIBC are at risk of recurrence orprogression to MIBC at prior or de novo sites. Over half of urothelial cancer regardless of site of origin harborloss of function mutations in the histone demethylase KDM6A (UTX) and in two highly homologous histonemethyltransferases KMT2C (MLL3) and KMT2D (MLL4). These proteins form the MLL3/4-COMPASS(COMplex of Proteins ASsociated with Set1)-like complex that regulate enhancer function partly throughmethylation of histones at enhancers. Enhancers are regions of DNA that regulate lineage specifictranscriptional programs. Recent studies have shown that patients with two urothelial carcinomas in far awaysites (ureter and bladder) harbor the same COMPASS-like mutation. Further sequencing of histologicallybenign urothelium identify frequent mutations in the complex at expand over time. Our hypothesis is that thesemutations under field-cancerization of the urothelium. Our lab has generated a genetically engineered mousemodel with deletion of Kmt2c Kmt2d or the combination in the urothelium. The urothelium of these miceexhibit no histologic abnormalities. However transcriptome analysis shows the urothelium exhibit increasedstemness and functional studies show they exhibit increased organoid forming abilities. When crossed into thePten conditional deletion mouse there was robust cooperativity in tumorigenesis. The overall objective of thisproposal is to utilize our recently generated mouse models of urothelial this COMPASS-like complex loss tomechanistically understand its role in tumor urothelial suppression. Specifically in Aim 1 we seek to determinethe stemness clonal dynamics oncogene and carcinogen susceptibility of urothelium harboring mutations inthis COMPASS-like complex using lineage tracing organoid culture and single-cell RNA-sequencing. In Aim2 we seek to determine the functional interplay between MLL3/4-COMPASS dysfunction and oncogeneactivation. In Aim 3 we will seek to define how loss of Kmt2c and Kmt2d in urothelial cells affect enhancer andpromoter function. Active enhancers are genomic regions of open chromatin with transcription factor bindingdivergent transcription of enhancer RNA and looping to promoters. We will study each step by global mappingof histone marks chromatin accessibility mRNA transcription of associated gene and looping to promotersusing state-of the art epigenetics techniques. 590257 +No NIH Category available Accountability;Achievement;Agency for International Development;Belief;Benchmarking;Biomedical Research;Businesses;Career Mobility;Charge;Collaborations;Complex;Creativeness;Critical Race Theory;Data;Data Collection;Decision Making;Development;Education;Effectiveness;Elements;Ensure;Environment;Equity;Evaluation;Faculty;Feedback;Goals;Grant;Human Resources;Incubators;Individual;Institution;Intervention;Knowledge;Leadership;Lesbian Gay Bisexual Transgender Queer Questioning;Measures;Mentors;Methods;Minority;Minority Groups;Modeling;Monitor;Organizational Policy;Outcome;Performance;Persons;Policies;Procedures;Process;Program Evaluation;Questioning individuals;Reporting;Research;Science;South Carolina;Strategic Planning;Structure;System;Teacher Professional Development;Testing;Time;Training;Universities;Woman;Work;career;cohort;experience;faculty support;flexibility;higher education;improved;innovation;insight;intersectionality;member;people of color;programs;recruit;social;success;theories Evaluation Core n/a NCI 10692909 9/11/23 0:00 RFA-RM-21-025 5U54CA272171-02 5 U54 CA 272171 2 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-X] 7213 78063247 "BRYAN, MICHELLE " Not Applicable 6 Unavailable 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC Domestic Higher Education 292080001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 205517 137931 67586 CORE SUMMARY EVALUATION COREThe FIIRRE Evaluation Core provides the assessment and evaluation expertise to measure the overall impactof the Faculty Initiative for Improved Recruitment Retention and Experience (FIIRRE) and the achievement ofaims for each of the Cores. The Evaluation Core is led by two experienced program evaluators (Dr. MichelleBryan and Pamela Gillam) with expertise in quality improvement strategic planning facilitation critical racetheory and intersectionality and program evaluation within educational settings. The Cores evaluation planharnesses the strengths of two well-established evaluation and monitoring frameworksUtilization FocusedEvaluation and Equity-Focused Developmental Evaluation. Importantly the entire evaluation will be conductedfrom a Culturally Responsive Evaluation approach recognizing that culturally defined beliefs and values arecentral elements of evaluation. These evaluation frameworks and approach align with the overall programframework for FIIRRE the Systems of Career Influences Model that depicts the interrelationship betweensystems of organizational policies practices and culture and personal choice decisions and their impact oncareer advancement. Grounding our evaluation plan in established theory ensures that our approach ispractical flexible and comprehensive. The Evaluation Core will accomplish the following aims: (1) Monitor andevaluate Core activities and provide timely feedback to FIIRRE leadership to improve quality and increaseefficiency; (2) Engage institutional leadership to align FIIRRE and institution-wide evaluation strategies andactivities towards achieving inclusive excellence; (3) Determine the impact and effectiveness of FIIRRE inachieving its goals including assessment against benchmarks of culture change faculty development andcareer advancement; and (4) Engage with FIRST awardees and the FIRST Coordination and EvaluationCenter in building the evidence for implementing and sustaining cultures of inclusive excellence. A variety ofqualitative and quantitative data collection approaches support our work plan recognizing that flexibility andfeasibility are necessary to optimize participation by key stakeholders (e.g. FIIRRE faculty cohort) and ensurethe sustainability of data collection (and reporting) efforts. The Evaluation Core will actively participate in theFIIRRE Leadership Team as well as work closely with the Internal and External Advisory Councils andinstitutional leaders to provide evaluation feedback assist with adjustment of specific programmatic activitiesand adjust tracking and evaluation processes over time to guide decision-making and accountability. Given themomentum established by UofSCs institutional leaders over the past two years towards achieving inclusiveexcellence FIIRRE can serve as the incubator to test existing and new strategies and methods that achieveinclusive excellence at multiple levels individual department unit and institutional. +No NIH Category available Academia;Address;Adoption;Cancer Center;Clinic;Clinical;Communities;Computer software;Data;Data Analytics;Data Collection;Data Science;Data Storage and Retrieval;Documentation;Education;Educational process of instructing;Event;Exercise;Explosion;Funding;Future;Galaxy;Geography;Goals;Heart;Historically Black Colleges and Universities;Home;Image;Informatics;Institution;Knowledge;Learning;Licensing;Location;Malignant Neoplasms;Marketing;Measurement;Medical;Minority-Serving Institution;Persons;Phase Transition;Principal Investigator;Provider;Reproducibility;Research;Research Personnel;Resources;Scientist;Site;Speed;Technology;Trainers Training;Training;United States National Institutes of Health;anticancer research;citizen science;community college;cost;education resources;experience;improved;informatics tool;informatics training;instructor;interest;learning materials;lectures;literacy;massive open online courses;meetings;member;multimodality;online course;open source;outreach;programs;prototype;skills;software development;success;tool;training opportunity;usability Scalable multi-mode education to increase use of ITCR tools by diverse analysts Project NarrativeWe propose to create a complete training resource including content and both online and offlinecourses to improve cancer informatics knowledge throughout the research enterprise. The project willcreate an informatics training network hosted at www.itcrtraining.org that can be used by everyonefrom community members to basic scientists to ITCR tool developers to medical doctors to principalinvestigators to improve their knowledge of informatics. NCI 10692904 9/1/23 0:00 RFA-CA-19-042 5UE5CA254170-04 5 UE5 CA 254170 4 "ELJANNE, MARIAM" 9/1/20 0:00 8/31/25 0:00 ZCA1-TCRB-T(M1) 7822075 "LEEK, JEFFREY T." "JEREMIAH, ROHAN DEXTER; WRIGHT, CARRIE " 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 528237 NCI 968464 64734 "Project Summary/AbstractWe propose to develop content for and deliver informatics training to a broad cross-section of citizensscientists and researchers in informatics. We will leverage and extend an existing training platform andcontent we have developed. We will improve cancer informatics literacy and the usability of existingITCR tools support future ITCR tool developers and teach informatics to a broad cross-section ofinterested parties. Our success will both deepen expertise within the field and broaden the exposure ofITCR tools within currently-unengaged research communities. Specifically we will: (1) develop andrelease a software platform for rapidly prototyping validating and sharing modular training materialsthat can be delivered in a range of formats from massive online open courses to in-person shortcourses to in depth semester long courses (2) develop informatics courses teaching not only specificuse of ITCR tools to solve concrete scientific challenges but also broadly the concepts of informatics to abroad community ranging from citizen scientists to NCI funded PIs (3) develop courses for ITCR tooldevelopers around usability documentation support and marketing to improve the impact of thesetools in the field and (4) deliver in person and ""train the trainer"" courses that will scale the impact ofour educational program both within NIH funded cancer centers and into currently underservedresearchers at community colleges minority serving institutions historically black colleges anduniversities and engaged citizens outside of academia. All software content and data developed byour program will be open source and made accessible to the broadest possible audience by leveragingour existing expertise in online and scalable in-person education along with our relationships toMOOC providers informatics platforms and developers. We will thus will dramatically increasecancer informatics knowledge and skill and speed the adoption and use of data to tackle importantproblems in cancer throughout the research enterprise." 528237 +No NIH Category available Accountability;Adoption;Advocate;Area;Award;Cell Nucleus;Collaborations;Communities;Decision Making;Discipline of Nursing;Discrimination;Education;Elements;Ensure;Evaluation;Faculty;Faculty Recruitment;Fostering;Funding;Goals;Health Sciences;Human Resources;Incentives;Individual;Infrastructure;Institution;Investments;Leadership;Mentors;Minority;Policies;Positioning Attribute;Process;Public Health Schools;Recommendation;Research;Research Personnel;Resources;Schools;Science;Secure;South Carolina;Sterile coverings;Strategic Planning;Students;System;United States National Institutes of Health;Universities;cohort;college;diversity and inclusion;early-career faculty;equity diversity and inclusion;experience;health disparity;health equity;improved;innovation;operation;organizational structure;outreach;policy recommendation;professor;programs;racial bias;racism;recruit;sociodemographics;success;tenure track Administrative Core n/a NCI 10692901 9/11/23 0:00 RFA-RM-21-025 5U54CA272171-02 5 U54 CA 272171 2 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-X] 7211 7749189 "LIESE, ANGELA D" Not Applicable 6 Unavailable 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC Domestic Higher Education 292080001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 3959972 2657699 1302273 CORE SUMMARY ADMINISTRATIVE COREThe proposed Faculty Initiative for Improved Recruitment Retention and Experience (FIIRRE) seeksto expand the diversity of our health sciences faculty and transform the culture policies and practices of theUniversity of South Carolina (UofSC) to promote inclusive excellence. The Administrative Core led by MPIsAngela Liese from the Arnold School of Public Health and Coretta Jenerette from the College of Nursing willensure the full integration of all FIIRRE cores drawing strong administrative intellectual and fiscal supportfrom our institutional leadership Internal and External Advisory Councils and other core personnel. Serving asthe nucleus of FIIRRE at UofSC the Administrative Core will: 1) provide the organizational structure seniorleadership and infrastructure necessary to enable the success of all core goals 2) oversee the administrativeand financial operations of FIIRRE including recruitment and retention of a cohort of ten new tenure-trackAssistant Professors who are committed to inclusive excellence and conduct health disparities andequity research 3) advocate for FIIRRE and serve as a liaison to institutional leadership funders and otherstakeholders and 4) identify and redress ways in which current policies and practices foster racial biasand other forms of discrimination at all levels of the institution including tenure and promotion. Our leaders areinterwoven into key leadership positions and decision-making committees within the institution enabling ourteam to introduce and help advance key policy and practice change recommendations from the ground up. Inaddition FIIRRE builds off the substantial institutional investments made towards inclusive excellenceat UofSC in the past five years including a Strategic Plan A Path towards Excellence that prioritizes diversityand inclusivity at all levels: executive faculty staff and student. Working closely with the Office of the Provostand Office of Diversity Equity and Inclusion at UofSC as well as other FIRST awardees and the Coordinationand Evaluation Center the Administrative Core will organize and manage FIIRREs many distinct activitiesprocesses and outreach efforts. +No NIH Category available Accountability;Address;African American;Area;Attitude;Biomedical Research;Black race;Businesses;Climate;Collaborations;Collection;Communities;Complement;Creativeness;Development;Development Plans;Discipline of Nursing;Effectiveness;Elements;Ensure;Environment;Equity;Ethnic Origin;Evaluation;Faculty;Goals;Grant;Health Sciences;Incentives;Incubators;Individual;Infrastructure;Institution;Institutional Policy;Institutional Practice;Institutional Racism;Intervention;Leadership;Lesbian Gay Bisexual Transgender;Lesbian Gay Bisexual Transgender Queer Questioning;Letters;Link;Measures;Mentors;Minority;Minority Groups;Minority Recruitment;Modeling;Nationalities;Persons;Policies;Process;Public Health Schools;Questioning individuals;Race;Recording of previous events;Research;Resources;Science;Sex Bias;South Carolina;Sterile coverings;Strategic Planning;Surveys;System;Teacher Professional Development;Training;Universities;Woman;cohort;college;diversity and inclusion;early-career faculty;environmental change;equity diversity and inclusion;evidence base;experience;faculty mentor;health disparity;health equity;improved;innovation;instrument;peer;people of color;professor;programs;queer;recruit;response;success;tenure track;working group Faculty Initiative for Improved Recruitment Retention and Experience (FIIRRE) Although diversity is a well-recognized driver of research innovation biomedical research institutions haveoften failed to effectively incorporate minoritized groups. In partnership with the University of South Carolinasleadership this project will transform institutional policies practices and culture toward inclusive excellencewith the aim of creating inclusive environmental change and in the process supporting a cohort of 10 tenure-track Assistant Professors. The results of this research will yield best practices and evidence-based models forinstitutional transformation toward inclusive excellence. NCI 10692900 9/11/23 0:00 RFA-RM-21-025 5U54CA272171-02 5 U54 CA 272171 2 "CALZOLA, JESSICA MARIE" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-MOSS-X(70)S] 7749189 "LIESE, ANGELA D" "FELDER, TISHA " 6 PUBLIC HEALTH & PREV MEDICINE 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF PUBLIC HEALTH 292080001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 4373670 OD 2935349 1438321 PROJECT SUMMARYDiversity enhances creativity and innovation in research but biomedical research institutions have generallyfailed to effectively incorporate minoritized groups such as individuals who identify as people of color womenand lesbian gay bisexual transgender or queer/questioning (LGBTQ) persons. Earlier diversity effortsfocused exclusively on intensified recruitment of minoritized faculty mentoring and training but manyinstitutions did not sustain their success because of insufficient change in institutional environments systemsand culture. Over the past two years the leadership of the University of South Carolina (UofSC) has beenintentional about transforming the institutional culture to one that embraces and expects a climate of diversityequity and inclusion (DEI). UofSCs Strategic Plan released in 2020 includes eight priorities which weredeveloped vetted and revised with intense participation of the campus community. The priorities includeStrategic Priority #2 Assemble and cultivate a world class faculty and staff and #4 Cultivate a more diverseequitable and inclusive campus culture. UofSC has demonstrated increased commitment to diversity inmultiple ways including hiring UofSCs first Black/African American Provost and elevating the Chief DiversityOfficer to the level of a Vice President. These efforts reflect UofSCs campaign to identify and remove factorssupporting systemic racism and gender-bias across all campus endeavors. In response to RFA-RM-21-025we have developed the Faculty Initiative for Improved Recruitment Retention & Experience (FIIRRE) using asystems science informed multi-level approach. FIIRRE aims to: (1) Develop cultivate and implementinstitutional programs and practices that become self-reinforcing in promoting inclusive excellence; (2) Achievesignificant and sustainable institutional culture change that supports inclusive excellence; (3) Recruit nurtureand retain a cohort of ten new tenure-track Assistant Professors who are committed to inclusive excellence;and (4) Collaborate with other FIRST awardees and the FIRST Coordination and Evaluation Center in thismulti-center initiative. The 10 tenure-track faculty will constitute the FIRST cohort at UofSC and will berecruited as a cluster hire within the area of health disparities and equity research. The FIIRRE AdministrativeCore Faculty Development Core and the Evaluation Core serve complementary purposes in support of theseoverarching aims. Initiated by two of UofSCs leading health science units the Arnold School of Public Healthand the College of Nursing FIIRRE will serve as an incubator and facilitator of institutional change. FIIRREleadership is varied in race/ethnicity academic rank nationality and institutional history with over a decade ofexperience working together in research and administrative capacities helping to ensure FIIRREs success.Strong existing connections with established diversity initiatives on campus will help complement and bolsterFIIRRE goals as will the unwavering institutional commitment to inclusive excellence by UofSCs leadership. 4373670 +No NIH Category available Advisory Committees;Affinity;Agar;Bar Codes;Binding;Biodistribution;Biological;Biology;Cancer Biology;Cancer cell line;Cell Communication;Cell Line;Cells;Characteristics;Chemical Engineering;Chemicals;Chemistry;Clinic;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Complex;Cytolysis;DNA;Detection;Development;Disease;Disease Resistance;Dose;Drug Delivery Systems;Drug Targeting;Environment;Evaluation;Flow Cytometry;Fluorescence;Formulation;Genes;Genetic;Genomics;Goals;Heterogeneity;Immune;Immunocompetent;Immunocompromised Host;In Vitro;Individual;Institution;Knock-out;Label;Magic;Malignant Neoplasms;Malignant neoplasm of ovary;Mass Fragmentography;Mass Spectrum Analysis;Mediating;Mentorship;Mesenchymal;Modality;Modeling;Mus;Organ;Patients;Play;Polymers;Population;Property;Recurrence;Research Personnel;Research Proposals;Sampling;Site;Sorting;Structure-Activity Relationship;Surface;Survival Rate;System;Techniques;Technology;Therapeutic Uses;Time;Tissues;Training;Translating;Translations;Tumor Biology;Validation;Work;anticancer research;aryl halide;cancer cell;carboxylate;carboxylation;career;chemotherapy;delivery vehicle;detection limit;genetic signature;high throughput analysis;in vivo;in vivo evaluation;materials science;multiple omics;nanocarrier;nanomedicine;nanoparticle;nanoparticle delivery;neoplastic cell;novel therapeutics;particle;pre-clinical;protein expression;screening;self assembly;success;targeted treatment;therapy resistant;tool;trafficking;transcriptome sequencing;tumor;tumor heterogeneity;uptake Understanding drug delivery through an integrated barcoding approach Project NarrativeNanoparticle translation to the clinic is lacking in large part due to limited accumulation in target disease sites aparticular problem for heterogeneous cancers like ovarian cancer which can be attributed to the complexity ofboth the biological environment and the nanoparticle constructs. There is an urgent need to develop tools todeconvolute the individual factors that contribute to nanoparticle accumulation and unlock the unrealizedpotential of cancer nanomedicine. Therefore this proposed study seeks to provide a holistic evaluation ofnanoparticle structure-function relationships by utilizing a new chemical barcoding strategy to identify materialsproperties associated with favorable biodistributions and tumor targeting enable the elucidation of geneticcomponents correlated with nanoparticle interactions and allow us to leverage the identified genetic signaturesfor more effective targeted drug delivery. NCI 10692864 7/25/23 0:00 PA-20-188 5R00CA255844-04 5 R00 CA 255844 4 "GRODZINSKI, PIOTR" 8/1/22 0:00 7/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11826207 "BOEHNKE, NATALIE " Not Applicable 5 ENGINEERING (ALL TYPES) 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN BIOMED ENGR/COL ENGR/ENGR STA 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 86053 NCI 166532 82468 Project SummaryDespite being hailed as the magic bullet that would selectively target and cure cancer only a handful ofnanoparticles have been successfully translated to the clinic and their full potential remains yet to be realized.In fact nanoparticle accumulation in tumors continues to be dismally low with less than 1% of the injected dosereaching its target. This is largely attributed to the complexity and heterogeneity of both the biologicalenvironment and nanoparticle constructs making it impossible to deconvolute individual factors contributing tonanoparticle targeting and accumulation in tumors. Therefore there is a critical need to better understand anddefine the attributes that define successful nanocarriers. This is particularly urgent in lethal cancers that stand tobenefit tremendously from new and targeted therapies like ovarian cancer which has a 25% 5-year survival rateand 70% recurrence rate following chemotherapy often leading to treatment resistant disease. To developeffective drug delivery strategies it is critically important to understand the characteristics of tumorsnanoparticles and their interactions such as by identifying the genetic features associated with high nanoparticleuptake and accumulation. To accomplish this the work proposed herein features a chemical barcoding approachto enable pooled high throughput analysis of nanoparticles in a pre-clinical context enabling the identificationand correlation of genetic features responsible for successful nanoparticle targeting through a multi-omicsapproach. Successful development of this barcoding platform will entail 1) rapid integrated in vitro screening ofpooled NP formulations 2) in vivo single system evaluation of nanoparticle accumulation at the tissue and cellularlevel and 3) use of pooled barcoded nanoparticles to correlate particle trafficking in patient derived models ofovarian cancer. This strategy will provide a holistic evaluation of nanoparticle structure-function relationshipswith tumor accumulation and enable the identification of genetic components implicated with meaningfulnanoparticle interactions allowing us to leverage these signatures to develop more effective targetednanoparticles to specific tumor cell populations. The proposed work will take place at MITs Koch Institute forIntegrative Cancer Research a premier institution for cancer research with state-of-the-art facilities under thementorship of Prof. Paula Hammond a renowned chemical engineer and polymer chemist with expertise in theself-assembly of materials and drug delivery. An advisory team has carefully been assembled consisting ofProfs. Stuart Schreiber and Angela Koehler for chemical biology and multi-omics analysis guidance Prof. JoanBrugge for her cancer biology expertise and Prof. Nathalie Agar for input on mass spectrometry-based analysis.Combined this research proposal and mentorship team will lay the scientific groundwork and provide thenecessary training for the applicant to reach her ultimate goal of successfully starting her independent academiccareer at the interface of chemistry biology and materials science. 86053 +No NIH Category available AIDS clinical trial group;AIDS related cancer;Ablation;Acquired Immunodeficiency Syndrome;Africa;African;Area;Botswana;COVID-19 Prevention Network;Caring;Cause of Death;Cervical;Cervical Cancer Screening;Cervical dysplasia;Cessation of life;Clinical Research;Clinical Trials;Clinical Trials Network;Clinical Trials Unit;Collaborations;Communities;Community Health Education;Consumption;Country;Cryptococcosis;Cryptococcus;Data;Devices;Dysplasia;Early Diagnosis;Early treatment;Economic Factors;Effectiveness;Enrollment;Ethics;Ethnic Origin;Evaluation;Female Adolescents;Geography;HIV;HIV diagnosis;Health Services Accessibility;Health system;High Prevalence;Human Papilloma Virus Vaccination;Human Papillomavirus;Immunotherapy;Impairment;Improve Access;Income;International;International Agencies;International Maternal Pediatric Adolescent AIDS Clinical Trials;Laboratories;Language;Lesion;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;Observational Study;Oncology;Outcome;Patient Recruitments;Patient risk;Patients;Performance;Persons;Population;Prevalence;Prevention;Preventive service;Protocols documentation;Quality Control;Relapse;Research;Research Personnel;Resources;Sampling;Site;Southern Africa;Target Populations;Techniques;Technology;Time;Training;Treatment Effectiveness;Tuberculosis;United States National Institutes of Health;Universal Coverage;Vaccines;Viral;Woman;access disparities;aged;antenatal care;antiretroviral therapy;breast cancer diagnosis;cancer diagnosis;cancer invasiveness;cancer prevention;cancer therapy;clinical research site;cohort;community engagement;comparative trial;data management;data quality;effectiveness evaluation;experience;improved;innovation;mortality;new technology;novel;participant enrollment;patient navigation;pragmatic trial;premalignant;prevent;programs;prospective;quality assurance;randomized trial;research study;screening;screening program;treatment optimization;treatment program;uptake Botswana CASCADE Clinical Trials Site Project NarrativeThe Botswana CASCADE Clinical Trials Site will study strategies for preventing cervical cancer in women livingwith HIV. Cervical cancer is the leading cause of death for women on HIV treatment in Botswana and currentapproaches have not succeeded in reaching population with effective preventative services. Studies to beconducted will focus on strategies to improve access to screening effectiveness of cervical screening and accessand treatment effectiveness of identified precancers. NCI 10692854 5/31/23 0:00 RFA-CA-21-047 5UG1CA275416-02 5 UG1 CA 275416 2 "FRECH, MARIA SILVINA" 9/5/22 0:00 5/31/27 0:00 ZCA1-SRB-F(M2)R 10343338 "DRYDEN-PETERSON, SCOTT " "RAMOGOLA-MASIRE, DOREEN " 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 399 Other Research-Related 2023 238011 NCI 213417 24594 Project Summary / AbstractSuccessful HIV treatment programs in Botswana and elsewhere in southern Africa have led to dramaticreductions in mortality from tuberculosis cryptococcosis and other non-cancer AIDS deaths. However cancerdeaths have not decreased and cervical cancer now is the leading cause of death for women living with HIV inthe region. Cervical cancer is preventable with early detection and treatment of precancerous lesions butchallenges of limited access to initial screening poor performance of initial screening technologies highprevalence of cervical precancers and persistent or relapsed dysplasia following therapy impair the impact ofprograms for women living with HIV. Working to develop strategies to these challenges we will establish theBotswana CASCADE Clinical Trials Site at BHP that will participate in and contribute to the following high-impact areas of research: 1) Enhancing cervical precancer screening uptake through patient and contextrelevant approaches including HPV self-sampling non-clinical screening venues and screening duringantenatal care; 2) Strategies and novel technologies to improve management of positive HPV initial screeningmaximize prevention of invasive cancer while minimizing patient risk and consumption of health systemresources; 3) Improving precancer treatment access treatment completion and outcomes; and 4) Optimizingtreatment approaches to cervical precancers including comparative trials of ablation techniques intervals ofrepeat evaluation and vaccines or other immunologic therapies. The Botswana CASCADE Clinical Trials Sitewill contribute to conducting high-quality clinical research studies provide context-relevant input ondeveloping trial concepts understand disparity in access by geography economic factors andlanguage/ethnicity and continue to develop local research capacity through mentoring and training. 238011 +No NIH Category available Adenocarcinoma;Antigens;Autologous;Biopsy;Cancer Model;Cancer Vaccines;Carcinoma;Chest;Clinical;Clinical Trials;Coculture Techniques;Collaborations;Computing Methodologies;Correlative Study;Cytotoxic T-Lymphocytes;Data;Detection;Disease Progression;Exhibits;Female;Frameshift Mutation;Genomics;Glass;Goals;Human;Image;Immune;Immune Targeting;Immune checkpoint inhibitor;Immunogenetics;Immunoprevention;Immunosuppression;Impairment;Infiltration;Intercept;Investigation;Lesion;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lung nodule;MHC Class I Genes;Major Histocompatibility Complex;Malignant neoplasm of lung;Methods;Modeling;Molecular;Mus;Mutation;Mutation Detection;Natural History;Nodule;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Ovary;Patients;Peptides;Phenotype;Physiological;Placenta;Prevalence;Prevention;Process;Proteins;RNA;RNA vaccine;Regulatory T-Lymphocyte;Resource Sharing;Solid;Solid Neoplasm;Source;T-Lymphocyte;Testing;Testis;Transgenic Mice;Tumor Antigens;Tumor Immunity;Uncertainty;Vaccination;Vaccines;antigen-specific T cells;biobank;cancer immunotherapy;checkpoint therapy;clinical investigation;cohort;computerized;computerized tools;cytotoxic;cytotoxic CD8 T cells;density;efficacy evaluation;efficacy testing;exome sequencing;experience;immune RNA;immunogenic;immunogenicity;improved;in vivo;insertion/deletion mutation;insight;interest;lipid nanoparticle;lung cancer screening;lung tumorigenesis;manufacture;minimally invasive;mouse model;multi-ethnic;mutant;nanoparticle;neoantigen vaccination;neoantigens;neoplastic;novel;pre-clinical;preclinical study;premalignant;prevent;protein expression;screening program;success;tomography;transcriptomics;tumor;tumor exome;tumor immunology;tumor-immune system interactions;vaccine candidate;vaccine development;vaccine efficacy;vaccine evaluation Lung Cancer Vaccine n/a NCI 10692845 8/11/23 0:00 RFA-CA-21-038 5U54CA272688-02 5 U54 CA 272688 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7203 1873540 "LIPKIN, STEVEN M" Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 440288 300195 140093 PROJECT SUMMARYComputerized chest tomography (CT) lung cancer screening programs have increased the detection of premalignant non-solid (NS) nodules that harbor preinvasive or minimally invasive adenocarcinoma. Given that NS nodules can progress to invasive adenocarcinoma (solid nodules) intercepting progression is considered an urgent clinical priority. However the cellular and molecular alterations that accompany disease progression arepoorly understood. NS nodules exhibit lower rates of HLA deletions than invasive/metastatic lung cancer and our integrated clinical and preclinical investigations have recently uncovered T cell-enriched immune microenvironments including elevated activated T regs in NS nodules. Global genomic analysis of NS nodules identified high tumor-associated antigen (TAA) XAGE-1b and several HLA-restricted neoantigens. These findings have led to the hypothesis that RNA-based vaccination against NS nodule-associated antigens and or neoantigens can drive activation of T helper and cytotoxic CD8+ T cells while reducing tumor-infiltrating Tregs to impair NS nodule progression to invasive adenocarcinoma.We will test this hypothesis through two Specific Aims. Aim 1 will determine the potential of lipo-nanoparticle RNA (LNP RNA) XAGE-1b vaccination in intercepting NS nodule progression in preclinical syngeneic models of NSCLC. A state-of-the-art LNP-XAGE-1b RNA vaccine will be manufactured and optimized in collaboration with the LNP-RNA shared resource facility. A novel physiologically relevant mouse model recapitulating the progression of human NS nodules will be used to determine the efficacy of the XAGE-1b vaccine in intercepting the progression of NSN to invasive carcinoma. Mechanisms associated with LNP RNA vaccine immune interception will be elucidated with comprehensive immune profiling approaches. Aim 2 will delineate the most immunogenic and cytotoxic patient lung NS nodule antigens and neoantigens identified in a multi-ethnic cohortof clinically annotated NS nodules for vaccine payloads. Human class I MHC (HLA) transgenic mice will identifythe most immunogenic lung NSN vaccine cargo in vivo. Patient-specific tumoroid/autologous T-cell cocultures and immunopeptidomics will be used to confirm immunogenicity and antigenic presentation on autologous patient HLA. Finally the cytotoxic potential of NS nodule patient neoantigen-specific T-cells against autologous tumoroids will be used to rank neoantigens.We expect to delineate the most immunogenic vaccine cargo together with informative correlative studies for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials and provide critical mechanistic insights into effective patient LNP RNA immune interception vaccines. +No NIH Category available Adenine;Affect;American;Amino Acids;Atlases;Autologous;Automobile Driving;Biological Assay;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;COVID-19;Cancer Burden;Cancer Patient;Cells;Clinical;Clinical Trials;Colonic Adenoma;Colorectal Adenocarcinoma;Colorectal Adenoma;Colorectal Cancer;Correlative Study;Cytotoxic T-Lymphocytes;DNA;Data;Disease;Future Generations;Genomics;Hereditary Nonpolyposis Colorectal Neoplasms;Heterozygote;Human;Immune checkpoint inhibitor;Immune response;Immunity;Immunologics;Immunoprevention;MHC Class I Genes;Malignant Neoplasms;Microsatellite Instability;Mismatch Repair;Mismatch Repair Deficiency;Mus;Mutate;Mutation;Normal Cell;Patients;Peptides;Proteins;RNA;RNA vaccination;Recurrence;Science;T-Lymphocyte;TGFBR2 gene;Technology;Testing;Transgenic Mice;Tumor Burden;Tumor-Infiltrating Lymphocytes;Vaccination;Vaccines;adenoma;cancer genome;colon cancer cell line;colon cancer patients;colorectal cancer risk;cytotoxic;first-in-human;gene repair;immune checkpoint;immunogenic;immunogenicity;in vivo;insertion/deletion mutation;insight;mouse model;nanoparticle;neoantigen vaccine;neoantigens;peptide vaccination;premalignant;repaired;tumor;tumor immunology;vaccine candidate;vaccine development Lynch Vaccine n/a NCI 10692841 8/11/23 0:00 RFA-CA-21-038 5U54CA272688-02 5 U54 CA 272688 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7202 1873540 "LIPKIN, STEVEN M" Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 360907 318969 41938 Project 1: Project Summary/Abstract Lynch syndrome (LS) affects ~1.2 million Americans and predisposes them to colorectal cancer (CRC) and other malignancies. LS normal cells acquire somatic second mutations and become DNA mismatch repair deficient (MMRD). MMRD tumors have exceptionally high numbers of frameshift proteins. MMRD mutation rates are so elevated that precisely the same recurrent mutations are shared among tumors from different patients. For example TGFBR2 has a 10bp adenine repeat that when mutated causes the identical frameshift protein (FSP) in ~80% of MMRD CRCs. Previously we showed that (a) 100% of MMRD CRC patients have CD8+ T cells reactive against MMRD rFSPs (b) performed first-in-human trials showing that peptide vaccination robustly upregulates T-cell immunity against rFSP in advanced MMRD cancer patients and (c) demonstrated functionally in LS mouse models that vaccination with only four mouse recurrent neoantigens increases CD8+ killer and CD4+ helper T-cell immune response reduces CRC burden and prolongs cancer-free survival. As new preliminary data we and CAP-IT CRI Computational Tumor Immunology Core (CTIC) Co-PI Getz a primary architect of NCI tumor genome atlases have (a) sequenced the largest number of LS colorectal adenomas and adenocarcinomas worldwide and identified many promising MMRD recurrent neoantigen vaccine candidates (b) used MMRD CRC cell lines LS patient colon adenoma derived tumoroids and the NCI CPTAC tumor atlas to confirm that recurrent neoantigens are bona fide expressed as neo-peptides in tumors and (c) showed that in mice lipo-nanoparticle RNA (LNP-RNA) rFSP vaccination is significantly more immunogenic than peptide vaccination. Here we propose to test the hypothesis that LNP-RNA rFSP vaccination elicits LS mouse CD8+/CD4+ immune response reduces tumor burden increases survival (AIM 1) and delineates the most immunogenic cytotoxic Lynch syndrome patient recurrent neoantigens (AIM 2). This project will identify the most immunogenic recurrent neoantigens for NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials. Importantly our studies will provide vital mechanistic insights into future generations of effective patient LNP RNA immunoprevention vaccines. +No NIH Category available Area;Atlases;Award;Cancer Patient;Cells;Clinical;Clonal Evolution;Collaborations;Data;Data Analyses;Epitopes;Genomics;Hereditary Nonpolyposis Colorectal Neoplasms;Immune;Immunoprevention;Lead;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mutation;Mutation Analysis;Nodule;Patients;Premalignant Neoplasm;Proteomics;RNA;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Science;Services;The Cancer Genome Atlas;Tumor Antigens;Vaccines;Validation;cancer genetics;computerized tools;experience;genomic data;immunogenicity;improved;innovation;insertion/deletion mutation;neoantigens;new technology;novel;programs;success;tool;tumor;tumor immunology;vaccine immunogenicity;working group The Computational Tumor Immunology Core (CTIC) n/a NCI 10692839 8/11/23 0:00 RFA-CA-21-038 5U54CA272688-02 5 U54 CA 272688 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7201 1873540 "LIPKIN, STEVEN M" Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 183927 177442 6485 CTIC Core: Project Summary/AbstractThe Computational Tumor Immunology Core (CTIC) will provide CAP-IT CRI researchers with state-of-the-artcomputational genomic tumor immunology immunopeptidomic and spatial genomic services to supportresearch projects for immunoprevention of patients with a. Lynch syndrome (LS; Project 1) b. lung cancer non-solid nodule (NSN) pre-malignant neoplasms (Project 2) and c. any new CAP-IT projects that are subsequentlyapproved by the CAP-IT program. CTIC investigators include accomplished leaders in computational cancergenetics tumor immunology single-cell profiling and spatial genomics. We have significant experience with allproposed analyses to be performed. As the CTIC areas of focus are dynamic and rapidly evolving we anticipateincorporating new technologies and computational strategies as they develop to help drive Projects 1 and 2. TheCTIC will successfully delineate LNP RNA immunoprevention and immune interception vaccines for LS and NSNpatients and provide necessary shared resources for the CAP-IT network-wide. +No NIH Category available Acceleration;Affect;Biochemical;Cancerous;Cell Separation;Cell physiology;Cells;Chemicals;Complex;Cytogenetics;Diagnostic;Diffusion;Disease;Drug Targeting;Drug resistance;Excision;Exhibits;Experimental Designs;Heterogeneity;Hour;Imides;Immune response;Individual;Isotopes;Label;Lead;Libraries;Liquid Chromatography;Literature;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Mediating;Methods;Molecular;Molecular Profiling;Multiple Myeloma;Natural regeneration;Noise;Patients;Peptides;Performance;Pharmaceutical Preparations;Phase;Phenotype;Pilot Projects;Plasma Cells;Population;Predisposition;Preparation;Process;Proteins;Proteome;Proteomics;RNA;Reagent;Resistance;Resolution;Role;Salts;Sampling;Solid;Sorting;System;Technology;Therapeutic;Therapy Evaluation;Time;Tissues;anticancer research;cancer cell;cancer therapy;cell type;cross reactivity;diagnosis evaluation;effective therapy;experimental study;immunoregulation;improved;innovation;instrument;liquid chromatography mass spectrometry;mass spectrometer;nano;nanoDroplet;neoplastic cell;new technology;novel;operation;personalized cancer therapy;predicting response;preservation;protein expression;protein profiling;response;single cell sequencing;single-cell RNA sequencing;tumor microenvironment;ubiquitin-protein ligase In-depth and label-free proteome profiling of hundreds of single cells per day PROJECT NARRATIVEThere are substantial gaps in our understanding of the role of the tumor microenvironment the interaction oftumor cell types and their specific responses to cancer therapies. Mass spectrometry-based proteomics enablesdeep molecular profiling of protein expression that is invaluable for cancer research diagnosis and therapyevaluation but it has lacked the sensitivity and throughput to extend these measurements to the single-cell levelfor large-scale experiments. We will develop a novel platform for in-depth single-cell profiling that combinesnanodroplet sample preparation with ultrahigh-performance and multiplexed liquid chromatography-massspectrometry with a measurement throughput of hundreds of cells per day which will greatly accelerate cancerresearch. NCI 10692837 8/16/23 0:00 RFA-CA-21-003 5R21CA272326-02 5 R21 CA 272326 2 "AMIN, ANOWARUL" 9/1/22 0:00 8/31/25 0:00 ZCA1-TCRB-D(M1) 9825066 "KELLY, RYAN T" Not Applicable 3 CHEMISTRY 9094012 JWSYC7RUMJD1 9094012 JWSYC7RUMJD1 US 40.226908 -111.6914 951901 BRIGHAM YOUNG UNIVERSITY PROVO UT SCHOOLS OF ARTS AND SCIENCES 846021231 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 173525 NCI 114538 58987 PROJECT SUMMARYCancer tissues exhibit a high degree of phenotypic heterogeneity and plasticity with cancerous tissuescomprising many different subpopulations of cells in various states. Quantifying this heterogeneity at the single-cell level and with molecular depth across large numbers of cells provides information that cannot be obtainedfrom bulk studies and that will ultimately lead to improved diagnostics and more effective treatments. Whilesingle-cell sequencing approaches are having a significant impact on cancer research proteins mediate the bulkof cellular function and are the targets of most therapeutics. Given that a compelling body of literature has shownthat the correlation between RNA and protein abundance is at best poor to moderate there is an urgent need todevelop new technologies for large-scale unbiased direct proteome profiling at the single-cell level. To fill thisgap mass spectrometry (MS)-based profiling of protein expression in single cells has very recently become areality due to more efficient sample processing workflows novel experimental designs and improved instrumentsensitivity. Label-free MS-based proteomics can currently quantify up to 1500 protein groups per cell across >4orders of magnitude of dynamic range but throughput has been limited to ~24 samples per day. This lowthroughput is inadequate to perform the large-scale statistically powered studies required to characterizeheterogeneity in cancer cell populations. To increase measurement throughput multiplexed workflows havebeen developed based on isobaric tandem mass tags (TMTs) that enable >10 single cells to be measured in anLC-MS analysis but these suffer from a number of significant drawbacks including isotopic contaminationdegraded quantitative accuracy when employing a carrier channel precursor coisolation with concomitant ratiocompression chemical noise resulting from cross-reactivities of TMT reagents with contaminants etc. Theoverall objective is to develop a platform that exceeds the throughput of current TMT-based workflows whilepreserving the depth of coverage and dynamic range of label-free workflows. We hypothesize that a robustmulticolumn ultra-high-performance nanoLC system with a 5-minute peptide elution window and a 100% dutycycle combined with novel MS1-level protein identification and quantification will enable label-free profiling of>2000 protein groups per cell at a throughput of up to 288 samples per day thus providing a providing a capabilityfor direct in-depth and large-scale protein quantification that is analogous to single-cell RNA-seq. Studies in Aim1 will focus on developing high-peak-capacity fast nanoLC separations as well as a novel sorbent-coatedsample-loop providing desalting and debris removal for robust long-term operation. In Aim 2 we will develop a4-column LC platform based on these rapid separations and a primarily MS1-based acquisition workflow toincreate duty cycle to 100% and maximize coverage in these rapid analyses. We will apply this technology toCD138+ single cells isolated from multiple myeloma patients to predict response to immunomodulatory imidedrugs (IMiDs). This project will establish an innovative measurement capability for individualizing cancer therapy. 173525 +No NIH Category available Acceleration;American Association of Cancer Research;American Society of Clinical Oncology;Automobile Driving;Award;Cancer Center;Cancer Research Project;Clinical;Clinical Trials;Collaborations;Contracts;Dana-Farber Cancer Institute;Database Management Systems;Databases;Division of Cancer Prevention;Doctor of Philosophy;Emerging Technologies;Ensure;Evaluation;Genetic Databases;Genomics;Goals;Health Insurance Portability and Accountability Act;Hereditary Nonpolyposis Colorectal Neoplasms;IACUC;Immune Targeting;Immunooncology;Immunoprevention;Individual;Institute of Medicine (U.S.);Institutional Review Boards;International;Journals;Lead;Leadership;Malignant neoplasm of lung;Medicine;Mission;National Cancer Institute;Patients;Prevention Research;Productivity;Program Research Project Grants;RNA;RNA vaccine;Reproduction spores;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Site;Time;Translating;Translations;Vaccines;Validation;archive data;cancer prevention;cancer risk;clinical translation;data archive;data management;data sharing;editorial;experience;individualized prevention;meetings;member;pre-clinical;prevent;programs;targeted agent;translational oncology;tumor immunology;working group CAP-IT CRI U54 ADMINISTRATIVE CORE n/a NCI 10692836 8/11/23 0:00 RFA-CA-21-038 5U54CA272688-02 5 U54 CA 272688 2 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U 7200 1873540 "LIPKIN, STEVEN M" Not Applicable 12 Unavailable 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY Domestic Higher Education 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 113758 66020 47738 Admin Core: Project Summary/AbstractA significant overall goal of CAP-IT is to identify and validate immunologically targeted agents for precisionprevention of individuals with increased cancer risk. The CAP-IT Center for RNA Immunoprevention (CRI)Administrative Core (AC) mission is to ensure that research project/Core teams maintain focus on this overallgoal. The AC will rapidly perform administrative functions that would otherwise serve as rate-limiting bottlenecksincluding IRB/IACUC regulatory compliance and the establishment of MTA/DTAs between multiple project sites.The AC will integrate CRI U54 into the CAP-IT network and drive intra-network as well as internationalcollaborations. To ensure CRI's scientific rigor and excellence we have assembled a scientifically andadministratively outstanding CRI External Advisory Board including the 2021 Lasker Award winner Dr. DrewWeissman (U. Penn). The AC shall also seamlessly integrate genomic databases and emerging technology asshared resources (such as liponanoparticle RNA vaccines and immunopeptidomics) with the CAP-IT U24 DRCC.1 +No NIH Category available Antigens;Architecture;Autologous;Award;Biotechnology;COVID-19;COVID-19 vaccine;Cancer Burden;Cessation of life;Clinic;Clinical;Clinical Trials;Clonal Evolution;Communicable Diseases;Computer Analysis;Data;Databases;Division of Cancer Prevention;Ensure;Genomics;Goals;Health Insurance Portability and Accountability Act;Hereditary Nonpolyposis Colorectal Neoplasms;Immune;Immunologic Surveillance;Immunoprevention;In Vitro;Individual;Infection;Inherited;Lesion;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Medical;Neisseria meningitidis;Nodule;Patients;Poliomyelitis;Predisposition;Premalignant Neoplasm;Prevention;Prevention strategy;Primary Cancer Prevention;RNA;RNA vaccination;RNA vaccine;Recording of previous events;Recurrence;Research;Resource Sharing;Role;Science;Services;Smoker;Syndrome;T-Lymphocyte;Technology;Translating;Tumor Antigens;Vaccines;Validation;Work;biobank;cancer genetics;cancer genome;cancer genomics;cancer immunotherapy;cancer predisposition;cancer prevention;cancer risk;clinical translation;cytotoxicity test;efficacy testing;experience;flexibility;forgetting;immune RNA;immunogenic;immunogenicity;in vivo;in vivo Model;individualized prevention;innovation;lipid nanoparticle;mouse model;neoantigens;patient population;pre-clinical;programs;success;transcriptome;translational pipeline;tumor;tumor immunology;vaccine discovery;vaccine formulation CAP-IT Center for LNP RNA Immunoprevention Overall Component: Project NarrativeAdvances in medical sciences led to the elucidation of infectious disease mechanisms and clinical translation ofpotent vaccines and therapies to reduce the death burden from common infections such as poliomeningococcus and many others that are now almost forgotten in the US because of these successes. Todayin the early 21st century we are building on the remarkable advances in our mechanistic understanding of thegenomic architecture of cancer and its predisposition. The CAP-IT CRI will focus on recent rapid advances inRNA vaccine technology cancer immune prevention and interception vaccines that have the potential tosubstantially reduce the cancer burden in the 21st century. NCI 10692835 8/11/23 0:00 RFA-CA-21-038 5U54CA272688-02 5 U54 CA 272688 2 "CLIFFORD, JOHN LEO" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U(M1) 1873540 "LIPKIN, STEVEN M" "ALTORKI, NASSER KHALED; MCGRAW, TIMOTHY E; MITTAL, VIVEK " 12 INTERNAL MEDICINE/MEDICINE 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Research Centers 2023 1098880 NCI 862626 236254 Overall Component: Project Summary/AbstractThe overall goal of CAP-IT Center for RNA Immunoprevention (CRI) is to pre-clinically delineate formulate andvalidate liponanoparticle RNA (LNP RNA) vaccines for precision prevention of individuals with increased cancerrisk. The PI is Dr. Lipkin an established leader in Cancer Prevention who has made several important clinicallytranslated contributions to the field. Project 1 will develop and validate an LNP RNA immunoprevention vaccinefor Lynch syndrome a genetic cancer predisposition syndrome with highly immunogenic recurrent neoantigensshared among cancers from different patients. Project 2 will develop and validate an LNP RNA immuneinterception vaccine for patients with lung non-solid nodule (NSN) pre-malignant neoplasms a lungadenocarcinoma precursor lesion. To achieve these goals we will use state-of-the-art technologies includingLNP RNA vaccine formulation computational genomic tumor immunology spatial genomics andimmunopeptidomics. To ensure CRI's scientific rigor and excellence we have assembled a scientificallyoutstanding CRI External Advisory Board (EAB) which includes 2021 Lasker Award winner Drew Weissman(Penn) for his work on LNP RNA COVID19 vaccines. Overall the CAP-IT CRI will develop state-of-the-art LNP RNAimmunoprevention and immune interception vaccines and provide a technologically powerful platform tojumpstart additional CAP-IT CRI LNP RNA vaccine projects. We anticipate that CAP-IT CRI will propel bothLynch syndrome and lung NSN vaccines to NCI PREVENT and CP-NET clinical trials within the next 5 yearsand FDA approval/clinical translation within ten years. 1098880 +No NIH Category available Acceleration;Achievement;Address;Advanced Malignant Neoplasm;Area;Award;Awareness;Cancer Survivor;Cancer Survivorship;Cancer health equity;Chicago;Cities;Clinical;Clinical Trials;Collaborations;Communities;Community Health;Community Networks;Community Outreach;Comprehensive Cancer Center;Continuity of Patient Care;Development;Disabled Persons;Disparity;Dissemination and Implementation;Early Diagnosis;Education;Education and Outreach;Educational Activities;Evaluation;Event;Evidence based practice;Faculty;Fostering;Funding;Geographic Locations;Grant;Health;Health Educators;Health Fairs;Human;Illinois;Immersion;Incidence;Individual;Inequity;Institution;Interview;Lead;Leadership;Learning;Linguistics;Localized Malignant Neoplasm;Low income;Malignant Neoplasms;Maps;Needs Assessment;Neighborhoods;Outreach Research;Penetrance;Persons;Phase;Population;Positioning Attribute;Prevention;Productivity;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Secure;Services;Sexual and Gender Minorities;Students;Surveys;Underserved Population;Universities;Vulnerable Populations;Work;anticancer research;cancer care;cancer education;cancer health disparity;cancer prevention;cancer therapy;citizen science;community center;community engagement;community organizations;community partnership;disability;education research;ethnic minority;evidence base;experience;forging;gender minority community;health disparity populations;health equity;improved;innovation;literacy;member;men of color;minority communities;mortality;neoplasm registry;outreach;peer;peer coaching;process evaluation;programs;racial minority;response;screening;survivorship;symposium;tool;underserved community Outreach Core n/a NCI 10692833 9/8/23 0:00 PAR-18-767 5U54CA203000-09 5 U54 CA 203000 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7199 1873807 "GIACHELLO, AIDA L" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 140320 90341 54204 OUTREACH CORE ABSTRACTCancer incidence and mortality rates for racial and ethnic minorities and other underserved and vulnerablepopulations are substantially higher in Chicago than the national average for most cancers (Illinois State CancerRegistry). Addressing these disparities demands culturally and linguistically relevant community-drivenapproaches. In 2015 a consortium comprised of community members and three major academic institutions inChicago University of Illinois at Chicago (UIC) Northeastern Illinois University (NEIU) and the Robert H. LurieComprehensive Cancer Center of Northwestern University (NU-LCC) secured NCI U54 funding to establish theChicago Cancer Health Equity Collaborative (ChicagoCHEC) which aims to foster rigorous and meaningfulresearch education training and community outreach/engagement to advance health equity. Through theoriginal U54 award the Outreach Core identified community needs and provided leadership and programmaticsupport for community-based cancer education engagement and outreach activities. In this renewal theproposed activities of the ChicagoCHEC Outreach Core will build upon the existing strengths prior and ongoingwork accomplishments and lessons learned from the first U54 award to elevate ChicagoCHECs collectiveimpact on reducing cancer inequities. A major area of the Outreach Cores focus for the next five years will beto develop targeted cancer support efforts for underserved and vulnerable populations. These include thefollowing non-mutually exclusive groups: people with disabilities sexual and gender minorities men of color andlow-income cancer survivors. Proposed community engagement approaches span the cancer continuumencompassing prevention screening and early detection community-based education and cancer treatmentand survivorship. Specific aims of the Outreach Core are to: (1) Foster community partnerships and conductongoing needs assessment to identify new and innovative areas of opportunity including outreach research forcommunity-engaged activities that will reach individuals from health disparities populations; (2) Implementoutreach and education activities across the cancer continuum; (3) Foster opportunities for building cancer healthequity research capacity among community partners faculty and students; (4) Plan implement and evaluateNCI National Outreach Network activities locally; and (5) Rigorously evaluate achievement and progress of theOutreach Cores stated aims using a comprehensive evaluation strategy. A highly effective and diverse tri-institutional leadership team with complementary expertise will lead these activities supported by experiencedCommunity Health Educators with strong clinical and community networks. A Community Steering Committeewill guide the development and implementation of the proposed outreach and engagement activities. TheOutreach Core will leverage each ChicagoCHEC partner academic institutions numerous ties to Chicagosdiverse neighborhoods and community organizations in its activities collectively aimed at advancing cancerhealth equity. +No NIH Category available Achievement;Advisory Committees;Award;Benchmarking;Cancer Research Project;Cancer health equity;Chicago;Clinical Sciences;Communication;Communities;Consultations;Counseling;Data;Data Analyses;Decision Making;Development;Educational workshop;Ensure;Evaluation;Faculty;Foundations;Funding;Funding Mechanisms;Goals;Grant;Health;Incubators;Infrastructure;Institution;Intervention Studies;Knowledge;Leadership;Learning;Logic;Mentors;Mentorship;Mission;Modeling;Monitor;Outcome;Performance;Pilot Projects;Process;Program Development;Progress Reports;Quasi-experiment;Recommendation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Running;Statistical Data Interpretation;Structure;Surveys;Time;Translational Research;Universities;Work;analytical tool;anticancer research;cancer health disparity;career;career development;catalyst;data tools;early-career faculty;experience;faculty mentor;health disparity;improved;innovation;mathematical model;member;novel;process improvement;programs;skills Planning and Evaluation Core n/a NCI 10692821 9/8/23 0:00 PAR-18-767 5U54CA203000-09 5 U54 CA 203000 9 9/24/15 0:00 8/31/25 0:00 ZCA1-SRB-T 7197 2115872 "HITSMAN, BRIAN L" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 232632 149773 89864 PLANNING AND EVALUATION CORE ABSTRACTOur Chicago Cancer Health Equity Collaborative (ChicagoCHEC) Planning and Evaluation Core (PEC) iscomprised of an exceptional team with complementary expertise and responsibility to lead the cores monitoringand evaluation activities. PEC members include: Drs. Kristi Holmes and Brian Hitsman from NU-LCC; RaymondFuller and Dr. Wamucii Njogu from NEIU; and Drs. Timothy Johnson and Lisa Sanchez-Johnsen from UIC. ThisRenewal application for the ChicagoCHEC PEC proposes to build on the infrastructure created programprogress and lessons learned from our first U54 award and continue to improve our integrated and responsivefoundation to support planning monitoring and evaluation. The PEC will continue to monitor progress throughongoing evaluation processes maximize resources identify novel directions for the Partnership in ongoingconsultation with the Administrative Core and report progress to institutional leaders and the NCI on a continualbasis. The PEC team will work closely with the Internal Advisory Committee (IAC) and the Program SteeringCommittee (PSC) and is composed of two teams: The Evaluation Action Team (EvAT) and the Mentoring andProject Team. The decisions made by the PEC will be guided by data systematically collected and organized bythe EvAT while the PECs Mentoring and Project Team will monitor the provision of support and mentorship ofChicagoCHECs early career faculty in addition to working closely with the Administrative Core to seedcollaborative tri-institutional cancer research projects and developmental pilots over the next five-year grantperiod. The overall specific aims of the PEC are to: (1) Conduct ongoing tracking and evaluation of all Partnershipactivities to inform planning improve processes maximize resources and communicate impact to stakeholdersover the duration of the ChicagoCHEC Partnership with support of the IAC PSC and NCI; (2) Create andsustain an ongoing Incubator and Catalyst Research Grant Program encouraging tri-institutional partnershipand a focus on cancer health equity; and (3) Bolster a pipeline of faculty focused on cancer research bycoordinating and monitoring career enhancement mentoring and professional development activities for earlycareer faculty. +No NIH Category available 3-Dimensional;ATP phosphohydrolase;Advisory Committees;Antineoplastic Agents;Apoptosis;Arginine;Biological Assay;Cancer Patient;Cancer cell line;Cell Culture Techniques;Cells;Cessation of life;Clinical;Data;Development;Disease;Down-Regulation;EZH2 gene;Epigenetic Process;Epithelial ovarian cancer;Foundations;Gene Expression;Genes;Goals;Growth;Heat Shock 70kD Protein Binding Protein;Heat-Shock Proteins 70;In Vitro;Invaded;Knock-out;Knowledge;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Mentors;Methylation;Methyltransferase;Modification;Molecular;Mutation;Oncogenes;Ovarian Serous Adenocarcinoma;Pathway interactions;Patients;Pennsylvania;Postdoctoral Fellow;Pre-Clinical Model;Proliferating;Protein-Arginine N-Methyltransferase;Proteins;Research;Research Personnel;Resources;Role;Serous;Site;Site-Directed Mutagenesis;Specificity;Testing;The Wistar Institute;Training;Training Support;Tumor Suppression;United States;Universities;brca gene;cancer cell;cancer type;career;career development;clinically relevant;coactivator-associated arginine methyltransferase 1;experimental study;gain of function;genetic makeup;genome-wide analysis;heat-shock proteins 40;in vivo;in vivo Model;inhibitor;loss of function;migration;mouse model;mutant;novel strategies;novel therapeutic intervention;overexpression;patient derived xenograft model;pre-doctoral;protein folding;skills;small molecule inhibitor;small molecule libraries;synergism;targeted treatment;tumor;two-dimensional Targeting HSP70 in CARM1-expressing epithelial ovarian cancer PROJECT NARRATIVEEpithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer-related deaths in the United States.EOC is a genetically heterogeneous disease and therefore it is imperative to develop novel therapeuticstrategies based on patients genetic makeup such as overexpression of an oncogene CARM1. This proposalwill lay a critical foundation to establish the use HSP70 inhibitors in CARM1-expressing epithelial ovarian cancerand if successful it will have an immediate impact on ovarian cancer patients. NCI 10692798 5/12/23 0:00 PA-19-130 5R00CA241395-04 5 R00 CA 241395 4 "LUO, RUIBAI" 4/1/22 0:00 3/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 12558089 "KARAKASHEV, SERGEY " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA SCHOOLS OF MEDICINE 191226003 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 157098 91902 PROJECT SUMMARYThe goals of this NCI Pathway to Independence Career Development proposal are to request support fortraining to develop expertise in developing novel therapeutic strategies for ovarian cancer while investigating therole of coactivator-associated arginine methyltransferase 1 (CARM1) in promoting sensitivity to HSP70 inhibition.K99/R00 support during this part of my career will be integral to my successful development as an independentcancer researcher. The training plan outlined in this proposal will take advantage of the extensive resources atThe Wistar Institute University of Pennsylvania as well as Temple University. My training will also be guided bythe advisory committee who have successfully mentored multiple predoctoral postdoctoral and clinical fellowsin academic careers. The scientific portion of this proposal focuses on experimentally determining the molecular mechanismunderlying the sensitivity of CARM1-expresing ovarian cancer cells to HSP70 inhibition. The proposed studiesare based on my previous findings that CARM1 is often overexpressed and functions as an oncogene in ovariancancer patients. High-grade serous ovarian cancer (HGSOC) has the highest rate of CARM1 amplification andoverexpression (~20% combined) among all cancer types. Moreover high CARM1 levels are associated withpoor survival in EOC patients. Thus it is imperative to develop novel approaches to target CARM1-expressingEOC. My preliminary data suggest CARM1-expressing cells are selectively sensitive to HSP70 inhibition. HSP70is a crucial part of the protein folding machinery and its levels are upregulated in multiple types of cancer.Interestingly HSP70 is a substrate for CARM1s enzymatic activity. However the effect of HSP70 modificationby CARM1 is not fully understood. Thus the major goal of this proposal is to determine whether CARM1-expressing EOC can be treated and ultimately eradicated by novel therapeutic strategies based on HSP70inhibition. Therefore I will explore the following scientific aims: 1) To elucidate the mechanistic basis underlyingthe selectivity against CARM1-high cells by HSP70 inhibition by using gain and loss of function assays inCARM1-high and CARM1-low expressing EOC cells. 2) To develop novel therapeutic strategies for CARM1-expressing EOCs based on HSP70 inhibition. The completion of the scientific aims in this proposal will helpdevelop my research skills and knowledge in the field of ovarian cancer and will lay a critical foundation toestablish the use HSP70 inhibitors in CARM1-high EOCs as a single agent or in combination with other promisingsmall-molecule inhibitors such as EZH2 inhibitors. 249000 +No NIH Category available 3-Dimensional;Address;Adult;Antigen Presentation;Biotechnology;Brain Mapping;Brain Neoplasms;Cell division;Cells;Clinical;Collaborations;Data;Ensure;Evolution;Failure;Funding;Genes;Genomics;Glioblastoma;Glioma;Goals;Growth;Human;Immune response;Immunogenomics;Immunosuppression;Individual;Infrastructure;Laboratory Research;Longevity;Malignant - descriptor;Malignant Neoplasms;Maps;Mutation;Neurosurgeon;Patients;Pharmaceutical Preparations;Play;Proliferating;Property;RNA-Directed DNA Polymerase;Regulation;Request for Applications;Research;Research Project Grants;Role;Sampling;Scientific Advances and Accomplishments;T cell receptor repertoire sequencing;T-Cell Receptor;Telomerase;Telomere Shortening;Therapeutic;Training;Translating;Tumor Volume;Wages;chemotherapy;epigenomics;immunogenic;in vivo;member;method development;mutant;neoantigens;neoplastic cell;new therapeutic target;novel therapeutics;personalized immunotherapy;promoter;recruit;sample collection;small molecule;targeted treatment;technology development;transcription factor;transcriptomics;translational goal;tumor;tumor heterogeneity The Immortality and Evolution of Adult Brain Tumors PROJECT NARRATIVEThe goals of this R50 project are to support ongoing NCI-funded research projects to 1) to useimmunogenomic analyses of spatially mapped brain tumor samples spanning maximal tumor volume todiscover tumor-wide neoantigens that elicit immune responses and which can be used to develop aplatform for personalized immunotherapies for brain tumor patients; and 2) to understand the mechanism bywhich tumor cells with the TERT promoter mutation acquire the ability to proliferate indefinitely (cellularimmortality) in order to develop targeted therapies for the large number of human tumors with this mutation. NCI 10692793 8/31/23 0:00 PAR-21-285 5R50CA274229-02 5 R50 CA 274229 2 "JOHNSON, ERIC MICHAEL" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-1(M1) 78422809 "HONG, CHIBO " Not Applicable 11 NEUROSURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 179819 NCI 111343 68476 PROJECT ABSTRACTThe Costello lab investigates cellular immortality and evolution in brain tumors with the goal of translatingour discoveries into new therapies. I play an essential role in our studies to understand and overcome thegenomic and epigenomic intra-tumor heterogeneity driven by tumor evolution that underlies therapeuticfailures. One translational goal is to identify mutations that produce immunogenic neoantigens that arepresent throughout the whole tumor to develop personalized immunotherapies in collaboration with Dr.Okada. Working with an interdisciplinary clinical team we developed a unique 3-dimensional whole tumorsampling approach in which we obtain 10 spatially mapped samples per tumor selected by theneurosurgeon to maximally represent the whole tumor. We have begun applying the genomictranscriptomic and T cell receptor (TCR) sequencing data I produced from these spatially mapped samplesto identify immunogenic neoantigens and their cognate TCR present throughout the tumor. I am also asignificant contributor to our tumor immortality studies. To proliferate indefinitely tumor cells must overcomethe normal limits on lifespan dictated in large part by telomere shortening a consequence of cell divisions inthe absence of telomerase activity. Eighty percent of glioblastoma and many other cancers overcome thislifespan barrier to achieve cellular immortality by acquiring a mutation in the promoter of TelomeraseReverse Transcriptase (TERT). We discovered that the TERT promoter mutation activates the normallysilent TERT gene and telomerase activity through selective recruitment of GABP a transcription factorwhich does not normally regulate TERT. Using experimental targeting of GABP we showed that TERTexpression is reduced selectively in cells with the TERT promoter mutation and when combined withchemotherapy it dramatically reduces GBM growth in vivo. Currently I am studying a newly discoveredhomeostatic control on GABP subunit expression and its relationship to TERT regulation. To translate thesemechanistic studies into a new therapy Dr. Costello co-founded a biotech startup which has discoveredsmall molecules with drug-like properties that reduce TERT in a mutation dependent manner. In addition toperforming bench research to address these translational goals my responsibilities include: (1)management and oversight of the labs infrastructure and tumor sample collection; (2) technology andmethods development for the group; (3) ensuring that all laboratory research is conducted safely inaccordance with regulatory requirements; and (4) training new lab members and individuals throughout theBrain Tumor Center. This R50 application requests salary support for these ongoing activities to advancethe scientific goals of the following NCI-funded projects: 3-D spatial approach to discover genomic effectorsof immunosuppression during malignant transformation (R01 CA244838); The Brain Tumor SPORE P1 ANew Therapeutic Target for TERT Promoter Mutant Glioma (2P50CA097257). 179819 +No NIH Category available Address;Adoption;Advertisements;Age;American;American Cancer Society;Area;Awareness;Behavior;Communication;Communication Tools;Communities;Computers;Ecosystem;Eligibility Determination;Facebook;Fostering;Goals;Health;Health behavior change;Healthcare Systems;Individual;Insurance Carriers;Intervention;Knowledge;Learning;Life;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Medicare;Methods;Misinformation;Mission;National Cancer Institute;Nature;Online Systems;Participant;Patients;Population;Public Health;Randomized;Randomized Controlled Trials;Recommendation;Research;Risk;Self Efficacy;Smoker;Testing;United States National Institutes of Health;United States Preventative Services Task Force;Work;anticancer research;compare effectiveness;design;disability;effectiveness testing;health belief;health communication;high risk;high risk population;human old age (65+);improved;innovation;interest;lung cancer screening;mortality;novel;patient population;recruit;screening;shared decision making;social media;support tools;trial design;uptake Leveraging Social Media to Increase Lung Cancer Screening Awareness Knowledge and Uptake in High-Risk Populations PROJECT NARRATIVEThe proposed research is relevant to public health because leveraging a social media platform to increaseawareness among individuals eligible for lung cancer screening is a novel untapped platform to reachvulnerable high-risk individuals. Thus the proposed research is relevant to the cancer research mission of theNational Cancer Institute and more broadly the National Institutes of Healths mission to seek fundamentalknowledge about the nature and behavior of individuals and the application of that knowledge to enhancehealth lengthen life and reduce illness and disability through early detection of lung cancer. NCI 10692788 8/16/23 0:00 PAR-19-348 5R01CA263662-03 5 R01 CA 263662 3 "BLAKE, KELLY D" 10/1/22 0:00 8/31/27 0:00 Health Promotion in Communities Study Section[HPC] 11849887 "CARTER-BAWA, LISA " Not Applicable 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 670094 NCI 415732 254362 PROJECT SUMMARY/ABSTRACTLung cancer screening is recommended by the U.S. Preventive Services Task Force (USPSTF) has thepotential to detect lung cancer at earlier more treatable stages. However population uptake of lung cancerscreening has been abysmal. It has been 7 years since the USPSTF released its official recommendation yetless than 5% of screening-eligible Americans have been screened. Screening-eligible individuals are generallyunaware about the option of finding lung cancer early through screening and our teams prior work revealedthat in addition to lack of awareness screening-eligible individuals in the U.S. do not screen when they areaware because of perceived barriers to screening. If high-risk patient populations are not aware that lungcancer screening exists then formative work is needed to increase awareness about screening. It is essentialto employ novel community-focused strategies to increase awareness about lung cancer screening to reachdiverse screening-eligible individuals who might not otherwise learn about the option to screen. Our long termgoal is to increase screening uptake among appropriate high-risk individuals nationwide. Our overall objectivein this application is to test the effectiveness of: 1) leveraging a social media-based platform to reachscreening-eligible individuals in the community upstream before they engage with the healthcare system and2) a novel tailored health communication and decision support intervention related to lung cancer screening(LungTalk). Our central hypothesis is two-fold: 1) Facebook targeted advertisement will be a successfulplatform to reach high-risk individuals unaware of lung cancer screening; and 2) tailored compared to non-tailored lung cancer screening information will increase knowledge and improve health beliefs about screeningand subsequent screening uptake. Our study is informed by our prior studies which led us to consider theimportance of increasing awareness and knowledge on a population level from the screening-eligibleindividuals perspective as a precursor to health behavior change. Successful use of Facebook to recruitscreening-eligible individuals in our prior studies also led us to consider how social media might be used toincrease awareness of lung cancer screening and as a platform to link the screening-eligible individual with atailored health communication and decision support intervention that has the potential to influence screeningbehavior and uptake. Using a randomized controlled trial design we will randomize 500 screening-eligibleindividuals recruited through Facebook nationwide to receive either a tailored intervention (LungTalk) or non-tailored ACS Lung Screening Informational Video. Specific aims are to (1) examine the use of a social mediaplatform to reach high-risk individuals eligible for lung screening; (2) compare the effectiveness of a computer-tailored health communication tool to a web-based ACS Lung Screening Informational Video to improve lungcancer screening: a) knowledge; b) health beliefs; and c) screening uptake and completion in a high-riskpopulation; and (3) Explore the sustainability of a social media-based approach among key stakeholders. 670094 +No NIH Category available 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;Ablation;Address;Air;Alveolar Cell;Carcinogen exposure;Carcinogens;Cell Communication;Cells;Chronic Obstructive Pulmonary Disease;Data;Development;Disease;Drug Screening;Early treatment;Ecosystem;Epithelium;Event;Evolution;Exhibits;Exposure to;Foundations;Growth;Human;Immune;Immunity;Inflammation;Inflammatory;Inflammatory Response;Injury;Intercept;Interleukin-1 beta;KRAS2 gene;Knowledge;Lesion;Liquid substance;Lung;Lung Adenocarcinoma;Lung Neoplasms;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Mus;Mutation;Neoplasms;Nontypable Haemophilus influenza;Normal Cell;Oncogenes;Oncogenic;Organoids;Pathologic;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Population;Prevention strategy;Process;Prognosis;Property;Public Health;Reporter;Resolution;Rest;Risk;Role;Saline;Signal Transduction;Smoker;Smoking;Somatic Mutation;Specimen;Structure of parenchyma of lung;TP53 gene;Tobacco;Tobacco-Associated Carcinogen;Visual;biomarker identification;cancer diagnosis;cell type;checkpoint inhibition;cytokine;high-throughput drug screening;human tissue;improved;insight;lung development;molecular subtypes;mouse model;multidisciplinary;mutant;neoplastic cell;novel;novel strategies;premalignant;prevent;progenitor;programs;receptor;screening;single-cell RNA sequencing;tobacco exposure;transcriptomics;treatment strategy;tumor;tumor initiation;tumorigenesis Elucidating the evolution of Krt8+ alveolar cells to Kras-mutant lung preneoplasia and cancer PROJECT NARRATIVELung adenocarcinoma (LUAD) with genetic alterations in the KRAS oncogene is the most common lung cancerdiagnosed in smokers and strategies to intercept this ominous malignancy heavily rest on understanding theearliest events in its development. While it is understood that tobacco carcinogen exposure results inwidespread injury in the lung in the form of molecular and inflammatory changes that commence in visuallynormal cells we still poorly understand how KRAS-mutant LUAD is conceived from the tobacco-exposed lung.This project will discern how a unique population of lung cells that arise following tobacco exposure evolve topremalignancy and KRAS-mutant LUAD discern mechanisms that promote their oncogenic progression aswell as identify drugs that can target these cells and prevent development of KRAS-mutant LUAD. NCI 10692783 8/1/23 0:00 PA-20-185 5R01CA272863-02 5 R01 CA 272863 2 "JOHNSON, RONALD L" 9/1/22 0:00 7/31/27 0:00 Cancer Prevention Study Section[CPSS] 10539538 "KADARA, HUMAM " "MOGHADDAM, SEYED JAVAD MIRHASSANI" 9 BIOCHEMISTRY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 586157 NCI 374999 211158 PROJECT SUMMARYA significant fraction of lung adenocarcinomas (LUADs) in lifetime smokers harbor somatic mutations in theKRAS oncogene (KM-LUADs). Due to enhanced screening KM-LUAD is increasingly being detected at earlierpathological stages thus posing a growing public health burden that warrants improved early treatment.Despite this urgency early changes that conceive KM-LUAD and that would thus likely comprise ideal targetsfor interception remain poorly characterized. Previously our group and others have shown that tobaccoexposure leads to a pervasive field of injury that is composed of molecular (e.g. KRAS mutations) andinflammatory changes in normal-appearing epithelium and in the lung and that are prevalent in the LUADsthemselves. We and others have also previously described molecular and immune changes including adecrement in host immunity that are associated with development of lung premalignant lesions (PMLs) andKM-LUAD. These earlier studies have shed light on events that are likely implicated in early lung tumordevelopment. Yet especially for a cancer like KM-LUAD that is causally related to smoking the identity andproperties of specific cell populations that trigger a field of injury as well as its progression to PML and KM-LUAD are not known. In our preliminary efforts we performed single-cell RNA-sequencing of lung tissues froma human-relevant mouse model of tobacco-associated KM-LUAD. We found a population of Krt8+ alveolarcells (KACs) that was greatly increased early on in lungs exposed to tobacco carcinogen but not control salineand that were also associated with tumor cell onset. KACs displayed intriguing properties that allow us tosurmise that they perhaps represent KM-LUAD progenitors: they amassed the same driver Kras mutationsfound in the resultant LUADs; they expressed transcriptomic programs and cell-cell interactions that are highlypertinent to KM-LUAD including augmented p53 as well as pro-inflammatory IL-1 and NF-B signaling; andtheir expression profiles were highly enriched in human PMLs and LUADs. We also found that KACs weremarkedly increased in the human LUAD ecosystem relative to matched normal lung. Our preliminary findingsmotivate the hypothesis that oncogenesis of KACs in concert with pro-inflammatory signaling mediatedby IL-1/NF-B underlie initiation and development of PML and KM-LUAD. To address our hypothesis wewill 1) characterize at single-cell resolution evolution of KACs to PML and KM-LUAD as well as determine therole of p53 signaling in this process; 2) discern the role of pro-inflammatory signaling in promoting evolution ofKACs to PML and KM-LUAD; and 3) use multiple approaches including drug screening to determine whethertargeting KACs will intercept PML and KM-LUAD development. At the conclusion of our studies we will haveunraveled novel paths in the phenotypic evolution of KM-LUAD as well as laid the foundation for developmentof new strategies that inhibit the inception of this dire malignancy. 586157 +No NIH Category available Address;Behavioral;Bioinformatics;Biometry;Biostatistics Shared Resource;Cancer Center;Cancer Research Project;Center for Translational Science Activities;City of Hope Comprehensive Cancer Center;Clinical;Collaborations;Communities;Comprehensive Cancer Center;Computational algorithm;Computerized Medical Record;Control Groups;DNA sequencing;Data;Databases;Development;Development Plans;Disparity;Doctor of Philosophy;Educational Activities;Ensure;Epidemiology;Experimental Designs;Genomics;Goals;Human Resources;Individual;Informatics;Institution;Intervention;Knowledge;Location;Logistics;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Medical;Mentors;Methodology;Molecular;NCI-Designated Cancer Center;Outcome;Outcome Study;Pathology;Population;Prevention;Principal Investigator;Procedures;Proteomics;Protocols documentation;Publications;Quality Control;Randomized;Reporting;Reproducibility;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Research Support;Resources;Sample Size;Scheme;Secure;Services;Site;South Carolina;Statistical Data Interpretation;Stratification;Testing;The Cancer Genome Atlas;Training;Translating;Translational Research;Universities;Update;Validation;Vendor;Virginia;analytical tool;biomedical informatics;cBioPortal;cancer health disparity;career development;central database;cohort;community engagement;comparison group;data integration;data management;data quality;design;experimental study;firewall;flexibility;genomic data;high dimensionality;improved;innovation;interest;mathematical model;member;novel;research study;social determinants;sociodemographics;success;transcriptome sequencing;web interface Biostatistics and Informatics Core BIOSTATISTICS AND BIOINFORMATICS CORE: PROJECT NARRATIVEThe Biostatistics and Bioinformatics Core (BBC) will serve as a tightly integrated component of the TRACERproviding the much needed biostatistical genomics and biomedical informatics expertise desired by theTRACER investigators. The services thus provided by BBC will add significant value to the realization of theTRACER goals and in the longer term will advance the TRACER team towards a successful P50 application. NCI 10692747 8/25/23 0:00 RFA-CA-19-034 5P20CA252717-03 5 P20 CA 252717 3 9/20/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 7176 8856579 "BANDYOPADHYAY, DIPANKAR " Not Applicable 4 Unavailable 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA Domestic Higher Education 232980568 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 116028 93368 22660 BIOSTATISTICS AND BIOINFORMATICS CORE: PROJECT SUMMARYThe overall objective of the TRACER Biostatistics and Bioinformatics Core (BBC) is to serve as the focal pointfrom which the TRACER investigators and career development candidates can draw the much neededbiostatistical genomics and biomedical informatics expertise needed for proper planning and execution of theirresearch projects. These services include assisting in experimental design study plan development hypothesesrefinement database integration and access data quality control sample size requirements and powercalculations analysis of the statistical design development of randomization and stratification proceduresinterim analyses analysis of completed results (which includes both biostatistical and genomics analyses)presentation of research findings and scientific publication to disseminate new findings in the prevention andtreatment of lung cancer. The BBC resource will be directed by Dr. Bandyopadhyay from VCU with corepersonnel included across the three TRACER sites. To materialize the TRACER objectives the BBC hasproposed 3 specific aims which broadly encompasses providing biostatistical and genomics analytics expertise(Aim 1) providing efficient data management integration and distribution (Aim 2) and provide the much neededbiostatistical training to TRACER investigators and community partners as well as exploring noveladvancements in biostatistical methodology in lung cancer (Aim 3). To achieve this BBC personnel in additionto their own research interactions with the TRACER members can also call on additional assistance from variousother biostatisticians bioinformaticians genomics experts and senior statistical analysts with significant cancerexpertise all integrated within the respective Biostatistics Shared Resources at the NCI-designated cancercenters at VCU MUSC and CoH. The BBC thus constitute a tightly integrated component of the TRACER andthe services provided will add significant value to the realization of TRACER goals which would not have beenachieved through alternative vendors. +No NIH Category available Address;Agreement;Artificial Intelligence;Bioinformatics;Biological Specimen Banks;Biometry;Blood specimen;Cancer Center;Cancer Patient;Center for Translational Science Activities;City of Hope Comprehensive Cancer Center;Clinical;Clinical Data;Collaborations;Collection;Confidentiality of Patient Information;Consent;Data;Data Element;Databases;Dedications;Development;Disease;Disparity;Documentation;Early Detection Research Network;Ensure;European ancestry;Excision;Faculty;Formalin;Freezing;Future;Health protection;Hospital Information Systems;Housing;Human;Individual;Informatics;Institution;Institutional Review Boards;Investigation;Lead;Link;Liquid substance;Malignant Neoplasms;Malignant neoplasm of lung;Massey Cancer Center at the Virginia Commonwealth University;Medical;Molecular;Molecular Analysis;National Cancer Institute;Outcome;Paraffin Embedding;Pathologic;Pathology;Pathology Report;Procedures;Process;Reproducibility;Research;Research Personnel;Research Project Grants;Secure;Site;Source;South Carolina;Specimen;Standardization;Techniques;Technology;Time;Tissue Banks;Tissue Embedding;Tissues;Translational Research;United States National Aeronautics and Space Administration;Universities;Virginia;Warm Ischemia;behavioral health;biobank;cancer health disparity;cancer risk;data integration;data repository;ethnic minority;health data;high risk;human tissue;programs;racial diversity;racial minority;sample collection;social determinants;social health determinants;translational goal;translational study Biospecimen Core BIOSPECIMEN/PATHOLOGY CORE: PROJECT NARRATIVEThis TRACER Biospecimen/Pathology Core (BPC) will collect biospecimens from racially diverse lung cancerpatients and individuals at high risk for lung cancer in support of cancer disparities research as well as providea central data repository that links each specimen with essential histopathologic clinical molecular and socialdeterminants of health data. The BPC will enhance TRACER supported investigations by factoring in multileveldeterminants of cancer risk and outcomes. NCI 10692741 8/25/23 0:00 RFA-CA-19-034 5P20CA252717-03 5 P20 CA 252717 3 9/20/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 8050 9244284 "IDOWU, MICHAEL O" Not Applicable 4 Unavailable 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA Domestic Higher Education 232980568 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 162827 131772 31055 BIOSPECIMEN-PATHOLOGY CORE: PROJECT SUMMARYMost biospecimens in the US are collected from individuals of Northern European ancestry limiting thegeneralizability of findings. There is an urgent need to increase the availability of high-quality biospecimens fromethnic and racial minorities for translational lung cancer disparities research. A significant goal of theTranslational Research Center in Lung Cancer Disparities (TRACER) Biospecimen/Pathology Core (BPC) is tocoordinate efforts related to collection processing storage and distribution of annotated human biospecimensfor all participating sites and projects including the a future pilot research projects supported by theDevelopmental Research Program (DRP). The TRACER BPC team brings together experts with a shareddedication to eradicating disparities and this union will be formalized by institutional agreements and standardoperating procedures (SOPs). The TRACER BPC will provide translational disparities researchers access to anexpanded array of biospecimens analytical techniques and annotations with clinical data as well as socialdeterminants of health data. The BPC Lead and Co-Leads are established leaders in lung cancer pathologybiorepositories cancer informatics geospatial analysis behavioral health and cancer biologists offeringmolecular analysis techniques all committed to disparities and translational research. TRACER BPCspecimens will be jointly housed at the Massey Cancer Center at Virginia Commonwealth University VCU) theHollings Cancer Center at the Medical University South Carolina (MUSC) and the City of Hope ComprehensiveCancer Center. VCU will be the central IRB andcommon SOPs data elements and platforms will be established.VCU will compile and integrate data and data will be uploaded to the Jet Propulsion Lab (JPL; NASA) server.JPL houses and integrates the Early Detection Research Network (EDRN) data. Housing TRACER data withJPL will facilitate future TRACER-EDRN collaborations. Aim 1 will provide a portal through which TRACERcollaborative investigators can acquire through uniform SOPs the human tissues fluids and blood samples forresearch projects of this P20 with high rigor and reproducibility. Aim 2 will collect and annotate specimensincluding demographic data clinical data histopathologic results molecular annotation and social determinantsof health data. Working with the TRACER Biostatistics and Bioinformatics Core TRACER investigators will haveaccess to a fully integrated centralized information source. Aim 3 will expand TRACER investigators access tocutting-edge technology and artificial intelligence analytics through a partnership with the National CancerInstitutes Early Detection Research Network (EDRN). +No NIH Category available Acute;Address;Adult;African American;African American population;Behavior;Behavioral;Belief;Bioinformatics;Biological;Biological Markers;Biological Process;Biometry;Black Populations;Black race;Center for Translational Science Activities;Chronic;Cigarette;Collection;Counseling;Disparity;Dose;Evidence based treatment;Exposure to;FDA approved;Hydrocortisone;Individual;Laboratories;Leadership;Maintenance;Malignant neoplasm of lung;Medicine;Metabolism;Modeling;Morbidity - disease rate;Nicotine;Nicotine Dependence;Observational Study;Outcome;Pathway interactions;Pattern;Pharmacotherapy;Physiological;Population;Prevention strategy;Process;Production;Psychological Factors;Reaction;Relapse;Research;Resource Sharing;Risk Factors;Smoke;Smoker;Smoking;Smoking Behavior;Smoking treatment;Stress;Sympathetic Nervous System;Tobacco;Work;biological adaptation to stress;cancer health disparity;cancer risk;cigarette craving;cigarette smoke;cigarette smoking;community engagement;coping;hypothalamic-pituitary-adrenal axis;insight;male;men;mortality;nicotine cessation;nicotine exposure;nicotine replacement;nicotine use;perceived stress;physiologic stressor;psychologic;psychosocial stressors;racial difference;racial disparity;racial minority;response;smoking cessation;smoking initiation;social factors;stressor;structural determinants;success;tobacco control;translational study Project 2: Smokers PROJECT NARRATIVECigarette smoking is a leading cause of morbidity and mortality from lung cancer among adults in the US; smoking cessation is the best preventive strategy for reducing lung cancer risk and addressing racial disparities in outcomes. Despite this many smokers are unwilling or unable to make a quit attempt and among those who try to quit smoking utilization of evidence-based treatment is poor especially in racial minorities. Stress relief and the avoidance of adverse psychological and physiological reactions are among the primary reasons for smoking initiation maintenance and relapse in all populations; there is an established relationship between perceived stress and smoking behaviors from observational studies. However stress responses have both psychological and physiological consequences that are important to smoking behaviors and cessation outcomes. Despite the significance of the HPA-axis pathway for both stress responses and nicotine addiction racial differences in physiological stress responses have not been examined between African American/Black(AA/Black) and white smokers. Under the leadership of an expert transdisciplinary investigative team that is supported by critical cores and shared resources for community engagement biospecimen collection storage and processing and biostatistics and bioinformatics in the Translational Research Center in Lung Cancer Disparities (TRACER) Project 2 will be the first to examine racial differences in HPA-axis functioning between AA/Black and white male smokers to achieve the following specific aims: Aim 1: Examine racial differences in acute physiological stress responses between AA/Black and white male smokers using a laboratory model. The association between acute physiological stress response and tobacco-related behaviors will also be evaluated.Hypotheses: AA/Black smokers will be more likely than white smokers to have a blunted cortisol response to an acute laboratory stressor. AA/Black smokers will also have significantly greater cigarette craving and be more likely to smoke following exposure to an acute physiological stressor compared to white smokers following an acute laboratory stressor. Aim 2: Evaluate racial differences in daily cortisol patterns between AA/Black and white male smokers. Hypotheses: AA/Black smokers will be more likely than white smokers to have blunted daily diurnal cortisol slopes. Compared to white smokers AA/Black smokers will have lower absolute cortisol values during the waking day. Aim 3: Identify factors that are important to acute and daily stress responses among AA/Black and white male smokers by examining acute and daily cortisol patterns based on exposure to chronic stressors. Hypotheses: Acute and daily cortisol responses will be associated with chronic stressors such that men who have greater exposure to SES structural and psychosocial stressors will have blunted acute and daily cortisol patterns. The relationship between acute and daily cortisol patterns nicotine metabolism and nicotine dependence will also be explored among AA/Black and white male smokers as part of this aim. NCI 10692738 8/25/23 0:00 RFA-CA-19-034 5P20CA252717-03 5 P20 CA 252717 3 9/20/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 8049 2404579 "HUGHES-HALBERT, CHANITA A." Not Applicable 4 Unavailable 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA Domestic Higher Education 232980568 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 145164 127083 18081 PROJECT 2: +No NIH Category available Animal Experimentation;Animals;Basic Science;Biological Assay;Biometry;Blinded;Chronic Lymphocytic Leukemia;Clinical;Clinical Data;Clinical Research;Correlative Study;Data;Data Set;Disease;Dissection;Epigenetic Process;Genetic;Genome;Goals;Laboratories;Laboratory Research;Molecular;Mus;Mutation;Outcome;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Proteomics;Reproducibility;Research Personnel;Research Project Grants;Resistance;Resources;Richter's Syndrome;Sampling;Services;Source;Techniques;Therapeutic Studies;Work;design;experimental analysis;experimental study;improved;insight;member;novel;novel therapeutics;personalized therapeutic;phenome;programs;repository;research study;response;single cell analysis;single cell technology;tumor Biostatistics PROJECT NARRATIVE - Core 4 BiostatisticsThe goal of Core 4 Biostatistics is to assure that all experiments conducted through this P01 centered aroundchronic lymphocytic leukemia and Richter's Syndrome have access to state-of-the-art statistical support for theirdesign and analysis. This extends to the basic science and murine experiments described as well as to theclinical and correlative studies undertaken by all the Projects as well as the Cores. This assures that the workperformed on this P01 will be robust and reproducible and thereby contribute to an improved understanding ofthese diseases. NCI 10692725 8/22/23 0:00 PAR-20-077 5P01CA206978-08 5 P01 CA 206978 8 9/1/16 0:00 8/31/26 0:00 ZCA1-SRB-K 7167 10287545 "ARYEE, MARTIN JOSEPH ANKRAH" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 59601 41089 18512 Project Summary/AbstractThe purpose of Core 4 Biostatistics is to provide statistical support to all the Projects in this P01. For theassociation between clinical outcome and the comprehensive molecular and proteomic dissection of Richter'ssyndrome (RS) as performed by Project 1 the Core will assemble and curate the clinical data provided byinternal and external collaborators and perform all analyses of association between these novel findings andappropriate clinical parameters. This will include working closely with Project to assess in cfDNA any RS-specificalternations that may predict this transformation. For all laboratory and animal studies of Projects 2 and 3 theCore will assure that the design conduct and analysis of experiments use robust statistical techniques that areappropriately implemented. For Project 2 this includes the single cell analyses of the tumor-intrinsic and tumor-extrinsic features as well as the longitudinal assessment of these features. The mice developing RS withcombinations of common CLL mutations (generated through this P01) will be assessed for response andresistance to novel therapies and analyzed by this Core. DBP studies are performed through Project 3 and theuse of the Core for clinical association will permit Project 3 to remain blinded to clinical outcomes whenperforming their assays assuring an unbiased assessment of their predictive ability. Through these aims thiscentral resource for the Projects will coordinate our insights into the trajectories from CLL to RS and support ourability to identify rational and personalized therapeutic strategies that will offer patients an improved chance ofcure. +No NIH Category available Acceleration;Amino Acids;Apoptotic;B-Lymphocytes;Biocompatible Materials;Biological Assay;Blood;Cells;Chronic Lymphocytic Leukemia;Communities;DNA;DNA copy number;Data;Data Set;Dependence;Disease;Disease Progression;Dissection;Doctor of Philosophy;Functional disorder;Gene set enrichment analysis;Genes;Genome;Genomics;Goals;Guidelines;Human;Investigation;Label;Liquid Chromatography;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Messenger RNA;Methods;Modification;Molecular;Mus;Mutation;Pathway Analysis;Pathway interactions;Patient-Focused Outcomes;Patients;Peptides;Pharmaceutical Preparations;Phase;Phosphopeptides;Phosphoproteins;Phosphorylation;Post Translational Modification Analysis;Post-Translational Protein Processing;Pre-Clinical Model;Protein Analysis;Protein Isoforms;Proteins;Proteome;Proteomics;RNA;RNA Splicing;Relapse;Resistance;Resources;Richter's Syndrome;Sampling;Signal Transduction;Site;Solid Neoplasm;Specificity;Stable Isotope Labeling;Structure;Technology;Therapeutic Intervention;Transcript;Variant;Work;biocomputing;bioinformatics tool;cancer cell;cloud based;data integration;experimental study;genomic data;improved;insight;interest;large cell Diffuse non-Hodgkin's lymphoma;molecular sequence database;mouse model;multiple omics;novel;personalized genomics;phenome;phosphoproteomics;pre-clinical;profiles in patients;proteogenomics;response;stable isotope;tandem mass spectrometry;targeted treatment;therapy resistant;transcriptomics;treatment response;tumor Proteomics NarrativeThe overarching goal of the Proteomics Core (Core 3) is to provide state-of-the-art mass spectrometry-based-proteomics and phosphoproteomics data and analyses in support of Projects 1-3; proteomics data will help toidentify cancer-relevant pathways triggered by somatic DNA variants or DNA copy number alterations (CNAs)and help to narrow target selection for potential therapeutic intervention of Richter's syndrome and relatedcancers. The resulting proteomic data including the critical quantitative and site-specific modificationinformation will be computationally analyzed and integrated with personalized genomic data usingbioinformatics tools integrated into the cloud-based pipeline PANOPLY. To enable more rapid and specificanalyses of proteins and phosphopeptides targets of interest emerging from the discovery experiments theproteomics core will develop high sensitivity targeted MS assays and apply these to analyze humanbiospecimens and preclinical samples in native and drug-perturbed states. NCI 10692723 8/22/23 0:00 PAR-20-077 5P01CA206978-08 5 P01 CA 206978 8 9/1/16 0:00 8/31/26 0:00 ZCA1-SRB-K 7166 1965067 "CARR, STEVEN A" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 188873 142713 46160 AbstractThe overarching goal of the Proteomics Core (Core 3) is to provide state-of-the-art mass spectrometry-based-proteomics and phosphoproteomics data and analyses in support of Projects 1-3. Genetic alterations in humancancer have been systematically mapped by genomics landscape studies in the past decade however the directconsequences of these alterations on the functional proteome are poorly understood. Deep scale massspectrometry (MS)-based proteomic data when integrated with genomic data (`proteogenomics') have beenshown to improve specificity for identifying cancer-relevant pathways triggered by somatic DNA variants or DNAcopy number alterations (CNAs) compared to genomic characterization alone and help to narrow targetselection for potential therapeutic intervention. Proteomics alone especially with deep quantitative profiling ofposttranslational modifications (PTM) provides information on signaling related to disease pathophysiology thatare largely opaque to genomics.Core 3 will apply micro-scaled mass spectrometry-based proteomics technologies we have developed that utilizehighly multiplexed stable-isotope mass tagging (TMT 16-plex) for precise relative quantification of the proteomeand phosphoproteome of very small amounts with very deep coverage for the study of transformation of chroniclymphocytic leukemia (CLL) to Richter's Syndrome (RS). The resulting proteomic data including the criticalquantitative and site-specific modification information will be integrated with personalized genomic data usingbioinformatics tools that have been integrated into the cloud-based pipeline PANOPLY. Multi-omics clusteringand analysis will be done to define the intrinsic structure of the integrated proteogenomes across baseline andtreated samples. We will extract proteogenomic features that drive the underlying cluster structure and willperform pathway-level analysis to further characterize each cluster in CLL and RS samples. Copy number tomRNA protein and phosphoprotein correlations will be done to determine cis- and trans-regulated genes.Pathways and molecular mechanisms underlying treatment response in patient and mouse models will beexplored using single sample Gene Set Enrichment Analysis (ssGSEA) and PTM Signature Enrichment Analysis(PTM-SEA) will be used to perform pathway analysis on phosphorylation data generated.To enable more rapid and specific analyses of proteins and phosphopeptides targets of interest emerging fromthe discovery experiments the proteomics core will develop high sensitivity targeted MS assays to be utilizedin Projects 1-3. Assays developed will use stable isotope-labeled standards for unambiguous identification andquantification and applied to human biospecimens and preclinical samples in native and drug-perturbed states. +No NIH Category available Address;Area;Automobile Driving;B-Cell Antigen Receptor;Biologic Characteristic;Biological;Biology;Biopsy;Cell Line;Cells;Chemotherapy-Oncologic Procedure;Chronic Lymphocytic Leukemia;Clinical;Clinical Trials;Collaborations;Complication;Credentialing;Data;Development;Diagnosis;Diagnostic;Disease;Disease model;Dissection;Doctor of Philosophy;Documentation;Drug resistance;Engineering;Engraftment;Evaluation;Fibrous capsule of kidney;Formalin;Foundations;Freezing;Future;Genetic;Genetic Polymorphism;Genome;Genomics;Goals;Grant;Hematologic Neoplasms;Hematopathology;Hematopoietic stem cells;Histologic;Histopathology;Human;Human Resources;Immunocompromised Host;Immunodeficient Mouse;Immunohistochemistry;Implant;In Vitro;Infrastructure;Injections;Institution;Lesion;Lymphoma;MS4A1 gene;Malignant Neoplasms;Mission;Modeling;Molecular;Morphology;Mus;Operative Surgical Procedures;PTPRC gene;Paraffin Embedding;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Preparation;Procedures;Process;Proteomics;Receptor Gene;Refractory;Reporting;Research;Research Personnel;Research Support;Resources;Rest;Richter's Syndrome;Risk;Sampling;Signal Transduction;Site;Slide;Small-Cell Lymphoma;Solid;Specimen;Stereotyping;Study Section;Tail;Testing;Tissue Microarray;Tissues;Translations;Transplantation;Tumor Bank;Validation;Variant;Veins;biomarker identification;candidate validation;cell bank;chromosome 13q loss;del(17p13);design;effective therapy;experimental study;genome editing;implantation;improved;in vivo;in vivo Model;innovation;interest;large cell Diffuse non-Hodgkin's lymphoma;lymphoid neoplasm;mouse model;novel;novel marker;participant enrollment;patient derived xenograft model;phenome;pre-clinical;programs;prospective;sample archive;subcutaneous;therapeutic target;tissue resource;tool;transcriptomics;treatment response;tumor;tumor microenvironment Pathology Project NarrativeThe mission of the Pathology Core (2) is to characterize and bank tumor samples from RS patients representinga full range of biologic characteristics as well as from engineered RS mouse models of disease. This tissueresource will enable the fundamental discoveries required to understand the pathogenesis of the disease andmove toward improved therapies and eventual cure. As part of this effort the Pathology Core will provide centralreview and resources for human and mouse RS pathology and generate a bank of patient-derived RS-PDXprimagraft models which would serve as an extraordinary resource for this study of RS. NCI 10692722 8/22/23 0:00 PAR-20-077 5P01CA206978-08 5 P01 CA 206978 8 9/1/16 0:00 8/31/26 0:00 ZCA1-SRB-K 7165 6410805 "CARRASCO, RUBEN D" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 114211 78738 35473 Project SummaryThis Pathology Core (2) will provide a seamless translational infrastructure to support the research on RS tissuesplanned in this application. This will include the ex vivo expansion of primary RS samples inimmunocompromised mice in an effort to generate in vivo RS primagraft models for provision of fresh or frozenRS cells for in vitro molecular and in vivo functional experiments. The RS samples will have full clinical annotationas well as molecular characterization (from Project 1/Core 3) and will be derived from patient samples alreadystored through the DFCI RS Biospecimen Core (1) as well as newly enrolled patients from DFCI and collaboratinginstitutions. These models are a significant and increasingly appreciated tool for the analysis of newly identifiedgenetic lesions associated signaling and survival pathways rational therapeutic targets and mechanisms ofdrug resistance. RS cells will be delivered by tail vein injection or directly implanted subcutaneously or beneaththe renal capsule. These primagraft models could then be used to characterize biology and assess response totherapy of the RS cells. This Pathology Core will also: (i) provide FFPE archived samples from RS patients (ii)provide histo-pathological analysis of human RS samples to be used in subsequent studies (iii) generate tissuemicroarrays (and slides of CLL/RS pairs for functional validation (iv) provide morphologic and histopathologicanalysis of mouse RS samples in engineered mice and (v) generate tissue arrays and slides to studyhistopathology and perform immunohistochemical characterization of mouse RS engineered mice. +No NIH Category available Award;Biology;Biopsy;Bone Marrow;Bone marrow biopsy;Cells;Chronic Lymphocytic Leukemia;Clinical;Clinical Trials;Collection;Data;Development;Dissection;Doctor of Philosophy;Early Diagnosis;Ensure;Evaluation;Event;Foundations;Future;Genetic;Genome;Infrastructure;Institution;Methods;Mission;Molecular;Molecular Profiling;Mononuclear;Nucleic Acids;Pathogenesis;Patient-Focused Outcomes;Patients;Plasma;Process;Prognosis;Reporting;Resources;Richter's Syndrome;Risk;Sampling;Science;Site;System;Therapeutic;Time;Tissues;Translational Research;biobank;cell bank;cell free DNA;design;high risk;improved;improved outcome;lymph nodes;novel;novel marker;participant enrollment;patient prognosis;peripheral blood;phenome;programs;repository;sample collection;standard of care;therapeutic target;timeline;tissue resource;treatment trial Biospecimens NarrativeCore 1 will generate a large repository of molecularly and clinically-annotated primary samples from patientswith Richter's syndrome and patients with chronic lymphocytic leukemia at high risk of developing Richter'ssyndrome. These primary samples will be obtained from patients on and off clinical trials at our center and willinclude extensive collection of cell-free DNA designed for early detection of RS. Samples from this Core willbe efficiently distributed to the Projects to provide the primary patient material essential to elucidating thepathogenesis and therapeutic vulnerabilities of Richter's syndrome. NCI 10692720 8/22/23 0:00 PAR-20-077 5P01CA206978-08 5 P01 CA 206978 8 9/1/16 0:00 8/31/26 0:00 ZCA1-SRB-K 5790 10331504 "DAVIDS, MATTHEW S" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 142763 98422 44341 Core 1 AbstractGiven the poor prognosis for patients with chronic lymphocytic leukemia (CLL) who develop Richtersyndrome (RS) an expanded molecular understanding of RS is critical both to understand whichpatients are at greatest risk and to develop improved therapeutic strategies. There is currently noeffective standard of care therapy for RS patients and this is likely to be a growing problem asincreasing numbers of CLL patients treated with novel agents are living longer putting them at risk ofdeveloping RS. The fundamental mission of Core 1 is to ensure a robust tissue resource of clinically-annotated primary samples from patients with RS treated both on and off clinical trials. Additionally wewill maximize opportunities to procure matched CLL sampleshighly feasible because of our long-established deep CLL sample repository-- so that clonal relationships between RS and antecedent CLLand molecular and functional differences between these two related entities can be studied. We willalso continue our systematic banking of cell and plasma samples from all CLL patients seen at ourcenter. We will emphasize banking those at high risk for developing RS both prior to any evidence oftransformation and at the time their CLL has progressed to RS for evaluation of cell-free DNA as amethod of early detection. In this fashion the resources of this Core will supply the Projects with thenecessary primary RS and CLL tissue to understand the genesis biology and most promisingtherapeutic targets in RS. We have established the infrastructure and a coordinated workflow to obtainfresh RS biopsies both from patients enrolled on treatment trials and those treated outside the trialsetting. We have well-established systems to efficiently distribute cellular and nucleic acid materialacross the Program for deep molecular profiling as described in the Projects. We have furthercoordinated with external clinical trial sites to share processing SOPs so that biopsy material can beobtained and processed in a uniform fashion across studies and institutions. We already have sufficientRS patient samples in our BioBanks to allow us to immediately begin to generate data through theProjects. Through the efforts detailed in this Core section we plan to significantly increase theavailability of such samples to fuel the science of the Projects throughout the timeline of this award andbeyond. These efforts will provide a firm foundation for future translation of the research findings intopotential novel biomarkers of RS development as well as the biology of RS itself and its potentialtherapeutic vulnerabilities thereby facilitating the development of novel clinical trials. +No NIH Category available Address;Apoptosis;Apoptotic;Appearance;BCL1 Oncogene;BCL2L1 gene;BH3 peptide;Back;Biological;Biological Assay;Biological Models;Cell Death;Cell physiology;Cells;Cessation of life;Chronic Lymphocytic Leukemia;Clinical;Clinical Trials;Collaborations;Coupled;Data;Dependence;Dissection;Drug Exposure;Drug Screening;Drug Targeting;Ensure;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Family;Funding;Genome;Genomic approach;Genomics;Goals;Human;Individual;Induction of Apoptosis;Intervention;Learning;Liquid substance;Lymphoma;MCL1 gene;Malignant neoplasm of lung;Maps;Measures;Medical;Methods;Mitochondria;Modeling;Molecular Abnormality;Occupations;Pathology;Patient-Focused Outcomes;Patients;Pattern;Permeability;Pharmaceutical Preparations;Proteins;Proteomics;Regulation;Resistance;Richter's Syndrome;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;Specimen;Techniques;Testing;Therapeutic;cancer cell;clinical predictors;companion diagnostics;drug sensitivity;early phase clinical trial;effective therapy;improved;in vivo;inhibitor;insight;mimetics;mouse model;mutant;novel;pharmacologic;phenome;precision medicine;predicting response;response;small molecule;success;transcriptomics;translational applications;tumor Functional identification of drug response and resistance in Richter's Syndrome NarrativeRichter's Syndrome (RS) is the appearance of an aggressive difficult-to-treat lymphoma from a prior case ofchronic lymphocytic leukemia. We have developed a novel method called BH3 profiling for identifying drugsthat coax cancer cells into destroying themselves. Here we propose to employ BH3 profiling on samples frompatients with RS to expand the therapeutic options for RS. NCI 10692718 8/22/23 0:00 PAR-20-077 5P01CA206978-08 5 P01 CA 206978 8 9/1/16 0:00 8/31/26 0:00 ZCA1-SRB-K 7162 1885707 "LETAI, ANTHONY G" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 285531 196846 88685 Summary (30 lines broad long-term)With the advent of more effective therapies in CLL there is a greater priority on identifying better treatment ofRichter's Syndrome (RS) as this has become one of the most important unmet medical needs to address forCLL patients. The main goals of this Project are to utilize functional precision medicine techniques to betterunderstand biological vulnerabilities in Richter's cells and to identify novel pharmacologic interventions toincrease apoptotic signaling in these cells. Our priority is on the direct study of viable samples from RS patientsobtained in collaboration with the Biospecimens core. We seek to identify the most promising combinations tosubsequently explore in early phase clinical trials for patients with RS funded by other mechanisms. The jobof precision medicine is to match the right patient to the right drug. A strategy of genomic sequencing hasyielded several successes such as treating EGFR mutant lung cancer with EGFR inhibitors; however to dateRS has not yielded to the identification of targetable genetic abnormalities and this will be the focus of Project1. In Project 3 we propose an alternative approach which we call functional precision medicine. Rather thanrely on static -omic data we propose to perturb cellular function in ways that allow us to identify active drugs.Central to this strategy is BH3 profiling a technique in which we expose mitochondria from living cells tosynthetic BH3 peptides and measure mitochondrial permeabilization. From this assay we can learn which anti-apoptotic proteins the cell relies on for survival whether BCL-2 BCL-XL MCL-1 some combination thereof ornone of these proteins. This information has direct translational application as clinical BH3 mimetic inhibitorsof all three listed proteins now exist. In fact BH3 profiling was used to direct therapy of the BCL-2 inhibitorvenetoclax to CLL and AML two indications for which venetoclax has now received FDA approval. Wepropose to use BH3 profiling to identify which BH3 mimetic(s) would be most active in RS. BH3 profiling canalso provide a summary measure of how close a cell is to the threshold of apoptosis. When coupled with abrief preceding drug exposure dynamic BH3 profiling (DBP) can identify drugs from any class that induceapoptotic signaling in cancer cells moving them closer to the threshold of apoptosis. We have previouslydemonstrated in several liquid and solid tumor contexts that this strategy accurately identifies drugs with in vivoactivity for individual tumors and can predict clinical response in patients. We propose to use DBP to identifyactive drugs after which we will explore their use in combination with each other and with the appropriate BH3mimetics identified above. As we identify drug vulnerabilities for the panel of RS samples to be studied in thisProject we will compare them with clinical genomic transcriptomic and proteomic annotations prepared byother Projects and Cores in this P01. We hope to use this information to gain insight into the upstreamsignaling mechanisms that drive drug-induced apoptotic signaling. +No NIH Category available ATAC-seq;Assessment tool;Atlases;Attention;B lymphoid malignancy;Biological Assay;Biological Markers;Biological Process;Biology;Blood;Cell physiology;Cells;Chromatin;Chromosome Mapping;Chronic Lymphocytic Leukemia;Clinical Trials;Collaborations;Collection;Data;Data Set;Detection;Diagnostic;Disease;Dissection;Early Diagnosis;Epigenetic Process;Event;Evolution;Funding;Future;Genetic;Genetic study;Genome;Genomics;Goals;Histology;Individual;Indolent;Lymphoma;Malignant Neoplasms;Manuscripts;Maps;Mass Spectrum Analysis;Molecular;Monitor;Mutate;Mutation;Outcome;Pathway interactions;Patient risk;Patient-Focused Outcomes;Patients;Pattern;Plasma;Proteins;Proteomics;Recurrence;Refractory;Relapse;Resolution;Richter's Syndrome;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Venipunctures;Work;analytical method;anticancer research;bisulfite sequencing;cell free DNA;chronic lymphocytic leukemia cell;clinical decision-making;cohort;data integration;detection assay;disorder control;epigenome;exome;exome sequencing;genome analysis;genome sequencing;high risk;histone methylation;improved;large cell Diffuse non-Hodgkin's lymphoma;leukemia;leukemic transformation;molecular subtypes;new therapeutic target;novel;outcome prediction;phenome;phosphoproteomics;predict clinical outcome;predicting response;prognostic model;risk stratification;single cell analysis;single-cell RNA sequencing;success;targeted treatment;therapeutic development;therapeutic target;therapeutically effective;tool;transcriptome sequencing;transcriptomics;whole genome Generating an atlas of Richter's Syndrome: from molecular understanding to outcome prediction detection and monitoring Narrative: Richters Syndrome (RS) occurs when a patients Chronic Lymphocytic Leukemia (CLL) transformsto an aggressive and often deadly lymphoma. Unfortunately when this occurs there are very few therapeuticoptions with limited success which is in part due to our lack of understanding of the biology underlying thisdisease and what triggers the transformation from an indolent leukemia into an aggressive lymphoma. In thisProject we will create a comprehensive atlas of the molecular features of RS and discover the changes thatdrive this transformation and use this atlas to develop tools for assessing a patients risk as well as a blood-based test for identifying and monitoring the emergence or recurrence of RS. NCI 10692712 8/22/23 0:00 PAR-20-077 5P01CA206978-08 5 P01 CA 206978 8 9/1/16 0:00 8/31/26 0:00 ZCA1-SRB-K 7159 9774810 "GETZ, GAD A" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 376109 284187 91922 Project Summary: Recent therapeutic advances have dramatically improved patient outcomes in chroniclymphocytic leukemia (CLL). However Richter's Syndrome (RS) which is the transformation of CLL to anaggressive lymphoma (that occurs in 0.5-1% of CLL patients annually) is often refractory to existing therapeuticapproaches. Building on the success of our current P01 in creating the world's largest map of genetic driversand subtypes of CLL (n=~1100) and using it to build prognostic models this renewal application seeks to applysimilar (and new) approaches to comprehensively map the genetic underpinnings of RS. Currently and incontrast to CLL little is known about the genetics clonal composition drivers and cell circuitry of RS and hencethere is neither a framework for molecularly based risk stratification nor targets for therapeutic development.Therefore understanding the molecular (genetic epigenetic and proteomic) underpinnings of the transformationfrom CLL to RS will create opportunities for more effective therapeutic interventions prediction of response andpotentially early detection all with the goal of improving patient outcome. To achieve these goals we proposeto: (1) Define the drivers of RS and delineate the relationship of RS to CLL and DLBCL. Using whole-exome andRNA sequencing we will study the genetic and transcriptomic landscape of >300 RS cases including analyzingtheir pre-transformation CLL and RS samples. We will then further delineate the genetic relationship betweenCLL and RS using whole-genome sequencing of a subset of cases and chart their epigenetic landscape usingchromatin and histone methylation profiling. Moreover we will trace the evolution of the CLL cells to RS anddetermine distinct patterns of genetic epigenetic and transcriptomic states at a single-cell resolution. Finallywe will combine these data to identify molecular subtypes of RS and associate them with outcome. (2) Definethe changes in cellular circuitry associated with transformation from CLL to RS. We will use the power ofmicroscaled proteomic and phosphoproteomic analysis to identify changes in the wiring of cellular processesassociated with transformation to RS and create a comprehensive proteomic map of RS. We will identifyderegulated signaling pathways and potential therapeutic targets. Finally we will integrate the proteomic data torefine the molecular subtypes identified above as well as develop a high-throughput proteomic assay fordetecting biomarkers of these subtypes and validate them in an independent set of RS patients. (3) Develop anon-invasive tool for RS detection and monitoring. Building on our understanding of the RS genome we will builda robust and inexpensive cell-free DNA assay based on low-pass whole-genome sequencing aimed at detectingRS-specific alterations in plasma samples. We will test whether we can detect RS clones in patients' blood tomonitor the emergence progression and relapse of RS. Together these Aims will create the first comprehensiveatlas of RS identify key pathways and potential therapeutic targets and build tools that could impact clinicaldecision making. +No NIH Category available Affect;American;Awareness;Cancer Patient;Caring;Cessation of life;Client satisfaction;Clinical;Communication;Consensus;Data Analyses;Distal;Distress;Elderly;Ensure;Face;Feasibility Studies;Fostering;Foundations;Gerontology;Goals;Health;Healthcare;Healthcare Systems;Hearing;Individual;International;Investigation;Life;Malignant Neoplasms;Measures;Mediating;Mediation;Mediator;Methodology;Methods;Modeling;Oncology;Outcome;Palliative Care;Patient Care;Patients;Persons;Process;Prognosis;Provider;Psychosocial Assessment and Care;Quality of life;Reporting;Research;Science;Severities;Site;Spiritual care;Statistical Data Interpretation;Structure;Symptoms;Testing;Training;Transcript;analytical tool;brief intervention;cancer care;clinical center;cost;design;end of life;experience;group intervention;human dignity;improved;innovation;interest;patient engagement;patient oriented;patient-clinician communication;preservation;pressure;primary outcome;psychosocial;reduce symptoms;response;secondary outcome;symposium;therapy outcome;tool Dignity Therapy for Older Cancer Patients: Identifying Mechanisms and Moderators PROJECT NARRATIVEDignity Therapy is a guided process of life review aimed at fostering dignity in patients suffering with cancerand other life-limiting illnesses. The proposed research aims to determine mechanisms by which DignityTherapy improves older cancer patients dignity at different levels of symptom severity. The proposedresearch integrates humanistic patient-centered constructs and rigorous analytic tools to determine how oldercancer patients can most benefit from this therapy. NCI 10692706 9/8/23 0:00 PAR-18-869 5R01CA253330-03 5 R01 CA 253330 3 "STRECK, BRENNAN PARMELEE" 9/10/21 0:00 8/31/24 0:00 Clinical Management in General Care Settings Study Section[CMGC] 8819525 "BYLUND, CARMA L." "BLUCK, SUSAN " 3 SURGERY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 341867 NCI 224175 117692 PROJECT SUMMARYNearly 600000 older Americans die a cancer-related death each year. Maintaining human dignity is central toquality of life for patients with serious illness. Our long-term goal is to foster optimal humanistic modes ofpatient-centered clinical communication. We focus in the proposed study on Dignity Therapy (DT) which wasdesigned to preserve cancer patients dignity despite declines in their health. Theoretically grounded ingerontological life review research DT involves a therapist guiding a patient to generate their own uniquestructured life narrative. Patients report benefits of DT but to date the mechanisms of DT have not beenempirically investigated. As the use of this therapy spreads internationally there is thus a pressing need todelineate precise mechanisms. The proposed study is the first to reliably analyze the content of older cancerpatients interactions with the therapist in DT sessions (N=280 older adults who received DT). Our designallows for investigation of two mechanisms theoretically central to improving patient dignity through DT. Theseproposed mechanisms empathic provider-patient communication during DT and richness of the patients lifenarrative produced during DT will be used analytically as predictors of pre-to-post-therapy change in dignityimpact. Our proposed study uses innovative methodological tools: it will employ both interactional and narrativeanalysis grounded in the patients own experience to establish mechanisms through which the therapy affectspatient dignity. Past research has suffered due to assessment of conceptually distal outcomes of receiving DT.In response the proposed outcomes have been chosen as proximal constructs closely guided by DTsconceptual underpinnings. Our primary outcome of interest is the extent to which the patients sense of dignityincreases from pre-to-posttest (i.e. Dignity Impact). Another aspect of the proposed study is to investigatewhen patients are most able to engage in DT. This will be accomplished through assessing whether extent ofdignity impact after DT is moderated by patients symptom severity. Together delineating mechanisms andidentifying best timing for patient engagement in DT will provide substantial progress in implementing DT as aform of psychosocial care for older cancer patients. Our interdisciplinary team ensures that study findings willbe implemented to improve DT training and delivery. This includes our innovative dissemination plan of hostinga Science of Care Summit with national opinion leaders. Our specific aims are as follows: SA1: Delineate therelation between empathic communication and higher patient dignity impact (primary outcome) pre-to-post-therapy. SA2: Investigate the relation between richness of the life narrative the patient is guided to produceduring DT and dignity impact (primary outcome) pre-to-post therapy.SA3: Identify the best-fitting model ofrelation of patient-provider empathic communication to post-therapy impact on patients dignity with narrativerichness as a mediator and patients symptom severity as a moderator (i.e. moderated-mediation analyses). 341867 +No NIH Category available Affect;Architecture;Bioinformatics;Cancer Model;Catalysis;Catalytic Domain;Cell Differentiation process;Cell Line;Cell Maintenance;Cells;Chromatin;Complex;Development;Differentiated Gene;Drug Targeting;EZH2 gene;Enzymes;Epigenetic Process;Exhibits;Focus Groups;Frequencies;Gene Expression;Gene Targeting;Genes;Genetic Transcription;Genome;Goals;Heterogeneity;Histones;Impairment;Individual;Knock-out;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Maps;Measures;Methods;Mutation;Neoplasm Metastasis;Nucleic Acid Regulatory Sequences;Ovarian;Pathway interactions;Phase;Polycomb;Population;Process;Regulator Genes;Role;Running;Technology;Testing;Therapeutic;Time;Training;Tumor Biology;Tumor Promotion;cancer cell;cancer stem cell;cancer therapy;cancer type;cell type;combinatorial;epigenetic regulation;epigenome;epigenomics;histone methyltransferase;human model;inhibitor;insight;knock-down;neoplastic cell;novel therapeutic intervention;novel therapeutics;ovarian neoplasm;overexpression;patient derived xenograft model;self-renewal;single-cell RNA sequencing;stem cell population;stem cell self renewal;targeted treatment;transcriptome;treatment effect;tumor;tumor growth;tumor heterogeneity;tumor progression;tumorigenesis Single cell chromatin profiling to study epigenetic alterations of ovarian tumors PROJECT NARRATIVEEpigenetic alterations in cancer cells promote tumor progression but tumor heterogeneity hinders ourunderstanding of this process. Uncovering cell type specific epigenetic features will enable a betterunderstanding of tumorigenesis and contribute to the development of targeted therapies. This project willexpand our understanding of how epigenetic regulators remodel different subpopulations of cancer cells inaggressive ovarian tumors. NCI 10692705 7/31/23 0:00 PA-20-188 5K99CA273420-02 5 K99 CA 273420 2 "SCHMIDT, MICHAEL K" 9/1/22 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 15692028 "GOPALAN, SNEHA " Not Applicable 2 ANATOMY/CELL BIOLOGY 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 124681 NCI 115445 9236 PROJECT SUMMARYAn understanding of how epigenetic changes rewire the regulatory network of cancer cells would facilitate thedevelopment of new therapeutic strategies. However tumor heterogeneity hinders the study of epigeneticlandscapes in cancer. I propose to leverage a new single-cell genome profiling technology I recently developedto map epigenetic changes in single cells allowing me to characterize different cell populations within ovariantumors including cancer stem cells (CSCs) and more differentiated cell types. These studies will uncover howthe epigenome is re-wired upon inhibition of epigenetic enzymes implicated in multiple cancers. EZH2 is ahistone methyltransferase that is often overexpressed in different types of cancer including ovarian cancerand inhibition of EZH2 has been shown to strongly reduce the aggressiveness of tumors by impairingmetastasis reducing invasiveness and promoting differentiation. Yet how EZH2 overexpression alters therepressive histone mark H3K27me3 in each tumor cell type remains unknown. I propose three Aims the firstof which will use a combination of single cell Multi-CUT&Taga single cell profiling technology I recentlydevelopedand scRNA-seq to characterize the epigenomic landscapes in each ovarian cancer cell type. InAim 2 I will examine how perturbation of EZH2 alters the epigenetic architecture of tumor sub-populationsincluding CSCs and identify how EZH2 promotes CSC self-renewal and tumor progression. Finally in Aim 3 Iwill uncover the roles of genes and pathways subjected to epigenomic remodeling in order to identify potentialweaknesses that can be exploited therapeutically. Successful completion of these studies will provideconsiderable insight into the epigenetic regulation of CSCs in ovarian cancers and candidates for newtherapies for ovarian cancer treatment. In addition these studies will provide extensive training in tumorbiology and single cell bioinformatics which will be essential for my goal of running an independent groupfocused on tumor epigenetics. 124681 +No NIH Category available Address;Adopted;Agreement;Big Data;Biological Markers;Breast Cancer Risk Factor;Calibration;Clinical Research;Communities;Data;Data Set;Ensure;Estrogens;Evaluation;Feasibility Studies;Gestational Diabetes;Goals;Hormonal;Individual;Logistic Regressions;Logistics;Malignant Neoplasms;Measures;Methods;Modeling;Outcome;Patients;Population;Publications;Research Design;Risk;Risk Marker;Sampling;Sampling Studies;Source;Statistical Methods;Target Populations;Testing;Validation;biomarker evaluation;breast density;case control;cost effective;design;disorder prevention;epidemiology study;flexibility;improved;innovation;metabolomics;model building;novel;outcome prediction;precision medicine;predictive modeling;risk prediction;risk prediction model;user friendly software Data and Information Integration for Risk Prediction in the Era of Big Data Project NarrativeToward precision medicine and precision disease prevention the overarching goal of thisproposal is to develop innovative statistical methods for accurate risk prediction. Weaddress three challenges that plague studies on the value of new predictors that adds tostandard predictors for improving predictive accuracy: lack of independent validation datalack of statistical methods for developing risk prediction models using individually-matchedcase-control data and lack of statistical methods to guide study design beyond standardpower calculation for testing predictor-outcome association. We will develop innovativestatistical methods to address these challenges. Our methods accompanied by user-friendlysoftware are expected to facilitate cost effective and timely biomarker evaluation for predictingbinary outcomes. NCI 10692693 8/23/23 0:00 PA-18-484 5R01CA236468-05 5 R01 CA 236468 5 "CHEN, HUANN-SHENG" 9/20/19 0:00 8/31/25 0:00 Biostatistical Methods and Research Design Study Section[BMRD] 8706115 "CHEN, JINBO " Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 399 Non-SBIR/STTR 2023 395357 NCI 267395 127962 AbstractToward precision medicine and precision disease prevention the overarching goal of this proposal is todevelop innovative statistical methods for accurate risk prediction. We address three challenges thatplague studies on the value of candidate risk predictors that adds to established predictors for improvedpredictive accuracy: there is often a lack of independent validation data the source population for thestudy sample and the target population of prediction are often different no statistical methods arecurrently available for developing risk prediction models using individually-matched case-control dataand there is a lack of statistical methods for helping assess study feasibility beyond standard powercalculation for testing predictor-outcome association. On the other hand data and information that areexternal to the study may well exist and can be exploited to alleviate these challenges. For example amodel with only standard predictors often exists and has been validated and the distribution of standardrisk predictors in the target population of prediction is often available. We propose that external data andinformation can be exploited to address the above-mentioned challenges for candidate predictorevaluation and develop innovative statistical methods to bring this idea to fruition. Consideringprediction of a binary outcome we propose a novel method to building logistic prediction models that areguaranteed to calibrate well in the target population an innovative method for risk prediction withindividually matched case-control data and a method to project the added value of candidate predictors tohelp assess study feasibility. Our methods accompanied by user-friendly software will facilitate costeffective and timely predictor evaluation for predicting binary outcomes. Our methods were motivated byand will be applied to several PI Chen's collaborative studies. 395357 +No NIH Category available Adjuvant;Affect;Antibodies;Bacteriophages;Biochemical;Biological Assay;Biology;Biophysics;Bladder;Cells;Cervical;Charge;Chemicals;Clinical;Collaborations;Communities;Comparative Study;Complex;Cytoprotection;Cytosine;DNA;Data;Deaminase;Development;Diagnosis;Drug resistance;Ensure;Enzyme-Linked Immunosorbent Assay;Enzymes;Escherichia coli;Estrogen receptor positive;Evolution;Family member;Flow Cytometry;Goals;Head and neck structure;Human;Immunoassay;Immunoglobulin G;Immunohistochemistry;Immunoprecipitation;Libraries;Lung;Malignant Neoplasms;Mammary Neoplasms;Measures;Mediating;Methods;Microscopy;Monoclonal Antibodies;Mus;Mutagenesis;Mutate;Mutation;Neoplasm Metastasis;Nucleic Acids;Oryctolagus cuniculus;Outcome;Primary Neoplasm;Procedures;Process;Production;Protocols documentation;Publications;Quality Control;Reagent;Recombinants;Reporting;Reproducibility;Research;Research Personnel;Resolution;Services;Single-Stranded DNA;Solubility;Standardization;Structure;Testing;Therapeutic;Time;Treatment Failure;United States National Institutes of Health;Uracil;Virus Diseases;Western Blotting;anticancer research;cancer cell;cancer diagnosis;cancer type;improved;malignant breast neoplasm;member;mouse model;multidisciplinary;overexpression;patient prognosis;prevent;programs;scaffold;small molecule;structural biology;therapy outcome;therapy resistant;translational goal;tumor CORE D NARRATIVEAPOBEC3B is a DNA-mutating enzyme frequently upregulated in cancer cells. Our Program is testing the unifying hypothesis that APOBEC3B inhibition as an adjuvant to primary treatment options will help to prevent detrimental mutation-driven outcomes such as drug resistance and metastasis. Core D Enzymes & Antibodies will expedite our short- and long-term goals by producing high-quality enzymes and monoclonal antibodies for use by the Program team its collaborators and the greater community of cancer researchers including an antibody that can be used clinically to diagnose APOBEC3B-positive tumors. NCI 10692669 8/4/23 0:00 PAR-18-290 5P01CA234228-05 5 P01 CA 234228 5 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L 7147 10320794 "CARPENTER, MICHAEL ALLEN" Not Applicable 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 76900 49613 27287 ABSTRACTAPOBEC enzymes are single-stranded DNA cytosine-to-uracil deaminases that normally protect cells from viral infections. One family member APOBEC3B (A3B) is overexpressed in over half of all breast tumors and its mutation signature is found in 20% of primary and 50% of metastatic breast tumors. A3B overexpressionand mutation signature have also been associated with therapy failure and poor overall survival. Our Program has shown that inhibition of A3B-mediated tumor evolution contributes to improved therapy outcomes in a mouse model of estrogen receptor-positive breast cancer. These data support our Programs unifying hypothesis that A3B inhibition as an adjuvant to primary treatment options will help to prevent detrimental mutation-driven outcomes such as drug resistance and metastasis. Our Program members are collaborating to test this hypothesis through 3 tightly integrated Projects focusing on the biology chemical biology and structural biology of A3B. These Projects are supported by 4 service Cores including Core D Enzymes &Antibodies which has 2 specific aims: Aim 1 is to produce recombinant APOBEC enzymes and to perform standard DNA deaminase assays with these enzymes which will allow standardization of APOBEC studies across labs and time. Aim 2 is to develop specific monoclonal antibodies for A3B and related human APOBEC3 enzymes. The availability of specific antibodies will move the Programs research forward and is important for the Programs translational goal of developing an antibody-based assay for diagnosing A3Bpositive tumors in order to inform patient prognosis and ultimately therapeutic plans. The reagents resulting from both Aims are vital for expediting the goals of each Project ensuring maximal rigor and reproducibilityacross Projects and collaborating labs and fueling Program collaborations and APOBEC research in the greater cancer research community. Overall despite its relatively modest size Core D is a powerful enabling feature of our Program. +No NIH Category available 3-Dimensional;Aging;BRCA1 gene;Binding;Binding Sites;Biochemical;Biological;Biological Assay;Biological Testing;Biology;Biophysics;CDK4 gene;Cells;Chemical Models;Chemicals;Clinical;Collaborations;Complex;Computer Models;Computing Methodologies;Cytosine;Cytosine deaminase;Data;Deamination;Defect;Development;Drug Kinetics;Drug resistance;Effectiveness;Enzymes;Estrogen receptor positive;Evolution;Excretory function;Generations;Goals;Graph;Inherited;Kinetics;Length;Ligands;Macromolecular Complexes;Malignant Neoplasms;Mammary Neoplasms;Metabolism;Metastatic breast cancer;Methylation;Modeling;Molecular;Monoclonal Antibodies;Mutagenesis;Mutation;Neoplasm Metastasis;Nucleic Acids;Nucleotides;Outcome;PIK3CA gene;Physiological;Primary Neoplasm;Process;Property;Proteins;Regulation;Reporting;Resolution;Roentgen Rays;Role;Single-Stranded DNA;Source;Structural Models;Structure;System;Techniques;Testing;The Cancer Genome Atlas;Thermodynamics;Time;Tumor Promotion;Uracil;Vertebral column;absorption;antiviral immunity;biophysical model;chemical binding;computational chemistry;data integration;data streams;data-driven model;design;experimental study;homologous recombination;improved;in silico;in vivo;inhibitor;innovation;insight;lead optimization;malignant breast neoplasm;model development;molecular dynamics;molecular recognition;multidisciplinary;nanosecond;neoplastic cell;novel;operation;prevent;programs;receptor;resistance mutation;screening;simulation;small molecule;structural biology;tumor CORE C CORE C COMPUTATIONAL CHEMISTRY & BIOPHYSICSNARRATIVE APOBEC is a recently discovered enzymatic source of mutation in breast cancer that promotes tumorevolution and reduces the effectiveness of current therapies by generating resistance mutations. Core C Computational Chemistry & Biophysics strengthens this Program's operations through the iterativedevelopment of atomic-level biophysical and chemical models in real time. The primary goals of Core C are todevelop informative 3D structural models of a variety of APOBEC proteins and related regulatory partners andto perform in silico small molecule screening and lead optimization to propel the Program toward its long-termgoal of inhibiting APOBEC mutagenesis in breast cancer and improving clinical outcomes. NCI 10692666 8/4/23 0:00 PAR-18-290 5P01CA234228-05 5 P01 CA 234228 5 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L 7146 8402151 "AMARO, ROMMIE E" Not Applicable 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 269481 266429 3052 CORE C COMPUTATIONAL CHEMISTRY & BIOPHYSICSABSTRACT APOBEC is a recently discovered enzymatic source of mutation in breast cancer. Multiple lines of evidenceindicate that APOBEC mutagenesis is an ongoing source of mutation in tumor cells and that the major enzymeresponsible is the single-stranded (ss)DNA cytosine deaminase APOBEC3B (A3B). Our Program is thereforeunited in testing the overarching hypothesis that A3B inhibition will prevent a large proportion of new mutationsin estrogen receptor-positive breast cancer thereby improving the durability of current treatments and resultingin better overall outcomes. Projects 1 2 and 3 are focused on testing this idea through a carefully organizedmultidisciplinary team involving biology chemical biology and structural biology approaches. Core C Computational Chemistry & Biophysics provides the computational modeling backbone to support theseProjects through 2 well-integrated specific aims. Aim 1 encompasses the development of physically detailed3D structural models of APOBEC biomolecular systems including those that prove challenging to resolveexperimentally such as the different macromolecular regulatory complexes being explored in Project 1 or full-length wild-type A3B in complex with ssDNA in Project 3. In these examples and others explicitly solvatedmolecular dynamics (MD) simulations will be used to predict atomic-level interactions and these dynamic 3-dimensional models will guide wet experiments by the Project teams. The resulting data will drive Core C todevelop further refined models for additional testing by the Project teams. Aim 2 consists of in silico smallmolecule screening and lead optimization. Innovative MD analysis frameworks such as Markov state modelingwill be used to extract long-timescale dynamics from many short-timescale simulations and elucidate thethermodynamic and kinetic landscapes of APOBEC enzymes that control molecular recognition and functionalactivity. A key strength of this approach is identification of cryptic pockets that are capable of binding chemicalprobes but are often absent from x-ray structures. A range of ligand- and receptor-based approaches will beemployed in silico to increase the diversity of APOBEC inhibitors. Core C will also perform lead optimization insilico including computational Absorption Distribution Metabolism Excretion / Pharmacokinetics (ADME/PK)optimization to help avoid potential chemical liabilities and maximize experimental efficiencies. Inhibitors andprobes will be developed through continual collaboration with Projects 2 and 1 and Core D. The biochemicaland biological testing of candidate molecules identified or predicted in silico will fuel additional rounds ofcomputational refinement ultimately leading to structural studies by Project 3 and in vivo tumor evolutionexperiments by Core B. +No NIH Category available 2'-Deoxythymidine;APOBEC3F gene;Achievement;Active Sites;Address;Adjuvant;Affinity;Binding;Biological Assay;C-terminal;CCL21 gene;Cancer Etiology;Catalytic Domain;Cells;Chemicals;Clinical;Closure by clamp;Complex;Computer Models;Crystallization;Cytosine;DNA;DNA Binding;DNA Damage;DNA Repair;DNA Sequence;DNA biosynthesis;Data;Deaminase;Deamination;Deoxycytidine;Development;Diagnosis;Dinucleoside Phosphates;Disease;Drug resistance;Endowment;Enzymes;Estrogen receptor positive;Evolution;Family;Family member;Foundations;Future;Genome;Genomics;Goals;Histidine;Human;In Vitro;Innate Immune Response;Knowledge;Length;Life;Malignant Neoplasms;Mediating;Molecular;Molecular Chaperones;Molecular Conformation;Monoclonal Antibodies;Mutagenesis;Mutation;N-terminal;Neoplasm Metastasis;Outcome;Pathogenicity;Patient-Focused Outcomes;Positioning Attribute;Process;Protein Engineering;Proteins;Publishing;RNA;Research;Residual state;Resistance;Resolution;Roentgen Rays;Role;Shapes;Single-Stranded DNA;Solid;Source;Specificity;Structure;System;Tamoxifen;Testing;Thymine;Uracil;Variant;Vertebral column;Virus;Work;activation-induced cytidine deaminase;analog;apoB mRNA editing catalytic subunit;base;cancer therapy;ddT (dideoxythymidine);drug resistance development;ds-DNA;genetic regulatory protein;improved;in vivo;inhibitor;malignant breast neoplasm;member;mouse model;novel;nucleobase;overexpression;preference;prevent;programs;structural biology;therapeutic target;therapy outcome;tumor;tumor heterogeneity PROJECT 3 PROJECT 3 STRUCTURAL BIOLOGY OF DNA DEAMINASES IN BREAST CANCERNARRATIVE We are using structural biology approaches to study the atomic structures of human APOBEC enzymesand how they interact with DNA substrates. Because APOBEC enzymes have dominant roles in tumorevolution and drug resistance in multiple cancers our research will provide critical information about how theseprocesses may be stopped to improve the overall efficacy of cancer therapies. NCI 10692660 8/4/23 0:00 PAR-18-290 5P01CA234228-05 5 P01 CA 234228 5 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L 7143 9807994 "AIHARA, HIDEKI " Not Applicable 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 351914 351914 0 PROJECT 3 STRUCTURAL BIOLOGY OF DNA DEAMINASES IN BREAST CANCERABSTRACT The hallmark activity of the APOBEC family of enzymes is deamination of cytosines to uracils (C-to-U) insingle-stranded (ss)DNA. This editing activity normally functions in the innate immune response by contributingto virus and transposon restriction. However recent studies by our labs and many others strongly indicate thatAPOBEC3B (A3B) is a major source of genomic mutations that drive the progression of multiple humancancers and the development of drug resistance. This finding that a cellular enzyme actively introducesmutations in cancer is in stark contrast to a more conventional view in which mutations in cancer are causedby DNA damage from exogenous sources or errors introduced during DNA replication or repair. Because A3Bis not an essential enzyme for life it is a promising target for anti-cancer therapies. Thus our Program'soverarching hypothesis is that A3B inhibition as an adjuvant to primary treatment options will help to preventdetrimental mutation-driven outcomes such as drug resistance and metastasis. However despite its strongrelevance to cancer as a potential therapeutic target it is not fully known how A3B engages ssDNA substrateshow it achieves high selectivity for ssDNA over RNA or how its DNA deaminase activity is regulated in cells.Moreover it is not known how related enzymes such as APOBEC3H (A3H) and APOBEC3F (A3F) withdifferent compositions of ssDNA-binding residues engage similar target sequences. In Project 3 we havestarted to address these issues by solving multiple A3B catalytic domain crystal structures and recentlyachieving co-crystal structures of ssDNA bound to a variant of the A3B catalytic domain as well as to therelated enzyme APOBEC3A (A3A). Aim 1 will build on this knowledge to further delineate the global ssDNAbinding mechanism of A3B and A3H. Aim 2 will examine the local dinucleotide targeting mechanism andpossible modes of inhibition of the APOBEC family of enzymes. Our goals are to gain deeper mechanisticunderstandings of the pathogenic APOBEC-mediated ssDNA cytosine deamination process and to establish asolid foundation for future development of APOBEC inhibitors for cancer therapies. These studies will propelour Program toward achieving its long-term goal of inhibiting APOBEC mutagenesis in breast cancer therebyslowing tumor evolution and improving overall therapeutic outcomes for patients. +No NIH Category available Acceleration;Achievement;Address;Advanced Development;Aging;Animal Model;Animals;Antibody Formation;Automobile Driving;BRCA1 gene;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biology;Biophysics;Breast Cancer Cell;Breast Cancer Model;Cellular Assay;Chemicals;Clinical;Collaborations;Complex;Cytoprotection;Cytosine;DNA;DNA Binding;DNA Sequence;Deaminase;Deamination;Defect;Deoxycytidine;Development;Drug resistance;Enzyme Inhibition;Enzymes;Estrogen receptor positive;Evolution;Foundations;Future;Goals;Inherited;Lead;Ligand Binding;Ligands;Malignant Neoplasms;Mammary Neoplasms;Mediating;Methods;Methylation;Modeling;Modification;Molecular;Mutagenesis;Mutate;Mutation;Neoplasm Metastasis;Nucleic Acid Probes;Nucleic Acids;Nucleotides;Oligonucleotides;Outcome;PIK3CA gene;Physiological;Positioning Attribute;Primary Neoplasm;Proteins;RNA;Reagent;Research;Resistance;Roentgen Rays;Role;Services;Single-Stranded DNA;Structure;Technology;Testing;Therapeutic;Treatment Failure;Uracil;Variant;Viral;Virus Diseases;Work;antiviral immunity;clinical translation;computational chemistry;design;drug development;drug discovery;drug resistance development;experimental study;feature detection;forging;homologous recombination;improved;in vivo;inhibitor;innovation;malignant breast neoplasm;molecular recognition;mouse model;multidisciplinary;novel;novel strategies;overexpression;preference;prevent;programs;small molecule;small molecule inhibitor;structural biology;therapeutic development;therapy outcome;tumor PROJECT 2 PROJECT 2 CHEMICAL BIOLOGY OF DNA DEAMINASES IN BREAST CANCERNARRATIVE APOBEC3B (A3B) is a DNA-mutating enzyme frequently activated in breast tumors which contributes tobreast tumor evolution including mutations that cause drug resistance. The long-term goal of this Program is totherapeutically inhibit A3B and thereby help to suppress detrimental outcomes such as drug resistance andmetastasis. Project 2 Chemical Biology of DNA Deaminases in Breast Cancer will contribute to thisoverarching goal by developing novel nucleic acid and small molecule A3B modulators that will serve asvaluable mechanistic probes of A3B function and provide lead compounds for future drug development. NCI 10692658 8/4/23 0:00 PAR-18-290 5P01CA234228-05 5 P01 CA 234228 5 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L 7142 8194521 "HARKI, DANIEL A" Not Applicable 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 362517 362517 0 PROJECT 2 CHEMICAL BIOLOGY OF DNA DEAMINASES IN BREAST CANCERABSTRACT APOBEC enzymes are single-stranded DNA cytosine-to-uracil deaminases that normally protect cells fromviral infections. However APOBEC3B (A3B) has been implicated in mutations in breast cancer that drive tumorevolution and contribute to the development of drug resistance and ultimately therapy failure. A3B isoverexpressed in over half of all estrogen receptor (ER)-positive breast tumors the most common type and isassociated with poor overall survival. Our Program has shown that inhibition of A3B-mediated tumor evolutionimproves therapy outcomes in a mouse model of ER-positive breast cancer. Our Programs unifyinghypothesis is that A3B inhibition will prevent a large proportion of new mutations in ER-positive breast cancerthereby improving the durability of current treatments and resulting in better overall outcomes. To address thishypothesis our Program is focused on understanding the biology of A3B in breast cancer cells (Project 1);developing innovative nucleic acid probes to molecularly characterize how A3B engages DNA substrates andsmall molecules to inhibit A3B-catalyzed breast cancer mutations (Project 2); and generating A3B x-raystructures with nucleic acids small molecules and protein ligands to understand the structural basis of A3B-mediated DNA mutagenesis and its inhibition to enable development of therapeutic compounds (Project 3).These activities will be supported by Service Cores for administration (Core A) animal models of A3B-drivenbreast cancer (Core B) computational chemistry and biophysics (Core C) and protein and antibody production(Core D). Project 2 Chemical Biology of DNA Deaminases in Breast Cancer will lead the chemical probediscovery efforts by 1) synthesizing complex nucleic acid ligands for A3B to characterize how A3Bdiscriminates 2-deoxycytidine from other nucleotides and to understand which nucleic acid features enableA3B to deaminate discrete DNA sequences including its overall preference for binding DNA versus RNA; and2) using complimentary technologies and approaches to develop first-in-class small molecule inhibitors of A3Bthat will be used in mechanistic cellular assays of A3B-driven breast cancer mutation (Project 1) structuralbiology studies to annotate A3B-ligand binding (Project 3) and therapeutic utility experiments in animal modelsof breast cancer (Core B). Our studies will be enabled by critical collaborations involving computational liganddesign (Core C) and access to high-quality biological reagents for assays (Core D) and our advances willposition our novel compounds for future therapeutic development. Potent selective chemical probes of A3Bwith in vivo activity as well as novel assays are the major anticipated deliverables of Project 2. As suchProject 2 will be the center of chemical innovation for the Program accelerating all Projects and contributing tothe achievement of our overall research objectives. +No NIH Category available Accounting;Adjuvant;Aging;Amino Acids;Base Excision Repairs;Biochemical;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer cell line;Breast Epithelial Cells;CDK4 gene;CRISPR screen;Cell Line;Cell Survival;Cells;Chemicals;Clinical;Collaborations;Compensation;Complex;Computer Models;Cytosine;DNA;DNA Damage;DNA Repair;DNA Repair Pathway;DNA glycosylase;Data Set;Deaminase;Deamination;Dependence;Development;Diagnosis;Diagnostic;Dinucleoside Phosphates;Disease;Drug resistance;Enzymes;Estrogen receptor positive;Event;Fluorescence;Future;Generations;Genetic;Genetic Transcription;Genomic Segment;Genomics;Goals;Knowledge;Lesion;Malignant Neoplasms;Mediating;Membrane Proteins;Methylation;Mismatch Repair;Molecular;Mutagenesis;Mutation;Neoplasm Metastasis;Nucleotides;Outcome;PIK3CA gene;Pathologic;Pathway Analysis;Pathway interactions;Physiological;Primary Neoplasm;Process;Proteins;Proteomics;RNA Splicing;Real-Time Systems;Recurrence;Regulation;Reporter;Reporting;Resistance;Role;Single-Stranded DNA;Source;Surface;System;Technology;Testing;Therapeutic;Therapeutic Intervention;Time;Uracil;antiviral immunity;base;base editing;breast cancer diagnosis;cancer cell;experimental study;homologous recombination;inhibitor;innovation;insight;malignant breast neoplasm;new technology;overexpression;preference;prevent;programs;protein protein interaction;rapid testing;small molecule;structural biology;technology development;therapeutic development;tumor PROJECT 1 NARRATIVEA major endogenous source of mutation has emerged with the discovery of APOBEC mutagenesis in breast and other cancers. Project 1 studies will yield innovative systems for quantification of APOBEC activity in living breast cancer cells and key insights into protein-level regulatory processes and downstream DNA repair pathways. This technology and mechanistic information will expedite Program efforts to diagnose and treat tumors that are evolving at higher rates due to APOBEC mutagenesis. NCI 10692656 8/4/23 0:00 PAR-18-290 5P01CA234228-05 5 P01 CA 234228 5 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L 7141 8004071 "HARRIS, REUBEN S" Not Applicable 20 Unavailable 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX Domestic Higher Education 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Non-SBIR/STTR 2023 267569 180557 87012 PROJECT 1 BIOLOGY OF DNA DEAMINASES IN BREAST CANCERABSTRACTEstrogen receptor (ER)-positive breast cancer is the most common form of breast cancer accounting for over 75% of invasive breast cancers diagnosed each year. The overall mutation landscape in ER-positive breast cancer is multifactorial but the DNA deaminase APOBEC3B (A3B) accounts for nearly 20% of base-substitution mutations in primary disease and over 50% in metastases. A3B is not expressed in normalmammary epithelial cells and becomes overexpressed in the majority of breast cancers. A3B overexpression correlates with poor clinical outcomes for ER-positive breast cancer including recurrence metastasis and drug resistance. Our Program is testing the overarching hypothesis that A3B inhibition as an adjuvant to primary treatment options will help to prevent detrimental mutation-driven outcomes such as drug resistance and metastasis. Project 1 will contribute directly to collaborative Program efforts to test this hypothesis through 3 specific aims. In Aim 1 we propose to develop reporter systems for quantifying A3B-mediated editing inliving cells including an innovative transportable reporter. In one potential application this system will enable rapid testing of candidate small molecule A3B inhibitors in a panel of breast cancer cell lines as candidate compounds are developed through the concerted activities of all Program components. In Aim 2 we will delineate mechanisms of protein-level A3B regulation in normal and breast cancer cells. These studies will focus on proteinprotein interactions prioritized by proteomics data sets. Comprehensive characterization of direct interactions is also anticipated to reveal potentially druggable surfaces for collaborative studies on chemical probes (Project 2) computational modeling (Core C) and structural biology (Project 3). In Aim 3 wewill address how A3B-catalyzed genomic uracil lesions are processed into error-free and mutagenic outcomes by different DNA repair pathways. These studies have the potential to reveal molecular dependencies in DNA repair that are specific to breast tumor cells undergoing elevated levels of DNA damage catalyzed by A3B. Thus Project 1 is an integral component of this overall Program because it will provide innovative assays for quantifying A3B activity in living breast cancer cells yield molecular insights into regulatory and potentially druggable protein surfaces and uncover genetic dependencies that may constitute new opportunities for diagnostic and therapeutic development. +No NIH Category available Address;Aging;Antibodies;Binding;Biological Assay;Biological Models;Biology;Biophysics;Breast Cancer Cell;Cell physiology;Cells;Chemicals;Chromosomal Rearrangement;Clinical;Complex;Cytosine;Cytosine deaminase;DNA;DNA Double Strand Break;DNA Repair Enzymes;DNA Transposable Elements;Data;Deamination;Defect;Development;Diagnosis;Disease;Disease Progression;Disease Resistance;Drug resistance;Enzymes;Estrogen receptor positive;Family;Foundations;Genomics;Goals;Inherited;Knowledge;Lead;Leadership;Lesion;Malignant Neoplasms;Mammary Neoplasms;Metastatic breast cancer;Mission;Molecular;Monoclonal Antibodies;Mutagenesis;Mutation;Neoplasm Metastasis;Nucleic Acids;Nucleotides;Oncoproteins;Outcome;PIK3CA gene;Patients;Persons;Primary Lesion;Primary Neoplasm;Process;Proteins;Publishing;Reagent;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Regulation;Reporter;Reporting;Research;Research Project Grants;Residual state;Resistance;Scientific Advances and Accomplishments;Services;Single-Stranded DNA;Site;Source;System;Techniques;Testing;The Cancer Genome Atlas;Therapeutic;Time;Uracil;Virus Replication;Water;Woman;Work;antibody diagnostic;anticancer research;base;biophysical techniques;brca gene;cancer recurrence;clinical care;clinical translation;computational chemistry;computerized tools;diagnostic assay;experience;homologous recombination;improved;inhibitor;innovation;interdisciplinary approach;malignant breast neoplasm;member;molecular recognition;mouse model;multidisciplinary;new technology;novel;novel diagnostics;overexpression;preference;prevent;programs;repaired;small molecule;structural biology;technology development;therapy outcome;therapy resistant;tumor;tumor heterogeneity;tumor progression APOBEC MUTAGENESIS IN BREAST CANCER OVERALL APOBEC MUTAGENESIS IN BREAST CANCERNARRATIVE Mutations continue to accumulate in breast cancer cells even after the cancer is first diagnosed andtreated leading to treatment-resistant disease and metastasis. APOBEC contributes to this mutagenesis inmany cancers and thus provides an opportunity to therapeutically slow or prevent cancer recurrence andprogression after initial treatment. Our Program takes a multidisciplinary approach to better understand themechanism of APOBEC mutagenesis in breast cancer with the goal of diagnosing and improving treatmentsfor patients whose tumors are fueled by this process. NCI 10692655 8/4/23 0:00 PAR-18-290 5P01CA234228-05 5 P01 CA 234228 5 "READ-CONNOLE, ELIZABETH LEE" 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L(M1) 8004071 "HARRIS, REUBEN S" "YEE, DOUGLAS " 20 BIOCHEMISTRY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 1683415 NCI 1550646 132769 OVERALL APOBEC MUTAGENESIS IN BREAST CANCERABSTRACT APOBEC signature mutations make up 20% of base-substitution mutations in primary tumors whichincreases to over 50% in metastases. Additional enrichment is often observed in estrogen receptor (ER)-positive disease. APOBEC-catalyzed C-to-U lesions in single-stranded (ss)DNA lead to signature C-to-T andC-to-G mutations within 5-TCA and 5-TCT trinucleotide motifs. In addition APOBEC-derived C-to-U lesionscan be (mis)processed by cellular DNA repair enzymes resulting in single- and double-stranded DNA breaksand more complex chromosomal rearrangements. APOBEC expression levels and mutagenesis correspondwith poor clinical outcomes such as shorter disease-free and overall survival in women with operable ER-positive breast cancer. Elevated APOBEC levels also predict poor overall survival for patients diagnosed withrecurrent ER-positive metastases. These and other published data demonstrate that APOBEC mutagenesis isongoing in breast tumor cells and underpin our overarching Program hypothesis that inhibiting APOBEC willprevent a large proportion of additional mutations from happening in residual ER-positive disease and willthereby improve the durability of current treatments and result in better overall therapeutic outcomes. Threemultidisciplinary Projects will work together in an integrated and comprehensive manner to test this idea.Project 1 will develop reporter systems for quantifying APOBEC activity in living cells and determine themolecular mechanisms responsible for APOBEC regulation and for genomic uracil processing in breast cancercells. Project 2 will use chemical biology approaches to investigate the mechanism of APOBEC-catalyzedssDNA deamination and will develop nucleic acid and small molecule probes to inhibit APOBEC activity.Project 3 will leverage structural and biophysical approaches to investigate global mechanisms for APOBECbinding to ssDNA as well as the local structural features important for target sequence preferences andinhibition of APOBEC enzymes in breast cancer. These Projects will be supported by service Cores foradministration murine models computational chemistry and biophysics and enzymes and antibodies. OurProgram is poised to have both immediate and long-term impact for ER-positive breast cancer: immediateimpact by producing novel technologies and a comprehensive understanding of the mechanism of APOBECmutagenesis and long-term impact on clinical translation through the development of technologies fordiagnosing APOBEC-positive disease and the creation of novel chemical matter to inhibit this mutationalprocess for therapeutic benefit. 1683415 +No NIH Category available Biological Models;Cancer Biology;Cell Adhesion Molecules;Cell Communication;Cell Separation;Cell Surface Proteins;Cell surface;Cells;Central Nervous System;Central Nervous System Leukemia;Chimeric Proteins;Coculture Techniques;Communication;Complex;Development;Developmental Biology;Diffusion;Engineering;Enzymes;Flow Cytometry;Glycine;Homing;Immune;Immune system;In Vitro;Injections;Integral Membrane Protein;Knock-in;Label;Leukemic Cell;Literature;Malignant Neoplasms;Measures;Methods;Microscopy;Mus;N-terminal;Neighborhoods;Neoplasm Metastasis;Pattern;Peptides;Peptidyltransferase;Proteins;Public Health;Radial;Reaction;Reagent;Resistance;Scheme;Signal Transduction;System;T-Lymphocyte;Technology;Testing;Time;Transgenic Mice;Transgenic Organisms;Transplantation;Wild Type Mouse;Work;cancer cell;cancer therapy;design;extracellular;fluorophore;in vivo;intercellular communication;interest;leukemia;migration;mouse model;new technology;novel;novel strategies;permissiveness;single cell analysis;single-cell RNA sequencing;sortase;stem cell biology;technology development;uptake Development of a Novel Method for the Identification and Characterization of Intercellular Communication in the Cancer Niche PUBLIC HEALTH STATEMENTThe complexity of intercellular communication combined with limitations to current technologies has resulted inan incomplete understanding of cell-cell interactions within the cancer niche despite its critical importance incancer biology and therapy. In this proposal we will address this shortcoming and develop a novel technologyfor comprehensively identifying and characterizing direct and indirect intercellular interactions in vivo. NCI 10692650 8/1/23 0:00 PAR-20-052 5R03CA269701-02 5 R03 CA 269701 2 "LI, JERRY" 9/1/22 0:00 8/31/24 0:00 ZCA1-SRB-K(J2)R 2091259 "GORDON, PETER M" Not Applicable 5 PEDIATRICS 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 77500 NCI 50000 27500 ABSTRACTIntercellular interactions and communication between cancer cells the cells that comprise their niches arecritical for many aspects of cancer development progression metastasis and therapy resistance. Theseinteractions are often dynamic transient and complex. Moreover intercellular communication occurs directlyby contact dependent cell-cell interactions and indirectly by the secretion of soluble factors into the localmicroenvironment. Current limitations to proximity dependent labeling strategies designed to identify andcharacterize direct and indirect cellular interaction partners in vivo include reagents that are toxic and/or limitthe isolation and subsequent characterization of interacting cells non-specific or large radius labeling (i.e.direct vs. indirect contacts) or a requirement to pre-engineer both interacting cells which obviates thepossibility of identifying novel cellular interaction partners. Thus a more ideal in vivo proximity dependentlabeling system would concurrently but differentially label both direct and indirect cellular contacts at multipletimepoints using technology that is compatible with an array of downstream analyses ranging from microscopyto single cell analyses. In this proposal we will address this shortcoming in current technologies forcomprehensively identifying and characterizing direct and indirect intercellular interactions in vivo. We will buildupon the literature and our preliminary work to develop a novel approach in which an engineered cancer cellor other cell of interest concurrently differentially and temporally fluorescently labels both direct and indirectcellular contacts within the cancer niche (Aims 1 and 2). Importantly labeled cells will be suitable for an arrayof downstream analyses such as microscopy flow cytometry and cell sorting followed by bulk or single cellanalyses. Accordingly as proof-of-concept we will then combine this niche labeling technology with single-cellRNA-seq to begin to define cellular contacts during early stages of central nervous system leukemiametastasis and niche development (Aim 3). 77500 +No NIH Category available Affinity Chromatography;Area;Asparagine;Bar Codes;Biological;Biological Assay;Biological Models;Biology;Brain;Cancer Biology;Cancer Patient;Carbohydrates;Cardiovascular system;Cell Adhesion;Cell Adhesion Molecules;Cell surface;Cells;Cessation of life;Clinical;Complex;Coupling;Disseminated Malignant Neoplasm;Distal;Distant;Enzymes;Epitopes;Extravasation;Fluorescence;Fucosyltransferase;Genetic Transcription;Glycoproteins;Glycoside Hydrolases;Homing;Immune;Immune Evasion;In Vitro;Invaded;Investigation;Knowledge;Laboratories;Lectin;Libraries;Link;Liver;Lung;Lymphatic System;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Melanoma Cell;Metastatic Melanoma;Metastatic malignant neoplasm to brain;MicroRNAs;Movement;Mutate;Neoplasm Metastasis;Neural Cell Adhesion Molecule L1;Non-Small-Cell Lung Carcinoma;Organ;Pathway interactions;Patients;Pattern;Polysaccharides;Primary Neoplasm;Process;Prognosis;Proliferating;Property;Protein Glycosylation;Proteins;Regulation;Research;Role;Sampling;Secondary to;Series;Serine;Shotguns;Signal Pathway;Site;Skin;Specificity;Structure;Systems Biology;Therapeutic;Threonine;Tissue Sample;Tissues;Tropism;Validation;Work;Xenograft Model;angiogenesis;bone;cancer cell;cancer type;candidate identification;candidate validation;capillary bed;carcinogenesis;cell motility;clinically relevant;data mining;differential expression;glycoproteomics;glycosylation;glycosyltransferase;high throughput screening;in vitro Assay;in vitro Model;in vivo;in vivo Model;innovation;insight;liquid chromatography mass spectrometry;lymph nodes;malignant phenotype;melanocyte;melanoma;metastatic process;mortality;neoplastic cell;novel therapeutics;posttranscriptional;programs;screening;small hairpin RNA;treatment site;tumor;tumor progression Glycosylation as a Regulator of Tropism of Melanoma Metastasis - Resubmission - 1 Project NarrativeThis project aims to identify glycan determinants and glycogenes involved in organ tropism of melanoma byglycan profiling of melanoma cells that have metastasized to various organs. We anticipate that identificationand validation of candidate glycogenes in vitro functional assays identification of key target glycoproteins andtheir mechanism of action will contribute to elucidate the basis for site-specificity of melanoma metastasis. NCI 10692647 8/16/23 0:00 PAR-18-467 5K22CA229600-03 5 K22 CA 229600 3 "JAKOWLEW, SONIA B" 9/1/21 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI(B)-I] 15069482 "AGRAWAL, PRAVEEN " Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 194400 NCI 180000 14400 Glycosylation as a regulator of tropism of melanoma metastasis Malignant melanoma is a type of cancer arising from melanocytes the pigmented cells of the skin.Metastases of tumors to secondary sites are the cause of 90% of cancer mortality. A salient feature ofmetastasis is the ability of a primary tumor to colonize secondary organs. This has prompted a quest to identifythe factors and mechanisms that support melanoma metastasis to specific organs as secondary sites (e.g.brain lung liver). One of the most devastating complications of melanoma is that around 50% of patients withmetastatic melanoma develop brain metastasis after which most patients survive less than 6 months. Patientswith brain metastasis don't benefit from new therapies and have extremely poor prognosis. Understanding thebasis to brain and other organs adaptation may reveal new therapies. Carbohydrates which are altered intumors are involved in immune evasion homing of cells to tissues survival and anchorage. Our recentclinically relevant study identified distinct glycosylation patterns of primary and metastatic melanoma.Moreover our preliminary studies of patient samples suggest that specific glycosylation patterns are a site-specific feature of metastasis. I hypothesize that adaptation of tumor cells to different secondary sites requires specific changes in cellsurface glycosylation. My proposed work will use innovative approaches to identify therapeutically relevantglycan structures and glycosylation enzymes as targets for anti-metastatic therapies. I will identify candidateglycans and glycogenes to regulate site-specific metastasis through glycan profiling of relevant in vivo modelsand high-throughput screens with a barcoded pooled shRNA library of glycogenes. Candidate glycans andglycogenes will be validated by lectin fluorescence and IHC analysis of melanoma patient FFPE samples. Wewill further validate candidate glycogenes using in vivo xenograft models and dissect their mechanism of actionthrough various in vitro assays. Further we will use a glycoproteomic strategy coupling lectin-affinitypurification with LC/MS shotgun protein identification to identify glycosylated proteins with a specific glycanmotif. Finally site-specific metastasis related glycoproteins would be investigated for their mechanism ofaction. The identification of glycans and glycosylation enzymes actively participating in melanoma tropism aswell as a precise understanding of their mechanism of action has the potential to provide a trove of glycanepitopes and enzymes that are unexplored as anti-tumor targets for the treatment of site-specific metastases. 194400 +No NIH Category available Address;Africa South of the Sahara;African;African American;African American population;Awareness;Behavior Therapy;Belief;Black Populations;Cancer Control;Cancer Etiology;Central Asia;Cervical;Cervical Cancer Screening;Cessation of life;Clinic Visits;Clinical Trials Design;Collection;Consent;Cross-Sectional Studies;Data;Death Rate;Developing Countries;Development;Development Plans;Diagnosis;Disparate;Disparity;Education;Emotional;Environment;Evidence based intervention;Extramural Activities;Frequencies;Fright;Funding;Future;Geographic Locations;Goals;Gynecologic;Health;Health Promotion;Health behavior;Health education;Healthcare Systems;Human Papillomavirus;Human papilloma virus infection;Immigrant;Incidence;Individual;Intervention;Intervention Studies;Irrigation;K-Series Research Career Programs;Kentucky;Knowledge;Lesion;Literature;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentored Research Scientist Development Award;Mentors;Methods;Minority;Minority Women;Modality;Modeling;Not Hispanic or Latino;Outcome Measure;Pattern;Physicians;Population;Population Heterogeneity;Population Study;Preventative vaccination;Prevention;Privatization;Quality of Care;Quasi-experiment;Research;Research Personnel;Resources;Role;Sampling;Screening for cancer;Screening procedure;Self Efficacy;Sensitivity and Specificity;South America;Structure;Subgroup;Swab;Testing;Training;Treatment Efficacy;Underserved Population;United States;Universities;Visit;Vulnerable Populations;Woman;access disparities;aged;anticancer research;behavior change;behavior influence;black men;black subgroup;black women;cancer health disparity;cancer prevention;career;career development;cervical cancer prevention;cost;detection method;ethnic disparity;evidence base;experience;health belief;health care availability;health knowledge;high risk;high risk population;innovation;intervention effect;mortality;peer;pilot test;poor health outcome;prevent;programs;racial disparity;racial population;randomized clinical trials;recruit;research study;satisfaction;screening;screening participation;skills;social;social cognitive theory;underserved minority;willingness Promoting Cervical Cancer Screening among African American and Sub-Saharan African Immigrant women PROJECT NARRATIVEDespite the availability of screening tools that can prevent cervical cancer Black women are burdened by highcervical cancer incidence and mortality. This project seeks to enhance cervical cancer screening among Blackwomen African Americans and sub-Saharan African immigrants by tailoring and pilot testing an evidence-basedintervention incorporating HPV self-sampling and peer-delivered education to promote cervical cancerscreening. NCI 10692624 8/21/23 0:00 PAR-18-365 5K01CA251487-04 5 K01 CA 251487 4 "VAHEDI, SHAHROOZ" 9/2/20 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 14387971 "ADEGBOYEGA, ADEBOLA O" Not Applicable 6 OTHER HEALTH PROFESSIONS 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF NURSING 405260001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 153428 NCI 142063 11365 PROJECT SUMMARY/ABSTRACTThe highest incidence rates of cervical cancer (CC) are in sub-Saharan Africa South Central Asia and SouthAmerica. In the United States (U.S.) CC ranks 14th in frequency. However in certain populations and geographicareas of the U.S. CC incidence and death rates are significantly higher due in part to racial and ethnic disparitiesin access utilization and quality of care all of which contribute to worse health outcomes. Black womenexperience a disparate burden of CC incidence and mortality having a higher risk of being diagnosed with anddying from CC than non-Hispanic White women. Appropriate and timely CC screening is a key factor inprevention. Leveraging the positive benefits of CC screening may reduce the CC disparate burden amongBlacks. Research studies typically treat Blacks as a homogeneous group despite differences within thispopulation. To begin to address a gap in the literature within the scope of a career development award thisstudy focuses specifically on two subgroups of Black women - African Americans (AA) and Sub-Saharan Africanimmigrants (SAI) given that there is paucity of research with SAI despite known cancer related disparities amongSAI women. To promote screening for these underserved minority women we will conduct research to betterunderstand factors that influence engagement in cancer screening practices and willingness to conduct HPVself-sampling in which women self-collect samples for HPV testing using a swab brush or lavage. Guided by thefindings we will develop and pilot test an innovative tailored intervention incorporating HPV self-sampling withpeer-delivered education. The specific aims are to (1) examine general awareness and cultural factors relatedto cancer control and prevention among AA and SAIs; (2) examine the socioecological barriers and facilitators toCC screening with HPV self-sampling to tailor an evidenced based cervical health promotion program in theseunderserved subgroups; and (3) assess feasibility acceptability and preliminary efficacy of the intervention. Theintervention entitled Health is Wealth: A Cervical Health Program will be pilot tested with 30 AA and 30 SAIwomen aged 30 to 65 years using a quasi-experimental design. These aims will also support the candidatescareer goal of developing an independent and extramurally funded program of research to promote cancercontrol and prevention for minority women. To further support this goal a mentored career development planconsisting of training in mixed methods adaptation and development of behavioral interventions randomizedclinical trial design and research team management is proposed. The rich research environment at theUniversity of Kentucky and the expertise of the mentoring team will provide the supplemental resources andsupport needed for the candidate to successfully complete the proposed research and training plans. As suchthis K01 award will provide the training mentoring and research experiences needed for the candidate tosuccessfully compete for a R01-level CC screening intervention study and expedite her career development. 153428 +No NIH Category available Adaptive Immune System;Biological Models;Biology;CRISPR library;CRISPR screen;CRISPR/Cas technology;Cancer Model;Cancer Patient;Caring;Cause of Death;Cells;Critical Pathways;Custom;Data;Dependence;Detection;Disease;Disseminated Malignant Neoplasm;Distal;Dropout;Experimental Models;Fellowship;Follow-Up Studies;Foundations;Genes;Genetic;Genetic Screening;Genetic Techniques;Goals;Growth;Heme;Immune;Immune Evasion;Immune system;Immunocompetent;Immunocompromised Host;Immunologic Surveillance;Immunology;In Vitro;Incidence;KRAS2 gene;Laboratories;Lead;Link;Liver;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Masks;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Modeling;Neoplasm Circulating Cells;Neoplasm Metastasis;Nutrient;Oncogenes;Organ;Oxygen;Pancreatic Ductal Adenocarcinoma;Pathway Analysis;Pathway interactions;Patients;Phase;Physiological;Population Heterogeneity;Postdoctoral Fellow;Primary Neoplasm;Prognosis;Refractory;Research;Research Personnel;Research Project Grants;Role;Series;Site;Splenectomy;Techniques;Therapeutic;Therapeutic Intervention;Training;Tumor Burden;Validation;Work;adaptive immune response;anticancer research;cancer cell;cancer therapy;candidate identification;career;design;experimental study;hands-on learning;heme biosynthesis;in vitro Model;in vivo;insight;metabolic abnormality assessment;mortality;mouse model;neoplastic cell;novel therapeutics;pancreatic cancer model;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pre-doctoral;skills;therapeutic target;therapy resistant;tissue culture;transplant model;tumor;tumor growth;tumor metabolism;tumor microenvironment Identifying Metabolic Vulnerabilities in Pancreatic Cancer Project NarrativePancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with unique metabolic rewiring making it highlyrefractory to the current standards of care. We have shown that these tumors become reliant on particularmetabolic pathways creating metabolic bottlenecks. In this proposal we will comprehensively define themetabolic dependencies of PDA tumors in vivo and assess the therapeutic potential of these pathways in mousemodels of cancer. NCI 10692576 8/9/23 0:00 RFA-CA-19-002 5K00CA245822-06 5 K00 CA 245822 6 "DAMICO, MARK W" 9/1/21 0:00 8/31/25 0:00 ZCA1-RTRB-R(A1) 15665250 "BIANCUR, DOUGLAS " Not Applicable 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 100486 NCI 93043 7443 Project Summary/Abstract Despite recent advances in cancer treatment pancreatic cancer (PDA) remains a devastating diseasewith increasing incidence. PDA is highly refractory to the current standards of care which is due in part to arewired metabolism that supports growth in an austere tumor microenvironment. Therefore elucidating themetabolic pathways critical for tumor growth is imperative to understanding the complexities of PDA biology aswell as identifying novel therapeutic opportunities. There is emerging evidence however that in vitro metabolismmay not be entirely reflective of the metabolic requirements of a tumor. Due to the difficulties of studyingmetabolism in vivo with conventional techniques a functional genetic CRISPR screening approach wasemployed to determine the metabolic liabilities of PDA tumors and comprehensively define critical metabolicpathways for primary tumor growth and metastasis. In the F99 phase of the proposal I analyzed CRISPR screening data to create a map of PDA metabolicdependencies in vivo. I will now use this map of PDA metabolic dependencies to determine critical pathways tosupport tumor growth and evaluate these pathways as potential therapeutic targets in orthotopic mouse modelsof pancreatic cancer. I will also determine the mechanism by which a metabolic pathway that supports growthin vivo is not required in vitro. Preliminary analysis of the CRISPR screen suggest that heme biosynthesis isrequired in vivo but is not essential to growth of PDA cells in vitro. I have designed a series of experiments todetermine how heme biosynthesis supports growth in tumors and how this dependency is masked by in vitroculture conditions. In the K00 phase of this proposal I will shift focus from the metabolism primary tumor to metastasis andthe immune system. PDA is highly metastatic and metastasis is the primary cause of mortality for most cancerpatients. Understanding the differences between the metabolism of primary and metastatic cancer will offerinsight into how to treat metastasized tumors and how to target cancer cell metabolism to increase immunesurveillance of circulating tumor cells. The proposed work will be the first comprehensive analysis of pathways that support PDA growth in vivoand will help identify candidates for therapeutic intervention. These experiments will also determine themetabolic differences between primary and metastatic tumors and how cancer cell metabolism interacts with thehosts immune system. These data will inform what metabolic pathways lead to immune evasion and if targetingthese pathways therapeutically will lead to a reduced primary tumor growth and metastatic tumor burden. 100486 +No NIH Category available American Cancer Society;Antibodies;Apoptotic;Aryl Hydrocarbon Receptor;Bone Marrow;Bone Marrow Neoplasms;CD28 gene;CD80 gene;CD86 gene;CTLA4-Ig;Cell Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Chemoresistance;Data;Dendritic Cells;Development;Diagnosis;Disease Progression;Disease Resistance;Down-Regulation;Drug resistance;Enzymes;Eragrostis;Funding;Goals;Hematologic Neoplasms;IRF4 gene;Interleukin-6;Kynurenine;Ligands;Malignant - descriptor;Mediating;Mediator;Metabolic;Molecular;Multiple Myeloma;NF-kappa B;Neoplasms;Non-Hodgkin's Lymphoma;PIK3CG gene;PRDM1 gene;Pathway interactions;Patients;Phase II Clinical Trials;Plasma Cells;Play;Production;Prognosis;Proliferating;Proto-Oncogene Proteins c-akt;Receptor Activation;Recurrent disease;Refractory;Refractory Disease;Regulation;Relapse;Resistance;Role;Second Primary Neoplasms;Signal Pathway;Signal Transduction Pathway;Stress;Structure of germinal center of lymph node;T-Cell Activation;T-Lymphocyte;Therapeutic;Translating;Treatment Failure;Tryptophan;Tryptophan 23 Dioxygenase;Up-Regulation;Work;aryl hydrocarbon receptor ligand;chemotherapeutic agent;chemotherapy;clinical efficacy;curative treatments;cytokine;in vivo Model;metabolic fitness;novel;novel therapeutic intervention;overexpression;phase 2 study;pre-clinical;prototype;receptor;transcription factor CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival The primary cause of disease relapse and patient death in multiple myeloma is the development ofchemotherapy resistant disease. We have found that a key mediator of this resistance is activation of the CD28receptor in myeloma cells. The overall goal of this proposal is to define the molecular mechanisms involved in CD28-augmented myeloma resistance and survival and develop novel therapeutic strategies to target them. NCI 10692569 9/7/23 0:00 PA-18-484 5R01CA121044-17 5 R01 CA 121044 17 "HOWCROFT, THOMAS K" 9/12/07 0:00 8/31/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6895846 "LEE, KELVIN P." Not Applicable 7 INTERNAL MEDICINE/MEDICINE 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 335089 NCI 225000 110089 Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident long-lived plasma cells (LLPC) thatcomprises 20% of all hematologic malignancies - second only to non-Hodgkins lymphoma. Despite newchemotherapeutic agents MM remains incurable. Although initially sensitive to chemotherapy the primarycause of treatment failure is the development of progressively more chemo-refractory disease whoseresistance is due to upregulation of pro-survival mechanisms. Thus defining the specific mechanisms ofmyeloma cell survival/drug resistance is essential for the development of curative treatment approaches inMM. It is now clear that myeloma cells are critically dependent on interactions with BM microenvironment (ME)for their survival just like their normal LLPC counterparts and these interactions play a major role in MMresistance to chemotherapy. Despite their central importance in myeloma survival however the specificmolecular and cellular components involved in these interactions remain poorly characterized. In our originalproposal we hypothesized that CD28 was playing significant pro-survival role in myeloma. Although it hasbeen primarily characterized as the prototype T cell costimulatory receptor involved in T cell activation andsurvival CD28 is also expressed on normal PC and MM. Work accomplished during the last funding cycle hasdemonstrated that CD28 activation through two downstream signaling pathways plays an essential role in thesurvival of both normal LLPC and MM cells and that therapeutically blocking CD28 activation leads to MM celldeath/resensitization to chemotherapy in preclinical in vivo models. Based on these findings and initialevidence for clinical efficacy we have just opened a phase II clinical trial of blocking CD28 activation inrefractory/relapsed MM (NCT02334865) More recently we have found that CD28 activation substantiallyenhances the metabolic fitness of MM cells which plays a major role in its pro-survival effect. In addition todirectly supporting MM survival we have found that MM CD28 also modulates the MM ME. CD28 engagementof its ligands CD80 and CD86 on stromal dendritic cells (DC) initiates CD80/CD86 backsignaling that inducesDC production of the pro-MM survival cytokine IL-6 and the immunosuppressive tryptophan (Trp)-catabolizingenzyme indoleamine 2 3 dioxygenase (IDO). We have also shown that CD86 expressed on MM cells hasindependent pro-survival function. More recently we have determined that kynurenine (Kyn produced by IDOdegradation of Trp) is an endogenous ligand for the aryl-hydrocarbon receptor (AhR) and AhR activation has asignificant but previously unrecognized pro-survival role in MM. The Specific Aims of this proposal are: 1).Characterize the effect of blocking CD28 activation on myeloma chemoresistance in a Phase 2 clinical trial inMM patients 2). Define how CD28 activation enhances the metabolic fitness of myeloma cells and 3).Determine the role of MM CD28-mediated modulation of DC in the BM ME in supporting MM survival. 335089 +No NIH Category available 4T1;Admixture;Africa;African;African Caribbean;African ancestry;Alcohols;Beds;Behavior;Biological;Breast Adenocarcinoma;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Feeding;Cell Line;Cell Nucleus;Cells;Collaborations;Country;Cytoplasm;Data;Engineering;Environmental Exposure;Epidemiologist;Ethnic Origin;Ethnic Population;European ancestry;Evolution;Frequencies;Gene Expression;Gene Expression Profile;Genes;Genetic;Genome;Genomics;Goals;Growth;Height;Herbert Irving Comprehensive Cancer Center;Heterogeneity;High Prevalence;Immune;Immune Evasion;Immune response;Immunofluorescence Immunologic;Immunohistochemistry;Inbred BALB C Mice;Institutional Racism;Invaded;Kenya;Life Style;Link;Malignant Neoplasms;Modeling;Molecular;Mus;Mutation;Neoadjuvant Therapy;Neoplasm Metastasis;New York;Nigeria;North Carolina;Nuclear;Outcome;Pathologist;Patients;Pattern;Population;Prediction of Response to Therapy;Predictive Value;Process;Property;Race;Reproductive History;Research Personnel;Role;Shapes;Somatic Mutation;The Cancer Genome Atlas;Tissue Microarray;Tissues;Tobacco;Tumor Biology;Tumor-Derived;United States;Universities;University Hospitals;Variant;Washington;Woman;Xenograft Model;access disparities;aggressive breast cancer;breast cancer survival;cancer biomarkers;cancer health disparity;cancer subtypes;cellular engineering;cohort;efficacy testing;exhaust;exome sequencing;extracellular vesicles;genetic signature;health care availability;high risk;improved;malignant breast neoplasm;multidisciplinary;multiple omics;non-genetic;outcome disparities;overexpression;pathogen exposure;patient stratification;pharmacologic;population genetic structure;predictive marker;prognostic model;prognostic value;protein biomarkers;racial diversity;racial population;response;socioeconomic disadvantage;survival prediction;therapy resistant;transcriptome sequencing;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions The Role of Kaiso as a predictive breast cancer biomarker in Africa and across the African Diaspora In a racially diverse breast cancer cohort from the South Eastern United States thelevels of the breast cancer biomarker Kaiso in the cytoplasm and the nucleus of breastcancer cells are each independent predictors of breast cancer survival based on race.Surprisingly the cytoplasmic Kaiso levels were also predictive of an immune exhaustedor immune-suppressed tumor microenvironment. In this study we propose to validatethese observations using 2 different breast cancer cohorts from Africa and across theAfrican diaspora; show how these predictive linkages are influenced by patient featuresgenetic ancestry and exposures tumor gene expression tumor patterns of somaticmutation and tumor mutational signature; and elucidate the mechanisms linking Kaisowith the breast cancer tumor microenvironment. NCI 10692567 8/17/23 0:00 PAR-18-654 5R01CA266040-02 5 R01 CA 266040 2 "NADEAU, CHRISTINE FRANCES" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-OBT-Y(55)R] 1926891 "GARDNER, KEVIN L." Not Applicable 13 PATHOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 702030 NCI 570171 131859 Around the world women of African ancestry and throughout the African Diaspora continue to perish from breastcancer at significantly higher rates than any other racial/ethnic group. Although much of these disparateoutcomes have been attributed to inequities in access to healthcare socioeconomic disadvantage and othercrippling exposures linked to institutional racism most studies also indicate a prominent role in tumor biology.Causal factors include i) higher frequencies of aggressive breast cancer subtypes associated with geneticancestry; ii) more aggressive biological behavior of low-risk breast cancers based-on race/ethnicity and ancestryand iii) decreased predictive value of prognostic gene signatures when applied to women of African heritage.Recently we have shown the subcellular localization of the breast cancer biomarker Kaiso (ZBTB33) in both thenucleus and cytoplasm of breast cancer cells were each more associated with biologically aggressive cancersand independent predictors of poor breast cancer survival and response to neoadjuvant therapy revealing thatcytoplasmic Kaiso was highly correlated with an immune-evasive or immune-suppressed tumormicroenvironment. Mechanistically cytoplasmic Kaiso was shown to be very highly correlated with the machineryinvolved in extracellular vesicle (EV) loading and secretion a process known to have a dramatic influence onthe micro-environment of the tumor bed and metastatic niche. In this study we will validate and extend theseobservations of the subcellular localization of Kaiso as an independent predictive biomarker of breast cancersurvival and the tumor micro-environment using two diverse breast cancer cohorts from Africa and across theAfrican diaspora. One from the Columbia University Herbert Irving Comprehensive Cancer Center (N=487) andthe other from the Aga Khan University Hospital Nairobi Kenya (N=237) (Specific Aim 1). Using a multi-omicapproach that will integrate the analysis of tissue microarrays (TMAs) quantitative multipleximmunofluorescence (qMIF) gene expression (RNA-seq) tumor mutational signatures and frequency (whole-exome sequencing) deep annotation of patient clinicopathological features environmental exposures andgenetic ancestry we will define prognostic models that will demonstrate the role of Kaiso in predicting breastcancer survival response to therapy and the role of genetic ancestry in breast cancer evolution and outcome(Specific Aim 1). We will also define how Kaiso modulates the influence of EV secretion on breast cancer growthinvasion metastasis and immune evasion in murine xenograft models using cells engineered for depleted orenhanced Kaiso expression (Specific Aim 2). These goals will be accomplished through a transatlanticcollaboration of a highly-specialized multi-disciplinary team of breast cancer pathologists tumor biologistsmolecular biologists biostatisticians bioinformaticians epidemiologists genome researchers and cancer healthdisparities investigators. 702030 +No NIH Category available Acetates;Address;Adult;Affect;American;American diet;Bacteroides;Base Sequence;Bifidobacterium;Bile Acids;Biological Markers;Black Populations;Body Weight decreased;Butyrates;Cardiac health;Cardiovascular Diseases;Categories;Chronic Disease;Clinical;Clostridium;Colorectal Cancer;Consumption;DASH diet;DNA Damage;Dairying;Data;Deoxycholic Acid;Diet;Diet Modification;Dietary Fiber;Dietary Intervention;Dietary Practices;Disparity;Environment;Fatty Acids;Fatty acid glycerol esters;Female;Fiber;Fruit;Fusobacterium;Goals;Health;Health Benefit;Health Promotion;Health Status;Incidence;Individual;Inflammation;Interleukin-6;Intervention;Knowledge;Lactobacillus;Lead;Leukocyte L1 Antigen Complex;Link;Literature;Lithocholic Acid;Metabolic;Metagenomics;Microbe;Modification;Not Hispanic or Latino;Obesity;Participant;Pathogenicity;Persons;Physicians;Physiological;Population;Population Heterogeneity;Porphyromonas;Prevention Research;Prevention approach;Preventive;Production;Propionates;Public Health;Race;Randomized;Recommendation;Research;Ribosomal RNA;Risk Factors;Risk Reduction;Ruminococcus;Sampling;Scientist;Structure;Taxonomy;Testing;Therapeutic;Time;United States;Vegetables;Volatile Fatty Acids;Work;arm;beta diversity;biobehavior;blood pressure reduction;cancer risk;colorectal cancer risk;colorectal cancer treatment;dietary;disorder risk;dysbiosis;efficacy testing;experimental study;feeding;gut bacteria;gut inflammation;gut microbiota;health disparity;improved;inflammatory marker;innovation;liver inflammation;male;microbial;microbiome;mortality;nutrition;outcome disparities;poor health outcome;public health relevance;rRNA Genes;racial difference;racial disparity;racial diversity;racial population;recruit;sex;systemic inflammatory response Determining the structural- and functional-level effects of diet-specific interventions on the gut microbiota of a diverse sample of Southern United States adults Public Health Relevance: Racial disparities persist between blacks and whites for colorectal cancer. Recentevidence suggests that the interaction of the gut microbiota and diet may contribute to disease risk. This studywill investigate how the Dietary Approaches to Stop Hypertension (DASH) diet affects the gut microbiota acrossracial groups which has the potential provide preliminary evidence for the DASH diet as a viable means forimproving the gut microbial environment thereby lowering CRC risk across racially diverse populations. NCI 10692552 5/16/23 0:00 PAR-18-869 5R01CA253219-04 5 R01 CA 253219 4 "KIM, YOUNG S" 6/1/21 0:00 5/31/26 0:00 Cancer Prevention Study Section[CPSS] 9563452 "CARSON, TIFFANY LASHAUN" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 366873 NCI 228822 138051 Racial disparities in colorectal cancer (CRC) incidence persist for blacks and whites. Given the previouswork of our team documenting racial differences in the gut microbiota of blacks and whites and the evidencesupporting the interaction between diet and the gut microbiota as a risk factor for colorectal cancer the study ofhow various diets affect the structure and function of the gut microbiota across racial groups is warranted.Previous research has shown that the gut microbiota can be rapidly altered by changes in diet. For exampleconsumption of an extremely high fiber (>50 grams) diet has produced changes in the gut microbiota that arebelieved to reduce cancer risk. The Dietary Approaches to Stop Hypertension (DASH) diet rich in fruitsvegetables whole grains and low-fat dairy is commonly recommended for heart health and has been shown tolower blood pressure and produce weight loss. However to our knowledge the effect of the DASH diet on thegut microbiota has not been studied. Because the DASH diet provides substantial fiber we hypothesize thatconsumption of the DASH diet will lead to improvements in the gut microbiota of non-Hispanic black and whiteadults. In this proposal we plan to investigate our hypothesis by recruiting a generally healthy sample of 112black and white adults from Birmingham AL to participate in a 28-day randomized controlled feeding study.Participants will be randomized to receive either the DASH diet or a standard American diet. All meals will beprovided by the study. Fecal samples will be collected at multiple time points before during and after the dietaryintervention and will be analyzed using PCR to amplify the V4 region of the 16S rRNA gene and to sequencebases using the MiSeq platform. Sequenced data will then be analyzed using QIIME. We hypothesize thatparticipants receiving the DASH diet will have a greater increase in alpha diversity and greater changes inabundances of CRC-associated microbes than participants receiving the standard American diet. We will alsoevaluate functional-level markers including bile acid and short chain fatty acid (SCFA) production andinflammatory markers. If our hypothesis is supported we expect to see reduced production of secondary bileacids (e.g. deoxycholic acid) greater SCFA production (e.g butyrate) and reduction in gut and systemicinflammation (e.g calprotectin IL-6) among participants receiving the DASH diet compared to the standardAmerican diet. Our findings will provide preliminary evidence for the DASH diet as an approach for cultivatinga healthier gut microbiota across racially diverse populations. These findings can impact clinical translationaland population-level approaches for modification of the gut microbiota to reduce risk of chronic diseases likeCRC. 366873 +No NIH Category available Adjuvant;Adjuvant Chemotherapy;Algorithms;Architecture;Biological Assay;Cancer Diagnostics;Cancer Patient;Clinic;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Collaborations;Complement;Computer software;Computers;Cytotoxic Chemotherapy;Data;Diagnosis;Diagnostic tests;Disease Outcome;Early Diagnosis;Economics;Epithelial;Excision;Exhibits;FDA approved;Genomics;Guidelines;Hematoxylin and Eosin Staining Method;Histologic;Image;Image Analysis;International;Link;Lung;Malignant neoplasm of lung;Measurement;Medicare/Medicaid;Molecular;Morphology;National Comprehensive Cancer Network;Non-Small-Cell Lung Carcinoma;Nuclear;Operative Surgical Procedures;Outcome;Pathologist;Patients;Pattern;Penetration;Performance;Production;Quality-Adjusted Life Years;Randomized Clinical Trials;Reading;Recurrence;Regulatory Pathway;Reporting;Resources;Risk;Shapes;Slide;System;Technology;Testing;Texture;Tissue Stains;Tissues;Training;Tumor-Infiltrating Lymphocytes;Validation;Visual;base;chemotherapy;cohort;companion diagnostics;computerized;cost;density;diagnostic assay;diagnostic tool;disorder risk;industry partner;innovation;low and middle-income countries;lung cancer screening;malignant breast neoplasm;mortality;oncotype;precision medicine;predicting response;predictive test;prognostic;prognostic assays;prospective;prototype;side effect;success;treatment effect;treatment response;tumor;tumor heterogeneity;years of life lost CHIRP Computerized Histologic Risk Predictor (CHiRP) for Early Stage Lung Cancers RELEVANCE: Even though many early stage non-small cell lung cancer (NSCLC) patients will be treated withchemotherapy following surgical resection of the tumor the vast majority of these early stage NSCLC patientswill not receive additional benefit from this adjuvant chemotherapy thus unnecessarily suffering the deleteriouseffects of treatment. We aim to develop and validate the first predictive companion diagnostic assay -computerized histologic risk predictor (CHiRP) - to identify which early stage NSCLC patients following surgerywill receive additional benefit from adjuvant chemotherapy. NCI 10692497 1/17/23 0:00 PA-21-268 7R01CA216579-06 7 R01 CA 216579 6 "OSSANDON, MIGUEL" 1/1/18 0:00 12/31/23 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 8352708 "MADABHUSHI, ANANT " "FU, PINGFU ; LLOYD, MARK ; SCHALPER, KURT A; VELCHETI, VAMSIDHAR " 5 BIOMEDICAL ENGINEERING 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 7/15/22 0:00 12/31/22 0:00 393 Non-SBIR/STTR 2022 431216 NCI 292040 139176 SUMMARY: In 2016 a total of 224390 patients in the US were diagnosed with non-small cell lung cancer(NSCLC) and 16% of these patients (35902) were diagnosed as early stage (I and II) and eligible for adjuvantcytotoxic chemotherapy (adj chemo). However more than 50% of these patients may have low risk disease andhence may not receive added benefit from adj chemo while suffering its side-effects. From an economicstandpoint unnecessary adj chemo for early stage NSCLC results in a loss of over $35000 for each quality-adjusted life year lost. With increased lung cancer screening we can expect an increase in diagnosis of earlystage NSCLC. Two large completed randomized clinical trials of NSCLC (International Adjuvant Lung CancerTrial (IALT) and JBR10) involving surgery with and without adj chemo only found survival benefit in higher stagepatients (>=Stage III). Unfortunately there are currently no validated predictive companion diagnostic (CDx) toolsto identify (1) which stage II NSCLC are at a lower risk for disease recurrence and hence will not receiveadditional benefit from adj chemo and (2) which stage 1A 1B patients are at elevated risk and hence will benefit?Extant genomic assays have only been shown to be prognostic (i.e. they predict mortality or recurrence) in earlystage NSCLC 15 but this does not imply they are predictive (i.e. they do not predict treatment response). Recently our group validated the computerized histologic risk predictor (CHiRP) an approach that reliessolely on computer extracted morphologic measurements (e.g. cellular orientation texture shape architecture)from standard H&E tissue slide images to predict early recurrence in early stage NSCLC. CHiRP has been shownto be prognostic with an accuracy>85% in three independent clinical cohorts (N=290); higher compared to whathas been previously reported for molecular based prognostic tests. However to show that CHiRP is predictivewe need access to randomized clinical trial data involving early stage NSCLC patients treated with surgery andsurgery+ adj chemo. The only two trials that fit these criteria are IALT and JBR10. Since molecular tests aretissue destructive validation is more difficult compared to a tissue non-destructive approach like CHiRP; clinicaltrial groups are often reluctant to share tissue blocks since it is a valuable resource. For this study we haveobtained preliminary approval for use of the slide images from IALT and JBR10 to establish CHiRP as apredictive Affordable Precision Medicine (APM) solution. This Academic-Industry partnership will leverage long-standing collaborations between (1) theMadabhushi group at Case Western who bring expertise in computational histomorphometric imaging (2) theVelcheti group at the Cleveland Clinic (CCF) with clinical expertise in treatment and management of early stageNSCLC and (3) Inspirata Inc. a cancer diagnostics company which has recently licensed a number ofhistomorphometry based technologies from the Madabhushi group and who will bring quality managementsystems and production software standards to help create a pre-commercial CHiRP test. 431216 +No NIH Category available Acids;Address;Advanced Development;Advanced Malignant Neoplasm;Adverse effects;Affect;Age;Animals;Apple;Atrophic;C26 tumor;Cancer Model;Cancer Patient;Cell model;Chemicals;Chemistry;Clinical;Clinical Research;Cultured Cells;Development;Dose;FDA approved;Fruit;Goals;Health;Herb;Human;KPC model;Lead;Legal patent;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medicine;Muscle Weakness;Muscle function;Muscular Atrophy;Natural Compound;Oral;Outcome;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physical Function;Physiological;Pre-Clinical Model;Property;Quality of life;Safety;Scientific Advances and Accomplishments;Series;Skeletal Muscle;Small Business Innovation Research Grant;Structure-Activity Relationship;Syndrome;Testing;Tissues;Work;cancer cachexia;cancer complication;cancer therapy;carcinogenesis;clinical development;commercialization;design;improved;in vivo;innovation;mRNA Expression;mortality;mouse model;muscle form;novel;novel therapeutics;pancreatic cancer model;pharmacologic;prevent;programs;response;sex;skeletal muscle wasting;success;tumor;tumor growth;ursolic acid Development of novel therapeutics for cancer cachexia PROJECT NARRATIVEIn patients who suffer from cancer muscle wasting is very common and has devastating consequencesincluding reduced quality of life and overall health interference with cancer treatment increased complicationsfrom cancer treatment and reduced survival. Unfortunately right now we do not have any medicines to helpprevent or treat muscle wasting in patients suffering from cancer. To help address this issue we propose aPhase II SBIR study to investigate and develop new and promising potential medicines for cancer-inducedmuscle wasting. NCI 10692001 3/7/23 0:00 PA-22-176 1R44CA277853-01A1 1 R44 CA 277853 1 A1 "WEBER, PATRICIA A" 4/1/23 0:00 3/31/25 0:00 Special Emphasis Panel[ZRG1-MOSS-D(10)B] 11495601 "EBERT, SCOTT MATTHEW" "ADAMS, CHRISTOPHER M; JUDGE, ANDREW ROBERT; JUDGE, SARAH M; TALLEY, JOHN JEFFREY" 1 Unavailable 78498658 M8CMYGLPB5H7 78498658 M8CMYGLPB5H7 US 41.708954 -91.60643 10032051 "EMMYON, INC." Rochester MN Domestic For-Profits 55902 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 395 SBIR/STTR 2023 990411 NCI 801618 124000 PROJECT SUMMARY / ABSTRACTCancer-induced skeletal muscle atrophy is a central and defining feature of the cancer cachexia syndrome ahighly prevalent condition that affects over 50% of patients with advanced cancer and over 500000 patientsper year in the U.S. In addition to being highly prevalent cancer-induced skeletal muscle atrophy hasdevastating consequences for patients; it reduces physical function and quality of life often complicates orprecludes cancer treatment and strongly predicts early mortality from cancer. Unfortunately a pharmacologictherapy for cancer-induced muscle atrophy does not exist. Thus cancer-induced skeletal muscle atrophyrepresents a highly significant unmet medical need with broad relevance to cancer patients. A major goal ofEmmyon Inc. is to discover and develop a pharmacologic therapy for cancer-induced skeletal muscleatrophy. To that end we recently discovered a natural compound that significantly reduces cancer-inducedmuscle atrophy in five well-established and distinct in vivo mouse models of cancer. We then used that naturalcompound as a lead in medicinal chemistry program and discovered and patented a confidential andproprietary chemical derivative (EMMY1-06) that appears to be significantly more potent and more efficaciousthan the lead compound in at least two distinct mouse models of cancer-induced muscle atrophy. In thisPhase II SBIR proposal we seek to continue this exciting work by advancing the development ofEMMY1-06 and related molecules as pharmaceuticals for cancer-induced skeletal muscle atrophy.Specifically we will further investigate EMMY1-06's safety efficacy and mechanisms of action in severaldistinct and complementary mouse models of cancer-induced muscle atrophy that involve multiple tumor typessexes and ages; these studies will significantly advance EMMY1-06 towards clinical development andcommercialization in SBIR Phase III. In parallel to our detailed studies of EMMY1-06 we will also designsynthesize and characterize novel compounds that are structurally related to EMMY1-06 seeking to discoveradditional compounds with pharmacologic properties that are similar to or perhaps even better than those ofEMMY1-06 in preclinical models of cancer-induced muscle atrophy. Together these studies will rigorouslyadvance the scientific understanding and commercial development of a highly promising new class ofpharmaceutical agents. Through this work we hope to ultimately discover and develop a newpharmacologic therapy that could broadly improve clinical outcomes for millions of patients whosuffer from cancer. 990411 +No NIH Category available Adjuvant;Anatomy;Animals;Binding;Biological;Body Weight;Brain;Breast;CD8-Positive T-Lymphocytes;Cancer Center;Cancer Patient;Cell Nucleus;Clinical;Clinical Treatment;Development;Diagnosis;Disease;Dose;Engineering;Genetic Engineering;Genomic DNA;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;Health;Histopathology;Home;Homing;Hour;IL2RA gene;Immune;Immune Tolerance;Immune system;Immunity;Immunologic Markers;Immunologics;Immunooncology;Immunosuppression;In complete remission;Interferon Type II;Interleukin-12;Interleukin-15;Intravenous;Lead;Legal patent;Licensing;Liver;Lung;Macrophage;Malignant Neoplasms;Measures;Medicine;Membrane;Metastatic Neoplasm to the Lung;Modeling;Mouse Mammary Tumor Virus;Mus;Natural Immunity;Neoplasm Metastasis;Organ;Organelles;Patients;Penetration;Peripheral;Pharmaceutical Preparations;Phase;Pre-Clinical Model;Primary Neoplasm;Property;Refractory;Regulatory T-Lymphocyte;Route;Safety;Serum;Surface;System;Systemic disease;Testing;Therapeutic;Therapeutic Agents;Time;Toxic effect;Treatment Efficacy;Tumor Immunity;Tumor Tissue;Work;adaptive immunity;anti-PD1 antibodies;anti-tumor immune response;bone;cancer cell;clinical development;conventional therapy;cytotoxic;delivery vehicle;design;effective therapy;efficacy evaluation;immune checkpoint blockade;improved;innovation;intravenous administration;malignant breast neoplasm;mesenchymal stromal cell;mouse model;neoplastic cell;phase 2 study;polyoma middle tumor antigen;pre-clinical;preservation;prevent;programs;response;success;targeted treatment;technology platform;therapeutic evaluation;therapeutically effective;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor heterogeneity;tumor microenvironment;tumorigenesis Development of CA-IL-12 for Triple Negative Breast Cancer Narrative.Cancer is a systemic disease and conventional treatment strategies that are administered systemically ultimately fail due toan inability to achieve antitumor efficacy at tolerable doses for the patient. Cytonus has developed a first-in-class precisiondelivery platform called CargocytesTM that is a safe and effective means to target therapeutic drugs to primary andsecondary tumors. In this phase II study we will evaluate the therapeutic efficacy of systemically-delivered locally-activemembrane-tethered or secreted IL-12 to induce durable systemic antitumor and antimetastatic immunity. NCI 10692000 8/31/23 0:00 PA-22-176 2R44CA250887-02A1 2 R44 CA 250887 2 A1 "POND, MONIQUE ADRIANNE" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-R(12)B] 1945816 "FILARDO, EDWARD J" Not Applicable 15 Unavailable 117145043 UBM9DERRCXZ9 117145043 UBM9DERRCXZ9 US 39.941592 -82.990083 10056416 "CYTONUS THERAPEUTICS, INC." COLUMBUS OH Domestic For-Profits 432062627 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1148542 NCI 819392 254012 Most cancer patients die as a result of metastatic disease and our inability to effectively deliver therapeutic drugs into theanatomical niches where cancer cells thrive. Thus there is a major unmet need to develop therapeutic strategies thateffectively target cancer cells in the local tumor microenvironment (TME) while minimizing peripheral toxicity. CytonusTherapeutics and UCSD Moores Cancer Center has co-developed a highly innovative first-in-class drug transporter platform(CargocytesTM) that is a safe and effective means to deliver therapeutic drugs to treat primary and secondary tumors.Cargocytes possess several unique features that we leverage for precision delivery of cancer therapeutics to patients withmetastatic disease. First Cargocytes possess innate tumor trophic properties and are engineered with additional homingcontrols that allow for precise predictable and safe delivery of therapeutic cargo to the TME. Moreover because they lacka rigid nucleus they clear critical FDA barriers to safety due to their inability to transfer or inappropriately express genomicDNA. In addition they are smaller and more malleable than nucleated carriers and better able to penetrate deep withintumor tissue and metastatic foci. Furthermore they retain all biosynthetic machinery and can express biological cargo withinthe TME. While Cargocytes can deliver a wide range of therapeutic cargoes they are ideally suited for locally deliveringpotent immune activating agents such as IL-12 into the immunologically cold TME.Our phase I proof-of-concept work shows that Cargocytes precisely deliver IL-12 into the TME deeply penetrating andinterdigitating within metastatic foci when delivered intratumorally or systemically and resulting in a dramatic reduction inmetastatic burden that can be measured within 24 hours. While this was demonstrated using Cargocytes that secrete IL-12(CA-IL-12) we have since focused on development of Cargocytes for intravenous delivery a more desirable administrationroute for clinical development and treatment of systemic metastatic disease. Therefore Phase II work will evaluate thepotential of intravenously administered Cargocytes to deliver secreted (CA-IL-12) or surface contained (CA-scIL-12) tobreast cancers that have metastasized to lungs or liver. Our hypothesis is that Cargocytes will home to metastases deliverIL-12 deep within disease foci and break immune tolerance when used in combination with ICB. This will lead to i) localand systemic antitumor immunity ii) a reduction in metastatic burden iii) improved tumor-free and overall survival andiv) durable antitumor immunity. Three specific aims are outlined to test this hypothesis. Aim 1 will determine the abilitiesof peripherally administered CA-scIL-12 and CA-IL-12 to locally deliver IL-12 to primary and secondary tumors and toreprogram innate and adaptive anti-tumor immune responses. Aim 2 will then evaluate the ability of our lead CA-IL-12medicine selected in aim 1 (CA-IL-12L) in combination with PD-1 antibody in the adjuvant setting to effectively treat ICBrefractory tumors and generate systemic antitumor and antimetastatic immunity. Aim 3 will test the therapeutic efficacy ofCA-IL-12L and ICB in a robust preclinical model of spontaneous breast oncogenesis that preserves tumor heterogeneity. 1148542 +No NIH Category available Acceleration;Address;Cancer Center;Cancer Control;Cancer Control Research;Cancer Control Research Program;Catchment Area;Clinic;Clinical;Clinical Services;Collaborations;Communities;Community Developments;County;Data;Evaluation;Evidence based practice;Feedback;Goals;Health;Health system;Healthcare;Healthcare Systems;Illinois;Incubators;Information Systems;Intervention;Intervention Studies;Laboratories;Leadership;Malignant Neoplasms;Measurement;Methods;Missouri;Monitor;Needs Assessment;Outcome;Patient-Focused Outcomes;Patients;Policies;Population;Positioning Attribute;Program Evaluation;Provider;Public Health;Reporting;Research;Research Personnel;Resources;Rural;Rural Health;Science;Services;Site;Structure;System;Time;Underserved Population;Universities;Vision;Washington;Work;cancer health disparity;cancer prevention;community organizations;community-level factor;data management;data resource;evidence base;experience;health data;implementation facilitation;implementation research;implementation science;implementation study;improved;innovation;medically underserved;member;multidisciplinary;neighborhood disadvantage;novel;programs;provider networks;social factors;social health determinants;underserved community Implementation Laboratory n/a NCI 10691930 8/21/23 0:00 RFA-CA-19-006 5P50CA244431-05 5 P50 CA 244431 5 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5883 8023991 "JAMES, AIMEE S" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 348478 221256 127222 PROJECT SUMMARY Implementation LaboratoryBackground and vision. As an Advanced Center the vision of the Washington University ImplementationScience Center for Cancer Control (WU-ISCCC) is to conduct implementation research to help eliminatecancer disparities in rural and other disadvantaged communities.Goal. The Implementation Lab hereafter called the Innovation Incubator through Incubator Membership aData Management Unit and a Practice Surveillance Unit will work closely with the WU-ISCCC ResearchProgram to facilitate implementation science research by connecting investigators to implementation sites inthe Membership convening community and clinical partners to review data and identify needs and prioritiesand support evaluation of program outcomes.Aims. The Incubator will:Aim 1. Establish leadership structure and functions that enable and support rapid-cycle and innovative implementation science in cancer control.Aim 2. Sustain and develop additional research partnerships with a range of healthcare systems and organizations/agencies committed to innovative implementation science projects that address social determinants of health and reduce cancer disparities.Aim 3. Support data systems and resources to manage multi-site projects collect rigorous data and produce timely reports to the project leaders and the WU-ISCCC leadership.Aim 4. Cultivate a surveillance unit to report on progress toward reducing cancer disparities in the populations across Siteman Cancer Center's 82-county catchment area.Aim 5. Draw on real-time clinical service data from health systems within BJC Healthcare and the BJC Collaborative network to monitor policies provider practices patient outcomes and progress in reducing cancer disparities.Innovations and impact. The Incubator will work to fulfill the overall goal of the WU-ISCCC to build a rigorousscientific evidence base for rapid-cycle implementation research to increase the reach external validity andsustainment of effective cancer control interventions. We will convene multi-sector partners to inform and actas settings for innovative and impactful research prioritizing rural and other underserved communities. TheIncubator will provide statistical and data support for rigorous execution of pilot and methods studies comingout of the Research Program supporting investigators from conceptualization and planning throughdissemination. These linkages and activities of the Incubator and our diverse Membership will position the WU-ISCCC to accelerate the innovation pace and impact of implementation science for cancer control andreduce cancer health disparities in our region and nationwide. +No NIH Category available Acceleration;Address;Cancer Center;Cancer Control;Characteristics;Communities;Development;Disparity population;Dissemination and Implementation;Environment;Evaluation;Fostering;Future;Goals;Incubators;Intervention;Investments;Laboratories;Measurement;Measures;Mentors;Methodology;Methods;Minority Groups;Outcome;Pilot Projects;Positioning Attribute;Process;Research;Research Activity;Research Personnel;Research Project Summaries;Resources;Rural;Rural Community;Science;System;Universities;Vision;Washington;Work;cancer health disparity;career;evidence base;implementation research;implementation science;implementation study;innovation;member;neighborhood disadvantage;programs;research and development;scale up;underserved community Research Program n/a NCI 10691928 8/21/23 0:00 RFA-CA-19-006 5P50CA244431-05 5 P50 CA 244431 5 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5882 2110411 "COLDITZ, GRAHAM A." Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 696125 441984 254141 PROJECT SUMMARY Research ProgramBackground and vision. As an Advanced Center the vision of the Washington University ImplementationScience Center for Cancer Control (WU-ISCCC) is to conduct implementation research to help eliminatecancer disparities in rural and other disadvantaged communities.Goal. The Research Program through the Implementation Studies Unit and the Methods Unit will contribute tothe development and oversight of the implementation science pilot studies methods and measurementstudies and other research activities of the WU-ISCCC. The Research Program will foster additionalinnovative studies and refine and apply a process to review score launch and support future studies.Aims. Three aims will achieve these goals:Aim 1. Conduct implementation science studies to address cancer disparities in disadvantaged and minority populations in rural and other underserved communities by: a) executing two pilot studies with continued support to R01-ready submissions and b) identifying additional pilot studies and ways to foster their development to focus innovation and applicability to our implementation science pilots in the WU-ISCCC.Aim 2. Apply systems science approaches to enhance methods and outcomes in implementation science and develop unique rapid-cycle methods in rural and underserved communities by: a) executing two methods pilot studies with continued support to R01-ready submissions and b) identifying additional methods pilot studies.Aim 3. Advance the innovation pipeline and promote regional and national dissemination of implementation science and measurement resources developed by the WU-ISCCC.Innovations and impact. The Research Program will work to fulfill the overall goal of the WU-ISCCC to build arigorous scientific evidence base for rapid-cycle implementation research to increase the reach externalvalidity and sustainment of effective cancer control interventions. Our focus is on disadvantaged and minoritypopulations in rural and other underserved communities. These characteristics will position the WU-ISCCC toaccelerate the innovation pace and impact of implementation science for cancer control in our region andnationwide. +No NIH Category available Accountability;Cancer Center;Cancer Control;Cancer Control Research;Clinical;Collaborations;Communication;Communities;Creativeness;Educational workshop;Effectiveness;Elements;Ensure;Environment;Ethnic Origin;Evaluation;Feedback;Fostering;Foundations;Funding;Goals;Guidelines;Health;Illinois;Infrastructure;Leadership;Logic;Maintenance;Malignant Neoplasms;Methods;Missouri;Modeling;Monitor;Persons;Positioning Attribute;Process;Productivity;Public Health;Recording of previous events;Records;Research;Research Personnel;Rural;Scholarship;Science;Scientific Evaluation;Series;Structure;System;Talents;Time;Training;Translating;Underrepresented Populations;United States National Institutes of Health;Universities;Vision;Washington;cancer health disparity;career;dissemination strategy;future implementation;implementation research;implementation science;innovation;meetings;neighborhood disadvantage;operation;organizational structure;outreach;racial minority;recruit;response;synergism;timeline Administrative Core n/a NCI 10691927 8/21/23 0:00 RFA-CA-19-006 5P50CA244431-05 5 P50 CA 244431 5 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5881 1885266 "BROWNSON, ROSS C" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 486195 308695 177500 PROJECT SUMMARY Administrative CoreBackground and vision. The Washington University Implementation Science Center for Cancer Control (WU-ISCCC) crosses multiple campuses and regions of Missouri and Illinois. The vision of the WU-ISCCC is toconduct implementation research to help eliminate cancer disparities in rural and other disadvantagedcommunities.Goal. The goal of the WU-ISCCC Administrative Core is to provide the structure for effective and efficientoperation and maintenance of the WU-ISCCC in compliance with NIH and University guidelines. TheAdministrative Core will support an environment of research excellence scientific innovation andtransdisciplinary scholarship which will lead to advances such as rapid-cycle studies and the use of systemsscience approaches.Leadership operational structures and processes. The Core will be co-led by Drs. Brownson and Colditz whowill implement an effective organizational structure to foster excellence in management and communication.Leaders and co-leaders of the various WU-ISCCC units will form the Executive Committee which will engageand maintain the creativity and leadership of the talented scholars and extensive partners involved in theCenter. Numerous organizational activities will strengthen our ties and lead to effective and efficient Centeroperations. We will hold a series of regular meetings and scientific gatherings (e.g. retreats) to share interimresults in real time across the Center and promote synergy among projects units and cores to ensuremaximum productivity. We will implement a focused plan to develop early career scholars into futureimplementation science leaders. The Center already diverse in make-up has specific plans to recruit under-represented groups (e.g. ethnic/racial minorities) and persons with a commitment to elimination of cancerdisparities and to engage partners outside the health sector. The Administrative Core is made up of two Units.The Network Unit will employ multiple methods to connect Developing and Advanced Centers with the broaderfield of implementation science. It will also conduct active dissemination strategies build capacity inimplementation science in cancer and foster meaningful participation in the Annual Consortium Meeting andother workshops. The Evaluation Unit has developed a Center logic model to guide efforts and will overseeevaluation of scientific and collaborative progress for each project and for the Center overall.Innovations and impact. The WU-ISCCC is positioned as the nexus for transdisciplinary implementationscience using multiple approaches for eliminating cancer disparities. We have substantial expertise and proventrack records to form the basis for scholarly excellence research synergy and efficiency and practice impact. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;Cancer Center;Cancer Control;Capital;Characteristics;Clinical;Communities;Complex;County;Creativeness;Development;Discipline;Disparity population;Ensure;Environment;Evidence based intervention;Fostering;Goals;Illinois;Incubators;Individual;Intervention;Investments;Laboratories;Leadership;Malignant Neoplasms;Methods;Minority Groups;Missouri;Outcome;Persons;Positioning Attribute;Provider;Public Health;Research;Research Personnel;Research Support;Resources;Rural;Science;Scientist;Sum;System;Universities;Vision;Washington;cancer health disparity;cancer prevention;cancer risk;career;evidence base;implementation barriers;implementation research;implementation science;innovation;interdisciplinary collaboration;member;neighborhood disadvantage;practice setting;synergism;underserved community Washington University Implementation Science Center for Cancer Control PROJECT NARRATIVE Overall ComponentThe goal of the WU-ISCCC is to conduct rigorous rapid-cycle implementation research to eliminate cancerdisparities among rural and other disadvantaged populations. Our Center will provide a significant return on thescientific investment resulting in innovations to advance cancer prevention and control. NCI 10691926 8/21/23 0:00 RFA-CA-19-006 5P50CA244431-05 5 P50 CA 244431 5 "VINSON, CYNTHIA" 9/18/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(A1) 1885266 "BROWNSON, ROSS C" "COLDITZ, GRAHAM A." 1 PUBLIC HEALTH & PREV MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF SOCIAL WELFARE/WORK 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 1530798 NCI 971935 558863 PROJECT SUMMARY Overall ComponentBackground and vision. As an Advanced Center the vision of the Washington University ImplementationScience Center for Cancer Control (WU-ISCCC) is to conduct implementation research to help eliminatecancer disparities in rural and other disadvantaged communities.Goal. The overall goal of the WU-ISCCC is to build a rigorous scientific evidence base for rapid-cycleimplementation research to increase the reach external validity and sustainability of effective cancer controlinterventions. Our goal and Center activities capture three distinct features: (1) a focus on elimination of cancerdisparities; (2) the need for rapid-cycle studies; and (3) the use of systems science approaches to enhancemethods and outcomes in implementation science.Setting. Our Center will be housed in an exceptional environment that fosters transdisciplinary collaborationcatalyzes new ideas and ensures support for research that finds solutions for complex implementationchallenges in real-world settings with high cancer disparities (rural and urban counties in Missouri and Illinois).Substantial matching contributions from Washington University will allow us to strategically invest in new ideas.Aims. The specific aims of the Center are to: (1) advance the field of implementation science in cancer controlby conducting innovative and impactful research; (2) expand an exceptional diverse team of implementationscience investigators and stakeholders; (3) organize and integrate Center components to facilitatetransdisciplinary team science; (4) develop an Implementation Laboratory (known as the InnovationIncubator) to serve as a conduit for innovative rapid-cycle and impactful research; and (5) address cancerdisparities by making it as easy as possible for disadvantaged populations to encounter use and benefit fromevidence-based interventions.Innovations and impact. The WU-ISCCC will be innovative and provide a significant return on the scientificinvestment. First our Center has distinctive features that include a combined focus on cancer disparities theapplication of strategies to conduct rapid-cycle studies and the use of systems science approaches. Secondwe have assembled a diverse world class team with strong linkages to multiple practice settings that will becritical parts of our Innovation Incubator. Third we will engage investigators from different disciplines andinvest in the development of early career scholars as cancer implementation scientists. Fourth we willstrategically and creatively disseminate products in ways that will benefit researchers practitioners andcommunity members. Fifth we have developed a focused strategy for collective integration of our projectscores and units to ensure that the WU-ISCCC impact is greater than the sum of its individual parts. Insummary the WU-ISCCC will be a national resource for furthering implementation science for eliminatingcancer disparities. 1530798 +No NIH Category available 3-Dimensional;ATAC-seq;Address;Advanced Malignant Neoplasm;Advisory Committees;Advocate;Affect;Anemia;Bar Codes;Bone Matrix;Brain;Breast;Breast Cancer Cell;Breast Cancer Model;Breast cancer metastasis;Calcium;Calcium Signaling;Cancer Etiology;Career Mobility;Cell Survival;Cells;Cessation of life;Chromatin;Clinical Management;Clinical Trials;Coculture Techniques;Coma;Complex;Comprehensive Cancer Center;DNA Sequence Alteration;DNA methylation profiling;Data;EZH2 gene;Endocrine;Epigenetic Process;Epithelium;Estrogen Receptors;Estrogen receptor positive;Estrogens;Evolution;FDA approved;FGF2 gene;FGFR1 gene;Fibroblast Growth Factor;Fostering;Gap Junctions;Genetic;Genetic Heterogeneity;Genetic Transcription;Genomics;Goals;Growth;Growth Factor;Heterogeneity;Hypercalcemia;Incidence;Individual;Inherited;Institution;International;Lesion;Libraries;Liver;Lung;Malignant Neoplasms;Maps;Mediating;Medicine;Mentors;Metastatic Neoplasm to the Bone;Micrometastasis;Molecular;Mutation;Neoplasm Metastasis;Numbness;Oncologist;Organ;Osteoblasts;Osteoclasts;Pain;Paralysed;Pathological fracture;Patients;Perfusion;Phase;Phenotype;Platelet-Derived Growth Factor;Positioning Attribute;Process;Proteomics;Receptor Protein-Tyrosine Kinases;Recurrence;Research;Resistance;Resources;Scientist;Senior Scientist;Signal Pathway;Signal Transduction;Site;Spatial Distribution;System;TRANCE protein;Techniques;Technology;Testing;Therapeutic;Tissue Microarray;Transforming Growth Factor beta;Validation;Variant;anticancer research;bone;cancer cell;cancer diagnosis;cancer subtypes;clinically relevant;college;conventional therapy;epigenetic drug;epigenomics;epithelial to mesenchymal transition;exome sequencing;in vivo evaluation;inflammatory breast cancer;laser capture microdissection;malignant breast neoplasm;mammary gland development;multiple omics;non-genomic;novel;novel therapeutic intervention;osteoblast differentiation;overexpression;parathyroid hormone-related protein;professor;public health relevance;receptor expression;single cell analysis;single-cell RNA sequencing;stemness;therapy resistant;trait;transcriptomics;treatment response;tumor;tumor growth;tumor heterogeneity;tumor progression Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis Project NarrativeGenetic and epigenetic complexities expand during tumor progression and complicate the clinical managementof cancer. Similarly the incidence of bone metastasis increases in advanced stages of cancer (> 50% rate). Ourstudy will deepen our understanding of epigenetic-driven intra-metastasis heterogeneity in breast cancer andreveal novel therapeutic approaches to overcome resistant metastases. NCI 10691920 8/25/23 0:00 PA-20-188 5R00CA263033-03 5 R00 CA 263033 3 "SNYDERWINE, ELIZABETH G" 9/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 15047221 "BADO, IGOR LANDRY" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 147337 101663 Project SummaryTitle: Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis.Metastasis is major cause of cancer-related death and is the most challenging to treat. Besides the well-studiedgenomic mutations in cancer our understanding of non-genomic alterations remains limited. The proposedapproach is to dissect the mechanisms of non-genomic intra-metastasis heterogeneity in breast cancer.Recently we demonstrated that osteoblasts (bone forming cells) promote a global alteration of chromatinorganization which associates with increased stemness epithelial to mesenchymal transition andoverexpression of multiple receptor tyrosine kinases included FGFR1 and PDGFR. Ultimately estrogensignaling was inhibited while endocrine resistance was increased. Mechanistically we identified FGF2/PDBF/EZH2 axis as a novel regulator of epigenetic reprogramming in breast cancer bone metastasis. However severaloutstanding questions remained unanswered: (i) what mechanisms drive phenotypic variations betweenneighboring cells in bone metastasis (ii) are epigenetic traits inheritable during metastasis progression and (ii)if yes how do they influence therapeutic response? In this project our goal is to understand the mechanisms ofintra-tumor heterogeneity in bone metastases and determine how epigenetic heterogeneity affects therapeuticresponse beyond the genetic heterogeneity that has been extensively studied. We aim to trace and dissect theepigenetic intra-tumor heterogeneity (eITH) using a cutting-edge barcoding strategy (K99 phase) identifyepigenetic modulators by integrating single cell multi-omics (K99-R00 phase) test new therapeutic approachesand eventually expand our findings to other breast cancer metastasis sites (R00 phase) including lung liver andbrain. Baylor College of Medicine (BCM) is an internationally renowned institution for breast cancer researchwhich gives me the opportunity to closely interact exchange ideas and share my findings with leading scientistsclinicians and patient advocates. For my career transition I assembled a team of senior scientists and expertsincluding my mentor Professor Xiang H-F Zhang who is well-established in breast cancer bone metastasis. Myco-mentor Professor Jeffrey Rosen is a distinguished scientist in mammary gland development and breastcancer modeling. Because of the clinical relevance of the project I also included Professor C. Kent Osbornefounding director of the Dan L. Duncan Comprehensive Cancer Center (DLDCCC) Professor Matthew J. Ellisa world-renowned oncologist and director of the Breast Center Dr. Bora Lim an expert in aggressive subtypesof breast cancer (e.g. inflammatory breast cancer) Professor Susan G. Hilsenbeck a distinguishedbiostatistician and Dr. Zhandong Liu a computational biologist and statistician with expertise in single cellanalysis. Adding the expertise of my advisory team to the rich intellectual resource and cutting-edge technologyavailable at BCM will facilitate my successful transition into an independent position at a top research institution. 249000 +No NIH Category available Acceleration;Address;Architecture;Barrier Contraception;Bayesian Method;Cancer Control;Cancer Control Research Program;Cohort Studies;Common Data Element;Consultations;Data;Development;Ecological momentary assessment;Educational workshop;Ensure;Ethnography;Evaluation;Evidence based intervention;Faculty;Feedback;Future;Goals;Individual;Intervention;Investigation;Knowledge;Laboratories;Lead;Measurement;Measures;Methodology;Methods;Monitor;Natural Language Processing;Outcome;Pathway interactions;Pilot Projects;Process;Reporting;Request for Proposals;Research;Research Personnel;Resource Sharing;Resources;Science;Series;Speed;Structure;Technology;Testing;Work;advanced analytics;analog;anticancer research;design;experimental study;field study;implementation barriers;implementation efforts;implementation intervention;implementation measures;implementation outcomes;implementation science;implementation strategy;implementation study;improved;innovation;meetings;method development;multidisciplinary;programs;rapid testing;relational database;symposium;uptake;usability;user centered design;user-friendly;virtual reality;web site Optimizing Implementation in Cancer Control: OPTICC - Research Program Core n/a NCI 10691917 9/4/23 0:00 RFA-CA-19-006 5P50CA244432-05 5 P50 CA 244432 5 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7020 11761120 "LEWIS, CARA CHARISSA" Not Applicable 7 Unavailable 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA Domestic Higher Education 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 398593 497183 94913 RESEARCH PROGRAM CORE SUMMARYThe overarching goal of the Research Program Core (RPC) within the Optimizing Implementation in CancerControl (OPTICC) Center is to support the rapid development testing and refinement of innovative methods tooptimizing implementation of evidence-based interventions (EBIs) for cancer control. The approach is to conducta series of implementation studies and methods and measurement studies that address four critical barriers tooptimizing EBI implementation in cancer control: underdeveloped methods for barrier identification and prioriti-zation incomplete knowledge of strategy mechanisms (a requisite for strategy-barrier matching); underutilizationof designs for optimizing strategies; and poor measurement of implementation constructs. OPTICC studies willspan three optimization stagesidentify and prioritize barriers match implementation strategies to barriers andoptimize implementation strategies through rapid testingand include measure development. The studies willleverage existing cancer control implementation efforts and respond to emerging priorities of our ImplementationLaboratory Partners. We will refine our innovative methods across studies. The rationale is that conducting mul-tiple studies concurrently across the three stages using shared resources will accelerate the speed of knowledgeaccumulation and method development with greater efficiency and economy than conducting independent stud-ies in isolation. The RPC has four specific aims. (1) Advance implementation science in cancer control by con-ducting innovative studies to optimize EBI implementation. Cancer research experts will be supported by Meth-ods Unit Faculty to lead two types of pilot studies that deploy OPTICC methods across the three optimizationstages to address Implementation Lab Partners priorities and overcome the four barriers stymying implementa-tion science in cancer control. (2) Improve measurement and methods in IS by developing reliable valid prag-matic measures of implementation constructs and refining innovative methods for optimizing EBI implementa-tion. We will prioritize developing measures and methods that are economical efficient and approved by stake-holders to ensure widespread uptake. (3) Curate usable knowledge to function as a national consultation re-source. We will develop toolkits guidance and workshops leveraging user centered design to ensure our prod-ucts made publicly available are ready for deployment. We will organize knowledge in a relational databasethat will synthesize learnings for the field. (4) Generate innovative methods and chart future directions. We williterate our current methods with input from OPTICC Study Leads Methods Unit Faculty Stakeholder and Sci-entific Advisory Boards Representatives from our Implementation Lab and individuals accessing our methodsonline. We will also develop new methods that leverage technology and advanced analytics. The OPTICC Centerhas the potential to transform implementation science by delivering new methods to optimize EBI implementationin cancer control that focus on constructing explicit representations of hypothesized causal pathways that con-nect strategies to mechanisms barriers and outcomes for planning evaluations and organizing evidence. +No NIH Category available Acceleration;Address;Adult;Area;Cancer Center;Cancer Control;Cancer Prevention Intervention;Caring;Communities;Community Health;Community Healthcare;Community Participation;Complex;Data;Dedications;Development;Ecosystem;Ensure;Equity;Evidence based intervention;Geographic Locations;Goals;Health Policy;Health Status;Healthcare;Incubators;Individual;Inequity;Intervention;Laboratories;Leadership;Link;Low Income Population;Mammographic screening;Methodological Studies;Methodology;Methods;Nature;Neighborhood Health Center;Persons;Physical activity;Pilot Projects;Population;Positioning Attribute;Prevention;Process;Recommendation;Reporting;Research;Research Methodology;Research Personnel;Resources;Screening for cancer;Source;System;Testing;Tobacco;cancer prevention;clinical practice;colorectal cancer screening;community setting;cost effective;cost effectiveness;data ecosystem;evidence base;health disparity;health equity;health inequalities;implementation context;implementation outcomes;implementation questions;implementation research;implementation science;implementation strategy;implementation study;improved;innovation;interest;nutrition;organizational structure;preventive intervention;programs;scale up;screening;success;uptake;vulnerable community;working group The Implementation Science Center for Cancer Control Equity - Research Program n/a NCI 10691908 8/7/23 0:00 RFA-CA-19-006 5P50CA244433-05 5 P50 CA 244433 5 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7015 1863832 "EMMONS, KAREN M." Not Applicable 7 Unavailable 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA Domestic Higher Education 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 647332 602819 190254 Abstract - Research ProgramThe goal of the Research Program is to develop innovative implementation and methods research inpartnership with the I-Lab and its participating CHCs that will lead to increased implementation of evidence-based (EB) cancer prevention and control interventions in vulnerable communities across the state. We alsoaim to increase the interest in and capacity of our investigator workforce for implementation science (IS)related to health equity and to support the development of implementation research capacity of our I-Lab CHCpartners.The Research Program has three primary components. First we will create a robust research setting thatintegrates a focus on IS and health equity to conduct implementation and methodologic research in our I-Labby: (1) creating a pipeline of research and methods projects that will address critical and emerging issues inimplementation of EB cancer prevention and control strategies; (2) providing resources to allow jr. investigatorsand I-Lab partners to ask and answer key implementation questions using our data ecosystem; (3) supportingan Implementation Science and Health Equity working group; and (4) tracking and evaluating Center success.Second we will conduct innovative pilot studies though the Implementation Studies Unit to improve uptake ofEBIs and their sustainability efficiency and acceptability. The initial pilots will focus on: (1) cross-cancerscreeningthat is determining if pairing CRC and mammography screening will increase uptake of individualand dual screening and reduce CHC staff burden; and (2) the extent to which CHCs are using evidence-basedinterventions (EBIs) for cancer prevention specifically in nutrition physical activity and tobacco and willidentify actionable factors in the implementation context that enabled use of EBIs.Third we will conduct innovative methodologic studies via the Methods Unit that address key issues including:(1) development and testing of a planned adaptation process the Equity-focused Adaptation Process for usein community settings; (2) development of cost- effectiveness methods for implementation strategies; and (3)development of strategies to address incomplete and missing EHR Data in IS studies.The Methods Unit will also develop an Implementation Research Methods Incubator (IRMI) to identify andaddress critical methodological challenges in on-going IS studies. +No NIH Category available Address;Area;Articulation;Cancer Center;Cancer Control;Cancer health equity;Clinical;Communities;Community Health;Data;Development;Ecosystem;Ensure;Equity;Ethics;Evaluation;Evidence based intervention;Faculty;Feedback;Goals;Leadership;Malignant Neoplasms;Mentors;Neighborhood Health Center;Outcome;Outcome Study;Pilot Projects;Play;Process;Productivity;Research;Research Personnel;Research Project Grants;Role;Structure;University resources;Vision;cancer prevention;care delivery;community engaged research;community engagement;data repository;design;health equity;implementation science;outreach;programs;uptake;working group The Implementation Science Center for Cancer Control Equity - Admin Core n/a NCI 10691904 8/7/23 0:00 RFA-CA-19-006 5P50CA244433-05 5 P50 CA 244433 5 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 7013 1863832 "EMMONS, KAREN M." Not Applicable 7 Unavailable 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA Domestic Higher Education 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 95467 201569 39639 Abstract - Admin CoreThe Administrative Core provides scientific and administrative leadership to ensure an integrated andsustained focus on the Centers aims to create an implementation science (IS) ecosystem focused on healthequity in community health centers across MA. The Core provides governance and coordination of centerscientific administrative and networking activities and will evaluate Center processes outcomes scientificand clinical impacts.The Core has three primary components. The Administrative team brings strong scientific community healthand administrative leadership as required to ensure a substantive and enduring focus on cancer health equityand implementation science by: (1) assembling a transdisciplinary team with scientific and community-basedexpertise; (2) providing strong transdisciplinary input through our governance and Advisory Board structure; (3)maintaining rigorous standards for community-engaged research quality of scientific and practice-basedproducts and ethical standards; and (4) providing strong coordination and fiscal administration of Centeractivities.The Network Unit connects the Center to other ISCCCs and Cancer Moonshot implementation centers and tostate and national community health center leadership by: (1) creating a mechanism for directly engaginginvestigators from Moonshot and other relevant IS into the planning and research functions of the Center; and(2) extend our networking to include national CHC leadership and care delivery structures.The Evaluation Unit is responsible for creating a data and evaluation ecosystem to evaluate and establish theCenters impact including: (1) establishing short and long-term metrics for productivity for all Centercomponents; (2) collecting reviewing and providing feedback on Center wide and project specific metrics; (3)providing statistical support for evaluating pilot outcomes; and (4) creating a robust data repository thatincludes clinical as well as community contextual data.The Administrative Core has been built to provide: (1) strong and inclusive governance; (2) mechanisms toarticulate the scientific vision and thematic foci of the center; (3) coordinated and collaborative activitiesacross the Center and other relevant University resources; and (4) advancement of the Centers themesthrough administrative support and continuous evaluation of Center activities. +No NIH Category available Address;Behavioral;Biological;Cancer Burden;Cancer Center;Cancer Control;Cancer Control Research;Cancer Intervention;Cancer Prevention Intervention;Clinical;Collaborations;Communities;Community Health;Complex;Data;Data Collection;Data Reporting;Development;Disparity;Early Diagnosis;Ecosystem;Educational Status;Ensure;Environment;Equity;Ethnic Origin;Evidence based intervention;Future;General Population;Geography;Goals;Healthcare;Income;Incubators;Inequity;Institution;Intervention;Laboratories;Leadership;Link;Low income;Malignant Neoplasms;Massachusetts;Measures;Methodology;Methods;Morbidity - disease rate;Nature;Neighborhood Health Center;Outcome;Participant;Pilot Projects;Policies;Population;Population Group;Prevention strategy;Preventive care;Primary Care;Race;Reporting;Research;Research Methodology;Resources;System;Testing;Underrepresented Populations;Vendor;cancer health disparity;cancer prevention;care delivery;clinical practice;community engagement;cost effective;cost effectiveness;data management;data visualization;design;ethnic diversity;evidence base;health disparity;health equity;health inequalities;implementation evaluation;implementation outcomes;implementation research;implementation science;implementation strategy;implementation study;improved;innovation;member;mortality;point of care;pressure;prevent;preventive intervention;racial disparity;racial diversity;scale up;screening;social;synergism The Implementation Science Center for Cancer Control Equity Project NarrativeThe Implementation Science Center for Cancer Control Equity (ISCCCE) focuses on improving communityhealth by addressing health equity in implementation science for cancer control in studies conducted incommunity health centers and the communities that they serve. NCI 10691903 8/7/23 0:00 RFA-CA-19-006 5P50CA244433-05 5 P50 CA 244433 5 "D'ANGELO, HEATHER" 9/20/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(A1) 1863832 "EMMONS, KAREN M." "TAVERAS BENAVIDEZ, ELSIE MIREYA" 7 SOCIAL SCIENCES 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 1087825 NCI 1249851 275196 Abstract - OverallAfter decades of research developing and testing interventions for cancer control we have the evidenceneeded to prevent more than half of all cancers. The impact of these strategies on cancer outcomes issignificant for both the general population and low income and under-represented groups that bear adisproportionate share of preventable cancer burden but evidence-based interventions have not beenuniformly used across population groups. Gaps in implementation of the evidence base can be seen for nearlyall known cancer prevention and early detection strategies. As a result we incur substantial avoidable cancermorbidity and mortality and tolerate preventable inequities.The Implementation Science Center for Cancer Control Equity (ISCCCE) will create an ecosystem for robustimplementation science (IS) related to cancer prevention and control in Massachusetts community healthcenters (CHCs) and their local communities. Our theme improving community health by integrating healthequity and implementation science for evidence-based cancer control reflects our critical mass of expertise incancer disparities IS and community-based cancer prevention and control research. Our grand challengeis to address the inequitable implementation and limited scale of evidence-based interventions by developingand testing implementation strategies aimed at narrowing health inequities and by advancing methods thatcarefully consider the low-resource complex nature of CHCs where adaptation and cost-effective solutions areneeded most. The implementation studies we conduct will address inequities within CHC clinical practice aswell as prevention interventions that link to community resources and assets. Our I-Lab is comprised of 31CHCs who are members of the Mass League of Community Health Centers and use a common EHR vendor-neutral population management system that has extensive reporting capability within and across CHCs whichwill allow us to study implementation outcomes in different geographic settings across the state using commonmeasures. Given that achieving equity in community health requires clinical community and policy-levelinterventions our pilots will also examine how to expand the impact and sustainability of CHCs cancerprevention efforts through effective partnerships in community and policy settings. Our Network Unit connectsus directly with other Moonshot IS initiatives and national community health leadership and expandsopportunities for collaboration and synergy building IS capacity in our own institutions and across the nation. 1087825 +No NIH Category available Address;Adherence;Adult;Behavior Therapy;Behavioral;Binding;Body Weight;Cardiovascular Diseases;Chronic Disease;Competence;Costs and Benefits;Dimensions;Effectiveness;Employee;Evidence based intervention;Government;Health;Health Benefit;Health Promotion;Health Services;Industry;Internet;Intervention;Interview;Investments;Knowledge;Maintenance;Malignant Neoplasms;Manufacturer;Measures;Musculoskeletal Pain;Non-Insulin-Dependent Diabetes Mellitus;Nonprofit Organizations;Occupations;Promoting Action on Research Implementation in Health Services framework;Public Health;Quality of life;Randomized;Reporting;Research;Risk;Risk Factors;Role;Societies;Speed;Testing;Time;Translating;Variant;Vendor;Work;Workplace;arm;cost;effectiveness evaluation;effectiveness testing;effectiveness trial;effectiveness/implementation hybrid;efficacy trial;ergonomics;flexibility;follow-up;implementation cost;implementation facilitation;implementation fidelity;implementation outcomes;implementation questions;implementation strategy;implementation trial;implementation/effectiveness;improved;incremental cost;innovation;intervention cost;intervention effect;intervention program;mortality;post implementation;preservation;prevent;primary outcome;programs;public health intervention;public health priorities;randomized trial;sedentary;sedentary lifestyle;social;therapy design;treatment arm;trend;trial design;work-study Stand & Move at Work II: Effectiveness and Implementation Project NarrativeSedentary behavior has emerged as an important target for public health interventions and workplaces are anideal setting to intervene. This project will test both the effectiveness and implementation of a multicomponentbehavioral intervention designed to support the use of sit-stand workstations at work. This project will lead toenhanced knowledge on the role of expert facilitators in workplace interventions and the effectiveness andcost-benefit of sit-stand workstations and an associated intervention for reducing sedentary time. NCI 10691900 9/9/23 0:00 PAR-19-274 5R01CA250527-04 5 R01 CA 250527 4 "PERNA, FRANK" 8/10/20 0:00 7/31/25 0:00 Dissemination and Implementation Research in Health Study Section[DIRH] 10649217 "BUMAN, MATTHEW P" "PEREIRA, MARK A" 4 Unavailable 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ Domestic Higher Education 852876011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 561681 NCI 476657 85024 Project SummarySedentary behavior (i.e. sitting) has emerged as an important risk factor for type 2 diabetes cardiovasculardisease some cancers and mortality. Working adults with desk-bound occupations accumulate large volumesof daily sedentary time. Sit-stand workstations are now the fastest growing employee benefit yet evidence-basedinterventions are not being implemented to support their use. Our team has completed the largest and mostdefinitive efficacy trial on the impact of an intervention to support use of sit-stand workstations and reducesedentary behavior in the workplace. Stand & Move at Work (SMW) is a multicomponent social-ecologicalbehavioral intervention tested in 24 industry government and academic worksites (N=630 workers). Interventioneffects included: (a) reductions in sedentary time at 12 months (~60 min/8 h workday) that were retained at 24-month follow-up (~30 min/8 h workday); (b) reduced body weight and improved chronic disease risk factorsamong those with high baseline risk; and (c) reduced musculoskeletal pain. We are now proposing a new trialthat tests the role of expert-based facilitation to enhance effectiveness and implementation of the SMWintervention. We use the Integrated - Promoting Action on Research Implementation in Health Services(iPARIHS) framework to inform our new trial through: (a) organizing our implementation outcomes from ourefficacy trial; (b) conducting industry-based discovery interviews; and (c) piloting our enhanced implementationstrategy in new worksites. We propose a 2-arm group-randomized hybrid effectiveness-implementation (type 2)trial to test the effectiveness of SMW for reducing sedentary time in the workplace and to test an implementationstrategy (i.e. expert facilitation) for improving implementation fidelity. Worksites (N=24) will be observed over 3months of sit-stand workstation use only and will then be randomized to 12 months of either: (a) SMW (web-delivered); or (b) SMW+ (web-delivered + expert facilitation). Our dual primary outcomes will be reductions inobjectively-measured sedentary time (effectiveness) and intervention fidelity (implementation) over 12 months.Because facilitation increases intervention cost we will also assess incremental cost benefit of our interventions(secondary aim). Finally we will explore fidelity as a driver of effectiveness examine within-worksite differencesin sedentary time pre- and post- implementation and measure organizational sustainability of effectiveness andimplementation at 24 months. The potential health benefits of sit-stand workstations and associated worksitehealth promotion programs will not be realized in the workforce at large until we test the most effective andefficient way to implement evidence-based interventions. This project is among the first initiatives to address thisgrowing trend in worksite health and will answer important questions related to effectiveness implementationand cost benefit. Optimal strategies for delivering the SMW intervention will be identified and new knowledge willbe generated on how facilitation can enhance implementation fidelity of workplace health initiatives both of whichwill increase the public health impact of evidence-based interventions. 561681 +No NIH Category available Academy;Acceleration;Address;Advocacy;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Collaborations;Complex;Development;Ensure;Environment;Epidemiology;Equity;Evaluation;Evidence based practice;Faculty;Feedback;Fostering;Funding;Future Generations;Goals;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Logic;Mentors;Methods;Minority;Mission;Modeling;Monitor;Outcome;Participant;Positioning Attribute;Privatization;Process;Program Evaluation;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Thinking;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;Work;career development;cohort;college;design;early-career faculty;evidence base;experience;faculty support;health communication;health equity;higher education;improved;interest;learning progression;meetings;model design;organizational climate;professor;programs;recruit;skills;success;synergism;theories Evaluation Core n/a NCI 10691896 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 7012 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 Unavailable 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY Domestic Higher Education 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 219800 140000 79800 Project Summary (Evaluation Core)The Cornell FIRST Evaluation Core will provide program evaluation of the Cornell FIRST Cohort program and work collaboratively with the FIRST CEC to ensure overall program evaluation and outcome tracking.The proposed activities in this core address our Monitoring and Evaluation Initiative to critically assess the progress of the program test our models to ensure that the above initiatives are generalizable that they are implemented in an effective manner and that lessons learned are incorporated throughout the program as it evolves. The activities of this core assess the primary NIH FIRST hypothesis that a cohort and cluster design model of faculty hiring sponsorship continual mentoring and professional development embedded within an institution implementing evidence-based practices will foster a culture ofacademic cultures of inclusive excellence. Assessing the primary NIH FIRST hypothesis requires a multi-faceted mixed-methods systems thinking approach. The Cornell FIRST Monitoring and Evaluation Initiative in collaboration with the FIRST CEC will follow a collaboratively developed program logic model and comprehensive evaluation plan. It will incorporate development and integration of program theory and program logic; integration of qualitative and quantitative mixed methods; the incorporation of a variety of stakeholders and participants; and both formative and summative design. We will do this by implementing Specific Aim #4 from the Overall Core to evaluate and learn from our hiring climate and faculty development approaches by identifying which strategies and activities are most effective and sustainable at an institutional scale by assessing and monitoring the FIRST programs and activities to ensure that they are meeting their planned goals provide continuous learning and program improvement feedback to the Cornell Institutional Steering Committee to ensure the highest success of the FIRST cohort through the aims strategies and activities and to ensure integration and synergy with FIRST CEC to facilitate overall FIRST program evaluation and outcome tracking. The evaluation will be carried out by a highly skilled team that includes two external evaluators with decades of equity focused evaluation experience in higher education including experience evaluating the NIH Diversity Program Consortium. +No NIH Category available Academy;Address;Adopted;Advocate;Area;Biological;Climate;Cognitive;Communication;Communities;Country;Development;Development Plans;Discipline;Early identification;Education;Educational process of instructing;Ensure;Environment;Faculty;Financial Support;Fostering;Funding;Future Generations;Grant;Growth;Guidelines;Health Sciences;Individual;Institution;Investments;Laboratories;Measurable;Mentors;Michigan;Minority;Modeling;Pathway interactions;Policies;Process;Program Development;Research;Risk;Role;STEM career;Services;Social Network;Soil;Structure;Teacher Professional Development;Testing;Training and Education;Travel;Universities;Woman;Writing;anti-racism;career development;career life balance;career networking;cohort;college;community building;design;early-career faculty;evidence base;experience;experimental study;faculty community;falls;implicit bias;innovation;marginalization;member;peer;programs;research and development;social;success Faculty Development n/a NCI 10691895 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 7011 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 Unavailable 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY Domestic Higher Education 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 219800 140000 79800 Project Summary (Faculty Development Core)Cornell University is ideally suited to develop and test innovative approaches to increase faculty diversity and to create a robust culture of inclusive excellence. Its multiple colleges operate with substantial autonomy and are laboratories for innovation leading Cornell to an enviable track record of designing innovative approaches that have been adopted around the country. These experiments have established programming and policies that have resulted in significant and measurable gains in both hiring and retention of faculty from diverse backgrounds including women. These policies have positively engaged faculty search committees in adopting best practices for inclusive hiring resulting in increased hiring of women and other individuals from underrepresented or minoritized backgrounds in STEM. Cornell also has a successful track record of combining institutional investments with federal programs to effect institutional culture change and make steady progress in increasing representational diversity of STEM faculty. Effective implementation of the best laid policies can fall short if systemic bias in policies and the academic environment into which we hire new faculty are not considered as part of a holistic process. Using the seed and soil model proposed by Dr. Beronda Montgomery of Michigan State University we propose a highly innovative Cornell FIRST Faculty Development Program that addresses both the seed (faculty member) and the soil (the community and climate) to ensure that FIRST faculty hires reach their full potential and succeed at Cornell. We hypothesizethat a robust evidence-based faculty development program across Cornell will create fertile ground (culture) for inclusive excellence and belonging and ensure that FIRST faculty are successful. We propose innovative programs for the FIRST cohort and other faculty who are underrepresented or marginalized in their fields by implementing our Faculty Development Initiative. Cornell will build FIRST faculty community by creating a sense of belonging in the discipline and across Cornell. We will connect FIRST faculty professionally and socially across their clusters and cohort within departmental units and research fields and across the university through a variety of formal and informal networking and community-building opportunities.Cornell will also foster individual research and career development for all FIRST faculty by providingtailored culturally relevant professional development opportunities to FIRST faculty to facilitate the successful start-up of their research programs communicate clear pathways for promotion and tenure and support success in their faculty roles. We expect that the Cornell FIRST program will successfully hire retain and support 10 new faculty underrepresented in their fields while fostering sustainable institutional culture change. These activities will result in increased diversity of the faculty in the biological biomedical and health sciencesat Cornell while contributing to the diversity of academy and future generations of the STEM workforce. +No NIH Category available Academy;Acceleration;Advocacy;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Complex;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Mentors;Minority;Mission;Modeling;Positioning Attribute;Privatization;Process;Public Health;Research;STEM career;Science;System;Systems Biology;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;organizational climate;professor;programs;recruit;success Cornell FIRST Administration Core Project NarrativeNot applicable per RFA-RM-20-022 NCI 10691894 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y] 7010 1921631 "AUGUST, AVERY " Not Applicable 19 Unavailable 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY Domestic Higher Education 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 4702150 2995000 1707150 Project Summary (Administrative Core)The Administrative Core for the Cornell FIRST program will support the hiring and retention of 10 new assistant professors from groups underrepresented in their fields while transforming institutional climate into a culture of inclusive excellence. The strength of Cornells program is its foundational roots as a complex private institution with a public mission with its founding based on support for diversity a culture of interdisciplinary research and a track record of catalyzing change at different scales that were institutionalized. Given Cornells success in establishing programs for the effective development and support of early-career faculty particularly those underrepresented in their fields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will be successful in an environment that supports advocacy through sponsorship consistent and individual-centered mentoring and evidence-based professional development. We further hypothesize that Cornells institutional culture and scientific excellence will be enhanced with the hiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring of faculty underrepresented in their fields across six colleges and 20 departments with a focus on retention career development and evaluation. The Administrative Core of the Cornell FIRST program will develop an inclusive FIRST Cohort search process that will lead to 10 hires in 3 clusters encompassing quantitative biomedical sciences infection biology and health equity; hire and retain a diverse FIRST cohort of new faculty taking advantage of Cornells existing interdisciplinary field system approach where faculty are organized by research interest rather than by department; and will foster sustainable institutional culture change to support FIRST Cohort faculty to enhance their development retention progression and promotion. Here Cornell will accelerate its Belonging at Cornell framework for developing a culture of Inclusive Excellence using a combination of institutional policies that impact hiring mentoring promotion and tenure salary equity and other initiatives aimed at enhancing compositional diversity retention and success of our faculty. We expect that the Cornell FIRST program will successfully hire retain and support 10 new faculty underrepresented in their fields while fostering sustainable institutional culture change. These activities will result in increased diversity of the faculty in the biological biomedical and health sciences at Cornell while contributing to the diversity of academy and future generations of the STEM workforce. +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NCATS 64153 36566 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 100719 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NCI 395836 225625 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 621461 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NIAID 427683 243778 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 671461 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NCCIH 128305 73133 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 201438 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NIAMS 32077 18283 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 50360 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NIA 142561 81259 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 223820 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NINR 14257 8125 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 22382 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 OD 1428603 814314 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 2242917 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NIEHS 213842 121889 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 335731 +No NIH Category available Academy;Acceleration;Advocacy;Area;Bacteriology;Behavioral Sciences;Biological;Biology;Biomedical Engineering;Climate;Complex;Data;Development;Environment;Epidemiology;Equity;Evaluation;Faculty;Fostering;Funding;Future Generations;Health Sciences;Immunology;Individual;Infection;Institution;Institutional Policy;Institutionalization;Interdisciplinary Study;Learning;Mentors;Minority;Mission;Modeling;Monitor;Positioning Attribute;Privatization;Public Health;Research;STEM career;Science;System;Systems Biology;Teacher Professional Development;Testing;Underrepresented Populations;United States National Institutes of Health;Universities;Wages;career;career development;cohort;college;early-career faculty;evidence base;faculty support;health communication;health equity;interest;marginalization;novel;organizational climate;professor;programs;recruit;success Cornell FIRST Project Narrative (Overall)Increasing faculty diversity in the biological biomedical and health sciences will contribute to the diversityof the academy and future generations of the STEM workforce. Cornell University aims to increase thenumber of minoritized faculty in the biological biomedical and health sciences through establishing an NIHFIRST Program at Cornell University. Cornell FIRST will support the hiring and retention of 10 new assistantprofessors from groups underrepresented in their fields while transforming institutional climate into a cultureof inclusive excellence. NCI 10691893 8/18/23 0:00 RFA-RM-20-022 5U54CA267738-03 5 U54 CA 267738 3 "CALZOLA, JESSICA MARIE" 9/21/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 MICROBIOLOGY/IMMUN/VIROLOGY 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY SCHOOLS OF VETERINARY MEDICINE 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Research Centers 2023 5141750 NIMH 427683 243778 Cornell University aims to increase the number of minoritized faculty in the biological biomedical andhealth sciences through establishing an NIH FIRST Program at Cornell University. Cornell FIRST willsupport the hiring and retention of 10 new assistant professors from groups underrepresented in their fieldswhile transforming institutional climate into a culture of inclusive excellence. The strength of Cornellsprogram is its foundational roots as a complex private institution with a public mission with its foundingbased on support for diversity a culture of interdisciplinary research and a track record of catalyzingchange at different scales that were institutionalized. Given Cornells success in establishing programs forthe effective development and support of early-career faculty particularly those underrepresented in theirfields Cornell is in an excellent position to test the hypothesis that FIRST Cohort faculty will besuccessful in an environment that supports advocacy through sponsorship consistent andindividual-centered mentoring and evidence-based professional development. We furtherhypothesize that Cornells institutional culture and scientific excellence will be enhanced with thehiring of a FIRST Cohort of diverse faculty. Cornells FIRST program features interdisciplinary hiring offaculty underrepresented in their fields across six colleges and 20 departments with a focus on retentioncareer development and evaluation. Cornell proposes 1) to hire a diverse cohort of 10 new faculty into3 research clusters taking advantage of Cornells existing interdisciplinary field system approach wherefaculty are organized by research interest rather than by department within broad areas of quantitativebiomedical sciences infection biology and health equity; 2) foster sustainable institutional culturechange using novel combinations of institutional policies that impact hiring mentoring promotion andtenure salary equity and other initiatives aimed at enhancing compositional diversity retention andsuccess; 3) enhance faculty development retention progression and promotion building on Cornellstrack record of successfully developing and implementing cutting edge programs that effectively supportfaculty through their career particularly those underrepresented in their fields; and 4) to evaluate and learnfrom our hiring climate and faculty development approaches by identifying which strategies andactivities are most effective and sustainable at an institutional scale assessing our progress to ensurethat they are developed and implemented in an effective manner and effectively interact with the FIRSTCEC. We expect that the Cornell FIRST program will successfully hire retain and support 10 new facultyunderrepresented in their fields while fostering sustainable institutional culture change to support inclusiveexcellence. Cornell FIRST will increase faculty diversity in the biological biomedical and health scienceswhile contributing to the diversity of academy and future generations of the STEM workforce. 671461 +No NIH Category available Alternative Therapies;Antigen Presentation;Antigen-Presenting Cells;Antigenic Specificity;Antigens;Autologous;Bioinformatics;Bypass;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Cross Presentation;Data;Dendritic Cell Vaccine;Dendritic Cells;Development;Elements;Epitopes;Generations;Human;Immunologic Adjuvants;Immunosuppression;Immunotherapy;In Vitro;Individual;Inflammation Mediators;Inflammatory;Lesion;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of ovary;Monitor;Mutate;Operative Surgical Procedures;Outcome;PD-1 blockade;Patients;Pattern;Peptides;Phenotype;Platinum;Population;Regulation;Role;Safety;T cell response;T cell therapy;Testing;Translating;Tumor Antigens;Tumor Burden;Tumor Immunity;Vaccination;Vaccines;antigen processing;antigen-specific T cells;cancer cell;cancer diagnosis;cancer therapy;checkpoint inhibition;chemotherapy;clinical application;clinical efficacy;cytotoxic;feasibility testing;immunoregulation;improved;in silico;individual patient;multiple omics;neoantigens;novel;novel therapeutics;pembrolizumab;prospective;response;standard care;standard of care;taxane;therapeutic effectiveness;therapeutic vaccine;therapeutically effective;tumor;vaccination strategy IRP-3 PROJECT NARRATIVE: Project 3 develops and tests a new immunization strategy to enhance the inductionof cytotoxic lymphocytes (CTLs) against multiple patient-specific tumor antigens by targeting cancer cellsendogenous dendritic cells (DCs) and ex vivo generated DCs. It tests the overall hypothesis that applying DCsloaded with synthetic patient-specific neoantigen peptides will bypass the existing mismatch between antigenspresent on patients' cancer cells and own DCs inducing CTLs particularly effective in killing OvCa tumors.Results of Project 3 will be translated into development of novel therapeutic vaccines and prospectively intonew modes of immune checkpoint inhibition and adoptive T cell therapies. NCI 10691889 8/1/23 0:00 PAR-18-313 5P50CA159981-09 5 P50 CA 159981 9 9/18/13 0:00 8/31/26 0:00 ZCA1-RPRB-8 7007 7087025 "KALINSKI, PAWEL " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 247705 270566 93758 ABSTRACT: Despite increasing efficacy for standard of care of ovarian cancer (OvCa) the overall five-yearsurvival of OvCa patients is only 47.6%. Polyclonal T cell responses against multiple cancer- and patient-specific antigens are the key element of effective cancer immunity and resulting outcomes.Project 3 develops and tests a new immunization strategy to enhance the induction of cytotoxic lymphocytes(CTLs) against multiple patient-specific epitopes by targeting cancer cells endogenous dendritic cells (DCs)and ex vivo generated DCs. We will compare the immunopeptidomes on OvCa cells and two populations ofDC specialized in CTL induction: ex-vivo generated alpha-type-1-polarized (DC1s) and endogenousconventional DCs (cDC1s) which share the inflammatory BATF3/IRF8 phenotype and elevated ability tocross-present multiple cancer-cell-associated antigens to CD8+ T cells.Combining our unique in vitro sensitization (IVS) and bioinformatics approaches we will test the overallhypothesis that the mismatch between immunopeptidomes of OvCa cells and DCs presenting antigensfrom cancer cells limits the therapeutic effectiveness of spontaneous and vaccination-induced CTLresponses. We further hypothesize that DC1s loaded with synthetic patient-specific neoantigen peptideswill bypass such mismatch inducing CTLs particularly effective in killing OvCa tumors. We propose thefollowing three Aims:Specific Aim 1: Compare the antigenic specificity of human CD8+ T cells induced by DCs loaded withautologous OvCa cells tumor-eluted peptides and patient-specific neoantigen peptides identified byin-silico approaches. We hypothesize that CTLs induced by autologous cancer cell-loaded DC1s orcDC1s contain large number of CTLs which are irrelevant for tumor recognition which deficit can becorrected by loading DCs with synthetic neoantigen peptides specific to each patient's OvCa cells.Specific Aim 2: Evaluate the immunopeptidome differences between OvCa cells and tumor-loadedDC1s and endogenous cDC1s and test the feasibility of their adjustment. We hypothesize thatimmune adjuvants and inflammatory mediators can be used to modulate APM patterns andimmunopeptidomes of DCs and OvCa cells to enhance the antigenic match between arising CTLs andautologous OvCa cells.Specific Aim 3: Determine the feasibility safety and clinical efficacy of DC1 vaccines loaded withpatient-specific neoantigen peptides combined with PD-1 blockade. Each patient will receive 8 coursesof DC1 vaccines loaded with patient-specific neoantigens and pembrolizumab. Guided by the results of Aim2 the patients may also receive systemic immune modulation to increase the visibility of their own OvCacells to DC1-induced CTLs and reduce immune suppression. Clinical efficacy will be monitored by iORR.Predicted Impact: Results of Project 3 will be translated into development of novel therapeutic vaccines andprospectively into new modes of immune checkpoint inhibition and adoptive T cell therapies. +No NIH Category available Ablation;Ascites;Bioinformatics;Biological Assay;Biometry;Blood specimen;Cancer Center Support Grant;Cell Culture Techniques;Cell Separation;Cells;Clinical Research Protocols;Clinical Trials;Collaborations;Computers and Advanced Instrumentation;Confusion;Cryopreservation;Cytometry;DNA methylation profiling;Data;Data Analyses;Databases;Development;Dimensions;Education;Ensure;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Equipment;Flow Cytometry;Genetic;Genomics;Genomics Shared Resource;Genus Hippocampus;Goals;Human Resources;Image;Immune;Immune response;Immunoassay;Immunogenomics;Immunologic Monitoring;Immunologics;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Individual;Infrastructure;Label;Laboratories;Malignant neoplasm of ovary;Management Information Systems;Measures;Metabolic;Methodology;Monitor;Morphology;Mutation;Outcome Measure;Pathology;Pathway Analysis;Patient Participation;Patients;Peptide Vaccines;Peptides;Performance;Peripheral Blood Mononuclear Cell;Procedures;Program Research Project Grants;Qualifying;Quality Control;RNA analysis;Reagent;Reproducibility;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Role;Running;Sampling;Slide;Specific qualifier value;Specimen;Stains;Standardization;Statistical Data Interpretation;T cell receptor repertoire sequencing;T cell response;T-Lymphocyte;Technology;Testing;Time;Tissues;Tumor Antigens;Vaccines;Validation;Work;antigen detection;assay development;career;cost;cytokine;data acquisition;data exchange;design;enzyme linked immunospot assay;exome sequencing;genomic data;genomic signature;head-to-head comparison;immune function;immunogenic;instrumentation;interest;multidimensional data;multiplexed imaging;neoantigens;neoplasm immunotherapy;next generation sequencing;novel;organizational structure;peripheral blood;programs;technology/technique;transcriptome;transcriptome sequencing;tumor;tumor microenvironment Immunogenomics Core NarrativeThe Immunogenomics Core will be responsible for accurate and reproducible monitoring of immune and genomicchanges in peripheral blood and tumor microenvironment in patients with ovarian cancer. The ImmunogenomicsCore will leverage the expertise of Center for Immunotherapy and Shared Resources at Roswell Park.Centralization and standardization of the performance of the immunologic and genomic assays will facilitatehead-to-head comparisons of the immune/genomic signatures and changes being induced by cutting-edgeimmunotherapies in the Roswell Park Ovarian Cancer SPORE. The Immunogenomics Core personnel will workclosely with Individual Research Project Leaders and Core Directors for accomplishing the projects anddiscovering novel findings through the immunologic and genomic data. NCI 10691885 8/1/23 0:00 PAR-18-313 5P50CA159981-09 5 P50 CA 159981 9 9/18/13 0:00 8/31/26 0:00 ZCA1-RPRB-8 7005 10962715 "MATSUZAKI, JUNKO " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 90266 127469 17739 AbstractThe primary objective of the Immunogenomics Core is to perform comprehensive immunophenotypingfunctional analyses and genetic and epigenetic monitoring in peripheral blood and the tumor microenvironmentand investigate tumor antigen-specific immune responses for the immunotherapeutic approaches beingdeveloped and tested in Individual Research Projects 1-3 of the Roswell Park Ovarian Cancer SPORE. It will bealso responsible for immunologic and genomic assays for Career Enhancement Program (CEP) andDevelopmental Research Program (DRP). In conjunction with the Biospecimen and Pathology Core morphologyand localization of immune cells on pre- and post-immunotherapy tumor sections will be analyzed by highlymultiplexed Imaging Mass Cytometry (IMC). Additionally in conjunction with the Biostatistics and BioinformaticsCore neoantigens transcriptome analysis epigenetic changes and TCR sequencing will be determined forIndividual Research Project 1 and 3. The Core will routinely provide SPORE investigators high quality state-of-the-art CyTOF IMC Seahorse assays cell culture cell isolation flow cytometry ELISPOT ELISA multiplexcytokine bead array RNA-seq whole exome sequencing TCR-seq and Methyl-Seq.The specific aims of the Immunogenomics Core are to:1) Design and optimize immunologic and genomic assays for Individual Research Projects CEP and DRP and provide state-of-the-art immunophenotyping transcriptome analysis TCR sequencing epigenetic changes and functional analyses of immune cells in peripheral blood and tumor microenvironment of patients who receive advanced immunotherapies in the Ovarian Cancer SPORE.2) Run whole exome sequencing for tumor and peripheral blood samples to identify mutations and HLA types and confirm T-cell reactivity against the predicted neoantigens for DC-peptide vaccine in Individual Research Project 3.In addition to these established immunoassays the Immunogenomics Core will be developing newmethodologies/markers and making them available to the SPORE investigators. It also has a significanteducational role working with all SPORE investigators including PIs technicians and young investigators ontheir assay development proper use of instrumentation and interpretation of their data. +No NIH Category available Acceleration;Address;Basic Science;Bioconductor;Bioinformatics;Biometry;Cancer Center Support Grant;Clinical;Clinical Sciences;Clinical Trials;Clinical Trials Data Monitoring Committees;Collaborations;Communities;Comprehension;Computer software;Data;Data Analyses;Data Collection;Data Commons;Data Coordinating Center;Dedications;Development;Ensure;Faculty;Formulation;Fostering;Foundations;Funding;Genomics;Goals;Gynecologic Oncology Group;Immunooncology;Immunotherapy;Individual;Infrastructure;International;Lead;Malignant Neoplasms;Malignant neoplasm of ovary;Manuscripts;Methodology;National Clinical Trials Network;Oncology;Outcome;Policies;Privacy;Procedures;Productivity;Program Research Project Grants;Protocol Compliance;PubMed;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Services;Techniques;Text;Translational Research;Translations;United States National Institutes of Health;anticancer research;bioinformatics resource;career;clinical application;clinical translation;data management;data portal;data repository;data sharing;data sharing networks;design;high standard;improved;member;novel;open source;prevent;programs;research study;translational oncology;web portal Biostatistics and Bioinformatics Core Project NarrativeThe deployment of appropriate analytic techniques and careful data management are an essentialcomponent for all Roswell Park Ovarian Cancer SPORE projects. The Biostatisticsand Bioinformatics Core will ensure that the essential biostatistics and bioinformatics supportand resources are readily available to all SPORE research projects. NCI 10691884 8/1/23 0:00 PAR-18-313 5P50CA159981-09 5 P50 CA 159981 9 9/18/13 0:00 8/31/26 0:00 ZCA1-RPRB-8 7004 7084656 "KARRISON, THEODORE GEORGE" Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 85760 82623 38749 PROJECT SUMMARY/ABSTRACTThe deployment of appropriate analytic techniques and careful data management are an essential componentfor all Roswell Park Ovarian Cancer SPORE projects. The Biostatistics and Bioinformatics Core (Core C) willensure that essential biostatistics and bioinformatics supports and resources are readily available to all SPOREresearch projects. The goals of the Core are to improve the productivity of the Individual Research Projectinvestigators reduce the barriers for access to analytic expertise maintain high standards for data collection andmanagement design and perform rigorous analytical strategies and foster a collaborative and supportiveresearch community.The Biostatistics and Bioinformatics Core will assist basic translational and clinical researchers of the SPOREwith proper formulation refinement and execution of study objectives by applying the appropriate biostatisticsand bioinformatics analyses and providing the appropriate interpretation of their results in terms of bothstrengths and limitations. We will ensure a priori that Developmental Research Program and CareerEnhancement Program projects are feasible from a biostatistical and bioinformatics perspective. TheBiostatistics and Bioinformatics Core will ensure that appropriate data are collected; the data are of the highestquality and meet regulatory standards for privacy; and the data are those required to answer a study questionnecessary for administrative reporting needed to establish protocol compliance and/or will be included in amanuscript. We will prepare Data Safety Monitoring Board reports and post clinical trial results to clinicaltrials.govin a timely and compliant manner and ensure compliance to NIH policy and assist with data sharing of SPOREdata via the NCI Cancer Research Data Commons infrastructure and similar NIH-designated data repositories.The Biostatistics and Bioinformatics Core will develop and implement new and novel statistical and bioinformaticsmethodology and the related software as needed to address all study objectives. We will implement softwaresolution and best practice to boost robust and reproducible research. Our proposed Biostatistics andBioinformatics Core will capitalize on a number of existing well-functioning NCI-funded units housed within theRoswell Park Department of Biostatistics and Bioinformatics. +No NIH Category available Address;Affect;Biological;Biological Assay;Biological Markers;Brain Neoplasms;Chromatin;Clinical;Clinical Management;CryoCore Gun;Cryopreservation;DNA;DNA Methylation;DNA Repair Enzymes;Data;Deamination;Devices;Disease;Eosine Yellowish;Epigenetic Process;Excision;Formalin;Freezing;Genetic Transcription;Glioblastoma;Goals;Histologic;Histology;Histopathology;Ice;Immunoprecipitation;Individual;Institution;Ischemia;Knowledge;Laboratories;MGMT gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Methods;Methylation;Modification;Output;Paraffin Embedding;Patients;Preparation;Procedures;Process;Protocols documentation;Research;Sampling;Science;Specimen;Stains;Standardization;Technology;Temperature;Testing;Thymine;Time;Tissue Banks;Tissue Embedding;Tissue Preservation;Tissue Sample;Tissues;Transportation;Validation;Variant;Warm Ischemia;biomarker discovery;cancer biomarkers;chemical fixation;clinically relevant;epigenetic marker;evidence base;methylation biomarker;multidisciplinary;neuropathology;novel;personalized medicine;preservation;prognostic;promoter;pyrosequencing;sample fixation;standard of care;statistics;temozolomide;tool;treatment response;tumor;tumor heterogeneity;tumorigenesis Influence of Pre-Analytical Factors in Globlastoma MGMT Promoter Methylation Biomarker Assay Pre-analytical processing of biological samples profoundly impacts data output in research and clinical settings.And yet the relative effects of variables associated with tissue collection preservation transport storagesampling and analytic processing on the reliability of epigenetic biomarkers in cancer studies including theuniformly lethal brain tumor glioblastoma have not been rigorously examined. This proposal addresses theneed to define pre-analytical variables in the clinically used glioblastoma MGMT promoter methylation biomarkerassay. NCI 10691883 6/19/23 0:00 PAR-18-947 5U01CA246503-04 5 U01 CA 246503 4 "RAO, ABHI" 6/1/20 0:00 5/31/25 0:00 ZCA1-RTRB-R(J3) 1864758 "BOMSZTYK, KAROL " "ROSTOMILY, ROBERT C" 7 INTERNAL MEDICINE/MEDICINE 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF MEDICINE 981959472 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 405793 NCI 265217 140576 Discovery of biomarkers and their clinical validation is critically important for personalized medicine. Forglioblastoma (GBM) a uniformly lethal brain cancer median survival is only 12-18 months with standard therapy.In GBM methylation of the DNA-repair enzyme MGMT gene promoter is an established prognostic epigeneticbiomarker which while potentially critical to guide standard-of-care temozolomide (TMZ) therapy is currentlyunderutilized. Further the lack of correlation between MGMT promoter methylation status and treatmentresponse in some patients may be related to technical aspects of pre-analytical processing. Thus there is anunmet need for evidence-based knowledge of pre-analytical variables in order to establish standardizedprotocols for the assessment of MGMT promoter methylation status in GBM. To study transcriptional and epigenetic alterations in disease we developed PIXUL-ChIP for high-throughput sample preparation and analysis of tissues. To facilitate sampling of frozen and FFPE tissues wedeveloped the CryoCore Gun for extracting multiple small tissue cores. These tools provide a powerful integratedplatform for simultaneous processing and analysis of multiple small samples from individual tumors. Pre-analytical processing of biological samples profoundly impacts data output. However the relativeimportance of variables encountered during tissue collection preservation transport storage sampling andanalytic processing for the reliability of assessment of epigenetic cancer biomarkers (including GBM) has notbeen rigorously examined. The goal of this U01 application is to define pre-analytical procedure variablesfor GBM biospecimens in order to minimize ex-vivo MGMT promoter methylation changes whilepreserving tissue integrity. The following aims are proposed. Aim1. To define the scope of intratumoral heterogeneity of GBM MGMT methylation and itsrelation to histology to guide sampling needs in individual tumors. Aim2. To test effects of ex-vivo warm ischemia on GBM MGMT promoter methylation analysis andhistology. Aim3. To define the effects of tissue freezing/cryostorage/thawing on GBM MGMT promotermethylation analysis and histology. Aim4. To define the effects of formalin fixation and paraffin embedding (FFPE) tissue preservationon GBM MGMT promoter methylation analysis. Advances in biospecimen science are critical to facilitate the discovery and use of epigenetic biomarkers.By interrogating standard variables associated with tissue collection preservation storage and sampling in aclinically relevant GBM epigenetic assay and through application of a novel device CryoCore Gun to sampletumor heterogeneity this proposal is highly aligned with the intent of the NCI Biospecimen Science U01 FOA. 405793 +No NIH Category available Address;Appointment;Area;Award;Basic Science;Biological Assay;Biomedical Research;Caliber;Career Mobility;Cellular biology;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communities;Computational Biology;Data;Dedications;Development;Development Plans;Diagnosis;Environment;Ethnic Population;Evaluation;Faculty;Fostering;Funding;Genetic;Health Care Research;Hematology;Immunology;Individual;Institution;Investigational Therapies;Knowledge;Medical Informatics;Memorial Sloan-Kettering Cancer Center;Mentors;Minority;Modeling;Molecular Biology;Oncology;Pathogenesis;Pathology;Peer Review;Physicians;Postdoctoral Fellow;Prevention;Qualifying;Receptor Cell;Recommendation;Research;Research Infrastructure;Research Personnel;Research Proposals;Resources;Scientist;Talents;Training;Translational Research;Universities;Woman;Work;Writing;career;career development;chimeric antigen receptor;chimeric antigen receptor T cells;clinical care;computational platform;experience;improved;leukemia;leukemia treatment;medical schools;member;patient derived xenograft model;programs;racial population;recruit;research faculty;social;tool;translational research program Career Enhancement Program PROJECT NARRATIVEThe Career Enhancement Program (CEP) provides support to talented junior faculty or established facultywho wish to attain additional training who are conducting research related to the diagnosis prevention ortreatment of leukemia. NCI 10691875 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 7001 9547114 "ABDEL-WAHAB, OMAR " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 16860 40837 32507 ABSTRACTThe MSK SPORE in Leukemia is dedicated to supporting the ongoing development of talented researcherswho are pursuing independent translational research programs in leukemia. The Career EnhancementProgram (CEP) will provide research awards to support the scholarly development of 1) junior faculty frombasic or clinical research backgrounds pursuing research related to the prevention diagnosis and treatment ofleukemia; 2) new or established faculty in other subject areas who wish to attain additional training andexperience that will allow them to address areas of unmet need related to leukemia research; and 3) seniorpostdoctoral fellows who will continue their research program in leukemia and who are within one year of afaculty appointment. The SPORE PIs Drs. Omar Abdel-Wahab and Martin Tallman will oversee the programand each brings considerable knowledge and expertise in basic clinical and translational science to CEPactivities. We will recruit up to two qualified investigators per year to receive CEP funding with possibility ofrenewal for a second year. Candidates may be suggested by members of the SPORE Executive CommitteeProject Leaders/Core Directors the Internal Advisory Board or at the recommendation of collaboratingindividuals where appropriate. To encourage scientific and social diversity among our applicants we will alsoreach outside established research networks and issue a Research Funding Announcement (RFA) annually toresearch departments across the Tri-institutional area (MSK Weill Cornell Medical College RockefellerUniversity). We will consider candidates pursuing research including but not limited to cell biologycomputational biology experimental therapeutics molecular biology genetics immunology hematologyoncology pathology and medical informatics. Applicants will be evaluated on their research proposal as wellas a career development plan written in coordination with a proposed mentor. Successful awardees will beevaluated monthly on their research progress and career development milestones achieved. The CEP iscommitted to supporting diversity among our leukemia research faculty and will work closely with theinstitution's Office of Diversity Programs to promote the career advancement of women and underrepresentedracial and ethnic groups in our healthcare research community. +No NIH Category available Basic Science;Biological Markers;Blood;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Communities;Community Physician;Computing Methodologies;Dedications;Development;Diagnosis;Disease Management;Doctor of Philosophy;Faculty;Funding;Goals;Grant;Hematologic Neoplasms;Home;Immunology;Incubators;Individual;Institution;Investigation;Malignant Neoplasms;Memorial Sloan-Kettering Cancer Center;Molecular Genetics;Monitor;Oncology;Pathogenesis;Patients;Peer Review;Pilot Projects;Policies;Prevention;Procedures;Program Research Project Grants;Refractory;Relapse;Research;Research Personnel;Research Priority;Research Project Grants;Research Proposals;Research Support;Science;Scientist;Series;Talents;Technology;Translational Research;Treatment Protocols;Underrepresented Minority;Universities;Woman;Work;bench-to-bedside translation;clinical predictors;community center;high reward;high risk;improved;innovation;leukemia;leukemia treatment;medical schools;meetings;member;new technology;novel;novel strategies;programs;relapse patients;response;targeted treatment;therapy resistant;translational cancer research;treatment response;working group Developmental Research Program NARRATIVEThe majority of leukemia patients relapse after initial therapies underscoring the need for improved targetedtherapies and better predictors of clinical response. The Developmental Research Program supportsinnovative pilot projects technologies and research collaborations that have the potential to improve thediagnosis prevention and/or treatment of leukemia. NCI 10691874 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 7000 7776127 "LEVINE, ROSS L" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 16860 40837 32507 ABSTRACTThe goal of the Developmental Research Program (DRP) of the Memorial Sloan Kettering Cancer CenterLeukemia SPORE is to provide seed funding for pilot projects that show potential to make meaningfuladvances in leukemia prevention diagnosis and/or treatment. Supplemented by institutional funds the DRPwill provide one to two years of funding to talented investigators or research teams from clinical and/or basicscience backgrounds from the MSK community neighboring institutions or in support of collaborations withother Leukemia SPOREs. We will invite candidates annually to submit research proposals for peer-review bya committee of experts in leukemia and translational cancer research. We will prioritize research proposals thatdescribe high-risk/high-reward hypothesis-driven work that has the potential to advance new avenues ofleukemia investigation or proposals that bring together exciting collaborative teams who will address ongoingproblems in the leukemia field using new approaches and technologies. Applicants for DRP funding shouldpossess an MD and/or PhD degree and should hold independent-investigator status as a faculty member orclinical researcher/research scientist at their institution. Applicants should have demonstrated a clearcommitment to translational cancer research related to leukemia. The DRP investigators will be considered fullmembers of the MSK SPORE in Leukemia and will participate ongoing meetings and research seminars(regular meetings and seminars held by the Leukemia Working Group Leukemia Disease Management TeamCenter of Hematologic Malignancies Science in Focus) as well as specialized SPORE meetings (annual multi-institutional SPORE Retreat; SPORE Seminar Series; monthly progress meetings). The DRP projects will bemonitored by the Executive Committee at monthly progress meetings and will be reviewed to evaluatepotential to grow into a full SPORE research project in the current or upcoming grant cycle. The DRPis committed to adhering to and supporting the MSK policies and procedures to promote diversity andstrengthen the participation of women and individuals from underrepresented minorities. +No NIH Category available Acute Myelocytic Leukemia;Acute leukemia;Address;Adult;Aftercare;Antigen Targeting;Antigens;Antitumor Response;CAR T cell therapy;CD19 gene;Cell surface;Characteristics;Chemoresistance;Clinical;Clinical Treatment;Correlative Study;Development;Disease;Disease Marker;Disease remission;Goals;Hematopoiesis;Hematopoietic stem cells;Human;IL18 gene;Immune Targeting;Immune response;Immunophenotyping;Incidence;Investigational Therapies;Large-Cell Lymphomas;Maximum Tolerated Dose;Mediating;Memorial Sloan-Kettering Cancer Center;Minority;Myeloid Cells;Natural regeneration;Outcome;Pathologic;Patients;Phase I Clinical Trials;Recurrent disease;Refractory;Regimen;Relapse;Remission Induction;Safety;Secondary to;Survival Rate;T cell response;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Transplantation;Treatment outcome;Vaccination;Variant;Vertebral column;acute myeloid leukemia cell;anti-tumor immune response;cancer cell;chemotherapy;chimeric antigen receptor T cells;cytokine;efficacy evaluation;immune cell infiltrate;immune clearance;immune reconstitution;immunogenicity;improved;leukemia;leukemia/lymphoma;leukemic stem cell;neoplastic cell;novel;patient derived xenograft model;pre-clinical;response;response biomarker;safety assessment;therapy development;tumor;tumor microenvironment Project 4: Chimeric Antigen Receptor T Cell Therapy for the Treatment of Acute Myeloid Leukemia NARRATIVEThere is a critical need to develop therapies to eliminate leukemia-stem cells (LSCs) as a treatment for acutemyeloid leukemia (AML). To this end we have developed a novel chimeric antigen receptor (CAR) T cellplatform targeting CD371 a cell surface marker present on the vast majority of AML cells and LSCs but absentfrom normal hematopoietic stem cells. We will determine the safety and efficacy of CD371-targeted IL18-secreting CAR T cells in patient-derived xenografts models and by conducting a phase I clinical trial inrelapsed/refractory AML patients. NCI 10691873 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6999 8642664 "BRENTJENS, RENIER JOSEPH" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 311223 204736 162971 ABSTRACTThere is an urgent and critical need for the development of leukemia stem cell (LSC)-directed therapeuticapproaches for the treatment of acute myeloid leukemia (AML). One such strategy is targeting antigens thatare specific to LSCs but absent from normal hematopoietic stem cells (HSCs). CD371 (CLEC12A CLL-1)which is present on mature myeloid cells has been described as one such targetable disease marker given itspresence on both bulk AML cells and LSCs. Although not ubiquitously expressed on all AML cells it isexpressed in up to 95% of AML patients is enriched on LSCs and chemoresistant AML subpopulations andmost importantly is absent on HSCs.We have successfully developed and validated a fully-human CD371-targeted chimeric antigen receptor (CAR)T cell product which also secretes IL-18. Given that our CD371-targeting motif is entirely human it is expectedto have reduced immunogenicity and thus minimizes host-mediated CAR T cell-directed immune elimination inthe context of constitutive IL18 secretion. In addition IL18 secretion is predicted to enhance CAR T cellpersistence and modulation the tumor microenvironment (TME) by increasing and activating immune cellinfiltrates leading to the induction of an endogenous T cell mediated anti-tumor immune-response capable oferadicating antigen-negative tumor cell subpopulations.Our central hypothesis is that CD371-targeted IL18-secreting CAR T cells will lead to eradication of antigen-positive chemoresistant and LSC subpopulations and the induction of an endogenous AML-reactive T cellresponse that will lead to elimination of antigen-negative disease without long-term HSC toxicity. This will betested in AML patient-derived xenograft models of heterogeneously antigen-positive disease (Aim 1) and aphase I clinical trial with CD371-targeted IL18-secreting CAR T cells in patients with relapsed/refractory AML(Aim 2). This effort will therefore assess the safety and efficacy of this novel CAR-T cell approach in bothpreclinical and clinical settings and will also address biomarkers of response and efficacy in numerouscorrelative studies (Aim 3). +No NIH Category available Acute Myelocytic Leukemia;Arginine;Biological Markers;Cell Death;Cell Line;Cells;Chronic Lymphocytic Leukemia;Clinical Trials;Complex;DNA Sequence Alteration;Data;Dependence;Development;Drug Screening;Dysmyelopoietic Syndromes;Enzyme Inhibition;Enzymes;Epigenetic Process;Evaluation;Family;Gene Expression;Genes;Genetic;Heterozygote;Histones;In Vitro;Leukemic Cell;Lymphoblastic Leukemia;Malignant Neoplasms;Mediating;Memorial Sloan-Kettering Cancer Center;Methylation;Molecular;Mutation;Myelogenous;Myeloid Leukemia;Non-Hodgkin's Lymphoma;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Phase I/II Clinical Trial;Phase I/II Trial;Proliferating;Protein Inhibition;Protein-Arginine N-Methyltransferase;Proteins;Proteome;RNA Splicing;Refractory;Research;Safety;Sampling;Solid Neoplasm;Spliceosome Assembly Pathway;Spliceosomes;Therapeutic;Time;Toxic effect;Treatment Efficacy;Work;Xenograft procedure;acute leukemia cell;antagonist;anti-cancer;cancer cell;cancer type;cell growth;cytotoxic;drug testing;early phase clinical trial;effective therapy;efficacy evaluation;epigenome;improved;in vivo;inhibitor;leukemia;leukemia treatment;mRNA Precursor;mutant;participant enrollment;preclinical study;predicting response;predictive marker;protein arginine methyltransferase 2;response;small hairpin RNA;small molecule;therapeutic target Project 3: Therapeutic inhibition of splicing through inhibition of protein arginine methylation in leukemia NARRATIVEWe recently found that inhibiting enzymes called protein arginine methyltranserases (PRMTs) may be aneffective treatment for leukemia. We propose to examine how patients treated with PRMT inhibitors respond atthe molecular level and to identify predictors of response such as genetic mutations in cancer cells whichcould help improve the efficacy of this therapy. PRMT inhibitors are now entering early phase clinical trials forother cancers and we expect this project to facilitate testing of these drugs in leukemia. NCI 10691870 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6998 9547114 "ABDEL-WAHAB, OMAR " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 311223 204737 162970 ABSTRACTLeukemias often display genetic alterations that result in dysregulation of the epigenome. To identify potentialepigenetic vulnerabilities we recently performed a paired in vitro and in vivo shRNA screen in a number ofacute leukemia cell lines. The results showed that myeloid as well as lymphoid leukemia cells are preferentiallydependent on protein arginine methyltransferase (PRMTs) a family of enzymes that dimethylate arginineresidues of many proteins. A number of prior studies have identified PRMT5 as a promising therapeutic targetin cancer which has led to an ongoing phase I clinical trial of a PRMT5 inhibitor for patients with refractorysolid tumors and Non-Hodgkin's lymphoma. However which substrates of PRMTs are most critical for anti-cancer effects of PRMT inhibition remains unknown and biomarkers predicting response to PRMT inhibitionare greatly needed.Toward understanding the anticancer effects of PRMT inhibitors we have also found that blocking PRMTfunction perturbs RNA splicing and that inhibiting either symmetric (mediated by PRMT5) or asymmetricdimethyl arginine methylation (by Type I PRMTs) results in strong preferential killing of spliceosomal mutantleukemias over their wild-type (WT) counterparts. Moreover we have observed synergistic effects ofcombining both type I with type II PRMT inhibition and/or inhibition of core spliceosome function. We thereforehypothesize that the main cytotoxic effect of PRMT inhibition results from modulation of splicing.We will examine our hypothesis by characterizing the effects of inhibiting type I PRMT or type II PRMTs onpre-mRNA splicing gene expression and the methyl-arginine proteome in WT or spliceosomal-mutantleukemia cells (Aim 1). We will also evalute whether combining inhibitors of type I PRMTs type II PRMTs andthe splicing factor SF3b enhances toxicity to myeloid and lymphoid leukemia cells and the relationshipbetween these inhibitors' efficacy and mutations in various splicing factor genes (Aim 2). Finally we will identiybiomarkers of efficacy of PRMT5 inhibition using samples from a phase I/II trial of GSK's small moleculePRMT5 antagonist (Aim 3) for the treatment of patients with refractory AML CMML and MDS.This project stands to greatly improve understanding of the molecular basis for the efficacy of PRMT inhibitorsin cancer and to advance these drugs toward clinical trials in leukemia. +No NIH Category available 17p;Acute Myelocytic Leukemia;Address;Animal Model;Antitumor Response;Biological;Cancer Model;Cell Line;Cessation of life;Chemoresistance;Chromatin;Chromosome abnormality;Chromosomes;Clinical;Clinical Trials;Collaborations;Complex;Cytogenetic Analysis;Data;Dependence;Development;Diagnosis;Disease;Disease model;Drug Targeting;Enzymes;Epigenetic Process;Event;FLT3 gene;Face;Frequencies;Gene Expression;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genome;Genomics;Genotype;Human;JAK2 gene;Karyotype;Karyotype determination procedure;Ketoglutarate Dehydrogenase Complex;Malignant Neoplasms;Memorial Sloan-Kettering Cancer Center;Metabolism;Methods;Modeling;Molecular;Mutation;Mutation Analysis;Oncogenes;Oncogenic;Oncoproteins;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Pre-Clinical Model;Prognosis;Proliferating;Proteins;Recurrence;Research;Research Personnel;Resistance;Resolution;Resources;Safety;Sampling;Solid;Specimen;Study models;System;TP53 gene;Testing;Therapeutic;Tumor Suppressor Genes;Tumor Suppressor Proteins;Work;actionable mutation;acute myeloid leukemia cell;antileukemic activity;candidate validation;chemotherapy;chromosome 5q loss;cohort;cost;diagnostic accuracy;digital;effective therapy;human disease;human model;improved;inhibitor;innovation;insight;leukemia;leukemia treatment;mouse model;mutant;new therapeutic target;next generation sequencing;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;pharmacologic;pre-clinical;preclinical study;programs;self-renewal;small molecule inhibitor;therapeutic development;therapeutic target;therapeutically effective;tool;transcriptome;transcriptome sequencing;tumor;tumorigenic;whole genome Project 2: Defining and exploiting genetic dependencies in complex karyotype AML NARRATIVEApproximately 10% of cases of acute myeloid leukemia (AML) have a complex karyotype (CK) meaning thatthe cancer displays 3 or more chromosomal abnormalities. These CK-AML patients face a dismal prognosisas there are no effective treatment options. In this project innovative genetic and modeling approaches will beused to better characterize human AML and to discover and validate targets for much-needed novel therapies. NCI 10691867 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6997 1928317 "LOWE, SCOTT W." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 311223 204737 162970 ABSTRACTComplex karyotype acute myeloid leukemia (CK AML) is defined by the presence of 3 or more detectablecytogenetic abnormalities and has one of the least favorable prognoses of any leukemia genotype. Genomiccharacterization indicates that this disease lacks conventional druggable oncoproteins but instead ischaracterized by a set of recurrent segmental deletions and mutations in the TP53 tumor suppressor gene thelatter of which are absent from normal karyotype AML and confer resistance to standard chemotherapies. Tobetter characterize the pathogenesis of CK AML and to develop new strategies to treat this disease we willexhaustively analyze the genomes of a large cohort of CK AML samples using a new low-cost high-resolutionplatform optimized in our group called digital karyotyping. These molecular features will be correlated withpatient outcomes data and used to generate murine and human models that accurately recapitulate CK AML-specific features. We will use these models to test a new therapeutic strategy for countering the pro-tumorigeniceffects of p53 loss. This concept builds on preliminary data showing that p53 loss can perturb cellular metabolismin a manner that alters gene expression and drives aberrant self-renewal and that reversing these effects withsmall molecule inhibitors can drive differentiation of p53-deficient AML. Specifically we have found that p53mutations reduce levels of the metabolite aKG producing similar effects of oncogenic IDH1/2 mutant proteinsthat have proven to be drug targets in other sub-types of AML. In models studied to date the tumor suppressiveeffects of p53 are recapitulated by inhibiting the TCA enzyme 2-oxoglutarate dehydrogenase (OGDH) and assuch we consider OGDH a prime candidate for validation and development in CK AML. Successful completionof the proposed research will produce a detailed understanding of the genetic changes that accompany CK AMLand allow for more faithful modeling of human disease. In addition we hypothesize that oxoglutaratedehydrogenase (OGDH) a promising therapeutic target for the treatment of CK AML. Validating our novel drugtarget will pave the way for clinical trials in this indication. Given the paucity of effective therapeutic options forpatients with CK AML the proposed studies address an urgent unmet clinical need. +No NIH Category available Acute Myelocytic Leukemia;Alleles;Biological Assay;Chemotherapy-Oncologic Procedure;Clinical;Clinical Research;Clinical Trials;Combined Modality Therapy;Core Facility;Coupled;Credentialing;Development;Disease;Dose;Enrollment;FLT3 gene;FLT3 inhibitor;Genes;Genetic study;Genomics;Genotype;Goals;In complete remission;Investigation;Isocitrates;Memorial Sloan-Kettering Cancer Center;Modeling;Molecular;Mutate;Mutation;Pathogenesis;Pathway interactions;Patients;Recurrence;Refractory;Relapse;Research Project Grants;Resistance;Role;Sampling;Science;Signal Transduction;Testing;Therapeutic;Therapeutic Trials;Treatment Efficacy;Validation;improved outcome;inhibitor;inhibitor therapy;insight;leukemia;mouse model;mutant;novel;novel therapeutic intervention;novel therapeutics;patient subsets;pre-clinical;preclinical study;prevent;programs;relapse patients;resistance mechanism;response;small molecule;targeted treatment;therapy resistant Project 1: Increasing therapeutic efficacy in isocitrate dehydrongenase (IDH)mutant acute myeloid leukemia (AML) NARRATIVEThe identification of IDH1/IDH2 mutations in acute myeloid leukemia (AML) led to the development andapproval of the first small molecule IDH1 (ivosidenib) and IDH2 (enasidenib) inhibitors for IDH1/2 mutant AML;however not all patients respond to IDH1/2 inhibition. We will use preclinical studies and analysis of primarysamples from patients treated with IDH1/2 inhibitors to delineate molecular predictors of sensitivity andresistance to IDH inhibitors and test novel combination therapeutic approaches to increase therapeuticefficacy in IDH1/2-mutant AML. The goal is to use this insight to test new therapeutic approaches inmechanism-based clinical trials aimed to improve outcomes in this molecularly defined AML subset. NCI 10691865 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6996 7776127 "LEVINE, ROSS L" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 311223 204737 162970 ABSTRACTWe and others have genetically and functionally characterized the contribution of recurrent somatic alterationsto acute myeloid leukemia (AML) pathogenesis including IDH1/IDH2 mutations. This has led to novel insightsinto AML pathogenesis and led to the identification and validation of IDH1/2 inhibitors as a therapeuticapproach in AML; the first small molecule IDH1 (ivosidenib) and IDH2 (enasidenib) inhibitors are now approvedfor relapsed/refractory IDH1/2 mutant AML. However not all patients respond to IDH1/2 inhibition and a subsetof patients relapse following responses to IDH inhibition. We will use preclinical studies and analysis of primarysamples from patients treated with IDH1/2 inhibitors to delineate molecular predictors of sensitivity andresistance to IDH inhibitors and to test new combination therapeutic approaches to increase therapeuticefficacy in IDH1/2-mutant AML. This will include mechanism-based clinical trials in genetically defined subsetsincluding a novel mechanism-based clinical trial combining FLT3 and IDH1/2 inhibition in patients withconcurrent mutations. Project 1 will interact with all 3 other Leukemia SPORE research projects and will utilizeall core facilities in this program. Our collaborative efforts will include genomic interrogation of patient samplespreclinical therapeutic and mechanistic studies and clinical trials with extensive correlative science aimed tonominate the best combination therapeutic approaches for AML patients with IDH1/2 mutations. +No NIH Category available Address;Bioinformatics;Biological Specimen Banks;Biometry;Biostatistics Core;Clinical Data;Clinical Research;Consult;Data;Data Analyses;Data Analytics;Databases;Dedications;Deposition;Development;Ensure;Experimental Designs;Formulation;Genomics;Goals;Graph;Hematologic Neoplasms;Individual;Laboratories;Leadership;Manuscripts;Memorial Sloan-Kettering Cancer Center;Methodology;Modification;Molecular;Monitor;Nature;Preparation;Publications;Reporting;Reproducibility;Reproduction spores;Research;Research Design;Research Personnel;Research Project Grants;Role;Sample Size;Science;Statistical Data Interpretation;Statistical Methods;System;Validation;Work;Writing;analytical method;clinical trial analysis;data format;design;experience;genome repository;genomic data;human tissue;laboratory experiment;leukemia;member;novel;public repository;translational goal Core 3: Biostatistics PROJECT NARRATIVEThe Biostatistics Core will provide direct support for study design rigorous statistical methods and timelyexecution of data analysis for all research projects and developmental projects in the MSK Leukemia SPORE. NCI 10691863 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6995 6878965 "GONEN, MITHAT " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 69033 69887 55630 ABSTRACTThe role of the Biostatistics Core is to support the investigators of the Leukemia SPORE in their researchefforts including laboratory experiments molecular studies and analysis of clinical trial and correlative data.Prior to the initiation of all studies Core staff will consult with SPORE investigators to discuss the underlyingscientific premise and translational goals of the project to help the investigators select the most efficient androbust analytical methods and to estimate sample sizes to ensure adequate power to address studyobjectives. In laboratory experiments Core members will assist in the formulation of the experimental designand in the analysis and interpretation of the data at the conclusion of the study. For molecular studies usinghuman tissues Core members will closely interface with the members of the Genomics Core and will haveprimary responsibility for merging molecular and clinical data and for performing appropriate statistical andbioinformatics analyses. The members of the Biostatistics Core will also work with SPORE investigators toformat data for publication and assist with deposition of genomic data into public repositories to facilitatevalidation of results by external investigators using their own analytical methods. For clinical studies they willwork with SPORE investigators to help set up effective systems to collect and track all required data. As theresearch project (RP) studies proceed Core staff will review project databases and monitor the quantity andquality of data collected and they will suggest modifications to the design and analysis plans as appropriate.When studies are finished the Core will conduct correct and efficient data analyses. They will also assistinvestigators with the preparation of any necessary graphs and tables the interpretation of results thepreparation of presentations and manuscripts and will consult on the design of subsequent research. If currentstatistical methodology does not adequately address a research question alternative methodologies will bedeveloped. We believe that this experienced and collaborative Core is well configured to provide the SPOREwith a high level of statistical leadership and support that will enhance the efficiency quality and quantitativerigor of its science. +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Animals;Autologous;Bioinformatics;Biological Products;Biological Specimen Banks;Biometry;Blood;Blood specimen;Bone Marrow;Cell Therapy;Clinical;Collaborations;Combined Modality Therapy;Communities;Complex;Consultations;DNA;Data;Databases;Dedications;Development;Disease;Disease Management;Doctor of Philosophy;Documentation;Ensure;Freezing;Gene Expression Profiling;Generations;Genetic study;Genetically Engineered Mouse;Genomics;Guidelines;Health Insurance Portability and Accountability Act;Hematology;Histologic;Hospital Units;Hospitals;Human;IL18 gene;Immunocompromised Host;Implant;Infrastructure;Institutional Review Boards;Karyotype;Label;Leadership;Memorial Sloan-Kettering Cancer Center;Mission;Modeling;Molecular;Mus;Nucleic Acids;Oncology;Pathology;Patients;Play;Pre-Clinical Model;Process;Proteins;Protocols documentation;RNA;RNA Splicing;Recording of previous events;Research;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Resources;Role;Safety;Sampling;Services;Specimen;Standardization;Support Groups;Testing;Therapeutic;Therapeutic Research;Therapeutic Studies;Tissue Banks;Tissues;Toxic effect;Toxicology;Translational Research;Translations;Transplantation;Treatment Efficacy;Tube;Whole Blood;Xenograft procedure;biobank;cancer therapy;chimeric antigen receptor T cells;clinical translation;clinically relevant;co-clinical trial;combinatorial;design;effective therapy;efficacy study;efficacy testing;human tissue;in vivo;in vivo Model;inhibitor;leukemia;leukemia treatment;mutant;novel;novel therapeutics;participant enrollment;patient privacy;pre-clinical;preclinical development;preclinical efficacy;preclinical trial;relational database;sample collection;therapy development;therapy resistant;tibia;tumor Core 2: Biospecimen NARRATIVEThe development of more effective therapies for cancer requires preclinical tumor models that closely mimicthe diseases being studied. The Biospecimen Core brings together specialized expertise in animal and patient-derived tumor modeling to create AML-specific tumor models and to test new strategies to treat AML patients. NCI 10691862 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6994 10386725 "DE STANCHINA, ELISA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 102437 88487 70435 ABSTRACTThe mission of the Biospecimen/Pathology Core will be to assist investigators with the development of preclinicalmodels that accurately reflect the genomic landscape of human acute myeloid leukemia (AML) and their use inpreclinical efficacy studies. The Core will play a central role in annotating distributing and tracking biospecimensfrom AML patients enrolled in biospecimen banking and therapeutic research protocols. Detailed biospecimenannotation including documentation of pre-analytic processing variables pathology findings and patient clinicalhistory will be recorded in robust relational databases. The Core will be composed of two highly integrated units:The Tissue Collection and PDX Modeling Unit will be responsible for providing access to human tissues andPDX models. The Mouse Hospital Unit will provide an integrated infrastructure to support pre- and co-clinicaltrials exploring efficacy of single agent and/or combinatorial treatments in relevant models using standardizedprotocols that mimic those used in patients. The MSK Mouse Hospital houses the only academic GLP-compliantfacility in the region providing investigators with the unique opportunity to perform GLP-compliant IND-enablingsafety toxicology studies for novel compounds and biologics in-house. The specific aims of the core are:Aim 1. To maintain and expand a model AML resource designed to annotate and distribute biospecimensfor translational AML research.Aim 2: To assist in the generation of AML PDX models and access to human tissues banked at MSKalong with their clinical and genomic annotation.Aim 3: To design and execute toxicity and therapeutic studies exploring tolerability and efficacy of singleagent and combination therapies against xenograft primary transplant and genetically engineeredmouse leukemia models (GEMMs).Each of the research projects relies extensively on the Biospecimen/Pathology Core to achieve their translationalresearch objectives. For RP 1 the core will help with delineating molecular predictors of sensitivity and resistanceto IDH inhibitors and testing novel combination therapeutic approaches to increase therapeutic efficacy inIDH1/2-mutant AML. For RP 2 the core will provide materials for complex karyotype (CK) AML genetic studiesaid in the generation of models that accurately recapitulate CK AML-specific features and use these models totest the tolerability and efficacy of novel OGDH inhibitors. For RP 3 the core will help with co-clinical trials ofPRMT5 inhibitors in PDX models and help perform preclinical in vivo studies of PRMT and other splicinginhibitors. For RP 4 the Core will support the group in establishing PDX models of AML to test the efficacy ofautologous CD371-targeted IL18-secreting CAR T cells. +No NIH Category available Achievement;Advocate;Biometry;Clinical;Clinical Research;Collaborations;Communication;Communities;Data Management Resources;Decision Making;Development;Education;Ensure;Equity;Extramural Activities;Financial Support;Fostering;General Population;Genomics;Grant;Health Services Accessibility;Human Resources;Individual;Infrastructure;Institution;Manuscripts;Medical;Memorial Sloan-Kettering Cancer Center;Monitor;National Cancer Institute;Occupational activity of managing finances;Patients;Pilot Projects;Publications;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Resources;Services;Support System;Training;Translational Research;career;clinical database;data management;data sharing;editorial;leukemia;meetings;outreach;patient oriented;programs;translational progress Administrative Core PROJECT NARRATIVEThe Administrative Core provides centralized scientific managerial and administrative oversight of the SPOREin Leukemia at Memorial Sloan Kettering Cancer Center. The core will leverage institutional resources andcoordinate institutional interactions as well as administrative fiscal regulatory and data management activitiesto facilitate efficient achievement of the translational research objectives. NCI 10691857 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N 6992 9547114 "ABDEL-WAHAB, OMAR " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 69032 69886 55631 ABSTRACTThe purpose of the Administrative Core is to support the translational research objectives of the MSKCCSPORE in Leukemia by serving as the organizational center optimizing collaboration among SPOREinvestigators within and outside MSKCC. The specific aims of the Administrative Core are (1) to provideeffective organization management and coordination for all educational clinical and scientific activities; (2) toprovide comprehensive centralized administrative and financial support to all the components of the SPORE:research projects cores CRP and DEP as well as interactions with EAB and IAB; and (3) To foster effectivecommunication with all key stake-holders both intramural and extramural including the broader scientificcommunity cross-institutional collaborators the NCI our patient advocate(s) and the general public. TheAdministration Core will be led by Omar Abdel-Wahab MD who will oversee all SPORE activities. TheAdministrative Core also includes personnel trained in financial management project management grantsadministration scientific and medical editing data management and administrative support. The capabilitiesand services centralized in the Administrative Core provide the following administrative and communicationsinfrastructure that serve all components of the SPORE: Scientific Oversight: monitor progress of the translational research objectives of the SPORE program including evaluating the progress of individual projects and making decisions regarding continuation/replacement projects Financial Management: serving as the centralized SPORE budgetary coordinator and financial manager Editorial Services: providing editorial services for manuscript publication and grants coordination Grants Administration: serve as administrative liaison to the National Cancer Institute ensuring the timely submission of all required reports and compliance with institutional and federal regulations Data Management System Support: assist relevant Cores in management and support of SPORE related research and clinical databases as well as maintaining a cohesive and functional data sharing plan Communication: foster communication and collaborative research within our SPORE as well as with other SPOREs in Leukemia and the wider scientific community Outreach: foster effective communication with the general public our patient advocate(s) and the broader patient community to ensure that SPORE clinical studies are patient-centered and to promote equitable access to treatment on SPORE studies Meetings Coordination: organize all SPORE related retreats and meetings and review of ongoing SPORE research projects cores and pilot projects as well as the solicitation of new pilot project +No NIH Category available Acute Myelocytic Leukemia;Address;Adult;Antigens;Area;Bioinformatics Shared Resource;Biological;Biological Models;Biometry;Cessation of life;Classification;Clinic;Clinical;Clinical Data;Clinical Investigator;Clinical Management;Clinical Trials;Collaborations;Complex;Computational Biology;DNA Sequence Alteration;Development;Disease;Dysmyelopoietic Syndromes;Eastern Cooperative Oncology Group;Ensure;Enzymes;Epigenetic Process;Evaluation;FLT3 gene;FLT3 inhibitor;Future Generations;Genetic;Genomic approach;Genomics;Goals;Hematopoietic stem cells;Human;IL18 gene;Immune;Immune Targeting;Immunotherapeutic agent;Immunotherapy;Incidence;Industry;Institution;Karyotype;Ketoglutarate Dehydrogenase Complex;Lead;Maintenance;Malignant Neoplasms;Medical;Memorial Sloan-Kettering Cancer Center;Mentorship;Metabolic;Molecular;Molecular Abnormality;Molecular Target;Morbidity - disease rate;Mutation;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmacologic Substance;Pharmacotherapy;Phase I/II Clinical Trial;Pilot Projects;Pre-Clinical Model;Preparation;Prognosis;Protein Inhibition;Protein-Arginine N-Methyltransferase;RNA Splicing;Recurrence;Reproduction spores;Research;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Risk;Safety;Sampling;Southwest Oncology Group;Spliceosomes;Survival Rate;TP53-mutant acute myeloid leukemia;Therapeutic;Therapy-Related Acute Myeloid Leukemia;Translating;Translational Research;Treatment Efficacy;United States Food and Drug Administration;Universities;adverse outcome;biomarker identification;cancer genetics;career;chimeric antigen receptor T cells;collaborative approach;data integration;early phase clinical trial;effective therapy;functional genomics;genomic biomarker;high risk;human tissue;improved;improved outcome;inhibitor;inhibitor therapy;innovation;insight;leukemia;leukemia treatment;leukemic stem cell;medical schools;molecular pathology;molecular subtypes;molecular targeted therapies;multidisciplinary;mutant;new therapeutic target;novel;novel marker;novel strategies;novel therapeutic intervention;novel therapeutics;pre-clinical;preclinical study;predicting response;premature;programs;relapse patients;resistance mechanism;response biomarker;stem cell biomarkers;targeted treatment;therapeutic target;therapy resistant;translational potential;treatment response;tumor The Memorial Sloan Kettering Cancer Center SPORE in Leukemia OVERALL NARRATIVEThere are currently no approved or effective therapies for most acute myeloid leukemia (AML) subtypes. Ourproposed SPORE in Leukemia has the potential to develop practice-changing approaches for AML evaluationand management and directly lead to improved patient outcomes for AML. We will achieve this by focusing ondeveloping novel targeted and immune therapies for AML and by studying sensitivity and resistance toestablished/emerging AML treatments using clinical samples and state-of-the-art patient tumor model systems. NCI 10691855 6/7/23 0:00 PAR-18-313 5P50CA254838-03 5 P50 CA 254838 3 "KUZMIN, IGOR A" 8/24/21 0:00 6/30/26 0:00 ZCA1-RPRB-N(O1)P 9547114 "ABDEL-WAHAB, OMAR " "STEIN, EYTAN " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 1621553 NCI 1217369 969027 OVERALL ABSTRACTDespite recent advances in the treatment of acute myeloid leukemia (AML) the majority of AML patients relapsefollowing treatment and the overall five-year survival rate for adults with AML remains 25-29%. Thus an urgentneed to improve therapy for AML patients remains. The MSK SPORE in Leukemia will leverage collective effortsto develop effective targeted therapies and immunotherapeutic approaches for several recurrent molecularsubtypes of AML including some which lack therapeutic options entirely. The overall translational aims of theMSK SPORE in Leukemia are to 1) interrogate genetic and molecular pathways required for AML initiation andmaintenance; 2) develop novel targeted therapies and immunotherapeutic approaches for AML based onrecurrent genomic alterations and leukemia stem-cell (LSC) specific markers; and 3) identify and validate themechanism of action therapeutic efficacy and predictors of response/resistance of mechanism-based therapiesfor AML patients. To pursue these aims we have assembled a multidisciplinary team with complementaryexpertise in the clinical management of AML cancer genetics cancer epigenetics functional genomicsmolecular pathology biostatistics computational biology and multiplatform data integration. We will pursuethese aims through four projects each addressing a different unmet need in the clinical management of AML.Project 1 will elucidate genetic and epigenetic mechanisms of IDH inhibitor therapeutic resistance and performa clinical trial exploring the efficacy and safety of combining the FLT3 inhibitor gilteritinib with mutant selectiveIDH1/2 inhibitors for FLT3/IDH-mutant AML. Project 2 will characterize the clinical molecular and biologicalfeatures of complex karyotype (CK) AML for which there is no treatment and validate a novel approach totargeting CK AML via inhibition of the metabolic enzyme oxoglutarate dehydrogenase (OGDH). Project 3 willevaluate a novel therapeutic approach for targeting common poor prognosis spliceosomal-mutant AML subtypesvia inhibition of protein arginine methyltransferases in preclinical models and a phase I/II clinical trial. Project 4will determine the safety and efficacy of a chimeric antigen receptor (CAR) T cell approach targeting a leukemiastem cell-specific antigen while sparing normal hematopoietic stem cells specifically a fully humanized CD371targeting CAR T cell platform bolstered by constitutive IL-18 secretion. All projects will be supported by theBiospecimen Biostatistics Genomics and Bioinformatics Shared Resource Cores which will assist withthe preparation and analysis of human tissues and genomic immune and clinical data and an AdministrativeCore to ensure project integration. Finally pilot projects in the Developmental Research Program and careermentorship via the Career Enhancement Program are fully integrated into the SPORE to ensure that a futuregeneration of researchers is prepared to further advance our long-term objectives of enhancing therapy reducingthe morbidity of treatments and ultimately eliminating this disease as a cause of premature death 1621553 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Prevention Biological;Clinical;Clinical Chemoprevention;Clinical Research;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs OTHER FUNCTIONS - CANCER PREVENTION AGENT DEVELOPMENT PROGRAM: EARLY PHASE CLINICAL RESEARCH n/a NCI 10691840 261201200034I-P00003-759101900129-1 N01 9/23/19 0:00 9/22/23 0:00 16187666 "BROWN, POWEL " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N R and D Contracts 2022 260813 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 260813 +No NIH Category available Address;Adjuvant Therapy;Adoption;Aerobic Exercise;Affect;Aftercare;Age-associated memory impairment;Aging;Area;Brain;Breast Cancer survivor;Cancer Survivorship;Characteristics;Clinical;Clinical Trials;Clinical effectiveness;Cognition;Cognitive;Cognitive deficits;Communities;Consensus;Data;Dissemination and Implementation;Distress;Education;Effectiveness;Effectiveness of Interventions;Elderly;Evidence based program;Exercise;Exercise Test;Exhibits;Fatigue;Fitness Centers;Funding;Goals;Gold;Health;Health education;Hybrids;Impaired cognition;Individual;Institutionalization;Intervention;Literature;Maintenance;Malignant Neoplasms;Measurement;Measures;Mediator of activation protein;Mind;Neuropsychology;Obesity;Outcome;Participant;Pathogenesis;Pathway interactions;Patient Self-Report;Performance;Physical activity;Population;Postmenopause;Protocols documentation;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Reporting;Research;Research Personnel;Research Support;Rest;Scientist;Short-Term Memory;Site;Stress;Structure;Survivors;Testing;Translations;Treatment Protocols;United States;United States National Institutes of Health;Woman;Work;aged;arm;attentional control;base;brain health;brain morphology;brain volume;breast cancer diagnosis;cancer therapy;cancer-related cognitive impairment;cardiorespiratory fitness;care delivery;chemotherapy;clinically significant;cognitive benefits;cognitive change;cognitive enhancement;cognitive function;cognitive performance;cognitive task;effectiveness testing;effectiveness/implementation design;executive function;exercise intervention;exercise program;exercise training;experience;follow-up;implementation outcomes;improved;information gathering;intervention delivery;neuroimaging;normal aging;novel;optimal treatments;post intervention;primary outcome;secondary outcome;standard care;success;white matter Enhancing cognitive function in breast cancer survivors through community-based aerobic exercise training Narrative:Up to 75% of breast cancer survivors suffer cognitive changes during treatment and over 45% experienceclinically significant cognitive decline pre- to post-treatment. Consistent evidence in older adults and growingevidence in breast cancer survivors suggests aerobic exercise training may reduce cancer-related cognitivedecline. This study will compare changes in cognitive function and brain health in post-menopausal breast cancersurvivors randomized to either: 1) a community-based aerobic exercise program; or 2) attentional control (healtheducation). NCI 10691808 8/22/23 0:00 PA-21-268 7R37CA252060-03 7 R37 CA 252060 3 "NELSON, WENDY" 8/22/23 0:00 7/31/27 0:00 "Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]" 12556041 "EHLERS, DIANE KRISTEN" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 8/22/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2022 443422 NCI 339944 103478 Project SummaryWomen aged 50+ years comprise 77% of breast cancer diagnoses and 93% of all breast cancer survivors (BCS).Unfortunately the interaction between cancer treatment and normal aging often results in a number of healthsequelae. Up to 75% of BCS suffer cognitive changes during treatment and over 45% experience clinicallysignificant cognitive decline pre- to post-treatment. An optimum treatment for cancer-related cognitiveimpairment (CRCI) is likely one integrating interventions known to improve cognition in similar populations suchas older adults. Our previous research supports the efficacy of moderate-intensity aerobic exercise training forimproving cognitive function in older adults without cancer. This work suggests that cardiorespiratory fitness (i.e.peak VO2) and brain structural and functional integrity (e.g. white matter microstructure resting state functionalconnectivity) may underlie exercise-induced changes in cognitive function. We recently applied an agingframework to gain preliminary information on the effects of physical activity on cognitive function in BCS. Ourwork in this area suggests that aerobic exercise training may similarly ameliorate cognitive decline due to cancerand that cancer-related fatigue may also represent a mechanism of exercises cognitive benefits in the contextof cancer. Our preliminary data in aging and cancer along with the well-documented benefits of exercise relativeto proposed CRCI mechanisms (e.g. cardiorespiratory fitness fatigue) provide a compelling argument insupport of aerobic exercise training for improving cognitive function in BCS. While evidence toward efficacy inthis area is growing few large trials have been conducted and none to our knowledge with consideration ofdissemination and implementation a priori. We propose a clinical trial in which post-menopausal BCS (3-24months post primary adjuvant therapy) will be randomized to a community-based aerobic exercise program orattentional control. This study utilizes a Hybrid Type I effectiveness-implementation design to investigate clinicaleffectiveness while gathering information on implementation success associated with our novel community-based approach. Our exercise protocol is based upon our previous studies with demonstrated efficacy in olderadults and our community-based approach is based upon our previous studies with demonstratedimplementation success in BCS and post-menopausal women without cancer. The specific aims are: 1) Examinethe effectiveness of a 6-month community-based aerobic exercise program compared to control on indicatorsof cognitive function (i.e. cognitive performance neuroimaging metrics of brain health self-reported cognitiveimpairment) in post-menopausal BCS; and 2) Gather information on the interventions potential for scalability asdefined by the RE-AIM framework (i.e. reach effectiveness adoption implementation maintenance). We willalso explore intervention interactions with clinical variables (e.g. moderators: chemotherapy treatment regimenobesity status) and potential pathways by which aerobic exercise compared to control influences cognitivefunction (i.e. mediators: neuroimaging outcomes cardiorespiratory fitness fatigue). 443422 +Aging; Cancer; Clinical Research; Complementary and Integrative Health; Health Disparities; Mental Health; Minority Health Evaluation Core n/a NCI 10691583 8/26/22 0:00 RFA-RM-20-022 5U54CA267738-02 5 U54 CA 267738 2 "CALZOLA, JESSICA MARIE" 9/1/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 6937 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 Unavailable 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY Domestic Higher Education 148502820 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 219800 140000 79800 Project Summary (Evaluation Core)The Cornell FIRST Evaluation Core will provide program evaluation of the Cornell FIRST Cohort program and work collaboratively with the FIRST CEC to ensure overall program evaluation and outcome tracking.The proposed activities in this core address our Monitoring and Evaluation Initiative to critically assess the progress of the program test our models to ensure that the above initiatives are generalizable that they are implemented in an effective manner and that lessons learned are incorporated throughout the program as it evolves. The activities of this core assess the primary NIH FIRST hypothesis that a cohort and cluster design model of faculty hiring sponsorship continual mentoring and professional development embedded within an institution implementing evidence-based practices will foster a culture ofacademic cultures of inclusive excellence. Assessing the primary NIH FIRST hypothesis requires a multi-faceted mixed-methods systems thinking approach. The Cornell FIRST Monitoring and Evaluation Initiative in collaboration with the FIRST CEC will follow a collaboratively developed program logic model and comprehensive evaluation plan. It will incorporate development and integration of program theory and program logic; integration of qualitative and quantitative mixed methods; the incorporation of a variety of stakeholders and participants; and both formative and summative design. We will do this by implementing Specific Aim #4 from the Overall Core to evaluate and learn from our hiring climate and faculty development approaches by identifying which strategies and activities are most effective and sustainable at an institutional scale by assessing and monitoring the FIRST programs and activities to ensure that they are meeting their planned goals provide continuous learning and program improvement feedback to the Cornell Institutional Steering Committee to ensure the highest success of the FIRST cohort through the aims strategies and activities and to ensure integration and synergy with FIRST CEC to facilitate overall FIRST program evaluation and outcome tracking. The evaluation will be carried out by a highly skilled team that includes two external evaluators with decades of equity focused evaluation experience in higher education including experience evaluating the NIH Diversity Program Consortium. +Aging; Cancer; Complementary and Integrative Health; Health Disparities; Mental Health; Minority Health; Women's Health Faculty Development n/a NCI 10691582 8/26/22 0:00 RFA-RM-20-022 5U54CA267738-02 5 U54 CA 267738 2 "CALZOLA, JESSICA MARIE" 9/1/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RPHB-Y(50)R] 6936 1921631 "AUGUST, AVERY " "KOTLIKOFF, MICHAEL I." 19 Unavailable 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY Domestic Higher Education 148502820 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 219800 140000 79800 Project Summary (Faculty Development Core)Cornell University is ideally suited to develop and test innovative approaches to increase faculty diversity and to create a robust culture of inclusive excellence. Its multiple colleges operate with substantial autonomy and are laboratories for innovation leading Cornell to an enviable track record of designing innovative approaches that have been adopted around the country. These experiments have established programming and policies that have resulted in significant and measurable gains in both hiring and retention of faculty from diverse backgrounds including women. These policies have positively engaged faculty search committees in adopting best practices for inclusive hiring resulting in increased hiring of women and other individuals from underrepresented or minoritized backgrounds in STEM. Cornell also has a successful track record of combining institutional investments with federal programs to effect institutional culture change and make steady progress in increasing representational diversity of STEM faculty. Effective implementation of the best laid policies can fall short if systemic bias in policies and the academic environment into which we hire new faculty are not considered as part of a holistic process. Using the seed and soil model proposed by Dr. Beronda Montgomery of Michigan State University we propose a highly innovative Cornell FIRST Faculty Development Program that addresses both the seed (faculty member) and the soil (the community and climate) to ensure that FIRST faculty hires reach their full potential and succeed at Cornell. We hypothesizethat a robust evidence-based faculty development program across Cornell will create fertile ground (culture) for inclusive excellence and belonging and ensure that FIRST faculty are successful. We propose innovative programs for the FIRST cohort and other faculty who are underrepresented or marginalized in their fields by implementing our Faculty Development Initiative. Cornell will build FIRST faculty community by creating a sense of belonging in the discipline and across Cornell. We will connect FIRST faculty professionally and socially across their clusters and cohort within departmental units and research fields and across the university through a variety of formal and informal networking and community-building opportunities.Cornell will also foster individual research and career development for all FIRST faculty by providingtailored culturally relevant professional development opportunities to FIRST faculty to facilitate the successful start-up of their research programs communicate clear pathways for promotion and tenure and support success in their faculty roles. We expect that the Cornell FIRST program will successfully hire retain and support 10 new faculty underrepresented in their fields while fostering sustainable institutional culture change. These activities will result in increased diversity of the faculty in the biological biomedical and health sciencesat Cornell while contributing to the diversity of academy and future generations of the STEM workforce. +No NIH Category available Address;American Cancer Society;Area;Behavior;Black race;Cancer Center Support Grant;Cardiovascular Diseases;Chinese;Chronic Disease;Clinical;Collaborations;Communities;Community Health;Community Health Education;Community Outreach;Diagnosis;Diet;Disparity;Doctor of Philosophy;Early Diagnosis;Education;Education and Outreach;Educational Activities;Face;Faculty;Funding;Health;Health Services Accessibility;Home;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Immigrant;Immigrant community;Incidence;Infrastructure;Latino;Lead;Life Style;Limited English Proficiency;Linguistics;Malignant Neoplasms;Medical;Memorial Sloan-Kettering Cancer Center;Methodology;Mexican;Minority;Modeling;Needs Assessment;New York City;Obesity;Occupational Groups;Occupations;Outcome;Outreach Research;Patients;Persons;Physical activity;Play;Policies;Population;Population Heterogeneity;Poverty;Prevention;Primary Prevention;Provider;Quality of Care;Recommendation;Research;Research Activity;Research Personnel;Resource Sharing;Risk;Risk Factors;Role;Screening for Prostate Cancer;Secondary Prevention;Services;Social Medicine;South Asian;Students;System;Tobacco;Translational Research;Translations;Underrepresented Minority;Work;anticancer research;cancer health disparity;cancer prevention;cancer risk;clinical trial enrollment;colorectal cancer screening;community engaged research;community engagement;community partnership;disparity reduction;economic determinant;education research;evidence base;health care availability;health determinants;health disparity;high school;improved;improved outcome;individualized prevention;medical schools;medically underserved;member;outcome disparities;outreach;personalized immunotherapy;physical conditioning;precision medicine;precision oncology;professor;program dissemination;programs;recruit;screening;socioeconomics;stem;underserved community;working group PCORE (Partnership Community Outreach Research and Education Core) Project NarrativeAs per solicitation PAR-18-767 (U54):Project Narrative: Do not complete. NCI 10691547 9/8/23 0:00 PAR-18-767 5U54CA132378-15 5 U54 CA 132378 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 6928 1882762 "DORN, JOAN MARION" Not Applicable 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 134293 84664 49629 One in three U.S. residents over 100 million people are minorities. Over 39 million are foreign-born. New YorkCity (NYC) is home to 3 million foreign-born. Among foreign-born New Yorkers 48.8% are limited Englishproficient (LEP) 27.8% did not graduate from high school and 19.8% are living in poverty. This large anddiverse population faces significant disparities in cancer incidence diagnosis treatment and outcomes. Thesedisparities are fueled by health information and systems access barriers and by an inadequate evidence-basewhich stems from insufficient representation in research and program implementation. These factors limit thebi-directional translation of discoveries between bench patient community and policy levels. Over the past 10years the PCORE (Partnership Community Outreach-Research-Education) Core has implemented trailblazingcommunity-engaged outreach and research and addressed socioeconomic determinants of health and gaps incancer outcomes and quality of care for large underserved communities including the CCNY community theHarlem community in which CCNY is embedded and the broader NYC community. Through partnerships andmodel program dissemination PCORE has also extended its activities across the U.S. and is a vital memberof several NCI and American Cancer Society Committees addressing the inclusion of diverse populations inresearch. Over the next 5 years PCORE will further grow the robust community-academic U54 partnershipand infrastructure for community-engaged outreach and translational research. PCORE has the following twoSpecific Aims: AIM 1. To build upon and strengthen PCORE's community-academic partnership assets tofurther develop implement systematically disseminate and sustain effective community-engaged cancerdisparities reduction outreach community and provider education service policy and research activities toaddress socioeconomic determinants (centering on health care access) of cancer outcomes and decreasedisparities in five priority areas (determined by community-engaged needs assessments and guided by the NCIBlue Ribbon Panel): a) Clinical trials enrollment including in precision medicine/precision prevention andimmunotherapy activities; b) Colorectal cancer screening and treatment access and completion; c) HPVprevention and screening for HPV-associated cancers; d) Prostate cancer screening treatment access andcompletion; and e) Cancer risk factors including tobacco obesity diet physical activity and occupation. AIM 2.To build the capacity of researchers and community members to engage the community in the conduct oftranslational research to reduce cancer disparities working in concert with the Linguistic and CulturalResponsiveness Shared Resource Core: a) To facilitate community engagement to further enhance andsustain community capacity building utilizing the extensive network developed by PCORE; b) To support theU54 Partnership Cores working groups and projects and to collaborate with the MSK P30 CCSG to engagelimited English proficient (LEP) and other diverse populations in their programs and studies. +No NIH Category available Academic advising;Area;Awareness;Basic Science;Behavioral;Behavioral Research;Biomedical Engineering;Biomedical Research;Cancer Biology;Career Choice;Clinical;Communities;Community Outreach;Data Analyses;Doctor of Philosophy;Education;Education and Outreach;Educational Curriculum;Educational workshop;Engineering;Enrollment;Ensure;Evaluation;Face;Faculty;Family;First Generation College Students;Funding;Future;Goals;Immersion;Immigrant family;Institution;Laboratories;Learning;Malignant Neoplasms;Manuscripts;Measures;Memorial Sloan-Kettering Cancer Center;Mentors;Mentorship;Monitor;Nanotechnology;Performance;Postdoctoral Fellow;Preparation;Procedures;Process;Research;Research Design;Research Personnel;Research Training;Resources;Series;Services;Socialization;Students;Training;Training Activity;Training Programs;Training and Education;Translational Research;Underrepresented Minority;United States National Institutes of Health;Writing;anticancer research;cancer health disparity;career;career development;community partnership;design;education research;experience;graduate student;hands on research;improved;innovation;member;minority communities;prevent;programs;recruit;skills;socioeconomic disadvantage;student mentoring;student participation;success;training opportunity;translational cancer research;undergraduate research;undergraduate student;underrepresented minority student Research Education Core Project NarrativeAs per solicitation PAR-18-767 (U54):Project Narrative: Do not complete. NCI 10691545 9/8/23 0:00 PAR-18-767 5U54CA132378-15 5 U54 CA 132378 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 6927 1922320 "HUBBARD, KAREN " Not Applicable 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 263090 165863 97227 Research Education CoreSince the inception of the NIH-funded CCNY-MSK U54 in 2008 we have developed and implementedapproaches to engage and mentor students and early stage investigators in cancer research. We haveprovided undergraduate and graduate students with hands-on research experiences developed cancer-relatedcurricula and have provided professional socialization and mentorship for students appropriate to theiracademic level and career interests. Also we have monitored the progress of our early stage investigators andprovided individualized resources to ensure their success. To expand our transdisciplinary research focus wehave hired several faculty members for the Partnership that have been integrated into our training efforts. Inthis competitive renewal we plan to recruit additional faculty who will enhance our translational focus inresearch and training and will broaden opportunities for our students. The majority of students at CCNYespecially those from underrepresented minority communities come from socioeconomically disadvantagedfamilies. Many of our students are also first generation college students and/or from immigrant families. Ourprogram is designed to provide opportunities for them to successfully conduct biomedical and behavioralresearch at CCNY and MSK and to provide mentorship and guidance towards career decisions. Our overallgoals are to: 1) Increase the number of competitively trained underrepresented minority students whoenroll in MD PhD or MD/PhD programs and specifically 2) Increase the numbers of these studentswho pursue cancer-related research careers and 3) Increase the research competitiveness of U54early stage investigators (ESI) (postdoctoral scholars and junior faculty). We will accomplish these goals by:a) Providing experiential activities and opportunities support services and Partnership activities to improve andincrease students' engagement and performance in cancer research related areas and professions; b)Providing academic counseling advisement and mentoring to students to ensure that they are aware of theopportunities and prerequisites for careers in cancer research; c) Providing translational research experiences(basic sciences; engineering; behavioral; clinical; and community-based) for each student prior to graduation;d) Providing resources for the career development of early stage investigators as well as closely monitoringtheir progress; e) Implementing an evaluation plan to measure the results of all program activities and theutilization of all resources; g) Developing and submitting proposals with the goal of providing sustainability ofour educational and training initiatives such as through R25 and IRACDA mechanisms. +No NIH Category available Advisory Committees;Collaborations;Community Outreach;Data;Decision Making;Development;Education;Education and Outreach;Ensure;Evaluation;Faculty;Funding;Goals;Grant;Institution;Linguistics;Memorial Sloan-Kettering Cancer Center;Mission;Monitor;Pilot Projects;Publications;Reach Effectiveness Adoption Implementation and Maintenance;Research Personnel;Research Proposals;Resource Sharing;Strategic Planning;Students;anticancer research;outreach;programs Planning and Evaluation Core Project NarrativeAs per solicitation PAR-18-767 (U54):Project Narrative: Do not complete. NCI 10691542 9/8/23 0:00 PAR-18-767 5U54CA132378-15 5 U54 CA 132378 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 6926 1922320 "HUBBARD, KAREN " Not Applicable 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 634862 400243 234619 Planning and Evaluation CoreThe Planning and Evaluation Core is composed of the Partnership's Internal Advisory Committee ProgramSteering Committee Executive Committee and external evaluators to provide oversight of the overallPartnership activities and programs. It will be responsible for all aspects of planning monitoring evaluationand tracking of Partnership activities. In addition this core serves as a platform from which the Partnership'sPIs can discuss strategic plans that can move the U54 Partnership towards new initiatives that strengthen thegoals and mission of both institutions. The specific goals and objectives are: 1) The Partnership PIs (Drs.Ahles Gany Hubbard and Barabino) will collaborate with the Internal Advisory Committee and the ProgramSteering Committee to ensure ongoing planning monitoring evaluation and tracking of Partnership activitiesincluding: a. Coordination and management of the solicitation of new research proposals; b. Review andselection of full and pilot projects for funding monitoring of project progress and decision making regardingdiscontinuation of funding for projects not meeting goals; c. Development of new initiatives based onopportunities presented on a national level (e.g. Blue Ribbon priorities RFAs and PARs issued) or at eitherinstitution; and d. Identification of faculty searches that are potentially synergistic with Partnership goals. 2)The Partnership PIs will monitor and evaluate all aspects of Partnership functioning in collaboration with theexternal evaluator Dr. Bosch: a. track pertinent data that monitors and assesses the Partnership's goals andobjectives such as publications and grant submissions by investigators student tracking data and communityoutreach assessments; b. monitor and evaluate all aspects of the proposed educational programs; c. utilizethe RE-AIM framework to monitor and evaluate all aspects of the proposed outreach(PCORE) activities; and d.ensure that the Linguistic and Cultural Responsiveness Shared Resource Core meets target metrics. +No NIH Category available Awareness;Community Health Education;Community Outreach;Development;Diamond;Education and Outreach;Educational process of instructing;Ensure;Faculty;Funding;Goals;Institution;Laboratory Research;Language;Linguistics;Manuals;Memorial Sloan-Kettering Cancer Center;Procedures;Research Personnel;Resource Sharing;Resources;Students;Update;anticancer research;career;community based participatory research;community partnership;education research;faculty support;meetings;programs;project-based learning;recruit;research facility;service learning;synergism Administrative Core Project NarrativeAs per solicitation PAR-18-767 (U54):Project Narrative: Do not complete. NCI 10691541 9/8/23 0:00 PAR-18-767 5U54CA132378-15 5 U54 CA 132378 15 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2 6925 1922320 "HUBBARD, KAREN " Not Applicable 12 Unavailable 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY Domestic Higher Education 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 170366 107406 62960 Administrative CoreThe Administrative Core includes the four PIs Drs. Ahles and Gany (MSKCC) and Drs. Hubbard andBarabino (CCNY) Research Education Core Leaders Dr. Hricak (MSKCC) with Dr. Hubbard PCORELeaders Dr. Leng (MSKCC) and Dr. Dorn (CCNY) Linguistic and Cultural Responsiveness Shared ResourceCore Leaders Drs. Gany and Diamond (MSKCC) and Drs. Uyar and Riob (CCNY) and the AdministrativeCore staff from both CCNY and MSKCC. The U54 Administrative Core coordinates all of the Partnershipactivities and ensures that the Partnership continues to function effectively and efficiently. Specifically theAdministrative Core will: 1) coordinate biweekly meetings of Partnership PIs quarterly meetings of theAdministrative Committee which includes the leaders of the Research Education Core and PartnershipCommunity Research and Education Core and quarterly IAC meetings as well as the Annual ProgramSteering Committee meeting; 2) meet with the Executive Committee on an annual basis to evaluate thepotential synergy between Partnership goals and new institutional initiatives including recruitment of newfaculty; 3) provide support for both institutions' research resources and facilities and to provide access to andawareness of these resources for Partnership investigators faculty and students; 4) coordinate with GMapRegion 4 (CDRN) to ensure that Partnership students have access to regional career resources; 5)coordinate student placements at either CCNY or MSKCC in research laboratories or service-based learningprojects and to provide administrative support for faculty that teach in Partnership courses; 6) provide fiscalplanning and management for all aspects of the Partnership including the distribution of developmentalfunds; and 7) maintain and update a manual of Standard Operating Procedures. +No NIH Category available Address;Affect;African American;Area;Award;Biomedical Engineering;Bone neoplasms;Breast Cancer Early Detection;Cancer Research Project;Cell Line;Cellular biology;Cities;Clinical;Collaborations;Communities;Community Health Aides;Community Networks;Community Outreach;Computers;Data;Deuterium Oxide;Development;Drug Delivery Systems;Education;Education and Outreach;Educational process of instructing;Elderly;Engineering;Environment;Ethnic Origin;Funding;Future;Genome Stability;Goals;Grant;Health Disparities Research;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Resources;Image;Immersion;Immunoglobulin Genes;Immunology;Institution;Institutional Policy;Intervention;Label;Latino;Limited English Proficiency;Linguistics;Low income;Malignant Neoplasms;Measures;Mechanics;Medical;Medical Imaging;Memorial Sloan-Kettering Cancer Center;Mentorship;Minority;Modeling;Multilingualism;New York;Obesity;Pilot Projects;Policies;Populations at Risk;Positioning Attribute;Raman Spectrum Analysis;Recording of previous events;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Risk Reduction;Role;Schools;Scientist;Series;Students;Testing;Training;Translational Research;Translations;Underrepresented Minority;United States Health Resources and Services Administration;Universities;Woman;anticancer research;cancer care;cancer cell;cancer clinical trial;cancer education;cancer health disparity;cancer risk;cancer subtypes;career;clinical care;college;colorectal cancer screening;community engaged research;computer science;disparity reduction;economic determinant;education research;experience;health disparity;high risk;improved;innovation;interest;low socioeconomic status;medical schools;medically underserved;molecular imaging;multiphoton microscopy;outreach;pedagogy;post-doctoral training;programs;screening;socioeconomics;student retention;success;translational cancer research;translational medicine;triple negative cancer;tumor;underrepresented minority student;underserved community;working group 1/2 CCNY-MSKCC Partnership for Cancer Research Education and Community Outreach NarrativeThis proposal describes our plans to continue and enhance the City College of New York - Memorial SloanKettering Cancer Center Partnership for Cancer Research Education and Community Outreach. The CCNY-MSKCC Partnership is a mutually beneficial cross-institutional collaboration that has promoted translationalresearch created an education pipeline for minority and low-income students to advance in cancer researchcareers and has established community networks and resources for conducting culturally-responsivecommunity engaged research among diverse at-risk populations in the New York area. NCI 10691540 9/8/23 0:00 PAR-18-767 5U54CA132378-15 5 U54 CA 132378 15 "WALI, ANIL" 9/26/08 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 1922320 "HUBBARD, KAREN " "AHLES, TIM ALAN; GANY, FRANCESCA M; VUONG, BAO Q" 12 BIOLOGY 603503991 L952KGDMSLV5 603503991 L952KGDMSLV5 US 40.819407 -73.950169 1605017 CITY COLLEGE OF NEW YORK NEW YORK NY SCHOOLS OF ARTS AND SCIENCES 100367207 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1522608 NCI 969814 552794 The CCNY-MSKCC Partnership has successfully created a mutually beneficial cross-institutional collaborationthat has emphasized research across the translational continuum the creation of an education pipeline forattracting minority and low-income students to careers in cancer research and the establishment of communitynetworks and resources for conducting linguistically and culturally-responsive community engaged researchamong diverse at-risk populations. Over the last five years areas of particular strength have been developedincluding: 1) rich collaborations between engineers and computer scientists at CCNY and clinicians and imagingexperts at MSKCC to develop innovative solutions to improve cancer care and 2) sustainable translationalhealth disparities research and activities that directly benefit underserved communities in New York and serveas national models in terms of: a) screening / identification of cancer risk factors that disproportionately affectminorities; b) socioeconomic determinants of access to and successful completion of treatment; and c) policychange. Consistent with these areas of emphases we propose two full projects that focus on: 1) Tumorensemble models to predict tumor dormancy and reactivation and testing how these models perform acrossvarious ethnic cell lines e.g. triple negative tumors that disproportionately affect African American women and2) Characterizing the Role of ATM in Immunoglobulin Gene Diversification and Genome Stability. Two proposedpilot projects include: 1) Raman spectroscopy with heavy water labeling and multiphoton microscopy to allowearly detection of breast cancer subtypes including triple negative cancers and 2) Development of MechanicalInterventions to Enhance Drug Delivery to Bone Tumors. New innovative Partnership components include: 1)development of the Linguistic and Cultural Responsiveness Shared Resource Core; 2) formation of theEngineering Health Disparities working group; and 3) new educational programs including the Scholars for theFuture program and the Certificate for Medical Translation and Interpretation. The Partnership specific aims areto: 1) Continue to develop outstanding cancer research programs in health disparities biomedicalengineering computer science / medical imaging cancer cell biology and immunology along theTranslational Research Continuum; 2) collaborate with diverse communities to conduct and facilitate trailblazingcancer disparities research and outreach education risk reduction and navigation activities to define andaddress cancer disparities with the goal of improving cancer care in the large medically underserved local andnational communities; 3) continue to develop and expand educational opportunities in a robust translationalcancer research environment to attract and retain students interested in cancer research (particularly minorityand low income students); these opportunities will be enhanced by educational opportunities and increasedmentorship and support; and 4) expand and integrate the personnel resources and environment needed forscientific collaboration across institutions and influence institutional policies in support of this objective. 1522608 +No NIH Category available Address;Affect;Amino Acids;Animal Model;Automobile Driving;BRAF gene;Biochemical;Biological Assay;Bladder;Breast Epithelial Cells;CDKN2A gene;CRISPR/Cas technology;Cancer Patient;Catalytic Domain;Cell model;Cells;Childhood Glioma;Chromatin;Chromatin Modeling;Chromatin Structure;Collaborations;Colorectal Neoplasms;DNA;DNA Binding;DNA Damage;Data;Development;Dominant-Negative Mutation;Engineering;Enzymes;Epigenetic Process;Gene Activation;Gene Expression;Gene Mutation;Genes;Genetic Transcription;Glutamic Acid;Goals;Head and neck structure;Heterogeneity;Histone Fold;Histone H2A;Histone H2B;Histones;Human;In Vitro;Incidence;Intervention;KRAS2 gene;Knock-in;Lesion;Lung;Lysine;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Mediating;Movement;Mutate;Mutation;Nucleosomes;Oncogene Deregulation;Oncogenes;Oncogenic;Oncoproteins;PIK3CA gene;Paper;Pathogenesis;Pathway interactions;Patients;Phosphatidylinositol 45-Diphosphate;Phosphotransferases;Process;Proteins;Publications;Recurrence;Regulator Genes;Repression;Resistance;Role;Signal Transduction;Signaling Molecule;Site;Structure;System;TP53 gene;Tail;Technology;Testing;Tobacco;Transcription Initiation;Tumor Suppressor Proteins;Xenograft Model;Yeasts;cBioPortal;cancer genome;cancer genomics;cell growth;cell immortalization;cell transformation;chromatin modification;dimer;epigenomic profiling;epigenomics;gene repression;gene therapy;genetic regulatory protein;genome sequencing;genome-wide analysis;genomic data;histone methyltransferase;inhibitor;lung carcinogenesis;mouse model;mutant;neoplastic cell;novel;oncohistone;prevent;protein complex;targeted treatment;transcription factor;treatment response;tumor;tumor heterogeneity;tumor progression;tumorigenesis;virtual Histone fold Mutations in Cancer Pathogenesis PROJECT NARRATIVEThis application studies a new class of oncogenic mutations that affect the structure and function ofhistone proteins that complex with DNA to form chromatin. We will determine how these mutationscooperate with oncogenes that cause aberrant signaling and mutant chromatin regulators to drivemalignancy tumor heterogeneity and therapy resistance. NCI 10691517 8/25/23 0:00 PA-20-185 5R01CA266078-02 5 R01 CA 266078 2 "FINGERMAN, IAN M" 8/26/22 0:00 8/31/27 0:00 Cancer Genetics Study Section[CG] 1900296 "LICHT, JONATHAN D." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 345749 NCI 230873 114876 PROJECT SUMMARYSignificance: By examination of cancer patient genomic datasets through the cBioPortal we identified a newclass of recurrent mutations in genes encoding histones H2A H2B H3 and H4. This supports an underlyingpremise supported by rigorous publications from many groups including ours that mutations of gene regulatorymachinery including histones are oncogenic drivers of human cancer. Many of these mutations affect residuesof the histone folds important for the interactions among histones required for integrity of the histone octamer.Others may affect histone interactions with the chromatin modeling machinery. Histone fold mutations are foundin 4% of lung (commonest tumor in US) and colorectal tumors 6% of head and neck and 12% of bladder cancer.Histone mutations are subclonal. Tumors with histone mutations were significantly more likely to harbormutations of oncogenic signaling molecules and tumor suppressive epigenetic regulators suggesting thathistone mutations augment the effect of other oncogenic lesions. Preliminary data: We characterized arecurrent mutation that changed amino acid 76 of histone H2B from glutamic acid to lysine (H2BE76K). Thismutation disrupts the interaction of the H2B/H2A dimer with the H3/H4 tetramer preventing formation of thehistone octamer. Our Cancer Discovery paper showed that H2BE76K inhibits formation of nucleosomes in vitroand in yeast. Expression of H2BE76K in human cells disrupts chromatin structure activates gene expressionpromotes cell growth and cooperates with PI3KCA to transform breast epithelial cells. We hypothesize thatmutations that disrupt histone structure create millions of dysfunctional nucleosomes. These may deregulategene expression and drive cancer development by creating new sites of open chromatin with loss ofnucleosome-mediated gene repression as well as by altered interactions with regulators of chromatin and geneexpression. Approach: We will use cell and mouse models and epigenome profiling to characterize theoncogenic mechanisms of histone mutations particularly in the transformation of lung cells through threespecific aims: 1) Elucidate mechanisms by which histone fold mutations alter cell growth gene expression andchromatin structure. 2) Determine how histone fold mutations cooperate with co-occurring oncogenes and tumorsuppressive chromatin regulators in cell and animal models. 3) Characterize the effects of histone mutations ontumor heterogeneity and response to therapy. Novelty: This proposal explores a new class of cancer-drivingmutations to uncover novel mechanisms of oncogenesis by chromatin disruption. We will use the latest versionsof gene editing to engineer histone mutations into cells analyze tumor cells with advanced technologies forgenome wide analysis of chromatin states and create new animal models. Impact: We will focus on lung cancerwhere we estimate up to 10000 patients/year will have tumors with histone mutations. The long-term objectiveof these studies is to uncover new mechanisms of oncogenesis that contribute to tumor progressionheterogeneity and therapy resistance with the aim of finding new targets and pathways for intervention. 345749 +No NIH Category available ANXA5 gene;Acetylation;Acetyltransferase;Affect;Alleles;Aneuploidy;Apoptosis;Apoptotic;Binding Sites;Biological Assay;Breeding;Bromodeoxyuridine;CASP3 gene;Categories;Cell Cycle;Cell Death Induction;Cell Line;Cell Proliferation;Cell Survival;Cells;Central Nervous System;ChIP-seq;Characteristics;Chromatin;Clinical;Code;Colcemid;Complex;DNA Damage;Development;Doxycycline;Ensure;Essential Genes;Feedback;Gene Expression;Gene Silencing;Gene set enrichment analysis;Genes;Genetic Transcription;Genetically Engineered Mouse;Genome;Genome Stability;Genomic Instability;Glioblastoma;Glioma;Gliomagenesis;Goals;Growth and Development function;Histone Acetylation;Histone H3;Histone H4;Homologous Gene;Impairment;Knock-out;Knowledge;Lysine;MYC Family Protein;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Modeling;Mouse Cell Line;Mus;Mutagens;Mutation;PI3K/AKT;PIK3CG gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Pattern;Pharmacotherapy;Physicians;Play;Proliferating;Proteins;RNA purification;Radiation therapy;Regulation;Research;Resources;Role;SAGA;Sampling;Science;Scientist;Signal Transduction;Site;T47D;Tamoxifen;Testis;The Cancer Genome Atlas;Tissues;Training;Transactivation;Treatment outcome;Tumor Burden;Tumor Suppressor Genes;Untranslated RNA;Western Blotting;Work;cancer cell;cancer genome;cancer genomics;cancer survival;cancer therapy;cancer type;career;cell type;chromatin isolation by RNA purification sequencing;chromatin remodeling;frontier;gain of function;genotoxicity;glycogen synthase kinase 3 beta;histone acetyltransferase;improved;in vivo;loss of function;mouse model;nestin protein;novel;novel therapeutics;outreach;overexpression;promoter;recruit;targeted treatment;translational potential;tumor;tumorigenesis Exploration of long non-coding RNAs as synthetic essential targets in Pten-deficient cancers Project NarrativeExploring the non-coding genome will help open up this vast frontier for the development of novel therapiesthat could far outreach what biomedical science has been able to accomplish up until now by only targeting theprotein-coding genome. In this proposal we will characterize a novel cancer-associated long non-coding RNAwith predicted functions in regulating histone acetylation Myc signaling and genome stability. The successfulcompletion of this project will highlight one example of how investigating the non-coding genome can lead toalternative strategies for targeting pathways that are widely considered to be undruggable such as Myc. NCI 10691506 9/8/23 0:00 PA-19-191 5F30CA243160-04 5 F30 CA 243160 4 "DAMICO, MARK W" 9/18/20 0:00 9/17/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 15554187 "CHEN, JASPER R" Not Applicable 9 BIOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/18/23 0:00 9/17/24 0:00 398 "Training, Individual" 2023 45912 NCI 45912 0 Project Summary/AbstractPTEN is one of the most frequently inactivated tumor suppressor genes across all cancer types. The loss ofPTEN activates PI3K/AKT which inhibits GSK3 thereby stabilizing Myc and contributing to oncogenesis. Mycrecruits histone acetyltransferases to increase chromatin accessibility of target genes involved in both cellproliferation and apoptosis. Among these histone acetyltransferases the Spt-Ada-Gcn5 acetyltransferase(SAGA) complex preferentially acetylates histone H3 lysine 9 and histone H4 lysine 16 to activate geneexpression. A pan-cancer analysis of mutually exclusive gene inactivation patterns identified a previouslyuncharacterized long non-coding RNA (lncRNA) as synthetic essential in the context of PTEN deficient cancer.Preliminary studies suggest that this lncRNA inhibits SAGA-mediated histone acetylation thereby inhibiting Myctransactivation of target genes. PTEN and lncRNA double-knockout SF-763 glioma cells showed Myc pathwayenrichment impaired cell viability and pronounced aneuploidy which was not observed in wild-type or singleknockout cell lines. We hypothesize that inhibition of SAGA-mediated acetylation by this lncRNA inhibits Myctransactivation of pro-apoptotic target genes and Myc-driven endoreduplication thereby promoting cancersurvival. This proposal will investigate the potential of targeting the poorly studied non-coding genome for cancertreatment advance our knowledge of the role of histone acetylation on cancer genomic stability (widely targetedusing genotoxic drugs and radiotherapy) and describe a novel mechanism for the regulation of Myc's dualfunctions in proliferation and apoptosis. We will verify lncRNA expression in cell lines from various cancer typesand in clinical samples to validate the pan-cancer relevance and translational potential of this study respectively.Annexin V and caspase 3/7 assays will be used to assess the hypothesis of Myc-driven apoptosis.Endoreduplication will also be probed using BrdU incorporation into colcemid-arrested cells. Chromatin isolationby RNA purification and chromatin immunoprecipitation sequencing will be used to demonstrate how the lncRNAinhibits histone acetylation by SAGA. To assess the role of the lncRNA in vivo we will functionally validate itsputative mouse homolog and generate a genetically engineered mouse model to characterize its effects on tumordevelopment. The lncRNA knockout allele will be bred into a Qki;Pten;Trp53 glioblastoma mouse model toassess the effects of lncRNA suppression in the context of Pten deletion. The training plan will address gaps inthe applicant's research and clinical abilities ensuring that he can successfully complete the proposed work andpreparing him for the next stage of his career. The training will be completed in Dr. Ronald DePinho's lab at MDAnderson where the applicant will have access to the resources facilities and most importantly colleaguesthat will nurture his continuing development and growth into a physician-scientist. 45912 +No NIH Category available Applied Research;Area;Basic Science;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Communication;Comprehensive Cancer Center;Dedications;Discipline;Doctor of Philosophy;Ensure;Faculty;Financial Support;Goals;Grant;Hematology;Individual;Investigation;Investigational Therapies;Laboratories;Malignant Neoplasms;Medical Oncology;Medicine;Mentored Clinical Scientist Development Program;Mentors;Minority Groups;Ohio;Oncology;Paper;Peer Review;Program Evaluation;Radiation Oncology;Research;Research Personnel;Resources;Structure;Surgical Oncology;Training;Training Programs;Underserved Population;Universities;Women's Group;anticancer research;cancer diagnosis;cancer prevention;career;career development;clinical translation;drug development;education research;effectiveness evaluation;interest;laboratory development;programs;recruit;success;survivorship;translational cancer research;translational scientist OSU K12 Training Grant in Oncology NarrativeThe overall goal of this renewal proposal led by John C. Byrd MD and William E. Carson III MD is to mentorand effectively train MD PhD DVM and MD/PhD faculty investigators with basic science and/or clinically-oriented approaches to translational research so that they may dedicate their careers to independent clinicalcancer research. NCI 10691504 6/30/23 0:00 PAR-18-292 5K12CA133250-15 5 K12 CA 133250 15 "DAMICO, MARK W" 9/9/08 0:00 6/30/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1871184 "CARSON, WILLIAM E." Not Applicable 3 SURGERY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 605618 NCI 750000 60000 Project Summary/AbstractThe goal of this proposal is to mentor and train junior faculty investigators in laboratory and/or clinical translationalcancer research. Implementation of this K12 program for the career development of laboratory-based(PhD/DVM/MD) and clinical (MD or MD/PhD) translational scientists in diverse areas of oncology will ensure acadre of highly-trained individuals who can communicate across disciplines to drive new advancements in howwe approach cancer diagnosis and management. This K12 program from The Ohio State UniversityComprehensive Cancer Center (OSUCCC) continues its focus on early drug development but now also extendsto cancer prevention control and survivorship research. The OSUCCC is clearly dedicated to research educationand providing outstanding career development and mentoring opportunities to promising junior faculty. TheDivisions of Hematology Medical Oncology Radiation Oncology and Surgical Oncology each have robustprograms that are continuously recruiting new junior faculty to facilitate expansion of our cancer program.Recruitment efforts also emphasize the inclusion of women minorities and underserved groups to increasediversity. This K12 grant fills an important need by extending research education career development andmentoring to junior faculty interested in establishing academic research careers. It is the only OSUCCC trainingprogram dedicated solely to faculty-level career development in cancer research and thus has no overlap withany of the OSU T32 training grants which focus on fellows. This strategy ensures continuity in training andprovides individuals a structured path to become independent clinical or translational investigators. The qualityof this K12 program and its success in training cancer researchers is exemplified by the career trajectories ofpast trainees their papers grants clinical trials and other scholarly activities that have driven new discoveries.The continued success of this program will be ensured by the overall strength and direction of the OSUCCC asdemonstrated by its recent peer review score of 10 (exceptional) financial support of this K12 program by theOSUCCC and by different Divisions and Departments and the enormous breadth of expertise and resourcesavailable at OSU. This K12 program seeks to train two types of investigators. The first includes MD and/or PhDfaculty who have outstanding basic science training and want to pursue laboratory-based investigation relatedto applied research in experimental therapeutics cancer prevention control and survivorship. The second groupincludes MD or MD/PhD faculty who want to pursue clinical research in experimental therapeutics and cancerprevention control or survivorship. Training plans are tailored to each individual trainee to facilitate theirsuccess with inclusion of a robust evaluation program to assess the effectiveness of the K12. The value of theOSU K12 program is best demonstrated by nearly all of the current and past K12 scholars remaining in academicmedicine and moving forward as independent laboratory or clinical investigators. 605618 +No NIH Category available ATAC-seq;Acute;Affect;Apoptosis;Apoptotic;B lymphoid malignancy;B-Lymphocytes;BCL2 gene;BCL2L1 gene;Binding;Binding Sites;Bioinformatics;Biological Markers;Biology;Bortezomib;CRISPR screen;Cell Line;Cell Survival;Cell surface;Cells;Cellular biology;Cessation of life;Characteristics;Chromatin;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Cytometry;Dependence;Development;Disease;Drug resistance;Family;Flow Cytometry;Foundations;Funding;Future;Gene Expression Profile;Genes;Genetic Transcription;Genetic study;Genomics;Goals;Grant;Heterogeneity;In Vitro;K-Series Research Career Programs;Laboratories;Leadership;MCL1 gene;Machine Learning;Malignant Neoplasms;Manuscripts;Measures;Mediating;Mentors;Molecular;Multiple Myeloma;New Agents;Pathogenesis;Patient Selection;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Phenotype;Physicians;Plasma Cells;Precision medicine trial;Proteasome Inhibitor;Protein Family;Proteins;Regulation;Research Technics;Resistance;Role;Sampling;Scientist;Signal Transduction;Source;Testing;Therapeutic;Training;Transcription Factor AP-1;Translating;United States National Institutes of Health;Work;Writing;biomarker driven;biomarker identification;career;differential expression;epigenomics;immune modulating agents;improved;inhibitor;knock-down;multidisciplinary;novel;novel drug class;novel marker;overexpression;patient subsets;precision medicine;predicting response;predictive signature;pro-apoptotic protein;programs;resistance mechanism;response;skills;standard of care;therapy resistant;transcription factor;transcriptome sequencing;treatment response;tumor Regulation of Bcl-2 dependence in multiple myeloma PROJECT NARRATIVEDespite numerous advances in the treatment of multiple myeloma it remains an incurable disease and noveltreatments are acutely needed. Bcl-2 family inhibitors such as venetoclax represent a promising new class ofdrugs however the mechanisms underlying intrinsic sensitivity or resistance to these drugs remain poorlyunderstood. We have identified a unique B cell-like signature in multiple myeloma and will investigate how thissignature affects response to Bcl-2 inhibitors and whether it can be used as a biomarker for future precisionmedicine driven trials. NCI 10691502 8/17/23 0:00 PA-20-203 5K08CA267055-02 5 K08 CA 267055 2 "BOULANGER-ESPEUT, CORINNE A" 9/1/22 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 14198600 "GUPTA, VIKAS ANAND" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA SCHOOLS OF MEDICINE 303221007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 242898 NCI 224906 17992 PROJECT SUMMARY/ABSTRACTMultiple myeloma is an incurable malignancy of plasma cells for which new treatments and precision guidedapproaches are acutely needed. Current treatments target the plasma cell biology thought to be common to allmyeloma. However response to these treatments is highly variable pointing to an underlying heterogeneity inbiology. One recently identified source of heterogeneity with important therapeutic implications involvesdependence on the Bcl-2 family of proteins which includes Bcl-2 Bcl-xL and Mcl-1. These proteins regulate cellsurvival and are the targets of a new class of drugs being studied for use in myeloma. Although both normalplasma cells and myeloma are typically dependent on Mcl-1 for survival a subset of myeloma with a B cell-likephenotype is Bcl-2 dependent and sensitive to venetoclax a Bcl-2 specific inhibitor. This B cell phenotype isnotable because B cells are also Bcl-2 dependent and B cell malignancies such as CLL are highly sensitive tovenetoclax. The objective of this proposal is to test the hypothesis that in a subset of myeloma B celltranscriptional and signaling networks remain active and contribute to Bcl-2 dependence and venetoclaxsensitivity as well as resistance to conventional plasma cell directed therapy. The studies proposed will definethe mechanisms of Bcl-2 family dependence in myeloma and identify biomarkers capable of selecting myelomapatients most likely to respond to Bcl-2 inhibitors such as venetoclax. Aim 1 will characterize the mechanisms ofBATF3 activity an AP-1 transcription factor that increases Bcl-2 dependence and sensitizes myeloma tovenetoclax using genomic and epigenomic analyses on cells with CRISPR mediated BATF3 overexpression orknockdown. Aim 2 will directly interrogate the origins of Bcl-2 dependence and intrinsic resistance to venetoclaxin myeloma using CRISPR screens targeting genes that are differentially expressed in venetoclax sensitive andresistant cells. Finally Aim 3 will utilize state of the art mass cytometry on ex vivo tested myeloma patientsamples to develop a novel biomarker that could be used for future precision medicine trials to predict responseto inhibitors of Bcl-2 Bcl-xL and Mcl-1. These studies will be conducted by Dr. Vikas Gupta whose long-termcareer goal is to become an independently funded physician-scientist studying the molecular pathogenesis ofmultiple myeloma. He is seeking an NIH K08 career development award to acquire the additional skills necessaryfor independence. With the help of a multi-disciplinary group of experts serving as mentors and advisors he willreceive hands on training in advanced research techniques such as targeted CRISPR screens RNA sequencingbioinformatics and mass cytometry as well as mentoring in manuscript and grant writing clinical trialdevelopment laboratory management and leadership skills. Completion of the work proposed here will lay thefoundation for future R01 applications studying approaches to overcome mechanisms of resistance to Bcl-2family inhibitors. 242898 +No NIH Category available Cancer Science;Data Science;programs Integrated Program in Cancer and Data Science NARRATIVEThe Integrated Program in Cancer and Data Science described in this T32 training applicationaddresses a grave issue with great relevance to public health. Large datasets and meta-analysis ofmultiple datasets are essential for understanding cancer at the population patient cell and molecularlevels and yet there are few training programs that put data analyses and data science at the center.This application will put data science and data scientists at the center of a program to doubly train pairsof promising postdoctoral fellows in Data Science and Cancer Research. NCI 10691491 8/14/23 0:00 PA-18-403 5T32CA233399-05 5 T32 CA 233399 5 "DAMICO, MARK W" 9/16/19 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1896485 "CRESS, WILLIAM DOUGLAS" "FLORES, ELSA R; WANG, XUEFENG " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 211392 NCI 388916 29033 PROJECT SUMMARYThe Integrated Program in Cancer and Data Science (hereafter the Program) administered by the NCI-designated Moffitt Comprehensive Cancer Center (Moffitt) trains the next generation of leaders inCancer and Data Science. This training program is overseen by an executive committee comprised ofthe three PIs who together have decades of training experience in translational basic and data science.Over thirty faculty members who work together at the interface of cancer research and data scienceserve as mentors and co-mentors. The Program is cross-disciplinary spanning every Division at Moffittincluding: 1) basic science; 2) population science; 3) clinical science; 4) translational science; and 5)data science. Postdoctoral trainees in the Program are paired into training teams that design amentored research project that addresses a critical issue in cancer utilizing data science approaches. Inaddition to research the Program includes structured coursework taken as appropriate and issupplemented by participation in many career development activities relevant to postdoctoral trainees.The Program is regularly and rigorously evaluated internally and externally in a process that measuresprogress of the trainees and the effectiveness of the Program. 211392 +No NIH Category available Agonist;Antibody-drug conjugates;Area;Award;Basic Cancer Research;Binding;Binding Sites;Biological;Biological Assay;Biopsy Specimen;Cancer Biology;Cancer Center;Cancer Model;Career Choice;Cell Line;Cell surface;Cells;Cessation of life;Chemicals;Clinic;Clinical Data;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Complement;Data;Diet;Diet Modification;Down-Regulation;Drug Combinations;Drug resistance;Educational workshop;Effectiveness;Experimental Models;FDA approved;Fatty Acids;Foundations;Funding;Genitourinary system;Genomic approach;Genomics;Goals;High Fat Diet;Immunohistochemistry;In Vitro;Knock-out;Laboratories;Lead;Luciferases;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Mediating;Mediator;Medicine;Membrane Proteins;Mentors;Mentorship;Methods;Microtubules;National Comprehensive Cancer Network;PPAR gamma;PPARG gene;Pathway interactions;Patient Selection;Patients;Pharmaceutical Preparations;Pre-Clinical Model;Radiation Oncology;Recording of previous events;Regulatory Pathway;Research;Research Personnel;Resistance;Resources;Role;Sampling;Signal Transduction;Small Interfering RNA;Structure;Surface;T cell therapy;Technology;Testing;Therapeutic;Therapeutic Uses;Thiazolidinediones;Training;Transforming Growth Factor beta;Transitional Cell Carcinoma;Translational Research;Urothelium;Work;antagonist;bladder transitional cell carcinoma;cancer cell;cancer drug resistance;checkpoint therapy;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;chromatin immunoprecipitation;clinically relevant;experience;hands on research;improved;in vivo;innovation;instructor;knock-down;malignant breast neoplasm;minority patient;mouse model;next generation sequencing;novel drug combination;overexpression;patient derived xenograft model;pharmacologic;professor;promoter;resistance mechanism;response;rosiglitazone;skills;targeted treatment;therapeutic target;transcription factor;transcriptomic profiling;transcriptomics;translational cancer research;translational potential;tumor;tumor metabolism Defining the roles of PPARgamma and TGFbeta in regulating NECTIN4 and resistance to NECTIN4-targeting therapies PROJECT NARRATIVEThe antibody-drug conjugate enfortumab vedotin (EV) which targets the surface protein NECTIN4 was recentlyFDA approved for patients with metastatic urothelial carcinoma but the mechanisms controlling sensitivity andresistance to EV are unknown. Using patient derived xenografts (PDX) cell lines and patient biopsy samples Ipropose to: 1) investigate the roles of the PPARg and TGFb pathways in regulating NECTIN4; 2) identify noveldrug combinations to increase NECTIN4 expression and enhance the efficacy of NECTIN4-targetingtherapeutics; and 3) determine mechanisms underlying EV resistance. Completion of this study may lead to newclinical trials to improve the effectiveness and overcome resistance to NECTIN4-targeting therapies and mayhave implications beyond urothelial carcinoma to inform therapeutic strategies for other NECTIN4-expressingcancers including breast lung and pancreatic cancer. NCI 10691485 6/21/23 0:00 PA-20-203 5K08CA273514-02 5 K08 CA 273514 2 "BOULANGER-ESPEUT, CORINNE A" 9/15/22 0:00 6/30/27 0:00 Career Development Study Section (J)[NCI-J] 8904318 "CHOU, JONATHAN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 268867 NCI 248951 19916 PROJECT SUMMARYThe goal of this K08 application is to provide Dr. Jonathan Chou an Instructor of Medicine at UCSF with theskills he will need to become an independently-funded laboratory investigator. Dr. Chou proposes to elucidatethe regulatory mechanisms of NECTIN4 the target of a newly approved antibody-drug conjugate (ADC) inmetastatic urothelial cancer called enfortumab vedotin (EV) and identify mechanisms of resistance using PDXand metastatic biopsy samples. The proposal builds on Dr. Chous recent work which showed that NECTIN4expression is enriched in luminal subtypes of bladder cancer and that increasing and decreasing NECTIN4 canenhance EV sensitivity or lead to resistance respectively. Dr. Chou hypothesizes that the transcription factorPPARG which regulates luminal bladder cancer cell identity and integrates fatty acid signaling is a directregulator of NECTIN4 and that transiently augmenting NECTIN4 expression in urothelial cancer cells willenhance the efficacy of NECTIN4-targeting therapies. In Aims 1 and 2 Dr. Chou will elucidate the mechanismunderlying this regulatory pathway and determine whether sensitivity to NECTIN4-targeted therapies can beenhanced by directly modulating the PPARg pathway using pharmacologic approaches biological modifiers anddietary alterations. In Aim 3 Dr. Chou will determine whether loss of PPARg or alternatively activation of theEMT-associated TGFb pathway downregulates NECTIN4 thus leading to resistance. He will leverage EV-resistant cell lines that he has generated patient-derived xenograft (PDX) models (established from minoritypatients treated at UCSF) as well as metastatic biopsy samples from UCSF patients treated on EV toaccomplish this Aim. Dr. Chous training and research plan includes a combination of structured coursework andworkshops one-on-one tutorials and hands-on research experience that will all take place at UCSF a world-renowned NCCN Cancer Center with a history of excellence in basic and translational cancer research. Dr.Chous training plan will complement his existing expertise to build a strong foundation in the following areas: 1)bladder cancer biology; 2) preclinical modeling of ADCs and adoptive T cell therapies; 3) cancer metabolism anddrug resistance; and 4) genomics and next-generation sequencing methods and analysis. The project will beconducted under the mentorship of Dr. Felix Feng Professor of Radiation Oncology and Associate Director forTranslational Sciences and co-mentored by Dr. Alan Ashworth Professor of Medicine and President of theUCSF Cancer Center. He has assembled a distinguished advisory panel with complementary expertise to guidehis research and career path. At the completion of this award Dr. Chou will have the relevant didactic andresearch experience to become a leader in bladder cancer models therapeutic targeting strategies and genomicapproaches to investigate drug resistance including to ADCs. If successful this project will also provide atranslational opportunity from the laboratory to the clinic to utilize dietary modifications and thiazolidinedionedrug combinations to augment responses and potentially reverse resistance to NECTIN4-targeting therapies. 268867 +No NIH Category available Adoption;Adverse effects;Affect;Allogenic;Antigen Presentation;Attention;Autologous;Blood;Cancer Patient;Cell Count;Cell Survival;Cell Therapy;Cell membrane;Cell physiology;Cells;Clinic;Clinical;Consumption;Cryopreservation;Crystallization;Culture Media;Cyclic GMP;Cytoprotection;Derivation procedure;Development;Dimethyl Sulfoxide;Dose;Dry Ice;Encapsulated;Engineering;Formulation;Freezing;Gel;Goals;Growth;Hematologic Neoplasms;Hematopoietic Neoplasms;Hydrogels;Ice;Immunotherapy;Infusion procedures;Institution;Letters;Licensing;Liquid substance;MHC Class I Genes;MHC antigen;Malignant Neoplasms;Methods;Minnesota;Molecular;NK cell therapy;Natural Killer Cell Immunotherapy;Natural Killer Cells;Nitrogen;Patients;Process;Production;Protocols documentation;Reagent;Relaxation;Risk;Solid Neoplasm;Speed;Standardization;Technology;Temperature;Testing;Therapeutic;Time;Transfusion;Tumor Escape;Universities;anticancer activity;cancer therapy;cell growth;chimeric antigen receptor T cells;clinical practice;cost;cost effectiveness;cryogenics;cytokine;cytotoxic;cytotoxicity;extracellular;fetal bovine serum;graft vs host disease;induced pluripotent stem cell;innovation;large scale production;manufacture;manufacturing capabilities;manufacturing facility;mechanical force;melting;novel;peripheral blood;preservation;programs;response Novel cryopreservation method for stabilization of manufactured therapeutic cells Novel Cytocompatible Encapsulation-based Vitrification Method for Natural Killer Cell Immunotherapy The main goal of this proposal is development and adaptation of a novel preservation and storage methodfor natural killer (NK) cells which are increasingly used in immunotherapy against blood cancers and solidtumor cancers. Lack of efficient and safe cryopreservation technologies for NK cells is a major roadblock forwide scale adoption of promising immunotherapies: Current cryopreservation limitations add strain on clinicalpractice introduce risks for contamination increase costs and most importantly decrease the potential forgreater access to patients as only institutions with advanced cell therapy manufacturing capabilities are able totreat patients. NCI 10691483 8/15/23 0:00 RFA-CA-20-019 5R21CA261734-03 5 R21 CA 261734 3 "AGRAWAL, LOKESH" 9/15/21 0:00 8/31/24 0:00 ZCA1-TCRB-Q(M2) 8799403 "AKSAN, ALPTEKIN " Not Applicable 5 ENGINEERING (ALL TYPES) 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN BIOMED ENGR/COL ENGR/ENGR STA 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 157448 NCI 106575 50873 Novel Cytocompatible Encapsulation-based Vitrification Method for Natural Killer Cell ImmunotherapySummary: Use of natural killer (NK) cells as immunotherapy against hematologic and solid tumor cancers hasgained much attention in the last few years. Critical advantages of NK cells include lack of risk for transfusion-associated graft-versus-host disease and decreased likelihood of tumor escape. The fact that NK cellsrecognize targets without needing MHC class I allows for the use of allogeneic products. At the University ofMinnesota co-I Dr. Miller and his NK cell Program team have treated over 400 cancer patients with donor NKcells and single dosing is a major limitation to fully test their anti-cancer activity. To allow for third party off-the-shelf large- scale manufacturing needed for multidose strategies we must be able to freeze and thaw NK cellson demand with minimal loss of viability and function. However current cryopreservation practice heavily relieson the use of toxic cryoprotectant agents (CPAs) such as dimethyl sulfoxide (DMSO) and freeze/thaw protocolsthat are not optimized for NK cells. As a result there is a) a significant decrease in post-thaw viability of the NKcells and b) loss of NK cell cytotoxicity and cytokine production function. PI Prof. Aksan's lab has recently developed a cytocompatible encapsulation-based vitrification method thatdoes not require cytotoxic and mutagenic CPAs. The main goal of this proposal is development andadaptation of this novel method to vitrify and preserve expanded blood and induced pluripotent stem cell(iPSC) derived NK cells. Our method avoids detrimental intra-/extracellular ice crystallization during coolingand re-crystallization during warming therefore eliminating freeze/thaw and cryogenic storage-induced loss ofviability and post-thaw function. To reach our main goal we will pursue the following specific aims: Specific Aim 1: Engineer the encapsulation gel and determine the cytocompatible CPA compositionsthat will inhibit intra-/extracellular ice crystallization and growth devitrification and eutectic meltingwhich are detrimental.Specific Aim 2: Maximize post-thaw NK cell viability and function using optimized freeze-thawprotocols.Specific Aim 3: Verify short and medium-term storage stability of NK cells at -80oC and in liquidnitrogen. 157448 +No NIH Category available Algorithms;Antibodies;Antigens;Atlases;Automated Annotation;Base Composition;Bioinformatics;Cell Separation;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Characteristics;Cloud Computing;Collaborations;Collection;Communities;Computer software;Computing Methodologies;Cost efficiency;Cytometry;Data;Data Set;Ecosystem;Educational workshop;Ensure;Flow Cytometry;Gene Expression Profile;Genes;Goals;Hematopoietic Neoplasms;Human;Immunohistochemistry;Informatics;Information Theory;Learning;Leukocytes;Malignant neoplasm of pancreas;Manuals;Maps;Measurement;Methods;Neoplasm Metastasis;Ontology;Pathogenesis;Performance;Phenotype;Population;Process;Proteins;Publishing;Reproducibility;Research;Research Personnel;Resolution;Standardization;Statistical Models;Technology;Testing;Tissues;Tumor Tissue;Work;anticancer research;cancer therapy;cell type;design;experimental study;fluorophore;immune cell infiltrate;learning algorithm;leukemia;neoplastic cell;open source;outreach;public repository;relational database;repository;single-cell RNA sequencing;therapy resistant;transcriptome;transcriptomics;tumor;tumor progression;web portal A data-driven bioinformatics platform for the design and analysis of multiplexed antibody-based cytometry experiments in cancer research NARRATIVEWe will develop deploy and disseminate new informatics technologies that leverage existing single-cell transcriptomic atlases to assist and automate the design and analyses of multiplexed antibody-based cytometry experiments in cancer research. These computational methods will be instrumental in ensuring standardized scalable and reproducible cytometry analyses of tumors with increased phenotypic resolution. By facilitating accurate characterizations of tumor cell ecosystems our research will impact advances in cancer treatment. NCI 10691480 7/13/23 0:00 RFA-CA-21-014 5U01CA269409-02 5 U01 CA 269409 2 "LI, JERRY" 9/1/22 0:00 8/31/25 0:00 ZCA1-TCRB-Q(M1) 14298850 "GONZALEZ CAMARA, PABLO " Not Applicable 3 GENETICS 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 374852 NCI 241599 133253 ABSTRACTTumor progression resistance to therapy and metastasis are closely related to the characteristics of the tumor cell ecosystem. Multiplexed antibody-based cytometry is the standard method for phenotypic characterization of tissue composition pathogenesis and immune infiltration with single-cell (and sometimes spatial) resolution. The identification of cell populations in these data is facilitated by algorithms that cluster cells according to their antigenic profile as well as by predefined sets of markers that have historically evolved by trial and error. However the annotation of these data is a manual subjective and laborious process that hinders the reproducibility and accuracy of the results. The design of antibody panels that include specific markers for all cell types and states present in a tissue is usually unfeasible and the efficiency of commonly used markers is unknown. Consequently cell clusters can differ little in their antigenic profile or contain a mixture of cell types. To overcome these limitations this project will develop informatics technologies that leverage existing single-cell transcriptomic atlases to assist and automate the design and analyses of multiplexed antibody-based cytometry experiments. Our working hypothesis is that the vast amount of available single-cell transcriptomic data of tissues can inform the design annotation and analysis of cytometry experiments. We will develop and evaluate informatics technologies for establishing reference antigenic profiles and optimal antibody panels based on single-cell proteotranscriptomic data (Aim 1 ) and for automating the identification annotation and gating of cell populations in multiplexed antibody-based cytometry experiments (Aim 2). These new computational methods will enable any researcher to 1) automatically identify and annotate cell populations in a cytometry dataset based on reference single-cell data hosted in a repository 2) define optimal gates for sorting cell populations 3) transfer gates across experiments 4) design optimal antibody panels for a given tissue or set of cell populations and 5) infer the gene expression profile of cells. We will implement these methods in an open-source software and online portal for the transcriptome-guided annotation and analysis of cytometry data of tumors and will closely work with end-users through several planned workshops and tutorials to maximize the utility and outreach of this platform (Aim 3). We will test our platform on leukemic and pancreatic cancer tissues profiled with spectral flow cytometry and multiplexed quantitative immunohistochemistry. The informatics technologies developed in this project will transform cancer research by boosting the phenotypic resolution accuracy and reproducibility of multiplexed antibody-based cytometry analyses of tumor tissues. 374852 +No NIH Category available ATAC-seq;Acceleration;Animal Model;Animals;Automobile Driving;Benign;Binding;Biology;CRISPR/Cas technology;Cancer Etiology;Cell Line;Cell Survival;Cells;ChIP-seq;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;Cutaneous Melanoma;DNA Sequence Alteration;Data;Development;Early Diagnosis;Early treatment;Embryo;Engineering;Enhancers;Epigenetic Process;Event;Gene Expression Profiling;Gene Silencing;Genetic Transcription;Goals;Growth;Human;Location;Malignant Conversion;Malignant Neoplasms;Mediating;Melanoma Cell;Modeling;Mole the mammal;Molecular;Mutation;Nature;Neural Crest;Nevus;Non-Invasive Detection;Normal Cell;Oncogenic;Pathway interactions;Patient-Focused Outcomes;Patients;Premalignant Cell;Process;Proteins;Publishing;Recurrence;Regulation;Reporter;Reporter Genes;Repression;Role;Skin;Skin Cancer;Sorting;System;TP53 gene;Testing;Transgenes;Transgenic Organisms;Up-Regulation;Visualization;Xenograft procedure;Zebrafish;cancer cell;cancer initiation;cancer therapy;design;driver mutation;enhanced green fluorescent protein;exome sequencing;experimental study;in vivo;innovation;loss of function;malignant state;melanocyte;melanoma;novel;overexpression;patient derived xenograft model;premalignant;prevent;programs;promoter;therapeutic target;transcription factor;transcriptome sequencing;tumor;tumor initiation;tumorigenesis Defining Transcriptional Regulators of Melanoma Initiation using Zebrafish Project NarrativeNormal cells frequently carry genetic changes or mutations that can cause cancer butfortunately only rarely form tumors. We aim to understand how these rare earliest steps in theformation of cancer are controlled for melanoma skin cancer. Our studies may allow us to detectand treat melanoma earlier and more effectively than is currently possible. NCI 10691465 7/18/23 0:00 PA-18-484 5R01CA240633-05 5 R01 CA 240633 5 "FINGERMAN, IAN M" 8/13/19 0:00 7/31/24 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10457518 "KAUFMAN, CHARLES KORE" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 353537 NCI 224468 129069 Project Summary/Abstract Within a group of cancer-prone cells that share an oncogenic mutation sometimes described as acancerized field only select cells transition to a malignant state. Due to the rarity and transient nature of theseevents cancer initiation has been difficult to study and remains incompletely understood. Identifying cells at theearliest stages of transformation and understanding the underlying mechanisms leading to their malignantconversion would allow for earlier detection and treatment of cancer which should lead to better patientoutcomes. Such is the case in the skin where non-cancerous overgrowths of pigmented melanocytes callednevi or moles harbor a potentially cancer-causing mutation termed BRAFV600E which is also found in over halfof melanoma cancers. Yet nevi rarely progress to invasive melanoma. To enable studies of melanoma initiation and the mechanisms driving this conversion to cancer wedeveloped a novel reporter of melanoma initiation in a zebrafish melanoma model (that relies on this sameBRAFV600E mutation) that expresses a fluorescent protein (EGFP) in the first cell of melanoma and can bevisualized in a live animal. Using this model we found that embryonic neural crest identity reemerges duringmelanoma initiation and that regulation of sox10 neural crest transcription factor levels in melanocytes is onekey control point in this process. In this proposal we will test the hypothesis that a specific subset of normally embryonic transcriptionalinputs modulates sox10 activity during melanoma initiation and that upregulation of neural crest transcriptionfactors -- in addition to and potentially upstream of sox10 -- directs this transition to malignancy. By defining therole of key transcriptional inputs in modulating sox10 in its native context we will understand the molecularmechanisms modulating the melanocyte to melanoma transition. We further identify additional neural cresttranscription factors that may modulate this process and determine their role and regulation in melanomainitiation. Finally we use human melanoma patient-derived xenografts (PDX) to further clarify if ongoingexpression of these factors is needed for melanoma viability or if their role is primarily during tumor initiation.Overall this proposal describes innovative approaches to determine the precise regulation of alteredtranscriptional and epigenetic programs driving melanoma cancer initiation which may define new and earlier-acting therapeutic targets for treating melanoma. 353537 +No NIH Category available Affinity;Animals;Anti-Idiotype Vaccine;Antibodies;Autoantibodies;BRCA2 gene;Binding;Biological Markers;Cancer cell line;Cell membrane;Cells;Chemotherapy and/or radiation;Clinic;DNA;DNA Damage;DNA Repair;DNA Repair Disorder;DNA Repair Inhibition;DNA Repair Pathway;DNA-dependent protein kinase;Development;Dropout;Glioma;Human;Isocitrate Dehydrogenase;Lupus;Malignant Neoplasms;Mus;Mutation;Nature;Nonhomologous DNA End Joining;Normal tissue morphology;PTEN gene;Pathway interactions;Patients;Penetration;Peptides;Phase I Clinical Trials;Phenotype;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Publishing;RNA;Radiation;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Tumor Tissue;Work;cancer cell;cancer therapy;chemotherapy;in vivo;inhibitor;leukemia;neoplastic cell;next generation;novel;novel therapeutics;pre-clinical;repaired;response;small hairpin RNA;small molecule;synergism;synthetic lethal interaction;tumor;tumor microenvironment Novel DNA Repair Inhibitors for Cancer Therapy Project Narrative. We seek to identify novel therapeutic agents that are selectively toxic to cancer cells and that specificallysensitize tumors to radiation or chemotherapy. We have discovered that a lupus-derived cell-penetratingautoantibody (3E10) inhibits DNA repair and can increase the sensitivity of cancer cells to radiation andchemotherapy but is otherwise non-toxic to human cells. We have also developed novel peptide conjugatesthat selectively target tumors and spare normal tissues and we will use these to deliver specific DNA repairinhibitors to cancer cells. We will investigate the mechanism of action of these agents and elucidate how theycan best be used for cancer therapy. NCI 10691464 7/18/23 0:00 PAR-16-411 5R35CA197574-07 5 R35 CA 197574 7 "VENKATACHALAM, SUNDARESAN" 8/1/17 0:00 7/31/24 0:00 ZCA1-RTRB-C(M2) 1871634 "GLAZER, PETER M" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 982379 NCI 588000 396900 Project Summary/Abstract. We seek to identify novel therapeutic agents that are selectively toxic to cancer cells and that specificallysensitize tumors to radiation or chemotherapy. We have discovered that a cell-penetrating lupus-derivedautoantibody (3E10) increases the sensitivity of cancer cells to radiation and to DNA-targeted chemotherapy.Importantly 3E10 by itself is synthetically lethal to BRCA2- and PTEN-deficient cancer cells but is otherwisenon-toxic to cells in culture or to mice. The antibody also showed no detectable toxicity in humans when testedin a phase I clinical trial in lupus patients as a putative anti-idiotype vaccine. We previously determined 3E10 tobe a potent inhibitor of homology-dependent repair (HDR) and we have now identified RAD51 as thefunctional target. We have also found that 3E10 is preferentially taken up in tumor tissue in vivo based on itsmechanism of cell penetration providing a further basis to pursue its development for cancer therapy. Thesenew results provide the basis to enhance the potency of 3E10 (by directed mutation affinity maturation andmulti-valent constructs) and to rationally develop therapeutic strategies by identifying synthetic lethalinteractions (via unbiased shRNA dropout screen and interrogation of curated cancer cell lines) anddetermining synergies with other agents as a prelude to pre-clinical animal tumor studies. We expect that3E10 will be synthetic lethal to cancers deficient in DNA repair and damage response pathways. We also have developed a strategy to selectively target DNA repair inhibitors to tumors by exploiting theacidic tumor microenvironment. We will use a pH low insertion peptide (pHLIP) that inserts directionally acrosscell membranes at low pH and delivers cargoes selectively into tumor cells in vivo. Focusing on DNA-PK in thenon-homologous end-joining pathway (NHEJ) of DNA repair we will build on advances made in collaborativework to develop tumor-targeted antisense and small molecule inhibition of DNA-PK. We will incorporate nextgeneration PNAs modified at the position to increase binding to RNA for potent antisense activity. This isbased on our promising proof-of-concept studies published in Nature demonstrating the in vivo anti-tumoractivity of pHLIP-PNA conjugates. We will also conjugate small molecule DNA-PK inhibitors to pHLIPleveraging potent molecules that have not advanced to the clinic because of normal tissue toxicity andconferring tumor selectivity. This work will provide a versatile platform to apply to other DNA repair targets. We have recently identified the oncometabolite 2-hydroxyglutarate (2HG) as a new biomarker of deficientDNA repair in human malignancies. We found that elevated levels of 2HG confer a BRCAness phenotype ofdeficient HDR that renders cancer cells sensitive to synthetic lethal killing by PARP inhibitors and by 3E10.2HG is produced by the neomorphic activity of isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations found ingliomas leukemia and other cancers. We will investigate the mechanism by which 2HG suppresses DNArepair and identify vulnerabilities that can be exploited for therapeutic gain in human tumors. 982379 +No NIH Category available Acceleration;Back;Benign;Biochemical;Biochemistry;Biological Assay;Biological Markers;Biopsy;Breast Cancer Patient;CDK2 gene;CDK4 gene;Cell Line;Clinical;Clinical Trials;Complex;Cyclin D1;Data;Development;Dissociation;Drug Targeting;ERBB2 gene;Effectiveness;Estrogens;Exhibits;Feedback;Flow Cytometry;Fulvestrant;Goals;Hormones;Immunohistochemistry;In Vitro;Letrozole;Malignant neoplasm of ovary;Mediating;Metastatic breast cancer;Methods;Oncogenic;Pathologic;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphorylation;Prediction of Response to Therapy;Progression-Free Survivals;Publishing;Refractory;Resistance;Resistance development;Savings;Signal Pathway;Stains;Stratification;Subgroup;Surrogate Endpoint;Surrogate Markers;Testing;Therapeutic;Time;Toxic effect;Tyrosine;Tyrosine Phosphorylation;Work;chemotherapy;clinically relevant;clinically significant;cohort;companion diagnostics;cost;cyclin-dependent kinase inhibitor 1B;diagnostic biomarker;differential expression;dimer;drug resistance development;drug-sensitive;improved;in vivo;in vivo Model;inhibitor;inhibitor therapy;malignant breast neoplasm;mammary epithelium;monomer;novel;novel diagnostics;novel therapeutics;patient derived xenograft model;patient response;precision medicine;predicting response;predictive marker;resistance mechanism;response;targeted treatment;tissue culture;triple-negative invasive breast carcinoma;tumor Tyrosine phosphorylation of p27Kip1 as a biomarker to identify Cdk4/6 inhibitor response PROJECT NARRATIVEThe goal of this project is to explore the utility of a novel diagnostic markerp27Kip1 pY88 to identify patients who would respond to the currently usedCDK4/6 inhibitors (CDK4i) Palbociclib Ribociclib and Abemaciclib. NCI 10691447 6/1/23 0:00 PA-20-185 5R01CA249667-03 5 R01 CA 249667 3 "DEY, SUMANA MUKHERJEE" 6/10/21 0:00 5/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 1864503 "BRISSETTE, JANICE L" Not Applicable 9 ANATOMY/CELL BIOLOGY 40796328 NJ14V2NZYM68 40796328 NJ14V2NZYM68 US 40.65537 -73.945077 5992616 SUNY DOWNSTATE MEDICAL CENTER BROOKLYN NY SCHOOLS OF MEDICINE 112032012 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 612351 NCI 401924 210427 SUMMARYWhile the CDK4 targeting drugs (CDK4i) Palbociclib Abemaciclib and Ribociclib have shown clinical promisein the treatment of metastatic breast cancer (BC) lack of a companion diagnostic to identify responsivepatients remains a problem. While CDK4i therapy increases progression-free survival (PFS) in somemetastatic HR+ patients many patients exhibit primary resistance to CDK4/6 inhibition and do not derive anybenefit from these agents switching to chemotherapy within 6 months. Development of a biomarker to identifythe presence of the active CDK4 target and therefore CDK4i sensitive patients would enable responsivemetastatic breast cancer patients to be pinpointed at the onset of therapy. As CDK4/6 is downstream of alloncogenic signaling pathways it is also likely that this class of drugs will have efficacy in at least a subset ofadditional tumor types and a biomarker for CDK4i responsiveness would accelerate the expansion of thisclass of therapy into tumor types such as metastatic Her2+ Triple negative breast or ovarian cancer whichhave few therapeutic options. A biomarker to predict effectiveness of CDK4i would mean more rapid benefit tothe correct patients a cost and time savings and reduced toxicity for patients who would not be benefited andextended use of these therapies across tumor types where novel therapies are desperately needed. Inessence: a biomarker would help get the right drug to the right patients. This translational project will focus onthe utility of a novel diagnostic marker p27Kip1 pY88 to identify patients who would respond to the currentlyused CDK4i therapy. In published and presented work we have shown that pY88 serves as a surrogatemarker for CDK4 activity and in turn CDK4i responsiveness in cell lines primary explant culture and now inbiopsies from patients treated clinically with CDK4i therapy. The goal of this RO1 project is to demonstratethat p27 pY is a diagnostic biomarker to identify CDK4/6i-responsive patients and then also toreconcile why pY might demarcate resistance by associating it to mechanisms of resistance with theidea that this will further inform potential uses of the CDK4/6i drugs. In Aims 1 and 2 (translational aims) weplan to test an IHC based assay to determine if pY88 can serve as a biomarker to predict significant PFSimprovement in patients with HR+/HER2- BC treated with CDK4/6i. In Aim 3 (mechanism aim) we willdetermine how pY status relates to CDK4/6i sensitivity and resistance. Aim 1: To test the ability of the pYbiomarker to predict significant PFS by comparing pY88 status in biopsy material from patients with HR+BC treated clinically with CDK4/6i with patient outcome data. Aim 2. To test the validated pY test inclinically relevant cohorts from two completed and ongoing clinical trials. Aim 3: To determine how pYstatus relates to CDK4/6i sensitivity and resistance by using biochemical studies to examine pY status inin vitro and in vivo models of CDK4/6i resistance. 612351 +No NIH Category available Adult;African American population;Area;Calibration;Cancer Intervention and Surveillance Modeling Network;Cessation of life;Clinical Trials;Colorectal Cancer;Continuity of Patient Care;Development;Diagnosis;Disease;Disparity;Economic Burden;Evaluation;Goals;Guidelines;Health;Hematologic Neoplasms;Incidence;Incubators;Intervention;Life;Modeling;Monoclonal gammopathy of uncertain significance;Multiple Birth Offspring;Multiple Myeloma;Neoplasms;Obesity;Patients;Pharmaceutical Preparations;Policies;Precancerous Conditions;Precision therapeutics;Prevention;Prevention strategy;Recommendation;Regimen;Reporting;Research;Risk;Risk Management;Route;Solid Neoplasm;Treatment Protocols;Universities;Washington;cancer care;cancer site;caucasian American;clinical practice;cohort;comparative;cost;cost-effectiveness evaluation;disease natural history;disparity reduction;evidence base;flexibility;health disparity;high risk;improved;innovation;malignant breast neoplasm;novel;novel strategies;population based;premalignant;prevent;process optimization;programs;progression risk;racial disparity;screening;survival outcome;survivorship;trend Comparative modeling of multiple myeloma across myeloma control continuuum: prevention treatment and disparity reduction PROJECT NARRATIVERELEVANCE: Multiple myeloma (MM) is a common incurable hematologic malignancy whose management isextremely costly with long-established disparities disproportionally inflicting African American populations.However MM lacks comparative modeling like the six cancer sites within the CISNET to guide its preventionand control policies. The proposed MM Incubator Program will develop such modeling to assess the value ofguideline recommended therapies and novel intervention strategies for MM prevention and control across MMcare continuum with the goals of reducing MM burden and disparities. NCI 10691407 8/8/23 0:00 RFA-CA-20-043 5U01CA265735-03 5 U01 CA 265735 3 "ZHU, LI" 9/20/21 0:00 8/31/26 0:00 ZCA1-SRB-F(A1)R 10675721 "CHANG, SU-HSIN " "COLDITZ, GRAHAM A.; WANG, SHIYI " 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 632304 NCI 483159 149145 PROJECT SUMMARY/ABSTRACTMultiple myeloma (MM) is a common and lethal hematologic malignancy. Treatments of MM have been rapidlyevolving. While these new treatments improve survival considerably the median survival still ranges from 43-83 months at diagnosis. Among all cancer sites the management of MM is the most costly which in part canbe attributable to guideline recommended multidrug regimens. Despite such significant health and economicburdens and rapid changing landscape for MM treatments MM is not one of the cancer sites in the CancerIntervention and Surveillance Modeling Network (CISNET). Therefore MM lacks comparative modeling to setgoals and policy prioritization in MM prevention and control. Moreover unlike breast cancer or colorectalcancer there exists no population-based screening for MM or risk managed strategies for those withpremalignant conditions (MGUS and smoldering MM). MM requires comparative modeling to evaluatepromising intervention strategies particularly at premalignant stages. To prevent/control this devastatingdisease it is imperative to demonstrate the potentials of these interventions before implementation. Moreovermarked racial disparities in MM (both incidence and survival) is long-established. Without any value-basedstrategies for prevention and treatment MM health disparities will continue to worsen. This Incubator Programwill include two modeling groups to conduct comparative modeling under the coordination of the coordinatingcenter. Our Program will evaluate novel strategies in preventing or treating MM with the goals of reducing theburden of MM and mitigating MM disparities. We plan to comparatively build calibrate and validate evidence-based MM modeling across the MM care continuum (Aim 1). Using the proposed comparatively modeling wewill (1) assess the impacts of novel MM prevention strategies in high-risk patients diagnosed with MGUS (Aim2); (2) evaluate the cost-effectiveness of novel treatment regimens as well as guideline-recommendedtreatments in patients diagnosed with MM (Aim 3); and (3) assess whether under what conditions and inwhich ways the goal of eliminating racial disparities can be achieved through the proposed novel interventionstrategies (Aim 4). The proposed MM Incubator Program is significant in its capability to 1) build evidence-based comparative modeling for MM a disease area that lacks of such modeling relative to the areas of solidtumors already with such modeling to guide interventions and policies; 2) provide evidence-based evaluationbefore implementation of any costly clinical trial; 3) explore novel interventions/treatments at various stages ofMM; and 4) examine the value of guideline-recommended therapies providing evidence to inform changes inguidelines and thus a shift in current clinical practice of MGUS and MM management. The proposedintervention strategies for MGUS and MM patients are innovative with the goals to prevent and control MMand reduce MM disparities. Successful completion of this study will provide evidence in tangible metrics to urgea paradigm shift from current MGUS/MM management. It is therefore a vital step to move the field forward. 632304 +No NIH Category available Biological;Biological Factors;Cancer Center;Clinical;Clinical Research;Collaborations;Communication;Complex;Data;Ensure;Feedback;Funding;General Hospitals;Goals;Health Sciences;Individual;Institution;Internet;Massachusetts;Medicine;Modeling;Monitor;Occupational activity of managing finances;Office of Administrative Management;Online Systems;Participant;Patients;Personnel Management;Photons;Physics;Policies;Program Research Project Grants;Progress Reports;Protons;Qualifying;Radiation therapy;Recommendation;Research;Research Personnel;Research Priority;Resources;Rice;Sampling;Schedule;Scientist;Services;Site;Telephone;Texas;Universities;austin;biological research;college;meetings;programs;senior faculty;symposium;telephone based Administrative Core ADMINISTRATIVE CORE - NARRATIVEThe purpose of Administrative Core is to provide centralized scientific and administrative managementfinancial control services and clerical and materials management support to all projects and cores. TheAdministrative Core will coordinate research among projects and cores monitor progress and resolveissues as they arise. It will provide necessary support for the organization and conduct of the SteeringCommittee /Internal Advisory Board meetings the annual Investigator Meeting and Retreat with theExternal Advisory Board and monthly or as-needed telephone video and web conferences. NCI 10691404 9/15/23 0:00 PAR-20-077 5P01CA261669-03 5 P01 CA 261669 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 6885 8636914 "HONG, THEODORE S" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 211248 181859 29389 ADMINISTRATIVE CORE - PROJECT SUMMARYThe purpose of Administrative Core (AC) is to provide the organizational administrative and fiscalmanagement of this P01 to develop and implement plans for monitoring the progress and to effectivelycoordinate and communicate within the P01. The AC is essential to ensure that this Program Project is able tosuccessfully conduct clinical studies and physics and biological research at all the collaborating institutions.Successful conduct of research in a complex multi-site program of this magnitude and significance requirescentralized scientific and administrative oversight.Aims of the Administrative Core are: (1) Provide centralized scientific and administrative oversightmanagement and clerical support to all Projects and Cores; organize and conduct the Internal SteeringCommittee (ISC) and the annual External Advisory Board (EAB) meetings; and provide support for the weeklymonthly and as-needed telephone and web-based online conferences. (2) Develop and implement plans foreffective coordination of research; facilitate the exchange of materials (e.g. biological samples) data modelsand information; coordinate communication among researchers; monitor progress; and report progress to theISC EAB and the NCI at appropriate intervals. (3) Provide fiscal management support and financial controlservices to individual projects and cores to ensure funds are expended appropriately and provide aid asneeded for personnel management.Drs. Theodore Hong (MGH) and Radhe Mohan (MDACC) the P01 MPIs will direct this Core and reviewprogress and decide policy matters relating to research priorities. The External Advisory Board comprised oftop scientists in the field will meet with investigators annually to review scientific progress and the direction ofresearch and make recommendations for the following year. The ISC composed of the highly qualified seniorfaculty at MGH and MDACC will meet twice annually and will provide feedback and ensure that resources forthe conduct of the proposed research are available. There will be numerous regularly scheduled scientific andadministrative meetings to coordinate activities at the multiple institutions involved to facilitate research andmonitor progress. +No NIH Category available Area;Back;Bioinformatics;Biological;Biological Assay;Biological Factors;Biological Markers;Brain;Breast;Cancer Patient;Cancer cell line;Cell Line;Cells;Characteristics;Clinical;Clinical Trials;Collection;Computational Technique;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Repair Pathway;DNA lesion;DNA mapping;Data;Defect;Deposition;Derivation procedure;Dose;Double Strand Break Repair;Esophagus;Excision;Funding;Future;Gene Expression Profile;Gene Mutation;Genomics;Goals;Individual;Institution;Interdisciplinary Study;Knowledge;Linear Energy Transfer;Liver;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Mission;Modeling;Mus;National Cancer Institute;Normal tissue morphology;Nucleosomes;Organoids;Pancreas;Pathway interactions;Patient Selection;Patients;Photons;Predisposition;Property;Protons;Public Health;Radiation;Radiation therapy;Reaction;Relative Biological Effectiveness;Research;Research Support;Resolution;Site;Specimen;Stratification;Stratification Factors;Study models;Techniques;Testing;Therapeutic;Toxic effect;Tumor Cell Biology;University of Texas M D Anderson Cancer Center;Validation;Variant;Xenograft Model;Xenograft procedure;biomarker identification;biomarker validation;biophysical model;cancer cell;cancer rehabilitation;cancer therapy;cancer type;candidate identification;candidate marker;clinically relevant;genomic biomarker;genomic locus;genomic profiles;improved;in vivo;individual patient;innovation;irradiation;molecular marker;novel;particle;pre-clinical;predicting response;predictive marker;proton beam;proton therapy;repaired;response;small molecule inhibitor;synergism;therapeutic DNA;tool;tumor Project 3: Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers. PROJECT 3 - NARRATIVEThe proposed research is relevant to public health in that the discovery of novel biological effects of protontherapy as well as biomarkers predictive of response is expected to transform our understanding of DNAdamage response following particle irradiation and identify patients who will have favorable responses toproton therapy. Thus the proposed studies are relevant to the National Cancer Institute and its mission tosupport research to improve cancer treatment and rehabilitation. NCI 10691401 9/15/23 0:00 PAR-20-077 5P01CA261669-03 5 P01 CA 261669 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 6884 2641684 "GROSSHANS, DAVID R" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 599870 570481 29389 Project 3 - SUMMARYWhile proton beam therapy (PBT) has superior physical characteristics compared to standard photonradiation its biological properties have been thought to be similar to photons. This is reflected in the use of ageneric relative biological effectiveness (RBE) of 1.1 to scale the physical dose delivered for both cancerand normal tissues. However pre-clinical data from our groups and others are emerging to indicate that theRBE of PBT varies and may be dependent on intrinsic tumor cell biology. Such RBE variations are likelygenomically defined and exist across individual tumors of a given cancer type. This is a vastly understudiedarea with potential for substantial clinical impact as we are advancing our ability to genomically profilecancers to identify candidate predictive biomarkers. Thus our overall objective is to establish distinctbiological properties of PBT relative to photon radiation and determine if these differential properties result invariable RBE values across genomically diverse tumors. By combining synergistic MGH and MDACCexpertise we will integrate advanced physical computation techniques with novel biological tools such asnucleosome-resolution genomic mapping of DNA double-strand breaks to study the hypothesized uniquebiological damage produced by protons. We will conduct the following Specific Aims: (1) Simulate DNAdamage induction and repair for proton vs photon irradiation; (2) Experimentally elucidate targetabledifferences in the induction and removal of DNA breaks following proton vs photon irradiation; (3) Identifycandidate genomic biomarkers that predict increased proton RBE in annotated cancer cell lines; (4) Validatebiomarker-correlated proton sensitivity in clinically relevant tumor models and in patients. These studies willleverage extensive pre-clinical tumor model collections as well as clinical trial specimens at both institutions.The knowledge gained will quickly influence the treatment of cancer patients through the introduction ofnovel clinical trials with stratification based on genomic biomarkers that predict sensitivity to PBT. +No NIH Category available Adaptive Immune System;Affect;Biological Factors;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Characteristics;Clinical;Computer Simulation;Cytometry;DNA Damage;Data;Databases;Development;Disease;Disease Outcome;Distant Metastasis;Dose;Fractionation;Future;Goals;Heterogeneity;Immune;Immune system;Immunity;Immunologic Surveillance;Immunosuppression;Immunotherapy;Incidence;Intensity-Modulated Radiotherapy;Ionizing radiation;Link;Location;Lymphocyte;Lymphocyte Count;Lymphocyte Depletion;Lymphocyte Subset;Lymphopenia;Machine Learning;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of esophagus;Malignant neoplasm of liver;Measures;Mediating;Mediator;Modality;Modeling;Outcome;Patient risk;Patients;Pattern;Phenotype;Photons;Pre-Clinical Model;Predictive Factor;Predisposition;Process;Prognostic Factor;Protons;Radiation;Radiation Dose Unit;Radiation Tolerance;Radiation therapy;Radiation-Induced Cancer;Recurrent disease;Regimen;Research;Risk;Roentgen Rays;Role;Selection for Treatments;Severities;Site;Solid Neoplasm;Structure;T cell clonality;T-Cell Receptor;T-Lymphocyte;T-cell diversity;Techniques;Testing;Time;Treatment outcome;Tumor Immunity;Tumor Volume;Vaccination;Work;cancer therapy;cancer type;clinical practice;clinical prognostic;clinical translation;clinically relevant;clinically significant;cytotoxic;cytotoxicity;evidence base;experimental study;functional status;high risk;immunological diversity;immunological status;improved;improved outcome;individual patient;optimal treatments;patient subsets;personalized approach;personalized care;personalized predictions;personalized strategies;population based;predictive modeling;preservation;prospective;proton therapy;radiation mitigation;radiation risk;risk mitigation;risk prediction;risk prediction model;side effect;therapy outcome;treatment optimization;treatment planning;tumor Project 2: Radiation-Induced Lymphopenia: Understanding Predictive Modeling and Developing Photon and Proton-Based Mitigation Strategies. Project 2 - NarrativeRadiation-Induced Lymphopenia: Understanding Predictive Modeling and Developing Photon and Proton-Based Mitigation StrategiesRadiation therapy (RT) a key pillar of cancer management causes a common yet often ignored side effect immune system suppression (i. e. radiation-induced lymphopenia [RIL]). Severe RIL has been linked to poorcancer treatment outcomes presumably due to the reduced tumor surveillance by the immune system therebyincreasing disease recurrence and distant metastasis after RT. We propose approaches to identify clinical anddosimetric factors that predict the risk and severity of RIL and understand the impact of RIL on the immunediversity and profile as it affects clinical outcomes; to develop models that can accurately predict the risk of RILindividualized to a patients baseline clinical factors; and to use such models in the optimization of radiationdose distributions to mitigate RIL and its impact on outcomes. NCI 10691398 9/15/23 0:00 PAR-20-077 5P01CA261669-03 5 P01 CA 261669 3 9/21/21 0:00 8/31/26 0:00 ZCA1-RPRB-L 6883 10298380 "LIN, STEVEN HSESHENG" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 578510 549121 29389 Project 2 - SummaryRadiation-Induced Lymphopenia: Understanding Predictive Modeling and Developing Photon and Proton-Based Mitigation StrategiesThere is accumulating evidence across many types of cancers that radiation-induced lymphopenia (RIL) iscommon but it is often ignored as an unavoidable side effect. Severe RIL has been shown to correlate withpoor disease-specific outcomes. Extensive use of radiotherapy (RT) in the curative management of solidtumors necessitates the development of RIL-mitigation strategies. We have compelling evidence of significantdifferences in the lymphocyte-sparing effects of proton therapy (PT) vs. photon (or x-ray) therapy (XRT)presumably attributable to the differences in their dose distribution patterns. Our work has furtherdemonstrated that both patient-specific and dosimetric factors contribute to the risk of severe RIL and T-cellclonality. Our hypotheses are as follows: (1) RIL predictive models that account for individual patientsusceptibilities and dosimetric factors will have clinically significant predictive power; (2) reducing dose tocirculating immune cells and immune structures at risk preserves not only the quantity but more importantlythe quality of lymphocytes which has a direct positive impact on cancer immunity and disease outcomes; (3)through the utilization of intensity-modulated proton and photon RT (IMPT and IMRT) employing individualizeddosimetric constraints derived from the models we will be able to select the optimum treatment modality(protons or photons) and develop patient-specific strategies to substantially mitigate RIL and its consequences.To test these hypotheses we propose three specific aims. In Aim 1 we will utilize our large databases ofmainly esophagus liver and brain cancer patients to improve our understanding of lymphocyte depletion as afunction of dosimetric and patient-specific baseline clinical factors and develop models to accurately predictindividualized severe RIL risk. In Aim 2 we will evaluate the clinical impact of the radiation treatment modalityon T-cell diversity immune repertoire and functional immune status. We will test the hypothesis that thequality of lymphocytes as measured by immune phenotyping T-cell diversity and functional immunity after RTis a major driver of clinical outcomes rather than just the absolute lymphocyte count. In Aim 3 we will assessthe validity of our models using independent retrospective and prospective data. We will also apply the modelsto select the optimum treatment modality and technique for a given patient and define the personalizeddosimetric constraints to be used to optimize proton and photon radiation dose distribution patterns to minimizeRIL severity and risk. Upon the completion of this project we will have a better understanding of how thebaseline clinical characteristics and proton and photon dosimetric factors impact RIL risk and severity T-celldiversity and functional immunity. Moreover we will have developed advanced proton and photon dosimetricstrategies to reduce RIL risk. Our research has the potential to better select the optimum modality for eachpatient to optimize IMPT and IMRT treatments to maximally mitigate lymphopenia to improve RT outcomesand to optimally integrate RT with immunotherapy strategies in the future. +No NIH Category available Achievement;Advanced Development;Affect;Articulation;Biological;Biological Factors;Biological Markers;Biometry;Cancer Center;Characteristics;Clinical;Clinical effectiveness;Collaborations;Complication;Data;Development;Disparate;Dose;Effectiveness;Equilibrium;Esophagus;General Hospitals;Genomics;Genotype;Glioma;Goals;Heterogeneity;Human;Immune system;Immunologic Factors;Immunologics;Immunosuppression;Intensity modulated proton therapy;Joints;Knowledge;Liver;Lymphopenia;Malignant Neoplasms;Massachusetts;Methods;Modality;Modeling;National Clinical Trials Network;Normal tissue morphology;Oncology;Outcome;Patient Selection;Patient-Focused Outcomes;Patients;Pattern;Photons;Population;Prediction of Response to Therapy;Program Research Project Grants;Property;Proton Radiation;Protons;Radiation;Radiation Dose Unit;Radiation Oncology;Radiation therapy;Randomized;Relative Biological Effectiveness;Research;Resources;Risk;Risk Factors;Role;Side;Statistical Models;Techniques;Technology;Therapeutic;Therapy trial;Toxic effect;Uncertainty;adverse outcome;cancer radiation therapy;cancer therapy;clinical application;cost;data management;design;dosimetry;follow-up;genomic biomarker;imaging biomarker;immunoregulation;improved;individual patient;personalized approach;population based;potential biomarker;precision medicine;predictive modeling;programs;proton beam;proton therapy;radiation mitigation;randomized trial;response;therapy design;treatment optimization;tumor Integrating patient-specific clinical and biological factors towards individualizing utilization of proton and photon radiation therapy. OVERALL PROJECT NARRATIVEAdvanced technologies in radiation therapy and the higher cost of proton therapy have engendered the need toaccurately compare photon and proton radiation treatment modalities based on their clinical effectiveness tofacilitate the improved selection of the optimum modality for cancer radiotherapy. As a follow up to our previousMD Anderson and Massachusetts General Hospital collaborative program projects which explored the clinicalapplicability of proton therapy in the proposed joint program project we will investigate the unique physicalbiological and immunomodulatory properties of proton therapy vs. photon therapy and apply the knowledge thusgained to develop precision medicine techniques to identify the patients most likely to benefit from protons andoptimize proton and photon therapy to maximize their effectiveness. This approach is a marked paradigm shiftfrom the conventional assumption that improved dosimetry alone or population-based (as opposed to precisionmedicine) techniques will lead to better outcomes with protons in unselected patients and reframes thediscussion for how patients should be assigned to a particular modality and their treatments optimized. NCI 10691396 9/15/23 0:00 PAR-20-077 5P01CA261669-03 5 P01 CA 261669 3 "OBCEMEA, CEFERINO H" 9/21/21 0:00 8/31/26 0:00 ZCA1-RPRB-L(M1)P 8636914 "HONG, THEODORE S" "MOHAN, RADHE " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 2722827 NCI 2517105 205722 OVERALL - SUMMARYThis is a joint application for a program project grant by Massachusetts General Hospital and MD AndersonCancer Center. The progress we made in our most recent program projects (a P01 and a U19) has been criti-cal to the clinical physical and biological aspects of proton therapy and its significance as an important cancertreatment modality. The main achievements of the recently completed U19 (end date 8/31/20) were (1) the de-velopment and activation of definitive esophagus liver and glioma randomized proton vs. photon therapy trialsin cooperation with NRG NCI and NCTN; (2) understanding and modeling the differences in response of nor-mal tissues to highly disparate proton and photon dose distribution patterns; (3) understanding the complexitiesof the biological effects of protons relative to photons; and (4) the development of advanced intensity modu-lated proton therapy incorporating physical uncertainties and the variable biological effectiveness of protons.Our research also revealed major gaps in the knowledge of the biological effects of protons significant limita-tions of the current population-based models of normal tissue and tumor response to protons vs. photons anduncertainty in the appropriateness of proton therapy in the face of heterogeneities in patient characteristics andtreatment techniques in unselected groups of patients. On the bright side our research also discovered thestrong potential of proton therapy to reduce suppression of the immune system which is commonly associatedwith photon therapy and has been shown to lead to adverse outcomes. The overall goals of the proposedP01 are (a) understanding relative clinical biological and immunosuppressive effects of proton therapy vs.photon therapy; (b) enhancing outcomes based on the physical biological and immunological properties ofprotons and photons; and (c) applying individualized (as opposed to population-based) approaches for the se-lection of the optimum radiation modality for each patient and to enhance the potential for outcomes with theuse of radiation dose distributions tailored to the individual patients baseline and tumor characteristics. Theachievement of these goals will be carried out in three projects. Project 1: Understanding Normal Tissue Tox-icity to Identify Patients Most Likely to Benefit from Proton vs. Photon Therapy; Project 2: Radiation-InducedLymphopenia (RIL): Understanding Predictive Modeling and Developing Photon and Proton-Based MitigationStrategies; and Project 3: Investigating Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanismsand Biomarkers. The projects are highly integrated in that decisions regarding treatment modality selectiontreatment technique and optimization to maximally enhance the therapeutic ratio cannot be accomplished byany one project alone. Such decisions must consider and balance normal tissue complications tumor re-sponse based on genotypic factors and radiation-induced immunosuppression. The three projects will be sup-ported by an Administrative Core and three resource cores: Core 1: Data Management and ComputationalSupport; Core 2: Translational Biospecimens and Imaging Biomarkers; and Core 3: Biostatistics. 2722827 +No NIH Category available Address;Algorithms;CLIA certified;Cells;Clinical;Code;Competence;Complex;Computational Biology;DNA Mutational Analysis;DNA Sequence Alteration;Data;Development;Doctor of Philosophy;Drug resistance;Evolution;Genome;Genome Data Analysis Network;Genomics;Graph;Joints;Link;Malignant Neoplasms;Medical Oncologist;Medicine;Methods;Mutation;Neoplasm Metastasis;New York;Organoids;Outcome;Pattern;Pharmaceutical Preparations;Phase;Play;Preparation;Primary Neoplasm;Process;Publications;Publishing;Recurrence;Research Personnel;Sampling;Specific qualifier value;Testing;Untranslated RNA;Variant;Visualization software;analysis pipeline;analytical tool;cancer genomics;cell type;clinical phenotype;clinically relevant;computer infrastructure;computerized tools;data management;data portal;drug relapse;exome sequencing;experience;genome sequencing;genome-wide;innovation;novel;precision medicine;response;single cell sequencing;tool;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor heterogeneity;whole genome The joint WCM-NYGC Center for Functional and Clinical Interpretation of Tumor Profiles NARRATIVEThe joint Weill Cornell Medicine-New York Genome Center (WCM-NYGC) Center for Functional andClinical Interpretation of Tumor Profiles will perform integrative analyses of coding and non-codingvariants to detect and unravel the function of specific classes of mutations and assess their clinicalpotential. NCI 10691395 8/31/23 0:00 RFA-CA-20-053 5U24CA264032-03 5 U24 CA 264032 3 "YANG, LIMING" 9/16/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 9758594 "ELEMENTO, OLIVIER " "ROBINE, NICOLAS ; STERNBERG, CORA " 12 PHYSIOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 397689 NCI 290287 107402 The Weill Cornell Medicine-New York Genome Center (WCM-NYGC) Center for Functional and ClinicalInterpretation of Tumor Profiles is submitted in response to RFA-CA-20-053. Continuing ourinvolvement in the Genome Data Analysis Network (GDAN) over the past five years and leveragingnovel algorithms and methods developed by our group the Center will perform integrative analyses ofcoding and non-coding variants to unravel the function of specific classes of mutations and assess theirclinical potential. As specified in the RFA we have chosen to focus on two Core Competencies: (1)DNA Mutations (in coding and non-coding regions somatic and/or germline) and (2) CopyNumber/PurityAnalysiswith a focus on complex structural variants.Our team has developed novel algorithmsand pipelines for the analysis of DNA mutations in coding and non-coding regions characterization ofcomplex structural variants tumor evolution and linked-read sequencing. We have developed threeSpecific Aims. In Aim 1 we will perform systematic clinical and functional annotation of coding and non-coding mutations. This includes (1) clinical annotation of coding variants (2) prioritization and functionalannotation of non-coding variants (3) integration of transcriptomic analyses such as cell typedeconvolution of impure tumor samples to provide stromal context to somatic variants (4) correlation ofvariants with clinical phenotypes including response to therapy. In Aim 2 we will analyze clinicallyrelevant signatures of genome-wide somatic alteration patterns. We will utilize our state-of-the-artanalytic tools for complex structural variant characterization and mutational topography to link (1)mutational processes and (2) cell-of-origin footprints to cancer outcome and drug response. We willalso (3) adapt our cutting-edge genome graph visualization tools to build interactive data portals forbrowsing complex structural variation patterns in impure samples. In Aim 3 we will dentify andcharacterize variants that drive tumor evolution using multi-samples analysis. We will apply our state-of-the-art computational tools to study structural variant evolution across multiple tumor samples to (1)identify drivers of drug resistance and relapse in matched primary and recurrence/metastasis samplesand (2) assess genomic divergence between primary tumors and matched tumor organoids. 397689 +No NIH Category available Adopted;Adult;African American;African American population;Algorithms;American;Area;Asbestos;Attention;Attitude;Benzene;Carcinogens;Cessation of life;Communities;Control Groups;Creativeness;Databases;Development;Diagnosis;Diffusion of Innovation;E-learning;Education;Educational Curriculum;Effectiveness;Employee;Evaluation;Exposure to;Focus Groups;Funding;Goals;Health;Health Care Costs;Hispanic Americans;Human Resources;Industry;International;Intervention;Learning;Literature;Malignant Neoplasms;Marketing;Mediating;Names;National Cancer Institute;National Institute of Environmental Health Sciences;Occupational;Occupations;Phase;Policies;Prevention Research;Principal Investigator;Process;Production;Protocols documentation;Publishing;Quality of life;Randomized Controlled Trials;Readiness;Recreation;Reporting;Research;Research Personnel;Resources;Risk;Safety;Schools;Skin Cancer;Small Business Innovation Research Grant;Specific qualifier value;Staging;Students;Surgeon;System;Testing;Training;Treatment Cost;Ultraviolet Rays;United States;Update;Vendor;Vinyl Chloride;Work;Workplace;commercialization;educational atmosphere;effectiveness testing;evidence base;high risk;implementation strategy;improved;innovation;keratinocyte;melanoma;primary outcome;programs;prototype;randomized trial;safety education;safety practice;school district;skin cancer prevention;solar ultraviolet radiation;sun protection;sun safety;technology platform;the sun;theories;trial enrollment;usability;vector SSW Works: A Virtual Learning Environment for Occupational Skin Cancer Prevention Americans who work outdoors are exposed to an extreme amount of solar ultraviolet radiation over a lifetimethat substantially increases their risk for developing skin cancer. In Phase I the feasibility of a virtual learningenvironment (VLE) for distributing our effective Sun Safe Workplaces (SSW) intervention to Americanemployers will be established with input from senior managers and Hispanic and African American outdoorworkers and development and evaluation of a prototype of the SSW Works VLE. In Phase II the full SSWWorks will be produced and tested for effectiveness at improving outdoor workers' sun protection in arandomized trial enrolling employers nationwide. NCI 10691387 8/31/23 0:00 PA-20-262 5R44CA257778-03 5 R44 CA 257778 3 "WEBER, PATRICIA A" 8/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-RPHB-Z(10)B] 7678026 "BULLER, MARY K" Not Applicable 7 Unavailable 117936042 NWQ2AMLQTLN6 117936042 NWQ2AMLQTLN6 US 39.74171 -105.155318 4368501 "KLEIN BUENDEL, INC." GOLDEN CO Domestic For-Profits 804013313 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 SBIR/STTR 2023 750792 NCI 425947 275728 Americans who work outdoors are exposed to an extreme amount of solar ultraviolet radiation (UV) over alifetime that substantially increases their risk for developing skin cancer. Annually skin cancer is diagnosed inover 3.5 million U.S. adults melanoma kills nearly 7000 Americans and treatment costs at least $8 billion.The U.S. Surgeon General has identified occupational sun safety as a national priority. Our team has spent thepast two decades developing a successful comprehensive approach to occupational sun protection in 5 trialsfunded largely by the National Cancer Institute. Sun Safe Workplaces (SSW) combines policy and education toincrease workplace actions on sun safety and employee sun protection practices. In this SBIR Fast-Trackapplication we will develop a virtual learning environment (VLE) SSW Works to distribute the SSW programto American workplaces. It will be comprised of a database content management (interactive toolbox) andmedia platform (trackable training) that tailors the SSW program to management's readiness to innovate onsun safety based Diffusion of Innovations Theory. SSW Works will better integrate SSW into safety training byimproving appropriateness for Hispanic and African American workers and conforming with the latest learningmanagement systems technology (LMS). Strong scientific premise comes from the published literature and our5 previous studies that demonstrated SSW is feasible and effective in public works public safety and outdoorrecreation workplaces. The Phase I specific aims will establish the feasibility of SSW Works by 1) creating andvalidating an algorithm to tailor resources and implementation strategies to employers' stages in the diffusionof innovations process; 2) identifying unique attitudes barriers and practices related to sun safety amongHispanic and African American employees in focus group discussion and adjusting the SSW content; and 3)creating a prototype of the SSW Works VLE including inputs staging algorithm and tailored report employeetraining compatible with a popular LMS and storyboards of brief videos for managers and employees andtesting it for feasibility and usability with managers and Hispanic and African American outdoor workers andconfirming that the training can operate within a popular LMS. In Phase II SSW Works will be fullyprogrammed and tested for effectiveness by achieving the specific aims of: 1) producing the full SSW Works inEnglish and Spanish for distribution of the evidence-based SSW and 2) conducting a randomized controlledtrial with 20 workplaces evaluating impact of SSW distributed over the SSW Works on employees' sun safetypractices (primary outcome). The primary hypothesis is: compared to employers in the minimal informationcontrol group employers assigned to receive SSW Works will have employees that practice more sunprotection at posttest. The SBIR Fast-Track research is significant and innovative. SSW Works will have highimpact and commercial potential because outdoor workforce is large and at very high risk for skin cancerimproving sun safety will reduce health care costs and save lives and there are few commercial competitors. 750792 +No NIH Category available Address;Administrative Efficiency;Adolescent;Adolescent and Young Adult;Adult;Advisory Committees;Advocate;Basic Science;Benefits and Risks;Biometry;Cancer Burden;Cancer Center;Cancer Control;Cancer Control Research Program;Cancer Research Network;Cancer Survivor;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Collection;Communication;Communities;Community Clinical Oncology Program;Comparative Study;Complement;Complex;Data;Data Reporting;Development;Dissemination and Implementation;Education;Electronic Health Record;Enrollment;Ensure;Environment;Equity;Evidence based practice;Faculty;Fostering;Foundations;Funding;Future;Goals;Grant;Guidelines;Information Dissemination;Institution;International;Intervention;Intervention Studies;Journals;Lead;Leadership;Malignant Neoplasms;Manuscripts;Medical;Mentors;Metadata;Minority;Mission;Modernization;National Cancer Institute;Natural Language Processing;Observational Study;Oncologist;Pathway interactions;Patient Outcomes Assessments;Patients;Policies;Population;Population Sciences;Prevention;Productivity;Publishing;Quality of life;Reporting;Reproducibility;Research;Research Personnel;Resources;Retrieval;Safety;Secure;Site;Southwest Oncology Group;Speed;Standardization;Statistical Data Interpretation;Structure;System;Teacher Professional Development;Training;Translational trial;Voice;Work;academic program;base;cancer care;cancer prevention;cancer risk;care delivery;community based participatory research;community engagement;data infrastructure;data management;design;disparity reduction;expectation;experience;global health;health care disparity;image translation;imaging biomarker;improved;innovation;meetings;member;multidisciplinary;novel;operation;organizational structure;programs;social media;software systems;student training;survivorship;symptom management;telehealth;tool;translational medicine;treatment risk;trial design;uptake;virtual;young adult SWOG NCORP Research Base PROJECT NARRATIVEThe overall mission of the SWOG National Cancer Institute Community Oncology Research ProgramResearch Base is to rapidly design activate and complete biologically-driven scientifically important andclinically meaningful studies in cancer prevention control and cancer care delivery in adults adolescents andyoung adults with or at risk for cancer and to improve quality of life and quality of survivorship for those withmalignancies. NCI 10691349 8/1/23 0:00 RFA-CA-18-015 5UG1CA189974-10 5 UG1 CA 189974 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-GRB-S(M1) 6765159 "BLANKE, CHARLES D." "HERSHMAN, DAWN ; TANGEN, CATHERINE M." 1 INTERNAL MEDICINE/MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 7117835 NCI 6797956 327814 PROJECT SUMMARY/ABSTRACTThe SWOG National Cancer Institute (NCI) Community Oncology Research Program (NCORP) Research Base(RB) has established itself as an innovative collaborative and integral part of the NCI's publicly fundedcooperative group enterprise. The overall mission of the SWOG NCORP RB is to rapidly design activate andcomplete biologically-driven scientifically important and clinically meaningful studies in cancer preventioncontrol and cancer care delivery in adults adolescents and young adults with or at risk for cancer and toimprove quality of life and quality of survivorship for those with malignancies. Over the last grant cycle the SWOGNCORP RB exceeded expectations with regard to scientific productivity rapid dissemination of resultsinclusiveness faculty and student training administrative efficiency novel and complex trial designs andadvancement of and incorporation of the patient voice into all aspects of our work. In particular the SWOGNCORP RB opens high-impact trials and conducts and completes them efficiently. During the reporting periodwe accrued a total of 11470 patients of which 9897 (86%) were placed onto SWOG-coordinated studies and1573 (14%) were SWOG sites enrolling onto non-SWOG studies. SWOG NCORP institutions provided 45% ofthe accrual (n=4451) to SWOG-coordinated studies. Our results are widely disseminated and have informedmultiple practice symptom management and survivorship guidelines. We published results from a large numberof studies conducted during the last two cycles (125 manuscripts; 58 abstracts) with 34% issued in journals withan impact factor > 10. Overall 96 NCORP site members were represented as authors in 54 NCORP manuscriptsand abstracts. Over the next grant cycle we will continue to expand our administrative and data infrastructurewith initiatives addressing patient reported outcomes a robust and modern data management and patientreported outcomes core enhanced engagement with community investigators and non-traditional partnersaugmented education and involvement of patient advocates and new quality initiatives. We will expand ourresearch efforts in healthcare disparities across all committees and we will collaboratively design conduct andaccrue to novel and practice changing studies in order to reduce the burden of cancer 7117835 +No NIH Category available Algorithms;Benign;Biological Markers;Boston;Bronchoscopy;Categories;Cells;Characteristics;Chest imaging;Clinical;Clinical Management;Collaborations;Coupled;Cytometry;Data;Detection;Diagnosis;Diagnostic Procedure;Diameter;Early Detection Research Network;Eligibility Determination;Gene Expression;Goals;Guidelines;Image;Image Analysis;Individual;Industrialization;Inferior nasal concha;Laboratories;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Modeling;Molecular;Neoplasm Circulating Cells;Nodule;Non-Invasive Detection;Nose;Observational Study;Patients;Performance;Peripheral Blood Mononuclear Cell;Persons;Population;Prevalence;Procedures;Recommendation;Risk;Sampling;Solid;Standardization;Testing;Time;Uncertainty;United States Preventative Services Task Force;Universities;Work;X-Ray Computed Tomography;biomarker development;biomarker discovery;biomarker performance;cancer biomarkers;chest computed tomography;clinically actionable;cohort;commercialization;computed tomography screening;deep learning;design;efficacy evaluation;follow-up;high risk;histological specimens;imaging biomarker;improved;laboratory development;learning network;low dose computed tomography;lung cancer screening;multimodality;patient stratification;risk stratification Biomarker Development Lab n/a NCI 10691336 7/14/23 0:00 RFA-CA-21-035 5U2CCA271898-02 5 U2C CA 271898 2 9/1/22 0:00 7/31/27 0:00 ZCA1-PCRB-D 5085 1914919 "DUBINETT, STEVEN M." Not Applicable 7 Unavailable 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA Domestic Higher Education 21182340 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 456366 456366 0 BIOMARKER DISCOVERY LAB ABSTRACTIncreases in the use of computed tomography (CT) for lung cancer (LC) screening and other indications hasdramatically multiplied the detection of indeterminate pulmonary nodules (IPNs) resulting in a clinicalmanagement challenge. The estimated annual US prevalence of incidentally detected pulmonary nodules was1.57 million persons. The number of nodules will continue to increase given the widespread use of CT and thenew recommendations that expand the screen-eligible population for annual low-dose CT screening. In patientspresenting with screen or incidentally detected IPNs the goal is to rapidly identify and treat malignant noduleswhile avoiding unnecessary follow-up or invasive procedures. However discriminating between benign andmalignant nodules is challenging especially among intermediate-risk IPNs where the clinical management is themost variable and false positivity rates are high. There is an urgent and unmet need to develop biomarkers tobetter risk-stratify intermediate risk IPNs to improve and standardize clinical management. The focus of thisBiomarker Discovery Lab (BDL) is to develop refine and validate non-invasive nasal gene expressioncirculating tumor cell (CTC) and CT image-based biomarkers in both screen and incidentally detected IPNs ofintermediate-risk. The goal of the BDL biomarkers is to transition a subset of intermediate-risk IPNs to 1) low-risk where they can be followed with CT surveillance or 2) high-risk where histologic sampling is commonlyperformed. We hypothesize that integrated biomarkers combining clinical molecular and imaging data as wellas longitudinal measurement of biomarkers (during follow-up surveillance) will maximize the stratification ofpatients with intermediate-risk IPNs into these clinically actionable groups. To achieve our goals we havepartnered via the Biomarker Reference Lab with two industrial partners and an academic advanced imageanalysis laboratory. Each of the industrial partners have CLIA-LDT tests for early detection of lung cancer thatwill be further validated in the setting of intermediate-risk IPN and tested as longitudinal biomarkers in large andunique cohorts of screen and incidentally detected IPNs. The BDL collaboration is designed to meet the goal ofsignificantly changing the risk stratification and clinical management of IPNs. +No NIH Category available Affect;Aftercare;Bar Codes;Behavior;Biodiversity;Biological;Biological Assay;Biological Models;Cell Communication;Cell model;Cells;Chemoresistance;Chemotaxis;Clinical;Clinical Trials Design;Coupled;Cues;Cytoplasm;DNA Sequence Alteration;Data;Disease;Ecosystem;Elasticity;Environment;Epigenetic Process;Equilibrium;Equipment and supply inventories;Exhibits;Exposure to;Extinction;Fluorescence;Gene Expression;Genetic;Genetic Transcription;Genome;Growth;Heterogeneity;Human;Individual;Invaded;Investigation;Kinetics;Malignant Epithelial Cell;Malignant Neoplasms;Markov Chains;Measurement;Measures;Membrane;Mesenchymal;Methods;Modeling;Mus;Neuroendocrine Cell;Neuroendocrine Tumors;Outcome;Patients;Pattern;Pharmacotherapy;Phenotype;Population;Population Dynamics;Primary Neoplasm;Registries;Relapse;Reporter;Research Personnel;Resistance;Resources;Role;Sampling;Statistical Models;System;Therapeutic;Time;Transcription Factor 3;Withholding Treatment;cancer cell;cancer heterogeneity;cancer survival;cell behavior;cell type;chemotherapy;clinically relevant;combat;discrete time;epigenetic drug;epigenome;experimental study;functional genomics;in vivo;innovation;insight;mathematical model;neural;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;prevent;programs;rapid growth;response;single-cell RNA sequencing;small cell lung carcinoma;standard of care;study population;therapy design;therapy resistant;transcription factor;translational model;treatment response;tumor;tumor heterogeneity;tumor initiation Cellular plasticity gives rise to phenotypic equilibrium in small cell lung carcinoma PROJECT NARRATIVEThe survival of cancer cells after chemotherapy is a major barrier to clinical cures. Small cell lung carcinomas(SCLC) exhibit a general pattern of initial sensitivity to chemotherapy with almost invariable progression aftertreatment cessation. Herein we show that SCLC tumors are highly adaptable to chemotherapy in large partbecause they undergo rapid cell state transitions. We posit that determining the form and function of SCLC'smulti-faceted and mutable states will advance new therapeutic strategies in this recalcitrant disease. NCI 10691334 7/13/23 0:00 PAR-19-361 5U01CA268052-02 5 U01 CA 268052 2 "JOHNSON, RONALD L" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U(M2) 11084348 "ABAZEED, MOHAMED E." Not Applicable 5 RADIATION-DIAGNOSTIC/ONCOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 455656 NCI 300963 154693 ABSTRACTSmall cell lung carcinoma (SCLC) is one of the most intractable human cancers to cure. It is an aggressive tumorcharacterized by rapid growth metastatic progression and initial response followed by almost invariableresistance to therapy. Studies to date have not resolved the extent that diverse genetic and epigenetic programsdrive SCLC and contribute to its lethality. We combined one of the largest and most diverse inventories ofpatient-derived xenograft models of SCLC globally with an ex vivo culture system that maintainstranscriptional fidelity with matched primary SCLC tumor to identify distinct and dynamic phenotypic states thatdiffer in functional attributes within individual tumors. We show that human SCLC tumors display distinctiveequilibria in the proportion of cells in various phenotypic (not merely transcriptional) states. We also show thatSCLC states are highly regulated by multivalent cellular plasticity and we measure the kinetics of this plasticityat the single cell level. Importantly standard of care chemotherapies in this disease preferentially kill specificcancer cell states. In this proposal we posit that understanding the facets of SCLC's intratumoral heterogeneitywill: 1) contribute to our understanding of a poorly characterized aspect of cancer heterogeneity; 2) reveal howstochasticity and/or ecological cues in single-cell behaviors promote phenotypic equilibrium in cancerpopulations; 3) provide insight into the biological and clinical behavior of SCLC; and 4) advance desperatelyneeded new therapeutic strategies of epigenetic reprogramming in this recalcitrant disease. Our team ofinvestigators have content expertise in several computational experimental and translational methods pertinentto this proposal including human-derived in vivo and ex vivo model systems single-cell RNA sequencing bulkgenetic and expression analysis single cell fluorescence tracking and mathematical and statistical modeling.Our integrative approach is poised to formulate and validate a unified model of cellular states and programdiversity in SCLC. If successful the characterization of malignant cell ontogenic programs (SA1) their plasticity(SA2) and the advancement of new therapies designed to combat plasticity by epigenetic reprogramming (SA3)will advance a unique scientific canvas for the study of this highly lethal disease. 455656 +No NIH Category available Academic Medical Centers;Address;Administrator;Agreement;Biological Markers;Boston;Clinical;Clinical Data;Clinical Research;Collaborations;Communication;Communities;Data;Data Collection;Decision Making;Development;Diagnosis;Early Detection Research Network;Enrollment;Ensure;Evaluation;Fostering;Funding;Goals;Institution;Laboratories;Leadership;Malignant neoplasm of lung;Modification;Molecular;Monitor;Policies;Principal Investigator;Privatization;Procedures;Process;Progress Reports;Protocols documentation;Publications;Qualifying;Research;Research Personnel;Resources;Site Visit;Standardization;Universities;Validation;Work;adjudication;biomarker development;biomarker discovery;biomarker evaluation;cancer biomarkers;clinic ready;clinical center;data warehouse;innovation;insight;investigator training;laboratory development;lung cancer screening;member;mortality;multidisciplinary;novel strategies;operation;programs;recruit;success;synergism;translational pipeline Admin Core n/a NCI 10691332 7/14/23 0:00 RFA-CA-21-035 5U2CCA271898-02 5 U2C CA 271898 2 9/1/22 0:00 7/31/27 0:00 ZCA1-PCRB-D 6879 9462381 "LENBURG, MARC ELLIOTT" Not Applicable 7 Unavailable 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA Domestic Higher Education 21182340 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 356632 216141 140491 ADMINISTRATIVE CORE ABSTRACTThe discovery-to-translation pipeline of the BU-UCLA Lung Cancer Biomarker Characterization Center isenabled by a multi-disciplinary team of investigators with diverse expertise. This Center is comprised of aBiomarker Development Laboratory and a Biomarker Reference Laboratory that each have three teams workingon different approaches to the early detection of lung cancer utilizing biospecimens and clinical data beingcollected in several large clinical studies. These teams are distributed across multiple institutions includinguniversities academic medical centers and two private companies. The operational complexity of the BU-UCLALung Cancer BCC will be effectively managed by the BCCs Administrative Core. The Administrative Core willstrengthen linkages within the Biomarker Discovery Lab and Biomarker Reference Lab components and helpthose investigators deliver on their respective milestones. It will further create strong linkages between theBiomarker Discovery Lab the Biomarker Reference Lab and the clinical studies via an Administrative Core-facilitated BU-UCLA BCC Steering Committee whose members will be the BCC Principal Investigators and co-Investigators. Sub committees of the Steering Committee will have responsibility for important center-wideactivities such as biomarker qualification review of clinical enrollment and clinical data adjudication ofdiagnoses selection of cases and controls biospecimen QC early-stage investigator training and thedissemination of the Centers work. The Administrative Core will also facilitate a BU-UCLA BCC ExecutiveCommittee made up of the MPI team that will provide oversight of the entire program and have final responsibilityfor Center decision-making as well as development and implementation of all policies procedures andprocesses. The Administrative Cores Internal and External Advisory Boards will provide regular externalevaluation of the BCCs progress while also helping maintain the Centers focus on addressing the mostimportant clinical problems using the most innovative approaches. Finally the Administrative Core will serve asthe interface between the BCC EDRN leadership and the NCI to ensure that the BCC conforms with the agreedpractices and principles of the EDRN ensure bidirectional exchange of findings and insights with other EDRNCenters coordinate with other EDRN Centers to support validation of EDRN-developed biomarkers andparticipate in collaborative projects. +No NIH Category available Adoption;Artificial Intelligence;Benign;Bioinformatics;Biological Assay;Biological Markers;Biological Sciences;Biometry;Blood;Boston;Bronchoscopy;Cancer Detection;Cancer Etiology;Cancer Research Project;Cancerous;Cells;Cessation of life;Classification;Clinical;Clinical Research;Collection;Complex;Consensus;Data;Detection;Diagnostic;Diagnostic Procedure;Diagnostic tests;Diameter;Disease;Early Detection Research Network;Ensure;Evolution;Excision;Funding;Gene Expression;Gene Expression Profile;Genomics;Goals;Image;Immunologic Markers;Incidental Findings;Individual;Inferior nasal concha;Infrastructure;Laboratories;Localized Disease;Lung;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Measures;Medical center;Medicare;Minority;Modality;Modeling;Names;Nasal Epithelium;Neoplasm Circulating Cells;Nested Case-Control Study;Nodule;Nose;Office Visits;Operative Surgical Procedures;Pathology;Patients;Performance;Peripheral Blood Mononuclear Cell;Population;Population Heterogeneity;Predictive Value;Protocols documentation;Pulmonology;Reproducibility;Research Design;Risk;Sampling;Solid;Speed;Standardization;Swab;Testing;Time;Tissue Sample;Training;Uncertainty;Universities;Work;X-Ray Computed Tomography;biomarker discovery;cancer biomarkers;cancer risk;chest computed tomography;clinical application;clinical assay development;clinical care;clinical epidemiology;commercial launch;computed tomography screening;cost;deep learning;follow-up;high risk population;imaging biomarker;improved;innovation;low dose computed tomography;lung cancer screening;minimally invasive;molecular diagnostics;molecular marker;mortality;multidisciplinary;nasal swab;novel;oncology program;patient population;performance tests;precision oncology;prevent;programs;prospective;radiomics;screening;screening program The Boston University - UCLA Lung Cancer Biomarker Characterization Center PROJECT NARRATIVELung cancer screening by chest CT can detect lung cancer earlier and make the disease less deadly; but evenamong nodules that are intermediate risk a small minority are cancerous. We will develop and validateinnovative biomarkers from nasal swabs blood and advanced imaging analysis for determining whichintermediate risk lung nodules detected via screening or detected incidentally as part of routine clinical care areactually lung cancers to speed treatment while minimizing invasive tests and clinical uncertainty related to benignnodules. We will partner with two molecular diagnostics companies to refine and standardize these biomarkersso that useful biomarkers can quickly be put to use. NCI 10691331 7/14/23 0:00 RFA-CA-21-035 5U2CCA271898-02 5 U2C CA 271898 2 "MARQUEZ, GUILLERMO" 9/1/22 0:00 7/31/27 0:00 ZCA1-PCRB-D(M1) 9462381 "LENBURG, MARC ELLIOTT" "BEANE, JENNIFER ELLEN; DUBINETT, STEVEN M.; HSU, WILLIAM " 7 INTERNAL MEDICINE/MEDICINE 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Other Research-Related 2023 942572 NCI 796265 146307 ABSTRACTScreen and incidentally detected intermediate risk indeterminant pulmonary nodules (IPN) represent a clinicaldilemma for which there is little consensus about appropriate follow up due to a lack of sensitive and specificapproaches for the detection of lung cancer absent invasive tissue sampling and concerns about costs andharms from invasive tissue sampling in this large clinical population. Minimally invasive approaches that couldaccurately reclassify individuals from the intermediate risk group (5-65% risk of malignancy) to either low (< 5%)or high (>65%) risk would reduce uncertainty and transform the diagnostic workup of intermediate risk IPN.Developing evaluating standardizing and validating such minimally invasive biomarkers so that they are readyfor clinical use is the goal of the proposed BU-UCLA Lung Cancer Biomarker Characterization Center (BCC). Inprevious EDRN-funded work we established lung-cancer associated gene expression patterns in nasalepithelium collected with a swab from the inferior turbinate as a lung cancer biomarker. A test based on thisinnovative approach to lung cancer detection is being launched for clinical use as a CLIA LDT by our long-timecollaborator Veracyte Inc. which is participating in this BCC. We will evaluate the nasal biomarker for lungcancer in the setting of intermediate risk IPN. To further improve the ability to clinically discriminate benign frommalignant intermediate risk IPN the BU-UCLA Lung Cancer Biomarker Discovery Lab embedded within the BCCwill develop and test lung cancer detection approaches that incorporate detection of circulating tumor cells (CTC)using a CLIA LDT assay from our collaborator LungLife AI Inc. as well as blood based immune biomarkersadvanced imaging biomarkers and refined nasal gene expression biomarkers. We will additionally determine iflongitudinal biomarker assessment improves lung cancer detection over cross-sectional measurements.Promising assays will be refined standardized and validated by the BU-UCLA Lung Cancer BiomarkerReference Lab embedded within the BCC to advance them toward clinical adoption. These studies are enabledby biospecimens and imaging data that are being prospectively collected from diverse populations of patientsundergoing workup for intermediate risk IPN in several large-scale ongoing clinical studies including VA LPOPDECAMP 1-Plus and UCLA IDx; lung cancer research programs at UCLA and Lahey; and our EDRNcollaborators at Nashville VA and Vanderbilt. The BU-UCLA Lung Cancer BCC Team has the required multi-disciplinary expertise in lung cancer translational and clinical pulmonary medicine biomarker discovery clinicalassay development biostatistics clinical epidemiology pathology imaging artificial intelligence biologicalsciences bioinformatics genomics and complex scientific program management to accomplish these goals. AnAdministrative Core embedded within the BCC will ensure that the BCC delivers on its aim to substantiallyadvance novel lung cancer biomarkers from discovery to clinical application and make significant contributionsto the Early Detection Research Network. 942572 +No NIH Category available Accounting;Address;Artificial Intelligence;Benign;Bioinformatics;Biological Markers;Biopsy;Blinded;Blood specimen;CA-125 Antigen;Cancer Center;Cancer Detection;Cancer Diagnostics;Cancer Intervention and Surveillance Modeling Network;Characteristics;Classification;Clinical;Clinical Data;Clinical Trials Design;Collaborations;Computer Models;Cost Effectiveness Analysis;Data;Diagnosis;Early Detection Research Network;Eligibility Determination;Epidemiology;France;Frequencies;Funding;Goals;Guidelines;Health Care Costs;Image;Image Analysis;Individual;Institution;International;Longitudinal cohort;Lung;Lung nodule;Malignant - descriptor;Malignant neoplasm of lung;Modeling;Nodule;Performance;Phase;Population;Process;Prospective cohort;Publishing;Pulmonary Emphysema;Pulmonary Surfactant-Associated Protein B;Pulmonology;Research Personnel;Resources;Risk;Risk Assessment;Risk Factors;Sampling;Sensitivity and Specificity;Smoking History;Stage at Diagnosis;Testing;Tumor stage;United States Preventative Services Task Force;Validation;Work;X-Ray Computed Tomography;biomarker discovery;biomarker panel;biomarker validation;blood-based biomarker;cancer biomarkers;cancer risk;cancer statistics;circulating biomarkers;cohort;computed tomography screening;cost effectiveness;deep learning model;demographics;diagnostic accuracy;follow-up;imaging biomarker;improved;low dose computed tomography;lung basal segment;lung cancer screening;meetings;models and simulation;performance tests;personalized screening;phase 3 study;precision oncology;protein biomarkers;radiomics;risk prediction model;screening;screening guidelines;screening program;success;validation studies Clinical Validation Center for Lung Cancer Early Detection A team of investigators with a track record of collaboration and relevant expertise is proposing aClinical Validation Center with two specific aims that are intended to validate blood basedbiomarkers and artificial intelligence based analysis of CT images as means to improve lungcancer screening. CVC investigators bring in substantial accomplishments relevant to the goalsof the CVC as well as substantial resources in the form of several lung cancer screening cohortswith imaging data and blood samples to contribute to the success of the CVC in achieving itsgoals. NCI 10691321 8/30/23 0:00 RFA-CA-21-033 5U01CA271888-02 5 U01 CA 271888 2 "MARQUEZ, GUILLERMO" 9/1/22 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 6588092 "HANASH, SAMIR M" Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1023059 NCI 784884 238175 AbstractThe lung cancer early detection CVC has two main goals: Specific Aim 1 is to develop a blood-based biomarker panel for personalized risk assessment modeled for its cost effectiveness. Tothis effect substantial validation work in phase 3 studies has been done using retrospectivelongitudinal cohorts to test the performance of a four-marker protein panel (4MP) as a means todetermine lung cancer risk and need for CT screening. The goal moving forward is to test the4MP alone and in combinations with other types of markers in the screening setting using lungcancer screening cohorts available to the CVC. The resulting marker panel in combination withsubject characteristics would identify subjects who are currently not eligible based on USPSTFcriteria that would benefit from CT screening based on their risk ultimately leading to a utility trialfor which a concept has been presented at a recent EDRN scientific meeting. The utility trialconcept also includes as an objective to test the value of biomarkers in informing subjects whoare currently eligible but not decided to undergo CT screening about their risk through a decisionsharing process. Specific Aim 2 will test the use of biomarkers and AI for interpretation of CTimages and to personalize the screening frequency and duration. Sub Aim 1 is intended to validatethe macrovasculature surrounding a nodule (vessel number) previously developed as abiomarker in an independent screening cohort. Sub Aim 2 is intended to develop a validatedintegrative computational model for improved early lung cancer detection that includes blood-based biomarkers CT features such as emphysema presence or absence of a nodule smallairways and subject characteristics for interpretation of CT images and to determine screeningfrequency. The model will be subjected to a cost effectiveness analysis compared to current lungcancer screening guidelines.The CVC represents a multi-institution multi-investigator effort with expertise in cancerbiomarkers and statistics; pulmonology and lung cancer; epidemiology; radiomics bioinformaticsand artificial intelligence; and clinical trial design simulation modeling and cost-effectivenessanalysis. The CVC brings in substantial accomplishments in biomarker discovery and validationrelated to lung cancer screening and in CT image analysis. In pursuit of its aims the CVC hasaccess to samples from a multitude of cohorts for validation studies. 1023059 +No NIH Category available Acute;Acute Lymphocytic Leukemia;Address;Adopted;Caring;Characteristics;Child;Child Care;Childhood Acute Lymphocytic Leukemia;Childhood Cancer Treatment;Childhood Leukemia;Clinical;Clinical Trials;Communication;Complex;Consent Forms;Dana-Farber Cancer Institute;Data;Decision Making;Development;Diagnosis;Disease;Early treatment;Emotional;Family;Feedback;Future;Genomics;Goals;Health;Individual;Information Centers;Informed Consent;Institution;Intervention;Interview;Knowledge;Late Effects;Learning;Long-Term Survivors;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Medical;Mentorship;Methodology;Modeling;Multi-Institutional Clinical Trial;Multicenter Trials;Newly Diagnosed;Outcome;Parents;Patients;Pediatric Oncology;Phase III Clinical Trials;Preparation;Printing;Prognosis;Provider;Quality of life;Randomized Controlled Trials;Research;Research Infrastructure;Research Methodology;Research Personnel;Risk;Seasons;Site;Survival Rate;Survivors;System;Testing;Time;Training Activity;Treatment Protocols;Work;Writing;absorption;acceptability and feasibility;acute toxicity;cancer diagnosis;cancer therapy;career;career development;chemotherapeutic agent;chemotherapy;cognitive interview;design;expectation;experience;health communication;health literacy;implementation science;improved;individualized medicine;innovation;leukemia treatment;mathematical ability;multidisciplinary;multimodality;novel;novel strategies;optimal treatments;personalized medicine;pilot test;pilot trial;prevent;prototype;randomized trial;response;risk stratification;side effect;skills;standard of care;survivorship;therapy development;transmission process;treatment effect;treatment strategy;tumor;web site Expectations for Pediatric Cancer Treatment (EXPECT): A Family-Centered Intervention to Prepare Parents for Pediatric Leukemia Therapy PROJECT NARRATIVEThough parents of children newly diagnosed with cancer desire detailed information about their children'santicipated short- and long-term outcomes many parent do not have a complete or accurate understanding ofwhat to expect from their child's treatment. These knowledge and information gaps prevent parents fromoptimally preparing for their children's futures and may hinder their engagement in care and decision-making.In the proposed study we will use stakeholder input to develop refine and then pilot-test a novel family-centered communication intervention with the ultimate goal of better informing parents of what to expectduring and after their child's cancer treatment. NCI 10691319 8/22/23 0:00 PA-19-117 5K08CA245036-05 5 K08 CA 245036 5 "RADAEV, SERGEY" 9/19/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 11888047 "GREENZANG, KATIE A." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 152566 NCI 141265 11301 PROJECT SUMMARY/ABSTRACTThough more than 80% of children with cancer will go on to be long-term survivors most experience bothacute toxicities and late effects of therapy. Despite providers' attempts to convey information about what toexpect from treatment in the short- and long-term numerous gaps in parental understanding remain. Mostparents do not have an accurate understanding of their child's prognosis or risk of late effects of treatment andas a result many feel poorly prepared for treatment experiences and survivorship. To address these gaps theproposed project will develop and pilot test Expectations for Pediatric Cancer Treatment (EXPECT) the firstfamily-centered intervention to improve communication and information about pediatric cancer therapy atdiagnosis. EXPECT will have two components written materials summarizing key information about treatmentand side effects for use during the informed consent conversation with providers and a website for parentswhich will contain more detailed information including videos of actual parents and children describing theirtreatment experiences. Using stakeholder interviews and iterative feedback we will develop and refineEXPECT for use in initial informed consent conversations in pediatric acute lymphoblastic leukemia (ALL) themost common malignancy of childhood. We will then test the intervention in 30 treatment conversations in ALLassessing feasibility and acceptability and evaluating preliminary outcomes relative to 30 parents who did notreceive the intervention. This proposal has the following 3 interrelated and complimentary aims: 1) Todetermine information needs and optimal strategies for sharing early treatment information through qualitativestakeholder interviews of parents survivors and providers. 2) To design and refine a prototype EXPECT usingAim 1 qualitative data and input from a multidisciplinary steering committee with disease and methodologicexpertise including parent advisors. 3) To evaluate feasibility acceptability and preliminary outcomes ofEXPECT in a pilot trial within the current Dana-Farber Cancer Institute (DFCI) ALL Consortium multi-institutional clinical trial. At the conclusion of the proposed study the resultant intervention EXPECT will beready for testing in a randomized controlled trial (planned R01). Throughout the study the PI Dr. Greenzangwill be supported by a seasoned mentorship team and advisory panel with expertise in health communicationintervention development and implementation science. She will engage in career development and trainingactivities focused on qualitative and quantitative research methods implementation science and conduct ofmulticenter trials to prepare her for a career as an independent investigator all while pioneering the firstpatient- and family-centered communication intervention in pediatric oncology. In so doing she will not onlydevelop an approach to optimally prepare all parents of children with cancer for their children's care duringtreatment and beyond but also expand our knowledge of what type of information patients and families desireat the time of cancer diagnosis and how best to transmit that information. 152566 +No NIH Category available Cancer Patient;Clinic;Clinical;Clinical Research;Clinical Trials;Combined Modality Therapy;Coupled;DNA;Development;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Genotype;Goals;In Vitro;Malignant Neoplasms;Malignant neoplasm of lung;Non-Small-Cell Lung Carcinoma;Oncogenic;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Plasma;Precision therapeutics;Process;Progression-Free Survivals;Receptor Inhibition;Signal Pathway;Signal Transduction;Toxic effect;Translating;Tyrosine Kinase Inhibitor;acquired drug resistance;anaplastic lymphoma kinase;cell free DNA;chemotherapy;drug resistance development;effective therapy;improved;improved outcome;in vivo;mutant;next generation;pre-clinical;preclinical study;prevent;resistance mechanism;response;success;tumor Development of Combination Therapies to Delay/Prevent Acquired Drug Resistance Project NarrativeThe development of drug resistance limits the long term success of genotype directed therapies includingEGFR inhibitors in EGFR mutant lung cancer. By identifying and evaluating EGFR inhibitor based combinationtherapies in vitro and in vivo coupled with clinical trials of such combinations with these analyses of plasmaderived DNA from on treatment lung cancer patients the studies in this proposal aim to improve the outcomeof EGFR mutant and other oncogenic subsets of lung cancer patients. NCI 10691316 9/7/23 0:00 PAR-17-494 5R35CA220497-06 5 R35 CA 220497 6 "UNDALE, ANITA H" 9/10/18 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 1861387 "JANNE, PASI A" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 1026576 NCI 588001 438575 Project SummaryThe use of genotype directed precision therapies including epidermal growth factor receptor (EGFR) andanaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in EGFR mutant or ALK rearranged non-small cell lung cancer (NSCLC) respectively is associated with improvements in both response rate (RR) andprogression free survival (PFS) compared to chemotherapy. However the PFS improvements are typicallyonly counted in months rather than years. Despite the development of next generation TKIs that can overcomespecific resistance mechanisms it is very unlikely that any patient will be cured from their advanced lungcancer using sequential single agent treatment. It is more than likely that significant improvements in patientoutcomes using precision therapies will only occur through the use of combination therapies. In the currentproposal we integrate pre-clinical in vitro and in vivo studies with clinical trials and serial non-invasive analysesof patient's tumors using cell free DNA to develop combination therapies. We focus primarily on EGFR mutantlung cancer as this is the largest subset of NSCLC patients treated with precision therapies and as there is adesperate need to developing more effective therapies for EGFR mutant patients. The approaches todeveloping combination therapies include a.) dual targeting of EGFR b.) vertical pathway inhibition (combiningEGFR inhibition with downstream signaling inhibition) and c.) parallel pathway inhibition (combining EGFRinhibition with other signaling pathways). Our strategy will focus on improving therapies for EGFR inhibitornave cancers as such cancers are genetically the most homogeneous and where improving treatmentapproaches will likely translates into the greatest clinical benefit by delaying and/or preventing the emergenceof acquired drug resistance. Our preclinical studies provide the rationale for the combination clinical studiesand their success (or lack thereof) and toxicity in the clinic will inform about additional preclinical approaches tofurther refine treatments. Through this iterative process our goal is to make significant improvements in theoutcome of EGFR mutant and other lung cancer patients treated with genotyped directed therapies. 1026576 +No NIH Category available 3-Dimensional;Affect;Africa;Age;Appearance;Architecture;Area;Artificial Intelligence;Benign;Biological Markers;Biopsy;Blood Vessels;Cancer Patient;Cells;Chest;Chronic;Clinical;Computer-Assisted Diagnosis;Decision Support Model;Detection;Development;Diagnosis;Diagnostic Specificity;Discrimination;Epidemiology;Granuloma;Granulomatous;HIV;HIV-1;HIV/AIDS;Health;High Prevalence;Human;Human Resources;Image;Immune;Immune response;Incidence;Incidental Findings;Infection;Link;Lung;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Medical center;Modeling;Molecular;Morphology;Nodule;Online Systems;Outcome;Patients;Pattern;Persons;Phenotype;Population;ROC Curve;Radiology Specialty;Reaction;Reader;Reporting;Risk;Roentgen Rays;Scanning;Sensitivity and Specificity;Services;Shapes;Specificity;Specimen;Standardization;Surface;Tanzania;Technology;Teleradiology;Texture;Thoracic Radiography;Tissues;Transference;Tuberculosis;Uganda;Validation;X-Ray Computed Tomography;chest computed tomography;cohort;computerized;imaging biomarker;improved;innovation;low dose computed tomography;lung cancer screening;lung imaging;novel;radiological imaging;radiologist;radiomics;respiratory;risk prediction;screening;screening program;skills;success;support tools;symptomatology;tool;web portal Artificial Intelligence for Lung Cancer Characterization in HIV affected populations in Uganda and Tanzania RELEVANCE Project 3In this project we will develop a radiomics based machine classifier called LunIRiS (Lung Image Risk Score) forpredicting risk of malignancy for a nodule on a chest computed tomography (CT) or X-ray scan for use in patientsin Uganda and Tanzania which has a higher prevalence of tuberculosis (TB) and hence TB- induced granulomas.Additionally we will seek to employ these tools to identify possibly differences in the radiographic phenotype onCT and chest X-rays between HIV+ and HIV- lung cancer patients and to employ these differences to developHIV status specific lung cancer screening models. NCI 10691312 8/10/23 0:00 RFA-CA-20-001 5U54CA254566-04 5 U54 CA 254566 4 9/21/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6873 8352708 "MADABHUSHI, ANANT " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 216036 151742 64295 ABSTRACT Project 3The age standardized rates (ASRs) show a steady rise in the incidence of lung cancer in Uganda and Tanzaniacompared to other cancers. Unfortunately there is no established lung cancer screening program in either ofTanzania or Uganda. The cases of lung cancer recorded have mostly been found incidentally on chest computedtomography (CT) scans done to establish the cause of patients' respiratory symptomatology. This problem ofdiagnostic specificity is exacerbated in Tanzania and Uganda on account of the high incidence of tuberculosis(TB) which can cause a chronic granulomatous reaction in the lungs manifesting as benign pulmonary noduleson CT and X-rays. Skilled personnel to acquire good quality chest x-ray and CT images and to interpret them islacking in most tertiary health centers in Uganda and Tanzania. Additionally the number of people living withHIV AIDS continues to rise and in 2014 it was reported that Tanzania had 1411829 people living with HIVAIDS. However very little is known about lung cancer and HIV in Africa. With the currently observed increasingincidence rates of lung cancer there is an urgent need to study the link between lung cancer and HIV in Ugandaand Tanzania. An additional intriguing question is whether the same radiographic criteria for lung cancerscreening should be uniformly applied across both HIV+ and HIV- patients. Our group has been developing new classes of radiomic (computerized feature analysis of radiographicscans) features for improved discrimination of malignant from benign lung nodules. For instance we have shownthat the tortuosity of nodule vasculature is substantially different between benign and malignant nodules.Additionally we have shown that radiomic features of the peri-nodular surface (immediately outside the lungnodule on CT and X-rays) were associated with degree of immune response on biopsy tissue specimens. Giventhat HIV patients tend to have a low immune cell population a reasonable conjecture is that the radiomicsignature on radiographic scans will reflect the absence of an immune signature. In this project we will develop a radiomics based machine classifier called LunIRiS (Lung Image RiskScore) for predicting risk of malignancy for a nodule on a chest CT or X-ray scan. We hypothesize that the newradiomic biomarkers can enable improved non-invasive lung diagnosis in Uganda and Tanzania which has ahigher prevalence of TB and hence TB induced granulomas. Additionally we will seek to employ these tools toidentify possibly differences in the radiographic phenotype on CT and chest X-rays between HIV+ and HIV- lungcancer patients and to employ these differences to develop HIV status specific lung cancer screening models.Finally the fourth objective will be to create a web-based deployment of LunIRiS to enable decision support andteleradiology based services between Cleveland and Uganda and Tanzania for improving lung nodule diagnosison screening LDCT scans. This partnership will allow for transference of technology and radiology expertise(through the web portal) for improved lung cancer screening in Uganda and Tanzania. +No NIH Category available Acceleration;Address;Adenocarcinoma;Africa;Africa South of the Sahara;African;Age;Aging;Biological Markers;Blood Cells;CD4 Positive T Lymphocytes;Cancer Patient;Cell Count;Country;DNA;DNA Methylation;Data;Development;Diagnosis;Disease;Disease Outcome;Disease Progression;Eastern Cooperative Oncology Group;Environmental Risk Factor;Epidemiologic Factors;Epidemiology;Equipment;Future;Genomics;Genotype;HIV;HIV Infections;HIV-1;Histology;Home;Image;Immune;Immunosuppression;Incidence;Individual;Indoor Air Pollution;Infection;International;Link;Lung Capacity;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medical center;Methylation;Molecular;Molecular Profiling;Multivariate Analysis;Mutation;Mutation Analysis;Outcome;Pathologic;Patients;Performance Status;Persons;Policies;Premature aging syndrome;Relative Risks;Reporting;Risk;Risk Factors;Role;Sampling;Smoker;Smoking;Somatic Mutation;South Africa;Squamous cell carcinoma;Tanzania;Technology;Technology Transfer;Tobacco smoking behavior;Training;Transference;Tuberculosis;Tyrosine Kinase Inhibitor;Uganda;University Hospitals;Viral Load result;Virus Diseases;World Health Organization;advanced disease;antiretroviral therapy;base;cancer risk;cohort;cooking;environmental tobacco smoke;methylation pattern;methylome;prospective;screening;standard of care;therapeutically effective Molecular determinants of lung cancer in HIV infected and uninfected individuals in Uganda and Tanzania RELEVANCE Project 2The molecular risks of lung cancer mutation and co-incidence of HIV and accelerated aging as a factor in lungcancer incidence and progression in two East African countries will be assessed. We will characterize lungcancer somatic mutations link them to HIV subtype/viral load/CD4 T cell counts and explore the hypothesizedrole of DNA methylome aging in HIV-infected versus HIV-uninfected individuals. We will also train and transfertechnological equipment to build capacity for lung cancer mutational analysis and DNA methylome aging forlung cancer and HIV in Uganda and Tanzania. NCI 10691309 8/10/23 0:00 RFA-CA-20-001 5U54CA254566-04 5 U54 CA 254566 4 9/21/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6872 6573086 "GERSON, STANTON L." Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 200857 176637 24221 ABSTRACT Project 2We will assess molecular risks and co-incidence of lung cancer HIV and accelerated aging as a factor in lungcancer incidence and progression in HIV infected patients. We will define the somatic mutations of lung cancerlink them to HIV subtype and explore the hypothesized role of DNA methylome aging in HIV- infected versusuninfected individuals as an associative factor that could potentially be utilized as a future biomarker to predictlikelihood of lung cancer development or disease progression. These data will provide the first comprehensiveassessment of somatic mutation burden in East African lung cancer which will guide access to therapeuticallyeffective agents to target actionable lung cancer mutations. These will be linked to risk factors associated withHIV including immunosuppression immune protection and accelerated aging that may increase the risk ofcancer in HIV+ individuals. These will help to discern whether epidemiological factors from Project 1 can projectrisk for lung cancer at the molecular level and whether together we can identify prominent factors linkingepidemiologic risk HIV-1 infection and lung cancer in East Africa. +No NIH Category available Africa;Africa South of the Sahara;Age;Air;Area;Biological Specimen Banks;Cancer Etiology;Caring;Cessation of life;Clinical;Clinical Distribution;Cohort Analysis;Collaborations;Cross-Sectional Studies;Data;Databases;Diagnosis;Disease;ERBB2 gene;Epidemiologist;Epidemiology;Epidermal Growth Factor Receptor;Etiology;Female;Genomics;Guidelines;HIV;HIV Infections;HIV-1;HIV/AIDS;Health Personnel;Histology;Histopathology;Image;Incidence;Individual;Infection;KRAS2 gene;Knowledge;Laboratories;Life;Link;Logistic Regressions;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Modification;Molecular;Mutation;Outcome;Patients;Persons;Phase;Physicians;Prevalence;Prevention program;Primary Prevention;ROS1 gene;Recurrence;Reporting;Research Proposals;Risk;Risk Factors;Role;Series;Sex Differences;Smoking;Smoking Behavior;Smoking Status;Somatic Mutation;Standardization;Tanzania;Thoracic Radiography;Time;Uganda;Universities;Woman;World Health Organization;antiretroviral therapy;cancer risk;cancer survival;case control;clinical epidemiology;design;innovation;lifetime risk;low and middle-income countries;male;men;mortality;multidisciplinary;personalized medicine;radiological imaging;residence;screening;screening program;sex;survival outcome;tumor progression;understudied cancer Characterization of the clinical epidemiology of lung cancer and relationship to HIV-1 infection in Uganda and Tanzania RELEVANCE Project 1This project will provide an overall picture of lung cancer in East Africa specifically in Uganda andTanzania and clarify the role of HIV-1 infection as a risk factor for lung cancer and progression. We willexamine the clinical and demographic features of patients with lung cancer HIV-1 infection statuslaboratory and radiographical findings and treatments administered as well as identify epidemiologicalrisk factors. NCI 10691307 8/10/23 0:00 RFA-CA-20-001 5U54CA254566-04 5 U54 CA 254566 4 9/21/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6871 15157764 "KASASA, SIMON " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 155740 132686 23055 ABSTRACT Project 1The innovation of our research proposal focuses on three main areas: 1) primary prevention; 2) screening; and3) personalized medicine. Currently several studies in the US and Africa have demonstrated that HIV-1 infectionincreases the risk of lifetime cancer risk particularly lung cancer. The etiology of lung cancer among HIV-1infected individuals is unknown but of great importance given the number of individuals who live infected withHIV-1. Here we will investigate potential risk factors for lung cancer such as geospatial residence indoor andoutdoor air quality and smoking behavior to better understand the underlying risk factors. This generalknowledge will serve to develop primary prevention programs designed to reduce adverse exposures thuslowering the onset of lung cancer disease. Beyond primary prevention our proposal will assess clinical featuresassociated with lung cancer risk and progression among those infected by HIV-1. This will provide the opportunityto develop screening programs based on HIV-1 infection status thus detecting disease at an earlier phase anddecreasing the overall mortality. For example TB may present as lung nodules during chest x-rays and patientswho actually have lung cancer have a delay in the diagnosis of lung cancer and life-saving treatments.Understanding this relationship will better enable physicians and health providers to provide comprehensivescreening. Lastly our proposal will expand the concept of personalized medicine by providing a descriptiveanalysis of somatic genomic mutations among lung cancer cases infected with HIV-1. This will provide the basisto examine for differences and provide optimal care under current guidelines. +No NIH Category available AIDS related cancer;Africa;Applications Grants;Area;Award;Biomedical Engineering;Cessation of life;Climate;Clinical Oncology;Collaborations;Communication;Country;Data;Development;Development Plans;Education;Educational workshop;Ensure;Environment;Epidemiology;Faculty;Funding;Future;Generations;Goals;Grant;HIV Seropositivity;HIV-1;Image;Income;Infection;Infrastructure;Institution;Interdisciplinary Study;International;International Health Problems;Joints;K-Series Research Career Programs;Leadership;Link;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Medical Oncology;Mentored Clinical Scientist Development Program;Mentors;Mentorship;Methods;Molecular;Molecular Medicine;Monitor;Online Systems;Pathology;Patients;Physicians;Pilot Projects;Program Development;Pulmonology;Qualifying;Radiation Oncology;Radiology Specialty;Recording of previous events;Regulation;Research;Research Personnel;Research Project Grants;Resources;Risk;Running;Scholars Program;Scientist;Site;Source;Talents;Technology;Tobacco;Training;Uganda;Universities;University Hospitals;Visit;Writing;career;career development;clinical epidemiology;experience;falls;imaging biomarker;innovation;meetings;next generation;novel;patient population;peer;peer coaching;programs;recruit;skills;success;webinar Developmental Core RELEVANCE - Developmental CoreLung cancer is a major national and international health problem resulting in more cancer deaths than anyother cancer. The rates are increasing in the low to middle income countries where the epidemiology outsidethe effect of tobacco is not well understood. HIV-positive patients are increased risk of developing lung cancer.By providing developmental and pilot funds to highly qualified investigators early in their career we can makedevelop novel ideas and grow the next generation of physician scientists tackling these issues. NCI 10691301 8/10/23 0:00 RFA-CA-20-001 5U54CA254566-04 5 U54 CA 254566 4 9/21/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6869 7852340 "DOWLATI, AFSHIN " Not Applicable 11 Unavailable 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH Domestic Higher Education 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 102862 67671 35192 ABSTRACT Developmental CoreThe goal of this Developmental Core is to provide the infrastructure and know-how to recruit and support juniorand new investigators to field of HIV-associated cancers and in particular lung cancer. The Core will recruit fundmonitor progress provide mentorship and support the presentation of ongoing/completed research projects atthree institutions across 3 countries. We will adapt methods and activities that have been used successfully inthe Case CCC which has a Paul Calabresi Career Development Award for Clinical Oncology (K12 ScholarsProgram) now in its 18th year of funding and the CWRU/UH CFAR to the specific requirements of this U54.Specifically this initiative will provide pilot grant support for 3 junior faculty from our partner institutions per year(leading to a total of up to 15 faculty in the program) which will be closely linked to mentoring and professionaldevelopment plans. Innovative aspects of the program will be the development of peer-to-peer mentoringprogram involving CWRU faculty who visit Uganda regularly and the extensive use of webinars and web-basedcommunication to run joint review panels workshops and hold mentoring committee meetings. In the currenthighly competitive funding environment the key to success is to provide consistent support as well as specificguidance when needed to junior investigators to allow generation of enough preliminary data for a submissionof a strong competitive grant application. Our 31-year history of close collaboration and the climate of mutualrespect that we have developed with our Ugandan colleagues (which will be extended to our Tanzaniancolleagues) form the basis for this novel and innovative Developmental Core. +No NIH Category available Academic Training;American Association of Cancer Research;American Society of Clinical Oncology;Area;Award;Basic Science;Budgets;Caliber;Cancer Biology;Cancer Center;Clinical;Clinical Trials;Colorectal Cancer;Country;Dedications;Development;Development Plans;Diagnosis;Disease;Early Diagnosis;Education;Eligibility Determination;Ensure;Feedback;Fellowship;Financial Support;Funding;Goals;Grant;Individual;Institution;International;Journals;Knowledge;Laboratories;Laboratory Research;Leadership;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Manuscripts;Mentors;Mentorship;Minority;Morbidity - disease rate;Nature;Oncology;Pathology;Patients;Peer Review;Physicians;Prevention;Process;Publications;Publishing;Qualifying;Quality of life;Research;Research Personnel;Research Project Grants;Scientist;Site;Survivors;Training;Training Programs;Translating;Translational Research;Underrepresented Populations;Universities;University of Texas M D Anderson Cancer Center;Woman;Writing;anticancer research;cancer diagnosis;career;career development;clinical care;clinical trial protocol;design;flexibility;gastrointestinal;improved;innovation;interest;meetings;member;mortality;next generation;programs;recruit;skills;symposium;training opportunity;translational approach;translational potential;translational research program;translational scientist Career Enhancement Program CAREER ENHANCEMENT PROGRAM: NarrativeThe Career Enhancement Program (CEP) in the MD Anderson Gastrointestinal Cancer SPORE is designed to develop and successfully train academic physician-scientists and basic scientists with an interest in translational research in the areas of diagnosis prevention and treatment of pancreatic cancer (PDAC) and colorectal cancer(CRC). The CEP will recruit with emphasis on minorities and women to provide up to 2 years of research funding to Awardees and pair them with a clinical and/or laboratory mentor and an individualized career development plan that will include coaching in grant and manuscript writing leadership training attendance at national meetings and completion and publication of a translational research project. Currently there are no training programs at MD Anderson focused on translational PDAC or CRC research which underscores the importance of programs such as the CEP; and of special note the CEP will also incorporate available mentorship and training opportunities at Johns Hopkins University our subcontract site for this SPORE broadening the scope of its reach beyond MD Anderson. NCI 10691289 7/11/23 0:00 PAR-18-313 5P50CA221707-05 5 P50 CA 221707 5 8/20/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 6867 8210070 "KOPETZ, SCOTT " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 145727 91218 54977 CAREER ENHANCEMENT PROGRAM: Summary/AbstractThe goal of the Career Enhancement Program (CEP) is to develop highly trained exceptional young investigators dedicated to translational research in the early detection prevention and treatment of pancreatic cancer (PDAC) and colorectal cancer (CRC). Ideally these investigators will ultimately help to reduce the morbidity and mortality from these diseases. The CEP will extend be available across both participating institutions MD Anderson and Johns Hopkins University broadening the scope of expertise and mentorship opportunities available to early career investigators. Underscoring the shared nature of our program the CEP will be led by Drs. Elizabeth Jaffee at Johns Hopkins and Dr Scott Kopetz at MD Anderson respectively. The CEP will A) recruit and train physicians and basic scientists to enable them to become highly skilled translational investigators in the field of PDAC or CRC B) provide specific knowledge of research in PDAC or CRC that will enhance the ability of awardees to conduct innovative translational science that will directly impact on the understanding and treatment of these diseases; and 3) re-direct individuals who have already shown considerable scientific promise into PDAC or CRC research. To achieve this goal the SPORE CEP will provide up to five awards of $50000 each annually for one year with a competitive option for renewal for an additional year funded from the SPORE and matching funds from MD Anderson and Johns Hopkins. We will aggressively recruit the most promising young investigators and institute an individualized development plan with clinical and laboratory mentors and a mentoring committee that will provide coaching in grant and manuscript writing leadership training networking with PDAC and CRC scholars (including key opinion leaders in concurrently funded SPORE programs around the country) and completing and publishing translational PDAC or CRC related manuscripts in high impact peer reviewed journals. The GI SPORE will utilize multiple programs inside and outside of the Institute to identify outstanding young investigators with an emphasis placed on recruiting qualified women and members of traditionally underrepresented groups. The CEP will also encourage and support awardee presentations at national or international meetings. The ultimate deliverable of our CEP is to train and cultivate the highest caliber of next generation translational research scientists in GI cancers. +No NIH Category available Area;Award;Basic Science;Budgets;Cancer Center;Clinical;Clinical Investigator;Collaborations;Colorectal Cancer;Communities;Complement;Data;Development;Direct Costs;Discipline;Disease;Educational Activities;Eligibility Determination;Environment;Evaluation;Financial Support;Funding;Future;Goals;Guidelines;Human;Incidence;Institution;Laboratories;Leadership;Letters;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Medical Oncology;Medical center;Minority Groups;Modeling;Monitor;National Cancer Institute;Nature;Pathology;Patients;Physicians;Pilot Projects;Population Research;Principal Investigator;Process;Productivity;Program Research Project Grants;Qualifying;Quality of life;Records;Reproduction spores;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Rest;Scientist;Selection Criteria;Specimen;Texas;Text;Translational Research;Translations;Underrepresented Minority;United States National Institutes of Health;Universities;Woman;Work;anticancer research;base;flexibility;gastrointestinal;high risk;improved;innovation;member;mid-career faculty;molecular pathology;mortality;patient population;professor;programs;recruit;sound;translational cancer research;translational study Developmental Research Program DEVELOPMENTAL RESEARCH PROGRAM: NarrativeThe Developmental Research Program (DRP) will support innovative and scientifically sound projects that investigate questions pertaining to translational research in colorectal and pancreatic cancer but which currently lack a human endpoint as defined by SPORE guidelines. This program will allow for the recruitment of new investigators into the gastrointestinal cancer research community and for the development of potential full projects for the Gastrointestinal Cancer SPORE. NCI 10691287 7/11/23 0:00 PAR-18-313 5P50CA221707-05 5 P50 CA 221707 5 8/20/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 6866 7626839 "MAITRA, ANIRBAN " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 145727 91217 54978 DEVELOPMENTAL RESEARCH PROGRAM: Summary/AbstractThe purpose of the Developmental Research Program (DRP) is to fund highly innovative translational studies incolorectal cancer (CRC) or pancreatic cancer (PDAC) that currently lack a human endpoint as mandated by the SPORE guidelines but that could become full SPORE projects with requisite DRP support or compete successfully for funding outside of the SPORE mechanism. The DRP provides a unique venue for making available critical financial support as well as disease-specific intellectual and resource expertise through a program that is rapidly responsive to new ideas or initiatives including from investigators whose current work may not focus exclusively in CRC or PDAC research. This program is rooted in a spirit of collaboration espoused by the GI SPORE leadership which has an extensive track record of bringing investigators from other disciplines into the field of CRC and/or PDAC research. The strength of the DRP rests in its ability to make available financial support needed to access all the critical expertise and resources within the entire GI SPORE including the proposed Cores. This will allow us to develop innovative investigator-initiated projects that have the potential to flourish into reliable and productive translational research projects along a path from basic and/or population research projects into research focused on human clinical specimens/patient populations. The DRP will be co led by principal investigators of the SPORE including Dr. Anirban Maitra the Scientific Director of the Sheikh Ahmed Center for Pancreatic Cancer Research and Professor in the Departments of Pathology and Translational Molecular Pathology at UT MD Anderson Cancer Center (UTMDACC) and Dr. Scott Kopetz Associate Professor and Deputy Chair for Translational Research in the Department of Gastrointestinal Medical Oncology. The DRP will incorporate not only UTMDACC but also our collaborating partner institution Johns Hopkins University (JHU) and other centers of excellence within the Texas Medical Center providing an unprecedented seedbed for promoting innovative translational research projects in PDAC and CRC. Pre proposals in the form of one page letters of intent (LOI) will be solicited by the Program and following review by the DRP leadership applicants of the responsive pre-proposals will be invited to submit a full proposal for review. The DRP Directors will help investigators submitting proposals to formulate translational research aims and plansrelevant to the overall themes of the GI SPORE as many applicants may not have prior expertise in this type of research. The overarching goal will be to facilitate research activities that will enable proposing a feasible human endpoint for future iterations of the funded proposal. This process will therefore be a major educational activity that is further anticipated to stimulate translational research in CRC or PDAC and encourage the participation of both basic science researchers and clinical investigators in translational research. +No NIH Category available Affect;Allografting;Apoptosis;Biological Assay;Biological Markers;Biopsy;Blood;Blood specimen;CLIA certified;Cancer Center;Carcinoma;Cellularity;Chemopreventive Agent;Clinical Distribution;Clinical Trials;Closure by clamp;Collection;Colorectal;Colorectal Cancer;Conduct Clinical Trials;Core Biopsy;Cryopreservation;Data;Databases;Derivation procedure;Development;Diagnosis;Documentation;Electronics;Endoscopic Biopsy;Ensure;Environment;Excision;Faculty;Familial Adenomatous Polyposis Syndrome;Formalin;Freezing;Funding;Grant;Guidelines;Hepatic;Histology;Histopathology;Human;Human Resources;IL6 gene;Image;Image Analysis;Immunohistochemistry;Immunotherapy;Informatics;Information Services;Information Systems;Infrastructure;Institution;Institutional Review Boards;Laboratories;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mucinous Neoplasm;Mus;Necrosis;Neoplasm Metastasis;Normal tissue morphology;Operative Surgical Procedures;Pancreas;Pancreatic Ductal Adenocarcinoma;Paraffin Embedding;Pathologist;Pathology;Pathology Report;Patient Care;Patients;Peer Review;Peptide Vaccines;Process;Proliferation Marker;Protocols documentation;Qualifying;Quality Control;Reporting;Research;Research Personnel;Research Project Grants;Resected;Resources;STAT3 gene;Sampling;Services;Specimen;Stains;Surgical Pathology;System;Technical Expertise;Testing;Time;Tissue Banks;Tissue Microarray;Tissue Sample;Tissues;Tumor Tissue;Tumor-Infiltrating Lymphocytes;University of Texas M D Anderson Cancer Center;Validation;Xenograft procedure;adenoma;automated image analysis;career;clinical care;co-clinical trial;colorectal cancer prevention;design;efficacy evaluation;gastrointestinal;inhibitor;metastatic colorectal;molecular pathology;participant enrollment;patient derived xenograft model;pre-clinical;predictive marker;programs;prospective;quantitative imaging;standard of care;tumor;vaccine evaluation Core 1: Biospecimen and Pathology Core CORE 1 BIOSPECIMEN AND PATHOLOGY: NarrativeCore will design and operationalize all preanalytical processes and data system related to blood and tissue samples from patients enrolled in this SPORE by utilizing pathology expertise from the Core pathologists and enhancing processes already in place at MD Anderson tissue bio specimen and pathology resources. NCI 10691277 7/11/23 0:00 PAR-18-313 5P50CA221707-05 5 P50 CA 221707 5 8/20/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 6861 8783318 "MARU, DIPEN M." Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 274128 171727 103284 CORE 1 BIOSPECIMEN AND PATHOLOGY: Summary/AbstractThe Biospecimen and Pathology Core will coordinate efforts related to collection processing storage and distribution of annotated human and murine biospecimens for all of the SPORE projects including the Career Enhancement Program (CEP) and Developmental Research Program (DRP). The Core will be co-led by two nationally reputed gastrointestinal/pancreatic pathologists Drs. Dipen Maru and Huamin Wang. For human biospecimens the core will interface with the MDACC Institutional Tissue Bank (ITB). Biospecimen resources from the lower gastrointestinal tissue bank include freshly collected/snap frozen and formalin fixed paraffin embedded tumor and normal specimens from more than 2500 resected hepatic colorectal metastases (including TMAs) freshly collected and snap frozen adenoma from 334 patients and formalin fixed paraffin embedded specimens from 870 or more patients with sporadic adenoma or familial adenomatous polyposis. Existing biospecimen resources available in the pancreatic bank and related IRB approved protocols include freshly collected/snap frozen tumor and normal tissue sample from Whipple resection for pancreatic ductal adenocarcinoma from 232 patients with formalin fixed paraffin embedded specimens and additional 672 patients including tissue microarrays from pancreatic ductal adenocarcinoma and intraductal pancreaticmucinous neoplasms. The Core will support Project 1 by coordinating prospective blood collection cryopreservation and transport with the ITB. Specifically Core faculty will prospectively collect process and distribute fresh tumor and normal samples from hepatic colorectal metastases after obtaining mirror image section for histology quality control. The Core will provide formalin fixed paraffin embedded samples of normal adenoma and carcinoma to Project 2. In addition the Core will provide biospecimen qualification servicesincluding but not limited to histopathologic characterization of human and murine tissues treated with STAT3 inhibitor and immunohistochemistry staining and interpretation including validation of p-STAT3 staining by automated image analysis in a CLIA-certified facility. The Core will provide freshly resected PDAC samples for patient derived xenografts and ex vivo live tissue sensitivity assay (LTSA) for Project 3. In addition the Core will provide histopathology characterization immunohistochemistry services and interpretation guidelines for both preclinical samples from the ongoing co-clinical trials as well as serial tissue biopsies obtained from the two clinical trials being conducted Project 3. The Core will also coordinate distribution of appropriate samples to investigators funded through the SPORE CEP and DRP grants. The Core personnel along with the ITB will enter detailed information related to all processes of biospecimen collection processing qualification distribution and analytes extraction into the Institutional Biospecimen Informatics platform known as Tissue Station. The Core activities will lead to enhancement of these functionalities of Tissue Station and design a new interface specific for GI SPORE in the Tissue Station. +No NIH Category available Address;Adherence;Administrator;Advocate;Awareness;Bioinformatics;Biometry;Budgets;Cancer Center;Cancer Center Support Grant;Catchment Area;Center Core Grants;Clinical Trials;Collaborations;Colorectal Cancer;Communication;Communities;Consult;Consultations;Country;County;Data Linkages;Decision Making;Deposition;Development;Ensure;Environment;Expenditure;Extramural Activities;Funding;Goals;Grant;Human Resources;Infrastructure;Institution;Joints;Leadership;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Manuscripts;Medical center;Minority;Mission;Monitor;Pathology;Patient advocacy;Patients;Preparation;Productivity;Progress Reports;Quality Control;Regulation;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Sampling;Site;System;Texas;Translating;Translational Research;Underrepresented Minority;Universities;Woman;anticancer research;career;clinical translation;data access;data exchange;data integration;data integrity;data quality;data sharing;design;experience;medically underserved;meetings;minority communities;multidisciplinary;operation;programs;quality assurance;translational research program;underserved community Administrative Core ADMINISTRATIVE CORE: Project NarrativeThe primary purpose of the Administrative Core of the MD Anderson Cancer Center SPORE in Gastrointestinal Cancers is to facilitate the integration of multidisciplinary investigators into a focused team that will further basic and clinical translational research in colorectal and pancreatic cancer. As a key part of the Institutional mission it will provide uninterrupted leadership and guidance and oversee data sharing and sample management along with general administrative support for all SPORE-related activities as well as comply with all federal mandates for budgeting and reporting of progress. NCI 10691276 7/11/23 0:00 PAR-18-313 5P50CA221707-05 5 P50 CA 221707 5 8/20/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 6860 8210070 "KOPETZ, SCOTT " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 273686 171451 103117 ADMINISTRATIVE CORE: Abstract/SummaryThe Administrative Core (AC) will provide all of the administrative and budgetary support to the MD Anderson Cancer Center Cancer SPORE in Gastrointestinal Cancers PIs and investigators and form the central hub for productive interactions within the SPORE community. It is co-directed by Drs. Scott Kopetz and Anirban Maitraand supported by a research program manager Dr. David Menter an experienced multi-investigator grant administrator and investigator. Both Dr Kopetz and Dr. Maitra have experience in overseeing multi-investigator grants that include Institutional Grants Cancer Center Core Grant Programs and Stand Up to Cancer Grants.The overall goal of the AC will be coordination and monitoring of 3 Projects 2 additional Cores as well as the Developmental Research (DRP) and Career Enhancement (CEP) Programs. The AC is designed to monitor research activity and provide stable and continuous leadership and direction that advances integration communication and collaboration among GI SPORE investigators within MD Anderson and among extramural institutions in particular our partner institution Johns Hopkins University (JHU). The AC will leverage the wide ranging scientific research and SPORE-related experience of both Internal and External Advisory Boards in critical decision-making steps. The AC will ensure fiscal management including personnel budgets and effort oversight facilitate communication interfacing with patient advocates organization of meetings manuscript preparation and progress and other reports to the NCI and GI SPORE committees and cross-communication of Cores and Programs. Of paramount importance is to ensure timely communication and consultation with the NCI Translational Research Program Director and staff for both adherence and deviations from stated programmatic goals. This Core is to also monitor scientific integrity and overall compliance with all institutional state federal and NCI regulations and requirements as well as quality assurance for data integrity including a change in the data integration plan with utilization of the new institutional clinical trial management system (CTMS) in lieu of Redcap which provides greater data linkage residing in the Biospecimen and Pathology Core (Core 1) and Biostatistics and Bioinformatics Core (Core 2). The AC will be responsible for oversight of DRP and CEP for completion of deliverables. The AC also facilitates routine convening of staff and management of all necessary meetings. The AC will also enhanced awareness of colorectal and pancreatic cancer research and patient advocacy in the community as well as ongoing needs of minority and underserved communities in Houston and Harris County catchment area. This core will also help leverage and facilitate translational GIcancer research efforts being conducted by extramural groups locally and in the US and globally through both horizontal and vertical collaborations within the SPORE framework. +No NIH Category available Adenocarcinoma;Adjuvant;Advocate;Agonist;Animal Model;Anti-CD40;Archives;Award;Bioinformatics;Biological;Biological Markers;Biometry;Cancer Center;Cancer Etiology;Cessation of life;Chemoprevention;Chronic;Clinic;Clinical;Clinical Trials;Collaborations;Colonic inflammation;Colorectal Cancer;Combined Modality Therapy;Combined Vaccines;Communities;Complement;Country;Data;Data Analyses;Dependence;Development;Diagnostic;Disease;Environment;Excision;Failure;Familial Adenomatous Polyposis Syndrome;Familial colorectal cancer;Funding;Future;Genetic Engineering;Goals;Grant;Hereditary Nonpolyposis Colorectal Neoplasms;Image;Immune;Immune checkpoint inhibitor;Immunotherapeutic agent;Inflammation;Inflammatory Bowel Diseases;Inherited;Institution;International;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mentors;Microsatellite Instability;Minority;Mitochondria;Molecular;Morbidity - disease rate;Mus;Oncogenic;Operative Surgical Procedures;Organoids;Outcome;Oxidative Phosphorylation;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathology;Patients;Peptide Vaccines;Pharmacodynamics;Phase;Pilot Projects;Populations at Risk;Positioning Attribute;Pre-Clinical Model;Prevention;Prevention Research;Prevention trial;Productivity;Pyruvate;Quality of life;Reporting;Research;Research Personnel;Resected;Residual Neoplasm;Resistance;Role;STAT3 gene;Sampling;Signal Pathway;Signal Transduction;Stat3 protein;Syndrome;TLR7 gene;Therapeutic;Translating;Translational Research;Ulcerative Colitis;Universities;Vaccination;Vaccine Therapy;Woman;Work;adenoma;anti-PD-1;anti-tumor immune response;cancer immunotherapy;career;chemotherapy;clinical care;clinical translation;colon cancer patients;colorectal cancer risk;colorectal cancer treatment;design;early-career faculty;efficacy testing;empowerment;first-in-human;high risk;imaging study;improved;inhibitor;innovation;metabolic imaging;metastatic colorectal;mortality;multidisciplinary;neoantigens;novel;novel therapeutics;pancreatic cancer model;patient derived xenograft model;pre-clinical;programs;prospective;radiological imaging;recruit;resistance mechanism;response;standard of care;translational impact;translational scientist;trial design;tumor DNA;tumor metabolism;vaccine trial MD Anderson Cancer Center SPORE in Gastrointestinal Cancer OVERALL: NarrativeThe MD Anderson Cancer Center SPORE in Gastrointestinal Cancer will investigate critical gaps in ourunderstanding and treatment of colorectal and pancreatic cancer by (1) developing and evaluating the effectof personalized peptide vaccine therapy in colorectal cancer patients to optimize the anti-tumor immuneresponse to be conducted in collaboration with Johns Hopkins University; (2) determining the biologicsignificance STAT3 protein pathway signaling using preclinical models along with performing a preventiontrial of a novel STAT3 inhibitor developed at MD Anderson; and (3) examining the response and resistancemechanisms to a novel cancer metabolism inhibitor targeting the mitochondria in preclinical models ofpancreatic cancer in parallel with an proposed clinical trial. These three projects will be complemented byresearch awards for early career investigator and innovative developmental grants designed to promotetranslational efforts that reduce the mortality and morbidity from these highly lethal cancers and improvethe quality of life of patients afflicted with these diseases. NCI 10691275 7/11/23 0:00 PAR-18-313 5P50CA221707-05 5 P50 CA 221707 5 "NOTHWEHR, STEVEN F" 8/20/19 0:00 5/31/24 0:00 ZCA1-RPRB-F(O1) 8210070 "KOPETZ, SCOTT " "MAITRA, ANIRBAN " 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 2203749 NCI 1442536 768629 OVERALL: Summary/AbstractThe overall goal of the MD Anderson SPORE in Gastrointestinal Cancer is to reduce mortality and morbidityrates from colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) and to improve the qualityof life of patients afflicted by these diseases. CRC is the 2nd most common cause of cancer-related deaths inthis country while PDAC is the 3rd most common cause underscoring the significance of the workundertaken in this proposal. Our multidisciplinary team will conduct highly innovative translational researchincluding first-in-human trials in order to further therapeutic options available to CRC and PDAC patients. TheGI SPORE will be jointly led by Scott Kopetz and Anirban Maitra who are accomplished translationalresearchers in CRC and PDAC respectively. We propose the following three projects: Project 1 will test theefficacy of a novel personalized peptide vaccine in the adjuvant setting in post-resection CRC patients andalso evaluate in preclinical models the most optimal combination therapies for vaccination in this disease.Project 1 will be a collaboration with Johns Hopkins University and represents the confluence of our sharedexpertise in cancer immunotherapy and immune correlatives. Project 2 will evaluate the role of oncogenicSTAT3 signaling in chronic inflammation-associated and hereditary CRC using a combination of geneticallyengineered animal models and patient-derived organoids (PDOs). In addition this project will conduct aprevention study with an internally-developed STAT3 inhibitor. Project 3 will evaluate biological correlatesof response and resistance (including metabolic imaging studies) to a novel inhibitor of oxidativephosphorylation (OXPHOS) in PDAC using our substantial repertoire of genetically annotated patient-derivedxenografts (PDXs). Further we will evaluate this OXPHOS inhibitor IACS-10759 in two clinical trialstargeting metastatic and locally advanced PDAC patients respectively with accompanying novel imaging andmolecular correlatives. An important objective of our program will be the recruiting of women and minoritiesto the field and mentoring of early career faculty through the Career Enhancement Program (CEP) andfunding of innovative pilot projects through the Developmental Research Program (DRP). An AdministrativeCore designed to maintain fiscal responsibility along with reporting and institutional compliance will supportall three projects. A Biospecimen and Pathology Core will support all clinical and research biospecimenneeds for the three projects and a Biostatistics and Bioinformatics Core will provide support for trial designand biostatistics. Established working relationships have been extremely productive on many fronts from awell-positioned team approach. Our overall GI SPORE team is strategically organized to effectively translateour preclinical concepts and novel targets rapidly into a clinical setting with the goal of significant impact onmortality rates from CRC and PDAC 2203749 +No NIH Category available Amino Acid Sequence;Antineoplastic Agents;Biochemical;Biology;Cancer Biology;Cancer Etiology;Cells;Chemicals;Chromatin;Chromosomal Instability;Chromosomes;Citric Acid Cycle;DNA;DNA Damage;DNA Topoisomerases;Drug Targeting;Enzymes;Eukaryotic DNA Topoisomerases II;Genetic;Goals;Human Chromosomes;Malignant Neoplasms;Methodology;Molecular Machines;Outcome;Play;Proteins;Research;Role;Site;Specificity;Superhelical DNA;Topoisomerase;Topoisomerase II;Variant;Work;cancer cell;cancer therapy;drug action;genetic information;genome integrity;improved;innovation;mutant Understanding and exploiting DNA topoisomerases in cancer biology NARRATIVEType II topoisomerases are molecular machines that untangle DNA and serve as targetsof frontline anticancer drugs. The present proposal seeks to better understand andimprove upon how anti-topoisomerase agents work; we will also determine how mutanttopoisomerase variants which are found in cancer cells may contribute to geneticdamage and chromosome instability. NCI 10691273 8/7/23 0:00 PAR-20-278 5R35CA263778-03 5 R35 CA 263778 3 "AMIN, ANOWARUL" 9/1/21 0:00 8/31/28 0:00 ZCA1-GRB-S(M1) 1868056 "BERGER, JAMES M" Not Applicable 7 PHYSIOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 867394 NCI 529706 337688 ABSTRACTThe appropriate control of DNA topology has a major impact on the stability and flow ofgenetic information. The present application focuses on type II DNA topoisomerasesmolecular machines that modulate DNA supercoiling and remove chromosomeentanglements by catalyzing the ATP-dependent transport of one DNA duplex throughanother. Type II topoisomerases play a frontline role in cancer biology as factors that canboth maintain and disrupt genome integrity; they are also demonstrated drug targets fortreating cancer.Our past research on eukaryotic topoisomerase II (topo II) has opened up new researchavenues for understanding cancer etiology and improving cancer treatment. The presentapplication will deliver groundbreaking solutions to key problems in the field including howcertain classes of anti-topo II drugs act on the enzyme how topo II is localized to key sitesof action where it resolves potentially deleterious chromosomal topologies and howaberrant topo II activity can promote DNA damage and genetic instability. We will alsoinvestigate innovative concepts and highly significant lines of inquiry raised by our newfindings such as how metabolites produced by the TCA cycle control topo II function.Our approach is distinguished by a comprehensive blend of biochemical structuralcomputational cell-based and chemical biology methodologies. High-impact outcomeswill include defining how topo II appropriately localizes with chromatin and partner proteinsto mitigate its natural DNA-damaging potential establishing how the specificity of anti-topoII agents can be improved to enhance their utility in cancer treatment and revealing thepotential for natural amino-acid sequence variation in type II topoisomerases to destabilizehuman chromosomes and act as cancer drivers. Past progress and unpublished findingsestablish the feasibility of our planned goals. 867394 +No NIH Category available Acinar Cell;Age;Animal Model;Biochemical;Biological;Cancer Etiology;Cellular Stress;Cessation of life;Chronic;Development;Disease;EIF-2alpha;Environmental Risk Factor;Etiology;Event;Functional disorder;Gene Mutation;Genes;Goals;High Fat Diet;Human;In Vitro;Inflammation;Inflammatory;Intervention;Investments;Lesion;Life;Link;Malignant neoplasm of pancreas;Mediating;Modeling;Mus;Mutation;Nature;Obesity;Oncogenic;PAR-2 Receptor;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pancreatitis;Pathogenesis;Pathway interactions;Patients;Penetrance;Phenotype;Play;Preventive;Property;Proteinase-Activated Receptors;Recurrence;Regulation;Risk;Risk Factors;Role;SRC gene;Signal Pathway;Signal Transduction;Smoking;TP53 gene;Testing;Therapeutic Intervention;Trypsin;Trypsinogen;acute pancreatitis;autosome;chronic pancreatitis;chymotrypsin C;cigarette smoking;endoplasmic reticulum stress;extracellular;genetic approach;hereditary pancreatitis;high risk;human disease;human tissue;improved;in vivo;inflammatory milieu;insight;mouse model;mutant;novel;pancreas development;pancreatic tumorigenesis;pharmacologic;premalignant;prevent;preventive intervention;protein expression;tool;transcription factor;transcription factor CHOP;transgene expression;tumorigenesis PRSS1 Mutation and Pancreatic Cancer Tumorigenesis Project Narrative: PRSS1 mutations cause human hereditary pancreatitis with high risk of developing to pancreatic cancer.We developed a novel mouse model by expressing a mutant human PRSS1 to study the mechanisms ofpancreatic cancer tumorigenesis. We expect these studies will significantly improve our understanding of thisdisease and provide new insights on interventions. NCI 10691268 8/31/23 0:00 PA-20-185 5R01CA255068-03 5 R01 CA 255068 3 "XU, WANPING" 9/1/21 0:00 8/31/27 0:00 Cancer Etiology Study Section[CE] 7855408 "JI, BAOAN " Not Applicable 5 Unavailable 153223151 GKPBCFV1QMM3 153223151 GKPBCFV1QMM3 US 30.264703 -81.444793 4976105 MAYO CLINIC JACKSONVILLE JACKSONVILLE FL Other Domestic Non-Profits 322241865 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 30693 NCI 19612 11081 Abstract: The 5-year relative survival of pancreatic ductal adenocarcinoma (PDA) patients is only 8%. PDA ispredicted to be the second-leading cause of cancer related death in the U.S. by 2030. Understanding the keysignaling mechanisms of tumorigenesis is critical for developing life-saving interventions. Hereditarypancreatitis (HP) an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) whicheventually develops into chronic pancreatitis (CP) has a cumulative risk of pancreatic cancer of 44% by age70 years. Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Unfortunatelythe development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in ourunderstanding of its pathophysiology which is mainly due to the practical difficulties in obtaining tissues fromhuman pancreas at early stages of the disease and the lack of animal models that recapitulate the human formof this disease. Recently we have developed a novel model of HP by expressing a common mutant of humanPRSS1 (PRSS1R122H) in mice (J Clin Invest. 2020 Jan 2;130(1):189-202). Transgenic expression of mutantPRSS1 caused severe AP which progresses to CP precancerous PanIN lesions and pancreatic cancer. Thismodel of HP will provide us with a powerful tool to fulfill our long-term goal of understanding the initiatingevents of HP and developing specific strategies to prevent its progression to pancreatic cancer. In thisproposal we will use our unique humanized pancreatitis model to test our central hypothesis that etiologicalfactors and PRSS1 gene mutation cooperatively cause pancreatic tumorigenesis by intra-acinar cell stresssignaling pathways and a trypsin receptor-mediated constant inflammatory milieu. We will characterize thesesignaling pathways in this newly developed HP model and investigate their roles in pancreatic cancertumorigenesis by both pharmacological and genetic approaches. We expect these studies will significantlyimprove our understanding of the pathogenesis of HP its progression to pancreatic cancer and provide newinsights for developing/testing novel preventive and therapeutic interventions. 30693 +No NIH Category available 3-Dimensional;Address;Alleles;Architecture;CRISPR/Cas technology;Cell Line;Cells;Chromatin Loop;Communication;Complex;DNA;DNA Methylation;DNA Sequence Alteration;DNA Sequence Rearrangement;DNA methylation profiling;Development;Disease;Distal;Engineering;Enhancers;Event;Gene Activation;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genome;Genome engineering;Goals;Growth;Haplotypes;Heterogeneity;Human;Human Cell Line;Inter-tumoral heterogeneity;Knowledge;Lead;Malignant Neoplasms;Methods;Minority;Modeling;Mutation;Normal tissue morphology;Oncogenes;Patients;Phase;Phenotype;Regulator Genes;Regulatory Element;Reporter;Role;SET gene;Sampling;Structure;Testing;Therapeutic;Variant;cancer cell;cancer genome;cancer subtypes;genetic variant;genome-wide;genomic locus;human disease;individual patient;multiple omics;new therapeutic target;novel;novel strategies;patient prognosis;personalized medicine;programs;promoter;response;risk stratification;tumor;tumor heterogeneity;tumorigenesis Investigating the effects of structural variants on 3D genome organization and gene regulation in cancer genomes NarrativeCancer can be caused by a certain class of DNA mutations called structural variants that break apart DNAthen re-join it incorrectly. This can cause DNA to fold improperly and can contribute to genes being turned oninappropriately; however when and where this leads to altered gene activation is not clear. This proposal willinvestigate when where and how structural variants cause DNA misfolding and inappropriate gene activationin cancer cells. NCI 10691262 8/10/23 0:00 RFA-RM-20-005 5U01CA260700-04 5 U01 CA 260700 4 "FINGERMAN, IAN M" 9/15/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-CB-S(70)R] 9445915 "DIXON, JESSE R" Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 693955 OD 380553 313402 AbstractThree-dimensional genome organization has emerged as a critical component for the proper regulation of geneexpression. Recent years have seen a rapid expansion of the understanding of many of the basic features thatdefine how genomes are organized in space inside of cells including the identification of features such as A/Bcompartments Topologically Associated Domains and chromatin loops. Furthermore there is evidence thatmutations that alter 3D genome organization can contribute to human disease. This is most evident for a classof mutations known as structural variants which includes translocations inversions tandem duplications anddeletions. When these mutations disrupt sequence features that are critical for 3D genome structure such asthe boundaries between Topologically Associating Domains this can lead to enhancer-promoter rewiringchanges in gene expression and phenotypic consequences. Such effects have been observed both in thecontext of germline structural variants that contribute to syndromic disorders of development as well as somaticstructural variants that can lead to cancer. While it has become clear that structural variants can alter 3Dgenome organization and gene expression more recent studies that comprehensively examined structuralvariants and gene expression indicate their relationship is considerably more complex. Specifically in only aminority of instances do structural variants lead to changes in expression of neighboring genes. Therefore whystructural variants can have dramatic consequences on 3D genome structure and gene expression in somecontexts but not others is currently unclear. This proposal will investigate the relationship between structuralvariants 3D genome organization and gene expression in cancer genomes with the goal of understandingwhere and when structural variants will actually lead to changes in gene expression that may contribute tooncogenesis. Specific aim 1 will test whether only specific sets genes are sensitive to structural variant inducedchanges in enhancer-promoter communication by examining changes in 3D genome structure and geneexpression in haplotype resolved human tumor samples. Specific aim 2 will use CRISPR/Cas9 genomeengineering to evaluate the effects of structural variant partner regions on induction of oncogene expression.Specific aim 3 will assess the role of intra-tumor heterogeneity on the effects of structural variants on 3Dgenome structure by using novel multi-omic methods for profiling DNA methylation and 3D genome structuresimultaneously within single cells derived from patient tumor samples. Successful completion of these aims willresult in a deeper understanding of the relationship between structural variation 3D genome organization andgene regulation in the context of cancer genomes. In the long term this will facilitate the use of informationderived from structural variants and 3D genome structure on determining patient prognosis and on identifyingnovel therapeutic targets in cancer. 693955 +No NIH Category available Address;Anxiety;Biological;Biological Specimen Banks;Biology;Biometry;Cancer Patient;Cessation of life;Characteristics;Clinical;Clinical Data;Clinical Management;Cohort Studies;Collection;Communication;Communities;DNA;Data;Databases;Decision Making;Diagnosis;Diet;Disease;Disease Progression;Disseminated Malignant Neoplasm;Eligibility Determination;Ensure;Epidemiology;Financial Hardship;Foundations;Funding;Future;Goals;Grant;Health;Individual;Infrastructure;Institution;Intervention;Left;Life Style;Malignant Neoplasms;Malignant neoplasm of prostate;Medical;Molecular;Monitor;Morbidity - disease rate;Newly Diagnosed;Outcome;Participant;Pathologic;Pathology;Patient-Focused Outcomes;Patients;Pattern;Physical activity;Plasma;Population;Prognostic Marker;Prospective Studies;Prostate;Protocols documentation;Public Health;Quality of life;Randomized;Recommendation;Recurrence;Regimen;Regrets;Research;Research Personnel;Resources;Sampling;Selection Criteria;Serinus;Serum;Specimen;Standardization;Technical Expertise;Testing;Tissues;Translating;Uncertainty;Urine;active method;adverse outcome;anticancer research;biomarker validation;cancer biomarkers;cancer care;cancer diagnosis;cancer epidemiology;cohort;comparative;curative treatments;design;economic evaluation;epidemiologic data;follow-up;improved;lifestyle factors;male;men;mortality;overtreatment;personalized approach;personalized management;preference;prospective;prostate cancer progression;prostate cancer risk;response;risk prediction model;risk stratification;side effect;success;surveillance study;tool;tumor behavior;tumor progression Prostate cancer Active Surveillance Study (PASS) Cohort: Infrastructure Support for Cancer Research PROJECT NARRATIVEThis project will support the infrastructure of the ongoing prospective multi-center Canary Prostate ActiveSurveillance Study (PASS) and will allow for the continued contribution of clinical data and biological samplesto researchers to personalize management of clinically localized prostate cancer. NCI 10691254 8/9/23 0:00 PAR-17-233 5U01CA224255-06 5 U01 CA 224255 6 "MAZURCHUK, RICHARD V" 9/20/19 0:00 8/31/24 0:00 ZCA1-RTRB-4(M1) 2046172 "LIN, DANIEL W." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1277646 NCI 1051918 225728 PROJECT SUMMARY/ABSTRACTWe propose to support the established Prostate cancer Active Surveillance Study (PASS) cohort which is alarge multi-institutional cohort of men with clinically localized prostate cancer who have elected activesurveillance to manage their cancer. With broad eligibility criteria designed to represent the population of menwho utilize active surveillance the cohort has over 2100 participants with extensive clinical andepidemiological data (demographic lifestyle quality of life long-term outcomes) and longitudinal biospecimens(germline DNA serum plasma urine and prostate tissue) collected according to a standardized protocol. Thecohort was established in 2008 in response to the growing evidence of prostate cancer overtreatment and theneed for a prospective study to discover and validate biomarkers of prostate cancer progression and toidentify determinants of cancer progression and patient outcomes. Over the past decade the cohort hasamassed a wealth of data and biospecimens so that it serves as the foundation for addressing criticalquestions relevant to the optimal personalized management of early stage prostate cancer.The successful funding of this application will support a robust infrastructure for PASS that in turn will ensurethe availability of PASS data and specimens to facilitate research addressing determinants of cancerprogression recurrence and outcomes. A substantial proportion of these research endeavors areencompassed in currently funded federal grants and the successful completion of the current and futureprojects relies on the continued success of the PASS enterprise. The impact of this cohort lies in its potential toinvestigate research questions of paramount importance: to identify better prognostic markers of prostatecancer aggressiveness; to understand the clinical management progression and outcomes of early stageprostate cancer; to tailor the approach of active surveillance based on individual characteristics andpreferences; to characterize associations between clinicopathologic factors patient lifestyle and diseasebiology; to develop new tools to communicate medical information to patients; and to understand decision-making among patients on active surveillance in particular with regards to quality of life anxiety and regret .The successful completion of these transformative research endeavors will address unmet needs in the mostcommonly diagnosed male cancer and substantially reduce the current public health burden of early stageprostate cancer. 1277646 +No NIH Category available Address;Adjuvant Therapy;Advocate;Affect;Aftercare;Area;Behavior Therapy;Behavior assessment;Cancer Center;Cancer Control;Cancer Control Research;Caring;Clinical;Clinical Research Associate;Clinical Trials;Clinical Trials Design;Collaborations;Collection;Communities;Community Clinical Oncology Program;Community Physician;Concept Review;Correlative Study;Credentialing;Data;Data Analyses;Data Collection;Data Coordinating Center;Development;Disease;Disparity;Elderly;Ensure;Evidence based intervention;Exposure to;Family;Funding;Gender;Genetic;Goals;Grant;Gynecologic Oncology Group;Health Disparities Research;Health Services Accessibility;Hospice Care;Image;Immunotherapy;Information Technology;Infrastructure;Institution;Intervention;Intervention Trial;Leadership;Localized Malignant Neoplasm;Lymphedema;Malignant Neoplasms;Mentorship;Methodology;Minority;Modality;Modification;Molecular;Monitor;National Cancer Institute;National Clinical Trials Network;National Surgical Adjuvant Breast and Bowel Project;Neurocognitive;Oncology;Outcome;Outcomes Research;Palliative Care;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Phase;Primary Care;Principal Investigator;Quality Control;Quality of life;Radiation Oncology;Radiation Therapy Oncology Group;Radiation therapy;Reporting;Research;Research Personnel;Resources;Risk Reduction;Rural Population;Security;Series;Sex Functioning;Site;Solid Neoplasm;Southwest Oncology Group;Survivors;Symptoms;Testing;Therapeutic Clinical Trial;Therapeutic Trials;Toxic effect;Training;Training Activity;Training Programs;Training and Education;Translational Research;Treatment-Related Cancer;Woman;Women's Health;Work;base;biomarker evaluation;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer risk;cancer therapy;care delivery;care outcomes;clinical imaging;clinical practice;cluster randomized design;community center;cost effectiveness;data integrity;data management;design;disorder risk;effectiveness testing;ethnic minority;evidence base;experience;health disparity;improved;innovation;member;multidisciplinary;next generation;programs;quality assurance;racial minority;screening;survivorship;symptom management;therapeutic evaluation;therapy design;treatment trial;trial design;underserved community NRG Oncology NCORP Research Base NRG Oncology NCORP research will significantly impact cancer prevention screening controland care delivery and bring state-of-the-art treatment trials to community centers where mostcancer treatments are delivered. NRG NCORP will conduct high impact studies for patientswith many types of solid tumors with a particular unique focus in both women's health andcancer control issues related to radiation therapy. To accomplish these aims NRG NCORP willengage fully with community physicians and patient advocates as well as the NCI and NCI-designated cancer centers to collaborate to improve cancer prevention and control cancer careand outcomes and quality of life for patients affected by cancer. NCI 10691227 8/1/23 0:00 RFA-CA-18-015 5UG1CA189867-10 5 UG1 CA 189867 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-GRB-S(M1) 6861630 "BRUNER, DEBORAH WATKINS" "WALKER, JOAN LESLIE" 3 Unavailable 78695317 TUS8D6ZGL9R3 78695317 TUS8D6ZGL9R3 US 39.953571 -75.167569 10033231 "NRG ONCOLOGY FOUNDATION, INC." PHILADELPHIA PA Research Institutes 191032800 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 10848989 NCI 13358416 94580 The objective of this proposal is to establish and maintain the NCORP (National CommunityOncology Research Program) for the NRG Oncology research base. The NRG NCORP is theresult of aligning the legacy CCOPs (Community Clinical Oncology Programs) from three NCICancer Cooperative Groups: NSABP RTOG and GOG. These groups together have overalmost 100 years of combined experience serving as CCOP Research Bases. NRG NCORPcomprised of a multi-disciplinary team of investigators and patient advocates is poised to carryout the objectives of: 1) designing and conducting cancer prevention control and screeningclinical trials; 2) designing and embedding patient reported outcomes in both primary NCOPRtrials as well as NRG therapeutic trials 3) designing and conducting cancer care deliveryresearch; 4) enhancing community access to treatment and imaging trials conducted under theNational Clinical Trials Network (NCTN) and 5) conducting primary intervention trials andintegrating health disparity research questions into cancer care delivery research and treatmenttrials. To allow NRG NCORP to meet these goals the group will: participate fully in NRGOncology leadership and will determine the scientific direction and prioritization of the NRGNCORP activities and resources and oversee the translational research clinical trial activitiesand correlative studies related to the aims of NRG NCORP. With the NRG Statistical and DataManagement Center (SDMC) this team will provide efficient methodologically up-to-date trialdesign with a focus on NCORP specific needs such as patient-reported repeated longitudinalassessments and cluster-randomized designs. NRG NCORP will provide study monitoringreporting and analysis; build an infrastructure to support our cancer care delivery researchagenda; provide comprehensive data management quality control and quality assuranceprograms to ensure high data integrity and timely data for analysis; leverage cutting edgeinformation technology emphasizing security timeliness and efficiency of data collection andmanagement; providing RT credentialing and quality assurance; and provide education andtraining for institutional Clinical Research Associates Study Chairs local Principal Investigatorsand others involved in the NRG NCORP research agenda. Further to accomplish these aimsNRG NCORP will engage fully with NCI-designated NCORP community physicians and patientadvocates as well as the NCI and other NCI-sponsored entities (cooperative groups cancercenters SPOREs) to collaborate across the NCTN to improve cancer prevention and controlcancer care and outcomes and quality of life for patients affected by cancer. 10848989 +No NIH Category available Address;Antibodies;Bar Codes;Behavior;Binding;Biological Models;Cancer Model;Cancer Patient;Cell Line;Cell Survival;Cells;Clinical Trials;Color;Combined Modality Therapy;Complex;DNA;Development;Disease;Drug Targeting;Drug resistance;Epidermal Growth Factor Receptor;FDA approved;Flow Cytometry;Future;Genomics;Heterogeneity;Image;Immune;Immunofluorescence Immunologic;In Situ;Label;MEKs;Malignant Neoplasms;Maps;Measures;Modeling;Monitor;Morphology;Mus;Mutation;Nature;Non-Small-Cell Lung Carcinoma;Optics;Performance;Periodicity;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Plasma;Proteins;Proteome;Proteomics;Protocols documentation;Reagent;Resistance;Resolution;Screening procedure;Signal Pathway;Signal Transduction;Specimen;Technology;Testing;Therapeutic;Tissues;Transgenic Organisms;Treatment Efficacy;Treatment outcome;Tyrosine Kinase Inhibitor;Validation;Western Blotting;Work;Xenograft Model;Xenograft procedure;behavior prediction;cancer therapy;cancer type;candidate identification;clinically relevant;combinatorial;curative treatments;drug distribution;drug standard;fluorescence imaging;imaging agent;imaging platform;improved;in vivo;inhibitor therapy;innovation;kinase inhibitor;mathematical model;molecular targeted therapies;mutational status;novel;patient derived xenograft model;predicting response;prediction algorithm;protein expression;proteomic signature;resistance mechanism;response;small molecule therapeutics;targeted cancer therapy;therapy outcome;therapy resistant;tool;treatment response;treatment strategy;tumor;tumor growth;tumor heterogeneity;tumor xenograft A Novel Fluorescence Imaging Platform to Predict Response to Combinatorial Tyrosine Kinase Inhibitors PROJECT NARRATIVEThe promise of molecularly targeted therapy for cancer patients has largely not been realized due to heteroge-neous resistance mechanisms where targeted monotherapy typically results in short term response not long-term cure. Unraveling the complexities of therapeutic resistance is challenging because it is a complex interplayof drug distribution and target engagement as well as multifaceted and dynamic interactions between the tumorand its microenvironment. We have developed critical new tools (i.e. Therapeutic Response Imaging throughProteomics and Optical Drug Distribution and binding TRIPODD) to quantify therapeutic efficacy and the corre-sponding resistance mechanisms to aid in crafting effective cancer treatment strategies. NCI 10691216 8/25/23 0:00 RFA-CA-21-003 5R21CA257942-02 5 R21 CA 257942 2 "OSSANDON, MIGUEL" 9/1/22 0:00 8/31/25 0:00 ZCA1-TCRB-J(O1) 9739313 "GIBBS, SUMMER LYNNE" Not Applicable 1 BIOMEDICAL ENGINEERING 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 193881 NCI 129631 64250 PROJECT SUMMARYDeregulation of kinase function in cell signaling pathways is implicated in numerous cancers. In response kinaseinhibitors (KIs) have been developed to interact with these kinases for highly specific treatment. Though nearly50 KIs have been FDA-approved KI monotherapy is seldom curative likely owing to tumor heterogeneity andacquired resistance. For example intra-tumoral heterogeneity can result in the treatment of sensitive cell sub-populations while simultaneously promoting the outgrowth of resistant persister cells. In response effectivecombination therapies must be tailored to known resistance mechanisms to efficiently engage with their targetsand exploit cellular vulnerabilities. However standard drug screening tools (e.g. plasma analysis western blot[WB]) are bulk in nature and no established technology exists to quantify KI target engagement concomitantwith local protein expression while assessing tumor response heterogeneity. To address these shortcomingsour group has (1) developed protocols to fluorescently label KIs (and other small molecule therapeutics) thatmimic the native drug (2) advanced a novel intracellular paired agent imaging (iPAI) platform to quantify drugtarget availability (DTA) with these fluorescent KIs and (3) established and validated a highly multiplexed im-munostaining strategy utilizing DNA barcoded antibodies enabling in situ cyclic immunofluorescence (cyCIF)imaging. In this proposal we will combine these three complementary innovations into a fluorescence imagingplatform we call TRIPODD (Therapeutic Response Imaging through Proteomics and Optical Drug Distributionand binding). Herein we will use TRIPODD to demonstrate the capability of iPAI to predict mono- and combina-torial KI drug response and uncover drug resistance mechanisms across whole tumor specimens with single-cell resolution. To achieve this iPAI will be expanded to three-color imaging (i.e. two-drug DTA) while cyCIF willbe applied to monitor proteomic therapeutic response to gain a mechanistic understanding of clinically relevantcombination therapy outcomes. Epidermal growth factor receptor mutation positive (EGFRmut+) non-small celllung carcinoma (NSCLC) which currently lacks curative treatment will serve as our model system. We hypoth-esize that TRIPODDas the first technology capable of comparing drug distribution and binding (iPAI) directlyto proteomic markers (cyCIF) at the cellular levelwill be critical to uncovering salient mechanisms of therapeuticresponse and resistance in NSCLC and ultimately enable tailored therapeutic strategy optimization based onpredictive algorithms. This hypothesis will be tested through the following specific aims: Aim 1: Demonstratethat TRIPODD can quantify targeted KI-monotherapy response. Aim 2: Establish TRIPODD protocols to accu-rately characterize KI-combinatorial therapy outcomes. Successful completion of this proposal will yield an opti-mized fluorescence imaging toolbox (TRIPODD) that will provide an unprecedented view of the spatial correla-tions between drug distribution/binding (iPAI) and the underlying tumor/microenvironment proteome (cyCIF)enabling mechanistic understanding of NSCLC treatment strategies. 193881 +No NIH Category available Acetates;Acute;Address;Adverse effects;Androgen Receptor;Androgens;Anemia;Angelica;Animal Cancer Model;Animal Model;Animals;Area Under Curve;Behavior;Biochemical;Biological Availability;Biological Markers;Blood;Cancer Burden;Cancer Patient;Cannabis;Caring;Castration;Cells;Chronic;Clinic;Clinical;Cytochrome P450;DNA Repair;Data;Decision Making;Disease;Disease Progression;Dose;Drug Kinetics;Drug Targeting;FDA approved;Face;Failure;Fatigue;Fish Oils;Food;Food Interactions;Fracture;Frequencies;Future;Goals;Gynecomastia;Half-Life;Health;Herbal supplement;Hot flushes;Human;IL8 gene;Immune;Immunologic Markers;Immunologic Surveillance;Immunophenotyping;Immunosuppression;Impotence;Inflammation;Inflammatory;Intercept;Knowledge;Koreans;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Medical Castration;Memory;Memory Loss;Messenger RNA;Metabolic;Microtubules;Modality;Mus;Nature;Oncology;Oral;Osteoporosis;Outcome;PSA level;Pain;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Pharmacogenetics;Phase;Phase I Clinical Trials;Phase I/II Trial;Plasma;Poly(ADP-ribose) Polymerase Inhibitor;Prevention;Prostate;Prostate Cancer therapy;Prostate-Specific Antigen;Publishing;Radiation therapy;Radical Prostatectomy;Randomized Controlled Trials;Raspberries;Recommendation;Recurrence;Reporting;Rodent;Safety;Secondary Prevention;Secondary to;Sexual Dysfunction;Signal Transduction;Tea;Testing;Therapeutic;Time;Tissues;Toxic effect;abiraterone;androgen deprivation therapy;anti-cancer;cancer recurrence;chemokine;cohort;curative treatments;cytokine;design;disorder prevention;dosage;efficacy evaluation;efficacy outcomes;enzalutamide;genetic signature;human study;human subject;in vivo;lean body mass;mortality;novel;patient population;pharmacodynamic biomarker;prevent;problem drinker;prostate cancer model;receptor;response;safety outcomes;side effect;soy;taxane Early clinial trials for Angelica herbal supplements for prostate cancer interception NarrativeThese early stage clinical trials take advantage of a niche prostate cancer patient cohort who have failed localcurative therapies to address a significant unmet clinical need in a sizable recurrent cancer patient populationwho would otherwise soon face androgen deprivation therapy (ADT) through medical or surgical castration. Notonly expensive ADT also causes many serious and unpleasant side effects including sexualdysfunction/impotence osteoporosis and bone fractures mode swings hot flashes fatigue loss of lean bodymass gynecomastia and anemia. In spite of multiple next-gen androgen and its receptor targeted drugs (e.g.abiraterone acetate enzalutamide) DNA-repair drugs (PARP inhibitors) and microtubule targeting taxane drugsindicated for managing more advanced stage diseases there is currently no FDA-approved modality before ADTto intercept or delay disease progression in the clinic practice. The trials will provide the first of its kind knowledgeof safety and preliminary efficacy of an AGN herbal supplement against prostate cancer at therapeutic dosageswith mechanisms of action distinct from the currently approved drugs and more favorable safety profiles. Thenovel dose-exposure pharmacokinetics and pharmacogenetics information from these trials will be applicable toother patient populations to evaluate prevention and therapy of other cancers as well as other diseases sinceAGN supplements have been sold for memory health and pain killing for nearly 2 decades. NCI 10691215 9/7/23 0:00 PAR-21-035 5R01CA260901-02 5 R01 CA 260901 2 "RISCUTA, GABRIELA" 9/1/22 0:00 8/31/27 0:00 Cancer Prevention Study Section[CPSS] 1866783 "LU, JUNXUAN " "JOSHI, MONIKA " 10 PHARMACOLOGY 129348186 TNKGNDAWB445 129348186 TNKGNDAWB445 US 40.264414 -76.674014 1524204 PENNSYLVANIA STATE UNIV HERSHEY MED CTR HERSHEY PA SCHOOLS OF MEDICINE 170332360 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 575924 NCI 346942 228982 PROJECT SUMMARYThe slow growing nature of most prostate cancers (PCa) provides multiple windows of opportunity to block ordelay disease progression to significantly reduce patient suffering and mortality. This is especially true followingthe failure of radical prostatectomy (RP) and radiation therapy (RT) of PCa prior to androgen deprivation therapy(ADT; i.e. medical or surgical castration). Biochemical recurrent PCa is sensitively indicated by rising bloodprostate specific antigen (PSA). ADT is not curative and causes many serious adverse effects. Our goal is todevelop Angelica gigas Nakai (AGN Korean Angelica) root ethanolic extract or its constituent(s) as a safer andpractical modality for PCa interception akin to secondary prevention to delay ADT or avoid it entirely. Wehypothesize that (1) the PCa interception efficacy of AGN and its pyranocoumarins in animal models isextendable into human PCa patients given sufficient AGN dosage and exposure duration; (2) multiplemechanisms including immune surveillance and suppression of inflammation contribute to the clinical cancerinterception activity. The scientific premise is based on the presence of novel active pyranocoumarin compoundsdistinct from those in soy tea fish oil raspberries mushrooms and cannabis and reported broad spectrum anti-cancer efficacy in animal cancer models. Moreover we have demonstrated a) Oral bioavailability and favorablepharmacokinetic (PK) metrics in rodents and in humans; b) Cytochrome P450 (CYP) 2C19 and 3A4 first-passconversion of pyranocoumarins decursin (D) and decursinol angelate (DA) to their metabolite decursinol (DOH);c) Proficient tissue retention of decursinol in mouse target prostate; d) Animal modeling of AGN and decursinolshowing independence of the androgen receptor axis avoiding side effects of ADT drugs and making blood PSAa reliable readout for cancer burden; e) AGN enhanced immune and decreased inflammatory gene signaturesin an animal PCa model; and f) A single AGN dose in human subjects increased natural killer [NK] mRNAsignature and decreased IL-8 chemokine mRNA in their peripheral blood mononuclear cells. We propose 3specific aims in post-RP and post-RT patients with rising plasma PSA that is clean (due to prostate alreadyremoved) and indicative of the biochemical recurrent PCa burden. Aim 1. Characterize pyranocoumarin PK doseresponse proportionality to AGN supplement and food effects in 12 patients to probe any metabolic ceiling andminimize food-herbal interaction. Aim 2. Evaluate safety and recurrent PCa (PSA)-interception efficacy of twicedaily AGN supplement in a Phase I/II trial with 36 patients. Aim 3. Measure acute- and repeated-dose PK metricsCYP 2C19 and 3A4 metabolizer status and changes of immune and inflammation biomarkers to correlate to PSAoutcomes. Impacts: The safety information and a favorable PSA response will guide future randomized controltrials to prevent or treat PCa and other cancers. The novel knowledge on PK dose response repeated dose PKbehavior CYP pharmacogenetics and the immune biomarkers not only fills in critical gaps for AGN supplementsin cancer patients but also is exportable to disease prevention and therapy beyond oncology. 575924 +No NIH Category available Applications Grants;Cancer Center;Development;Ensure;Extramural Activities;Faculty;Fostering;Funding;Future;Goals;Grant;Institution;Measures;Monitor;Paper;Patient Care;Peer Review;Pilot Projects;Procedures;Process;Program Development;Progress Reports;Publications;Research;Research Personnel;Research Project Summaries;Resources;Review Committee;Skin Cancer;Skin Carcinoma;The Wistar Institute;Underrepresented Minority;Woman;Writing;anticancer research;cancer research center director;expectation;high standard;interest;melanoma;minority scientist;programs;recruit;research and development;research study;success Developmental Research Program Project Narrative Developmental Research ProgramThe Development Research Program of the Wistar/UPenn SPORE will promote translational melanoma and skincancer research by providing a mechanism for stimulating grant applications for pilot projects. The applicationsgo through committee review with formal procedures for monitoring progress and ensuring integration within theSPORE. Pilot projects have a potential to make a large impact on melanoma and skin cancer patient care oncethey advance to full projects or to externally-funded grants. NCI 10691207 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7 6852 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 83039 46499 36540 Project Summary Developmental Research ProgramIn the previous cycle the Wistar/UPenn SPORE Development Research Program (DRP) was led by Dr. RobertVonderheide who has since become the Cancer Center Director of the Abramson Cancer Center. The DRPrecruited a diverse array of investigators from many fields into melanoma and skin cancer research. The resulthas been an outstanding number of high impact papers extramural grants and two projects graduating from theDRP into full projects in this application. Building on this success Dr. Meenhard Herlyn and Dr. Ravi Amaravadithe co-Directors of this SPORE grant will serve as DRP co-Directors in the new cycle. The overall goals of theDRP in the new grant period remain to advance high quality research foster new ideas and move researchstudies from pilot to project status. A second goal of the DRP is to create opportunities for the scientificdevelopment of junior faculty or senior investigators who are interested in transitioning into skin cancer research.Our approach is summarized in 2 specific aims and is enabled by a strong commitment for an exceptional levelof institutional support from The Wistar Institute and UPenn. The DRP will in particular welcome projects onnon-melanoma skin cancers and topics not covered by the funded full Projects. Aim 1 is to attract select andfund the most outstanding proposals with significant potential to benefit the Skin Cancer SPORE andtranslational skin cancer research. Specific research projects are summarized that represent all cancers of theskin. Aim 2 is to support and integrate the selected pilot projects into the SPORE program with establishedprocesses to review and monitor progress. Women and underrepresented minorities will be strongly encouragedto participate. The DRP has a transparent peer-reviewed selection process that incorporates defined criteria forfunding decisions. We require that DRP awardees be active in SPORE functions use the SPORE Core resourceand provide formal written progress reports. Within the context of the DRP we have established high standardsand expectations of the investigators and have established a formal process to review and monitor progress offunded pilot projects. The Program measures success by publications extramural funding stimulating new aimsin existing SPORE Projects and elevation to full projects for the future. +No NIH Category available Agonist;Biological;Biological Assay;Biology;Blocking Antibodies;Blood;Cell Communication;Cells;Cellular biology;Clinical;Clinical Research;Clinical Trials;Cutaneous Melanoma;Data;Defect;Dendritic Cells;Development;Disease;Distant;Future;Gatekeeping;Genetic Transcription;Goals;Health;Hematogenous;Hematogenous Spread;Human;Immune;Immunity;Immunologic Surveillance;Immunologics;Immunophenotyping;Immunotherapy;Investigation;Leadership;Localized Disease;Lymphatic;Lymphatic Metastasis;Lymphatic Spread;Lymphatic System;Macrophage;Malignant Neoplasms;Metastatic Neoplasm to Lymph Nodes;Modeling;Mus;Myelogenous;Myeloid Cells;Neoadjuvant Therapy;Neoplasm Metastasis;Operative Surgical Procedures;Organ;Outcome;PD-1 blockade;Pathogenesis;Pathologic;Patients;Phase II Clinical Trials;Pliability;Population;Positive Lymph Node;Primary Neoplasm;Productivity;Randomized;Recurrence;Recurrent disease;Research Design;Research Personnel;Role;Sampling;Sentinel Lymph Node;Shapes;Skin;Skin Cancer;Surveys;T-Lymphocyte;Testing;Tissues;Tumor Antigens;Tumor Burden;Tumor Tissue;Work;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;anti-tumor immune response;antigen-specific T cells;cancer cell;cancer infiltrating T cells;clinical effect;clinical practice;clinical risk;clinically significant;cohort;design;draining lymph node;exhaust;exhaustion;high risk;humanized mouse;immune health;immune resistance;improved;improved outcome;instructor;lymph nodes;melanoma;mortality;mouse model;novel;patient derived xenograft model;pembrolizumab;peripheral blood;phase II trial;pre-clinical;prevent;resistance mechanism;response;restraint;sensor;survival outcome;therapy resistant;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Neoadjuvant immunotherapy approaches to early stage melanoma Project Narrative Project 3Patients with high-risk Stage II melanoma have an unacceptably high mortality rate with surgical treatment alone.In this study we will test the hypothesis that neoadjuvant immunotherapy can be used to reshape the tumormicroenvironment in the draining lymph node to limit or eradicate the disseminated malignant cells thusincreasing cure rates. We will determine the clinical and immunological impact of neoadjuvant anti-PD1 antibodytherapy in high risk clinical Stage II melanoma and identify new rational combinations for high-risk Stage IImelanoma. NCI 10691206 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7 6851 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 440937 353308 87629 Project Summary Project 3There is an unmet need to improve the survival of patients with high-risk Stage II melanoma. Currently thetreatment for Stage II melanoma is surveillance despite unacceptably high recurrence and mortality ratesobserved with surgery alone. The sentinel lymph node (SLN) is the first lymph node drained by a primary tumorand is not only a target for metastasizing cancer cells but also an immunological sensor of tumor antigensreleased by primary cutaneous melanoma. Our preliminary data in a draining lymph node (LN) metastasis modelshows striking increases in myeloid cell populations prior to and during melanoma metastasis to the LN. Wepropose that these changes in the LN may compromise its ability to act (i) as a gatekeeper to prevent melanomaspread via the lymphatics and (ii) as an instructor of antigen-specific T cell immunity capable of controlling localdisease and intervening on hematogenous spread. Thus our overall hypothesis is that the capacity of theSLN to protect against locoregional and distant melanoma spread is dependent on its immune healthwhich is pliable and determined by the immunostimulatory capacity of lymph node-resident myeloidcells. In Aim 1 Drs. Karakousis (Clinical co-Project Leader (PL)) and Schuchter (co-Investigator (I)) will conductan investigator-initiated Phase II clinical trial of neoadjuvant pembrolizumab in clinical Stage IIB/C melanoma.Using primary tumors and sentinel LNs (SLN) from both this clinical trial and stage-matched historical cohortswe will determine the effects of immunotherapy on the immunophenotype and anti-metastatic capacity of theSLN. We will use a combination of unbiased global profiling strategies pioneered by Dr. Wherry (co-I) andhypothesis-driven approaches guided by our discoveries into the role of macrophages in preparing the metastaticniche (Beatty Applied co-PL) to determine therapy-associated changes in SLN-positive and -negative patients.Studies in syngeneic models will then inform the role of myeloid cell subsets in directing changes in LN biologytriggered by melanoma development and their impact on anti-PD1 therapy. Aim 2 will test the hypothesis thatthe immunostimulatory capacity of lymph node dendritic cells determines the likelihood of response to anti-PD1therapy. Under the leadership of co-PLs Drs. Herlyn and Beatty we will use multiplex tissue- and cell-basedassays to analyze samples collected from our Phase II trial and stage-matched historical controls with the goalto define T cell interactions with myeloid cells including dendritic cells and their impact on treatment responseand clinical outcomes. In addition we will determine if clinically-available TLR agonists can enhance theimmunostimulatory capacity of the draining LN and in doing so improve the efficacy of anti-PD-1 therapy usinghumanized mice challenged with patient-derived xenografts which model early stage melanoma with high fidelity.Impact: We anticipate neoadjuvant immunotherapy will substantially reduce SLN positivity rates warranting futurerandomized studies designed to change clinical practice. We expect to identify the SLN as an importantdeterminant of melanoma pathogenesis and clinical outcomes to immunotherapy. +No NIH Category available Address;Affect;Antineoplastic Agents;Attention;Autophagocytosis;BRAF gene;Biological Markers;Biopsy;Biotechnology;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Chemicals;Chloroquine;Clinic;Clinical;Clinical Research;Clinical Trials;Collaborations;Data;Dendritic Cells;Development;Effectiveness;Future;Generations;Genetic;Glean;Goals;Histologic;Hydroxychloroquine;Imaging technology;Immune;Immune checkpoint inhibitor;Immunity;Immunologic Tests;Immunotherapeutic agent;Immunotherapy;Impairment;In Vitro;Institution;Interferon Activation;Interferons;Knockout Mice;Knowledge;MEK inhibition;Macrophage;Macrophage Activation;Malignant Neoplasms;Measures;Modeling;Molecular Target;Mus;Myelogenous;Myeloid Cells;Nivolumab;Pathway interactions;Patients;Phase I/II Trial;Phenotype;Plasma;Positron-Emission Tomography;Pre-Clinical Model;Proteome;Refractory;Regimen;Resistance;Safety;Sampling;Series;Signal Transduction;Skin Cancer;Specificity;Systems Biology;T-Lymphocyte;Techniques;Testing;Treatment Protocols;Tumor-associated macrophages;Tumor-infiltrating immune cells;Work;anti-CTLA4;anti-PD-1;anti-PD1 antibodies;cancer cell;cell type;checkpoint inhibition;chemotherapy;clinical investigation;clinically relevant;drug development;genetic analysis;improved;in vivo;inhibition of autophagy;inhibitor;ipilimumab;lysosomal proteins;melanoma;mouse model;mutant;neoplastic cell;new therapeutic target;next generation;novel;novel strategies;novel therapeutic intervention;pre-clinical;preclinical study;preclinical trial;randomized trial;resistance mechanism;response;response biomarker;targeted treatment;therapy resistant;thioesterase PPT1 gene product;tumor;tumor growth;tumor microenvironment Targeting autophagy to enhance immune checkpoint inhibition Project Narrative Project 2We have identified autophagy to be a major mechanism of resistance to melanoma therapy and an attractivetarget for new drugs in melanoma and other cancers. This proposal will address a major unanswered question:Can targeting autophagy enhance the effectiveness of immunotherapy in melanoma? Knowledge gleaned fromthis work will provide a fundamental understanding of how autophagy inhibition can improve the response rateof immunotherapy and should lead to development of a potentially new treatment regimen for advancedmelanoma patients that could improve survival in future clinical trials. NCI 10691205 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7 6850 8183362 "AMARAVADI, RAVI K" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 449729 449729 0 Project Summary Project 2A new approach that can overcome resistance to immune checkpoint inhibition (ICI) is a major unmet need forStage IV melanoma patients. The overall goal of this project is to determine if combined ICI with autophagyinhibition can address this unmet need. Autophagy is a key resistance mechanism to chemotherapy and targetedtherapy. More recently our work and the work of others has implicated autophagy as a resistance mechanism toimmunotherapy. This raises a number of questions about which is the best approach to target autophagy and inwhich cell types is it most critical to target autophagy within the tumor microenvironment. This project willleverage deep collaborations with emerging biotechnology companies that have developed next generationchemical lysosomal and non-lysosomal autophagy inhibitors that are headed to the clinic. The following aims willtest our overall hypothesis that lysosomal autophagy inhibition results in focused cellular pathway perturbationsin cancer cells and immune cells that enhance the efficacy of ICI: Specific Aim 1 will determine the mechanismby which novel clinical grade autophagy inhibitors modulate tumor-immune interactions during ICI focusing oneffects on myeloid tumor T cell and other immune cell phenotypes. We will compare the ability of each of theseinhibitors to augment combined anti-PD-1 and anti CTLA-4 Ab in clinically relevant mouse models. We will focuson PPT1 a lysosomal thioesterase that regulates autophagy and the major molecular target of chloroquinederivatives and an exciting new target for cancer drug development. We will utilize our novel conditional Ppt1KO mouse model to compare the effects of ICI combined with Ppt1 KO in tumor cells dendritic cells and myeloidcells and compare genetic inhibition to chemical Ppt1 inhibition on melanoma tumor growth. In Specific Aim 2will determine changes in immunoprofiles of the TME in patients and preclinical models treated with combinedICI and autophagy inhibition. We will conduct the LIMIT melanoma trial an adaptive phase I/II trial of nivolumab+ HCQ and nivolumab + ipilimumab + HCQ in Stage IV melanoma patients. Novel PET imaging technologieswill be used to track CD8+ T-cells in tumors and correlate CD8+ signal with histological CD8+ analysis andclinical response. In related pre-clinical mouse studies we will use unbiased approaches to achieve acomprehensive view of changes in melanoma tumors treated with ICI and HCQ or ICI and DC661 during earlyresponse and resistance. Impact: Our study will identify the mechanism by which autophagy inhibitors modulatethe TME while providing the preclinical rationale for launching next generation clinical trials using novelautophagy inhibitors more potent and specific than HCQ in ICI combination regimens. Our clinical trial will providevaluable safety and clinical activity data that will also guide the development of more potent and specificautophagy inhibitors. +No NIH Category available Academia;Biological Assay;Biological Markers;Blood;CD8-Positive T-Lymphocytes;Cell physiology;Cell secretion;Circulation;Clinical;Coculture Techniques;Combined Modality Therapy;Data;Development;Diameter;Dimensions;Encapsulated;Foundations;Future;Goals;Immune checkpoint inhibitor;Immunologics;Immunosuppression;Immunotherapy;In Vitro;Individual;Industry;Infrastructure;Institution;Intervention;Knowledge;Lipids;Macrophage;Measurement;Measures;Mediating;Melanoma Cell;Metastatic Melanoma;Methods;Mus;Mutation;Myeloid Cells;Nature;Nivolumab;Outcome;Patient Selection;Patient-Focused Outcomes;Patients;Plasma;Play;Prediction of Response to Therapy;Proliferating;Resistance;Role;Sampling;Sensitivity and Specificity;Series;Skin Cancer;System;T cell infiltration;T-Cell Proliferation;T-Lymphocyte;Testing;Therapeutic;Time;Toxic effect;Tumor Promotion;Tumor Tissue;Tumor-associated macrophages;Validation;Vesicle;Work;alternative treatment;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;biomarker development;cancer type;checkpoint inhibition;clinical application;clinical decision-making;clinical development;clinical diagnostics;clinical practice;clinically relevant;exhaustion;exosome;experimental study;extracellular;humanized mouse;immune checkpoint;immune resistance;improved;improved outcome;interest;ipilimumab;liquid biopsy;melanoma;mouse model;nanosized;neoplastic cell;novel;novel therapeutic intervention;patient derived xenograft model;patient response;patient stratification;pembrolizumab;personalized immunotherapy;predicting response;predictive marker;prevent;programmed cell death ligand 1;programmed cell death protein 1;responders and non-responders;response;tool;treatment optimization;tumor;tumor growth;tumor progression Targeting exosomal PDL1 to improve immunotherapy Project Narrative - Project 1Despite the recent progress in immune checkpoint inhibition (ICI)-based therapies the patient response rate islow. Rationale-based biomarker development is urgently needed to stratify responders and non-respondersthereby providing decision-enabling information to clinicians and patients. The study of tumor- and macrophage-derived exosomes proposed in this application will unveil novel mechanisms of immune suppression and helpdevelop a quantitative liquid biopsy-based tool that enables clinicians to predict patient response to ICI-basedtherapies. NCI 10691204 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7 6849 6668203 "GUO, WEI " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 413618 413618 0 Project Summary - Project 1Immune checkpoint inhibitors (ICI) such as anti-PD-1 antibodies have revolutionized anti-tumor therapy for manytypes of cancers including metastatic melanoma. However the patient response rates are low. Combinedtherapies such as ipilimumab and nivolumab produce a higher response rate but are associated with significanttoxicities. A major unmet need is to develop quantitative assays that stratify patients who will respond to anti-PD-1 therapy to avoid unnecessary toxicities and direct non-responders to alternative treatments. Such a pre-treatment or early on-treatment predictor would provide decision-enabling information to clinicians to optimizethe treatment of melanoma patients. While there is enormous interest and intensive efforts from both academiaand industry to identify predictors to response to ICI the current biomarkers are suboptimal and early on-treatment biomarkers are not available for any cancer types. Exosomes are nano-sized vesicles secreted bycells to the extracellular milieu. We found that metastatic melanoma cells secrete exosomes enriched with PD-L1 which suppress the function of CD8+ T cells in circulation and facilitate tumor growth. In patients plasma thelevel of circulating exosomal PD-L1 (exPD-L1) and its change during the course of anti-PD-1 treatment areassociated with the patient response to anti-PD-1 therapy (Chen et al. Nature 2018). Most recently we foundthat tumor associated macrophages (TAM) also secrete exosomes that carry PD-L1 (TAM-exPD-L1) whichcan be selectively and quantitatively measured in patient blood. TAM exosomes effectively suppress theproliferation and function of CD8 T cells. The overarching goals of Project 1 are to develop a quantitative liquidbiopsy-based tool that enables clinicians to predict the patient response to ICI-based therapies and tounderstand the role of TAM-derived exosomes in immune suppression. In Aim 1 we will test the hypothesis thatexPD-L1 and especially TAM-exPD-L1 individually or in combination are effective predictors of patientresponse to ICI. We perform the assays using a large multi-institutional validation set of patient samples acrossdifferent major therapeutic contexts taking advantage of the unique infrastructure SPORE offers. In Aim 2 wewill systematically investigate the pivotal roles of TAM-derived exosomes in immune suppression usingmelanoma-macrophage co-culture system humanized mouse system and exosomes purified directly frompatient tumor tissues. Together our work will establish exosomal PD-L1 as a rationale-based clinically relevantstratifier that warrants future development for clinical diagnostics. The proposed study will also unveil a role ofTAM exosomes in immune suppression which will not only advance our understanding of immune suppressionat new dimensions but also helps develop novel therapeutic approaches to improve the treatment of patientswith melanoma. +No NIH Category available Abramson Cancer Center at the University of Pennsylvania;Address;Archives;Area;Big Data;Bioinformatics;Biological Markers;Biometry;Biostatistics Core;Biostatistics Shared Resource;Clinical Research;Clinical Trials;Collaborations;Data;Data Discovery;Data Set;Development;Ensure;Environment;Epidemiology;Evaluation;Experimental Designs;Faculty;Foundations;Human Resources;Individual;Knowledge;Laboratory Study;Manuscripts;Measurement;Methodology;Methods;Pathology;Patient Care;Play;Preparation;Publications;Randomized;Reporting;Research;Research Activity;Research Design;Research Methodology;Research Personnel;Research Project Grants;Role;Sample Size;Skin Cancer;Solid;Source;Statistical Data Interpretation;Statistical Models;Testing;The Wistar Institute;bioinformatics infrastructure;career;data management;design;experience;experimental study;meetings;melanoma;member;programs;public database;research study;study population;success Biostatistics and Bioinformatics Core Project Narrative Biostatistics and Bioinformatics Core CCollaboration between the Biostatistics and Bioinformatics Core and the research investigators conductingSPORE-related studies will insure that the SPORE research studies will have strong bioinformaticsinfrastructure high quality study designs and tailored statistical analysis plans that will provide a solid foundationfor each studys conclusions. This will ensure Scientific Rigor and enhance the impact of discoveries on the careof patients with melanoma and other skin cancers. NCI 10691203 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7 6848 2403294 "GIMOTTY, PHYLLIS A." Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 235628 235628 0 Project Summary Bioinformatics and Biostatistics Core CThe Biostatistics Core has been an integral part of the first Wistar/UPenn SPORE in Skin Cancer (2001-2009;2014-2019). Core C functionality and interaction with skin cancer researchers on both campuses has remainedintact throughout the last 19 years resulting in many high impact publications reporting key advances inmelanoma. To meet the changing needs of the Projects and anticipated needs of the Pilot Programs Core Chas become the Biostatistics & Bioinformatics Core. Core C key personnel will continue to play a critical role inthe statistical design statistical analysis and dissemination of research results for all experimental and clinicalstudies defined within the Projects as well as the Career Enhancement Program (CEP) and DevelopmentalResearch Programs (DRP) research activities. The members of this core include two senior biostatisticians anda bioinformatician who have complementary expertise extensive collaborations with SPORE investigatorsknowledge of new developments in biostatistical and bioinformatics methods and their application to researchproposed in the SPORE and an extensive publication record that reflects their expertise in melanoma and otherskin cancers. The biostatisticians are members of the Division of Biostatistics of the Department of Biostatisticsand Epidemiology and are part of the Biostatistics Shared Resource of the Abramson Cancer Center at theUniversity of Pennsylvania. The bioinformatician is a faculty member of the Wistar Institute. The Biostatistics andBioinformatics Core key personnel will provide expertise and experience in five key areas. The first is to providea robust computational and data management environment for datasets developed by the research projects andthe Biospecimen and Pathology Core (Core B). The second is to provide expertise on research methodologiesto design and implement rigorous laboratory studies biomarker studies and clinical trials. The third is to provideexpertise on statistical methodologies critical to each research project. These activities include plans for the datapreprocessing and analysis for big data discovery studies testing proposed statistical hypotheses as well as thedevelopment of statistical models. The fourth is to conduct evaluations of different methodologies to identify themost effective approach developing new methods when standard methods are not appropriate and to conductdiscovery studies using archived public databases relevant to the research projects. The fifth is to provide expertinterpretation of research data and collaboration with Project investigators to make scientifically and statisticallyappropriate statements as well as to assist in the preparation of scientific abstracts presentations andmanuscripts. All of the Core C key personnel have played a major role in designing the Projects in this SPOREapplication and expect to play an instrumental role in the success of the next cycle. +No NIH Category available Acceleration;Advisory Committees;Advocate;Award;Cancer Center;Cementation;Clinical Trials;Collaborations;Collection;Communication;Country;Development;Ensure;Environment;Faculty;Fostering;Funding;Goals;Grant;Guidelines;IACUC;Infrastructure;Institution;Institutional Review Boards;Leadership;Patient Care;Patients;Pilot Projects;Policies;Progress Reports;Recording of previous events;Regulation;Research;Research Personnel;Resource Allocation;Resource Sharing;Retirement;Role;Running;Series;Services;Site;Skin Cancer;Structure;Talents;Technology;The Wistar Institute;Translational Research;Vertebrates;Work;career;conflict resolution;data sharing;design;experience;human subject;lectures;meetings;melanoma;member;organizational structure;programs;symposium;webinar Administrative Core Project Narrative Core AThe overall goal of the Administrative Core is to provide the administrative structure for the efficient and fairreview and allocation of resources scientific and regulatory oversight and to act as a conduit for the rapidexecution of SPORE goals. Core A will facilitate the sharing of resources the communication between theinvestigators and provide oversight for the awarding of career enhancement and pilot awards. This Coreincludes a clinical trials advisory committee specifically designed to accelerate the pace of translationalresearch a key objective of this SPORE proposal. NCI 10691201 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7 6846 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 193575 130482 63093 Project Summary Core AThe essential services provided by the Administrative Core include:Administrative support for all the investigatorsin each Project and Core fiscal management and oversight for all components of the Program Project andorganization and communication of all SPORE meetings and activities. The overall goal of this Core is efficientstewardship of the SPORE. The roles of the Administrative Core co-Directors and administrative staff are tofacilitate communication while stimulating scientific and technological interactions. This will be achieved by 1)Establishing an administrative structure to provide support and management for all Projects Cores and PilotProject activities 2) Fostering collaborative research and 3) Ensuring compliance with regulatory andgovernmental guidelines. Overall The Administrative Core A of this SPORE is designed to provide scientificleadership effective communication and an administrative support structure to ensure the coordination of allSPORE activities. +No NIH Category available Acceleration;Address;Adjuvant;Antibody Therapy;Autophagocytosis;BRAF gene;Biological;Biological Assay;Biological Markers;Blood;CD8-Positive T-Lymphocytes;Cancer Patient;Clinical;Clinical Investigator;Clinical Management;Clinical Trials;Collaborations;Combination immunotherapy;Cutaneous T-cell lymphoma;Data;Death Rate;Dendritic Cells;Development;Disease;Disease Progression;Disease regression;Dose;Drug Design;Early treatment;Funding;Genetic;Genomics;Immune;Immune checkpoint inhibitor;Immune response;Immunologics;Immunotherapeutic agent;Immunotherapy;Impairment;In complete remission;Institution;Intervention Trial;Knowledge;Leadership;Learning;Life;Lymphoma cell;Macrophage;Malignant Neoplasms;Measurement;Medicine;Mentors;Merkel cell carcinoma;Mission;Molecular Target;Nature;Neoadjuvant Therapy;Nivolumab;Operative Surgical Procedures;Pathologic;Pathway interactions;Patient Selection;Patients;Peripheral;Prediction of Response to Therapy;Recording of previous events;Refractory;Regimen;Reporting;Research;Research Design;Research Personnel;Resources;Scientist;Sensitivity and Specificity;Series;Skin;Skin Cancer;Skin Carcinoma;T-Lymphocyte;The Wistar Institute;Therapeutic;Toxic effect;Translating;Treatment-related toxicity;Tumor Bank;Tumor-associated macrophages;Work;anti-PD1 antibodies;anti-PD1 therapy;base;bench to bedside;career;cell killing;checkpoint inhibition;cohort;design;disorder risk;effective therapy;exosome;experience;high risk;improved;industry partner;inhibition of autophagy;inhibitor;innovation;insight;ipilimumab;melanoma;mutant;neoplastic cell;novel;novel drug combination;novel strategies;novel therapeutic intervention;pembrolizumab;pre-clinical;preclinical study;predicting response;predictive marker;programmed cell death ligand 1;programs;response;response biomarker;side effect;skin squamous cell carcinoma;targeted treatment;treatment response;tumor microenvironment;tumor progression;tumorigenic SPORE in Skin Cancer Project Narrative OverallDespite major advances the death rate from skin cancer remains unacceptably high. In this proposal 3 Projectsaddress the challenges of immunotherapy in melanoma by identifying predictors of response to therapy novelcombinations of drugs designed to enhance response new approaches to the timing of therapy administrationand the examination of novel tumor microenvironments and their effect on therapy response. This SPOREs 3Cores and Developmental Programs are designed to bring together clinical investigators and basic scientists inhighly translational efforts to accelerate the pace of therapy for patients suffering from melanoma and other skincancers including cutaneous squamous cell carcinoma (cSCC) cutaneous T cell lymphoma (CTCL) or Merkelcell carcinoma. NCI 10691200 8/23/23 0:00 PAR-18-313 5P50CA261608-03 5 P50 CA 261608 3 "KUZMIN, IGOR A" 9/3/21 0:00 7/31/26 0:00 ZCA1-RPRB-7(M1)P 2795105 "HERLYN, MEENHARD F" "AMARAVADI, RAVI K" 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 2186705 NCI 1962903 223802 Project Summary OverallThis Wistar/UPenn Skin SPORE represents a highly successful and longstanding collaboration. Immunecheckpoint inhibition has revolutionized melanoma therapy to the point where every high-risk melanoma patientwill be treated at some point with these agents. However many major questions remain on how best to usethese immune therapeutics. Project 1 will address the unmet need to find an effective biomarker to selectpatients for single agent versus combination immunotherapy. Many patients start treatment with ipilimumab andnivolumab when they may have responded to anti-PD-1 antibody (Ab) alone exposing these patientsunnecessarily to the toxicity of combination checkpoint inhibition. Project 1 builds on a fundamental discoverymade through our Developmental Research Program (DRP) that exosomal PD-L1 is an immunosuppressivefactor secreted by melanomas. We propose rigorous clinical utility studies designed to demonstrate this blood-based measurement as a highly sensitive and specific predictive biomarker for anti-PD-1 antibody (Ab)-basedtherapy. Project 2 will address a second unmet need for a safer and effective combination regimen that promisesto be effective in anti-PD-1 Ab refractory patients. Based on extensive preclinical data and a new moleculartarget in the autophagy pathway we have developed a clinical trial of combined anti-PD1 Ab and autophagyinhibition a new strategy for reprogramming tumor-associated macrophages to enhance the efficacy of T cellkilling. Project 3 fills a major gap in the treatment of early disease by conducting a clinical trial with anti-PD1 Abin Stage IIB/C melanoma patients. Besides in-depth characterization of the immune response the Projectspreclinical studies will lead to new strategies for enhancing the immune stimulatory capacity of dendritic cells inthe tumor microenvironment. These three highly translational Projects are supported by longstanding Cores thathave a proven track record of adapting to the rapidly changing needs of melanoma and non-melanoma skincancer researchers. Each Project was chosen by the current SPORE leadership for its potential for significanceimpact and innovation. Together they have the potential to advance therapeutically exploitable biological insightsinto new clinically important therapies of patients with melanoma. Funding from the SPORE has provided uswith important advantages including a mature collective translational mindset an efficiently functioning tumorbank and a highly evolved framework of collaboration between The Wistar Institute and UPenn. The SPOREhas allowed us to bolster horizontal and vertical collaborations with academic and industry partners throughoutthe world. The Career Enhancement Program and DRP have enabled transition to new leadership have formedthe three Projects proposed and have allowed our research to reach into other cancers of the skin includingSCC CTCL and Merkel Cell carcinoma. These programs will continue to be supported robustly by stronginstitutional support from both Wistar and UPenn. Funding of this SPORE will bring new advances from thebench to the bedside and fulfill our overall mission of improving survival for skin cancer patients. 2186705 +Aging; Behavioral and Social Science; Cancer; Clinical Research; HIV/AIDS; Health Services; Infectious Diseases; Patient Safety; Prevention AIDS/HIV problem;Acquired Immunodeficiency Syndrome;Acute;Address;Admission activity;Affect;Age;Aging;Area;Cancer Center;Cancer Hospital;Cancer Patient;Caring;Clinical;Computerized Medical Record;Data;Databases;Early identification;Face;Failure;Foundations;Frequencies;Funding;Guidelines;HIV;HIV Seronegativity;HIV therapy;Health;Hospitalization;Immunosuppression;Information Systems;Inpatients;Institutes;Institution;Knowledge;Life Expectancy;Link;Malignant Neoplasms;Measurement;Measures;Mental Health;Modernization;Muslim religion;Outcome;Outcome Measure;Palliative Care;Patient Outcomes Assessments;Patient-Centered Care;Patients;Personal Satisfaction;Persons;Population;Psyche structure;Public Health;Quality of life;Radiation Oncologist;Recurrence;Reduce health disparities;Reporting;Research;Research Personnel;Research Priority;Retrospective Studies;Severities;Symptoms;Time;Toxic effect;Treatment Side Effects;Treatment outcome;Treatment-related toxicity;United States National Institutes of Health;Visit;Vulnerable Populations;Work;acute toxicity;antiretroviral therapy;cancer care;cancer health disparity;cancer recurrence;cancer site;cancer survival;cancer therapy;cancer type;care outcomes;experience;improved;improved outcome;insight;marginalized population;mortality;patient oriented;social;social stigma;symptom treatment;treatment comparison Cancer Center Administration PROJECT NARRATIVEThe proposed research is relevant to public health because it addresses disparities in cancer outcomes amongpeople living with HIV by generating actionable research to improve the provision of cancer care to this vulnerable population. The NIH HIV/AIDS Research Priorities and Guidelines for Determining AIDS Funding (NOT-OD-15-137 NOT-OD-20-018) has designated Research to Reduce Health Disparities as a high priority area. Our proposal addresses this priority and will generate fundamental insights needed to improve equity in cancer care and outcomes for this population. NCI 10690812 9/9/22 0:00 PA-20-272 3P30CA042014-33S5 3 P30 CA 42014 33 S5 "PTAK, KRZYSZTOF" 5/9/97 0:00 4/30/25 0:00 6753 12111480 "LLOYD, SCOTT " Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 Research Centers 2022 199860 140658 59202 PROJECT ABSTRACTCancer is a large and growing problem among people living with HIV (PLWH). PLWH are far less likely to receive cancer treatment compared to uninfected counterparts. Even PLWH that receive cancer treatment experience worse cancer survival suggesting that there are additional drivers of outcomes disparities. The disparity in cancer treatment and survival is especially concerning given the near normal life expectancy of PLWH in the era of antiretroviral therapy and the mortality burden faced by PLWH who develop cancer. Although PLWH experience more clinician-reported cancer treatment toxicity leading to early discontinuation of cancer treatment and hospital admission little is known about the patient perspective of cancer treatment toxicity. Patient-reported outcomes (PROs) provide unique information on how delivered care affects patient health and well-being and are predictors of poor cancer outcomes in the general cancer population. In Aim 1 we will assess the type frequency and severity of PROs for PLWH compared to cancer patients without HIV using the validated PROMIS to measure physical mental and social health for all cancer sites. We hypothesize that PLWH with cancer will experience more frequent and severe symptoms compared to HIVnegative cancer patients. In Aim 2 we will examine the relationship between PROs and cancer outcomes including treatment completion treatment delays inpatient admission cancer recurrence and survival. We hypothesize that higher patient-reported symptom burden will be associated with adverse treatment outcomes particularly among PLWH. This retrospective study will identify disparities in cancer treatment toxicity for PLWH and HIV-negative cancer patients utilizing a validated PRO and measure associations between toxicity and real world clinical outcomes. Early identification and management of cancer treatment side effects will improve patient-centered personalized and equitable cancer care for PLWH thereby reducing cancer disparities and improving survival for this marginalized population. +No NIH Category available Androgen Antagonists;Antiandrogen Therapy;Biochemistry;Cancer Relapse;Disease;Doctor of Philosophy;Drug Modulation;Epigenetic Process;Exhibits;Funding;Histology;Histopathology;Human;Journals;Laboratories;Malignant neoplasm of prostate;Mediator;Molecular;Molecular Biology;Molecular Genetics;Mus;Mutation;Neoplasm Metastasis;Neuroendocrine Prostate Cancer;Neurosecretory Systems;Nutritional Science;Pharmacology;Postdoctoral Fellow;Publishing;RB1 gene;Research;Resistance;Science;Specimen;Testing;Validation;Variant;Wages;Work;androgen deprivation therapy;anticancer research;experience;improved;mouse model;novel;novel therapeutic intervention;programs;prostate cancer metastasis;prostate cancer model;resistance mechanism;response;skills;therapy resistant;transdifferentiation;treatment response;tumor;tumor progression Evaluating candidate mediators of prostate cancer metastasis and neuro endocrine prostate cancer (NEPC) trans differentiation Prostate cancer remains a lethal disease because tumors inevitably become resistant toandrogen deprivation therapy. An increasingly appreciated resistance mechanism involvestransformation of prostate cancer to neuroendocrine variants. We hypothesize mutation of theRB1 gene drives this transformation and will test this hypothesis and explore novel therapeuticapproaches to treat this lethal form of prostate cancer. NCI 10690775 9/6/23 0:00 PAR-18-341 5R50CA221786-05 5 R50 CA 221786 5 "HILDESHEIM, JEFFREY" 9/14/18 0:00 8/31/24 0:00 ZCA1-SRB-1(A1) 12287242 "CHINNAM, MEENALAKSHMI " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 130212 NCI 75793 54419 Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with alteredlineage marker expression suggesting lineage plasticity facilitates therapeutic resistance.Mechanisms underlying prostate cancer lineage plasticity are unknown. Our recent workpublished in Science uses mouse models of prostate cancer to demonstrate Rb1 and Trp53cooperate to suppress prostate cancer lineage plasticity metastasis and antiandrogenresistance. The research program funded by R01 CA207757 proposes to identify molecularmechanisms underlying Rb1 and Trp53 function in this context and assess a novel therapeuticapproach using epigenetic modulating drugs to improve responses to therapy. This R50application proposes salary support for Meenalakshmi Chinnam Ph.D. to support the R01CA207757 research program. Dr. Chinnam works as a Research Associate in the laboratory ofDr. David Goodrich unit director on this application. Dr. Chinnam has made significantcontributions to Dr. Goodrich's research programs since 2004 and her work has been publishedin well-regarded journals. Dr. Chinnam is a skilled experimentalist with a broad background inpharmacology molecular biology molecular genetics biochemistry and nutrition sciences. Shehas over 13 years of experience in cancer research. Relevant to this application Dr. Chinnamhas considerable experience using mouse models of prostate cancer and characterizing thehistopathology of both mouse and human prostate cancer specimens. Dr. Chinnam will leveragethis expertise to help generate and characterize novel mouse models proposed in R01CA207757 to elucidate how Ezh2 or E2f1 activity influence lineage plasticity cancerprogression and response to antiandrogens. She will also characterize human prostate cancerspecimens for cross-species validation. Dr. Chinnam's contributions will be essential forsuccessful completion of the R01 CA207757 research program. 130212 +No NIH Category available Address;Age;American;Area;Basic Science;Bioinformatics;Cancer Burden;Cancer Center;Cancer Control;Cessation of life;Clinical;Clinical Oncology;Collaborations;Colombia;Colombian;Complement;Country;Demography;Development;Educational Curriculum;Ethics;European;Foundations;Funding;Funding Opportunities;Goals;Healthcare;Home;Individual;Infection Control;Institution;Knowledge;Latin America;Latin American;Latino Population;Lead;Life Expectancy;Malignant Neoplasms;Mentors;Mutation;National Cancer Institute;Oncology;Patients;Peru;Peruvian;Physicians;Population;Postdoctoral Fellow;Precision therapeutics;Principal Investigator;Provider;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Development;Resources;Risk Assessment;Science;Solid;Training;Training Programs;United States National Institutes of Health;Universities;anticancer research;biobank;cancer care;cancer epidemiology;cancer genetics;cancer risk;cancer therapy;cloud based;experience;graduate student;health care availability;human capital;improved;individualized prevention;low and middle-income countries;multidisciplinary;pre-clinical;precision cancer prevention;precision oncology;programs;skills;tool UC Davis Multi-Disciplinary Cancer Research Training Program to Advance Precision Cancer Prevention and Care in Latin America. PROJECT NARRATIVEThe UC Davis Multidisciplinary Cancer Research Training Program to Advance Precision Cancer Preventionand Care in Latin America will offer a range of curricular research and career development activities to LatinAmerican trainees with the goal of developing expertise in clinical cancer research and precision cancermedicine. This program will allow the trainees to implement and lead cutting-edge cancer research relevant forand in their home LMIC countries. NCI 10690763 8/17/23 0:00 RFA-CA-20-031 5D43CA260869-02 5 D43 CA 260869 2 "SIVARAM, SUDHA" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-F(J1)R 11805960 "CARVAJAL CARMONA, LUIS GUILLERMO" "FEJERMAN, LAURA " 4 BIOCHEMISTRY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 270000 NCI 250000 20000 PROJECT SUMMARYImprovements in health care access and infection control have led to life expectancy increases in Low- andMiddle-Income Countries (LMICs) in Latin America. As the population ages the Latin American cancer burdenhas dramatically increased. By 2030 Latin America is expected to have annual averages of 1.6M new cancercases and 1M cancer deaths. A Latin America Lancet Oncology Commission report highlighted the smallamount of preclinical and clinical oncology research originating in the region as a limitation to control cancerburden. Colombia and Peru the Latin American LMICs with the first and second largest populations havestate-funded national cancer institutes (NCIs) that are cancer treatment reference centers and which leadnational efforts in cancer control and care. However cancer risk assessment and patient treatment at theseinstitutions is primarily based on tools developed in North American and European patients. Despite havingexceptional researchers and physicians most cancer centers in Latin America lack training programs thatwould allow them to develop or adapt precision prevention or treatment tools that are appropriate to theancestry or mutation profiles of individuals from the region. The current funding opportunity is the idealprogram to formalize and enhance ongoing collaborations between US-based healthcare researchers andproviders in Colombia and Peru. It will provide a solid foundation for precision oncology research knowledgetransfer and to build local human capital necessary to develop precision cancer medicine in Latin America.Building on our extensive expertise on Latin American population demography cancer epidemiology andgenetics NIH funded cancer studies in Latino populations and a strong track record of research collaborationand training with Colombian and Peruvian researchers the overall goals of the UC Davis MultidisciplinaryCancer Research Training Program to Advance Precision Cancer Prevention and Care in Latin America are to:1) Enhance local capacity for precision cancer medicine research in Colombia and Peru by implementing acurriculum that complements and addresses gaps in local training programs and provides hands on experienceand support for research project development relevant to the region 2) Provide hands on training on researchresource development including ethics training biobanking best practices and cloud-based bioinformatics; and3) allocate pilot funding for mentored research for basic science and clinically-oriented term trainees. Wepropose to establish a curriculum to train graduate students and postdoctoral/clinical fellows in precisiononcology research. We will prepare trainees to implement and share their new skills in their home countriesand to collaborate with U.S-based investigators. We will leverage ongoing collaborations among the programPrincipal Investigators universities and NCIs of Colombia and Peru to identify relevant areas of research thatcould be enhanced by the training program. 270000 +No NIH Category available Acceleration;Award;Biopsy Specimen;Cancer Institute of New Jersey;Cells;Data;Development;Diagnosis;Folic Acid Antagonists;Functional disorder;Goals;Growth;Immune;Institution;Isotopes;Leadership;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Metabolic;Metabolism;Methods;Modernization;Mus;Oncogenes;Play;Positioning Attribute;Protocols documentation;Research;Resolution;Role;Selection for Treatments;Signal Transduction;Specialist;Technology;Tracer;asparaginase;fluorodeoxyglucose positron emission tomography;improved;in vivo;insight;mass spectrometric imaging;metabolomics;novel;novel diagnostics;novel therapeutics;tool;tumor;tumor metabolism;tumor microenvironment Revealing cancer metabolism via mass spectrometry and isotope tracers Metabolism plays a fundamental role in cancer growth diagnosis and treatment. I propose todevelop improved mass spectrometry and isotope tracer technologies for quantitation of cancermetabolism and to apply the technology to reveal tumor metabolic activity. The resultingunderstanding of metabolite levels and fluxes in cancer will open new therapeutic anddiagnostic opportunities. NCI 10690727 9/7/23 0:00 PAR-20-287 5R50CA211437-08 5 R50 CA 211437 8 "AMIN, ANOWARUL" 9/19/16 0:00 8/31/26 0:00 ZCA1-SRB-1(A2) 10869597 "LU, WENYUN " Not Applicable 12 NONE 2484665 NJ1YPQXQG7U5 2484665 NJ1YPQXQG7U5 US 40.345441 -74.655866 6661401 PRINCETON UNIVERSITY Princeton NJ UNIVERSITY-WIDE 85406000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 125134 NCI 77243 47891 Project Summary/AbstractMetabolism plays a fundamental role in cancer growth diagnosis (e.g. FDG-PET) and treatment (e.g.antifolates asparaginase). Over the past decade research into cancer metabolism has flourishedcontextualized by the realization that metabolic changes in cancer are triggered by oncogene signaling andaccelerated by the emergence of new measurement tools. This NCI Research Specialist Award will studycancer metabolism using the most important modern tools: mass spectrometry and isotope tracers. Workingtogether with Unit Director Joshua Rabinowitz and his lab and a diverse set of collaborators from RutgersCancer Institute of New Jersey and other leading institutions I aim over the next 5 years to achieve thefollowing: (1) Optimize LC-MS-based metabolomic methods focusing on ultrasensitive measurementsappropriate for small biopsy samples and on novel metabolite identification via untargeted metabolomics. (2)Develop and optimize the imaging mass spectrometry methods for spatial metabolomics. (3) Combine thesemethods with isotope tracers to determine fluxes in tumors in vivo. Rabinowitz and I have a long-standingleadership position in isotope tracer methods for quantitating metabolic fluxes. We have recently developedprotocols for infusing a wide variety of 13C 15N and 2H-tracers into mice with the goal of enabling quantitationof tumor metabolic flux. We are pushing to enable these measurements also by mass spectrometry imagingeventually with single cell resolution. Resulting data will provide critical insights into the metabolicpathophysiology of cancer and immune cells in the native tumor microenvironment and will thereby informtreatment selection strategies and the development of novel therapeutics. 125134 +No NIH Category available Animal Model;Animals;Awareness;Behavior;Biological;Biological Markers;Cell Count;Cell Density;Cell physiology;Cells;Characteristics;Classification;Climate;Clinical;Complement;Complex;Cultured Tumor Cells;Data;Dependence;Detection;Diagnosis;Ecosystem;Event;Exhibits;Exposure to;Genes;Genetic;Goals;Growth;In Vitro;Indolent;Lesion;Link;Malignant Neoplasms;Mathematics;Measurable;Measures;Microscopic;Modeling;Molecular Profiling;Mus;Mutation;Pathway interactions;Patients;Pattern;Phase;Phenotype;Population;Population Dynamics;Population Growth;Population Process;Pre-Clinical Model;Recurrence;Regulator Genes;Regulatory Pathway;Relapse;Research Personnel;Resolution;Risk;Scheme;Screening for cancer;Signal Transduction;Stochastic Processes;Stratification;System;Systems Theory;Testing;Titrations;Translating;Tumor Escape;Work;austin;cancer cell;cancer genome;cancer invasiveness;cell dimension;design;driver mutation;dynamic system;experimental study;gene regulatory network;genome sequencing;high dimensionality;in vivo;indexing;mouse model;mutant;neoplastic cell;non-genetic;novel strategies;prognostic;single cell analysis;theories;transcriptome;transcriptome sequencing;tumor;tumor progression Instability of Cancer Cell States in Tumor progression (ICCS) NARRATIVESystematic cancer screening has led to a surge of cases of clinically invisible dormant tumors raising the im-portant question for every diagnosed patient of whether a microscopic lesion poses a risk of becoming an inva-sive cancer or not. This project is motivated by a new theory of complex systems that explains their tippingpoint behaviors and uses a new scheme of single-cell resolution molecular profiling of minuscule tumor cellpopulations and tunable mouse tumors to study how tipping point dynamics drives a dormant tumor to becomedestabilized and become poised between staying dormant or taking-off and grow. The new approach couldbe used to detect when the dormant tumor enters the phase of instability that precedes an escape from dor-mancy to become clinical. NCI 10690722 8/28/23 0:00 PA-20-185 5R01CA255536-03 5 R01 CA 255536 3 "MILLER, DAVID J" 9/21/21 0:00 8/31/26 0:00 Modeling and Analysis of Biological Systems Study Section[MABS] 9454292 "HUANG, SUI " "BROCK, AMY " 7 Unavailable 135646524 SMK9PCMKXED6 135646524 SMK9PCMKXED6 US 47.622538 -122.337533 4106301 INSTITUTE FOR SYSTEMS BIOLOGY SEATTLE WA Research Institutes 981095263 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 486752 NCI 343978 142774 PROJECT SUMMARYICCS2020-A1This multi-PI project conducts experiments to study cell state instability in tumor cells motivated by the theory ofcritical transitions (CT). CTs are abrupt shifts of behavior of a complex non-linear system and are preceded bysystem state destabilization. A cancer cell population represents a statistical ensemble of cells each of which isa nonlinear stochastic dynamical system. The latter is embodied by the gene regulatory network (GRN) and cellsare normally in stable attractor states. We hypothesize that cancer cells in small lesions can be poised betweeneither staying dormant or exiting dormancy (escape) and that this binary decision is a CT. This implies that tobe in such a poised state the cell state has to be destabilized. Thus detecting cell state instability manifest inthe cell transcriptomes can discern if a small tumor is safely in a stable state or poised in the above sense. Manyan observation suggests that cell density of the dormant tumor may be a bifurcation parameter that drives GRNdynamics via instability toward the CT at which a cancer cell population can jump to the state of steady growth.SPECIFIC AIMS. The proposed study is experimental but grounded in theory: Cell state instability is manifest inan increase of the quantity IC that we derived from theory and requires single-cell (sc) transcriptomes in a popu-lation to compute (=dynamics of a statistical ensemble of GRNs). Aim 1 (in vitro) uses large ensembles of micro-cultures (=cancer cell populations) to quantitatively show destabilization and bifurcations of growth behaviors.Aim 2 (in vivo) reevaluates old mouse tumor models in a new scheme that exposes the binary decision (dor-mancy vs. tumor-take) to test the hypothesis that clinical dormancy escape is preceded by cell state instability.APPROACH: In Aim 1 using massively-parallel micro-cultures bulk RNASeq and scRNAseq we examine hith-erto undistinguished growth modes of cancer cells and measure bistability as a function of cell density (dormancyvs. take-off). In Aim 2 we examine our intriguing observations in many mouse models: under specific condi-tions identified by titrating inoculum cell numbers in creating dormant tumors some mice exhibit stable dor-mancy and others a robust tumor-take despite same initial conditions. This finding suggests a poised state anddefines a bistable regime. Tumor models using cells studied in Aim 1 will be evaluated in our scheme to exposebistable behaviors and Ic computed from scRNAseq data. We anticipate that tumors in unstable dormancy poisedto take-off display higher cell state instability (higher IC) than the stably dormant tumors. But sc-transcriptomeswill also reveal the genes that drive the CT and how they are linked to the risk of impending dormancy escape.SIGNIFICANCE: While this first-in-its-class study analyzes abstract principles rather than specific molecules itspotential impact is tangible: It predicts the fate trajectory of indolent tumors in a new way complementing currentquest for molecular signatures to classify tumors by prognostic groups by detecting in single-cell resolution cellpopulation data signs of destabilization that herald an approach to the CT or tipping point of dormancy escape.This work also raises awareness of non-linear behaviors for the design of more relevant animal tumor models. 486752 +No NIH Category available Acceleration;Adult;Affect;Aftercare;Award;Benign;Biological;Biology;Biopsy Specimen;Bromodomain;Bromodomains and extra-terminal domain inhibitor;CDKN2A gene;Caring;Cause of Death;Cessation of life;Characteristics;Childhood;Clinic;Clinical;Clinical Research;Clinical Trials;Collagen;Combined Modality Therapy;Complex;Data;Deformity;Development;Evaluation;Event;Evolution;Extracellular Matrix;Extracellular Matrix Proteins;Fibroblasts;Funding;Genetic study;Genetically Engineered Mouse;Genome;Genomics;Goals;Heterozygote;Histologic;Human;In complete remission;Indolent;Investigational Therapies;Laboratories;Lesion;MEKs;Maintenance;Malignant - descriptor;Modeling;Molecular Analysis;Molecular Target;Morbidity - disease rate;Mutation;Neoplastic Schwann Cell;Nerve;Nerve Sheath Tumors;Neurofibromatosis 1;Neurofibrosarcoma;Operative Surgical Procedures;PTPN11 gene;Paralysed;Pathology;Patients;Pharmaceutical Preparations;Pharmacodynamics;Play;Plexiform Neurofibroma;Pre-Clinical Model;Prevention;Preventive;Property;Radiation;Reading Frames;Refractory;Research Personnel;Role;Sampling;Schwann Cells;Signal Transduction;Structure;Systems Biology;Technology;Testing;Therapeutic;Therapeutic Studies;Translating;Translations;anticancer treatment;chemotherapy;clinical translation;early phase clinical trial;hyperactive Ras;improved;inhibitor;insight;molecular targeted therapies;mortality;mouse model;multimodality;mutant;neurofibroma;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;phase II trial;pre-clinical;preclinical evaluation;preclinical study;premalignant;premature;prevent;programs;response;sarcoma;synergism;therapeutic target;tool;transcriptome;translational study;tumor;tumor initiation;tumor microenvironment;tumorigenic PROJECT 1: From Neurofibroma to MPNST: Models Biology and Translation to Clinic NARRATIVE (Project 1)Plexiform neurofibroma (PNF) and their progression to malignant peripheral nerve sheath tumor (MPNST) isthe leading cause of morbidity and premature death in patients with neurofibromatosis type 1. This projectleverages patient derived samples genetically engineered mouse models and state-of-the art tools in systemsbiology to inform the clinical translation of molecularly targeted therapies across the PNF-to-MPNSTcontinuum. NCI 10690679 8/14/23 0:00 PAR-18-313 5U54CA196519-08 5 U54 CA 196519 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 6717 1962260 "CLAPP, DAVID W" Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 543627 475009 68618 ABSTRACT (Project 1)Plexiform neurofibromas (PNF) are a hallmark manifestation of neurofibromatosis type 1 (NF1) that affect up to50% of patients and causes lifelong morbidity. A subset of PNF progress to atypical neurofibroma (ANF) and/ormalignant peripheral nerve sheath tumors (MPNST). These treatment refractory sarcomas represent theleading cause of death in NF1 patients. Clinical genomic studies and novel genetically engineered mouse(GEM) models led and developed by Project 1 investigators have provided strong evidence that loss ofCDKN2A (INK4A) and/or its alternate reading frame (ARF) is a key driver event in the majority of NF1-associated ANF and MPNST. These models will serve as tractable platforms for characterizing key events inthe evolution of PNF to MPNST and for preclinical evaluation of novel experimental therapeutics.Our studies to date have identified the first two broadly clinically effective drugs for PNF the MEK inhibitorselumetinib and the multi-RTK inhibitor cabozantinib. Mechanistic insights from preclinical models and initialphase 2 trials showed that selumetinib and cabozantinib have distinct pharmacodynamic characteristics inboth the molecular targets within neoplastic Schwann cells as well as the tumor microenvironment.Collectively these results suggest that combining these two drugs may enhance efficacy in PNF and perhapsimpede the progression to ANF and MPNST. The heterozygous NF1 mutant tumor microenvironment isessential in PNF development and thus is a key consideration for implementing more effective combinationtherapies. Although collagen and other extracellular matrix (ECM) proteins are primary constituents of the PNFmicroenvironment their respective roles in tumor initiation and maintenance remain unexplored.To inform ongoing translational efforts to develop novel therapies for NF1 patients affected by tumors acrossthe PNF-ANF-MPNST continuum we will accomplish the following: (1) Identify actionable therapeutic targetswithin NF1+/- fibroblasts and ECM proteins of the tumor microenvironment that interact with neoplasticSchwann cells to accelerate PNF formation and maintenance; (2) Extend preclinical studies in novel GEM andPDX models to investigate potential synergism of therapeutic combinations (including MEKi BETi SHP-2 andcabozantinib) in treating existing PNF ANF and MPNST as well as in preventing malignant transformation ofprecursor lesions; (3) Conduct an early phase clinical trial of MEKi and cabozantinb combination therapy inPNF that may extend to more advanced nerve sheath tumors (ANF and MPNST) as informed by ongoingpreclinical studies; (4) Leverage state-of-the-art technologies in Omics (Core B) and Biospecimen/Pathology(Core C) to define adaptive responses of PNF ANF and MPNST in GEM models as well as patient biopsyspecimens by evaluation of the genome transcriptome and functionally enriched kinome before and aftertreatment. +No NIH Category available Address;Anatomy;Animals;Award;Biological;Biological Specimen Banks;Blood specimen;Catalogs;Central Nervous System Neoplasms;Clinic;Communication;Communication Tools;Communities;Data;Development;Diagnosis;Diagnostic;Disease model;Disease susceptibility;Electronics;Ensure;Evaluation;Fatty acid glycerol esters;Future;Genomics;Goals;Human;Image;In Vitro;Laboratories;Lead;Location;Malignant Childhood Neoplasm;Malignant Neoplasms;Microscopy;Molecular;Mus;Necrosis;Neurofibromatosis 1;Normal tissue morphology;Organ;Pathogenesis;Pathologic;Pathologist;Pathology;Patients;Peripheral Nervous System;Photomicrography;Play;Procedures;Protocols documentation;Quality Control;Recurrent disease;Research;Research Personnel;Residual state;Resources;Retrieval;Risk;Role;Sampling;Signal Pathway;Stains;Standardization;Technology;Text;Time;Tissue Sample;Tissue Stains;Tissues;Update;biobank;digital pathology;geographic barrier;hyperactive Ras;imaging study;leukemogenesis;novel therapeutics;pathology imaging;programs;sarcoma;success;treatment response;tumor;virtual;web site Biospecimen and Pathology Core NARRATIVE BIOSPECIMEN/PATHOLOGY COREThis core will store all samples collected in the three projects in a central location. This core will alsocoordinate uniform evaluation of all samples in a pathology laboratory. This core will also send samples asdirected for analysis within the SPORE and also to researchers worldwide. NCI 10690678 8/14/23 0:00 PAR-18-313 5U54CA196519-08 5 U54 CA 196519 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 6716 1918857 "FOROUD, TATIANA M." Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 161094 135906 25188 ABSTRACT BIOSPECIMEN/PATHOLOGY COREThe overarching goal of this SPORE is to understand the biological underpinnings of hyperactivated p21raspathway signals in the pathogenesis of childhood malignancies of neurofibromatosis type 1 and to bring newtherapies to the clinic. Each project explores this theme using a different disease model. However all projectsinterweave human mouse and in vitro studies to identify factors that modify the effects of Ras. To ensure thesuccess of these studies complementary cutting-edge technologies will be used to address key questionsrelated to disease susceptibility likelihood of disease relapse and risk for other malignancies.The Biospecimen and Pathology Core will receive human and mouse samples from all four projects in theSPORE. The core will also provide pathological review of all samples and will make these data available to allSPORE investigators and the broader research community. The specific aims of this core are:Aim 1: Maintain and update the DHART SPORE website as an effective internal and externalcommunication tool.Aim 2: Utilize uniform biospecimen receipt tracking and distribution procedures for samples collected as partof DHART SPORE projects.Aim 3: Apply uniform pathology protocols for the characterization of human and animal samplescollected as part of DHART SPORE projects. +No NIH Category available Address;Bioinformatics;Biological;Biology;Cell Proliferation;Cell Survival;Cells;Chemicals;Collaborations;Computational Biology;Consultations;Data;Data Analyses;Data Set;Development;Disease;FRAP1 gene;Funding;Gene Expression;Genetic;Genetically Engineered Mouse;Genome;Genomics;Genotype;Goals;Group Meetings;Human;Informatics;Institution;Knowledge;Laboratories;MEKs;Malignant Neoplasms;Medical center;Methodology;Methods;Modeling;Molecular;Molecular Analysis;Molecular Profiling;Morbidity - disease rate;Multiomic Data;Mus;Mutation;Mutation Spectra;NF1 gene;Neoplasms;Neurofibromatosis 1;PIK3CG gene;Pathology;Pathway Analysis;Pathway interactions;Performance;Phosphotransferases;Process;Proteomics;Proto-Oncogene Proteins c-akt;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Sampling;Services;Signal Pathway;Signal Transduction;Specimen;Synapses;System;Technology;Therapeutic;autosome;data and analysis portal;data exchange;data integration;data management;design;effective therapy;exome sequencing;experimental study;functional loss;hyperactive Ras;informatics infrastructure;inhibitor;loss of function;molecular targeted therapies;mortality;neurofibroma;next generation sequencing;novel;novel therapeutics;patient derived xenograft model;ras GTPase-Activating Proteins;response;response biomarker;single-cell RNA sequencing;targeted exome sequencing;targeted treatment;therapeutic candidate;therapeutic target;therapy resistant;transcriptome;transcriptome sequencing;treatment response;tumor;tumor initiation;tumor progression;web portal;working group Omics Core PROJECT NARRATIVE OMICS CORENF1 malignancies have high morbidity and mortality with no clear effective therapies. The Omics Core willprovide essential state-of-the-art next-generation sequencing kinome activity assessments and informaticsinfrastructure to allow Projects 1-3 to determine and define new therapeutic treatments for NF1 malignancies. NCI 10690677 8/14/23 0:00 PAR-18-313 5U54CA196519-08 5 U54 CA 196519 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 6715 8636465 "LIU, YUNLONG " Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 381059 243665 137394 PROJECT SUMMARY/ABSTRACT OMICS COREThe Developmental and Hyperactive Ras Tumor (DHART) SPORE was designed to integrate multipleresearch projects all with the goal of identifying novel molecular therapeutic strategies for NF1-relatedmalignancies. Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by mutationsin the NF1 gene which encodes neurofibromin. Functional loss of neurofibromin a Ras-GTPase activatingprotein (GAP) leads to hyperactive Ras signaling and dysregulation of multiple cell signaling pathwaysimpacting cell proliferation and survival such as Raf-MEK-ERK and PI3K-AKT-mTOR. The overall goal of theOmics Core (Core B) is to provide state-of-the-art support for research design consultation performance ofgenomics and kinomics experiments and integrated data analysis to DHART investigators to elucidatechanges during NF1-related tumor development and in response to therapy. Built upon institutional genomicscores (Center for Medical Genomics) a newly established kinome laboratory and a bioinformatics researchcenter (Center for Computational Biology and Bioinformatics) Core B also interacts intensively with other coresfor supporting the DHART investigators. Upon receipt of tracked samples (including mouse and humanneurofibromas JMML GBM and models of NF1-related subsequent neoplasms) from theBiospecimen/Pathology Core C the following technologies and informatics platforms will be employed: 1. CoreB will process samples for bulk RNA sequencing single-cell RNA sequencing whole exome sequencing ortargeted exome sequencing. 2. The Omics Core will analyze and annotate all RNAseq and exome sequencingdata for transfer to Synapse the Sage portal for data analysis 2. The Kinome Core will utilize establishedchemical proteomics methodology to provide functional activity-based global kinome profiles of NF1-relatedspecimens defining baseline kinome state effects of specific genotype or genetic perturbations and responseto targeted inhibitors. 3. In collaboration with the Administrative Core A and Sage Bionetworks integrativeanalyses will be performed to provide comprehensive molecular profiles of genotype-driven gene expressionand functional kinome profiles. The profiles will be studied for both putative response biomarkers and forcandidate therapeutic targets. Synapse a web portal maintained by Sage will allow access by SPOREinvestigators of all data obtained by the Omics and Biospecimen/Pathology Cores where findings will beannotated and made more broadly useful to all investigators involved in the SPORE. This data managementportal will provide a unique resource for accessing and interpreting data generated by the three projectsBiospecimens and Pathology Core and Omics Core. +No NIH Category available Acceleration;Address;Adolescent and Young Adult;Advisory Committees;Area;Authorization documentation;Basic Science;California;Cancer Center;Cancer Patient;Catchment Area;Child;Clinical Trials;Cloud Computing;Collaborations;Communication;Communities;Consult;Consultations;Data;Data Analyses;Data Commons;Databases;Decision Making;Development;Educational workshop;Ensure;Environment;Evaluation;Funding;Goals;Indiana;Infrastructure;Institution;Leadership;Malignant Neoplasms;Memorial Sloan-Kettering Cancer Center;Metadata;NF1 gene;NF1 mutation;National Cancer Institute;Office of Administrative Management;Organization administrative structures;Orphan;Participant;Pathology;Patient Care;Patients;Pediatric Hospitals;Pediatric Oncology;Pediatric Oncology Group;Pennsylvania;Performance;Philadelphia;Preparation;Process;Productivity;Progress Reports;Publications;Rare Diseases;Regulation;Reporting;Reproducibility;Reproduction spores;Research;Research Personnel;Research Project Grants;Resources;San Francisco;Science;Services;Signal Transduction;Site;Strategic vision;Structure;Supercomputing;Synapses;Texas;Translational Research;Travel;Universities;authority;career;computing resources;data integration;data management;data sharing;data visualization;driver mutation;hyperactive Ras;innovation;meetings;member;molecular targeted therapies;novel;novel therapeutics;patient population;preclinical trial;programs;public-private partnership;timeline;tool;translational research program;tumor Administrative Core PROJECT NARRATIVE ADMINISTRATIVE CORE (CORE A)The DHART SPORE currently encompasses three highly integrated projects and three cores with the goal ofimplementing effective targeted molecular therapies for neoplasms and cancers characterized by NF1mutations by conducting integrated mechanistically based translational research. The goal of theAdministrative Core is to provide scientific and administrative oversight for all the program components of theDHART SPORE. The core will provide the overall organizational framework by which researcherscommunicate and interact manage finances coordinate the review of progress of the research projectsscientific cores and developmental programs (DRP & CEP) consult with the members of the External andInternal Advisory boards coordinate the overall data integration and analysis of the DHART SPORE andcontinue to refine our infrastructure to enable sharing of data generated by our studies with other internal andexternal NF-collaborative consortiums. NCI 10690676 8/14/23 0:00 PAR-18-313 5U54CA196519-08 5 U54 CA 196519 8 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N 6714 1962260 "CLAPP, DAVID W" Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 80436 58201 22235 ABSTRACT ADMINISTRATIVE CORE (CORE A)The Developmental and Hyperactive Ras Tumor (DHART) SPORE was funded in 2015 with the goal ofimplementing effective targeted molecular therapies for neoplasms and cancers characterized by NF1mutations by conducting integrated mechanistically based translational research. The studies proposed in ourrenewal will continue to address the fundamental problem of hyperactive Ras signaling in cancer. Theprogram consists of three research projects and three core components. Innovative aspects of the DHARTSPORE include: (1) a focus on advancing the science and care of patients with orphan diseases; (2) a strongemphasis on tumors arising in young children adolescents and young adults; (3) studies of diverse tumortypes that share a common driver mutation; and (4) an investigative team drawn from leading researchcenters across the nation to promote integration of preclinical and clinical trials expertise and patient access.The goal of the Administrative Core is to provide scientific and administrative oversight for all the programcomponents of the DHART SPORE. This core serves as the central point for all administrative activities andessential services including being the organizing unit for the coordination integration and communication forall components. These coordinating components include: 1) providing the overall organizational framework bywhich researchers communicate and interact/collaborate 2) managing finances 3) supporting the coordinationof the review of progress of the research projects scientific cores and developmental programs (DRP andCEP) 4) consulting with the members of the External and Internal Advisory boards 5) coordinating the overalldata integration and analysis of the DHART SPORE and 6) continuing to establish and refine the infrastructureto support the meaningful sharing of data and information generated through our studies with other internal andexternal NF-collaborative consortiums. +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Address;Adolescent and Young Adult;Affect;Alleles;Benefits and Risks;Benign;Binding;Biological;Biological Markers;Cancer Biology;Cell Lineage;Central Nervous System Neoplasms;Child;Childhood;Clinical;Clinical Investigator;Clinical Trials;Core Facility;Development;Disease Progression;Funding;GTPase-Activating Proteins;Genetic;Genetically Engineered Mouse;Glioblastoma;Goals;Guanine Nucleotides;Guanosine Triphosphate;Hematopoietic Neoplasms;High Prevalence;Human;Hydrolysis;Incidence;Inherited;Juvenile Myelomonocytic Leukemia;Learning Disabilities;Lung Adenocarcinoma;MEK inhibition;Malignant Neoplasms;Medical;Molecular;Molecular Analysis;Morbidity - disease rate;Mutation;NF1 gene;Neurofibromatosis 1;Neurofibrosarcoma;Organ;Orphan;Output;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Physicians;Plexiform Neurofibroma;Population;Pre-Clinical Model;Predisposition;Premature Mortality;Prevention;Prognostic Marker;Publications;Research Personnel;Resistance;Risk;Role;Sampling;Scientist;Signal Transduction;Skin Pigmentation;Syndrome;System;Therapeutic;Therapeutic Studies;Tissues;Translational Research;Tumor Suppressor Genes;Work;acquired drug resistance;cancer initiation;cancer predisposition;cancer therapy;comparative;developmental disease;driver mutation;drug response prediction;genome-wide;hyperactive Ras;improved outcome;melanoma;member;molecular targeted therapies;mortality;neoplastic;next generation;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;patient oriented;preclinical trial;predictive marker;premalignant;programs;protein function;rare cancer;ras GTPase-Activating Proteins;response;risk stratification;sarcoma;skeletal dysplasia;skin lesion;targeted treatment;translational cancer research;translational scientist;translational therapeutics;treatment response;tumor Developmental and Hyperactive Ras Tumor (DHART) SPORE NARRATIVE OVERALLThe overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPORE is to implement effectivetargeted therapies for neoplasms and cancers characterized by mutations in the NF1 tumor suppressor gene(TSG) by conducting integrated mechanistically based translational research. Using novel geneticallyengineered mice patient derived xenografts and robust Omics we will delineate mutations that contribute tocancer pathogenesis and uncover new biomarkers of drug response and resistance that will inform thedevelopment of next generation treatments. NCI 10690675 8/14/23 0:00 PAR-18-313 5U54CA196519-08 5 U54 CA 196519 8 "NOTHWEHR, STEVEN F" 9/1/15 0:00 8/31/26 0:00 ZCA1-RPRB-N(M1)P 1962260 "CLAPP, DAVID W" "SHANNON, KEVIN M." 7 PEDIATRICS 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2139494 NCI 1822157 317337 ABSTRACT OVERALL Neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome of agroup of developmental disorders that are collectively termed Rasopathies. Germline NF1 mutations causeneurofibromatosis type 1 (NF1) a multi-system developmental disorder that is also the most common inheritedcancer predisposition syndrome. NF1 is of exceptional importance in cancer biology because it encodes aGTPase activating protein (GAP) called neurofibromin that binds to active Ras-GTP and terminates signalingby accelerating guanine nucleotide hydrolysis. Thus NF1 inactivation and somatic cancer-associated RASmutations result in constitutively elevated Ras-GTP levels and aberrant activation of Ras-regulated kinaseeffector pathways in susceptible cell lineages. A markedly increased incidence of developing specific benignand malignant tumors is a hallmark of NF1 that results in substantial morbidity and mortality that affectchildren adolescents and young adults (AYAs) in a range of tissues. Investigating NF1-associated tumorsrepresents a unique opportunity to interrogate therapeutic responses and mechanisms of intrinsic and acquireddrug resistance in cancers that are initiated by a mutation that directly enhances Ras output. Given the centralimportance of aberrant Ras/GAP function in human cancer and the emerging role of somatic NF1 mutations incommon sporadic malignancies achieving the goals of this SPORE will broadly advance translational cancerresearch and treatment. The overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPOREis to implement effective targeted therapies for neoplasms and cancers characterized by mutations in the NF1tumor suppressor gene (TSG) by conducting integrated mechanistically based translational research. TheDHART SPORE deploys novel organizing principles and approaches to address the key challenge of how toaccelerate new therapies for uncommon (orphan) benign and malignant tumors across an organ spectrumwith a common driver mutation. The DHART SPORE is comprised of a highly integrated group of translationalscientists that are addressing central issues for implementing mechanism-based treatments for rare tumorsdriven by hyperactive Ras signaling in the pediatric adolescent and young adult (AYA) population. Across allthree projects state-of-the-art core facilities will inform the patient-oriented therapeutic and prevention aspectsby delineating mutations that contribute to cancer pathogenesis and by uncovering new biomarkers of drugresponse and resistance that will inform the development of next generation treatments. Achieving theobjectives of the proposed Projects 1-3 will not only improve the outcomes of NF1 and non-NF1 patients withspecific cancers but has the potential to inform new therapeutic approaches for the substantial proportion ofhuman cancers characterized by somatic NF1 and RAS mutations that have implications for enhancing thetreatment of the ~1/3rd of all cancers with somatic RAS mutations. 2139494 +No NIH Category available Address;Affect;Algorithms;Animal Model;Biochemical;Biological Assay;Biology;Biopsy;Cancer Etiology;Carbon;Cessation of life;Characteristics;Chemicals;Cisplatin;Clinical Trials;Coenzymes;DNA;DNA Damage;Data;Data Analyses;Development;Dose;Effectiveness;Evaluation;Exposure to;Failure;Feedback;Genotoxic Stress;Glycolysis;Goals;Grant;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Head and neck structure;Heterogeneity;Human;Human Papillomavirus;Image;In Vitro;Individual;Knowledge;Lactate Dehydrogenase;Link;Magnetic Resonance Imaging;Measurable;Measurement;Measures;Metabolic;Metabolic Pathway;Mission;Modeling;Mus;Mutagens;Nicotinamide adenine dinucleotide;Non-Invasive Detection;Oxidation-Reduction;Patient Recruitments;Patients;Pre-Clinical Model;Public Health;Publishing;Pyruvate;Radiation therapy;Reaction;Recycling;Regimen;Research;Resistance;Resistance development;Resolution;Selection Criteria;Sensitivity and Specificity;Series;Shunt Device;Solid Neoplasm;Testing;Therapeutic;Time;Toxic effect;Translational Research;Treatment Effectiveness;Treatment Failure;Treatment Protocols;Tumor Burden;Tumor Volume;United States;United States National Institutes of Health;Work;Xenograft procedure;cell injury;cell killing;chemotherapeutic agent;chemotherapy;clinical application;clinically relevant;design;drug testing;effective therapy;first-in-human;imaging biomarker;imaging modality;imaging probe;in vivo;individual patient;innovation;inorganic phosphate;insight;interest;metabolic imaging;metabolic phenotype;metabolomics;minimally invasive;neoplastic cell;non-invasive imaging;novel;oral lesion;oxidation;patient derived xenograft model;personalized management;precision oncology;preclinical trial;predicting response;predictive modeling;prospective;quantitative imaging;randomized trial;response;standard of care;success;targeted agent;transcriptomics;treatment optimization;treatment response;tumor;tumor growth;tumor metabolism Leveraging Hyperpolarized MRI for Precision Oncology Approaches in Head and Neck Cancer NARRATIVEThe proposed translational research will use real-time metabolic imaging (hyperpolarized MRI) to assess tumorresponse to genotoxic stress induced by cisplatin in head and neck squamous cell carcinoma (HSNCC). Thework is relevant to public health because this approach will provide a basis for adaptive changes to maximizetreatment effectiveness and personalize the management of not only HNSCC but also other solid tumors. Asgenotoxic agents remain the mainstay treatment for most solid tumors this will be a true first step towards aprecision oncology approach that we have been seeking for nearly half a century. NCI 10690660 9/1/23 0:00 PA-20-185 5R01CA280980-02 5 R01 CA 280980 2 "WANG, CHIAYENG" 9/1/22 0:00 8/31/27 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 1880052 "LAI, STEPHEN Y" "BANKSON, JAMES A; SANDULACHE, VLAD C" 9 SURGERY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 657066 NCI 451806 205260 PROJECT SUMMARY/ABSTRACTHead and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide.Genotoxic agents including radiation therapy (RT) and cisplatin (CDDP) are treatments that damage cellularDNA. RT and CDDP are the current standard of care in multiple solid tumors including HNSCC. CDDP is themost commonly used chemotherapeutic agent in HNSCC proving superior to novel targeted agents in recentlarge randomized trials. Despite this high rates of treatment failure persist in patients who develop resistancefollowing this toxic chemotherapy. Treatment failure is uniformly fatal. However no robust predictors ofacquired cisplatin resistance or tumor response exist. Given this critical unmet need we have focused our effortson the assessment of tumor response using minimally invasive quantitative imaging (hyperpolarized magneticresonance imaging; HP-MRI) while patients are undergoing therapy. We showed that CDDP and other genotoxicagents trigger measurable fluctuations in tumor cell metabolism detectable through HP-MRI with [1-13C]-pyruvatein real time (confirmed by conventional biochemical assays). Genotoxic stress suppresses the apparent rate ofpyruvate conversion into lactate (kPL) via lactate dehydrogenase (LDH) in a manner that correlates with anti-tumor effectiveness. We therefore hypothesize that changes in kPL provide unique insight into metabolicchanges induced by cisplatin that can be used to optimize response to therapy in HNSCC. In Aim 1 we will characterize baseline HP-MRI parameters such as kPL across the spectrum of HNSCCsubtypes and validate the relationship between CDDP and associated shifts in carbon flux. We will also identifymetabolomic differences in HNSCC models that affect baseline values of metabolic imaging biomarkers andmodulate apparent changes induced by cisplatin. In Aim 2 we will integrate the dose-response data from Aim 1to develop a predictive model of response to CDDP based on metabolic imaging parameters. We will use asimple algorithm to adjust therapeutic dose based on HP-MRI data in animal models of HNSCC to maximizetumor growth delay and test whether thresholds suggestive of strong response can be used to select the moreeffective treatment regimen when multiple regimens are tested in parallel. In Aim 3 we will conduct a first-in-human evaluation of changes in HP-MRI to detect shifts in carbon flux following CDDP in HNSCC patients. Wewill correlate changes in metabolic imaging parameters with the baseline metabolic phenotype of tumors asdetermined from metabolomic analysis and direct measurements of tumor LDH. Successful completion of thisstudy will establish HP-MRI as a non-invasive imaging modality able to predict response to treatmentwhich will be a noteworthy first step towards a precision oncology approach that we have been seeking for nearlyhalf a century. Thus the proposed research is relevant to the part of the NIHs mission that pertains to developingand applying fundamental knowledge that will help to reduce the burdens of human illness and addresses directlythe recently published Notice of Special Interest: Precision Imaging of Oral Lesions (NOT-DE-21-010). 657066 +No NIH Category available Abstinence;Address;Adoption;Adult;Age;Behavioral;Biochemical;Carbon Monoxide;Cardiovascular Diseases;Caring;Cause of Death;Chronic Obstructive Pulmonary Disease;Cigarette;Clinic;Clinical;Clinical Practice Guideline;Clinical Trials;Cost effectiveness research;Cotinine;Counseling;Data;Development;Effectiveness;Enrollment;Epidemiologist;Evidence based intervention;Exhalation;Gender;Goals;Guidelines;HIV;Home;Incidence;Infrastructure;Intervention;Lung;Maintenance;Malignant Neoplasms;Measures;Mediator;Motivation;Outcome;PF4 Gene;Participant;Patient Self-Report;Patients;Persons;Phase;Policies;Population;Prevalence;Psychologist;Randomized;Randomized Controlled Trials;Research;Resource-limited setting;Resources;Risk Factors;Scientist;Self Efficacy;Smoke;Smoker;Smoking;Smoking Cessation Intervention;South Africa;South African;Stress;Target Populations;Time;Tobacco Use Cessation;Tobacco smoking behavior;Tuberculosis;Urine;Variant;Woman;Work;antiretroviral therapy;arm;budget impact;comorbidity;cost;cost comparison;cost effective;cost effectiveness;craving;design;effective intervention;effectiveness/implementation study;efficacy evaluation;epidemiology study;evidence base;health related quality of life;high risk;implementation cost;implementation determinants;implementation evaluation;implementation fidelity;implementation/effectiveness;intervention effect;men;nicotine craving;nicotine gum;nicotine patch;nicotine replacement;patient screening;peer;peer support;peri-urban;primary care setting;primary outcome;programs;public health relevance;scale up;screening;secondary outcome;service delivery;smoking abstinence;smoking cessation;smoking initiation;smoking prevalence;smoking-related disease;social;stressor;success;therapy development;tobacco screening;treatment optimization;treatment strategy;urban setting;varenicline Evaluating smoking cessation interventions for PWH in South Africa: Efficacy implementation and cost-effectiveness. NARRATIVE (Public Health Relevance)People with HIV who smoke have little access to resources to help them quit and smoking cessationinterventions are needed that can be scaled within existing HIV care infrastructure. We will evaluate howsmoking cessation strategies known to work in other populations may support people with HIV in South Africaquit smoking utilizing the existing infrastructure of routine HIV care. We will assess the ability of these smokingcessation interventions to help PWH quit as well as how feasible acceptable and cost-effective they are inthis setting to inform ways to bring the program to scale. NCI 10690653 8/21/23 0:00 RFA-CA-20-037 5U01CA261626-03 5 U01 CA 261626 3 "RICCIARDONE, MARIE D" 9/15/21 0:00 8/31/27 0:00 ZCA1-SRB-2(M1) 8135255 "GOLUB, JONATHAN E." "MARTINSON, NEIL A" 7 GENETICS 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 167600 NCI 677057 81202 PROJECT SUMMARY/ABSTRACTThe purpose of this project is to optimize a smoking cessation program for PWH in South Africa by evaluatingthe efficacy implementation and cost-effectiveness of evidence-based smoking cessation interventions withdemonstrated success in other low-resource settings. South Africa is home to 7.5 million people with HIV (PWH)nearly 20% of the global burden. South Africa also has one of the highest annual tuberculosis (TB) incidencesglobally (520/100000) and an increasing burden of cardiovascular disease and chronic obstructive pulmonarydisease (COPD). Smoking is a risk factor for TB the leading cause of death among PWH. Further PWH are athigh risk for other smoking-related diseases including cardiovascular disease and pulmonary comorbidities inaddition to TB. In South Africa tobacco smoking is prolific; we have found 52% of men and 13% of women withHIV to be current smokers. South African policy supports screening for smoking and smoking cessation effortsfor PWH; these are included in the South African National antiretroviral therapy (ART) guidelines the SouthAfrican STG-EML and the South African clinical practice guidelines. Currently screening for smoking in primarycare settings is low and delivery of smoking cessation interventions even lower. Effective strategies to supportsmoking cessation among PWH are necessary to reduce the burden of HIV- and smoking-associatedcomorbidities. We have found that social and interpersonal stressors and difficulty managing cravings arebarriers to cessation among PWH who smoke in South Africa. Interventions developed for low-resourced settingsoften address these proximal predictors and mediators of cessation and can be easily adapted for South Africaprovided they result in meaningful smoking abstinence rates and are feasible to implement. We will evaluate fourevidence-based smoking cessation interventions that address these identified challenges: (1) intensivebehavioral counseling (2) peer counseling (3) combination nicotine replacement therapy and (4) varenicline.Intervention development is guided by the Multiphase Optimization Treatment Strategy (MOST) a frameworkfor developing optimizing and evaluating interventions with consideration of time and financial resources aswell as feasibility of implementation and cost. During this optimization phase of MOST our first aim will evaluatethe main and interaction effects of these interventions among PWH. The second aim will characterizeimplementation determinants of delivery of these smoking cessation interventions using the ReachEffectiveness Adoptions Implementation Maintenance (RE-AIM) framework to inform scale-up andsustainability. The third aim will compare the costs cost-effectiveness and budget impact of smoking cessationinterventions implemented as a routine program. Results will inform the development of a smoking cessationtreatment package optimized for PWH engaged in the South African HIV program. 167600 +No NIH Category available Address;Adult;Affect;Affective;African American population;Arousal;Attention;Behavioral;Behavioral Research;Cancer Control;Cancer Etiology;Characteristics;Cigar;Cigarette;Consumption;Data;Descriptor;Development;Disease;Disparity;Effectiveness;Electromyography;Elements;Excision;Face;Future;Goals;Health;Image;Influentials;Knowledge;Laboratory Study;Legal;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of larynx;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Marketing;Measures;Online Systems;Outcome;Participant;Patient Self-Report;Persons;Policies;Probability Samples;Psychophysiology;Randomized Controlled Trials;Reaction;Regulation;Research;Research Project Grants;Risk;Rotation;Smoke;Smoking;Smoking Behavior;Taxation;Taxes;Testing;Text;Tobacco;Tobacco-Related Carcinoma;United States Food and Drug Administration;behavior influence;behavioral outcome;cancer prevention;cancer risk;cigarette user;cigarette warning label;cigarillos;court;demographics;effectiveness evaluation;experimental study;improved;malignant mouth neoplasm;negative affect;novel;programs;research study;response;visual tracking;warning label;young adult Little Cigar and Cigarillo Warnings to Reduce Tobacco-Related Cancers and Disease PROJECT NARRATIVEThe research project will develop effective warnings for little cigars and cigarillos (LCCs) whichcause cancer. Scientific findings will provide novel evidence regarding the effectiveness ofnewly developed LCC warning text changes to other LCC warning characteristics (i.e.increased warning size added images) and changes to LCC pack characteristics (removal offlavor descriptors). New warnings will be compared with currently mandated LCC warningsusing a suite of outcomes (self-reported perceived effectiveness of warnings LCC quitintentions LCC smoking behaviors and psychophysiological reactions to warnings includingattention arousal and affect) to inform future efforts to strengthen LCC warnings on packs. NCI 10690621 8/25/23 0:00 PAR-18-559 5R01CA240732-05 5 R01 CA 240732 5 "KAUFMAN, ANNETTE R" 9/2/19 0:00 8/31/24 0:00 Community Influences on Health Behavior Study Section[CIHB] 1903735 "GOLDSTEIN, ADAM O" Not Applicable 4 FAMILY MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 77 Non-SBIR/STTR 2023 454476 OD 312994 141482 ABSTRACTOver 4 million US adults regularly smoke cigars which causes multiple cancers including oralesophageal pancreatic laryngeal and lung cancer. Little cigar and cigarillo (LCC) use amongadults has dramatically increased over the last decade because of disparities in taxationbetween cigarettes and cigars LCC pack sizes that make cigar products affordable andregulations such as flavor bans that exist for cigarettes but not for cigars. Little research hasexamined the effectiveness of currently mandated little cigar and cigarillo (LCC) warnings.Research from studies of cigarette warnings suggests that effective LCC warnings shouldemploy images that illustrate negative health effects associated with use and a large warninglabel prominently displayed on the pack and that removal of flavor descriptors may improveattention to warning messages. However research specific to cigarettes cannot adequatelyinform LCC warning development due to the differences in product characteristics userdemographics and high legal bar for tobacco warnings. No research exists on the potentialimpact of such changes on LCC use among current LCC users. Our proposed study will fill theexisting gaps by understanding which LCC warning characteristics (i.e. content format size)are most influential in reducing LCC use and how an additional LCC policy the removal offlavor descriptors on packaging influences the impact of LCC warnings. In Aim 1 we will useexisting research and expert review to develop new text and pictorial LCC warnings and test thenew warnings using online experiments to identify warnings that adult LCC users perceive asmost effective. We will conduct a national web-based RCT in Aim 2 to examine whether themost effective warnings with images from Aim 1 increase quit intentions among adult LCCusers compared to the currently mandated warnings and a control condition. While our Aim 2study will assess how improved warnings influence LCC behavioral intentions our Aim 3 willassess whether flavor descriptors on LCC packages distract from warnings reducing theirimpact. In Aim 3 we will conduct an in-person laboratory study among adult LCC users usingobjective measures of attention (eye tracking) affect (facial electromyography) and arousal(electrodermal activity) to determine how flavor descriptors influence the effectiveness ofimproved warnings compared to currently mandated warnings. The proposed study will fillcritical gaps regarding which characteristics make LCC warning labels most effective andprovide needed evidence on how LCC warnings influence LCC behavioral intentions. Ouroverarching goal is to develop effective LCC warnings that reduce cancer and other health risks. 454476 +No NIH Category available Ablation;Acceleration;Actins;Amino Acids;Automobile Driving;Bioenergetics;Biological;Bypass;Cancer Etiology;Cancer Patient;Cell physiology;Cells;Cessation of life;Cytoskeleton;Data;Development;Evaluation;Extracellular Protein;Fibroblasts;Glucose;Glutamine;Immune;Immune checkpoint inhibitor;In Vitro;Link;Liquid substance;Malignant Neoplasms;Malignant neoplasm of pancreas;Metabolic;Metabolism;Modality;Molecular;Nutrient;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Phase;Phenotype;Play;Process;Property;Proteins;Publishing;Regulation;Research;Role;Route;Signal Transduction;Source;Starvation;Strategic Planning;Stress;Stromal Cells;Supporting Cell;Testing;Therapeutic;Time;United States;Work;cancer cell;cell type;chemotherapy;deprivation;extracellular;fitness;in vivo;mouse model;neoplastic cell;novel;novel therapeutics;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pharmacologic;sensor;tumor;tumor growth;tumor microenvironment;uptake Regulation and Function of Stromal Macropinocytosis in Pancreatic Ductal Adenocarcinoma PROJECT NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer-relateddeaths in the United States and has been recognized as a recalcitrant cancer that requires acceleratedresearch via the implementation of a long-term strategic plan. PDAC tumors have scarce nutrients and tobypass this nutrient deficiency cancer cells use an endocytic process called macropinocytosis as an aminoacid supply route. We have identified that tumor support cells called stromal cells also use macropinocytosisfor their survival and we propose to study how this uptake pathway works in these cells and whether itrepresents a vulnerability that can be targeted in PDAC therapy. NCI 10690596 8/22/23 0:00 PA-20-185 5R01CA254806-03 5 R01 CA 254806 3 "WOODHOUSE, ELIZABETH" 9/1/21 0:00 8/31/26 0:00 Tumor Microenvironment Study Section[TME] 10376567 "COMMISSO, COSIMO " Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 574084 NCI 294401 279683 PROJECT SUMMARYRecent years have witnessed an appreciation of the role that metabolic adaptation plays in conferring survivaladvantages to cells that encounter the harsh nutrient-poor conditions of the tumor microenvironment. Ofparticular relevance to this proposal is the now widely accepted notion that macropinocytosis an endocyticmechanism of fluid-phase uptake functions in tumors as an amino acid supply route. By stimulating the uptakeof extracellular protein and targeting it for lysosomal degradation macropinocytosis provides cells with asource of protein-derived amino acids allowing tumors to circumvent amino acid depletion and survive nutrientstress. Pancreatic ductal adenocarcinoma (PDAC) tumors are deficient in glutamine a vital nutrient thatsupports tumor growth. Our published work in PDAC cells has established that glutamine depletion has thecapacity to modulate macropinocytosis dialing the process up or down as required. Interestingly ourpreliminary data presented in this proposal demonstrate for the first time that glutamine scarcity can alsostimulate macropinocytosis in cancer-associated fibroblasts (CAFs). Mechanistically we have attributedglutamine stress-induced macropinocytic uptake in CAFs to a CAMKK2-AMPK signal that leads to the Rac1-dependent actin cytoskeleton dynamics that are required for macropinocytosis. AMPK is a bioenergetic stresssensor that is most often studied in the context of glucose starvation which unlike glutamine depletion doesnot boost CAF macropinocytosis. Notably not much is known about AMPK activation and function duringglutamine depletion. Our preliminary studies suggest that macropinocytosis has a dual purpose in CAFs itcan serve to sustain CAF viability and function and it can provide secreted amino acids to nourish the tumorcells. Importantly our in vivo and in vitro examinations of macropinocytosis in normal fibroblasts as well as inCAFs originating from other tumor types suggest that glutamine depletion-induced stromal uptake is unique topancreatic CAFs. Based on these data our central hypothesis is that glutamine scarcity selectively drivesCAMKK2-AMPK-dependent macropinocytosis in CAFs and that stromal macropinocytosis is a process thatcan be harnessed in PDAC therapy. In this proposal we will 1) examine the molecular mechanisms driving theselective role of glutamine in CAF macropinocytosis 2) functionally characterize stromal macropinocytosis inPDAC and 3) determine whether the stromal reorganization that occurs with macropinocytosis inhibition canbe leveraged for PDAC therapy. This project will be of great significance novelty and impact as it willconstitute the first evaluation of the role of macropinocytosis in the PDAC tumor stroma and the first analysis toselectively link glutamine starvation to CAMKK2-AMPK signaling. Moreover because macropinocytosis isimportant in both the tumor cells and the stroma our work could have tremendous impact on the developmentof novel therapeutic modalities for PDAC. 574084 +No NIH Category available 3-Dimensional;Accounting;American;Area;Behavior;Biological Markers;Biopsy;Cancer Detection;Cessation of life;Clinical;Clinical Trials;Colorectal;Contrast Media;Core Biopsy;Dedications;Detection;Developing Countries;Diagnosis;Disease;Early Diagnosis;Early treatment;Elasticity;Engineering;European;Evaluation;Gadolinium;Geography;Gleason Grade for Prostate Cancer;Histopathology;Home;Image;Imaging technology;Industry;Intervention;Kidney Failure;Kinetics;Lead;Left;Lesion;Localized Malignant Neoplasm;Lung;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Medial;Meta-Analysis;Methods;Microbubbles;Morbidity - disease rate;Neighborhoods;Ovarian;PSA screening;Participant;Pathologic;Patients;Pilot Projects;Predictive Value;Prostate;Prostate Cancer therapy;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;ROC Curve;Radical Prostatectomy;Randomized;Rectum;Resources;Scanning;Scientist;Screening for Prostate Cancer;Signal Transduction;Specificity;Structure of base of prostate;System;Techniques;Time;Tissues;Transrectal Ultrasound;Ultrasonography;Viscosity;Visualization;cancer diagnosis;clinically significant;contrast enhanced;cost;cost effective;cost effective intervention;cost effective treatment;detection method;diagnostic accuracy;editorial;improved;industry partner;male;men;mortality;new technology;novel;novel marker;overtreatment;portability;rectal;screening;screening program;socioeconomics;standard of care;technology/technique;treatment program;ultrasound;viscoelasticity Prostate Cancer Diagnosis by Multiparametric Ultrasound Project NarrativeThis project will develop a novel cost-effective Intervention 3D multi-parametric ultrasound imaging (mp-US)for selectively guiding biopsies to detect clinically significant PCa in patients and demonstrate that 3D mp-US iscomparable (i.e. non-inferior) to mp-MRI (the clinical intervention). Thus at the end of this project our partnershipwill deliver an accurate 3D mp-US system ready for clinical deployment.mp-US prostate rev3 narrative DRAFT October 2 2019 11:56AM 1 NCI 10690579 8/18/23 0:00 PAR-18-559 5R01CA252311-04 5 R01 CA 252311 4 "MAZURCHUK, RICHARD V" 7/1/20 0:00 6/30/25 0:00 Clinical Translational Imaging Science Study Section[CTIS] 1968356 "FORSBERG, FLEMMING " "HALPERN, ETHAN J" 2 RADIATION-DIAGNOSTIC/ONCOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 561765 NCI 472480 89285 Prostate cancer (PCa) is the most frequently diagnosed cancer among American males accounting for 20% ofnew cancer diagnoses but PCa is directly responsible for only 9% of cancer related deaths. PSA screeningfacilitates the detection of PCa but many of the cancers detected by PSA screening are low to intermediategrade resulting in overtreatment of non-aggressive PCa. Recent studies suggest an urgent need to selectivelyidentify clinically significant PCa that will result in cost-effective treatment of PCa. In the past few yearsmultiparametric MRI (mp-MRI) has become the standard of care for diagnosis of aggressive PCa. Although mp-MRI guided biopsy can selectively detect higher grade PCa lesions several recent studies acknowledge that aconsiderable number of clinically important lesions are missed by mp-MRI. Furthermore given the high cost ofMRI the geographic variability in the availability of MRI systems the inexact methods used to register and fuseMRI with ultrasound for biopsy and the dangers of Gadolinium in patients with renal insufficiency there is aneed for a more cost-effective alternative to detect high-grade PCa. Recent studies have demonstrated thatcontrast-enhanced ultrasound (CEUS) can selectively detect patients with clinically significant PCa. Newmethods have been proposed to enhance conventional ultrasound detection of PCa including subharmonicimaging (SHI) contrast-enhanced ultrasound dispersion imaging (CUDI) and viscoelastography. The objectiveof this project is to develop a system capable of a multiparametric combination of ultrasound techniques (mp-US) for detection of clinically significant PCa. We will compare 3D mp-US and mp-MRI to identify significantPCa (defined as: Gleason score 7 a single core with > 50% involvement or > 25% of biopsy cores positive forPCa or as Gleason grade group 2 PSA > 10 or clinical stage of cT2b or worse). The first year of the study willbe dedicated to implementation of our mp-US technique on a commercially available 3D transrectal probe andto adapting a MRI-based fusion/registration system to mp-US. During the second year we will optimize mp-USwith a machine learning approach based upon pathologic correlation with 50 radical prostatectomy patients.The final 3 years of the study will be dedicated to a clinical trial with 300 participants suspected of having PCa.Each participant will receive an experimental intervention in the form of biopsy of up to 3 suspicious areasidentified by transrectal ultrasound evaluation of the prostate with mp-US. For comparison a maximum of 3targeted biopsy cores will also be obtained from each participant based on mp-MRI (the clinical intervention).Following the targeted biopsy each participant will also receive a systematic biopsy (standard of care) consistingof 6 laterally directed biopsy cores and 6 medially directed biopsy cores. The study is powered to demonstratethat targeted biopsy based upon mp-US is not inferior to targeted biopsy based upon mp-MRI. 561765 +No NIH Category available ATAC-seq;Agammaglobulinaemia tyrosine kinase;American;Architecture;Archives;Automobile Driving;Biological Assay;Blood;Blood specimen;CAR T cell therapy;Cell Compartmentation;Cell Separation;Cell Therapy;Cell physiology;Cells;Chromatin;Chronic;Chronic Lymphocytic Leukemia;Clinical;Clinical Data;Combined Modality Therapy;Cyclophosphamide;Data;Decision Aid;Decision Making;Disease;Disease Progression;Disease remission;Drug resistance;Early treatment;Epigenetic Process;Fostering;Future;Gene Activation;Gene Expression;Generations;Genetic;Goals;Health;Immune;Immune system;Immuno-Chemotherapy;Immunotherapeutic agent;Immunotherapy;Individual;International Prognostic Index;Knowledge;Learning;Leukemic Cell;Longitudinal Studies;Methylation;Modeling;Modernization;Molecular;Mutation;Outcome;Outcome Study;PLCG2 gene;Pathway interactions;Patient-Focused Outcomes;Patients;Phase III Clinical Trials;Phenotype;Prognostic Factor;Progression-Free Survivals;Progressive Disease;Publishing;Recurrent disease;Refractory;Regulatory Pathway;Relapse;Residual Neoplasm;Residual state;Resistance;Risk;Sampling;Somatic Mutation;T-Lymphocyte;Techniques;Testing;Therapeutic;Time;Toxic effect;Tumor Burden;Tyrosine Kinase Inhibitor;Validation;Work;arm;cell killing;chimeric antigen receptor T cells;chronic T-cell leukemia;chronic lymphocytic leukemia cell;cohort;comparative;design;epigenomics;exhaust;fitness;fludarabine;follow-up;high dimensionality;improved;innovation;insight;leukemia treatment;molecular marker;multiple omics;novel;novel therapeutics;patient population;patient subsets;phase III trial;phase change;predict clinical outcome;predictive tools;pressure;prognostic model;prognostic tool;relapse patients;relapse prediction;response;restoration;risk prediction;rituximab;statistical and machine learning;targeted sequencing;targeted treatment;transcriptome sequencing;transcriptomics Outcomes for CLL patients treated with novel therapy PROJECT NARRATIVEThese scientific studies assess important ways that Ibrutinib-based therapy for upfront therapy of CLL patientscan be evaluated adding important decision parameters on who would benefit the most from this approachstrategies on how to best treat refractory or relapsed patients and on the most opportune times to utilize bloodT cells for immunotherapy. In total this collective analysis will provide critical insights on this therapeuticapproach and in this fashion improve the health of individuals with this disease. NCI 10690564 8/23/23 0:00 PA-20-185 5R01CA251801-03 5 R01 CA 251801 3 "BHARTI, SANITA" 9/15/21 0:00 8/31/26 0:00 Cancer Biomarkers Study Section[CBSS] 2106100 "KAY, NEIL E" "SHANAFELT, TAIT D" 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 614982 NCI 513079 101903 PROJECT SUMMARY/ABSTRACTWe have recently conducted and published a game changing phase 3 clinical North American Intergroup(NAIG) trial (E1912) for chronic lymphocytic leukemia (CLL) therapy which tested a combination of Ibrutiniband Rituximab (IR) vs. the prior gold standard chemoimmunotherapy (CIT): fludarabine cyclophosphamideand rituximab (FCR). This trial showed that both progression free survival (PFS) and overall survival (OS) aresuperior with IR and subsequently was the driving factor in FDA approval for frontline use of IR in progressivepreviously untreated CLL in the spring of 2020. While our work revealed distinct clinical advantages to non-CITapproaches a number of new questions have emerged with respect to how best apply this advance.The durability of the response to first-line ibrutinib-based therapy is highly variable and requires indefinitetreatment exposing patients to the risk of chronic toxicity and selective pressure that may foster resistantclones. The ability to more accurately predict the durability of response could help identify patients more likelyto have long term remission with ibrutinib therapy (candidates for time limited therapy) and those more likely tohave a short duration of response whom may benefit from intensive combination therapy with alternative novelagents. We wish to develop a unique model(s) incorporating multiple key prognostic factors that will have ahigh level of confidence in predicting patient outcomes to novel therapy combination.Our initial study on patients treated on IR arm of E1912 found a subset of patients on the IR arm with evidencefor emerging mutations and changes in their clonal architecture predicting relapse. The exact mechanisms forrelapse need to be defined as we predict that these patients will be difficult to treat and alternative strategiesneeded. We found that IR therapy was uniquely able to reactivate the previously exhausted T cell killing activitydirected against the leukemic CLL cells. While we have some information on the mechanism(s) for this muchremains to be learned and also the exact timing for achieving the maximal restoration of T cell function orfitness. This beneficial impact on T cell function will also be studied as it relates to generation of CAR T cells asthese cells are powerful inducers of immunotherapy which is itself capable of removing residual CLL tumorburden. We hypothesize that the outcome of the studies will add significant and important information on howto best select non-chemotherapy for CLL patients and also the treatment impact on the immune system. Thesegoals will be accomplished through the following specific aims:Aim 1: Develop an Integrated Model to Predict Clinical Outcomes for CLL Patients Treated with Novel Agents.Aim 2: Determine the Genetic Epigenetic and Transcriptomic Changes in Ibrutinib Treated CLL.Aim 3: Characterize the Impact of Ibrutinib Treatment on T-cell Fitness to Guide Application ofImmunotherapy. 614982 +No NIH Category available Abscopal effect;Affect;Agonist;Anti-CD40;Antigen Presentation;Antigens;Bilateral;Breast Melanoma;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cells;Cessation of life;Clinical;Clonal Expansion;Contralateral;Cross Presentation;Data;Dendritic Cells;Development;Distant;Distant Metastasis;Event;FLT3 gene;Foundations;Future;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologic Memory;Immunologic Stimulation;Immunologics;Immunotherapy;In Situ;In complete remission;Infiltration;Investigation;Knowledge;Lesion;Ligands;Lung;Lymphoid;Malignant Neoplasms;Mediating;Metastatic breast cancer;Metastatic malignant neoplasm to brain;Modeling;Mus;Myelogenous;Neoplasm Metastasis;Outcome;PD-1/PD-L1;Patients;Phenotype;Poly I-C;Pre-Clinical Model;Primary Neoplasm;Property;Radiation;Radiation therapy;Radioimmunotherapy;Refractory;Regimen;Research;Resistance;Role;Sampling;Shapes;Solid;T cell infiltration;T cell receptor repertoire sequencing;T cell response;T-Lymphocyte;T-cell inflamed;T-cell receptor repertoire;TLR3 gene;TNFRSF5 gene;Testing;Therapeutic;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Unresectable;Work;adaptive immune response;anti-PD-1/PD-L1;anti-PD-L1 antibodies;anti-PD-L1 therapy;cancer cell;cancer infiltrating T cells;cancer therapy;combinatorial;cytotoxic;draining lymph node;effective therapy;immunogenic;immunogenicity;immunoregulation;improved;in vivo;insight;interest;malignant breast neoplasm;mouse model;neoplastic cell;novel;peripheral blood;radiation effect;response;stem;subcutaneous;targeted treatment;trafficking;tumor;tumor eradication;tumor initiation;tumor microenvironment;tumor-immune system interactions In situ radioimmunotherapy to maximize the engagement of conventional type 1 dendritic cells against non-T cell-inflamed tumors PROJECT NARRATIVEWhile immune-stimulating effects of radiation therapy have been recognized how it works andhow it can be enhanced remain to be elucidated. This proposal aims to investigate the therapeuticefficacy of a novel combinatorial treatment involving intratumoral immunotherapy and radiationand understand the interaction between radiation and the host immune response using preclinicalmodels and clinical samples. This project is expected to advance our knowledge of combiningradiation therapy with immunotherapy and make significant contributions to cancer treatment. NCI 10690556 8/29/23 0:00 PA-20-185 5R01CA255240-03 5 R01 CA 255240 3 "CAPALA, JACEK" 8/1/21 0:00 7/31/26 0:00 Radiation Therapeutics and Biology Study Section[RTB] 11308005 "ITO, FUMITO " Not Applicable 37 SURGERY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 400868 NCI 242950 157918 Radiation therapy (RT) is known to exert direct cytotoxic effects on tumor cells; however recent research isrevealing its influence on the immunogenicity of tumors thus affecting the overall outcome of RT. While RTalone is usually insufficient to overcome the immunosuppressive tumor microenvironment (TME) strategies toboost immune-stimulating effects of RT are under intensive investigation. To date most of the focus has beenplaced on immunomodulation after RT in particular in combination with immune checkpoint inhibitors. Little isknown about how manipulation of the TME before RT can impact on immunogenicity and therapeutic efficacy ofRT. A growing body of evidence reveals that Batf3-dependent conventional type 1 dendritic cells (cDC1) rarelyfound within the tumor myeloid compartment have the important capacity of cross-presenting tumor-associatedantigens (TAA) to CD8+ T cells and act as `master regulators' for the T cell response in cancer. We hypothesizethat in situ induction and activation of cDC1 enhances the therapeutic efficacy and immunogenicity of RT. Totest this hypothesis we developed a combinatorial in situ radioimmunotherapy comprised of in situ administrationof: 1) Flt3L to mobilize cDC1 to the TME; 2) RT to promote immunogenic death of cancer cells and maturationof DC; and 3) dual TLR3/CD40 stimulation to activate antigen-loaded cDC1 for priming of tumor-specific CD8+ Tcells. Our new data using multiple syngeneic orthotopic murine models of poorly immunogenic tumorsinsensitive to anti-PD-L1 therapy reveal that in situ radioimmunotherapy elicits de novo adaptive T cell responsesthat are characterized by novel clonotypes and stem-like Tcf1+ Slamf6+ phenotypes renders tumors responsiveto anti-PD-L1 antibody mediates durable complete responses and develops tumor-specific systemicimmunological memory. Compelling evidence suggests that immunogenicity of RT can be enhanced by in situinduction and activation of cDC1; however immunomodulatory effect of in situ radioimmunotherapy againstdistant metastatic tumors remains unclear. cDC1 prime CD4+ T cells as well as CD8+ T cells but the role of CD4+T cells in in situ radioimmunotherapy remains elusive. In addition it remains unknown whether in situradioimmunotherapy overcomes poor T-cell infiltration in human non-T cell-inflamed tumors. In this proposalwe will elucidate the roles of CD4+ T cells in augmenting antitumor efficacy of in situ radioimmunotherapy (Aim1). Additionally we will seek to better understand the mechanisms underlying the immunomodulatory effect ofin situ radioimmunotherapy targeting non-irradiated distant metastatic tumors (Aim 2). Finally in Aim 3 we willseek to determine the alteration of the human TME in patients with unresectable and metastatic breast cancertreated with in situ radioimmunotherapy. These studies will add essential mechanistic understanding to how RTand the immune system interact and provide insight into the clinical potential of in situ radioimmunotherapyagainst non-T cell-inflamed tumors insensitive to anti-PD-L1 therapy. 400868 +No NIH Category available Adopted;Aftercare;Age;Biological Assay;Biological Markers;Blood;CLIA certified;Cancer Patient;Cause of Death;Cessation of life;Clinical;Clinical Trials;Collection;DNA;Data;Detection;Disease;Disease Marker;Early Diagnosis;Early treatment;Endocrine;Evaluation;Genome;Genomics;Goals;HPV oropharyngeal cancer;HPV-High Risk;Human Papilloma Virus Vaccination;Human Papillomavirus;Human papillomavirus 16;Incidence;Intervention;Laboratories;Lead;Malignant neoplasm of cervix uteri;Measurement;Measures;Metastatic/Recurrent;Monitor;Neurosecretory Systems;Ovarian;Patients;Performance;Plasma;Prognosis;Prostate;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Risk;Saliva;Salivary;Site;Stratification;Testing;Thyroid Gland;Time;Translating;United States;Validation;burden of illness;cancer recurrence;clinically relevant;cohort;cost;disorder control;high risk;improved;men;multi-site trial;novel;patient stratification;performance tests;predictive test;prevent;prognostic;prognostic assays;prospective;risk prediction;salivary assay;standard of care;treatment stratification;tumor Plasma and saliva biomarkers of disease status in HPV related oropharynx cancer Human Papilloma Virus (HPV) related oropharynx cancer (HPVOPC) is increasing in the US and nowexceeds the incidence of cervical cancer and but it is difficult to identify patients who are at high risk forrecurrence. Recent studies have indicated that HPV16 DNA in plasma or salivary rinses may be used as anearly marker for recurrence of HPVOPC and this could provide a window of opportunity to intervene and treator prevent recurrence. This proposal tests the performance of prognostic test for HPVOPC in blood and salivain a clinical setting. NCI 10690548 8/16/23 0:00 PA-18-484 5R01CA243393-05 5 R01 CA 243393 5 "DEY, SUMANA MUKHERJEE" 8/8/19 0:00 7/31/24 0:00 Cancer Biomarkers Study Section[CBSS] 1900169 "CALIFANO, JOSEPH A" Not Applicable 50 SURGERY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 260710 NCI 204884 55826 Human Papilloma Virus (HPV) related oropharynx cancer (HPVOPC) is increasing in the US and nowexceeds the incidence of cervical cancer. Patients with recurrent HPVOPC have an improved survival whencompared to HPV negative OPC patients and a majority of these patients have an opportunity for durabledisease control. In general these data imply that effective early detection of recurrent disease in HPVOPCpatients offers an opportunity to effectively salvage patients with recurrent/metastatic disease.Recent studies have indicated that HPV16 DNA in plasma or salivary rinses may be used as a marker fordisease in HPVOPC and that there may adequate lead time between detection and recurrence to clinicallyintervene in patients with HPV16 DNA in saliva and/or plasma. Accordingly we have developed a novelgenomic based saliva/plasma test for HPV16 DNA in a CLIA certified clinical laboratory. The overallhypothesis of this proposal is that validation of a HPV16 DNA assay in plasma/salivary rinse as a biomarker forhigh risk HPVOPC in a prospective trial will provide independent prognostic data facilitate treatmentstratification for patients at high risk of recurrence and provide lead-time to detection of recurrence that willallow for earlier detection and treatment. This will identify a high-risk cohort of patients with HPVOPC forwhom prognosis can be improved with intensified surveillance and treatment.We anticipate that rigorous evaluation of the potential of HPV16 DNA in plasma and saliva in HPVOPCpatients will establish the value of this biomarker in identification of patients at high risk for recurrence and canbe rapidly translated to clinical usage. 260710 +No NIH Category available Acceleration;Affect;Africa;Africa South of the Sahara;African;Antigen Presentation;Biological;Biological Markers;Biopsy;Blood;CXCL1 gene;Cells;Cervical;Cervical dysplasia;Cervix Uteri;Clinical;Collection;Country;DNA Tumor Viruses;Data;Development;Diagnosis;Differentiation and Growth;Disease;Dysplasia;Environment;Epidemiology;Extracellular Matrix;Fingerprint;Fostering;Future;Gene Expression;Genetic;Genetic Polymorphism;Genetic Variation;Goals;HIV;HIV Infections;HIV Seropositivity;HIV/AIDS;HPV-High Risk;Healthcare;High Prevalence;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immune response;Immunologic Adjuvants;Immunologic Surveillance;Immunomodulators;Infection;Innate Immune System;Investigation;Kenya;Knowledge;Lesion;Life Cycle Stages;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Mediating;Modification;Morbidity - disease rate;Natural Immunity;Oncogenes;Pathology;Pathway interactions;Prevalence;Prevention;Preventive vaccine;Proteins;RNA;Research Personnel;Research Technics;Retroviridae;Risk;Risk Factors;SLPI gene;Sampling;Signal Transduction;Swab;TERT gene;Target Populations;Tissues;Uganda;Variant;Viral;Viral Oncogene;Visual;Woman;Work;antiretroviral therapy;biomarker validation;cancer diagnosis;cancer risk;cell growth;cellular targeting;clinical examination;clinical risk;co-infection;epidemiology study;experimental study;genetic risk factor;genome sequencing;high risk;improved;insight;low and middle-income countries;mortality;peripheral blood;predictive marker;premalignant;prospective;risk stratification;screening;skills;specific biomarkers;synergism;timeline;tumor microenvironment;tumor progression;virus genetics;virus host interaction;whole genome Project 3-- Determining biological and viral factors associated with clinical progression of cervical dysplasia in HIV-infected women NarrativeRecognizing that high-risk HPVs cause cervical cancer and HIV can accelerate its development andprogression we will compare clinical screening examinations to collected biologic samples in order to quantifyexpression of functional biomarkers and identify HPV through typing and sequencing. These biomarkersrepresent the dysregulation human papillomavirus and HIV cause in their hosts; as such by determining theexpression and association of these biomarkers with clinical disease and the virologic fingerprint of high-riskHPV found in Kenya and Uganda we will create a roadmap to discriminate between women with greater risk forHPV-associated precancerous lesions both with and without HIV co-infection. NCI 10690528 8/2/23 0:00 RFA-CA-20-001 5U54CA254518-04 5 U54 CA 254518 4 9/7/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6685 7682292 "KATZENELLENBOGEN, RACHEL ADRIA" Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 160102 123564 36538 Abstract High-risk human papillomaviruses (HR HPVs) are the causative agent for cervical cancer with more than80% of cases clustered in low and middle income countries (LMIC) and a further concentration in Africancountries like Kenya and Uganda. There are preventive vaccines against HPV but less than 2% of the worldstarget population has received them. This leaves millions of women at risk for cervical cancer. We need tounderstand how HR HPV affects its host cell dysregulates its environment and in regions with high rates of co-infection of HR HPV and HIV synergizes with HIV to drive cancer development and progression in women. The greatest clinical risk factor for cervical cancer development is a persistent HR HPV infection. WhenHR HPV infects the cervix it changes the typical sequential activation of cellular growth and differentiationpathways both to support the HR HPV infection and to foster cancer development. In the presence of HIV thepathways and functions of HR HPV infected host cells are further disrupted leading a more rapid progression tocancer. We hypothesize that HR HPV infections manifest in predictable cellular gene expression changes thatare detectable in cervical samples biopsy tissues and peripheral blood. With HIV co-infection we hypothesizean additional overlapping subset of augmented or unique gene expression changes are also detectable. As acollective these changes can serve as functional biomarkers to prospectively identify precancerous lesions andin the context of her HIV status to stratify a womans future cervical cancer risk. Identifying and validating thesebiomarkers is the goal of Specific Aim 1. In addition to cellular biomarkers that predict cancer risk the type and variant of HR HPVs is an importantpredictor of morbidity and mortality associated with a cervical cancer diagnosis. Currently there is a lack offoundational data on the genetic landscape of variants of HPV 16 the most common HR HPV type in invasivecervical cancers in Kenya and Uganda. We hypothesize that specific HPV 16 variants add to this regions cervicalcancer risk; generating detailed data on HPV 16 variants is the goal of Specific Aim 2.Our specific aims are: (1) Determine differences in host gene expression that prospectively discriminateamong HIV+ and HIV- women the risk for cervical dysplasia and precancerous lesions. We will leverage thesynchronous collection of cervical swabs and tissue blood and a clinical exam by visual inspection to quantifyhost gene expression changes linked to pathology. (2) Determine the HPV 16 variants found in HIV+ and HIV-women. We will investigate HPV 16 variants and conduct whole genome sequencing to create a detailed pictureof HPV 16 genetic polymorphisms. Through investigations of HR HPV its host cells and HR HPV in the contextof HIV we will determine the biologic and virologic signatures designating a HIV+ or HIV- woman at risk forcervical cancer development and progression. Studies for both aims will be performed in Kenya and Ugandaexpanding scientific research techniques and future pipelines of investigators in Sub-Saharan Africa. +No NIH Category available AIDS related cancer;Acceleration;Acetic Acids;Aflatoxins;Africa;Africa South of the Sahara;Biopsy;CD4 Lymphocyte Count;Caring;Cervical Cancer Screening;Cervical Intraepithelial Neoplasia;Cervical dysplasia;Clinical;Cost Effectiveness Analysis;Country;DNA;Data;Databases;Detection;Exposure to;HIV;HIV/AIDS;HPV-High Risk;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immune system;Immunosuppression;Immunosuppressive Agents;Impairment;Incidence;Infrastructure;Kenya;Literature;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Medical;Methods;Mycotoxins;Natural History;Oncogenic;Outcome;Plasma;Policies;Prevalence;Research;Risk;Risk Factors;Screening procedure;Swab;Testing;Training;Uganda;Vagina;Viral load measurement;Virus;Visual;Woman;antiretroviral therapy;carcinogenicity;cofactor;cost;design;experience;immune reconstitution;improved;insight;prevent;programs;screening Project 1-Preventing cervical cancer in HIV-infected women NarrativeOur objective is to help eradicate cervical cancer in HIV-infected Kenyan/Ugandan women by 1) evaluatingHPV DNA testing of self-collected vaginal swabs combined with VIA in screening and 2) determine if aflatoxinis a risk factor for oncogenic HPV detection and cervical cancer. NCI 10690517 8/2/23 0:00 RFA-CA-20-001 5U54CA254518-04 5 U54 CA 254518 4 9/7/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 7538 1903522 "BROWN, DARRON R" Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 129989 125204 4785 AbstractIn contrast to other HIV-associated cancers the incidence of cervical cancer has not declined in the era ofantiretroviral therapy (ART) and is the most common cancer among Kenyan and Ugandan women. Thesecountries each have high HIV prevalence which greatly accelerates the progression of cervical cancer even inwomen receiving ART and achieving reconstituted immune systems. Better methods of screening areneeded and we need to understand cofactors related to HPV infection the virus that causes cervical cancer.The long-term objective of our project is to help eradicate cervical cancer in HIV-infected Kenyan and Ugandanwomen. We will test our approach in a study of HIV-infected women. First we will evaluate HR-HPV DNAtesting of self-collected vaginal swabs combined with VIA in detecting biopsy-proven cervical intraepithelialneoplasia grades 2 3 or worse (CIN 2/3+) in HIV-infected women living in Kenya or Uganda. Wehypothesized that detection of biopsy-proven CIN 2/3+ is higher among HIV-infected women with both HR-HPV DNA positivity and VIA abnormality compared to those with only one or neither of these tests positive.Second we will determine if aflatoxin a carcinogenic and immunosuppressive compound found incontaminated corn is a risk factor for oncogenic HPV detection and cervical cancer among HIV-infectedKenyan and Ugandan women. We hypothesize that regardless of HIV-status aflatoxin is a risk factor for HR-HPV detection HR-HPV persistence and biopsy-proven CIN 2/3+ that the impact of aflatoxin on HR-HPVdetection HR-HPV persistence and biopsy-proven CIN 2/3+ will be significantly greater in HIV-infectedwomen than in HIV-uninfected women and that the immunosuppressive effects of aflatoxin impair the hostsability to control HIV in spite of ART use. Accomplishment of our aims will help improve care for all women inKenya and Uganda and help in the battle against cervical cancer in HIV-infected women. +No NIH Category available AIDS related cancer;Acquired Immunodeficiency Syndrome;Africa;Africa South of the Sahara;African;Age;American;Area;Behavioral;Biological;Biology;Biometry;CD4 Lymphocyte Count;Cancer Burden;Caring;Cessation of life;Clinical;Collaborations;Consent;Country;Data;Databases;Developed Countries;Development;Diagnosis;Disease;Disparity;Environment;Environmental Risk Factor;Epidemiology;Fostering;Funding;Goals;HIV;HIV Infections;HIV/AIDS;HPV-High Risk;Healthcare;Home;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Immunohistochemistry;Incidence;Infection;Infrastructure;Institution;International;Investigation;Kenya;Knowledge;Laboratories;Lesion;Link;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Molecular;Oncogenic;Oncology;Outcomes Research;Participant;Pathology;Patients;Pilot Projects;Population;Prevalence;Prevention;Prevention program;Process;Research;Research Personnel;Resources;Risk;Role;Sampling;Science;Scientist;Secure;Services;Site;Specimen;Techniques;Technology;Testing;Tissues;Total Quality Management;Training;Uganda;Universities;Viral;Woman;Work;antiretroviral therapy;biobank;cancer care;career;chronic infection;data management;data sharing networks;epidemiologic data;genome sequencing;immune reconstitution;improved;improved outcome;low and middle-income countries;member;next generation sequencing;pathogen;population health;premalignant;programs;prospective;routine screening;screening;screening program;skills;treatment program;whole genome Translational Core NarrativeOur objective in the translational biology core (TBC) is to support the three projects in this proposal enhancethe research capabilities in Kenya and Uganda and to foster young African investigators as they begin theircareers in science and the study of HIV-associated cancers. NCI 10690499 8/2/23 0:00 RFA-CA-20-001 5U54CA254518-04 5 U54 CA 254518 4 9/7/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6677 11028221 "ERMEL, AARON " Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 74256 68046 6210 AbstractThe majority of new cancers that were diagnosed and the majority of cancer related deaths worldwide occurredin low-and-middle income countries (LMICs) in 2018. This is in striking contrast to more developed countrieswhere cancer care and outcomes are improving. One driver of this difference is the human immunodeficiencyvirus (HIV) which predisposes those who are infected to develop certain cancers. Despite the burden of cancerin LMICs there is a lack of organized research and support services to see to the successful outcomes ofresearch programs. In the case of cervical cancer the confluence of high HIV prevalence disparity in resourcesand lack of infrastructure in research results in high burden of what could be a preventable disease. The overallobjective of this proposal is to improve the screening prevention and knowledge of the mechanisms of cancerdevelopment as it relates to cervical cancer in Kenyan and Ugandan women. In HIV-infected women anduninfected women cervical cancer is caused by persistent infection of human papillomavirus (HPV). Thoughinfection with HPV is relatively common only a small percentage of women will develop cervical cancer.Environmental factors unique to Kenya and Uganda may also contribute to the increase in cervical cancer burdenin this area of the world. There is also a lack of understanding of the human molecular mechanisms and viral(HPV and HIV) work together to promote cancer development. The investigation of how all of these factors(environmental viral human behavioral and biological) interact in Kenyan and Ugandan women is the overallobjective of this program project. The role of the Translational Biology Core (TBC) is to support the scientificendeavors outlined in the three projects and to provide an environment conducive to the training of new Africanscientists in the field of HIV-associated malignancies. Not only will the TBC process and store samples collectedduring the study period it will also continue augment the biorepository that will provide samples for ongoingresearch in Oncology in East Africa. As a part of this proposal the TBC will be improving data sharing resourcesin partnership with the International Epidemiology Databases to Evaluate AIDS in East Africa (IeDEA-EA) so thatdata generated in Kenya and Uganda can be freely shared among members of the consortium. In doing so thecare provided to women in Kenya and Uganda with cervical cancer will improve. +No NIH Category available AIDS related cancer;Advisory Committees;Africa;American;Biology;Biometry;Collaborations;Communication;Communities;Community Outreach;Country;Data;Development;Goals;HIV/AIDS;Human Papilloma Virus-Related Malignant Neoplasm;Information Dissemination;Institution;Malignant neoplasm of cervix uteri;Morbidity - disease rate;North America;Participant;Pilot Projects;Research;Research Infrastructure;Research Personnel;Services;Woman;adjudication;community engagement;data management;inter-institutional;member;mortality Administrative Core NarrativeThe overall goal of the Administrative and Coordination Core is to oversee the administration of the East AfricaConsortium for HPV and Cervical Cancer (EACHC) in Women Living with HIV/AIDS. The A&C Core alsocoordinates the activities of all investigators involved on three projects and the three additional cores and tofacilitate communication within and between the North American Ugandan and Kenyan institutions and otherorganizations in which the EACHC will directly interact. NCI 10690496 8/2/23 0:00 RFA-CA-20-001 5U54CA254518-04 5 U54 CA 254518 4 9/7/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6675 2189007 "LOEHRER, PATRICK J." Not Applicable 7 Unavailable 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN Domestic Higher Education 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 210416 161487 48930 AbstractThe goal of the Administrative and Coordinating (A&C) Core is to oversee the administration of the East AfricaConsortium for HPV and Cervical Cancer (EACHC) in Women Living with HIV/AIDS. The A&C Core coordinatesthe activities of all investigators involved on three projects and the three additional cores (Biostatistics and DataManagement; Translational Biology; and Developmental) and to facilitate communication within and betweenthe North American Ugandan and Kenyan institutions and other organizations in which the EACHC will directlyinteract. The Administrative and Coordinating Core will also be responsible for dissemination of informationwithin participants of the EACHC and outside of the EACHC through an External Advisory Committee whichwill provide additional advice on pilot projects and on mechanisms to enhance community outreach andengagement.The rationale for central communication and data flow through this centralized approach is to maximize intra-institutional inter-institutional and inter-country collaborations through this unique partnership and to adjudicateany potential conflicts as they arise.The specific services provided by this Core follow from its Aims:Specific Aim 1: To facilitate communication resolve potential conflicts and maximize the research infrastructuresupporting the investigators of each of the EACHC projects and cores;Specific Aim 2: To disseminate research findings between the consortium members in East Africa and NorthAmerica; andSpecific Aim 3: To leverage the research conducted by the EACHC with the community stakeholders with otherexternal entities to impact the morbidity and mortality of cervical cancer and other AIDS-associated malignancies.These aims will be accomplished through the Partnership Coordinating Activities and with assistance from theExternal Advisory Board as outlined herein. +No NIH Category available AIDS related cancer;Acetic Acids;Aflatoxins;Africa;Africa South of the Sahara;African;Biological;Biological Factors;Biological Markers;Biometry;Cervical;Cervical Cancer Screening;Cervical Intraepithelial Neoplasia;Cervical dysplasia;Cervix Neoplasms;Clinical;Communicable Diseases;DNA;Data;Dedications;Development;Diagnosis;Environmental Risk Factor;Epidemiology;Goals;HIV;HIV/AIDS;HPV-High Risk;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Incidence;Ingestion;Kenya;Knowledge;Lesion;Local Therapy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;Natural History;Nurses;Outcome;Physicians;Pilot Projects;Prevalence;Research;Research Infrastructure;Research Personnel;Resource Sharing;Scientist;Testing;Training;Training Programs;Translational Research;Triage;Uganda;Viral;Visual;Woman;antiretroviral therapy;carcinogenesis;career;cervical carcinogenesis;cofactor;data management;design;international partnership;loop electrosurgical excision procedure;low and middle-income countries;premalignant;prevent;programs;screening The East Africa Consortium for HPV and Cervical Cancer in Women living with HIV/AIDS Overall NarrativeWorldwide cervical cancer remains one of the most common malignancies in women particularly in those whoare HIV-infected. The core objective of this application is to better elucidate the natural history of humanpapillomavirus infection and the development of cervical cancer in HIV-infected women. These include to clarifythe cofactors involved in carcinogenesis the persistence and progression of cervical intraepithelial neoplasia(CIN) after local therapies and to identify new viral and cellular biomarkers that will ultimately assist in screeningtriage and treatment. NCI 10690495 8/2/23 0:00 RFA-CA-20-001 5U54CA254518-04 5 U54 CA 254518 4 "DOMINGUEZ, GERALDINA" 9/7/20 0:00 8/31/25 0:00 ZCA1-TCRB-D(M1) 2189007 "LOEHRER, PATRICK J." "BROWN, DARRON R; NAKALEMBE, MIRIAM ; ORANGO, ELKANAH OMENGE" 7 INTERNAL MEDICINE/MEDICINE 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 923799 NCI 781734 122066 Overall AbstractSub-Saharan Africa contains 70% of the worlds diagnosed cases of HIV/AIDS with both Uganda and Kenya atits epicenter (12% and 7% prevalence respectively). Within East Africa cervical cancer remains one of the mostcommon malignancies in women. HIV is a contributing factor for cervical carcinogenesis with HIV-infectedwomen having a greater incidence and persistence of human papilloma virus (HPV) infections cervical cancerand precancerous cervical lesions. In contrast to other HIV-associated cancers the incidence of cervical cancerhas not declined in the era of antiretroviral therapy.The core objective of this application is to better elucidate the natural history of HPV infection and cervical cancerin HIV-infected women including the cofactors involved in carcinogenesis the persistence and progression ofcervical intraepithelial neoplasia (CIN) after LEEP and to identify new viral and cellular biomarkers that will assistin screening triage and treatment.Our central hypothesis is that the incidence persistence and spectrum of high risk (HR) HPV are substantiallygreater in HIV-infected East African women and that this explains the higher incidence of cervical neoplasia.We further hypothesize that these and other modifiable factors such as aflatoxin ingestion disproportionatelyand adversely influence outcomes of local therapies such as Loop Electrosurgical Excision Procedure (LEEP)in HIV-infected women.The specific aims for the East Africa Consortium for HPV and Cervical Cancer (EACHC) in Women Living withHIV/AIDS are:Specific Aim 1. To establish a sustainable research infrastructure for an international partnership to conductimpactful research in HPV and cervical cancer in women living with HIV/AIDSSpecific Aim 2. To design and execute three integrated projects that advance the knowledge of theenvironmental and biologic factors leading to cervical cancer in East Africa: Project 1- Preventing cervical cancer in HIV-infected women Project 2- Understanding CIN2+ among HIV infected women after LEEP: An epidemiological and immunohistochemical study Project 3- Determining biological and viral factors associated with clinical progression of cervical dysplasia in HIV-infected womenSpecific Aim 3. To increase the research workforce capacity in East Africa through mentoring training programsand targeted pilot projects 903799 +No NIH Category available AIDS related cancer;Acetic Acids;Aflatoxins;Africa;Africa South of the Sahara;African;Biological;Biological Factors;Biological Markers;Biometry;Cervical;Cervical Cancer Screening;Cervical Intraepithelial Neoplasia;Cervical dysplasia;Cervix Neoplasms;Clinical;Communicable Diseases;DNA;Data;Dedications;Development;Diagnosis;Environmental Risk Factor;Epidemiology;Goals;HIV;HIV/AIDS;HPV-High Risk;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Incidence;Ingestion;Kenya;Knowledge;Lesion;Local Therapy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;Natural History;Nurses;Outcome;Physicians;Pilot Projects;Prevalence;Research;Research Infrastructure;Research Personnel;Resource Sharing;Scientist;Testing;Training;Training Programs;Translational Research;Triage;Uganda;Viral;Visual;Woman;antiretroviral therapy;carcinogenesis;career;cervical carcinogenesis;cofactor;data management;design;international partnership;loop electrosurgical excision procedure;low and middle-income countries;premalignant;prevent;programs;screening The East Africa Consortium for HPV and Cervical Cancer in Women living with HIV/AIDS Overall NarrativeWorldwide cervical cancer remains one of the most common malignancies in women particularly in those whoare HIV-infected. The core objective of this application is to better elucidate the natural history of humanpapillomavirus infection and the development of cervical cancer in HIV-infected women. These include to clarifythe cofactors involved in carcinogenesis the persistence and progression of cervical intraepithelial neoplasia(CIN) after local therapies and to identify new viral and cellular biomarkers that will ultimately assist in screeningtriage and treatment. NCI 10690495 8/2/23 0:00 RFA-CA-20-001 5U54CA254518-04 5 U54 CA 254518 4 "DOMINGUEZ, GERALDINA" 9/7/20 0:00 8/31/25 0:00 ZCA1-TCRB-D(M1) 2189007 "LOEHRER, PATRICK J." "BROWN, DARRON R; NAKALEMBE, MIRIAM ; ORANGO, ELKANAH OMENGE" 7 INTERNAL MEDICINE/MEDICINE 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 923799 FIC 17299 2701 Overall AbstractSub-Saharan Africa contains 70% of the worlds diagnosed cases of HIV/AIDS with both Uganda and Kenya atits epicenter (12% and 7% prevalence respectively). Within East Africa cervical cancer remains one of the mostcommon malignancies in women. HIV is a contributing factor for cervical carcinogenesis with HIV-infectedwomen having a greater incidence and persistence of human papilloma virus (HPV) infections cervical cancerand precancerous cervical lesions. In contrast to other HIV-associated cancers the incidence of cervical cancerhas not declined in the era of antiretroviral therapy.The core objective of this application is to better elucidate the natural history of HPV infection and cervical cancerin HIV-infected women including the cofactors involved in carcinogenesis the persistence and progression ofcervical intraepithelial neoplasia (CIN) after LEEP and to identify new viral and cellular biomarkers that will assistin screening triage and treatment.Our central hypothesis is that the incidence persistence and spectrum of high risk (HR) HPV are substantiallygreater in HIV-infected East African women and that this explains the higher incidence of cervical neoplasia.We further hypothesize that these and other modifiable factors such as aflatoxin ingestion disproportionatelyand adversely influence outcomes of local therapies such as Loop Electrosurgical Excision Procedure (LEEP)in HIV-infected women.The specific aims for the East Africa Consortium for HPV and Cervical Cancer (EACHC) in Women Living withHIV/AIDS are:Specific Aim 1. To establish a sustainable research infrastructure for an international partnership to conductimpactful research in HPV and cervical cancer in women living with HIV/AIDSSpecific Aim 2. To design and execute three integrated projects that advance the knowledge of theenvironmental and biologic factors leading to cervical cancer in East Africa: Project 1- Preventing cervical cancer in HIV-infected women Project 2- Understanding CIN2+ among HIV infected women after LEEP: An epidemiological and immunohistochemical study Project 3- Determining biological and viral factors associated with clinical progression of cervical dysplasia in HIV-infected womenSpecific Aim 3. To increase the research workforce capacity in East Africa through mentoring training programsand targeted pilot projects 20000 +No NIH Category available Address;Age;Aging;Agreement;Ancillary Study;Area;Aspirin;Behavior;Beta Carotene;Biological Assay;Biological Markers;Biological Specimen Banks;Blood;Blood specimen;Cardiovascular Diseases;Cause of Death;Cessation of life;Characteristics;Chemoprotection;Chronic Disease;Classification;Clinical;Cohort Studies;Collaborations;DNA;Data;Data Collection;Death Certificates;Development;Devices;Disease;Dose;Erythrocytes;Evaluation;Event;Funding;Funding Agency;Funding Mechanisms;Future;Genes;Genetic;Genotype;Grant;Growth;Health;Individual;Infrastructure;Knowledge;Leadership;Maintenance;Malignant Neoplasms;Measures;Medical Records;Metabolic Diseases;Methodology;Methods;Monitor;Morbidity - disease rate;Multiple Cancer Sites;Outcome;Paper;Participant;Patient Self-Report;Pattern;Phenotype;Physical activity;Physical assessment;Plasma;Primary Cancer Prevention;Productivity;Public Health Practice;Publishing;Quality Control;Questionnaires;Randomized;Recommendation;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Risk Factors;Role;Sampling;Self-Examination;Site;Testing;Time;Translating;United States Centers for Medicare and Medicaid Services;Update;Validation;Vitamin E;Woman;Women's Health;Work;cancer epidemiology;cancer prevention;cohort;cost effective;data integration;data management;data quality;data sharing;epidemiology study;exome;follow-up;gene environment interaction;genetic analysis;genetic association;genetic information;genome wide association study;genome-wide;improved;member;mortality;neoplasm resource;observational cohort study;randomized trial;rare cancer;research study;sedentary lifestyle;tumor;virtual;web site Women's Health Study: Infrastructure support for cohort follow-up This proposal seeks support over the next 5 years for the infrastructure of the Women's Health Study a large-scale cancer epidemiology cohort of 39876 women followed since 1992. Data are available on a wide range ofcharacteristics chronic disease development blood biomarkers genetic information and objectively measuredphysical activity and sedentary behavior. Continued follow-up is crucial for building on the enormous amount ofdata already collected in order to answer critical questions related to cancer. NCI 10690494 9/11/23 0:00 PAR-17-233 5U01CA182913-10 5 U01 CA 182913 10 "LAM, TRAM K" 9/17/14 0:00 8/31/24 0:00 ZCA1-RTRB-Y(O1) 1876593 "BURING, JULIE E." "LEE, I-MIN " 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 629372 NCI 391618 309379 This proposal seeks infrastructure support only for core functions to conduct 5 years of continued follow-up ofthe Women's Health Study (WHS) under PAR-17-233. The WHS began in 1992 as a randomized trial testingaspirin beta-carotene and vitamin E for prevention of cancer and cardiovascular disease (CVD) in 39876healthy women over age 45. Prior to randomization 28345 women (71%) provided a blood sample: all havebeen assayed for a wide range of biomarkers; genome-wide association studies (GWAS) have beencompleted on >25000 and exome chip genotyping on >22000. The trial ended in 2004 and 33682 (or 89%of surviving women were willing to be followed observationally. Women report via yearly questionnaires on awide range of exposures and endpoints; we confirm self-reported cancer and CVD endpoints with medicalrecords and cause of death by medical records and/or death certificates. Device-assessed 7-day physicalactivity and sedentary behavior has been collected on 17708 women. The WHS is unique in having extensivegenetic data as well as objectively-assessed physical activity and sedentary behavior in such a large cohort.Follow-up is excellent: after almost 24 years morbidity follow-up is still 89.6%% and mortality follow-up isvirtually 100%. As the average age of living participants is 77.1 years event rates are increasing substantially:at the end of current funding (8/31/19) 7769 confirmed cancers will have occurred; by the end of the proposedfunding cycle (8/31/24) 10869 cancers will be confirmed. This will substantially increase WHS's ability toaddress important cancer questions including examination of site-specific cancers rare cancers and tumor-specific characteristics. The WHS has actively shared data with internal and external researchers resulting in650 papers published 106 funded grants using WHS data and collaboration in 22 NCI Cohort Consortiumprojects. Currently none of the ancillary studies provides funding for ascertainment and validation of cancer(and CVD) endpoints.In the proposed funding period we will continue the WHS infrastructure including the follow-up and evaluationof self-reported exposures and endpoints and maintenance of the WHS biospecimen repository to furtherfacilitate data sharing and collaboration. WHS is also committed to continuing to provide leadership in researchaims related to gene-based prediction of incident disease and gene-environment interactions; improvedassessments of physical activity and sedentary behavior to study associations with health outcomes andevaluation of long-term chemoprotection of low-dose aspirin. Independent funding will be sought over the nextperiod to address specific hypotheses in these areas. In the next 5 years continued infrastructure support andfollow-up is crucial for maximizing the cost-effective use of this valuable large-scale cancer cohort of womenwith a rich resource of already collected phenotypic and genetic data particularly since many WHS findingshave been and can be directly translated to clinical and public health practice or formal recommendations. 629372 +No NIH Category available Affect;Area;Behavior;Behavioral;Brain;Brain region;Budgets;Cancer Control;Cellular Phone;Cigarette;Cigarette Smoker;Communication Research;Control Groups;Correlation Studies;Cues;Data;Ecological momentary assessment;Environment;Experimental Designs;Exposure to;Failure;Functional Magnetic Resonance Imaging;Habits;Health;Individual;Instruction;Intervention;Laboratories;Laboratory Study;Link;Location;Maps;Marketing;Measures;Medial;Mediating;Methods;Outcome;Participant;Pharmaceutical Preparations;Phase;Philadelphia;Photography;Policies;Policy Making;Process;Protocols documentation;Reaction;Regulation;Reporting;Research;Sales;Science;Smoker;Smoking;Smoking Behavior;Specificity;Standardization;Survey Methodology;Surveys;Testing;Tobacco Industry;United States;Visual;Water;Work;behavior observation;cancer prevention;cigarette craving;cigarette smoke;cigarette smoking;craving;cue reactivity;design;dosage;experimental study;functional MRI scan;innovation;insight;interdisciplinary approach;neural;neuroimaging;non-smoking;novel;novel strategies;preventable death;response;smoking cessation;smoking cue;tobacco advertising;tobacco control Cancer prevention through neural and geospatial examination of tobacco marketing effects in smokers Project NarrativeRecent work suggests detrimental links between exposure to point-of-sale tobacco marketing (POSTM; wherethe tobacco industry currently focuses most of its marketing budget) increases in cigarette cravings and thefailure to quit smoking. We will combine innovative methods in communication research including mobile-phone based geolocation tracking ecological momentary assessment (EMA) and functional magneticresonance imaging (fMRI) to test whether repeated real-world exposure to POSTM affects cigarette smokingbehavior and whether this is mediated by heightened craving and neural responses to POSTM. Understandingthe causal mechanisms linking environmental POSTM cues and later cue reactivity craving and behavior willprovide information to cancer prevention control and regulatory efforts in ways not possible without thisresearch. NCI 10690456 8/11/23 0:00 PAR-18-638 5R01CA229305-05 5 R01 CA 229305 5 "BLAKE, KELLY D" 4/4/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-RPHB-R(56)R] 10485301 "FALK, EMILY " Not Applicable 3 NONE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF ARTS AND SCIENCES 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 805357 NCI 502788 302569 Project Summary / AbstractCigarette smoking is the leading cause of preventable death and illness in the United States and throughout the developed world. Currently the tobacco industry focuses over 80% of its marketing budget in the retail environment. Recent work suggests detrimental links between exposure to point-of-sale tobacco marketing (POSTM) increases in cigarette cravings and the failure to quit smoking. Understanding how individuals are influenced by and react to their natural environments when making health decisions is thus critical to cancer control efforts. We propose to use an innovative set of methods to test whether repeated real-world exposure to POSTM affects smoking behavior and whether this is mediated by heightened craving and neural responses to POSTM. Our novel multi-method approach to communication research includes mobile-phone based geolocation tracking ecological momentary assessment (EMA) and functional magnetic resonance imaging (fMRI). By adding the ecological validity of observational field methods to the mechanistic insight of neuroimaging and causal inferences from an experimental design we aim to significantly advance actionable insight about POSTM effects in cancer control. Research utilizing geospatial location tracking and survey methods suggests that high levels of POSTM exposure may increase craving; however correlational studies preclude mechanistic explanations and causal inferences about POSTM effects. Relatedly laboratory studies have documented neural and behavioral reactivity to standardized visual smoking cues such as photographs of cigarettes but the brains response to naturalistic POSTM exposure has not been explored. We hypothesize that exposure to POSTM increases brain responses to smoking cues as well as subjective craving leading to increased smoking behavior. To test this we will follow 180 daily smokers with geospatial location tracking and EMA to assess whether longitudinal fluctuations in real-world POSTM exposure are associated with moment-to-moment cigarette craving and smoking behavior (Aim 1) and whether these processes are related to differences in neural smoking cue reactivity (Aim 2). Finally we will conduct an experiment that manipulates naturalistic exposure to POSTM to test whether these effects are causal (Aim 3). In the experimental phase two groups of participants will enter and make a small purchase (e.g. water) at a retail outlet with or without POSTM displays 5 times per week for 4 weeks while a third control group will not change their habits. We will measure neural responses and subjective cravings to POSTM exposure in all groups before and after the experimental manipulation. Protocol feasibility and dosage has been established through extensive pilot work. Increases in smoking behavior craving and/or neural cue reactivity in response to increased POSTM exposure would strongly implicate causal evidence for POSTM exposure which is much needed for science-based policy making and could inform cancer control efforts.causal evidence for POSTM exposure which is much needed for science-based policy making and could inform cancer control efforts. 805357 +No NIH Category available Affinity;Alleles;Animal Experiments;Animal Model;Award;Bibliography;Binding;Biochemical;Biochemistry;Biology;C-terminal;Cancer Biology;Cell Line;Cell Proliferation;Cell model;Cells;Characteristics;Collaborations;Colorectal Cancer;Complement;Complementarity Determining Regions;Complex;Data;Dedications;Development;E-learning;Event;FRAP1 gene;Fostering;Future;Genes;Guanosine Diphosphate;Guanosine Triphosphate;In Vitro;Institution;K-ras mouse model;KRAS oncogenesis;KRAS2 gene;KRASG12D;Knock-out;Learning;Lung;Lung Adenocarcinoma;Lung Neoplasms;MAPK8 gene;MEKKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Mediating;Mentors;Mentorship;Metabolism;Modeling;Molecular;Molecular Conformation;Mus;Mutate;Mutation;Oncogenic;Oncoproteins;Organ;Organoids;Pancreas;Pancreatic Adenocarcinoma;Pathway interactions;Patients;Personal Behavior;Phase;Phosphorylation;Phosphotransferases;Physiology;Positioning Attribute;Principal Investigator;Process;Prognosis;Property;Protein Isoforms;Proteins;Recombinants;Refractory;Research;Research Personnel;Resources;Role;Series;Signal Transduction;Specificity;Stomach;Stress;Structure;System;Testing;Therapeutic;Time;Training;Tumor Biology;Tumor Burden;Validation;Work;Yeasts;biochemical model;career;career development;design;experience;experimental study;fly;gain of function mutation;in vivo;innovation;insight;interest;knock-down;malignant phenotype;member;migration;model organism;mouse genome;mutant;novel;novel therapeutic intervention;skills;standard of care;tool;tumor;tumor growth;tumor initiation;tumorigenesis The role of Sin1 in Kras-driven cancer PROJECT NARRATIVEKRAS is the most commonly mutated gene in cancer and despite extensive research in the field the moleculareffectors that orchestrate its oncogenic potential remain understudied. Here we propose the study andcharacterization of a novel KRAS-specific protein effector Sin1 by using biochemical cellular and animalmodels. Our work will lead to novel insights into the tumor biology of oncogenic KRAS and inspire innovativetherapeutic approaches. NCI 10690455 8/15/23 0:00 PA-19-130 5R00CA245122-05 5 R00 CA 245122 5 "GHOSH-JANJIGIAN, SHARMISTHA" 9/1/21 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 14585964 "CASTEL, PAU " Not Applicable 12 BIOCHEMISTRY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 146903 102097 PROJECT SUMMARYMutations in KRAS are among the most frequent in cancer particularly in certain poor prognosis subtypessuch as lung and pancreatic adenocarcinomas. Extensive evidence suggests that KRAS is a cancer driver andmost tumors remain addicted to this oncoprotein. Biochemically KRAS acts as a molecular binary switch thatcycles between a GTP-bound active state and a GDP-bound inactive state and KRAS oncogenic mutationsfavor the active conformation. In the active state KRAS associates with protein effectors that propagate thedownstream signal and contribute to the malignant phenotype. In this proposal I describe the discovery of Sin1as a novel potential KRAS effector and hypothesize its role in contributing to the initiation of KRAS-drivenmalignancies. Through this application I plan a series of advanced biochemical and structural experimentsaimed at determining whether Sin1 acts as a canonical Ras effector. Given the essential role of Ras effectorsduring tumorigenesis this project will also study the effect of Sin1 depletion in animal models and organoidcultures transformed by an activated form of KRAS. Previous studies have shown that Sin1 is an essentialcomponent of the mTOR complex 2 (mTORC2) which regulates kinase phosphorylation metabolism and isitself central to proliferative signaling in cancer but the contribution of KRAS in this context has not beenestablished at the molecular level. Moreover early studies in model organisms have shown that Sin1 is acomponent of the stress mitogenic pathways by interacting with MEKK2 and JNK. This proposal will addresshow Sin1 may act at the intersection of these two pathways and KRAS: I will determine through the use ofspecific Sin1 separation-of-function mutants whether the mechanisms of this potential KRAS effector aremTORC2-dependent or independent. If successful the results of this project will have a significant impact inthe field of KRAS signaling in particular and the cancer biology in general: the characterization of a novelKRAS-specific effector critical for tumorigenesis. The results of this study could provide a strong rationale fornovel therapeutic approaches targeting previously uncharacterized KRAS effectors a potential boon forpatients with KRAS-driven malignancies.As part of my career development I have put together a specific plan that includes activities for my mentoredphase (K99) that are aimed at facilitating my transition to an independent principal investigator position (R00)including: a) Discussion with supervisor and advisory panel; b) Experience from personally conducting theresearch; c) Mentoring experience; d) Institutional developmental resources and coursework; and e) Onlinelearning resources and bibliography. These activities will also be complemented by a strong mentorship fromthe cancer researchers Dr. Frank McCormick who will advise on the biochemistry and the members of myadvisory panel Dr. Allan Balmain who will advise on KRAS mouse models and Dr. Calvin Kuo who will adviseon the organoid work. They have committed to provide technical conceptual and mentoring support. Twoadditional activities will be carried out during my K99 phase to complement my research skills; the first willinvolve learning how to isolate culture and work with organoids derived from different organs; while thesecond will be a conceptual and technical training in mass spectrometry in collaboration with Dr. AnatolyUrisman who will help identify key interactors and effectors of Sin1. This award would provide me with thenecessary tools time and resources to gain deeper insights into the biology of KRAS and Sin1 signaling aswell as fostering the necessary collaborations and skills to transition into an independent academic career. 249000 +No NIH Category available Acute;Affect;Androgen Receptor;Androgens;Apoptosis;Apoptotic;Automobile Driving;BAX gene;BCL2 gene;BCL2L1 gene;BCL2L11 gene;BRCA2 gene;Binding;Biological Markers;Blood Platelets;Castrate sensitive prostate cancer;Castration;Cellular Stress;Clinical;Clinical Trials;Combined Modality Therapy;DNA Sequence Alteration;Data;Dependence;Exposure to;FDA approved;Gene Amplification;Gene Deletion;Hematologic Neoplasms;MCL1 gene;Malignant neoplasm of prostate;Mediator;Medical Castration;Metastatic Prostate Cancer;Mitochondria;Modeling;Pathway interactions;Patients;Pharmaceutical Preparations;Protein Family;Proteins;RB1 gene;Recurrence;Role;Signal Transduction;Solid Neoplasm;Thrombocytopenia;Toxic effect;VCaP;androgen deprivation therapy;castration resistant prostate cancer;efficacy evaluation;in vivo;inhibitor;mimetics;preclinical study;pro-apoptotic protein;prostate cancer cell;response;standard care;targeted agent;tumor;ubiquitin ligase Prostate Cancer Vulnerabilities to BH3 Mimetic Drugs We propose that available BH3 mimetic drugs such as navitoclax (targeting BCL2/BCLXL) andnewly emerging BH3 mimetics that target MCL1 can be exploited in prostate cancer (PC) to lowerthe apoptotic threshold and in subsets with certain genomic alterations or in combination withappropriate agents can generate marked apoptosis and hence durable responses. Identificationof genomic alterations and optimal combination therapies that exploit these drugs and the uniquevulnerabilities of PC cells is the overall objective of this proposal. NCI 10690430 5/22/23 0:00 PA-20-185 5R01CA262536-03 5 R01 CA 262536 3 "KONDAPAKA, SUDHIR B" 6/1/21 0:00 5/31/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1863884 "BALK, STEVEN P." Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 392306 NCI 224175 168131 The anti-apoptotic BCL2 family proteins (including BCL2 BCLXL and MCL1) act by neutralizing BAX and BAKand by inhibiting the BH3-only pro-apoptotic proteins that can activate BAX/BAK. BH3-mimetics are drugs thatenhance apoptosis by binding to and inhibiting BCL2 BCLXL or MCL1. Navitoclax inhibits BCL2 and BCLXLand has single-agent activity in hematological malignancies but causes thrombocytopenia due to BCLXLinhibition. A BCL2-specific BH3-mimetic that spares platelets venetoclax is similarly active and FDA approvedfor several hematological malignancies. Unfortunately these currently clinically available BH3-mimetics havelimited single agent activity in most solid tumors which appears to substantially reflect a greater role for MCL1.BH3 mimetic drugs that inhibit MCL1 have more recently been developed and are in early trials but preclinicalstudies from us and others suggest that it will in most cases be necessary to inhibit both BCLXL and MCL1 toachieve robust apoptotic responses and it is likely that toxicity will limit the ability to combine BCL2/BCLXL andMCL1 inhibitors in patients. Although BH3 mimetics have limited efficacy as single agents in PC they may haveactivity in subsets of PC with genomic alterations affecting apoptotic pathways. We recently identified themitochondrial ubiquitin ligase MARCH5 as the primary mediator MCL1 degradation in response to cellular stressand found that MARCH5 gene deletion that occurs in up to ~5% of CRPC can sensitize to BH3 mimetic drugs.Other alterations that increase MCL1 expression (including MCL1 gene amplification) are also frequent in PCand can confer increased MCL1 dependence. Conversely our preliminary data indicate that PC withBRCA2/RB1 loss may be highly dependent on BCLXL. Based on these data Aim 1 is to identify and characterizegenomic alterations that may be used as robust biomarkers for clinical trials of single agent BH3 mimetic therapy.While a subset of PC may be responsive to single agent BH3 mimetic drugs fully exploiting these drugs willlikely require the identification of synergistic combination therapies. Indeed we have previously identified anumber of available drugs that can markedly enhance MCL1 degradation and sensitize to navitoclax. ThereforeAim 2 is to identify combination therapies that exploit BH3 mimetic agents to drive apoptotic responses in CRPC.Finally we hypothesize that castration-sensitive prostate cancer (CSPC) cells exposed to intensive androgensignaling inhibition may have a reduced apoptotic threshold and be vulnerable at least transiently to the additionof a BH3 mimetic drug. Therefore Aim 2 will also determine whether BH3 mimetics can be used to exploitvulnerabilities generated acutely by intensive ASI in CSPC. Overall we hypothesize that BH3 mimetic drugs willbe highly effective in a subset of genetically defined CRPCs and more broadly in combination with other targetedagents. The Specific Aims are 1) Identify genomic alterations in prostate cancer that sensitize to BH3 mimeticdrugs and 2) Identify BH3 mimetic combination therapies that are effective in prostate cancer 392306 +No NIH Category available Academic Medical Centers;Active Learning;Address;Adult;Awareness;Biometry;Cancer Patient;Cancer Survivor;Caring;Clinic;Clinic Visits;Collaborations;Computerized Medical Record;Counseling;Data Science;Development Plans;Diagnosis;Drug Prescriptions;Evidence based practice;Evidence based treatment;Face;Familiarity;Focus Groups;Future;Goals;Guidelines;Health Services Research;Hospitals;Interview;K-Series Research Career Programs;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Medical;Memorial Sloan-Kettering Cancer Center;Mentors;Methods;Morbidity - disease rate;Newly Diagnosed;Oncology;Outcome;Patient-Focused Outcomes;Patients;Pattern;Peripheral;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;Prevalence;Primary Care;Process;Provider;Qualitative Methods;Qualitative Research;Quality of life;Recurrence;Recurrent Malignant Neoplasm;Research;Research Methodology;Research Personnel;Research Priority;Research Project Grants;Research Proposals;Risk;Risk Factors;Science;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Surgical Oncology;Tobacco;Training;United States;Urologic Oncology;Urologist;Urology;Variant;Veterans;Veterans Health Administration;Vulnerable Populations;cancer diagnosis;cancer recurrence;care delivery;career development;clinical decision support;comorbidity;data warehouse;evidence base;implementation science;implementation strategy;implementation study;improved;improved outcome;innovation;member;mortality;multidisciplinary;nicotine replacement;novel;patient screening;preservation;recruit;research and development;screening;skills;smoking cessation;support tools;theories;treatment strategy Optimizing Smoking Cessation Treatment for Patients with Bladder Cancer PROJECT NARRATIVEBladder cancer is caused by smoking and continued smoking after diagnosis leads to significantand preventable morbidity and mortality. Bladder cancer patients rely principally on theirurologist for medical guidance but urology providers do not frequently use evidence-basedpractices (EBPs) that screen patients for smoking and provide them with the necessarycounseling and medications to quit. In this study we will characterize use of smoking cessationEBPs in the urology clinic then adapt and pilot a strategy to facilitate use of these EBPs in theurology clinic for patients with bladder cancer. NCI 10690426 8/28/23 0:00 PA-20-203 5K08CA259452-02 5 K08 CA 259452 2 "BIAN, YANSONG" 9/1/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 14187647 "MATULEWICZ, RICHARD STEVEN" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 194124 NCI 179744 14380 Smoking is the leading risk factor for bladder cancer and is estimated to account for half of the 80000 new diagnoses each year in the United States. Patients who quit after diagnosis have improved quality-of-life lower risk of recurrence and a 3-fold lower chance of dying from bladder cancer compared to those who continue to smoke. Yet only one in 5 urologists delivers smoking cessation treatment to patients and considerable gaps in patient awareness and guideline-concordant screening and referral exist in the urology setting. These factors contribute to adults with bladder cancer being the least likely to quit smoking after diagnosis compared to all other cancer survivors. Increased use of evidence-based smoking cessation treatment will improve outcomes for the estimated 100000 patients with bladder cancer who continue to smoke. The proposed research project aims to investigate and optimize the delivery of evidence-based smoking cessation treatment for patients with bladder cancer at Memorial Sloan Kettering Cancer Center (MSK). Specific Aim 1 will evaluate how smoking cessation treatment is given to patients with bladder cancer by quantifying practice patterns and exploring factors associated with sub-optimal care delivery. Specific Aim 2 will identify determinants of smoking cessation treatment using qualitative methods that will help elucidate multi-level determinants of evidence-based practices. Specific Aim 3 will adapt our current tobacco treatment strategy to the urology context using theory-based implementation science methods informed by our mixed-methods explanatory study (Aims 1 and 2) and will pilot promising strategies. The proposed research represents a significant step towards understanding and improving the delivery of evidence-based smoking cessation treatment for patients with bladder cancer. Our findings will establish a theory-based paradigm to facilitate smoking cessation treatment within diverse surgical oncology contexts at MSK while improving patient outcomes and advancing the field of implementation science. The proposed research project is accompanied by a training plan that will provide the candidate with critical expertise in advanced biostatistics and data science qualitative research methods and implementation science. This will be accomplished through a detailed plan that involves coursework collaboration and experiential learning corresponding to each Specific Aim of the study. This career development and training plan will give the candidate a set of skills unique among urologists and will be guided by a world-class group of mentors and collaborators at a premier academic medical center and partner hospitals. The members of this multidisciplinary team will each contribute unique expertise to the candidates novel and innovative career development plan and research proposal. This career development award will position him to make significant contributions in the future as an independent investigator in health services research and urologic oncology. 194124 +Cancer Amendment;Area;Clinical Trials;Clinical Trials Database;Consultations;Contractor;Data;Databases;Development;Elements;Ensure;Equipment and supply inventories;Extramural Activities;Letters;Persons;Preparation;Process;Protocols documentation;Quality Control;Reporting;Research Personnel;Services;Technology;Work;abstracting;acronyms;cohesion;meetings;programs;protocol development;response Protocol Information Office (PIO) Support Services n/a NCI 10690414 261201800045C-P00008-9999-1 N01 9/24/18 0:00 9/23/23 0:00 16187766 "BRYANT-DAVIS, WANDA " Not Applicable 11 Unavailable 146014373 LXQRK5BR85F1 146014373 LXQRK5BR85F1 US 38.792695 -77.060392 10027818 "ARSERVICES, LTD" LORTON VA Domestic For-Profits 220791961 UNITED STATES N R and D Contracts 2022 730673 NCI The objective of this requirement is to provide support to the NCI DCP Protocol Information Office (PIO). (A list of acronyms terms and definitions are provided at the end of this Statement of Work.) The scope is divided into five fully integrated and cohesive project areas. The five project areas are described in more detail in the Specific Aims. 730673 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Prevention Biological;Clinical;Clinical Chemoprevention;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs CORE INFRASTRUCTURE SUPPORT FOR THE CANCER PREVENTION AGENT DEVELOPMENT PROGRAM n/a NCI 10690412 261201200031I-P00003-759101900130-1 N01 9/23/19 0:00 9/22/23 0:00 16187657 "CHOW, SHERRY " Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N R and D Contracts 2022 242912 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials. The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 242912 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Networking and Information Technology R&D (NITRD); Patient Safety Clinical Data;Clinical Management;Clinical Trials;Clinical Trials Network;Community Clinical Oncology Program;Computer software;Data;Data Management Resources;Foundations;Health Professional;Investigational Therapies;Maintenance;Malignant Neoplasms;Medidata;National Clinical Trials Network;Physicians;Research Personnel;Safety;Services;data management;electronic data;operation;programs;tool Hosting Maintenance and Professional services for Rave and Medidata Rave Integrated Software n/a NCI 10690410 261201800033I-P00007-26100001-1 N02 9/1/18 0:00 8/31/23 0:00 16145856 "KRAVATZ, GREGG " Not Applicable Unavailable 840371087 V25NDJFKMKA1 840371087 V25NDJFKMKA1 US -471915 NEW YORK NY Other Domestic Non-Profits 10014 UNITED STATES N R and D Contracts 2022 7314450 NCI Medidata Rave is an Electronic Data Management (EDC) and Clinical Data Management System (CDMS). An EDC/CDMS is the primary tool utilized by researchers physicians and other health care professionals to communicate and track scientific and safety data related to an experimental cancer trial. By extension an EDC/CDMS serves as the foundation for clinical trial operations and conduct. The primary NCI users of Medidata Rave are the National Clinical Trials Network (NCTN) Experimental Therapeutics Clinical Trials Network (ETCTN) National Community Clinical Oncology Program (NCORP) and several smaller NCI multi-center consortia. In addition Medidata Rave supports multiple NCI Divisions and Programs. 7314450 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Prevention Biological;Clinical;Clinical Chemoprevention;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs CORE INFRASTRUCTURE SUPPORT FOR THE CANCER PREVENTION AGENT DEVELOPMENT PROGRAM n/a NCI 10690408 261201200042I-P00004-759101900129-1 N01 9/23/19 0:00 9/22/23 0:00 16187684 "LIMBURG, PAUL " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N R and D Contracts 2022 54197 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinicaltrials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 54197 +Bioengineering; Cancer; Cervical Cancer; Clinical Research; Comparative Effectiveness Research; Cost Effectiveness Research; HPV and/or Cervical Cancer Vaccines; Health Services; Immunization; Infectious Diseases; Prevention; Sexually Transmitted Infections; Vaccine Related; Women's Health Address;Adolescent;Australia;CD4 Lymphocyte Count;Cancer Burden;Cancer Control;Cancer Intervention and Surveillance Modeling Network;Cervical;Cervical Cancer Screening;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Comparative Carcinogenesis;Cost Effectiveness Analysis;Country;Data;Decision Making;Development;Disease;Disease Outcome;Effectiveness;Ensure;Evaluation;Guidelines;HIV;Health;Health Benefit;Health Policy;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Infection;Information Dissemination;Kenya;Knowledge;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Modeling;Netherlands;New Mexico;North Dakota;Outcome;Policies;Policy Maker;Population;Preventative vaccination;Prevention strategy;Process;Public Health;Reporting;Research Personnel;Risk;Route;Series;South Africa;Technology;Testing;Time;Uganda;United States;Update;Vaccinated;Vaccination;Vaccines;Woman;base;cancer health disparity;cervical cancer prevention;cervical carcinogenesis;co-infection;cohort;comparative;comparative effectiveness;cost;cost effective;cost effectiveness;disparity reduction;effectiveness evaluation;evidence base;human model;improved;innovation;low and middle-income countries;mathematical model;new technology;programs;scale up;screening;screening guidelines;sexually transmitted virus;tool;vaccination strategy;working group Comparative Modeling to Inform Cervical Cancer Control Policies Project NarrativeNew technologies including screening tests and vaccines against human papillomavirus (HPV) a sexually-transmitted virus known to cause cervical cancer are dramatically changing the landscape of cervical cancercontrol in the US and worldwide. In order to address important evidence gaps our CISNET-Cervical workinggroup consisting of five teams who have been at the forefront of modeling cervical cancer prevention overthe last decade will continue this comparative modeling collaboration to evaluate the harms benefits andcost-effectiveness of screening and vaccination strategies and disseminate findings to inform health policiesand decisions. NCI 10690116 9/1/22 0:00 RFA-CA-19-054 3U01CA253912-03S1 3 U01 CA 253912 3 S1 "TATALOVICH, ZARIA" 9/8/20 0:00 8/31/25 0:00 ZCA1-SRB-T(M3) 8689652 "KIM, JANE JOOYUN" "BARNABAS, RUANNE VANESSA; CANFELL, KAREN ; DE KOK, INGE MCM; KULASINGAM, SHALINI L." 7 PUBLIC HEALTH & PREV MEDICINE 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 393 Non-SBIR/STTR 2022 42462 NCI 27587 14875 Project SummaryDespite successful cervical cancer screening in the United States (US) over 13000 women develop and 4000women die from cervical cancer each year. The discovery of human papillomavirus (HPV) as the necessarycause of cervical cancer precipitated a surge of new evidence and development of innovative HPV-basedtechnologies both screening and prophylactic vaccination that have allowed for significant changes in ourapproach to cervical cancer control over the past two decades. These new technologies represent tremendousopportunities for effective equitable and efficient cervical cancer programs in the US but also pose significantchallenges for decision-making. Given the limited availability of outcomes data for new screening andvaccination approaches from empirical studies policy-makers have become uniquely reliant on mathematicalmodeling to provide a synthesized evidence base for decision-making for cervical cancer control strategies.These models can be used to integrate the most up-to-date data extrapolate short-term findings into long-termoutcomes and evaluate what-if scenarios that would otherwise be impractical or infeasible to conduct inclinical studies. The proposed CISNET project will represent the continued productive collaboration of fiveindependent modeling groups from the US Australia and the Netherlands that will leverage a series of state-of-the-art mathematical models of HPV and cervical carcinogenesis for comparative modeling. We will pursueanalyses related to the impact of newly-revised screening and HPV vaccination guidelines the comparativeeffectiveness of forthcoming screening and HPV vaccination strategies and approaches the optimal routes forreducing cervical cancer disparities the potential for cervical cancer elimination in the US and optimalscreening and vaccination strategies in women living with HIV. Our efforts will also involve wide disseminationof findings to various stakeholders to increase transparency and confidence in model-based analyses. 42462 +No NIH Category available Address;Appointment;Area;Award;Basic Science;Biochemistry;Biological;Biology;Biophysics;Collaborations;Colon Carcinoma;Communities;Development;Diagnosis;Discipline;Faculty;Fellowship Program;Fostering;Foundations;Funding;Generations;Genetic;Goals;Growth;Human;Infrastructure;Institution;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant neoplasm of thorax;Medical;Medical Oncology;Medical Research;Mentors;Minority Recruitment;Molecular;Pathology;Patients;Pharmacology;Physicians;Prevention;Procedures;Process;Pulmonology;Research;Research Personnel;Science;Scientist;Solid;Talents;Training;Translational Research;United States National Institutes of Health;Work;Yale Cancer Center;anticancer research;base;career;clinical center;clinical investigation;design;interest;knowledge base;malignant breast neoplasm;medical schools;next generation;novel;personalized medicine;programs;recruit;translational impact;translational research program;translational scientist Yale SPORE in Lung Cancer Career Enhancement Program PROGRAM NARRATIVEThe Yale SPORE in Lung Cancers Career Enhancement Program is a key program to foster the developmentof the next generation of physician scientists focused on conducting research in the area of human thoracicmalignancies to advance discoveries in the prevention diagnosis and treatment of lung cancer. NCI 10690096 8/7/23 0:00 PAR-18-313 5P50CA196530-09 5 P50 CA 196530 9 8/26/15 0:00 7/31/25 0:00 ZCA1-RPRB-6 6592 6671108 "KLUGER, HARRIET M." Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 92245 55103 37195 PROGRAM SUMMARYThe number of physician-scientists working in lung cancer has not kept pace with the overall growth of themedical research community or with the growth in our basic knowledge base resulting in an increasing numberof unrealized basic and translational research opportunities. Yale is uniquely suited to helping rebuild this basewith our strong commitment to translational research. The Career Enhancement Program (CEP) of the YaleSPORE in Lung Cancer (YSILC) has been designed to contribute substantively to ongoing efforts and newinitiatives attempting to address this problem. The goal of the CEP is to educate a new generation ofinvestigators committed to translational research in lung cancer. The CEP has substantial institutionalcommitment both in terms of funding and infrastructure. For example our translational research office at Yale(also led by Dr. Herbst YSILC PI) has been committed to providing early seed funding and translationalsupport to young investigators early in their research careers. Potential CEP candidates include promisingjunior faculty who are interested in establishing their careers in translational lung cancer research and/orestablished investigators whose previous research has been in other areas and would like to transition intolung cancer focused research. Junior faculty awardees will be paired with mentors who are more establishedlung cancer investigators with a documented record of successful mentoring. In this way the YSILC willstimulate the development of the next generation of physician scientists addressing the most challengingissues in lung cancer research. +No NIH Category available Agreement;Area;Award;Biology;Budgets;Caliber;Carcinogenesis Mechanism;Clinical;Collaborations;Committee Members;Communities;Consultations;Development;Direct Costs;Early Diagnosis;Electronic Mail;Ensure;Financial Support;Fostering;Funding;Funding Mechanisms;Future;Goals;Guidelines;Human;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Monitor;Morbidity - disease rate;Outcome;Pilot Projects;Prediction of Response to Therapy;Process;Productivity;Program Research Project Grants;Recruitment Activity;Research;Research Personnel;Research Project Grants;Resource Sharing;Risk Assessment;Study Section;United States National Institutes of Health;Woman;Work;Yale Cancer Center;anticancer research;cancer therapy;innovation;meetings;member;minority investigator;mortality;new therapeutic target;novel;novel therapeutics;personalized medicine;prognosis biomarker;programs;recruit;translational potential;translational research program;tumorigenesis Yale SPORE in Lung Cancer Developmental Research Program PROGRAM NARRATIVEThe objective of this Developmental Research Program is to foster and develop innovative lung cancertranslational research programs with objectives that align with the overall goals of the Yale SPORE in LungCancer. Projects of the highest caliber will be sought to possibly serve as replacements for the primarySPORE projects should productivity lag or other unforeseen circumstances arise. NCI 10690091 8/7/23 0:00 PAR-18-313 5P50CA196530-09 5 P50 CA 196530 9 8/26/15 0:00 7/31/25 0:00 ZCA1-RPRB-6 6590 1925253 "HERBST, ROY S" Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 101394 60569 40883 PROGRAM SUMMARYThe primary goal of the Developmental Research Program (DRP) of the Yale SPORE in Lung Cancer (YSILC)is to identify and fund innovative pilot projects that possess translational potential for making an impact in thefield of lung cancer in the areas of risk assessment; early detection; biomarkers for prognosis therapy andprediction; biology; and novel treatment approaches. Investigators and projects of funded developmentalresearch projects are strongly encouraged to collaborate with other investigators within and outside of Yaleincluding other SPORE research communities with the goal that these projects will evolve into independent fullSPORE projects or equivalent scale studies. The objective of the YSILC DRP is to develop innovative lungcancer translational research programs. To achieve this goal we propose the following three specific aims:Specific Aim 1. To identify and recruit innovative pilot projects with translational potential for lung cancer.Specific Aim 2. To support new research opportunities for lung cancer by funding innovative pilot projects.Specific Aim 3. To enhance collaborations between SPORE full research projects and DRP investigators(current and potential) and to promote DRP projects to potential full SPORE or equivalent scale projects.Pilot projects funded by the DRP mechanism are strongly encouraged to collaborate with intra- and inter-SPORE projects. Projects making significant progress will be considered for incorporation into a full project ifthere are any programmatic needs and upon agreement of the YSILC leadership in consultation with theInternal Advisory Board External Advisory Board and NCI staff. +No NIH Category available Acceleration;Address;African American population;Age;Apoptosis;Area;Bile Acids;Biological Assay;Body Weight decreased;Breast Cancer Cell;Breast Cancer Model;Cancer Etiology;Cancer Patient;Carcinogens;Cells;Centenarian;Chronic;Coculture Techniques;Complement;Cytometry;DNA;DNA Damage;Data;Diet;Dietary Administration;Dietary Supplementation;Etiology;Exposure to;Failure;Female;Funding;Genomic Instability;Goals;Heterogeneity;High Fat Diet;Human;Immune;Immunity;Immunotherapy;In Vitro;Incidence;Inflammation;Inflammatory;Intervention;Intervention Studies;Investigation;Knowledge;Lead;Life Style;Link;Lithocholic Acid;Longevity;Macrophage;Malignant Neoplasms;Measures;Mediating;Mediator;Metabolic;Metabolic dysfunction;Metagenomics;Microbe;Minority;Mission;Modeling;Mouse Strains;Mus;Obese Mice;Obesity;Obesity associated cancer;Observational Study;Outcome;Outcome Measure;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Population;Population Heterogeneity;Pre-Clinical Model;Predisposition;Publishing;Qualifying;Race;Reactive Oxygen Species;Research;Risk;Risk Assessment;Risk Management;Signal Transduction;Study models;T-Lymphocyte;Testing;Therapeutic;Thinness;Transgenic Model;Translating;Woman;aged;bariatric surgery;cancer cell;cancer initiation;cancer risk;carcinogenicity;cell transformation;design;gut microbes;healthy weight;human subject;improved;innovation;malignant breast neoplasm;metabolomics;microbial;microbiome;mouse model;obese patients;obese person;obesogenic;oxidative damage;premalignant;preventive intervention;programs;response;risk mitigation;therapy outcome;tumor Determining the contribution of microbial-derived metabolites to protective immunity in obesity-driven cancer risk. NARRATIVE:Obesity is broadly associated with both increased incidences of a variety of cancers and a chronicinflammatory state. Our interdisciplinary team with expertise in cancer obesity microbiomeimmunometabolism will test if obesity-altered gut microbes enhance cancer risk through dysregulatedprotective immunity which leads to changes in the immune milieu that increase cancer cell transformation andinitiation. These studies will increase understanding of obesity-associated cancer risk and point to potentialinterventions to alleviate this risk or treat existing cancers. NCI 10690087 9/5/23 0:00 RFA-CA-21-021 5U01CA272541-02 5 U01 CA 272541 2 "DASCHNER, PHILLIP J" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-2(M2) 2196764 "MAKOWSKI-HAYES, LIZA " "PIERRE, JOSEPH F; RATHMELL, JEFFREY C." 9 INTERNAL MEDICINE/MEDICINE 941884009 X1M1PN3KG3E7 941884009 X1M1PN3KG3E7 US 35.138829 -90.033163 578302 UNIVERSITY OF TENNESSEE HEALTH SCI CTR MEMPHIS TN SCHOOLS OF MEDICINE 381034903 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 978693 NCI 801429 177264 SUMMARY: Obesity is associated with increased risk for 13 cancers. Critical questions are how and to whatextent underlying mechanisms of obesity-mediated increases in chronic inflammation may increase cancer riskin a failure of protective immunity. This knowledge gap represents an untapped opportunity that our multidis-ciplinary team is uniquely qualified to explore with a mission to improve understanding of cancer risk. We havepreviously shown obesity alters T cell and macrophage functions that could decrease anti-tumor protectionsand have expertise in human studies essential for this interdisciplinary challenge. Our objective is to identifyassociations in human subjects and test mechanisms of mediators of cancer risk in various pre-clinical modelsalong an obesitymicrobes metabolites protective immunity axis. Our hypothesis is that obesity-alteredgut microbes enhance cancer risk through dysregulated protective immunity that allows increased initiation.Aim 1 will define obesity-mediated dysregulation of microbial-derived metabolites and impacts on immune phe-notypes and protective immunity in human subjects at greater risk for cancer by examining diverse subjects1a) of varied age and adiposity; and 1b) obese patients pre- and post- bariatric surgery. Donors will be drawnfrom the Memphis area which offers a highly diverse population with 65% African Americans with a high inci-dence of obesity. Patient analyses will inform studies in complementary pre-clinical models to allow for mecha-nistic investigation to identify conserved mechanisms in the pre-cancer microenvironment. Aim 2 will deter-mine the impact of microbially-derived metabolites on cancer risk by examining immune cells in spontaneoustransgenic models of breast cancer with established heterogeneity in latency obesogenic response to high fatdiet circulating bile acids and gut microbes. Aim 3 will test dietary administration of a specific microbially-de-rived metabolite or microbe on protective immunity in complementary carcinogenic and syngeneic models ofobesity-mediated breast cancer respectively. Human subject and murine model studies complemented by exvivo and in vitro studies will test underlying mechanisms to determine how microbially-modified metabolitesmay impact immune-cancer cell crosstalk. Collaborative funds for cross-consortium activities are reserved forrisk assessment across heterogenous lean and obese populations and models across aims to add synergisticimpact to our findings through NCIs Metabolic Dysregulation and Cancer Risk Program. In sum outcomes willdefine beneficial microbially-derived metabolites that impact protective immunity to reduce cancer initiation.Thus the strategy of this proposal is conceptually original innovative and significant to define conserved un-derlying mechanisms that suppress cancer risk. Findings generated will have high impact because the obesity-associated etiological impacts on risk will be heterogeneous and this study is designed to investigate thosevaried mechanisms to translate to better risk management to improve patient outcomes. 978693 +No NIH Category available African American;Aliquot;Anatomy;Archives;Baltimore;Basic Cancer Research;Benign;Biometry;Blood;Bone Marrow;Cancer Biology;Cancer Center;Catchment Area;Cigarette;Clinical Oncology;Clinical Research;Complex;Comprehensive Cancer Center;Confidentiality of Patient Information;Consultations;County;DNA;Data Analyses;Data Set;Databases;Diagnosis;Diagnostic;Disease;Doctor of Medicine;Epidemiology;Ethics;Faculty;Flow Cytometry;Formalin;Freezing;Funding;Genomics;Goals;Grant;Health Insurance Portability and Accountability Act;Histology;Human;Image Analysis;Immunotherapy;Infrastructure;Institutional Review Boards;Investigational Therapies;Journal of the National Cancer Institute;Journals;Knowledge;Laboratories;Malignant Neoplasms;Manuscripts;Maryland;Medical;Medical center;Methods;Mission;Molecular Biology;Mononuclear;Normal tissue morphology;Oncology;Paraffin Embedding;Pathologic;Pathology;Patients;Peer Review;Pharmacy Schools;Plasma;Population Sciences;Preparation;Process;Proteomics;Public Health Schools;Publications;RNA;Research;Research Design;Research Personnel;Research Support;Resources;Sampling;School Dentistry;Services;Source;Specimen;Strategic Planning;System;Techniques;Tissue Banks;Tissue Embedding;Tissue Microarray;Tissue Procurements;Tissue Sample;Tissues;Translating;Translational Research;Tumor Tissue;Universities;Xenograft procedure;acronyms;biobank;cancer health disparity;cancer type;clinical application;college;cost effective;digital imaging;feasibility research;follow-up;histotechnology;hormone related cancer;human tissue;in vivo;innovation;medical schools;member;neoplasm immunotherapy;pathology imaging;peripheral blood;programs;protocol development;racial disparity;structural biology;surgical service;tissue archive;tissue processing;translational cancer research;tumor;tumor immunology;virology Pathology and Biorepository Shared Service n/a NCI 10690082 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6586 9462908 "IOFFE, OLGA " Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 1 1 0 19.0 Abstract: Pathology Biorepository Shared ServiceThe Pathology Biorepository Shared Service (PBSS) provides access to high-quality banked patient sampleswhile maintaining patient confidentiality for studies aimed at understanding the biology cancer with an ultimategoal of translating this knowledge into diagnostic and clinical applications. PBSS provides pathology histologyand histotechnology services to assist with procurement analyses and clinicopathology of human tissues.PBSS has long-standing expertise gained from a well-established relationship with NCI and from access toexisting expertise and archives. PBSS provides tissue bank services for surgical specimens. Frozen tissuearchives contain over 13000 aliquots of diseased and benign tissue including 9500 aliquots of matched same-patient tumor and normal tissue and more than 25000 frozen peripheral blood and bone marrow mononuclearisolates/plasma samples. PBSS provides customized tissue collection and access to over 1870000 formalin-fixed paraffin-embedded tissue blocks from pathologic diagnoses obtained at the University of Maryland MedicalCenter. A database contains demographic epidemiologic pathologic and follow-up patient information. Of thetumor samples 30% were from African-American patients representative of the UMGCCC catchment areawhich facilitates high-impact racial disparity studies. PBSS provides unique value-added services based oncooperation with the UMSOM Anatomic Pathology Department including diagnostic pathology biobankingsophisticated histotechnology and digital image analysis. Ioffe (HRC) and Staats (HRC) direct the PBSS. PBSSexperts provide consultation regarding study design optimal use of human tissue samples IRB and HIPAAcompliance and data interpretation. PBSS interacts with other shared services to provide high-quality specimensnecessary for RNA/DNA extraction in vivo xenograft preparation proteomic studies and clinicopathologicdataset acquisition. A Faculty Oversight Committee composed of PBSS users provides guidance on currentservices and strategic planning. UMGCCC program members receive priority access to biobanking tumor tissueexamination protocol development and research support. PBSS provides efficient turnaround times andprioritizes funded UMGCCC members. PBSS services are highly competitive with other academic andcommercial sources and a 25% UMGCCC-funded subsidy is provided to Cancer Center members. In 2019PBSS supported studies by 70 investigators 42 (60%) of whom are UMGCCC members. In 2019 PBSSsupported $21.8 million of total funding. $15.5 million of this funding was cancer-related and peer reviewed.PBSS supported 158 cancer-related publications from 2015 to 2019 including publications in high-impactjournals including as J Clin Oncol JAMA Oncology Blood and J Natl Cancer Inst and Cancer Immunology. +No NIH Category available Acceleration;Advisory Services;Animals;Baltimore;Bioluminescence;Biomedical Engineering;Biometry;Blood;Blood - brain barrier anatomy;Cancer Center;Cell Nucleus;Center Core Grants;Cerebrovascular Circulation;Cerebrum;Clinical;Clinical Oncology;Clinical Research;Clinical Trials;Comprehensive Cancer Center;Consult;Consultations;Data Analyses;Data Collection;Development;Discipline of Nuclear Medicine;Doctor of Philosophy;Drug Delivery Systems;Education;Electron Microscopy;Electrons;Equipment;Experimental Designs;Faculty;Flow Cytometry;Fluorescence;Focused Ultrasound;Functional Imaging;Funding;Genomics;Grant;Health Services Accessibility;Human;Image;Image Analysis;Imaging technology;Immunoelectron Microscopy;Institution;Intellectual Property;Interdisciplinary Study;Interventional Ultrasonography;Investigational Therapies;Journals;Knowledge;Laboratories;Liquid substance;Magnetic Resonance Imaging;Malignant Neoplasms;Maryland;Medicine;Mission;Molecular Biology;Nature;New England;Nuclear;Oncology;Pathology;Pathway interactions;Peer Review;Population Sciences;Positron-Emission Tomography;Publications;Publishing;Radiology Specialty;Reagent;Research;Research Design;Research Personnel;Resources;Sampling;Scanning Electron Microscopy;Services;Site;Strategic Planning;Students;Technology;Therapeutic;Training;Translating;Translational Research;Universities;Work;acronyms;anticancer research;biobank;biomarker discovery;cellular imaging;clinical investigation;clinical practice;clinical translation;college;confocal imaging;design;experimental study;hormone related cancer;human imaging;image guided;image guided intervention;imaging biomarker;imaging facilities;imaging modality;instrument;live cell imaging;medical schools;member;metabolic abnormality assessment;microPET/CT;multidisciplinary;neoplasm immunotherapy;neurosurgery;novel;novel imaging technology;pre-clinical;programs;quantitative imaging;structural biology;structural imaging;success;tissue fixing;tool;translational pipeline;transmission process;tumor immunology;whole animal imaging Imaging Shared Service n/a NCI 10690080 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6584 7004534 "GULLAPALLI, RAO P" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 1 1 0 18.0 Abstract: Imaging Shared ServiceThe Imaging Shared Service (ISS) provides UMGCCC members with a wide array of state-of-the-art imagingservices including structural and functional imaging of cells and imaging of whole animals and humans. ISSassists with experimental design data analysis data interpretation and training to leverage advanced imagingservices accelerate discovery and develop a robust translational pipeline. ISS resources include state-of-the-art confocal imaging for live cells fixed tissues ex vivo samples and whole animals. ISS electron microscopyservice provides transmission electron and scanning electron microscopy (conventional and cryo-samples) andimmuno-electron microscopy to meet the needs of UMGCCC investigators. Whole-animal imaging is facilitatedby a vast array of instruments including whole-animal bioluminescence and fluorescence micro-PET/CT small-animal MRI for preclinical work high-field MRI combined PET/MRI and CT services to meet the needs ofinvestigators. ISS also provides unique technologies such as dynamic nuclear hyperpolarization using C-13 andother nuclei to study metabolic flux in cancer and MR-guided focused ultrasound for interventions that permitdrug delivery across the bloodbrain barrier. ISS offers an important platform for clinical translation that facilitatesclinical trials. Given the multidisciplinary nature of ISS its leaders and members interact extensively with othershared services and with investigators in all UMGCCC programs. ISS also provides educational opportunitiesand onsite training to facilitate the design execution and analysis of a wide variety of experiments. Staffmembers of ISS some of whom are supported by the P30 grant are experts who help users to define and refinestudy designs assess research needs and provide guidance. ISS advisory sessions often include consults frommembers of the Biostatistics Shared Service. ISS is committed to providing value-added state-of-the-art servicesto educate faculty staff fellows and students and to offering advanced imaging technology to UMGCCCinvestigators. ISS provides streamlined access to services that prioritizes UMGCCC members with peer-reviewed funding. An internal Faculty Oversight Committee consisting of ISS users provides advice on coremanagement of ISS and helps to develop strategic planning for new ISS equipment. ISS has very high utilization.In 2019 ISS supported studies by 88 investigators 58 (65.9%) of whom were affiliated with UMGCCC. ISSusers represent all UMGCCC research programs. In 2019 ISS supported $32.8 million of total funding. $17million this funding was cancer-related and peer reviewed. ISS supported 239 cancer-related publications from2015 to 2019 including those published in such high-impact journals as Radiology Journal of Cerebral Blood. +No NIH Category available Acceleration;Antibodies;Area;Baltimore;Biology;Biometry;Biotechnology;CAR T cell therapy;Cancer Biology;Cancer Center;Cell Separation;Cell Therapy;Cells;Clinical;Clinical Trials;Color;Communication;Compensation;Comprehensive Cancer Center;Consultations;Containment;Cytometry;Data;Data Analyses;Doctor of Medicine;Doctor of Philosophy;Equipment;Experimental Designs;Fees;Flow Cytometry;Funding;Generations;Genomics;Grant;Hospitals;Image;Image Cytometry;Immune system;Immunology;Immunophenotyping;Institution;Instruction;Investigational Therapies;Journals;Laboratories;Malignant Neoplasms;Maryland;Measurement;Mission;Molecular Biology;Monitor;Nature;Noise;Pathology;Patients;Peer Review;Play;Population;Population Sciences;Production;Protein translocation;Publications;Publishing;Quality Control;Reproducibility;Research Design;Research Personnel;Research Support;Sampling;Services;Sorting;Source;Sterility;Strategic Planning;Structure;Technology;Titrations;Training;United States National Academy of Sciences;Universities;Washington;acronyms;anticancer research;biobank;cost effective;design;education resources;experience;extracellular vesicles;high dimensionality;hormone related cancer;innovation;instrument;instrumentation;lectures;member;neoplasm immunotherapy;novel;operation;programs;structural biology;success;therapy development;training opportunity;tumor immunology Flow Cytometry Shared Service n/a NCI 10690079 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6583 14906915 "FAN, XIAOXUAN " Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 1 1 0 16.0 Abstract: Flow Cytometry Shared ServiceThe Flow Cytometry Shared Service (FCSS) provides investigators at the University of Maryland Marlene andStewart Greenebaum Comprehensive Cancer Center (UMGCCC) with essential services that support researchin immunology and cancer biology requiring flow cytometry and with analytical (spectral and mass cytometry)and cell sorting capabilities. FCSS provides convenient access to cost-effective and high-quality servicesmanaged by expert staff. FCSS was the first facility in the Baltimore/Washington area with both mass andspectral cytometry instrumentation. The two Helios mass cytometers enable simultaneous measurement oflarge numbers of parameters (currently >50 parameters/cell) with minimum compensation. Using the new-generation Cytek Aurora spectral cytometers FCSS has developed in-house 23- and 30-colorimmunophenotyping plug-and-play use panels. The MoFlo Astrios advanced cell sorter provides the ability tosimultaneously sort six populations under BSL-2 containment. A Miltenyi MACSQuant Analyzer 10 is housed inthis space which is only accessible to FCSS staff and is used to analyze clinical samples for CAR-T cell therapydeveloped in our Fannie Angelos GMP Laboratory for Cellular Therapeutics. These state-of-the-artinstruments offer innovative approaches to study immunology and cancer biology and to monitor novelclinical trials. FCSS is staffed by technical experts with decades of experience in the operation of flowcytometers/sorters and mass cytometers. The monthly lectures presented by the FCSS director are attended bynearby members of academic institutions hospitals and biotech companies and the lectures are widelyconsidered a great educational resource. An internal scientific advisory board consisting of FCSS users providesguidance to FCSS and helps develop strategic planning for new equipment and technologies. FCSS provideseasy access to flow cytometry services. Cancer Center investigators with peer-reviewed funding are prioritized.FCSS services are highly cost-effective as the fee structure is competitive with other academic and commercialsources and a 25% UMGCCC-funded subsidy is given to Cancer Center members. FCSS is highly utilized. In2019 FCSS supported studies by 90 total investigators 42 (46.7%) of whom were UMGCCC members. FCSSsupported $62.4 million of total funding. $27.3 million of this funding was cancer-related all of which was peerreviewed. FCSS supported 213 cancer-related publications from 2015 to 2019 including those published in suchhigh-impact journals as PNAS Nature and Nature Communications. +No NIH Category available Artificial Intelligence;Basic Science;Big Data;Bioinformatics;Biomedical Research;Biometry;Biostatistics Core;Cancer Center;Cancer Research Project;Clinical;Clinical Cancer Center;Clinical Oncology;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Comprehensive Cancer Center;Computing Methodologies;Consultations;Data;Data Analyses;Data Analytics;Data Collection;Data Set;Data Sources;Databases;Doctor of Philosophy;Educational process of instructing;Educational workshop;Environment;Epidemiology;Extramural Activities;Faculty;Familiarity;Flow Cytometry;Fostering;Foundations;Funding;Genomics;Grant;Health Sciences;Human;Image;Interdisciplinary Study;Investigational Therapies;Investigator-Initiated Research;Journals;Knowledge;Laboratories;Link;Machine Learning;Malignant Neoplasms;Maryland;Medical;Medicare;Medicine;Mentors;Methodology;Methods;Mission;Molecular Biology;NCI Center for Cancer Research;Nature;Oncology;Outcome Study;Pathology;Peer Review;Pilot Projects;Population;Population Research;Population Sciences;Protocols documentation;Public Health;Publications;Publishing;Registries;Reporting;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Resources;Science;Scientist;Services;Statistical Methods;Students;System;Systems Biology;Terminology;The Cancer Genome Atlas;Time;Training;Translational Research;Universities;Wages;acronyms;analytical method;anticancer research;biobank;biomarker discovery;cancer cell;college;data mining;education resources;experience;faculty support;gene regulatory network;high dimensionality;hormone related cancer;innovation;mathematical methods;medical schools;member;neoplasm immunotherapy;peer support;personalized medicine;population health;pre-clinical;pre-clinical research;programs;service member;skills;structural biology;training opportunity;tumor immunology Biostatistics Shared Service n/a NCI 10690076 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6582 9034112 "BENTZEN, SOREN M" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 1 1 0 15.0 Abstract: Biostatistics Shared Service (BSS)The Biostatistics Shared Service (BSS) fosters and sustains excellence in quantitative cancer research at theUniversity of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) coveringthe whole spectrum from basic science to translational and clinical research and population health science. BSSprovides in-depth knowledge of and access to state-of-the-art biostatistics and bioinformatics methodswhich are augmented by domain expertise in several fields of cancer research. BSS supports CancerCenter pilot projects aids in conceptualizing and developing research projects and applications for fundingadvises on study design and data capture performs state-of-the-art data analyses and contributes to theinterpretation and reporting of study outcomes. BSS supports statistical bioinformatics projects and increasinglyapplies artificial intelligence and machine learning when collaborating on projects. BSS has experience in theanalysis of large population registries for example the National Cancer Database the SEER and the SEER-Medicare linked datasets and can assist investigators to access these resources. When needed BSS facultydevelop and implement data analytical methods that directly support UMGCCC projects. BSS faculty areencouraged to pursue project-specific funding for independent investigator-initiated research in statisticalmethodology. An important part of the BSS mission is to train UMGCCC faculty and students in quantitativebiomedical research methods through teaching mentoring and workshops. The UMGCCC supports BSS as animportant component of the Division of Biostatistics and Bioinformatics (DBB) in the Department of Epidemiologyand Public Health which also serves as the biostatistics core for the University of Maryland School of Medicine(UMSOM) and supports the Institute for Clinical and Translational Research. BSS faculty are in part supportedby funded investigator projects. This creates a stimulating environment for the activities of BSS andprovides value-added access for UMGCCC members to a wider range of innovative methodologicalexpertise. BSS statisticians participate actively in many UMGCCC collaborations providing advice on specificissues and often are coinvestigators. BSS draws on the expertise of a team of enthusiastic and highly skilledbiostatisticians bioinformaticians and administrative staff: 13 Ph.D.-level biostatisticians/bioinformaticians 2master's-level data analysts and 1 FTE administrative coordinator all working together to support the fiveUMGCCC research programs. In 2019 BSS supported 153 total investigators including 43 UMGCCC-affiliatedfaculty (28.1%). In 2019 BSS supported $15.7 million of cancer-related funding all of which was peer reviewed.BSS supported 278 cancer-related publications from 2015 to 2019 including those published in high-impactjournals such as Nature Reviews Cancer Nature Medicine Journal of Clinical Oncology and Cancer Cell. +No NIH Category available African American;Androgen Receptor;Androgens;Animal Model;Binding Proteins;Biological Availability;Biotechnology;Body mass index;Cancer Etiology;Cancer Patient;Castration;Caucasians;Cell Line;Cell Membrane Permeability;Cell Survival;Cells;Cessation of life;Cholesterol;Clinical;Collaborations;Data;Diagnosis;Drug Combinations;Enzymes;FASN gene;FDA approved;Future;Genes;Goals;High Fat Diet;In Situ;In Vitro;Incidence;Lead;Ligand Binding Domain;Link;Lipids;Malignant Neoplasms;Malignant neoplasm of prostate;Membrane Lipids;Metabolic;Metabolism;Missense Mutation;Mus;Obesity;Oncogenic;Oral;Outcome;PIK3CG gene;Pathway interactions;Patient Selection;Patients;Pharmaceutical Preparations;Post-Translational Protein Processing;Production;Proliferating;Property;Publications;Regulatory Element;Resistance;Risk;Role;SRE-1 binding protein;Safety;Series;Signal Transduction;Solid Neoplasm;Solubility;Specimen;Sterols;Testing;Therapeutic;Tissues;United States;Unsaturated Fatty Acids;Variant;Veterans;Xenograft Model;Xenograft procedure;abiraterone;anticancer activity;aqueous;cancer cell;castration resistant prostate cancer;cohort;design;docetaxel;enzalutamide;first-in-human;improved;in vivo;in vivo Model;inhibitor;innovation;lipid biosynthesis;lipid metabolism;lipidome;lipidomics;mTOR Signaling Pathway;male;men;mortality;neoplastic cell;novel;novel therapeutics;overexpression;patient derived xenograft model;pre-clinical;preclinical study;prostate cancer cell;prostate cancer model;prostate cancer progression;protein activation;protein expression;small molecule inhibitor;therapeutic target;transcription factor;transcriptome;tumor;uptake Targeting Castration Resistant Prostate Cancer via Potent Inhibition of Signaling Lipids Project NarrativeIncreased lipid production is essential for cancer cell survival and numerous recent publications indicate acentral role for the SREBP pathway in various cancers including prostate cancer. African American maleswhoalready have 2.6 times higher mortality from prostate cancer than Caucasian malesappear to have up to four-fold greater risk of developing prostate cancer in the context of obesity. Our proposed studies will help generatea rich body of evidence supporting successful targeting of lipid signaling for the treatment of lethal prostatecancer. NCI 10690074 8/22/23 0:00 PA-20-185 5R01CA251560-02 5 R01 CA 251560 2 "GREENBERG, WILLIAM A" 9/1/22 0:00 8/31/27 0:00 Developmental Therapeutics Study Section[DT] 8765750 "KAOCHAR, SALMA " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 475058 NCI 370209 104849 SummaryMetastatic castration resistant prostate cancer is uniformly fatal representing the second-leading cause ofcancer-related death among men in the United States. Despite therapeutic advances with docetaxel abirateroneand enzalutamide prostate cancer progression to lethal castration-resistant prostate cancer (CRPC) remains amajor clinical problem. Rapidly proliferating cancer cells upregulate de novo lipogenesis and cholesterolsynthesis pathways in order to provide lipids for membrane formation and lipid modification of proteins and tosupport energy production. The sterol regulatory element binding proteins (SREBPs) are master regulatorytranscription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturatedfatty acids. The SREBPs are frequently overexpressed in prostate cancer and other solid tumors and areassociated with tumor aggressiveness and unfavorable outcomes. Interestingly emerging studies suggest thatin African American (AA) prostate cancer patients - who already have 1.6 times higher prostate cancer incidenceand 2.6 times higher mortality from prostate cancer than Caucasian males - the androgen receptor andPI3K/Akt/mTOR signaling pathways are more active than in Caucasian prostate cancer patients frequentlyresulting in even greater increase in lipid metabolism. Androgen receptor and the PI3K/Akt signaling can activatethe transcription factor MNX1 leading to induction of SREBP1 which controls expression of numerous lipogenicgenes including FASN and alters the metabolic state of the prostate cancer cell. Inactivation of SREBPsrepresents a novel mechanism by which metabolically-driven tumors can be targeted. The overarching goal ofthis preclinical study is to establish key proof-of-concept efficacy and safety data for the use of SREBP inhibitorsagainst prostate cancer cells using extensive in vitro and in vivo models. Our proposed studies are focused on1) defining the function of SREBPs in prostate cancer and identifying biologically significant lipid products ofSREBP activation 2) evaluating effects and mechanisms of a small molecule inhibitor of SREBP in vitro and 3)assessing the anticancer activity of SREBP inhibitors alone and in combination with existing drugs using cellline xenograft and innovative patient-derived xenograft models of prostate cancer. 475058 +No NIH Category available Address;Adult;Adverse event;Award;Baltimore;Biological Specimen Banks;Biometry;Calendar;Cancer Center;Cancer Center Support Grant;Cancer Therapy Evaluation Program;Categories;Childhood;Clinical;Clinical Cancer Center;Clinical Management;Clinical Research;Clinical Trials;Clinical Trials Design;Collection;Committee Members;Communication;Comprehensive Cancer Center;Consent;Data;Dedications;Diagnosis;Disease;Doctor of Medicine;Enrollment;Ensure;Faculty;Flow Cytometry;Focus Groups;Funding;Genomics;Goals;Grant;Group Meetings;Guidelines;Human;Image;Industry;Institution;Institutional Review Boards;Intervention;Interview;Investigational Therapies;Laboratories;Letters;Malignant Neoplasms;Maryland;Medical;Methodology;Minor;Modality;Modification;Molecular Biology;Monitor;National Cancer Institute;Nature;Office Management;Pathology;Pattern;Peer Review;Phase;Population Sciences;Principal Investigator;Procedures;Process;Protocols documentation;Radiation Oncology;Reporting;Research;Research Personnel;Resources;Review Committee;Safety;Sample Size;Services;Surveys;System;Technology;Universities;Writing;acronyms;anticancer research;biobank;biological specimen archives;cancer clinical trial;cancer prevention;college;cost;expedited review;hormone related cancer;human subject;improved;medical schools;meetings;member;minimal risk;neoplasm immunotherapy;pediatric department;post-market;pre-clinical;programs;quality assurance;structural biology;tumor immunology;virology;young adult Protocol Review and Monitoring System n/a NCI 10690073 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6581 14546480 "DUONG, VU H." Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 58943 38151 20792 8.0 Abstract: Protocol Review and Monitoring System (PRMS)The Protocol Review and Monitoring System (PRMS) of the University of Maryland Marlene and StewartGreenebaum Comprehensive Cancer Center (UMGCCC) is a two-step system. Step 1 occurs atDisease/Modality Focused Group (DFG) meetings where faculty and staff involved in specific disease teamsdiscuss current and proposed clinical trials. Step 2 involves the Clinical Research Committee (CRC) whichreviews all new cancer-related protocols for scientific merit methodology competing studies in the portfolio andreasonability of accrual goals before submission to the Institutional Review Board (IRB). The CRC ensures anexpert biostatistics review of clinical trial design and calculation of sample size for each institutional and selectednon-institutional protocols. CRC reviews the Data Safety Monitoring plan to ensure sufficiency and receives DFGand UMGCCC Protocol Feasibility Committee input to ensure proper prioritization and utilization of resources.CRC continually reviews accrual to studies supported by UMGCCC and closes poorly accruing trials. FinallyCRC provides scientific review for issues that arise relating to accrual safety or adverse events noted by theData Safety Monitoring/Quality Assurance Committee and addresses IRB questions. During the 2019 calendaryear the CRC performed full committee level reviews of 123 protocols; 71 were approved as written 31 wereapproved with minor modifications 15 were approved with major modifications requiring re-review and 6 weredeferred. An expedited review process exists for research that is deemed to pose minimal risk based onUniversity of MarylandBaltimore IRB guidelines and that involves chart reviews interviews or surveys studiesof archived biospecimens collection/banking of biospecimens during routine clinical procedures Phase IIIindustry-sponsored trials or any Phase IV postmarketing study seeking more information on safety and efficacy.During CY2019 expedited review approved 21 studies. To further refine the use of CRC resources a newcategory of review (Acknowledgment Review) was created in 2019 to allow for UMGCCC CRC acknowledgmentof research approved by the National Cancer Institute (NCI) Central Institutional Review Board (CIRB) or ofstudies that have undergone external peer review (e.g. approved by the PRMS of another NCI-designatedcancer center or consortium trial). During CY2019 172 trials were monitored for accrual and any protocols notaccruing at a rate suggesting successful completion of targeted enrollment within three to five years weretargeted for corrective action. In CY2019 UMGCCC received the Most Improved award granted by ForteResearch for achieving a 90-day reduction in overall trial activation including a 9-day reduction in CRC approval.Sixty-five warning letters were issued resulting in closure of 11 protocols in CY2020. During FY2019 costs tosupport PRMS exceeded $800000 of which $40479 in funding was from Cancer Center Support Grants. +No NIH Category available Age Years;Architecture;Asian population;Baltimore;Biometry;Cancer Center Support Grant;Catchment Area;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Trials;Clinical Trials Data Monitoring Committees;Complement;Comprehensive Cancer Center;Data;Data Collection;Databases;Dedications;Disease;Doctor of Medicine;Doctor of Philosophy;Enrollment;Ensure;Equipment and supply inventories;Flow Cytometry;Focus Groups;Fostering;Funding;Genomics;Grant;Human;Human Resources;Image;Individual;Industry;Information Technology;Institution;Intervention;Intervention Trial;Investigational Therapies;Laboratories;Leadership;Longevity;Malignant Neoplasms;Maryland;Measures;Medical;Medical center;Minority;Mission;Modality;Molecular Biology;Monitor;National Cancer Institute;Nurses;Office Management;Oncology;Pathology;Patients;Peer Review;Persons;Phase;Play;Population Sciences;Protocols documentation;Quality Control;Reporting;Research;Research Activity;Research Personnel;Safety;Services;Site;System;Therapeutic Trials;Underrepresented Minority;Universities;Wages;Woman;Work;acronyms;biobank;cancer clinical trial;cancer therapy;clinical implementation;college;cost;cost effective;data management;data quality;data quality/integrity;health disparity;health equity promotion;hormone related cancer;human old age (65+);improved;innovation;investigator-initiated trial;medical schools;member;minimal risk;neoplasm immunotherapy;oncology trial;operation;participant enrollment;patient oriented;patient safety;pediatric patients;phase I trial;phase II trial;programs;protocol development;quality assurance;structural biology;trial enrollment;tumor immunology;virology Clinical Protocol and Data Management n/a NCI 10690070 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6580 9673729 "EMADI, ASHKAN " Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 274032 177367 96665 7.0. Abstract: Clinical Protocol and Data ManagementClinical Protocol and Data Management (CPDM): The Clinical Research Management Office (CRMO)provides clinical trial management services to more than 35 investigators and oversees high-quality conduct andreporting of all cancer clinical trials at the University of Maryland Marlene and Stewart GreenebaumComprehensive Cancer Center (UMGCCC) and the University of Maryland network sites. Comprising more than50 full-time equivalent personnel CRMO works closely with UMGCCC Disease/Modality Focused Groups (DFG)to manage a robust cancer clinical trial portfolio that prioritizes institutionally and externally peer-reviewed trialsand complements UMGCCC's patient catchment area. CRMO utilizes the OnCore database to track theconduct of and patient accrual to all oncology clinical trials and to centrally report clinical research activities toUMGCCC leadership. During the last grant period (CY20152019) CRMO supported the activation of 381interventional clinical trials resulting in 2029 interventional trial enrollments during the reporting period. DuringFY2019 costs to support CPDM were $4569709 of which $204148 were funded by the CCSG. Data andSafety Monitoring: UMGCCC's Data Safety Monitoring/Quality Assurance Committee (DSM/QAC) serves thedata safety monitoring function for protocols that do not have an external data and safety monitoring board(DSMB). The DSM/QAC annually reviews safety information for patients accrued to all oncology protocolsconsidered greater than minimal risk as defined in the UMGCCC-approved DSM Plan. This includesinvestigator-initiated trials of any phase all Phase I trials and selected industry Phase II trials without a sponsor-appointed DSMB as well as multi-institutional investigator-initiated trials for which UMGCCC is the coordinatingcenter. During FY2019 costs to support DSM/QAC were $93938 of which $23592 were funded by the CCSG.This funding supported the annual review of 344 trials during the reporting period as well as a percentage ofsalaries for three staff members. Inclusion of Women and Minorities in Clinical Research: UMGCCCcontinues to demonstrate a robust enrollment of women and minorities into clinical trials. Among the 2029 peopleenrolled into interventional trials from CY2015CY2019 1146 (56 percent) were women. Overall minorityaccrual to clinical trials is 56 percent. This includes 48.2 percent underrepresented minorities as well as 7.8percent Asians the latter reflecting clinical trials examining health disparities in that group. Underrepresentedminority accrual to therapeutic trials is 34.7 percent. Inclusion of Individuals Across the Life Span in ClinicalResearch: UMGCCC is strongly committed to including individuals across the life span into clinical research. Ofthe 2029 people enrolled into interventional trials from CY2015CY2019 448 (22 percent) were older than 65years of age and an average of 17 percent of all new UMGCCC pediatric patients were enrolled intointerventional trials annually. +No NIH Category available Academic Medical Centers;Acceleration;Baltimore;Basic Science;Biological Sciences;Biometry;Budgets;Cancer Biology;Cancer Center;Cancer Center Support Grant;Catchment Area;Cigarette;Clinical;Clinical Research;Clinical Trials;Communication;Comprehensive Cancer Center;Core Facility;Data Analyses;Development Plans;Doctor of Philosophy;Ensure;Environment;Experimental Designs;Faculty;Feedback;Financial Support;Flow Cytometry;Fostering;Foundations;Funding;Future;Genomics;Grant;Image;Immunology;Investigational Therapies;Investments;Laboratories;Leadership;Malignant Neoplasms;Maryland;Mission;Molecular Biology;NCI Center for Cancer Research;Online Systems;Pathology;Patient Care;Patients;Population Sciences;Process;Quality Control;Research;Research Personnel;Resource Sharing;Resources;Role;Science;Services;Strategic Planning;Structure;Surveys;Technology;Translational Research;Universities;Wages;Work;acronyms;anticancer research;biobank;biomedical resource;clinical care;cost;expectation;genome sciences;hormone related cancer;innovation;innovative technologies;instrument;instrumentation;interest;lectures;medical schools;meetings;member;nanopore;neoplasm immunotherapy;new technology;novel;novel diagnostics;novel therapeutics;programs;restraint;service delivery;structural biology;success;translational study;tumor immunology Shared Resource Management n/a NCI 10690067 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6578 1875496 "AMBULOS, NICHOLAS P" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 597844 386954 210890 6.0 Abstract: Shared Service ManagementShared Service Management ensures that the shared services meet and exceed expectations of investigatorsat the University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCCC) and that eachshared service functions to enhance and accelerate the pace of discovery in cancer biology immunology cancermechanisms populations science and translational and clinical cancer research that meets the needs of patientsin our catchment area. UMGCCC supports seven shared services: Biostatistics Flow Cytometry GenomicsImaging Pathology and Biorepository Translational Laboratory and Structural Biology. Dr. Nicholas Ambulosserves as the associate director for Shared Services and as director of the University of Maryland School ofMedicine (UMSOM) Center for Innovative Biomedical Resources which houses the UMSOM core facilities. Thisdual role enables him to manage these complimentary sets of state-of-the-art resources without duplicatingservices. The shared service management team also includes Mr. Robert Mitchell associate director forAdministration; Dr. Richard Eckert UMGCC deputy director and associate director for Basic Science; Dr. RenaLapidus assistant director for Shared Services (AstDSS); and three administrative staff. A key to successfulshared service management is open and transparent communication with UMGCCC leadership andinvestigators. Multiple mechanisms allow users to provide critical feedback. Each shared service has a FacultyOversight Committee (FOC) that meets twice annually sponsors user surveys provides mechanisms for web-based feedback and presents lectures on the shared services to key stakeholders. Communication enablesusers and shared service directors to work as partners to acquire new cutting-edge instrumentation and to offernew services. UMGCCC provides considerable financial support for shared services including salary supportdirect operational support funds for pilot grants that use the shared services and funds for purchasing newinstrumentation. UMGCCC has invested $25 million in funding during the past 5 years to help procure state-of-the-art instrumentation for most shared services. In return the share services create a dynamic environment inwhich the shared services accelerate the pace of research and provide innovation to enable discoveries thatlead to new diagnostics and therapeutics. Shared services impact all five research programs providing supportfor basic discovery science translational research clinical trials and clinical care. Integration within theUniversity of Maryland Institute for Clinical and Translational Research (ICTR) enables UMGCCC members toaccess ICTR funds which can be used to purchase shared services. Shared service management guidesstrategic planning to develop future services and technologies and works with shared service directors usersand UMGCCC leadership to determine the best mechanisms for procuring new technology. +No NIH Category available African American;Area;Baltimore;Cancer Center;Cancer Control;Capital;Catchment Area;Cities;Communication;Communities;Community Outreach;Comprehensive Cancer Center;County;Data;Doctor of Philosophy;Ensure;Ethnic Origin;Evidence based intervention;Future;Goals;Grant;Guidelines;Health;Health Policy;Income;Infrastructure;Investigational Therapies;Leadership;Malignant Neoplasms;Maryland;Molecular Biology;NCI Center for Cancer Research;Needs Assessment;Population;Population Sciences;Positioning Attribute;Process;Public Health;Race;Research;Research Priority;Risk Factors;Strategic Planning;Tobacco use;United States;Universities;Work;acronyms;anticancer research;biotin carboxyl carrier protein;cancer health disparity;cancer risk;clinical trial enrollment;college;community engagement;community partnership;demographics;evidence base;experience;hormone related cancer;neoplasm immunotherapy;programs;public education;recruit;socioeconomics;structural biology;tumor immunology;tumor registry Community Outreach and Engagement n/a NCI 10690066 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6577 6282299 "KNOTT, CHERYL L" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 82600 53463 29137 5.0 Abstract: Community Outreach and EngagementThe University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC)serves a catchment area of 5.4 million Marylanders living in a 10-county region of central Maryland that surroundsthe Cancer Center reflects the Baltimore-DC corridor and includes the Maryland State capital of Annapolis.Eighty percent of our analytic tumor registry cases originate in this area which is notably 32% African American.Baltimore City is 62% African American and has a median income substantially lower and tobacco use ratesconsiderably higher than averages in Maryland and the United States. These factors make racial/ethnic andsocioeconomically rooted cancer disparities a critical priority for the Cancer Center. UMGCCC bringsconsiderable infrastructure to support community outreach and engagement (COE) activities including anexperienced core team a highly engaged and cancer-focused Community Advisory Board a cadre of lay CancerHealth Ambassadors recruited from the catchment area and a host of longstanding community partnerships thatfacilitate and support our work. We apply this infrastructure to the overall goal of COE: apply communityoutreach and engagement strategies to inform UMGCCC research and make an impact along the cancercontinuum in the catchment area with a particular focus on eliminating cancer disparities. The aims of COE areto describe the UMGCCC catchment area using a data-driven approach conduct evidence-based and impactfulcancer control activities and apply COE strategies to inform research and support integration of COE throughoutthe UMGCCC Programs. This involves communicating community needs to UMGCCC leadership and ensuringthat clinical trial enrollments reflect the demographics of our catchment area and that research priorities arealigned with our COE strategic planning process. Our four-pronged strategic planning process used to identifyCOE priorities activities and metrics includes analysis of catchment area data community needs assessmentCommunity Advisory Board engagement and UMGCCC leadership and program inreach. This process guidedUMGCCC activities during the past grant cycle and drives our future plans with regard to priority populationspartnerships cancer risk factors and cancers of focus. Therefore we are well positioned to make a significantimpact along the cancer continuum in our catchment area in the years ahead. +No NIH Category available Area;Baltimore;Basic Science;Biometry;Cancer Center;Cancer Center Support Grant;Cigarette;Clinical;Clinical Research;Collaborations;Comprehensive Cancer Center;Data;Development;Discipline;Doctor of Medicine;Extramural Activities;Faculty;Faculty Recruitment;Flow Cytometry;Funding;Future;Genomics;Grant;Image;Institution;Investigational Therapies;Investments;Laboratories;Malignant Neoplasms;Maryland;Mission;Molecular Biology;NCI Center for Cancer Research;Pathology;Pilot Projects;Population Sciences;Process;Research;Research Personnel;Research Project Grants;Research Training;Scientist;Services;Strategic Planning;Structure;Talents;Teacher Professional Development;Training;Universities;acronyms;biobank;faculty research;faculty support;hormone related cancer;innovation;medical schools;member;neoplasm immunotherapy;novel;programs;recruit;research faculty;structural biology;tumor immunology Developmental Funds n/a NCI 10690063 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6576 1967833 "CULLEN, KEVIN J." Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 566429 366621 199808 4.0 Abstract: Developmental FundsDevelopmental funds support the University of Maryland Marlene and Stewart Greenebaum ComprehensiveCancer Center's (UMGCCC's) mission by facilitating recruitment of new faculty in areas of strategic need andby supporting pilot studies necessary to develop research so that it can compete for extramural funding.UMGCCC has also used Cancer Center Support Grant (CCSG) pilot funds to support didactic clinical researchtraining for new faculty. In the last funding cycle $701806 in CCSG funds were invested in faculty recruitmentfor the Population Science Program. In contrast $1.8 million in pilot research funds ($373832 from CCSG) wereallocated in the last cycle. These pilot grants resulted in $14.2 million of new extramural funding. In additionUMGCCC invested more than $11.3 million in funds to recruit new basic and clinical research faculty. Thisfunding was leveraged by an additional $24.1 million in departmental and institutional funds to support basicscience and clinical recruits who are members of UMGCCC. These recruits have significantly enhanced all fiveUMGCCC research programs. In the current application $179000 in CCSG developmental funds are requestedto support UMGCCC investigators' pilot projects and provide preliminary data for future external funding of novelprojects. Because of a need identified as part of our strategic planning process $148093 per year in CCSGdevelopmental funding is requested to support faculty development in areas of strategic need. These funds willbe used to help newly recruited clinical research faculty complete certificate training in clinical research.UMGCCC is committed to enhancing the clinical research capabilities of new faculty in multiple cancerdisciplines. +No NIH Category available Administrator;Advisory Committees;Applications Grants;Baltimore;Biometry;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Survivorship;Catchment Area;Cell Therapy;Cigarette;Clinical Cancer Center;Clinical Research;Collaborations;Community Outreach;Comprehensive Cancer Center;Counseling;Country;County;Cutaneous;Doctor of Medicine;Evaluation;Evolution;Flow Cytometry;Funding;Future;Genomics;Goals;Grant;Human;Human Resources;Image;Investigational Therapies;Laboratories;Leadership;Malignant Neoplasms;Maryland;Medical;Medical center;Medicine;Molecular Biology;Monitor;Names;Pathology;Pharmacy Schools;Population Research;Population Sciences;Process;Public Health Schools;Qualifying;Recommendation;Research;Research Personnel;School Dentistry;Scientist;Secure;Series;Services;Structure;System;Technology;Translational Research;Universities;Work;acronyms;biobank;cancer imaging;cancer research center director;cohort;college;community engagement;cost;design;hormone related cancer;imaging program;medical schools;meetings;neoplasm immunotherapy;new technology;programs;recruit;structural biology;tumor immunology;virology Leadership Planning and Evaluation n/a NCI 10690062 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6575 1967833 "CULLEN, KEVIN J." Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 357958 231688 126270 3.0 Abstract: Leadership Planning and EvaluationThe University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) hasa robust program planning and evaluation process which includes several groups with internal and externalexpertise. These groups monitor the scientific activities of UMGCCC evaluate new scientific opportunities anddefine future strategic scientific needs of the Cancer Center with regard to personnel facilities and technologies.UMGCCC leadership includes a team of highly qualified scientists and administrators who work together tomonitor the status of the Cancer Center and move it forward. UMGCCC director Dr. Kevin Cullen meets regularlywith Dr. Richard Eckert UMGCCC deputy director and the P30 executive committee which comprises theassociate directors and administrative leadership. This group is responsible for establishing scientific prioritiesfor the Cancer Center including recruitment priorities. It also monitors all the internal and external planning andevaluation functions described in this section.In addition UMGCCC regularly engages external experts to evaluate and advise UMGCCC leadership on thestructure and function of its shared services and research programs. Each shared service and program has beenindependently evaluated and received formal recommendations.UMGCCC is fortunate to rely on the expertise and counsel of the External Scientific Advisory Committee whichconsists of one senior Cancer Center administrator and 10 senior cancer investigators from around the countryall of whom provide a range of expertise in Cancer Center clinical translational and population research as wellas administration.Program planning and evaluation are critical to the overall function of UMGCCC and its evolution. Numerouschanges that have resulted from this process are evident in this grant application and reflect the commitment ofUMGCCC to conduct regular comprehensive evaluations of all its components. +No NIH Category available AXIN1 protein;Ablation;Adverse event;Antibodies;Antibody Therapy;Antigens;Basic Science;Binding;Biological Markers;Biological Response Modifiers;Biology;Blocking Antibodies;Cancer Patient;Cell Culture System;Cells;Cellular Structures;Chemotherapy and/or radiation;Chemotherapy-Oncologic Procedure;Classification;Clinic;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Combined Modality Therapy;Cytometry;Data;Dose;Flow Cytometry;Foundations;Future;Hodgkin Disease;Homologous Gene;Hospitals;Human;IgG4;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune system;Immunity;Immunofluorescence Immunologic;Immunoglobulins;Immunosuppression;Immunosuppressive Agents;Immunotherapy;In Vitro;Infiltration;Interferon Type II;Lectin;Ligands;Macrophage;Macrophage Colony-Stimulating Factor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Molecular;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mus;Myeloid Cells;Names;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phase I/II Clinical Trial;Phase II Clinical Trials;Phenotype;Proteins;Research Personnel;Resistance;Role;Safety;Sialic Acids;Solid Neoplasm;Specimen;T cell regulation;T cell response;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Translational Research;Tumor Immunity;Tumor Promotion;Tumor Tissue;Tumor-Infiltrating Lymphocytes;Tumor-infiltrating immune cells;Work;anti-4-1BB;antigen-specific T cells;biomarker validation;cancer cell;cancer immunotherapy;cancer infiltrating T cells;cancer therapy;checkpoint therapy;cohort;cytokine;design;effective therapy;effector T cell;genome-wide;immune function;immunomodulatory therapies;improved;in vivo;inhibitor therapy;melanoma;mouse model;neoplastic cell;novel strategies;novel therapeutic intervention;patient derived xenograft model;patient response;personalized medicine;potential biomarker;prevent;programmed cell death ligand 1;programmed cell death protein 1;prospective;receptor;resistance mechanism;response;safety testing;tool;treatment response;tumor;tumor immunology;tumor microenvironment;validation studies Project 1: Siglec15 as a new target for lung cancer immunotherapy PROJECT NARRATIVERecent advances in immune modulating therapies such as antibodies that target PD-1/B7-H1(PD-L1) haveshown efficacy in the treatment of NSCLC however response rates although higher than traditionalchemotherapy regimens remain low. Studies identifying and understanding the mechanisms that result ininhibition of the immune system to target tumor are imperative to develop more effective therapies. In thisproposal we investigate the role of siglec-15 a molecule recently identified as an immune regulator inpromoting a tumor phenotype that restricts tumor infiltrating T cell activation and we explore potentialbiomarkers and combination treatment approaches to improve NSCLC therapeutic responses. NCI 10690060 8/7/23 0:00 PAR-18-313 5P50CA196530-09 5 P50 CA 196530 9 8/26/15 0:00 7/31/25 0:00 ZCA1-RPRB-6 6574 6190120 "CHEN, LIEPING " Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 354923 212016 143111 PROJECT SUMMARYThe inability of tumor infiltrating lymphocytes (TILs) to target and kill tumor cells is a major hurdle in treatingmany malignancies. New treatment strategies that block immune inhibitory mechanisms such as antibodiesthat block the interaction of programmed death-1 (PD-1) with its ligand B7 homolog 1 (B7-H1 also known asPD-L1) have shown promising efficacy in the clinic. Termed checkpoint inhibitor therapy these drugs havebeen approved for many indications including melanoma Hodgkin lymphoma and lung cancer and areincreasingly being used in combination or in conjunction with other cancer therapies such as chemotherapyand radiation. Although checkpoint inhibitor treatments have resulted in durable clinical responses in a largeproportion of cases many patients present with tumor types that do not respond to treatment. For instance~26% of NSCLC cases which are negative for B7-H1/PD-L1 and positive for TILs have been shown to beresistant to anti-PD-1/B7-H1(PD-L1) (anti-PD) therapy. This type of NSCLC denoted as Type III is suspectedto harbor a mechanism of immune inhibition distinct from other NSCLC types which has been found to bedriven at least in part by sialic acid binding immunoglobulin-like lectin 15 (siglec-15). Siglec-15 expression ismutually exclusive from B7-H1/PD-L1 expression in NSCLC cohorts and has been shown to inhibit T cellproliferation and effector function. Blocking of siglec-15 using anti-siglec-15 (S15) monoclonal antibody (mAb)is therapeutic in mouse models and human cell culture systems and results in amplified T cell responses.Based on these findings a phase I/II dose escalation safety and tolerability clinical trial for S15 mAbtreatment in patients with advanced or metastatic solid tumors is on-going. Although preliminary studies havegenerated promising results with regard to the potential efficacy of S15 mAb in the clinic the mechanism ofS15-mediated immune suppression remains unknown. Furthermore to enhance and improve treatmentresponse rates more work must be done to identify pertinent biomarkers for S15 mAb therapy and modes thatmodulate S15 expression. Finally developing combination strategies that alter the tumor microenvironment(TME) such that conversion of the tumor Type is achieved is imperative for successful targeting and killing oftumor by immune cells and in attaining increased patient response rates to available checkpoint inhibitortherapies. A newly generated immune PDX (iPDX) mouse model which uses patient-derived tumor tissue torecapitulate and manipulate immune cell responses in the TME will be utilized to investigate these topicsspecifically in the NSCLC setting. A proposed investigator-initiated phase II clinical trial in patients with S15+advanced NSCLC who have progressed on PD-1 axis inhibitor therapy will evaluate S15 mAb efficacy andsupport biomarker validation studies. Strategies to combine S15 mAb with other agents such as anti-FGL1and anti-4-1BB/CD137 to improve therapeutic effect will also be explored. Taken together the studiesproposed here will improve our understanding of the NSCLC TME and enhance therapeutic approaches. +No NIH Category available Adverse effects;Antitumor Response;Baltimore;Basic Science;Biometry;Calibration;Cancer Burden;Catchment Area;Cell Therapy;Cells;Cigarette;Clinical Trials;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;County;Dedications;Development;Direct Costs;Disease;Doctor of Medicine;Doctor of Philosophy;Flow Cytometry;Funding;Funding Agency;Genomics;Goals;Grant;Human;Image;Immune;Immunosuppression;Immunotherapy;Infection;Inflammation;Inflammatory Response;Interdisciplinary Education;Interdisciplinary Study;Investigational Therapies;Journals;Knowledge;Laboratories;Malignant - descriptor;Malignant Neoplasms;Maryland;Medical;Medical center;Molecular Biology;Monitor;NCI Center for Cancer Research;Pathology;Peer Review;Pharmacy Schools;Population Sciences;Public Health Schools;Publications;Regulatory Pathway;Research;Research Personnel;Research Support;Role;School Dentistry;Services;Signal Transduction;Source;System;Translating;Translational trial;Treatment Protocols;Universities;acronyms;biobank;cancer cell;cancer immunotherapy;cell growth;college;community engagement;faculty support;hormone related cancer;immunoregulation;innovation;medical schools;member;neoplasm immunotherapy;novel diagnostics;novel therapeutics;programs;structural biology;tumor;tumor immunology;virology Tumor Immunology and Immunotherapy Program n/a NCI 10690058 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6573 9851892 "CAO, XUEFANG " Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 50965 32987 17978 14.0 Abstract: Tumor Immunology and Immunotherapy (TII) ProgramThe TII Program is an interdisciplinary program that pursues highly innovative basic science research andtranslational/clinical trials. The overall goal of the TII Program is to develop and implement immune-basedstrategies to monitor and treat cancer. To achieve this goal the program focuses on three research aims: Aim 1:Cell-based and regulatory pathway-targeted cancer immunotherapiesDevelop cell-based and regulatorypathway-targeted cancer immunotherapies that are capable of reducing or monitoring malignant cell growth.Aim 2: Calibrating immune regulationDevelop strategies to overcome tumor-induced immunosuppressionand to mitigate immunotherapy-related adverse effects. Aim 3: Cancer and inflammationElucidate the rolesof infection and inflammatory responses in cancer development. The TII Program is an interdisciplinary researchand educational program. Program members are dedicated to understanding the immune regulation of malignantdisease and translating this knowledge into the development of novel diagnostic and treatment regimens. TheTII Program has 35 members including 18 full members and 17 associate members who conduct cancer-focused research supported by $16.6 million annual direct cost funding ($21.7 million total) including $1.9 million(11.2%) from NCI and $10.5 million from other peer-reviewed sources. TII Program members receive $4.3 millionannually from nonpeer-reviewed funding sources. During this funding period TII members authored 371cancer-related publications of which 15% resulted from intraprogrammatic 30% from interprogrammatic and6% from intra and interprogrammatic collaborations; 64% of publications include collaborations with externalinvestigators reflecting the high national impact of the TII Program and 14% of TII publications were in journalswith an impact factor 10. The research efforts of TII faculty are supported by extensive use of all sharedservices. The TII Program is integrated with the other research programs at the University of Maryland Marleneand Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) and TII interacts with CommunityOutreach and Engagement (COE) as a bridge to identify the needs of communities in our catchment area. +No NIH Category available Baltimore;Behavior;Behavior Therapy;Behavioral;Biometry;Cancer Control;Cancer Etiology;Cancer Survivorship;Catchment Area;Cigarette;Collaborations;Communication;Communities;Community Outreach;Comprehensive Cancer Center;County;Direct Costs;Doctor of Philosophy;Early Diagnosis;Epidemiology;Equity;Faculty;Flow Cytometry;Fostering;Funding;Funding Agency;Genetic;Genomics;Goals;Grant;Health behavior;Human;Image;Individual;Infection;Intervention;Investigational Therapies;Laboratories;Life Style;Malignant Neoplasms;Maryland;Master of Public Health;Medical;Medical center;Molecular;Molecular Biology;Molecular Epidemiology;Outcome;Pain;Pathology;Peer Review;Pharmacy Schools;Population;Population Sciences;Psychosocial Influences;Public Health Schools;Publications;Recommendation;Research;Research Personnel;Research Support;Risk Assessment;School Dentistry;Schools;Services;Source;System;Translating;Treatment-Related Cancer;United States;Universities;acronyms;anticancer research;biobank;cancer health disparity;cancer prevention;college;community engagement;hormone related cancer;implementation science;medical schools;medically underserved population;member;neoplasm immunotherapy;prevent;programs;structural biology;training opportunity;tumor immunology;virology Population Science Program n/a NCI 10690055 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6572 1918119 "DORGAN, JOANNE F" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 52749 34142 18607 13.0 Abstract: Population Science (PS) ProgramThe overall goals of the PS Program are to identify determinants of cancer etiology cancer-related behaviorand outcomes and to translate basic discovery into behavioral interventions to prevent and control cancer. Toachieve these goals the program focuses on three aims: Aim 1: Epidemiology of infection- and hormone-related cancers to identify the molecular genetic and lifestyle determinants of infection- and hormone-relatedcancers in the United States and globally; Aim 2: Equity in cancer prevention and early detection to identifypsychosocial influences on cancer-related health behaviors and to develop and evaluate interventions that fosterrecommended cancer-related behaviors particularly in medically underserved populations; and Aim 3: Canceroutcomes to identify mechanisms of cancer treatment-related pain and to characterize individual- treatment-and community-level influences on disparities in cancer outcomes. The PS Program has 41 members including24 full members and 17 associate members who conduct cancer-focused research supported by $7.7 millionannual direct cost funding ($10.1 million total) including $0.92 million (12%) from NCI and $5.3 million from otherpeer-reviewed sources. PS Program members receive $1.4 million annually from nonpeer-reviewed fundingsources. During this funding period PS members authored 396 cancer-related publications of which 23%resulted from intraprogrammatic 15% from interprogrammatic and 4% from intra and interprogrammaticcollaborations. Of these publications 85% include collaborations with external investigators reflecting the highnational impact of the PS Program. Of the PS publications 10% have an impact factor 10. PS faculty makeextensive use of the Biostatistics (BSS) and Genomics (GSS) shared services and provide extensive trainingopportunities. The PS Program has a strong focus on cancer disparities and on research serving individuals inthe UMGCCC catchment area. This includes a close relationship with Community Outreach and Engagement(COE) to prioritize catchment area cancer research conduct community cancer control activities and integrateCOE into PS research. +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;Affect;African American population;Aromatase Inhibitors;Baltimore;Basic Science;Biology;Biometry;Breast cancer metastasis;Catchment Area;Cigarette;Clinical Research;Clinical Trials;Collaborations;Community Outreach;Comprehensive Cancer Center;County;Development;Diagnosis;Doctor of Medicine;Doctor of Philosophy;Enrollment;Flow Cytometry;Funding;Funding Agency;Genomics;Goals;Grant;Hormones;Human;Image;Interdisciplinary Study;Intervention Trial;Investigational Therapies;Laboratories;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maryland;Mediating;Medical;Medical center;Mission;Molecular Biology;Morbidity - disease rate;NCI Center for Cancer Research;Neoplasm Metastasis;Pathology;Patients;Peer Review;Pharmaceutical Preparations;Pharmacy Schools;Phase III Clinical Trials;Physiology;Population Sciences;Public Health Schools;Publications;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Research;Research Personnel;Research Priority;Resistance;Resistance development;Resources;School Dentistry;Services;Source;System;Therapeutic Intervention;Tissues;Translational Research;Underrepresented Minority;Universities;Work;acronyms;anticancer research;biobank;cancer health disparity;cancer imaging;cancer recurrence;cancer stem cell;cancer therapy;college;community engagement;demographics;disparity reduction;hormone related cancer;hormone therapy;improved;malignant breast neoplasm;medical schools;member;mortality;neoplasm immunotherapy;new technology;precision medicine;professor;programs;recruit;response;structural biology;targeted treatment;therapeutic target;treatment response;tumor;tumor immunology;virology Hormone Related Cancers Program n/a NCI 10690051 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6569 6948120 "MARTIN, STUART S" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 39587 25622 13965 11.0 Abstract: Hormone Related Cancers (HRC) ProgramThe overarching goal of the HRC Program at the University of Maryland Marlene and Stewart GreenebaumComprehensive Cancer Center (UMGCCC) is to reduce the morbidity and mortality of cancers that arise fromhormone-related tissues. To achieve this mission the program focuses on three specific aims: Aim 1: Identifytargets in hormone-related cancers that mediate innate and acquired resistance improves theunderstanding of how cancers resist hormonal therapies or develop resistance during recurrence; Aim 2: Targetmechanisms that regulate cancer stem cells and promote metastasis with a focus on defining andtherapeutically targeting mechanisms of cancer recurrence; and Aim 3: Develop strategies to improvediagnosis inform treatment and evaluate treatment response to apply new technologies that advancecancer imaging and accelerate analysis of tumor drug response for precision medicine. To achieve these threeaims HRC members are supported by collaborators and resources throughout other UMGCCC programs aswell as exceptional shared services. The HRC Program has 46 members including 30 full members and 16associate members who conduct basic translational and clinical research chiefly in breast prostate andovarian cancer with $8.7 million direct annual funding ($11.0 million total) including $3.4 million (39%) from NCIand $2.6 million from other peer-reviewed sources. HRC Program members receive $2.7 million annually fromnonpeer-reviewed funding sources. During this funding period HRC members authored 506 cancer-relatedpublications of which 17% resulted from intraprogrammatic 28% from interprogrammatic 6% from intra andinterprogrammatic collaborations; and 60% of publications include collaborations with external investigatorsreflecting the high national impact of the HRC Program. HRC Program members manage numerous clinicaltrials. During this grant period the HRC Program enrolled 1412 patients on clinical trials including 213 oninterventional trials (200 therapeutic interventional) and 1199 patients on non-interventional trials. 41.5% ofpatients were underrepresented minorities reflecting the demographics of the catchment area. The researchprograms of HRC members utilize all of the UMGCCC shared services. The HRC Program collaborates with theother four UMGCCC Research Programs and engages community outreach and engagement to identify andaddress the cancer research priorities of the catchment area. +No NIH Category available Achievement;Address;Applications Grants;Award;Bioinformatics;Biology;Biometry;Biostatistics Shared Resource;Cancer Center;Clinical Data;Clinical Trials;Collaborations;Communities;Computational Biology;Data;Data Collection;Data Management Resources;Deposition;Development;Ensure;Fostering;Funding;Goals;Guidelines;Individual;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Medical Informatics;Medical center;Methods;Monitor;Play;Policies;Postdoctoral Fellow;Process;Publications;Publishing;Regulation;Reporting;Research;Research Design;Research Personnel;Role;Science;Services;Skin Cancer;Training;Training and Education;United States National Institutes of Health;Visit;analytical method;anticancer research;career;clinical biomarkers;cost effective;data management;data reduction;design;experience;innovation;interest;next generation;novel;personalized medicine;posters;programs;public repository;student training;training opportunity Core B: Biostatistics and Bioinformatics Core CORE B: PROJECT NARRATIVEWith a stellar team of biostatisticians and bioinformaticians the Core will provide the whole spectrum of analyticsupport to all SPORE projects and investigators. The Core will ensure that all studies are properly designed andexecuted and that data are properly managed analyzed reported published and shared. NCI 10690047 8/7/23 0:00 PAR-18-313 5P50CA196530-09 5 P50 CA 196530 9 8/26/15 0:00 7/31/25 0:00 ZCA1-RPRB-6 6567 8798938 "MA, SHUANGGE " Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 225551 134735 90946 CORE B: PROJECT SUMMARYThe main objective of the Biostatistics and Bioinformatics Core is to collaborate with all YSILC (Yale SPORE inLung Cancer) investigators to address analytical needs arising from individual projects. In the present awardperiod the Core has been a critical and effective component of the YSILC. In the next award period we willfurther strengthen our effort. We will keep our open door policy and interact with all YSILC investigators on aregular basis. The Core will keep playing a critical role in accomplishing the projects goals by ensuring that allstudies are rigorously designed executed analyzed and reported. We will also take an important role in datamanagement and ensure that all data are properly managed and protected. All NIH guidelines on data publicationand sharing will be properly followed. The Core will also contribute to the YSILC and broader lung cancercommunity by developing more effective analytics and by being involved in training and education.The specific aims are as follows. Aim 1: Provide strong biostatistical and bioinformatics support to allYSILC projects and investigators. The Core will maintain regular and dynamic interactions with allinvestigators. We will be available to all investigators of the projects other Cores and projects funded throughthe Developmental Research Program (DRP) and Career Enhancement Program (CEP). The Core has beenand will remain actively involved in the whole spectrum of study design. In execution we will ensure that theplans are rigorously followed. We will closely monitor study progress conduct regular monitoring and analysisand revisit/revise study designs if needed. After data collection is completed we will conduct comprehensiveanalysis using existing as well as new methods and assist in preparing manuscripts abstracts posters andgrant applications. Aim 2: Provide effective data management for all projects. Our Core along with theAdministrative and Biospecimen Cores will offer cost-effective and efficient data management services using acentralized data management system which will reduce data management burden for individual investigatorsand projects and also guarantee the uniformity of collected data. We will ensure that downstream analyses arefully taken into consideration in the process and that all NIH data-sharing regulations are properly followed whichincludes depositing properly curated data to public repositories. Aim 3: Develop innovative biostatistical andbioinformatics methods. The Core has been and will keep developing and implementing state-of-the-art newanalysis methods tailored to lung cancer data. This effort will facilitate more effective utilization of the YSILCdata foster lung cancer analytic research and benefit the broad research community.The Core will be co-led by Drs. Hongyu Zhao (bioinformatics) and Shuangge Ma (biostatistics). A stellar teamhas been assembled with extensive experiences and all the necessary expertise. +No NIH Category available American Cancer Society;Assessment tool;Baltimore;Basic Science;Biological Sciences;Biometry;Cancer Biology;Cancer Control;Cancer Diagnostics;Career Mobility;Catchment Area;Cigarette;Cities;Clinical;Clinical Research;Communities;Community Outreach;Comprehensive Cancer Center;Continuing Education;County;Databases;Discipline;Doctor of Philosophy;Education;Educational Activities;Faculty;Fellowship;Flow Cytometry;Funding;Genomics;Goals;Grant;Image;Individual;Infrastructure;Institution;Investigational Therapies;Journals;Laboratories;Leadership;Malignant Neoplasms;Maryland;Medical;Mentors;Minority-Serving Institution;Mission;Molecular Biology;NCI Center for Cancer Research;National Cancer Institute;Oncology;Outcome;Pathology;Pharmacy Schools;Physicians;Population Sciences;Postbaccalaureate;Postdoctoral Fellow;Prevention Research;Publications;Research;Research Activity;Research Personnel;Research Training;Schools;Scientist;Series;Services;Stream;Students;System;Talents;Training;Training Programs;Training and Education;Translational Research;Underrepresented Students;United States National Institutes of Health;Universities;acronyms;analytical tool;anticancer research;biobank;cancer education;cancer therapy;career;career development;clinical care;college;community engagement;doctoral student;experience;frontier;high school;hormone related cancer;innovation;junior high school;medical schools;member;multidisciplinary;neoplasm immunotherapy;next generation;outreach;pre-doctoral;programs;structural biology;synergism;tumor immunology;undergraduate student;underrepresented minority student Cancer Research Training and Education Coordination n/a NCI 10690046 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6566 7040487 "ANTALIS, TONI M" Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 32675 21148 11527 9.0 Abstract: Cancer Research Career Enhancement and Related ActivitiesEducation and training of next-generation cancer researchers is essential to continue the top-quality basictranslational clinical and prevention research required to control cancer in Maryland and around the world.Cancer Research Career Enhancement and Related Activities (CRCERA) at the University of MarylandMarlene and Stuart Greenebaum Comprehensive Cancer Center (UMGCCC) include cancer educationresearch training career development and continuing education programs that stream through our communityfrom middle school through postdoctoral education. Cancer education and research training are integratedseamlessly across UMGCCC basic and translational research and the clinical activities. Educational and careeradvancement activities are leveraged across the pipeline programs and with partners in our surroundingcatchment area the University of MarylandCollege Park the University of MarylandBaltimore County TowsonUniversity and Morgan State University. CRCERA are coordinated by the UMGCCC Training and EducationSteering Committee which is chaired by the associate director of Training and Education and is composed ofUMGCCC senior leadership directors of formal education and training programs and education partners in theparticipating schools of the University of MarylandBaltimore (UMB). During the previous funding period thecancer training programs provided research experiences and career development opportunities for more than730 students across the training and education continuum. These programs are supported by 17 NationalInstitutes of Health grants; 3 additional cancer-focused or cancer-related institutional training grants including 2grants from the National Cancer Institute; and several individual fellowships. CRCERA are expanding to supportthe goals of inspiring educating training and developing the careers of the next generation of cancerresearchers from diverse backgrounds and multiple disciplines. UMGCCC will achieve this goal through threespecific aims: (a) coordinate and support innovative research programs and transformative experiences thatencourage students to explore careers in cancer research and that will enhance UMGCCC research clinicalactivities and community outreach; (b) expand infrastructure and analytical tools for assessing metrics andoutcomes of existing and developing CRCERA to provide the most effective programs possible; and (c) build ondiversity-focused early pipeline programs by expanding partnerships with minority institutions and enhancingstakeholder connections throughout the catchment area to encourage talented underrepresented students topursue careers in cancer research and clinical care. UMGCCC programs faculty and administrative staff andshared services support these aims. +No NIH Category available Address;Agreement;Area;Award;Baltimore;Biometry;Budgets;Cancer Center;Cancer Center Support Grant;Catchment Area;Cigarette;Clinical;Clinical Research;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Contracts;County;Data Analyses;Development;Doctor of Medicine;Education;Education and Outreach;Ensure;Equipment;Evaluation;Faculty;Flow Cytometry;Fostering;Funding;Genomics;Grant;Human;Human Resources;Image;Informatics;Information Technology;Infrastructure;Institution;Interdisciplinary Study;Investigational Therapies;Laboratories;Leadership;Location;Malignant Neoplasms;Marketing;Maryland;Medical;Medical center;Mentors;Mission;Molecular Biology;Monitor;Pathology;Pharmacy Schools;Pilot Projects;Population Sciences;Principal Investigator;Process;Public Health Schools;Recommendation;Reporting;Research;Research Activity;Resources;School Dentistry;Science;Services;State Government;Strategic Planning;Surveys;System;Training;Training and Education;Translational Research;Universities;Vision;Wages;acronyms;anticancer research;biobank;clinical practice;college;community engagement;computer network;hormone related cancer;innovation;medical schools;meetings;member;neoplasm immunotherapy;population based;programs;recruit;square foot;structural biology;symposium;translational cancer research;tumor immunology;virology Administrative Core n/a NCI 10690045 8/30/23 0:00 PAR-20-043 5P30CA134274-16 5 P30 CA 134274 16 8/8/08 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6565 1967833 "CULLEN, KEVIN J." Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 120237 77823 42414 2.0 Abstract: Administrative CoreThe UMGCCC Administrative Core includes the Senior Leadership Team and Center Administration. The SeniorLeadership Team establishes the overall strategic direction and research mission for UMGCCC and CenterAdministration operationalizes this vision through interactions with internal and external stakeholders. CenterAdministration provides infrastructure to support the Cancer Center Support Grant and to promote the cancerresearch activities of its 225 members with a particular focus on facilitating transdisciplinary and population-based translational cancer research. The administration supports the director senior leaders program leadersshared services directors and UMGCCC members in carrying out the Cancer Center mission through effectivestrategic planning and evaluation operational management and centralized resources. UMGCCCadministration oversees a $36.1 million operating budget (FY2019) including clinical practice grant and fiscalmanagement and other administrative services for faculty and staff members; five established researchprograms; one developing program; and seven shared services in addition to the (a) Training and Education and(b) Community Outreach and Engagement components. The administrative staff is responsible for humanresources and administering partial salary support for over 150 full-time equivalents. Many of these reside inCancer Centercontrolled space (213705 gross square feet) which the administrative staff also manages.Administrative responsibilities include management of Cancer Center membership finances personnel grantsand contracts clinical research agreements and trials purchasing philanthropy and providing administrative andfinancial oversight to UMGCCC shared services; overseeing space utilization and common equipment;facilitating recruitment efforts; managing Cancer Center meetings and membership; and coordinating andfacilitating pilot award programs and Cancer Center planning and evaluation activities (leadership andprogrammatic meetings seminars annual symposia and retreats and internal and external board meetings).The administrative staff also support communication to the 225 UMGCCC members the Community AdvisoryBoard and the university as a whole as well as support legislative activities regarding the Cancer Center acrossthe State. The administrative team monitors and reports on member accomplishments funding and cancer-related activity to the Research Council and other advisory groups as a part of the annual membershipevaluation. Conducting surveys and evaluation for planning are also functions of the central administrative staff. +No NIH Category available Acute Myelocytic Leukemia;Acute T Cell Leukemia;Affinity;Allogenic;Area;Back;Basic Science;Bispecific Antibodies;Bone Marrow;CD7 gene;CXCR4 gene;Chemosensitization;Clinical Research;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Complication;Effector Cell;Engraftment;Failure;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;IFNGR1 gene;IL3RA gene;IL8RB gene;Immune;Immunotherapeutic agent;Immunotherapy;Infusion procedures;Integrin alpha4beta1;JAK1 gene;JAK2 gene;Malignant Neoplasms;Marrow;Methods;Monoclonal Antibodies;Natural Killer Cells;Natural regeneration;Patients;Phase I Clinical Trials;Pre-Clinical Model;Progressive Disease;Reagent;Recurrent disease;Refractory;Relapse;Research;Signal Pathway;Stromal Cell-Derived Factor 1;System;T-Lymphocyte;Testing;Translating;Vascular Cell Adhesion Molecule-1;acute lymphoblastic leukemia cell;bench to bedside;cancer genomics;career;chemotherapy;chimeric antigen receptor T cells;curative treatments;design;early phase clinical trial;efficacy testing;first-in-human;graft vs host disease;graft vs leukemia effect;inhibitor;leukemia;leukemia relapse;novel;preclinical study;prevent;programs;success;targeted agent;targeted treatment;transplantation therapy Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies PROJECT NARRATIVEAllogeneic hematopoietic stem cell transplant (HSCT) is the only curative therapy for many patients withhematologic malignancies and marrow failure states. We will overcome many of the major limitations tosuccessful HSCT by designing and testing in clinical trials our basic science observations which have identifiedoptimal methods of mobilizing stem cells for HSCT and for sensitizing acute myelogenous leukemia (AML) tochemotherapy by developing and implementing novel methods to prevent graft-versus-host disease (GvHD)the major complication of allogeneic HSCT and by developing novel immunotherapies for AML and T-ALL. NCI 10690042 9/11/23 0:00 PAR-16-411 5R35CA210084-07 5 R35 CA 210084 7 "SONG, MIN-KYUNG H" 9/7/17 0:00 8/31/24 0:00 ZCA1-GRB-I(M2) 1927565 "DIPERSIO, JOHN F." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 894296 NCI 588000 308700 PROJECT SUMMARY/ABSTRACTAllogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative therapy for many patientswith hematologic malignancies and marrow failure states. Key obstacles to the success of HSCT includecollecting optimal numbers of hematopoietic stem/progenitor cells (HSPCs) capable of multilineage anddurable engraftment control of graft-versus-host disease (GvHD) and treating disease recurrence both beforeand especially after HSCT. I have focused my career over the last 20 years on overcoming these threeobstacles to HSCT through the use of a bench-to-bedside and back again research approach. My researchprogram over the next seven years will use our strengths in preclinical modeling cancer genomics and thedesign and execution of early phase clinical trials to (1) develop novel methods to target the hematopoieticniche for optimal HSPC mobilization and chemosensitization of acute myeloid leukemia (AML) (2) target theinterferon gamma receptor (IFNR) and IL-6R signaling pathways via use of selective and balanced JAK1/2inhibitors to mitigate GvHD while maintaining graft vs. leukemia (GvL) after allo-HSCT and (3) design and testnovel AML and T cell acute lymphoblastic leukemia (T-ALL) immunotherapeutics. Successful HSCT requiresthe infusion of a sufficient number of HSPCs that are capable of homing to the bone marrow cavity andregenerating durable trilineage hematopoiesis in a timely fashion. In our first research area we will use newstrategies to enhance HSPC mobilization and leukemia chemosensitization via targeted modulation of theCXCR4/CXCL12 VLA-4/VCAM-1 and/or CXCR2/Gro- axes. Managing the threat of GvHD while maximizingthe beneficial GvL effect would broaden the scope and usefulness of allo-HSCT. In our second major researcharea we will perform preclinical and clinical studies to determine if targeting IFNR IL-6R and/or JAK1/JAK2can mitigate GvHD while maintaining GvL after T cell replete allo-HSCT. Finally since many patients with AMLdie from progressive disease after relapse our third research area will develop and translate into early phaseclinical trials novel bi- and tri-specific monoclonal antibody reagents for the treatment of AML relapse beforeand after HSCT. We will complete first-in-man phase I clinical trials of MGD006 a CD123xCD3 Dual AffinityRe-Targeting (DART) bispecific antibody-based molecule and AMV564 a CD33xCD3 Tandem Diabody inpatients with relapsed/refractory AML. While these trials are ongoing we are identifying novel targets forimmunotherapy in AML and testing the efficacy of new retargeting agents that engage either T cells NK cellsor other immune effector cells to kill AML blasts expressing CD123 CD33 or the novel targets. Finally sinceno targeted therapies currently exist for T-ALL we are developing allogeneic chimeric antigen receptor T cells(CAR-T) to CD7 a T and NK cell marker that is highly expressed in T cell malignancies and in up to 40% ofAML cases. To prevent normal T cell fratricide and alloreactivity we are using the CRISPR/Cas-9 system todelete CD7 and the TCR chain from donor T cells prior to transduction with the CD7 CAR. 894296 +No NIH Category available Acceleration;Achievement;Advocacy;Advocate;Basic Science;Biology;Clinical;Clinical Research;Collaborations;Communication;Consultations;Data;Development;Disputes;Ensure;Evaluation;Foundations;Funding;Future;Goals;Grant;Human Resources;Human Subject Research;Infrastructure;Institution;Laboratory Finding;Leadership;Malignant neoplasm of lung;Monitor;National Cancer Advisory Board;National Cancer Institute;Occupational activity of managing finances;Patients;Philanthropic Fund;Preparation;Principal Investigator;Privatization;Program Evaluation;Progress Reports;Publications;Regulation;Research;Research Personnel;Research Priority;Resources;Series;Source;Translational Research;Translations;United States National Institutes of Health;Universities;Yale Cancer Center;anticancer research;career;cost effective;meetings;neoplasm resource;novel;operation;outreach;personalized medicine;programs;success;symposium;timeline;translational applications;translational cancer research;website development Core A: Administrative Core PROJECT NARRATIVEThe Administration Core (Core A) is essential for leading the Yale SPORE in Lung Cancer (YSILC). The Coreprovides scientific financial and administrative oversight for all YSILC activities and make critical decisionsregarding project oversight and management. NCI 10690041 8/7/23 0:00 PAR-18-313 5P50CA196530-09 5 P50 CA 196530 9 8/26/15 0:00 7/31/25 0:00 ZCA1-RPRB-6 6564 1925253 "HERBST, ROY S" Not Applicable 3 Unavailable 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT Domestic Higher Education 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 161959 96748 65305 CORE SUMMARYThe Administrative Core (Core A) is directed by Roy Herbst Principal Investigator of the Yale SPORE in LungCancer (YSILC) and co-directed by Ed Kaftan with support from the program financial management team.Careful oversight by the Administrative Core will be critical to ensure the success of the Yale SPORE in LungCancer. Core A is an extension of existing infrastructure provided by YCC Research Administration to supportand facilitate transdisciplinary research efforts. The Administrative Core serves as the central coordinationpoint for all YSILC investigators with responsibility for monitoring the progress of all projects and cores towarda translational/clinical endpoint. The Core Director and Co-Director along with the YISLC Co-PI (Dr. Chen)have responsibility for leading the YSILC program setting translational research priorities identifying newtranslational research opportunities from emerging data monitoring the progress of all projects cores anddevelopmental projects and determining changes in direction of projects cores and translational research asneeded. Interactions among YSILC investigators is facilitated by Core A to accelerate the translation oflaboratory findings into the proposed and future clinical studies. If required the Core A Director will manageconflicts among YSILC investigators. As a team the Core personnel monitors finances maintainscommunications among project and core leaders and coordinates meetings including the weekly lung cancertranslational group seminar series monthly meetings of the Executive Committee annual meetings of theInternal/External Advisory boards and the annual YSILC SEP and DRP Symposium. In addition to thesefunctions the Core is the primary interface with the NCI other lung cancer SPOREs Yale Cancer Center andYale University and coordinates outreach efforts including publications (internal and external) websitedevelopment seminars patient/research advocacy activities and fundraising programs. Through theseadministrative activities Core A is essential to the organization of the YSILC program to developing awidespread culture of lung cancer basic/clinical/translational research at Yale and to the efficient achievementof the stated program objectives with the ultimate goal of a significant clinical impact for patients with lungcancer. +No NIH Category available Address;Adoption;Animal Disease Models;Area;Award;Biochemical;Biochemistry;Bioinformatics;Biological;Biological Assay;Biology;Biometry;Biopsy;Blood;Brain;Brain Neoplasms;Cancer Etiology;Cancer Hospital;Cancer Patient;Cell surface;Cells;Central Nervous System;Cessation of life;Clinical;Clinical Research;Clinical Trials;Comprehensive Cancer Center;Connecticut;DNA Sequence Alteration;Development;Diagnosis;Disease;Drug resistance;Environment;Epidermal Growth Factor Receptor;Epigenetic Process;Frequencies;Funding;Gene Expression;Generations;Genetic;Genomics;Goals;Grant;Human;Human Cell Line;Immune;Immune response;Immunologics;Immunooncology;Immunosuppressive Agents;Immunotherapy;In Vitro;Liquid substance;Lung Adenocarcinoma;Macrophage;Malignant Neoplasms;Malignant neoplasm of lung;Metastatic Neoplasm to the Central Nervous System;Metastatic malignant neoplasm to brain;Molecular;Morbidity - disease rate;Mutation;Myeloid Cells;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Outcome;Pathology;Pathway interactions;Patient Selection;Patients;Physicians;Pre-Clinical Model;Production;Productivity;Proteins;Protocols documentation;Pulmonary Challenge;Recording of previous events;Refractory Disease;Reproduction spores;Research;Research Personnel;Resistance;Resource Sharing;Sampling;Scientist;Selection for Treatments;Solid Neoplasm;Source;Speed;Structure;T-Lymphocyte;Testing;Translating;Tyrosine Kinase Inhibitor;United States;Yale Cancer Center;anticancer research;bench to bedside;biomarker development;biomarker evaluation;cancer cell;cancer drug resistance;cancer therapy;career;clinical application;clinical care;clinically actionable;combat;design;effectiveness evaluation;improved;in vivo;innovation;mortality;mouse model;mutant;next generation;novel;novel therapeutic intervention;novel therapeutics;outreach;personalized medicine;pharmacologic;prevent;programmed cell death ligand 1;programs;prospective;resistance mechanism;targeted treatment;translational cancer research;translational research program;translational scientist;translational study;tumor;tumor microenvironment;tumor progression Yale SPORE in Lung Cancer (YSILC): The Biology and Personalized Treatment of Lung Cancer OVERALL NARRATIVELung cancer is the number one cause of cancer death in the United States and the Yale SPORE in LungCancer is designed to identify novel biologic pathways and test new therapeutic approaches to interfere withlung cancer progression and metastasis. All three projects in the SPORE will initiate Yale-led novel clinicaltrials and will promote bench to bedside research within the center. This program has the potential to makesignificant impact in guiding the selection of therapies most likely to provide benefit to lung cancer patients withtreatment refractory disease in the primary or metastatic setting. NCI 10690040 8/7/23 0:00 PAR-18-313 5P50CA196530-09 5 P50 CA 196530 9 "UJHAZY, PETER" 8/26/15 0:00 7/31/25 0:00 ZCA1-RPRB-6(O1) 1925253 "HERBST, ROY S" "POLITI, KATERINA ABIGAIL" 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 2069846 NCI 1236900 834137 YALE SPORE IN LUNG CANCER (YSILC) OVERALL SUMMARYThe Biology and Personalized Treatment of Primary and Metastatic Lung Cancer: The YSILC unitestranslational scientists spanning diverse areas of cancer research to converge on addressing the challenge oflung cancer. The goal of the YSILC is to reduce mortality from lung cancer through development of noveltherapeutics and treatment approaches that are based on an understanding of targetable biochemical andimmunological pathways involved in progression of lung cancer acquisition of resistance and development ofmetastasis The YSILC translational research team will accomplish this objective through three projects:Project 1: Test the hypotheses that Siglec-15 (S15) is a major immune suppressor in PD-L1/B7-H1-negativelung cancer and that blockade of S15 can be efficacious for a subset of lung cancer patients; Project 2:Evaluate mechanism-based approaches to counter tyrosine kinase inhibitor resistance in EGFR-mutant lungcancer; Project 3: Targeting lung cancer metastasis and drug resistance in the central nervous system. Thereare three Cores (Administrative; Biostatistics and Bioinformatics; and Biospecimen Pathology and Genomics)to support the projects and their clinical aims mechanistic studies and evaluation of biomarkers for clinicalapplication. Strong Developmental Research and Career Enhancement Programs (DRP CEP) with ahistory of choosing diverse and productive projects with good outcomes are also proposed. The highlycoordinated YSILC projects cores and programs are focused on developing novel lung cancer therapies withanalysis of patient samples cell-based assays production of human cell lines and animal models of diseaseas a guide to design prospective trials that translate these innovative targeted approaches to clinical therapies.Each of these projects has a clinical trial (either investigator-initiated or NCI-based) designed to test thesensitivity and resistance of the new therapy with molecular correlates. The expected translational outcomes ofthe program include: (1) a highly coordinated and focused development of a novel immune agent discoveredduring our current SPORE research; (2) an improved understanding of genetic and epigenetic mechanisms ofresistance to EGFR therapies and how to combat it; (3) an understanding of the mechanism underlying brainmetastasis; (4) expanding the breadth of lung cancer research by developing the next generation ofinvestigators and encouraging established investigators in other fields to pursue studies on lung cancerthrough our CEP and DRP programs. 2069846 +No NIH Category available 3-Dimensional;Amino Acids;Antibodies;Antigen Presentation Pathway;Antigens;Biopsy;Bispecific Antibodies;Cell Line;Cell surface;Cervix carcinoma;Complex;Cytotoxic agent;Development;Dose;Engineering;Epitopes;HLA-A gene;Half-Life;Histocompatibility Antigens Class I;Histocompatibility Antigens Class II;Human;Human Papillomavirus;Immune;Immunotherapy;In Vitro;Insulin Receptor;MHC Class I Genes;Malignant - descriptor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mass Spectrum Analysis;Membrane Proteins;Methods;Molecular Conformation;Monoclonal Antibodies;Monoclonal Antibody Therapy;Oncoproteins;Peptides;Pharmaceutical Preparations;Phosphopeptides;Phosphorylation;Proteins;Radiation;Reproducibility;Serine/Threonine Phosphorylation;Specificity;Structure;T cell therapy;T-Cell Receptor;Testing;Therapeutic;Toxin;Treatment Efficacy;Tumor Antigens;cancer cell;chimeric antigen receptor;cost;flexibility;immunogenic;in vivo;neoantigens;novel;side effect;tool;tumor Developing therapeutic TCR mimic monoclonal antibodies for cancer This project aimed at developing two new class of mAbs eg TCRm mAbs specific for HPV-E7 and pIRS2-derived epitopes in the context of HLA-A*02:01 molecule. If successful this approach could bring a novel andwidely applicable therapy to various human cancers. NCI 10690038 8/15/23 0:00 PAR-21-285 5R50CA265328-02 5 R50 CA 265328 2 "SALOMON, RACHELLE" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-1(M1) 6678877 "DAO, TAO " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 135201 NCI 76385 58816 T cell receptor mimic (TCRm) mAbs. TCRm mAbs represent a new class of mAbs structurally identical totraditional mAbs. However while traditional mAbs recognize 3D conformational structure of a surface proteinTCRm mAbs recognize peptides (9-10 amino acids) derived from intracellular proteins displayed on cellsurface by MHC class I molecules the complexes traditionally recognized by TCR. This allows an antibody tohave access to vast majority truly tumor-specific antigens most of them are intracellular proteins. Theadvantages of mAb therapy are well known that include their high target specificity high efficacy limited sideeffects prolonged half-life availability low cost and infrequent dosing. In addition to the immune effectorfunctions of a mAb mAb can also serve as antigen-specific vehicles that can deliver more potent cytotoxicagents such as toxins drugs or radiation. Finally mAbs can be engineered into chimeric antigen receptorsor bi-specific antibodies in order to enhance the specificity and the potency of T cell therapy.This project aimed at developing novel TCRm mAbs specific for two important validated and tumor-specificantigens as described below. Combining the best inherent features of both TCR recognition and the flexibilityand potency of the mAbs as drugs the new TCRm mAbs could offer a potent controllable and widelyapplicable therapy.1. Developing TCRm mAb to HPV-E7-derived epitope in the context of HLA-A*02:01. Human papillomavirus (HPV) causes hundreds of thousands of cancers worldwide. Most cervical carcinoma cells constitutivelyexpress HPV type 16 E6 and E7 oncoproteins which provide an ideal and specific target for immunotherapies.We selected an immunogenic epitope derived from E7 protein (E7 p11-19) presented by HLA-A*02:01 as thetarget for the TCRm mAb. This epitope has been reproducibly detected in a majority of cervical cancer biopsiesand cell lines in the context of HLA-A*02:01 molecule by mass spectrometry.2. Developing TCRm mAb to pIRS2 in the context of HLA-A*02:01. Dysregulated protein phosphorylationis a hallmark of malignant transformation. Phosphorylation of serine and threonine residues is retained onpeptides during MHC class I and class II antigen processing and presentation on the cell surface. Thereforephosphopeptides derived from inappropriate phosphorylation of various proteins in malignant cells representan extraordinary class of tumor specific neoantigens that are also widely expressed and not patient-specific.We hypothesize that phosphopeptides could be used as shared tumor specific neoantigens. We selected aphosphopeptide of insulin receptor substrate2 (pIRS21097-1105) in the context of HLA-A*02:01 as the targetfor the TCRm development. This epitope has been identified in various cancer cells by mass spectrometry.We have a set of experimental tools and methods to select characterize specific mAbs and to test theirtherapeutic efficacy both in vitro and in vivo. 135201 +No NIH Category available Address;Affect;African American;African ancestry;Age;Apoptosis;Apoptotic;Biological;Biological Assay;Biological Markers;Biology;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer cell line;Breast Epithelial Cells;Breast Feeding;Breast biopsy;Cancer Biology;Cell Communication;Cell Death;Cell Line;Cessation of life;Characteristics;Chronic;Clinical;Clonal Evolution;Coculture Techniques;Communities;DNA Damage;Data;Data Set;Diagnosis;Disease;Disease Resistance;Disparity;Drug resistance;Embolism;Epigenetic Process;Ethnic Origin;Exhibits;Exposure to;Gene Expression;Genes;Genomic Instability;Growth;Health Services Accessibility;Homeostasis;Hormone Receptor;Immunohistochemistry;Implant;In Vitro;Incidence;Infiltration;Inflammation;Inflammatory;International;Invaded;Lead;Lesion;Life;Link;Macrophage;Mammary Gland Parenchyma;Mammary gland;Maps;Mediating;Medical;Modeling;Molecular;Multi-Drug Resistance;Multiparity;Mutation;Neoplasm Metastasis;Normal Cell;Not Hispanic or Latino;Observational epidemiology;Organoids;Outcome;Pathway interactions;Patients;Pattern;Phenotype;Pregnancy;Premalignant Cell;Primary Neoplasm;Proliferating;Public Health;Race;Reproductive History;Research;Resistance;Risk Factors;Scientist;Signal Transduction;Skin;Socioeconomic Status;Stimulus;Stress;Stress Response Signaling;Stromal Neoplasm;Symptoms;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;Treatment Efficacy;Tumor Stem Cells;Tumor-associated macrophages;United States;Variant;Woman;Work;Zoledronic Acid;aggressive breast cancer;biological adaptation to stress;cancer cell;cancer health disparity;cancer subtypes;cell immortalization;cohort;determinants of treatment resistance;environmental agent;environmental change;epidemiology study;genetic signature;hazard;health determinants;health disparity;high body mass index;in vivo Model;inflammatory breast cancer;intercellular communication;malignant breast neoplasm;mammary;modifiable risk;molecular subtypes;monocyte;mouse model;neoplastic cell;novel;pharmacologic;prevent;response;stem cells;stressor;targeted treatment;therapy outcome;therapy resistant;trait;tumor;tumor growth;tumor heterogeneity;tumor initiation;tumor microenvironment;tumor progression;tumorigenic Molecular Determinants of Health Disparities in Inflammatory Breast Cancer Inflammatory breast cancer (IBC) a highly lethal form of breast cancer disproportionately affects AfricanAmerican (AA) compared with non-Hispanic White women (W) with hazard ratios for death 30% higher in AAcompared to W even after adjusting for socioeconomic position age at diagnosis treatment and hormonereceptor status. Recently we discovered that this disparity may be the result of a heightened adaptive stressresponse signaling in the tumor microenvironment of AA linked to IBC risk factors which can lead to greatercapacity for clonal evolution of death-resistant tumor cells contributing to aggressive therapy-resistant disease.As the incidence is rising and targets for therapy are scant IBC has the potential to become a major publichealth disparity concern. This study has the potential to lead to new treatment options provide a biomarker forstress related progression and therapy resistance in AA-IBC and predict those who would benefit from thesetargeted approaches. NCI 10690036 8/28/23 0:00 PAR-18-654 5R01CA264529-03 5 R01 CA 264529 3 "BERA, TAPAN K" 9/20/21 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-J(55)R] 10001178 "DEVI, GAYATHRI " Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 491802 NCI 356610 135192 Inflammatory breast cancer (IBC) the most lethal form of breast cancer is a health disparity. IBChas a greater incidence and younger presentation in African Ancestry women (AA) compared with white women(W). IBC is also particularly aggressive in AA who exhibit substantially shorter median survival compared to Wirrespective of molecular subtype. The underlying causes of this disparity in clinical outcome much of whichremains after controlling for medical coverage and treatment access are poorly understood severely limitingpotential strategies to close this gap. Our proposed work addresses the critical unanswered questions - Whattumor biological mechanisms drive the more aggressive IBC biology in AA) and how can these mechanisms bemodulated therapeutically? Our epidemiological studies identify that modifiable risk factors like reproductivefactors (early age at first pregnancy multiparity and lack of breastfeeding) and high body mass index (BMI) areassociated with poor therapeutic outcomes and survival among AA-IBC compared to W-IBC. These stressorshave the potential to cause persistent inflammation in the mammary gland. A basic survival mechanism that isintrinsic in both normal and cancer cells is the ability to constantly respond and adapt to stress stimuli (likemutations life-stressors environmental changes therapy) referred to as adaptive stress response (ASR).Linking these observations is our identification of ASR gene sets in IBC cells exposed to stress stimuli that showrace-specific differences in expression. These datasets lead to our overarching hypotheses that 1. aheightened adaptive stress response consisting of NFB activation suppression of programmed cell death andpro-tumorigenic macrophages promotes outgrowth of invasive metastatic and treatment resistant tumor cells inAA-IBC; 2. pharmacologic inhibition of the ASR pathway in conjunction with macrophage inhibition will suppressIBC growth and dissemination. To test this hypothesis we propose Aims to (1) investigate whether AA- and W-derived normal breast epithelial cells and IBC cell lines promote monocyte differentiation using a panel ofimmortalized cell lines from core breast biopsies of AA and W healthy women and IBC cells in co-culture assayswith monocytes and how ASR pro-survival markers correlate with stromal patterns of stem cells andmacrophages in patient tissues by gene expression and immunohistochemistry analysis; (2) implant AA- and W-patient derived IBC cell lines with differential NFB activity in a novel macrophage-induced early lesion murinemodel to spatially query tumor-stromal cell interactions and host macrophage infiltration during tumor initiation;(3) investigate the ability of clinically available agents birinapant a cell death booster and zoledronic acid amacrophage depleting agent to inhibit growth of tumor organoids derived from AA-IBC drug resistant variants inthe early lesion murine model. Successful completion of this project will lead to new treatment options for IBCpatients with a high unmet medical need. Importantly new AA- and W- bio-specimens PDX and derivative celllines and IBC-specific models resulting from the proposed work will be available to the scientific community. 491802 +No NIH Category available Address;Admixture;Algorithms;Automobile Driving;Cancer Diagnostics;Cells;Chromosome Structures;Chromosome abnormality;Chromosomes;Classification Scheme;Clinical;Clinical Data;Clinical Trials;Communities;Competence;Complex;DNA;DNA Damage;DNA Repair;DNA Sequence Rearrangement;DNA analysis;Data;Dedications;Development;Diagnosis;Event;Evolution;Genome;Genome Data Analysis Center;Genome Data Analysis Network;Genomics;Genotype;Haplotypes;Heterogeneity;Human;Human Resources;Immersion;Inflammatory Infiltrate;International;Leadership;Link;Malignant Neoplasms;Methods;Methylation;Molecular;Mutation;Mutation Analysis;Patients;Pattern;Phase;Physicians;Play;Ploidies;RNA;Recording of previous events;Recurrence;Repetitive Sequence;Research;Resolution;Role;SNP genotyping;Sampling;Scientist;Shapes;Structure;The Cancer Genome Atlas;Therapeutic;Variant;Visualization software;Work;admixture mapping;arm;cancer genome;cancer subtypes;cell free DNA;chromothripsis;circulating DNA;data integration;exome;experience;genome sequencing;genome wide association study;genomic locus;improved;innovation;insight;molecular subtypes;nanopore;novel therapeutic intervention;reconstruction;repaired;single cell analysis;tool;tumor;whole genome;working group Center for the Comprehensive Analysis of Cancer Somatic Copy-Number Alterations Rearrangements and Long-Read Sequencing Data Project narrativeSomatic copy-number alterations (SCNAs) and the rearrangements that generate them aretogether with mutations the major somatic genome alterations in human cancer andunderstanding them yields insights into how to diagnose and treat cancers. We have extensiveexperience in developing methods to detect and interpret SCNAs and rearrangements and haveapplied these methods across tens of thousands of tumors discovering new molecular subtypesof cancer that may benefit from new therapeutic strategies. We propose to renew our GenomicsData Analysis Center that will specialize in conducting state-of-the-art analyses of SCNAs andrearrangements from both short read and long read sequencing data to answer clinically andbiologically relevant questions that are tailored to the needs of the wider Genomics Data AnalysisNetwork. NCI 10690035 8/22/23 0:00 RFA-CA-20-053 5U24CA264029-03 5 U24 CA 264029 3 "YANG, LIMING" 9/20/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 7791227 "BEROUKHIM, RAMEEN " "CHERNIACK, ANDREW DAVID" 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 376320 NCI 235200 141120 AbstractWe propose to continue our established Genomics Data Analysis Center for the analysis ofstructural variants in cancer including somatic copy-number alterations (SCNAs) andrearrangements addressing the Copy Number competency required by GDAN. We also addcapabilities to analyze long- and linked-read data addressing a second competency. We ledSCNA analyses throughout The Cancer Genome Atlas (TCGA) and the first iteration of theGenomics Data Analysis Network (GDAN). We also co-led the Structural Variations WorkingGroup of the International Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes(PCAWG). For these efforts we have developed a large suite of tools and deep expertisecovering all aspects of analysis of SVs in cancer. Specifically we will accomplish five Aims: InAims 1 and 2 we will determine SCNA and rearrangement profiles from either short-read (wholeexome or whole genome) or long-/linked-read sequencing data and determine germlinegenotypes parental haplotypes and ancestry groups. The haplotype information will be used toimprove our copy-number resolution. In Aim 3 we reconstruct the tumor genome and itsevolutionary history. We evaluate sample heterogeneity including tumor purity ploidy andsubclonal alterations and phase rearrangements to homologous chromosomesdeterminingsomatic distances between all pairs of loci. Using these data we determine mechanisms of DNAdamage and repair and infer the events that occurred over tumor evolution. In Aim 4 we integratedata across samples to identify SVs and genomic loci that impact tumor evolution detectassociations with other molecular and clinical features and evaluate potential SCNA-determinedsubclasses. Moreover we perform association and admixture analyses with the germlinegenotypes detected in Aim 1. In Aim 5 we indicate ways in which we will immerse ourselveswithin the GDAN and disseminate our analysis results both within the GDAN and to the widercommunity. Within this we offer secondary competencies in single-cell and circulating DNAanalysis. Our GDAC will provide a comprehensive analysis of the roles of structural variations incancer development and progression through treatment among GDAN samples. We will alsooptimize interactions with the wider GDAN and scientific community to make maximal use of thesedata. 376320 +No NIH Category available Adenoviruses;Algorithms;Anus;Biological Assay;Biopsy;California;Cellular Immunology;Cervical;Clinic;Clinical;Clinical Research;Clinical Trials;Comprehensive Cancer Center;DNA;Data;Diagnostic;Disease;Disease regression;Ensure;Equipment;Grant;HIV;HIV Seropositivity;HPV-High Risk;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immune response;Laboratories;Leadership;Lesion;Malignant Neoplasms;Measures;Mentorship;Mexico;Participant;Pathology;Population;Prevention;Probiotics;Procedures;Protocols documentation;Puerto Rico;Quality Control;Reporting;Research;Research Personnel;Risk Reduction;Role;Safety;Sampling;Science;Scientist;Site;Specimen;Squamous intraepithelial lesion;Techniques;Technology Transfer;Testing;Training;Training Programs;Training Support;Universities;Woman;Work;career;career development;cell mediated immune response;cervical cancer prevention;data management;disorder prevention;high risk;laboratory facility;men;microbiome analysis;microbiome research;microbiota profiles;primary outcome;programs;quality assurance;research study;screening;statistics;therapeutic HPV vaccinations;therapeutic HPV vaccine;therapeutic vaccine;vaccine trial;virtual;working group CAMPO Central Laboratory Core The CAMPO Central Laboratory Core will perform laboratory assays in support of the three clinical researchstudies to be performed as part of the CAMPO Clinical Trials Program. It will also perform correlative sciencestudies using clinical samples obtained from research participants in order to answer important questionsabout how different treatment approaches may work to treat cancer precursors or reduce the risk of persistentHPV infection. NCI 10690034 8/7/23 0:00 RFA-CA-18-018 5U54CA242646-05 5 U54 CA 242646 5 9/12/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6563 8893994 "DARRAGH, TERESA MARIE" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 304553 254473 50080 The California-Mexico-Puerto Rico (CAMPO) Consortium will perform three clinical research studiesfocused on the prevention of cervical cancer among HIV-positive women in Mexico and Puerto Rico. Study 1will examine new screening algorithms for cervical high-grade squamous intraepithelial lesions (HSIL) in 4000HIV-positive women in Mexico and Puerto Rico. Study 2 will evaluate the impact of anogenital probiotic use onanal and cervical microbiota profiles and the relationship to anal and cervical HSIL regression in 600 HIVpositive women and men as well as reduction of high-risk HPV DNA persistence among those with no lesions.Study 3 will evaluate the safety and efficacy of a multivalent replication-defective adenovirus-basedtherapeutic HPV vaccine to treat cervical and anal HSIL in 300 HIV-positive women and men and identifyimmune response correlates of HSIL regression. Working with the Data Management and Statistics Core theAdministrative and Coordinating Core and the Clinical Trials Program the Central Laboratory Core (CLC) willperform laboratory assays for each of the three studies. The aims of the CLC are: (1) To perform laboratoryassays required to achieve the primary aims of the clinical research studies conducted within the CAMPOConsortiums Clinical Trials Program; (2) To perform laboratory assays for correlative science studies for theCAMPO Consortium; (3) To expand research capacity of consortium partners in Mexico and Puerto Ricothrough technology transfer; (4) To participate in rigorous quality control programs to ensure the validity oflaboratory data; and (5) To support training and career development of early career investigators in laboratorybased research. The CLC will be led by Dr. Alejandro Garcia-Carranca of INCan and co-led by Drs. FilipaGodoy-Vitorino of UPR and Joel Palefsky of UCSF. Similar to the other CAMPO Cores the CLC will becomprised of a network of investigators and facilities across the three Consortium sites working closelytogether but with each site tasked with a role based on their specific expertise. The CLC will have both virtualand physical components with CLC laboratory facilities at INCan INSP and the Condesa Clinic in Mexico theUniversity of Puerto Rico Comprehensive Cancer Center the University of Puerto Rico Clinical Trials Centerand UCSF. The network will use GlobalTraceTM to track and ship laboratory specimens between the sites. TheCLC will form working groups centered on CAMPOs scientific agenda- HPV diagnostics microbiome researchand cellular immunology- with representation from scientists at each site and will participate on CAMPOClinical Trials Program study protocol teams. The CLC will perform a rigorous quality assurance program andreport results on a regular basis to CAMPO leadership. +No NIH Category available Acyltransferase;Autophagocytosis;Binding;CDH1 gene;CRISPR-mediated transcriptional activation;Cell Death;Cell Survival;Cell membrane;Cell physiology;Cells;Cessation of life;Citric Acid Cycle;Communication;Cytoprotection;Development;Disease;E-Cadherin;Endometrial Carcinoma;Energy Metabolism;Energy-Generating Resources;Enzymes;FRAP1 gene;Feedback;Funding;Genetic;Genetic Annotation;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Homeostasis;Iron;Ischemia;Lipid Peroxidation;Lipids;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of urinary bladder;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Modification;Molecular;Neoplasm Metastasis;Neurofibromin 2;Oncogenic;Organoids;Oxidation-Reduction;PIK3CG gene;Pancreatic Ductal Adenocarcinoma;Pathologic Processes;Pathway interactions;Patients;Phospholipids;Physiological;Predisposition;Process;Prognosis;Property;Proto-Oncogene Proteins c-akt;Regulation;Role;Series;Signal Pathway;Signal Transduction;Stress;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;Triglycerides;Validation;Xenograft procedure;cancer cell;cancer invasiveness;cancer therapy;cancer type;clinically relevant;cohort;effective therapy;experimental study;genetic information;insight;lipid biosynthesis;lipid metabolism;lipidomics;live cell imaging;membrane activity;metabolomics;mouse model;novel;organ injury;overexpression;oxidation;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pharmacologic;screening;success;tumor;tumor metabolism;tumorigenesis;whole genome Ferroptosis Cellular Metabolism and Cancer NarrativeSuccess of the proposed study will lead to an in-depth understanding of the molecular basis of ferroptosis andits interplay with cellular metabolism and provide insights into the development of novel mechanism-basedcancer therapies. NCI 10690013 8/24/23 0:00 PA-20-185 5R01CA204232-07 5 R01 CA 204232 7 "SALNIKOW, KONSTANTIN" 2/1/17 0:00 8/31/27 0:00 Cellular Signaling and Regulatory Systems Study Section[CSRS] 8020423 "JIANG, XUEJUN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 405771 NCI 229249 176522 Ferroptosis Cellular Metabolism and CancerAbstract Ferroptosis is a form of non-apoptotic cell death driven by cellular metabolism and iron-dependent lipidperoxidation. Although the physiological role of ferroptosis remains elusive mounting evidence has establishedthat ferroptosis impacts various pathological processes including cancer. This competitive renewal proposal isbuilt upon what we have achieved during the previous funding cycle and aims to further elucidate the molecularbasis of ferroptosis its interplay with metabolism and its role in cancer. In the previous funding period we foundthat multiple cellular metabolic pathways such as autophagy glutaminolysis and strikingly the normal metabolicactivity of mitochondria contribute to ferroptotic death. We also found that the CDH1-NF2-Hippo-YAP and PI3K-AKT-mTOR-SREBP signaling pathways both highly relevant to cancer regulate ferroptosis through modulatingcellular iron homeostasis and lipid metabolism. Moreover via a whole genome CRISPR/cas9-activation screenwe identified several lipid modifying enzymes as novel ferroptosis suppressors further underscoring the intimaterelationship between lipid metabolism and ferroptosis. Importantly our TCGA analysis indicates overexpressionof one of these enzymes MBOAT2 predicts poor prognosis in multiple cancer types including liver cancerbladder cancer and pancreatic ductal adenocarcinoma (PDAC). Based on these preliminary results the centralhypothesis of the grant is that lipid modification regulates cancer cell metabolism invasiveness and ferroptosisthrough modulating cellular lipid storage and membrane composition; and targeting MBOAT2 in combinationwith ferroptosis induction holds cancer therapeutic potential. To investigate this hypothesis and to define theunderlying mechanisms we will tackle following questions. First what is the mechanism by which these lipidmodifiers protect cells fromferroptosisdo they dictate lipid peroxidation viaaltering specific phospholipidspeciesand do they communicate with SREBP a master transcriptional regulator of lipogenesis and a potent ferroptosissuppressor (Aim-1)? Second do these lipid modifiers modulate cellular properties such as cellular storage oflipids as energy source and plasma membrane plasticity? As these cellular properties impact cancer cellinvasive/metastatic capability metabolism and likely redox homeostasis is there a functional interplay betweenferroptosis and these cancer-relevant cellular processes (Aim-2)? Third and directly relevant to cancer treatment(Aim-3) by using patient-derived tumor organoids xenograft mouse models and genetically engineered mousemodels (GEMM) we will investigate how our newly-identified ferroptosis suppressors modulate tumorigenesismetastasis and the responsiveness of cancer cells to ferroptosis induction and assess whether the combinationof MBOAT2 inhibition with ferroptosis induction can be an effective therapy for the treatment of cancer in whichMBOAT2 overexpression predicts poor prognosis (we will focus on PDAC in this proposal). Success of theproposed study will lead to an in-depth mechanistic understanding of ferroptosis and its interplay with cellularmetabolism and provide insights into the development of novel mechanism-based cancer therapies. 405771 +No NIH Category available Algorithms;Cancer Patient;Cardiac;Caring;Clinical;Clinical Research;Computer software;Data;Detection;Development;Devices;Diagnosis;Diagnostic;Dose;Effectiveness;Evaluation;FDA approved;FOLH1 gene;Functional Imaging;Future;Goals;Hyperacusis;Image;Imaging Techniques;Kinetics;Label;Legal patent;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Marketing;Measures;Medical Device;Motion;Myocardial perfusion;Neuroendocrine Tumors;Noise;Notification;Oncology;Output;Patient Care;Patients;Performance;Phase;Play;Population;Positron-Emission Tomography;Preservation Technique;Protocols documentation;Radionuclide therapy;Rest;Safety;Scanning;Schedule;Selection for Treatments;Signal Transduction;Site;Small Business Innovation Research Grant;Staging;Stress;Techniques;Technology;Testing;Therapeutic Effect;Time;Tracer;Translating;Validation;cancer imaging;clinical risk;cost;design;detection sensitivity;dosimetry;fluorodeoxyglucose;image guided;improved;neuroendocrine differentiation;new technology;novel;predicting response;prognostic;prospective;prototype;rapid technique;routine imaging;targeted treatment;theranostics;tool;treatment response;treatment strategy;tumor;uptake;usability;verification and validation;whole body imaging Dual-Tracer PET Tumor Imaging NarrativeThis project will develop a new way to perform positron emission tomography (PET) scans that can acquiretwice as much informationessentially performing two scans in one. This new technology will allowcancer patients to receive a more valuable PET scan that will improve their diagnostic workup and helpdecide which treatment strategy will be most effective. Ultimately this will result in both more effective andmore affordable care by providing a more complete diagnosis as well as precisely determining the besttreatment for each patient. NCI 10690000 7/26/23 0:00 PA-21-259 5R44CA257522-03 5 R44 CA 257522 3 "REGMI, SAROJ GOPAL" 12/1/20 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Z(10)B] 6940511 "KADRMAS, DAN J" Not Applicable 1 Unavailable 78299996 MN1MX5EDMMD7 78299996 MN1MX5EDMMD7 US 40.756362 -111.826562 10031336 "MULTIFUNCTIONAL IMAGING, INC." South Ogden UT Domestic For-Profits 844034807 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 692035 NCI 573671 73091 Abstract Positron emission tomography (PET including PET/CT and PET/MRI) with 18F-fluorodeoxyglucose(FDG) plays a key role in diagnosing and staging a wide variety of malignant tumors assessing tumorgrade and evaluating response to therapy. The advent of other recently-approved tracers particularlythose with theranostic partners is opening a new era of imaging where the uptake of PET tracers candirectly predict the effectiveness of certain targeted therapies. Such theranostic tracers image differentaspects of tumor function than traditional diagnostic tracers (e.g. FDG) and they provide complementaryimages with different detection and staging performance across different levels of tumor differentiation andgrade. The ability to routinely image multiple PET tracers in each patient would provide increaseddiagnostic performance improved grading and staging information and combine predictive theranosticimaging with the diagnostic workup. However current technology requires that separate scans beperformed for each tracerusually on separate daysresulting in high cost scheduling and logisticalchallenges and undue burden on the patient. This project will remove those obstacles by developingsimultaneous dual-tracer PET tumor imaging techniquesproviding accurate images of two PET tracers ina single scan and making these techniques available for general clinical use. Multifunctional Imaging LLC(MFI) has previously developed a software medical device mfiVerse which enables both rest and stressmyocardial perfusion PET images to be obtained in a single scan in as little at 15 min. This SBIR projectwill expand the software capabilities to also support dual-tracer PET cancer imaginga much broader setof applications that will serve many more clinical needs and markedly increase market demand for thisproduct. A new technique for simultaneously imaging tracers such as FDG+DOTATATE and FDG+PSMAin a single dual-tracer PET scan will be developed. Combined imaging of FDG+DOTATATE will improveimaging performance of both well- and poorly-differentiated neuroendocrine tumors (NETs) whilesimultaneously predicting response to targeted radionuclide therapy with Lu177 DOTATATE. Similarlycombined imaging of FDG+PSMA will improve characterization of both well- and poorly-differentiatedprostate cancer tumors while at the same time predicting response to targeted radionuclide therapy withLu177 PSMA. This Phase II project will complete development of the new dual-tracer technique andthoroughly evaluate it in a prospective clinical study of 60 patients with prostate cancer or NETs acquiringall of the verification and validation data necessary to demonstrate the safety and efficacy of the approach.Completion of this project will create a first-of-its-kind medical device for simultaneous dual-tracer PETimaging which after subsequent regulatory approval will enable routine clinical use of dual-tracer PETtumor imaging to improve diagnostic evaluation of patients with prostate cancer or NETs. Futureenhancements will expand support to other tracer combinations and imaging indications providingimproved diagnostic evaluation and image-guided selection of therapies for a broad population of cancerpatients. 692035 +No NIH Category available 3-Dimensional;Adjuvant;Animal Model;Autopsy;Biodistribution;Biological;Biomedical Engineering;Blood - brain barrier anatomy;Brain;Brain Glioblastoma;Brain Neoplasms;Brain region;Cancer Biology;Chemoresistance;Chemotherapy and/or radiation;Chlorotoxin;Chronic Kidney Failure;Clinic;Contrast Media;Data;Dose;Excision;FDA approved;Focused Ultrasound Therapy;Gadolinium;Generations;Glioblastoma;Goals;Growth;Heating;Human;Image;Imaging Device;Imaging Techniques;Implant;Injections;Iron;Knowledge;Link;Liver;Location;Lung;Magnetic Resonance Imaging;Magnetic nanoparticles;Magnetism;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mentors;Methods;Modeling;Monitor;Mus;Nanotechnology;Neurology;Operative Surgical Procedures;Organ;Ovarian;Pancreas;Pathology;Patients;Penetration;Peptides;Positron-Emission Tomography;Primary Brain Neoplasms;Program Development;Property;Prostate;Publishing;Radiation therapy;Recurrence;Relaxation;Renal clearance function;Research;Research Personnel;Resistance;Resolution;Safety;Scientist;Signal Transduction;Site;Solid Neoplasm;Spleen;Survival Rate;Techniques;Therapeutic;Three-Dimensional Imaging;Tissues;Training;Tumor Cell Line;Tumor Tissue;Unresectable;bioimaging;biomaterial compatibility;biomedical imaging;brain tissue;brain tumor imaging;cancer imaging;career;career development;chemotherapy;clinical application;contrast imaging;cost effective;design;dosage;experience;high resolution imaging;image guided;image guided therapy;imaging study;implantation;improved;intravenous administration;intravenous injection;iron oxide nanoparticle;medical schools;meter;millimeter;mortality;multidisciplinary;nanomaterials;nanomedicine;nanoparticle;neural implant;neuroimaging;neuropathology;neurosurgery;novel;particle;programs;radioresistant;radiotracer;research and development;response;subcutaneous;superparamagnetism;targeted imaging;therapy resistant;tool;tumor;tumor ablation;tumor microenvironment;tumor xenograft;uptake Magnetic Particle Imaging (MPI) for Imaging and Magnetothermal Therapy of Brain Tumors Project NarrativeAggressive types of brain tumors (such as glioblastoma multiforme or GBM) respond poorly to the currenttreatments of surgery radiotherapy and chemotherapy. This research proposes to solve this challenge with amultifunctional magnetic nanoparticle agent that simultaneously delivers contrast for a novel bio-imagingtechnique called magnetic particle imaging (MPI) as well as magnetothermal therapy of the inoperable deepbrain tumors. Sensitive and selective image-guided ablation of tumor is possible because these optimizednanoparticles only accumulate in the brain tumor tissue and we envision that this two-armed approach mayhave utility with many other types of solid tumors such as pancreatic lung and prostate. NCI 10689975 8/9/23 0:00 PA-19-130 5R00CA234208-04 5 R00 CA 234208 4 "SALVADOR MORALES, CAROLINA" 8/16/22 0:00 7/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 14371012 "ARAMI, HAMED " Not Applicable 4 ENGINEERING (ALL TYPES) 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ BIOMED ENGR/COL ENGR/ENGR STA 852876011 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Non-SBIR/STTR 2023 244020 NCI 163061 80959 Project Summary: This proposal describes a five-year research and career development program to prepareDr. Hamed Arami for a career as an independent investigator. This program will build upon Dr. Aramismultidisciplinary background as a bioengineer scientist trained in nanomedicine and basic cancer imaging byproviding expertise in brain cancer biology and image-guided therapy of brain tumors using Magnetic ParticleImaging (MPI). The PI will be mentored at Stanford Medical School by Drs. Sanjiv S. Gambhir (Main mentorbasic cancer biology cancer pathology and cancer nanotechnology) Heike Daldrup-Link (co-mentor magneticnanomedicine imaging and therapeutics) Max Wintermark (co-mentor neuroimaging and brain MPI) MelanieHayden (co-mentor neurosurgery and neurology) and Bob Sinclair (co-mentor nanomaterials characterization).Treatment of malignant primary brain tumors particularly glioblastoma multiforme (GBM) is challenging becauseof GBM resistant to chemotherapy and radiotherapy. Also there are different types of GBM tumors that are notoperable due to their locations in the brain (e.g. deep brain regions). In addition routine GBM imaging in clinicsare based on using gadolinium-based magnetic resonance imaging contrast agents. However using thesegadolinium-based contrast agents raises major concerns for GBM patients suffering from chronic kidneydisease which can be resolved by using nanoparticle contrast agents that do not show any renal clearance dueto their larger size. The overall goal of the proposed research is to use MPI as a two-armed and high-resolutionapproach for safer imaging and magnetothermal therapy of the GBM. Four types of brain tumors with differentlevels of aggressiveness will be studied to identify the feasibility of the proposed method in different brain tumormicroenvironments. Recently I developed methods for tuning iron oxide nanoparticles (NPs) to generate highresolution (i.e. ~600 m) MPI images with ultra-high contrast agent mass sensitivity of less than ~550pg Fe/L.I have used MPI for three-dimensional targeted imaging of the U87 brain tumors in mice after intravenousinjection of these NPs. Additionally in separate studies I demonstrated the feasibility of the MPI for selectivemagnetothermal therapy of the U87 tumors when NPs were directly injected into tumors. In this project I willfirst evaluate MPI and heat generation efficiency of the NPs at different brain depths to further identify ideal NPsdesign and imaging criteria for general brain tumor imaging or local magnetothermal therapy with MPI (Aim 1).Then I will evaluate MPI for targeted 3D imaging of four different types of intracranially implanted brain tumorsafter intravenous injection of the nanoparticles followed by nanoparticle biodistribution studies (Aim 2). FinallyI will use intratumoral injection of my tumor-penetrating NPs for MPI-guided magnetothermal therapy of the deepbrain tumors (representative models for inoperable GBM) followed by in-depth survival and neuropathologicalstudies (Aim 3). Iron oxide nanoparticles have been approved by FDA for several clinical applications and wehope that this method will ultimately find applications to many other types of solid tumors. 244020 +No NIH Category available Address;Advanced Development;Apoptosis;Area;Ascorbic Acid;Award;Chromatin Remodeling Factor;DNA Methylation;DNA Methyltransferase Inhibitor;Data Analyses;Double-Stranded RNA;Effectiveness;Endogenous Retroviruses;Epigenetic Process;Freedom;Funding;Future;Generations;Immune signaling;Inhibition of Cancer Cell Growth;Interferons;Lead;Lysine;Malignant Neoplasms;Methyltransferase;Molecular;Mutation;Publications;Repetitive Sequence;Research;Research Support;Role;Security;Specialist;Structure;Techniques;Viral;Work;cancer cell;cancer therapy;career;career development;design;epigenetic drug;epigenetic regulation;epigenetic therapy;epigenome;epigenomics;improved;inhibitor;insight;interest;novel strategies;patient response;programs;response;targeted treatment Research Specialist Support-Targeting DNA Methylation and the Cancer Epigenome PROJECT NARRATIVEThis proposal will support Dr. Minmin Liu as a Research Specialist allowing her to develop a stable and thrivingcareer that will be essential to the research program directed by Dr. Peter A. Jones in the field of cancerepigenetics. Dr. Liu is uniquely suited based on her strong research background her expertise in second-generation sequencing techniques and computational data analysis for epigenetic/epigenomics studies and herproven record of significant scientific contributions. Dr. Liu's expertise will generate new insights into themechanism of epigenetic regulation in cancer and will provide novel approaches to enhancing the efficacy ofepigenetic therapies against cancer through the activation of endogenous retroviruses. NCI 10689966 8/23/23 0:00 PAR-18-888 5R50CA243878-05 5 R50 CA 243878 5 "SHARMAN, ANU" 9/20/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 14576574 "LIU, MINMIN " Not Applicable 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 87121 NCI 45853 41268 PROJECT SUMMARY / ABSTRACTDr. Minmin Liu and the Unit Director Dr. Peter A. Jones have worked closely since 2012 and have generated asignificant number of high-quality publications that have had a major impact on the field of cancer epigenetics.Dr. Liu made the discovery that in cancer cells treatment with vitamin C or G9Ai (G9A lysine methyltransferaseinhibitor) synergistically enhances the effects of 5-aza-CdR a DNA methyltransferase inhibitor (DNMTi). Theunderlying mechanism is through increased expression of endogenous retroviruses (ERVs) and activation of ananti-viral interferon response which inhibits cancer cell growth and causes apoptosis. These findings sparkedher interest in further exploring the roles of repetitive elements (including ERVs) in cancer immune signaling andin understanding the molecular mechanisms of their expression in cancer cells. Because her studies suggestthat ERVs are important targets of epigenetic therapy further research in this area is likely to advance thedevelopment of targeted therapies that have improved efficacy in cancer treatment.The objective of this proposal is to support Dr. Liu's career development as a research specialist in makingsignificant contributions to Dr. Jones' established research program which is funded by NCI. Dr. Liu is currentlyaddressing the following questions. 1) Why are there so many mutations in chromatin modifiers and what arethe effects of these mutations on the structure of the epigenome? 2) What double-stranded RNAs (such asERVs) are activated by 5-aza-CdR and how do these relate to cellular responses? 3) Can we designcombinations of epigenetic drugs that might increase the effectiveness of 5-azanucleoside treatment? The aimsfor her future studies are to define the roles of ERVs in cancer immune signaling and to identify regulators fortheir expression. These projects will provide new insights for our understanding of the epigenome holistically andwill lead toward novel strategies that increase patient response to epigenetic therapies. This award will enableDr. Liu to have the freedom and security to advance her research in cancer epigenetics and to support theresearch program of the Jones group. 87121 +No NIH Category available Address;Admission activity;Bachelor's Degree;Bioethics;Cancer Biology;Cancer Center;Career Choice;Career Exploration;Childhood;Communication;Communities;Community Health Education;Community Outreach;Complement;Data;Development;Development Plans;Disparity;Doctor's Degree;Early Intervention;Economics;Education;Educational Activities;Educational process of instructing;Enrollment;Exposure to;Faculty;Family;Feedback;Fostering;Generations;Goals;Graduate Education;Healthcare;High School Student;Individual;Knowledge;Laboratory Research;Lead;Learning;Mentors;Minority;Mission;Oral;Outcome;Peer Review;Positioning Attribute;Prevention education;Process;Publications;Research;Research Training;Role;STEM career;Science;Science Technology Engineering and Mathematics Education;Scientist;Students;Support System;Time;Training;Training Programs;Underrepresented Minority;Underrepresented Students;anticancer research;cancer care;cancer health disparity;cancer prevention;career;career awareness;career development;design;education research;experience;faculty mentor;hands on research;high school;high school program;innovation;interest;intervention program;minority communities;minority engagement;minority scientist;minority student;minority undergraduate;novel;outreach;posters;prevent;programs;public health relevance;recruit;recruitment science;responsible research conduct;skill acquisition;skills;student training;success;summer research;undergraduate student UPWARDS Training Program (Underrepresented Minorities Working Towards Research Diversity in Science) UPWARDS Training ProgramPublic Health Relevance Statement/Project NarrativeAs a recognized leader in cancer research MD Anderson Cancer Center is well poised to address the criticallack of diversity plaguing the cancer research workforce and educational pipeline via early interventionprograms that foster sustained interest in cancer research for young scientists. Our comprehensiveUPWARDS Training Program (Underrepresented Minorities Working Towards Research Diversity in Science)addresses major barriers deterring and preventing many minority students from pursuing and succeeding ingraduate programs and in cancer research careers. The UPWARDS Training Program will cultivate highschool and undergraduate minority scientists with the goal of increasing diversity in biomedical graduateprograms and in the cancer research workforce through 1) minority-focused recruitment 2) hands-on cancerresearch experiences 3) a strong mentoring and career/professional development 4) education andengagement of minority communities and younger generations in the STEM pipeline through outreach andcommunity education activities and 5) a rigorous assessment plan with dissemination of best practices. NCI 10689964 8/28/23 0:00 PAR-17-059 5R25CA240137-04 5 R25 CA 240137 4 "GHOSH, SANGEETA AHUJA" 9/3/20 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1859727 "KEYOMARSI, KHANDAN " "WATOWICH, STEPHANIE S" 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 430381 NCI 399361 31020 PROJECT SUMMARY/ABSTRACTAs a recognized leader in cancer research1 MD Anderson Cancer Center is well poised to address asignificant lack of diversity in the cancer research workforce that contributes to considerable disparities.2-6 Wewill do so via early intervention programs that foster sustained interest in cancer research in studentsunderrepresented and minority in Science (URMS). Since 2011 we have directed a summer undergraduatetraining program encompassing 345 trainees (from 2011-2018) including 120 URMS. Significantly outcomesfor URMS and non-minority trainees in our program are indistinguishable; URMS and non-minority alumni areenrolled in or have completed STEM bachelors (98.8% vs 98.1%) and doctoral (both 67.1%) degrees and areretained in STEM education or workforce (98.3% vs 98.6% respectively). Built upon these successes we havedesigned a comprehensive cancer research training program for high school and undergraduate URMS via theR25 YES initiative. In our URMS-focused program we address major barriers in URMS pursuit and success inSTEM including: limited 1) research experience 2) career path knowledge and 3) scientific identity formationand exposure to science; 4) underdeveloped professionalism and communication skills; 5) inadequateresearch educational and career mentoring; and 6) barriers in the graduate application process. Ourproposed UPWARDS Training Program (Underrepresented Minorities Working Towards Research Diversity inScience) has 3 tracks: full-time 12-week summer research for 1) high-schoolers and 2) undergraduates and 3)part-time 40-week research for undergraduates. Within each track we propose the following aims to addressthe aforementioned barriers: Aim 1) Employ focused URMS recruitment and holistic strategies for programinclusion and deliver didactic learning and hands-on cancer research experiences through a cadre ofoutstanding mentoring faculty. Aim 2) Develop and deliver individualized mentoring career explorationand professional development that stimulates graduate education and cancer research career pursuit.Aim 3) Educate and inspire URMS communities young generations in the STEM pipeline and thefamilies and support systems of our students through training STEM outreach and hands-onengagement. We will encourage our trainees to lead and encourage their communities and youngergenerations through hands-on STEM outreach activities and design and delivery of community education.Aim 4) Implement and maintain a rigorous assessment program with continual appraisal and enactment ofnovel evidence-driven best practices derived from these efforts. Lastly we commit to disseminating ourfindings and best practices via peer-reviewed publications. Through the UPWARDS Program we will buildupon our prior experiences and best practices to launch a cancer research training program specificallydesigned to fit the needs of URMS trainees in our local community and nationally. We anticipate our efforts willeffectively increase diversity in the STEM educational pipeline and cancer research workforce. 430381 +No NIH Category available 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone;Affect;Biological Availability;CD44 gene;Cancer Etiology;Carcinogens;Cells;Cessation of life;Chemoprevention;Cystine;Cytotoxic T-Lymphocytes;Data;Development;Disulfiram;Dose;Encapsulated;Endowment;Epigenetic Process;Erinaceidae;Exhibits;Frequencies;Generations;Genetic;Genotype;Glutamates;Immune;Immune checkpoint inhibitor;Immunosuppression;Immunotherapy;K-ras Gene;KRAS2 gene;Literature;Longevity;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mus;Mutation;Non-Small-Cell Lung Carcinoma;Oxidative Stress;Pharmaceutical Preparations;Population;Proliferating;Property;Proteins;Reporting;Role;Serum;Signal Pathway;Small Interfering RNA;Solid;Sulfasalazine;Testing;Tobacco smoke;Treatment Efficacy;Tumor Burden;United States;aldehyde dehydrogenase 1;anti-cancer;antitumor effect;cancer stem cell;cancer therapy;combinatorial;drug repurposing;efficacy evaluation;immune checkpoint;immunoregulation;lipid nanoparticle;lung cancer cell;lung cancer prevention;lung development;lung tumorigenesis;member;mutant;nano;neoplastic cell;overexpression;pharmacologic;prevent;programmed cell death ligand 1;self-renewal;smoothened signaling pathway;stem cell genes;stem cell population;stem cells;tumor;tumorigenesis;tumorigenic Lung cancer prevention and treatment by targeting ALDH1 and CD44 expressing putative lung cancer stem cells PROJECT NARRATIVEPutative cancer stem cells (CSCs) are the cells from which cancer is believed to arise from and thereforetargeting lung CSCs with safe and effective drugs could prevent the development of the malignancy. NCI 10689962 8/10/23 0:00 PA-18-484 5R01CA231210-05 5 R01 CA 231210 5 "PERLOFF, MARJORIE" 9/17/19 0:00 8/31/24 0:00 Cancer Prevention Study Section[CPSS] 8784800 "KASSIE, FEKADU " Not Applicable 5 INTERNAL MEDICINE/MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 345230 NCI 224175 121055 PROJECT SUMMARYLung cancer is the leading cause of cancer-related death in the United States. About 90% of lung cancer casesare associated with genetic/epigenetic changes induced by tobacco smoke (TS). Although all types of lungcells could be affected by TS the effect on stem cells is particularly alarming owing to their longevity andpropensity for transformation. Therefore selective targeting of altered stem cells known as cancer stem cells(CSCs) could prevent the development of lung cancer. In this application we will test the hypothesis thattargeting of uniquely tumorigenic putative CSCs expressing high levels of aldehyde dehydrogenase 1(ALDH1H)and CD44 (CD44H) with the combination of the repurposed drugs disulfiram (DSF) and sulfasalazine (SAS)which are nano-formulated to enhance bioavailability will suppress the development and progression ofcarcinogen-induced and spontaneous lung tumor in mice. These hypotheses will be tested by the followingthree specific aims:Specific Aim 1: Determine the efficacy of SLN-DSF SLN-SAS and SLN-DSF+SAS to suppress NNK- ormutant K-ras induced lung tumorigenesis by targeting ALDH1HCD44H subpopulations of lung cells. In this aimmice treated with NNK or harboring mutations in K-ras gene will be given the drugs and modulation of tumorburden frequency of ALDH1HCD44H lung tumor cells and CSC-associated proteins will be analyzed.Specific Aim 2: Determine the immunosuppressive effects of ALDH1HCD44H putative LCSCs and whether theanti-cancer effects of SLN-DSF-SAS are mediated at least in part via immunomodulatory mechanism and itspotential to enhance the therapeutic efficacy of anti-PD-L1 immune checkpoint inhibitors. Hypothesis:Overexpression of PD-L1 by ALDH1HCD44H lung tumor cells endows them immunosuppressive properties andmodulation of these properties by SLN-DSF-SAS could potentiate anti-PD-L1-induced rescuing ofdysfunctional cytotoxic T cells and tumor destruction.Specific Aim 3: Determine the role of common NSCLC genetic alterations in the generation proliferation self-renewal and tumor propagating efficiency of ALDH1HCD44H putative CSCs and if these effects are modulatedby SLN-DSF+SAS. Hypothesis: The genotype of transformed lung cells could be an important determinant ofthe self-renewal and tumor-propagating potential of ALDH1H CD44H fractions.Impact: Targeting ALDH1H CD44H putative CSCs is a new paradigm shift in lung cancer prevention andtreatment as these cells are believed to be the cell of origin of cancer. 345230 +No NIH Category available Address;Animal Model;Area;Artificial Intelligence;Attention;Automation;Biochemical;Biological;Biological Assay;Biomedical Research;Carcinoma;Cell Extracts;Cells;Chemicals;Chemistry;Clinical;Clinical Protocols;Collecting Cell;Collection;Complex;Computer software;Coupling;Data;Development;Disease;Dissection;Dyes;Epithelial Cells;Epithelium;Fatigue;Fibroblasts;Film;Foundations;Goals;Hand;Heterogeneity;Histology;Human;Hybrids;Image;Imaging technology;Immune;Intervention;Label;Lasers;Learning;Light;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Microdissection;Microscopic;Microscopy;Molecular;Molecular Analysis;Morphology;Nature;Optics;Pathologist;Performance;Polymers;Population;Positioning Attribute;Preparation;Process;Prostate;RNA;Reaction;Research;Sampling;Slice;Slide;Solid;Specificity;Specimen;Spectrum Analysis;Speed;Spottings;Stains;Stromal Cells;Structure;Supervision;System;Technology;Testing;Thinness;Time;Tissue Model;Tissue Stains;Tissues;Tube;Twin Multiple Birth;Validation;Variant;Visualization;anticancer research;artificial intelligence algorithm;cell type;clinical application;clinical care;clinical diagnostics;design;design and construction;fabrication;high throughput analysis;imaging system;improved;infrared microscopy;instrument;instrumentation;interest;laser capture microdissection;mixed cell culture;molecular pathology;next generation sequencing;premalignant;preservation;prototype;spectroscopic imaging;tumor;tumor microenvironment;user-friendly Spectroscopy Assisted Laser Microdissection Project NarrativeThis project seeks to systematically develop and validate a new instrument for laser microdissection (LM). Thisinfrared spectroscopic imaging powered prototype will recognize cells without staining automates the lasercapture of these cells and allows them to be extracted for biochemical assays at faster speed and higheraccuracy than available with current technology. Since LM is critical to sample preparation in complex tissuethis project will make tissue-based analyses high throughput automated and easier to use in biomedicalresearch and in clinical protocols. NCI 10689945 8/30/23 0:00 RFA-CA-20-019 5R21CA263147-03 5 R21 CA 263147 3 "AMIN, ANOWARUL" 9/1/21 0:00 8/31/24 0:00 ZCA1-TCRB-Q(M2) 8460402 "BHARGAVA, ROHIT " Not Applicable 13 ENGINEERING (ALL TYPES) 41544081 Y8CWNJRCNN91 41544081 Y8CWNJRCNN91 US 40.116857 -88.228755 577704 UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN CHAMPAIGN IL BIOMED ENGR/COL ENGR/ENGR STA 618207473 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 159706 NCI 106575 53131 AbstractMolecular understanding of tumors relies greatly on appropriate samples to be prepared from epithelial cells intissues. Epithelial cells however are often surrounded by other cell types and extracting pure populations ofthese cells is crucial for correct biospecimen preparation and resulting accuracy of molecular assays. Lasermicrodissection (LM) has contributed immensely in this effort due to its high spatial specificity in the extractionof defined cell populations and ease of use. While LM has enhanced the precision of biochemical analysisseveral drawbacks remain. The necessity of staining and human supervision limits throughput molecular yieldand purity of samples. There is little explicit control or confidence in the purity of extracted cell populationswhile it is difficult to extract multiple cells from the same sample. Combining the morphologic specificity ofmicroscopy and molecular sensitivity of spectroscopy infrared (IR) spectroscopic imaging been employed toautomate histopathologic recognition in complex tissues using artificial intelligence algorithms applied ofspectral data. This project will demonstrate a completely automated instrument by coupling LM with IRmicroscopy. Termed spectroscopy-assisted laser microdissection (SLaM) the developed prototype will bevalidated using state of the art IR imaging systems and commercial LCM in terms of accuracy speed and typefidelity. Last the approach will be applied to extract cells of different types from the same prostate sample todemonstrate the capability to multiplex LM (muxLM) from the same tissue. The project directly addresses theneed to reduce the time- and labor-intensive nature of LM. SLaM can maximize the quality and utility ofbiological samples used for downstream analyses by automation high throughput and precision while enablinga comprehensive acquisition of cells without user fatigue or error thereby providing a sample of higher integrityand quality for cancer molecular analysis. 159706 +No NIH Category available Address;Adult;Aftercare;Antineoplastic Agents;Binding;Biodistribution;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cells;Central Nervous System;Chemistry;Clinic;Clinical;Collaborations;Combined Modality Therapy;Cryoultramicrotomy;Cytoprotection;Data;Development;Dextrans;Disease;Dose;Drug Delivery Systems;Drug Kinetics;Dyes;Effectiveness;Excision;Exhibits;Extracellular Matrix;Glioblastoma;Glioma;Glycoproteins;Guidelines;Harvest;Human;IACUC;In Vitro;Inductively Coupled Plasma Mass Spectrometry;Injections;Intervention;Intracranial Neoplasms;Kinetics;Magnetic Resonance Imaging;Malignant Neoplasms;Maximum Tolerated Dose;Measures;Modeling;Mus;Nature;Normal tissue morphology;Nude Mice;Operative Surgical Procedures;Organ;Organoids;Patients;Peptides;Permeability;Pharmaceutical Preparations;Pharmacodynamics;Plasma;Platinum;Primary Brain Neoplasms;Prodrugs;Protein Isoforms;Quality of life;Radiation therapy;Recombinant Proteins;Recurrence;Research;Serum;Specificity;Specimen;Surface;Therapeutic;Time;Tissues;Toxic effect;Treatment Efficacy;Xenograft Model;Xenograft procedure;blood-brain barrier crossing;blood-brain barrier disruption;blood-brain barrier penetration;brain tissue;brevican;cancer therapy;chemotherapy;cyanine dye 5;cytotoxicity;effective therapy;efficacious treatment;efficacy evaluation;improved;in vivo;innovation;intravenous injection;mouse model;neoplastic cell;neuro-oncology;novel;novel therapeutics;pharmacokinetics and pharmacodynamics;pre-clinical;prevent;standard of care;stem cells;success;targeted delivery;temozolomide;therapeutic target;tool;tumor;uptake Targeting platinum(IV) prodrug to GBM tumors using a brevican-binding peptide Project NarrativeGlioblastoma (GBM) is the most common and deadliest primary brain tumor and current standard-of-care hasdemonstrated limited success. We propose to develop a novel peptide-platinum(IV) drug conjugate that canselectively recognize and target GBM tumors. Findings from this proposal could ultimately benefit GBM patientsin the clinic through extending survival and improving quality of life. NCI 10689939 8/31/23 0:00 PAR-20-271 5R01CA272573-02 5 R01 CA 272573 2 "FORRY, SUZANNE L" 9/1/22 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-Y(56)R] 12101324 "CHO, CHOI-FONG " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 657248 NCI 438610 218638 Project Summary/AbstractDespite recent progress in cancer therapy the brain tumor glioblastoma (GBM) remains an extremelychallenging disease and new therapies are much needed. One of the biggest obstacles to effective treatmentof GBM is the presence of the blood-brain barrier (BBB) which prevents the passage of most drugs into thebrain. The highly invasive nature of GBM means there are always cells that remain after surgery in otherwisenormal brain tissue and these cells are protected behind the BBB preventing many therapeutics from reachingthem. To address this we have formed a collaboration between Chos pre-clinical GBM therapeutics group atBWH (PI) and Pentelutes peptide chemistry group at MIT (Co-I) to develop a new therapeutics to 1) specificallytarget GBM cells and 2) cross the BBB. Our collaboration has identified a novel peptide called BTP-7 that canspecifically target GBM cells and penetrate the BBB serving as a promising agent to deliver potent anti-cancerdrugs to the tumor. The Pt(IV) drug has widespread clinical use for cancer treatment but it is unable to crossthe BBB leading to low brain uptake and limiting its effectiveness for treating GBM. Here we propose to attachPt(IV) to BTP-7 (Pt(IV)-BTP-7) with the aim to increase Pt(IV) drug delivery to intracranial GBM tumors. Ourspecific aims (SA) are as follows: SA 1. Analyze Pt(IV)-BTP-7 specificity to dg-Bcan and potential to cross theBBB in vitro. SA 2. Investigate the biodistribution (BD) pharmacokinetics (PK) and pharmacodynamics (PD) ofPt(IV)-BTP-7 in GBM bearing mice. SA 3. Evaluate the efficacy of Pt(IV)-BTP-7 drug in orthotopic GBM mousemodels. Our research findings could lead to the development of a highly efficacious therapeutic to benefit GBMpatients. 657248 +No NIH Category available Algorithms;Automobile Driving;Behavior;Benign;Biological Markers;Cancer Detection;Cessation of life;Clinical;Complement;Development;Disease;Early treatment;Equilibrium;Event;Evolution;Goals;Immune response;Immunologics;Indolent;Investigation;Lesion;Malignant - descriptor;Malignant Neoplasms;Melanocytic Neoplasm;Methods;Molecular;Molecular Analysis;Mutation;Outcome;Patients;Primary Lesion;Prognostic Marker;Taxonomy;Testing;Translating;Validation;advanced disease;cancer genome;cancer prevention;cohort;diagnostic algorithm;diagnostic biomarker;follow-up;genetic evolution;high risk population;immune cell infiltrate;improved;improved outcome;insight;melanoma;multiple omics;neoplastic;neoplastic cell;prognostic algorithm;risk stratification;screening;sound;tumor;tumor-immune system interactions Molecular and immunologic evolution of melanomas from pre-neoplastic lesions Project NarrativeUnderstanding the earliest molecular and cellular events associated with melanoma initiation and evolution is alimiting factor in the development of improved risk stratification algorithms for pre-neoplastic lesions and earlystage cancers necessary for cancer prevention and detection. This project investigates genetic alterations andimmune cell infiltrates in melanocytic neoplasms of various evolutionary stages and subtypes to develop amolecular taxonomy that will provide diagnostic biomarkers to distinguish between benign and malignant lesionsand prognostic biomarkers to distinguish biologically indolent versus aggressive tumors in need of additionaltreatment. The results of our investigation will overcome the limiting factors and result in improved outcomes. NCI 10689916 9/12/23 0:00 PAR-16-411 5R35CA220481-07 5 R35 CA 220481 7 "THURIN, MAGDALENA" 9/15/17 0:00 8/31/24 0:00 ZCA1-GRB-I(M2) 6877640 "BASTIAN, BORIS C." Not Applicable 11 DERMATOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 920052 NCI 588000 343980 Project Summary/AbstractTremendous advances in the molecular analysis of melanomas and their immune microenvironmenthave provided mechanistic insights which in turn have translated into remarkable improvements totreat and even cure patients with advanced disease. However many patients still succumb to theirdisease in part because treatment starts too late. Identifying patients in need of systemic treatmentearlier and removing pre-neoplastic lesions before they evolve into cancer are promising effective waysto reduce melanoma-related deaths. Current screening methods can detect lesions with a broadspectrum of natural behavior-- from those with lethal potential to the completely benign. There is anurgent need to develop precision molecular tests to: (1) Distinguish between benign and malignant lesions (i.e. diagnostic biomarkers); (2) Differentiate biologically indolent versus aggressive tumors in need of additional treatment (i.e. prognostic biomarkers); (3) Identify high-risk individuals who should be screened (i.e. screening biomarkers).My group is performing multi-omics studies on primary lesions to study the earliest molecular andcellular events associated with melanoma initiation and evolution to obtain key insights that areessential to improve risk stratification of early stage cancers cancer prevention and detection.Characterizing the genetic evolution of main melanoma subtypes as they develop from their respectivepre-neoplastic lesions is one major goal of this proposal as is developing a biomarker-based taxonomywhich will serve as framework for developing significantly advanced diagnostic and prognosticalgorithms. Studies of the tumor genome will be complemented by characterization of the compositionand functional state of immune cell infiltrates during melanoma evolution to shed light on the interactionbetween the immune cell infiltrate and tumor cells. The combined analysis of tumor genomes and hostresponse will reveal key mechanisms driving elimination equilibrium and ultimate escape and allowus to extract biomarkers which will undergo validation in patients with known outcomes with the goalto develop clinically sound tests. Specifically we will formulate candidate algorithms that can (i) betteranticipate metastatic dissemination than current methods and (ii) predict whether a pre-neoplasticlesion is likely to progress to melanoma and validate them using patient cohorts with known follow-upinformation. 920052 +No NIH Category available Address;Anti-Progestin;Area;Binding;Cells;Cessation of life;Clinical;Data;Disease;Disease Resistance;Endocrine;Estrogen Antagonists;Estrogen Receptors;Estrogen receptor positive;Growth and Development function;Health;Human;Immune;Immune checkpoint inhibitor;Immunity;Immunologics;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Interferons;Intervention;Knowledge;Malignant Neoplasms;Mammary Neoplasms;Mediating;Mission;Modeling;Mus;Outcome;Pathway interactions;Precision therapeutics;Progesterone;Progesterone Receptors;Public Health;Refractory;Research;Resistance development;Role;STAT1 gene;Signal Pathway;Signal Transduction;T cell infiltration;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Toxic effect;Transgenic Organisms;Tumor Immunity;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Vaccines;Woman;anti-PD-1/PD-L1;anti-PD-L1;anti-PD-L1 antibodies;anti-PD-L1 therapy;breast cancer progression;cancer classification;efficacy testing;hormone receptor-positive;hormone therapy;immune cell infiltrate;immune checkpoint blockade;immune resistance;immunoregulation;improved;innovation;malignant breast neoplasm;mammary;neoplastic cell;new therapeutic target;novel;novel strategies;novel therapeutics;resistance mechanism;response;synergism;targeted treatment;therapeutic target;treatment response;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Targeting the Progesterone Receptor as a Novel Means to Increase Efficacy of Immune Checkpoint Inhibitors in Hormone Receptor Positive Breast Cancer RELEVANCE TO PUBLIC HEALTHThe proposed research is relevant to public health because it seeks to mechanistically understand howprogesterone receptor contributes to tumor immunosuppression and how targeting its signaling might allow foreffective immunotherapy in combination with immune checkpoint blockade immunotherapies. This knowledgewill ultimately improve the efficacy of immunotherapies in breast cancer extend the range of these combinationsto different tumor types and reduce the toxicity of these combinations. Thus the proposed research is relevantto the part of the NIHs mission that pertains to developing innovative research strategies and their applicationto protect and improve human health. NCI 10689878 8/1/23 0:00 PAR-20-292 5R21CA274044-02 5 R21 CA 274044 2 "SOMMERS, CONNIE L" 8/24/22 0:00 7/31/24 0:00 ZCA1-SRB-F(M1) 6727210 "HAGAN, CHRISTY " "HARTMAN, ZACHARY CONRAD" 3 BIOCHEMISTRY 16060860 YXJGGNC5J269 16060860 YXJGGNC5J269 US 39.026584 -94.636347 1484303 UNIVERSITY OF KANSAS MEDICAL CENTER KANSAS CITY KS SCHOOLS OF MEDICINE 661608500 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 216691 NCI 153695 62996 ABSTRACTApproximately 75% of all breast cancers (BC) are classified as hormone receptor positive (HR+) the majorityexpressing both Estrogen and Progesterone Receptors (ER/PR). Although several classes of anti-estrogenendocrine therapies exist for these cancers ~30% of women with ER+ breast cancer develop resistance anddie from metastatic disease. Thus new therapies are desperately needed for HR+ cancers which constitutethe majority of deaths from BC. While multiple therapies target ER and ER-signaling pathways therapiestargeting PR have not yet been employed as its role in BC remains unclear. Our recent studies have revealeda significant immune modulatory role for PR in BC. Specifically our early studies demonstrated a clear role forPR in suppressing cell intrinsic interferon responses through STAT1/2 inhibition. Recently using transgenic PRmodels and orthotopic mouse PR+ BC lines we demonstrated that PR expression results in enhanced tumordevelopment and growth which is dependent upon adaptive anti-tumor immunity and altered immuneinfiltration into the mammary tumor microenvironment. These findings are congruent with clinical observationsthat HR+ BC have a striking reduction of tumor infiltrating lymphocytes in comparison to other BCs and areless responsive to immune checkpoint inhibitors (ICIs) such as anti-PD-L1 therapy. Thus our past and currentstudies strongly suggest that HR+ BC immunosuppression is mediated by tumor cell PR expression andimmunomodulation of the local tumor microenvironment (TME). We hypothesize that therapeutic targeting ofPR will fundamentally alter the immunosuppressive mammary microenvironment and afford more robustresponses of HR+ BC following treatment with ICIs. We will test this hypothesis in the following Aims: 1)Determine the anti-tumor utility of anti-progestins with anti-PD-L1 ICI as a means to elicit anti-tumor immunityagainst HR+ breast cancer. 2) Determine the anti-tumor utility of an optimal Ad-PR vaccine with anti-PD-L1ICIs as a means to elicit anti-tumor immunity against HR+ breast cancer. These studies we will determine ifblocking PR can activate localized anti-tumor immunity thereby sensitizing HR+ breast cancers to treatmentwith ICIs. In our first aim we will determine if anti-progestin blockade of PR signaling can reverse localizedimmunosuppression of PR+ mammary tumors and if this approach synergizes with ICI combinations. In oursecond aim we will utilize a novel PR-targeting vaccine to stimulate T cell immunity against PR as a novelmeans to drive T cell infiltration into HR+ tumors and invigorate local anti-tumor immunity. The PR vaccine willbe tested alone and in combination with ICIs as an additional approach to sensitive these tumors to treatmentwith ICIs. If successful these studies could enable our understanding of PR immune modulation in BC andallow for new approaches to immunologically treat HR+ BC which has been refractory to currentimmunotherapeutic interventions. 216691 +No NIH Category available Authorization documentation;Automation;Behavioral Sciences;Biometry;Bone Marrow Transplantation;Cancer Center;Cancer Center Support Grant;Clinical Trials;Committee Members;Discipline;Ensure;Focus Groups;Goals;Guidelines;Gynecologic Oncology;Health;Health Sciences;Industrialization;Industry;Institution;Institutional Review Boards;Intervention;Leadership;Malignant Neoplasms;Medical Oncology;Monitor;NCI-Designated Cancer Center;Participant;Pathology;Patients;Pediatric Oncology;Peer Review;Performance;Persons;Pharmacy facility;Placebos;Population;Process;Protocols documentation;Psychology;Public Health;Radiation Oncology;Radiology Specialty;Reporting;Research;Research Design;Research Personnel;Review Committee;Risk;Source;Standardization;Surgical Oncology;System;Toxic effect;United States National Institutes of Health;University resources;Work;anticancer research;authority;behavioral outcome;cancer diagnosis;design;expectation;human subject;improved;meetings;prospective;protocol development;research study;sound;timeline Protocol Review and Monitoring System n/a NCI 10689876 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6532 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 215621 136902 78719 PROTOCOL REVIEW AND MONITORING SYSTEM: PROJECT SUMMARYThe Siteman Cancer Center Protocol Review and Monitoring Committee (PRMC) serves in the capacity ofProtocol Review and Monitoring System as mandated by the NCI. It has operated under continuous NCI approvalsince 2001 and it fulfills the NCI expectation that all NCI-designated cancer centers scientifically evaluate andprioritize all cancer center trials derived and supported from institutional sources (including those originating fromother cancer centers) or from industry. In 2018 the committee met 33 times and reviewed 183 protocols ofwhich 52 were investigator-initiated protocols; an additional 239 protocols were reviewed administratively by aco-chair. PRMC also provides a mechanism for monitoring all cancer research studies at the institution forscientific progress carrying with it the authority to close any studies that are not making sufficient scientificprogress or meeting accrual or performance standards. Committee members have expertise in all relevantdisciplines with reviewers from Medical Oncology Radiation Oncology Surgical Oncology Bone MarrowTransplant Gynecologic Oncology Pediatric Oncology Radiology Pathology Psychology Public HealthSciences Behavioral Sciences Biostatistics Pharmacy and Protocol Development. Improvements made over this cycle include: Workflow streamlining and automation through leveraging features of the OnCore Clinical Trials Management System; Enhanced efficiency through elimination of redundancies in the submission process including superfluous submission documents; Increased consistency between PRMC and WU IRB submissions; Standardization of investigator-initiated studies following implementation of review by the Siteman Cancer Center Protocol Development team as part of PRMC. +No NIH Category available Area;Cancer Center;Cancer Center Support Grant;Catchment Area;Childhood;Clinical Data;Clinical Protocols;Clinical Research;Clinical Treatment;Clinical Trials;Data;Data Collection;Development;Education;Ensure;Growth;Industry;Information Systems;Infrastructure;Institution;Institutional Review Boards;Intervention;Intervention Trial;Minority;Mission;Monitor;Monitoring Clinical Trials;Occupational activity of managing finances;Participant;Patients;Performance;Population;Protocols documentation;Reporting;Research;Research Personnel;Review Committee;Services;System;Technology;Time;Training;anticancer research;clinical trial readiness;data management;electronic data capture system;empowerment;experience;innovation;investigator-initiated trial;medically underserved;member;minority patient;online repository;patient population;process improvement;protocol development;quality assurance;real time monitoring;recruit;rural underserved;timeline Clinical Protocol and Data Management n/a NCI 10689868 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6528 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 635122 403252 231870 CLINICAL PROTOCOL AND DATA MANAGEMENT: PROJECT SUMMARYThe mission of the Clinical Trials Core (CTC) is to support SCC members in the development and conduct ofclinical research of the highest quality by providing them with access to an effective efficient and economicalteam specializing exclusively in cancer research. This allows for the coordination of robust investigator-initiatedtrials (IIT) innovative industry-sponsored trials and active participation in cooperative groups and consortia. TheCTC offers comprehensive services in protocol development scientific review regulatory submission studycoordination data collection education training financial management and quality assurance. The CTC hasexperienced continued growth during the project period with a staffing increase of 52% (256 staff memberstoday). This resulted from a corresponding increase in clinical trial accrual. When comparing the five-yearaverage from the current project period to the previous project period interventional clinical trial accrualincreased 77% while interventional treatment clinical trial accrual increased 25%. There has also been a 30%increase in activation of new pediatric clinical trials a targeted area for growth within the CTC. Project growthincludes a 52% increase in the submission of new IITs managed by Protocol Development across the projectperiod. The CTC has pursued opportunities to reduce protocol activation timelines across all trial types utilizingcommercial IRBs to reduce IRB approval time by 38% for industry-sponsored trials and by allowing administrativescientific review for institutional trials that have already received scientific review committee approval at anotherNCI cancer center resulting in a reduction of 14 days. In addition the CTC employs technology to report keyperformance metrics and empower investigators with real-time data related to their projects. In 2015 the CTClaunched the OnCore Clinical Trial Management System (CTMS) which facilitates submission to the PRMSserves as a web-based repository for documents that have received regulatory approval houses an electronicdata capture system for institutional clinical trials readily accessible by investigators and statisticians and trackskey metrics including protocol- and accrual-based data regularly utilized in process improvement projects. Theimplementation of the OnCore CTMS provided opportunities for enhanced real-time monitoring of clinical trialaccrual for inclusion of minority rural and medically underserved patients and in 2018 SCCs overall patientpopulation included 15.5% minority patients but boasted 28.1% minority accrual to interventional trials. +No NIH Category available Advisory Committees;Annual Reports;Authorization documentation;Award;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Cancer Center;Clinical Research;Clinical Trials;Collaborations;Committee Membership;Communication;Communities;Community Outreach;Consensus;Decision Making;Discipline;Eligibility Determination;Evaluation;Family;Feedback;Fostering;Funding;Future;Healthcare;Hospitals;Institution;Investments;Joints;Leadership;Mission;Parents;Patients;Peer Review;Performance;Play;Policies;Productivity;Recommendation;Reporting;Research;Resource Sharing;Review Committee;Role;Shapes;Strategic Planning;Structure;Training and Education;Translational Research;Universities;Update;Vision;Washington;Work;anticancer research;authority;cancer research center director;community engagement;follower of religion Jewish;improved;medical schools;meetings;member;operation;programs;research and development;synergism;working group Leadership Planning and Evaluation n/a NCI 10689863 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6526 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 388751 246826 141925 LEADERSHIP PLANNING AND EVALUATION: PROJECT SUMMARYSiteman Cancer Center (SCC) Director Timothy Eberlein sets the vision for SCC creates policy and buildsconsensus prior to implementation of key decisions. He has broad authority and is the ultimate arbiter for allscientific and administrative matters with Senior Leadership (SL) providing critical support and advice. The SLchaired by the Director is SCCs central decision-making and internal advisory body. SL vets all SCC strategiespriorities policies and budgetary decisions. SL is structured to facilitate research productivity; promote cross-program and cross-discipline collaboration; and leverage institutional strengths to increase SCCs impact in theregion nation and field of cancer research. SLs collective expertise and institutional influence help to foster andfurther SCCs vision and mission while integrating research efforts and promoting transdisciplinary andtranslational research relevant to the catchment area. Continuous evaluation of SCC progress and planning for future initiatives is accomplished with the directionof specialized external and internal advisory committees under the oversight of the SCC Director and SL. TheExternal Advisory Committee (EAC) plays an essential role shaping SCCs direction through an intensive annualreview and report on strengths and key opportunities for improvement. EAC reviews SCCs leadership structureresearch programs education and training initiatives administration/operations and overall scientific impact inthe catchment area. Other important committees that include members external to Washington University (WU)are the Community Advisory Board and Patient and Family Advisory Council.SCC relies on several internal advisory committees and working groups to fulfill key functions: Guide strategic planning Joint Office of Strategic Planning SCC Strategic Plan Steering Committee; Review SCCs clinical trial portfolio accruals and activation Clinical Research Committee; Set research program priorities Program-Specific Leadership Committees; Evaluate shared resource performance needs and relevance to SCC member research Shared Resource Review; Conduct peer-review of funding requests and make recommendations for funding Siteman Investment Program Research Development Award mechanism; and Review new member applications and eligibility of existing members SCC Membership Committee.SCCs access to institutional leaders reflects the Centers prominence and priority within its parent institutionsWU School of Medicine (WUSM) and Barnes-Jewish Hospital (BJH). The elevated stature of SCC within WUand BJH affords the Director unique access to the WU Chancellor and BJC HealthCare CEO (biannual meetings)and the BJH President and WUSM Dean (monthly meetings). +No NIH Category available Advanced Malignant Neoplasm;Award;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Sciences;Clinical Trials;Collaborations;Communities;Critiques;Development;Direct Costs;Faculty;Faculty Recruitment;Fostering;Foundations;Funding;Funding Mechanisms;Funding Opportunities;Future;Genomics;Grant;Image;Immunology;Incentives;Infrastructure;Investments;Leadership;Malignant Neoplasms;Mentors;Modeling;Monitor;NCI Center for Cancer Research;Outcome;Output;Peer Review;Peer Review Grants;Policies;Population Sciences;Prevention;Process;Productivity;Publications;Recurrence;Research;Research Personnel;Research Support;Science;Strategic Planning;United States National Institutes of Health;Vision;career;clinical practice;cost;design;improved;innovation;meetings;member;multidisciplinary;novel;novel strategies;programs;recruit;research and development;success;tool Developmental Funds n/a NCI 10689860 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6525 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 295237 187452 107785 DEVELOPMENTAL FUNDS: PROJECT SUMMARYSiteman Cancer Centers (SCCs) Siteman Investment Program (SIP) includes a portfolio of funding mechanismsthat support innovative scientific research through competitive funding opportunities; investments in ourcommunity catchment and faculty; and strategic recruitment efforts to strengthen and diversify SCCs scientificresearch portfolio. SCCs current five-year strategic plan as well as the needs of SCCs catchment area providethe foundation for all funding decisions. SCC Senior Leadership (SL) designed the SIP to align closely with theiroverall vision for the center with the highest priority placed on promotion of transdisciplinary translational andcollaborative research. Funding received from the Cancer Center Support Grant (CCSG) Developmental Funds component issignificantly augmented by SCC philanthropic assets to provide approximately $4 million ($4M) per year to SCCmembers through the SIP Research Development Award (RDA) biannual funding opportunity. SCC SL designedSIP RDA to include a rigorous peer-review process modeled after the NIH review process. SCC SL and SCCAdministration closely monitor program outcomes for progress and productivity including participation by juniorinvestigators. Since 2015 24 Pre-R01 awardees (42%) were junior investigators who collectively received $4.5Min SIP RDA funding. Of those 24 11 (46%) have already leveraged at least one external award collectivelytotaling $13.5M in directs. The SIP RDA program also includes a mentoring opportunity for unfunded applicantsincluding junior faculty to meet with the SIP RDA chair to discuss critiques and improvements at the end of thereview cycle. The success rate for resubmissions is 37% which suggests that these meetings are valuable forunfunded SIP RDA applicants who reapply in future funding cycles. From 20132017 SCC awarded a total of $23.6M through the SIP to investigators across all seven of SCCsresearch programs. To date SCC faculty have leveraged $120M in direct costs ($173M total costs) in externalfunding. This $120M includes 44 NCI awards ($83.5M 70% of total leveraged) and 31 NIH and other cancerpeer-reviewed grants ($28.5M 23% of total leveraged); thus 93% of all dollars leveraged from the SIP comefrom peer-reviewed awards. In the next project period SCC will grow its commitment to and investment in SIPto significantly advance cancer discovery through support of novel and collaborative research recurring annualinvestment for faculty recruitment and by providing funding for unfunded and/or underfunded investigator-initiated clinical trials. Funding from CCSG Developmental Funds will continue to be awarded to SCC membersthrough the SIP RDA program. +No NIH Category available Acceleration;Address;African American;Annual Reports;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Survivor;Catchment Area;Clinical;Clinical Research;Clinical Services;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Community Outreach;Comprehensive Cancer Center;County;Data;Development;Diagnosis;Disparity;Education;Education and Outreach;Educational Materials;Ensure;Evaluation;Exhibits;Foundations;Geography;Goals;Health Disparities Research;Health Services Accessibility;Health Status;Illinois;Incidence;Infrastructure;Insurance Coverage;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Medically Underserved Area;Minority;Minority Groups;Missouri;Monitor;NCI Center for Cancer Research;Outcome Assessment;Patients;Population;Provider;Race;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Role;Rural;Rural Population;Science;Scientific Advances and Accomplishments;Solid;System;Translational Research;Translations;Underserved Population;Urban Population;Work;cancer health disparity;clinical practice;community based participatory research;community building;community engagement;community organizations;community partnership;demographics;falls;malignant breast neoplasm;mortality;outreach;patient oriented;programs;racial disparity;research to practice;response;rural area;working group Community Outreach and Engagement n/a NCI 10689850 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6522 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 325230 206495 118735 COMMUNITY OUTREACH AND ENGAGEMENT: PROJECT SUMMARYThe catchment area of Siteman Cancer Center (SCC) spans 82 counties across Missouri and Illinois. Thecounties exhibit significantly different levels of health coverage and overall cancer burden. The population of thecatchment is extremely diverse with 15% of the population living in a rural area and 29% in a MedicallyUnderserved Area (MUA). Minority populations in the catchment make up 20.5% of the total population.However a significantly higher proportion of SCC patients who are African-American live in a MUA (31.3%)compared to White patients (25.2%). Our catchment area as a whole carries a disproportionately high cancerburden with increased incidence of late stage diagnoses and a high cancer mortality. In fact a significantpercentage of SCC catchment counties fall within the highest US quartile for breast lung prostate and colorectalcancer mortality. To address the disparities and cancer burden in our catchment SCC investigators havedeveloped tailored educational materials cancer-specific community partnerships a clinical trial participationmonitoring system and expanded clinical services as part of SCCs Comprehensive Outreach Strategy. SCCsCommunity Outreach and Engagement (COE) component builds on this foundation with the goal to sustainpartnerships and assure that all cancer patients and communities can benefit from clinical and scientificadvances. SCCs COE component addresses and monitors disparities among underserved populationsspecifically racial (minority) geography (rural) access to services (medically underserved areas) and theirinteraction. SCCs COE component is organized into an Internal Advisory Board (IAB); a Community AdvisoryBoard (CAB); a Clinical Studies Outreach (CSO) team; and six and one-half full-time equivalents staff. Thesegroups work together to accomplish the COE aims: (1) Monitor and evaluate the cancer burden and relateddisparities in the SCC catchment; (2) Accelerate the implementation of outreach education and clinicalresources in collaboration with communities to reduce the cancer burden and related disparities in the SCCcatchment; and (3) Support research to reduce the cancer burden and related disparities in the SCC catchmentthrough: (3a) Support for community-based and health disparities research and (3b) Continuous evaluation andeducation to promote diversity in clinical trial participation. To achieve these aims COE will build upon existingstrong community and regional partnerships that have emanated from SCCs critical role as a provider andresearch center in our catchment area. By achieving the above aims SCC will ensure that the center is bestaddressing the impact of cancer in our catchment and is developing a solid infrastructure for sustaining positiveimpacts and strengthening translation of SCC research to clinical practice. Together these aims work to reducethe cancer burden and related disparities in SCCs catchment. +No NIH Category available Address;Area;Atlases;Award;Bioinformatics;Brain Neoplasms;Breast;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Research Project;Cellular biology;Chemoresistance;Chest;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Collaborations;Colonic Neoplasms;Colorectal;DNA Repair;DNA Sequence Alteration;Data;Defect;Development;Developmental Therapeutics Program;Direct Costs;Disease;Disparate;Education;Educational Activities;Elements;Endometrial;Enrollment;Evolution;Focus Groups;Funding;Genetic;Genitourinary system;Genome;Genomics;Germ-Line Mutation;Glioblastoma;Goals;Group Meetings;Gynecologic Oncology;Head and Neck Cancer;Head and neck structure;Human;Immune;Immunotherapy;Impact evaluation;Innovative Therapy;Institution;Intervention;Intervention Trial;Kidney;Knowledge;Leadership;Learning;Link;Lung;Maintenance;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of urinary bladder;Mammary Neoplasms;Maps;Mediating;Medical Oncology;Mentored Clinical Scientist Development Program;Mentorship;Methods;Mismatch Repair Deficiency;Modeling;Molecular;Molecular Abnormality;Neoplasm Metastasis;Oncology;Ovarian;Pancreatic Adenocarcinoma;Paper;Patient Selection;Patient-Focused Outcomes;Patients;Peer Review;Pharmaceutical Preparations;Phase;Positioning Attribute;Pre-Clinical Model;Predisposition;Prostatic Neoplasms;Proteomics;Publications;Publishing;Quality of life;Research;Research Personnel;Resistance;Resource Sharing;Resources;Role;Sex Differences;Sex Differentiation;Site;Solid Neoplasm;Specialist;Specimen;Technology;The Cancer Genome Atlas;Therapeutic;Training;Translating;Translational Research;UV-induced melanoma;Universities;Washington;Work;burden of illness;cancer cell;cancer risk;cancer site;cancer survival;cancer therapy;cancer type;chemotherapy;clinical application;design;drug discovery;early phase clinical trial;epigenomics;first-in-human;gastrointestinal;improved;inhibitor;innovation;ketogenic diet;knowledge base;malignant breast neoplasm;medical schools;meetings;member;metabolomics;new therapeutic target;novel;novel strategies;novel therapeutics;programs;prospective;response;sex;spatiotemporal;success;synergism;targeted treatment;therapy outcome;therapy resistant;treatment trial;trial enrollment;tumor;tumor immunology;tumor initiation;working group 11 Solid Tumor Therapeutics Program n/a NCI 10689844 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6520 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 100450 63778 36672 SOLID TUMOR THERAPEUTICS PROGRAM (STTP): PROJECT SUMMARYThe Solid Tumor Therapeutics Program (STTP) is focused on discovering somatic and germline genomicalterations that are either shared or unique across various solid tumor malignancies and translating thesediscoveries into novel therapeutics that will improve the quality of life and survival for cancer patients. Twofundamental thematic areas (Genomics Technologies and Discovery and Developmental Therapeutics [DT])were organized to promote disease-specific studies in neuro head and neck thoracic gastrointestinalgenitourinary and gynecologic oncology. The STTP is coordinated through a leadership committee researchmeetings seminars retreats and other educational activities. Training for junior investigators is implementedthrough a mentorship plan and is supported through NCI-funded T32 (HD007499) K12 (CA167540) and Clinicaland Translational Scientific Award (CTSA) educational programs. We identified areas of institutional strengthand developed three research aims for the next project period. Aim 1. Develop innovative therapeuticstrategies by identifying genomic epigenomic proteomic and metabolomic (omic) alterations thatoccur in solid tumors and by mapping their spatiotemporal evolution using preclinical models and tumorspecimens. Aim 2. Determine how genomic alterations interact with immune landscapes in solid tumormalignancies; identifying these potential synergies will improve therapeutic outcomes. Aim 3. Explorethe relationships among germline variants and their effects on cancer susceptibility and treatment insolid tumor malignancies and evaluate sex-specific effects on cancer biology. These aims are designedto elucidate the effects of genetic instabilities DNA repair defects and specific inhibitors on solid tumor initiationmaintenance progression and chemoresistance. The STTP leadership facilitates and encourages collaborativeinteractions between disease-specific investigators and translational experts to promote translational and clinicalresearch. These interactions are achieved through working-group meetings focus-group meetings seminarsand funded programs such as the NCI U54 CA224083 PDX clinical trial network and the NCI U2C CA233303Washington University Human Tumor Atlas Research Center which will construct detailed 4D atlases for breastcancer glioblastoma and pancreatic adenocarcinoma. The STTP has 47 members from 13 departments atWashington University School of Medicine. The STTP is supported by a total of $25.9 million direct costs incancer-related funding $5.8 million in NCI funding and $5.8 million in other peer-reviewed funding. STTPmembers published 1723 papers during 20142018 with 33% resulting from inter-programmatic collaborationsand 24% resulting from intra-programmatic collaborations. During 20142018 STTP members participated in1511 clinical trials 56% of which were interventional trials. These trials enrolled 32867 patients with 6274enrolled in interventional trials 4597 in interventional treatment trials 1354 in institutional interventionaltreatment trials and 1274 in early phase or first-in-human interventional treatment trials. +No NIH Category available Adhesions;Adipocytes;Affect;Area;Basic Science;Biochemical;Blood Vessels;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Survivor;Cell Communication;Cell Proliferation;Cells;Clinic;Clinical Trials;Collaborations;Communication;Complex;Dedications;Development;Disease;Engineering;Epigenetic Process;Epithelial Cells;Extracellular Matrix;Fibroblasts;Focus Groups;Fostering;Functional disorder;Funding;Funding Agency;Future;Genetic;Goals;Grant;Growth Factor;Immune;Individual;Journals;Malignant Neoplasms;Maps;Metabolic;Metabolism;Modality;Molecular;Mutation;NCI Center for Cancer Research;Neoplasm Metastasis;Paper;Pathway interactions;Patient Care;Patients;Peer Review;Pharmaceutical Preparations;Physicians;Play;Positioning Attribute;Process;Publications;Publishing;Quality of life;Research;Research Personnel;Resistance;Schools;Scientist;Signal Pathway;Stromal Cells;Stromal Neoplasm;Structural Protein;Structure;Therapeutic;Tissues;Translating;Translations;cancer cell;cancer therapy;cell motility;comorbidity;cytokine;design;fighting;functional genomics;improved;innovation;intercellular communication;member;metabolomics;mortality;multidisciplinary;neoplastic cell;novel therapeutic intervention;novel therapeutics;programs;research and development;success;therapeutic target;therapy development;translational scientist;tumor microenvironment;tumor progression;tumorigenesis;working group 10 Mechanisms of Cancer Biology Program n/a NCI 10689839 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6518 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 69442 44090 25352 MECHANISMS OF CANCER BIOLOGY PROGRAM (MCBP): PROJECT SUMMARYThe long-term goal of the Mechanisms of Cancer Biology Program (MCBP) is to identify and map the complexcellular mechanisms that drive cancer development progression and metastasis. To accomplish this goalmembers of the MCBP are identifying factors (biochemical and physical) signaling pathways and the cellularbasis for the communication between tumor and stromal cells that drives tumorigenesis. Together this approachwill lay the framework for the design of specific therapeutic modalities. The MCBP is organized around twoworking groups termed the (1) Cell Autonomous Cancer Drivers (CACD) and (2) Cancer Cell NonautonomousDrivers (CCND). Recognizing the importance of the co-morbidities associated not only with the disease but thetreatments deployed to fight it MCBP is developing a third group referred to as Cancer Co-Morbidity Drivers(CCMD). Together these thematic groups include individuals working to discover how cell autonomous mutationsand stromal cells extracellular matrix structural proteins growth factors and cytokines interact to modulatetumorigenesis. Further as cancer therapies become more effective at reducing mortality cancer survivors areincreasingly faced with therapy-induced co-morbidities that can significantly impact their quality of life. ThusMCBP members also focus on the mechanisms that drive therapy-induced co-morbidities. The MCBP primarilyperforms basic cancer biology research and discovery and is structured to interface with other programs withinthe Siteman Cancer Center (SCC) that are positioned to translate research breakthroughs into patient careparticularly in genetics molecular and cellular cancer biology and functional genomics. The MCBP membersare currently developing a number of therapeutic drugs that were identified using this approach which arediscussed in the body of the grant. The MCBP is dedicated to achieving the following two goals: (1) identify key molecules and pathways (i.e.targets) within tumor cells and the tumor-stromal interactions that regulate tumor cell proliferation survival andmetastasis and develop therapeutic strategies to target these key molecules and/or pathways; and (2) developselect inter-programmatic working groups to facilitate the translation of the results from Goal 1. Each workinggroup focuses on the central importance of intracellular communication within incipient tumor cells andintercellular communication between tumor cells and the stromal microenvironment. Each member has specificexpertise and shared goals that are utilized to develop a robust research program with strong intra- and inter-programmatic collaborations. MCBP has 40 members from 12 departments and three schools and is supportedby $15.1 million in funding with $4.3 million from the NCI and $7.2 million from other peer-reviewed fundingsources. MCBP members published 711 peer-reviewed papers during 20142018 with 142 (20%) papers injournals with impact factors 10. MCBP members also engaged in extensive collaborative interactions with 172(24%) inter- and 108 (15%) intra-programmatic publications. +No NIH Category available Achievement;Area;Basic Science;Benign;Biological Assay;Body Weight decreased;Breast Cancer Risk Factor;Breast Cancer Treatment;Breast Cancer survivor;Breast Cancer therapy;CLIA certified;Cancer Center Support Grant;Cancer Research Project;Cells;Child;Childhood;Clinical;Clinical Oncology;Clinical Research;Clinical Sciences;Clinical Trials;Cohort Studies;Collaborations;Communication;DNA Vaccines;Development;Diagnosis;Diet;Disease;Disparity;Etiology;Funding;Future;Genetic;Genome;Genomic approach;Genomics;Genotype;Goals;Growth;Height;Human;Human Subject Research;Image;Immunobiology;Incidence;Individual;Institution;International;Investments;Journal of the National Cancer Institute;Journals;Leadership;Lesion;Life Style;Malignant Neoplasms;Molecular;Morbidity - disease rate;Mus;Nature;Neoplasm Metastasis;Operative Surgical Procedures;Outcome;Paper;Pathology;Patient-Focused Outcomes;Patients;Peer Review;Population Sciences;Positioning Attribute;Predisposition;Prevention program;Prevention strategy;Productivity;Proteomics;Publications;Publishing;Reporting;Research;Research Personnel;Risk;Risk Factors;Role;Schools;Signal Transduction Pathway;Somatic Mutation;Therapeutic;Tissue Banks;Translating;Translational Research;Universities;Validation;Washington;Woman;breast cancer progression;cancer clinical trial;cancer genomics;clinical application;clinical investigation;clinical translation;clinically relevant;design;disparity reduction;drug-sensitive;genomic predictors;immunogenic;implementation strategy;improved;malignant breast neoplasm;member;mortality;multidisciplinary;novel;novel therapeutic intervention;patient derived xenograft model;personalized strategies;personalized therapeutic;pre-clinical;predictive marker;premalignant;programs;prospective;risk variant;successful intervention;therapeutic target;tumor microenvironment;vaccine development;working group 09 Breast Cancer Research Program n/a NCI 10689833 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6516 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 68375 43413 24962 BREAST CANCER RESEARCH PROGRAM (BCRP): PROJECT SUMMARYThe long-term goals of the Breast Cancer Research Program (BCRP) are to define the fundamental mechanismsthat regulate breast cancer pathology and then use this information to develop personalized strategies for theprevention diagnosis and treatment of all stages and subtypes of breast cancer. The BCRP leadershipestablished collaborative working groups in clinical basic and population sciences to identify and develop novelimplementation strategies for the diagnosis and treatment of breast cancer. These three groups are guided bythe hypothesis that advances in basic and population sciences can be leveraged to enhance the clinical impactin successfully treating breast cancer. These translational efforts have been organized around three specificaims. Aim 1. Discover identify and validate novel personalized clinical targets for breast cancer. Aim 2. Utilizeinstitutional expertise in basic sciences to define the molecular mechanisms that drive breast cancer progressionand metastasis in individuals. Aim 3. Reduce disparities in breast cancer mortality by identifying personalizedrisk factors and developing targeted prevention and genomic strategies. The BCRP contains 19 members from four departments and two schools. Current funding exceeds $7.9million with $3.0 million from the NCI and $1.8 million from other peer-reviewed funding. BCRP memberspublished 456 papers during 2014-2018 with 42% inter-programmatic publications and 24% intra-programmaticpublications; that included contributions to Cell Nature Nature Communications Nature Genetics Cell ReportsJournal of Clinical Investigation Journal of Clinical Oncology and Journal of the National Cancer Institute. Thebroad-ranging achievements and future objectives of the BCRP can be organized into three main research areas:clinical and translational research basic research and disparities-based research. +No NIH Category available Academia;Acceleration;Address;Animal Model;Animals;Area;Artificial Intelligence;Automobile Driving;Award;Basic Cancer Research;Basic Science;Behavior;Binding;Biological;Cancer Biology;Cancer Center;Cancer Center Support Grant;Chemotherapy and/or radiation;Clinic;Clinical;Collaborations;Creativeness;Data;Detection;Development;Diagnosis;Diagnostic Procedure;Educational workshop;Engineering;Environment;Event;Extramural Activities;Faculty;Financial Support;Fostering;Funding;Funding Opportunities;Goals;Grant;Human;Hybrids;Image;Image-Guided Surgery;Imaging Device;Imaging technology;Industry;Informatics;Information Retrieval;Institution;Investments;Knowledge;Lasers;Leadership;Magnetic Resonance Imaging;Malignant Neoplasms;Mentors;Methodology;Methods;Molecular;Monitor;Multimodal Imaging;Multiple Myeloma;NMR Spectroscopy;Nature;Optics;PET/CT scan;Patient-Focused Outcomes;Patients;Peer Review;Phenotype;Pilot Projects;Positron-Emission Tomography;Prediction of Response to Therapy;Process;Productivity;Property;Publications;Radioisotopes;Recording of previous events;Research;Research Activity;Research Infrastructure;Research Personnel;Resolution;Resource Sharing;Resources;Scholarship;Schools;Science;Signal Transduction;Students;System;Testing;Therapeutic;Training;Translating;Translational Research;Translations;Treatment Protocols;Treatment outcome;United States National Institutes of Health;Vision;cancer diagnosis;cancer imaging;cancer therapy;clinical decision-making;clinical translation;data mining;deep learning;detector;fluorescence molecular tomography;image guided;imaging agent;imaging biomarker;imaging facilities;imaging informatics;imaging modality;imaging probe;imaging program;imaging system;improved;in vivo Cellular and Molecular Imaging Centers;industry partner;innovation;insight;instrument;instrumentation;lectures;machine learning algorithm;member;microPET;molecular imaging;multidisciplinary;nanotherapy;next generation;novel;optoacoustic tomography;patient response;photoacoustic imaging;physical science;pre-clinical;programs;proton beam;quantitative imaging;radiation response;radiomics;response;skills;student mentoring;student training;targeted treatment;theranostics;tool;translational pipeline;treatment response;tumor;tumor progression;ultrasound 08 Oncologic Imaging Program n/a NCI 10689828 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6514 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 67182 42655 24527 ONCOLOGIC IMAGING PROGRAM (OIP): PROJECT SUMMARYThe Oncologic Imaging Program (OIP) develops novel imaging agents and innovative methods for radionuclideMR ultrasound optical and hybrid imaging technologies including photoacoustic imaging and theranostics.Application of artificial intelligence and informatics platforms to solve advanced oncologic imaging challengesdemonstrates the evolving nature of OIP. OIPs major goals are to facilitate new research initiatives expandongoing collaborations mentor junior faculty train students and fellows and develop new methods to solvefundamental and clinical cancer imaging needs. These goals will be achieved through intra- and inter-programmatic activities and external partnerships. OIPs highest priorities include developing imaging agentsand technologies for detecting diagnosing and treating cancer and expanding our knowledge of animal modelsused for basic cancer research. OIP activities will pursue four specific aims. (1) Develop innovative imaginginstruments and methods for diagnostic and theranostic applications and image-guided cancer therapies. (2)Develop new molecular imaging agents and theranostics for accurate detection and assessment of tumor-specific properties as well as for monitoring therapeutic response to improve treatment outcomes. (3) Advanceapplications of quantitative imaging (QI) to elucidate the molecular mechanisms driving cancer progression andtreatment responses via deep learning and radiomics. (4) Educate train and mentor students fellows and juniorfaculty in cancer imaging research. OIP will continue to develop strong intra- and inter-programmaticcollaborations industry partnerships and integrated trainee support to champion collective innovation in cancerimaging research and clinical translation. The program currently includes 36 members from seven departmentsand three schools. The extensive collaborative network of OIP members has resulted in more than $10.1 millionin current grant awards of which $5.4 million is NCI funding and $2.5 million is other peer-reviewed funding andan additional $5 million in NIH S10 large instrument grant funding. OIP research is anchored by one NCI-fundedresearch center (Center for Multiple Myeloma Nanotherapy [U54 CA199092]) the institutionally supportedMolecular Imaging Center (continuation of previous NCI-supported ICMIC [CA094056]) three NIH-supportedResource Centers (Gropler P41 EB025815 Marcus U24 CA204854 Shoghi U24 CA209837) two imagingtraining grants (Culver T32 EB014855 Woodard T32 EB021955) and more than 1104 publications in thecurrent project period of which 28% are inter-programmatic 26% are intra-programmatic and 10% with impactfactor >10. OIP research has been accelerated by recent installation of several new instruments includingPET/CT scanner (Siemens Vision) micro PET/CT microPET/MR GE SPINlab hyperpolarization unit OxfordInstruments PulsarTM benchtop permanent-magnet-based 1.5-T NMR spectrometer fluorescence moleculartomography system multispectral optoacoustic tomography system and IVIS-CT multimodal imaging system.Clinical translation of new discoveries will remain the cornerstone of OIP. +No NIH Category available Acceleration;Achievement;Address;Administrator;Area;Basic Science;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Catchment Area;Cells;Chemoprevention;Cigarette;Cities;Clinical;Clinical Medicine;Clinical Research;Collaborations;Colon Carcinoma;Communities;Comprehensive Cancer Center;County;Data Analytics;Detection;Diagnosis;Discipline;Disparity;Dissemination and Implementation;Early Diagnosis;Economics;Enrollment;Environment;Epidemiology;Equity;Ethnic Origin;Evidence based intervention;Evidence based practice;Exhibits;Family;Federally Qualified Health Center;Funding;Genetic study;Geography;Goals;Health;Health Benefit;Health Disparities Research;Health system;Illinois;Incidence;Individual;Intervention;Intervention Studies;Lead;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Manuscripts;Medicaid;Methods;Missouri;Nicotine Dependence;Outcome;Participant;Peer Review;Policies;Policy Maker;Policy Research;Population;Prevention;Preventive service;Provider;Psychology;Public Health;Public Health Practice;Publishing;Race;Religion;Research;Research Activity;Research Personnel;Research Priority;Resource Sharing;Rest;Risk;Risk Factors;Rural;Rural Health;Schools;Scientist;Screening for cancer;Societies;Statistical Data Interpretation;Taxes;Tobacco use;Tobacco-Related Carcinoma;Training;Translational Research;Translations;Universities;Washington;anticancer research;cancer health disparity;cancer prevention;career;cigarette smoking;clinical practice;community setting;dissemination science;ethnic minority;implementation design;implementation research;implementation science;improved;innovation;lung cancer screening;malignant breast neoplasm;member;mortality;patient oriented;population health;prevent;programs;racial minority;smoking cessation;socioeconomic diversity;survivorship;translational impact 06 Prevention and Control Program n/a NCI 10689823 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6513 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 63301 40191 23110 PREVENTION AND CONTROL PROGRAM (PCP): PROJECT SUMMARYCancer continues to pose a major threat to public health nationally and in the Siteman Cancer Center (SCC)catchment area. The pioneering transdisciplinary and translational research within the SCC Prevention andControl Program (PCP) is aimed at reducing the cancer burden and spans from prevention to early detectionthrough survival. Adding to the robust depth and breadth of PCP expertise research within the program spansfrom the cell to society and includes basic science large data analytics clinical and community-basedintervention and implementation research as well as policy research in clinical and community settings. Building on PCPs impactful and practice-changing research from the past five years and based on key needsin the SCC catchment and beyond the PCP will address the following specific aims: Aim 1. Reduce the impact of tobacco use and resultant cancers by conducting research across the continuum from prevention to detection and cessation. Aim 2. Reduce cancer health disparities through rigorous research in cancer prevention and control. Aim 3. Advance dissemination and implementation science methods to reduce the cancer burden. PCPs research priorities are responsive to and reflective of the catchment area. Cigarette smoking rates areabove average in our catchment; lung cancer rates are above the national average. Our catchment includesracial/ethnic geographic and socioeconomic diversity and within this diversity are disparities in cancerscreening detection and survival. Similar to the rest of the nation we observe delays in the implementation ofevidence-based practice across many settings. Our unique and diverse catchment includes parts of Missouriwhich has the lowest cigarette taxes in the nation and lacks Medicaid expansion and parts of Illinois which hasa more stringent cigarette policy and expanded Medicaid. Together this results in a microcosm in which to studytobacco use cancer disparities and implementation science. PCP membership includes experts in diverse disciplines such as psychology epidemiology biostatisticseconomics public health clinical medicine and basic science. The program has 38 members from eightdepartments and two schools at Washington University. The PCP is supported by $8.3 million in funding ofwhich $5.1M is from NCI and $2.4M is other cancer-focused peer-reviewed. In the current project period PCPmembers published 1096 manuscripts of which 25% and 25% represent inter- and intra-programmaticcollaborations respectively. In 2018 the PCP had 7355 total enrollments into clinical studies of which 38%were interventional. Forty percent of the interventional enrollments represented racial and ethnic minorityparticipants. With these assets and this record of past achievement the PCP is poised to make substantialimpacts on public health and clinical practices and policies related to cancer control that will benefit the health ofthe population. +No NIH Category available Acute Myelocytic Leukemia;Acute T Cell Leukemia;African American;Area;Award;Basic Science;CXCR4 gene;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cellular biology;Cellular immunotherapy;Clinical;Clinical Trials;Clonal Evolution;Collaborations;Community Outreach;Data;Development;Direct Costs;Disease;Dysmyelopoietic Syndromes;Epigenetic Process;Fellowship;Female;Fostering;Foundations;Funding;Genes;Genetic;Genomics;Goals;Grant;Grant Review;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Heterogeneity;Hispanic;Immunology;Immunotherapy;Institution;International;Intervention;Intervention Trial;Investments;Journals;K-Series Research Career Programs;Latino;Leadership;Leukemic Cell;Lymphoma;Malignant - descriptor;Malignant Neoplasms;Minority;Minority Participation;Multiple Myeloma;Mutate;Myelodysplastic/Myeloproliferative Disease;Myeloproliferative disease;NF-kappa B;Newly Diagnosed;Paper;Pathway interactions;Patients;Peer Review;Program Research Project Grants;Program Reviews;Publishing;Recurrence;Reporting;Research;Research Personnel;Role;Signal Transduction;Societies;Stem cell transplant;Support Groups;Therapeutic Intervention;Training;Translating;Translational Research;United States National Institutes of Health;Universities;Washington;cancer cell;cancer genome;cancer genomics;chemotherapy;community engagement;experience;fundamental research;improved;indexing;inhibitor therapy;innovation;leukemia;leukemia/lymphoma;medical schools;medically underserved population;meetings;member;nanotherapy;next generation sequencing;novel;novel strategies;novel therapeutics;prevent;programs;research and development;senior faculty;success;therapy resistant;translational goal;translational potential;treatment response;treatment strategy;tumor immunology;working group 04 Hematopoietic Development and Malignancy Program n/a NCI 10689816 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6510 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 67539 42882 24657 HEMATOPOIETIC DEVELOPMENT AND MALIGNANCY PROGRAM (HDMP): PROJECT SUMMARYThe long-term goals of the Hematopoietic Development and Malignancy Program (HDMP) are to identify basicmechanisms regulating normal and malignant hematopoiesis and develop innovative strategies to preventstratify and treat hematopoietic malignancies. The HDMP has 30 members from three departments atWashington University School of Medicine. HDMP members are supported by $22.4 million direct costs incancer-related funding including $5.3 million direct costs from the NCI and $4.5 million direct costs from otherpeer-reviewed cancer-related funding. HDMP members published 760 papers during the current project periodwith 20% resulting from inter-programmatic collaborations 26% from intra-programmatic collaborations and30% published in journals with an impact factor 10. HDMP members participated in 551 clinical trials involvinghematologic malignancies or stem cell transplantation including 357 interventional trials. Basic sciencetranslation remains a top priority for the HDMP. In the current project period 25 investigator-initiated clinical trialswere developed from fundamental research performed (at least in part) at Siteman Cancer Center including 22investigator-initiated therapeutic interventional trials. Total interventional accruals were 2961 of which 2761(93%) were interventional treatment. The interventional treatment accrual rate (as a function of reportedhematologic malignancy index cases) was 38% in 2018. Working groups in leukemia lymphoma myeloma andmyelodysplastic syndromes/myeloproliferative neoplasms were established to develop review prioritize andconduct translational research. Each working group is organized around three themes: cancer genomicsdevelopment of immunotherapies and cancer biology. The HDMP fosters collaborative translational researchand trains junior investigators through research seminars journal clubs work-in-progress meetings and anannual retreat. Program leaders have identified areas of institutional strength and developed four specifictranslational aims.Aim 1: Leverage local expertise in cancer genomics to identify key genetic and epigenetic alterations inhematopoietic malignancies and develop their translational potential.Aim 2: Develop fundamental discoveries in immunology into novel immunotherapies targetinghematopoietic malignancies. A particular area of focus is the development of novel cellular immunotherapiesfor hematopoietic malignancies.Aim 3: Translate fundamental discoveries in cancer cell biology into novel strategies to treathematopoietic malignancies and/or improve stem cell transplantation.Aim 4: Identify and develop junior investigators in hematopoietic malignancies. +No NIH Category available ABCG2 gene;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cells;Clinical Trials;Collaborations;Communities;Comprehensive Cancer Center;Disease;Effectiveness;Environment;Experimental Models;Funding;Future;Goals;Immune;Immune system;Immunologics;Immunology;Immunotherapy;Infrastructure;Intervention;Intervention Trial;Laboratories;Malignant Neoplasms;Manuscripts;Mission;Modeling;NCI Center for Cancer Research;Nature;Peer Review;Physicians;Publishing;Research;Research Personnel;Resource Sharing;Resources;Role;Scientist;Testing;Translating;Translational Research;Translations;Universities;Washington;anti-tumor immune response;cancer immunotherapy;cancer initiation;clinical translation;clinically relevant;collaborative environment;immunotherapy clinical trials;medical schools;member;novel;novel therapeutics;programs;tumor;tumor immunology;tumor microenvironment 03 Tumor Immunology Program n/a NCI 10689808 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6505 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 67185 42657 24528 TUMOR IMMUNOLOGY PROGRAM (TIP): PROJECT SUMMARYFor more than 30 years the immunology community at Washington University School of Medicine (WUSM) hashad a strong reputation for the significant breadth and depth of its contributions to the field of immunology andits highly interactive/collaborative nature. A strategic decision was made 20 years ago to promote basic scienceresearch in tumor immunology and establish an infrastructure to facilitate clinical translation of cancerimmunotherapies at Siteman Cancer Center (SCC) and WUSM through the creation of a Tumor ImmunologyProgram (TIP) as an integral component of the newly forming NCI-designated Comprehensive Cancer Center.This was a prescient strategic decision and the number of SCC laboratories currently performing researchrelated to tumor immunology has increased significantly. Of note there has been a concomitant increase in thenumber of laboratories participating in translational tumor immunology research and the number of investigator-initiated cancer immunotherapy clinical trials in the current project period. This increase in translational researchhas been achieved through the creation of an environment that facilitates and encourages interactions andcollaborations between basic scientists and physician-scientists particularly between SCC research programsand where state-of-the-art resources and infrastructure are available to catalyze the translation of these basicscience research findings into novel therapeutic opportunities. Thus because of the environment that was established by the SCC the highly interactive environment nowextends across the basic immunology tumor immunology and cancer immunotherapy research communities.TIP members are conducting research and discovery within four central themes: (1) developing and/or expandingnew models that recapitulate the dynamic interplay between the immune system and cancer; (2) identifyingmolecules that serve as targets of the innate and adaptive anti-tumor immune response and developingstrategies targeting these molecules; (3) defining the roles of immune cells in the tumor microenvironment andelsewhere in promoting or suppressing anti-tumor immune responses; and (4) translating basic immunologicresearch into clinically relevant tests interventions and clinical trials. The TIP has 23 members from six departments at WUSM. The program is supported by $13.7 million infunding with $2.91 million from the NCI and $5.10 million from other peer-reviewed funding. During the currentproject period TIP members published 647 manuscripts with 39% from inter-programmatic collaborations and21% from intra-programmatic collaborations. During the current project period TIP members initiated orsupported 256 cancer immunotherapy clinical trials. Although the accruals to these were allocated to SCCsdisease-focused research programs (STTP BCRP and HDMP) TIP members facilitated accrual to these trials(1544 interventional treatment accruals including 501 (32%) to investigator-initiated studies). +No NIH Category available Acceleration;Address;Algorithms;Area;Bioinformatics;Biological;Cancer Biology;Cancer Center;Charge;Clinical;Clinical Trials;Clinical Trials Design;Communities;Competence;Computer software;Data;Data Analyses;Data Set;Detection;Development;Disease;Distributed Systems;Dreams;Ensure;Evolution;Future;Genetic Heterogeneity;Genomic approach;Genomics;Goals;Heterogeneity;Individual;Infrastructure;Intervention;Knowledge;Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Manuals;Messenger RNA;Methodology;Methods;Mutation;Neoplasm Metastasis;Pathway Analysis;Pathway interactions;Patients;Pharmacologic Substance;Prevention strategy;Process;Prognostic Marker;Quality Control;Research;Research Personnel;Resistance;Running;Sampling;Services;Site;Specialized Center;Survival Rate;System;Systems Integration;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Training;Update;Variant;Visualization;Work;bioinformatics tool;cancer genomics;cancer initiation;cancer prevention;cell free DNA;clinical care;cluster computing;complex data;computer infrastructure;computerized tools;data analysis pipeline;data integration;diagnostic biomarker;experience;genetic evolution;genomic data;improved;innovation;multidisciplinary;novel;novel diagnostics;novel strategies;patient subsets;precision medicine;programs;response;single-cell RNA sequencing;success;therapy resistant;transcriptome sequencing;treatment strategy;tumor;tumor DNA;working group OHSU Center for Specialized Data Analysis as part of the GDAN Project NarrativeThe GDAN represents an attempt to bring retrospective precision medicine to the NCI's clinical trialinfrastructure. As such it is a great opportunity to learn why trials that have occurred worked at a broad level oridentify patients who likely benefited from therapy even when the trials were not successful. Our participationin this network will bring the most robust approaches for mutation calling and expression analysis will bringnovel pathway analysis approaches and will bring an analysis of tumor genetic heterogeneity and evolution. NCI 10689802 8/22/23 0:00 RFA-CA-20-053 5U24CA264007-03 5 U24 CA 264007 3 "YANG, LIMING" 9/1/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 10321999 "ELLROTT, KYLE " "SPELLMAN, PAUL T." 1 GENETICS 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 362207 NCI 235199 127008 Project SummaryRecent advances in therapeutics have improved survival rates for many cancers. However nearly allmetastatic tumors are incurable and resistance to therapeutic interventions is nearly universal. There aremany reasons for our lack of progress-foremost of which is lack of understanding of mechanisms of responseand resistance and lack of markers to identify subsets of patients ideally-suited for specific treatments.Our team brings enormous experience in TCGA and other multi-disciplinary coordinated projects such asBEAT-AML and the Stand Up to Cancer West Coast Prostate Cancer Dream Team. The Cancer GenomeAtlas (TCGA) was successful because multi-disciplinary teams worked together to create new and innovativeknowledge about cancer and we intend to ensure that the GDAN is equally successful. In this application wehave assembled a team of proven investigators from four of the different TCGA groups to extend thesuccesses of TCGA to the projects managed by the Center for Cancer Genomics. Our team will continue ouroutstanding capabilities at analyzing and interpreting cancer genomic data by deploying data analysis pipelinesthat support the key capabilities of the network.In addition to the our experience in coordinated network studies we bring experience with clinical trial designand interpretation. Further the team has deep expertise at building the computational infrastructure necessaryfor the GDAN to succeed. For example in the domain of distributed computing we have deploy pipelines forexecution at many sites. We also bring novel methods for integrative pathways and analysis. Finally we bringour experiences with competitive challenges that ensure that we can identify and deploy the most effectivemethods for genomic data analyses.Using these strengths we will support the GDAN and the Analysis Working Groups (AWGs) that it serves withtwo principal objectives. The first objective and second objective per the RFA are the Development ofinnovative bioinformatics and computational tools and methodologies which will allow us to make clinical andbiological correlations and to Conduct Integrative analysis of data sets generated by GCCs using thebioinformatics tools developed by each GDAC. We will achieve these objectives in five specific aims oneadministrative aim to support the GDAN and four aims one for each of the areas where we propose acompetency. 362207 +No NIH Category available 3-Dimensional;ABCG2 gene;Acceleration;Animals;Area;Artificial Intelligence;Basic Science;Biological Assay;Biological Process;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Cell physiology;Cells;Cellular Structures;Consultations;Consumption;Contrast Media;Custom;Data Analyses;Data Set;Dedications;Detection;Development;Dimensions;Education;Educational workshop;Electron Microscopy;Electrons;Ensure;Equipment;Experimental Designs;Face;Fluorescence;Funding;Future;Gastric Tissue;Generations;Goals;Human Resources;Image;Image Analysis;Imaging Techniques;Imaging technology;Individual;Informatics;Institution;Investments;Ions;Journals;Laboratories;Laboratory Research;Learning;Light;Malignant Neoplasms;Methodology;Microscope;Microscopic;Microscopy;Morphology;Mus;Neoplasm Metastasis;Optics;Organism;Organoids;Physiological;Preparation;Property;Research;Research Personnel;Resolution;Resource Sharing;Roentgen Rays;Sampling;Scanning Electron Microscopy;Services;Specialist;Specimen;Speed;Structure;System;Technical Expertise;Techniques;Technology;Time;Tissue Microarray;Tissue imaging;Tissues;Training;Translational Research;United States National Institutes of Health;Universities;Visualization;Washington;Work;X ray microscopy;analysis pipeline;anticancer research;bone;cancer cell;cell behavior;cellular imaging;cost;data acquisition;design;fluorescence microscope;improved;innovation;instrumentation;intravital microscopy;lectures;light microscopy;long bone;loss of function;member;microscopic imaging;molecular imaging;mouse model;nanoscale;neoplastic cell;novel;operation;programs;quantitative imaging;research study;single molecule;superresolution imaging;superresolution microscopy;technology platform;tool;translational study;treatment strategy;tumor progression;two-dimensional;two-photon Washington University Center for Cellular Imaging n/a NCI 10689800 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6501 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 221426 140588 80838 WASHINGTON UNIVERSITY CENTER FOR CELLULAR IMAGING (WUCCI) SHARED RESOURCE:PROJECT SUMMARYElucidating the mechanisms involved in the development and progression of cancer requires a deepunderstanding of how changes in tissue / cellular structure relate to loss of function. Imaging technologies haveevolved rapidly over the last decade generating vast improvements in resolution sensitivity and speed andcreating fundamentally new opportunities for studying biological processes across many orders of magnitude inreal-time in living cells and organisms. The Washington University Center for Cellular Imaging (WUCCI) provides(i) reliable and affordable access to cutting-edge light and electron microscopy instrumentation (ii) expertguidance in imaging assay design specimen preparation image acquisition and analysis (iii) educationalopportunities in the form of hands-on trainings lunch and learn lectures workshops and a monthly journal cluband (iv) novel imaging and analysis methodologies. As a new Cancer Center Support Grant (CCSG) sharedresource (SR) WUCCI will provide an integrated approach to investigate the structure and dynamic behavior ofcells and tissues in cancer-related studies. By leveraging a significant institutional investment SCC researchersgain instant access to a wide variety of advanced cellular microscopy tools which will serve to accelerate thepace expand the scope and improve the efficiency of their research. WUCCI services meet the uniquerequirements of numerous investigators over a wide range of basic and translational research as well as attractnew investigators into the cancer research arena. Importantly users benefit from the in-depth technical expertiseof the Director (James Fitzpatrick) and technical staff with regard to experimental design and interpretation ofdata. Over the past three years WUCCI has worked with multiple SCC researchers to implement new imagingassays. These have included the application of two-photon intravital microscopy to longitudinally trackdisseminated tumor cells in a mouse model of dormancy (Sheila Stewart [MCBP]) the development of x-raycontrast agents to delineate metastatic tumor boundaries in murine long bones (Katherine Weilbeacher[BCRP]) and the application of focused ion beam-scanning electron microscopy (FIB-SEM) serial block faceimaging to acquire three-dimensional volumes of mouse gastric tissue at the nanoscale (Jason Mills [MCBP]).In 2018 WUCCI served 235 research laboratories 75 of which were SCC investigators whose usagerepresented ~20% of the overall SR consumption. Future plans for the next project period include the acquisitionof a light-sheet fluorescence microscope recently funded by the NIH S10 program for the high-speed volumetricimaging of living organoids and cleared tissues as well as the implementation of the Visiopharm OncotopixIHC and ISH image analysis platform. We anticipate that requests for WUCCI services will continue to growgiven the need for advanced microscopic imaging and analysis in the study of cancer. Thus WUCCI as a newCCSG shared resource will provide essential services to SCC investigators throughout the next project period. +No NIH Category available Accounting;Award;Brain Neoplasms;California;Cancer Center;Clinical;Clinical Research;Clinical Services;Clinical Trials;Collaborations;Communication;Complex;Data;Decision Making;Ensure;Fertilization;Funding;Glioblastoma;Goals;Grant;Immunotherapy;Individual;Institution;Manuscripts;Monitor;Neurology;Neurosurgical Procedures;Operations Research;Organization and Administration;Participant;Pilot Projects;Preparation;Principal Investigator;Productivity;Progress Reports;Qualifying;Recommendation;Reporting;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;San Francisco;Schedule;Supervision;Testing;United States National Institutes of Health;Universities;Vision;data sharing;design;experience;follow-up;industry partner;meetings;member;neuro-oncology;operation;preclinical study;programs;research study Administrative and Clinical Services Core n/a NCI 10689796 8/17/23 0:00 RFA-CA-20-047 5U19CA264338-03 5 U19 CA 264338 3 9/10/21 0:00 8/31/26 0:00 ZCA1-TCRB-D 6499 9011483 "BUTOWSKI, NICHOLAS A" Not Applicable 11 Unavailable 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA Domestic Higher Education 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 218939 153227 65712 SUMMARY ABSTRACTThe co-directors of the Administrative Core (AC) will be Drs. Nicholas Butowski (UCSF) and Roger Stupp (NU)who will share administrative and clinical responsibilities to provide oversight of the procedural and technicalaspects of the planned projects and cores ensuring compliance and scientific integrity of all components of thegrant. They are also the co-PIs of this U19. Dr. Susan Chang will serve as co-investigator of the AC and provideextensive expertise in managing grants. The core leaders are accomplished brain tumor researchers wellqualified to supervise this U19 collaboration and ensure its productivity. Based on executive committee andinternal advisory board recommendations the core directors will make final decisions on any issues that involvethe timely progression of the projects. Further the core directors they will have overall scientific and financialresponsibility for this U19. They will disburse funds and will receive regular accounting of the financial status ofeach project.The overall objective of the AC is to promote and facilitate the interactions of the members of this U19 providenecessary clinical research infrastructure and/or support for the projects and coordinate activities of the U19investigators. The specific aims of the AC are to provide administrative and clinical services to all our projects inorder to accomplish their Specific Aims and Research Strategies. Administrative support will include fiscal grantsmanagement clerical support for progress reports and manuscript preparation organization of regular meetingsamong participants and organization and administration of the Internal Advisory Board (IAB). The AdministrativeCore also facilitates communication with the Network Coordinating Center (NCC) and GTN Steering Committee. +No NIH Category available Acceleration;Address;Adult;Antibodies;Antigens;Back;Biological Assay;Biological Markers;Biotechnology;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cell Therapy;Cells;Characteristics;Clinic;Clinical;Clinical Investigator;Clinical Treatment;Clinical Trials;Collaborations;Combination immunotherapy;Comprehensive Cancer Center;Cytotoxic Chemotherapy;Dedications;Development;Devices;Dose;Doxorubicin;Drug Kinetics;Failure;Family;Fostering;Funding;Genetic;Glioblastoma;Goals;Grant;Hematologic Neoplasms;Heterogeneity;Homing;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Monitoring;Immunotherapy;Industry;Institution;International;Investigation;Knowledge;Laboratories;Lead;MAP Kinase Gene;Malignant Neoplasms;Mediating;Modeling;Mus;Neoadjuvant Therapy;Operative Surgical Procedures;Organ;Patient-Focused Outcomes;Patients;Peripheral;Pharmaceutical Preparations;Pharmacotherapy;Pilot Projects;Population;Pre-Clinical Model;Primary Brain Neoplasms;Prior Therapy;Prognostic Marker;Quality of life;Radiation;Recurrence;Research;Research Personnel;Research Project Grants;Resected;Resources;Role;Safety;Scientist;Site;Solid Neoplasm;Sonication;Structure;System;T-Lymphocyte;Technology;Testing;Therapeutic;Tissues;Toxic effect;Translating;Translational Research;Treatment Efficacy;Tumor Tissue;United States National Institutes of Health;Universities;anti-PD-1;anti-PD1 therapy;base;bevacizumab;blood-brain barrier disruption;brain tissue;checkpoint therapy;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;clinical investigation;clinical translation;cohort;combinatorial;design;early phase clinical trial;electric field;epidermal growth factor receptor VIII;exhaustion;experience;first-in-human;immune checkpoint blockade;immunogenic;immunoregulation;immunotherapy clinical trials;improved;in vivo;in vivo evaluation;innovation;manufacture;neoplasm immunotherapy;neoplastic cell;neuro-oncology;notch protein;novel;patient population;personalized medicine;pre-clinical;predictive marker;prevent;programs;prospective;response;synergism;targeted treatment;temozolomide;translational scientist;tumor;tumor heterogeneity;tumor-immune system interactions;ultrasound Advancing treatment and understanding of immunotherapy in glioblastoma NARRATIVENumerous attempts of drug therapy to substantially impact the outcome of patients suffering from glioblastomahave failed over the last 15 years. Indeed the approval of temozolomide chemotherapy dates back to 2005and bevacizumab will improve quality of life of some patients however failed to prolong survival. Reasons forfailures are tumor heterogeneity the exquisitely immunosuppressive microenvironment of glioblastoma theblood-brain barrier preventing sufficient drug concentrations in the brain investigations of single agents to anunselected patient population rather than combinatorial approaches and biomarker-based treatments ofenriched populations. Our U19 proposal unites renowned translational and clinical investigators from two topand NIH-funded institutions with a strength and dedicated research in brain tumors evaluating and comparingdifferent approaches of optimized immunotherapy against glioblastoma. We leverage collaboration andpipeline(s) of innovative biotechnology companies who will support our proposal with drugs devices but alsowith access to their expertise and experts platforms and laboratory investigations as needed. Thus this U-19grant will enable and facilitate a powerful new consortium that will synergize and is able to efficiently translatepreclinical findings to meaningful early clinical trials and treatments for patients suffering from glioblastoma. NCI 10689795 8/17/23 0:00 RFA-CA-20-047 5U19CA264338-03 5 U19 CA 264338 3 "HUBBARD, LEAH" 9/10/21 0:00 8/31/26 0:00 ZCA1-TCRB-D(A1) 9011483 "BUTOWSKI, NICHOLAS A" "STUPP, ROGER " 11 NEUROSURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 821970 NCI 647583 174387 SUMMARY/ABSTRACTImmunotherapy holds great promise for the treatment of glioblastoma; still certain characteristics of glioblastomapresent inherent therapeutic challenges. Herein two experienced interdisciplinary laboratory and clinical teamsat UCSFs Helen Diller Family Comprehensive Cancer Center and Northwestern University's Robert H. LurieComprehensive Cancer Center join efforts to develop innovative immunotherapy approaches againstglioblastoma. This proposal leverages industry and institutional support to address three specific objectives: 1)to improve our understanding of the role of immunotherapy approaches in glioblastoma; 2) to improve ourunderstanding of how to overcome the limitation the blood brain barrier and 3) to develop innovativeimmunotherapy treatments for glioblastoma with associated early clinical trials focused on patients sufferingfrom recurrent glioblastoma.Project 1 coordinated from Northwestern will build on the team's preclinical results in mouse brain tumor modelsdemonstrating an immunomodulatory and sensitization effect when immune checkpoint inhibitor therapy ispreceded by a immunogenic dose of doxorubicin an effect that can be further enhanced by ultrasound-basedBBB opening. Support by innovative biotech companies (Agenus AstraZeneca Carthera) provide drugs ordevices for preclinical and clinical investigation as well as specific expertise assays and technology forinvestigations at both institutions making this collaboration a very powerful consortium. The ensuing clinical trialwill investigate the novel anti-PD1 checkpoint inhibitor balstilimab in conjunction with doxorubicin with andwithout sonication for BBB opening. By administration of immune therapy prior to surgery (induction therapyneoadjuvant treatment) the immune effect enables us to evaluate in vivo immune response in the resected braintissue. We have previously identified pERk/MAPK activation as a biomarker for benefit from anti-PD1 treatmentin recurrent glioblastoma; this and other markers will be explored furthermore. Four prospectively treated cohortswill be treated with and without induction therapy and with and without BBB opening. Translational endpointsinclude immune response (tumor tissue peripheral) and drug tissue concentration.Project 2 coordinated from UCSF is a study based on the exciting novel synthetic Notch synNotch receptorCART system and pioneering T cell circuits that recognize tumor cells based on a prime-and-kill strategy. Inthis system the first antigen which is expressed exclusively on GBM cells (EGFRvIII) primes the T cells toinduce expression of a CAR that recognizes IL-13R2 and EphA2 thereby eradicating GBM cells expressingeither EphA2 or IL-132. Project 2's team hypothesizes that synNotch CART cells can revolutionize the CARTtherapy for glioblastoma by overcoming the challenges of off-tumor toxicity antigen heterogeneity and CARTcell exhaustion. Thus these synNotch-CART cells are hypothesized to be significantly more efficacious thanconventional constitutively expressed IL-13R2/EphA2 CART cells. Investigators will optimize the efficacy ofthe lead agent and test this hypothesis in the first in human clinical trial of this new class of agents in glioblastomapatients.This U19 proposal also has set aside funds for support of the distinctly important trans-GTN pilot projects andfor two cores (Administrative Immune Monitoring & Biospecimen) that will support the efforts of the two projects.By addressing the overall specific objectives described the research proposed in this U19 application has a highlikelihood of changing the way immunotherapy is understood and utilized in glioblastoma. The innovativeresearch described in this proposal will take advantage of the exceptional resources assembled by the well-established collaborative group of clinical and basic scientists at UCSF and Northwestern. 821970 +No NIH Category available Accreditation;American;Archives;Basic Science;Biological Markers;Blood Cells;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cells;Clinical;Clinical Trials;Clinical Trials Cooperative Group;Clinical Trials Network;Collection;Computer software;Consensus;Consent;Consultations;Cryopreservation;DNA;Dissociation;Fostering;Freezing;Future;Histologic;Histology;Human;Immunologic Monitoring;Informatics;Infrastructure;Institution;Intelligence;Investigational Therapies;Journals;Laboratories;Lead;Leadership;Liquid substance;Malignant Neoplasms;Metagenomics;Methodology;Methods;Molecular Biology;National Cancer Institute;National Clinical Trials Network;Non-Malignant;Nucleic Acids;Operative Surgical Procedures;Pathologist;Pathology;Patients;Peer Review;Plasma;Procedures;Process;Proteomics;Publications;Publishing;RNA;Research;Research Personnel;Resected;Resource Sharing;Resources;Role;Sampling;Scientist;Serum;Services;Solid;Solid Neoplasm;Specialized Program of Research Excellence;Specimen;Standardization;System;The Cancer Genome Atlas;Therapeutic Clinical Trial;Tissue Procurements;Tissues;Training;Translating;Translational Research;Universities;Washington;Work;anticancer research;biobank;biological specimen archives;cancer biomarkers;cancer clinical trial;cancer genomics;cancer initiation;cell free DNA;clinical translation;clinically relevant;college;cost effective;design;exosome;human tissue;improved;informatics tool;interest;member;next generation;novel;programs;prospective;quality assurance;research study;sample collection;single cell analysis;tissue processing;translational cancer research;translational study;tumor Tissue Procurement Core n/a NCI 10689793 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6498 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 270226 171572 98654 TISSUE PROCUREMENT CORE (TPC) SHARED RESOURCE: PROJECT SUMMARYThe Siteman Cancer Center (SCC) Tissue Procurement Core (TPC) is a College of American Pathologists(CAP)-accredited shared laboratory resource that enables patient-based cancer research using human tissuesand biofluids. The TPC provides highly cost-effective services for patient tissue and fluid specimen collectionprocessing tracking and storage in order to support institutional and multi-institutional investigator-initiatedtherapeutic clinical trials. The TPC also provides biospecimen resources and expertise to rapidly transform basicscience discoveries into clinically relevant translational cancer research. This includes simplified and transparentaccess to an archived collection of surgically resected frozen tumor and patient-matched non-malignant solidtissues (peripheral blood cells serum and plasma) from consenting cancer patients tissue histology servicesand pathologist consultation nucleic acid (RNA / DNA) isolation and quality assurance. Over the past five yearsthe TPC has collected and processed over 200000 human biospecimens for clinical trials and translationalstudies for SCC members. TPC-supported activities have resulted in more than 50 peer-reviewed publicationsalmost half of which have been published in high impact journals (Thomson Reuters impact factor of 10 orgreater). The TPC has also contributed biospecimens and scientific leadership on a national scale to NationalCancer Institute biospecimen-based initiatives such as the Clinical Proteomic Tumor Analysis Consortium(CPTAC) Specimen Resource Locator (SRL) and National Clinical Trials Network (NCTN). Over the next projectperiod continuing emphasis will be placed on developing and standardizing state-of-the-art biospecimenprocessing and storage methods for cell-free DNA single cell analysis exosomes and metagenomics to supportnext-generation translational cancer research. +No NIH Category available Address;Animal Cancer Model;Animal Model;Animals;Biological Models;Cancer Center;Cancer Center Support Grant;Cancer Detection;Cancer Model;Clinic;Collaborations;Communities;Computer software;Consult;Consultations;Data Analyses;Data Set;Development;Diagnostic;Discipline;Discipline of Nuclear Medicine;Disease model;Drug Kinetics;Education;Educational workshop;Ensure;Funding;Goals;Grant;Hamsters;Image;Image Analysis;Imaging Device;Imaging Techniques;Imaging technology;Infrastructure;Institution;Laboratory Animal Models;Laboratory Animals;Longitudinal Studies;Magnetic Resonance;Magnetic Resonance Imaging;Maintenance;Malignant Neoplasms;Manuscripts;Mission;Modality;Molecular;Molecular Biology;Mus;NCI Center for Cancer Research;Optical Tomography;Optics;Pathology;Peer Review;Population;Positron-Emission Tomography;Preparation;Procedures;Productivity;Protocols documentation;Radio;Radiology Specialty;Rattus;Research;Research Design;Research Personnel;Research Support;Resource Sharing;Resources;Sampling;Scientist;Small Animal Imaging Resource Programs;Technology;Textiles;Therapeutic;Therapeutic Agents;Therapeutic Clinical Trial;Time;Training;Transgenic Animals;Translating;Translations;Treatment Efficacy;X-Ray Computed Tomography;animal imaging;anticancer research;bioluminescence imaging;cancer health disparity;cancer imaging;experience;fluorescence imaging;frontier;image translation;imaging biomarker;imaging facilities;imaging program;instrument;interest;journal article;member;metabolic abnormality assessment;optical imaging;pre-clinical;preclinical imaging;programs;protocol development;quantitative imaging;radiotracer;research and development;single photon emission computed tomography;symposium;tomography;translational potential Small Animal Cancer Imaging n/a NCI 10689790 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6497 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 327406 207877 119529 SMALL ANIMAL CANCER IMAGING (SACI) SHARED RESOURCE: PROJECT SUMMARYWith the revolution in molecular biology transgenic animal models in particular mice have become anindispensable part of the cancer research armamentarium. The Siteman Cancer Centers (SCC) Small AnimalCancer Imaging (SACI) Shared Resource (SR) (initially established under the auspices of the NCIs Small AnimalImaging Resource Program) addresses the need for nondestructive imaging and analysis of small animallaboratory models of cancer. It provides state-of-the-art facilities and infrastructure for magnetic resonanceimaging positron emission tomography X-ray computed tomography single-photon emission computedtomography and optical (including Cerenkov) imaging of mice rats and other small laboratory animals thatserve as models of cancer. SACI combines instrumental and intellectual capabilities found at few other institutions and serves a broadcommunity of cancer scientists who have a pressing need for quantitative image analysis of small animalmodel systems. The principal functions of SACI are to provide SCC members: i) access to and maintenanceof small animal magnetic resonance nuclear medicine and optical imaging scanners for cancer research; ii)technology expertise and consultation in study design protocol development and data analysis/interpretation.In addition to supporting cancer research applications of small animal imaging SACI also provides researchand development at the frontier of imaging technology in an effort to make the most powerful new imagingstrategies available to its community of users. The SR is organized around three modality-specific imagingcomponents: (i) nuclear medicine (ii) magnetic resonance and (iii) optical. An overarching goal is translation tothe clinic of imaging protocols and therapeutic agents developed and validated with small animal models. ThusSACI directly supports the mission of the SCC by supporting basic discovery cancer research and cancerimaging protocols with translational potential. +No NIH Category available Basic Science;Cancer Center;Cancer Center Support Grant;Cell Separation;Cells;Clinical Trials;Color;Competence;Complex;Computer software;Confusion;Contract Services;Cytometry;Data;Data Analyses;Development;Discipline;Education;Ensure;Experimental Designs;Failure;Flow Cytometry;Flow Cytometry Shared Resource;Genetic;Health Services Accessibility;Hour;Industry;Instruction;Lasers;Learning;Maintenance;Manufacturer;Marketing;Mission;Nomenclature;Patient Schedules;Price;Process;Reagent;Recovery;Research Personnel;Science;Services;Sorting;Standardization;Target Populations;Techniques;Technology;Time;Training;Training and Education;Vendor;Visualization;Work;anticancer research;cost;craving;data management;experimental study;flexibility;instrumentation;member;new technology;operation;repaired;response;success;synergism;tool Siteman Flow Cytometry n/a NCI 10689786 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6496 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 281536 178753 102783 SITEMAN FLOW CYTOMETRY (SFC) SHARED RESOURCE: PROJECT SUMMARYIn the current project period Siteman Flow Cytometry (SFC) has grown to meet the increasing needs for flowcytometry from Siteman Cancer Center (SCC) members. SFC now offers 10 flow cytometry analyzers from 8-27 colors and four cell sorters from 10-22 colors. All analyzers all data workstations and one self-service cellsorter are available 24/7. The remaining three cell sorters are operated by proficient staff Monday through Fridayfrom 9:00 am to 5:00 pm with flexibility. In the current project period SFC has prioritized customer educationand training especially in experiment design and process. Rather than focusing merely on the operation ofinstrumentation and software the education helps users become much more apt to achieve success the firsttime when facing a new level of flow cytometry multiplexing. SFC is heavily involved in the developmentpartnerships with flow cytometer manufacturers intending to reach 60 parameters for quantitative analysis usingspectral flow instrumentation and 50 parameters for cell sorting within the next two years. These partnershipswith industry have consistently helped SFC obtained substantial pricing accommodation on new instrumentation.This has in turn reduced the cost basis of the assets for SFC customers and has increased value to the usersby ensuring they have access to cutting-edge technology. SFCs focus on and ability to maintain and repair itsown instrumentation leads to minimal down time and instant response to problems that inevitably occur in allfluidic instrumentation. This repair and maintenance effort extends capacity and utilization and the ability toforego several service contracts also reduces cost basis and adds value to SFCs users. +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Aftercare;Agreement;Algorithmic Analysis;Area;Basic Science;Bioinformatics;Biological Assay;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cells;Clinical;Clinical Trials;Collaborations;Complex;Comprehensive Cancer Center;Computer software;Critiques;Data;Data Analyses;Data Discovery;Development;Enzymes;Equipment;Experimental Designs;Faculty;Funding;Future;Generations;Genes;Genome;Genomics;Goals;Guidelines;Human;Label;Laboratories;Leadership;Libraries;Malignant Neoplasms;Malignant neoplasm of ovary;Mass Spectrum Analysis;Metabolic;Methods;NCI Center for Cancer Research;National Cancer Institute;North Carolina;Outcome;Peptide Sequence Determination;Peptides;Pharmaceutical Preparations;Phosphorylation Site;Phosphotransferases;Post-Translational Protein Processing;Protein Kinase;Proteins;Proteome;Proteomics;Proteomics Shared Resource;Protocols documentation;Publications;Reproducibility;Research;Resource Sharing;Sampling;Science;Services;Site;Specificity;Specimen;Stable Isotope Labeling;Standardization;Technology;Translational Research;United States National Institutes of Health;Universities;Validation;Washington;Work;analysis pipeline;automated analysis;bioinformatics resource;bioinformatics tool;cancer type;clinical practice;cohort;computer cluster;computerized tools;data acquisition;density;design;experience;genome resource;improved;instrumentation;large scale data;medical schools;member;migration;multiplex assay;new technology;next generation;phosphoproteomics;programs;protein protein interaction;proteogenomics;recruit;repository;response;software development;tool;tumor Proteomics Shared Resource n/a NCI 10689779 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6493 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 276939 175834 101105 PROTEOMICS SHARED RESOURCE (PSR): PROJECT SUMMARYThe Siteman Cancer Center (SCC) Proteomics Share Resource (PSR) has been a major contributor to theemerging field of proteogenomics with a track record of high impact publications and external funding. The PSRis poised to continue as leaders in the field in the next five years using reproducible and repeatable deep-scaleproteomics ( 10000 genes) and phosphoproteomics ( 37000 sites) and the harmonized protocol that was co-developed with the National Cancer Institute Clinical Proteomics Tumor Analysis Consortium (CPTAC). Studiesare underway with comprehensively characterized Acute Myeloid Leukemia and pre/post treatment ovariancancer cohorts (Aim 1). In the current project period PSR has developed high-precision assays for absolutequantification (copies/cell) of 361 of the 526 protein kinases in the human kinome using CPTAC guidelines forvalidation toward FDA approval and clinical utility. The PSR proposes to have complete coverage of the humankinome by 2023 and to continue applying and developing cancer-type specific panels for PDX and human drugtrials (Aim 2). Proteomics is on the cusp of next generation instrumentation that will lead to quantification of allexpressed proteins and generate wider coverage of post-translational modifications. Using these new platformsand in collaboration with the recently-established Washington University School of Medicine (WUSM) MassSpectrometry Center the PSR will develop new services for SCC members and increase the value and utility ofproteogenomic analysis in support of SCC research programs (Aim 3). Future directions for the next projectperiod include an emphasis on expanding services and enhancing cross-core interface to improve userexperience and interpretation of data. PSR will continue to develop software in collaboration with thebioinformatic resources of the Genome Technology Access Center (GTAC) and The McDonnell GenomeInstitute (MGI) with the overarching goal of providing tools for more efficient interpretation of high-densityproteogenomic data. WUSM recently recruited two faculty members who will contribute to PSR plans to expandservices in the next project period. Ben Major (MCBP) from the Lineberger Comprehensive Cancer Center atthe University of North Carolina will serve as PSR Faculty Advisor and actualize expansion of PSR services inthe area of proximity-labeling mass spectrometry for high-specificity characterization of intracellular complexesin cancer biology. With the successful recruitment of Dennis Goldfarb to WUSM and his agreement to collaborateon development of new MS and bioinformatics tools for proteogenomics PSR will offer members new capabilitiesfor facile discovery and hypothesis generation. +No NIH Category available Artificial Intelligence;Big Data;Biostatistics Shared Resource;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Research;Clinical Sciences;Collection;Complex;Computer software;Consultations;Custom;Data;Data Analytics;Data Collection;Data Commons;Data Discovery;Data Mart;Data Set;Development;Electronic Health Record;Faculty;Grant;Health care facility;Healthcare;Informatics;Information Management;Information Systems;Institution;Knowledge Management;Machine Learning;Malignant Neoplasms;Mentored Clinical Scientist Development Program;Methodology;Methods;Natural Language Processing;Online Systems;Patients;Performance;Persons;Phenotype;Physicians;Population;Preparation;Public Health;Publications;Reporting;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Services;Site;Support System;Techniques;Technology;Testing;Text;Tissue Procurements;Training;Translational Research;Triage;United States National Institutes of Health;Universities;Washington;Work;biomedical informatics;community center;data integration;data management;data modeling;data resource;data submission;data tools;data warehouse;deep learning;design;electronic data;electronic health record system;instrument;medical schools;member;multiscale data;operation;programs;software development;technology platform;theories;tool Informatics Core Services n/a NCI 10689773 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6490 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 260507 165401 95106 INFORMATICS CORE SERVICES (ICS) SHARED RESOURCE: PROJECT SUMMARYInformatics Core Services (ICS) provides a wide range of biomedical informatics and data analytics support tocancer-focused researchers at Siteman Cancer Center (SCC) and throughout Washington University School ofMedicine (WUSM). ICS provides electronic health record (EHR) data brokerage and electronic data captureservices to support clinical and translational research at WUSM. As part of these services ICS operates theResearch Data Core which contains data from Washington University Physicians and BJC HealthCareelectronic health records spanning over 20 years. ICS provides billable services to broker access to deidentifiedlimited and fully identified EHR data. ICS also performs extensive analytics and software development utilizingEHR data including the use of natural language processing tools for data extraction. Access to ICS expertisemethods and tools is initiated through the submission of web-based requests for services followed by in-personconsultative project planning sessions or by direct consultations that lead to the engagement of ICS faculty andstaff at an appropriate level given project needs. Services are triaged tracked implemented and supportedusing a systematic and Agile project management methodology and tools that span all aspects of ICSsoperations. Over the last grant period ICS contributed to more than 100 cancer-focused SCC memberpublications and 20 types of NIH-NCI grants including more than 30 R01 10 T32 and numerous U24 U54P50 P30 R37 K12 R21 U10 and U01 grants. ICS has three shared resource (SR) services underdevelopment in preparation for the next grant period: synthetic data service (MDClone) that transforms realpatient data into a statistically-similar synthetic derivative clinical natural language processing to enable theability to extract data from free text and capabilities to support SCC investigators with data deposition into currentor emergent data commons platforms. +No NIH Category available Alleles;Animal Cancer Model;Antibodies;Antigens;Bar Codes;Basic Science;Biological Assay;Biological Markers;Blood specimen;CD4 Positive T Lymphocytes;Cancer Center;Cancer Center Support Grant;Cancer Vaccines;Categories;Cells;Clinical;Clinical Investigator;Clinical Trials;Complex;Computers and Advanced Instrumentation;Custom;Cytometry;DNA;Data;Data Analyses;Development;Disease;Doctor of Philosophy;Equipment and supply inventories;Experimental Designs;Flow Cytometry;Freezing;Generations;HLA-A gene;Health Services Accessibility;Heavy Metals;Hospitals;Human;Image;Imaging technology;Immune;Immune response;Immunity;Immunoassay;Immunologic Monitoring;Immunologics;Immunology;Immunooncology;Immunophenotyping;Immunotherapy;Institution;International;Investigation;Label;Laboratories;Laboratory Personnel;Leukapheresis;MHC Class I Genes;MHC Class II Genes;Malignant Neoplasms;Metals;Molecular;Monitor;Monoclonal Antibodies;Mus;Nucleic Acids;Outcome;Pathway interactions;Patients;Population;Preparation;Process;Proliferating;Proteins;Protocols documentation;Recovery;Research;Research Personnel;Resolution;Resource Sharing;Role;Sampling;Scientist;Services;Signal Pathway;Site;Space Perception;Stains;Structure;System;Technology;Testing;Tissue Sample;Training;Training Programs;Treatment Protocols;Treatment outcome;Universities;Validation;Vendor;Visualization;Washington;Work;antibody libraries;archive data;bench to bedside;cancer immunotherapy;cancer therapy;cytokine;data acquisition;data archive;data sharing;design;enzyme linked immunospot assay;experience;flexibility;fluorophore;follower of religion Jewish;instrumentation;laboratory experience;light microscopy;neoantigens;new technology;novel;novel therapeutic intervention;novel therapeutics;programs;response;scaffold;synergism;targeted cancer therapy;targeted treatment;tissue biomarkers;tissue processing;tool;translational research program;translational study;treatment strategy;tumor;tumor immunology Immunomonitoring Laboratory n/a NCI 10689768 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6488 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 257487 163484 94003 IMMUNOMONITORING LABORATORY (IML) SHARED RESOURCE: PROJECT SUMMARYThe Immunomonitoring Laboratory (IML) is a shared resource (SR) facility within the Bursky Center for HumanImmunology and Immunotherapy Programs established in 2013. The IML provides the structure instrumentationand expertise to monitor the impact of specific immunotherapies on patient immunologic profiles interrogatemechanisms and pathways related to treatment protocols and advance the conceptual basis for targetedtreatment strategies. In addition the IML monitors developing immune responses to new therapies in animalmodels of cancer treatment to elucidate novel therapeutic strategies or develop unique processes to evaluatetreatment outcomes in translational studies and new clinical trials. The IML is composed of four integrated groupsthat include cytometry (conventional flow cytometry analyses mass cytometry [CyTOF2] and imaging masscytometry) immune monitoring (multiplex analysis and functional assays) custom tetramer development(currently with an inventory of over 50 HLA alleles) and tissue processing related to IML projects. The IML hasrecently brought on board two imaging technologies: a Hyperion CyTOF capable of detecting > 40 distinct metal-labeled biomarkers from tissue sections and a CODEX system that can visualize >40 unique DNA barcodedbiomarkers from frozen or FFPE sections using light microscopy. These two state-of-the-art technologies willallow investigators to visualize the spatial orientation of interacting immune stromal and tumor components andallow scientists to see the interaction between cells and understand the molecular and cellular basis of complexdiseases that arise as these interactions become abnormal. In the current project period the IML has grown the number of laboratories serviced by 3-fold and more thandoubled the number of Siteman Cancer Center (SCC) users along with supporting a number of ongoing clinicaltrials. The IML continues to acquire new technologies as specialized tools become available to meet the needsof our Washington University (WU) SCC and Barnes-Jewish Hospital (BJH) clinicians and scientists. In additionto our new Hyperion and CODEX technologies the IML is currently developing MHC class II tetramers that willbe available in the coming months to track and quantitate antigen specific CD4 T cells in response toimmunotherapy. In addition the IML is actively working with other institutions to harmonize validation assays fortetramer staining of patient samples. The IML works to customize assays for maximal data recovery from raresamples has the flexibility to develop new protocols and has been responsive to calls for the newesttechnologies to support our clinicians and scientists. +No NIH Category available 3-Dimensional;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Research;Clinical Trials;Dedications;Development;Discipline of Nuclear Medicine;Ensure;Evaluation;Functional Imaging;Goals;Image;Imaging Device;Industry;Institution;Laboratories;Magnetic Resonance Imaging;Measurement;Medical center;Metabolic;Monitor;National Clinical Trials Network;Phase;Physicians;Play;Positron-Emission Tomography;Protocol Compliance;Qualifying;Quality Control;Radiology Specialty;Reproducibility;Research;Research Personnel;Resource Sharing;Services;Site;Software Tools;Specific qualifier value;Therapeutic Intervention;Therapeutic Trials;Tumor Biology;Tumor Markers;Tumor Volume;Universities;Washington;X-Ray Computed Tomography;anatomic imaging;anticancer research;cancer clinical trial;data exchange;imaging biomarker;imaging modality;imaging science;imaging study;improved;medical schools;member;molecular imaging;novel;novel strategies;participant enrollment;protocol development;quantitative imaging;radiologist;response;success;treatment response;tumor Imaging and Response Assessment Core n/a NCI 10689765 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6486 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 313852 199271 114581 IMAGING AND RESPONSE ASSESSMENT CORE (IRAC) SHARED RESOURCE: PROJECT SUMMARYThe Imaging and Response Assessment Core (IRAC) is a shared resource (SR) operated by the Department ofRadiology within the Washington University School of Medicine (WUSM). The IRAC facilitates research byproviding support services and analysis for both standard and novel imaging methods used for characterizingtumor biology and predicting and monitoring response to therapy in patients enrolled in clinical trials performedat the Siteman Cancer Center (SCC). To accomplish this the IRAC provides a variety of services to investigatorsincluding: 1) assistance with protocol development; 2) imaging-related regulatory services; 3) site qualification;4) coordination of imaging examinations to ensure protocol compliance; 5) data transfer to trial sponsors orexternal core laboratories; and 6) tumor measurements on both anatomical and functional imaging studiesperformed by dedicated radiologists and nuclear medicine physicians. Additionally the IRAC implements newsoftware tools to improve the accuracy and reproducibility of tumor measurements and to allow for incorporationof newer approaches of tumor measurement (for example three-dimensional volumetric measurements andmetabolic tumor volume) into clinical trials at SCC. The overall goal of IRAC is to increase the impact that quantitative imaging plays in clinical cancer research.The IRAC provides unique imaging management and analysis services that are not available elsewhere withinthe WUSM. The SCC has a large portfolio of clinical trials that use computed tomography (CT) magneticresonance imaging (MRI) and positron emission tomography (PET) and the IRAC contributes to the overallsuccess of SCC trials by providing these imaging support services to investigators. +No NIH Category available Acceleration;Bioinformatics;Biostatistics Core;Brain;Budgets;Collaborations;Communication;Data Set;Development;Ensure;Equity;Fostering;Goals;Grant;Individual;Institution;Investigation;Laboratories;Monitor;Neoplasms;Principal Investigator;Productivity;Progress Reports;Reporting;Research;Research Personnel;Resources;Saint Jude Children's Research Hospital;Schedule;Site;Strategic Planning;United States National Institutes of Health;Universities;Videoconferencing;Visit;Work;conflict resolution;data integration;meetings;member;programs;success;synergism CORE A - Administration Core NarrativeThe Administrative Core functions as a central resource to maximize interactions through efficient coordinationof the individual Projects and Core Laboratories so that the Program as a whole can achieve its goals. The Corefacilitates interactions between Program members monitors progress and core usage and is responsible foradministrative oversight and budget management. NCI 10689764 9/8/23 0:00 PAR-20-077 5P01CA096832-18 5 P01 CA 96832 18 4/1/03 0:00 8/31/26 0:00 ZCA1-RPRB-H 6485 1924585 "BAKER, SUZANNE J" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 15567 8971 6596 Summary/AbstractThe Administrative Core functions as a central resource to maximize interactions through efficient coordinationof the four individual Projects and two Scientific Cores so that the Program as a whole can achieve its goals. Dr.Baker the Principal Investigator of the P01 serves as the director of the Administrative Core and she will haveprimary responsibility for the overall conduct of the Program Project. The Administrative Core will continue toorganize regular Program meetings of the Project and Core Leaders to facilitate communication maximizecollaborative interactions among the individual members of the Program and to provide a forum to share andmonitor progress of the group. The Core will also organize regular work-in-progress seminars given by lab staffand Leaders from each Project and Scientific Core to report progress foster collaboration and provideinformation about conceptual and technical advances. Dr. Gilbertson participates in Program meetings fromCambridge University through videoconferencing. The Administrative Core is responsible for generaladministrative oversight of all of the Projects and Cores and budgetary management of the program.Centralization of these activities promotes efficient management of program resources and will significantlyfacilitate communication between Project and Core Leaders. The Administrative Core will provide centralizedadministrative assistant support and will assist with scheduling of monthly program meetings of Project andCore Leaders regular discussions and interactions with the Internal Advisory Board External Advisory Boardvisits and preparing quarterly and yearly financial reports and yearly progress reports. Dr. Baker will ensurethat the research performed through this Program Project is in compliance with NIH and Institutionalrequirements. +No NIH Category available Address;Affect;Animal Hospitals;Antibodies;Antibody-drug conjugates;Biochemical;Biological;Biological Assay;Biological Process;Blood - brain barrier anatomy;Brain;CTNNB1 gene;Cell Fate Control;Cell Surface Proteins;Cell membrane;Cells;Cellular Stress;ChIP-seq;Chemotherapy and/or radiation;Child;Clinical;Clinical Trials;Combined Modality Therapy;Complement;Conventional Surgery;Data;Development;Drug Kinetics;Funding;Genes;Genetic;Genetic Transcription;Genomics;Goals;Hospitals;House mice;Immune response;Immunotherapy;In Vitro;Link;Malignant - descriptor;Maps;Mediating;Molecular;Mus;Mutate;Mutation;Neoplasms;Operative Surgical Procedures;Outcome;Paracrine Communication;Patients;Pattern;Pharmacodynamics;Phenotype;Preclinical Testing;Predisposition;Process;Proteome;RNA Helicase;Radiation therapy;Regulation;Resistance;SHH gene;Series;Signal Transduction;Survivors;Testing;Therapy trial;Toxic effect;Translating;Translations;Tumor Subtype;Work;biological adaptation to stress;blood-brain barrier disruption;chemotherapy;curative treatments;hindbrain;in vivo;insight;irradiation;medulloblastoma;mouse model;mutant;neoplastic cell;nerve stem cell;neurodevelopment;neurosurgery;novel;novel therapeutics;paralogous gene;pre-clinical;side effect;targeted treatment;therapeutically effective;transcriptome sequencing;treatment response;tumor Regulation of Cell Fate and Treatment Response in WNT Medulloblastoma PROJECT NARRATIVEMedulloblastoma (MB) comprises four distinct subtypes with different cellular and molecular origins and differentclinical outcomes. We will investigate how DDX3X the second most frequently mutated MB gene affecting threeMB subtypes patterns the hindbrain and suppresses MB. We will identify novel effective therapeutic approachesto minimize debilitating long-term toxicities for patients with the WNT-MB subtype. NCI 10689762 9/8/23 0:00 PAR-20-077 5P01CA096832-18 5 P01 CA 96832 18 4/1/03 0:00 8/31/26 0:00 ZCA1-RPRB-H 6484 14091257 "GILBERTSON, RICHARD " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 236943 234882 2061 ABSTRACTWe have identified mutations in the X-linked RNA helicase DDX3X as the second most frequent mutation inmedulloblastoma (MB). We now show that DDX3X: (i) orchestrates normal hindbrain patterning anddevelopment; (ii) suppresses the initiation of Wnt and Shh MB; (iii) restricts the susceptibility of specific NPCs togenerate these tumors; and (iv) serves as a `rheostat' in the stress response regulating global patterns of genetranscription and translation and live-die `decisions. Our studies also helped explain why WNT-MBs areeminently curable. We showed that paracrine signals driven by mutant CTNNB1 in WNT-MB disrupts the bloodbrain barrier (BBB) permitting the accumulation of high levels of intra-tumoral chemotherapy and a robusttherapeutic response. Here we will continue our focus on WNT-MB to address three new Specific Aims that will:determine how DDX3X regulates cell fate decisions in the normal and malignant hindbrain; generate novelimmunotherapies of WNT MB; and translate new treatments of WNT MB to clinical trial. +No NIH Category available Acceleration;Accreditation;Area;Artificial Intelligence platform;Basic Science;Bioinformatics;Biological Assay;Biological Markers;CLIA certified;Cancer Center;Cancer Center Support Grant;Cancer Patient;Clinical;Clinical and Translational Science Awards;Collaborations;Data Analyses;Dedications;Development;Diagnostic;Environment;Experimental Designs;Faculty;Fee-for-Service Plans;Floor;Genome;Genomics;Goals;Informatics;Infrastructure;Laboratories;Machine Learning;Malignant Neoplasms;Memory;Microarray Analysis;Modeling;Nature;Oncology;Polymerase Chain Reaction;Positioning Attribute;Preparation;Procedures;Program Research Project Grants;Publications;Quality Control;Research;Research Personnel;Resource Sharing;Sampling;Scientist;Services;Specimen;Technology;Translations;Universities;Validation;Vision;Washington;Work;analytical tool;cancer clinical trial;cancer genomics;clinical care;clinical sequencing;computational platform;cost effective;data management;design;disorder prevention;exome;fighting;forest;innovative technologies;invention;member;neoantigens;next generation;next generation sequencing;novel;operation;service providers;square foot;structural genomics;tool;vaccine trial Genome Technology Access Center n/a NCI 10689761 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6483 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 330610 209911 120699 GENOME TECHNOLOGY ACCESS CENTER (GTAC) SHARED RESOURCE: PROJECT SUMMARYCancer genomics is widely studied and integral to the understanding treatment and prevention of the disease.The Genome Technology Access Center (GTAC) a shared resource within the McDonnell Genome Institute(MGI) is one of the largest genomic centers in the nation and provides full access to its considerable assaystools technology and expertise to Siteman Cancer Center (SCC) members to enable advances in the fightagainst cancer. The common infrastructure of GTAC occupies 27000 sq ft. of space and is staffed byapproximately 75 scientists and technicians that support both service functions and program project research.Within this space GTAC operates both research specific and CAP/CLIA-certified clinical genomics operations. As GTAC is a SCC-supported facility the close working relationship between GTAC faculty and staff andcancer researchers streamlines the design execution and interpretation of all applied genomic assays.Furthermore the dual nature as both a research and CAP/CLIA-certified clinical genomics service provider offersinvestigators a complete translational path for their research efforts. The GTAC provides next-generationsequencing (NGS) microarray analyses high-throughput PCR and a number of other specialized services. NGSmicroarrays and PCR are also available within the CAP/CLIA-certified laboratories. The combination of scale availability and expertise in the application of genomic technologies has enableda great deal of impactful research. During the project period the GTAC (~500) and MGI (~1400) have enableda combined 1900 publications as reference/acknowledgment co-authors or authors with a substantialpercentage dedicated to oncology research. Within this substantial body of research key advances include thedevelopment of a laboratory and bioinformatic workflow to support neo-epitope selection in vaccine trials thedevelopment of new clinical assays including the AML exome and Myeloseq and the invention of novelcomputational platforms such as COMPBIO. +No NIH Category available Alleles;Animal Model;Area;Automation;Blood coagulation;CD34 gene;CRISPR screen;CRISPR/Cas technology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Model;Cancer cell line;Cell Count;Cell Differentiation process;Cell Line;Cell model;Cells;Characteristics;Chromosomes;Clone Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Consultations;Cost Savings;DNA;Data Analyses;Deposition;Development;Disease;Disease model;Electroporation;Embryo;Engineering;Ensure;Epigenetic Process;Ethnic Origin;Gene Activation;Gene Silencing;Generations;Genes;Genetic;Genome;Genome engineering;Genomics;Goals;Guide RNA;Hematopoietic stem cells;Kidney;Libraries;LoxP-flanked allele;Macrophage;Malignant Neoplasms;Mediating;Methods;Microinjections;Mus;Neoplasm Metastasis;Neurons;Oligonucleotides;Organism;Patients;Peripheral;Pharmaceutical Preparations;Phase;Physiological;Proliferating;Protocols documentation;Publishing;Reagent;Reproducibility;Research Personnel;Resource Sharing;Ribonucleoproteins;Sampling;Services;Short Tandem Repeat;Site;Specificity;Speed;Surveys;System;Technology;Testing;Time;Tissue Expansion;Tissues;Universities;Variant;Washington;Whole Blood;base editor;cell growth;cell type;design;differentiation protocol;ethnic diversity;experience;flexibility;functional genomics;genetic manipulation;genetic variant;genome sequencing;human embryonic stem cell;improved;induced pluripotent stem cell;interest;member;mouse model;nerve stem cell;next generation sequencing;nuclease;process improvement;programs;repository;screening;success;timeline;tool;treatment response;tumor;tumor growth;whole genome Genome Engineering and iPSC Center n/a NCI 10689753 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6480 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 257489 163485 94004 GENOME ENGINEERING AND iPSC CENTER (GEiC) SHARED RESOURCE: PROJECT SUMMARY(iPSC: induced pluripotent stem cells)The past five years witnessed the extraordinary development of CRISPR technology for genome manipulation.The Genome Engineering and iPSC Center (GEiC) shared resource (SR) grows as the technology matures. Atlast renewal the GEiC was a new SR with five FTEs at a fairly early stage of establishing CRISPR-involvingworkflows. Today we have 14.5 FTEs with a wide range of service offerings to meet the various needs and levelsof Siteman Cancer Center (SCC) members on cell (both cancer and iPS cells) and animal models. In the pastfive years the GEiC has completed over 500 engineering projects in various cancer cell lines and another 200in iPSC and hESCs designed and validated reagents for over 350 mouse models validated 3500 gRNAsbanked over 400 patient samples and reprogrammed over 110 lines of patient-derived iPSCs. New services launched include 1) banking and reprogramming from whole blood including clotted bloodallowing great flexibility for patient sample submission 2) differentiation of iPSCs into various tissue types neuralstem cells peripheral neuronal cells hematopoietic stem cells CD34+ cells and macrophages 3) libraryconstruction for CRISPR screens and data analysis 4) reagents for CRISPR-mediated gene activation andinactivation and the use of base editor for introducing SNPs without cleaving the chromosomes 5) nextgeneration sequencing-based short tandem repeat (STR) profiling for cell line authentication. Additionally wemade significant process improvement in cell and animal model creation such as optimized single cell cloningefficiency during gene editing of iPSCs increased efficiency and consistency of SNP introduction by usingCRISPR ribonucleoprotein complex with end protected single stranded oligo DNA donors and electroporationof single-cell mouse embryos instead of microinjection which allows us to achieve over 95% success rate onobtaining the challenging conditional alleles (floxing) in mice. In the next project period we will build on our success and strive to make disease modeling more relevantand accessible to SCC members. We will expand the tissue types that can be differentiated from iPSCs andestablish protocols for simultaneous reprogramming and editing of iPSCs for speedier disease/correctedisogenic pair creation and for reversible immortalization to proliferate primary cell types without losing theirphysiological characteristics. We are also working on establishing a repository for healthy iPSC controls ofvarious ethnic backgrounds and further improving genome engineering efficiency in cells and embryos throughautomation and process improvement. In the meantime we will keep up with advancement in the fields ofgenome engineering and iPSCs and ensure SCC members are served with the most up-to-date technologies. +No NIH Category available 3-Dimensional;ACVR1 gene;Acceleration;Address;Anaplastic astrocytoma;Automobile Driving;Bioinformatics;Biometry;Brain;Brain Stem;Brain Stem Glioma;Brain Stem Neoplasms;CRISPR/Cas technology;Cell Line;Cell Lineage;Cells;Child;Childhood Brain Neoplasm;Childhood Brain Stem Neoplasm;Childhood Glioma;Complement;Complex;Data;Dependence;Development;Diffuse intrinsic pontine glioma;Embryo;Embryonic Induction;Epigenetic Process;Etiology;Event;FRAP1 gene;Gene Expression Profile;Genes;Genetically Engineered Mouse;Glioma;Gliomagenesis;Goals;Growth;H3 K27M mutation;Heterogeneity;Histone H3;Incidence;Induced Mutation;Invaded;Investigation;Knock-in Mouse;Lesion;Link;Location;Maintenance;Mediating;Methylation;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mutate;Mutation;Neonatal;Neoplasms;Oncogenic;Organ;PIK3CA gene;PIK3CG gene;Pathogenesis;Pathway Analysis;Pathway interactions;Patients;Pattern;Phenotype;Physiological;Polycomb;Recurrence;Regulation;Research;Role;Signal Transduction;Solvents;Source;Structure;Supratentorial;TP53 gene;Therapeutic;Three-Dimensional Imaging;Xenograft procedure;age related;cell type;design;experimental study;glial cell development;glioma cell line;hindbrain;improved;in vivo;inhibitor;insight;knock-down;loss of function;loss of function mutation;medulloblastoma;mortality;mouse model;neuropathology;novel;oligodendrocyte lineage;oligodendrocyte progenitor;patient derived xenograft model;precision medicine;preference;promoter;response;spatiotemporal;stem cells;therapeutic target;transcriptome;treatment response;tumor;tumor growth;tumor initiation;tumorigenesis Molecular Pathogenesis of Pediatric High-Grade Glioma Project 1 NarrativeDiffuse intrinsic pontine gliomas (DIPG) are incurable brainstem tumors arising almost exclusively in children.This project will determine how disrupted glial development contributes to DIPG tumorigenesis why particularmutations are selectively associated with brainstem or midline gliomas and what molecular features modulatetumor response to inhibitors of pathways mutated in DIPG. NCI 10689751 9/8/23 0:00 PAR-20-077 5P01CA096832-18 5 P01 CA 96832 18 4/1/03 0:00 8/31/26 0:00 ZCA1-RPRB-H 6479 1924585 "BAKER, SUZANNE J" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 451768 251981 199787 Project SummaryDiffuse intrinsic pontine glioma (DIPG) is an incurable childhood brainstem tumor with an intimateconnection between developmental context and tumor etiology. We and others identified histone H3K27M mutations in 80% of DIPG and midline high-grade glioma. Multiple lines of evidence from ourgroup and others show oligodendrocyte progenitor cells (OPCs) as the predominant cell-type expressionsignature in DIPG. It remains unclear why the K27M selective advantage is so strongly associated withmidline and hindbrain development and spatiotemporal differences in the impact of K27M onoligodendrocyte lineage cell state has not been investigated. We will employ genetically engineered mice(GEM) in which H3.3 K27M is regulated by the endogenous promoter to study regional and age-dependent effects of epigenetic dysregulation and tumorigenesis in the physiological context of a fulldeveloping brain. We hypothesize that the cell state in which K27M confers a selective advantageremains essential for tumor maintenance. Therefore regulators of cell state may be dependencies forDIPG even if their expression is not directly dysregulated by K27M. We will evaluate candidate K27Mtargets and regulators of OPC cell state to determine if these can override the effects of K27M indeveloping oligodendrocyte lineage and inhibit DIPG growth and/or survival. We will also leveragemultiple GEM models combining relevant DIPG mutations to investigate spatiotemporal selection in earlystages of gliomagenesis and later patterns of glioma invasion in the context of 3-dimensional brainstructure. Other recurrent DIPG mutations are potential therapeutic targets including ACVR1 mutationsfound exclusively in DIPG and PI3K pathway mutations found in pediatric high-grade gliomas from alllocations and arising as later events in tumorigenesis. We will use patient-derived DIPG cell lines andorthotopic xenografts and brain-penetrant selective pathway inhibitors to determine the independent andcooperative effects of dysregulated ACVR1 and PI3K/mTOR signaling on DIPG tumor growth and toinvestigate heterogeneity in therapeutic response. The proposed studies are well-integrated with theoverall programmatic goal to improve understanding and treatment of diffuse intrinsic pontine glioma andmedulloblastoma which cause devastating mortality and morbidity in children. Integrating themespursued in this Project and other Projects in the P01 include investigations of epigenetic dysregulation(with Project 2) connections between disrupted development and tumorigenesis (with Projects 3 and 4)and therapeutic vulnerabilities of pediatric brain tumors (with Projects 2 and 4). The Research Cores willprovide expert support in Bioinformatics and Biostatistics (Core B) and Neuropathology (Core C). +No NIH Category available ACVR1 gene;Address;Antibody-drug conjugates;Automobile Driving;Basic Science;Biological Models;Biometry;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cancer Etiology;Cell Lineage;Cell membrane;Cells;Child;Childhood;Childhood Brain Neoplasm;Childhood Glioma;Clinical Trials;Collaborations;Competence;Complex;Data;Dependence;Development;Developmental Process;Diffuse intrinsic pontine glioma;Disease;Drug Combinations;Epigenetic Process;Experimental Designs;FDA approved;FRAP1 gene;Functional disorder;Funding;Genes;Goals;Growth;H3 K27M mutation;Heterogeneity;Immunotherapy;Maintenance;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Maps;Methyltransferase;Molecular;Morbidity - disease rate;Mutate;Mutation;Neoplasms;PIK3CG gene;Paper;Pathogenesis;Pathway interactions;Pediatric Neoplasm;Pharmaceutical Preparations;Phenotype;Play;Preclinical Testing;Predisposition;Productivity;Proteome;Publishing;Regulation;Research Personnel;Resources;Role;SHH gene;SMYD3 gene;Seminal;Series;Solid;Source;Study models;Susceptibility Gene;Techniques;Testing;Therapeutic;Therapeutic Intervention;Transcriptional Regulation;Translating;Translational Regulation;Translations;Tumor Subtype;Variant;Work;antibody test;biological adaptation to stress;cancer predisposition;childhood cancer mortality;data integration;drug testing;epigenome;experience;experimental study;hindbrain;human disease;improved;inhibitor;insight;loss of function;mTOR inhibition;medulloblastoma;member;mortality;neuropathology;next generation sequence data;novel;novel therapeutics;oligodendrocyte lineage;patient derived xenograft model;programs;response;spatiotemporal;success;therapeutic evaluation;therapeutic target;transcriptome;translational impact;treatment response;tumor;tumor initiation;tumorigenesis NORMAL & NEOPLASTIC GROWTH IN THE BRAIN Overall Program NarrativeBrain tumors are the most common pediatric solid malignancies and the leading cause of cancer-related deathin children. This program will continue to advance understanding of the mechanisms driving diffuse intrinsicpontine glioma and multiple subtypes of medulloblastoma. The Program also investigates therapeuticvulnerabilities for these childhood brain tumors that inflict significant morbidity and mortality. NCI 10689750 9/8/23 0:00 PAR-20-077 5P01CA096832-18 5 P01 CA 96832 18 "FINGERMAN, IAN M" 4/1/03 0:00 8/31/26 0:00 ZCA1-RPRB-H(M1)P 1924585 "BAKER, SUZANNE J" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1864889 NCI 1143610 721279 Overall Program SummaryBrain tumors are the most common pediatric solid malignancies and the leading cause of cancer-related deathin children. The long-term goal of this Program Project is to improve understanding and treatment of diffuseintrinsic pontine glioma (DIPG) and medulloblastoma (MB) which cause devastating mortality and morbidity inchildren. Over the last funding period P01 investigators Baker Roussel and Gilbertson demonstrated importantcontributions of epigenetic dysregulation in DIPG and MB a role for pediatric brain tumor mutations in stressresponse and therapeutic vulnerabilities in MB subtypes. P01 Investigator Northcott joins as a new Projectleader with a proposal based on the discovery of a new MB cancer predisposition gene. This highly interactiveteam proposes an integrated series of experiments to leverage recent progress and the most advancedtechniques to investigate aberrant cell fate/cell state regulation to determine the contribution of epigenometranscriptome and proteome dysregulation to disrupted development and tumorigenesis and to identifydevelopmental and epigenetic functional dependencies and test therapeutic vulnerabilities of pediatric hindbraintumors. In Project 1 S Baker is focused on the contribution of H3K27M mutations in disrupted developmenttumor initiation and spatiotemporal selectivity of tumorigenesis and how cooperative contributions of ACVR1and PI3K/mTOR pathways influence heterogeneity of therapeutic response to selective inhibitors. In Project 2M Roussel investigates the role of the methyltransferase SMYD3 and tests drug combinations that enhanceefficacy of methyltransferase inhibitors in the Group 3 MB subtype. In Project 3 P Northcott evaluates how lossof function in ELP1 drives MB predisposition perturbs regulation of translation elongation and cooperates withother mutations in the SHH-MB subtype. In Project 4 R Gilbertson investigates how DDX3X mutations disruptcell fate decisions transcription and translation regulation and investigates novel therapies to exploit thedefective blood-brain-barrier in WNT-MB. All four projects rely on the outstanding expertise in Core B where allnext-generation sequence data will be analyzed including integrated cross-comparison of data from multipleprojects and rigorous biostatistical approaches will be applied for experimental design and interpretation. CoreC is integral to all projects and will provide expert neuropathological review of all tumor models studied in theprogram to assess their similarity and relevance to primary human disease and will assist with phenotypeanalyses and optimizing immunohistochemical analyses. The collective efforts of the Program will impact ourunderstanding of disease pathogenesis of DIPG and MB extend beyond pediatric hindbrain tumors to enhanceunderstanding of how aberrant regulation of the epigenome transcriptome and proteome disrupt normaldevelopment and contribute to cancer. Our success is guaranteed by our strong track record of productivecollaborations the unique resources and the outstanding Cores to facilitate the acquisition exchange andintegration of data. 1864889 +No NIH Category available Applications Grants;Area;Award;Behavioral;Biological Markers;Biometry;Biostatistics Shared Resource;Biotechnology;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Collaborations;Communities;Comparative Effectiveness Research;Computer Systems;Computer software;Consultations;Data;Data Analyses;Data Collection;Databases;Development;Disease;Doctor of Philosophy;Electronic Health Record;Ensure;Evaluation Studies;Faculty;Funding;Futility;Goals;Growth;Immunotherapeutic agent;Infrastructure;Institution;Intervention;Investments;Journals;Life Cycle Stages;Malignant Neoplasms;Manuscripts;Methodology;Methods;Monitor;Multi-Institutional Clinical Trial;NCI Center for Cancer Research;National Cancer Institute;Peer Review;Persons;Phase;Precision Medicine Initiative;Preventive;Procedures;Productivity;Protocols documentation;Publications;Randomized;Reproducibility;Research;Research Design;Research Methodology;Research Personnel;Research Project Grants;Research Proposals;Resource Sharing;Resources;Role;Safety;Sample Size;Science;Services;Statistical Data Interpretation;Statistical Methods;Study Section;Toxic effect;Training;Translational Research;Validation;anticancer research;biomarker discovery;cancer immunotherapeutics;data management;design;early phase clinical trial;genomic data;health record;high dimensionality;innovation;instructor;member;novel;outreach;patient safety;pre-clinical;programs;protocol development;quality assurance;recruit;risk prediction;risk stratification;sound;spatiotemporal;student mentoring;tool Biostatistics Shared Resource n/a NCI 10689749 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6478 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 300566 190836 109730 BIOSTASTICS SHARED RESOURCE (BSR): PROJECT SUMMARYThe Biostatistics Shared Resource (BSR) provides Siteman Cancer Center (SCC) research programs withaccess to cancer-focused statistical expertise including design of early phase clinical trials longitudinal dataanalysis biomarker discovery statistical methods for high dimensional genomic data and risk prediction/riskstratification development and validation. BSR statisticians are integrally involved in all seven SCC researchprograms with 142 SCC member users in 2018. They function as scientific collaborators in clinical trial andinterventional protocols; advising on and participating in study design creating and managing researchdatabases overseeing statistically relevant issues in trial/project implementation conducting interim and finaldata analyses presenting research data/methods and interpreting results. BSR contributes to research rigorand reproducibility through active involvement in scientific review and oversight activities. In collaboration withthe SCC Clinical Trials Core (CTC) BSR statisticians develop study-specific data collection forms and conductdata monitoring. BSR faculty serve on the SCC Protocol Review and Monitoring Committee (PRMC) and theSCC Quality Assurance and Safety Monitoring Committee (QASMC) providing statistical reviews of all newprotocols and assuring proper statistical conduct of all active protocols. BSR faculty collaborate on numerousNational Cancer Institute-funded projects and have contributed significantly to the high quality science andresearch productivity of SCC programs. In the current project period alone BSR faculty have authored over250 peer-reviewed statistical methodology and cancer-related publications with 44 in high-impact journals(Thomson Reuters impact factor of 10 or greater). This contribution illustrates the wide range of research andmethodologic expertise available to SCC members through the BSR. In the next project period BSR willcontinue to grow with increased capacity in statistical support for electronic health record-based comparativeeffectiveness research cancer immunotherapeutic trials biomarker studies and precision medicine initiatives. +No NIH Category available Acceleration;Address;Algorithms;B-Lymphocytes;Biological Assay;Cancer Burden;Cancer Etiology;Caribbean region;Caring;Cessation of life;Child;Clinic;Clinical;Clinical Trials;Collaborations;Collection;Communication;Country;Dedications;Diagnosis;Dominican Republic;Dose;Ensure;Future;Future Generations;General Population;Goals;HIV;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Immunotherapy;Incidence;Infrastructure;Interruption;Laboratories;Latin America;Lesion;Malignant neoplasm of cervix uteri;Minority;Modeling;Monitor;National Cancer Institute;Persons;Peru;Population;Prevention;Prevention approach;Prevention strategy;Primary Care;Primary Prevention;Productivity;Protocols documentation;Provider;Quality Control;Regimen;Research Personnel;Resource-limited setting;Resources;Safety;Sampling;Schedule;Site;Statistical Data Interpretation;Time;Training;Triage;Vaccination;Vaccines;Visit;Vulnerable Populations;Woman;Work;cancer prevention;cancer therapy;cervical cancer prevention;cost;data management;design;effectiveness testing;experience;immunogenicity;improved;low and middle-income countries;mortality;new technology;novel;novel strategies;premalignant;programs;recruit;response;screening;statistics;success;treatment strategy Project-002 The Cervical Cancer Prevention Partnership (C2P2) program is a collaboration between investigators in theUS (Seattle) Peru (Lima) and the Dominican Republic (Santo Domingo). It has the following goals: 1) buildingstrong and collaborative partnerships both among investigators at these sites and between site investigatorsand the National Cancer Institute and 2) conducting trials in Peru and the Dominican Republic to address thecervical cancer prevention and treatment needs of HIV-infected populations. NCI 10689747 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6477 2478519 "MADELEINE, MARGARET M" "CABELLO, ROBINSON ; DUERR, ANN C" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 475984 441498 185814 Worldwide cervical cancer is the fourth leading cause of cancer incidence and mortality; 80% of cervicalcancers arise and 87% of cervical cancer deaths occur in low and lower-middle income countries. In Perucervical cancer is diagnosed at a rate of 17 per 100000 women per year and in the DR at 23 per 100000annually among women in the general population. The burden of cervical cancer is substantially increasedamong women living with HIV (WLWH) although the exact rates are not well described. Although HPVvaccines are safe and effective as primary prevention they have limited availability in low resource settingsand the optimal regimen of vaccine doses for HIV-infected persons in such settings has not been defined.Furthermore delivery of cervical cancer prevention and treatment of precursors for WLWH in low- and middle-incomecountries is impeded by approaches that are often costly require multiple visits and extensive providertraining. Moreover many of these are not suitable for delivery within an HIV primary care model.The Cervical Cancer Prevention Partnership (C2P2) Center involves two clinical trial sites in Peru and theDominican Republic and three cores (Administrative and Coordinating Core Statistics and Data ManagementCore and Central Laboratory Core) in Seattle. Investigators in the C2P2 Center will jointly design conduct andanalyze three clinical trials with the goal of moving toward elimination of cervical cancer among highlyvulnerable populations with HIV in low resource settings in Latin America and the Caribbean (LAC). We seekto improve the quality and efficiency of prevention strategies using new approaches that will augment theexisting infrastructure at local HIV clinics in Peru and the Dominican Republic (DR). The aims of theproposed Clinical Trials Center span the continuum of cervical cancer prevention from vaccinationthrough treatment. The trials we propose will address these technical issues and provide a more direct pipelinefor prevention. In this C2P2 Center our overarching aims are: Specific Aim 1: To test the effectiveness of novel approaches to cervical cancer prevention in high-burdenHIV-infected populations in Peru and the DR by performing three clinical trials. One will assessthe ability of HPV vaccination regimens to elicit long-lasting B cell responses and two will assess novelscreening triage and treatment approaches that will improve the quality and reach of prevention inlow-resource settings throughout the LAC region. Specific Aim 2: To build a robust multidirectional collaboration between study investigators at all sitesthat serves the needs of providers who care for women living with HIV. The Center will engage withleaders in the region to enhance the sustainability of efforts that target future elimination of cervicalcancer through multiple high-impact prevention and treatment strategies. +No NIH Category available Acceleration;Address;Algorithms;B-Lymphocytes;Biological Assay;Cancer Burden;Cancer Etiology;Caribbean region;Caring;Cessation of life;Child;Clinic;Clinical;Clinical Trials;Collaborations;Collection;Communication;Country;Dedications;Diagnosis;Dominican Republic;Dose;Ensure;Future;Future Generations;General Population;Goals;HIV;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Immunotherapy;Incidence;Infrastructure;Interruption;Laboratories;Latin America;Lesion;Malignant neoplasm of cervix uteri;Minority;Modeling;Monitor;National Cancer Institute;Persons;Peru;Population;Prevention;Prevention approach;Prevention strategy;Primary Care;Primary Prevention;Productivity;Protocols documentation;Provider;Quality Control;Regimen;Research Personnel;Resource-limited setting;Resources;Safety;Sampling;Schedule;Site;Statistical Data Interpretation;Time;Training;Triage;Vaccination;Vaccines;Visit;Vulnerable Populations;Woman;Work;cancer prevention;cancer therapy;cervical cancer prevention;cost;data management;design;effectiveness testing;experience;immunogenicity;improved;low and middle-income countries;mortality;new technology;novel;novel strategies;premalignant;programs;recruit;response;screening;statistics;success;treatment strategy Project-001 The Cervical Cancer Prevention Partnership (C2P2) program is a collaboration between investigators in theUS (Seattle) Peru (Lima) and the Dominican Republic (Santo Domingo). It has the following goals: 1) buildingstrong and collaborative partnerships both among investigators at these sites and between site investigatorsand the National Cancer Institute and 2) conducting trials in Peru and the Dominican Republic to address thecervical cancer prevention and treatment needs of HIV-infected populations. NCI 10689744 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6476 2478519 "MADELEINE, MARGARET M" "CABELLO, ROBINSON ; DUERR, ANN C" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 234732 326055 20435 Worldwide cervical cancer is the fourth leading cause of cancer incidence and mortality; 80% of cervicalcancers arise and 87% of cervical cancer deaths occur in low and lower-middle income countries. In Perucervical cancer is diagnosed at a rate of 17 per 100000 women per year and in the DR at 23 per 100000annually among women in the general population. The burden of cervical cancer is substantially increasedamong women living with HIV (WLWH) although the exact rates are not well described. Although HPVvaccines are safe and effective as primary prevention they have limited availability in low resource settingsand the optimal regimen of vaccine doses for HIV-infected persons in such settings has not been defined.Furthermore delivery of cervical cancer prevention and treatment of precursors for WLWH in low- and middle-incomecountries is impeded by approaches that are often costly require multiple visits and extensive providertraining. Moreover many of these are not suitable for delivery within an HIV primary care model.The Cervical Cancer Prevention Partnership (C2P2) Center involves two clinical trial sites in Peru and theDominican Republic and three cores (Administrative and Coordinating Core Statistics and Data ManagementCore and Central Laboratory Core) in Seattle. Investigators in the C2P2 Center will jointly design conduct andanalyze three clinical trials with the goal of moving toward elimination of cervical cancer among highlyvulnerable populations with HIV in low resource settings in Latin America and the Caribbean (LAC). We seekto improve the quality and efficiency of prevention strategies using new approaches that will augment theexisting infrastructure at local HIV clinics in Peru and the Dominican Republic (DR). The aims of theproposed Clinical Trials Center span the continuum of cervical cancer prevention from vaccinationthrough treatment. The trials we propose will address these technical issues and provide a more direct pipelinefor prevention. In this C2P2 Center our overarching aims are: Specific Aim 1: To test the effectiveness of novel approaches to cervical cancer prevention in high-burdenHIV-infected populations in Peru and the DR by performing three clinical trials. One will assessthe ability of HPV vaccination regimens to elicit long-lasting B cell responses and two will assess novelscreening triage and treatment approaches that will improve the quality and reach of prevention inlow-resource settings throughout the LAC region. Specific Aim 2: To build a robust multidirectional collaboration between study investigators at all sitesthat serves the needs of providers who care for women living with HIV. The Center will engage withleaders in the region to enhance the sustainability of efforts that target future elimination of cervicalcancer through multiple high-impact prevention and treatment strategies. +No NIH Category available Advertising;Area;Award;Basic Science;Biomedical Research;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cancer Research Project;Career Choice;Clinical Research;Communities;Critical Thinking;Data;Doctor of Philosophy;Education;Educational Activities;Educational Status;Educational workshop;Eligibility Determination;Ensure;Environment;Evaluation;Faculty;Foundations;Funding;Funding Agency;Future;Goals;Grant;Individual;Infrastructure;Institution;Knowledge;Leadership;Learning;Malignant Neoplasms;Mentored Clinical Scientist Development Program;Mentors;Mentorship;Minority Recruitment;Monitor;NCI Center for Cancer Research;Participant;Patient-Focused Outcomes;Patients;Physicians;Recommendation;Recording of previous events;Reporting;Research;Research Personnel;Research Training;Resources;Safety;Science;Scientist;Structure;Students;Teacher Professional Development;Training;Training Activity;Training Programs;Training and Education;Translational Research;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Vocational Guidance;Washington;Writing;anticancer research;cancer education;career;career development;community based participatory research;design;diversity and inclusion;education planning;education research;experience;high school;improved;interest;medical schools;medical specialties;meetings;member;minority trainee;minority undergraduate;programs;quality assurance;research and development;resilience;skills;success;symposium;training opportunity;undergraduate student;working group Cancer Research Career Enhancement and Related Activities n/a NCI 10689743 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6475 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 201138 127707 73431 CANCER RESEARCH CAREER ENHANCEMENT AND RELATED ACTIVITIES: PROJECT SUMMARYSiteman Cancer Center (SCC) has a strong research training environment and a long-standing record of traineesuccess. Rooted in the robust educational infrastructure of Washington University SCC enhances training andeducation initiatives available to cancer researchers and efforts to develop a more diverse cancer researchworkforce. The SCC Cancer Research Career Enhancement (CRCE) will build upon these current efforts to:1. Provide new cancer education opportunities at SCC that fill specific existing training gaps by funding new specific cancer research programs supplementing existing programs to enable more SCC member participants supporting travel to select scientific meetings and sponsoring seminars and workshops.2. Coordinate existing research education and training activities at Washington University by sharing and promoting didactic courses and other training opportunities across the spectrum from undergraduate to junior faculty. We also share lessons learned from the Cancer Biology Training Consortium (CaBTraC) meetings and the eight F eight K four T32 two K99/R00 and one K12 Calabresi award from the NCI to help identify additional training grant opportunities and slots for eligible candidates.3. Ensure effective training opportunities for underrepresented minorities (URMs) by funding the Community Research Fellows Training program requiring inclusion and diversity training for faculty and staff expanding URM recruitment for cancer research training and enhancing URM retention efforts.4. Develop new initiatives to enhance education and training opportunities by expanding existing SCC CRCE opportunities to better support the cancer research workforce and improve programming through structured evaluation and filling of existing training gaps. New efforts will include establishment of a Cancer Biology PhD program additional grant writing support hosting team science symposia as well as expansion of cancer biology courses workshops and clinical research programs across other training programs. We will also develop workshops and provide mentoring for continued development of faculty as well as for community scientists and physicians in emerging areas of cancer research.We believe the current and future SCC CRCE programming will transform the future cancer research workforce.The CRCE will do this by providing the training education and mentorship needed to successfully advancetrainees to independence. We will build upon successful existing programs and streamline efforts to train cancerresearchers throughout all specialties of the SCC. We will target some of the key needs of trainees developingfocused mentorship supportive research communities tailored career guidance and practical understanding ofavailable funding sources and grant submissions. With this foundation of support in place we believe ourinvestigators will transition to independence more quickly have the ability to focus on their patients and researchand will result in making significant contributions to cancer research and patient outcomes. +No NIH Category available Anatomy;Anogenital cancer;Antibodies;Award;Binding;Biological;Biological Assay;Biological Specimen Banks;Biopsy;Blood specimen;Board Certification;Cells;Cervical;Clinical Data;Collection;Communication;Complex;Correlative Study;DNA Viruses;Drug or chemical Tissue Distribution;Ensure;Fred Hutchinson Cancer Research Center;Future;Genotype;Grant;Histology;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human Resources;Immune;Immune Tolerance;Immunohistochemistry;Immunooncology;Industry;Institution;Laboratories;Laboratory Research;Laboratory Scientists;Laboratory Study;Leadership;Malignant Neoplasms;Memory B-Lymphocyte;Mission;Names;Papillomavirus;Pathologist;Pathology;Peripheral Blood Mononuclear Cell;Phenotype;Play;Procedures;Protocols documentation;Quality Control;Recurrence;Research Personnel;Resource Sharing;Role;Running;Sampling;Sampling Studies;Serology test;Services;Shipping;Site;Specific qualifier value;Specimen;Stress;Techniques;Technology Transfer;Testing;Tissue Banks;Tissue Sample;Tissues;Training;Work;anti-tumor immune response;biomarker development;cancer prevention;clinically relevant;epidemiology study;experience;high risk;immunopathology;laboratory experience;predicting response;quality assurance;response;tumor;tumor microenvironment Central Laboratory Core n/a NCI 10689741 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6474 10194844 "CARTER, JOSEPH JOHN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 121793 108401 50547 PROJECT SUMMARY CENTRAL LABORATORY CORE The Central Laboratory Core (CLC) will be based in Seattle within the laboratory of Dr. DeniseGalloway (co-chair of Trial 1) and include the robust services of our Shared Resources Facilities at the FredHutchinson Cancer Research Center (Fred Hutch). While Dr. Galloway is best known for her work on the rolehigh-risk human papillomaviruses (HPV) play in anogenital cancers her lab is broadly focused on the role thatsmall DNA viruses play in cancer. To aid in epidemiologic studies the Galloway lab has developed serologicassays to detect and characterize papillomavirus-specific antibodies. These latter assays will be conducted inthe CLC for trials 1 and 3 (see below). The CLC will oversee and efficiently manage and coordinate acquisition and shipping of protocol-specified biological specimens (with relevant clinical data) to appropriate laboratories for testing and to thecentral tumor/specimen repository for storage of specimens for future correlative laboratory studies. Dr. Joseph(Jody) Carter will lead the Core and manage the CLC in Seattle and will be available to advise the LACpartner institutions if required on management of sample storage testing and shipping of protocol-specificspecimens and storage of samples for current trial endpoints and for future studies. The Core will work witheach trial team to develop standard-operating protocols (SOPs) for each protocol. Dr. Carter has over 25 yearsof experience as a laboratory leader and will help each of the trials develop consistent approaches to qualitycontrol for each of the laboratory assays. Laboratory and pathology oversite provided in the Laboratory Core will be effectively matrixed witheffort provided by Fred Hutch personnel named within the trials. For example the extensive work on HPV-specific memory B cell responses conducted by Dr. Galloway's lab is included in Trial 1 but shares personneland objectives with the CLC. Placement of the CLC at the Fred Hutch will also allow access to Fred HutchShared Resources for example the Immunopathology Lab directed by Dr. Robert Pierce. Dr. Pierce is aBoard-certified Anatomic Pathologist with a strong academic and industry background in immuno-oncology.His laboratory research is focused on mechanisms of tumor-induced immune tolerance by which tumors canescape anti-tumor immune responses including natural and therapy-induced responses. He is expert in usingmultiparametric immunohistochemistry (IHC) panels to quantitatively analyze the phenotype and tissuedistribution of immune cells within the tumor microenvironment and in the development of biomarkers topredict responses to immuno-oncology treatments. Although the details of Trials 2 and 3 (delayed onset trials)will be finalized only after the grant is awarded we anticipate the Dr. Pierce will participate in training andquality assurance for pathology for trials 2 and 3 and for the correlative studies proposed for trial 3. +No NIH Category available Address;Age;Algorithms;Appointment;Bioinformatics;Biometry;Caribbean region;Child;Clinical Data;Clinical Trials;Clinical Trials Unit;Collaborations;Colposcopy;Communicable Diseases;Data;Data Collection;Data Management Resources;Diagnosis;Dominican Republic;Dose;Enrollment;Ensure;Epidemiology;Goals;HIV;HIV/AIDS;Health Sciences;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Immune;Immunotherapy;Individual;Information Dissemination;Infrastructure;International;Interruption;Latin America;Leadership;Lesion;Malignant neoplasm of cervix uteri;Methods;Mission;Monitor;Operative Surgical Procedures;Pap smear;Papillomavirus Transforming Protein E6;Persons;Peru;Physical environment;Play;Politics;Prevention;Prevention Research;Preventive Medicine;Public Health;Publications;Reporting;Research;Resource-limited setting;Role;Safety;Schedule;Science;Scientific Advances and Accomplishments;Secure;Security;Services;Sirolimus;Statistical Data Interpretation;Statistical Methods;Testing;Time;Triage;Universities;Vaccination;Vaccines;Visual;Vulnerable Populations;Washington;Woman;Work;Youth;automated visual evaluation;cancer prevention;cervical cancer prevention;clinical center;clinical database;co-clinical trial;collaborative environment;data management;design;electronic data;flexibility;immunogenicity;improved;innovation;member;new technology;point of care;premalignant;primary endpoint;professor;programs;response;screening;secondary endpoint;standard of care;statistical center;tool;treatment strategy;trial design Data Management and Statistical Core n/a NCI 10689738 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6473 12598528 "DASGUPTA, SAYAN " Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 334300 297541 138745 PROJECT SUMMARY - DATA MANAGEMENT AND STATISTICAL CORE (DMSC)The Data Management and Statistical Core (DMSC) will provide effective statistical planning and datamanagement support to optimize the successful accomplishment of the scientific aims of the Cervical CancerPrevention Partnership (C2P2) Center in Peru and the Dominican Republic. The DMSC will support theproposed Clinical Trials Program that will span the continuum of cervical cancer prevention from vaccinationthrough treatment. The clinical trials will use a new combination of prevention and treatment methods aimed atpoint-of-care and low-infrastructure support to address the burden of HPV-related cancers in HIV-infectedpersons in low-resource settings. The ultimate intent of these trials is to advance the field toward theelimination of cervical cancer among vulnerable populations with HIV. Trial 1 will identify new dosing schedulesto improve the immunogenicity of HPV vaccination among children living with HIV (CLWH). Trial 2 willascertain the contribution of new technologies to refine algorithms for screening and triage of women living withHIV (WLWH). Trial 3 will assess non-surgical immune-based treatments of precancerous lesions to interruptprogression to cervical cancer in WLWH. In Aim 1 the DMSC will provide design and analysis support for thethree clinical trials; in Aim 2 the DMSC will provide secure data management and safety monitoring services;and in Aim 3 the DMSC will advance the mission of the science through the application of innovative statisticalanalysis and methods. The DMSC leader Dr. Chen will collaborate closely with the Partnership Centersscientific leadership in the Administrative and Coordinating Core and Clinical Trial Co-Chairs to developefficient and high-quality trials that will impact the prevention of cervical cancer in the Latin America/Caribbeanregion. +No NIH Category available Accounting;Area;Award;Budgets;Businesses;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Research;Clinical Trials;Collaborations;Communication;Community Outreach;Contracts;Counseling;Development;Endowment;Ensure;Faculty;Funding;Funding Opportunities;Goals;Grant;Hospitals;Individual;Informatics;Infrastructure;Institution;Institutional Review Boards;Investments;Knowledge;Leadership;Marketing;NCI Center for Cancer Research;Oncology;Parents;Problem Solving;Process;Reporting;Research;Research Personnel;Resource Sharing;Resources;Services;Strategic Planning;Talents;Technology;Training and Education;Universities;Vision;Washington;anticancer research;cancer research center director;career;community engagement;expectation;experience;follower of religion Jewish;medical schools;member;oncology service;operation;outreach;programs;recruit;research and development;working group Cancer Center Administration n/a NCI 10689737 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 6472 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 Unavailable 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO Domestic Higher Education 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 410446 260601 149845 CANCER CENTER ADMINISTRATION: PROJECT SUMMARYThe Siteman Cancer Center (SCC) Administration (SCC-A) oversees all of the centers research clinical andfinancial operations. SCC-A is led by two members of SCCs Senior Leadership (SL): Nick Fisher ExecutiveDirector of Research and Business Administration and Christina Longnecker Vice President of OncologyServices. Both Fisher and Longnecker have a direct reporting line and access to the SCC Director TimothyEberlein. Together this administration team ensures critical connections between all research (Fisher) andclinical (Longnecker) areas within SCC as well as coordination across satellite network and collaborativepartners. Their close collaboration and interaction ensures that all SCC initiatives are well integrated and servethe scientific goals of the center and its two parent institutions Washington University School of Medicine andBarnes-Jewish Hospital. As Executive Director Fishers primary responsibilities include leading all SCC research functions; providingexecutive administrative leadership to the Director SL as well as program and shared resource leaders in allaspects of CCSG and SCC operations; serving on all key SCC committees including all SL sub-committees andoncology strategic planning working groups; and assisting in the recruitment of new faculty and new SCCmembers. Fisher is supported by a large talented team. Together they provide the necessary organizationalinfrastructure to comply with NCI reporting requirements meet the expectations of SL and individual facultysupport SCCs vision and strategic plan and oversee institutional initiatives. The SCC-A leadership team hasextensive knowledge with nearly 70 combined years of experience in research and CCSG administrationfacility/resource management clinical research community outreach informatics and financial operations. Moving forward Fisher will continue to lead the SCC-A team in maintaining an adaptive organizationalinfrastructure that supports SCC members in scientific discovery aligns with overarching national CCSG goalsand engages key stakeholders in priority-setting and problem-solving. +No NIH Category available Acetic Acids;Address;Adjuvant;Affect;Age;Algorithms;Area;Biological Assay;Caribbean region;Cervical;Cervical Cancer Screening;Cervical Intraepithelial Neoplasia;Cessation of life;Child;Clinical;Clinical Trials;Colposcopy;Communities;Correlative Study;Country;Cytology;Detection;Diagnosis;Disease;Dominican Republic;Dose;Enrollment;Goals;HIV;HIV Infections;Health;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Imaging technology;Immune;Immunoprevention;Improve Access;Incidence;Infrastructure;International;Latin America;Lesion;Licensing;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Memory B-Lymphocyte;Methods;Monoclonal Antibodies;Operative Surgical Procedures;Outcome;Pap smear;Papillomavirus Transforming Protein E6;Participant;Patients;Persons;Peru;Population;Populations at Risk;Prevention;Provider;Quality of life;Randomized Controlled Trials;Recurrence;Regimen;Repeat Surgery;Reproducibility;Research;Resources;Risk;Schedule;Sirolimus;Site;Testing;Time;Triage;Vaccination;Vaccines;Visual;Woman;Youth;automated visual evaluation;booster vaccine;cancer prevention;cervical cancer prevention;design;experience;girls;high risk;implementation facilitation;improved;improved outcome;low and middle-income countries;new technology;novel;overtreatment;point of care;premalignant;prevent;prevention service;programs;progression risk;response;screening;standard of care;treatment strategy;tumor microenvironment Clinical Trials Program n/a NCI 10689736 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6471 2478519 "MADELEINE, MARGARET M" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 401630 413147 130094 PROJECT SUMMARY CLINICAL TRIALS PROGRAMThe goal of the Clinical Trials Program is to address the dual burden of HIV infection and HPV-associatedcervical cancer in Latin America and the Caribbean (LAC). Over 270000 women die every year of cervicalcancer and it disproportionately affects women in low- and middle-income countries (LMICs) whereapproximately 90% of cervical cancer deaths occur. Peru and the Dominican Republic experience a 3-foldhigher incidence of cervical cancer than the US as well as high rates of HIV infection especially in vulnerablekey populations. Women and children living with HIV (WLWH and CLWH) are more likely to have persistentHPV and high-grade lesions and they are at higher risk of progression to cancer than HIV-uninfected women.Addressing the needs of HIV-infected persons at risk for HPV-associated cancers in LMICs involves improvingaccess to HPV vaccines and more effective screening for and treatment of cervical high-grade lesions. Insteadof replicating the infrastructure needed for screening used in high-resource settings the clinical trials proposedhere seek to use a new combination of prevention and treatment methods aimed at point-of-care with low-infrastructure support. We will leverage and strengthen existing research capacity in Seattle and the LAC sitesto explore sustainable solutions that are acceptable to local providers and patients. This includes investigatingoptimal HPV vaccine schedules for HIV+ children assessing new HPV tests and visual imaging technologiesto help clinicians to perform high-quality screening and triage and testing non-surgical approaches to improveoutcomes of cervical cancer precursors among WLWH. Toward this goal we will conduct three clinical trials:Trial 1: HPV immunoprevention by vaccination of unexposed children is not optimized for children living withHIV (CLWH). We will compare longer-term immune (anamnestic) responses among HIV-infected youth (ages9-13 at the time of enrollment) after 1 2 or 3 doses of 9-valent HPV vaccine.Trial 2: Cervical cancer screening and triage among WLWH needs to be optimized to improve detection ofprecancerous lesions reduce overtreatment and facilitate implementation. We will develop a more efficientalgorithm to detect high-grade lesions (CIN2/3) by assessing standard of care (Pap test and visual inspectionwith acetic acid) HPV testing and newer technologies including HPV E6/E7 expression and enhanced visualinspection (EVA) with automated visual evaluation (AVE) comparable to colposcopy.Trial 3: Evaluating non-surgical strategies for treatment of high-grade lesions (CIN2/3) diagnosed inWLWH from Trial 2 in a 2x2 factorial trial of 9-valent HPV vaccine and sirolimus initiated before surgery.These trials will be framed by the Cervical Cancer Prevention Partnership (C2P2) Center that bringstogether collaborators in Peru the Dominican Republic Seattle with international external scientific andcommunity advisors. The teams have extensive experience conducting high-quality clinical trials and workingto prevent HPV-related cancers in LMICs and improve health and quality of life for persons living with HIV. +No NIH Category available Acceleration;Accountability;Adoption;Advocate;Biological Assay;CLC Gene;Cancer Burden;Caribbean region;Cessation of life;Child;Clinical;Clinical Services;Clinical Trials;Communication;Communities;Country;Credentialing;Data;Dominican Republic;Fostering;Goals;Grant;Guidelines;HIV;Heart;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Income;Information Dissemination;Infrastructure;Institution;International;Interruption;Laboratories;Laboratory Procedures;Latin American;Lead;Leadership;Lesion;Malignant neoplasm of cervix uteri;Methods;Modeling;Monitor;Outcome;Paper;Periodicals;Persons;Peru;Policies;Population;Preventative vaccination;Prevention;Primary Prevention;Problem Solving;Productivity;Protocols documentation;Publications;Publishing;Qualifying;Quality Control;Records;Reporting;Research;Research Personnel;Resources;Risk;Safety;Schedule;Science;Scientific Advances and Accomplishments;Secondary Prevention;Services;Site;Structure;Training;Translating;Triage;Update;Vaccination;Woman;Work;cancer prevention;cancer risk;cervical cancer prevention;co-clinical trial;data management;experience;human subject;improved;meetings;member;novel strategies;participant safety;patient safety;premalignant;prevent;recruit;screening;skills training;success;tertiary prevention;tool Administrative and Coordinating Core n/a NCI 10689735 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R 6470 2478519 "MADELEINE, MARGARET M" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 329133 315021 122089 The overarching goal of the Administrative and Coordinating Core (ACC) is to provide effective leadership tooptimize the successful accomplishment of the scientific aims of the Cervical Cancer PreventionPartnership (C2P2) Center in Peru and the Dominican Republic. The management team for the ACC includesthree investigators: a Peru-based investigator Dr. Robinson Cabello MPI and two Seattle-basedinvestigators Dr. Duerr (MPI and Co-Chair Trial 1) and Dr. Madeleine (Contact MPI Co-Investigator Trials 2and 3). Together they will provide scientific direction enhance productivity liaise with the NCI and monitorsafety quality recruitment and progress toward each of the Aims of the Clinical Trials and service Cores. TheAims of the ACC are as follows: Aim 1 of the ACC is to organize the C2P2 Center by distributing responsibilityand accountability throughout the C2P2 Center. The ACC will implement the Triple C (CommunicationCooperation and Coordination) model of project management. This organizational approach will be groundedin meeting regional needs and in respect for working with LAC partners who will lead and sustain the cuttingedge changes we develop together through integrated and interdisciplinary team science. Aim 2 is to facilitatecommunication and scheduling at all levels of the partnership. The ACC will foster high-level and bidirectional coordination and cooperation directly with unit leaders (Clinical Trial Co-Chairs and service CoreLeaders) across the C2P2 Center (i.e. Core teams Clinical Trial teams institutions) and with externaladvisors (i.e. External Scientific Advisory Group and the cross-cutting Partnership Center CoordinatingCommittee). Aim 3 of the ACC is to lead all trial monitoring and regulatory coordination activities with theassistance of the Data Coordinating Core. The first priority of the ACC is patient safety at both trial sties. Aim 4of the ACC will provide training and dissemination of findings. The ACC will administratively support theClinical Trial Co-Chairs through cross-institutional training as needed to refine laboratory assay quality controldata management skills training and streamlined organizational infrastructure building that will enhance thesuccess of the matrixed partnership. All trial findings will be disseminated through published papers andpresentations in the region and at international meetings of policy and guideline makers who will be able to useour trial findings to accelerate progress toward elimination of cervical cancer through prevention. The ACC willprovide leadership to accomplish the overall scientific goal of the C2P2 Center to improve the quality andefficiency of cervical cancer prevention in the region. +No NIH Category available ATAC-seq;Advanced Malignant Neoplasm;Area;Award;Back;Bioinformatics;Biological;Cancer Center;Cancer Patient;Cell Lineage;Cells;Cellular Assay;Clinical;Code;Collection;Competence;DNA Sequence Alteration;Data;Data Analyses;Detection;Diagnosis;Emerging Technologies;Epigenetic Process;Evolution;Genes;Genetic Complementation Test;Genetic Transcription;Genomics;Germ-Line Mutation;Goals;Heterogeneity;Histology;Human;Individual;Inherited;Letters;Link;Malignant Neoplasms;Medicine;Methods;Methylation;MicroRNAs;Molecular;Mutation;Pathogenicity;Pathway interactions;Pattern;Penetrance;Population;Predisposition;Production;Quality Control;RNA Splicing;Sequence Analysis;Somatic Mutation;System;Technology;Traction;Trees;Twin Multiple Birth;Untranslated RNA;Variant;Work;XCL1 gene;anticancer research;bioinformatics tool;cancer genomics;cancer type;cell type;cohort;combinatorial;data exchange;data integration;deep learning;digital imaging;disorder subtype;exome sequencing;genome sequencing;genomic data;improved;insight;neoplastic cell;new technology;programs;single-cell RNA sequencing;tool;transcriptome;transcriptome sequencing;transcriptomics;treatment strategy;tumor;tumor microenvironment;whole genome Deep exploration of drivers evolution and microenvironment toward discovering principal themes in cancer Project NarrativeUnderstanding the whole spectrum of inherited and acquired genetic changes using established and emergingtechnologies will lead to effective diagnosis and treatment strategies for each patient's cancer. We undertakethis work using a comprehensive suite of established bioinformatics tools to examine mutations and germlinepredisposition tumor cell populations evolution and the tumor microenvironment; and integrate thesedynamics into larger themes in cancer. NCI 10689729 8/28/23 0:00 RFA-CA-20-053 5U24CA264010-03 5 U24 CA 264010 3 "YANG, LIMING" 9/1/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 9766169 "DING, LI " "GOVINDAN, RAMASWAMY " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 374458 NCI 268519 105939 Summary/AbstractTremendous progress on cancer has been made at the molecular level over the past decade largely due tothe broad application of high throughput large-scale bulk whole genome exome and RNA sequencing. Inparticular the discovery of numerous medium to high-penetrance drivers characterization of pathogenicgermline variants and the revelation of many-to-many relationships of genes and pathways have brought afuller view of the combinatorial complexity of cancer. Indeed newer technologies like single-cell and spatialgenomics methods are now augmenting bulk sequence data to power deeper studies of cancer dynamicssuch as heterogeneity evolution and interaction with the microenvironment. The current view is that suchadvanced data augmented by improved bioinformatics analysis tools and larger well-curated cohorts willenable medicine to push beyond statistical descriptions toward a genuine deterministic understanding ofcancer. Toward this goal our proposal seeks to extend and apply established bioinformatics systems tointegrate the above technologies and leverage our broad range of capabilities and to support the NCI GenomicCharacterization Network (NCI-GCN) and Center for Cancer Genomics (CCG) via three specific aims: (1)annotating and interpreting coding and non-coding somatic and germline alterations (2) characterizing tumorcell populations evolution and the tumor microenvironment and (3) unlocking biological and clinical insights atboth the individual and cross-cancer (Pan-Cancer) levels to discern basic themes across the major humancancers. Our approach involves fluencies in four areas of core competence outlined in the program RFA: DNAmutations long-read sequence analysis scRNA-Seq analysis and spatial genomics data analysis (withconnection to digital imaging analysis). 374458 +No NIH Category available Area;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Patient;Catchment Area;Clinical Trials;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;County;Data;Development;Diverse Workforce;Exclusion;Funding;Genomics;Grant;Health Services Accessibility;Hematopoietic;Hospitals;Illinois;Imaging technology;Immunology;Immunotherapy;Incidence;Institution;Interdisciplinary Study;Intervention;Malignant Neoplasms;Methods;Mission;Missouri;Molecular;Neoplasm Metastasis;Pathway interactions;Patient Care;Patients;Prevention;Prevention strategy;Publications;Regional Cancer;Research;Research Personnel;Resource Sharing;Risk Factors;Risk Reduction;Schools;Science;Screening for cancer;Solid Neoplasm;Speed;Strategic Planning;Talents;Therapeutic;Time;Tissues;Training and Education;Translating;Translational Research;Underserved Population;Universities;Washington;anticancer research;bench to bedside;burden of illness;cancer care;cancer diagnosis;cancer imaging;cancer therapy;clinical care;community partnership;disparity reduction;follower of religion Jewish;imaging science;implementation science;innovation;malignant breast neoplasm;member;mortality;multidisciplinary;novel;patient population;personalized medicine;prevent;programs;success;tumor immunology;tumor progression Cancer Center Support Grant OVERALL: PROJECT NARRATIVEThe Alvin J. Siteman Cancer Center (SCC) at Washington University and Barnes-Jewish Hospital is a NCIdesignated Comprehensive Cancer Center whose mission is to prevent cancer in the community and transformcancer patient care through scientific discovery. SCC accomplishes this mission through strong researchprograms shared resource support education and training pilot funding programs and community outreach.The translational research and scientific discovery facilitated by our seven multidisciplinary research programsand 10 shared resources (11th requested in this application) is driven by the needs of patients in our 82-countycatchment area throughout Missouri and southern lllinois. NCI 10689717 6/13/23 0:00 PAR-17-095 5P30CA091842-22 5 P30 CA 91842 22 "ROBERSON, SONYA" 8/2/01 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 1891624 "EBERLEIN, TIMOTHY J" Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 397 Research Centers 2023 6073063 NCI 3855913 2217150 OVERALL: PROJECT SUMMARYThe Alvin J. Siteman Cancer Center (SCC) at Washington University and Barnes-Jewish Hospital is a NCIdesignated Comprehensive Cancer Center whose mission is to prevent cancer in the community and transformcancer patient care through scientific discovery. SCC accomplishes this mission through strong researchprograms shared resource support education and training pilot funding programs and community outreach.The translational research and scientific discovery facilitated by our seven multidisciplinary research programsand 10 shared resources (11th requested in this application) is driven by the needs of patients in our 82-countycatchment area throughout Missouri and southern Illinois. The center applies the exceptional talent among our 230 members from four schools and 23 departmentsto further understand the mechanisms of cancer pathways speed the conduit from bench to bedside andimplement prevention strategies that impact cancer screening incidence and mortality in our catchment area. SCCs Breast Cancer Research Hematopoietic Development and Malignancy Mechanisms of CancerBiology Oncologic Imaging Prevention and Control Solid Tumor Therapeutics and Tumor ImmunologyResearch Programs promote novel multidisciplinary cancer research and encourage intra inter and cross-institution collaboration. Success is evidenced by SCCs key metrics in the project period; data below are currentas of this application and each represents an all-time high for the center: NCI funding $41.0M direct excluding CCSG dollars Number of large collaborative grants 72 Interventional clinical trial accruals 5071 in 2018 Total cancer-focused publications 1148 in 2018; 35% intra- or inter-programmatic High Impact Publications 201 in 2018 (> 10.0 IF) In the next five years SCC will advance its mission through exceptional research and clinical care withspecial emphasis on four overarching scientific themes chosen to optimally harness and magnify the centersimpact on cancer in the field and in our catchment. These scientific pillars are: genomics and its application toclinical care; innovation in imaging technologies and their use in cancer diagnosis and treatment; immunologyand the enhancement of patient care using unique immune therapies; and prevention to reduce the burden ofdisease in the population of patients we serve. These core strengths align with SCCs current strategic plan andinform research program aims objectives and initiatives. 6073063 +No NIH Category available 3-Dimensional;ATAC-seq;Advisory Committees;Affect;Autocrine Communication;Award;Binding;Bromodomain;CSF1R gene;Cancer Etiology;Cell Line;Cells;Chromatin;Clinical;Communication;DNA Binding;DNA Binding Domain;Data;Development Plans;Diagnosis;Disease;Epigenetic Process;Esophageal Squamous Cell Carcinoma;Esophageal carcinoma;Event;Faculty;Foundations;Future;Genetic;Genetic Transcription;Genomics;Goals;Grant;Homologous Gene;Human;In Vitro;Institution;Invaded;M cell;Macrophage;Macrophage Colony-Stimulating Factor;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of esophagus;Manuscripts;Mediating;Mediator;Medical center;Mentorship;Metastatic Neoplasm to the Lung;Missense Mutation;Modeling;Molecular Conformation;Mus;Mutate;Mutation;Neoplasm Metastasis;Oncogenic;Organoids;Outcome;Pathway interactions;Patients;Positioning Attribute;Postdoctoral Fellow;Pre-Clinical Model;Primary Neoplasm;Prognosis;Proliferating;Property;Reader;Recurrence;Resources;Role;Scientist;Signal Pathway;Signal Transduction;Squamous cell carcinoma;Survival Rate;TP53 gene;Testing;Therapeutic;Thinking;Training;Tumor Cell Invasion;Tumor Promotion;Tumor Suppressor Proteins;Tumor-associated macrophages;Universities;Up-Regulation;Work;Writing;anticancer research;base editing;cancer type;career;career development;collaborative environment;effective therapy;gain of function;improved;in vivo;in vivo Model;metastatic esophageal;migration;mortality;mouse model;mutant;neoplastic cell;new therapeutic target;novel therapeutic intervention;pharmacologic;programs;receptor;skills;small hairpin RNA;small molecule;tenure track;transcriptome sequencing;transcriptomics;tumor;tumor growth;tumorigenesis;tumorigenic Elucidation of mutant p53-medidated mechanisms in promoting metastatic esophageal cancer PROJECT NARRATIVEEsophageal cancer is a devastating disease with the majority of patients being diagnosed after the tumor hasmetastasized leaving patients with the 5-year relative survival rate of only 5%. The proposed work seeks tobetter understand the underlying mechanisms of metastasis in esophageal carcinoma as well as to target theidentified pathway in pre-clinical models. Overall in the long term this study will introduce more effective andtargeted treatments to patients with metastatic esophageal cancer and potentially other deadly cancers withsimilar genetic and epigenetic properties. NCI 10689716 8/23/23 0:00 PA-21-051 5F31CA275369-02 5 F31 CA 275369 2 "BOULANGER-ESPEUT, CORINNE A" 9/1/22 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16291675 "EFE, GIZEM " Not Applicable 13 GENETICS 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 46843 NCI 46843 0 PROJECT SUMMARYEsophageal Squamous Cell Carcinoma (ESCC) the predominant subtype of esophageal cancer worldwide isone of the most known lethal cancers. The prognosis of metastatic ESCC is dismal with a 5-year relative survivalrate of only 5%. Mutations in TP53 (mouse homolog Trp53) which are detected in approximately 70% of ESCCpatients contribute to tumor metastasis and poor prognosis. To understand the mechanisms of Trp53R172H-mediated metastasis which is one of the hotspot mutations in ESCC we utilized mouse models and performedRNA-Seq on metastatic ESCC cells generated from this model from which I identified Colony stimulating factor-1 (Csf-1) to be significantly upregulated. While it is canonically involved in polarization of tumor-associatedmacrophages through binding to its receptor CSF-1R my data demonstrate the existence of autocrine signalingthat is potentially co-regulated by epigenetic reader Bromodomain-Containing Domain 4 (BRD4). Theoverarching hypothesis of this study is that CSF-1/CSF-1R autocrine signaling is one of the major mechanismsby which missense TP53 mutations can promote invasion and lung metastasis in ESCC. I will test this hypothesisthrough the following interrelated Specific Aims: (1) Elucidate the role of Trp53R172H-mediated CSF-1/CSF-1Rsignaling pathway in promoting invasion and lung metastasis in ESCC (2) Investigate BRD4 as a candidate co-regulator of Trp53R172H that contributes to CSF-1 upregulation and assess the anti-tumorigenic efficacy ofinhibiting BRD4 and (3) Delineate the tumorigenic as well as epigenetic/transcriptomic states mediated bymissense p53 mutations recurrent in ESCC patients and impact upon CSF-1/CSF-1R signaling. To accomplishAim 1 I will assess the role of CSF-1/CSF-1R signaling in proliferation migration primary tumor and 3D organoidformation invasion and lung metastasis as well as its downstream effectors through utilizing in vitro andcomplementary in vivo approaches. I will accomplish Aim 2 by studying the direct interaction of p53-R172H andBRD4 and also their shared DNA binding motifs through CUT&RUN-Seq. Additionally I will genetically deleteand pharmacologically inhibit BRD4 to evaluate their effects on tumorigenesis and lung metastasis. Toaccomplish Aim 3 I will introduce p53 mutations through base editing and evaluate their distinct roles in pro-oncogenic activities. I will also investigate how these mutations affect the transcriptional expression of factors inCSF-1/CSF-1R signaling pathway during metastasis and also conduct single-cell ATAC-Seq on mouse primaryand metastatic tumors to evaluate their chromatin accessibility. This study will elucidate the tumor cell intrinsicmechanisms underlying ESCC metastasis which will ultimately open new avenues in developing therapeuticstrategies for metastatic ESCC patients that can be extended to other SCCs. I will develop skills in analyticalthinking technical approaches scientific communication grant and manuscript writing and mentorship with thesupport and resources available through my sponsors advisory committee and graduate program which will becritical to accomplish my long-standing career goal to become a tenure-track faculty to conduct cancer research. 46843 +No NIH Category available Acceleration;Address;Algorithms;B-Lymphocytes;Biological Assay;Cancer Burden;Cancer Etiology;Caribbean region;Caring;Cessation of life;Child;Clinic;Clinical;Clinical Trials;Collaborations;Collection;Communication;Country;Dedications;Diagnosis;Dominican Republic;Dose;Ensure;Future;Future Generations;General Population;Goals;HIV;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Immunotherapy;Incidence;Infrastructure;Interruption;Laboratories;Latin America;Lesion;Malignant neoplasm of cervix uteri;Minority;Modeling;Monitor;National Cancer Institute;Persons;Peru;Population;Prevention;Prevention approach;Prevention strategy;Primary Care;Primary Prevention;Productivity;Protocols documentation;Provider;Quality Control;Regimen;Research Personnel;Resource-limited setting;Resources;Safety;Sampling;Schedule;Site;Statistical Data Interpretation;Time;Training;Triage;Vaccination;Vaccines;Visit;Vulnerable Populations;Woman;Work;cancer prevention;cancer therapy;cervical cancer prevention;cost;data management;design;effectiveness testing;experience;immunogenicity;improved;low and middle-income countries;mortality;new technology;novel;novel strategies;premalignant;programs;recruit;response;screening;statistics;success;treatment strategy Colaboracion Evita: HPV-Related Cancer Prevention Partnership Center PROJECT NARRATIVE - OVERALLThe Cervical Cancer Prevention Partnership (C2P2) program is a collaboration between investigators in theUS (Seattle) Peru (Lima) and the Dominican Republic (Santo Domingo). It has the following goals: 1) buildingstrong and collaborative partnerships both among investigators at these sites and between site investigatorsand the National Cancer Institute and 2) conducting trials in Peru and the Dominican Republic to address thecervical cancer prevention and treatment needs of HIV-infected populations. NCI 10689708 8/28/23 0:00 RFA-CA-18-018 5U54CA242977-06 5 U54 CA 242977 6 "FRECH, MARIA SILVINA" 9/18/19 0:00 7/31/25 0:00 ZCA1-RTRB-R(M2) 2478519 "MADELEINE, MARGARET M" "CABELLO, ROBINSON ; DESCHAMPS, MARIE MARCELLE H.; DONASTORG, YEYCY A.; DUERR, ANN C" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Research Centers 2023 1897572 NCI 1901663 647724 PROJECT SUMMARY OVERALLWorldwide cervical cancer is the fourth leading cause of cancer incidence and mortality; 80% of cervicalcancers arise and 87% of cervical cancer deaths occur in low and lower-middle income countries. In Perucervical cancer is diagnosed at a rate of 17 per 100000 women per year and in the DR at 23 per 100000annually among women in the general population. The burden of cervical cancer is substantially increasedamong women living with HIV (WLWH) although the exact rates are not well described. Although HPVvaccines are safe and effective as primary prevention they have limited availability in low resource settingsand the optimal regimen of vaccine doses for HIV-infected persons in such settings has not been defined.Furthermore delivery of cervical cancer prevention and treatment of precursors for WLWH in low- and middle-income countries is impeded by approaches that are often costly require multiple visits and extensive providertraining. Moreover many of these are not suitable for delivery within an HIV primary care model.The Cervical Cancer Prevention Partnership (C2P2) Center involves two clinical trial sites in Peru and theDominican Republic and three cores (Administrative and Coordinating Core Statistics and Data ManagementCore and Central Laboratory Core) in Seattle. Investigators in the C2P2 Center will jointly design conduct andanalyze three clinical trials with the goal of moving toward elimination of cervical cancer among highlyvulnerable populations with HIV in low resource settings in Latin America and the Caribbean (LAC). We seekto improve the quality and efficiency of prevention strategies using new approaches that will augment theexisting infrastructure at local HIV clinics in Peru and the Dominican Republic (DR). The aims of theproposed Clinical Trials Center span the continuum of cervical cancer prevention from vaccinationthrough treatment. The trials we propose will address these technical issues and provide a more direct pipelinefor prevention. In this C2P2 Center our overarching aims are: Specific Aim 1: To test the effectiveness of novel approaches to cervical cancer prevention in high- burden HIV-infected populations in Peru and the DR by performing three clinical trials. One will assess the ability of HPV vaccination regimens to elicit long-lasting B cell responses and two will assess novel screening triage and treatment approaches that will improve the quality and reach of prevention in low-resource settings throughout the LAC region. Specific Aim 2: To build a robust multidirectional collaboration between study investigators at all sites that serves the needs of providers who care for women living with HIV. The Center will engage with leaders in the region to enhance the sustainability of efforts that target future elimination of cervical cancer through multiple high-impact prevention and treatment strategies. 1897572 +No NIH Category available Advanced Malignant Neoplasm;Adverse effects;Age;Aspirin;Award;Biological Markers;Cancer Patient;Cells;Chemoprevention;Clinic;Clinical;Clinical Trials;Data;Dedications;Dose;Effectiveness;Etiology;Future;Goals;Harm Reduction;Hemorrhage;Individual;Integration Host Factors;International;Intervention;Investigation;Malignant Neoplasms;Modeling;Molecular;Molecular Epidemiology;Oncology;Patients;Physicians;Population;Population Study;Prevention Research;Prevention approach;Prospective cohort study;Recommendation;Reporting;Research;Research Personnel;Resolution;Risk Reduction;Source;System;Target Populations;Testing;United States Preventative Services Task Force;Validation;Work;anticancer activity;biobank;biomarker driven;cancer prevention;career;cohort;colorectal cancer prevention;colorectal cancer risk;cost efficient;empowerment;evidence base;gut microbiome;human data;human tissue;improved;individualized prevention;novel;novel strategies;personalized approach;prevent;preventive intervention;programs;rapid testing;research vision;risk stratification;risk/benefit ratio;tool Precision Prevention Research Program PROJECT NARRATIVEAlthough substantial evidence demonstrating that low-dose aspirin (LDA) reduces risk of colorectal cancer (CRC)and likely other cancers has led to formal recommendations for LDA to prevent CRC there remains a high unmetneed to provide to develop precision biomarkers to optimize targeting populations for treatment with a favorablerisk-benefit ratio. In this Outstanding Investigator Award I propose a Precision Prevention Research Program toenhance molecularly characterized prospective cohort studies to test hypotheses that can then be tested forcausality through cost-efficient biomarker-driven clinical cohorts in which human tissues can be leveraged todevelop living biobanks for rapid translational testing. These complementary approaches will empower myresearch team to study the entire continuum from healthy individuals to advanced cancer patients and fromsingle cells to large populations to obtain a more complete multifaceted view of how interventions can be tailoredto prevent cancer. NCI 10689700 9/5/23 0:00 PAR-19-349 5R35CA253185-04 5 R35 CA 253185 4 "UMAR, ASAD" 9/1/20 0:00 8/31/27 0:00 ZCA1-GRB-S(M1) 7609343 "CHAN, ANDREW T" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 987838 NCI 587999 399839 PROJECT ABSTRACTAs an internationally recognized physician-investigator I have dedicated my career to the prevention ofcolorectal cancer (CRC). My most substantial contributions have influenced the evidence base supportingaspirins effectiveness in reducing the risk of CRC and uncovered key molecular mechanisms underlying its anti-cancer activity. This work has helped advance the field to a first-if-its-kind milestone recommendation forpopulation use of aspirin for cancer prevention by the US Preventive Services Task Force. However growingdata demonstrates that the effect of aspirin may differ according to host factors including the gut microbiomeand age suggesting that a one-size-fits-all approach to aspirin chemoprevention is limited. Thus developingnovel approaches to prevention through molecular risk stratification is a high priority. Building on my expertisein molecular epidemiology clinical trials the gut microbiome and clinical cancer prevention my research visionis to develop a comprehensive Precision Prevention Research Program (PPRP) through this NCI OutstandingInvestigator Award. The overarching goal of this PPRP is to leverage complementary sources of human dataincluding population-based studies clinical cohorts and living biobanks to study the entire continuum fromhealthy individuals to advanced cancer patients and with resolution from single cells to large populations toacquire a more complete multifaceted view of how interventions can be tailored to prevent cancer. Our PPRPfacilitates mechanistic discovery in population studies that can lead to rapid testing of novel molecularly-inspiredbiomarkers in clinical cohorts creating opportunity for living biobanks for rigorous validation and advancedmechanistic investigation. Moreover this model is reciprocal. Our clinical cohorts and translational tools usingpatient-derived experimental systems may also identify novel mechanisms that can be examined within thecontext of our population studies to confirm their relevance to cancer and improve generalizability. Through thisR35 I will develop and expand this PPRP through expansion of my work in aspirin chemoprevention. Aspirin isan exemplar agent to develop this platform since efficacy for CRC prevention has already been established andits association with adverse effects such as bleeding necessitate a tailored approach. As the Lancet OncologyCommission report concluded: Perhaps the most promising precision-based approach to cancer prevention inthe near future involves molecular selection for repurposed low-dose aspirin and in view of aspirins potentialadverse effects (e.g. bleeding) tailoring aspirin use is a high priority. By enhancing understanding of aspirinsmode of action this proposal may lead to novel mechanistic biomarkers or complementary preventativeinterventions that may maximize the benefits of aspirin while minimizing the harms. Over the long-term I envisionthat this work will provide proof-of-concept for expansion of the PPRP program as a cost-efficient platform withinwhich to move additional cancer preventive interventions rapidly into the clinic. 987838 +No NIH Category available Academic Medical Centers;Algorithms;Artificial Intelligence;Biopsy;Cancer Etiology;Cessation of life;Characteristics;Clinic;Clinical;Colon Carcinoma;Colonic Polyps;Cyst;Cystic Neoplasm;Data;Data Set;Detection;Development;Diagnosis;Diagnostic;Disease;Early Diagnosis;Epithelial cyst;European;Evaluation;Excision;Goals;Guidelines;High Prevalence;Histopathology;Image;In Situ Lesion;Individual;International;Lesion;MRI Scans;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Medical center;Methods;Modeling;Morbidity - disease rate;Mucinous Cystadenoma;Mucinous Neoplasm;Multicenter Studies;Names;Noninfiltrating Intraductal Carcinoma;Operative Surgical Procedures;Organ;Outcome;Outcomes Research;Pancreas;Pancreatectomy;Pancreatic Cyst;Pancreatic cystic neoplasia;Papillary;Patient Triage;Patient-Focused Outcomes;Patients;Performance;Prognosis;Property;Radiology Specialty;Recommendation;Reference Standards;Research;Risk;Scanning;Sensitivity and Specificity;Series;Serous Cystadenoma;Side;Structure;Surveillance Program;Survival Rate;System;Technology;Testing;Time;Trust;United States;Universities;Unnecessary Surgery;Visual;automated algorithm;cancer invasiveness;cancer type;capsule;clinical center;clinical decision-making;cost;deep learning;deep learning algorithm;design;detection method;detection platform;diagnostic accuracy;diagnostic tool;efficacy validation;experimental study;follow-up;high risk;improved;learning strategy;malignant breast neoplasm;mortality;novel diagnostics;pancreatic neoplasm;premalignant;prognostic significance;radiological imaging;radiologist;radiomics;risk stratification;screening;stem;tool Cyst-X: Interpretable Deep Learning Based Risk Stratification of Pancreatic Cystic Tumors Project NarrativeUnlike other common cancers for which early detection and surgical resection have reduced cancer deaths (e.g.colon polyps for colon cancer ductal carcinoma in situ lesions and breast cancer) pancreas cancer precursorssuch as commonly observed pancreatic cysts are poorly understood. Towards the long-term goal of earlydetection of pancreatic cancer our objective in this proposal is to accurately detect and characterize pancreaticcysts before they turn into aggressive cancer. The outcome of this research will be a new diagnostic tool namedCyst-X which will establish a better clinical strategy than the current guidelines by recommending a moreselective use of invasive testing surgery and surveillance. NCI 10689657 4/4/23 0:00 PA-19-056 5R01CA246704-04 5 R01 CA 246704 4 "AVULA, LEELA RANI" 3/1/20 0:00 2/28/25 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 12578658 "BAGCI, ULAS " Not Applicable 5 RADIATION-DIAGNOSTIC/ONCOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 394 Non-SBIR/STTR 2023 488720 NCI 357145 131575 Project SummaryThe overall goal of this project is to develop a new diagnostic tool called Cyst-X for accurate detection andcharacterization of pre-cancerous pancreatic cysts and improve patient outcome through precise decisions(surgical resection or surveillance). Pancreatic cancer is the most fatal cancer among all cancers due to its poorprognosis and lack of early detection methods. Unlike other common cancers where precursor lesions are wellknown (colon polyps-colon cancer ductal carcinoma in situ (DCIS)-breast cancer) pancreas cancer precursors(cysts) are poorly understood. Diagnosing pancreatic cancer at earlier stages may decrease mortality andmorbidity rates of this lethal disease. One major approach for diagnosing pancreatic cancer at earlier stages isto target pancreatic precancerous pancreatic neoplasms (cysts) before they turn into invasive cancer. Once cystsare detected with radiology imaging such as magnetic resonance imaging (MRI) they should be characterizedwith respect to their malignant potential. Low-risk cysts remain harmless; hence patients should remain undersurveillance program. On the other hand high-risk cysts can progress into an aggressive cancer thereforepatients should undergo surgical resection if possible. Despite this international guidelines for risk stratificationof pancreatic cysts are woefully deficient (55-76% accuracy for determining characteristics of low-risk vs highrisk cystic tumors while only 40-50% accuracy detecting cysts with MRI). Combined these critical barriersindicate that there is an urgent need for improving characterization of pancreatic cystic tumors. Based on ourpreliminary results which support the development of an image-based diagnostic decision tool we hypothesizethat our proposed Cyst-X will produce higher diagnostic accuracy for characterizing pancreatic cysts and providebetter patient management compared to the current guidelines. Towards this overarching hypothesis we willfirst use powerful deep learning methods (specifically deep capsule networks) for automatically detecting andsegmenting the pancreas and pancreatic cysts from multi-sequence MRI scans (Aim 1). Next we will create aninterpretable image-based diagnosis model for characterizing pancreatic cysts (Aim 2). Accuratecharacterization is necessary for such a diagnostic model; however emphasis will also be placed oninterpretability of the machine generated diagnostic model. Visual explanation of the discriminative features willhelp radiologists obtain higher decision rates in patient management. In Aim 3 we will validate the proposedCyst-X framework in a multi-center study. A total of 1200 multi-sequence MRI scans will be collected from threeparticipating clinical centers (Mayo Clinic Columbia University Medical Center Erasmus Medical Center).Comprehensive evaluations will be made to test the validity and generalizability of Cyst-X. All evaluations will bemade with respect to the international guidelines and biopsy proven ground truths. Our proposed study has wideimplications: specifically in the long term it will influence early diagnosis of pancreatic cancer and clinicaldecision making to improve survival rates of pancreatic cancer. 488720 +No NIH Category available 3-Dimensional;Address;Affect;Anesthesia procedures;Anxiety;Biopsy;Blood;Bone Marrow;Bone neoplasms;Cadaver;Child;Childhood;Clinical;Clinical Management;Clinical Trials;Development;Diagnosis;Early treatment;Electricity;Engineering;Environment;Epiphysial cartilage;Evaluation;Exposure to;Family;Femur;Goals;Image Guided Biopsy;Institutional Review Boards;Intervention;Ionizing radiation;Leg;Leg Bones;Lesion;Life;Limb structure;Location;MRI Scans;Magnetic Resonance Imaging;Malignant Neoplasms;Medical center;Metals;Morphologic artifacts;Motion;Motor;Musculoskeletal;Needles;Operating Rooms;Operative Surgical Procedures;Patient Care;Patients;Pediatrics;Phase I Clinical Trials;Physicians;Physics;Procedures;Process;Radiation;Radiation exposure;Research Personnel;Risk;Robot;Robotics;Roentgen Rays;Sampling;Sampling Errors;Second Primary Neoplasms;Secure;Speed;System;Systems Integration;Technology;Testing;Thermal Ablation Therapy;Time;Tissue Sample;Tissues;Visualization;Work;X-Ray Computed Tomography;accurate diagnosis;bone;bone visualization;cancer clinical trial;cancer diagnosis;cancer therapy;clinical decision-making;clinical practice;design;early phase clinical trial;feasibility trial;image guided;improved;long bone;novel;optical sensor;pain symptom;patient population;pediatric patients;programs;rapid diagnosis;safety and feasibility;sample fixation;soft tissue;tibia;tool;trauma exposure;ultrasound Pneumatic Drill and Robot for MRI-Guided Pediatrics Long Bone Biopsy Project NarrativeThe diagnosis of pediatric musculoskeletal lesions is often based on MR images which may require a biopsy(tissue sample) and a separate procedure. By developing an MR compatible robot and conducting the firsttrials in children we aim to speed the biopsy process and streamline clinical decision making for improvedpatient care. NCI 10689655 8/18/23 0:00 PAR-18-560 5R01CA248191-04 5 R01 CA 248191 4 "DARDZINSKI, BERNARD JOSEPH" 3/1/20 0:00 8/31/24 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 3054713 "CLEARY, KEVIN R." "SHARMA, KARUN V" 98 Unavailable 143983562 M3KHEEYRM1S6 143983562 M3KHEEYRM1S6 US 38.927274 -77.014396 1518602 CHILDREN'S RESEARCH INSTITUTE WASHINGTON DC Research Institutes 200102916 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 513993 NCI 355555 158438 ABSTRACT The overall goal of this proposal is to complete a Phase I clinical trial of bone biopsy in pediatric patientsusing the novel MRI safe robot developed in our previous work. This robot will facilitate accurate MRI-guidedbone biopsy and enable a new clinical workflow to reduce time to sampling and evaluation of tissue obtainedfrom suspicious bone lesions. Our team has been developing small footprint MRI compatible robots to enableprecision needle placement without radiation exposure to the patient or physician. In previous work wedesigned built and evaluated a novel MRI safe needle guidance robot to provide accurate targeting of lesionsin the long bones of the leg. The robot is actuated by unique pneumatic stepper motors and is entirely metaland electricity free which allows it to work in the MRI environment completely free of artifacts. Targets weresuccessfully reached using a long bone mockup in our 1.5T Siemens Aera MRI with an average 3D error of1.39 mm and maximum error of 1.89 mm. We then completed a leg cadaver study in the tibia and femur. Thecadaver study showed the need to develop an MRI-safe drill which will be the focus of Specific Aim 1. We willfollow these technical developments with additional cadaver studies in Specific Aim 2 followed by regulatoryapprovals and a clinical safety and feasibility trial in 20 pediatric patients in Specific Aim 3.Our specific aimsare to:1. Develop essential new components for our MRI-safe robot specifically a new pneumatic power MRI safe bone biopsy drill and a support/fixation mechanism for securing the leg to the MRI table.2. Complete additional cadaver studies to test the robot drill and mounting mechanism and confirm the proposed clinical workflow and the accuracy of the integrated system.3. Obtain regulatory approvals for the Phase I clinical trial including FDA and IRB approval followed by a safety and feasibility clinical trial of bone biopsy on 20 pediatric subjects using the MRI-safe robot and drill. 513993 +No NIH Category available Address;Antitumor Response;BRCA1 gene;Biological Markers;Breast Cancer Model;Breast Cancer Patient;Breast Cancer Treatment;CD8-Positive T-Lymphocytes;CRISPR screen;CXCL9 gene;CXCR3 gene;Cells;Clinical;Clinical Data;Clinical Research;Combination immunotherapy;Data;Data Set;Disease;ERBB2 gene;Electroporation;Electroporation Therapy;Engineering;Funding;Gene Targeting;Generations;Genes;Goals;Grant;Half-Life;Immune;Immune checkpoint inhibitor;Immunologics;Immunotherapy;Individual;Infiltration;Injections;Interleukin-12;K22 Award;Lesion;Licensing;Ligands;Mammary Neoplasms;Modeling;Molecular;Monitor;Oncogenes;Oncogenic;Outcome;PD-1/PD-L1;PTEN gene;Paclitaxel;Pathway interactions;Patients;Plasmids;Productivity;Progression-Free Survivals;Proteins;Publishing;Recombinant Interleukin-12;Recurrence;Research;Research Design;Resources;Role;Signal Transduction;Site;T cell infiltration;T-Lymphocyte;T-Lymphocyte Epitopes;TP53 gene;Testing;Time;Toxic effect;Transgenic Organisms;Translating;Treatment Protocols;Up-Regulation;Work;adaptive immune response;anti-PD-L1;anti-PD-L1 therapy;anti-tumor immune response;cancer infiltrating T cells;cancer type;chemokine;design;disorder control;follow-up;genetic signature;genomic tools;immune activation;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;immunogenic;improved;improved outcome;individualized medicine;insight;knock-down;malignant breast neoplasm;migration;molecular subtypes;mouse model;phase 2 study;pre-clinical;prognostic;programs;receptor;response;single-cell RNA sequencing;survival outcome;systemic toxicity;trafficking;transcriptome sequencing;triple-negative invasive breast carcinoma;tumor;tumor microenvironment Intratumoral immunotherapy to enhance T cell infiltration and augment immune checkpoint blockade responses across molecular subtypes of breast cancer A recently approved therapy for triple-negative breast cancer (TNBC) targets the PD1/PDL1 immunecheckpoint pathway to reinvigorate an anti-tumor immune response however the majority of patients do notrespond. Gaining insights into the unknown barriers to an effective anti-tumor immune response is a criticalunmet need that will benefit from new mouse models that more closely recapitulate the patients tumormicroenvironment and more sophisticated genomic tools and analysis. This proposal seeks to understand whichpatients will benefit and how to increase the number of responders across all molecular subtypes of breastcancer using intratumoral immunotherapy that augments T cell infiltration directly. NCI 10689654 8/25/23 0:00 PAR-18-467 5K22CA262340-02 5 K22 CA 262340 2 "JAKOWLEW, SONIA B" 9/1/22 0:00 8/31/25 0:00 ZCA1-RTRB-R(M2) 8776187 "CROSBY, ERIKA J" Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 117573 NCI 108864 8709 1 Abstract 2 Breast cancer (BC) encompasses multiple diseases made up of different molecular subtypes that are 3 characterized by distinct oncogenic drivers and unique treatment regimens. Despite these differences across all 4 subtypes individuals with advanced recurrent or metastatic disease still have limited treatment options and 5 poor overall survival outcomes. Immunotherapies offer an opportunity to treat patients regardless of molecular 6 subtypes. This proposal leverages intratumoral (IT) immunotherapy as an alternative to license treated lesions 7 to yield productive ratios of T cells to suppressive immune subsets while amplifying immune checkpoint axes 8 and ultimately increasing sensitivity to immune checkpoint inhibitors (ICI). Using a model of TNBC and single 9 cell RNA sequencing we demonstrate that IT plasmid IL-12 (pIL-12) can convert poorly immunogenic/low10 TIL tumors into highly inflamed immunologically active lesions through the coordinated upregulation of the11 CXCR3 axis in infiltrating immune cells that impacts the migration differentiation and activation of both12 innate and adaptive immune cells. This CXCR3 signature was also significantly enhanced in patients that had13 an increase in CD8 T cell infiltration into treated tumors post IT pIL-12 therapy and prognostic of improved14 overall survival. We hypothesize that targeting the CXCR3 axis IT will enhance TILs and convert patients into15 ICI responders across all molecular subtypes of BC. The proposed work will leverage this preliminary data in16 the following 3 aims: 1.) Demonstrate increased infiltration of tumor-specific T cells following IT pIL-12-EP17 treatment and validate the induction of a CXCR3 or trafficking-associated gene signature in ICI responders 2.)18 Evaluate the role of trafficking-associated proteins in enhancing responsiveness to anti-PDL1 in TNBC using a19 CRISPR based screen; 3.) Assess IT injection of plasmid CXCL9 to determine if direct targeting of the CXCR320 axis is sufficient to enhance T cell infiltration. Dr. Crosbys long-term goal is to build a research program that21 contributes to an understanding of immune cell infiltration into tumors to better design combine and predict22 responses to immunotherapies with a specific focus on BC. A critical impediment to these types of studies is23 the lack of oncogene-driven spontaneous BC tumor models which hampers the translational applicability of24 many pre-clinical findings. Key resources for Dr. Crosbys independent research are the spontaneous HER2-25 driven and p53/BRCA1/PTEN-driven TNBC models that she has created published and will uniquely possess26 to perform these and many other studies. Addressing the basic question of how to enhance T cell infiltration27 into tumors has significant implications for changing the paradigm of treatment for BC patients particularly28 using an intratumoral plasmid approach that is easily altered to follow up on newly identified targets. The29 funding provided by this K22 award will protect Dr. Crosbys research time to develop and publish these30 foundational studies which will support subsequent R01 grant submissions. 117573 +No NIH Category available Address;African American;Animal Model;Azacitidine;Behavior;Biological Models;Castration;Caucasians;Cell Culture Techniques;Cells;Clinical;Clinical Data;DNA;DNA Methylation;DNA Methyltransferase Inhibitor;Data;Data Set;Decitabine;Development;Disease;Disease Outcome;Early Diagnosis;Future;Genes;Genetic Transcription;Gleason Grade for Prostate Cancer;Goals;Growth;Indolent;Intervention;Invaded;Investigation;Knowledge;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Measurable;Measurement;Metastatic Prostate Cancer;Methods;Methylation;Micrometastasis;Mission;Modeling;Molecular;Morbidity - disease rate;Mus;Neoplasm Metastasis;Pathologic;Pathway interactions;Patient-Focused Outcomes;Patients;Phenotype;Prostate;Prostate Cancer therapy;Rectum;Resistance;Risk;Role;Sampling;Signal Transduction;Specimen;TWIST1 gene;Testing;Tissues;Transferase;Treatment outcome;United States National Institutes of Health;anticancer research;cancer health disparity;cell motility;conventional therapy;demethylation;digital;early onset;effective therapy;enzalutamide;epigenetic regulation;ethnic disparity;experimental study;health disparity;in vitro activity;in vivo;in vivo Model;inhibitor;innovation;knock-down;mRNA Expression;men;mortality;novel;patient stratification;prognostic indicator;promoter;prostate cancer cell;prostate cancer metastasis;protein expression;racial disparity;rectal;tibia;tool;transcription factor;tumor;tumor xenograft Prostate Cancer Health Disparity: Role of PDEF In African American (AA) men prostate cancer is characterized by higheraggressiveness early onset more extensive metastases and increased mortality ratescompared to those in Caucasian men. Conventional therapies produce a high rate ofcure for patients with localized prostate cancer but there is no effective treatment forintervention in metastatic prostate cancer. Currently-used prognostic indicators (Digitalrectal exam PSA measurement and Gleason score) do not predict metastases riskaccurately. These facts underline the urgent yet unmet need for identification andcharacterization of new targets that can help distinguish between aggressive andmetastatic prostate cancer from an indolent disease. Our goal is to address this vitalknowledge gap by characterizing the role of Prostate Derived Ets Transcription Factor(PDEF) in PCa aggressiveness thereby reducing the prostate cancer-related healthdisparity between African American (AA) and Caucasian men. We propose a novel andunique causative link between PDEF and metastases. Our proposal also detailsmechanistic experiments that may help to patient stratification and use PDEF expressionas a means to stratify patients to demethylating agents. Our studies will pave the wayfor routine clinical use of PDEF as an independent predictor of metastases risk. NCI 10689652 9/8/23 0:00 PAR-18-654 5R01CA242839-04 5 R01 CA 242839 4 "NADEAU, CHRISTINE FRANCES" 7/1/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OBT-B(55)R] 1859413 "KOUL, HARI K" Not Applicable 2 UROLOGY 782627814 M7KCJ79FAVH5 782627814 M7KCJ79FAVH5 US 29.957378 -90.082793 577902 LSU HEALTH SCIENCES CENTER NEW ORLEANS LA SCHOOLS OF MEDICINE 701127021 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 329537 NCI 224175 105362 In African American (AA) men prostate cancer is characterized by higher aggressiveness more extensivemetastases early onset and increased mortality rates compared to those in Caucasian men. We propose toevaluate role of PDEF (Prostate Derived Ets Factor) and TWIST-1 in PCa health disparity. The studiesproposed in this application are driven by our novel observations that there is graded decrease in PDEF levelsin prostate cancer cells with increasing aggressive phenotype and in prostate cancer tissue sections ofpatients. We also observed in multiple clinical data sets that PDEF mRNA expression is decreased in highGleason grade PCa and in tumor metastasis. Moreover we observed a reciprocal relationship between PDEFand Twist-1 expression in PCa tissues and that PDEF and Twist-1 expression could predict PCa patientsurvival. In preliminary studies we observed that PDEF expression is decreased in prostate cancer cells fromAA men and in cells with aggressive phenotype and experimental modulation of PDEF expression modulatescell migration and clonogenic activity in part by promoting luminal differentiation. These exciting preliminarydata form the basis of our proposed hypothesis: First that In African American Men PDEF could serve as afunctional marker for distinguishing aggressive prostate cancer from an indolent disease. Second that PDEFfunctions as a metastasis suppressor in prostate cancer in part by modulating expression of Twist-1 and thirdthat Loss of PDEF can help us stratify PCa patients that might respond to DNA methyl transferase inhibitors.We propose three aims to test these hypothesis. AIM 1: To establish differences in expression levels of PDEFbetween grade-matched Prostate Cancer specimens from African American and Caucasian men and correlatethese with patient outcomes; AIM 2: To determine the role of PDEF in PCa metastasis and racial disparityusing in vivo model systems and ; *AIM 3: To evaluate if prostate cancers with PDEF loss respond morefavorably to combination of ADT (Enzalutamide) and DNA methyl-transferase inhibitors (azacytidine anddecitabine) as compared to ATD alone. The proposed studies are innovative as these will enhanceunderstanding of role of PDEF in suppressing prostate cancer metastasis and help us evaluate usefulness ofPDEF/Twist-1 in early detection of patients that may harbor aggressive prostate cancer with enhancedmetastatic potential. The impact of our study will be on the development of a new method to distinguishaggressive and metastatic phenotype of prostate cancer from an indolent disease which will particularlybenefit AA men and reduce ethnic disparity in in prostate cancer treatment outcomes. 329537 +Cancer; Genetics Affect;Alleles;Aneuploidy;Antineoplastic Agents;Biochemical;C-terminal;Cancer Etiology;Cell Cycle;Cell Cycle Arrest;Cell Proliferation;Cell division;Cell physiology;Chromatin;Chromosomal Instability;Chromosomal Stability;DNA Damage;DNA Repair;Development;Drug Design;Excision;Genes;Genome Stability;Genomic Instability;Genotoxic Stress;Glioblastoma;Human;In Vitro;Individual;Inherited;Lead;Lipids;MG132;Maintenance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mitosis;Mitotic;Molecular;Molecular Analysis;Molecular Target;Monoubiquitination;Mus;Mutate;Mutation;Normal Cell;Nuclear;Nuclear Import;Nuclear Translocation;PDPK1 gene;PTEN gene;Phosphatidylinositol 45-Diphosphate;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Polyubiquitination;Post-Translational Protein Processing;Predisposition;Process;Protein Kinase;RNA Interference;Regulation;Reporting;Research;Role;Second Messenger Systems;Serine;Signal Pathway;Signal Transduction;Tail;Testing;Threonine;Tumor Suppressor Proteins;Work;angiogenesis;cell growth;drug development;in vitro Model;in vivo;interest;malignant breast neoplasm;mouse model;multicatalytic endopeptidase complex;phosphatidylinositol 345-triphosphate;phosphatidylinositol 34-diphosphate;segregation;tumor;tumorigenesis;ubiquitin-protein ligase Chromatin PTEN: Its Regulation And Functions NARRATIVE PTEN is a key negative regulator of cell proliferation that primarily functions to inhibit the PI3K/Aktsignaling axis and guards against chromosomal instability during cell division. This proposal plans toelucidate the molecular mechanism by which chromatin PTEN functions in mitosis as well as understandhow chromatin PTEN is regulated during cell division. These studies are of great significance for ourunderstanding of how normal cells suppress chromosomal instability aneuploidy and tumorigenesis. NCI 10689348 9/9/22 0:00 PA-16-160 3R01CA213159-05S2 3 R01 CA 213159 5 S2 "WITKIN, KEREN L" 8/1/17 0:00 7/31/23 0:00 Cancer Etiology Study Section[CE] 1878808 "DAI, WEI " Not Applicable 12 PUBLIC HEALTH & PREV MEDICINE 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 8/1/21 0:00 7/31/23 0:00 393 Non-SBIR/STTR 2022 87632 NCI 51700 35932 Chromatin PTEN: Its Regulation And Function Phosphatase and tensin homolog (PTEN) functions as a major negative regulator of the PI3K signalingpathway. PTEN is frequently mutated in a variety of human malignancies including glioblastoma prostatecancer and breast cancer. Inherited PTEN mutations cause cancer-susceptibility conditions. PTEN is alsoknown to have nuclear/chromatin functions deregulation of which apparently causes chromosomal instability.However the exact functions of chromatin PTEN and its molecular regulation remain poorly understood. Pastresearch shows that proper subcellular localization of PTEN after genotoxic stress is regulated by molecularmechanisms that involve post-translational modifications. We recently demonstrated that chromatin PTENsignificantly increases during mitosis coinciding with an increase in PTEN phosphorylation in the C-terminaltail. Biochemical and molecular analyses revealed that Plk1 was responsible for PTEN phosphorylation onS380 a residue not targeted by any other known kinases. We and others have shown that PTEN specificallyinteracts with Cdh1 (APC/CCdh1) and WWP2 two ubiquitin E3 ligases. Chromatin PTEN removal during mitoticexit and the physical interaction between PTEN and Cdh1 was a proteasome-dependnent process.Furthermore we observed that a cleaved form of WWP2 specifically is enriched during G2 and mitotic stagescorrelating with chromatin PTEN accumulation. WWP2 silencing accelerates mitotic progression. Wehypothesize that chromatin PTEN plays a crucial role in mitotic progression whose subcellularlocalization and function are controlled by Plk1 Cdh1 and WWP2 and that its molecular deregulationleads to chromosomal instability and tumor development. To test the validity of our hypothesis we willdetermine whether and how phosphorylation facilitates chromatin translocation of PTEN dissect the role ofPTEN ubiquitin E3 ligases in regulating its stability and study the phosphatase-independent function of PTENin supressing chromosomal instability and tumor development using both in vivo and in vitro models. Ourproposed studies will not only elucidate the molecular mechanism by which chromatin PTEN is regulatedduring the cell cycle but will also reveal how PTEN functions in maintaining chromosomal stability andsuppressing malignant transformation. This line of research can lead to the identification of new moleculartargets in the PTEN regulatory network that can be explored for cancer drug designs and development. 87632 +No NIH Category available 3-Dimensional;Address;Aerobic;Algorithms;Anatomy;Animals;Artificial Intelligence;Biological;Biological Models;Biometry;Cancer Patient;Cancerous;Carbon;Cell Line;Cells;Charge;Chordoma;Clinical;Clinical Data;Collaborations;Communities;Complication;Computational Technique;Computing Methodologies;Consensus;Custom;Data;Data Set;Development;Disease;Dose;Effectiveness;European;Evaluation;Event;Goals;Head;High-LET Radiation;Human;Human Cell Line;Hypoxia;Implementation readiness;In Vitro;Ions;Japanese;Knowledge;Linear Energy Transfer;Machine Learning;Mammalian Cell;Measurement;Measures;Medical;Methods;Modeling;Modernization;Molecular;Monte Carlo Method;Mus;Normal tissue morphology;Organ;Patients;Pattern;Pelvis;Performance;Photons;Physics;Probability;Procedures;Prostate;Protons;Radiation Oncology;Radiation therapy;Radiobiology;Radiology Specialty;Relative Biological Effectiveness;Research;Research Design;Rodent;Roentgen Rays;Scanning;Science;Structure;Techniques;Technology;Testing;Therapy trial;Tissues;Validation;absorption;cancer cell;clinical application;clinical efficacy;clinical implementation;clinical practice;computer science;design;dosimetry;flasks;improved;in vivo;innovation;ionization;irradiation;mathematical algorithm;mathematical sciences;member;nanoscale;novel;optimal treatments;particle;particle beam;particle therapy;predictive modeling;prospective;prostate cancer cell;radiation response;response;side effect;simulation;treatment planning;tumor;tumor xenograft Ionization Detail - Biologically based treatment planning for particle therapy beyond LET-RBE Project NarrativeProton and ion therapy have the potential to provide effective tumor control in cancer patients while minimizingthe side effects of radiotherapy. Optimal treatment requires accurate knowledge of the biological effectivenessof the beams which is directly impacted by the patterns of ionization produced in the patient. In this proposalwe develop and evaluate innovative methods to use ionization detail for planning particle beam therapy. NCI 10689288 8/28/23 0:00 PA-20-185 5R01CA266467-02 5 R01 CA 266467 2 "OBCEMEA, CEFERINO H" 9/1/22 0:00 8/31/27 0:00 Radiation Therapeutics and Biology Study Section[RTB] 7621859 "FADDEGON, BRUCE " "JAEKEL, OLIVER ; MAO, JIAN-HUA ; SCHULTE, REINHARD W." 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 581657 NCI 527677 53980 Project SummaryCurrent proton and ion therapy treatment planning procedures utilize either the physical quantity linearenergy transfer (LET) as a surrogate for biological effectiveness or make use of relative biologicaleffectiveness (RBE) models that convert absorbed dose to biologically weighted dose assumed to be iso-effective to photons. LET is indeed important clinically for planning treatments with charged particles butthere are known problems. Ion beams with the same LET can have different RBE depending on particle typeand energy. Therefore LET by itself is not an ideal parameter to use in radiation treatment planning (RTP).For clinical application of carbon therapy RBE-models have been developed. However comparisons ofdifferent RBE models used for carbon therapy have shown that dose prescriptions implemented with theEuropean local effect model or the Japanese National Institute of Radiological Sciences mixed beam modelcan be up to 15% different. We use the term ionization detail (ID) to mean the detailed distribution ofionizing events along a particle track on the nanometer scale. Our chief hypothesis which issupported by strong prior evidence is that ID can predict better than LET and existing RBEmodels the biological effects associated with high-LET radiation. We have previously shown howID can be used together with these models to improve their performance providing a path for integratingID-based RTP into clinical practice. Our approach could lead to a consensus in proton and ion therapy RTP.With four Specific Aims we have chosen a translational and stepwise approach to build an ID-basedprediction model. We will test this model for different endpoints and model systems ranging from in vitrocell and molecular data obtained by irradiating human cancer cells in flasks and anatomical phantoms toin vivo mice/human tumor data. We will develop advanced algorithms and computational GPU-based methods and use them for effective inverse treatment planning with actively scanned proton and ionbeams. This technology will be applied to demonstrate the practicality and evaluate the clinical efficacy of ourapproach in prostate and chordoma treatments first prospectively in human-size pelvis and head phantomsand finally retrospectively in patients treated for these diseases. We have assembled a strong team with thecomplementary expertise needed for this project. Members of our team have all successfullycollaborated together. Upon completion we will provide a rigorously tested and validated approach toID-based particle RTP that will be available for cross-correlation with existing clinical data and forcareful testing in prospective clinical particle therapy trials. 581657 +No NIH Category available Address;Adult;Alternative Splicing;Big Data;Biological Models;Biology;Brain Neoplasms;Clinical;Data;Data Analyses;Development;Diagnostic;Disease;Embryo;Embryonic Development;Ependymoma;FDA approved;Gene Fusion;Genetically Engineered Mouse;Genomics;Glioma;Grant;Human;Laboratories;Malignant Neoplasms;Microtus;Modeling;Molecular;Mus;Patients;Pharmaceutical Preparations;Population;RNA Splicing;Role;Technology;Testing;Therapeutic;Therapeutic Studies;Tissues;Variant;Visualization software;Work;human data;improved;large datasets;meningioma;mouse model;rare cancer;therapeutic target;treatment response;tumor;tumorigenesis The role and mechanism of alternative RNA splice variants and gene fusions as drivers of cancer NarrativeHuman brain tumors are genomic heterogeneous within the tumor population and very large datasets of clinicaland molecular data on large numbers of patients have been created. Over the past 25 years my laboratoryhas worked on modeling brain tumors in mice and correlating those findings with data from human brain tumorpatients and have developed unique big data visualization tools that allow the interactive interpretation of thesedata. We are now using our mouse modeling technology to understand the biology of rare tumors driven bygene fusions and the role of RNA splicing variants of TrkB in development and oncogenesis. NCI 10689283 9/11/23 0:00 PAR-20-278 5R35CA253119-04 5 R35 CA 253119 4 "MILLER, DAVID J" 9/21/21 0:00 8/31/28 0:00 ZCA1-GRB-S(M1) 2067406 "HOLLAND, ERIC C." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 839885 NCI 588000 446880 AbstractMy lab has been the leader in the field of mouse modeling for brain tumors over the past 15 years. We havedeveloped a suite of genetically engineered mouse models that are demonstrably representative of humangliomas and other tumor types. These models have been used to inform treatment options for clinical agentsand this now enables us to propose these models are suitable testbeds for testing potential major improvementsto how these diseases are treated. We have three projects. 1) We are understanding the central role of specificsplice variants of TrkB in embryonic development and oncogenesis throughout the body. The RCAS modelingsystem has been used here to show that forced expression of the embryonic splice variant in adult tissuesleads to cancer formation broadly. In this project we will investigate the mechanisms of oncogenesis for thissplice variant and determine if it could be a good diagnostic or therapeutic target. 2) We are now using themodeling system developed for glioma to address the biology of rare tumors driven by gene fusions. In thisgrant we propose to understand the mechanisms of oncogenesis for YAP1 gene fusions in the rare tumorsependymoma porocarcinoma and aggressive meningioma (all for which we have YAP1 gene fusion drivenmodels currently). 3) And we will use these mouse models to study therapeutic response and identifytherapeutic strategies for these fusion driven tumors including identification of FDA approved drugs that wouldintervene downstream of the action of the gene fusion. 839885 +No NIH Category available Adult;Advocacy;Agreement;American;Area;Asian;Asian Americans;Asian population;Behavioral;California;Cancer Control;Cancer Etiology;Cancer Patient;Caregivers;Caring;Cause of Death;Chinese;Collaborations;Communication;Competence;Data;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Early Diagnosis;East Asian;Emotions;Ethnic Population;Faculty;Family;Focus Groups;Fostering;Future;Goals;Guidelines;Hispanic;Immigrant;Incidence;Intervention;Interview;Knowledge;Korean American;Koreans;Language;Latinx;Literature;Malignant Neoplasms;Medical;Mentorship;Methods;Modality;Not Hispanic or Latino;Oncology;Outcome;Participant;Patient Outcomes Assessments;Patients;Persons;Phase;Philosophy;Population;Positioning Attribute;Process;Provider;Qualifying;Quality of Care;Quality of life;Randomized Controlled Trials;Research;Research Methodology;Research Personnel;Resource Development;Resources;Structure;Supportive care;Surveys;Survival Rate;Symptoms;Testing;Training;Vietnamese;Work;Writing;active method;cancer care;cancer survival;care delivery;care outcomes;career;coping;cultural values;demographics;design;experience;functional disability;improved;improved outcome;informant;innovation;malignant breast neoplasm;mortality;preference;psychosocial;psychosocial resources;response;skills;social;southeast Asian;survivorship;tenure track;therapy development Supportive Care Needs in Asian Americans with Metastatic Cancer Project NarrativeCancer incidence is expected to increase to 23.6 million by 2030 worldwide and cancer isthe leading cause of death for Asian Americans whose numbers are rapidly rising to reach40 million by 2050. Despite instances of greater cancer-specific mortality compared to otherAsians and likely limited access to high-quality care due many experiencing languagebarriers (~50%) very little is known about supportive care needs in Chinese- Vietnamese-and Korean-Americans with metastatic cancers. This project will fill a critical gap in ourunderstanding and develop culturally relevant and scalable psychosocial resources aimedat improving the quality of life of Chinese- Vietnamese- and Korean-Americans withmetastatic cancers. NCI 10689259 7/21/23 0:00 RFA-CA-19-029 5R00CA246058-04 5 R00 CA 246058 4 "GUIDA, JENNIFER LYN" 7/1/20 0:00 8/31/25 0:00 ZCA1-TCRB-T(O2) 15168136 "KIM, JACQUELINE H. J." Not Applicable 47 INTERNAL MEDICINE/MEDICINE 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 244019 NCI 155426 88593 Project SummaryCancer is the leading cause of death for Asian Americans the fastest growing U.S. immigrant group projectedto outnumber Latinx Americans by 2065. Provision of high-quality supportive care for Asian American cancerpatients with metastatic disease is critically needed; however there is a dearth of literature on this topic. Withinthe Asian American population Confucian-heritage East Asian and Southeast Asian ethnic groups sharecultural values and norms relevant to tailoring cancer care and a goal of the K99 phase is to generate mixed-methods data on supportive care needs specifically for Chinese- Vietnamese- and Korean-descent (CVK)patients with metastatic cancer. Findings from the K99 phase will be shared with research participants andapplied collaboratively to develop culturally relevant supportive care resources in the R00 phase. The overalltraining objective of this Early K99/R00 is to provide Dr. Kim with additional years of mentorship to become ahighly qualified independent investigator at the intersection of culture and supportive oncology. Training goalsinclude developing competencies in: 1) patient/family-centered and stakeholder-engaged cancer careresearch 2) patient-reported outcomes needs and preferences in metastatic cancer 3) advanced mixed-methods research particularly for working with non-English speaking participants and 4) psychosocialintervention development in cancer. Through the proposed training Dr. Kims background in qualitative andquantitative research culturally-grounded research in Asian American populations and cancer-related copingprocesses will be integrated to solidify expertise in mixed methods and cultural implications forpsychosocial/behavioral cancer control as she transitions into an independent tenure-track faculty position.During the K99 phase Dr. Kim will be under the primary mentorship of Dr. Annette Stanton at UCLA alongsidea strong co-mentorship team of experts (Drs. Marjorie Kagawa-Singer Qian Lu Anna Lau) committed toadvancing Dr. Kims career. The proposed research will also document participants reflections about theexperience of collaborative research for developing future guidelines on inclusive research practices thatpromote advocacy. Dr. Kims long-term plan is to develop test and disseminate supportive care resources andinterventions that are culturally relevant and scalable toward the ultimate goals of facilitating quality care andimproving outcomes in understudied populations with metastatic cancer. 244019 +No NIH Category available Address;Advisory Committees;Area;Basic Cancer Research;Basic Science;Behavioral Sciences;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Catchment Area;Clinic;Clinical;Clinical Trials;Communication;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Continuity of Patient Care;Data Analyses;Data Collection;Database Management Systems;Device or Instrument Development;Doctor of Philosophy;Education;Ensure;Equipment;Equipment and Supplies;Extramural Activities;Faculty;Funding;Goals;Grant;Health Services Accessibility;Intake;Intervention Trial;Lead;Leadership;Libraries;Malignant Neoplasms;Methodology;NCI Center for Cancer Research;New Mexico;Observational Study;Peer Review;Peer Review Grants;Pilot Projects;Policies;Population;Population Sciences;Principal Investigator;Procedures;Process;Protocols documentation;Reporting;Research;Research Design;Research Methodology;Research Personnel;Research Support;Resource Allocation;Resource Sharing;Resources;Role;Services;Site Visit;Structure;Surveys;System;Techniques;Technology;Training;Translational Research;Travel;Universities;Work;anticancer research;behavior measurement;cancer care;community engagement;cost effective;cost estimate;data management;ethnic diversity;experience;innovation;meetings;member;personalized approach;programs;racial diversity;rapid growth;recruit;research and development;research study;translational cancer research;web page;working group Behavioral Measurement and Population Science n/a NCI 10689245 9/8/23 0:00 PAR-20-043 5P30CA118100-18 5 P30 CA 118100 18 9/26/05 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6322 9803600 "GUEST, DOLORES " Not Applicable 1 Unavailable 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM Domestic Higher Education 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 79725 52624 27101 Behavioral Measurement and Population Science Shared ResourceProject Summary/AbstractThe University of New Mexico Comprehensive Cancer Center (UNMCCC) Behavioral Measurement andPopulation Science Shared Resource (BMPS) supports basic and translational cancer research by providing acontinuum of services including research design and development data collection and data managementqualitative data analysis accrual reporting facilitation and training to UNMCCC members and non-memberusers. Resource Director Andrew Sussman Ph.D. MCRP (CCPS) and Associate Director Dolores GuestPh.D. RD (CCPS) supervise BMPS which is operated by a full-time staff including experienced Cancer Control& Population Science (CCPS) researchers. The Cancer Center Research Administration (CCRA) supports theadministrative needs of the Resource which includes fiscal management hiring purchasing requests related tosupplies and equipment and travel reimbursements. BMPS leadership oversee billing and usage and manageall project tracking. The Resource Director and staff work closely with UNMCCC research programs to developnew methodologies that promote innovative basic and translational research goals. BMPS actively facilitates anddisseminates information about new population science technologies by maintaining an up-to-date web pageand library and by giving presentations at UNMCCC meetings and retreats. During the previous 5-year projectperiod 22 Principal Investigators 21 of which are UNMCCC members from two of UNMCCCs three ResearchPrograms used BMPS to support 16 peer-reviewed grant funded projects 20 peer-reviewed Cancer Center pilotprojects and an additional 7 CCSG Supplement and 1 P20 Supplement studies for a total of 44 projects. +No NIH Category available Accreditation;Advanced Malignant Neoplasm;Affect;Aliquot;American;American Indians;Archives;Basic Cancer Research;Basic Science;Biological Specimen Banks;Blood;Blood specimen;Bone Marrow;Budgets;COVID-19 pandemic;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Certification;Clinical;Clinical Research;Clinical Sciences;Collection;Communication;Community Outreach;Computerized Medical Record;Consent;Cryopreserved Cell;DNA;Data;Databases;Date of birth;Dedications;Diagnosis;Diagnostic;Doctor of Philosophy;Education;Equipment;Ethnic Origin;Ethnic Population;Faculty;Formalin;Freezing;Funding;Goals;Grant;Guidelines;Hematologic Neoplasms;Hispanic;Hispanic Populations;Hospitals;Human;Image;Immunofluorescence Immunologic;Information Systems;Institutional Review Boards;Ischemia;Leadership;Link;Malignant Neoplasms;Medical;Methodology;Methods;Names;Native Americans;New Mexico;Normal tissue morphology;Not Hispanic or Latino;Nursing Faculty;Outcome;Outreach Research;Pamphlets;Paraffin Embedding;Pathologist;Pathology;Patient-Focused Outcomes;Patients;Peer Review Grants;Plasma;Population;Population Heterogeneity;Population Sciences;Precision Medicine Initiative;Procedures;Process;Publications;RNA;Race;Reporting;Research;Research Personnel;Resource Sharing;Resources;Saliva;Sampling;Serum;Services;Slide;Source;Specimen;Stains;System;Technology;Tissue Banks;Tissue Expansion;Tissue Stains;Tissues;Training Programs;Translational Research;Tumor Bank;Universities;Update;Virginia;Whole Blood;Work;animal tissue;anticancer research;biobank;cancer care;cancer genome;cancer health disparity;cancer therapy;college;community engagement;cost effective;digital imaging;electronic data;evidence base;experience;falls;genome sequencing;human tissue;innovation;meetings;member;neoplasm registry;patient engagement;programs;repository;sample collection;translational cancer research;tumor;tumor registry;web page;web site Human Tissue Repository and Tissue Analysis n/a NCI 10689242 9/8/23 0:00 PAR-20-043 5P30CA118100-18 5 P30 CA 118100 18 9/26/05 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6320 1894302 "MCCANCE, DENNIS J." Not Applicable 1 Unavailable 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM Domestic Higher Education 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 106751 70463 36288 Project Summary/Abstract - Human Tissue Repository & Tissue Analysis Shared ResourceThe UNMCCC Human Tissue Repository and Tissue Analysis Shared Resource (HTR Tissue) supports basicand translational cancer research by providing cost effective tumor and matched normal tissue either as frozenor Formalin-Fixed Paraffin-Embedded (FFPE) aliquots to UNMCCC members and non-member users. ScientificDirector Dennis J. McCance Ph.D. (CT) supervises the Resource which is operated by a full-time staffincluding experienced wet lab research technicians plus a digital imaging expert providing services aligned withthe College of American Pathologist (CAP) Accreditation Program. The UNMCCC and the UNM HSCDepartment of Pathology jointly manage the Resource which provides several essential services includingsectioning H&E immunohistochemical or immunofluorescence staining of tissue sections and digital imagingand annotation of stained specimens. The Resource currently houses > 40000 biospecimens with >20000frozen and >13000 FFPE biospecimens and >6000 blood samples (whole blood serum plasma and bothfrozen and cryo-preserved cells) that reflect the race/ethnicity of our population in New Mexico with 36% of thesamples from Hispanic 49% from non-Hispanic white and 12% from Native American and 3% otherrace/ethnicities. During the last grant period we dispensed 1196 tissue specimens 1496 slides for DNA/RNAextraction and processed 4000 animal tissues. As the Cancer Center has developed its precision medicineinitiative and joined the ORIEN consortium HTR Tissue has expanded the tissue collection to include bloodand/or saliva from all consented patients (germline control) and blood and bone marrow from patients withhematological malignancies (New Services). The Resource maintains a database of the collected tissues(TissueMetrix) with critical information on the patient (e.g. name date of birth and race/ethnicity) tissue sourceand diagnosis and other variables including the method of tissue collection ischemic times and how the tissuewas processed after receipt by the HTR Tissue. Projects billing and usage are tracked through a centralized online system. The Resource Director and staff work closely with the Research Programs to develop newmethodologies that promote innovative basic and translational research goals and the Resource activelyfacilitates and disseminates information about new imaging and annotation technologies by maintaining an upto-date web page and by giving presentations at UNMCCC meetings and retreats. During the previous 5-yearproject period 101 investigators of whom 59 were UNMCCC members from all 3 UNMCCC Research Programsused the Resource. The Resource contributed to 38 cancer focused publications by the UNMCCC users whowere supported by 120 peer-reviewed grants. In the reporting year of July 2019 June 2020 the CCSGsupported 17% of the Resource budget with UNMCCC members responsible for 74% of Resource usage. +No NIH Category available 3-Dimensional;Address;Algorithmic Analysis;Award;Basic Cancer Research;Biological Assay;Biophysics;Cancer Biology;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell physiology;Cells;Cellular biology;Collaborations;Color;Comprehensive Cancer Center;Computer software;Development;Doctor of Philosophy;Education;Educational Activities;Ensure;Equipment;Faculty;Feedback;Fluorescence;Fluorescence Microscopy;Future;Goals;Grant;Human Resources;Image;Image Analysis;Imaging Techniques;Imaging technology;Investigation;Laboratories;Malignant - descriptor;Methods;Microscope;Microscopy;Molecular and Cellular Biology;NCI Center for Cancer Research;New Mexico;Newsletter;Oncogenic;Online Systems;Peer Review Grants;Phase;Pilot Projects;Postdoctoral Fellow;Preparation;Publications;Research;Research Personnel;Reservations;Resistance;Resource Sharing;Resources;Sampling;Schedule;Services;Signal Transduction;Solvents;Surveys;System;Techniques;Technology;Tissue imaging;Tissues;Training;Universities;University resources;Update;Visualization;anticancer research;assay development;cancer cell;cell behavior;cell fixing;cellular imaging;cost effective;cost effectiveness;experience;fluorescence imaging;graduate student;imaging capabilities;imaging modality;imaging platform;innovation;instrument;instrumentation;lectures;light microscopy;meetings;member;meter;microscopic imaging;molecular imaging;multimodality;nanoscale;new technology;novel;particle;programs;prospective;protein protein interaction;quantitative imaging;single molecule;superresolution imaging;technology development;temporal measurement;translational cancer research;ultra high resolution;web page;web site Fluorescence Microscopy and Cell Imaging n/a NCI 10689239 9/8/23 0:00 PAR-20-043 5P30CA118100-18 5 P30 CA 118100 18 9/26/05 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6318 8783243 "LIDKE, DIANE " Not Applicable 1 Unavailable 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM Domestic Higher Education 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 92864 61297 31567 Project Summary/Abstract - FLUORESCENCE MICROSCOPY & CELL IMAGING SHARED RESOURCEThe UNMCCC Fluorescence Microscopy & Cell Imaging Shared Resource (Microscopy) supports basic and translational cancer research by providing state-of-the-art instrumentation and software for quantitative multiscale and multi-modal fluorescence imaging to UNMCCC members and non-member users. Faculty Director Diane Lidke Ph.D. (CMO) supervises the Resource which is operated by Michael Paffett Ph.D. a full-time staff with broad expertise in fluorescence microscopy instrumentation. The UNMCCC Research Administration manages the Resource which provides access to 11 commercial instruments for fluorescence phase or brightfield imaging as well as multiple software platforms for image analysis. In addition CCC members have access to the Super-Resolution Core directed by Keith Lidke Ph.D. (CMO) that houses cutting-edge and developmental instrumentation for single molecule super-resolution and hyperspectral imaging. The SuperResolution core is further supported by Michael Wester Ph.D. who is an expert in single molecule image analysis. This partnership provides UNMCCC members with technologies not available at other Cancer Centersand the opportunity to develop new imaging and analysis approaches to specifically address outstanding questions in cancer biology. The expense and significant expertise required to purchase maintain and operate such a diverse suite of instrumentation is prohibitive for most users and underscores the value added by the Resource. Microscopy actively facilitates and disseminates information about new cellular imaging technologies by maintaining an up-to-date web page and by giving presentations at UNMCCC meetings and retreats.Resource faculty and staff also contribute to multiple education activities including courses focused on microscopy that attract graduate students and postdocs from UNMCCC member labs. Reservations billing and usage are tracked through a centralized on-line system. During the previous 5-year project period 59 UNMCCC member laboratories from three UNMCCC Research Programs used the Resource resulting in 67 publications. In the previous period UNMCCC members were responsible for 61% of total Resource usage by billing and were supported by 132 peer-reviewed grants and 8 UNMCCC pilot projects. +No NIH Category available Adopted;Animal Model;Applications Grants;Automobile Driving;Basic Cancer Research;Basic Science;Biological;Cancer Center;Cancer Center Support Grant;Cell Separation;Cells;Clinical;Cloning;Collaborations;Complex;Computer software;Contracts;Cytometry;Data Analyses;Data Set;Deposition;Development;Doctor of Philosophy;Education;Equipment;Experimental Designs;Faculty;Feedback;Fees;Flow Cytometry;Flow Cytometry Shared Resource;Fluorescence;Funding;Goals;Growth;Heterogeneity;Individual;Institution;Instruction;International;Interruption;Licensing;Link;Malignant Neoplasms;Methodology;Mission;Modernization;Molecular;New Mexico;Newsletter;Online Systems;Outcome;Patients;Peer Review Grants;Play;Population;Price;Publications;Research;Research Personnel;Reservations;Resource Sharing;Resources;Role;Sampling;Science;Services;Societies;Speed;Sterility;Structure;System;Techniques;Technology;Therapeutic;Training;Translational Research;Universities;Update;Work;animal imaging;anticancer research;cost effective;cost estimate;drug discovery;humanized mouse;improved;innovation;innovative technologies;instrumentation;interest;meetings;member;mouse model;new technology;programs;protein expression;single cell analysis;tool;transcriptome sequencing;translational cancer research;tumor;web page;webinar Flow Cytometry n/a NCI 10689238 9/8/23 0:00 PAR-20-043 5P30CA118100-18 5 P30 CA 118100 18 9/26/05 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6317 9203925 "GILLETTE, JENNIFER " Not Applicable 1 Unavailable 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM Domestic Higher Education 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 77159 50931 26228 Project Summary/Abstract - FLOW CYTOMETRY SHARED RESOURCEThe UNMCCC Flow Cytometry Shared Resource (Flow Cytometry) supports basic and translational cancer research by providing cost-effective full service flow cytometry services and high-speed sterile sorting of cells including the analysis of patient samples to UNMCCC members and non-member users. Faculty Director Jennifer Gillette Ph.D. (CMO) supervises the Resource which is operated by a full-time core technical director Wade Johnson Ph.D. The UNMCCC Research Administration manages the Resource which provides several types of flow cytometry services including instrumentation for complex multi-panel analysis as well as single cell sorting into microplate wells for cloning PCR and RNA-sequencing analysis. Reservations billing and usage are tracked through a centralized on-line system. Additionally the Resource manages the flow cytometry data analysis contract for the institution which individual labs can buy into at a reduced price. The Resource Director and staff work closely with UNMCCC research programs to develop new methodologies that promote innovative basic and translational research goals. Moreover the Resource actively promotes and disseminates information about new flow cytometry and data analysis techniques by maintaining an up-to-date web page and by giving presentations at UNMCCC meetings and retreats. Finally the Resource Director and staff actively engage in the education mission of the UNMCCC through training and participation in several graduate level courses. During the previous 5-year project period 58 UNMCCC members from 3 UNMCCC Research Programs were responsible for 75% of total Resource usage. Additionally the Resource supported 146 publications and 128 peer-reviewed grants. +No NIH Category available Access to Information;Applications Grants;Awareness;Bioinformatics;Bioinformatics Shared Resource;Cancer Center;Cancer Center Support Grant;Collaborations;Complex;Comprehensive Cancer Center;Computer software;Custom;Data;Data Analyses;Data Set;Databases;Dedications;Doctor of Philosophy;Drug Targeting;Education;Engineering;Equipment;Faculty;Fostering;Funding;Genomics;Goals;Grant;Informatics;Knowledge;Knowledge Management;Legal patent;Link;Malignant Neoplasms;Manuscripts;Methodology;Methods;Modeling;NCI Center for Cancer Research;New Mexico;Newsletter;Nucleic Acids;Oncogenes;Pharmaceutical Preparations;Play;Publications;Publishing;Quality Control;RNA;Research;Research Design;Research Personnel;Reservations;Resource Sharing;Resources;Role;Schools;Services;Students;Techniques;Technology;United States National Institutes of Health;Universities;Update;Variant;Work;anticancer research;bioinformatics pipeline;bioinformatics resource;bioinformatics tool;cancer genome;cancer genomics;cheminformatics;computing resources;cost effective;design;falls;genome sequencing;genomic data;genomic tools;high throughput analysis;high-throughput drug screening;improved;innovation;innovative technologies;instrumentation;lectures;meetings;member;multidimensional data;news;novel;patient engagement;population based;programs;recruit;secondary analysis;skills;tool;web page Bioinformatics n/a NCI 10689237 9/8/23 0:00 PAR-20-043 5P30CA118100-18 5 P30 CA 118100 18 9/26/05 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6316 1881486 "EDWARDS, JEREMY S" Not Applicable 1 Unavailable 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM Domestic Higher Education 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 90520 59750 30770 BIOINFORMATICS SHARED RESOURCEProject Summary/AbstractThe UNMCCC Bioinformatics Shared Resource supports basic and advanced bioinformatics needs includinganalysis of high throughput genomic sequencing high-throughput drug screening cheminformatics targetanalytics and pharmacoinformatics. Faculty Director Yan Guo Ph.D. (CMO) supervises the Resource with twoadditional associate directors Jeremy Edwards Ph.D. (CMO) and Tudor Opera Ph.D. (CT). The BioinformaticsShared Resource is operated by two full-time staff. The Cancer Center Research Administration manages theResource which provides several types of services including quality control processing and analysis of newlygenerated genomics data secondary analysis of existing genomics data study design manuscript and grantsupport. Reservations billing and usage are tracked through an in-house developed SQL database. TheResource Director and staff worked closely with the Research Programs to develop new methodologies thatpromote innovative basic and genomics research goals and the Resource actively facilitates and disseminatesinformation about new bioinformatics technologies by maintaining an up-to-date web page and by givingpresentations/seminars at UNMCCC meetings and retreats. During the previous 5-yr project period 35 PIs usedservices from the Bioinformatics Shared Resources a substantial increase from the 24 users from the previousperiod. Among them 30 were UNMCCC members from the three Research Programs. Also during the lastcycle the Bioinformatics Shared Resources assisted with the publication of 20 scientific manuscripts.Furthermore the Bioinformatics Shared Resource supported the submission of 28 national grants (20 NCI and8 non-NCI). Nine of them were funded and are currently supporting activites in the Bioinformatics SharedResource. Nine grants are currently pending review. +No NIH Category available Address;Advisory Committees;Age;Age Years;American Indians;Biological Markers;Black race;Budgets;Cancer Center Support Grant;Cancer Patient;Catchment Area;Center for Translational Science Activities;Childhood;Clinical;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Clinical Research Protocols;Clinical Trials;Clinical Trials Network;Communities;Community Clinical Oncology Program;Community Health;Community Networks;Community Participation;Community Practice;Comprehensive Cancer Center;Contracts;Critiques;Data;Development;Disease;Disparity;Doctor of Philosophy;Ensure;Ethnic Population;Evaluation;Funding;Future;Goals;Graduation Rates;Grant;Health Personnel;Hispanic;Improve Access;Incidence;Industry;Informatics;Infrastructure;Institution;Intervention;Intervention Trial;Investments;Latinx;Malignant Neoplasms;Medicaid;Mentors;Mexican;Minority;Mission;Modeling;Modernization;Monitor;NCI Center for Cancer Research;New Mexico;Not Hispanic or Latino;Oncologist;Patients;Pattern;Performance;Persons;Physician Executives;Physicians;Population;Poverty;Prevention;Protocols documentation;Recommendation;Regulation;Research;Research Infrastructure;Research Personnel;Resource Sharing;Rural Population;Safety;Science;Site;Structure;Therapeutic Trials;Training;Translating;Translational Research;Translations;Underserved Population;Uninsured;Universities;Update;Woman;aged;anticancer research;cancer care;cancer clinical trial;cancer genome;cancer health disparity;care delivery;community engagement;data management;data warehouse;early phase trial;ethnic minority;genome sequencing;high school;improved;innovation;investigator-initiated trial;neoplasm registry;operation;organizational structure;patient engagement;patient safety;personalized intervention;precision medicine;process improvement;programs;quality assurance;racial minority;racial population;recruit;response;screening;severe COVID-19;trial design;tumor registry;waiver;working group Clinical Protocol and Data Management n/a NCI 10689233 9/8/23 0:00 PAR-20-043 5P30CA118100-18 5 P30 CA 118100 18 9/26/05 0:00 8/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 6313 16222873 "BROWN GLABERMAN, URSA " Not Applicable 1 Unavailable 829868723 G389MFAYJNG9 829868723 G389MFAYJNG9 US 35.090968 -106.617544 10021612 UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR ALBUQUERQUE NM Domestic Higher Education 871310001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 175491 115835 59656 ABSTRACT: Funded in part as a Minority/Underserved NCI Community Oncology Research Program (NCORP; 2UG1CA189856-06; Muller PI (CT)) Clinical Protocol and Data Management (CPDM) at the University of New Mexico Comprehensive Cancer Center (UNMCCC) is overseen by a centralized Clinical Research Office (CRO) for all cancer clinical research performed at UNMCCC and within our statewide 501c3 cancer clinical trials network with community health providers (The New Mexico Cancer Care Alliance; NMCCA). The overarching goals of CPDM are to provide expert high quality central management to ensure all cancer clinical trials: 1) are aligned with UNMCCC science; 2) address cancer patterns and needs of the diverse New Mexico catchment area; 3) are performed under the highest quality and rigor; 4) meet federal and institutional regulations; and 5) are monitored for performance compliance and patient safety. Clinical research at UNMCCC is led by Carolyn Muller MD (Associate Director for Clinical Research (CT))and Ursa Brown-Glaberman MD (Medical Director of the CRO/CPDM (CT)). In 2018 to assure operational improvement efficiency and increased compliance the UNMCCC recognized the need to modernize and restructure the relationship between UNM and NMCCA. With assistance from Huron Consulting a robust evaluation and process improvement project began leading to a new collaborative model implemented in 2019-2020. This model assures continued community participation by retaining the NMCCA 501c3 but moved and centralized all operations and staff (budgeting/contracting trial activation regulatory quality assurance auditing/ monitoring training and informatics) within the UNMCCC CRO/CPDM now serving both UNMCCC and NMCCA. While necessitating a slowing of accruals in 2019-2020 the new structure is ensuringhigher quality performance increased CPDM oversight greater community engagement and catchment areaimpact and is poised to achieve more robust accrual in the future. In this grant period within our catchment areas population of 2.1 million people (63% racial/ethnic minorities 40% insured by Medicaid and 13.4% (age 18-64) uninsured) there were 7395 total accruals (2654 intervention and 4741 non-intervention). While COVID-19 severely impacted accruals in 2020 in 2019 CPDM supported the recruitment of 1361 accrualsto 206 active clinical research protocols at UNMCCC (455 interventional and 906 non-interventional accruals) and 149 total accruals (135 interventional and 14 non-interventional 93% supporting NCORP) from NMCCAaffiliate sites. The CPDM performs robust auditing and data safety monitoring of investigator-initiated trials (IITs) across all sites engaged in UNM IITs under the 2020 updated DSMP. In 2019 and 2020 Q1-2 women represented 82% and 76% of interventional trial accruals respectively. Accruals of Hispanic (32% 43%) and American Indian (10% 9%) data across intervention trials align with the race and ethnic population of cancer patients in NM (2019 2020). Intervention accruals span all ages with 28% > 65 years of age in 2019. +No NIH Category available Malignant Female Reproductive System Neoplasm;Patient-Focused Outcomes;Research Training;Urologic Cancer Patient-Centered Outcomes Research Training in Urologic and Gynecologic Cancers (PCORT UroGynCan) PROJECT NARRATIVEThrough mentored research training and career development of the next generation of interdisciplinary teammembers leaders and innovators in health services and patient-centered outcomes clinical epidemiologyand dissemination and implementation the UCLA Patient-Centered Outcomes Research Training in Urologicand Gynecologic Cancers (PCORT UroGynCan) program will increase the pace and volume of scientificdiscovery and innovation in the diagnosis treatment and prevention of urologic and gynecologic cancers andadvance our knowledge of delivery and implementation strategies for proven interventions in real-worldpractice and community settings. In closing the gap between evidence-based interventions and their uptakeacross diverse health services settings and populations including historically underserved populations whomanifest wide disparities in health status PCORT UroGynCan will contribute to improved health systemperformance as well as outcomes and health-related quality of life of patients and their families. NCI 10689207 9/20/23 0:00 PA-18-403 5T32CA251072-04 5 T32 CA 251072 4 "DAMICO, MARK W" 9/1/20 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 2098730 "LITWIN, MARK S." "KRAKOW, DEBORAH " 36 UROLOGY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 375344 NCI 401216 26177 PROJECT SUMMARY/ABSTRACTThe proposed new mentored postdoctoral training program at UCLA Patient-Centered Outcomes ResearchTraining in Urologic and Gynecologic Cancers (PCORT UroGynCan) is designed to prepare outstandingpostdoctoral scholars (including MD PhD MD/PhD ScD DrPH and PharmD) for research careers focused ondevelopment and uptake of new scientific discoveries and innovations that improve the design delivery andoutcomes of reproductive system cancer care at the individual population and health care system levels. Inthe current era of declining numbers of health scientists nationwide particularly among clinical providers andof expanding necessity to bridge the gap between research and practice across diverse real-world settings ofhealth services and systems as well as demographically diverse populations the PCORT UroGynCan programwill train next-generation researchers to formulate and conduct studies in close collaboration with andresponsive to the actual interests needs and priorities of health care system stakeholders. To illuminate andbetter understand variation in practice and outcomes and the barriers of T4 translation the interdisciplinarycurriculum and mentored hands-on research opportunities of the new T32 program interweave the scientificexpertise and mentoring experience of 27 multidisciplinary faculty who are committed to collaborative team-based cross-training and research in health services and patient-centered outcomes clinical epidemiologyand dissemination and implementation including the newly emerging field of learning health systems. With fourpostdoctoral trainees per year each for a 2- or potentially 3-year appointment instantiating for workforceexpansion multidisciplinary cohorts of PCOR-dedicated trainees both experienced in and newly attracted toresearch in urologic and gynecologic oncology PCORT UroGynCan will leverage topically germane resourcesof education training and career development programs at UCLA for the core curriculum and protected time toachieve the following specific aims: (1) expand the multidisciplinary knowledge base of evidence-basedpractice as it relates to reproductive system cancer care; (2) provide didactic and hands-on research training inthe intellectual and philosophical foundation of rapid and sustainable uptake of novel proven interventionswithin the broader research enterprise of translational medicine; (3) develop trainees' scientific writing skills forpresentations publications and grants; (4) provide an academic environment that enables development of theresearch skills and experience needed for successful independent scientific careers as members and leadersof interdisciplinary teams dedicated to improving patient and population outcomes and health systemperformance in urologic and gynecologic oncology; and (5) model research-empowering teaching andmentoring skills for trainees' development including their eventual replication of research training and careerdevelopment programs in health system stakeholder-partnered improvements of reproductive system cancercare as their careers evolve into stable scientific independence. 375344 +No NIH Category available 3-Dimensional;Ashkenazim;Autologous;Automobile Driving;BRCA mutations;Biological Assay;Cancer Model;Cell Line;Clinical;Clinical Data;Clinical Trials;Communities;Competence;Complement;DNA Damage;DNA Repair;Data;Disease;Drug Screening;Drug Utilization;Drug resistance;Elements;Endothelial Cells;Exhibits;FDA approved;Fibroblasts;Funding;Genotype;High Prevalence;Human;In Vitro;Institution;International;Libraries;Link;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Modeling;Mutate;Mutation;Pancreatic Adenocarcinoma;Patients;Pharmaceutical Preparations;Phenotype;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Positioning Attribute;Precision medicine trial;Research;Research Personnel;Resistance;Sampling;Scientist;Therapeutic;Work;actionable mutation;anticancer research;bioprinting;brca gene;clinical translation;drug discovery;drug efficacy;drug response prediction;drug sensitivity;experience;experimental study;high risk population;homologous recombination;improved;in vitro Model;in vivo;inhibitor therapy;innovation;member;mouse model;multidisciplinary;mutant;novel;novel therapeutic intervention;novel therapeutics;oncology program;pancreatic cancer patients;patient population;patient subsets;personalized approach;personalized medicine;personalized therapeutic;pre-clinical;precision oncology;repaired;resistance mechanism;response;success;targeted treatment;three-dimensional modeling;translational impact;treatment response;tumor;tumor microenvironment Developing a patient derived model platform to treat BRCA1/2-mutant pancreatic cancers Project NarrativeTherapies targeted towards patients whose tumors harbor BRCA1/2 mutations including PARP inhibitors havegenerated much excitement in the pancreatic cancer research community. However some patients whoinitially respond to targeted therapy still ultimately succumb to this disease while others do not respond at all.Our proposed studies will develop and validate a platform to provide new and innovative therapeutic strategiesto treat patients with pancreatic cancer. NCI 10689186 8/1/23 0:00 PAR-20-292 5R21CA263996-02 5 R21 CA 263996 2 "CHEN, WEIWEI" 8/1/22 0:00 7/31/24 0:00 ZCA1-TCRB-V(M1)S 8439029 "BRODY, JONATHAN " "SEARS, ROSALIE C" 1 SURGERY 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 158826 NCI 124666 34160 ABSTRACTUp to 17% of pancreatic adenocarcinoma (PDAC) patients' tumors harbor mutations that are vulnerable toexploitation through DNA-damage response and repair (DDR) inhibitory strategies. In fact nearly 10% ofunselected PDACs harbor BRCA1/2 mutations and a higher prevalence exists in high-risk populations (e.g.up to 20% of Ashkenazi Jews). The scientific basis for this study is that PDAC patients who harbor BRCA1/2mutations are exquisitely sensitive to platinum- and/or poly ADP ribose polymerase inhibitor (PARPi)-basedtherapies due to synthetic lethality. The rigor of prior research relates to our efforts to leverage a promisingpersonalized approach to targeting BRCA1/2-mutated PDACs where a precedent has been established by theinvestigators' collective pre-clinical and clinical work. Although this current best-in-class personalizedapproach for the treatment of BRCA1/2-altered PDACs is promising it is limited a range of resistancemechanisms. The primary and translational impact of our proposal is that we are taking the first steps indeveloping and validating an ex vivo platform that will identify novel therapeutic strategies and thus may informpersonalized therapeutic approaches for patients with BRCA1/2 mutant PDACs. Our international team ofexperts focused on this subset of PDACs is uniquely positioned to develop this platform utilizing our Patient-Derived Models of Cancer (PDMCs) obtained from an established BRCA-PANC consortium (supported byeach institution) and through our ongoing suite of funded clinical trials. We will begin with a large panel of well-validated patient-derived cell lines (PDCLs) from patients with documented resistance or sensitivity toolaparib. In Aim 1 we will assess the functional integrity of the network in BRCA1/2-altered PDCLs allowingus to determine whether DDR competence in PDCLs aligns with drug resistance or sensitivity. We will furtherutilize this platform to screen a panel of available FDA-approved drugs in the context of functional DDRcompetence. Once completed we will have identified novel drug sensitivities of BRCA1/2-deficient PDACtumors with known DDR capabilities. In Aim 2 we will expand our 2D studies and employ an established 3Dbioprinted model to determine the influence of the tumor microenvironment on drug sensitivity and resistance.Moreover we will depict and identify components of the tumor microenvironment that are driving drugresistance. Finally we validate our in vitro models in a pilot pre-clinical in vivo experiment. Overall we plan todeliver the following milestones: 1) evaluate the DDR competence of BRCA1/2-deficient PDCLs and how thisrelates to innate resistance; 2) identify FDA-approved drugs that may be used to target this subset of resistantPDACs; and 3) determine the significance of the tumor microenvironment and how its elements may impactdrug efficacy. This work will provide the framework for a novel ex vivo platform that could be: a) utilized fordrug discovery for a subset of PDAC patients in desperate need of new therapies and b) ultimately acomplementary assay plugged into our precision medicine trials. 158826 +No NIH Category available AFP gene;Acceleration;Advocate;Africa;Africa South of the Sahara;African;Age;Albumins;Antigens;Attenuated;Behavioral;Biological Markers;Birth;CD4 Lymphocyte Count;Cancer Etiology;Cessation of life;Chronic Hepatitis B;Cirrhosis;Clinical;Clinical Research;Country;Data;Development;Diagnostic;Dose;Eligibility Determination;Etiology;Fibrosis;Foundations;Funding;Genotype;Goals;Guidelines;HIV;HIV Infections;Hepatitis B Infection;Hepatitis B Surface Antigens;Hepatitis B Vaccines;Hepatitis B Virus;Hepatitis B e Antigens;Hepatitis C virus;Human;Image;Incidence;Individual;Infection;Interruption;Interview;Investigation;Liver Fibrosis;Malignant Neoplasms;Medical;Mentors;Monitor;Mutation;Outcome;Oxidative Stress;Oxidative Stress Pathway;Participant;Pathogenesis;Pathology;Patients;Persons;Population;Population Attributable Risks;Population Research;Prevention;Preventive vaccine;Primary carcinoma of the liver cells;Process;Prospective cohort;Questionnaires;RNA;Research;Research Infrastructure;Research Personnel;Resources;Risk;Risk Factors;Sampling;Schistosoma mansonii infection;Senegal;Serum;Serum Albumin;Standardization;Tenofovir;Testing;Translational Research;Treatment Protocols;Uganda;Universities;Viral;Virus Diseases;Virus Replication;Visit;alpha-Fetoproteins;antiretroviral therapy;cell injury;chronic infection;co-infection;cohort;data quality;design;dosimetry;elastography;high risk;high risk population;insight;novel;novel marker;recruit;response;screening;sociodemographics;study population;treatment as prevention;treatment response;ultrasound;vaccine acceptance;viral DNA;virus core Antiviral treatment as prevention for HBV- and HBV/HIV-associated hepatocellular carcinoma n/a NCI 10689163 8/9/23 0:00 RFA-CA-20-001 5U54CA254565-04 5 U54 CA 254565 4 9/9/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6287 8420758 "KIRK, GREGORY D" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 270293 238094 32199 Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa and as patients with HIV livelonger the HCC burden may increase. In prior studies our team identified chronic infection with hepatitis Band C viruses (HBV HCV) HIV and Schistosomiasis mansoni as independent risk factors for HCC. Comparedto the US HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of onlymonths. Proposed is an East and West African partnership between colleagues at Makerere University inUganda Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellularcarcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research mentoringand clinical activities in both countries our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatmentsto interrupt or reverse the impact of these HCC-causing infections. Consortium activities are designed toenhance both the clinical population and translational research infrastructure and individual Africaninvestigator capacity to conduct high-level collaborative investigation of HIV chronic infections and HCC. Inthis project we will form a large prospective cohort of HBV and HBV/HIV co-infected persons with balancedrecruitment from both Uganda and Senegal. Guideline-appropriate antiviral treatment against HBV will beinitiated and HCC surveillance with ultrasound and alpha-fetoprotein performed. Baseline and six-month studyvisits will collect questionnaire clinical ultrasound and elastography data. We will define clinical outcomes ofHBV treatment in terms of reduced standard and novel viral biomarkers stabilization and regression of liverfibrosis and reduced incidence of HCC. In parallel using a novel albumin adductomics approach we willinvestigate changes in oxidative stress pathways and identify novel biomarkers relevant for both HBV and HIVinfections. For each of these analyses HIV co-infection is evaluated as a key effect modifier. The impact ofthese studies will be to inform treatment and screening approaches and potentially identify novel biomarkersfor guiding HBV management and HCC prevention. +No NIH Category available Advocate;Africa;Africa South of the Sahara;African;Age;Award;Career Mobility;Clinical;Clinical Research;Collaborations;Complement;Country;Development;Fostering;Funding;Goals;HIV;Hepatitis B Infection;Hepatitis B Virus;Hepatitis C virus;Individual;Infection;Interruption;Investments;Lead;Link;Malignant Neoplasms;Malignant neoplasm of liver;Medical;Mentors;Mentorship;Mission;Patients;Peer Review;Pilot Projects;Play;Primary carcinoma of the liver cells;Process;Publications;Qualifying;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Risk Factors;Role;Schistosoma mansonii infection;Senegal;Talents;Training Activity;Training Programs;Uganda;Universities;anticancer research;career;career development;chronic infection;design;faculty mentor;global health;innovation;next generation;peer;programs;recruit;senior faculty;skills;success H2A Developmental Core n/a NCI 10689162 8/9/23 0:00 RFA-CA-20-001 5U54CA254565-04 5 U54 CA 254565 4 9/9/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6286 8420758 "KIRK, GREGORY D" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 73386 73386 0 Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa and as patients with HIV livelonger the HCC burden may increase. In prior studies our team identified chronic infection with hepatitis Band C viruses (HBV HCV) HIV and Schistosomiasis mansoni as independent risk factors for HCC. Comparedto the US HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of onlymonths. Proposed is an East and West African partnership between colleagues at Makerere University inUganda Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellularcarcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research mentoringand clinical activities in both countries our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatmentsto interrupt or reverse the impact of these HCC-causing infections. We will accomplish this objective bydeveloping local capacity and performing important research. The H2A Scholar Award provides synergisticfunding to early-stage African investigators for both individual career development activities and a mentoredpilot project utilizing the substantive Consortium resources. Designation of Scholars will alternate yearlybetween Uganda and Senegal and opportunities to link across countries and with Hopkins will actively bepursued. Our approach of providing early-stage African investigators with substantive pilot project resourcesand pairing them with a Hopkins mentor will maximize the return on investment. The ultimate goal is to developa cadre of talented qualified African investigators to serve as leaders in the field of HIV and HCC research. +No NIH Category available Adherence;Advocate;Africa;Africa South of the Sahara;African;Age;Behavioral;Clinical;Complex;Country;Data;Data Collection;Data Element;Data Set;Development;Electronics;Ensure;Europe;Evaluation;Goals;HIV;Hepatitis B Infection;Hepatitis B Virus;Hepatitis C virus;Hospitals;Image;Infection;Interruption;Interview;Laboratories;Language;Lead;Leadership;Malignant Neoplasms;Measurement;Measures;Medical;Mentors;Methods;Monitor;Participant;Patients;Performance;Periodicals;Pilot Projects;Primary carcinoma of the liver cells;Procedures;Process;Protocols documentation;Questionnaires;Research;Research Personnel;Resources;Risk Factors;Role;Schistosoma mansonii infection;Secondary to;Senegal;Site;Standardization;Switzerland;Technology Transfer;Telemedicine;Testing;Training;Uganda;Universities;career;chronic infection;clinical research site;cohort;data dictionary;data harmonization;data integration;data quality;design;experience;novel;quality assurance;recruit;research study;response H2A Clinical Core n/a NCI 10689161 8/9/23 0:00 RFA-CA-20-001 5U54CA254565-04 5 U54 CA 254565 4 9/9/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6285 8838107 "AIZIRE, JIM " Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 83531 64752 18779 Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa and as patients with HIV livelonger the HCC burden may increase. In prior studies our team identified chronic infection with hepatitis Band C viruses (HBV HCV) HIV and Schistosomiasis mansoni as independent risk factors for HCC. Comparedto the US HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of onlymonths. Proposed is an East and West African partnership between colleagues at Makerere University inUganda Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellularcarcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research mentoringand clinical activities in both countries our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatmentsto interrupt or reverse the impact of these HCC-causing infections. We will accomplish this objective bydeveloping local capacity and performing important research. The Consortium represents a complexpartnership between investigators staff hospitals and universities in 4 countries representing East and WestAfrica Switzerland and USA with 6 clinical sites 4 primary laboratories and ~20 coinvestigators speakingEnglish and French. The Clinical and Data Quality Core (CDQ) is designed to support the standardizedrigorous data collection management and analysis of Consortium data. CDQ will ensure that high quality datais rigorously collected that assessment of clinical measurements and laboratory testing be standardizedbetween sites that data harmonization be effectively performed and that high quality analytical datasets beproduced in a timely manner. CDQ Core provides support for both Projects and to pilot projects through theDevelopmental Core. Support to both the scientific and capacity development objectives ensures thatcomprehensive systematic and rigorous data collection management and analysis in Consortium projects willappropriately maximize resources and have a high likelihood of scientific impact. +No NIH Category available Accounting;Advocate;Africa;Africa South of the Sahara;African;Age;Biological Specimen Banks;Cell Nucleus;Clinical;Collaborations;Communication;Communities;Computer software;Country;Data Collection;Database Management Systems;Development;Documentation;Education;Electronic Mail;Ensure;Equity;Face;Generations;Goals;Grant;HIV;Hepatitis B Infection;Hepatitis B Virus;Hepatitis C virus;Human;Infection;International;Interruption;Lead;Leadership;Link;Malignant Neoplasms;Medical;Mentors;Monitor;Online Systems;Patient Recruitments;Patients;Peer Review;Periodicals;Policies;Preparation;Primary carcinoma of the liver cells;Problem Solving;Progress Reports;Public Relations;Publications;Reporting;Research;Research Personnel;Resources;Review Literature;Risk Factors;Role;Schistosoma mansonii infection;Senegal;Site;Structure;Supervision;Training;Uganda;Universities;Work;chronic infection;data harmonization;data sharing;expectation;human subject protection;meetings;organizational structure;participant retention;programs;symposium;web site H2A Admin Core n/a NCI 10689158 8/9/23 0:00 RFA-CA-20-001 5U54CA254565-04 5 U54 CA 254565 4 9/9/20 0:00 8/31/25 0:00 ZCA1-TCRB-D 6283 8420758 "KIRK, GREGORY D" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 211902 175175 36727 Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa and as patients with HIV livelonger the HCC burden may increase. In prior studies our team identified chronic infection with hepatitis Band C viruses (HBV HCV) HIV and Schistosomiasis mansoni as independent risk factors for HCC. Comparedto the US HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of onlymonths. Proposed is an East and West African partnership between colleagues at Makerere University inUganda Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellularcarcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research mentoringand clinical activities in both countries our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatmentsto interrupt or reverse the impact of these HCC-causing infections. The Administrative and CoordinatingCore (ACC) will provide overall leadership for implementing the scientific agenda of the H2A consortium. Usingbest practices from decades of international research collaboration the H2A Consortium proposes an effectiveorganizational structure and strong leadership with a track record of international research collaboration. Theorganizational framework builds upon the ongoing close working relationship between prior co-PIs fromUganda and Hopkins and welcomes the Senegalese team as equal partners. The ACC will establishtransparent structures to support rigorous study oversight effective communication and efficient problem-solving. The H2A Consortium effectively integrates ACC activities within a closely interacting SteeringCommittee (SC) comprised of the Overall Co-Leaders and the Project /Core PIs. For each Project or Core theleadership represents an equitable partnership with PIs from each site sharing responsibilities. This leadershipnucleus is further supported by an External Advisory Panel (EAP) and a Community Advisory Panel (CAP)with collaborative links to NCI Program leadership and other U54 Consortia sites. The impact of our integratedresearch and capacity development activities will be establishment of the H2A Consortium as partneredCenters of Excellence on HIV and HCC in East and West Africa. +No NIH Category available Address;Adopted;Advocate;Africa;Africa South of the Sahara;African;Age;Aging;Award;Biological Markers;Cause of Death;Chronic;Clinical;Clinical Data;Clinical Research;Collaborations;Country;Data;Development;Early identification;Epidemiology;Etiology;Funding;Goals;HIV;HIV Infections;Hepatitis B Infection;Hepatitis B Therapy;Hepatitis B Virus;Hepatitis C virus;Hepatocarcinogenesis;Human;Immune response;Incidence;Individual;Infection;Infrastructure;Interruption;Intervention;Investigation;Investments;Lead;Liver;Liver Fibrosis;Liver diseases;Malignant Neoplasms;Measurement;Medical;Mentors;Monitor;Oncogenes;Pathway interactions;Patients;Persons;Pilot Projects;Population;Population Research;Praziquantel;Prevention strategy;Primary carcinoma of the liver cells;Process;Prospective cohort;Research;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Resource-limited setting;Resources;Risk;Risk Factors;Schistosoma mansonii infection;Senegal;Serum Albumin;Translational Research;Uganda;United States National Institutes of Health;Universities;Viral hepatitis;antiretroviral therapy;biobank;biomarker discovery;career development;chronic infection;clinical translation;co-infection;cohort;curative treatments;data quality;design;effective therapy;high risk population;improved;innovation;mortality;multidisciplinary;novel;novel marker;predictive marker;prevent;prospective;recruit;response;scale up;screening;success;translational study;treatment strategy HIV and HCC in Africa: The H2A Consortium Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa and as patientswith HIV live longer the burden of HCC may increase. The proposed Consortium will conductclinical research projects in Uganda and Senegal to investigate if and how treatment of HCC-causing infections may prevent HCC. In parallel Consortium resources are applied towardsdeveloping human and clinical research capacity in both countries to address the growingproblem of HIV and HCC. NCI 10689156 8/9/23 0:00 RFA-CA-20-001 5U54CA254565-04 5 U54 CA 254565 4 "DOMINGUEZ, GERALDINA" 9/9/20 0:00 8/31/25 0:00 ZCA1-TCRB-D(M1) 8420758 "KIRK, GREGORY D" "OCAMA, PONSIANO " 7 PUBLIC HEALTH & PREV MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF PUBLIC HEALTH 212182680 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 990369 NCI 845577 144792 Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa and as patients with HIV livelonger the HCC burden may increase. In prior studies our team identified chronic infection with hepatitis Band C viruses (HBV HCV) HIV and Schistosomiasis mansoni as independent risk factors for HCC. Comparedto the US HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of onlymonths. Proposed is an East and West African partnership between colleagues at Makerere University inUganda Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellularcarcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research mentoringand clinical activities in both countries our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatmentsto interrupt or reverse the impact of these HCC-causing infections. We will accomplish this objective bydeveloping local capacity and performing important research. Consortium activities are designed to enhanceboth the clinical population and translational research infrastructure and individual African investigator capacityto conduct high-level collaborative investigation of HIV chronic infections and HCC. First we will form a largeprospective cohort of HBV and HBV/HIV co-infected persons to define who needs HBV treatment determineclinical responses and characterize breakthrough HCC while investigating novel biomarkers. To understandour data demonstrating synergistic interaction between chronic HBV and Sm infections we will examine HBVclinical and immunological responses in the periphery and the liver in response to Sm treatment. HIV isinvestigated as a key modifier of these relationships in both projects. Integrated within our scientific agendaearly-stage African investigators will be provided mentoring and career development support while conductinga collaborative pilot project leveraging Consortium resources. The impact of our integrated research andcapacity development activities will be establishment of the H2A Consortium as partnered Centers ofExcellence on HIV and HCC in East and West Africa. 990369 +No NIH Category available Ablation;Abraxane;Affect;Age of Onset;Albumins;Award;Backcrossings;Binding;Biological Assay;Biological Models;Blood Vessels;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Risk Factor;Breast Cancer cell line;Breast Cancer therapy;Breeding;Cell Line;Chromosome 3;Chromosome Mapping;Chromosomes;Clinical;Data;Dependence;Disease;Disease-Free Survival;Distant;Dose;Drug Carriers;Drug Delivery Systems;Endothelium;Environment;Estrogen receptor positive;Experimental Genetics;Extravasation;Fatty acid glycerol esters;Female;Fluorescence;Formulation;Genes;Genetic;Germ-Line Mutation;Growth;Hematogenous;Heritability;Human;Image;Imaging Device;Immunity;Immunocompetent;Immunocompromised Host;Inbred Strain;Incidence;Inherited;Link;Liposomal Doxorubicin;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Maps;Measurable;Mediating;Modeling;Molecular;Molecular Target;Monoclonal Antibodies;Morphology;Neoplasm Metastasis;Neoplasms in Vascular Tissue;Non-Malignant;Norway;Optics;Paclitaxel;Parents;Perfusion;Pharmaceutical Preparations;Phenotype;Proliferating;Rat Strains;Rat Transgene;Rattus;Recovery;Reporting;Research;Resistance;Role;Sequence Analysis;Severe Combined Immunodeficiency;Signal Transduction;Testing;Time;Tissues;Toxic effect;Treatment Efficacy;Tumor Angiogenesis;Tumor Promotion;Tumorigenicity;Variant;Vascular remodeling;Xenograft Model;Xenograft procedure;angiogenesis;antibody conjugate;breast cancer progression;cancer cell;cancer therapy;causal variant;comparative;congenic;consomic;contrast imaging;density;genetic manipulation;genetic variant;image guided;improved;in vivo evaluation;innovation;insight;intravital microscopy;malignant breast neoplasm;mammary;nanoGold;nanocarrier;nanomedicine;nanoparticle;nanotherapy;neoplastic cell;non-invasive imaging;notch protein;novel;overexpression;patient derived xenograft model;pharmacologic;photothermal therapy;prognostic;prognostic indicator;receptor;response;risk variant;salt sensitive;therapeutic nanoparticles;tool;transcriptome sequencing;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression;tumor xenograft;tumorigenesis;uptake;vasculogenesis;whole body imaging Leveraging genetic mapping for personalized targeting of breast cancer microenvironment We have identified germline variants that impact breast cancer risk and therapy response through the tumormicroenvironment. In this renewal application we will leverage these findings and a novel tool (ConsomicXenograft Model) for elucidating the mechanisms of increased breast cancer therapy resistance and drugdelivery barriers in the tumor microenvironment. NCI 10689152 8/23/23 0:00 PA-20-185 5R01CA193343-07 5 R01 CA 193343 7 "DEY, SUMANA MUKHERJEE" 4/1/15 0:00 7/31/27 0:00 Developmental Therapeutics Study Section[DT] 8567773 "JOSHI, AMIT " Not Applicable 4 PHYSIOLOGY 937639060 E8VWJXMMUQ67 937639060 E8VWJXMMUQ67 US 43.04575 -88.020374 46001 MEDICAL COLLEGE OF WISCONSIN MILWAUKEE WI SCHOOLS OF MEDICINE 532263548 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 349713 NCI 224175 125538 Breast cancer is the most prevalent female malignancy and is highly heritable yet the majority of breast cancerrisk remains undefined. Heritable factors underlie most aspects of breast cancer risk [e.g. incidence age-ofonset metastatic progression and disease-free survival]. In addition to variants that impact tumor cells directly(i.e. tumorigenicity) heritability is implicated in multiple components of the tumor microenvironment [e.g.tissue remodeling angiogenesis and immunity] which also impact tumorigenesis and progression. Howeverthe genetic variant(s) underlying differences in the tumor microenvironment have rarely been the focus ofgenetic mapping studies and as such remain poorly defined. In the parent R01 project we defined thesegermline factors and discovered the role of notch-DLL4 expression of 3rd Chromosome on salt sensitive rat asgoverning tumor proliferation metastasis as well as nanoparticle uptake and therapy response in humantumor xenografts. These findings were made by leveraging a new model of breast cancer(termed the Consomic Xenograft Model - CXM) that focused on genetic mapping of strain-specific variant(s)that impact tumor progression through the tumor microenvironment. A consomic rat is one in which an entirechromosome is introgressed into the isogenic background of another inbred strain by selective breeding. Thusobserved phenotypes can be linked to single chromosomes and then further elucidated by comparativesequence analysis and/or selective backcrossing to yield smaller congenics. In CXM the consomic andparental strains are converted to SCID (severe combined immunodeficiency) so that orthotopicallyxenografted human breast cancer cells can be tested in vivo. Because the human breast cancer cells are notvaried between strains any differences in breast cancer progression and metastasis drug delivery andtherapy response or resistance are due solely to genetic differences in the tumor microenvironment notthe malignant cancer cells. We will leverage our discovery of the role of notch-DLL4 expression differences onnanocarrier uptake distribution and therapy response and the consomic and congenic rat strains to assess: (1) Define the morphologic features and molecular mechanisms in tumor endothelium which govern drugcarrier permeation retention and clearance and their dependence on inherited genes (2) Identify the impact ofco-targeting notch-DLL4 in tumor endothelium with three nanoparticle mediated drug delivery systems onnanoparticle transport tumor distribution and therapy response in a panel of representative breast cancermodel systems and (3) Demonstrate the role of inherited tumor micro-environment targeting for treating distantmetastatic disease in immunocompromised and immunocompetent consomic rat strains. These studies willprovide mechanistic insight to the role of the tumor microenvironment in drug delivery and response tonanoparticle therapies. 349713 +No NIH Category available 3-Methylcholanthrene;Address;Adipose tissue;Alzheimer's Disease;Alzheimer's disease model;Appearance;Applications Grants;Arterial Fatty Streak;Attention;Awards and Prizes;Binding;Blocking Antibodies;Breast Cancer Model;CTLA4 gene;Cancer Patient;Cancer cell line;Catabolism;Cause of Death;Cell Line;Cell surface;Cessation of life;Cholesterol;Cholesterol Esters;Chronic;Cleaved cell;Colorectal;Complement;Complex;Data;Defect;Diagnosis;Disease;Disease model;Fibrosis;Foam Cells;Generations;Genes;Genetic study;Goals;High Fat Diet;Host Defense;Human;ITAM;Immune;Immune response;Immune system;Immunologic Receptors;Immunosuppression;Immunotherapy;Infiltration;Knowledge;Lipid Binding;Lipids;Lipoprotein Binding;Lipoproteins;Lung;MC38;Macrophage;Malignant Neoplasms;Mediating;Membrane;Metabolism;Metalloproteases;Methylcholanthrene;Microglia;Modeling;Monoclonal Antibodies;Mouse Mammary Tumor Virus;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Newly Diagnosed;Nobel Prize;Oncology;Pathway interactions;Patients;Peripheral;Phospholipids;Population;Pre-Clinical Model;Process;Reporting;Resolution;Risk Factors;Senile Plaques;Shapes;Signal Transduction;Subcutaneous Injections;TREM2 gene;Testing;Therapeutic;Tissues;Transgenic Mice;Tumor-infiltrating immune cells;United States;Variant;Virus Diseases;anti-CTLA-4 therapy;anti-PD-1;antitumor effect;cancer immunotherapy;cancer therapy;carcinogenesis;checkpoint therapy;chemotherapy;chronic inflammatory disease;effector T cell;human cancer mouse model;humanized mouse;immune checkpoint blockade;immunosuppressive macrophages;improved;inhibiting antibody;lipid metabolism;malignant breast neoplasm;mouse model;neoplastic cell;novel therapeutic intervention;patient subsets;polyoma middle tumor antigen;prevent;programmed cell death protein 1;programs;receptor;response;standard care;subcutaneous;success;targeted cancer therapy;transmission process;tumor;tumor growth;tumor microenvironment Targeting TREM2 to boost anti-cancer therapy PROJECT NARRATIVEThere is an urgent need to identify new targets to improve present cancer immunotherapies andto make them effective in a larger subset of patients. In this grant application we identify TREM2a receptor present on immune cells that infiltrate the tumor as a promising target for cancertherapy in combination with other immune checkpoint blockade strategies. NCI 10689150 8/18/23 0:00 PA-20-185 5R01CA262684-03 5 R01 CA 262684 3 "SINGH, ANJU" 9/1/21 0:00 8/31/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 7360179 "COLONNA, MARCO " Not Applicable 1 PATHOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 432265 NCI 274454 157811 PROJECT SUMMARYCancer is a leading cause of death and disease. The recent success of immune checkpoint therapy (ICT) hasrevolutionized tumor therapy indicating that manipulation of the immune system is an effective strategy to treatcancer. MAbs inhibiting CTLA-4 and PD-1 have been extensively shown to unleash T cell effector functions tocontrol tumors in both mice and some cancer patients. However ICT is incompletely effective for certain tumorswhich escape using multiple mechanisms one of which is the generation of a tumor microenvironment rich inimmunosuppressive myeloid cells. TREM2 is an immune receptor expressed by tissue macrophages that bindsphospholipids and lipoproteins and transmits intracellular signals through the ITAM pathway. RecentlyTREM2+ macrophages have been reported in many human tumors. In our preliminary data we demonstrate thatTREM2-deficiency or mouse TREM2 blockade with the mAb 178 curbs subcutaneous tumor growth of the 3-methylcholanthrene (MCA) cell line and leads to complete tumor regression when associated with suboptimalPD-1 immunotherapy. Furthermore high-resolution analysis of the tumor cell infiltrate in the MCA model revealscomplex remodeling of the myeloid cell landscape in Trem2/ and anti-TREM2 treated mice. The overall goal ofthis application is to advance our understanding of the therapeutic impact of TREM2 blockade in mouse modelsand human cancer. In Aim 1 we show that TREM2 targeting enhances ICT mediated by anti-PD1; we proposeto determine whether TREM2 deficiency or blockade impact other tumor therapies such as anti-CTLA4 andchemotherapy which elicit different types of immune responses. The impact of TREM2 will be assessed usinginjected MCA cell lines and the spontaneous MMTV-PyMT model of breast cancer. In Aim 2 we will define themechanisms through which anti-TREM2 impacts the tumor microenvironment. Given that a) immunosuppressivemacrophages depend on lipid metabolism and accumulate lipid droplets; b) TREM2 promotes foam cell formationby binding lipoproteins; and c) anti-TREM2 mAb blocks lipid binding to TREM2 we will test the hypothesis thatTREM2 blockade converts tumor macrophages from immunosuppressive to immunostimulatory by blocking lipiddroplet accumulation and foam cell formation. We will also test an alternative mechanism based on theobservation that TREM2 is cleaved from the cell surface by ADAM metalloproteases generating soluble TREM2(sTREM2) which promotes survival of macrophages in various disease models. We will test the hypothesis thatlack of sTREM2 in a transgenic mouse with uncleavable TREM2 prevents survival of immunosuppressive tumormacrophages. In Aim 3 we show unpublished data indicating that anti-human TREM2 mAb 21E10 delays tumorgrowth of an injected MCA cell line in mice expressing human TREM2 in place of mouse TREM2. Therefore wewill determine whether TREM2 blockade with a specific mAb can be extended to a preclinical model expressingthe human TREM2 receptor. Overall this proposal will advance our knowledge of a novel therapeutic approachbased on TREM2 that broadens our armamentarium for targeting immunosuppressive myeloid cells in tumors. 432265 +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Alleles;Cell Line;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;DNA Methylation;DNA Modification Methylases;DNMT3a;Dependence;Development;Disease;Epigenetic Process;Event;FLT3 gene;Funding;Gene Expression;Genes;Genetic Transcription;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic System;Hematopoietic stem cells;Homeobox Genes;Human;Human Cell Line;Lymphoid;Malignant Neoplasms;Methylation;Modeling;Molecular;Mus;Mutate;Mutation;Myelogenous;NPM1 gene;Nuclear;Phase;Premalignant Cell;Process;Progress Reports;Sampling;Shapes;Site;Tumor Suppressor Proteins;Umbilical Cord Blood;Work;acute myeloid leukemia cell;cell type;dosage;epigenome;epigenomics;human DNA;improved;insight;leukemia;leukemia/lymphoma;mouse model;mutant;novel therapeutic intervention;premalignant;progenitor;protein expression;self-renewal;stem;stem cells;stem-like cell;tumor DNMT3A in Development of Hematologic Malignancies NarrativeDNMT3A is one the most frequently mutated tumor suppressors in human leukemias. Thesestudies will uncover the mechanisms through which its loss predisposes to leukemia potentiallyleading to new therapeutic strategies. NCI 10689132 8/24/23 0:00 PA-18-484 5R01CA183252-10 5 R01 CA 183252 10 "JHAPPAN, CHAMELLI" 9/11/14 0:00 8/31/24 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 7354242 "GOODELL, MARGARET A." Not Applicable 9 ANATOMY/CELL BIOLOGY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 522576 NCI 326610 195966 AbstractDNA METHYLTRANSFERASE 3A (DNMT3A) has emerged over the past ~8 years as one of themost important tumor suppressors in the hematopoietic system being mutated across most typesof human hematologic malignancies and found in greater than 20% of acute myeloid leukemias(AMLs) as well as acute lymphoid leukemias (ALLs) and lymphomas. Through mechanisms thatare not understood DNMT3A mutations are thought to provide a fertile ground for secondarymutations which drive the frank malignancy. In the previous funding period we sought to establishand study a reliable tumor model of DNMT3A-associated malignancies using the recognizedcollaboration between DNMT3A-mutation and the internal tandem duplication (ITD) of FLT3 whichresults in highly penetrant malignancies of both myeloid and lymphoid types. Here we will studythe very earliest events that represent the transition from clonal hematopoiesis to malignacy. Wehypothesize that DNMT3A mutations and NPM1 mutations collaborate effectively by enforcingcomplementary epigenetic changes that serve to maintain mutated cells in an HSC-like state. Weexpect that a key effect of this dysregulation is aberrant expression of HOX genes that drives self-renewal. We will dissect the mechanisms through which this occurs here using mouse modelshuman cell lines and human primary samples. Our long-term goal is to use insights developedhere to enforce differentiation and develop new therapeutic strategies. We will (1) Identify theepigenetic and molecular changes associated with the development of malignancies fromDnmt3a-deficient hematopoietic progenitors. Using mice that have mutant alleles of Dnmt3a-KOand inducible NPM1c we will examine the concerted changes that occur at the epigenetic andtranscriptional levels in pre-malignant stem and progenitor cells. (2) Examine the dependenciesof AML with mutated DNMT3A NPM1 and FLT3-ITD. We hypothesize this common sub-type ofAML is dependent on the sustained expression of particular genes such as Hox and Meis1. Wewill examine this and other potential dependencies using CRISPR KO or targeted DNAmethylation. (3) Examine in human DNMT3A-mutated AML cells epigenome remodeling anddependencies. We will validate targets identified in Aims 1 and 2 and explore the value of specificmodulators such as nuclear re- localization of NPM1 correction of the DNMT3A-mutant alleleand re-methylation of specific target sites. These studies will reveal the stepwise epigenomicchanges that occur due to loss of DNMT3A that lead to AML as well as some of theirdependencies. This will lead to an improved understanding of how loss of DNMT3A promotesmalignancies and potentially to new therapeutic strategies due to identification of new targets. 522576 +No NIH Category available Algorithms;Atlases;Back;Bioinformatics;Biological;Biology;Biometry;Cancer Biology;Cancer Center;Cells;Clinical;Cluster Analysis;Collaborations;Communication;Communities;Competence;Complex;Computational Biology;Computer software;Computing Methodologies;Consult;Consultations;Data;Data Analyses;Data Set;Dedications;Detection;Development;Diagnosis;Disease;Doctor of Philosophy;Experimental Designs;FAIR principles;Faculty;Future;Generations;Genome Data Analysis Center;Goals;Institution;Instruction;Laboratory Research;Leadership;Malignant Neoplasms;Medicine;Methodology;Mission;Modeling;Molecular Profiling;Morphologic artifacts;Pathway interactions;Phase;Process;Protein Array;Protein Array Analysis;Proteomics;Quality Control;Reproducibility;Research;Research Personnel;Research Project Grants;Sampling;Schedule;Software Engineering;System;The Cancer Genome Atlas;Time;Translating;Visualization;Work;bioinformatics tool;cancer genomics;computerized tools;computing resources;data integration;experience;innovation;member;molecular scale;multidisciplinary;multiple omics;prevent;programs;resistance mechanism;segregation;single cell sequencing;software systems;surveillance data;therapy resistant;tool;trend;tumor;working group A Genome Data Analysis Center Focused on Batch Effect Analysis and Data Integration * * * * NARRATIVE * * * *The principal goals of the Genome Data Analysis Center (GDAC) proposed here are (i) to perform batch effectsidentification quantitation diagnosis and (when appropriate) correction proactively and as requested by theNetwork; (ii) to contribute when useful to integrated cluster analysis RPPA proteomic data analysis and high-level interactive visualization of omic data (including single-cell sequencing data); (iii) to communicate results toother network members project stakeholders and the scientific community. The GDAC will primarily supportprojects managed by the Center for Cancer Genomics (CCG) whose principal goal is better understanding ofthe biology of cancer and mechanisms of resistance to therapy. NCI 10689115 8/23/23 0:00 RFA-CA-20-053 5U24CA264006-03 5 U24 CA 264006 3 "YANG, LIMING" 9/22/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 11290009 "AKBANI, REHAN " "BROOM, BRADLEY MCINTOSH; WEINSTEIN, JOHN N" 9 BIOSTATISTICS & OTHER MATH SCI 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 317719 NCI 243977 151266 * * * * PROJECT SUMMARY * * * *Abstract: Technical batch effects pose a fundamental challenge to quality control and reproducibility of evensingle-laboratory research projects but the possibilities for serious error are greatly magnified in complex multi-institutional enterprises such as the cancer molecular profiling projects being undertaken by the NCI Center forCancer Genomics (CCG). To aid in detection quantitation interpretation and (when appropriate) correction fortechnical batch effects in such data we have developed the MBatch software system. MBatch provedindispensable for quality-control surveillance of data in The Cancer Genome Atlas (TCGA) and ongoing CCGprojects. But detecting and quantitating batch effects (or trend effects or statistical outliers) are just the first stepsin a process. The next steps involve detective work in collaboration with those who generated the data drawingupon expertise in integrative analysis across data types pathways and systems-level biology. That detectivework usually succeeds in diagnosing the cause of a batch effect as technical or biological. If technical thencomputational methods to ameliorate the batch effect can be applied (judiciously). The primary aim of the proposed Genome Data Analysis Center (GDAC) is to continue to translate thatsuccessful quality-control model to the CCGs other current and future large-scale molecular profiling projectsWe will be ready to do that on Day 1. We will continue to enhance and extend the power of MBatch andincorporate a number of innovative new algorithms tools and interactive visualizations into it (OmicPioneer-scMutBatch CarDEC and CorNet). Evaluating and correcting batch effects is a complex process so we willcollaborate with other GDACs and data generating centers to determine the influence of artifacts on any analysisresults they produce. The second aim is to contribute and enhance additional competencies. We are preparedto (i) provide integrated cluster solutions to segregate cases into biologically relevant groups; (ii) provide toolsand expertise for high-level visualization of omic data (including single-cell data); and (iii) analyze RPPAproteomic data from the subset of projects that generate such data. Our final aim is to communicate results anddistribute corrected data back to other network members project stakeholders and the scientific community. We bring a number of assets to the table including multidisciplinary expertise in bioinformatics biostatisticssoftware engineering cancer biology and cancer medicine; PIs with a combined 40+ years of experience inmolecular profiling of cancers; expertise gained in 10 years of doing the batch effects surveillance for TCGA andother CCG projects; a highly professional software engineering team with a track record of producing high-endbioinformatics tools; extensive computing resources including one of the most powerful academic clusters in theworld; and close working relationships with first-class basic translational and clinical researchers across MDAnderson one of the foremost cancer centers in the U.S. The bottom-line mission of the GDAC will be to aid theresearch communitys effort to understand cancer and to prevent detect diagnose and treat it more effectively. 317719 +No NIH Category available Address;Antibodies;Antigen Targeting;Antigens;Autoantibodies;Autoantigens;B-Lymphocytes;Binding;Biological Markers;Biological Models;Blood;CAR T cell therapy;Cancer Model;Cancer Patient;Cancer cell line;Cell surface;Cells;Clinical;Complex;Data Set;Development;Diagnosis;Discrimination;Disease;Dose;Down-Regulation;Engineering;Epitopes;Failure;Genetically Engineered Mouse;Hand;High Prevalence;Human;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunobiology;Immunocompetent;Immunology;Immunosuppression;Immunotherapy;In Vitro;Infiltration;Libraries;Ligand Binding Domain;Liquid substance;Lymphoma;Major Histocompatibility Complex;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Multiple Myeloma;Neurologic;Normal tissue morphology;Paraneoplastic Syndromes;Patients;Phenotype;Plasma;Post-Translational Protein Processing;Pre-Clinical Model;Prevalence;Production;Sensitivity and Specificity;Signal Transduction;Smoking;Solid Neoplasm;Surface Antigens;Surrogate Markers;Survival Rate;Symptoms;Syndrome;T cell therapy;T-Cell Activation;TFRC gene;TP53 gene;Testing;Therapeutic;Tissues;Toxic effect;Translating;Tumor Antigens;Tumor Tissue;antigen binding;blood-based biomarker;cancer immunotherapy;cancer survival;cancer therapy;chimeric antigen receptor T cells;clinically relevant;cytokine;design;effective therapy;engineered T cells;exhaustion;immune cell infiltrate;immunogenic;immunogenicity;in vivo;in vivo evaluation;innovation;insight;leukemia;mouse model;neoantigens;neoplastic cell;novel;novel strategies;patient derived xenograft model;pre-clinical;preclinical study;programmed cell death ligand 1;protein complex;receptor;response;small cell lung carcinoma;success;trafficking;tumor;tumorigenesis Translating Autoantibodies Into Chimeric Antigen Receptor-T cell Therapy for Small Cell Lung Cancer Project NarrativeSmall cell lung cancer (SCLC) is a highly aggressive recalcitrant and deadly cancer with no effective treatment.We have found that SCLC leads to production of neoantigens and autoantibodies the binding sequence of whichcan be engineered into chimeric antigen receptor T cells (CAR-Ts) that could provide a badly needed newavenue for SCLC treatment. NCI 10689108 8/9/23 0:00 PAR-19-361 5U01CA268066-02 5 U01 CA 268066 2 "FORRY, SUZANNE L" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-U(M2) 11599679 "LASTWIKA, KRISTIN J" "RIDDELL, STANLEY R." 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 591527 NCI 340737 250790 AbstractFor the last 30 years the 5-year survival rate of small cell lung cancer (SCLC) has been less than 7% despitethe addition of immune checkpoint inhibitors as treatment options. Therapies like immune checkpoint inhibitorsthat aim to reengage an immune response may not succeed for SCLC as previous studies have showndownregulation of MHC molecules low PD-L1 expression and limited immune infiltration. However SCLC isoften associated with autoantibody-driven Paraneoplastic Syndromes providing evidence for theimmunogenicity of SCLC. We propose that chimeric antigen receptor T cells (CAR-Ts) as a novel approach forSCLC immunotherapy that overcomes impediments to endogenous immunity. CAR-Ts are syntheticallyengineered to fuse antibody ligand binding domains with costimulatory components that activate T cells afterengagement of cell surface antigens and have had considerable success in leukemia lymphoma and multiplemyeloma. The microenvironment of SCLC is phenotypically closer to CAR-T responsive lymphoma than manysolid tumors where CAR-Ts have thus far had limited success. A challenge for CAR-T cells in many solid tumorsis the identification of target antigens that are tumor-specific. We have identified 13 novel cell surface antigenand here will prioritize 3 with high prevalence in SCLC. Each of these antigens have post-translationalmodifications that act as neoantigens and lead to autoantibody production in a high percentage of SCLC cases.We will capture these neoantigen-autoantibodies from SCLC patient-derived B cells sequence the tumor specificbinding sequences and design and test CARs constructed from the single chain variable fragments (scFvs).The benefit of isolating autoantibodies from SCLC patients to detect tumor-specific neoantigens is three-fold: 1.The antigens identified have already proven to be immunogenic; 2. The variable regions of these humanautoantibodies can be directly engineered into ligand binding domains of CAR-T cells; and 3. Autoantibodiescan be detected in the blood of patients and serve as tissue surrogate biomarkers to guide CAR-T cell targetselection. The CAR-T cells we develop will be rigorously tested in multiple preclinical models that addresscomplementary but non-overlapping therapeutic barriers. These include testing CAR-T cell tumor infiltrationefficacy and toxicity in a library of genetically diverse SCLC patient derived xenografts and identifying thenovercoming immunosuppressive mechanisms in the immune competent Rb/p53 genetically engineered mousemodel. Our team of experts in lung cancer autoantibody biomarkers immunology and CAR-T cells is wellequipped to execute the development of novel immunotherapies that are desperately needed in SCLC. 591527 +No NIH Category available Affect;Androgen Receptor;Androgens;Apoptosis;Automobile Driving;Binding;Biochemical;Biological Markers;Breeding;Cancer Patient;Castration;Catalytic Domain;Cell Nucleus;Cells;Clinic;Clinical Research;Clinical Trials;Complex;Creativeness;Cytokine-Inducible Kinase;Cytoplasmic Receptors;Data;Development;Disease;Disease Progression;Drug resistance;Enhancers;Epigenetic Process;Event;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Health;Homologous Gene;Investigation;Knock-out;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Methylation;Mission;Mitotic;Mus;Neuroendocrine Prostate Cancer;Oncogenic;Operative Surgical Procedures;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Phosphorylation;Polycomb;Prostate;Public Health;Receptor Signaling;Research;Resistance;Resources;Role;Signal Pathway;Signal Transduction;Specimen;System;Testing;Therapeutic;Transcriptional Activation;United States National Institutes of Health;Withdrawal;Work;Xenograft Model;abiraterone;androgen sensitive;cancer therapy;castration resistant prostate cancer;design;diagnostic biomarker;effective therapy;enzalutamide;gene repression;genetic approach;improved;inhibitor;innovation;mouse model;mutant;novel;novel marker;novel strategies;patient derived xenograft model;pharmacologic;programs;prostate cancer cell;prostate cancer model;prostate cancer progression;success;therapeutic target;tumor Overcoming Drug Resistance of Castration-Resistant Prostate Cancer NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signaling pathwaysthat drive castration-resistant prostate cancer. These studies will establish new avenues of investigation todevelop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NIH's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer. NCI 10689102 6/14/23 0:00 PA-20-185 5R01CA157429-10 5 R01 CA 157429 10 "FORRY, SUZANNE L" 9/1/11 0:00 6/30/27 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8042648 "LIU, XIAOQI " Not Applicable 6 PHARMACOLOGY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 289496 NCI 190000 99496 Title: Overcoming drug resistance of castration-resistant prostate cancerAbstractBecause androgen receptor (AR) signaling is essential for development of prostate cancer (PCa) includingcastration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) are becoming the first linetreatment for CRPC. However the limited success of ASIs makes it urgent to develop approaches to treatASI-resistant CRPC. EZH2 (enhancer of zeste homolog 2) the catalytic subunit of the Polycomb RepressiveComplex (PRC2) responsible for H3K27me3 and gene repression has been identified as a promising targetin PCa. However it was also discovered that oncogenic function of EZH2 in CRPC is PRC2-independent.Thus identifying regulators that control EZH2 function is of significance as it may provide an avenue toenhance the efficacy of EZH2 inhibitors (EZH2i) in CRPC. The long-term goals of this study are to identifydruggable signaling pathways that offer effective treatment options for patients with ASI-resistant CRPC.The objective is to define the role of polo-like kinase 1 (Plk1) in regulating EZH2 to exploit this pathway asa therapeutic target for ASI-resistant CRPC patients and to examine whether Plk1-dependentphosphorylation of EZH2 is a novel biomarker for CRPC. The central hypothesis is that Plk1 phosphorylationof EZH2 leads to a functional switch from PRC2-dependent gene repression to PRC2-independent but AR-dependent transcription activation eventually contributing to disease progression into CRPC stage. Ourdata show that Plk1 inhibition leads to an increased level of H3K27me3 and that Plk1 directly phosphorylatesEZH2 at T144. We also show that Plk1 phosphorylation of EZH2 results in decreased levels of H3K27me3destabilization of the PRC2 complex and increased association between EZH2 and AR. Our hypothesis willbe tested by pursuing three Aims - (1) to dissect how Plk1 phosphorylation of EZH2 regulates the PRC2complex; (2) to test whether expression of unphosphorylatable EZH2 antagonizes PCa progression andenhances the efficacy of EZH2i in genetically engineered mouse (GEM) models; and (3) to determinewhether Plk1 inhibitor (Plk1i) plus EZH2i is a novel approach to treat ASI-resistant CRPC and whetherpT144-EZH2 is a novel biomarker for CRPC. These complementary aims will be accomplished usingbiochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mousemodels culture systems and patient-derived xenograft (PDX) methodologies. The rationale for the researchis that it will probe the importance of Plk1 to PRC2 complex examine whether a combination of Plk1i withEZH2i is a novel approach to treat ASI-resistant CRPC and ask whether pT144-EZH2 is a new biomarkerto predict PCa progression. This contribution is significant because if positive the results of the proposedstudy will support an immediate clinical trial for Plk1i plus EZH2i to treat ASI-resistant CRPC. The researchis innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditionalview that Plk1 functions solely to regulate mitotic events. 289496 +No NIH Category available Acute Myelocytic Leukemia;Automobile Driving;Biological;Biological Sciences;Breast Cancer cell line;Cancer Model;Cause of Death;Cessation of life;Characteristics;Complex;DNA;Data;Data Analyses;Development;Diagnosis;Disease;Education;Emerging Technologies;Ensure;Epigenetic Process;Event;Generations;Genetic;Genome;Genomics;Hot Spot;Length;Libraries;Malignant Neoplasms;Methods;Methylation;Oncologist;Organoids;Outcome;Preparation;RNA;RNA Splicing;RNA analysis;Research;Research Personnel;Resource Sharing;Role;Running;SKBR3;Services;Stretching;Techniques;Technology;Transcript;Variant;Work;anticancer research;cancer diagnosis;cancer genomics;cancer subtypes;cancer therapy;cost;diagnostic tool;innovation;insertion/deletion mutation;instrument;mRNA Precursor;malignant breast neoplasm;molecular modeling;nanopore;next generation;novel diagnostics;operation;point of care testing;tool;transcriptome sequencing;treatment choice;tumorigenesis The Development and Optimization of Long-Read Sequencing Applications to Cancer Genomics in a Core Setting Cancer is a leading cause of death worldwide with more than 14 million new cases and 8 million deathseach year. While great strides have been made in understanding the genomic mechanisms that drivecancer development and progression the complex genetic and epigenetic profile of this disease requiresnew and innovative approaches to probe its biological drivers. The ability to sequence its genomeparticularly in long contiguous stretches using techniques such as those we are developing andimplementing provides an essential tool to understand the genomic characteristics that can beexploited to facilitate better diagnosis and treatment options. NCI 10689098 8/31/23 0:00 PAR-18-887 5R50CA243890-05 5 R50 CA 243890 5 "JOHNSON, ERIC MICHAEL" 9/11/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 14081116 "GOODWIN, SARA " Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 122709 NCI 63911 58798 Cancer is a highly complex and heterogeneous disease governed by a multitude of genomic mechanisms.Sequencing technologies have been essential to driving research into new methods of cancer diagnosis andtreatment. As sequencing has increased in throughput and decreased in cost research has revealed genomiccomplexities not previously appreciated. As these complexities are revealed new methods must be developedto investigate them. The work of the Next-Generation Shared Resource (NGSSR) Core focuses on makingemerging technologies in sequencing available and developing their applications to biological science. Inrecent years long-read sequencing has been applied to cancer genomics. The NGSSR has been andcontinues to be on the forefront of long-read sequencing. In 2011 CSHL acquired the first generation of long-read sequencing instruments. This technology was shown to be invaluable to studies of the SK-BR-3 breastcancer cell line revealing that many structural variations some with fusion transcripts are not detected byshort-read methods. Given these results the NGSSR has continued to explore long-read sequencingtechnologies. These methods are currently being developed to support an array of projects at CSHL includinghigh depth Oxford Nanopore and PacBio sequencing of breast cancer organoids to better understand themechanisms driving tumorigenesis and to validate organoids as molecular models of cancer. By leveraging theunique Oxford Nanopore ability to detect methylation along with sequencing data possible cancer specificmethylation profiles correlated with rearrangement hot spots in breast cancers have been identified. TheNGSSR has also developed a pipeline exploiting Oxford Nanopore technology to detect large insertions anddeletions in Acute Myeloid Leukemia (AML). These variations are known to be markers for outcome thusdriving treatment choice. This method can facilitate point-of-care testing for AML subtype providing a newdiagnostic tool to oncologists. Full length RNA sequencing and analysis is also being developed by theNGSSR to quantify alternative pre-mRNA splicing events. These splicing events can be used to characterizecancer subtype and to explore the mechanisms of cancer development and progression. The role of theNGSSR in these projects has been to develop methods to work with the technologies and the materials to beexamined. This includes all steps from DNA/RNA extraction library preparation and data analysis. Theservices and education/advice the NGSSR provides about these technologies gives CSHL researchers atremendous boost in their research endeavors. In addition to conducting independent research the NGSSRcore manager will continue to run the day-to-day operation of the NGSSR ensuring that all sequencing relatedstudies at CSHL using both new and old methods are of the highest quality to facilitate ground breakingcancer research. 122709 +No NIH Category available Acceleration;Address;Adoption;California;Caring;Characteristics;Clinic;Colonoscopy;Colorectal Cancer;County;Data;Data Collection;Data Set;Diagnostic;Early Diagnosis;Education;Environment;Evaluation;Evidence based intervention;Frontline worker;Goals;Health;Health Technology;Incidence;Individual;Infrastructure;Intervention;Interview;Maintenance;Malignant Neoplasms;Measures;Methods;Navigation System;Neighborhood Health Center;Nonprofit Organizations;Outcome;Patients;Phase;Practical Robust Implementation and Sustainability Model;Provider;Public Health Informatics;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Rural;Site;Standardization;System;Test Result;Testing;Underserved Population;United States Preventative Services Task Force;Work;acceptability and feasibility;aged;arm;colorectal cancer prevention;colorectal cancer screening;cost;effectiveness evaluation;electronic health record system;experience;feasibility testing;follow-up;health disparity populations;implementation evaluation;implementation strategy;improved;mortality;outreach;patient navigation;patient oriented;phase 2 study;pilot test;post implementation;pragmatic intervention;pragmatic randomized trial;randomized trial;scale up;screening;technology platform;treatment as usual;uptake CRC-HUB-SPOKE: A ColoRectal Cancer screening Hub for Southern California community health centers. The project addresses the extremely low colorectal cancer (CRC) screening and follow-up rates in community health centers (CHCs) in San Diego County. Low rates of screening and follow-up in patients served by CHCs highlight an opportunity to improve early detection and decrease the burden of CRC in our region. Our overarching hypothesis is that a Hub-and-Spoke multilevel intervention that combines centralized strategies implemented or coordinated by an umbrella CHC organization (hub) to regional CHCs (spokes) and their patients is an effective scalable and sustainable approach to optimize CRC screening follow-up and referral-to-care regionally NCI 10689096 9/1/23 0:00 RFA-CA-19-018 5UH3CA233314-05 5 UH3 CA 233314 5 "GRIMES, GENEVIEVE M" 9/19/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-AARR-N(52)R] 1971389 "MARTINEZ, MARIA ELENA" "GUPTA, SAMIR ; HILL, LINDA L; NODORA, JESSE ; ROESCH, SCOTT " 50 FAMILY MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 784225 NCI 679172 119623 Colorectal cancer (CRC) screening and appropriate follow-up can reduce incidence and mortality. The US Preventive Services Task Force (USPSTF) recommends CRC screening through a variety of invasive and non-invasive tests for individuals aged 50 to 75 years. Evidence-based interventions (EBIs) and other strategies exist to promote CRC screening but adoption and implementation of these are limited especially in CHCs. Our hypothesis is that a Hub and Spoke multilevel intervention will be superior to usual care. The hub will be Health Quality Partners of Southern California (HQP) a non-profit organization comprised of 16 CHC systems (spokes) serving 135 rural and urban clinic sites. We propose a 2-phase study to pilot and optimize (Phase I) and rigorously test (Phase II) the Hub and Spoke approach and its impact on CRC screening follow-up and usual care. UG3 Planning/Exploratory Phase AIM: Pilot test the feasibility acceptability and preliminary outcomes of a multilevel intervention for CRC screening follow-up and referral-to-care using a mixed methods approach. The intervention includes HQP hub-based delivery of centralized mailed FIT to patients served by individual CHCs-spokes plus complimentary provider and clinic-level interventions at CHCs and coordination of a standardized navigation strategy delivered by CHCs for abnormal FIT follow-up. UH3 Implementation Phase. We will conduct a 2-arm pragmatic randomized trial to assess impact of a regionally-developed multilevel intervention to increase CRC screening follow-up and referral-to-care among CHC patients. The trial will be guided by the Pragmatic Robust Implementation and Sustainability Model (PRISM) which includes outcomes from the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework and expands them with contextual constructs. Aim 1. Assess effectivenessof the multilevel intervention based on: 1) improvement in proportion up-to-date with screening 3 years post implementation; 2) proportion with abnormal FIT who complete diagnostic colonoscopy within 6 months; and 3) proportion with CRC completing first treatment evaluation. Aim 2. Evaluate the implementation scalability and sustainability of a multilevel implementation strategy. Implementation will be evaluated with a mixed methods approach using the RE-AIM outcomes of Reach Adoption and Implementation as well as the PRISM constructs of Intervention Characteristics and Recipients from perspective of multiple stakeholders (i.e. patients front-line staff and operational leaders). We will also calculate replication costs. Scalability and Sustainability will be evaluated using the RE-AIM outcome of Maintenance and the PRISM constructs of Implementation & Sustainability Infrastructure and External Environment. Our study will help accelerate progress in CRC prevention in underserved populations by identifying multilevel intervention strategies that are scalable to additional CHCs in the region with potential for larger scale implementation. 784225 +No NIH Category available Address;Adjuvant Therapy;Biological Markers;CRISPR/Cas technology;Cells;Cessation of life;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinical;Code;Colorectal Cancer;Cytotoxic Chemotherapy;DNA topoisomerase II alpha;Data;Disease;Disease-Free Survival;Distant;Drug Screening;Epigenetic Process;Exposure to;FDA approved;Fluorouracil;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;In Vitro;Knock-out;Large-Scale Sequencing;Length;Longterm Follow-up;Meta-Analysis;Metastatic/Recurrent;Methods;Modality;Modeling;Molecular;Monitor;Mutate;Neoplasm Metastasis;Nuclear;Oncogenic;Operative Surgical Procedures;Organoids;Patients;Phenotype;Primary Neoplasm;Prognosis;Prognostic Marker;Protein Isoforms;Proteins;RNA;Regimen;Regulation;Repression;Research;Resistance;Risk;Role;Sampling;Site;Staging;Stratification;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;Topoisomerase Inhibitors;Transcript;Tumor Biology;Validation;cancer therapy;chemotherapy;chromatin immunoprecipitation;clinical outcome assessment;cohort;colon cancer patients;colorectal cancer metastasis;colorectal cancer progression;differential expression;epigenetic regulation;experimental study;high risk;in vivo;insight;metastatic colorectal;molecular phenotype;patient derived xenograft model;prospective;recruit;response;side effect;therapy resistant;transcriptome sequencing;translational impact;tumor;tumorigenesis The role of RAMS11 in colorectal cancer progression and treatment resistance PROJECT NARRATIVEAlthough early stage colorectal cancer (CRC) is curable (with surgery and adjuvant therapy) metastatic coloncancer is usually lethal. Therefore our proposal focuses on understanding the regulatory mechanism of alncRNA our lab discovered to promote oncogenic phenotypes and treatment resistance through its interactionswith protein-coding genes. Further we will address the current lack of reliable biomarkers to assess clinicaloutcome by investigating whether this lncRNA can be used to determine which localized CRC tumors are likelyto progress and metastasize. NCI 10689094 8/4/23 0:00 PA-20-185 5R01CA251539-03 5 R01 CA 251539 3 "WATSON, JOANNA M" 8/10/21 0:00 7/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 9231962 "MAHER, CHRISTOPHER A" "FIELDS, RYAN C" 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 567677 NCI 360430 207247 PROJECT SUMMARY/ABSTRACTAlthough early stage colorectal cancer (CRC) is curable with surgery there is a critical need to stratify high-riskearly stage patients that would benefit from adjuvant treatment. In contrast to early stage CRC late-stagemetastatic CRC (mCRC) is usually lethal presenting a critical need to match treatment modalities to patientsbased on molecular phenotyping. To address these unmet clinical needs the proposed study aims tounderstand the molecular mechanisms enabling primary CRCs to metastasize with the longer-term goal ofrationally guiding treatment decisions. While transcriptome sequencing has provided an unbiased method fordiscovering lncRNAs existing large-scale sequencing projects are comprised of predominantly primary tumorswithout matched metastatic samples. This represents a critical barrier to studying lncRNAs involved in theprogression of primary to metastatic disease. To address this gap we conducted the first meta-analysis ofnormal primary and distant metastatic tissues across CRC patients to identify differentially expressed RNAsAssociated with Metastasis (RAMS). We prioritized a previously uncharacterized nuclear localized lncRNARAMS11 since: (1) its expression correlated with metastatic progression (2) its expression associated withpoor disease-free survival across multiple independent patient cohorts and (3) it promoted oncogenicphenotypes in vitro and in vivo. Further subsequent mechanistic experiments demonstrated RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) to transcriptionally activate Topoisomerase II alpha(TOP2). This provides a strong rationale for our hypothesis that RAMS11 interacts with CBX4 toepigenetically regulate genes to promote oncogenic phenotypes and treatment resistance. This study will focuson dissecting how RAMS11 dependent CBX4 target gene regulation confers oncogenic phenotypes in vitroand in vivo. We will also assess whether RAMS11 can help identify high-risk CRC patients and its role inchemotherapy resistance. Overall our proposal will significantly advance the lncRNA tumor biology field byproviding mechanistic insight into RAMS11 epigenetic regulation to promote mCRC. Our research hastranslational impact by evaluating the potential role of RAMS11 to stratify CRC patients at high-risk of developrecurrent/metastatic disease that would benefit from specific adjuvant therapies. 567677 +No NIH Category available Address;Affect;Androgen Receptor;Anti-Inflammatory Agents;Attenuated;Biochemical;Biological;Biopsy;Blood specimen;Cancer Cell Growth;Cancer Detection;Cancer Etiology;Cancer Patient;Cells;Cessation of life;Clinical Research;Clinical Trials;Consumption;Correlative Study;Dietary Intervention;Dose Limiting;Effectiveness;Eligibility Determination;Exhibits;Feedback;Future;Genes;Hormones;Human;Immune;Immune response;Immunosuppression;In complete remission;Incidence;Infiltration;Inflammation Mediators;Intake;Interleukin-15;Knock-out;Localized Disease;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Molecular;Mus;Myeloid-derived suppressor cells;Outcome;PSA level;Patients;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Polyamines;Population;Prostate-Specific Antigen;Prostatectomy;Prostatic Neoplasms;Radiation;Radical Prostatectomy;Randomized;Recurrence;Recurrent disease;Regimen;Risk;Screening for Prostate Cancer;Testing;Tissues;Toxic effect;Transgenic Mice;Translational Research;Treatment Protocols;Tumor-infiltrating immune cells;Work;aging population;androgen deprivation therapy;antitumor effect;arginase;arm;cancer therapy;cancer type;cohort;dietary;experience;experimental study;immune function;immunoregulation;improved;men;novel;partial response;patient population;patient response;phase 1 study;phase II trial;pre-clinical;preclinical study;profiles in patients;prostate cancer cell;prostate cancer model;prostate cancer progression;response;side effect;study population;tumor (PQ11) Immune modulatory effects of white button mushroom in prostate cancer - A translational research Project NarrativeOur findings from a recent Phase 1 clinical trial suggest that white button mushroom (WBM) may attenuate theprogression of prostate cancer by modulating the activity of certain immune cells and other immune functions.We propose a Phase 2 clinical trial to further define the novel immune regulatory effects of WBM in patientswith biochemically recurrent prostate cancer and those who have not received treatment and are under activesurveillance. The clinical trial and associated preclinical studies will determine the molecular changesassociated with the immune modulating effects of WBM which could lead to new dietary regimens and otherapproaches to delay progression of prostate cancer or improve the efficacy of androgen deprivation therapy. NCI 10689092 9/1/23 0:00 RFA-CA-18-019 5R01CA227230-05 5 R01 CA 227230 5 "XI, DAN" 9/1/19 0:00 8/31/24 0:00 ZCA1-SRB-5(M1)S 1868737 "CHEN, SHIUAN " "LAU, CLAYTON ; TWARDOWSKI, PRZEMYSLAW WIKTOR" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 644198 NCI 393775 250423 Project SummaryProstate cancer is the most common cancer and the second leading cause of cancer-related deaths in men.Given the increasing proportion of the aging population and common application of prostate cancer screeningthe incidence of prostate cancer has increased over the last two decades and detection of cancer at earlyphases is more common. Accumulating evidence from clinical and preclinical studies demonstrates that whitebutton mushroom (WBM) has beneficial effects on prostate cancer. Therefore we propose a transdisciplinaryapproach to address Provocative Question 11: Through what mechanisms do diet and nutritionalinterventions affect the response to cancer treatment? Specifically we will determine the mechanisms throughwhich consumption of WBM leads to reduction of prostate-specific antigen (PSA) levels in biochemicallyrecurrent prostate cancer (BRPC) patients and those who are therapy nave favorable risk and under activesurveillance. Our previous Phase 1 study of WBM demonstrated biological activity and a low toxicity profile inBRPC patients. Results showed that 36% of the study population had some decline in PSA levels after ~3months of WBM treatment and no dose limiting toxicities were observed. Our analysis of trial blood samplessuggested potential mechanisms of action; complete response patients had significantly higher levels of IL-15and most patients exhibited therapy-associated declines in myeloid-derived suppressor cells (MDSCs) aftertherapy. Our preliminary studies and the work of others further suggest that WBM inhibits arginase activity.Because MDSCs exert an immunosuppressive activity through release of arginase this suggests a possiblemechanism through which WBM may affect immune function. In addition inhibition of arginase by WBM canlead to decreased polyamine levels which in turn decreases expression of the androgen receptor (AR) andAR-regulated genes such as PSA suggesting an additional mechanism through which WBM may act. Basedon these findings we hypothesize that the progression of prostate cancer may be attenuated by inhibitingMDSCs and modulating other immune functions through WBM consumption. We propose three specific aimsto test this hypothesis: 1. To examine the PSA suppressing effect of WBM in patients with BRPC and who aretherapy nave favorable risk and under active surveillance through a Phase 2 clinical trial. 2. To determine thedirect and immune-mediated antitumor effects of WBM in blood specimens and biopsy tissue from prostatecancer patients. We will also assess the levels of IL-15 and correlate to WBM response in our proposed Phase2 trial. 3. To define the cellular and molecular mechanisms underlying WBM effects on the tumor-associatedimmune cell populations in preclinical syngeneic prostate tumor models including IL-15 knockout andtransgenic mice for determining the effect of IL-15 on WBM-mediated immune modulations. Collectively weexpect the proposed studies to lead to new dietary regimens and other approaches to reduce or mitigate theprogression of prostate cancer or improve the efficacy of androgen deprivation therapy. 644198 +No NIH Category available Affect;Binding;Chromatin;Chronic;Cytokine Signaling;DNA;DNA Modification Process;Development;Dioxygenases;Enzymes;Epigenetic Process;Family;Foundations;Fumarates;Funding;Gene Activation;Gene Expression;Genes;HIV;Hematopoietic Neoplasms;Histone Deacetylase;Human;Hypermethylation;Immunotherapy;Impairment;Inflammation;Inflammatory;Interferons;Interleukin-6;Intrahepatic Cholangiocarcinoma;Investigation;Isocitrate Dehydrogenase;Liver;Lymphomagenesis;Malignant Neoplasms;Mediating;Metabolic;Methylation;Mouse Strains;Mus;Mutation;NFKB Signaling Pathway;Pathogenesis;Pathway interactions;Play;Primary Neoplasm;Production;Proteins;Recurrent tumor;Regulation;Repression;Resistance;Resolution;Role;Series;Signal Pathway;Signal Transduction;Solid Neoplasm;Succinates;Suggestion;T cell infiltration;Technology;Testing;Therapeutic;Tumor Immunity;Tumor Promotion;Tumor Suppression;Tumor-Derived;WT1 gene;alpha ketoglutarate;antagonist;cancer genomics;chemokine;cytokine;demethylation;design;gene discovery;gene repression;genetic analysis;histone demethylase;histone modification;improved;in vivo;loss of function mutation;member;mutant;neoplasm immunotherapy;novel;programs;promoter;recruit;response;transcription factor;tumor;ubiquitin-protein ligase;vpr Gene Products Function and Mechanism of TET Regulation of Tumor Immunity Project NarrativeThe central hypothesis of this investigation is that TET DNA dioxygenase has a previously unrecognizedimportant function in mediating the JAK-STAT and NF-B signaling pathways to regulate tumor immunity.Non- mutational inactivation of TET occurs frequently in solid tumors of different types and impairs anti-tumorimmunity. Stimulating TET activity represents an opportunity for improving immunotherapy of solid tumors. NCI 10689090 9/12/23 0:00 PA-18-484 5R01CA163834-10 5 R01 CA 163834 10 "OKANO, PAUL" 3/1/12 0:00 8/31/24 0:00 Cancer Genetics Study Section[CG] 1861018 "BALDWIN, ALBERT SIDNEY" Not Applicable 4 BIOCHEMISTRY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 313048 NCI 201317 111731 Project AbstractNearly half of newly discovered cancer driver genes discovered by the cancer genomic studies encode proteinsinvolved in histone or DNA modification including the TET family of DNA dioxygenases. Loss-of-functionmutations in TET genes occur early and frequently in human hematopoietic malignancy. Mutations in TET geneshowever are uncommon in solid tumors. Instead TET activity is significantly reduced in different types of humantumors. We do not know the significance of decreased TET activity in solid tumors. In this study we hypothesizethat TET has a previously unrecognized key function in both the JAK-STAT and NF- pathways. Inactivation ofTET in results in chronic tumor-promoting inflammation and escape from anti-tumor immunity. Thus stimulatingTET activity represents a viable opportunity to enhance antitumor immunity and to improve immunotherapy. Wewill test this hypothesis by defining the following aspects of TET2 activity: The function and mechanism ofTET2 in the JAK-STAT pathway and in tumor immunity (Aim 1); The regulation of TET2 and tumorimmunity by reversible monoubiquitylation (Aim 2); and The catalytically independent function andmechanism of TET2 in tumor suppression (Aim 3). During the past funding period we have made the following discoveries that significantly affect the TETfield and that form the foundation for this investigation: (1) Multiple oncometabolites produced or accumulated bymutations in different metabolic enzymes act as antagonists -ketoglutarate (KG) and inhibit multiple KG-dependent enzymes including TET enzymes. (2) TET activity is dynamically regulated in vivo. (3) Developmentof solid tumors of many different types is associated with a substantial decrease in TET activity. (4) TET isreversibly monoubiquitylated by CRL4VprBP E3 ligase and UPS15 deubiquitylase enhancing and impairing TETactivity respectively. This regulation is disrupted by multiple recurrent tumor-derived mutations in TET2. (5) HIVprotein Vpr reprograms CRL4VprBP E3 ligase to catalyze polyubiquitylation and degradation of TET proteins tosustain the expression of pro-inflammatory cytokine and promote HIV pathogenesis. (6) Multiple sequence-specific transcription factors (TFs) recruit TET2 to their target genes including members of NF-B and STATfamilies. (7) Loss of TET2 function in tumors impairs interferon signaling chemokine production and T cellinfiltration and confers resistance to tumor immunity and immunotherapy. This investigation is built on our pioneering and extensive study of the then newly discovered TETenzymes. It will investigate a novel aspect of cytokine signaling and tumor immunity regulationby TET-mediated DNA demethylation. It will use newly developed technology and mouse strains to determine how TETproteins regulate gene expression by catalytically-dependent and -independent mechanisms. It will explore anovel regulation of TET by reversible monoubiquitylation and the therapeutic opportunity of this regulation. Thisinvestigation represents the first exploration on the function and mechanism of TET in tumor immunity. 313048 +No NIH Category available Address;Antibodies;Area;B-Lymphocytes;Binding;Biochemical;Biogenesis;Biology;Blood Platelets;Cancer Biology;Cancer Control;Cell surface;Client;Clinical;Clinical Trials;Collaborations;Complex;Degradation Pathway;Development;Docking;Endoplasmic Reticulum;Eragrostis;Foundations;GRP94;Goals;Growth Factor Receptors;Heat-Shock Proteins 90;Human;Immune;Immune Tolerance;Immune checkpoint inhibitor;Immunity;Immunologics;Immunotherapeutic agent;Immunotherapy;Insulin-Like Growth Factor I;Insulin-Like Growth Factor II;Integrins;LRRC32 gene;Laboratories;Malignant Neoplasms;Manuscripts;Mediating;Membrane Glycoproteins;Molecular;Molecular Chaperones;Myelogenous;Nature;Oncogenic;PD-1/PD-L1;Pathway interactions;Pharmaceutical Preparations;Phase;Play;Pre-Clinical Model;Proteins;Publishing;Quality Control;Regulation;Regulatory T-Lymphocyte;Renaissance;Resistance;Role;Signal Pathway;Signal Transduction;Structural Biologist;Suppressor-Effector T-Lymphocytes;Surface;T cell therapy;T-Lymphocyte;Therapeutic;Thrombin;Transforming Growth Factor beta;Translational Research;Tumor Escape;VWF gene;anti-cancer;cancer cell;cancer immunotherapeutics;cancer immunotherapy;cancer therapy;cell growth;cell type;chimeric antigen receptor;convict;design;effector T cell;engineered T cells;genetic approach;immune checkpoint;immune resistance;inhibitor;insight;leucine-rich repeat protein;migration;new therapeutic target;next generation;novel;novel therapeutics;overexpression;paralogous gene;pre-clinical;preclinical study;protein degradation;receptor;response;side effect;targeted treatment;tumor microenvironment;tumorigenesis Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy PROJECT NARRATIVEThis study addresses how a chaperone molecule called GRP94 controls cancer and determines the best strategyto target GRP94 for cancer immunotherapy. Significant discoveries have been made regarding the roles ofGRP94 in controlling the pathway of transforming growth factor beta (TGFb). Several therapeutic leads haveemerged in blocking the GRP94-TGFb pathway; further in-depth study of GRP94 will advance novel therapiesfor cancer. NCI 10689068 8/10/23 0:00 PA-20-185 5R01CA262069-03 5 R01 CA 262069 3 "HU, ZHANG-ZHI" 9/1/21 0:00 8/31/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 6609948 "LI, ZIHAI " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 537921 NCI 354430 183491 PROJECT SUMMARYAs a ubiquitous HSP90 paralog in the endoplasmic reticulum (ER) GRP94 plays important roles in protein qualitycontrol in the secretory pathway by participating in both the unfolded protein response and the ER-associatedprotein degradation pathway. My laboratory has demonstrated that GRP94 is a strategically important target forcancer because it controls multiple key molecular pathways in cell growth migration immune tolerance anddifferentiation including integrins TLRs IGF-II Wnt co-receptor LRP6 and GARP (or LRRC32). GARP(Glycoprotein A Repetitions Predominant) is responsible for surface docking and activation of latent TGFb anda focus of this proposal We have made significant contributions to this area through immunological andbiochemical studies including: 1) that GARP is an important molecule for cancer immune evasion via regulatingmultiple cell types (e.g. cancer cells platelets regulatory T cells B cells). 2) We discovered a novel mechanismof TGFb activation from cell surface GARP-TGFb complex via proteolytic cleavage of GARP. 3) GARP has beenfound to be aberrantly expressed in multiple human cancers to promote oncogenesis via both cancer cell-intrinsicand -extrinsic mechanisms. 4) Preclinical studies suggest that GARP is a novel therapeutic target for cancerimmunotherapy. These accomplishments have deepened our conviction that the study of GRP94 and its clientnetwork will lead to better understanding of this chaperone biology in cancer and to development of novel cancertherapeutics alone or in combination with approved immunotherapeutic agents. In the next phase of the studywe will address the hypothesis that GRP94/GARP-targeted therapy applied to multiple vulnerable cancers willovercome immune resistance to checkpoint inhibitors.First we will determine the roles and molecular mechanism involved in GRP94 regulation of TGFb biogenesisactivation and signaling. This aim will focus on structural analysis of the GRP94-GARP complex and on resolvingmechanisms of GRP94 in folding two other molecules important in regulating TGFb signaling: LRRC33 andLRG1. Second we will develop novel cancer immunotherapeutic strategies targeting GRP94 and GARP. Thegoal is to advance the top first-in-class agent(s) among several pre-clinical leads through a milestone-drivenstrategy. This includes agents to inhibit GARP cleavage GARP-specific antibodies drug-like GRP94-selectiveinhibitors antibodies against the cell surface GRP94 (ectoGRP94) preferentially expressed on cancer cells andT cells engineered to express chimeric antigen receptor (CAR) composed of a single-chain antibody againstectoGRP94 fused with T cell signaling motifs (GRP94-CAR-T). Overall the impact of this study lies infundamental understanding of GRP94 in regulating the TGFb pathway and in developing promising nextgeneration immunotherapeutic agents. 537921 +No NIH Category available Address;Africa South of the Sahara;Awareness;Biological Assay;Cameroon;Cancer Etiology;Clinic;Clinical;Clinics and Hospitals;Cold Chains;Country;Data;Development Plans;Drops;Drug Screening;Educational workshop;Ethics;Ethiopia;Goals;Health;High Pressure Liquid Chromatography;Hospitals;Image;Injectable;Kenya;Left;Malawi;Malignant Neoplasms;Manufacturer;Marketing;Medicine;Methods;Modeling;Motivation;Needs Assessment;North Carolina;Nurses;Oncology;Paper;Participant;Patients;Performance;Pharmaceutical Preparations;Pharmacists;Pharmacologic Substance;Phase;Pilot Projects;Play;Privatization;Protocols documentation;Reporting;Research Personnel;Resource-limited setting;Resources;Sampling;Scientist;Screening Result;Site;Surveys;System;Technology;Technology Transfer;Telephone;Testing;Training;Validation;Vertebral column;Vial device;Work;cancer therapy;chemotherapy;cost-effectiveness evaluation;drug quality;empowerment;improved;low and middle-income countries;manufacture;multidisciplinary;neural network;new technology;outreach;post-market;programs;screening;smartphone application;supply chain;symposium;therapy outcome;validation studies Adapting a point of use test card the chemoPAD for protecting chemotherapy drug quality in sub-Saharan Africa Adapting a point of use test card the chemoPAD for protectingchemotherapy drug quality in sub-Saharan AfricaProject NarrativeMany low- and middle-income countries dont have the resources to test the quality of chemotherapy drugseven though bad quality or fake chemotherapy medicines can cause cancer treatments to fail.This project will create inexpensive test cards and a free phone app to detect bad quality chemotherapymedicines at the point of use in hospitals and cancer clinics.Our team of scientists oncology pharmacists doctors supply chain experts and drug regulators in EthiopiaMalawi Kenya and Cameroon will test the technology to make sure it can detect bad quality chemotherapydrugs before the drugs are given to patients.1 NCI 10689048 8/17/23 0:00 RFA-CA-21-030 5U01CA269195-02 5 U01 CA 269195 2 "DIVI, RAO L" 8/23/22 0:00 7/31/27 0:00 ZCA1-TCRB-Q(J2) 8668224 "LIEBERMAN, MARYA " Not Applicable 2 CHEMISTRY 824910376 FPU6XGFXMBE9 824910376 FPU6XGFXMBE9 US 41.693901 -86.239284 6169301 UNIVERSITY OF NOTRE DAME NOTRE DAME IN SCHOOLS OF ARTS AND SCIENCES 465565708 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 461516 NCI 430851 30665 Adapting a point of use test card the chemoPAD for protecting chemotherapy drug quality in sub-Saharan AfricaProject Summary/AbstractGoal: validate a new technology for detecting bad quality chemotherapy products at the point of use.Motivation: Chemotherapy medicines form the backbone of affordable cancer treatment in low- and middle-income countries (LMICs) yet LMICs often lack technical and regulatory capacity to evaluate the quality ofchemotherapy products. There is currently no commercial technology to screen for bad quality chemotherapyproducts at the point of use in LMIC settings and the drug regulators in Ethiopia Malawi Kenya andCameroon do not conduct post-market surveillance testing on chemotherapy products.Activities: The technology that will be validated called SpotCheck consists of an inexpensive paper testcard (the chemoPAD) and a cell phone app. We will first adapt the chemoPAD to screen eight types ofinjectable chemotherapy drugs. The phone apps neural network will be trained to identify products that arefalsified or contain less than 65% of the stated API content. Clinical academic and supply chain partners inEthiopia Malawi Cameroon and Kenya will conduct annual situation awareness and quality surveys of 320chemotherapy products per year; the results will enable a team of researchers at U. North Carolina to modelthe markets for chemotherapy products and evaluate the cost-effectiveness of the SpotCheck system. After atechnical performance milestone is passed we will tailor the clinical validation of SpotCheck to suit the localneeds clinical workflows and regulatory capacity in each site. The validation of the SpotCheck system willproceed through a planning and ethical approval milestone (Y3 in Ethiopia and Malawi and Y4 in Kenya andCameroon) and three clinical phases: proficiency study clinical validation and implementation pilot.Proficiency testing will demonstrate that oncology pharmacists and nurses can use SpotCheck with accuracy>85% to detect SF products. Clinical validation will establish whether SpotCheck works correctly in a clinicalsetting on authentic products rather than proficiency samples. The implementation pilot study will probeSpotChecks ability to test the drops left over in product vials after patient treatments are prepared in thehospital; this method of use would allow sustainable implementation of SpotCheck in many hospitals andclinics in low-resource settings. Technology transfer efforts will empower LMIC partners to produce thechemoPAD locally and integrate the cell phone app into regulatory reporting systems.Impact: This project will help to fill the huge evidence gap about the quality of chemo drugs in LMICs make itharder for manufacturers and distributors to sell bad quality products and improve the quality of products thatare used to treat patients in LMICs.1 461516 +No NIH Category available Advisory Committees;Anatomy;Antigen Presentation;Antigens;Area;Biological Assay;CD3 Antigens;Cell Culture System;Cell Line;Cell model;Cell-Mediated Cytolysis;Cells;Cellular immunotherapy;Clinical Services;Communication;Coupled;Cytolysis;Cytotoxic Chemotherapy;Dana-Farber Cancer Institute;Data;Defect;Development;Down-Regulation;Elements;Endogenous Retroviruses;Epigenetic Process;Epitopes;Expression Profiling;Faculty;Flow Cytometry;Future;Gene Expression Profiling;Genetic;Genetic Transcription;Genomics;Goals;Heterogeneity;Histocompatibility Antigens Class I;Homing;Hospitals;Immune;Immune Targeting;Immunobiology;Immunofluorescence Immunologic;Immunologics;Immunophenotyping;Immunotherapy;In Vitro;Inflammatory;International;Knowledge;Laboratories;Leadership;Leukocytes;Ligands;Lung;MHC Class I Genes;Malignant Epithelial Cell;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Medicine;Mentors;Mesenchymal;Methods;Minor;Modality;Modeling;Molecular;Mutation;Natural Killer Cell toxicity;Natural Killer Cells;Neuroendocrine Carcinoma;Neurosecretory Systems;PTPRC gene;Pathology;Patients;Peptides;Phenotype;Physicians;Population;Predisposition;Proteins;Publishing;Recovery;Refractory;Refractory Disease;Regulation;Research;Resistance;Resolution;Sampling;Scientist;Slide;Source;Specimen;Survival Rate;System;T-Lymphocyte;Testing;Therapeutic;Training;Training Programs;Tumor Antigens;Vascularization;Woman;Work;anti-tumor immune response;career;career development;cell mediated immune response;chemotherapy;clinical training;derepression;epigenetic regulation;experience;experimental study;immune cell infiltrate;immune checkpoint blockade;immunogenic;immunogenicity;immunoregulation;improved;in silico;in vitro Assay;in vivo;insight;medical schools;meetings;mid-career faculty;molecular diagnostics;molecular pathology;neoplastic cell;novel;novel marker;novel vaccines;oncofetal antigen;programmed cell death ligand 1;programs;response;skills;small cell lung carcinoma;three dimensional cell culture;three-dimensional modeling;tool;transcriptome sequencing;tumor;tumor immunology;tumor microenvironment;tumor-immune system interactions Targeting the immunologic vulnerabilities of small cell lung carcinoma PROJECT NARRATIVESmall cell lung cancer (SCLC) remains relatively refractory to multiple therapeutic modalities including immunecheckpoint blockade despite its high tumor mutation burden. This proposal seeks to exploit newfoundimmunologic vulnerabilities of SCLC conferred by epigenetic control of MHC Class I antigen presentation.Rational targeting of distinct immunologic subtypes of SCLC could lead to a deeper understanding of epigeneticmodulation of immunogenicity and ultimately novel immunotherapies for this treatment-refractory tumor. NCI 10689031 8/17/23 0:00 PA-20-203 5K08CA270077-02 5 K08 CA 270077 2 "LIM, SUSAN E" 9/1/22 0:00 8/31/27 0:00 Career Development Study Section (J)[NCI-J] 8798307 "MAHADEVAN, NAVIN " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 207930 NCI 192528 15402 PROJECT SUMMARY/ABSTRACTThis K08 proposal describes a five-year career development training program in tumor immunobiology. Dr. NavinR. Mahadevan has completed clinical training in Anatomic and Molecular and Genetic Pathology at Brigham andWomens Hospital and Harvard Medical School (HMS) and will pursue this research program with the goal oftransitioning to an independent laboratory-based career investigating cell-intrinsic and -extrinsic mechanisms ofimmune regulation in the tumor microenvironment along with a minor component of clinical service in diagnosticmolecular pathology. In this training program Dr. Mahadevan will develop further expertise in the study of tumorimmunogenicity and acquire new skills in the areas of antigen discovery and high-resolution slide-basedexpression profiling which will critically inform his future studies. His mentor Dr. David Barbie (AssociateProfessor of Medicine at the Dana-Farber Cancer Institute and HMS) is an leader in the field of translationaltumor immunology with an excellent track record in mentoring trainees including those who have successfullybecome independent laboratory-based faculty at major academic centers. Dr. Mahadevan has also assembledan Advisory Committee with complementary expertise in tumor immunology (Drs. Sharpe and Rodig)epigenetics and immunotherapy (Dr. Uppaluri) and computational genomics (Dr. Van Allen) and extensiveexperience in mentoring physician-scientists to independent careers. Dr. Mahadevan will further supplement histraining with didactic courses to deepen his scientific knowledge leadership and communication and willregularly present his work at national and international meetings. The primary objective of Dr. Mahadevans proposed research is to elucidate the immunologicvulnerabilities of small cell lung carcinoma (SCLC). Dr. Mahadevan provides preliminary data identifying animmunogenic subtype of SCLC that depresses MHC Class I (MHC I) antigen presentation and may beresponsive to immune checkpoint blockade in patients. This proposal will leverage this new understanding ofSCLC immunobiology to rationally elucidate immunologically vulnerabilities of these distinct SCLC subtypes. Immunologic and functional assays will be employed to test three independent but related questionsfollowing from this hypothesis: (1) the tumor microenvironmental consequences of MHC I derepression by SCLC;(2) the sensitivity of MHC I low SCLC to natural killer cell-mediated cytotoxicity; (3) the epigenetic regulation andpotential immunogenicity of MHC I-restricted antigens derepressed in MHC I high SCLC. These studies will leadto a deeper understanding of distinct SCLC immunophenotypes and attendant anti-tumor immune responseswhich could lead to the identification of novel biomarkers and development of effective immunotherapies for thistreatment-refractory disease. 207930 +No NIH Category available Acetylation;Address;Adult;Animal Experiments;Animal Model;Apoptosis;Binding;Binding Proteins;Biological Assay;Biology;CREBBP gene;CRISPR/Cas technology;Cardiac;Cell Death;Cell Line;Cell Survival;Cells;Cellular Assay;Chemicals;Chemotherapy and/or radiation;Child;Childhood;Childhood Solid Neoplasm;Clinical;Collaborations;Compensation;Coupled;Dana-Farber Cancer Institute;Data;Dependence;Development;Disease;Dropout;Drug Targeting;EP300 gene;Enhancers;Environment;Enzymes;Foundations;Frequencies;Gene Expression;Generations;Genes;Genetic Transcription;Goals;Grant;Growth;In Vitro;Infertility;Institution;Investigation;Investigational Therapies;Knock-in;Knowledge;Laboratories;Lead;Leadership;Learning;MYC Family Protein;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mentors;Methods;Mission;Modeling;Molecular;Mutate;Mutation;Neuroblastoma;Normal Cell;Normal tissue morphology;Oncogenes;Oncogenic;Patients;Pediatrics;Pharmaceutical Preparations;Preparation;Production;Protac;Proteins;Public Health;Qi;Reporter Genes;Research;Risk;Role;Scientific Advances and Accomplishments;Scientist;Second Primary Cancers;Solid Neoplasm;Specificity;Surveys;Survivors;Technology;Testing;Therapeutic;Time;Toxic effect;Training;Treatment-related toxicity;Western Blotting;Work;Writing;assay development;biological heterogeneity;cancer therapy;career;career development;cell growth;cell killing;chemotherapeutic agent;chemotherapy;clinical heterogeneity;combinatorial;design;drug discovery;epigenomics;exome;experience;experimental study;high risk;histone acetyltransferase;improved;in vitro Assay;in vivo;in vivo Model;innovation;instructor;mRNA Expression;member;mouse model;neoplastic cell;neuroblastoma cell;novel;novel strategies;novel therapeutic intervention;novel therapeutics;paralogous gene;patient derived xenograft model;skills;small molecule;survival outcome;targeted agent;targeted treatment;therapeutic target;tool;training opportunity;transcription factor;tumor;tumor growth Targeting EP300 a selective dependency in neuroblastoma PROJECT NARRATIVEThe proposed research is relevant to public health because studying new chemical and molecular approachesto inhibition of high-risk childhood neuroblastoma may result in novel approaches to treatment of this devastatingchildhood cancer as well as other EP300-dependent cancers. The strategy described here in which existingand newly-generated agents targeting the known neuroblastoma dependency EP300 are assessed alone andin combination with conventional chemotherapy agents is highly relevant to the NCI mission of developing noveltherapeutic approaches to advance scientific knowledge improve survival outcomes and reduce the toxicities ofcancer therapy. NCI 10689023 8/11/23 0:00 PA-19-117 5K08CA245251-04 5 K08 CA 245251 4 "BIAN, YANSONG" 9/14/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 14185643 "DURBIN, ADAM DAVID" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 272282 NCI 252113 20169 PROJECT DESCRIPTION/ABSTRACTDespite increases in treatment intensity children with high-risk neuroblastoma (NB) have poor survival andsignificant post-therapy toxicities. The candidate is an Instructor in Pediatrics with 80% protected time forresearch who is committed to developing novel therapeutics that are desperately needed to improve the lives ofchildren with NB. This is a challenge due to the paucity of currently targetable oncogenic mutations in this tumor.A recent survey identified the histone acetyltransferase (HAT) enzyme EP300 but not its paralog CBP as aselective dependency in NB. This identifies an opportunity to inhibit EP300 without severe toxicity as CBP maycompensate for EP300 in many normal cells. To this end the candidate has developed a proteolysis-targetedchimaera (PROTAC) on-target molecule (JQAD1) that degrades EP300 with limited effects on CBP in vitro andin vivo. JQAD1 causes tumor growth delay in vivo with limited toxicity and is therefore an excellent starting pointfor developing combinatorial strategies for tumor cell killing. Thus this proposal builds on a strong foundation ofpreliminary data to address the central hypothesis that optimized EP300-targeting strategies can be developedto maximize NB cell death while limiting off-target toxicity using structurally-guided chemical biology with faithfulin vivo NB modeling. This will be pursued in two specific aims: 1) To experimentally determine the most potentcombinations of EP300 degraders and chemotherapies in vitro and in vivo; and 2) To develop improved potencysecond-generation JQAD compounds with enhanced on- and off-target specificity. In the first aim toappropriately prepare EP300 degraders for clinical use experiments will identify effective combinations ofconventional chemotherapy agents and JQAD1. The mechanisms of combinatorial compound function andtractability of this approach will be established in vitro and in PDX models reflecting the biological and clinicalheterogeneity of NB. In the second aim second-generation JQAD molecules will be generated using structurally-based compound development. These will be tested for effects on EP300 using novel fluorescent in-cell assaysand in mechanistic assays of EP300 function. This proposal is innovative because it uses mechanisticapproaches involving state-of-the-art gene knockins compound development and PROTAC technologies toidentify methods to maximize tumor cell death and minimize toxicity. It is significant because targeting EP300alone represents an ideal strategy to kill NB cells and limit toxicity to normal tissues. This proposal is designedto provide intensive training and mentoring in chemical biology animal modeling and experimental therapeuticsas well as mentoring in grant writing leadership training and managerial skills thereby conferring the necessaryskills for an optimal transition to independence. The environment for this proposal is ideal including scientificexperts necessary to complete this work a strong institutional commitment and ideal guidance of his mentorsDrs. Kim Stegmaier and Jun Qi. Thus this proposal will facilitate his career goals of becoming an independentlaboratory-based clinician-scientist focused on discovery and therapeutic targeting in cancer. 272282 +Acquired Cognitive Impairment; Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Brain Disorders; Cancer; Neurosciences; Orphan Drug; Ovarian Cancer; Prevention; Rare Diseases; Women's Health Adult;Affect;Anabolism;Antineoplastic Agents;Behavioral;Brain;Brain region;Cancer Survivor;Cell division;Cell physiology;Cisplatin;Clinical Trials;Coenzymes;Cognitive;Cognitive deficits;Confocal Microscopy;DNA Repair;Data;Dendrites;Dendritic Spines;Development;Enhancers;Ensure;Enzymes;Functional disorder;Gliosis;Glycolysis;Goals;Hippocampus (Brain);Impaired cognition;Impairment;Laboratories;Learning;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Medical;Memory;Memory impairment;Metabolic;Metabolic Pathway;Metabolism;Molecular;Morphology;Mus;Neuronal Dysfunction;Neurons;Niacinamide;Nicotinamide Mononucleotide;Nicotinamide adenine dinucleotide;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Platinum;Play;Process;Quality of life;Role;Safety;Supplementation;Testing;Therapeutic;Transferase;Translational Research;United States;Work;age related neurodegeneration;aged;base;behavior test;cancer therapy;chemobrain;chemotherapy;clinically relevant;cognitive function;cohort;comorbidity;drug development;effective therapy;enzyme activity;healthspan;improved;insight;mouse genetics;mouse model;myelination;neurogenesis;neurotoxicity;novel;novel therapeutic intervention;older patient;overexpression;patient derived xenograft model;prevent;side effect;stem;therapeutic target;therapeutically effective PQ#12; Targeting Nampt-mediated NAD+ metabolism in chemobrain PROJECT NARRATIVE In the United States cognitive dysfunction stemming from chemotherapy is a major adverse conditionaffecting approximately 14 million cancer survivors. Unfortunately the underlying pathophysiologicalmechanisms remain unknown. The findings of this proposal are crucial towards elucidating a role for theNampt-mediated NAD+ metabolic pathway in improving neuronal and cognitive dysfunction resulting fromchemobrain. This understanding will provide insight into development of novel therapeutic interventions thattarget chemotherapy-induced cognitive dysfunction. NCI 10688638 9/1/22 0:00 RFA-CA-18-019 3R01CA242158-05S1 3 R01 CA 242158 5 S1 "CHEN, WEIWEI" 8/8/19 0:00 7/31/24 0:00 ZCA1-SRB-2(M2)S 10001078 "JANG, MI-HYEON " Not Applicable 10 NEUROSURGERY 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF MEDICINE 71073001 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 395 Non-SBIR/STTR 2022 136019 NCI 86636 49383 PROJECT SUMMARY Chemotherapy-induced cognitive dysfunction (referred to as chemobrain) negatively impacts cancersurvivors and has emerged as a significant medical problem. To date no effective treatment exists due to thelimited understanding of the mechanisms that drive chemotherapy-induced cognitive impairments. To provideeffective therapeutic strategies for this emergent medical problem this application aims to answer ProvocativeQuestion #12: What are the molecular and cellular mechanisms that underlie the development of cancertherapy-induced severe adverse sequelae? While the underlying molecular pathways vulnerable tochemotherapy-induced neurotoxicity are not well understood recent results from our laboratory indicate theNampt-mediated NAD+ pathway is a promising therapeutic target for chemobrain. Using the platinum-basedchemotherapy compound cisplatin we demonstrate its efficacy in suppressing the nicotinamide phosphoribosyltransferase (Nampt)-mediated NAD+ metabolic pathway. Cisplatin-mediated suppression of Nampt-NAD+metabolism leads to neurogenic dysfunction of the adult mouse hippocampus and memory impairments.Remarkably we found that by increasing NAD+ levels via administration of the NAD+ precursor nicotinamidemononucleotide (NMN) we can effectively reverse cisplatin-induced deficits in neuronal dendrite morphologyand memory function thus emphasizing the therapeutic potential of NAD+ metabolism in amelioration ofchemobrain. Based on these observations our central hypothesis is that increasing Nampt or NAD+ levelsprevent cisplatin-induced impairments in neuronal and cognitive function. Our findings represent a noveltherapeutic strategy for chemobrain. To test this novel hypothesis Aim 1 will determine whether increasingNAD+ levels through NMN supplementation can improve cisplatin-induced deficits in neuronal and cognitivefunction in both young and aged mice. In addition our translational proposal will ensure the safety of NMN as wewill determine if NMN has a detrimental impact on anti-neoplastic activity of cisplatin using patient-derivedxenograft (PDX) mouse models. Subsequently Aim 2 will elucidate if genetically increasing Nampt levels canprevent impairments in neuronal morphology and cognitive function. We will also evaluate if P7C3 a Namptenzyme activity enhancer can improve cisplatin-induced chemobrain in young and aged mice. Our proposedwork will provide critical pathophysiological mechanisms and improve our understanding of the Nampt-mediatedNAD+ metabolic pathway in order to improve chemotherapy-induced cognitive dysfunction. Ultimately thefindings will provide a framework by which safe and effective therapeutic strategies may be utilized in patientsundergoing cancer treatment so as to minimize or reverse neuronal and memory dysfunction. 136019 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunotherapy; Orphan Drug; Pediatric; Pediatric Cancer; Rare Diseases Adult;Anti-CD40;Award;Biological Markers;Biological Response Modifier Therapy;Biopsy;Cancer Center;Clinical Trials;Conduct Clinical Trials;Credentialing;Dendritic Cells;Educational workshop;FLT3 ligand;Failure;Future;Goals;Growth Factor;IL7 gene;Immune response;Immunologic Monitoring;Immunomodulators;Immunotherapeutic agent;Industry;Infrastructure;Institution;Interleukin-15;Interleukin-2;Knowledge;Leadership;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Myelogenous;Myeloid-derived suppressor cells;Natural Killer Cells;North America;Oncology;Orphan;PD-1 inhibitors;Patients;Pharmaceutical Preparations;Phase;Sea;Specimen;T-Lymphocyte;Testing;Therapeutic;Universities;anti-PD-1;anti-PD-L1;cancer immunotherapy;cancer therapy;clinical practice;immunotherapy trials;improved;innovation;investigator-initiated trial;macrophage;member;monocyte;operation;pediatric patients;statistical center;success;trial design Cancer Immunotherapy Trials Network Central Operations and Statistical Center NARRATIVEThe Cancer Immunotherapy Trials Network (CITN) is focused on initiating clinical trials with immunotherapyagents (drugs) deemed as high priority by the field but which are otherwise difficult to access. As aconsequence over the past 6 years the CITN and the member institutions (preeminent universities and cancercenters in North America) have been able to test 7 high priority agents in a variety of different cancers. Eachtrial has provided important new knowledge as to how best to use these agents in oncology patients with twoagents providing substantially improved standard cancer therapy. NCI 10688632 9/6/22 0:00 RFA-CA-16-501 3UM1CA154967-12S1 3 UM1 CA 154967 12 S1 "HENDERSON, LORI A" 9/22/10 0:00 8/31/23 0:00 ZCA1-RPRB-O(A1) 1872563 "DAVIDSON, NANCY ELLEN" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 4/1/22 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2022 600000 NCI 600000 0 Project SummaryThe Cancer Immunotherapy Trials Network (CITN) came about from discussions at the 2007 NCIImmunotherapy Agent Workshop in which high-priority agents were identified that showed the potential tobenefit patients with cancerbut that were not yet broadly available for investigator-initiated trials (IITs). Since2007 a sea change has occurred in the field of cancer immunotherapy resulting from the success of anti-PD1and anti-PD-L1. However most of the priority agents identified in the NCI Workshop are still not broadlyavailable for academic IITs.Since the original award in 2011 the CITN focused on testing these high-priority agents including 5 of the top8 ranked agents that hit targets critical for optimal immune responses. CITN trials are among the few academicIITs of these agents and each trial has defined biologic and therapeutic principles. Two trials have led tochanges in clinical practice. The abbreviated Specific Aims for the CITN are as follows:Aim 1: (a) to continue to conduct innovative early phase multicenter immunotherapy trials for adult cancersusing high-priority immunomodulatory agents; (b) to form a Pediatric CITN (PedCITN) to conduct innovativeearly phase multicenter immunotherapy trials for pediatric cancers using high-priority immunomodulatoryagents; (c) to provide leadership infrastructure and statistical support for the conduct of these clinical trials;(d) to continue to access high-priority agents central to immune responses and not broadly available for IITsAim 2: to coordinate studies with Cancer Immune Monitoring and Analysis Center (CIMAC) and other labs forspecimen analysis (immune monitoring biomarker credentialing) of adult and pediatric patients on CITN trialsScientific Goals of the CITN1. Continue trials with T cell and natural killer cell activator and growth factor IL-15 homeostatic T cell growth factor IL-7 dendritic cell activator anti-CD40 dendritic cell growth factor Flt3L and IDO inhibitor anti-PD12. Continue trials with anti-PD1 for orphan and ultra-orphan indications including pediatric cancers3. Conduct biopsy-intense trials to identify actionable causes of anti-PD1 failure and linked to therapeutic administration of potential rescue agents4. Conduct trials to assess therapies that eliminate or activate the myeloid monocytes/macrophage and/or myeloid-derived suppressor cells that reside within most cancers5. Conduct multicenter Phase I and early Phase II immunotherapy trials for pediatric patients with cancerThe results will inform future trial designs and improve the understanding of these high-priority agents. CITNtrials are designed to identify paths to regulatory approval and will likely change standard practice or spurconfirmatory pivotal trials by NCI cooperative groups and industry for adult and pediatric cancers. 600000 +Aging; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Patient Safety; Prevention Academic Medical Centers;Address;Advocate;Aging;Area;Attention;Behavior;Blood;Cancer Burden;Cancer Patient;Cancer Research Project;Caregivers;Clinical;Clinical Oncology;Clinical Research;Clinical Trials;Collaborations;Collection;Committee Membership;Communities;Community Clinical Oncology Program;Companions;Data;Data Reporting;Databases;Development;Diagnosis;Disease;Education;Elderly;Functional disorder;Funding;Funding Opportunities;Grant;Health;Human;Incidence;Intervention;Intervention Studies;Maintenance;Malignant Neoplasms;Manuscripts;Mentors;Mentorship;Metastatic Neoplasm to the Bone;Metastatic malignant neoplasm to brain;Minority;Minority Groups;Mission;Monitor;Morbidity - disease rate;National Cancer Institute;National Clinical Trials Network;Natural History;Nausea and Vomiting;Oncologist;Oncology;Outcome;Outcome Assessment;Outcomes Research;Parents;Patient Outcomes Assessments;Patients;Pharmacologic Substance;Population;Prevalence;Prevention;Publishing;Quality of life;Research;Research Methodology;Research Personnel;Research Priority;Risk;Site;Source;Symptoms;Technology;Tissue Sample;Toxic effect;Training;Translational Research;Tumor Tissue;Underserved Population;United States;Work;base;cancer care;cancer clinical trial;cancer health disparity;cancer prevention;cancer risk;cancer therapy;care delivery;chemotherapy;clinically relevant;clinically significant;curative treatments;data sharing;disparity elimination;disparity reduction;experience;financial toxicity;health disparity;high risk;improved;innovation;mortality;multidisciplinary;next generation;novel;older patient;premalignant;prevent;programs;reduce symptoms;repository;skeletal-related events;survivorship;translational oncology;treatment trial;underserved community;underserved minority Alliance NCORP Research Base Alliance NCORP Research BaseProject NarrativeThe Alliance NCI Community Oncology Research Program (NCORP) Research Base conductsresearch in cancer prevention cancer symptom control and cancer care delivery with a specialemphasis on minority underserved and older patients and with a strong commitment to buildingcollegial relationships with NCORP Community sites and Minority/Underserved Communitysites. The Alliance NCORP seeks to continue its mission into the next grant cycle of generatingpractice-changing research that directly and favorably impacts the lives of cancer patients andthose at risk for cancer. NCI 10688630 8/26/22 0:00 RFA-CA-18-015 3UG1CA189823-09S1 3 UG1 CA 189823 9 S1 "MCCASKILL-STEVENS, WORTA J" 8/1/14 0:00 7/31/25 0:00 ZCA1-GRB-S(M1) 6356949 "GEORGE, SUZANNE " "HAHN, OLWEN ; PASKETT, ELECTRA D." 7 Unavailable 117404554 F4BMNBQK9BM1 117404554 F4BMNBQK9BM1 US 41.879725 -87.636406 10060073 ALLIANCE NCTN FOUNDATION CHICAGO IL Other Domestic Non-Profits 606064404 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 399 Other Research-Related 2022 15290 NCI 13900 1390 Alliance NCORP Research BaseProject Summary/AbstractThe Alliance for Clinical Trials in Oncology (Alliance) one of five National Clinical Trials Network groupsserves as the parent organization for the Alliance NCI Community Oncology Research Program (NCORP)Research Base (Alliance NCORP). The Alliance NCORP conducts interventional and observational clinicaland translational research as well as database studies all of which address important questions relevant tocancer prevention symptom control and cancer care delivery. In addition the Alliance NCORP conductsclinically important quality of life studies that are embedded within cancer treatment trials. It places specialemphasis on minority underserved and older patients at risk for or diagnosed with cancer and on buildingstrong collegial relationships with NCORP Community sites and Minority/Underserved Community sites. TheAlliance NCORP committee membership includes rich representation from both community-based andacademic medical centers as well as patient advocates thus generating research results relevant to cancerpatients across the United States. The Alliance NCORP also emphasizes mentorship and training of juniorinvestigators. Over this past grant cycle i.e. since August 2014 the Alliance NCORP has published 148manuscripts and abstracts. This work has included practice-changing research in such areas as theprevention of chemotherapy-induced nausea and vomiting the prevention of skeletal-related events fromosseous metastases the management of brain metastases and the integration of patient-reported outcomesinto cancer clinical trials. The Alliance NCORP conducts translational research that requires the collection oftumor tissue premalignant tissue samples blood and other human biospecimens; and shares data andbiospecimens for pooled analyses and other scientific collaborations. These biospecimens create aninvaluable repository for understanding clinical observations from a mechanistic standpoint. The AllianceNCORP also collaborates broadly with other NCI-funded investigators and consortia as well as withinvestigators supported through non-NCI sources. This practice-changing research and the scientificquestions answered by the Alliance NCORP provide meaningful and innovative contributions to clinical andtranslational oncology which can be conducted only within a publicly-funded research network. 15290 +Biotechnology; Cancer; HIV/AIDS Academic Medical Centers;Basic Science;Bioinformatics;Biological Assay;Biology;Cancer Biology;Cancer Center Support Grant;Cells;Cerebrospinal Fluid;Clinical;Clinical Research;Clinical Trials;Collaborations;Complex;Comprehensive Cancer Center;Cultured Cells;DNA Adducts;Data Analyses;Development;Disease;Doctor of Philosophy;Duct (organ) structure;Extramural Activities;Feces;Funding;Goals;Grant;Infrastructure;Investigational Therapies;Irrigation;Knowledge;Laboratories;Liquid substance;Malignant Neoplasms;Methods;Mission;Modification;Molecular;New Jersey;Peptides;Plasma;Primary carcinoma of the liver cells;Principal Investigator;Process;Proteins;Proteomics;Proteomics Shared Resource;Publications;RNA Splicing;Research;Research Personnel;Resolution;Resource Sharing;Sampling;Science;Scientist;Serum;Services;Site;Technology;Time;Tissues;Training;Translational Research;United States National Institutes of Health;Universities;Urine;Variant;Washington;Water;anticancer research;arm;base;data acquisition;data reduction;exosome;experience;experimental study;glycoproteomics;industry partner;innovation;lipidomics;liquid chromatography mass spectrometry;malignant breast neoplasm;member;metabolome;metabolomics;method development;molecular oncology;multiple reaction monitoring;novel;operation;phosphoproteomics;programs;protein metabolite;small molecule;tool Shared Resource - Proteomics & Metabolomics Shared Resource n/a NCI 10688611 9/2/22 0:00 PA-20-272 3P30CA051008-29S1 3 P30 CA 51008 29 S1 "HE, MIN" 9/1/22 0:00 4/30/23 0:00 6220 11295207 "MA, JUNFENG " Not Applicable 98 Unavailable 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC Domestic Higher Education 200570001 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 Research Centers 2022 249572 160180 89392 ABSTRACT The molecular characterization of disease processes has become an indispensable component of current cancer research. The mission of the Proteomics & Metabolomics Shared Resource (PMSR) is to provide state-of-the- art chromatographic and mass spectrometric services for proteomics and metabolomics applications. The PMSR was established in 2006 for proteomics and expanded to metabolomics in 2008. Since the last review PMSRs activity and throughput have expanded dramatically; the PMSR provided services to 22 Georgetown Lombardi Comprehensive Cancer Center (LCCC) members in fiscal year (FY) 2017. Radoslav Goldman PhD oversaw proteomics operations through 03/2018 at which time he stepped down to focus on directing his newly formed Glycoscience Center. Byers replaced Goldman. Byers is the founder and a former director of the PMSR. Proteomics services include optimizing workflows and developing specialized services which include identifying proteins and peptides and their modifications and quantification. Targeted liquid chromatography-mass spectrometry (LC-MS) experiments for specific proteins and their modifications facilitate the conduct of translational research applications. Cheema manages the metabolomics component. The metabolomics component includes comprehensive metabolomics and lipidomics profiling services from a variety of matrices including tissue and cultured cells and biofluids such as serum plasma and urine. The PMSR has developed and optimized methods for protein and metabolite extraction from complex matrices such as cells feces ductal lavage fluid and cerebrospinal fluid. The proteomics and metabolomics services also include multiple reaction monitoring (MRM)-based targeted quantification and metabolomics services further include high-resolution MS for small molecules. The Waters Corporation recognized the metabolomics component as a Center of Innovation. Waters has continually supported high-impact science resulting in multiple extramurally funded grants with a metabolomics focus in at least one specific aim. +No NIH Category available 2019-nCoV;Acute-Phase Proteins;Age;Antibody Response;Antigen-Antibody Complex;Asian population;Autoimmune Diseases;Behavioral;Biological Response Modifiers;Black Populations;Blood Circulation;COVID-19;COVID-19 patient;COVID-19 treatment;California;Cancer Patient;Catchment Area;Clinical;Complement;Conflict (Psychology);Data;Diabetes Mellitus;Diet;Eicosanoids;Elderly;Enrollment;Environment;Ethnic Origin;Exhibits;Geographic Locations;Health Personnel;Health system;Healthcare Systems;Heterogeneity;Hispanic;Household;Hypertension;Immune;Immunity;Immunoglobulin G;Immunoglobulin M;Individual;Individual Differences;Infection;Inflammation Mediators;Inflammatory;Inflammatory Response;Influenza;Infrastructure;Knowledge;Latinx population;Life Style;Lipids;Longitudinal cohort;Longitudinal cohort study;Maps;Measures;Mediator of activation protein;Metabolic;Methods;Minority;Molecular;Molecular Profiling;Morbidity - disease rate;Natural History;Nature;Obesity;Outcome;Participant;Patients;Pattern;Peripheral;Persons;Population;Population Heterogeneity;Populations at Risk;Predisposition;Race;Recovery;Recovery of Function;Reporting;Resistance;Resistance to infection;Resolution;Resources;Risk;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;Serology;Signal Transduction;Smoking;Socioeconomic Status;Symptoms;Testing;Therapeutic immunosuppression;Time;Variant;Viral;Woman;Work;aged;antibody detection;base;cancer therapy;clinical predictors;co-infection;cohort;comorbidity;cytokine;disorder risk;experience;high risk;immune reconstitution;infection risk;men;metropolitan;predictive signature;prospective;racial and ethnic;racial minority;response;sex;trait CORALE-SeroNet Project 1 n/a NCI 10688399 9/21/22 0:00 RFA-CA-20-038 4U54CA260591-02 4 U54 CA 260591 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6041 9537080 "FIGUEIREDO, JANE C." Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 366809 246884 119925 ABSTRACT Pressing questions pertain to the consistently observed paradoxes regarding the variable nature of host susceptibility and response to SARS-CoV-2. We and others have reported on more active spread and greater morbidity among older persons and ethnic/racial minorities especially with certain comorbidities and metabolic. To date the evidence to date suggests that while some individuals exhibit a particular vulnerability to SARS-CoV- 2 (i.e. susceptibility) many others have an intrinsic or acquired relative immunity (i.e. resistance) to infection or disease risk or both for unknown reasons. Further compounding the enigmatic nature of SARS-CoV-2 risk is the conflicting data on measures of immunity. We and others have found that the extent to which individuals exhibit a post-infectious IgG antibody response to SARS-CoV-2 is highly variable many persons have no antibodies detected in the peripheral circulation within weeks to months following resolution of symptoms. We hypothesize that: (H1) the natural history of response to SARS-CoV-2 exposure is marked by discernible patterns of susceptibility vs resistance that vary by demographic clinical and host-environment factors; and (H2) divergent clinical trajectories are driven by underlying inter-individual differences in the complex immune- inflammatory response to SARS-CoV-2 exposure. Based on early observations and emerging data we anticipate four potential clinical trajectories among exposed individuals: (i) those with exposure but apparently no infection; (ii) infection with minimal to no symptoms then persistent immunity; (ii) infection with symptoms recovery persistent immunity; and (iv) infection recovery re-infection. To test these hypotheses we propose to leverage our existing CORALE study (n=10370) a prospective longitudinal cohort study at a major metropolitan healthcare system in Southern California. Our catchment area includes large numbers of Hispanic/LatinX Black and Asian individuals across the age range representing high-risk and understudied populations; in turn our health system is one of the nations highest volume centers for treating COVID-19 patients. Our specific aims are to: (1) identify distinct trajectories and determinants of susceptibility and immunity to SARS-CoV-2; and (2) identify distinct immune-inflammatory profiles (including bioactive lipid eicosanoids acute phase proteins cytokines and their derivatives) associated with susceptibility and immunity to SARS-CoV-2. We will use both baseline measures and perform serial SARS-CoV-2 serologic measures (IgG + IgM) to longitudinally map serologic response with clinical and functional measures and define specific trajectories of susceptibility vs resistance (i.e. variations in degree of vulnerability to infection and illness rate of recovery and ability to maintain durable clinical immunity to re-infection or co-infection by other viral illnesses such as influenza). Lastly we will examine heterogeneity in trajectories by sex age race/ethnicity socioeconomic status and host-environment modifiers (e.g. smoking diet and other lifestyle/behavioral factors). This CORALE-SeroNet Project 1 will identify the clinical and molecular profiles that signal robust immune reconstitution and functional recovery following SARS-CoV-2 exposure in multiple diverse populations including understudied minorities. +No NIH Category available Address;Affect;Basic Science;Behavioral;Bioethics Consultants;COVID-19;COVID-19 pandemic;COVID-19 risk;COVID-19 testing;COVID-19 vaccination;Caregivers;Clinical;Collaborations;Communication;Communication Tools;Decision Making;Development;Diabetes Mellitus;Disease;Effectiveness;Ensure;Exposure to;Face;Family;Fright;General Population;Government;Health;Health Personnel;Health Services;Health behavior change;Heart Diseases;Household;Immune system;Immunity;Individual;Infection;Internet;Interview;Knowledge;Lung diseases;Malignant Neoplasms;Measures;Methods;Mission;Modality;Organizational Change;Outcome;Patients;Perception;Persons;Population;Provider;Public Health;Research;Research Methodology;Resolution;Risk;Role;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;Science;Serology;Serology test;Site;Source;Stigmatization;Surveys;Test Result;Testing;Time;Translating;Update;Vaccination;Vaccines;Viral;Virus;Work;cancer therapy;coronavirus disease;cost;disease transmission;empowered;experience;first responder;follow-up;health communication;high risk;implementation science;improved;improved outcome;infection risk;insight;news;pandemic disease;personal protective equipment;population health;response;social media;tool;transmission process;uptake;web site Project 3: Responding to Changing Serological and Viral Information around COVID-19 (RESPOND) n/a NCI 10688397 9/19/22 0:00 RFA-CA-20-038 4U54CA260582-02 4 U54 CA 260582 2 9/18/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6039 8722029 "MCALEARNEY, ANN SCHECK" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 141622 89919 51703 Project SummaryResponding to the COVID-19 pandemic requires research to understand how the virus is transmitted what typesof protection are most effective how immunity is acquired and persists and how to best encourage people tomake use of available testing and vaccines. As our understanding of serologic and viral testing opportunities andimplications of test results improves so too does our ability to provide guidance to individuals at higher risk fromexposure such as first responders and their household contacts as well as the general public. Communicationabout the risks related to COVID-19 which is reliable and tailored to the appropriate audience empowersindividuals to make the best decisions to protect themselves. Further when a vaccine becomes available athorough understanding of the barriers and perceptions related to vaccination will be critical for promoting andfacilitating uptake. Translating new basic science discoveries quickly and to the appropriate audiences will thusensure the effectiveness of initiatives that can address the spread of COVID-19.To that end Project 3 Responding to Changing Serological and Viral Information around COVID-19(RESPOND) seeks to leverage information and discoveries from Projects 1 and 2 as well as fromcollaborations with other SeroNet Centers and Components to develop actionable communication tools fororganizations and individuals to empower them to utilize the most up-to-date information to guide their decisions.Using a mixed methods approach including qualitative interviews and surveys in Year 1 we will first develop abaseline understanding of the communication mechanisms used by stakeholder organizations such asgovernment and administrative health agencies healthcare provider organizations and employers of individualsat higher risk of exposure and disease transmission. We will also assess baseline understanding of COVID-19risks and testing options by individuals at higher risk including first responders and their household contacts aswell as patients undergoing cancer treatment. In Years 2-5 we will continue our mixed methods approachthrough follow-up interviews and surveys incorporating new information learned Projects 1 and 2 and fromSeroNet collaborators. Throughout the study we will disseminate our findings through a project websitepresenting communication best practices and providing tools we develop for specific stakeholder audiences aswell as the general public. +No NIH Category available 2019-nCoV;African American;African American population;Ambulatory Care Facilities;Antibodies;Asian;Bioinformatics;Blood;COVID-19;COVID-19 patient;COVID-19 risk;COVID-19 testing;COVID-19 treatment;California;Catchment Area;Clinical;Clinical Data;Clinics and Hospitals;Cohort Studies;Collaborations;Collection;Communities;Consent;Data;Data Analytics;Data Reporting;Databases;Diagnosis;Electronic Health Record;Electronic Mail;Employee;Enrollment;Epidemiologist;Epidemiology;Evaluation;Evaluation Studies;Funding;Geographic Locations;Goals;Hawthorne Effect;Health Personnel;Heart;Hispanic;Hispanic Populations;Home;Household;Immune;Immune response;Immunocompromised Host;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Laboratories;Latino Population;Latinx;Link;Los Angeles;Malignant Neoplasms;Medical;Medical Records;Medical center;Methodology;Outcome;Participant;Pathologist;Patient Recruitments;Patients;Persons;Population;Population Heterogeneity;Procedures;Process;Protocols documentation;Questionnaires;Records;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Risk;Serology;Specimen;Standardization;System;Technology;Testing;Time;Translational Research;Virus;base;biobank;clinically relevant;cohort;cost efficient;data harmonization;data management;data sharing;design;digital;experience;fight against;follow-up;genetic linkage analysis;laboratory equipment;member;novel virus;pandemic disease;participant enrollment;patient oriented;patient portal;programs;prospective;recruit;response;routine screening;sample collection;user-friendly;virtual patient CORALE-SeroNet Recruitment and Biobanking Core n/a NCI 10688396 9/21/22 0:00 RFA-CA-20-038 4U54CA260591-02 4 U54 CA 260591 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6038 9537080 "FIGUEIREDO, JANE C." Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 396401 246702 149699 PROJECT SUMMARY/ABSTRACT for the Recruitment and BioBanking Core The Recruitment and Biobanking Core (RBC) will serve as a Resource Support Core for 3 full Research Projects. This core provides a standardized system for patient identification and recruitment longitudinal follow- up using active and passive methodologies biospecimen collection tracking processing storage and distribution; access to state-of-the-art laboratory technologies provided in Core 2; linkage to medical records and other relevant external databases; computational and statistical support; and enables future research in collaboration with SeroNET and beyond. Importantly this core leverages already implemented cutting-edge initiatives underway at Cedars-Sinai namely: (1) Biobanking Research Protocol that universally permits patients to participate in research by utilizing and storing their biospecimens and conducting follow-up procedures for research purposes; (2) Cedars-Sinai Accelerator which has funded start-up companies (e.g. Hawthorne Effect) to develop and implement integrated technological platforms to provide timely accurate data from patients as well as networks to facilitate remote data and biospecimens collections; and (3) Cedars-Sinais Employee Cohort that has conducted timely repeated questionnaire assessments repeated biospecimen collection and repeated SARS-CoV-2 testing on >6000 Essential Health Care Workers. The RBC will merge these activities into a centralized approach with the following goals: 1. Expand Recruitment and Prospective Follow-Up: Cedars-Sinai COVID-19 Risk Associations and Longitudinal Evaluation (CORALE) study leverages the expansive Cedars- Sinai network including two large medical centers and multiple outpatient clinics. The fully integrated Epic based electronic health record (EHR) known as CS-Link allows for rapid connection with over >1M individuals and permits digital enrollment consent and data entry and tracking via a virtual patient portal. Cedars-Sinais diverse catchment area in central Los Angeles allows a unique opportunity unparalleled in other parts of the U.S. to bring together large diverse populations (including large numbers of Hispanics/Latinos and African Americans). Electronic communication data entry and remote biospecimen collection capabilities enable rapid and cost- efficient longitudinal follow-up. 2. Biospecimen Collection Processing and Storage: We will collect process store and track all biospecimens using LabvantageTM a user-friendly laboratory tracking system already implemented and supported directly by the Cedars-Sinai Biobank and Translational Research Core Laboratory. 3. Data Management Linkage and Analyses: We will link demographic clinical epidemiologic and outcomes data from our centralized EHR with the biospecimens and participant reported data. Our bioinformatic and computational shared resources will provide analytical support. 4. Expand Capacities for Future Research: We will provide access to state-of-the-art technologies available through the integration of our Core with our existing Shared Resources and enable data sharing with internal and external investigators in SeroNET. +No NIH Category available 2019-nCoV;Address;Administrative Coordination;Advisory Committees;Advocate;Annual Reports;Basic Science;Bioinformatics;Budgets;COVID-19 susceptibility;Clinical Research;Clinical Sciences;Collaborations;Communication;Communities;Data Set;Educational workshop;Ensure;Evaluation;Feedback;Generations;Goals;Immune;Immunity;Inflammatory Response;Infrastructure;Investigation;Knowledge;Leadership;Letters;Monitor;Participant;Patients;Policies;Population Sciences;Preparation;Productivity;Progress Reports;Publications;Reporting;Research;Research Personnel;Research Project Grants;Resource Allocation;Resource Sharing;Resources;Scientist;Services;Structure;Therapeutic;Training Activity;Translating;Translational Research;Translations;Vision;Work;biobank;data dissemination;data sharing;meetings;operation;organizational structure;programs;public repository;recruit CORALE-SeroNet Admin Core n/a NCI 10688395 9/21/22 0:00 RFA-CA-20-038 4U54CA260591-02 4 U54 CA 260591 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6037 10217223 "CHENG, SUSAN " Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 317093 197344 119749 ABSTRACT for Administrative Core The Administrative Core will provide a centralized coordinated infrastructure for effectively supporting evaluating and stimulating progress towards the overall scientific goals of the CORALE-SeroNet U54 Program. The Core led by the Program Directors (Drs. Susan Cheng Jane Figueiredo and Michael Karin) will interact with Internal and External Advisory Committees and a Community Advisory Board and will provide regular feedback on programmatic initiatives and progress toward achieving the following goals. First to provide leadership to ensure overall program productivity and effective collaboration across the SeroNET consortium. The Administrative Core will provide: (a) centralized and efficient administrative support and coordination of all CORALE-U54 activities and all collaborative efforts across the SeroNet consortium; (b) regular monitoring and evaluation of all project activities and generation of reports for internal and external stakeholders including assessments of opportunities for translation between basic and clinical research and the most effective allocation of resources; (c) engagement with advisory committees and external organizations including other SeroNet centers and external investigators regarding progress toward the overall goals of SeroNet and opportunities for augmenting or integrating scientific and training activities; (d) financial administrative support to ensure appropriate management of budgets and financial resources; (e) support to ensure research compliance and integrity of all research programs; and (f) administrative coordination for the dissemination of data and results including data sharing and publication of all research findings. In particular the Leadership Administrative Core has an active communication plan and resources for disseminating our ongoing findings to the broader clinical research and lay communities. Second the Administrative core will provide organizational structure and management support for the Resource Cores. The Administrative Core will provide an efficient and centralized administrative structure to support all activities of the two Cores: (a) Recruitment and Biobanking Core (RBC) and (b) the Immune Bioanalytics Core (IBC). Thirdly. The Administrative Core will provide organizational structure and management to collaborate within SeroNet and beyond. Our vision is to develop and manage a research program that will integrate our team of population clinical translational and basic science scientists and unique patients resources with the broader scientific community led by SeroNET to meet the urgent need to understand the underlying mechanisms and potential therapeutic approaches to address key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity. +No NIH Category available Address;Biological;Biological Assay;COVID-19 pandemic;Clinical Trials Data Monitoring Committees;Code;Data;Data Analyses;Data Collection;Data Reporting;Development;Ensure;Epidemiology;Factor Analysis;Genetic Transcription;Goals;Human Resources;Immunologics;Knowledge;Laboratories;Lead;Maintenance;Measurement;Methodology;Methods;Observational Study;Outcome Measure;Participant;Phase;Procedures;Process;Psychometrics;Quality Control;Reporting;Reproducibility;Research;Research Design;Research Personnel;Resources;Sample Size;Science;Secure;Security;Serology test;Services;Sociology;Standardization;Statistical Data Interpretation;Statistical Models;Statistical sensitivity;Surveys;Testing;Visual;Visualization;Work;base;cognitive interview;complex data;coronavirus disease;data integration;data integrity;data management;data quality;design;improved outcome;meetings;pilot test;primary outcome;repository Core C: Data Management and Analysis n/a NCI 10688389 9/19/22 0:00 RFA-CA-20-038 4U54CA260582-02 4 U54 CA 260582 2 9/18/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6031 8665590 "FERNANDEZ, SOLEDAD A" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 207760 135177 72583 Project Summary Core CThe principal objective of the Data Management and Analysis Core (Core C) is to provide project investigatorsa centralized resource for quantitative expertise. Statistical and methodological issues will be addressed at allstages: from the initial design of laboratory assays and observational studies to the maintenance of data qualityto the analysis of complex data. In support of this objective Specific Aims of Core C are: Aim 1. Collaboratewith project investigators to align study design and analysis with research questions. Core C will assistresearchers at the design stage by: formulating biological immunological epidemiological and sociologicalquestions as testable statistical hypotheses; devising efficient study designs and matching these with appropriatestatistical models; determining sample sizes necessary to ensure high power while controlling Type I error.Survey development will utilize appropriate methods (e.g. cognitive interviewing or pilot testing) to ensure thatthey are psychometrically appropriate. Core personnel will ensure that: the chosen designs and surveys avoidbiases and decrease measurement errors; the selected primary outcome measures will answer specific researchquestions; and the statistical analysis plans will use data to answer the research questions under realistic andtransparent assumptions. Aim 2. Provide services and support for data collection and management toensure: integrity security and accessibility; processing and quality control; sharing across projects;and creating a centralized repository of all survey instruments analysis procedures and results. Topromote data integration across projects Core C will create a centralized repository of all data that will be secureand accessible to investigators. Quantitative data will be cleaned merged and de-identified. Missing and outlyingdata reports will be provided to the investigators. Developed surveys will be content validated and furthervalidated by psychometric analyses as appropriate. Qualitative data will follow a rigorous transcription and codingprocess. To ensure high data integrity and availability for statistical modeling Core C will implement rigorousquality control and processing procedures using approaches such as normalization filtering and visualization.Aim 3. Provide services and support for data analysis and interpretation phases of all projects. Core Cservices will include: (i) formal hypothesis tests for laboratory epidemiological and qualitative data that ensurestrong conclusions (ii) exploratory analyses that lead to new or refined hypotheses (iii) statistical modeling andsensitivity analyses of complex data and (iv) visual displays that clarify conclusions. In accordance with criticalprinciples of rigor and reproducibility in science Core C biostatisticians will work closely with investigators todevelop comprehensive analysis plans that distinguish between formal testing and exploratory analyses.Qualitative data (e.g. cognitive interviews) will be analyzed following a standardized coding process. +No NIH Category available 2019-nCoV;Acute;Adult;Antibodies;Antibody Response;Antibody-mediated protection;Area;Asthma;Biological;Blood;Blood specimen;COVID-19;COVID-19 patient;COVID-19 survivors;Cancer Patient;Centers for Disease Control and Prevention (U.S.);Child;Childhood;Childhood Asthma;Clinical;Clinical Data;Collection;Communities;Data;Data Collection;Development;Elderly;Enrollment;Ensure;Ethics;Funding;Goals;Guidelines;Health Sciences;Hematologic Neoplasms;Hospitalization;Hospitals;Immune response;Immunity;Immunoassay;Individual;Infection;Inpatients;Laboratories;Longevity;Longitudinal Studies;Louisiana;Maintenance;Malignant Neoplasms;Methodology;Nucleoproteins;Outpatients;Patient Recruitments;Patients;Process;Protocols documentation;Reproducibility;Research;Research Personnel;Residual state;Resources;Role;SARS-CoV-2 infection;Sampling;Serology;Serum;Site;Solid Neoplasm;Source;Specimen;Syndrome;Time;Universities;Work;acute infection;chemotherapy;cohort;coronavirus disease;design;human subject;population based;recruit;response;sample collection;success;syndromic surveillance SARS-CoV-2 Clinical Cohort Core n/a NCI 10688387 9/20/22 0:00 RFA-CA-20-038 4U54CA260581-02 4 U54 CA 260581 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6029 9708742 "FUSCO, DAHLENE NICOLE" Not Applicable 1 Unavailable 53785812 XNY5ULPU8EN6 53785812 XNY5ULPU8EN6 US 29.935429 -90.12279 8424601 TULANE UNIVERSITY OF LOUISIANA NEW ORLEANS LA Domestic Higher Education 701185665 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 207212 136853 70359 Clinical Cohort Core SummaryAn efficient reliable and comprehensive source of clinical data and biological specimens is essential to thedesign and implementation of the Tulane University COVID Antibody and Immunity Network (TUCAIN). U54Center. The Clinical Cohort Core will fill this need by bringing together outstanding investigators who are currentlyleading a diversity of patient cohorts from across the lifespan that are highly relevant to this proposal. The overallgoal of this Core is to develop and maintain a diverse set of cohorts made up of human subjects from childhoodto the elderly and to longitudinally collect clinical data and biological specimens required to complete bothTUCAIN and SeroNet activities. The Core will support the Immunoassay Core as well as both Projects 1 & 2 byproviding a centralized team for patient recruitment demographic and clinical data collection and serial samplecollection and processing. In this role the Core will also be responsible for maintaining all ethics approvals aswell as maintaining electronic sample logs and providing samples and clinical data to Projects 1 & 2 as needed.The Clinical Cohort Core will be responsible for the following Specific Aims: (1) Coordinate the safe and efficientcollection of serial samples from enrolled subjects. By centralizing sample collection and processing as well asdata collection we will enhance the rigor and reproducibility of all work done by this Center. (2) Leverage existingCOVID-19 cohorts. Several TUCAIN investigators have already established cohorts of COVID-19 patientsrecruited during hospitalization for their acute infection. Samples and clinical collected as part of these studieswill be made available to TUCAIN and SeroNet. (3) Build on existing cohorts of COVID-19 survivors recruitedfrom the community. TUCAIN investigators have been at the forefront of the COVID-19 response and have wellestablished cohorts of subjects with laboratory-confirmed or perceived infection. Data and biological samplesfrom these cohorts will be available to TUCAIN and SeroNet. (4) Leverage existing funds supporting a pediatricasthma cohort to perform syndromic surveillance. We will utilize samples collected as part of an existing cohortof children. By following them for at least three years we will be able to identify changes in the serologicalresponse over time. (5) Establish a large cohort of patients with solid and hematologic tumors. This cohort willserve as a critical resource for understanding the impact of malignancies and chemotherapy on the serologicalresponse to SARS-CoV-2 infection. These valuable resources will allow investigators at Tulane and the widerscientific community to pursue a multitude of studies on the serological response to SARS-CoV-2. Successfuldevelopment and management of these cohorts will significantly enhance the research potential of theImmunoassay Core and Projects 1 & 2 as well as the larger goals of SeroNet. +No NIH Category available 2019-nCoV;Address;Affect;Area;Autoimmune Diseases;Basic Science;COVID-19;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;California;Caring;Characteristics;Chronic Disease;Clinical;Clinical Sciences;Cohort Studies;Collaborations;Communities;Coronavirus;Data;Data Analyses;Data Collection;Disease;Enrollment;Ensure;Epidemiologist;Evaluation;Evaluation Studies;Exposure to;Foundations;Funding;Goals;Health;Health Personnel;Health system;Healthcare Systems;Home;Immune;Immunity;Immunologist;Individual;Infection;Inflammatory Response;Infrastructure;Institution;Knowledge;Los Angeles;Malignant Neoplasms;Metabolic Diseases;Minority;Molecular Profiling;Natural History;Nature;Outcome;Patients;Pattern;Persons;Population Heterogeneity;Population Sciences;Populations at Risk;Predisposition;Public Health;Publishing;Recovery;Recovery of Function;Reporting;Request for Applications;Research;Research Personnel;Research Project Grants;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;Scientific Advances and Accomplishments;Scientist;Seeds;Seroprevalences;Signal Transduction;Structure;Subgroup;Techniques;Therapeutic;Translational Research;Viral;Virus;Vulnerable Populations;World Health Organization;base;biobank;clinical phenotype;disorder risk;experience;immune function;immune reconstitution;innate immune function;insight;novel;operation;pandemic disease;programs;racial and ethnic;recruit;response;severe COVID-19;trait;translational scientist Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2 NARRATIVE: OverviewOur study will be centered on the ethnically/racially diverse population served by our health system in LosAngeles given then critical need for more knowledge regarding the determinants of COVID-19 related risks inthese minority subgroups. Leveraging our collective experience resources and infrastructure at major academicinstitutions from across Southern California (Cedars Sinai UCSD UCLA and USC) we will advance thescientific enterprise through the three distinct yet closely integrated research Projects: Project 1 will elucidatethe natural history and longitudinal trajectories that represent the diversity of SARS-CoV-2 exposure infectionrecovery and clinical immunity patterns across the spectrum of persons at risk; Project 2 will investigate thedeterminants of SARS-CoV-2 response in persons with altered innate immune function with a focus onindividuals with pre-infection susceptibility traits (e.g. metabolic disease states); and Project 3 will investigatethe determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus onindividuals with immune-altered status arising from select malignancies autoimmune disease and/or theirdirected therapies. NCI 10688386 9/21/22 0:00 RFA-CA-20-038 4U54CA260591-02 4 U54 CA 260591 2 "PATRIOTIS, CHRISTOS F" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 9537080 "FIGUEIREDO, JANE C." "KARIN, MICHAEL ; MERCHANT, AKIL " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Research Centers 2022 1738155 NCI 1157542 580613 C6 ASBTRACT OverviewEvery day Californians continue to experience high levels of exposure to the novel severe acute respiratorycoronavirus 2 (SARS-CoV-2) virus. There is an ever-growing urgent need to better understand the nature ofexposures course of illness and recovery and potential for immunity among persons at particularly heightenedrisk for the worst COVID-19 outcomes. As part of a rapid scientific response to the present public health crisiswe convened on March 18 2020 a collaborative of frontline clinicians and scientists to form the Coronavirus RiskAssociations and Longitudinal Evaluation (CORALE) studies (corale-study.org). We established two base studycohorts with enrollment centered on (i) patients with suspected or confirmed COVID-19 treated in our healthsystem (currently N>8300) and on (ii) healthcare workers directly or indirectly involved in delivering their care(currently N=6679). In response to NIH RFA-CA-20-038 we are now highly motivated and prepared to leverageour existing infrastructure to directly address the critical need for comprehensive longitudinal data collection andanalyses to advanced our understanding of SARS-CoV-2 risks the course of disease the nature of recoveryand the potential for immunity across populations at risk. By establishing the CORALE-SeroNet U54 programour goal will be to form a robust and sustainable structure of academic activities centered on investigating theresponses elicited by SARS-CoV-2 exposure and the extent to which carefully phenotyped clinical and molecularprofiles can signal robust immune reconstitution and complete functional recovery. Our study will be centeredon the ethnically/racially diverse population served by our health system in Los Angeles given then critical needfor more knowledge regarding the determinants of COVID-19 related risks in these minority subgroups. Ourscientific objectives will be achieved by an outstanding collaborative team of clinician-scientists epidemiologistsimmunologists basic and translational scientists analytical chemists and biostatisticians. Leveraging ourcollective experience resources and infrastructure at major academic institutions from across SouthernCalifornia (Cedars Sinai UCSD UCLA and USC) we will advance the scientific enterprise through the threedistinct yet closely integrated research Projects: Project 1 will elucidate the natural history and longitudinaltrajectories that represent the diversity of SARS-CoV-2 exposure infection recovery and clinical immunitypatterns across the spectrum of persons at risk. Project 2 will investigate the determinants of SARS-CoV-2response in persons with altered innate immune function with a focus on individuals with pre-infectionsusceptibility traits (e.g. metabolic disease states); and Project 3 will investigate the determinants of SARS-CoV-2 response in persons with altered adaptive immune function with a focus on individuals with immune-altered status arising from select malignancies autoimmune disease and/or their directed therapies. As a wholethis research program will integrate population clinical translational and basic science resources with a world-class investigator team to meet the urgent need for new mechanistic insights and therapeutic approaches toaddress key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity. 1738155 +No NIH Category available Achievement;Address;COVID-19 pandemic;COVID-19 severity;Clinical;Collaborations;Common Data Element;Communicable Diseases;Communication;Communities;Data;Electronic Mail;Ensure;Environment;Environment Design;Evaluation;Evaluation Reports;Faculty;Fostering;Goals;Human Resources;Immune System Diseases;Immune response;Infrastructure;Institutes;Investigation;Laboratories;Lead;Learning;Monitor;Outcome;Paper;Performance;Principal Investigator;Procedures;Program Evaluation;Progress Reports;Reagent;Reporting;Research;Research Personnel;Research Project Grants;Risk;Science;Seasons;Serology;Serology test;Structure;System;Thinking;Videoconferencing;Work;community center;coronavirus disease;data sharing;experience;graduate student;health management;improved;improved outcome;meetings;member;operation;patient safety;population health;ranpirnase;research study;success;symposium;web site Core A: Administration n/a NCI 10688385 9/19/22 0:00 RFA-CA-20-038 4U54CA260582-02 4 U54 CA 260582 2 9/18/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6028 8722029 "MCALEARNEY, ANN SCHECK" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 303092 192439 110653 Core A: SummaryCore A the Administrative Core of the Center for Serological Testing to Improve Outcomes fromPandemic COVID-19 (STOP-COVID) will ensure management and coordination of all STOP-COVID researchas well as appropriate communications and integration both across our Center and with the other componentsof the broader SeroNet. Core A is focused on Management Communication Networking and Evaluationactivities through the following aims: 1) Provide research oversight establishing Center management andcommunication structures; 2) Ensure integration of our Center with the SeroNet via meetings networking andcoordination of opportunities for Trans-Network Collaborations and Data Sharing and 3) Oversee CenterProgram Evaluation and Reporting monitoring Center progress. Core A will also ensure the data collectedacross the Center to STOP-COVID Center conform with the agreed practices and principles of the SeroNetStandard Operating Procedures (SOPs) Common Data Elements (CDEs) and data sharing plan as approvedby the SeroNet Steering Committee. The members of Core A will work together to foster an environmentof transdisciplinary research excellence to ensure achievement of all aims of the STOP-COVID Centerand its embedded Research Projects and Cores. +No NIH Category available 2019-nCoV;ACE2;Address;Age;Antibodies;Antiviral Agents;Bioinformatics;Biological Assay;COVID-19;COVID-19 pandemic;COVID-19 risk;COVID-19 susceptibility;COVID-19 treatment;COVID-19 vaccine;Cancer Patient;Cells;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Collection;Data;Data Science Core;Data Set;Defect;Development;Disease;Emergency Situation;Epithelial;Epithelial Cells;Evaluation;Exhibits;Future;Genetic Transcription;Genomic approach;Histology;Human;Immune;Immune Sera;Immune response;Individual;Infection;Influenza A virus;Interferons;Kidney;Knowledge;Lung;Lung Neoplasms;Lung diseases;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methods;Molecular;Monitor;Monkeys;Natural Immunity;Normal Cell;Normal tissue morphology;Patients;Pharmaceutical Preparations;Population;Predisposition;Preparation;Prevention strategy;Production;Proteins;Resistance;Resources;Risk;SARS-CoV-2 antibody;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sample Size;Sampling;Serology;Smoking;Smoking Status;Specificity;Sum;Tissues;Tobacco smoking behavior;Vaccination;Vaccines;Viral;Virus Diseases;Virus Receptors;Virus Replication;acquired immunity;adaptive immunity;airway epithelium;antibody-dependent cell cytotoxicity;antiviral immunity;base;cancer cell;cohort;comorbidity;cytokine;demographics;experimental study;gender diversity;individual patient;individual variation;influenzavirus;insight;inter-individual variation;lung cancer cell;molecular subtypes;mortality;multidisciplinary;neoplastic cell;neutralizing antibody;novel therapeutic intervention;pandemic influenza;patient population;permissiveness;pre-clinical;prevent;protective efficacy;protein expression;receptor;remdesivir;respiratory;respiratory virus;response;screening panel;severe COVID-19;single-cell RNA sequencing;transcriptomics;tumor;vaccine distribution;vaccine strategy Project 2: Susceptibility of Lung Cancer Cells to SARS- CoV-2 Infection and Antibody-Mediated Neutralization n/a NCI 10688382 9/19/22 0:00 RFA-CA-20-038 4U54CA260560-02 4 U54 CA 260560 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6025 2104524 "GARCIA-SASTRE, ADOLFO " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 395967 312305 83662 PROJECT 2: ABSTRACTProject 2 is based on evidence that lung cancer patients have higher susceptibility to SARS-CoV-2 infection andincreased risk of severe disease and mortality. This increased vulnerability is likely due to a combination offactors including immune-suppressing effects of the cancer itself or its treatment age pre-existingcomorbidities or smoking. Moreover the potential elevated levels of the receptor for SARS-CoV-2 ACE2protein in tumor and tumor-adjacent normal tissues observed in cancer patients and in lungs of tobacco smokingindividuals likely contributes to the susceptibility of these patients to SARS-CoV-2. Tumor cells are also knownto be more permissive to viral replication due to defects in innate antiviral immunity. The potential for increasedSARS-CoV-2 amplification in lung cancer cells might be a major factor contributing to enhanced COVID-19disease in lung cancer patients. An increased susceptibility to viral infection and replication in lung cells in thesepatients might also impact the ability of neutralizing antibodies to block viral replication making lung cancerpatients more susceptible to SARS-CoV-2 infection and less able to become immune. Thus a betterunderstanding of the factors that impact SARS-CoV-2 replication in lung cancer and normal lung cells is neededfor devising strategies to reduce the risk of lung cancer patients for severe COVID-19 disease and for evaluationof the protective efficacy of future SARS-CoV-2 vaccines in these patients. To address these knowledge gapsin Aim 1 we will identify factors associated with the inter-individual variation in susceptibility to infection by SARS-CoV-2 using an existing unique panel of human lung derived cancer and normal epithelial cells and relate thesefactors to key clinical demographic and molecular features. We will use a combination of virological andgenomics approaches transcriptomics and scRNAseq assays. The specificity of the susceptibility to SARS-CoV-2 infection will be evaluated by comparison to other respiratory viruses such as influenza viruses. In Aim2 we will characterize the functional activity of antibodies and antivirals in susceptible lung cancer and normallung epithelial cells. Together with Project 1 we will determine the neutralizing potency of various antisera insusceptible lung cancer cells versus non-cancer respiratory tissue and antibody dependent cellular cytotoxicityactivities of antibodies in lung cancer versus normal lung epithelial cells. Lastly we will determine the preclinicalactivity of drugs under clinical trial consideration in lung cancer cells vs. non-cancer respiratory tissue. Successfulcompletion of these aims depend on our multi-disciplinary team the clinical cohorts biospecimens and resourcesprovided by the Clinical and Data Sciences Cores and coordinated with overall U54 activities by theAdministrative Core. In sum these studies will provide new information on the determinants of the susceptibilityof lung cancer patients to SARS-CoV-2 infection and uncover potential new therapeutic strategies. +No NIH Category available 2019-nCoV;Acute;Acute Respiratory Distress Syndrome;Address;Animal Model;Antibodies;Antigen-Antibody Complex;Antigens;Applied Research;Automobile Driving;B-Lymphocyte Subsets;Basic Science;Binding;Biological;Biological Assay;Blood;Blood Coagulation Disorders;COVID-19;COVID-19 impact;COVID-19 pathogenesis;COVID-19 patient;COVID-19 severity;COVID-19 treatment;Cessation of life;Clinical;Collaborations;Collection;Data;Databases;Development;Disease;Disease Outbreaks;Drug or chemical Tissue Distribution;Enrollment;Epidemic;Ferritin;Fibrin fragment D;Frequencies;Funding;Human;Illness Days;Immune;Immune response;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunologic Markers;Immunologics;Individual;Infection;Inflammation;Inflammatory;Infrastructure;Infusion procedures;Institution;Interruption;Kinetics;Libraries;Light;Link;Measures;Memory B-Lymphocyte;Molecular;Mucous Membrane;Mus;North Carolina;Outcome;Participant;Passive Immunotherapy;Patients;Phase;Plasma;Plasma Cells;Pneumonia;Property;Proteins;Randomized;Recombinants;Recovery;Research;Research Personnel;Resolution;SARS coronavirus;SARS-CoV-2 antibody;SARS-CoV-2 antigen;SARS-CoV-2 infection;Sampling;Serology;Serum;Site;Specificity;Specimen;Speed;Syndrome;System;Testing;Therapeutic;Therapeutic Studies;Tissues;Unit of Measure;Viral;Viral Respiratory Tract Infection;Virus;Virus Replication;attenuation;base;biobank;cohort;convalescent plasma;cytokine;demographics;immune activation;immunoregulation;inflammatory marker;innovation;investigator-initiated trial;metabolomics;mortality;mouse model;mucosal site;neutralizing antibody;novel;pandemic disease;pathogen;plasma cell development;polyclonal antibody;post SARS-CoV-2 infection;prevent;receptor binding;repository;response;severe COVID-19;technology development;trafficking;translational model;treatment program Project 2: Characterizing humoral responses to SARS-CoV-2 and the immunological and biological effects of plasma therapy for severe Covid-19 n/a NCI 10688380 9/19/22 0:00 RFA-CA-20-038 4U54CA260543-02 4 U54 CA 260543 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6024 10812731 "BARTELT, LUTHER A" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 351656 226145 125511 AbstractThis SeroNet Center of Excellence in SARS-CoV2 basic and applied research will use human clinical samples and smallanimal models to illuminate the molecular mechanisms driving serological and humoral immune responses to thispandemic pathogen. Here we outline Project 2 which will investigate the influence of polyclonal antibodies present inconvalescent plasma on the virologic and immunobiological outcomes and immune responses in patients treated withconvalescent plasma for severe SARS-CoV-2 infection the agent of Covid-19. This project leverages the robustinfrastructure for collection and infusion of CCP as therapy at our institution. Serum and mucosal samples collected fromCCP donors and CCP recipients provide a comprehensive and longitudinal biorepository to examine the fundamentalimmunobiological properties of antibodies in CCP. Samples are provided by participants enrolled in an integrated butseparately funded investigator-initiated trial of convalescent plasma therapy at our institution. Project 2 Aim 1 willprovide an in-depth analysis that addresses whether neutralizing and/or non-neutralizing antibodies in CCP accelerateviral clearance and resolve inflammation in blood and mucosal compartments. CCP containing different concentrationsof neutralizing antibodies will also be tested in a novel translational model of SARS-CoV-2 mouse challenge with Project1. In Project 2 Aim 2 we will employ novel recombinant antigen development technologies and systems serology (CoreB) and Ig seq (Core C) to define the isotype-specific properties of antibodies in donor CCP units and measure thetrafficking of these antibodies in CCP recipients. Project 2 Aim 3 will longitudinally follow CCP recipients to evaluate theinfluence of CCP therapy on de novo development of long lived plasma blasts and memory B cells. This projectcontributes critically to Project 1 in the serocenter by the provision of a robust clinical-immunobiological repository ofCCP donors and recipients. Interactions with Project 3 allow for comparisons between these cohorts and otherobservational cohorts of patients with SARS-CoV-2 infection who did not receive CCP. Facilitated by Core A Cores Band C provide innovative assays necessary to address long-standing questions regarding differential antiviral andimmunomodulatory properties of specific antibodies in convalescent plasma. The virological and immunobiological datagenerated in this proposal can be linked to a granular database of individual demographics and clinical variables inpatients with SARS-CoV-2 infection. The integration of this Project within the serocenter and the potential to linkbiological observations to clinical outcomes in our parallel randomized therapeutic study in which hospitalized COVID-19 patients receive either standard or high-neutralizing titer CCP will allow this Project to contribute substantially to theunderstanding of the immune response to SARS-CoV2. +No NIH Category available 2019-nCoV;Address;Advocate;Age;Antibodies;Antibody Response;Binding;Biological Assay;COVID-19;COVID-19 pandemic;COVID-19 vaccination;COVID-19 vaccine;Cancer Control;Cancer Patient;Cells;Clinical;Clinical Sciences;Clinical Trials;Collaborations;Complement;Coronavirus;Data Science Core;Demographic Impact;Development;Epithelial Cells;Ethnic Origin;Fc Receptor;Future;Gender;General Population;Generations;Glycoproteins;Hamsters;Histology;Immune;Immune response;Immunity;Incidence;Individual;Infection;Kinetics;Knowledge;Longevity;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Patients;Persons;Policies;Population;Predisposition;Preparation;Race;Regimen;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Serology;Smoking History;Smoking Status;Specimen;Statistical Data Interpretation;Testing;Vaccinated;Vaccination;Vaccines;Viral;Viral Antigens;Viral Proteins;Virus;Vulnerable Populations;Work;base;cancer therapy;case control;comorbidity;comparative;cytokine;demographics;design;infection rate;insight;inter-individual variation;lung cancer cell;mortality;neutralizing antibody;patient response;power analysis;prospective;protective efficacy;receptor;response;seropositive;severe COVID-19;trait;translational scientist;vaccine candidate;vaccine response;vaccine trial;viral entry inhibitor;virology Project 1: Characterization of the Antibody Response to SARS-CoV-2 in Lung Cancer Patients n/a NCI 10688379 9/19/22 0:00 RFA-CA-20-038 4U54CA260560-02 4 U54 CA 260560 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6023 11243077 "KRAMMER, FLORIAN " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 226649 224869 1780 PROJECT 1: ABSTRACTCurrent information indicates that in persons without cancer natural infection with SARS-CoV-2 as well asvaccination with COVID-19 vaccine candidates induce antibody responses to the spike protein of the viruswhich should be protective against future infection. Lung cancer patients who become infected with SARS-CoV-2 appear to develop severe COVID-19 with a high (35-40%) mortality rate indicating we urgently need toplan for vaccine trials in this vulnerable population. Currently we have major knowledge gaps to fill inpreparation for such vaccine studies. These include: is there a higher incidence of SARS-CoV-2 in lung cancerpatients compared to the general population? Do lung cancer patients mount a comparable antibody responsein terms of quantity quality and longevity to people without lung cancer? Equally important are information inlung cancer patients on the role of age gender smoking status histology and types of treatment for lungcancer on both SARS-CoV-2 infection rate and generation of antibody responses. Through prospectiveanalyses of lung cancer cases (N= 1000) and matched controls (N = 1000) this Project Characterization ofthe Antibody Response to SARS-CoV-2 in Lung Cancer Patients will provide answers to these importantquestions through study of 4 specific aims and the use of our U54 Administrative Clinical and DataSciences Cores. Aim 1: Characterize the incident magnitude and functionality of the antibody response toSARS-CoV-2 in lung cancer patients versus non-lung cancer controls. Aim 2: Compare the longevity of theantibody response against SARS-CoV-2 in lung cancer patients versus non-lung cancer controls. Aim 3:Evaluate the impact of patient demographics and cancer-associated clinical factors on the antibody responsein lung cancer patients. And Aim 4: Characterize antibody responses to SARS-CoV-2 vaccination in lungcancer patients versus non-lung cancer controls. The patient serology specimens will also be studied for viralneutralizing functionality in collaboration with U54 Project 2. We have assembled a world-class team of lungcancer clinical translational investigators serology and virology experts and patient advocates to addressthese key issues. The results of this Project will have a significant impact on lung cancer patient managementduring the COVID-19 pandemic and even greater impact on designing optimal SARS-CoV-2 vaccinationregimens for lung cancer patients. +No NIH Category available 2019-nCoV;Acute Respiratory Distress Syndrome;Address;Antibodies;Antibody Formation;Antibody Repertoire;Antibody Response;Antibody Therapy;Antibody-Dependent Enhancement;Applied Research;Biological Assay;Blood Coagulation Disorders;COVID-19;COVID-19 assay;COVID-19 pandemic;COVID-19 patient;COVID-19 treatment;Cessation of life;China;Chiroptera;Clinical Immunology;Collaborations;Collection;Coronavirus;Coronavirus Infections;Country;Data;Diagnostic Reagent;Disease;Disease Outbreaks;Epidemic;Epitopes;Future;Glycoproteins;Goals;Human;Immune;Immunity;Immunoglobulin A;Immunoglobulin G;Immunology;In Vitro;Infection;Inflammatory;Intervention;Investigation;Kinetics;Lentivirus;Maps;Measures;Memory B-Lymphocyte;Middle East;Middle East Respiratory Syndrome;Middle East Respiratory Syndrome Coronavirus;Modeling;Mucosal Immunity;Mucous Membrane;Mus;North Carolina;Outcome;Pathogenicity;Persons;Play;Pneumonia;Population;Public Health;Reagent;Recombinants;Role;SARS coronavirus;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sampling;Sarbecovirus;Serodiagnoses;Serology;Serum;Severe Acute Respiratory Syndrome;Specificity;Study models;Technology;Texas;Therapeutic antibodies;Time;Translational Research;Treatment Protocols;Vaccination;Viral;Virus;Work;Zoonoses;aged;clinical care;cohort;convalescent plasma;design;diagnostic assay;human disease;human model;improved;in vivo;insight;mouse model;neutralizing antibody;new technology;novel;novel coronavirus;novel diagnostics;pandemic disease;post SARS-CoV-2 infection;prevent;programs;respiratory;response;reverse genetics;time use;vaccine candidate;zoonotic coronavirus Project 1: Serological Correlates of SARS CoV2 Immunity and Disease n/a NCI 10688377 9/19/22 0:00 RFA-CA-20-038 4U54CA260543-02 4 U54 CA 260543 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6021 1885536 "BARIC, RALPH S" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 350149 225176 124973 AbstractZoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century includingSevere Acute Respiratory Coronavirus (SARS-CoV) in 2003 and the Middle East Respiratory coronavirus(MERS-CoV) in 2012. In Dec 2019 a third novel CoV designated SARS-CoV-2 emerged in Wuhan China andhas caused over 13 million cases >570000 deaths in >220 countries. In the expanding US epidemic SARS-CoV2 has caused >137000 deaths and significantly more severe infections characterized by pneumonia severeacute respiratory distress syndrome (ARDS) coagulopathies and inflammatory disorders. Incredibly carefulanalyses of zoonotic bat CoV has revealed the presence of numerous group 2b SARS-like group 2c MERS-likeand remarkably group 1 strains that replicate efficiently in primary human airway or gut enteroid cultures. Toprepare for future CoV calamities defined diagnostic assays and serologic investigations are essential fortracking current and future outbreaks and evaluate type specific and broad serologic immunity associated withpopulation immunity. The goal of this U54 Center Program is to develop novel type- and group-specific serologicand neutralization assays (Project 1-Baric Project 2- Core B and C) designed to characterize the serologicalrepertoire and to identify key domain-specific mucosal and systemic neutralizing and non-neutralizing antibodiesafter SARS-CoV-2 infection. One key underlying hypothesis is that IgA and IgG repertoires are different acrossmucosal and systemic compartments and target unique and overlapping epitope domains in the SARS-CoV2 Sglycoprotein. Another underlying hypothesis is that intervention strategies can altered the memory B cell andantibody repertoires in mucosal and serologic compartments. Finally the program develops novel mouse modelsof human disease designed to mechanistically address fundamental immune innate and adaptive interactionsassociated with protective immunity. The Project uses novel technologies basic and applied strategies to builda portfolio of reagents that map track and treat SARS-CoV2 and other SARS-like group 2b CoV of the future.In Aim 1 we evaluate the kinetics magnitude durability of type specific neutralizing antibody responses afterinfection. Aim 2 characterizes the breadth of the mucosal and systemic serologic repertoires acrossSarbecoviruses. In Aim 3 we characterize the antibodies in the mucosal and serum serologic repertoires usinga variety of in vitro and in vivo platforms designed to reveal correlates associated with protective immunity. Toachieve our goals the project interfaces closely with other projects and cores within the Center. +No NIH Category available 2019-nCoV;Address;Adopted;Advisory Committees;Age;Antibodies;Antibody Response;Biological Assay;Blinded;Blood;Blood specimen;COVID-19 risk;Cancer Control;Cancer Patient;Clinical;Clinical Research;Clinical Trials;Collection;Colorado;Comprehensive Cancer Center;Control Groups;Data;Data Science Core;Databases;Development;Doctor of Philosophy;Elements;Enrollment;Ethnic Origin;Foundations;Freezing;Gender;Health Insurance Portability and Accountability Act;Human;Individual;Infection;Infrastructure;Institutes;Institution;Institutional Review Boards;Leadership;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Medical Oncology;Medical center;Minority Groups;Mission;Molecular;Monitor;Mutation;Names;Participant;Pathology;Patient Recruitments;Patients;Pharmaceutical Preparations;Pharmacology Shared Resource;Population Control;Privacy;Process;Publications;Reporting;Research;Research Personnel;Resources;Role;SARS-CoV-2 infection;Safety;Sampling;Science;Serology;Site;Skin Cancer;Smoking History;Southwest Oncology Group;Specimen;System;Thoracic Oncology;Tobacco smoking behavior;Translational Research;Underserved Population;Universities;Ursidae Family;Vaccines;Work;anticancer research;base;biobank;design;distinguished professor;experience;interest;low dose computed tomography;lung cancer screening;minority children;operation;professor;programs;prospective;protocol development;recruit;routine screening;sample collection;screening program;translational medicine;translational scientist;vaccine-induced antibodies Clinical Core n/a NCI 10688375 9/19/22 0:00 RFA-CA-20-038 4U54CA260560-02 4 U54 CA 260560 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6020 7749175 "MACK, PHILIP C" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 397182 298667 98515 CLINICAL CORE: ABSTRACTThe central mission of the Clinical Core (CC) is to oversee all aspects of clinical study development patientrecruitment and specimen collection for analysis in the Centers scientific projects. The CC is led by Drs. PaulBunn Philip Mack and Jorge Gomez. Together with co-investigators Dr. Brody (Director of Mount Sinai CancerBiorepository) and Drs. Henschke and Yankelevitz (Directors of the Mount Sinai Lung Cancer ScreeningNetwork) the CC brings to bear a wealth of experience in clinical trials development translational medicine andbiorepository management. As described in Aim 1 the CC will be responsible for development complianceIRB-approval implementation and monitoring of the clinical study that serves as the basis for this U54 Center.A foremost responsibility of the CC will be to rigorously maintain all regulatory safety privacy confidentiality andcompliance elements necessary for clinical study enrollment. Leveraging the experience and infrastructure ofthe Mount Sinai Tisch Cancer Institute Clinical Trials Office the CC will oversee all study enrollment followingall HIPAA and regulatory compliance elements. While developed and managed by the CC the study will beimplemented in close partnership with the Data Science Core and Project Investigators under the guidanceof the Center leadership and Steering Committee. In Aim 2 the CC will Identify and enroll lung cancer andcontrol subjects onto the study collecting the required longitudinal clinical information and serial bloodspecimens. Lung cancer patients will be recruited mostly from Mount Sinai. Some patients of special interest(younger minorities) will be recruited through the GO2 Foundation for Lung Cancer network. Non-lung cancermatched controls will be recruited from the Mount Sinai Lung Cancer Screening Program and will be composedof individuals with no evidence of lung cancer and no active cancer within the last 5 years (except skin cancer)matched by age gender ethnicity and tobacco smoking history. As vaccines become available recruitment willsegue from studying antibody response to natural infection with SARS-CoV-2 to vaccine-induced antibodiesresponses. Aim 3 addresses the collection processing storage encoding and delivery of high-qualityspecimens to Project Investigators. From all study participants blood specimens will be collected prospectivelyat baseline and 3 6 12 and 24 month following enrollment. The CC will serve as a conduit between the Projectsand the Data Science Core by providing HIPAA-compliant data and samples that have been anonymized to theproject investigators conducting assays. The CC will utilize the existing infrastructure of the Tisch CancerInstitutes Biorepository maintaining its own partitioned password-protected database and dedicated well-monitored freezer space. +No NIH Category available 2019-nCoV;Abate;Advisory Committees;Affinity;Antibodies;Antibody Repertoire;Antibody Response;Area;B cell repertoire;B-Lymphocytes;Binding;Biological Assay;Blood Circulation;COVID-19;COVID-19 pandemic;Categories;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical Trials;Clonality;Cloning;Computerized Medical Record;Coronavirus;County;Data;Data Set;Disease;Disease Outbreaks;Enzyme-Linked Immunosorbent Assay;Epitope Mapping;Epitopes;Future;Geographic state;Half-Life;Home;Human;Immune;Immunoglobulin A;Immunoglobulin G;Immunoglobulins;Individual;Infection;Institutional Review Boards;Kinetics;Letters;Masks;Methodology;Middle East Respiratory Syndrome Coronavirus;Molecular;Molecular Analysis;Monitor;Monoclonal Antibodies;Mucous Membrane;Natural History;Nature;North Carolina;Outcomes Research;Patients;Pattern;Persons;Phase;Policies;Population;Prevalence;Proteins;Proteomics;Protocols documentation;Research;Resolution;Role;SARS coronavirus;Scourge;Serology;Serum;Source;Specificity;Specimen;Study Subject;Survivors;Symptoms;Techniques;Testing;Texas;Time;Transfusion;Translating;Viral;Virus;Work;austin;base;cohort;comparative;convalescent plasma;cross reactivity;experimental study;human monoclonal antibodies;in vivo;mouse model;neutralizing antibody;neutralizing monoclonal antibodies;response;sample collection;social;virtual;zoonotic coronavirus Core C: Immunoglobulin Proteomics in COVID-19 n/a NCI 10688374 9/19/22 0:00 RFA-CA-20-038 4U54CA260543-02 4 U54 CA 260543 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6019 2184281 "IPPOLITO, GREGORY C" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 180753 116240 64513 AbstractResearch Core C will be integral to the examination of serological antibody repertoires in COVID-19 studysubjects as well as in convalescent plasmas obtained from survivors. Core C will employ a set of uniqueexperimental techniques including a proteomic methodology (Ig-seq) for the identification of the monoclonalsequences and for determining the epitope specificity and function of the secreted component immunoglobulins(IgG and IgA) comprising the polyclonal response to SARS-CoV-2. The UT Core will examine the persistence ofindividual serum mAb clonotypes as a function of time and also the relationships between the IgA and IgGrepertoires in circulation and in BAL. To date all human SARS-CoV-2-reactive antibodies have been isolatedexclusively from B cells transiently circulating in the periphery. The significance of the abundance durability andinterconnectivity of serological antibodiesIgG versus IgA neutralizing versus non-neutralizing mucosal versussystemicshall become clear as this research core comprehensively analyzes the molecular composition ofanti-viral IgG and IgA and traces the B-cell subpopulations from which they arose. These studies will be enabledby robust sample collections from UNC Chapel Hill and from UT Austin. We expect that the experimentaloutcomes of Research Core C will clarify (i) the extent of antibody breadth and potency of the constituent IgGand IgA in the serological repertoires and role in protection (via viral blockade or through Fc dependentmechanisms) against endemic and zoonotic coronaviruses in mouse models (Project 1) and (ii) the detailedmolecular-level characterization of convalescent plasmas used for transfusion therapy in a COVID-19 clinicaltrial (Project 2). Comparative analyses shall be performed to determine adaptive immune signatures which mayexplain differential patterns among asymptomatic oligosymptomatic and severe disease. This research will becritical to our understanding the nature and complexity of human antibody responses against the SARS-CoV-2pandemic scourge. +No NIH Category available 2019-nCoV;Affinity;Antibodies;Antibody Response;Antigen Receptors;Antigens;B-Lymphocytes;Biological Assay;Containment;Coronavirus;Coronavirus spike protein;Enzyme-Linked Immunosorbent Assay;Exposure to;Fc Receptor;Goals;Gold;Health care facility;Immune;Immune Sera;Immunoglobulin Genes;Individual;Infection;Label;Length;Mammalian Cell;Measures;Methods;Middle East Respiratory Syndrome;N-terminal;North Carolina;Nucleocapsid;Paralysed;Pathogenicity;Pattern;Persons;Production;Property;Proteins;Recombinants;Research;Research Project Grants;Resource Sharing;SARS coronavirus;Science;Serology;Serology test;Serum;Site;Sorting - Cell Movement;Specificity;Structure;System;Testing;Vaccines;Viral;Viral Pathogenesis;Virus;base;detection assay;human coronavirus;milligram;pandemic disease;receptor binding Core B: Shared Resource Core For Characterizing Antibody Responses To SARS-CoV-2 And Other Pathogenic Human Coronaviruses n/a NCI 10688373 9/19/22 0:00 RFA-CA-20-038 4U54CA260543-02 4 U54 CA 260543 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6018 1943608 "DESILVA, ARAVINDA M." Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 380115 380115 0 AbstractHigh-quality recombinant antigens and reliable and accurate SARS-CoV-2 serological assays are urgentlyneeded for surveillance and for defining the immune mechanisms of viral pathogenesis viral clearance andprotection against reinfection. Core B of the UNC SARS-CoV-2 Serological Sciences Center of Excellence willapply state-of-the-art strategies to establish methods for the production of milligram quantities of homogeneousrecombinant spike protein CoV antigens with versatile tags and site-specific labels and use these antigens todevelop sensitive and reliable singleplex and multiplex Ab detection assays. Core B will interact and support allthe projects driven by the center and collaborators' by providing recombinant antigens and serological assays tocharacterize the serum antibody response elucidate Fc effector functional profiles and isolate and sequenceantigen-specific immunoglobulin gene repertoire. +No NIH Category available 2019-nCoV;Adherence;Administrator;Advocate;Age;Antibodies;Antibody Response;Area;Basic Science;Budgets;COVID-19;COVID-19 susceptibility;Cancer Center;Cancer Patient;Caregivers;Clinical;Clinical Research;Collaborations;Colorado;Communication;Complex;Consult;Data Science Core;Doctor of Medicine;Doctor of Philosophy;Ensure;Epidemiology;Ethnic Origin;Expenditure;Foundations;Gender;Health system;Hearing;Infection;Institutes;Institution;Interdisciplinary Study;International;Laboratories;Leadership;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of thorax;Medical;Monitor;National Cancer Institute;Office of Administrative Management;Patient Monitoring;Patient Recruitments;Patient advocacy;Patients;Preparation;Preventive measure;Principal Investigator;Progress Reports;Publications;Reporting;Research;Research Activity;Research Personnel;Resource Sharing;Resources;SARS-CoV-2 antibody;SARS-CoV-2 infection;Science;Serology;Services;Socioeconomic Status;Texas;Thoracic Oncology;TimeLine;Travel;Universities;Vaccination;Vaccines;Videoconferencing;Voice;Work;advocacy organizations;anticancer research;base;cohort;data sharing;design;distinguished professor;experience;human subject;individual responsibility;inter-institutional;medical schools;meetings;professor;programs;recruit;symposium;synergism;translational cancer research;translational research program;vaccinology;virology Administrative Core n/a NCI 10688372 9/19/22 0:00 RFA-CA-20-038 4U54CA260560-02 4 U54 CA 260560 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6017 7822511 "HIRSCH, FRED R" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 458807 283490 175317 ADMINISTRATIVE CORE: ABSTRACT Our inter-institutional U54 Serological Sciences Center of Excellence (U54) Administrative Coreprovides scientific and administrative oversight for all of the U54s Projects and Cores. It also provides the maininterface with patient advocates NCI program staff external and internal advisory boards NCI SeroNet activitiesother Lung Cancer NCI Networks and collaborating institutions. The Centers Administrative Core is led by threeworld leaders in lung cancer translational research founders of the COVID-19 Lung Cancer Consortium (CLCC)who all have extensive experience leading large and complex lung cancer translational research programs: Dr.Fred R. Hirsch at the Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai Dr. John Minna atUTSW and Dr. Paul A. Bunn Jr. at the University of Colorado. The Administration Core PIs will work closely withthe U54 overall Co-PI (Dr. Adolfo Garcia-Sastre) the U54s Steering Committee which consists of the overallPIs the Administrative Core PIs the Project and Core PIs and a representative for our partner organization thepatient advocacy organization GO2 Foundation for Lung Cancer. The U54s Steering Committee will have theassistance and advice of an Internal Advisory Board (IAB) and an External Advisory Board (EAB). The IABwill be established within the Mount Sinai Health System and will provide scientific advice and smooth access torequired institutional resources. The EAB consists of international leaders in thoracic oncology and in medicalvirology and vaccinology and will assist with providing scientific advice and evaluating scientific progress with aspecial focus on lung cancer implications. The specific aims of the Administrative Core are: AIM 1: Directthe overall scientific integration and administrative management of the U54 and ensure effective communicationbetween U54 Project and Core investigators; AIM 2: Oversee Administration of Patient Cohorts Clinical StudiesFinancial Reporting and Regulatory Aspects; and AIM 3: Manage connection of the U54 with the NCI SeroNetand other lung cancer research (e.g. NCI Lung-SPORE) and patient advocacy networks. Thus theAdministrative Core will help this U54 to maximize its potential both internally (Mount Sinai UTSW andUniversity of Colorado) and inter-institutionally including interactions with the NCI Serological Sciences Networkand the Frederick National Laboratory for Cancer Research (FNLCR).Successful completion of our U54 activities is expected to substantially increase our understanding of theassociation between lung cancer SARS-CoV-2 antibody response based on infection or vaccination andultimately be of significant service in designing lung cancer patient-specific SARS-CoV-2 preventive measures. +No NIH Category available 2019-nCoV;Address;Automobile Driving;COVID-19;Clinical;Collaborations;Common Data Element;Community Networks;Consent;Data;Disease;Enrollment;Ensure;Experimental Designs;Future;Goals;Grant;Human;Human Resources;Immune response;Infection;Infrastructure;Institutional Review Boards;Knowledge;Laboratories;Leadership;North Carolina;Pathogenesis;Patients;Procedures;Protocols documentation;Research;Research Infrastructure;Research Project Grants;Resource Sharing;Role;Sampling;Science;Serology;Services;Structure;Therapeutic Intervention;Vaccination;Virus Diseases;cohort;data repository;data sharing;design;programs;recruit;response;sample collection Core A: Administrative Core n/a NCI 10688371 9/19/22 0:00 RFA-CA-20-038 4U54CA260543-02 4 U54 CA 260543 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6016 1885536 "BARIC, RALPH S" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 328769 211427 117342 AbstractThe overall purpose of the FOA is to establish Serological Sciences Centers of Excellence with the goal ofidentifying and advancing research opportunities to characterize the immune responses elicited by SARS-CoV-2 viral infection. The UNC Center for Excellence in SARS-CoV2 Serologic Research addresses this RFA byperforming basic and applied serological research to characterize the immune responses elicited by SARS-CoV-2 viral infection understand mechanisms driving the broad immune responses determine modifiers of theimmune response and identify serological correlates of disease pathogenesis and protection against futureinfection. Administrative Core A is specifically responsive to this RFA in that it has been structured to manageand coordinate all activities associated with our Center. In addition Administrative Core A will serve as the liaisonbetween the all Centers for Excellence within the Serological Sciences Network (SeroNet) as well as othercomponents of SeroNet including but not limited to Serological Sciences Research Projects (U01) the FNLCRSerology Laboratory Serological Capacity Building Centers (CBC) and a Serological Sciences NetworkCoordinating Center (SSNCC). Administrative Core A will provide leadership administrative support andinfrastructure for Research Projects 1 2 and 3 (Project) and two Shared Resource Cores B and C (Cores).Additionl responsibilities of our Administrative Core A include ensuring the data collected across the Programconform with the agreed practice and principles of the SeroNet Standard Operating Procedures (SOPs)Common Data Elements (CDEs) and data sharing plan as approved by the SeroNet Steering Committee. Thusas outlined in Fig 1 the Administrative Core A will 1: Fiscally Manage Oversee Facilitate and Evaluate Intra-Program Collaboration Among Projects & Cores; 2: Provide Infrastructure for Human Cohort RecruitmentSample Collection Tracking & Sharing 3: Develop Trans-SeroNet Collaborations and Collaborative Grants. Asoutlined in the Overview the UNC Center Research Program Team is already highly intellectually and technicallyintegrated building upon many multi-dimensional collaborations. As part of the Team structure we have builtlayers with distinct yet complementary roles and responsibilities which will promote integrated experimentaldesign execution and interpretation to address the current crisis and allow us to apply knowledgecollaboratively. This will be supported by a Translational Services Initiative which thus has the infrastructureneeded for recruiting sufficient patients and collecting samples necessary to support Projects 1-3 and Cores Band C. In addition it will result in a bio/data repository in which samples that span the course natural diseasetherapeutic interventions and potentially vaccination responses. In addition our Programs Annual ResearchRetreats and our SeroNet Collaborative Pilot and Feasibility Grant Mechanism will connect and integrate ourProgram Projects and Cores with the broader SeroNet community further advancing research opportunities tocharacterize the immune responses elicited by SARS-CoV-2 viral infection. +No NIH Category available 2019-nCoV;ACE2;Adult;Advocate;Age;Aggressive course;Antibodies;Antibody Response;Bioinformatics;Biology;Biometry;Budgets;COVID-19;COVID-19 mortality;COVID-19 patient;COVID-19 susceptibility;COVID-19 vaccination;COVID-19 vaccine;Cancer Patient;Cardiopulmonary;Cells;Characteristics;Clinical;Clinical Sciences;Clinical Trials;Complement;Contracts;Control Groups;Cytoprotection;Data Science;Data Science Core;Demographic Factors;Development;Disease;Doctor of Philosophy;Epithelial Cells;Ethnic Origin;Fatality rate;Gender;Histology;Immune;Immune response;Incidence;Individual;Infection;Informatics;Kinetics;Knowledge;Longevity;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Morbidity - disease rate;Normal tissue morphology;Patient Recruitments;Patients;Persons;Play;Population Control;Predisposition;Race;Recording of previous events;Research;Risk Factors;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Science;Serology;Seroprevalences;Smoking;Smoking History;Tobacco;Vaccination;Vaccines;Viral;Viral Load result;Virus;Virus Diseases;Virus Replication;base;cancer therapy;cigarette smoking;comorbidity;data dissemination;human subject;inter-individual variation;lung cancer cell;member;multidisciplinary;neoplastic cell;neutralizing antibody;patient population;programs;protective efficacy;public database;response;sample collection;tumor;vaccine trial Vulnerability of SARS- CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses OVERALL: Vulnerability of SARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody AnalysesProgram Director: Fred R. Hirsch MD PhD; Co-PI: Adolfo Garcia-Sastre PhD. PROJECT NARRATIVEThe overarching research theme for the Serological Center of Excellence at Mount Sinai NY is to understandfactors contributing to the vulnerability of SARS-CoV-2 infection in patients with lung cancer through serologicalanalysis of antibody response and to characterize and compare the antibody response to SARS-CoV-2 infectionor SARS-CoV-2 vaccines in patients with lung cancer compared to a matched healthy control group. NCI 10688370 9/19/22 0:00 RFA-CA-20-038 4U54CA260560-02 4 U54 CA 260560 2 "MARQUEZ, GUILLERMO" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 7822511 "HIRSCH, FRED R" "GARCIA-SASTRE, ADOLFO " 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Research Centers 2022 2044217 NCI 1454012 590205 C6;Reg-CV OVERALL ABSTRACTThe overarching research theme for the Mount Sinai U54 Serological Center of Excellence Vulnerability ofSARS-CoV-2 Infection in Lung Cancer Based on Serological Antibody Analyses is to fill the vital knowledgegap in factors contributing to the great vulnerability of lung cancer patients to morbidity and mortality from SARS-CoV-2 infection through serological analysis of antibody responses and studies of inter-individual variation inpatient-derived lung tumor and epithelial cells to SARS-CoV-2 infection. We will characterize and compare lungcancer patients antibody responses to SARS-CoV-2 infection or SARS-CoV-2 vaccines with a matched non-lung cancer control group; quantitate differences in SARS-CoV-2 viral replication in lung cancer and normal lungepithelial cells from different lung cancer patients; and quantitate differences in neutralizing antibody responsesin lung cancer patients. This information is urgently needed to enact vaccine and other strategies for protectinglung cancer patients against development of COVID-19. While antibodies induced by infection or vaccines areprotective against many viruses it has not yet been established if antibodies to SARS-CoV-2 are protective howmuch and what types of antibody are needed for protection and how long protection will last are unknown.Likewise we do not know if lung cancer patients can mount an effective immune response and if different aspectsof lung cancer or its treatment influences this immune response. Our overall hypothesis is that lung cancerpatients have a different (e. g. weaker) antibody response to SARS-CoV-2 infection compared to persons withoutlung cancer and that their lung cancer or lung epithelial cells play a role in viral replication of host responseswhich together could explain the aggressive course and high fatality rate demonstrated in lung cancer patientswith COVID-19. Our U54 will determine whether natural infection or SARS-CoV-2 vaccines (forecast fordeployment) will give comparable serological antibody responses longitudinally in 1000 lung cancer patientsand a matched non-lung cancer control group (1000 individuals); and determine if there are differences inantibody responses related to age gender tobacco history and race/ethnicity. The U54 proposal has twoProjects and three Cores (Administrative Clinical and Data Sciences). Project 1: Characterization of theAntibody Response to SARS-CoV-2 in Lung Cancer Patients quantitatively characterizes anti-SARs-CoV-2antibody responses and their functionality longitudinally in lung cancer patients compared to a control populationafter natural infection and vaccination and relates the serological response characteristics to key clinicaldemographic information. Project 2: Susceptibility of Lung Cancer Cells to SARS-CoV-2 Infection and Antibody-Mediated Neutralization determines the inter-individual variation in lung cancers and lung epithelial cells tosupport SARS-CoV-2 viral replication the inter-individual variation of antibodies to neutralize viral infection andhow these host viral responses relate to host cell characteristics and important clinical demographic information. 2044217 +No NIH Category available 2019-nCoV;Algorithmic Analysis;Alleles;Antibodies;Antigens;Automobile Driving;B-Lymphocytes;Biological Assay;Blood;Blood Cells;CD8-Positive T-Lymphocytes;COVID-19;COVID-19 patient;Cell physiology;Cells;Characteristics;Chromatin;Clinical;Clinical Data;Clinical Virology;Collaborations;Communities;Computational algorithm;Data;Data Analyses;Data Set;Databases;Disease;Ensure;Epigenetic Process;Epitopes;Female;Gene Expression Profile;Genetic;Genetic Transcription;Genome;Genomics;Goals;Human;Immunity;Immunologics;Individual;Infection;Link;Lymphocyte;Measurement;Measures;Modeling;Molecular Analysis;Mucous Membrane;Patients;Peptides;Phenotype;Privatization;Process;Proteins;Respiratory Mucosa;Role;SARS-CoV-2 antigen;SARS-CoV-2 immunity;Sampling;Serology;Sex Bias;Site;Specificity;T cell receptor repertoire sequencing;T cell response;T memory cell;T-Cell Immunologic Specificity;T-Lymphocyte;Technology;Testing;Tissues;Transposase;Vaccination;Vaccines;Variant;Viral;Viral Antigens;Virus;Woman;Work;X Inactivation;alpha-beta T-Cell Receptor;antigen-specific T cells;base;cohort;coronavirus disease;cytotoxic;design;early phase clinical trial;genome-wide;genomic tools;high throughput technology;human coronavirus;human leukocyte antigen testing;immune activation;improved outcome;innovation;interest;molecular phenotype;next generation sequencing;novel;pandemic disease;peptide based vaccine;post SARS-CoV-2 infection;programs;response;tool;transcriptome;transcriptome sequencing;vaccination strategy Project 3: T Cells n/a NCI 10688369 9/19/22 0:00 RFA-CA-20-038 4U54CA260517-02 4 U54 CA 260517 2 9/23/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6015 1884203 "DAVIS, MARK MORRIS" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 344830 222041 122789 PROJECT 3: SUMMARYCOVID-19 is currently a global pandemic but human T cell responses contributing to the quantity and quality ofSARS-CoV-2 specific antibodies or acting by cytotoxic mechanisms on infected cells remain poorly understood.In this U54 Project we will study virus-specific T cell immunity in the blood as well as the respiratory mucosaltissues where the virus is likely to initiate infection. We will also compare responses to natural infection withthose generated by a peptide-based vaccine in early clinical trials and in other vaccines approved during this 5-year study. Our groups have previously developed a suite of innovative high-throughput technologies andcomputational algorithms to enable the analysis of TCR alpha beta sequences transcriptional profiles andepigenetic states in primary T cells from human samples providing a comprehensive view of T cell specificityand molecular phenotype. We hypothesize that a critical component of immunity to SARS-CoV-2 is the antigen-specificity phenotype and epigenetic durability of the T cell response and the goal of this study is to measurethese components using high-throughput genomic tools to inform clinical profiles of protective immunity and thedesign of effective vaccination strategies. In the first aim we will build a comprehensive database of TCRsspecific for SARS-CoV-2 and its variants to identify private and shared TCR specificities associated with diseaseresponse and immunity. In the second aim we will pair TCR specificities with transcriptional and epigeneticphenotypes in SARS-CoV-2-specific T cells to identify immunotypes of the virus-specific T cell response. In thethird aim we will investigate the role of epigenetic changes due to X chromosome inactivation in lymphocytes insex bias in COVID-19 immunity. We will pursue these aims in the context of several large patient cohorts ofCOVID-19 patients convalescent donors and healthy subjects developed by the Clinical Virology Core and allT cell response data will be integrated with serology and B cell measurements in collaboration with Projects 1and 2. Altogether our studies will guide efforts to understand: (1) the diversity and specificity of antigen-specificT cell responses in COVID-19 patients (2) the phenotypes and durability of T cell memory in recoveredindividuals (3) relationships between T and B cell responses to SARS-CoV-2 and (4) T cell responsesstimulated by vaccination compared to natural infection. +No NIH Category available 2019-nCoV;Antibodies;Antibody Response;Antibody titer measurement;Autoimmunity;COVID-19 pandemic;COVID-19 patient;COVID-19 survivors;Cells;Characteristics;Clinical;Complement;Complement Activation;Complement-Dependent Cytotoxicity;Data;Disease;Enrollment;Goals;Immune response;Immunity;Immunoglobulin A;Immunoglobulin Class Switching;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Individual;Infection;Kinetics;Linear Regressions;Measures;Mediating;Methods;Modeling;Pathogenesis;Pathology;Patients;Phase;Plasma;Population;Positioning Attribute;Prospective cohort;Proteins;Public Health;Regression Analysis;Research Personnel;Research Project Grants;Resolution;Resources;Role;SARS-CoV-2 antibody;SARS-CoV-2 immune response;SARS-CoV-2 infection;SARS-CoV-2 spike protein;Sampling;Serology;Serology test;Serum;Severity of illness;Time;Vaccination;Variant;Virion;Virus;Work;antibody-dependent cell cytotoxicity;cohort;convalescent plasma;dimer;experience;influenza infection;male;neutralizing antibody;pandemic disease;post SARS-CoV-2 infection;prospective;receptor binding;response;sample fixation;severe COVID-19;vaccine development;virology Project 3: Defining the antibody landscape after SARS-CoV-2 infection n/a NCI 10688368 9/19/22 0:00 RFA-CA-20-038 4U54CA260492-02 4 U54 CA 260492 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6014 3088131 "KLEIN, SABRA L." Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 432172 263922 168250 Research Project 3 SummaryThere are insufficient data regarding the long-term humoral immune responses induced after SARS-CoV-2infection. Our preliminary data indicate that there is variation in the magnitude and duration of antibodyresponses following SARS-CoV-2 infection. While IgG and IgA antibodies against spike (S) and the receptorbinding domain of S (S-RBD) appear to remain constant over time neutralizing antibody (nAb) titers wane andare not detected in up to 25% of infected individuals who have detectable anti-S and anti-S-RBD antibodies.We have also observed that during the convalescent phase of SARS-CoV-2 infection individuals with moresevere COVID-19 (i.e. hospitalized older and male patients) have significantly greater serological responsesto SARS-CoV-2. The antibody responses mediating protection from re-infection are not defined and neitherare responses that may mediate greater pathology. From studies of other viruses it is clear that a variety ofantibody functions contribute to protection from re-infection and modulate disease severity. Both nAbs andnon-nAbs can mediate a number of different activities which include complement activation and antibody-dependent cellular cytotoxicity (ADCC) which may contribute to pathogenesis as well as protections fromSARS-CoV-2. The overarching goal of JH-EPICS Research Project 3 is to analyze the magnitude and durationof the total as well as functional antibody responses after SARS-CoV-2 infection. We have developed a coreset of serological assays to be applied to a prospective demographically diverse cohort of hospitalized patientspresenting with mild moderate and severe COVID-19 disease. Plasma samples have and will continue to becollected at multiple timepoints from enrollment through one year post-enrollment. Aim 1 will systematicallyevaluate antibody isotype switching and the subclasses and quality of the immunoglobulins (IgG IgM and IgA[monomeric and dimeric]) that recognize the SARS-CoV-2 S and S-RBD. Aim 2 will characterize the kineticsand duration of the neutralizing antibody response against SARS-CoV-2 and the ability of viruses to escapefrom nAbs. Finally Aim 3 will analyze the function of non-neutralizing SARS-CoV-2-specific serologicalresponse by assessing ADCC complement-mediated cytotoxicity and complement fixation activity towardSARS-CoV-2 virus particles and virus-infected cells. Using linear regression analyses and modeling of thesedata in the context of clinical and demographic information we are uniquely positioned to determine themodifiers that drive a protective antibody response following SARS-CoV-2 infection or eventually vaccination. +No NIH Category available 2019-nCoV;Acute;Affinity;Age;Antibodies;Antibody Response;Antibody Specificity;Antigens;B-Cell Activation;B-Cell Antigen Receptor;B-Lymphocyte Subsets;B-Lymphocytes;Bar Codes;Biological Assay;Biopsy;Biopsy Specimen;Blood;Blood specimen;COVID-19;COVID-19 severity;Cell Differentiation process;Cells;Clinical;Clinical Data;Clinical Virology;Clonal Evolution;Clonal Expansion;Clone Cells;Communities;DNA;Data;Data Analyses;Databases;Disease;Epitopes;Ethnic Origin;Frequencies;Funding;Immune response;Immunity;Immunofluorescence Microscopy;Immunoglobulin Genes;Immunoglobulin Somatic Hypermutation;Immunoglobulin-Secreting Cells;Immunologic Receptors;Individual;Infection;Joints;Libraries;Light;Link;Measures;Memory B-Lymphocyte;Monoclonal Antibodies;Mucous Membrane;Mutate;Nose;Patients;Phenotype;Plasma Cells;Plasmablast;Population;Population Group;Resources;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sampling;Serology;Serum;Site;Sorting - Cell Movement;Specificity;Specimen;Structure of mucous membrane of nose;T cell response;T-Lymphocyte;TFRC gene;Time;Vaccination;Vaccines;Viral Antigens;Virus;Work;Yeasts;base;cohort;deep sequencing;design;effectiveness evaluation;expectation;follow-up;immune checkpoint blockade;improved;interest;long term memory;monoclonal antibody production;neutralizing antibody;patient response;peptide based vaccine;peripheral blood;prognostic value;response;sex;synergism;transcriptome;vaccine response Project 2: B Cells n/a NCI 10688367 9/19/22 0:00 RFA-CA-20-038 4U54CA260517-02 4 U54 CA 260517 2 9/23/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6013 10429455 "BOYD, SCOTT DEXTER" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 455383 293228 162155 PROJECT 2: SUMMARYThe B cell and plasma cell populations that give rise to serum and mucosal antibodies will ultimately determinethe effectiveness and duration of an individuals humoral immune response to SARS-CoV-2 infection. We willuse several mutually-supporting strategies to analyze these cells in the Boyd lab: single B cell phenotyping Bcell receptor (BCR) deep sequencing and determination of antigen specificity with DNA-barcoded antigentetramers; bulk B cell immunoglobulin gene repertoire sequencing; and monoclonal antibody production fromantigen-specific B cells. In complementary strategy the Jardetzky lab will make use of yeast display libraries ofpatient-derived single-chain antibody variable fragments (ScFv) enriched for native heavy-light chain pairing todetermine the antigen specificity of hundreds to thousands of antigen-specific clones per patient. In longitudinalperipheral blood samples and nasal biopsy samples we will thoroughly characterize antigen-specific B cellclones in patient responses to SARS-CoV-2. We hypothesize that with these data we will be able to determinewhich features of B cell clonal responses to SARS-CoV-2 are associated with differences in COVID-19 diseaseseverity and differences between populations groups stratified by age sex ethnicity and pre-existingconditions or dysregulated immunity in the context of checkpoint blockade treatment. We further hypothesizethat analysis of memory B cell populations together with serological responses may predict which individualswill have longer-lasting humoral protection against reexposure to SARS-CoV-2. Finally we will evaluate the Bcell responses stimulated by natural infection compared to vaccination beginning with the Covaxx peptide-based vaccine cohort but with the expectation that additional vaccines will be approved for use during theperiod of this project funding. In addition to studying aspects of the B cell responses that differ among theseclinical scenarios we will search for features such as convergent virus-specific BCRs of highly similarsequences shared between different individuals that may have prognostic value for example by revealing thatan individual has a potent neutralizing antibody response to SARS-CoV-2. Our Aims are the following:Specific Aim 1: Analyze B cell responses in acute COVID-19 disease.Specific Aim 2: Evaluate the formation of B cell memory to SARS-CoV-2.Specific Aim 3: Analyze mucosal B cell and plasma cell responses to SARS-CoV-2 compared to responses ofB cells in the blood. +No NIH Category available North Carolina Seronet Center for Excellence Project NarrativeOur highly integrated Center uses novel technologies and reagents to build a portfolio of critical reagentsdesigned to map track and potentially treat SARS-CoV2 and related infections in the future while addressingfundamental questions into the molecular and immunologic mechanisms that regulate serologic responses inthe mucosal and systemic compartments after natural infection or medical interventions. NCI 10688366 9/19/22 0:00 RFA-CA-20-038 4U54CA260543-02 4 U54 CA 260543 2 "READ-CONNOLE, ELIZABETH LEE" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 1885536 "BARIC, RALPH S" "WOLFGANG, MATTHEW C" 4 PUBLIC HEALTH & PREV MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PUBLIC HEALTH 275995023 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Research Centers 2022 2018073 NCI 1433464 584609 C6;Reg-CV Abstract.The UNC Center for Excellence in SARS-CoV2 Serologic Research uses basic and applied researchstrategies to improve our understanding of the molecular and cellular mechanisms driving serological andhumoral immune responses after SARS-CoV2 infection. Our overall goals are to 1) characterize the immuneresponses elicited to SARS-CoV2 infection 2) understand the mechanisms driving the serological humoral andcellular immune responses 3) determine modifiers of the serologic memory and 4) determine the serologicalcorrelates of disease pathogenesis and protection against future infection. The program includes threeResearch Projects led by internationally renowned exerts in coronavirus emergence pathogenesis and immunity(Project 1: Baric) clinical and translational mucosal and systemic immune correlates of disease (Project 2:Bartelt & Margolis) and host-pathogen interactions driving innate and serological immunity (Project 3: Wallet& Maile). Program-wide support is provided by an Administrative Core A and two Shared Resource Cores B andC. Core A includes a robust infrastructure for programmatic oversight as well as participant recruitment samplecollection tracking and sharing (Core A: Baric & Wallet). Core B is led by world renowned experts incharacterization of human antibodies in protection and pathogenesis of disease (Core B: de Silva &Lakshmanane) and will provide recombinant spike protein antigens from SARS-CoV-2 as well as antigen-specific serological assays required for accomplishing the aims of all three Research Projects. Core C is led byserological experts (Core C: Ippolitto Georgiou & Lavinder) who have revolutionized techniques tocomprehensively analyze the molecular composition of the serological antibody repertoire (IgG and IgA) and thecellular antibody repertoire (i.e. B cell receptor) and thus will delineate these repertoires in and isolate humanmonoclonal antibodies from SARS-CoV-2+ individuals in cohorts defined in each Research Project. All threeResearch Projects are integrated and each require the support of all three Cores. To this end Project 1 willcharacterize the breadth and potency of polyclonal neutralizing antibody responses as well as determine thekinetics magnitude and durability of the type-specific and cross neutralizing responses in both the systemic andmucosal compartments. Project 2 will determine the durability and the breadth of anti-SARS-CoV-2 serumantibodies and memory B-cells generated among convalescent plasma donors as well as determine the effectof convalescent plasma on the innate adaptive and antibody repertoire in recipients. Project 3 will reveal innateimmune signatures as a function of serology across the span of natural disease as well as identify signatureswhich promote development of protective vs. pathogenic antibody repertoires while delineating mechanisms ofantibody mediated activation and suppression of innate immune function which drives severe vs. mild diseaserespectively. The integrated expertise of our Team is necessary and sufficient to address the novel cross-cuttinghypotheses put forth which will improve our understanding of SARS-CoV2 serological and humoral immunity. 2018073 +No NIH Category available 2019-nCoV;Acute Respiratory Distress Syndrome;Antibodies;Avian Influenza;Biological Assay;CASP1 gene;COVID-19;COVID-19 pathogenesis;COVID-19 patient;Carnitine Palmitoyltransferase I;Cell Death;Cell Line;Cell physiology;Cell surface;Clinical Markers;Clinical Trials;Critical Illness;Data;Disease;Disease Progression;Endocytosis;Enzymes;Epidemic;Flow Cytometry;Foundations;Genes;Goals;HIV;Hepatitis C virus;Hexokinase 2;Human;Immune;Immune response;Immune signaling;Immunity;Impairment;In Vitro;Incubated;Inflammasome;Inflammation;Inflammatory;Influenza;Influenza A Virus H5N1 Subtype;Influenza A Virus H7N9 Subtype;Interferons;Interleukin Receptor;Interleukin-1;Interleukin-1 beta;Interleukin-18;Interleukin-6;Interleukin-8;Interleukins;Investigation;Malignant Neoplasms;Measures;Mediating;Metabolic;Mitochondria;Monoclonal Antibodies;Myeloid Cells;Myeloid-derived suppressor cells;Obesity;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Persons;Plasma;Population;Production;Proteins;Recovery;Research Project Grants;Resources;Role;SARS coronavirus;SARS-CoV-2 antibody;SARS-CoV-2 infection;SARS-CoV-2 pathogenesis;Severity of illness;Signal Transduction;Simplexvirus;Stains;Testing;Therapeutic Intervention;Viral;Viral Pathogenesis;Virulent;Virus;Virus Diseases;Work;anakinra;antagonist;antiviral immunity;base;cell type;chemokine;chronic infection;cytokine;experience;fatty acid oxidation;glucose metabolism;influenza virus strain;inhibitor;macrophage;metabolic profile;novel;respiratory infection virus;respiratory virus;response;severe COVID-19;single cell analysis;single-cell RNA sequencing;targeted treatment;transcriptome sequencing Project 1: Mechanisms of innate sensing and pathogenesis of SARS-CoV-2 n/a NCI 10688362 9/19/22 0:00 RFA-CA-20-038 4U54CA260492-02 4 U54 CA 260492 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6009 7289265 "COX, ANDREA L" Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 302099 184488 117611 Understanding immune responses that contribute to severe COVID-19 is essential to identify patients likely tobecome critically ill and to discern which pathways to target for therapeutic intervention. The inflammasome isan antiviral and proinflammatory pathway activated by many viruses but its role in COVID-19 has not beendefined fully. Inflammasome activation results in an inflammatory type of cell death called pyroptosis as well asthe release of proinflammatory cytokines that include interleukin (IL)-18. Inflammasome cytokines are central toviral control but excessive or prolonged activation enhances pathogenesis of numerous respiratory virusinfections including avian influenza and SARS-CoV-1. Having extensively studied the role of inflammasomecytokines in the pathogenesis of multiple other viral infections we measured IL-18 and 36 other cytokines andchemokines in plasma from patients with COVID-19. While most were not significantly different in COVID-19IL-18 and IL-1 receptor antagonist (RA) levels are elevated in intubated patients with COVID-19 versus non-intubated COVID-19 and hospitalized influenza patients. Incubation of human macrophages with SARS-CoV-2in vitro produced IL-18 IL-1 IL-RA IL-6 and IL-8. We used a human macrophage cell-line with variousinflammasome genes disrupted to show that caspase-1 and NLRP3 are required for SARS-CoV-2 activation ofthe inflammasome. We will establish the mechanism by which SARS-CoV-2 activates the inflammasome anddetermine how inhibition of this pathway alters innate immune signaling using a panel of endocytosis inhibitorsmacrophage cell lines with specific inflammasome and other innate sensing genes disrupted and specificinhibitors of innate sensing in primary human macrophages. Early investigations suggest that antibodies (Abs)modulate innate sensing of SARS-CoV-2. To test whether Abs produced during COVID-19 alter innatesignaling we will incubate SARS-CoV-2 with monoclonal Abs or patient sera inoculate primary or immortalizedmacrophages and measure supernatant cytokines. To investigate cellular function we developed a flowcytometry-based platform that enables single cell analysis of traditional cell surface markers combined withintracellular staining for proteins involved in metabolic programming. Using this platform we identified myeloidderived suppressor cells (MDSCs) with distinct metabolic profiles that correlated with severe COVID-19.Prolonged inflammation induces MDSCs in cancer obesity and chronic infections. We will use single cell RNAsequencing to characterize these novel MDSCs and assess how cytokines produced in COVID-19 regulateMDSC metabolic programming. The overall goal is to define the mechanism by which SARS-CoV-2 activatesinflammatory pathways Ab modulation the role of MDSCs and how they intersect to mediate SARS-CoV-2immune control and pathology. This will identify targets for therapeutic intervention that minimize inflammatorypathology without impairing antiviral immunity as the foundation of novel clinical trials and markers of diseaseprogression that allow targeting resources to patients most likely to experience severe disease. +No NIH Category available 2019-nCoV;Achievement;Address;Biometry;COVID-19 patient;Clinical;Clinical Virology;Collaborations;Communication;Communities;Data;Data Analyses;Disease;Ensure;Goals;Mentors;Patient-Focused Outcomes;Patients;Reporting;Research;Research Personnel;Resources;Risk;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Science;Scientist;Secure;Serology;Structure;Teleconferences;Time;Training;Translations;adaptive immune response;collaborative environment;data management;data repository;database of Genotypes and Phenotypes;insight;medically underserved population;meetings;member;novel diagnostics;novel therapeutics;organizational structure;patient population Admin Core n/a NCI 10688361 9/19/22 0:00 RFA-CA-20-038 4U54CA260517-02 4 U54 CA 260517 2 9/23/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6008 10429455 "BOYD, SCOTT DEXTER" Not Applicable 16 Unavailable 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA Domestic Higher Education 943052004 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 Research Centers 2022 253936 163513 90423 ADMINISTRATIVE AND DATA ANALYSIS CORE: SUMMARYThe Administrative and Data Analysis Core of the Stanford U54 SARS-CoV-2 Serological Sciences Center ofExcellence will be responsible for providing overall management data coordination and oversight for theCenter. The Core will establish and maintain the administrative structure and functions of the U54 Center tofacilitate communications among investigators to promote their productive collaboration and among allCenter investigators and staff to coordinate efforts identify and resolve problems and establish a strongcollaborative environment to achieve the aims of the U54 to combine a deep mechanistic analysis of theadaptive immune responses of COVID-19 patients with a focus on studying underrepresented and at-riskpatient populations to determine the factors that result in effective and durable immunity to SARS-CoV-2infection. This Core will also contribute to integrated data analysis of the results from all Projects and theClinical and Virology Core in support of the Centers research goals. +No NIH Category available 2019-nCoV;Acute;Address;African American population;Agonist;Antibodies;Antigen Targeting;Attention;Award;B-Lymphocytes;Biopsy;Blood;COVID-19;COVID-19 diagnosis;COVID-19 patient;COVID-19 test;Cancer Patient;Caucasians;Cells;Clinical;Collaborations;Communities;Convalescence;Data;Data Set;Disease;Elderly;Evaluation;Female;Hispanic Americans;Human;Immune;Immune response;Immune system;Immunity;Immunologic Memory;Immunologics;Individual;Infection;Institution;Knowledge;Laboratories;Longitudinal Studies;Mucosal Immune Responses;Mucous Membrane;Nose;Patient Recruitments;Patients;Peripheral Blood Mononuclear Cell;Phenotype;Physicians;Plasma;Plasma Cells;Populations at Risk;Prognosis;Protocols documentation;Research;Risk;Route;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Science;Serology;Severity of illness;Site;T cell response;T-Lymphocyte;Testing;Tissue Sample;Toll-like receptors;Translational Research;Translations;Vaccination;Validation;Viral Antigens;adaptive immune response;adaptive immunity;base;clinical development;cohort;data sharing;immune checkpoint blockade;interest;male;medically underserved;medically underserved population;member;mucosal site;novel therapeutic intervention;pandemic coronavirus;pandemic disease;patient population;research clinical testing;response;tool;vaccine candidate;vaccine trial;young adult Mechanisms and Duration of Immunity to SARS-CoV-2 OVERALL: NARRATIVEWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world. We willemphasize deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanningserological B cell and T cell responses; analysis of immune responses in the blood as well as mucosal tissuesites; comparing immune responses induced by infection to those induced by candidate vaccines; and payingparticular attention to the understanding the clinical needs and immune responses of underservedunderrepresented and at-risk patient populations. Within these parameters we will attempt to determine thefactors that result in effective and durable immunity to SARS-CoV-2 infection and provide useful knowledge andtools for physicians and patients. NCI 10688360 9/19/22 0:00 RFA-CA-20-038 4U54CA260517-02 4 U54 CA 260517 2 "LIU, YIN" 9/23/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 10429455 "BOYD, SCOTT DEXTER" Not Applicable 16 PATHOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Research Centers 2022 1980075 NCI 1275000 705075 C6 OVERALL: SUMMARYWe propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as amember of the SeroNet consortium gathered to address the urgent need for better understanding of humanimmune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world.Our Center will be based on four scientific pillars: Deep mechanistic analysis of the adaptive immune responses of COVID-19 patients spanning serological B cell and T cell responses Analysis of immune responses in the blood as well as mucosal sites Comparing immune responses induced by infection to those induced by candidate vaccines and Studying medically underserved underrepresented and at-risk patient populationsWithin these parameters we will attempt to determine the factors that result in effective and durable immunityto SARS-CoV-2 infection.We are dedicated to broad collaboration rapid sharing of data and technical knowledge nimbleness inresponding to the rapidly changing pandemic and rapid translation of research findings to CLIA Lab clinicaltesting and development of new therapeutic approaches. We feel these are the best routes forward foraddressing gaps in our understanding of the determinants of protective immunity to SARS-CoV-2 andproviding useful tools for physicians and patients. 1980075 +No NIH Category available 2019-nCoV;Antibody Response;COVID-19;COVID-19 patient;COVID-19 treatment;COVID-19 vaccine;Collection;Communication;Communities;Data;Development;Ensure;Evaluation;Fostering;Funding;Goals;Immune response;Immunity;Information Dissemination;International;Leadership;Mentors;Molecular Target;Pathogenesis;Peripheral Blood Mononuclear Cell;Procedures;Professional Organizations;Progress Reports;Publications;Research;Research Personnel;Research Project Grants;Sampling;Serology;Site Visit;Specimen;T-Lymphocyte;United States National Institutes of Health;Universities;biobank;cellular targeting;data dissemination;data sharing;meetings;outreach;severe COVID-19;skills;social media;vaccine-induced immunity;web site JH-EPICS Administrative Core n/a NCI 10688357 9/19/22 0:00 RFA-CA-20-038 4U54CA260492-02 4 U54 CA 260492 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 6005 3088131 "KLEIN, SABRA L." Not Applicable 7 Unavailable 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD Domestic Higher Education 212182680 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 444660 271548 173112 JH-EPICS ADMINISTRATIVE CORE SUMMARYThe primary goal of the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS) is to systematically evaluate innate T cell and antibody responses to SARS-CoV-2 in peripheral bloodmononuclear cells and serological samples from COVID-19 patients. Through in depth analyses the JH-EPICS will identify the modifiers of the immune response and severe COVID-19 and isolate the cellular andmolecular targets for COVID-19 treatments as well as the correlates of protection necessary for SARS-CoV-2vaccine-induced immunity. The primary objective of the JH-EPICS Administrative Core (AC) is to providecentralized management leadership mentoring sharing and dissemination of the data from the proposedResearch Projects and Cores in JH-EPICS to ensure that the overarching research goals can be met. The firstAim under the Multiple PI leadership of Drs. Sabra Klein and Andrea Cox will be to provide administrative andbudgetary management as well as scientific leadership and communication for JH-EPICS. The JH-EPICS ACwill distribute funds organize monthly research meetings and ensure integration of the JH-EPICS into theCOVID-19 research and educational networks at Johns Hopkins University. The AC will also develop standardoperating procedures for reviewing requests for specimens from the biorepository and their distribution as wellas the collection processing and sharing of data generated by the JH-EPICS and approved by the SeroNetSteering Committee. The second Aim of the JH-EPICS AC will be to foster engagement with SeroNet andother network activities. The JH-EPICS AC will participate in all trans-SeroNet initiatives includingestablishment of trans-SeroNet collaborative research projects. Finally the third Aim of the JH-EPICS AC willbe to enhance dissemination of research findings from the JH-EPICS and establish an evaluation plan.Dissemination of research findings from the JH-EPICS will involve publications and dissemination of results atthe annual SeroNet meeting national and international meetings of professional societies and the monthlyCenter-wise research meetings. Development of a JH-EPICS website and social media presence will furtherassist with dissemination of research findings to a broader audience. Finally the JH-EPICS AC will establish arigorous evaluation plan including annual progress reports site visits and requested documents (e.g. SOPs)from NIH. The goal will be to ensure appropriate management and productive dissemination of research anddata from JH-EPICS to the broader community including through public outreach. +No NIH Category available 2019-nCoV;Address;Affect;Age;Antibodies;Antibody Response;Antibody-mediated protection;Antigens;Basic Science;Biometry;COVID-19;COVID-19 patient;COVID-19 severity;Cell surface;Cells;Cessation of life;Clinical;Clinical Sciences;Collaborations;Communicable Diseases;Complement;Complex;Coupled;Data Analyses;Development;Diabetes Mellitus;Disease;Ensure;Enzyme-Linked Immunosorbent Assay;Epidemiologic Monitoring;Epidemiology;Ethnic Origin;Evaluation;Flow Cytometry;Foundations;Gender;Goals;HIV;Health;Healthcare Systems;Heart Diseases;Human;Immune;Immune response;Immunity;Immunoglobulin Class Switching;Immunology;Immunomodulators;Infant;Infection;Inflammasome;Inflammatory Response;Infrastructure;Interdisciplinary Study;International;Leadership;Mediating;Metabolic;Methods;Mission;Modeling;Monoclonal Antibody Therapy;Myeloid-derived suppressor cells;Outcome;Pathogenesis;Pathologic;Pathology;Patients;Peripheral Blood Mononuclear Cell;Persons;Population;Prospective cohort;Proteins;Protocols documentation;Public Health;Race;Reagent;Regimen;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Respiratory Tract Infections;Risk;SARS-CoV-2 antibody;SARS-CoV-2 immune response;SARS-CoV-2 immunity;SARS-CoV-2 infection;Sampling;Science;Serology;Serology test;Severity of illness;Sex Differences;Solid;Stains;Statistical Data Interpretation;Statistical Models;Surrogate Markers;Symptoms;T-Lymphocyte;Testing;Therapeutic;Training;Translational Research;Ursidae Family;Vaccine Design;Viral;Viral Pathogenesis;Virus;age difference;antibody-dependent cell cytotoxicity;base;biosafety level 3 facility;comorbidity;experimental study;gender difference;innate immune sensing;insight;intersectionality;male;neutralizing antibody;new therapeutic target;novel;novel marker;organ transplant recipient;pandemic disease;racial difference;rational design;response;sample fixation;severe COVID-19;sex;single cell analysis;therapeutic evaluation;therapy development;vaccine candidate;vaccine development;vaccine evaluation;virology Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS) Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)Overall NarrativeThe goal of the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)is to define the immune responses that can either protect or harm during infection. The JH-EPICS team willevaluate the immune responses required to detect the presence of SARS-CoV-2 initiate inflammatoryresponses eliminate infected cells and engage the antibody responses against the virus in COVID-19patients. Using statistical analyses and modeling JH-EPICS will identify the variables such as demographic(e.g. age sex gender race and ethnicity) and clinical (e.g. severity of COVID-19 and comorbidities) factorsthat predict COVID-19 immune responses and outcomes. NCI 10688356 9/19/22 0:00 RFA-CA-20-038 4U54CA260492-02 4 U54 CA 260492 2 "KUO, LILLIAN S" 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I(A) 3088131 "KLEIN, SABRA L." "COX, ANDREA L" 7 MICROBIOLOGY/IMMUN/VIROLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF PUBLIC HEALTH 212182680 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Research Centers 2022 2079261 NCI 1269778 809483 C6;Reg-CV Johns Hopkins has broad expertise in the science of human health with viral immunity pathogenesisepidemiology biostatistics and surveillance emerging as integral components of the multidisciplinary researchmounted at Johns Hopkins during the current pandemic. We propose development of a Serological SciencesCenter of Excellence: the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2(JH-EPICS). The overarching goal of JH-EPICS is to distinguish immune responses that protect from thosethat cause pathology during infection. Under the Multiple PI leadership of Drs. Klein and Cox the JH-EPICSAdministrative Core will ensure resources and samples are available to systematically evaluate innate T celland antibody responses to SARS-CoV-2 in peripheral blood mononuclear cells and serological samples fromCOVID-19 patients sampled longitudinally. JH-EPICS contains three interconnecting Research Projects (RPs).RP1 focuses on innate immune sensing and activation of the human inflammasome by SARS-CoV-2 withevaluation of how anti-SARS-CoV-2 antibodies modulate innate sensing. RP2 uses a novel flow-cytometrybased platform that enables single cell analysis of traditional cell surface markers combined with intracellularstaining for proteins involved in metabolic programming. Using this platform we have identified distinct myeloidderived suppressor cells (MDSCs) and T cells abundant in COVID-19. RP1 will characterize these MDSCswhile RP2 will explore novel populations of T cells identified in COVID-19 patients. RP2 will also define novelbiomarkers in order to predict severity of disease track the course of disease and define novel surrogatemarkers for testing therapeutic regimens. Together RP1 and RP2 will identify novel therapeutic targets. InRP3 the magnitude duration and class switching of SARS-CoV-2-specific antibody isotypes as well as virus-specific neutralizing antibody responses will be analyzed and compared with non-neutralizing antibodyfunctions e.g. complement fixation and antibody-dependent cellular cytotoxicity using a novel core set ofserological assays. A centralized Virology Reagent Core will provide antigen for ELISAs reagents to identifyvirus-specific immune cell populations inactivated SARS-CoV-2 viruses methods for quantifying SARS-CoV-2 and access to biosafety level 3 facilities and training needed to perform any experiments involving liveSARS-CoV-2. The Analysis Resource Core will provide statistical modeling and analysis to frame and testhypotheses about the mechanisms mediating the severity of COVID-19 as well as the intersectionality of sexgender age and racial differences in immune mechanisms of COVID-19. In concert with the trans-networkcollaborations this research will provide significant insights into pathologic immune responses to SARS-CoV-2identification of novel therapeutic targets and definition of immunity against SARS-CoV-2 infection. Byuncovering the correlates of protective immunity JH-EPICS research will further enhance vaccine design andevaluation of vaccine candidates. 2079261 +No NIH Category available 2019-nCoV;Address;Antibodies;Antibody Response;Antibody titer measurement;Antigens;Biological Assay;Blood;COVID-19;COVID-19 pandemic;COVID-19 screening;COVID-19 surveillance;COVID-19 vaccine;Clinical;Communities;Disease Outbreaks;Employee;Essential worker;Food Services;General Population;Goals;HIV/HCV;Health;Health Personnel;Hordeolum;Human;Immunity;Immunoassay;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Individual;Infection;Laboratories;Liquid substance;Measures;Methodology;Methods;Microspheres;Mission;Modeling;National Cancer Institute;National Institute of Allergy and Infectious Disease;New York;Population;Principal Investigator;Proteins;SARS-CoV-2 antibody;SARS-CoV-2 antigen;SARS-CoV-2 exposure;SARS-CoV-2 immunity;Saliva;Sampling;Schools;Science;Sensitivity and Specificity;Serology;Serology test;Seroprevalences;Serum;Spottings;Technology;Testing;Time;United States;Virus;Work;base;co-infection;cohort;convalescent plasma;first responder;immunological status;improved;member;minimally invasive;neutralizing antibody;neutralizing monoclonal antibodies;nonhuman primate;pre-clinical;saliva sample;sample collection;serosurveillance;serosurvey;vaccine candidate;vaccine trial;vaccinology High-Throughput Dried Blood Spot (HT-DBS) Technologies in SARS COV-2 Serology and Vaccinology Project NarrativeThis project will improve validate and advance the use of dried blood spot technologies toenable population-wide serological testing for SARS COV-2 exposure and immunity inaccordance with the mission of the Serological Sciences Network (SeroNet) established by theNational Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute(NCI). NCI 10688352 9/16/22 0:00 RFA-CA-20-039 4U01CA260508-02 4 U01 CA 260508 2 "KOHAAR, INDU" 9/30/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 1876035 "MANTIS, NICHOLAS J." Not Applicable 20 Unavailable 153695478 LQK1DD1EYZK9 153695478 LQK1DD1EYZK9 US 42.645888 -73.797658 5966012 WADSWORTH CENTER MENANDS NY Research Institutes 122042893 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2022 592301 NCI 426860 165441 C6 Project SummaryAs the COVID-19 pandemic continues to spread across the United States it is imperative that we implementtechnologies to screen large swaths of the population for the presence of antibodies to SARS-CoV-2.Serological surveillance not only affords a measure of virus exposure within a community at large but alsoprovides information necessary to predict outbreak dynamics. Furthermore as our understanding of howhumoral factors contribute to controlling (and possibly exacerbating) COVID-19 it will be essential to havemethods in place to measure the quantity and quality of antibodies associated with both natural SARS-CoV-2 exposure and candidate SARS-CoV-2 vaccines. This U01 proposal seeks to advance the use of dried bloodspots (DBS) in conjunction with a Luminex-based microsphere immunoassay (MIA) to enable high-throughput(HT) population-wide serological surveillance for SARS-CoV-2. Specifically the proposal will expand the HT-DBS assay to capture the breadth and complexity of SARS-CoV-2 antibody responses following naturalinfection and develop a high-throughput competitive immunoassay (CIA) as a surrogate measure of SARS-CoV-2 neutralizing antibody titers in DBS. The proposed platform technologies to be developed at theWadsworth Center will contribute directly to NCIs mission to develop validate improve and implementserological testing and associated technologies to address the COVID-19 pandemic. 592301 +No NIH Category available 2019-nCoV;Antibodies;Antibody Response;Antibody titer measurement;Automobile Driving;COVID-19 pandemic;COVID-19 therapeutics;COVID-19 vaccination;COVID-19 vaccine;Cessation of life;Clinical;Coronavirus;Data;Development;Disease;Disease Outcome;Dose;Europe;Human;Humoral Immunities;Immune;Immunity;Immunologics;Individual;Infection;Infection Control;Institution;Intervention;Israel;Kinetics;Knowledge;Macaca mulatta;Mediating;Medical center;Phase;Population;Resolution;SARS-CoV-2 antibody;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 spike protein;Schedule;Science;Serology;United States;Vaccinated;Vaccination;Vaccine Clinical Trial;Vaccinee;Vaccines;antigen binding;efficacy testing;follow-up;insight;neutralizing antibody;nonhuman primate;post SARS-CoV-2 infection;prevent;success;transmission process;vaccine development;vector-based vaccine Immunologic Signatures of SARS-CoV-2 Vaccination and Disease SUMMARYThis project seeks to define the humoral correlates of immunity following infection as well as the durability ofthis protective humoral immunity both following natural infection or vaccination to inform vaccine development. NCI 10688351 9/20/22 0:00 RFA-CA-20-039 4U01CA260476-02 4 U01 CA 260476 2 "KUO, LILLIAN S" 9/30/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 6849698 "BAROUCH, DAN H." Not Applicable 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2022 725409 NCI 554889 170520 C6 ABSTRACTThe development of a SARS-CoV-2 vaccine may be critical to ending the COVID-19 pandemic. However acritical gap in knowledge is the lack of understanding of correlates of SARS-CoV-2 immunity in humans.Our preliminary data suggest that antibodies correlate with protection following vaccination in nonhumanprimates and that unique antibody functional profiles appear to predict disease outcome in natural infection inhumans. Our data also point to a converging antibody profile including both the antigen-binding domain drivingneutralization and Fc-mediated effector functions driving protective immunity. Another gap in knowledge is theunknown durability of protective immunity following SARS-CoV-2 infection and vaccination in humans.Our preliminary data suggest that antibody titers may wane quickly following SARS-CoV-2 infection in humansbut larger studies and longer follow-up are needed to define the kinetics of antibody responses in convalescentindividuals. Moreover the durability of vaccine-elicited antibody responses remains to be determined.We hypothesize that both convalescent and vaccinated humans will develop the functional antibodysignature that correlates with vaccine protection against SARS-CoV-2 challenge in rhesus macaques.We further hypothesize that vaccination will induce antibodies with greater durability than those inducedby natural infection and that an immunologic correlate of durability can be defined.Specific Aim 1. Define the antibody profiles following SARS-CoV-2 infection or vaccination that correlatewith protection. We will dissect the functional antibody responses elicited in SARS-CoV-2 infected individualsand in SARS-CoV-2 vaccinated individuals to provide insight into correlates of protection.Specific Aim 2. Define the immunologic correlates of durability of SARS-CoV-2 antibody responsesfollowing infection or vaccination. We will compare the durability of antibody responses induced in SARS-CoV-2 infected and vaccinated individuals and we will define an immunologic correlate of durability. 725409 +No NIH Category available 2019-nCoV;African American;African American population;Anti-Inflammatory Agents;Antibodies;Attenuated;Attitude;Behavior;Biological Assay;Biological Markers;Biological Process;Biological Sciences;COVID-19;COVID-19 disparity;COVID-19 pandemic effects;COVID-19 testing;Cities;Clinical;Cognition;Collaborations;Collection;Communication;Communities;Early Diagnosis;Evaluation;Funding;Goals;Health;Health Resources;Healthcare;Herd Immunity;Home;Incidence;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Knowledge;Lead;Link;Malignant Neoplasms;Measures;Medical;Methods;Michigan;Mission;Pathway interactions;Population;Prevalence;Process;Public Health;Race;Recovery;Registries;Research;Research Personnel;Risk;Role;Route;SARS-CoV-2 antibody;SARS-CoV-2 infection;SARS-CoV-2 positive;Saliva;Salivary;Serology;Services;Severities;Skin;Testing;United States;Water;biobehavior;experience;grasp;health communication;improved;innovation;insight;interest;mortality;novel;programs;racial difference;racial disparity;racial minority population;racism;response;salivary assay;screening;social health determinants;stem;transmission process;uptake Culturally-targeted communication to promote SARS-CoV-2 antibody testing in saliva: Enabling evaluation of inflammatory pathways in COVID-19 racial disparities Project NarrativeThe proposed project is relevant to public health because communicating effectively to African Americansabout SARS-CoV-2 antibody testing as well as providing an option of at-home non-invasive antibodyscreening in saliva could enhance uptake of antibody testing among African Americans a racial minoritypopulation that has been especially impacted by the COVID-19 pandemic. Greater uptake of antibody testingamong African Americans is also critical to better grasping how inflammatory process contribute to racialdisparities in SARS-CoV-2 infection and recovery. The proposed research is relevant to the NCI mission toconduct and fund research that improves early detection and diagnosis and reduces cancer-related disparities. NCI 10688350 9/22/22 0:00 RFA-CA-20-039 4U01CA260469-02 4 U01 CA 260469 2 "BLAKE, KELLY D" 9/22/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 9341233 "LUCAS, TODD WILLIAM" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 193247145 R28EKN92ZTZ9 193247145 R28EKN92ZTZ9 US 42.653979 -84.492032 5245901 MICHIGAN STATE UNIVERSITY EAST LANSING MI SCHOOLS OF MEDICINE 488242600 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2022 630937 NCI 418583 212354 C6 Project SummaryAfrican Americans develop and die from SARS-CoV-2 infection more than any other racial group in the UnitedStates including in majority African American cities such as Flint Michigan. SARS-CoV-2 disparities stem frommany interconnected causes. Yet connections to inflammatory biological processes in COVID-19 disparitiesremain largely unknown. Evaluating inflammatory responses can be facilitated by SARS-CoV-2 antibodytesting which can be used to identify and compare inflammation among those with and without confirmedSARS-CoV-2 infection and to conduct cross-race comparisons of inflammatory factors. However AfricanAmericans will be reluctant to partake in conventional antibody testing programs due to medical mistrust andexperiences with racism that are salient in the COVID-19 era. There is thus an urgent need to develop anddeploy culturally-relevant communication and antibody testing programs. Our long-term goal is to identify andreduce unjust COVID-19 racial disparities. The immediate objective is to better encourage understanding anduptake of SARS-CoV-2 antibody testing. The central hypothesis is that African-Americans will be receptive toantibody testing when benefits and limitations are communicated in a culturally effective manner and whennon-invasive salivary collection methods and assays are used. Our rationale is that combining culturallyeffective health communication with salivary testing will reduce mistrust and promote uptake that can lead tobetter grasping the role of inflammation in COVID-19 disparities. Our aims are to 1) develop and compareeffects of a general versus culturally-targeted video about antibody testing on African American and White Flintresidents antibody testing attitudes and uptake; 2) identify and compare effects of a general versus culturally-targeted video on activation of medical mistrust and racism-related cognition among African Americans whenconsidering antibody testing; 3) measure and identify multi-analyte inflammatory biomarker profiles among FlintRegistry enrollees who complete salivary antibody testing and compare inflammatory biomarker profiles byrace and antibody status. In collaboration with clinical and community partners we will prepare and evaluategeneral and culturally-targeted video tutorials about SARS-CoV-2 antibody testing. These brief videos will bedistributed to the Flint community through the Flint Registry a highly visible local health resource exchange.In collaboration with leading salivary bioscience experts we will furnish an opportunity to engage in at-homesalivary antibody screening a non-invasive route to antibody testing that is highly suited to disparities-oriented COVID-19 research. The proposed research is innovative and significant in highlighting that culturally-targeted communication and non-invasive antibody testing are vital to propelling disparities-orientedinflammatory COVID-19 research. Knowledge to be gained includes video tutorials and insights aboutcommunity-facing salivary collection that can be immediately disseminated across SeroNet to better promoteincluding racial monitories in ongoing studies of inflammation and antibody testing. 630937 +No NIH Category available 2019-nCoV;Address;Animal Model;Antibody Response;CD8-Positive T-Lymphocytes;COVID-19 patient;COVID-19 severity;Cessation of life;Chemotherapy-Oncologic Procedure;Child;China;Chronic;Clinical;Consensus;Coronavirus;Coupled;Data;Development;Disease;Disease Outcome;Generations;Genetic Variation;Goals;Hematological Disease;Herd Immunity;Immune;Immune response;Immunity;Immunocompetence;Individual;Infection;Lead;Maintenance;Malignant Neoplasms;Middle East Respiratory Syndrome;Natural History;Nature;Patient-Focused Outcomes;Patients;Pattern;Play;Population;Preventive vaccine;Recovery;Research Personnel;Resistance;Resolution;Role;SARS coronavirus;SARS-CoV-2 antibody;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 infection history;SARS-CoV-2 variant;Secondary to;Serology test;Severe Acute Respiratory Syndrome;Severity of illness;Sickle Cell Anemia;Stratification;Suggestion;Symptoms;System;T cell response;Testing;Therapeutic Monoclonal Antibodies;Time;Translating;Upper respiratory tract;Vaccines;Variant;Viral;Viral Antibodies;Virus;Virus Replication;Virus Shedding;acute infection;adaptive immune response;adaptive immunity;base;chemotherapy;clinical phenotype;cohort;convalescent plasma;defined contribution;human monoclonal antibodies;immunoregulation;improved;in vivo;insight;microbial;novel;novel coronavirus;optimism;pandemic disease;passive immunoprophylaxis;patient population;patient subsets;prevent;response;study population;unvaccinated;vaccine candidate;vaccine development Adaptive Immunity and Persistent SARS-CoV-2 Replication Project Narrative:Children undergoing cancer chemotherapy and those with hematologic disorders such as sicklecell disease have been observed to shed the novel coronavirus SARS-CoV-2 for prolongedperiods often without significant clinical disease. As these children have varying levels ofimmune competence we propose that deficits in immune responsiveness leads to inadequatecontrol of virus replication and shedding. The proposed studies will define the relationshipbetween adaptive immunity and virus replication/shedding including the contribution of viralvariants that could arise during poorly controlled virus replication in children with ineffectiveimmune responses. NCI 10688349 9/20/22 0:00 RFA-CA-20-039 4U01CA260462-02 4 U01 CA 260462 2 "SINGH, ANJU" 9/22/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 1866460 "BOPPANA, SURESH B" "BRITT, WILLIAM JARVIS; PINNINTI, SWETHA GEETHA " 7 PEDIATRICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2022 599569 NCI 403750 195819 C6 Project Summary/AbstractThe pandemic caused by the novel coronavirus SARS-CoV-2 (SARS2) has so far infected greater than3.5 million individuals and resulted in >138000 deaths in the US. Although it has been suggested thatadaptive immunity plays an important role in improving clinical outcomes of patients infected withSARS2 protective immune responses have not been specifically defined. Also the variability in clinicaldisease and outcome in patients with SARS2 infection has not been explained based on qualitative andquantitative antiviral immune responses. Interestingly a significant proportion of children with presumeddeficits in immune competence secondary to cancer chemotherapy and hematologic disorders havebeen observed to shed virus from the upper respiratory tract for prolonged periods of time (>4 weeks)even after complete resolution of clinical symptoms. This finding raises the possibility that specificqualitative or quantitative deficits in adaptive immune responses in some individuals can result inincomplete control of virus replication and prolonged virus shedding. Therefore an understanding of theimmune responses that lead to control of virus shedding could help define correlates of protectiveimmunity and perhaps more importantly determine the potential value of vaccines to limit spread ofSARS2 to unvaccinated populations. The major goal of our studies is to quantify adaptive immuneresponses to SARS2 in a cohort of children with varying levels immune responsiveness and to relatethese responses to the control of virus shedding in the upper respiratory tract thus allowing stratificationimmune reactivity and control of virus replication. Defining relationships between variations in immunecompetence and virus shedding could provide novel insight into the level and nature of adaptiveimmunity more specifically antiviral antibodies that can restrict or eliminate viral shedding in SARS2infected patients. Our studies will also identify SARS2 variants that arise during poorly controlled virusreplication in these patients as prolonged virus replication coupled with ineffective immunity offers anideal opportunity for the generation of viral variants. Analysis of these variants in terms of the quality andquantity of SARS2 antibody responses will help elucidate the role of SARS2 sequence variation andpersistent virus replication as a mechanism for prolonged virus replication. Together these studies willtest our hypothesis that variations in immune responsiveness contribute to prolonged viral replicationand shedding. 599569 +No NIH Category available Cancer Control;Training;cancer prevention Interdisciplinary Training in Cancer Prevention and Control Project NarrativeBuilding on our history of training cancer prevention and control researchers we are submitting a competingcontinuation of Interdisciplinary Training in Cancer Prevention and Control. Our competing continuationfocuses on recruitment of diverse trainees who are supported by a training program integrating all aspects ofcancer health disparities. NCI 10688284 8/28/23 0:00 PA-20-142 5T32CA117865-17 5 T32 CA 117865 17 "DAMICO, MARK W" 9/18/06 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1864817 "CHAMPION, VICTORIA LEE" "MOSHER, CATHERINE E" 7 NONE 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF NURSING 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 245251 NCI 256988 16479 Project AbstractIn 2006 the National Cancer Institute began supporting transdisciplinary training in behavioral oncology atIndiana University initially with an R25T mechanism which transitioned to a T32 in 2016. In response to PA-20-142 we seek to continue this T32 training program. During the last 10 years 83% of completed predoctoraltrainees (10 of 12) accepted postdoctoral fellowships at prestigious research institutions five traineescompleted F31 applications of which 60% were funded and the average number of publications per traineewas 9.4. Of the 13 predoctoral trainees 23% were from racial minority populations. Ten postdoctoral traineeshave completed their training and 78% accepted tenure-track academic positions; an additional traineeaccepted a prestigious research position at the FDA focused on tobacco research. Two postdoctoral traineeshave submitted K99/R00 applications of which one was funded and the second received a score of 40. Thetrainee who received this score accepted a tenure-track position and will submit a K23 based on the K99/R00.A total of 33% of postdoctoral trainees have been from racial minority populations. The average number ofpublications per postdoctoral trainee was 9.5.This T32 program resides in a strong research-intensive environment which includes the Indiana UniversitySimon Comprehensive Cancer Center (IUSCCC) a health science campus and over 100 research instituteslaboratories and specialized programs available to trainees. The program is led by a stellar and dedicatedteam of transdisciplinary mentors. The IUSCCC and other schools involved in this training program havecommitted over $1100000 for the next five years in support of this training program.The political social and economic turmoil evidenced in events of the last year underscore the many disparitiesthat exist in our country which directly impact significant inequities in cancer outcomes. We believe that thedisparate cancer burden faced by our underserved populations can best be addressed by training fellows thatreflect the diversity of our state and nation while prioritizing approaches to reducing disparities in cancerprevention and control research. Therefore our aims are to: 1) recruit well-qualified applicants including thosefrom diverse disciplines and underrepresented backgrounds; 2) provide a rigorous training program across thecontinuum of cancer prevention and control science with established and committed research mentors and anintegrated focus on cancer equity; and 3) Prepare trainees with the knowledge skills and opportunities thatsupport independent peer-reviewed research leading to reduced cancer morbidity and mortality across allpopulations. We retain successful strategies from the current training program while adding innovativeopportunities that reflect our changing society. A strong mentoring team and training platform support theacquisition of defined outcome competencies. This competing continuation is co-led by Drs. Victoria Championand Catherine Mosher whose disciplinary backgrounds and research foci provide complementary skills. 245251 +No NIH Category available Activities of Daily Living;Adjuvant;Agonist;Amputation;Animal Cancer Model;Animal Model;Antigen-Presenting Cells;Antigens;Bioinformatics;Biological;Biological Assay;Biological Markers;Biological Models;Blood;CCR1 gene;CD8-Positive T-Lymphocytes;Cancer Model;Canis familiaris;Carboplatin;Cells;Clinical Trials;Clone Cells;Collaborations;Credentialing;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Dendritic cell activation;Disease;Effectiveness;Elements;Enrollment;Ensure;Evolution;Excision;Exhibits;Failure;Flow Cytometry;Future;Generations;Genetic;Goals;Human;IL8RA gene;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunologic Markers;Immunologics;Immunooncology;Immunotherapy;Inflammasome;Interleukin-1 beta;Link;Losartan;Lung;Lymph Node Tissue;Lysophosphatidylcholines;Malignant Neoplasms;Metastatic Neoplasm to the Lung;Metastatic Osteosarcoma;Microscopic;Modeling;Mus;Nature;Neoplasm Metastasis;Nucleotides;Oral;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Plasma;Population;Pre-Clinical Model;Primary Neoplasm;Process;Production;Progression-Free Survivals;Randomized;Reagent;Regimen;Relapse;Residual state;Resistance;Resources;Sampling;Series;Signal Transduction;Single Nucleotide Polymorphism;Site;Somatic Mutation;Stimulus;T cell response;T memory cell;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Tissue Sample;Translations;Tumor Immunity;Tumor Markers;Tumor-Derived;Vaccination;Vaccines;Validation;Variant;Whole Blood;Work;anti-tumor immune response;antigen-specific T cells;aspirate;biobank;cancer genome;cell free DNA;checkpoint inhibition;chemotherapy;clinical efficacy;clinical translation;comparative genomics;conditioning;cytokine;design;draining lymph node;exome sequencing;immunomodulatory therapies;improved;in vivo;industry partner;inhibitor;kinase inhibitor;lymph nodes;migration;mouse model;neoantigens;neoplastic cell;novel;novel strategies;novel therapeutic intervention;novel vaccines;objective response rate;osteosarcoma;peptide I;programmed cell death protein 1;prospective;randomized clinical trials;resiquimod;response;standard of care;tool;transcriptomics;translational medicine;translational oncology;treatment response;tumor;tumor microenvironment;tumor-immune system interactions;vaccine platform;vaccine response Generation of tumor specific immunity in canine osteosarcoma through dendritic cell hyperactivation PROJECT NARRATIVERecent data indicate that effective and durable immune responses are optimally generated when key antigenpresenting cells (dendritic cells DCs) enter a state of hyperactivation during which they exhibit enhancedfunctional capacities including robust migration to local lymph glands and sustained production of key cytokines.In mouse models of cancer DC hyperactivation combined with lysate derived from tumors induces durable anti-tumor immune responses even in the setting of resistance to classic immunotherapies such as checkpointinhibitors. The studies in this proposal will use spontaneous canine osteosarcoma as a bridging animal modelto credential and optimize a novel vaccine platform designed to induce hyperactivation of DCs in vivo completea series of tumor and immune biomarker analyses to dissect correlates of response to treatment and create ablueprint for application of this new approach to human patients with osteosarcoma. NCI 10688274 8/3/23 0:00 RFA-CA-21-050 5U01CA272268-02 5 U01 CA 272268 2 "SOMMERS, CONNIE L" 9/1/22 0:00 8/31/27 0:00 ZCA1-RTRB-C(M1) 1857945 "LONDON, CHERYL A" "RICHMOND, JILLIAN M" 7 VETERINARY SCIENCES 39318308 C1F5LNUF7W86 39318308 C1F5LNUF7W86 US 42.3498 -71.06149 8422704 TUFTS UNIVERSITY BOSTON BOSTON MA SCHOOLS OF VETERINARY MEDICINE 21111901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 657791 NCI 516284 141507 PROJECT SUMMARYDespite substantial improvements in therapeutic strategies generating robust anti-tumor immune responses inhuman cancers with a lower somatic mutation burden remains a substantial challenge. Recent data indicate thata critical player in this process dendritic cells (DCs) fail to effectively elicit efficient and durable T cell responsesunless they have entered a unique state of hyperactivation. In this setting DCs exhibit enhanced migration tolocal lymph nodes (LNs) and sustained secretion of IL-1 a cytokine critical for memory T cell formation. Inmouse tumor models vaccination with whole tumor lysate plus an adjuvant consisting of the TLR 7/8 agonistR848 (resiquimod) in combination with a unique isolated lysophosphatidylcholine (22:0 Lyso PC) promotes DChyperactivation expansion of antigen specific CD8+ T cells and robust rejection of tumors. While these findingsare encouraging and suggest that identification of specific neoantigens is not necessary to prime and expand apool of cytotoxic T cells (CTLs) validation and optimization of this approach necessitates the use of a modelsystem that more closely recapitulates human cancers with respect to immune landscape. As such the purposeof this proposal is to use spontaneous canine cancer specifically osteosarcoma (OS) as a bridginganimal model to validate the utility of DC hyperactivation as a foundational element for generation ofrobust anti-tumor immunity. The central hypothesis to be tested in this application is that combininghyperactivation of DCs with WTL derived neoantigen will expand a diverse and tumor-specific population of CTLscapable of eliminating residual microscopic metastatic OS tumor cells in dogs following primary tumor removal(amputation). We further predict that combining DC hyperactivation/WTL with a novel tumor microenvironment(TME) conditioning regimen consisting of toceranib/losartan/ladarixin will enhance the objective response ratein dogs that develop macroscopic lung metastasis. To accomplish this we will conduct a prospective randomizedclinical trial in dogs with OS combining amputation and standard of care carboplatin chemotherapy with adjuvantalone or adjuvant+WTL. Dogs that develop lung metastasis will then be treated with the TME conditioningregimen in combination with adjuvant+WTL. A biobank of tissue samples and blood will be collected from dogsenrolled in these trials including matched primary/metastatic tumors and associated LNs whole blood plasmaPBMCs cell-free DNA and samples from the vaccine draining LNs. These will be used to perform a set ofcomplementary assays designed to characterize the immune microenvironment and tumor genome over thecourse of relapse/resistance credential a novel neoantigen prediction pipeline and evaluate antigen specific Tcell responses. An outstanding team with complementary sets of expertise across clinical trials translationaloncology comparative genomics and immuno-oncology has been assembled to ensure stated milestones areachieved. This is bolstered by a dynamic collaboration with our industry partner Corner Therapeutics which iscommitted to supporting this work to facilitate optimization and successful translation into human patients. 657791 +No NIH Category available Academic Medical Centers;Antibodies;Antigens;Attention;Autoantibodies;Bacterial Antigens;Benign;Biochemical;Biological Assay;Biological Markers;Biopsy;Blinded;Blood Tests;Boston;Breast;CA-125 Antigen;CLIA certified;Cancer Center;Cancer Detection;Cancer Patient;Categories;Cells;Clinical;Collaborations;Collection;Complement;Custom;Detection;Development;Diagnosis;Diagnostic;Discrimination;Disease;Early Detection Research Network;Engineering;Ensure;Enzyme-Linked Immunosorbent Assay;Exclusion;Fungal Antigens;Genes;German population;Glycoproteins;Goals;Human;Human Genome;Immune;Immune response;Immunologist;Individual;Infection;Laboratories;Length;Lung;Lung diseases;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mammography;Measures;Methods;Microbe;Morbidity - disease rate;Multicenter Studies;NCI Center for Cancer Research;Nucleic Acids;Pathogenesis;Performance;Phase;Plasmids;Play;Population;Predictive Value;Protein Array;Protein Array Analysis;Protein Glycosylation;Protein Microchips;Proteins;Proteome;Proteomics;Reporting;Role;Sampling;Screening Result;Screening for Ovarian Cancer;Screening for cancer;Serology;Serum Proteins;System;Target Populations;Technology;Testing;Time;Transvaginal Ultrasound;Ultrasonography;Universities;Unnecessary Surgery;Validation;Viral Antigens;Woman;Work;X-Ray Computed Tomography;antimicrobial;biomarker development;biomarker discovery;biomarker signature;biomarker validation;cancer biomarkers;cancer cell;candidate marker;chest computed tomography;circulating biomarkers;cohort;density;diagnostic assay;experience;imaging modality;immunogenic;immunoregulation;improved;infection rate;innovation;malignant breast neoplasm;microbial;microorganism;mortality;novel;protein biomarkers;repository;response;screening;success;validation studies Biomarker Developmental Laboratory n/a NCI 10688271 9/11/23 0:00 RFA-CA-21-035 5U2CCA271903-02 5 U2C CA 271903 2 9/1/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 5995 1931214 "ANDERSON, KAREN S." Not Applicable 4 Unavailable 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ Domestic Higher Education 852876011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 367883 283941 83942 Project Summary/AbstractCancer screening can detect cancer early and reduce mortality. However high false positive rates and lowsensitivities of lung (LC) and ovarian cancer (OC) screening result in unnecessary surgeries and missedcancers. Our overarching goal is to develop circulating biochemical biomarkers that reduce the false positiverate of the CT scan for LC and increase the positive predictive value of OC screening in combination withCA125 and trans-vaginal ultrasound (TVUS). We hypothesize that LC and OC patients have different antibodyimmune responses from subjects with benign diseases that can be explored for detecting cancer and excludingnon-cancer. We will take a systems approach working with 3 types of antibodies: autoantibodies anti-microbialantibodies and anti-aberrant glycoprotein antibodies. Our proposal builds on our extensive experience withcancer biomarker discovery and immunoproteomics technology. Our previous results on autoantibodybiomarkers have been confirmed in blinded PRoBE phase 2 multicenter validation studies. Our results showedthat autoantibody biomarkers are highly specific for cancer; although multiple autoantibodies are needed foradequate predictive value. There is increased attention to the role microbes play in cancer vs. benign diseasedevelopment which can be observed by different overall infection rates and / or immune responses to differentindividual antigens from various microbes. Aberrant protein glycosylation is a hallmark of LC and OC and wewill exploit our unique capability to display glycosylated proteins in high throughput. The successfulimplementation of our study entails high throughput methods for assessing antibodies at the proteome level.With EDRN support we have developed a set of innovative immunoproteomics technologies namely high-density nucleic acid programmable protein array (HD-NAPPA) contra-capture protein array (CCPA) andmultiple in solution protein array (MISPA) that combined with the largest full-length human and microbial genecollection (DNASU plasmid repository) enable us to study antibodies against the full human proteomemicrobial proteomes and the human O-glycoproteome for antibody biomarker signatures in cancer. Ourprevious success Videssa Breast which is a CLIA-certified blood test for breast cancer used clinically withmammography includes a panel of both autoantibody markers and serum protein markers. As with Videssawe will also use the Meso Scale Diagnostics (MSD) MultiArray platform to assess reported serum proteinmarkers for their utility to complement our antibody markers for LC and OC. We will collaborate with experts onLC and OC screening at Vanderbilt University Medical Center Boston University MD Anderson CancerCenter and German Cancer Research Center who will also provide access to high quality well-characterizedsamples from our target populations. We will perform Phase I (PRoBE) discovery by screening protein arrayswith cancer and control sera for cancer- or control-specific antibodies. Candidate biomarkers for both LC andOC will be Phase 2-validated using ELISA or MISPA assays. +No NIH Category available Adherence;Agreement;Arizona;Basic Science;Biocompatible Materials;Biological Markers;Boston;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Diagnostic;Early Detection Research Network;Ensure;Evaluation;Goals;Infrastructure;Institutional Review Boards;Intellectual Property;Laboratories;Leadership;Maintenance;Occupational activity of managing finances;Reporting;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Schedule;Site;Translational Research;Universities;biomarker discovery;biomarker validation;cancer biomarkers;community engagement;data sharing;design;material transfer agreement;meetings;operation;organizational structure;success High-throughput immunoproteomics for cancer biomarker discovery n/a NCI 10688269 9/11/23 0:00 RFA-CA-21-035 5U2CCA271903-02 5 U2C CA 271903 2 9/1/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 5994 6770746 "LABAER, JOSHUA " Not Applicable 4 Unavailable 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ Domestic Higher Education 852876011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 309525 225583 83942 AbstractThe goals of the Administrative Core are to provide the organizational financial communication networking andresource infrastructure required for the success of the Biomarker Discovery Lab and the Biomarker ReferenceLab. Although the research activities in each project are of paramount importance the Administrative Core willserve as the hub through which the Center is organized. The Administration Core will facilitate leadershipdirection of the research financial management and administrative activities to coordinate the clinical and basicscience activities of the ASU Biomarker Characterization Center (ASU-BCC) for each project efficiently.Importantly the Administrative Core will schedule full and focused team meetings. It will facilitate resourcesharing among the ASU BCC projects as well coordinate collaboration with other EDRN sites with the ultimategoal of sharing research findings and advances. The Administrative Core will set the overall organizationalstructure of the Center direct communication within the Center and between the Center and the EDRN SteeringCommittee with NCI partners as well as communication of the results of the Center to the greater community. +No NIH Category available ART protein;Academic Medical Centers;Address;Adoption;Antibodies;Autoantibodies;Autoantigens;B-Lymphocyte Epitopes;B-Lymphocytes;Benign;Binding;Biological Assay;Biological Markers;Blinded;Blood Tests;Boston;Breast;CLIA certified;Cancer Center;Cancer Control;Cancer Detection;Cancer Patient;Cancer Vaccines;Carcinogenesis Mechanism;Clinical;Collaborations;Collection;Complement;Data;Development;Diagnostic;Disease;Early Detection Research Network;Early Diagnosis;Environment;Enzyme-Linked Immunosorbent Assay;Epitopes;Funding;Future;Genes;German population;Glycoproteins;Goals;Heterogeneity;Human;Human Papillomavirus;Image;Immune;Immune Sera;Immune response;Immunity;Immunoassay;Immunoglobulin G;Immunologic Markers;Immunology;Individual;Laboratories;Length;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Measures;Methods;Migration Assay;Monitor;Morbidity - disease rate;Mutation;NCI Center for Cancer Research;Nodule;Nucleic Acids;Ovarian;Persons;Phase;Phase III Clinical Trials;Plasmids;Polysaccharides;Post-Translational Protein Processing;Predictive Value;Production;Protein Array;Protein Glycosylation;Proteins;Proteome;Proteomics;Reproducibility;Sampling;Screening for Ovarian Cancer;Screening for cancer;Serology;Serology test;Serum;Specificity;Speed;Structural Protein;Structure;Symptoms;System;Technology;Tumor Antigens;Universities;Vaccine Design;Vaccines;Validation;antimicrobial;assay development;base;biomarker discovery;biomarker panel;biomarker signature;cancer biomarkers;cancer diagnosis;candidate marker;circulating biomarkers;clinical application;clinical assay development;clinical diagnosis;clinical diagnostics;clinical implementation;coronavirus disease;density;design;diagnostic platform;disease heterogeneity;experience;glycosylation;glycosyltransferase;immunogenic;immunogenicity;improved;improved outcome;innovation;instrument;lung cancer screening;microbial;microorganism antigen;migration;mortality;multiplex assay;novel;operation;polypeptide;prevent;protein biomarkers;protein expression;protein structure;rapid detection;rapid technique;repository;respiratory pathogen;screening;serological marker;skills;specific biomarkers;structural glycoprotein;technology development;tumor;validation studies High-throughput immunoproteomics for cancer biomarker discovery Project NarrativeWe hypothesize that circulating antibodies can be measured as specific biomarkers of lung and ovarian cancers.We will use state of the art immune profiling to discover and validate select protein and immune biomarkers forlung and ovarian cancer. NCI 10688268 9/11/23 0:00 RFA-CA-21-035 5U2CCA271903-02 5 U2C CA 271903 2 "PATRIOTIS, CHRISTOS F" 9/1/22 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 6770746 "LABAER, JOSHUA " "ANDERSON, KAREN S." 4 MISCELLANEOUS 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ ORGANIZED RESEARCH UNITS 852876011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 962182 NCI 710357 251825 Project Summary/AbstractThe goal of the ASU Biomarker Characterization Center is to improve ovarian and lung cancer screening throughthe development of biologically-relevant circulating immune biomarkers. The scientific approach of our Center isbased on several fundamental principles. First that altered cancer protein expression structure and post-translational modifications induce host autoantibodies to create circulating biomarkers. Second that alterationsin microbial antigen expression (such as respiratory pathogens) also induce immunity often detected in benignrather than malignant disease. Third that the protein modifications as well as the immune response to theseneoantigenic structures are heterogeneous between people and that serologic biomarkers may complementcirculating protein biomarkers. We will take a systems immunology approach to discover three types ofantibodies anti-microbial antibodies autoantibodies and anti-aberrant glycoprotein antibodies. Our proposalbuilds on our extensive experiences with cancer biomarker discovery and immunoproteomics technologydevelopment. Our previous results on autoantibody biomarkers have been confirmed in blinded phase 2multicenter validation studies and led to a CLIA-certified commercial blood test. Our results have shown thatmultiplexed panels of autoantibodies are required for adequate predictive value. With prior EDRN support wehave developed a set of innovative immunoproteomics technologies namely high-density nucleic acidprogrammable protein array (HD-NAPPA) contra-capture protein array (CCPA) and multiplexed in solutionprotein array (MISPA) that together with the largest full-length human and microbial gene collection at ourDNASU plasmid repository enable us to study antibodies against the full human proteome microbial proteomesand the human O-glycoproteome for antibody biomarker signatures in cancer. Our Meso Scale Diagnostics(MSD) team has fielded over 3000 instruments worldwide and over 700 commercially available biomarker assaykits. Our expertise at serologic assay development was selected by Operation Warp Speed to use the V-PLEXserology panels as the basis of its standard binding assays for immunogenicity assessments in all funded PhaseIII clinical trials of COVID vaccines. We will use our MSD MultiArray platform to migrate the top serologic andprotein markers for their utility in our target clinical applications. We will collaborate with experts on lung andovarian cancer screening at Vanderbilt University Medical Center Boston University MD Anderson CancerCenter and German Cancer Research Center who will also provide access to high-quality well-characterizedsamples to develop circulating biomarkers to enhance ovarian cancer screening or to distinguish benign frommalignant pulmonary nodules. Adhering to the principles of PRoBE design we will perform Phase I discovery byscreening protein arrays with cancer patient and control sera for cancer or control-specific antibodies. Candidatebiomarkers for both lung and ovarian cancers will undergo Phase 2 validation. 962182 +No NIH Category available Address;Adult;Affect;Age;Age of Onset;Alaska Native;American;American Indians;Asian;Asian population;Award;Biometry;Black Populations;Black race;California;Cancer Burden;Cancer Etiology;Caring;Cessation of life;Colorectal Cancer;Communities;Complement;County;Data;Decision Making;Diagnosis;Disparate;Disparity;Education;Effectiveness;Electronic Health Record;Eligibility Determination;Ensure;Epidemiology;Ethnic Population;Excision;Future;Gastroenterology;Goals;Health Disparities Research;Health Services Research;Health behavior;Health system;Hispanic;Incidence;Influentials;Interview;Knowledge;Latino Population;Malignant Neoplasms;Medicaid;Medical;Mentorship;Methodology;Not Hispanic or Latino;Outcome;Pathway interactions;Patient risk;Patients;Phase;Polyps;Population;Provider;Qualifying;Qualitative Research;Quality of Care;Randomized;Randomized Controlled Trials;Recommendation;Research;Research Methodology;Research Personnel;Research Support;Risk;Running;Sample Size;Screening for cancer;Signal Transduction;Surveys;Testing;Training;Uninsured;United States;United States Preventative Services Task Force;Universities;Update;age group;cancer epidemiology;cancer health disparity;cancer type;career;career development;colorectal cancer risk;colorectal cancer screening;comparative effectiveness trial;early onset colorectal cancer;early screening;experience;health disparity;health equity;low socioeconomic status;mortality;outreach;participant interview;pilot trial;prevent;racial population;randomized trial;recruit;risk perception;screening;screening disparities;screening policy;screening program;skills;sociodemographic disparity;sociodemographics;treatment as usual;trial comparing;uptake Optimal early colorectal cancer screening initiation PROJECT NARRATIVE Increases in early age onset colorectal cancer (EOCRC) incidence over the last two decades informed arecent United States Preventive Services Task Force recommendation to initiate CRC screening earlier at age45 instead of age 50. In the newly eligible population of adults ages 45-49 it is unclear 1) if they are willing toundergo screening 2) if screening disparities will emerge in this younger age group without a targeted strategyand 3) whether this group will respond to current strategies for promoting screening through usual care andoutreach. The proposed study intends to address these evidence gaps by conducting a pilot trial surveys andinterviews to characterize the acceptability of CRC screening among adults ages 45-49 and then use thesedata to inform a larger randomized trial comparing an active outreach strategy to usual care with theoverarching goal to maximize screening uptake and prevent screening disparities. NCI 10688267 8/31/23 0:00 PA-20-187 5K99CA267181-02 5 K99 CA 267181 2 "SCHMIDT, MICHAEL K" 9/1/22 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 12547687 "DEMB, JOSHUA BRIAN" Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 116948 NCI 108285 8663 PROJECT SUMMARY Colorectal cancer (CRC) accounts for 8% of cancer incidence and 9% of cancer-related mortality in theUnited States (US). About 11% of CRC cases are diagnosed before age 50known as early age onset CRC(EOCRC)with incidence and mortality rates increasing 1.6% and 1% per year between 2005-2014 and anunequal burden among Asian American Indian/Alaska Native Black and Hispanic racial/ethnic groups andthose with Medicaid or uninsured. The increasing EOCRC burden informed a US Preventive Services TaskForce (USPSTF) recommendation to initiate CRC screening among average risk adults starting at age 45rather than 50. This recommendation would expand CRC screening to 21 million Americans with 4 millionmore turning 45 each year. There is a lack of evidence to inform how to optimize impact of CRC screeningamong adults ages 45-49. Specifically there are three critical knowledge gaps: 1) we lack informationregarding acceptability of CRC screening among those ages 45-49 and have not investigated factors thatmight influence CRC screening uptake among this newly eligible population 2) there are concerns that CRCscreening disparities that exist among adults ages 50 are likely to emerge in this younger age group without atargeted screening strategy and 3) it is unclear whether this age group will respond to current CRC screeningpractice or more active outreach. The central objective of this proposal is to develop a targeted CRC screeningstrategy among adults ages 45-49 to maximize screening uptake and prevent cancer disparities. Our study willrecruit adults ages 45-49 receiving care within a large health system to answer these questions. First we willcharacterize the acceptability of CRC screening by running a pilot trial to establish feasibility of a larger trial(Aim 1a) and conduct surveys and interviews regarding factors influencing CRC screening uptake (Aim 1b) tohighlight effective strategies for implementing screening among adults ages 45-49. Next we will use these pilotdata to inform a randomized controlled trial of the comparative effectiveness of an active outreach strategyincluding mailed fecal immunochemical test versus usual care for optimizing uptake and preventing emergenceof CRC screening disparities (Aim 2). This research plan is complemented by a training plan to enhance theapplicants background in epidemiology and biostatistics with new training in 1) randomized controlled trialsmethodology 2) health behavior and medical decision making research 3) health equity and disparitiesresearch and 4) survey and qualitative research methods. Our study will be the most comprehensiveexamination of early CRC screening initiation in the US to date and will provide context to the updated CRCscreening policy and a potential framework for wider implementation of earlier CRC screening in adults ages45-49. It also offers a high-quality career development opportunity to develop key skills to become a qualifiedindependent investigator. 116948 +No NIH Category available Adoptive Cell Transfers;BARD1 gene;BRCA1 gene;Basic Science;Biochemical;Biological Assay;Biology;Breast;CRISPR library;Cancer Biology;Cells;Clinical;Clinical Trials;Collaborations;Complex;Computer software;Critiques;Cytotoxic agent;DNA;DNA Damage;DNA Repair;DNA Repair Pathway;Data;Engineering;Excision;FDA approved;Follow-Up Studies;Funding;Genetic;Histology;Human;Image Analysis;Immune;Immunity;Immunotherapy;In Vitro;In complete remission;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Modeling;Mus;Organoids;Ovary;Pathogenesis;Pathologic;Pathway interactions;Pharmaceutical Preparations;Phenocopy;Phosphoproteins;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Prediction of Response to Therapy;Productivity;Proteins;Proteomics;Recording of previous events;Recurrence;Reporter;Research;Role;Signal Transduction;Stimulator of Interferon Genes;Testing;Translating;Transplantation;Treatment Efficacy;Treatment outcome;Tumor Biology;Tumor Immunity;Western Blotting;Work;Writing;Xenograft procedure;cancer cell;cancer immunotherapy;cancer therapy;clinical translation;clinically actionable;clinically relevant;confocal imaging;digital imaging;domain mapping;drug repurposing;experience;genetic manipulation;homologous recombination;human model;humanized mouse;immune checkpoint blockade;immunogenicity;improved;in vitro Assay;in vitro testing;in vivo;in vivo evaluation;insight;loss of function;melanoma;mouse model;mutant;novel;p53-binding protein 1;pharmacologic;programmed cell death ligand 1;response;response biomarker;small molecule;success;transcriptome sequencing;translational potential;treatment response;treatment strategy;tumor Bladder cancer PD-L1 control of homologous recombination: Basic mechanisms applied to novel treatments Bladder cancer is the costliest cancer to treat due to repeated recurrences and low cure rates. We show thatPD-L1 expressed on bladder cancer modulates the DNA damage repair response to afford important basicmechanistic insights into DNA damage repair and to help show how such data can develop effective bladdercancer treatments including with novel pharmacologicPD-L1 depletion drugs. These findings are related toimproved treatment strategies in many other important cancers including melanoma and those of breast andovary. NCI 10688261 8/21/23 0:00 PAR-19-183 5R01CA268641-02 5 R01 CA 268641 2 "VENKATACHALAM, SUNDARESAN" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-OTC1-M(80)S] 7143137 "CURIEL, TYLER J." "ZHAO, WEIXING WILSON" 2 Unavailable 150883460 LLLYTJ6LYD21 150883460 LLLYTJ6LYD21 US 43.637006 -72.252383 10051750 DARTMOUTH-HITCHCOCK CLINIC LEBANON NH Independent Hospitals 37560001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 620740 NCI 460079 160661 ThisrevisedMPI proposal assembles experts in bladder cancer tumor biology DNA damage response (DDR)and pre-clinical models with a long-standing history of productive collaborations to study effects of intracellularbladder cancer PD-L1 signals on BRCA1-mediated DDR and how such signals alter sensitivity to PARPinhibitors and immune checkpoint blockade immunotherapy in orthotopic/metastatic mouse and human models.We test transplantable mouse bladder cancer lines MB49 and MBT-2 and the human bladder cancer lines RT4UM-UC3 and UM-UC14 representing basal and luminal histologies plus new PDX xenograft and organoidmodels and our novel GEMM all per reviewer request. Intracellular PD-L1 signals are interrogated using controlversus genetically manipulated tumors and other approachesincluding new non-biochemical approaches perreviewer request. We will use these clinically relevant models together to test our overarching hypothesis thatbladder cancer PD-L1 signals promote the homologous recombination DDR pathway that suppressesPARP inhibitor and immune checkpoint blockade immunotherapy efficacy.Aim 1: Define mechanisms for PD-L1-mediated control of HR. We will use well-validated geneticbiochemical and pharmacologic approaches plus definitive cell reporter assays for homologous recombinationRNA-seq proteomics RPPA immunoblotsCRISPR library screens organoidsand digital imaging with imageanalysis software to understand how PD-L1 regulates BRCA1 functionality and to test mechanisms includingfor tumor immunogenicity. We identified FDA-approved pharmacologic agents that we repurposed to depletetumor PD-L1 and inhibit HR for which we define mechanisms.Aim 2: Define treatment consequences of PD-L1 controlled homologous recombination/BRCA1 effects.Control versus genetically PD-L1 depleted cells with genetic perturbations of BRCA1 and related molecules willbe tested for in vivo effects by challenging engineered cells into mice and treating with single agents orcombinations based on findings from Aim 1 to assess treatment efficacy and specific mechanisms. We usetransplantable syngeneic mouse models and human xenograft and humanized mouse modelsin which we have extensive experience. Notably we will assess tumor microenvironmental and immunecontributions to treatments using genetically immune altered mice adoptive cell transfers and immuneblocking/neutralizing molecules. In vivo data are mechanistically refined in in vitro assays in which we are expert.PDX organoids 620740 +No NIH Category available Actomyosin;Adherens Junction;Adhesions;Basement membrane;Blood Vessels;Breast Cancer Cell;CD44 gene;Cathepsins;Cell Cycle Arrest;Cell Death;Cell Nucleus;Cell Reprogramming;Cell Survival;Cell-Cell Adhesion;Cells;Cellular Stress;Chromatin;Chromatin Structure;Circulation;Clinical;Coagulation Process;Computer Models;Cytometry;Cytoplasm;Cytoskeleton;Data;Distant;Distant Metastasis;Down-Regulation;Endothelium;Engineering;Environment;Extravasation;Growth;Individual;Intercellular Junctions;Intervention;Kinetics;Lamin Type A;Liquid substance;Liver;Matrix Metalloproteinases;Mechanical Stress;Mechanics;Mediating;Melanoma Cell;Metastatic Neoplasm to the Liver;Metastatic Skin Cancer;Microanatomy;Modeling;Molecular;Molecular Conformation;Molecular Target;Monitor;Movement;Mus;Neoplasm Circulating Cells;Neoplasm Metastasis;Nuclear;Organ;Outcome;Pathway interactions;Peptide Hydrolases;Probability;Process;Proliferating;Regulation;Scheme;Secure;Site;Skin;Solid;Stress;Survival Rate;System;Testing;Tissue imaging;Tissues;Variant;Vascular remodeling;Vulnerable Populations;cancer cell;cell motility;coping;early onset;experience;fitness;in silico;in vivo;in vivo Model;intravital microscopy;live cell microscopy;mechanical properties;migration;mouse model;multiphoton microscopy;neoplastic cell;novel;prevent;programs;response;shear stress;success;tissue stress;transcriptomics;triple-negative invasive breast carcinoma;vascular bed;vascular stress Project 2: Mechanochemical Mechanisms and Vulnerabilities of Individual and Collective Organ-Preferential Metastasis In Vivo Project 2: NARRATIVEMetastatic organ colonization by circulating tumor cells in vivo differs in mechanical challenge between organsites and single-cell and collective metastasis modes. Using intravital microscopy of single or clustered tumorcells during liver and skin metastasis we will identify novel molecular mechanisms of mechano-adaptationsecuring survival dormancy and outgrowth and potential intervention points to prevent metastasis. NCI 10688251 8/22/23 0:00 RFA-CA-20-029 5U54CA261694-03 5 U54 CA 261694 3 9/17/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 5990 9296134 "FRIEDL, PETER " Not Applicable 7 Unavailable 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA Domestic Higher Education 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 409849 370942 38907 Project 2: SUMMARYOrgan colonization and survival of circulating tumor cells (CTCs) depends on a response program in tumorcells (TCs) termed mechano-adaptation to cope with mechanical and molecular stresses on the cytoplasmand nucleus experienced during intravascular arrest and extravasation. The strength and duration ofmechanical stress differs in vascular beds among organs such as liver and skin and further differs betweenindividual-cell and collective organ colonization. Molecular systems implicated in the mechano-adaptation ofCTCs include coordinated cell-cell adhesions cytoskeletal contractility protease systems and deformationor the nucleus which cooperate to secure multistep movement into the secondary site and TC survival. Wehypothesize that successful metastasis in vivo depends on an adaptive interplay between the mechanicaland molecular intra- and perivascular stresses present at distant site and the coping ability of CTCs toovercome these stresses. By coordinated cell-cell adhesion cytoskeletal contractility deformation of thenucleus and protease systems we predict that mechano-adaptation secures individual-cell and collective TCsurvival and further mediates lasting reprogramming towards growth or dormancy. Consequently weanticipate that interfering with cell mechanical adaptation strategies will increase cell stress support CTCdeath and diminish metastatic organ colonization. By combining intravital microscopy in mouse modelscomputational modeling (Core A) and transcriptomic and chromatin structure analyses (Core B) we willaddress the rate-limiting steps of single-cell and collective organ colonization of triple-negative breast cancerand melanoma cells to skin and liver. In Aim 1 we will examine the mechanisms of collective and single-cellorgan colonization and metastatic outcomes by interfering with adherens junctions (p120-catenin) andintravascular coagulation. In Aim 2 we will identify the rate-limiting steps of cytoskeletal and nuclearmechanics and the ability to remodel the vascular wall during single-cell and collective organ colonization.Targeted interference with CD44-mediated adhesion to perivascular substrate actomyosin contractilitynuclear deformability by lamin A/C expression variation and the ability to reorganize the basement membranewill be performed. In Aim 3 we will identify the molecular responses underlying stress-induced mechano-adaptation and associated effects on nuclear chromatin conformation using transcriptomic and ultrastructuralanalyses combined with computational modeling. Identified key pathways implicated in mediating mechano-adaptation and TC survival cell cycle arrest (dormancy) and outgrowth will be inhibited by combinedmolecular interference to limit TC survival and both single-cell and collective metastasis. This project willdeliver an integrated view on cell migration molecular reprogramming fate decisions and reveal potentialintervention points to enhance tumor cell elimination in transit. +No NIH Category available Actomyosin;Adhesions;Animal Model;Batimastat;Blood Platelets;Blood Vessels;Blood flow;Breast Cancer Cell;Breast cancer metastasis;CD44 gene;Cell Adhesion;Cell Survival;Cells;Cessation of life;Chromatin;Chromatin Structure;Circulation;Clinical;Coagulation Process;Computer Models;Coping Skills;Cytoskeleton;Dermis;Endothelial Cells;Endothelium;Engineering;Environment;Event;Exhibits;Exposure to;Extravasation;Fibrin;Generations;Genetic Complementation Test;Genetic Transcription;Geometry;Hematology;Human;Immune;In Vitro;Individual;Intervention;Knowledge;Lamin Type A;Lesion;Liver;Matrix Metalloproteinases;Measures;Mechanical Stress;Mechanics;Mediating;Microscopic;Modeling;Molecular;Morphology;Neoplasm Circulating Cells;Neoplasm Metastasis;Nuclear;Organ;Organ Model;Outcome;Peripheral;Phenotype;Physical environment;Population;Probability;Process;Proliferating;Property;Proteolysis;Resolution;Rho-associated kinase;Role;Signal Pathway;Source;Stress;Stromal Cells;Study models;System;Techniques;Testing;Therapeutic;Thrombus;Tissues;Tropism;cancer cell;coping;coping mechanism;design;druggable target;experience;experimental study;extracellular;hemodynamics;high resolution imaging;human disease;inhibitor;insight;kinase inhibitor;knock-down;migration;monolayer;neoplastic cell;novel therapeutic intervention;novel therapeutics;overexpression;permissiveness;pressure;prevent;self assembly;shear stress;single-cell RNA sequencing;stressor;transcriptomics;triple-negative invasive breast carcinoma Project1: The role of intravascular pressure and shear stress on tumor cell arrest survival and proliferation in the microvascular niche n/a NCI 10688247 8/22/23 0:00 RFA-CA-20-029 5U54CA261694-03 5 U54 CA 261694 3 9/17/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 5988 1961918 "KAMM, ROGER D" Not Applicable 7 Unavailable 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA Domestic Higher Education 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 237667 198760 38907 Project 1: SUMMARYMetastatic colonization requires that circulating tumor cells (CTCs) overcome the physical stressors and homeostaticbarriers that make successful metastasis an unlikely outcome. Very little is known about metastatic subpopulations theadaptations that allow them to circumvent homeostatic barriers and the mechanisms used to cope with these stressorsand either proliferate or enter into dormancy. The intravascular environment is known to be inhospitable to CTCs yetseveral lines of clinical evidence indicate that physical interactions with activated platelets fibrin thrombi immune cellsand the formation of clusters with other cancer cells influences metastatic potential. Furthermore the mechanism ofextravasation within the microvasculature is mediated by endothelial interactions cytoskeletal forces nucleardeformations and matrix proteolysis. It has long been recognized that metastatic tropism is determined by intrinsicorgan properties. We hypothesize that secondary colonization is the culmination of a sequence of low probabilityevents for which only a small subpopulation of CTCs has adapted to cope with these stressors. To investigate themechanisms of arrest extravasation and colonization we have developed in vitro vascular networks that recapitulatethe geometry and function of the microvascular networks where circulating tumor cells initiate metastatic lesions.Importantly we are able to precisely engineer the microvascular environment by controlling cellular constituentsextracellular components and the physical stressors to systematically distinguish the effect of specific perturbations oncancer cell arrest transmigration and colonization with high temporal and spatial resolution. In Aim 1 we createcancer cell thrombi and clusters to determine the effect of interactions with platelets fibrin and cancer cells on thearrest transmigration and colonization. In Aim 2 we extend the capabilities of our microvascular platforms torecapitulate the organ-specific microvascular environments of liver and dermis to examine combined effects of differentflow and endothelial barrier function. In Aim 3 we will use specific molecular interventions to target tumor celladhesion contractility nuclear deformability and matrix degradation to quantify the effect on intravascular adhesiontransendothelial migration and long-term extravascular fate. In Aim 4 we will measure nuclear deformation andquantify chromatin reorganization during transmigration and determine if quantitative measures of chromatinreorganization fates extravasated cells to a dormant phenotype (Core B). Taken together we hypothesize thatmethodical in vitro observation combined with and validated by intravital studies (Project 2) and computationalmodeling (Core A) will lead to new insights regarding the specific mechanisms that enable CTCs to circumvent physicalstressors. By engineering the physical environment we will generate the knowledge leading to novel therapeuticopportunities to block or reverse the coping phenotype. +No NIH Category available Achievement;Address;Administrator;Advisory Committees;Advocate;Agreement;Applications Grants;Award;Biochemical;Breast Cancer Patient;Cells;Cessation of life;Chromatin;Chromatin Structure;Circulation;Clinical Data;Collaborations;Communication;Communities;Computer Models;Dana-Farber Cancer Institute;Data;Data Commons;Data Set;Development;Disease;Disease Progression;Disseminated Malignant Neoplasm;Ensure;Environment;Evaluation;Exposure to;Fostering;Gene Expression Profile;Grant;In Vitro;Institution;Intervention;Knowledge;Lead;Leadership;Malignant Neoplasms;Mechanics;Mission;Modeling;Molecular;Monitor;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;Pathology;Patients;Pennsylvania;Phenotype;Pilot Projects;Program Reviews;Proliferating;Protocols documentation;Publications;Quality Control;Records;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Resource Sharing;Schedule;Scientist;Series;Signal Transduction;Site Visit;Source;Stress;Stromal Cells;Structure;Technology;Texas;Tissues;Universities;Validation;Videoconferencing;Visit;anticancer research;data quality;data sharing;high resolution imaging;in silico;in vivo;meetings;member;metadata standards;multidisciplinary;neoplastic cell;programs;repository;research data dissemination;response;skill acquisition;stressor;symposium;timeline;transcriptome;transcriptomics;tumor microenvironment;virtual;web site;webinar;working group Admin: Mechanical determinants of organ-selective metastatic colonization dormancy and outgrowth n/a NCI 10688245 8/22/23 0:00 RFA-CA-20-029 5U54CA261694-03 5 U54 CA 261694 3 9/17/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 5987 1961918 "KAMM, ROGER D" Not Applicable 7 Unavailable 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA Domestic Higher Education 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 189318 150410 38908 Administrative Core: SUMMARY We propose to bring together an unparalleled team comprised of five leaders in metastatic cancerresearch across five institutions (MIT University of Pennsylvania Northwestern University MD Anderson at TheUniversity of Texas and the Dana Farber Cancer Institute at Harvard University). The proposed MetNet CenterAdministrative Core will be led by co-MPI Prof. Roger Kamm. The day-to-day administration of this grant will bemanaged by the Center Administrator located at MIT who will be responsible for maintaining all records relativeto this award and will establish and monitor agreements with affiliated institutions. Additionally centeradministration will be supported by a Data Manager who will be located at Harvard under the co-direction of Dr.Franziska Michor. The Data Manager will sit on the Resource and Data Sharing Working Group of MetNet andwill be responsible for the co-development (in collaboration with the Center Administrator) of the MetNet Centerswebsite discussions regarding standard metadata fields determine whether there will be pre-publication of datasharing across the MetNet create SOPs for MetNet data upload in conjunction with the different NCI CancerResearch Data Commons and lead the conversations about data quality control cross validation andreproducibility. An External Advisory Committee (EAC) will be formed bringing together investigators withexpertise in fields related to cancer metastasis and the tumor microenvironment. The EAC is envisioned as agroup of highly active members engaged to advise the MetNet Center leadership on scientific direction andreview progress evaluation research strategies and implementation leadership and dissemination all in theeffort to maximize the impact of the center. The MetNet center will enhance the translational value and potentialimpact of its research by engaging a Patient Advocate who will be a member of the EAC as a reviewer andevaluator of the pilot project grant applications and will be invited to attend the monthly research webinars andparticipate in the quarterly Co-MPI meetings and the Annual Site Visit. To foster collaboration and further supportmulti-institutional communication wide reaching knowledge dissemination and provide the MetNet Centertrainees opportunities for enhancing their technical and professional development skills the Administrative Corewill support a virtual monthly seminar series and will offer intra-MetNet Center research exchanges and $50000pilot projects. In Aim 1 the Administrative Core will oversee and coordinate the project mission establishmultidisciplinary project oversight and establish timeline milestones with videoconferencing and face-to-facemeetings. In Aim 2 we will develop coordinate schedule and evaluate research meetings research symposiaand the visiting scientists programs that are critical to our research mission and dissemination. In Aim 3 we willcreate the MetNet Centers website to: facilitate communication on program achievements; act as the accesspoint for enquiries from external researchers; serve as publicly-facing source of accessible research results toinform the breast cancer patient community; and serve as a central and accessible repository for all Centergenerated protocols. +No NIH Category available 3-Dimensional;Address;Adhesions;Adhesives;Affect;Basement membrane;Biological Assay;Blood Platelets;Breast Melanoma;Cell Communication;Cell Death;Cell Survival;Cells;Cessation of life;Chromatin;Chromatin Structure;Circulation;Complex;Computer Analysis;Cytoskeleton;Dermis;Disease;Disseminated Malignant Neoplasm;Endothelium;Environment;Extracellular Matrix;Extravasation;Fibrin;Gene Expression;Genomics;Goals;Image;In Vitro;Individual;Intervention;Liver;Malignant Neoplasms;Measurement;Mechanics;Methods;Microcirculation;Modeling;Molecular;Neoplasm Circulating Cells;Neoplasm Metastasis;Nuclear;Organ;Organ Specificity;Pathway interactions;Phenotype;Primary Neoplasm;Probability;Process;Proliferating;Property;Resolution;Role;Site;Stress;Techniques;Technology;Therapeutic;Thrombus;Time;Tissues;Tumor Cell Invasion;Vision;Work;cell behavior;cell type;computer studies;coping;experience;experimental study;hemodynamics;in vitro Model;in vivo;insight;intravital imaging;metastatic process;migration;monolayer;mortality;neoplastic cell;novel therapeutics;prevent;programs;response;shear stress;stressor;transcriptome;transcriptomics;triple-negative invasive breast carcinoma Mechanical determinants of organ-selective metastatic colonization dormancy and outgrowth U54 CENTER: NARRATIVEMetastatic organ colonization by circulating tumor cells depends on a response program in tumor cellstermed mechano-adaptation to cope with mechanical and molecular stresses. In this U54 MetNet Centerwe will integrate mechanical genomic and ultrastructural information during metatastatic organ colonizationand identify mechanical mechanisms of tumor cell fate decisions and identify pathways and potentialtherapeutic strategies to eliminate tumor cells prior to metastasis. NCI 10688244 8/22/23 0:00 RFA-CA-20-029 5U54CA261694-03 5 U54 CA 261694 3 "NADEAU, CHRISTINE FRANCES" 9/17/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y(M1) 1961918 "KAMM, ROGER D" "SHENOY, VIVEK " 7 ENGINEERING (ALL TYPES) 1425594 E2NYLCDML6V1 1425594 E2NYLCDML6V1 US 42.359128 -71.093339 4911501 MASSACHUSETTS INSTITUTE OF TECHNOLOGY CAMBRIDGE MA BIOMED ENGR/COL ENGR/ENGR STA 21421029 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1553418 NCI 1358882 194536 Overall: PROJECT SUMMARYMetastatic disease is responsible for the vast majority of cancer mortality. Understanding of the fundamentalmechanisms leading to metastatic cancer has been hampered by the need for models that replicate the step-wise metastatic process in vivo yet are amenable to tight control and facilitate high-resolution time-lapseimaging and quantitative analysis of cell behavior. Over the past decade our team has developed in vivo andin vitro methods capable of simulating many steps of the metastatic cascade including tumor cell invasionintravasation trapping in the microcirculation or adhesion to the vessel walls and extravasation into thesurrounding extracellular matrix. In parallel we have developed computational studies that provided detailedinsights often not possible through experiments. This collective prior work has shed new light on central aspectsof single-cell and collective cell behavior during metastasis and identified mechanical adaptations andvulnerabilities of the tumor cell with promise for targeted interventions. The goal of our proposed U54 Center isto employ these developed assays and methods in combination with new measurement techniques to interrogatethe full spectrum of stressors experienced by tumor cells in the metastatic niche during arrest and extravasationand couple these with parallel studies of changes in chromatin structure and the transcriptome of tumor cells(Core B). These changes are critical to mechano-adaptation of the tumor cells towards an organ-preferentialinitiation of a metastatic colony or transition to dormancy. A hallmark of our proposed center is the use of state-of-the-art in vitro (Project 1) and in vivo (Project 2) experiments and computation (Core A) to uncover and probethe factors that ultimately determine tumor cell fate. We anticipate that such integrated studies will provide newinsights into metastatic cancer not possible by the use of any method alone and enhance our ability to identifyand screen for new therapies to inhibit the tendency for metastatic spread of disease. 1553418 +No NIH Category available Acute Myelocytic Leukemia;Adopted;Adult;Aging;Autophagocytosis;Biology;Blood;Cell Maintenance;Cell Separation;Cells;Cellular Metabolic Process;Clinical;Clonality;Communication;Disease Progression;Fostering;Functional disorder;Gene Targeting;Generations;Genomics;Glucose;Glycolysis;Goals;Hematopoietic Stem Cell subsets;Hematopoietic stem cells;Heterogeneity;Human;Image;Imaging Techniques;Link;Lysosomes;Maintenance;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Molecular;Mus;Myeloid Leukemia;Myeloproliferative disease;Nutrient;Organelles;Outcome;Pathogenesis;Patients;Population Heterogeneity;Preleukemia;Process;Property;Recurrence;Recycling;Regulation;Relapse;Repression;Resistance;Sampling;Testing;Time;Treatment Failure;Work;design;hematopoietic stem cell quiescence;high resolution imaging;improved;in vivo;leukemia;leukemia treatment;leukemic stem cell;leukemic transformation;molecular dynamics;mouse model;preservation;stem;stem cell division;stem cell population;stem cells;therapeutic target;therapy design;therapy outcome Lysosomes and their Communications with Mitochondria in Leukemic Stem Cell Disease Progression PROJECT NARRATIVEStudies proposed here are designed to elucidate the contribution of the alteration of cellular organellesspecifically lysosomes and their communication with mitochondria in blood forming stem and progenitor cellprogression towards producing leukemic stem cells. These studies are devised to uncover targetablemetabolic mechanisms that promote therapy-resistance in leukemias. NCI 10688239 8/2/23 0:00 PA-20-185 5R01CA205975-07 5 R01 CA 205975 7 "KLAUZINSKA, MALGORZATA" 9/1/16 0:00 8/31/27 0:00 Molecular Oncogenesis Study Section[MONC] 2106196 "GHAFFARI, SAGHI " Not Applicable 13 ANATOMY/CELL BIOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 393348 NCI 232750 160598 PROJECT SUMMARY/ABSTRACTLeukemia therapy remains challenging and options are limited for a large fraction of patients who relapse.Growing evidence suggests that the therapy outcome and failure in myeloid leukemias are intimately linkedto properties of leukemic stem cells (LSCs). Quiescence is a fundamental property shared between LSCsand normal hematopoietic stem cells (HSCs). Thus targeting quiescent leukemic stem cells is essential for asuccessful long-lasting leukemia therapy. Achieving this goal requires identification of building blocks of stemcell quiescence and an in-depth understanding of mechanisms that wire them together. By exploitingmitochondrial heterogeneity we identified discrete deeply quiescent and potent subsets of mouse and humanHSCs. This led us to our discovery that lysosomal activity is heterogeneous in HSCs and key in maintainingtheir quiescence. We find lysosomes retain damaged mitochondria and that they are critical to themaintenance of HSC quiescence and metabolism. We have extended these studies to myeloid leukemiasusing both a mouse model of pre-leukemia and leukemia as well as leukemic patients samples and find thatleukemic stem cell populations are heterogeneous distinctively in their lysosomal and mitochondrialproperties. Based on our combined results we propose to investigate the implications of lysosomalheterogeneity for LSC isolation generation and maintenance. In Aim 1 we will take advantage of combinedlysosomal and mitochondrial heterogeneity to select LSCs subsets for further investigating their distinctfunction related to their lysosomal and mitochondrial alterations; in Aim 2 we will investigate the modulationof lysosomal-mediated metabolic pathways in LSC subsets; and in Aim 3 we will investigate the potential ofdysregulated lysosomes in mediating the generation of pre-leukemic stem cells. Altogether these studies arelikely to improve our approaches for isolating LSCs and our understanding of LSC generation andmaintenance. 393348 +No NIH Category available Affect;Apoptosis;Brain Neoplasms;Cancer cell line;Cell Death;Cell Energetics;Cell Line;Cell Proliferation;Cell Survival;Cells;Chromosome Segregation;Chromosomes;Clinical;Coin;Computing Methodologies;Cytotoxic Chemotherapy;DNA;DNA Damage;DNA sequencing;Data;Diploidy;Disease;Dose;Drug Monitoring;Drug Targeting;Endowment;Environment;Event;Evolution;Fluorescence Microscopy;Gastric Tissue;Generations;Genetic Materials;Genome;Genomic Segment;Genomics;Glioblastoma;Glucose;Growth;Haploidy;Human Genome Project;Image;In Vitro;Joints;Knowledge;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Measures;Medicine;Microtubules;Mitotic;Modeling;Outcome;Oxygen;Parents;Patients;Pharmaceutical Preparations;Phase;Phenotype;Ploidies;Population;Population Heterogeneity;Process;Prognosis;Proliferating;Research;Resistance;Resources;Risk;Role;S phase;Somatic Cell;Spatial Distribution;Stomach;Stomach Neoplasms;Testing;Time;Tissues;Validation;Vinblastine;brain tissue;cancer cell;cancer type;chromosome missegregation;cost;expectation;experimental study;fitness;gastric cancer cell;imaging platform;in silico;in vivo;inorganic phosphate;malignant stomach neoplasm;mathematical methods;mathematical model;migration;neoplastic cell;prevent;programs;replication stress;response;segregation;single cell sequencing;single-cell RNA sequencing;transcriptome;translational potential;tumor;tumor DNA;tumor heterogeneity;tumor metabolism Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy NARRATIVEUpon completion of the human genome project there was immense expectation that the newly gainedinformation would bring critical understanding as well as cure for diseases such as cancer. But the complexityof the genome revealed a huge chasm between measuring and understandingjoint interpretation of genomesand transcriptomes is a bottleneck to progress in medicine where advances stagnate compared to advances inquantification and manipulation. We examine genomes in the context of the resource environment thatsurrounds their respective carrier cells and aim to understand energetic contingencies for the evolution ofresistance to cytotoxic therapies. NCI 10688196 8/29/23 0:00 PA-20-185 5R37CA266727-02 5 R37 CA 266727 2 "MILLER, DAVID J" 9/1/22 0:00 8/31/27 0:00 Modeling and Analysis of Biological Systems Study Section[MABS] 12597628 "ANDOR, NOEMI " Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 532569 NCI 316065 216504 SUMMARYTraditional phase I dose-finding strategies monitor drug response only for two weeks based on the assumptionthat it will suce to observe how therapy aects doubling time of a homogeneous population over 2-4generations. But with the paradigm shift that most cancers are heterogeneous comes an urgent need to considerthat therapy-induced shifts in population composition manifest over longer time frames. We previously coinedthe tip-over hypothesis of DNA damage therapy sensitivity proposing that cytotoxic therapy is eective if it pushesa cells somatic copy number alteration (SCNA) load above a tipping point. Variable proximity of co-existingtumor cells to this tipping point imply that dose-response relations need not be monotonic. Cytotoxic therapy candrive one cell into apoptosis while skyrocketing another cell into malignant proliferation. As the developers ofwidely used computational and mathematical methods with established research programs in tumormetabolism and with a broad record of modeling dynamic processes and integrating various omics- andimaging platforms our team brings complementary expertise to develop a personalized cytotoxic therapy strategythat confines therapy-induced selection of resistant clones. We will test the potential of tumor cell DNA content anddNTP substrate availability to predict a tumors vulnerability to increasing SCNA rate. Hereby theaforementioned tipping point is accounted for not by elevated SCNA load alone but by an inability of the tissuemicro-environment (TME) to provide the necessary resources. Experiments are proposed in stomach and braintumorstwo cancer types whose TME can aord vastly dierent amounts of DNA. Our preliminary studiesshow that energetic costs of DNA content levels required for >75% SCNA load do not in the absence of cytotoxictherapy justify the masking benefits they bring. In particular we showed that limiting dNTP concentrationsamplify divergence in S-phase duration between high- and low-ploidy cells. Our hypothesis is that cytotoxictherapy causes a net-increase in fitness of tumors that exceed the SCNA tipping point. This hypothesis isfounded on two unexpected recent findings: (i) integrated single-cell RNA- and DNA-sequencing analyses ofstomach cancer cells suggests that the risk of cell death immediately after an SCNA event rather than just SCNArate impacts clonal diversity. Aim 1 will integrate single cell sequencing with imaging and mathematicalmodeling of heterogeneous populations that evolve through chromosome missegregations to examine observedSCNA landscapes and missegregation tolerances and to predict effective cytotoxic therapy doses. (ii) Evenminimal changes in DNA content among co-existing clones within the same Glioblastoma can result insignificantly longer S-phases. Aim 2 will evaluate Oxygen Phosphate and Glucose as rate-limiting substrates ofdNTP synthesis of co-evolving subpopulations in stomach and brain tissue environments. This is the first studyto investigate if and how clinical decisions can benefit from integrating a tumor environments energeticprovision with the energetic demands of cancer cells genomic makeup. 532569 +No NIH Category available Acute T Cell Leukemia;Adult Precursor T Lymphoblastic Leukemia;BTG2 Gene;Cell Adhesion;Cell Reprogramming;Cells;Chemoresistance;Child;Childhood;Childhood Acute Lymphocytic Leukemia;Childhood Leukemia;Childhood Precursor T Lymphoblastic Leukemia;Chromatin;Chromatin Loop;Complex;Critical Pathways;Data;Development;Disease;Enhancers;Failure;Frequencies;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Glucocorticoid Receptor;Glucocorticoids;Goals;Heterogeneity;Human;Inflammatory;Knowledge;Label;Leukemic Cell;Lymphoid Cell;Malignant Neoplasms;Measures;Mediating;Mitotic;Modeling;Mus;NOTCH1 gene;Natural regeneration;Nucleosomes;Oncogenic;Pathogenesis;Pathway interactions;Patients;Polycomb;Population;Property;Recording of previous events;Relapse;Repressor Proteins;Research;Residual Neoplasm;Resistance;Resolution;Selection for Treatments;Small Interfering RNA;T-Lymphocyte;TAL1 gene;Testing;Thymus Gland;Translating;Treatment Failure;Work;acute T-cell lymphoblastic leukemia cell;chemotherapy;chromosome conformation capture;estrogen-related receptor;improved;in vivo;inhibitor;knock-down;leukemia;leukemia initiating cell;leukemia treatment;leukemogenesis;mRNA Stability;new therapeutic target;notch protein;novel;patient derived xenograft model;prevent;progenitor;prognostic indicator;programs;promoter;prospective;receptor binding;relapse patients;relapse prevention;resistance gene;response;self-renewal;single-cell RNA sequencing;stem cells;targeted treatment;therapy resistant;transcriptomics;treatment response Mechanism(s) of TAL1- and NOTCH1-mediated Leukemogenesis Project NarrativeT cell acute lymphoblastic leukemia patients that fail to respond to glucocorticoid (GC) therapy often relapse andsuccumb to disease. We identified new GC-resistance genes and a subpopulation of slow-cycling leukemia cellsthat is present in patients who fail therapy and relapse. We will use this information to reverse GC resistanceand interfere with dormancy to prevent relapse in children with leukemia. NCI 10688193 6/20/23 0:00 PA-20-185 5R01CA096899-17 5 R01 CA 96899 17 "FORRY, SUZANNE L" 8/1/04 0:00 6/30/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 1946839 "KELLIHER, MICHELLE ALICE" Not Applicable 2 ANATOMY/CELL BIOLOGY 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 397813 NCI 237500 160313 Project Summary/AbstractDespite significant advances in T cell acute lymphoblastic leukemia (T-ALL) therapy 25% of patients relapse.Recent evidence suggests that failure to eliminate dormant leukemia-initiating cells (L-IC) underlies relapse.Efforts to prospectively isolate L-IC from ALL patients to define the critical pathways of L-IC dormancy andchemoresistance have thus far been unsuccessful.Research from my lab has shown that mouse double negative DN stage 3 (DN3) thymic progenitors are enrichedin L-IC that contribute to resistance to Notch targeted therapy however the L-IC remains an undefined subset ofthe leukemic DN3 population. To identify the L-IC we profiled leukemia progression in vivo at the single cell leveland uncovered dormant and proliferative DN3 clusters that are transcriptionally distinct. In Aim 1 we will usenucleosome labeling to track the mitotic history of dormant and proliferative DN3 leukemic cells to functionallyassess their ability to initiate leukemia and tolerate chemotherapy in vivo. We will also use scRNA-seq to profilechemotherapy response in vivo in order to determine whether chemotherapy enriches for dormant DN3 or selectsfor additional DN3 heterogeneity. We find Btg2 known to mediate T cell quiescence by deadenylating Mycenriched in mouse dormant DN3 leukemic cells and in ALL patient label retaining cells and ALL patients withminimal residual disease leading us to hypothesize that Btg2 regulates dormancy in mouse and human L-IC.We will test this hypothesis in Aim 2 by deleting Btg2 in mouse DN3 cells and examining effects on Mycexpression dormancy and L-IC frequency. Dormancy may also reflect Polycomb repressor complex (PRC) 2mediated silencing of the Myc enhancer as we find PRC targets enriched in dormant DN3. We will use CUT&Tagto interrogate the Myc enhancer to uncover how Myc is suppressed in these Notch1-active dormant DN3 cells.The work proposed in Aim 3 builds on our siRNA screen to identify glucocorticoid (GC) resistance genesassociated with relapse. We identified Estrogen Related Receptor b (ESRRb) as a novel GC resistance genethat we find under-expressed in therapy resistant ALL patients. We demonstrate that ESRRb silencing interfereswith GC target gene expression by unclear mechanisms. We will determine if ESRRb increases glucocorticoidreceptor (GR) binding and mediates chromatin looping to potentiate GR transcription. Finally the knowledgegained in mouse T-ALL models will be translated to human T-ALL by determining the effect(s) of ESRRbactivation on the GC response and overall survival in GC resistant or relapsed pediatric T-ALL patient-derivedxenografts. Together these studies will advance understanding of T-ALL pathogenesis and therapy failure byidentifying the dormant L-IC signature revealing Btg2 and Myc as critical regulators of L-IC dormancy and bydeveloping novel GC re-sensitizing strategies to prevent relapse in pediatric T-ALL patients. 397813 +No NIH Category available Address;Algorithms;Animals;Biological Markers;Biopsy;Blood Vessels;Breast Cancer Patient;Breast Cancer Treatment;Cancer Biology;Cancer Patient;Carboplatin;Caring;Cellularity;Clinical;Clinical Trials;Combined Modality Therapy;Communities;Consensus;Coupled;Data;Development;Diffusion Magnetic Resonance Imaging;Disease;Disease Progression;Evaluation;Funding;Genomics;Goals;Healthcare;Human;Image;Imaging technology;Immunotherapy;In complete remission;Informatics;Machine Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Mass Spectrum Analysis;Methodology;Methods;Molecular;Molecular Target;Mus;Neoadjuvant Therapy;Online Systems;Pathologic;Patient-Focused Outcomes;Patient-derived xenograft models of breast cancer;Patients;Phenotype;Physiological;Prediction of Response to Therapy;Prognosis;Proteins;Recurrence;Regimen;Reproducibility;Research;Research Personnel;Resource Informatics;Resources;Science;Signal Transduction;Surrogate Endpoint;Testing;Time;Treatment Efficacy;Treatment Protocols;Work;animal data;arm;bioinformatics resource;candidate identification;chemotherapy;co-clinical trial;cohort;contrast enhanced;data resource;data sharing;docetaxel;exome;high resolution imaging;human data;human model;imaging biomarker;imaging modality;improved;indexing;informatics tool;innovation;interest;mRNA Expression;machine learning algorithm;machine learning model;magnetic resonance imaging biomarker;malignant breast neoplasm;molecular marker;novel;online resource;optimal treatments;participant enrollment;patient derived xenograft model;personalized therapeutic;pre-clinical;preclinical trial;predicting response;predictive marker;predictive modeling;prospective;quantitative imaging;repaired;response;response biomarker;targeted treatment;tool;transcriptome sequencing;treatment response;triple-negative invasive breast carcinoma;tumor INTEGRATING OMICS AND QUANTITATIVE IMAGING DATA IN CO-CLINICAL TRIALS TO PREDICT TREATMENT RESPONSE IN TRIPLE NEGATIVE BREAST CANCER Project NarrativeDetermining the optimal therapies for a specific triple negative breast cancer tumor is currently not possible asthe number of possible treatment combinations is too large to evaluate experimentally in clinical trials. Ourproposed methods that leverage patient derived xenografts and machine learning analysis of integrated `omicsand quantitative imaging data will provide the cancer community with a rational iterative combined pre-clinicaland clinical trial approach and supporting data resource for making progressively more refined andpersonalized therapeutic regimens in these patients. Our methods and tools will likely also generalize to othercancers and could therefore substantially benefit the care of all cancer patients. NCI 10688170 8/17/23 0:00 PAR-18-841 5U24CA226110-05 5 U24 CA 226110 5 "ZHANG, HUIMING" 9/19/19 0:00 8/31/24 0:00 ZCA1-SRB-X(M1) 1972445 "LEWIS, MICHAEL T." "RUBIN, DANIEL L; YANKEELOV, THOMAS E" 9 ANATOMY/CELL BIOLOGY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Other Research-Related 2023 620231 NCI 512438 107793 Project SummaryTriple negative breast cancer (TNBC) is a very challenging disease because it is biologically aggressive thereare no targeted therapies and consequently patients have poor prognosis. Although immunotherapy ispromising for treating many cancers TNBC lacks specific molecular targets no predictive biomarkers tochemotherapy response have yet been identified and treatment response is difficult to evaluate using currentbiomarker assessments. Patient-derived xenograft (PDX) models of TNBC offer the exciting opportunity ofevaluating this disease in terms of molecular features (e.g. genomic copy number whole exome sequence andmRNA expression) to identify candidate omic biomarkers that best predict the ultimate response to treatmentand could provide surrogate endpoints to validate novel imaging biomarkers in co-clinical trial human trails.Moreover emerging quantitative MRI methods such as dynamic contrast enhanced magnetic resonanceimaging (DCE-MRI) and diffusion weighted MRI (DW-MRI) contain rich physiological signals in the images forpredicting treatment response but it is challenging to integrate both animal and human data to reliably predict thetreatment response. A paradigm of co-clinical trials is emerging in which new treatments are evaluated inanimals and the results guide treatments in clinical trials but there is a paucity of informatics tools and resourcesto enable analyses in such animal-to-human work. We believe that an informatics-based methodology thatintegrates molecular `omics' and imaging data will propel advances in TNBC by enabling development ofmachine learning models to predict the response to therapies. In order to develop research resources that willencourage consensus on how quantitative imaging methods are optimized to improve the quality of imagingresults for co-clinical trials we will leverage an ongoing co-clinical trial we are undertaking to pursue the followingspecific aims: (1) Identify molecular biomarkers that predict response in TNBC patient-derived xenografts (PDX);(2) Identify quantitative MRI biomarkers that predict response in TNBC patient-derived xenografts; and (3)Evaluate our informatics tools in a prospective co-clinical trial. Our proposed research is significant andinnovative because it leverages advances in basic cancer biology state-of-the-art imaging technologies andinformatics methods to develop a resource to catalyze discovery in this important disease. Our PDX-basedapproach will provide the cancer community with a rational iterative combined pre-clinical and clinicalmethodology and supporting data resource for making progressively more refined and personalized therapeuticregimens for TNBC patients. Our methods and tools will likely also generalize to other cancers and couldtherefore substantially benefit the care of all cancer patients. 620231 +No NIH Category available Adult;African American;Age;American Cancer Society;Archives;Bioinformatics;Biological Markers;Blood;Carcinoma;Clinical;Cohort Studies;Collaborations;Colon;Colorectal;Colorectal Cancer;Communities;Complement;Data;Decision Modeling;Diabetes Mellitus;Diagnostic;Diet;Early Diagnosis;Early identification;Endotoxemia;Endotoxins;Epidemiology;Etiology;Guidelines;High Fat Diet;Histology;Immune response;Incidence;Inflammation;Inflammatory Bowel Diseases;Investigation;Life;Life Cycle Stages;Life Style;Life course epidemiology;Link;Longevity;Measurement;Mediating;Meta-Analysis;Modeling;Molecular;Neoplasms;Nurses' Health Study;Obesity;Pathologic;Pathway interactions;Plasma;Play;Population;Positioning Attribute;Prevention;Process;Prospective cohort;Proteomics;Recommendation;Relative Risks;Reporting;Research Personnel;Research Priority;Resources;Risk;Risk Factors;Role;Testing;Time;Unhealthy Diet;Update;adenoma;biomarker discovery;cancer diagnosis;carcinogenesis;circulating biomarkers;colon carcinogenesis;colon tumorigenesis;colorectal cancer screening;cost;cost efficient;early onset;early onset colorectal cancer;early onset colorectal neoplasm;emerging adult;gut dysbiosis;improved;inflammatory marker;insight;lifestyle data;lifestyle factors;microbial;models and simulation;multidisciplinary;novel;novel marker;personalized screening;prospective;protein protein interaction;screening;screening guidelines;sedentary;sedentary lifestyle;simulation;systematic review;systemic inflammatory response;young adult Obesity sedentary behaviors and diet quality for prevention and early detection of early-onset colorectal neoplasia PROJECT NARRATIVEThe rising incidence in colorectal cancer (CRC) diagnosed under age 50 has resulted in updated guidelines fromthe American Cancer Society (ACS) advising average-risk screening begin at age 45 rather than 50. Howeverthe etiology of early-onset CRC and contributors for this rise remain unclear. Our investigations into the role ofmid-adulthood and early-life obesity sedentary behaviors and poor diet associated with risk of early-onsetadvanced adenoma as well as biomarker discoveries of both early-onset advanced adenoma/CRC will advancethe understanding of the etiology of early-onset CRC and shed light on prevention. Our estimation of theexplained portion of the rising incidence as well as the improvement of the simulations used to support the 2018ACS screening guideline by incorporating meta-analyzed early-onset CRC specific risk factors/estimates will bea significant step forward toward optimal screening in younger adults. NCI 10688157 6/23/23 0:00 PA-19-056 5R37CA246175-04 5 R37 CA 246175 4 "UMAR, ASAD" 7/1/20 0:00 6/30/25 0:00 Cancer Prevention Study Section[CPSS] 14101466 "CAO, YIN " Not Applicable 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 521636 NCI 397765 123871 PROJECT SUMMARY/ABSTRACTThe rising incidence in early-onset colorectal cancer (CRC diagnosed before 50) has resulted in updatedAmerican Cancer Society (ACS) guideline advising average-risk screening begin at age 45 rather than 50.Debates centered around the substantial cost and resources of adding 21 million adults at very low risk to thescreening pool and further personalize screening strategies was a priority. Identifying the contributors of therising incidence are the first steps but thus far an unmet need. Lifestyle factors that preceded and mirrored therapid rise of early-onset CRC including obesity prolong sitting and poor diet may play a critical role. Ourpreliminary data support the importance of obesity and sedentary behaviors and early-onset CRC are more likelyto be processed from traditional adenoma-carcinoma sequence compared to CRC diagnosed after age 65.Therefore investigation into risk factors for early-onset advanced adenoma the major targets of screening willilluminate insights of colorectal carcinogenesis at younger ages. Accumulating data suggest that microbialtranslocation/endotoxemia which triggers subsequent inflammation and immune response and augmented byabove-mentioned lifestyle factors might be an emerging pathway. We hypothesized that obesity prolongedsitting and poor diet quality increase risk of early-onset advanced adenoma through increasing endotoxemiaand inflammation and contribute to the rise of early-onset CRC. To test these hypotheses we will leveragelifestyle data collected throughout life course in two well-characterized prospective cohort (Nurses Health StudyII [NHSII]) and Southern Community Cohort Study (SCCS) with archived pre-diagnostic blood complementedby decision modeling using the Microsimulation Screening AnalysisColon (MISCANColon) the model used toinform the ACS screening guideline. Specifically we will first examine prospectively the associations betweenmid-adulthood and early-life obesity sedentary behaviors and diet quality and risk of early-onset advancedadenoma (Aim 1). We will then investigate into the independent and mediating role of pre-diagnostic plasmamarkers of endotoxemia and inflammation in early-onset neoplasia leveraging a cost-efficient and reliableproteomic platform. Such profiling will also allow for untargeted discoveries of protein-protein interactions toidentify novel networks/targets (Aim 2). Finally we will conduct a meta-analysis to identify early-onset CRCspecific risk factors and quantify the relative risks and integrate these findings to the MISCAN-Colon to estimatethe contributions of secular changes of lifestyle to the rise of early-onset CRC and to improve the simulationsused to support the 2018 ACS screening guideline using early-onset CRC specific risk factors/estimates (Aim3). Our established team led by an early stage investigator focused on early-onset CRC and leaders inepidemiology bioinformatics biomarker measurement and discoveries and decision modeling offersunparalleled expertise. This investigation will illuminate significant insights into the etiology of early-onset CRCand will be a significant step forward to optimal/personalized CRC screening among younger adults. 521636 +No NIH Category available Accounting;Adult;Age;American Indians;Area;Cancer Center;Cancer Patient;Cancer Survivor;Career Mobility;Caring;Cessation of life;Cherokee Indian;Cherokee Nation Oklahoma;Chronic;Clinic;Consolidated Framework for Implementation Research;Counseling;Data;Diagnosis;Enrollment;Ethnic Population;Evidence based intervention;Future;General Population;Goals;Health Expenditures;Health system;Healthcare;High Prevalence;Incidence;Individual;Intervention;Intervention Studies;Interview;Malignant Neoplasms;Mental Health;Mentors;Methods;Morbidity - disease rate;National Health Interview Survey;Oklahoma;Oncologist;Oncology;Participant;Patients;Persons;Pharmaceutical Preparations;Population;Prevalence;Primary Care;Provider;Relapse;Reporting;Research;Research Personnel;Reservations;Resources;Risk;Role;Second Primary Cancers;Smoking;Survivors;System;Time;Tobacco;Tobacco Use Cessation;Tobacco use;Tobacco-Related Carcinoma;Tribes;United States;United States Indian Health Service;Universities;Work;anticancer research;cancer care;cancer diagnosis;care systems;compare effectiveness;education research;evidence base;experience;former smoker;future implementation;graduate student;health care service;health disparity;implementation research;implementation strategy;improved;insight;medical specialties;member;mortality;primary care provider;productivity loss;professional students;programs;quitline;racial population;reduce tobacco use;smoking cessation;success;tobacco cessation intervention;tobacco user;tribal health;undergraduate student;vaping Tobacco Cessation among American Indian Cancer Survivors in Cherokee Nation NarrativeThis study will identify common barriers and facilitators in receiving smoking cessation counseling and/ortreatment among Cherokee Nation cancer survivors. We expect to identify implementation strategies that areacceptable to survivors and providers and plan for future interventions studies. These results will facilitate carebetween the tribal health system and external specialty care clinics. NCI 10688152 8/21/23 0:00 PAR-18-911 5P20CA253258-04 5 P20 CA 253258 4 9/15/20 0:00 8/31/24 0:00 ZCA1-SRB-T 8853 14226585 "JANITZ, AMANDA E" Not Applicable 5 Unavailable 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK Domestic Higher Education 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 32308 22281 10027 AbstractTobacco use is the leading cause of morbidity and mortality in the US accounting for 30% of cancer deathsand resulting in more than $300 billion in annual health care expenditures and productivity loss. AmericanIndian (AI) adults continue to have a higher prevalence of tobacco use (32%) compared to any otherrace/ethnic group (13%-25%) in the US and experience disproportionate rates of tobacco-related morbidity andmortality. In addition AI individuals in Oklahoma have the highest age-adjusted cancer incidence (637 per100000) and mortality (255 per 100000) rates compared to other racial groups. Continued use of tobaccoafter a cancer diagnosis increases the risk of secondary cancers and mortality compared to non-tobacco users.Cherokee Nation is the largest tribe in the United States with more than 378000 enrolled members andreducing tobacco use is one of the tribe's top priorities. Cherokee Nation works with Indian Health Service(IHS) to provide healthcare services for the AI population within their reservation area. Because of this systemany referral for specialty care not provided by Cherokee Nation must obtain approval through the IHSPurchased and Referred Care system which may complicate oncology care. Furthermore it is unclearwhether AI cancer survivors routinely receive tobacco cessation treatment during their oncology care or whilereceiving primary care within the Cherokee Nation Health System. Our long-term goal is to reduce theprevalence of tobacco use among cancer survivors in Cherokee Nation. Our study aims to 1) evaluate tobaccocessation experiences among AI cancer survivors in Cherokee Nation; 2) identify current tobacco cessationpractices in primary care and oncology settings along with facilitators and barriers to delivering cessationtreatment to Cherokee Nation cancer patients; and 3) develop tailored strategies to increase implementationand reach of tobacco cessation treatment for cancer survivors in Cherokee Nation. This study will provideinsight into current practices and needs related to tobacco cessation for AI cancer survivors in CherokeeNation. This project will provide preliminary data for an R01 proposal to compare the effectiveness ofimplementation strategies aimed at improving tobacco cessation treatment provided to cancer survivors. It willalso provide opportunities for future implementation research focused on other evidence-based interventionsfor cancer survivors in Cherokee Nation. +No NIH Category available Address;Advanced Malignant Neoplasm;Advisory Committees;Ally;Cancer Center;Cancer health equity;Cherokee Indian;Cherokee Nation Oklahoma;Collaborations;Communication;Complex;Decision Making;Education;Educational Activities;Ensure;Evaluation;Fostering;Foundations;Funding;Future;Goals;Grant;Growth;Infrastructure;Institution;Joints;Leadership;Malignant Neoplasms;Mentorship;Monitor;Oklahoma;Pilot Projects;Procedures;Program Evaluation;Research;Research Activity;Site;Structure;Students;Tobacco;Training Activity;Tribes;Underrepresented Students;Universities;Work;anticancer research;cancer education;cancer health disparity;data sharing;design;education research;experience;health disparity populations;implementation process;innovation;novel;programs;success OUHSC Admin Core n/a NCI 10688143 8/21/23 0:00 PAR-18-911 5P20CA253258-04 5 P20 CA 253258 4 9/15/20 0:00 8/31/24 0:00 ZCA1-SRB-T 5961 6831787 "DOESCHER, MARK P" Not Applicable 5 Unavailable 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK Domestic Higher Education 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 89086 61439 27647 AbstractThe Administrative Core of the Cherokee Nation/Oklahoma State University (OSU) and StephensonCancer Center (SCC) Collaborative Partnership for Cancer Research (the Collaborative) provides theorganizational hub for the jointly conducted cancer-related research and cancer research education activities ofthis planning project. The Collaborative is novel yet organizationally complex as it enhances the success of aprior Cherokee Nation-SCC partnership through the addition of OSU as an academic ally for the tribe. Toaddress this complexity the Administrative Core establishes shared leadership between the participatinginstitutions an Internal Advisory Committee and procedures for regular communication and decision makingwithin the partnership. The research and training activities of the Collaborative are integrated and mutuallyreinforcing with the ultimate goal of providing Cherokee Nation with the capacity to pursue independentresearch in cancer disparities focusing on tobacco. The Administrative Core specific aims are to: 1) Provide joint leadership and infrastructure to provide the operational support including fiscal management to ensure the integration of the diverse components of the Collaborative; 2) Conduct rigorous planning and implementation processes for pilot research and cancer research education; 3) Conduct program evaluation to gauge overall success of the Collaborative in achieving targets and milestones; and 4) Pursue funding to ensure sustainability of our efforts to address cancer disparities at Cherokee Nation for both research and cancer research education.A major goal of this feasibility grant is to build the foundation for future tribally engaged cancer research. TheAdministrative Core proposed herein is essential to this effort as it ensures that all aspects of the program areintegrated into a collaborative effort addressing cancer disparities for Cherokee Nation. +No NIH Category available Accreditation;Address;Advisory Committees;Affect;Ally;American Indians;Area;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cherokee Indian;Cherokee Nation Oklahoma;Clinical;County;Disparity;Education Projects;Education and Outreach;Environment;Foundations;Grant;Health Services;High Prevalence;Hospitals;Indian reservation;Infrastructure;Joints;Link;Location;Malignant Neoplasms;Mentors;Mission;National Cancer Institute;Oklahoma;Osteopathic Medicine;Persons;Population;Psychologist;Psychology;Public Health;Research;Research Activity;Research Personnel;Research Project Grants;Reservations;SEER Program;Site;Students;System;Tobacco;Tobacco use;Training;Training and Education;Tribes;United States;Universities;Work;anticancer research;cancer health disparity;cancer risk;curriculum development;education research;experience;graduate student;health care delivery;innovation;interest;medical schools;neoplasm registry;next generation;outcome disparities;outreach;professional students;programs;tobacco control;tribal Nation;tribal community;undergraduate student 1/2 Cherokee Nation/OSU and SCC Collaborative Partnership for Cancer Research Narrative. American Indian tribal communities suffer disproportionately from cancer disparities. This planninggrant will expand authentic tribal capacity to address cancer disparities through a coordinated program ofjointly executed pilot research directly involving early-stage investigators and students and through specificcancer research curriculum development and outreach activities. NCI 10688142 8/21/23 0:00 PAR-18-911 5P20CA253258-04 5 P20 CA 253258 4 "RODRIGUEZ, LARITZA MARIA" 9/15/20 0:00 8/31/24 0:00 ZCA1-SRB-T(M1)S 6831787 "DOESCHER, MARK P" Not Applicable 5 FAMILY MEDICINE 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 192951 NCI 133070 59881 AbstractCancer disparities continue to impact the tribal nations within Oklahoma disproportionately. The proposedCherokee Nation/Oklahoma State University (OSU) and Stephenson Cancer Center (SCC) Collaborative hasfour specific aims to achieve its overall mission of developing durable capacity in the context of an AmericanIndian tribal nation for research on cancer disparities: 1. to strengthen administrative infrastructure including a joint Internal Advisory Committee capable of integrating research research education and outreach efforts among the Cherokee Nation OSU and the SCC; 2. to conduct innovative pilot research in tobacco use and cancer risk capable of seeding large-scale research projects performed in the Cherokee Nation setting; 3. to train the next generation of cancer researchers prepared to engage meaningfully with the Cherokee Nation and other tribal nations in the context of this research focusing on early-stage investigators (ESIs) graduate professional and undergraduate students; and 4. to evaluate our work in order to optimize the impact of pilot research projects and cancer research education and outreach activities and guide continued expansion of Collaborative activities to address cancer disparities.Our excitement about the Collaborative centers on the opportunity to expand tribal capacity for cancerdisparities research through a coordinated program of pilot research directly involving ESIs and students inscholarly work to address cancer disparities particularly those resulting from tobacco and through specificcancer research curriculum development and outreach activities. The addition of OSU which has remarkableassets in the education and training of American Indian students and ESIs including a new medical schoolcreated in partnership with the Cherokee Nation provides a unique environment in which a tribe a universityserving large numbers of AI students and a research-intensive cancer center will work collectively to reducethe unacceptable burden of cancer that continues to affect far too many AI people. 192951 +No NIH Category available Adaptor Signaling Protein;Address;Adverse effects;Adverse event;Animal Model;Antibodies;Antigen Targeting;Antigens;Beds;Biocompatible Materials;Biodistribution;Biological Availability;Bone Marrow;Breast Cancer Model;CAR T cell therapy;CD3 Antigens;CRISPR/Cas technology;Cell Line;Cell Therapy;Cells;Chitosan;Clinical Medicine;Clinical Skills;Communication;Coupling;Data Analyses;Deposition;Development;Development Plans;Drug Delivery Systems;ERBB2 gene;Encapsulated;Excision;Exhibits;Goals;Growth;Hematologic Neoplasms;Immune response;Immunology;Immunotherapy;Implant;In Vitro;Individual;Interdisciplinary Study;Interleukin-15;Knock-out;Knowledge;Laboratories;Leucine Zippers;Logic;Malignant Neoplasms;Malignant neoplasm of ovary;Mentors;Methods;Modality;Modeling;Molecular Biology;Monitor;Monoclonal Antibodies;Mus;Operative Surgical Procedures;Organ;Physicians;Population;Prevention;Proliferating;Proteins;ROR1 gene;Reporting;Research;Research Personnel;Research Project Grants;Risk Reduction;SKBR3;Safety;Scientist;Shapes;Signal Transduction;Site;Solid Neoplasm;Specificity;Spleen;Surface;Surgical Mesh;Surgical sutures;Surgically-Created Resection Cavity;System;T cell anergy;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;Techniques;Testing;Therapeutic;Tissues;Toxic effect;Training;Tumor Antigens;Tumor Debulking;bioluminescence imaging;chimeric antigen receptor;chimeric antigen receptor T cells;cytokine;cytokine release syndrome;cytotoxic;density;design;draining lymph node;efficacy evaluation;exhaustion;genetically modified cells;implantation;improved;in vivo;insight;malignant breast neoplasm;mouse model;multidisciplinary;nanofiber;nanopolymer;novel;novel therapeutics;prevent;programmed cell death protein 1;scaffold;skills;spatiotemporal;stem cells;success;therapy development;tumor;tumor microenvironment;tumor-immune system interactions Development of a Surgical Drug Delivery System for Enhancement of CAR T Cell Activity Project NarrativeThis proposal describes the training and mentoring of Mr. Eric Bressler and his research project to treat solidtumors using a novel biomaterial in conjunction with a split and programmable chimeric antigen receptor (CAR)T cell system. Using this system he describes a method for overcoming barriers to efficacy of CAR T cells insolid tumors specifically poor T cell persistence in the tumor microenvironment lack of specific antigens andtreatment-limiting adverse effects. The capability of this novel therapeutic system to promote CAR T cellproliferation prevent antigen escape and mitigate adverse events will be evaluated. NCI 10688135 8/7/23 0:00 PA-21-050 5F30CA257566-03 5 F30 CA 257566 3 "BIAN, YANSONG" 9/9/21 0:00 9/8/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 12343470 "BRESSLER, ERIC " Not Applicable 7 ENGINEERING (ALL TYPES) 49435266 THL6A6JLE1S7 49435266 THL6A6JLE1S7 US 42.349594 -71.099726 10001093 BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) BOSTON MA BIOMED ENGR/COL ENGR/ENGR STA 22151390 UNITED STATES N 9/9/23 0:00 9/8/24 0:00 321 "Training, Individual" 2023 52694 NCI 52694 0 Project Summary and Abstract Chimeric antigen receptor (CAR) T cells are genetically engineered T lymphocytes designed to senseantigens and mount an immune response. Though CAR T cells have received FDA approval for the treatmentof several hematologic malignancies success in solid tumors is limited by a lack of specific antigens theimmunosuppressive tumor microenvironment and treatment-limiting adverse effects such as on-target off-tumortoxicity and cytokine release syndrome. Though investigators report strategies for mitigating these limitationssuch as biomaterials for reshaping the tumor microenvironment and logic-gated CAR T cells to prevent non-specific toxicity no proposed strategy has overcome each of these barriers. To surmount these limitations Ipropose the use of a novel surgical mesh for implantation into the tumor resection cavity. This mesh will be usedin conjunction with a split CAR T cell called a zipCAR which uses a detached adaptor protein (a zipFv) tosense antigens. The mesh is composed of polymeric nanofibers with a matrix of chitosan deposited within thepores. The mesh supplies the zipFv adaptor protein cytokines (IL-15) and T cell stimulatory antibodies (-CD3/28). I hypothesize that the use of this surgical mesh will overcome the barriers to CAR T cell therapyin solid tumors by: (1) opposing T cell anergy and promoting proliferation in the resection cavity (2)preventing antigen escape via encapsulation of zipFvs targeting multiple antigens and (3) impartingspatiotemporal control over CAR T cell activity. Aim 1 of this proposal demonstrates the proliferationadvantage of the mesh by monitoring CAR T cell proliferation in a murine model of HER2+ breast cancer. Aim 2of this proposal demonstrates the efficacy and safety advantages of the meshes in a model of operativedebulking of ovarian cancer. To demonstrate prevention of antigen escape ROR1- and HER2-deficient OVCAR3cell lines will be created using CRISPR-Cas9 knockouts. In a murine model of antigen escape these cells willbe used to demonstrate superior efficacy in mice treated with zipCAR T cells and meshes loaded with zipFvsagainst both antigens. To demonstrate superior safety meshes will be utilized in the same model of ovariancancer with mice that are irradiated to upregulate ROR1 expression in non-hematopoietic stem cells in the bonemarrow and spleen allowing observation of on-target off-tumor toxicity. This proposal builds around four key components of critical research and clinical skills to support mydevelopment into an independent physician scientist: (1) an interdisciplinary research project focusing onnovel surgical biomaterials for enhancement of CAR T cell activity; (2) multi-disciplinary mentoring from Drs.Grinstaff (biomaterials) Wong (immunotherapy); and Colson (clinical medicine animal models andimmunology) (3) academic physician scientist training in research conduct and communication skills (4)commitment to an individual development plan (IDP) to guide my training goals. 52694 +No NIH Category available Algorithms;Binding;Bioinformatics;Biological;Biology;Breast Cancer Model;Breast cancer metastasis;Cell Communication;Cells;Cellular biology;Chromatin;Clinical;Colorectal Cancer;Computational Biology;Computational algorithm;Computing Methodologies;DNA;Data;Data Set;Disease;Distal;Elements;Fire - disasters;Gene Expression;Gene Expression Profiling;Generations;Genes;Genetic Transcription;Glean;Interruption;Malignant Neoplasms;Metabolic;Metabolite Interaction;Metastatic to;Methodology;Methods;Modeling;Molecular;Neoplasm Metastasis;Organ;Pathway Analysis;Pathway interactions;Phenotype;Primary Neoplasm;Proteomics;RNA;RNA-Binding Proteins;Regulatory Element;Regulon;Reporter;Research Personnel;Series;Site;System;Systems Biology;Universities;cancer cell;cell type;colorectal cancer metastasis;empowerment;experimental study;gene network;innovation;insight;mRNA sequencing;malignant breast neoplasm;metabolic abnormality assessment;metabolomics;metastasis prevention;novel;pharmacologic;prevent;programs;ribosome profiling;single cell sequencing;sound;technology development;therapeutic target;transcription factor;transcriptome;transcriptomics Single-Cell & Computational Biology Core n/a NCI 10688118 8/17/23 0:00 RFA-CA-20-029 5U54CA261701-03 5 U54 CA 261701 3 9/23/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 5960 10377558 "BIRSOY, KIVANC " Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 314488 327209 66624 SUMMARYThe Single-Cell Sequencing and Computational Biology Core B will be the central hub for devising andimplementing all Single-Cell Sequencing experiments as well as the application of powerful computationalalgorithms to such data as well as other bulk mRNA sequencing and metabolomic data to generate integratedmodels of gene networks and regulatory factors underlying metastatic progression. All three Center Projects willapproach metastasis systematically relying on the generation of transcriptomic ribosomal profiling single-cellsequencing proteomic metabolomic and chromatic accessibility data. As such this Center will rely heavily onrigorous and statistically sound Computational Biology and Bioinformatics approaches pioneered by SaeedTavazoie a leader in Systems Biology who will be a co-leader of this Core. Similarly all three Projects willextensively employ Single-Cell Sequencing methods to define and characterize cell-cell interactions and cellulargene expression states within metastatic tumors and to develop novel single-cell methods. Junyue Cao a leaderin Single-Cell Sequencing technology development and application will be a co-leader of this Core. Thecombined Systems-level focus of these investigators applied to the multi-layered data generated from distinctstages of metastatic progression will enable the establishment of an unprecedented integrated Systems-levelmodel of breast and colorectal cancer metastasisproviding the framework for further mechanistic studies thatwill refine this model ultimately revealing critical nodes that when interrupted genetically or pharmacologicallywill prevent and eradicate metastatic disease. Computational methods that will be foremost applied to theproblem of metastatic progression include:1. iPAGE: an information-theoretic Pathway Analysis of Gene Expression algorithm that allows the systematic discovery of pathways that are differentially modulated across transcriptomes of any cell-types.2. FIRE: an information-theoretic algorithm that identifies local DNA and RNA elements that underlie gene expression changes uncovering associated transcription factors and RNA-binding proteins that govern suchprograms.3. TEISER: an algorithm that discovers RNA regulatory elements from transcriptomes enabling identification of their trans-binding factors.4. An algorithm that integrates transcriptomic and phenotypic features (such as survival) from large-scale cancer compendia to implicate critical clinically-associated genes. +No NIH Category available 4T1;Address;Affinity;Area;Breast;Breast Cancer Cell;Breast cancer metastasis;CRISPR screen;CRISPR/Cas technology;Cancer Model;Cell Communication;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Colon Carcinoma;Computational Biology;Dependence;Distant;Environment;Enzymes;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Screening;Goals;Knowledge;Liver;Lung;MC38;Maps;Metabolic;Metabolic stress;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Methods;Modeling;Molecular;Neoplasm Circulating Cells;Neoplasm Metastasis;Non-Malignant;Normal Cell;Nutrient;Nutrient availability;Organ;Organelles;Oxygen;Pathway interactions;Population;Process;Repression;Role;Site;Starvation;System;Techniques;Testing;Therapeutic;Tissues;Work;cancer cell;cancer heterogeneity;cell type;epigenome;experience;extracellular;gain of function;genetic approach;in vivo;innovation;loss of function;lung colonization;metabolomics;multidisciplinary;multiphoton microscopy;multiple omics;neoplastic cell;photoactivation;programs;single cell sequencing;small molecule;transcriptome;transcriptomics;treatment response;tumor Project 3: The role of microenvironmental metabolites on metastatic progression n/a NCI 10688117 8/17/23 0:00 RFA-CA-20-029 5U54CA261701-03 5 U54 CA 261701 3 9/23/21 0:00 8/31/26 0:00 ZCA1-RTRB-Y 5959 10377558 "BIRSOY, KIVANC " Not Applicable 12 Unavailable 71037113 LHGDNJMZ64Y1 71037113 LHGDNJMZ64Y1 US 40.763746 -73.955386 7056601 ROCKEFELLER UNIVERSITY NEW YORK NY Domestic Higher Education 100656399 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 321984 217759 157029 Project SummaryMetabolic programs are particularly relevant during metastasis as it is an inefficient process comprising severalconsecutive steps with only a small proportion of circulating tumor cells generating a metastatic lesion. Theinefficiency is largely attributable to the host organ environments which impose metabolic limitations on cancercells. Indeed cancer cells are frequently starved for nutrients and oxygen in distant organ environments due topoor vasculature. To endure unfavorable nutrient conditions during the metastatic cascade disseminated tumorcells require substantial metabolic rewiring that enables them to grow at the primary and metastatic sites.Additionally cancer cells metabolically interact with each other and with normal cell types or upregulatealternative pathways to overcome these metabolic limitations in their environment. Integration of nutrientavailability from the local environment with metabolic adaptation signatures in cancer cells is key tounderstanding how cancer cells interact with the surrounding cells and extracellular nutrients. Furthermore asre-population of cancer cells at a new organ site creates challenges for effective anti-tumor therapeuticstrategies there is an unmet basic and clinical need to better understand the molecular interplay between themetastatic site and tumor cells. Therefore in this proposal we will test the hypothesis that distant organ sitesimpose metabolic restrictions that cancer cells need to overcome for metastatic colonization. To address thiswe will employ a comprehensive unbiased approach that combines multiple genetic transcriptomic andmetabolomics techniques. These approaches will enable us to dissect the metabolic heterogeneity of cancercells and other cell types in distant organ sites. In the first aim we will systematically map metabolicdependencies of breast cancer cells during colonization of the lung and liver using CRISPR-based loss and gainof function approaches. In our preliminary work we have already identified potential candidates that are involvedin breast cancer metastasis to lung. In the second aim we will investigate the role of niche cells by combiningcell-specific metabolomics and single-cell sequencing approaches in multiple metastasis models and in responseto therapy. The Birsoy lab has recently pioneered the use of metabolism focused CRISPR screens to studymultiple aspects of cellular metabolism in cancer models. The Cao and Saeed Tavazoie labs have expertise insingle cell transcriptomics and computational biology. By integrating gene expression profiles and metabolomicinformation generated by this collaborative multidisciplinary effort our work will provide entry points for identifyingpathways that may be activated or repressed during the course of metastatic colonization and in response totherapy. +No NIH Category available Address;Adopted;Africa South of the Sahara;Cancer Burden;Cancer Control;Case Management;Cellular Phone;Cervical Cancer Screening;Clinic;Clinical;Cluster randomized trial;Collaborations;Communities;Community Health;Computerized Medical Record;Counseling;Country;Data;Data Collection;Decision Making;Development;Education and Outreach;Effectiveness;Electronics;Eligibility Determination;Ensure;Focus Groups;Future;Guidelines;Health;Health care facility;Health system;Healthcare;Human Papilloma Virus Vaccination;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human Resources;Individual;Information Management;Infrastructure;International;Intervention;Interview;Kenya;Knowledge;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Modeling;Morbidity - disease rate;Patient Education;Patients;Performance;Phase;Pilot Projects;Play;Prevention;Prevention program;Prevention strategy;Process;Program Effectiveness;Program Evaluation;Protocols documentation;Provider;Recommendation;Research;Research Design;Resource-limited setting;Role;Sampling;Services;Specimen;Surveys;System;Technology;Test Result;Testing;Time and Motion Studies;Training;Underserved Population;United States;Vaccination;Woman;Work;World Health Organization;acceptability and feasibility;age group;aged;arm;cancer risk;cervical cancer prevention;cost;design;digital;digital health;digital platform;effectiveness clinical trial;effectiveness evaluation;effectiveness trial;effectiveness/implementation design;effectiveness/implementation study;evidence base;experience;falls;follow-up;implementation determinants;implementation facilitators;implementation strategy;improved;innovation;low and middle-income countries;mHealth;mobile application;mortality;open source;prevent;prevention service;programs;prototype;randomized clinical trials;recruit;reproductive;risk perception;scale up;screening;screening program;tool;uptake;usability;volunteer mSaada: A Mobile Health Tool to Improve Cervical Cancer Screening in western Kenya Project NarrativemHealth may facilitate the wider introduction of human papillomavirus-based cervical cancer screeningprograms in low- and middle-income countries such as Kenya by supporting specimen and patient trackingpatient education service reminders and counseling support. We propose to develop and evaluate the impactof an integrated digital platform with a mobile application for use by community health volunteers (CHVs)building on a prototype developed to address gaps in CHV-led cervical cancer screening programs identified inprevious work in the region. The study will also help determine the impact of a mobile application to supportcervical cancer prevention services in Kenya as well as the personnel and infrastructure needs andimplementation strategy for scale-up and sustainability in similar low-resource settings. NCI 10688110 8/1/23 0:00 PAR-21-303 5R21CA274665-02 5 R21 CA 274665 2 "PEARLMAN, PAUL C" 8/22/22 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-HDM-J(56)] 8508113 "HUCHKO, MEGAN J" Not Applicable 4 OBSTETRICS & GYNECOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 160693 NCI 113840 46853 AbstractCervical cancer is the most common cancer among women in many low- and middle-income countriesincluding Kenya. This is mainly due to the lack of screening which remains the cornerstone of prevention forthe over one hundred million reproductive-aged women who fall outside the target age group or live incountries where the human papillomavirus (HPV) vaccination is not available. While HPV-based screening hasthe potential to be incorporated into simplified protocols the laboratory testing component requires programs tohave capacity to track specimens results and patient follow-up which can be a challenge in settings withlimited healthcare infrastructure and no electronic medical records. Further low baseline knowledge of HPVand cervical cancer risk in the community is associated with low rates of screening and follow-up makingeffective outreach and education a key component of screening programs. This work is often done bycommunity health volunteers (CHVs) with limited content-specific training. We propose to fill these gapsthrough an integrated digital platform that includes a mobile app (mSaada) that supports CHVs with patient andspecimen tracking and follow-up and counseling and protocol support. In the R21 phase of this project we will:(1) work with key stakeholders and local and international developers to finalize the mSaada platform buildingon the existing prototype to add patient and specimen tracking functionality; and (2) carry out a pilot study toidentify the patient provider and health system factors necessary to design a trial to evaluate mSaadaeffectiveness and implementation factors. We will carry out a six-month pilot in two health facilities providingHPV-based screening and use performance metrics including system usage rates workflow observations andqualitative data to guide the planning of a cluster-randomized clinical trial (c-RCT) to determine effectiveness ofmSaada. In the R33 phase of the project we will use a hybrid implementation effectiveness design to: (1)conduct an 18-month c-RCT across 12 health facilities to determine the impact of mSaada on cervical cancerscreening uptake treatment acquisition and cervical cancer knowledge levels among women in the community;and (2) measure the requisite implementation factors for mSaada effectiveness sustainability and scale-up.The rigorous study design will allow us to determine the clinical impact of mSaada ensure the local andregional infrastructure has the capacity necessary for sustainability and develop strategies for widespreadimplementation and scale-up. Collaboration with key stakeholders from the Kenya Ministry of Health willfacilitate the development of a long-term sustainability plan as the country moves toward HPV-based cervicalcancer screening. We anticipate the mSaada platform will play a pivotal role in facilitating the introduction ofHPV-based screening programs that can reach women in settings with limited health care infrastructure. 160693 +No NIH Category available ABCB1 gene;ATP-binding cassette transport;Active Biological Transport;Address;Agreement;Allografting;Antineoplastic Agents;Area;Binding;Biodistribution;Biological Models;Cancer Patient;Cancer cell line;Carrier Proteins;Cell Survival;Cells;Coculture Techniques;Cohort Studies;Coupling;Data;Development;Diffusion;Disseminated Malignant Neoplasm;Drug Efflux;Drug Transport;Drug resistance;Enzyme Tests;Enzymes;Exhibits;Extracellular Space;Goals;Immune;Immune response;Immune system;Immunocompetent;Immunomodulators;Immunotherapeutic agent;Immunotherapy;In Vitro;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methods;Modality;Multi-Drug Resistance;Mus;Outcome;Pharmaceutical Preparations;Phenotype;Predisposition;Process;Prodrugs;Progression-Free Survivals;RNA Interference;Reporting;Research;Resistance development;Specificity;Techniques;Testing;Therapeutic;Toxic effect;Treatment Efficacy;Tumor Escape;Tumor Volume;Work;acquired drug resistance;anti-cancer;anti-cancer therapeutic;cancer cell;cancer drug resistance;cancer immunotherapy;cancer therapy;cancer type;chemotherapy;conventional therapy;cytotoxic;drug metabolism;immune modulating agents;immunogenicity;in vivo;in vivo Model;inhibitor;mortality;mouse model;multidrug resistant cancer;nanomedicine;novel drug class;novel therapeutics;overexpression;programs;prostate cancer model;rational design;refractory cancer;side effect;small molecule;synthetic enzyme;tumor metabolism;tumor microenvironment;tumorigenesis Exploiting Cancer Metabolism and Drug Efflux with Bystander-Assisted Immunotherapy PROJECT NARRATIVE. The ability of cancers to develop resistance to chemotherapy is a longstanding problemthat causes significant mortality. Our research program develops a new class of drug that hijacks the metabolismof drug-resistant cancer cells causing the body's own immune system to recognize and clear the cancer. Weenvision that this technique could be developed into a new type of therapy that has both fewer side-effects thanconventional chemotherapy and enhanced efficacy relative to established immunotherapies. NCI 10688097 8/18/23 0:00 PAR-16-228 5R01CA234115-05 5 R01 CA 234115 5 "VENKATACHALAM, SUNDARESAN" 7/1/22 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-OTC-Y(55)R] 11515563 "MANCINI, ROCK " Not Applicable 8 CHEMISTRY 41065129 T6J6AF3AM8M8 41065129 T6J6AF3AM8M8 US 39.510303 -84.735381 1522802 MIAMI UNIVERSITY OXFORD OXFORD OH SCHOOLS OF ARTS AND SCIENCES 450561602 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 1 NCI 1 0 ABSTRACT. Two hallmarks of drug resistance in cancers are irregular metabolism and drug efflux. In multidrug-resistant cancers both of these processes disarm the efficacy of chemotherapeutics ultimately resulting in de-creased chemotherapeutic efficacy and increased mortality. Several strategies in development attempt to miti-gate the effects of drug resistance by modulating specific metabolic pathways or disrupting drug efflux. Specifi-cally these strategies include inhibitors interference RNAs and nanomedicine approaches. However a funda-mental challenge to these strategies is the off-target toxicity that arises from disrupting metabolism or drug effluxmediated by P-glycoprotein (P-gp) as these mechanisms are also critical to a number of healthy processesthroughout the body. To address this our long-term objective is to develop a therapeutic strategy that exploitsboth of these mechanisms of drug resistance in tandem to generate a therapeutic anti-cancer immune repsonse.Our central hypothesis is that rationally designed prodrugs can co-opt cancer cell metabolism and drug efflux tocause an anti-cancer immune response via a mechanism of action we have termed Bystander Assisted Immu-noTherapy (BAIT). In BAIT an enzyme-directed prodrug is first metabolized to an immunotherapeutic metaboliteby the irregular metabolism of multidrug-resistant cancer cells. Next the immunotherapeutic is transported viaP-gp-mediated drug efflux to the extracellular space. This results in the activation of bystander immune cells inlocal proximity which initiate an anti-cancer immune response. Because BAIT requires tandem metabolism anddrug efflux we anticipate a uniquely enhanced specificity for multidrug-resistant phenotypes that exhibit both ofthese processes. To develop rationally designed BAIT prodrugs we first identify small-molecule immunothera-peutics that are susceptible to drug efflux. In concurrent studies we also develop synthetic enzyme-directinggroups that modulate the activity of immunotherapeutics and are specifically removed by enzymes expressed inthe irregular metabolism of multidrug-resistant cancer cells. Combining these two research areas we generateenzyme-directed BAIT prodrugs that confer immunogenicity to multidrug-resistant cancers. In-vitro this is con-firmed in co-cultures of immune cells and cancer cell lines that express these metabolic enzymes and P-gp. In-vivo we use a murine model system for prostate cancer (TRAMP-C2 allograft) to demonstrate that BAIT pro-drugs result in lowered toxicity decreased tumor volume and increased progression-free survival relative toconventional immunotherapeutics in immunocompetent mice. Taken together we envision that this research willestablish BAIT as a therapeutic strategy that is enhanced rather than disarmed by drug resistance. It is ourlong-term vision that this strategy could be widely applicable to multidrug-resistant cancers that evade the actionof conventional therapies through altered metabolisms and drug efflux. 1 +No NIH Category available Acceleration;Adverse effects;Affect;Aftercare;Attention;Australia;Awareness;Benefits and Risks;Brain;Brain Neoplasms;Canada;Cancer Center;Cancer Patient;Child;Childhood Brain Neoplasm;Childhood Injury;Clinical;Cognitive;Costs and Benefits;Cranial Irradiation;Data;Decision Making;Deposition;Development;Disease;Dose;Education;Exhibits;Face;Family;Fatigue;Goals;Hospitals;Impact evaluation;Impaired cognition;Knowledge;Late Effects;Lead;Life;Longitudinal cohort;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Mediating;Medical;Methodology;Modality;Modeling;Neurocognitive;Neurocognitive Deficit;Normal tissue morphology;North America;Occupational;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology Group;Photons;Physicians;Population;Positioning Attribute;Process;Protocols documentation;Protons;Quality of life;Radiation;Radiation Toxicity;Radiation therapy;Research;Research Infrastructure;Risk;Sampling;Short-Term Memory;Site;Social Problems;Socioeconomic Status;Survivors;Symptoms;Texas;Time;Tissues;Toxic effect;Treatment Protocols;Treatment-related toxicity;Work;brain tissue;clinically significant;cognitive function;cohort;contextual factors;cost;daily functioning;design;disability;disorder control;experience;functional independence;functional outcomes;improved;member;multidisciplinary;neurodevelopment;neurotoxicity;predictive modeling;preservation;prospective;proton beam;radiation delivery;recruit;reduce symptoms;social;standard of care;survivorship;theories;treatment group;tumor;x-ray irradiation Comparison of Symptom Burden/Toxicity Neurocognitive Change and Functional Outcomes in Pediatric Brain Tumor Patients Treated with Proton vs. Photon Radiotherapy. PROJECT NARRATIVEMany consider proton beam radiotherapy (PBRT) to be a promising treatment for children with brain tumors asit may preserve cognitive functioning without sacrificing disease control. This will be the first large-scale studyto prospectively compare symptom burden treatment toxicity and neurocognitive change between patientstreated with PBRT vs. conventional photon radiotherapy on comparable treatment protocols and to assessimportant measures of daily functioning that will quantify the clinical significance of any differences identifiedbetween groups in survivorship. Ultimately this line of research is intended to: (1) help physicians and familiesbetter understand the relative effect of PBRT on symptoms and neurocognitive functioning to inform treatmentdecisions and (2) provide functional outcome data to be used toward justifying or reconciling the high cost andaccess limitations currently associated with PBRT. NCI 10688096 8/31/23 0:00 PA-19-056 5R01CA249988-03 5 R01 CA 249988 3 "SCHWEPPE, CATHERINE ANN" 3/1/21 0:00 8/31/26 0:00 Nursing and Related Clinical Sciences Study Section[NRCS] 8195518 "KAHALLEY, LISA SCHUM" "HINDS, PAMELA S; MABBOTT, DONALD " 9 PEDIATRICS 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 1278132 NCI 1017803 260329 PROJECT SUMMARY Most children treated for cancer in the US will achieve long-term survival and survivorship presents uniquechallenges for this growing population. Pediatric brain tumor survivors in particular are at risk forneurocognitive impairments educational difficulties social problems and medical disabilities. Cranial radiationtherapy is an essential lifesaving treatment but is associated with cognitive decline. Proton beam radiationtherapy (PBRT) is one of the most promising recent advances in pediatric brain tumor treatment. The proposedmedical advantage of PBRT lies in the precision of radiation delivery with proton beams depositing maximumdose to clinical targets while minimizing radiation to surrounding tissues. By reducing dose to healthy braintissue PBRT may spare cognitive functioning and reduce symptom burden better than conventional photon orx-ray irradiation (XRT) leading to greater functional independence in survivorship. Using a model-based accelerated longitudinal cohort comparison design we will compare symptomburden/toxicity neurocognitive change and functional outcomes at multiple data points from start of radiationthrough late survivorship in patients treated with PBRT versus XRT. The following aims are proposed: (1) tocompare symptom burden and toxicity by RT type in pediatric brain tumor patients and survivors (2) tocompare change in neurocognitive outcomes over time by RT type (3) to compare functional outcomes inearly and late survivorship by RT type and (4) to examine relations among symptom burden/toxicityneurocognitive function and functional outcomes as a function of RT type. This proposal is consistent with NCIs objective to reduce the long-term adverse effects of cancer and itstreatment in children and to improve the quality of life for cancer patients survivors and their families.Neurocognitive late effects lead to significant educational social and occupational limitations for manysurvivors greatly affecting their quality of life and functional independence long-term. Research is needed todetermine which treatments are best able to limit the suffering associated with symptom burden and post-treatment neurocognitive decline. Our results will have clinical value providing a timely comparison ofsymptoms neurocognitive changes and functional outcomes between PBRT and XRT groups that will guideclinicians and families on the range of outcomes to expect after PBRT. 1278132 +No NIH Category available Adaptive Behaviors;Automobile Driving;Autopsy;Award;Biological Assay;Breast;Cancer Patient;Cells;Clonal Evolution;Colorectal;DNA sequencing;Dedications;Development;Disease;Disseminated Malignant Neoplasm;Dysplasia;Endometrial;Epigenetic Process;Event;Evolution;Exhibits;Gene Mutation;Genetic Heterogeneity;Genetic Transcription;Glucose;Glutamine;Growth;Heterogeneity;Histologic;Human;Individual;Island;Knowledge;Lesion;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mentors;Mentorship;Metabolic;Nature;Neoplasm Metastasis;Neoplasms;Nutrient;Nutrient availability;Operative Surgical Procedures;Organ;Pancreas;Pancreatic duct;Pathology;Patients;Pattern;Phylogenetic Analysis;Primary Neoplasm;Process;Publications;Reproducibility;Research;Resected;Resolution;Resources;Sampling;Science;Scientist;Shapes;Site;Somatic Mutation;System;Technical Expertise;Time;Tissues;Training;Validation;Work;cancer cell;cancer genetics;career;cell motility;clinically relevant;computerized tools;deprivation;experimental study;fitness;genetic variant;glucose metabolism;human tissue;improved;interest;melanoma;metabolomics;migration;multimodality;novel;novel strategies;pancreatic cancer cells;pancreatic cancer patients;pancreatic neoplasm;patient derived xenograft model;programs;sample collection;single cell sequencing;single-cell RNA sequencing;skills;treatment and outcome;tumor Experimental evolution of pancreatic cancer PROJECT NARRATIVEThis proposal is dedicated to novel experimental and sequencing strategies to quantify pancreatic cancer evo-lution one aspect at a time. This approach has high potential for clinical relevance because the strategy seeksto resolve individual factors that drive the aggressive evolution of pancreatic cancer. Quantitatively definingthese influences will significantly improve efforts to intervene and circumvent this typically lethal cancer. NCI 10688093 8/10/23 0:00 PA-19-130 5R00CA229979-04 5 R00 CA 229979 4 "AULT, GRACE S" 9/9/19 0:00 7/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 10610378 "MAKOHON-MOORE, ALVIN " Not Applicable 5 Unavailable 42797571 LV8GL8MLU9A3 42797571 LV8GL8MLU9A3 US 40.883415 -74.055652 3117901 HACKENSACK UNIVERSITY MEDICAL CENTER HACKENSACK NJ Independent Hospitals 76011915 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 140599 108401 PROJECT SUMMARY/ABSTRACTThis proposal describes a training plan to develop my academic and scientific career focusing on the experi-mental evolution of pancreatic cancer. The award's purpose is to advance my scientific independence with aresearch program seeking to quantify multiple facets of pancreatic cancer evolution. During the K99 award pe-riod my mentor will be Dr. Iacobuzio-Donahue a world-expert in pancreatic cancer genetics evolution andpathology. Dr. Iacobuzio-Donahue has a well-established interest in cancer genetics and experimental strate-gies to define evolutionary patterns. My co-mentors will be Drs. Sohrab Shah and Dana Pe'er. Each has a longtrack record of mentorship many of the scientists and clinicians they have mentored have advanced to fruitfulacademic careers. In addition Memorial Sloan Kettering (MSK) will provide support and resources for conduct-ing the research outlined in this proposal including my training plan and successful transition to academic in-dependence.The research strategy of this proposal seeks to 1) enhance my scientific knowledge and technical skills relatedto tumor evolution and 2) develop a novel approach to isolate and quantify multiple facets of pancreatic can-cer. This work will also extend my scientific background from the phylogenetics of human tumors to experi-mental strategies and novel evolutionary patterns of cancer evolution. Specific Aim 1 seeks to quantify tem-poral dynamics of nutrient deprived pancreatic metastatic cells with real-time sampling and single cell sequenc-ing and Specific Aim 2 will define spatial diversity and migration of pancreatic cancer subclones using autopsytissues patient derived xenografts single cell sequencing and phylogenetic analysis. During the two-year K99period of this award experiments and sample collection for Specific Aims 1 and 2 will be completed. In the 3-year R00 award period validation experiments and sequencing analysis will be subsequently completed to de-termine the evolutionary dynamics of pancreatic cancer cells.The long-term objective of this proposed research is to better define various influences of pancreatic cancerevolution. The proposed experimental strategy has the potential to 1) quantify tumor evolution one aspect at atime and 2) replay evolutionary events to delineate reproducibility. Given the aggressiveness of pancreaticcancer new strategies like the proposed approach are urgently needed to quantify and thwart the evolutionaryinfluences driving this disease ultimately to improve patient treatment and outcomes. 249000 +No NIH Category available Affect;Age;Biological Assay;Biological Markers;Biometry;Biopsy;Biopsy Specimen;Blood;Caring;Cell Count;Clinical;Clinical Trials;Clinical effectiveness;Collection;Cutaneous Lymphoma;Cutaneous T-cell lymphoma;DNA;DNA Damage;Data;Dermatology;Diagnosis;Disease;Disease Progression;Epitopes;Fixatives;Formalin;Freezing;Future;Gel;Gene Expression;Genes;Goals;High-Throughput Nucleotide Sequencing;Histologic;Histology;Human;Immunology;Immunotherapy;Industrialization;Industry;Link;Malignant - descriptor;Measurement;Measures;Non-Hodgkin's Lymphoma;Nucleic Acids;Oncology;Pathology;Patients;Performance;Placebo Control;Procedures;Proteins;RNA;Randomized;Reproducibility;Reverse Transcriptase Polymerase Chain Reaction;Sampling;Skin;Specimen;T cell receptor repertoire sequencing;T-Cell Receptor;T-Cell Receptor Genes;T-Lymphocyte;Techniques;Temperature;Testing;Time;Tissue Banks;Tissues;cancer type;disorder risk;histological studies;indexing;innovation;lymph nodes;next generation;phase III trial;preservation;resiquimod;response;skin lesion;tissue processing;treatment response;tumor Optimizing pre-analytic sample handling for high throughput TCR sequencing in cutaneous T cell lymphoma Project NarrativeHigh throughput sequencing of the rearranged T cell receptor genes (HTS) is an approach that profiles T cellsin the tissue and has enhanced the ability to diagnose and manage patients with cutaneous T cell lymphoma(CTCL). However the formalin used to preserve skin biopsy specimens damages DNA and affects readings ina way that could lead to errors in patient diagnosis and care. We seek to identify new fixatives and tissue handlingprocedures that enable multiple different analyses to be accurately carried out on small skin biopsies obtainedin CTCL clinical trials including HTS readings histologic studies and measures of gene expression. NCI 10688079 6/2/23 0:00 PAR-18-947 5U01CA253190-04 5 U01 CA 253190 4 "RAO, ABHI" 9/1/20 0:00 5/31/25 0:00 ZCA1-RPRB-8(M2) 1879756 "CLARK, RACHAEL ANN" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 397067 NCI 237455 159612 Summary/AbstractHigh throughput sequencing of the rearranged T cell receptor genes (HTS) has transformed the diagnosis careand assessment of therapeutic responses in patients with cutaneous T cell lymphoma (CTCL) and this assay isbecoming the gold standard in CTCL clinical trials. HTS results are highly reproducible in frozen CTCL skinbiopsies but the formalin used to preserve skin biopsies in many clinical trials degrades DNA and affects HTSmeasurements potentially causing errors in patient diagnosis assessment of responses and choices of therapy.We seek to identify a single uniform tissue processing approach for small CTCL skin biopsies that will giveaccurate and reproducible HTS results support DNA RNA and protein measurements maintain excellenthistology and preserve remaining tissue for future measurement of emerging biomarkers. In Aim 1 we identifyoptimal tissue transport conditions and test non-cross-linking fixatives for their ability to support nucleic acidprotein and histologic studies on small skin biopsies. Aim 2 studies the effects of storage time and temperatureon nucleic acid integrity histologic performance and HTS readings and tests two approaches to mitigate theeffects of DNA degradation on HTS measurements. Aim 3 provides real world testing of our optimized samplehandling procedures using them to study skin biopsies obtained in the industry sponsored randomized placebo-controlled phase III trial of topical resiquimod gel in CTCL. Our overall goals are to establish new best tissuehandling practices for future clinical trials and to establish corrections that allow accurate analyses of existingspecimens. HTS is now frequently used in many cancer types to measure tumor T cell numbers diversity andresponses to immune therapies. The optimized tissue handling procedures we identify therefore have thepotential to be useful in many cancer types. 397067 +No NIH Category available Aftercare;Animal Model;Biological Markers;Blocking Antibodies;CD47 gene;Cell physiology;Cell surface;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Communities;Computer software;Consensus;Darkness;Data;Data Pooling;Development;Diagnosis;Disease;Eating;Elements;FDA approved;Goals;Growth;Healthcare;Histology;Hour;Image;Imaging Device;Imaging Techniques;Immunotherapy;Industry;Injections;Institution;Integral Membrane Protein;Intravenous;Investigation;Learning;Magnetic Resonance Imaging;Malignant Neoplasms;Maps;Methods;Monitor;Monoclonal Antibodies;Monoclonal Antibody Therapy;Multi-Institutional Clinical Trial;Necrosis;Neoplasm Metastasis;Operative Surgical Procedures;Outcome Measure;Patient-Focused Outcomes;Patients;Phagocytes;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Positioning Attribute;Prediction of Response to Therapy;Protocols documentation;Reference Standards;Reproducibility;Research;Research Personnel;Resources;SHPS-1 protein;Signal Transduction;Speed;Standardization;Testing;Therapeutic;Time;Translating;Tumor-associated macrophages;Work;anticancer activity;cancer cell;cancer clinical trial;cancer imaging;cancer immunotherapy;cancer therapy;chemotherapy;clinical application;clinical imaging;clinical investigation;clinical translation;co-clinical trial;comparative efficacy;design;efficacy study;ferumoxytol;first-in-human;imaging approach;imaging biomarker;imaging modality;imaging study;immunomodulatory therapies;improved;improved outcome;in vivo;interest;intravenous injection;iron oxide nanoparticle;iron supplement;mouse model;nanoparticle;neoplastic cell;next generation;novel;novel therapeutics;off-label use;osteosarcoma;patient population;pediatric patients;pre-clinical;preclinical imaging;preclinical study;predicting response;quantitative imaging;receptor;response;sarcoma;treatment response;treatment stratification;tumor;tumor eradication;tumor growth;tumor progression;uptake;web-accessible Co-Clinical Research Resource for Imaging Tumor Associated Macrophages PROJECT NARRATIVEOur project is designed to develop a quantitative imaging (QI) tool for monitoring tumor response to cancerimmunotherapies that activate tumor associated macrophages (TAM). We will optimize and validate pre-clinical QI methods for TAM imaging in established mouse models implement the optimized methods in a co-clinical trial and populate a web-accessible research resource with all the data methods and resultscollected from these investigations. Our TAM imaging resource will allow other investigators to evaluate theirown images with standardized protocols participate in centralized analyses of pooled data and generatenovel hypotheses for cancer immunotherapy response assessments. NCI 10688045 8/4/23 0:00 PAR-18-841 5U24CA264298-03 5 U24 CA 264298 3 "ZHANG, HUIMING" 9/15/21 0:00 8/31/26 0:00 ZCA1-SRB-X(M1) 8527084 "DALDRUP-LINK, HEIKE ELIZABETH" "RUBIN, DANIEL L" 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 639130 NCI 495546 280015 Co-Clinical Research Resource for Imaging Tumor Associated MacrophagesABSTRACTThe development of quantitative imaging (QI) methods for monitoring cancer therapy response hasbeen transformative for the development of novel cancer therapeutics. QI efforts have positioned imaging asa key element in the design of clinical trials for cancer therapy response assessment. Hence there isincreased interest by the academic and industry sectors to use web accessible research resources anddevelop consensus approaches to validate QI methods for the next generation of clinical trials. This isparticularly relevant for assessment of cancer immunotherapy since immunotherapy does not lead to adecrease in tumor size at least not in the immediate post-treatment phase. Therefore we urgently need newQI tools that can monitor tumor response to novel immunotherapies. The overall goal of our project is tooptimize and validate preclinical and clinical imaging techniques for in vivo quantification of tumorassociated macrophages (TAM) in osteosarcomas. Recent evidence has shown that the abundant TAMresponse in the microenvironment of bone sarcomas can be employed to directly attack cancer cells.Blockade of the cell surface molecule CD47 expressed on sarcoma cells resulted in activation of phagocyticanti-cancer activity from TAM and efficiently eradicated tumor cells in mouse models of osteosarcoma. 26Preclinical studies have been finalized and a multi-center phase I clinical trial is currently being planned withexpected start date in 2021. To solve the unmet clinical need for a QI tool to monitor response to new TAM-modulating therapies our team developed a quantitative TAM imaging test which relies on intravenousinjection of the iron supplement ferumoxytol. Ferumoxytol is composed of iron oxide nanoparticles which arephagocytosed by TAM and can be quantified with T2*-weighted MRI 45. Since ferumoxytol is FDA-approvedand can be used off label as a TAM biomarker it is immediately clinically available. We showed thatferumoxytol-MRI can detect TAM in osteosarcomas in mouse models 21 and patients 25. Through thisproject we will (a) optimize and validate pre-clinical quantitative imaging methods for TAM imaging inan established mouse model of osteosarcoma (b) implement the optimized methods in a co-clinicaltrial in patients with osteosarcoma who are undergoing immunotherapy with CD47 mAb and finally(c) populate a web-accessible research resource with all the data methods and results collectedfrom the co-clinical investigations. Developing the proposed imaging test could represent a significantbreakthrough for clinicians as a new means for treatment stratification and new gold-standard imaging test forpredicting treatment response of novel immunotherapies. Our QI imaging test could be utilized to comparethe efficacy of different immune-modulating therapies in preclinical settings and translate the most primisingcandidates to the clinic. Since the development of new therapeutic drugs is expensive and take years tocomplete the immediate value and heath care impact of our QI tool could be immense. 639130 +No NIH Category available Address;Adenosine;Adrenergic Agents;Affect;Agonist;Antigens;Anxiety;Apoptosis;Automobile Driving;Biological;Bone Marrow;CD8-Positive T-Lymphocytes;Cancer Patient;Catabolism;Cell Death;Cell Death Induction;Cell Death Process;Cell Line;Cell Maturation;Cell Survival;Cell physiology;Cells;Cessation of life;Chronic;Chronic stress;Clinical;Clinical Research;Coculture Techniques;Cultured Tumor Cells;Cyclic AMP;Data;Dendritic Cells;Distant;Dose;Enzymes;Event;Future;Generations;Genetic;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Guidelines;HMGB1 gene;Human;Immune;Immune response;Immunologic Stimulation;Immunologics;Impairment;Implant;In Vitro;Innate Immune Response;Irradiated tumor;Isoproterenol;Lead;Malignant Neoplasms;Measures;Mediating;Molecular;Mouse Strains;Mus;Necrosis;Neoplasm Metastasis;Neurotransmitters;Norepinephrine;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Phagocytosis;Physiological;Play;Process;Production;Proliferating;Propranolol;Publishing;Quality of life;Radiation;Radiation Dose Unit;Radiation therapy;Regimen;Research;Resistance;Role;Series;Signal Induction;Signal Pathway;Signal Transduction;Stimulator of Interferon Genes;Stress;Sympathetic Nervous System;T-Cell Activation;Technology;Testing;Time;Tumor Antigens;Tumor Cell Line;Tumor Immunity;adaptive immunity;adrenergic stress;antagonist;anti-tumor immune response;antigen detection;beta-adrenergic receptor;calreticulin;cancer cell;cancer therapy;cell injury;cell type;cytokine;experience;experimental study;genetic approach;immune activation;immunogenic;immunogenic cell death;improved;in situ vaccine;in vivo;interest;irradiation;knock-down;lymph nodes;migration;neoplastic cell;novel;pharmacologic;radiation effect;radiation resistance;radiation response;receptor;recruit;response;stress reduction;therapy resistant;trafficking;tumor;tumor microenvironment The impact of chronic stress on radiation induced cell death and the anti-tumor immune response NarrativeResistance to radiation therapy is a major clinical concern when treating patients with cancer and understandingthe biological mechanisms driving this process is an important next step in improving patient outcomes. The goalof this proposal is to define how chronic stress mediated by the sympathetic nervous system and -adrenergicsignaling induces tumor cell intrinsic resistance to irradiation and to determine whether these changes in tumorcell death affect key activators of anti-tumor immunity like dendritic cells. Ultimately the studies within thisproposal have the potential to define a novel mechanism of tumor cell mediated radioresistance lay thegroundwork for future clinical studies and improve patient outcomes. NCI 10688044 8/31/23 0:00 PA-21-050 5F30CA265127-03 5 F30 CA 265127 3 "BIAN, YANSONG" 9/1/21 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16279585 "MACDONALD, CAMERON RIKER" Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 321 "Training, Individual" 2023 52694 NCI 52694 0 Radiation Therapy (RT) is a common form of cancer treatment that can be effective in treating numerousmalignancies. Two key components of an effective RT regimen are a dose of irradiation that is sufficient to causetumor cell death and an innate immune response driven by dendritic cells and fueled by the debris from dyingtumor cells that goes on to activate anti-tumor adaptive immunity. Collectively this process has come to beknown as the in situ vaccine effect of radiation. Unfortunately for many patients a deficiency in one of these twokey components can occur from the onset of treatment or develop over time and result in resistance to RT. Forexample if an insufficient amount of tumor cell death occurs from a given dose of radiation not only will morelive cancer cells remain within the tumor but this lack of cell death will also ultimately limit the activation andrecruitment of adaptive immune cells. Without adaptive immune activation the remaining live cells within thetumor and potential metastases that could be present throughout the body can survive and proliferate. We havedetermined that chronic stress mediated by -adrenergic signaling is capable of inducing tumor cell resistanceto irradiation induced cell death in vitro and we have also determined that this same stress results in a subduedanti-tumor immune response generated from RT in vivo. The goal of this proposal is to resolve the mechanismthrough which adrenergic stress induces tumor cell radioresistance and to determine whether this change in celldeath is driving the immunologic changes observed in vivo in addition to the direct effects of stress on immunecells. To address these goals we will use pharmacologic and genetic approaches to induce or inhibit signalingcascades downstream of the 1 2 and 3-ARs and determine which receptor and which signaling pathwaysare responsible for the observed increase in tumor cell survival after irradiation. We will define how this signalingdrives survival by evaluating cell death pathways including apoptosis necrosis and necroptosis and determinewhether inhibiting this signaling also leads to a potentially more immune stimulating tumor microenvironment. Todo so we will assess cGAS/STING signaling and damage associated molecular pattern (DAMP) production(including ATP HMGB1 and Calreticulin) in vitro. Using a series of co-culture experiments where dendritic cells(DCs) are cultured with irradiated tumor cells experiencing varying levels of -AR signaling we will evaluatewhether changes in the radiation induced cell death processes described above affect DC maturation andfunction. In vivo we will utilize various -AR deficient mouse strains to evaluate whether increased -ARsignaling in tumor cells alone is sufficient to drive resistance to therapy and impaired anti-tumor immunity.Changes in DAMP production in vivo will also be evaluated. Taken together this project has the potential toproduce paradigm shifting discoveries which outline a new and important mechanism of radiation resistance thatis driven by the human physiologic response to chronic stress and anxiety -adrenergic signaling. Ultimatelythese discoveries could enhance the efficacy RT improve patient outcomes and increase patient quality of life. 52694 +No NIH Category available Ablation;Address;Adult;Affinity Chromatography;Animals;Antibodies;Automobile Driving;Basal cell carcinoma;Binding;Biochemical;Biological Assay;Biological Models;CRISPR interference;Cancer cell line;Cell Line;Cell Maintenance;Cell Proliferation;Cells;Childhood Brain Neoplasm;Cilia;Co-Immunoprecipitations;Congenital Disorders;Cryoelectron Microscopy;Data;Development;Disease;Erinaceidae;Family;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Homeostasis;Human Biology;Immunofluorescence Immunologic;Knowledge;LLC-PK1 Cells;Label;Ligand Binding;Lipid Binding;Lipids;Luciferases;Malignant Neoplasms;Malignant neoplasm of brain;Mass Spectrum Analysis;Mediating;Membrane Transport Proteins;Modeling;Mutate;Patch Tests;Pathway interactions;Patients;Pediatric Neoplasm;Peroxidases;Proteins;Proteomics;Recurrence;Regulation;Reporter;Signal Transduction;Signaling Molecule;Sterols;Structure;Surface;System;Testing;Time;Tissues;Tumor Suppressor Proteins;United States;Vertebrates;Western Blotting;Work;ascorbate;base;experimental study;functional genomics;hedgehog signal transduction;human disease;improved;innovation;insight;lipidomics;medulloblastoma;medulloblastoma cell line;migration;novel;novel therapeutics;prevent;programs;smoothened signaling pathway;spatiotemporal;stem cells;tool;transcription factor Understanding Patched1 protein and lipid interactions in cilia PROJECT NARRATIVEHedgehog signal transduction through primary cilia directs gene expression programs that are critical fordevelopment and adult tissue homeostasis. Patched1 is a tumor suppressor that inhibits ciliary Hedgehogsignaling but how Patched1 localizes to cilia and inhibits the Hedgehog pathway are unknown. To address theseunresolved questions the goals of this proposal are to define the proteins that are necessary for Patched1accumulation and activity in cilia and to determine if Patched1 inhibits Smoothened throughcompartmentalization of ciliary lipids. NCI 10688019 9/1/23 0:00 PA-21-049 5F30CA265147-03 5 F30 CA 265147 3 "DAMICO, MARK W" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F05-U(20)L] 15120558 "DAGGUBATI, VIKAS " Not Applicable 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACT Spatiotemporal regulation of signaling molecules is critical for development and adult tissue homeostasis. TheHedgehog pathway which is conserved across metazoan animals controls cell proliferation differentiationmigration and stem cell maintenance. In vertebrates Hedgehog signals are transduced through primary ciliathat project from the surface of most cells including cells in cancers that are driven by misactivation of theHedgehog pathway. The tumor suppressor Patched1 localizes to cilia and inhibits Smoothened a Hedgehogpathway activator. Upon pathway activation Patched1 leaves cilia and allows Smoothened to activate thedownstream Hedgehog transcriptional program. How Patched1 localizes to cilia and inhibits Smoothened remainunknown. The central hypothesis of this proposal is that a dynamic network of protein interactions allow Patched1to accumulate in cilia and regulate the ciliary lipid microenvironment to inhibit Hedgehog signal transduction. Totest this the objective of this proposal is to define the ciliary protein interactions necessary for localization ofPatched1 to the cilia and to determine if Patched1 regulates Smoothened by regulating the ciliary lipidmicroenvironment. To address the gaps in our understanding of Hedgehog signaling I will leverage recent technical advancesin proteomic proximity-labeling mass spectrometry lipidomic mass spectrometry and functional genomics usingnovel model systems I have generated for this proposal. In Aim 1 I will interrogate 5 protein interactors ofPatched1 that are associated with human disease and may underlie Patched1 accumulation and activity inprimary cilia. In Aim 2 I will define the impact of Patched1 on the ciliary lipid microenvironment. Combined theseaims will elucidate the biochemical mechanism by which Patched1 regulates Hedgehog signaling. Hedgehogpathway misactivation drives medulloblastoma the most common pediatric brain tumor and basal cellcarcinoma the most common cancer in the United States. Thus this proposal will incorporate Hh-associatedcancer cell lines to determine if ciliary proteins and lipids underlying Patched1 functions are conserved acrossdevelopmental and disease contexts. In sum understanding how Patched1 the most recurrently mutated genein Hh-associated cancers inhibits Hedgehog signaling will provide significant insights into human biology andpotentially provide avenues for novel therapies. 52694 +No NIH Category available Address;Adjuvant Therapy;Age;Age Years;Aging;Archives;Behavior;Behavioral;Behavioral Research;Biological;Biological Markers;Blood;Blood specimen;Brain;Cancer Etiology;Cancer Patient;Cancer Survivor;Cancer Survivorship;Caring;Cells;Cessation of life;Collaborations;Collection;Communities;DNA;Data;Data Analyses;Data Element;Databases;Diagnostic;Diet;Documentation;Educational Materials;Enrollment;Environment;Erythrocytes;Etiology;Fostering;Funding;Genetic Predisposition to Disease;Genomics;Genotype-Tissue Expression Project;Goals;Guidelines;Health;Health Policy;Incidence;Information Systems;Infrastructure;International;Life Cycle Stages;Life Style;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Mammography;Measures;Mediating;Medicare claim;Modernization;Multiple Cancer Sites;Neighborhoods;Nurses' Health Study;Nursing Research;Outcome;Participant;Patients;Phase;Phenotype;Physical activity;Plasma;Population;Process;Publications;Quality of life;Questionnaires;Recurrence;Registries;Research;Research Personnel;Resource Sharing;Resources;Sampling;Scientist;Serous;Specimen;Structure of nail of toe;System;The Cancer Genome Atlas;Tissue Banks;Tissues;Tumor Tissue;Update;Urine;Visualization;Woman;biobank;biological research;cancer epidemiology;cancer prevention;cancer risk;cancer site;cancer survival;cancer therapy;clinical practice;cohort;complex data;cost;data management;data resource;data sharing;data tools;data visualization;follow-up;genomic data;health data;human old age (65+);indexing;large datasets;middle age;mortality;multidisciplinary;neoplasm registry;neoplasm resource;novel;repository;research study;screening;tool;tumor;user-friendly;virtual Long Term Multidisciplinary Study of Cancer in Women: The Nurses Health Study NARRATIVEWe propose to continue the follow-up of the Nurses' Health Study (NHS) a Cancer Epidemiology Cohort of121700 women enrolled in 1976 at ages 30 to 55 years. Data include repeated measures of diet physicalactivity and other exposures over 42 years of follow-up as well as blood urine buccal cells and tumor tissuebiospecimens. Cohort follow-up is reaching the most informative phase for older ages and is a uniqueresource for scientific aims that integrate exposures over the life course including diet other lifestyle variablesbiomarkers genetic predisposition and mediating variables in relation to cancer risk and survival. A major aimis to foster greater widespread utilization of this resource. NCI 10688005 6/22/23 0:00 PAR-17-233 5UM1CA186107-10 5 UM1 CA 186107 10 "SIMONDS, NAOKO ISHIBE" 7/22/14 0:00 6/30/24 0:00 ZCA1-RTRB-Y(O1) 8692463 "ELIASSEN, A. HEATHER " "STAMPFER, MEIR " 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 1500747 NCI 896659 604243 ABSTRACTThis is a competing renewal of a UM1 application to support the infrastructure of the original Nurses HealthStudy (NHS) begun in 1976. The accumulated resources of NHS provide exceptional opportunities foridentifying new paradigms in cancer prevention etiology and survival. The resources encompass: lifestyle dietand health data from 20 biennial questionnaires spanning 4 decades from 121700 women; linked residentialdata on environment and neighborhood; blood samples from 32826 participants in mid-life; a 2nd blood andmorning urine in 18743 of these women 10 years later; buccal cells from 33040 women without blood; 62641toenail samples; 6027 pre-diagnostic mammograms; tissue blocks from >14000 patients across 16 cancers.The scientific contributions of NHS have been equally exceptional. During this funding periodaccomplishments include: >400 cancer-related publications; nearly 300 resource-sharing projects byexternal investigators and pooling projects/consortia (a 130% increase since 2014); and participation in33 cancer consortia including 22 NCI consortia. Most importantly NHS research has meaningfully guidednational and international cancer guidelines on issues ranging from diet to adjuvant treatment.Our overarching goals here are to (1) efficiently expand resources with collection of key new dataelements and specimens and (2) maximize the application and sharing of existing resourcesfacilitating their transformation into novel cancer discoveries. First NHS women are now >70 years ofage. Over 1/3 of cancers in the US occur after age 75 and half of cancer survivors are 70+ years. Manycancer phenotype distributions appear to change with age (e.g. serous ovarian cancer becomes morecommon). Moreover in the next 15 years the proportion of the US population >70 years will grow by 60%.Thus continued data and tumor tissue collection in NHS is critical to inform new behavioral and biologicalresearch on cancer etiology survival and quality of life in aging. Specifically in the next funding period we willcontinue to: collect questionnaire data on behavior quality of life and health in aging; document cancers/deaths; link with cancer and death registries and Medicare claims to enhance follow-up; maintain our bio-repository; collect new tissue blocks. Second we have had great accomplishments in data use/sharing butthis could be further increased to harness the brain-power of more cancer scientists. Mastering the largecomplex data systems with decades of accumulated data elements is a challenge that inhibits efficiency ofdata sharing. In the next funding period we propose to update and modernize our data systems to growsupport a large community of users via user-friendly tools for data management visualization and analysis.This will be done in an exciting collaboration with The Broad Institute which is leading and developing similarplatforms for The Cancer Genome Atlas the Genotype-Tissue Expression (GTEx) project and others. 1500747 +No NIH Category available Acceleration;Accelerometer;Adopted;Adult;Ankle;Behavior;Behavioral;Categories;Chronic Disease;Communities;Community Actions;Data;Development;Devices;Disease;Dose;Ecological momentary assessment;Ensure;Feedback;Goals;Head;Health;Health behavior;Hour;Human;Imagery;Intervention;Intervention Studies;Knowledge;Label;Light;Location;Measurement;Measures;Methods;Modeling;Monitor;Motion;Movement;National Health and Nutrition Examination Survey;Outcome Measure;Participant;Performance;Physical activity;Polysomnography;Posture;Procedures;Protocols documentation;Public Health;Publishing;Research;Research Personnel;Sampling Studies;Science;Sleep;Sleep Stages;Techniques;Time;Uncertainty;Validation;Wrist;actigraphy;biobank;epidemiology study;fitness;improved;interest;novel;novel strategies;response;sedentary lifestyle;surveillance study;tool;wrist worn device Accelerating the development of novel methods to measure 24-hr physical behavior Project NarrativeAccurate measurement of physical activity sedentary behavior and sleep is necessary to support newscience on behavior-related dose-response for major health conditions. We propose to develop novelmethods to measure 24-hour physical behavior as well as a procedure via which those methods can becompared to others. We aim to help the research community to converge on methods that use thedevices to accurately measure physical activity type and intensity sedentary behavior and posture andsleep in adults. NCI 10687994 9/1/23 0:00 PA-18-856 5R01CA252966-04 5 R01 CA 252966 4 "WOLFF-HUGHES, DANA L" 7/2/20 0:00 6/30/25 0:00 "Kidney, Nutrition, Obesity and Diabetes Study Section[KNOD]" 7667301 "INTILLE, STEPHEN S" "JOHN, DINESH " 7 NONE 1423631 HLTMVS2JZBS6 1423631 HLTMVS2JZBS6 US 42.340048 -71.088892 6116101 NORTHEASTERN UNIVERSITY BOSTON MA SCHOOLS OF ARTS AND SCIENCES 21155005 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 10340 NCI 450699 214453 Project Summary/AbstractAccurate measurement of human behavior using devices could significantly advance current knowledge on thedose-response relationships between chronic diseases and behaviors such as physical activity sedentarybehavior and sleep. The primary objective of this proposal is to develop valid approaches to measure 24-hourphysical behavior as well as to demonstrate a procedure via which those approaches can be compared toothers. We aim to help the research community to converge on methods that use devices to accuratelymeasure physical activity type and intensity sedentary behavior and posture and sleep in adults. Manypromising methods have been proposed to measure behavior from activity monitors. Unfortunately thesemethods which are now being proposed in large numbers are typically validated on small amounts of data.Thus they may perform well on lab data but fail when used in the field on large-scale epidemiological orintervention studies. Moreover the performance of different methods is rarely compared head-to-headcreating uncertainty for public health researchers about which are the best to use. Quantifying the relativeperformance of methods that produce similar outcome measures but use different devices or on-body devicelocations is even more unusual. We will make it easy for researchers interested in physical activitymeasurement to meaningfully compare performance between new methods and confidently apply thosemethods to both large-scale surveillance studies and longitudinal interventions. The project has four specificaims: (1) Collect well-annotated data of physical activity sedentary behavior and sleep (2) Use the data fromAim 1 to develop and validate approaches that yield 24-hour estimates of free-living physical activity (typeintensity) sedentary behavior (type posture) and sleep (wake/sleep stages) (3) Develop and incrementallyrefine a suite of tools that researchers can use to easily deploy advanced approaches to measure physicalactivity sedentary behavior and sleep even for large data and (4) Use the data and new approaches (Aims 1and 3) to host four competitions evaluating models where all entries submitted by other researchers will bedirectly compared ranked and improved. The goal is to help researchers converge on gold standard methodsto robustly measure physical activity using common monitor configurations as well as those devices andconfigurations likely to be used soon. 10340 +No NIH Category available Adoption;Advanced Development;Affect;Algorithms;Area;Benign;Benign Melanocytic Nevus;Biological Markers;Biopsy;Cellular Morphology;Clinical;Clinical Research;Collaborations;Collagen;Computer software;Connective Tissue;Cutaneous Melanoma;Data Analyses;Dermatology;Dermoscopy;Devices;Diagnosis;Discriminant Analysis;Disease;Early Diagnosis;Elastin Fiber;Electronics;Environment;Fluorescence;Generations;Germany;Histopathology;Image;Image Analysis;Imaging Device;Imaging Techniques;Interobserver Variability;Keratin;Label;Lasers;Lesion;Lesion by Stage;Maps;Mechanics;Medical Care Costs;Melanins;Melanocytic Neoplasm;Metabolism;Methods;Microscope;Microscopic;Modality;Molecular;Morphology;Motion;Nature;Negative Finding;Optics;Pathology;Patients;Performance;Physicians;Physiological;Reporting;Research Personnel;Resolution;Safety;Scanning;Side;Signal Transduction;Skin;Skin Tissue;Specific qualifier value;Speed;Standardization;Structure;Superficial Lesion;System;Technology;Testing;Time;Tissues;Training;Treatment Cost;United States;Universities;Validation;application programming interface;clinical imaging;cost;data acquisition;data standards;deep learning;ex vivo imaging;imaging detection;imaging platform;imaging study;improved;in vivo;in vivo imaging;indexing;industry partner;innovation;instrument;melanocyte;melanoma;metabolic imaging;multi-photon;multidisciplinary;multiphoton microscopy;non-invasive imaging;optical imaging;performance tests;portability;prototype;real-time images;restoration;second harmonic;software development;standard of care;submicron;temporal measurement;tool;translational study;two-dimensional;two-photon Fast large area multiphoton exoscope (FLAME) for improving early detection of melanoma Project NarrativeIn partnership with Vidrio Technologies and Tufts University we develop a fast large area multiphotonexoscope (FLAME) for clinicians as a powerful imaging tool for non-invasive real-time quantitativeassessment at the bedside that would not require specialized training. We integrate safety features establishimaging stability to physiological motion and then test the performance of this device by evaluating its ability toprovide in-vivo quantitative optical endpoints with sufficiently high predictive power to reliably distinguishbenign from early melanoma lesions. Completion of these studies will establish the practical utility and value ofFLAME as a non-invasive bedside tool for clinical skin imaging. NCI 10687990 8/24/23 0:00 PAR-20-155 5R01CA259019-02 5 R01 CA 259019 2 "MAZURCHUK, RICHARD V" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 10409019 "BALU, MIHAELA " "KELLY, KRISTEN M" 47 SURGERY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 605352 NCI 408363 196989 Project Summary Early detection of melanoma is a key factor in improving patient survival and decreasing treatmentcosts. The sensitivity of dermoscopy the standard of care in the diagnosis of melanocytic lesions wasreported to be highly variable ranging between 68-96% depending on the proficiency of the physician and thestage of the lesion. Low sensitivity reflects high rates of false-negative findings which delay diagnosis andtreatment. Thus doctors must err on the side of caution which leads to an excess of unnecessary biopsies andincreased medical costs. Distinguishing cutaneous melanoma from benign melanocytic nevi with high accuracybased on dermoscopy remains a challenge even when in the hands of expert clinicians since this approachonly offers a two-dimensional image of the lesion's superficial structure. Ultimately a biopsy is necessary fordefinitive diagnosis by the dermatopathologist but this too may be affected by inter-observer variabilityresulting in discordant conclusions. A study performed at the Melanoma Center at UCSF estimated that214500 to 643500 cases of melanocytic neoplasms in the United States would be diagnosed differently byanother dermatopathologist annually which has significant consequences for the patient regardless of thenature of the lesion. We propose to develop and clinically evaluate a fast large area multiphoton exoscope(FLAME) as a tool for non-invasive imaging and early detection of melanoma in order to reduce false positivesand false negatives in both dermoscopy and histopathology. Multiphoton microscopy (MPM) is a nonlinearoptical imaging technique that provides unique structural and molecular contrast based on endogenous signalssuch as second harmonic generation from collagen and two-photon excited fluorescence from NAD(P)H/FAD+keratin melanin and elastin fibers. In preliminary studies we demonstrated that macroscopic areas of skin(cm2 scale) could be mapped out with microscopic resolution within ~2 minutes by combining optical andmechanical scanning mechanisms with deep learning image restoration. As required by PAR-20-155 ouracademic-industrial partnership will deliver a powerful MPM imaging tool to clinicians for non-invasive real-time quantitative assessment at the bedside that would not require specialized training. Our proposedapplication is for early diagnosis of melanoma but the approach will have wider impact for rapid in vivocharacterization of cellular morphologic and metabolic imaging endpoints in patients. Our specifics aims are:(1) to develop FLAME a compact portable MPM prototype system for rapid depth-resolved in vivo imaging ofskin over macroscopic areas (cm2-scale) with microscopic resolution and enhanced molecular contrast; (2) toimplement safety features and demonstrate the technical feasibility; (3) to test the performance of FLAME byevaluating its ability to provide in vivo quantitative optical endpoints with sufficiently high predictive power toreliably distinguish benign from early melanoma lesions. We are a multi-disciplinary team of investigators fromUC Irvine Vidrio Technologies LLC and Tufts University with 3 to 8 years record of collaboration. 605352 +No NIH Category available Address;Animal Model;Bioinformatics;Biological;Biological Assay;Biological Process;Blood;Brain;Cancer Biology;Cancer Patient;Cell Death;Cell Survival;Cells;Cessation of life;ChIP-seq;Chemicals;Circulation;Clinical;Clinical Research;Co-Immunoprecipitations;Comet Assay;Country;Cultured Cells;Curative Surgery;DNA Damage;DNA Repair;Data;Development;Diagnosis;Disease;Epidermal Growth Factor Receptor;Epigenetic Process;Excision;Gamma-H2AX;Genome Stability;Genotoxic Stress;Goals;Growth;Human;Hypoxia;Immunofluorescence Immunologic;Immunohistochemistry;Immunotherapy;Impairment;In Vitro;Injections;Invaded;Ionizing radiation;KRAS2 gene;KRASG12D;Knowledge;Laboratories;Ligation;LoxP-flanked allele;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Methylation;Methyltransferase;Migration Assay;Mission;Modality;Modeling;Molecular;Monitor;Mus;National Cancer Institute;Neoplasm Metastasis;Newly Diagnosed;Non-Small-Cell Lung Carcinoma;Nude Mice;Pathway interactions;Patients;Platinum;Proliferating;Proteins;Quality of life;Reactive Oxygen Species;Research;Role;Series;Site;Solid Neoplasm;Stream;Stress;Systemic Therapy;TP53 gene;Techniques;Therapeutic;Tissue Sample;Tissues;Transcriptional Regulation;Ubiquitination;United States;Work;advanced disease;cancer survival;chemotherapy;demethylation;driver mutation;expectation;functional genomics;genomic biomarker;immune cell infiltrate;improved;in vivo;in vivo Model;inhibitor;knock-down;lung cancer cell;mortality;mutant;novel;preservation;prevent;response;small hairpin RNA;standard of care;synergism;therapeutic target;therapy development;transcriptome sequencing;tumor;tumor microenvironment Determining the Molecular Contributions of KDM2A in NSCLC Metastasis PROJECT NARRATIVE.Non-Small Cell Lung Cancer is the highest mortality cancer in the United States. In this project I willinvestigate how an epigenetic regulator KDM2A controls the metastasis of Non-Small Cell Lung Cancer tofacilitate development of new treatments for the disease. The proposed work is relevant to the mission of theNational Cancer Institute because it will provide a possible treatment for the country's deadliest cancer. NCI 10687982 8/22/23 0:00 PA-20-246 5F31CA261126-03 5 F31 CA 261126 3 "ODEH, HANA M" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 16606927 "KRAVITZ, CAROLYN " Not Applicable 3 PATHOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 32601 NCI 32601 0 PROJECT SUMMARY Non-Small Cell Lung Cancer (NSCLC) remains the highest mortality cancer in the United States withapproximately 70% of patients not eligible for curative surgical resection at diagnosis. Thus the advent ofnovel systemic therapeutics especially those which are efficacious for metastatic disease is of primaryimportance. A functional genomic screen conducted in our laboratory identified the H3K36 demethylaseKDM2A as a regulator of KRAS/P53 mutant NSCLC metastasis. KDM2A is known to also have roles in DNAdamage repair thus I hypothesize that KDM2A is important to preserving the genomic stability of NSCLC cellsby mediating genotoxic stress and to metastasis by controlling transcriptional responses to the tumormicroenvironment. The primary aims of this project are to elucidate the molecular mechanism by whichKDM2A promotes NSCLC proliferation/survival and to determine the steps of the metastatic cascade for whichKDM2A is important. To answer these questions I will leverage bioinformatic analysis functional mutants andanimal models. In Aim 1 I will use functional mutants of KDM2A to assay importance of each functionaldomain to proliferation and survival as well as assaying the impact of KDM2A loss on markers of genomicstress. In Aim 2 I will use in vivo models of metastasis to examine the molecular functions of KDM2A that areimportant to various steps of the metastatic cascade as well as using a variety of injection and assaytechniques to pinpoint the step(s) of the cascade at which KDM2A is important. The completion of this projectwill reveal the molecular mechanism of a novel potential clinical target of advanced NSCLC. My project iseasily translatable to clinical research as a research grade chemical inhibitor of KDM2A exists and could beoptimized for clinical deployment. 32601 +No NIH Category available Affect;Antibiotic Therapy;Antibiotics;Antibodies;Antitumor Response;Astrocytes;Biological Assay;Brain;Brain Neoplasms;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Central Nervous System;Control Groups;Data;Development;Endothelial Cells;Environment;Etiology;Frequencies;Genetic Models;Histopathology;Immune;Immune response;Immune signaling;Immune system;Immunity;Immunofluorescence Immunologic;Immunology procedure;Immunotherapy;In Situ;Incidence;Inflammatory;Inflammatory Response;Light;Malignant Neoplasms;Malignant neoplasm of lung;Mediator;Metastasis Suppression;Metastatic malignant neoplasm to brain;Microglia;Molecular;Mus;Myelogenous;Myeloid Cells;Neoplasm Metastasis;Neurons;Peripheral;Phenotype;Play;Prevention strategy;Process;Proto-Oncogene Protein c-kit;Regulation;Role;Shapes;Signal Transduction;Signaling Molecule;Spatial Distribution;Stains;T cell differentiation;T-Cell Depletion;T-Cell Proliferation;T-Lymphocyte;Therapeutic;Transgenic Mice;Transplantation;Tumor Promotion;Volatile Fatty Acids;anti-PD-L1 antibodies;brain behavior;brain remodeling;brain shape;brain tissue;cancer immunotherapy;cell type;clinical application;combinatorial;differential expression;dysbiosis;effector T cell;fatty acid supplementation;genetic signature;gut dysbiosis;gut microbiota;gut-brain axis;immune checkpoint blockade;improved;in vivo;insight;malignant breast neoplasm;melanoma;microbiota;mortality;mouse model;neoplastic cell;neutrophil;novel;patient prognosis;rational design;response;single cell analysis;treatment group;treatment strategy;tumor;tumor progression Dissecting Gut Microbiota Modulation on Brain Metastasis Progression PROJECT NARRATIVEThis study investigates the mechanisms by which the gut microbiota influences brain metastasis outgrowth.The specific aims of this project will evaluate the impact and functional significance of gut-derived signalingmolecules in brain metastasis outgrowth and cross-talk of brain-resident myeloid cells with peripherally-derivedmyeloid and T lymphocytes. Furthermore this study will also assess a clinically applicable therapeutic strategycombining microbiota modulation and immunotherapy to treat brain metastasis. NCI 10687978 8/22/23 0:00 PA-20-246 5F31CA261046-04 5 F31 CA 261046 4 "ODEH, HANA M" 9/1/21 0:00 9/30/24 0:00 Special Emphasis Panel[ZRG1-F09C-Q(20)L] 16257955 "GOLOMB, SAMANTHA M" Not Applicable 30 PATHOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 Project Summary/AbstractBrain metastasis is the development of secondary tumors within brain tissue which are typically derived frommelanoma lung cancer and breast cancer. The prognosis for patients with brain metastasis is devastatinglypoor with a median survival of less than six months. To reduce brain metastasis incidence and cancermortality rationally-designed therapeutic approaches targeting the mechanistic underpinnings of brainmetastasis progression is imperative. It is increasingly appreciated that the immune cells within the brain metastatic niche have indisputable andubiquitous roles in regulating brain tumor progression. Yet the regulation of CNS immunity by peripheral andsystemic factors during brain metastatic colonization and outgrowth are not completely understood. The gutmicrobiota composition plays a crucial role in regulating the hosts peripheral immune system correlates withanti-cancer immunotherapy efficacy and has a profound influence on brain behavior and function by reshapingthe brain immune niche. In this study we aim to identify how gut microbiota modulation reshapes the brainsimmune landscape and subsequently influences the metastatic niche and progression of brain metastasis.Antibiotic-induced gut microbiota dysbiosis led to a significant increase in brain metastasis burden in contrastto a vehicle-treated control group suggesting that gut microbiota dysbiosis remodeled the brain metastaticniche to a tumor-promoting environment. Using single-cell analysis we revealed compositional andtranscriptional differences of immune cells within the brain metastatic niche of mice with and without gutdysbiosis. These findings suggest that gut dysbiosis affects specific immune cell types to promote brainmetastasis outgrowth. Here we propose to dissect the roles of these immune cell types in promoting brainmetastasis outgrowth under gut dysbiosis conditions. Furthermore we will elucidate the spatial distribution ofeffector immune cells within the brain metastatic niche and functional impact of gut-derived signaling moleculesin brain metastasis outgrowth. Understanding the constituents and host-intrinsic regulators of the brainmetastatic niche shaped through gut-brain communication will guide the development of novel and feasiblebrain metastasis prevention strategies through gut microbiota modulation. 47694 +No NIH Category available 20 year old;Academic degree;Adolescent;Age;American;Area;Attention;Awareness;COVID-19 pandemic;Cancer Center;Cancer Patient;Career Choice;Cause of Death;Cessation of life;Child;Childhood;Clinical Research;Diagnosis;Disease;Disparity;Doctor of Pharmacy;Doctor of Philosophy;Early Diagnosis;Education;Electronic Mail;Epidemiology;Faculty;Family;Family Practice;Female;Fostering;Friends;Goals;Gynecologic;Health Occupations;Institution;Journals;Knowledge;Laboratory Research;Learning;Longterm Follow-up;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Medical;Medical Oncologist;Medical Students;Mentors;Minority;Oncologist;Oncology;Operative Surgical Procedures;Participant;Pediatric Oncologist;Pediatric Oncology;Peer Review;Persons;Physicians;Population;Prevention;Program Evaluation;Program Reviews;Publications;Publishing;Qualifying;Radiation;Research;Research Personnel;Research Project Grants;Saint Jude Children's Research Hospital;Science;Scientist;Series;Site;Students;Surgical Oncology;Surveys;Survival Rate;Techniques;Testing;Time;Translating;Underrepresented Minority;Underrepresented Populations;United States;Universities;Work;Writing;academic program;anticancer research;biomedical profession;cancer diagnosis;cancer education;cancer therapy;career;childhood cancer survivor;cohort;design;empowerment;experience;faculty mentor;improved;interest;meetings;minority student;pediatrician;pre-doctoral;programs;recruit;symposium;undergraduate student;urologic;virtual;web site PEDIATRIC ONCOLOGY EDUCATION (YEARS 38 - 42) The Pediatric Oncology Education (POE) Program gives students high quality contemporarycancer-related research experience introduces them to the latest pediatric cancer research andtreatment and encourages their pursuit of cancer-related careers. NCI 10687971 3/27/23 0:00 PAR-21-067 5R25CA023944-39 5 R25 CA 23944 39 "ELJANNE, MARIAM" 7/1/78 0:00 4/30/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1888706 "GRONEMEYER, SUZANNE A." Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 398 Other Research-Related 2023 432000 NCI 400000 32000 Pediatric cancer is the leading cause of death in childhood from medical conditions in the US. Thuspediatric cancer education is important for pediatricians and family medicine physicians so that cancer can bediagnosed early when it is most curable. Cancer research is vital to developing cancer cures. Since 1978 ourPediatric Oncology Education (POE) program has provided knowledge and experience to motivate promisingstudents to consider careers in cancer research and related areas. Particular attention is given to includingstudents from groups under-represented among oncology scientists and clinicians. Program participants areoutstanding pre-doctoral biomedical science and health professions students interested in oncology careers. All participants are US citizens or permanent residents who can be at St. Jude for either 10 weeks (medicalstudents) or 11 weeks (all others). They are matched with a St. Jude faculty mentor with similar researchinterests and participate in the mentors ongoing research program. They attend institutional researchconferences and a daily Lunch & Learn series designed specifically for them. They shadow an oncologist andobserve in surgery. They give a PowerPoint presentation on their research project in the Lunch & Learn seriesand submit a project manuscript written in the style for submission to a journal in which their mentor publishes. The POE program is advertised by our web site by email to over 6000 US university science faculty andcancer researchers at ~600 US universities and research institutions and by St Jude Academic Programsrecruiters at numerous major scientific meetings including the major under-represented-minority (URM)science student meetings. Each year about 500 students apply for the program. The 2019 acceptance ratewas 9.1% (49 of 537 applicants) and the class average undergraduate GPA was 3.8. Of the 286 participantsin 2015-2019 52 (18.2 %) were URM and 186 (65.0%) were females. Unfortunately the COVID-19 pandemicforced us to cancel our 2020 program. Our 2021 program will provide remote virtual research experiences. Ongoing evaluation of the program is provided by pre- and post-experience testing of the studentsknowledge of pediatric cancer and related areas and by post-experience surveys completed by all studentsand mentors. Experienced cancer educators from prominent cancer centers review the program as on-siteconsultants. We have long-term follow-up for 1354 (99.3%) of 1363 alumni. Of the 1151 alumni who havecompleted their academic degree work 991 (86.1%) hold a doctorate including 211 (79.9%) of the 264 URMin the cohort. Alumni include 55 PhDs 29 MD/PhDs and 5 PharmD/PhDs. Another 61 are currently in a PhDMD/PhD or PharmD/PhD program. POE alumni include 34 pediatric oncologists 18 medical oncologists 34surgical radiation or gynecological/urological oncologists and 12 medical physicists. 1997-2019 programparticipants are co-authors on some 440 peer-reviewed St. Jude publications. PI/PD Suzanne GronemeyerPhD is a Margaret Hay Edwards Medalist and a Fellow of the American Association for Cancer Education. 432000 +Biotechnology; Cancer; Clinical Research Affinity;Antibodies;Antibody Formation;Biological Assay;Clinical;Clinical Trials;Laboratories;Mass Spectrum Analysis;Measurement;Monitor;National Cancer Institute;Proteome;Proteomics;Reagent;anticancer research;base;pre-clinical research;programs;tumor Proteomic and Antibody Production and Characterization n/a NCI 10687911 75N91019D00024-P00003-759102000029-1 N01 9/25/20 0:00 9/24/25 0:00 77873750 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 6991846 NCI The National Cancer Institute (NCI)s Clinical Proteomic Tumor Analysis Consortium (CPTAC) comprises of an Antibody Program that comprehensively characterizes affinity reagents for cancer research via its Antibody Characterization Laboratory (ACL) located at the Frederick National Laboratory for Cancer Research (FNLCR) in Frederick MD. Within the ACL a Proteomic Characterization Laboratory (PCL) pilot is to be established for comprehensive Mass Spectrometry (MS)-based proteomic characterization (global- and phospho-proteomes) and targeted (fit-for-purpose) assays. 6991846 +Brain Cancer; Brain Disorders; Cancer; Clinical Research; Neurosciences; Pediatric; Pediatric Cancer; Rare Diseases Aliquot;Brain;Brain Neoplasms;Cancer Model;Childhood;Clinical;Clinical Data;Communities;Contracts;DNA;DNA sequencing;Data;Data Element;Diffuse intrinsic pontine glioma;Enrollment;Ensure;Funding;Generations;Genomic Data Commons;Infrastructure;Institutional Review Boards;Laboratories;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Normal tissue morphology;Operative Surgical Procedures;Parents;Patients;Policies;Process;Protocols documentation;Reporting;Resources;Sampling;Solid;Time;Tissues;Treatment outcome;Tumor Tissue;chemoradiation;data sharing;follow-up;human subject;programs;sample collection;transcriptome sequencing;tumor CANCER MODELS FROM PEDIATRIC BRAIN AND SOLID CANCERS (CMDC) n/a NCI 10687910 75N91019D00024-P00004-759102000035-1 N01 9/28/20 0:00 6/30/24 0:00 77878846 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 504803 NCI Under this contract the plan is to support the generation of ~90 pediatric NGCMs of which ~20 are from brain tumors including diffuse intrinsic pontine gliomas. It is expected that existing CMDCs are best poised to respond to this need as they have infrastructure in place for some of the process. Since the HCMI models materials and data generated under this project are considered Community Resources each laboratory has to ensure that all models delivered allow downstream use and distribution is unencumbered. The regulatory and technical requirements for this contract are listed below:1.The models will require a sufficient aliquot of the parent tumor tissue for DNA and RNA sequencing (~2ug each) and DNA from normal case-matched sample clinical data at the time of sample collection and at a minimum of 3 months follow-up once treatment (surgery chemo- radiation- or other- therapies) has been initiated. This latter depends on the proposed pipeline and will be finalized when the CMDC is funded.2.The list of the general clinical data is attached. In addition a number of pediatric cancer specifics clinical report forms are already available (see https://ocg.cancer.gov/programs/hcmi/resources) and additional cancer-specific data elements would be agreed upon for new types of tumors once a contract is initiated. It is essential that all required clinical data elements as annotated in the CRFs (https://ocg.cancer.gov/programs/hcmi/resources) are collected.3.The cancer models will be developed from tissue obtained under an IRB-approved human subjects protocol which informs the patient and their guardian about the project including the fact that these models: a.may be a perpetual resource b.the tumor as well as normal tissue will be sequenced c.clinical data will be collected including outcome of treatment 3 months or longer after enrollment d.the data sharing policy with data made available through controlled access at the NCIs Genomic Data Commonse.the models are distributed through a 3rd party f.the patients will not benefit from participating and g.results will not be shared with patients or their doctor. 504803 +No NIH Category available Address;Adult;Agreement;Algorithms;Animals;Bioluminescence;Blinded;Brain;Brain Neoplasms;Calibration;Canis familiaris;Catheters;Charge;Chemistry;Cholesterol;Clinical Research;Combined Modality Therapy;Convection;Custom;Data;Distant;Dose;Encapsulated;Enrollment;Glioblastoma;Glioma;Goals;Hour;Infusion procedures;Injections;Isotopes;Laboratories;Laboratory Study;Lipids;Liposomes;Luciferases;Malignant Glioma;Malignant neoplasm of brain;Methods;Modeling;Nanotechnology;National Cancer Institute;Normal tissue morphology;Operative Surgical Procedures;Organ;Pathologic;Patients;Pharmaceutical Preparations;Phase;Prospective Studies;Protocols documentation;Radiation;Radiation Dose Unit;Radiation therapy;Radioactivity;Radiobiology;Radioisotopes;Radionuclide therapy;Rattus;Reagent;Recommendation;Recurrence;Residual Neoplasm;Rhenium;Route;Safety;Scheme;Shapes;Site;Techniques;Testing;Therapeutic;Time;Tissues;Toxic effect;U251;United States Food and Drug Administration;Xenograft Model;absorption;animal data;aqueous;arm;chelation;chemotherapy;clinical development;cohort;efficacy evaluation;experience;experimental study;good laboratory practice;improved;lipophilicity;manufacture;mathematical model;nanoliposome;nanoparticle;novel therapeutics;open label;particle;phase 1 study;primary endpoint;radiation absorbed dose;radiological imaging;safety study;simulation;spatiotemporal;technology development;tumor Clinical Development of Rhenium Nanoliposomes (RNL186) for Glioblastoma PROJECT NARRATIVE186RNL is a new therapeutic which contains particle of radiation enclosed in a liposome. Animal data suggeststhis therapy will prolong survival in patients with brain tumors. This project will test in patients whether this newform of therapy is able to safely treat glioblastoma and improve patient survival. NCI 10687851 9/1/23 0:00 PAR-18-560 5R01CA235800-05 5 R01 CA 235800 5 "CAPALA, JACEK" 9/9/19 0:00 8/31/24 0:00 Clinical Oncology Study Section[CONC] 9487595 "BRENNER, ANDREW JACOB" Not Applicable 20 INTERNAL MEDICINE/MEDICINE 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 547212 NCI 463589 83623 Glioblastoma (GBM) is the most common and most aggressive of the primary malignant brain tumor in adultswith a median overall survival of 19.6 months following multi-modality therapy. The main limiting factor indelivering a tumoricidal radiation dose is the toxicity to surrounding brain. Therapeutic radionuclides due to ashort tissue path and differences in radiobiology have the potential to extend the therapeutic window for radiationin GBM. However a carrier is needed to deliver the isotope to the brain and maintain its localization at thedesired site as otherwise they quickly disperse. Liposomal encapsulation has the potential to facilitateradioisotope retention within the tissue but a method for the efficient loading of liposomes with the radioisotopeswas needed. This has been an essential limiting factor in the development of this technology and has now beensuccessfully addressed. To overcome this we have developed an encapsulation method using a customlipophilic molecule (BMEDA) that carries the rhenium radionuclides into the aqueous compartment of theliposome nanoparticles. The final investigational product is Rhenium nanoliposomes (186RNL).To characterize the retention tolerability and activity of 186RNL we performed intratumoral infusions of 186RNLin rats bearing glioblastoma tumors. Increasing doses as high as 30-fold typical external beam doses consistentlyshowed that animals tolerated all doses without evidence of harm and were associated with marked survivaldifferences. In addition many of the rats had no residual tumor. A toxicity study was performed in beagles with186RNL or blank control nanoliposomes and produced no significant changes systemically or in the brains of dogsat 24 hours or 14 Days. In order to further characterize the drug product and address chemistry manufacturingand control concerns of FDA we entered into a collaborative agreement with the NanotechnologyCharacterization Laboratory (NCL) of the National Cancer Institute (NCI). NCL was provided with manufacturingprotocols reagents and representative lots manufactured at the UTHSA. No significant difference was observedbetween RNL manufactured at the two sites and with marked stability of final product observed. The drug wascleared by the FDA to proceed to clinical study shortly thereafter. It is our specific hypothesis that 186RNL cansafely be administered to patients with recurrent progressive GBM at much higher radiation doses than can beachieved with current techniques and that treatment with 186RNL will markedly improve survival in GBM patients.Continued clinical development is warranted. We therefore propose to test the maximum tolerable dose and safetyprofile of 186RNL in patients with recurrent glioma determine the efficacy of 186RNL in recurrent glioblastoma andto develop and validate a mathematical model to predict the distribution of 186RNL. The immediate goal of thisAim is to use early time point patient-specific data to calibrate a mechanism-based model thereby allowing forthe accurate prediction of the distribution of 186RNL as a function of time. This model will be developed usingdata established in Aim 1 then used before delivery of 186RNL in the selection of the optimal point of injection inin Aim 2. 547212 +No NIH Category available Malignant Neoplasms;Molecular Molecular and Cellular Mechanisms in Cancer PROJECT NARRATIVEThe goal of this application is to continue a highly successful training program that has produced diverse andbroadly trained scientists over the last 15 years. This highly trained workforce of basic scientists andphysician/scientists will be at the forefront of cancer research in the coming decades and will assumeleadership roles to produce the scientific data to improve diagnosis survival rates and quality of life ofindividuals with cancer. NCI 10687834 8/31/23 0:00 PA-18-403 5T32CA108462-19 5 T32 CA 108462 19 "DAMICO, MARK W" 9/1/04 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1865459 "GOGA, ANDREI " Not Applicable 11 ANATOMY/CELL BIOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 558696 NCI 582584 45007 PROJECT SUMMARY!The objective of this training program is to provide post-doctoral fellows with didactic and research experiencein cellular and molecular aspects of cancer to prepare them for independent investigative careers in basic andtranslational cancer research. The program forms the core of cancer biology training in the Helen Diller FamilyComprehensive Cancer Center (HDCCC) at the University of California San Francisco (UCSF). The facultywho are all members of the HDCCC consists of basic researchers laboratory-based physician-scientists andmore applied clinician-investigators who share common interests in the multifaceted fields of cellular molecularand structural biology applied to the understanding of mechanisms of cancer initiation progression diagnosisand therapy. The areas of didactic and research training will expose trainees to a spectrum of approachesconcepts and opportunities from altered gene and protein structure and expression cancer microenvironmentand immunity cell cycling and signaling to differentiation and development. The goal of this approach is tofurther the understanding of cancer incidence and progression so that the trainees will have an appropriateperspective to approaching basic cancer research as well as to address prevention biomarkers andtranslation to patients. Post-doctoral trainees will join one of 37 research groups involved in studying thesebasic mechanisms. To broaden their experience the trainees will have secondary mentors and will beencouraged to seek out collaborations with other research groups at UCSF or outside. Because of thesignificance and need for training in Bioinformatics and Computational Biology for modern cancer research wehave initiated a workshop for our trainees taught by the Program faculty. Trainees will have access to all theacademic resources available at UCSF. In this way trainees will be provided with an in-depth researchexperience in an environment that covers the broad forefront of molecular and cellular dysregulation in cancer.Seminar programs research-in-progress discussions and journal clubs complement the research training.Trainees must have a Ph.D. or equivalent degree in cell or molecular biology genetics biochemistry or anapplicable discipline or an M.D. or M.D. Ph.D. The trainees will be selected on the basis of pastaccomplishments and promise course work grades achieved suitability for the research projects and acommitment to a research career. Trainees will receive a stipend for an average of 2 years but will be part ofthe program throughout their training period of at least 3 years. The program will consist of 8 traineescomplemented by the larger group of other trainees in the host laboratories to make a significant critical massof basic cancer researchers in the CCC. Upon completion of the program it is anticipated that the trainees willcontinue careers in basic and translational cancer research in academic institutions governmental agencies orthe biotechnology industry. 558696 +No NIH Category available Brain Neoplasms;Research;Training Programs Training Program in Translational Brain Tumor Research Project Relevance: Adult brain cancer continues to be a significant challenge to clinicians with over 20000cases diagnosed per year and the mortality rate still among the highest of all cancers. Because the prognosisfor individuals with the most common types of brain cancer remains poor it is of critical importance that newtherapies be developed. This proposal requests funds to support a training program that takes promising younginvestigators and trains them to understand brain tumor biology and therapy as an integrated whole. Investigatorstrained in this stimulating translational and comprehensive manner will provide competent leadership for futureresearch efforts aimed at improved treatments and outcomes for brain tumor patients. NCI 10687818 8/11/23 0:00 PA-18-403 5T32CA151022-14 5 T32 CA 151022 14 "DAMICO, MARK W" 9/1/10 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 6867892 "COSTELLO, JOSEPH F" Not Applicable 11 NEUROSURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 534382 NCI 564190 41714 Project SummaryThe objective of this program is to provide predoctoral and postdoctoral training for individuals interested incareers in translational brain tumor research. Despite the best efforts of neurosurgeons neuro-oncologistsand laboratory-based scientists brain cancer remains among the most deadly of all malignancies.Improvements in brain cancer therapy have come slowly in part because of the relative dearth of individualstrained in a manner that allows them to communicate with both clinicians and lab-based investigators. This isa renewal application for years 11-15 of the T32 Training Grant in Translational Brain Tumor Research at theUniversity of California San Francisco. The UCSF Brain Tumor Center is the largest program in the nationthat focuses on developing translational brain tumor investigators of the future; individuals who can moveseamlessly between clinical and laboratory worlds and in doing so can more effectively contribute to thedevelopment of new therapeutic interventions for brain tumors. We intend to build upon the training successesin the previous cycles maintaining the number of trainees and mentors. This application requests support fora postdoctoral and predoctoral Training Program (three postdoctoral trainees 1 predoctoral trainees). Thepostdoctoral trainees are selected from the labs and clinics of the faculty and the predoc trainee is drawn fromthe top-tier students in the Biomedical Sciences Program. The faculty of the Program consists of 23 mentorsand a core of 19 research labs whose work has made the UCSF brain tumor community one of the mostproductive and recognized in the world. Over the course of the two years of support requested the traineeswork with the PIs of these labs and clinics to develop and complete meaningful and significant translationalbrain tumor research projects and in the process become fluent in laboratory-based and clinical researchtechniques. The basic science trainees also have unique supervised experiences in clinical neuropathologyclinical neuro-oncology clinical trial design and a new neurosurgery experience component. At the same timetrainees take part in a faculty-led didactic curriculum uniquely focused on brain tumor-related issues and whichallow trainees to develop a common language with which to discuss and understand brain tumor biologydiagnostic and therapeutic modalities and unresolved problems in the field. Additional courses and trainingevents that encourage effective speaking and writing are included and there is an extensive selection ofexisting courses to help tailor the educational experience of individual trainees. Evaluation and mentoringmechanisms are included to help ensure success in the program and in attaining future career goals. TheUCSF T32 Program in Translational Brain Tumor Research has a strong track record of attracting well-qualifiedindividuals and in successfully preparing investigators to lead translational brain tumor research teamsnationally and internationally and joining in the fight against brain cancer. 534382 +No NIH Category available Address;Affect;African American;American;Anatomy;Awareness;Bar Codes;Biological Response Modifier Therapy;Biology;Cancer Patient;Cell Line;Cells;Development;Drug Exposure;Drug resistance;European;Evolution;Future;Health Services Accessibility;High-Risk Cancer;Hormones;Immune system;Immunocompetent;Malignant neoplasm of prostate;Metastatic Neoplasm to the Bone;Modeling;Molecular;Molecular Profiling;Molecular Target;Nature;Oncogenic;Organoids;Patients;Population;Prostate;Surveillance Program;System;Therapeutic;Tissues;Vision;androgen sensitive;cohort;effective therapy;high risk;in vivo;in vivo Model;mortality;participant enrollment;premalignant;targeted treatment;treatment response;tumor;tumor progression;tumorigenesis;tumorigenic Simulating Ancestrally Unbiased Tumor Evolution To Interrogate Drug Resistance PROJECT NARRATIVELarge molecular profiling cohorts of patient tumors are underrepresented for non-EuropeanAmerican patients and in vivo models rarely recapitulate molecular features or therapeuticvulnerabilities enriched in these tumors. Inspired by my own patients the centerpiece of thisproposal is the development of BRUTE (BaRcoded Unsupervised Tumor Evolution FIGURE) animmunocompetent organoid-based tumor graft system which faithfully recapitulates features ofnon-European American patient tumors. Using modified versions of this system we willinvestigate in an ancestrally unbiased manner how the anatomic niche affects drug resistancethe biology of future drug-resistant cells among the precancerous bulk population and how totarget molecular alterations enriched among non-European American patients. NCI 10687776 9/19/23 0:00 RFA-RM-22-019 1DP2CA290244-01 1 DP2 CA 290244 1 "GHOSH-JANJIGIAN, SHARMISTHA" 9/19/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RCCS-A(70)] 10910664 "BOSE, ROHIT " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/19/23 0:00 8/31/26 0:00 310 Non-SBIR/STTR 2023 1453500 OD 900000 553500 PROJECT SUMMARYAmong cancer patients of distinct ancestries there are molecular differences in the composition of their tumorsand their responses to therapies. These molecular distinctions extend well beyond germline differences andencompass somatic and non-mutational alterations as well. Compared to European-American patients African-American prostate cancer patients have a markedly higher risk of both developing and dying from prostatecancer. This mortality is related to inevitable drug resistance and often from bone metastases. Although access-to-care contributes there is also a higher risk of cancer progression for African-American patients enrolled inactive surveillance programs. Collectively there is evidence that molecular distinctions enriched among differentancestries can play a role in altering tumorigenesis and response to therapies.There are significant challenges in addressing the above. Large molecular profiling cohorts of patient tumorsare underrepresented for non-European American patients and there are only limited cell-lines derived fromsuch patients. We also need effective ways to rapidly model tumor evolution in vivo in an immunocompetentand hormone-sensitive manner to develop corresponding therapies that are biologically relevant.To address these significant challenges my central vision is to interrogate tumor evolution in an ancestrallyunbiased manner. This would enable us to identify powerful driver molecular alterations that are currentlyunderappreciated due to the limited nature of existing non-European American patient cohorts and also developeffective therapies against such tumors. Inspired by a subset of my own patients the centerpiece of this proposalis the development of BRUTE (BaRcoded Unsupervised Tumor Evolution FIGURE) an immunocompetentorganoid-based tumor graft system. The first proof-of-principle iteration of BRUTE tumors in an androgen-dependent prostate-tissue derived system strongly identified ERF and other underappreciated oncogenicalterations enriched uniquely among African-American patients.Using our tractable BRUTE system and orthologous approaches we will investigate in an ancestrally unbiasedmanner A) how the anatomic niche and immune system alter the selection of tumorigenic and drug-resistantcells B) the biology of the future drug-resistant cells among the precancerous bulk population and C) how totarget the molecular alterations that are enriched among non-European American patients.This is the first tumor evolution system of which we are aware that spontaneously recapitulates molecular driveralterations observed in underrepresented patient cohorts. Thus we can use it to ask: why are African-Americanprostate cancer patients more likely to die of bone metastases than European-American patients? Can wedetect and eliminate the future drug resistant cells in underrepresented patients tumors prior to drug exposure?And can we develop targeted therapies to exploit the molecular alterations observed in African-Americanprostate cancer patients? 1453500 +No NIH Category available Achievement;Anatomy;Bar Codes;Behavior;Biology;Cells;Development;Disease;Disease Progression;Engineering;Enterobacteria phage P1 Cre recombinase;Environment;Future;Gene Activation;Genetic Models;Genetic Recombination;Genetically Engineered Mouse;Goals;Head;Head of pancreas;Histologic;Human;Inter-tumoral heterogeneity;Lesion;Light;Link;Location;Malignant Neoplasms;Malignant neoplasm of pancreas;Methods;Modeling;Molecular;Mutation;Oncogenes;Oncogenic;Organ;Pattern;Phenotype;Positioning Attribute;Prognosis;Protein Engineering;Proteins;Regulation;Research;Specificity;System;Tail;Tail of pancreas;Technology;Tissues;Tumor Biology;Tumor Suppressor Proteins;anticancer research;clinical phenotype;clinically significant;human disease;in vivo;inducible Cre;insight;molecular phenotype;mouse model;novel;novel strategies;optogenetics;pancreatic neoplasm;recombinase;regional difference;screening;single cell sequencing;spatiotemporal;stem;targeted treatment;tumor;tumor heterogeneity Optogenetic engineering of tumor topography in native tissue environments Project Narrative: The anatomic site of tumor formation within a tissue is a major contributor to inter-tumoralheterogeneity. However understanding the mechanistic link between tumor topography and disease progressionhas been limited by the lack of genetic models that can recapitulate the spatial and phenotypic patterns of humandisease. Thus developing optogenetic based models to enable precise spatiotemporal in vivo control of tumorformation could overcome these limitations and facilitate future mechanistic studies into how local tissueenvironments influence tumor heterogeneity and enable development of targeted therapies. NCI 10687660 9/22/23 0:00 RFA-RM-22-019 1DP2CA290967-01 1 DP2 CA 290967 1 "JOHNSON, ERIC MICHAEL" 9/22/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RCCS-L(70)] 10936064 "MADDIPATI, RAVIKANTH " Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/22/23 0:00 8/31/26 0:00 393 Non-SBIR/STTR 2023 1437358 OD 876438 560920 Project Summary: In nearly every cancer tumors demonstrate a predilection for certain locations within a tissueand this is associated with unique clinical phenotypes. For example in pancreatic cancer lesions that arise inthe head of the pancreas have a better prognosis and favorable histological subtypes compared to thosedeveloping in the tail. Thus the anatomic position of a tumor within an organ can provide the context on whichmutations act to define clinical and molecular phenotypes. Despite the clinical significance the mechanisms thatdetermine regional differences in tumor phenotypes remains enigmatic. The overall goal of this proposal is todevelop novel approaches to gain mechanistic insights into how anatomic position directs tumor phenotypes. A major technical gap in our ability to interrogate tumor topography in disease progression is the lack ofrelevant genetic models that recapitulate spatial patterns and behaviors of human cancers. For examplepancreatic tumors can be readily generated in multiple murine models. However localizing tumor formation tothe head or tail of the pancreas is not possible. This stems from current tumor models that use Cre-recombinasetechnology to induce oncogenic transformation by activating oncogenes or deleting tumor suppressors in tissues.While tissue specificity can be achieved in some cases targeting Cre activity and by extension oncogenicmutations to specific anatomic locations in a tissue is not possible and limits spatial control of tumor formation. To overcome these limitations we propose to add a layer of spatial/regional control to tumor induction ingenetically engineered murine models (GEMMs). We accomplish this by developing and leveraging optogenetictechnologies for cancer research. Optogenetics involves introducing genetically encoded light sensitive proteinsto a cell that can be activated by light and enables spatially defined protein regulation in tissues. Here we proposeto engineer an optogenetic recombinase platform that allows for control of Cre activity with targeted light beamsto enable precise spatial and temporal control of tumor formation. Though risky we employ a systematic strategyto accomplish this. First we will combine protein engineering with in vivo barcoded screening methods to developa novel photoactivable Cre capable of eliminating background recombinase activity while maintaining robustrecombination with light. Second we will develop this construct into an optogenetic-Cre GEMM and optimizeparameters to enable precise gene activation at a regional and single-cell level. Finally we will integrate thissystem into Cre inducible oncogene models to generate tumors within defined anatomic locations andcharacterize their phenotypes and molecular features with single-cell sequencing technologies. The potential to control spatiotemporal patterns of tumor development in vivo would be a majorachievement in cancer research. This will transform our ability to model spatial patterns of human cancers andstudy the impact on tumor biology. Furthermore our technology could advance research beyond cancer as thebiology of many diseases are influenced by anatomic location but cannot be interrogated with existing models. 1437358 +No NIH Category available Automobile Driving;Binding;Binding Sites;Bioinformatics;Cell physiology;Cells;Complex;Consensus;DNA;DNA Binding;DNA Binding Domain;DNA Folding;Disease;Event;Gene Expression;Genes;Goals;Growth;Homeostasis;Immune response;In Vitro;Libraries;Logic;Malignant Neoplasms;Mediating;Molecular;Mutation;Nerve Degeneration;Pathologic;Play;Proteins;Regulation;Resolution;Role;Virus Diseases;cofactor;design;disease-causing mutation;human disease;in silico;interest;loss of function;novel;recruit;therapeutically effective;transcription factor Uncovering the regulatory logic of gene expression encoded by disordered regions Transcription factors are proteins that determine which genes are turned on or off in acell at any given moment. Mutations in transcription factors cause many diseases(notably cancer) yet because we often dont understand how these mutations influencetranscription factor function we generally dont have good ways to interpret why thesemutations cause disease. Here we have discovered a previously uncharacterized layerof regulation in transcription factor-mediated gene expression which we will dissect tobetter understand how mutations cause human disease. NCI 10687601 8/25/23 0:00 RFA-RM-22-019 1DP2CA290639-01 1 DP2 CA 290639 1 "AMIN, ANOWARUL" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RCCS-L(70)] 14073446 "HOLEHOUSE, ALEX S" Not Applicable 1 BIOCHEMISTRY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/26 0:00 310 Non-SBIR/STTR 2023 1399500 OD 900000 499500 Cellular state identity and function are primarily determined by the genes expressed at a givenmoment. Many diseases are characterized by dysregulation of gene expression leading toinappropriate gain/loss of function that can drive proliferative growth (cancer) impedehomeostasis (neurodegeneration) or rewire the immune response (viral infection). Limitations inour understanding of the complex pleiotropic and inherently adaptive molecular mechanismsthat underlie pathological changes in gene expression are a significant barrier to our ability todesign effective therapeutic strategies to alleviate these conditions.Eukaryotic gene expression is a coordinated event driven by an array of cellular processes.Among the various molecular components transcription factors are arguably the coredeterminant of expression. Transcription factors are modular proteins that possess DNA-specificbinding domains and facilitate the recruitment of additional co-factors that drive (or occasionallysuppress) gene expression. Our understanding of how the folded DNA binding domainsrecognize consensus DNA binding sites is relatively mature. In contrast we lag behind in ahigh-resolution understanding of other domains' various roles. Of particular interesttranscription factors are enriched for intrinsically disordered regions. These regions are oftenconsidered to play a role in driving gene expression as activation domains - regions thatdetermine the strength of gene expression. However both numerous high-throughput studiesand systematic bioinformatic analyses predict that on average only 15% of any giventranscription factor is strictly required for robust gene expression. This raises a question: what isthe remaining 85% of each transcription factor IDR doing?This proposal centers on the discovery that transcription factor IDRs play a second previouslyunappreciated role in coordinating gene expression. We will dissect this new role to decode theunderlying molecular logic. This will involve using rational sequence design to probe thesequence-determinants of gene expression through a novel library-based approach. This will becombined with in vitro and in silico analyses to disentangle the molecular basis for ourobservations. Our ultimate goal is to understand how the mutations that appear in transcriptionfactors IDRs can alter gene expression in non-intuitive and pathological ways. 1399500 +Biotechnology; Cancer; Cancer Genomics; Childhood Leukemia; Genetics; Health Disparities; Hematology; Human Genome; Minority Health; Pediatric; Pediatric Cancer; Rare Diseases Acute T Cell Leukemia;Apoptotic;BHLH Protein;Binding;Binding Sites;Biological;Bromodomain;CRISPR/Cas technology;Cancer Center;Cell Death;Cell Line;Cell Survival;Cells;Cellular biology;Chromatin;Clinical;Clinical Treatment;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complex;Computer Models;Data;Data Set;Development;Emu species;Epigenetic Process;Event;Family;Gene Expression Profiling;Genes;Genetic Transcription;Genome;Hematologic Neoplasms;Human;Human Cell Line;KDM5B gene;Knock-out;Lead;Lymphoma;Lymphoma cell;Malignant Neoplasms;Mediating;Mediator of activation protein;Mentors;Modeling;Mus;Mutagenesis;Mutation;Oncogenes;Oncogenic;Pathway interactions;Promoter Regions;Proto-Oncogenes;Regulation;Relapse;Repression;Research;Role;Sampling;Signal Transduction;Systems Biology;Testing;Tetanus Helper Peptide;Therapeutic;Time;Transcription Repressor;Transgenic Model;Transgenic Organisms;Tumor Suppressor Proteins;Up-Regulation;Xenograft procedure;acute T-cell lymphoblastic leukemia cell;bioluminescence imaging;c-myc Genes;cancer cell;cancer initiation;cancer subtypes;chromatin immunoprecipitation;comparative;experimental study;gene repression;genetically modified cells;genome-wide;histone demethylase;in vivo;inhibitor;member;mouse model;novel;novel therapeutic intervention;novel therapeutics;oncogene addiction;overexpression;programs;response;therapeutic target;transcription factor;transcriptome sequencing;treatment strategy;tumor;tumor progression;tumorigenesis;tumorigenic;vector KDM5B Mediates Cell Survival in MYC-Dependent T-ALL Project NarrativeThe transcriptional repressor KDM5B is silenced by c-MYC a transcription factor known to regulate asignificant portion of the genome and drives the development of many cancers. The opposing roles of KDM5Band MYC have not yet been studied and these experiments will determine the biological consequences ofmodulating KDM5B pathways in T-cell acute lymphoblastic leukemia (T-ALL). This research is translationaland will identify potential new therapeutic strategies for the clinical treatment of MYC-dependent T-ALL.! NCI 10687355 9/2/22 0:00 PAR-18-364 3K01CA234453-04S1 3 K01 CA 234453 4 S1 "VAHEDI, SHAHROOZ" 9/17/18 0:00 8/31/23 0:00 Career Development Study Section (J)[NCI-J] 8790729 "LIEFWALKER, DANIEL F" Not Applicable 1 GENETICS 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/1/21 0:00 8/31/23 0:00 398 Other Research-Related 2022 182925 NCI 169375 13550 Project Summary/Abstract Cancer is a complex landscape of aberrant cell signaling programs initiated by oncogenes. The causaloncogene drives the preponderance of accumulated mutations that enable tumorigenesis. Cancers arising thisway can be reliant on the initiating oncogene a term known as oncogene addiction. The proto-oncogene c-MYC is a transcription factor that regulates much of the genome and is deregulated in many cancers. Thetransgenic E-tTA/Tet-O-MYC mouse model of T-cell acute lymphoblastic leukemia (T-ALL) allows formodulation of c-MYC expression (ON vs OFF). When c-MYC is expressed T-ALL progression is observedand when c-MYC expression is revoked tumor regression occurs. Using cells and microarray data from this model we employed a nested effects model (NEM) that infershierarchical relationships anchored to master transcription factors that govern critical aspects of cell biology.We identified a critical node governed by a class of histone demethylases influencing transcriptional availabilityacross the genome. KDM5B/JARID1b is known as a transcriptional repressor and is downregulated in the T-ALL model when c-MYC is overexpressed. Using CRISPR/Cas9 mediated mutagenesis to disrupt KDM5Bexpression we observed a potent reduction in cell death when c-MYC expression is abrogated; suggestingKDM5B mediates cell death responses in T-ALL. The central hypothesis is that KDM5B acts as a tumorsuppressor in c-MYC-dependent T-ALL. We propose the following three aims to test this hypothesis. Aim 1 will determine if c-MYC directly suppresses KDM5B expression and whether this is critical in c-MYC-dependent T-ALL. Chromatin Immunoprecipitation (ChIP) of c-MYC at the promoter regions of KDM5Bwill identify whether direct regulation is required. Aim 2 will identify the mechanism through which KDM5Bregulates cell survival in c-MYC-dependent T-ALL. Using RNA-seq and ChIP-seq approaches we will uncovercritical c-MYC and KDM5B regulated gene programs and dissect the pathways unique to KDM5B. Aim 3 willdiscover how KDM5B influences tumor development in vivo. Genetically modified cell lines that over-expressKDM5B as well as KDM5B knockout cells will be injected into syngeneic hosts to determine KDM5B influenceon tumor development in vivo. Preliminary data suggests that lymphoma cells treated with the bromodomaininhibitor JQ1 undergo cell death only if c-MYC is downregulated and KDM5B is upregulated. Human T-ALLcell lines responsive to JQ1 will be injected into NOD-SCIDIL-2Rg-/- (NSG) mice and tumor progression will betracked by bioluminescent imaging (BLI). Additionally primary human lymphoma samples will be injected intoNDG mice and treated with the BET inhibitor JQ1. These studies are the basis of an independent research program and demonstrate a novel paradigm inunderstanding how c-MYC promotes tumor development through repression of a tumor suppressive epigeneticlandscape regulated by KDM5B and identify therapeutic options for treating c-MYC-induced T-ALL.! 182925 +Aging; Bioengineering; Biotechnology; Genetics; Human Genome; Precision Medicine 3-Dimensional;Adopted;Adoption;Aging;Antibodies;Aorta;Area;Atlases;Automation;Bar Codes;Biomedical Engineering;Cardiac;Cardiovascular system;Cells;Communities;Computer Analysis;DNA;Data;Data Set;Databases;Development;Devices;Discrimination;Disease;Embryo;Environment;Extracellular Matrix;Extracellular Matrix Proteins;Fluorescent in Situ Hybridization;Formalin;Freezing;Generations;Genes;Genomic approach;Glass;Head;Health;Heart;Histology;Human;Human BioMolecular Atlas Program;Human body;Image;In Situ;Individual;Injections;Kidney;Longevity;Manuals;Measurement;Messenger RNA;Methods;Microfluidics;Molecular;Morphology;Motivation;Mus;Nature;Organ;Organogenesis;Paraffin Embedding;Phase;Physiology;Preparation;Procedures;Process;Proteins;Proteome;Protocols documentation;Public Health;RNA;Research;Research Personnel;Resolution;Role;Sampling;Skin;Slide;Solid;Specimen;Spottings;Surgeon;System;Technology;Tissue Embedding;Tissue Sample;Tissue atlas;Tissue imaging;Tissues;Validation;Variant;base;cost;extracellular;genome-wide;high throughput technology;human data;human tissue;improved;interest;molecular imaging;monolayer;multiple omics;next generation sequencing;novel;novel strategies;paraform;process optimization;rheumatologist;scale up;single molecule;single-cell RNA sequencing;synergism;tissue mapping;tissue mosaicism;transcriptome;transcriptome sequencing;transcriptomics High-spatial-resolution ECM-inclusive multi-omics sequencing of human PFA and FFPE tissue slides PROJECT NARRATIVEThis project aims to develop a transformative technology for high-throughput high-spatial-resolution and high-content co-mapping of transcriptome and proteome in human PFA or FFPE tissue samples prepared usingstandard tissue histology process. It can be applied to a wide range of human tissues to generate the referencebiomolecular atlas of human tissues and organs rapidly and cost-effectively. It will improve our understanding ofaging or disease development throughput the life span and the health-disease continuum in the areas ofsignificant public health interest. NCI 10687349 9/6/22 0:00 RFA-RM-20-001 4UH3CA257393-03 4 UH3 CA 257393 3 "SRINIVAS, POTHUR R" 9/10/20 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-IMST-M(50)R] 9372328 "FAN, RONG " Not Applicable 3 ENGINEERING (ALL TYPES) 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT BIOMED ENGR/COL ENGR/ENGR STA 65208327 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 310 Non-SBIR/STTR 2022 600000 OD 358209 241791 SUMMARYThis project focuses on the accelerated development of a high-spatial-resolution sequencing technology for theco-mapping of transcriptomes and proteomes (hsrTP-seq) via deterministic barcoding in tissue which will bevalidated with paraformaldehyde(PFA)-fixed and formalin-fixed paraffin-embedded (FFPE) human tissuespecimens. This is a fundamentally new approach as compared to any existing spatial omics technologies. Thecore idea is to molecularly barcode RNAs proteins or other biomolecular information in tissues using a novelmicrofluidic in situ barcoding method. The tissue slide after barcoding remains morphologically intact butconsists of a mosaic of tissue pixels each of which has a distinct DNA barcode. The size of the pixels is assmall as ~5-10m which is close to the size of individual cells. It is built upon the power of Illuminas NextGeneration Sequencing (NGS) systems to achieve significantly higher sample high-throughput lower cost andthe elimination of laborious procedures for repeated single-molecule imaging as in seqFISH. It will demonstratehigh-spatial-resolution (~5-10m pixel size) high-throughput (up to 100 tissue samples flow barcoded per dayper operator) and high-content (genome-wide mRNAs proteins and non-cellular environment). Using a panelof DNA-tagged antibodies against extracellular matrix (ECM) proteins this approach further allows for spatialomics sequencing to include the mapping of non-cellular components which are completely missing in scRNA-seq or current spatial transcriptomics technologies. It is uniquely suited for mapping human collagenoustissues including heart aorta skin and kidney to improve our understanding of the role of ECM in normalphysiology disease and aging. We will pursue the following specific aims. In the UG3 phase we will develop aset of new devices to significantly increase the tissue mapping area (4mmx4mm) develop a proteome-scale(~500 proteins co-analyzed) and ECM-inclusive spatial sequencing and develop a novel tissue optimizationprotocol performed on the same tissue slide for hsrTP-seq and generate a set of 3D spatial transcriptome-proteome atlas data from human heart or aorta. In the UH3 phase we will further develop a multi-pin injectionhead to increase sample throughput (up to 100 samples per day) and the mapping area (1.2cmx1.2cm) forfurther scale up and automation develop a new in-tissue template switching method to retain intact tissuesection after hsrTP-seq for conducting other measurements on the same tissue slide and constructing 3Dtissue atlas and finally develop an optimized PFA and FFPE tissue protocol to generate the 3D multi-omicstissue atlas data (>20 tissue sections per sample) from the human heart aorta skin and kidney. 600000 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Prevention; Rural Health; Social Determinants of Health Address;American Indians;Benchmarking;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Clinical;Clinical Data;Clinical Protocols;Clinical Trials;Cytometry;Data;Development;Diagnosis;Direct Costs;Disease;Education;Enrollment;Environment;Environment Design;Foundations;Funding;Goals;Health Professional;Health Technology;Incidence;Intervention;Leadership;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Medical Research;Mission;Molecular Biology;Monitor;NCI-Designated Cancer Center;Nature;Newly Diagnosed;Oklahoma;Oncology;Pathology;Patient-Focused Outcomes;Patients;Peer Review;Physicians;Population;Prevention;Privatization;Protocols documentation;Reporting;Research;Research Design;Research Personnel;Research Training;Resource Sharing;Rural;Safety;Science;Secure;Services;Source;Statutes and Laws;Structure;Tissues;Training;Universities;base;cancer education;cancer health disparity;cancer prevention;cancer research center director;career;data management;high standard;mHealth;member;mortality;multidisciplinary;next generation;organizational structure;pre-clinical;programs;recruit;standard of care;translational cancer research;treatment research;treatment trial;underserved area Stephenson Cancer Center - Cancer Center Support Grant OVERALL PROJECT NARRATIVEOklahoma currently ranks 7th highest among all states for cancer mortality rates and 2nd in cancer incidenceand mortality rates among the 15 states currently without an NCI-designated cancer center. To address thiscancer burden the Stephenson Cancer Center serves as a major source of discovery into the nature of cancerand of the development of more effective approaches to cancer prevention diagnosis and therapy for thebenefit of patients in Oklahoma and the nation. NCI 10687301 8/24/22 0:00 PAR-17-095 3P30CA225520-05S1 3 P30 CA 225520 5 S1 "SHAFIK, HASNAA" 5/1/18 0:00 4/30/23 0:00 Cancer Centers Study Section (A)[NCI-A] 2488117 "MANNEL, ROBERT S." Not Applicable 5 OBSTETRICS & GYNECOLOGY 878648294 GY8NMUZQXVS7 878648294 GY8NMUZQXVS7 US 35.47459 -97.505034 1524003 UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR OKLAHOMA CITY OK SCHOOLS OF MEDICINE 731043609 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 397 Research Centers 2022 115000 NCI 79310 35690 OVERALL ABSTRACTOklahoma currently ranks 7th highest among all states for cancer mortality rates and 2nd in cancer incidenceand mortality rates among the 15 states currently without an NCI-designated cancer center. To address thiscancer burden the State passed bipartisan-supported legislation in 2001 directing the University of Oklahomato create an academic cancer center that would provide statewide leadership in cancer education preventiontreatment and research. Acting on this mandate the University established the Stephenson Cancer Center(SCC) a matrix-based academic cancer center with a mission of reducing the burden of cancer in Oklahoma acatchment area underserved by NCI-designated cancer centers. An essential partner in advancing this missionis the Oklahoma Medical Research Foundation (OMRF) the SCC's proposed consortium partner.Under the leadership of Robert Mannel MD who was appointed Director in 2006 the SCC has securedinstitutional and other commitments totaling $383.7 million of state university and philanthropic dollars over thepast ten years which have been used to recruit new cancer researchers and oncology physicians add newphysical space and develop formal research programs and new shared resources. The level of support for theSCC constitutes the largest public private biomedical initiative ever launched in the State and has resulted inan academic cancer center that has achieved the following benchmarks during the reporting period (CY2016): $18371115 in overall funding base (peer-reviewed cancer-relevant) (direct costs). $8981794 in NCI research and training funding (direct costs). $34234985 in total funding (direct costs). 96 full and associate members representing 32 different academic departments. 278609 sf. of total physical space (research clinical administrative). $33.1 million in annual discretionary funds under the control of the SCC Director. 2727 newly diagnosed and treated patients with 612 enrollments on interventional treatment trials.The SCC has developed an organizational structure and environment designed to promote transdisciplinaryteam-based science move ideas along the translational continuum and stimulate research that impacts theSCC catchment area. This structure includes three formal research programs: Preclinical Translational CancerResearch (PTCR) Gynecologic Cancers (GC) and Cancer Prevention and Control (CPC). SCC memberresearch is supported by four formal shared resource facilities: Biostatistics and Research Design MolecularBiology and Cytometry Research Tissue Pathology and Mobile Health Technology. Centralized ClinicalProtocol and Data Management Data and Safety Monitoring and Protocol Review and Monitoring functionsoversee and support the SCC's robust clinical trials program. 115000 +No NIH Category available Acetylcholine;Affinity;Animals;Antibodies;Antibody Affinity;Antibody Formation;Antigen Presentation;Antigen Targeting;Antigen-Presenting Cells;Antigens;Architecture;Area;Back;Biogenic Amine Receptors;Biological Sciences;Biomedical Research;Cell Surface Receptors;Cells;Central Nervous System;Chemistry;Clinic;Collection;Communities;Custom;Cytometry;Data;Data Set;Democracy;Detergents;Diagnostic;Directed Molecular Evolution;Docking;Dopamine;Elements;Engineering;Epinephrine;Evolution;Explosion;G-Protein-Coupled Receptors;Generations;Genes;Genetic;Histology;Human;Hybridomas;Image;Immune checkpoint inhibitor;Immune system;Immunization;Immunize;Immunoglobulin Fragments;Immunoprecipitation;Libraries;Machine Learning;Medical Research;Medicine;Methods;Modeling;Molecular;Molecular Biology;Molecular Conformation;Monoclonal Antibodies;Neurobiology;Neurosciences;Neurotransmitters;Nobel Prize;Outcome;Pathogen detection;Phage Display;Pharmaceutical Preparations;Pheromone;Play;Process;Production;Productivity;Proliferating;Protein Engineering;Proteins;Proteome;Public Health;Reagent;Research;Research Personnel;Role;Signal Transduction;Specificity;Speed;Surface;System;Techniques;Testing;Therapeutic;Training;Tube;Update;V(D)J Recombination;Western Blotting;Yeasts;addiction;antibody engineering;antibody libraries;antigen binding;biomarker discovery;cancer therapy;cost;crowdsourcing;decision research;design;empowerment;epidemic response;experimental study;follow-up;improved;in vivo;innovation;insight;interest;machine learning algorithm;machine learning model;nanobodies;new technology;novel;receptor;response;scaffold;structural biology;tool Making antibody generation rapid scalable and democratic through machine learning and continuous evolution Project NarrativeThis proposal will provide a system for the scalable continuous evolution and computational design of antibodies againstuser-selected antigens. Antibodies are critical tools in medical research and are the basis for numerous therapies but thegeneration of custom antibodies against new targets is a difficult and specialized task. The system proposed will turnantibody generation into a routine and widely accessible process for researchers in almost any field. NCI 10687279 8/3/23 0:00 RFA-RM-19-007 5R01CA260415-04 5 R01 CA 260415 4 "LI, JERRY" 9/10/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-BCMB-A(51)] 11610185 "LIU, CHANG C" "KRUSE, ANDREW ; MARKS, DEBORA S" 47 BIOMEDICAL ENGINEERING 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA BIOMED ENGR/COL ENGR/ENGR STA 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 310 Non-SBIR/STTR 2023 1667876 OD 1475922 191954 Project Summary/AbstractIt is hard to overstate the importance of monoclonal antibodies in the life sciences. Antibodies are critical tools in biomedicalresearch and diagnostics (e.g. western blotting immunoprecipitation cytometry biomarker discovery and histology) areone of the most rapidly growing class of therapeutics and are the basis for myriad new strategies in cancer therapy such ascheckpoint inhibitors that are revolutionizing treatment. Unfortunately current methods for the generation of customantibodies including animal immunization and phage display are slow costly inaccessible to most researchers and oftenunsuccessful. We propose Autonomously EvolvinG Yeast-displayed antibodieS (AEGYS) a system for the continuous andrapid evolution of high-quality antibodies against custom antigens that requires only the simple culturing of yeast cells. Webelieve this can be achieved by combining cutting-edge generative machine learning algorithms for antibody library designwith a new technology for in vivo continuous evolution and a yeast antigen-presenting cell that we will engineer. Ifsuccessful AEGYS should have a transformative impact across the whole of biomedicine by turning monoclonal antibodygeneration into a rapid scalable and accessible process where any lab with standard molecular biology capabilities cangenerate custom antibodies on demand simply by immunizing a test tube of yeast cells with an antigen. We anticipatethat this democratization of antibody generation will also result in an explosion of crowdsourced antibody sequence datathat will train our machine learning algorithms to design better antibody libraries for AEGYS starting a virtuous cycle. Weourselves will use AEGYS to generate a panel of subtype- and conformation-specific nanobodies against biogenic aminereceptors including those that respond to acetylcholine adrenaline dopamine and other neurotransmitters so that we canunderstand their role in neurobiology and addiction.! 1667876 +No NIH Category available Cancer Biology;Training Programs Training Program in Cancer Biology Project NarrativeCancer biology research within this institutional multidisciplinary training program is aimed at elucidating themolecular mechanisms responsible for initiation and progression of human cancer. Translational research isalso directed at improving diagnosis and therapies for this terrible disease and our training faculty havemade discoveries that have led to new cancer therapies. Both pre- and postdoctoral trainees participate inrigorous didactic as well as state-of-the-art laboratory and/or computational research training with theearliest cadre having now established academic careers in cancer research. NCI 10687218 8/15/23 0:00 PA-18-403 5T32CA078207-24 5 T32 CA 78207 24 "LIM, SUSAN E" 7/20/99 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1967818 "AARONSON, STUART A" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 662736 NCI 621422 41314 Project SummaryThe Icahn School of Medicine at Mount Sinai proposes to continue a highly successful Training Program inCancer Biology for 5 predoctoral students and 5 postdoctoral fellows. The planned duration is up to 2 yearsfor each predoctoral slot and up to 3 years for each postdoctoral slot. The projected number of individuals tobe trained over the proposed project period is 15 predoctoral and 10 postdoctoral fellows. Its leadership hasextensive experience in cancer research mentoring and a well-documented commitment to both graduateeducation and postdoctoral training. This institutional program encompasses training faculty from 6 basicand 4 clinical departments as well as 12 matrix institutes and involves laboratory and computationalresearch. The dynamic and interdisciplinary nature of the Program is evidenced by co- authored papersand multi-investigator grants. All faculty members have peer-reviewed R01 or R01-equivalent supportfrom funding agencies for cancer-related studies. The Program attracts and develops a cadre of outstandingPh.D. and M.D. Ph.D. students and postdoctoral fellows with our earliest trainees having establishedcancer-focused research careers at prestigious institutions. The curriculum for predoctoral andpostdoctoral trainees involves common elements including several new advanced didactic and multi-modalcancer biology courses and advanced electives which impart state-of-the-art training in emergingtechnologies critical to basic and translational cancer investigations. All trainees also participate inregular conferences which further expose them to clinical aspects of cancer. There are important specifictraining elements for each component as well. There is a rigorous evaluation and selection process andthe program is both cognizant of and actively involved in diversity recruitment. New components of theprogram also include additional training venues to specifically aid postdoctoral trainees in seekingacademic positions and a formal training faculty track in which promising junior faculty members mayapply with a training faculty member to co-mentor a highly qualified trainee an approach providingmentorship by the training faculty member both of the trainee and the faculty co-mentor. The program hascontributed importantly to the remarkable increase in cancer research and NCI funding over the pastdecade. Mount Sinai has also made enormous commitments in resources and facilities benefitting theProgram including support for specific elements by the Tisch Cancer Institute an NCI designated CancerCenter and the Department of Oncological Sciences. Trainees work closely with faculty drawn fromthroughout Mount Sinai ensuring that their training is both rigorous and sufficiently broad in scope totake into account practical issues faced by physicians in preventing and treating cancer. 662736 +No NIH Category available AIDS related cancer;Acceleration;Accounting;Address;Age;Aging;Biological;Biological Aging;Blood;Blood Cells;Cancer Burden;Cancer Center;Cancer Patient;Cancer Relapse;Cardiovascular Diseases;Cause of Death;Cessation of life;Chronic Disease;Chronology;Clinical;Clinical Management;Consent;DNA;DNA Methylation;Data;Development;Diagnosis;Disease;Ensure;Epigenetic Process;Evaluation;Evolution;Female;Future;Gait speed;Gastrointestinal Neoplasms;Gender;General Population;Genomics;Goals;Gynecologic;Gynecologic Oncology;HIV;HIV Seronegativity;Hematopoiesis;Hematopoietic stem cells;Immune System Diseases;Incidence;Individual;Inferior;Inflammation;Institution;Investigation;Knowledge;Life Expectancy;Link;Malignant Neoplasms;Measures;Modification;Monitor;Mutation;Neoplasm Metastasis;Oncology;Outcome;Patients;Persons;Prevalence;Process;Prognosis;Protocols documentation;Race;Recurrent disease;Refractory;Reporting;Risk Factors;Role;Sample Size;Sampling;Selection for Treatments;Site;Solid Neoplasm;Time;Translating;Tumor Tissue;Vital Status;Work;adverse outcome;age group;age related;anti aging;antiretroviral therapy;bead chip;biomarker identification;cancer complication;cancer diagnosis;cancer therapy;cohort;experience;follow-up;functional status;gastrointestinal;genomic biomarker;human old age (65+);improved;instrumental activity of daily living;male;men;mortality;mortality risk;next generation sequencing;novel;novel strategies;outcome disparities;programs;prospective;sample collection;tool;translational impact;tumor HIV Genomic Aging Project in Oncology (HIV-GAP) PROJECT NARRATIVEProposal Title: HIV Genomic Aging Project in Oncology (HIV-GAP)Patients with HIV (PWH) who are diagnosed with cancer have inferior outcomes compared to their tumorsite/stage-matched counterparts without HIV. Our preliminary data suggest that PWH and cancer experienceadvanced biological aging and that this accelerated aging may adversely impact prognosis. We thereforepropose a multi-institutional prospective investigation of the role of genomic biomarkers of aging as risk factorsfor adverse outcomes in 200 PWH and 200 matched HIV-uninfected cancer patients with the goal of identifyingbiomarkers that can guide tailored clinical management strategies to improve cancer outcomes in PWH. NCI 10687211 8/7/23 0:00 PAR-21-068 5R01CA268973-03 5 R01 CA 268973 3 "DOMINGUEZ, GERALDINA" 9/20/21 0:00 8/31/26 0:00 HIV Comorbidities and Clinical Studies Study Section[HCCS] 15721499 "COGHILL, ANNA " "GILLIS, NANCY " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 759346 NCI 500473 258873 ABSTRACT. People with HIV (PWH) experience higher cancer mortality and increased likelihood of cancerrelapse after initial therapy compared to HIV-uninfected cancer patients. Our prior work demonstrated that theseHIV-associated cancer outcome disparities persist after accounting for known risk factors. A novel approach toidentify targetable drivers of the poor cancer outcomes experienced by PWH is urgently needed to improveprognosis. We posit that cancer outcomes in PWH are negatively impacted by prolonged immune dysfunctionthat results in accelerated biological aging. Biological aging can be quantified using genomic biomarkers suchas DNA methylation translated into epigenetic clocks and presence of age-related clonal hematopoiesis (ARCH).The overarching goal of this proposal is to compare biological age measured using genomic biomarkersbetween cancer patients with versus without HIV and to quantify associations between measured biological agewith important clinical outcomes. Previous studies in PWH (without cancer) indicate that HIV-infected individualshave higher biological age calculated using blood-based epigenetic clocks compared to their chronological age.This accelerated aging was associated with increased mortality. ARCH has also been reportedly increased inPWH. ARCH is characterized by acquired mutations that expand over time in blood cells. Accumulation of thesemutations is linked to increased inflammation and adverse outcomes. Data suggest that ARCH may be twice asprevalent in PWH (without cancer) compared to HIV-uninfected persons. Thus there is evidence for a linkbetween HIV and advanced genomic aging in PWH (without cancer) which warrants exploration in the contextof cancer. To preliminarily explore our hypothesis we sequenced blood DNA from 30 solid tumor patients (15PWH and 15 HIV-uninfected) matched on chronological age. Our preliminary data indicate that genomic agingis more advanced in cancer patients with HIV. We observed significantly higher epigenetic-based biological agein the PWH. We detected ARCH mutations in 3 PWH but 0 HIV-uninfected patients. The median survival in PWHwas only 2 years compared to 9 years in HIV-uninfected patients; most striking was the <1-year median survivalin the PWH with ARCH. In this proposal we will utilize an established protocol at Moffitt Cancer Center andHuntsman Cancer Institute to prospectively collect biospecimens from 400 cancer patients (200 with and 200without HIV). The investigation is timely and compelling given that cancer is now a leading cause of death inPWH and incidence is increasing. We propose the following aims: 1) Compare the biological age of cancerpatients with versus without HIV using epigenetic clocks; 2) Compare baseline prevalence and therapy-relatedevolution of ARCH between cancer patients with and without HIV; and 3) Quantify the association betweengenomic biomarkers of aging and clinical outcomes including aging-related functional assessments. This studywill address the critical knowledge gap of whether cancer patients with HIV are biologically older than age-matched cancer patients without HIV and whether this advanced aging contributes to poor cancer outcomes. 759346 +No NIH Category available 20 year old;Accounting;Address;Adult;Age;Age Years;Amendment;Anatomy;Animals;Antibiotics;Anxiety;Biological;Biometry;Birth;Birth Weight;California;Cancer Control;Cancer Etiology;Carcinogens;Case Series;Case/Control Studies;Cessation of life;Characteristics;Chemicals;Child;Colorectal Cancer;Computerized Medical Record;Country;Data;Developed Countries;Development;Diabetes Mellitus;Diagnosis;Diet;Disease;Environmental Exposure;Epidemic;Epidemiologist;Epidemiology;Exposure to;Food Contamination;Foundations;Fright;Gastroenterology;Hereditary Neoplastic Syndromes;High birth weight infant;Hormones;Human;Incidence;Income;Individual;Interruption;Knowledge;Late-Onset Disorder;Life Style;Link;Literature;Malignant Neoplasms;Molecular;Nested Case-Control Study;Obesity;Pathologic;Pathway interactions;Pharmacoepidemiology;Physical activity;Play;Positioning Attribute;Prevention;Prevention strategy;Private Sector;Public Health;Public Sector;Quality of life;Race;Research Design;Risk;Risk Factors;Role;Sample Size;Sampling;Somatomedins;Study Subject;Subgroup;Symptoms;System;Testing;United States;Water;Weight Gain;age group;cancer diagnosis;cancer site;carcinogenesis;cohort;colorectal cancer risk;density;early life exposure;early onset;early onset colorectal cancer;early screening;early-onset colorectal carcinogenesis;ethnic diversity;experience;gut dysbiosis;gut microbiome;improved;in utero;insight;mRNA Differential Displays;novel;population based;prenatal;public health intervention;risk prediction;risk prediction model;screening;sedentary lifestyle;stem cells;trend;young adult A Case-Control Study to Evaluate Broad-Spectrum Antibiotic use and High Birth Weight as Potential Risk Factors for Early-Onset Colorectal Cancer Project NarrativeWe propose to investigate the effects of broad-spectrum antibiotic use and high birth weight on risk of early-onset colorectal cancer (eoCRC) leveraging a large eoCRC case series population-based controls andcomprehensive longitudinal electronic medical records. We expect our findings to advance knowledge oneoCRC etiology and inform novel prevention and targeted screening strategies. NCI 10687185 8/14/23 0:00 RFA-CA-20-004 5R01CA258160-03 5 R01 CA 258160 3 "MAHABIR, SOMDAT" 9/15/21 0:00 8/31/24 0:00 ZCA1-RPRB-8(M2)R 9170669 "CHAO, CHUN R." Not Applicable 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 360475 NCI 251838 108637 Project AbstractThe incidence of colorectal cancer in young adults under age 50 (referred to as early onset colorectal cancer[eoCRC]) has been rising by a striking 2% per year in the United States since the 1990s. Even more notably asignificant increase in eoCRC is experienced by every 5-year age group from as young as age 20 years. Theaccompanying human toll should not be understated considering the mirroring rise of deaths due to eoCRCand the loss in quality of life given that most eoCRC are diagnosed at advanced stages. Despite urgent needsto interrupt this trajectory factors responsible for the rise of eoCRC are unknown rendering the developmentof effective cancer control strategies difficult. This study seeks to shed light on eoCRC risk factors that maycontribute to the rising incidence of this disease directly addressing Provocative Question1 from RFA-CA-20-004: What are the underlying causes of the unexplained rising incidence in early-onset cancers? Evidencesuggests that eoCRC may be a distinct disease subset with differential key risk factors from late-onset CRC.To date studies that investigated eoCRC etiology remain sparse and they mostly focused on the role ofestablished risk factors for late-onset CRC such as obesity diet and physical activities. There has been ageneral lack of studies that evaluate the role of alternative risk factors such as those that involve gut dysbiosisand early life exposures in eoCRC etiology. To fill this critical gap we will test novel hypotheses on the roles ofbroad-spectrum antibiotic use and high birth weight in eoCRC etiology. Use of broad-spectrum antibioticsresults in intense and long-lasting gut dysbiosis which is strongly implicated in CRC carcinogenesis. Furtheranimal studies and recent epidemiologic evidence supports the role of broad-spectrum antibiotics as CRCcarcinogens. High birth weight likely reflecting altered in-utero programming of key hormone pathways such asthe insulin-like growth factor system and higher number of stem cells at risk for carcinogenesis has beenlinked to risk of other young-onset cancers and late-onset CRC. Further both broad-spectrum antibiotic useand high birth weight have been on the rise for decades preceding the rise of eoCRC. We will use apopulation-based nested case-control study design including ~1100 eoCRC cases diagnosed between 2009-2021 at Kaiser Permanente Southern California (KPSC) to carry out the following Specific Aims: (SA1) Testthe hypothesis that greater exposure to broad-spectrum antibiotics increases risk of eoCRC; and (SA2)Test the hypothesis that high birth weight increases risk of eoCRC. KPSC's unique strengths includelarge sample size comprehensive electronic medical records long-term membership retention and greatracial/ethnic diversity. At the completion of these aims we expect to (1) offer new insights into thecarcinogenesis of eoCRC; (2) facilitate the development of eoCRC risk prediction models; (3) inform targetedearly screening strategies; and (3) inform novel prevention strategies to amend this devastating epidemic. 360475 +No NIH Category available Address;Anthracenes;Autophagocytosis;Bacteria;Binding;Bioinformatics;Body Weight;Cancer Etiology;Carcinogens;Cell Line;Cell Proliferation;Cell physiology;Cessation of life;Chronic;Clinical;Crohn's disease;Data;Development;Diabetes Mellitus;Disease;Future;Gene Expression;Genes;Goals;Health;Hepatocarcinogenesis;High Fat Diet;Hyperglycemia;Hyperlipidemia;Incidence;Individual;Inflammation;Inflammatory;Innate Immune Response;Innate Immune System;Insulin Resistance;Liver;Liver neoplasms;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolism;Metformin;Methods;Mission;Mitochondria;Molecular;Monitor;Mus;Mutation;Natural Immunity;Obesity;Obesity associated liver disease;Pathway interactions;Pattern recognition receptor;Phosphotransferases;Predisposition;Prevention;Primary carcinoma of the liver cells;Principal Investigator;Process;Proteins;Public Health;Publishing;Regulation;Research;Risk Factors;Role;Role Concepts;STK11 gene;Testing;United States National Institutes of Health;adenylate kinase;biological adaptation to stress;cancer therapy;colitis associated cancer;diet-induced obesity;differential expression;dimethylbenzanthracene;experimental study;fatty liver disease;hepatocellular carcinoma cell line;in vivo;knock-down;lipid biosynthesis;liver cancer model;liver development;microbiota;mouse model;non-alcoholic fatty liver disease;obese person;obesity development;obesity prevention;obesity treatment;overexpression;programs;protein activation;pup;tumorigenesis;tumorigenic Role of Nod2 and AMP-kinase in obesity-associated liver cancer The current project will identify the role of innate immunity proteins in the susceptibility toobesity-dependent liver cancer in mice. The proposed research is relevant to publichealth because the current prevention and treatment of obesity and obesity-associatedliver diseases is inadequate and this research will allow future development of newprevention and treatment methods. This research is relevant to the part of NIH missionpertaining to the treatment and prevention of obesity and obesity-associated liverdiseases. NCI 10687174 8/9/23 0:00 PAR-20-052 5R03CA273471-02 5 R03 CA 273471 2 "LUO, RUIBAI" 9/1/22 0:00 8/31/24 0:00 ZCA1-TCRB-V(M1)S 8646661 "GUPTA, DIPIKA " Not Applicable 7 BIOCHEMISTRY 603007902 SHHBRBAPSM35 603007902; 625168166 DKNHLK3NBPH7; DL9MTNNKWYR9; GY8GKRUWM7D5; HA48EWMJFV47; HCNBFNDANNV5; HCRDU7BNPZ13; HCWTYJ7KQ4U6; HEBLAL94JHP7; NKCRSKVJBXE3; SHHBRBAPSM35; TA1NYNZ27LQ7; WJJRCLJ936C8; X51WYC1QEPD7; XNBJV454V2W1; YCJNP5NJYCY1; YW8WNKKANDR9 US 39.779213 -86.175288 577806 INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS INDIANAPOLIS IN SCHOOLS OF MEDICINE 462022915 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 79250 NCI 50000 29250 Liver cancer is one of the fastest increasing causes of cancer-related deaths in the U.S. andworldwide. There are approximately 700000 deaths worldwide each year due to liver cancer. Risk factorsfor liver cancer include nonalcoholic fatty liver disease diabetes and obesity and the rising incidence inthese diseases is paralleled with an increasing incidence in liver cancer. The development of hepatocellularcarcinoma the major subtype of liver cancer is a multistep process and often starts with chronicinflammation. However the molecular and cellular causes of inflammation remain poorly understood. Nod2 is a bacterial innate immunity protein and Nod2 deficiency is associated with inflammatorydiseases diet-induced obesity and metabolic dysfunction and obesity-dependent liver cancer. Preliminarydata using a mouse model for hepatocellular carcinoma predicts that the development of livertumorigenesis in Nod2-deficient mice on high fat diet (HFD) is associated with an inhibition of the AMP-dependent kinase (AMPK) pathway. AMPK is a master regulator of metabolic reprogramming and cellproliferation. However the role of the AMPK pathway in liver tumorigenesis in Nod2-deficient mice has notbeen demonstrated. In the current project the hypothesis that there is decreased activation of the AMPK pathway in Nod2-/-tumorigenic mice which contributes to the development of hepatic tumors in these mice will be tested. In Aim1 the role of Nod2 in the activation of the AMPK pathway will be determined. WT and Nod2-/- mice will betreated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD (DMBA+HFD) toinduce liver tumors and regulation of proteins in the AMPK pathway will be determined in the liver. In Aim 2the role of the AMPK pathway in the development of obesity-dependent hepatic tumors in Nod2-/- mice will bedetermined. Nod2-/- DMBA+HFD mice will be treated with metformin to activate AMPK and monitored for thedevelopment of hepatic tumors. The results from these experiments will provide proof-of-concept for the role ofNod2 in activation of the AMPK pathway and for the role of this pathway in protection from the development ofhepatocellular carcinoma and will provide preliminary data for future in-depth studies to determine themolecular basis of obesity-dependent liver cancer. 79250 +No NIH Category available Abstinence;Address;Adherence;Aging;Awareness;Behavior;Behavioral;Biochemical;CD4 Lymphocyte Count;Caring;Cause of Death;Cellular Phone;Characteristics;Cigarette;Clinic;Clinical;Clinical Data;Cognitive;Cohort Studies;Communicable Diseases;Community Healthcare;Counseling;Data;Depressed mood;Effectiveness;Enrollment;Exercise;General Population;Geography;Goals;HIV;HIV disparities;Health;Health Personnel;Health behavior;Hour;Immunologic Markers;Immunologics;Individual;Infection;Intervention;Knowledge;Malignant Neoplasms;Medical;Modeling;Moods;Motivation;Nicotine Dependence;Outcome;Participant;Patient Self-Report;Patients;Persons;Pharmaceutical Preparations;Pharmacotherapy;Pharmacy facility;Practice Guidelines;Prevalence;Process;Provider;Public Health;Race;Randomized;Randomized Controlled Trials;Readiness;Request for Applications;Research;Research Infrastructure;Research Personnel;Risk;Sampling;Self Efficacy;Series;Services;Site;Smoke;Smoker;Smoking;Smoking History;Societies;Stress;Telephone;Testing;Text;Text Messaging;Time;Tobacco Use Cessation;Tobacco use;United States Department of Veterans Affairs;Veterans;Veterans Health Administration;Viral;Voice;Wellness Program;Work;antiretroviral therapy;arm;care systems;co-infection;comorbid depression;comorbidity;compare effectiveness;data resource;design;evidence base;experience;follow-up;health care delivery;health disparity;health goals;immunological status;improved;indexing;innovation;interest;medication compliance;mortality;mortality risk;motivational enhancement therapy;motivational intervention;nicotine replacement;nicotine use;non-smoker;nutrition;pilot test;primary outcome;programs;prolonged abstinence;quitline;recruit;remote delivery;response;secondary outcome;skills;smoking abstinence;smoking cessation;smoking prevalence;standard care;stress management;substance use;theories;therapy design;treatment adherence;treatment comparison Improving the Reach and Effectiveness of Smoking Cessation Services Targeted to Veterans Living with HIV NARRATIVEPeople living with HIV are recognized as a priority group for targeting smoking cessation but standard carecessation treatments reach or benefit only a small proportion of these individuals. To address disparities inhealth outcomes and care for smokers living with HIV interventions are needed which can engage smokerswho are not yet ready to quit or seek treatment as well as to assist those ready to quit smoking. This projectwill compare the effectiveness of an HIV-specific comprehensive wellness intervention designed to have broadappeal to smokers living with HIV to the effectiveness of standard care services that include referral to theNational VA Quitline and SmokefreeVET texting program. Participants in both arms will have access topharmacotherapy available through their Veterans Affairs (VA) healthcare providers. NCI 10687166 9/7/23 0:00 RFA-CA-18-027 5R01CA243907-05 5 R01 CA 243907 5 "CICCOLO, JOSEPH THOMAS" 9/19/19 0:00 8/31/25 0:00 ZCA1-RTRB-U(A1) 8835480 "CROTHERS, KRISTINA ANNE" "CATZ, SHERYL L; MCCLURE, JENNIFER B" 9 Unavailable 928470061 DRRKVZVXSND3 928470061 DRRKVZVXSND3 US 47.562729 -122.308098 10004600 SEATTLE INST FOR BIOMEDICAL/CLINICAL RES SEATTLE WA Research Institutes 981081532 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 250000 NIMHD 221845 28155 PROJECT SUMMARY Tobacco use remains the leading preventable cause of death and illness in our society and smokingrates are disproportionately high among people living with HIV. NCI nicotine dependence researchers andHIV clinicians have all called for research to evaluate targeted and tailored smoking cessation programs forsmokers living with HIV (SLWH) leading to the current request for applications (RFA-CA-18-027). Researchsuggests SLWH are largely unaware of the HIV-specific deleterious effects of smoking and often lackmotivation and confidence in their ability to quit. For these reasons we developed the Wellness Intervention forSmokers with HIV (WISH). WISH is grounded in the Information-Motivation-Behavioral Skills (IMB) Model anddelivered remotely by mobile phone (voice and text message). The program is designed for all SLWHregardless of their initial motivation to quit. WISH follows evidence-based best practice guidelines for nicotinedependence treatment but is innovative in its use of a more comprehensive wellness approach. That is theintervention addresses both smoking and a number of other personally relevant health behaviors (such astreatment adherence stress/mood nutrition other substance use etc.) making it relevant and engaging to allSLWH not just those ready to stop smoking. For those not yet ready to quit WISH is designed to build andstrengthen motivation and self-efficacy for quitting while smokers also work on other personal health goals.Once ready to quit smoking participants receive evidence-based cognitive-behavioral counseling andencouragement to use nicotine replacement therapy (NRT) or other appropriate pharmacotherapy. WISHbuilds on our extensive experience creating motivationally-enhanced cessation interventions and has beenpilot tested with SLWH. In this trial we will compare the effectiveness of WISH to standard care servicesoffered through the National VA Quitline and the SmokefreeVET texting program NCI-supported tobaccocessation services available to all Veterans. Participants in both arms can receive phone/ text counseling andhave access to pharmacotherapy through VA. Primary outcomes will be biochemically confirmed 7-day pointprevalence smoking abstinence and presence of any 24-hour intentional quit attempts. Secondary outcomeswill include prolonged abstinence change in cigarettes per day intermediate change process outcomes basedon the IMB model as well as metrics of intervention reach and implementation. Consistent with RFA goals wewill also describe comorbidities and explore intervention impact on markers of immune status and mortality riskusing the outstanding clinical data resources available through the Veterans Aging Cohort Study (VACS). Ifeffective WISH could meaningfully reduce smoking among HIV+ Veterans nationwide. To support this goaldissemination efforts are planned in Year 5 to share the WISH program with the National VA Quitline. BecauseVA is the largest U.S. provider of HIV care this research has the potential for significant public health impact. 250000 +No NIH Category available 3-Dimensional;Address;Affect;Attention;Breast Cancer Detection;Cancer Detection;Cognitive;Cognitive Science;Data;Detection;Digital Breast Tomosynthesis;Digital Mammography;Educational workshop;Electroencephalography;Goals;Grant;Image;Imaging technology;Institution;Knowledge;Life;Malignant Neoplasms;Mammography;Medical Imaging;Memory;Mentors;Methodology;Methods;Mission;Modality;Multiple Abnormalities;Outcome;Public Health;Radiology Specialty;Research;Research Personnel;Research Technics;Screening for cancer;Screening procedure;Short-Term Memory;Techniques;Testing;Three-Dimensional Image;Three-Dimensional Imaging;Time;Training;United States;United States National Institutes of Health;Visual;Woman;Work;attentional bias;breast imaging;cancer diagnosis;cancer imaging;improved;innovation;malignant breast neoplasm;meetings;mental representation;neural;neuromechanism;novel;oculomotor;radiological imaging;radiologist;satisfaction;tomosynthesis;virtual;visual tracking Cognitive Science to Radiology: Using EEG and Eye-tracking to Determine Why How and When Novices and Radiologists Miss Signs of Breast Cancer in Multiple-abnormality Mammography and Tomosynthesis The proposed research is relevant to public health because it represents a novel way tocombine cognitive science research techniques with radiological imaging to determinefrom neural and oculomotor analyses the extent to which the detection of one cancerimpacts the detection of an additional cancer. It will also assess the impact thattomosynthesis compared to mammography and expertise has on multiple-abnormalitymiss rates in breast cancer detection. Thus the proposed research is relevant to thepart of the NIHs mission that aims to reduce illness and lengthening life by improvingearly cancer detection. NCI 10687151 8/21/23 0:00 PA-20-188 5K99CA267163-02 5 K99 CA 267163 2 "SCHMIDT, MICHAEL K" 9/1/22 0:00 8/30/24 0:00 Transition to Independence Study Section (I)[NCI-I] 15941369 "ADAMO, STEPHEN " Not Applicable 10 PSYCHOLOGY 150805653 RD7MXJV7DKT9 150805653 RD7MXJV7DKT9 US 28.601027 -81.197266 513805 UNIVERSITY OF CENTRAL FLORIDA ORLANDO FL SCHOOLS OF ARTS AND SCIENCES 328263231 UNITED STATES N 8/31/23 0:00 8/30/24 0:00 398 Other Research-Related 2023 125299 NCI 116018 9281 Satisfaction of Search (SOS) where an abnormality is missed after a previous abnormality was found is apervasive problem across different types of images yet their impact on breast cancer detection is un-known. Radiology and cognitive science have independently investigated why how and when SOS oc-curs. The objectives of this grant are to bridge cognitive science research techniques with radiology to de-termine: 1) the neural underpinnings of SOS 2) the extent to which SOS affects breast cancer detection3) the extent to which advancements in imaging technology alleviates SOS and 4) how expertise affectsSOS error rates. My central hypothesis is SOS contributes to breast cancer misses because a found ab-normality becomes an attentional template. An attentional template is known in cognitive science as anenhanced representation of a target maintained within memory and biases attention in search. The ra-tionale for this project is when a first target is detected it becomes an attentional template that utilizes andbiases attention necessary for detecting subsequent targets making searchers prone to SOS. HoweverSOS may be mitigated: 1) by changing search strategies to counteract a first target becoming an atten-tional template 2) with advances in imaging technology and 3) with expertise in breast cancer detection.These influences need to be investigated to determine the extent to which they can alleviate SOS. Thiswork will pursue four specific aims to test the central hypothesis: 1) identify a mechanistic account forSOS 2) determine the extent to which SOS accounts for breast cancer misses 3) compare SOS betweenmammography and tomosynthesis and 4) compare SOS error rates between different levels of expertise.The research proposed is innovative because it will: 1) identify a mechanism responsible for SOS; 2) useEEG and eye-tracking to study the neural basis of SOS; 3) use realistic virtual breast images to investi-gate the extent to which SOS affects breast cancer detection; 4) determine the extent to which the SOSresults from simplified search displays replicate in realistic-looking medical images; 5) be the first timeSOS is investigated with 3D imaging; and 6) determine the extent to which SOS rates vary by expertise inbreast cancer detection. The proposed research is significant because: 1) it will develop a neural under-standing of how SOS contributes to cancer detection; 2) determine how SOS varies across differentsearch modalities and by expertise; and 3) ultimately improve breast cancer detection by determining howthese influences impact SOS rates. To complete the proposed research in pursuit of his long-term goal ofbecoming an independent researcher at a Tier-I institution the PI will train using EEG and eye-tracking.His training will include auditing graduate courses attending workshops weekly meetings/training with hismentors and bi-annual assessments of his EEG/eye-tracking expertise with his mentors. 125299 +No NIH Category available 3-Dimensional;Address;Adverse event;Ascites;Biodistribution;Blood Circulation;Cancer Etiology;Cancer Model;Cause of Death;Cessation of life;Chemoresistance;Clinical;Data;Deposition;Development;Diagnosis;Disease;Dose;Drug Kinetics;Evaluation;Extravasation;Goals;Greater sac of peritoneum;Holmium;Human;Intravenous;Isotopes;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Methods;Modeling;Morbidity - disease rate;Mus;Neoplasm Metastasis;Nude Mice;Organ;Ovarian;Particle Size;Patient-Focused Outcomes;Patients;Peritoneal;Phase;Prognosis;Radiation;Radiation Dose Unit;Radiation exposure;Radiation therapy;Radioactive;Radioisotopes;Radiometry;Radionuclide therapy;Recurrence;Recurrent disease;Safety;Silicon Dioxide;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Therapeutic;Time;Tissues;Toxic effect;Toxicology;Tumor Burden;Tumor Tissue;United States;Woman;Xenograft Model;cancer therapy;chemoradiation;chemotherapeutic agent;chemotherapy;clinical development;dosimetry;effective therapy;efficacy evaluation;efficacy study;improved;in vivo;in vivo Model;internal radiation;intraperitoneal;mortality;mouse model;nanocarrier;nanomedicine;nanoparticle;nanoparticle delivery;physical property;pre-clinical;programs;radiochemical;side effect;stoichiometry;success;systemic toxicity;targeted delivery;technology development;treatment strategy;tumor Nanoparticle-based Intraperitoneal Delivery of Combined Chemo-radiotherapy for Treatment of Ovarian Cancer Metastases PROJECT NARRATIVEOvarian cancer is the fifth most common cause of cancer-related death among women. Current treatmentoptions are often ineffective as highlighted by the high recurrence and chemoresistance rates. NamiTherapeutics is developing an improved treatment option for late-stage ovarian cancer that involves targeteddelivery of nanoparticles that contain a radiation-emitting isotope called holmium-166. The treatment is tumor-specific which reduces side effects and can be used with current chemotherapeutic agents. Successfuldevelopment of the technology has the potential to greatly enhance patient outcomes. NCI 10687104 9/1/23 0:00 PA-21-259 5R44CA239989-03 5 R44 CA 239989 3 "POND, MONIQUE ADRIANNE" 9/11/19 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-OTC1-R(11)B] 8177120 "JAY, MICHAEL " Not Applicable 2 Unavailable 81126078 KNJLDH2XCWG6 81126078 KNJLDH2XCWG6 US 41.795253 -72.264022 10051877 NAMI THERAPEUTICS CORP. STORRS CT Domestic For-Profits 62682013 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 SBIR/STTR 2023 971041 NCI 737068 171457 PROJECT SUMMARYOvarian cancer is the second most common gynecologic cancer in the United States and the most commoncause of death among women with gynecologic malignancies. Despite advances in treatment strategiesperitoneal metastasis remains the primary cause of morbidity and mortality in ovarian cancer. Recent studieshave suggested that treatment of peritoneal metastasis through intraperitoneal (IP) delivery of therapeutics canimprove patient outcomes; however there are currently no effective IP-delivered therapies for addressingperitoneal metastasis especially for chemoresistant and recurrent patients. Nami Therapeutics (Nami) isdeveloping an IP-based delivery treatment option for late-stage ovarian cancer. Namis approach involvesholmium-166 (166Ho)-containing mesoporous silica nanoparticle (166Ho-MSN)-based radionuclide therapy. 166Ho-MSNs present a unique approach for treating advanced ovarian cancer in the form of a tumor-specificradioisotope-containing nanocarrier for internal radiation therapy. Using IP administration 166Ho-MSNs will bedelivered directly to the peritoneal cavity where they specifically target tumor tissues limiting radiation exposurethroughout the body via blood circulation and in turn limiting systemic side effects that are common to othernanomedicines and chemotherapeutic agents delivered intravenously. Nami successfully completed a Phase ISTTR program that demonstrated (1) enhanced survival in a mouse model of ovarian cancer by treatment with166Ho-MSNs alone and in combination with chemotherapy; and (2) a favorable safety profile of non-radioactive165Ho-MSNs in tissues and in systemic toxicity assessments. The Phase I data package supports furtherdevelopment of the technology through a Phase II program that has a goal of generating a data package tosubmit to the FDA to support of clinical development. Specifically Aim 1 will involve efforts to generateregulatory-compliant holmium-containing nanoparticles. Aim 2 will focus on generating a target product profilethrough the execution of in vivo efficacy studies and Aim 3 will involve the execution of critical toxicity biokineticand dosimetry studies. Successful completion of the Phase II program will result in a regulatory submission tothe FDA to allow for the execution of clinical safety and efficacy evaluations of 166Ho-MSNs for treating ovariancancer metastases. 971041 +No NIH Category available Address;Artificial Intelligence;Back;Basic Science;Cancer Center;Cancer Patient;Clinical;Clinical Management;Clinical Oncology;Clinical Research;Clinical Trials;Clinical Trials Database;Clinical assessments;Data;Data Set;Databases;Diagnostic;Disease;Disease Progression;Disease model;Evaluation;Feedback;Functional Imaging;Gene Expression Profiling;Goals;Hodgkin Disease;Human;Image;Image Analysis;Imaging Device;Informatics;Investments;Laboratories;Lesion;Lymphoma;Machine Learning;Malignant Neoplasms;Manuals;Maps;Measurement;Measures;Metabolic;Metabolism;Morphology;Multi-Institutional Clinical Trial;NCI-Designated Cancer Center;Nodal;Pathology;Pathway interactions;Patients;Performance;Phenotype;Positron-Emission Tomography;Quantitative Evaluations;Relapse;Reliability of Results;Reporting;Research Personnel;Risk;Scanning;Scientific Advances and Accomplishments;Services;Solid Neoplasm;Source;Staging;Standardization;Structure;Surrogate Endpoint;System;Technology;Time;Training;Translating;Treatment Protocols;Tumor Burden;Work;X-Ray Computed Tomography;anatomic imaging;automated segmentation;burden of illness;cancer clinical trial;cancer imaging;cancer therapy;clinical practice;cloud based;cohort;commercialization;design;experience;glucose metabolism;imaging Segmentation;improved;industry partner;innovation;lymph nodes;multidisciplinary;new technology;novel;novel therapeutics;participant enrollment;precision medicine;prognostic indicator;quantitative imaging;radiologist;success;task analysis;tool;treatment effect;treatment response;treatment strategy;tumor;usability Lymph Node Quantification System for Multisite Clinical Trials Project NarrativeAdvanced quantitative imaging is underutilized in oncologic clinical practice and research because the timeinvestment entailed in manual lesion segmentation remains prohibitive. This partnership proposes to integratemachine learning based quantitative imaging tools into the existing Precision Imaging Metrics LLC clinical trialimage management system. We will use data from the centralized Tumor Imaging Metrics Core at the Dana-Farber/Harvard Cancer Center to produce ground truth training data and develop semi-automated multimodali-ty lesion analysis for patients with cancer. NCI 10687096 8/8/23 0:00 PAR-18-530 5R01CA235589-05 5 R01 CA 235589 5 "ZHANG, YANTIAN" 9/1/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 1881109 "KIKINIS, RON " "HARRIS, GORDON J" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 595794 NCI 513440 82354 Project Summary / AbstractIn patients with lymphomas and other cancers quantitative evaluation of the extent of tumor burden is im-portant for staging restaging and assessment of therapeutic response or relapse; yet measurement of overalltumor burden is challenging with current tools particularly when lymph nodes are confluent or difficult to fullydifferentiate from surrounding structures. Precision medicine and novel therapeutics are emphasizing the needto introduce a risk-adapted approach to tailor appropriate treatment strategies for cancer patients. The ability toquantitatively assess cancer phenotypes with functional and anatomical imaging that could efficiently and ac-curately map patients to gene expression profiling clinical information matching cohorts and novel treatmentregimens could potentially result in more optimal management of patients with cancer. This Academic-Industry Partnership aims to translate recently developed technologies for semi-automated image segmentation and quantification of lymph nodes into robust tools and integrate them into anexisting cloud-based system for management of multicenter oncology clinical trials. The ability to semi-automatically segment lymph node pathology with computed tomography (CT) as well as quantify nodal me-tabolism with positron emission tomography (PET) will enable comprehensive tracking of morphological andfunctional changes related to disease progression and treatment response. Since 2004 the Dana-Farber/Harvard Cancer Center's (DF/HCC) Tumor Imaging Metrics Core (TIMC)has developed the Precision Imaging Metrics LLC (PIM) platform to manage clinical trial image assessmentworkflows. Currently there are nearly 50000 consistently measured lymph node measurements in the TIMCdatabase. The PIM system is used to make over 20000 time point imaging assessments per year at eight NCI-designated Cancer Centers and aims to grow quickly by transitioning to a fully cloud-hosted system. Given sufficient training data state-of-the-art machine learning and artificial intelligence (AI) technolo-gies can meet or even exceed human performance on specific imaging analysis tasks. Recent studies haveindicated that AI-based lymph node segmentation from CT scans is nearing human performance levels andwe will extend and translate this work into a commercial tool. Specifically our aim is to translate recent ad-vancements in AI-based segmentation into deployable services and integrate these services into the clinicaltrial workflow. The proposed system will be designed to incorporate expert feedback provided by image ana-lysts and radiologists back into the ground truth dataset allowing for continuous improvement in accuracy andclinical acceptance. We will extend our semi-automatic CT segmentation technologies to quantify lymph nodemetabolism in PET/CT using lymphoma as the model disease. Integration of these technologies with PIM willprovide an ongoing source of consistently measured quantitative data across a network of cancer centers. 595794 +No NIH Category available Acceleration;Address;Cell Survival;Cell model;Cells;Clinical;Communities;Complex;DNA;Data Set;Diagnostic;Drug resistance;Gene Expression;Genetic Predisposition to Disease;Genomics;Immune;Maps;Mediating;Methods;Minority;Modeling;Molecular;Organoids;Patients;Pre-Clinical Model;Primary Neoplasm;RNA;Research;Research Proposals;Testing;drug action;drug response prediction;drug sensitivity;in situ sequencing;insight;neoplastic cell;precision oncology;public health relevance;tumor;tumor microenvironment Making cancer precision medicine real: bottlenecks and opportunities PROJECT NARRATIVE / PUBLIC HEALTH RELEVANCEDespite the allure of cancer precision medicine at present most patients do not benefit from this approach.Only a minority of patients receive therapy that is guided by the molecular features of their tumor. Thisresearch proposal aims to open the scientific bottlenecks that currently limit the utility of cancer precisionmedicine. NCI 10687086 9/7/23 0:00 PAR-18-880 5R35CA242457-05 5 R35 CA 242457 5 "SALNIKOW, KONSTANTIN" 9/16/19 0:00 8/31/26 0:00 ZCA1-RPRB-N(M1) 1899925 "GOLUB, TODD R." Not Applicable 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1003799 NCI 587019 416784 PROJECT SUMMARYThe concept of cancer precision medicine is simple: patient treatments are guided by the molecular features oftheir tumor. In practice however the situation is more complex. Only a minority of patients at present benefitfrom the approach. A number of scientific challenges must be overcome before cancer precision medicine canbecome a reality for all patients. These challenges are the focus on the present research proposal. Forexample we now know that gene expression not DNA-level aberrations are the most predictive of drugresponse and yet the entire clinical genomic testing enterprise is focused on DNA. We therefore need todevelop methods suitable for quantitative RNA-based diagnostics likely using emerging single cell and in situsequencing methods. In addition we must develop comprehensive maps using preclinical models that make itpossible to predict drug sensitivity (and genetic vulnerabilities) given the molecular features of the tumor. Thiswill require expanding our repertoire of cell models (to include organoids short-term primary tumor culturesand models that combine tumor cells and immune cells) developing more sophisticated read-outs of drugaction beyond viability and also developing new insights into the influence of the tumor microenvironment onmediating cell survival and drug resistance. The present proposal aims to address these challenges over the 7years ahead by developing new methods and datasets that will accelerate cancer precision medicine researchthroughout the research community. 1003799 +No NIH Category available Biometry;Training Programs;anticancer research Training Program in Biostatistics for Cancer Research PROJECT NARRATIVECombining the educational and research resources available at Rice University and the M.D. Anderson CancerCenter with practical experience will enable trainees upon completion of the program to make fundamentalcontributions to cancer research working alongside biomedical investigators. Such close collaboration will leadto more efficient study designs and data analysis methodologies enabling rapid translation of biologicalknowledge provided by biomedical big data and biological theories to clinical application. NCI 10687082 9/20/23 0:00 PA-18-403 5T32CA096520-18 5 T32 CA 96520 18 "BOULANGER-ESPEUT, CORINNE A" 8/1/03 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 2447996 "KIMMEL, MAREK " "YUAN, YING " 9 BIOSTATISTICS & OTHER MATH SCI 50299031 K51LECU1G8N3 50299031 K51LECU1G8N3 US 29.717236 -95.402761 9291001 RICE UNIVERSITY HOUSTON TX BIOMED ENGR/COL ENGR/ENGR STA 770051827 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 316298 NCI 297350 18948 Project Summary/AbstractThis application is for continuation of a training program in biostatistics with a specific focus on cancer researchthat supports three graduate students and two postdoctoral researchers each year. The explosion of big datain biomedical research especially cancer has led to new challenges and opportunities to extract informationfrom these data to inform novel approaches for early detection prevention and precision therapy strategies totreat cancer. The increasingly competitive world of drug development also necessitates more efficient clinicaltrial designs to gather information on new treatments efficacy and safety profiles. These challenges bringquantitative scientists especially biostatisticians to the forefront of cancer research to develop efficient robustand reproducible methods for analyzing complex biomedical data and adaptive clinical trial designs.Multidisciplinary research teams are at the heart of modern cancer research requiring communication andmutual understanding for success. Effective biostatistical collaboration requires broad training in statisticsprobability computing as well as cancer biology medical ethics and effective communication to collaborators.The Department of Statistics Rice University and the Department of Biostatistics and Department ofBioinformatics and Computational Biology at the University of Texas M. D. Anderson Cancer Center(UTMDACC) have joined forces with their collaborators in the clinical basic and population sciences todevelop a unique training program that combines their respective strengths to train biostatisticians in cancerresearch. The goal of this Training Program is to prepare a new generation of biostatisticians who will workside-by-side with biomedical investigators in modern cancer research. Our program aims to provide traineeswith: (1) Rigorous training in statistics and probability (2) Practical experience in basic and clinical cancerresearch (2) Training in biological aspects of cancer medical research ethics and effective communication.Predoctoral trainees in the program follow standard PhD coursework for students in Statistics at Rice withadditional coursework in biostatistics biologic ethics and communication as well as special seminars andworkshops at both institutions plus hands-on experience in summer internship and laboratory rotations.Postdoctoral trainees have access to the same coursework and hands-on experiences plus will gain grant-writing experience during their training. With faculty expertise in Bayesian methods decision theory cancerclinical trials cancer screening survival analysis statistical genetics genomics bioinformatics and statisticalcomputing trainees will receive a broad background in biostatistics for modern cancer research with improvedrigorous admissions evaluation and development procedures to ensure success in producing researchers. 316298 +No NIH Category available Active Learning;Address;Adoption;Advanced Malignant Neoplasm;Attention;Award;Cancer Education Grant Program;Cancer Patient;Cessation of life;Clinical;Communication;Communities;Counseling;Data;Data Collection;Discipline;Dissemination and Implementation;Distress;Ensure;Evaluation;Event;Evidence based intervention;Faculty;Feeling hopeless;Funding;Goals;Institution;International;Intervention;Learning;Maintenance;Manuals;Medical;Memorial Sloan-Kettering Cancer Center;Mental Depression;Methodology;Modeling;National Cancer Institute;Oncology;Palliative Care;Participant;Patients;Personal Satisfaction;Play;Psychological reinforcement;Psychosocial Assessment and Care;Psychotherapy;Qualifying;Quality of life;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Research;Research Institute;Role;Spirituality;Testing;Time;Training;Training Programs;Translations;United States National Institutes of Health;Waiting Lists;cancer care;cancer therapy;care providers;care systems;clinical practice;coping;education research;effective intervention;end of life care;evidence base;follow-up;implementation facilitation;improved;innovation;interest;intervention program;multidisciplinary;multimodality;novel;physical symptom;programs;psychologic;psychosocial;satisfaction;skill acquisition;skills;success;webinar Meaning-Centered Psychotherapy Training Program for Cancer Care Clinicians Project NarrativeMeaning-Centered Psychotherapy (MCP) developed by Breitbart and colleagues at Memorial Sloan KetteringCancer Center is the only empirically-supported treatment that has clearly demonstrated efficacy in improvingquality of life and spiritual well-being and in alleviating existential distress loss of meaning despair and physicalsymptom burden distress in patients with advanced cancer. As a result there has been overwhelming demandfor MCP training from multidisciplinary palliative and cancer care clinicians across settings. The continuation ofthis R25-supported (R25CA190169; P.I. W. Breitbart) research education program in MCP intervention skills willaddress a critical growing need to train clinicians in evidence-based interventions and to disseminate MCP toadvanced cancer patients in need of effective psychosocial care. NCI 10687062 7/26/23 0:00 PAR-18-477 5R25CA190169-09 5 R25 CA 190169 9 "ZAHIR, NASTARAN" 9/1/15 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1866034 "BREITBART, WILLIAM " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 311355 NCI 288292 23063 Project Summary/AbstractThe overall objective of this project entitled Meaning-Centered Psychotherapy Training for Cancer CareProviders (MCPT) is to continue facilitate the implementation and dissemination of Meaning-CenteredPsychotherapy (MCP) a Research-Tested Intervention Program (RTIP) through a multi-modal training programfor cancer care clinicians. There is extensive evidence demonstrating a need for interventions targetingdepression hopelessness loss of meaning and spiritual and existential distress in patients coping with thechallenges of advanced cancer. To address this need Breitbart and colleagues developed MCP as an innovativeand novel intervention to enhance meaning and reduce despair in advanced cancer patients living in the face ofdeath. Since our National Institute of Health (NIH) R25 grant was funded we have successfully developed MCPTand trained 297 clinicians from a wide variety of clinical institutions and settings. As proposed we utilized theRE-AIM framework comprised of five distinct factors: 1) Reach 2) Efficacy 3) Adoption 4) Implementation and5) Maintenance to evaluate the impact of the MCPT program on the translation of MCP into clinical practice.Preliminary results indicate that trainees are extremely satisfied with the MCPT program have become proficientin the delivery of MCP have successfully implemented MCP in their own clinical settings and are maintainingor improving their MCP skills post-training. We are applying for a 5-year renewal of this R25 grant to capitalizeon overwhelming interest expressed by cancer care clinicians in our innovative immersive training and to furtherdisseminate MCP to advanced cancer patients in need of evidence-based psychosocial care. We will offer thistraining to an additional 336 clinicians during years 6-10 and enhance the follow-up components of the trainingto further improve MCP skill maintenance adoption and implementation in clinical practice. This will also enableus to continue to collect data on the implementation of MCP with patients in the real world across diverseclinical settings. The long-term goal of this project is to disseminate MCP to a wide variety of cancer and palliativecare treatment settings through the training of a large diverse cadre of clinicians. Thus the specific aims of thisstudy are to: Aim 1: Provide and further develop a training program in MCP for cancer care clinicians frommultiple disciplines who provide psycho-oncology and psychosocial palliative care services for cancer patients;Aim 2: Evaluate trainees MCP skill acquisition through facilitators ratings of MCPT participants and participantssatisfaction with the program and adoption implementation and maintenance of skills; and Aim 3: Evaluate theimpact of enhanced follow-up training and engagement in MCP community activities on MCP implementationand skill maintenance. 311355 +No NIH Category available Address;Animal Experimentation;Anthracycline;Antihypertensive Agents;Antineoplastic Agents;Arrhythmia;Automobile Driving;Autophagocytosis;Biological Markers;Biological Models;Biology;Blood Pressure;Blood Vessels;Cancer Patient;Canis familiaris;Cardiac Myocytes;Cardiotoxicity;Cardiovascular Abnormalities;Cardiovascular Models;Cardiovascular system;Cells;Characteristics;Clinical;Combined Modality Therapy;Credentialing;Data;Development;Dissection;Dose;Doxorubicin;Drug Combinations;Drug Exposure;Early Diagnosis;Early Intervention;Echocardiography;Endothelial Cells;Endothelin;Event;Exhibits;Exposure to;Future;Goals;Health;Heart failure;Human;Hypertension;Image;Immune checkpoint inhibitor;Immunotherapeutic agent;Impairment;In Vitro;Intervention;KDR gene;Laboratories;Long Term Survivorship;Longevity;Malignant Neoplasms;Medical;Methodology;Modality;Modeling;Molecular;Monitor;Mus;New Agents;Outcome;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphopeptides;Process;Prospective Studies;Protocols documentation;Quality of life;Research Design;Rodent;Rodent Model;Sampling;Systemic hypertension;Therapeutic;Therapeutic Intervention;Toxic effect;Translations;Treatment-Related Cancer;Tyrosine Kinase Inhibitor;Untranslated RNA;Validation;Whole Organism;Work;biomarker validation;cancer care;cancer therapy;cardioprotection;clinically relevant;comorbidity;data integration;early detection biomarkers;effective intervention;effective therapy;efficacy evaluation;experience;imaging modality;implementation facilitation;improved;improved outcome;in vivo;in vivo Model;inhibitor;innovation;instrumentation;longitudinal analysis;mouse model;novel;novel therapeutics;prediction algorithm;predictive marker;prevent;prospective;research clinical testing;response;small molecule inhibitor;survivorship;timeline;treatment strategy Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity As cancer outcomes improve with advances in early detection and the use of novel therapeutic modalities (smallmolecule inhibitors immunotherapeutics) cardiovascular (CV) toxicities have become increasingly moreapparent significantly impacting quality of life and overall survivorship. Despite efforts to model these toxicitiesusing standard approaches in research animals there are no established biomarkers to predict no standardpractices to prevent and no effective protocols to treat many of these complications. The overarching goal ofthis application is to leverage a cross-species modeling platform that integrates data generated from mice dogswith spontaneous cancer and human cancer patients to critically interrogate and then validate mechanisticdrivers of and therapeutic strategies for both known and emergent CV toxicities thereby more effectivelyaddressing this unmet medical need and ultimately improving patient related outcomes. NCI 10687058 8/25/23 0:00 PAR-17-244 5R01CA243542-05 5 R01 CA 243542 5 "NADEAU, CHRISTINE FRANCES" 9/1/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-J(55)R] 1868805 "JAFFE, IRIS Z" "LONDON, CHERYL A" 7 Unavailable 79532263 MY2ERHGDV956 79532263 MY2ERHGDV956 US 42.349512 -71.063308 130301 TUFTS MEDICAL CENTER BOSTON MA Independent Hospitals 21111552 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 597582 NCI 431267 166315 As survival improves with advances in cancer care cardiovascular (CV) complications associated with treatmenthave become more prevalent. Effects of traditional chemotherapeutics are generally well known butincorporation of small molecule inhibitors and immunotherapeutics has led to the emergence of new andunexpected toxicities. The mechanistic drivers underlying many of these have not been well characterizedundermining both appropriate monitoring and effective intervention. This is further complicated by reliance uponmodels of CV toxicity that do not fully recapitulate the complicated landscape of human cancer. While in vitrostudies permit dissection of cellular and molecular alterations in response to drug exposure they lack context ofthe whole organism that contributes to pathogenesis. Rodent models have been instrumental in definingfundamental characteristics of treatment induced CV complications but there are significant differences induration of exposure to therapeutics and an absence of co-morbidities that likely influence outcome. Moreovertheir small size and short lifespan limit instrumentation longitudinal analysis and repeated sampling. Pet dogswith spontaneous cancer are routinely treated with anti-cancer agents known to produce CV toxicity includingdoxorubicin tyrosine kinase inhibitors and more recently immune checkpoint inhibitors and may thus providean opportunity for mechanistic interrogation in a more clinically relevant context to bridge the gap from cells andmice to humans. Their larger size and longer lifespan permit the use of prospective study designs in the settingof standard cancer treatment that more closely represent the human experience thereby overcoming somelimitations of rodent models. As such the fundamental premise underlying this proposal is that no singlemodel system of cancer treatment-induced CV toxicity is sufficient to effectively interrogate mechanisticdrivers and assess approaches to therapeutic intervention. Instead a coordinated integrated effort acrossthe landscape of multiple in vitro and in vivo model systems is required to efficiently identify and validatebiomarkers for early intervention evaluate novel treatments to address complications and ultimately developalgorithms for predicting potential CV toxicity in the setting of combination therapy. We therefore propose thatinclusion of data generated from dogs with spontaneous cancer treated with agents known to induceCV toxicity will permit a more accurate characterization and confirmation of key mechanistic drivers andtherapeutic intervention strategies critical for advancing human outcomes. To accomplish this we createda non-reductionist multi-species framework for analyzing data generated in the laboratory mouse models dogswith spontaneous cancer and human patients. The studies in this proposal will credential and optimize thisnovel platform using two established yet unique CV toxicities that constrain effective treatment in cancer patients-anthracycline induced cardiotoxicity and VEGFRI induced hypertension- ultimately creating a blueprint to betteraddress both existing and emergent cancer treatment induced CV toxicities and enhance long-term survivorship. 597582 +No NIH Category available Address;Adult;Advanced Development;Affect;Area;Bile Acids;Biological Assay;Central obesity;Child;Cirrhosis;Clinic;Clinical;Communities;Country;County;Data;Development;Diabetes Mellitus;Diet;Early Intervention;Enrollment;Equipment;Fatty Acids;Fibrosis;Funding;Health;Hepatic;High Prevalence;Hispanic;Hispanic Populations;Incidence;Infiltration;Joints;Ligands;Liver;Liver Fibrosis;Macrophage;Mass Spectrum Analysis;Measurement;Measures;Mediator;Modeling;Molecular;Molecular Profiling;Mus;Obesity;Obesity Epidemic;Participant;Patient Schedules;Patients;Performance;Pilot Projects;Plasma;Play;Population;Population Attributable Risks;Population Study;Prevalence;Prevention;Prevention strategy;Primary carcinoma of the liver cells;Publications;Reporting;Research;Resources;Risk;Risk Factors;Role;Serum;Signal Transduction;Site;South Texas;Staging;Study Subject;Target Populations;Texas;Tissues;United States;University of Texas M D Anderson Cancer Center;chronic liver disease;clinically significant;cohort;diabetic;elastography;gut microbiome;gut microbiota;health disparity;high risk;hispanic community;liver biopsy;liver injury;male;microbiome;molecular marker;mortality;multidisciplinary;non-alcoholic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;participant enrollment;preventive intervention;programs;progression risk;prospective;screening;sequencing platform;simple steatosis;study population;surveillance strategy;translational goal;vibration Project 3: Non-invasive assessment of liver fibrosis stage and progression in obesity and diabetes: a Hispanic population study Project 3 - NARRATIVEThere is an alarming high prevalence of chronic liver disease advanced liver fibrosis including cirrhosis andhepatocellular carcinoma (HCC) in Hispanic population in South Texas. Obesity diabetes and non-alcoholicsteatohepatistis (NASH) were identified as the major risk factors with NASH affecting close to 20% of thispopulation including children. To address the magnitude of this growing health disparity problem and identifythose at high risk for HCC who would benefit from surveillance and prevention strategies we propose toscreen a large number of obese and diabetic Hispanics for liver fibrosis and identify non-invasive markers ofliver fibrosis stage and progression. NCI 10687043 8/21/23 0:00 PAR-18-313 5P50CA217674-05 5 P50 CA 217674 5 9/25/19 0:00 8/31/24 0:00 ZCA1-RPRB-8 5844 6625582 "BERETTA, LAURA " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 531220 396181 155683 PROJECT 3 SUMMARY/ASTRACTHCC incidence and mortality rates are rapidly increasing in the United States in part due to the epidemics ofobesity and diabetes. The greatest increase has been seen in Hispanics in South Texas. Our studies in theCameron County Hispanic Cohort (CCHC) established from a community with high rates of obesity (52%) anddiabetes (28%) showed that chronic liver disease is also common (42%). Non-alcoholic fatty liver disease(NAFLD) the most common liver manifestation of obesity and diabetes ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). Advanced fibrosis is the main risk factor for HCC in NAFLD patients. We firstreported a 3.5% prevalence of advanced fibrosis in CCHC with a remarkable population attributable fraction of65% for central obesity. We then implemented liver fibrosis screening in CCHC using vibration-controlledtransient elastography (VCTE) and reported a 14% prevalence of clinically significant fibrosis (stage F2). Theprevalence of significant liver fibrosis reached 28% in obese and diabetic subjects. Strong associationsbetween gut microbiota changes and progression of NAFLD to NASH and HCC have been reported and bileacids are important mediators in this gut-liver cross-talk. Furthermore we identified fatty acids as non-invasivemarkers of NAFLD activitiy and liver fibrosis in patients with NAFLD. Our long-term translational goal is todetermine the contributing factors and molecular drivers of liver fibrosis in obese and diabetic Hispanics inSouth Texas the community in the United States with the highest rate of HCC and identify those at risk ofprogression to advanced fibrosis and therefore HCC so preventive interventions can be implemented. Wehypothesize that demographic clinical and molecular (microbiome features bile acids fatty acids)parameters are associated with liver fibrosis stages in obese Hispanics with diabetes. We hypothesize furtherthat a model based on these parameters will predict fast fibrosis progression and thus increased risk for HCCdevelopment in these subjects. We will enroll 900 obese and diabetic CCHC subjects and 500 obese anddiabetic Hispanic patients scheduled for liver biopsy at participating liver clinics. All study participants will bescreened for liver fibrosis with VCTE and plasma bile acids plasma fatty acids and gut microbiome featureswill be measured. Study participants identified with fibrosis F2 will be followed prospectively and liver fibrosiswill be again assessed by VCTE and/or liver biopsy at 36 months. In Aim 1 we will determine the performanceof VCTE against liver fibrosis for fibrosis staging in the study population. We will also determine the prevalenceand risk factors associated with liver fibrosis in obese and diabetic Hispanics in South Texas. In Aim 2 we willidentify the molecular markers among those measured that are associated with liver fibrosis stages. In Aim 3we will identify a model incorporating selected parameters from Aim 1 and molecular markers from Aim 2 inpredicting fast liver fibrosis progression in obese Hispanics with diabetes. The impact of this project would bereduction of HCC mortality rates through early intervention and prevention. +No NIH Category available Acetates;American Cancer Society;Asia;Benign;Biology;Brain;Breast;Cessation of life;Cirrhosis;Clinical;Clinical Management;Clinical Oncology;Clinical Research;Clinical Trials;Colon;Colon Carcinoma;Data;Data Analyses;Decision Making;Detection;Diagnosis;Diagnostic;Diagnostic Imaging;Diagnostic tests;Discrimination;Effectiveness;Eligibility Determination;Evaluation;Excision;Exhibits;Feasibility Studies;Future;Glutamates;Glutamic Acid;Goals;Healthcare;Human;Image;Imaging Device;Incidence;Individual;Intervention;Lesion;Liver;Liver neoplasms;Lung;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of liver;Malignant neoplasm of lung;Measures;Methodology;Methods;Modality;Molecular;Oncology;Operative Surgical Procedures;Pathology;Patient Care;Patient Schedules;Patient Selection;Patients;Pattern;Pilot Projects;Positron-Emission Tomography;Primary Malignant Neoplasm of Liver;Primary Neoplasm;Primary carcinoma of the liver cells;Protocols documentation;Randomized;Role;Safety;Schedule;Sensitivity and Specificity;Specimen;Staging;Standardization;Testing;Tracer;Transplant Recipients;Tumor Tissue;United States;X-Ray Computed Tomography;anatomic imaging;clinical imaging;cohort;comorbidity;fluorodeoxyglucose;imaging approach;imaging modality;imaging study;immunohistochemical markers;improved;innovation;insight;liver transplantation;malignant breast neoplasm;metabolic profile;molecular imaging;non-invasive imaging;novel;novel diagnostics;personalized care;personalized decision;pharmacokinetic model;precision oncology;prevent;prospective;quantitative imaging;research clinical testing;standard of care;statistics;tool;tumor;tumor behavior;tumor metabolism;uptake Quantitative PET Imaging of Hepatocellular Carcinoma (HCC) PROJECT NARRATIVE: Quantitative PET Imaging of Hepatocellular CarcinomaClinical decisions regarding the treatment of patients with hepatocellular carcinoma (HCC) remain largely guidedby conventional anatomical imaging modalities. This application proposes the clinical evaluation of an innovativePET imaging tracer that may personalize decision making in the care of patients with HCC. NCI 10687038 9/6/23 0:00 PAR-18-560 5R01CA239694-04 5 R01 CA 239694 4 "PEREZ, J MANUEL" 9/22/20 0:00 8/31/25 0:00 Clinical Translational Imaging Science Study Section[CTIS] 8028499 "MANNING, HENRY CHARLES" Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 577171 NCI 356278 220893 PROJECT SUMMARY/ABSTRACT: Quantitative PET Imaging of Hepatocellular CarcinomaClinical decisions regarding the treatment of patients with hepatocellular carcinoma (HCC) remain largely guidedby conventional anatomical imaging modalities. These methods namely magnetic resonance imaging (MRI)and x-ray computed tomography (CT) provide little information about the cellular and molecular underpinningsof individual tumors. HCC is the most common primary tumor of the liver and represents a major healthcarechallenge in the United States (US) and elsewhere. The American Cancer Society estimates diagnosis of greaterthan 42000 new cases of liver cancer in the US this year. In contrast to cancers more frequently diagnosed inthe US and for which precision cancer medicine is routinely employed such as colon or breast incidence of livercancer and liver cancer-associated deaths are both increasing. Improved tools to detect HCC at early potentiallycurable stages and tools to predict future tumor behavior are urgently needed. Molecular imaging with positronemission tomography (PET) is uniquely poised to provide those tools yet novel tracers are required. Thesensitivity of routine 18F-FDG PET the most commonly utilized approach in clinical oncology is limited in HCCand other tracers that exhibit greater potential such as 11C-acetate suffer technical limitations that prevent theirbroad clinical use. The overarching goal of this application is to clinically evaluate an innovative PET imagingtracer that has the potential to personalize decision making in the care of patients with HCC. We propose toconduct the first quantitative imaging clinical trial of (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid (18F-FSPG) PETin the setting of HCC. As an emerging PET tracer reflecting tumor glutamate transport 18F-FSPG PET has shownclinical safety and efficacy in multiple tumor settings including breast lung and brain cancer. Our preliminarydata in a pilot cohort of Vanderbilt patients as well as a pilot clinical study conducted in Asia (n = 5) suggest thefeasibility of using 18F-FSPG PET to improve the detection of HCCs even among cirrhosis a comorbidity thatdiminishes the effectiveness of conventional imaging approaches. Our study has three Specific Aims. In patientsundergoing surgery for treatment of HCC we will (1) evaluate the relationship between 18F-FSPG PET pathologyand cancer metabolism; (2) compare 18F-FSPG PET with standard-of-care (SOC) diagnostic imaging in patientswith HCC and benign liver lesions; and (3) compare uptake of 18F-FSPG with 11C-acetate and 18F-FDG in HCCand background liver. This study has the potential to establish a new role for non-invasive molecular imaging inthe delivery of individualized cancer care for patients with HCC. 577171 +No NIH Category available Adjuvant;Adverse event;Affect;Attenuated;BAY 54-9085;Binding;CD3 Antigens;CD8-Positive T-Lymphocytes;CD80 gene;CD86 gene;CD8B1 gene;CTLA4 gene;Cancer Etiology;Cells;Clinical;Clinical Trials;Collaborations;Combined Modality Therapy;Development;Eligibility Determination;Event;Excision;Fibrosis;Goals;Immune;Immune Targeting;Immune response;Immunity;Immunotherapy;Infiltration;Ligands;Macrophage;Malignant Epithelial Cell;Molecular;Mus;Neoadjuvant Therapy;Nivolumab;Operative Surgical Procedures;Outcome;Pathologic;Pathway interactions;Patients;Perioperative;Pharmaceutical Preparations;Primary carcinoma of the liver cells;Proliferating;Protein Tyrosine Kinase;Randomized;Recurrence;Recurrent tumor;Regimen;Regulatory T-Lymphocyte;Reporting;Resectable;Resected;Sampling;Signal Transduction;T cell infiltration;T-Lymphocyte;TNF gene;Testing;Therapeutic;Treatment Efficacy;University of Texas M D Anderson Cancer Center;Unresectable;anti-PD-1;anti-PD1 therapy;anti-tumor immune response;arm;cancer cell;cancer infiltrating T cells;cell killing;checkpoint receptors;checkpoint therapy;curative treatments;effector T cell;immune cell infiltrate;immune checkpoint;immunoregulation;improved;improved outcome;inhibitor;innovation;ipilimumab;kinase inhibitor;liver transplantation;mortality;mouse model;novel;novel drug combination;overexpression;partial response;programmed cell death ligand 1;programmed cell death protein 1;randomized trial;response;response biomarker;targeted treatment;therapeutically effective;three-arm clinical trial;translational goal;treatment response;tumor Project 1: Targeting the PD-1 pathway in HCC Project 1 - Narrative Our recent studies on resected hepatocellular carcinoma (HCC) found tumor-infiltrating T cells expressing PD- 1 and CTLA-4 surrounded by a dense macrophage infiltrate rich in checkpoint ligands justifying a trial to test innovative immunotherapy in HCC. The goal of Project 1 is to evaluate the ability of immunotherapy drugs to down size HCC tumors to make them amenable for resection and also to study their ability to lower the high rate of HCC tumor recurrence after surgery. We will also evaluate novel drug combination strategies by simultaneously targeting immune checkpoint signaling and checkpoint molecule expression. NCI 10687037 8/21/23 0:00 PAR-18-313 5P50CA217674-05 5 P50 CA 217674 5 9/25/19 0:00 8/31/24 0:00 ZCA1-RPRB-8 5842 9879860 "KASEB, AHMED " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 364537 232501 144151 Project 1 SUMMARY/ABSTRACT The multi-kinase inhibitors sorafenib (first-line use) and regorafenib (second-line use) have been approved for the treatment of advanced HCC; however the overall survival improves by less than 3 months and the overall response rates are low (<10%). Resection and liver transplantation are curative treatments for HCC; however less than 20% of HCC patients are eligible for resection and early recurrence is frequent (50% in 2 years). Because the predominant molecular alterations in HCC are not druggable targeting immune checkpoints such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may be a promising alternative strategy. The anti-PD1 drug nivolumab was recently approved for HCC therapy. With a 20% response rate anti-PD1 therapy is encouraging opening opportunities for more effective therapeutic approaches. In resected HCC samples we found tumor-infiltrating T cells expressing PD-1 and CTLA-4 surrounded by a dense macrophage infiltrate rich in the checkpoint ligands PD-L1 and PD-L2. While increased immune response by targeting PD-1 and CTLA-4 pathways has been reported in unresectable HCC immunotherapy strategies have not yet been evaluated in neoadjuvant (pre-surgery) and adjuvant (post-surgery) settings. In a pilot randomized perioperative trial with nivolumab ipilimumab (anti-CTLA-4) for resectable HCC we observed complete pathologic responses in 2 cases that correlated with an increase in CD8+ T cell infiltration and CD8/Treg ratio. Based on the 6 patients accrued to date none had drug related events that led to delaying or canceling surgery and we didnt encounter grade 3 or 4 adverse events. The tyrosine kinase c-MET is overexpressed in HCC and multiple c-MET inhibitors have been developed and evaluated in clinical trials in HCC. However the reported outcomes were disappointing. We showed that c-MET inhibitors upregulate PD-L1 expression in HCC cells which may allow HCC cells to escape from T cell killing. We further showed that the combination of c-MET inhibitors and anti-PD-1 synergistically suppresses HCC development in mice. Our long- term translational goal is to modulate immune cells in HCC microenvironment to improve outcome in patients with advanced HCC or resectable HCC. We hypothesize that neoadjuvant immune checkpoint therapy in HCC can trigger an immune response which may lead to delay in recurrence or increased resectability and that immune infiltration or fibrosis stage can affect treatment response. We also hypothesize that the efficacy of HCC immunotherapy can be improved by simultaneously targeting immune checkpoint signaling and checkpoint molecule expression. In Aim 1 we propose a neoadjuvant/adjuvant clinical trial targeting PD-1 CTLA4 in surgical HCC patients to delay recurrence and in locally advanced unresectable HCC patients to increase resectability. In Aim 2 we will evaluate novel combination therapies including anti-PD-1 and agents upregulating PD-L1 expression such as c-MET inhibitors in HCC. The impact of this project would be increased access to surgery for a larger number of HCC patients and improve overall survival in patients with advanced HCC. +No NIH Category available Advisory Committees;Advocate;Affect;Bioinformatics;Biometry;Budgets;Cancer Center Support Grant;Clinical Trials;Collaborations;Communication;Communities;Development;Disputes;Educational workshop;Electronic Mail;Ensure;Event;Expenditure;Health education;Institution;Joints;Leadership;Mentors;Minority;Minority Groups;Minority Recruitment;Monitor;Notification;Patients;Policies;Policy Compliance;Primary carcinoma of the liver cells;Process;Program Development;Publications;Quality Control;Regulation;Reporting;Research;Resolution;Resource Sharing;Schedule;Side;System;Texas;Translational Research;Underserved Population;University of Texas M D Anderson Cancer Center;Woman;career;career development;community center;data quality;data sharing;lectures;meetings;outreach;programs;quality assurance;recruit;research and development;symposium;translational engagement;translational research program Administrative Core Administrative Core - NARRATIVEThe Administrative Core interfaces with the NCI and provides scientific administrative and financial oversightfor all Projects and Cores and the Developmental Research and Career Enhancement Programs of the MDAnderson Hepatocellular Carcinoma SPORE. NCI 10687032 8/21/23 0:00 PAR-18-313 5P50CA217674-05 5 P50 CA 217674 5 9/25/19 0:00 8/31/24 0:00 ZCA1-RPRB-8 5839 6625582 "BERETTA, LAURA " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 273916 174704 108316 Administrative Core - SUMMARY/ ABSTRACTThe responsibilities of the Administrative Core include monitoring and planning of scientific activities providingscientific direction for the SPORE ensuring an interdisciplinary translational research emphasis and integrationwithin MD Anderson and NCI Translational Research Programs. The Administrative Core is managed by twoco-directors (Drs. Laura Beretta and Ahmed Kaseb) who will preside over the scientific quality of the SPOREand ensure communication cooperation and integration between components of the SPORE. Administrativeduties will be managed by Dr. Tiffany Calderone Program Coordinator who will oversee the SPORE activitiesand budget. Ms. Lynne Nugyen and Ms. Cassandra Harris Project Director and Health Education Managerrespectively in the Center for Community-Engaged Translational Research will facilitate recruitment ofminorities and women to the SPORE clinical trials and will serve as the community liaison for outreach efforts.Ms. Ersulan Hampton Project Director in Translational Research Administration will serve as a consultant forjoint initiatives with other MD Anderson SPORES and the Institution CCSG. The Administrative Core providesleadership and coordinates the activities of the Executive Committee (which consists of all Project co-leadersand Core co-directors) the Internal Advisory Committee the External Advisory Committee and the SPOREAdvocates. The objectives of the Administrative Core are: 1) to oversee all projects and cores; 2) to overseethe Developmental Research and Career Development programs; 3) to convene all meetings of the SPOREExecutive Committee Internal/External Advisory Committees and Advocate Advisory Committee; 4) toschedule and organize all necessary meetings including monthly scientific meetings lectures symposia andattendance at any NCI-sponsored meetings/workshops; 5) to coordinate data quality control and qualityassurance in conjunction with the Internal Review and Monitoring Committees of MD Anderson 6) to monitorand oversee all fiscal and budgetary issues; 7) to initiate collaborative research with other SPOREs throughelectronic communications or joint meetings; 8) to communicate with the NCI Project Officer and other NCIstaff to prepare all required reports and publications; 9) to notify the NCI Project Officer promptly of importantdevelopments that affect the management of the SPORE either positively or negatively; 10) to assurecompliance with all general governmental and NCI regulations and requirements; and 11) to establish andimplement policies for recruitment of women and minorities. Additional objectives of the Administrative Corewill be to organize with the support of UT System and MD Anderson annual scientific conferences on HCCand annual community events directed to minorities and underserved populations in Texas particularly affectedby hepatocellular carcinoma. . +No NIH Category available Address;Adjuvant;Affect;BAY 54-9085;Basic Science;Bile Acids;Biological Availability;Biological Markers;Cancer Center;Cancer Etiology;Catchment Area;Cells;Cessation of life;Chronic Disease;Cirrhosis;Clinical Trials;County;Curative Surgery;Data;Death Rate;Diabetes Mellitus;Diagnosis;Early Intervention;Excision;FDA approved;Fatty Acids;Fibrosis;Geography;Goals;Hispanic Populations;Immune;Immune Targeting;Immunotherapy;Incidence;Liver;Liver Fibrosis;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of thyroid;Measures;Mexico;Neoadjuvant Therapy;Newly Diagnosed;Nivolumab;Obesity;Operative Surgical Procedures;Oral;Participant;Patients;Performance;Pharmaceutical Preparations;Phosphorylation;Placebos;Plasma;Postoperative Period;Primary carcinoma of the liver cells;Prognosis;Prospective Studies;Prospective cohort;Proteins;Recurrence;Recurrent tumor;Resectable;Resected;Risk;STAT3 gene;Signal Transduction;South Texas;Survival Rate;Systemic Therapy;Target Populations;Texas;Therapeutic;Translational Research;Tyrosine Kinase Inhibitor;Underserved Population;United States;University of Texas M D Anderson Cancer Center;advanced disease;anti-PD-1;anti-tumor immune response;antitumor effect;arm;biobank;biomarker development;cancer diagnosis;cancer site;care seeking;checkpoint therapy;chronic liver disease;diabetic;elastography;gut microbiome;immune checkpoint;immunoregulation;improved;improved outcome;inhibitor;innovation;liver biopsy;liver injury;liver transplantation;mortality;non-alcoholic;nonalcoholic steatohepatitis;patient population;prognostic significance;programmed cell death ligand 1;response;screening;trend;tumor;tumor behavior;tumor growth;vibration The University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma Overall - NARRATIVEThe overall goal of the University of Texas MD Anderson Cancer Center SPORE in HepatocellularCarcinoma (HCC) is to improve outcomes for HCC patients and reduce HCC incidence. HCC is the 2ndleading cause of cancer death worldwide and in the United States while death rates declined for all cancerscombined and for most cancer sites deaths from HCC increased at the highest rate of all cancer sites. In thisSPORE application 3 projects together with 3 cores will combine clinical trials basic and translationalresearch to address the most urgent and unmet needs in the management of patients with HCC or at risk ofdeveloping HCC. NCI 10687031 8/21/23 0:00 PAR-18-313 5P50CA217674-05 5 P50 CA 217674 5 "NOTHWEHR, STEVEN F" 9/25/19 0:00 8/31/24 0:00 ZCA1-RPRB-8(M1) 6625582 "BERETTA, LAURA " "KASEB, AHMED " 9 MICROBIOLOGY/IMMUN/VIROLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 2206679 NCI 1464788 818220 Overall - SUMMARY/ABSTRACTThe overall goal of the University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma(HCC) is to improve outcomes for HCC patients and reduce the mortality rates of HCC through earlyintervention. HCC is the 2nd leading cause of cancer death worldwide with 854000 new cases diagnosedglobally and 810000 deaths in 2015. The incidence of new HCC cases globally is projected to rise to1341344 cases by 2035. In the United States (U.S.) while death rates declined for all cancers combined andfor most cancer sites in the past 10 years deaths from HCC increased at the highest rate of all cancer sitesand HCC incidence rates increased sharply second only to thyroid cancer. The burden of HCC is not equallydistributed throughout the U.S. the highest incidence being observed in States on the Mexico-US Border.Texas ranks second in incidence of HCC with a 5-year rate of 11.4 cases per 100000 compared to the nationrate of 7.6. Within Texas Hispanics in counties bordering Mexico have the highest rates of HCC in the U.S.with 37.5 diagnosed cases per 100000. Reflecting the rising incidence trends the number of HCC patientsseeking care at MD Anderson Cancer Center has increased every year from 277 patients in 2013 to 580patients in 2017 a 2-fold increase over the most recent 5 years. The relative 5-year survival rate for HCC is16%. The poor prognosis of HCC is due to multiple factors: 1) the vast majority of HCC cases are diagnosed atan advanced stage not amenable to curative surgical treatment (resection or liver transplantation); 2) evenresected cases suffer from high rates of recurrence (up to 50% in 2 years and 70% in 5 years); 3) HCC oftenoccurs in the context of advanced chronic liver disease cirrhosis in particular limiting treatment options; 4) theonly FDA-approved first line systemic therapy is sorafenib which offers a 2.8 months improvement in overallsurvival and a dismal response rate of 2%; and 5) the recently approved second line therapy are anothertyrosine kinase inhibitor regorafenib and the immunotherapy drug nivolumab but again improvement in overallsurvival and response rates are very low. In this SPORE application 3 projects together with 3 cores will: 1)evaluate the effect of checkpoint therapy in neoadjuvant and adjuvant HCC settings and determine optimalcombinations with checkpoint therapeutics to enhance the anti-tumor immune response; 2) determine theprognostic significance of phosphorylated STAT3 as a biomarker for postoperative recurrence and evaluateTTI-101 (C188-9) a STAT3 inhibitor developed in-house as a post-operative adjuvant; 3) evaluate thecombination of nivolumab and TTI-101 in the treatment of patients with advanced stage HCC; 4) performextensive screening for liver fibrosis in obese and diabetic Hispanics in South Texas and identify non-invasivebiomarkers of fibrosis stage and progression in this underserved population highly affected by non-alcoholicsteatohepatitis and HCC. 2206679 +No NIH Category available Apoptosis;BRCA mutations;BRCA1 Mutation;BRCA2 Mutation;Back;Biological Markers;Cell Cycle Arrest;Cell Cycle Progression;Cells;Chemical Structure;Chemotherapy and/or radiation;Clinical Research;Clinical Treatment;Clinical Trials;Compensation;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Sequence Alteration;Defect;Double Strand Break Repair;FDA approved;Growth;Impairment;In Vitro;Ionizing radiation;Lesion;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Molecular;NAD+ kinase;NADP;Normal Cell;Phosphoric Monoester Hydrolases;Phosphorylation;Poly(ADP-ribose) Polymerase Inhibitor;Post-Translational Protein Processing;Radiation Induced DNA Damage;Radiation induced double strand break;Radiation therapy;Regulation;Research Project Grants;Role;Signal Transduction;Testing;Therapeutic;Treatment-Related Cancer;antagonist;cancer cell;cancer therapy;chemotherapy;design;experimental study;in vivo;neoplastic cell;novel;novel therapeutic intervention;ovarian neoplasm;potential biomarker;recruit;repaired;response;sensor;triple-negative invasive breast carcinoma;tumor;tumor DNA Ionizing Radiation-Induced DNA damage repair Although PARP inhibitors have been approved by FDA for the treatment of BRCA tumors recent clinicalstudies suggest that not all the BRCA tumors respond well to PARP inhibitors and other regulators maymediate cellular sensitivity to PARP inhibitors. In our preliminary studies we found that NADP+ is a novelendogenous PARP inhibitor. In this proposal we plan to examine the mechanism by which NADP+ participatesin DNA damage repair and if NADP+ can serve as a biomarker and a sensitizer for cancer therapy includingchemotherapy and radiation therapy. NCI 10687029 7/26/23 0:00 PA-18-484 5R01CA130899-15 5 R01 CA 130899 15 "WEINREICH, MICHAEL DALE" 5/1/09 0:00 8/31/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 1879238 "LIU, YILUN " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 418000 NCI 237500 180500 PARP inhibitors have been used in the clinical treatment for tumors with BRCA1 or BRCA2 mutations. Themajor function of PARP inhibitors is to suppress PARP1 and PARP2 mediated poly(ADP-ribosyl)ation aunique posttranslational modification mainly induced in DNA damage. Suppression of PARylation by PARPinhibitors abolishes early recruitment of DNA damage response factors and impairs DNA damage repair.Because PARylation is a very transient posttranslational modification normal cells have other repairmechanism to compensate for the loss of PARylation-dependent DNA damage response. However a set oftumor cells harbor genetic mutations such as BRCA1/2 mutations which have already led to impaired DSBrepair. With additional PARP inhibitor treatment to abolish PARylation-dependent DNA damage responsethese tumor cells will undergo apoptosis. Thus PARP inhibitor treatment selectively kills tumor cells with DNAdamage repair defects such as BRCA tumors. However recent clinical trials suggest that only a set of BRCA tumors respond effectively to the PARPinhibitor treatment. Moreover accumulated evidence indicates that PARP inhibitor treatment is able tosuppress the growth of other types of tumor besides BRCA tumors. Thus to extend the therapeutic potential ofPARP inhibitors in cancer treatment we explored biomarkers for the PARP inhibitor treatment. Interestinglywe found that NADP+ an NAD+ derivative can suppress the activity of PARPs both in vitro and in vivo. Thuswe hypothesize that NADP+ is an endogenous PARP inhibitor and the high level of NADP+ in tumor cells isable to sensitize tumor cells for DNA damaging related cancer therapy including chemotherapy and radiationtherapy. In this application we plan to examine 1) the role of NADP+ in poly(ADP-ribosyl)ation-dependent DNAdamage repair; 2) the molecular mechanism that regulates the cellular level of NADP+; 3) the role of NADP+ insensitizing tumor cells to DNA damaging-associated cancer therapy. Taken together the proposed study will not only reveal novel molecular mechanism in DNA damage repairbut also identify novel therapeutic approach for cancer treatment. 418000 +No NIH Category available Award;Cancer Detection;Cancer Patient;Clinical;Clinical Trials;Colorado;Doctor of Philosophy;Foundations;Funding;Future;Genomics;Goals;Health;Health system;Journals;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Natural History;Peer Review;Productivity;Recurrence;Regimen;Research;Risk;Specialist;Time;Translational Research;Treatment outcome;Treatment-Related Cancer;Work;anticancer research;cancer care;cancer diagnosis;cancer therapy;career;community setting;individualized medicine;lung cancer screening;meetings;prognostic;screening;treatment choice;treatment pattern;treatment risk Natural History of Lung Cancer Diagnosed Within and Across Diverse Health Systems Implementing Lung Cancer Screening Project NarrativeNikki Carroll MS supports the Cancer and Genomics Research Core at the Kaiser PermanenteColorado Institute for Health Research. Her work has made significant contributions totranslational research in cancer treatment patterns and outcomes that occur in real world clinicalsettings (as opposed to clinical trial settings). Support from this award will allow her to continueher focus in cancer research with an emphasis on treatment and risk of recurrence in thecontext of screen-detected cancers. NCI 10687017 8/2/23 0:00 PAR-19-290 5R50CA251966-04 5 R50 CA 251966 4 "MARCUS, PAMELA M" 8/10/20 0:00 7/31/25 0:00 ZCA1-SRB-1(M2)S 16179636 "CARROLL, NIKKI " Not Applicable 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 150171 NCI 90926 59245 Project Summary/AbstractThe goal of this application is to support Nikki Carroll MS as a Research Specialist andBiostatistician at Kaiser Permanente Colorado Institute for Health Research. She supports theCancer and Genomics Research Core under the direction of Debra Ritzwoller PhD. The core ofMs. Carrolls productive and successful career as a Research Specialist and Biostatistician is incancer related treatment patterns and outcomes. This Research Specialist award would allow 5years of funding to maintain protected time for Ms. Carroll to work exclusively on supporting andleading cancer research aimed at generating real-world evidence on cancer care that occursoutside of clinical trials. In particular she will study the treatment patterns and risk of recurrenceamong those with screen detected lung cancer compared to lung cancers diagnosed outside ofscreening. These results could impact prognostic estimates treatment choices and future trialsto develop tailored treatment and surveillance regimens for early-stage screen-detected lungcancer patients and set the foundation for future studies of the natural history of lung cancerscreening in community settings. Results will be broadly disseminated through local andnational meetings as well as peer-reviewed journal manuscripts. 150171 +No NIH Category available Applications Grants;Ascites;Binding;Biological Markers;Blood Vessels;CA-125 Antigen;Cancer Model;Cancer Patient;Cell surface;Cessation of life;Classification;Clear Cell;Clinical;Collaborations;Data;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Down-Regulation;Drainage procedure;Early Diagnosis;Endothelium;Epithelial ovarian cancer;Epithelium;Failure;Female;Female Genital Diseases;Foundations;Genes;Genetic;Goals;Greater sac of peritoneum;Growth Factor;Histologic;Human;Implant;Intra-abdominal;KDR gene;Liquid substance;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Medical;Membrane;Mesenchymal;Microfluidic Microchips;Microfluidics;Modeling;Molecular Target;Monoclonal Antibodies;Mucinous;Mus;Nature;Neoplasm Metastasis;Neoplasms in Vascular Tissue;Oncogenes;Organoids;Ovarian Serous Adenocarcinoma;Ovary;Pathway interactions;Patients;Peritoneal;Peritoneal Fluid;Peritoneal lavage;Pharmaceutical Preparations;Platinum;Prions;Process;Prognosis;Proliferating;Proteins;Recurrence;Reporting;Research;Resistance;Role;Rupture;Sampling;Screening for Ovarian Cancer;Sensitivity and Specificity;Serous;Serum;Signal Pathway;Signal Transduction;Site;Squamous cell carcinoma;Survival Rate;Testing;Testis;Therapeutic;Time;Tissues;Translating;Transvaginal Ultrasound;Treatment Efficacy;Tumor Angiogenesis;Up-Regulation;Vascular Endothelial Growth Factors;Woman;angiogenesis;cancer cell;carcinogenesis;chemotherapy;clinical diagnosis;detection method;diagnostic tool;doppel protein;druggable target;effective therapy;improved;indexing;insight;male fertility;malignant ascites;molecular marker;mortality;novel;novel marker;novel therapeutic intervention;ovarian neoplasm;prion-like;programs;receptor;reproductive organ;restraint;side effect;targeted treatment;therapeutic target;tumor;tumor endothelial marker 8;tumor progression The role of tumor endothelium-specific prion-gene PRND in epithelial ovarian cancer NARRATIVEOvarian cancer is the deadliest gynecological disease that accounts for approximately 140000 annual femaledeaths worldwide and because of the ovarian cancers highly aggressive nature the overall survival rate inovarian cancer patients remains poor despite of recent advances in targeted therapies. We have identified anovel player Doppel in the blood vessels of tumors and found that Doppel collaborates with tumors in creatingnew blood vessels for them by controlling the actions of VEGF. Since this protein has no known function infemale reproductive organs we now propose to study the applicability of Doppel as a therapeutic option and toits role in the formation malignant ascites in epithelial ovarian cancer. NCI 10687005 8/3/23 0:00 PAR-21-061 5R21CA264627-02 5 R21 CA 264627 2 "RODRIGUEZ, LARITZA MARIA" 9/1/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OBT-D(55)R] 16171554 "AL-HILAL, TASLIM A" Not Applicable 16 BIOSTATISTICS & OTHER MATH SCI 132051285 C1DEGMMKC7W7 132051285 C1DEGMMKC7W7 US 31.770518 -106.504149 578405 UNIVERSITY OF TEXAS EL PASO EL PASO TX SCHOOLS OF ARTS AND SCIENCES 799680001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 173855 NCI 114538 59317 Project SummaryAmong all of the gynecological cancers ovarian cancer shows high clinical challenge because it is difficult to bedetected in the early stage and it has the highest mortality rate. Despite advances and the development ofdiagnostic tools such as biomarkers and detection techniques ovarian cancer remains a fatal cancer with highprogression. There are different types of ovarian cancer based on histological classification; Epithelial OvarianCancer (EOC) is the most common. EOC is identified in over 80% of women at late-stage with complicationsinclude the spread of tumor implants throughout the peritoneal cavity. Thus it is necessary to find newbiomarkers with high specificity and sensitivity to detect ovarian cancer in the early stages of disease. Recentlywe identified a highly conserved membrane-associated prion-like protein Doppel that express only in tumors andregulate the functions of VEGF in tumors. Furthermore we demonstrated that Doppel interacts and collaborateswith VEGFR2 to stimulate tumor angiogenesis. Previous studies thus confirmed our conjecture that Doppel is aTEC-specific marker and an optimal target for anti-tumor therapy. We hypothesize that Doppel drives ovariancancer progression. The ultimate goals of this proposal are to evaluate whether Doppel expression could beutilized as an EOC-specific serum biomarker and to develop a novel therapeutic strategy by targeting Doppelagainst both platinum-sensitive and platinum-resistant EOCs. The two specific aims of this study are: (1) Toassess Doppel as a serum biomarker and the degree of Doppel expression in ovarian cancers and (2) To studythe role of Doppel in malignant ascites formation in a microfluidic-based organoid and orthotopic model of EOC.We will shed lights into the processes that regulate and intensify the Doppel-regulated ascites formation inovarian tumors. The proposed research will elucidate the relationship between Doppel expression malignantascites formation and neoangiogenesis in ovarian cancers. The homologous similarity between human andmurine Doppel protein also suggest that a candidate mouse anti-Doppel mAb can be translated into clinical useby humanizing it. 173855 +No NIH Category available Acute Myelocytic Leukemia;Advisory Committees;Biological Assay;Blood;CRISPR screen;Cancer Center;Cell physiology;Cells;Clinical;Complex;Custom;Data;Dependence;Development;Disease model;Education;Environment;Evaluation;Faculty;Gene Expression;Gene Expression Regulation;Gene Mutation;Genetic;Genetic Screening;Genetic Transcription;Goals;Hematologic Neoplasms;Hematology;Hematopoiesis;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Human;Immunology;In Vitro;Individual;Institution;Intelligence;Investigation;Knockout Mice;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mediating;Medical Oncology;Medicine;Memorial Sloan-Kettering Cancer Center;Mentors;Mentorship;Modeling;Molecular;Mus;Mutation;Myelogenous;Myeloproliferative disease;Pathogenesis;Patient Care;Pharmaceutical Preparations;Phase I/II Trial;Physicians;Physiology;Play;Privatization;Production;Proteins;RNA Binding;RNA Processing;RNA Recognition Motif;RNA Splicing;RNA-Binding Proteins;Research;Role;Safety;Scientist;Somatic Mutation;Sulfonamides;Therapeutic;Therapeutic Index;Tissues;Toxic effect;Training;Translations;Ubiquitin;Work;acute myeloid leukemia cell;anti-cancer;cancer cell;cancer type;career;cell type;conditional knockout;experience;experimental study;functional genomics;in vivo;innovation;insight;leukemia;leukemia initiating cell;member;mouse model;novel;novel therapeutics;patient derived xenograft model;patient population;pharmacologic;progenitor;programs;protein function;side effect;skills;tenure track;therapeutic evaluation;ubiquitin ligase Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis PROJECT NARRATIVEA class of drugs called the `anti-cancer sulfonamides' were recently discovered to work by targeting anddestroying a key cellular protein called RBM39. We have recently shown that a form of blood cancer known asacute myeloid leukemia (AML) which have mutations of genes involved in RNA splicing are particularlysensitive to these drugs; we now seek to understand more about the function of RBM39 in the normal body(including normal blood production) as well as its function in the development of blood cancers. We hope thatthis research will both help us understand more about how blood cancers develop and to more intelligentlyoptimize the anti-cancer sulfonamides to minimize side-effects from destroying RBM39 in non-cancerous cells. NCI 10686988 6/19/23 0:00 PA-19-117 5K08CA245242-04 5 K08 CA 245242 4 "BIAN, YANSONG" 7/1/22 0:00 6/30/25 0:00 Career Development Study Section (J)[NCI-J] 14647164 "LU, SYDNEY X" Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 241634 NCI 223735 17899 PROJECT SUMMARY/ABSTRACTResearch: RNA binding proteins (RBPs) regulate diverse cellular processes including transcriptiontranslation and regulation of gene expression and are frequently dysregulated in cancers. Through anunbiased genetic screen aimed at identifying cancer-specific RBP dependencies we recently identifieda specific requirement for RBM39 in malignant myeloid cancers and that cancers bearing RNA splicingfactor mutations as being particularly sensitive to the anti-cancer sulfonamides. RBM39 is an RBP thatfunctions in RNA splicing and recently a class of clinical-grade anti-cancer sulfonamide compoundswere demonstrated to degrade RBM39 protein by co-opting the Ddb1/CUL4 ubiquitin-ligase complex astheir mechanism of action. Thus the primary goal of this project is to assess differential andtissue-specific requirements for RBM39 in normal hematopoiesis versus myeloid malignanciesand to assess requirements for RBM39 for leukemia initiation and maintenance. This proposal willutilize a novel conditional knockout (cKO) mouse for Rbm39 and several associated newly developed invitro and in vivo murine models to pursue this goal. We expect these investigations to further ourunderstanding of the role of RBM39 in normal physiology and cancer as well as provide newtherapeutic insights into the on- and off-target toxicities of the anti-cancer sulfonamides. These goalsare particularly timely given that several of these molecules have already proven excellent safety inmultiple phase I/II trials and are now ripe for therapeutic testing in a patient population most likely tobenefit from RBM39 degradation. Candidate: Dr. Sydney X. Lu is a graduating hematology & medicaloncology fellow in the Department of Medicine at MSKCC. He aims to become an independent tenure-track physician-scientist investigating the molecular pathogenesis of hematological malignancies througha combination of genetics functional genomics and murine modeling. Dr.Lu has outlined a five-year periodof mentored training to strengthen his skills in functional genomics and disease modeling. This trainingperiod will be carried out under the mentorship of Dr. Omar Abdel-Wahab a leader in the functionalgenomics of hematopoietic malignancies. Dr. Lu has also assembled an advisory committee composed ofDrs. Ross Levine Martin Tallman Michael Kharas and Christine Mayr who will help guide his trainingand research. Environment: MSKCC is the world's oldest and largest private cancer center devotingmore than 130 years to exceptional patient care innovative research and outstanding educationalprograms. MSKCC exposes trainees to an exceptionally robust academic research environment with astrong commitment and track record of successfully supporting junior faculty who are seeking careersas independent physician-scientists. 241634 +No NIH Category available Active Learning;Age;Applications Grants;Area;Award;Bachelor's Degree;Biomedical Research;Black race;Cancer Science;Caring;Cities;Collaborations;Community Outreach;Comprehensive Cancer Center;Depressed mood;Disparity population;Education;Education Projects;Educational Activities;Educational Curriculum;Educational process of instructing;Ethnic Origin;Ethnic Population;Faculty;Family;Fostering;Friends;Funding;Goals;Grant;Health Promotion and Education;Healthcare;High School Faculty;High School Student;Hispanic;Household;Immersion;Income;Intervention;Knowledge;Learning;Malignant Neoplasms;Mentors;Mentorship;Middle School Student;Minority Groups;Ohio;Population;Poverty;Prevention Research;Process;Psychological reinforcement;Research;Research Personnel;Risk Reduction;Schools;Science;Students;Training;Underrepresented Minority;United States National Institutes of Health;Universities;Work;Youth;anticancer research;cancer care;cancer education;cancer health disparity;cancer prevention;cancer risk;career;college;community engagement;curriculum development;curriculum enhancement;design;disparity elimination;experience;faculty mentor;family building;graduate school;health care delivery;health care disparity;health disparity;high school;improved;innovation;interest;junior high school;medical schools;member;metropolitan;minority communities;outreach;programs;school district;science teacher;skills;suburb;teacher;undergraduate student;underrepresented minority student;university student;urban school Case CCC Youth Engaged in Science 09/01/2022-08/31/2027 PROJECT NARRATIVEThe R25 YES Program under the auspices of the Case CCC will develop and implement cancer education research immersion community outreach and curriculum development targeted at middle school high school and undergraduate college students as well as to their teachers families and friends to foster better understanding of the cancer process promote risk reduction strategies encourage elimination of cancer disparities and stimulate pursuit of careers in cancer research and healthcare delivery. NCI 10686983 8/14/23 0:00 RFA-CA-21-020 5R25CA221718-07 5 R25 CA 221718 7 "LOPEZ, BELEM G" 9/18/17 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 8803653 "BERGER, NATHAN A." Not Applicable 11 PUBLIC HEALTH & PREV MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 315251 NCI 400000 32000 PROJECT SUMMARY/ABSTRACTThe overall objective of this R25 Youth Enjoy Science (YES) Grant Application from the Case Comprehensive Cancer Center Case Western Reserve University Cleveland Ohio aims to support develop and implement exciting education research immersion outreach and curriculum development activities to attract and mentor URM students in middle and high school progressing to college undergraduate and science teachers to enhance diversity of the cancer healthcare and research workforce. This program is a partnership between the Case CCC supporting all cancer related research efforts at CWRU with the surrounding area schools of the Cleveland Metropolitan School District and East Cleveland Schools both of which are an economically and academically challenged urban school districts. Cleveland is recognized as being one of the poorest major cities in the U.S. This R25 program for URM students their teachers and families build and expands on our successful high school student targeted Scientific Enrichment and Opportunity Program and our experience with the R25 YES Program. These programs have been developed to engage promising high school students from the CMSD to interact with the SOM faculty to participate in exciting longitudinal research experience to enhance student interest in pursuing careers in biomedical research and healthcare professions especially as they relate to cancer. The R25 YES Program extends and enhances our efforts to provide a coordinated sequentially integrated approach consisting of 1) Learn to Beat Cancer a program targeted to engage URM Cleveland area middle school students their families and teachers to become knowledgeable about cancer prevention and cancer research opportunities; 2) Research to Beat Cancer a program designed to attract promising URM Cleveland high school and undergraduate students to cancer education and research immersion opportunities at the Case CCC; and 3) Teach to Beat Cancer a program designed to provide special research and education opportunities for teachers of URM students to enhance their cancer related knowledge and education skills engage in curriculum development and enhance their enthusiasm and ability to promote careers in cancer research and diversity in the biomedical work force as well as to further engage the community for increased interaction with the Case CCC. 315251 +No NIH Category available Astrocytes;Binding;Biology;CRISPR/Cas technology;Cell Differentiation process;Cell Nucleus;Cell membrane;Cells;Chimeric Proteins;Coculture Techniques;Complex;Coupled;Cytoplasm;Disease;Emerging Technologies;Engineering;Ensure;Event;Excision;Family;Gene Expression;Genetic Transcription;Genome engineering;Genomics;Hour;Human;Imaging technology;Ions;Kinetics;Knock-in;Knowledge;Label;Laboratories;Life;Ligands;Light;Location;Malignant Neoplasms;Mammals;Mass Spectrum Analysis;Measures;Membrane;Microscopy;Modeling;Molecular;Monitor;Movement;Optics;Output;Pathogenesis;Pathogenicity;Pathway interactions;Physiological;Process;Proteins;Proteolysis;Proteomics;Receptor Activation;Resolution;Scanning Electron Microscopy;Series;Signal Transduction;Signal Transduction Pathway;Site;System;Technology;Therapeutic;Time;Travel;Visualization;Visualization software;Work;adaptive optics;endosome membrane;experimental study;extracellular;frontier;gamma secretase;in vivo;inhibitor;notch protein;optical lattices;receptor;recruit;response;spatiotemporal;stoichiometry;transmission process Dynamics of Notch Signaling Project NarrativeSignal transduction pathways underlie the very basis of life and are often critical targets for disease therapeutics.This work focuses on the molecular events of Notch signaling which exerts a critical influence on celldifferentiation in mammals and its misregulation is associated with diverse diseases including the pathogenesisof many human cancers. This work will use two emerging technologies proximity labeling and lattice light sheetmicroscopy to provide unprecedented resolution in both space and time of the fundamental events required fortransmission of physiologic Notch signals in living cells. NCI 10686971 8/8/23 0:00 PA-20-185 5R01CA272484-02 5 R01 CA 272484 2 "AMIN, ANOWARUL" 9/1/22 0:00 8/31/27 0:00 Cellular Signaling and Regulatory Systems Study Section[CSRS] 1884664 "BLACKLOW, STEPHEN C." Not Applicable 7 BIOCHEMISTRY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 647956 NCI 485582 162374 Project SummarySignal transduction pathways underlie the very basis of life and are often critical targets for disease therapeutics.Yet precise understanding of the intracellular dynamics kinetics and stoichiometry of how signals aretransmitted knowledge that is critical to capturing a holistic and more accurate view of signaling processes has not been attainable for many pathways due to technological barriers to observing signaling events in realtime in cells. Recent advances in technology including proximity labeling approaches and light sheetmicroscopy are finally now presenting solutions to knit together our fragmented view of signaling in vivo. Buildingon the expertise of the Blacklow laboratory in Notch signaling mechanism with the expertise of the Kirchhausenlaboratory in advanced microscopy we propose to use the Notch signaling system as a model to define preciselythe series of events required for Notch signal activation in normal and pathogenic states and in so doing developapproaches and computational visualization tools that can be broadly applied to other pathways and systems.Notch signaling is an ideal model signaling system for this work because it exerts a critical influence on celldifferentiation in all metazoans and its misregulation is associated with diverse diseases including thepathogenesis of many human cancers. Moreover fundamental facets of this signaling mechanism including thedynamics of ligand and receptor molecules the stoichiometry of ligand-receptor complexes at sites of activationthe timing and location of activating Notch proteolysis and the path of Notch from plasma membrane to nucleusremain incompletely understood. Here we will address these gaps in knowledge by using APEX proximitylabeling coupled with quantitative mass spectrometry to elucidate the pathway for passage of the Notchintracellular domain from plasma membrane to nucleus and by implementing lattice light sheet microscopy tovisualize the molecular events of Notch signal transduction. In preliminary work we have used CRISPR/Cas9genomic labeling in SVG-A immortalized astrocytes to create a Notch-APEX2 fusion protein for proximitylabeling and our preliminary analysis of a pilot experiment reveals dynamic changes in the labeling of proteinsin different cellular compartments as a function of time confirming the feasibility of this approach. We have alsoengineered fluorescently labeled receptor and ligand knockin proteins for LLSM. Now we will use this approachto quantify the number of receptor and ligand molecules that come together at the site of cell-cell contact as afunction of time and determine how many copies of each must be present to induce receptor cleavage andactivate target gene expression. Successful completion of these aims will provide unprecedented resolution inboth space and time of the fundamental events required for physiologic Notch signal transduction in living cells.We expect to not only answer long-standing questions about the molecular events involved in activation of Notchsignals but to also open up a whole new realm of biology to mechanistic analysis. 647956 +No NIH Category available Abstinence;Acquired Immunodeficiency Syndrome;Address;Adoption;Adult;Africa;Africa South of the Sahara;African;Behavioral;Biochemical;Bupropion;California;Caring;Cessation of life;Clinic;Clinical;Communities;Community Health;Counseling;Country;County;Data;Diagnosis;Disease;Education;Enrollment;Epidemic;Evaluation;Family;General Population;Guidelines;HIV;HIV Infections;Health;Health Personnel;Health care facility;Heart Diseases;Intervention;Kenya;Malignant Neoplasms;Medical Research;Modeling;Morbidity - disease rate;Participant;Patient Self-Report;Patients;Persons;Pharmacotherapy;Policies;Population;Prevalence;Primary Care;Randomized Controlled Trials;Recommendation;Reporting;Research;Research Institute;Risk;San Francisco;Services;Site;Smokeless;Smoking;Socioeconomic Status;Telemedicine;Telephone;Testing;Tobacco;Tobacco Dependence;Tobacco Use Cessation;Tobacco use;Universities;Woman;antiretroviral therapy;brief advice;brief intervention;clinical care;comorbidity;comparative cost effectiveness;compare effectiveness;coping;cost effective;cost effectiveness;evidence base;evidence based guidelines;experience;formative assessment;group intervention;high risk;improved;innovation;men;mortality;nicotine replacement;primary care setting;quitline;recruit;reduce tobacco use;response;scale up;social culture;symposium;tobacco cessation intervention;tobacco control;tobacco user Integrating tobacco use cessation into HIV Care and Treatment in Ministry of Health Facilities in Kisumu County Kenya PROJECT NARRATIVEPeople living with HIV (PLHIV) have higher rates of tobacco use than the general population and higher ratesof disease and death compared with PLHIV who do not use tobacco. Support for tobacco use cessation forPLHIV is needed. This project will evaluate the impact (tobacco use cessation rates) of integrating an intensivetobacco use cessation intervention (compared to integrating a brief intervention) into HIV care clinics in KisumuCounty Kenya. NCI 10686945 8/17/23 0:00 RFA-CA-20-037 5U01CA261620-03 5 U01 CA 261620 3 "RICCIARDONE, MARIE D" 9/16/21 0:00 8/31/26 0:00 ZCA1-SRB-2(M1) 8879004 "BIALOUS, STELLA AGUINAGA" Not Applicable 11 OTHER HEALTH PROFESSIONS 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF NURSING 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 719121 NCI 513214 205907 ABSTRACTPeople living with HIV (PLHIV) are more likely to use tobacco than the general population. PLHIV who usetobacco have higher mortality rates and risk for co-morbidities including diseases caused by tobacco whencompared to PLHIV who do not use tobacco. Sub-Saharan African continues to be the epicenter of HIVinfection while experiencing an increase in tobacco consumption. There is evidence that PLHIV in Africa aremore likely to use tobacco than the general population. Kenya is an example of a country coping with the dualepidemic of HIV and tobacco with an estimated 1.5 million PLHIV and 2.5 million tobacco users. HIV remainsone of the country's leading causes of morbidity and mortality with an estimated 46000 adults acquired HIVand 25000 persons died of HIV in 2018. Tobacco use among the general population is estimated to be 11.6%(19.1% among men and 4.5% among women). The impact of tobacco use among PLHIV in Kenya has yet tobe fully understood. There have been no research or initiatives in Kenya to support PLHIV to quit tobacco usein a primary care setting a gap that this proposal seeks to address. In 2017 Kenya's Ministry of Healthlaunched the National Guidelines for Tobacco Dependence Treatment and Cessation. This project willevaluate integration of the Guidelines' interventions into HIV care clinics through the Family AIDS Care &Education Services (FACES). FACES is a 16 years-partnership between the Kenya Medical ResearchInstitute the University of California San Francisco and the Kisumu County Ministry of Health. FACES havetested over 1.5 million people for HIV diagnosing over 21000 people and currently serves over 51000 PLHIVon ART in 61 sites in Kisumu County. We will conduct a cluster randomized controlled trial at 20 FACES-supported clinics recruiting 580 patients to compare the effectiveness and cost-effectiveness of an intensive(Nicotine Replacement Therapy and Bupropion 12 sessions of behavioral counseling through in-person andtelemedicine approaches (telephone and texts) and provision of a quitline number) versus a brief (one-timecounseling plus the quitline number) intervention. We hypothesize that 15% of intensive intervention groupparticipants will achieve biochemically verified 7-day Point Prevalence Abstinence at 12 months compared tothe brief intervention group quit rate of 5%. We will offer the intensive intervention to brief intervention groupparticipants who continue to use tobacco at 12 months. Prior to the trial we will conduct a formative evaluationto tailor the Guidelines to PLHIV and after the trail we will assess assessing barriers to and facilitators ofadoption implementation and factors associated with scalability/sustainability of the intervention. Theproposed study will determine the most cost-effective strategy to integrate tobacco use cessation within HIVcare in a community health setting. The project's results will inform policies to scale up tobacco dependencetreatment within HIV primary care centers across the country and serve as a model for the region. 719121 +No NIH Category available Oncology;Training Programs;comparative UC Davis Comparative Oncology Training Program Project NarrativeThe UC Davis Comparative Oncology T32 program will provide an outstanding environment for biomedicalresearch training. The goal is to train 1) veterinarian- and physician-scientists and 2) graduate studentspursuing dual DVM-PhD degrees to integrate the study of companion animals which have naturallyoccurring cancers with human cancer biology and therapy (comparative oncology). This will create a newgeneration of scientists engaged in basic and translational cancer research that advances the health ofpeople and animals. NCI 10686927 9/1/23 0:00 PA-18-403 5T32CA251007-04 5 T32 CA 251007 4 "DAMICO, MARK W" 9/1/20 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 2091014 "CHEN, XINBIN " "CANTER, ROBERT J.; KENT, MICHAEL SEAN" 4 VETERINARY SCIENCES 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF VETERINARY MEDICINE 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 290518 NCI 427870 32550 Project Summary/AbstractPreclinical animal models have been the foundation for the development of novel cancer therapies. Historicallythis foundation has relied on mouse models. While mouse models are fundamentally important the models areinsufficient and need to be complemented. Companion animals are an important combination of outbredanimals that have spontaneous cancer development with an intact immune system and have environmentaland epigenetic exposures as humans. Tackling complex cancer research problems should includeinvestigators with broad experience across animal and human species presenting a unique opportunity forDVMs and MDs to have a crucial role in basic to translational research. Veterinarians can strengthencomparative approaches essential to multidisciplinary research accelerating innovative treatments for animalsand humans. Medical doctors bring a patient-centered approach linking biology with clinical therapy.Unfortunately recruiting and retaining biomedical scientists with comparative oncology expertise especiallyDVM or MD clinician-scientists continues to be a challenging issue facing the broader research community.The Comparative Oncology Training Program (T32) will provide an outstanding environment to trainpredoctoral (DVM/PhD) students and post-DVM or post-MD fellows who are interested in cancer research. Toaccomplish this goal Drs. Chen Kent and Canter (MPIs) organized a diverse team of twenty-seven UC Davisfaculty mentors from the School of Veterinary Medicine School of Medicine College of Biological ScienceCollege of Agricultural and Environmental Sciences and College of Engineering. The faculty mentors areaccomplished biomedical investigators with NCI or cancer-related funding. The proposed program will leveragethe NCI-designated UC Davis Comprehensive Cancer Center and will be fully integrated into the Centerscancer education program. The T32 programs objectives are to: 1) recruit and retain a diverse group ofclinician-scientists that prepares them to become future leaders in academia government service and publichealth 2) expose the T32 scholars to cancer-focused career paths and 3) train the scholars to usecomparative medicine to address human cancer biology. The objectives will be accomplished by providing upto 3-year funding support for DVM/PhD dual-degree predoctoral students and post-DVM or post-MDpostdoctoral fellows. During the training the T32 scholars will enhance their knowledge through tailoredcoursework mentored research multidisciplinary interactions and career development activities. By the endof the grant period we expect to train eleven professionals encompassing two dual-degree DVM/PhDstudents seven post-DVM fellows and two post-MD fellows to become highly-qualified basic and translationalcomparative oncology researchers. 290518 +No NIH Category available Acceleration;Address;Admission activity;Adult;Basic Science;Body mass index;Budgets;Cancer Center;Cancer Control;Cancer Survivor;Categories;Clinical Sciences;Communities;Complex;Country;Development;Disease;Dissemination and Implementation;Educational workshop;Elderly;Extramural Activities;Faculty;Feedback;Funding;Goals;Grant;Hybrids;Immunotherapy;Incidence;Individual;Institution;Intervention;Investments;Journals;Knowledge;Low Prevalence;Low income;Malignant Neoplasms;Manuscripts;Mentors;Mentorship;Mission;Newsletter;Obesity;Obesity associated cancer;Oncology;Participant;Patient Care;Patients;Peer Review;Persons;Population;Population Sciences;Populations at Risk;Prevalence;Principal Investigator;Public Health Schools;Publications;Publishing;Research;Research Personnel;Resources;Risk Factors;Role;Scientist;Training;Training Programs;Unhealthy Diet;Work;Yale Cancer Center;anticancer research;cancer risk;career;career development;clinical care;clinical training;education research;energy balance;ethnic minority;evidence base;faculty mentor;immune function;improved;innovation;lifestyle intervention;microbiome;mortality;next generation;novel;peer coaching;physical inactivity;population health;programs;racial minority;recruit;residence;rural setting;skills;training opportunity;virtual;virtual education;webinar Transdisciplinary Research in Energetics and Cancer (TREC) Training Grant NarrativeThe overall goal of this NCI R25 competitive renewal research education program is to offer evaluate anddisseminate a transdisciplinary research in energetics and cancer (TREC) Training Program with virtualeducational programs a 5-day in-person workshop and a year-long mentorship program for early careerinvestigators with the goal of enhancing the ability of participants to conduct innovative transdisciplinaryresearch in energetics and cancer research and clinical care. Our TREC Training Program is highly innovativein that currently no training opportunity course or workshop exists that focuses on energetics and cancerresearch. The overall impact of this transdisciplinary training program will be defined by the degree to whichprogram participants produce novel and innovative research approaches and discoveries (through fundingpresentations and publications) which in turn may improve the health of the population at risk for cancer aswell as cancer survivors. NCI 10686914 8/21/23 0:00 PAR-18-477 5R25CA203650-08 5 R25 CA 203650 8 "ZAHIR, NASTARAN" 7/1/16 0:00 8/31/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 6577070 "IRWIN, MELINDA L" Not Applicable 3 PUBLIC HEALTH & PREV MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 317043 NCI 300000 17186 AbstractGiven the rising prevalence of obesity poor diet and physical inactivity known in combination as energybalance or energetics as well as their associations with cancer incidence and mortality innovative researchclinical care and training of scientists are needed to lower the prevalence of these risk factors and in turn lowercancer incidence and mortality rates. In September 2020 the NCI released its Fiscal Year 2022 Budgetproposal which includes obesity and cancer as a featured scientific topic and training the next generation ofcancer researchers as a key investment. With NCI R25 support from 2016-2021 we developed and offered anannual one-week in-residence Transdisciplinary Research in Energetics and Cancer (TREC) Training Coursefollowed by a yearlong mentoring program that focused on energy balance and cancer research across thecancer control continuum. The overall goals of this Program were to educate train and mentor 100 earlycareer investigators called TREC Fellows from diverse academic backgrounds (i.e. basic clinical andpopulation sciences) in transdisciplinary research in energetics and cancer. For the first four years of TRECwe admitted and trained 97 Fellows from 57 different institutions. We are in our 5th year of our TREC Programand expect to recruit 20 more Fellows for a total of 117 Fellows completing the TREC Training Program.TREC Fellows have published 270 manuscripts in peer-reviewed journals with 62 published manuscriptsincluding the TREC Fellow as first or senior author and including a TREC Faculty and/or Fellow as co-author.Since completing the Program TREC Fellows have received 31 extramural grants as principal investigator.Building upon the strengths of the previous five years but responsive to additional opportunities for training andfurther dissemination of the course the goals of our competitive renewal are: 1) to offer a hybrid TRECTraining Program with virtual TREC Faculty-led programs before the in-person workshop focused onincreasing content knowledge; 2) followed by a 5-day in-person workshop focused on the Fellows researchnetworking and professional development; and 3) year-long mentorship between the Fellow and FacultyMentor and Peer Mentor. Led by Dr. Melinda Irwin and drawing from the resources of the Yale School of PublicHealth Yale Cancer Center and ~20 expert TREC Faculty from across the country and 100+ TREC Fellowalumni from around the world our TREC Program is innovative in that currently no training opportunity existsthat focuses on energetics and cancer research. Our goal is to continue the TREC mission of training scientiststo develop a cadre of well-trained diverse researchers. The overall impact of this program will be defined bythe degree to which TREC Fellows produce innovative research approaches and discoveries therebyaccelerating the dissemination and implementation of evidence-based approaches into everyday practice andpatient care in turn improving the health of the population at risk for cancer as well as cancer survivors. 317043 +No NIH Category available Ablation;Astrocytes;Binding;Binding Proteins;Biological Assay;Biotinylation;CDC2 gene;Cell Death;Cell Nucleus;Cells;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNA Damage;DNA Repair;Data;Development;Double Strand Break Repair;Engineering;Engraftment;Generations;Glioblastoma;Glioma;Homologous Protein;In Vitro;Ionizing radiation;Knock-in;Knock-in Mouse;Lipids;Malignant - descriptor;Malignant Neoplasms;Mediating;Methods;Missense Mutation;Modality;Modeling;Molecular;Mus;Mutagens;Mutate;Mutation;N-terminal;Nuclear;Oncogenic;PIK3CG gene;PTEN gene;Patients;Peptides;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Post-Translational Protein Processing;Primary Brain Neoplasms;Publishing;Radiation Tolerance;Radiation therapy;Radiosensitization;Recurrence;Regulation;Resistance;Role;Signal Transduction;Site-Directed Mutagenesis;Streptavidin;Testing;Therapeutic;Transfection;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tyrosine Phosphorylation;Validation;aurora B kinase;chemotherapy;design;epidermal growth factor receptor VIII;experimental study;homologous recombination;in vivo;inhibitor;mimetics;molecular dynamics;mouse model;neoplastic cell;novel;novel therapeutics;overexpression;pharmacologic;prevent;radiation resistance;recruit;response;standard of care;stem-like cell;therapy resistant;tumor Investigating PTEN:Ki-67 interaction and its role in DNA damage repair Project NarrativeResistance to therapy that induces tumor cell death through DNA damage such as elicited by ionizing radiation(IR) is common in many cancers1012. This project aims to characterize known PTEN protein interactions in thecell nucleus to interrogate the mechanisms through which this tumor suppressor gene confers such resistance.Methods for disrupting these interactions will be tested for their effect on IR sensitivity homologousrecombination chromatin regulation and their potential use in the development of novel therapeutics. NCI 10686913 9/8/23 0:00 PA-21-051 5F31CA257380-03 5 F31 CA 257380 3 "BOULANGER-ESPEUT, CORINNE A" 9/15/21 0:00 9/14/24 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 16089861 "JONES, BRANDON MARSHALL" Not Applicable 50 OTHER BASIC SCIENCES 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF ARTS AND SCIENCES 920930621 UNITED STATES N 9/15/23 0:00 9/14/24 0:00 398 "Training, Individual" 2023 40623 NCI 40623 0 Project SummaryGlioblastoma (GBM) is the most aggressive and common malignant primary brain tumor1. Standard of care forGBM patients involves chemotherapy and ionizing radiation (IR) which induce DNA damage to kill tumor cells;however resistance to these treatment modalities commonly develop through various mechanisms24. One novelmechanism of radioresistance identified in the Furnari lab is through enhanced homologous recombination (HR)DNA damage response (DDR) mediated by nuclear-localized tyrosine-phosphorylated PTEN (pY240-PTEN)recruited to chromatin through interaction with the PP1 Binding Domain (PP1BD) of Ki-675. PTEN (Phosphataseand Tensin Homolog) is known to play an important tumor-suppressive role and is found to be mutated inapproximately 40% of GBMs6. While PTEN cytosolic lipid phosphatase activity inhibition of PI3K signaling hasbeen well established78 the function of nuclear PTEN remains less clear. A Y240F-PTEN knock-in mouse modelhas shown that loss of Y240 phosphorylation results in IR sensitivity5. Preliminary experiments also indicatePTEN:Ki-67 interaction can be disrupted by overexpressed PP1 which binds to the RVxF small linearinteracting motif (SLiM) located in the Ki-67 PP1BD and through use of a competitor peptide based on the Ki-67-Repoman SLiM (KiR-SLiM)59. I hypothesize that Ki-67 dependent pY240-PTEN facilitated DDR isregulated by currently uncharacterized interactions within SLiMs of the Ki-67 PP1BD and thatcharacterization of these interactions will enable development of complex-disrupting peptides capableof radiosensitizing glioma cells. I will firstly identify residues in the Ki-67 KiR-SLiM motif that are essential forpY240-PTEN interaction. This will be accomplished via streptavidin pulldown of N-terminal biotinylated peptidesdesigned based on the KiR-SLiM. Orthogonally Ki-67 minigene constructs harboring mutation of the identifiedPP1BD residues will be utilized in GBM models to examine their effects on PTEN:Ki-67 interaction as well asDDR HR chromatin accessibility and colony formation efficiency. Competitor peptides will be designed basedon candidate Ki-67 residues and evaluated for their ability to disrupt PTEN:Ki-67 interaction and radiosensitizeglioma cells. Secondly regulation of pY240-PTEN:Ki-67 interaction by posttranslational modification of Ki-67SLiMs by aurora B kinase and cyclin dependent kinase 1 will be investigated through site directed mutagenesisand pharmacological inhibition. Discoveries regarding SLiM regulation will be incorporated into competitorpeptides to optimize specific disruption of the pY240-PTEN:Ki-67 complex. Lastly mutations determined to havethe greatest impact on pY240-PTEN:Ki-67 interactions will be CRISPR edited into oncogenic mouse astrocyteswith WT versus knock-in Y240F PTEN and the effects of these mutations will be investigated in vitro and in vivo5.Overall this project aims to characterize the regulation and critical molecular interactions between pY240-PTENand Ki-67 culminating in strategies that will disrupt these interactions to enhance the efficacy of radiotherapy. 40623 +No NIH Category available Address;Adult;Affect;Biological Assay;Biological Markers;Biopsy;Blood;Brain Neoplasms;Central Nervous System Neoplasms;Cerebrospinal Fluid;Clinical;Collection;Data;Detection;Development;Diagnosis;Gene Frequency;Genes;Glioma;Lesion;Liquid substance;Magnetic Resonance Imaging;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Metabolic;Metabolic Pathway;Metabolism;Methodology;Methods;Molecular;Monitor;Morbidity - disease rate;Mutate;Mutation;Mutation Detection;Neoplasm Metastasis;Neoplasms;Nucleic Acids;Oncogenic;Patient Monitoring;Patients;Primary Neoplasm;Production;Public Health;Recurrent tumor;Research;Sampling;Sensitivity and Specificity;Source;Tissue Sample;Tissues;Tumor Burden;Tumor Tissue;Tumor Volume;Tumor-Derived;Validation;assay development;brain parenchyma;brain surgery;cancer cell;cancer type;clinical implementation;clinical practice;digital;effective therapy;experimental study;innovation;liquid biopsy;metabolomics;mortality;mutant;next generation sequencing;novel;novel strategies;pediatric patients;precision medicine;repository;targeted treatment;treatment response;tumor;tumor DNA Development and Validation of a CSF Liquid Biopsy for Molecular Characterization and Monitoring of Patients with Central Nervous System Tumors Project NarrativeThe proposed research is relevant to the public health because primary and metastatic central nervous system(CNS) tumors are associated with high morbidity and mortality; and few effective therapies are currentlyavailable. Upon conclusion of the study we will have developed and validated a CSF liquid biopsy assay forearly molecular characterization and monitoring of primary or metastatic tumors affecting the CNS. This willfacilitate the incorporation of precision medicine strategies in the management of adult and pediatric patientswith primary or metastatic CNS tumors and avoid the need for brain surgery in some patients. NCI 10686901 7/28/23 0:00 PAR-18-337 5K08CA241651-05 5 K08 CA 241651 5 "RODRIGUEZ, LARITZA MARIA" 9/11/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 15137301 "BALLESTER, LEOMAR Y" Not Applicable 9 PATHOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 260634 NCI 241328 19306 Project Summary/AbstractPrimary and metastatic central nervous system tumors (CNS) are associated with a high degree of morbidityand mortality. There is a need for new and more effective strategies for diagnosing treating and monitoringpatients with primary and metastatic CNS tumors. Methodologies that address the need for molecularinformation that is required for the use of precision medicine and targeted therapies in patients with CNStumors are limited. A liquid biopsy assay will facilitate early molecular characterization and monitoring ofpatients with CNS tumors and will revolutionize patient management. Studies have shown that blood is not asuitable fluid for the detection of tumor-derived biomarkers in patients with CNS malignancies. In contrastcerebrospinal fluid (CSF) due to its proximity to the brain parenchyma is a source of informative biomarkers(e.g. circulating tumor DNA (ctDNA) and metabolites). We hypothesize that it is possible to perform pre-operative molecular characterization and monitoring of patients with CNS tumors by analyzing ctDNA andmetabolites in the CSF. Moreover our prediction is that the levels of these biomarkers will correlate with tumorburden. We anticipate that quantification of these biomarkers in the CSF will facilitate monitoring patients withCNS cancer for tumor recurrence and response to therapies. Our preliminary experiments show that we canisolate ctDNA from small volumes of CSF and detect mutations by next generation sequencing (NGS) anddroplet digital PCR (ddPCR) at a mutant allele frequency of 0.25% and 0.1% respectively. We have alsoidentified tumor-specific metabolic signatures in the CSF and our data shows higher levels of D-2-hydroglyglutarate in the CSF of patients with CNS tumors harboring an IDH1/IDH2 mutation. We propose topursue two specific aims to develop a CSF-liquid biopsy assay: (1) Validation of a next generation sequencing(NGS) assay to quantify tumor DNA in CSF; (2) To perform metabolomic analysis of ~125 tumor-derivedmetabolites in CSF. This multi-platform approach will allow comparisons of sensitivity and specificity amongvarious methodologies and cross correlation of results between platforms. Volumetric analysis of CNS lesionsin MRI will allow us to evaluate the potential of each biomarker for quantifying CNS tumor burden. Weanticipate that these studies will culminate in the clinical implementation of a liquid biopsy assay to facilitatediagnosis and the use of targeted therapies in adult of pediatric patients with primary or metastatic CNStumors. 260634 +No NIH Category available Adopted;Algorithms;American Cancer Society;Benign;Biological Markers;Biomedical Engineering;Biopsy;Blinded;Cancer Patient;Carcinoma;Characteristics;Chicago;Clinic;Clinical;Clinical Management;Clinical Research;Coenzymes;Collaborations;Collagen;Data;Databases;Dentists;Detection;Diagnosis;Diagnostic;Drops;Dysplasia;Early Diagnosis;Endoscopes;Endoscopy;Epithelium;Evaluation;Excision;Face;Fluorescence;Frequencies;Future;Geometry;Goals;Health Professional;Histopathology;Image;Imaging Device;In Situ;Intraepithelial Neoplasia;Lesion;Life Expectancy;Malignant Epithelial Cell;Malignant Neoplasms;Metabolic;Metabolism;Mild Dysplasia;Minor Surgical Procedures;Mitochondria;Modality;Monitor;Monitoring for Recurrence;Neck;Operative Surgical Procedures;Optics;Oral;Oral Stage;Oral cavity;Oropharyngeal;Pathologic;Patient Recruitments;Patients;Pilot Projects;Predictive Value;Quality of life;Recurrence;Recurrent disease;Reporting;Research Personnel;Research Project Grants;Screening for Oral Cancer;Screening for cancer;Screening procedure;Sensitivity and Specificity;Specificity;Speed;Stains;Survival Rate;System;Technology;Testing;Time;Tissues;Work;automated algorithm;biomarker panel;cancer invasiveness;clinically relevant;computerized tools;cost;cost effective;design;diagnostic tool;early screening;exfoliative cytology;experience;fluorescence lifetime imaging;image processing;imaging biomarker;improved;in vivo;in vivo fluorescence;in vivo imaging;machine learning algorithm;malignant mouth neoplasm;noninvasive diagnosis;novel;optical imaging;oral cavity epithelium;oral dysplasia;oral lesion;precision medicine;prospective;salivary assay;success;tool;tumor;tumor progression;volunteer Endogenous fluorescence lifetime endoscopy for early detection of oral cancer and dysplasia Early detection of both new and recurrent oral cancer holds great promise for improving both the survival rate and the quality of live of these patients. The proposed work is to develop a clinical tool capable of quantifying noninvasively different biomarkers associated to oral epithelial cancer progression and detecting early stage oral cancer and dysplasia. Such tool will revolutionize oral epithelial cancer management by allowing not only early screening and diagnosis but also treatment guidance and monitoring for disease recurrence. NCI 10686883 8/3/23 0:00 PA-16-160 5R01CA218739-07 5 R01 CA 218739 7 "SALVADOR MORALES, CAROLINA" 2/2/18 0:00 8/31/24 0:00 Biomedical Imaging Technology A Study Section[BMIT-A] 8800452 "JO, JAVIER ANTONIO" Not Applicable 4 ENGINEERING (ALL TYPES) 848348348 EVTSTTLCEWS5 848348348 EVTSTTLCEWS5 US 35.209223 -97.443781 1524002 UNIVERSITY OF OKLAHOMA NORMAN OK BIOMED ENGR/COL ENGR/ENGR STA 730199705 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 288816 NCI 198504 90312 The American Cancer Society estimates that 48330 new cases of cancer in the oral cavity and pharynx will be reported this year. When diagnosed at early stages the 5-year survival rate is 83%. However when diagnosed at intermediate or advance stages the 5-year survival rate drops to 62% and 38% respectively. In addition while early stage treatment may only require minor surgery to remove the localized tumor later stage treatment could require surgical removal of parts of the face and neck hence drastically reducing the patients quality of life. Unfortunately benign oral lesions are sometimes difficult to distinguish from dysplasia or early invasive cancer even for healthcare professionals. As a result only 31% of patients are diagnosed at early stages despite the fact that the oral cavity is easily accessible for direct examination. Hence there is a critical need for new clinical technologies for reliable early diagnosis of oral cancer and dysplasia. Several screening tools for oral cancer have been commercially available including exfoliative cytology vital staining salivary test and optical interrogation; however none of them have been demonstrated to be capable of clinically relevant sensitivity and specificity. We hypothesize that several biomarkers for oral cancer and dysplasia can be accurately quantified by endogenous fluorescence lifetime imaging (FLIM) thus enabling levels of sensitivity and specificity adequate for early detection. This bioengineering research grant focuses on developing and validating a cost-effective wide-field multispectral FLIM endoscope for noninvasive in situ detection of oral cancer and dysplasia. To that end we have developed three specific aims. Aim 1: To design and build a cost-effective multispectral FLIM endoscope for in vivo imaging of epithelial tissue in the oral cavity. Aim 2: To develop algorithms for fast and automated FLIM based early detection of oral epithelial cancer and dysplasia. Aim 3: To quantify prospectively in a pilot clinical study the capability of the proposed FLIM endoscopic tools for noninvasively early detection of oral epithelial cancer and dysplasia. The successful completion of these aims will result in a novel accurate and cost-effective clinical tool for noninvasive in situ early detection of cancer and dysplasia. Such a tool could potentially help to improve significantly both the life expectancy and the quality of life for the more than 33000 oral cancer patients being diagnosed each year at intermediate and advance stages. Beyond early diagnosis this tool could also assist at every step involved on the clinical management of oral cancer patients including treatment guidance and monitoring of disease recurrence. Finally the demonstrated success of this clinical tool in oral epithelial cancer will herald future success with other cancers of epithelial origin which accounts for more than 80% of all cancers. 288816 +No NIH Category available Acceleration;Androgen Receptor;Androgens;Animal Model;Award;Bladder;Castration;Clinic;Clinical;Clinical Research;Common Neoplasm;Diagnosis;Doctor of Medicine;Ensure;Foundations;Funding;Future;Genitourinary system;Goals;Hormones;Human Resources;IACUC;Influentials;Institutional Review Boards;Kidney;Knowledge;Laboratories;Laboratory Personnel;Localized Disease;Malignant Neoplasms;Malignant neoplasm of prostate;Medical Castration;Metastatic Prostate Cancer;Methods;Mus;Operative Surgical Procedures;Outcome;Pharmacotherapy;Postdoctoral Fellow;Preparation;Prostate;Protocols documentation;Receptor Signaling;Regulation;Research;Research Design;Research Personnel;Resistance;Role;Safety;Scientist;Specialist;Steroids;Students;Technical Expertise;Techniques;Therapeutic;Training;Translational Research;Urogenital Cancer;Work;androgen deprivation therapy;anticancer research;bench to bedside;castration resistant prostate cancer;diagnostic tool;experimental study;in vivo;innovation;institutional biosafety committee;interdisciplinary collaboration;intratumoral androgen;new therapeutic target;programs;prostate cancer cell;resistance mechanism;response;skills;therapy resistant;translational study;tumor progression Translational science specialist in genitourinary cancers NARRATIVECastration-resistant prostate cancer is lethal and remains incurable and the NCI-funded research programdirected by Dr. Nima Sharifi seeks to understand mechanisms of resistance and identify new treatments. Ourrecently established Genitourinary Malignancy Research Center (GUMRC) is an interdisciplinary collaborationof research scientists and clinicians that focuses on understanding diagnosing and treating bladder kidney andprostate malignancy. This award will allow me to serve in complementary roles as a technical expert leadingexperiments in Dr. Sharifi's lab and Program Manager for the GUMRC. NCI 10686880 8/1/23 0:00 PAR-19-291 5R50CA251961-04 5 R50 CA 251961 4 "HILDESHEIM, JEFFREY" 8/13/20 0:00 7/31/25 0:00 ZCA1-SRB-1(M1)S 12563096 "BERK, MICHAEL P." Not Applicable 11 OTHER BASIC SCIENCES 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 165535 NCI 102817 62718 ABSTRACTThis Research Specialist proposal will support my 2 main roles in my Unit Director's (Nima Sharifi M.D.) researchprogram. My primary role is focused on laboratory management animal model (mouse) projects and clinicalstudies in my Unit Director's laboratory while my secondary role is as Program Manager for the GenitourinaryMalignancies Research Center (GUMRC) which is led by my Unit Director. For the Unit Director's laboratory inaddition to maintaining safety and compliance of all research personnel I am essential to the advancement oflaboratory techniques diagnostic tools and critical planning required to meet the goals of our NCI-funded andother cancer research. I am significantly involved in all in vivo animal model work including preparation andsubmission of all protocols to the Institutional Animal Care and Use Committee (IACUC) as well as the surgicaland technical portions of the experiments. I am instrumental in training our unit's personnel (clinical fellowsresidents postdocs technologists and students) in these critical techniques (both in vivo and lab based) in aneffort to maintain scientific congruence while ensuring that laboratory personnel adhere to IACUC InstitutionalReview Board and Institutional Biosafety Committee rules and regulations. For my Unit Director's laboratory ourprimary focus remains on prostate cancer. While treatment of localized disease results in favorable outcomesmetastatic prostate cancer remains incurable. The frontline treatment for advanced metastatic prostate canceris medical or surgical castration to reduce androgen hormone levels referred to as androgen deprivation therapy(ADT). When successful ADT reduces intratumoral androgens resulting in absence of androgen receptor (AR)signaling. However these tumors commonly develop ADT-resistance and are termed castration-resistantprostate cancer (CRPC). Our research goals focus on how prostate cancer cells can produce their own steroidsin response to ADT thus leading to cancer progression. By understanding the foundations of CRPC and themechanisms that drive therapeutic resistance we aim to identify new drug targets and treatments for diagnosisand treatment. For my Unit Director's clinical studies and extending into our GUMRC I participate in studyconceptualization and function as the intermediary between the Unit Director and our clinical collaborators. TheGUMRC is focused on basic and translational studies of GU malignancies (prostate bladder and kidney). Thecenter is an inter-disciplinary translational partnership that leverages Cleveland Clinic's research and clinicalstrengths to accelerate bench-to-bedside therapeutic discoveries. This Research Specialist award will allow meto 1) continue to provide my expertise in study design and technical skills for current and future NCI-funded GUprojects as well as to develop innovative methods to better achieve our goals and 2) develop greater knowledgeand the skills needed for effective program coordination and management that will enable our GUMRC to makerapid and influential advances in the treatment of GU malignancies. 165535 +No NIH Category available Adenine;Affinity;Base Pair Mismatch;Base Pairing;Binding;Biodistribution;Biological;Cell Proliferation;Cells;Chemicals;Clinical Management;Colorectal Cancer;Complex;Critical Pathways;Cytosine;DNA;DNA Binding;DNA Minor Groove Binding;DNA Repair;DNA Repair Pathway;Data;Development;Diagnostic;Eukaryotic Cell;Evaluation;Exhibits;Exposure to;Family;Family member;Generations;Genome;Genomic DNA;Halogens;Hand;Hereditary Nonpolyposis Colorectal Neoplasms;High Pressure Liquid Chromatography;Human;I131 isotope;In Vitro;Investigation;Iodine;Iodine Radioisotopes;Label;Ligands;Major Groove;Malignant Neoplasms;Mismatch Repair;Mismatch Repair Deficiency;Mus;Mutation;Nucleotides;Patient-Focused Outcomes;Patients;Performance;Phenanthrolines;Play;Polymerase;Positron;Positron-Emission Tomography;Prognosis;Protein Family;Radiation therapy;Radio;Radiolabeled;Radiopharmaceuticals;Rhodium;Role;Single Nucleotide Polymorphism;Site;Solid Neoplasm;Specificity;Syndrome;Technology;Thermodynamics;Thin Layer Chromatography;Toxic effect;Validation;Variant;Wit;Work;Xenograft procedure;analog;base;cancer cell;cellular development;chemical synthesis;colon cancer cell line;dosimetry;experimental study;gene repair;genome integrity;genotoxicity;imaging agent;improved;in vivo;in vivo evaluation;innovation;mouse model;novel;nuclear imaging;radiotracer;scaffold;subcutaneous;theranostics;therapeutic target;tool;tumor;tumor behavior;tumor growth;tumorigenesis Leveraging Metalloinsertors for the PET Imaging and Endoradiotherapy of MMR-Deficient Cancers PROJECT NARRATIVE The mismatch repair (MMR) machinery of the cell is responsible for detecting and correcting mispairedbasepairs in the genome. Cells with damaged MMR machinery are unable to repair DNA mismatches makingthem prone to the accumulation of mutations and ultimately tumorigenesis; to wit up to 20% of solid tumors -including hereditary nonpolyposis colorectal cancer - have been shown to be MMR-deficient. In the proposalat hand we describe our plan to harness octahedral rhodium complexes that bind DNA mismatches with highspecificity and affinity to create a pair of radioiodinated radiopharmaceuticals for the PET imaging andendoradiotherapy of MMR-deficient colorectal cancer. NCI 10686864 8/3/23 0:00 PA-21-051 5F31CA275334-02 5 F31 CA 275334 2 "ODEH, HANA M" 8/15/22 0:00 8/14/24 0:00 Special Emphasis Panel[ZRG1-F15-P(20)L] 78464523 "DELANEY, SAMANTHA PATRICIA" Not Applicable 12 CHEMISTRY 620127915 EK93EZLLBSC4 620127915 EK93EZLLBSC4 US 40.768737 -73.965182 1605019 HUNTER COLLEGE NEW YORK NY SCHOOLS OF ARTS AND SCIENCES 100655024 UNITED STATES N 8/15/23 0:00 8/14/24 0:00 398 "Training, Individual" 2023 33176 NCI 33176 0 PROJECT SUMMARY / ABSTRACT DNA repair pathways are critical for maintaining the integrity of the genome. Yet polymerase errors andexposure to genotoxic chemicals may lead to the dysregulation of the mismatch repair (MMR) machinery thefamily of proteins responsible for identifying and correcting mispaired bases in genomic DNA. When thismachinery malfunctions - or is absent altogether - single base mismatches can accumulate making cellsprone to the generation of single nucleotide polymorphisms (SNPs) and eventually tumorigenesis. Indeed upto 20% of all solid tumors have been shown to be MMR-deficient. Most notably MMR-deficiency plays asignificant role in the development of hereditary nonpolyposis colorectal cancer (HNPCC). The last twenty yearshave witnessed the development of octahedral rhodium complexes that selectively and specifically bind DNAmismatches. These compounds known as metalloinsertors have been shown to exhibit preferential anti-proliferative effects in vitro in MMR-deficient vs. MMR-proficient colorectal cancer cells and to inhibit tumorgrowth in vivo in a murine model of colorectal cancer. This F31 proposal is focused on the synthesis in vitro evaluation and in vivo validation of a novel family ofradiopharmaceuticals based on the mismatch-targeting metalloinsertor RhPBC. We first plan to synthesize non-radioactive natI-RhPBC to facilitate the chemical and biological characterization of the probe. Subsequently wewill create analogues of the metalloinsertor labeled with radioisotopes of iodine - either positron-emitting iodine-124 (124I; t1/2 ~ 4.2 d) or -emitting iodine-131 (131I; t1/2 ~ 8.0 d) - to create radiopharmaceuticals for PET imagingand endoradiotherapy respectively. Specific Aim 1 will be focused on the chemical synthesis and analysis ofall three compounds (natI-RhPBC 124I-RhPBC and 131I-RhPBC) as well as the biological characterization and invitro evaluation of the compounds in a pair of isogenic human colorectal cancer cell lines that are identical exceptfor their MMR-proficiency (HCT116N) or MMR-deficiency (HCT116O). In Specific Aim 2 PET imaging andbiodistribution experiments will be used to evaluate the in vivo performance of 124I-RhPBC as a diagnostic andtheranostic imaging agent in a murine model MMR-deficient colorectal cancer. And finally Specific Aim 3 willbe centered on the in vivo evaluation of 131I-RhPBC as a radiotherapeutic using biodistribution studies dosimetrycalculations and longitudinal therapy studies in a murine models of MMR-deficient colorectal cancer. We contend that this project is both highly innovative and highly impactful. To the best of our knowledgeDNA mismatches have never before been a target for nuclear imaging and therapy and octahedral rhodiumcomplexes have not been harnessed as scaffolds for radiotracers. In the short term this work could produce animaging agent that could be a useful tool in the clinical management of patients with MMR-deficient tumors. Inthe longer term this investigation could also yield a first-in-class radiotherapeutic that could be used against avariety of MMR-deficient tumors improving prognoses and outcomes for patients with these malignancies. 33176 +No NIH Category available Animals;Antidiarrheals;Antineoplastic Agents;Atrophic;Attenuated;Bacteria;Beta-glucuronidase;Biliary;Biological Products;Cessation of life;Chai Hu;Chinese;Chinese Traditional Medicine;Clinical;Clinical Research;Clinical Trials;Cyclosporine;Diarrhea;Dose;Double-Blind Method;Down-Regulation;Drug Exposure;Drug Kinetics;Drug Metabolic Detoxication;Drug resistance;Enzyme Activation;Enzymes;Excretory function;Glucuronides;Glucuronosyltransferase;Goals;Hospitalization;Human;In Vitro;Incidence;Inflammation;Inflammatory;Intestines;Investigational Therapies;Malignant Neoplasms;Malignant neoplasm of pancreas;Medical;Methods;Modeling;Mucositis;Mus;Natural Products;Pathway interactions;Patients;Pharmaceutical Preparations;Phase II Clinical Trials;Phytochemical;Plasma;Prevention;Prodrugs;Quality Control;Quality of life;Raloxifene;Randomized;Recovery;Research;Running;SN-38;SN-38G;Safety;Signal Transduction;Testing;Therapeutic;Tight Junctions;Tissues;Toll-like receptors;Toxic effect;Treatment Efficacy;Treatment outcome;Villus;attenuation;cancer care;cancer therapy;chemotherapeutic agent;chemotherapy;cytokine;design;dietary supplements;experience;functional restoration;improved;in vivo Model;irinotecan;malignant stomach neoplasm;metastatic colorectal;novel;novel strategies;pharmacokinetics and pharmacodynamics;preservation;prevent;primary outcome;receptor;refractory cancer;response;secondary endpoint;side effect;success;targeted agent Mechanistic and Pharmacokinetic Studies of Classical Chinese Formula Xiao Chai Hu Tang Against Irinotecan-Induced Gut Toxicities Project Narrative.Irinotecan is an effective chemotherapeutic agent that is widely used for the treatment of cancers that are notsensitive to other drugs. Its clinical use is severely limited by the severe diarrhea that results in poor quality oflife hospitalization and even death. The purpose of this research is to develop and test a classical ChineseMedicine formula called Xiao-Chai-Hu-Tang (with hundreds of years of recorded human use) to reduce severediarrhea so patients will have less side effects and perhaps even better therapeutic efficacy. Both animal studiesand human clinical trials are proposed to determine the mechanism(s) by which XCHT act an effective agent toalleviate irinotecan-related severe diarrhea. NCI 10686830 9/11/23 0:00 RFA-CA-19-009 5R01CA246209-04 5 R01 CA 246209 4 "XI, DAN" 9/11/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OBT-N(50)R] 1955698 "HU, MING " Not Applicable 18 PHARMACOLOGY 36837920 QKWEF8XLMTT3 36837920 QKWEF8XLMTT3 US 29.718091 -95.336483 1449402 UNIVERSITY OF HOUSTON HOUSTON TX SCHOOLS OF PHARMACY 772042610 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 192957 NCI 143935 49022 AbstractIrinotecan a prodrug of SN-38 is used to treat many types of metastatic and drug-resistant cancers and oftenrepresents the therapy of the last resort. Unfortunately a large percentage (up to 40%) of these patients willexperience serious (Grade 2) and severe (Grade 3-4) delayed-onset diarrhea (SDOD) which really downgradepatients quality of life. SDOD may lead to prolonged hospitalization and even death in some instances. Thelong-term goal of our research is to develop experimental therapeutics and/or nutritional supplemental approachto reduce SDOD so patients can sustain their chemotherapy. Our recent studies have shown that inactivationof intestinal UDP-glucuronosyltransferases (UGTs) by SN-38 is a new mechanism by which SN-38 causesSDOD and that a Traditional Chinese Medicine Xiao-Chai-Hu-Tang (XCHT) could attenuate the inactivation ofintestinal UGTs in mice. Therefore the central hypothesis of this current proposal is Therefore we hypothesizethat XCHT will prevent or reduce irinotecan-induced SDOD by attenuating the decline in UGT activities reducinggut SN-38 exposure and promoting the recovery of gut UGT activities. We plan to test this hypothesis using fourSpecific Aims: (1) perform phytochemical biopharmaceutical and pharmacokinetic characterization of XCHT toenable quality control systemic and intestinal drug exposure determinations and to provide bioanalyticalmethods and pharmacokinetic parameters needed for a clinical study and PK/PD modeling; (2) validate plasmaraloxifene-4-glucuronide levels as a probe to changes in intestinal Ugt/UGT activity; (3) Perform mouse co-trial studies to support human mechanistic trials and to determine the mechanisms of action of XCHT againstirinotecan-induced SDOD using both in vitro and in vivo models; and (4) Conduct a mechanistic clinical trial usinga randomized double-blind design with a safety Run-In to determine if XCHT can attenuate human intestinalUGT decrease and reduce incidence of Grade 3 or higher diarrhea caused by irinotecan chemotherapy. Asidefrom these primary outcomes we will also determine if levels of Ral-4-G a probe of intestinal UGT activities is(negatively) correlated with systemic levels of inflammatory cytokines. Success gained through this research willprovide a new mechanism by which we can target to treat SDOD caused by irinotecan chemotherapy. 192957 +No NIH Category available Adipocytes;Affect;Androgen Receptor;Androgens;Animal Model;Animals;Bypass;Cancer Patient;Cancer cell line;Castration;Cell Survival;Cells;Complement;Dinoprostone;Disease;Dose;Event;Excision;Gene Expression;Genes;Genetic Transcription;Goals;Growth;Habitats;Harvest;Hormones;Human;Human Cell Line;IL1R1 gene;Interleukin-1 beta;Knowledge;LNCaP;Lesion;Life Expectancy;Long-Term Care;Malignant - descriptor;Malignant neoplasm of prostate;Mesalamine;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;MicroRNAs;Mixed Neoplasm;Modality;Modeling;Molecular;Molecular Biology;Mus;Neoplasm Metastasis;Osteoblasts;Osteoclasts;PC3 cell line;Patients;Phenotype;Process;Prostate Cancer therapy;RANTES;Receptor Inhibition;Receptor Signaling;Regulation;Reporting;Resistance;Role;Structure;System;Testing;Testosterone;Therapeutic;Transcriptional Regulation;Tumor Tissue;Tumor-Derived;Up-Regulation;VCaP;advanced prostate cancer;androgen deprivation therapy;antagonist;autocrine;bone;cancer cell;castration resistant prostate cancer;celecoxib;cell stroma;chemokine;cyclooxygenase 2;cytokine;deprivation;derepression;enzalutamide;experimental study;gene repression;human tissue;improved;inhibitor;mesenchymal stromal cell;neoplastic cell;new therapeutic target;osteopontin;paracrine;patient derived xenograft model;pre-clinical;promoter;prostate cancer cell;receptor;receptor binding;receptor expression;receptor-mediated signaling;recruit;release factor;response;skeletal;targeted treatment;therapy outcome;tumor Interleukin-1beta and AR-negative tumor cells in metastatic castrate-resistant prostate cancer Skeletal metastases are detected in >90% of patients with advanced prostate cancer and eventually aredeterminant contributors to their demise. Current standards of care extend life expectancy but do not cure themetastatic stage of this disease.While the events sustaining skeletal metastasis have not been fully defined our preliminary studies implicateprostate cancer cells lacking the Androgen Receptor (AR) or with this receptor functionally blocked andexpressing the cytokine Interleukin-1beta (IL-1) in establishing a microenvironment conducive to tumorcolonization and resistance to AR-targeting therapies. We intend to reveal the molecular mechanisticunderpinning of this process and identify novel therapeutic targets to be pursued in combination to the AR-targeting therapeutics currently available. NCI 10686804 8/10/23 0:00 PA-20-185 5R01CA259358-02 5 R01 CA 259358 2 "BENAVIDEZ, JUSTIN MICHAEL" 9/1/22 0:00 8/31/27 0:00 Tumor Progression and Metastasis Study Section[TPM] 7882822 "FATATIS, ALESSANDRO " Not Applicable 3 PHARMACOLOGY 2604817 XF3XM9642N96 2604817 XF3XM9642N96 US 39.954073 -75.186541 2205901 DREXEL UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191043443 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 381733 NCI 251969 129764 Treatment of prostate cancer patients relies heavily on therapeutic strategies depriving tumor cells of thetranscriptional activity of the Androgen Receptor (AR). Despite their initial efficacy androgen-deprivationtherapies (ADT) are eventually circumvented by the emergence of castrate-resistant prostate cancer (CRPC)which is characterized by skeletal metastases in more than 90% of patients.We have recently demonstrated that approximately 30% of bone-metastatic prostate cancer cells lack AR(ARNeg) and express Interleukin-1 (IL-1). Our hypothesis is that ARNeg cancer cells by secreting IL-1establish a supportive bone habitat allows ARPos cells to withstand androgen-deprivation and AR inhibition.Thus a major goal of this proposal is to define the modalities by which ARNeg/IL-1 cancer cells sustainskeletal colonization in prostate cancer under androgen-deprived conditions.This proposal is structured in three aims: Aim 1. IL-1 involvement in ADT resistance; Aim 2. Role of bonestroma in IL-1 induced regulation of ARPos cells; Aim 3. Regulation of IL-1 expression by AR.The proposed studies will employ animal models of metastasis human cell lines PDX-derived cells andhuman tissue amples to ascertain the functional role of IL-1 in skeletal colonization of prostate cancer cellsdiscriminating between direct autocrine-paracrine effects on cancer cells and targeting cells of the tumor-associated bone stroma. Furthermore we will identify the bone stroma cells targeted by IL-1 and evaluatethree stromal factors secreted in response to IL-1 for the ability to induce AR signaling and expression of AR-regulated genes. Finally using a combination of molecular biology approaches we will define the mechanismfor the transcriptional regulation of IL-1 by the AR and the translational control exerted on this cytokine bymiRNAs.Our studies will define the unique role of ARNeg prostate cancer cells in metastases and provide conceptual andpre-clinical ground for complementary strategies to improve therapeutic outcomes. 381733 +No NIH Category available Ablation;Acute Myelocytic Leukemia;Binding;Biochemical;Biological Assay;CRISPR screen;Cell Cycle;Cell Differentiation process;Cell Proliferation;Cell Survival;Cells;ChIP-seq;Chimeric Proteins;Chromatin;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNMT3a;Data;Differentiation Therapy;Disease;Disease Progression;Disease remission;ENL Protein;Epigenetic Process;FLT3 gene;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Hematologic Neoplasms;Hematopoiesis;Human;Impairment;In Vitro;Individual;KDM1A gene;Knock-out;MLL-AF9;MLL-rearranged leukemia;Mass Spectrum Analysis;Methodology;Methods;Methylcellulose;Modeling;Molecular;Mus;Myelogenous;Oncogenes;Patients;Pharmaceutical Preparations;Play;Progranulocytes;Proliferating;Reader;Role;Sampling;Scheme;Tertiary Protein Structure;Testing;Therapeutic;Toxic effect;Work;Xenograft Model;acute myeloid leukemia cell;burden of illness;chemotherapy;combinatorial;design;epigenome;epigenomics;histone acetyltransferase;histone-binding proteins;in vivo;inhibitor;mouse model;mutant;novel;programs;promoter;protein complex;recruit;response;self-renewal;small molecule;stemness;success;synergism;targeted treatment;therapeutic evaluation;therapeutic target;transcription factor;transcriptome;transcriptome sequencing;transplant model;treatment effect Investigating the role of KAT6A in MLL-rearranged acute myeloid leukemia Project NarrativeAcute myeloid leukemia (AML) is the most lethal hematological malignancy and alternatives to chemotherapysuch as differentiation therapy are greatly needed. We recently found that the H3K9 histone acetyltransferaseKAT6A cooperates with the H3K9ac reader protein ENL to promote stemness and proliferation in AML. Herewe aim to determine the molecular mechanisms by which KAT6A and ENL cooperate to drive leukemogenicgene expression programs and to identify the genetic subtypes of AML that are most sensitive to KAT6Ainhibition. NCI 10686801 8/2/23 0:00 PA-20-185 5R01CA266641-02 5 R01 CA 266641 2 "KLAUZINSKA, MALGORZATA" 9/1/22 0:00 8/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 8437988 "BLANCO, MARIO ANDRES" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 365525 NCI 231821 133704 Acute myeloid leukemia (AML) is a disease of blocked differentiation in which blasts fail to matureand proliferate continuously. Differentiation therapy which aims to reactivate latent maturationprograms and induce cell cycle exit is curative in the promyelocytic (APL) AML subtype but not inother AML subtypes. Epigenetic factors help sustain the differentiation block and inhibitors ofregulators such as the LSD1 BRD4 and DOT1L has recently been shown to re-activate myeloiddifferentiation programs in selected AML models. However these inhibitors generally do not achieveterminal differentiation and disease remission. Accordingly there is significant need to identify moreregulators of the AML differentiation block and to test whether their inhibitors can induce terminaldifferentiation when used individually or in combination regiments. To identify novel regulators of AMLdifferentiation we recently performed a chromatin-focused CRISPR sgRNA screen using gain-of-differentiation as a readout. This screen identified the H3K9 histone acetyltransferase KAT6A as akey driver of AML differentiation arrest and mechanistic work showed that KAT6A and the H3K9achistone binding protein ENL closely cooperate to active promoters of AML oncogenes. We confirmedthat both genetic (CRISPR) and small molecule inhibition of KAT6A markedly induces differentiationand reduces proliferation most commonly in MLL-rearranged (MLL-r) AMLs and also in selectedMLL-wild type (MLL-WT) AMLs. Further KAT6A inhibitors synergize with inhibitors of either LSD1 orDOT1L to induce near-terminal differentiation and fully halt proliferation in vitro. This proposal hasthree goals: First we will determine the mechanisms by which KAT6A and ENL are recruited tochromatin and activate transcription. We will identify the protein domains in KAT6A and the MOZcomplex it resides in that are responsible for its binding to chromatin at MLL-AF9 targets and non-MLL-AF9 targets. We will also identify any transcription factors interacting with KAT6A and ENL andtest their effect on recruitment of the KAT6A-ENL module to chromatin. Our second goal is to test thetherapeutic potential of targeting KAT6A individually or in combination with LSD1 or DOT1Linhibitors in genetically-defined AML mouse models. We will employ an Mll-Af9 model and aDnm3a/Flt3-ITD model and test the effect of inhibitor treatment schemes on disease progression andoverall survival. We will also test the effect of inhibitor treatments on normal hematopoiesis. Our thirdgoal will be to test the response of clinical AML patient samples to inhibition of KAT6A individually orin combination with LSD1 or DOT1L inhibitors. We will perform drug response assays in MLL-r andMLL-WT samples in vitro using OP9 feeder layer culturing methodology and will also perform PDXtransplant models and test the response to KAT6A and LSD1 or DOT1L inhibitors in vivo. 365525 +No NIH Category available Acute;Acute Myelocytic Leukemia;Address;Anxiety;Beds;Behavior;Behavior Therapy;Behavioral Symptoms;Cancer Patient;Chronic;Chronic Disease;Chronic Insomnia;Client satisfaction;Cognitive;Cognitive Therapy;Combined Modality Therapy;Coping Skills;Disease Progression;Disease remission;Distress;Exacerbated Insomnia;Exercise;Expert Opinion;Family;Fatigue;Focus Groups;Foundations;Future;Goals;Hematologic Neoplasms;Home;Hospitalization;Immunocompromised Host;Immunologic Markers;Individual;Inpatients;Intervention;Learning;Length;Link;Lymphoblastic lymphoma;Malignant Neoplasms;Manuals;Meditation;Mental Depression;Methodology;Mindfulness Training;Mission;Napping;National Cancer Institute;Neurosecretory Systems;Non-Hodgkin's Lymphoma;Outcome;Pain;Participant;Patients;Pharmaceutical Preparations;Phase;Pilot Projects;Population;Predisposing Factor;Procedures;Process;Protocols documentation;Provider;Questionnaires;Randomized;Reporting;Research;Research Personnel;Scanning;Self Efficacy;Severities;Sleep;Sleep disturbances;Sleeplessness;Standardization;Stimulus;Structure;Survival Rate;Symptoms;Techniques;Testing;Thinking;Time;Training;Vulnerable Populations;Work;acceptability and feasibility;anxiety symptoms;arm;chemotherapy;cost effective;depressive symptoms;disorder risk;efficacy trial;experience;heuristics;high risk;immunosuppressed;improved;information gathering;leukemia/lymphoma;mindfulness;novel strategies;pain symptom;pharmacologic;phase 1 study;phase 2 study;pilot test;poor sleep;post intervention;primary outcome;programs;response;rumination;satisfaction;secondary outcome;skills;sleep difficulty;sleep pattern;sleep quality;symptom management;symptomatic improvement;theories;tumor progression Mindfulness and Cognitive Behavioral Therapy for Sleep in Cancer Project NarrativeTreatment for hematologic malignancy involves a rigorous 4 to 6-week hospitalization for inductionchemotherapy that can leave patients with significant insomnia and daytime symptom burden (e.g. fatiguepain and distress) once discharged home. Chronic insomnia puts cancer patients at elevated risk for diseaseprogression yet treatment for insomnia in cancer is often limited to suboptimal pharmacological approaches.Behavioral interventions for insomnia are efficacious and cost-effective though understudied in this vulnerablepopulation; the proposed research addresses critical symptom management needs of hematologic cancerpatients by adapting and testing an intervention that combines mindfulness-based sleep techniques withbehavioral symptom management strategies to treat both nighttime sleep disturbance and daytime fatiguepain and distress reported 1-4 weeks after discharge from inpatient chemotherapy. NCI 10686464 3/29/23 0:00 PA-20-272 3F32CA260951-02S1 3 F32 CA 260951 2 S1 "ODEH, HANA M" 12/1/22 0:00 3/31/24 0:00 16181710 "FISHER, HANNAH M" Not Applicable 4 PSYCHIATRY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 12/1/22 0:00 3/31/23 0:00 398 "Training, Individual" 2023 2500 NCI 2500 0 Hematologic cancer patients are at high risk for developing insomnia and daytime fatigue pain and distress inthe months after inpatient treatment. Extended hospitalization for chemotherapy can activate predisposingfactors (e.g. hyperarousal) and precipitate poor sleep patterns. Lack of sleep and subsequent worry aboutpoor sleep quality may negatively impact daytime fatigue pain and distress and lead to problematic behaviorsthat further exacerbate insomnia (e.g. napping/extended time in bed medication use). Sleep difficulties canbecome chronic as patients struggle to disengage from thoughts about insomnia and its interference to valuedactivities. Chronic insomnia places cancer patients at elevated risk for disease progression. Mindfulness-BasedTherapy for Insomnia (MBTI) is new group-based treatment that combines sleep restriction and stimuluscontrol with mindfulness principles and meditations to treat insomnia reduce rumination and promote positiveresponses to poor sleep (e.g. less time in bed less medication). To date MBTI has not been applied tohematologic cancer patients who are particularly prone to both nighttime sleep disturbance and daytimefatigue pain and distress in the months following discharge from inpatient chemotherapy. Adaptations to MBTIare warranted to better address the unique challenges facing immunosuppressed hematologic cancer patientswith insomnia fatigue pain and distress after demanding inpatient treatments. The proposed study seeks toadapt and assess an MBTI protocol that includes mindfulness-based sleep techniques and training in copingskills for daytime fatigue pain and distress. Participants will be hematologic cancer patients endorsinginsomnia fatigue pain and distress 1-4 weeks after discharge from inpatient chemotherapy. Phase I aims touse information gathered from patient (N=3) and provider (N=1) focus groups to adapt MBTI for individualtreatment and improved symptom management. Intervention content and procedures will be further refinedthrough iterative user testing (N=5). We hypothesize these activities will result in a manualized adapted MBTIprotocol including patient materials and a structured therapist manual to standardize the intervention. Phase IIaims to conduct a single-arm pilot study (N=30) to assess the feasibility acceptability and examine pre- topost-intervention outcomes. We hypothesize that participants will report improvement in the primary outcomeof insomnia symptoms (i.e. severity and interference) and secondary outcomes (i.e. fatigue pain anxiety anddepressive symptoms hyperarousal mindfulness and self-efficacy for symptom management). Consistentwith the National Cancer Institutes mission to reduce suffering from cancer this project initiates a program ofresearch focused on critical symptom management needs for the understudied hematologic cancer population.Positive results from this study would provide support for a larger methodologically rigorous randomizedefficacy trial. Future work might examine the effects of adapted MBTI on neuroendocrine and immune markersthat are linked to sleep and have implications for cancer progression. 2500 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunization; Minority Health; Precision Medicine; Prostate Cancer; Urologic Diseases Animal Model;Antibodies;Antibody Therapy;Antibody-drug conjugates;Apoptosis;Aspirate substance;Biopsy;Bone Marrow;Bone Marrow Neoplasms;Cancer Patient;Carcinoma;Cell Death;Cell Therapy;Cell surface;Cells;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Coculture Techniques;Collagen;Complex;Coupled;Data;Disease;Disseminated Malignant Neoplasm;Economics;Endothelial Cells;Endothelium;Environment;Failure;Future;Human Resources;Hydrogels;Immune;Investments;Malignant Neoplasms;Measures;Mediating;Metastatic Neoplasm to the Bone;Modeling;Natural Killer Cells;Neoplasm Metastasis;Oncology;Osteoblasts;Osteoclasts;Outcome;Patients;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Phase II/III Clinical Trial;Physiology;Play;Positioning Attribute;Prognosis;Proliferating;Prostatic Neoplasms;Resistance;Resources;Role;SN-38;Sampling;Selection for Treatments;Solid Neoplasm;Stimulus;Stromal Cells;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Microarray;Topoisomerase Inhibitors;Topoisomerase-I Inhibitor;Toxic effect;Treatment Efficacy;Treatment outcome;Vascularization;base;cancer cell;cancer type;castration resistant prostate cancer;cell type;cytotoxic;design;effective therapy;efficacy clinical trial;environmental change;humanized antibody;improved;in vitro Model;in vivo;induced pluripotent stem cell;innovation;men;monocyte;multidisciplinary;neoplastic cell;novel therapeutics;patient population;patient stratification;peripheral blood;phase II trial;phase III trial;pre-clinical;predicting response;receptor;responders and non-responders;response;screening;success;synergism;targeted treatment;therapy development;therapy resistant;tool;transcriptomics;treatment responders;treatment response;trial design;tumor;tumor growth;tumor microenvironment Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics Project NarrativeThere is a critical unmet need for improved models to enable more effective clinical trial design.This proposal will test the utility of a bone marrow tissue chip to identify patients with metastaticcastrate resistant prostate cancer most likely to have a response to a candidate new cell-surface targeted therapeutic agent currently in Phase II/III clinical trials. NCI 10686449 9/20/22 0:00 RFA-TR-19-014 4UH3CA260692-03 4 UH3 CA 260692 3 "MCKEE, TAWNYA C" 9/15/20 0:00 8/31/25 0:00 ZTR1-TC-7(01) 1923039 "BEEBE, DAVID J" "LANG, JOSHUA MICHAEL" 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Non-SBIR/STTR 2022 777500 NCI 416366 231084 Project Summary: Rates of FDA approval for oncology drugs in clinical trials are low and often clinical trialfailures are driven by pre-screening of therapies in models that cannot adequately replicate patient physiology.The tumor microenvironment (TME) is highly complex consisting of multiple cell types including stromal cellsimmune cells and vasculature. The interplay between tumor cells and neighboring cells in the TME results inenvironmental changes that can support tumor growth vascularization and metastasis and thus plays animportant role in prognosis and treatment efficacy (e.g. by modulating resistance). It is important for clinicalprescreening models to include the TME to assess how treatment efficacy can be impacted by this multicellularcrosstalk. For men with advanced castrate resistant prostate cancer (CRPC) that have progressed tometastasis the disease is invariably lethal as current therapies are not curative. 90% of these patients havedeveloped bone metastases but the bone microenvironment has been historically difficult to model in animalmodels or traditional co-culture. Therefore in vitro models of the bone marrow TME are urgently needed toimprove pre-screening of novel therapeutics improve clinical trial design outcomes and expedite muchneeded treatments to the clinic. Here we propose to create a tissue chip model of the bone marrowmicroenvironment for testing metastatic CRPC therapeutics. Patient-derived prostate tumor spheroids modelthe solid tumor embedded in a collagen hydrogel surrounded by multiple resident bone marrow stromal cellsderived from bone marrow aspirates immune cells and iPSC endothelial cell vasculature. Cell-surface targetedtherapies such as IMMU-132 have great potential for treatment of metastatic cancers. IMMU-132 is anantibody drug conjugate with an antibody against Trop 2 a receptor expressed on tumor cells coupled to thedrug SN-38. SN-38 is a topoisomerase inhibitor that induced apoptosis in rapidly proliferating cells. We haveaccess to samples and data from a Phase II trial of IMMU-132 in metastatic CRPC which will allow us tovalidate our bone marrow tissue chip model. In the UG3 phase we will optimize our bone marrow tissue chipmodel and demonstrate that normal and disease chip environments replicate the in vivo physiology. We willalso validate the chip for measuring responses to cell surface targeted therapies. In the UH3 we will useclinical trial data to build tissue chips that represent patients who respond and do not respond to IMMU-132and validate these models. These chips will be used to determine mechanisms of TME-induced treatmentresistance and identify signatures of response for use in stratifying patients for more efficient clinical trials. Thechips can also be used to screen multiple different cell-surface targeted therapies helping direct therapy choicein future trials. The bone marrow tissue chips can be easily adapted for any cancer type that has bonemetastases and can measure a range of cell surface targeted therapies. These chips have the potential to be apowerful tool for improving clinical trial success rates in therapies for metastatic cancer. 647450 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Immunization; Minority Health; Precision Medicine; Prostate Cancer; Urologic Diseases Animal Model;Antibodies;Antibody Therapy;Antibody-drug conjugates;Apoptosis;Aspirate substance;Biopsy;Bone Marrow;Bone Marrow Neoplasms;Cancer Patient;Carcinoma;Cell Death;Cell Therapy;Cell surface;Cells;Clinic;Clinical;Clinical Trials;Clinical Trials Design;Coculture Techniques;Collagen;Complex;Coupled;Data;Disease;Disseminated Malignant Neoplasm;Economics;Endothelial Cells;Endothelium;Environment;Failure;Future;Human Resources;Hydrogels;Immune;Investments;Malignant Neoplasms;Measures;Mediating;Metastatic Neoplasm to the Bone;Modeling;Natural Killer Cells;Neoplasm Metastasis;Oncology;Osteoblasts;Osteoclasts;Outcome;Patients;Pharmaceutical Preparations;Phase;Phase II Clinical Trials;Phase II/III Clinical Trial;Physiology;Play;Positioning Attribute;Prognosis;Proliferating;Prostatic Neoplasms;Resistance;Resources;Role;SN-38;Sampling;Selection for Treatments;Solid Neoplasm;Stimulus;Stromal Cells;Testing;Therapeutic;Therapeutic Agents;Time;Tissue Microarray;Topoisomerase Inhibitors;Topoisomerase-I Inhibitor;Toxic effect;Treatment Efficacy;Treatment outcome;Vascularization;base;cancer cell;cancer type;castration resistant prostate cancer;cell type;cytotoxic;design;effective therapy;efficacy clinical trial;environmental change;humanized antibody;improved;in vitro Model;in vivo;induced pluripotent stem cell;innovation;men;monocyte;multidisciplinary;neoplastic cell;novel therapeutics;patient population;patient stratification;peripheral blood;phase II trial;phase III trial;pre-clinical;predicting response;receptor;responders and non-responders;response;screening;success;synergism;targeted treatment;therapy development;therapy resistant;tool;transcriptomics;treatment responders;treatment response;trial design;tumor;tumor growth;tumor microenvironment Mechanisms of microenvironment mediated resistance to cancer cell surface targeted therapeutics Project NarrativeThere is a critical unmet need for improved models to enable more effective clinical trial design.This proposal will test the utility of a bone marrow tissue chip to identify patients with metastaticcastrate resistant prostate cancer most likely to have a response to a candidate new cell-surface targeted therapeutic agent currently in Phase II/III clinical trials. NCI 10686449 9/20/22 0:00 RFA-TR-19-014 4UH3CA260692-03 4 UH3 CA 260692 3 "MCKEE, TAWNYA C" 9/15/20 0:00 8/31/25 0:00 ZTR1-TC-7(01) 1923039 "BEEBE, DAVID J" "LANG, JOSHUA MICHAEL" 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 394 Non-SBIR/STTR 2022 777500 NCATS 83634 46416 Project Summary: Rates of FDA approval for oncology drugs in clinical trials are low and often clinical trialfailures are driven by pre-screening of therapies in models that cannot adequately replicate patient physiology.The tumor microenvironment (TME) is highly complex consisting of multiple cell types including stromal cellsimmune cells and vasculature. The interplay between tumor cells and neighboring cells in the TME results inenvironmental changes that can support tumor growth vascularization and metastasis and thus plays animportant role in prognosis and treatment efficacy (e.g. by modulating resistance). It is important for clinicalprescreening models to include the TME to assess how treatment efficacy can be impacted by this multicellularcrosstalk. For men with advanced castrate resistant prostate cancer (CRPC) that have progressed tometastasis the disease is invariably lethal as current therapies are not curative. 90% of these patients havedeveloped bone metastases but the bone microenvironment has been historically difficult to model in animalmodels or traditional co-culture. Therefore in vitro models of the bone marrow TME are urgently needed toimprove pre-screening of novel therapeutics improve clinical trial design outcomes and expedite muchneeded treatments to the clinic. Here we propose to create a tissue chip model of the bone marrowmicroenvironment for testing metastatic CRPC therapeutics. Patient-derived prostate tumor spheroids modelthe solid tumor embedded in a collagen hydrogel surrounded by multiple resident bone marrow stromal cellsderived from bone marrow aspirates immune cells and iPSC endothelial cell vasculature. Cell-surface targetedtherapies such as IMMU-132 have great potential for treatment of metastatic cancers. IMMU-132 is anantibody drug conjugate with an antibody against Trop 2 a receptor expressed on tumor cells coupled to thedrug SN-38. SN-38 is a topoisomerase inhibitor that induced apoptosis in rapidly proliferating cells. We haveaccess to samples and data from a Phase II trial of IMMU-132 in metastatic CRPC which will allow us tovalidate our bone marrow tissue chip model. In the UG3 phase we will optimize our bone marrow tissue chipmodel and demonstrate that normal and disease chip environments replicate the in vivo physiology. We willalso validate the chip for measuring responses to cell surface targeted therapies. In the UH3 we will useclinical trial data to build tissue chips that represent patients who respond and do not respond to IMMU-132and validate these models. These chips will be used to determine mechanisms of TME-induced treatmentresistance and identify signatures of response for use in stratifying patients for more efficient clinical trials. Thechips can also be used to screen multiple different cell-surface targeted therapies helping direct therapy choicein future trials. The bone marrow tissue chips can be easily adapted for any cancer type that has bonemetastases and can measure a range of cell surface targeted therapies. These chips have the potential to be apowerful tool for improving clinical trial success rates in therapies for metastatic cancer. 130050 +No NIH Category available ATAC-seq;Acetylation;Affect;Algorithms;Alleles;Allelic Imbalance;Automobile Driving;Benign;Binding Sites;Biological Assay;Biology;CRISPR/Cas technology;Cell Line;ChIP-seq;Chromatin;Chromosomes;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Communities;Complex;Data;Data Set;Disease;Elements;Enhancers;Epigenetic Process;Evaluation;Gene Expression;Gene Expression Profiling;Generations;Genes;Genetic;Genetic Code;Genetic Transcription;Genome;Genotype;Goals;Heritability;Heterozygote;High-Throughput Nucleotide Sequencing;Human;Human Genetics;Hybrids;Individual;Libraries;Link;Location;Malignant neoplasm of prostate;Maps;Measurement;Measures;Mediating;Mendelian disorder;Mendelian randomization;Methods;Modeling;Molecular;Open Reading Frames;Pathogenesis;Pathogenicity;Population;Prevention;Prostate;Proteins;Quantitative Trait Loci;RNA;Regulatory Element;Risk;Sampling;Signal Transduction;Site;Specimen;Structure;Susceptibility Gene;Testing;Transcript;Transposase;Untranslated RNA;Validation;Variant;cancer risk;candidate identification;candidate validation;causal variant;chromatin immunoprecipitation;disorder risk;epigenome;epigenome editing;epigenomics;genetic risk factor;genetic variant;genome editing;genome wide association study;genome-wide;genome-wide analysis;histone modification;in vivo;innovation;large scale data;novel;prostate cancer risk;risk variant;scale up;tool;trait;transcription factor;transcriptome sequencing;transcriptomics;tumor Elucidating prostate cancer risk mechanisms through large-scale cistrome wide association studies Project NarrativeTo date most genetic risk factors for complex traits are located outside of known genes. This proposal focuseson developing rigorous strategies for identifying the actual causal variants underlying complex traits usingnovel and powerful methods. Employing these strategies will lead to a more profound understanding of thegenetic mechanisms that drive disease risk. NCI 10686418 7/27/23 0:00 PA-20-185 5R01CA262577-02 5 R01 CA 262577 2 "LI, JERRY" 9/1/22 0:00 8/31/27 0:00 Genetics of Health and Disease Study Section[GHD] 6362098 "FREEDMAN, MATTHEW L" "GIMELBRANT, ALEXANDER ; GUSEV, ALEXANDER " 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 660477 NCI 438406 222071 PROJECT SUMMARY/ABSTRACTIn stark contrast to Mendelian disorders the majority of complex trait-associated common variants map tonon-protein coding regions. Since there is a less well-developed genetic code for the much larger non-protein coding portion of the genome identifying the gene(s) and causal alleles underlying non-Mendelian/complex traits presents a challenge. Given the rapidity with which genome wide associationstudies (GWAS) are discovering regions associated with complex traits causal allele and susceptibilitygene identification have become severe bottlenecks. The overall goal of this proposal is to outline arigorous and comprehensive strategy to discover functionally causal variants and their target genes. Whilethe proposal focuses on prostate cancer the strategies can be applied to any non-protein coding locus.The central hypothesis is that cancer risk loci are regulatory elements. Recent data convincinglydemonstrate that GWAS loci are enriched for regulatory elements. Regulatory elements control the level ofexpression of genes. Causal variants are difficult to discover because the scientific community is less adeptat annotating the non-protein coding portion of the genome. This proposal seeks to develop a novelcomputational and statistical framework to prioritize candidate causal variants and then to experimentallyvalidate these predictions. The proposal will jointly model quantitative trait loci (QTL) and allelic imbalance(AI) signals in epigenetic data (ChIP-seq and ATAC-seq) and transcripts (RNA-seq) in a novel frameworkthat we term cistrome wide association studies (CWAS). The most significant CWAS loci will be subjectedto epigenome and genome editing to functionally characterize and identify causal variants.Aim 1 will utilize novel experimental methods to create the large-scale datasets that will inform Aim 2. Theultimate goal of Aim 1 is to perform H3K27 acetylation and AR chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) to annotate active enhancers Assay for Transposase-AccessibleChromatin (ATAC-seq) to identify open chromatin and RNA-seq. All of these data will be subjected to targetenrichment at a predefined set of variants which will enable the rigorous and systematic measurement of AIat heterozygote sites. Aim 2 will utilize these data in a structured framework to computationally identifystatistically significant CWAS prostate risk loci that. These loci will be experimentally tested in Aim 3 whereClustered Regularly Interspaced Short Palindromic Repeats (CRISPR) evaluation of the candidatecausal variants will be performed.At the completion of this project we fully anticipate that we will have begun to unravel the causal (i.e.pathogenic) variants that initiate human prostate cancer. Discovering the mechanisms underlying humantraits will not only inform the biology of disease but may also reveal opportunities to more rationallyintervene in treatment and prevention. 660477 +No NIH Category available Ablation;Acetylation;Acetyltransferase;Acute Myelocytic Leukemia;Affect;Antibodies;Anticodon;Base Pairing;Bioinformatics;Biological Process;Cancer Cell Growth;Career Mobility;Cell Proliferation;Cells;Chemicals;Code;Codon Nucleotides;Data;Deposition;Development Plans;Enzymes;Exhibits;Foundations;Gene Expression Regulation;Generations;Genetic Code;Goals;Growth;Health;Hematopoietic;Human;Human Genetics;Intramural Research Program;Knowledge;Leadership;Light;Malignant Neoplasms;Mentors;Messenger RNA;Modification;Molecular;National Cancer Institute;Normal Cell;Nucleotides;Pathway interactions;Phase;Post-Translational Protein Processing;Postdoctoral Fellow;Prevalence;Process;Proliferating;RNA;Research;Research Proposals;Resources;Role;Solid;Testing;Therapeutic;Thermodynamics;Training;Transcript;Transfer RNA;Translational Regulation;Translations;Universities;acute myeloid leukemia cell;cancer cell;cancer therapy;career;career development;druggable target;epitranscriptome;novel;novel therapeutic intervention;programs;skills Mechanisms of translation regulation by N4-acetylcytidine in cancer cells Project Narrative: N4-acetylcytidine (ac4C) is an RNA modification catalyzed by the enzymeNAT10. NAT10 is dysregulated and promotes proliferation in multiple cancers including acutemyeloid leukemia (AML). Thus this proposal will expand our knowledge on how NAT10-catalyzedac4C promotes proliferation in cancer cells and will provide solid foundations to furnish noveltherapeutic strategies in AML. NCI 10686411 8/30/23 0:00 PA-19-130 5R00CA245035-04 5 R00 CA 245035 4 "KLAUZINSKA, MALGORZATA" 12/1/19 0:00 8/31/24 0:00 ZCA1-RTRB-B(O1) 15606106 "ARANGO, DANIEL " Not Applicable 5 PHARMACOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 155625 93375 Project Summary/AbstractTranslation of messenger RNAs (mRNA) is commonly dysregulated in cancer cells highlighting regulatorymechanisms in translation as potential targets for cancer treatment. Chemical modifications of mRNA known asthe epitranscriptome have emerged as a new layer of translation regulation. Yet the types and prevalence ofmRNA modifications as well as their roles in cancer remain poorly understood. N4-acetylcytidine (ac4C) is anovel mRNA modification that directly enhances translation efficiency of target mRNAs representing a new andsignificant layer of translational regulation. Of substantial relevance to cancer the enzyme that catalyzes thedeposition of ac4C N-acetyltransferase 10 (NAT10) is commonly dysregulated in cancers whereas NAT10depletion specifically decreases growth of cancer cells including acute myeloid leukemia (AML) cells. In light ofthese observations this proposal stipulates that NAT10-catalyzed ac4C promotes proliferation of AML cells byenhancing translation efficiency. During the K99 phase this study aims to investigate the molecular mechanismsof mRNA acetylation (Aim 1) and the mechanisms by which ac4C promotes translation efficiency (Aim 2). In theR00 phase this proposal aims to evaluate whether NAT10-catalyzed ac4C promotes AML growth by enhancingtranslation of proliferation-promoting factors (Aim 3). The overall long-term goals of this study are to expand ourunderstanding of the epitranscriptome and the mechanisms that dynamically regulate translation efficiency incancer cells using this knowledge to implement novel therapeutic strategies for human conditions wheretranslation is altered including AML and other cancers. My career goal is to develop an independent high-qualityresearch program for the benefit of human health. To achieve these goals I built a career development planwhich includes this research proposal and a plan for training mentoring and networking to expand my researchbioinformatical leadership and mentoring skills. The K99 phase will be developed in the Intramural ResearchProgram of the National Cancer Institute (NCI) and will be mentored by Dr. Shalini Oberdoerffer (NCI) and co-mentored by Dr. Jeffery Coller (Case Western Reserve University). The NCI Intramural Research Program offersstrong well-established research programs and multiple resources for career development and transition ofpostdoctoral fellows. 249000 +No NIH Category available Allografting;Area;CDK4 gene;Cancer Cell Growth;Cell Cycle Proteins;Cell Cycle Regulation;Cell Proliferation;Cell physiology;Cells;Complex;Cyclin D1;Cyclins;Dana-Farber Cancer Institute;Development;Genetic;Genetically Engineered Mouse;Glioblastoma;Human;Injections;Knock-in;Knock-in Mouse;Knock-out;Knockout Mice;Laboratories;Malignant Neoplasms;Modeling;Mouse Strains;Mus;Mutation;Normal Cell;Patients;Play;Processed Genes;Proteins;Research;Role;Specialist;T-Cell Leukemia;Testing;Therapeutic;Tumor Immunity;Xenograft Model;Xenograft procedure;blastocyst;cancer cell;cancer therapy;conditional knockout;cyclin C;cyclin G1;design;embryonic stem cell;experimental study;genetic manipulation;genomic locus;immune checkpoint blockade;in vivo;insight;knock-down;melanoma;mouse development;mouse model;mutant;neoplastic cell;pluripotency factor;stemness;tumor;tumor initiation Functions of Cyclin/CDK complexes in development and cancer Project NarrativeThe Research Specialist is working on functions of cyclin/CDK complexes in development and cancer. Bycreating different cyclin/CDK knockout and knock-in mouse strains and using mouse xenograft/allograftmodels we aim to delineate the requirement for cyclin/CDK complexes in normal cell proliferation versus incancer cell growth/survival. We hope that understanding the mechanism of cell cycle regulation in vivo willlead to new insight on designing therapeutic strategies for cancer treatment. NCI 10686395 8/25/23 0:00 PAR-18-888 5R50CA243769-05 5 R50 CA 243769 5 "LUO, RUIBAI" 9/11/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 2263916 "GENG, YAN " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 179618 NCI 100909 78709 Project SummaryDr. Peter Sicinski's laboratory at the Dana-Farber Cancer Institute studies the functions of cell cycle proteins innormal development and in cancer. For the past 20 years we have created many mouse knockout or knock-instrains including mice either lacking cyclins or CDKs or expressing modified cyclins or CDKs. Using thosemice we delineated the requirement for cell cycle proteins during normal mouse development and in tumorformation/progression. As an expert in generating and analyzing genetically engineered mouse models Dr.Yan Geng the Research Specialist has been leading the efforts in Dr. Sicinski's lab to create differentcyclin/CDK mutant strains. Particularly she has played a crucial role in the following areas: 1) design thegenetic targeting strategies for knockout cyclin genes or knock-in mutations/tags into a cyclin or CDK genelocus; 2) supervise the technical processes for gene manipulation in embryonic stem (ES) cells and creatingchimeric mice by blastocyst injection of ES cells; 3) design and perform the experiments using mouse tumormodels including xenograft/allograft models. Currently the Research Specialist is making a new mouse strainof conditional knockout Cdk19. Using this strain we plan to investigate the effect of Cdk19 loss together withloss of cyclin C in T-cell leukemia. Combining Cdk19 knockout with cyclin C knockout we hope to create amouse model that faithfully mimicking human T-cell leukemia. The Research Specialist is also leading thestudy of G1 cyclins' function in cancer cell stemness. As we have found that G1 cyclins directly regulate theprotein levels of pluripotency factors Oct4 Sox2 and Nanog not only in embryonic stem cells but also inglioblastoma tumor initiating cells we will investigate whether decreasing the levels/activities of G1 cyclinswould impact on the stemness of tumor cells. We will use a xenograft model to test whether knocking downthe G1 cyclins will induce differentiation of glioblastoma cells thus to eliminate/reduce their potential to formtumors in vivo. Recently we have found that cyclin D/CDK4/6 play roles in cancer immunity. Using tumorallograft mouse models the Research Specialist is going to explore whether inhibition of cyclin D/CDK4/6would enhance the efficacy of anti-immune checkpoint blockade in treatment of melanoma. We hope that thisstudy will lead to a new combinational therapeutic strategy for melanoma patients. 179618 +No NIH Category available 3-Dimensional;Adult;Animal Experimentation;Animals;Area;Basic Science;Biochemical;Biological;Biopsy Specimen;Brain;Brain Neoplasms;Caring;Cell Respiration;Cells;Cerebrum;Chemotherapy and/or radiation;Citric Acid Cycle;Clinic;Clinical;Clinical Treatment;Computer software;Data;Detection;Deuterium;Development;Diagnosis;Disease;Energy Metabolism;Engineering;Fatality rate;Functional disorder;Funding;Future;Glioblastoma;Glucose;Glutamates;Glutamine;Glycolysis;Glycolysis Inhibition;Goals;Human;Human body;Image;Imaging Techniques;Imaging technology;Immune;Infiltration;Intake;Interdisciplinary Study;Intravenous infusion procedures;Label;Magnetic Resonance;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Measurement;Measures;Metabolic;Metabolic Marker;Methods;Minnesota;Mitochondria;Modality;Modeling;Monitor;Mutation;Neurosurgeon;Noise;Normal tissue morphology;Oncology;Operative Surgical Procedures;Oral;Outcome;Pathologic;Pathology;Patients;Physiologic pulse;Pilot Projects;Positron-Emission Tomography;Production;Prognosis;Property;Pyruvate;RF coil;Radiation therapy;Research;Research Personnel;Resistance;Resolution;Signal Transduction;Site;Specificity;Specimen;Techniques;Technology;Testing;Time;Training;United States National Institutes of Health;Universities;Warburg Effect;Work;aerobic glycolysis;anticancer research;brain disorder diagnosis;brain morphology;brain tissue;cancer cell;clinical diagnosis;contrast imaging;cost effective;data analysis pipeline;expectation;fluorodeoxyglucose;glucose metabolism;glucose uptake;high dimensionality;human imaging;image processing;imaging modality;imaging study;improved;in vivo;indexing;innovation;kinetic model;magnetic field;magnetic resonance spectroscopic imaging;metabolic imaging;metabolic rate;neuro-oncology;neurochemistry;neuroimaging;neuropathology;novel;novel imaging technique;novel therapeutics;oxidation;quantitative imaging;software development;spatiotemporal;spectroscopic imaging;success;therapeutic development;tool;treatment response;tumor;tumor heterogeneity;tumor progression;ultra high resolution Development of Quantitative Deuterium MRS Imaging for Human Brain Tumor Application at Ultrahigh Field PROJECT NARRATIVEThis project aims to develop and validate a novel metabolic imaging technique based on the in vivo deuteriummagnetic resonance spectroscopy (DMRS) approach for quantitative assessment of one key brain tumorhallmark termed the Warburg effect with high sensitivity specificity and unprecedent spatial resolution. Thesuccess of the project will provide an innovative noninvasive and cost-effective neuroimaging tool forimproving clinical diagnosis and treatment management of brain tumor patients and other diseases. NCI 10686390 9/6/23 0:00 PA-18-484 5R01CA240953-05 5 R01 CA 240953 5 "LIN, CHARLES" 8/1/19 0:00 7/31/25 0:00 Clinical Translational Imaging Science Study Section[CTIS] 2272586 "CHEN, WEI " "CHEN, CLARK CHIN-CHUNG; LIANG, ZHI-PEI " 5 RADIATION-DIAGNOSTIC/ONCOLOGY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 529985 NCI 367778 162207 PROJECT SUMMARY Glioblastoma (GBM) is the most aggressive form of human cancers with very high fatality rate and shortsurvival time and the cancer cells aggressively infiltrate the brain and are intrinsically resistant tochemotherapy and radiation therapy. Intra-tumoral heterogeneity is a major challenge in therapeuticdevelopment for GBM patients because surgical acquisition of clinical specimens cannot be used to monitorthe tumor progression and/or the underlying metabolic changes. Various neuroimaging methods have beenused to study the morphology of the brain tumors. However the need for noninvasively characterizing the braintumors and their metabolic features has not been met which should be critical for prognosis or for monitoringthe tumor progression and response to treatment. It is well known that a common hallmark of the cancer cellsis disrupted glucose metabolism in which upregulated glycolysis is accompanied by inhibited mitochondrialoxidation i.e. the Warburg effect. Imaging the Warburg effect and its spatial variability in brain tumors is anew attempt that can have a major impact on cancer research particularly in the treatment of GBM becausetherapies aimed at reversing the Warburg effect have shown promise in GBM ; however great efforts areneeded to develop novel metabolic imaging techniques to achieve the capabilities sought by clinicians. We have recently initiated a project aiming to develop a neuroimaging technique based on deuterium (2H)MRS (DMRS) detection of 2H-labeled brain metabolites following an administration of D-Glucose-66-d2 (d66).Our preliminary results indicate that the dynamic DMRS imaging can determine the cerebral metabolic rates ofglucose (CMRGlc) and TCA cycle (VTCA) thus the lactate production rate (CMRLac) in addition to theconcentrations of deuterium-labeled glucose (Glc) mixed glutamate/glutamine (Glx) and lactate (Lac) in livingbrains. Furthermore we demonstrated for the first time that the uncoupling between the glycolysis andoxidation in brain tumor can be quantitatively imaged via mapping the [Lac]/[Glx] ratio defined as an index ofWarburg effect (IWE); and it has been shown that IWE is highly sensitive for distinguishing brain tumor fromsurrounding normal tissues. In this application we are seeking NIH funding support to move forward with theDMRS imaging development through: i) integrated hardware and software development and the ultrahigh fieldMR technology to further boost signal-to-noise ratio (SNR) spectral resolution and spatiotemporal resolution; ii)testing the ultrahigh resolution DMRS imaging in healthy subject and tumor patients and establishing aquantification model and imaging processing pipeline for future application; and iii) comparing the DMRSimaging results with the neuropathological and immunohistochemical findings of the biospecimens tounderstand the correlation between the DMRSI measurements and biological features of brain tumor. Ourinterdisciplinary research team with unique expertise is ready for a full-scale development of this highlyinnovative and cost-effective neuroimaging essential for basic research and clinic application in neuro-oncology. 529985 +No NIH Category available Basic Science;Biological;Biological Assay;Chemopreventive Agent;Clinic;Clinical;Clinical Distribution;Clinical Trials;Contracts;Data;Decision Making;Dermal;Development;Documentation;Drug Formulations;Ensure;Epidermis;Formulation;Funding;Generations;Human;In Vitro;Individual;Investigational New Drug Application;Laboratories;Methods;Modeling;Monitor;New Agents;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacology and Toxicology;Pharmacy (field);Prevention;Production;Property;Quality Control;Regulatory Affairs;Research Personnel;Safety;Sampling;Selection Criteria;Services;Skin;Skin Cancer;Skin Carcinoma;Solubility;Time;Topical agent;Topical application;Toxic effect;Toxicology;Translating;Translations;absorption;chemical stability;clinical development;clinical translation;drug development;efficacy evaluation;in vivo;in vivo Bioassay;lipophilicity;manufacture;novel therapeutics;pre-clinical;programs;quality assurance;research clinical testing;residence Core D: Drug Development PROJECT NARRATIVE Core D (Myrdal) Drug Development The Drug Development Core is an essential component of the Program Project in coordinating the expertise in pharmacology/toxicology pharmaceutics manufacturing and regulatory affairs that enable decision making to circumvent problems with epidermal delivery that normally hinder development of otherwise promising topical agents and to optimize the crucial selection criteria for advancement of new agents to clinical testing. The Core will additionally provide drug formulation support for all three projects and provide the manufacturing toxicology and regulatory support necessary to move agents into Project 3 clinical trials. NCI 10686383 9/1/23 0:00 PAR-18-290 5P01CA229112-05 5 P01 CA 229112 5 9/10/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5714 8613871 "MANSOUR, HEIDI M." Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 109264 63166 55795 ABSTRACT Core D (Myrdal) Drug Development The Drug Development Core will serve the individual Projects and the Program Project as a whole by providing necessary services and a unique combination of expertise in pharmacology/toxicology pharmaceutics manufacturing and regulatory affairs that enable the clinical translation of topical agents. This objective will be accomplished by the following Specific Aims: 1) To prepare stable formulations of promising new agents that can be safely and effectively delivered to the epidermis following topical application through a) preformulation activities b) formulation development and c) determination of percutaneous absorption and dermal toxicity; and 2) Facilitate the translation of agents into the clinic by a) performing preclinical toxicology studies consistent with GLP practices and monitoring the stability of the formulation lots used in these studies and b) coordinating and preparing New Drug (IND) applications for FDA approval and supervising production and distribution of clinical grade supply for human trials in Project 3. Implementation of these aims will allow Project Leaders the ability to circumvent problems with epidermal delivery which may hinder development of otherwise promising topical agents and optimize the crucial selection criteria for advancement of new agents to clinical testing. This will greatly enhance the ability to translate basic science discoveries into new skin cancer chemopreventive drugs. +No NIH Category available Actinic keratosis;Address;Apoptotic;Architecture;Biological;Biological Assay;Biological Markers;Biological Specimen Banks;Biopsy;Biostatistics Core;Cells;Clinical Trials;Collaborations;Collection;Exposure to;Formalin;Freezing;Hematoxylin and Eosin Staining Method;Histopathology;Human;Institution;Laboratories;Light;Maps;Measurement;Molecular Target;Mus;Paraffin Embedding;Pathway interactions;Phase;Phosphoproteins;Prevention;Procedures;Protein Microarray Assay;Protein Microchips;Proteins;Protocols documentation;Reproducibility;Resource Development;Resources;Sampling;Services;Shipping;Signal Transduction;Signaling Protein;Skin;Skin Carcinoma;Slide;Specimen;Stains;Standardization;Sunburn;TLR4 gene;Thick;Tissue Microarray;clinical development;cost;cost effective;laser capture microdissection;method development;molecular marker;mouse model;novel;programs;sample collection;skin damage;skin squamous cell carcinoma;sun damage;sun protection;tissue preparation;tissue processing Core C: Molecular Targets PROJECT NARRATIVECore C (Chow Petricoin) Molecular TargetsThe Molecular Targets Core is an essential component of the Program Project. It will provide standardizedprocedures for sample collection and processing and serve as a collection tracking storage and distributionpoint for biological samples. It is a resource and service for carrying out the necessary biomarker analysesproposed in this application. NCI 10686380 9/1/23 0:00 PAR-18-290 5P01CA229112-05 5 P01 CA 229112 5 9/10/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5712 1878826 "CHOW, H-H. SHERRY" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 303549 257451 55795 ABSTRACTCore C (Chow Petricoin) Molecular TargetsThe Molecular Targets Core is a multi-functional core. The Core provides a collection tracking storage anddistribution point for biological samples and is a resource and service for carrying out the necessary laboratoryanalyses proposed in this application. Furthermore the Molecular Targets Core is an essential component ofthe Program Project in that it allows the Projects to address Specific Aims in a consistent reproducible and cost-effective manner with regards to the identification of molecular markers. The Core will interact in a significantmanner with all Projects and the other cores. Additionally the Core has put into place detailed forms and SOPsand is an essential resource for development of clinical and murine protocols as well as sample managementfor a continually growing biospecimen repository. In collaboration with the Biostatistics Core (Core B) MolecularTargets Core will carry-out sample analyses and interact with each Project on the transfer and/or analysis ofsamples as well as on the management and interpretation of the results. The Core providesimmunohistochemical method development and analysis. The Core also provides Reverse Phase ProteinMicroarray (RPPA) a multiplexed quantitative measurement of multiple signaling proteins many of which arephosphoproteins from biological specimens. RPPA represents a novel means of quantitative measurement ofhundreds of proteins from a single specimen. +No NIH Category available Address;Annual Reports;Applications Grants;Arizona;Award;Basic Science;Bioinformatics;Biometry;Biostatistics Shared Resource;Cancer Center;Clinical;Clinical Cancer Center;Clinical Trials;Clinical Trials Data Monitoring Committees;Collaborations;Computers;Conceptions;Consultations;Core Grant;Data;Data Analyses;Data Collection;Databases;Development;Electronic Mail;Ensure;Faculty;Financial Support;Funding;Goals;Grant;Human Resources;Individual;Information Retrieval;Information Storage;Infrastructure;Journals;Knowledge;Manuscripts;Methodology;Methods;National Cancer Institute;Nature;Pathway interactions;Peer Review;Phase;Policies;Preparation;Prevention;Procedures;Program Research Project Grants;Progress Reports;Publications;Quality Control;Reporting;Research;Research Design;Research Personnel;Role;Sample Size;Schedule;Services;Skin Carcinoma;Statistical Data Interpretation;Statistical Study;Universities;Work;data management;data quality;design;meetings;member;power analysis;programs;technical report;translational goal Core B: Biostatistics and Bioinformatics PROJECT NARRATIVECore B (Hu Roe) Biostatistics and BioinformaticsThe Biostatistics and Bioinformatics Core collaborates with all investigators in this Program Project byproviding statistical and bioinformatics support for the design conduct and analysis of all projects includingdata management and computing support. The Biostatistics and Bioinformatics Core provides servicesnecessary for the acquisition and dissemination of valid scientific knowledge by all projects. NCI 10686376 9/1/23 0:00 PAR-18-290 5P01CA229112-05 5 P01 CA 229112 5 9/10/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5710 7839486 "HU, CHENGCHENG " Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 139382 93285 55795 ABSTRACTCore B (Hu Roe) Biostatistics and BioinformaticsThe goal of the Biostatistics and Bioinformatics Core is to facilitate the Targeted Prevention for Non-MelanomaSkin Cancer Program Project Grant (PPG) scientific objectives by integrating strong statistical study designaccurate and organized data and appropriate statistical analyses and interpretation into all projects. TheBiostatistics and Bioinformatics faculty and staff will be intimately involved in the conception designimplementation analysis and reporting of research conducted in the PPG. Core B personnel work not only ondesign data management and analysis issues an essential role but also develop a logical framework for thescientific approach applied to PPG research questions and help to ensure valid interpretation of the results.The specific aims of Core B are:Aim 1. To provide statistical collaboration in the design execution and analysis of all projects.Aim 2. To develop procedures for data collection and to build and maintain computer databases forinformation storage and retrieval.Aim 3. To provide reports on individual study progress data for the UACC Data and Safety MonitoringBoard (DSMB) and reports for the Scientific Advisory Board (SAB) meetings.The Core B support activities have been combined into a single core to facilitate interactions among thebiostatisticians and bioinformaticians involved in PPG projects. The interactive nature of PPG activitiesfacilitates the involvement of both the Biostatistics and Bioinformatics personnel within the projects. Thetranslational goal is to facilitate integration of project results among the basic science clinical bioinformaticsand biostatistician investigators. +No NIH Category available Affect;Albers-Schonberg disease;Blood Vessels;Bone Density;Cachexia;Cancer Model;Cancer Patient;Cells;Coagulation Process;Code;Communication;Complex;DNA;Development;Distant;Epigenetic Process;Genetic;Growth;Hematopoietic;Heterogeneity;Immune system;Immunosuppression;Inflammation;Interruption;Liver Failure;Malignant - descriptor;Malignant Neoplasms;Metabolic;Muscle;Neoplasm Metastasis;Neuropathy;Organ;Osteoporosis;Proteins;Regulation;Role;Shapes;Systemic disease;Tissues;Tumor-Derived;Untranslated RNA;body system;chemokine;cytokine;exosome;interdisciplinary approach;lung failure;nanovesicle;neoplastic cell;novel;novel strategies;particle;targeted treatment;tumor Systemic regulation of metastasis Project NarrativeCancer is a systemic disease. Cancer growth and metastasis relies not only on the intrinsic aberrant geneticand epigenetic makeup of tumor cells but also on the tumor-induced systemic factors which impact cells inlocal and distant microenvironments affecting all organ systems in the body. This proposal aims to dissect thecomplex interactions between the tumor and its host using multidisciplinary approaches paving the way torational targeted therapies that can effectively hinder metastasis. NCI 10686375 8/25/23 0:00 PAR-17-494 5R35CA232093-06 5 R35 CA 232093 6 "SNYDERWINE, ELIZABETH G" 9/18/18 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 6484128 "LYDEN, DAVID CHARLES" Not Applicable 12 PEDIATRICS 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 973323 NCI 588000 408660 Project SummaryCancer is a systemic disease. Its growth and malignant progression relies not only on the intrinsic aberrantgenetic and epigenetic makeup of tumor cells but also on the tumor-induced systemic factors which impactcells in local and distant microenvironments. Importantly there is dynamic crosstalk between the tumor-educated tissues and organs and the tumor itself especially during metastatic progression. As the tumorreshapes its local microenvironment coaxing it to support cancer growth it exerts systemic effects conqueringthe immune system and distant organs leading not only to metastasis but also to vascular changes (vascularleakiness coagulation) muscular and metabolic changes (cachexia) liver and lung failure changes in bonedensity (osteoporosis or osteopetrosis) and neuropathies but maybe above all inflammation and immunesuppression. The tumor exerts its systemic effects coaxing the various organ systems of the host to supportcancer growth through tumor-secreted factors such as soluble factors (cytokines and chemokines) andexosomes (and exomeres the novel particles we recently discovered) nanovesicles that carry complex cargoincluding proteins metabolites DNA and coding as well as non-coding RNAs. The development of effectiveanti-metastatic therapies is predicated on our understanding of these iterative and complex interactionsbetween the tumor and its host and on devising ways to interrupt this communication. We developed novelapproaches to analyze the heterogeneity and functional roles of tumor-derived exosomes and exomeres inmetastasis as well as their capacity to induce systemic changes. Ultimately we propose to explore thepossibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic cells couldreverse immunosuppression pre-metastatic niche formation and the systemic effects of cancer. In summarywe will focus on studying the mechanisms through which exosomes and exosomes regulate immune systemmobilization metabolic changes and plasticity of pre-metastatic and metastatic niches in cancer models andpatients. 973323 +No NIH Category available Accounting;Administrative Personnel;Arizona;Bioinformatics;Biometry;Budgets;Businesses;Cancer Center;Clinic;Collaborations;Communication;Documentation;Ensure;Equity;Expenditure;Funding;Goals;Grant;Human Resources;Information Dissemination;Institution;Institutional Review Boards;Location;Organization and Administration;Prevention;Principal Investigator;Progress Reports;Publications;Reporting;Research;Research Personnel;Resources;Schedule;Services;Skin Carcinoma;Training;Travel;United States National Institutes of Health;Universities;Update;Work;cost;meetings;payment;program costs;programs Core A: Administration n/a NCI 10686374 9/1/23 0:00 PAR-18-290 5P01CA229112-05 5 P01 CA 229112 5 9/10/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5709 8531398 "CURIEL-LEWANDROWSKI, CLARA " Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 163883 117785 55796 ABSTRACTCore A (Curiel Dong) AdministrationThe objective of the Administration Core is to provide overall administrative and scientific support for the ProgramProject. The Core is responsible for administration and organization fiscal management research integrationcommunication research management and research coordination and is vital to all activities of the ProgramProject. The Administration Core interacts directly with each Project and Core in support of this goal. Theadministrative functions of this Program Project involve the coordination and integration of the entire proposal.Dr. Clara Curiel serves as the contact Principal Investigator for this Program and the Leader of the AdministrationCore and provides scientific oversight to all Project and Cores. The Administration Core maintains fiscal as wellas scientific responsibility and provides general day-to-day core support for the Program. The AdministrationCore works closely with the University of Arizona Cancer Center Business Office to ensure that timely budgetupdates are provided to all investigators. The Core initiates subcontracts with other institutions and reviewsinvoices and documentation prior to payment to the subcontractors. The Core approves and allocates funds tosupport consultants travel and publication costs for the Program. The Core works with the investigators theUACC Business Office and the University of Arizona Sponsored Projects staff to ensure appropriate expenditureof grant funds. Additionally the Core coordinates communication within the Program by scheduling twice-monthly meetings of all investigators and staff to facilitate communication and research collaboration. Additionalmeetings coordinated by the Core include meetings with outside consultants and the external Scientific AdvisoryBoard. These meetings are essential for ensuring consistent communication and collaboration. AdministrationCore staff are responsible for reporting activity to the University of Arizona IRB and to the NIH. They also serveas an administrative and research resource to the Project and Core investigators and staff. +No NIH Category available Actinic keratosis;Acute;Adult;Age;Archives;Behavioral;Biological Availability;Biological Markers;Bromides;Cancer Etiology;Characteristics;Chemoprevention;Chronic;Clinical;Clinical Pharmacology;Collaborations;Collection;Cutaneous;Development;Drug Targeting;Dysplasia;Exposure to;Formulation;Funding Mechanisms;General Population;Goals;Health Care Costs;Human;Human Volunteers;Immunohistochemistry;Incidence;Individual;Intervention;KRP protein;Lead;Lesion;Light;Link;Lymphokine-Activated Killer Cells;Malignant Neoplasms;Modeling;Morbidity - disease rate;Mus;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phosphoproteins;Phototherapy;Population;Prevalence;Prevention;Prevention strategy;Preventive;Preventive Medicine;Process;Protein Activation Pathway;Protein Array Analysis;Protein Kinase;Protein Microarray Assay;Protein Microchips;Proteins;Risk;Safety;Sampling;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Societies;Standardization;Stress;Sun Exposure;TLR4 gene;Testing;Therapeutic;Topical agent;Topical application;UV induced;Ultraviolet Rays;aging population;cancer chemoprevention;carcinogenesis;carcinogenicity;clinical development;clinical efficacy;clinically relevant;cohort;effective intervention;efficacious intervention;exposed human population;inhibitor;interest;keratinocyte;laser capture microdissection;mortality;multidisciplinary;neoplastic;network architecture;novel;novel therapeutics;p53 related protein kinase;patient population;personalized medicine;pharmacologic;phase 1 study;phase 2 study;phase I trial;pre-clinical;preventive intervention;prospective;protein kinase inhibitor;response;safety assessment;skin cancer prevention;skin damage;skin squamous cell carcinoma;small molecule;small molecule inhibitor;sun damage;sun protection;translational study Project 3: Translational Studies and Clinical Pharmacology of TLR4 and TOPK Signaling Pathway Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin PROJECT NARRATIVEProject 3 (Curiel Chow) Translational Studies and Clinical Pharmacology of TLR4 and TOPK Inhibitors for Prevention of Squamous Cell Carcinoma of the SkinSkin cancer is the most common cancer worldwide with a tremendous healthcare cost for an agingpopulation. The intent of this Project is to develop effective pharmacological small molecule inhibitors to preventskin cancer caused by long-term sun exposure facilitating a personalized preventive medicine approach forcutaneous squamous cell carcinoma. If successful this Project will lead to new drugs that can lower theincidence of keratinocytic skin cancers. NCI 10686373 9/1/23 0:00 PAR-18-290 5P01CA229112-05 5 P01 CA 229112 5 9/10/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5708 8531398 "CURIEL-LEWANDROWSKI, CLARA " Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 227489 181391 55796 ABSTRACTProject 3 (CurielChow) Translational Studies and Clinical Pharmacology of TLR4 and TOPK Signaling Pathway Inhibitors for Prevention of Squamous Cell Carcinoma of the SkinOne out of three new cancers is a skin cancer making skin cancer the most common malignancy worldwide.Approximately 5 million cases of non-melanoma skin cancer (NMSC) occur annually in the US. Cutaneoussquamous cell carcinoma (cSCC) represents 20-25% of all NMSC. The incidence of cSCC is expected tocontinue to increase as the population ages and behavioral barriers to sun protection persist. Therefore thereis an increasing and substantial impact to society on morbidity and health care costs associated with NMSC($8.1 billion/year) and actinic keratoses (AK) (preneoplastic cSCC lesions; > 1 billion/year).The overall goal of this project is to determine the clinical relevance of Toll-like Receptor 4 (TLR4) and T-LAKcell-originated protein kinase (TOPK) / p53-related protein kinase (PRPK) signaling pathways in ultraviolet lightinduced human skin carcinogenesis process leading to cSCC development. Furthermore we propose todevelop effective pharmacological small molecule inhibitors of these pathways to etsablish a personalizedmedicine approach to this population in need of more effective intervention in the prevention setting. Thehypothesis for this project is that TOPK/ PRPK and TLR4 drive UV-induced carcinogenic signaling pathways inhuman skin which can be pharmacologically targeted for effective topical prevention of cutaneous cSCC. Ourapproach to validate the encouraging preclinical results presented in projects 1 and 2 in chronically UVexposed human skin includes the assessment of the activation state of these pathways in our robust archiveand prospective collection of clinically annotated matched human samples ranging from sun protected skin(SP) sun damaged (SD) AK to cSCC (Aim 1). The protein/phosphoprotein network architecture for TLR4 andTOPK/PRPK will be assessed through IHC and reverse phase protein microarray (RPPA) analysis. Ultimatelywe envision to identfy a subset of biomarkers by IHC that can allow us to accurately select the cohort ofpatients that will benefit from a targeted intervention using one of the small molecule inhibitors proposed in thisapplication. To asses the modulatory effect of the proposed inhibitors in human skin we are using astandardized acute solar simulated light (SSL) model (Aim 2). As part of this effort we will be evaluating theeffect of acute SSL exposure on the pathways of interest using SD skin (Aim 2a). Susbsequently smallmolecule inhibitors will be introduced to the acute human SSL model to determine direct targeted effects (Aim2b). Our final aim will assess safety and phamacodynamics of the proposed TLR4 or TOPK/PRPK smallmolecule inhibitors in a Phase 1 study (Aim 3).This multidisciplinary translational proposal focuses on the novel identification of complementary cellularsignaling network and their relationship with other established pathways in skin carcinogenesis to guide theselection and early clinical development of targeted topical small molecule inhibitors. This will facilitate apersonalized based approach for the therapeutic prevention of cSCC. +No NIH Category available Articulation;Award;Benchmarking;Breast;Camellia sinensis;Cells;Cellular biology;Characteristics;Deposition;Desmoplastic;Diagnosis;Disease;Down-Regulation;Drug resistance;Environment;Epithelial Cells;Epithelial-Stromal Communication;Epithelium;Extracellular Matrix;Fibroblasts;Funding;Generations;Goals;Hypoxia;Immune response;Immunohistochemistry;In Vitro;Laboratories;Macrophage;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mesenchymal;Metaplastic Carcinoma;Metaplastic carcinoma of the breast;Modeling;Mus;Outcome;Patients;Phenotype;Play;Positioning Attribute;Post-Translational Protein Processing;Property;Protein Biochemistry;Proteins;Proteomics;Recurrence;Regimen;Repression;Research;Role;Signal Pathway;Specialist;Specimen;Stress;Stromal Cells;Stromal Change;Testing;Therapeutic;Tissues;Up-Regulation;Veterinarians;Xenograft Model;breast tumorigenesis;cancer subtypes;cancer type;clinically relevant;comparative;data mining;design;experience;gene expression database;in vivo;insight;interest;malignant breast neoplasm;mouse model;multidisciplinary;novel;programs;relapse risk;response;risk minimization;three dimensional cell culture;tumor;tumor growth;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Defining a Stromal Signature that Facilitates Progression of Lethal Cancers Project NarrativeMy proposed activity is articulated around the concept that stromal tissue components play a key role intumorigenesis and that combining therapeutic regimens aimed at normalizing the stroma with currentmalignant epithelium-centered therapies will minimize risk of relapse due to drug resistance. I will focus onidentifying key extracellular matrix drivers of progression for a rare but lethal type of cancer metaplasticcarcinomas for which there is no known therapy. I am well poised to carry out successfully the benchmarks Ihave delineated to reach the proposed goals owing to my background as biochemist cell biologist andveterinarian combined with my many-fold involvement both at the scientific and programmatic levels insuccessful multidisciplinary and highly translational projects. NCI 10686372 8/31/23 0:00 PAR-18-888 5R50CA211543-05 5 R50 CA 211543 5 "HILDESHEIM, JEFFREY" 9/13/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 3158439 "GASCARD, PHILIPPE " Not Applicable 11 PATHOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 247013 NCI 152949 94064 Project Summary/AbstractThe activity proposed in this Research Specialist Award application is in line with the long-standing goals of Dr.Thea Tlsty (the Unit Director)'s currently NCI-funded research program which currently supports myactivity/effort: i) understand dynamic mechanisms underlying cellular plasticity and tissue response to stress;and ii) explore the role of tissue microenvironment and how these multiple factors contribute to tumor initiationand progression. These efforts are particularly worthwhile when dealing with the most lethal type of breastcancer metaplastic breast cancers (MBCs). Identifying tissue components and signaling pathways thatcontribute to the emergence of these cancers in order to design more successful therapies for patientsdiagnosed with MBCs is indeed of the outmost clinical relevance. This application is the result of my personaltwist on the long-term interest of the Tlsty laboratory on the role of stromal-epithelial interactions in breasttumorigenesis. Its core concept relies on the increasingly appreciated notion that cancer progression requiresan instructive tumor microenvironment (TME). Generation of a TME results from: acquisition of a cancer-associated broblast signature a shift in macrophage type alterations of ECM characteristics that eitherfacilitate or counteract tumor growth a corrupted immune response an expanded and leaky vasculature andas a correlate an hypoxic environment and increased epithelial cell plasticity. Such phenotypes are exemplifiedin aggressive tumors characterized by a desmoplastic stroma with extensive and altered ECM depositiontypified by MBCs. Thus the imbalance in ECM composition seen in MBCs is the result of extensive structuraland functional stromal changes that result from alterations in both stromal and epithelial cell properties. Ourprovocative prediction that a specific ECM/stromal make-up may identify cancers with the poorest outcomeacross breast cancer subtypes (luminal Her2-positive basal-like) may be of high clinical relevance not only forMBCs and basal-like cancers but also for luminal breast cancers with late recurrence. To gain valuableinsights I will: i) identify stromal drivers (and repressors) of progression of MBCs through comparativeproteomic analysis of ECM from breast tumor (including MBC) and disease-free breast specimens with anemphasis on post-translational modification status; ii) interrogate gene expression databases for upregulation(or down-regulation) of these ECM proteins across breast cancer subtypes (luminal Her2-positive basalclaudin low) through data mining; iii) test the ability of some of these ECM proteins to drive (or repress) cellplasticity (multilineage commitment and epithelial mesenchymal transition) in vitro using 3D cell culture models;and iv) confirm in vivo the pro- (or anti-)metaplastic/tumorigenic activity of these ECM proteins in murinexenograft models. My extensive experience in protein biochemistry cell biology and characterization of mousemodels combined with my recent interest in data mining and multiplex immunohistochemistry place me in anoptimal position for the novel pursuit of ECM alterations underlying progression of MBCs. 247013 +No NIH Category available Actinic keratosis;Acute;Adjuvant;Age;Animal Model;Arizona;Basal cell carcinoma;Basic Science;Bioinformatics;Biological Markers;Carcinoma in Situ;Chemoprevention;Chemopreventive Agent;Clinical;Coupled;Dangerousness;Development;Drug Targeting;Epithelium;Experimental Models;Goals;Health;Health Care Costs;Histologic;Human;Incidence;Individual;Institution;Intraepithelial Neoplasia;Knowledge;Laboratories;Lesion;Light;Malignant Neoplasms;Medical;Modeling;Molecular Target;Morbidity - disease rate;Mus;Neoadjuvant Therapy;Neoplasms;Operative Surgical Procedures;Pathway Analysis;Pathway interactions;Persons;Pharmaceutical Preparations;Pharmacology;Phase I Clinical Trials;Preclinical Testing;Prevention;Prevention Research;Prevention approach;Prevention strategy;Preventive;Program Research Project Grants;Proteins;Proteomics;Recurrence;Research;Risk Reduction;Role;Safety;Signal Pathway;Signal Transduction;Signal Transduction Induction;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Squamous cell carcinoma;Systems Biology;TLR4 gene;Testing;Tissue Sample;Topical application;Translational Research;UV induced;Universities;cancer therapy;clinical practice;cost;design;disorder risk;drug candidate;drug development;high risk;human subject;human tissue;in vivo;innovation;interest;keratinocyte;molecular targeted therapies;mortality;mouse model;multidisciplinary;new technology;novel;novel therapeutics;phase 1 study;pre-clinical;precision medicine;preclinical study;premalignant;prevent;preventive intervention;programs;reflectance confocal microscopy;skin cancer prevention;skin damage;skin squamous cell carcinoma;small molecule inhibitor;solar ultraviolet radiation;sun damage;tertiary prevention;translational cancer research;translational research program Targeted Prevention for Non-Melanoma Skin Cancer PROJECT NARRATIVEOverall Targeted Prevention for Non-Melanoma Skin CancerThe overall goal of the Targeted Prevention for Non-Melanoma Skin Cancer P01 is to employ novel technologiesand develop molecularly targeted chemopreventive strategies to dramatically reduce the risk of squamous cellcarcinoma of the skin (cSCC). Reducing the incidence of cSCC skin cancers and actinic keratoses (AKs) wouldnot only reduce their potentially severe morbidity and mortality but also dramatically reduce the multibillion dollarhealth bill associated with surgical and medical treatments required for non-melanoma skin cancers and AKs. NCI 10686365 9/1/23 0:00 PAR-18-290 5P01CA229112-05 5 P01 CA 229112 5 "MALONE, WINFRED F" 9/10/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(J1) 8531398 "CURIEL-LEWANDROWSKI, CLARA " "WONDRAK, GEORG T" 7 INTERNAL MEDICINE/MEDICINE 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1301234 NCI 978549 390569 ABSTRACTOverall Targeted Prevention for Non-Melanoma Skin CancerSkin cancer is the most common malignancy worldwide. One out of three new cancers is a skin cancer.Approximately 5 million cases of non-melanoma skin cancer (NMSC) basal cell carcinoma (BCC) andcutaneous squamous cell carcinomas (cSCC) occur annually. Incidence rates for NMSC continue to risecreating a substantial impact on morbidity and health care costs that account for $8.1 billion/year for skin cancertreatment. The majority of these lesions represent keratinocytic neoplasms. The overall goal of this multi-institutional Program Project Grant (PPG) is to employ novel technologies and develop new targeted preventionstrategies to eradicate intraepithelial neoplasias in the skin (e.g. actinic keratosis squamous cell carcinoma insitu) and thereby to dramatically reduce the risk of cSCC. To achieve this goal we will conduct a multilevelprogram of rational drug development including: 1) to assess in experimental models and human studies thesignificance of TLR4 and TOPK/PRPK signaling pathways in skin carcinogenesis leading to cSCC development;2) to evaluate the relationship between TLR4 and TOPK/PRPK activation and previously established signalingpathways of relevance in AK and cSCC development; 3) to identify and develop novel therapeutic preventiveagents that specifically hit these molecular targets in cSCC mouse models and effectively modulate theirsignaling pathways; 4) to test the most promising target-specific agents in preclinical pharmacology models; and5) to assess target engagement and safety of selected agents through pilot and Phase 1 clinical trials.Knowledge of the key molecular targets in solar ultraviolet (UV) radiation signaling pathways and thedevelopment of multiple topically administered agents that can hit and effectively modulate these targetsultimately will allow for precision medicine based approaches in cSCC prevention. While the two basic scienceprojects (Projects 1 and 2) aim to identify and validate UV-induced signaling pathways and agents that modulatethese targets the clinical project (Project 3) will undertake the task of moving leading candidate drugs frommouse models into acute solar simulated light studies and Phase 1 clinical trials. Novel technologies includesignaling network analysis using state-of-the-art proteomic arrays coupled with the latest exploratory anddownstream bioinformatic approaches and in vivo reflectance confocal microscopy for non-invasive assessmentand selection of tissue samples in human skin. This highly integrated and translational research based programproject emphasizing a multidisciplinary precision medicine approach for the prevention of cSCC of the skin canalso serve as a model for preventing other epithelial malignancies. 1301234 +No NIH Category available Address;Adopted;Behavior;Black race;Cancer Center;Cancer Patient;Characteristics;Classification;Clinic;Clinic Visits;Clinical;Communication;Community Hospitals;Comprehension;Consultations;County Hospitals;Decision Making;Diagnosis;Disclosure;Disparity;Distress;Education;Educational Materials;Equity;Ethnic Origin;Evaluation;Family;Future;Genetic;Genetic Counseling;Genetic Risk;Genetic Transformation;Genomic medicine;Haitian;Health Personnel;Hereditary Malignant Neoplasm;Hereditary Neoplastic Syndromes;Intervention;Knowledge;Language;Latino;Learning;Linguistics;Mainstreaming;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Medical;Medical Oncology;Memorial Sloan-Kettering Cancer Center;Methods;Minority;Modeling;Oncologist;Outcome;Pamphlets;Pathogenicity;Patients;Population Heterogeneity;Predisposition;Race;Randomized;Recommendation;Research;Research Design;Research Methodology;Risk;Risk Assessment;Risk Management;Site;Telephone;Test Result;Testing;Time;Update;Variant;Videoconferencing;behavioral outcome;behavioral response;brca gene;cancer risk;cancer therapy;cognitive interview;empowerment;ethnic diversity;experimental study;genetic counselor;genetic panel test;genetic testing;genetic variant;health literacy;hereditary risk;high school;improved;literacy;malignant breast neoplasm;medically underserved;non-genetic;patient population;primary outcome;prospective;psychosocial;racial diversity;randomized clinical trials;response;satisfaction;sex;standard of care;telegenetics;testing uptake;treatment choice;uptake;variant of unknown significance Prospective Trial of a Linguistically and Culturally Appropriate Mainstreaming Model for Hereditary Cancer Multigene Panel Testing Among Diverse Cancer Patients PROJECT NARRATIVEThe objective of this study is to develop test and evaluate a linguistically and culturally appropriatemainstreaming model for hereditary cancer multigene panel testing among cancer patients diverse inrace/ethnicity language and education. This project would make a major contribution by transforming geneticcounseling and testing practice and promote effective risk communication decision making and moreequitable delivery of genomic medicine to those at risk of hereditary cancer syndromes. NCI 10686348 7/10/23 0:00 RFA-CA-20-006 5U01CA243644-04 5 U01 CA 243644 4 "NELSON, WENDY" 9/16/20 0:00 8/31/26 0:00 ZCA1-TCRB-T(A1) 11856998 "HAMILTON, JADA GABRIELLE" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 744686 NCI 485830 347108 PROJECT SUMMARYEfficient yet effective models for delivering genetic counseling and testing are sorely needed to meetincreasing demands for timely genetic risk information. Traditional germline genetic testing models whichinclude in-depth genetic counseling both before and after testing are time intensive and place substantialdemands on the limited genetic counselor workforce. A mainstreaming model which allows for non-geneticshealthcare providers to order genetic testing without pre-test genetic counseling with support from geneticcounselors at the time of result disclosure has shown promise. Yet past evaluations of mainstreaming modelshave been hampered by serious limitations: Studies were restricted to the context of BRCA1/2 testing and donot reflect the growing use of multigene panel testing (MGPT); rarely used rigorous experimental study designsor evaluated theoretically-relevant decision-making psychosocial and communication outcomes; have notcapitalized on opportunities to improve post-test clinical and familial communication; and neither included noraddressed informational needs of minority and medically underserved patients. We overcome these limitationswith the proposed study the objective of which is to develop test and evaluate a linguistically and culturallyappropriate mainstreaming (LCAM) model for hereditary cancer MGPT among cancer patients diverse inrace/ethnicity language and education. We will first use formative research methods including transcreationand cognitive interviewing to adapt existing pre-test educational materials and post-test clinical communicationmaterials for use among the diverse population treated at our community hospital partnering sites (KingsCounty Hospital Center Queens Cancer Center). Next we will conduct an RCT involving English HaitianCreole or Spanish-speaking patients diagnosed with breast ovarian pancreatic or prostate cancer (N=500).Patients will be randomized to obtain access to cancer MGPT through either: i) standard-of-care wherein in-depth pre-test and post-test genetic counseling are provided via telegenetics (i.e. videoconferencing deliveredat the site clinic) with standard post-test clinical communication materials or ii) LCAM intervention whereinpatients receive the adapted pre-test educational materials with testing ordered by their oncologist followed bypost-test genetic counseling provided via telephone with adapted clinical communication materials. Patientswill complete assessments of decision-making psychosocial and behavioral outcomes at baseline upondeciding whether to have MGPT and at 1-week and 6-months following receipt of their test results. Long-termengagement among patients who receive a variant of uncertain significance (VUS) result will also be exploredone year after result receipt through uptake of an offer to discuss any changes in cancer risk or variantreclassification and an additional assessment. This research has the potential to transform genetic counselingand testing practice by promoting effective risk communication decision making and more equitable deliveryof genomic medicine to those at risk of hereditary cancer syndromes. 744686 +No NIH Category available Address;Area;Biology;Cancer Biology;Chemicals;Chemistry;Clinic;Development;Diagnosis;Discipline;Disease;Engineering;Foundations;Genomics;Human;Image;Imaging technology;Label;Laboratories;Malignant Neoplasms;Measures;Medical Imaging;Methodology;Methods;Molecular;Monitor;Organism;Pathway interactions;Pharmacology;Phenotype;Radiochemistry;Techniques;Time;Tissues;Translating;Treatment outcome;Visualization;Work;anatomic imaging;cancer imaging;cancer therapy;clinical translation;detector;imaging agent;improved;in vivo imaging;insight;molecular imaging;new therapeutic target;non-invasive imaging;novel;pre-clinical;predicting response;programs;response;theranostics;translational research program;tumor heterogeneity Annotating Cancer Biology through Non-Invasive Molecular Imaging NARRATIVEThe advent of molecular imaging has prompted a paradigm shift in medical imaging as a whole from itsfoundations in purely anatomical imaging towards techniques aimed at probing tissue phenotype and function.We have for many years exploited aberrant targets associated with cancer in order to better diagnose stage andmonitor this disease. In this R35 we plan to highlight three highly integrated areas within the context of ourexpertise and insights that will have a significant impact on cancer treatment outcomes. NCI 10686347 7/19/23 0:00 PAR-18-880 5R35CA232130-05 5 R35 CA 232130 5 "WANG, YISONG" 9/4/19 0:00 8/31/26 0:00 ZCA1-RPRB-N(M1) 7614079 "LEWIS, JASON S." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1056048 NCI 588000 468048 ABSTRACTMolecular imaging (MI) originated in the need to better understand the fundamental molecular pathways insideorganisms in a noninvasive manner. Over the past two decades two factors have acted in concert to fuel theascent of molecular imaging in both the laboratory and the clinic: (1) an increased understanding of themolecular mechanisms of disease and (2) the continued development of in vivo imaging technologies rangingfrom improved detectors to novel labeling methodologies. We have established a vibrant and state-of-the-artlaboratory-based translational research program. The Lewis lab portfolio is situated at the intersection of variousdisciplines radiochemistry cancer biology chemistry pharmacology and engineering. Our program hasalready demonstrated that our work is not just to generate an image but also to non-invasively andquantitatively measure target biology within a cancer. Even with the extensive preclinical advances in cancerimaging that we have accomplished and the unparalleled visualization of cancer biology we have achieved ourability to translate our findings cannot be understated. Our program has excelled in the clinical translation of newimaging agents providing new insights into cancer biology in humans. In the realms of this R35 we plan to focuson three main areas of discovery: (1) Can our successful imaging agents be transformed into theranostic agentswith the ability to quantify the target through non-invasive imaging while providing concomitant lethality? (2) Howcan our theranostic agents be optimally deployed to quantitatively and non-invasively interrogate and treat tumorheterogeneity? (3) Following conventional and/or novel targeted therapies can we image cancer-specificpathways to provide immediate and real-time predictors of response? We will exploit recent findings and novelmethods to answer these questions using an integrated set of imaging chemical genomic and cancer biologyapproaches. As such the questions posed above will be of more general relevance and will allow us to addressconcepts related to the interactions between imaging therapy and response. 1056048 +No NIH Category available Adoptive Immunotherapy;Adoptive Transfer;Antigen Targeting;Antigens;B lymphoid malignancy;CD19 gene;CD276 gene;Cancer Model;Cells;Cellular immunotherapy;Clinical;Cross Reactions;Cytotoxic T-Lymphocytes;Data;Development;Effector Cell;Engineering;Family;Genetic;Goals;Human;Human Engineering;Immune;Immunocompetent;Immunosuppression;Immunotherapy;Integral Membrane Protein;Interleukin-12;Letters;Link;Lytic;Malignant neoplasm of ovary;Mediating;Modeling;Modification;Monoclonal Antibodies;Mus;Myeloid-derived suppressor cells;Normal tissue morphology;Organ;Pathway interactions;Patients;Phenotype;Pre-Clinical Model;Predisposition;Property;Publications;Publishing;Recurrence;Recurrent disease;Refractory;Relapse;Reporting;SELL gene;Shapes;Signal Transduction;Site;Solid Neoplasm;Specificity;T-Lymphocyte;Technology;Testing;Therapeutic;Toxic effect;Tumor Escape;Tumor-associated macrophages;Up-Regulation;Vitamin D;Woman;Xenograft procedure;angiogenesis;cancer cell;chimeric antigen receptor;chimeric antigen receptor T cells;clinical application;cross reactivity;cytokine;effector T cell;efficacy study;engineered T cells;experimental study;immune checkpoint blockade;mouse model;neoplastic cell;novel;prevent;programs;receptor;response;safety study;stem;tumor;tumor heterogeneity;tumor microenvironment;tumor-immune system interactions Cellular Immunotherapy of Ovarian Cancer Project NarrativeThe majority of women with ovarian cancer (OC) suffer disease recurrence and have then very limitedtherapeutic options. Immunotherapy in the form of checkpoint blockade has shown objective responses in lessthan 15% of patients with recurrent or refractory OC. Therefore the development of more potentimmunotherapy approaches such as chimeric antigen receptor (CAR) T cells is critical in these patients. Wewill explore whether immune cells called natural killer T cells (NKTs) upon genetic modification can attack OCcells and other cells of the tumor microenvironment. NCI 10686345 8/23/23 0:00 PA-18-484 5R01CA243543-05 5 R01 CA 243543 5 "HU, ZHANG-ZHI" 9/1/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-H(02)M] 8141432 "DOTTI, GIANPIETRO " Not Applicable 4 MICROBIOLOGY/IMMUN/VIROLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 387206 NCI 257547 129659 Project AbstractThe majority of women with relapsed and advanced ovarian cancer (OC) have then very limited therapeuticoptions. Checkpoint blockade has shown objective responses in less than 15% in patients. Therefore thedevelopment of more potent immunotherapy approaches such as chimeric antigen receptor (CAR) T cells(CAR-Ts) is critical in these patients. We have identified B7-H3 as a valid target for CAR-Ts in OC. We havegenerated B7-H3.CAR-Ts and successfully tested them in solid tumor models including OC models. In additionsince the B7-H3.CAR we have developed cross-reacts with mB7-H3 we conducted efficacy and safety studiesin immunocompetent mice showing antitumor activity without toxicity. Having identified and validated B7-H3 asa target for OC in this application we aim at overcoming the tumor microenvironment (TME)immunosuppression in OC to fully exploit the potential of the CAR technology. The TME in OC is characterizedby a cellular network that promotes angiogenesis and shapes immunosuppressive cells. In particular tumorassociated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs) are abundant in the TME ofOC and inhibit effector T cells. As compared to T cells NKTs possess the innate property to co-localize withTAMs and to exploit lytic effects on TAMs in a CD1d-dependent manner via their invariant TCR (iTCR). Wehave published and generated additional preliminary data showing that CAR-expressing human NKTs are dualspecific targeting both tumor cells via CAR and TAMs via native iTCR. Furthermore we have generatedpreliminary data showing that human NKTs can also be engineered to release IL-12 a cytokine known toreprogram MDSCs. We hypothesize that NKTs engineered to express the B7-H3.CAR and IL-12 will overcomecritical challenges of adoptive immunotherapy of solid tumors: effector cell localization to the tumor siteselective killing of tumor cells via B7-H3.CAR elimination of tumor-protective TAMs via CD1d engagement bythe iTCR and reprogramming of MDSCs via IL-12. Our new preliminary data also revealed that IL-12 potentlyenhances CD62L-associated stem-like program in NKTs likely via a novel mechanism associated with uniquevitamin D signature. We thus hypothesize that human NKTs may have an intrinsic plasticity not previouslyappreciated and that IL-12 may reprogram NKTs to a more immature phenotype via vitamin D pathway. Threespecific Aims are proposed:Aim 1: To evaluate whether B7-H3.CAR and IL-12 engineering of NKTs and native iTCR cooperate in targetingOC cells and shaping the TME in an immunocompetent murine model.Aim 2: To mechanistically assess how IL-12 expressed by NKTs promotes NKTs with longer persistence uponadoptive transfer.Aim 3: To evaluate the antitumor activity of engineered human NKTs in Human-Immune Tumor (HIT) mice. 387206 +No NIH Category available Malignant Neoplasms;community based participatory research;palliative;psychosocial Psychosocial Palliative and Community Research in Cancer Project NarrativeThis program continues to serve as a national resource for training outstanding newinvestigators in Psycho-oncology. NCI 10686344 9/11/23 0:00 PA-18-403 5T32CA009461-40 5 T32 CA 9461 40 "LIM, SUSAN E" 9/1/19 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1891862 "HAY, JENNIFER L" "OSTROFF, JAMIE S" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 579757 NCI 540916 38841 AbstractThis T32 institutional training grant initially awarded in 1984 was the first to provide support forresearch training in psycho-oncology. Having maintained a highly productive research trainingprogram that has kept pace with NCI research priorities and sustained a superb training record infacilitating the early career development of a diverse and well-trained roster of fellowshipalumna(e) this grant received consecutive five-year renewals in 1989 1994 1999 2004 2009and 2014. It is the oldest research training program in the United States dedicated solely topreparing new investigators for independent research careers focusing on the psychosocial andbehavioral issues across the cancer control continuum. Now in its 34th year this T32 InstitutionalResearch Training Program has successfully trained a cadre of 155 new investigators in psycho-oncology (124 postdoctoral and 31 predoctoral fellows) with at least 75% of former postdoctoraltrainees now building academic research careers in cancer centers medical centers universitiesand other research settings throughout the United States. This track record provides compellingevidence that this program continues to be one of the foremost sites for research training inpsycho-oncology. The current application requests an additional five years of research trainingsupport. With evident growth in the depth and breadth of the portfolio of psycho-oncologyresearch and research training resources there are now 13 Primary Research Mentors and 24Other Mentors who provide depth and breadth in psycho-oncology research and constitute ourParticipating Research Training Faculty. Trainees receive a strong didactic curriculum and workin an apprentice model with the opportunity to work on a wide variety of current and plannedprojects. led by faculty mentors. We propose continuation of our six postdoctoral and twopredoctoral training slots. In the next five years we intend to enhance our training track record byexpanding the range of research training opportunities strengthening our didactic curriculum andbuilding upon our past success in recruiting and retaining under-represented scientists. Eachcomponent of the program will be evaluated annually by participating faculty trainees andmembers of an External Advisory Committee to ensure that this program continues to serve as anational resource for training outstanding new investigators in psycho-oncology. 579757 +No NIH Category available AIDS Malignancy Consortium;AIDS related cancer;Acquired Immunodeficiency Syndrome;Adherence;Adult;Affect;Africa South of the Sahara;African American;Area;Arizona;Basic Science;Biological;Biological Specimen Banks;Caribbean region;Cause of Death;Cessation of life;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Collection;Complex;Consent;Data;Data Pooling;Development;Economic Burden;Eligibility Determination;Ensure;Epidemic;Equipment and supply inventories;Equity;Evolution;Fostering;Freezing;Funding;Geographic Locations;Goals;Growth;HIV;HIV/AIDS;Head;Health;Hepatitis B Virus;Hepatitis C virus;Hispanic Americans;Hodgkin Disease;Human Herpesvirus 4;Human Papillomavirus;Incidence;Individual;Infection;Informatics;Institution;International;Kaposi Sarcoma;Latin America;Latin American;Leadership;Link;Liquid substance;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Marketing;Medical;Methodology;Mission;Morbidity - disease rate;Network Infrastructure;Non-Hodgkin's Lymphoma;Outcome;Pathogenesis;Pathologic;Patients;Persons;Play;Prevalence;Process;Public Health;Reporting;Research;Research Personnel;Research Support;Resources;Risk;Risk Factors;Role;Sample Size;Sampling;Science;Scientist;Site;Smoking;Specimen;Standardization;Structure;Technology;Testing;Time;Tissue Sample;Translational Research;Tumor Tissue;U-Series Cooperative Agreements;United States;United States National Institutes of Health;Universities;Viral;Washington;Work;aging population;antiretroviral therapy;biobank;cancer epidemiology;cancer risk;cancer specimen resource;cancer therapy;cancer type;co-infection;cofactor;epidemiologic data;fitness;immune function;informatics infrastructure;men;mortality;new technology;novel;older patient;outreach;programs;sample collection;skills;success;tumor microenvironment;virtual;virtual repository;virus related cancer;working group AIDS and Cancer Specimen Resource (ACSR) Project NarrativeThe AIDS Cancer and Specimen Resource (ACSR) will supply biospecimens and clinical data toindividuals investigating HIV associated cancers. It will also support the AIDS Malignancy Clinical TrialsConsortium (AMC) by providing support for its biorepository functions in the United States sub-SaharanAfrica and Latin America. NCI 10686329 8/30/23 0:00 RFA-CA-18-012 5UM1CA181255-10 5 UM1 CA 181255 10 "LIDDELL HUPPI, REBECCA" 9/23/13 0:00 8/31/24 0:00 ZCA1-RPRB-J(M2) 7125737 "BETHONY, JEFFREY MICHAEL" "MCGRATH, MICHAEL SHANNON" 98 MICROBIOLOGY/IMMUN/VIROLOGY 43990498 ECR5E2LU5BL6 43990498 ECR5E2LU5BL6 US 38.898075 -77.043933 2863301 GEORGE WASHINGTON UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200520042 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 4831082 NCI 3975279 855803 AbstractThe AIDS epidemic initially recognized in the early 1980's currently affects more than 35 million peopleworldwide. Infection with the human immunodeficiency virus (HIV) is associated with a wide range of long termhealth complications including the development of cancer currently a major cause of death among persons livingwith HIV/AIDS. The early form of the AIDS and Cancer Specimen Resource (ACSR) was established in 1994 asa cooperative agreement with the NCI with a mission to provide high quality biospecimens to researchers amission still paramount for the current ACSR.Principle investigators (MPIs) from the two legacy sites (GWU and UCSF) oversee the function of the ACSR toensure the adherence to NCI best practices in this multinational program. The ACSR is currently the custodianfor specimen collections from more than 20000 individuals and makes these biospecimens available to eligibleresearchers studying HIV and cancer through an established specimen application process. In the past fiveyears investigators from more than 50 institutions have received research material from the ACSR. In additionthe ACSR has provided the centralized biospecimen collection and distribution functions for the AIDS MalignancyConsortium (AMC) which represents the NCI-funded international network of more than 30 clinical institutionsinvolved in testing novel cancer therapies in HIV-infected individuals. The ACSR is structured into regionalbiospecimen repositories (RBRs) located in distinct geographical regions that reflect the US and global HIVepidemic and are unified (virtually) by an informatics infrastructure managed by the Hub for IntegratedInformatics and Research Support (HIIRS). The RBRs are distinct but complementary in their diverse functionswith collaborative interactions fostered through the Governing Committee and ACSR-wide Working Groups thataccomplish activities related to Science and Technology Marketing and Outreach Informatics and QualityManagement.As the HIV epidemic has evolved the types of cancers and the technologies used to study them have alsochanged. The newly reconfigured ACSR will have two divisions both focused on obtaining the most importantwell-annotated (demographic clinical pathological and outcomes data) biospecimens for research as definedby investigator inquiries and the ACSR's scientific advisory board. The two MPIs respectively will head thenational and international AMC support program and the scientific direction of the ACSR. Both MPIs will workwithin the structure of the ACSR to obtain and provide to researcher's specimens most important for research inthe current epidemic. Specific Aims include: 1) Acquire store and equitably distribute tumor tissues andbiological fluids from individuals with HIV-associated malignancies (AIDS-defining cancers and non-AIDSdefining cancers) to meet the biospecimen needs of researchers in HIV-associated malignancies; and 2)Promote the success of AMC clinical trials through mutually beneficial collaborations. 4831082 +No NIH Category available Address;Affect;Biological Models;Carbon;Cell Culture Techniques;Cultured Cells;DNA Methylation;Data;Dependence;Diet;Diet and Nutrition;Dietary Factors;Environment;Enzymes;Epigenetic Process;Fluorouracil;Funding;Gene Deletion;Genes;Genetic;Genetically Engineered Mouse;Genomics;Glycine;Health;Insecta;Investigation;Laboratories;Longevity;Malignant Neoplasms;Mammals;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methionine;Methionine Metabolism Pathway;Methods;Methylation;Modeling;Molecular;Nature;Nutrient availability;Observational Study;Oncogenes;Outcome;Oxidation-Reduction;Pathway interactions;Pharmacology;Phenotype;Phosphorylases;Plasma;Predisposition;Proliferating;Property;Radiation;Radiation Dose Unit;Radiobiology;Radiosensitization;Reaction;Resistance;Role;Serine;Therapeutic;Tumor Suppressor Genes;Undifferentiated;Work;Xenograft Model;anti-cancer;cancer cell;cancer genetics;chemotherapy;clinically relevant;colon cancer patients;dietary;dietary manipulation;dietary requirement;dietary restriction;drug development;experimental study;histone methylation;in vivo;metabolomics;mouse model;nucleotide metabolism;patient derived xenograft model;pre-clinical;programs;radiation response;response;sarcoma;synergism;targeted treatment;treatment response;tumor;tumor growth;tumor metabolism Dietary methionine and cancer Diet and nutrition can affect metabolic pathways and determine the requirements of cancer cellmetabolism. This work explores a specific aspect of diet dietary methionine which we have shown tohave anti-tumor properties and now we will explore the nature of its anti-cancer effects. NCI 10686225 9/15/23 0:00 PA-20-185 5R01CA193256-08 5 R01 CA 193256 8 "XI, DAN" 8/14/15 0:00 7/31/26 0:00 Tumor Cell Biology Study Section[TCB] 9556953 "LOCASALE, JASON W." Not Applicable 4 PHARMACOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 352550 NCI 221935 130615 Nutrient availability (i.e. diet) can affect metabolic pathways and determine the requirements of cancercell metabolism to as large a degree as the metabolic genes that are reprogrammed in tumors.Previous work from us and others has shown that 1.) methionine availability affects one carbon cycleflux DNA and histone methylation and thus epigenetic programming 2.) dietary methionine restrictionpromotes metabolic health and extends insect and mammalian lifespan two anti-cancer phenotypes3.) deletions of genes that affect methionine metabolism in tumors render them susceptible.Nevertheless how this dietary factor (and diet in general) can influence cancer outcome is largelyunknown. Our preliminary data shows that methionine restriction delays tumor growth in colorectalcancer patient derived xenograft (CRC PDX) models and sensitizes a genetically engineered mousesarcoma model to radiation. These findings led us to propose an investigation to define themechanisms underlying these phenotypes. We will consider the following aims. In aim 1 we seek toidentify molecular determinants of sensitivity to methionine restriction. We will employ a metabolomicsapproach using a metabolite profiling platform and flux analysis method our laboratory has developedto investigate the metabolic changes in cancer cells that are induced by methionine restriction. We willnext investigate the epigenetic role that methionine metabolism in tumor growth. The outcome willdetermine the metabolic and epigenetic adaptations that are modulated through dietary methioninemetabolism. In aim 2 we will determine why the sarcomas are resistant to methionine restriction butrespond to dietary methionine restriction and radiation in a synergistic manner. The outcome will definethe metabolic and epigenetic mechanisms that occur in order to resist dietary manipulation ofmethionine metabolism but leads to a synergy effect of dietary methionine restriction and radiation. Inaim 3 we will determine the role of methionine availability from diet in methylthioadenosinephosphorylase (MTAP)-deleted cancers. MTAP is an enzyme essential for the methionine salvagepathway and recent studies have shown that deletions in MTAP confer additional dependencies onmethylation reactions. The outcome using MTAP dietary methionine and methionine metabolism as amodel system will characterize the metabolic interaction between dietary methionine and MTAPdeletion and lead to a newfound understanding of the interaction between genetics and environmentparticularly diet and nutrition in mediating cancer outcome. 352550 +No NIH Category available Address;Biological Assay;Biological Markers;Biological Models;Biopsy;Biopsy Specimen;Cancer Patient;Clinical;Clinical Sensitivity;Clinical Trials;Collection;DNA Damage;Diagnosis;Disease;Etoposide;Formalin;Gene Expression;Gene Expression Profile;Genes;Genetic;Guidelines;Heterogeneity;Immune response;Immune system;Immunocompromised Host;In Situ Hybridization;Individual;Inter-tumoral heterogeneity;Interferons;Investigational Therapies;Learning;Malignant Neoplasms;Mediating;Modeling;Molecular;Mus;Mutation;NOR Mouse;National Comprehensive Cancer Network;Nature;Neoplasm Circulating Cells;Outcome;Paraffin Embedding;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phase I/II Trial;Platinum;Population;Prognosis;Property;RNA;Recording of previous events;Regimen;Relapse;Resistance;Role;Sampling;Signal Transduction;Solid Neoplasm;Specimen;Stimulator of Interferon Genes;Testing;Time;Tissue Sample;Topotecan;Translational Research;Validation;Variant;Xenograft procedure;arm;biomarker driven;chemotherapy;co-clinical trial;comparative;cytokine;drug sensitivity;effusion;epigenetic silencing;established cell line;experience;experimental study;genetic signature;individual patient;knockout gene;mouse model;novel;pathogen;patient derived xenograft model;patient population;patient response;pharmacologic;resistance mechanism;response;small cell lung carcinoma;targeted treatment;temozolomide;treatment response;trial design;tumor Dissecting and overcoming cross-resistance to DNA damaging agents in SCLC Project NarrativeSmall cell lung cancer (SCLC) is initially sensitive to chemotherapy. However relapse is nearly inevitable atwhich point SCLC becomes resistant to many similar therapies. We have grown tumors from patients beforeand after relapse directly in mice and will use these to learn how SCLC becomes resistant after relapse. NCI 10686224 8/7/23 0:00 PA-19-117 5K08CA237832-04 5 K08 CA 237832 4 "RADAEV, SERGEY" 8/1/20 0:00 7/31/25 0:00 Career Development Study Section (J)[NCI-J] 12392196 "DRAPKIN, BENJAMIN J" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 246878 NCI 228591 18287 Project SummarySmall cell lung cancer (SCLC) afflicts more than 30000 patients per year and is rapidly fatal in 95% of caseswith median survival is less than one year. Belying this grim prognosis treatment-naive SCLC is highlysensitive to chemotherapy. However relapse is nearly inevitable and relapsed SCLC presents two obstaclesthat have been insurmountable for at least 30 years: cross-resistance to chemotherapy and absence ofbiomarker-driven targeted therapy.Following relapse resistance often extends beyond etoposide/platinum (EP) to other DNA damaging agents.Although topotecan is the only approved second-line therapy for SCLC the NCCN guidelines list 10 agents ofroughly equivalent efficacy. None are particularly effective in unselected patients and a disease that was oncehighly chemosensitive becomes inexorably progressive. However the molecular determinants of cross-resistance in SCLC remain unclear. Although critically important cross-resistance is difficult to studyexperimentally as it requires a model system that faithfully reproduces clinical outcomes and is adequatelypowered to capture inter-tumoral molecular heterogeneity across a population of patients.We have generated a panel of 44 SCLC patient-derived xenograft models (PDXs) from biopsy specimens andcirculating tumor cells (CTCs). Our panel includes successive models from individual patients at time pointsbefore and after specific lines of therapy with detailed information about the corresponding clinical response.For both standard chemotherapy and experimental agents in clinical trial these models faithfully mirror patientresponses. However unlike the patient experience multiple strategies can be compared for identical tumors.We propose to use these models to directly compare three clinical strategies that depend on induction of DNAdamage: standard first line EP second line topotecan anad a promising experimental regimen olaparib plustemozolomide (OT) currently in a phase I/II trial at MGH. Individually these PDX population trials are designedto reveal biomarkers of sensitivity and mechanisms of resistance for promising experimental therapies.Collectively through comparative analysis with reference to the clinical histories of each model they present anovel opportunity to model cross-resistance a problem that has beleaguered management of SCLC for overthree decades. 246878 +No NIH Category available Abdomen;Address;Adipocytes;Adipose tissue;Adult;Aerobic Exercise;Biological Markers;Biopsy;Blood;Breast Cancer survivor;C-reactive protein;CD8-Positive T-Lymphocytes;Cancer Prognosis;Cancer Survivor;Chronic;Complex;Control Groups;Crowns;Development;Diabetes Mellitus;Disease-Free Survival;Distant;Dose;Dual-Energy X-Ray Absorptiometry;Economic Burden;Exercise;Fatty acid glycerol esters;Foundations;Guidelines;Heart Diseases;IL8 gene;Inflammation;Inflammation Mediators;Inflammatory;Insulin Resistance;Interleukin-6;Investigation;Knowledge;Lead;Least-Squares Analysis;Leptin;Leucocytic infiltrate;Link;Macrophage;Malignant Neoplasms;Measurement;Measures;Mediating;Mediator;Metabolic;Methods;Movement;Obesity;Organ;Overweight;Phase;Phase II Clinical Trials;Phase III Clinical Trials;Phenotype;Population;Postmenopause;Prognosis;Recurrence;Research;Signal Transduction;Source;Structure;Survival Rate;TNF gene;Thinness;Time;Treatment Side Effects;Work;adipokines;adiponectin;attentional control;attenuation;breast cancer progression;cancer therapy;comorbidity;cytokine;design;exercise intervention;exercise program;exercise regimen;improved;inflammatory marker;innovation;malignant breast neoplasm;mathematical model;mode of exercise;mortality;novel;prognostic;programs;resistance exercise;sarcopenic obesity;subcutaneous;systemic inflammatory response;tumor progression;tumorigenesis Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors Targeting chronic inflammation related to obesity with exercise has the potential to improve prognosis andcomorbidities related to heart disease and diabetes in obese postmenopausal breast cancer survivors. Ourproposal seeks to determine appropriate exercise regimens to reduce chronic inflammation and improveprognosis that can be set forth as specific exercise guidelines to improve cancer prognosis. NCI 10686204 8/16/23 0:00 PAR-16-122 5R01CA214385-06 5 R01 CA 214385 6 "PERNA, FRANK" 9/1/18 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-PSE-K(57)R] 10366548 "DIELI-CONWRIGHT, CHRISTINA " Not Applicable 7 NONE 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA ORGANIZED RESEARCH UNITS 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 610690 NCI 431567 179123 Targeting chronic inflammation related to obesity with exercise has the potential to improve prognosis in obesepostmenopausal breast cancer survivors. Obesity is considered a leading modifiable contributor to breastcancer mortality worldwide due to its association with increased recurrence and decreased overall survivalrate. A central mechanism by which obesity stimulates cancer progression is through chronic low-gradeinflammation in adipose tissue. In particular white adipose tissue (WAT) is a metabolically complex organcomprised of adipocytes capable of secreting adipokines and proinflammatory cytokines related totumorigenesis. Chronic inflammation of WAT includes accumulation of adipose tissue macrophages (ATMs).Specifically the ATM M1 phenotype elevated with obesity provides a rich source of cytokines which are keymediators of obesity-associated insulin resistance. Gains in fat mass and a decline in lean mass known assarcopenic obesity are observed as a treatment side effect further contributing to the development of WATand subsequent elevated M1 expression. Favorably exercise-induced changes in sarcopenic obesity lead to areduction in M1 ATMs and increase in M2 ATMs known to protect against insulin resistance by attenuatinginflammation. However it is unknown what impact this may have on cancer prognosis and what forms ofexercise are most effective at reducing chronic inflammation. Our general hypothesis is that exercise designedto target chronic inflammation and associated sarcopenic obesity will improve prognosis in obesepostmenopausal breast cancer survivors. We propose a Phase II RCT to compare the effects of two combinedaerobic and resistance exercise interventions relative to an attention control group among early-stage obesepostmenopausal breast cancer survivors who have completed primary cancer therapy. This proposal willaddress the following aims: 1) determine the effects of exercise on obesity-associated chronic inflammation; 2)examine the effects of exercise on sarcopenic obesity; 3) determine the effects of exercise on breast cancerprognosis and to assess whether reductions in chronic inflammation are associated with breast cancerprognosis. This study is innovative because a) we will target adipose tissue inflammatory biomarkers toimprove cancer prognosis b) derive a mathematical model that employs measureable markers of inflammationto predict prognosis c) utilize a novel biopsy method to obtain deep subcutaneous abdominal adipose tissue toaddress a mechanistic prognostic question and d) employ a unique periodized circuit-style exercise design toreduce chronic inflammation. If the aims are achieved findings from this study will generate new knowledgeabout exercise guidelines for breast cancer survivors most likely to improve prognosis.! 610690 +No NIH Category available Appointment;Area;Biomedical Research;Biometry;Clinical;Clinical Research;Collaborations;Complex;Coupled;Data Science;Development;Discipline;Educational Curriculum;Educational process of instructing;Educational workshop;Epidemiology;Faculty;Feasibility Studies;Fostering;Foundations;Funding;Genetic;Genomics;Goals;Grant;Health Disparities Research;Hybrids;Impact evaluation;Intervention;Learning;Malignant Neoplasms;Mentors;Mentorship;Minority;Minority Groups;National Human Genome Research Institute;National Institute of General Medical Sciences;Persons;Play;Population;Positioning Attribute;Postdoctoral Fellow;Productivity;Race;Research;Research Methodology;Research Personnel;Research Project Grants;Research Support;Research Training;Role;Science;Series;Services;Site;Stream;Students;Training;Training and Education;Underrepresented Minority;Universities;anticancer research;biological systems;cancer genomics;cancer health disparity;community engaged research;design;doctoral student;early-career faculty;education research;equity diversity and inclusion;faculty community;genome sciences;health disparity;innovation;insight;lectures;medical schools;member;minority investigator;novel;people of color;programs;response;skills;statistics;success;undergraduate student;university student;virtual Cancer research education program (C-REP) Project Narrative: TRAINING AND EDUCATION PROGRAMDiverse investigators play an integral role in identifying novel research questions perspectives and solutionsto complex biomedical challenges. Yet diversifying the biomedical research workforce remains a majorchallenge in the US despite the fact that underrepresented minorities make up the most rapidly growingsegment of the US population. Thus in a unique partnership between the Icahn School of Medicine at MountSinai and Hampton University we propose to provide hybrid training and education to increase the researchcapacity engagement and success of the HU scientific workforce with particular emphasis on genetics andgenomics and cancer disparities research. NCI 10686195 9/8/23 0:00 PAR-18-911 5P20CA264076-03 5 P20 CA 264076 3 9/21/21 0:00 8/31/25 0:00 ZCA1-SRB-2 5682 9550274 "BENN, EMMA KATHERINE TARA" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 158378 93715 64663 PROJECT SUMMARY: TRAINING AND EDUCATION PROGRAM While minority faculty in the clinical and translational sector may provide an innovative perspective fromwhich we identify problems disproportionately plaguing populations of color they often lack the researchcapacity needed to both rigorously evaluate the causal predictors of these problems and identify mechanisticmodes of intervention for the elimination of health disparities. Moreover minority investigators encounter majorbarriers to successful competition for federal research funding which include but are not limited to: inadequateresearch training a lack of opportunities for professional development insufficient mentorship and inadequatesupport for research focused on minority populations (Shavers 2005). Thus in response to PAR-18-911 our goal is to partner with Hampton University (HU) faculty in orderto provide hybrid training and education to increase HU research capacity in the area of cancer genomics andhealth disparities while also providing a rigorous curriculum in introductory and advanced biostatistics anddata science clinical genome science epidemiology community-engaged research health disparitiesresearch and clinical research methods. The curriculum will be administered through online asynchronous andsynchronous lectures coupled with intensive on-site training sessions in Years 2 through 4 of the proposedfour-year partnership. Our objectives are to: 1) successfully implement the online cancer genomics researchtraining and education program; 2) design and successfully implement the on-site research training educationprogram; and 3) conduct a rigorous evaluation of the impact of the proposed training and education programon building research capacity and increasing research engagement and productivity. Additionally HU will beproviding extensive insight and guidance to help foster a culture of inclusion diversity and equity amongmembers of the ISMMS research workforce through a series of in-person and virtual lectures. In summary we are confident that our proposed comprehensive online and on-site training andeducation program will increase the competitive success of federal grant submissions by HU faculty for cancerhealth disparities genomics research projects while also providing them with an optimal skill-set that they candisseminate to the larger HU community of faculty and students. +No NIH Category available Ablation;Algorithms;Anatomic Models;Anatomy;Biomechanics;Cessation of life;Clinical;Computer software;Data;Dedications;Diagnosis;Elasticity;Elements;Eligibility Determination;Ensure;Excision;Goals;Image;Incidence;Inflammation;Intervention;Interventional Imaging;Laboratories;Liver;Liver neoplasms;Local Therapy;Location;Magnetic Resonance;Malignant neoplasm of liver;Maps;Metastatic Neoplasm to the Liver;Methods;Modality;Modeling;Molecular Conformation;Monitor;Morphologic artifacts;Normal tissue morphology;Operative Surgical Procedures;Patients;Phase;Procedures;Progression-Free Survivals;Publishing;Recurrence;Residual Neoplasm;Second Primary Cancers;Series;Survival Rate;Technology;Testing;Thermal Ablation Therapy;Time;Tissue Model;Tissues;Traction;Treatment Efficacy;Tumor Tissue;Water;Work;X-Ray Computed Tomography;biomechanical model;curative treatments;efficacy evaluation;image guided;image registration;imaging probe;improved;innovation;liver ablation;mathematical model;post intervention;randomized clinical trials;response;standard of care;success;tool;tumor;tumor ablation;tumor progression Anatomical Modeling to Improve the Precision of Image Guided Liver Ablation Liver tumor involvement by either primary or secondary malignancies responsible for over 1 million deaths peryear worldwide can be treated with image-guided percutaneous thermal ablation (PTA) with 5-year overallsurvival rates comparable to surgical series. In order to achieve optimal results following PTA rates of residualtumor or recurrence should be minimized which can be achieved with adequate minimal ablation margins of atleast 5 mm around. The use of anatomical modeling to map the tumor defined on pre-treatment images ontothe intra-procedural image and post-ablation image has the potential to improve the ablation margin andincrease local control rates. NCI 10686184 8/29/23 0:00 PAR-18-530 5R01CA235564-05 5 R01 CA 235564 5 "TATA, DARAYASH B" 9/1/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 8681158 "BROCK, KRISTY " "ODISIO, BRUNO C" 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 330870 NCI 235374 95496 Primary and secondary liver cancers are increasing in incidence and are collectively responsible for over1 million deaths per year worldwide. Among the curative treatments available for liver cancers surgical resectionis considered the standard of care. Unfortunately less than 20% of patients are eligible for such resection at thetime of the diagnosis. Image-guided percutaneous thermal ablation (PTA) has become a widely utilized optionfor patients not eligible for surgery with local control success rates ranging from 55% to 85% (4-6). In order to achieve optimal results following PTA rates of residual tumor or recurrence should beminimized (6 8) which can be achieved by providing adequate minimal ablation margins around the tumor. Tomeet this goal it is critical to have high-quality intra-procedurally imaging that offers information in respect precisedefinition of extent of the target tumor confirmation of ablation probe placement at the target tumor(s) andaccurate ablation margins assessment. Currently there are no commercially available tools that enable anaccurate method for tumor mapping and ablation assessment while taking in consideration biomechanicalconformational changes associated with the ablation therapy. Based in our preliminary work we hypothesize that local tumor control following ablation of liver cancerswill be improved with the application of a dedicated anatomical linear elastic biomechanical model for treatmentguidance and efficacy assessment by enabling accurate identification and targeting of the tumor and providingintra-procedural assessment of the ablation respectively. This hypothesis will be tested through three specificaims. Firstly we will optimize the anatomical modeling liver ablation guidance in the RayStation Platform byvalidating the accuracy of the linear elastic biomechanical models of the liver for the application of mapping thetumor defined on the pre-interventional images onto the intra-procedural images obtained just prior to ablation;Secondly we will evaluate the impact of this model on local tumor control following liver ablation by conductinga phase II randomized clinical trial; Finally we will optimize the biomechanical model to enable modeling of thelocal changes in the tumor and surrounding normal tissue resulting from the ablation. We believe that the integration of accurate precise and efficient biomechanical modeling tools todetermine the tumor location at the time of ablation and to monitor the ablation margin will improve local tumorcontrol rates in patients with liver cancers potentially improving overall survival rates. The ability to performdeformable image registration to map the tumor identified on pre-intervention imaging in the presence ofartifacts from the ablation probe and with little to no contrast within the liver presents a significant challenge tomost intensity-based algorithms. The use of a biomechanical-based model in this application is poised to makea significant impact potentially enabling local control for the 20% of patients who fail this therapy. The integrationof this technology into the RayStation platform ensures that this technology is widely available to patients. 330870 +No NIH Category available Applications Grants;Area;Biological Products;Cancer Center;Cancer Center Support Grant;Cancer Vaccines;Cell physiology;Cells;Cellular Metabolic Process;Characteristics;Chemicals;Collaborations;Combined Modality Therapy;Development;Direct Costs;Disease;Doctor of Philosophy;Drug resistance;Environment;Epigenetic Process;Faculty;Funding;Genomic approach;Genomics Shared Resource;Goals;Grant;Growth;Human Microbiome;Immune;Immune mediated destruction;Immune system;Immunotherapy;Infection;Inflammation;Invaded;Knowledge;Lead;Malignant Neoplasms;Metabolic;Modeling;Molecular;Molecular Structure;Neoplasm Metastasis;Oncologist;Oncology;Outcome;Process;Productivity;Property;Proteomics;Publications;Publishing;Regulation;Research;Research Personnel;Role;Signal Transduction;Stromal Cells;Therapeutic;Tumor Escape;Tumor Promotion;Work;angiogenesis;cancer cell;cancer imaging;cancer therapy;cell motility;cell type;functional genomics;individual patient;insight;interest;meetings;member;microbiome;neoplastic cell;novel;novel strategies;novel therapeutics;permissiveness;personalized immunotherapy;programs;recruit;targeted treatment;therapeutic target;transcriptomics;translational study;tumor;tumor growth;tumor immunology;tumor microenvironment;tumor progression;vaccinology Tumor Microenvironment and Cancer Immunology n/a NCI 10686170 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5678 1940901 "BRADLEY, LINDA MAC PHERSON" Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 47964 24597 23367 ABSTRACT TUMOR MICROENVIRONMENT AND CANCER IMMUNOLOGY PROGRAMThe overarching goal of the Tumor Microenvironment and Cancer Immunology (TMCI) Program is to define howthe dynamic interplay among cancer cells immune cells stromal components and vasculature regulates thegrowth and dissemination of malignancies and in so doing identify therapeutic approaches to modulate themicroenvironment and tumor growth. The Program consists of 13 faculty (one a new recruit) and five adjunctmembers and integrates members whose expertise includes cell migration/invasion molecular structures cellsignaling cell metabolism and angiogenesis with members whose work encompasses therapeutic targeting ofinnate and adaptive immune cells and the influence of the microbiome on tumor- and immune cell-directedcancer therapies. This complementary expertise is organized around three interacting themes: (1) ActivatingInvasion and Metastasis; (2) Avoiding Immune Destruction and (3) Tumor Promoting Inflammation. Thesethemes encompass many of the molecular processes that coordinate the formation of the microenvironment thatenables progressive tumor growth and metastasis. Members interact on several of levels including monthlyfaculty meetings program-led seminars (48 in the last funding period) strategic meetings organized around newcollaborative opportunities (for example the interface of the human microbiome and cancer) and collaborativegrants. Program funding is strong with current total annual grant funding of $4.4M (direct costs) ($2.6M fromNCI 58%). Members currently lead 28 grants including 15 R01s (nine from NCI) and lead or participate in threeP01s (two from NCI) and multiple other grants. Over the last funding period members have participated in 34(32%) collaborative grants. Our productivity is reflected in 224 cancer-relevant publications in the last fundingperiod of which 31% were collaborative (19% intra- and 12% inter-programmatic). In 2018 we published 42cancer-relevant publications of which 21% were intra- and 5% inter-programmatic. TMCI members havepioneered novel approaches to interrogate the fundamental properties of tumor cells and other cell types withintumors and are developing immune cell- and tumor-targeted therapies. Members are participating intranslational initiatives through the Oncology Disease Teams C3 Cancer Center Council and the San DiegoCenter for Precision Immunotherapy which support collaborations with local oncologists to enable largecollaborative grants applications. In recognition of the role of the immune system in combatting cancer a keygoal of the Program is to build and further strengthen expertise in cancer immunology by hiring at least twoadditional faculty including one with expertise in vaccinology. Key scientific goals are to extend the use ofinfection models to inform studies to harness the immune system for immunotherapy and cancer vaccines aswell as to integrate single-cell transcriptomics proteomics epigenetics and metabolic profiling and imaging ofcancer cells immune cells and stromal cells in tumors to achieve new insights into the regulation of tumor growthoutcomes and cellular processes that lead to drug resistance and immune evasion by tumors. +No NIH Category available Acceleration;Adenoviruses;Adopted;Automation;Bioinformatics Shared Resource;Biological Assay;CRISPR library;CRISPR screen;CRISPR/Cas technology;Cancer Center;Cancer Center Support Grant;Cell Line;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Communication;Computer software;Contract Services;Core Facility;Cultured Cells;Custom;Data;Data Analyses;Dedications;Doctor of Philosophy;Employee;Engineering;Equipment;Experimental Designs;Faculty;Feedback;Gene Activation;Gene Family;Genetic;Genetic Screening;Genomics Shared Resource;Goals;Grant;Guide RNA;Image;Institution;Label;Laboratories;Leadership;Libraries;Maintenance;Malignant Neoplasms;Methods;MicroRNAs;Microscopy;Miniaturization;Mutation;Patients;Preparation;Publications;RNA Interference;Reagent;Research;Research Personnel;Resource Sharing;Science;Scientist;Services;Small Interfering RNA;Statistical Data Interpretation;Supporting Cell;Surveys;System;Technology;Time;Viral;Viral Vector;Work;antagonist;assay development;cost effectiveness;design;exome;functional genomics;gene repression;genome-wide;high throughput screening;inhibitor;meetings;member;nucleic acid delivery;programs;repaired;repository;screening;small hairpin RNA;small molecule libraries;tool;vector;whole genome Functional Genomics n/a NCI 10686149 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5672 1885588 "CHANDA, SUMIT K" Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 305953 156899 149054 ABSTRACT FUNCTIONAL GENOMICS SHARED RESOURCE The central goal of the Functional Genomics Shared Resource which is managed by the Cancer Center is to provide services and tools for Center members to perform RNAi and CRISPR-CAS9 genetic screens in cultured cells. Core staff interact with Center faculty members throughout their projects starting with project conceptualization and feasibility assessment through to the final verification of targets identified in the screens. The Core utilizes the extensive amount of HTS equipment available in the Prebys Center and the Chemical Library Screening Core. In addition to the wealth of expertise brought by the staff the Core serves as a repository for reagents assays and technical information which are shared with Cancer Center researchers. The Core provides a variety of libraries for functional genomics analysis including a genome-wide siRNA library and comprehensive miRNA activator and inhibitor libraries broad shRNA libraries as well as targeted arrayed and genome-wide pooled CRISPR libraries. The Core's primary effort is dedicated to genetic screening via RNAi and CRISPR-Cas9 although significant time is also currently dedicated to engineering of cell lines. Within the Core the main laboratory focuses on cellular genetics while the viral vector laboratory specializes in high-quality vector preparation in a centralized facility with expert staff and produces an array of sophisticated viral systems to enable nucleic acid delivery. Both laboratories are also actively involved in developing tools tailored to the specific needs of Center researchers. Functional Genomics operates in close connection with other Shared Resources at SBP. Thus the Core utilizes automation and high-throughput imaging support from the adjacent Chemical Library Screening Shared Resource; interacts with the Bioinformatics Shared Resource to perform statistical analysis of the raw data and design custom CRISPR libraries; and uses the sequencing services of the Genomics Shared Resource to execute CRISPR-Cas9 screens. Overall the Functional Genomics Core has strived to maintain its place at the forefront of cellular genetics and nucleic acid delivery by adopting state-of- the-art technologies implementing methods to fill technology gaps and adapting methods to fulfill the specific needs of the Cancer Center. In the past 5 years the Core was used by a total of 45 Center members representing all three programs and it supported at least 29 cancer-related publications by Cancer Center members. +No NIH Category available Achievement;Address;Age;Aging;Air Pollution;Aliquot;Area;Authorization documentation;Award;Biological Markers;Blood specimen;California;Cessation of life;Characteristics;Clinical;Cloud Computing;Cohort Studies;Collaborations;Collection;Communities;Complement;Complex;Data;Data Analyses;Data Collection;Data Commons;Data Mart;Emergency department visit;Ensure;Environment;Environment Design;Environmental Exposure;Epidemiology;Essential worker;Etiology;FAIR principles;Female;Foundations;Future;Goals;Green space;Health;Health Planning;Health Services;Health Services Research;Hospitalization;Individual;Infrastructure;Inpatients;Light;Link;Longitudinal Studies;Maintenance;Malignant Neoplasms;Manuals;Medicare;Medicare claim;Metadata;Modernization;Outcome;Outpatients;Participant;Phase;Positioning Attribute;Process;Protocol Compliance;Public Health;Reporting;Reproducibility;Request for Proposals;Research;Research Personnel;Resources;Sampling;Sampling Studies;Secure;Services;Shipping;Solid;Specimen;Surveys;Time;UV Radiation Exposure;Update;Vital Status;anticancer research;application programming interface;authority;built environment;cancer epidemiology;cancer risk;cancer therapy;climate data;cloud based;cohort;comorbidity;data modeling;data sharing;data visualization;data warehouse;disorder risk;eligible participant;extreme weather;flexibility;follow-up;handheld mobile device;health care service utilization;high risk;human old age (65+);innovation;mortality;neoplasm registry;operation;patient engagement;phenotypic data;preservation;prospective;research study;resilience;social;social vulnerability;survivorship;teacher;tool;volunteer Innovative Infrastructure to Enhance and Sustain the California Teachers Study Cohort PROJECT NARRATIVEThis proposal requests support to maintain the high-quality data and streamline the innovative infrastructure ofthe prospective California Teachers Study (CTS).During the next five years as the CTS's 133477 female participants pass through ages of high disease riskwe will conduct efficient linkages that capture new cancer inpatient and outpatient hospitalization mortalityand geospatial data.Together with the CTS's commitment to facilitating open and broader use of its resources this will createadditional opportunities for impactful research on understudied areas of cancer risk and outcomes. NCI 10686141 8/25/23 0:00 PAR-17-233 5U01CA199277-09 5 U01 CA 199277 9 "MAHABIR, SOMDAT" 9/1/15 0:00 8/31/25 0:00 ZCA1-RTRB-4(M2) 10290448 "LACEY, JAMES V" "MARTINEZ, MARIA ELENA" 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1096051 NCI 745540 359058 PROJECT SUMMARY / ABSTRACTThe California Teachers Study (CTS) has collected high-quality and detailed exposure biospecimens cancerand clinical endpoint data on 133477 female volunteers followed since 1995. The cancers hospitalizationsand deaths to date are less than half of the total endpoints projected to occur in the CTS over the next 30years. In the next 5 years CTS follow-up will include over 37000 cancers; 455000 hospitalizations; and41000 deaths. This provides a solid foundation for collaborative research using these unique resources. Since2013 the CTS collected new blood samples from 14674 participants. Cloud computing and integrated mobiledevices generated rich phenotype data and exceptionally low pre-analytical variability for 488000 aliquots thatare being stored as CTS follow-up continues. Since 2015 the CTS modernized its data collection storage andanalysis infrastructure by implementing a secure data warehouse and flexible analytics environment designedfor high-quality and integrated epidemiologic analysis. The CTS includes secure user authentication &authorization; a collaborative workspace with documents data visualizations tools and workflows; metadata;application programming interface (API) capabilities; and a scalable data model. The CTS is now positioned tostreamline its resources for long-term sustainability. The goals of this competing renewal are to preserveexisting resources that enable research and strategically expand areas that create high-value opportunities.First we will maintain existing CTS data and extend passive follow-up through efficient cancer hospitalizationand mortality linkages. These ongoing linkages will generate additional endpoints used for future etiologicconsortial aging and other research. Second we will store the 488000 high-quality biospecimens collectedsince 2013. These specimens are all currently available to everyone; ongoing storage will ensure that theyremain available to everyone. Third we will expand capacity by integrating additional targeted geospatial dataon climate extreme weather built environment community characteristics health access environmentalexposures social vulnerability and community resilience. The new CTS infrastructure efficiently enableseveryone regardless of their GIS expertise to rigorously incorporate individual-level geospatial exposures intotheir analyses. Fourth because most participants are now over age 65 we will link the CTS with Medicareoutpatient data to complement existing data and expand infrastructure for aging survivorship comorbidity andhealth services research. The recent CTS infrastructure updates added research-ready efficiencies to manageand process complex geospatial administrative claims and other CTS data in ways that help all researchersespecially those outside the CTS conduct integrative rigorous and reproducible research. The CTS is aninnovation leader with primed assets and decades of promising future research potential. This competingrenewal will maintain high-value CTS resources that can address understudied research areas facilitatebroader use by the entire scientific community and streamline the CTS for long-term sustainability. 1096051 +No NIH Category available Acceleration;Advanced Development;Award;Basic Science;Biochemical Process;Biological Assay;Biology;Cancer Center;Cancer Center Support Grant;Carbon Dioxide;Cell physiology;Chemicals;Collection;Communication;Computer software;Contract Services;Core Facility;Data;Data Analyses;Dedications;Detection;Development;Doctor of Philosophy;Drug Kinetics;Employee;Equipment;Experimental Designs;Faculty;Feedback;Genomics;Goals;Grant;Growth;In Vitro;Infrastructure;Institution;Laboratories;Lead;Leadership;Libraries;Liquid substance;Maintenance;Malignant Neoplasms;Molecular Bank;Pathogenesis;Pharmaceutical Chemistry;Pharmaceutical Preparations;Philanthropic Fund;Production;Property;Publications;Research;Research Personnel;Resource Sharing;Resources;Science;Scientist;Services;Surveys;System;Technology;Temperature;Translating;Translations;United States National Institutes of Health;Validation;Work;assay development;cellular targeting;cost effectiveness;drug discovery;drug metabolism;follow-up;high throughput screening;in vivo;instrument;instrumentation;live cell imaging;meetings;member;multiparametric imaging;novel;preclinical development;programs;repaired;screening;small molecule;small molecule libraries;square foot;tumor;tumor initiation;validation studies Chemical Library Screening n/a NCI 10686139 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5668 10443574 "JACKSON, MICHAEL " Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 199448 102281 97167 ABSTRACT CHEMICAL LIBRARY SCREENING SHARED RESOURCEThe Chemical Library Screening (CLS) Shared Resource is managed by the Cancer Center. This resource offersCenter scientists the ability to develop and conduct small- and large-scale chemical library screens and performhit optimization and validation for generating selective probes/leads modulating biochemical and cellularprocesses in cancer. In addition CLS provides faculty with access to technology expertise and infrastructureresources to develop novel assays for characterizing cellular targets involved in tumor initiation and pathogenesisand to advance the development of new lead molecules for anti-tumor therapies. CLS consists of four specializedbut highly integrated facilities: High-Throughput Assay Development (HT-AD) Compound Management andHigh-Throughput Screening (CM-HTS) High-Content Screening (HCS) and Medicinal Chemistry and DrugMetabolism/Pharmacokinetics (MedChem/DMPK). The facilities physically reside within the Conrad PrebysCenter for Chemical Genomics (Prebys Center) at SBP which occupies more than 12000 sq. ft. of laboratoryspace and houses substantial HTS and HCS assay development and screening instrumentation capabilities.CLS has access to a broad spectrum of diverse and focused small-molecule collections several integrated liquidhandling systems and a plethora of detection instruments capable of performing assays in any mode includinglive-cell image-based assays requiring temperature and CO2 control. The Prebys Center grew out of the CancerCenter's CLS Shared Resource which was initiated in the 2003 CCSG renewal. This support has been leveragedwith several large grant awards and philanthropic funds. Initially awarded a grant as one of ten NIH MolecularLibraries Screening Network Comprehensive Centers the Prebys Center was later selected as one of four NIH-designated Molecular Libraries Probe Production Centers Network comprehensive screening centers. It is alsoone of seven dedicated Centers for the NCI Chemical Biology Consortium (CBC). Despite the growth of thePrebys Center the CLS Core remains of crucial importance to Center investigators because it provides animportant interactive entry point to ensure that they derive the maximum scientific benefit from these world classchemical biology and drug discovery capabilities enabling both fundamental and translational scientificendeavors. In the past 5 years the Core has additionally enabled >100 assay development projects for CancerCenter investigators resulting in >25 full HTS campaigns to support the goal of early translation. It has providedservices for 36 Center investigators representing all three programs. The data generated have supported 24successful grants from 16 Center members and numerous publications including 20 publications co-authoredby CLS staff. +No NIH Category available Acceleration;Affinity Chromatography;Automation;Cancer Center;Cancer Center Support Grant;Communication;Computer software;Contract Services;Core Facility;Coupled;Data Analyses;Development;Doctor of Philosophy;Drug Targeting;Employee;Epitopes;Equipment;Experimental Designs;Faculty;Feedback;Funding;Generations;Grant;Histones;Institution;Label;Laboratories;Leadership;Location;Maintenance;Malignant Neoplasms;Mass Spectrum Analysis;Methodology;Methods;Mission;Pathway interactions;Post Translational Modification Analysis;Post-Translational Protein Processing;Preparation;Proteins;Proteomics;Proteomics Shared Resource;Publications;Research;Research Design;Research Personnel;Resource Sharing;Sampling;Science;Scientist;Services;Surveys;System;Technology;Training;Work;biomarker discovery;cost effective;cost effectiveness;drug discovery;meetings;member;phosphoproteomics;programs;protein protein interaction;recruit;repaired;tool Proteomics n/a NCI 10686137 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5667 8800373 "DIAZ MECO CONDE, MARIA TERESA" Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 253525 130013 123512 ABSTRACT PROTEOMICS SHARED RESOURCE The mission of the Proteomics Shared Resource is to provide cost-effective state-of the-art analytical proteomics services to investigators of the Cancer Center. During the past funding period the Core was upgraded as a result of a major initiative by SBP which provided more than $2.5M in support for the purchase of new equipment. This upgraded equipment included two Thermo Fusion Lumos systems Q-Exactive Plus and TSQ Quantiva systems all with appropriate coupled LC systems. Additionally there was addition of a Bravo AssayMap automation system for sample preparation and the recruitment of highly trained proteomics scientiststhe Core staff now includes three Ph.D.-level scientists. The Proteomics Core provides a full array of services including study design sample preparation and the generation analysis and interpretation of data. In addition to straightforward protein identification the Core supports work involving cutting-edge proteomics methodologies including labeled and label-free quantitative proteomics and both focused and global post-translational modification (PTM) analyses. In the past several years the Core has additionally taken on larger scale high throughput projects. The Core also supports affinity purification coupled to mass spectrometry (APMS) using proximity labeling and epitope tagging technologies to study proteinprotein interactions. More recently the Core has worked closely with Cancer Center laboratories to implement new proteomics technologies including histone PTM profiling biomarker discovery in biofluids and drug target identification. Over the past funding period the Proteomics Core has provided services to 41 Center members representing all three programs and this work has supported at least 43 cancer-relevant publications. +No NIH Category available Affect;Apoptosis;Biochemical;Biological Assay;Biological Models;Brain;Breast Cancer Treatment;Bypass;Cancer Patient;Cells;Chemicals;Cisplatin;Combined Modality Therapy;Cyclin-Dependent Kinases;Data;Development;Disease;Disseminated Malignant Neoplasm;Dose;Drug Kinetics;Drug Targeting;Drug Tolerance;Drug resistance;ERBB2 gene;Enhancers;Enzymes;Epigenetic Process;Epithelium;Evaluation;FRAP1 gene;Fatty acid glycerol esters;Future;Genes;Genetic Transcription;Goals;Growth Factor Receptors;Image;Immune system;Immunocompetent;Investigational Drugs;KRAS2 gene;Lead;Ligands;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mesenchymal;Metabolism;Microsomes;Mission;Modeling;Molecular;Molecular Probes;Mutation;Neoplasm Metastasis;New Agents;Non-Small-Cell Lung Carcinoma;Oncogenes;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Proliferating;Property;Proteomics;Receptor Signaling;Reporter;Reporting;Research;Resistance;Resistance development;Role;Signal Transduction;Solubility;Stress;Structure;Testing;Transcription Alteration;Transcription Process;Transcriptional Regulation;Trastuzumab;United States National Institutes of Health;Work;Xenograft Model;acquired drug resistance;analog;anti-cancer;anti-cancer therapeutic;anticancer activity;cancer cell;chemotherapy;clinical development;combat;design;disability;epigenetic regulation;first-in-human;fluorescence imaging;immune resistance;immunoregulation;improved;in vivo;ineffective therapies;inhibitor;innovation;insight;kinase inhibitor;lung cancer cell;malignant breast neoplasm;mammary;neoplastic cell;novel;novel strategies;novel therapeutics;overexpression;patient derived xenograft model;phosphoproteomics;posttranscriptional;pre-clinical;prevent;programs;research clinical testing;resistance mechanism;response;safety assessment;single-cell RNA sequencing;small molecule;stressor;success;targeted agent;targeted treatment;therapy resistant;three-dimensional modeling;transcriptome sequencing;translational approach;treatment response;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression Developing CDK12 inhibitors to overcome therapy resistance in HER2+ and KRAS driven breast and lung cancers Project NarrativeAlthough targeted anti-cancer therapeutics have improved patient outcomes benefits can be short-lived andnew approaches are needed to prevent the emergence of drug resistance. We aim to determine if CDK12/13inhibition can prevent drug resistance in combination with targeted agents and use our new inhibitors to revealthe complexities of acquired drug resistance. Thus the proposed research is directly relevant to NIHs mission to fuel discovery reduce illness and disability. NCI 10686136 8/4/23 0:00 PA-20-185 5R01CA262530-03 5 R01 CA 262530 3 "AGYIN, JOSEPH KOFI" 7/12/21 0:00 6/30/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 9621640 "DUCKETT, DEREK RONALD" "HAURA, ERIC B.; MONASTYRSKYI, ANDRII " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 666289 NCI 404547 261742 Project SummaryAlthough the development of targeted therapies has improved overall cancer patient survival adaptiveresponses by tumor cells can render these treatments ineffective. The development of agents that block adaptiveresponses thereby increasing treatment durability is desperately needed. We and others have demonstratedthat inhibitors of the transcriptional cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) are strong candidatesto combat acquired drug resistance. The long-term goal of this proposal is to develop a highly effective CDK12/13inhibitor with an aggregate set of properties suitable to advance as a safety assessment candidate to overcometherapy resistance in both TNBC and HER2+ breast cancers and KRAS inhibitor-resistant NSCLCs. The overallobjective in this application is to identify targets and pathways altered by treatment-directed CDK12/13 rewiringand develop new therapeutics that render this rewiring - an exploitable vulnerability. The central hypothesis isthat CDK12/13 acts as a driver of transcriptional and post-transcriptional adaptation and that targeting CDK12/13will block drug-induced escape and improve treatment response in breast and lung cancer. The rationale for thisproject posits that: (i) multiple malignancies hijack CDK12/13 to provoke transcriptional and signaling plasticityas an adaptive stress resistance mechanism and (ii) elucidation of mechanisms underpinning compound actionwill offer a strong scientific framework that will facilitate future clinical development of these new agents forimproved patient outcome. The central hypothesis will be tested by pursuing three Specific Aims: (1) Optimizethe drug-like properties of in-house CDK12/13 specific inhibitors; (2) Define and validate the mechanismswhereby CDK12/13 inhibition prevents or reverses treatment resistance in TNBC and HER2+ breast cancers (3)Define and validate the mechanisms whereby CDK12/13 inhibition prevents or reverses KRASG12C inhibitorresistance in NSCLC. Accordingly using a battery of approaches we will: a) optimize key CDK12/13 inhibitorparameters to deliver a safety assessment candidate; b) define and validate the transcriptional and translationalmechanisms whereby SR-4835 provokes resensitization to chemotherapy and c) validate cell-basedobservations in pre-clinical xenograft models. The research approach of our Multi-PI application is innovativeas our team has developed exceptionally selective and novel small molecule CDK12/13 in vivo active molecularprobes that will enable (i) interrogation of the roles of CDK12/13 during adaptation to treatment resistance (ii)evaluation that disrupting transcriptional control will counter-resistance mechanisms providing lasting moredurable anti-cancer responses or even cures; and (iii) understanding of the critical signaling nodes that drivedrug resistance. The proposed research is highly significant and provides a strong scientific rationale for thecontinued development of novel CDK12/13 inhibitors. We submit that insight into the molecular underpinningsof the master effectors of CDK12 and CDK13-driven signaling together with an optimized CDK12/13 inhibitorwill offer new opportunities for improved combination treatments for breast and lung cancer. 666289 +No NIH Category available ATAC-seq;Acceleration;Bioinformatics;Biological;CRISPR library;Cancer Center;Cancer Center Support Grant;Cells;ChIP-seq;Chromium;Collaborations;Communication;Complex Analysis;Computer software;Contract Services;Core Facility;Cost Effectiveness Analysis;Data;Data Analyses;Disease;Doctor of Philosophy;Employee;Epigenetic Process;Equipment;Experimental Designs;Faculty;Feedback;Flow Cytometry;Funding;Gene Expression Profiling;Genomics;Genomics Shared Resource;Grant;High-Throughput Nucleotide Sequencing;Human Cell Line;Individual;Institution;Large-Scale Sequencing;Leadership;Libraries;Maintenance;Malignant Neoplasms;Nucleic Acids;Outsourcing;Pathway interactions;Phage Display;Preparation;Promega;Publications;Research;Research Personnel;Resource Sharing;Resources;Science;Scientist;Sequence Analysis;Services;Surveys;System;Technology;Work;analysis pipeline;automated analysis;cost;cost effectiveness;design;exome sequencing;experience;experimental study;meetings;member;multiple omics;next generation sequencing;programs;recruit;repaired;single cell sequencing;single-cell RNA sequencing;success;transcriptome sequencing Genomics n/a NCI 10686134 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5666 6483311 "ADAMS, PETER D." Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 267074 136961 130113 ABSTRACT GENOMICS SHARED RESOURCEThe Genomics Shared Resource is managed by the Cancer Center and provides full nucleic acid-to-dataservices from library preparation to basic data analysis focused primarily on next-generation sequencing (NGS)applications. Most of the services currently offered by the Core have been added in the last 5 years following therecruitment of Dr. Brian James as the Facility Director in 2013. The Core upgrades in the past funding periodinclude Illumina-based sequencing on the NextSeq 500 automated library preparation using the EppendorfepMotion 5075 single-cell sequencing on the 10x Genomics Chromium and Bio-Rad ddSeq platforms andhuman cell line authentication using the Promega GenePrint 10 system. In addition to RNA-seq services offeredinclude ChIP-seq ATAC-seq single-cell RNA-seq exome-seq CRISPR libraries and phage display libraries.Since the Genomics Core began offering NGS service it has worked with the majority of Cancer Center memberlabs. In many cases this was the lab's first experience with high-throughput sequencing technology and theCore was instrumental in helping the investigators to design execute and interpret these experiments.Integrated basic NGS bioinformatic analysis is included as part of the service. This is a critical component inassuring the quality of the data produced and facilitating the eventual scientific success of the Center members.The Genomics Core provides broad support with 41 Center labs having used the Core in the last 5 years andit has supported at least 46 cancer-related publications. +No NIH Category available Acceleration;Antibodies;Cancer Center;Cancer Center Support Grant;Cell Separation;Cells;Collaborations;Color;Communication;Computer software;Contract Services;Core Facility;Cytometry;Data Analyses;Development;Doctor of Philosophy;Emerging Technologies;Employee;Equipment;Evaluation;Experimental Designs;Faculty;Feedback;Flow Cytometry;Flow Cytometry Shared Resource;Funding;Grant;Image;Image Cytometry;Immune;Immunophenotyping;Institution;Lasers;Leadership;Licensing;Maintenance;Malignant Neoplasms;Manuscripts;Microfluidics;Monitor;NCI-Designated Cancer Center;Patients;Phenotype;Population;Preparation;Protocols documentation;Publications;Research;Research Personnel;Resource Sharing;Science;Scientist;Services;Site;Solid Neoplasm;Sorting;Speed;Stains;Surveys;Suspensions;Technology;Training;Work;cost effectiveness;experience;experimental study;instrument;instrumentation;investigator training;meetings;member;programs;repaired;skills;technology platform;tumor Flow Cytometry n/a NCI 10686131 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5665 10366409 "DESHPANDE, ANIRUDDHA J." Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 212310 108877 103433 ABSTRACT FLOW CYTOMETRY SHARED RESOURCE The Flow Cytometry Shared Resource offers Cancer Center members multi-parametric evaluation and high- speed enrichment of phenotypically distinct cell populations. The Core provides full-service high-speed cell sorting performed by expert operators utilizing two BD Aria instruments in biosafety enclosures. For analytical cytometry investigators have a choice of either full-service analysis by Core staff or receiving training and then independently using one of six analytical flow cytometers. Those analytical cytometers available 24/7 to trained users include two BD Fortessas the newer of which is a 5-laser 18-color instrument and an ImageStreamX MkII imaging flow cytometer with four lasers and 12 imaging channels. Many of the Core's cytometers have autoloaders enabling larger-scale experiments. Analysis software is available in the Core or via the Institutional site license. This broadly used Core is managed by the CC and receives support from the Institute for instrumentation purchase and maintenance. In the last funding period three major technology platforms were acquired and imaging flow cytometry was launched as a new service. The Core Director Mr. Altman and staff have combined experience of more than 30 years in NCI-designated Cancer Center Flow Cytometry Cores and they provide comprehensive technical guidance at any stage of a project from experimental design through manuscript preparation. The Flow Cytometry Core is broadly used as in the last 5 years it was used by 46 Cancer Center labs representing all three programs and the Core contributed to at least 75 cancer-related publications. +No NIH Category available Acceleration;Area;Biological;Biology;Cancer Center;Cancer Center Support Grant;Chemistry;Collaborations;Communication;Complex;Computer software;Contract Services;Core Facility;Cryoelectron Microscopy;Crystallization;Data Analyses;Detection;Devices;Doctor of Philosophy;Electrons;Employee;Equipment;Experimental Designs;Faculty;Feedback;Fluorescence;Goals;Grant;Image;Incubators;Individual;Infrastructure;Institution;Interferometry;Laboratories;Leadership;Length;Ligands;Maintenance;Malignant Neoplasms;Mission;Molecular;Nuclear Magnetic Resonance;Optics;Phase;Protein Analysis;Proteins;Publications;Research;Resource Sharing;Resources;Robotics;Roentgen Rays;Science;Scientist;Services;Spectrometry;Spectrophotometry;Structure;Surface Plasmon Resonance;Surveys;Technology;Time;Titan;Training;Visualization;Work;X ray diffraction analysis;X-Ray Crystallography;biological systems;biophysical analysis;cost effectiveness;detector;instrument;instrumentation;interdisciplinary approach;meetings;member;operation;programs;protein function;protein protein interaction;protein structure;repaired;solid state;solid state nuclear magnetic resonance;structural biology;tomography Structural Biology n/a NCI 10686130 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5664 3152673 "MARASSI, FRANCESCA M" Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 255364 130956 124408 ABSTRACT STRUCTURAL BIOLOGY SHARED RESOURCEThe mission of the Structural Biology Shared Resource is to advance our understanding of the molecular basisof cancer by giving Cancer Center scientists access to equipment technology and expertise for structural andbiophysical studies of biological molecules. Structural biology enables multi-scale visualization of molecular andsupramolecular structure and dynamics with the ultimate goal of characterizing biological systems in theirfunctional native states. This requires a multidisciplinary approach that spans the ranges of length and timescales effective in biology. The Core managed by the Center maintains state-of-the-art equipment developstechnology provides service and promotes collaborative activities with Cancer Center scientists. There are fourcentral and complementary areas of structural biology: nuclear magnetic resonance (NMR) X-raycrystallography the recently added electron cryo-microscopy and cellular tomography (cryo-EM and ET) andthe long-standing biomolecular analysis facility. These technologies are typically not available in individualCenter member laboratories owing to their expense and complexity of operation. Core equipment supportingNMR includes two 600 MHz instruments with cryoprobes a wide bore 500 MHz spectrometer set up for solidstate analysis and a highly automated 400 MHz instrument supporting chemistry. X-ray crystallographyequipment includes a robotic dispenser and two automated imaging incubators (5 and 20) a Rigaku FRESuperBright X-ray diffractometer with two independent beams and detectors. Cryo-EM analysis is supported bya Thermo Titan Krios with a 4Kx4K Falcon III direct electron detection device and a phase plate as well as aTecnai 12 Spirit G2 equipped with a 4Kx4K CCD. Finally equipment supporting biomolecular analysis includesan analytical ultracentrifuge DSC UV/vis spectrometry Fluorescence spectrophotometer two ITC instrumentsand MST. The three Ph.D.-level Core staff maintain the equipment train users and in the case of biomolecularanalysis provide full-service analysis. For structural biology analysis Core users can collaborate with Core stafffor smaller projects or collaborate with expert structural biology groups in the Cancer Center to pursue morecomplex projects. A number of such successful collaborations are described in the Research Plan. In the past 5years the Core was used by 16 Center labs representing all three programs and supported 62 cancer-relatedpublications. +No NIH Category available AGTR2 gene;Acceleration;Algorithmic Analysis;Calendar;Cancer Center;Cancer Center Support Grant;Cells;Communication;Computer Workstations;Computer software;Contract Services;Core Facility;Cryoultramicrotomy;Data;Data Analyses;Doctor of Philosophy;Documentation;Employee;Equipment;Experimental Designs;Faculty;Feedback;Fluorescence;Fluorescence Resonance Energy Transfer;Grant;Histologic;Histology;Hybrids;Image;Image Analysis;Imaging technology;Immunofluorescence Immunologic;Immunohistochemistry;In Situ Hybridization;Institution;Institutional Review Boards;Label;Laboratories;Lasers;Leadership;Light;Maintenance;Malignant Neoplasms;Microscope;Microscopy;Mission;Pathology;Preparation;Publications;Research;Research Personnel;Reservations;Resolution;Resource Sharing;Scanning;Science;Scientist;Services;Slide;Stains;Surveys;System;Technology;Tissues;Training;Transcript;Work;cellular imaging;cost effectiveness;fluorescence microscope;human tissue;imaging facilities;instrument;instrumentation;intravital microscopy;live cell imaging;meetings;member;multi-photon;programs;reconstruction;repaired;superresolution microscopy;ultra high resolution Cell Imaging and Histology n/a NCI 10686128 6/7/23 0:00 PAR-17-095 5P30CA030199-42 5 P30 CA 30199 42 5/1/97 0:00 4/30/25 0:00 ZCA1-RTRB-Y 5663 8050668 "EMERLING, BROOKE M" Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 Research Centers 2023 206585 105941 100644 ABSTRACT CELL IMAGING AND HISTOLOGY SHARED RESOURCEThe mission of the Cell Imaging and Histology Shared Resource which is managed by the Cancer Center is toprovide state-of-the-art imaging and histological services to Center researchers. The Core offers theinstrumentation expertise training and service to enable advanced cellular imaging and data analysis. The CellImaging facility's technology includes a recently acquired hybrid confocal/super-resolution Nikon A1 microscopesystem equipped for live-cell imaging as well as three other confocal microscope systemsa Zeiss LSM 710NLO laser point scanning system equipped with a multiphoton laser An Olympus FloView 1000 and a Yokogawaspinning disk confocal microscope. In addition the facility has six other fluorescence microscopes supporting awide range of imaging technologies such as FRET TIRF live cell and time-lapse imaging. Most of the advancedmicroscopes at SBP are located within the facility. The facility's computer workstations provide access to imageanalysis software packages including Image-Pro plus MetaMorph Volocity and Imaris 8.0 as well as Nikonsoftware for off-line reconstruction of Nikon Super-Resolution data. The Histology facility services includepreparation and cryosectioning of tissues; automated staining for H&E (Leica XLf) and immunohistochemistryimmunofluorescence and in situ hybridization (Leica Bond RX). The facility's Aperio slide scanners (AT2 and FLScanScopes Leica) provide automated high-resolution scanning of whole IHC or fluorescence stained slides fordata documentation analysis storage and dissemination. The facility also provides assistance in obtaininghuman tissues including assistance with IRB and MTA issues. Both the adjacent Cell Imaging and Histologyfacilities provide user training or full-service. Trained microscope users have 24/7 access to the equipment withreservations for each instrument made through an on-line iLab calendar. The Core is very broadly usedin thepast 5 years the Core has contributed to research in 47 Cancer Center member laboratories representing allthree Center programs and assisted in projects resulting in more than 190 cancer-relevant publications. +No NIH Category available Advisory Committees;Area;Biological;Biological Markers;Breast;Cancer Center Support Grant;Cancer Prevention Trial;Cancer Science;Cities;Clinic;Clinical;Clinical Research;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Communication;Comprehensive Cancer Center;Conduct Clinical Trials;Consultations;Development;Disease;Dose;Drug Delivery Systems;Ensure;Evaluation;Fostering;Fright;Genetic Predisposition to Disease;Goals;Incidence;Individual;Institution;Intervention;Investigation;Knowledge;Leadership;Lesion;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mentors;Methods;Monitor;Mutation;New Agents;Organ;Pancreas;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Physicians;Population;Prevention;Prevention Research;Process;Reproducibility;Research;Research Infrastructure;Research Personnel;Resources;Science;Scientist;Site;Sum;Technology;Testing;Toxic effect;Transdermal substance administration;Universities;Work;biomarker selection;cancer chemoprevention;cancer prevention;cancer therapy;cancer type;design;drug repurposing;early phase clinical trial;early phase trial;improved;innovation;malignant breast neoplasm;malignant oropharynx neoplasm;member;nanoarchitecture;novel;novel marker;predictive marker;programs;protocol development;recruit;reduce symptoms;success;targeted agent;trial design Northwestern Cancer Prevention Consortium PROJECT NARRATIVE Although there have been tremendous advances in cancer therapy cancer remains afeared disabling and lethal disease; its prevention through the use of medications that will haltor reverse early lesions has particular promise since the complexity of changes that allow fullydeveloped cancer to evade treatment has not yet occurred. We will conduct clinical trials to testmedications that appear promising for the purposes of cancer prevention; these trials will tell uswhether a particular medication is worth testing in larger trials how it works and who will bemost likely to benefit from it. We will in particular focus on common cancers (breast colon);those that are both common and lethal (lung); and those that are lethal and often fail treatment(liver pancreas). NCI 10686120 7/21/23 0:00 RFA-CA-18-029 5UG1CA242643-05 5 UG1 CA 242643 5 "JOHNSEY, DONALD" 9/3/19 0:00 7/31/25 0:00 ZCA1-TCRB-O(M1) 1942839 "KHAN, SEEMA AHSAN" Not Applicable 5 SURGERY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1935399 NCI 1224900 710499 Northwestern University proposes to continue to lead a consortium of organizations the Northwestern CancerPrevention Consortium (NCPC) to design and conduct early phase clinical trials aimed at developing newoptions for the prevention of cancer. To date NCPC trials 19 in total have accrued 534 patients (354 from the2003 consortium and 175 from the 2012 consortium) targeting multiple organ sites and a variety of agents. Wehave tested innovative concepts e.g. transdermal drug delivery and utilized novel biomarkers such asnanocytological alterations. Our proposal to renew the NCPC under the leadership of Seema A. Khan MDincludes academic partners included in the current consortium and new members who are expected to addimportant strengths to it (the University of Toronto and City of Hope). In the new cycle of the NCPC we willcontinue to build on promising approaches based on prior or ongoing successful trials while providingoversight consultation and administrative support to cancer prevention research teams. We will assist in thedesign of cancer prevention trials in proposal and protocol development and in the implementation of suchtrials. Our overarching goal is to continue our contributions to cancer prevention sciencethrough the development of innovative transformative early phase trials testing new conceptualapproaches that will enable clinical advances in the prevention of cancer. Our Aims are to 1.Advance high priorities in cancer prevention for maximum impact on cancer incidence when these areadvanced into clinical use. These priorities include (i) investigate novel agents and repurposed agents thattarget mutations and pathways known to be important in the development of cancer (ii) novel orestablished biomarkers to identify individuals most like to predict benefit from a given approach (iii) trialsthat will result in unifying biological themes across different organ sites leading to protection against morethan one cancer type (iv) test innovative dosing and delivery methods to reduce the symptom andtoxicity burden for users of cancer prevention agents. 2. Provide consultation scientific guidance andmentoring to consortium investigators who are proposing new trial concepts; assist consortium investigatorsthrough trial design initiation conduct and analysis; and to serve as the administrative hub of theconsortium. We will foster communication collaboration and sharing of available resourcesbetween consortium members and across consortia to maximize impact of clinical trials testing similarinterventions or in similar populations. Serve as a liaison between the consortium and the NCI DCP bymaintaining and improving an NCPC 3. Advance the science of cancer prevention through evaluationand selection of innovative or transformative concepts that result in progress that is greater than the sumof knowledge gained from the specific goals of an individual trial. We will be guided in this processby an Advisory Committee with a diverse background in cancer prevention research. 1935399 +No NIH Category available Adherence;Biological Markers;Biometry;Cancer Burden;Clinical;Collaborations;Collection;Communication;Communities;Community Outreach;Computer Analysis;Computer software;Data;Data Analyses;Data Collection;Data Coordinating Center;Data Management Resources;Data Science;Data Security;Development;Discipline;Early Detection Research Network;Early Diagnosis;Educational workshop;Ensure;Evaluation;Evaluation Studies;Fred Hutchinson Cancer Research Center;Funding;Image;Informatics;Information Networks;Information Technology;Infrastructure;Lead;Leadership;Manuals;Manuscripts;Methodology;Mission;Modeling;Monitor;Multi-Institutional Clinical Trial;Multicenter Studies;NIH Grants and Contracts;Observational Study;Preparation;Procedures;Protocols documentation;Public Health;Publishing;Quality Control;Reporting;Research;Research Design;Research Personnel;Resource Informatics;Scientific Advances and Accomplishments;Scientist;Secure;Services;Software Design;Specific qualifier value;Specimen;System;Telephone;Testing;Time;Universities;Washington;Women's Health;Work;anticancer research;biomarker evaluation;biomedical informatics;cancer biomarkers;data management;data quality;data sharing;data submission;data warehouse;experience;innovation;meetings;network informatics;operation;outreach;protocol development;quality assurance;response;sample collection;software development;statistical service;success;symposium;tool;validation studies;web site The Early Detection Research Network: Data Management and Coordinating Center Project NarrativeThe proposed study is highly relevant to public health because early detection has great potential to reducecancer burden. Rigorous evaluation of biomarker tests for their clinical utility is imperative for public health. NCI 10686108 7/27/23 0:00 RFA-CA-21-034 5U24CA086368-23 5 U24 CA 86368 23 "MARQUEZ, GUILLERMO" 4/14/00 0:00 7/31/27 0:00 ZCA1-PCRB-D(M1) 2110020 "FENG, ZIDING " "ETZIONI, RUTH D; ZHENG, YINGYE " 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Other Research-Related 2023 8841413 NCI 7357428 1672721 Project SummaryThe key for the Early Detection Research Network (EDRN)'s success lies in good communication amongscientists in multiple disciplines; efficient evaluation and prioritization of promising biomarkers; and rigorousvalidation studies to demonstrate their clinical utility. The overall aims of the proposed renewal of the DataManagement and Coordinating Center (DMCC) are to (i) provide coordination of EDRN in order to enhancecommunication and collaboration among EDRN investigators and with general scientific communities; (ii)coordinate EDRN validation studies and provide leadership in data science; (iii) disseminate cancer biomarkerinformation to broader scientific communities and the public; and (iv) manage the EDRN Core funds. Under thedirection of the EDRN Steering Committee the DMCC will 1) perform network coordination and outreach andpromote collaborations among scientific investigators by providing support for EDRN meetings and workshopsdeveloping and maintaining EDRN secure websites and listservs producing and maintaining all EDRNdocuments and maintaining the online review system for applications submitted to the EDRN; 2) supportEDRN validation studies by developing and maintaining validation study data management systems; workingwith EDRN investigators on study design protocol development data forms and study manuals; coordinatingand monitoring studies; tracking specimens; and performing QA/QC and study evaluation; and provide andpromote best statistical and computational practices to EDRN studies; 3) work with the NCI and JPL to provideinformatics resources for the EDRN Secure Web site for data security data warehousing and data sharingand a Public Web site for dissemination; and 4) work closely with the EDRN SC and the NCI ProjectCoordinator and Fred Hutch OSR to timely activate the core funds after the EDRN SC approval and ensure thecompliance of all regulatory requirements for sub-award management. 8841413 +No NIH Category available Actin-Binding Protein;Actins;Affect;Agonist;Angiogenesis Inhibitors;Attenuated;Automobile Driving;Autophagocytosis;Bioenergetics;Biological Process;Biology;Blood Vessels;Cell Proliferation;Cell secretion;Cessation of life;Clear cell renal cell carcinoma;Clinical;Cytoskeleton;Data;Deterioration;Disease;Endothelium;Gene Expression;Genetic;Glycolysis;Goals;Growth;Human;Hypoxia;Immunologics;In Vitro;Kidney;Link;Malignant Epithelial Cell;Mediating;Mediator;Mentors;Microvascular Permeability;Mitochondria;Molecular Target;Neoplasms in Vascular Tissue;Outcome;Paracrine Communication;Pathologic;Patients;Perfusion;Pharmaceutical Preparations;Phenotype;Physiological;Play;Polymers;Process;Refractory Disease;Regulation;Renal Cell Carcinoma;Renal carcinoma;Resistance;Resistance development;Respiration;Rest;Retina;Role;Signal Transduction;Testing;Therapeutic;Training;Tumor Cell Migration;Tumor Promotion;Vaccines;Vascular Endothelial Cell;Vascular Endothelial Growth Factors;Vascularization;advanced disease;angiogenesis;antagonist;cell motility;extracellular;improved;in vivo;neoplastic cell;normoxia;novel;overexpression;paracrine;patient prognosis;polymerization;profilin;receptor;small molecule;small molecule inhibitor;targeted treatment;therapeutic target;therapy outcome;therapy resistant;treatment strategy;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenic;ultrasound;virtual Profilin as a Novel Target for Vascular Normalization in Renal Cancer Project NarrativeClear cell renal cell carcinoma is the most common type of renal cell carcinoma which is characterized by ahighly vascular tumor microenvironment and initially responds well to anti-angiogenic therapies. Despite thisalmost all patients develop resistance to these therapies and thus improved therapies are urgently needed totreating patients affected by this disease. In this study we propose utilizing a novel small molecule inhibitorand vaccine to target Profilin1 as a putative target for vascular normalization and treatment for renal cellcarcinoma. NCI 10686091 8/25/23 0:00 PA-20-188 5K99CA267180-02 5 K99 CA 267180 2 "SCHMIDT, MICHAEL K" 9/1/22 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 12588098 "GAU, DAVID MARTIN" Not Applicable 12 BIOMEDICAL ENGINEERING 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA BIOMED ENGR/COL ENGR/ENGR STA 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 126047 NCI 116710 9337 Project Summary AbstractRenal cell carcinoma (RCC) is estimated to result in 76080 new cases and 13780 deaths in 2021. Clear cellrenal cell carcinoma (ccRCC) is the most common subtype of RCC (>75% of RCC patients) and ischaracterized by a high vascularized tumor microenvironment (TME). Anti- angiogenic and vascularnormalization (VN) inducing therapies are initially effective almost all patients develop resistance to thesetherapies. Therefore there is a need to identify alternative fundamental therapies for ccRCC. Our lab andothers have demonstrated that actin cytoskeleton plays a key role in regulation of vascular endothelial cell(VEC) in angiogenesis and barrier function. Furthermore it has been demonstrated that Profilin1 (Pfn1) is animportant regulator of actin-driven processes such as cell migration and proliferation (including in VECaffecting angiogenic potential). Pfn1 is also overexpressed in human ccRCC and higher expression of Pfn1has been linked to poor clinical outcome and advanced disease features. The goal of this study is to furtherdemonstrate Pfn1s fundamental role in regulation of progression of ccRCC through modulation of tumor-promoted vascularization and that Pfn1 serves as a therapeutic target for RCC. Our preliminary datademonstrates that overexpressed Pfn1 is primarily found in tumor-associated VEC (TAEC). We furtherdemonstrate that loss of Pfn1 by genetic deletion in vivo or inhibition of Pfn1 by small molecule inhibitorreduces aberrant vascularization in various pathological settings (including retina and kidney) and attenuatesRCC progression in vivo. Aim 1 of this proposal seeks to test a postulate that endothelial Pfn1 promotes a pro-tumorigenic TME driving tumor progression in ccRCC and can be diminished by tumor-localized delivery ofnovel small molecule antagonist of Pfn1-actin interaction. Aim 2 of this proposal will test a postulate that Pfn1regulates the intrinsic angiogenic capability of VEC through augmenting mitochondrial function. Aim 3 tests apostulate that VEC-secreted Pfn1 acts as a paracrine signaling mediator to promote ccRCC aggressiveness.Aims 1 and 2 will mostly be performed in the K99 mentored stage during which I will continue my training incontrast-enabled ultrasound immuno- and mitochondrial biology. These trainings will be pivotal in mytransition to independence in the R00 stage where Aim 3 and the rest of Aim 2 will be executed. 126047 +No NIH Category available Adverse effects;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Antibodies;Antigenic Specificity;Autoimmune Diseases;Bacteria;Bacteroides;Biopsy;CTLA4 gene;Cancer Model;Cancer Patient;Cannulations;Cell Separation;Cell Wall;Cells;Chemosensitization;Clinical Research;Communities;Complement;Consensus;Cytotoxic T-Lymphocytes;Diet;Disease remission;Distal;Event;Feces;Genes;Genetic Diseases;Genetic Engineering;Gnotobiotic;Growth;Histologic;Human;IRF3 gene;Immune;Immune Targeting;Immune response;Immune system;Immunotherapy;Implant;Individual;Intestines;Lead;Libraries;Life;Lipid A;Lung Adenocarcinoma;Lung Neoplasms;Lymph;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metagenomics;Microbe;Microscopic;Mismatch Repair;Modeling;Molecular Mimicry;Molecular Target;Mus;Mutation;Myeloid Cells;Normal tissue morphology;Organism;PD-1/PD-L1;Patients;Pattern recognition receptor;Peptides;Plasma;Polysaccharides;Population;Predisposition;Proteins;Proteomics;Research;Role;Serum;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Specimen;Stains;T-Lymphocyte;T-cell receptor repertoire;Testing;Therapeutic;Tissues;Toxic effect;Treatment Efficacy;Tumor Immunity;Tumor Tissue;Wild Type Mouse;Work;adaptive immunity;anti-PD-1;anti-PD1 therapy;anti-tumor immune response;antitumor effect;autoimmune pathogenesis;autoimmune toxicity;cell killing;cellular targeting;checkpoint therapy;cohort;commensal bacteria;commensal microbes;design;experience;fecal transplantation;gut microbiome;gut microbiota;immune checkpoint blockade;immunogenic;immunogenicity;improved;in vitro testing;insight;lung cancer cell;mesenteric lymph node;mesenteric lymphatics;metabolomics;microbial;microbial products;microbiome;microbiota;microorganism antigen;mouse model;neoantigens;neoplastic cell;pre-clinical;programmed cell death ligand 1;rational design;reconstitution;responders and non-responders;response;response biomarker;transcriptome sequencing;transcriptomics;transmission process;treatment response;tumor;tumor growth;tumor microenvironment Mechanism of microbiota-mediated potentiation of checkpoint blockade efficacy in lung cancer Project NarrativeThis research will further our understanding of why certain cancer patients respond better than others toimmunotherapy. By determining which features of our intestinal microbiome contribute to enhancing ormitigating response to therapy it may become possible to design better immunotherapies. This could result inmore frequent therapeutic responses among cancer patients and in more durable remissions. NCI 10686041 7/27/23 0:00 PAR-19-193 5R01CA255635-03 5 R01 CA 255635 3 "DASCHNER, PHILLIP J" 8/1/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 1872627 "LITTMAN, DAN " Not Applicable 12 PATHOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 560724 NCI 330810 229914 The discovery that the host immune system can be harnessed to attack solid tumors and improve overallsurvival for patients has been transformative. However only certain tumors are responsive to immunecheckpoint blockade and an unpredictable fraction maintain durable remissions. In addition similarlyunpredictable toxicity can manifest with diverse autoimmune attack of normal tissue. Beyond PD-L1 stainingand mutational burden we have limited biomarkers of response and we have no predictors of autoimmunetoxicities. Recent studies have highlighted the contribution of the intestinal microbiota to successful PD-1/PD-L1 and CTLA-4 antibody blockade. There is however no consensus as to which microbes promote effectiveanti-tumor immune responses and we lack an understanding of the mechanisms involved. In our proposedstudies we will seek to identify human gut-associated bacterial species and products that enhance control oflung adenocarcinoma growth following anti-PD-1 immunotherapy. We will then characterize the host cellularand molecular targets of the bacteria and their products. In preliminary studies we identified a strain ofBacteroides vulgatus that promotes autoimmune disease and also restricts growth of implanted lung cancercells in anti-PD-1-treated mice. This tumor model will be used to assess the immune-potentiating roles of B.vulgatus genes such as those involved in synthesis of capsular polysaccharides and Lipid A and to screenbacterial libraries prepared from patient super-responders to identify species and consortia that are mosteffective at supporting inhibition of tumor growth. We have also developed an autochthonous lung cancermodel in which neoantigens accumulate due to targeting of the mismatch repair machinery and we will assessthe ability of the candidate microbes to function in a therapeutic mode after growth of the spontaneous tumorsis established. We will then characterize differences in metabolites and proteins within lymph draining theintestine of mice colonized with immunotherapy-potentiating or control microbes and candidate molecules willbe evaluated for their activity in the tumor models. Lastly we will seek to identify the innate signaling pathwaysand the relevant host target cells that convey microbial signals to the tumor microenvironment thus enhancingimmune control of tumor growth following anti-PD-1 administration. Since tumor cell killing is mediated bycytotoxic T cells we will also determine if there are shared antigenic specificities between tumors and themicrobiota. These studies will be complemented by spatial transcriptomic analyses of tumormicroenvironments from mice with and without immunotherapy-potentiating microbiota. Serum from responderand non-responder lung cancer patients will be evaluated for the presence of microbiome-dependent productsidentified in the mouse model and tumor tissue specimens will be subjected to spatial transcriptomics analysisto determine if there are features shared with tumors in mice. Together these studies can provide insights fordesigning rational strategies to utilize microbiota for potentiation of immune checkpoint blockade in cancer. 560724 +No NIH Category available Address;Arizona;Bioinformatics;Biometry;Cancer Center;Cancer Research Project;Collaborations;Communication;Communities;Development;Educational workshop;Ensure;Evaluation;Extramural Activities;Faculty;Feedback;Funding;Funding Opportunities;Goals;Grant;Health Disparities Research;Institution;Leadership;Learning;Manuscripts;Measures;Mentors;Methodology;Native Americans;Participant;Play;Population;Positioning Attribute;Preparation;Process;Publications;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Services;Study Section;System;Technology;Time Management;Training;Universities;Writing;anticancer research;cancer health disparity;cancer prevention;career;community engagement;design;education research;experience;inter-institutional;next generation;outreach;research and development;skills;success;tool Shared Resource Core - GUIDeS n/a NCI 10686022 8/25/23 0:00 PAR-18-767 5U54CA143924-15 5 U54 CA 143924 15 9/1/09 0:00 8/31/24 0:00 ZCA1-SRB-2 5633 1915322 "HEIMARK, RONALD L." Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 64163 44135 23611 PROJECT SUMMARY/ABSTRACT: GUIDeS SHARED RESOURCEGoals of the Partnership for Native American Cancer Prevention (NACP) include expanding the number of NativeAmerican investigators working in cancer research and increasing the total number of investigators focused oncancer health disparities within the Native American communities of Arizona. This fifteen-year partnershipbetween Northern Arizona University (NAU) and the University of Arizona Cancer Center (UACC) has madesignificant progress toward these goals with increasing numbers of successful early stage investigators (ESIs)and junior investigators (JIs) engaged in cancer research and cancer health disparities research within the NativeAmerican population. Numerous ESIs and JIs from the earlier years of the partnership have now establishedindependent research careers with successful academic rank promotions. This success has primarily beenachieved through intentional and collaborative research and career mentoring. In fact some of the earlier NACP-associated ESIs and JIs including Native Americans now hold leadership positions within the NACP and areplaying a critical role in training the next generation of NACP investigators.The NACP leadership team for this renewal application proposes to build and expand on the success learningexperiences and participant feedback from current and prior project periods by implementing a new-sharedresource called GUIDeS or Guiding U54 Investigator Development to Sustainability. This shared resource willorganize and facilitate a range of new services and career enhancement opportunities primarily targeted forESIs and JIs. The GUIDeS Shared Resource has been strategically designed to interface with the other NACPcomponents Outreach Research Education Planning and Evaluation Administrative and NACP-sponsoredresearch projects to ensure services and expertise across NACP are available to ESIs and JIs and that ESIsand JIs are fully integrated into the full range of NACP activities and research collaborations between NAUUACC and the Native American communities it serves.Specifically GUIDeS will: 1) assist ESIs and JIs through the process of developing a rigorously designed cancerresearch project and identifying potential funding opportunities; 2) pair them with senior NACP faculty researchermentors and other inter-institutional collaborators for the development of their projects and resulting grants andpublications; 3) navigate them through the university system in developing the regulatory financial andinstitutional requirements for conducting and submitting research to extramural agencies; 4) afford opportunitiesto participate in grant development workshops and mock study sections as well as access to grant writing andproposal development services; 5) provide biostatistics and bioinformatics support services as well asstreamlined access to experts in Native American-based community engagement specifically regardingresearch (Outreach Core); and 6) support their development of effective organizational time management andresearch communication skills e.g. seminar presentation and manuscript preparation. +No NIH Category available Academy;Address;Advisory Committees;Age;Agreement;American;American Indians;Arizona;Cancer Burden;Cancer Center;Cancer Control;Cause of Death;Collaborations;Communities;Competence;Development;Diagnosis;Educational Activities;Fostering;Funding;Goals;Health Disparities Research;Health Status;Healthcare;Healthcare Systems;Knowledge;Laws;Lead;Leadership;Malignant Neoplasms;Morbidity - disease rate;National Cancer Institute;Native Americans;Outcome;Outcomes Research;Patients;Prevention Research;Prevention program;Provider;Pueblo Race;Research;Research Personnel;Research Project Grants;Resource Sharing;Risk Factors;Screening for cancer;Student recruitment;Students;System;Techniques;Training;Translating;Translational Research;Tribes;Universities;Work;anticancer research;cancer care;cancer education;cancer prevention;cancer therapy;catalyst;community based participatory research;community partnership;design;education research;evidence base;experience;geographic barrier;health care delivery;health care service;improved;innovation;institutional capacity;investigator training;literacy;low socioeconomic status;mortality;non-Native;outreach;programs;protective factors;racial population;resilience;screening;skills;social;translational cancer research;tribal community Outreach Core n/a NCI 10686019 8/25/23 0:00 PAR-18-767 5U54CA143924-15 5 U54 CA 143924 15 9/1/09 0:00 8/31/24 0:00 ZCA1-SRB-2 5632 8042072 "GACHUPIN, FRANCINE C" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 176014 117001 62596 PROJECT SUMMARY/ABSTRACT: OUTREACH COREAmerican Indians experience worse outcomes and lower chances of survival than other racial groups in the USfor cancer and cancer is the second leading cause of death for American Indians over the age of 45 years.High rates of mortality and morbidity are attributed to delays and obstacles in seeking and receiving cancercare. Limited funds allocated to Native American health care lower socioeconomic status and cultural socialand geographic barriers to cancer care impede patients' ability to participate in screening diagnosis andtreatment. Low levels of health care literacy mistrust in the health care delivery system and dissatisfactionand cultural discordance with providers are further challenges specific to Native Americans. Despiteimprovements in cancer screening techniques and major developments in cancer treatment in past decadestribal communities do not benefit equally from these advances. Furthermore relatively little of theadvancements in cancer research addresses the specific vulnerabilities and strengths in these communities.The Partnership for Native American Cancer Prevention (NACP) Outreach Core will integrate findings from therapidly growing fields of resilience and research translation with the challenges common in health disparitiesresearch to recognize and enhance community capacities support university-community partnership andinvestigator training and disseminate outcomes from research efforts.Aim 1. Increase University of Arizona Cancer Center (UACC) and Northern Arizona University (NAU)researchers' and students' knowledge of Native Americans' cancer burden current cancer control programscancer-related needs and health care systems to enhance institutional capacities to design sustainablerelevant cancer research and prevention programs.Aim 2. Enhance skills and competency of NACP-supported students and investigators regarding best researchpractices when engaging in research with tribal communities.Aim 3. Offer an innovative dissemination academy to students and investigators designed to augment theirabilities to apply and translate NACP research results through enhanced health care services andcommunity-based education activities.Aim 4. Contribute to the National Cancer Institute's National Outreach Network (NON) and collaborate withNACP's Community Advisory Committee (CAC) to develop prioritize implement and evaluate requestedcancer-related activities to benefit Native American communities. +No NIH Category available Acceleration;Active Learning;Address;Arizona;Award;Cancer Center;Collaborations;Communities;Complement;Critical Thinking;Degree Completion;Degree program;Disparity;Drops;Education;Educational Curriculum;Enrollment;Ensure;Ethnic Population;Evaluation;Funding;Goals;Graduation Rates;Grant;Health Sciences;Institution;Internet;Joints;Laboratory Research;Malignant Neoplasms;Mentors;Modeling;Native Americans;Navajo;Outcome;Paper;Peer Review;Positioning Attribute;Postdoctoral Fellow;Process;Publications;Reporting;Research;Research Personnel;Research Training;Resource Sharing;Resources;Science;Scientist;Services;Students;Training;United States National Institutes of Health;Universities;Work;Writing;cancer education;cancer health disparity;cancer prevention;education research;experience;faculty mentor;graduate student;mid-career faculty;outreach;programs;racial population;recruit;responsible research conduct;socioeconomics;student participation;success;tribal Nation;tribal community;undergraduate student Research Education Core n/a NCI 10686017 8/25/23 0:00 PAR-18-767 5U54CA143924-15 5 U54 CA 143924 15 9/1/09 0:00 8/31/24 0:00 ZCA1-SRB-2 5631 10162095 "BEA, JENNIFER WRIGHT" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 170812 117000 57395 PROJECT SUMMARY/ABSTRACT: RESEARCH EDUCATION COREThe Research Education Core will engage students from the undergraduate to the doctoral level andcomplement other federally-supported mechanisms at NAU and the UACC. The NACP will continue one-on-one student research experiences with NACP-associated faculty and expand curricular offerings acrossinstitutions. The Research Education Core will promote guided grant writing experiences in collaboration withthe GUIDeS Shared Resource to increase the number of Native American scholars entering the CUREpipeline. Finally the Core will continue its strong partnership with the Planning and Evaluation and OutreachCores to provide validated outcomes and cancer education to students' communities. The specific aims are to:Aim 1. Develop a new undergraduate cancer disparities course as a joint effort between NAU andUACC. The course will include NACP-associated faculty from both institutions and fill gaps in existing curricula.Coursework will cover cancer disparities research with tribal communities scientific writing critical thinkingand Responsible Conduct of Research training. The course will enroll 20-30 students per year.Aim 2. Provide research experiences to further grow the Native American biomedical workforce. NACP-associated faculty will continue to offer hands-on experiential learning opportunities within researchlaboratories focused on cancer and/or Native American cancer health disparities. The goal is to mentor andtrain at least 18 Native American undergraduate students per year and assist in the transition of at least 35Native American students into advanced biomedical degree programs with a continued focus in cancer.Aim 3. Create programming and support services to promote CURE pipeline applications from NativeAmerican graduate students and postdoctoral trainees. Activities will entail: 1) recruiting NACP scholarswho want to become independent cancer researchers; 2) guiding scholars to NACP institutional and nationalresources for developing competitive CURE pipeline proposals; and 3) mentoring faculty to work with theirscholars to obtain competitive CURE funding and begin developing a publication track record. The aim is todevelop six CURE submissions and ensure every scholar co-authors one paper.Expected Impact: The expected impact after five years is that the Research Education Core will haveprovided cancer disparities curriculum to >100 undergraduates engaged 18 students a year in researchexperiences mentored 35 Native American students into advanced degree programs and developed 10CURE applications with NACP mentors. +No NIH Category available Acceleration;Anatomy;Bioinformatics;Biological Assay;Biological Markers;Biological Specimen Banks;Biology;Biomedical Engineering;Bladder;Bladder Urothelium;Cancer Detection;Cancer Patient;Cancer cell line;Cells;Charge;Clinical;Clinical Oncology;Clinical Trials;Collection;Consensus;Correlative Study;Coupled;Coupling;Decision Making;Detection;Devices;Diagnostic;Generations;Genitourinary system;Glean;Graft Rejection;Guidelines;Human;Image;Image Analysis;Immune checkpoint inhibitor;Immunotherapy;Investigation;Kidney;Kidney Transplantation;Laboratories;Light;Location;Magnetism;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Measures;Membrane;Messenger RNA;Molecular;Molecular Profiling;Monitor;Nanotechnology;Neoplasm Metastasis;Nucleic Acids;Oncologist;Patients;Performance;Pharmacodynamics;Physics;Prostate;Proteins;Protocols documentation;Reaction;Regimen;Regression Analysis;Research Personnel;Sampling;Signal Transduction;Source;Surface;System;Systems Biology;Testing;Time;Traction;Tumor Immunity;Urine;Urogenital Cancer;X-Ray Computed Tomography;biomarker panel;cancer therapy;cell bank;clinical imaging;clinical investigation;commercialization;effective therapy;exosome;expectation;experience;extracellular vesicles;imaging modality;improved;innovation;insight;instrumentation;liquid biopsy;multidisciplinary;nanoGold;nanometer;nanoplasmonic;novel;novel marker;peripheral blood;personalized immunotherapy;plasmonics;pre-clinical;pressure;prospective;repository;response;sensor;tool;translational study;treatment strategy;tumor;tumor microenvironment;tumor-immune system interactions;urinary High throughput nanoplasmonic exosome testing (NEXT) of immunotherapies in bladder cancer We propose to advance a novel liquid biopsy focused on urine to monitor bladder cancer patientsunder immunotherapy treatment. We will specifically exploit urinary extracellular vesicles (uEVs) as anovel biomarker and molecularly profile them using an enhanced nanoplasmonic-electrochemicalplatform. Our translational study will critically evaluate and establish this new EV assay for accurateand timelier bladder cancer cancer detection and treatment monitoring. NCI 10686016 8/28/23 0:00 PAR-20-116 5R01CA264363-03 5 R01 CA 264363 3 "MCKEE, TAWNYA C" 8/6/21 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-IMST-A(55)R] 1949625 "CASTRO, CESAR M" "LEE, HAKHO " 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 433516 NCI 258045 175471 Challenges. Once metastatic only 5 out of 100 patients are alive at ve years. Immune checkpointinhibitors have demonstrated increasing clinical traction yet conventional imaging such as CT scansstruggle to accurately assess tumor response in this treatment context. Serially accessible sources oftumor and host biomarkers could add earlier insights into response this informing timely go / no-godecision making to render precision immunotherapy. Innovation: In light of needed pre-competitivenanotechnology tools for EV investigation to ll temporal and scientic gaps precluding accurateimmunotherapy-based treatment monitoring our group developed and validated a magneto-electrochemical platform without need for EV purication and capable of 96 parallel readouts within45 minutes. This proposal exploits the bladder's intimate anatomical location within the genitourinarysystem; urine would thus provide us with rich repositories of bladder cancer EVs. We previouslydemonstrated feasibility of urine EV testing in kidney transplant rejection. Through increased excitedcharges generated by inducing plasmonic resonance in gold nanoparticles we recently acceleratedelectrochemical reactions within our most current and scalable platform to achieve 12-fold signalincrease from EV surface markers. We hypothesize that advancing our nanoplasmonic EV sensor forhuman urine and optimizing assay protocols to measure intra-EV and surface markers could identifyhigh value bladder cancer and host biomarkers (protein and mRNA) to better examine their interplayover time and under treatment pressures. We propose three specic aim: AIM 1: To optimize ournanoplasmonic sensor (NEXT) assay and instrumentation for high-throughput urine-based analysesand comprehensive proling of both surface and intra-EV markers. AIM 2: To employ pre-clinical andbanked biospecimens for NEXT analyses to examine proling performance and inform optimalbiomarker panel. AIM 3: Use NEXT to prospectively monitor and prole urinary EVs from patientsundergoing immunotherapy-based therapies for bladder cancer. Impact: Our highly complementarygroup of accomplished investigators bring to bear longstanding expertise and translational experiencein EV biology bioengineering systems biology bioinformatics and clinical oncology. If successful oururinary nanoplasmonic EV platform would add critical actionable insights into immunotherapy-basedtreatments of advanced bladder cancers with promise in other prevalent genitourinary cancers suchas kidney and prostate. 433516 +No NIH Category available Advanced Malignant Neoplasm;Advisory Committees;Arizona;Awareness;Cancer Burden;Cancer Center;Cancer health equity;Cervical dysplasia;Communication;Communities;Data;Development;Doctor's Degree;Education;Ensure;Evaluation;Feedback;Goals;Helicobacter pylori;Human Papillomavirus;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Monitor;National Cancer Institute;Native Americans;Nitric Oxide;Outcome;Population;Positioning Attribute;Prevention Research;Principal Investigator;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Services;Signal Transduction;Students;System;Training;Tribes;Universities;Work;anticancer research;cancer health disparity;cancer prevention;community engaged research;community engagement;cultural competence;design;education research;experience;health disparity;improved;malignant breast neoplasm;malignant stomach neoplasm;member;outreach;programs;screening;screening guidelines;success;tribal Nation;triple-negative invasive breast carcinoma;tumor microenvironment;undergraduate student;uptake;vaginal microbiome Planning and Evaluation Core n/a NCI 10686014 8/25/23 0:00 PAR-18-767 5U54CA143924-15 5 U54 CA 143924 15 9/1/09 0:00 8/31/24 0:00 ZCA1-SRB-2 5629 1885440 "BURGESS, JEFFEREY L." Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 673914 441366 236131 PROJECT SUMMARY/ABSTRACT: PLANNING AND EVALUATION COREThe purpose of the Partnership for Native American Cancer Preventions (NACP) Planning and EvaluationCore is to monitor and evaluate all partnership activities on a continuous basis as well as provide the oversightof the selection of new Research Projects. This Core serves each of the NACP components ensuring that theymaintain a scope of work that demonstrates progress toward the overall goals for this 16- year partnershipbetween the Northern Arizona University (NAU) and the University of Arizona Cancer Center (UACC). ThePlanning and Evaluation Core engages five entities: NACPs Executive Committee (EC) made up of themultiple Principal Investigators (MPIs) Core Co-Leaders the professional evaluator and PartnershipManagers; the Internal Advisory Committee (IAC) consisting of research and education leaders from bothinstitutions outside the direct responsibilities of NACP; the Community Advisory Committee (CAC)composed of community members that hold leadership positions within tribes; the Program SteeringCommittee (PSC) an external advisory board comprised of nationally recognized experts in cancer researchhealth disparities including Native American-specific cancer disparities and training of biomedical researchersand the officers and leaders of the National Cancer InstitutesCenter to Reduce Cancer Health Disparities(CRCHD) and itsPartnerships to Advance Cancer Health Equity (PACHE) program. The EC IAC CACPSC and CRCHD will provide expert unbiased rigorous evaluation of partnership progress and recommendimprovements and new directions as NACP evolves. The Planning and Evaluation Core will focus on thefollowing Specific Aims:Aim 1. Build and maintain an interactive and comprehensive feedback system using mixed methods data toallow leadership to employ data-driven formative development and summative evaluation of all NACPcomponents.Aim 2. Engage the IAC in internal planning and assessing of NACPs research and core activities to align andleverage the strengths of NAU and the UACC.Aim 3. Apply the unbiased and expert external evaluation and guidance of the CAC PSC and PACHE tocontinually improve the partnerships efforts across all components to reach its overall goals.Aim 4. Utilize the IAC CAC and PSC in the unbiased selection of new Research Projects and monitoring oftheir scientific progress.Expected Impact: The goals of NACP are to 1) reduce the cancer burden within the Native Americanpopulation through research and community engagement; 2) expand the number of Native Americaninvestigators working in cancer research; and 3) and increase the total number of investigators focused oncancer health disparities within the Native American communities of Arizona. +No NIH Category available Address;Administrator;Adoption;Advance Care Planning;Advanced Malignant Neoplasm;Advocacy;Advocate;African American;African American population;American Society of Clinical Oncology;Awareness;Cancer Center;Caregivers;Caring;Chronic Disease;Communication;Communities;Community Health Aides;Community Healthcare;Complement;Conflict (Psychology);Consolidated Framework for Implementation Research;Development;Disease;Disparity;Dissemination and Implementation;Documentation;Economic Factors;Education;Effectiveness;Enrollment;Ensure;Evaluation;Evidence based practice;Family;Focus Groups;Funding;Goals;HIV/AIDS;Health;Health Services Accessibility;Health education;Healthcare;Healthcare Systems;Home;Hospitals;Hybrids;Improve Access;Individual;Intervention;Interview;Investigation;Knowledge;Link;Malignant Neoplasms;Medical Care Team;Methods;Modeling;Motivation;Oncologist;Outcome;Pain management;Palliative Care;Patient Care;Patient advocacy;Patients;Persons;Philosophy;Physicians;Pilot Projects;Population;Public Health;Quality of Care;Quality of life;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Recommendation;Research;Resources;Role;Scanning;Services;Site;Social Work;System;Techniques;Training;Tuberculosis;Underserved Population;United States National Institutes of Health;Work;barrier to care;cancer care;care delivery;care outcomes;care systems;compare effectiveness;contextual factors;cultural competence;cultural values;design;disparity reduction;effectiveness-implementation randomized trial;empowerment;end of life;end of life care;ethnic disparity;evidence base;experience;family burden;health care delivery;health care disparity;high risk;hospice environment;implementation barriers;implementation evaluation;implementation facilitation;implementation intervention;implementation/effectiveness;improved;informant;intervention refinement;member;palliative;physical symptom;pragmatic trial;process evaluation;psychological symptom;racial disparity;research to practice;satisfaction;skills;social health determinants;standard care;successful intervention;underserved community;uptake Dissemination and Implementation of a Community Health Worker Intervention for Disparities in Palliative Care (DeCIDE PC) NarrativePalliative care is an effective means of improving quality of life for patients with incurable diseases. Howeverracial disparities exist in the utilization of palliative care services with African American patients significantly lesslikely than white patients to access or receive palliative care a factor that can result in African American patientsfailing to receive care aligned with their goals and wishes. We will examine an approach that integrates thesupport of Community Health Workers non-clinician public health workers who provide culturally sensitivehealth education information and advocacy to enhance palliative care among African American patients withadvanced cancer. NCI 10686013 8/16/23 0:00 PAR-19-274 5R01CA252101-03 5 R01 CA 252101 3 "JENSEN, ROXANNE ELAINE" 8/1/21 0:00 7/31/27 0:00 Dissemination and Implementation Research in Health Study Section[DIRH] 9038635 "JOHNSTON, FABIAN M" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 1 NCI 1 0 SUMMARYPalliative care can reduce physical and psychological symptoms improve quality of life and ensure goal-concordant care at the end-of-life for patients with advanced cancer. There are persistent and worseningdisparities in end-of-life outcomes for African American patients which are confounded by the lower likelihood ofthis population to access and receive palliative care. The basis for these disparities are multi-factorial and at theend of life barriers include personal or cultural values in conflict with hospice philosophy a lack of awareness ofhospice services concern about burdening family economic factors and/or mistrust of the healthcare system.The addition of individuals to the care team with a nuanced skillset focused on addressing such barriers to careis a promising approach to enhance palliative care uptake. Community Health Workers (CHWs) are non-clinicianculturally competent public health workers whose role is to promote access to services provide health educationsupport care delivery and promote advocacy in underserved populations. CHWs supplement care for patientswith advanced chronic diseases including HIV/AIDS tuberculosis and cancer and their impact on improvingcare in these settings is well-established. We developed an integrated CHW model the Dissemination andImplementation of a Community Health Worker Intervention for Disparities in Palliative Care (DECIDE PC) thatutilizes CHWs as care team members to augment palliative care outcomes for underserved patients withadvanced-stage illnesses. In DECIDE PC CHWs are trained to provide advocacy support motivationempowerment and education regarding palliative and end-of-life care to patients and their caregivers. Ourpreliminary experience suggests that CHWs can improve palliative care outcomes and improve patient andcaregiver satisfaction with care.Our long-term goal is to reduce disparities in palliative care for African Americans with advanced cancer.Integration of CHWs as members of the healthcare team may be an effective means to improve access to andenhance the uptake of palliative care in this population. To explore this we will conduct a randomizedeffectiveness-implementation pragmatic trial at four diverse cancer centers to 1. compare the effectiveness ofthe DECIDE PC intervention versus standard care in improving palliative care outcomes including quality of lifereceipt of quality communication advance care planning documentation/discussion and hospice use and 2.evaluate contextual factors that influence the effectiveness fidelity and adoption of the DECIDE PC intervention.We anticipate this work will establish the effectiveness of a CHW-based palliative care intervention in a prioritypopulation and generate generalizable knowledge to guide the development and implementation of interventionsto increase the use of palliative care services in underserved populations. 1 +No NIH Category available Training Programs;cancer health disparity Cancer Related Health Disparities Training Program PROJECT NARRATIVECancer mortality has declined in the U.S. yet striking racial/ethnic and socioeconomic disparities in cancerincidence mortality screening prevention treatment and survivorship persist. This training programaddresses a critical need to train diverse individuals to conduct community-engaged and multi-level multi-domain interventions to reduce cancer-related health disparities in under-resourced and disadvantagedpopulations. NCI 10686011 9/1/23 0:00 PA-18-403 5T32CA163184-13 5 T32 CA 163184 13 "LIM, SUSAN E" 9/15/16 0:00 8/31/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 7608807 "ALLEN, MICHELE L" "STEPANOV, IRINA " 5 FAMILY MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 327839 NCI 422346 26671 PROJECT ABSTRACT/SUMMARYThis is a proposal for the competing continuation of the University of Minnesota T32 Cancer Health DisparitiesTraining Program funded by NCI since 2011. Disparities in cancer incidence prevalence screening treatmentand survivorship are persistent with persons from socioeconomically under-resourced and disadvantagedpopulations and racial/ethnic minorities disproportionately burdened. This program meets the essential need totrain a diverse cadre of investigators to address cancer health disparities through innovative multi-level andmulti-domain interventions and community-engaged research. The primary goal of our T32 Program is toprepare predoctoral and postdoctoral trainees with the knowledge skills and experiences necessary toconduct cancer related intervention research with populations experiencing health disparities. Our 3 TrainingAims are to: 1) to increase the number of predoctoral and postdoctoral trainees committed to intervention andtranslational research addressing cancer disparities by leveraging the strengths of the current training programincluding curricular mentored research and career development components; 2) each year prepare threepredoctoral and three postdoctoral trainees to reduce cancer related health disparities; and 3) enhance thediversity of the research workforce in cancer related health disparities by committing to recruiting at least 50%of trainees from backgrounds underrepresented in research. We seek to educate researchers who are wellprepared to design implement and disseminate innovative community-engaged interventions to reducecancer related disparities. With this renewal we also will pursue three initiatives that are responsive to traineefeedback and innovations in health equity research. First our leadership mentorship and curriculum havebeen aligned with scientific approaches to health disparities research focused on multiple levels and domainsof influence along the cancer continuum. Second the role of our Community Mentors has been transformed tofacilitate increased opportunities for trainees to acquire skills and experiences in community-engagedresearch. Finally we will expand the focus on intervention development to address trainee recommendationsfor education in intervention implementation. Our training program is designed to prepare investigators skilledin intervention and translational research to reduce cancer health disparities with a focus on communityengaged research. We will achieve our goals through an enriching mentored experience didactic training andcollaborative research training and projects. Overall our proposal is highly aligned with the NCI priorities forAdvancing Public Health in Cancer. 327839 +No NIH Category available Address;Advisory Committees;Alaska Native;American Indians;Americas;Arizona;Award;Cancer Burden;Cancer Center;Cancer health equity;Categories;Charge;Collaborations;Communication;Communities;Comprehensive Cancer Center;Data;Development;Documentation;Ensure;Evaluation;Exhibits;Faculty;Funding;Goals;Health Disparities Research;Indigenous;Individual;Institution;Investments;Lead;Leadership;Location;Medical;Mentors;Modeling;Names;National Cancer Institute;Native Americans;Native Hawaiian;Navajo;Occupational activity of managing finances;Office of Administrative Management;Persons;Population;Principal Investigator;Process;Race;Research;Research Personnel;Research Project Grants;Resource Sharing;Role;Services;Strategic Planning;Terminology;Tribes;Underrepresented Students;United States National Institutes of Health;Universities;anticancer research;cancer education;cancer health disparity;cancer prevention;career development;community engagement;education research;experience;health definition;health disparity populations;inter-institutional;outreach;programs;recruit;success;tribal community Administrative Core n/a NCI 10686010 8/25/23 0:00 PAR-18-767 5U54CA143924-15 5 U54 CA 143924 15 9/1/09 0:00 8/31/24 0:00 ZCA1-SRB-2 5628 1888513 "BRIEHL, MARGARET M" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 273485 180500 96568 SUMMARY/ABSTRACT: ADMINISTRATIVE CORE The Partnership for Native American Cancer Prevention (NACP) is a 16-year collaboration betweenNorthern Arizona University (NAU an institution serving underserved heath disparity populations andunderrepresented students (ISUPS)) and the University of Arizona Cancer Center (UACC a National CancerInstitute-designated comprehensive cancer center). The overarching goals of the NACP are to reduce thecancer burden within the Native American population through research and community engagement; expandthe number of Native American investigators working in cancer research; and increase the total number ofinvestigators focused on cancer health disparities within the Native American communities of Arizona. The NACP Administrative Core is the organizational component that brings together the inter-institutional leadership to coordinate goals and aims of the Partnership. Additionally the Core ensures thateach of the other components of NACP (Cores Shared Resource and research projects) have aims andactivities that align with these goals. The Administrative Core provides essential administrative servicesacross these components to guarantee effective and efficient coordination financial management anddocumentation of all activities as well as facilitates the interactions with the three NACP advisory committees Internal Advisory Committee Program Steering Committee and the Community Advisory Committee. Giventhe 255-mile distance separating the two institutions and the dispersed locations of many of the advisors theAdministrative Core's fundamental roles must include promoting effective communications as well. TheAdministrative Core will also initiate recruitment of Early Stage Investigators focused on cancer healthdisparity research that will serve tribal communities. To ensure the success of NACP's goals and strategic plan outlined throughout this application theAdministrative Core is charged with the following aims: Aim 1. Engage a Partnership leadership team that integrates all Research Projects Cores and SharedResource activities in support of NACP goals. Aim 2. Provide administrative management for the entire partnership including facilitating communicationbetween Cores and Projects and fiscal management of all components. Aim 3. Coordinate the participation of the Internal Advisory Committee Program Steering Committeeand Community Advisory Committee within NACP's planning and evaluation activities. Aim 4. Initiate the recruitment process of Early Stage Investigators to enable their successful careerdevelopment and to increase the number of Native American investigators at both institutions. +No NIH Category available Address;Age;Applications Grants;Arizona;Basic Science;Biological;Biomedical Research;Cancer Burden;Cancer Center;Cancer Death Rates;Cancer health equity;Cause of Death;Collaborations;Communities;Comprehensive Cancer Center;Degree program;Development;Disparity;Disparity population;Education;Educational Activities;Educational Curriculum;Ethnic Population;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Health Disparities Research;Inequity;Institution;Intervention;Joints;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;NCI Center for Cancer Research;National Cancer Institute;Native Americans;Navajo;Outcome;Pilot Projects;Population;Positioning Attribute;Publications;Research;Research Personnel;Research Project Grants;Research Support;Research Training;Resource Sharing;Screening for cancer;Services;Students;Techniques;Training;Translating;Tribes;Trust;Underrepresented Populations;Underrepresented Students;United States;United States National Institutes of Health;Universities;Workforce Development;Writing;anticancer research;biomedical scientist;cancer education;cancer health disparity;cancer prevention;cancer survival;cancer therapy;career development;clinical practice;community engaged research;community engagement;community partnership;cultural competence;design;education research;expectation;experience;forging;graduate student;health disparity;health disparity populations;health inequalities;improved;insight;malignant stomach neoplasm;outreach;programs;racial population;recruit;screening;socioeconomics;success;tribal Nation;tribal community;undergraduate student 2/2 Partnership for Native American Cancer Prevention NARRATIVEThe Partnership for Native American Cancer Prevention (NACP) is well-situated to impact cancer healthdisparities for Native Americans in the Southwest. The goals of the NACP are to further increase: the cancerresearch at Northern Arizona University the cancer health disparities research at the University of ArizonaCancer Center cancer research education capacity for Native American researchers and the number ofNative American students and investigators in the cancer disparities workforce. We strive to make NACP thenationally-recognized leader in cancer disparities research education and outreach activities focused on theneeds and concerns of tribal communities. NCI 10686002 8/25/23 0:00 PAR-18-767 5U54CA143924-15 5 U54 CA 143924 15 "REVILLEZA, MARIA" 9/1/09 0:00 8/31/24 0:00 ZCA1-SRB-2(A1)R 8042072 "GACHUPIN, FRANCINE C" "HERBST-KRALOVETZ, MELISSA MARIE" 7 FAMILY MEDICINE 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1358388 NCI 900002 476301 PROJECT SUMMARY/ABSTRCT: OVERALLThe Partnership for Native American Cancer Prevention (NACP) is uniquely positioned to address cancerhealth inequities in Native American communities. Cancer is the second leading cause of death for NativeAmericans over the age of 45 years. Despite improvements in cancer screening techniques and majordevelopments in cancer treatment in past decades tribal communities have not benefited equally from theseadvances. Further the NIH recognizes that Native Americans have the lowest representation of allunderrepresented groups in the biomedical research workforce which contributes to the overall cancer healthinequities for this population. NACP began in 2002 as a partnership between Northern Arizona University(NAU) as the institution serving underserved health disparity populations and underrepresented students andthe University of Arizona Cancer Center (UACC) as the Comprehensive Cancer Center. The overarchinggoals of NACP are to increase NAU's cancer research and UACC's cancer health disparities capacities byhonoring existing and establishing new Native American community partnerships. To meet these goals thefollowing aims are proposed: Aim 1. Conduct Pilot Research Projects and Full Research Projects whichaddress Native American cancer disparities and reflect community concerns; Aim 2. Recruit and supportNative American faculty focused on cancer research; Aim 3. Create a new shared resource called GuidingU54 Investigator Development to Sustainability (GUIDeS) with the goal to facilitate the transition of NACP-affiliated Early Stage Investigators/Junior Investigators to research independence; Aim 4. Expand andimplement cancer disparities research education with a focus on Native American students across NAU/UAundergraduate and graduate programs; Aim 5. Integrate community engagement principles into all NACPactivities facilitating dissemination of the Partnership's research findings and the National Outreach Network'sinitiatives to Native American communities. To achieve these Aims two Full and one Pilot project areproposed; two have Native American co-leaders. One of the Full projects and the Pilot project combine basicscience and community engaged research to address gastric and cervical cancer; death rates for thesecancers are higher in Native American populations. We propose Administrative Planning and EvaluationResearch Education Outreach and GUIDeS Cores to support the research projects and integrate activitiesacross the Partnership. NAU and UACC commit institutional funds to support new projects and NativeAmerican investigators. New priorities in this proposal are community engaged research that will impact cancerscreening rates recruitment and mentoring of Native American early stage investigators grant writing activitiesto sustain Native American-focused cancer disparities research and initiatives and joint research educationcurricula to develop a stronger Native American biomedical workforce. By the end of the proposed fundingperiod NACP will move Native Americans in Arizona closer to cancer health equity. 1358388 +No NIH Category available Education;cancer prevention;programs Harvard Education Program in Cancer Prevention Control Project NarrativeThis training program is in its 24th year and has trained 116 fellows in transdisciplinaryapproaches to cancer prevention and control. Eighty-eight percent of trainees currently hold aresearch-focused position. The maturity of this Program extensive resources available throughHarvard and synergy across the focal training areas provide an outstanding platform for trainingthe next generation of cancer prevention scientists. NCI 10685982 8/16/23 0:00 PA-18-403 5T32CA057711-30 5 T32 CA 57711 30 "LIM, SUSAN E" 9/2/19 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1863832 "EMMONS, KAREN M." "FRAZIER, ANNE LINDSAY" 7 SOCIAL SCIENCES 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 487858 NCI 511504 32760 Program SummaryThe Harvard Education Program in Cancer Prevention and Control in its 24th year is a dynamic transdisciplinarycollaboration that brings together the extensive expertise of the Harvard T.H. Chan School of Public Health theDana-Farber Cancer Institute and Dana-Farber/Harvard Cancer Center and Harvard Catalyst |The HarvardClinical and Translational Science Center. We have trained 116 (60 predoc 56 postdoc) fellows intransdisciplinary approaches to cancer prevention and control and 88% of trainees currently hold a research-focused position. In this renewal we are requesting continued support for 4 predoctoral and 4 postdoctoraltrainees each year who have an average length of training of 4 years and 2 years respectively. The overall goalof the Program is to train fellows to become the next generation of scientists who are: (1) knowledgeable aboutthe current state of the science of cancer prevention and control; (2) skilled in transdisciplinary research; (3)skilled in formulating and writing research proposals and scientific manuscripts for publication; and (4) anchoredin peer and professional networks that support continual professional development and access to resources totranslate their knowledge into new cancer research areas. Transdisciplinary training will be further enhanced byleveraging a new transdisciplinary PhD program in Population Health Sciences that integrates training in fivepublic health disciplines and by instituting a new approach to mentorship known as developmental networks which creates diverse mentoring teams. We have also added new indicators of transdisciplinary training intoour evaluation plan. We have identified 5 focal areas in which trainees will receive robust training and researchexperiences including: (1) cancer disparities; (2) global cancer prevention; (3) implementation science; (4) healthcommunication; and (5) population health science. Robust and engaged internal and external advisorycommittees and 25 very strong mentors with extensive research portfolios ensure that the program will continueto thrive and innovate in cancer prevention training. The maturity of this Program extensive resources availablethrough Harvard and synergy across the focal training areas provide an outstanding platform for training the nextgeneration of cancer prevention scientists. 487858 +No NIH Category available Adverse effects;Affect;Afferent Neurons;Aftercare;Axon;Brain;Cancer Control;Cancer Patient;Cancer Survivor;Cells;Chemotherapy-induced peripheral neuropathy;Cisplatin;Clinical Data;Clinical Research;Clinical Trials;Cognitive deficits;Cytosol;Data;Deacetylation;Development;Disease;Drug Design;Ensure;Epigenetic Process;FDA approved;Goals;HDAC6 gene;Health;Heat-Shock Proteins 90;Histone Deacetylase;Histone Deacetylase Inhibitor;Histones;Impaired cognition;Impairment;Intervention;Malignant Neoplasms;Mediating;Mitochondria;Modeling;Mus;Neurodegenerative Disorders;Neuroimmune;Neurons;Nociceptors;Outcome;Oxidative Stress;Pathway interactions;Patients;Peripheral;Peripheral Nerves;Permeability;Pharmaceutical Preparations;Population;Prevention;Proteins;Public Health;Quality of life;Reporting;Research;Resolution;Solid;Spinal Ganglia;Synaptosomes;T-Lymphocyte;Testing;Therapeutic;Time;Toxic effect;Tubulin;United States Food and Drug Administration;anti-cancer;antitumor effect;cancer therapy;chemobrain;chemotherapy;chemotherapy induced neuropathy;clinical application;improved;inhibitor;innovation;mitochondrial dysfunction;neuroinflammation;neurotoxic;neurotoxicity;new therapeutic target;novel;novel strategies;novel therapeutics;pre-clinical;preclinical study;preservation;prevent;repaired;restoration;side effect;survivorship;treatment effect;tumor;white matter PQ12 Targeting HDAC6 for Chemotherapy-Induced Neuropathy and Chemobrain PROJECT NARRATIVEThe proposed research is relevant and significant for public health because we anticipate identifying HDAC6 asa novel therapeutic target for prevention as well as reversal of two frequent neurotoxic side effects of cancertreatment: chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitiveimpairment (CICI). CIPN and CICI significantly reduce quality of life during treatment of patients with cancerand often last long into survivorship. Clinical trials to examine the effect of HDAC6 inhibitors on tumor controlare already underway and therefore rapid clinical application of HDAC6 inhibitors to manage CIPN and CICIupon succesful completion of this project should be realistic. NCI 10685944 6/9/23 0:00 RFA-CA-17-017 5R01CA227064-06 5 R01 CA 227064 6 "SCHWEPPE, CATHERINE ANN" 5/22/18 0:00 4/30/24 0:00 ZCA1-SRB-A(J1)R 12153444 "GRACE, PETER M" "SHEPHERD, ANDREW JOHN" 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 359431 NCI 220722 138709 SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairment(CICI) are major side effects of cancer treatment that frequently persist long into survivorship. No drugs havebeen approved by the US Food and Drug Administration to prevent and/or adequately manage CIPN and CICI.This application aims at filling this void. A concern when designing drugs to manage CIPN and CICI is thatthey should not impair tumor control. Ideally agents to control these neurotoxicities should also enhancetumor control. Recent findings indicate that inhibitors of histone deacetylase 6 (HDAC6) meet these goals. HDAC6 de-acetylates non-histone cytosolic proteins like tubulin without inducing epigenetic changes.Recent preclinical and clinical data show promise for HDAC6 inhibitors to improve tumor control. Werecently showed that HDAC6 inhibition fully reverses established CIPN in cisplatin-treated mice. This wasassociated with restoration of mitochondrial health in sensory neurons. Preliminary data indicate that co-administration of HDAC6 inhibitors protect against CIPN by preventing mitochondrial damage. Additionalpreliminary data indicate that HDAC6 inhibition also reverses established CICI and associated brainmitochondrial damage. Our hypothesis is that HDAC6 inhibition prevents and reverses CIPN and CICI in mice with or withouttumors by targeting mitochondrial health oxidative stress and downstream neuroimmune pathways. We willtest our hypothesis in 3 specific aims: Aim1: Determine the capacity of HDAC6 inhibitors to prevent CIPN inmice with or without tumors. Aim 2: Determine the effect of HDAC6 inhibition on established CIPN. Aim 3:Determine whether the beneficial effects of HDAC6 inhibition extend to CICI. In aims 1 and 3 we willinvestigate the effect of HDAC6 inhibitors on tumor control and ensure that HDAC6 inhibitors also preventCIPN and CICI in the presence of a tumor. This study is innovative because we propose to target HDAC6 activity in neurons to controlneurotoxicities while at the same time enhancing cancer control. The expected outcome is significant becauseit will identify HDAC6 inhibition as a realistic novel approach to control CIPN and CICI. This will increase thequality of life of millions of cancer patients and survivors. Clinical trials to examine the effect of HDAC6inhibitors on tumor control are already underway and therefore the expected results of this project shouldrapidly convince clinicians to examine the value of HDAC6 inhibitors for management of both CIPN and CICI.Identification of HDAC6 inhibitors as drugs that can be used after completion of chemotherapy to completelyresolve established CIPN and CICI will be of great benefit for cancer survivors suffering every day fromthese persistent neurotoxicities. 359431 +No NIH Category available Ablation;Address;Agonist;Agrin;Articulation;Astrocytes;Autopsy;Basement membrane;Binding;Blood Vessels;Bone Marrow;Brain;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer cell line;Breast cancer metastasis;Cancer Patient;Cell Proliferation;Clinical;Clinical Data;Cues;Curiosities;Data;Deposition;Development;Disease;Dystroglycan;Early Diagnosis;Enzymes;Goals;Human;Individual;Investigation;Laminin;Lesion;Liver;Lung;Malignant Neoplasms;Measures;Mediating;Metastatic breast cancer;Metastatic malignant neoplasm to brain;Mutation;Neoplasm Metastasis;Organ;Outcome Measure;Ovary;Pathway interactions;Patients;Penetrance;Phase;Publishing;Recording of previous events;Resources;Seminal;Signal Transduction;Signaling Molecule;Site;Soil;Specimen;Suppressor-Effector T-Lymphocytes;Systemic Therapy;Testing;Therapeutic;Time;Transgenic Mice;Transgenic Model;Woman;Work;Xenograft Model;bone;glycosylation;high dimensionality;in vivo;innovation;intravital imaging;knock-down;malignant breast neoplasm;metastasis prevention;mouse model;mutant;neoplastic cell;palliative;prevent;prophylactic;receptor;theories Defining and characterizing microenvironmental drivers of disseminated tumor cell dormancy in brain Project NarrativeBrain metastases are a growing problem across cancers. They can take many years to manifest but are lethalonce they do. Here we propose to investigate breast tumor cells upon their arrival to the brain in order todefine the cues that make them dormant and to unravel the consequent signaling. We believe that solvingthese mysteries will inspire approaches to prevent brain metastasis by leveraging our discoveries forprophylactic therapies. NCI 10685943 4/5/23 0:00 PA-19-056 5R01CA252874-05 5 R01 CA 252874 5 "GRIL, BRUNILDE M" 5/5/20 0:00 4/30/25 0:00 Tumor Microenvironment Study Section[TME] 8087685 "GHAJAR, CYRUS M" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 475250 NCI 270028 205222 Project Summary Brain metastases arise later than metastases at other sites. Once they do they are rapidly debilitating andlethal. The time it takes for brain metastases to emerge suggests that a dormancy phase is involved. Thisnotion is supported by clinical and experimental data. Indeed our own preliminary data show that breastcancer cells become dormant upon entering the brain and that emerging from this state is the rate-limiting stepof metastasis. These data indicate that targeting dormant disseminated tumor cells (DTCs) is a logicalapproach to brain metastasis prevention. However despite a growing understanding of dormancy mechanismsin common metastatic sites like lung and bone marrow a parallel understanding of how DTCs are driven into adormant state in brain has not developed. The overarching goal of this proposal is to address this issue. Wewill formulate a basic framework for how the brain microenvironment drives DTCs into a dormant state withsupport from clinical specimens so that we can leverage this understanding for therapies that keep DTCsdormant indefinitely. Our recent investigations have revealed that dormant DTCs occupy the brains vascular niche whereperivascular astrocytes suppress their outgrowth. We suspect that astrocytic contributions to the parenchymalbasement membrane are responsible for DTC suppression and that these contributions converge on acommon receptor: dystroglycan. Therefore our hypotheses are that: (i) astrocytic basement membrane is akey driver of DTC dormancy and (ii) dystroglycan function must remain intact for DTCs to interpret thesesignals. We will test these hypotheses through two specific aims: Aim 1. Determine whether astrocytic basement membrane promotes and sustains DTC dormancy. Aim 2. Elucidate the dystroglycan-mediated signaling axis that effects DTC quiescence in brain. We have brought every relevant resource to bear in order to address these aims. These resources span: (i)long-term intravital imaging to determine the fate of DTCs following ablation of DTC-associated astrocytes; (ii)transgenic mice to measure the outcome of ablating astrocyte derived basement membrane molecules on DTCfate; (iii) rare clinical specimens to establish whether astrocytes and astrocytic basement membrane are asso-ciated with dormant DTCs in humans; and (iv) a host of mutant over- and under- expression constructs tosolve how dystroglycan functions from the outside-in to drive DTC quiescence. The significance and innovation of this work lie in the identification of the first dormancy drivers in brainultimately to unravel dystroglycan-driven signaling that effects disseminated breast tumor cell quiescence. Thiswork will set the stage for agonists of dystroglycan function that serve as prophylactics for brain metastasisprevention. 475250 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Patient Safety Amendment;Cancer Therapy Evaluation Program;Cancer Trials Support Unit;Clinical Trials;Communication;Contractor;Goals;Letters;Process;Protocols documentation;Research Personnel;Standardization;Support Contracts;Time;Writing;clinical development;programs TASK ORDER 5A: CENTRALIZED PROTOCOL WRITING SUPPORT; CONTRACT TITLE: CANCER TRIALS SUPPORT UNIT CTSU. n/a NCI 10685654 75N91022D00014-0-759102200001-2 N01 8/1/22 0:00 7/31/23 0:00 78802111 "CARAVOULIAS, CHRISTINA " Not Applicable 8 Unavailable 57052391 FAA2LVENETH4 57052391 FAA2LVENETH4 US 39.02704 -77.126432 1603501 "TECHNICAL RESOURCES INTERNATIONAL, INC." BETHESDA MD Domestic For-Profits 208171197 UNITED STATES N R and D Contracts 2022 738397 NCI The Contractor shall reduce the administrative burden of protocol writing for investigators by establishing implementing and maintaining a CTEP Centralized Protocol Writing Support (CPWS) program which shall include but is not limited to processes for standardized communication document writing and tracking to streamline the development of clinical trials. The contractor shall provide standardized centralized Protocol ICD writing support to select studies as directed by CTEP from Letter of Intent (LOI) approval through initial Protocol approval. This task order would also cover potential amendments after approval of the COR. The goals are to reduce the time from LOI approval to protocol approval and to minimize the number of protocol revisions to less than two. 738397 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS Cancer Trials Support Unit;Contractor;Contracts;Procedures;Recommendation;Reporting;Standardization;Summary Reports;Work;base;meetings;programs;symposium TASK ORDER 1A -PROJECT KICKOFF MEETING; CONTRACT TITLE: CANCER TRIALS SUPPORT UNIT CTSU. n/a NCI 10685653 75N91022D00014-0-759102200001-1 N01 8/1/22 0:00 7/31/23 0:00 78802111 "CARAVOULIAS, CHRISTINA " Not Applicable 8 Unavailable 57052391 FAA2LVENETH4 57052391 FAA2LVENETH4 US 39.02704 -77.126432 1603501 "TECHNICAL RESOURCES INTERNATIONAL, INC." BETHESDA MD Domestic For-Profits 208171197 UNITED STATES N R and D Contracts 2022 1402 NCI The contractor will attend a Kick-off Programmatic Meeting by conference call with the Contracting Officers Representative (COR) Contracting Officer (CO) and other Program and Office of Acquisition Staff where the Contractor shall provide a presentation and participate in discussion of best practices and other standardized procedures that will be used under all Task Orders for the Base Statement of Work as well as discussion of potential expansion or improvement of the CTSU program. The contractor will also submit a Meeting Summary Report that includes the Contractors recommendations for best practices potential expansion and improvement of the CTSU Program. The report shall also include a summary of the Programmatic Meeting. 1402 +Cancer Address;Advisory Committees;Antineoplastic Agents;Authorship;Biological;Biological Assay;Biometry;Biostatistics Core;Budgets;Chemicals;Chicago;Collaborations;Cyanobacterium;Data;Data Display;Databases;Dependence;Development;Disputes;Drug Kinetics;Effectiveness;Ensure;Evaluation;Fostering;Goals;Grant;Housing;Illinois;Industrialization;Information Dissemination;Information Services;Institution;Investigation;Laboratories;Leadership;Lichen - organism;Malignant Neoplasms;Methods;Modeling;Molds;North Carolina;Occupational activity of managing finances;Ohio;Organization administrative structures;Persons;Pharmaceutical Chemistry;Pharmacologic Substance;Plants;Program Effectiveness;Program Efficiency;Program Research Project Grants;Provider;Research;Research Personnel;Research Project Grants;Resources;Scientist;Statistical Methods;Structure;Teleconferences;Telephone;Time;Training;Universities;Validation;Visual;Work;chemotherapeutic agent;computerized data processing;design;experimental analysis;experimental study;fungus;meetings;member;multidimensional data;novel;operation;preservation;programs;symposium;tumor Core A: Administrative and Biostatistics Core n/a NCI 10685637 8/17/22 7:39 PAR-18-290 3P01CA125066-13S1 3 P01 CA 125066 13 S1 "FU, YALI" 7/1/07 0:00 4/30/25 0:00 ZCA1-TCRB-Q(O1) 6314 1877686 "KINGHORN, ALAN DOUGLAS" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 5/1/22 0:00 4/30/23 0:00 Non-SBIR/STTR 2022 202276 129664 72612 PROJECT SUMMARY ADMINISTRATIVE AND BIOSTATISTICS CORE (CORE A)The overall goals of the Administrative and Biostatistics Core (Core A) are to 1) continue to provide a structureto facilitate effective interactions toward the accomplishment of the aims of this Program Project and specifically to foster and promote the goals of the Program and each component (cores and projects) by providing scientific direction administrative and budgetary support oversight integration of program activities and the industrial partner and ensuring operational efficiency; and 2) to continue to provide biostatistics and other statistical support for the P01. The following are the objectives of Core A: 1) provide research direction by setting the research agenda focused on the discovery of novel chemicals from selected tropical rainforest plants as well as lichens cyanobacteria and filamentous fungi for development as cancer chemotherapeutic agents particularly for tumors not cured by present treatment methods. 2) Ensure operational efficiency for Program componentsby providing centralized grant administration information dissemination budget data processing and exchangeof information and services. 3) Promote integration of the Research Projects and Cores to promote interactionamong the three primary universities represented by the investigators and relevant external entities and 4) provide biostatistics support for the three Projects and the two Cores of the P01 Program. Core A will continue to ensure that all components of the Program work seamlessly together to accomplish the overall and specific project goals of the P01 Program. +No NIH Category available Adoptive Cell Transfers;Adult;Bar Codes;Binding;Biochemical;Cell Differentiation process;Cell physiology;Cells;Chronic;Colon Carcinoma;Colonic Polyps;Data;Enterocolitis;Enzymes;Epithelial Cells;Epithelium;Genetic Epistasis;Homeostasis;Human;IL17 gene;Immune;Inflammation;Inflammation Mediators;Interleukins;Intestinal Cancer;Intestinal Neoplasms;Intestines;Knock-in Mouse;Length;Life;Lymphocyte;Malignant - descriptor;Malignant Neoplasms;Mediating;Molecular;Mus;Population;Predisposition;Process;Proliferating;Proteomics;Radiation Chimera;Risk;Role;Small Intestinal Polyp;T-Lymphocyte;Testing;Tissue Preservation;Tissues;Ubiquitin;Ubiquitination;cell transformation;colitis associated cancer;colon cancer prevention;colorectal cancer risk;cytokine;gut inflammation;in vivo;intercellular communication;interleukin-22;intestinal epithelium;intestinal homeostasis;mouse model;novel;paracrine;preservation;restraint;single-cell RNA sequencing;transcriptomics Ubiquitination Intestinal Homeostasis and Cancer Project NarrativeUnder normal conditions epithelial cells reside in close association with immune cells in the intestine and areciprocal dialogue among these components maintains intestinal homeostasis. Disruption of this homeostaticstate can lead to chronic intestinal inflammation and increased risk for colorectal cancer. Our studies aim toarrive at a mechanistic understanding of how A20 also known as TNFAIP3 preserves normal intestinaldifferentiation and protects against colitis associated cancer. NCI 10685627 8/16/23 0:00 PA-20-185 5R01CA266755-02 5 R01 CA 266755 2 "XU, WANPING" 9/1/22 0:00 8/31/27 0:00 Digestive and Nutrient Physiology and Diseases Study Section [DNPD] 1872380 "MA, AVERIL I" Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 439632 NCI 272218 167414 AbstractAdult intestinal tissues are maintained in a normal functional state despite rapidly proliferating anddifferentiating intestinal epithelial cell populations that replenish the epithelium layer every 6-7 days. Intestinalepithelial cells reside in close association with both adaptive and innate immune cells of the gut. A reciprocaland dynamic dialogue among these components maintains intestinal homeostasis and is mediated in part byparacrine cytokine and interleukin networks. Intestinal inflammation predisposes intestinal epithelial cells (IEC)to malignant transformation via incompletely understood mechanisms. We have generated a novel knock-inmouse line that spontaneously develops perturbed IEC differentiation gut elongation and have a highsusceptibility to colon cancer. These mice provide us with a unique opportunity to discover the keyinflammatory mediators that regulate intestinal homeostasis and drive IEC transformation. Usingtranscriptomic proteomic genetic epistasis and cellular approaches our preliminary data implicate selectedimmune cytokines in these processes. 439632 +No NIH Category available Adjuvant Therapy;Algorithms;Area;Artificial Intelligence;Assessment tool;Biopsy;Breast Cancer Detection;Cancer Research Project;Categories;Classification;Clinical;Clinical Data;Computer Vision Systems;Core Biopsy;Data;Data Science;Development;Development Plans;Diagnosis;Duct (organ) structure;Eligibility Determination;Future;Goals;Growth;Guidelines;Histopathology;Hormone Receptor;Incidence;Indolent;Information Systems;Institution;Knowledge;Laboratories;Machine Learning;Malignant Epithelial Cell;Mammographic Density;Mammography;Medical Imaging;Medical center;Morbidity - disease rate;Natural Language Processing;Newly Diagnosed;Noninfiltrating Intraductal Carcinoma;Operative Surgical Procedures;Pathology;Patients;Performance;Positioning Attribute;Proliferating;Radiation therapy;Radiology Specialty;Randomized Controlled Trials;Recommendation;Regimen;Reporting;Research;Research Project Grants;Retrospective cohort;Risk;Risk Marker;Safety;Slide;Surveillance Program;Training;Treatment Protocols;Validation;Woman;Work;aggressive therapy;artificial intelligence algorithm;breast imaging;cancer invasiveness;career;career development;clinical center;clinical implementation;clinical practice;complex data;computer science;convolutional neural network;cost;deep learning;diverse data;experience;hormone therapy;image guided;improved outcome;machine learning classifier;machine learning model;malignant breast neoplasm;medical schools;overtreatment;patient health information;patient stratification;predictive tools;professor;prognostic model;prognostic tool;prospective;radiologist;random forest;research clinical testing;risk prediction;risk stratification;skills;standard care;surgery outcome;tool;tumor Development and Clinical Implementation of an Artificial Intelligence Tool to Predict Risk of Upgrade of Ductal Carcinoma In Situ PROJECT NARRATIVEEvery year more than 60000 women are diagnosed with ductal carcinoma in situ (DCIS) which is also knownas noninvasive or Stage 0 breast cancer and undergo an aggressive treatment regimen involving surgeryradiation and hormonal therapy. We propose to develop and implement a robust tool using artificialintelligence to pre-operatively predict the risk that DCIS will upgrade to invasive cancer at surgery.Development of a highly reliable prognostic tool could identify the subset of women who may not needaggressive treatment decrease the morbidity and costs associated with overtreatment and support moretargeted and precise treatment options for women diagnosed with DCIS. NCI 10685615 8/22/23 0:00 PA-18-373 5K08CA241365-05 5 K08 CA 241365 5 "RADAEV, SERGEY" 7/1/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 12060893 "BAHL, MANISHA " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 261328 NCI 241970 19358 PROJECT SUMMARY/ABSTRACT This proposal presents a five-year career development plan focused on data science and artificialintelligence (AI) and the application of AI to improve outcomes in women with ductal carcinoma in situ (DCIS).The candidate is a Radiologist at MGH and an Assistant Professor of Radiology at Harvard Medical School.The proposal builds upon the candidates previous research and clinical experiences in breast imaging andalso upon a strong ongoing research partnership between MGH and MITs Computer Science and ArtificialIntelligence Laboratory (CSAIL). The candidates long-term career goal is to become a leader in academicbreast imaging by investigating and applying AI to critical areas in breast cancer detection diagnosis andtreatment. The proposed research project and advanced didactic training at Harvard and MIT will position thecandidate with a unique set of knowledge and skills in data science and AI that will enable her to develop anindependent cancer research program that focuses on applications of AI to breast imaging. The incidence of DCIS has dramatically increased over the past 40 years with an estimated 63960diagnoses in 2018. Current guidelines recommend that DCIS be treated with surgery radiation and endocrinetherapy but there remains considerable controversy over whether this regimen represents overtreatment forthose women with indolent non-hazardous DCIS. Given concerns about overtreatment there are currentlythree randomized controlled trials underway to evaluate the safety and efficacy of active surveillance versusstandard treatment and critical to the implementation of active surveillance programs is careful selection ofeligible patients. The goal of the proposed project is to develop a robust AI tool that incorporates clinical datamammographic imaging and biopsy histopathology slides for pre-operatively predicting the risk of concurrentinvasive cancer in women with DCIS. The tool will be built using machine learning deep learning andcomputer vision. Incorporation of mammographic imaging and histopathology slides into the AI tool will besupported by the MGH & BWH Center for Clinical Data Science (CCDS) and the MGH Department ofPathology. After development and validation of the AI tool based on a retrospective cohort of 1400 womendiagnosed with DCIS at MGH the tool will then be integrated into MGHs mammography information systemand used to categorize new cases of DCIS. The specific aims are: (1) to develop a robust AI tool that predictsthe risk of upgrade of DCIS diagnosed by image-guided core needle biopsy to invasive cancer at surgery and(2) to implement and evaluate the AI tool in clinical practice. Use of this tool could identify the subset of womenwho are appropriate candidates for active surveillance decrease the morbidity and costs of overtreatment andsupport more targeted and precise treatment options for women diagnosed with DCIS. 261328 +No NIH Category available Adaptor Signaling Protein;Address;Adoptive Cell Transfers;Advanced Malignant Neoplasm;Affinity;Antigen Targeting;Antitumor Response;Applications Grants;Attention;Australia;Autologous Tumor-Infiltrating Lymphocyte;Avidity;Biological Assay;Biological Sciences;Biomanufacturing;Canada;Cell Line;Cell Survival;Cell Therapy;Cell surface;Cells;Cellular immunotherapy;Chemotherapy-Oncologic Procedure;Clinical;Clinical Trials;Collaborations;Colorado;Contracts;Cytokine Receptors;Cytotoxic T-Lymphocytes;Deposition;Development;Dose;Eligibility Determination;Engineered Gene;Engineering;Engraftment;Europe;Future;Genetic Engineering;Goals;Head and neck structure;Homing;Human;Immune;Immunotherapy;Infusion procedures;Intellectual Property;Interleukin-2;Japan;Laboratories;Lead;Legal patent;Licensing;MHC antigen;Malignant Neoplasms;Marketing;Medical;Methods;Modeling;Mus;MyD88 protein;Patients;Penetration;Phase;Phase I Clinical Trials;Process;Property;Publishing;Recording of previous events;Recurrence;Refractory;Regimen;Research;Retroviral Vector;Safety;Signal Transduction;Small Business Innovation Research Grant;Solid;Solid Neoplasm;Stress;Survival Rate;T cell infiltration;T cell response;T-Cell Receptor;T-Lymphocyte;Technology;Therapeutic;Therapy trial;Toxic effect;Tumor Antigens;Tumor Immunity;Tumor Promotion;Tumor-Infiltrating Lymphocytes;Universities;Viral Vector;Virus;assay development;cancer clinical trial;cancer therapy;cancer type;chemotherapy;chimeric antigen receptor;conditioning;cytotoxic;drug development;engineered T cells;exhaust;exhaustion;experience;experimental study;extracellular;first-in-human;gene delivery system;immunogenic;interest;manufacture;manufacturing facility;manufacturing organization;manufacturing process;melanoma;member;mouse model;neoantigens;neoplastic cell;next generation;novel;operation;patient subsets;pre-clinical;programs;receptor;response;safety assessment;sarcoma;technology platform;therapy development;tumor;tumor infiltrating lymphocyte therapy;viral gene delivery Next Generation Autologous TIL Cancer Therapy: Development of GMP manufacturing process Project NarrativeT cell-based immunotherapies such as tumor infiltrating lymphocytes (TILs) have revolutionized the treatment ofa number of different cancers including advanced melanoma. However most patients still do not benefit fromthis form of therapy because few immune cells penetrate the tumor and show transient antitumor activity. Wehave developed a novel genetically engineered TIL therapy that overcomes multiple impediments toconventional TIL therapy. NCI 10685604 8/15/23 0:00 PA-21-259 5R44CA268313-02 5 R44 CA 268313 2 "FRANCA-KOH, JONATHAN C" 9/1/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-V(13)B] 1972295 "GONZALEZ, RENE " Not Applicable 6 Unavailable 117626000 QAE3GETX9Z88 117626000 QAE3GETX9Z88 US 39.747514 -104.84674 10062608 "TRAMPOLINE PHARMA, INC." AURORA CO Domestic For-Profits 800457335 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 1000000 NCI 815000 122250 The overall goal of this Phase II SBIR grant proposal is to research and develop the GMP manufacturingprocess for next-generation tumor infiltrating lymphocyte (TIL) cancer therapeutic for solid tumors. In clinicaltrials TIL-based immunotherapies have demonstrated tumor regression and increased survival rates againstdifferent cancer types. Despite these encouraging clinical results durable antitumor responses are typicallyobserved in a subset of patients with advanced cancers like melanoma. This stresses the need to developmore effective TIL-based strategies and to expand efficacy against different cancer types. TIL therapies arehindered in part by low TIL accumulation into tumors low persistence weak T cell receptor (TCR) affinityand/or avidity as well as the low expression of tumor antigens on the cells surface. Additionally the presenceof suppressive signals on T cells such as Lag3 Tim3 CD39 pose a major obstacle to generating effective andlong-lived antitumor T cell responses. In our published and preliminary studies activating MyD88 signaling inhuman or mouse T cells increases antitumor activity and prolongs T cell survival. By fusing the high affinityCD8 (extracellular) to MyD88 (intracellular; CD8:MyD88) we have developed a novel and universal platformthat activates MyD88 signaling strictly upon the engagement of the TCR with the MHC-antigen on tumor cells.CD8:MyD88 expression in TILs cells substantially increases responses to weak and suboptimal levels oftumor antigens including neoantigens and in preliminary studies has demonstrated the extraordinary propertyof reducing the T cells entry into an exhausted state. Importantly the use of the CD8 co-receptor representsa universal approach to enhancing T cell responses and can be used in patients regardless of the patientsHLA type. Through this SBIR Phase II application we propose the following aims. Aim 1 will researchdevelop and manufacture GMP grade g-retroviral vectors. Here we will generate high virus titer-producingCD8a:MyD88-EGFRt PG-13 cell lines accompanying analytical assays and manufacture the GMPCD8a:MyD88-EGFRt g-retroviral vectors. For this aim we are partnering with a commercial contractdevelopment manufacturing organization (CDMO) Vigene Biosciences to generate GMP viral vectors. In Aim2 we propose to develop and manufacture GMP CD8a:MYD88 engineered TILs (coR8:AMPTM TILs). Incollaboration with the Gates Manufacturing Facility (GBF) at the University of Colorado Anschutz MedicalCampus (UCAMC) we will conduct process & analytical assay QC release assay develop and manufacture ofGMP grade coR8:AMPTM TILs. The successful completion of these aims will lead to the pre-IND and IND filingswith the FDA for a Phase I clinical trial in patients with immune refractory solid tumors. This activity will beconducted in collaboration with the UCAMCs Cell Therapy Operations Program (CTOP) GatesBiomanufacturing Facility and our team members who have extensive experience in cell therapy drugdevelopment. 1000000 +No NIH Category available Address;Adoptive Immunotherapy;Antibodies;Antigen Presentation;Antigens;B lymphoid malignancy;Biological Assay;Bispecific Antibodies;Brain;Brain Neoplasms;Bulky Disease;Bypass;CD19 gene;CTLA4 gene;Cell secretion;Cells;Central Nervous System;Clinical;Clinical Trials;Data;Disease;Disease Progression;Drug Kinetics;Engineering;Epidermal Growth Factor Receptor;Epitope spreading;FDA approved;Genetic Engineering;Glioblastoma;Glioma;Goals;Heterogeneity;Human;Immune;Immunosuppression;Immunotherapy;Infusion procedures;Intracranial Neoplasms;Intravenous infusion procedures;Investigational New Drug Application;Lung;Malignant - descriptor;Malignant Neoplasms;Mediating;Membrane Proteins;Modeling;Mutation;Normal tissue morphology;Oncogenic;PD-1/PD-L1;PDL1 pathway;Patients;Penetration;Peripheral;Pharmaceutical Preparations;Phase I Clinical Trials;Primary Brain Neoplasms;Recurrence;Regulatory T-Lymphocyte;Role;Route;Sampling;Site;Skin;Solid Neoplasm;Surface Antigens;T cell infiltration;T-Lymphocyte;T-cell receptor repertoire;Testing;Toxic effect;Toxicity Tests;Tumor Escape;Work;Xenograft Model;bi-specific T cell engager;blood-brain barrier crossing;blood-brain barrier penetration;brain tissue;chimeric antigen receptor;chimeric antigen receptor T cells;clinical development;clinical efficacy;cytotoxic;design;effector T cell;engineered T cells;epidermal growth factor receptor VIII;first-in-human;high dimensionality;immune checkpoint blockade;immunoengineering;leukemia/lymphoma;model design;mouse model;neoplastic cell;novel;patient derived xenograft model;personalized immunotherapy;preclinical study;receptor;response;side effect;trafficking;tumor;tumor heterogeneity;tumor microenvironment;tumor progression Overcoming tumor heterogeneity in glioblastoma with multi-targeted CAR T cells secreting bispecific antibodies PROJECT NARRATIVEImmune therapies have the potential to cure cancer. Immune T cells that have been engineered with receptorscalled CARs have been very effective in leukemia and lymphoma but less effective in glioblastoma and othersolid tumors in part because the tumor cells don't all express the target of the CAR. We propose to test newways of engineering immune cells so that they can recognize more than one target on tumor cells andtherefore avoid having the tumor escape from the CAR-T cells. NCI 10685596 9/4/23 0:00 PA-18-484 5R01CA238268-05 5 R01 CA 238268 5 "BOURCIER, KATARZYNA" 9/20/19 0:00 8/31/24 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 10066497 "MAUS, MARCELA VALDERRAMA" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 545246 NCI 335395 209851 "PROJECT SUMMARY Glioblastoma (GBM) is uniformly lethal and is the most common malignant primary brain tumor.Immunotherapy promises a precise approach and the hope of durability. One way to deliver precisionimmunotherapy is with genetically-engineered T cells designed to express a target-specific chimeric antigenreceptor or CAR. In 2017 CAR T cells targeting CD19 were approved by the FDA for B cell malignancies andseveral CARs targeting GBM have been described recently. We have developed CARs that target the EGFRvIIItumor mutation and demonstrated their activity in preclinical studies and in a first-in-human clinical trial. Wefound that peripheral infusion of CART-EGFRvIII cells was safe and led to elimination of EGFRvIII-expressingglioma cells in patients. However despite CART-EGFRvIII trafficking to intracranial tumors and targeting ofEGFRvIII the patients ultimately had outgrowth of EGFRvIII-negative disease and tumor progression. Thuswhile the CAR T cell platform certainly holds great promise a critical barrier to clinical impact for brain tumors istargeting a single antigen in an inherently heterogeneous disease. In addition our study also demonstrated anadaptive increase in immunosuppression within the tumor microenvironment; specifically the endogenous T cellinfiltrate increased in the tumor but consisted largely of immune-suppressive regulatory T cells (TRegs) ratherthan effector T cells reflective of antitumor epitope spreading. To simultaneously address antigenic heterogeneityand promote local antitumor activity in GBM we have now modified CART-EGFRvIII to secrete bispecificantibodies known as bispecific T cell engagers (BiTEs) against wild-type EGFR which is not expressed in thenormal brain but is nearly always expressed in GBM. Delivering BiTES to the brain using T cells as carriers isalso attractive because antibodies do not effectively cross the blood-brain barrier. The overall goal of this workis to develop a safe and effective immunotherapy for patients with GBM. We test the hypothesis that anti-EGFRvIII CAR T cells designed to secrete anti-EGFR BiTEs (CAR-BiTE) will lead to potent and durableresponses in models of heterogeneous GBM. We will test their mechanism of action by quantifying secretion ofBiTEs and systematically testing the role of bystander T cells (Aim 1). Next we will determine the optimal routeof administration of CAR-BiTE products and the pharmacokinetics and biostribution of these two-in-one active""drugs (Aim 2). These data are expected to lead to an Investigational New Drug (IND) application and Phase Iclinical trial of CART-vIII/BiTE-EGFR in patients with recurrent glioblastoma. Finally CAR-BiTEs represent aplatform that can target multiple combinations of antigens. In Aim 3 we will identify targetable antigens in primaryglioma samples and test CAR-BiTEs targeting three or more antigens." 545246 +No NIH Category available Abdomen;Address;Adoptive Transfer;Adult;Advanced Malignant Neoplasm;Amino Acid Sequence;Antibiotics;Antigens;Antitumor Response;Bacteria;Body mass index;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Cellular Assay;Clinical;Data;Diet;Disease Progression;Disease remission;Education;Effectiveness;Environmental Risk Factor;Exposure to;Gender;Genetic;Germ-Free;Goals;Grant;Granzyme;Human;Human Microbiome;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunology;In Vitro;Integration Host Factors;Interferon Type II;Intestines;Malignant Neoplasms;Metastatic Melanoma;Microbiology;Modeling;Molecular;Mus;Oral Administration;Patients;Pre-Clinical Model;Probiotics;Production;Progressive Disease;Research;Role;Sequence Homologs;Testing;Treatment Efficacy;Weight;Yogurt;adaptive immune response;anticancer activity;cancer immunotherapy;cancer therapy;checkpoint therapy;draining lymph node;gut bacteria;gut microbiome;gut microbiota;human study;immune checkpoint;immunogenic;immunoregulation;in vivo;individual patient;innovation;insight;melanoma;mesenteric lymph node;microbial;microbiome;microbiota;microbiota profiles;microorganism;neoantigens;novel;novel strategies;pre-clinical;probiotic therapy;programmed cell death protein 1;recruit;response;translational oncology;translational study;treatment response;tumor Role of Gut Microbiota in Modulating Immune Checkpoint Inhibitory Therapy for Cancer The effectiveness of immune checkpoint inhibitor therapy a form of cancer immunotherapy is associated withthe presence of specific intestinal bacteria. In this grant we propose to explore the mechanisms by which gutbacteria the tumor and environmental factors modulate the efficacy of immune checkpoint inhibitor therapy. NCI 10685566 7/31/23 0:00 RFA-CA-18-019 5R01CA231303-05 5 R01 CA 231303 5 "SOMMERS, CONNIE L" 9/1/19 0:00 8/31/24 0:00 ZCA1-SRB-5(M1)S 7935794 "KOH, ANDREW Y" "HOMSI, JADE ; PASARE, CHANDRASHEKHAR " 30 PEDIATRICS 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 516179 NCI 423876 92303 Immune checkpoint inhibitor therapy (ICT) unleashes the immune system resulting in durable remissions in upto 50% of patients with previously incurable cancers such as metastatic melanoma. But the host factors thatmodulate or dictate ICT response are poorly understood. Recent preclinical data suggests that specific gutmicrobiota are required for optimizing response to ICT. These commensal gut microbiota augment hostadaptive immune responses specifically host immune cells needed for anti-cancer activity. We recentlyshowed that adult melanoma patients who respond to ICT have a distinct gut microbiota signature compared topatients with progressive disease. In preliminary data we demonstrated that precision probiotic therapy (usingthe specific bacteria that we identified in our clinical/translational study) augmented the efficacy of ICT in micewith melanoma whereas a probiotic commonly found in yogurt did not. Microbiota dictated a reduction in PD-1expressing CD4 and CD8 T cells in mesenteric lymph nodes (MLNs) following ICT. Of note these specific gutmicrobiota had a greater number of protein sequences homologous to human melanoma neoantigens whencompared to the ineffective yogurt probiotic. Further these gut microbiota induced CD4 and CD8 T cellproduction of IFN-gamma and Granzyme B. Interestingly mice without draining lymph nodes in the gut did notrespond to ICT. ICT promoted gut microbiota translocation into MLNs. Finally oral administration of heat-killedgut microbiota did not augment ICT efficacy suggesting that live bacteria are required for augmenting ICT.Therefore our central hypothesis is that only gut microbiota that have both high immunogenic potential and theability to translocate into the abdominal draining lymph nodes will facilitate activation/education of immune cellsand thus augment ICT efficacy. To test this hypothesis we will pursue the following three specific aims. Firstwe will further define both gut microbiome and tumor genetic differences in melanoma patients who respond toICT compared to those with disease progression. Second we will identify environmental and microbial factorsthat dictate gut microbiota translocation into mesenteric lymph nodes. Third we will elucidate the mechanismsby which gut microbiota modulate host immune cell anti-tumor response by performing in vitro functionalimmune cell assays to determine if and how specific gut microbiota prime immune cells and in vivo studies toidentify the specific immune cells recruited by gut microbiota. These studies will lay the groundwork for thefollowing innovations: 1) a novel mechanism by which gut microbiota activate immune defenses against cancerand 2) a novel approach (precision probiotics) for optimizing ICT efficacy in advanced cancer patients. 516179 +No NIH Category available 3-Dimensional;Abbreviations;Adipose tissue;Anisotropy;Anterior;Anxiety;Benign;Biopsy;Breast;Breast Cancer Detection;Callback;Cancerous;Caring;Cephalic;Chest wall structure;Clinical;Clinical Data;Clinical Trials;Cone;Data;Dedications;Diagnosis;Diagnostic Imaging;Digital Breast Tomosynthesis;Electromagnetic Energy;Entropy;Generations;Grant;Health Care Costs;High Risk Woman;Human;Image;Image Analysis;Imaging technology;Laplacian;Laws;Left;Localized Lesion;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Mammographic screening;Mastectomy;Measures;Medical;Memory;Methods;Modeling;Morphologic artifacts;Motion;Noise;Participant;Performance;Pilot Projects;Probability;ROC Curve;Radiation Dose Unit;Radiation exposure;Randomized;Reader;Reading;Receiver Operating Characteristics;Research;Resolution;Scanning;Schedule;Shapes;Side;Signal Transduction;Specificity;Specimen;Stress;Structure;System;Systems Development;Texture;Three-dimensional analysis;Time;Tissues;Translations;Woman;X-Ray Computed Tomography;breast density;breast imaging;calcification;density;design;experience;follow-up;human subject;improved;infancy;next generation;radiologist;reconstruction;recruit;response;screening;tomosynthesis;trend;tumor;ultra high resolution;volunteer Next-Generation Tomosynthesis Pilot Study PROJECT NARRATIVEAlthough clinical tomosynthesis systems for breast cancer screening are designed to scan in only one direction(left-to-right) we have built a next-generation tomosynthesis system which can also scan in the posteroanterioror perpendicular direction. The aim of this grant is to perform a pilot study of this new imaging technology withvolunteers using radiologists' interpretations of the images in combination with clinical follow-up data todetermine if the new scanning method would facilitate a lower call-back rate without reducing sensitivity. We willalso perform quantitative analyses of the segmented breast volume to demonstrate that there is suppression ofcone-beam artifacts and will calculate density and texture measures as surrogate metrics of detectability andtissue superposition effects which we expect to be improved by the new scanning method. NCI 10685548 9/1/23 0:00 PA-20-185 5R37CA273959-02 5 R37 CA 273959 2 "MAZURCHUK, RICHARD V" 8/17/22 0:00 6/30/26 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 15224484 "ACCIAVATTI, RAYMOND JOSEPH" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 364284 NCI 224175 140109 PROJECT SUMMARYEven with the latest digital breast tomosynthesis (DBT) systems breast cancer screening continues to sufferfrom poor specificity. Only about 5% of women called-back from screening are ultimately found to have a biopsy-proven cancer. Clinical DBT systems suffer from anisotropies in image quality since the scanning motion isrestricted to one direction (left-to-right). We built a next-generation tomosynthesis (NGT) system that is capableof scanning in the shape of a T. With phantoms and mastectomy specimens we have shown that this designmitigates cone-beam artifacts tissue superposition effects and anisotropies in super-resolution. As the next stepin our research we will perform a pilot study with volunteers recruiting women referred for diagnostic imagingor biopsy as well as women having abbreviated magnetic resonance imaging (MRI). Projection images will beacquired in such a way that we can generate reconstructions from two scanning methods (conventional and T).Each scanning method will be analyzed separately by radiologists in different reading sessions. We will mitigatepotential concerns about radiation exposure by restricting the study to one view (cranial-caudal) instead of twoviews. We have put together a team with a unique set of strengths including the developers of the NGT systemthree radiologists two statisticians and experts in density and texture analysis. This proposal is divided into twospecific aims. (Aim 1): Assess radiologists' performance in a pilot study of the NGT system with volunteers. Wewill investigate whether the T scan brings down the call-back rate of screening without reducing sensitivity.Radiologists will also rate the overall probability of malignancy and these scores will be analyzed in combinationwith clinical follow-up data to show that radiologists' ability to characterize findings is improved with the T scanspecifically by using jackknife alternative free-response receiver operating characteristic (JAFROC) methods.(Aim 2): Perform quantitative analysis of the 3D breast outline segmentation texture and density. With breastphantoms we have previously shown that the breast volume is overestimated in the conventional scan and iscalculated more accurately in the T scan. We aim to show that the same result holds in human subjects bycalculating volume differences between the two scanning methods. Additionally we will analyze power-law noiseand higher-order non-Gaussian texture measures as surrogate metrics of detectability and tissue superpositioneffects which we expect to be improved by the T scan. Finally we will analyze whether percent densitycalculations differ between the two scanning methods since we expect fewer out-of-plane artifacts in the T scan.Although the new method of scanning is not being used as part of the volunteers' medical care the overall impactof this study is to demonstrate improvements in specificity and thus the potential to minimize the number ofdiagnostic imaging exams and biopsies lower healthcare costs and minimize the total radiation dose combiningscreening and diagnostic imaging. Women with dense breasts will especially benefit from this new design sincedense tissue can obscure findings in a conventional DBT scan making them harder to characterize. 364284 +No NIH Category available Affect;Antibiotics;Antibodies;Antibody Response;Asian population;Atrophic;Atrophic Gastritis;Bacteria;Biological;Biological Assay;Biological Markers;Bismuth;Black Populations;Body mass index;Cancer Etiology;Cells;Characteristics;Chronic stress;Clinical Trials;Cohort Studies;Communities;Country;Crowding;Data;Development;Diagnosis;Diagnostic;Diet;Disease;Disparity;Far East;Funding;Future;Genes;Goals;Helicobacter Infections;Helicobacter pylori;Helicobacter pylori induced gastric cancer;Hepatitis B Virus;Hepatitis C virus;Hispanic Populations;Household;Human Papillomavirus;Immune response;Incidence;Individual;Infection;Infectious Agent;Inflammation;Knowledge;Laboratory Study;Lesion;Malignant Neoplasms;Mass Screening;Mediating;Minority Groups;Modeling;Neighborhoods;Nested Case-Control Study;Not Hispanic or Latino;Patients;Pattern;Pepsinogens;Persons;Population Heterogeneity;Prevalence;Prevention Guidelines;Prospective cohort;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Proteins;Proton Pump Inhibitors;Race;Risk;Risk Factors;Role;Screening for Gastric Cancer;Smoking;Smoking Status;Societies;Specimen;Stomach;Survival Rate;Time;United States;Virulence Factors;Women's Health;biomarker validation;black men;cancer diagnosis;cancer risk;carcinogenicity;cohort;cost effective;ethnic minority;falls;gastric cancer prevention;high risk;improved;individualized prevention;malignant stomach neoplasm;men;mortality;mortality disparity;multi-ethnic;novel;outcome disparities;people of color;predictive tools;premalignant;racial difference;racial disparity;racial minority;residential segregation;risk prediction;screening guidelines;social health determinants Delineating the underlying reasons for the racial disparity in gastric cancer incidence in the United States PROJECT NARRATIVEGastric cancer is significantly more common among Black Asian and Hispanic individuals than among whites inthe US and moreover individuals who self-identify as belonging to any one of these three minority groups are alsomore likely to die from this highly fatal cancer which is generally asymptomatic until late stage when treatmentis no longer effective. Most gastric cancers are caused by infection with the bacteria Helicobacter pylori (H. pylori)which is also more common among people of color than among whites but even among all H. pylori-infectedindividuals people of color are still more likely to develop and die from gastric cancer. This project seeks tounderstand the underlying reasons for the racial disparities to enable identification of key predictors to allow usto identify those at highest risk for gastric cancer among whom H. pylori eradication and gastric cancer preventionare a high priority. NCI 10685530 8/28/23 0:00 PA-20-185 5R01CA267842-02 5 R01 CA 267842 2 "LAM, TRAM K" 9/1/22 0:00 8/31/27 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 10222844 "EPPLEIN, MEIRA " Not Applicable 4 PUBLIC HEALTH & PREV MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 627947 NCI 462163 165784 ABSTRACTThe burden of gastric cancer falls disproportionately on racial/ethnic minorities in the US with incidence rates amongBlacks Asians and Hispanics two- to three-fold higher than that among non-Hispanic whites. Further individuals who self-identify as belonging to any of these three groups are also more likely to die from gastric cancer and comparing Blackmen to White men specifically this mortality disparity is greater than that for all other cancers. In the US gastric cancerhas a particularly low survival rate (32% at 5-years) as it is generally asymptomatic until late-stage when treatment is nolonger effective. Each year in the US 26000 people are diagnosed with gastric cancer and over 10000 people die of thedisease. Moreover the racial disparity in gastric cancer continues to grow over time. And yet the underlying reasons forthis racial disparity in gastric cancer incidence in the US are substantially understudied. The predominant cause of gastriccancer is infection with the common bacterium Helicobacter pylori (H. pylori). H. pylori is more prevalent among peopleof color than non-Hispanic whites and in fact H. pylori is the worlds single leading carcinogenic infectious agentresponsible for an estimated 36.9% of the over 2.2 million infection-associated cancers diagnosed in 2018 more eventhan those attributed to human papillomavirus (31.5%) or the Hepatitis B and C viruses combined (23.5%). Currentlyhowever little is known about whether the disparity in gastric cancer is a result of differences in H. pylori prevalence hostresponse to H. pylori or differences in other risk factors that might affect the development of gastric cancer. Thesepotential other risk factors include key individual and neighborhood characteristics that differ greatly by race such ashousehold crowding and residential segregation which could increase the risk of H. pylori infection contribute to chronicstress and induce a more severe immune response. Our goal is to fill the gap in knowledge of risk factors for H. pylori-associated gastric cancer to provide the understanding of the underlying factors that indicate who is at high risk of gastriccancer in the US. To do this we will build a nested case-control study of approximately 800 non-cardia gastric cancer casesand 2:1 matched controls utilizing prospective cohort data from a diverse population in the US (67% non-white) from 4NCI-funded cohorts with pre-diagnostic specimens available: Multiethnic Cohort Study (MEC); Prostate Lung Colorectaland Ovarian Cancer Screening Trial (PLCO); Southern Community Cohort Study (SCCS); and Womens Health Initiative(WHI). We will assay these biospecimens for antibody levels to H. pylori-specific proteins and for pepsinogen (a validatedmarker of gastric atrophy) thoroughly assess individual and neighborhood factors that are associated with gastric cancerrisk and determine what drives the differences in race by H. pylori antibody levels and atrophy and resulting gastric cancerrisk. Finally we will develop an integrated cells to society modeling framework to assess the impact of socialdeterminants of health on the patterns of H. pylori antibody levels gastric atrophy and resulting disparities in gastriccancer. Ultimately these findings will provide the information needed to allow for targeting of high-risk patients for theclinical trials necessary to create screening guidelines for the prevention and early detection of gastric cancer in the USand will help clinicians with precision prevention by laying the groundwork for the building of a risk prediction tool. 627947 +No NIH Category available Acceleration;Address;Age;Aging;Area;Behavioral Sciences;Biological;Biometry;Blood;Cancer Control;Cardiology;Cardiovascular system;Caregivers;Caring;Chemotherapy and/or radiation;Clinical Research;Collaborations;Collection;Communities;Community Clinical Oncology Program;Comprehensive Cancer Center;Country;Data;Development;Disparity;Dissemination and Implementation;Early treatment;Enrollment;Faculty;Family;Funding;Future;Goals;Health Sciences;Health Services Research;Image;Individual;Infrastructure;Interdisciplinary Study;Intervention;Investigation;Late Effects;Liquid substance;Malignant Neoplasms;Mentors;Minority;NCI Center for Cancer Research;NCI-Designated Cancer Center;Neurocognitive;Neurosciences;Oncology;Outcome;Participant;Patients;Personal Satisfaction;Postdoctoral Fellow;Prevention;Primary Care;Process;Protocols documentation;Public Health;Radiation therapy;Research;Research Activity;Research Design;Research Personnel;Resources;Salivary;Sampling;Science;Site;Specimen;Students;Supportive care;Symptoms;Toxic effect;Training;Treatment Efficacy;Treatment outcome;Underserved Population;Urine;Woman;base;biobank;cancer care;cancer complication;cancer health disparity;cancer site;cancer therapy;care delivery;care systems;chemotherapy;clinical investigation;early-career faculty;ethnic minority;ethnic minority population;evidence base;forest;health disparity;improved;innovation;knowledge translation;medical schools;multidisciplinary;next generation;novel;patient oriented;patient population;protocol development;racial minority;recruit;research study;rural dwellers;survivorship;underserved community;underserved minority Wake Forest NCORP Research Base The Wake Forest NCORP Research Base develops and implements multi-site Cancer Control and Cancer CareDelivery (CCDR) clinical research studies in partnership with NCORP Community and Minority/UnderservedCommunity Sites to improve patient well-being and the quality of cancer care. NCI 10685528 7/21/23 0:00 RFA-CA-18-015 5UG1CA189824-10 5 UG1 CA 189824 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-GRB-S(M1) 1880766 "LESSER, GLENN J" "WEAVER, KATHRYN ELIZABETH" 5 INTERNAL MEDICINE/MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 3738633 NCI 3827259 1987382 The overarching goal of the Wake Forest NCORP Cancer Center Research Base (WF NCORP RB) is to improvepatient well-being and the quality of cancer care by developing implementing and successfully completinginnovative and feasible Cancer Control and Cancer Care Delivery (CCDR) clinical research studies. For nearlytwo decades as a CCOP and now NCORP Research Base Wake Forest has maintained an exclusive focus onCancer Control and CCDR studies and has emphasized efficient operational processes and extensiveinteractions with our NCORP Community Site and Minority Underserved Community Site partners. During thefirst 4 years of the NCORP network the WF NCORP RB: opened 7 Cancer Control and 3 CCDR studies; enrolled1140 participants on WF NCORP RB studies; obtained approval for 5 additional concepts and protocols bringingthe total remaining and planned accrual for active and pending trials to over 4420 participants; and achieved a33% accrual rate of racial/ethnic minority participants as well as 68% women 14% rural residents and 26% age65 or greater. Over the next 6 years we will build on and strengthen this highly successful platform byaccomplishing the following Specific Aims: Specific Aim 1: Extend our cancer control clinical research activitiesin the following areas: cardiovascular complications of cancer therapy; radiation and chemotherapy-inducedneurocognitive toxicities; and additional cancer and treatment-related symptoms and related-outcomesprioritized by NCI steering committees and those commonly associated with novel emerging treatmentparadigms. Specific Aim 2: Elucidate and intervene upon patient family clinician and organizational factorsthat influence cancer care delivery emphasizing survivorship care informal cancer caregivers andimplementation of evidence-based supportive care services. Specific Aim 3: Illuminate biological mechanismsunderlying cancer and treatment-related symptoms and toxicities in new and innovative multidisciplinarycollaborative studies taking advantage of our growing biobank of blood urine and salivary fluid specimens.Specific Aim 4: Identify and address determinants of cancer disparities via disparities-focused studiesintegrated aims focused on underserved populations and targeted recruitment of racial and ethnic minority andunderserved populations across all Wake Forest NCORP research investigations. Specific Aim 5: Train thenext generation of Cancer Control and CCDR researchers through mentoring and involvement of early careerfaculty oncology trainees post-doctoral fellows and students in WF NCORP activities. Our ongoing andproposed Cancer Control and CCDR studies will continue to improve oncology care by informing best practicesfor symptom and late effect management as well as efficient patient-centered evidence-based cancer caredelivery for diverse patient populations. In the next funding period the WF NCORP RB will help accelerate thetranslation of knowledge in cancer control and cancer care delivery through close partnership with communityand minority underserved sites and studies designed for future dissemination and implementation. 3738633 +No NIH Category available ATAC-seq;Address;Adenocarcinoma;Alleles;Automobile Driving;CRISPR/Cas technology;Cancer Etiology;Cancerous;Cell Lineage;Cells;Cellular Structures;Cessation of life;Chief Cell;Chronic;Clonal Evolution;Derivation procedure;Dysplasia;Epigenetic Process;Evolution;Gastric Adenocarcinoma;Gastric Intraepithelial Neoplasia;Gastric Parietal Cells;Gene Activation;Gene Mutation;Genes;Genetic;Genetic Transcription;Goals;Heterogeneity;Human;In Vitro;Inflammation;Injury;Intestinal Intraepithelial Neoplasia;Intestinal Metaplasia;Lesion;Malignant Neoplasms;Metaplasia;Modeling;Molecular;Mucous Membrane;Mus;Mutation;Neoplastic Processes;Oncogenes;Oncogenic;Organoids;Pathway interactions;Patients;Phase;Population;Process;Production;Property;Recovery;Reporter;Role;Sampling;Signal Pathway;Source;Stomach;Therapeutic Intervention;Time;Transgenic Mice;cancer cell;cancer stem cell;carcinogenicity;cell type;epigenome;gastric cancer prevention;gastric carcinogenesis;gastric corpus;high risk;in vivo;malignant stomach neoplasm;mouse model;neoplastic;novel;precursor cell;premalignant;programs;promoter;response;response to injury;single-cell RNA sequencing;spasmolytic polypeptide;stem cells;transcriptome;transdifferentiation;tumor progression Cell plasticity in the origin of gastric carcinogenesis NARRATIVEGastric cancer develops within a carcinogenic cascade from pre-cancerous metaplasia to dysplasia andadenocarcinoma. While the pre-cancerous metaplasia is possibly reversible a key cell population which isresponsible for mucosal recovery or neoplastic progression is to be defined. In this study we will definemechanisms that control the cell lineage conversion of reparative SPEM cells which are a major cellcomponent of dysplasia towards incomplete IM and more cancerous cell lineages. NCI 10685511 8/23/23 0:00 RFA-CA-21-026 5R01CA272687-02 5 R01 CA 272687 2 "YASSIN, RIHAB R" 9/1/22 0:00 8/31/27 0:00 ZCA1-RPRB-6(M)2 11760284 "CHOI, EUNYOUNG " "GOLDENRING, JAMES RICHARD" 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1013248 NCI 588000 425248 ABSTRACTGastric cancer is the 4th leading cause of cancer-related death worldwide and it most commonly developswithin a carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma. Metaplasiasfirst arise as a response to injury through the chief cell transdifferentiation into spasmolytic polypeptide-expressing metaplasia (SPEM) cells. While this initial process is possibly reversible oncogenic geneactivation or chronic inflammation can activate SPEM cell plasticity which promotes SPEM cell progression tointestinal metaplasia (IM) and dysplasia. This neoplastic process may also lead to transcriptional andepigenetic changes and incite cell lineage conversion where multiple intermediate cell types are producedthat can evolve into cancerous cells including dysplastic stem cells which may arise during the neoplastictransition. Furthermore the oncogenic gene mutation burden may be associated with the cell lineageconversion and diversification of the dysplastic stem cells to cancerous cells. However it is not clear whetherthe SPEM cell plasticity is responsible for the cell heterogeneity and evolution of pre-cancerous metaplasia toincomplete IM which carries a higher risk of patient progression to dysplasia and what mechanisms areinvolved in the carcinogenic process. We therefore hypothesize that SPEM cells are key gastric cancerprecursor cells which display functional properties and cell lineage conversion capacity to drive metaplasiaprogression to dysplasia. Our overarching goal is to define mechanisms that control the cell lineageconversion of reparative SPEM cells towards incomplete IM and more cancerous cell lineages which display ahigher mutational burden. To address these questions directly we have established novel in vivo transgenicmouse models and in vitro metaplastic or dysplastic organoid models derived from transgenic mouse stomachsfollowing induction of active Kras or from human patient samples with metaplasia or dysplasia. Using thesenovel models we will assess critical SPEM cell lineage derivation and define cell populations that account forthe key transcriptional and epigenetic changes arising during metaplasia progression. We will pursue threespecific aims: First we will assess functional properties of SPEM cells during mucosal recovery or neoplasticprogression following mucosal injury. Second we will examine regulatory mechanisms of cell lineagediversification and conversion during metaplasia progression. Third we will investigate molecular mechanismsdriving cell linage diversification and clonal evolution of dysplastic stem cells to adenocarcinoma. Our studieswill define critical transition points which lead to neoplastic transitions for SPEM cells as the origin of gastriccarcinogenesis. An understanding of regulatory mechanisms in cell plasticity and the ability to reverse suchtransitions could lead to therapeutic interventions to prevent gastric cancer. 1013248 +No NIH Category available Age;Awareness;BRCA mutations;Breast Cancer Patient;Cancer-Predisposing Gene;Case Study;Cessation of life;Characteristics;Classification;Clinical;Collection;Communication;DNA;Data;Data Set;Decision Making;Development;Devices;Disease;Evaluation;Excision;Exclusion;Exposure to;Future;General Population;Germ-Line Mutation;Global Awareness;Grant;Hereditary Malignant Neoplasm;High Prevalence;High Risk Woman;Implant;Incidence;Infiltration;Internal Breast Prosthesis;Journals;Ki-1 Large-Cell Lymphoma;Length;Liquid substance;Literature;Lymphoma;Lymphomagenesis;Malignant Neoplasms;Malignant lymphoid neoplasm;Malignant neoplasm of ovary;Mammaplasty;Manufacturer;Marketing;Mastectomy;Memorial Sloan-Kettering Cancer Center;Methods;Mutation;Nature;Netherlands;Operative Surgical Procedures;Patients;Persons;Physicians;Plastic Surgical Procedures;Population;Predisposition;Prevalence;Procedures;Prospective cohort;Publishing;Radiation therapy;Reconstructive Surgical Procedures;Records;Relative Risks;Reporting;Rest;Risk;Risk Assessment;Risk Estimate;Risk Factors;Role;Sales;Saline;Silicones;Surface;Surgeon;T-Cell Lymphoma;Testing;Texture;Tissues;United States Food and Drug Administration;Update;Woman;World Health Organization;breast surgery;capsule;chemotherapy;cohort;comparison group;epidemiology study;follow-up;high risk;improved;insight;lymph nodes;malignant breast neoplasm;mutational status;reconstruction;risk prediction;targeted sequencing;tumor Impact of germline mutations on the development of breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) in women with textured breast implants Project NarrativeCurrently risk factors for breast-implant associated anaplastic large cell lymphoma (BIAALCL) among womenwith textured breast implants are not known as well as the potential role of germline mutations includingBRCA and other hereditary cancer susceptibility genes. Using our unique datasets we will address thisquestion in a cohort of women with textured implants followed long term where BIAALCL cases have beenidentified and in a cohort where germline mutational status of cancer susceptibility genes is known. Theseresults will help inform decision making for women with implants in place as well as women considering breastreconstruction with implants after mastectomy for breast cancer. NCI 10685505 9/8/23 0:00 PAR-20-052 5R03CA267435-02 5 R03 CA 267435 2 "GALLICCHIO, LISA M" 8/17/22 0:00 7/31/24 0:00 ZCA1-SRB-F(M1) 16614917 "GHIONE, PAOLA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 88500 NCI 50000 38500 Breast implant-associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma thatarises as a fluid collection or mass near textured breast implants. The lymphoma is usually confined to the fluidsurrounding the implants or to the capsule a fibrous tissue around the implants but in 10-20% of the cases itcan spread to lymph nodes or present as an infiltrating mass. BIA-ALCL is treated successfully with implantremoval and capsulectomy in most patients but ~20% require chemotherapy and/or radiotherapy.Since the first description of BIA-ALCL in 1997 733 total unique cases have been reported with 36 patientdeaths leading to warning communications from the FDA in 2011 and 2016 and ultimately to the recall fromthe market of textured implants produced by one of the most popular manufacturers in 2019. Global awarenessof this disease was thus increased leading to improved identification and reporting of cases as well as to anurgent need for risk prediction for women with implants in place currently estimated to be 10s of millionsworldwide. Although some women choose to remove the implants the risk of getting BIA-ALCL from exposureto textured implants is low and could be related to specific variables that remain largely unknown. Ourcollaborative group through Memorial Sloan Kettering Cancer Center (MSKCC) has reported the incidence ofBIA-ALCL in a cohort of more than 3500 women with textured breast implants followed long term after surgeryfor breast cancer (BC). In this cohort the Cordeiro Cohort unique in its nature 11 patients developed BIA-ALCL after an exposure of 7-10 years. This is the highest incidence described so far in the literature howeverno particular variable (related to the type of BC exposure to chemo or radiation therapy filling of the implantswith saline or silicone) was related to higher risk of lymphoma. Our collaborators from the Netherlands CancerInstitute have recently reported preliminary data suggesting BRCA mutations might be more frequent in BIA-ALCL cases than in the rest of the population. Within our cohort of 3500 women with implants followed longterm many patients were tested for BRCA mutations and/or were included in the MSK-IMPACT study a broadtumor targeted sequencing effort that included the analysis of normal DNA to filter out germline mutations fromthe tumor results. This unusual and absolutely unique combination of studies conducted on this population mayallow us to determine if BRCA and other germline mutations are related to lymphomagenesis in people withbreast implants and the relative risk of women with germline mutations to develop BIA-ALCL. This in turn willinform decision making for women with implants and their physicians on procedures such as textured implantremoval and reconstruction after mastectomy for women at higher risk of lymphoma. The identification ofgermline mutations that might be related to lymphomagenesis will lead to future grant submissions andevaluations of these mechanisms in other lymphoma subtypes thus representing a milestone in our approachto the disease. 88500 +No NIH Category available Ablation;Acceleration;Address;Adrenergic Receptor;Animal Model;Antineoplastic Agents;Automobile Driving;Back;Bile Acid Biosynthesis Pathway;Bile Acids;Biological Markers;CREB1 gene;Cancer Etiology;Cessation of life;ChIP-seq;Cholestasis;Chronic;Chronotherapy;Circadian Dysregulation;Cirrhosis;Clinical Data;Clinical Research;Coupled;Disease Progression;EP300 gene;Early Diagnosis;Enhancers;Epidemic;Etiology;Failure;Fatty acid glycerol esters;Fibrosis;Functional disorder;Genes;Hawaii;Hepatic;Hepatitis C;Hepatitis C virus;Hepatocarcinogenesis;Homeostasis;Hour;Human;Immunosuppression;Impairment;Incidence;Individual;Intrahepatic Cholestasis;Jet Lag Syndrome;Knowledge;Lead;Length;Light;Link;Liver;Malignant Neoplasms;Mediating;Mediator;Metabolic;Metabolic Control;Metabolic dysfunction;Metabolic syndrome;Molecular;Mus;Nuclear Receptors;Obesity;Obesity Epidemic;Oncogene Deregulation;Oncogenic;Organ;Pathologic;Pathology;Pathway interactions;Periodicity;Phase;Population;Prevalence;Prevention;Prevention approach;Primary carcinoma of the liver cells;Propranolol;Publishing;Resistance;Risk;Risk Factors;Role;Schedule;Security;Serum;Signal Transduction;Societies;Somatic Mutation;Sympathetic Nervous System;Testing;Therapeutic;Therapeutic Index;Toxic effect;Tumor Promotion;Wild Type Mouse;anti-cancer;anti-cancer therapeutic;cancer prevention;cancer therapy;circadian;clinically relevant;design;direct application;gene network;genetic signature;liver injury;liver metabolism;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;premalignant;prevent;receptor;shift work;transcriptome sequencing;tumor initiation;tumor progression;tumorigenesis Sympathetic circadian dysfunction in obesity-related hepatocarcinogenesis Project NarrativeThis project addresses the fundamental mechanisms connecting circadian dysfunction to hepatocarcinogenesis.It will characterize the role of circadian dysfunction of the sympathetic nervous system (SNS) in non-alcoholicfatty liver disease (NAFLD) induced spontaneous hepatocellular carcinoma (HCC) and test the predicted abilityof -blocker propranolol to suppress circadian disruption induced liver pathologies and HCC. The resultsgenerated from these studies will have outstanding potential for near-term therapeutic options in HCC preventionand treatment in humans. NCI 10685480 9/1/23 0:00 RFA-CA-18-019 5R01CA238988-05 5 R01 CA 238988 5 "GREEN, PAIGE A" 9/1/19 0:00 8/31/24 0:00 ZCA1-RTRB-U(J1)R 7777082 "FU, LONING NONE" "MOORE, DAVID D" 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 424987 NCI 284691 140296 Project Summary This RO1 application directly addresses NCI PQ6 by investigating the role of circadian dysfunction of thesympathetic nervous system (SNS) in hepatocarcinogenesis. Retrospective clinical studies strongly suggest thatsympathetic dysfunction is a key etiologic factor in human cancers and that -blockers are potential anticanceragents. However the role of sympathetic dysfunction in tumorigenesis and the mechanisms of -blocker-directedanticancer effects are significant knowledge gaps. We will define the molecular basis for the impact of circadiandysregulation of the sympathetic nervous system (SNS) on spontaneous hepatocarcinogenesis and test theability of -blockers to prevent non-alcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma(HCC). The incidence of HCC has increased >3-fold since the 1980s and it is currently the fastest rising cause ofcancer-related death in the U.S. The increase in HCC incidence is coupled with the prevalence of obesityobesity-related NAFLD and chronic circadian disruption. NAFLD is now emerging as the leading driver of HCCin the 21st century. However no efficient approaches for prevention early diagnosis and treatment of NAFLD-induced HCC are available. We discovered that chronic circadian dysfunction induces obesity-related metabolicsyndrome NAFLD and HCC in normal chow fed wild-type mice following a pathophysiological pathway strikinglysimilar to that observed in obese humans. We identified intrahepatic cholestasis as the key proximalpathophysiological mechanism that stimulates the progression from NAFLD to nonalcoholic steatohepatitis(NASH) fibrosis and eventually hepatocarcinogenesis. We demonstrated that circadian dysfunction of -adrenergic receptor (ADR)-mediated sympathetic signaling is an essential molecular mechanism that drivesnuclear receptor dysfunction cholestasis and oncogenic activation to promote HCC. We propose 3 broad aims to study the role of sympathetic dysfunction in hepatocarcinogenesis: 1)Characterize hepatic gene deregulation signatures associated with ADR-mediated SNS circadian dysfunctionby ChIPseq and RNAseq. 2) Define ADR circadian dysfunction induced serum and hepatic bile acid profilesliver pathologies HCC risk and the premalignant gene signature driving HCC initiation. 3) Define the role of -blocker propranolol in prevention of circadian dysfunction-induced NAFLD-associated HCC.Our studies will not only define the role of sympathetic circadian dysfunction in NFALD-induced oncogenicactivation and hepatocarcinogenesis but also provide an unprecedented opportunity to design -blocker-directed personalized and complementary strategies for anti-HCC chronotherapy. 424987 +No NIH Category available Address;Adolescent;Age;Attitude;Behavior;Behavioral Model;Brain;California;Cluster randomized trial;Communities;Data;Dissemination and Implementation;Education;Educational Curriculum;Effectiveness;Electronic cigarette;Ethnic Origin;Evaluation;Exposure to;Happiness;Health;Health education;Heart;High School Student;Interview;Knowledge;Link;Lung;Marijuana;Marketing;Mental Depression;Mental Health;Middle School Student;Modeling;Nicotine Dependence;Outcome;Participant;Persons;Planning Theory;Prevention;Prevention program;Property;Race;Randomized;Reporting;Research;Resistance;Resources;Schools;Socioeconomic Status;Students;Surveys;Testing;Tobacco;Tobacco use;United States;United States National Institutes of Health;Youth;acceptability and feasibility;addiction liability;adolescent health;aged;cigarette smoking;combustible cigarette;community based participatory research;design;efficacy testing;electronic cigarette use;follow-up;future implementation;high school;improved;interest;intervention effect;novel;optimism;peer;physical conditioning;pilot test;positive youth development;prevent;programs;random forest;skills;social media;stress reduction;teacher;theories;therapy development;tobacco prevention;tool;treatment arm;treatment effect;vaping Evaluation of the Be Vape Free Curriculum of the Tobacco Prevention Toolkit Use of e-cigarettes has dramatically increased among adolescents; however few prevention programsfocusing on prevention and escalation of e-cigarettes have been developed tested or widely disseminatedthroughout the U.S. We have developed a novel Be Vape-Free school-based curriculum aimed at changinghigh school students attitudes towards misperceptions about intentions to use and actual use of e-cigaretteswhich will be evaluated for changes in adolescents knowledge attitudes intentions and actual use. NCI 10685468 9/7/23 0:00 RFA-DA-21-009 5R01CA263121-03 5 R01 CA 263121 3 "MAYNE, RACHEL G" 9/2/21 0:00 8/31/26 0:00 ZDA1-YXF-U(05)R 6777674 "HALPERN-FELSHER, BONNIE L" Not Applicable 16 PEDIATRICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 752699 NCI 478208 274491 Electronic cigarettes (e-cigarettes e-cigs vapes ENDS) are the most widely used tobacco product amongadolescents aged 12-18. Despite clear connections between e-cigarette use nicotine addiction and physicaland mental health outcomes adolescents continue to harbor misperceptions about e-cigarettes perpetuatedby exposure to marketing and flavors and a lack of understanding about their harms and addictive properties.While schools have historically provided a key venue in which to implement tobacco prevention programsmost school-based tobacco prevention programs focus on conventional cigarette smoking only have hadmixed results and have several gaps in their educational content on e-cigarettes. Further studies have rarelydetermined if there are specific groups for whom e-cigarette prevention and cessation programs are and arenot helping. Using a community-based participatory research approach we developed the Be Vape-FreeCurriculum a free 5-session school-based education prevention and reduction (de-escalation) program formiddle and high school students. This curriculum is part of and includes the most effective components of theTobacco Prevention Toolkit a free online comprehensive tobacco prevention program used by thousands ofschools and educators across the United States having reached more than 1.7 million middle and highschools students. Aligning with the NIH Stage Model for Behavioral Intervention Development we haveaddressed 3 of the 6 stages needed to adequately develop evaluate refine and fully implement anddisseminate our Be Vape-Free Curriculum. Thus the Specific Aims of this project are to: (1) Determinewhether the Be Vape-Free Curriculum is effective in increasing middle and high school students knowledge ofe-cigarettes and resistance to using and decreasing their positive attitudes towards and intentions to use e-cigarettes; (2) Determine whether the Be Vape-Free Curriculum is effective in changing middle and high schoolstudents actual use of e-cigarettes (including preventing initiation continuation escalation; encouragingdecreased use and cessation; and use of e-cigarettes with other tobacco and marijuana products); and (3)Examine the heterogenous treatment effects (HTE) of the intervention identifying both those who benefit themost and those who do not benefit from the curriculum. We will employ a cluster-randomized trial stepped-wedge design with 60 middle and 60 high schools in California (n=10800 students). Schools will berandomized to either the treatment (Be Vape-Free Curriculum) or delay-in-treatment arm (i.e. standard healtheducation first year and Be Vape-Free curriculum in second year) with all students followed for another 12months. The timing of this proposed research is extremely important as we have outstanding momentum haveestablished an extensive team of school and community partners and stakeholders have numerous schoolsalready interested in using the Be Vape-Free Curriculum and have garnered tremendous support from theCalifornia Department of Education and schools. 752699 +No NIH Category available Address;Affinity;Binding;Biological Assay;Biological Markers;Biological Sciences;Biology;Blood;CA-19-9 Antigen;Cancer Etiology;Cessation of life;Characteristics;Chelating Agents;Chemistry;Clinic;Clinical;Communities;Comparative Study;Coupled;Data;Desmoplastic;Detection;Development;Development Plans;Diagnostic;Disease;Drug Kinetics;Evaluation;Excision;Fibroblasts;Fibrosis;Funding;Funding Mechanisms;Futility;Gallium;Goals;Image;Imaging Techniques;Immune;Immunophenotyping;Infrastructure;Investigation;KRAS2 gene;Knowledge;Lead;Lesion;Licensing;Malignant Neoplasms;Malignant neoplasm of pancreas;Medical;Membrane;Metabolic;Methodology;Modeling;Molecular Target;Morbidity - disease rate;Neoadjuvant Therapy;Neoplasm Metastasis;Normal tissue morphology;Operative Surgical Procedures;Outcome;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Peptide Hydrolases;Physiological;Play;Positioning Attribute;Positron-Emission Tomography;Prognosis;Property;Provider;Quinolones;Radiation therapy;Radioactivity;Reader;Recurrence;Reference Standards;Regulatory Pathway;Resectable;Resources;Risk Reduction;Role;Sensitivity and Specificity;Specimen;Staging;Surgical Models;Techniques;Technology;Testing;Therapeutic;Tissue Sample;Toxic effect;Translating;Translations;Validation;cancer imaging;carcinogenesis;clinical development;clinical imaging;clinical investigation;clinical practice;clinical translation;contrast imaging;cost;detection sensitivity;expectation;fibroblast-activating factor;flexibility;fluorodeoxyglucose positron emission tomography;follow-up;imaging properties;improved;in vivo;industry partner;inhibitor;innovation;insight;instrumentation;liquid biopsy;manufacture;meetings;molecular imaging;mortality;multidisciplinary;nanomolar;neoplastic cell;novel;novel imaging technique;novel marker;novel therapeutic intervention;novel therapeutics;outcome prediction;personalized medicine;prognostic;prospective;protein expression;radiologist;radiotracer;response;targeted imaging;theranostics;therapy resistant;tool;translational barrier;tumor;tumor DNA;tumor growth;tumor microenvironment;uptake Quantitative In Vivo 68Ga-Fibroblast-Activation-Protein-Inhibitors (FAPI)-46 PET Imaging of Cancer-Associated Fibroblasts (CAFs) in Pancreatic Ductal Adenocarcinoma (PDA) PROJECT NARRATIVEPancreatic cancer is a lethal disease. There is an urgent need to develop precision tools for improved stagingand development of personalized therapy approaches. The goal of our academic-industrial partnership (AIP) -Mayo Clinic and Sofie Biosciences - is to execute a coherent strategy for the potential FDA approval andclinical translation of a novel imaging technique 68Ga-FAP-inhibitor (FAPI)-46 PET which can address theunmet clinical needs in pancreatic cancer as well as improve our understanding of the biology of the disease. NCI 10685439 8/15/23 0:00 PAR-20-155 5R01CA272628-02 5 R01 CA 272628 2 "TANDON, PUSHPA" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 14811339 "GOENKA, AJIT HARISHKUMAR" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 592291 NCI 408796 183495 PROJECT SUMMARYPancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the USA and isanticipated to become the second leading cause by 2030. Its characteristic desmoplastic stroma constituting6070% of its volume is one of the critical factors that contributes to the dismal outcomes. Fibroblast activationprotein (FAP)-expressing Cancer-Associated Fibroblasts (CAFs) are one of the most important stromalconstituents because they play a fundamental role in the carcinogenesis fibrosis tumor growth metastasesand treatment resistance. FAP expression in PDA is an independent predictor of poor outcomes. Lack ofnoninvasive tools to precisely profile CAF identity and function both temporally and spatially in vivo is a criticalbarrier for translation of existing knowledge of the tumor microenvironment to address unmet clinical needs.68Ga-FAP-inhibitor (FAPI)-46 has emerged as a PET radiotracer with optimal properties for FAP-targeted clinicalimaging and theranostics in PDA. These include low nanomolar affinity to FAP near-complete internalization ofradioactivity bound to FAP absence of physiologic uptake rapid blood clearance and prolonged tumor retentionand operational characteristics that offer tremendous flexibility to suit the clinical context PET scanner profileand workflow for patients with PDA. Traditionally long regulatory and reimbursement approval pathways coupledwith high costs of comparative studies have delayed clinical access to promising precision tools such as 68Ga-FAPI-46 PET. Thus for the clinical translation of a theranostic radiotracer such as 68Ga-FAPI-46 an academic-industrial partnership (AIP) based on complementary strengths and a coherent clinical development strategy isneeded to reduce the risk and raise the likelihood of meeting FDA standards and consumer expectations. OurAIP - Mayo Clinic and Sofie Biosciences (SOFIE) - will undertake a clinical investigation in compliance withFDA standards to form the basis of a new drug application (NDA) with the goal to deliver a new capability to endusers consistent with this FOAs intent. Our hypothesis is that 68Ga-FAPI-46 PET will be an accurate techniqueto detect and quantify CAFs and that metrics derived from 68Ga-FAPI-46 PET will be novel biomarkers in PDA.In Aim 1 using immunophenotyping as the reference standard the sensitivity and specificity of 68Ga-FAPI-46PET will be evaluated for the detection and quantification of CAFs in PDA along with inter-reader and intra-reader reliability and the dynamic changes in 68Ga-FAPI-46 PET biomarkers in response to neoadjuvanttreatment. In Aim 2 68Ga-FAPI-46 PET will be compared correlated and combined with other mechanisticallydistinct investigations to improve pre-surgical staging and to predict post-surgical outcomes. Our AIP has thepotential to deliver a noninvasive molecular imaging assay that can provide greater insight into disease biologyimpact clinical practice predict outcomes potentiate existing therapeutics and yield a pathway to noveltherapeutic approaches. Given the wide and evolving role of FAPI imaging and theranostics our AIP has thepotential to scale our impact beyond PDA to other oncologic and non-oncologic applications. 592291 +No NIH Category available Amplifiers;Bacteria;Bar Codes;Benchmarking;Biodistribution;Biological;Biological Markers;Biology;Biosensor;Blood;Blood Tests;Body Fluids;Cancer Biology;Cancer Diagnostics;Cancerous;Carcinoembryonic Antigen;Cells;Classification;Colorectal Cancer;Complex;Coupled;Cyclic Peptides;Data;Detection;Development;Diagnostic;Disease;Drug Kinetics;Early Diagnosis;Enzymes;Excision;FDA approved;Fluorogenic Substrate;Future;Gene Expression;Genes;Genetic;Genetic Engineering;Genetic Transcription;Growth;Human;Hydrolysis;Image;In Situ;Inbred BALB C Mice;Kinetics;LS174T colon cancer cell line;Liver;Logic;Longitudinal Studies;Malignant Neoplasms;Mammalian Cell;Mass Spectrum Analysis;Metastatic Neoplasm to the Liver;Modeling;Molecular;Monitor;Neoplasm Metastasis;Noise;Non-Invasive Detection;Patient-Focused Outcomes;Peptide Fragments;Peptide Hydrolases;Peptides;Performance;Play;Preclinical Testing;Production;Proteins;Recombinants;Reporter;Role;Safety;Sampling;Screening for cancer;Serum;Shapes;Signal Transduction;Site;Specificity;T cell response;T cell therapy;Testing;Thermal Ablation Therapy;Tissues;Tumor Antigens;Urine;Validation;Xenograft Model;Xenograft procedure;antigen test;candidate identification;clinically relevant;colorectal cancer screening;design;detection limit;differential expression;early detection biomarkers;engineered T cells;fluorophore;immunogenicity;improved;in vivo;iron oxide nanoparticle;mathematical model;microCT;models and simulation;mouse model;neoplastic cell;pre-clinical;preclinical evaluation;predictive modeling;radiological imaging;sensor;synthetic biology;systemic toxicity;tumor;tumor specificity;validation studies AND-gated Synthetic Biomarkers for Early Detection of Liver Metastasis PROJECT NARRATIVEAdvances in synthetic biology will play a fundamental role in shaping the future of cancer diagnostics towardearlier and more specific detection of disease. This proposal seeks to develop a new class of protease-activatable biosensors that implement Boolean AND logic for early detection of colorectal cancer liver metastasis. NCI 10685432 8/28/23 0:00 RFA-CA-20-054 5U01CA265711-03 5 U01 CA 265711 3 "SORG, BRIAN S" 9/23/21 0:00 8/31/26 0:00 ZCA1-TCRB-Q(A1) 10554748 "KWONG, GABRIEL A" "QIU, PENG " 5 ENGINEERING (ALL TYPES) 97394084 EMW9FC8J3HN4 97394084 EMW9FC8J3HN4 US 33.781897 -84.404009 676603 GEORGIA INSTITUTE OF TECHNOLOGY ATLANTA GA BIOMED ENGR/COL ENGR/ENGR STA 303320415 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 592796 NCI 266305 154991 PROJECT SUMMARYAdvances in synthetic biology will play a fundamental role in shaping the future of cancer diagnostics towardearlier and more specific detection of disease. For example whole-cell biosensors such as bacteria have beengenetically engineered to perform complex functions such as signal amplification to detect clinically relevantbiomarkers in human urine and serum. In mammalian cells sense-and-respond components that employBoolean logic have been demonstrated for multiplexed control of engineered T cell therapies thereby increasingthe specificity of tumor sensing and reducing systemic toxicity. These advances highlight the promise of syntheticbiology when applied to cancer yet the vast majority of these strategies rely on genetic circuits and make use ofnon-mammalian protein components. Such circuits are complex and raise safety and immunogenicity concernsfor regulatory approval especially in the context of in vivo early cancer detection where repeated administrationsof biosensors are likely needed to monitor for nascent disease. This proposal seeks to develop a new class ofdiagnostics called AND-gated synthetic biomarkers for early detection of cancer metastasis. Syntheticbiomarkers are an emerging class of activatable biological sensors that are designed to be administeredsystemically query sites of early disease and harness tumor-dependent activation mechanisms such asdysregulated protease activity to drive production of a reporter. These reporters can then be detectednoninvasively from blood urine or other bodily fluid samples. Proteases play key biological roles across themajor hallmarks of metastasis and are particularly potent molecular amplifiers by catalyzing the irreversiblehydrolysis of peptide bonds allowing a single protease to turnover thousands of substrates. AND-gated syntheticbiomarkers will be applied for early detection of colorectal cancer (CRC) liver metastasis. Although the liver is acommon site for metastatic spread from primary CRC regional resection of liver-isolated metastases can leadto potentially curative results. Yet early detection of CRC liver metastases at a size when they are mostresponsive to therapy (12 mm) remains challenging by radiographic imaging such as CT and FDA-approvedblood test such as the carcinoembryonic antigen (CEA) test. To design AND-gated synthetic biomarkers for CRCliver metastasis pairwise combinations of proteases will be selected based on differential RNA expression inCRC liver metastases compared to healthy liver tissue. Multivariate mathematical models will be developed tounderstand how design parameters enhance specificity and cooperativity compared to experimental results.Syngeneic and xenograft models of CRC liver metastasis will be used for preclinical validation studies to allowbenchmarking against CT and CEA. This proposal will lay the groundwork for earlier detection of cancermetastasis by programmable synthetic biomarkers. 421296 +No NIH Category available Amplifiers;Bacteria;Bar Codes;Benchmarking;Biodistribution;Biological;Biological Markers;Biology;Biosensor;Blood;Blood Tests;Body Fluids;Cancer Biology;Cancer Diagnostics;Cancerous;Carcinoembryonic Antigen;Cells;Classification;Colorectal Cancer;Complex;Coupled;Cyclic Peptides;Data;Detection;Development;Diagnostic;Disease;Drug Kinetics;Early Diagnosis;Enzymes;Excision;FDA approved;Fluorogenic Substrate;Future;Gene Expression;Genes;Genetic;Genetic Engineering;Genetic Transcription;Growth;Human;Hydrolysis;Image;In Situ;Inbred BALB C Mice;Kinetics;LS174T colon cancer cell line;Liver;Logic;Longitudinal Studies;Malignant Neoplasms;Mammalian Cell;Mass Spectrum Analysis;Metastatic Neoplasm to the Liver;Modeling;Molecular;Monitor;Neoplasm Metastasis;Noise;Non-Invasive Detection;Patient-Focused Outcomes;Peptide Fragments;Peptide Hydrolases;Peptides;Performance;Play;Preclinical Testing;Production;Proteins;Recombinants;Reporter;Role;Safety;Sampling;Screening for cancer;Serum;Shapes;Signal Transduction;Site;Specificity;T cell response;T cell therapy;Testing;Thermal Ablation Therapy;Tissues;Tumor Antigens;Urine;Validation;Xenograft Model;Xenograft procedure;antigen test;candidate identification;clinically relevant;colorectal cancer screening;design;detection limit;differential expression;early detection biomarkers;engineered T cells;fluorophore;immunogenicity;improved;in vivo;iron oxide nanoparticle;mathematical model;microCT;models and simulation;mouse model;neoplastic cell;pre-clinical;preclinical evaluation;predictive modeling;radiological imaging;sensor;synthetic biology;systemic toxicity;tumor;tumor specificity;validation studies AND-gated Synthetic Biomarkers for Early Detection of Liver Metastasis PROJECT NARRATIVEAdvances in synthetic biology will play a fundamental role in shaping the future of cancer diagnostics towardearlier and more specific detection of disease. This proposal seeks to develop a new class of protease-activatable biosensors that implement Boolean AND logic for early detection of colorectal cancer liver metastasis. NCI 10685432 8/28/23 0:00 RFA-CA-20-054 5U01CA265711-03 5 U01 CA 265711 3 "SORG, BRIAN S" 9/23/21 0:00 8/31/26 0:00 ZCA1-TCRB-Q(A1) 10554748 "KWONG, GABRIEL A" "QIU, PENG " 5 ENGINEERING (ALL TYPES) 97394084 EMW9FC8J3HN4 97394084 EMW9FC8J3HN4 US 33.781897 -84.404009 676603 GEORGIA INSTITUTE OF TECHNOLOGY ATLANTA GA BIOMED ENGR/COL ENGR/ENGR STA 303320415 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 592796 NIBIB 108408 63092 PROJECT SUMMARYAdvances in synthetic biology will play a fundamental role in shaping the future of cancer diagnostics towardearlier and more specific detection of disease. For example whole-cell biosensors such as bacteria have beengenetically engineered to perform complex functions such as signal amplification to detect clinically relevantbiomarkers in human urine and serum. In mammalian cells sense-and-respond components that employBoolean logic have been demonstrated for multiplexed control of engineered T cell therapies thereby increasingthe specificity of tumor sensing and reducing systemic toxicity. These advances highlight the promise of syntheticbiology when applied to cancer yet the vast majority of these strategies rely on genetic circuits and make use ofnon-mammalian protein components. Such circuits are complex and raise safety and immunogenicity concernsfor regulatory approval especially in the context of in vivo early cancer detection where repeated administrationsof biosensors are likely needed to monitor for nascent disease. This proposal seeks to develop a new class ofdiagnostics called AND-gated synthetic biomarkers for early detection of cancer metastasis. Syntheticbiomarkers are an emerging class of activatable biological sensors that are designed to be administeredsystemically query sites of early disease and harness tumor-dependent activation mechanisms such asdysregulated protease activity to drive production of a reporter. These reporters can then be detectednoninvasively from blood urine or other bodily fluid samples. Proteases play key biological roles across themajor hallmarks of metastasis and are particularly potent molecular amplifiers by catalyzing the irreversiblehydrolysis of peptide bonds allowing a single protease to turnover thousands of substrates. AND-gated syntheticbiomarkers will be applied for early detection of colorectal cancer (CRC) liver metastasis. Although the liver is acommon site for metastatic spread from primary CRC regional resection of liver-isolated metastases can leadto potentially curative results. Yet early detection of CRC liver metastases at a size when they are mostresponsive to therapy (12 mm) remains challenging by radiographic imaging such as CT and FDA-approvedblood test such as the carcinoembryonic antigen (CEA) test. To design AND-gated synthetic biomarkers for CRCliver metastasis pairwise combinations of proteases will be selected based on differential RNA expression inCRC liver metastases compared to healthy liver tissue. Multivariate mathematical models will be developed tounderstand how design parameters enhance specificity and cooperativity compared to experimental results.Syngeneic and xenograft models of CRC liver metastasis will be used for preclinical validation studies to allowbenchmarking against CT and CEA. This proposal will lay the groundwork for earlier detection of cancermetastasis by programmable synthetic biomarkers. 171500 +No NIH Category available Academic advising;Area;Award;Biology;Communities;Dedications;Diagnosis;Disabled Persons;Environment;Fostering;Funding;Goals;Grant;Head and Neck Cancer;Health Sciences;Hematology;Image;Institution;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Medical Oncology;Mentors;Minority Groups;Oncology;Peer Review;Physicians;Pilot Projects;Prevention;Program Development;Publishing;Quality of life;Research;Research Personnel;Scientist;Secure;Talents;Training;Translational Research;United States National Institutes of Health;Universities;anticancer research;career;career development;improved;medical schools;molecular oncology;physician-scientist training program;programs;success;translational physician;women with disabilities Career Enhancement Program PROJECT NARRATIVEThe Emory Lung Cancer SPORE Career Enhancement Program (CEP) intends to support pilot projects andthe mentoring of early career academic physician-scientists clinician-investigators and laboratory-basedscientists who wish to develop a career in translational research in the areas of diagnosis imaging preventiontreatment and improvement in quality of life in lung cancer. The proposed CEP aims to provide anenvironment that enables talented early career investigators to engage in a 2-year mentored researchprogram to facilitate their success and their academic career development in terms of achieving independentinvestigator status and to enhance diversity among the lung cancer research community. NCI 10685430 6/8/23 0:00 PAR-18-313 5P50CA217691-05 5 P50 CA 217691 5 7/10/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 5521 7797023 "MARCUS, ADAM I." Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 86069 54784 31285 PROJECT SUMMARY/ABSTRACTEmory Universitys Lung Cancer SPORE aims to promote the advancement of early career lung cancerinvestigators through the conduct of a Career Enhancement Program (CEP). The goals of the proposed LungCancer SPORE CEP are to provide training and guidance for academic physician-scientists clinician-investigators and laboratory-based scientists who wish to dedicate their efforts to translational research in theareas of diagnosis imaging prevention treatment and improvement in quality of life in lung cancer and toenhance diversity among the lung cancer research community. The SPORE CEP will build on the strongcommitment of the Emory Winship Cancer Institute and the associated School of Medicine Departments to thecareer development of junior investigators which has included 18 career development program awardees as partof Emorys previous head and neck cancer SPORE and an ongoing T32 training grant in molecular oncology.The proposed CEP aims to provide an environment that enables talented early career investigators to engage ina 2-year mentored research program and to facilitate their success and their academic career development interms of achieving independent investigator status. Specific aims for the CEP are as follows: Aim 1: To attractand mentor a talented group of early career investigators towards a career in translational lung cancer research;Aim 2: To engage biologists scientists and physicians present at Emory University and local partner researchinstitutions in the state of Georgia in translational lung cancer research; Aim 3: To enhance diversity among thelung cancer research community by encouraging minority individuals women and individuals with disabilities toapply for CEP support; and Aim 4: To foster and guide emerging strategies for the study of the biologyprevention and long term treatment of lung cancer. On average 2 projects will be funded annually. Additionalsupport for the CEP has been secured from matching funds from the Winship Cancer Institute Emory UniversitySchool of Medicine and the Woodruff Health Sciences Center. +No NIH Category available American Cancer Society;Award;Clinical Research;Collaborations;Development;Evolution;Extramural Activities;Fostering;Foundations;Funding;Future;Goals;Grant;Head and Neck Cancer;Institution;Investments;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Monitor;Nature;Outcome;Patient Care;Peer Review;Peer Review Grants;Pilot Projects;Process;Program Research Project Grants;Publications;Request for Proposals;Research;Research Personnel;Research Project Grants;Research Proposals;Series;Source;Translational Research;United States National Institutes of Health;Universities;anticancer research;career development;high reward;high risk;innovation;novel;preclinical study;programs;success;translational study Developmental Research Program PROJECT NARRATIVEThe SPORE Developmental Research Program (DRP) provides funding to support new and innovative pilotprojects in lung cancer that have the potential to expand into full research projects in the future includingthose of high risk-high reward nature. The DRP aims to foster collaborative research between Emoryinvestigators and investigators at other institutions and to enhance translational research in lung cancer byincreasing the number of meritorious investigators working on lung cancer. NCI 10685427 6/8/23 0:00 PAR-18-313 5P50CA217691-05 5 P50 CA 217691 5 7/10/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 5519 1893676 "FU, HAIAN " Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 76785 48832 27953 PROJECT SUMMARY/ABSTRACTEmory Universitys Lung Cancer SPORE aims to pursue new and innovative research opportunities in the lungcancer field through the implementation of the Developmental Research Program (DRP). The DRP will solicitevaluate and fund the most meritorious pilot projects monitor progress twice annually and promote the mostsuccessful pilot projects into full projects funded by the SPORE and/or other sources. The goals of the DRPare to identify and support meritorious proposals that might expand into full research projects focused on lungcancer in the future including those of high risk-high reward projects that might otherwise not be funded; tofoster collaborative research between Emory investigators and investigators at other institutions; and toenhance translational research in lung cancer by increasing the number of investigators working in this field.The Winship Cancer Institute (Winship) of Emory University has a strong track record in conducting successfulpilot project programs. Through the Winship Invest$ program Winship has awarded 165 pilot grants with atotal of over $7.7M in funding since 2012. Our track record is illustrated by the DRP in Emorys head and neckcancer SPORE (funded from 2006-2013) that awarded 17 pilot projects which evolved into 15 full projectsfunded by NIH or foundations such as the American Cancer Society and the publication of 34 research articlesand 4 review articles. Winship is also a recipient of the Institutional Research Grant funded by the AmericanCancer Society that supports pilot research projects. Specific aims for the DRP are as follows: Aim 1: Tosolicit research proposals by sending request for proposals (RFP) to all possible applicants at EmoryUniversity and other research and medical institutions throughout the state of Georgia; Aim 2: To identify themost outstanding and novel proposals to fund through a clearly defined and well-established review process.Led by a DRP Committee applications will be reviewed by a panel of leaders of all projects cores/programsand other researchers in relevant fields following NIH review criteria; and Aim 3: To monitor the progress offunded peer-reviewed pilot projects using a series of metrics including the evolution of projects into majorprojects (e.g. R01s full SPORE projects) publications investigator career development etc. We expect thatannually 2 novel projects in basic translational and clinical studies will be funded and completion of thesehigh-risk but innovative studies will result in strong publications additional peer-reviewed grants and thedevelopment of a larger and stronger group of investigators focusing on the translational study of lung cancer. +No NIH Category available Agonist;Animal Cancer Model;Antineoplastic Agents;Apoptosis;Apoptotic;Attenuated;Bax protein;Binding;Biological;C-terminal;Cancer Patient;Cell Death;Cells;Chemical Structure;Chemotherapy and/or radiation;Cisplatin;Development;Failure;Family member;Genetic Engineering;Homo;Human;In Vitro;Induction of Apoptosis;Ionizing radiation;KRAS2 gene;KRASG12D;Lead;Link;Lung Neoplasms;MAPK3 gene;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mitochondria;Modeling;Molecular Conformation;Mutation;Non-Small-Cell Lung Carcinoma;PDPK1 gene;PI3K/AKT;PIK3CG gene;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphorylation Site;Phosphotransferases;Physiological;Play;Prognostic Marker;Proliferating;Property;Protein Dephosphorylation;Proto-Oncogene Proteins c-akt;Radiation;Radiation therapy;Radio;Regimen;Reporting;Repression;Resistance;Role;Serine;Signal Induction;Signal Transduction;Site;T-Lymphocyte;TP53 gene;Tail;Testing;Therapeutic Intervention;Treatment outcome;Tumor Tissue;Universities;Xenograft procedure;analog;anti-cancer;cancer therapy;cell killing;checkpoint inhibition;chemoradiation;chemotherapy;draining lymph node;lung cancer cell;mTOR Inhibitor;mTOR inhibition;member;mitochondrial membrane;mutant;novel;novel strategies;patient derived xenograft model;peripheral blood;predictive marker;programmed cell death protein 1;radiation resistance;radioresistant;small molecule;stem;therapeutic target;therapy resistant;tumor Project 3: Targeting Bax signaling to overcome treatment resistance in NSCLC Our group has identified stem-like T cells that undergo proliferation after immune checkpoint inhibition. We willcharacterize these cells in lung tumors draining lymph nodes and peripheral blood and study their correlationwith treatment outcome. In addition we will study a novel combination regimen of mTOR inhibition and PD1inhibition in lung cancer patients. NCI 10685423 6/8/23 0:00 PAR-18-313 5P50CA217691-05 5 P50 CA 217691 5 7/10/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 5517 6877992 "DENG, XINGMING " Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 346329 221617 124712 SummaryBax functions as an essential gateway to apoptotic cell death. Targeting Bax provides a common pathway totreat NSCLC patients with KRAS or p53 mutations and to overcome resistance to radiotherapy andchemotherapy. We previously discovered that the serine (S)184 phosphorylation site of Bax is a critical switchto functionally control Baxs proapoptotic activity. AKT and PKC have been identified as physiological Baxkinases that can directly phosphorylate Bax at the S184 site leading to inactivation of its proapoptotic function.It is known that KRAS and p53 mutations can activate the PI3K/AKT survival pathway leading to increasedresistance to radiotherapy or chemotherapy in various cancers including lung cancer. Increased levels ofphospho-Bax (pBax) were observed in tumor tissues in patients with non-small cell lung cancer (NSCLC). Wehypothesize that pBax may serve as a new predictive and prognostic biomarker in NSCLC. Expression ofKRAS G12D mutant or p53 R273H mutant or treatment with radiation cisplatin or RAD001 resulted inactivation of AKT and/or PKC leading to increased phosphorylation of Bax which may contribute to radio-chemo- or rapalog resistance. Development of small molecules that activate Bax may provide a novelapproach for the treatment of mutant KRAS or mutant p53 lung cancer or for overcoming radio- chemo- orrapalog resistance. We have identified a novel Bax activator CYD-2-11 that selectively binds the S184 pocketof Bax protein but does not bind other Bcl2 family members. CYD-2-11 not only reverses radioresistance butalso overcomes rapalog resistance in vitro. CYD-2-11 potently represses lung cancer xenografts by activatingBax and inducing apoptosis in tumor tissues. To characterize and develop this novel Bax activator for thetreatment of resistant lung cancer we propose two specific aims: (1) To determine whether and how KRASand p53 mutations regulate Bax activity and treatment resistance in human lung cancer cells. Studies willdetermine whether pBax is a novel prognostic biomarker or therapeutic target in patients with NSCLC; (2) Todevelop novel small molecule Bax activator (CYD-2-11) by targeting the structural pocket around the Baxphosphorylation site for lung cancer therapy. Studies will test the antitumor efficacy of CYD-2-11 alone or incombination with ionizing radiation chemotherapy and/or mTOR inhibitor in patient-derived xenograft (PDX)radioresistant and genetically engineered mutant KRAS-driven lung cancer animal models. By targeting Baxwe expect to develop a new class of anti-cancer agents and combination strategies for lung cancer treatment. +No NIH Category available ABCG2 gene;Address;Aftercare;Animal Model;Binding;Biological Markers;Biopsy;Biopsy Specimen;Blood;Blood specimen;Bone Marrow;Cancer Etiology;Cancer Model;Cancer Patient;Caring;Cell Culture Techniques;Cell Line;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;Collection;Correlative Study;Cytotoxic Chemotherapy;Data;Dedications;Development;Dose;EGFR inhibition;Enrollment;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;FDA approved;Family;Generations;Genetic;Guidelines;Human;Immune;Immune response;Immune system;Immunologic Markers;Immunosuppression;Implant;Innate Immune Response;International;Knock-out;Knockout Mice;Ligands;Lung;MERTK gene;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator;Modeling;Monitor;Multicenter Studies;Mus;Mutate;Mutation;National Comprehensive Cancer Network;Natural Immunity;Neoplasm Metastasis;New Agents;Newly Diagnosed;Non-Small-Cell Lung Carcinoma;Oncogenic;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase Ib Clinical Trial;Phenotype;Phosphorylation;Prognosis;Quality of life;Receptor Protein-Tyrosine Kinases;Recombinants;Recommendation;Research Personnel;Resistance;Resistance development;Role;Safety;Sampling;Signal Transduction;Testing;Therapeutic;Therapeutic Effect;Translating;Tumor Immunity;Tumor-associated macrophages;Tyrosine Kinase Inhibitor;Universities;cell killing;chemokine;clinical application;cohort;cytokine;cytotoxic;first-in-human;immune cell infiltrate;immune function;improved;improved outcome;inhibitor;inhibitor therapy;kinase inhibitor;lung cancer cell;mouse model;mutant;mutational status;neoplastic cell;novel;novel strategies;patient derived xenograft model;patient response;permissiveness;pharmacodynamic biomarker;potential biomarker;pre-clinical;preclinical study;programs;resistance mechanism;resistance mutation;response biomarker;small hairpin RNA;subcutaneous;targeted treatment;therapeutic target;tumor;tumor growth;tumor microenvironment;tumorigenesis Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC Project Narrative:This proposal includes a phase 1b clinical trial of MRX-2843 and osimertinib in patients with advanced EGFRMTNSCLC and may lead to development of more effective and less toxic therapies to improve survival and qualityof life for lung cancer patients. Correlative studies are included in the trial to identify potential biomarkers thatcould be used to monitor target inhibition and/or immune response in patients treated with the combination.Preclinical studies will also be conducted using animal models to expand our understanding of the direct andimmune-mediated mechanisms by which MERTK contributes to tumorigenesis and resistance to EGFRinhibition in EGFRMT NSCLC. NCI 10685418 6/8/23 0:00 PAR-18-313 5P50CA217691-05 5 P50 CA 217691 5 7/10/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 5514 1945686 "GRAHAM, DOUGLAS K" Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 354544 226883 127661 Summary/Abstract:Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death in the US.EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes for patients who have non-small cell lung cancer(NSCLC) with an activating EGFR mutation (EGFRMT) but many tumors do not respond and most that do willbecome resistant in 9-12 months. Osimertinib a 3rd generation EGFR TKI has recently advanced to frontlinetherapy for EGFRMT NSCLC irrespective of T790M mutation but treatment options remain limited for patientswho develop resistant tumors. This proposal describes preclinical studies to evaluate inhibition of the MERTKreceptor tyrosine kinase in combination with EGFR TKIs for treatment of EGFRMT NSCLC and includes a phase1b clinical trial to test the combination in these patients. 70% of NSCLCs have abnormally high levels of MERTKand inhibition in tumor cells decreases tumor growth in mice. MERTK is also present in immune cells in the tumormicroenvironment where it suppresses the anti-tumor innate immune response. Our data suggest that inhibitionof MERTK reprograms the immune system to attack the tumor. MERTK can also mediate resistance to EGFRTKIs including osimertinib suggesting that MERTK inhibition will sensitize EGFRMT tumors to treatment withEGFR TKIs and may decrease development of resistance. These data identify MERTK as a new target in NSCLCand implicate MERTK-targeted inhibitors as an unprecedented opportunity to provide a three-prongedtherapeutic approach in a single drug leading to (1) direct tumor cell killing (2) activation of anti-tumor innateimmunity and (3) increased sensitivity to EGFR TKI therapy. To test this idea and generate drugs that can beused in humans we developed MERTK-selective TKIs including MRX-2843. MRX-2843 is effective asmonotherapy in mice and increases sensitivity to EGFR TKIs in EGFRMT NSCLC cells. The proposed studiesuse MRX-2843 and other MERTK inhibitors to investigate the effects of combined MERTK and EGFR inhibitionin cell culture and mouse models of EGFRMT NSCLC including models with tumor cells implanted directly in thelung models derived from fresh patient samples and models of tumor cell metastasis. Mice with mertk knock-out will also be used to determine the effects of MERTK inhibition in the tumor microenvironment and its impacton anti-tumor immunity. Additional studies will determine how MERTK inhibition in the immune system leads totumor rejection. Finally a highlight of this project is the dedicated clinical trial of MRX-2843 and osimertinib inpatients with advanced EGFRMT NSCLC a study that includes 2 expansion cohorts with paired collection of pre-and post-treatment tumor biopsies and blood samples to evaluate biomarkers of MERTK inhibition includingchanges in immune function following treatment with MRX-2843. The results from the clinical trial andassociated studies will provide more effective and less toxic treatment options leading to optimized care andimproved survival for patients with EGFRMT NSCLC. +No NIH Category available Address;Adjuvant Study;Aftercare;Blood;CD28 Antigens;CD28 gene;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Characteristics;Clinical;Combined Modality Therapy;Data;Deuterium;Effector Cell;Epigenetic Process;Excision;FRAP1 gene;Genetic Transcription;Goals;Immune checkpoint inhibitor;Immune response;Immunity;Immunofluorescence Immunologic;Immunologic Factors;Immunologics;Immunotherapy;Infiltration;Investigation;Label;Location;Lung Neoplasms;Malignant neoplasm of lung;Measures;Monitor;Neoadjuvant Study;Neoadjuvant Therapy;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;PD-1 blockade;Patients;Phenotype;Play;Population;Proliferating;Regimen;Resected;Role;Signal Transduction;Site;T cell receptor repertoire sequencing;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Techniques;Testing;Therapy trial;Tissues;Treatment outcome;Tumor Tissue;Universities;anti-cancer;cancer therapy;checkpoint inhibition;clinical efficacy;cytokine;draining lymph node;efficacy study;exhaust;exhaustion;improved;in vivo;mTOR Inhibitor;mTOR inhibition;mouse model;neoplastic cell;novel;peripheral blood;predictive marker;programmed cell death protein 1;response;stem;stem-like cell;targeted treatment;tumor Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC Our group has identified stem-like T cells that undergo proliferation after immune checkpoint inhibition. We willcharacterize these cells in lung tumors draining lymph nodes and peripheral blood and study their correlationwith treatment outcome. In addition we will study a novel combination regimen of mTOR inhibition and PD1inhibition in lung cancer patients. NCI 10685415 6/8/23 0:00 PAR-18-313 5P50CA217691-05 5 P50 CA 217691 5 7/10/19 0:00 5/31/24 0:00 ZCA1-RPRB-F 5513 1869189 "AHMED, RAFI " Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 513707 367798 145909 Programmed cell death-1 (PD-1) targeted therapies have changed the landscape of lung cancer treatment1.While some impressive results have been generated the mechanisms that dictate which patients will or willnot respond to this treatment are not well defined. It is important to understand the immunological factorsassociated with clinical responses not only to improve current therapies but also to identify predictivebiomarkers. We have recently identified a novel population of PD-1+ TCF-1+ CD28+ CD8 T cells with stem-cell-like features in a mouse model of T cell exhaustion6-8. The proliferative burst of CD8 T cells after PD-1blockade comes from this stem-like CD8 T cell population and is dependent on signals from costimulatorymolecule CD28. Importantly our preliminary data suggest that stem-like CD8 T cells are present in non-smallcell lung cancer (NSCLC) patients. Based on our observations we hypothesize that the stem- like CD8 T cellsplay a critical role in successful PD-1 targeted therapies in NSCLC patients. One of the major goals of thisproposal is to identify and characterize these stem-like CD8 T cells in NSCLC patients. Another important pointto be addressed in this proposal is if the presence of these stem-like CD8 T cells correlates with proliferativeresponses of CD8 T cells as well as clinical efficacy of the immunotherapies. The following Specific Aims areproposed to achieve our goals:Aim 1: To identify and characterize the phenotype location and function of stem-like CD8 T-cells inlung cancer patients. Aim 1a. Characterize the transcriptional epigenetic and functional characteristics oftumor infiltrating stem-like CD8 T cells in NSCLC; Aim 1b. Determine the clonal relationship between T-cellpopulations in tumor draining lymph node and blood using TCR sequencing.Aim 2: To study the efficacy and immune responses of combined inhibition of PD-1 and mTOR in aneo-adjuvant therapy trial in NSCLC patients. Aim 2a. To examine the clinical efficacy of the combinedinhibition of PD-1 and mTOR in a neo-adjuvant therapy trial for patients with early stage NSCLC. Aim 2b. Toexamine the correlation between immune responses and clinical efficacy of the combination therapy.Aim 3: To evaluate T cell dynamics in lung cancer patients using in vivo deuterium labeling. Aim 3a. Tomeasure proliferation in T cell populations in NSCLC patients using in vivo deuterium labeling. Aim 3b. Todetermine the CD8 T cell populations that proliferate in response to mTOR and PD1 blockade using in vivodeuterium labeling. +No NIH Category available 3-Dimensional;Adoption;Algorithms;Anatomy;Architecture;Biological Markers;Biopsy;Brain;Brain Mapping;Brain Neoplasms;Brain imaging;Brain region;Caring;Child;Clinical;Clinical Trials;Cognitive;Computer software;Craniotomy;Data;Development;Devices;Diagnosis;Excision;Failure;Functional Magnetic Resonance Imaging;Funding;Glioblastoma;Glioma;Goals;Image;Imaging technology;Infrastructure;Investigation;Knowledge;Lesion;Machine Learning;Magnetic Resonance Imaging;Malignant Glioma;Maps;Methods;Navigation System;Neuroanatomy;Neuronavigation;Neurons;Neurosurgeon;Operative Surgical Procedures;Outcome;Output;Pathologic;Patient Care;Patient Participation;Patient imaging;Patient-Focused Outcomes;Patients;Performance;Population;Procedures;Productivity;Prognosis;Progression-Free Survivals;Public Health;Quality Control;Quality of life;Research;Rest;Sedation procedure;Surgeon;System;Systems Integration;Techniques;Technology;Time;United States Food and Drug Administration;Universities;Validation;Visualization;Washington;Work;analysis pipeline;brain tumor resection;clinical decision support;clinical decision-making;clinically relevant;convolutional neural network;effective therapy;experience;functional status;improved;individualized medicine;industry partner;innovation;insight;machine learning algorithm;multilayer perceptron;neurosurgery;next generation;operation;personalized approach;preservation;prognostic;prognostic algorithm;prognostic of survival;prospective;radiomics;success;survival prediction;tool;treatment optimization;treatment planning;tumor Advancing Neurosurgical Neuronavigation Using Resting State MRI and Machine Learning Project NarrativeThe proposed research is an academic industry partnership that will make available to neurosurgeons and neuro-oncologists a neuronavigation capability that will optimize treatment of patients with brain tumors by moreefficiently and accurately localizing critical brain regions and providing prognostic information on the patientssurvival. This development is relevant to public health because it will assist clinicians to personalize patienttreatment planning including surgical strategy and subsequent oncologic care. Towards this end we proposeto create an imaging technology package that will integrate advanced machine learning techniques using restingstate functional magnetic resonance imaging with an existing widely used neuro-anatomic navigation systemcurrently used by neurosurgeons. The integrated system which will include anatomic functional and prognosticinformation will provide a more comprehensive patient assessment to maximize safe and effective treatment. NCI 10685402 7/20/23 0:00 PAR-20-155 5R01CA203861-07 5 R01 CA 203861 7 "ESPEY, MICHAEL G" 1/17/17 0:00 6/30/27 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 2084466 "LEUTHARDT, ERIC CLAUDE" "SHIMONY, JOSHUA S" 1 NEUROSURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 553502 NCI 375223 178279 Abstract. Long-term survival of patients with glioblastomas (GBM) are associated with two competing priorities:1) gross total resection and 2) preservation of the patients function. Stereotactic navigation in whichreconstructed magnetic resonance images (MRI) of the brain are used for real-time intraoperative anatomicguidance has become an essential tool for tumor resection. Further there are emerging insights that glioma-specific perturbations of the functional organization of the brain impact the patients survival. However thecurrent barrier is that there is no FDA approved navigation system that enables the surgeon to visualize thefunctional architecture of the brain and the impact a tumor has on the brains network organization to informprognosis. Resting state functional MRI (rs-fMRI) has emerged as a powerful tool for mapping clinically relevantbrain networks and defining critical glioma-neuronal interactions. rs-fMRI is highly efficient task independentand multiple resting state networks (RSNs) can be mapped simultaneously. With this in mind the long-term goalof our research is to improve treatment survival and quality of life for patients with brain tumors by improvingthe identification of eloquent cortex and providing actionable metrics for survival prognosis to best tailor apatients care. In our first Academic Industry Partnership between Washington University and Medtronic we wereextremely productive in creating an integrated brain-mapping navigation technology using rs-fMRI. Specificallywe created a robust image acquisition/analysis pipeline that includes pre-processing of raw data quality controlanalytics and clinical validation demonstrating superior performance over task-based fMRI. We have also beenleaders in deriving prognostic radiomic biomarkers from rs-fMRI. In this continuation we will build on thesesuccesses. The overall objective is to create advanced rs-fMRI machine learning (ML) tools to more efficientlyand accurately define functional cortex and provide preoperative prognostic metrics of survival as acomprehensive surgical/care navigation system. We have the expertise infrastructure and data to advance rs-fMRI to be a powerful tool for neurosurgical decision support. The proposal entails three specific aims: 1)Advance an ML algorithm to enable more accurate and data efficient rs-fMRI brain-mapping software 2) Createan rs-fMRI ML algorithm to preoperatively predict survival in glioblastoma (GBM) patients and 3) Validate impactof mapping and prognostic algorithms on clinical decision making in prospective feasibility clinical trial. Theexpected outcome of this work will be an integrated imaging/surgical navigation technology using rs-fMRI forclinical decision support with defined performance clinical validation and a regulatory path for FDA clearance.Thus this proposal is innovative because 1) the software will map networks with substantially shorter imageacquisition times thus enabling more widespread adoption and 2) provide critical pre-operative survival insightsto inform surgical decisions. This work is significant because it will disseminate technology that fundamentallyenhances more tailored approaches to improving patient outcomes and quality of life. 553502 +No NIH Category available Antineoplastic Agents;Basic Cancer Research;Behavior;Cell Surface Receptors;Cell Survival;Cell surface;Cells;Cellular Stress;Cues;Drug resistance;Endothelial Cells;Evolution;FDA approved;Genetic;Goals;Hypoxia;Individual;Integrin alphaV;Integrin alphaVbeta3;Integrins;Lead;Malignant Neoplasms;Mediating;Neoplasm Metastasis;Pathway interactions;Pharmaceutical Preparations;Phenotype;Physiological;Process;Research;Stress;Supporting Cell;Therapeutic;angiogenesis;cancer therapy;career;neoplastic cell;new therapeutic target;nutrient deprivation;phase III trial;prevent;programs;response;stem;stress tolerance;translational cancer research;tumor;tumor microenvironment;tumor progression Attacking stress tolerance in cancer Project NarrativeMy research has focused on the overarching theme of how cell surface receptors mediate an invasivephenotype by promoting adaptations that support cell survival in the face of stress. While this is a criticalcomponent of physiological remodeling processes such as angiogenesis tumor cells often hijack these samepathways to promote metastasis and tumor progression. Throughout my career I have emphasized thecombination of basic and translational cancer research which has resulted in one cancer drug recentlyapproved by the FDA and a second drug that has successfully completed Phase III trials. NCI 10685400 8/31/23 0:00 PAR-17-494 5R35CA220512-06 5 R35 CA 220512 6 "WATSON, JOANNA M" 9/18/18 0:00 8/31/25 0:00 ZCA1-RTRB-C(M3) 3101943 "CHERESH, DAVID A" Not Applicable 50 PATHOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 882960 NCI 587787 340916 Project Summary/AbstractMy career began with the identification of cell surface markers on invasive cells and led to the discovery ofhow integrins v3 and v5 on endothelial cells respond to cues within the tumor microenvironment topromote angiogenesis. I later demonstrated that V integrins on tumor cells use these same fundamentalpathways to achieve aggressive invasive and metastatic behavior. Now my R35 proposal represents afurther evolution of these concepts to ask how tumor cells undergo reprogramming in response to cellularstresses including hypoxia nutrient deprivation or cancer therapy. We find that v3 expression can beinduced by stress to reprogram tumor cells toward a stress-tolerant drug-resistant stem-like state that isassociated with tumor progression and metastasis for a wide range of cancers. Because individual tumors usethis integrin to overcome unique challenges we will define how v3 activates downstream effectors that varybetween tumor type genetic profile and microenvironment. The overall goal of my future research program isto understand how such tumors use integrin v3 to gain stress tolerance so that we can devise ways to attackthis process therapeutically. This proposed research will not only lead to a fundamental understanding of howtumors adapt to therapy or microenvironmental stress but it should identify new druggable targets to limitcancer progression by preventing or overcoming tumor cell drug resistance and stress tolerance. 882960 +No NIH Category available 3-Dimensional;Acceleration;Adopted;Affect;Age;Aging;Asthma;Atopic Dermatitis;Biological;Bystander Effect;Cardiovascular Diseases;Cell Aging;Cell Culture Techniques;Cells;Characteristics;Chronic;Chronology;Complex;Controlled Environment;Data;Dermal;Dermis;Development;Disease;Distant;Environment;Environmental Risk Factor;Epidermis;Evaluation;Exposure to;Fibroblasts;Freezing;Frequencies;Gender;Generations;Genes;Goals;Heart;Histologic;Human;Hyperpigmentation;In Vitro;Individual;Inflammation;Joints;Kidney;Libraries;Longevity;Lung;Lupus;Maps;Mediating;Microfluidics;Modeling;Muscle;Organ;Paracrine Communication;Pharmaceutical Preparations;Phase;Phenotype;Physiological;Play;Process;Protocols documentation;Psoriasis;Psoriatic Arthritis;Psychological reinforcement;Public Health;Risk Factors;Role;Skin;Skin Aging;Skin Cancer;Skin Physiology;Skin Pigmentation;Skin Tissue;Structure;Techniques;Testing;Time;Tissue Engineering;Tissue Model;Tissues;Ultraviolet Rays;Universities;Vascular Endothelial Cell;age group;age related;analytical tool;bioprinting;cell type;cytokine;efficacy evaluation;experimental study;innovation;keratinocyte;melanocyte;melanoma;metabolomics;multiple omics;multiplex assay;novel drug class;novel strategies;paracrine;senescence;sex;skin disorder;tissue culture;tissue mapping;tool;transcriptomics Senescence-on-a-chip: Building a microphysiological 3D skin model NARRATIVEHuman skin like all other tissues undergoes an intrinsic aging process during an individuals lifespan knownas chronological aging as well as photoaging since the skin is constantly exposed to environmental factorssuch as UV radiation (UVR) which is recognized as the major risk factor for the development of many skincancers.In the skin there is an age-associated accumulation of senescent melanocytes keratinocytes and fibroblastscapable of expressing the senescence-associated secretory phenotype (SASP) which promotes inflammationand have a profound deleterious effect on skin structure and integrity.We will generate 3D skin models that encompass critical biological variables for mapping senescent cells intissues and will include: 1) both genders; 2) the full range of skin pigmentation phototypes; and 3) age rangesacross the human lifespan to investigate the mechanisms leading to senescence in the skin and test newapproaches to treat age-related conditions. NCI 10685382 8/21/23 0:00 RFA-RM-22-004 5UG3CA275686-02 5 UG3 CA 275686 2 "JHAPPAN, CHAMELLI" 8/5/22 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-CB-K(70)R] 6378222 "CHRISTIANO, ANGELA M" Not Applicable 13 DERMATOLOGY 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 549999 OD 334346 215653 PROJECT SUMMARYAging is an increasingly emergent public health issue in large part because it is accompanied by a higherfrequency of chronic age-related diseases. Aging occurs naturally as a consequence of time (upon repeatedcellular replication) and is influenced by a number of environmental factors. Human skin like all other tissuesundergoes an intrinsic aging process during an individuals lifespan known as chronological aging. Additionallythe skin is constantly exposed to environmental factors such as UV radiation (UVR) which is recognized as themajor risk factor for the development of many skin cancers and accelerated skin aging known as photoagingwhich is associated with hyperpigmentation and accelerated melanoma formation. In the skin there is an age-associated accumulation of senescent melanocytes keratinocytes and fibroblasts capable of expressing thesenescence-associated secretory phenotype (SASP) which promotes inflammation through a complex networkof auto- and paracrine reinforcement that modifies the tissue microenvironment and has a profound deleteriouseffect on skin structure and integrity. Thus it is necessary to determine the characteristics of the major skin-resident cell types undergoing senescence as well as their individual SASP profiles expressed duringchronological and extrinsically-induced aging that play a role in the establishment of a skin microenvironmentconducive to age-related disorders. Our lab has developed sophisticated 3D skin models that recapitulatenormal skin physiology within a microfluidic platform in vitro which can combined with other organs in a modulartissue-on-a-chip platform. 3D engineered tissues cultured in microfluidic platforms are powerful tools torecapitulate physiological conditions and investigate physiological phenomena in a controlled environment. Wewill generate 3D skin models that encompass critical biological variables for mapping senescent cells in tissuesand will encompass: 1) both genders; 2) the full range of skin pigmentation phototypes; and 3) age ranges acrossthe human lifespan. Our skin microfluidic platform combined with innovative techniques such as spatialtranscriptomics represents a powerful new tool to investigate the mechanisms leading to senescence in the skinand new approaches to revert age-related conditions. This proposal will have immediate and seamlessintegration into the recently established CUSTMAP Center at Columbia University which is one of the foundingTissue Mapping Centers of the SenNet consortium. Microfluidic tissue models can be customized for many ofthe tissues represented across the SenNet enabling the generation of a wide range of senescence-on-a-chipplatforms for the Consortium. 549999 +No NIH Category available Acidosis;Acute;Address;Affect;Aneuploidy;Bar Codes;Benign;Biological Models;Biology;Breast Cancer Cell;Breast Carcinogenesis;Breast Epithelial Cells;Cancer Biology;Cell Survival;Cells;Chromatin;Clone Cells;Comedo;Computer Analysis;Data;Databases;Disease;Disseminated Malignant Neoplasm;Duct (organ) structure;Ecology;Environment;Epigenetic Process;Epithelial Cells;Evolution;Exhibits;Expression Profiling;Fermentation;Gene Silencing;Genes;Genetic;Genets;Genome;Genomics;Glucose;HK2 gene;Heritability;Human;Hypoxia;Immunohistochemistry;In Situ Lesion;Investigation;Lasers;MCF10A cells;Machine Learning;Malignant Neoplasms;Maps;Metabolic;Modification;Molecular;Monitor;Multiple Myeloma;Mutation;Nature;Noninfiltrating Intraductal Carcinoma;Normal Cell;Outcome;Oxygen;Pathway interactions;Patients;Pattern;Periodicity;Phenotype;Point Mutation;Process;Proteins;Quantitative Reverse Transcriptase PCR;SLC2A1 gene;Sampling;Starvation;Stress;System;Systems Biology;Techniques;Technology;Testing;The Cancer Genome Atlas;Tissue Microarray;Warburg Effect;Work;aerobic glycolysis;carcinogenesis;epigenome;epigenomics;exome sequencing;fitness;machine learning algorithm;malignant breast neoplasm;mathematical model;metabolic phenotype;neoplastic cell;novel;nutrient deprivation;overexpression;premalignant;single-cell RNA sequencing;stem;stressor;transcriptome;transcriptomics;tumorigenic Ecology and Evolution of Breast Carcinogenesis NarrativeThis proposal tries to answer a major question in carcinogenesis: How do harsh microenvironments select forhardwired metabolic phenotypes such as Warburg Effect leading to carcinogenesis? Combining three hightechnology approaches of cancer evolutionary biology mathematical modeling and system biology we proposeto decipher the relationship between microenvironmental stress-induced genome evolution that results inhardwired phenotypic adaptation represented by a WE as an initiator of cancer. Solving this problem will havesignificance as it is a long-standing problem in cancer biology. NCI 10685316 9/8/23 0:00 PAR-19-101 5U01CA261841-04 5 U01 CA 261841 4 "MILLER, DAVID J" 9/15/21 0:00 8/31/26 0:00 ZCA1-TCRB-Q(M1) 11876169 "DAMAGHI, MEHDI " "SILVA, ARIOSTO S" 1 PATHOLOGY 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY SCHOOLS OF MEDICINE 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 648685 NCI 528549 314486 Abstract: In early breast carcinogenesis neoplastic cells grow in multiple layers towards the lumens of ductswhich subjects the periluminal cells to harsh conditions of low oxygen low pH and nutrient deprivation.Adaptation to these harsh conditions is a pre-requisite for survival of incipient tumor cells. Adaptations are initiallyacute and reversible but eventually Darwinian selection results in cells with hardwired phenotypes. A prominentexample of this is aerobic glycolysis or the Warburg Effect (WE) wherein cells are hard-wired to fermentglucose even in the presence of oxygen. Notably a WE is highly correlated with a cancers metastatic potentialand poor outcome. Hence a major question in carcinogenesis is: What are the mechanisms by which a harshmicroenvironment eventually selects for hard-wired (heritable) phenotypes such as a WE?. Rather than simplyselection of pre-existing phenotypes we contend that the microenvironment actively induces phenotypic diversitythrough a systematic set of epigenetic and genetic alterations. To address this question we combine preliminary data from three different approaches that are all focusedon the eco-evolutionary dynamics occurring during carcinogenesis: In the first we have subjected benign breastcancer and epithelial cells to harsh conditions encountered in DCIS and have observed that the cells that survivethese selections exhibit a WE. We selected three clones and applied single cell RNA sequencing and single cellATAQ sequencing as well as whole exome sequencing to map the transcriptome epigenome and mutationpatterns of the selected clones compared to their parental normal cells. This will form the model system to beanalyzed throughout the current proposal. In the second line of investigation we have documented the profoundepigenetic changes that occur during progression of multiple myeloma (MM) from pre-malignant to metabolicallyactive disease. We hypothesize that these observations in MM can provide a framework to predict and interpretthe changes that breast cancer cells undergo as they transition from a benign non-glycolytic to an aggressiveglycolytic state. In the third line of investigation we have outlined a continuum starting with epigenetic changesand show how these result in permanent mutational or chromosomal changes. This latter work provides aframework with which to predict and interpret how microenvironment-induced epigenetic changes can eventuallylead to hardwired genetic changes that are observed in aggressive glycolytic breast cancer. By combining theseapproaches we propose to decipher the mechanisms whereby microenvironmental stress-induced genomeevolution results in hard-wired phenotypic adaptations represented by a WE. At the end this study we expect to have a more complete and comprehensive understanding of theenvironmentally-induced epigenetic and genetic changes that occur during carcinogenesis and how these relateto hard-wired phenotypic profiles as exemplified by the Warburg Effect. 648685 +No NIH Category available 4T1;Adopted;Animals;Antineoplastic Agents;Apoptosis;Autophagocytosis;Biogenesis;Bioinformatics;Biological;Biology;Biometry;Breast Cancer Cell;Cancer Biology;Cancer Model;Cessation of life;Chemicals;Complex;Data;Development;Disease;Drug Kinetics;Drug Targeting;Electron Transport;Environment;Exhibits;FRAP1 gene;Fostering;Goals;Gold;Gold Compounds;Growth;Impairment;In Vitro;Inbred BALB C Mice;Knowledge;Lead;Libraries;Ligands;Locales;Malignant Neoplasms;Maximum Tolerated Dose;Medical;Metabolic;Metastatic Neoplasm to the Liver;Mitochondria;Modeling;Modification;Morphology;Mus;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmacodynamics;Process;Prognostic Marker;Property;Proteins;Proteomics;Regimen;Research;Respiration;Respiratory Chain;Specificity;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Therapeutic Agents;Therapeutic Index;Toxic effect;Work;analog;anti-cancer;anticancer activity;antitumor agent;antitumor effect;cancer cell;cell growth;clinical efficacy;clinical subtypes;comparative;drug development;drug discovery;effective therapy;improved;in vitro Assay;in vivo;innovation;insight;malignant breast neoplasm;mitochondrial dysfunction;mouse model;nanomolar;new therapeutic target;novel;novel strategies;novel therapeutic intervention;patient derived xenograft model;prevent;programs;rational design;response;scaffold;small molecule;targeted agent;targeted treatment;therapeutic target;tool;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor xenograft;uptake Gold-derived therapeutic compounds for disease application PROJECT NARRATIVE: Gold-derived compounds modulate mitochondrial function and exhibit efficaciousanticancer activity. Combining the unique structural and reactive features of gold compounds with mechanism-of-action studies provide a new platform for the discovery of mitochondria-targeted anticancer agents. Thisproposal seeks to expand potent gold chemotherapeutic libraries guided by functional biology to elucidate theirmode of action and inhibit metastatic tumor in vivo while sparing normal tissue. NCI 10685301 7/12/23 0:00 PA-20-185 5R01CA258421-03 5 R01 CA 258421 3 "FU, YALI" 8/4/21 0:00 7/31/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 11956743 "AWUAH, SAMUEL GORMAN" Not Applicable 6 CHEMISTRY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF ARTS AND SCIENCES 405260001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 341404 NCI 224175 117229 PROJECT SUMMARY/ABSTRACT. Gold-derived anticancer compounds are promising therapeutic agents fordisease applications including cancer. Triple negative breast cancer (TNBC) is an aggressive clinical subtypeof breast cancer that lacks effective therapy. Approximately 66% of all breast cancer deaths are TNBC-relatedhence pragmatic treatment options are sorely needed. Our research program seeks to harness the unique spatialproperties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for new targetedtherapeutic regimen to eliminate TNBC. We have developed gold compound libraries with different scaffolds anddistinct mode of action in TNBC cells including modulating mitochondrial biogenesis and morphology. Thecompounds display high potency in the nanomolar range with >30-fold selectivity to cancer cells over normalcells. Comparative profiling using the NCI-60 screen confirmed toxicity of a lead compound AuPhos against apanel of breast cancer including TNBC. Preliminary maximum tolerated dose studies in BALB/c mice suggestthat different classes of gold compounds can be well tolerated in animals. Additionally AuPhos exerts profoundantitumor effect and prevents liver metastasis in the metastatic 4T1 TNBC mouse model. Mechanism of actionstudies suggest that the gold compounds target different mitochondrial processes including mitochondrialbiogenesis or morphology. We hypothesize that synthetic modification of the gold scaffold will enable thedevelopment of a suite of gold-based drugs that are targeted to different mitochondrial locales and biologicaltargets to eliminate TNBC. We will test the hypothesis in this project via the following aims: Aim 1) optimizechemically and functionally diverse gold anticancer agents; Aim 2) Delineate the mechanism of gold-basedmodulation of mitochondrial function; and Aim 3) Determine the therapeutic index of optimized gold compoundsin TNBC mouse models. The outcomes of this project will 1) provide novel gold-based compounds with specificityfor mitochondrial function to eliminate TNBC; 2) delineate the mechanism of TNBC inhibition by the developedgold-based compounds; and 3) establish in vivo efficacy and pharmacodynamics of gold anticancer agents.Critically the compounds generated will provide impetus for targeted therapies for TNBC which is an unmetneed. 341404 +No NIH Category available Academia;Address;Area;Basic Science;Biotechnology;Cancer Biology;Cancer Center;Cancer Etiology;Career Choice;Cell Death;Cell Survival;Cells;Clinical;Clinical Oncology;Communication;Complement;Computational Biology;Country;DNA Repair;Data;Dedications;Diagnosis;Discipline;Educational process of instructing;Environment;Epigenetic Process;Evaluation;Exposure to;Faculty;Genes;Geography;Goals;Government Agencies;Graduate Education;Grant;Health;Healthcare;Home;Hospitals;Immunology;Immunotherapy;Individual;Institution;International;Knowledge;Laboratories;Laboratory Research;Learning;Malignant Neoplasms;Medicine;Mentors;Methods;Mind;Mission;Molecular Carcinogenesis;Mutagenesis;Neoplasm Metastasis;Oncology;Participant;Postdoctoral Fellow;Preparation;Prevention;Procedures;Qualifying;Research;Research Methodology;Research Personnel;Research Project Grants;Science;Scientist;Series;Students;Supervision;Talents;Techniques;Technology;Texas;Training;Training and Education;Translational Research;University of Texas M D Anderson Cancer Center;Virus;Work;academic program;angiogenesis;anticancer research;austin;cancer genetics;cancer genomics;cancer initiation;cancer therapy;career;career development;comparative;design;experience;faculty mentor;field trip;graduate school;graduate student;hands on research;interest;laboratory experience;lectures;member;model organism;next generation;nonhuman primate;oral communication;posters;programs;research facility;skills;stem cells;student participation;summer internship;summer program;summer research;summer student;symposium;targeted treatment;undergraduate student;videoconference;viral carcinogenesis MD Anderson Science Park Summer Program in Cancer Research SPCR NARRATIVEThe Summer Program in Cancer Research will support the participation of twelve (12) academically talentedundergraduate students in an authentic hands-on laboratory research experience for ten weeks during thesummer break. The primary objective of the program is to promote careers in cancer research and oncology andprepare students to pursue graduate education in science research and health care. Under the direction offaculty and laboratory staff mentors students will receive training in laboratory techniques and researchprocedures that will increase technical acuity communication skills and self-confidence in entering the cancerresearch field as well as develop sustained mentor relationships which further promote long-term pursuit of basicscience and clinical careers in cancer research. NCI 10685275 8/17/23 0:00 PAR-18-478 5R25CA181004-10 5 R25 CA 181004 10 "RADAEV, SERGEY" 8/11/14 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 6771379 "CHANDRA, JOYA " "BEDFORD, MARK T." 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 192025 NCI 199863 15989 PROJECT SUMMARYThe goal of the Summer Program in Cancer Research (SPCR) is to provide talented undergraduate studentswith a research project-based laboratory experience and exposure to different science and health disciplinesworking to address the causes diagnosis prevention and treatment of cancer. The Program objective is topromote careers in cancer research and clinical oncology which is in line with the NCI mission to attract andtrain the best minds to become the next generation of cancer researchers. This goal will be accomplished througha formalized 10-week program during which participants will work on an individualized research project underthe supervision of a faculty mentor. The MD Anderson Science Park campus in Smithville Texas provides aunique environment for young scientists to engage in cutting-edge research using state-of-the-art technologieswhile working in a park-like setting. Participating faculty members are not only committed educators but alsointernationally recognized experts in the fields of cancer genetics and genomics epigenetics DNA repair andmutagenesis stem cells immunology and mechanisms of cell death and survival. Students will also gain anappreciation for other areas of cancer biology such as viral carcinogenesis angiogenesis and metastasisthrough a Program lecture series complemented by additional lectures video conferenced from Houstondesigned for all summer students at MD Anderson. An appreciation for the wide variety of research beingperformed at MD Anderson will also be gained through field trip experiences to the MD Anderson main campusand hospital in Houston and the Keeling Center for Comparative Medicine. Students will be exposed to thevariety of career options available to individuals interested in cancer research through career developmentlectures and a Careers in Science Panel Discussion. Students will also learn how to organize a scientificpresentation including background information hypothesis methods results and conclusions and will honetheir oral communication skills in preparation for a culminating Scientific Symposium where students presenttheir research projects to departmental faculty trainees and staff. Past programmatic evaluations demonstratethat the SPCR is an important contributor to the career development of participating students and influencedtheir decision and ability to pursue graduate or other training leading to careers in cancer-related research andmedicine. 192025 +No NIH Category available 18F-fluorothymidine;Avidity;Biological;Biological Markers;Biology;Bone Tissue;Cell Nucleolus;Cell Nucleus;Cell Survival;Cells;Chromosomal translocation;Clinic;Clinical;Correlative Study;Data;Dependence;Disease model;Dose;Dose Limiting;Drug resistance;EWS-FLI1 fusion protein;Evaluation;Ewings sarcoma;FLI1 Transcription Factor;Future;Gene Expression;Gene Expression Profiling;Gene Structure;Gene set enrichment analysis;Genes;Genetic;Genetic Transcription;Goals;Hour;In Vitro;Infusion procedures;Localized Disease;Manuscripts;Mediating;Messenger RNA;Mutation;NR0B1 gene;Neoplasm Metastasis;Oncogenes;Patients;Pharmaceutical Preparations;Positron-Emission Tomography;Pre-Clinical Model;Preparation;Proliferating;Property;Proteins;Publishing;Recurrence;Recurrent disease;Research Design;Safety;Sampling;Schedule;Series;Serum;Soft tissue sarcoma;TK1 gene;Testing;Therapeutic;Time;Translating;Work;Xenograft Model;actionable mutation;chemotherapy;collaborative approach;genetic signature;imaging biomarker;improved;in vivo;inhibitor;insight;irinotecan;multimodality;novel;patient derived xenograft model;phase 1 designs;pre-clinical;preclinical study;programs;promoter;protein expression;response;t(11;22)(q24;q12);therapeutic target;transcription factor;transcriptome;transcriptome sequencing;treatment response;tumor;tumor growth;tumorigenesis A collaborative approach to analyze and target the EWS-FLI1 transcription factor in patients with Ewing sarcoma Project NarrativeThe EWS-FLI1 transcription factor drives expression of the genes responsible for Ewing sarcoma tumorgrowth. The goal of this study is to establish the dose and schedule of trabectedin and irinotecan that is able toblock EWS-FLI1 activity. In addition we will determine if 18F-FLT can be used as a biomarker of this blockadeand perform a series of correlative biological studies designed to provide insight into the biology andtherapeutic targeting of EWS-FLI1. NCI 10685251 7/31/23 0:00 PAR-18-646 5U01CA236220-05 5 U01 CA 236220 5 "UNDALE, ANITA H" 7/1/19 0:00 6/30/24 0:00 ZCA1-RTRB-4(O1) 10824831 "GROHAR, PATRICK J" Not Applicable 6 Unavailable 186146911 G9GQJWPKUZP9 186146911 G9GQJWPKUZP9 US 42.319986 -83.682759 10021144 SARC Ann Arbor MI Other Domestic Non-Profits 481059484 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 111060 NCI 422792 36258 Project AbstractIt has been known for more than 25 years that Ewing sarcoma cells are absolutely dependent on the EWS-FLI1 transcription factor for cell survival. EWS-FLI1 is a dysregulated transcription factor formed by thet(11;22)(q24;q12) chromosomal translocation. This fusion oncogene alters the expression of over 500 genesto establish a transcriptional program responsible for tumorigenesis and progression. Despite this knowndependence the clinical realization of an EWS-FLI1 inhibitor has not been achieved. We have previouslyshown that trabectedin interferes with EWS-FLI1 activity. We showed that the drug blocks expression of EWS-FLI1 downstream targets including the very specific target gene NR0B1. We demonstrated reversal ofexpression at the promoter mRNA and protein levels both in vitro and in vivo in xenograft models of thedisease. In addition we showed that the drug reverses the gene signature of EWS-FLI1 using gene expressionprofiling and Gene Set Enrichment Analysis (GSEA). We subsequently determined the mechanism of EWS-FLI1 suppression. Treatment of Ewing sarcoma cells with trabectedin redistributes EWS-FLI1 within thenucleus to the nucleolus. Importantly this redistribution of EWS-FLI1 is extremely concentration dependentrequiring relatively high but clinically achievable concentrations of the drug. In addition irinotecan can bothamplify and sustain the trabectedin mediated block of EWS-FLI1 activity. Therefore the goal of this study is touse the combination of trabectedin and irinotecan to achieve the therapeutic suppression of EWS-FLI1. Inorder to accomplish this in aim 1 we will establish the optimal dose and schedule of administration oftrabectedin in combination with low dose irinotecan. We will use a traditional 3 + 3 phase I design andadminister trabectedin as a 1-hour infusion in order to achieve the highest serum concentration of drugpossible. We will then perform a limited dose escalation of irinotecan to both amplify and sustain suppressionof EWS-FLI1. In aim 2 we will determine if we can use 18F-FLT as a biomarker of EWS-FLI1 suppression. Wehave demonstrated that silencing of EWS-FLI1 suppresses expression of the proteins responsible for 18F-FLTactivity ENT1 ENT2 and TK1. This results in a loss of PET avidity of Ewing sarcoma cells with EWS-FLI1suppression in preclinical models of the disease. In this study we will determine if these effects translate topatients. Finally in aim 3 we will do a series of correlative studies to characterize the EWS-FLI1transcriptome for the first time in patients. We will perform both single cell and bulk tumor RNA sequencing toidentify the putative EWS-FLI1 targets for the first time in the clinic. We will organize the gene signatures intotranscriptional networks compare the results to preclinical data and establish a series of Patient DerivedXenografts (PDXs). This will provide insight into mechanisms of tumorigenesis and drug resistance. Insummary if the goals of this study are achieved we will achieve the therapeutic suppression of EWS-FLI1clinical evidence of suppression and the first evaluation of the EWS-FLI1 transcriptome in the clinic. 111060 +No NIH Category available Molecular;Therapeutic;Training Programs;anticancer research Cancer Research Training Program: From Molecular Mechanisms to Therapeutic Strategies NARRATIVEThe Cancer Research Training Program (CRTP) described herein is designed to prepare the next generationof young investigators for successful careers in cancer research. By providing trainees with the practical skillsto perform high-quality research the foundational knowledge to cultivate a process of life-long learning andthe skills to be part of a dynamic and interactive research team the CRTP will help to create a new generationof cancer researchers who are uniquely prepared to make inroads into understanding and treating cancer. NCI 10685245 6/7/23 0:00 PA-20-142 5T32CA009109-47 5 T32 CA 9109 47 "BOULANGER-ESPEUT, CORINNE A" 7/1/76 0:00 6/30/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9560372 "DUDLEY, ANDREW CARL" "RUTKOWSKI, MELANIE R" 5 MICROBIOLOGY/IMMUN/VIROLOGY 65391526 JJG6HU8PA4S5 65391526 JJG6HU8PA4S5 US 38.050527 -78.500531 1526402 UNIVERSITY OF VIRGINIA CHARLOTTESVILLE VA SCHOOLS OF MEDICINE 229044195 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 427685 NCI 407952 20796 ABSTRACTThe Cancer Research Training Program (CRTP) at the University of Virginia brings together faculty andtrainees with a common interest in cancer biology to participate in an integrated program of cancer researcheducation and discovery. The overall objective of the CRTP is to empower the next generation of cancerresearchers with the tools to become future leaders in the quest to understand oncological processes andimprove patient outcomes. We accomplish these goals through intensive cancer research training coupled withacademic and professional development activities. Together these provide the trainees with (1) a broad-basedknowledge of fundamental principles in cancer biology; (2) the ability to define and solve vital researchquestions using the most current approaches and techniques in the constantly changing landscape ofbiomedical research; and (3) the skills to partner with basic scientists translational researchers clinicaltrialists clinicians and cancer patients/survivors to promote discovery and improved outcomes. This renewalapplication incorporates a new leadership structure prompted by the addition of Dr. Andrew Dudley as part of amulti-PI team with the current PI Dr. Amy Bouton. We request support for 8 predoctoral trainees who willparticipate in longitudinal training that includes laboratory research formal course work programmaticactivities exposure to clinical/translational aspects of cancer programming in professional/careerdevelopment and community outreach opportunities. The 42 CRTP faculty mentors provide a robust and fullyintegrated platform through which the program delivers this training. Most importantly the CRTP takesadvantage of the robust cancer research community provided by the NCI-designated UVA Cancer Center. Thisaffords the trainees an opportunity to apply their own experiences in basic cancer research to the need forimproved diagnosis and treatments in cancer care. The CRTP has experienced much success over its almost44-year history. As we move into the next funding period we challenge ourselves to meet the changinglandscape of cancer research through constant assessment and evolution of the program. In this regard wehave incorporated a number of new initiatives designed to reinforce community-building provide newopportunities for applied learning and professional development and promote dialogues between trainees andcancer patients/survivors. This renewal application also includes important new enhancements focused ontraining in rigor and reproducibility mentor training and the establishment of an Advisory Committee forDiversity & Inclusion. The full array of CRTP activities together with a dedicated faculty talented cadre oftrainees and vibrant cancer research community all contribute to producing CRTP alumni who are well-positioned to become lifelong learners and future leaders in the continually evolving field of cancer research. 427685 +No NIH Category available Adjuvant;Adverse event;Alcohol consumption;Anatomy;Animals;Anti-Inflammatory Agents;Apoptosis;Bacteria;Biological;Cancer Patient;Cell Proliferation;Cells;Chronic;Clinical;Clinical Trials;Communities;Complex;Dental Hygiene;Detection;Development;Diet;Dietary intake;Disease;Dose;Elements;Enrollment;Environment;Environmental Risk Factor;Enzyme-Linked Immunosorbent Assay;Evolution;Excision;Food Additives;Food Preservatives;Frequencies;Future;Goals;Gram-Positive Bacteria;Growth;Head and Neck Cancer;Heavy Drinking;Homeostasis;Human;Human Microbiome;Human Papilloma Virus Vaccination;Human papilloma virus infection;Immunohistochemistry;Immunotherapy;In Vitro;Incidence;Individual;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Investigation;Link;Malignant Neoplasms;Maximum Tolerated Dose;Measures;Mediating;Metastatic/Recurrent;Microbial Biofilms;Mouth Diseases;Nisin;Operative Surgical Procedures;Oral;Oral Characters;Oral Stage;Oral cavity;Organism;Outcome;Participant;Patient-Focused Outcomes;Patients;Periodontal Diseases;Perioperative Adjuvant Therapy;Phase;Population;Prevalence;Progression-Free Survivals;Protozoa;Quantitative Reverse Transcriptase PCR;Radiation therapy;Recurrence;Regimen;Research;Resistance;Risk;Risk Factors;Role;Safety;Saliva;Sampling;Shotguns;Signaling Molecule;Specimen;Structure;Survival Rate;Therapeutic;Tissue-Specific Gene Expression;Tissues;Tobacco use;Toll-like receptors;Treatment Protocols;Virus;anti-cancer;antimicrobial;antitumor effect;bactericide;bacteriocin;base;cancer cell;cancer recurrence;cancer risk;cancer therapy;cancer type;carcinogenesis;carcinogenicity;cell motility;chemokine;cohort;cytokine;demographics;dental biofilm;differential expression;disorder risk;dysbiosis;effective therapy;fungus;head and neck cancer prevention;high risk population;immunoregulation;improved;improved outcome;in vivo;insight;malignant mouth neoplasm;malignant oropharynx neoplasm;metagenomic sequencing;microbial;microbial composition;migration;modifiable risk;mouse model;mouth squamous cell carcinoma;multiple omics;novel;novel therapeutics;oral bacteria;oral microbiome;oral plaque;oral tumorigenesis;pathogen;pathogenic bacteria;primary endpoint;rRNA Genes;response;saliva sample;smoking cessation;targeted treatment;time use;transcriptome sequencing;treatment duration;treatment response;tumor;tumor progression;tumorigenesis;tumorigenic Oral microbiome and inflammatory status in antimicrobially-treated oral cancer patients PROJECT NARRATIVEThe food additive nisin has been increasingly recognized for its broad-spectrum bactericidal action andimmunomodulatory effects in both animals and humans; however its clinical benefit in improving outcomes ofhuman oral cancer patients has not been explored. Here we will conduct a Phase I/IIa trial of nisin in patientswith oral squamous cell carcinoma to establish tolerability and feasibility of the treatment regimen. In parallelwe will analyze patient biological samples for nisin-induced changes in oral microbiome diversity inflammasomeexpression and anti-cancer cellular responses which we predict are the mechanisms through which nisinpromotes an anti-tumorigenic environment and protects against oral cancer. NCI 10685029 12/15/22 0:00 PA-18-902 7R01CA269950-02 7 R01 CA 269950 2 "XI, DAN" 6/13/22 0:00 5/31/27 0:00 Cancer Prevention Study Section[CPSS] 6431827 "KAPILA, YVONNE L" "YOM, SUE S." 36 NONE 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF DENTISTRY/ORAL HYGN 900952000 UNITED STATES N 9/1/22 0:00 5/31/23 0:00 395 Non-SBIR/STTR 2022 664088 NCI 546841 117247 ABSTRACTThe incidence of oral squamous cell carcinoma (OSCC) the most common type of head and neck cancercontinues to rise among numerous demographic groups in the US yet its 5-year survival rate has not improvedfor several decades. Despite advances in targeted therapy immunotherapy and other novel adjuvant regimenspatients with locoregionally advanced and recurrent/metastatic disease continue to have extremely pooroutcomes underscoring the need for more effective treatments for OSCC which often goes undiagnosed untilit has reached late stages. Primary risk factors for OSCC include tobacco use alcohol consumption and fororopharyngeal cancers HPV infection but cancer incidence is influenced by additional elements such asanatomic site patient demographics and likely the individuals oral microbiome. Given that cases of OSCC areincreasing despite targeted head and neck cancer prevention efforts in the US such as smoking cessation andHPV vaccination there is a strong rationale for exploring other modifiable risk factors that together with newtherapies can improve outcomes for patients with OSCC as well as other aggressive head and neck cancers.The oral microbiome is a complex and dynamic community of commensal organisms that can becomeimbalanced (dysbiotic) in response to dietary intake tobacco and alcohol use and poor dental hygiene.Dysbiosis can pre-dispose an individual to oral disease including cancer by enriching for bacterial pathogensthat promote carcinogenesis secrete carcinogenic compounds and promote chronic inflammation. Thusreversing oral dysbiosis is a promising approach for protecting against tumorigenesis. The food additive nisinwhich is bactericidal against a broad range of pathogens has been shown to restore oral microbiome diversitysuppress inflammation and stimulate anti-tumor cellular responses in vitro and in a polymicrobial mouse modelof oral cancer while maintaining its well-established safety profile. However the potential clinical benefit of nisinfor treating OSCC in humans has not been investigated. Here we propose a Phase I/IIa trial to establish thetolerability and feasibility of administering nisin to OSCC patients who represent high-risk populations. In parallelwe will perform mechanistic studies of nisin and its effects on oral microbiome community structureinflammasome expression and anti-cancer cellular responses of the study participants. We will also analyze theemergence of nisin resistance among key oral bacteria which could provide insight into circumventing nisinresistance in other clinical contexts. We hypothesize that nisin will be well-tolerated among OSCC patients andwill counter dysbiosis by inhibiting bacterial pathogen growth and promoting an anti-tumorigenic environment viaimmunomodulation and anti-cancer cell activity. Our long-term goals are to validate nisin as a promisingcandidate for OSCC treatment and demonstrate that oral dysbiosis is a major driver of tumorigenesis in humansthat can be manipulated thus highlighting the important yet mostly unrecognized protective role thatantimicrobials can exert against cancer in humans. 664088 +No NIH Category available Affect;Arizona;Biochemical;Biological;Biological Markers;Chemoprevention;Chronic Disease;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Collaborations;Contracts;Data;Development;Dose;Drug Delivery Systems;Evaluation;Foundations;Funding;Genomics;Human Resources;Immune;Immunologic Surveillance;Immunomodulators;Immunoprevention;Incidence;Intercept;Lead;Leadership;Lesion;Longterm Follow-up;Lung;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of prostate;Manuscripts;Metabolic;Molecular;Molecular Target;Normal tissue morphology;Nutraceutical;Organ;Organizational Affiliation;Participant;Pathologist;Pathway interactions;Phase;Physicians;Preparation;Preventive;Process;Regulation;Research;Safety;Schedule;Site;Skin Carcinoma;Surrogate Endpoint;Tissues;Translational Research;Universities;Urologic Cancer;Work;biomarker identification;cancer clinical trial;cancer invasiveness;cancer prevention;carcinogenesis;clinical development;clinically relevant;design;drug repurposing;early phase clinical trial;efficacy trial;epidemiology study;experience;insight;interest;malignant breast neoplasm;medical specialties;melanoma;new technology;novel;pharmacokinetics and pharmacodynamics;phase III trial;potential biomarker;preclinical study;premalignant;prevention clinical trial;primary endpoint;protocol development;response;skin cancer prevention;surveillance network;translational scientist University of Arizona Cancer Prevention Clinical Trials Network (UA CP-CTNet) PROJECT NARRATIVEAdvances in molecular understanding of the process of cancer development and progression including genomicmetabolic and immune hallmarks have led to the study of an increasing number of agents to intercept the earlyphases of cancer development for cancer prevention. The overall objective of University of Arizona CancerPrevention Clinical Trials Network is to perform early phase clinical trials to evaluate the biologic effects ofputative preventive agents and to determine clinically relevant correlates in order to identify agents with goodsafety profiles and preliminary efficacy. Scientific and clinical evidence generated from these early phase cancerprevention clinical trials will contribute significantly to the decision for further clinical development of putativeagents for cancer prevention. NCI 10684914 8/7/23 0:00 RFA-CA-18-029 5UG1CA242596-05 5 UG1 CA 242596 5 "JOHNSEY, DONALD" 8/16/19 0:00 7/31/25 0:00 ZCA1-TCRB-O(M1) 1878826 "CHOW, H-H. SHERRY" "BAUMAN, JULIE E" 7 INTERNAL MEDICINE/MEDICINE 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1507039 NCI 2283048 418186 PROJECT SUMMARYAdvances in molecular understanding of the process of carcinogenesis have led to the study of an increasingnumber of agents to intercept the early phases of cancer development including the recent interest inimmunoprevention. The overall objective of University of Arizona Cancer Prevention Clinical Trials Network (UACP-CTNet) is to perform early phase clinical trials to evaluate the biologic effects of putative preventive agentsand to determine clinically relevant correlates in order to identify agents with good safety profiles and preliminaryefficacy for definitive Phase III trials.The UA CP-CTNet consists of a team of physicians from diverse specialties statisticians clinical staff datamanagers pathologists translational scientists and other personnel with extensive experience in early phaseclinical trials of cancer preventive agents and in translational research in various organ sites.Specifically the UA CP-CTNet will: Efficiently design and conduct Phase 0/I/II clinical trials to assess the cancer preventive potential of repurposed drugs that affect multiple chronic diseases well-characterized nutraceutical agents regional/topical drug delivery and immune modulators identified from translational research epidemiological studies and/or clinical research. Characterize the clinical activity and biological effects of putative cancer preventive agents on their defined molecular/biochemical targets the immune surveillance network surrogate endpoints associated with carcinogenesis and other biological effect markers identified in preclinical studies. Develop further scientific insights into the mechanisms of cancer prevention by the agents studied and to develop novel potential markers as determinants of response and for selecting subpopulations who may differentially benefit from the studied agent.Through the proposed research we expect to conduct rigorously designed early phase cancer prevention clinicaltrials that determine the clinical activity and biological effects of potential preventive agents. The researchfindings will further scientific insights into the mechanisms of cancer prevention and develop novel potentialbiomarkers as determinants of response. Scientific and clinical evidence generated from these early phasecancer prevention clinical trials will contribute significantly to go-no go decisions for further clinical developmentof putative agents for cancer prevention. 1507039 +No NIH Category available Address;Adherence;Adopted;Advocate;Applications Grants;Area;Behavior Therapy;Cancer Control;Cancer Etiology;Caring;Cessation of life;Characteristics;Clinic;Clinical;Colonoscopy;Colorectal Cancer;Communication;Communities;Complement;Data;Development;Diagnostic;Documentation;Electronic Health Record;Environment;Equitable healthcare;Evaluation;Evidence based intervention;Failure;Feces;Federally Qualified Health Center;Focus Groups;Fred Hutchinson Cancer Research Center;Frequencies;Funding;Gastroenterologist;Gastroenterology;Goals;Health;Health Policy;Health Services;Health system;Individual;Intervention;Interview;K-Series Research Career Programs;Lung;Malignant Neoplasms;Medical;Medical center;Mentors;Mentorship;Methods;Nurses;Outcomes Research;Pathway interactions;Patient Preferences;Patients;Physician Executives;Population;Prospective Studies;Provider;Qualitative Methods;Qualitative Research;Reporting;Research;Research Methodology;Research Personnel;Resources;Scientist;Screening Result;Statistical Models;Structure;System;Test Result;Testing;Training;Training Programs;Treatment Efficacy;Universities;Washington;Work;behavior change;cancer prevention;career;clinical care;colorectal cancer prevention;colorectal cancer screening;contextual factors;design;effective intervention;efficacy evaluation;experience;follow-up;implementation science;improved;innovation;intervention mapping;medical specialties;medically underserved;medically underserved population;method development;mortality;multilevel analysis;novel;performance tests;pilot test;randomized trial;research and development;safety net;screening;skills;social cognitive theory;success;therapy development Developing an intervention to improve follow-up of abnormal fecal immunochemical test results in a safety-net population using a mixed methods approach Project NarrativeFailure to complete a diagnostic colonoscopy after an abnormal fecal immunochemical test (FIT) increasescolorectal cancer (CRC)-mortality by up to 3-fold. Yet in medically underserved settings where FIT is thecornerstone of CRC screening approximately 50% of patients with an abnormal FIT do not complete a diagnosticcolonoscopy within 1 year of their result. Using a mixed methods approach the proposed project will addressthis persistent challenge in CRC prevention and control by developing an evidence-based intervention to improvefollow-up of abnormal FIT results in a large safety-net health system. NCI 10684912 7/27/23 0:00 PAR-18-337 5K08CA241296-06 5 K08 CA 241296 6 "RODRIGUEZ, LARITZA MARIA" 9/1/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 11656799 "ISSAKA, RACHEL B." Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 223603 NCI 207040 16563 Project SummaryRachel Issaka MD MAS long-term career goal is to become an independent researcher and leader indeveloping implementing and evaluating interventions to reduce colorectal cancer (CRC) mortality in medicallyunderserved populations. She has identified improving follow-up of abnormal fecal immunochemical test (FIT)results as a critical issue to address to achieve this goal. This proposal describes a 5-year comprehensiveprogram of training and mentored research for an academic career in health outcomes research. The researchagenda is in line with one of NCIs five scientific goals: to improve cancer prevention and control. In this goaladvancing health care equity in medically underserved populations is an area of special focus. While Dr. Issakahas a strong background in clinical gastroenterology and safety-net systems-level research this K08 will providekey training in advanced multilevel statistical modeling qualitative research methods mixed methods researchand intervention development. FIT is promoted over colonoscopy for CRC screening in federally qualified healthcenters (FQHCs) and safety-net health systems due to patient preference and limited colonoscopy resources.For FIT-based screening to effectively reduce CRC-mortality abnormal results must be followed by a diagnosticcolonoscopy. However FQHCs and safety-net health systems do not consistently track follow-up of abnormalFIT results and failure to complete a diagnostic colonoscopy increases CRC-mortality by up to 3-fold. Researchsuggests approximately 50% of safety-net patients with an abnormal FIT do not complete a diagnosticcolonoscopy within 1 year of their result. This highlights the importance of identifying and describing the barriersto diagnostic colonoscopy completion after abnormal FIT results in order to develop effective interventions. Thestudys specific aims are: (1) using mixed methods identify the potentially modifiable patient provider and clinic-level barriers to diagnostic colonoscopy in patients with abnormal FIT results in a large safety-net health system;and (2) based upon intervention targets identified in Aim 1 develop a pilot intervention to improve diagnosticcolonoscopy completion in a safety-net population with abnormal FIT results. Dr. Issakas mentorship teamincluding world-renowned gastroenterologists health services researchers qualitative and mixed methodsexperts and implementation scientists will provide experiential guidance to complement her didactic training.These factors in addition to the supportive research environments at the Fred Hutchinson Cancer ResearchCenter and the University of Washington will enable her to achieve the proposed project aims. Upon completionof the proposed research and training Dr. Issaka will submit a competitive R-level grant application to test thepilot intervention in a randomized trial and will possess the skills and experience to make sustained and impactfulcontributions to reduce CRC-mortality through evidence-based interventions that improve follow-up of abnormalFIT results. 223603 +No NIH Category available Address;Adherence;Age;Area;Behavior Therapy;Behavioral;Benchmarking;Cancer Burden;Cancer Center;Cancer Etiology;Cancer Survivor;Cancer Survivorship;Caring;Clinical;Cognitive;Counseling;Data;Education;Ensure;Environment;Family;Focus Groups;Foundations;Friends;Future;General Population;Goals;Health;Health Personnel;Health Psychology;Health behavior;Intervention;Interview;Lead;Life;Link;Literature;Malignant Neoplasms;Mediation;Mental Health;Modification;Morbidity - disease rate;Motivation;Outcome;Participant;Persons;Positioning Attribute;Protocols documentation;Psychology;Qualifying;Quality of life;Randomized Controlled Trials;Recommendation;Recording of previous events;Reporting;Research;Resources;Sampling;Series;Shapes;Survivors;Target Populations;Technology;Telephone;Time;Update;Vocation;Work;acceptability and feasibility;attentional control;behavioral outcome;cancer care;cancer diagnosis;cancer therapy;care providers;chatbot;coping;critical period;depressive symptoms;efficacy outcomes;efficacy trial;experience;feasibility testing;health care availability;informant;innovation;intervention delivery;mHealth;novel;pilot test;population based;preference;programs;psychological outcomes;psychosocial;recruit;satisfaction;secondary outcome;skills;social media;substance use;survivorship;tailored messaging;trend;videoconference;young adult An mHealth Positive Psychology Intervention to Reduce Cancer Burden in Young Adult Cancer Survivors PROJECT NARRATIVEWe aim to refine and pilot test an 8-week phone- and app-based intervention (AWAKE) to promote hope andthereby mitigate life disruption caused by cancer diagnosis and treatment among young adults (YAs); ourproposal involves (Aim 1) formative research among YA survivors and healthcare providers; and (Aim 2) anRCT of AWAKE vs. attention control among 150 YA cancer survivors. The proposed research is innovative inits use of: 1) a novel intervention target hope as a mechanism for addressing goal-disruption and QOLamong YA survivors; and 2) novel mHealth components and population-based recruitment strategy (via socialmedia) that are particularly relevant to YA survivors and those with potentially limited access to healthcare.This proposal has potential high impact due to the number of YA cancer survivors for whom AWAKE may berelevant AWAKEs potential utility in enhancing hope and quality of life among YAs and its reach/scalability. NCI 10684909 7/24/23 0:00 RFA-CA-20-028 5R21CA261884-02 5 R21 CA 261884 2 "MOLLICA, MICHELLE A" 8/16/22 0:00 7/31/24 0:00 ZCA1-SRB-T(J1) 8307334 "BERG, CARLA J" "AREM, HANNAH " 98 PUBLIC HEALTH & PREV MEDICINE 43990498 ECR5E2LU5BL6 43990498 ECR5E2LU5BL6 US 38.898075 -77.043933 2863301 GEORGE WASHINGTON UNIVERSITY WASHINGTON DC SCHOOLS OF PUBLIC HEALTH 200520042 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 188045 NCI 137969 50076 PROJECT SUMMARY/ABSTRACTYoung adulthood (YA) is a critical time in shaping life trajectories related to educational financial and familygoals among others. Unfortunately cancer diagnosis/treatment and its psychosocial sequelae disrupt thiscritical period for some YAs. This life goal disturbance is related to poorer psychological outcomes particularlyamong YAs; however goal revision and reprioritization lead to more positive psychological outcomes. Thusgoal negotiation is a critical part of survivorship. Understanding psychosocial determinants of positivepsychological and behavioral outcomes is critical for developing effective behavioral interventions. Within therich positive psychology literature the construct of hope is one particularly relevant factor for YA cancersurvivors; hope has been defined as a positive cognitive state based on a sense of successful goal-directeddetermination and planning to meet these goals. In the general population and in cancer survivors hope isrelated to better quality of life (QOL) mental health health behaviors and coping with illness/cancer. Our teampioneered an mHealth intervention (i.e. app-based with phone-based counseling) called Achieving WellnessAfter Kancer in Early life (AWAKE) aimed at increasing hope among YA survivors thereby re-engaging them inlong-term life goals across domains (e.g. vocational familial) and ultimately increasing QOL. In an 8-weekpilot RCT of 56 YAs recruited from 2 cancer centers AWAKE demonstrated feasibility (95% retention)acceptability (e.g. high satisfaction) and promising trends in changes in hope QOL depressive symptomsand health behaviors (e.g. substance use) in YA survivors. This proposal builds on our prior work to updateAWAKE (e.g. its technology) enhance its reach and increase our ability to examine its effects. Our specificaims are to: 1) conduct formative research examining YA cancer survivor preferences on phone-basedcounseling with app support to enhance AWAKE; and 2) test the feasibility acceptability and preliminaryefficacy of AWAKE vs. attention control (AC) via an 8-week RCT of 150 YA cancer survivors. The proposedresearch is innovative in its use of a novel intervention target hope as a mechanism for addressing goal-disruption and QOL among YA survivors and its use of novel mHealth components and population-basedrecruitment strategy (via social media) that are particularly relevant to YA survivors and those with potentiallylimited access to healthcare. This proposal is responsive to RFA-CA-20-028 and has potential high impactdue to the number of YA cancer survivors for whom AWAKE may be relevant AWAKEs potential utility inreducing cancer-related morbidity and disrupted life goals and its reach/scalability. Our team is uniquely-qualified to conduct this research based on our complementary skills and expertise and our collaborativehistory. Findings will provide the foundation for future research examining AWAKEs efficacy generalizabilityand scalability and will also catalyze research to address limitations in cancer survivorship care via mHealth. 188045 +No NIH Category available Cancer Control;Training Programs;biobehavior;cancer prevention Biobehavioral Cancer Prevention and Control Training Program (BCPT) NarrativeCancer is the second leading cause of death in the United States. The Biobehavioral CancerPrevention and Control Training Program (BCPT) prepares pre-doctoral and post-doctoraltrainees for careers that will address the challenge of cancer prevention and control. The BCPTis a joint effort of departments in the Schools of Public Health Medicine Pharmacy andNursing at the University of Washington the Fred Hutchinson Cancer Research Center andaffiliated institutions including the Seattle Cancer Care Alliance. NCI 10684906 9/6/23 0:00 PA-20-142 5T32CA092408-22 5 T32 CA 92408 22 "BOULANGER-ESPEUT, CORINNE A" 9/1/01 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 7842275 "HANNON, MARGARET A" Not Applicable 7 ADMINISTRATION 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA SCHOOLS OF PUBLIC HEALTH 981959472 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 220923 NCI 283840 16787 ABSTRACT The Biobehavioral Cancer Prevention and Control Training Program (BCPT) a 20-year collaborationbetween the University of Washington and the Fred Hutchinson Cancer Research Center providesinterdisciplinary research training to pre-doctoral and post-doctoral trainees to prepare them to be the nextgeneration of leaders in cancer control research. The objectives of the program for the next 5 years are to: 1)recruit excellent and diverse pre-doctoral and post-doctoral applicants from social and behavioral science-based disciplines as well as PhD or MD-trained basic or clinician scientists who wish to add a social andbehavioral sciences perspective to their cancer research; 2) provide trainees with an exceptionalinterdisciplinary training experience that includes expert mentorship research experience in active cancerprevention and control projects and leadership opportunities within those projects and within the traineecommunity; and 3) skill development in grant writing preparing scientific manuscripts and oral presentationsfor conferences and career planning. We propose to support two pre-doctoral and four post-doctoral traineeseach year; ideally each trainee would be supported for two years and we would support at least 18 traineesover the 5-year period. We will also maintain our affiliate program to extend BCPT training and mentoringopportunities to other trainees funded from different sources. The unique collaboration between the University of Washington and the Fred Hutchinson CancerResearch Center provides a rich array of qualified mentors formal coursework and cancer research projectstrainees engage with. We engaged faculty from multiple academic settings to train and support BCPT trainees;these faculty will be a major presence in the next five years of training. Formal coursework at the University ofWashington is provided within the School of Public Health Departments of Health Systems and PopulationHealth Epidemiology and Biostatistics the School's interdisciplinary programs in Public Health Genetics andPublic Health Nutrition the School of Pharmacy as well as within the School of Nursing for appropriatecandidates. Doctoral programs are offered in all these departments. Trainees will complete researchexperience with their mentors at the Fred Hutchinson Cancer Center the Seattle Cancer Care Alliance andthe University of Washington. Over the life of BCPT we have appointed 34 predoctoral fellows 19 postdoctoralfellows and have provided support to 20 affiliated fellows (who were not funded through BCPT). The vastmajority of our trainees have completed BCPT and gone on to research careers in cancer control. The BCPTprovides trainees the knowledge skills and professional experiences they require to transition to successfulcareers in cancer prevention and control. 220923 +No NIH Category available ATAC-seq;Age;Attention;Base Sequence;Binding Sites;Biological Assay;Cancer Biology;Cancer Center;Cancer Detection;Cancer Model;Categories;Cells;ChIP-seq;Chemoresistance;Chromatin;Clinical;Clinical Data;Clinical Trials;Cluster Analysis;Code;Competence;Complement;Custom;Cytosine;DNA;DNA Integration;DNA Methylation;DNA Modification Process;DNA Sequence Alteration;Data;Data Analyses;Defect;Development;Enhancers;Epigenetic Process;Event;Evolution;Formalin;Functional disorder;Gastrointestinal Neoplasms;Genes;Genome;Genome Data Analysis Network;Genomics;Growth;Higher Order Chromatin Structure;Human;Hypermethylation;MLH1 gene;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Methylation;Microsatellite Instability;Mismatch Repair;Mitosis;Molecular;Mutation;Nature;Oncogene Activation;Outcome;Paraffin Embedding;Pathway Analysis;Play;Prevalence;Productivity;Proteins;Proteomics;Quality Control;Race;Reader;Recurrent Malignant Neoplasm;Role;Sampling;Somatic Mutation;Specimen;Tumor Suppressor Genes;Validation;Variant;bioinformatics tool;bisulfite;bisulfite sequencing;cancer cell;cancer classification;cancer genome;cancer genomics;cancer recurrence;cancer subtypes;chromatin remodeling;clinical trial analysis;clinically relevant;data harmonization;determinants of treatment resistance;driver mutation;epigenetic silencing;epigenomic profiling;epigenomics;exceptional responders;gene repair;genetic information;histone methylation;histone modification;innovation;insight;interest;molecular pathology;mouse model;multiple data types;novel;programs;promoter;sample fixation;sex;temporal measurement;tool;transcription factor;transcriptome sequencing;transcriptomics;tumor Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC) PROJECT NARRATIVECancer arises from the loss of control of growth in cells. Although attention has focused mostly on geneticmutations as the origin of these defects it has become clear that changes in the epigenetic control of geneactivity also contribute to this loss of growth control. This project aims to provide epigenetic analysis of clinicaltrial epigenomic data to advance our understanding of how epigenetic defects impact cancer biology andclinical outcome. NCI 10684894 8/22/23 0:00 RFA-CA-20-053 5U24CA264023-03 5 U24 CA 264023 3 "YANG, LIMING" 9/1/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 2083858 "LAIRD, PETER W" "SHEN, HUI " 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 446881 NCI 235201 211680 PROJECT SUMMARY / ABSTRACT The widespread nature of epigenetic abnormalities in human cancers has become increasingly appreciatedin the past decade with clinical impacts in cancer detection cancer classification chemoresistance predictionand therapy. Large-scale cancer genomic screens have revealed a previously unrecognized prevalence ofsomatic mutations among epigenetic regulators in human cancers including chromatin remodelers as well ashistone or DNA methylation readers writers and erasers. Epigenetic alterations can serve as driver events incancer by inactivating tumor-suppressor genes. The finding that these silencing events are mutually exclusivewith structural or mutational inactivation of the same gene reinforces the functional significance of epigeneticsilencing. The majority of cases of microsatellite instability in sporadic human tumors can be attributed toepigenetic silencing of the MLH1 mismatch repair gene. Clearly epigenetic mechanisms play a key role inhuman cancer and a comprehensive molecular characterization of cancer should include epigenomic profiling.In 2015 we established an Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC) to providespecialized expertise in epigenomic data analysis as part of the Genome Data Analysis Network (GDAN). Wehave made major contributions to the GDAN in the past five years developing cutting-edge DNA methylationbioinformatics tools leading analysis teams in PanCanAtlas ATAC-Seq Pan-Gastrointestinal (Pan-GI)Cancers and Tumor Molecular Pathology (TMP) and making major contributions to the ExceptionalResponders (ER) study testicular germcell tumors (TGCT) data harmonization (QC) CCG AncestryInformative Markers (AIM) and many other projects. Here we propose to sustain this productive activity in acontinuation of the ICE-DAC lending our deep expertise in epigenomic data analysis to collaborativeintegrative genomic and epigenomic analyses of clinical specimens within the NCI GDAN. In Specific Aim 1we will provide advanced specialized analysis of bulk and single-cell cancer epigenomic data generated byprograms within the NCI Center for Cancer Genomics. We have developed various tools for epigeneticanalysis and implemented an automated workflow to provide timely primary data analysis for AWGs. InSpecific Aim 2 we will implement innovative tools to extract additional information from specialized data types.This Aim maximizes the utility of the data generated and adds to the rigor of analysis by providing orthogonalvalidation. These analyses will include prediction of common covariates (such as sex age and race) for thesamples analysis of tumor purity and composition inferences of genetic information (including geneticmutation copy number and large structural variants) all from the DNA methylation assays. In Specific Aim 3we will integrate epigenomic data with other genomic transcriptomic proteomic and clinical data to derivebiologically and clinically relevant novel insights. Our deep expertise in specialized epigenomics will address acore competency required in GDAN and complement other genomic analyses of clinical trial samples. 446881 +No NIH Category available Acute Myelocytic Leukemia;American;Androgen Antagonists;Antineoplastic Agents;Apoptosis;Apoptotic;BAX gene;BCL-2 Protein;BCL2 gene;BCL2L1 gene;BCL2L11 gene;Binding;Binding Proteins;Binding Sites;Biochemical;Biology;C-terminal;Cardiolipins;Cell Death;Cell Line;Cell Membrane Permeability;Cells;Cellular Stress;Cessation of life;Clinic;Clinical;Cytoplasm;Data;Development;Disease;Enzyme Inhibitor Drugs;Epithelium;Exposure to;FDA approved;Family;Family member;Funding;Glucocorticoids;Hematologic Neoplasms;Hematopoietic;Hematopoietic Neoplasms;Higher Order Chromatin Structure;Hormonal;Human;In Vitro;Induction of Apoptosis;Lead;Leukemic Cell;Leukocytes;Life;Lipid Binding;Lymphoid Cell;Lymphoma cell;MCL1 gene;MEKs;Malignant Neoplasms;Mediating;Membrane Lipids;Mitochondria;Molecular;Morphology;Mus;Myeloid Cells;Nature;Outer Mitochondrial Membrane;PIK3CG gene;PMAIP1 gene;Pathway interactions;Pattern;Peptides;Permeability;Phase;Play;Positioning Attribute;Preclinical Testing;Process;Protein Family;Proteins;Proto-Oncogene Proteins c-akt;Regimen;Regulation;Role;Sampling;Seminal;Specimen;Stimulus;Structure;Testing;Therapeutic;Tissues;antagonist;anticancer treatment;base;biophysical analysis;cancer cell;cancer therapy;cell type;cytotoxicity;design;dimer;drug sensitivity;effective therapy;experimental study;improved;in vivo;inhibitor;insight;interest;leukemia;leukemia treatment;mTOR Inhibitor;member;mimetics;monomer;novel;paralogous gene;postnatal;research clinical testing;resistance mechanism;response;restraint;small molecule;structural determinants;targeted agent;targeted treatment;truncated BID protein;tumor BAK Autoactivation in Hematological Malignancies PROJECT NARRATIVEMembers of the BCL2 protein family regulate life/death decisions by modulating mitochondrial outer membranepermeability. Our previous results have demonstrated that the pro-apoptotic family member BAK is constitutivelyactivated in a subset of acute myeloid leukemia (AML) samples as well as leukemia and lymphoma cell linespriming them to respond to certain treatments. With an eye toward improving AML therapy this project focuseson i) understanding the cellular and biochemical bases for this constitutive BAK activation and ii) determining theimplications of constitutive BAK activation for respose to AML treatment in the clinic using as an example theresponse to a novel regimen of targeted agents that is currently being developed for use in AML. NCI 10684892 7/12/23 0:00 PA-19-056 5R01CA225996-04 5 R01 CA 225996 4 "BOURCIER, KATARZYNA" 7/1/20 0:00 6/30/25 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 1861030 "KAUFMANN, SCOTT H" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 356438 NCI 224175 132263 ABSTRACTThe mitochondrial apoptotic pathway plays a critical role in the response to various cellular stresses includingtargeted anticancer therapies. This pathway is regulated by interactions between various members of the BCL2family of proteins. In particular BAX and BAK play an indispensible role in this pathway by permeabilizing themitochondrial outer membrane (MOM). While BAX plays a predominant role in epithelial tissues especially inpostnatal life BAK is particularly abundant in normal white blood cells leukemia cell lines and clinical leukemiaspecimens. Our previous studies have demonstrated that BAK activation is initiated by two distinct processes:i) Transient binding of BH3-only members of the BCL2 family in response to certain stimuli (e.g. transient bindingof NOXA which is upregulated in response to the NEDD8 activating enzyme inhibitor pevonedistat) andii) concentration-dependent BAK autoactivation a process we initially described. Once activated BAK formsmultimers that permeabilize the MOM. Our recent studies indicate that this MOM permeabilization involves theaction of a C-terminal lipid binding domain that is externalized upon BAK activation and interacts with the MOMlipid cardiolipin. Counterbalancing this pro-apoptotic effect however BAK can be bound and neutralized by anti-apoptotic BCL2 paralogs in lymphohematopoietic cell lines and primary acute myeloid leukemia (AML)specimens. Importantly the response of these cells to BH3 mimetics proapoptotic small molecules thatselectively bind and neutralize BCL2 BCLXL and/or MCL1 reflects which of the anti-apoptotic BCL2 familymember(s) constitutively bind BAK. Collectively these observations lead to the hypothesis that AMLs withhigher BAK levels will harbor more constitutively activated BAK and will be particularly sensitive to BH3mimetics as well as targeted therapies that activate BH3-only proteins. We now propose three aims thatwill test this hypothesis and provide additional insight into the action of BAK in AML during anti-leukemic therapy.First we will assess the mechanisms responsible for high BAK expression in some AMLs but not others becausehigh BAK expression contributes to BAK autoactivation. Second we will determine the biochemical basis forBAK autoactivation and subsequent restraint by anti-apoptotic BCL2 family members because this partially-activated-and-then-restrained BAK is the species poised to kill leukemia cells upon exposure to BH3 mimeticsand targeted therapies that upregulate BH3-only proteins. Third we will assess the relationship between highBAK expression BAK restraint by various anti-apoptotic BCL2 family members and response of clinical AML toa novel pevonedistat-containing combination undergoing early phase clinical testing thereby assessing thepotential importance of constitutive BAK activation in the clinical setting. These studies which build on our recentadvances in understanding the action of BAK at the molecular level are collectively designed to enhance currentunderstanding of BCL2 family biology and simultaneously provide new insight into a potentially importantdeterminant of AML sensitivity in the clinic. 356438 +No NIH Category available Address;Affect;Antibodies;Autopsy;Benchmarking;Benign;Biological;Biological Assay;Biological Markers;Biological Sciences;Biopsy;Biopsy Specimen;Categories;Cells;Classification;Clinic;Clinical;Clinical Management;Collaborations;Contracts;Cooperative Human Tissue Network;Cytology;DNA Sequence Alteration;Data;Detection;Development;Diagnosis;Diagnostic;Diagnostic Imaging;Diagnostic tests;Disease;Documentation;Early Diagnosis;Excision;Feasibility Studies;Fine needle aspiration biopsy;Fluorogenic Substrate;Frequencies;Genetic Risk;Genomics;Goals;Guidelines;Image;Indiana;Industry Standard;Institutional Review Boards;Laboratories;Lesion;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of thyroid;Measures;Molecular;Molecular Analysis;Monitor;Nodule;Nucleotides;Operative Surgical Procedures;Pathologic;Pathology;Patient risk;Patients;Peptide Hydrolases;Performance;Persons;Phase;Predictive Value;Prevalence;Prospective cohort;Proteins;Proteolysis;Proteomics;Readiness;Reporting;Resected;Retrospective cohort;Risk;Risk Marker;Sampling;Science;Scientific Advances and Accomplishments;Sensitivity and Specificity;Source;Specificity;Technology;Testing;Thyroid Gland;Thyroid Nodule;Thyroidectomy;Tissue Sample;Tissues;Ultrasonography;United States;Universities;Unnecessary Surgery;Validation;Work;biobank;biomarker discovery;cancer invasiveness;clinical center;clinical decision-making;clinical practice;cohort;commercialization;cost;detection limit;diagnostic accuracy;diagnostic assay;diagnostic biomarker;diagnostic tool;enzyme activity;improved;innovation;mortality;novel marker;patient stratification;precision medicine;premalignant;prognostic;programs;prospective;rapid test;risk stratification;standard of care;technology validation;tool;ultrasound;validation studies Development of a multi-analyte diagnostic assay to improve the risk stratification of indeterminate thyroid nodules Project NarrativeEarly diagnosis is the single most important tool to delay or avoid cancer-related mortality. Many peopleundergoing diagnostic imaging today are found to have nodules in their thyroid which in some casesare malignant; however it is currently very difficult to predict which nodules are true malignant lesionsand which will remain benign and asymptomatic. Using our previously validated technology we havediscovered functional biomarkers to differentiate benign from malignant thyroid nodules. In the currentproposal we aim to further develop these novel markers into a diagnostic assay to facilitate earlydetection of malignancy as well as to avoid unnecessary and costly surgeries for cases with benignnodules. NCI 10684875 7/17/23 0:00 PA-21-259 5R44CA254649-03 5 R44 CA 254649 3 "FRANCA-KOH, JONATHAN C" 8/15/22 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-OTC-V(13)B] 2291085 "KNUDSEN, GISELLE M" Not Applicable 15 Unavailable 78643292 W1XRNVJNQLL6 78643292 W1XRNVJNQLL6 US 37.775338 -122.459041 10042998 "ALAUNUS BIOSCIENCES, INC." SOUTH SAN FRANCISCO CA Domestic For-Profits 940806883 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 SBIR/STTR 2023 696026 NCI 559066 91426 AbstractWidespread use of sensitive imaging in clinical practice has resulted in incidental thyroid nodulesbeing discovered with increasing frequency creating a unique opportunity to detect and removelesions at early stages of malignancy. The majority of these incidental nodules remain benign andasymptomatic but 10-20% are found to be malignant on surgical excision resulting in a critical needfor improved diagnostics as 75% of patients currently undergo unnecessary thyroidectomies toremove benign nodules. The current standard of care includes collecting a tissue biopsy byultrasound-guided fine needle aspiration: these samples are tested by cytology which looks foraberrant cells and for genetic risk markers. These diagnostic tests are characterized by poorspecificity and a third of all tested nodules are still classified as indeterminate and need to beresected for a pathological diagnosis. We originally hypothesized that dysregulated proteolysis atype of enzyme activity that is a hallmark of invasive cancer might yield discriminating levels ofactivity in FNA tissue from benign and malignant nodules. In Phase I work we leveraged the AlaunusBiosciences Inc. diagnostic pipeline a platform that allows innovative proteomics-based biomarkerdiscovery to identify and characterize a set of protease activities (functional markers) that aresignificantly increased in malignant nodules. We then developed fluorogenic substrate assays tomonitor these activities using small volumes of biological samples. In parallel we also discoveredadditional mass-based markers that can be measured with standard antibody-based assays. Ourinvestigational multi-analyte diagnostic assay has the potential to differentiate malignant from benignthyroid tissue with sensitivity and specificity >90%. In this Phase II proposal we aim to performtechnical and clinical validation studies required to advance the assay to readiness for clinical use inthe early diagnosis of indeterminate thyroid nodules. In Aim 1 we will benchmark the clinical utility ofour selected protein and functional biomarkers in surgical tissue to evaluate scoring establishdiagnostic thresholds and report on key assay parameters. In Aim 2 we will perform acomprehensive technical assessment of the laboratory performance of the assay to satisfy industrystandards. In Aim 3 we will create an independent cohort of FNA tissue samples through our IRB-approved biobanking efforts at UCSF UCLA and IU to be used for a robust prospective validation ofthe clinical usefulness of the assay. Our goal is to develop a rapid assay that improves patientstratification over current standard diagnostic markers guides clinical decision-making to avoidunnecessary surgical intervention and transforms the clinical management of these challenginglesions. 696026 +No NIH Category available Adolescent and Young Adult;Affect;Applied Genetics;Beds;Behavior;Biological Assay;Biosensor;Bone Tissue;Buffers;Cancer Biology;Caveolins;Cell Survival;Cells;Cellular Morphology;Child;Clinical Trials;Collaborations;Complement;Data;Disease;Disseminated Malignant Neoplasm;Embryo;Enabling Factors;Engraftment;Environment;Epigenetic Process;Event;Ewings sarcoma;Failure;Fishes;Genetic;Genetic Models;Genome;Genomics;Goals;Heterogeneity;Human;Image;Imaging technology;In Situ;Intrinsic factor;Link;MAP Kinase Gene;Malignant Bone Neoplasm;Mechanics;Membrane;Metabolic;Metastatic/Recurrent;Microscopy;Morphology;Multimodal Imaging;Mus;Neoplasm Metastasis;Optics;Organ;Organism;Outcome;Oxygen;Pathway interactions;Patients;Pattern;Phenotype;Population;Primary Neoplasm;Property;Recurrence;Research;Resolution;Role;Signal Pathway;Signal Transduction;Site;Survival Rate;System;Testing;Tissues;Treatment-related toxicity;Visit;Visualization;WNT Signaling Pathway;Whole Organism;Xenograft Model;Xenograft procedure;Zebrafish;adverse outcome;cancer cell;caveolin 1;cell behavior;chemotherapy;childhood sarcoma;driver mutation;functional adaptation;genetic manipulation;high resolution imaging;imaging capabilities;in vivo;insight;mouse model;multimodality;neoplastic cell;novel strategies;optogenetics;prevent;quantitative imaging;sarcoma;soft tissue;tool;tumor;tumor microenvironment;tumor xenograft Cancer Biology Research Test-Bed Unit 1: Effects of cell-intrinsic and cell-extrinsic signaling and mechanics on metastasis patterns of pediatric sarcomas n/a NCI 10684864 8/9/23 0:00 RFA-CA-21-002 5U54CA268072-03 5 U54 CA 268072 3 9/24/21 0:00 8/31/26 0:00 ZCA1-SRB-X 5450 1930435 "AMATRUDA, JAMES F" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 391117 326511 79412 Ewing sarcoma a malignant tumor of bone and soft tissue affecting children adolescents and young adults. Forthe one-third of Ewing sarcoma patients who develop metastasis the long-term survival rate remains less than30%. Decades of clinical trials with ever-increasing intensity of chemotherapy have increased the toxicity oftreatment but have not affected the poor outcome of metastatic disease. This failure to adequately treatmetastases indicates that new approaches are needed to better understand the genesis of metastatic cells fromthe primary tumor and behavior of these cells in the in vivo microenvironment. Though there has been substantialprogress in genomic profiling of tumors these assays are unlikely to identify major determinants of metastaticbehavior. This is because i) Ewing sarcomas typically have quiet genomes with few identifiable drivermutations; and ii) adverse outcomes may arise due to the functional adaptations of a small population of cells tothe tumor microenvironment driven by epigenetic metabolic morphologic or non-cell autonomous mechanisms.The broad goal of this project is thus to determine how extrinsic and intrinsic factors influence Ewing sarcomacell fates at the metastatic site. A significant barrier to better understanding has been the lack of experimentalsystems that can probe heterogeneity of cell functional states at whole-organism single-cell and subcellularlevels. Recent findings suggest that modulation of cell-mechanical features via the caveolin-1 and WNT signalingpathways may contribute to Ewing sarcoma metastasis however the mechanisms of this adaptation are notknown. As a system to visualize the heterogeneous functional properties of the metastatic cell population shedfrom a primary tumor we leverage the zebrafish embryo as a host organism for human tumor xenografts. Ewingsarcoma cells readily engraft into zebrafish embryos and directly interact with the microenvironment of fullyfunctional organs. The optical clarity of the fish allows us to perform multi-modal imaging to 1) identify hosttissues associated with recurrent metastatic events; 2) define morphologic changes in cells undergoingmetastatic adaptation in vivo; and 3) probe the activity of cancer cell signaling pathways in metastatic cells atsubcellular resolution. Using powerful genetic tools and specific biosensors we will exploit the quantitativeimaging technology developed by TDU-1 to probe the role of caveolin-1 and WNT-dependent signaling in Ewingsarcoma metastasis. These studies will be complemented by parallel assays in mouse models and human Ewingsarcoma tumors enabled by collaboration with TDU-2. Ultimately these findings will inform strategies aimed atpreventing or eliminating metastasis via targeting signaling mechanisms. We will determine effects ofmicroenvironmental interactions on morphology and signaling of metastatic tumor cells; test the contribution ofCaveolin-1 to metastatic cell adaptation to host environments; and probe the role of WNT signaling in Ewingsarcoma metastasis in genetic models. Ultimately these results will inform novel strategies to prevent orameliorate metastasis in patients with Ewing sarcoma. +No NIH Category available 3-Dimensional;Acceleration;Address;Automation;Automobile Driving;Back;Biochemical;Biological;Biological Assay;Biosensor;CRISPR/Cas technology;Cell Line;Cells;Cellular Morphology;Chemicals;Chemistry;Communities;Computer Systems;Computer Vision Systems;Computer software;Computing Methodologies;Cues;Data Analyses;Development;Dimensions;Dyes;Electromagnetics;Engineering;Event;Feedback;Fostering;Frequencies;Goals;Heterogeneity;Image;Immunofluorescence Immunologic;In Situ;Intelligence;Interleukin-2;Intrinsic factor;Label;Laboratories;Light;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measurement;Mechanics;Mediating;Metabolic;Methods;Microscope;Microscopy;Microtomy;Molecular;Molecular Analysis;Morphology;Neoplasm Metastasis;Nodule;Nutrient availability;Optics;Organ;Organism;Oxidation-Reduction;Performance;Periodicity;Physics;Preparation;Process;Proteins;Proteomics;Reagent;Refractive Indices;Resolution;Risk;Robotics;Sampling;Signal Transduction;Site;Slice;Solid Neoplasm;Solvents;Specimen;Speed;Technology;Testing;Thick;Thinness;Three-Dimensional Imaging;Tissue Preservation;Tissue imaging;Tissues;Transcript;Travel;Validation;automated analysis;cancer cell;cancer initiation;design;fluorescence imaging;high resolution imaging;imaging approach;imaging system;improved;innovation;insight;instrument;meter;multiplexed imaging;nano;next generation;programs;stressor;usability Technical Development Unit 2: Intelligent Hyperspectral Imaging of Subcellular Molecular States at the Whole Organ Level n/a NCI 10684861 8/9/23 0:00 RFA-CA-21-002 5U54CA268072-03 5 U54 CA 268072 3 9/24/21 0:00 8/31/26 0:00 ZCA1-SRB-X 5449 12256238 "DEAN, KEVIN MICHAEL" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 460626 396020 79412 PROJECT SUMMARY/ABSTRACTCancers of different types preferentially metastasize to different tissues and specific sites in these tissues. Whythis is true remains poorly understood but is likely to involve a combination of cell intrinsic factors (e.g. theability of a cell to survive differences in mitogenic factors nutrient availability or context-specific stressors) andextrinsic effects (tissue-specific mechanical and biochemical cues). Gaining molecular insight into eventsinvolved in metastatic colonization is challenging because such events are rare colonies are initially smalland potential sites of colonization are widely distributed. The focus of this TDU is the development validationand dissemination of innovative toolkits for deep multiplexed tissue imaging; these toolkits will be developed inclose association with our RTBs and provided to the wider CCBIR consortium. When mature the methods wedescribed will enable quantitative measurement of molecular processes involving ~60 proteins or otherbiomolecules at subcellular resolution in a preserved tissue context. In Aim 1 we will assemble a self-drivingmultiscale microscope that leverages advances in tissue clearing fully automated high-speed and high-resolution light-sheet fluorescence imaging and computer vision to identify the earliest events in metastasisincluding the colonization of a tissue by a single metastatic cell. This microscope will have mesoscopic andnanoscopic imaging modes. The mesoscopic module has computationally controlled magnification (0.63X to6.3X) and provides ~5-10 m isotropic resolution throughout a 2.1-21mm field of view. The nanoscopic moduleprovides ~330nm isotropic resolution throughout a 300 m field of view. Biological features (metastaticcolonies) will be rapidly and efficiently identified with the mesoscopic module and interrogated at highresolution using the nanoscopic module. Aim 2 will involve development of physically and chemicallyaccelerated 60-plex cyclic immunofluorescence assays of tissue sections thick enough(~200 m) to fullyencompass a metastatic colony and its tissue niche. Thick section highly multiplexed and high-resolutionimaging will then be combined with CRISPR-Cas9 engineered cell lines from the RTBs to test specifichypotheses about signaling differentiation and morphological mechanisms involved in metastasis. Support forspatial transcript profiling and tissue proteomics will aid with integration into more gnomically focused NCIprograms. Aim 3 will develop a fully automated multi-technology microscope able to accurately describemetastatic heterogeneity in a statistically robust fashion. The instrument will combine deep isotropic resolutionimaging with highly multiplexed methods via automated sample handling labeling imaging and analysis. Thisnext-generation microscope will involve several generalizable technologies for comprehensively profiling rareevents in metastasis and also cancer initiation which is another rare event. Together the approaches wedescribe are expected to substantially advance our understanding of one of the least characterized and mostlethal features of solid tumors. +No NIH Category available 3-Dimensional;Anatomy;Animals;Atlases;Automobile Driving;Behavior;Behavioral;Biological Assay;Cell physiology;Cells;Characteristics;Compensation;Detection;Development;Disease;Disparate;Embryo;Endowment;Environmental Risk Factor;Evolution;Fluorescence Microscopy;Genomics;Heterogeneity;Human;Image;In Situ;Individual;Intelligence;Lasers;Light;Lighting;Machine Learning;Malignant Neoplasms;Maps;Metastatic/Recurrent;Microscope;Microscopy;Molecular;Molecular Probes;Monitor;Morphology;Multimodal Imaging;Neoplasm Metastasis;Optics;Organism;Pathway interactions;Pattern;Phase;Phenotype;Population;Process;Proliferating;Property;Resolution;Signal Transduction;Site;Source;Spottings;Stretching;System;Technology;Time;Tissues;Variant;Visualization;Whole Organism;Xenograft Model;Xenograft procedure;Zebrafish;adaptive optics;analysis pipeline;arm;cancer cell;cell behavior;cell type;cellular imaging;computational pipelines;fluorescence imaging;functional plasticity;high resolution imaging;imaging capabilities;model organism;multimodality;next generation sequencing;non-genomic;novel;optogenetics;prevent;programs;single cell sequencing;software development;submicron;technology development;transcriptomics;tumor;tumor xenograft Technical Development Unit 1: Intelligent live imaging of metastasis patterns and subcellular molecular states at the whole organism level n/a NCI 10684859 8/9/23 0:00 RFA-CA-21-002 5U54CA268072-03 5 U54 CA 268072 3 9/24/21 0:00 8/31/26 0:00 ZCA1-SRB-X 5448 12105406 "FIOLKA, RETO PAUL" Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 241686 177081 79412 Project SummaryFluorescence microscopy combined with the optically transparent Zebrafish xenograft model has the potentialto unravel the functional heterogeneity and adaptation of cancer cells that underlies their metastatic potential.However this requires bridging disparate scales as metastatic sites can form across an entire organism andcancer cells within need to be imaged with sub-micron 3D resolution. Further low occupancy of specificmetastatic niches requires imaging many xenografts. This stretches the capabilities of current microscopetechnology as they fail to provide high-throughput high-spatial resolution and whole organism imagingcapability at the same time. To break through this boundary we will develop a new multi-modal microscope toautonomously image both at the organism and subcellular scale in a high-throughput fashion. An optogeneticmodule further allows to manipulate pathways or photo-convert selected cancer cells for either tracking orsingle cell sequencing approaches. A computational pipeline will automatically detect and select recurringmetastatic sites across many xenografts for high-resolution imaging. This will allow for the first time thequantitative comparison of functional states such as morphology survival and proliferation and signalingbetween different niches. We anticipate that the combination of multi-modal microscopy and the computationalpipelines for autonomous imaging will shed new light on key aspects of functional heterogeneity in cancermetastasis. +No NIH Category available 3-Dimensional;Administrative Coordination;Atlas of Cancer Mortality in the United States;Authorship;Bioinformatics;Budgets;Cancer Biology;Cells;Charge;Childhood Melanoma;Collaborations;Communication;Communities;Computer software;Consensus;Core Facility;Development;Development Plans;Educational workshop;Environment;Fostering;Goals;Grant;High Performance Computing;Home;Human Resources;Image;In Situ;Infrastructure;Inosine Dialdehyde;Institution;Investments;Leadership;Learning;Malignant Neoplasms;Medical center;Metabolic;Microscopy;Molecular;Morphology;Neoplasm Metastasis;Outcomes Research;Participant;Policies;Population;Reagent;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resolution;Resource Sharing;Running;Science;Structure;Systems Biology;Technology;Testing;Tissues;Trainers Training;Work;anticancer research;cancer cell;cancer imaging;cellular imaging;childhood sarcoma;data sharing;experience;hackathon;imaging platform;meetings;outreach;programs Administration and Coordination Core n/a NCI 10684858 8/9/23 0:00 RFA-CA-21-002 5U54CA268072-03 5 U54 CA 268072 3 9/24/21 0:00 8/31/26 0:00 ZCA1-SRB-X 5447 6620738 "DANUSER, GAUDENZ " Not Applicable 30 Unavailable 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX Domestic Higher Education 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 150834 86228 79413 Project SummaryFor our program we propose an administrative structure that centers on the board of 6 PIs. The board ischaired by Gaudenz Danuser in a first-among-equals mode. The PI board will make all decisions for theprogram science policies budget personnel outreach based on consensus-seeking. All 6 PIs have long-standing scientific relations in various configurations. In the unexpected case that consensus building fails thePI board will be able to seek guidance by the External Advisory Board.Charged by the PI board Danuser will be responsible to implement activities that enable efficient team science(Aim 1) resource sharing with the community (Aim 2) and outreach (Aim 3). Key activities include: Organization of a team meeting structure enabling optimal collaboration with appropriate communication channels; Implementing policies on sharing data and authorship that foster unrestricted team science; Formation and engagement with an advisory board that will scientifically inspire and help with the mitigation of challenges that may arise in a team science project; Provision of infrastructure for dissemination of hardware software and reagents; Organization of a workshop for small groups of microscopy core facility managers with the goals of gaining over early adopters of the program technology while training the trainers; Organization of pilot grants within the UTSW cancer research community to interact with the program; Organization of a visitor program targeting cancer biologists and cell biologists at research institutions with large URM populations; Organization of two scientific workshops.Danuser will be assisted by the administrative team of the Lyda Hill Department of Bioinformatics and Cecil H.and Ida Green Center for Molecular Systems Biology he chairs at UT Southwestern Medical Center. +No NIH Category available 3-Dimensional;Acceleration;Adaptor Signaling Protein;Adopted;Affect;Algorithms;Architecture;Automobile Driving;Biological;Biological Assay;Biological Models;Blood Vessels;Cancer Biology;Cancer Etiology;Carcinoma in Situ;Cells;Cellular Morphology;Cellular biology;Cessation of life;Chemicals;Clinical Treatment;Communities;Computer Vision Systems;Core Facility;Data;Development;Disease;Distant;Educational workshop;Embryo;Environment;Environmental Risk Factor;Event;Ewings sarcoma;Extracellular Matrix;Extravasation;Goals;Heterogeneity;Human;Image;Imaging Device;Immunofluorescence Immunologic;In Situ;Individual;Informatics;Institution;Intelligence;Intrinsic factor;Invaded;Investigation;Label;Light;Malignant - descriptor;Malignant Bone Neoplasm;Malignant Neoplasms;Membrane;Membrane Proteins;Metabolic;Metabolism;Methods;Microscope;Microscopy;Molecular;Molecular Analysis;Molecular Probes;Morphology;Mus;NCI Center for Cancer Research;Neoplasm Metastasis;Oncogenic;Optics;Organ;Organism;Pattern;Periodicity;Physiological;Pilot Projects;Play;Primary Neoplasm;Process;Proliferating;Property;Research;Research Personnel;Resolution;Role;Sampling;Series;Side;Signal Transduction;Site;Solid Neoplasm;Specimen;Speed;Subgroup;System;Technology;Testing;Thick;Tissue imaging;Tissues;Training;Tropism;Variant;WNT Signaling Pathway;Work;Xenograft procedure;Zebrafish;cancer cell;caveolin 1;cell behavior;childhood sarcoma;cloud based;dimensional analysis;experimental study;fluorescence imaging;functional adaptation;high dimensionality;high resolution imaging;high throughput screening;imaging approach;imaging platform;imaging probe;imaging program;intravital imaging;lipid metabolism;live cell imaging;lymphatic vessel;melanoma;molecular imaging;multimodality;multiplexed imaging;nano;novel;outreach;programs;quantitative imaging;response;technology development;tumor xenograft Imaging mechanisms of metastatic tumor formation in situ Project NarrativeWe propose a cancer cell imaging program to probe the mechanisms of metastatic tumor formation in thecontext of the host environment. This critical step in the development of metastatic disease is likely to beaccompanied by vulnerabilities of the cancer cells that could be exploited for clinical treatment. The proposedwork will establish novel microscopy with unprecedented resolution while maintaining sufficient experimentalthroughput to discover the relevant metastasis-driving processes at the single cell level. NCI 10684857 8/9/23 0:00 RFA-CA-21-002 5U54CA268072-03 5 U54 CA 268072 3 "BECKER, STEVEN" 9/24/21 0:00 8/31/26 0:00 ZCA1-SRB-X(O1) 6620738 "DANUSER, GAUDENZ " Not Applicable 30 BIOMEDICAL ENGINEERING 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 1536482 NCI 1213453 397061 Project SummaryIn response to the RFA for a Cellular Cancer Biology Imaging Program we propose a program focused onimaging and molecularly probing the cell biological events that drive the formation of new metastatic tumors.Specifically we will address two questions: 1) How does the intersection of shifts in cell-intrinsic and cell-extrinsic signals associated with shifts in expression of the membrane adaptor protein Caveolin-1 affect themetastatic propensity of pediatric sarcoma (Research Testbed Unit 1)? 2) What are the effects of cell-intrinsicand cell-extrinsic variation in lipid metabolism on melanoma metastasis patterns (Research Testbed Unit 2)?Answers to both questions depend on technology to capture the molecular metabolic and morphologicalstates of individual metastatic cells as they colonize the distant site: In the Technology Development Unit-1 wewill develop a multi-modal multi-scale live imaging platform to investigate the effects of intersectingmicroenvironmental variation across an organism and cell intrinsic heterogeneity on metastatic spreading. Theplatform will leverage the exquisite optical and physiological properties of the zebrafish embryos to watch atonce how cells form human tumor xenografts spread to multiple distant sites where they form metastatictumors. The microscope will allow seamless switching between a high-throughput screening mode observingthe metastatic patterns in tens to hundreds of embryos in one experiment and a high-resolution imaging modewith fully isotropic resolution of 300 nm in XYZ that allows detailed analysis of the molecular metabolicmorphologic and proliferation/survival states of individual cells within an emerging metastatic niche. In theTechnology Development Unit-2 we will develop a multi-scale imaging platform to investigate by hyper-spectralanalysis the molecular metabolic morphological and functional states of metastatic cells across entire mouseorgans. The platform will leverage advances in tissue clearing fully automated high-speed and high-resolutionlight-sheet fluorescence imaging and computer vision to integrate a mesoscopic imaging mode for fastacquisition of volumes of up to 20 x 20 x 20 mm at a ~5-10 micron isotropic resolution with a nanoscopicimaging mode providing 300 nm XYZ-resolution throughout a 300 micron field of view anywhere in the organ.Biological features can thus be rapidly identified and immediately interrogated with high subcellular resolution.We will then develop physically and chemically accelerated 60-plex cyclic immunofluorescence assays tocomprehensively characterize the molecular metabolic and architectural states of colonizing cells and theirsurroundings in the metastatic niche in thick (~200 microns) tissue sections. To accurately describe metastaticheterogeneity the entire system including sample handling labeling and imaging will be fully automated andoperated in a high-throughput fashion. Our goal with this system is to enable comprehensive profiling ofheterogeneous cell metastatic cell behavior in 100s of intact tissue specimens. Together these platforms willgenerate versatile imaging tools for a new era of in situ cancer cell biology. 1536482 +No NIH Category available 3-Dimensional;Ablation;Adenocarcinoma Cell;Advanced Malignant Neoplasm;Advisory Committees;American;Antineoplastic Agents;Area;Award;Bioinformatics;Biology;CRISPR/Cas technology;Cancer Biology;Cancer Etiology;Cells;Chemoresistance;Clinical;Complementary DNA;Data;Development;Development Plans;Educational workshop;Environment;Evolution;Foundations;Funding;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genomics;Goals;Histology;Human;Institution;Laboratories;Lung Adenocarcinoma;Lung Neoplasms;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medical Oncologist;Medical Oncology;Medicine;Memorial Sloan-Kettering Cancer Center;Mentors;Methods;Modeling;Molecular;Molecular Biology;Molecular Biology Techniques;Pathway interactions;Patients;Phenotype;Physicians;Play;Proteins;Reporter;Reproducibility;Research;Research Personnel;Research Project Summaries;Resistance;Role;Scientist;Source;Stress;System;Systems Biology;Testing;Therapeutic;Time;Training;Translating;Tumor Burden;Tumor stage;United States;Work;Xenograft Model;allotransplant;cancer cell;cancer genetics;carcinogenesis;career;career development;chemotherapy;clinical training;experience;experimental study;expression vector;human disease;improved;in vivo;in vivo Model;inhibitor;insight;instructor;mortality;mouse model;novel;novel strategies;novel therapeutics;overexpression;patient derived xenograft model;pharmacologic;programs;response;sarcoma;single cell mRNA sequencing;small hairpin RNA;synergism;tenure track;therapy resistant;transcription factor;transcriptome;transdifferentiation;translational cancer research;tumor;tumor heterogeneity;tumor progression Determining the role and function of a high plasticity cell state in lung adenocarcinoma PROJECT NARRATIVETumor plasticity plays a key role in the development of tumor heterogeneity and a tumors resistance tochemotherapy. We discovered a high plasticity cell state that appears to drive tumor evolution and therapyresistance in lung adenocarcinoma. Clarifying what role this highly plastic cell state plays during tumorprogression and determining the molecular drivers behind this critical state will improve our fundamentalunderstanding of how advanced cancer states develop and resist antineoplastic therapies. NCI 10684835 7/14/23 0:00 PA-20-203 5K08CA267072-02 5 K08 CA 267072 2 "BIAN, YANSONG" 8/22/22 0:00 7/31/27 0:00 Career Development Study Section (J)[NCI-J] 15141371 "CHAN, JASON EARL" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 249526 NCI 231043 18483 PROJECT SUMMARYRESEARCH: Lung cancer remains one of the deadliest cancers in the United States in part due to tumorplasticity that drives intratumoral heterogeneity and leads to therapy resistance. In order to understand howplasticity impacts tumors we profiled single cell transcriptomes from genetically engineered mouse lung tumorsat various stages. We observed a set of reproducible transcriptional states whose diversity increased over time.Interestingly we identified and transcriptionally defined a high plasticity cell state that arose in every tumor. Weprofiled this cell state and identified a robust potential for phenotypic switching an increased potential forspheroid formation in tumor sphere cultures an increased proliferative potential and tumor forming ability inallotransplant models and an enrichment of this plastic cell state after chemotherapeutic stress in vivo. Weidentified a similar plastic cell state in both primary human lung adenocarcinoma tumors and patient-derivedxenograft models and we found the cell state to be associated with worse survival for patients. Thus our worksuggests that the high plasticity cell state drives tumor progression and resistance to therapy in lungadenocarcinoma. To better understand the functional role of the high plasticity cell state I propose to i)interrogate the function of the high plasticity cell state in lung adenocarcinoma progression and treatmentresistance and ii) define the transcriptional drivers controlling the high plasticity cell state. This work will providea functional and molecular definition of the high plasticity cell state which will provide new therapies for lungadenocarcinoma.CANDIDATE & ENVIRONMENT: Dr. Jason E. Chan is an Instructor in the Department of Medicine at MemorialSloan Kettering Cancer Center (MSKCC). His goal is to become an independent tenure-track physician-scientistinvestigating tumor plasticity and tumor evolution. He has delineated a 5-year career plan that builds upon hisbackground in bioinformatics and systems biology genetics mouse models molecular biology and clinicaltraining in medical oncology. This project will provide the ideal training for Dr. Chan to use state of the artgenomics and molecular biology techniques mouse models and patient-derived xenografts to dissect the roleof the high plasticity cell state during carcinogenesis. Dr. Chan will be co-mentored by Dr. Tuomas Tammelaand Dr. Scott Lowe of the Cancer Biology and Genetics Program at MSKCC. The candidates careerdevelopment plan includes coursework workshops mentoring from an interdisciplinary advisory committeecomprising of distinguished basic scientists and medical oncologists and research experience in the supportiveacademic institutional environment of MSKCC a center of excellence in translational cancer research.Successful completion of the project will lead to new approaches for treating patients and will provide afoundation for Dr. Chan to become an independent investigator with his own R01 funded laboratory. 249526 +No NIH Category available Address;Animal Model;Antineoplastic Agents;Apoptosis;Automobile Driving;Biological Markers;Biopsy;Breast Cancer Patient;Cancer Patient;Cancerous;Cell Communication;Cell model;Cells;Cessation of life;Clinical;Clinical Trials;Combined Modality Therapy;Cutaneous;Cutaneous T-cell lymphoma;Data;Development;Devices;Dose;Drug Screening;Drug usage;Evaluation;Familiarity;Freezing;Future;Genetic;Genomics;Goals;Grain;Heterogeneity;Histologic;Hour;Human;Image;Immune;Immunofluorescence Immunologic;Immunophenotyping;Immunotherapy;Implant;In Situ;In Vitro;Incidence;Investigation;Investigational Drugs;Lesion;Location;Malignant - descriptor;Malignant Neoplasms;Measures;Medical;Methods;Microscopic;Molecular;Molecular Abnormality;Morbidity - disease rate;Mus;Mutation;Needles;New Agents;Oncogenes;Oncogenic;Pathway interactions;Patients;Periodicity;Peripheral;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phenotype;Pilot Projects;Population;Positioning Attribute;Predictive Value;Proliferating;Property;Proteins;Rapid screening;Resistance;Resolution;Rice;Risk;Sampling;Signal Transduction;Signaling Protein;Skin;Skin Tissue;Specimen;T-Cell Lymphoma;T-Lymphocyte;Testing;Therapeutic;Time;Tissues;biomarker panel;cancer therapy;cancer type;clinical development;clinical predictors;clinical trial enrollment;clinically relevant;combinatorial;cost effective;drug candidate;drug development;drug sensitivity;drug testing;effective therapy;exome sequencing;first-in-human;genome sequencing;implantation;improved;in vivo Model;individual patient;innovation;malignant breast neoplasm;microdevice;millimeter;mouse model;neoplastic cell;novel;optimal treatments;patient response;potential biomarker;precision medicine;precision oncology;predicting response;predictive marker;response;response biomarker;safety and feasibility;screening;senescence;side effect;skin lesion;standard of care;systemic toxicity;tissue fixing;tool;treatment response;treatment strategy;tumor;tumor microenvironment;tumor-immune system interactions Evaluation of an implantable microdevice for rapid cancer drug screening directly in T cell lymphoma patients ProjectNarrative:AdvancedcutaneousTcelllymphoma(CTCL)andperipheralTcelllymphoma(PTCL)haveverypoorsurvivalduetolimitedeffectivetreatmentsandlackofpredictivemarkersforselectingtheoptimaltherapyforeachpatient.Hereweproposetheuseofaninnovativelab-in-a-patientdevicesmallerthanagrainofricethatcanbeinserteddirectlyintoapatientstumorforrapiddrugscreening.Ourstudyisthecriticalfirststeptowarddeterminingiftheimplantablemicrodevicemayhelpselectwhatexperimentaldrugsshouldbetestedinpatientsandultimatelyhelpchosewhichapprovedcancerdrugismosteffectivetotreatapatientscancer. NCI 10684824 6/20/23 0:00 PAR-18-560 5R37CA252312-04 5 R37 CA 252312 4 "SONG, MIN-KYUNG H" 7/1/20 0:00 6/30/25 0:00 Clinical Oncology Study Section[CONC] 15228025 "LAROCCA, CECILIA " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 702007 NCI 480997 221010 Project Summary/Abstract:Advanced cutaneous T cell lymphoma (CTCL) and peripheral T cell lymphoma (PTCL) have very poor survivaldue to limited effective treatments. Three major obstacles have stalled drug development: 1) the low number ofpatients with each T-cell lymphoma (TCL) subtype which limits sample availability and clinical trial enrollment;2) genetic and tissue microenvironment variability across subtypes; and 3) a lack of cellular and animal modelsto test immunotherapies. Thus there is a major scientific gap in the development of new treatments for TCL.Here we propose the use of an innovative implantable microdevice (MD) smaller than a grain of rice that isplaced directly into a patient's cancerous lesion to screen drugs and to identify the most effective cancer drugto treat TCL on a personalized level. Our MD delivers up to 20 drugs of any class into non-overlapping regionsof a tumor. It is delivered into the skin with a small needle and retrieved in 3 days by excising the device alongwith a few millimeters of surrounding cancer tissue with a standard skin biopsy tool. This device allows testingdrugs directly inside the living tumor with microdoses thereby avoiding the risk of systemic side effects. Drugsensitivity is determined by histologic assessment of the tumor surrounding the device. The MD and themethod for processing and analyzing tissue has been validated across multiple cancer types in mouse modelsand is being evaluated in an ongoing pilot study in breast cancer. The specific aims of these studies will be to:i) determine the safety and feasibility of implanting and retrieving the MD in skin lesions of TCL; ii) assess localresponsiveness of TCL to cancer treatments delivered via the MD through microscopic assessments usinghighly multiplexed cyclic immunofluorescence a novel platform capable of characterizing subcellular changesin the native immune microenvironment following drug treatment with over 30 markers and iii) correlategenetic abnormalities of TCL with drug response to identify potential biomarkers of response and to determineif the MD can be used to predict clinical response by correlating the local tissue response to drug with apatient's clinical response to the same drug when given systemically. We hypothesize that in situ tissueprofiling of drugs in TCL can predict systemic responses to standard of care therapies and therefore can serveas a rapid screen for multiple investigational single or combination treatments. Additionally genomic andimmunophenotypic analysis of tumors may assist in identification of predictive biomarkers of treatment. Theresults of our studies will focus clinical trial efforts toward the most promising treatment strategies and usher inthe era of precision medicine in TCL. 702007 +No NIH Category available Address;Advanced Development;Animal Model;Animals;Anthracycline;Antigens;Biodistribution;Biological Assay;Breast Cancer Patient;CD2 gene;Carboplatin;Cisplatin;Clinic;Clinical;Clinical Oncology;Combined Modality Therapy;Crossover Design;Data;Development;Disease;Dose;Drug Combinations;Drug Delivery Systems;Drug Kinetics;Excipients;Genetically Engineered Mouse;Goals;Good Manufacturing Process;Human;Hydrophobicity;Immune;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotherapy;In complete remission;Investigational Therapies;Isogenic transplantation;Lead;Macaca mulatta;Malignant Neoplasms;Medical;Micelles;Modeling;Mus;Nanotechnology;Neoadjuvant Therapy;Neoplasm Metastasis;PET/CT scan;Paclitaxel;Pathologic;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Phase I/II Trial;Plasma;Platinum;Polymers;Postoperative Period;Pre-Clinical Model;Procedures;Prodrugs;Prognosis;Rattus;Recurrent disease;Reproducibility;Resources;Rodent;Safety;Sampling;Solubility;Study models;TP53 gene;Taxes;Technology;Testing;Therapeutic;Translations;Treatment outcome;Vertebral column;Visceral metastasis;Work;antitumor effect;cancer cell;cancer subtypes;chemotherapy;copolymer;drug development;good laboratory practice;human disease;improved;malignant breast neoplasm;manufacture;mouse model;nanoformulation;nanoparticle;nanotherapeutic;nonhuman primate;novel;novel strategies;pharmacologic;pre-clinical;programs;response;safety assessment;small molecule;standard of care;success;synergism;taxane;triple-negative invasive breast carcinoma;tumor;tumor microenvironment TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION Project NarrativeThe goal of this proposal is to obtain pre-clinical data to enable the translation of a novel nanotechnology-basedimmunotherapeutic drug to treat triple negative breast cancer that is currently associated with poor prognosis.We use nanotechnology for combination therapy with two drugs in the same nanoparticle allowing drugs to attackcancer cells in a collaborative fashion and produce greater antitumor effect. We will develop validated proceduresfor manufacturing and analysis of the combination therapeutic and assess its safety delivery to tumors andefficacy in comparison with the standard therapeutics in animal models that recapitulate human disease. NCI 10684815 9/8/23 0:00 PAR-20-116 5R01CA264488-03 5 R01 CA 264488 3 "FU, YALI" 8/1/21 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-IMST-A(55)R] 1878357 "KABANOV, ALEXANDER V" Not Applicable 4 PHARMACOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PHARMACY 275995023 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 496337 NCI 386366 214433 TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATIONThe goal of this proposal is to obtain pre-clinical data to enable the translation of a novel nanotechnology-baseddrug combination to treat triple negative breast cancer (TNBC). TNBC accounts for 10-20% of breast cancersand is associated with relatively poor prognosis earlier disease recurrence and higher number of visceralmetastases. Chemotherapy in particular with anthracyclines and taxanes remains the backbone medicalmanagement for both early and metastatic TNBC but a significant proportion of patients with early-stage TNBCunfortunately develop metastatic disease. Combination treatments using platinates and taxanes were shown toincrease pathologic complete response rates in TNBC and improve survival in neoadjuvant treatment settings.We propose to use nanotechnology to improve the treatment of TNBC by co-delivering platinum and taxanedrugs in the same nanoparticle to attack cancer cells in a synergistic fashion and produce greater antitumoreffect. To address poor miscibility and drug loading of platinates and taxanes in many nanoparticles we proposeto use a high capacity polymeric micelles (PMs) of poly(2-oxazolne) (POx) block copolymers to incorporatedrugs. In preliminary work we developed POXOL-CP PMs a combination of PTX and hydrophobic cisplatinprodrug co-loaded in POx block copolymer micelles that has shown pharmacological synergy of solubilizeddrugs better delivery of both drugs to tumors and improved efficacy in several animal models compared to thesmall molecule agents or their combination administered separately. The goal of this proposal is to obtainadditional pre-GLP data for our new combination nanotherapeutic in rodent and non-human primate (NHP)models develop validated assays and procedures for POXOL-CP PMs further demonstrate its safety andefficacy and establish path for translation of POXOL-CP PMs to the clinic for TNBC patients. The projectaddresses the following aims: 1) Manufacture reproducible stable and safe POXOL-CP PMs validate its safetyand improved drug delivery to tumors in a mouse model of TNBC; 2) Demonstrate activity of POXOL-CP PMscompared to standard of care in Orthotopic Syngeneic Transplant (OST) and Genetically Engineered MouseModels (GEMM) of TNBC that recapitulate the human disease. 3) Assess safety and PK profiles of POXOL-CPPMs in rat and NHP models. We will follow Good Experimental Practice (GEP) in data keeping and recordingand develop Standard Operating Procedures (SOP) and follow guidance of a clinical and translational panel. Ifsuccessful the results of this project will allow forming data package to support the Good Laboratory Practice(GLP) and Good Manufacturing Practice (GMP) work and compete for NCI Experimental Therapeutics (NExT)program and/or other resources to advance development of POXOL-CP PMs on a path to the clinic to improvetreatment outcomes for patients with TNBC. 496337 +No NIH Category available Antibody-Producing Cells;Antisense Oligonucleotides;B-Lymphocytes;Biological Markers;Bone Marrow;Bortezomib;Cancer Control;Cell Survival;Cell Transplantation;Cells;Cellular Assay;Clinical;Combined Modality Therapy;Data;Detection;Development;Disease;Double-Stranded RNA;Drug Combinations;Drug resistance;Drug usage;Gene Expression;Generations;Genes;Genetic;Genetic Transcription;Growth Factor;Hematopoietic Neoplasms;Hematopoietic stem cells;Human;Immune response;Impairment;In Vitro;Inflammation;Inflammatory;Interferon Activation;Interferons;Investigation;Knowledge;Lead;Link;Lymphoid Cell;Malignant - descriptor;Malignant Neoplasms;Mission;Modeling;Molecular;Molecular Target;Multiple Myeloma;Natural regeneration;Outcome;PF4 Gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Plasma Cell Neoplasm;Plasma Cells;Play;Positioning Attribute;Pre-Clinical Model;Printing;Proteins;Public Health;RNA;RNA-targeting therapy;Recurrent disease;Refractory;Relapse;Research;Role;Sampling;Signal Transduction;Stromal Cells;Survival Rate;System;Testing;Therapeutic;Therapeutic Effect;Translations;United States;United States National Institutes of Health;Work;adenosine deaminase;burden of illness;cancer cell;cancer stem cell;cell growth;clinical translation;clinically relevant;cytokine;disability;experience;high risk;in vivo;in vivo Model;inhibitor;inhibitor therapy;innovation;knock-down;lenalidomide;novel;novel therapeutics;paracrine;plasma cell development;pre-clinical;prevent;progenitor;programs;response;self-renewal;small hairpin RNA;small molecule;standard of care;stem cell biology;stem cell genes;stem cell population;stem cells;stem-like cell;stemness;synergism;targeted treatment;therapeutic evaluation;therapeutic target;transcription factor;tumor Core transcriptional regulators of malignant stem cell generation in multiple myeloma NARRATIVEThe proposed research is relevant to public health because it will expand fundamental knowledge of themolecular factors that govern malignant stem cell generation in multiple myeloma the second most commonblood cancer in the United States. The interferon-response factor 4 (IRF4) pathway contributes to malignanttumor cell growth and survival in this fatal disease however the extent to which IRF4 controls cancer stem cellactivity remains unknown. This project is relevant to NIHs mission because it will test a novel RNA-basedinhibitor in pre-clinical combination drug treatment studies that have high potential to help reduce illness anddisability for patients with multiple myeloma. NCI 10684811 9/8/23 0:00 PA-20-185 5R37CA252040-03 5 R37 CA 252040 3 "HOWCROFT, THOMAS K" 9/16/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 12188144 "CREWS, LESLIE A" Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 354197 NCI 224175 130022 ABSTRACTMultiple myeloma is a fatal plasma cell neoplasm that is characterized by the malignant expansion of abnormalantibody-producing cells. Despite recent therapeutic advances most patients eventually relapse. Such high-risk patients typically have an overall survival rate of less than one year. These poor clinical outcomes occur asa result of uncontrolled regeneration of malignant stem-like cells in protective inflammatorymicroenvironments. However the precise transcriptional determinants of myeloma stemness in the bonemarrow niche remain poorly understood. One intriguing candidate is a key B-cell transcription factor andmyeloma cell survival factor interferon response factor-4 (IRF4). IRF4 also governs normal plasma celldevelopment and immune responses to inflammation however the extent to which IRF4 promotes malignantprogenitor generation in lymphoid or plasma cell neoplasms is unknown. A 50% reduction in IRF4 expressioncan disrupt myeloma cell survival but IRF4 remains undeveloped as a therapeutic target because transcriptionfactors are difficult to inhibit using traditional small molecule strategies. To overcome this challenge proof-of-concept studies were performed to evaluate novel RNA-targeted therapeutic agents that directly inhibit humanIRF4 RNA expression and protein translation. Based on extensive preliminary data that characterized IRF4expression and activity in clinically-relevant in vitro and in vivo models the central hypothesis of this project isthat inhibition of IRF4 will disrupt stem cell pathway activation in multiple myeloma and synergize withstandard-of-care drugs to reduce overall disease burden and prevent malignant stem cell generation. In thecontext of three independent yet conceptually interrelated aims this hypothesis will be tested incomprehensive molecular and cellular assays through a rigorous scientific approach. Aim 1: Interrogating therole of IRF4 in functional myeloma stem cell generation. This aim will determine the cell-intrinsic mechanismsthat link IRF4 to myeloma regeneration. Aim 2: IRF4 inhibitor monotherapy and combination drug treatment inpre-clinical models of multiple myeloma. This aim will develop combination drug treatment and biomarkerdetection strategies that leverage selective IRF4 inhibition. Aim 3: Elucidating the bone marrowmicroenvironment-derived signals that promote IRF4 pathway activation in myeloma regeneration. This aim willelucidate the paracrine mechanisms underlying myeloma regeneration and the activity of a novel cancertherapeutic. The proposed research will set the stage for rapid clinical translation of more selectivecombination therapies for myeloma. The research team unites cancer and stem cell biology experts myelomaclinicians and collaborators who are highly experienced in the translation of novel therapeutics for cancer.Together this project is positioned to advance the rapid clinical translation of IRF4 inhibitor therapy formyeloma. These investigations will also open up new avenues for targeting malignant stem cell generation inother cancers and inflammation-associated diseases. 354197 +No NIH Category available 2-arachidonylglycerol;Address;Agonist;Anabolism;Applications Grants;Arachidonic Acids;Attenuated;Binding;Breast;CNR2 gene;Cannabidiol;Cells;Central Nervous System;Cisplatin;Clinical;Coxibs;Data;Diglycerides;Dose Limiting;Endocannabinoids;Enzyme Inhibition;Enzymes;FAAH inhibitor;Fatty Acids;Genetic;Head and Neck Cancer;Hydrolysis;Injury to Kidney;Intervention;Investigation;Kidney;Kidney Diseases;Knockout Mice;Ligands;Lung;Malignant Neoplasms;Metabolic;Monoacylglycerol Lipases;Mus;N-arachidonylphosphatidylethanolamine;Organ;Ovarian;PTGS2 gene;Patients;Peripheral;Play;Prevention strategy;Probability;Production;Reporting;Role;Route;Serine Hydrolase;Signal Pathway;Solid;Supplementation;Testing;Therapeutic;Toxic effect;Tubular formation;anandamide;antagonist;anticancer treatment;autocrine;cannabinoid receptor;endogenous cannabinoid system;enzyme biosynthesis;fatty acid amide hydrolase;kidney dysfunction;lipoprotein lipase;nephrotoxicity;novel;novel strategies;novel therapeutic intervention;novel therapeutics;paracrine;pharmacologic;prevent;receptor;renal damage;systemic intervention;targeted delivery;therapeutic target;tissue injury;tumor Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin. Fatty acid amide hydrolase (FAAH) is an enzyme to degrade endocannabinoid anandamide (AEA) and thatinhibition of FAAH to increase AEA level has been shown to protect kidneys. As kidney injury is a primary doselimiting toxicity in the clinical utility of cisplatin a potent first-line therapy for many cancers inhibition of FAAH isproposed as a novel therapy against cisplatin-induced kidney toxicity and allows the continuation of anticancertreatment with cisplatin. NCI 10684803 7/20/23 0:00 PAR-20-292 5R21CA274012-02 5 R21 CA 274012 2 "VENKATACHALAM, SUNDARESAN" 8/16/22 0:00 7/31/24 0:00 ZCA1-PCRB-9(M1)S 8641182 "LI, NINGJUN " Not Applicable 4 PHARMACOLOGY 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 174276 NCI 114538 59738 Nephrotoxicity is a primary dose-limiting toxicity for cisplatin a potent first-line therapy for many solidmalignancies. The mechanistic basis for cisplatin-induced kidney damage is not fully understood and no efficientmanagement strategies are currently available. The endocannabinoid (EC) system which has been initiallyfocused on the central nervous system also plays important roles in the peripheral organs including the kidneys.The most well-characterized ECs are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The biosynthesisof AEA is through the hydrolysis of N-arachidonoyl-phosphatidyl-ethanolamines via at least three distinctbiosynthetic routes. The 2-AG is produced by diacylglycerol lipases which hydrolyze 2-arachidonoyl-containingdiacylglycerols (DAG) to generate 2-AG. After production ECs bind to the local cannabinoid receptors (CB1 andCB2) in an autocrine or paracrine manner. It has been shown that EC system participates in different kidneydiseases including cisplatin-induced nephrotoxicity (CIN) and that interventions of CB receptors are promisingtherapeutic strategies. Surprisingly majority of studies focus on CB receptors and little is known about roles ofECs metabolic enzymes in kidney damages. It is important to address this significant gap and imperative toinvestigate the role of ECs enzymes in kidney diseases. A recent study showed that in cisplatin-treated miceAEA was significantly increased while 2-AG had no change in the kidneys and that inhibition of CB1 receptorsattenuated the cisplatin-induced renal dysfunction suggesting that endocannabinoid system through CB1receptors promotes cisplatin-induced kidney injury. We initially intended to test whether FAAH inhibition whichresults in increased levels of AEA would aggravate the CIN. Surprisingly CIN was dramatically attenuated inFAAH KO mice suggesting that the increased levels of AEA is actually protective in CIN. The elevation of AEAlevels after FAAH inhibition could also result in reduced levels of AEA-FAAH-derived arachidonic acid (AA) andincreased levels of AEA-COX2-derived prostamides. Our preliminary data demonstrated that the protection byFAAH inhibitor was reversed by the substrate-selective COX2 inhibitor LM4131 (inhibits AEA-COX2 not AA-COX2) but not by the supplementation of AA nor the blocking CB receptors. Based on the above informationthe hypothesis to be tested is that FAAH inhibition protects the kidneys against CIN via AEA-COX2-derivedprostamides. The following Aims are proposed to test the hypotheses. Aim 1: To determine whether inhibitionof FAAH protects the kidneys against CIN. Studies will use genetic and pharmacological as well as both systemicand kidney-targeted approaches for FAAH inhibition. Aim 2: to determine whether AEA-COX2-derivedprostamides are the downstream signaling pathway responsible for the renoprotection after FAAH inhibition inCIN. Aim 3: To establish that inhibition of FAAH will not interfere with the antitumor actions of cisplatin. Thefindings from these proposed studies will suggest that inhibition of FAAH is new therapeutic strategy for theprevention and treatment of CIN. 174276 +No NIH Category available Advanced Malignant Neoplasm;Area;Award;Biological Assay;Cancer Center;Cancer Center Support Grant;Caring;Catchment Area;Collaborations;Communities;Core Facility;Development;Education;Environment;Experimental Designs;Funding;Genomics;Grant;Health;High-Throughput Nucleotide Sequencing;Hispanic Populations;Infrastructure;Journals;Knowledge;Leadership;Letters;Malignant Childhood Neoplasm;Malignant Neoplasms;Methodology;Mission;NCI Center for Cancer Research;Peer Review;Procedures;Protocols documentation;Publications;Qualifying;Research;Research Personnel;Research Project Grants;Research Project Summaries;Resource Sharing;Scientist;Secure;Services;Specialist;Strategic Planning;Technology;Technology Assessment;Texas;Training;United States National Institutes of Health;Universities;anticancer research;cancer genome;cancer genomics;career development;improved;innovation;instrumentation;member;next generation sequencing;programs;recruit;skills;success;technology validation Advancing Cancer Research Through Next Generation Sequencing at Mays Cancer Center of UT Health San Antonio Project NarrativeThis R50 application seeks fund to support Dr. Zhao Lai Director of the Next-Generation Sequencing SharedResource (NGSSR) of the NCI-designated Mays Cancer Center at the University of Texas Health San Antonio.The NGSSR heavily used by Cancer Center members and investigators in the San Antonio area has a strongfocus on its unique Hispanic population and provides cutting-edge high throughput sequencing expertise andanalytical capacities to support diverse genomic applications. Dr. Lai a highly skilled and well-trained genomicsscientist is a critical member who leads a cutting-edge scientific team in the NGSSR that supports andcontributes intellectually to many NCI-funded projects through its expert genomic analyses. NCI 10684795 8/25/23 0:00 PAR-21-286 5R50CA265339-02 5 R50 CA 265339 2 "JOHNSON, ERIC MICHAEL" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-1(M1) 12033189 "LAI, ZHAO " Not Applicable 20 GENETICS 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 191363 NCI 123460 67903 Project SummaryThis Research Specialist (Core-based Scientist) R50 application seeks support for Dr. Zhao Lai Director of theNext-Generation Sequencing Shared Resource (NGSSR) in the NCI-designated Mays Cancer Center (MCC;Ruben Mesa PI) at the University of Texas Health San Antonio (UTHSA). Next-generation sequencing (NGS)is one of the most significant technological advances in cancer genome research. Dr. Lais mission through theNGSSR is to provide the cutting-edge genomics technology to the cancer community of MCC. The NGSSRbegan in 2011 as a core facility with a focus on genomics of pediatric cancer research. Dr. Lai was recruited asa highly qualified genomics scientist to lead the NGS facility. In 2014 the core was integrated into the CancerCenter Support Grant (CCSG) as a Shared Resource. As the NGSSR Director since its inception Dr. Lai hasguided the development of every aspect of this highly regarded Shared Resource (scored Outstanding in thesuccessful CCSG renewal in 2020). She has developed and executed strategic plans for technology assessmentand implementation trained and supervised staff scientists and created all standard operating procedures. Dr.Lai has secured two NIH S10 Shared Instrumentation grants to significantly enhance the genomic infrastructureat UTHSA continuously established new protocols to expand NGS services to support diverse cancer researchapplications. She continues to assist investigators NGS projects ranging from experimental design throughsubsequent interpretation of experimental results and establishes the extensive collaboration to developintegrative assays and customized protocols that contribute to the long-term success of the MCCs researchprogram. Under her scientific leadership the NGSSR has quickly become an essential component in the MCCand fundamentally transformed the genomics research environment for its members. Since 2011 the NGSSRsCancer Center users have nearly quadrupled. Currently the NGSSR supports >42 Cancer Center members and18 NCI-funded research projects. Dr. Lais knowledge of NGS technology and her key intellectual contribution toNGS applications in many NCI-funded research projects have been widely recognized (see Letters of Support)with the NGSSRs contributions to over 100 publications many in high-impact peer-reviewed journals. Thisproposed R50 award will provide a more stable financial basis for the NGS facility further concentrate Dr. Laisefforts on cancer-oriented methodology development application innovation and service improvement and offerher more opportunities in career development in cancer genomics. This award will also allow the NGSSR tocontinue providing cutting-edge sequencing technology services education and training to MCC cancerresearch community to provide better care for the unique Hispanic population in our catchment area. 191363 +No NIH Category available Adoption;Cancer Center;Cancer Control;Caring;Collaborations;Common Data Element;Communities;Community Health Networks;Complex;Data;Data Analytics;Data Element;Data Sources;Development;Disparity;Dissemination and Implementation;Electronic Health Record;Ensure;Epidemiologist;Equity;Evidence based intervention;Geographic Locations;Gold;Health;Healthcare Systems;Household;Imprisonment;Informatics;Infrastructure;International;Knowledge;Laboratories;Leadership;Medicaid;Medical;Monitor;Neighborhood Health Center;Oregon;Patients;Prevention;Primary Care;Provider;Publications;Research;Research Personnel;Research Project Grants;Rural;Sampling;Science;Scientist;Screening for cancer;Testing;Underserved Population;Uninsured;Universities;Work;data harmonization;data management;data quality;data resource;data sharing;data warehouse;design;experience;federal poverty level;implementation science;implementation strategy;improved;insurance claims;member;multidisciplinary;neoplasm registry;novel;patient engagement;practice setting;practice-based research network;programs;research in practice;research study;school based health center;social health determinants;success;transgender Implementation Laboratory n/a NCI 10684782 9/1/23 0:00 RFA-CA-19-006 5P50CA244289-05 5 P50 CA 244289 5 9/19/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5442 8032571 "GOLD, RACHEL " Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 234856 225462 9394 IMPLEMENTATION LABORATORY PROJECT SUMMARYThe OCHIN practice-based research network (PBRN) of >500 community health centers (CHCs) across 20states will serve as the Implementation Laboratory for the Building Research in Implementation andDissemination to close Gaps and achieve Equity in Cancer Control (BRIDGE-C2) Center. The OCHIN PBRNhas the nation's largest network of CHCs sharing a centrally-hosted electronic health record (EHR) and ateam of researchers quality improvement coaches and informaticists capable of supporting a large portfolio ofdissemination and implementation research studies. OCHIN's member CHCs provide care for an underservedpopulation of nearly 2.6 million patients of whom 62% are from households earning <138% of the federalpoverty level 49% are insured by Medicaid and 21% are uninsured. OCHIN hosts the CHCs' shared EHRand has built a centralized data warehouse that includes longitudinal data elements for all patients acrossthese CHCs. The BRIDGE-C2 Center's Implementation Laboratory will leverage and enhance the robustOCHIN PBRN (Aim 1a) and be led by an implementation scientist supported by a multi-disciplinary team (Aim1b). The Implementation Laboratory will engage stakeholders from the >500 CHC practices in research andcoordinate dissemination of new knowledge to CHCs (Aim 2). The Laboratory will establish a DataManagement Unit to build and maintain a data warehouse that supports the work of the BRIDGE-C2 Centercoordinate data sharing and regulatory requirements ensure data quality and harmonization and liaise withother laboratories across the Implementation Science Centers for Cancer Control consortium to developcommon data elements and metric definitions that impact adoption of cancer screening and preventionevidence-based interventions (Aim 3). The Laboratory will also establish a Practice Surveillance Unit to enableidentification of critical cancer screening and prevention disparities to target in future research and rapidly andcontinuously monitor the progress and sustainability of strategies designed to enhance the implementation ofevidence-based interventions in CHCs (Aim 4). The Implementation Laboratory will build on the foundationalwork that created the OCHIN PBRN. The diversity of practices in the Laboratory (e.g. rural/urban large/smalldifferent geographic regions) and the inclusion of specialized programs for vulnerable subpopulationsstrengthens the likelihood that findings will be relevant to many different CHC settings. Further our ability toselect a diverse sample of practices for BRIDGE-C2 Center research studies will enable the development ofimplementation strategies and support strategies to be spread to many other primary care networks. Thus theImplementation Laboratory is well-poised to work with the Center to take on the grand challenge of advancingimplementation science to improve cancer screening and prevention in underserved populations. +No NIH Category available Acceleration;Address;Adoption;Area;Cancer Control;Caring;Cervical Cancer Screening;Data;Development;Dissemination and Implementation;Ensure;Equity;Evidence based intervention;Feedback;Future;Generations;Goals;Infrastructure;Intervention;Knowledge;Laboratories;Leadership;Learning;Maintenance;Maps;Measures;Methods;Mind;Modeling;Monitor;Pap smear;Pilot Projects;Prevention;Primary Care;Process;Program Research Project Grants;Randomized;Reduce health disparities;Research;Research Design;Research Personnel;Research Project Summaries;Science;Scientist;Screening for cancer;Techniques;Testing;Tobacco Use Cessation;Underserved Population;Visual;Work;cancer health disparity;design;expectation;follow-up;health information technology;implementation framework;implementation intervention;implementation science;implementation strategy;implementation study;improved;innovation;member;multidisciplinary;novel;primary care setting;programs;success;surveillance data;technological innovation;therapy design;tool;trend Research Program n/a NCI 10684779 9/1/23 0:00 RFA-CA-19-006 5P50CA244289-05 5 P50 CA 244289 5 9/19/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5441 11703978 "HUGUET, NATHALIE " Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 821544 613916 207628 RESEARCH PROGRAM PROJECT SUMMARYThe Research Program will address the grand challenge of advancing implementation science toimprove cancer screening and prevention in underserved populations by developing and conductingrapid cycle testing of innovative approaches to implementing evidence-based interventions (EBIs). Thepartnership between the BRIDGE-C2 Center's Research Program and Implementation Laboratory will facilitateand accelerate robust and relevant science to address disparities in cancer screening and prevention. Toaccomplish this the Research Program will establish an Implementation Studies Unit and a Methods Unit.These units build upon extensive expertise in conducting implementation science research and in developingand applying novel mixed methods approaches to cancer screening and prevention issues in partnership withand in primary care. The Center will also conduct four initial pilots in the Implementation Laboratory and useemergent findings to inform future projects. We selected two research pilot projects to study theimplementation of interventions designed to increase rates of (1) cervical cancer screening (Pap tests) andfollow-up care and (2) improve tobacco cessation support. Following a similar engaged approach the twoMethods Pilots will assess how to precisely design and tailor HIT tools and other implementation strategies fora diverse group of member practices which is a high priority for the Implementation Laboratory. These pilotprojects that emerged from engagement of a multidisciplinary team of stakeholders serve as the initial seedsfrom which to launch the Center and to build new knowledge methods and capacity to improve cancerscreening and prevention in CHCs. The multi-disciplinary leadership of the Research Program will establishprocesses new expectations and capacity for discussing data and trends (including use of visual techniquesand stories to ensure conversation and engage a wide and varied group of stakeholders) and develop andprioritize new project ideas and rapidly and broadly disseminate findings. The Center has the capability todesign studies with sustainability in mind and develop and test innovative interventions that promotemaintenance of an EBI to inform when `boosters' are needed and minimize regression to the mean which iscommon in practice change and implementation work. The Research Program infrastructure is designed toidentify implement and disseminate strategies in primary care settings that are most effective in improvingsustained implementation of cancer screening and prevention EBIs with the ultimate goal of reducing healthdisparities. +No NIH Category available Area;Cancer Center;Cancer Control;Collaborations;Communication;Communities;Complex;Coupled;Dedications;Development;Dissemination and Implementation;Ensure;Equity;Evaluation;Evidence based intervention;Feedback;Future;Goals;Infrastructure;Institution;International;Knowledge;Laboratories;Learning;Logistics;Mentors;Mentorship;Mission;Modeling;Monitor;Neighborhood Health Center;Office of Administrative Management;Outcome;Pilot Projects;Positioning Attribute;Prevention;Primary Care;Process;Publications;Quality of Care;Research;Research Personnel;Resource Development;Resources;Running;Scientist;Screening for cancer;Senior Scientist;Shapes;Structure;Time;Training;Underserved Population;Update;Work;cancer health disparity;career;career development;community setting;disparity reduction;experience;implementation framework;implementation research;implementation science;improved;meetings;member;multidisciplinary;operation;population health;practice-based research network;primary care setting;programs;research study;success;traditional care Administrative Core n/a NCI 10684776 9/1/23 0:00 RFA-CA-19-006 5P50CA244289-05 5 P50 CA 244289 5 9/19/19 0:00 8/31/24 0:00 ZCA1-RPRB-L 5440 7895491 "DEVOE, JENNIFER E" Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 374882 253440 121442 ADMINISTRATIVE CORE PROJECT SUMMARYThe BRIDGE-C2 Center will be governed by a Steering Committee and managed by an Administrative Corethat will coordinate oversee and evaluate all activities of the Center. The Administrative Core will serve as ahub that supports and ensures a tight connection between the BRIDGE-C2 Center's Research Program andthe Implementation Laboratory. The specific aims of the Administrative Core are to: (1) Oversee manage andsupport the operations of the BRIDGE-C2 Center including serving as the coordination hub to organize andtrack all BRIDGE-C2 Center activities and progress; (2) Develop structured programs and connections that willadvance the field of implementation science including the establishment of a dedicated InvestigatorDevelopment Unit to organize career development resources mentoring and connections to existinginstitutional and national programs for new and mid-level investigators; (3) Establish a Network Unit with thecapacity for bidirectional knowledge sharing to synthesize and harmonize information sharing within andacross the BRIDGE-C2 Center organizations and working to rapidly advance implementation science learnfrom other members of the Implementation Science Centers for Cancer Control consortium and widelydisseminate the BRIDGE-C2 Center findings to the broader community; (4) Establish an Evaluation Unit tocontinuously assess the progress of the BRIDGE-C2 Center in meeting all of its goals and objectives and toregularly update Center leaders with feedback as to the designated evaluation team's findings. TheAdministrative Core will house centralized logistics and operational resources to support all units across theBRIDGE-C2 Center and will include the three units outlined above (Aims 2 3 4). Specific priorities for thesethree units include: the Investigator Development Unit supported by the overall Administrative Core team willwork closely with the Research Program to coordinate the process of developing prioritizing and selectingfuture pilot projects and will support the Scientific Mentorship Panel; the Network Unit will support engagementand communication internally across all BRIDGE-C2 Center units and will also be the hub for the Center'scollaboration and connection with external entities; the Evaluation Unit will monitor and assess the impact ofthe BRIDGE-C2 Center's efforts broadly and will also highlighting progress in priority activities such areas astraining implementation scientists enhancing analytical resources available to the Center's ImplementationLaboratory engaging relevant community-based and national stakeholders advancing the implementationscience field and broadly disseminating findings. Our direct connection to hundreds of front-line primary careCHCs across multiple states and our well-established and unique community-academic partnerships positionthe BRIDGE-C2 Center for success in conducting relevant and impactful implementation research studiesimplementing successful strategies rapidly and sharing findings with diverse groups of stakeholders. +No NIH Category available Acceleration;Address;Adoption;Area;Cancer Control;Caring;Cell Nucleus;Cervical Cancer Screening;Characteristics;Collaborations;Community Networks;Development;Disparity;Dissemination and Implementation;Electronic Health Record;Equity;Evaluation;Evidence based intervention;Health;Health Services;Infrastructure;Knowledge;Laboratories;Leadership;Link;Low income;Malignant Neoplasms;Mentors;Methodology;Methods;Modeling;Neighborhood Health Center;Oregon;Patients;Persons;Pilot Projects;Population;Prevention;Prevention Research;Preventive healthcare;Primary Care;Primary Health Care;Process;Provider;Reduce health disparities;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Rural;Science;Scientist;Screening for cancer;Sexual and Gender Minorities;Testing;Tobacco Use Cessation;Training;Underserved Population;Uninsured;Universities;Vulnerable Populations;Work;cancer care;cancer prevention;career;career networking;cost;design;disparity elimination;disparity gap;disparity reduction;ethnic minority;evidence base;experience;follow-up;implementation evaluation;implementation framework;implementation science;implementation strategy;improved;innovation;multidisciplinary;novel;practice-based research network;pragmatic trial;preventive intervention;primary care practice;primary care provider;primary care setting;primary care team;programs;racial minority;scale up;surveillance data;traditional care;training opportunity Building Research in Implementation and Dissemination to close Gaps and achieve Equity in Cancer Control (BRIDGE-C2) Center NARRATIVEThe BRIDGE-C2 Center will take on the grand challenge of advancing implementation science toimprove cancer screening and prevention in underserved populations. This work is urgently neededbecause cancer screening and prevention evidence-based interventions are not equitably delivered. NCI 10684775 9/1/23 0:00 RFA-CA-19-006 5P50CA244289-05 5 P50 CA 244289 5 "CZAJKOWSKI, SUSAN" 9/19/19 0:00 8/31/24 0:00 ZCA1-RPRB-L(A1) 7895491 "DEVOE, JENNIFER E" "HUGUET, NATHALIE " 1 FAMILY MEDICINE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Research Centers 2023 1431282 NCI 1092818 338464 OVERALL PROJECT SUMMARYThe Building Research in Implementation and Dissemination to close Gaps and achieve Equity in CancerControl (BRIDGE-C2) Center will take on the grand challenge of advancing implementation science toimprove cancer screening and prevention in underserved populations. This work is urgently neededbecause cancer screening and prevention disparities exist with regard to delivery of evidence-basedinterventions (EBIs). Effective strategies to improve implementation of EBIs in primary care community healthcenters (CHCs) that can eliminate these disparities are not known or poorly understood. Implementationscience can contribute new knowledge that will transform CHCs' ability to serve the nation's most vulnerablepopulations. The BRIDGE-C2 Center will: 1) create a sustainable infrastructure for developing conducting andcontinuously evaluating implementation strategies that enhance primary care's ability to equitably deliverevidence-based cancer screening and prevention interventions to all people emphasizing closing care gapsfor vulnerable populations; 2) build capacity and training opportunities and engage a multi-disciplinary team ofimplementation science and methods experts to facilitate the development of innovative approaches relevantto our grand challenge; and 3) identify strategies to improve implementation of cancer screening andprevention EBIs in primary care and conduct research / develop pragmatic methods to tailor enhance andsupport the adoption and sustainability of these strategies. We will build on the strong established partnershipsbetween researchers at Oregon Health & Science (OHSU) primary care the OHSU Knight Cancer Instituteand the OCHIN Implementation Laboratory (a well-established national network of >500 CHCs that share anelectronic health record through the OCHIN Practice-Based Research Network). The BRIDGE-C2 Center willconduct pilot studies that develop and test strategies to improve implementation of EBIs rapidly scale upsuccessful pilots to conduct large scale pragmatic trials and widely disseminate effective innovations toprimary care practices caring for underserved populations. Woven throughout these activities will be theCenter's focus on mentoring and training early career implementation scientists and leveraging collaborationsto increase implementation science capacity. The Center's Administrative Core will serve as the nucleus thatbridges the Research Program and Implementation Laboratory providing support for research activitiesleadership governance investigator development dissemination evaluation and a connection to the nationalISCCC network. Our first two research pilots aim to improve cervical cancer screening and follow-up care andtobacco cessation. Our first two methods pilots will create novel capabilities to predict needed implementationsupport based on provider and practice characteristics. We will spread our discoveries and create mechanismsfor widely disseminating our findings and innovations to scientific professional and community networks toincrease implementation of cancer screening and prevention EBIs and decrease health disparities. 1431282 +No NIH Category available Cancer Biology;Training Programs Training Program in the Biology of Cancer Cancer is the 2nd major cause of human mortality. Consequently PhDs and MD/PhDs specificallytrained in the discipline of Cancer Biology and professionally involved in cancer research educationpolicy and clinical care are a critical national health need. This training grant currently in its 35th yearis a cornerstone of a unique interdisciplinary graduate program designed to train the next generationof cancer biologists to meet this urgent national need. NCI 10684765 8/28/23 0:00 PA-20-142 5T32CA009531-37 5 T32 CA 9531 37 "LIM, SUSAN E" 9/1/85 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1955379 "MATHERLY, LARRY H" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 189264 NCI 197048 10398 Cancer is the 2nd major cause of human mortality in the US. It is our view that an interdisciplinary graduatecurriculum with a focus on the biology of cancer that interfaces with clinicians engaged in cancer diagnosis andtreatment provides an excellent means of training specialists with a sufficient breadth of perspective forsuccessful careers in cancer research education clinical care or policy. This is an application for renewal of aT32 training grant currently in its 35th year to support 6 pre-doctoral students in Cancer Biology at Wayne StateUniversity (WSU) and the Barbara Ann Karmanos Cancer Institute (KCI). Trainees include PhD and MD/PhDcandidates primarily from the Cancer Biology Graduate Program (CBGP) in the Department of Oncology alongwith a smaller number of trainees from other affiliated PhD programs at WSU. Training draws from theoutstanding clinical and research facilities at WSU/KCI and the expertise of 20 accomplished preceptors in areasincluding neoplastic development invasion and metastasis cancer drug discovery cancer immunology andpopulation studies and cancer disparities. This T32 training grant provides an important cornerstone of ourtraining program in the biology of cancer at WSU/KCI. The CBGP offers specialized didactic training in basic andtranslational principles of Cancer Biology along with seminars by nationally/internationally recognized speakersstudent-faculty research retreats and opportunities to attend national/international research conferences. PhDstudents are introduced to state-of-the-art research methods in molecular and cell biology chemical biologypharmacology immunology and epidemiology and to cutting-edge technologies through the KCI researchcores while performing hypothesis-based cancer research. Students round with oncologists in the KCI CancerHospital and receive didactic training on clinical research by academic physicians who lead our clinical trials.Training in the responsible conduct of research rigorous experimental design and data science is provided.Value added educational opportunities for T32 fellows include a workshop on F30/F31 fellowship preparationa T32 research mini-symposium enhanced career networking specialized technology workshops and researchconferences training in community outreach and individualized career mentoring. The goals of our T32 trainingprogram are to develop scientists with a strong foundational training and perspective in Cancer Biology withoutstanding capacities for critical thinking effective communication and networking skills needed for professionalsuccess in the coming decades. Reflecting our emphasis at KCI/WSU on reducing cancer disparities anadditional goal of our training program is to encourage workforce diversity by educating trainees from diversebackgrounds. As documented in this application T32 CA009531 has trained an accomplished group of cancerbiologists including underrepresented minorities who have assumed professional positions throughout theUnited States where through their educational research and related efforts they continue to combat thisdevastating disease. 189264 +No NIH Category available 3 year old;Address;Adipocytes;Adipose tissue;Adult;African American;African American population;Age Years;American;Animal Experiments;Animals;Anti-Inflammatory Agents;Antiinflammatory Effect;Bacteria;Biological Assay;C-reactive protein;Cancer Control;Cancer Intervention;Cancer Model;Cells;Child;Chronic;Clinical Trials;Colon Carcinoma;Colorectal Cancer;Communication;Complement;Complement 2;Consumption;Diet;Dietary Intervention;Disparity;Enrollment;Epidemiology;European;Goals;Grant;Health;High Fat Diet;Human;Incidence;Inflammation;Inflammation Mediators;Inflammatory;Influentials;Infrastructure;Insulin;Insulin Resistance;Insulin-Like Growth Factor I;Interleukin-6;Intervention;Intervention Trial;Laboratory Animals;Link;Literature;Macrophage;Malignant Neoplasms;Mediator;Medical;Metabolic;Metabolic dysfunction;Modeling;Obese Mice;Obesity;Obesity associated cancer;Outcome;Paper;Parents;Pathogenesis;Population;Publishing;Race;Risk;Role;Science;Somatomedins;South Carolina;Study models;System;TNF gene;Testing;Unhealthy Diet;Universities;Work;adenoma;adiponectin;anticancer research;associated symptom;cancer epidemiology;cancer health disparity;cancer prevention;carcinogenesis;colorectal cancer progression;colorectal cancer risk;cytokine;dietary;early onset colorectal cancer;epidemiology study;experience;experimental study;fecal transplantation;gut microbes;gut microbiota;high risk;human study;in vivo;inflammatory marker;intestinal barrier;lifestyle intervention;microbiome;microbiome signature;microbiota;mouse model;obesity in children;pre-clinical;prevent;programs;protective effect;protective factors;racial difference;racial identity;response;systemic inflammatory response;tumorigenesis A Transdisciplinary Approach to Investigating Metabolic Dysregulation in Obese Parent and Child Dyads and Risk of Colorectal Cancer Metabolic dysregulation an important manifestation of inflammation may hold the key for addressing thegrowing problem of Early-Onset CRC (EOCRC) (i.e. <50 years) and numerous other obesity-related cancers.The proposed work draws on experience that we have accumulated in working with inflammation andmetabolic dysregulation in particular in both laboratory animal experiments and human studies and that havecontributed many hundreds of papers and thousands of citations to the medical literature over the last 10years. Results from this work which meld our wide-ranging experience in transdisciplinary science haveimportant implications for advancing the science and real practical implications for addressing cancer-relateddisparities that have consistently disfavor African Americans a group that is uniquely metabolically obese (i.e.evince symptoms associated with obesity at lower levels of overall adiposity). NCI 10684760 8/1/23 0:00 RFA-CA-21-021 5U01CA272977-02 5 U01 CA 272977 2 "ROSS, SHARON A" 8/16/22 0:00 7/31/27 0:00 ZCA1-SRB-2(M2) 1946358 "HEBERT, JAMES R" "HOFSETH, LORNE J; MURPHY, ELIZABETH ANGELA" 6 PUBLIC HEALTH & PREV MEDICINE 41387846 J22LNTMEDP73 41387846 J22LNTMEDP73 US 33.999623 -81.028249 1524302 UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA COLUMBIA SC SCHOOLS OF PUBLIC HEALTH 292080001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 1104672 NCI 1162292 547463 This U01 project leverages our expertise in the epidemiology of colorectal cancer (CRC); disparities; obesity;metabolic dysregulation an important manifestation of inflammation; the microbiome; animal CRC models; andlifestyle intervention trials to address the growing problem of Early-Onset CRC (EOCRC) (i.e. <50 years).Adiposity and diet drive metabolic dysregulation. So understanding the interaction between diet and adiposityare key to understanding the genesis of EOCRC and an array of other obesity-related cancers). This projectwill address the absence of critical clinical trials and mechanistic studies involving lifestyle interventions forEOCRC. We intend to address this gap; and have the transdisciplinary team representing complementarybackgrounds to do so. We focus on dietary modulation of gut microbes to reduce metaflammation andsubsequent metabolic dysfunction in obesity with a goal of preventing EOCRC. We will perform 1) an anti-inflammatory dietary intervention trial in dyads of adults and children at elevated risk for CRC. We also willconduct a complementary mechanistic animal study that builds on and leverages our expertise in mechanisticstudies on obesity and CRC. This work is supported by infrastructure that we have built over the past decadesin two key centers at the University of South Carolina (UofSC): (1) Center for Colon Cancer Research (CCCR2002 - present which specializes in mouse models of CRC); and (2) the Cancer Prevention and ControlProgram (CPCP 2000 - present which specializes in the epidemiology of cancer and lifestyle interventiontrials for cancer with a focus on cancer disparities. The two projects that comprise the proposed grant addresstwo Specific Aims that are represented by the human study and laboratory animal experiment: i.e. 1: Toestablish the metabolic protective effects of an anti-inflammatory diet in obese high-risk African-American (AA) and European-American (EA) adults and children in reducing inflammation as indicated byHomeostatic Model Assessment for Insulin Resistance (HOMA-IR) IGF-1 Tumor Necrosis Factor alpha(TNF) Interleukin 6 (IL-6) and C-Reactive Protein (CRP) and a creating more favorable microbiomesignature; 2: To establish gut microbes as mediators between anti-inflammatory dietary input andreversal of metabolic dysfunction and associated CRC risk. This complements the human study bycarrying out pre-clinical murine model studies with similar inputs (diet) intermediate endpoints (inflammationmicrobiome) and outcomes (CRC-related). We hypothesize that an anti-inflammatory dietary intervention willreduce metabolic dysfunction and metainflammation through regulatory effects on gut microbiota.Results from this work will address the role of metabolic dysregulation in relation to factors that are known tobe important in carcinogenesis that therefore could have profound effects on EOCRC have implications forother obesity-related cancers and have great promise for moving the field forward by addressing mechanismsthat drive large health-related disparities that consistently disfavor African Americans. 1104672 +No NIH Category available Affinity;Amino Acids;Androgen Antagonists;Androgen Receptor;Animal Model;Binding;Binding Sites;Biological Assay;Biology;Cancer Cell Growth;Cancer Etiology;Castration;Cell Culture Techniques;Cell model;Cessation of life;Characteristics;DNA-Binding Proteins;Disease;Disease Progression;Drug Design;Drug Kinetics;Embryo;Generations;Genetic Transcription;Goals;Growth;Hybrids;In Vitro;Individual;Life Expectancy;Localized Disease;Luciferases;Malignant Neoplasms;Malignant neoplasm of prostate;Maps;Modeling;Molecular;Monitor;Mus;Mutagenesis;Mutation;N-terminal;Pathway interactions;Patients;Peptides;Peptoids;Periodicity;Pharmacodynamics;Pharmacology;Pre-Clinical Model;Prognosis;Proliferating;Prostatic Neoplasms;Protein Engineering;Proteins;Protocols documentation;Research;Resistance;Resistance development;Signal Transduction;Site;Structure;Surface;Survival Rate;Testing;Up-Regulation;WNT Signaling Pathway;Xenograft procedure;Zebrafish;abiraterone;beta catenin;castration resistant prostate cancer;design;enzalutamide;in vivo;in vivo Model;inhibitor;insight;men;novel therapeutic intervention;peptidomimetics;prostate cancer cell;protein protein interaction;rational design;response;small molecule;subcutaneous;therapeutic target;three dimensional cell culture;transcription factor;tumor;tumor growth;tumor microenvironment Suppression of Prostate Cancer Project NarrativeOur studies show that cyclic peptoids have the potential to interfere with -catenin/TCF interaction and inhibitprostate cancer growth. We propose to study their mechanism of action in cells and animal models ofcastration resistant prostate cancer. NCI 10684749 8/16/23 0:00 PAR-20-292 5R21CA262963-02 5 R21 CA 262963 2 "KONDAPAKA, SUDHIR B" 9/1/22 0:00 8/31/24 0:00 ZCA1-TCRB-5(M1)S 1933989 "LOGAN, SUSAN K." Not Applicable 12 UROLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 194142 NCI 114538 79604 Project SummaryAs many as 20% of aggressive prostate cancers have mutations resulting in upregulation of Wnt/-cateninsignaling. Importantly recent analysis identified the Wnt/-catenin pathway as the foremost differentiallymodulated pathway among treatment-resistant individuals. We used structure-based design of peptidomimeticoligomers to discover new molecules capable of inhibiting Wnt/-catenin signaling and prostate cancer cellgrowth. We identified macrocycle 13 as a potent inhibitor of Wnt/-catenin signaling. In this proposal we outlinea strategy to use macrocycle 13 in models of castration resistant prostate cancer (CPRC) and to explore thebiology of Wnt/-catenin in prostate cancer. The hypothesis underlying of this project is that oligomermacrocycles can be rationally designed to inhibit the -catenin/TCF interaction thereby inhibiting prostatecancer tumor growth. Our specific aims are to 1) test macrocycle 13 inhibition of -catenin/TCF in in vivomodels of aggressive prostate cancer and 2) determine macrocycle 13/-catenin binding characteristics.Altogether we expect that completion of our research goals will provide new molecular insight into Wnt/-catenin signaling in prostate cancer. 194142 +No NIH Category available Area;Award;Bioinformatics;Biology;Cancer Biology;Cells;Colorectal Cancer;Complex;Dedications;Desmoplastic;Funding;Grant;Inflammation;Inflammatory;Knowledge;Laboratories;Malignant Neoplasms;Medicine;Mesenchymal;Metabolic;Metabolism;Modeling;Molecular;Pathology;Process;Prognosis;Research;Role;Scientist;Seminal;Signal Transduction;Specialist;Technical Expertise;Time;Training;Wages;bioinformatics tool;cancer type;design;effective therapy;human disease;in vivo;in vivo Model;mouse model;new therapeutic target;novel;programs;success;tumor microenvironment;tumor progression Dissecting the in vivo stromal metabolic and inflammatory crosstalk in colorectal cancer PROJECT NARRATIVEThe tumor microenvironment is a critical driver of cancer progression in colorectal cancer (CRC). Dr. Duransapplication to the R50 Research Specialist Award will support Dr. Moscats research program focused on the roleof the tumor microenvironment in CRC. Unveiling the mechanisms that control this crosstalk is crucial to find newtherapeutic targets for CRC. NCI 10684748 8/22/23 0:00 PAR-21-285 5R50CA265332-02 5 R50 CA 265332 2 "LUO, RUIBAI" 8/16/22 0:00 7/31/27 0:00 ZCA1-SRB-1(M1) 10728208 "DURAN MOLINA, MARIA ANGELES " Not Applicable 12 PATHOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 177778 NCI 104884 72894 SUMMARYThis proposal seeks Dr. Angeles Durans salary support as a Research Specialist to support Dr. Jorge Moscatsresearch program at the Weill Cornell Medicine Department of Pathology and Laboratory Medicine to study therole of the tumor microenvironment (TME) in colorectal cancer (CRC). Dissecting the role of these complexcellular interactions requires scientists with an in-depth understanding of the biology of these processes but alsowith the required technical expertise in in vivo mouse models that faithfully recapitulate human disease as wellas the necessary bioinformatics tools to interrogate the TME of these models at the single-cell level. Thereforewith this Research Specialist Award we intend to provide stable research opportunities for the exceptionalscientist Angeles Duran to develop impactful research in this area of expertise. She has made seminalcontributions in signaling inflammation metabolism and cancer and has a strong interdisciplinary training thatwill be critical for the success of the project. She will contribute to the research program focused on defining themolecular and cellular mechanisms that drives mesenchymal CRC a desmoplastic and of poor prognosis type ofcancer. With her expertise in cancer biology and her capacity to apply novel mouse models and bioinformaticsapproaches she is filling a unique niche within the Moscat lab that will provide continuity stability and detailedscientific knowledge to achieve the aims of the NCI-funded grants. She will support this project with scientificallyimpactful in vivo models and bioinformatics approaches. Dr. Durans long-time expertise and dedication willadvance our understanding of the role of TME in cancer progression to help design more effective therapies. 177778 +No NIH Category available Acceleration;Acute;Address;Adjuvant Therapy;Age;Aging;Attenuated;Biological Aging;Biological Assay;Biological Markers;Biological Process;Blood;Body Composition;Body Size;Body measure procedure;Breast Cancer Treatment;Cancer Patient;Cancer Survivor;Cell Aging;Chemotherapy-Oncologic Procedure;Chronology;Clinical Trials;Collaborations;Collection;Colon Carcinoma;Colorectal Cancer;Cyclin-Dependent Kinase Inhibitor 2A;DNA;DNA Damage;DNA Methylation;Diagnosis;Diet;Disease;Dose;Early treatment;Educational Intervention;Elderly;Epigenetic Process;Face;Geriatric Assessment;Health;High Prevalence;Incidence;Individual;Intervention;Malignant Neoplasms;Measures;Modification;Morbidity - disease rate;Muscle function;Muscular Atrophy;Outcome;Participant;Patients;Pattern;Phenotype;Physical Fitness;Physical Function;Physical activity;Prognosis;Recording of previous events;Resources;Risk;Shapes;Telomerase;Thinness;Time;Toxic effect;Toxicity due to chemotherapy;Treatment-related toxicity;United States;Woman;age related;biomarker validation;cancer diagnosis;cancer therapy;chemotherapy;cohort;colon cancer patients;colon cancer treatment;colorectal cancer treatment;comorbidity;experience;frailty;functional decline;functional disability;health related quality of life;high risk;improved;insight;malignant breast neoplasm;men;mortality;multimodality;muscle form;novel;personalized approach;physical conditioning;prevent;prognostic;rate of change;reduced muscle mass;resistance exercise;risk minimization;risk mitigation;sarcopenia;side effect;skeletal muscle wasting;tool;treatment as usual Characterizing the Risk of Chemotherapy Side Effects Based on Epigenetic Age and Modification by Resistance Training Intervention Chemotherapy toxicity during colon cancer treatment creates an acute and long-term healthburden for patients and it is extremely common. Our study will inform novel appraisal of whetherepigenetic age can be used to identify colon cancer patients at high risk for chemotherapy toxicitydose reductions and delays and whether a resistance training intervention can reduce the rateof epigenetic aging to mitigate that risk. We contend epigenetic age has the capacity to informmore personalized approaches to treating colon cancer patients to improve long-term outcomes. NCI 10684747 8/23/23 0:00 PA-20-185 5R37CA263064-03 5 R37 CA 263064 3 "GALLICCHIO, LISA M" 9/8/21 0:00 8/31/24 0:00 Aging Systems and Geriatrics Study Section[ASG] 10991164 "BINDER, ALEXANDRA MARGARET LYNN" Not Applicable 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 636830 NCI 534188 102642 There is strong evidence that cancer treatment contributes to increased co-morbidity functionaldecline and accelerated biologic aging. Resistance training (RT) interventions may help tominimize this functional decline by increasing lean mass and strength. Patients diagnosed withcolon cancer are particularly likely to benefit from RT interventions given the high prevalence ofinvoluntary loss of skeletal muscle mass (sarcopenia) at diagnosis which is associated withchemotherapy-associated toxicities and poor prognosis. Geriatric assessment which measuresfacets of functional aging can improve the prediction of chemotoxicity risk to guide treatmentdecisions. However application of this tool is frequently limited by the resources required forassessment. Epigenetic clocks which predict chronologic or phenotypic age based on specificpatterns of DNA methylation (DNAm) are easy to assay well-validated markers of biologic aging.Epigenetic age acceleration (AgeAccel; DNAm-estimated age adjusting for chronologic age) hasbeen associated with indicators of decreased muscle mass and function. We hypothesize thatcolon cancer patients with increased AgeAccel will be at greater risk for chemotherapy toxicitiesdose reductions and delays that AgeAccel will increase during colon cancer chemotherapy andthat a RT intervention can reduce the rate of epigenetic aging. We plan to address this scientificpremise in collaboration with the Resistance Training to Reduce Chemotoxicity in Colon Cancer(FORCE) clinical trial. This clinical trial of RT in stage II and III colon cancer patients includesDNA and multi-modal measures of body composition collected at the beginning and end ofchemotherapy. Our first primary aim will evaluate the relationship between several measures ofAgeAccel at baseline and incidence of grade 3 and 4 chemotoxicities dose reductions and delaysamong FORCE participants. We anticipate that increased baseline AgeAccel will be associatedwith an increased incidence of these outcomes and that RT can reduce the strength of theseassociations. Our second primary aim will assess the rate of epigenetic aging during treatmentand whether this rate is modified by RT. We expect that AgeAccel will be higher at the end ofchemotherapy relative to the beginning and that the rate of epigenetic aging will be attenuated inthe RT group. Together these analyses will provide novel insight into the biologic processes ofaging that predict tolerance of cancer treatment and inform appraisal of whether AgeAccel mayserve as a useful tool to guide treatment decisions. 636830 +No NIH Category available Abstinence;Accounting;Address;Adult;Affect;Area;Attention;Biochemical;CD4 Lymphocyte Count;Caring;Cessation Research;Chronic Obstructive Pulmonary Disease;Control Groups;Counseling;Data;Elements;Enrollment;Ensure;Epidemic;Evidence based program;Face;Florida;Future;General Population;Geography;HIV;HIV/AIDS;Health;Health Benefit;Heart Diseases;Individual;Internet;Intervention;Knowledge;Life;Life Expectancy;Light;Literature;Loneliness;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Mediator;Mental Depression;Meta-Analysis;Methodology;Modeling;Motivation;Nicotine Dependence;Online Systems;Outcome;Participant;Persons;Population;Positioning Attribute;Prevalence;Prevention;Pulmonary Emphysema;Randomized;Randomized Controlled Trials;Research;Research Personnel;Role;Science;Self Efficacy;Services;Smoke;Smoker;Smoking;Smoking Cessation Intervention;Stroke;Technology;Tobacco;Tobacco Use Cessation;Tobacco use;Training;Travel;Treatment Efficacy;Treatment outcome;Underserved Population;United States National Institutes of Health;Videoconferencing;Viral Load result;Voice;cancer survival;comorbidity;cost;cost effectiveness;design;eHealth;economic evaluation;effectiveness measure;efficacy evaluation;fighting;follow-up;health disparity;improved;innovation;insight;intervention effect;knowledge base;mortality;nicotine replacement;novel;pilot trial;post intervention;primary outcome;program costs;programs;prolonged abstinence;prospective;recruit;response;skills;smoking cessation;social cognitive theory;standard care;stressor;therapy design;treatment effect;treatment program;treatment strategy The Positively Quit Trial: Addressing disproportionate smoking rates among people living with HIV PROJECT NARRATIVESmoking rates among persons living with HIV (PLH) in the US are triple those in the general adultpopulation and PLH are much less likely to quit smokingpossibly due to the HIV-specificstressors they face. To address the need for program that address their particular needs thisstudy will compare two group-based video-conferencing PLH programs in terms of their effectson smoking cessation and how cessation affects HIV-related health outcomes. As the first studyof its kind the proposed research will yield important insights into a program that could be madewidely available to reach PLH smokers throughout the US. NCI 10684746 7/26/23 0:00 PAR-18-559 5R01CA243800-05 5 R01 CA 243800 5 "CICCOLO, JOSEPH THOMAS" 8/1/19 0:00 7/31/25 0:00 HIV/AIDS Intra- and Inter-personal Determinants and Behavioral Interventions Study Section[HIBI] 9846933 "MARHEFKA, STEPHANIE LYNN" Not Applicable 15 NONE 69687242 NKAZLXLL7Z91 69687242 NKAZLXLL7Z91 US 28.074039 -82.395963 513807 UNIVERSITY OF SOUTH FLORIDA TAMPA FL SCHOOLS OF NURSING 33612 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 510872 NCI 361732 149140 PROJECT SUMMARYWhat we know: There are 1.1 million persons living with HIV (PLH) in the US: at least 40% smoke and mostwant to quit. Almost none are currently accessing smoking cessation interventions designed to meet their specificneeds and concerns. PLH who smoke have high rates of nicotine dependence depression and loneliness. Lungcancer due to tobacco use is a leading killer of people living with HIV (PLH) accounting for up to 61.5% ofmortality. PLH who smoke reduce their life expectancy by 12.3 years on average. The lack of access to proveneffective and HIV-tailored tobacco cessation services represents a health disparity of the first order. Eighty-onepercent of PLH use the Internet and most do so on their own technologymaking group-based video-conferencingaccessed through the Internet a promising avenue to deliver smoking cessation treatment.Although cessation programs are widely offered to the general public there are no evidence-based programsavailable specifically for PLH and none found effective long-term for this population; no programs provide group-based video-conferencing (VG for video-groups); and no PLH-specific programs provide smoking cessationbooster sessions. What we will do: In this rigorous trial the efficacy of a PLH-specific cessation program (PSF-VG) guided by the Social Cognitive Theory will be compared to an attention matched control condition (AMC;prevention with positives) in a randomized control trial. Participants will be N=482 PLH smokers recruited fromFlorida who are motivated to quit within the next 30 days. All participants will be offered nicotine replacementtherapy and brief cessation counseling in addition to an 8-session intervention with booster sessions (PSF-VGor AMC). The primary outcome will be biochemically confirmed 7-day point prevalence abstinence at 12 monthsfollow-up although 30-day point prevalence abstinence and sustained abstinence (continuous abstinence post-quit day after a 2-week grace period) will be assessed as well. We will also determine the cost per additionalquit an important cost-effectiveness measure for smoking cessation. We will examine model-driven hypothesesabout the mediators of treatment outcome (e.g. knowledge motivation to quit self-efficacy) and explore effectson CD4 count and virologic suppression. Implications: 1) This trial will represent one of the most rigorous trialsof tobacco cessation among PLH to date given the AMC and 360-day follow-up period. 2) Establishing the long-term efficacy of a VG smoking cessation program for PLH which reaches PLH where they are will representan enormous advance in the fight against tobacco use in PLH and provide a clearer understanding of the role oftargeted ehealth health interventions in comprehensive HIV care. 3) Determining the costs associated with thisprogram will be critical for making real world implementation decisions. 4) Establishing effect mediators will helpidentify to what extent PSF-VG is working as intended and help build the mechanistic science of HIV smokingcessation. 5) Examining changes in CD4 and viral load will add to our understanding about how smokingcessation confers benefits for health in PLH. Thus this study will likely have a high impact on the field. 510872 +No NIH Category available Address;Archives;Ascites;Autopsy;Award;Blood;Cancer Center;Cancer Patient;Cancer Research Project;Cessation of life;Collaborations;Collection;DNA;Disease;Distant Metastasis;Drug or chemical Tissue Distribution;Focus Groups;Freezing;Funding;Grant;Hour;Human;Individual;Institution;International;Knowledge;Laboratories;Leadership;Liquid substance;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Medical center;Modeling;Molecular;Nebraska;Neoplasm Circulating Cells;Normal tissue morphology;Oncology;Organ;Organoids;Patients;Play;Postdoctoral Fellow;Primary Neoplasm;Process;Prostate;Proteins;RNA;Research;Research Personnel;Research Project Grants;Research Training;Residual state;Resources;Role;Sampling;Specialist;Specimen;TNFRSF5 gene;Tissues;Training;Universities;Work;Xenograft procedure;anticancer research;biobank;blood-based biomarker;design;experience;innovation;mid-career faculty;programs;success;volunteer Critical Resources Provided by UNMC RAP Biorepository Stimulate Cancer Research Project NarrativeThe Rapid Autopsy Program (RAP) biorepository for Pancreas and Prostate Cancer serves as a unique andhighly utilized core associated with several NCI funded programs of research in pancreatic and prostate cancerat UNMC and outside institutions. As Director of the program Dr. Grandgenett plays a major role in expandingthe collection and in the annotation and distribution of these biospecimens. The Director's contribution isessential to the continued success of the program and those dependent on it. NCI 10684745 9/7/23 0:00 PAR-20-287 5R50CA211462-08 5 R50 CA 211462 8 "NOTHWEHR, STEVEN F" 9/15/16 0:00 8/31/26 0:00 ZCA1-SRB-1(A2) 8731990 "GRANDGENETT, PAUL M" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 144703 NCI 94269 50434 Project SummaryThe highly innovative Rapid Autopsy Program (RAP) addresses a major limitation in pancreatic and prostatecancer research: the lack of quality human specimens of cancer representing all stages of disease. Thisprogram led by Dr. Paul M. Grandgenett which includes rapid collection of large quantities of all organs andfluids within 5 hours of death is a unique program in the world and is designed to maintain cellular andmolecular integrity of the tissue. The RAP is a core component of the University of Nebraska Medical Center(UNMC) Pancreatic Cancer Research program and the GU Oncology Focus Group that is tasked with thecollection archiving and distribution of tissues and fluids from patients that have recently passed with pancreasor prostate cancer. The Unit Director of the Pancreatic Cancer Research program at the Fred and PamelaBuffett Cancer Center is Dr. Michael A. Hollingsworth while the prostate group is led by Dr. Surinder Batra andDr. Shawna Boyle. Dr. Grandgenett a Research Associate Professor under Dr. Hollingsworth's aegis is thedirector of the RAP and the applicant for this Research Specialist Award. The rapid autopsy program operateswithin the Pancreatic Cancer Research Program at UNMC and is important to and currently funded in part by:a pancreatic cancer SPORE p50 grant; ongoing and pending P01 and U01 grants and several R01 grants toindividual investigators. Dr. Grandgenett personally directs the collection of primary tumor residual unaffectedtissues distant metastases all unaffected tissues as well as fluids such as blood and ascites for all PDAC andProstate cancer patients. He has also established an extensive normal tissue acquisition program that is highlyutilized. Dr. Grandgenett determines in advance how specific samples will be prioritized based on the needs offunded projects both at UNMC and at other institutions. Currently Dr. Grandgenett provides fresh samples tomultiple laboratories at UNMC and outside-UNMC conducting research on blood-based biomarkers (proteinsRNA DNA) circulating tumor cells patient-derived modeling including organoids and xenografts and otherprocesses. The remaining samples are snap frozen maintained in long-term storage and made availablethrough request and collaboration for local national and international cancer studies. Key roles of Dr.Grandgenett is to coordinate the training and participation of the thirty RAP volunteers and to work withcollaborators to determine the samples necessary for their research project to modify our SOP as needed toobtain those samples confirm specimen quality and then to distribute those samples to investigators. It isessential for the leadership of this resource to be a highly trained Research Specialist with extensiveexperience through participation in the autopsies a comprehensive knowledge of patient sample availabilityas well as the ability to interact on a scientific level with each investigator. Dr. Grandgenett has a major role inall aspects of the collection processing annotation and distribution of these biospecimens and plays a vitalrole in expanding collaborative projects with investigators at UNMC and on a national and international level. 144703 +No NIH Category available Adult;Aminolevulinic Acid;Area;Biological;Biophotonics;Child;Clinical;Clinical Research;Collection;Computer software;Confocal Microscopy;Data;Devices;Diffuse;Engineering;Excision;FDA approved;Fluorescence;Future;Glioma;Histology;Image;Image Analysis;Image-Guided Surgery;Imaging Techniques;Imaging technology;Immunohistochemistry;Location;Machine Learning;Magnetic Resonance Imaging;Mechanics;Methods;Microscope;Microscopic;Microscopy;Molecular;Nature;Neurologic;Neuronavigation;Operative Surgical Procedures;Optics;Outcome;Pathologist;Patient-Focused Outcomes;Patients;Pattern;Performance;Postoperative Period;Procedures;Progression-Free Survivals;Proliferating;Public Health;Quality of life;Randomized;Recurrence;Recurrent disease;Reporting;Residual state;Resolution;Sampling;Sampling Biases;Specimen;Speed;Sterility;Surgeon;Surgical margins;Techniques;Technology;Time;Tissues;Training;Tumor Burden;Validation;Visualization;automated algorithm;brain tissue;clinically relevant;design;fluorescence-guided surgery;high resolution imaging;image guided;image processing;imaging modality;improved;in vivo;indexing;industry partner;innovation;instrumentation;lens;microscopic imaging;neoplastic cell;neurosurgery;overexpression;prototype;radiological imaging;survival outcome;tumor In vivo dual-axis confocal microscopy of 5-ALA-induced PpIX to guide low-grade glioma resections Relevance to public healthWe are developing a set of technologies to enable real-time intraoperative microscopy of the final resectionmargins of low-grade glioma (LGG) patients who have been administered with 5-ALA prior to surgery (FDAapproved in 2017). These quantitative and sensitive imaging techniques have the potential to improve theextent of resection for LGG patients and therefore to improve patient outcomes such as overall survival andprogression-free survival (time to recurrence). NCI 10684738 5/17/23 0:00 PAR-18-530 5R01CA244170-04 5 R01 CA 244170 4 "SALVADOR MORALES, CAROLINA" 6/1/20 0:00 5/31/25 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 9106336 "LIU, JONATHAN T.C." "SANAI, NADER " 7 ENGINEERING (ALL TYPES) 605799469 HD1WMN6945W6 605799469 HD1WMN6945W6 US 47.660307 -122.315168 9087701 UNIVERSITY OF WASHINGTON SEATTLE WA BIOMED ENGR/COL ENGR/ENGR STA 981959472 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 539354 NCI 443724 95630 SummaryExtent-of-resection is correlated with glioma patient outcomes such as progression-free survival. Image-guidance technologies based on MRI and now fluorescence-guided surgery (FGS) have been developed toimprove the surgeons ability to visualize gross tumor margins. However there are fundamental limitations towide-field imaging methods such as MRI and FGS such as poor sensitivity to detect disseminated tumor cellsat the infiltrative margins of diffuse gliomas as well as the non-quantitative and subjective nature of imageinterpretation. With the emergence of FGS using 5-ALA and its recent approval by the FDA in 2017 the gapbetween low-grade glioma (LGG) and high-grade glioma (HGG) patients in terms of extent of resection willlikely widen since LGGs rarely generate sufficient PpIX fluorescence to be detected via wide-field FGS.Consequently there is a clear need for improved intraoperative techniques with the sensitivity to detect andquantify residual LGGs at the margins of the tumor cavity in order to improve the extent of resection and delayrecurrence. We have shown that high-resolution confocal microscopy has the sensitivity to visualize the sparsesub-cellular expression of PpIX in LGG patients treated with 5-ALA even beyond the radiographic margins.Therefore we will optimize a handheld optical-sectioning microscope to image 5-ALA-induced PpIX at the finalresection margins in LGG patients together with real-time video mosaicking to facilitate the imaging of largetissue areas which will minimize sampling bias when imaging heterogeneous brain tissues (Aim 1). In order tofacilitate the clinical acceptance of these techniques we will establish a relationship between the microscopicpatterns of PpIX expression and well-established biological metrics such as tumor burden and proliferative index(Aim 2). Finally we will explore the hypothesis that quantitative microscopic imaging of PpIX of the resectionmargins is predictive of extent of resection as currently defined by post-operative MRI which would suggest thatit has value for optimizing resections to minimize and/or delay recurrence (Aim 3). Collectively these resultswill pave the way for future randomized controlled clinical studies to optimize resection procedures and outcomesfor LGG patients (adults and children) many of whom can have good survival outcomes and quality of life. 539354 +No NIH Category available Address;Affect;Benign;Binding;Biological Assay;Biological Markers;Blood specimen;CA-19-9 Antigen;CD44 gene;CLIA certified;Cancer Detection;Cells;Circulation;Clinical;Complex;Detection;Development;Diagnosis;Diagnostic;Disease;Early Diagnosis;Early treatment;Excision;Exhibits;Family history of;Guidelines;Image;Individual;Inherited;Laboratories;Lesion;Longitudinal Studies;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Manuals;Methods;Microfabrication;Modeling;Monitor;Mus;Neoadjuvant Therapy;Neoplasm Metastasis;Non-Malignant;Operative Surgical Procedures;Pancreas;Pancreatitis;Patients;Performance;Pilot Projects;Plasma;Predictive Cancer Model;Procedures;Proteins;Protocols documentation;Reader;Reagent;Regimen;Reporting;Reproducibility;Research;Resectable;Resistance;Resolution;Sampling;Sensitivity and Specificity;Serum;Source;Specificity;Surface;Syndrome;TACSTD1 gene;Therapeutic;Time;Treatment outcome;Tumor stage;Tumor-Derived;Urine;Validation;Variant;Vesicle;Work;advanced disease;antibody detection;cancer diagnosis;cancer initiation;cancer stem cell;cancer therapy;candidate validation;clinical translation;cohort;design;detection assay;digital;disorder control;early screening;extracellular vesicles;fabrication;human disease;human model;improved;improved outcome;longitudinal analysis;minimally invasive;mouse model;nanoparticle;nanoplasmonic;novel;novel marker;pancreatic cancer model;pancreatic cancer patients;pre-clinical;premalignant;response;sample collection;success;translational impact;treatment response;tumor;tumor initiation Digital Nanoplasmonic Quantification of Tumor-derived Extracellular Vesicles in Plasma Microsamples NARRATIVEExtracellular vesicles (EVs) hold great promise as biomarkers for minimally-invasive disease detection butmost current EV analysis methods are low-throughput and require EV pre-isolation steps which can greatlydecrease their reproducibility and are impractical for clinical use. To address this problem we have developeda rapid robust and isolation-free nanoparticle-based EV assay that directly quantitates tumor-derived EVs inserum or plasma samples to diagnose pancreatic cancer (PC) including early disease with highreproducibility sensitivity and specificity. This proposal is designed to automate and further improve theaccuracy and reproducibility of our novel assay with a single vesicle resultion for PC diagnosis and performanalytical validation of this assay according to Clinical and Laboratory Standards Institute guidelines in CLIA-certified laboratory. NCI 10684737 8/2/23 0:00 PAR-19-156 5U01CA252965-04 5 U01 CA 252965 4 "GRODZINSKI, PIOTR" 9/25/20 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-SBIB-N(55)R] 10898749 "HU, TONY Y." "LU, HUA ; SEN, SUBRATA " 1 BIOCHEMISTRY 53785812 XNY5ULPU8EN6 53785812 XNY5ULPU8EN6 US 29.935429 -90.12279 8424601 TULANE UNIVERSITY OF LOUISIANA NEW ORLEANS LA SCHOOLS OF MEDICINE 701185665 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 566198 NCI 497032 100267 ABSTRACT Extracellular vesicles (EVs) hold great potential as novel biomarkers for minimally invasive detection of earlystage tumors since tumors abundantly secrete EVs that accumulate in the circulation and these EVs cantransport factors that regulate tumor initiation progression and metastasis. However most current EV analysismethods require pre-isolation of EVs prior to analysis and are low-throughput and impractical for clinical use. Werecently developed a rapid robust isolation-free and inexpensive assay that directly quantifies tumor-derivedEVs in small volumes (1~5 L) of serum or plasma. In this assay EVs that bind probes specific for two differentEV target proteins produce a distance-regulated nanoplasmon-enhanced scattering (nPES) effect that allowssensitive detection of specific EVs. In a pilot study we used a nPES assay for a pancreatic cancer (PC)-associated EV marker to distinguish PC cases from non-malignant controls (patients with pancreatitis andhealthy individuals) with high reproducibility specificity and sensitivity. This assay also differentiated PC tumorstages and tumor responses to neoadjuvant outperforming CA19-9 a biomarker widely used for PC therapyassessment. Our nPES assay platform has multiple features required for research and clinical translation: 1) Itis rapid high-throughput and inexpensive; 2) it does not employ EV isolation avoiding a major source of EVassay variation; 3) it robustly and reproducibly quantifies EV biomarkers from small volumes of serum plasmaor urine allowing its use in longitudinal analysis of mouse models of human disease; and 4) it can be readilyadapted to diagnose and monitor cancers that express other EV biomarkers. Based on the success of our pilotstudy we propose to develop and validate an automated and highly reproducible nPES EV assay to allow rapidand accurate PC diagnosis in clinical settings. We hypothesize that a nPES-based digital EV reader will equalor outperform the analytical performance of our current manual assay. We will build a diagnostic EV assay modelfor early PC detection by examining the ability of proteins reported to be enriched on the surface of EVs derivedfrom PC stem cells or PC-initiating cells (e.g. CD44 CD133 and EpCAM) to diagnose patients with early stagePC and to differentiate them from patients with pre-malignant pancreatic lesions hereditary syndromes or familyhistory of PC and individuals with normal pancreases. Specifically we propose to: 1) Development andfabrication of Chip-nPES platform to achieve single EV resolution; 2) automate and refine our nPES-baseddigital EV reader to enhance assay reliability and reproducibility. We will also select and validate candidateEV capture and detection antibodies for PC diagnosis; 3) establish and evaluate a diagnostic model thatintegrates EV biomarkers with known cancer-associations; and 4) perform a pre-clinical validation of this assayin a third-party laboratory. The successful results of this work would have a significant translational impact incancer management through reliable and accessible screens for early detection of pancreatic cancer. 566198 +No NIH Category available Biliary;Bone Marrow;Breast;Bypass;Cancer Etiology;Cancer Model;Cells;Cessation of life;Chemotherapy-Oncologic Procedure;Clinical;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Cytotoxic Chemotherapy;DNA;Data;Data Set;Disease;Dose;Effectiveness;Engraftment;Environment;Fluorouracil;Genes;Head and neck structure;Hematopoietic;Human;Immune;Immune system;Immunocompetent;Immunodeficient Mouse;In Vitro;Interferon Type I;Interferons;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Modality;Modeling;Molecular;Mus;Outcome;Pancreas;Pathway interactions;Patients;Pharmaceutical Preparations;Physicians;Play;Production;Proteins;RNA;Resistance;Role;STING agonists;Scientist;Small Intestines;Stimulator of Interferon Genes;Stomach;T-Lymphocyte;Testing;Therapeutic;Treatment Efficacy;Tumor Burden;Tumor Immunity;Tumor Tissue;United States;Vertebral column;Work;anti-cancer;cancer cell;chemotherapy;colon cancer patients;cytotoxicity;humanized mouse;immunoregulation;in vivo;mouse model;patient derived xenograft model;prognostic;resistance mechanism;response;treatment response;tumor;tumor microenvironment;tumor-immune system interactions Role of immune regulation in colorectal cancer chemotherapeutic response PROJECT NARRATIVEColorectal cancer is the second leading cause of cancer-related death in the United States. Chemotherapy isused in advanced stage colorectal cancers yet the resistance mechanisms are not fully known. This project isaimed at understanding the role of immune system in regulating chemotherapy response in colon cancer. NCI 10684736 8/30/23 0:00 PA-20-185 5R01CA256530-03 5 R01 CA 256530 3 "SINGH, ANJU" 9/1/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 9761842 "LU, JUN " Not Applicable 3 GENETICS 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 480179 NCI 313503 166676 PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer death in the United States.Conventional cytotoxic chemotherapy remains a key treatment modality for advanced-stage diseaseprolonging overall survival yet clinical responses vary substantially among patients. The most widelyused chemotherapy regimens for CRC are formulated with 5-fluorouracil (5-FU) as the backbone. Theeffects of 5-FU have been extensively studied in vitro and in immunodeficient mice. However whatunderlies 5-FUs anti-cancer efficacy in vivo in immunocompetent settings remains poorly understoodthe understanding of which will be critical for devising more effective and/or less toxic strategies againstCRC. It is well recognized that cancer-cell-intrinsic sensitivity to 5-FU in vitro can partially explainresponsiveness to 5-FU in vivo with the underlying model that for intrinsically sensitive cancers 5-FUreduces tumor burden primarily through direct cytotoxicity on cancer cells. However whether thisconventional model is accurate in immunocompetent hosts is not clear. Based on preliminary data wepropose to test a revised model for how 5-FU is effective in immunocompetent settings: 5-FU-inducedreduction of tumor-burden requires two components cancer cells intrinsic sensitivity to the drug toprime the response and a distinct requirement for immune modulation to play a major role in reducingtumor burden. Lacking either component will reduce 5-FU efficacy in vivo. We will test this revisedmodel through three complementary aims. In the first aim we will test the dual requirements of cancer-cell-intrinsic chemosensitivity and immune modulation for effective response to 5-FU in vivo. In thesecond aim we will determine the molecular and cellular basis of the immune modulation that reducestumor burden. In the third aim we will investigate the relationship between the cGAS-STING pathwayand chemotherapy response of human colon tumors. Findings from these studies have the potentialto transform our understanding of how 5-FU works in vivo and build a bridge between 5-FUeffectiveness and anti-tumor immunity. This project also has the potential to unveil new prognostic andtherapeutic strategies for CRC patients. Given that 5-FU is also used in other malignancies (e.g.pancreas gastric biliary small intestinal breast head and neck) our studies have treatmentimplications well beyond CRC. 480179 +No NIH Category available ATM gene;Address;Adjuvant;African American;African American population;Age;Alleles;Award;BARD1 gene;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer therapy;CDH1 gene;CHEK2 gene;Clinical;Cohort Studies;Collaborations;Data;Decision Making;Disease;Estrogen receptor negative;Estrogen receptor positive;Exhibits;Family;Family history of;Gene Mutation;Genes;Genetic;Genetic Predisposition to Disease;Genetic study;Goals;Guidelines;Hereditary Malignant Neoplasm;Heritability;Individual;Inherited;Malignant Neoplasms;Mammary Neoplasms;Medical;Medical Genetics;Metastatic breast cancer;Minority Groups;Modeling;Mutate;NF1 gene;Neoadjuvant Therapy;Outcome;PALB2 gene;PTEN gene;Pathogenicity;Patients;Penetrance;Population;RAD51C gene;Risk;Risk Assessment;Risk Estimate;Risk Management;Series;Susceptibility Gene;TP53 gene;Test Result;Variant;Vision;cancer clinical trial;cancer predisposition;cancer risk;clinical application;clinically relevant;genetic panel test;genetic testing;genetic variant;improved;lifetime risk;malignant breast neoplasm;mutation carrier;novel;rare variant;risk variant;targeted treatment;translational study;treatment response;triple-negative invasive breast carcinoma;variant of unknown significance Resolving the cancer relevance of predisposition gene mutations PROJECT NARRATIVEI have led many of the genetic studies of breast cancer predisposition with the goal of providing improvedhereditary cancer genetic testing and personalized risk assessment for the population. Here I outline my visionfor advancing the field of breast cancer predisposition through a series of translational studies that will result inimproved risk estimation and determination of the value of directed therapy for many of these individuals.These studies represent a significant step towards eliminating many of the issues faced by patients receivingclinical genetic testing for breast cancer. NCI 10684726 8/31/23 0:00 PAR-19-349 5R35CA253187-04 5 R35 CA 253187 4 "ROTUNNO, MELISSA" 9/1/20 0:00 8/31/27 0:00 ZCA1-GRB-S(M1) 1899922 "COUCH, FERGUS JOSEPH" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 570912 NCI 587087 346381 Breast cancer has a strong heritable component with approximately 15% of patients exhibiting a family historyof the disease. My group recently established that inherited variants in 12 genes (ATM BARD1 BRCA1 BRCA2CDH1 CHEK2 NF1 PALB2 PTEN RAD51C RAD51D and TP53) predispose to breast cancer (1 2) thatvariants in all 12 genes increase risks of breast cancer in minority populations (3) and that variants in certaingenes predispose only to estrogen receptor (ER) positive (ATM and CHEK2) or ER negative and triple negativebreast cancer (TNBC) (BARD1 RAD51C and RAD51D) (4-6). Despite these major advances clinical applicationof the information is still lacking. In addition up to 50% of the familial risk of breast cancer remains unexplained.Under this award we plan to address clinically relevant issues including improved application of genetic testingresults for risk management of patients and improved selection of breast cancer therapy. In addition we aim toidentify new breast cancer predisposition genes that account for the missing heritability. The proposed studiesare unified under a theme of advancing understanding of predisposition genetics. The studies are as follows:A. Age-specific and population-specific cancer risk assessment for predisposition gene variants. Results fromhereditary multigene panel testing has limited clinical utility because only lifetime risk estimates of cancer by age80 are available. Here we will estimate 5 and 10-year risks of breast cancer so that patients can make decisionsabout medical management. In addition we have evidence that specific genes have much higher penetrance inAfrican Americans. We will determine the penetrance of predisposition gene variants using a large AfricanAmerican cohort study in order to modify risk management guidelines for this population.B. Functional characterization of predisposition gene variants. Variants of uncertain significance (VUS)identified by genetic testing remain a major problem for individuals receiving clinical genetic testing. We aim tocombine high-throughput functional analysis of VUS in ATM BRCA2 and PALB2 genes with genetic data fromfamilies in integrated models to determine the clinical relevance of many VUS alterations.C. Therapeutic response for breast cancer predisposition genes. The responsiveness of breast tumorsassociated with predisposition gene variants to standard or targeted therapy is only known for BRCA1 andBRCA2 mutation carriers. Here we aim to identify all patients with pathogenic variants in the commonly mutatedBRCA1 BRCA2 PALB2 ATM and CHEK2 genes from a series of neo-adjuvant adjuvant and metastatic breastcancer clinical trials and to assess response to therapy and outcome.D. Identification of novel breast cancer predisposition alleles. The common and rare risk alleles for breastcancer account for only 50% of the familial risk in the population. In an effort to identify the missing heritabilitywe will collaborate with Regeneron Inc. through our SIMPLEXO consortium to identify common and rare allelesassociated with breast cancer risk in 45000 breast cancer patients. 570912 +No NIH Category available 4D Imaging;Actins;Address;Adenine Nucleotide Translocase;Adopted;Animals;Ants;Basic Science;Behavior;Biosensor;Brain;Caenorhabditis elegans;Cell Line;Cell Survival;Cells;Chemicals;Clinical Research;Clinical Trials;Compensation;Data;Developmental Process;Distant Metastasis;Event;Excision;Experimental Models;Extracellular Matrix;Extracellular Matrix Degradation;F-Actin;Fluorescence;Genes;Genetic;Glioblastoma;Goals;Human;Immunologic Surveillance;In Vitro;Invaded;Localized Malignant Neoplasm;Malignant Neoplasms;Matrix Metalloproteinases;Metabolic;Mission;Mitochondria;Modeling;Neoplasm Metastasis;Output;Oxidative Stress;Pathway interactions;Penetration;Pharmacologic Substance;Polymers;Porosity;Production;Proteins;Proteolysis;Public Health;RNA Interference;Reporter;Research;Role;Site;Slice;Testing;Therapeutic;Time;Tissues;Tumor Cell Invasion;Tumor-Derived;United States National Institutes of Health;Work;brain tissue;cancer cell;cancer invasiveness;cancer therapy;clinically relevant;combinatorial;confocal imaging;efficacy testing;genetic analysis;improved;in vivo;in vivo Model;inhibitor;knock-down;live cell imaging;mutant;neoplastic cell;overexpression;patient prognosis;polymerization;prevent;programs;response;tissue culture;tumor;tumor progression Targeting invasive plasticity by inhibiting mitochondrial adaptations to matrix metalloproteinase loss Cell invasion through extracellular matrix allows tumors to spread and become lethal. Theproposed research will increase our understanding of how invasive cells adapt to overcome anti-invasive therapies. The proposed work is relevant to the mission of NIH to improve public healthas it will create a pipeline to develop combinational approaches to more effectively target invasivecancer cells and directly improve patient prognosis. NCI 10684722 7/21/23 0:00 PAR-21-061 5R21CA264632-02 5 R21 CA 264632 2 "RODRIGUEZ, LARITZA MARIA" 8/16/22 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-OBT-J(55)R] 11184241 "KELLEY, LAURA CATHERINE" Not Applicable 4 BIOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF ARTS AND SCIENCES 277054673 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 184406 NCI 114538 69868 Tumor cell invasion through extracellular matrix (ECM) facilitates localized and distant cancer spreadwhich is the most lethal aspect of cancer. The ability of cells to switch between distinct invasive modestermed plasticity or adaptation when faced with varying physical or chemical challenges underlies theinability to develop anti-invasive therapies. Identifying targetable adaptive responses to halt invasion hasbeen hindered by the lack of experimental models to identify characterize and test the loss of keymolecules that facilitate plasticity. To address this critical need we have focused on matrixmetalloproteinases (MMPs) which have been targeted in extensive clinical trials because of their strongassociation with cancer and role in degrading ECM. Anti-MMP therapies however have been ineffectivelikely because of invasive plasticity. To identify and understand how invasive cells adapt to MMP losswe are using the in vivo model of anchor cell (AC) invasion in C. elegans. We found that the geneticremoval of MMPs results in an adaptive invasion response where instead of ECM degradation the ACincreases F-actin polymerization to forcefully penetrate ECM. Using MMP-null animals we performed thefirst synergistic invasion screen to pinpoint genes that promote adaptive AC invasion and identified themitochondrial ATP/ADP translocase ant-1.1 as the strongest candidate. ANTs have multiplemitochondrial functions (ATP/ADP exchange mitophagy mitochondrial dynamics) and the ANT-1.1protein is highly enriched in AC mitochondria that polarize to the site of ECM invasion. ANT-1.1knockdown in MMP-null animals prevents adaptive F-actin formation and inhibits AC invasion. The overallobjective of this application is to (Aim 1) elucidate how ant-1.1 promotes adaptive invasion after MMPloss in C. elegans and (Aim 2) determine if the concurrent loss of MMP and ANT activity in a 4-Dorganotypic brain slice model of glioblastoma (GBM) blocks invasive activity. Our central hypothesis isthat understanding how ANT-1.1 functions in mitochondrial for adaptive invasion will facilitate targetingANTs along with MMPs in a clinically relevant brain slice model of GBM invasion. To understand howANT-1.1 promotes adaptive invasion will use genetic analysis fluorescence reporters metabolicbiosensors cell-specific metabolic analysis and quantitative live-cell imaging. We will then usequantitative confocal imaging to directly test the efficacy of combined ANT and MMP therapies on GBMcell invasion. We expect to establish how ANT-1.1 functions within mitochondria to facilitate adaptiveinvasion (possibly through multiple functions) and to develop combined therapeutic approaches toeffectively block GBM invasion. These contributions will be significant as they will reveal how invasivecells adaptively invade in the absence of MMPs and establish a pipeline that can be used to identify andcharacterize synergistic invasive targets resulting in more effective cancer therapies. 184406 +No NIH Category available Acceleration;Adoption;Algorithms;Bayesian Modeling;Biological Process;Cancer Etiology;Cancer Patient;Cancer Research Project;Carcinogens;Chinese;Clinical;Communities;Computer software;Computing Methodologies;Credentialing;Cytidine Deaminase;Data;Data Set;Disadvantaged;Ensure;Etiology;Evolution;Family;Fingerprint;Funding;Genomics;Goals;Hemorrhage;Human;Individual;Informatics;Institution;Joints;Knowledge;Learning;Malignant Neoplasms;Meta-Analysis;Methods;Modeling;Mutation;Noise;Parameter Estimation;Patients;Pattern;Probability;Procedures;Process;Research Personnel;Sampling;Software Tools;Statistical Methods;Subgroup;Techniques;Technology;Time;Uncertainty;Variant;Visualization;anticancer research;base;cBioPortal;cancer genome;cancer genomics;cigarette smoke;cohort;flexibility;genome analysis;high dimensionality;improved;insight;interest;large scale data;method development;novel;operation;predictive signature;protein activation;software development;targeted sequencing;tool;tumor Utilizing Bayesian modeling to improve mutational signature inference in large-scale datasets Characterizing mutational signatures can reveal insights into tumor etiology and evolution. Current computationalmethods that perform mutational signature inference such as non-negative matrix factorization (NMF) haveseveral limitations including a lack of ability to predict signatures in individual samples perform joint learning ofknown and novel signatures cluster tumors into subgroups and perform model selection. We will develop novelstatistical methods more accurate variational inference procedures and an interactive R/Shiny interface with acloud backend to allow both computational and non-computational users to better characterize mutationalpatterns in their tumor cohorts and predict signatures in single clinical samples. NCI 10684720 8/23/23 0:00 RFA-CA-20-008 5U01CA253500-03 5 U01 CA 253500 3 "MILLER, DAVID J" 9/17/21 0:00 8/31/24 0:00 ZCA1-RTRB-R(M3) 9196918 "CAMPBELL, JOSHUA D" "YAJIMA, MASANAO " 7 INTERNAL MEDICINE/MEDICINE 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF MEDICINE 21182340 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 401084 NCI 244019 158612 The goals of this proposal are to develop novel statistical methods more accurate inference procedures andinteractive software tools to perform mutational signature deconvolution in cancer samples. Mutationalsignatures are patterns of co-occurring mutations that can reveal insights into a cancer's etiology and evolution.Currently non-negative matrix factorization (NMF) is the gold-standard for mutational signature deconvolution.However NMF has several deficiencies in that it cannot do the following things: 1) predict signatures in newsamples 2) perform joint learning of known and novel signatures at the same time 3) alleviate problems fromsignature bleeding 4) cluster tumors into subgroups based on mutational signature profiles and 5) characterizeuncertainty in model fit. In this proposal we will develop a novel Bayesian hierarchical models that overcomethe limitations of NMF. Furthermore there is a lack of interactive software for mutational signature inference andvisualization for non-computational users. We will also develop an R/Shiny interface on top of our R package tofacilitate data preprocessing inference and visualization of large-scale datasets. This interface will have a cloudbackend to facilitate computationally intensive operations. Overall this software will streamline mutationalsignature analysis for noncomputational researchers and will have the capability to interface with other projectsfrom the Informatics Technology for Cancer Research (ITCR) program. Finally we will analyze a novel targetedsequencing dataset from Chinese patients and perform a meta-analysis of all publicly available variants togenerate a novel reference set of mutational signatures for investigators to use in their own studies. Overall ourtools will be of great interest to the cancer community as it will provide greater insights into mutational signaturepatterns and will be useful in clinical settings to reveal insights into cancer etiology. 401084 +No NIH Category available Academic Medical Centers;Aliquot;Benign;Biological Markers;Biopsy;Blinded;Blood;Blood Tests;Cancer Patient;Categories;Chest;Classification;Clinical;Collection;Communication;Communities;Consent;Data;Diagnosis;Diagnostic;Disease;Early Detection Research Network;Early Diagnosis;Enrollment;Epithelium;Evaluation;Funding;Goals;Histoplasmosis;Image;Lung;Lung nodule;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Nodule;Outcome;Patients;Phase;Pilot Projects;Play;Population;Population Heterogeneity;Procedures;Research Design;Resources;Risk;Risk Assessment;Risk Estimate;Role;Sample Size;Site;Specimen;Testing;Time;Translating;United States;Universities;Validation;Washington;X-Ray Computed Tomography;biobank;bioinformatics infrastructure;biomarker validation;cancer biomarkers;cancer diagnosis;cancer risk;candidate validation;clinical biomarkers;clinical implementation;clinical practice;clinical trial implementation;cohort;computerized;convolutional neural network;deep learning;diagnostic accuracy;diagnostic biomarker;imaging biomarker;implementation trial;improved;industry partner;innovation;lung cancer screening;lung lesion;medical schools;mortality;new technology;patient screening;population health;prospective;radiomics;randomized clinical trials;recruit;sample collection;screening;support network Clinical Utility of a Combined Biomarker Approach to Diagnose Lung Cancer PROJECT NARRATIVEDoctors continue to struggle to diagnose lung cancer early when it is most curable. Lung cancer screening alongwith breakthroughs in blood tests and sophisticated computerized imaging may help solve this problem. Wepropose to enroll a diverse population with suspicious lung lesions in a trial to test these new technologies andalso validate new ones for clinical use. NCI 10684713 8/29/23 0:00 RFA-CA-21-033 5U01CA152662-12 5 U01 CA 152662 12 "MARQUEZ, GUILLERMO" 8/16/10 0:00 8/31/27 0:00 ZCA1-PCRB-D(M1) 9563977 "GROGAN, ERIC L" "DEPPEN, STEPHEN " 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1001446 NCI 726168 344522 PROJECT SUMMARYLung cancer remains the number one cancer killer in the United States and clinically useful biomarkers areneeded to improve early detection and diagnosis. The objectives of this proposal for our continuing ClinicalValidation Center are to push early lung cancer detection biomarkers into clinical practice while continuing toserve as a core resource to the EDRN as well as to our academic and industry partners. Our overall objectiveis to demonstrate that biospecimen and imaging biomarkers will provide clinical utility to diagnose lung cancerby reducing the number of invasive procedures performed for benign disease and the time to diagnosis forcancer. Aim 1 will seek to demonstrate clinical utility of a combined biomarker and radiomic approach forproviding Indeterminate Pulmonary Nodule (IPN) diagnoses. We will expand the existing lung specimen andimaging biorepository available to the scientific community demonstrate the clinical utility of combinationbiospecimen and radiomic biomarkers and validate additional candidate lung cancer risk biomarkers. We willdiversify the population and enhance statistical power by recruiting from existing partnerships funded by priorEDRN funding: Meharry Medical College and Washington University in St. Louis. We seek to accomplish threeobjectives in this aim: 1) to validate the combined approach of hsCYFRA 21-1 cancer biomarker radiomic(HealthMyne) biomarker and a Histoplasmosis benign biomarker (MiraVista) in the EDRN Lung Team Project 2and National Lung Screening Trial reference cohorts 2) to determine the clinical utility of the Histoplasmosis testfollowed by a Combined Biomarker Model (hsCYFRA21-1 radiomics and Mayo Model) in a Phase 4 randomizedclinical trial and 3) to validate new candidate blood and epithelial biomarkers in Phase 2 and 3 prospective-specimen-collection and retrospective-blinded-evaluation (PRoBE) design studies for the early diagnosis of lungcancer. In Aim 2 we will validate radiomic risk assessment platforms in IPNs and conduct a pilot clinicalimplementation trial in screening discovered IPNs. We will leverage the robust bioinformatics infrastructure atVanderbilt University Medical Center to capture and deidentify 800 thoracic CT scans in patients with IPNs. ALung Cancer Prediction Convolutional Neural Network (LCP-CNN) and the HealthMyne radiomic model will becompared to each other and against the Lung-RADS categories. We will perform a prospective pilot evaluationof the best performing model in Lung-RADS category 3 and 4 IPNs. To accomplish Aim 2 we will: 1) comparethe accuracy of LCP-CNN and HealthMyne radiomics 2) determine the LCP-CCN's ability to reclassify nodulesin screening patients in a prospective clinical implementation pilot study. At the completion of this proposal wewill have 1) evaluated clinical utility of combining lung cancer biospecimen and imaging biomarkers 2) developeda platform within current practice to present an imaging biomarker approach to improve IPN risk assessmentand 3) enhanced the biorepository resource for the EDRN and collaborative use. 1001446 +No NIH Category available Acupressure;Acupuncture Therapy;Adherence;Affect;Aftercare;American Society of Clinical Oncology;Analgesics;Anti-Inflammatory Agents;Basal Ganglia;Biological Markers;Bortezomib;Brain;Cancer Patient;Cancer Survivor;Cells;Characteristics;China;Clinical;Clinical Trials;Data;Demographic Factors;Dose;Ear;Ear Acupuncture;Ecological momentary assessment;Equilibrium;Esthesia;Ethnic Origin;Europe;Exercise;Fatigue;Fingers;Functional Magnetic Resonance Imaging;Functional disorder;Gender;Goals;Hand;Health Care Costs;Image;Inflammation;Inflammatory;Interferon Type II;Interleukin-1 beta;Interleukin-2;Interleukin-6;Intervention;Late Effects;Licensing;Macrophage;Malignant Neoplasms;Measures;Mediating;Monitor;Needles;Neurons;Numbness;Opioid;Outcome;Pain;Pain Threshold;Pain management;Participant;Patient Self-Report;Patients;Peripheral Nervous System;Pharmaceutical Preparations;Physical Function;Placebo Effect;Placebos;Plasma;Platinum;Provider;Psychophysics;Quality of life;Race;Randomized Controlled Trials;Recommendation;Regulation;Reporting;Resources;Self Management;Sensory;Sensory Thresholds;Severities;Signal Transduction;Sleep;Specificity;Stimulus;Survival Rate;Symptoms;TNF gene;Taiwan;Testing;Time;Toes;Vinca Alkaloids;active method;afferent nerve;cancer therapy;chemotherapy;chemotherapy induced neuropathy;cognitive control;cytokine;design;duloxetine;effective therapy;efficacy evaluation;executive function;expectation;experience;fall risk;foot;functional disability;improved;indexing;innovation;morphine equivalent;neuroimaging;opioid overuse;opioid use;pain inhibition;pain perception;pain relief;persistent symptom;primary endpoint;primary outcome;secondary outcome;sex;side effect;skills;smartphone application;taxane;tool;treatment as usual Auricular Point Acupressure to Manage Chemotherapy Induced Neuropathy Chemotherapy-induced neuropathy (CIN)pain numbness and/or tingling distributed in the hands and feetproduces persistent symptoms affecting sensation and balance in cancer survivors. Up to 50% of cancersurvivors still suffer from CIN 6 years after treatment with a 1.8-fold increased risk of falls which negativelyimpacts quality of life. We propose to test auricular point acupressure (APA)a non-invasive andnonpharmacological patient managed strategyas an innovative solution for CIN. NCI 10684707 8/11/23 0:00 PA-18-141 5R01CA245054-04 5 R01 CA 245054 4 "ALTSHULER, RACHEL DINA" 9/1/20 0:00 5/31/25 0:00 Clinical Management of Patients in Community-based Settings Study Section[CMPC] 8223918 "JOHNSON, CONSTANCE MARGARET" "LUKKAHATAI, NADA " 18 MISCELLANEOUS 800771594 ZUFBNVZ587D4 800771594 ZUFBNVZ587D4 US 29.703025 -95.403303 578417 UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON HOUSTON TX SCHOOLS OF NURSING 770305400 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 656481 NCI 527768 128713 More than 60% cancer patients experience chemotherapy-induced neuropathy (CIN) a severe side effect ofchemotherapy (including platinum drugs vinca alkaloids taxanes and/or bortezomib). CIN may causetreatment delays dose reductions or discontinuation of therapy which can affect survival rates. Withimproved cancer treatments and longer survival the late effects of CIN continue to produce a significantburden in up to 50% of cancer survivors who are suffering from CIN 6 years after treatment with a 1.8-foldincreased risk of falls. CIN continues to cause significant functional disability negatively impacts quality oflife and significantly demands high health care costs and resource use.We propose to test auricular point acupressure (APA)a non-invasive and nonpharmacological patientmanaged strategyas an innovative solution for CIN. APA is developed from auricular acupuncture whichis an invasive (using needles) and passive treatment (administered by a licensed practitioner). APA is anon-invasive and active treatment for patients with pain. It involves needleless acupuncture-like stimulationof ear points. Small seeds are taped on specific ear points by a skilled provider and patients press on theseeds to stimulate ear points three times daily three minutes per time for a total of nine minutes per day toachieve pain relief. APA provides pain relief within 12 minutes after ear stimulation and sustains pain relieffor one month after a 4-week APA intervention. APA is popular in Taiwan China and Europe. Though itsuse is sparse in the U.S. a limited number of clinical trials have supported APA in pain management.This study will provide vital information to gain a comprehensive understanding of underlying mechanism ofAPA on CIN and provide strong impetus for including APA as part of CIN management in clinical settings. 656481 +No NIH Category available Adaptive Immune System;Area;Astrocytes;Biological Markers;Brain;Cell Communication;Cell Therapy;Cells;Cessation of life;Clinical;Cross Presentation;Cytoplasm;Cytotoxic T-Lymphocytes;DNA cassette;Dependovirus;Disease;Early Diagnosis;Endowment;Evaluation;Glioblastoma;Goals;Infiltration;Innate Immune System;Life Support Systems;Ligands;Macrophage;Malignant Neoplasms;Microglia;Morbidity - disease rate;Neurosurgeon;Normal Cell;Nucleic Acids;Phenotype;Plasma;Proteins;RNA;Research Personnel;Seasons;Serum;T-Lymphocyte;Therapeutic;Tumor Antigens;Vesicle;antimicrobial peptide;arm;brain cell;cell type;combinatorial;design;exhaust;extracellular vesicles;forging;insight;neoplastic cell;novel;novel therapeutics;programs;promoter;response;standard of care;tumor;tumor growth;tumorigenic;vector;vesicular release The power of extracellular vesicles in glioblastoma NarrativeA seasoned team will elaborate on extracellular vesicles released from glioblastoma for use as biomarkers ofclinical response. Studies will focus on how these extracellular vesicles subjugate normal cells in themicroenvirons in support of tumor growth and how these insights can be exploited to design novel modes oftherapy. NCI 10684687 8/8/23 0:00 PAR-17-494 5R35CA232103-06 5 R35 CA 232103 6 "SALOMON, RACHELLE" 9/6/18 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 1867698 "BREAKEFIELD, XANDRA OWENS" Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 989360 NCI 588000 401360 Project Summary/AbstractGlioblastomas remain one of the most deadly cancers with no breakthroughs in therapy for the past 20 years.Xandra Breakefield has made critical discoveries demonstrating that these tumor cells release extracellularvesicles containing informative nucleic acids and proteins that convert normal brain cells to tumor supportivecells. Working with a team of seasoned investigators she has continued to make breakthrough advances in theuse of these vesicles as biomarkers in elucidating the means by which they subjugate microglia and othercells in their microenvirons and in exploring how they may be channeled for therapeutic purposes. This teamconsisting of Drs. Breakefield Joseph El Khoury/Suzanne Hickman (microglia experts) Thorsten Mempel (Tlymphocyte expert) Marike Broekman (neurosurgeon) and Casey Maguire (vector expert) will advance theseinsights in three interrelated areas: biomarkers cell-to-cell communication and therapy. Studies are designedto increase sensitivity and reveal clinical correlates of RNA and protein in extracellular vesicle biomarkers fromserum/plasma with goals of early detection informing therapeutic decisions and longitudinal evaluation. Theywill explore how tumor extracellular vesicles participate in changing the phenotype of microglia macrophagesand astrocytes in the tumor microenvirons such that they become a life support system for the tumor indefiance of therapy. These insights will be forged into new therapeutic concepts with a focus on engaging theinnate and adaptive immune systems to arm the brain against the tumor. This will include increasing crosspresentation of extracellular vesicle-derived tumor antigens via microglia to infiltrating T lymphocytes using co-stimulatory molecules. Microglia associated with the tumor will be endowed with increased capacity to releaseanti-microbial peptides which are also anti-tumorigenic to reawaken their sense of the presence of the tumorand to down-regulate program death-ligands that exhaust cytotoxic T lymphocytes. Tumor-associated cellsincluding reactive astrocytes microglia and macrophages will be manipulated using systemically administeredadeno-associated virus and other vectors (which are clinically compatible) carrying transgene cassettes underpromoters that are strongly up-regulated in cells near the tumor but not in the same cell types in other parts ofthe brain. Vesicles produced by these cells will also be used to deliver therapeutic cargo to tumors cells toprovide sustained therapeutic impact. These studies acknowledge the cytoplasmic continuum of cancer amongall the cell types that make up the tumor mass and strike at this supportive microenvironment which sustainsthe tumor. Therapeutic strategies are designed to be combinatorial with standard-of-care without increasingmorbidity for this devastating disease that has defied current therapeutic approaches. 989360 +No NIH Category available Address;Anatomy;Area;Automobile Driving;BRAF gene;Benign;Biological Assay;Biological Models;Biology;Biopsy;CDKN2A gene;Cell Cycle;Cells;Chemoprevention;Classification;Clinic;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Cutaneous Melanoma;Data;Data Set;Dermatologist;Detection;Development;Diagnosis;Disease;Drug Delivery Systems;Early Diagnosis;Early identification;Engineering;Environment;Event;G2/M Arrest;Genes;Genetic;Genetically Engineered Mouse;Genomics;Goals;Growth;Histologic;Human;Human Engineering;In Vitro;Incidence;Interruption;Knowledge;Lesion;MAP Kinase Gene;Malignant - descriptor;Measurement;Mediating;Mediator;Melanocytic nevus;Methods;MicroRNAs;Modeling;Mole the mammal;Molecular;Molecular Profiling;Mutation;Neoplasms;Nevi and Melanomas;Nevus;Oncogenes;PTEN gene;Pathologist;Patients;Physicians;Pilot Projects;Positioning Attribute;Prevention;Prevention strategy;Regulation;Reporting;Reproducibility;Role;Sampling;Signal Transduction;Skin Cancer;Skin Pigmentation;Specificity;Survival Rate;System;Techniques;Testing;Training;Transcript;Tumor Suppressor Proteins;Validation;aurora B kinase;benign state;cohort;detection method;diagnostic accuracy;differential expression;driver mutation;early screening;high risk;high risk population;improved;in vivo;in vivo Model;in vivo evaluation;inhibitor;innovation;mRNA Expression;melanocyte;melanoma;melanoma biomarkers;melanomagenesis;miRNA expression profiling;novel;novel strategies;pre-clinical;prevent;screening;senescence;skin lesion;transcriptomic profiling;tumor;tumor progression Nevus associated microRNAs as mediators of BRAF-induced growth arrest and biomarkers of melanoma progression Project NarrativeMelanomas are pigmented skin cancers that can be difficult to distinguish from benign moles even for trainedprimary physicians and dermatologists and can be deadly if overlooked. Based upon the genes and regulatorymolecules that distinguish moles from melanomas the proposed project explores new methods for detectingand preventing the transformation of moles into melanomas. NCI 10684681 7/25/23 0:00 PA-20-185 5R01CA229896-03 5 R01 CA 229896 3 "WEINREICH, MICHAEL DALE" 8/24/21 0:00 7/31/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 11759281 "JUDSON-TORRES, ROBERT LAIRD" Not Applicable 1 DERMATOLOGY 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 341867 NCI 224175 117692 SummaryA single driver mutation BRAFV600E drives half of all melanomas. However in the majority of casesacquisition of BRAFV600E instead drives benign tumors such as melanocytic nevi (the common mole). We seekto decipher the intracellular mechanisms that prevent full transformation and harness this knowledge todevelop candidate early diagnosis and chemoprevention strategies. We have discovered a signature ofmicroRNAs (miRNA) as the most differentially expressed transcripts distinguishing nevi from either normalmelanocytes or melanomas. We have reported that expression of these miRNAs classifies biopsied pigmentedneoplasms with high diagnostic accuracy. To determine whether knowledge of these miRNAs could aid in theprevention of melanoma: First we conducted a comprehensive identification and functional screen of thetargets of the most predictive miRNA MIR211-5p. Using freshly isolated and CRISPR engineered humannormal nevus and melanoma melanocytes we identified inhibition of AURKB expression as a criticalmechanism driving both BRAFV600E and MIR211-5p associated growth arrest in vitro. Therefore in Aim 1 ourobjective is to assess the roll of the MIR211-5p/AURKB axis in nevus formation and transformation in vivo andthe efficacy of disrupting this axis in melanoma chemoprevention. Second we generated a non-invasive assayfor miRNA screening of pigmented lesions prior to biopsy. In a small pilot study we found the high accuracy ofclassification of melanocytic neoplasia was retained. In Aim 2 our objective is to validate the utility of usingnon-invasive profiling of the miRNA signature to screen pigmented skin lesions.Three advances distinguish our proposal. The first is the reproducibility of our miRNA classifier currentlyvalidated on six independent datasets. Second our model systems for this diseaseengineered primaryhuman melanocytes nevi and melanomas combined with an in vivo system that recapitulates both thegenetics and progression of melanomaputs us in a unique position to control for context-specific effectswhen studying these critical events. Third is our development of a non-invasive miRNA profiling assay amolecular profiling technique that is both non-invasive and lesion-specific. Our team consisting of experts inboth the basic biology of miRNA and melanoma in vivo models of melanoma topical drug delivery and thedaily practice of melanoma surveillance allows us to comprehensively tackle this project.This project has both basic and clinical potential significance. Our studies explore novel explanations for nevusinitiation driven by observations made from clinical lesions. We expect these studies to directly result in anincrease in the early detection of melanomas and preclinical validation of a strategy for topicalchemoprevention for particularly high-risk individuals and/oror anatomic areas. 341867 +No NIH Category available ALCAM gene;Acute Myelocytic Leukemia;Adult;Animal Model;Antibodies;Apolipoprotein E;Behavior;Biology;Blood Banks;Blood Transfusion;CCL3 gene;CTLA4 gene;Cell Lineage;Cell Surface Receptors;Cell Survival;Clinical;Cytoplasm;Data;Databases;Development;Development Plans;Event;Exhibits;FLT3 inhibitor;Foundations;Functional disorder;Future;Goals;Hematologic Neoplasms;Human;ITIM;Immune;Immune response;Immunity;Immunoglobulins;Immunosuppression;Immunotherapy;Infiltration;Leukemic Cell;Leukemic Infiltration;Leukocytes;Ligands;Liposomes;Malignant Neoplasms;Mediating;Mediator;Medical center;Membrane Glycoproteins;Mentors;Mutation;Organ;PD-1/PD-L1;Pathology;Patients;Physicians;Prognosis;Proliferating;Protein Tyrosine Phosphatase;Proteins;Reporting;Research;Role;STAT3 gene;Scientist;Signal Pathway;Signal Transduction;Signaling Molecule;Solid;Surface;Survival Rate;T-Cell Proliferation;T-Lymphocyte;Testing;Texas;The Cancer Genome Atlas;Universities;Up-Regulation;Vision;acute myeloid leukemia cell;adult leukemia;arginase;burden of illness;career development;cell motility;expectation;experience;experimental study;extracellular;immunoregulation;improved;inhibitor;instructor;knockout gene;leukemia;leukocyte activation;leukocyte mediator;member;migration;monocyte;new therapeutic target;novel;receptor;receptor expression;response;side effect;skills;synergism;transfusion medicine;tumor;tumor immunology;tumor microenvironment The role of LILRB4 in AML progression and immune suppression Project NarrativeAcute myeloid leukemia (AML) remains one of the most common adult leukemia but the prognosis remains poorleading to significant disease burden. We have recently identified immunomodulatory surface receptor LILRB4as an important player in AML biology and a potential novel therapeutic target but the signaling cascade ofLILRB4 remains incompletely understood. The proposed research will explore the signal transduction of immunemodulatory receptor LILRB4 in AML with the vision that LILRB4 signaling involves multiple signaling moleculesthat interact with each other to fine-tune the functional effect of LILRB4. NCI 10684679 8/18/23 0:00 PA-18-373 5K08CA234544-05 5 K08 CA 234544 5 "RADAEV, SERGEY" 9/1/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 14679023 "KIM, JAEHYUP " Not Applicable 30 PATHOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 131374 NCI 121643 9731 Project Summary/AbstractThis proposal presents a five-year research career development plan with a focus on the study of animmunomodulatory surface receptor Leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) and its rolein acute myeloid leukemia (AML). The candidate is currently an Assistant Instructor at the University of TexasSouthwestern Medical Center in the department of Pathology division of Blood Banking and TransfusionMedicine. The outlined proposal builds on the candidates previous research and clinical experience in cancerimmunology by integrating new domains of expertise by primary mentor Dr. Alec Zhang: immunomodulatorysurface immunoreceptor tyrosine-based inhibitory motif (ITIM) containing receptors and AML. The candidateexpects to develop interdisciplinary skills from didactic activities and proposed experiments to make a successfultransition to an independent physician scientist with an expertise in the immune modulation of hematologicmalignancies.AML is one of the most common leukemia in adult that account for about 1.3% of new cancer cases in the US.Prognosis of AML remains poor despite therapy partly due to the gaps in understanding the immunomodulationin AML. The candidate recently reported the role of LILRB4 a member of ITIM containing immunomodulatoryreceptor in AML pathophysiology by suppressing T cell immune response and promoting migration of AML cells.In addition to the functional roles the candidate also helped identify a hitherto unknown ligand of LILRB4(Apolipoprotein E) and down-stream signaling pathways involving SHP-2 and uPAR/Arginase. Howeverpreliminary data suggest that the activation and signal transduction of LILRB4 is unlikely a simple linear eventbut rather involve multiple molecules. In addition to Apolipoprotein E CD166 has been reported as a ligand ofLILRB4. Also preliminary data suggest the role of STAT3 and CCL3 in the T cell suppression and AML cellmigration mediated by LILRB4. This project aims to identify the signaling molecules contributing to LILRB4 signalin AML and clarify their functional significance. As such the aims of this proposal are 1) Study the role ofinteraction between apolipoprotein E and CD166 on LILRB4 activation 2) Determine the cytoplasmic mediatorsof LILRB4 signaling responsible for the infiltration of leukemia cells and inhibition of T cell immunity and 3)Identify the downstream targets of LILRB4 signaling in leukemia development. Upon successful completion thescientific objectives of this proposal are expected to deepen our understanding of the role of LILRB4 in AML withpotential implications for better understanding the signaling pathways of other ITIM containing immunemodulatory receptors. 131374 +No NIH Category available Antineoplastic Agents;Apoptosis;Cell Proliferation;Characteristics;Clinic;Competence;Complex;Credentialing;Cytoskeleton;Diagnosis;Disease;Disease Progression;Disparate;Drug resistance;Economics;Environment;Exposure to;Financial Hardship;Gene Expression;Genetic;Heterogeneity;Homeostasis;Human;Hypoxia;Immunotherapy;Invaded;Investments;Malignant - descriptor;Malignant Neoplasms;Metabolism;Mitochondria;Molecular;Morbidity - disease rate;Neoplasm Metastasis;Nutrient;Oncogenes;Organelles;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Population;Process;Proteins;Role;Stress;Toxic effect;Treatment Failure;Tumor Biology;Tumor Promotion;Tumor-Associated Process;Work;Xenograft procedure;cancer type;cell motility;coping;cost;disease heterogeneity;drug discovery;fitness;genetic makeup;improved;innovation;molecular drug target;mortality;mouse model;neoplastic cell;novel;personalized medicine;response;social;therapeutic target;trait;tumor;tumor heterogeneity;tumor microenvironment Tumor Plasticity PROJECTNARRATIVEDespiteanunprecedentedunderstandingofcancergenesandtheirpathwaysadiagnosisofmalignancystillcarriessignificantmorbidityandmortality.Afundamentalbarriertocancercuresistheabilityoftumorcellstocontinuouslyadapttotheirenvironmentandselectnewtraitsofaggressivediseasesuchassustainedcellproliferationheightenedsurvivalandthepropensitytometastasize.Overthepastdecadeourworkdemonstratedthatthisprocessoftumoradaptationorplasticityistheresultofaninterconnectednetworkofdisparatecellularresponsescenteredonreprogrammingofmitochondrialfunctions.Thestudiesproposedinthepresentapplicationwilldissectthebiologyoftumorplasticityasanovelhallmarkofcancerandactionabletherapeutictargetinadvanced-stagedisease. NCI 10684678 8/10/23 0:00 PAR-16-411 5R35CA220446-07 5 R35 CA 220446 7 "WATSON, JOANNA M" 9/1/17 0:00 8/31/24 0:00 ZCA1-RTRB-C(M2) 1882783 "ALTIERI, DARIO C" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1117200 NCI 588000 529200 PROJECTSUMMARYDespitehalfacenturyofsocialandeconomicinvestmentsanunprecedentedunderstandingofcancergenesandtheirpathwaysandanarsenalofnewmolecularandimmunologicaltherapiesadiagnosisofmalignancystillcarriessignificantmorbidityandmortality.Heraldedasabreakthroughforcancercuresthepromiseofpersonalizedmedicinewhereeverypatientreceivestherightdrugfortherighttypeofcancerbasedongeneticmakeupisyettoberealized.Infactmostmolecularly-targeteddrugshavebeendisappointingintheclinicproducingonlyshort-livedresponsesoftenatstaggeringcostsandfinancialhardshipforthepatientsonlytobesupplantedbytheemergenceofdrug-resistantandmetastaticdisease.Weknowthattheextraordinaryheterogeneityofhumantumorswithhundredsofmalignantclonesinconstantcompetitionandcooperationwitheachotherisamajorreasonfortreatmentfailurebutanin-depthunderstandingofthisprocesshasremainedsurprisinglyelusive.Workcarriedoutbyourgroupoverthepasttenyearshasfocusedonmechanismsoftumoradaptationorplasticityasnovelfundamentaldriversofdiseaseheterogeneityandworsepatientoutcome.Wefoundthatstressconditionstypicalofthetumormicroenvironmentwhetherhypoxiashortageofnutrientsproteintoxicityorexposuretomoleculartherapyactivateacoordinatedsetofcellularresponsesanetworkthatsustainscellproliferationpromotessurvivalreconfiguresmetabolismstimulatesgeneexpressionandheightenscellmotilityandinvasion.Theneteffectforthemalignantpopulationisnotonlyimprovedfitnesstocopewithanunfavorablemicroenvironmentbutalsotheacquisitionofnewtraitscharacteristicofaggressivediseaseincludingdrug-resistanceandmetastaticcompetence.Unexpectedlyweidentifiedreprogrammingofmitochondrialfunctionsasanobligatoryhubforthisprocessenablingorganelle-cytoskeletondynamicsassemblyofnovelapoptosis-regulatorycomplex(es)andretrogradegeneexpression.Thereforethehypothesisthattumorplasticityimpartscellulardiversityinresponsetostresspropagatestumorheterogeneityandpromotestheacquisitionofaggressivediseasetraitsthroughmitochondrialreprogrammingcanbeformulatedandwillconstitutethefocusofthepresentapplication.Theproposedstudieswilldissectthecellularandmolecularrequirementsoftumorplasticityasanovelhallmarkofcancercredentialitsrelevanceinxenograftandgeneticmousemodelsoflocalizedandmetastaticdiseaseandexploitemergingvulnerabilitiesofthesepathwaysforinnovativecancerdrugdiscovery.Theresultswillestablishtumorplasticityasanoveldriverofdiseaseprogressionreachacomprehensiveblueprintoftheroleofmitochondrialhomeostasisincancerandvalidatenewactionabletherapeutictargetsforpatientswithlate-stagedisease. 1117200 +No NIH Category available Absence of pain sensation;Adverse effects;Affect;Anabolism;Analgesics;Attenuated;Behavioral;Biochemical;Biophysics;Bone Pain;Bone neoplasms;Brain;Brain Stem;CNR1 gene;Cancer Model;Cancer Pain Management;Cells;Central Nervous System;Clinical;Data;Derivation procedure;Development;Disseminated Malignant Neoplasm;Electrophysiology (science);Endocannabinoids;Enzyme Inhibition;Goals;Hydrolysis;Hyperalgesia;In Vitro;Inflammatory;Knowledge;Life;Malignant Bone Neoplasm;Malignant Neoplasms;Mediating;Membrane;Metastatic Neoplasm to the Bone;Molecular;Nervous System;Neurons;Nociception;Nociceptors;Omega-3 Fatty Acids;Opioid;Outcome;Pain;Pain management;Pathway interactions;Patients;Peripheral;Peripheral Nervous System;Polyunsaturated Fatty Acids;Posterior Horn Cells;Property;Prostaglandin Inhibition;Prostaglandins;Research;Role;Spinal;Spinal Cord;Techniques;Testing;Therapeutic;Tissues;Ventilatory Depression;Vertebral column;addiction;antinociception;bone;cancer pain;cancer therapy;cannabinoid receptor;carcinogenesis;effectiveness evaluation;endocannabinoid signaling;evidence base;experience;imaging approach;in vivo;innovation;interdisciplinary approach;lipid mediator;motor impairment;mouse model;non-opioid analgesic;novel;preference;receptor;response;side effect;success;transmission process;treatment strategy Treatment of cancer pain by lipid mediator Resolvin D1: role of Prostaglandin and Endocannabinoid signaling Bone destruction from primary or metastatic cancer is associated with severe pain that is difficult to treat.Opioids are often used for cancer pain but are associated with many serious side effects and non-opioidalternatives are needed. We will determine the effectiveness and mechanisms underlying antinociceptiveproperties of Resolvin D1 in a mouse model of bone cancer pain. NCI 10684674 7/27/23 0:00 PA-20-185 5R01CA263777-03 5 R01 CA 263777 3 "ALTSHULER, RACHEL DINA" 8/5/21 0:00 7/31/26 0:00 Neurobiology of Pain and Itch Study Section [NPI] 10517518 "KHASABOV, SERGEY G" Not Applicable 5 DENTISTRY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF DENTISTRY/ORAL HYGN 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 433204 NCI 281362 151842 Pain associated with primary and metastatic bone tumors is often severe and difficult to manage. Opioids arefirst-line treatment for severe cancer pain but their side effects including tolerance addiction and respiratorydepression limit their use. The search for opioid alternatives with high analgesic efficacy and low adverseeffects has yielded limited success. Long-term goal is to identify novel effective and safe alternatives toopioids for pain treatment. This project is focused on Resolvin D1 (RvD1) an endogenous derivative of -3polyunsaturated fatty acids as a possible therapeutic for cancer pain. Using a mouse model of bone cancerpain. Preliminary data show that systemic administration of RvD1 decreased cancer-evoked hyperalgesiaattenuated sensitization of nociceptors and nociceptive dorsal horn neurons and reduced descendingfacilitation while increasing descending inhibition of nociceptive transmission from the rostral ventromedialmedulla (RVM). RvD1 did not impair motor function and did not produce place preference suggesting it is notaddictive. The overall objective in this proposal is to determine peripheral and central underlying mechanismsof RvD1 exerts analgesia. The central hypothesis is that systemic administration of RvD1 inhibits enzymesinvolved in the biosynthesis of pronociceptive prostaglandins (PGs) and the hydrolysis of antinociceptiveendocannabinoids (eCBs) that reduce sensitization of nociceptive neurons and inhibit descending facilitation.Preliminary data suggest that increased PGs and decreased eCBs in the DRG spinal cord and RVMcontribute to neuronal sensitization and pain during cancer. Because RvD1 increased eCBs role of differenttypes of cannabinoid receptors in RvD1 produced antinociception will be elucidated. The central hypothesis willbe tested in three specific aims. 1) Identify molecular mechanisms of RvD1 antinociception in the peripheraland central nervous system; 2) Determine functional effects of RvD1 on nociceptive primary afferent and spinalneurons during cancer-induced bone pain; and 3) Determine functional effects of RvD1 on descendingfacilitation and inhibition from the RVM. For the first aim biochemical and molecular approaches will be used todetermine changes in prostaglandin and endocannabinoid signaling during the development of cancer- painand the effects of Resolvin D1. The second aim will investigate the effects of Resolvin D1 on sensitization ofnociceptors and dorsal horn neurons using in vivo electrophysiological and in vitro [Ca2+]i-imagingapproaches. The third aim will evaluate the effects of RvD1 on descending facilitation and inhibition bydetermining if RvD1 reduces activity of ON cells and increases activity of OFF cells in the RVM and how itaffect nociceptive transmission in spinal dorsal horn neurons. The proposed research is innovative because itwill uncover novel mechanisms by which RvD1 reduces cancer pain. This project is significant because it willprovide a mechanistic-based justification for RvD1 as a safe and effective approach to manage cancer pain. 433204 +No NIH Category available Age;Auxins;BODIPY;Biological Assay;Biology;Bioluminescence;Biotin;Cancer cell line;Cell Death;Cell Proliferation;Cell Survival;Cells;Chemosensitization;Chemotherapy and/or radiation;Data;Development;Epithelial Cells;Event;Generations;Genetic Transcription;Grant;Human;In Vitro;Ionizing radiation;Lead;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Neoplasm Metastasis;Paclitaxel;Pancreas;Pharmaceutical Preparations;Play;Process;Quality Control;RNA;RNA Degradation;RNA Splicing;RNA-targeting therapy;Radiation;Reagent;Regimen;Role;System;Technology;Testing;Therapeutic;Therapeutic Intervention;Toxic effect;Transcript;Xenograft Model;Xenograft procedure;anti-cancer;cancer cell;cellular targeting;chemotherapeutic agent;exosome;gemcitabine;in vivo;in vivo evaluation;inhibitor;innovation;lead optimization;neoplastic cell;new therapeutic target;novel;pancreas xenograft;pancreatic PDX models;pancreatic cancer cells;pancreatic cancer model;pharmacophore;posttranscriptional;pre-clinical;protein degradation;small hairpin RNA;small molecule;small molecule inhibitor;synergism;therapeutic target;tumor;tumor growth Targeting the RNA Exosome for Cancer Therapeutics In this proposal small molecule inhibitors of the novel therapeutic target the RNAexosome will be developed and assessed in a pancreatic cancer model. The hypothesisto be tested is that cancer cells are more dependent on RNA exosome activity due to theneed to remove the excess amounts of aberrantly spliced transcripts. NCI 10684671 6/29/23 0:00 PA-18-484 5R01CA213214-05 5 R01 CA 213214 5 "FU, YALI" 8/1/19 0:00 7/31/24 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 1858113 "LJUNGMAN, MATS " "NEAMATI, NOURI ; SAHAI, VAIBHAV " 6 RADIATION-DIAGNOSTIC/ONCOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 479616 NCI 307446 172170 The RNA exosome is a RNA degradation machinery that plays a critical role in RNA quality control bydegrading erroneous or incorrectly spliced RNAs. In many cancers such as pancreatic cancer the splicingprocess is compromised resulting in the generation of large amounts of aberrant transcripts. We hypothesizethat cancer cells are uniquely dependent on RNA exosome activity to remove excess amounts ofaberrant transcripts and that the RNA exosome therefore may be an impactful new target fortherapeutic intervention for pancreatic cancer. We have developed a set of first-in-class small moleculeinhibitors of the RNA exosome and will in this proposal refine these compounds and assess their tumor-targeting efficacy for pancreatic cancer in three specific Aims. In Aim 1 a lead optimization campaign will beinitiated of our first-in-class RNA exosome inhibitors. The refined compounds will be evaluated for their RNAexosome-targeting activities using both in vitro and cell-based RNA exosome activity assays and we willidentify their cellular targets. In Aim 2 the potencies of the 10 top RNA exosome inhibitors will be assessed byMTT and clonogenic survival assays to select the top three compounds for in vivo studies. These top threecompounds will then be used in combination with either ionizing radiation or gemcitabine to assess synergy.Inducible shRNA and auxin-inducible protein degradation technologies will be used to inactivate the RNAexosome and these systems will be compared with the top three inhibitors to explore fundamental mechanismsof action of the RNA exosome in transcriptional and post-transcriptional events. In Aim 3 we will test the 3most promising compounds in a PDX orthotopic model for pancreatic cancer either alone or in combinationregimens with gemcitabine and nab-paclitaxel. This is a very innovative proposal exploring a novel cancertherapeutic target and highly focused on the development of new impactful treatments for pancreatic cancer.Upon the successful completion of this grant period we intend to perform IND-enabling studies of the bestcandidate compounds. 479616 +No NIH Category available Apoptosis;Apoptotic;Area;Arithmetic;BCL2 gene;Caspase;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Childhood;Databases;Equation;Family;Future;Genome;Goals;Laboratories;Life;Malignant Neoplasms;Mitochondria;Molecular;Necrosis;Pathology;Pathway interactions;Patient-Focused Outcomes;Permeability;Process;Proteins;Regulation;Research;Resistance;Saint Jude Children's Research Hospital;Stimulus;Testing;The Cancer Genome Atlas;Therapeutic;Tissues;Work;Xenograft Model;programs;success;tool Mechanisms of Regulated Cell Death NarrativeEvasion of core cell death pathways is a hallmark of cancer. The PI has consistently madehighly impactful contributions to our understanding of the fundamental mechanisms of regulatedcell death especially in the areas of apoptosis and necroptosis. The project described in thisapplication will significantly extend this understanding and how it relates to cancer. NCI 10684665 9/5/23 0:00 PAR-17-494 5R35CA231620-06 5 R35 CA 231620 6 "SALNIKOW, KONSTANTIN" 9/1/18 0:00 8/31/25 0:00 ZCA1-RTRB-C(M3) 1857694 "GREEN, DOUGLAS R" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1041091 NCI 588000 467460 A simple arithmetic of life is this: if cells in a tissue divide more frequently than they die the tissue grows; ifcells die more frequently than they divide the tissue shrinks. This basic principle is enshrined as a hallmarkof cancerfor a cancer to exist it must evade cell death mechanisms that would shift this equation to attrition.For three decades my laboratory has worked to understand the core pathways of regulated cell death and howthey are controlled at the molecular level. This program of research the continuation of which is proposed inthis application explores the processes of regulated cell death in the forms of apoptosis and necroptosis andseeks to understand how they are tied to other cellular physiologies as they must be. Three general goals ofthis research are outlined as questions as follows. A. What are the mechanisms of cell survival inapoptosis/necroptosis and how do these integrate with cell life? Here we use the concept of persisters cellsthat survive the activation of core apoptotic or necroptotic pathways to probe the pathways that whenengaged restrict these core pathways to enable transient resistance to the stimulus. We prioritize our hitsbased on those whose expression correlates with patient outcome in cancer databases including the TCGAand St. Jude Pediatric Genome Project. These are tested in cancer xenograft models. B. How do diverseprocesses of cellular life integrate with the core mechanisms of apoptosis? The mitochondrial pathway ofapoptosis is generally known to depend on the activation of the Bcl-2 family effectors Bax and Bak by BH3-only proteins. We will continue to explore alternative mechanisms of mitochondrial permeabilization and howthey are regulated by components of the cellular physiology. Prioritization and testing is as above. C. How dodiverse processes of cellular life integrate with the mechanisms of necroptosis? Necroptosis is a form ofregulated necrosis that is actively inhibited by the action of a caspase normally associated with apoptosis (buthere with cell survival). We will continue our studies into the activation and regulation of necroptosis in relationto cellular physiology and develop tools to probe its activation in the context of cancer and other pathologies.While the understanding of the core pathways of cell death have led to one approved cancer therapeutic ourcontinued life and death efforts set the stage for future success in this critical arena. 1041091 +No NIH Category available Affect;Attention;Awareness;Behavioral;Body Image;Books;Brain;Chemotherapy-induced peripheral neuropathy;Clinical assessments;Consent;Data;Development;Dose Limiting;Eating;Educational process of instructing;Exercise;Exercise Therapy;Exhibits;FDA approved;Functional Magnetic Resonance Imaging;Functional disorder;Hand;Home;Human;IL8 gene;Inflammation;Inflammatory;Insula of Reil;Interleukin-1 beta;Interleukin-10;Interleukin-6;Interoception;Intervention;Knowledge;Learning;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Measures;Muscle Cramp;Neuropathy;Numbness;Pain;Pamphlets;Pathway interactions;Patient Self-Report;Patient risk;Patients;Phase;Physiological;Placebos;Platinum;Play;Process;Questionnaires;Randomized;Randomized Controlled Trials;Reporting;Research;Role;Sensory;Serum;Severities;Sterile coverings;Symptoms;System;Tactile;Testing;Thalamic structure;Time;Toxic effect;Walking;Work;Writing;anakinra;bodily sensation;cancer therapy;chemotherapy;comparison control;cytokine;effective intervention;effective therapy;experience;follow-up;foot;improved;innovation;malignant breast neoplasm;member;mortality;neural;neurotoxic;nutrition;nutrition education;peripheral nerve damage;prevent;randomized clinical trials;resistance exercise;systemic inflammatory response;taxane;theories Effects of exercise during platinum chemotherapy on neuropathy: examining the interoceptive brain system and inflammation PROJECT NARRATIVEOver half of all patients receiving platinum-based chemotherapy for gastrointestinal cancers experience a dose-limiting toxicity called chemotherapy-induced peripheral neuropathy (CIPN) which involves numbness tinglingpain and sensitivity to cold in the hands and feet. There are few effective treatments for CIPN because thedevelopment of CIPN is not well understood. This project will learn more about whether exercise can reduceCIPN and how the brain and inflammation might play roles in this process to ultimately help alleviate the burdenof chemotherapy on treating patients with cancer. NCI 10684640 8/31/23 0:00 PAR-20-292 5R21CA259422-02 5 R21 CA 259422 2 "GOOD, MARGE" 9/1/22 0:00 8/31/24 0:00 ZCA1-RPRB-8(O2)S 10865150 "KLECKNER, IAN ROBERT" Not Applicable 7 NONE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF NURSING 212011508 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 176961 NCI 114538 62423 PROJECT SUMMARY/ABSTRACTChemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting toxicity that affects over 65% ofpatients receiving platinum-based chemotherapy for gastrointestinal cancers. Not only does CIPN increasemortality by limiting the dose of chemotherapy CIPN affects walking writing eating and dressing via numbnesstingling pain cold sensitivity and cramping in the hands and feet. There are no FDA-approved treatments forCIPN because we need a greater understanding of the pathophysiology of CIPN and mechanisms of action ofpromising treatments for CIPN. In addition most research on CIPN in humans has focused on taxane-basedchemotherapy in patients with breast cancer. Here we are focusing on platinum-based chemotherapy in patientswith gastrointestinal cancers because taxane- and platinum-induced CIPN are both very common but exhibitdistinct signs symptoms and mechanisms of toxicities and may respond differently to a given treatment. Thisproject is motivated by an innovative perspective that CIPN symptoms are not due simply to peripheral nervedamage but rather that CIPN symptoms are worsened by damage to the interoceptive brain systemwhichprocesses sensations from the bodyas well as systemic inflammation.This is a Phase II randomized clinical trial to assess the effects of 12 weeks of exercise during platinumchemotherapy on CIPN interoception and inflammation in 60 patients with gastrointestinal cancer. The specificaims of this project are to assess the effects of exercise vs. nutrition education (control) on: (1) patient reportedCIPN (2) clinical assessments of CIPN (tactile sensitivity and cold-induced pain) (3) interoception (functionalconnectivity in the interoceptive brain system and self-report) and (4) inflammation (serum inflammatorycytokines).This is the first study to examine the effects of exercise during platinum chemotherapy on CIPN and to examineroles of interoception and inflammation in the treatment of platinum-induced CIPN. Results from this study willinform an R01 application to more definitively assess this theory of CIPN and exercise. If this work is successfulwe will have identified an effective intervention (exercise) for alleviating CIPN and we will have a betterunderstanding of how exercise alleviates CIPN (i.e. interoception and inflammation). We believe this knowledgecan be applied to improve prediction tracking sub-typing and treatment of CIPN using exercise or otherinterventions that affect these pathways. This will ultimately help alleviate the burden of chemotherapy on treatingpatients with cancer. 176961 +No NIH Category available 8q24;Affect;African American;Asian;Automobile Driving;BRCA1 gene;BRCA2 gene;Biological;Biological Assay;Biology;Breast;Breast Cancer Model;CISH gene;CRISPR interference;CRISPR/Cas technology;Candidate Disease Gene;Cellular biology;Clinical;Code;Complex;Computing Methodologies;DNA;Data Set;Development;Disease;Dryness;Elements;Epidemiology;Etiology;European;Experimental Models;Gene Expression;Gene Expression Profiling;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Code;Genetic Predisposition to Disease;Genetic Variation;Genetic study;Genotype;Goals;Hispanic ancestry;Hormonal;Human;Human Genetics;Incidence;Individual;Leadership;Luciferases;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maps;Mediating;Mendelian disorder;Meta-Analysis;Methodology;Methods;Modeling;Molecular;Molecular Target;Mutation;Open Reading Frames;Ovarian;Pathogenesis;Pathway Analysis;Pathway interactions;Persons;Phenotype;Population;Positioning Attribute;Predisposition;Prevention strategy;Prostate;Regional Cancer;Regulator Genes;Regulatory Element;Research Personnel;Resolution;Risk;Risk Factors;Role;Susceptibility Gene;Tissues;Transcriptional Regulation;Untranslated RNA;Variant;Work;c-myc Genes;cancer risk;cancer type;candidate identification;candidate validation;case control;chromosome conformation capture;disorder risk;epigenomics;gene interaction;genetic association;genetic information;genetic variant;genome editing;genome wide association study;genome-wide;genomic locus;in vitro Model;knock-down;malignant breast neoplasm;molecular marker;neoplastic;novel;overexpression;pleiotropism;risk prediction;risk variant;screening;trait;transcriptomics Common biology underlying pleiotropic breast prostate and ovarian cancer risk loci PROJECT NARRATIVEGenetic studies have found hundreds of common genetic variations in the population that affect a persons riskof a multitude of different diseases including cancer but for most of these variants we neither know thefunctional reasons why they cause disease nor the genes they interact with to drive disease development. Inthis proposal we plan to use a combination of functional assays genetic information and computationalmethods to work out the function of known genetic variants that influence breast prostate and ovarian cancerrisk because these cancers share common risk factors and biology and there are strong reasons to believethat some of the same genes are responsible for causing all three cancer types. We hope these approachesand the methods we use can work out the function of genetic variants and genes that cause disease leadingto clinical benefits to individuals on a population level particularly in developing new risk prediction andprevention strategies to reduce breast prostate and ovarian cancer incidence. NCI 10684639 9/1/23 0:00 PA-20-185 5R01CA259058-02 5 R01 CA 259058 2 "FINGERMAN, IAN M" 9/1/22 0:00 8/31/27 0:00 Genetics of Health and Disease Study Section[GHD] 9610981 "GAYTHER, SIMON ANDREW" "FREEDMAN, MATTHEW L; KAR, SIDDHARTHA " 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 622687 NCI 484574 138113 ABSTRACTA fundamental goal of human genetics is to decipher the relationship between genotype and phenotype.Genome-wide association studies (GWAS) have identified thousands of common variants associated withnumerous traits and diseases; but for the vast majority of genetic associations the underlying functionalmechanisms are unknown. The key challenges in elucidating the biology underlying GWAS risk loci are: (i)to identify the susceptibility gene(s) at risk loci and their functional role in disease pathogenesis; (ii) to identifythe causal risk variant(s) initiating disease development; and (iii) to establish the regulatory mechanisms bywhich risk variant(s) affect target gene expressionAn emerging feature of common variant risk loci is pleiotropy where a risk locus shows evidence ofsusceptibility to two or more phenotypes. Breast prostate and ovarian cancers share common etiologies.GWAS have so far identified more than 400 confirmed risk loci for these cancers. We have performed a meta-analysis of breast prostate and ovarian cancers identifying more than 100 novel pleiotropic risk regions thatsuggest these cancers have a shared genetic component and similar underlying biology. Substantially largergenotyping studies continue to be performed in the human population and for these cancers which will providethe opportunity to identify additional breast prostate and ovarian cancer pleiotropic risk loci. Our groups havealso developed functional assays including chromosome conformation capture CRISPR/Cas9 genomeediting and experimental models of breast prostate and ovarian cancer that enables us to establish theunderlying biology driving neoplastic development at these risk loci in these cancer types.The overarching goals of this study are to identify shared genetic susceptibility alleles for breast prostate andovarian (BPO) cancers driven by non-coding DNA variation and to establish the shared functionalmechanisms that underlie disease risk for these cancers. The specific aims are: (1) To identify the crediblecausal risk variants regulatory targets and candidate genes at pleiotropic BPO risk loci; (2) To utilize functionalscreening assays to prioritize causal risk variants regulatory targets and candidate genes at BPO risk loci; (3)To determine causality for risk variants candidate genes and regulatory elements at BPO risk loci. 622687 +No NIH Category available Adherence;Adjuvant;Aromatase Inhibitors;Biological;Biological Factors;Breast Cancer Prevention;Characteristics;Classification;Clinical;Complex;Diagnosis;Disease;Dose;Etiology;Exemestane;Future;Genes;Genomics;Genotype;Goals;Heritability;Internet;Intervention;Letrozole;Malignant Neoplasms;Measures;Metabolism;Methods;Modeling;Molecular;Nature;Outcome;Pathway interactions;Patient Self-Report;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Population;Postdoctoral Fellow;Postmenopause;Precision Health;Recurrence;Recurrent Malignant Neoplasm;Regimen;Reporting;Research;Research Personnel;Risk;Role;Sampling;Severities;Source;Subgroup;Survivors;Symptoms;Time;Toxic effect;Training;Woman;Work;absorption;anastrozole;biobehavior;cancer recurrence;career;cohort;exosome;experience;genomic variation;gut microbiome;gut microbiota;hormone receptor-positive;improved;inhibitor therapy;insight;malignant breast neoplasm;medication compliance;microbiome research;multiple omics;personalized health care;post-doctoral training;side effect;standard of care;symptom management;tailored health care;therapy development;treatment planning;treatment response;tumor A Multi-omics Approach to Examine Symptoms and Medication Adherence in Women with Breast Cancer Project Narrative: A substantial proportion of women are not adherent to aromatase inhibitor(AI) therapy primarily due to their experience of highly variable treatment- and/or disease-related symptoms. Symptoms and adherence especially their impact on each other have notbeen well-characterized temporally nor have potential biologic mechanisms related to AIabsorption distribution metabolism and elimination (ADME). The purpose of the proposedF99/K00 training and research will utilize a biobehavioral multi-omics approach to gain adeeper understanding of the temporal variability and interplay of symptoms adherence andomics to guide future interventions and their timing in women with breast cancer. NCI 10684626 7/12/23 0:00 RFA-CA-19-057 5K00CA253771-04 5 K00 CA 253771 4 "DAMICO, MARK W" 8/1/20 0:00 7/31/26 0:00 ZCA1-SRB-H(M1) 12156826 "MCCALL, MAURA KINDELAN" Not Applicable 11 NONE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF NURSING 441061712 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Other Research-Related 2023 95930 NCI 89157 6773 A Multi-Omics Approach to Examine Symptoms and Medication Adherence in Women with BreastCancerBreast cancer is most prevalent in postmenopausal women and 3.4 million U.S. women are survivors. Mostwomen with breast cancer are postmenopausal at the time of diagnosis and at least 70% of tumors arehormone receptor positive (HR+). Aromatase inhibitors effectively prevent BC recurrence and current standardincludes adjuvant aromatase inhibitor (AI) therapy in a once daily standard dose regimen for a minimum of fiveyears. However AI adherence is a significant problem. Up to one third of women do not fill their initial AIprescription adherence to AIs averaged 48% in the first year and adherence decreases in subsequent 2-5years. AI-attributed symptoms are the leading reason for not adhering to AI regimens and a major barrier to AIadherence. Moreover AI-related symptom type and severity are highly variable among women. The source ofsymptom variability is unknown. The etiology of symptoms experienced during AI therapy may have biologicalunderpinnings yet little is known about factors in AI (anastrozole letrozole exemestane) absorptiondistribution metabolism and elimination (ADME) pathways and the resulting symptoms. Symptoms andadherence especially their relationship to each other have not been well-characterized temporally. Furtherpotential biologic mechanisms related to AI absorption distribution metabolism and elimination (ADME) forAIs have not been fully characterized.The dissertation project (F99) will examine temporal patterns of AI symptoms and adherence and theirrelationship over the first 18 months of AI therapy. It will also explore the role of genotypic (ADME) andphenotypic factors in symptoms experienced and AI adherence. The postdoctoral project (K00 phase) willincorporate two additional molecular methodsmicrobiomics and exosomics. They will be described and theirpotential role in AI symptoms experienced and adherence will be explored.The purpose of the proposed F99/K00 training and research is to utilize a biobehavioral multi-omics approachto gain a deeper understanding of the complex web of AI symptoms and adherence including the temporalvariability among women and the interplay between symptoms and adherence. It will provide insight intopotential biological mechanisms by describing molecular and phenotypic characteristics associated withsymptoms and adherence. Ultimately this research will inform future symptom management and adherenceinterventions and their timing. 95930 +No NIH Category available Active Learning;Address;Adherence;Adopted;Advocate;Aftercare;Cancer Center;Cancer Control;Cancer Survivor;Cancer Survivorship;Caregivers;Caring;Clinical;Communities;Community Developments;Community Health;Community Health Aides;Cost Analysis;Counseling;County;Data;Development;Distal;Division of Cancer Control and Population Sciences;Early Diagnosis;Economics;Exploration Preparation Implementation and Sustainment;Face;Financial Hardship;Financial Support;Future;Geography;Goals;Health;Health Care Costs;Health Professional;Incidence;Intervention;Interview;Light;Link;Literature;Malignant neoplasm of lung;Managed Care;Mentors;Mentorship;Methods;Modeling;Monitor;Oncologist;Outcome;Participant;Patients;Phase;PrP gene;Preparation;Process;Program Development;Provider;Recommendation;Recurrence;Research;Research Project Grants;Resources;Role;Rural;Rural Appalachia;Rural Community;Site;Social Workers;Specialist;Support Groups;Survival Rate;Survivors;Training;Travel;Treatment outcome;Trust;Universities;Urban Health;Visit;acceptability and feasibility;barrier to care;cancer care;cancer health disparity;care coordination;career;clinical care;community engagement;disparity elimination;early screening;effectiveness/implementation trial;feasibility testing;follow-up;health disparity;implementation cost;implementation evaluation;implementation framework;implementation science;improved;improved outcome;insight;medically underserved;member;outcome disparities;patient navigation;patient navigator;programs;rural area;rural dwellers;rurality;screening;side effect;skills;social;social health determinants;socioeconomics;success;survival disparity;survivorship;symptom management;telehealth;therapy development;trial design;urban setting Improving adherence to posttreatment follow-up care for rural lung cancer survivors through a community-clinical survivorship care team model Project Narrative:Rural community health workers embedded in clinical survivorship care teamsCHW-clinical survivorship careteamsis a strategy to improve fragmented rural survivorship care adherence to follow-up and facilitatelinkages to local resources to overcome socio-economic barriers to care. This project will examine thefeasibility acceptability and implementation of a pilot telehealth CHW-clinical survivorship care teamintervention focused on resource referrals and connections symptom management between follow-up carevisits and improving adherence to post treatment follow-up care recommendations of lung cancer survivorsfrom rural areas. This research will contribute to the lack of literature addressing the implementation ofsurvivorship care models to improve rural survivorship outcomes and eliminate disparities in rural-urbansurvival rates. NCI 10684621 8/24/23 0:00 PAR-18-364 5K01CA262342-03 5 K01 CA 262342 3 "VAHEDI, SHAHROOZ" 9/3/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 11935374 "LEWIS-THAMES, MARQUITA W." Not Applicable 5 PUBLIC HEALTH & PREV MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 130632 NCI 120956 9676 Project/Summary: Rural lung cancer survival rates have lagged behind the national average for decades. A keycontributor to recent survival disparities is fragmented survivorship care leaving rural survivors without supportsto facilitate survivorship care and adherence to follow-up care. Rural survivors often receive their care fromspecialists located in distal urban centers where travel social and financial burdens threaten adherence tofollow-up care. Further urban healthcare professionals are unaware of rural resources and encumbered byfinding rural community resources needed to overcome barriers to care. Thus a community-clinical survivorshipcare team is a promising strategy to improve timely follow-up care and provide linkages to community resources.A rural community health worker (CHW) that is knowledgeable about local resources and the socio-economicbarriers to survivorship care is a fitting community agent on a community-clinical team. The success ofcommunity-clinical care teams to improve care coordination and health outcomes is well documented but fewof these studies investigate rural survivorship care or the integration of a CHW in the team model. Also a gap inthe literature exists regarding the implementation of a CHW-clinical survivorship care team model to improverural survivorship outcomes. To address this critical gap the research examines the implementation of a CHW-clinical survivorship care team to improve adherence to follow-up care for rural lung cancer survivors. The aimsof this project are to 1) assess perspectives on desired CHW roles and their processes for interacting with clinicalcare team members in a community-clinical survivorship care team; 2) test the feasibility and initial acceptabilityof CENTRAL and 3) evaluate the implementation of CENTRAL to identify factors that influence its sustaineduse in a multi-site effectiveness-implementation trial design R01. CENTRAL will be adapted from an existingpatient navigation research program and interviews with key stakeholders to inform CHW roles and processesfor working with clinical care teams (Aim 1). Dr. Lewis-Thames will pilot CENTRAL (N=60) with rural lung cancersurvivors to assess its acceptability and feasibility (Aim 2). Aim 3 will provide insights on facilitators and barriersof implementing CENTRAL via the EPIS (exploration preparation implementation sustainment) implementationframework through an analysis of implementation costs and interviews with CENTRAL participants CHWs andproviders. This K01 involves a training plan consisting of coursework seminars experiential learning andmentorship by an established team of experts. The research is conducted at Northwestern University andaffiliated rural-serving Cancer Centers which offer superior facilities and resources to provide training inintervention development and adaption implementation science cost-analysis and rural survivorship care. Theoutlined training plan will enable Dr. Lewis-Thames to accomplish her long-term career goal to become anindependent cancer disparities implementation. The proposed project is relevant to the NCI's Division of CancerControl and Population Science research emphasis on rural cancer control and health disparities. 130632 +Behavioral and Social Science; Brain Disorders; Cancer; Chronic Pain; Clinical Research; Clinical Trials and Supportive Activities; Complementary and Integrative Health; Depression; Health Disparities; Hematology; Mental Health; Mental Illness; Minority Health; Pain Research; Prevention; Rare Diseases; Sleep Research; Women's Health Address;Aftercare;Anxiety;Attention;Behavioral;Biological;Biological Markers;Blood;Blood specimen;Breast Cancer Patient;Cancer Patient;Cellular Phone;Chronic;Clinical;Cognitive;Cognitive Therapy;Consumption;Control Groups;Data;Dependence;Diagnosis;Disease;Distress;Dose;Double-Blind Method;Dysmyelopoietic Syndromes;Elderly;Ethnic Origin;Evidence based treatment;Fatigue;Gender;Health education;Hematologic Neoplasms;IL8 gene;Inflammation;Interleukin-6;Intervention;Knowledge;Lead;Lymph;Lymphoma;Malignant Neoplasms;Measurement;Measures;Mediation;Meditation;Mental Depression;Methods;Middle Insomnia;Multiple Myeloma;Myeloproliferative disease;Outcome;Pain;Participant;Patient Recruitments;Patient Representative;Patient Self-Report;Patients;Persons;Pharmaceutical Preparations;Physical Function;Pittsburgh Sleep Quality Index;Placebos;Quality of life;Race;Randomized;Reporting;Research;Residual Neoplasm;Resources;Risk;Schedule;Self Management;Severities;Sleep;Sleep Disorders;Sleep disturbances;Sleeplessness;Solid Neoplasm;Survivors;Symptoms;TNF gene;Testing;Time;Transportation;Work;actigraphy;active control;base;cancer care;cancer diagnosis;cancer pharmacology;cancer subtypes;care providers;cognitive function;depressive symptoms;diaries;effectiveness evaluation;efficacy testing;emotional distress;empowered;experience;falls;follow-up;health management;improved;improved outcome;indexing;industry partner;inflammatory marker;innovation;interest;leukemia;leukemia/lymphoma;malignant breast neoplasm;mindfulness intervention;mobile application;novel;patient-level barriers;persistent symptom;podcast;post intervention;primary outcome;psychologic;secondary outcome;side effect;smartphone Application;survivorship;uptake Consumer-based meditation app Calm for treatment of sleep disturbance in hematological cancer patients Project NarrativeChronic hematological cancer (CHC) patients are characterized by long term and high symptom burdenincluding up to 65% reporting chronic sleep disturbances that are also often associated with inflammationfatigue and emotional distress (anxiety and depression). Meditation is an effective non-pharmacologic strategyto self-manage and improve cancer-related symptoms and mediation delivered via mobile applications mayaddress cancer patients barriers to in-person interventions (i.e. fatigue pain transportation schedulingdifficulties) without the time and expertise limitations of cognitive behavioral therapy for insomnia (CBT-I) andside effect risks from medication. This study is the first to test a commercially available smartphone-basedmeditation application to self-manage sleep disturbance inflammation fatigue and emotional distress (anxietydepression) among CHC patients and to explore the sustained effects of meditation compared to a healtheducation podcast control group. NCI 10684545 9/2/22 0:00 PA-21-268 7R01CA262041-02 7 R01 CA 262041 2 "ST GERMAIN, DIANE" 4/1/22 0:00 3/31/27 0:00 "Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]" 8749160 "HUBERTY, JENNIFER LYNNE" "MESA, RUBEN A." 20 INTERNAL MEDICINE/MEDICINE 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/1/22 0:00 3/31/23 0:00 395 Non-SBIR/STTR 2022 479816 NCI 312617 167199 Hematological cancers a group of cancer sub-types that include blood- and lymph-related disorders (i.e. leukemia lymphoma myeloma myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS) account for 11% of all cancer diagnoses in the US. Chronic hematological cancer (CHC) patients (i.e. chronic leukemias low grade lymphomas myeloma myelodysplastic syndrome and myeloproliferative neoplasms [MPNs]) have extended disease courses that are often different from solid tumor cancers facing chronic sleep disturbances often associated with inflammation fatigue and emotional distress (anxiety and depression) which often persist into survivorship. Medications are most commonly prescribed for cancer patients with sleep disturbance; however they often come with side effects and risk for long-term dependence. Cognitive behavioral therapy for insomnia (CBT-I) is the most studied and first line of therapy for treating sleep disturbances in cancer patients but CBT-I is time-consuming resource-intensive and not easily accessible for all cancer patients. There is a need for long-term accessible non-pharmacologic interventions targeting sleep in CHC patients. Meditation is a safe and effective non-pharmacologic approach for improving a range of cancer-related symptoms. However meditation interventions have typically been delivered in-person limiting uptake and widespread dissemination due to patient-reported barriers. Smartphone applications (apps) are a novel intervention approach for delivering meditation and address cancer patients barriers to participating in in-person interventions (i.e. fatigue pain transportation and scheduling difficulties) without the time and expertise limitations of CBT-I and side effect risks from medication. Calm is a popular and highly reviewed consumer- based smartphone app that provides an innovative accessible and scalable platform through which to deliver meditation to CHC patients. We propose a double-blind RCT to determine the effectiveness of an eight-week app-based wellness intervention (i.e. active daily meditation intervention [Calm] or the placebo health education podcast control group [POD]) to reduce sleep disturbance (primary outcome) markers of inflammation (TNF-a IL-6 IL-8 and CRP) fatigue and emotional distress (anxiety depression) (secondary outcomes) in CHC patients. Assessments will occur at baseline post-intervention (eight weeks from baseline) and follow-up (20 weeks from baseline). Participants (N=276) will be randomized to an intervention (10 min/day Calm meditation) (n=138) or control (10 min/day health education podcast) group (n=138). We will remotely collect blood samples for biomarker measurement. This study will fill a knowledge and rigor gap regarding the delivery of smartphone- based meditation as an intervention for sleep and provide new data on sustained effects in CHC patients to reduce sleep disturbance. 479816 +Aging; Basic Behavioral and Social Science; Behavioral and Social Science; Biotechnology; Cancer; Cancer Genomics; Caregiving Research; Clinical Research; Clinical Trials and Supportive Activities; Genetics; Health Disparities; Human Genome; Minority Health; Prostate Cancer; Rural Health; Social Determinants of Health; Urologic Diseases Address;Adoption;Adult;African American;Alabama;Biochemical;Cancer Biology;Cancer Prognosis;Caregivers;Communication;Communities;Comprehension;Data;Diagnosis;Diffusion of Innovation;Disadvantaged;Education;Educational Background;Educational workshop;Ethnic group;Focus Groups;Funding;Genetic;Genomic medicine;Genomics;Geographic Locations;Goals;Group Interviews;Health Benefit;Health Sciences;Impairment;Incidence;Knowledge;Literature;Louisiana;Low Literacy Population;Low income;Malignant neoplasm of prostate;Maryland;Mentors;Methods;Microarray Analysis;Minority;Mission;Mississippi;National Comprehensive Cancer Network;National Human Genome Research Institute;Neoplasm Metastasis;North Carolina;Nurses;Participant;Patients;Prognosis;Prostate Cancer therapy;Prostatectomy;Public Health;Race;Radiation;Recurrence;Research;Risk;Rural;Rural Population;South Carolina;Structure;Technology;Time;Tissues;Training;Treatment outcome;United States;United States National Institutes of Health;Virginia;base;cancer education;cancer health disparity;design;directed attention;efficacy evaluation;evidence based guidelines;genetic technology;genetic testing;genome sciences;health disparity;health literacy;improved;innovation;literacy;low socioeconomic status;mRNA Expression;mathematical ability;men;mortality;next generation sequencing;novel;novel strategies;oncotype;prognostic;prognostic value;programs;randomized controlled study;skills;theories;treatment planning Genetic Literacy and Patient-Caregiver Communication of Prognostic Genetic Technology for Localized Prostate Cancer Project NarrativeWith this greater certainty regarding prognosis men with localized prostate cancer are now equipped with tomake better treatment planning decisions. This project is designed to investigate the understanding ofprognostic genetic technology and patient-caregiver communication in African American and rural White menwith localized prostate cancer. NCI 10684529 9/1/22 0:00 PA-21-268 7K01CA230193-03 7 K01 CA 230193 3 "VAHEDI, SHAHROOZ" 9/1/22 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 11049144 "COBRAN, EWAN KEMAR" Not Applicable 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 398 Other Research-Related 2022 168264 NCI 155800 12464 Project Summary/AbstractNovel genomic technology such as microarray analyses and next-generation sequencing have improved theunderstanding of prostate cancer biology and prognosis. The National Comprehensive Cancer Network(NCCN) in 2016 recommended that patients and clinicians consider tissue-based genetic tests for localizedprostate cancer. However while much enthusiasm currently exits for the rapidly increasing field of genomicmedicine the use of multi-gene mRNA expression panels raises the potential for further divergence in prostatecancer treatment outcomes by race and low socioeconomic status. We know that health disparities persist inlow income groups despite the existence of evidence-based guidelines and that adoption of state-of-the-artmethods often lag behind in these groups.The goals of this NCI K01 application are to (1) explore how men with localized prostate cancer and theircaregivers comprehend prognostic genetic technology and (2) examine how an educational video aboutgenetics impacts patient-caregiver communication of prognostic genetic technology. The study rationale is thatwithout direct attention to genomic comprehension the enthusiasm that exists in the rapidly increasing field ofprostate cancer genomic medicine may not translate into health benefits for men with localized prostatecancer. The central hypotheses are (1) men and caregivers with lower levels of education will demonstrate asevere lack of genomic comprehension of tissue-based genetic tests for localized prostate cancer; and (2)tailored prostate cancer education communication coaching and a genomic literacy educational video willsignificantly improve patient-caregiver communication in a low literacy population.The study approach is innovative because it applies a mixed-methods community-engagement researchframework to explore how African American and rural White men with localized prostate cancercomprehend and interpret data generated from genetic technology. The proposed research is significantbecause of its potential to improve public health by (1) improving the understanding of prognostic genetics inminority low income and rural populations and (2) engage and educate these diverse communities aboutgenomics. The proposed research in combination with a structured mentoring and training plan that includesdidactic course and workshops is designed to facilitate Dr. Ewan Cobrans long term goal of developing anindependently-funded research program in prostate cancer disparities consistent with the mission of theNCI. 168264 +No NIH Category available Accounting;Address;African American;African American population;Age;Attention;Behavior;Black American;Black race;COVID-19 pandemic;Cessation of life;Cigar;Cigar Smoking;Cigarette;Cognition;Consumption;Data;Decision Making;Effectiveness;Ensure;Exposure to;Future;Goals;Health;Heart Diseases;Image;Knowledge;Life;Literature;Litigation;Lung diseases;Malignant Neoplasms;Methods;Morbidity - disease rate;Nicotine Dependence;Outcome;Participant;Poison;Policies;Public Health;Randomized;Randomized Controlled Trials;Reporting;Research;Research Personnel;Research Priority;Risk;Sampling;Smoke;Smoker;Smoking;Smoking Behavior;Sorting - Cell Movement;Surgeon;Testing;Text;Time;Tobacco;United States Food and Drug Administration;Vulnerable Populations;Work;aged;authority;behavioral economics;cigarillos;communication behavior;economic value;emotional reaction;follow-up;mortality;non-cigarette tobacco product;premature;recruit;tobacco products;uptake;warning label;young adult The Impact of Cigarillo Warnings on Purchasing and Smoking Behaviors Among Young Adult Cigarillo Users Project NarrativeCigarillo smoking rates among young adults in the U.S. are a public health concern. Despite significant healtheffects associated with cigarillo smoking many young adults believe cigarillos to be safer and less addictivethan cigarettes contributing to tobacco-related morbidity and mortality. This project will address gaps in how toeffectively communicate the risks of cigarillo smoking to young adults to inform regulatory decision -making forcigarillo warnings. NCI 10684481 9/16/22 0:00 PA-21-268 7R01CA260460-03 7 R01 CA 260460 3 "RODITIS, MARIA LEIA" 6/1/21 0:00 4/30/24 0:00 Special Emphasis Panel[ZRG1-RPHB-W(57)R] 12505354 "CORNACCHIONE ROSS, JENNIFER JANE" Not Applicable 7 PUBLIC HEALTH & PREV MEDICINE 604483045 FBYMGMHW4X95 604483045 FBYMGMHW4X95 US 42.33639 -71.07097 894901 BOSTON UNIVERSITY MEDICAL CAMPUS BOSTON MA SCHOOLS OF PUBLIC HEALTH 21182340 UNITED STATES N 9/1/22 0:00 4/30/23 0:00 77 Non-SBIR/STTR 2022 314208 OD 284833 144727 Project SummaryCigarillo use remains a public health concern particularly among vulnerable populations. Young adultsincluding those who are Black or African American have the highest rates of cigarillo use. Cigarillo smokinghas many negative health effects is associated with using other tobacco products such as cigarettes andcigarillo smoke contains many toxic chemicals. Additionally some young adults believe cigarillos to be lessharmful and less addictive than cigarettes encouraging uptake and continued use. Significant knowledge gapsexist in our understanding of how to effectively communicate the risks of cigarillo smoking but one effectivestrategy is through warning labels. Cigarillos are under the regulatory authority of the Food and DrugAdministration (FDA) and the FDA has mandated the implementation of six text-only warnings for cigarillos.This R01 application will address gaps in the literature about the effectiveness of cigarillo warnings byextending our previous research where we developed pictorial warnings for cigarillos. The specific aims of theproposed study are to: (1) Examine the impact of a pictorial cigarillo warning policy among young adult cigarillosmokers purchasing behaviors using a behavioral economics framework; and (2) examine the impact ofrepeated exposure to pictorial versus cigarillo warnings on cigarillo smoking intentions and behaviors. Ourstudy focuses on young adult and Black/African American frequent cigarillo users ages 21-34 because theyhave the highest rates of cigarillo use. We will first develop an online shopping task using the ExperimentalTobacco Marketplace and examine the impact of different cigarillo warning manipulations (pictorial FDA text-only Surgeon General text-only) on cigarillo purchasing cigarillo demand and substitution of other tobaccoproducts. We will then recruit another sample of young adult and Black/African American frequent cigarillousers to participate in a 6-week randomized control trial where they will be exposed to cigarillo warningsweekly to examine the impact of the warnings on cigarillo smoking intentions and behaviors. The goal of thisresearch is to increase the effectiveness of warning labels to discourage cigarillo use among young adultsincluding those who are Black or African American. The results of this timely project could inform the FDAsrulemaking for cigarillo warnings thereby reducing tobacco-related morbidity and mortality. 314208 +Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Lung; Lung Cancer; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD) 3D Print;Address;Adoption;Algorithms;Anatomy;Appearance;Beauty;Behavior;Biological Models;Clinic;Clinical;Complex;Data;Databases;Dependence;Derivation procedure;Development;Diagnostic;Dictionary;Digital Libraries;Dimensions;Dose;Ensure;Evaluation;Genes;Image;Image Analysis;Imaging Techniques;Lead;Lesion;Libraries;Lung;Lung CAT Scan;Lung nodule;Machine Learning;Measures;Medical Imaging;Methods;Modeling;Nodule;Noise;Non-linear Models;Outcome;Output;Patients;Performance;Play;Predictive Analytics;Property;Protocols documentation;Radiation Dose Unit;Research;Role;Sampling;Scanning;Scheme;Shapes;Signal Transduction;Source;Statistical Models;System;Techniques;Technology;Texture;Training;Transcend;Work;X-Ray Computed Tomography;base;clinical application;clinical translation;clinically relevant;data-driven model;deep learning;deep learning algorithm;deep neural network;design;exhaustion;flexibility;imaging system;improved;insight;interest;low dose computed tomography;lung cancer screening;lung lesion;machine learning method;neural network;novel;predicting response;public database;quantitative imaging;radiomics;reconstruction;response;screening;shape analysis;simulation;success;targeted imaging Nonlinear performance analysis and prediction for robust low dose lung CT PROJECT NARRATIVEMajor research efforts have been devoted to the development of nonlinear reconstruction algorithms frommodel-based reconstruction to deep learning these algorithms have demonstrated many advantages such asimproved image quality reduced radiation dose and additional diagnostic information that are not achievablewith traditional linear reconstructions. However only a disproportionately small number has reach the clinicdue to the lack of a predictive image quality analysis framework to quantify diagnostic performance controlalgorithm behavior and ensure consistent performance for robust clinical deployment. The propose effort usea combination of analytic and machine learning approaches to drive much-needed quantitative assessmentstandards that directly relate image quality to diagnostic performance and establish optimal strategies forrobust reliable clinical deployment of nonlinear algorithms. NCI 10684375 9/1/22 0:00 PA-21-268 7R01CA249538-03 7 R01 CA 249538 3 "TANDON, PUSHPA" 1/1/22 0:00 12/31/24 0:00 Imaging Technology Development Study Section[ITD] 14318598 "GANG, JIANAN GRACE" Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/22 0:00 12/31/22 0:00 394 Non-SBIR/STTR 2022 285869 NCI 215741 70128 1PROJECT SUMMARY / ABSTRACT 2 Nonlinear algorithms such as model-based reconstruction (MBR) and deep learning (DL) reconstruction have 3 sparked tremendous research interest in recent years. Compared to traditional linear approaches the nonline- 4 arity of these algorithm transcends traditional signal-to-noise requirement and offer flexibility to draw information 5 from a variety of sources (e.g. statistical model prior image dictionary training data). MBR has enabled numer- 6 ous advancements including low-dose CT and advanced scanning protocols. Deep learning algorithms are rap- 7 idly emerging and have demonstrated superior dose vs. image quality tradeoffs in research settings. However 8 widespread clinical adoption of nonlinear algorithms has been impeded by the lack of a lack of systematic quan- 9 titative methods for performance analysis. Nonlinear methods come with numerous dependencies on the imag-10 ing techniques the imaging target and the prior information and the data itself. The relationship between these11 dependencies and image quality is often opaque. Furthermore improper selection of algorithmic parameters can12 lead to erroneous features (e.g. smaller lesions texture) in the reconstruction. Therefore methods to quantify13 and predict performance permit efficient and quantifiable performance evaluation to provide the robust control14 and understanding of imaging output necessary for reliable clinical application and regulatory oversight.15 We propose to establish a robust predictive framework for performance assessment and optimization that can16 be generalized to any reconstruction method. We quantify performance in turns of the perturbation response and17 covariance as a function of imaging techniques system configurations patient anatomy and importantly the18 perturbation itself. The perturbation response quantifies the appearance (e.g. biases blurs distortions) and19 together with the covariance allows the computation of more complex metrics such as task-based performance20 and radiomic measures including size shape and texture information. We illustrate utility of the approach in lung21 imaging with the following specific aims: Aim 1: Develop a lesion library and generate perturbations encom-22 passing clinically relevant features. We will extract lesions from public databases and develop methods lesion23 emulation in for realistic CT simulation and physical data via 3D printing technology. Aim 2: Develop a gener-24 alized prediction framework for perturbation response and covariance. Using analytical and neural network25 modeling we will establish a framework that predicts perturbation response and covariance across imaging26 scenarios for classes of algorithms with increasing data-dependence including MBR with a Huber penalty MBR27 with dictionary regularization and a deep learning reconstructor. Aim 3: Develop assessment and optimiza-28 tion strategies to drive robust low dose lung screening CT methods. We will optimize and adapt nonlinear29 algorithms and protocols for lung cancer screening to achieve faithful representations of clinical features. This30 work has the potential to drive much-needed quantitative assessment standards that directly relate image quality31 to diagnostic performance and optimal strategies for robust reliable clinical deployment of nonlinear algorithms.32 285869 +No NIH Category available Adult T-Cell Leukemia/Lymphoma;Affect;Biological;Biological Assay;Biopsy;Blood;Categories;Classification;Clinical;Clinical Data;Clinical Laboratory Improvement Amendments;Clinical Pathology;Clinical Trials;Complex;DNA;DNA Maintenance;DNA Sequence Alteration;Detection;Diagnosis;Diagnostic;Disease;Disease Progression;Ensure;Evaluation;Extranodal;Formalin;Freezing;Future;GATA3 gene;Gene Expression;Gene Expression Profile;Genes;Genetic;Genotype;Goals;Immunoblastic Lymphadenopathy;Immunophenotyping;International;Ki-1 Large-Cell Lymphoma;Laboratories;Lesion;Logistics;Measures;Messenger RNA;Methods;Molecular;Monitor;Morphology;Mutation;Non-Hodgkin's Lymphoma;Outcome;Paraffin Embedding;Patients;Performance;Peripheral;Plasma;Plasma Cells;Procedures;Process;Prognosis;Protocols documentation;RNA;Reproducibility;Sampling;Sensitivity and Specificity;Somatic Mutation;Specific qualifier value;Specimen;Standardization;Subgroup;T-Cell Lymphoma;Techniques;Tissue Banks;Tissue Embedding;Tissues;Translating;Transportation;Western World;accurate diagnosis;anaplastic lymphoma kinase;cell free DNA;clinical application;clinical center;clinical practice;diagnostic accuracy;diagnostic algorithm;diagnostic assay;diagnostic signature;diagnostic tool;diagnostic value;disease diagnosis;evidence base;genetic signature;genome analysis;improved;liquid biopsy;nano-string;new technology;novel diagnostics;predicting response;preservation;prognostic;prognostic algorithm;prognostic assays;prognostication;prospective;sample fixation;tissue processing;treatment response;tumor;tumor DNA;whole genome Pre-analytical variables of bioanalytes affecting the accuracy of PTCL diagnostic and prognostic genetic signatures Project Narrative Peripheral T-cell lymphoma (PTCL) is a group of heterogeneous disease entities with varied clinico-pathologic features and ~ 30-50% of PTCL cases remain unclassifiable in current clinical practice. Using noveltechnological advances we identified robust molecular classifiers and distinct genetic profiles which can aid inmolecular subclassification of PTCL. We plan to establish standardized evidence-based procedures on bio-specimen processing for the optimal preservation of bio-analytes to ensure accurate and reproducible downstreamassay performance using tissue and liquid biopsy of PTCL. NCI 10684317 8/8/23 0:00 PAR-18-947 5U01CA253218-03 5 U01 CA 253218 3 "GUAN, PING" 9/20/21 0:00 8/31/26 0:00 ZCA1-RTRB-4(M1) 11101912 "IQBAL, JAVEED " "CHAN, WING C.; MURTAZA, MUHAMMED " 2 PATHOLOGY 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 359942 NCI 298424 61518 Abstract Peripheral T-cell lymphomas (PTCL) represent approximately 12-15% of all NHL in the western world and areassociated with dismal prognosis. Furthermore the diagnosis is challenging as 30-50% of PTCL cases cannot beassigned to a specific entity and are categorized as PTCL-not otherwise specified (PTCL-NOS). We have definedrobust gene expression signatures that can differentiate the five common PTCLs entities: angioimmunoblastic T-celllymphoma (AITL) anaplastic lymphoma kinase positive anaplastic large-cell lymphoma (ALK (+) ALCL) ALK-negative anaplastic large-cell lymphoma (ALK (-) ALCL) adult T-cell leukemia/lymphoma (ATLL) and extra-nodalnatural killer/T-cell lymphoma (ENKTCL). PTCL-NOS can be divided into two distinct biological and prognosticsubgroups (PTCL-TBX21 and PTCL-GATA3 subgroups). We translated the RNA based diagnostic and prognosticalgorithms for formalin fixed paraffin embedded (FFPE) tissues for widespread clinical usage with high sensitivity andspecificity. We also identified distinguishing genetic lesions in PTCL subtypes using corresponding DNA anddemonstrated that such lesion can be validated using shallow whole genome analysis (sWGA) in correspondingplasma cell-free DNA thus liquid biopsy can aid in diagnosis and disease monitoring. Since the biospecimen processing and hence quality varies significantly in routine clinical pathology laboratoriesthe reliability of RNA or DNA based signatures need to be evaluated under variable circumstances. It is essential todetermine how the robustness of the assay may be affected by pre-analytical variables before the novel diagnostictools can be applied to large studies or routine clinical practice. We hypothesize that a comprehensive evaluation ofpre-analytical variables of biospecimen will lead to optimized bio-specimen procurement framework leading toimproved diagnostic accuracy and reproducibility in tissue and liquid biopsy setting and can be standardized in aninter-CLIA lab setting for routine clinical practice/trials. This proposal aims to establish standardized evidence-basedprocedures on bio-specimen (RNA/DNA) processing storage and transportation to ensure accurate reproducibleassay performance. The identified conditions and parameters will be validated on prospective samples preferably in aclinical trial setting so findings can be correlated with clinical data. Thus three specific aims are proposed:Specific Aim 1: To determine pre-analytical variables that affects the reliability of RNA-based assays inFFPE tissueSpecific Aim 2: To identify pre-analytical factors affecting circulating tumor DNA (ct-DNA) detection andquantification in patients with PTCLSpecific Aim 3: To validate harmonization of the pre-analytical variables in improving PTCL diagnostic orprognostic assay in an inter-CLIA (Clinical Laboratory Improvement Amendments) lab setting The studies will lead to robust protocols that optimize the preservation biomolecules in tissue biopsies or plasma toensure accuracy and reproducibility of molecular assays improving PTCL classification and prognostication. 359942 +No NIH Category available Cancer Control;Grant;Training;cancer prevention Cancer Prevention And Control Training Grant (CAPACITY) Project NarrativeThe prevention of cancer and the delivery of high quality innovative care to cancer patients are highpriorities for researchers clinicians and the general public. The overall goal of the CAPACiTy training grantis to provide an integrated career development postdoctoral training program for PhD/MD fellows in theskills and competencies needed to conduct rigorous and impactful research in cancer prevention andcontrol. Through research mentorship coursework research experiences and professional seminarstrainees will emerge as well-trained independent scholars. NCI 10684296 8/16/23 0:00 PA-18-403 5T32CA122061-16 5 T32 CA 122061 16 "LIM, SUSAN E" 8/1/19 0:00 7/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1883963 "AVIS, NANCY E" "FOLEY, KRISTIE L" 5 PUBLIC HEALTH & PREV MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 136279 NCI 231660 16853 This renewal application seeks continued support for our training grant in cancer prevention and control. Wehave had two funding cycles of our R25 Postdoctoral Training Program in Cancer Survivorship (R25CA122061). We are now seeking to renew this training grant as we transition from the R25 to a T32mechanism. Given the additional breadth and funding of our current Comprehensive Cancer Centers CancerPrevention and Control (CPC) Program faculty we are expanding our focus on cancer survivorship to includeother CPC areas. This training program CAPACiTy:Cancer Prevention and Control Training Program will trainnine postdoctoral fellows in the conduct of cancer prevention in control research with a focus in cancersurvivorship healthy lifestyles and cancer care delivery. The R25 grant initially funded in August 2008 andsubsequently renewed for five years in August 2014 (11 years of funding to date) has provided support formentored training of fourteen highly successful investigators who remain committed to careers in academicresearch. The overall goal of CAPACiTy is to provide an integrated career development pathway centered ontraining PhD/MD fellows in the skills and competencies needed to conduct research in cancer prevention andcontrol (CPC). The number of research-intensive faculty and extramural funding in our CPC program hasnearly doubled since our initial R25 application. CAPACiTy provides a specialized curriculum and a tailoredprogram for each trainee that combines formal coursework mentorship and research experience. The tailoredprogram can also lead to an M.S. degree in Clinical and Translational Science. All trainees receive formaltraining in cancer prevention and control NIH grant preparation training in the responsible conduct ofresearch and participate in interdisciplinary seminars and interest groups. Trainees benefit from the resourcesprovided by our Comprehensive Cancer Center Clinical and Translational Science Institute Wake ForestNCORP Research Base ECOG-ACRIN Research Base and a well-funded cadre of faculty mentors. Althoughtraining is individually tailored according to the knowledge and experience of trainees all trainees are expectedto emerge from their training with the following competencies: 1) Knowledge skills and competencies in themeasurement of research outcomes specific to cancer prevention and control; 2) Knowledge skills andcompetencies in the design and conduct of human observational and/or interventional clinical trial research;3) Methodological expertise in a specific technology or research skill/technique; 4) Enhanced critical thinkingand scientific knowledge in cancer prevention and control; 5) Enhanced professional skills (e.g. writing oralcommunication skills grant writing); and 6) A resource network to support further career advancement as anindependent investigator. 136279 +No NIH Category available Animal Model;Animals;Antibodies;Antigens;B lymphoid malignancy;B-Cell Lymphomas;Back;Bar Codes;Binding;Biology;Biopsy;Breast Carcinoma;CD28 gene;Cancer Biology;Canis familiaris;Cell physiology;Cells;Cellular biology;Cellular immunotherapy;Chemicals;Chimeric Proteins;Coculture Techniques;Complement;Contracts;Disease remission;Engraftment;Enzyme-Linked Immunosorbent Assay;Ethics;Evolution;Fc Receptor;Functional disorder;Future;Generations;Genetic;Health;Hematologic Neoplasms;Home;Human;Immune;Immune system;Immunocompetent;Immunodeficient Mouse;Immunologic Deficiency Syndromes;In Vitro;Inbreeding;Incidence;Individual;Infusion procedures;Interferon Type II;Interleukin-2;Kinetics;Lentivirus Vector;MS4A1 gene;Malignant Neoplasms;Measurement;Measures;Methods;Modeling;Molecular;Mus;Neuroblastoma;Nucleotides;Patients;Phenotype;Procedures;Production;Receptor Signaling;Refractory;Relapse;Research;Sampling;Scientist;Solid Neoplasm;T cell infiltration;T-Cell Homing Receptors;T-Cell Receptor;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Training;Translating;Treatment Efficacy;Tumor Antigens;Tumor Cell Line;Veterinarians;Video Microscopy;Xenograft Model;antitumor effect;canine model;career;cellular transduction;chimeric antigen receptor;chimeric antigen receptor T cells;complement system;cost;design;doctoral student;driving force;efficacy evaluation;in vivo;in vivo imaging system;melanoma;mouse model;novel;novel strategies;osteosarcoma;pre-clinical;preclinical efficacy;restraint;single cell sequencing;success;timeline;trafficking;transcriptome sequencing;translational model;tumor;tumor growth Dogs as a high fidelity high throughput model to evaluate CAR-T cell function and dysfunction Project NarrativeCAR-T cells have demonstrated value in the treatment of hematological malignancies though their efficacy in solidtumors is lacking. This proposal will establish an outbred immunocompetent canine model of CAR-T therapy for solidtumors to identify molecular predictors of CAR-T cell homing and persistence in tumors. This model will be used for toevaluate novel CAR-T therapy approaches prior to human trials. NCI 10684292 9/8/23 0:00 PA-21-052 5F31CA265165-03 5 F31 CA 265165 3 "DIBELLO, ANTHONY THOMAS" 9/15/21 0:00 9/14/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16570778 "BRILL, SAMUEL " Not Applicable 2 OTHER CLINICAL SCIENCES 785979618 LT9CXX8L19G1 785979618 LT9CXX8L19G1 US 40.57951 -105.081267 1725201 COLORADO STATE UNIVERSITY FORT COLLINS CO SCHOOLS OF VETERINARY MEDICINE 805232002 UNITED STATES N 9/15/23 0:00 9/14/24 0:00 398 "Training, Individual" 2023 39682 NCI 39682 0 Project SummaryThis proposal aims to train a dual-degree DVM-PhD student for a career as a lab animal veterinarian and independentscientist. The research outlined in this proposal will develop a pre-clinical platform to evaluate CAR-T therapy in a caninemodel. Chimeric antigen receptor (CAR)-T cells have induced up to 90% remission rates for treatmentrelapsed/refractory B cell malignancies. While mice have been instrumental to CAR-T progress CAR-T therapy for solidtumors have been hampered by this inbred immunodeficient model. Pet dogs are a higher fidelity translational modeldue to their outbred genetics intact immune system high incidence of cancer and similar cancer biology.A CAR is a fusion protein comprised of a T cell receptor signaling domain costimulatory domain and an antibody basedbinding domain. CARs are introduced to patients T cells ex vivo enabling the T cells to directly recognize tumor antigen.CAR-T cells are a living therapy wherein the efficacy of the treatment relies not only on the design of the CAR but alsohow the CAR-T cells are able to home to the tumor and elicit anti-tumor effects. The CAR helps T cells to recognize thetumor but the trafficking persistence and effector function of these cells relies heavily on intrinsic T cell biology. Toadequately assess CAR-T cell function in vivo design of the CAR (Aim 1) and patient T cell biology (Aim 2) will beevaluated.Aim 1 Determine optimal CAR design for targeting tumor associated antigens GD2 FolR1 and CD20. CAR constructswill be designed for the tumor associated antigens GD2 FolR1 and CD20. These CARs will be introduced to primarycanine T cells via a lentiviral vector. The CAR-T cells will be evaluated for efficacy against antigen positive tumors by IFNELISA IL-2 ELISA and Incucyte live cell videomicroscopy. Each of these constructs will be tested with CAR costimulatorydomains 4-1BB and CD28. The CAR constructs with the strongest reactivity will be further evaluated with an NOD scidgamma (NSG) mouse xenograft model measuring tumor growth inhibition and CAR-T expansion in vivo.Aim 2 Determine which subset of CAR-T cells preferentially traffic and persist in the tumor in vivo. To evaluate therespective contribution of CAR-T cell subsets to anti-tumor efficacy in vivo semi-random nucleotide barcodes will beadded to the CAR constructs allowing for the tracking of clonal lineage during CAR-T production infusion and post-engraftment in mice. Using single cell sequencing clonal diversity of the CAR-T infusion product will be compared toclonal diversity intratumorally. Subsets of CAR-T that preferentially home to and expand in the tumor will be identified.Together these aims will set the basis for future studies of CAR-T therapy in a canine model. Aim 1 will provide acandidate CAR construct to be evaluated in a canine model. Aim 2 will provide a method for understanding how CAR-Tcells traffic to and persist within a tumor in vivo. This platform will be used to screen and refine novel approaches toCAR-T therapy in a high-fidelity high-throughput animal model. 39682 +No NIH Category available Advanced Malignant Neoplasm;African American;African American population;Area;Award;Cities;Clinical;Collaborations;Communication;Communities;Comprehensive Cancer Center;Development;Disease;Disparity;Early Diagnosis;Faculty;Fostering;Funding;Future;Goals;Grant;Health;Health Disparities Research;Human Resources;Incidence;Infrastructure;Intervention;Laboratories;Malignant Neoplasms;Mentors;Methodology;Methods;Mission;Monitor;Morbidity - disease rate;Patients;Pilot Projects;Population Sciences;Prevention;Process;Program Research Project Grants;Program Reviews;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Resources;Review Committee;Science;Stage at Diagnosis;Structure;Translating;Translational Research;Underrepresented Minority;United States;Universities;Writing;cancer health disparity;disparity reduction;human subject;innovation;meetings;mortality;novel;programs;racial disparity;recruit;sound;translational impact;translational potential;treatment response Developmental Research Program Project NarrativeCancer health disparities in incidence stage at diagnosis response to treatment and survival represent aformidable health problem in the United States. To encourage the development of new strategies for reducingcancer health disparities the DRP will solicit review and provide funding for pilot projects involving innovativeresearch aimed at the elimination of race-related disparities. NCI 10684289 8/16/23 0:00 RFA-CA-19-034 5P20CA262735-03 5 P20 CA 262735 3 9/20/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 5348 1967939 "BEPLER, GEROLD " Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 81227 52745 28482 Project SummaryThe primary goal of the Developmental Research Program (DRP) of this P20 application is to advance the cancerhealth disparities research mission at the Karmanos Cancer Institute (KCI) by developing innovative researchprojects that are scientifically sound and translatable. The DRP provides a unique opportunity for soliciting newresearch ideas and encourages development of cancer health disparities projects with high translationalpotential. These projects provide investigators with the resources to conduct high-impact translational researchconsistent with our P20 SPORE's objectives. The goals will be achieved through the following specific aims: 1)Solicitation of DRP proposals through a highly structured process by leveraging the existing administrativestructure of the KCI; 2) Review applications for new and renewal projects by a DRP Review Committee whichwill recommend up to two new applications and two renewal applications for funding to the Executive Committee(except for the first year where two new projects will be supported); 3) Monitor and evaluate funded projects forprogress and translational potential and assess their potential to become full P50 SPORE-ready translationalprojects; and 4) Integrate DRP investigators into the SPORE community by requiring participation in monthlymeetings and group communications and by providing opportunities for expanded collaborations. We will utilizeKCI's existing infrastructure for the DRP to meet the translational objectives of the P20 SPORE and leveragealready established mechanisms to solicit applications. These mechanisms also serve to foster excellentscience in cancer health disparities recruit new faculty to areas of focus mentor junior faculty and encourageresearch collaborations. PIs of new and renewal DRP projects will be required to submit written summaries ofresearch accomplishments to the DRP Committee after 10 months and present these at one of the monthlymeetings of the Executive Committee comprised of the co-leaders of the SPORE projects and core directors.This meeting will be used to determine whether the DRP projects are sufficiently meritorious for considerationas full translational projects by the Internal Advisory Board followed by the EAB and the P20 Cancer ActionCouncil as part of a future Detroit Cancer Health Disparities P50 SPORE application. This program willencourage participation from a broad range of investigators at KCI and Wayne State University by providingsupport for pilot projects with the potential to develop into impactful translational projects. It also encouragesand facilitates the development of new research directions methodologies and collaborations. Importantly KCIhas committed to provide the required funds annually for the DRP to fund up to two new projects every year ata maximum of $50000 per project per year (with the potential of renewal for up to two projects per year in years2 and 3). +No NIH Category available Acceleration;African American;Ancillary Study;Biological;Biological Assay;Biological Specimen database;Cancer Patient;Charge;Clinical;Collection;Communities;Comprehensive Cancer Center;Confidentiality of Patient Information;Core Facility;Data;Development;Diagnosis;Disease;Disparity in diagnosis;Doctor of Philosophy;Ensure;Ethnic Origin;Freezing;Future;Genomics;Goals;Guidelines;Health Disparities Research;Histologic;Human;Institution;Institutional Review Boards;Malignant Neoplasms;Malignant neoplasm of lung;Microscopic;Molecular;Nature;Outcome;Pathologic;Pathologist;Pathology;Patient Care;Patients;Process;Prognosis;Prognostic Marker;Program Research Project Grants;Protocols documentation;Quality Control;Race;Reduce health disparities;Research;Research Personnel;Research Project Grants;Research Support;Resource Development;Resource Sharing;Sampling;Sampling Studies;Science;Services;Specimen;Stains;System;Technology;Testing;Therapeutic Intervention;Tissue Microarray;Tissue Sample;Tissue Stains;Tissues;Translational Research;Update;Xenograft procedure;accurate diagnosis;biobank;cancer biomarkers;cancer health disparity;cancer risk;cancer therapy;design;human tissue;improved;innovation;metropolitan;minority patient;molecular array;neoplasm resource;new therapeutic target;novel;patient population;programs;therapeutic biomarker;therapeutic development BCS Core Project NarrativeThe Biospecimen Core's goal is to ensure that high-quality biospecimens collected while ensuring compliancewith federal and institutional guidelines are delivered in a timely manner to P20 SPORE investigators and toprovide pathologic and molecular analytic expertise to support the innovative and translational cancer healthdisparities research projects in this application. NCI 10684286 8/16/23 0:00 RFA-CA-19-034 5P20CA262735-03 5 P20 CA 262735 3 9/20/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 5347 8761779 "BOERNER, JULIE LYNN" Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 125695 81620 44075 Project SummaryThe Biospecimen Core directed by the Director of the Biobanking and Correlative Sciences (BCS) Core atKarmanos Cancer Institute Dr. Julie Boerner PhD and co-directed by Dr. Fulvio Lonardo expert lung cancerpathologist will provide the highest quality biological specimens to support the research of investigators for thisP20 application. This Core facility is charged with collecting banking and transferring fresh and frozen humantissue samples for investigative purposes. As part of this process the Biospecimen Core will provide correlativeclinical information for biospecimens while maintaining strict patient confidentiality using the well-establishedHonest Broker system and ensuring that requesting investigators have proper protocol review and IRB approval.This specific collection of biospecimens is focused on overcoming the lack of biospecimens from minoritypatients that plagues race/ethnicity-related researcher questions. The goal of this P20 SPORE Core is to ensurethat high-quality biospecimens collected while ensuring compliance with federal and institutional guidelines aredelivered in a timely manner to P20 SPORE investigators and to provide pathologic and molecular analyticexpertise to support the innovative and translational cancer health disparities research projects in thisapplication. The specific aims of Biospecimen Core are the following: Specific Aim 1: To collect process andbank cancer tissue and associated biological samples with ongoing quality control to ensure timely distributionof appropriately diagnosed high-quality samples to investigators and collaborators on all P20 SPORE projectsfor molecular and genomic analysis for culture and for xenograft assays and for ancestry informative markersto further define patient race; Specific Aim 2: Perform high quality immunohistochemical staining and providepathological interpretation of stained tissue sections to investigators and collaborators on all P20 SPOREprojects; Specific Aim 3: Generate tissue microarrays using samples from African American cancer patients foruse in future projects and made available to the broader research community to support expanded efforts in thereduction of cancer health disparities; Specific Aim 4: To maintain and update a central Detroit P20 SPOREdatabase of biospecimens from cancer patients collected at KCI that is annotated with demographic clinicaland pathologic data and provide access to data and specimens; and Specific Aim 5: To actively participate inthe design of pathology/ancillary studies of P20 SPORE projects the Developmental Research Programprojects and projects for consideration for a full P50 SPORE application including providing input on suitabilityfor samples for studies proposed histologic characterization immunohistochemical analyses and microscopicscoring and construction of study specific tissue microarrays. Together these aims will allow the BiospecimenCore to have a significant clinical impact in this P20 application as it has a large collection of valuable andappropriate specimens that are immediately available to the research projects. +No NIH Category available Accounting;Administrator;Affect;Attitude;Behavior;Breast;COVID-19 pandemic;Cancer Center;Caring;Cessation of life;Client satisfaction;Clinical Services;Colon Carcinoma;Colorectal;Colorectal Cancer;Communication;Continuity of Patient Care;Diagnosis;Disparity;Equity;Ethnic Origin;Goals;Health Disparities Research;Health Personnel;Health Services Accessibility;Healthcare Systems;Home;Individual;Integrated Health Care Systems;Intervention;Intervention Studies;Interview;Knowledge;Label;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measures;Medical;Methods;Mission;Modeling;National Institute on Minority Health and Health Disparities;Oncology;Outcome;Participant;Patient Care;Patients;Performance;Play;Populations at Risk;Poverty;Program Sustainability;Prostate;Provider;Public Health;Race;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Research;Role;Services;Single-Payer System;Structure;Time;United States;Veterans;Veterans Health Administration;Visit;Vulnerable Populations;Woman;cancer care;cancer health disparity;cancer subtypes;cancer therapy;care coordination;cost;cost outcomes;digital;effectiveness evaluation;effectiveness testing;effectiveness/implementation study;effectiveness/implementation trial;experience;hands-on learning;health care disparity;health care service utilization;health equity;health equity promotion;health management;implementation outcomes;improved;innovation;intervention cost;malignant breast neoplasm;men;mortality;oncology program;population health;pragmatic trial;programs;risk minimization;rurality;satisfaction;screening;service delivery;social determinants;social health determinants;successful intervention;telehealth;teleoncology;virtual;virtual delivery Pragmatic Trial - Telehealth Research and Innovation for Veterans with Cancer (THRIVE). n/a NCI 10684282 8/9/23 0:00 RFA-CA-21-029 5P50CA271358-02 5 P50 CA 271358 2 8/15/22 0:00 7/31/27 0:00 ZCA1-SRB-2 5345 10826329 "MAKAROV, DANIL V." Not Applicable 12 Unavailable 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY Domestic Higher Education 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 308396 181945 126451 Four cancers lung colorectal prostate and breast account for nearly half of all cancer deaths among menand women in the United States. Social determinants of telehealth (SDTH) such as race/ethnicity poverty andrurality individually and in additive or synergistic combinations play an important role in access to andoutcomes from cancer care often accounting for the observed cancer care disparities. Veterans HealthAdministration (VA) is the largest integrated provider of cancer care in the US and provides state of the artcancer care to millions of veterans. Yet even within VA routinely praised for its equal access to care modeldisparities in cancer care persist. However while VA serves a population at risk for SDTH driven healthcaredisparities it also leverages the advantages of an integrated national single-payer system such as carecoordination and telehealth to improve health equity.Widespread use of telehelath in oncology creates both challenges and opportunities to expand access andimprove care. In some cases however reliance on telehealth may widen the digital divide for those withlimited ability to access it. A major knowledge gap exists regarding the optimal way to integrate telehealth intooncology practice across the care continuum. Our overarching aim is to improve the quality and equity ofcancer care across the United States by leveraging lessons learned applying telehealth treating veterans withcancer in VAs integrated health care system.The objective of the pragmatic trial to test the effectiveness of an existing ongoing clinical service the VANational TeleOncology program (NTO) a multilevel telehealth population health management program. Wepropose a stepped wedge cluster randomized hybrid effectiveness-implementation study of NTO amongveterans diagnosed with prostate lung colon and breast cancers in VA. Using the NIMHD Health DisparitiesResearch Framework we will employ mixed methods to explore the association across SDTH between NTOand 1) service delivery outcomes 2) hierarchical cancer outcomes and 3) implementation outcomes.Specifically the aims of the pragmatic trial are to: (1) Evaluate the effect of a comprehensive multilevel virtualoncology program to promote telehealth engagement on stakeholder (patient provider administrator) cancercare experience across SDTH; (2) Evaluate the effect of a comprehensive multilevel virtual oncology programon quality of cancer care in veterans diagnosed with lung colorectal prostate and breast cancer across SDTH;and (3) Determine the impact and cost of a comprehensive multilevel teleoncology program.Our proposed hybrid effectiveness implementation trial to evaluate a comprehensive virtual oncology programto promote telehealth engagement and health equity has high potential for scalability and public health impactboth within and outside of VA. +No NIH Category available Adherence;African American;African American population;Age;Area;Automobile Driving;Behavioral;Biological Markers;Cancer Patient;Caring;Characteristics;Chemotherapy and/or radiation;Cities;Clinical Trials;Consolidation Therapy;County;DNA Sequence Alteration;Demographic Factors;Disease;Disparity;Documentation;Dose;Emergency Situation;Enrollment;Equity;Goals;Histology;Hospitalization;Immune;Immune checkpoint inhibitor;Immunotherapy;Individual;Intervention;Knowledge;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Moods;Non-Small-Cell Lung Carcinoma;Outcome;Pathway interactions;Patients;Platinum;Population;Quality of life;Race;Reporting;Research;Risk;Risk Factors;Risk Reduction;Sampling;Self Efficacy;Smoking History;Socioeconomic Status;Symptoms;Testing;Time;Treatment Side Effects;Unresectable;Visit;cancer diagnosis;cancer health disparity;cancer therapy;chemotherapy;clinical trial enrollment;comorbidity;cost;high risk;immune-related adverse events;improved;improved outcome;metropolitan;outcome prediction;racial difference;racial disparity;racial diversity;response;sex;side effect;sociodemographics;standard care;standard of care;treatment effect;treatment response;treatment trial;tumor;urgent care Project 2 Project NarrativeWhile immune checkpoint inhibitors (ICIs) hold promise for improved outcomes among lung cancer patients littleis known about potential differences by race with respect to the effects of treatment largely due to a lack ofinclusion of African American patients in the clinical trials leading to FDA approvals. Thus there is a critical needto understand whether African American and white patients are differentially impacted by ICI treatment and toexplore predictors of these differences. Without the documentation and understanding of factors drivingdisparities we cannot evaluate what interventions may be needed to reduce racial disparities or how to targetintervention to patients specific and culturally relevant needs. NCI 10684281 8/16/23 0:00 RFA-CA-19-034 5P20CA262735-03 5 P20 CA 262735 3 9/20/21 0:00 8/31/24 0:00 ZCA1-RPRB-M 5344 8269175 "HARPER, FELICITY " Not Applicable 13 Unavailable 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI Domestic Higher Education 482024000 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 289930 188266 101664 Project SummaryOne of the most significant advancements in lung cancer treatment has been the introduction of immunecheckpoint inhibitors (ICIs) which either as single agents or in combination with platinum-based chemotherapyare now front-line therapy for most patients with metastatic non-small cell lung cancer (NSCLC). While treatmentresponse rates can be remarkable side effects especially immune-related adverse events (irAEs) are of majorconcern. When uncontrolled side effects can result in unscheduled care increased out-of-pocket costs forpatients and treatment delays or discontinuation. African Americans continue to have worse outcomes after alung cancer diagnosis than whites and there are known differences between African Americans and whites withrespect to many aspects of cancer treatment including time to initiation and dose of chemotherapy symptomburden and even treatment of side effects. However little is known about potential differences by race withrespect to response to ICI treatment largely due to a lack of inclusion of African American patients in the clinicaltrials leading to FDA approvals. Thus there is a critical need to explore whether African American and whitepatients are differentially impacted by side effects related to ICI treatment. The specific aims are to: 1)Characterize patient-reported side effects and quality of life and clinician-assessed irAEs associated with ICItreatment in a group of African American and white lung cancer patients being treated in a standard care setting;and 2) Identify the sociodemographic individual and disease-specific determinants of patient-reported sideeffects and quality of life and irAEs associated with ICI treatment and characterize differences by race. WhileICIs holds promise for improved outcomes little is known about whether potential predictors of patient-reportedside effects and quality of life and irAEs vary by race. This study will directly evaluate multi-level predictors inresponse to ICI treatment in African American and white patients. Understanding the sociodemographicindividual and disease-specific determinants of these outcomes in lung cancer patients provides the basis formoving towards a more equity-focused approach to the use of ICIs. By identifying drivers of potential disparitieswe can better identify patients at high risk for side effects and irAEs develop interventions to reduce risk factorsthereby improving patient quality of life and reducing racial disparities in outcomes. +No NIH Category available 3-Dimensional;Aging;Animal Model;Body Fluids;Cells;Cetuximab;Culture Media;Data;Development;Endosomes;Endothelial Cells;Endothelium;Epidermal Growth Factor Receptor;Epithelial Cells;Epithelium;Extracellular Space;Gene Expression;Goals;HIV;HIV Infections;HIV Seronegativity;HIV Seropositivity;HIV/AIDS;Herpesviridae Infections;Histologic;Human;Human Herpesvirus 8;Immune;Incidence;Infection;Inflammatory;Kaposi Sarcoma;Link;Malignant Neoplasms;Mediating;Methods;Mitogen-Activated Protein Kinases;Modeling;Molecular;Monoclonal Antibodies;Morbidity - disease rate;Mucous Membrane;Multicentric Angiofollicular Lymphoid Hyperplasia;Oncogenic;Oral;Oral cavity;Oral mucous membrane structure;Outcome;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Persons;Play;Population;Predisposition;Process;Publishing;RNA;Receptor Signaling;Research;Response Elements;Role;Route;Saliva;Stratum Basale;Syndrome;System;T-Lymphocyte;TLR3 gene;Testing;Tissue Model;Tissues;Tonsil;Transactivation;Vascular Endothelium;Vesicle;Viral;Viral Genes;Virus;Virus Diseases;cell type;cytokine;exosome;extracellular vesicles;gammaherpesvirus;in vitro Model;in vivo;infection risk;lytic replication;mortality;nanoparticle;novel therapeutic intervention;oral cavity epithelium;oral infection;prevent;primary effusion lymphoma;response;single-cell RNA sequencing;success;transcriptome;transmission process Role of HIV in KSHV oral transmission Project NarrativeKaposi sarcoma herpesvirus (KSHV) infection can cause Kaposis sarcoma (KS) a major malignancy leads tomortality and morbidity in people living with HIV/AIDS. Saliva from people with HIV infection containsnanoparticle-like extracellular vesicles that increase KSHV infection. This research will help us find a new methodto prevent KSHV infection and transmission in populations living with HIV and people with high HIV infectionrisks. NCI 10684278 8/30/23 0:00 RFA-CA-20-046 5R01CA264910-03 5 R01 CA 264910 3 "READ-CONNOLE, ELIZABETH LEE" 9/20/21 0:00 8/31/26 0:00 ZCA1-RPRB-L(M2)R 9249064 "JIN, GE " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 645047 NCI 400650 244397 Project Summary/AbstractKaposi sarcoma (KS) remains one of the most common malignancies in people living with HIV/AIDS worldwide.Kaposi sarcoma herpesvirus (KSHV) also called human herpesvirus-8 (HHV-8) is the causal agent for KS. Theoral mucosa is the first target of KSHV infection once the virus is in the oral cavity. However the initial infectionprocess of the mucosa by KSHV has never been studied mainly due to lack of an in vitro model to recapitulatethe viral infection in vivo and nonexistence of an animal model for KSHV infection. We have created the 3-dimentional (3-D) organotypic culture as an oral mucosal mimic resembling a stratified oral mucosa with thepotential for histological assessment of the KSHV infection/transmission process. Our studies show that KSHVinfection in the 3-D oral mucosa model is enhanced by saliva extracellular vesicles (EVs) particularly exosomesfrom HIV patients. Exosomes purified from the saliva of HIV patients or from culture media of HIV-infected Tcells contain similar HIV-specific cargos including HIV TAR RNA. KSHV entry into target cells and its infectivityare increased by HIV-positive saliva exosomes in primary and immortalized human oral epithelial cells. FurtherKSHV infection and transmission to the suprabasal cells in the 3-D organotypic culture are enhanced by HIV-positive exosomes. Increased KSHV infectivity by HIV-positive exosomes is attributed to the HIV TAR RNA withinthe vesicles and epidermal growth factor receptor (EGFR) of host cells. Inhibition of EGFR by Cetuximab amonoclonal antibody to EGFR blocks KSHV infection enhanced by HIV-positive exosomes. Taken togetherthese data lead us to hypothesize that HIV-positive exosomes promote KSHV infection and transmission throughthe oral route and are responsible for increased incidence of KSHV infection in people living with HIV. To testthis hypothesis we plan to 1) assess KSHV transmission and infection through the oral route with the 3-Dcultures of oral mucosal and tonsil tissues incorporated with peripheral blood mononuclear cells (PBMCs) aswell as the epithelium-endothelium model. KSHV infection and transmission through the epithelial barrier toimmune and endothelial cells in response to HIV+ saliva exosomes will be assessed; 2) delineate the mechanismby which HIV-positive exosomes promote KSHV oral transmission using the 3-D tissue models. We will applysingle cell RNAseq to identify cell-specific changes in transcriptome of the oral mucosal and tonsil 3-D tissuemodels following KSHV infection in response to HIV+ exosomes; and 3) elucidate the role of EGFR-dependentmitogen-activated protein kinase activation in enhanced KSHV transmission by HIV-positive exosomes. Successof the proposed research will advance our understanding of KSHV oral transmission at the molecular level andthe underlying mechanisms for developing potential novel therapeutic strategies. 645047 +No NIH Category available Affect;Algorithms;Biometry;Cancer Center;Cancer Etiology;Cessation of life;Clinical;Clinical Trials;Collaborations;Colorectal;Colorectal Cancer;Computer software;Data;Data Set;Decision Making;Development;Diagnostic;Disease;Disease Progression;Ensure;Excision;Eye;Goals;Hepatic;Human;Image;Image Analysis;Infusion procedures;Institution;Link;Malignant Neoplasms;Malignant neoplasm of liver;Manufacturer;Medical Oncology;Medical center;Metastatic Neoplasm to the Liver;Methods;Modeling;Network-based;Operative Surgical Procedures;Outcome;Pathology;Pathway interactions;Patient Selection;Patients;Pattern;Performance;Phase;Phase I/II Trial;Prediction of Response to Therapy;Prognostic Marker;Prospective Studies;Publications;Radiology Specialty;Recurrence;Regional Chemotherapy;Reproducibility;Research;Resolution;Scanning;Series;Specificity;Standardization;System;Technology;Testing;The Cancer Imaging Archive;Therapeutic;Training;United States;University of Texas M D Anderson Cancer Center;Update;Validation;Venous;Western World;X-Ray Computed Tomography;biomarker validation;cancer care;cancer diagnosis;chemotherapy;clinical care;colon cancer patients;comparative;contrast enhanced computed tomography;convolutional neural network;cost;design;efficacy trial;experience;high risk;imaging biomarker;imaging modality;improved;indexing;individualized medicine;innovation;mortality;novel;novel marker;personalized cancer therapy;personalized medicine;phantom model;precision medicine;predicting response;prediction algorithm;prevent;prognostic;programs;prospective;quantitative imaging;radiomics;reconstruction;response;response biomarker;specific biomarkers;tool Development and Validation of Prognostic Radiomic Markers of Response and Recurrence for Patients with Colorectal Liver Metastases NARRATIVEImprovements in the resolution of CT imaging over a decade ago have created an abundance of data thatcontain information invisible to the human eye which can be capitalized upon to create predictive treatmentalgorithms. This proposal aims to validate optimize and standardize our novel CT-based imaging markers thatpredict response to therapy hepatic recurrence and survival in patients with colorectal liver metastases.These findings will help us move from the treat everyone to help a few paradigm of cancer care to fulfill thepromise of precision medicine and improve the cure rate for colorectal cancer patients. NCI 10684268 8/25/23 0:00 PA-18-484 5R01CA233888-05 5 R01 CA 233888 5 "WANG, YISONG" 3/1/19 0:00 8/31/24 0:00 Medical Imaging Study Section[MEDI] 10769337 "DO, RICHARD KINH GIAN" "CHUN, YUN SHIN; SIMPSON, AMBER " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 659173 NCI 463722 195451 SUMMARYColorectal cancer is the second leading cause of cancer-related mortality in the United States. More than 50%of patients with colorectal cancer will develop liver metastases in their lifetime with a dismal <10% survivingpast three years. A major therapeutic problem in this disease is that no markers prognostic of hepaticrecurrence or predictive of response prior to treatment are known. The goal of this research is to fill this gap byproviding non-invasive and objective prognostic quantitative imaging markers for personalized treatment ofcolorectal liver metastases (CRLM). Our single-institution data support that quantitative imaging featuresextracted from routine CT scans predict volumetric response to systemic and regional chemotherapy andidentify patients at high risk of hepatic recurrence and poor survival. Progress in developing these novelmarkers is limited by a lack of optimization standardization and validation all critical barriers to clinical use.The objectives of this application are to develop and validate robust imaging features by standardizing imageacquisition to improve automated tools for clinical trial use and to validate the predictive power of imagingfeatures with external data. We have partnered with University of Texas MD Anderson Cancer CenterRensselaer Polytechnic Institute and GE Research facilitating the widespread integration of the proposedtechnology into medical centers worldwide. Our central hypothesis is that quantitative CT-based imagingfeatures provide novel and robust indices for predicting response hepatic recurrence and survival in CRLMpatients. Specifically we will (1) validate predictive and prognostic imaging features with external data (2)prospectively assess repeatability and reproducibility of contrast-enhanced CT imaging features and (3)develop an integrated rawdiomics pipeline by fully utilizing sinogram data. We have assembled a critical massof experts in surgery medical oncology pathology radiology biostatistics and image analysis. Combined withthe largest clinical experience in CRLM in the western world this application is a unique and unrivaledopportunity to define radiomics of CRLM. Integration into existing clinical workflows means that small medicalcenters without highly specialized radiology groups would benefit from predictive algorithms developed at twohigh-volume centers via a low-cost software update. Successful completion of our aims will provide validatedprognostic imaging markers with a pathway to routine clinical use which are of paramount importance toimproving patient survival of this deadly disease. 659173 +No NIH Category available ARID1A gene;Ablation;Biological;Biological Models;Biology;CRISPR/Cas technology;Cancer Biology;Cancer Cell Growth;Cancer Etiology;Cancer cell line;Cells;Chemicals;Chromatin;Chromatin Remodeling Factor;Complex;Data;Development;Disease;Epidermal Growth Factor Receptor;Epigenetic Process;Foundations;Frequencies;Future;Gene Expression;Gene Targeting;Genes;Genetic;Genetically Engineered Mouse;Genomics;Goals;Growth;Heterozygote;Immunotherapy;In Vitro;Knowledge;Lead;Malignant neoplasm of lung;Mediating;Mus;Mutate;Mutation;Names;Non-Small-Cell Lung Carcinoma;Pathway interactions;Patients;Pharmacodynamics;Positioning Attribute;Protac;Proteins;Reporting;Resistance;Role;SMARCA2 gene;SMARCA4 gene;Sucrose;Technology;Therapeutic;Therapeutic Index;Validation;Xenograft Model;Xenograft procedure;analog;cancer cell;cancer subtypes;clinical development;clinical translation;drug mechanism;efficacy testing;experimental study;genetic approach;improved;in vivo;inhibitor;insight;interest;loss of function;lung cancer cell;mortality;mutant;novel;novel therapeutics;patient derived xenograft model;pre-clinical;preclinical development;programmed cell death ligand 1;resistance mechanism;small molecule;targeted treatment;therapeutic target;therapeutically effective;tumor;tumor growth Targeting SMARCA2 as a therapeutic strategy in SMARCA4 mutant lung cancer Project narrativeDespite promising new therapeutics lung cancer remains a devastating disease and is the top cause of cancermortality. We and others recently showed that a a protein named SMARCA2 is essential for growth of a subtypeof lung cancer and discovered a potent chemical molecule that degrades this protein. In this proposal we aim toperform in depth biological studies to better understand the mechanism of the growth inhibitory activity ofSMARCA2 degradation using chemical biology and genetic approaches as well as explore the therapeuticpotential of SMARCA2 degradation by our molecule in such tumors. NCI 10684259 8/1/23 0:00 PA-20-185 5R01CA272945-02 5 R01 CA 272945 2 "VENKATACHALAM, SUNDARESAN" 7/1/22 0:00 6/30/27 0:00 Special Emphasis Panel[ZRG1-OTC1-M(80)S] 14325721 "LISSANU, YONATHAN " Not Applicable 9 SURGERY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 526882 NCI 325236 201646 Project Summary Lung cancer is the top cause of cancer mortality. Despite recent advances the majority of patients withlung cancer lack effective therapeutic options underscoring the dire need for additional treatment approaches.Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complexincluding SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stagedisease making it the most frequently mutated complex in lung cancer. Recent reports and our own data haveidentified the paralogue SMARCA2 to be synthetic lethal to SMARCA4. However identifying selective inhibitorsof SMARCA2 has been challenging. Hence we have developed novel SMARCA2 degrading small moleculesbased on the proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23 our leadSMARCA2 PROTAC potently and selectively induces degradation of SMARCA2. We further showed that YD23selectively inhibits growth of SMARCA4 mutant lung cancer cells. Mechanistically we showed that YD23 induceschanges in chromatin accessibility only in SMARCA4 deficient cells. Taking these observations together we hypothesize that SMARCA2 degradation using YD23 is anattractive therapeutic strategy with promising therapeutic index in lung cancers with inactivating mutations inSMARCA4. The major objective of the proposed study is to provide preclinical evidence to guide futuredevelopment of YD23 (or its analogs) in patients with SMARCA4 mutant lung cancer. While we have shownmarked sensitivity of SMARCA4 mutant lung cancer cell lines to YD23 we still do not know the detailedmechanistic basis for this activity. Hence we intend to perform gene expression epigenetic and chromatinaccessibility studies followed by integrative analysis to triangulate on direct target genes whose chromatinlandscape is altered by presence or absence of SMARCA2 in SMARCA4 mutant cancer cells. While our in vitrocancer cell growth inhibitory studies are encouraging a systematic exploration in vivo using various orthogonalmodel systems is required to aid the preclinical development of SMARCA2 degraders. Thus we propose todetermine the potential of YD23 mediated SMARCA2 degradation in SMARCA4 mutant xenograft and patientderived xenograft (PDX) model systems. Due to the unique microenvironment of lung cancer we will also testefficacy of YD23 in GEM models of lung cancer. Finally SMARCA2 as a synthetic lethal partner of SMARCA4has so far been described by in vitro experiments. In vivo genetic validation is critical to unequivocallydemonstrate the requirement of a gene of interest in the development of a genetically defined subtype of cancer.Thus we aim to perform CRISPR-Cas9 mediated Smarca2 genetic ablation to determine the extent of itsinvolvement in the development and biology of Smarca4 mutant GEM models. In conclusion our study isexpected to provide mechanistic insight into the synthetic lethal genetic relationship between SMARCA2 andSMARCA4 and lay the foundation for future clinical development of SMARCA2 degraders as therapeutics. 526882 +No NIH Category available Academic achievement;Acute Lymphocytic Leukemia;Address;Affect;Age;Attention;Attention deficit hyperactivity disorder;Behavior;Boston;Brain Neoplasms;Central Nervous System;Child;Childhood Acute Lymphocytic Leukemia;Childhood Brain Neoplasm;Clinical Trials;Cognitive;Cognitive remediation;Compensation;Cranial Irradiation;Data;Development;Disease;Electronics;Enrollment;Environment;Excision;FDA approved;Family;Goals;Home;Impairment;Intervention;Intervention Studies;Late Effects;Learning;Letters;Life;Malignant Childhood Neoplasm;Measures;Methotrexate;Outcome;Parents;Participant;Patients;Pediatric Oncology;Performance;Persons;Pilot Projects;Population;Quality of life;Questionnaires;Radiation therapy;Randomized;Randomized Controlled Trials;Regulation;Research;Risk;Schools;Short-Term Memory;Site;Socialization;Structure;Survival Rate;Survivors;Tablet Computer;Testing;Thinking;Time;Training;Training Programs;Vocation;Youth;acceptability and feasibility;active control;active control group;attentional control;blood-brain barrier crossing;blood-brain tumor barrier;cancer therapy;chemotherapy;childhood cancer survivor;cognitive ability;cognitive function;cognitive load;cognitive skill;cognitive training;cohort;compliance behavior;design;digital;efficacy trial;executive function;experience;functional improvement;improved;interest;neural;neurocognitive test;performance based measurement;post intervention;programs;randomized trial;satisfaction;skills;social relationships;spelling;technical report;treatment adherence;treatment effect FAACS: Feasibility/Acceptability of Attentional-Control Training in Survivors Project Narrative:Survivors of pediatric acute lymphoblastic leukemia (ALL) and brain tumors (BT) often developproblems with learning attention and other thinking skills after finishing treatment. Theseproblems can make it more difficult for them to learn at school get along with people and besuccessful in daily activities. We propose to test whether a program that has been shown tohelp improve attention skills in other groups of children EndeavorRx is feasible and helpful to agroup of survivors of BT and ALL. NCI 10684249 7/28/23 0:00 RFA-CA-20-028 5R21CA261877-02 5 R21 CA 261877 2 "NELSON, WENDY" 9/1/22 0:00 8/31/24 0:00 ZCA1-SRB-T(J1) 11771201 "HARDY, STEVEN " Not Applicable 98 Unavailable 143983562 M3KHEEYRM1S6 143983562 M3KHEEYRM1S6 US 38.927274 -77.014396 1518602 CHILDREN'S RESEARCH INSTITUTE WASHINGTON DC Research Institutes 200102916 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 211033 NCI 171324 39709 PROJECT SUMMARY/ABSTRACTSurvival rates are increasing for common pediatric cancers including acute lymphoblastic leukemia (ALL) andbrain tumors; yet the life-saving treatments for these cancers place survivors at heightened risk for sustainedcognitive effects. Longitudinal research has shown that the cognitive burden of ALL and pediatric brain tumorsmay consist of impairments in attention working memory and executive functioning which results in long-termdisruption to daily living socialization academic achievement and quality of life. Few non-pharmacologicalinterventions exist to ameliorate these cognitive late effects but the results have been promising. The mostwidely studied intervention Cogmed is an electronic cognitive training program that has been shown toimprove working memory but has not resulted in broad functional improvement. Thus it may be that a multi-domain approach is needed to generalize treatment effects to real-world functioning. Endeavor an FDA-approved electronic attentional-control training program may be one intervention to help compensate for theexecutive functioning difficulties experienced by survivors. Although the program has been efficacious for youthwith Attention-Deficit/Hyperactivity Disorder (ADHD) it has not yet been tested among survivors of childhoodALL or brain tumor. Therefore a pilot randomized controlled trial is proposed to assess the feasibilityacceptability and preliminary efficacy of Endeavor. Survivors of ALL or brain tumor who are between the agesof 8 and 16 and have been off-therapy for at least one year will be included. The goal is to enroll 40participants across three pediatric oncology centers. Patients will participate in either the Endeavorintervention which includes 25-30 minute sessions per day 5 days per week for one month or an activecontrol condition. Patients will undergo neurocognitive testing pre- and post-intervention and parents willcomplete questionnaires regarding their childs functioning. It is hypothesized that this attentional-controltraining program will be both acceptable and feasible with sufficient enrollment positive satisfaction ratingsand at least 80% treatment compliance. It is also anticipated that participants will show increases inperformance-based and parent-rated attention as compared to those in the active control condition. Theseresults will be essential to our conceptualization of the utility of Endeavor and will inform a larger randomizedtrial of the efficacy of this training program. Taken together this pilot study will have important implications forthe development of cognitive remediation options for survivors of childhood ALL and brain tumor. 211033 +No NIH Category available Achievement;American Association of Cancer Research;Attention;Cancer Center;Career Mobility;Clinical;Collaborations;Consultations;Dana-Farber Cancer Institute;Dedications;Diagnosis;Educational process of instructing;Environment;Extramural Activities;Faculty;Fostering;Funding;Gender;Goals;Grant;Gynecologic Oncology;Hospitals;Individual;Institution;International;Israel;Leadership;Malignant neoplasm of ovary;Measures;Medical center;Mentors;Minority Recruitment;Monitor;New England;Oncology;Outcome;Outcome Measure;Paper;Patients;Peer Review;Persons;Population;Process;Public Health;Publications;Published Comment;Research Personnel;Resources;Secure;Societies;Source;Supervision;Talents;Training;Training Programs;Translating;Translational Research;Work;anticancer research;cancer therapy;candidate selection;career;career development;drug development;ethnic diversity;faculty support;gender diversity;instructor;medical schools;member;novel therapeutics;professor;programs;rapid growth;recruit;senior faculty;success;translational cancer research;translational impact;translational scientist Career Enhancement Program (CEP) Project Narrative CAREER ENHANCEMENT PROGRAM The overall goal of the Career Enhancement program (CEP) will be to increase the breadth and depth of the ovarian cancer translational investigator pool at the DF/HCC and across the US. We expect to train individuals who will become 2025s National / International leaders in the pathobiology diagnosis treatment and control of Ovarian Cancers. The CEP will enhance the impact of the SPORE on the public health of the US population in four principal ways: 1) The CEP will select and train new ovarian cancer investigators for translational research; 2) Every candidate selected will be prioritized to require clear translational impact of their work which can be translated to patients within ovarian cancer within a 5 year period; 3) the CEP will prioritize gender and ethnic diversity during the selection process to enhance the breadth of investigators serving the US population in all its diversity; 4) the CEP is commented to long term mentoring and career development to deliver new faculty through the early faculty stage and allow them to establish themselves as mature independent investigators. NCI 10684244 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5339 1949625 "CASTRO, CESAR M" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 131004 75171 56338 Project Summary CAREER ENHANCEMENT PROGRAM THE OVERALL OBJECTIVE of the Career Advancement Program will be: to increase the breadth and depth of the ovarian cancer translational investigator pool at the DF/HCC and across the US. We expect to train individuals who will become 2025s National / International leaders in the pathobiology diagnosis treatment and control of Ovarian Cancers. The program will be led by Dr. David Spriggs one of the overall SPORE PIs and with the ongoing advice and consultation of Drs DAndrea and Dr. Steve Cannistra. Dr. Spriggs has a long track record of successful recruiting and mentoring new academic investigators into new drug development and ovarian cancer treatment. The Specific aims will define the Career Enhancement Program: Aim 1. Identify appropriate candidates primarily junior faculty members seeking to become independent investigators in ovarian cancer research provide and secure funding for these investigators and assure SPORE resources for awardees. This group will include applicants from the rich DFHCC pool of fellows and junior faculty as well as candidates from the other New England Institutions Collaborating SPOREs and national candidates solicited from AACR and the Society of Gynecologic Oncology. We are particularly committed to increase the diversity of the peer reviewed translational science investigators in ovarian cancer. Selection will rely on the entire SPORE leadership and be confirmed by the EAB. Aim 2. Promote a mentoring environment and plan that will assist the career enhancement and success of the CEP awardees. Through the environment in the DF/HCC we will create individualized training programs (IDPs)for every funded junior faculty person and build a team of scientific clinical and personal mentors around each one; Aim 3. Monitor the scientific and academic progress of the awardees and the program. Particular attention will be given transition points such as the instructor/assistant professor interface and the attainment of RO1 equivalent funding which will mark transition to full independence. Short term outcome measures will include publication of high impact papers and the submission of extramural peer reviewed funding. Long term outcomes will be persistence in ovarian cancer translational research as measured by continuing peer reviewed publication in ovarian cancer research and achievement of senior faculty status at academic institutions 5-7 years after completion of the CEP completion. The majority of support will come from a variety of institutional sources from the DFHCC the DFCI the Beth Israel Deaconess Medical Center and the MGH. Specific plans for the identification recruitment and mentoring of a diverse awardee pool will incorporate resources for specific gender and minority recruitment efforts from Harvard Medical School and the individual hospitals involved in the SPORE. +No NIH Category available Advocate;Attention;Award;Budgets;Cancer Center;Complement;Decision Making;Development;Diagnosis;Early Diagnosis;Ensure;Equilibrium;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Institution;Malignant neoplasm of ovary;Mentors;Mentorship;Methods;Minority;Mission;Monitor;Pilot Projects;Prevention;Process;Productivity;Program Research Project Grants;Progress Reports;Reproduction spores;Request for Applications;Research;Research Activity;Research Personnel;Resistance;Resources;Specific qualifier value;Translational Research;Woman;community center;high risk;innovation;novel;programs;research and development;sound;success;synergism;timeline;translational potential Developmental Research Program (DRP) PROJECT NARRATIVE DEVELOPMENTAL RESEARCH PROGRAMThe goals of the Developmental Research Program (DRP) are to successfully identify fund monitor andsupport high risk/high potential pilot projects that take maximum advantage of new research opportunitieswithin the Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE and to maintain this Programthroughout the entire grant term. The success of this Ovarian Cancer SPORE DRP will be dependent uponour ability to engage researchers within and outside of the DF/HCC community who can contribute novel ideasto the diagnosis and treatment of ovarian cancer. Priority will be based upon the novelty of the proposalsevidence to support that the project can be completed within specified timelines and budget proposal and aproven track record of accomplishment and productivity by the investigator; those projects that havedemonstrated great progress and translational research potential will have the potential to become full SPOREProjects but only with the approval of the DF/HCC Ovarian Cancer DRP Executive Committee. NCI 10684241 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5338 1941071 "MATULONIS, URSULA ANNE" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 149725 93892 56338 PROJECT SUMMARY/ABSTRACT - DEVELOPMENTAL RESEARCH PROGRAM RESEARCH PLANThe overall goals of the Dana-Farber/Harvard Cancer Center (DF/HCC) Ovarian Cancer SPOREDevelopmental Research Program (DRP) are to support high risk/high potential pilot projects that takemaximum advantage of new research opportunities within the DF/HCC Ovarian Cancer SPORE and tomaintain this Program throughout the entire grant term. The selection and monitoring process will be led bythe DRP Directors Drs. Ursula Matulonis Stephen Cannistra and Alan DAndrea with oversight from the otherSPORE leader Dr. Spriggs. The DF/HCC Ovarian Cancer DRP Executive Committee (EC) which iscomprised on the DF/HCC SPORE committee the External Advisory Board the Internal Advisory Board (IAB)and the Ovarian Cancer Advocate Core of this Ovarian Cancer SPORE Project will directly participate in thereview scoring and selection of DRP Projects. The DRP will encourage applications from minorities andwomen as well as high risk/high payoff projects. Full access to DF/HCC Ovarian Cancer SPORE resourcesincluding Core access will be available to DRP Projects. Those projects that have demonstrated greatprogress and translational research potential will have the potential to become full SPORE Projects but onlywith the approval of the DF/HCC Ovarian Cancer DRP EC. Funding for the DRP is comprised partly from theOvarian Cancer SPORE budget as well as significantly from DF/HCC institutions. +No NIH Category available Aftercare;Apoptotic;BCL1 Oncogene;BCL2 gene;BCL2L1 gene;BCL2L11 gene;BIM Bcl-2-binding protein;Biopsy;Cancer Center;Cancer Therapy Evaluation Program;Carcinoma;Cells;Chemoresistance;Clinical;Clinical Trials;Combined Modality Therapy;DNA Damage;DNA Sequence Alteration;Data;Development;Diagnosis;Dose;Drug Combinations;Epithelial ovarian cancer;Exposure to;Fibroblasts;Genes;Genetic;Genomics;Grant;Histologic;Histology;Human;Immune;Knowledge;MAP3K1 gene;MEK inhibition;MEKs;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Metabolic;Modeling;Molecular;Mucinous;Mutate;Mutation Analysis;Oral;Organoids;Ovarian Carcinoma;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phase II Clinical Trials;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Pre-Clinical Model;Progression-Free Survivals;Protein-Serine-Threonine Kinases;Proteins;Proteomics;Protocols documentation;Public Health;Ras/Raf;Recommendation;Recurrence;Refractory;Relapse;Research;Resistance;Safety;Sampling;Schedule;Serine;Serous;Signal Pathway;Testing;Therapeutic;Toxic effect;Tumor Cell Line;cancer subtypes;cancer type;chemotherapy;clinical efficacy;efficacy evaluation;efficacy testing;enzyme activity;imaging approach;in situ imaging;inhibitor;mutant;novel therapeutic intervention;novel therapeutics;ovarian neoplasm;participant enrollment;patient derived xenograft model;phase 1 study;phase 2 study;pre-clinical;preclinical study;refractory cancer;response;targeted treatment;therapy resistant;treatment duration;treatment response;tumor;tumor microenvironment Evaluation of the Efficacy of Trametinib + Navitoclax in recurrent ovarian carcinoma Project 3Project Narrative:Based on evidence that the RAS-ERK pathway is activated in a large percentage of ovarian cancers andevidence of efficacy of combined MEK- BCL-2/XL inhibition in (1) preclinical PDX models of chemoresistanthigh grade serous ovarian cancer (HGSC) (2) preclinical studies showing efficacy of combined MEK and BCL-2/XL inhibition in Ras mutant tumors and (3) a Phase 1 clinical trial showing safety and tolerability of combinedtreatment with trametinib (MEK inhibitor) and navitoclax (BCL-2/XL inhibitor) we hypothesize that combinationMEK and BCL- 2/XL inhibition will have activity in refractory/relapsed ovarian cancer. To test this hypothesiswe will carry out a phase II clinical trial to test the efficacy of combined treatment with trametinib and navitoclaxin recurrent platinum-resistant and refractory ovarian cancers harboring alterations in Ras and Raf pathwaygenes along with HGSC and low grade serous RAS wild type cancers . An active and ongoing study Dana-Farber/Harvard Cancer Center (DF/HCC) Protocol 13-505 (CTEP 9525 supported by U01CA062490NCT02079740) is a phase 1 study that has tested the combination of the oral MEK inhibitor trametinib with theoral BCL-2 XL inhibitor navitoclax. The public health impact of this project includes the development of newtherapeutic options for patients with hard to treat recurrent ovarian cancer. NCI 10684234 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5336 1941071 "MATULONIS, URSULA ANNE" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 383397 327564 56338 Project 3: Project SummaryEpithelial ovarian cancer is comprised of several subtypes differentiated by histology and molecular compositionwith varying levels of platinum sensitivity based on specific histology. High grade serous carcinoma (HGSC) isthe most common and is sensitive to platinum drugs and poly (ADP ribose) polymerase (PARP) inhibitors.However with subsequent exposure to treatment recurrent HGSC becomes increasingly platinum and PARPinhibitor resistant. Additionally other histologic subtypes such as low grade serous and mucinous ovariancancers sometimes RAS mutated often display platinum resistance at initial diagnosis and new treatmentstrategies are needed for these patients whose cancers are either RAS mutated or RAS wild-type. The overallobjective of this proposal is to investigate the clinical efficacy of a combination therapy targeting the Ras-ERKpathway serine threonine kinase MEK and two anti-apoptotic proteins BCL2 and BCLXL. Based on evidencethat the RAS-ERK pathway is activated in a large percentage of ovarian cancers and evidence of efficacy ofcombined MEK- BCL-2/XL inhibition in (1) preclinical PDX models of chemoresistant high grade serous ovariancancer (HGSC) (2) preclinical studies showing efficacy of combined MEK and BCL-2/XL inhibition in Ras mutanttumors and (3) a Phase 1 clinical trial showing safety and tolerability of combined treatment with trametinib(MEK inhibitor) and navitoclax (BCL-2/XL inhibitor) we hypothesize that combination MEK and BCL-2/XLinhibition will have activity in refractory/relapsed ovarian cancer. To test this hypothesis we will carry out aphase II clinical trial to test the efficacy of combined treatment with trametinib and navitoclax in recurrentplatinum-resistant and refractory HGSOC and low grade serous cancer in addition to ovarian cancers harboringalterations in Ras and Raf pathway genes. An active and ongoing study Dana-Farber/Harvard Cancer Center(DF/HCC) Protocol 13-505 (CTEP 9525 supported by U01CA062490 NCT02079740) is a phase 1 study thathas tested the combination of the oral MEK inhibitor trametinib with the oral BCL-2 XL inhibitor navitoclax. Thistrial has been open to accrual since March 2014 has tested different dose schedules and has established arecommended phase 2 dose (RP2D). This RP2D from CTEP 9525 will be used in our Phase II study proposedin this project and is entitled A Phase 2 study of combination trametinib and navitoclax in recurrent ovariancancer. We will investigate genetic and proteomic markers that correlate with efficacy. In addition we willinvestigate therapeutic approaches to enhance the efficacy of this combination in pre-clinical studies.These studies promise to provide information critical to the identification of a new therapeutic strategy to treatresistant ovarian cancers which if effective could potentially extend the lives of patients with recurrent ovariancancer. +No NIH Category available Academic Medical Centers;Advanced Malignant Neoplasm;African American;Alternative Splicing;American;Biological Assay;Biological Markers;Biological Sciences;Biopsy;Clinical;Collaborations;Communities;DNA;Data;Development;Diagnosis;Diagnostic tests;Disease;ERG gene;Early Detection Research Network;Early Diagnosis;Expression Profiling;Formalin;Future;Gene Fusion;Guidelines;Health;In Situ Hybridization;Incidence;Individual;Industry;Knowledge;Laboratories;Libraries;Licensing;Malignant Neoplasms;Malignant neoplasm of prostate;Michigan;Minority Groups;Mission;Mutation;New York;Outcome;PSA screening;Paraffin Embedding;Pathology;Population;Populations at Risk;Procedures;Productivity;Prognosis;Prostate;Prostatectomy;Prostatic Diseases;RNA;RNA Splicing;Research;Sampling;Screening for Prostate Cancer;Selection for Treatments;Spices;Standardization;TMPRSS2 gene;Testing;Texas;Tissue Embedding;Tissues;Transcript;Translating;Translations;United States;Universities;Untranslated RNA;Urine;Validation;Variant;Virginia;Work;biomarker validation;cancer biomarkers;circular RNA;clinical development;clinical sequencing;cohort;commercialization;curative treatments;detection test;diagnostic biomarker;fusion gene;health care economics;improved;industry partner;insertion/deletion mutation;medical schools;men;mortality;multidisciplinary;novel diagnostics;novel marker;overtreatment;personalized predictions;personalized risk prediction;precision oncology;prognostic assays;programs;prostate cancer risk;serum PSA;shared decision making;specific biomarkers;success;transcriptome;transcriptome sequencing;transcriptomics Biomarker Developmental Laboratory n/a NCI 10684233 7/19/23 0:00 RFA-CA-21-035 5U2CCA271854-02 5 U2C CA 271854 2 8/15/22 0:00 7/31/27 0:00 ZCA1-PCRB-D 5335 1866290 "CHINNAIYAN, ARUL M" Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 244444 156695 87749 Project Summary/AbstractThis application proposes the formation of the Michigan-Vanderbilt University Medical Center (VUMC) EDRNBiomarker Characterization Center (BCC). This BCC represents a collaborative multi-disciplinary team ofacademic (University of Michigan (U-M) and VUMC) and industry (LynxDx) partners focused on discoveringdeveloping and scaling clinical-grade assays for the early detection of aggressive prostate cancer. Throughprevious EDRN efforts our team characterized multiple important prostate cancer biomarkers most notably theTMPRSS2-ETS gene fusions. Through collaboration with an EDRN Clinical Validation Center (CVC; Dr. SandaPI) we developed validated and clinically implemented MyProstateScore (MPS) an early detection testincorporating urine quantification of two prostate cancer-specific transcriptsthe TMPRSS2:ERG gene fusionand the long non-coding RNA (lncRNA) PCA3. Introduced in our CLIA laboratory MPS informs shared decisionmaking after PSA testing based on individualized risk predictions of aggressive prostate cancer on biopsy. Herepairing the cancer-specific components of the MPS test with recent discovery of high-grade cancer-specificbiomarkers we outline the development optimization and clinical validation of the next generation of diagnostictests capable of reliably selectively detecting potentially lethal cancers that stand to benefit from early curativetreatment. Our Biomarker Developmental Laboratory (BDL) will employ the experimental platform MPS-SEQfor capture RNA-seq analysis of urine samples to detect aggressive prostate cancer transcripts lncRNAscircular RNAs fusion transcripts mutations indels and splice variants. Our Biomarker Reference Laboratory(BRL) will in parallel develop a clinical grade urine assay MPS-50 for the multiplex QPCR analysis of up to 50amplicons. While the first 50 amplicons of MPS-50 have already been nominated future improvements of theassay content and platform will be informed by work carried out in our BDL. To fuel these studies our BCC hasidentified urine biospecimen cohorts collected under rigorous standard operating procedures in compliance withPRoBE criteria including the Michigan Prostate SPORE Emory University the Center for Prostate DiseaseResearch University of Texas San Antonio Health Eastern Virginia Medical School and VUMC/MeharryMedical College. The overall Aims of this BCC serve to develop assess and optimize MPS-SEQ and MPS-50for identifying high-grade prostate cancer in diverse at-risk populations. Our BRL will also focus on standardizingclinically-validated biomarker assays for consistent and reliable use in accordance with CLIA/CAP guidelines atthe U-M Center for Translational Pathology in order to facilitate network consortium studies and at LynxDx inorder to scale commercialize and obtain FDA approvals. As recognized by the EDRN novel biomarkers specificfor aggressive prostate cancer are urgently needed. Importantly our mission and efforts extend beyond our BCCand prostate cancer as we actively participate in the EDRN biomarker community and support continuedcollaborative efforts with other BCCs and CVCs to advance the overall EDRN mission. +No NIH Category available Academic Medical Centers;Administrator;Agreement;Area;Biological Assay;Biological Markers;Biopsy;Clinical;Collaborations;Common Data Element;Communities;Data;Data Analyses;Data Coordinating Center;Development;Diagnostic tests;Disease;ERG gene;Early Detection Research Network;Early Diagnosis;Ensure;Funding;Future;Gene Fusion;Goals;Guidelines;Health;Industry;Informed Consent;Institution;Institutional Review Boards;Investigation;Knowledge;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of prostate;Manuscripts;Methods;Michigan;Mission;Monitor;Mutation;Network Infrastructure;Occupational activity of managing finances;PSA screening;Pathology;Populations at Risk;Principal Investigator;Procedures;Progress Reports;Prostate;Prostatic Diseases;RNA Splicing;Reporting;Research;Research Personnel;Resources;Sampling;Screening for Prostate Cancer;Specimen;Standardization;Structure of base of prostate;TMPRSS2 gene;Testing;Texas;Transcript;Translating;Translations;Travel;Universities;University resources;Untranslated RNA;Urine;Validation;Variant;Virginia;Vision;Work;antigen test;biobank;biomarker development;biomarker validation;cancer biomarkers;circular RNA;cohort;commercialization;curative treatments;data sharing;data submission;detection test;improved;industry partner;insertion/deletion mutation;medical schools;meetings;multidisciplinary;next generation;novel;novel diagnostics;novel marker;operation;personalized risk prediction;programs;protocol development;screening;serum PSA;shared decision making;specific biomarkers;success;transcriptome sequencing;transcriptomics;translational goal;urinary;validation studies Administrative Core n/a NCI 10684228 7/19/23 0:00 RFA-CA-21-035 5U2CCA271854-02 5 U2C CA 271854 2 8/15/22 0:00 7/31/27 0:00 ZCA1-PCRB-D 5334 1866290 "CHINNAIYAN, ARUL M" Not Applicable 6 Unavailable 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI Domestic Higher Education 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 418701 280502 138199 Project Summary/AbstractThis application proposes the formation of the Michigan-Vanderbilt University Medical Center (VUMC) EDRNBiomarker Characterization Center (BCC). This BCC represents a collaborative multi-disciplinary team ofacademic (University of Michigan (U-M) and VUMC) and industry (LynxDx) partners focused on discoveringdeveloping and scaling clinical-grade assays for the early detection of aggressive prostate cancer. Throughprevious EDRN efforts our team characterized multiple important prostate cancer biomarkers most notably theTMPRSS2-ETS gene fusions. Through collaboration with an EDRN Clinical Validation Center (CVC; Dr. SandaPI) we developed validated and clinically implemented MyProstateScore (MPS) an early detection testincorporating urine quantification of two prostate cancer-specific transcriptsthe TMPRSS2:ERG gene fusionand the long non-coding RNA (lncRNA) PCA3. Introduced in our CLIA laboratory MPS informs shared decisionmaking after PSA testing based on individualized risk predictions of aggressive prostate cancer on biopsy. Herepairing the cancer-specific components of the MPS test with recent discovery of high-grade cancer-specificbiomarkers we outline the development optimization and clinical validation of the next generation of diagnostictests capable of reliably selectively detecting potentially lethal cancers that stand to benefit from early curativetreatment. Our Biomarker Developmental Laboratory (BDL) will employ the experimental platform MPS-SEQfor capture RNA-seq analysis of urine samples to detect aggressive prostate cancer transcripts lncRNAscircular RNAs fusion transcripts mutations indels and splice variants. Our Biomarker Reference Laboratory(BRL) will in parallel develop a clinical grade urine assay MPS-50 for the multiplex QPCR analysis of up to 50amplicons. While the first 50 amplicons of MPS-50 have already been nominated future improvements of theassay content and platform will be informed by work carried out in our BDL. To fuel these studies our BCC hasidentified urine biospecimen cohorts collected under rigorous standard operating procedures in compliance withPRoBE criteria including the Michigan Prostate SPORE Emory University the Center for Prostate DiseaseResearch University of Texas San Antonio Health Eastern Virginia Medical School and VUMC/MeharryMedical College. The overall Aims of this BCC serve to develop assess and optimize MPS-SEQ and MPS-50for identifying high-grade prostate cancer in diverse at-risk populations. Our BRL will also focus on standardizingclinically-validated biomarker assays for consistent and reliable use in accordance with CLIA/CAP guidelines atthe U-M Center for Translational Pathology in order to facilitate network consortium studies and at LynxDx inorder to scale commercialize and obtain FDA approvals. As recognized by the EDRN novel biomarkers specificfor aggressive prostate cancer are urgently needed. Importantly our mission and efforts extend beyond our BCCand prostate cancer as we actively participate in the EDRN biomarker community and support continuedcollaborative efforts with other BCCs and CVCs to advance the overall EDRN mission. +No NIH Category available Address;Adjuvant Chemotherapy;Agonist;Antigen Targeting;Antigens;Autoimmune;Autologous;Autologous Tumor Cell;Binding;Biological;Biological Markers;Biological Models;Biological Testing;Biometry;Biopsy;Blood;Blood specimen;Cancer Center;Cancer Vaccines;Cells;Clinical;Clinical Trials;Combined Vaccines;Data;Development;Disease;Disease Progression;Disease remission;Effectiveness;Epithelial ovarian cancer;Epitopes;Event;Evolution;Exhibits;Feasibility Studies;Funding;Genetic;Genomics;Glioblastoma;Grant;Human;Immune;Immune response;Immune system;Immunity;Immunize;Immunoglobulins;Immunologic Adjuvants;Immunologics;Immunotherapy;In Situ;In complete remission;Institutional Review Boards;Malignant Neoplasms;Malignant neoplasm of ovary;Monoclonal Antibodies;Mutate;Mutation;Nature;Neoadjuvant Therapy;Newly Diagnosed;Nivolumab;Organoids;Pathology;Pathway interactions;Patients;Peptides;Platinum;Poly ICLC;Proteins;Protocols documentation;Recurrence;Residual Neoplasm;Residual state;Residual volume;Safety;Site;Somatic Mutation;Specimen;T cell response;T-Cell Immunologic Specificity;T-Lymphocyte;TLR3 gene;Testing;Therapeutic;Time;Toxic effect;Tumor Antigens;Tumor Immunity;Tumor-infiltrating immune cells;Vaccines;anti-PD1 therapy;antigen-specific T cells;cancer therapy;cancer vaccination;central tolerance;chemotherapy;computerized tools;design;exome sequencing;genetic evolution;immune cell infiltrate;immune checkpoint blockade;immunogenic;improved;insight;melanoma;mouse model;neoantigen vaccine;neoantigens;neoplastic cell;novel;ovarian neoplasm;phase 1 study;prediction algorithm;pressure;programmed cell death protein 1;prospective test;response;safety and feasibility;side effect;standard of care;synergism;transcriptome;transcriptome sequencing;tumor;vaccine evaluation Project 2: Combined personal neoantigen-targeting cancer vaccines with immune checkpoint blockade for ovarian cancer Project NarrativeCheckpoint blockade monotherapy exhibits only modest activity against ovarian cancer. Building on our abilityto identify cancer determinants that can be recognized by the immune system (so-called antigens) from patienttumors including from ovarian cancer that are optimal because they are expressed only on tumor cells (and notnormal cells) and are highly immunostimulatory and based on promising data supporting new cancer vaccinationefforts to target these personal tumor antigens that may synergize effectively with checkpoint blockade therapythis proposal aims to investigate the therapeutic potential and biologic activity of this novel immunotherapystrategy for ovarian cancer. NCI 10684225 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5333 10851719 "KONSTANTINOPOULOS, PANAGIOTIS " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 297580 241747 56338 Project SummaryAlthough epithelial ovarian cancer (EOC) is initially a chemosensitive disease it is infrequently cured bystandard-of-care (SOC) platinum-based chemotherapy. Given the abundant evidence indicating that ovariantumors are immunogenic several immunotherapy approaches have been previously evaluated in this diseasebut without evidence of potent anti-tumor immunity or clinical activity. Immune checkpoint blockade (CPB)therapy which has revolutionized treatment of multiple cancers has demonstrated only modest effectiveness inEOC highlighting the urgent need of new strategies to extend the benefit of CPB in this disease. Over recentyears we have developed new computational tools to identify immunogenic candidate patient-specific mutatedepitopes (also called neoantigens) that are capable of stimulating tumor-specific T cell responses. Advances inprediction algorithms generated by our team now provide opportunities for studying the feasibility of generatingneoantigen vaccines in tumors with intermediate mutation load (Abelin Immunity 2017) such as EOC and forthe testing of how the vaccine can be administered in conjunction with SOC therapy. This promising activity hasled us to prospectively test the targeting of personal neopeptides as cancer vaccines and we have demonstratedthe safety feasibility and immunologic activity of immunizing patients with advanced melanoma (Ott Nature2017) and glioblastoma (Keskin Nature 2019) with personal vaccines consisting of up to 20 mutated epitopesper patient delivered as synthetic long peptides (20-30mers) admixed with the potent immune adjuvant poly-ICLC a TLR3 agonist (called Neovax). In these proof-of-concept studies some of the induced neoantigen-specific T cell responses could recognize autologous tumor cells. Moreover complete responses with sustainedremissions were observed in patients when anti-PD1 therapy was administered in addition to neoantigenvaccine. Based on these promising results we now propose to evaluate in a new clinical trial the combinedadministration of personal neoantigen-targeted cancer vaccines together with CPB therapy for low residualvolume EOC. We hypothesize that this approach will effectively expand existing tumor-reactive T-cells andbroaden the T-cell repertoire to include new tumor-specific T-cells and thereby generating highly specific anti-tumor immunity with fewer autoimmune side effects. We will evaluate the feasibility and safety of Neovax incombination with nivolumab in EOC (Aim 1). Through integrated characterization of circulating blood immuneresponses with in situ changes in the tumor and tumor-infiltrating immune cells at serial time points across thecourse of therapy including in the event of disease progression we seek to elucidate candidate mechanisms ofresponse and non-response to vaccine and CPB therapy (Aims 2 and 3). +No NIH Category available Address;Affective;American Society of Clinical Oncology;Area;Behavior;Behavioral;Cancer Advocacy;Clinical;Cognitive;Collaborations;Communication;Communities;Community Practice;Consolidated Framework for Implementation Research;Counseling;Data;Disclosure;Distress;Education;Effectiveness;Eligibility Determination;Evidence based practice;Family history of;Funding;Future;Genetic;Genetic Carriers;Genetic Counseling;Genetic Models;Genetic Services;Health Services Accessibility;Hereditary Malignant Neoplasm;Hybrids;Intervention;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Medical;Medical Genetics;Methods;Modeling;National Health Interview Survey;Oncology;Online Systems;Outcome;Participant;Patient Recruitments;Patient-Focused Outcomes;Patients;Pennsylvania;Predisposition;Provider;Randomized;Reaction;Recommendation;Reporting;Research;Risk;Risk Reduction;Sampling;Screening for cancer;Secure;Self Direction;Services;Specialist;Telephone;Test Result;Testing;Time;Uncertainty;United States National Institutes of Health;Visit;arm;behavioral outcome;cancer care;cancer genetics;cancer predisposition;clinical practice;clinically significant;design;eHealth;effectiveness evaluation;effectiveness/implementation study;future implementation;genetic counselor;genetic testing;implementation barriers;improved;interest;malignant breast neoplasm;novel;patient population;precision medicine;process evaluation;programs;provider communication;recruit;screening;screening guidelines;sociodemographic factors;telegenetics;testing uptake;treatment as usual;uptake;videoconference A Randomized Hybrid Type I effectiveness-implementation study of an Ehealth delivery Alternative for Cancer genetic testing for Hereditary cancer predisposition (eREACH) In the eREACH study we will evaluate a theoretically and stake-holder informed eHealth delivery alternative totraditional genetic counseling recruiting a nationally representative population of patients who are candidatesfor genetic testing for cancer susceptibility. We expect this research to significantly inform how best to deliverand communicate results of genetic testing in a way that provides access for all patients across the US whilemaintaining adequate understanding and clinical use of genetic test results. NCI 10684221 9/20/23 0:00 RFA-CA-20-006 5U01CA243702-04 5 U01 CA 243702 4 "NELSON, WENDY" 9/17/20 0:00 8/31/25 0:00 ZCA1-TCRB-T(A1) 8157921 "BRADBURY, ANGELA R." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 785824 NCI 522158 263666 Germline cancer genetic testing has become a standard evidence-based practice with established risk reductionand cancer screening guidelines for genetic carriers. Yet access to genetic specialists is limited in many areasin the US and <20% of eligible patients with a personal or family history of breast or ovarian cancer completegenetic testing. Thus there is an urgent need to consider alternative delivery models to increase access anduptake of genetic testing while maintaining adequate patient cognitive affective and behavioral outcomes. Ourresearch has shown that providing remote services increases uptake of genetic testing in community practicesincreases uptake of genetic testing. Preliminary data from our ongoing NIH-funded RESPECT study hasrevealed high interest in a web-based eHealth alternative to traditional pre-test counseling and no significant nodifferences in pre- and post-disclosure outcomes when the web-based eHealth intervention is utilized ascompared to participants who received traditional pre-test genetic counselor. To address the clinically significantneed for alternative delivery models to increase access and uptake of cancer genetic testing while maintainingadequate patient cognitive affective and behavioral outcomes we propose to recruit a nationally diverse real-world sample of 1000 patients who have access barriers to genetic testing and to conduct a Hybrid Type 1effectiveness-implementation study to evaluate web-based eHealth delivery alternatives for genetic educationand testing. We hypothesize that our theoretically and stakeholder informed eHealth delivery alternatives canprovide equal or better uptake of testing and outcomes of genetic testing as compared to the traditional modelof pre- and post-test counseling with a genetic counselor. We will partner with several cancer advocacy groups(ASCO breastcancer.org Cancer Support Community Pennsylvania Prostate Cancer Coalition) to recruitpatients to this randomized non-inferiority study using a modified 2x2 design (Aims 1-2). In Arm 1 traditionalpre-test (visit 1) and post-test (visit 2: disclosure) counseling will be provided remotely through the national PennTelegenetics Program and compared to delivery arms where patients can complete pre-test and/or disclosure ofresults through a self-directed web-based eHealth intervention either in place of or as an adjunct to traditionalgenetic counseling. Concurrently we will conduct a CFIR (Consolidated Framework for ImplementationResearch)-informed process evaluation to understand moderators of intervention usage and patient outcomesand facilitators and barriers to future implementation and sustainability of this novel eHealth alternative deliverymodel for genetic services both within and beyond cancer care (Aim 3). We hypothesize that a rigorouslydeveloped theoretically and stake-holder informed eHealth delivery alternative provided through a centralizedTelegenetics Program has the potential to provide equal or improved patient outcomes while reducing geneticprovider time and providing access to services in community practices where access to genetic services hasbeen limited providing opportunities to realize the promise of precision medicine in oncology. 785824 +No NIH Category available Apoptosis;Architecture;Biological Assay;Biological Markers;Biological Models;Biopsy;Cancer Center;Cancer cell line;Cell Culture Techniques;Cell Line;Cells;Clinical;Clinical Trials;Collection;DNA Repair;Development;Drug Combinations;Drug Evaluation;Drug resistance;Environment;Generations;Genes;Goals;Grant;Guidelines;Gynecologic Oncology Group;ITGB2 gene;In Vitro;Infrastructure;Investigation;Laboratories;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Modeling;Mus;Mutation;Newly Diagnosed Disease;Organoids;Ovarian;Paracentesis;Participant;Patients;Platinum;Poly(ADP-ribose) Polymerase Inhibitor;Primary Cell Cultures;Protocols documentation;Publications;Recurrent disease;Reproducibility;Research;Research Personnel;Residual Neoplasm;Resistance;Resistance development;Sampling;Serous;Services;Therapeutic procedure;Thoracentesis;Tissue Banks;Validation;Work;Xenograft Model;cancer therapy;chemotherapy;design;drug sensitivity;drug testing;functional loss;functional status;in vivo;infrastructure development;inhibitor;insight;mouse model;neoplastic cell;novel strategies;patient derived xenograft model;programs;repository;response;restoration;sample collection;therapeutic target;therapy resistant;treatment response;tumor;tumorigenic Organoid Mouse Model and Biomarker NARRATIVE - Core 3: Organoid Model Systems and Biomarkers Core The overarching goals of the Organoids Model Systems and Biomarkers Core are to provide tissuecollection infrastructure murine PDX models and HGSC organoid models for combination drug testing andbiomarker analysis. The core will be utilized by all three projects of the Dana-Farber/Harvard Cancer CenterOvarian Cancer SPORE program. NCI 10684211 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5330 2120370 "D'ANDREA, ALAN D." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 196772 140939 56338 PROJECT SUMMARY - Core 3: Organoid Model Systems and Biomarkers Core The overall purpose of the Organoids Model Systems and Biomarkers Core of this Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE application is to provide core services to the threeprojects and to the other cores. The core will be directed by Drs. Alan DAndrea Joyce Liu and Neil Horowitz.A primary feature of the core is our recent advances in the generation of short-term ovarian cancer organoidcultures which closely mimic the tumor from which they are derived (Hill SJ Decker B Roberts EA HorowitzNS Muto MG Worley MJ Feltmate CM Nucci MR Swisher EM Nguyen H Yang C Morizane RKochupurakkal B Do KT Konstantinopoulos PA Liu JF Bonventre JV Matulonis UA Shapiro GI BerkowitzRS Crum CP DAndrea AD. Prediction of DNA Repair Inhibitor Response in Short Term Patient-derivedOvarian Cancer Organoids. Cancer Discov. 2018 Sep 13. pii: CD-18-0474. doi: 10.1158/2159-8290.CD-18-0474.). The core is divided into three aims pertaining to 1) the development of infrastructure from HGSC tissuecollection 2) the use of PDX models to assess drug combinations in vivo and 3) the use of HGSC organoidsto assess drug combinations in vitro. The core will provide these studies as well as relevant DNA repair andapoptosis biomarkers to the clinical trialists in the thee projects. The core will provide 1) ovarian cancer tissuecollection infrastructure for participants in the SPORE 2) the generation and analysis of short-term ovariancancer organoid cultures and 3) the generation and analysis of murine PDX models of ovarian cancer. +No NIH Category available Academic Medical Centers;African American population;Alternative Splicing;Biological Assay;Biological Markers;Biopsy;Cancer Patient;Certification;Clinical;Clinical Treatment;Collaborations;Communities;Development;Diagnosis;Diagnostic tests;Disease;ERG gene;Early Detection Research Network;Early Diagnosis;Future;Gene Fusion;Generations;Goals;Guidelines;Health;Incidence;Indolent;Industry;Laboratories;Malignant Neoplasms;Malignant neoplasm of prostate;Metastatic Prostate Cancer;Michigan;Minority Enrollment;Minority Groups;Mission;Mutation;New York;PSA screening;Pathology;Patients;Performance;Population;Population Heterogeneity;Populations at Risk;Procedures;Prostate;Prostatic Diseases;RNA Splicing;Reproduction spores;Research;Research Design;Research Personnel;Running;Sampling;Screening for Prostate Cancer;Specificity;Standardization;TMPRSS2 gene;Testing;Texas;Therapeutic Intervention;Time;Transcript;United States;Universities;Untranslated RNA;Urine;Validation;Variant;Virginia;Work;biomarker validation;cancer biomarkers;circular RNA;clinically significant;cohort;commercialization;curative treatments;detection test;early detection biomarkers;health disparity;improved;industry partner;insertion/deletion mutation;medical schools;men;mortality;multidisciplinary;next generation;novel;novel diagnostics;novel marker;overtreatment;personalized risk prediction;prevent;shared decision making;specific biomarkers;transcriptome sequencing;transcriptomics;urinary Michigan-VUMC Biomarker Characterization Center Project NarrativeThere is a critical need for a new generation of prostate cancer biomarkers capable of accurately detectingaggressive cancers at a localized curable stage. The overarching goal of this project is to selectively identifythose patients with potentially lethal prostate cancers that stand to benefit from early definitive treatment whilepreventing unnecessary testing overdiagnosis and subsequent overtreatment in the remaining population. Toachieve this goal we have assembled the Michigan-Vanderbilt University Medical Center EDRN BiomarkerCharacterization Center which represents a multi-disciplinary team of accomplished academic and industryinvestigators committed to discovering developing and scaling clinical-grade assays for the early detection ofaggressive forms of prostate cancer. NCI 10684207 7/19/23 0:00 RFA-CA-21-035 5U2CCA271854-02 5 U2C CA 271854 2 "KOHAAR, INDU" 8/15/22 0:00 7/31/27 0:00 ZCA1-PCRB-D(M1) 1866290 "CHINNAIYAN, ARUL M" "TOSOIAN, JEFFREY J" 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Other Research-Related 2023 936416 NCI 660393 276023 Project Summary/AbstractThis application proposes the formation of the Michigan-Vanderbilt University Medical Center (VUMC) EDRNBiomarker Characterization Center (BCC). This BCC represents a collaborative multi-disciplinary team ofacademic (University of Michigan (U-M) and VUMC) and industry (LynxDx) partners focused on discoveringdeveloping and scaling clinical-grade assays for the early detection of aggressive prostate cancer. Throughprevious EDRN efforts our team characterized multiple important prostate cancer biomarkers most notably theTMPRSS2-ETS gene fusions. Through collaboration with an EDRN Clinical Validation Center (CVC; Dr. SandaPI) we developed validated and clinically implemented MyProstateScore (MPS) an early detection testincorporating urine quantification of two prostate cancer-specific transcriptsthe TMPRSS2:ERG gene fusionand the long non-coding RNA (lncRNA) PCA3. Introduced in our CLIA laboratory MPS informs shared decisionmaking after PSA testing based on individualized risk predictions of aggressive prostate cancer on biopsy. Herepairing the cancer-specific components of the MPS test with recent discovery of high-grade cancer-specificbiomarkers we outline the development optimization and clinical validation of the next generation of diagnostictests capable of reliably selectively detecting potentially lethal cancers that stand to benefit from early curativetreatment. Our Biomarker Developmental Laboratory (BDL) will employ the experimental platform MPS-SEQfor capture RNA-seq analysis of urine samples to detect aggressive prostate cancer transcripts lncRNAscircular RNAs fusion transcripts mutations indels and splice variants. Our Biomarker Reference Laboratory(BRL) will in parallel develop a clinical grade urine assay MPS-50 for the multiplex QPCR analysis of up to 50amplicons. While the first 50 amplicons of MPS-50 have already been nominated future improvements of theassay content and platform will be informed by work carried out in our BDL. To fuel these studies our BCC hasidentified urine biospecimen cohorts collected under rigorous standard operating procedures in compliance withPRoBE criteria including the Michigan Prostate SPORE Emory University the Center for Prostate DiseaseResearch University of Texas San Antonio Health Eastern Virginia Medical School and VUMC/MeharryMedical College. The overall Aims of this BCC serve to develop assess and optimize MPS-SEQ and MPS-50for identifying high-grade prostate cancer in diverse at-risk populations. Our BRL will also focus on standardizingclinically-validated biomarker assays for consistent and reliable use in accordance with CLIA/CAP guidelines atthe U-M Center for Translational Pathology in order to facilitate network consortium studies and at LynxDx inorder to scale commercialize and obtain FDA approvals. As recognized by the EDRN novel biomarkers specificfor aggressive prostate cancer are urgently needed. Importantly our mission and efforts extend beyond our BCCand prostate cancer as we actively participate in the EDRN biomarker community and support continuedcollaborative efforts with other BCCs and CVCs to advance the overall EDRN mission. 936416 +No NIH Category available Address;Antibodies;Archives;Attention;Award;Biological Markers;Biological Models;Biostatistics Core;Blood;Cancer Center;Case Study;Clinical Research;Clinical Trials;Collaborations;Consent;Dana-Farber Cancer Institute;Data;Data Analyses;Deposition;Destinations;Eligibility Determination;Ensure;Experimental Designs;Freezing;Fresh Tissue;Frozen Sections;Generations;Glean;Goals;Grant;Guidelines;Human;Human Resources;Immune response;Immunofluorescence Immunologic;Immunophenotyping;Individual;Institution;Institutional Review Boards;Laboratories;Life;Malignant neoplasm of ovary;Mission;Monitor;Morphology;Normal tissue morphology;Organoids;Outcome;Ovarian;Ovarian Serous Adenocarcinoma;Paraffin Embedding;Participant;Pathologic;Pathologist;Pathology;Patient-Focused Outcomes;Patients;Procedures;Process;Protocols documentation;Quality Control;Reproduction spores;Research;Research Activity;Research Personnel;Retrieval;Sampling;Schedule;Services;Site;Standardization;Strategic vision;Tissue Banks;Tissue Sample;Tissue Stains;Tissues;Triage;Tumor Tissue;Update;Vaccines;Visual;Woman;Work;design;experience;experimental study;human tissue;innovation;insight;model organism;novel therapeutics;operation;patient derived xenograft model;quality assurance;repository;tissue fixing;treatment response;vaccine trial Pathology Core PROJECT NARRATIVE The research proposed in this ovarian cancer SPORE application requires various forms of fresh human tumor and normal tissue that has been properly collected and uniformly processed. This centralized pathology core will work with each project and other core to ensure that appropriate human tumor tissue is collected and allocated for all proposed research and also deposited in the appropriate tissue banks for later research. In addition core pathologists will work with each project to provide expert pathologic interpretation of all human tissue studies overall allowing for generation of the most accurate data and experimental interpretation and maximizing the research that is done from these valuable human samples. NCI 10684201 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5327 78658081 "KOLIN, DAVID " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 293522 237690 56338 PROJECT SUMMARY The Pathology Core is responsible for overseeing the realm of human tissue which is ultimately the life blood of the translational projects proposed in this DF/HCC Ovarian Spore application. The primary mission of the Pathology Core is to ground the projects in the visual realities of tissue cyto-morphology as the individual project directors explore new therapies and biomarkers of therapeutic response. The first aim of this core is to ensure that the projects are in compliance with IRB-approved protocols. The second aim will be to ensure access to the highest quality tissue. This task is multifaceted and entails close coordination between core investigators and personnel involved in consenting patients delivering tissues to the Frozen Section room for allocation and transporting the tissue to the proper destination. In this setting quality of service pertains to both the condition of the tissue and the precision with which the tissue is analyzed to ensure that the proper cellular components are selected for study. The third aim for this core will be to provide expert histopathologic interpretation when needed and aid in experimental design and execution when tissue is utilized. All of these aims will be executed in the context of each individual project and other cores. In Project 1 the core will be involved in tissue allocation for sequencing organoid or patient-derived xenograft generation and paraffin embedding and sectioning. The core will aid in antibody optimization immunohistochemical staining of tissue sections and interpretation of results obtained on tissue in the context of multiple clinical trials. In Project 2 involving a vaccine trial critical tasks will include allocation of fresh tissue for all activities surrounding vaccine generation and organoid generation as well as for generating paraffin embedded sections. The core will help to assess immune response at the tissue level through multi-plex immunofluorescence analysis to help maximize the information that can be gleaned. In Project 3 the core will aid with fresh frozen and fixed tissue acquisition and allocation to allow for the varied analyses to be performed in the context of a clinical trial. Moreover the core investigators must be ever cognizant of maintaining the tissue banks at each site and providing tissue for the Organoid model organisms and biomarkers core as well as aiding the biostatistics core in interpretation of immunohistochemical results with respect to patient outcomes. Amidst this panoply of diverse tasks the core investigators must maintain an organized hierarchy of task assignment and carefully set priorities. This will be achieved by experienced pathologist-investigators who will interact regularly and effectively to integrate the work being done across multiple institutions and develop protocols and procedures with established safeguards of quality assurance. Finally this integrated Pathology Core will be dynamic with attention to weaknesses in the data interpretation and consideration of innovative approaches prompted by either necessity or opportunity. +No NIH Category available 3-Dimensional;Affect;Anabolism;Cancer Etiology;Cancer Patient;Caring;Cells;Cessation of life;Clinical;Coculture Techniques;Data;Development Plans;Diagnosis;Disease;Endothelium;Event;Faculty;Fibroblasts;Fluorescence;Fractionated radiotherapy;Glucose;Glycobiology;Glycoproteins;Goals;Harvest;Hexosamines;Immune;Impairment;In Situ;In Vitro;Lead;Lung Adenocarcinoma;Lung Neoplasms;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Measures;Mentors;Mesenchymal;Metabolic;Metabolic Marker;Metabolic Pathway;Modeling;Modification;Molecular Target;Neighborhoods;Organoids;Outcome;Outcome Measure;Pathway interactions;Patients;Pattern;Phenotype;Phosphorylation;Polysaccharides;Post-Translational Protein Processing;Primary Neoplasm;Protein Glycosylation;Protein Region;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Radiobiology;Refractory;Research Personnel;Resolution;Resources;Role;Signal Transduction;Stromal Cells;Stromal Neoplasm;Structure;Systems Biology;Techniques;Testing;Therapeutic;Thoracic Oncology;Time;Tissues;Treatment Failure;Visualization;Work;biocomputing;cancer cell;cancer survival;cell behavior;cell dimension;cell type;glycoproteomics;glycosylation;imaging modality;improved;in vivo;innovation;insight;multiplexed imaging;new therapeutic target;novel strategies;preservation;prevent;radiation resistance;radioresistant;sugar;survival outcome;tenure track;tool;treatment response;tumor;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumorigenesis Exploring O-glycoproteomics to prevent metabolic radioresistance in the tumor microenvironment PROJECT NARRATIVERadiotherapy is often the only curative option for patients with inoperable tumors but metabolic radioresistanceis one of the main reason for radiotherapy failure. This work highlights metabolic cooperation in the tumormicroenvironment by measuring post-translational sugar modifications on proteins e.g. the O-glycoproteomeresulting from metabolic reprogramming toward the hexosamine biosynthesis pathway. Our main goal is toidentify new drug targets involved in radioresistance and improve survival outcome in patients with inoperabletumors. NCI 10684199 7/20/23 0:00 PA-20-188 5K99CA255586-02 5 K99 CA 255586 2 "SCHMIDT, MICHAEL K" 9/1/22 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 15079687 "BOUCHARD, GINA " Not Applicable 16 BIOSTATISTICS & OTHER MATH SCI 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 157788 NCI 146100 11688 PROJECT SUMMARYRadiotherapy (RT) is often the only curative option for patients with inoperable tumors. However radiation isalso known to impair tumor metabolism leading to radioresistance the main reason for RT failure. Metabolicreprogramming (MR) in cancer is defined as the ability of the tumor to rewire its energy to fulfill the needs fortumorigenesis and progression. Our group observed for the first time that MR toward the HexosamineBiosynthesis Pathway (HBP) an understudied glucose pathway leading to protein glycosylation is associatedwith poor survival in the lung adenocarcinoma. Precisely we showed that this metabolic switch happens primarilyin Cancer-Associated Fibroblasts (CAFs). This suggests that CAFs redirect their glucose toward HBP whichincreases O-glycosylation a Post-Translational Modification (PTM) known to modulate radioresistance.However very little is known about 1) which proteins are O-glycosylated after MR toward HBP and 2)how these PTMs affect the cellular behavior and modulate radioresistance. My preliminary results showthat metabolic cooperation between cancer and stromal cells alters protein O-glycosylation in both cell types.Therefore I hypothesize that tumor-stroma crosstalk in the Tumor Microenvironment (TME) leading tochanges in the O-glycoproteome plays a role in radioresistance. To validate this hypothesis we developeda novel approach that precisely measures the outcome of MR towards HBP (e.g. O-glycoproteome) inthe context of tumor-stroma crosstalk. We propose to apply this technique to tumor-stroma organoidsdesignated here as assembloids that recapitulate metabolically heterogeneous cell neighborhoods andcharacterize their O-glycoproteome before and after RT. First to visualize HBP metabolic heterogeneity in theTME I will construct an in-situ map of the primary tumor compartments (endothelial malignant fibroblast andimmune) enriched for HBP metabolic markers and glycoform structures using CODEX. CODEX is a cutting-edge multiplexed imaging method that allows for single-cell quantification of up to 50 markers in situ (aim 1).Then I will deconvolute cell neighborhoods using machine learning and clustering biocomputational approachesto quantify and inform which neighborhoods are active regions of protein O-glycosylation. In aim 2 I willrecapitulate HBP-enriched cell neighborhoods using a 3D assembloid model irradiate them then characterizemetabolic radioresistance patterns using CODEX. Lastly in aim 3 I will analyze the O-glycoproteome and spatialinformation of radioresistant assembloids. The O-glycoproteins or upstream drivers to O-glycosylation involvedin critical tumor-stroma interactions will be inhibited in an attempt to restore radiosensitivity. The resulting datawill generate the first hypothesis synthesis tool exploring an understudied dimension of cell signaling the O-glycoproteome. They will lead to the discovery of new molecular targets involved in both tumor metabolism andstromal interactions with the primary goal of improving RT response in cancer patients with inoperable tumors. 157788 +No NIH Category available Advocate;Authorization documentation;Cancer Burden;Cancer Center;Clinical;Collaborations;Communities;Development;Drops;Ensure;Feedback;Funding;Goals;Grant;Gynecologic Oncology;Institution;Leadership;Malignant neoplasm of ovary;Monitor;Patients;Performance;Recommendation;Reproduction spores;Research;Research Personnel;Resources;Role;Structure;Supervision;Time;Translational Research;Work;authority;career;experience;flexibility;improved;oncology program;programs;resistance mechanism;success Core A: Administrative Core PROJECT NARRATIVE Administrative CoreThe overarching goals of the Administrative Core of this Dana-Farber/Harvard Cancer Center (DF/HCC)Ovarian Cancer SPORE application are to provide leadership and administrative oversight of the overallSPORE grant integration of the SPORE components and the overall Ovarian Cancer SPORE within the Dana-Farber/Harvard Cancer Center (DF/HCC) and promote and engage activities that allow the success of theOvarian Cancer SPORE Projects Cores the Developmental Research Program (DRP) and the CareerEnhancement Program (CEP). NCI 10684197 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6 5325 2120370 "D'ANDREA, ALAN D." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 147655 91822 56339 PROJECT SUMMARYAdministrative CoreThe overarching goals of the Administrative Core of this Dana-Farber/Harvard Cancer Center (DF/HCC)Ovarian Cancer SPORE application are to provide leadership and administrative oversight of the overall grantintegration of the SPORE components as well as integration of the overall Ovarian Cancer SPORE within theDana-Farber/Harvard Cancer Center (DF/HCC) and promote and engage activities that allow the success ofthe Ovarian Cancer SPORE Projects Cores the Developmental Research Program (DRP) and the CareerEnhancement Program (CEP). Drs. Matulonis DAndrea and Spriggs will work within the multi-PI/PDframework. The Leaders of this Ovarian Cancer SPORE grant Drs. Matulonis DAndrea and Spriggs willwork directly with the DF/HCC SPORE Committee the External Advisory Board (EAB) the Internal AdvisoryBoard (IAB) and the Ovarian Cancer SPORE Advocate Board to obtain recommendations and feedback andimplement them into the DF/HCC Ovarian Cancer SPORE components and the overall grant. The OverallDirectors of this SPORE grant Drs. Matulonis DAndrea and Spriggs will equally closely monitor projectsthroughout the entirety of the granting period and in return give constant and real time input; they will alsohave the authority to alter funding based upon project performance and they will do this collaboratively. Thestructure of this SPORE grant will allow close supervision of all Projects and Cores and flexibility to allowproject revision based on oversight feedback and whether underperforming projects should be droppedaltogether or replaced. The SPORE PIs/PDs will ensure and facilitate interaction among the projects as well asaccess to SPORE resources such as Cores. The DRP and CEP will function as a critical pipeline ofscientifically and clinically noteworthy projects and investigators that could be incorporated into the SPOREbased on the advice of the advisory boards (EAB and IAB) and the DRP and CEP leadership; Drs. Matulonisand Spriggs will have direct oversight of the DRP and CEP. +No NIH Category available Address;Advocate;Antigen Targeting;Area;BCL1 Oncogene;Basic Science;Biological;Biological Markers;Biological Models;Biometry;Cancer Center;Cancer Patient;Cancer Vaccines;Clinical;Clinical Trials;Clinical Trials Design;Collaborations;Companions;Correlative Study;DNA Repair;Dana-Farber Cancer Institute;Decision Making;Dedications;Development;Drug Combinations;Funding;General Hospitals;Generations;Goals;Grant;Gynecologic Oncology;Hospitals;Human;Immunotherapy;In Vitro;Institution;International;Investigation;Israel;Laboratories;Leadership;MEKs;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Massachusetts;Mediating;Mucinous;Mutation;Newly Diagnosed;Occupational activity of managing finances;Organoids;Ovarian Carcinoma;Pathology;Patient-Focused Outcomes;Patients;Poly(ADP-ribose) Polymerase Inhibitor;Principal Investigator;Recurrence;Refractory Disease;Relapse;Research;Research Personnel;Resistance;Role;Scientist;Serous;Solid Neoplasm;Specialized Program of Research Excellence;Structure;Technology;Therapeutic;Woman;Writing;anticancer research;cancer therapy;career;clinical development;design;drug development;drug sensitivity;efficacy evaluation;experience;extracellular;immune checkpoint blockade;improved;improved outcome;inhibitor;innovation;medical schools;member;neoantigens;novel;novel drug combination;novel vaccines;oncology program;predictive marker;programs;resistance mechanism;response;senior faculty;translational progress;tumor;tumor progression;vaccine trial Dana Farber/Harvard Cancer Center Ovarian Cancer SPORE grant Narrative (Overall) This is an Ovarian Cancer SPORE resubmission (A1) application submitted by a team of investigatorsfrom the Dana-Farber/Harvard Cancer Center (DF/HCC). The SPORE contains three projects and four coreswhich are highly interactive. It also contains a Developmental Research Program (DRP) and a CareerEnhancement Program (CEP). The program is focused on the broadest and most urgent questions in ovariancancer therapy including novel drug combinations and immunotherapy. NCI 10684196 7/28/23 0:00 PAR-18-313 5P50CA240243-04 5 P50 CA 240243 4 "BASA JANAKIRAM, NAVEENA" 8/3/20 0:00 7/31/25 0:00 ZCA1-RPRB-6(M1) 2120370 "D'ANDREA, ALAN D." "CASTRO, CESAR M; MATULONIS, URSULA ANNE" 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 2245572 NCI 1743076 507043 Project Summary (Overall) The Overall section of this Ovarian Cancer SPORE application describes the BackgroundSpecific Aims Innovation and Research Plan of the three projects and four cores. We emphasize intra-SPORE collaborations and development of clinical trials with companion biomarkers. Through this SPOREapplication we have tried to address several of the most urgent questions in ovarian cancer therapy. FirstPARP inhibitors are a new and essential feature of high grade serous ovarian cancer (HGSC) therapy butmany patients eventually have cancer progression on these agents. Accordingly in Project 1 we havedesigned clinical trials with drug combinations and correlative studies which will allow us to systematicallyextend the use of PARP inhibitors. Second we recognize the emerging impact of immunotherapy on solidtumor treatment. Thus in Project 2 we have designed a novel vaccine trial for ovarian cancer patients. ThirdHGSC patients with primary refractory disease or those patients with recurrence whose cancer harborunderlying RAS mutations such as low grade serous or mucinous cancers pose a particularly difficult clinicalproblem. Accordingly in Project 3 we will explore novel non-platinum drug combinations such as thecombination of a BCL inhibitor and a MEK inhibitor and will examine predictive biomarkers and tumorresponses evident in the extracellular activity. The Specific Aims of this DF/HCC ovarian cancer SPORE are asfollows: Aim 1 (Project 1): ATR inhibitor-mediated reversal of PARP inhibitor resistance in high-grade serousovarian cancer (HGSOC); Aim 2 (Project 2): Combined personal neoantigen-targeting cancer vaccines withimmune checkpoint blockade for ovarian cancer; Aim 3 (Project 3): Evaluation of the Efficacy of Trametinib +Navitoclax in recurrent ovarian carcinoma. 2245572 +No NIH Category available Apoptosis;Automobile Driving;B-Cell Lymphomas;Binding;Cancer Etiology;Cell Proliferation;Cells;Complex;DNA;DNA Binding;DNA Binding Domain;Data;Dependence;Dimerization;Event;Gene Expression;Genes;Genetic Transcription;Growth;Hematopoiesis;Hematopoietic stem cells;Heterodimerization;Higher Order Chromatin Structure;Human;In Vitro;Lead;Lung Adenocarcinoma;Lymphoma;MAX gene;MYC Family Protein;MYC gene;Malignant Neoplasms;Mediating;Metabolic;Metabolism;Molecular;Mus;Mutation;Neoplasm Metastasis;Neoplasms;Normal Cell;Oncogenic;Pancreatic Adenocarcinoma;Phenotype;Point Mutation;Production;Proliferating;Proteins;Proto-Oncogene Proteins c-myc;Public Health;Regulation;Research;Resistance;Role;Tumor Suppression;biological systems;cancer therapy;cell growth;cell motility;chromatin modification;loss of function;member;novel strategies;novel therapeutic intervention;programs;self-renewal;transcription factor;transcriptional reprogramming;tumor;tumor initiation;tumor progression The MYC Transcription Factor Network and the Path to Cancer The Myc protein is an essential regulator of growth in all normal cells but in many cancers Myc is escapesnormal controls and supports high rates of growth needed for tumor progression. In this proposal we willdetermine what events contribute to activation of Myc in tumors and devise approaches to inhibit Myc function.This research is relevant to public health because it will ultimately lead a better understanding of the causes forcancer and provide new approaches to cancer therapy. NCI 10684160 9/15/23 0:00 PAR-17-494 5R35CA231989-07 5 R35 CA 231989 7 "GHOSH-JANJIGIAN, SHARMISTHA" 9/1/18 0:00 8/31/25 0:00 ZCA1-RTRB-C(M3) 1877681 "EISENMAN, ROBERT NEIL" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1034880 NCI 588000 446880 Myc proteins are essential for normal cellular growth and proliferation. However when its normal regulationis compromised (i.e. deregulated) Myc promotes initiation and progression of a broad spectrum of humancancers. Myc has been long known to be a transcription factor that heterodimerizes with the Max protein inorder to specifically recognize DNA. When deregulated Myc-Max alters gene expression programs resultingin metabolic and growth related changes that in turn support tumor progression. Recent studies show Myc-Max does not function alone but is part of a larger transcriptional network of related yet functionally dis-tinct factors that heterodimerize with either Max or the Max-like protein MLX or both. In order to understandand control Myc's role in the etiology of cancer it will be essential to define how Myc both depends on andinfluences the extended network. This application builds on 3 broad aspects of our ongoing studies:Transcriptional reprogramming of metabolism: We had earlier uncovered a critical role for Mlx and its hetero-dimeric partner MondoA in the metabolism and survival of several Myc-driven tumors. Focusing on pancre-atic adenocarcinoma we will examine cross-talk and functional dependencies involving Myc in the context ofits extended network that may be exploited to identify new therapeutic strategies. Moreover Myc and theother network proteins are transcription factors and we will determine their shared target genes and their co-operative effects on chromatin modifications and higher order structure as well as gene expression.Tumor suppression mediated by Mga a member of the Myc Network: Mga is a large and unusual transcrip-tion factor with two distinct DNA binding domains one of which dimerizes with Max binds DNA and is fre-quently subject to deletion or mutation in a wide range of neoplasms. However little is known about Mga'soncogenic functions. Our very recent findings that Mga loss of function results in altered cell motility in vitroand rapid lung adenocarcinoma formation in mice provide a biological system to elucidate Mga's capacity tosuppress cancer. We will define regions in Mga essential for DNA binding identify transcriptional complexesassociated with Mga and assess how loss of Mga leads to tumor initiation progression and metastasis.Molecular alterations driving Myc oncogenicity: we introduced a point mutation (T58A) associated with B celllymphomas and AML within the phosphodegron of the endogenous murine myc gene. In these mice Myc-T58A is regulated normally with no overt changes in tissue growth or proliferation. Yet we find that myc-T58Amice display increased hematopoietic progenitor cell self-renewal and resistance to apoptosis and developlong-latency AML or lymphoma. Our data show that the Myc-T58A mutation alters the association of Mycwith a specific co-regulatory complex. We hypothesize that this altered binding modifies expression of a sub-population of Myc target genes during hematopoiesis resulting in production of tumor initiating cells. We planto elucidate the underlying molecular basis for the T58A phenotype in these tumor-prone mice. 1034880 +No NIH Category available Acetylation;Actomyosin;Address;Ants;Apical;Apoptosis;Area;Basement membrane;Biological Assay;Biological Models;Candidate Disease Gene;Cell physiology;Cells;Collaborations;Drosophila genus;Environment;Epithelial Cells;Epithelium;Exposure to;Extracellular Matrix;Filopodia;Gene Mutation;Genes;Genetic;Genetic Epistasis;Growth;Growth Associated Protein 43;HDAC6 gene;Inflammatory;Internet;Malignant - descriptor;Malignant Neoplasms;Measures;Mechanical Stress;Mechanics;Mediating;Microtubules;Modeling;Modification;Molecular;Mutation;Outcome;Play;Process;Protein-Lysine 6-Oxidase;Research;Role;Side;Signal Pathway;Signal Transduction;Spottings;Structure;Technology;Testing;Tissues;Tumor Suppressor Genes;Tumor Suppressor Proteins;Wing;Work;cancer type;carcinogenesis;cell transformation;experimental study;genetic manipulation;imaginal disc;insight;loss of function;mutant;neoplastic;neoplastic cell;trait;tumor;tumor initiation;tumorigenesis;tumorigenic;uncontrolled cell growth Tissue Microenvironment ant Tumor Hotspots in Drosophila PROJECT NARRATIVEThe proposed studies address how tissue-intrinsic microenvironments regulate the tumorigenesis of neoplastictumor-suppressor mutant cells in a Drosophila model system. The outcomes from this project will advance ourunderstandings of the molecular and cellular mechanisms underlying early stages of tumorigenesis. NCI 10684153 8/4/23 0:00 PA-18-484 5R01CA227789-06 5 R01 CA 227789 6 "WOODHOUSE, ELIZABETH" 6/1/19 0:00 8/31/24 0:00 Intercellular Interactions Study Section[ICI] 7694512 "DENG, WU-MIN " Not Applicable 1 BIOCHEMISTRY 53785812 XNY5ULPU8EN6 53785812 XNY5ULPU8EN6 US 29.935429 -90.12279 8424601 TULANE UNIVERSITY OF LOUISIANA NEW ORLEANS LA SCHOOLS OF MEDICINE 701185665 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 340746 NCI 224175 116571 PROJECT SUMMARY / ABSTRACTDuring carcinogenesis transformed epithelial cells evolve into a malignant neoplasm through a multistepprocess whereby the transformed cells acquire traits that enable them to become tumorigenic and ultimatelymalignant. Although many genes have been identified as involved in different steps of cancer-cell progressionlittle is known of the initial steps of tumorigenesis wherein mutant cells deviate from the robustly organizedmicroenvironment to undergo uncontrolled overgrowth.In this proposal we will use the Drosophila model to dissect genetically how endogenous tissuemicroenvironment contributes to tumor formation. This work is part of our long-term effort in deciphering themolecular and cellular mechanisms that govern the early steps of tumorigenesis in epithelial tissues. In ouranalysis of conserved neoplastic tumor-suppressor genes (nTSGs) using the Drosophila wing imaginal discmodel system we found specific regions in the wing hinge in which tumors always originate. In these specifictumor hotspots nTSG loss-of-function (LOF) pro-tumor cells delaminate from the apical side of the epitheliumand start tumorigenic overgrowth by exploiting endogenous JAK-STAT inflammatory signaling activity. Incontrast the pro-tumor cells in tumor coldspots the wing pouch area are extruded from the basal side of theepithelial layer and undergo apoptosis. The wing hinge tumor hotspot area displays a network of specific androbust basal structures including enriched microtubules a web of intertwining filopodia and tightly laminatedbasement membranes. The epithelial organization in these specific regions is hypothesized to create thetumor hotspot a favorable tissue-intrinsic microenvironment which forces pro-tumor cells to delaminate fromthe epithelial layer and enter an environment that is suitable for tumorigenesis. In the proposed studies we willdetermine how specific tissue cytoarchitectural traits local intrinsic signaling and differential cell competitionare involved in tumor hotspot formation in the wing disc model by pursuing the following three specific aims:(1) To determine how cytoarchitectural structures regulate the delamination direction of pro-tumor cells intumor hotspots; (2) To determine how JAK-STAT signaling is involved in hotspot tumorigenesis; and (3) Todetermine the role of cell competition in tumor hotspot and coldspot differentiation in the wing disc.These three specific aims are independent from each other and can be executed separately. The significanceof our proposed studies lies in their implications directly related to early stages of tumorigenesis. Given theconservation of the epithelial cytoarchitectural structures cell competition mechanisms and the significant roleinflammatory signaling pathways play during various types of cancer tumorigenesis is likely to be initiated fromtumor hotspots by a similar mechanism in many epithelial tissues. Understanding these regulatorymechanisms will therefore provide new insights into how tissue-intrinsic microenvironment determines whethertumors can actually be induced after cells acquiring cancer-promoting mutations. 340746 +No NIH Category available Abscopal effect;Address;Affect;Aftercare;Antibodies;Antigen Presentation;Antigen-Presenting Cells;Antigens;CD4 Positive T Lymphocytes;CD8B1 gene;CPG-oligonucleotide;Cancer Patient;Cancer Vaccines;Cells;Chemistry;Clinical;Combination immunotherapy;Coupled;Data;Dendritic cell activation;Disease;Disseminated Malignant Neoplasm;Dose;Extracellular Matrix;Fibroblasts;Genes;Goals;HPV-negative head and neck cancer;Hafnium;Head;Head and Neck Cancer;Head and Neck Squamous Cell Carcinoma;Human Papillomavirus;Hydroxyl Radical;Immune;Immune checkpoint inhibitor;Immune system;Immunologic Adjuvants;Immunologic Memory;Immunologics;Immunotherapy;Infiltration;Interferon Type I;Interferon Type II;Interferons;Irradiated tumor;Localized Malignant Neoplasm;Macrophage;Malignant Neoplasms;Malignant Squamous Cell Neoplasm;Mediating;Metals;Metastatic/Recurrent;Methods;Mission;Modeling;Molecular;Mouth Neoplasms;Mus;PD-1 blockade;PD-1/PD-L1;PD-L1 blockade;Pathway interactions;Patients;Porphyrins;Process;Proliferating;Proteins;Public Health;RNA;Radiation;Radiation Dose Unit;Radiation therapy;Radiation-Sensitizing Agents;Recurrent Malignant Neoplasm;Research;Resistance;Roentgen Rays;Signal Transduction;Singlet Oxygen;Squamous cell carcinoma;Stimulator of Interferon Genes;Surface;T cell infiltration;T cell response;T-Cell Activation;T-Cell Proliferation;Testing;Toxic effect;Treatment outcome;United States National Institutes of Health;adaptive immune response;anti-cancer;antitumor effect;cancer recurrence;checkpoint therapy;chemotherapy;clinically relevant;effective therapy;effector T cell;genetic signature;immune activation;immune cell infiltrate;immune checkpoint blockade;immune stimulatory agent;improved;innate immune mechanisms;innovation;irradiation;micronucleus;nanomedicine;nanoscale;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;palliative;particle;programmed cell death protein 1;radioresistant;response;synergism;systemic toxicity;tumor;tumor eradication;tumor microenvironment;tumor-immune system interactions;x-ray irradiation Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers PROJECT NARRATIVEThe goal of this project is to define the mechanisms by which radioenhancing nanoscale metal-organicframework (nMOF) particles can be combined with immunostimulatory CpG to alter the immunemicroenvironment in order to facilitate checkpoint blockade immunotherapies in head and neck cancer. Theproposed research is relevant to the NIH's mission because X-ray irradiation represents a significant treatmentoption for many cancer patients and nMOFs possess a unique advantage by enabling the more effectiveradiotherapy-radiodynamic therapy at palliative X-ray doses. The proposed research is relevant to public healthbecause this new therapeutic strategy can synergize with current checkpoint blockade immunotherapy to treatlocalized recurrent and metastatic cancers. NCI 10684142 7/10/23 0:00 PAR-17-240 5R01CA253655-04 5 R01 CA 253655 4 "CAPALA, JACEK" 7/1/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-IMST-H(55)R] 7909108 "LIN, WENBIN " "WEICHSELBAUM, RALPH R" 1 CHEMISTRY 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF ARTS AND SCIENCES 606372612 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 494273 NCI 316025 178248 Checkpoint blockade antibodies targeting PD-1 have demonstrated improved survival in metastatic head andneck squamous cell carcinomas (HNSCC) patients by reactivating effector T cells that have infiltrated thetumor microenvironment. However PD-1 blockade still has low overall response rates approximating 18%suggesting that the different treatment outcomes are due to intrinsic differences in the patients' diseases suchas tumor microenvironments. Recently we have developed a new class of radioenhancers nanoscale metal-organic frameworks (nMOFs) that can alter the immune microenvironment. Constructed via coordinationbetween hafnium-oxo clusters and porphyrin-like molecules nMOFs generate both hydroxyl radicals andsinglet oxygen in a process termed radiotherapy-radiodynamic therapy (RT-RDT). The objective in thisapplication is to define the mechanisms by which RT-RDT and nMOF-enabled immunotherapy alter theimmune microenvironment in order to sensitize HNSCCs to checkpoint blockade. Our central hypothesis isthat nMOFs can deliver the CpG oligodeoxynucleotides and synergize with RT-RDT-induced antigen releaseand Type I IFN expression which stimulates CD8+ and CD4+ T cell proliferation and infiltration into HNSCCs toregress both irradiated and non-irradiated tumors treated with PD-1/PD-L1 blockade. The goal for thisproposed research is to identify a novel therapy and define the mechanisms by which it alters the immunemicroenvironment to sensitize HNSCCs and possibly other cancers to current clinical immunotherapies. Thisproject will use innovative molecularly tunable nMOFs having unprecedented radioenhancement via the uniqueRT-RDT mechanism. This proposal is significant because it addresses an unmet need of treating radioresistantand metastatic HNSCCs both directly via RT-RDT and by acting as an immunostimulant to enhance theefficacy of existing checkpoint inhibitors. This proposal will test the central hypothesis by pursuing four specificaims: (1) define the cellular mechanisms of innate immune activation after RT-RDT; (2) determine how RT-RDT affects the tumor microenvironment in squamous cell cancers; (3) evaluate the contributions of differentimmune components on the efficacy of RT-RDT and immunotherapy combinations; and (4) determine effectivetherapies for HNSCCs resistant to PD-1/PD-L1 blockade. Aim 1 will treat cells and ex vivo stimulated orcultured immune components with nMOFs and radiation to determine how RT-RDT initiates STING and Type Iinterferon signaling in the tumor microenvironment. Aim 2 will determine how the tumor microenvironment andextracellular matrix are affected by nMOF-mediated RT-RDT. Aim 3 will evaluate the contribution of differentimmune components to the anticancer efficacy of nMOFs. Aim 4 will use primary oral tumor models that areresistant to PD-1/PD-L1 blockade as a model to identify novel immunotherapy combinations that synergizewith RT-RDT. Ultimately this project will afford new therapeutic strategies using clinically relevantnanomedicines to enhance both the radiation therapy and immunological rejection of HNSCCs. 494273 +No NIH Category available Acute Myelocytic Leukemia;Adenosine;Affect;Affinity;Binding;Blood Cells;CD34 gene;Cancer cell line;Cell Differentiation process;Cell Line;Cell Nucleus;Cell Proliferation;Cells;Clinical;Cytoplasm;Cytosol;Data;Development;Disease;Enzymes;Exhibits;Family;G3BP1 gene;Gene Expression Alteration;Gene Expression Regulation;Hematopoiesis;Human;Human Cell Line;Immunofluorescence Immunologic;Immunoglobulin Fragments;Leukemic Cell;Link;Malignant - descriptor;Malignant Neoplasms;Maps;Mediating;Messenger RNA;Metabolism;Methods;Methylation;Methyltransferase;Modification;Mouse Cell Line;Nucleotides;Patients;Pattern;Population;Process;Proliferating;Protein Deregulation;Proteins;RNA Editing;Reader;Regulation;Ribosomal RNA;Role;Sampling;Signal Transduction;Site;Small Nuclear RNA;Stains;Technology;Testing;Tissues;Transcript;Translations;Umbilical Cord Blood;Visualization;acute myeloid leukemia cell;antibody detection;cancer type;cell type;cellular engineering;detection method;epitranscriptome;epitranscriptomics;gain of function;genome wide screen;hematopoietic differentiation;inhibitor;insight;leukemia;leukemogenesis;loss of function;mRNA Stability;mRNA Transcript Degradation;method development;myeloid leukemia cell;new technology;novel;paralogous gene;polyadenylated messenger RNA;programs;protein expression;recruit;self-renewal;stem cell self renewal;stem cells;transcriptome;tumor progression Mechanisms and functions of N6-methyladenosine (m6A) in cancer PROJECT NARRATIVERecent studies have shown that mRNA can be dynamically regulated by methylation of specific adenosineresidues to form N6-methyladenosine (m6A) an epitranscriptomic mark that occurs on a subset of mRNAs.m6A appears to be particularly important in cancer and our recent studies suggest that m6A has importantroles in promoting acute myeloid leukemia. To determine how m6A promotes cancer this project will resultin new technologies to map and decipher the role of m6A in specific leukemia-related cellular subtypes andwill determine mechanisms by which m6A promotes stem cell self-renewal to promote leukemogenesis. NCI 10684134 7/20/23 0:00 PA-18-484 5R01CA186702-10 5 R01 CA 186702 10 "MAAS, STEFAN" 9/10/14 0:00 8/31/24 0:00 Cancer Etiology Study Section[CE] 1890113 "JAFFREY, SAMIE R" "KHARAS, MICHAEL " 12 PHARMACOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 550845 NCI 417189 133656 SUMMARYAn important mechanism of gene expression regulation is dynamically regulated and possibly reversiblenucleotide modifications in mRNA. These modifications can have marked effects on mRNA stabilitytranslation and other aspects of mRNA metabolism. We had a founding role in this field by developing thetechnology for transcriptome-wide mapping of N6-methyladenosine (m6A). Our mapping study provided thefirst evidence that m6A could be dynamically regulated and potentially impart new functions in mRNA. Werecently showed that acute myeloid leukemia (AML) cells exhibit elevated levels of METTL3 and METTL14 theheterodimer that acts as the m6A-forming methyltransferase. We found that m6A promotes self-renewal inAML and in CD34+ stem cells and depletion of m6A triggers a differentiation program. Thus m6A has criticalroles in hematopoietic differentiation at specific stages of development and this process is deregulated inAML. Therefore precise characterization of these stage-specific patterns of m6A at a transcriptome-wide levelis critical to understand how m6A affects developmental transitions. Developing new methods to map m6A inthe rare cell populations relevant to hematopoiesis and AML would help to reveal how this epitranscriptomicmodification is critical for the regulation and deregulation of differentiation seen in AML and possibly othercancers. Additionally the effects of m6A are largely thought to reflect the actions of specific reader proteinswhich bind m6A in mRNA to affect its fate in cells. The major readers are YTHDC1 in the nucleus and theYTHDF family in the cytoplasm which comprise three nearly identical paralogs and which may haveredundant functions. In order to significantly advance our understanding of the role of m6A in AML thespecific aims of this proposal are: (1) To visualize and map m6A in mRNA in a cell-type specific manner.Here we describe the development of methods for detecting and mapping m6A in a cell type-specific mannerand their application to understand m6A dynamics in hematopoiesis and AML. (2) To define the functionalrequirement for the m6A reader YTHDC1 in normal blood cells and in AML. Based on a genome-widescreen and our preliminary data YTHDC1 is a strong candidate for the reader that may mediate major aspectsof the effect of m6A in AML. Here we assess the functional role for YTHDC1 in both normal and malignanthematopoiesis using human cord blood cells AML cell lines and primary AML patients. (3) To determine theroles and regulation of the YTHDF cytosolic m6A readers on mRNA fate. The YTHDF proteins appear tobe the major regulators of m6A mRNAs in the cytosol. We will determine how YTHDF proteins are regulated tomediate their m6A-mRNA destabilizing effects and if YTHDF proteins influence cellular differentiation andproliferation in cancer cell lines and in AML. Overall our project will develop new enabling technologies forstudying m6A in cancer and test mechanisms by which the m6A readers contribute to cancer progression. 550845 +No NIH Category available Acceleration;Apoptosis;Articulation;B cell differentiation;B lymphoid malignancy;B-Lymphocytes;Biological Markers;Biology;Bone Marrow;Cancer Biology;Cancerous;Cell Death;Cell Survival;Cells;Cellular biology;Cessation of life;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;DNA Damage;DNA Repair;DNA Sequence Alteration;DNA analysis;Data;Development;Disease;Educational workshop;Generations;Genetic;Genomic Instability;Genomics;Goals;Heavy-Chain Immunoglobulins;Hematologic Neoplasms;Immunoglobulins;Impairment;Innovative Therapy;International;Investigation;Knock-out;Knowledge;Life;Link;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mentors;Modeling;Molecular;Monoclonal gammopathy of uncertain significance;Multiple Myeloma;Mutation;Nuclear;Oncogenic;Oncology;Outcome;Pathogenesis;Pathologic;Physiological;Plasma Cells;Precancerous Conditions;Proliferating;Protein Biosynthesis;Proteins;Proteomics;Public Health;Publishing;Research;Research Personnel;Rest;Secondary to;Stress;Structure of germinal center of lymph node;Technology;Testing;Tetracyclines;Time;Transfection;Transgenic Mice;Tumor Suppressor Genes;UBC gene;Ubiquitin;Western Blotting;Western World;Work;career;design;driver mutation;experimental study;innovation;knock-down;meetings;molecular targeted therapies;mouse model;multicatalytic endopeptidase complex;novel;novel therapeutics;plasma cell differentiation;protein degradation;proteotoxicity;response;small hairpin RNA Functional Consequences of Ubiquitin Depletion During B Lymphocyte Differentiation Project NarrativeWe previously showed that normal plasma cells and cancerous multiple myeloma (MM) cells haveabundant inefficient immunoglobulin synthesis and impaired protein degradation resulting inaccumulation of polyubiquitinated proteins and proteotoxic stress. We recently discovered that criticaldepletion of ubiquitin a small protein necessary for both protein degradation and DNA repair occursduring B lymphocyte differentiation. We hypothesize that functional ubiquitin depletion during B celldifferentiation is a novel cancer-causing mechanism by impairing DNA repair paving the way fordevelopment of innovative therapies in MM and potentially other cancers. NCI 10684125 8/1/23 0:00 PA-19-117 5K08CA245100-04 5 K08 CA 245100 4 "LIM, SUSAN E" 8/13/20 0:00 7/31/25 0:00 Career Development Study Section (J)[NCI-J] 15080869 "BIANCHI, GIADA " Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 207255 NCI 192211 15044 Project Summary/AbstractMultiple myeloma (MM) is an incurable cancer of terminally differentiated plasma cells (PC)characterized by abundant immunoglobulin (Ig) synthesis. Most PC are short lived and die only a fewdays after differentiation through unclear molecular mechanisms. MM pathogenesis also remain elusivewith no single genetic driver mutation but pervasive DNA damage. We have previously shownincreased cargo of polyubiquitinated (polyUb) proteins and decreased proteasome activity indifferentiating B lymphocytes and we hypothesized proteotoxicity as driver of PC death. By usingabsolute mass spectrometry (AQUA) to quantify ubiquitin (Ub) in the same B cell differentiation modelour preliminary data show that 60% free Ub depletion occurs in PC compared to resting B cellsconcomitantly with maximal Ig secretion and apoptosis. Second we discovered that cells surviving longterm post differentiation can be identified and display markers of ongoing DNA damage. As Ub isnecessary for proper DNA damage response (DDR) polyUb protein degradation and DDR compete forthe same Ub pool. Based on our work we propose a unifying model for short-lived PC death and MMpathogenesis centered on critical Ub depletion. Our core hypothesis is that in PC proteotoxic stresssecondary to sustained Ig synthesis leads to free Ub depletion thus causing impaired DDR. Most PCwill be unable to recover from this crisis however a small subset of genomically unstable PC maysurvive presumably due to accumulation of survival promoting mutations constituting a premalignantstate for MM. We further hypothesize that Ub gene Ubc may be a haploinsufficient tumor suppressorgenes in B cell malignancies. Herein the applicant Dr. Giada Bianchi presents a comprehensive planto test these hypotheses articulated in 2 specific aims: (1) to probe a causative link between Ig synthesisUb depletion and apoptosis in PC; and (2) to evaluate whether Ub depletion is sufficient to causegenomic instability in PC and drive MM pathogenesis. Data gathered during the course of ourinvestigation will provide novel data regarding the biology of normal and malignant PC and potentiallyuncover a novel oncogenic mechanism - functional depletion of Ub - with applicability to othermalignancies and opportunity for innovative molecularly targeted therapies. To this end Dr. Bianchihas carefully selected a mentoring committee and collaborators who are world-renowned experts in UbMM DDR proteomics and B cell biology. Such team will provide knowledge models and technologiesto render the testing of Dr. Bianchis hypotheses feasible within the proposed 5-year frame. Theapplicants mentoring committee has furthermore designed a detailed career plan based on regularmeeting attendance of workshops classes and international meetings which will further accelerate thetrajectory of Dr. Bianchi to become an independent investigator in cancer biology in the next 5 years. 207255 +No NIH Category available Aftercare;Androgen Receptor;Androgen Therapy;Androgens;Anti-Inflammatory Agents;Antitumor Response;Biological Assay;Bone Diseases;Bone Marrow;Bone neoplasms;Cancer Patient;Cells;ChIP-seq;Clinical Trials;Co-Immunoprecipitations;Development;Diagnosis;Disease;Disease Progression;Dose;Enterobacteria phage P1 Cre recombinase;Environment;Gene Expression;Generations;Genetic;Gonadotropin Hormone Releasing Hormone;Growth;Hormones;Immune;Immune Evasion;Immune response;Immunotherapeutic agent;Immunotherapy;In Vitro;Knock-out;Knockout Mice;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Modeling;Molecular;Mus;Neoplasm Metastasis;Nonmetastatic;Outcome;Pain;Patient-Focused Outcomes;Patients;Pilot Projects;Prostate;Protein-Serine-Threonine Kinases;Receptor Signaling;Receptors Adrenergic beta-1;Recurrent Malignant Neoplasm;Regulation;Research;Research Design;Resistance;Role;Signal Transduction;Site;Stanolone;Testing;Testosterone;Therapeutic;Transforming Growth Factor beta;Transforming Growth Factor beta Receptors;androgen deprivation therapy;antagonist;anti-tumor immune response;bone;cancer recurrence;carcinogenesis;castration resistant prostate cancer;clinical translation;conditional knockout;cytokine;cytotoxic;diagnostic tool;efficacious treatment;enzalutamide;first responder;fracture risk;functional group;high risk;improved;in vivo;inhibitor;knock-down;mouse model;neutrophil;new therapeutic target;novel;peripheral blood;pre-clinical;prevent;prostate cancer metastasis;prostate cancer progression;receptor;response;standard of care;targeted treatment;therapy outcome;transcriptome;transcriptome sequencing;treatment group;tumor;tumor growth;tumor immunology;tumor progression Leveraging PMN immune response to overcome ADT resistance in bone metastatic prostate cancer PROJECT NARRATIVEBone metastatic prostate cancer is currently incurable and patients typically survive only 2-3 years afterdiagnosis. Standard of care androgen-targeted therapy drives cancer resistance and immune evasioncontributing to cancer recurrence. This proposal aims to utilize neutrophils the most abundant bone immunecell as a candidate target for enhancing current therapies through neutrophil-driven anti-tumor immuneresponse. NCI 10684116 8/1/23 0:00 PA-20-185 5R01CA274605-02 5 R01 CA 274605 2 "KUO, LILLIAN S" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-OTC1-M(80)S] 11345798 "COOK, LEAH MARIE" Not Applicable 2 PATHOLOGY 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 344109 NCI 224175 119934 Metastatic castration-resistant prostate cancer (mCRPC) is deadly and currently incurable. Approximately 90%of patients CRPC become resistant to 2nd line androgen deprivation therapy (ADT; which primarily targetandrogen receptor (AR) signaling and present with bone metastatic disease. Although ADT remains a beneficialtherapy for mCRPC patients mechanisms of cancer resistance in mCRPC and specifically in the boneenvironment the most frequent site of CRPC metastasis is poorly understood. Understanding contributingfactors to PCa disease progression is needed for further development of efficacious therapies. ADT waspreviously shown to be critical for differentiation and function of polymorphonuclear leukocytes/neutrophils(PMNs) which are first responder innate immune cells that comprise ~40-50% of the bone marrow cavity. Werecently showed that PMNs are protective against bone metastatic prostate cancer (BM-PCa) however the PMNanti-tumoral immune response diminishes as the tumor progresses. To examine PMN phenotypical changesthroughout PCa progression in patients my group functionally and molecularly characterized peripheral bloodPMNs from PCa patients at different stages: 1) Localized PCa 2) bone metastatic hormone-sensitive (mCSPC)and 3) mCRPC patient. We found that PMN function was highly suppressed by 2nd line ADT through increasedreceptor 1 expression of transforming growth factor beta (TGF) an anti-inflammatory cytokine important forpromoting BM-PCa and cancer-induced bone disease. Using preclinical bone metastasis mouse models wewere able to significantly suppress mCRPC growth in bone using 2nd line ADT in combination with either bipolarandrogen therapy (BAT; exogenous testosterone) to boost PMN anti-tumor response OR PMN-specific geneticdeletion of TR1. Based on our preliminary findings we hypothesize that: anti-tumor PMNs are suppressed/switched off by androgen regulation via TR1 signaling and this can be leveraged to improve mCRPCoutcomes. This will be tested in the following aims: Aim 1. Define the impact of androgen regulation on PMNanti-tumor immune response. Aim 2. Determine the mechanism of TR1-mediated PMN immune response inBM-PCa. Aim 3. Delineate the therapeutic potential of dual TR1/AR regulation for improving mCRPCtherapeutic outcomes. Primary Objective: To develop a novel immunotherapeutic strategy for treating BM-PCaby enhancing PMN anti-tumor response and overcoming PCa resistance to ADT. Study Design: For Aim 1we will identify the impact of androgen signaling on PMN polarization ex vivo (using patient-derived PMNs andmouse bone marrow PMNs) and in vivo using normal PCa non-metastatic and bone metastatic PCa cells) andin vivo (using mouse intratibial bone metastasis models). For Aim 2 we will delineate the role of TR1 in PMNresponse to mCRPC using TR1 knockout models. For Aim 3 we will define the therapeutic potential for usingcombination BAT with a novel bone-targeted TR1 inhibitor. 344109 +No NIH Category available 3-Dimensional;ATAC-seq;Acute Myelocytic Leukemia;Architecture;Automobile Driving;BCL2 gene;Biological Assay;Biological Markers;Blood Vessels;Bone Marrow;Cell Communication;Cell Differentiation process;Cell Line;Cell model;Cells;Clinical;Clinical Trials;Clonal Evolution;Collaborations;Combination Drug Therapy;Combined Modality Therapy;Complex;Correlative Study;Data;Detection;Development;Disease;Drug Combinations;Drug resistance;Early Diagnosis;Epigenetic Process;Evaluation;Evolution;FLT3 gene;Flow Cytometry;Future;Gene Expression;Goals;Human;Human Resources;Image;Immune;Immunosuppression;Immunotherapy;Institution;Intervention;Leukemic Cell;Measures;Metabolic;Methodology;Methods;Modeling;Mutation;Natural Killer Cells;Newly Diagnosed;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Process;Proteins;Recurrent disease;Regimen;Relapse;Research Personnel;Resistance;Resistance development;Sampling;Signal Transduction;Specimen;Stromal Cells;T-Lymphocyte;Techniques;Technology;Testing;Therapeutic;Therapy Clinical Trials;Time;Transcript;Translating;Translations;Validation;Work;acquired drug resistance;acute myeloid leukemia cell;bone engineering;clinical translation;deep sequencing;detection method;drug testing;high throughput screening;improved;inhibitor;leukemia;longitudinal analysis;metabolomics;mutational status;neoplastic cell;novel;novel drug combination;novel therapeutics;operation;participant enrollment;predictive signature;prevent;resistance mechanism;resistance mutation;response;single cell analysis;single-cell RNA sequencing;small molecule;targeted treatment;therapy resistant;three-dimensional modeling;translational potential;tumor Translating Improved Pairing and Timing of Drug Combination Strategies n/a NCI 10684113 9/8/23 0:00 RFA-CA-21-052 5U54CA224019-06 5 U54 CA 224019 6 9/30/17 0:00 8/31/27 0:00 ZCA1-SRB-E 9089 1894087 "DRUKER, BRIAN J" Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 304147 197499 106648 PROJECT SUMMARY: Project 3The goal of this Project is to translate newly discovered mechanisms of acquired drug resistance in acute myeloidleukemia (AML) from Projects 1 and 2 into novel drug combinations that can be deployed early in diseaseevolution to prevent disease relapse and improve patient outcomes. Disease relapse in AML is fueled by acomplex cross-talk of tumor cells adapting with support from the bone marrow microenvironment. Our prior workwhich was conducted by Leads and Personnel in this Project collaborating closely with Projects 1 and 2 as partof the OHSU DRSN U54 the predecessor to ARTNet has shown that acquired drug resistance in AMLproceeds via a multi-stage process. Early resistance is driven by cell state changes stimulated from tumor-extrinsic signals and this early resistance eventually transitions to a late stage of resistance with features ofclonal evolution. Understanding this process creates immediate translational opportunities for intervention duringthe early stage of resistance. Indeed our work from the DRSN Center has already led to novel drug combinationsthat have been translated into clinical to mitigate resistance to important new therapies for AML such as FLT3and BCL2 inhibitors. This prior work has led to a central hypothesis that delineation of pathways drivingearly detection of drug resistance will lead to the development of improved drug combinations at theearliest time possible to overcome resistance and improve patient outcomes. For this project ourimmediate goals are to prioritize the most promising drug combinations and most reliable resistancesignatures for clinical translation. To accomplish these goals three Aims are proposed: 1) Evaluatesignatures of resistance using primary AML samples in ex vivo assays: We will use our long-standing expertiseof testing primary AML patient samples against drug combinations using both high-throughput screeningplatforms imaging and flow-based readouts to evaluate phenotypic effects in single-cells and an advanced 3Dmodel of the bone marrow microenvironment that facilitates long-term drug testing of primary patient samples(Humarrow). 2) Longitudinal evaluation of samples from patients receiving rational therapeutic regimens: We willperform detailed characterization of longitudinal specimens from patients enrolled on our cutting-edgecombination therapy clinical trials to evaluate signatures of resistance at early stages of therapy. 3) Employsensitive detection techniques to detect low levels of resistance in primary samples: We will use single-cell andcell enrichment analytical techniques in specimens from newly diagnosed and early-stage AML patients to definethe earliest point at which resistance signatures can be detected. All of these data will inform and refine the workof Projects 1 and 2 and will be leveraged to support the development of future clinical trials and clinically-informative signatures of acquired drug resistance. Collectively this work will identify new regimens to treatpatients at the earliest possible stage thereby preventing disease relapse and improving durable outcomes. +No NIH Category available ATAC-seq;Acute Myelocytic Leukemia;Aftercare;Architecture;BCL2 gene;Biology;Bone Marrow;CRISPR screen;Cell Line;Cell Survival;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Coculture Techniques;Combined Modality Therapy;Communication;Complex;DNA sequencing;Data;Data Set;Development;Drug Combinations;Drug Modulation;Drug Sensitization;Drug resistance;Engineering;Environment;Epigenetic Process;Event;Evolution;Exposure to;FGF2 gene;FLT3 gene;FLT3 inhibitor;Flow Cytometry;Funding;Gene Expression;Genetic;Genetic Heterogeneity;Goals;Growth;Growth Factor;Heterogeneity;Immune;Immune Evasion;Immune Targeting;Immune signaling;Immunofluorescence Immunologic;Immunologic Factors;Inflammatory;Interleukin-1;JAK2 gene;Leukemic Cell;MEKs;Malignant - descriptor;Maps;Mediating;Methylation;Modeling;Molecular;Multiomic Data;Mutation;Natural Killer Cells;Organoids;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Process;Proteomics;Recurrent disease;Refractory;Refractory Disease;Relapse;Residual state;Resistance;Role;Route;Sampling;Screening Result;Shapes;Signal Pathway;Signal Transduction;Stress;Stromal Cells;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;acquired drug resistance;acute myeloid leukemia cell;cancer cell;cytokine;data integration;deep sequencing;disorder control;drug resistance development;drug sensitivity;genome-wide;immunoregulation;improved;inhibitor;leukemia;monocyte;neoplastic cell;network models;new combination therapies;novel;novel therapeutic intervention;predictive modeling;progenitor;resistance mechanism;response;screening;single-cell RNA sequencing;small molecule inhibitor;targeted treatment;therapeutic target;therapy resistant;transcriptome sequencing;transcriptomics;translational impact;treatment response;tumor;tumor microenvironment Trajectory and Architecture of Microenvironment-Mediated Resistance in AML n/a NCI 10684108 9/8/23 0:00 RFA-CA-21-052 5U54CA224019-06 5 U54 CA 224019 6 9/30/17 0:00 8/31/27 0:00 ZCA1-SRB-E 9088 9886789 "AGARWAL, ANUPRIYA " Not Applicable 1 Unavailable 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR Domestic Higher Education 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 304153 197502 106651 PROJECT SUMMARY/ABSTRACT: Project 2Outcomes for acute myeloid leukemia (AML) patients have improved little over four decades. This is largely dueto the development of acquired drug resistance and refractory disease. Thus there is an urgent need for newstrategies to target residual AML cells or refractory clones before they trigger disease relapse. The tumormicroenvironment is a key factor in the development of malignant progression and therapy resistance. The bi-directional communication between cancer cells and microenvironmental cells is much more complex thaninitially perceived. Thus one strategy to reduce relapse is to target the signaling mediated by growth factorssecreted by stromal or immune cells within the bone marrow microenvironment that play a critical role inpromoting leukemia cell survival development of drug resistance and immune evasion. Therefore the long-term goal of this project is to deconvolute the comprehensive network of events and cellular heterogeneity thatcontribute to acquired resistance in a context dependent manner to identify new therapeutic approaches. As partof our prior U54 DRSN funding omics-based analysis of 350 primary AML patient samples found that multiplesecreted cytokines and immune factors may contribute to drug resistance. Therefore we hypothesize thatreprogramming of the bone marrow niche modulates drug response and drives acquired resistance in AML.Comprehensive understanding of these mechanisms will lead to the identification of new combination therapies.We will focus on 5 essential therapeutic targets in AML: BCL2 FLT3 JAK2 MEK and epigenetic pathways andwill address this hypothesis following three well integrated aims. In Aim 1 we will map microenvironmentalsignatures and tumor cross-talk mechanisms against drug response features of AML by performing single cellgene expression and epigenetic analyses in the context of bone marrow niche. Tumor microenvironment cross-talk will be further explored in Aim 2 focusing on monocytes and stromal cells and in the context of NK and Tcells in Aim 3 by performing CRISPR/Cas screening with co-culture platforms. Identified targets/pathways willbe validated to fully define microenvironmental mechanisms of acquired drug resistance. These results will buildpredictive models of signaling crosstalk in response to therapeutic stress and identify combination therapies toovercome acquired resistance particularly in the context of the microenvironment. We will test the effect of theseinhibitors on cell viability cellular heterogeneity differentiation and target inhibition using multi-parametric flowcytometry and immunofluorescence analysis. We will integrate these findings with Project 1 and prioritizedtargets will be tested for their translational impact in Project 3. Overall elucidating the influence ofmicroenvironment-driven signaling on drug response and survival of AML cells will help identify novel tractabletargets for combination therapies to overcome acquired drug resistance in AML. +No NIH Category available Animals;Brain;Cells;Clinical;Collaborations;Development;Engineering;Ensure;Glioblastoma;Goals;Grant;Growth;Human Resources;Image;Immune checkpoint inhibitor;Immunology;Immunosuppression;Immunotherapy;Implant;Implantation procedure;Individual;Infection;Institution;Intracranial Neoplasms;Investigational Therapies;Luciferases;Magnetic Resonance Imaging;Maintenance;Modeling;Modification;Molecular;Monitor;Mouse Cell Line;Mus;Oncolytic;Oncolytic viruses;Operative Surgical Procedures;Performance;Quality Control;Reproducibility;Research;Research Personnel;Research Project Grants;Resistance;Resources;Sampling Biases;Service provision;Services;Signal Transduction;Simplexvirus;T-Lymphocyte;Technical Expertise;Techniques;Testing;Time;Transgenes;Tumorigenicity;United States National Institutes of Health;Validation;bioluminescence imaging;comparative;exome sequencing;experimental study;immune checkpoint;implantation;improved;interest;member;neoantigens;programs;receptor;repository;serial imaging;tumor Core 3: Mouse GBM models and Imaging Core NarrativeCore 3 will provide services to Projects 2 3 and 4 by providing well characterized mouse GBM cells and byperforming the intracranial implantation procedures to establish GBMs in mouse brains. Monitoring of GBMgrowth will be performed utilizing small animal MRIs and bioluminescence imaging. NCI 10684054 6/27/23 0:00 PAR-18-290 5P01CA236749-04 5 P01 CA 236749 4 7/3/20 0:00 6/30/25 0:00 ZCA1-RPRB-6 5290 2785736 "CHIOCCA, E. ANTONIO" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 247517 138278 109239 Core 3 AbstractTo ensure reproducibility rigor and harmonization amongst the mouse glioblastoma (GBM) models utilized byProjects 2 3 and 4 we have established a mouse GBM model Core that is exclusively utilized for this ProgramProject and does not exist within participating Institutions. The Core provides broad centralized access to acentral repository responsible for the maintenance and testing of mouse GBM tumors and professional expertiserelated to their stereotactic implantation into mouse brains and the analysis including imaging of intracranialGBMs. It also has been providing mouse GBM neoantigen discovery and validation. This would include accessto mouse cell lines and their derivatives critical to the experimental aims. This is more easily accomplishedthrough the Core and not as easily done through individual (e.g. R01) granting mechanisms or through existingNIH sponsored service cores at the P01 institutions. This will be accomplished by pursuing two specific aims:generate and maintain a repository of mouse GBM cells engineer GBM cells that express transgenes of interestand identify and validate mouse GBM neoantigens (Aim 1) and provide the technical expertise and performancefor the stereotactic implantation of mouse GBMs in brains and for their serial imaging (Aim 2). The provision ofthese services for 3 of the 4 Projects will reduce expense will reduce technical and sample bias and will ensurethat the 3 Projects will employ the same well characterized mouse GBM cells that are implanted and imaged byexpert technical personnel. +No NIH Category available Accounting;Achievement;Affect;Authorship;Budgets;Clinical;Collaborations;Communication;Coordination and Collaboration;Data;Development;Effectiveness;Ensure;Evaluation;Evaluation Research;Expenditure;Glioblastoma;Grant;Immunosuppression;Individual;Institution;Investigation;Laboratories;Monitor;Online Systems;Outcome;Program Research Project Grants;Publications;Reagent;Recommendation;Reporting;Research;Research Personnel;Resolution;Resources;Services;T-Lymphocyte;Telephone;Time;computerized data processing;data sharing;design;immunotherapy clinical trials;meetings;member;novel;operation;programs;shared database;symposium;tool;verbal Administrative Core n/a NCI 10684048 6/27/23 0:00 PAR-18-290 5P01CA236749-04 5 P01 CA 236749 4 7/3/20 0:00 6/30/25 0:00 ZCA1-RPRB-6 5287 2785736 "CHIOCCA, E. ANTONIO" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 172512 108172 64340 PROJECT SUMMARY ADMINISTRATIVE CORE (CORE A)In this competing renewal P01 application the Administrative Core (Core A) will continue to provide criticalcentralized grant administration data processing communication processing and budget management for allthe projects and cores. This Core will also serve to amalgamate the investigators their experimental findingsand their ideas evaluation of research efforts and critically direct the summary efforts toward maintaining ahighly integrated program outcome. The Core functions to: 1). Provide administrative services to theinvestigators. This includes the management of project supplies filing development of memos meetingminutes and communications covering all operations including publications; 2). Organize Program-relatedmeetings. Organize monthly or bi-monthly meetings/conferences of all PPG investigators; quarterly meetingsof the Program Steering Committee; annual meeting of the Internal/External Scientific Advisory Boards 3).Maintain integration activities. These include data sharing rapid publication efforts and identify and instituteother novel activities critical to maintaining and strengthening the integration of the program. 4). Provideoverall fiscal review accounting and real time budgets analyses. This includes reports verbalcommunications reviews and forward-looking projections on expenditures.This Core is essential for the program integration and effective communication of the scientific program. +No NIH Category available Address;Adherence;Asian;Asian Americans;Asian Indian;Automobile Driving;Behavioral;Biological;California;Cancer Patient;Caring;Cessation of life;Characteristics;Chinese;Consensus;Data;Data Sources;Disease;Disparity;Ethnic Origin;Ethnic Population;Female;Filipino;Future;Geographic Locations;Grant;Guidelines;Health Disparities Research;Heterogeneity;Histology;Home;Incidence;Japanese;Koreans;Light;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;National Comprehensive Cancer Network;Operative Surgical Procedures;Patients;Pilot Projects;Population;Population Heterogeneity;Primary Neoplasm;Publishing;Race;SEER Program;Socioeconomic Factors;United States;Vietnamese;Woman;Work;cancer health disparity;cancer survival;cancer therapy;chemotherapy;data registry;improved;neoplasm registry;ovarian neoplasm;programs;public health priorities;racial population;social;socioeconomics;surveillance data;survival disparity;treatment planning;tumor Examining the disparities in ovarian cancer survival among Asian Americans Pilot Project 2: Project NarrativeOvarian cancer survival is highest among Asian Americans relative to other races but it is not the same acrossall Asian subethnic groups. Given the importance of the Asian American populations heterogeneity whenstudying cancer our pilot project will examine tumor characteristics and treatment care by Asian subethnicgroup to clarify ovarian cancers ethnic-specific survival disparities. The findings of this work will shed light onthe underlying factors driving the ethnic-specific differences observed to inform strategies for addressing thishighly fatal disease. NCI 10684042 8/15/23 0:00 PAR-18-911 5P20CA253251-03 5 P20 CA 253251 3 9/22/21 0:00 8/31/25 0:00 ZCA1-SRB-2 5285 11497038 "LEE, ALICE " Not Applicable 45 Unavailable 106670755 VQ5WK498QDC6 106670755 VQ5WK498QDC6 US 33.8781 -117.884245 513603 CALIFORNIA STATE UNIVERSITY FULLERTON FULLERTON CA Domestic Higher Education 928313014 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 8036 12561 5276 Pilot Project 2: Project SummaryOvarian cancer is a highly fatal disease with a five-year relative survival of less than 50%. However ovariancancer survival is not the same for all women. Asian American ovarian cancer patients have the highest survivalacross all major racial groups however the Asian American population is heterogeneous. Studies have shownthat analyzing Asian Americans as a single group overlooks important ethnic-specific disparities and this hasbeen observed for ovarian cancer. Hence this pilot project aims to better understand these disparities using datafrom the California Cancer Registry (CCR). The CCR is an ideal data source for this project given that it includesdetailed demographic socioeconomic tumor and treatment information by Asian subethnic group and coversthe geographic region in the United States that is home to the largest number of Asian Americans.Our preliminary analyses of Asian American ovarian cancer patients using data in the CCR showed ethnic-specific percent differences for several survival-related characteristics. To clarify these differences Aim 1 of thisproject will examine the association between Asian subethnic group and ovarian cancer tumor characteristics.Certain Asian subethnic groups may be more likely to present with ovarian cancers of a particular grade stageor histology hence the ethnic-specific survival disparities may be attributed to the tumors themselves. Aim 2 ofthis project will examine whether receipt of National Comprehensive Cancer Network (NCCN) guideline adherentcare and its association with ovarian cancer survival differ across Asian subethnic groups. NCCN guidelineconsensus statements reflect the most current and accepted standard for cancer treatment hence the ethnic-specific survival disparities may be attributed to the treatment and care received. Certain Asian subethnic groupsmay be more likely to receive NCCN adherent care and receipt of that care may be differentially associated withsurvival.Given the fatality of ovarian cancer understanding why some women die from ovarian cancer while others donot is a public health priority. Few ovarian cancer studies have focused on Asian Americans hence this pilotproject will not only shed light on an understudied segment of the population but will do so in a way thatrecognizes the importance of the populations heterogeneity so ethnic-specific disparities are not overlooked.Understanding how ovarian tumors and treatment care may differ by Asian subethnic group will inform the futurework that is needed to understand the underlying factors contributing to ovarian cancer disparities and survivaloverall. +No NIH Category available Automobile Driving;Brain;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CTLA4 gene;Cell physiology;Cells;Cerebral Edema;Clinical Management;Clinical Trials;Collaborations;Complement;Cytokine Signaling;Data;Dexamethasone;Dose;Excision;Failure;Functional disorder;Gene Expression;Genes;Glioblastoma;Glucocorticoids;Human;Immune;Immune response;Immune system;Immunosuppression;Immunosuppressive Agents;Immunotherapy;Individual;Inflammation;Investigation;KLRB1 gene;Knowledge;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of lung;Mediating;Mediator;Modeling;Mus;Operative Surgical Procedures;Pathway interactions;Patients;Play;Population;Pre-Clinical Model;RNA;Regulatory T-Lymphocyte;Renal carcinoma;Reporter;Resistance;Role;Signal Transduction;Site;Statistical Data Interpretation;T-Lymphocyte;Testing;Therapeutic;Time;Treatment outcome;Tumor-Infiltrating Lymphocytes;Vaccines;anti-CTLA4;anti-PD-1;anti-tumor immune response;biocomputing;cancer immunotherapy;checkpoint receptors;cytokine;effector T cell;exhaustion;fighting;hormonal signals;immune cell infiltrate;immune checkpoint;immune checkpoint blockade;immunoregulation;improved;melanoma;mouse model;novel;prevent;programmed cell death protein 1;programs;receptor;receptor expression;receptor function;response;single-cell RNA sequencing;steroid hormone;success;synergism;tumor;tumor growth;tumor microenvironment Proj 4: Triggers for the Induction of T Cell Dysfunction on T cells in Glioblastoma PROJECT NARRATIVEGlioblastome multiforme (GBM) is a deadly form of brain cancer that is not benefitting from current advances inimmune-based therapies. This could be due to the inherent state of immune suppression that serves to preventunwanted inflammation in the brain. The proposed studies will advance our knowledge of how immunoregulatorycytokine signaling acts together with steroid hormone signaling to suppress anti-tumor immune responses inGBM. NCI 10684037 6/27/23 0:00 PAR-18-290 5P01CA236749-04 5 P01 CA 236749 4 7/3/20 0:00 6/30/25 0:00 ZCA1-RPRB-6 5283 1878275 "KUCHROO, VIJAY K." Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 436798 244021 192777 PROJECT SUMMARYTherapies that block co-inhibitory or checkpoint receptors (eg. CTLA-4 PD-1) have realized the potential of theimmune system to successfully fight multiple cancers including melanoma lung and renal cancer.Unfortunately patients with glioblastoma (GBM) have not benefitted from these checkpoint blockade therapies.This likely reflects the fact that the brain is a site of immune privilege; it has set up a state of inherent immunesuppression in order to prevent inflammation that would be detrimental to the host. This immune suppressedstate likely underlies the failure of current immunotherapies in GBM. The lack of response to anti-CTLA-4 andanti-PD-1 in GBM raises the issue of whether alternative checkpoints are active in the GBM tumormicroenvironment (TME) which need to be identified and exploited to achieve the promise of immunotherapyfor GBM. Moreover GBM patients routinely undergo treatment with high dose glucocorticoid (GC eg. Decadron)a potent immune suppressive agent prior to surgical resection and during treatment. This raises the importantissue of whether glucocorticoid therapy plays an important role in enhancing the immune suppressed statepresent in GBM which in turn further antagonizes the potential of checkpoint blockade therapy.We have identified that the immunoregulatory cytokine IL-27 is a key driver of a co-inhibitory module of genesthat contains several novel receptors that function as checkpoint receptors. Further we have identified that bothexogenous as well as endogenous GC can promote the expression of multiple checkpoint receptors and thatGC cooperates with IL-27 to promote expression of the co-inhibitory module and expression of gene programsassociated with T cell dysfunction. Based on our preliminary data we hypothesize that IL-27 and glucocorticoidsignaling act in the GBM TME to promote the expression of checkpoint receptors and set the stage for a dominantimmune suppression. Indeed interrogation of the single-cell RNA profiles of the immune infiltrate in human GBMshows significant expression of the IL-27-induced co-inhibitory gene module and signatures indicating active GCsignaling. Achieving a thorough understanding of the IL-27 and glucocorticoid signaling circuits within the GBMTME will not only provide a means to understand how GBM tumors set a state of immune suppression but alsoprovide a set of novel targets for improving the immune response to GBM. We propose the following specificaims: 1) Determine the impact of the IL-27 signaling circuit in the GBM tumor microenvironment and 2) Determinehow glucocorticoid (GC) signaling contributes to checkpoint receptor expression and induction of a state ofimmune suppression in GBM. +No NIH Category available Adult;Affect;Biological Assay;CD8-Positive T-Lymphocytes;CDK4 gene;CTLA4 blockade;CTLA4 gene;Caring;Cell Cycle;Cells;Clinical Trials;Combined Modality Therapy;Data;Development;Future;Genetic Transcription;Glioblastoma;Goals;Harvest;Immune;Immunocompetent;Immunologic Memory;Immunologics;Immunosuppression;KLRB1 gene;Maintenance;Malignant Neoplasms;Malignant neoplasm of brain;Mediator;Memory;Modeling;Mus;Oncolytic;Oncolytic viruses;Outcome;PD-1 blockade;Pathway interactions;Patient-Focused Outcomes;Patients;Peptide Vaccines;Phase I Clinical Trials;Prognosis;Regimen;Selection for Treatments;T cell differentiation;T cell infiltration;T cell response;T memory cell;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;Vaccination;Vaccine Therapy;Vaccines;anti-CTLA-4 therapy;anti-PD-1;anti-PD1 therapy;anti-tumor immune response;cell population study;cell type;checkpoint inhibition;combinatorial;design;efficacy testing;expectation;immune checkpoint blockade;immunogenic cell death;improved;insight;mouse model;novel therapeutics;peptide vaccination;pre-clinical;programmed cell death ligand 1;programmed cell death protein 1;rational design;response;small molecule;targeted treatment;tumor;tumor microenvironment;tumor-immune system interactions Proj. 2: Combining immune checkpoint blockade with T cell activation Narrative Project 2Project 2 will evaluate the ability of vaccination oncolytic viruses or targeted therapies to improve Immunecheckpoint blockade (CPB) therapy using immune competent GBM mouse models and determine how CPBtiming and sequence in these combinatorial approaches affects T cell memory and therapeutic efficacy. Thesestudies will inform rational selection of therapies for augmenting effects of CPB in GBM patients. NCI 10684020 6/27/23 0:00 PAR-18-290 5P01CA236749-04 5 P01 CA 236749 4 7/3/20 0:00 6/30/25 0:00 ZCA1-RPRB-6 5280 2785736 "CHIOCCA, E. ANTONIO" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 475430 390172 85258 Summary Project 2Immune Checkpoint blockade (CPB) has revolutionized the care for many cancers but clinical trials using anti-PD-1 ICB have not had significant efficacy in GBM. GBM has a profoundly immunosuppressive tumormicroenvironment (TME) promoted by immunosuppressive cell types pathways and mediators. Thus it is notsurprising that single CPB did not meet therapeutic expectations. The goal of Project 2 is to improve patientoutcomes following anti-PD-1/ CTLA-4 therapy in GBM by identifying rational combination therapy approaches.We hypothesize that combining therapies to improve T cell priming and activation with anti-PD-1/ CTLA-4 therapywill significantly increase response rates in GBM converting these immunologically cold tumors into hottumors. Based on our preliminary data showing that selective loss of PD-1 at different stages of T celldifferentiation can either promote or antagonize effector and memory differentiation we further hypothesize thatthe timing of PD-1/ CTLA-4 blockade in combinatorial regimens may critically influence protective anti-tumor Tcell responses. Project 2 will test these hypotheses using three complementary approaches that evaluate timingof PD-1 blockade combined with vaccination oncolytic virus vaccine therapy or targeted therapies in thefollowing aims: 1- Determine the effect of peptide vaccination combined with anti-PD-1/ CTLA-4 therapyon the establishment of anti-tumor immune responses and development of immunological memory; 2-Test if addition of an oncolytic virus boost to GBM cell vaccine further increases sensitivity to anti-PD-1/ CTLA-4; and 3- Evaluate the ability of small molecule CDK4/6 targeted therapies to enhance therapeuticbenefit of anti-PD-1/ CTLA-4 in GBM models. Interactions with all Projects and utilization of all Cores aredescribed in the Proposal. Our findings will provide optimal ways to combine therapies and insights into theimmunosuppressive GBM microenvironment. These data will directly inform the rationale design of combinationtherapies for future clinical trials for GBM patients. +No NIH Category available Achievement;Address;Attenuated;Biometry;Brain Neoplasms;CD4 Positive T Lymphocytes;CD8B1 gene;CDK4 gene;Cells;Clinical;Clinical Trials;Collaborations;Combination immunotherapy;Combined Vaccines;Complex;Computer Analysis;Data;Dendritic Cell Vaccine;Environment;Failure;Genomics;Glioblastoma;Glucocorticoids;Goals;Human;Image;Immune;Immune response;Immune system;Immunobiology;Immunophenotyping;Immunosuppression;Immunotherapy;KLRB1 gene;Long-Term Survivors;Malignant Neoplasms;Methods;Modality;Modeling;Mus;Newly Diagnosed;Oncolytic viruses;PD-1 blockade;Pathway interactions;Patients;Peptide Vaccines;Peptides;Phase Ib Trial;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Safety;Sampling;Services;Signal Pathway;Signal Transduction;Standardization;T cell infiltration;T memory cell;T-Cell Activation;T-Lymphocyte;Technology;Testing;Treatment Efficacy;Tumor Immunity;Vaccines;anti-PD-1;anti-cancer;attenuation;biocomputing;cancer type;checkpoint receptors;clinical application;clinical translation;cohort;computerized tools;effector T cell;epidermal growth factor receptor VIII;immune checkpoint blockade;immunoregulation;immunotherapy clinical trials;immunotherapy trials;improved;inhibitor;innovation;insight;mouse model;neoantigen vaccine;neoantigens;neuro-oncology;novel;palliate;pre-clinical;preclinical trial;programmed cell death protein 1;programs;response;single-cell RNA sequencing;success;tumor;tumor-immune system interactions Understanding and Overcoming T cell Immunosuppression in Glioblastoma PROJECT NARRATIVE - OVERALLGlioblastoma (GBM) remains one of the deadliest cancers. We will research how to improve the bodysimmune cells recognition and destruction of GBM cells by understanding how to better activate T cells in thetumors environment. Our group will perform a clinical trial of a novel personalized vaccine but also study howto make this even more efficacious in mouse models of GBM in order to get the bodys immune system toreject GBMs. NCI 10684011 6/27/23 0:00 PAR-18-290 5P01CA236749-04 5 P01 CA 236749 4 "UNDALE, ANITA H" 7/3/20 0:00 6/30/25 0:00 ZCA1-RPRB-6(J1) 2785736 "CHIOCCA, E. ANTONIO" "REARDON, DAVID A" 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 2810976 NCI 2359362 451614 AbstractGlioblastoma (GBM) remains a formidable cancer to treat with only anecdotal examples of long-term survivors.Recently immunotherapy has seen multiple successes against various types of cancer but several recentclinical trials of this modality in GBM have not been successful. It is evident that two inter-related factors in thecomplex immunobiology of GBM have thwarted therapeutic efficacy: the existence of multipleimmunosuppressive mechanisms and the significant lymphodepletion in the GBM microenvironment. Theoverarching goal of the Program Project is to address the problem of insufficient T cell activation and marked Tcell attenuation in the GBM microenvironment. We will test the overall hypothesis that promotion of CD8+and CD4+ T cell functionality can overcome the highly immunosuppressive mechanisms of GBM. Acorollary to this hypothesis is that preclinical and clinical trials of immunotherapy combinations will providean effective approach to GBM treatment. We have assembled a highly interactive and interdisciplinary teamof 11 investigators in 4 highly integrated Research Projects supported by 4 Cores. This team (some of whomhave been working together for more than two decades) brings deep expertise in immunobiology neuro-oncology clinical trials genomics and computational analyses to mechanistically study these two critical factors.We plan to study how immune checkpoint blockade can be combined with other T cell activatingimmunotherapies both in a clinical trial (Project 1) and in preclinical mouse models (Project 2). We propose tostudy novel immunosuppressive pathways in human GBMs based on CD161/ Clec2D (Project 3) IL-27 andendogenous glucocorticoid signaling (Project 4) and understand how these can be overcome to improve theanti-tumor function of CD4 and CD8 effector T cells. Core services will provide sophisticated genomic (Core 1)biocomputational/ biostatistical (Core 2) and mouse modeling/ imaging (Core 3) approaches to these Projects.This Program Project will thus provide significant mechanistic insights into the immunosuppressivemicroenvironment of GBM into preclinical avenues of how to activate T cells against these tumors and finallyinto a novel clinical trial to target personalized GBM neoantigens in humans. 2810976 +No NIH Category available Achievement;Address;Aftercare;Age;Area;Award;Behavior;Behavioral;Behavioral Symptoms;Breast Cancer survivor;Cancer Intervention;Cancer Survivor;Caring;Clinical;Clinical Trials Design;Cognitive;Consultations;Coping Skills;Data;Development;Diagnosis;Diet;Distress;Economics;Education;Educational process of instructing;Fatigue;Focus Groups;Funding;Germ cell tumor;Goals;Guidelines;Health;Healthcare;Hematologic Neoplasms;Home;Hybrids;Institute of Medicine (U.S.);Intervention;Late Effects;Lead;Life;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediating;Mediator;Melanoma Cell;Mentors;Monitor;National Cancer Institute;Notification;Oncology;Outcome;Outcome Study;Pain;Participant;Patient Outcomes Assessments;Patients;Pattern;Personal Satisfaction;Persons;Physical activity;Provider;Psychologist;Randomized;Recommendation;Research;Research Design;Research Personnel;Resources;Schools;Self Efficacy;Severities;Statistical Methods;Structure;Survival Rate;Survivors;Symptoms;Technology;Teenagers;Testing;Time;Training;Underserved Population;Waiting Lists;Weight maintenance regimen;Work;acceptability and feasibility;aged;arm;cancer cell;cancer therapy;cancer type;career;emotional distress;evidence base;experience;feasibility testing;follow-up;improved;intervention delivery;intervention refinement;mHealth;malignant breast neoplasm;member;mobile application;novel;oncology program;participant retention;peer;peer support;physical symptom;pilot trial;prevent;programs;prototype;psychological symptom;randomized clinical trials;recruit;skills;skills training;social;social cognitive theory;social relationships;survivorship;symptom management;symptomatic improvement;therapy design;treatment arm;young adult Improving Symptom Management for Survivors of Young Adult Cancer Project NarrativeSymptom interference is common for survivors of young adult cancer (aged 18-39 at diagnosis) and impactstheir abilities to achieve normative life goals (e.g. education careers independence romantic/socialrelationships) as well as adhere to recommended follow-up care. Assistance with symptom management hasbeen rated by young adult survivors as an important and unmet healthcare need; however skill-based symptommanagement interventions have typically been tested among older cancer survivors and have not targeted theunique developmental needs of those diagnosed as young adults. The proposed research advances the healthand wellbeing of young adult cancer survivors by creating a developmentally appropriate hybrid in-person/mHealth behavioral symptom management intervention which addresses variables (i.e. symptoms andsymptom interference) consistently linked to significant social economic and health burden. NCI 10684000 8/2/23 0:00 PA-19-116 5K08CA245107-05 5 K08 CA 245107 5 "RADAEV, SERGEY" 9/11/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 12495414 "DORFMAN, CAROLINE " Not Applicable 4 PSYCHIATRY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 171444 NCI 158744 12700 More than 60000 young adults (YAs) aged 18-39 are diagnosed with cancer in the US each year. Advances intreatment have yielded five year survival rates >70% suggesting that the majority of YAs will become long-termcancer survivors. Symptom (e.g. pain fatigue distress) interference is common for YA cancer survivors andimpacts their abilities to achieve normative life goals (e.g. returning to work/school achieving autonomypursuing social/romantic relationships) and adhere to recommended follow-up care. Symptom management hasbeen identified as a significant issue in the transition to survivorship for YAs by the Institute of Medicine andNational Cancer Institute and assistance with symptom management is rated as an important and unmet needby YA survivors. Yet behavioral symptom management interventions have not targeted the needs of thosediagnosed as YAs. The proposed study aims to develop and test the feasibility and acceptability of a novelbehavioral symptom management intervention designed for survivors of YA cancer (cancer types: hematologicbreast or gastrointestinal cancers melanoma or germ cell tumors). The hybrid intervention will include in-person group sessions and an integrated mobile application. The intervention will provide peer support whilealso teaching skills to improve symptoms symptom interference and self-efficacy for symptom management.The mobile application will assist with symptom monitoring home skills practice and connecting with groupmembers. The preliminary version of the intervention will be guided by the research teams prior work developingand testing symptom management interventions for cancer survivors national guidelines for YA oncologyconsultation with an expert advisory board and input from patient (3 groups n=10/group) and provider (1 groupN=10) stakeholders obtained during focus groups. The intervention will be further refined following review bypatient user testers (n=10). Next feasibility acceptability and distributions of change over time as well asrelationships between outcome variables will be examined through a pilot randomized clinical trial of thedeveloped intervention. Participants (N=60) will be randomized to intervention or wait-list control arms. Primarystudy outcomes are symptom (pain fatigue distress) severity and symptom interference. Self-efficacy andsupport will also be examined as mediators of change in outcome variables. The proposed study has the potentialto make several significant contributions by targeting an underserved group of cancer survivors addressing acritical gap in care and addressing variables consistently linked to social economic and health burden for YAs.It will also provide important information about approaches to identify recruit and retain YA cancer survivors inresearch and provide pilot data for a larger trial. Formal training in the following areas will strengthen the PIsability to become an independent investigator developing evaluating and disseminating interventions for YAcancer survivors: 1) clinical trial design and statistical methods 2) use of mHealth technology for research andintervention delivery 3) needs of cancer survivors diagnosed as YAs and 4) professional development. 171444 +No NIH Category available Acute;Acute Lymphocytic Leukemia;Address;Adolescent;Advisory Committees;Area;Award;Child;Childhood Acute Lymphocytic Leukemia;Clinical;Clinical Research;Collaborations;Core Facility;Data;Development;Discipline;Disparity;Eligibility Determination;Ensure;Epidemiologist;Equity;Ethnic Origin;Faculty;Funding;Future;Genetic;Grant;Grant Review;Health Disparities Research;Human;Institution;Interdisciplinary Study;Investigation;Latino;Malignant Childhood Neoplasm;Mentorship;Mission;Molecular;Monitor;Outcome;Peer Review Grants;Physicians;Pilot Projects;Prediction of Response to Therapy;Recording of previous events;Records;Reporting;Research;Research Personnel;Research Project Grants;Scientist;Site;System;Translational Research;Treatment-related toxicity;United States National Institutes of Health;Work;cancer health disparity;cost;ethnic disparity;high reward;high risk;improved outcome;innovation;member;novel strategies;outcome disparities;phenotypic data;programs Developmental Research Program DEVELOPMENTAL RESEARCH PROGRAM (DRP) NARRATIVEThe objective of the Developmental Research Program (DRP) of this SPORE planning study is to support thedevelopment and successful completion of innovative high-risk/high-reward pilot projects that aim tounderstand or reduce outcome ethnicity-based disparities in childhood acute lymphoblastic leukemia (ALL).Funding decisions will be made by the DRP committee which will consider work with strong scientific merit thatis perceived as high-risk/high-impact in relation to ALL disparity research. Additionally we have assembled astrong Advisory Committee which together with the DRP Committee will facilitate the transition/developmentof pilot grant data to work that is independently funded with potential inclusion in our future P50 application. NCI 10683997 8/2/23 0:00 RFA-CA-19-034 5P20CA262733-03 5 P20 CA 262733 3 8/20/21 0:00 7/31/24 0:00 ZCA1-RPRB-M 5273 10243691 "GRAMATGES, MARIA MONICA" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 73330 47436 25894 DEVELOPMENTAL RESEARCH PROGRAM (DRP) SUMMARY/ABSTRACTThe objective of the Developmental Research Program (DRP) of this SPORE planning study is to support thedevelopment and successful completion of innovative high-risk/high-reward pilot projects that aim tounderstand or reduce outcome ethnicity-based disparities in childhood acute lymphoblastic leukemia (ALL).This program will be co-led by Dr. Maria Monica Gramatges a physician scientist and Dr. Philip Lupo amolecular epidemiologist. Drs. Gramatges and Lupo each have strong track records in translational researchinvestigating genetic and molecular predictors of treatment-related toxicities in childhood cancer. Theircomplementary disciplines and history of collaboration evidence a strong commitment of the DRP to supportingmultidisciplinary research. DRP-supported projects may be clinical or translational but must address ethnicdisparities in ALL treatment-related toxicities (acute or late onset). Eligibility to apply for a DRP Pilot Grant willextend to any faculty member of an institution participating in this application. Proposals will be scored usingthe NIH 9 point system and selection for funding will be jointly determined by the DRP Committee.Membership to the DRP Committee will be distributed equally across all participating sites to ensure equity andtransparency in award distribution and will include faculty with expertise in clinical and translational researchand who have a strong track record of participation in grant peer review. Criteria for funding will be work withstrong scientific merit that is perceived as high-risk/high-impact in the above listed areas of concentration.Proposals representing collaborations between participating institutions will also be prioritized as willproposals from junior faculty and new investigators (those with no prior independent federal funding) and thoseconsidered likely to result in future independent funding. All Pilot Grants will be awarded for one year with anopportunity for a one-time one-year renewal at the end of the first year. In addition to grant review andselection the DRP Committee will be responsible for monitoring and oversight of funded projects via regularreview of progress and final reports. The DRP's core mission is to provide grant awardees with 1) fundingsupport 2) access to core facilities and 3) mentorship during the award period. A total of $75000 will bebudgeted to support funding of three Pilot Awards in Year 1 at $25000 per award and $90000 per year ineach subsequent year to support funding two Pilot Awards per year plus two renewals at $20000 per renewal.All Pilot Grant PI's will be provided with access to the designated Cores with no associated cost and will berequired to use at least one Core. The DRP Committee will assign each funded project an Advisory Committeewith relevant expertise who will provide mentorship and guidance that is specific to each project. A key role ofthe Advisory Committee together with the DRP Committee will be to facilitate the transition/development ofPilot Grant data to work that is independently funded with potential inclusion in a future P50 application. +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Acute leukemia;Adolescent;Adult;Aliquot;Applications Grants;Biological Factors;Biology;Blood;Blood specimen;Bone Marrow;Bone Marrow Cells;Cancer Center;Catalogs;Cells;Cerebrospinal Fluid;Child;Childhood Acute Lymphocytic Leukemia;Clinical;Clinical Trials;Code;Collection;Comprehensive Cancer Center;Core Facility;DNA;Data;Databases;Dedications;Development;Disparity;Doctor of Philosophy;Ensure;Ethnic Origin;Ethnic Population;Freezing;Frequencies;Future;Genetic;Goals;Grant;Health;Hepatotoxicity;Hodgkin Disease;Information Storage;Latino;Leukocytes;Liquid substance;Location;Malignant Neoplasms;Medicine;Methotrexate;Mononuclear;Patients;Pediatric Oncology Group;Pediatrics;Peripheral Blood Mononuclear Cell;Pilot Projects;Plasma;Population Sciences;Postdoctoral Fellow;Procedures;Process;Research;Research Project Grants;Research Support;Resources;Sampling;Services;Shipping;Site;Specimen;Texas;Therapeutic;Time;Tissues;Translational Research;Treatment-related toxicity;Tumor Biology;Vulnerable Populations;biobank;cancer health disparity;cancer prevention;central database;college;ethnic disparity;experience;experimental study;improved outcome;insight;leukemia/lymphoma;member;mid-career faculty;neurotoxicity;outcome disparities;peripheral blood;professor;programs;racial population;recruit;sample collection;social health determinants;tenure track;translational research program;translational study Biospecimen Processing and Storage Core NARRATIVE Biospecimen Processing and Storage Core (Core B)Latino children with acute lymphoblastic leukemia (ALL) have a higher frequency of treatment-relatedtoxicities compared to other racial/ethnic groups. Multiple factors likely contribute to these disparities inthis vulnerable population of children including underlying germline genetics tumor biology and socialdeterminants of health. The Biospecimen Processing and Storage Core will serve as the central locationwhere biospecimens will be processed and stored to support research that can provide insights into thebiological factors underlying ethnic cancer health disparities in childhood ALL. NCI 10683994 8/2/23 0:00 RFA-CA-19-034 5P20CA262733-03 5 P20 CA 262733 3 8/20/21 0:00 7/31/24 0:00 ZCA1-RPRB-M 5271 1939831 "HORTON, TERZAH M" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 164367 114277 50090 PROJECT SUMMARY Biospecimen Processing and Storage Core (Core B)The proposed cancer health disparities translational research program in this P20 planning grantapplication relies on the submission of serial peripheral blood bone marrow and cerebrospinal fluid (CSF)specimens from children and adolescents with acute lymphoblastic leukemia (ALL) across theparticipating clinical recruitment sites of the Reducing Ethnic Disparities in Acute Leukemia (REDIAL)Consortium. The Biospecimen Processing and Storage Core (BPSC) will serve as the central locationwhere these samples will be processed into the materials needed for the specific studies in ResearchProjects 1 (treatment-associated hepatotoxicity) and 2 (methotrexate neurotoxicity) as well asdetermination of genetic ancestry for use across all projects and biobanking of material that will beavailable for pilot projects through the Developmental Research Program (DRP). This Core will supportthe collection shipping processing and storage of patient samples from each study site as well asprovide up-to-date and accurate sample annotation. The Core will follow previously developed standardoperating procedures to ensure uniform collection and processing for optimal sample yield and quality.The Aims of the Core are to: 1) Receive and catalog blood bone marrow and CSF provided by theConsortium sites; 2) Process all patient samples to isolate plasma peripheral blood mononuclear cellsand bone marrow mononuclear cells and separate blasts from non-blasts where appropriate; 3) Allocateand distribute samples to Projects; and 4) Maintain a biobank of samples for future research. The resultingbiobank will become an extremely valuable resource for this and future translational studies examiningethnic disparities in childhood ALL. +No NIH Category available Antigens;Biological Assay;Cancer Patient;Cancer Vaccines;Cells;Dana-Farber Cancer Institute;Dedications;Detection;Development;Funding;Generations;Genomics;Genotype;Immune;Immunity;Immunogenomics;Immunotherapy;Investigation;Laboratories;Malignant Neoplasms;Membrane Proteins;Molecular;Monitor;Pathway interactions;Persons;Population;RNA;Research;Resources;Sampling;T-cell receptor repertoire;Techniques;Technology;Thinking;Tumor Immunity;cancer cell;cancer genomics;cancer therapy;cancer type;design;genomic platform;immunotherapy trials;insight;neoplastic cell;novel;novel strategies;patient response;pressure;programs;protein expression;single cell analysis;transcriptome;transcriptome sequencing;tumor immunology;tumor microenvironment;tumor-immune system interactions Single cell investigation of co-evolution in cancer cells and host cell immune microenvironment Project NarrativeNew advances in the field of cancer immunology and genomics have transformed the waypeople are thinking about the importance of immunotherapy in cancer treatment; a remainingquestion of current immunotherapy is how the cancer cells and microenviroment immune cellsevolve during therapy and how to increase the cancer patient response rate. Here we proposeto use novel single cell/genomics technologies to understand both the changes in cellularcircuitry underlying malignancy initiation progression and transformation and also the co-evolving changes in the tumor microenvironment. These aims will be pursued in the context ofexisting NCI-funded research programs in Translational Immunogenomics Laboratory directedby Dr. Catherine Wu at Dana-Farber Cancer Institute. NCI 10683993 7/20/23 0:00 PAR-19-290 5R50CA251956-04 5 R50 CA 251956 4 "DUGLAS TABOR, YVONNE" 8/15/20 0:00 7/31/25 0:00 ZCA1-SRB-1(M2)S 8907671 "LI, SHUQIANG " Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 144770 NCI 81791 62979 Project SummaryHow cancer cells co-evolve with their host microenvironment immune cells remains a criticalquestion in immunotherapy. The Wu lab focuses on the study of antigen-specific interactionsand their involvement in the cellular and molecular pathways underlying anti-tumor immunity.The DFCI Translational Immunogenomics Laboratory (TIGL) was created to expand technologyand computational capabilities developed within the Wu Lab and provide a dedicated resourcefor immunogenomic analysis across different cancer types. My current portfolio of projects isfocused on designing the development of single cell/genomics techniques to understand thecrosstalk between tumor cells and immune cell populations within the tumor microenvironmentand the selective pressure they mutually exert on each other. In particular: (i) I have developedthe sensitive and robust rhTCRseq to determine paired alpha and beta-TCR clonotypes insingle cells as well as to perform TCR repertoire analysis in bulk RNA samples. It has alreadyrevealed novel insights regarding the impact of immunotherapies such as cancer vaccines onthe generation of antigen-specific immunity and is being widely applied to the monitoring ofother immunotherapy trials. (ii) For plate-based single-cell analysis and for bulk RNA samples Ihave developed a novel strategy to perform qPCR and transcriptome sequencing. In addition Ihave implemented a droplet-based 10x Genomics platform to study single cell transcriptomeand surface protein expression in the same single cells. (iii) I have expertise in generatingtargeted multiplex RNA assays aimed at simultaneous detection of genotype and transcriptomeinformation at the single cell level. Altogether these diverse approaches have been and arebeing applied to several NCI-funded projects in the Wu Lab. Our new initiatives focus on thefurther development and implementation of novel single cell genomics technologies and theirapplications. 144770 +No NIH Category available 3-Dimensional;Address;Anatomy;Architecture;Artificial Intelligence;Binding;Blinded;Brain;Clinic;Clinical;Clinical Management;Clinical Treatment;Computer Assisted;Data;Detection;Diagnosis;Dose;Equilibrium;Expert Systems;Feedback;Image;Industrialization;Inferior;Injections;Institution;Lesion;Magnetic Resonance Imaging;Medical;Metastatic malignant neoplasm to brain;Michigan;Neoplasm Metastasis;New York;North Carolina;Patient imaging;Patients;Performance;Physicians;Quality of life;Radiation Dose Unit;Radiation Oncologist;Radiation therapy;Radiosurgery;Research Personnel;Role;Structure;System;Techniques;Technology;Testing;Therapeutic;Time;Training;Translating;Tumor Volume;Uncertainty;Universities;Variant;clinical imaging;deep learning;deep neural network;detection method;detector;improved;industry partner;neural network;object recognition;radiologist;response;tool;treatment planning;treatment response;tumor A clinical tool for automated detection and delineation of intracranial metastases from MRI Project NarrativeAs the management of multiple intracranial metastases is rapidly evolving the demands fordetection and delineation of a large number of potentially very small metastatic lesions in thebrain on 3D magnetic resonance images (MRI) are increasing dramatically. We aim to developan artificial intelligence (AI) system to assist both the radiologist as well as radiation oncologistin their roles in management of patients with multiple tumors metastatic to the brain. Theintended clinical utilities of the system will be evaluated through observer studies and radiationdose analyses. NCI 10683991 7/7/23 0:00 PAR-20-155 5R01CA262182-03 5 R01 CA 262182 3 "BEIER, HOPE THOMAS" 8/1/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 6623452 "CAO, YUE " Not Applicable 6 RADIATION-DIAGNOSTIC/ONCOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 351135 NCI 316687 34448 As the management of multiple intracranial metastases is rapidly evolving the demands fordetection and delineation of a large number of potentially very small metastatic lesions in thebrain on 3D magnetic resonance images (MRI) are increasing dramatically. Artificial intelligence(AI) systems can assist both the radiologist as well as radiation oncologist in their roles inmanagement of patients with multiple tumors metastatic to the brain. In response to PAR-20-155 we have assembled an academic-industrial partnership including investigators from threeacademic institutes and an industrial AI team to develop translate and validate AI systems toaddress this unmet clinical question. In this proposal a neural network system based uponmultiple scale 3D fully convolutional one-stage objective detectors containing segmentationheads will be optimized and investigated. Training and testing data will be provided from clinicalimages of patients treated with radiosurgery to multiple small metastases acquired from threeacademic centers curated by experts and augmented by addition of realistic synthetic lesionsinjected into images. The clinical utility of the network will be investigated for its ability to assista) radiologists in detecting multiple metastases accurately and efficiently and b) radiationoncologists in delineating multiple metastatic lesions to support selection of therapeutic strategiesand planning of treatments. 351135 +No NIH Category available Acute Lymphocytic Leukemia;Acute leukemia;Address;Adolescent;Adverse event;Affect;Bilirubin;Biological;Biological Markers;Blood;Blood specimen;Body fat;Body mass index;Child;Childhood;Childhood Acute Lymphocytic Leukemia;Clinical;Complication;Data;Diagnosis;Diagnostic;Disease-Free Survival;Disparity;Dose Limiting;Ethnic Origin;Etiology;Fatty acid glycerol esters;Functional disorder;Genetic;Genetic Predisposition to Disease;Genetic Variation;Genomics;Genotype;Glucose;Goals;Hepatic;Hepatotoxicity;Incidence;Individual;Inflammation;Inherited;Institution;Intake;Intervention;Investigation;Latino;Latino Population;Leukemia Acute Lymphoblastic Chemotherapy;Lipids;Liver;Magnetic Resonance Imaging;Metabolic;Metabolic Pathway;Methods;Molecular Epidemiology;Monitor;Morbidity - disease rate;Neoadjuvant Therapy;Newly Diagnosed;Nutritional;Obesity;Pathway interactions;Patient Self-Report;Patients;Pediatric Oncology;Pediatric cohort;Pharmacogenomics;Pharmacometabolomics;Phase;Phenotype;Prediction of Response to Therapy;Predisposition;Prevalence;Quality of life;Quantitative Trait Loci;Regimen;Relapse;Research;Research Personnel;Resources;Risk;Risk Factors;Role;Sampling;Severities;Survival Rate;Susceptibility Gene;Therapeutic;Toxic effect;Treatment Efficacy;Treatment Protocols;Treatment outcome;Treatment-related toxicity;Variant;Work;acute liver injury;admixture mapping;adverse outcome;amino acid metabolism;cancer therapy;chemotherapy;cohort;ethnic difference;ethnic disparity;ethnic diversity;experience;genetic variant;genomic data;high risk;improved;improved outcome;innovation;insight;leukemia relapse;leukemia treatment;liver function;metabolomics;modifiable risk;multi-ethnic;multiple omics;non-alcoholic fatty liver disease;novel marker;outcome disparities;pediatric patients;prospective;response;risk stratification;segregation;targeted delivery;therapeutic target;translational potential;treatment disparity;treatment risk Etiology and impact of ethnic disparities in therapy-associated hepatotoxicity among children and adolescents treated for ALL Project NarrativeThe proposed research which builds upon existing resources to study an adverse consequence of cancertherapy addresses key gaps in our understanding of treatment-associated hepatoxicity an adverse event whichdisproportionally affects Latino patients. This study will combine demographic clinical metabolomic andgenomic data with an emphasis on identifying novel biomarkers and modifiable therapeutic targets to reducethe burden of treatment-related toxicity among the most vulnerable pediatric patients with ALL. This avenue ofresearch has the significant translational potential to inform the delivery of targeted interventions to patients athigh risk for TAH with the ultimate goal of reducing ethnic disparities in ALL treatment outcomes. NCI 10683986 8/2/23 0:00 RFA-CA-19-034 5P20CA262733-03 5 P20 CA 262733 3 8/20/21 0:00 7/31/24 0:00 ZCA1-RPRB-M 5268 12358769 "BROWN, AUSTIN L" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 67644 62915 4729 Project SummaryThis proposal seeks to integrate clinical demographic metabolomic and genomic data to advance ourunderstanding of ethnic disparities in treatment-related hepatoxicity (TAH) during induction therapy for pediatricacute lymphoblastic leukemia (ALL). Improved treatment regimens for pediatric (ALL) have resulted in survivalrates exceeding 90%; however nearly a quarter of patients experience TAH. Emerging evidence from our grouphas identified striking ethnic disparities in the incidence of TAH. Specifically Latino patients with ALL appearparticularly vulnerable to dose-limiting TAH potentially compromising treatment efficacy during the critical initialinduction phase and contributing to well-established disparities in pediatric ALL relapse and survival. Thisproposal pursues the central hypothesis that risk of TAH is greater in Latino patients as compared to non-Latinopatients due to a combination of inherited and potentially modifiable risk factors. Our preliminary data suggestethnic disparities in TAH incidence are exacerbated but not fully explained by ethnic variation in obesity and thatthe abundance of key metabolites in the blood associated with liver function which are likely influenced bytreatment exposures and inherited genetic variation may serve as powerful biomarkers of TAH risk. Informedby our preliminary data the specific research aims of this Project will examine: 1) to what extent ethnic variabilityin obesity and associated hepatic dysfunction contribute to ethnic differences in the incidence of TAH duringpediatric ALL induction therapy; 2) whether consistent and recognizable changes induced by ALL chemotherapyin the metabolomic pathways involved in liver function are predictive of TAH; and 3) how genetic variationmodifies individual susceptibility to TAH. This Project which is jointly led by investigators with expertise inpediatric oncology (Drs. Huynh and Orgel) and molecular epidemiology (Dr. Brown) builds on the rich resourcesavailable in the ethnically diverse multi-institutional Reducing Ethnic Disparities in Acute Leukemia (REDIAL)consortium. Leveraging the Retrospective (n=2958) and Prospective (n=1369) REDIAL Cohorts this projectwill systematically evaluate and follow an additional 600 newly diagnosed cases of pediatric ALL. Thus thisinnovative proposal will establish one of the largest prospective investigations of TAH in a multi-ethnic cohort ofpediatric patients with ALL. The comprehensive research plan outlined here will address key gaps in ourunderstanding of ethnic disparities in the incidence and etiology of TAH and serve as a unique resource ofpreliminary data to support future research endeavors. Ultimately we anticipate that this work will inform risk-stratified approaches to safely deliver curative induction chemotherapy to Latino children and adolescentstreated for ALL to improve their overall survival. +No NIH Category available ARID1A gene;ATAC-seq;ATP6AP1 gene;Amino Acids;Autophagocytosis;B-Cell Lymphomas;B-Cell Neoplasm;B-Cell NonHodgkins Lymphoma;B-Lymphocytes;Binding;Binding Sites;Biological;Biology;CCL17 gene;Cell Line;Cell Survival;Cells;Cellular biology;Characteristics;Chronic Lymphocytic Leukemia;DNA Binding;DNA Binding Domain;Data;Dependence;Disease;Disease remission;Ecosystem;Enhancers;FRAP1 gene;Follicular Lymphoma;Follow-Up Studies;Frequencies;Future;Gene Expression;Gene Modified;Gene Mutation;Genes;Genetic Transcription;Histones;Hodgkin Disease;Human;Immuno-Chemotherapy;Immunotherapy;In Vitro;Incidence;Intercistronic Region;Interleukin-4;Introns;Link;Lymphoma;Lymphoma cell;Mantle Cell Lymphoma;Maps;Mediastinal;Molecular;Mutate;Mutation;Non-Hodgkin's Lymphoma;Non-Malignant;Pathway interactions;Patients;Pharmaceutical Preparations;Property;Proteins;Publishing;Recombinants;Recurrence;Relapse;Repression;Role;STAT protein;STAT6 Transcription Factor;STAT6 gene;Structure of germinal center of lymph node;Survival Rate;T-Lymphocyte Subsets;Work;data integration;experimental study;gain of function;genome-wide;improved;in vivo;inhibitor;innovation;large cell Diffuse non-Hodgkin's lymphoma;lymph nodes;mutant;new therapeutic target;novel;novel therapeutics;preference;programs;promoter;side effect;standard of care;targeted treatment;therapeutic target;therapy development;transcription factor;transcriptome The Biology of Mutant STAT6 in Follicular Lymphoma Follicular lymphoma (FL) constitutes the second most common B-cell Non-Hodgkin's lymphoma (B-NHL) withan annual incidence of ~15000 cases and more than 100000 patients in the US living with the disease. Despiteimprovements in the survival of FL patients the disease remains incurable and patients go through cycles oftreatment remission and relapse. In this proposal we outline our approach for the study of common STAT6mutations that drive this disease with possible future opportunities for novel therapy development. NCI 10683966 7/31/23 0:00 PA-20-185 5R01CA260677-02 5 R01 CA 260677 2 "JHAPPAN, CHAMELLI" 9/1/22 0:00 8/31/27 0:00 Cancer Genetics Study Section[CG] 8638284 "MALEK, SAMI NIMER" Not Applicable 6 INTERNAL MEDICINE/MEDICINE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 349713 NCI 224175 125538 Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma (NHL) in the US with over100000 patients living with the disease. While survival rates at 10 years have improved almost all patients withFL receive multiple chemo- or immunotherapies over their lifetime and most eventually relapse and progress.There exists no highly effective targeted therapy for FL and the standard of care for FL patients remains largelybased on chemoimmunotherapy. New drugs like the BTK inhibitor ibrutinib and the PIK3CD/PI3K inhibitoridealisib have improved the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).However these drugs are less effective in FL or are linked to serious side effects. Over the last eight years we have contributed to the discovery and initial functional characterization ofrecurrent mutations in FL including in the SWI/SNF component ARID1A linker histones (HIST1H1 B-E) IRF8the mTOR regulator RRAGC various components of the autophagy and mTOR regulator vATPase (ATP6V1B2VMA21) and STAT6. One of the important genes that emerged from our efforts is Signal Transducer andActivator of Transcription (STAT6) which is mutated in 11-23% of all FL and transformed FL (tFL). Frequentmutations in STAT6 have also been described in primary mediastinal B cell lymphoma (PMBCL) Hodgkin'slymphoma (HL) and diffuse large B cell lymphoma (DLBCL). STAT6 is part of the IL-4/JAK/STAT6 survival axisof B cells which is also activated by elevated IL-4 levels present in FL LNs. The FL-associated mutations inSTAT6 target amino acid hotspots which are located in the STAT6 DNA binding domain. We have demonstratedthat mutated STAT6 proteins result in the hyper activation of the expression of known STAT6 target genes (e.g.FCER2 CISH CCL17 NFIL3). The identification of these gain-of-function properties changed the prevailingview of lymphoma-associated STAT6 mutations which previously were believed to be hypomorphs. There remain however important unanswered questions pertaining to the molecular properties and functionalconsequences of mutated (MUT) STAT6 in lymphoma that are the focus of this proposal. These include thedelineation of genome-wide binding sites of MUT as compared with WT STAT6 in B cells and the completecharacterization of the genes that are transcriptionally regulated by MUT STAT6. Furthermore the propertiesand biological consequences of the transcriptional programs that are activated or repressed by STAT6 in FL Bcells or normal germinal center B cells are largely unknown. There is also untapped potential for the futuretargeting of the IL-4/JAK/STAT6 axis in FL and our proposed studies aim at providing the rationale to informsuch studies. Finally we will explore the interactions between STAT6 MUT FL B cells and the FL lymphnoderesident microenvironment especially with regards to T cell subsets. 349713 +No NIH Category available Adjuvant;Adoption;Apoptosis;Bar Codes;Breast Cancer Model;CDK2 gene;CDK4 gene;Cell Cycle Progression;Cell Cycle Regulation;Cell Line;Cells;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;DNA Sequence Alteration;Data;Disease;ESR1 gene;Endocrine;Estrogen Receptors;Estrogen Therapy;Estrogen receptor positive;Evaluation;Fulvestrant;Future;Generations;Genes;Genetic Transcription;Genomics;Growth;Growth Factor;Ligand Binding Domain;Mammary Neoplasms;Messenger RNA;Metastatic breast cancer;Modeling;Molecular;Mutation;Neoplasm Metastasis;Outcome;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phosphorylation;Phosphorylation Site;Plasma Cells;Polymerase;Progression-Free Survivals;Proliferation Marker;Property;Publishing;RNA;RNA Polymerase II;Receptor Gene;Resistance;Resistance development;Retrospective Studies;Role;Sampling;Signal Pathway;Systemic Therapy;Tamoxifen;Testing;Therapeutic;Transcript;Western Blotting;Work;adjuvant endocrine therapy;advanced breast cancer;cancer therapy;cell free DNA;chemotherapy;clinical development;cyclin-dependent kinase-activating kinase;design;drug testing;effective therapy;efficacy testing;exhaust;genome-wide;global run on sequencing;hormone therapy;improved;improved outcome;in vivo evaluation;inhibitor;malignant breast neoplasm;mortality;mutant;novel drug class;novel therapeutic intervention;novel therapeutics;optimal treatments;patient derived xenograft model;pharmacodynamic biomarker;pre-clinical;preclinical study;resistance mechanism;standard of care;therapy resistant;transcriptome sequencing;tumor;virtual CDK7 inhibitors as a new strategy to overcome treatment resistance in ER+ metastatic breast cancer Project NarrativeMetastatic estrogen receptor positive (ER+) breast cancer is the leading cause of breast cancer mortality. Wewill investigate the role of CDK7 inhibitors as a therapeutic strategy in metastatic ER+ breast cancer. Resultsfrom this study could lead to a new paradigm in the treatment of patients with metastatic ER+ breast cancer. NCI 10683956 7/25/23 0:00 PA-18-484 5R01CA237414-05 5 R01 CA 237414 5 "CHEN, WEIWEI" 8/16/19 0:00 7/31/24 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8489036 "JESELSOHN, RINATH M." Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 370191 NCI 224175 146016 Project Abstract The majority of breast cancers are estrogen receptor positive (ER+) and ER+ breast cancer is the leadingcause of breast cancer mortality. Despite the widespread adoption of adjuvant endocrine therapy for patientswith ER+ breast cancer almost all patients with ER+ metastatic disease will eventually develop resistance toendocrine treatments. A number of mechanisms of endocrine resistance were proposed but for the most thesewere predominantly based on preclinical evidence. Recently our group and a number of other groups identifiedestrogen receptor (ER) ligand-binding domain (LBD) mutations as the most prevalent genomic mechanism ofendocrine resistance identified in patients with ER+ metastatic breast cancer. These mutations are associatedwith decreased overall survival in ER+ metastatic breast cancer. The addition of CDK4/6 inhibitors (CDK4/6i) toendocrine treatment has been shown to improve progression free survival in patients with metastatic ER+ breastcancer but have not been shown to improve overall survival. Despite this advance patients with metastaticdisease invariably develop resistance to this combined therapy exhaust other chemotherapy options andultimately die of their disease. There is an urgent need to develop new therapeutic strategies to overcomeresistance to endocrine treatment and CDK4/6i. Our preliminary data suggests that selective inhibition of CDK7 can overcome resistance to endocrineresistance driven by the ER mutations and resistance to CDK4/6i. CDK7 has key roles in transcriptional and cellcycle regulation. SY1365 is a selective CDK7 inhibitor that is in early stages of clinical development for cancertreatment. This study is designed to comprehensively study the activity of SY1365 as a single agent and incombination with fulvestrant for the treatment of ER mutant endocrine resistant and CDK4/6i resistant ER+metastatic breast cancer. We will investigate the mechanisms by which CDK7 inhibition exerts anti-tumor activityand overcomes resistance to endocrine treatment driven by the ER mutations and resistance to CDK4/6i.Because CDK7 phosphorylates RNA polymerase II and also functions as a CDK-activating kinase we will testthe effects of SY1365 on nascent RNA and mRNA transcripts CDK2 phosphorylation and cell cycle progressionin ER+ breast cancer models. We will study mechanisms of resistance to CDK7 inhibition and synthetic lethalvulnerabilities in the presence of SY1365. Lastly we will test the activity of SY1365 in endocrine resistant andCDK4/6i resistant PDX models derived from metastatic tumors from patients with ER+ disease. Results from this study have the potential to lead to a clinical trial testing the efficacy and on target activityof a new class of drugs selective CDK7 inhibitors for the treatment of endocrine and CDK4/6i resistant ER+metastatic breast cancer. These results could lead to a new therapeutic strategy to improve outcomes in asubstantial number of patients with metastatic ER+ breast cancer. 370191 +No NIH Category available Address;Antibodies;Blood;Breast Lymphoma;Cells;Central Nervous System;Central Nervous System Diseases;Central Nervous System Melanoma;Cerebrospinal Fluid;Clinical;Clinical Trials;Complication;Cytology;Diagnosis;Disease;Evaluation;Exclusion;Exhibits;FDA approved;Future;Goals;IL2 gene;Immune;Immunotherapy;Incidence;Institution;Interleukin-2;Intravenous;Leptomeninges;Lymphocyte;Maximum Tolerated Dose;Medical;Metastatic Melanoma;Metastatic Neoplasm to the Central Nervous System;Metastatic Neoplasm to the Leptomeninges;Metastatic malignant neoplasm to brain;Minority;Molecular;Morbidity - disease rate;Mutation;Mutation Detection;Neoplasm Metastasis;Neurologic Deficit;Neurologic Examination;Nivolumab;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phase;Phase 1/1b Clinical Trial;Prognosis;Resources;Safety;Sampling;Site;Somatic Mutation;Standardization;Surface;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Therapeutic antibodies;Time;Toxic effect;Translational Research;Trastuzumab;Treatment Failure;Treatment-related toxicity;Tumor Tissue;University of Texas M D Anderson Cancer Center;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;anti-tumor immune response;cancer cell;cancer therapy;cancer type;clinical diagnosis;cytokine;design;disorder control;effective therapy;experience;first-in-human;immunoregulation;improved;inhibiting antibody;intravenous administration;malignant breast neoplasm;melanoma;mortality;neuro-oncology;next generation sequencing;novel;novel therapeutic intervention;patient population;pembrolizumab;programmed cell death protein 1;prospective;radiological imaging;response;rituximab;safety assessment;targeted treatment;treatment and outcome;treatment response;treatment site;tumor DNA;tumor-immune system interactions;working group Project 2 Intrathecal Anti-PD-1 Immunotherapy for Metastatic Melanoma Patients with Leptomeningeal Disease (LMD) Project 2: Project Narrative Patients with leptomeningeal disease (LMD) from melanoma have a very poor prognosis and very few treatment options. We will conduct the first-ever clinical trial to determine the safety maximum tolerated dose efficacy and immune and molecular effects of combined intrathecal and intravenous treatment with the antiPD1 antibody nivolumab in metastatic melanoma patients with LMD. The results of these studies will provide critical information about this novel therapeutic approach increase our understanding of the pathogenesis of LMD and inform the design of future clinical trials for this patient population. NCI 10683952 6/23/23 0:00 PAR-18-313 5P50CA221703-05 5 P50 CA 221703 5 7/16/19 0:00 5/31/24 0:00 ZCA1-RPRB-0 5257 11255052 "GLITZA, ISABELLA CLAUDIA" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 309602 225002 135002 Project 2: Project Summary/ Abstract Antibodies that inhibit PD-1 on the surface of T cells have revolutionized the treatment and outcomes of patients with metastatic melanoma. However metastasis to the central nervous system (CNS) remains a common and devastating complication of advanced melanoma and the CNS is a frequent site of treatment failure for current therapies. There are multiple treatment options for melanoma patients with parenchymal brain metastases. In contrast there are very few treatment options for patients that develop leptomeningeal disease (LMD). LMD can cause significant neurological deficits and the median survival for melanoma patients with LMD is less than 2 months. Thus there is a critical unmet need to develop more effective treatments for patients with LMD from melanoma. Previous experience with trastuzumab and rituximab in breast cancer and lymphoma respectively have demonstrated that intrathecal (IT) administration of cancer therapies can increase drug levels in the cerebrospinal fluid (CSF) and clinical benefit in patients with LMD. Our unique and long-term experience with intrathecal IL2 (IT IL2) has similarly demonstrated that intrathecal immunotherapy can achieve durable disease control and survival in a subset of melanoma patients with LMD. However long-term survival with IT IL2 is rare and treatment-related toxicity with IT IL2 is universal. Thus there remains an unmet need for therapies for LMD that are more active and less toxic. We hypothesize that IT administration of anti-PD-1 antibodies will be safe and induce an anti-tumor immune response in the CSF in metastatic melanoma patients with LMD. In order to test this hypothesis in Aim 1 we will conduct a novel phase I/Ib study to determine the safety and maximum tolerated dose of combined IT and intravenous (IV) administration of the anti-PD-1 antibody nivolumab in metastatic melanoma patients with LMD. This is trial which has recently been approved by the FDA will be the first to assess the safety of IT anti-PD-1 and it represents an important new option for patients with LMD. In Aim 2 CSF and blood collected from patients in the trial at multiple timepoints will be analyzed for immune cell subsets and cytokines. The results will be analyzed to characterize the effects of IT + IV nivolumab treatment and to improve our understanding of theimmune microenvironment of the CSF. In Aim 3 cell-free tumor DNA (ctDNA) isolated CSF and blood will undergo next generation sequencing (NGS) to detect and quantify somatic mutations. Results will be used to evaluate changes in mutation burden and profile over time and to compare mutations detected in the CSF to those detected in blood and in tumor tissue. Together these studies address an unmet clinical need for new treatment options for melanoma patients with LMD and to improve our understanding of the molecular and immune features of this aggressive disease. The results of these studies will also provide important information to prioritize and optimize future trials for patients with LMD from melanoma and other cancer types. +No NIH Category available Adult;American;Anti-Inflammatory Agents;Bilateral;Biological;Biological Markers;Blood;Body Weight decreased;Body fat;Breast;Breast Cancer Risk Factor;Breast Epithelial Cells;Breast Feeding;Cancer Etiology;Carotenoids;Cells;Chemopreventive Agent;Consumption;Counseling;DNA Methylation;Data;Diet;Dietary Assessment;Dietary Intervention;Event;Food;Future;Growth;Human Milk;Infant;Infant Health;Inflammation;Inflammatory;Intake;Intervention;Intervention Studies;Intervention Trial;Knowledge;Lactation;Level of Evidence;Life Cycle Stages;Link;Literature;Longterm Follow-up;Massachusetts;Maternal Health;Measurement;Measures;Modeling;Molecular;Monitor;Mothers;Motivation;Nutrient;Observational Study;Organ;Participant;Pathway interactions;Population;Postpartum Period;Postpartum Women;Pregnancy;Prevention;Property;Puberty;Questionnaires;Randomized;Recommendation;Reporting;Research Design;Resources;Risk;Risk Reduction;Sampling;Skin;Testing;Vegetables;Weaning;Weight;Weight Gain;Woman;anticancer research;behavior change;cancer prevention;comparison control;cytokine;dietary control;dietary guidelines;fruits and vegetables;healthy weight;improved;in vivo;malignant breast neoplasm;maternal weight;mother nutrition;nursing mothers;older women;postpartum breast cancer;postpartum weight;pregnancy-associated breast cancer;prevent;recruit;stool sample;study population;treatment arm;young woman Fruit and vegetable intervention in lactating women to reduce breast cancer risk: effects on breast cell DNA methylation breast inflammation and weight Project NarrativeResults from the proposed intervention study in lactating women will determine if a diet rich in nutrient-densefruits and vegetables can alter breast cell DNA methylation and cytokine levels in breastmilk in a mannerconsistent with reduced breast cancer risk and help women achieve and maintain a healthy postpartumweight. This study offers a new model for improving maternal diets and can provide in vivo mechanisticevidence of the link between fruits and vegetables and breast cancer risk. NCI 10683950 5/5/23 0:00 PAR-18-559 5R01CA230478-05 5 R01 CA 230478 5 "ROSS, SHARON A" 6/6/19 0:00 5/31/24 0:00 Cancer Prevention Study Section[CPSS] 1910140 "ARCARO, KATHLEEN FRANCES" "SIBEKO, LINDIWE ; STURGEON, SUSAN R" 2 VETERINARY SCIENCES 153926712 VGJHK59NMPK9 153926712 VGJHK59NMPK9 US 42.386914 -72.521131 850904 UNIVERSITY OF MASSACHUSETTS AMHERST HADLEY MA EARTH SCIENCES/RESOURCES 10359450 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 792645 NCI 496956 295689 Project Summary/AbstractFruit and vegetable intervention in lactating women to reduce breast cancer risk: effects on breast cellDNA methylation breast inflammation and weightMechanistic data show that compounds in fruits and vegetables have anti-inflammatory and anti-carcinogenicproperties that can reduce breast cancer risk. However observational and interventional studies have providedmixed results and a recent report by the American Institute for Cancer Research (AICR) concludes that thedata are insufficient but suggestive that non-starchy vegetables and foods containing carotenoids reduce risk.Measurement error relatively low levels of carotenoid-rich fruit and vegetable intake in the study populationsemphasis on diet in later adulthood and confounding factors likely contribute to the weak associations.Therefore we will conduct a randomized diet intervention trial in young women to assess the extent to which atleast 8 to 10 daily servings of deeply pigmented and nutrient dense fruits and vegetables reduces biomarkersof breast cancer risk. The intervention is focused on breastfeeding women because: 1) pregnancy andlactation are normal early life course events; 2) the risk of pregnancy-associated breast cancer (PABC) isincreased for up to 10 years postpartum; 3) a dietary intervention to reverse the detrimental molecular changesassociated with puberty and pregnancy is more likely to be successful in younger than in older women; 4) adiet rich in fruits and vegetables is hypothesized to reduce the inflammation during lactation/weaning and lowerPABC risk; 5) postpartum lactating women may be a highly motivated population; and 6) breastmilk providesaccess to the breast microenvironment and breast epithelial cells to noninvasively assess the diet interventiondirectly in the breast. Four hundred nursing mothers will be randomly assigned to either the intervention arm inwhich they are asked to increase fruit and vegetable intake to at least 8 to 10 daily servings for one year or toa control condition in which participants receive a dietary guideline for breastfeeding mothers. Women in theintervention arm will receive counseling and boxes of fruits and vegetables for the first 20 weeks after whichthey will continue to receive counseling. Changes in DNA methylation and cytokine profiles in breastmilk will beevaluated. Maternal weight and body fat distribution and infant growth will be monitored. These results willgreatly expand our knowledge of how diet alters molecular pathways in a specific organ ultimately contributingto both breast cancer etiology and prevention. Additionally objective favorable results observed in the breastsof young women can potentially contribute to important behavior changes aimed at reducing risk. 792645 +No NIH Category available AKT Signaling Pathway;Address;BRAF gene;Blood;Blood specimen;CD8-Positive T-Lymphocytes;Cell Survival;Cell physiology;Cells;Clinic;Clinical;Clinical Trials;Cohort Analysis;Combination immunotherapy;Combined Modality Therapy;Cutaneous Melanoma;Dependence;Disease;Dose;Drug Kinetics;FDA approved;Future;Immune;Immune checkpoint inhibitor;Immune response;Immunocompetent;Immunosuppression;Immunotherapy;In Vitro;Inferior;Infiltration;Invaded;Malignant Neoplasms;Mediating;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Mus;Oncogenic;Outcome;PIK3CG gene;PTEN gene;Pathway interactions;Patients;Pharmacodynamics;Phase;Phase I/II Clinical Trial;Pre-Clinical Model;Prognosis;Protein Isoforms;Proto-Oncogene Proteins c-akt;Recommendation;Refractory;Regimen;Resistance;Role;Safety;Sampling;Schedule;Signal Pathway;Somatic Mutation;T cell infiltration;T-Lymphocyte;TCR Activation;Testing;Toxic effect;Translations;Treatment outcome;Tumor Suppressor Proteins;Tumor Tissue;University of Texas M D Anderson Cancer Center;Vascular Endothelial Growth Factors;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;anti-tumor immune response;biomarker development;cancer immunotherapy;cancer type;checkpoint therapy;clinical application;cohort;combinatorial;cytokine;effective therapy;effector T cell;experience;immune activation;immune function;immunoregulation;improved;in vivo;inhibitor;loss of function;melanoma;mutant;neoplastic cell;novel;pembrolizumab;preclinical study;programmed cell death protein 1;resistance mechanism;response;targeted treatment;trafficking;treatment effect;tumor;tumor growth Project 1 Targeting the PI3K Pathway to Overcome Resistance to Immunotherapy in Melanomas with Loss of PTEN Project 1: Project NarrativeOur previous studies demonstrated that loss of function of the tumor suppressor PTEN in melanomas activatesthe oncogenic PI3K-AKT pathway and thereby suppresses the anti-tumor immune response and promotesresistance to anti-PD-1 immunotherapy. In this SPORE project we will analyze biospecimens collected from anovel phase I/II clinical trial of combination therapy with the selective PI3K inhibitor GSK2636771 and the anti-PD-1 antibody pembrolizumab in PD-1-refractory metastatic melanoma patients with loss of PTEN to determineif this regimen inhibits the PI3K-AKT pathway promotes anti-tumor immune function and overcomes clinicalresistance to anti-PD-1. We will also use preclinical models to investigate additional strategies to further improvethe efficacy of anti-PD-1 immunotherapy in tumors with PTEN loss. NCI 10683948 6/23/23 0:00 PAR-18-313 5P50CA221703-05 5 P50 CA 221703 5 7/16/19 0:00 5/31/24 0:00 ZCA1-RPRB-0 5256 9439732 "DAVIES, MICHAEL " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 412494 299779 179869 Project 1: Project Summary/AbstractCutaneous melanomas (CM) have a very high rate of somatic mutations and oncogenic drivers are identifiedin the majority of patients. PTEN a tumor suppressor that regulates the oncogenic PI3K-AKT signalingpathway demonstrates complete loss of expression in up to 30% of these tumors. Our previous studiesshowed that loss of PTEN is associated with shorter overall survival in stage III melanoma patients and withinferior outcomes with targeted therapies in patients with stage IV disease. Building upon these studiesrecently we investigated the impact of PTEN loss on the anti-tumor immune response and immunotherapy.Initial preclinical studies demonstrated that loss of PTEN in melanomas increases the expression ofimmunosuppressive cytokines decreases the intratumoral infiltration of critical effector T cells and causesresistance to T-cell mediated immunotherapy in vitro and in vivo. Analyses of cohorts of advanced melanomapatients showed that loss of PTEN was associated with decreased CD8+ T cell infiltration in stage III melanomapatients and significantly decreased response rates to FDA approved anti-PD-1 antibodies in stage IV disease.Treatment with GSK2636771 an isoform-specific inhibitor of PI3K decreased AKT activation increased Tcell infiltration and increased the efficacy of anti-PD-1 checkpoint inhibitor therapy in vivo in animmunocompetent model of PTEN-null PD-1-resistant melanoma. Notably GSK2636771 did not harm theviability or function of immune cells consistent with the selective dependence on PI3K in cells with PTENloss. Based on these studies we hypothesize that inhibition of the PI3K-AKT pathway will overcome resistanceto anti-PD-1 immunotherapy in melanomas with loss of PTEN. To test this hypothesis and address the unmetneed for effective therapies for PD-1-refractory patients we are conducting a phase I/II clinical trial ofGSK2636771 in combination with the anti-PD-1 antibody pembrolizumab in metastatic melanoma patientswith PTEN loss that failed to respond to anti-PD-1. Blood and tumor samples will be collected prior to andduring treatment as well as at progression to improve our understanding of the effects of this regimen and theresults of the trial. In Aim 1 we will determine the effects of this treatment on the activation of the PI3K-AKTpathway and the relationship between pathway inhibition GSK2636771 steady-state levels and treatmentoutcomes. In Aim 2 we will evaluate the immune effects of the combination treatment by evaluating tumor andblood samples for the presence and changes in immune cell subsets and immunoregulatory cytokines whichwill also be compared to clinical responsiveness. In Aim 3 we will use preclinical models to evaluate intermittentdosing and combinatorial approaches with additional isoform-selective PI3K inhibitors as strategies to furtherimprove the efficacy of GSK2636771 with anti-PD-1. These studies will improve our understanding of the roleof the PI3K-AKT pathway in the anti-tumor immune response and immunotherapy resistance and help identifyadditional rational strategies for future testing in this and other cancers with PTEN loss. +No NIH Category available Address;Animal Cancer Model;Bile duct carcinoma;Biological;Biophysics;Cell Communication;Cells;Cholangiocarcinoma;Combined Modality Therapy;Cytometry;Cytotoxic T-Lymphocytes;Data;Desmoplastic;Development;Flow Cytometry;Goals;Hepatic;Human;Immune;Immune Tolerance;Immune response;Immunologics;Immunotherapy;Implant;Investigation;Knockout Mice;Kupffer Cells;Ligands;Liver;Liver neoplasms;Lymphocyte Function;Macrophage;Macrophage Colony-Stimulating Factor Receptor;Malignant Neoplasms;Mediating;Mediator;MicroRNAs;Modeling;Molecular;Mus;Oncogenes;Oncogenic;Phenotype;Receptor Inhibition;Research;Role;T-Lymphocyte;Technology;Testing;Therapeutic;Tumor Biology;Tumor Burden;Tumor Promotion;Tumor Suppression;Tumor-infiltrating immune cells;Wild Type Mouse;cancer cell;carcinogenesis;checkpoint inhibition;design;effector T cell;exhaustion;experimental study;extracellular vesicles;immune checkpoint;immune checkpoint blockade;implantation;innovation;intrahepatic;knockout animal;mouse model;novel;programmed cell death ligand 1;programmed cell death protein 1;programs;prototype;receptor;response;restraint;success;targeted treatment;therapeutic target;transplant model;treatment strategy;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions The Pro-Tumor Immunologic Niche of the Liver PROJECT NARRATIVEThe proposal examines how the immune cells respond to bile duct cancer by using unique animal models ofthis cancer. The goal of our research is to understand how a type of immune cell in the liver termedmacrophages aids the progression of bile duct cancer. This information will help identify approaches toinhibit these pro-tumor macrophages and provide treatment strategies for this devastating and highly lethalhuman malignancy. NCI 10683946 8/18/23 0:00 PA-18-373 5K08CA236874-05 5 K08 CA 236874 5 "BIAN, YANSONG" 9/1/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 11727735 "ILYAS, SUMERA I." Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 242898 NCI 224906 17992 PROJECT ABSTRACTThe OVERALL OBJECTIVES of this proposal are to unravel the mechanisms by which hepatic macrophagespromote immune tolerance to cholangiocarcinoma (CCA) with the therapeutic goal of defining combination im-mune-directed therapies to treat this highly lethal cancer. A desmoplastic malignancy CCA is characterized bya rich multi-cellular tumor stroma including an abundance of pro-tumor macrophages. We have establishedtwo unique CCA murine models with desmoplasia: i) an oncogene-driven model to study CCA carcinogenesisand ii) a syngeneic orthotopic model to study CCA progression. We are now poised to exploit these models toexamine the tumor immune microenvironment (TIME) in CCA initiation and progression. Our preliminary datasuggest that expression of the immune checkpoint molecule programmed cell death ligand-1 (PD-L1) on hostimmune cells of the TIME may be more potent than cancer cell expressed PD-L1 in facilitating tumor progres-sion. In our preliminary experiments we have discovered that although murine CCA cells have abundant PD-L1 expression orthotopic implantation of these cells into the liver of PD-L1 knockout mice results in a signifi-cantly reduced tumor burden compared with wild type mice. Our preliminary data also demonstrate that he-patic macrophages including resident Kupffer cells express PD-L1 in CCA and CCA cell-derived extracellularvesicles (EVs) increase PD-L1 expression in hepatic macrophages. Finally we have demonstrated thatmacrophage-directed therapy with colony stimulating factor 1 receptor (CSF1R) inhibition or checkpoint inhibi-tion with PD-L1 blockade is tumor suppressive. Based on these novel observations we have formulated theCENTRAL HYPOTHESIS of the proposal that the liver manifests a pro-tumor immune tolerogenic niche inCCA mediated by PD-L1 positive hepatic macrophages which can be overcome by combination immune-directed therapies reprogramming macrophages as an anti-tumor therapeutic strategy. Our following inde-pendent SPECIFIC AIMS will test three integrated hypotheses. First we will directly test the hypothesis thatCCA cell derived EVs contain oncogenic microRNAs that reprogram hepatic macrophages to a PD-L1 positivepro-tumor phenotype. Second we will test the hypothesis that PD-L1 positive pro-tumor hepatic macrophagesmediate intrahepatic T lymphocyte exhaustion. Third using our murine models of CCA carcinogenesis andprogression we will test the hypothesis that the combination of macrophage-directed therapy plus checkpointinhibition restrains both CCA carcinogenesis and tumor progression. We propose to employ current and com-plementary molecular and cell biological approaches as well as biophysical technologies such as flow cytom-etry and mass cytometry to test this hypothesis. This proposal which is technically and conceptuallyinnovative is also highly significant because it identifies new mechanisms for therapeutically targeting CCAnamely combining therapies promoting both cytotoxic T cell and macrophage anti-tumor activity. 242898 +No NIH Category available Address;Adopted;Algorithms;Animal Model;Award;Bioconductor;Bioinformatics;Biological Markers;Biometry;Cancer Center;Cell Line;Clinical;Clinical Data;Clinical Research;Clinical Trials;Clinical Trials Design;Code;Collaborations;Complex;Computer Analysis;Conduct Clinical Trials;Confidentiality of Patient Information;Data;Data Analyses;Databases;Development;Ensure;Epidemiology;Experimental Designs;Genomics;Human Resources;Immunologics;Laboratories;Libraries;Link;Manuscripts;Methods;Pathology;Patients;Phase;Play;Proteomics;Publications;Reporting;Research;Research Personnel;Research Project Grants;Resources;Role;Services;Statistical Data Interpretation;Statistical Methods;Structure;Technology;University of Texas M D Anderson Cancer Center;Writing;bioinformatics resource;biomarker discovery;career;clinical database;data management;design;experimental study;genome analysis;genomic data;high dimensionality;innovation;laboratory experiment;meetings;melanoma;member;novel;open source;pre-clinical;predictive marker;programs;sound;tissue resource;tool;translational study;trial design;web-accessible Core 3-Biostatistics Core 3: Project NarrativeThe Biostatistics and Bioinformatics Core (Core 3) of the Melanoma SPORE will play an integral role in thedesign of clinical trials including data management and active collaborative research. It will also providecomprehensive management of the quantitative aspects of all three projects as well as developmentalresearch projects and career enhancement projects as and when awarded. NCI 10683945 6/23/23 0:00 PAR-18-313 5P50CA221703-05 5 P50 CA 221703 5 7/16/19 0:00 5/31/24 0:00 ZCA1-RPRB-0 5255 2409579 "LEE, J. JACK " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 261178 189811 113887 Core 3: Project Summary/AbstractThe Biostatistics and Bioinformatics Core 3 provides comprehensive service to guide design ofexperiments to optimize quantitative data analysis and to maintain statistical justification and interpretation ofresults. Specifically Core 3 will implement sound experimental design principles that are tailored to addressspecific scientific questions for each project. Core 3 will also carry out data analyses using suitable statisticalmethods and bioinformatics algorithms and will contribute to the interpretation of results through writtenreports and frequent interactions with project investigators. Whenever appropriate Core 3 will develop newanalysis tools to address new challenges in the analysis of various data especially high-throughput genomicand proteomic data. Members of Core 3 will participate in monthly SPORE meetings with all projectinvestigators ensuring that statistical and data analysis/management issues are carefully considered duringall phases of each SPORE experiment. Thus from inception to reporting and publication basic laboratoryand translational experiments will benefit from the SPORE program that will be used to augment existing MDAnderson Cancer Center biostatistics resources. +No NIH Category available Accounting;Address;Area;Biological Markers;Biological Specimen Banks;Biopsy;Biostatistics Core;Blood;Cancer Center Support Grant;Cell Line;Cerebrospinal Fluid;Clinical;Clinical Data;Collaborations;Collection;DNA;Data;Data Element;Databases;Detection;Development;Distant Metastasis;Ensure;Evaluation;Fostering;Fresh Tissue;Future;Gene Expression Profiling;Genetic Transcription;Goals;Guidelines;Histologic;Image Analysis;Image Guided Biopsy;Immune;Immunohistochemistry;Immunologics;Infrastructure;Laboratories;Lesion;Liquid substance;Lymphocyte Harvest;Measurement;Molecular;Molecular Analysis;Neoplasm Metastasis;Outcome;Pathologic;Pathology;Patient Care;Patients;Performance;Prevention;Primary Neoplasm;Procedures;Process;Prognostic Marker;Proteins;RNA;RNA analysis;Recording of previous events;Recurrence;Research;Research Infrastructure;Research Methodology;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Sampling;Skin;Specific qualifier value;Specimen;Staging;Standardization;Statistical Data Interpretation;Systemic Therapy;Tissue Banks;Tissue Sample;Tissues;Transact;Translating;Translational Research;Tumor-Infiltrating Lymphocytes;University of Texas M D Anderson Cancer Center;Uveal Melanoma;Work;biomarker identification;clinical database;clinically relevant;disorder prevention;experience;follow-up;human tissue;improved;melanoma;mucosal melanoma;multidisciplinary;nano-string;novel;novel therapeutic intervention;patient derived xenograft model;predictive marker;programs;prospective;relational database;response;success;therapy resistant;tissue processing;tissue resource;translational impact;tumor Core 2-MelCore biospecimens Core 2: Project NarrativeThe understanding and treatment of melanoma continues to rapidly evolve. Building upon 15 years of SPOREexperience and in order to support impactful translational research Core 2 has developed capabilities to meetthe dynamic needs of current future and legacy research projects of the melanoma SPORE through theacquisition processing tracking storage distribution and integration of high-quality clinical data and well-annotated biospecimens along with the development of new analytical approaches. The high impacttranslational research infrastructure that Core 2 demonstrates will significantly contribute to our efforts toaddress critical unmet needs in melanoma and ultimately to improve clinical outcomes in patients withmelanoma. NCI 10683944 6/23/23 0:00 PAR-18-313 5P50CA221703-05 5 P50 CA 221703 5 7/16/19 0:00 5/31/24 0:00 ZCA1-RPRB-0 5254 7662187 "GERSHENWALD, JEFFREY E" Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 239175 173820 104292 Core 2: Project Summary/AbstractOver the past 15 years the primary goal of the MD Anderson SPORE in Melanoma has been to translate ourfundamental understanding of melanoma into improved patient care by improving melanoma preventiondetection and therapy. Building upon this experience and to further this goal it is essential to continue toconduct high-impact well-planned translational research involving well-annotated curated biospecimens andrelevant clinical data to identify the pathophysiologic mechanisms of melanoma and the metastatic cascadeidentify biomarkers and targets for antitumor therapy and evaluating the mechanisms of response andresistance in new treatment strategies. The Melanoma Clinical Database Tissue Resource andTranslational Pathology Core (Core 2) will maintain a comprehensive prospective relational databasecontaining detailed clinical pathologic and outcome data for patients with melanoma seen and treatedat MD Anderson. Core 2 will also procure and process tissue blood and cerebrospinal fluid specimensin support of the SPORE Projects and will facilitate the downstream analysis for histopathologic featuresincluding immunohistochemistry with image analysis and molecular analysis of prospectivelycollected melanoma specimens as well as archival material. A noteworthy addition for the currentSPORE submission is the development and integration of the uveal melanoma database module as wellas the addition of an automated request module for sample distribution to facilitate all SPORE-based andother research projects. The current proposal includes expanded efforts and infrastructure tosupport the optimization of fresh tissue collection and processing of distant metastases from image-guided biopsies analyte (DNA RNA protein) extraction from prospectively collected and archival tissuesamples suitable for molecular and immunological interrogation and the conduct of NanoString geneexpression profiling. The samples and/or analytes isolated from biospecimens will be distributed toSPORE projects and other investigators in accordance with our Core operating procedures and Core2 will work with each of the SPORE projects CCSG Cores collaborator laboratories and with theAdministrative and Biostatistics Cores to ensure maximum efficiency of tissue/derivatives. Together Core 2will be a resource for clinicopathologic data well-annotated biospecimens and for optimized acquisitionprocessing distribution and analyses that facilitate integration of conventional biomarkers molecular andimmunologic data with clinicopathologic treatment recurrence and follow-up. Overall theseapproaches will facilitate the discovery of clinically impactful predictive and prognostic biomarkers as wellas enhanced approaches to anti-tumor therapy across several clinically unmet needs for patients withmelanoma. This centralized resource will contribute significantly to the success of the multidisciplinaryand translational research projects outlined in this proposal. +No NIH Category available Advocate;Appointment;Award;Bioinformatics;Biometry;Clinical;Clinical Trials;Collaborations;Communication;Consensus;Consultations;Data Commons;Development;Discipline;Disease;Ensure;Funding;Goals;Institution;Leadership;Maintenance;Mentors;Minority;Monitor;Patient Care;Patients;Peer Review;Policies;Preparation;Process;Publications;Quality Control;Regulation;Reporting;Research;Research Personnel;Resources;Role;Schedule;Scientist;Site;Skin Cancer;United States National Institutes of Health;University of Texas M D Anderson Cancer Center;Woman;career;data quality;data repository;data sharing;data standards;experience;flexibility;interdisciplinary approach;lectures;meetings;melanoma;programs;quality assurance;recruit;symposium Administrative Core 1 Administrative Core 1: Project Narrative The Administrative Core (Core 1) will be responsible for the successful execution and management of all SPORE activities related to financial oversight and coordination organization of all necessary meetings and publicity and record keeping for all projects and the two other cores. This group will also provide regulatory oversight activities for clinical trials; ensure compliance with all institutional federal and NCI-specific regulations; and oversee the peer-review and oversight processes of the Career Enhancement Program and Developmental Research Program. The core will be led by Drs. Patrick Hwu Elizabeth Grimm and Jeffrey Lee. NCI 10683943 6/23/23 0:00 PAR-18-313 5P50CA221703-05 5 P50 CA 221703 5 7/16/19 0:00 5/31/24 0:00 ZCA1-RPRB-0 5253 9439732 "DAVIES, MICHAEL " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Research Centers 2023 243350 176855 106112 Adminstrative Core 1: Project Summary/AbstractWithin the SPORE framework the Administrative Core (Core 1) will be responsible for incorporating thediverse scientific disciplines of the SPORE investigators into a highly integrated interdisciplinary approachfocused on achieving excellence in translational melanoma research towards a significant impact on the careof patients battling this disease. The primary goal of this group is to assure the successful continued oversightand coordination of all projects cores and developmental and career enhancement programs through expertguidance in fiscal management centralized communication and general administration for all activities. Thiscore will be led by three outstanding scientists and well-established mentors who currently hold high-leveladministrative research and/or clinical appointments at MD Anderson and possess decades of combinedleadership experience: Drs. Patrick Hwu Elizabeth Grimm and Jeffrey E. Lee.Specific responsibilities of the Administrative Core include the following: Compliance with all institutional federal and NIH/NCI regulations and requirements. Communication and consultation with the NCI project officer and other NCI staff including preparationof all required reports publications and other requested communications. Monitoring data quality control and assurance activities in conjunction with the Biostatistics andBioinformatics Core (Core 3). Optimization of clinical trial efforts including monitoring and enhancing accrual progress of relatedSPORE clinical trials through the Clinical Trials Management Resource (co-directed by Dr. Hwu andLee) housed within this Administrative Core. Maintenance of fiscal and budgetary responsibilities including implementing the SPORE flexibilityoption as appropriate through ongoing assessments of program progress and justifications for fundingallocations/reallocations. Convening all necessary meetings including the Executive Committee Internal and External AdvisoryBoards (IAB/EAB) scientific meetings research meetings lectures and symposia includingscheduling development and distribution of meeting materials and recording minutes as appropriate. Coordination and funding of Patient Advocate activities. Establishment and monitoring of policies for recruitment and retention of women and minorities in thisprogram. Coordination with other SPORE sites to initiate and enhance collaborative research efforts co-sponsor a yearly Skin Cancer conference and pursue opportunities for high potential DevelopmentalResearch Program (DRP) and Career Enhancement Program (CEP) applications fromcollaborating investigators. +No NIH Category available Address;Adjuvant;Adoptive Cell Transfers;Adult;Affinity;Bioinformatics;Biometry;Carrier Proteins;Cause of Death;Central Nervous System;Cessation of life;Clinical;Clinical Research;Clinical Trials;Common Neoplasm;Communication;Community Health;Cutaneous Melanoma;Cytotoxic T-Lymphocytes;Data Analyses;Development;Disease;Distant Metastasis;Ensure;Epitopes;Experimental Designs;Eye Neoplasms;Faculty;Funding;Future;Genomics;Goals;Immune;Immune checkpoint inhibitor;Immune response;Immunologics;Immunology;Immunotherapeutic agent;Immunotherapy;In complete remission;Incidence;Investigation;Knowledge;Left;Leptomeninges;Malignant Neoplasms;Melanosomes;Mentors;Metastatic Melanoma;Metastatic Neoplasm to the Central Nervous System;Molecular;Molecular Biology;Nivolumab;Non-Cutaneous Melanoma;Outcome;PD-1 blockade;PIK3CG gene;PTEN gene;Pathogenesis;Pathology;Pathway interactions;Patients;Pilot Projects;Population;Refractory;Research;Research Personnel;Resistance;Resources;Safety;Service provision;Services;Site;Skin Cancer;Survival Rate;Testing;Therapeutic;Toxic effect;Translating;Translational Research;Treatment Failure;University of Texas M D Anderson Cancer Center;Uveal Melanoma;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;burden of illness;career;clinical database;clinical investigation;combinatorial;data sharing;effective therapy;experience;global health;immunogenic;improved;insight;meetings;melanoma;microbiome;mortality;multidisciplinary;novel;novel strategies;novel therapeutic intervention;novel therapeutics;patient subsets;programmed cell death protein 1;programs;research study;resistance mechanism;response;targeted treatment;therapy resistant;tissue resource;treatment site;treatment strategy;tumor The University of Texas MD Anderson Cancer Center SPORE in Melanoma Overall: NarrativeAn unprecedented number of novel and highly potent agents including the revolutionary checkpoint inhibitorshave changed the landscape of melanoma therapy in recent years; however only small subsets of patientsshow meaningful clinical benefit many experience significant toxicity and resistance to these therapies is anongoing challenge. Our SPORE in Melanoma seeks to develop new rational and more effectivecombinatorial therapy approaches to identify effective treatment strategies for patients with critical unmetneeds including those battling advanced refractory cutaneous and uveal melanoma and leptomeningealdisease. To that end we will explore novel approaches including various forms of adoptive cell therapies andmicrobiome modulation to enhance our understanding of the immune response and ultimately extend thepotential clinical benefits of these novel therapies to all patients with melanoma. NCI 10683940 6/23/23 0:00 PAR-18-313 5P50CA221703-05 5 P50 CA 221703 5 "KUZMIN, IGOR A" 7/16/19 0:00 5/31/24 0:00 ZCA1-RPRB-0(O1) 9439732 "DAVIES, MICHAEL " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 397 Research Centers 2023 2070386 NCI 1504650 902790 Overall: Project Summary/AbstractMelanoma is the deadliest form of skin cancer with an increasing incidence and mortality and a 5-yearsurvival rate less than 20% for patients with metastatic disease. Several recent landmark genomic andimmunologic studies have generated important new insights into the pathogenesis drivers and regulators ofthis disease translating into the approval of both targeted and immune therapies for patients with metastaticdisease. While targeted therapies have achieved high response rates they are generally transient; likewiseimmunotherapies bring about dramatic long-term complete responses but only in a subset of patients andoften with serious toxicities. Despite the progress that has been made several key challenges remain tomaximizing the clinical benefit of immunotherapy: 1) poorly understood markers and mechanisms ofresistance to immunotherapy and a lack of effective strategies to overcome them; 2) limited experience orefficacy in patients with central nervous system involvement a common metastatic site and cause of death formelanoma and other cancers; and 3) lack of any benefit from single-agent immunotherapies in patients withnon-cutaneous melanomas particularly the uveal melanoma subtype. The central hypothesis of this SPOREproposal is that an integrated analysis of immune and molecular features in patients with advancedmelanoma will improve our understanding of response and resistance to immunotherapy and lead tomore effective treatments. To test this hypothesis we will focus on the most critical unmet needs ofmelanoma patients building on current immunotherapeutic strategies and developing our own novelconcepts to identify more effective treatment options by pursuing the following specific aims: Address resistance to the PD-1 immune checkpoint inhibitor through inhibition of the PI3K pathway in PTEN- null metastatic melanoma patients (Project 1). Determine the clinical utility of PD-1 blockade using nivolumab administered intrathecally in metastatic melanoma patients with leptomeningeal disease (Project 2). Evaluate a new therapeutic strategy for uveal melanoma that uses adoptive cell therapy to target an immunogenic epitope of melanosomal transport protein SLC45A2 (Project 3).Three cores (Administrative Core Clinical Database Tissue Resource and Translational Pathology Core[Core 2] and Biostatistics and Bioinformatics Core [Core 3]) provide specialized services to support our SPOREinvestigators and their proposed research studies. Together these three projects and cores and ourDevelopmental Research and Career Enhancement Programs will provide a comprehensive attack on criticalunmet needs for patients battling these deadly manifestations of melanoma and pave the way for othercancers with limited therapeutic options. 2070386 +No NIH Category available Address;Attenuated;Automobile Driving;Biological Models;Blood Vessels;Blood capillaries;CXCL1 gene;Cancer Patient;Cell secretion;Cells;Cessation of life;Chromatin;Classification;Clear cell renal cell carcinoma;Clinical;Clinical Management;Competence;Data;Diagnosis;Diagnostic Neoplasm Staging;Disease;Disease Management;Distal;EPHA2 gene;Enrollment;Eph Family Receptors;Excision;Experimental Models;Family;Family member;Genes;Genetic Transcription;Genomic Segment;Growth;Histologic;Homeobox;IL8RB gene;Image;Immediate-Early Genes;Immune;Immunologic Surveillance;Infiltration;Innovative Therapy;Invaded;Kidney Neoplasms;Knowledge;Ligands;Lymphatic;MRI Scans;Macrophage;Mediating;Microscopic;Modeling;Myelogenous;Myeloid Cells;Neoplasm Metastasis;Nephrectomy;Nonmetastatic;Operative Surgical Procedures;Organ;Organoids;Patients;Peer Review;Phosphotransferases;Primary Neoplasm;Regimen;Renal carcinoma;Resected;Residual Neoplasm;Role;Signal Transduction;Structure;Survival Rate;Therapeutic;Thrombus;Transcription Factor AP-1;Transforming Growth Factor beta;Tumor Promotion;Work;X-Ray Computed Tomography;antagonist;cancer cell;cancer genomics;chemokine;clinical practice;cytokine;epithelial to mesenchymal transition;follow-up;genetic manipulation;immune cell infiltrate;improved;in vivo Model;inhibitor;migration;mimicry;neoplastic cell;neutrophil;nuclease;patient derived xenograft model;pharmacologic;programs;prospective;receptor;recruit;response;single cell sequencing;standard of care;survival outcome;trait;transcription factor;transcriptomics;tumor;tumor heterogeneity ccRCC Metastatic Competency Determinants Metastatic disease or the spread of cancer cells from invasive primary tumor to distal organs through vasculatureor lymphatics is responsible for majority of patient deaths and remains a clinical challenge. However not allinvasive tumors are metastatic. We identified targetable metastatic competence determinants by performingcomprehensive integrated analysis of invasive metastatic and non-metastatic ccRCC tumors. NCI 10683925 7/10/23 0:00 PA-20-185 5R01CA258629-02 5 R01 CA 258629 2 "SNYDERWINE, ELIZABETH G" 8/15/22 0:00 7/31/27 0:00 Tumor Progression and Metastasis Study Section[TPM] 12322920 "MALLADI, SRINIVAS " Not Applicable 30 PATHOLOGY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 396783 NCI 241941 154842 Metastatic disease or the spread of cancer cells from invasive primary tumor to distal organs through vasculatureor lymphatics is responsible for majority of patient deaths and remains a clinical challenge. Not all invasive tumorsare metastatic therefore defining the determinants of metastatic competence and identifying cancer patientslikely to develop metastasis or have residual disease is critical for clinical management of disease. Intratumorheterogeneity inability to precisely isolate tumor cells from the invasive front and limited access to clinical follow-up data present a major challenge to identify metastatic competency determinants.Invasive intravascular growth is observed in approximately 15% of ccRCC patients as tumor thrombus. Thisinvasive tumor extension can be accurately identified using cross sectional imaging including computerizedtomography and magnetic resonance imaging scans and is valuable for tumor staging. We investigated resectedinvasive primary tumors with clearly defined extension into the vasculature to identify ccRCC invasion andmetastasis determinants. Approximately fifty percent of ccRCC patients with intravascular tumor extensiondevelop metastasis post nephrectomy and treatment and have poor survival outcome. Comprehensivetranscriptomic analysis of metastatic and non-metastatic invasive ccRCC tumors with intravascular extensionidentified metastatic competence determinants.Our central hypothesis is that metastatic competence of invasive ccRCC tumors is dependent on PRRX1 drivenvasculogenic mimicry and the ability of chemotactic cytokines to recruit CXCR2 positive infiltrating immune cellsto the invasive front that promote dissemination and colonization to distal organs. Pharmacologic and conditionalgenetic manipulation of PRRX1 and CXCL1 ligands in experimental model systems resulted in attenuatedmetastasis.We will investigate the role of PRRX1 mediated vasculogenic mimicry in driving metastasis and assess theimpact of TGF- inhibitor on metastatic progression. We will also elucidate the role of CXCL1 in drivingmetastasis and assess the impact of CXCR2 antagonist on metastatic progression. We anticipate this projectwill decipher pathophysiologic mechanisms determining metastatic competency of invasive ccRCC and developinnovative therapies to disrupt metastatic competence which in combination with current standard of careregimens will result in effective management of metastatic disease. 396783 +No NIH Category available Address;Adjuvant;Adjuvant Therapy;Advanced Malignant Neoplasm;Algorithms;Biological;Biological Markers;Biopsy;Cancer Relapse;Cause of Death;Cells;Chronic;Climate;Clinical;Complement;Cutaneous Melanoma;Data;Detection;Development;Diagnosis;Disabled Persons;Disease;Down-Regulation;Early Intervention;Excision;Excision biopsy;Fostering;Goals;Human;Image;Immune;Immune System Diseases;Immune response;Immunologic Surveillance;Immunologics;Immunosuppression;Immunotherapy;In Vitro;Intercellular Fluid;Intervention;Knowledge;Laboratories;Liquid substance;Location;Lymph;Lymph Node Dissections;Lymphatic;Lymphatic System;Machine Learning;Malignant Neoplasms;Mediating;Mediator;Melanoma Cell;Metastatic Melanoma;Metastatic Neoplasm to Lymph Nodes;Microanatomy;Micrometastasis;Modeling;National Comprehensive Cancer Network;Natural History;Neoplasm Metastasis;Operative Surgical Procedures;Pathologic;Patient risk;Patients;Pattern;Primary Neoplasm;Process;Prognosis;Prognostic Factor;Recommendation;Recurrence;Recurrent Malignant Neoplasm;Relapse;Risk;Risk Assessment;Risk Factors;S100A9 gene;Sentinel Lymph Node;Series;Signal Transduction;Site;Solid;Solid Neoplasm;Surveys;Systemic Therapy;Testing;Therapeutic;Tissues;Translating;Tumor-Associated Process;Tumor-Derived;Work;cancer cell;cancer recurrence;carcinogenesis;clinical risk;clinically relevant;digital;draining lymph node;extracellular vesicles;follow-up;imaging approach;imaging biomarker;imaging modality;immune function;immunoregulation;improved;innovation;insight;lymph nodes;lymphatic circulation;lymphatic vessel;melanoma;multiplexed imaging;neoplastic cell;novel;patient stratification;predictive tools;preservation;prognostic;prognostic signature;prognostic tool;prognostic value;radiological imaging;relapse risk;risk prediction;risk stratification;therapeutic target;tool;tumor;tumor microenvironment;virtual Quantitative assessment of pre-metastatic immune subversion as a risk factor for melanoma relapse PROJECT NARRATIVEEven with the most recent therapeutic advances metastasis remains the leading cause of death in patientswith cancer. In virtually all solid tumors metastasis occurs via the lymphatic circulation; however little is knownabout the factors that ultimately sculpt this process. Thus in the current application we will seek to definecritical lymph-derived factors responsible for mediating pre-metastatic niche immune downregulation in thetumor-draining lymph node in order to identify and develop both prognostic tools and therapeutic counter-measures capable of meaningful clinical impact in patients undergoing primary surgical resection of cutaneousmalignant melanoma. NCI 10683924 8/23/23 0:00 PAR-19-264 5R01CA260259-02 5 R01 CA 260259 2 "OSSANDON, MIGUEL" 9/1/22 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-A(59)R] 6088286 "MARKOVIC, SVETOMIR NENAD" Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 610829 NCI 384169 226660 PROJECT SUMMARY/ABSTRACTThere is a fundamental gap in understanding the immunological paradox by which solid tumors firstmetastasize via lymphatic channels into the immune-rich lymph node. During this process immunesurveillance is disabled ultimately allowing metastatic dissemination to the precise location where it should befirst eliminatedthe tumor-draining sentinel lymph node (SLN). While notably prognostic it is clear themetastatic status of the SLN alone is not sufficient in determining patients risk or relapse. Thereforeunderstanding the mechanisms underlining this chronic process of tumor mediated regionalimmunosuppression commonly referred to as pre-metastatic niche (PMN) formation in the SLN will lendsignificant insights for developing improved prognostic and therapeutic tools to detect and reverse cancerdissemination early in the natural history of metastatic progression. Our long term goal is to developtherapeutic strategies capable of overcoming the immune compromise of the SLN PMN and thereby disruptthe first stage of cancer metastasis. Therefore the objective of the current work is to mechanisticallyinterrogate the process by which the subcellular component of the primary tumor lymphatic effluent directlymediates PMN formation. The central hypothesis proposes that in solid tumors subcellular mediators derivedfrom the primary tumor microenvironment actively traffic through the lymphatics and in a cargo-dependentmanner create a PMN in the tumor-draining SLN. This hypothesis has been formulated on the basis ofpreliminary data produced in the applicants laboratory; namely the discovery and characterization ofhuman lymphatic extracellular vesicles (L-EV) which have a demonstrated capacity to modulateimmune function. The rationale asserts that in elucidating the factors and signatures that define PMNformation in the SLN the knowledge gained will be significant as it will identify histopathologic biomarkers thatcould aid in patient risk stratification beyond the presence of melanoma cells in the SLN. Guided by strongpreliminary data this hypothesis will be tested in two specific aims: 1) identify mechanisms whereby lymphaticsubcellular factors promote immune dysfunction in the pre-metastatic SLN beyond those already identified (i.e.S100A9); 2) evaluate the prognostic utility of these immune-modulating factors in predicting risk of recurrenceby considering the comprehensive interactive cellular landscape that defines the immunologicallycompromised SLN. The approach is innovative as it will use a mechanism-driven model to identify subcellularfactors from a previously uncharacterized biological fluid human lymph (Aim 1) complemented by a novelmultiplexed biomarker imaging approach in order to survey the SLN immunological landscape in a quantitativeand spatially preserved manner to ultimately translate predictive features into clinically amenable platforms(Aim 2). Such findings will result in a refined definition of early-stage patients at risk of relapse and in need ofearlier interventions. 610829 +No NIH Category available 3-Dimensional;Affect;Apoptosis;Automobile Driving;Biological Markers;Cancer Etiology;Cells;Cessation of life;Chromatin;Clustered Regularly Interspaced Short Palindromic Repeats;Colon;Colon Carcinoma;Colonic Neoplasms;Complex;DNA;Data;Disease;Epithelium;Gene Expression;Gene Expression Regulation;Genes;Genomics;Goals;Health;Human;Immunodeficient Mouse;KRAS2 gene;Knock-out;Laboratories;MADH4 gene;Malignant Neoplasms;Mediating;Molecular;Mutation;NMR Spectroscopy;Nuclear;Oncogenes;Oncogenic;Organoids;Patients;Phenotype;Play;Process;Proliferating;Proteins;RNA Binding;Recurrence;Role;Site;Structure;TP53 gene;Testing;The Cancer Genome Atlas;Tissues;Treatment Failure;Tumor Cell Line;United States;Untranslated RNA;Up-Regulation;Validation;Work;Xenograft Model;Xenograft procedure;cancer cell;cancer type;chromatin isolation by RNA purification sequencing;cohort;colon cancer cell line;colon tumorigenesis;experimental study;genome-wide;genomic locus;in vivo;knock-down;new therapeutic target;novel;novel therapeutics;overexpression;protein complex;recruit;targeted treatment;therapeutic RNA;transcriptome sequencing;tumor;tumor microenvironment Mechanisms of lincDUSP Oncogenic Effects in Colon Cancer General audience summary:Human cells encode ~20000 long non-coding RNAs (lncRNAs) but only a small fractionof lncRNAs has been functionally investigated despite their key roles in human healthand disease including many cancers. In our current proposal we will investigate a novellncRNA lincDUSP that appears to function as an oncogene during colon tumorigenesisand could potentially serve as a biomarker or target for therapy. NCI 10683922 9/11/23 0:00 PA-16-160 5R01CA217992-05 5 R01 CA 217992 5 "WEINREICH, MICHAEL DALE" 9/1/18 0:00 8/31/24 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 8877980 "LAFRAMBOISE, THOMAS LOUIS" Not Applicable 11 GENETICS 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 360922 NCI 224175 136747 PI: Khalil AhmadTechnical Abstract:Colon cancer is the second leading cause of cancer-related death in the United States largelydue to frequent treatment failure and recurrence. Recent studies including work from ourlaboratory have demonstrated that regulatory long intergenic non-coding RNAs (lincRNAs) aremajor players in the process of colon tumorigenesis and could emerge as novel therapeutictargets. In this proposal we have identified and functionally characterized a novel lincRNAreferred to as lincDUSP that exerts an oncogenic effect in colon cancer cells. Knockdown oflincDUSP significantly abrogates the tumor phenotype including decreased proliferation andcolony formation and increased apoptosis. These studies have also revealed that lincDUSPregulates numerous genes by directly interacting with chromatin and potentially recruitingprotein complexes to specific genomic loci. In aim 1 of this proposal we will further test theoncogenic function of lincDUSP in vivo using a xenograft model and also assess the role oflincDUSP in driving colon tumorigenesis using 3D organoids. In aim 2 we will investigate themolecular mechanisms of lincDUSP by assessing its role in gene regulation and characterizethe protein complexes that are required for lincDUSP oncogenic activity. Lastly we willdetermine the secondary structure of lincDUSP that facilitates its interaction with DNA andproteins. The completion of the proposed studies could lead to establishing lincDUSP as a noveloncogenic lincRNA with direct impact on colon tumorigenesis and possibly as a target fortherapy. 360922 +Cancer SUPPORT FOR THE SEER-CAHPS INITIATIVE n/a NCI 10683921 75N91020F00215-P00002-0-1 N02 8/31/22 0:00 8/30/23 0:00 77839069 "BOGGS, ABBEY " Not Applicable 4 Unavailable 4868105 JJHCMK4NT5N3 4868105 JJHCMK4NT5N3 US 35.9138 -78.848911 6939101 RESEARCH TRIANGLE INSTITUTE RESEARCH TRIANGLE PARK NC Research Institutes 277092194 UNITED STATES N R and D Contracts 2022 191814 NCI SCIENTIFIC EXPERTISE TECHNICAL ASSISTANCE PROGRAMMING AND ANALYTICALASSISTANCE TO SUPPORT THE SEER-CAHPS INITIATIVE 191814 +Cancer; Prevention Cancer Control;Cancer Surveillance Research Program;Contracts;Data;Data Collection;Data Linkages;Development;Division of Cancer Control and Population Sciences;Generations;Information Systems;Knowledge;Maintenance;Malignant Neoplasms;Methodology;Methods;Population Research;Qi;Quality Control;Recommendation;Science;Statistical Models;Testing;United States National Institutes of Health;Visualization;annotation system;cancer statistics;case finding;data mining;data quality;novel;population based;programs;simulation;tool;usability PROFESSIONAL SUPPORT FOR CANCER CONTROL AND POPULATION BASED RESEARCH NIH/NCI/DCCPS SURVEILLANCE RESEARCH PROGRAM n/a NCI 10683916 26116004B91021F00210-P00002-0-1 N02 8/16/21 0:00 8/15/23 0:00 78316759 "DUNN, MARSHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2022 1626009 NCI This contract provides support for the activities related to: cancer data collection quality control analysis dissemination of reliable population-based cancer statistics geospatial data systems statistical modeling and other novel methodological and technological solutions relevant to cancer surveillance. 1626009 +No NIH Category available 3-Dimensional;Adverse effects;Agonist;Antigen-Presenting Cells;Antigens;Autoimmune Diseases;Biotechnology;CD8-Positive T-Lymphocytes;Cell Death;Cells;Chronic;Clinical;Clinical Trials;Combination immunotherapy;Combined Modality Therapy;Cutaneous T-cell lymphoma;Data;Development;Devices;Dose;Doxorubicin;Drug Delivery Systems;Epitope spreading;FDA approved;Future;Generations;Goals;Heterogeneity;Immune;Immune checkpoint inhibitor;Immune response;Immunity;Immunocompetent;Immunosuppression;Immunotherapy;In Situ;Inflammatory;Injections;Kinetics;Laboratories;Malignant Neoplasms;Needles;Organ Transplantation;Pathologic;Pathway interactions;Patients;Performance;Pharmaceutical Preparations;Phase Ib/II Clinical Trial;Positioning Attribute;Recurrence;Risk;Safety;Skin;Skin Cancer;Skin Neoplasms;Solid;Solid Neoplasm;Source;Stimulator of Interferon Genes;T-Lymphocyte;Technology;Therapeutic immunosuppression;Toxic effect;Translating;Transplant Recipients;Transplantation;Tumor Antigens;Tumor Immunity;Work;anti-PD1 antibodies;cancer cell;cancer therapy;chemotherapeutic agent;chemotherapy;clinical application;clinical efficacy;cohort;fitness;flexibility;immune clearance;immune modulating agents;immune stimulant;immunogenic;immunogenic cell death;immunosuppressed;immunotherapy clinical trials;improved;local drug delivery;melanoma;neoplasm immunotherapy;neoplastic cell;next generation;novel;novel therapeutic intervention;patient population;peripheral blood;pre-clinical;preclinical study;prevent;programs;response;safety study;skin squamous cell carcinoma;tumor;tumor eradication;tumor heterogeneity;tumor microenvironment;virtual Project 3: Localized microneedle-directed combination immunotherapy for cSCC Project 3: Project NarrativeThis project evaluates a novel combination immunotherapy approach applicable to a broad range of accessibleskin cancers. Specifically we will target both a potent chemotherapeutic agent to induce immunogenic celldeath and an innate immune stimulant specifically to the 3D space of the tumor microenvironment ofcutaneous squamous cell carcinomas. These studies represent the first tumor immunotherapy clinical trialsutilizing localized spatially and kinetically controlled delivery of a synergistically acting combination therapy. NCI 10683759 9/8/23 0:00 PAR-18-313 5P50CA254865-03 5 P50 CA 254865 3 8/15/21 0:00 6/30/26 0:00 ZCA1-RPRB-7 5219 1860503 "FALO, LOUIS D" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 352649 232500 137175 Project Summary/Abstract: Project 3This project evaluates a novel combination immunotherapy approach applicable to a broad range of accessibleskin cancers. Specifically we will target both a potent chemotherapeutic agent to induce immunogenic celldeath and an innate immune stimulant specifically to the 3D space of the tumor microenvironment (TME) ofcutaneous squamous cell carcinomas (cSCCs). This strategy is enabled by a dissolvable microneedle array(MNA) device developed and produced in our laboratories. These studies represent the first tumorimmunotherapy clinical trials utilizing spatially and kinetically controlled delivery of a synergistically actingcombination therapy. This approach uniquely enables individualized patient-specific immunotherapy throughlow dose localized drug delivery obviating obstacles related to tumor and antigen heterogeneity andreducing/preventing adverse effects associated with systemic exposure. Thus the strategy could be applicableto a large patient population including those who are immunosuppressed or have or are at risk for autoimmunediseases as well as a broad range of skin cancers through a completely non-specific and generalizable MNAband-aid-like delivery platform. Our hypothesis is that in situ MNA-directed immunotherapy (MNA-IT) will killtumor cells locally and induce a proinflammatory TME enabling immune elimination of the treated tumor whilepotentially inducing durable systemic immunity. It is supported by both preclinical studies and results from ourown clinical trials. To evaluate MNA-IT in patients with cSCCs we will perform an iterative phase Ib/II clinicaltrial evaluating MNA-IT single and combination therapies utilizing dissolving MNAs to deliver doxorubicin aSTING agonist or both directly to the TME of cSCCs. This will be evaluated in both immunocompetentpatients and in immunosuppressed transplant recipients. We will evaluate safety clinical and pathologicresponses and explore therapy-induced changes in the TME and peripheral blood before during and aftertherapy. Through forward reaching pre-clinical studies we will develop a next-generation combination MNA-IT to achieve sustained release of immune checkpoint inhibitors in the TME to support a sustained pro-inflammatory TME favoring the induction of systemic tumor immunity. +No NIH Category available Address;Arizona;Authorization documentation;Awareness;Bupropion;California;Colorado;Combination Drug Therapy;Communities;Continuing Education;Counseling;Development;E-learning;Education;Educational process of instructing;Ensure;Evaluation;Excision;FDA approved;Faculty;Feedback;Funding;Future;Goals;Grant;Health;Health Expenditures;Health Personnel;Health Professional;Hour;Human Resources;Idaho;Indiana;Individual;Kentucky;Laws;Licensing;Maine;Methodology;Methods;Minor;Morbidity - disease rate;New Mexico;Online Systems;Oregon;Participant;Patient Care;Patients;Persons;Pharmaceutical Preparations;Pharmacists;Pharmacy Schools;Pharmacy Students;Pharmacy facility;Phase;Population;Process;Program Development;Protocols documentation;Provider;Role;Schools;Series;Site;Smoke;Smoker;Speed;Statutes and Laws;Students;Surveys;Tobacco;Tobacco Use Cessation;Tobacco use;Trainers Training;Training;Training Programs;United States;United States Public Health Service;Work;authority;care outcomes;effective therapy;evidence base;experience;innovation;meetings;member;mortality;nicotine replacement;novel strategies;program dissemination;programs;quitline;response;skills;smoking cessation;theories;tobacco user;varenicline Advancing the Role of Pharmacy in Tobacco Cessation NARRATIVEIn recent years numerous states have passed legislation granting pharmacists the authority to prescribe smokingcessation medications. While the passage of legislation is an essential first step the second step elevating thetobacco cessation counseling skills of pharmacists is equally important. This project aims to partner with keyorganizations to develop and implement trainings for all members of the pharmacy profession: pharmacistspharmacy technicians and preceptors of pharmacy students (i.e. the nations future pharmacists) therebyenhancing the impact of this legislation in meeting its intended patient care outcomes. NCI 10683740 8/17/23 0:00 PAR-18-477 5R25CA236637-05 5 R25 CA 236637 5 "ZAHIR, NASTARAN" 9/18/19 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 3105492 "HUDMON, KAREN S" Not Applicable 4 PHARMACOLOGY 72051394 YRXVL4JYCEF5 72051394 YRXVL4JYCEF5 US 40.41872 -86.910361 1481402 PURDUE UNIVERSITY WEST LAFAYETTE IN SCHOOLS OF PHARMACY 47906 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 242296 NCI 296748 21326 Although most tobacco users would like to quit the majority do not receive professional assistance and fewerthan 5% who try to quit on their own are successful. The most effective approach for quitting combinespharmacotherapy with counseling yet few clinicians routinely address tobacco use in practice. In recent years onlyminor advancements have been made toward increasing the proportion of patients who receive professionalassistance or use FDA-approved cessation medications and novel approaches are needed to disrupt the status quo. One largely untapped yet highly accessible population of providers is pharmacists. In 2004 New Mexicoimplemented the first protocol granting pharmacists authority to prescribe smoking cessation medications andeight additional states recently have signed similar legislation into law (with another 14 states in the process).While the passage of legislation is an essential first step the second step preparing the profession to act onthese new prescriptive authorities is equally important. The primary objective of this R25 application is to provide assistance to states attempting to advancepharmacys role in tobacco cessation. Through partnerships with key organizations we will develop anddisseminate training programs for all members of the pharmacy profession: pharmacists pharmacy techniciansand pharmacist preceptors who host experiential training sites for pharmacy students. Program development anddissemination will be grounded in theory building upon strong methodology established in our teams prior work.More broadly we will build bridges between the pharmacy profession State Departments of Health and tobaccoquitlines thereby providing patients with increased access to evidence-based methods for quitting.The specific aims of this R25 application are to:AIM 1. Develop a suite of live and enduring web-based tobacco cessation training programs for (a) pharmacy personnel including pharmacists and technicians and (b) pharmacist preceptors who host experiential training sites for pharmacy students.AIM 2. In a pilot Phase I (Years 01/02) conduct a series of 5 live training programs for Indiana pharmacists and launch web-based trainings for Indiana pharmacists and technicians.AIM 3. Revise materials as appropriate based on feedback from Phase I participants prior to a full-launch Phase II (Years 0205) providing live and web-based trainings in states where pharmacists can prescribe smoking cessation medications. Overall an estimated 5680 pharmacists and 1000 technicians will be trained.AIM 4. Apply a mixed methods evaluation approach to estimate the reach and impact of the training programs.This proposed educational initiative is both timely and neededimportantly it capitalizes on heightenedawareness due to recent legislative advances and it builds upon our teams decades of experience in trainingpharmacists technicians and students to assist their patients with the cessation of tobacco use. 242296 +No NIH Category available Address;Advisory Committees;Binding;Cancer Biology;Cancer Etiology;Cell Line;Cell secretion;Cells;Cessation of life;Chromatin;Chromatin Structure;Communication;Data;Dependence;Development;Disease;Eligibility Determination;Engineering;Enhancers;Epigenetic Process;Event;Evolution;Exhibits;Extracellular Matrix;Gene Abnormality;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Heterogeneity;Histologic;Histones;Homeostasis;Human;Immune;Immunoprecipitation;Institution;Intervention;Investigation;KRASG12D;Knock-out;Lung Adenocarcinoma;Malignant Neoplasms;Maps;Mediating;Mentorship;Modeling;Mutation;Normal tissue morphology;Oncogenes;Oncogenic;Organoids;Patient-Focused Outcomes;Patients;Population;Positioning Attribute;Postdoctoral Fellow;Regulator Genes;Reproducibility;Research;Research Ethics;Resources;Role;Sampling;Secure;Series;Shapes;Slide;Somatic Mutation;Stromal Neoplasm;System;TP53 gene;Technology;Therapeutic;Tissues;Training;Training Activity;Transcriptional Activation;Tumor stage;Tumor-Derived;Work;cancer cell;cancer initiation;career development;chromatin remodeling;cofactor;driver mutation;epigenomics;experimental study;extracellular;genome-wide;graduate school;human disease;in vivo;mouse model;neoplastic cell;novel;overexpression;patient subsets;post-doctoral training;programs;skills;targeted treatment;transcription factor;tumor;tumor heterogeneity;tumor initiation;tumor microenvironment;tumor progression Investigating the role of RUNX2 activation across cancer evolution in lung adenocarcinoma Project NarrativeLung adenocarcinoma is a heterogeneous malignancy that demonstrates marked shifts in cellular identityduring tumor evolution. The overarching regulatory mechanisms that maintain these cell states in normaltissues and those disrupted during cancer progression are not well characterized. This proposal outlines aseries of experiments to investigate the role of the transcription factor RUNX2 in late stages of cancerprogression which leads to activation of abnormal gene expression programs which may serve as potentialtherapeutic vulnerabilities. NCI 10683738 8/18/23 0:00 PAR-18-467 5K22CA258957-03 5 K22 CA 258957 3 "JAKOWLEW, SONIA B" 9/1/21 0:00 8/31/24 0:00 ZCA1-RTRB-R(J1) 11647336 "LAFAVE, LINDSAY MARIE" Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 194400 NCI 180000 14400 Project SummaryLung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death; however only a subset ofpatients are eligible for targeted therapies based on the presence of mutations in certain oncogenic drivers. Inaddition many therapeutic approaches target cancer-initiating events yet tumor cells acquire alternativedependencies during tumor progression. In this proposal I aim to interrogate tumor progression in a geneticallyengineered mouse (GEM) model of lung adenocarcinoma termed the KP (KrasG12D/+; p53f/f) model whichfaithfully recapitulates features of human disease. Transcriptional dysregulation occurs across KP tumorprogression and is not explained by the acquisition of somatic mutations suggesting that tumor evolution isdriven predominantly by epigenetic mechanisms. In previous work leveraging single-cell chromatin profiling Idetermined that KP tumors were marked by substantial epigenetic intratumoral heterogeneity. Interestingly Ifound that late-stage populations of tumor cells exhibited progressive activation of RUNX2 transcriptionalactivity. In addition RUNX2 activated cells have increased chromatin accessibility surrounding genes involvedin extracellular secretion; however the mechanism(s) by which RUNX2 alters chromatin state and geneexpression programs is not well-established. Based on this and other data my central hypothesis is thatRUNX2 functions as a master regulatory transcription factor during late-stage tumor progression thataberrantly initiates gene programs that serve to i) reshape the local tumor microenvironment ii) facilitatedifferential stromal/immune composition and iii) contribute to increased intratumoral heterogeneity. My firstaim will interrogate the global chromatin changes and identify RUNX2-associated cofactors in RUNX2-activated cells. The second aim will specifically focus on the role of RUNX2 activation on the remodeling ofthe local tumor microenvironment. The third aim will more broadly assess the spatial localization ofheterogeneous gene expression programs in late-stage cancer cells. This proposal seeks to build on resultsgenerated during my postdoctoral training and will serve as the initial focus of my independent research group.My background in cancer biology and epigenetics from my graduate school training paired with my extensiveexpertise in GEM models and epigenomic technologies from my postdoctoral training positions me for asuccessful transition to independence. As part of this grant I will assemble an advisory team at my institutionto support my transition and career development training activities outlined in this proposal. I will takeadvantage of the varied resources at my postdoctoral institutions and the institution where I secure anindependent position to develop skills related to mentorship communication and research ethics. Overall theoutlined training plain in this proposal will greatly support my continued development with the goal of makingsubstantial contributions in the fields of epigenetics and cancer biology. 194400 +No NIH Category available Abdomen;Abdominal Cavity;Acetates;Adhesions;Adipocytes;Adipose tissue;Adjuvant Chemotherapy;Biochemical;Biological Assay;Biology;Cancer Patient;Cause of Death;Cellular Assay;Characteristics;Chemoresistance;Data;Disease;Effector Cell;Epithelium;Fibroblasts;Glucose;Immune;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Intra-abdominal;Invaded;Label;Laboratories;Lipids;Macrophage;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Metabolic;Metabolism;Methods;Methyltransferase;Natural Killer Cells;Neoadjuvant Therapy;Neoplasm Metastasis;Omentum;Operative Surgical Procedures;Organ;Patients;Primary Neoplasm;Process;Production;Recurrence;Resistance;Role;Stromal Cells;Structure;T-Lymphocyte;Testing;Tumor Tissue;Visceral;adipokines;cancer cell;cell type;chemotherapy;confocal imaging;defined contribution;exhaustion;experience;immune function;in vivo;insight;long chain fatty acid;mass spectrometric imaging;metabolomics;migration;mouse model;oxidation;research clinical testing;screening;small molecule inhibitor;therapy resistant;three dimensional cell culture;treatment response;tumor;tumor microenvironment;tumor progression Metabolic reprogramming of the tumor microenvironment and therapy resistance PROJECT NARRATIVEOvarian cancer most frequently metastasizes to the adipocyte-rich omentum and recurrences most frequentlyoccur at adipose tissue depots. In this project we will investigate the effect of metabolic reprogramming beforeand after chemotherapy on immune function and therapy response. NCI 10683721 7/17/23 0:00 PAR-20-278 5R35CA264619-03 5 R35 CA 264619 3 "MERCER, NATALIA" 8/17/21 0:00 7/31/28 0:00 ZCA1-GRB-S(M1) 8053642 "LENGYEL, ERNST " Not Applicable 1 OBSTETRICS & GYNECOLOGY 5421136 ZUE9HKT2CLC9 5421136 ZUE9HKT2CLC9 US 41.789554 -87.601172 1413601 UNIVERSITY OF CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606372612 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 964319 NCI 587999 376320 PROJECT SUMMARY/ABSTRACTMetastatic ovarian cancer (OvCa) is the leading cause of death from gynecologic cancer. Despite aggressivechemotherapy and surgery most patients (80%) experience intraabdominal progression or recurrence to visceraladipose tissue in the abdominal cavity. For more than 15 years my laboratory has concentrated on elucidatingthe biology of OvCa metastasis focusing on understanding how deregulation of the tumor microenvironment(TME) promotes OvCa metastasis and chemotherapy resistance. We defined the contribution of multiple stromalcell types to metastasis revealing a critical role for a methyltransferase (NNMT) in the reprogramming of normalfibroblasts into cancer-associated fibroblasts through metabolic remodeling. Additionally we answered thedecades-old question of why abdominally metastasizing tumors have a propensity to metastasize to theomentum finding that adipokines attract cancer cells to adipose tissue and that adipocytes provide long-chainfatty acids to cancer cells for energy production through -oxidation. However fundamental questions remainabout metabolic processes in OvCa progression. How are OvCa metastases metabolically different from primarytumors? Which fuels/metabolites are altered after chemotherapy and how do they contribute to chemotherapyresistance? Given that immunotherapies are effective in several epithelial tumors one of the more puzzling andtimely questions is why checkpoint inhibitors are ineffective in OvCa. My hypothesis is that cancer associatedadipocytes contribute to therapy resistance and immune effector cell exhaustion through the lipid-drivenmetabolic reprogramming of the TME. We have adapted methods to perform in vivo metabolic flux analysis inOvCa patients by infusing labeled metabolites (non-radioactive 13C-glucose acetate) and are working onmethods to optimize compartment resolved metabolomics on tumor tissue using imaging mass spectrometry.These data will allow us to define metabolic changes in cancer immune and stromal cells before and afterneoadjuvant chemotherapy. The hypotheses generated by these studies will be tested with wide-rangingexperimental approaches using primary organotypic 3D cultures and mouse models. Our experimental approachwill span functional cellular assays (to study adhesion migration and invasion) confocal imaging biochemicalactivity assays and newly devised methods to test the functionality of natural killer cells T-cells andmacrophages in vitro and in vivo. Compartment-specific insights into metabolic changes in the tumor organ willbe employed to develop high-throughout screening campaigns. These should discover small molecule inhibitorsthat can be optimized through an established and structured process towards clinical testing. We believe thatby targeting metabolic processes identified in the tumor organ we can greatly enhance anti-tumor therapyresponse in OvCa potentially halting the inexorable progression characteristic of this deadly disease. 964319 +No NIH Category available Binding;Cell membrane;Cells;Cellular Metabolic Process;Cellular biology;Cholesterol;Colorectal;Cre-LoxP;Data;Endosomes;Fibroblasts;Genetic Recombination;Glucose;Glucose Transporter;Goals;Growth;Hepatic;Hepatic Stellate Cell;Hepatocyte;In Vitro;Injections;Intervention;Invaded;Knock-out;Knockout Mice;Lipids;Liver;Liver diseases;Liver neoplasms;Malignant Neoplasms;Mediating;Metabolic;Metastatic Neoplasm to the Liver;Methods;Mus;Myofibroblast;Neoplasm Metastasis;Phosphorylation;Plasma;Portal vein structure;Protein Isoforms;Proteins;Regulation;SLC2A1 gene;Signal Pathway;Signal Transduction;Sphingolipids;TGFB1 gene;Testing;Transforming Growth Factor beta;Transforming Growth Factor beta Receptors;Tumor Promotion;Tumor-Derived;Work;aerobic glycolysis;cancer cell;cancer imaging;glucose transport;glucose uptake;implantation;in vivo;knock-down;liver development;mouse model;neoplastic cell;novel;prevent;programs;protein-tyrosine kinase c-src;rab GTP-Binding Proteins;response;trafficking;tumor;tumor microenvironment;vasodilator-stimulated phosphoprotein Hepatic Stellate Cell Regulation of Metastatic Growth in the Liver RELEVANCEIn response to cancer invasion of the liver hepatic stellate cells (HSCs) are activated into myofibroblasts bytumor-derived factors such as TGF and the activated-HSC/myofibroblasts in turn promote liver metastasis.This proposal will study how TGF promotes plasma membrane glucose transporter 1 and glucose transportinto HSCs that fuels activation of HSCs into metastasis-promoting myofibroblasts. The results will advance ourunderstanding of HSC biology and help identify new targets to inhibit HSC activation and the prometastaticliver microenvironment. NCI 10683707 7/11/23 0:00 PA-20-185 5R01CA160069-13 5 R01 CA 160069 13 "SNYDERWINE, ELIZABETH G" 9/1/11 0:00 7/31/27 0:00 Hepatobiliary Pathophysiology Study Section[HBPP] 8254145 "KANG, NINGLING " Not Applicable 5 INTERNAL MEDICINE/MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 377625 NCI 237500 140125 The development of liver metastasis is dependent upon bidirectional interactions between cancer cells andthe liver microenvironment. Transforming growth factor beta (TGF) released from cancer cells and otherresident liver cells induces activation of hepatic stellate cells (HSCs) into myofibroblasts that in turnpromote liver metastasis. The long-term goal of our program is to define mechanisms governing HSCactivation and develop strategies to target HSCs and the prometastatic liver microenvironment. Recentadvances suggest that HSCs are fueled by aerobic glycolysis glutaminolysis and free cholesterol butmechanistic regulation of HSC metabolism is not fully defined. Glucose transporter 1 (Glut1) is apredominant glucose transporter isoform expressed by hepatic fibroblasts and it has to be on the plasmamembrane for glucose to be transported into cells. Our Preliminary Data demonstrate that TGF1 inducesendosome-to-plasma-membrane translocation of Glut1 and glucose uptake into HSCs by a mechanismdependent on non-receptor tyrosine kinase c-Src (Src) and vasodilator-stimulated phosphoprotein(VASP). While Src interacts with the small Rab GTPase Rab11 and Glut1 at the endosome VASP interactswith Glut1 at the plasma membrane. Additionally knockdown of Glut1 suppresses myofibroblastic activation ofHSCs in vitro and tumor-promoting effects of HSCs in a tumor/HSC co-implantation mouse model. Thesefindings led to the Central Hypothesis that the TGF1-induced localization of Glut1 on the plasma membraneand the subsequent glucose transport into HSCs that fuels HSC activation are mediated by Src at theendosome and VASP at the plasma membrane. In Aim 1 we will study how Src promotes Glut1 traffickingtowards the plasma membrane with a focus on its regulation on Rab11 activation at the endosome. We willalso investigate how Src is activated in TGF1-stimulated HSCs. In Aim 2 we will elucidate how VASP retainsGlut1 at the plasma membrane and promotes glucose transport into HSCs. We will also interrogate whether alipid signaling pathway induces VASP phosphorylation in TGF1-stimulated HSCs. In Aim 3 we will useconditional SLC2A1/Glut1 knockout mice and portal vein tumor injection to test if HSC-specific Glut1 deletionsuppresses HSC activation and colorectal liver metastasis in mice. We will also co-inject HSCs and tumor cellsinto the livers of mice to test if the interplay between Src and VASP modulates plasma membrane Glut1glucose transport into HSCs and HSC activation within the hepatic tumor microenvironment. The proposedwork will reveal novel mechanisms related to metabolic regulation of HSC activation induced by TGF whichwill help to identify new targets to inhibit HSC activation and the prometastatic liver microenvironment. 377625 +No NIH Category available Adhesions;Area;Biological;Biological Models;Biology;Biomedical Engineering;Cancer Patient;Cell Adhesion;Cell-Cell Adhesion;Cells;Collaborations;Development;Disease;Esthesia;Event;Faculty;Fostering;Functional disorder;Funding;Goals;Health;Immersion;Institution;Intercellular Junctions;International;Invaded;London;Malignant Neoplasms;Molecular;Neoplasm Metastasis;Participant;Postdoctoral Fellow;Process;Request for Applications;Research;Research Personnel;Scientist;Signal Transduction;Socialization;System;Techniques;Tumor Cell Invasion;Woman;cancer subtypes;college;experience;forging;graduate student;improved;insight;mechanical signal;mechanotransduction;meetings;novel;peer;professor;programs;recruit;symposium;tumor;undergraduate student 2023 Cell Contact and Adhesion Gordon Research Conference and Gordon Research Seminar NarrativeThis application requests funds to support the 2023 Gordon Research Conference on Cell Contact & Adhesionon June 25-June 30 2023 and its associated Gordon Research Seminar for undergraduates graduate studentsand postdoctoral fellows from June 24-25 both at Colby Sawyer College in New London NH. The goal of thismeeting is to catalyze durable collaborative relationships among basic scientists and cancer researchersthat will uncover novel insight into the molecular mechanisms underlying tumor cell invasion andmetastasis. The insight gained from this conference will cause investigators to embark into new areas andforge new collaborations. The ultimate consequence will be a greater potential to make scientific breakthroughsthat ultimately could improve the lives of cancer patients. NCI 10683618 3/13/23 0:00 PA-21-151 1R13CA281325-01 1 R13 CA 281325 1 "NADEAU, CHRISTINE FRANCES" 4/1/23 0:00 8/31/23 0:00 ZCA1-PCRB-9(J1) 1925393 "DEMALI, KRIS A" Not Applicable 2 Unavailable 75712877 XL5ANMKWN557 75712877 XL5ANMKWN557 US 41.480003 -71.569648 2988701 GORDON RESEARCH CONFERENCES East Greenwich RI Domestic For-Profits 28183465 UNITED STATES N 4/1/23 0:00 8/31/23 0:00 396 Other Research-Related 2023 13375 NCI 13375 0 Project SummaryThis application requests funds to support the 2023 Gordon Research Conference on Cell Contact & Adhesionon June 25-June 30 2023 and its associated Gordon Research Seminar for undergraduates graduatestudents and postdoctoral fellows from June 24-25 both at Colby Sawyer College in New London NH. Thegoal of this meeting is to catalyze durable collaborative relationships among basic scientists andcancer researchers that will uncover novel insight into the molecular mechanisms underlying tumorcell invasion and metastasis. To achieve this goal the organizing committee has recruited speakers whoare international leaders who seek to understand cell-cell adhesion in development and cancer. The speakersuse a variety of techniques model systems and investigate different cancer subtypes. Additionally the list ofspeakers includes the leaders in the field as well as up-and-coming new investigators. Currently theprogram consists of 25 speakers including 12 women (48%) and two under-represented scientists. Seveninvited speakers are junior faculty (29%) and nine come from institutions outside the USA (36%). Key infostering interactions at this conference is: (1) a total immersion experience in which scientists of all levels notonly attend scientific discussions together but also reside and socialize with one another and (2) theincorporation of a Gordon Research Seminar prior to the conference in which junior scientists assemble as agroup and listen and discussion research presentations by their peers. 13375 +No NIH Category available Advertisements;American;Area;Award;Biological Markers;COVID-19 impact;California;Cancer Burden;Cancer Center;Cancer Control;Cancer Control Research;Collaborations;Committee Membership;Communication;Communities;Community Clinical Oncology Program;Congresses;Dedications;Development;Discipline;Educational workshop;Electronic Mail;Event;Fostering;Funding;Future;Goals;Grant;Health Professional;Institution;Integrative Medicine;Intervention;Journals;Leadership;Malignant Neoplasms;Manuscripts;Mentors;Minority;Mission;Oncology;Paper;Participant;Peer Review;Policies;Prevention;Preventive;Primary Prevention;Public Health;Publishing;Request for Applications;Research Personnel;Research Proposals;Role;Scientific Advances and Accomplishments;Scientist;Screening for cancer;Secondary Prevention;Societies;Surveys;Training;Translating;Translations;Travel;Update;cancer epidemiology;cancer prevention;career;career development;climate change;collaborative environment;community science;demographics;design;diversity and inclusion;experience;innovation;interdisciplinary approach;lectures;meetings;member;minority investigator;multidisciplinary;non-smoking;novel;posters;programs;public health relevance;satisfaction;special interest group;success;symposium;tertiary prevention;training opportunity;webinar 2023 Annual Conference Grant: American Society of Preventive Oncology Project Narrative - Public Health RelevanceThe American Society of Preventive Oncology (ASPO) is a distinctive society that emphasizes multidisciplinaryapproaches to cancer prevention and control research; ASPO fulfills a unique niche enhancing the health of the publicand supporting the continued development of investigators involved in cancer prevention and control. This applicationrequests partial supportincluding travel funds for minority and early career investigators and community scientistsfor ASPOs 47th Annual Meeting to be held at the Hilton San Diego Bayfront San Diego California March 12-14 2023.The events and activities available at ASPOs 2023 Annual Meeting will influence scientific collaboration and cancercommunications beyond the conference. NCI 10683559 3/7/23 0:00 PA-21-151 1R13CA281329-01 1 R13 CA 281329 1 "WANG, WENDY" 3/7/23 0:00 2/29/24 0:00 ZCA1-PCRB-9(J1) 1971389 "MARTINEZ, MARIA ELENA" Not Applicable 7 Unavailable 117585272 YMDNPNHVYXA4 117585272 YMDNPNHVYXA4 US 39.908748 -86.116502 10061137 "AMERICAN SOCIETY OF PREVENTIVE ONCOLOGY, INC." INDIANAPOLIS IN Other Domestic Non-Profits 462402685 UNITED STATES N 3/7/23 0:00 2/29/24 0:00 393 Other Research-Related 2023 50000 NCI 50000 0 ABSTRACTThe mission of the American Society of Preventive Oncology (ASPO) is the exchange and translation of scientificinformation to reduce the cancer burden and for the continued development of investigators involved in cancerprevention and control. The 47th ASPO Annual Meeting will be held at the Hilton San Diego Bayfront March 12-14 2023.The specific aims of the annual meeting and this conference grant are to: 1) provide multidisciplinary forums for theexchange of scientific information; 2) foster implementation and broaden dissemination of scientific discoveries; and 3)provide exceptional professional development to investigators at any career stage but especially early careerinvestigators to maximize their potential for success.This application requests partial support for the 2023 Annual Meeting which is a keystone of this multidisciplinaryorganization and the preventive oncology community. ASPOs annual meeting provides a high-quality program thatfosters new opportunities for early career mid-career and senior investigators whose careers are focused on theprimary secondary and tertiary prevention of cancer.The 2023 Meeting consists of 4 symposia 2 lunch roundtable sessions 4 submitted paper sessions 2 award lectures 4Special Interest Group breakfast sessions a networking mixer a poster session andfor the fourth yeara CommunityScience program. Pre-meeting workshops include multiple professional development sessions a meeting of cancercenter Associate Directors and Program Leaders for Cancer Prevention and Control and a meeting for NCI training grantdirectors. Breakfast roundtable discussions are organized by Special Interest Groups tasked to move the field forward inspecific topical areas highly relevant to the ASPO mission.Meeting planning takes satisfaction surveys from previous annual meetings into account. Abstracts will be solicitedbeginning in September 2022. The 16 abstracts receiving the highest peer reviewed rankings will be published in CancerEpidemiology Biomarkers & Prevention and presented during paper sessions and the poster session. Over 175 postersare anticipated be presented.Multiple initiatives including this conference grantwhich requests travel support for minority investigators earlycareer scientists and community scientistsenhance the diversity of the meeting attendees program committee andinvited speakers. All meetings are held in non-smoking ADA accessible conference facilities. Journal and onlineadvertisements email and direct mail will publicize the meeting. Over 400 participants are expected to attend. Speakersand participants are from multiple disciplines in cancer prevention and control research and represent fields concernedwith translating evidence into effective prevention and control programs. By fostering communication amongmultidisciplinary professionals ASPO meetings have been extraordinarily successful at reaching the societys goals ofsupporting mentoring encouraging dialogue and promoting innovative progress in cancer prevention and control. 50000 +Cancer; Lung; Lung Cancer; Microbiome Address;Adenocarcinoma;Antibiotic Therapy;Antibiotics;Area;Asthma;Award;Bacteria;Bacterial Infections;Binding;Bioinformatics;Biology;Boston;Cancer Etiology;Cancer Patient;Cessation of life;Clinical;Collaborations;Communities;Complex;Cystic Fibrosis;Development;Disease;Distal;Engineering;Gene Expression Profile;Genes;Genetic;Genetically Engineered Mouse;Germ-Free;Goals;Growth;Human;Human body;Immune;Immune response;Immune system;Immunology;Immunophenotyping;Individual;Inflammation;Institutes;Interdisciplinary Study;Intestines;Laboratory Research;Lesion;Lower respiratory tract structure;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lung diseases;Lung infections;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Microbe;Microbiology;Modeling;Molecular;Mus;Nebulizer;Non-Small-Cell Lung Carcinoma;Oral;Outcome;Pathogenesis;Pathway interactions;Pharmacology;Phase;Physiological;Point Mutation;Research;Research Activity;Research Personnel;Resources;Respiratory System;Role;Shapes;Site;Sterility;T cell response;TP53 gene;Therapeutic Intervention;Time;Training;Training Activity;Tumor Burden;Tumor Promotion;aerosolized;airway obstruction;cancer therapy;career;career development;commensal microbes;experience;experimental study;frontier;germ free condition;gut microbiome;gut microbiota;human disease;in vivo;insight;loss of function;lung microbiota;lung tumorigenesis;microbial community;microbiota;mouse model;neoplastic cell;neutrophil;new therapeutic target;novel;skills;targeted treatment;tool;training opportunity;treatment response;tumor;tumor growth;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis; T cells Investigating immune-microbiota interaction in lung cancer Project NarrativeCommensal microbiota has emerged as an important regulator of both tumorigenesisand cancer response to therapy by modulating tumor microenvironment and hostimmune system yet its role in lung cancer has not been elucidated so far. Here wepropose to investigate the role of local (lung) and distal (intestinal) microbiota in non-small-cell lung cancer (NSCLC) the leading cause of cancer-related death globally.Using advanced generically-engineered mouse models we will interrogate the complexinteractions between commensal microbiota host immune system and developing tumorcells to elucidate the cellular and molecular mechanism(s) by which microbiota promotestumor initiation and progression with the goal of identifying novel therapeutic targets forNSCLC.! NCI 10683419 9/1/22 0:00 PA-16-193 3R00CA226400-05S1 3 R00 CA 226400 5 S1 "DASCHNER, PHILLIP J" 7/1/20 0:00 12/31/23 0:00 NSS 12628430 "JIN, CHENGCHENG " Not Applicable 3 BIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 7/1/22 0:00 12/31/23 0:00 396 Non-SBIR/STTR 2022 59500 OD 36616 22884 Project Summary/AbstractCommensal microbiota inhabits multiple human body sites primarily in the intestine and also along therespiratory tract including the lung. Intestinal microbiota has emerged as an important regulator oftumorigenesis and therapeutic response in several cancers yet its role in lung cancer has not been clearlyunderstood. Changes in the lung microbiota have been associated with several pulmonary disorders; bacterialinfections are highly common in lung cancer patients and closely related to clinical outcomes but theunderlying biology has been elusive. Therefore the proposed study aims to investigate the role of local (lung)and distal (intestinal) microbiota in lung cancer development by using a genetically-engineered mouse modelthat recapitulates the activating point mutation of Kras and loss of p53 in human lung adenocarcinoma. Ourpreliminary results showed that tumor growth was associated with increased bacterial burden and alteredmicrobiota composition in the lung while systemic depletion of microbiota significantly reduced inflammationand tumor burden suggesting that the development of a disordered microbiota may induce a dysregulatedimmune response to promote lung cancer progression. Here we propose to further interrogate the complexinteractions among commensal microbiota the host immune system and developing tumor cells to elucidatethe cellular and molecular mechanism(s) by which microbiota promotes tumor initiation and progression.Specifically we will (1) establish the role of microbiota-induced T cells in lung tumorigenesis (2) determinethe effector mechanism(s) of T cells in mediating microbiota-driven tumor promotion (3) identify the tumor-promoting bacteria in the lung or intestinal microbiota. While the current research aims to reveal the role ofcommensal microbiota in lung cancer by shaping the tumor associated immune response continued efforts inthe independent phase of this award will be focused on identifying the bacterial species and responding hostpathways involved in tumor promotion which may be targeted for therapeutic intervention in lung cancer.My career goal is to independently direct an academic research laboratory addressing questions pertaining tothe biology and mechanism of immune-microbiota interaction in cancer. While I have extensive experience instudying immunology and microbiota and the use of genetic mouse models the K99 phase of this project willallow me to receive further training in advanced bioinformatics and microbiology skills and to develop novelgene-editing tools in vivo using autochthonous mouse models of lung cancer. Moreover I will take advantageof the superb training opportunities and resources available at the MIT/Broad Institute and further establishcollaborations and networks with the strong multidisciplinary research communities in the Boston area. Theseproposed training and research activities will greatly promote my career development towards an independentinvestigator in the frontier of research on immune-microbiota interaction a rising field that can significantlyextend our understanding of cancer and provide us guidance towards more effective cancer therapies. 59500 +No NIH Category available Cells;Coupled;Development;Epigenetic Process;Epithelial Cells;Epithelium;Event;Experimental Models;Exposure to;Fibrosis;Genes;Goals;Growth;Homeostasis;Human;Immune Evasion;Immunotherapy;Knowledge;Link;Lung Adenocarcinoma;Malignant Neoplasms;Mediating;Mesenchymal;Natural regeneration;Nature;Neoplasm Metastasis;Normal Cell;Organ;Pancreatic Ductal Adenocarcinoma;Phenotype;Regulation;Relapse;Residual Neoplasm;Resistance;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Tissues;Transforming Growth Factor beta;Tumor Biology;Tumor Cell Invasion;Tumor Promotion;Tumor Suppression;Work;cancer cell;embryonic stem cell;fibrogenesis;neoplastic cell;stem;stem cells;therapy resistant;transcription factor;tumor;tumor growth;tumorigenesis The TGF Signaling Pathway in Development and Cancer PROJECT NARRATIVEBuilding on long-standing expertise of this lab on TGF signaling in development regeneration and cancer thisproject will elucidate how TGF regulates epithelial phenotypic plasticity in concert with intra-tumoral fibrosis topromote tumor invasion and metastasis and how TGF stimulates entry of metastasis-initiating into quiescentimmune-evasive states that support their survival as residual disease. This work will increase our understandingof how to target TGF in order to suppress metastatic relapse and resistance to therapy.1 NCI 10683414 7/19/23 0:00 PAR-19-349 5R35CA252978-04 5 R35 CA 252978 4 "XU, WANPING" 9/1/20 0:00 8/31/27 0:00 ZCA1-GRB-S(M1) 1894200 "MASSAGUE, JOAN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1040760 NCI 588000 452760 PROJECT SUMMARY/ABSTRACTPhenotypic plasticity and its regulation by contextual signals is of central importance to tumor biology. TGF isa major regulator of cell phenotype during development tissue homeostasis regeneration and cancer. Our long-term goal is to elucidate TGF signaling and the principles that govern its effects on normal and neoplastic cells.This proposal is based on our long-standing contributions to delineating the TGF signal transduction pathwayits context-dependent effects and its aberrant activity in tumorigenesis and metastasis. The proposed workbuilds on recent progress towards understanding how TGF-activated SMAD transcription factors regulatedifferentiation in stem and progenitor cells (Aragn et al Genes Dev. 2019; Wang et al Cell Stem Cell 2017) thebasis for TGF-mediated tumor suppression and the evasion of this effect (David et al Cell 2016; Huang et alCancer Disc. 2019) and the development of experimental models of dormant metastasis to expose the role ofTGF in this poorly understood yet highly significant aspect of cancer (Malladi et al Cell 2016). Moreover werecently elucidated how TGF triggers epithelial-mesenchymal transitions (EMTs) in pancreatic ductaladenocarcinoma (PDA) lung adenocarcinoma (LUAD) and embryonic stem (ES) cells and how thesephenotypic plasticity events are coupled either to fibrogenesis or to differentiation depending on the epigeneticcontext (Su et al Nature 2019). Based on these advances and unique experimental models and human tumorsingle-cell analytics that we have developed we will address long-standing questions of growing importance:How does TGF signaling regulate epithelial cell plasticity in development and cancer? What is the roleof TGF-induced intra-tumoral fibrosis during tumorigenesis? What is the relevance of this mechanismto TGF-induced organ fibrosis? How does TGF drive metastasis-initiating cells into EMT-linked growtharrest? Does this state render cancer cells immune-evasive during metastasis dormancy? To investigatethese questions we will dissect an obscure RAS effector RREB1 which we recently identified as a key partnerof TGF-activated SMAD transcription factors in the induction of fibrogenic and developmental EMTs. We willelucidate the role of EMT-linked intra-tumoral fibrosis in tumor growth and metastasis. Focusing on metastasis-initiating cells we will follow recent evidence that TGF imposes a quiescent immune evasive state that provideslong-term survival to dormant metastasis cells and potentially resistance immunotherapy. Collectively thesestudies will provide knowledge and experimental models to delineate the role of TGF in fibrosis tumor invasionand metastasis and will better define how and when to target TGF in cancer. 1040760 +No NIH Category available Acceleration;Address;Advanced Malignant Neoplasm;American;Area;Artificial Intelligence;Behavior;Cancer Center;Cancer Control;Caring;Collaborations;Continuity of Patient Care;Data;Data Pooling;Development;Doctor of Philosophy;Ensure;Evidence based practice;Funding;Grant;Health;Healthcare;Incubators;Individual;Investments;Laboratories;Leadership;Learning;Life;Link;Literature;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measurement;Measures;Methodology;Methods;Mission;Nature;Oral;Outcome;Patients;Pennsylvania;Pilot Projects;Prevention;Process;Psychiatry;Public Health;Quality of Care;Research;Research Activity;Research Personnel;Resources;Scientific Advances and Accomplishments;Talents;Testing;Tobacco Use Cessation;Tobacco use;Universities;Variant;behavioral economics;bone;cancer care;cancer therapy;care delivery;chemotherapy;comparative;compliance behavior;design;evidence base;heuristics;high reward;implementation science;implementation strategy;implementation study;improved;improved outcome;infancy;innovation;insight;lens;malignant breast neoplasm;multidisciplinary;programs;reduce tobacco use;response;screening;survivorship;symptom management;therapy adherence;uptake Research Program n/a NCI 10683409 8/9/23 0:00 RFA-CA-19-006 5P50CA244690-04 5 P50 CA 244690 4 8/1/20 0:00 7/31/25 0:00 ZCA1-RPRB-L 6094 10099824 "BUTTENHEIM, ALISON MEREDITH" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 623251 404905 253064 The grand challenge addressed by the Penn Implementation Science Center in Cancer Control (ISC3) is to apply insights from behavioral economics to rapidly accelerate the pace at which we deploy evidence-based practices for patients with cancer thereby improving cancer care quality and outcomes. Our Research Program led by Drs. Beidas (implementation science expert) and Buttenheim (behavioral economics expert) will oversee the development and testing of implementation strategies within the Implementation Laboratory. Our implementation strategy design and testing approach includes the patient and clinician as targets and is informed by behavioral economics to nudge individuals to make optimal decisions for implementing evidence-based care. The Penn ISC3 is built on three principles. First implementation science has not leveraged the rich literature from behav- ioral economics which has elucidated many of the heuristics that underlie decisions and behaviors contributing to suboptimal health outcomes. Approaches from behavioral economics have not been applied systematically alongside implementation science to improve cancer care; these approaches aim to accelerate uptake of evi- dence-based practices. Second implementation science has not applied methods to fail fast and learn quickly which we will incorporate through the application of rapid cycle approaches. Third research to identify mecha- nisms of the implementation strategies to improve uptake of evidence-based practices is in its infancy. The Research Program includes investigators with expertise in implementation science behavioral economics can- cer care delivery research healthcare innovation measurement and mixed methods. In the first two years we propose three Signature Pilot Projects (SPPs) and two Methods Projects that both support the SPPs and ad- vance the science of implementation with an eye towards rapid learning. SPP 1 (Jenssen/Leone) tests patient- and clinician-directed implementation strategies to increase referral to tobacco cessation programs in patients receiving cancer treatment. SPP 2 (Bekelman/Patel) tests patient- and clinician-directed implementation strate- gies to increase use of higher-value bone modifying agents in patients with advanced breast lung and prostate cancer. Common methods and measures link these projects to provide pooled data to accomplish our objectives of testing multilevel implementation strategies to elucidate mechanisms and targets. SPP 3 (Bekelman/Rendle) the most exploratory and high-reward SPP will test a patient-directed implementation strategy that leverages artificial intelligence and machine learning to promote oral chemotherapy adherence and symptom management. Methods Project 1 will develop a toolkit for the application of rapid cycle approaches (Asch/Buttenheim); Methods Project 2 will use qualitative comparative analysis to characterize multilevel contextual variation and mechanisms (Barg/Rendle). The scientific advances to come out of the Research Program will have a significant public health impact consistent with NCI priorities by rapidly improving uptake of evidence-based practices to improve cancer care quality and outcomes for millions of Americans with cancer. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page +No NIH Category available Area;Cancer Control;Caring;Collaborations;Communication;Communities;Data;Development;Discipline;Educational Activities;Ensure;Environment;Evaluation;Funding;Goals;Growth;Interdisciplinary Study;Intranet;Laboratories;Malignant Neoplasms;Manuscripts;Methodology;Methods;Mission;Monitor;Newsletter;Oncology;Pennsylvania;Pilot Projects;Policy Maker;Preparation;Principal Investigator;Problem Solving;Public Health;Publications;Reporting;Research;Research Personnel;Research Project Grants;Research Support;Resource Allocation;Scholars Program;Science;Series;Services;Site;Structure;Sum;Translating;United States National Institutes of Health;Universities;Vision;Vocabulary;anticancer research;behavioral economics;cancer care;care delivery;data sharing;experience;health care delivery;implementation science;improved;meetings;multidisciplinary;novel;outreach;programs;recruit;success;synergism;visiting scholar;web site Administrative Core n/a NCI 10683404 8/9/23 0:00 RFA-CA-19-006 5P50CA244690-04 5 P50 CA 244690 4 8/1/20 0:00 7/31/25 0:00 ZCA1-RPRB-L 5125 9176446 "BEIDAS, RINAD SARY" Not Applicable 3 Unavailable 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA Domestic Higher Education 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 139073 106948 66843 This P50 application represents a novel interdisciplinary center at the intersection of behavioral economics and implementation science in pursuit of improving cancer care delivery. The Administrative Core for the University of Pennsylvania Implementation Science Center in Cancer Control (Penn ISC3) will provide overarching operational and scientific oversight. It will be led by the three Penn ISC3 Principal Investigators Drs. Beidas Bekelman and Schnoll in collaboration with an Internal Executive Committee and an External Advisory Board. The Specific Aims of the Administrative Core are as follows: 1) To provide essential management and integration of Penn ISC3 activities (operational structure)which will include administrative support meeting coordination and ensuring the effective use of the Internal Executive Committee and an External Advisory Board; (2) To serve as the hub for implementation science (IS) research in cancer at Penn (IS outreach) which will involve coordination of educational activities drawing upon essential partnerships at Penn engage in activities to ensure communication engaging with other centers funded through this mechanism and coordinating an annual retreat; (3) To coordinate communication and dissemination of the Centers research findings build research capacity and collaboration with other Moonshot awardees and support a national implementation science and cancer research community (network unit); and (4) To support monitor and evaluate Center progress (evaluation unit) which will ensure completion of proposed studies determine the broader impact of the Center and help to translate the results of the proposed studies into subsequent funded research projects. The overarching priority for the Administrative Core is to ensure that the impact of the Penn ISC3 is robust and greater than the sum of its parts. It will do so by coordinating services and maximizing synergies among the Research Program Implementation Laboratory and other center activities. The Administrative Core will interface with the Research Program (Project PIs and Methods Unit) regularly to ensure that each entity is meeting goals and objectives and problem solve as necessary. The proposed Penn ISC3 will bring together junior and senior investigators from multiple disciplines which will create a fertile environment with the long-term goal of improving cancer care delivery and exerting a sustained impact on public health in partnership with key stakeholders. Ultimately the Penn ISC3 Administrative Core will create a culture of exceptional science and ensure the Centers success by stimulating and guiding new conceptual and methodological advancements supporting the growth of IS and cancer research at Penn and nationally and advancing the science of implementation within oncology care. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page +No NIH Category available Active Immunotherapy;Address;Allogenic;Animal Model;Antibody Therapy;Autologous;B-Lymphocytes;Biological Products;Biopsy;Blood;Bone Marrow Aspiration;Cancer Etiology;Cancer Patient;Cells;Clinical Trials;Complex;Data;Development;Doctor of Philosophy;Drug usage;Engraftment;Exhibits;Failure;Flow Cytometry;Functional disorder;Gene Expression Profile;Genetic;Genetic Transcription;Genomic approach;Genomics;Goals;Growth;Growth Factor;Harvest;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic System;Hematopoietic stem cells;Human;Immune;Immune System Diseases;Immune system;Immunofluorescence Immunologic;Immunooncology;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Individual;Innate Immune System;Institutional Review Boards;Intervention;Knowledge;Location;Macrophage;Manuscripts;Medical Oncology;Mentorship;Methods;Minority;Modeling;Mus;Myelogenous;Myeloid Cells;Natural Killer Cells;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Physicians;Physiological;Population;Postdoctoral Fellow;Pre-Clinical Model;Preparation;Principal Investigator;Proteomics;Protocols documentation;Research;Research Personnel;Role;Sampling;Scientist;System;T-Lymphocyte;Time;Tissues;Training;Treatment Failure;Tumor Promotion;Tumor-associated macrophages;Tumor-infiltrating immune cells;Vascular Endothelial Growth Factors;anti-PD-L1;bevacizumab;career;clinical training;drug action;drug efficacy;exhaust;exhaustion;genomic data;hematopoietic engraftment;humanized mouse;immune cell infiltrate;improved;improved outcome;individual patient;melanoma;mortality;mouse development;mouse model;neoplastic cell;patient derived xenograft model;patient response;pembrolizumab;peripheral blood;receptor;response;treatment response;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Autologous Humanized Mouse Model of Non-Small Cell Lung Cancer (NSCLC) to Investigate the Tumor-Immune Landscape and Its Response to Treatment NARRATIVEImmunotherapies hold great promise for the treatment of non-small cell lung cancer (NSCLC) but the efficacyof these drugs is limited by the complex interplay of immune and tumor cells in each particular patient. Thisproposal will use specialized animal models that can incorporate an individual patients tumor and immune cellsinto one model to better understand mechanisms of drug action and failure. The results will advance ourunderstanding of immunotherapy and thereby improve response rates for patients with NSCLC. NCI 10683397 7/28/23 0:00 PA-19-117 5K08CA245211-05 5 K08 CA 245211 5 "LIM, SUSAN E" 9/17/19 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 8096664 "CHIORAZZI, MICHAEL " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 148177 NCI 137201 10976 PROJECT SUMMARYNon-small cell lung cancer (NSCLC) remains the major cause of cancer mortality across the globe despiteexciting advances in immune-based therapies. These therapies while dramatically effective in some patientsare ineffective in the majority of NSCLC patients. The causes of treatment failure remain incompletely understoodas is the role of the local tumor microenvironment (TME) in influencing tumor growth both in the presence andabsence of these therapies.To better study human tumor-immune interactions and immunotherapeutics we have developed a humanizedmouse model that supports the engraftment of mice bearing a matched human hematopoietic system and tumorfrom an individual NSCLC patient. In addition this model is unique in its support of functional myeloid cells aspart of the innate immune system. We propose to use these autologously-engrafted humanized NSCLC PDXmodels to study the TME in detail employing flow cytometric immunostaining and single cell genomic analysesto characterize the transcriptional and proteomic states of the cells present. We will correlate tumor growth tospecific cell populations identified with these methods enhancing our understanding of the pathways active intumor- vs blood-resident immune cells and identifying established and possibly new networks of immunedysfunction in the TME. Armed with this knowledge we will probe the pathways active in these patient modelsusing drugs specific to the immune exhaustion and tumor promoting mechanisms we identify. Our goal is to gaina deeper understanding of how the TME and immunotherapeutics interact and to develop these immune avatarmice as models that may predict a patients response to a particular immunotherapy.The principal investigator is a physician-scientist with a PhD in genetics and post-doctoral and clinical trainingin Medical Oncology. His career goal is to become an independent investigator studying tumor-immuneinteractions. The proposed K08 training plan will provide the candidate with mentorship and coursework to buildthe expertise necessary to execute the proposed project and become independent in the field of translationalimmuno-oncology. 148177 +No NIH Category available Amino Acids;Aminoacylation;Antibodies;Anticodon;Antineoplastic Agents;Automobile Driving;Behavior;Biological Process;Cancer Biology;Cells;Charge;Codon Nucleotides;Complement;Complex;DNA;Development;Drug Screening;Drug Targeting;Elongation Factor;Engineering;Enzymes;Epigenetic Process;Escherichia coli;Eukaryotic Cell;Foundations;Hand;Hydrogen Bonding;Immunoassay;In Vitro;Information Systems;JAK2 gene;Japanese;Letters;Ligase;Lysine;Malignant Neoplasms;Measures;Modernization;Modification;Molecular;Molecular Evolution;Nucleotides;Outcome;Performance;Pharmaceutical Preparations;Phenotype;Phosphoserine;Phosphotyrosine;Positioning Attribute;Post-Translational Protein Processing;Posttranslational Amino Acid Modification;Procedures;Protein Engineering;Proteins;Proteomics;Purines;Pyrimidines;RNA;Research;Research Personnel;Ribosomes;Risk;Services;Site;Specific qualifier value;Speed;Standardization;System;Technology;Thermodynamics;Time;Transfer RNA;Transfer RNA Aminoacylation;Translations;Tyrosine;United States National Institutes of Health;Vision;Work;Writing;anticancer research;cancer cell;cancer proteomics;clinically relevant;drug related cancer;experimental study;genetic information;improved;inhibitor;prohibitin;protein protein interaction;success;synthetic biology;therapeutic protein;tool High Quality Proteins with Multiple Post Translational Modifications High Quality Proteins with Multiple Post Translational Modifications Foundation for Applied Molecular Evolution Shuichi HoshikaNARRATIVE Central to much modern cancer research are proteomics and related epigenetic studies that require tools todistinguish proteins as they are actually present in cancer cells. Central to the development of cancertherapeutics are the proteins as actually present in cancer cells to screen drugs that target them.Unfortunately such proteins are rarely composed of just the canonical 20 amino acids; they also usuallyinclude additional amino acids that influence their folding behavior and performance both in cancer-drivingmolecular biological processes and in their interaction with anti-cancer drugs. Also unfortunately proteins asthey actually exist in cancer cells are difficult to obtain and impossible to obtain in pure form. The proposedtechnology will make rapidly and inexpensively pure proteins in the forms that they are actually found incancer cells. In doing so it will revolutionize all of cancer proteomic research speeding work to understandwhat cancer is how it behaves and how it can be stopped. NCI 10683396 8/14/23 0:00 RFA-CA-20-017 5R21CA251043-03 5 R21 CA 251043 3 "AMIN, ANOWARUL" 9/22/21 0:00 8/31/24 0:00 ZCA1-TCRB-J(M1) 10140327 "HOSHIKA, SHUICHI " Not Applicable 3 Unavailable 134136394 GX1TUDQ8F9M5 134136394 GX1TUDQ8F9M5 US 29.781585 -82.47305 10003112 FOUNDATION FOR APPLIED MOLECULAR EVOLUTN ALACHUA FL Research Institutes 326159544 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 153664 NCI 114538 39126 "High Quality Proteins with Multiple Post Translational Modifications Foundation for Applied Molecular Evolution Shuichi HoshikaABSTRACT The proposed technology will make by in vitro translation (IVT) proteins that hold non-canonical aminoacids normally put in only by post-translational modification (PTM). The immediate deliverable will be tech-nology that delivers proteins with three PTM-AAs (acetyllysine phosphserine phosphotyrosine) incorporatedin many exact positions in long (300 - 1100 amino acid proteins are used) proteins with >95% occupancy. The NCI itself motivated this proposal by its calls for tools to make such proteins which cancer researchersneed throughout cancer proteomics. Today such proteins are available only via isolation from living eukaryoticcells. These are rarely pure. Our pure PTM proteins will be used to get antibodies identify PTM signatures ofcancers standardize quantitative immunoassays as standards discover inhibitors and drugs for cancer-relatedenzymes in their drug-relevant forms and study protein-protein interactions. These will be obtained rapidlyand inexpensively in their own labs (with in vitro translation kits) or via service companies (as for antibodies). As Performance Measures the NCI defined ""useable amounts"" to be ""0.5 to 1 mg of protein"" with ""50-80% modification at the specified site"". Our technology will do better generating 1-10 mg of protein with>95% modification for three different PTM amino acids at many specified sites. Behind this project is an ongoing revolution in the synthetic biology of DNA and RNA (xNA) that deliveredexpanded xNA enhanced in 2019 by the PI. Artificial xNA looks like standard xNA. However it adds pairs byshuffling hydrogen bonding groups allowing expanded xNA to write more AA words in a protein lexicon. Consistent with an IMAT R21 format this project will prove concepts de-risk procedures and take enoughsteps to guide the NCI as it seeks to complete this transformative technology. We will use only 8 ""hachimoji""nucleotides to systematically add in three Aims these PTM-AAs while developing the concepts to control theinteractions that must be controlled to meet this grand challenge: (i) between hachimoji codons and anticodonsduring translation (ii) between synthetases and hachimoji anticodons during aminoacylation and (iii) betweenorthogonal hachimoji charged tRNAs and parts of the E. coli ribosome complex. Even with this limited scopethe technology will be transformative because of the importance of these PTM-AAs. As Aims are met ourability to meet Performance Measures will be shown by making Prohibitin 2 (7 exemplars of these 3 PTM-AAs)using enhanced IVT (eIVT) . As a long term deliverable since 8-letter DNA can deliver 512 codons all PTM AAs can be incorporated intoproteins using this technology a more transformative outcome. Next as researchers advance IVT and movehachimoji DNA into living cells even more transformative outcomes are possible in a long term vision." 153664 +No NIH Category available Address;Adipocytes;Adipose tissue;Affect;Basic Science;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Cellular Metabolic Process;Chronic;Clinical;Collaborations;Consumption;Data;Development;FABP4 gene;Fatty acid glycerol esters;Fish Oils;Funding Opportunities;Health;High Fat Diet;Holden Comprehensive Cancer Center at the University of Iowa;Human;Immune;Immunosuppression;Immunotherapy;Inflammation;Insulin;Interleukin-6;Knockout Mice;Leptin;Link;Linoleic Acids;Lipids;Macrophage;Mammary Neoplasms;Measures;Mediating;Metabolic;Modeling;Molecular;Molecular Chaperones;Monoclonal Antibodies;Mus;Obesity;Oleic Acids;Olive oil preparation;Omega-3 Fatty Acids;PDL1 pathway;Palmitic Acids;Pathway interactions;Peripheral;Phenotype;Physician Executives;Postmenopause;Prevention;Prevention strategy;Regulation;Research;Risk;Role;Sampling;Serum;Shapes;Source;Specimen;Therapeutic antibodies;Thinness;Tissues;Treatment Efficacy;Tumor-associated macrophages;Unsaturated Fats;Woman;Xenograft procedure;adiponectin;cancer clinical trial;cancer immunotherapy;cancer risk;cocoa butter;conditional knockout;design;diet-induced obesity;epidemiology study;extracellular;fatty acid-binding proteins;humanized antibody;improved;insight;lipid metabolism;malignant breast neoplasm;metabolic profile;monocyte;mortality;mouse model;new therapeutic target;novel;novel strategies;novel therapeutic intervention;obesity biomarkers;oxidation;programs;response;saturated fat;therapeutic biomarker;tumor;tumor growth;tumorigenic Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk Project NarrativeData obtained from this proposal are expected to establish A-FABP as a novel therapeutic target andbiomarker for HFD-induced obesity/breast cancer risk. This proposal will not only have basic scienceramifications for understanding how A-FABP shapes dysregulated lipid metabolism and functions of TAMs andbreast cancer cells but will also have significant clinical implications for prevention and immunotherapy ofobesity-associated BC. NCI 10683379 8/1/23 0:00 RFA-CA-21-021 5U01CA272424-02 5 U01 CA 272424 2 "DASCHNER, PHILLIP J" 8/12/22 0:00 7/31/27 0:00 ZCA1-SRB-2(M2) 9620088 "LI, BING " Not Applicable 1 PATHOLOGY 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF MEDICINE 522421320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 1152838 NCI 747542 405296 The objective of this proposal is to determine how high fat diet (HFD)-induced lipid dysregulation links obesitywith increased breast cancer (BC) risk. Epidemiologic studies have confirmed that obesity increases the riskand mortality of BC but the molecular mechanisms of obesity/breast cancer associations remain largelyunknown. Our recent studies demonstrate that lipid chaperone A-FABP (adipose fatty acid binding protein alsoknown as FABP4) promotes obesity-associated BC by intracellular regulating pro-tumor activity in tumorassociated macrophages (TAMs) and extracellular enhancing aggressive phenotype of BC cells. Thus A-FABP might represent a new factor linking dysregulated lipid metabolism with obesity/BC risk. Moreover weobserved that obesity can be induced by consumption of different types of HFDs including saturated fats (e.g.cocoa butter) or unsaturated fats (e.g. olive oil fish oil). However only cocoa butter HFD-induced obesity wasassociated with increased A-FABP expression and mammary tumor growth. These observations suggest anovel concept that not all HFD-induced obesity is tumorigenic. Given the undefined links underlying obesity-induced BC risk we hypothesized that HFDs rich in saturated fats promote BC risk through A-FABP-mediatedimmune and metabolic regulations. As such A-FABP offers a novel therapeutic target and biomarker forobesity-associated BC risk. Three complementary but independent specific aims are designed to address ourcentral hypothesis. Aim 1 is to determine the molecular mechanisms by which different HFDs upregulate A-FABP for BC risk. We will identify which HFDs promote mammary tumor risk and further dissect how the badfat drives intracellular A-FABP expression in TAMs and promotes extracellular A-FABP secretion fromadipocytes. Aim 2 is to delineate the downstream metabolic mechanisms of HFD-upregulated A-FABP in BCrisk and immunotherapy. We will delineate how intracellular A-FABP in TAMs regulates the FA oxidation(FAO)/HIF2/PD-L1 pathway for immune suppressive function followed by delineation of how extracellular A-FABP reprograms lipid metabolic profile in BC cells to enhance their aggressive phenotype. We will furtherevaluate if blocking A-FABP activity with our unique humanized antibodies improves A-FABP-inducedmetabolic dysregulation and reduces obesity/BC risk. Aim 3 is to evaluate A-FABP as a biomarker for obesity-associated BC in humans. We will determine the function of A-FABP in peripheral monocytes and measure thelevels of soluble A-FABP in serum and A-FABP expression in tumor stroma using specimens collected fromlean and obese women with or without BC. Successful completion of this proposal will determine the badHFDs in promoting BC risk and identify the molecular and metabolic mechanisms by which A-FABP mediatesthe pro-tumorigenic activities in HFD-induced obesity/BC risk. 1152838 +No NIH Category available 3-Dimensional;Achievement;Acoustics;Algorithms;Angiography;Area;Biological Markers;Biomedical Engineering;Blood Vessels;Clinical;Clinical Trials;Collaborations;Contrast Media;Data;Detection;Development;Devices;Diagnostic;Disease;Early Diagnosis;Frequencies;Future;Genetic Predisposition to Disease;Goals;Human;Image;Imaging Techniques;Imaging technology;Lesion;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of liver;Mammary Neoplasms;Mechanics;Microbubbles;Modality;Modeling;Motion;Mus;Noise;Patients;Penetration;Performance;Population;Process;Productivity;Public Health;Receiver Operating Characteristics;Recovery;Renal carcinoma;Research;Resolution;Rodent;Screening for cancer;Sensitivity and Specificity;Signal Transduction;Specificity;Structure;System;Techniques;Technology;Testing;Three-Dimensional Imaging;Time;Tissues;Transducers;Translations;Ultrasonography;Universities;Validation;Visualization;angiogenesis;animal imaging;animal tissue;breast lesion;cancer biomarkers;clinical application;clinical imaging;clinical translation;contrast enhanced;contrast imaging;cost;density;design;fabrication;human imaging;human tissue;imaging approach;imaging modality;improved;in vivo;indexing;industry partner;innovative technologies;lens;malignant breast neoplasm;molecular imaging;molecular marker;new technology;next generation;novel;performance tests;portability;pre-clinical;prototype;spatiotemporal;superresolution imaging;tool;transmission process;treatment response;ultra high resolution;ultrasound;volunteer Academic-Industrial Partnership for Translation of Acoustic Angiography RELEVANCE TO PUBLIC HEALTHThis project is a continuation of a collaboration which aims to develop new tools and approaches for imaging themicrovasculature with ultrasound. Data suggests that imaging the microvasculature will provide us with animproved ability to detect and differentiate cancer in humans and if successful our approach may lead to a newlow-cost safe portable imaging modality that is better at early detection of cancers than currently availablemodalities. To pursue this we will develop new ultrasound hardware and imaging approaches and test theirperformance in preclinical and clinical populations. NCI 10683366 8/16/23 0:00 PAR-19-158 5R01CA189479-07 5 R01 CA 189479 7 "PEREZ, J MANUEL" 9/4/14 0:00 8/31/26 0:00 Imaging Technology Development Study Section[ITD] 9239482 "DAYTON, PAUL A" Not Applicable 4 BIOMEDICAL ENGINEERING 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 509185 NCI 407515 101670 PROJECT SUMMARYWe aim to renew a highly productive collaboration that has developed revolutionary new ultrasound imaginghardware and processing approaches. Our innovative technologies have enabled high-signal-to-noise and high-resolution contrast-enhanced microvascular imaging. Specifically we developed the worlds first ultra-broadbandco-axial dual-frequency linear arrays which enable transmission of ultrasound at low frequencies and receptionof high-frequency content from microbubbles well beyond their 7th harmonic. These transducers enablesuperharmonic imaging which provides high-resolution contrast images of the microvasculature with essentiallyno tissue background and is used for visualizing vessels on the order of 100 microns in both animal and humantissues. Significantly we have utilized these tools to image microvascular angiogenesis known for decades tobe a biomarker of cancer yet not previously possible to image directly with ultrasound. Our acousticangiography imaging readily shows drastic differences in microvasculature density and structure betweenmalignant cancers and healthy tissue providing superior sensitivity and specificity to early micro-breast tumorsin mice genetically predisposed to breast cancer. Furthermore our excellent superharmonic signal separationenables super-resolution imaging without the cumbersome spatiotemporal filtering approaches otherwise usedfor this process which are readily corrupted by tissue motion or slow flow. Our next generation approach willenable outstanding microvascular resolution (<100 um) in deep tissue (4-8 cm) despite slow microvascular flowand with robustness to tissue motion. Despite our advances in hardware and imaging techniques challengesremain to make our technology optimal for imaging human cancers. The shallow focal depth of the arraysdesigned in the prior project period limited by prototype array and lens designs and carried over from theiroriginal small-animal imaging applications is far from optimized for the 3-4 cm depth needed to image suspiciousbreast lesions in humans. In this renewal we will direct the development and optimization of dual-frequencyarrays specifically for deeper clinical imaging (targeting depths up to 8cm). Our loss in resolution due to lowerfrequency bandwidths will be recovered by superharmonic super-resolution processing. We have demonstratedthis approach with excellent results using the prototype dual frequency arrays enabling recovery of sub-100micron resolution even with frequencies that can penetrate 6-8 cm. Furthermore since microvascular imagingprovides the most diagnostic information when acquired in 3D we will develop the first dual-frequency 2D arrays.Successful completion of these aims will advance ultrasound imaging closer to a practical clinical modality foridentifying and assessing angiogenic and molecular biomarkers of cancer with high specificity and sensitivity forfuture applications such as differentiation of suspicious lesions assessment of response to therapy and earlydetection. Combined with the hardware development we will optimize acoustic parameters developbeamforming and imaging strategies and test performance in preclinical and clinical populations. 509185 +No NIH Category available 3-Dimensional;Adipocytes;Adipose tissue;Automobile Driving;Bone Marrow;Cancer Model;Cell Culture Techniques;Cells;Disease Progression;Drug resistance;Environment;FABP4 gene;FABP5 gene;Fatty Acids;Fatty acid glycerol esters;Goals;Growth;Hematopoietic Neoplasms;In Vitro;Individual;Intervention;Lead;Link;Malignant Neoplasms;Multiple Myeloma;Mus;Mutate;Nature;Patients;Persons;Plasma Cells;Proteins;Quality of life;Research;Risk;Role;Signal Transduction;Silk;Soil;Source;Specialist;Testing;Tissue Engineering;Work;bone;cancer drug resistance;cytokine;experimental study;fatty acid-binding proteins;high body mass index;improved;in vivo Model;mouse model;neoplastic cell;novel;novel therapeutics;response;scaffold;tumor;tumor growth;tumor progression Research Specialist Support for Defining the Roles of Bone Marrow Adipocytes and FABP4/5 Signaling in Multiple Myeloma Project NarrativeThe overall goal of this application is to change how multiple myeloma an incurable blood cancer isunderstood and treated. We will discover new forms of cancer drug resistance that are driven by fat cell-derived factors. Thus we will expose new interventions to overcome drug resistance to improve survival andquality of life for myeloma patients and patients with other cancers that grow in the bone. NCI 10683321 7/24/23 0:00 PAR-21-285 5R50CA265331-02 5 R50 CA 265331 2 "FORRY, SUZANNE L" 8/12/22 0:00 7/31/27 0:00 ZCA1-SRB-1(M1) 77855856 "CAMPBELL, HEATHER F" Not Applicable 1 Unavailable 71732663 MAYKB1LWD5U9 71732663 MAYKB1LWD5U9 US 43.653164 -70.275471 4757601 MAINEHEALTH PORTLAND ME Independent Hospitals 41023175 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 99576 NCI 57893 41683 Project SummaryCancer develops and ultimately flourishes due to both the nature of the tumor cells themselves as well as themicroenvironment or soil in which the tumor thrives. Multiple myeloma a blood cancer that results frommutated plasma cells grows in the rich soil of the bone marrow causing breakdown of the bone. The risk ofdeveloping myeloma is greater in older individuals and people with high body mass index who also typicallyhave more bone marrow adipose tissue or fat than younger or leaner individuals. However the relationshipbetween bone marrow adipocytes (fat cells) and myeloma cells as well as the specific mechanisms by whichbone marrow adipocytes modulate myeloma disease progression are not well understood. Therefore we aimto identify novel therapeutic avenues for the treatment of multiple myeloma patients by unlocking newvulnerabilities specific to the interactions between myeloma cells and bone marrow adipocytes which canserve as a source of fatty acids and pro-myeloma cytokines. Our cell culture studies suggest bone marrowadipocytes induce drug resistance in myeloma cells- recapitulating a common problem for myeloma patients.We have found that one mechanism of cross-talk linking adipocytes with myeloma cells is through proteinscalled fatty acid-binding proteins 4 and 5 (FABP4 and FABP5). We will analyze how bone marrow adipocytescontribute to myeloma by using novel three-dimensional (3D) tissue engineered cancer models whichconsist of bone marrow adipocytes and myeloma cells grown together on silk scaffolds. By growing myelomacells in these 3D mini-bone environments we can determine how myeloma cells change in response toadipocytes and discover new ways to target this interaction. We will also use our novel mouse models tostudy bone marrow adipocyte- myeloma crosstalk by increasing or removing bone marrow adipocytes in miceand quantifying effects on tumor growth and drug resistance. We will use these in vitro and in vivo models tospecifically test the role of FABP4 and FABP5 in tumor progression and drug resistance and work toward ourlong-term goal to better understand the molecules and mechanisms driving multiple myeloma growth in thebone marrow and how cancer hijacks this niche for its own purposes. This proposal supports this endeavorby providing support for a Research Specialist to further develop lead and execute the experimentsdescribed which interrogate a novel part of the cellular soil (the bone marrow adipocyte) in which tumorcells or seeds land and grow. 99576 +No NIH Category available Advisory Committees;Agreement;American Indians;Biomedical Research;Cancer Center;Chairperson;Cherokee Indian;Comanche;Communities;Community Health;Community Outreach;Development;Disparity;Early Diagnosis;Education;Education and Outreach;Educational Curriculum;Educational Materials;Educational process of instructing;Enrollment;Event;Eye;Family;Fostering;Funding;Future;General Population;Health Sciences;Health Status;Health system;Healthcare;High School Faculty;High School Student;Hour;Human Resources;Infrastructure;Institution;Kiowa;Laboratory Research;Malignant Neoplasms;Medical Students;Medicine;Mentors;Mentorship;Middle School Faculty;Middle School Student;Native Americans;Oklahoma;Osteopathic Medicine;Participant;Pathway interactions;Patients;Population;Prevention education;Public Health;Research;Research Training;Role;Rural;STEM field;STEM program;Schools;Science;Screening for cancer;Students;Training;Training Programs;Tribes;Underrepresented Populations;United States National Institutes of Health;Universities;Wichita;Youth;anticancer research;cancer education;cancer health disparity;cancer prevention;cancer type;career;cohort;college;cost;curriculum development;early screening;experience;faculty mentor;hands on research;health care availability;health disparity;high school;higher education;interest;intertribal;junior high school;matriculation;member;mortality;outreach;programs;recruit;research and development;response;screening;student participation;summer program;teacher;tribal community;tribal health;undergraduate student;underserved students Native American Youths Enjoy Science - YES Oklahoma PROJECT NARRATIVEMuch of the extreme Native American cancer disparities are due to cancer types where early screening andaccess to healthcare have the largest impact suggesting that these disparities could be mitigated with a strongerNative American healthcare workforce and infrastructure and yet the most underrepresented population inscience and medicine are Native Americans. In response we provide an intensive 8 week summer course thatserves as a primer for cancer research along with curriculum development and outreach activities that willdirectly impact >76 participants annually and indirectly impact thousands of underserved students teachersfamilies and community members over five years. NCI 10683304 7/17/23 0:00 RFA-CA-21-020 5R25CA274172-02 5 R25 CA 274172 2 "LOPEZ, BELEM G" 8/12/22 0:00 7/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9753517 "LEWIS, CECIL M" "RAMESH, RAJAGOPAL ; SMITH, KENT " 4 SOCIAL SCIENCES 848348348 EVTSTTLCEWS5 848348348 EVTSTTLCEWS5 US 35.209223 -97.443781 1524002 UNIVERSITY OF OKLAHOMA NORMAN OK SCHOOLS OF ARTS AND SCIENCES 730199705 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 399160 NCI 382565 16595 PROJECT SUMMARYThe YES Oklahoma program provides a pathway that sustains an enhanced representation of OklahomaAmerican Indian students in cancer research. Our program is supported by the Tribal President of the Wichitaand Affiliated Tribes the Kiowa Tribe Higher Education and the Chairman of the Comanche Nation as well assuperintendents representing our partnering schools. Our institutional support is substantial including >$70000annually and over 20 faculty mentors. Native American (NA) professionals are underrepresented in STEM fieldsparticularly those in biomedical research and near-absent in cancer research. This STEM discrepancy hasrealized impacts on community health. There is a substantial NA health disparity in cancer occurrence andmortality rates of various cancers and much of these disparities occur with cancer types where regularscreening early detection and access to healthcare have a large impact. Compared to the general populationwhere there has been considerable advancement over the last 20 years in lowering cancer-associated mortalitysuch reductions have not been observed for NA groups. This suggests that a more robust NA healthcareworkforce and infrastructure one with strong ties to their communities could reduce these rates. In our aimswe propose a research training strategy where NA high school students interested in biomedical careers canengage in hands on scientific research and professionalization activities with a strong emphasis in cancerresearch. YES Oklahoma Scholars will include a cohort of rising high school NA juniors and seniors engaged inan 8-week summer course on professional development and cancer research (Aim 1); YES Oklahoma Teachers(Aim 2) will include a cohort of middle and high school teachers from partner schools who will participate in an8-week summer training event that includes research and curriculum development. Teachers will recruit futureYES Oklahoma Scholars from their classroom populations. This classroom cohort are the YES OklahomaTrainees who engage is a Teachers YES Oklahoma curriculum that includes laboratory research experiencesand local YES Oklahoma outreach activities. Together the PIs Scholars Teachers and Trainees along withcommunity stakeholders and tribes will form our YES Oklahoma Outreach Team and they will participate inevents focused on families communities and intertribal activities and cancer prevention education (Aim 3). TheYES Oklahoma program will directly impact over 76 participants (72 NA students and 4 teachers) annually andthe combined outreach events will indirectly impact thousands of underserved students teachers families andcommunity members. The net result is that the program would have established a pathway of NA studentsentering the STEM program and ultimately into biomedical sciences. 399160 +No NIH Category available Address;Adherence;Behavioral;Budgets;Cancer Patient;Cancer Survivor;Caregivers;Caring;Clinic;Clinical;Cluster randomized trial;Communication;Control Groups;Costs and Benefits;Decision Making;Diagnosis;Distress;Dose;Employment;Enrollment;Evaluation;Face;Facilities and Administrative Costs;Financial Hardship;Financial Support;Health;Health Insurance;Healthcare;Healthcare Systems;Insurance Coverage;Integrated Health Care Systems;Intervention;Intervention Trial;Leadership;Malignant Neoplasms;Medical;Methods;Modeling;Newly Diagnosed;Oncology;Outcome;Pacific Northwest;Participant;Patient Participation;Patient Preferences;Patient Self-Report;Patients;Persons;Quality of life;Randomized;Recurrent Malignant Neoplasm;Reporting;Research;Resources;Risk;Risk Reduction;Services;Severities;Site;Symptoms;Testing;Time;Travel;Treatment Cost;Washington;Work;cancer care;cancer recurrence;care costs;care preference;clinical decision-making;comparison group;cost;cost estimate;design;experience;follow-up;group intervention;health related quality of life;health service use;human centered design;improved;innovation;interest;intervention participants;member;mortality risk;novel;outreach;patient oriented;prevent;primary outcome;prospective;psychologic;randomized trial;secondary outcome;theories;treatment adherence CAF: clinic-based intervention to address financial hardship for people with cancer PROJECT NARRATIVEThe CAF study (Cancer Financial Experience) is among the first trials to assess the impact of financialnavigation in preventing financial hardship in people with cancer. We developed this novel theory-informedintervention building on pilot work and human-centered design methods in partnership with the participatingoncology clinic staff and leadership. Using a randomized trial with step wedge design we will assess theimpact of the CAF intervention on financial hardship (primary outcome) and health-related quality of lifecancer-related material and psychological financial hardship patient-centered communication experiencesand time to initiation of treatment (secondary outcomes) as well as a mixed-methods evaluation of factorsinfluencing variability in dose received by intervention participants. NCI 10683298 8/21/23 0:00 PAR-18-559 5R01CA237322-05 5 R01 CA 237322 5 "SARMA, ELIZABETH ANNE" 9/1/19 0:00 8/31/24 0:00 Nursing and Related Clinical Sciences Study Section[NRCS] 14811188 "FIGUEROA GRAY, MARLAINE " "BANEGAS, MATTHEW P; HENRIKSON, NORA B" 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 525826 NCI 443134 82692 PROJECT SUMMARYFinancial hardship from cancer is prevalent among people with cancer and related to several adverseintermediate and health outcomes including quality of life treatment adherence and survival. Communicationabout out of pocket costs early in the treatment trajectory could help to prevent or lessen financial hardship.CAF is a randomized trial with step wedge design to test the novel CAF (Cancer Financial Experience)intervention. The intervention is based on the research team's prior studies informed by a conceptualframework of how patient-centered communication can improve health and designed with clinic teammembers and patients using human-centered design methods. Our aims are:Aim 1: Compare self-reported financial hardship and between patients receiving the CAF intervention versusa comparison group at 12-month follow up. Aim 1a: Compare self-reported health-related quality of life between patients receiving the CAF intervention versus a comparison group at 12-month follow up.Aim 2: Compare health service use between patients receiving the CAF intervention versus a comparisongroup at 12-month follow up.Aim 3: Assess patient-level factors influencing variability in dose of the CAF intervention.Newly diagnosed cancer patients (n=750) will be randomized to receive either (a) a resource sheet listingfinancial support resources or (b) a financial navigator-based intervention that will include 6 months ofpersonalized outreach and assistance with cost concerns including coordination with the oncology teamprovision of out of pocket cost estimates to support shared clinical decision-making patient planning andbudgeting and referral to financial assistance resources as needed. Oncology clinics in two integrated healthsystems in the Pacific Northwest (Kaiser Permanente Washington and Kaiser Permanente Northwest) will bethe setting for the study. Our primary outcome of interest is financial distress at 12-month follow-up. Secondaryoutcomes include health-related quality of life financial hardship due to cancer patient assessment ofcommunication experiences and time to initiation of treatment.The CAF study represents one of the first trials of an intervention focused on mitigating patient financialhardship. It is theory-informed and clinic-based aligned with patient preferences and has been developedfollowing extensive stakeholder input. By design it will provide high quality prospective evidence on thepotential benefits of cost of care communication on patient-relevant cancer outcomes. 525826 +No NIH Category available Adult;Affinity;Apoptosis;Apoptotic;BCL1 Oncogene;Binding;Binding Sites;Biochemistry;Biology;Cancer Biology;Cancer Patient;Cancer Relapse;Cancer Research Project;Cellular biology;Cessation of life;Chemicals;Chemistry;Chemoresistance;Child;Clinical Trials;Consultations;Cysteine;Development;Equilibrium;Family;Funding;Genetic Transcription;Goals;Human;Hydrocarbons;Investigational Therapies;Life;Maintenance;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Metabolism;Mining;Mitochondria;Modality;Oncogenic;Pathologic;Pediatric Oncologist;Pharmaceutical Preparations;Preclinical Testing;Production;Protein Family;Proteins;Proteomics;Radiolabeled;Reagent;Research;Running;Shapes;Signal Transduction;Specialist;Spin Labels;Surface;Therapeutic;Translations;Variant;alpha helix;analog;anticancer research;cancer cell;cancer therapy;cellular imaging;design;in vivo imaging;innovation;insight;member;next generation;novel therapeutics;overexpression;programs;prototype;stapled peptide;structural biology;therapeutic development;therapeutic target;tool Stapled Peptides for Protein Interaction Research and Therapeutic Targeting in Human Cancer PROJECT NARRATIVE New chemical tools and drug modalities are urgently needed to dissect and target the pathologic proteininteractions that drive human cancer. We synthesize and deploy hydrocarbon-stapled peptides whichrecapitulate the shape stability and bioactivity of natural a-helical interaction motifs to interrogate thebiochemistry structural biology proteomics and cell biology of cancer-causing proteins. By applying stapledpeptides in a diversity of cancer projects that span deregulated apoptosis transcription and metabolism we arecommitted to achieving fresh insight into fundamental oncogenic mechanisms and to advancing new treatmentsfor cancer patients. NCI 10683259 8/22/23 0:00 PAR-20-288 5R50CA211399-08 5 R50 CA 211399 8 "LUO, RUIBAI" 9/15/16 0:00 8/31/26 0:00 ZCA1-SRB-1(A1) 9036737 "BIRD, GREGORY HOWARD" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 332082 NCI 186563 145519 PROJECT SUMMARY / ABSTRACT Deregulated protein interactions contribute to the development maintenance and chemoresistance of humancancer. The critical contact points of cancer-causing proteins are often mediated by so-called helix-in-grooveinteractions whereby an alpha-helical subcomponent of one protein inserts into the surface groove of anotherto drive oncogenic signaling. For example BCL-2 family proteins regulate the critical balance between cellularlife and death and cancer cells overexpress the anti-apoptotic members which contain a surface groove thateffectively traps the killer helix of pro-apoptotic members to enforce cellular immortality. We have inserted all-hydrocarbon struts into natural alpha-helices to restore their shape stability and bioactivity so that they can beused as both powerful chemical tools to dissect oncogenic protein interactions and as prototype therapeutics todrug them. Over the last 15 years I have developed special expertise in the design of stapled peptides fordiverse applications in cancer research and treatment. I have generated spin-labeled analogs for NMR structuralanalyses photoreactive constructs for rapid binding-site analysis by mass spectrometry cysteine-reactivevariants for covalent targeting of oncogenic proteins fluorescent derivatives for binding affinity quantitation andcellular imaging radiolabeled constructs for in vivo imaging and iteratively-optimized analogs for preclinicaltesting and translation. The remarkable impact of stapled peptides is best reflected by their capacity to identifynew cancer targets mechanisms and druggable binding sites and their advancement to clinical trials in adultsand children with relapsed cancers. The goal of this competitive renewal application is to continue to expand thebreadth and depth of stapled peptide innovation in support of critical cancer research programs that harnessthese reagents in proteomic discovery structural determination mechanism-of-action studies and therapeuticdevelopment. Specifically I aim to robustly support the NCI-funded R35 research program of my Unit DirectorDr. Loren Walensky who as a chemical biologist and pediatric oncologist focuses on characterizing the BCL-2family interaction mechanisms that drive human cancer by neutralizing the mitochondrial apoptosis pathway.Reactivating apoptosis in cancer is essential to overcoming chemoresistance and the pathologic alpha-helicalinteractions of the BCL-2 family are ideally suited for interrogation by stapled peptides. In running the StapledPeptide Design Group of the Walensky lab and Dana-Farbers Program in Cancer Chemical Biology I ampersonally responsible for developing and optimizing the chemistry that drives stapled peptide innovations andcreating a high-throughput consultation production purification quantitation and characterization workflow thatis also relied upon by dozens of our internal and external collaborators. As a Research Specialist operating atthe interface of chemistry cancer biology and experimental therapeutics I am committed to mining the potentialof next-generation stapled peptides to advance our understanding of fundamental oncogenic mechanisms andto create novel therapeutics for cancer treatment. 332082 +No NIH Category available Affective;Afferent Neurons;Aftercare;Analgesics;Anti-Inflammatory Agents;Antibodies;Binding;Blocking Antibodies;Blood;Breast;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Patient;Cell Communication;Cell secretion;Cells;Chemotherapy-induced peripheral neuropathy;Coculture Techniques;Color;Communication;Conflict (Psychology);Confocal Microscopy;Data;Data Set;Dose Limiting;Estradiol;Estrogen Receptor alpha;Estrogen Therapy;Estrogen decline;Estrogen deficiency;Estrogens;Female;Flow Cytometry;Histocompatibility Antigens Class II;Hormones;Hypersensitivity;Immune;In Vitro;Inflammation;Injury;Interleukin-10;Interleukin-4;Intravenous;Lead;MHC Class II Genes;Malignant neoplasm of ovary;Measures;Mechanics;Methods;Motivation;Multiple Sclerosis;Mus;Neuroglia;Neuroimmunomodulation;Neuronal Injury;Neurons;Neuropathy;Non-Small-Cell Lung Carcinoma;Ovarian;Paclitaxel;Patients;Peripheral Nervous System Diseases;Pharmaceutical Preparations;Postmenopause;Preventive measure;Production;Proliferating;Proteins;Publishing;Reporting;Risk;Role;Severities;Sex Differences;Signal Transduction;Source;Spinal Ganglia;System;T cell response;T-Cell Activation;T-Cell Depletion;T-Cell Proliferation;T-Lymphocyte;Tactile;Testing;Therapeutic Intervention;Visualization;Woman;aluminum sulfate;antinociception;cancer therapy;chemotherapeutic agent;copolymer 1;cytokine;experimental study;in vivo;male;malignant breast neoplasm;neuroprotection;novel;painful neuropathy;paracrine;prevent;prophylactic;response;screening;transcriptome sequencing Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy Project NarrativeChemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painfulneuropathy posing a major challenge to the successful treatment of cancer. Post-menopausal breast andovarian cancer patients are more at risk for developing paclitaxel-induced peripheral neuropathy.Characterizing neuron-immune communication and enhancing endogenous analgesic CD4+ T cells mayprovide a means for prophylactic and therapeutic intervention. NCI 10683252 8/1/23 0:00 PA-20-185 5R01CA267554-02 5 R01 CA 267554 2 "ALTSHULER, RACHEL DINA" 8/15/22 0:00 7/31/27 0:00 Neurobiology of Pain and Itch Study Section [NPI] 11726904 "GOODE, DIANA J" Not Applicable 1 OTHER BASIC SCIENCES 71735252 HVE6K4YS3B51 71735252 HVE6K4YS3B51 US 43.458691 -70.388902 1197101 UNIVERSITY OF NEW ENGLAND BIDDEFORD ME SCHOOLS OF OSTEOPATHIC MEDICINE 40059526 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 341745 NIGMS 225352 94648 Project Summary/AbstractChemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painfulneuropathy posing a major challenge to the successful treatment of cancer. Recent reports demonstrate thatmale mice lacking T cells have prolonged mechanical hypersensitivity after treatment with paclitaxel (PTX)and only the intravenous transfer of CD8+ but not CD4+ T cells reduced the hypersensitivity. Our preliminaryin vivo data demonstrates female mice have 2-fold more CD4+ T cells in the DRG than male andovariectomized (OVX) female mice and neuronal injury induced by PTX robustly increases anti-inflammatoryCD4+ T cells in the DRG only in estrogen-competent female mice. CD4+ T cell depletion in female mice prior toPTX results in an increase in mechanical hypersensitivity 3 days post-PTX. Our results suggest a previouslyunexplored hormone and sex difference in CD4+ T cells and the severity of chemotherapy-induced peripheralneuropathy (CIPN). PTX is primarily used to treat ovarian breast and non-small cell lung cancer with post-menopausal patients at an increased risk of CIPN; therefore preventative measures would be invaluable forwomen. The mechanism by which CD4+ T cells reduce the severity of PIPN is unknown. In our preliminarystudies DRG neurons from female mice have the capacity to activate CD4+ T cells to secrete anti-inflammatory cytokines. Published RNA-seq datasets of DRG neurons show that DRG neurons expressMHCII a protein directly involved in T cell activation. Our central hypothesis is that PTX administration infemale mice increases MHCII on sensory neurons to stimulate the paracrine release of anti-inflammatorycytokines by resident CD4+ T cells to suppress CIPN. In Aim 1 we will determine the extent to which estrogen-driven CD4+ T cells reduce the severity of PTX-induced peripheral neuropathy. Estrogen is known to induceproliferation of blood CD4+ T cells but it is unknown if this occurs in the DRG. We predict that estrogensignaling in CD4+ T cells will increase the number of resident CD4+ T cells in the DRG to secrete anti-inflammatory cytokines in response to PTX. We expect CD4+ T cells to ameliorate CIPN in female but notmale mice. In Aim 2 we will quantify the extent PTX can enhance MHCII on DRG neurons to induce anti-inflammatory CD4+ T cell cytokine production. We predict PTX-induced inflammation will increase neuronalMHCII to elicit an anti-inflammatory CD4+ T cell response in the DRG of female but not male mice. In Aim 3we will determine the degree in vivo activation of neuroprotective CD4+ T cells can reduce and reverse PTX-induced peripheral neuropathy. We predict that activated CD4+ T cells will dampen and reverse CIPN infemale but not male mice unless pre-treated with estrogen. Completion of these aims will provide compellingevidence that CD4+ T cells in the DRG of females are neuroprotective and anti-nociceptive and can beexploited to prevent or resolve CIPN. Neuronal MHCII-dependent activation of CD4+ T cells represents a novelmechanism for neuro-immune communication that could be utilized for therapeutic intervention. 320000 +No NIH Category available Affective;Afferent Neurons;Aftercare;Analgesics;Anti-Inflammatory Agents;Antibodies;Binding;Blocking Antibodies;Blood;Breast;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Patient;Cell Communication;Cell secretion;Cells;Chemotherapy-induced peripheral neuropathy;Coculture Techniques;Color;Communication;Conflict (Psychology);Confocal Microscopy;Data;Data Set;Dose Limiting;Estradiol;Estrogen Receptor alpha;Estrogen Therapy;Estrogen decline;Estrogen deficiency;Estrogens;Female;Flow Cytometry;Histocompatibility Antigens Class II;Hormones;Hypersensitivity;Immune;In Vitro;Inflammation;Injury;Interleukin-10;Interleukin-4;Intravenous;Lead;MHC Class II Genes;Malignant neoplasm of ovary;Measures;Mechanics;Methods;Motivation;Multiple Sclerosis;Mus;Neuroglia;Neuroimmunomodulation;Neuronal Injury;Neurons;Neuropathy;Non-Small-Cell Lung Carcinoma;Ovarian;Paclitaxel;Patients;Peripheral Nervous System Diseases;Pharmaceutical Preparations;Postmenopause;Preventive measure;Production;Proliferating;Proteins;Publishing;Reporting;Risk;Role;Severities;Sex Differences;Signal Transduction;Source;Spinal Ganglia;System;T cell response;T-Cell Activation;T-Cell Depletion;T-Cell Proliferation;T-Lymphocyte;Tactile;Testing;Therapeutic Intervention;Visualization;Woman;aluminum sulfate;antinociception;cancer therapy;chemotherapeutic agent;copolymer 1;cytokine;experimental study;in vivo;male;malignant breast neoplasm;neuroprotection;novel;painful neuropathy;paracrine;prevent;prophylactic;response;screening;transcriptome sequencing Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy Project NarrativeChemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painfulneuropathy posing a major challenge to the successful treatment of cancer. Post-menopausal breast andovarian cancer patients are more at risk for developing paclitaxel-induced peripheral neuropathy.Characterizing neuron-immune communication and enhancing endogenous analgesic CD4+ T cells mayprovide a means for prophylactic and therapeutic intervention. NCI 10683252 8/1/23 0:00 PA-20-185 5R01CA267554-02 5 R01 CA 267554 2 "ALTSHULER, RACHEL DINA" 8/15/22 0:00 7/31/27 0:00 Neurobiology of Pain and Itch Study Section [NPI] 11726904 "GOODE, DIANA J" Not Applicable 1 OTHER BASIC SCIENCES 71735252 HVE6K4YS3B51 71735252 HVE6K4YS3B51 US 43.458691 -70.388902 1197101 UNIVERSITY OF NEW ENGLAND BIDDEFORD ME SCHOOLS OF OSTEOPATHIC MEDICINE 40059526 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 341745 NCI 15314 6431 Project Summary/AbstractChemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painfulneuropathy posing a major challenge to the successful treatment of cancer. Recent reports demonstrate thatmale mice lacking T cells have prolonged mechanical hypersensitivity after treatment with paclitaxel (PTX)and only the intravenous transfer of CD8+ but not CD4+ T cells reduced the hypersensitivity. Our preliminaryin vivo data demonstrates female mice have 2-fold more CD4+ T cells in the DRG than male andovariectomized (OVX) female mice and neuronal injury induced by PTX robustly increases anti-inflammatoryCD4+ T cells in the DRG only in estrogen-competent female mice. CD4+ T cell depletion in female mice prior toPTX results in an increase in mechanical hypersensitivity 3 days post-PTX. Our results suggest a previouslyunexplored hormone and sex difference in CD4+ T cells and the severity of chemotherapy-induced peripheralneuropathy (CIPN). PTX is primarily used to treat ovarian breast and non-small cell lung cancer with post-menopausal patients at an increased risk of CIPN; therefore preventative measures would be invaluable forwomen. The mechanism by which CD4+ T cells reduce the severity of PIPN is unknown. In our preliminarystudies DRG neurons from female mice have the capacity to activate CD4+ T cells to secrete anti-inflammatory cytokines. Published RNA-seq datasets of DRG neurons show that DRG neurons expressMHCII a protein directly involved in T cell activation. Our central hypothesis is that PTX administration infemale mice increases MHCII on sensory neurons to stimulate the paracrine release of anti-inflammatorycytokines by resident CD4+ T cells to suppress CIPN. In Aim 1 we will determine the extent to which estrogen-driven CD4+ T cells reduce the severity of PTX-induced peripheral neuropathy. Estrogen is known to induceproliferation of blood CD4+ T cells but it is unknown if this occurs in the DRG. We predict that estrogensignaling in CD4+ T cells will increase the number of resident CD4+ T cells in the DRG to secrete anti-inflammatory cytokines in response to PTX. We expect CD4+ T cells to ameliorate CIPN in female but notmale mice. In Aim 2 we will quantify the extent PTX can enhance MHCII on DRG neurons to induce anti-inflammatory CD4+ T cell cytokine production. We predict PTX-induced inflammation will increase neuronalMHCII to elicit an anti-inflammatory CD4+ T cell response in the DRG of female but not male mice. In Aim 3we will determine the degree in vivo activation of neuroprotective CD4+ T cells can reduce and reverse PTX-induced peripheral neuropathy. We predict that activated CD4+ T cells will dampen and reverse CIPN infemale but not male mice unless pre-treated with estrogen. Completion of these aims will provide compellingevidence that CD4+ T cells in the DRG of females are neuroprotective and anti-nociceptive and can beexploited to prevent or resolve CIPN. Neuronal MHCII-dependent activation of CD4+ T cells represents a novelmechanism for neuro-immune communication that could be utilized for therapeutic intervention. 21745 +No NIH Category available Address;Affect;Area;Articulation;Behavior;COVID-19 pandemic;Cancer Center;Cancer Patient;Caring;Communication;Competence;Comprehensive Cancer Center;Confusion;Continuity of Patient Care;Disease;Education;Effectiveness;Electronic Health Record;Electronic Mail;Electronics;Elements;Emergency Situation;Ensure;Environment;Evaluation;Florida;Fright;Future;Goals;Health;Healthcare;Individual;Instruction;Intervention;Intervention Studies;Interview;Knowledge;Language;Learning;Malignant Neoplasms;Measures;Methods;Modeling;Naturopathic Doctor;Oncology;Online Systems;Outcome;Participant;Patients;Perception;Periodicals;Pharmaceutical Preparations;Pilot Projects;Process;Protocols documentation;Random Allocation;Reaction;Recommendation;Relapse;Reporting;Research;Secure;Specific qualifier value;Specificity;Structure;Surveys;Techniques;Technology;Text;Training;Training Programs;Universities;Writing;acceptability and feasibility;acronyms;active method;cancer care;cancer therapy;design;digital;electronic health record system;evidence base;experience;feasibility testing;health care quality;health communication;improved;information organization;innovation;insight;interactive tool;medical specialties;patient oriented;patient-clinician communication;provider communication;psychological distress;psychosocial;satisfaction;skills;skills training;stress reduction;usability;web app S.E.N.D.: Developing a web-based interactive guide to enhance patient-clinician electronic communication by focusing on specificity expressing concerns need and directness Project NarrativeThis project aims to improve cancer patients online communication using secure messaging by developingand evaluating a web-based application designed to help patients craft effective messages. Since patients donot receive any guidance or instruction about how to write electronic messages to clinicians we will utilizemixed methods such as interviews and surveys to provide patients with techniques focusing on specificityexpressing concerns stating needs and directness. Patients will complete an online survey about theirexperience using the application and clinicians will rate messages pre- and post-application. NCI 10683245 6/13/23 0:00 PAR-20-052 5R03CA273617-02 5 R03 CA 273617 2 "EVERSON, NICOLE MARIE" 8/3/22 0:00 6/30/24 0:00 ZCA1-RTRB-B(M1)S 8819525 "BYLUND, CARMA L." Not Applicable 3 SURGERY 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL SCHOOLS OF MEDICINE 326115500 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 76250 NCI 50000 26250 Project SummaryThe use of secure messaging (SM) is increasingly being relied upon for cancer communication. SM can improvecare and provide an outlet for patient-clinician communication. However patients are uncertain about how to useSM effectively to communicate with clinicians and clinicians have cited difficulties understanding the goals ofpatients messages. The long-term goal is to perform a wide-scale implementation to integrate the evidence-based online interactive tool with the electronic health record (EHR) system to facilitate quality health carecommunication between patients and clinicians. The objective of this proposal is to test the feasibility andacceptability of the application to enhance patients message writing skills by conducting interviews with cancerpatients followed by surveying patients after they have used the application and finally rating messagespre/post-application for clarity directness organization and structure. The rationale of this proposal is that justlike in face-to-face communication training developing materials that focus on specific communicationchallenges can enhance how patients communicate with clinicians leading to higher efficiency satisfactionknowledge and self-efficacious behavior. Ensured by the strong track record of the team comprising Alpert (PI)an expert in cancer patients health communication using technology Bylunds (Co-I) extensive experiencedeveloping communication skills training programs Markhams (Co-I) specialty in cancer care Wangs (Co-I)methods and analysis expertise Murphys (Co-I) experience interacting with patients using SM and supportedby the UF Health Cancer Center our three aims are realistic to be completed within the specified timeframe andhold the potential to greatly enhance the quality of communication. Our study is innovative because we willprovide a theoretically grounded interactive intervention to help patients learn specific communication skillsrelated to SM and evaluate its effectiveness by including clinicians as message raters. Our study would alsoprovide valuable insights into how clinicians perceive quality SM communication enabling future interventionsfocusing on clinicians techniques to responding to messages. The proposed research is significant becausealthough SM is widely used no guidance about how to use it effectively is currently provided. The anticipatedpositive impact of this project is that it will provide evidence to confirm that education for SM is necessary andeffective. A multi-level intervention will be planned to integrate the application into the EHR to be suited for awide variety of disease areas. 76250 +No NIH Category available Award;Bioinformatics;Bioinformatics Shared Resource;Cancer Center;Cancer Center Support Grant;Collaborations;Colon;Computational Biology;Computing Methodologies;Data;Data Set;Databases;Diagnosis;Elements;Environment;Experimental Designs;Goals;Hematopoietic Neoplasms;Lung;Malignant Neoplasms;Methods;Ovarian;Prostate;Research;Research Personnel;Research Project Grants;Resources;Role;The Wistar Institute;cancer prevention;data analysis pipeline;high throughput analysis;knowledgebase;melanoma;member;programs Integrative Approach to Comprehensive Analysis of High Throughput Data on a Cancer Center Level Project NarrativeThe application is aimed to support cancer-related research efforts of The Wistar Institute investigators throughcomputational expertise provided by Bioinformatics Shared Resource. Focus of the supported projects involveexperiments designed to understand basic mechanisms of cancers including melanoma ovarian prostatevarious blood cancers lung colon and many others with the final goal of developing methods for cancerprevention diagnosis and treatment. NCI 10683223 8/24/23 0:00 PAR-20-287 5R50CA211199-08 5 R50 CA 211199 8 "BERA, TAPAN K" 9/15/16 0:00 8/31/26 0:00 ZCA1-SRB-1(A2) 10441510 "KOSSENKOV, ANDREW V" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 150262 NCI 82097 68165 Project SummaryBioinformatics Facility supported by the Cancer Center Support Grant (CCSG) awarded to the Wistar Institutecollaborates with the vast majority of cancer center members on multiple research projects. My role as a ScientificDirector of the Bioinformatics Facility is to be engaged on all steps of many of those research programs. Theinstitute-wide involvement in cancer-related studies allows me to develop comprehensive data analysespipelines applicable across multiple programs as well as to re-use result elements including databasessummarized and annotated datasets and other integrative resources in analyses customized to particularstudies. In combination with project-specific research efforts which in turn contribute to the existingknowledgebase the integrative approach provides a robust scientific environment for applying methods ofcomputational biology to various cancer-related studies as demonstrated in the application. 150262 +No NIH Category available Achievement;Address;Admission activity;Awareness;Behavioral;Biological;Biomedical Research;California;Cancer Burden;Cancer Center;Cancer Control;Cancer Control Research;Clinical;Collaborations;Color;Communities;Community Outreach;Country;Cultural Backgrounds;Databases;Dentistry;Development;Discipline;Discipline of Nursing;Disparity;Drops;Education;Educational Status;Educational process of instructing;Educational workshop;Engineering;Enrollment;Ethnic Population;Event;Exposure to;Gender;Geography;Goals;Health;Individual;Interdisciplinary Study;Intervention;Laboratories;Learning;Malignant Neoplasms;Medical;Medicine;Mentors;Molecular Biology;Monitor;Morbidity - disease rate;NCI-Designated Cancer Center;Nanotechnology;National Cancer Institute;Oncology;Participant;Pathway interactions;Pharmacology;Population;Psychology;Public Health;Public Speaking;Research;Research Activity;Research Personnel;Resolution;Review Literature;STEM program;Schedule;Science;Science Technology Engineering and Mathematics;Secure;Sex Orientation;Solid;Student recruitment;Students;Subgroup;Time;Time Management;Training;Underrepresented Students;United States;United States National Institutes of Health;Universities;Woman;Work;Writing;Youth;academic preparation;age group;biobehavior;cancer genetics;cancer health disparity;career;clinical care;design;drug discovery;education research;experience;faculty research;graduate school;graduate school preparation;hands on research;hands-on learning;health disparity;innovation;laboratory experience;learning strategy;matriculation;meetings;mortality;multidisciplinary;neighborhood disadvantage;programs;racial population;recruit;religious group;science education;skills;socioeconomic disadvantage;socioeconomics;student participation;student retention;success;symposium;text searching;theories;training opportunity;translational cancer research;tumor registry;undergraduate student Multidisciplinary Educational Approach to Reducing Cancer Disparities San Diegos three NCI-designated Cancer Centers are collaborating in this Youth Enjoy ScienceResearch Education (YES) Program an intensive laboratory classroom and community-basedlearning opportunity to help UCSD students from underrepresented communities advance to thegraduate levels of education needed to pursue cancer-related health and science careers. Studentparticipants are matched with faculty research mentors who give the students hands-onexperiences in cancer-related research and discuss how their labs research focus could helpaddress cancer disparities. Students classroom and workshops teach students about cancerdisparities and give students hands-on experiences creating and delivering interventions to helpreduce cancer disparities in their community. NCI 10683194 8/22/23 0:00 PAR-17-059 5R25CA221779-05 5 R25 CA 221779 5 "LOPEZ, BELEM G" 9/1/19 0:00 8/31/24 0:00 ZCA1-RPRB-Z(O2) 2028219 "GUTKIND, JORGE SILVIO " "SADLER, GEORGIA ROBINS" 50 PHARMACOLOGY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 352007 NCI 431245 34500 PROJECT SUMMARY/ABSTRACTIncreasing the diversity of cancer researchers and clinicians is a key strategy for finding innovative cancercontrol solutions and reducing cancer disparities. This Youth Enjoy Science Research Education (YES)Program will increase the diversity of University of California San Diego (UCSD) graduates who are pursuinggraduate/professional training in the sciences. This YES Program is grounded on the Transformative LearningTheory and UCSD's 16 years of experience conducting UCSD's successful CURE Program. This YESProgram will increase the number of women and underrepresented students from diverse scientific disciplineswho are prepared for graduate school admission with a focus on addressing cancer and cancer disparities.Specifically YES students participate in classroom and laboratory learning activities that raise theirunderstanding of cancer and the nation's and the world's cancer disparities. Thus cancer disparities and howthey are identified and resolved become the common theme that interconnects this YES Program's variouslearning activities. Students approach the issues related to cancer disparities from the perspective of theirindividual laboratory training classes and workshops their own cultural backgrounds community outreachevents they deploy and their chosen academic and professional pathways. San Diego's three NCI-designatedcancer centers (UCSD Salk Institute for Biological Studies and Sanford Burnham Prebys Medical DiscoveryInstitute) invite the YES students to work and learn in the basic behavioral clinical and translational cancerresearch labs of their top cancer researchers. In their labs and classrooms the YES students gain a solidunderstanding of cancer and the many bio-behavioral issues related to the development and exacerbation ofcancer disparities and the possible resolutions. With this information and their literature review students learnhow to work on multidisciplinary teams as they develop programs to help reduce their community's cancermorbidity and mortality rates. Through these activities students learn that throughout their lives they can playa role in reducing cancer disparities. To help YES students' reach their full academic personal andprofessional potential they are also offered supplementary learning experiences e.g. public speaking goalsetting and time management writing conducting literature search and synthesis skills and experiencespresenting and discussing their research work with professional and lay audiences. Students also prepare andsubmit abstracts to present their research findings at research symposia and national scientific meetings.Mentoring of the YES Program students continues throughout their time at UCSD and on to graduate school.Thus the premise of this YES program is that this learning opportunity will give the students hands-onresearch experiences and skills that will help them to secure admission to graduate level STEM programs andcareers in cancer control research always with a focus on reducing cancer disparities. 352007 +No NIH Category available Address;Adherence;Area;Bahamas;Behavior;Biological Markers;Biopsy;British Columbia;Calibration;Cancer Control;Cancer Etiology;Cancer Intervention;Cancer Intervention and Surveillance Modeling Network;Cessation of life;Clinical;Clinical Sciences;Clinical Trials;Country;Data;Data Set;Data Sources;Decision Making;Development;Diagnosis;Diagnostic;Disease;Disease model;Early Diagnosis;Event;Fred Hutchinson Cancer Research Center;Frustration;Funding Opportunities;Hormonal;Image;Imaging Device;Imaging technology;Incidence;Individual;International;Intervention;Lead;Leadership;Learning;London;Long-Term Effects;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Michigan;Modeling;Modernization;Natural History;Neoplasm Metastasis;Outcome;PSA screening;Patient Care;Patient Selection;Patients;Police;Policies;Population;Population Sciences;Positioning Attribute;Precision therapeutics;Process;Prostate;Prostate Cancer therapy;Radical Prostatectomy;Recording of previous events;Recurrence;Reduce health disparities;Research Personnel;Resources;Risk;Risk Estimate;Route;Salvage Therapy;Saudi Arabia;Screening for Prostate Cancer;Solid;Solid Neoplasm;Source;Statistical Methods;Stratification;Techniques;Technology;Testing;Therapeutic;Time;United Kingdom;United States;Universities;Urologic Oncology;Validation;Work;advanced disease;black men;cancer diagnosis;college;cost;curative treatments;disease natural history;disorder risk;early screening;evidence base;genetic testing;high risk men;high risk population;improved;individual patient;individualized prevention;innovation;interdisciplinary approach;men;models and simulation;mortality;novel;novel marker;overtreatment;personalized care;personalized intervention;personalized medicine;personalized screening;process optimization;prostate biopsy;prostate cancer model;racial disparity;randomized trial;risk stratification;screening;screening policy;treatment strategy;trend;working group Modeling Precision Interventions for Prostate Cancer Control PROJECT NARRATIVEThe most effective ways to personalize the prevention and treatment of prostate cancer using data from anindividual patient are unknown. Our team of investigators applies a unique inter-disciplinary approach thatcombines available data with modern statistical techniques to understand long-term effects of prostate cancerinterventions. In this application we will evaluate personalizing patient care including screening high-risk menmore frequently using biomarkers and imaging tests to select patients for biopsy using patient and cancerfeatures to determine when and which kinds of treatment to offer and practical approaches for reducing racialdisparities. This work will advance the evidence necessary to make informed decisions about individualizedscreening and treatment for this most common cancer in men. NCI 10683180 9/11/23 0:00 RFA-CA-19-054 5U01CA253915-05 5 U01 CA 253915 5 "ZHU, LI" 9/10/20 0:00 8/31/25 0:00 ZCA1-SRB-T(M3) 1883893 "ETZIONI, RUTH D" "PASHAYAN, NORA ; RIZOPOULOS, DIMITRIS ; TSODIKOV, ALEXANDER " 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1235150 NCI 986762 248388 PROJECT SUMMARY/ABSTRACTProstate cancer is the most common solid tumor in men and the second most common cause of cancer deathin the United States. The Cancer Intervention and Surveillance Modeling Network (CISNET) Prostate WorkingGroup (PWG) was formed in the year 2000 to address a wide range of questions about effective prostatecancer control. The PWG studied the rapid increase in prostate cancer diagnoses after PSA screening startedin the late 1980s to estimate lead time and overdiagnosis associated with the test. The PWG studied thedecline in prostate cancer mortality that began in the early 1990s to quantify the plausible contributions of PSAscreening and changes in primary treatments. The PWG also studied how to interpret trends in racialdisparities in incidence and survival how to manage men with low-risk disease on active surveillance and howto reconcile apparently discordant randomized trials of PSA screening and radical prostatectomy.In recent years technologies surrounding prostate cancer screening and treatment have evolved rapidly andopportunities to improve patient care using personalized data abound. Genetic testing can identify men atincreased risk for developing aggressive disease new biomarkers and imaging tools can help men avoidunnecessary biopsies and new hormonal treatments can lengthen survival for men with advanced disease.The objective of this application is to extend PWG models to evaluate optimal ways to utilize personalized datato improve patient care while limiting harms and costs. We will determine whether we can improve earlydetection using novel stratification approaches and whether we can safely limit overtreatment and other harmsby tailored choices of primary and secondary therapies. These approaches will be applied in the United Statesand in international cancer control settings with different resources and priorities.Our specific aims are as follows. Aim 1: Precision early detection including risk-stratified screening and biopsyusing genetic tests novel biomarkers and imaging technology. Aim 2: Precision active surveillance includingadaptive biopsy intervals and imaging technology. Aim 3: Precision treatment including type and timing ofinitial and salvage therapies. Aim 4: Targeting screening biopsy and treatment policies to reduce racialdisparities. Aim 5: Prioritizing screening and treatment interventions in international settings. These aims arehighly responsive to the funding opportunity announcement addressing 7 of the 9 targeted priority areas tovarying degrees. Our cumulative expertise in prostate modeling our existing models and our close ties withclinical experts who provide access to large high-quality datasets for model validation and calibration put us ina strong position to answer critical and impactful questions about how best to control this most common cancerin men. 1235150 +No NIH Category available Address;Alcohols;Antibodies;Automobile Driving;Back;Biological Markers;Biology;Bladder;Breast;CDC2 gene;Cancer Center;Cancer Prevention Trial;Chemicals;Chronic;Clinical;Clinical Trials;Clinical Trials Design;Collaborations;Colon;Colon Carcinoma;Conduct Clinical Trials;Data;Dose;Ensure;Environment;Epidemic;Epigenetic Process;Epithelial Cells;Epithelium;Esophageal Tissue;Esophagus;Funding;Genes;Genetic;Genetic Polymorphism;Genitourinary system;Goals;Grant;In Situ;Individual;Infectious Agent;Inflammation;Inflammation Mediators;Inflammatory;Infrastructure;Institution;Interruption;Iron Chelation;JAK1 gene;Lead;Letters;Life Style;Link;Logistics;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Measures;Mesenchymal;Metabolic;Metabolic syndrome;Methodology;Methods;Michigan;Molecular;Molecular Target;Neoplasms;New Agents;Normal Cell;Obesity;Obesity associated cancer;Organ;Organizational Affiliation;Oxidative Stress;Participant;Pathway interactions;Patient Recruitments;Pharmaceutical Preparations;Phase;Play;Prevention;Prevention strategy;Prevention trial;Preventive;Process;Proliferating;Prostate;Protocols documentation;Regulation;Resources;Role;STAT3 gene;Safety;Sampling;Schedule;Science;Site;Solid Neoplasm;Source;Speed;Stress;System;Technology;Testing;Therapeutic;Therapeutic Index;Tissue Sample;Tissues;Universities;Vision;biomarker driven;breast density;cancer cell;cancer prevention;cancer risk;cancer stem cell;carcinogenesis;cell type;cellular targeting;cytokine;design;drug repurposing;drug testing;dysbiosis;early phase clinical trial;early phase trial;experience;high risk population;high throughput technology;human tissue;immune activation;malignant breast neoplasm;microbial;mortality;neoplastic;novel;novel strategies;obesity prevention;operation;participant retention;pharmacokinetics and pharmacodynamics;phase III trial;preclinical study;prevent;progenitor;programs;promoter;receptor;response;self-renewal;sound;stem cell population;stem cell proliferation;stem cell self renewal;stem cells;stem-like cell;stemness;synergism;targeted agent;trial design;tumor initiation Early Phase Clinical Cancer Prevention Consortium Project NarrativeThe process by which normal cells turn into cancer cells requires changes in stem-like cells that are present inall organs. Our environment life style and genetics all play roles in creating local inflammation that drives thetransformation of normal stem cells into cancer cells. The Early Phase Clinical Prevention Consortium plans toidentify and test drugs that interrupt these processes with a goal of ultimately reducing mortality from cancer. NCI 10683160 7/11/23 0:00 RFA-CA-19-031 5UG1CA242632-04 5 UG1 CA 242632 4 "JOHNSEY, DONALD" 7/7/20 0:00 6/30/25 0:00 ZCA1-SRB-X(J3) 1870444 "BRENNER, DEAN E." "DJURIC, ZORA " 6 INTERNAL MEDICINE/MEDICINE 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 399 Other Research-Related 2023 1538896 NCI 2387506 345326 Project SummaryThe Early Phase Clinical Cancer Prevention Consortium proposes to develop implement and complete earlyclinical trials targeting cellular stemness. Most cancers display a hierarchical organization that is driven by apopulation of cells that are stem-like. Inflammatory stress drives increased stem cell self-renewal acrossdifferent organ sites. The sources of chronic inflammatory stess include obesity explosures (alcohol chemicals)infectious agents microbial dysbiosis and genetic polymorphisms. Of these the obesity-associated metabolicsyndrome associated is reaching epidemic proportions. This consortium addresses the overarching hypothesisthat inflammatory-induced shifts in the tissue stromal environment increase stem cell self-renewal and enhanceepithelial mesenchymal transformation. These shifts can be reversed or dampened by biomarker driven dosingof clinical preventive agents either alone or in combination. We select agents that target the adverse metabolicmilieu resulting from inflammatory exposures and driving stem cell proliferation. The Consortium proposes thefollowing aims: 1. To develop and submit at least three proposals each year for early phase trials for theprevention of obesity-related cancers (colon lower esophagus breast prostate bladder); 2. To conduct 1 to 3early phase cancer prevention trials per year within the fiscal capacity of the grant that include evaluatingtranslational endpoints in biospecimens asssessing the pharmacokinetics and pharmacodynamics andobtaining mechanistic proof-of-principle data; and 3. To manage all aspects of study operations while complyingwith all applicable rules and regulations for the conduct of clinical trials. The University of Michigan Rogel CancerCenter is the lead organization of a consortium consisting of 9 institutions of which all are within NCI Core FundedCancer Centers. The intellectual diversity and strong academic accomplishement of our consortium permitsdeep intellectual engagement combined with the experienced logistics of participant recruitment and retentionand the infrastructure support available in NCI supported cancer centers. We have established processes toensure rapid turn-around of letters of intent and protocol documents uniform sample handling management andshipment and rapid analysis of biosamples. The Consortium will collaborate with other the CP-CTNet consortiato create synergies of science and resources enabling paradigm shifts that rapidly test and prioritize agents forPhase III trials conducted in individuals at increased risk of cancer. 1538896 +No NIH Category available Activities of Daily Living;Address;Affect;Affinity;Aggressive Clinical Course;Antitumor Response;Apoptosis;Applications Grants;Architecture;B-Cell Antigen Receptor;B-lymphocyte Cancer;Binding;Biochemical;Biological;Biology;CD8-Positive T-Lymphocytes;CD8B1 gene;Categories;Cell Surface Receptors;Cell Survival;Cell physiology;Cells;Chronic Lymphocytic Leukemia;Clinical;Clinical Trials;Data;Development;Disease;Disease Progression;FDA approved;Funding;Goals;Immune;Immunity;In Vitro;Interleukin-10;Investigation;Kinetics;Knowledge;Lead;Lymphocyte;Maintenance;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolism;Molecular;Monoclonal Antibodies;Multiple Myeloma;Mus;NAD+ Nucleosidase;Nature;Non-Small-Cell Lung Carcinoma;Pathway interactions;Patients;Pattern;Phase II Clinical Trials;Phosphorylation;Population;Process;Prognosis;Prognostic Marker;Property;Receptor Cell;Receptor Signaling;Regulatory T-Lymphocyte;Role;Sampling;Serum;Signal Transduction;Signaling Protein;Sorting;Surface;Surface Antigens;T cell clonality;T cell receptor repertoire sequencing;T cell response;T-Cell Receptor;T-Lymphocyte;TNF gene;Therapeutic;Therapeutic Effect;Time;Transgenic Mice;Uncertainty;Waldenstrom Macroglobulinemia;cancer cell;cell growth;cell killing;chronic T-cell leukemia;chronic lymphocytic leukemia cell;clinical remission;clinically relevant;cytokine;cytotoxic CD8 T cells;hematopoietic tissue;in vivo;inhibitor;insight;leukemia;metabolic fitness;mutant;neoplastic cell;novel;phase 2 study;prognostic;receptor;response;small molecule inhibitor;targeted treatment;therapeutic target;transmission process;tumor;tumor microenvironment Therapeutic implication of CD38 in CLL Project NarrativeCD38 is a multifunctional ecto-enyzme / co-receptor which is primarily expressed on thesurface of B and T-lymphocytes and in chronic lymphocytic leukemia (CLL) patients itsincreased expression on the B-CLL lymphocytes is associated with an aggressive diseasecourse and poor prognosis. How CD38 is preferentially utilized by the CLL cells and the tumor-supportive T-cells in their microenvironment and whether targeted disruption of CD38 in CLLpatients will yield clinical benefit remains unknown. This grant application (and through use ofprimary samples on an accompanying Phase II clinical trial) will investigate the biologicalproperties of CD38 in CLL and T-cells that cooperatively drive disease progression and howtargeted inhibition of CD38 in patients with an anti-CD38 monoclonal antibody can potentiallyrestore anti-tumor T-cell immunity and provide increased clinical benefit to patients sufferingfrom CLL. NCI 10683157 8/14/23 0:00 PA-18-484 5R01CA233790-05 5 R01 CA 233790 5 "JHAPPAN, CHAMELLI" 9/4/19 0:00 8/31/24 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7270347 "CHANAN-KHAN, ASHER A" "CHINI, EDUARDO N" 5 Unavailable 153223151 GKPBCFV1QMM3 153223151 GKPBCFV1QMM3 US 30.264703 -81.444793 4976105 MAYO CLINIC JACKSONVILLE JACKSONVILLE FL Other Domestic Non-Profits 322241865 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 565086 NCI 440487 124599 Project SummaryThe objective of this proposal is to decipher the mechanisms involved in CD38 signaling in patients withchronic lymphocytic leukemia (CLL a B-cell cancer); how its increased expression drives an aggressive clinicalcourse and whether its targeted therapeutic disruption can be beneficial for patients. CD38 is expressed on allhematopoietic tissues and functions as both an ecto-enzyme to regulate NAD metabolism and as a co-receptorto amplify signaling through the B-cell receptor (BCR) on B-cells and the T-cell receptor (TCR) on T-cells.Increased CD38 expression on CLL cells is associated with an unfavorable disease course in patients;resulting in shorter overall survival and time to treatment. While the role of CD38 as a negative prognosticmarker in CLL has been established for over 2 decades the therapeutic benefit to be derived by patients fromits targeted inhibition has till date remained an open-ended subject. Much of this uncertainty has been due tolack of high-affinity clinical-grade agents that can bind and inhibit CD38; thus resulting in our inability to studythe effects of CD38 disruption on CLL biology. Indeed with the availability of Daratumumab (Dara anti-CD38mAb FDA-approved in multiple myeloma) as well as several other anti-CD38 mAbs and small moleculeinhibitors in development this issue will for the first time be appropriately addressed; by our group. Ourpreliminary data strongly indicates that targeting CD38 has a direct lethal effect on CLL cells reduces thepopulation of tumor-supportive T-regulatory cells (Tregs) and increases the quantity and functional capacity oftumor-specific CD8+ T-cells. These are novel observations and will be examined through the following aimswhere we will: 1. Determine the molecular processes of how CD38 activity in CLL cells promotes diseaseprogression. 2. Elucidate the role of CD38 in the suppression of anti-tumor T-cell responses in vitro and in vivo.3. Evaluate effects of Dara-based therapy in CLL patients on a phase II clinical trial. While the first two aimsare highly mechanistic in nature results from their completion will guide studies in Aim 3 where we willexamine changes in CD38 enzymatic/receptorial activity and in the T-cell architecture in patients who are onDara-based treatment (on an accompanying but separately funded phase II study). Thus our long-term goalsare to understand the fundamentals of CD38 biology in the tumor cells themselves and in neighboring cellswithin the tumor microenvironment. Mechanistic insight into the processes engaged upon CD38 inhibition willpropel more effective development of anti-CD38 treatments and no doubt lead to a paradigm shift- elevatingCD38 from the category of a prognostic marker to a bonafide therapeutic target in CLL. 565086 +No NIH Category available Antigen-Presenting Cells;Antigens;Archives;Biological Assay;Cancer Patient;Cancer cell line;Cancerous;Cells;Clinical;Colon Carcinoma;Colorectal Cancer;Cytotoxic T-Lymphocytes;Dendritic Cells;Detection;Double-Stranded RNA;Epigenetic Process;Evolution;Family;Genetic Transcription;Goals;Human;Immune;Immune response;Immune signaling;Immune system;Immunohistochemistry;Immunologic Markers;Immunologic Receptors;Immunologics;Immunotherapy;In Situ Hybridization;In Vitro;Individual;Innate Immune Response;Innate Immune System;Length;Link;Machine Learning;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Measures;Mediating;Methods;Modeling;Molecular Biology;Normal tissue morphology;Oncornaviruses;Outcome;Pathway interactions;Patients;Pattern;Phenotype;Physics;Plasma;Procedures;Production;Prognosis;Property;RNA;RNA analysis;Recording of previous events;Repetitive Sequence;Role;Sampling;Solid Neoplasm;Source;Spatial Distribution;Statistical Models;Structure;System;Technology;Transcript;Treatment Efficacy;Tumor Immunity;Validation;Virus;cancer immunotherapy;cohort;cost;cytokine;design;exosome;experience;fitness;immune activation;immune checkpoint blockade;in silico;in vitro Assay;in vivo;interdisciplinary approach;liquid biopsy;mathematical model;mimicry;neoantigens;novel;novel marker;pathogen;patient subsets;receptor;response;role model;single molecule;stem;therapeutic target;tool;transcriptome sequencing;transcriptomics;treatment response;tumor;tumor immunology;tumor microenvironment;tumor-immune system interactions;uptake A Statistical Physics Framework for Understanding the Role of Repeat RNA in Tumor Immunity PROJECT NARRATIVEAn emerging paradigm in cancer immunology states that the aberrant transcription of repeat RNA in cancer is acritical mechanism for engaging tumor intrinsic and extrinsic immune and regulatory factors and an untappedsource of potential therapeutic targets. Using a set of approaches from statistical physics our team predictedrepeat RNA stimulates receptors of the innate immune system confirmed this hypothesis in a key subset ofimmune cells and showed classes of repeat RNA can correlate with response to immunotherapies. Our goal isto identify the classes of structural and sequence features of repeat mediated immune activation in solid tumorsand clarify their specific consequences for tumor evolution the state of the immune microenvironment andcancer immunotherapies. NCI 10683142 8/24/23 0:00 PAR-19-101 5U01CA228963-04 5 U01 CA 228963 4 "MILLER, DAVID J" 9/15/20 0:00 8/31/25 0:00 ZCA1-TCRB-V(A1) 10520786 "GREENBAUM, BENJAMIN " "TING, DAVID TSAI" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 636517 NCI 765584 87837 PROJECT SUMMARYTranscriptional dysregulation in tumors can induce the abundant expression of repetitive elements incancerous cells compared to normal tissues where they are often transcriptionally silent. Such transcriptshave been associated with better outcomes to cancer immunotherapies as they can modulate the tumorimmune microenvironment and generate an under-quantified source of tumor neoantigens. Therefore it hasbeen hypothesized that the aberrant transcription of repeat RNA is both a critical mechanism for initiating theimmune response in the tumor microenvironment and an untapped source of potential therapeutic targets.Using a set of approaches from statistical physics our team predicted repetitive element RNA directlystimulates receptors of the innate immune system confirmed this hypothesis in a key subset of immune cellsand showed repeat expression can correlate with response to checkpoint blockade immunotherapies. RepeatRNA is therefore both a novel biomarker for the innate immune response in cancer and a potential therapeutictarget to modulate tumor immunity.We will utilize a set of tools developed by our team from statistical physics to characterize repeat RNArecognition by innate immune receptors in silico and their role in tumor-immune co-evolution both with andwithout the application of immunotherapy (Aim 1). Next we will characterize the spatial context of repeatRNAs in the tumor immune microenvironment and the co-localization of predicted immunostimulatory RNA withactivation of immune signaling along with in depth immune-phenotyping of the state of the immunemicroenvironment in vivo (Aim 2). Finally we will perform functional validation of our predictions on humanimmune cells to validate mechanisms of recognition and the specific immune subsets responsible for repeatrecognition via a set of in vitro assays (Aim 3). Our goal is to use approaches from statistical physics toquantify the role of repetitive elements in tumor immunology their rules of recognition by innate immunereceptors and their part in facilitating cytolytic T cell activity. In doing so we will combine novel RNA detectiontechnologies to study their spatial distribution and localization in cancers; state of the art immune-phenotyping;and mathematical models to characterize their direct role in tumor evolution. We hypothesize that our approachfrom statistical physics will identify the key structural and sequence features of repeat mediated immuneactivation in solid tumors and shed light on their specific consequences for tumor evolution and therapeuticefficacy. 636517 +No NIH Category available BRCA mutations;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Breast;Breast Cancer Prevention;Breast Cancer Risk Factor;Cell Lineage;Cell Proliferation;Cells;Cytometry;DNA Damage;Development;Evolution;Goals;High Risk Woman;High-Risk Cancer;Histology;Human;Image;Immunocompromised Host;Immunofluorescence Immunologic;In Situ;Inherited;Intervention;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary Neoplasms;Masks;Mus;Mutation;Organoids;Periodicity;Population;Population Analysis;Premalignant Cell;Premalignant Change;Proliferation Marker;Quality of life;RNA;Structure;Surface;Susceptibility Gene;Technology;Tissues;Woman;brca gene;diagnostic strategy;high risk;high risk population;malignant breast neoplasm;mammary;mutant;mutation carrier;novel diagnostics;premalignant;prevent;programs;prophylactic;prophylactic mastectomy;psychologic;reconstitution;single cell analysis;single cell technology;single-cell RNA sequencing;tool;tumor;tumor progression;tumorigenesis Tracking the evolution of breast cancer through single cell analyses of premalignant breast tissues from women at high risk for cancer development Project Narrative:The only effective means of breast cancer prevention in women with inherited BRCA mutations is prophylacticmastectomy which while effective raises issues relating to quality of life and other psychological and physicalconsequences. The overarching objective of this application is to develop strategies to detect and eliminatepre-malignant cells in breast tissues from high-risk women. To accomplish this goal we have used state-of-the-art single-cell technologies to detect and isolate subpopulations of breast cells that accumulate in BRCA1and BRCA2 mutation carriers and propose studies to determine how these subpopulations contribute to tumordevelopment and what causes their accumulation in order to develop strategies to interfere with cancerdevelopment in high-risk women. NCI 10683138 7/28/23 0:00 PAR-18-880 5R35CA242428-05 5 R35 CA 242428 5 "HILDESHEIM, JEFFREY" 9/1/19 0:00 8/31/26 0:00 ZCA1-RPRB-N(M1) 2211633 "BRUGGE, JOAN SIEFERT" Not Applicable 7 ANATOMY/CELL BIOLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 996660 NCI 588000 408660 Abstract:The overarching objective of the proposed studies is to identify and characterize early premalignant changes inbreast tissues from women that carry genetic alterations associated with a high risk of breast cancer to ultimatelydevelop strategies to detect and prevent the development of breast cancer. To accomplish this goal we haveoptimized three technologies to profile single breast mammary cells (MECs): (1) CyTOF mass cytometry to allowtracking in parallel of >30 cell lineage and proliferation markers (2) single cell RNA sequencing to identifyexpression programs of cell populations enriched in mutation-carriers and (3) multi-plex cyclic immunofluorescenceimaging (CyCIF) to simultaneous image >50 markers in situ. These technologies make it possible to detectdifferences in small populations of cells that would be masked by bulk population analyses. To date we haveprofiled breast tissues from over 30 women with wild-type or mutant BRCA1 or BRCA2 by CyTOF and haveidentified distinct previously unrecognized subpopulations of cells that are enriched in breast tissues from BRCA1and/or BRCA2 carriers. These enriched subpopulations may represent cells that are either directly on the path tomalignancy or indirectly contribute to the development of cancer in these high-risk women. We have identified RNAsignatures associated with these enriched subpopulations which include surface markers to isolate them frombreast tissue to investigate both these possibilities and to track them within breast tumors. The signaturesassociated with one of the enriched populations have provided clues as to the basis for their accumulation as wellas potential strategies to prevent their accumulation. Using CyCIF we have been able to identify enrichedsubpopulations of cells in situ within breast tissues and track their association with aberrant histologies. We havealso developed organoid cultures that maintain all of the major MEC lineages as well as the BRCA1/2-enrichedpopulations and that are able to reconstitute glandular structures in immunocompromised mice. We believe thatthese tools provide an unprecedented opportunity to track the development of human cancer. In the proposedstudies we will investigate whether and how the BRCA1/2+/mut-enriched subpopulations contribute totumorigenesis in mutation carriers. We will also investigate the basis for the enrichment of these populations andthe contribution of DNA damage to their enrichment. Later stage studies will focus on the development of strategiesto interfere with tumor progression and importantly to develop novel diagnostic strategies to inform on the timing ofprophylactic interventions. In addition we will examine tissues from women who carry mutations in other breastcancer predisposition genes to establish whether similar subpopulations are detected in other high-risk individuals.And lastly we will examine the possibility that these cells represent cells-of-origin of sporadic breast tumors thatarise more broadly in the population. 996660 +No NIH Category available Address;Alternative Splicing;B-Lymphocytes;Biogenesis;Biological;Biological Assay;Blood;CRISPR screen;Cancer Biology;Cell Cycle Regulation;Cell Line;Cell Survival;Cell physiology;Cells;Chemoresistance;Chronic Lymphocytic Leukemia;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Computer Analysis;Critical Pathways;Data;Detection;Development;Diagnostic;Disease;Disease Progression;Engineering;Genes;Genetic Transcription;Genomics;Goals;Hematologic Neoplasms;Hematopoietic Neoplasms;Link;Liquid substance;Malignant Neoplasms;Malignant lymphoid neoplasm;Messenger RNA;Methods;Molecular;Mutate;Mutation;Myeloproliferative disease;Output;Pathway interactions;Patients;Play;Production;RNA;RNA Splicing;RNA-Binding Proteins;Recurrence;Regulator Genes;Repetitive Sequence;Reporter;Research;Role;SRSF2 gene;Screening procedure;Signal Transduction;Somatic Mutation;System;Technology;Therapeutic;Tissues;U1 small nuclear RNA;United States;cancer cell;cancer diagnosis;circular RNA;cis acting element;clinically significant;leukemia;leukemogenesis;mutant;novel;novel therapeutics;potential biomarker;protein transport;prototype;screening;targeted treatment;therapeutic target;tool;transcriptome;tumor;tumorigenesis Impact of RNA splicing factor mutations on circular RNA biogenesis in leukemia PROJECT NARRATIVEBlood malignancies are characterized by recurrent somatic mutations in RNA splicing factors that drive aberrantsplicing to promote leukemogenesis. Recently a novel species of RNA called circular RNAs (circRNA) wasdiscovered to be aberrantly expressed in many types of liquid cancers yet the role of RNA splicing factorsmutations on the biogenesis of these molecules if any in promoting leukemogenesis is not known. Establishinga link between known RNA splicing factor mutations and circRNAs could define a novel regulatory axis that canbe exploited for targeted therapy of these diseases. NCI 10683114 8/22/23 0:00 PA-20-251 5F31CA261110-03 5 F31 CA 261110 3 "DIBELLO, ANTHONY THOMAS" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16254143 "FERNANDEZ, MIKE " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 31784 NCI 31784 0 PROJECT SUMMARY/ABSTRACTApproximately 10% of new cancer diagnoses in the United States are hematological malignancies that includea spectrum of blood cancers and related disorders. In chronic lymphocytic leukemia (CLL) and myeloidneoplasms somatic hotspot mutations frequently occur in five RNA splicing factors (SFs): SF3B1 SRSF2U2AF1 ZRSR2 and genes encoding the U1 snRNA. These mutations drive aberrant splicing of mRNAs topromote leukemogenesis. Recently a novel class of RNAs called circular RNA (circRNA) was found to beaberrantly expressed in many types of liquid tumors. Unlike mRNAs that form through normal splicing to producelinear RNAs circRNAs are produced through backsplicing that results in RNA circularization. Because ofadvances to detection and annotation methods circRNAs are now known to possess functional and clinicalsignificances suggesting a novel role in cancer biology. However to date their precise role in hematologicalmalignancies namely leukemia remains undefined. The long-term goal is to investigate the functions andtherapeutic potentials of circRNAs. Moreover the role of SF mutations (SF3B1 SRSF2 U2AF1 ZRSR2 andgenes encoding the U1 snRNA) in the aberrant expression of circRNAs remains unknown. Thus the overallobjective is to link SF mutations to aberrant circRNA expressions. To this end I hypothesize that mutations inSF3B1 and other SFs such as SRSF2 U2AF1 ZRSR2 and genes encoding the U1 snRNA upregulate circRNAabundance to promote leukemogenesis. The rationale for this research is that linking SF mutations to aberrantexpressions of circRNAs would define a novel regulatory axis unlocking new therapeutic opportunities fortreating leukemia. Preliminary data from CLL patient B cells and cell lines showed that mutant SF3B1 promotedaberrant expression of circRNAs in biological important molecular pathways such as protein transport and cellcycle regulation. To identify circRNAs critical for cell survival I have validated the emergent CRISPR CasRXtechnology as a tool for screening circRNAs. I have also prototyped an experimental workflow for validating thefunctions of these circRNAs. Additionally to further determine the role of SF mutations on circRNA biogenesiscell lines with somatic mutations for SF3B1 SRSF2 U2AF1 ZRSR2 and genes encoding the U1 snRNA havebeen established. Finally I have engineered cell-based and minigene-based reporter systems to investigate themechanisms of backsplicing. Using this collection of tools I propose the following aims: to identify and validatethe functional impact of SF mutation-associated circRNA in leukemia (Aim 1) and to determine themechanism of backsplicing (Aim 2). I expect the findings from this proposal will define a novel regulatory axislinking SF mutations and circRNAs aberrant expressions to leukemogenesis. 31784 +No NIH Category available Grant;Surgical Oncology;Training Surgical Oncology Training Grant Project NarrativeWe are proposing an innovative new training program to encourage surgical residents to pursueclinician-scientist careers in surgical oncology and position them for leadership roles in the field.The program is unique in that it will not only train surgical oncologists in the biology methods andclinical science of cancer but will also teach them how to shepherd their research advancesthrough the complex regulations and delivery environment of our modern healthcare system. NCI 10683105 6/30/23 0:00 PA-18-403 5T32CA251070-04 5 T32 CA 251070 4 "DAMICO, MARK W" 7/15/20 0:00 6/30/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 2108851 "ESSERMAN, LAURA J" Not Applicable 11 SURGERY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Institutional" 2023 313954 NCI 329368 24109 The Department of Surgery at the University of California San Francisco is one of the leading surgicaldepartments in the world and has a rich history of scientific educational and clinical advancements. We areproposing an innovative new training program to encourage surgical residents to pursue clinician-scientistcareers in surgical oncology and position them for leadership roles in the field. The practice of cancer care haschanged considerably over the last 5 years with the introduction of a plethora of targeted agents and newtechnologies. Now more than ever surgical oncologists are required to have a broad understanding of thebiological bases of cancer and its treatment as well as training in modern clinical and translationalmethodologies. To be leaders in the field and make real improvements in cancer care however they must alsobe able to confidently navigate both the regulatory processes and the complex healthcare delivery environmentin which we work.This program will be the first on the West Coast to explicitly support surgical residents in oncology research. Itwill also be the only T32 that explicitly incorporates training in regulatory research and innovation integratingthis with translational/clinical sciences and health services/implementation science. The core of this trainingprogram are mentored research projects which will focus on one of the three themes but with the guidance offaculty mentors will include aspects of all three themes. Among the unique opportunities presented in thisprogram is the option for short-term placement at the FDA to address problems in regulatory science. Anotherimportant aspect of the program is a series of courses and workshops designed to develop the leadership skillsnecessary to evoke positive change guide productive research projects and teams and create a diverse andinclusive work environment. We will initially fund two positions each year for two years which will be available tothird year surgery residents undertaking their research elective. An external advisory board of leaders inoncology trials implementation science and education will advise the program.The program is led by Dr. Laura Esserman who has demonstrated her commitment to training throughout hercareer and who has the full and conscientious support of the department and institution for this program. Therich research environment of UCSF Department of Surgery the carefully selected faculty mentors and theavailability of numerous large-scale research programs provides ample opportunity for meaningful mentoredresearch projects that will provide strong foundations for trainees future careers as clinician-scientists. 313954 +No NIH Category available Adaptive Immune System;Address;Affect;Animal Model;Area;Biological Markers;Blood - brain barrier anatomy;Bone Marrow;CD8-Positive T-Lymphocytes;CD8B1 gene;Cd68;Cell Communication;Cells;Central Nervous System;Central Nervous System Neoplasms;Clinical Trials;Data;Effector Cell;Exposure to;Failure;Frequencies;Genetically Engineered Mouse;Glioblastoma;Glioma;Gliomagenesis;Human;Immune;Immune checkpoint inhibitor;Immune response;Immunologic Surveillance;Immunologics;Immunology;Immunosuppression;Immunotherapy;Infiltration;Innate Immune System;Intravenous;Knock-out;Ligands;Lymphopenia;Macrophage;Malignant Glioma;Malignant Neoplasms;Mediating;Metastatic Neoplasm to the Central Nervous System;Metastatic malignant neoplasm to brain;Microglia;Modeling;Mus;Myelogenous;Natural Immunity;Patients;Peripheral;Phenotype;Population;Primary Brain Neoplasms;Property;Role;STAT3 gene;Secondary to;T cell response;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;Tumor Promotion;Tumor-infiltrating immune cells;Undifferentiated;Validation;Wild Type Mouse;Work;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;arm;cancer infiltrating T cells;cancer therapy;checkpoint inhibition;chemokine;clinical predictors;cytotoxic;effector T cell;exhaust;human data;human subject;immune checkpoint;immune function;immune modulating agents;immunoregulation;in vivo;intravenous administration;monocyte;mouse model;osteopontin;patient subsets;programmed cell death protein 1;recruit;response;restraint;synergism;treatment response;tumor;tumor microenvironment;tumor progression;tumor-immune system interactions Modulation of Microglia and T Cell Interactions in Malignant Glioma NarrativeAlthough anti-PD-1 treatment has shown efficacy against brain metastases indicating that the blood-brain-barrieris not an impediment to immunotherapy clinical trial results of anti-PD-1 in glioblastoma patients have beendisappointing with only a subset of patients likely benefiting. Glioblastomas typically have minimal tumor T cellinfiltration but are highly infiltrated with macrophages and microglia that express PD-1. This proposal will clarifywhich immune cells that anti-PD-1 antibodies engage how this interaction modulates anti-tumor immunereactivity in the setting of lymphopenia and if these therapeutics gain access into the central nervous systemtumor microenvironment. NCI 10683098 6/30/23 0:00 PA-20-185 5R01CA120813-15 5 R01 CA 120813 15 "SINGH, ANJU" 1/10/07 0:00 6/30/26 0:00 Clinical Neuroimmunology and Brain Tumors Study Section[CNBT] 6098896 "HEIMBERGER, AMY BETH" "RAO, GANESH " 5 NEUROSURGERY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 287999 NCI 241014 46985 ABSTRACTImmunotherapy has revolutionized cancer treatment by reversing the immune suppression of cytotoxic anti-tumor CD8+ effector T cells. However glioblastoma patients have profound lymphopenia and immunecheckpoint inhibition treatment does not restore T cell immune function. Extensive characterization by our grouphas demonstrated that glioblastoma is fundamentally different relative to other malignancies in its preferentialenrichment of innate immune cells such as macrophages and microglia that are recruited to the tumormicroenvironment. These innate immune cells are tumor supportive. In a genetically-engineered mouse model(GEMM) of glioblastoma we recapitulated lympophenia using a CD8 knockout (KO) background and foundmarked enrichment of PD-1 expressing macrophages in the murine glioma microenvironment similar toobservations made in human glioblastoma patients. We evaluated the effect of anti-PD-1 Ab deliveredintravenously in glioblastoma-bearing wild-type mice and in the CD8 KO background and found therapeuticbenefit even in the absence of the CD8 effector T cell. Both peripheral monocyte-derived macrophages andresident microglia were reduced within the glioblastoma microenvironment in mice treated with the anti-PD-1 Ab.As such our overall study hypothesis is that anti-PD-1 exerts therapeutic immune modulatory effects againstglioblastoma through innate immunity in the central nervous system (CNS). This proposal will address multiplecrucial questions to the field including: 1) Does the anti-PD-1 Ab cross into the CNS to exert a therapeutic effect;2) what immune cells other than the CD8 T cell are contributing to the therapeutic effect of this agent; 3) arethe immune cells that are mediating the therapeutic effect arising from the periphery or are they intrinsic to theCNS; and 4) how does the glioblastoma immune microenvironment change in response to treatment? Toaddress these questions we will use contemporary murine models of glioma that closely approximate humanglioblastoma and manipulate both the innate and adaptive immune systems to dissect the impact and importanceof each in the context of anti-PD-1 treatment. Validation will be carried out using data from human subjectstreated with anti-PD-1. By clarifying the mechanistic role of anti-PD-1 therapeutic activity we may identify thesubset of glioblastoma patients that are capable of responding to this type of strategy. This is a significant areaof unmet need if glioblastoma patients are to benefit from immunotherapy. These studies may also reveal thatanti-PD-1 treatment has a dual role on both the innate and adaptive immune system and when one arm is notoperational this agent toggles its modulatory properties to the dominant immune arm. 287999 +No NIH Category available Address;Adjuvant Therapy;Attenuated;Automobile Driving;Biology;Bladder Neoplasm;CASP1 gene;Cancer Model;Cancer Patient;Cells;Cessation of life;Chemoresistance;Clinical;DNA;Dinoprostone;Drug Targeting;Epithelium;Extravasation;FDA approved;Funding;Genetic;Goals;HMGB1 gene;Immune;Immune response;Immuno-Chemotherapy;Immunosuppression;Inflammasome;Interleukin-1 beta;Intervention Studies;Knock-out;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Molecular;Mus;Myelogenous;Myeloid-derived suppressor cells;Nature;PTGS2 gene;Pathway interactions;Patients;Peptide Hydrolases;Pharmaceutical Preparations;Population;Process;Proliferating;Publishing;Regulation;Reporting;Research;Research Project Grants;Residual Neoplasm;Rest;Signal Pathway;Signal Transduction;T-Lymphocyte;TLR4 gene;Testing;Transcription Repressor;Treatment Efficacy;United States;Up-Regulation;WFDC2 gene;antagonist;anti-tumor immune response;cancer cell;cancer prevention;cancer stem cell;cancer survival;cancer therapy;cancer type;cell injury;chemotherapy;clinical translation;cytotoxic;druggable target;ds-DNA;extracellular;improved;in vivo;inhibitor;innovation;insight;muscle invasive bladder cancer;neoplastic cell;novel strategies;patient response;pharmacologic;prevent;programs;protein complex;receptor;response;sensor;stem cells;success;synergism;therapeutic target;therapeutically effective;treatment response;tumor;tumor microenvironment;tumor xenograft;tumor-immune system interactions;wound;wound response Targeting tumor repopulation and the immune microenvironment to overcome chemoresistance NARRATIVEPoor response to chemotherapy poses a major obstacle for muscle-invasive bladder cancer patients sincechemotherapy only generates a dismal 5% improvement in overall survival. The success of chemotherapynot only results from its direct cytotoxic effects on tumor cells but also depends on 1) a wound response ofcancer stem cells to repopulate tumors and 2) an effective anti-tumoral immune response. Our proposal willinvestigate the above two understudied phenomena with the long-term goal to exploit these processes fortherapeutic targeting. NCI 10683096 8/4/23 0:00 PAR-19-183 5R01CA255609-04 5 R01 CA 255609 4 "MERCER, NATALIA" 8/1/21 0:00 7/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 8781273 "CHAN, KEITH SYSON " Not Applicable 9 Unavailable 185641052 XJUCJAYJWYV1 185641052 XJUCJAYJWYV1 US 29.707454 -95.399168 10005742 METHODIST HOSPITAL RESEARCH INSTITUTE HOUSTON TX Other Domestic Non-Profits 77030 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 418910 NCI 259387 159523 PROJECT SUMMARYThis application is in response to PAR-19-183: Biology of Bladder Cancer. Muscle invasive bladder cancer(MIBC) claims approximately 18000 deaths annually in the United States. Funding and research devoted tothis cancer-type are significantly under-proportioned. An unmet clinical need for MIBC treatment lies in thepoor patient response towards chemotherapy with treatments providing only a dismal 5% improvement inoverall survival. The long-term goal of this application is to address this urgent need for adjuvant therapiesto improve chemotherapeutic response. The success of chemotherapy is historically thought to solely dependon its direct cytotoxic effects on tumor cells. However there is growing evidence as shown by our ownresearch and others that chemotherapeutic efficacy is also dependent on 1) successful prevention of cancerstem cells in repopulating residual tumors and 2) an effective anti-tumoral immune response. These twophenomena are often investigated separately but their possible synergy has been overlooked. Our researchproject is conceptually innovative to examine a common upstream pathway that regulates both tumorrepopulation and immune response. We hypothesize that the inhibition of this common pathway will providean effective therapeutic target for clinical translation. Our specific aims include: Aim 1) Decipher this pathwayby investigating the non-canonical downstream mechanism leading to the extracellular release of pleiotropicfactors. This is significant since these extracellular factors can modulate both tumor repopulation andimmune response. Aim 2) Evaluate how these extracellular factors and their cognate receptors drive therepopulation of quiescent cancer stem cells. Aim 3) Investigate how inhibition of this upstream pathway cancollectively abrogate tumor repopulation and immunosuppression and thus enhance chemotherapeuticresponse. Success of this proposal will pose drug targets capable of augmenting patient response tochemotherapy. Moreover these findings will provide insights to how these drugs can reestablish animmunostimulatory tumor microenvironment in MIBCs. In summary the studies outlined in this proposal aresignificant to address an unmet need i.e. to improve a dismal response of MIBC patients to standardchemotherapy. The conceptual advance from this study will likely extend beyond MIBC to benefit patientsfrom other epithelial malignancies. 418910 +No NIH Category available 19 year old;Address;Adolescence;Adolescent;Adult;Affect;Age;Age Years;Area;Attitude;Behavior;Cancer Etiology;Centers for Disease Control and Prevention (U.S.);Childhood;Community Pharmacy;Cost of Illness;Disease;Dose;Female;Financial Hardship;Future;Gardasil;Goals;Healthy People 2020;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Immunity;Immunization;Immunization Programs;Individual;Individual Differences;Intention;Intervention;Knowledge;Learning;Literature;Malignant neoplasm of penis;Mediating;Methods;Minority;Modeling;Not Hispanic or Latino;Online Systems;Persons;Pilot Projects;Population;Positioning Attribute;Predisposition;Prevention;Prevention approach;Public Health;Randomized;Reader;Recommendation;Research;Safety;Schools;Science;Self Efficacy;Specific qualifier value;Surveys;Survivors;System;Teenagers;Testing;Texas;Theoretical model;Treatment Efficacy;United States;Vaccinated;Vaccination;Woman;Writing;aged;burden of illness;cancer invasiveness;cancer prevention;college;design;evidence base;follow-up;health care delivery;implementation intervention;improved;infection rate;innovation;insight;male;men;novel;prevent;primary outcome;public health relevance;social group;social norm;stakeholder perspectives;statistics;success;theories;university student;unvaccinated;vaccination outcome;vaccine acceptance;vaccine access;web-based intervention;young adult;young man;young woman Promoting HPV Vaccination among Young Adults in Texas Project Narrative/Public Health Relevance Statement HPV infection rates are unacceptably high among both females (58%) and males (38%) aged 20-24 inthe US and there is an urgent need to reduce HPV infection by providing catch-up HPV vaccination to youngadults aged 18-26 years. We expect the study to identify effective components of a multi-level intervention toimprove HPV vaccination uptake and provide important insights into HPV vaccination uptake among youngadults. The study will have significant impacts on science and practice by inspiring future preventionapproaches that include multiple levels of influence to improve HPV vaccinations and by setting a new path toprovide evidence-based strategies tailored for young adults aged 18-26 years to promote catch-up HPVvaccination and prevent HPV related cancer. NCI 10683076 8/15/23 0:00 PAR-18-559 5R01CA248216-03 5 R01 CA 248216 3 "KOBRIN, SARAH" 8/1/21 0:00 7/31/26 0:00 Community-Level Health Promotion Study Section[CLHP] 8714872 "LU, QIAN " Not Applicable 9 MISCELLANEOUS 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 658053 NCI 406206 251847 Project summary Human papillomavirus (HPV) vaccine is important because it protects against cancers caused by HPVinfection. Nearly 79 million people are currently infected in the United States and about 14 million peoplebecome infected with HPV each year. HPV infection can cause cancers in both women and men and thefinancial burdens of these HPV-related diseases cost more than $8 billion per year in the US. The mostrecently approved HPV vaccination can prevent up to 74% of HPV-associated invasive cancers. Thus HPVvaccination is one of the most profound opportunities in cancer prevention today. The Centers for DiseaseControl and Prevention (CDC) recommends HPV vaccines through age 26. Among adults1826 years HPVvaccination completion is unacceptably low whereas HPV infection rates are unacceptably high. There is alsoa lack of interventions to improve HPV vaccination rates among young adults who were not vaccinated duringchildhood. In the area of HPV vaccination uptake males have disproportionately low rates and minorities havelower rates of completing the vaccinations compared to non-Hispanic whites. This study aims to fill in theimportant gaps by using a 2 by 3 factorial design to test the independent and combined effects of a multilevelintervention: school-based HPV vaccine administration (no access vs. access) at the system level and web-based narratives (no access vs. video vs. written) at the individual level. This intervention is developed based on pilot studies and socio-ecological models that recognize theimpact multiple levels of influence have on behaviors. The 2 by 3 factorial design results in six groups: )standard CDC information about HPV vaccination (control); 2) video narratives about HPV vaccination; 3)written narratives about HPV vaccination; 4) access to HPV vaccine at school combined with standard CDCinformation 5) access to HPV vaccine at school combined with video narratives or 6) access to HPV vaccineat school combined with written narratives . This design allows us to investigate the independent and combinedeffects of tailored narratives and school-based vaccine access on HPV vaccination. College students aged 18-26 who are not previously vaccinated against HPV will be randomly assigned to one of the six groups. Primaryoutcomes are HPV vaccine initiation and completion at 3- and 9-month follow-ups respectively. This study hasimplications for creating a new paradigm in HPV vaccination by inspiring future new research directions thatinclude multiple levels of influence to improve HPV vaccinations. This study will make a significant positiveimpact on public health as it is using evidence-based strategies tailored for young adults aged 18-26 years topromote catch up HPV vaccination. If successful the web-based intervention can be easily disseminatedbecause it is brief and scalable. School-based HPV vaccinations can be implemented on college campuses inthe future to improve healthcare delivery. Success and lessons learned in this study will inform futurestrategies to develop tailored narrative messages for different social groups. 658053 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Prevention Biological;Clinical;Clinical Chemoprevention;Clinical Research;Clinical Trials;Conduct Clinical Trials;Contractor;Data;Development;Division of Cancer Prevention;Drug Industry;Funding;Guidelines;Individual;Infrastructure;Maintenance;Malignant Neoplasms;Molecular Target;Monitor;National Cancer Institute;Outcome;Performance;Phase;Prevention;Preventive;Program Development;Safety;Site;Visit;cancer prevention;clinically relevant;data management;early phase clinical trial;interest;laboratory experiment;meetings;prevention clinical trial;programs CANCER PREVENTION AGENT DEVELOPMENT PROGRAM: EARLY PHASE CLINICAL RESEARCH n/a NCI 10683047 261201200033I-P00003-759101900129-1 N01 9/23/21 0:00 9/22/23 0:00 16187660 "BAILEY, HOWARD " Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N R and D Contracts 2022 107482 NCI The National Cancer Institute (NCI) Division of Cancer Prevention (DCP) Phase 0/I/II Cancer Prevention Clinical Trials Program supports early clinical trials to rapidly evaluate the clinical activity and biologic effects of cancer preventive agents of interest to DCP. The agents to be studied shall include agents developed by the pharmaceutical industry and provided to DCP for collaborative development commercially available agents and agents developed by DCP. The objectives of this Task Order are to provide the core infrastructure to support the conduct of the clinical trials.The Contractor shall conduct early clinical trials (Phase 0 I and II) of DCP-sponsored agents evaluate biologic effects of these agents on their molecular targets evaluate other relevant biologic effects and determine clinically relevant outcomes/correlates. This Task Order calls for the maintenance of the administrative core infrastructure to support the clinical and laboratory activities. These activities include but are not limited to: a. Maintaining the infrastructure to conduct and complete Early Phase Chemoprevention Clinical Trials. b) Revising the Data and Safety Monitoring Plan and Multi-Institutional Monitoring Plan plans as required for DCP approval following guidelines established in the DCP approved plans in order to support the conduct of NCI clinical trials. See http://prevention.cancer.gov/clinical trials/management/consortia. c) Serving as the liaison between DCP NCI and sub-contractors performing individual clinical trials. d) Monitoring the performance of individual studies both remotely and via on-site monitoring visits. e) Providing data management to support trial conduct. f) Participating in annual meetings i.e. Scientific and I-SCORE Individual clinical trials shall be funded under separate Task Orders. 107482 +Biotechnology; Cancer; Genetics; Hematology; Lymphatic Research; Lymphoma; Rare Diseases Alleles;Alternative Splicing;Antibodies;B-Cell Activation;B-Cell Development;B-Cell Neoplasm;B-Cell NonHodgkins Lymphoma;B-Lymphocyte Subsets;B-Lymphocytes;Blood;C-terminal;CRISPR/Cas technology;Catalytic Domain;Cell Cycle;Cell Maturation;Cell physiology;Cells;Complex;Cysteine;DNA Damage;Data;Defect;Development;Disease;Disease Progression;Evolution;Frameshift Mutation;Future;Genes;Genetic;Genetic Transcription;Goals;Lead;Length;Lymphoid;Lymphoma;Lymphoma cell;Lymphomagenesis;Malignant Neoplasms;Mantle Cell Lymphoma;Mantle Zone;Messenger RNA;Modeling;Molecular;Mus;Mutant Strains Mice;Mutate;Mutation;Non-Hodgkin's Lymphoma;Nonsense Codon;Pathogenesis;Pathway interactions;Patients;Phenotype;Plasma Cells;Population;Protein Splicing;Proteins;Proteomics;Publishing;RNA Splicing;Role;Sampling;Signal Transduction;Spleen;Spliceosomes;Structure of germinal center of lymph node;Survival Rate;System;Technology;Testing;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Ubiquitin;Up-Regulation;base;cohort;conditional mutant;drug discovery;effective therapy;functional disability;insight;knock-down;lymph nodes;migration;mouse model;multicatalytic endopeptidase complex;mutant;new therapeutic target;next generation sequencing;novel;overexpression;protein degradation;protein expression;scaffold;therapeutic target;tool;tumor;ubiquitin-protein ligase Dissecting the Role Ubiquitin E3 Ligase UBR5 in Lymphomagenesis NarrativeThe ubiquitin E3 ligase UBR5 is one of the most commonly mutated genes (~18%) in mantle cell lymphoma(MCL) with the majority of mutations identified in UBR5 were frame shift mutations found within the HECTdomain. Here we will study the molecular function of ubiquitin E3 ligase UBR5 mutations in lymphomagensis.Deciphering the role of the UBR5 and pathways dysregulated by mutations in mantle cell lymphoma willprovide clues to lymphoma transformation with the goal of identifying targets for future therapeutics. NCI 10682906 9/2/22 0:00 PA-21-268 7R37CA262635-02 7 R37 CA 262635 2 "JHAPPAN, CHAMELLI" 8/1/21 0:00 7/31/26 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10974463 "BUCKLEY, SHANNON " Not Applicable 1 INTERNAL MEDICINE/MEDICINE 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 396 Non-SBIR/STTR 2022 413664 NCI 276075 137589 ABSTRACTMantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkins lymphoma. Unfortunately limitedtherapies for MCL are currently available suggesting a need to further unravel molecular mechanismsregulating transformation and progression of the disease. The majority of MCL patients have a t(11;14)translocation leading to overexpression of CyclinD1 resulting in extensive proliferation and block indifferentiation originating in the mantle zone of the lymph node however additional mutations are necessary fortransformation. Next generation sequencing has identified a number of novel mutations in MCL patientsincluding the ubiquitin E3 ligase UBR5. E3 ubiquitin ligases serve as the substrate-recognizing component forprotein degradation by the ubiquitin proteasome system. In a cohort of 196 MCL patients UBR5 was the 3rdmost frequently mutated gene and ~60% of the mutations were found within the HECT domain of UBR5 whichcan accept and transfer ubiquitin molecules to the substrate. In order to understand the role of UBR5 HECTdomain in B-lymphoid development we generated a conditional mouse using novel CRISPR/Cas 9 technology.Loss of the HECT domain leads to a block in pre-germinal center B cells in the spleen with a reduction of bothB1 and marginal B cell subsets. In addition follicular B cells in the spleen are phenotypically abnormal and failto terminally differentiate to anti-body secreting plasma cells. Proteomic studies reveal up-regulation of proteinsassociated with mRNA splicing via the spliceosome in B cells lacking the HECT domain of UBR5. Thesestudies suggest that 1) cooperation of UBR5 mutations along with expression of cyclinD1 may led to diseaseprogression of mantle cell lymphoma (Aim 1) 2) understanding molecular mechanism of UBR5 mutationscould provide potential therapeutic targets in MCL (Aim 2) and 3) aberrant expression of U5 spliceosomeproteins block B cell maturation and promote lymphomagenesis (Aim 3). In this application we propose studiesto understand the role of UBR5 and its interacting proteins in B-cell lymphomagenesis and define molecularpathways regulated by UBR5 in B-cells. Our goal of the proposed studies is to provide insights to mantle celllymphoma transformation progression and potential future therapeutics targets. 413664 +Behavioral and Social Science; Bioengineering; Biotechnology; Cancer; Cancer Genomics; Genetics; Health Disparities; Human Genome; Networking and Information Technology R&D (NITRD); Sexual and Gender Minorities (SGM/LGBT*) Algorithms;Area;Bioinformatics;Bioinformatics Shared Resource;Budgets;Cancer Center Support Grant;Clinical Data;Complex;Computational Biology;DNA;Data;Data Collection;Data Set;Data Storage and Retrieval;Evaluation;Faculty;Fostering;Funding;Future;Gender Identity;Genomics Shared Resource;Goals;Grant;Immunologic Monitoring;Immunooncology;Informatics;Institution;Leadership;Left;Literature;Malignant Neoplasms;Metagenomics;Oncology;Participant;Patients;Pediatric Hospitals;Population Sciences;Process;Proteomics;Protocols documentation;Publications;Records;Research;Research Personnel;Resource Sharing;Services;Sex Orientation;Source;Technology;The Cancer Genome Atlas;Third Generation Sequencing;Untranslated RNA;Visual;Work;anticancer research;arm;biobank;biomedical informatics;cancer care;data analysis pipeline;data de-identification;data management;data visualization;data warehouse;drug sensitivity;falls;genomic data;improved;instrumentation;member;metabolomics;next generation sequencing;novel;programs;single cell sequencing;tool Shared Resource 01: Biomedical Informatics (BISR) n/a NCI 10682702 8/25/22 0:00 PA-20-272 3P30CA016058-46S3 3 P30 CA 16058 46 S3 "SHAFIK, HASNAA" 9/1/22 0:00 11/30/25 0:00 9978 7811753 "COOMBES, KEVIN ROBERT" Not Applicable 3 Unavailable 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH Domestic Higher Education 432101016 UNITED STATES N 12/1/21 0:00 11/30/22 0:00 Research Centers 2022 100000 63492 36508 PROJECT SUMMARY BIOINFORMATICS SHARED RESOURCE (BISR)The BISR is an essential shared resource that supports a wide range of studies with bioinformatics andcomputational biology needs ranging from next generation sequencing (NGS) to data management in populationscience studies. Housed within the Department of BMI the BISR's goal is to leverage a variety of informaticsservices ranging from analysis of omics datasets to patient/participant-centered data instrumentation accessand management tools and processes. The Specific Aims of the BSR are to: 1) Provide state of the artbioinformatics and computational biology services; and 2) Provide OSUCCC investigators with servicesexpertise and access to technology platforms in support of heterogeneous and multi-dimensional biomedicaldata management requirements. Over the current grant cycle Drs. Kevin Coombes (TT) and Lang Li (CB)assumed leadership of BISR replacing Drs. Philip Payne and Jeffrey Parvin. During the current funding cycle aMemorandum of Understanding (MOU) was established for the Department of Biomedical Informatics (BMI) andthe OSUCCC to support 5 faculty at 10% per year for 3 years within BISR as they transition to grant funding ona rolling basis to provide non-chargeable cancer focused bioinformatics work for OSUCCC membership and/orcancer focused researchers. Additional major changes for BISR include supporting the enhancement of theGenomics Shared Resource (GSR) to incorporate newly developed shared services with Nationwide Children'sHospital (NCH); and added capabilities to support studies involving data from single-cell sequencing long-read(third generation) sequencing metabolomics and metagenomics. BISR has added five new faculty to supportthe areas of (1) computational optimization for drug sensitivity prediction (Cheng) (2) proteomics and functionalannotation of DNA non-coding regions (Zhang) (3) metabolomics and metagenomics (Mathe) (4) single-cellsequencing (Ma) and (5) long-read sequencing (Au). BISR supported Biospecimen Services Shared Resource(BSSR) projects (Total Cancer Care [TCC] and the Oncology Research Information Exchange Network [ORIEN])by establishing a data warehouse of patient records with de-identified data. During the current funding cycle theBISR supported 115 publications (25 > 10 impact factor) 134 users and 32 NCI grants including 5 P01s 2 P50s13 R01s 3 R21s 1 R50 2 U01s 1 U10 1 UG1 involving members from all five programs. Over the next grantcycle BISR will enhance services for integromics e.g. the integration of disparate source of both omics andclinical data. BISR will be a critical part of the Immune Monitoring and Discovery Platform (IMDP) an overarchingapproach for fostering interactions among shared resources for complex immuno-oncology projects. The annualbudget of the BISR is $1122279 yet the CCSG request is $106905. As such the BISR leverages extensiveinstitutional support and seeks only 9.5% support from CCSG funds. +Cancer; Orphan Drug; Ovarian Cancer; Rare Diseases; Women's Health 3-Dimensional;ATP phosphohydrolase;Advisory Committees;Antineoplastic Agents;Apoptosis;Arginine;Biological Assay;Cancer Patient;Cancer cell line;Cell Culture Techniques;Cells;Cessation of life;Clinical;Data;Development;Dimensions;Disease;Down-Regulation;EZH2 gene;Epigenetic Process;Epithelial ovarian cancer;Foundations;Gene Expression;Genes;Goals;Growth;Heat Shock 70kD Protein Binding Protein;Heat-Shock Proteins 70;In Vitro;Knock-out;Knowledge;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Mentors;Methylation;Methyltransferase;Modification;Molecular;Mutation;Oncogenes;Ovarian Serous Adenocarcinoma;Pathway interactions;Patients;Pennsylvania;Pre-Clinical Model;Protein-Arginine N-Methyltransferase;Proteins;Research;Research Personnel;Resources;Role;Serous;Site;Site-Directed Mutagenesis;Specificity;Testing;The Wistar Institute;Training;Training Support;Tumor Suppression;United States;Universities;base;brca gene;cancer cell;cancer type;career;career development;clinically relevant;coactivator-associated arginine methyltransferase 1;experimental study;genetic makeup;genome-wide analysis;heat-shock proteins 40;in vivo;in vivo Model;inhibitor;loss of function;migration;mouse model;mutant;novel strategies;novel therapeutic intervention;overexpression;patient derived xenograft model;pre-doctoral;protein folding;skills;small molecule inhibitor;small molecule libraries;targeted treatment;tumor;two-dimensional Targeting HSP70 in CARM1-expressing epithelial ovarian cancer PROJECT NARRATIVEEpithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer-related deaths in the United States.EOC is a genetically heterogeneous disease and therefore it is imperative to develop novel therapeuticstrategies based on patients genetic makeup such as overexpression of an oncogene CARM1. This proposalwill lay a critical foundation to establish the use HSP70 inhibitors in CARM1-expressing epithelial ovarian cancerand if successful it will have an immediate impact on ovarian cancer patients. NCI 10682656 8/29/22 0:00 PA-19-130 4R00CA241395-03 4 R00 CA 241395 3 "LUO, RUIBAI" 4/1/22 0:00 3/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 12558089 "KARAKASHEV, SERGEY " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 57123192 QD4MGHFDJKU1 57123192 QD4MGHFDJKU1 US 39.980272 -75.157051 8240301 TEMPLE UNIV OF THE COMMONWEALTH PHILADELPHIA PA SCHOOLS OF MEDICINE 191226003 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 398 Non-SBIR/STTR 2022 249000 NCI 157098 91902 PROJECT SUMMARYThe goals of this NCI Pathway to Independence Career Development proposal are to request support fortraining to develop expertise in developing novel therapeutic strategies for ovarian cancer while investigating therole of coactivator-associated arginine methyltransferase 1 (CARM1) in promoting sensitivity to HSP70 inhibition.K99/R00 support during this part of my career will be integral to my successful development as an independentcancer researcher. The training plan outlined in this proposal will take advantage of the extensive resources atThe Wistar Institute University of Pennsylvania as well as Temple University. My training will also be guided bythe advisory committee who have successfully mentored multiple predoctoral postdoctoral and clinical fellowsin academic careers. The scientific portion of this proposal focuses on experimentally determining the molecular mechanismunderlying the sensitivity of CARM1-expresing ovarian cancer cells to HSP70 inhibition. The proposed studiesare based on my previous findings that CARM1 is often overexpressed and functions as an oncogene in ovariancancer patients. High-grade serous ovarian cancer (HGSOC) has the highest rate of CARM1 amplification andoverexpression (~20% combined) among all cancer types. Moreover high CARM1 levels are associated withpoor survival in EOC patients. Thus it is imperative to develop novel approaches to target CARM1-expressingEOC. My preliminary data suggest CARM1-expressing cells are selectively sensitive to HSP70 inhibition. HSP70is a crucial part of the protein folding machinery and its levels are upregulated in multiple types of cancer.Interestingly HSP70 is a substrate for CARM1s enzymatic activity. However the effect of HSP70 modificationby CARM1 is not fully understood. Thus the major goal of this proposal is to determine whether CARM1-expressing EOC can be treated and ultimately eradicated by novel therapeutic strategies based on HSP70inhibition. Therefore I will explore the following scientific aims: 1) To elucidate the mechanistic basis underlyingthe selectivity against CARM1-high cells by HSP70 inhibition by using gain and loss of function assays inCARM1-high and CARM1-low expressing EOC cells. 2) To develop novel therapeutic strategies for CARM1-expressing EOCs based on HSP70 inhibition. The completion of the scientific aims in this proposal will helpdevelop my research skills and knowledge in the field of ovarian cancer and will lay a critical foundation toestablish the use HSP70 inhibitors in CARM1-high EOCs as a single agent or in combination with other promisingsmall-molecule inhibitors such as EZH2 inhibitors. 249000 +Cancer; Digestive Diseases; Pancreatic Cancer; Rare Diseases; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human Address;Affect;Agar;Anchorage-Independent Growth;Automobile Driving;Biological Assay;Blood Circulation;Breast;Breast cancer metastasis;Cancer Etiology;Cell Line;Cells;Cessation of life;Characteristics;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Disease Progression;Distal;Doxycycline;Future;Gene Expression Profile;Genes;Genetically Engineered Mouse;Glutathione S-Transferase;Growth;Human;Hydrophobicity;In Vitro;Incidence;Lesion;Liver;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metastatic Adenocarcinoma;Metastatic to;Modality;Modeling;Molecular;Neoplasm Metastasis;Outcome;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Patient-Focused Outcomes;Patients;Pattern;Play;Population;Primary Neoplasm;Proteins;Reduced Glutathione;Research;Role;Solid Neoplasm;Specimen;Stains;Survival Rate;System;TP53 gene;Testing;Therapeutic;Tissue-Specific Gene Expression;Tissues;Validation;Work;base;cancer cell;cell growth;differential expression;efficacy testing;experimental study;human tissue;in vivo;inhibitor;insight;knock-down;lung metastatic;malignant breast neoplasm;mortality;mouse model;non-genetic;novel;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;pre-clinical;self-renewal;small hairpin RNA;small molecule inhibitor;therapeutic target;transcriptome sequencing;tumor;tumor growth Role of Gstt1 in metastatic maintenance and self-renewal in PDA PROJECT NARRATIVEThe primary cause of cancer-related mortality is distal metastasis particularly in pancreatic cancer patientswhere the high incidence of extra-pancreatic metastasis upon diagnosis results in poor patient outcomes. Whilethe genetic mutations that cause pancreatic cancer have been extensively studied there has been little workdone to explain the mechanisms behind metastatic tumor growth and as a consequence limited treatmentmodalities to treat this disease. Here we have identified Gstt1 as a regulator of metastasis and this proposalwill provide insight into Gstt1-driven vulnerabilities to treat pancreatic cancer metastasis. NCI 10682655 9/13/22 0:00 PA-19-130 4R00CA252600-03 4 R00 CA 252600 3 "AULT, GRACE S" 9/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11756641 "FERRER, CHRISTINA " Not Applicable 7 PHARMACOLOGY 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 398 Non-SBIR/STTR 2022 249000 NCI 161165 87835 PROJECT SUMMARYOnly 0.01% of cancer cells enter circulation survive & produce metastasis however metastatic diseaseaccounts for 90% of cancer-related deaths. In pancreatic ductal adenocarcinoma (PDA) the majority of patientspresent with extra-pancreatic invasion and metastatic disease for which the there is a dismal five-year survivalrate and no specific therapeutic strategies directed at the treatment of metastatic disease. Notably much of theresearch into the mechanisms of metastasis has been focused on identifying early drivers within primary tumorshowever the identification of central drivers of metastatic outgrowth within established lesions largely remainunexplored. Recently we have demonstrated that SIRT6 inactivation dramatically accelerates PDAdevelopment resulting in highly aggressive metastatic disease in the Kras-p53 GEM model. Employing thishighly aggressive PDA metastasis model in addition to an established breast cancer metastasis model thisstudy aims to identify potential vulnerabilities of metastatic lesions that could be exploited to treat patients withadvanced metastatic disease. Performing unbiased RNA-Seq on matched primary and metastatic tissuesfollowed by a newly developed 96-well soft agar screen we identified factors that are uniquely required foranchorage-independent growth of established metastatic cells. Utilizing this functional screen and validation wehave identified Gstt1 (glutathione S-transferase theta 1) as a top candidate driver of metastatic outgrowth inmultiple mouse models of metastasis. Preliminary data demonstrates that Gstt1 is differentially expressed inmetastatic cell lines compared to matched primary-derived cell lines and inhibition of Gstt1 significantly reducedmetastatic potential of metastases-derived cells without affecting primary tumor growth suggesting an importantrole for Gstt1 in the outgrowth of established metastatic lesions. Additionally within metastatic lesions Gstt1shows a heterogenous expression pattern where Gstt1high cells represent an aggressive non-proliferative sub-population. Additionally we have demonstrated that Gstt1 is required for the formation of tumor spheres in breastand PDA metastatic-derived cell lines in vitro suggesting a role for Gstt1 as a driver of self-renewal in metastaticcells. In this proposal we seek to identify characteristics unique to Gstt1high PDA-derived metastatic lesions. Theproposed studies will provide important preclinical demonstration of whether Gstt1 and its downstream targetsare required for sustained growth of metastatic tumors thus identifying a possible therapeutic window for thissubset of metastatic PDA. 249000 +Bioengineering; Biotechnology; Cancer; Nanotechnology; Women's Health Advisory Committees;Affinity;Agar;Bar Codes;Binding;Biodistribution;Biological;Biology;Cancer Biology;Cancer cell line;Cell Communication;Cell Line;Cells;Characteristics;Chemical Engineering;Chemicals;Chemistry;Clinic;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Complex;Cytolysis;DNA;Detection;Development;Disease;Disease Resistance;Dose;Drug Delivery Systems;Drug Targeting;Environment;Evaluation;Flow Cytometry;Fluorescence;Formulation;Genes;Genetic;Genomics;Goals;Heterogeneity;Immune;Immunocompetent;Immunocompromised Host;In Vitro;Individual;Institutes;Institution;Knock-out;Label;Magic;Malignant Neoplasms;Malignant neoplasm of ovary;Mass Fragmentography;Mass Spectrum Analysis;Mediating;Mentorship;Mesenchymal;Modality;Modeling;Mus;Organ;Patients;Play;Polymers;Population;Property;Recurrence;Research Personnel;Research Proposals;Sampling;Site;Structure-Activity Relationship;Surface;Survival Rate;System;Techniques;Technology;Therapeutic Uses;Time;Tissues;Training;Translating;Translations;Tumor Biology;Validation;Work;anticancer research;aryl halide;base;cancer cell;carboxylate;career;chemotherapy;delivery vehicle;detection limit;genetic signature;high throughput analysis;in vivo;in vivo evaluation;materials science;multiple omics;nanocarrier;nanomedicine;nanoparticle;nanoparticle delivery;neoplastic cell;novel therapeutics;particle;pre-clinical;protein expression;screening;self assembly;success;targeted treatment;therapy resistant;tool;trafficking;transcriptome sequencing;tumor;tumor heterogeneity;uptake Understanding drug delivery through an integrated barcoding approach Project NarrativeNanoparticle translation to the clinic is lacking in large part due to limited accumulation in target disease sites aparticular problem for heterogeneous cancers like ovarian cancer which can be attributed to the complexity ofboth the biological environment and the nanoparticle constructs. There is an urgent need to develop tools todeconvolute the individual factors that contribute to nanoparticle accumulation and unlock the unrealizedpotential of cancer nanomedicine. Therefore this proposed study seeks to provide a holistic evaluation ofnanoparticle structure-function relationships by utilizing a new chemical barcoding strategy to identify materialsproperties associated with favorable biodistributions and tumor targeting enable the elucidation of geneticcomponents correlated with nanoparticle interactions and allow us to leverage the identified genetic signaturesfor more effective targeted drug delivery. NCI 10682653 8/29/22 0:00 PA-20-188 4R00CA255844-03 4 R00 CA 255844 3 "GRODZINSKI, PIOTR" 8/1/22 0:00 7/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11826207 "BOEHNKE, NATALIE " Not Applicable 5 ENGINEERING (ALL TYPES) 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN BIOMED ENGR/COL ENGR/ENGR STA 554552070 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 394 Non-SBIR/STTR 2022 249000 NCI 166532 82468 Project SummaryDespite being hailed as the magic bullet that would selectively target and cure cancer only a handful ofnanoparticles have been successfully translated to the clinic and their full potential remains yet to be realized.In fact nanoparticle accumulation in tumors continues to be dismally low with less than 1% of the injected dosereaching its target. This is largely attributed to the complexity and heterogeneity of both the biologicalenvironment and nanoparticle constructs making it impossible to deconvolute individual factors contributing tonanoparticle targeting and accumulation in tumors. Therefore there is a critical need to better understand anddefine the attributes that define successful nanocarriers. This is particularly urgent in lethal cancers that stand tobenefit tremendously from new and targeted therapies like ovarian cancer which has a 25% 5-year survival rateand 70% recurrence rate following chemotherapy often leading to treatment resistant disease. To developeffective drug delivery strategies it is critically important to understand the characteristics of tumorsnanoparticles and their interactions such as by identifying the genetic features associated with high nanoparticleuptake and accumulation. To accomplish this the work proposed herein features a chemical barcoding approachto enable pooled high throughput analysis of nanoparticles in a pre-clinical context enabling the identificationand correlation of genetic features responsible for successful nanoparticle targeting through a multi-omicsapproach. Successful development of this barcoding platform will entail 1) rapid integrated in vitro screening ofpooled NP formulations 2) in vivo single system evaluation of nanoparticle accumulation at the tissue and cellularlevel and 3) use of pooled barcoded nanoparticles to correlate particle trafficking in patient derived models ofovarian cancer. This strategy will provide a holistic evaluation of nanoparticle structure-function relationshipswith tumor accumulation and enable the identification of genetic components implicated with meaningfulnanoparticle interactions allowing us to leverage these signatures to develop more effective targetednanoparticles to specific tumor cell populations. The proposed work will take place at MITs Koch Institute forIntegrative Cancer Research a premier institution for cancer research with state-of-the-art facilities under thementorship of Prof. Paula Hammond a renowned chemical engineer and polymer chemist with expertise in theself-assembly of materials and drug delivery. An advisory team has carefully been assembled consisting ofProfs. Stuart Schreiber and Angela Koehler for chemical biology and multi-omics analysis guidance Prof. JoanBrugge for her cancer biology expertise and Prof. Nathalie Agar for input on mass spectrometry-based analysis.Combined this research proposal and mentorship team will lay the scientific groundwork and provide thenecessary training for the applicant to reach her ultimate goal of successfully starting her independent academiccareer at the interface of chemistry biology and materials science. 249000 +No NIH Category available Academic Medical Centers;Address;Adherence;Adoption;Adult;Advocacy;Alabama;Basic Science;Breast Cancer Detection;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Caregivers;Caring;Catchment Area;Cervical Cancer Screening;Characteristics;Childhood;Classification;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Colon Carcinoma;Communities;Community Health Education;Community Outreach;Comprehensive Cancer Center;Counseling;County;Coupled;Cutaneous Melanoma;Development;Dissemination and Implementation;Doctor of Philosophy;Early Diagnosis;Education;Evidence based practice;Genetic Counseling;Geography;Guidelines;Health;Health Knowledge Attitudes Practice;Health Policy;Health Services Accessibility;High Prevalence;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Improve Access;Incidence;Inherited;Kentucky;Leadership;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mission;Modeling;Molecular;NCI Center for Cancer Research;Obesity;Obesity associated cancer;Outcome;Patients;Personal Satisfaction;Policies;Population;Population Heterogeneity;Population Sciences;Prevention;Prevention Guidelines;Rectal Cancer;Research;Research Personnel;Research Priority;Rural;Screening for cancer;Site;System;Technology;Tennessee;Therapeutic;Tobacco Use Cessation;Translating;Underrepresented Populations;Work;bench to bedside;cancer care;cancer education;cancer health disparity;cancer prevention;colorectal cancer screening;community center;community engagement;design;disparity reduction;empowerment;ethnic disparity;ethnic diversity;evidence base;evidence based guidelines;fundamental research;genetic testing;geographic disparity;health care settings;health disparity;improved;literate;lung cancer screening;malignant oropharynx neoplasm;minority patient;mortality;obesity prevention;obesity treatment;outreach;patient navigation;programs;racial disparity;racial diversity;recruit;research study;rural area;rural patients;screening;screening guidelines;smoking cessation;survivorship;tobacco screening;tumor;urban area Community Outreach and Engagement CCSG COMPONENT 005 COMMUNITY OUTREACH AND ENGAGEMENTPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Community Outreach andEngagement. NCI 10682648 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9934 1891854 "FRIEDMAN, DEBRA L" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 255402 147631 107771 CCSG COMPONENT 005 COMMUNITY OUTREACH AND ENGAGEMENTPROJECT SUMMARY/ABSTRACTVanderbilt-Ingram Cancer Center (VICC) is located in a region with some of the highest cancer incidence andmortality rates in the US. As the only NCI-designated Comprehensive Cancer Center serving both adult andpediatric populations in Tennessee (TN) VICC encompasses a geographically wide and demographicallydiverse catchment area of 123 counties across TN western Kentucky (KY) and northern Alabama (AL) fromwhich 90% of VICC cancer patients currently are drawn. Seventy of the 123 counties (57%) are classified asrural in which 25% of the catchment area population lives. VICC Community Outreach and Engagement (COE)under the leadership of Associate Director Pamela Hull PhD (CO) integrates with VICC Research Programsand administrative initiatives to reduce the cancer burden and disparities within the catchment area and beyond.In a bi-directional manner leveraging relationships with patients and community stakeholders COE obtains inputfrom the community on priorities for research cancer control and care and works with VICC research programsand community partners to bring those prioritized initiatives out to the community. The specific aims of COE areto: 1) Assess and prioritize cancer-related needs and opportunities in the catchment area; 2) Inform and facilitateprogrammatic research that is responsive to identified cancer-related needs and community-driven priorities;and 3) Promote the implementation and dissemination of evidence-based cancer prevention control and care.Community-driven priorities identified through COE include cancer prevention initiatives improved access tocare through technology holistic treatment and support implementation of evidence-based practice and policyadvancing discoveries and research advocacy. VICC conducts basic clinical and population science researchthat addresses catchment area needs and aligns with these community-driven priorities. COE staff collaboratewith partners to meet evolving community-identified needs through a variety of collaborative community outreachactivities. Working together with partners and stakeholders VICC community-informed research and cancercontrol activities synergistically contribute to empowering healthy and cancer literate communities in ourcatchment area and beyond. The impact of these efforts is already evident in improved practices at VanderbiltUniversity Medical Center (VUMC) and affiliated sites including newly available tobacco screening/counselingenhanced patient navigation expanded reach of lung cancer screening and improved adherence to breastcolorectal and cervical cancer screening guidelines HPV vaccination and inherited cancer screening. Movingforward focus will be placed on metrics of increased accruals to research studies; improvements in cancer-related knowledge attitudes and behavior; and expanded implementation of evidence-based guidelines andhealth policies. Together with community partners VICC positively impacts the catchment area by enabling asystems approach to cancer advancing fundamental research and translating discoveries from the bench to theclinic community and population in the catchment area nationally and globally. +No NIH Category available Address;Affect;Area;Attention;Biometry;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Data;Clinical Research;Clinical Trials;Committee Members;Committee Membership;Communities;Community Outreach;Complement;Discipline of obstetrics;Disease;Doctor of Philosophy;Eligibility Determination;Ensure;Environment;Evaluation;Experimental Designs;Extramural Activities;Eye;Faculty;Financial Support;Funding;Goals;Gynecologic Oncology;Gynecology;Hematology;Individual;Institution;Institutional Review Boards;Intervention;Intervention Trial;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medicine;Mentors;Methods;Minority Groups;Monitor;Monitoring Clinical Trials;NCI Center for Cancer Research;Nurses;Oncology;Participant;Patient Monitoring;Patients;Physicians;Procedures;Process;Protocols documentation;Rare Diseases;Recommendation;Reproducibility;Research;Research Design;Research Personnel;Review Committee;Role;Science;Services;Strategic Planning;Students;System;Tissues;Work;black women;cancer care;cancer subtypes;community engagement;demographics;design;experience;health disparity;malignant breast neoplasm;meetings;member;patient safety;professor;responsible research conduct;sound;translational potential;treatment trial;triple-negative invasive breast carcinoma Protocol Review and Monitoring System CCSG COMPONENT 004 PROTOCOL REVIEW AND MONITORING SYSTEMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Protocol Review and MonitoringSystem Core. NCI 10682647 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9933 10497769 "CRISPENS, MARTA ANN" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 238308 137750 100558 CCSG COMPONENT 004 PROTOCOL REVIEW AND MONITORING SYSTEMPROTOCOL SUMMARY/ABSTRACTThe Scientific Review Committee (SRC) ensures that all cancer-relevant interventional trials conducted underthe auspices of Vanderbilt-Ingram Cancer Center (VICC) are of the highest scientific quality follow responsibleconduct of research principles and have significant potential impact for patients. In addition there is anintentional focus to develop a portfolio of interventional trials that meet the needs of the catchment area andassure diversity of participants and inclusion across the lifespan. Protocols requiring full committee review areevaluated for appropriate scientific rationale clearly defined specific aims achievable study endpoints researchintegrity a plausible biostatistical plan feasibility and a well-justified ability to accrue eligible patients from theVICC catchment area. These criteria exist to ensure that the study design supports the completion of its scientificgoals. This focus on the scientific integrity of the trial clearly sets the SRC's role apart from the VanderbiltInstitutional Review Board (IRB) in that the SRC is focused on sound science with potential of translation tocancer care while the IRB is primarily concerned with patient safety. The SRC and IRB have two separatefunctions and yet both complement each other by ensuring the integrity of the study through a sound scientificapproach while also considering the protection of all participants. The IRB does not play a role in determiningthe extent of Cancer Center support that a protocol should receive. However the SRC is responsible forprioritizing each protocol and providing recommendations regarding Cancer Center support which includes CTOwork queue management and financial support for institutional trials or those not fully funded by an extramuralsponsor.In addition to ensuring a high level of scientific merit and appropriate prioritization of VICC interventional trialsthe SRC oversees the progress of all active interventional protocols by routinely monitoring the patient accrualand closing studies that do not demonstrate scientific progress and adequate accrual. Low accruing studiesinvolving rare diseases and studies that advance key areas of focus and align with the Cancer Center's strategicplans will be given special consideration. The SRC will also review any protocol changes that have a significantimpact on the design or scientific rationale for an ongoing interventional trial. The SRC also reviews trials toensure that they are consistent with VICC's commitment to addressing health disparities in clinical trialparticipation. The SRC provides special attention to trials targeting cancers that disproportionately affect minoritypopulations. +No NIH Category available Acceleration;Adult;Affect;Age;Basic Cancer Research;Biological Markers;Black Populations;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Caring;Catchment Area;Cell Therapy;Child;Childhood;Clinical;Clinical Cancer Center;Clinical Data;Clinical Investigator;Clinical Management;Clinical Practice Guideline;Clinical Protocols;Clinical Trials;Complex;Contracts;Data;Detection;Disease;Economically Deprived Population;Enrollment;Ensure;Faculty;Fostering;Gender;Goals;Good Clinical Practice;Immunotherapy;Infrastructure;Institution;International;Intervention Trial;Latino Population;Literature;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mediation;Minority;Minority Groups;Mission;Modality;Molecular Biology;Molecular Target;Monitor;Nursing Research;Patient Participation;Patients;Population;Population Sciences;Populations at Risk;Prevention;Process;Program Development;Protocols documentation;Publishing;Race;Recommendation;Reporting;Research;Research Personnel;Safety;Services;Specimen;Specimen Handling;Structure;Supportive care;System;Toxic effect;Training;Treatment Protocols;Underserved Population;United States National Institutes of Health;Woman;Work;bench to bedside;cancer prevention;cancer risk;cohort;data integrity;data management;end of life;improved;improved outcome;industry partner;investigator-initiated trial;operation;organizational structure;participant enrollment;patient safety;patient subsets;population health;process improvement;quality assurance;sample collection;sarcoma;socioeconomic disadvantage;sound;standard of care;symposium;targeted agent;tool;translational cancer research;translational scientist;trial design;triple-negative invasive breast carcinoma;young adult Clinical Protocol and Data Management CCSG COMPONENT 003 CLINICAL PROTOCOL AND DATA MANAGEMENTPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Clinical Protocol and DataManagement Core. NCI 10682646 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9932 14746587 "DAVIS, ELIZABETH J" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 791885 457737 334148 CCSG COMPONENT 003 CLINICAL PROTOCOL AND DATA MANAGEMENTPROJECT SUMMARY/ABSTRACTThe Vanderbilt-Ingram Cancer Center (VICC) Clinical and Protocol Data Management team (CPDM) knowninternally as the VICC Clinical Trials Office (CTO) provides investigators conducting translational and clinicalinvestigators with the infrastructure necessary to conduct scientifically meritorious research on a local andnational level. CPDM services are available to all Vanderbilt investigators conducting cancer-relevant trials. TheCTO is operationally organized by Disease Team (DT) and provides regulatory and data management servicesresearch nursing support as well as contract and budget negotiation quality assurance data and safetymonitoring and multi-center investigator-initiated trial (IIT) development programs. VICC places the highestpriority on the safety of patients participating in research trials and continually strives to foster and maintain thehighest level of oversight and compliance across the clinical and research enterprise. As a result of this long-standing commitment to research excellence every interventional trial conducted at VICC must include a planfor data and safety monitoring. The NCI-approved VICC Data and Safety Monitoring Plan (DSMP) was revisedand approved by the NCI in 2019. The plan outlines that while each PI is responsible for day to day oversight oftheir protocol the initial scientific review conducted by the VICC SRC includes the assignment of a more detailedprotocol-specific plan for DSMC oversight based on the DSMP. Per the plan the DSMC is independent of theSRC and has the right to modify the SRC recommendations within the parameters of the DSMP. Since the lastreporting period the CTO has made continuous process improvements and expansions within several servicelines to adapt to the increasing complexity of cancer trials while developing new workflows to capitalize onopportunities provided by the Epic transition. The results of these changes are anticipated to reduce trial openingtimes and improve ability of investigators to meet accrual goals moving forward. During the project period thetotal number of protocols managed by the CTO has increased by 27%. Among the trials conducted at VICC inCY18 118 of the 452 (26%) protocols open to accrual were were initiated or significantly influenced by VICCinvestigators even when sponsored by industry partners. Importantly VICC investigators have enrolled 492patients to National Group studies during the project period. VICC is committed to providing or supportingexcellent care and access to trials for the catchment area and ensuring the appropriate representation of womenminorities and children as well as offer the mix of trial targeting underserved populations in the catchment areaincluding Blacks and Latinos and socioeconomically disadvantaged populations. The CTO will continue torespond to and support the needs of its investigators by adapting its processes and workflows as the landscapeof research advances and remains committed to cancer prevention and improving outcomes for cancer patients. +No NIH Category available Antineoplastic Agents;Area;Behavior;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Categories;Clinical;Collaborations;Communities;Complement;Continuity of Patient Care;Coupled;Decision Making;Disparity;Doctor of Philosophy;Early Diagnosis;Equilibrium;Fostering;Funding;Future;Health;Health Services Accessibility;Health behavior;Healthcare;High Prevalence;Human Papilloma Virus Vaccine;Imaging Techniques;Improve Access;Incidence;Individual;Insurance;Intervention;Laboratories;Leadership;Malignant Neoplasms;Mentorship;Mission;NCI-Designated Cancer Center;Obesity;Outcome;Patient-Focused Outcomes;Peer Review;Policies;Population;Populations at Risk;Positioning Attribute;Prevention;Program Research Project Grants;Public Health;Publications;Research;Research Personnel;Risk;Schools;Science;Therapeutic Clinical Trial;Tobacco Use Cessation;Tobacco use;Toxic effect;Training;behavior test;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer therapy;care delivery;community center;comparative effectiveness;comparative treatment;cost;implementation science;improved;improved outcome;innovation;interest;lung cancer screening;member;mortality;obesity prevention;outreach;patient oriented;patient safety;population based;prevent;programs;screening;skills;smoking cessation;therapy development;treatment strategy;vaccine acceptance Cancer Health Outcomes and Control Research Program PROJECT 008 CANCER HEALTH OUTCOMES AND CONTROL RESEARCH PROGRAMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Cancer Health Outcomes and ControlResearch Program. NCI 10682643 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9929 1891854 "FRIEDMAN, DEBRA L" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 124453 71938 52515 PROJECT 008 CANCER HEALTH OUTCOMES AND CONTROL RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe overarching mission of the Cancer Health Outcomes and Control Research Program (CO) is to fosterresearch that can engage and reach out to the catchment area community to reduce the public health burden ofcancer across the entire care continuum and to improve health-related outcomes for those at risk for or with adiagnosis of cancer. This research which spans basic clinical and population-based science across the cancercare continuum. can be broadly categorized into three thematic domains: 1) prevention and early detection; 2)patient-centered health outcomes during and following cancer treatment; and 3) implementation of healthcareinterventions and policy to improve cancer care delivery and decrease cancer health disparities. CO will conductresearch across these three domains through the following Specific Aims:Aim 1. Identify and evaluate strategies targeted to cancer prevention and early detection and developand test behavioral- and laboratory-based interventions in healthy and at-risk populationsAim 2. Assess and compare patient-centered outcomes during and following cancer therapy in order toinform development of treatment strategies that best balance efficacy with toxicityAim 3. Develop and implement healthcare interventions and policies on a population practice orindividual level that improve access to and delivery of care to minimize the burden of cancer in the VICCcatchment area and nationallyAlongside these scientific aims the Program will develop opportunities to promote intra- and inter-programmaticresearch training and mentorship with engagement of and outreach to the VICC community in a bidirectionalmanner to meet its mission.There are 29 program members from 14 departments and 5 schools with $8.9M in total peer-reviewed fundingand NCI making up 47% ($4.2M). Out of 477 publications 15% are intra-programmatic and 19% are inter-programmatic. Members also have 257 collaborative publications with investigators at other NCI-designatedcancer centers. +No NIH Category available Acceleration;Address;Adverse event;Affect;Allogenic;Antineoplastic Agents;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Therapy;Clinic;Clinical;Clinical Cancer Center;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Communities;Continuity of Patient Care;Correlative Study;Development;Discipline;Disease;Disparate;Doctor of Philosophy;Effector Cell;Evolution;Fertilization;Funding;Future;Goals;Grant;Growth;Hematologic Neoplasms;Immune;Immune checkpoint inhibitor;Immune system;Immunooncology;Immunotherapy;Industry;Institution;International;Intervention;Investigation;Laboratories;Laboratory Scientists;Lead;Leadership;Malignant Neoplasms;Mission;Molecular;Multi-Institutional Clinical Trial;NCI Center for Cancer Research;NCI-Designated Cancer Center;Oncology;Patient-Focused Outcomes;Patients;Peer Review;Policies;Positioning Attribute;Practice Management;Productivity;Program Research Project Grants;Publications;Research;Research Personnel;Risk;Role;Schools;Science;Scientific Advances and Accomplishments;Solid;Standardization;Stem cell transplant;Structure;Surgical Oncology;Testing;Therapeutic;Therapeutic Agents;Time;Toxic effect;Translating;Translational Research;Work;bench to bedside;cancer care;cancer therapy;experience;graft vs host disease;hematopoietic cell transplantation;implementation facilitation;improved;industry partner;innovation;insight;member;multidisciplinary;neoplastic;new therapeutic target;next generation;novel;precision medicine;precision oncology;prevent;programs;resistance mechanism;skills;targeted treatment;translational oncology;translational scientist;treatment response Translational Research and Interventional Oncology Research Program PROJECT 006 TRANSLATIONAL RESEARCH AND INTERVENTIONAL ONCOLOGYRESEARCH PROGRAMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Translational Research andInterventional Oncology Research Program. NCI 10682641 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9927 11524626 "JOHNSON, DOUGLAS B" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 124453 71938 52515 PROJECT 006 TRANSLATIONAL RESEARCH AND INTERVENTIONAL ONCOLOGYRESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe Translational Research and Interventional Oncology Research Program (TR) is an integratedtransdisciplinary program that provides the opportunity for clinical investigators and laboratory scientists tocollaboratively address the rapidly changing landscape of cancer therapy. TR traverses multiple disciplinesincluding precision oncology clinical trials cellular therapy immuno-oncology and immune-toxicity and TRleaders aim to enhance the vital cross-fertilization across disparate fields that can improve oncologic practice.Over the past five years TR members have continued to lead large multi-center clinical trials and have remainedscientifically productive with increased funding. The prior funding cycle has seen growth at both ends of thatspectrum in addition to strong productivity in terms of publications and federal grant funding. TR aspires topromote and advance all facets of bi-directional translational oncology in solid and hematological malignancieswith the main purpose of optimizing patient outcomes that align with serving the needs of the Vanderbilt-IngramCancer Center (VICC) catchment area and beyond. The specific aims are targeted to lead development andimplementation of practice-changing discoveries including the oversight of clinical trials that are innovativeinvestigator-initiated and/or accrue on national and international stages. The translational scientists in TR aim toperform paradigm-shifting research that further informs the next generation of clinical trials. The advent ofimmuno-oncology has identified a rapidly evolving unmet need to address the identification of patients at risk ofimmune-toxicity and to standardize best practices for management of those toxicities. TR membership is well-positioned to lead the field of immune-toxicity across the spectrum of checkpoint inhibitors immune-cellulartherapy and allogeneic stem cell transplantations. There are 37 program members from seven departments andtwo schools with $5.5M in total peer-reviewed funding and NCI making up 47% ($2.6M). Out of 826 publications16% are intra-programmatic and 24% are inter-programmatic. Members also have 546 collaborative publicationswith investigators at other NCI-designated cancer centers. +No NIH Category available Academic Medical Centers;Adopted;Area;Basic Science;Berlin;Biological Markers;Biology;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Catchment Area;Cessation of life;Cetuximab;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Collaborations;Colorectal Cancer;Data;Development;Diagnosis;Diagnostic Imaging;Disease;Doctor of Philosophy;Dysplasia;Education;Epidemiology;Epidermal Growth Factor Receptor;Etiology;Extramural Activities;Faculty;Fc Receptor;Fostering;Foundations;Funding;Gastric Metaplasia;Gastrointestinal Neoplasms;Helicobacter pylori;Helicobacter pylori induced carcinogenesis;Hepatitis C;Human Papillomavirus;Immunity;Incidence;Infection;Inflammation;Investigation;Jordan;Knowledge;Leadership;Learning;Malignant Neoplasms;Malignant neoplasm of anus;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mentors;Methods;Modality;NCI Center for Cancer Research;Neuroendocrine Carcinoma;Pancreas;Pathogenesis;Patient Care;Patient-Focused Outcomes;Patients;Peer Review;Pharmacology;Postdoctoral Fellow;Prevention;Prevention strategy;Primary carcinoma of the liver cells;Process;Prognosis;Program Research Project Grants;Publications;Receptor Signaling;Research;Research Personnel;Resistance;Resource Sharing;Risk Factors;Role;Schools;Scientist;Series;Small Intestines;Source;Students;Talents;Technology;Therapeutic;Training;Translating;Translational Research;Translations;United States;Work;advanced disease;aging population;anticancer research;body system;cancer genetics;cancer prevention;carcinogenesis;career;career development;clinical application;clinical care;community center;empowerment;gastroesophageal cancer;imaging modality;improved;malignant stomach neoplasm;member;metastatic colorectal;method development;microbiome;microbiome research;mortality;neuroendocrine cancer;new technology;next generation;nonalcoholic steatohepatitis;novel;novel diagnostics;novel strategies;panitumumab;pre-clinical;prevent;programs;recruit;resistance mechanism;response;success;synergism;targeted treatment;therapy resistant;tumor microenvironment;tumor progression Gastrointestinal Cancer Research Program PROJECT 005 GASTROINTESTINAL CANCER RESEARCH PROGRAMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Gastrointestinal Cancer ResearchProgram. NCI 10682640 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9926 1898854 "BEAUCHAMP, ROBERT DANIEL" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 89432 51695 37737 PROJECT 005 GASTROINTESTINAL CANCER RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTTaken together gastrointestinal cancers (GI cancers) kill more patients per year than cancers from any otherorgan system. In 2019 328030 new GI cancers will be diagnosed resulting in 165460 deaths in the US.Additionally many of the GI cancers are rising in incidence for a variety of reasons such as the aging populationinflammation (pancreatic gastric and esophageal cancers) human papillomavirus (anal cancer) hepatitis Cand non-alcoholic steatohepatitis (hepatocellular cancer) as well as unknown causes (neuroendocrine cancers).Vanderbilt-Ingram Cancer Center (VICC) has prioritized GI cancers into a research program because thesediseases and their risk factors are more common and lethal in the catchment area as well as the strength ofVICC investigators in this field of research. Throughout its existence the Gastrointestinal Cancer ResearchProgram (GI) has been built on two core strengths: epidermal growth factor receptor (EGFR) signaling inmetastatic colorectal cancer (mCRC) and the role of Helicobacter pylori (H. pylori) in the pathogenesis of gastriccancer (GC). GI investigators continue to define mechanisms of resistance to EGFR targeted therapies andmethods to overcome this resistance. GI members are ideally suited to conduct microbiome research particularlyH. pylori its pathogenesis in GC the differential sensitivity to H. Pylori carcinogenesis and the development ofmethods to prevent these cancers. Building on this core GI has expanded its research across the spectrum ofGI cancers and members have extended their capabilities to understand diagnose prevent and treat GI cancersthrough intra- inter-programmatic and extramural collaborations. GI members seek to continue the Program'sstrong longstanding track record of success through the study of processes underlying etiology pathogenesisand progression; the exploration of the roles of infection inflammation and immunity; studies of novel agentsand diagnostic imaging modalities treatment resistance mechanisms and biomarkers to improve patientoutcomes; and translation of this new knowledge into clinical application. GI will also continue to mentor andtrain the next generation of GI cancer scientists. GI co-Leaders Cathy Eng MD and R. Daniel Beauchamp MDwork to integrate the members' efforts within GI and VICC. They will work with GI members other VICC researchprograms and the shared resources to continue fostering collaboration and conduct high impact cancer research.They will also encourage GI members to adopt and translate new technologies for greater clinical impact andcontinue successful recruitment strategies to engage new investigators in strategic areas prioritized by theProgram. There are 35 members from eight departments and three schools with $9.6M in total peer-reviewedfunding and NCI making up 49% ($4.7M); of 615 publications 21% are intra-programmatic and 25% are inter-programmatic. Members have 299 collaborative publications with investigators at other NCI-centers. +No NIH Category available Academic Medical Centers;Address;Back;Basic Science;Bioinformatics;Biotechnology;Breast;Breast Cancer therapy;Breast Epithelial Cells;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Caring;Catchment Area;Cellular biology;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Design;Collaborations;DNA Repository;Data;Development;Doctor of Philosophy;Drug resistance;Epidemiology;Faculty;Fostering;Funding;Genetic;Genomics;Goals;Guidelines;Healthcare;Immunotherapy;Incubators;Industry;Institution;International;Intervention;Intervention Trial;Laboratories;Life Style;Mammary Neoplasms;Medical Oncology;Medicine;Mentors;Methods;Molecular Biology;Molecular Epidemiology;Monitor;NCI-Designated Cancer Center;Obesity;Outcome;Patients;Peer Review;Pilot Projects;Play;Population Research;Program Research Project Grants;Protocols documentation;Publications;Quality of life;Radiation Oncology;Reduce health disparities;Reporting;Research;Research Personnel;Role;Running;Safety;Schools;Series;Signal Transduction;Specialized Program of Research Excellence;Surgical Oncology;Technology;Tissue Banks;Toxic effect;Translating;Translational Research;Translations;Universities;bench to bedside;breast pathology;cancer care;cancer subtypes;care delivery;cell free DNA;clinical investigation;health disparity;improved;innovation;interest;liquid biopsy;malignant breast neoplasm;meetings;member;mortality disparity;multidisciplinary;next generation;novel;population based;predictive marker;professor;programs;recruit;training opportunity;treatment trial Breast Cancer Research Program PROJECT 004 BREAST CANCER RESEARCH PROGRAMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Breast Cancer Research Program. NCI 10682639 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9925 10166490 "BALKO, JUSTIN M" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 89432 51695 37737 PROJECT 004 BREAST CANCER RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe Breast Cancer Research Program (BC) has a strong emphasis on high-impact collaborative multi-disciplinary and mechanism-based research encompassing breast epithelial cell and molecular biology geneticsand genomics immunotherapy basic science-driven translational and clinical research innovative clinical trialsand molecular epidemiology. To address the needs of the Vanderbilt-Ingram Cancer Center (VICC) catchmentarea Specific Aims of the Program are:Aim 1. To discover predictive biomarkers and mechanisms of drug resistance in specific breast cancer subtypesand translate these findings to clinical trials.Aim 2. To reduce health disparities in breast cancer focusing on the impact of genomics obesity healthcareuse and lifestyle on breast cancer outcomes.Aim 3. To optimize care delivery in breast cancer focusing on novel methods for dissemination of new data andcutting-edge technologies as well as implementation of recent guidelines and approved therapies for breastcancerOngoing basic and translational discoveries from BC and other programs provide a steady pipeline for novelinterventional trials with innovative approaches. These discoveries and translation to clinical studies areenhanced by a global systematic liquid biopsy (cell-free DNA [cfDNA]) and tissue repository protocol for all stagesand types of breast cancer. These trials are part of a robust interventional portfolio with an abundance ofgenomically-driven trials and accruals to interventional treatment trials (17% of our patients) which is comparableto the national average (16%) for the past and current project periods. BC also has extensive scientificcollaborations with multiple national and international institutions as well as consortia and pharma.There are 27 program members from 11 departments and three schools with $6.7M in total peer-reviewedfunding and NCI making up 43% ($2.9M) including a Specialized Programs of Research Excellence (SPORE)in Breast Cancer. Member expertise includes cellular signaling molecular biology breast pathology geneticsgenomic profiling bioinformatics medical surgical and radiation oncology clinical trial design epidemiology andquality of life studies. Out of 396 publications 20% are intra-programmatic and 34% are inter-programmatic.Members also have 185 collaborative publications with investigators at other NCI-designated cancer centers. +No NIH Category available ABCB1 gene;Acceleration;Affect;Affinity;Androgen Receptor;Apoptotic;Automobile Driving;Basic Science;Biological Availability;Biology;Biomedical Engineering;CRISPR/Cas technology;Cancer Center;Cancer Center Support Grant;Cancer Intervention;Catchment Area;Cell Cycle;Cell Cycle Regulation;Cell Differentiation process;Cells;Cellular biology;Chemicals;Chemoresistance;Chimera organism;Clinic;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Communication;Cytometry;Dependence;Development;Doctor of Philosophy;EGF gene;Educational workshop;Effectiveness;Ensure;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Erinaceidae;Faculty;Fostering;Funding;Future;Gene Expression;Genus Capra;Goals;Heterogeneity;Human;Image Cytometry;Investigation;Knock-in;Leadership;Light;Malignant Neoplasms;Mentors;Mentorship;Methods;Microscopy;Mission;Modernization;Mus;Mutation;NCI-Designated Cancer Center;Pathway interactions;Patients;Peer Review;Pharmaceutical Preparations;Physics;Play;Population Programs;Program Research Project Grants;Proliferating;Publications;Recording of previous events;Reproducibility;Research;Research Personnel;Resource Sharing;Role;SHH gene;Schools;Science;Scientist;Signal Pathway;Signal Transduction;Structural Models;Students;Technology;Testing;Therapeutic;Therapeutic Intervention;Training;Translating;Translations;Tumor Cell Biology;Work;anticancer research;bench to bedside;cancer cell;cancer initiation;computerized tools;cost;design;drug discovery;genome editing;industry partner;inhibitor;instrumentation;meetings;member;multi drug transporter;new technology;new therapeutic target;novel;novel therapeutics;population based;programs;resistance mechanism;response;single-cell RNA sequencing;small molecule;stem cell proliferation;stem cells;superresolution microscopy;therapeutic target;tumor;tumor progression;tumorigenesis Cancer Cell Biology Research Program PROJECT 002 SIGNAL TRANSDUCTION AND CHEMICAL BIOLOGY RESEARCH PROGRAMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Signal Transduction and ChemicalBiology Research Program. NCI 10682637 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9923 1865821 "CHEN, JIN " Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 82784 74601 8183 PROJECT 002 SIGNAL TRANSDUCTION AND CHEMICAL BIOLOGY RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTThe Signal Transduction and Chemical Biology Research Program (ST) pursues fundamental cancer researchto understand patient- and cancer-specific rewiring of signaling networks and the cell cycle and howstem/progenitor cell plasticity and heterogeneity contribute to tumorigenesis. This information is used to identifynew targets that could be the focus of future drug discovery efforts. Accordingly an overarching goal of ST is todevelop novel and/or test small molecule leads against important drivers of cancer initiation and progression andaid the optimization of `leads' to drugs so that ST discoveries can be translated to the clinic as new cancerinterventions. The major role of ST leadership is to ensure communication between clinical investigatorspopulation-based researchers and basic scientists to ensure that potentially translatable findings are explored.ST leadership and Vanderbilt-Ingram Cancer Center (VICC) sponsor meetings and retreats to ensure thatcommunication of the basic science discoveries is robust. Program goals will be accomplished by: 1) performingcutting-edge research in single cell biology stem cells and signaling networks to identify key targets that conferselective dependencies in human cancers; 2) promoting cutting edge research in chemical biology anddevelopment of new cancer therapeutics; and 3) stimulating interactions among the Program membership toaccelerate discovery mentor junior faculty foster collaborations with clinical programs promote technologiessuch as scRNA-seq super-resolution microscopy mass cytometry and PROTACS and work closely with VICCShared Resources to develop new instrumentation for cancer discovery. There are 44 program members from13 departments and four schools with $11M in total peer-reviewed funding and NCI making up 39% ($4.3M).Out of 372 publications 15% are intra-programmatic and 34% are inter-programmatic. Members also have 115collaborative publications with investigators at other NCI-designated cancer centers. +No NIH Category available Acceleration;Age;Alabama;American;American Society of Clinical Oncology;Anthracycline;Award;Cancer Patient;Cancer Survivorship;Charge;Chronic;Clinical Trials Cooperative Group;Collaborations;Coupled;Development;Dose;Epidemiology;Funding;Future;Genetic;Genetic Predisposition to Disease;Goals;Health;Incidence;Infrastructure;Intervention;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Modeling;Molecular;Molecular Biology;Morbidity - disease rate;Myocardial dysfunction;Neoplasms;Newly Diagnosed;Oncology;Outcome;Outcomes Research;Pathogenesis;Patients;Pediatric Oncology;Pediatric Oncology Group;Peer Review;Pharmacogenomics;Physicians;Population;Premature Mortality;Prevention;Publications;Qualifying;Radiation;Research;Research Personnel;Risk;Role;Shapes;Societies;Therapeutic;Therapeutic Agents;Universities;anticancer research;childhood cancer survivor;clinical investigation;cohort;experience;genetic signature;high risk;improved;indexing;inter-individual variation;interpatient variability;leukemia/lymphoma;member;novel;personalized management;response;risk prediction;risk prediction model;survivorship;treatment risk Mitigating Long-term Treatment-related Morbidity in Childhood Cancer Survivors Childhood cancer survivors are at an inordinately high life-long risk of anthracycline-related cardiac dysfunction(CD) and radiation-related subsequent neoplasms (SNs). Although there is a dose-response relation betweenthese therapeutic agents and CD or SN there is significant inter-patient variability in risk suggesting themoderating role of genetic predisposition. This Outstanding Investigator Award application breaks new groundby harnessing and merging novel concepts from the field of molecular biology pharmacogenomics and cancersurvivorship to identify childhood cancer patients by their personal risk of CD or SN such that personalizedmanagement approaches can be instituted to mitigate this burden of morbidity. NCI 10682635 8/10/23 0:00 PAR-17-494 5R35CA220502-06 5 R35 CA 220502 6 "MOLLICA, MICHELLE A" 9/1/18 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 1879986 "BHATIA, SMITA " Not Applicable 7 PEDIATRICS 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCHOOLS OF MEDICINE 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 868290 NCI 746547 168864 Cancer Relevance and Scientific Rationale: Childhood cancer survivors are at a life-long risk of chronic healthconditions; by age 50 the cumulative incidence of life-threatening/fatal chronic health conditions is 53%. Thetwo leading causes of premature mortality in childhood cancer survivors are radiation-related subsequentneoplasms (SNs) and anthracycline-related cardiac dysfunction (CD). Radiation and anthracyclines are bothused in >60% of children with cancer and there are no plans in the foreseeable future to eliminate these agents.Although there is a dose-response relation between radiation and SN and between anthracyclines and CD(regardless of the underlying primary cancer) there is significant inter-patient variability in the risk suggestingthe moderating role of genetic predisposition. The high burden of morbidity coupled with the inter-individualvariability in risk suggests a need and an opportunity to identify patients at highest risk for treatment-relatedmorbidity such that targeted interventions can be instituted. Broad Plan: This application harnesses and mergesnovel concepts from the field of molecular biology pharmacogenomics and cancer survivorship to identify cancerpatients by their personal risk of SN or CD. This award also attempts to understand the molecular pathogenesisof these complications to inform future development of targeted prevention/therapeutic strategies. The necessaryinfrastructure for the proposed research including banked annotated biospecimens (n=13450) and pre-existingcollaborations with the necessary expertise will be leveraged in this application. The goals are to: i) develop arisk prediction model for radiation-related SN and anthracycline-related CD in childhood cancer survivors; ii)replicate the optimized model in an independent cohort of childhood cancer survivors; iii) apply the optimizedmodel to newly-diagnosed children with cancer to predict the risk of incident SN/CD; iv) determine the functionalrelevance of the genetic signatures. Qualifications: I am the founding Director of the Institute for CancerOutcomes and Survivorship at the University of Alabama at Birmingham. I have over 20y of experienceconducting cancer outcomes research that bridges the fields of oncology epidemiology and genetics. Since2000 I have been charged with shaping the pediatric oncology survivorship research agenda within theChildren's Oncology Group an NCI-supported clinical trials group devoted exclusively to pediatric cancerresearch across 220 centers. I am currently serving as chair-elect for the ASCO survivorship committee. I am aLeukemia Lymphoma Scholar a recipient of the Frank H Oski award and am an elected member of the AmericanSociety of Clinical Investigation and the Association for American Physicians. I have been continuously fundedby NCI since 2000. With over 235 peer-reviewed publications and 15220 citations (9300 since 2012) myGoogle Scholar H-INDEX is 66 (54 since 2012) and my i10-index is 182 (167 since 2012). I am fully committedto improving the long-term health of our childhood cancer survivors and I strongly believe that findings from thisapplication will accelerate the pace to reduce the burden of morbidity in this population. 868290 +No NIH Category available Adopted;Adult;Affect;Antimetabolites;Antimitotic Agents;Area;Base Pairing;Basic Science;Biochemistry;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Cancer Patient;Carcinogen Metabolism;Catchment Area;Cell Cycle;Cell division;Cell physiology;Cellular biology;Chromatin;Chromosome Segregation;Chromosome abnormality;Clinical;Clinical Trials;Collaborations;DNA;DNA Damage;DNA Repair;DNA Sequence Alteration;DNA biosynthesis;DNA lesion;Data;Development;Doctor of Philosophy;Drug Targeting;Drug usage;Ensure;Environment;Epigenetic Process;Experimental Designs;Faculty;Fostering;Foundations;Funding;Gene Expression;Gene Expression Profile;Genetic;Genetic Diseases;Genome;Genomic Instability;Genomics;Goals;Grant;Heart;Immune Evasion;Immune system;Individual;Knowledge;Laboratories;Leadership;Life;Link;Maintenance;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Mentors;Methods;Mission;Mutagenesis;NCI Center for Cancer Research;NCI-Designated Cancer Center;Neoplasm Metastasis;Normal Cell;Outcome;Paper;Pathway interactions;Peer Review;Pilot Projects;Process;Program Research Project Grants;Proliferating;Proteomics;Publications;Publishing;Radiation;Regulatory Pathway;Reproducibility;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Schools;Science;Scientist;Specialized Program of Research Excellence;Talents;Technology;Therapeutic;Therapeutic Intervention;Training;Translating;Translations;Tumor Suppressor Proteins;United States National Institutes of Health;Work;bench to bedside;cancer cell;cancer therapy;cancer type;chemotherapy;collaborative environment;community center;design;disease-causing mutation;empowerment;epigenome;genome integrity;improved;loss of function mutation;malignant breast neoplasm;member;model organism;new technology;next generation;novel;novel therapeutics;programs;protein function;recruit;repaired;response;self-renewal;structural biology;targeted treatment;treatment and outcome;tumorigenesis Genome Maintenance Research Program PROJECT 001 GENOME MAINTENANCE RESEARCH PROGRAMPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Genome Maintenance ResearchProgram. NCI 10682632 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9921 2436424 "CORTEZ, DAVID K" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 89828 81645 8183 PROJECT 001 GENOME MAINTENANCE RESEARCH PROGRAMPROJECT SUMMARY/ABSTRACTMembers of the Genome Maintenance Research Program (GM) are basic science researchers integrated by thecommon goal of understanding processes affecting the integrity expression and duplication of the genome.Research themes within GM include carcinogen metabolism cell division cycle control chromatin andepigenetics DNA replication and repair DNA damage responses and gene expression. Discovery science thatelucidates basic mechanisms cancer etiology and opportunities for therapeutic intervention is at the heart ofGM. Program leaders foster interactions among GM members and between the Vanderbilt-Ingram CancerCenter (VICC) Research Programs that propel basic discoveries from the bench to clinical practice. In additionthe Program aims to support new research initiatives build the research infrastructure necessary for discoverymentor and educate junior members and trainees and create a dynamic and collaborative environment thatadvances science faster and further than would be possible as individual laboratories. GM members alsoparticipate in two NCI-funded Specialized Programs of Research Excellence (SPOREs) in Gastrointestinal andBreast cancers and several NIH training grants. GM houses the intellectual resources to support over 75 clinicaltrials open to accrual at VICC that use drugs that target DNA. In short GM acts as the organizing entity for allcancer-focused DNA research at Vanderbilt. The GM members' research links to and has impact for all of themajor cancer types within the VICC catchment area.There are 23 program members from seven departments and two schools with $9.1M in total peer-reviewedfunding and NCI making up 39% ($3.5M). Out of 332 publications 13% are intra-programmatic and 23% areinter-programmatic. Members also have 106 collaborative publications with investigators at other NCI-designated cancer centers. +No NIH Category available Academic Medical Centers;Animal Experimentation;Animal Model;Animals;Antibodies;Biological;Cancer Center;Cancer Center Support Grant;Cells;Clinical;Clinical Pathology;Communities;Comparative Pathology;Computer software;Consultations;Cooperative Human Tissue Network;Diagnostic Services;Effectiveness;Ensure;Equipment;Experimental Designs;Fluorescence;Frozen Sections;Funding;Histologic;Histology;Histopathology;Human;Human Pathology;Human Resources;Image Analysis;Immunofluorescence Immunologic;Immunohistochemistry;Individual;Institutional Review Boards;Investigation;Malignant Neoplasms;Mentors;Methods;Modernization;NCI Center for Cancer Research;Operating Rooms;Paraffin;Pathologist;Pathology;Performance;Phenotype;Population;Preparation;Procedures;Protocols documentation;Reproducibility;Research;Research Personnel;Resource Sharing;Resources;Scanning;Services;Slide;Specimen;Stains;Students;Technology;Tennessee;Tissue Microarray;Tissue Model;Tissue Stains;Tissues;Training;Universities;Veterinary Pathology;animal tissue;anticancer research;design;digital;digital imaging;histological stains;human model;human tissue;imaging capabilities;imaging system;instrumentation;laser capture microdissection;medical schools;member;mouse model;pre-clinical;programs;research study;robotic system;tissue biomarkers;tissue preparation;tissue processing;tissue resource Translational Pathology Shared Resource CORE 012 TRANSLATIONAL PATHOLOGY SHARED RESOURCEPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Translational Pathology SharedResource. NCI 10682627 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9918 1861886 "GOLDENRING, JAMES RICHARD" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 386802 223585 163217 CORE 012 TRANSLATIONAL PATHOLOGY SHARED RESOURCEPROJECT SUMMARY/ABSTRACT Obtaining processing and staining of tissue specimens and quantification and interpretation of tissuebiomarkers are central to the performance of modern cancer research. The Translational Pathology SharedResource (TPSR) provides Vanderbilt-Ingram Cancer Center (VICC) investigators with a full range of pathologyservices and technologies to support cancer research. The TPSR capitalizes on Vanderbilt expertise bringingtogether key components to provide a comprehensive array cancer tissue services for VICC investigatorsincluding research histology veterinary and human pathology expertise tissue acquisition and digital histology.Through a partnership with the Western Division of the NCI-funded Cooperative Human Tissue Network (CHTN)the TPSR coordinates the procurement and processing of human tissues obtained from both the operating roomand clinical settings under IRB-approved protocols. The TPSR provides full research histopathology servicesincluding processing embedding sectioning and staining of both human and animal model tissues. The TPSRalso performs a wide range of automated immunostaining protocols that can be customized to investigatorneeds. Both paraffin and frozen sectioning of specimens can be performed for investigators. The TPSR housesa robotic system for automated assembly of tissue microarrays from multiple tissue blocks which provides anexceptional new capability for VICC researchers. The Shared Resource also provides investigators with accessto laser capture microdissection instrumentation for isolation of discrete cell populations from tissue sections. Asan adjunct to the array of staining and immunostaining procedures available the TPSR provides automatedwhole-slide scanning of both brightfield and fluorescence staining as well as access to quantitative software fordigital image analysis. In addition TPSR provides investigators working with animal models access tocomparative pathology services which includes a full line of clinical pathology diagnostic services and pathologyphenotyping of mouse models for VICC investigators. Finally veterinary and human pathologists provideconsultative services in both human and animal pathology for cancer research studies. The TPSR provides thefull range of pathology services advanced technologies and expertise to support all aspects of cancer researchrelated to the analysis of human and animal tissue specimens and thus facilitate leading cancer discovery. +No NIH Category available Ablation;Adhesions;Animal Model;Architecture;Behavior;Biochemical;Biology;Biophysics;Blood Vessels;CD44 Antigens;CD44 gene;Cancer Etiology;Cell Adhesion Molecules;Cells;Cessation of life;Characteristics;Chemicals;Clinical;Clinical Trials;Complex;Country;Development;Diffusion;Disease;Disease Resistance;Drug Kinetics;Drug resistance;Engineering;Epithelial Cells;Epithelium;Evolution;Fostering;Generations;Genetic;Genetic Engineering;Glean;Glycosaminoglycans;Grant;Growth;HMMR gene;Histopathology;Hyaluronan;ICAM1 gene;Immune;Immunoglobulin Class Switching;Immunologics;Immunosuppression;In Vitro;Incidence;Investigation;Knowledge;Laboratories;Learning;Liquid substance;Malignant Neoplasms;Malignant neoplasm of pancreas;Mechanics;Mediating;Minority;Molecular;Mutate;Neoplasm Metastasis;Normal tissue morphology;Organ;Pancreatic Ductal Adenocarcinoma;Paracrine Communication;Pathogenesis;Patients;Penetration;Perfusion;Pharmaceutical Preparations;Physiology;Process;Prognosis;Property;Proteins;Proteoglycan;Reaction;Resistance;Role;Sea;Series;Signal Pathway;Signal Transduction;Surface;Syndrome;T cell response;Testing;Therapeutic;Therapeutic Agents;Water;Work;autocrine;cancer stem cell;cell type;design;effector T cell;human disease;hypoperfusion;improved;interstitial;mortality;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;pancreatic cancer cells;pancreatic cancer model;paracrine;pharmacokinetics and pharmacodynamics;pressure;prevent;programs;receptor;therapy resistant;tumor OVERCOMING STROMAL BARRIERS TO THERAPEUTICS IN PANCREAS CANCER PROJECT NARRATIVEPancreas cancer kills essentially every patient it afflicts and with a rising incidence and unabatedmortality it is now the third leading cause of cancer-related deaths in this country. We have developedgenetically engineered animal models of pancreas cancer that have exposed unique points ofvulnerability for the development of new treatments. We propose a systematic program of investigationto target distinct components of the stromal reaction in pancreas cancer as the basis for new treatmentstrategies against this highly resistant disease. NCI 10682621 9/6/23 0:00 PA-20-185 5R01CA161112-14 5 R01 CA 161112 14 "FORRY, SUZANNE L" 8/11/22 0:00 5/31/27 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 1926329 "HINGORANI, SUNIL R" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 497998 NCI 354953 143045 PROJECT SUMMARYPancreatic ductal adenocarcinomas (PDA) are unrivaled in their lethality. PDAs have the highest 1-year 5-year and 10-year mortalities of any cancer and are expected to become the second-leadingcause of cancer-related death by 2030. An invasive PDA represents the coordinated evolution of cell-intrinsic and extrinsic processes and capabilities that subvert and repurpose the dictums of normaltissue composition architecture and physiology to foster unbridled growth and colonization. This neworganizational entity is constructed largely at the behest of the mutated epithelial cell. The resultingPDA neo-organ contains a minority of tumor epithelial cells amidst a heterogeneous sea of non-epithelial cells; a complex interstitial stew of proteins proteoglycans and glycosaminoglycans togetherwith both freely mobile and complexed water; and a paucity of vessels that otherwise resemble anormal vasculature in lacking fenestrae or interendothelial junctions but that are collapsed underintense interstitial pressures. We have undertaken a systematic exploration of the cell autonomous andnon-cell autonomous processes that drive PDA pathogenesis and resistance. We have developedgenetically engineered animal models that faithfully recapitulate the clinical syndrome metastaticbehavior histopathology and molecular features of the human disease as primary platforms to bothuncover critical principles of disease biology and to rigorously test strategies to overcome them.Through such investigations we have identified unusually high concentrations of intratumoralhyaluronan (HA) as the primary culprit in the extraordinarily elevated interstitial pressures in PDA thatin turn cause the vascular collapse and hypoperfusion characteristic of this disease. The stromalbarrier to perfusion also serves as a primary mechanism of drug resistance in limiting the penetration ofsystemically delivered agents. We have additionally identified multiple mechanisms of immunesuppression that prevent the development of an endogenous effector T cell response. Collectivelythese unique aspects of stromal biology in PDA conspire to create a drug- and immune-privilegedsanctuary for unimpeded growth of the pancreas cancer cell. Very recently we have elaboratedstrategies to overcome critical aspects of these physical and immunological barriers to therapyrevealing a perhaps unexpected degree of vulnerability once the barriers are breached. We describe aseries of continuing investigations into this overarching strategy of stromal re-engineering to build uponthe significant inroads made and the important lessons learned in the hopes of radicallytransforming the approach and prognosis for this formidable disease. 497998 +No NIH Category available Achievement;Adverse event;Bioinformatics;Biological;Biological Assay;Biological Markers;Biostatistics Shared Resource;Blood;Cancer Center;Cancer Center Support Grant;Cancer Control;Case/Control Studies;Clinical;Clinical Investigator;Clinics and Hospitals;Collection;Communities;Computer Assisted;Consultations;DNA;Data;Data Collection;Data Science;Diet;Doctor of Philosophy;Effectiveness;Ensure;Environmental Exposure;Epidemiologist;Epidemiology;Faculty;Family;Feces;Genetic;Genetic Markers;Genotype;Goals;Health;Immunohistochemistry;Individual;Industry Standard;Interviewer;Investments;Journals;Laboratories;Malignant Neoplasms;Manuscripts;Medical Records;Mentorship;Metagenomics;Methods;Mission;Molecular;Molecular Epidemiology;Monitor;NCI Center for Cancer Research;Nature;Oral cavity;Outcome Study;Participant;Patient Recruitments;Peer Review;Pharmaceutical Preparations;Population;Population Research;Population Sciences;Population Study;Postdoctoral Fellow;Prevention;Procedures;Prospective cohort;Prospective cohort study;Protocols documentation;Publications;Publishing;Quality Control;Quality of life;RNA;Recording of previous events;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Retrieval;Saliva;Sampling;Services;Stains;Students;Surveys;Symptoms;System;Telephone Interviews;Tennessee;Time;Tissues;Training;United States;Universities;Urine;Variant;Work;anticancer research;biobank;cancer epidemiology;cost;cost efficient;deep sequencing;design;doctoral student;epidemiology study;experience;genome sciences;improved;medical schools;member;metatranscriptomics;microbiome research;molecular marker;nano-string;new technology;next generation;participant enrollment;population based;programs;randomized trial;recruit;research study;responsible research conduct;sample collection;service utilization;translational study Survey and Biospecimen Shared Resource CORE 011 SURVEY AND BIOSPECIMEN SHARED RESOURCEPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Survey and Biospecimen SharedResource. NCI 10682619 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9914 8034494 "CAI, QIUYIN " Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 138971 80330 58641 CORE 011 SURVEY AND BIOSPECIMEN SHARED RESOUCEPROJECT SUMMARY/ABSTRACTThe mission of the Survey and Biospecimen Shared Resource (SBSR) is to provide high-quality survey andlaboratory services to support the Vanderbilt-Ingram Cancer Center (VICC) research community inclusive of ourVICC members and partners at Meharry Medical College Tennessee State University and other NCI CancerCenters. This mission is fulfilled through two distinct but complementary functions: survey research services andlaboratory services. The survey services include consultation for study design or implementation surveyprogramming participant enrollment computer-assisted telephone interviewing medical record review andstudy mailings. The laboratory services include consultation for study design biospecimen collectionprocessing storage and retrieval DNA/RNA extraction genotyping and biomarker assays. The SBSR alsomanages biorepositories for multiple studies including from three large prospective cohort studies and severallarge case-control studies. The scientific co-Directors of the SBSR have directed studies involving data andbiologic sample collection from more than 200000 study participants in the United States and abroad. Thus theSBSR provides VICC members with access to significant expertise and capabilities in large-scale population-based research; avoids the start-up costs associated with hiring and training staff for data collection and sampleprocessing; shares experienced research staff to reduce study costs; implements rigorous quality controlprotocols; and enables high quality specimen and data collection and processing. The major scientificachievement of the SBSR is reflected in the service utilization and publications. The SBSR supports multiplestudies that are recruiting participants collecting survey data and/or biospecimens or performing biologicalassays on collected samples. Twenty-six VICC members have benefited from the services of the resource toimprove study design and research quality. VICC members with peer-reviewed support account for 91% and98% of total service usage for the laboratory services and survey services respectively. This shared resourcehas supported the publication of over 200 cancer-related manuscripts published since 2015 including in journalssuch as JAMA Nature Nature Genetics JNCI and Cancer Research. Through the implementation and sharingof best practices the SBSR staff demonstrates to users the effectiveness of a rigorous approach to the conductof population-based research which enables individual investigators students fellows and staff to betterincorporate these practices into their research programs. Thus the SBSR services are critical for the researchconducted by VICC members across multiple VICC research programs. +No NIH Category available Automation;Bioinformatics;Biological;Biological Assay;Cancer Center;Cancer Center Support Grant;Chromium;Classification;Communities;DNA;DNA sequencing;Data;Data Analyses;Dryness;Effectiveness;Ensure;Experimental Designs;Formalin;Gene Expression;Genome;Genomic approach;Genomics;Genotype;Goals;Improve Access;Individual;Informatics;Laboratories;Libraries;Manuals;Mentors;Mentorship;Methods;Mission;Modernization;NCI Center for Cancer Research;Nucleic Acids;Paraffin Embedding;Performance;Phase;Play;Preparation;Process;Quality Control;RNA;Reproducibility;Reproducibility of Results;Research;Research Design;Research Personnel;Research Project Grants;Resource Sharing;Resources;Role;Sampling;Science;Services;Somatic Mutation;Students;Technology;Tennessee;Time;Tissue Embedding;Training;Translating;Universities;Variant;Vision;Visualization;Work;biobank;computerized data processing;cost;data integrity;data management;data quality;design;experimental study;flexibility;genome sciences;genomic data;improved;innovation;medical schools;member;nanopore;new technology;next generation sequencing;novel strategies;programs;responsible research conduct;sample collection;single cell sequencing;single cell technology;tool;transcriptome;transcriptome sequencing;whole genome Genomic Sciences Shared Resource CORE 009 GENOMIC SCIENCES SHARED RESOURCEPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Genomic Sciences Shared Resource. NCI 10682610 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9911 7694738 "MALLAL, SIMON ALEXANDER" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 360139 208173 151966 CORE 009 GENOMIC SCIENCES SHARED RESOURCEPROJECT SUMMARY/ABSTRACT The mission of the Genomic Sciences Shared Resource (GSSR) is to bring new and powerful genomicsapproaches to the Vanderbilt-Ingram Cancer Center (VICC) research community inclusive of our VICC membersand partners at Meharry Medical College Tennessee State University and other NCI centers. The vision of theGSSR is to rapidly translate the most powerful modern and enabling genomics technologies to practice andmake these accessible to investigators. The GSSR seeks to maximize responsiveness to unmet scientific needsand partner with VICC investigators to develop and operationalize new processes platforms applicationsassays and dry lab pipelines. To support investigators with their important work the GSSR offers high levelscientific concierge support. This includes advice on appropriate technology sample collection processing andextraction biobanking and storage and quality assessment. The GSSR offers project management and studydesign to protect sample and data integrity data management and analysis. The GSSR seeks continuousimprovement in quality cost scalability and turn-around time as well as an increase in the range ofassays/applications and sample types across both wet and dry laboratory phases. GSSR has found that theneed for genomic data analysis is increasing rapidly for many VICC investigators. Thus over the next iterationof the CCSG the shared resource plans to increase bioinformatic support for users including the processing ofdata to deliver intermediate results (i.e. count table for RNAseq variant calls for DNAseq etc.) as well as providetools for analysis and visualization with ongoing high-level expertise provided in the GSSR. Importantly theGSSR supports researchers in the design of rigorous experimental approaches that are transparent andreproducible. The GSSR accomplishes these goals through training informal mentorship and service providedby the core. The GSSR staff are particularly well suited to facilitating good experimental design and validatedmethods providing authentication services for key biological resources and in defining and establishing rigorousmethods for acquiring and analyzing genomic datasets. +No NIH Category available Accidents;Animal Experimentation;Animals;Biological;Birth;Breeding;CRISPR/Cas technology;Cancer Center;Cancer Center Support Grant;Cells;Cellular biology;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Communities;Complex;Cryopreservation;Cytoplasm;DNA;Derivation procedure;Disasters;Effectiveness;Embryo;Embryo Transfer;Engineering;Ensure;Epitopes;Experimental Designs;Female;Fertilization in Vitro;Gene Deletion;Gene Modified;Gene Targeting;Generations;Genes;Genomic approach;Genotype;Germ;Goals;Heterozygote;Individual;Injections;Institution;Insurance;Knowledge;Mammalian Oviducts;Mediating;Mentors;Mentorship;Methods;Microinjections;Mission;Modeling;Modification;Molecular Biology;Mus;Mutant Strains Mice;NCI Center for Cancer Research;NIH Mouse;Nonhomologous DNA End Joining;Outcome;Point Mutation;Policies;Preparation;Proteins;Publishing;Qualifying;Reagent;Reporting;Reproducibility;Reproductive Techniques;Research;Research Personnel;Resource Sharing;Resources;Ribonucleoproteins;Sampling;Service delivery model;Services;Shipping;Single-Stranded DNA;Source;Students;Technology;Tennessee;Time;Training;Transgenic Mice;Tumor Biology;Universities;Uterus;Validation;assisted reproduction;blastocyst;cost;cost effective;design;embryo cryopreservation;embryonic stem cell;experimental study;genome editing;germ free condition;improved;medical schools;member;mouse model;novel;operation;preservation;programs;pup;reconstitution;repaired;repository;responsible research conduct;screening;skills;sperm cryopreservation;success Genome Editing Shared Resource CORE 008 GENOME EDITING SHARED RESOURCEPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Genome Editing Shared Resource. NCI 10682606 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9909 1888144 "MAGNUSON, MARK A" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 171743 171743 0 CORE 008 GENOME EDITING SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe mission of the Genome Editing Shared Resource (GESR) previously the Transgenic Mouse/EmbryonicStem Cell Shared Resource is to enable the Vanderbilt-Ingram Cancer Center (VICC) research communityinclusive of our VICC members and partners at Meharry Medical College Tennessee State University and otherNCI Cancer Centers to efficiently generate store and share genetically-altered mouse models. GESR whichhas been in existence for over 25 years has undergone major changes over the past five years. Five priorservice lines oriented around gene targeting in mouse embryonic stem cells (mESCs) became unnecessary afterthe discovery of CRISPR/Cas9. Thus in late 2015 GESR shifted its focus towards improving the efficiency andoutcomes of CRISPR/Cas9-mediated gene editing in one and two cell mouse embryos. Since then over 800mutant mice from 97 CRISPR/Cas9 experiments have been generated with a 100% technical success rate forthe past twenty-six projects. GESR now provides a full-service approach where the resource performs projectdesign pre-injection reagent validation post-injection analysis of the resulting pups and breeding of the firstgeneration to provide the investigator with a correctly edited heterozygous mouse. Investigators no longer needextensive molecular biology skills or even much knowledge about CRISPR/Cas9 gene editing strategies. Tosupport the sharing of these new CRISPR-generated lines GESR has become more proactive in encouragingthe use of core cryopreservation services. In house cryopreservation of mouse lines improves colonymanagement and enables specific pathogen free stocks to be sent as cryopreserved germplasm to otherinstitutions. The resource continues to reconstitute cryopreserved mouse lines that are requested by VICCinvestigators from other investigators or that exist within external repositories by performing both in vitrofertilization and embryo transfer. Finally the resource has established and are striving to expand a VanderbiltCryopreserved Mouse Repository (VCMR). The VCMR facilitates compliance with NIH Mouse Sharing Policiesand enables storage and distribution of mice from Vanderbilt without the continued involvement of investigators.All microinjection and embryo transfer services are performed in a specific pathogen free barrier facility.Together the combination of services provided by the GESR enables VICC members and other Vanderbiltinvestigators to efficiently generate and maintain novel genome-edited mouse models to study multiple aspectsof cell and tumor biology using sophisticated mouse models. +No NIH Category available Aerosols;Antibodies;Bar Codes;Biological Assay;Cancer Center;Cancer Center Support Grant;Cell Separation;Cells;Clinical Trials;Clinical stratification;Color;Complex;Computer software;Computers and Advanced Instrumentation;Containment;Custom;Cytometry;Data Analyses;Education;Elements;Ensure;Equipment;Experimental Designs;Faculty;Flow Cytometry;Flow Cytometry Shared Resource;Funding;Future;Goals;Grant;Human Resources;Immune;Immunophenotyping;Individual;Instruction;Lasers;Maintenance;Malignant Neoplasms;Methods;Mission;Modernization;NCI Center for Cancer Research;Performance;Phenotype;Population;Preparation;Property;Protocols documentation;Publications;Reproducibility;Research;Research Personnel;Resource Sharing;Resources;Running;Sampling;Schedule;Services;Sorting;Speed;Stains;Techniques;Time;Tissues;Training;Training and Education;Work;base;catalyst;cell preparation;cost;cost effective;experimental study;genome sciences;immune cell infiltrate;improved;instrument;instrumentation;member;multidisciplinary;neoplastic cell;new technology;progenitor;protocol development;resource guides;single-cell RNA sequencing;skills;stem;student training;success;tumor Flow Cytometry Shared Resource CORE 007 FLOW CYTOMETRY SHARED RESOURCEPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Flow Cytometry Shared Resource. NCI 10682605 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9908 7011070 "HIEBERT, SCOTT W" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 126489 73115 53374 CORE 007 FLOW CYTOMETRY SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe Flow Cytometry Shared Resource (FCSR) supports the goals of the Vanderbilt-Ingram Cancer Center(VICC) by providing state-of-the-art equipment and expertise to analyze and sort individual cells for VICCmembers. The FCSR works closely with VICC members to efficiently develop and refine their experimentsinvolving flow cytometry on cancer-related samples. Cells and tissues isolated from the various cancer milieusrequire specialized techniques and skills to optimize assays and interpret data which the FCSR possesses. Theoverall strategy and goals of the FCSR are guided and developed to meet the needs of the VICC membersspecifically as a major user component and scientific catalyst at Vanderbilt. A key component of the sharedresource is the expertise that has been developed over the past 10 years within the team. This team is able tokeep the cytometers running at maximal efficiency and assist users to ensure the success of both analytical andsorting cytometry. The staff is very proud of our educational service as we are able to train students fellows andfaculty to use the cytometers to ensure rigor and reproducibility while also providing 24/7 access. New servicelines include optimization of cell sorting for single cell RNAseq in conjunction with the Genome Sciences SharedResource (GSSR). In addition the FCSR has acquired a four laser Cytek Aurora spectral cytometer that iscapable of 24 color analysis. We expect during the next funding cycle to add additional spectral cytometers toenable lower cost deep phenotyping of cells requiring up to 30-35 markers. We also plan to add a spectral flowcytometer with sorting capabilities to allow deep analysis of tumor samples and sorting of tumor cells and/or cellsfrom the microenvironment (immune or stromal) using a single panel of antibodies. These new acquisitions allowthe FCSR and VICC members to stay at the cutting edge of cell phenotyping and isolation. +No NIH Category available 3-Dimensional;Address;Air;Applications Grants;Architecture;Area;Award;Biological Assay;Biological Markers;Buffers;Cell Extracts;Cell Separation;Cells;Clinical;Clinical Research;Collaborations;Collection;Cytolysis;DNA;Data;Dedications;Development;Development Plans;Diagnosis;Digestion;Disease;Drug Targeting;Early Intervention;Education;Educational workshop;Environment;Exhibits;Fluorescence;Fluorescent in Situ Hybridization;Fred Hutchinson Cancer Research Center;Funding;Future;Genomics;Goals;Human;Image;Individual;Invaded;K-Series Research Career Programs;Label;Laboratories;Light;Lymphovascular;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of prostate;Manuals;Mentors;Mentorship;Methods;Microscope;Microscopy;Molecular;Molecular Analysis;Molecular Profiling;Monitor;Morphology;NIH Program Announcements;Neoplasm Metastasis;Optics;Pathologist;Patients;Phase;Phenotype;Play;Population;Postdoctoral Fellow;Primary Neoplasm;Process;Prostate;Prostate carcinoma;Proteomics;Protocols documentation;Radical Prostatectomy;Recurrence;Relaxation;Research;Research Personnel;Research Project Grants;Resolution;Role;Sampling;Sensitivity and Specificity;Series;Slice;Slide;Specimen;Stains;System;TMPRSS2 gene;Technology;Thick;Thinness;Three-Dimensional Imaging;Time;Tissues;Training;Training Programs;Tumor Cell Invasion;United States National Institutes of Health;Universities;Validation;Washington;analog;anticancer research;aspirate;cancer diagnosis;candidate identification;career;career development;design;diagnostic strategy;effective therapy;follow-up;image guided;imaging approach;imaging modality;improved;indexing;innovation;knowledgebase;laser capture microdissection;lectures;lymphatic Invasion;meetings;meter;microscopic imaging;molecular marker;mortality;neoplastic cell;novel;novel diagnostics;optical imaging;preservation;programs;prostate cancer metastasis;rare cancer;skills;targeted treatment;therapy resistant;transcriptomics;treatment strategy Light-sheet micro-aspiration microscopy for the isolation and analysis of rare tumor cells from intact clinical specimens PROJECT NARRATIVERare tumor cells are known to play an outsized role in many of the most challenging problems in cancer butare difficult to identify and isolate with current methods for downstream analysis. To address this need thisproject aims to design fabricate and demonstrate the utility of a novel light-sheet micro-aspiration microscopeoptimized for identifying and isolating individual rare tumor cells. Downstream molecular analysis of these cells(enabled by our technology) will allow for the identification of new biomarkers and drug targets leading toimproved cancer diagnosis monitoring and treatment. NCI 10682604 8/4/23 0:00 PA-18-398 5R00CA240681-05 5 R00 CA 240681 5 "ZHANG, YANTIAN" 7/1/19 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 14298325 "GLASER, ADAM K" Not Applicable 7 Unavailable 137210949 NFHEUCKBFMU4 137210949 NFHEUCKBFMU4 US 47.650084 -122.351604 10012306 ALLEN INSTITUTE SEATTLE WA Research Institutes 981094307 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 248541 NCI 139630 108911 PROJECT SUMMARYThis grant application responds to Program Announcement Number PA-18-398 and outlines a training andresearch program which will prepare me for a long-term research career focused on the development of opticalimaging methods to better understand diagnose and treat human prostate cancer. The proposal outlines amentored-training program which places me under the direct guidance of a team of NIH funded researchersfrom the University of Washington (UW) and the neighboring Fred Hutchinson Cancer Research Center(FHCRC). My training plan involves three complimentary areas of focus: (1) receiving further training in tissueclearing and labeling (2) obtaining educational and hands-on training in single-cell isolation and analysis and(3) developing a knowledge-base in molecular assays and prostate cancer to facilitate meaningful futurecollaborations with experts in these fields. To achieve these goals I will use the funding to dedicate time forattending graduate courses workshops training seminars grand rounds lectures and most importantly regularmeetings with my entire career award team as outlined in my career development plan. The research projectcomponent of the proposal is driven by the fact that rare cell populations are known to play an outsized role inmany of the most challenging problems in cancer and downstream profiling (i.e. genomics proteomics andtranscriptomics) of these individual cells can therefore allow for more-effective therapies targeted against theseoften-hidden lynchpins of the disease. Despite this single-cell isolation (the process by which individual cellsare targeted and collected for further study) is still technically challenging with current methods particularly forrare tumor cells. This is particularly problematic as these rare tumor cells often dictate metastasis treatmentresistance and recurrence all of which ultimately result in patient mortality. While this challenge exists fornearly all forms of cancer this proposal will focus specifically on metastatic tumor cells which have invaded thelympho-vascular space in prostate cancer as the isolation and analysis of these rare cells can enable thedevelopment of new diagnostic and treatment strategies. To achieve this I propose to build upon my post-doctoral research and with the necessary training above develop a novel light-sheet micro-aspirationmicroscope which will enable the isolation of these rare tumor cells from intact clinical specimens for the firsttime. The project is comprised of three specific aims: (1) development of a multi-resolution open-top light-sheetmicroscope system for identifying rare tumor cells; (2) combined demonstration of light-sheet microscopy withmicro-aspiration for isolating rare tumor cells; and (3) proof-of-concept clinical validation of the system forisolating rare invading tumor cells from human prostate tissues with lympho-vascular invasion. The prostatecancer research environment at UW and the FHCRC is an ideal place for me to train and pursue this researchproject and with the guidance of my mentorship team I will successfully complete this career developmentaward and pursue my long-term career goal of becoming an independent investigator. 248541 +No NIH Category available Acetylation;Affinity Chromatography;Cancer Center;Cancer Center Support Grant;Chemicals;Collaborations;Communities;Complex;Complex Mixtures;Consultations;Data Analyses;Dedications;Deuterium;Dimensions;Doctor of Philosophy;Effectiveness;Elements;Ensure;Experimental Designs;Goals;High Pressure Liquid Chromatography;Histology;Hydrogen;Image;Individual;Inductively Coupled Plasma Mass Spectrometry;Isotope Labeling;Label;Laboratories;Laboratory Personnel;Leadership;Location;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Mentorship;Methods;Mission;Modification;Molecular Profiling;NCI Center for Cancer Research;Peptides;Pharmaceutical Preparations;Phosphorylation;Post Translational Modification Analysis;Post-Translational Protein Processing;Postdoctoral Fellow;Preparation;Procedures;Protein Analysis;Proteins;Proteome;Proteomics;Proteomics Shared Resource;Reproducibility;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Role;Sampling;Services;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stable Isotope Labeling;Students;System;Techniques;Technology;Tennessee;Tissue imaging;Tissues;Training;Training and Education;Ubiquitination;Universities;Validation;assay development;cost effective;crosslink;data acquisition;design;experimental analysis;experimental study;instrument;instrumentation;laboratory facility;large datasets;mass spectrometric imaging;medical schools;member;metabolomics;multiple reaction monitoring;new technology;novel strategies;programs;protein crosslink;protein expression;protein profiling;protein protein interaction;responsible research conduct;service delivery;skills;small molecule;tool Bioanalytics and Proteomics Shared Resource CORE 003 BIOANALYTICS AND PROTEOMICS SHARED RESOURCEPROJECT NARRATIVEPer the PAR-13-386 FOA the project narrative is not applicable for the Bioanalytics and Proteomics SharedResource. NCI 10682589 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9902 6691073 "CAPRIOLI, RICHARD M" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 419217 419217 0 CORE 003 BIOANALYTICS AND PROTEOMICS SHARED RESOURCEPROJECT SUMMARY/ABSTRACTThe mission of the Bioanalytics and Proteomics Shared Resource (BPSR) is to provide cost-effective state-of-the-art instrumentation and analytical expertise in mass spectrometry to investigators. The BPSR is centrallylocated on the Vanderbilt campus and is composed of three components that provide the following analyticalservices: 1) drug and metabolomics analysis 2) comprehensive proteomics analysis and 3) molecular profilingand tissue imaging. BPSR staff provide consultation on experimental design and sample preparation as well asperform all aspects of mass spectrometry analyses and data analysis. LC-MS/MS GC-MS and MALDI-TOFinstruments are available for small molecule drug and metabolite analysis. LC-MS/MS instrumentation isavailable for proteomics analysis including multiple orbitrap systems. A variety of MALDI-based instruments areprovided for molecular profiling and tissue imaging experiments. In addition inductively coupled plasma massspectrometry (ICP-MS) capabilities are offered for elemental analysis and tissue imaging. Specific servicesinclude identification and quantification of small molecules in biofluids and tissues identification andquantification of proteins and their modifications by either stable isotope labeling (SILAC and TMT/iTRAQ) orlabel free methods crosslinking and hydrogen-deuterium exchange for protein-protein interaction analysis andimaging of small molecules and proteins in tissues using imaging mass spectrometry. The BPSR staff provideeducation and training in sample preparation instrument-based experiments and data analysis to VICCinvestigators and their laboratory personnel. Lastly the BPSR collaborates with VICC investigators to continueto offer the latest cutting-edge technology and methods in biomolecular mass spectrometry analysis for high-impact cancer discovery. +No NIH Category available Active Learning;Address;Advisory Committees;Area;Basic Science;Cancer Biology;Cancer Center;Cancer Center Support Grant;Catchment Area;Cessation of life;Clinical;Clinical Research;Clinical Sciences;Communities;Complement;Creativeness;Dedications;Development;Doctor of Philosophy;Ecosystem;Education;Education and Outreach;Educational Activities;Educational Curriculum;Ensure;Environment;Ethics;Extramural Activities;Faculty;Financial Support;Foundations;Funding;Future;Grant;Growth;Incidence;Individual;Infrastructure;Institution;Investments;Lead;Leadership;Malignant Neoplasms;Medical Students;Mentored Clinical Scientist Development Program;Mentors;Mentorship;Mission;Modeling;Modernization;Morbidity - disease rate;NCI Center for Cancer Research;National Research Service Awards;Outcome;Patient Care;Patient-Centered Care;Peer Review;Physicians;Population Heterogeneity;Population Sciences;Postdoctoral Fellow;Preparation;Prevention;Research;Research Personnel;Research Training;Resources;Rural;Scientist;Series;Students;Study Section;Tennessee;Training;Training Activity;Training Programs;Training and Education;Translational Research;Translations;Underrepresented Minority;Vision;Writing;anticancer research;cancer care;cancer education;care providers;career;career development;clinical practice;clinical training;early-career faculty;education research;evidence base;graduate student;innovation;kindergarten;learning strategy;literacy;member;mortality;next generation;population based;profession allied to medicine;programs;recruit;responsible research conduct;skills;training opportunity;twelfth grade;undergraduate student Cancer Research Career Enhancement and Related Activities CORE 001 CANCER RESEARCH CAREER ENHANCEMENT AND RELATED ACTIVITIESPROJECT NARRATIVEPer the PAR-17-095 FOA the project narrative is not applicable for the Cancer Research CareerEnhancement and Related Activities. NCI 10682581 8/7/23 0:00 PAR-17-095 5P30CA068485-28 5 P30 CA 68485 28 9/1/98 0:00 8/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9898 7011070 "HIEBERT, SCOTT W" Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 169288 121526 47762 CORE 001 CANCER RESEARCH CAREER ENHANCEMENT AND RELATED ACTIVITIESPROJECT SUMMARY/ABSTRACTEnsuring the highest quality cancer research education training and career development is key to the missionof the Vanderbilt-Ingram Cancer Center (VICC). VICC leadership and membership have catalyzed andpropelled Vanderbilts nationally recognized strengths in the training and mentoring of graduate studentsresidents postdoctoral fellows and faculty in cancer research careers to advance discovery and translation.VICC recruits and invests in the career development of researchers clinicians and allied-health professionalsencompassing the spectrum of the cancer space; from basic population-based translational and clinicalresearch to clinical practice and patient care. VICC through significant annual investment has created andfacilitated robust and comprehensive cancer-focused training education and mentoring activities. More than525 faculty over 3400 allied-health professionals and over 1900 trainees (graduate students postdoctoralfellows medical students resident trainees and clinical fellows) have participated in VICC-sponsorededucational and training activities since 2015 including ethics and responsible conduct of research and ongoingtraining of clinical fellows and staff. These activities are essential for the development of the next generation ofcancer researchers and clinicians and provide the foundation on which the greatest changes in cancerincidence morbidity and mortality will emerge. VICC has been deliberate in addressing the issues of diversityin our workforce providing enriching mentorship to >4000 underrepresented minority (URM) Kindergartenthrough 12th grade (K-12) students (our future workforce) undergraduate students graduate/postdoctoralresearchers medical students and early career faculty. VICC members participate in the Vanderbilt AugmentingScholar Preparation and Integration with Research Related Endeavors (ASPIRE) and STEM educationaloutreach to >6000 K-12 and undergraduate students per year. Notably the key education and training activitiesaddress the academic challenges of rural Tennessee and the diverse population of the VICC catchment areaand extends these approaches globally. Academic and professional development activities are available to alltrainees and faculty through intensive mentored research engagement and/or formal research training includingformal curricula in cancer biology. Further 21 cancer-related T32 training programs support cancer careerdevelopment for trainees (six NCI-funded catalyzed by VICC leadership) four institutional K12 awards alongwith numerous individual F NRSA ACS Komen and DOD grants. Early career faculty benefit from team-based inter-disciplinary mentoring through advisory committees grant writing studios and mock study sections. +No NIH Category available 3-Dimensional;Advisory Committees;Affect;Amino Acids;Binding;Bioinformatics;Biology;Breast Cancer Cell;Breast Cancer cell line;CRISPR screen;Cancer Biology;Cell Proliferation;Cells;Chromatin;Chromatin Remodeling Factor;Code;Complex;Core Facility;Data;Data Set;Deacetylase;Dependence;Development;Developmental Biology;Disease;Educational workshop;Environment;Enzymes;Epidermis;Epigenetic Process;Fostering;Foundations;Gene Expression;Genes;Genetic Transcription;Genomics;Goals;HDAC1 gene;Histone Deacetylation;Histones;Homeostasis;Human;Human Cell Line;In Vitro;K-Series Research Career Programs;Knockout Mice;Knowledge;Malignant Neoplasms;Malignant neoplasm of prostate;Mammals;Mediating;Mentors;Mentorship;MicroRNAs;Modeling;Modification;Molecular;NuRD complex;Open Reading Frames;Pathway interactions;Peptides;Phenotype;Process;Proliferating;Proteins;Proteomics;RNA;Regulation;Research;Role;Running;Signal Pathway;Skin;Skin wound healing;Techniques;Testing;Thick;Tissues;Training;Translating;Tumor Promotion;Undifferentiated;Untranslated RNA;cancer cell;cancer therapy;career;cell motility;chromatin remodeling;data integration;differential expression;epigenetic regulation;experience;experimental study;in vivo;innovation;keratinocyte;knock-down;malignant breast neoplasm;migration;mouse model;new therapeutic target;novel;programs;prostate cancer cell;prostate cancer cell line;protein function;ribosome profiling;skin wound;transcriptome;transcriptome sequencing;tumor;tumor progression;tumorigenesis;wound;wound closure;wound healing The Roles of a Novel Microprotein in Wound Healing and Cancer Project NarrativeAdvances in genomics and proteomics have uncovered thousands of previously unannotated small proteinsmany of which are encoded on genes implicated in cancer. This proposal seeks to characterize the mechanismof one such novel microprotein with roles in cutaneous wound healing and tumor progression. Successfulcompletion of these studies will enhance our knowledge of how regulators of wound healing are hijacked bycancer and may provide a new target for the development of cancer therapies. NCI 10682567 7/21/23 0:00 PAR-18-364 5K01CA249038-03 5 K01 CA 249038 3 "VAHEDI, SHAHROOZ" 9/1/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 10589723 "MARTINEZ, THOMAS FARID" Not Applicable 47 PHARMACOLOGY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF PHARMACY 926970001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 171972 NCI 159233 12739 Project SummaryThe pathways that regulate processes necessary for wound healing such as proliferation and migration areoften co-opted by tumors leading to their description as wounds that do not heal. Therefore identifying novelgenes involved in wound healing and understanding how they are dysregulated in cancer may provide newtargets for therapeutic efforts. We recently discovered thousands of small open reading frames that encodeproteins <100 amino acids dubbed microproteins. Among these was a 10 kDa microprotein encoded on thelncRNA Terminal Differentiation-Induced non-coding RNA (TINCR) which is a critical inducer of terminaldifferentiation in the epidermis and regulator of cancer cell proliferation and migration. TINCR microprotein(TINCR-MP) is highly conserved across mammals strongly suggesting that it is functional. Compellingpreliminary data demonstrate that in human skin models TINCR-MP downregulates signaling pathways involvedin wound healing and that it interacts with histone modifying enzymes that have functions in differentiation andcancer. Furthermore while TINCR-MP is expressed during epidermal differentiation it is unnecessary fordifferentiation making its function separate from the differentiation promoting activity of TINCR RNA. The centralhypothesis is that TINCR-MP acts as a brake for proliferation and migration during wound healing throughalterations to the epigenetic landscape and that this function is hijacked in cancer cells to promote tumorprogression. The goals of this proposal are thus: 1) to determine the role of TINCR-MP in cutaneous woundrepair processes and establish whether TINCR-MP effects on wound healing are driven by epigeneticmodifications 2) to determine the extent to which TINCR-MP regulates proliferation and migration in prostateand breast cancer cell lines and establish its effects on epigenetic and subsequent gene expression changesand 3) to identify additional microproteins regulated during differentiation that affect cancer proliferation.Successful completion of these aims will reveal an important microprotein that functions in wound healing andtumor progression as well as new microproteins to investigate. The candidate Dr. Thomas Martinez plans todevelop an independent research program focused on characterizing microproteins that function in bothdifferentiation and cancer. The opportunities offered by this Career Development Award will allow Dr. Martinezto deepen his knowledge of developmental biology epigenetics and cancer biology. He will also gain experienceutilizing 3D ex vivo skin models in vivo mouse models and techniques for analyzing the epigenetic landscape.Dr. Martinez will conduct these studies under the mentorship of Dr. Alan Saghatelian expert on peptide biologyas well as co-mentors Dr. Diana Hargreaves and Dr. George Sen experts on chromatin remodeling complexesin disease and epidermal homeostasis respectively. Dr. Martinezs Advisory Committee will also help foster hisscientific and academic career goals. The Salk Institute provides an ideal environment with expertly run corefacilities and ample seminars and workshops to prepare trainees for independent academic careers. 171972 +No NIH Category available Activin Receptor;Biological Process;Cancer Biology;Cancer Etiology;Cell Surface Receptors;Cell surface;Cessation of life;Chemoresistance;Data;Disease;Event;Funding;GOLPH3 gene;Genes;Glucosamine;Golgi Apparatus;Growth;Human;Immunotherapy;In Vitro;Incidence;Invaded;KRASG12D;Knock-out;Knowledge;Ligands;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Modeling;Molecular;Mutate;Mutation;Myosin ATPase;Neoplasm Metastasis;Pathogenesis;Pathway interactions;Phenotype;Prognosis;Public Health;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Solid Neoplasm;Somatic Mutation;Specimen;Structure;Survival Rate;TGF-beta type I receptor;Therapeutic;Transforming Growth Factor beta;Transforming Growth Factor beta Receptors;cancer cell;cancer initiation;derepression;gemcitabine;glycosylation;in vivo;in vivo Model;inhibitor;insight;loss of function;mouse model;novel;pancreatic cancer cells;pancreatic cancer model;pancreatic cancer patients;pancreatic tumorigenesis;predictive marker;receptor;receptor expression;receptor-mediated signaling;targeted treatment;trafficking;tumor progression Role of ALK4 in Regulating Receptor Trafficking and Pancreatic Cancer Biology Activin receptor-like kinase 4 (ALK4) is a type I transforming growth factor- (TGF-) superfamily receptor thatis mutated in a broad spectrum of human cancers with frequent loss of ALK4 expression associated with apoorer prognosis. While ALK4 has been identified in an unbiased screen as a gene whose disruption enhancesRas mediated pancreatic tumorigenesis in vivo the role and mechanism of action of ALK4 loss of function incancer progression is largely unknown. We have uncovered a novel mechanism by which ALK4 regulatesGolgi ribbon formation/extension to regulate receptor trafficking and signaling. Here we will investigatemechanisms by which loss of function of ALK4 regulates Golgi body structure/function to regulate receptortrafficking signaling and cancer biology in pancreatic cancer cells. These studies are important to perform andrelevant to public health as these mechanistic insights will define the biological functions of ALK4 in the contextof pancreatic cancer increase understanding of the role of loss of ALK4 function in regulating pancreaticcancer progression and aid in targeting ALK4 and ALK4-regulated signaling pathways for the treatment ofpatients with pancreatic cancers and other solid tumors with loss of ALK4 function. NCI 10682545 8/11/23 0:00 PA-18-484 5R01CA226925-05 5 R01 CA 226925 5 "XU, WANPING" 9/19/19 0:00 8/31/24 0:00 Molecular Oncogenesis Study Section[MONC] 1931205 "BLOBE, GERARD C" Not Applicable 4 INTERNAL MEDICINE/MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 394579 NCI 248454 146125 Pancreatic cancer is an aggressive and difficult to treat disease with an overall 5-year survival rate of 3-5%. Theincidence of pancreatic cancer is increasing and it is projected to be the 2nd leading cause of cancer death within5 years. Despite detailed knowledge of its molecular pathogenesis targeted therapies have had minimal impactand immunotherapy has been ineffective. Activin receptor-like kinase 4 (ALK4) is a type I transforming growthfactor- (TGF-) superfamily receptor that mediates signaling for several TGF- superfamily ligands. Mutationor copy number loss of ALK4 occurs in 35% of pancreatic cancer patients with loss of ALK4 expressionassociated with a poorer prognosis. In addition ALK4 has been identified in an unbiased screen as a genewhose disruption enhances Ras mediated pancreatic tumorigenesis in vivo. We demonstrate that loss of ALK4expression increases type I (TRI/ALK5) and type II (TRII) TGF- receptor (TR) levels leading to increasedactivation of canonical TGF- signaling enhanced acquisition of EMT markers and phenotypes and increasedcancer invasion and metastasis in vivo. We also find that ALK4 selectively regulates the cell surface expressionof receptors by promoting their glycosylation and processing/trafficking to the cell surface through effects onGolgi ribbon formation/extension which may be regulated by the interaction of the Golgi regulator GOLPH3with myosin 18A. Based on these preliminary results we hypothesize that loss of ALK4 function promotespancreatic cancer progression and chemotherapy resistance by promoting Golgi ribbon formation/extension toincrease TR receptor glycosylation and trafficking to the cell surface increasing TR cell surface levelsdownstream signaling and cancer biology. We further hypothesize that blocking these effects in pancreaticcancer patients with loss of ALK4 function may provide therapeutic benefit. We propose three Specific Aims.Aim 1: The mechanism by which loss of ALK4 promotes TGF- signaling will be explored including definingeffects on Golgi ribbon formation/extension. Aim 2: We will define whether loss of ALK4 expression in pancreaticcancer cells facilitates cancer initiation and/or progression or resistance to gemcitabine in pancreatic cancermodels in vivo. Aim 3: We will define whether pancreatic cancer specimens with ALK4 loss have increased TGF- signaling and Golgi ribbon formation/extension and whether loss of ALK4 creates unique vulnerabilities inthese pancreatic cancer patients which can be exploited for therapeutic benefit. These studies will define novelmechanisms by which ALK4 loss regulates TGF- signaling and downstream pancreatic cancer biology andcould identify ALK4 loss as a predictive biomarker for anti-TGF- approaches in pancreatic cancer and otherhuman cancers with mutation or loss of ALK4 expression.! 394579 +No NIH Category available Affect;Animal Cancer Model;Apoptosis;Applications Grants;Bile Acids;Cancer Research Project;Cell model;Chemicals;Colon;Colon Carcinoma;Disease;Fatty Acids;Funding;Goals;Grant;Hepatocarcinogenesis;Lead;Liver;Malignant Neoplasms;Malignant neoplasm of liver;National Institute of Diabetes and Digestive and Kidney Diseases;Natural Compound;Organ;Outcome Study;Pathway interactions;Peer Review;Positioning Attribute;Prevention;Preventive;Primary carcinoma of the liver cells;Publications;Research;Role;Signal Transduction;Small Business Innovation Research Grant;Specialist;Tretinoin;Tumor Suppressor Proteins;Volatile Fatty Acids;Work;alternative treatment;anti-cancer;anticancer research;cancer cell;cancer therapy;carcinogenesis;career;combat;effective therapy;gut microbes;gut microbiota;gut-liver axis;liver inflammation;mouse model;novel strategies;programs;treatment strategy Gut microbiota-derived signaling in liver carcinogenesis and cancer treatment PROJECT NARRATIVEThe funded NCI grant (R01 CA222490) titled Liver Cancer Therapy by miR-22 and Its Inducers studies theeffect of gut-derived signaling through miR-22 induction to combat liver cancer. The current application willprovide Dr. Ying Hu the Research Specialist a protected and stable position to facilitate the completion of theNCI-funded grant. The outcome of this study can benefit both prevention and treatment of liver as well as coloncancer because the targeted pathway is responsible for carcinogenesis in both organs. NCI 10682541 8/24/23 0:00 PAR-18-888 5R50CA243787-05 5 R50 CA 243787 5 "DUGLAS TABOR, YVONNE" 9/19/19 0:00 8/31/24 0:00 ZCA1-SRB-1(A1)S 11327284 "HU, YING " Not Applicable 4 PATHOLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 86263 NCI 54944 31319 PROJECT ABSTRACTHepatocellular carcinoma (HCC) is a deadly disease with limited treatment options. Therefore there is anurgent need to develop alternative treatments for liver cancer which is the primary goal of this applicationunder the existing research program (1R01 CA222490). An effective cancer treatment strategy should targetthe pathways by which cancer arises in the first place. Emerging evidence also reveals that gut microbiota-derived signaling is not only implicated in colon cancer but also affects hepatic inflammation and livercarcinogenesis. Thus to develop targeted strategies for liver cancer treatment it is important to uncover themechanism of gut-derived signaling in the liver. The Research Specialist (Dr. Ying Hu) and Unit Director (Dr.Yu-Jui Yvonne Wan) have worked together for the past 8 years starting in 2011 and have generated 11 peer-reviewed publications in cancer research. Dr. Wan's research programs have been sponsored by a long-termcontinuously funded R01 grant NCI R01 CA053596 (1991-2016) and a cooperative U grant NCI U01CA179582 (2014-2019 lead PI) NCI R01 CA222490 (2018-2023) and NIDDK R01 DK092100 (2011-2017).Dr. Hu has participated in all of these above-mentioned projects and has a thorough understanding of how Dr.Wan's cancer research program evolved. Dr. Hu has unique expertise in the gut-liver axis as well as inorthotopic liver and colon cancer animal models. She has conducted extensive research using both liver andcolon cancer cells and mouse models to study the pathways controlled by natural compounds present in thegut and liver including bile acids (BAs) retinoic acid (RA) and short-chain fatty acids (SCFAs). Our researchprogram (1R01 CA222490) focuses on these natural chemicals which are directly or indirectly produced by gutmicrobes and are able to induce the tumor suppressor miR-22 in the liver and colon. Thus miR-22 and itsinducers can not only induce cancer cell apoptosis and arrest but also provide a preventive means to stopcancer reoccurrence leading to an effective treatment strategy. The applicant Ying Hu has worked closelywith Dr. Wan in developing plans to achieve the following goals: Aim 1 studies the mechanism by which miR-22 has an anti-cancer effect by studying the downstream targets of miR-22. Aim 2 examines the role of miR-22in liver cancer treatment using orthotopic liver cancer mouse models. Aim 3 analyzes the role of miR-22inducers in liver cancer treatment. Successful completion of the proposed studies will lead to novel strategiesto treat liver cancer as well as colon cancer via miR-22 targeted pathways. The funds freed-up due to fundingof the current application will allow us to develop other collaborative programs that will lead to submission of anSBIR grant application to advance Dr. Hu's career goals. Dr. Wan is the primary support Unit Director who willcontinue to work with Dr. Hu to plan direct and execute the proposed research. 86263 +No NIH Category available Bayesian Network;Biological;Biological Assay;Blood;Blood Cells;Blood Tests;Breast Cancer Patient;Cancer Center;Cancer Patient;Cancer Relapse;Cities;Clinical;Collaborations;Color;Computational Biology;Computer Analysis;Computer Models;Control Groups;Cytokine Signaling;Data;Data Analyses;Data Set;Defect;Development;Diagnosis;Disease;Elements;Estrogen receptor positive;Flow Cytometry;Gene Expression;Genetic;Goals;Helper-Inducer T-Lymphocyte;Histology;Hormonal;Human;Image Analysis;Immune;Immune System Diseases;Immune response;Immune signaling;Immune system;Individual;Knowledge;Malignant Neoplasms;Mammary Neoplasms;Mathematics;Measures;Methods;Modeling;Molecular;Network-based;Oncologist;Outcome;Patients;Pattern;Peripheral Blood Mononuclear Cell;Persons;Phenotype;Post-Translational Protein Processing;Process;Regulatory T-Lymphocyte;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Structure;System;Systems Biology;Technology;Testing;Time;Tissues;Training;Tumor Tissue;Tumor-infiltrating immune cells;Work;archived data;cancer therapy;cancer type;clinically relevant;computer framework;computerized tools;cytokine;data integration;data modeling;data-driven model;dynamic system;experience;high dimensionality;immunological diversity;immunoregulation;improved;improved outcome;interest;malignant breast neoplasm;mathematical methods;mathematical model;monocyte;multidisciplinary;multimodality;neoplastic cell;novel;novel strategies;peripheral blood;predict clinical outcome;predictive modeling;prognostic;prospective;single-cell RNA sequencing;tool;tumor Experimental-Computational Synthesis of Altered Immune Signaling in Breast Cancer Project NarrativeThis proposal seeks to build experimental and computational tools necessary to understand and characterizethe immune signaling network in healthy individuals and patients with breast cancer. This is important becausethe proposed studies provide a framework to understand how information flows within the immune system andhow breast cancer disrupts the immune network. The tools and methods to be developed will be applicable toother cancers and diseases. NCI 10682540 8/16/23 0:00 PAR-16-131 5U01CA232216-05 5 U01 CA 232216 5 "ZAMISCH, MONICA" 9/16/19 0:00 8/31/24 0:00 ZCA1-SRB-C(M1) 1950120 "LEE, PETER POON-HANG" "ROCKNE, RUSSELL CHRISTIAN; RODIN, ANDREI " 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 183872 NCI 347898 264402 PROJECT SUMMARY/ABSTRACTThis integrated experimentalcomputational proposal seeks to unravel the complexity of immune signalingnetworks in healthy individuals and patients with estrogen receptor-positive breast cancer (ER+ BC). Our goalis to identify and characterize at a systems level the dynamical flow of information through immune signalingnetworks in healthy individuals and ER+ BC patients and to understand how immune signaling defects atdiagnosis reflect patients' immune responses leading to different clinical outcomes.This work and its approach are motivated by our experience in immune signaling in cancer and our existingcollaborations with oncologists and computational biologists at the City of Hope Cancer Center. We have shownthat approximately 40% of ER+ BC patients harbor defects in their immune signaling network specifically insignaling molecules called cytokines. Importantly our preliminary data revealed major cytokine signalingabnormalities within immune cells from the peripheral blood of ER+ BC patients which reflect immune activitywithin tumors and can predict cancer relapse years later. We believe that understanding how these cytokinesinteract with each other and other critical elements of the immune signaling network can ultimately lead toimproved cancer treatments. Because the individual components of signaling networks interact in complicatedand difficult-to-predict ways we propose to apply a systems biology computational modeling approach. First wepropose to experimentally capture a rich data set of biological variables (molecular genetic and cellular data)using state-of-the-art technologies in peripheral blood collected from healthy people (Aim 1) and patients withER+ BC (Aim 2). We will integrate these data into Bayesian networks a way of modeling the data that will allowus to mathematically and statistically describe the relationships between cancer and measured variables. Wewill also perform high-dimensional histology and spatial image analysis of human ER+ breast tumors (Aim 3)then apply Bayesian networks and dynamical mathematical models to identify common immune featuresbetween tumor tissue (Aim 3) and peripheral blood (Aims 1 and 2) which we will also correlate with outcome.Impact and deliverables. This proposal will begin unraveling the complexity of the immune signaling networkfrom a systems biology perspective. Significant outcomes of the proposed studies will include i) identification atthe systems biology level of a prognostic and clinically relevant immune phenotype that is characterized bydefects in signaling networks in ER+ BC and ii) development of a data-driven computational framework for thestudy of immune signaling and its defects as a dynamical system in cancer patients with such signaling defects.Our approach should be broadly applicable to other types of cancers and immunological diseases. Thereforean important deliverable will be a computational systems biology data analysis toolkit to construct interrogateand dissect immune signaling networks that can be shared with other groups and applied to other diseases. 183872 +No NIH Category available Administrator;Adopted;Budgets;Cancer Center;Cancer Patient;Cancer Survivor;Caring;Clinic;Clinical;Clinical Oncology;Collaborations;Communication;Data;Data Collection;Decision Making;Electronic Health Record;Electronics;Enrollment;Ensure;Health;Health Promotion;Health Services Accessibility;Healthcare promotion;Hospitals;Human;Individual;Infrastructure;Institutional Review Boards;Intervention;Knowledge;Malignant Neoplasms;Medicine;Monitor;Nature;Nurses;Oncology;Outcome;Patients;Pilot Projects;Policies;Pragmatic clinical trial;Provider;Quality of Care;Randomized Controlled Trials;Research;Research Methodology;Research Project Grants;Research Support;Risk Behaviors;Safety;Services;Site;System;Technology;Tobacco Use Cessation;Tobacco use;Translating;Translations;Treatment outcome;Work;cancer care;cancer risk;cancer therapy;care delivery;clinical infrastructure;clinical practice;data warehouse;digital;electronic health record system;evidence base;health disparity;implementation facilitation;obesity treatment;operation;patient health information;patient portal;patient-clinician communication;physical inactivity;population based;pragmatic trial;preference;programs;repository;telehealth;tool;trial design;working group Clinical Practice Network n/a NCI 10682527 7/21/23 0:00 RFA-CA-21-029 5P50CA271353-02 5 P50 CA 271353 2 8/1/22 0:00 7/31/27 0:00 ZCA1-SRB-2 9887 2115872 "HITSMAN, BRIAN L" Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 178040 121813 56227 Abstract Clinical Practice NetworkThe Clinical Practice Network is the vehicle that will facilitate clinical intervention and data collection for theScalable TELeheaLth Cancer CARe (STELLAR) Centers research program and then translate study findingsinto comprehensive cancer care. The Centers research program can be seen as filling gaps in knowledgeabout how to optimize the cancer care sociotechnical system to deliver telehealth treatment for obesityphysical inactivity and tobacco use in cancer patients and cancer survivors in a manner that maximizes cancercare access quality patient-clinician communication and cancer treatment outcomes. The network willleverage the same clinical practice network that we established for the population-based Lurie Cancer CenterTobacco Cessation Program which has been part of the NCI Cancer Center Cessation Initiative (C3I) since2018. Our practice network will comprise 11 hospitals across the 4 Northwestern Medicine (NM) Regions(Central North Northwest West). NMs 52 oncology clinics are fully integrated by a single telehealthinfrastructure (Doximity) a single EHR-system (Epic) and a single comprehensive and integrhoatedrepository of all clinical and research data (Enterprise Data Warehouse). The Clinical Practice Networkwill implement and maintain the Centers electronic and clinical infrastructure in close collaboration with theAdministrative and Research and Methods Core and with administrators quality leaders oncology clinical andoperations leads and nurse navigators across NM. The Clinical Practice Network will include two workinggroups to facilitate the implementation of STELLARs telehealth research program. The technical aspect of thisoptimization will be carried out by the Infrastructure Workflow Team that will align Epic the patient portal(MyChart) and the wearable and app components of the system to support seamless integration oftechnologies needed for STELLAR. The human aspect of the optimization will be carried out by aStakeholder/Clinical Workflow Team that will align treatment of cancer risk behaviors seamlessly into existingworkflows for cancer care delivery. Guided by the Policy Advisory Group and Internal Advisory Board theClinical Practice Network will mount STELLAR Centers Pilot Studies and Pragmatic Clinical Trial. These willin turn provide a robust evidence base to drive the translation and the integration of sustainable telehealthtreatment of cancer risk behaviors across NM. +No NIH Category available Acceleration;Address;Aftercare;Antigens;Biometry;Blood;CD8-Positive T-Lymphocytes;Cancer Patient;Cells;Chronic;Clinical;Clinical Trials;Clone Cells;Collection;Data;Dendritic Cells;Development;Dose;Equilibrium;Failure;Frequencies;Genetic Transcription;Goals;Homeostasis;Human;Immunofluorescence Immunologic;Immunology;Impairment;Inflammation;Knowledge;Malignant Neoplasms;Minority;Modeling;Neoadjuvant Therapy;Outcome;PD-1 blockade;Participant;Pathology;Patients;Population;Positioning Attribute;Production;Proliferating;RNA;Research Personnel;Resolution;Role;Signal Transduction;Stress;Structure;Study Subject;Supporting Cell;T cell differentiation;T cell infiltration;T cell receptor repertoire sequencing;T cell response;T-Cell Depletion;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Time;Translating;Viral Cancer;Virus Diseases;anti-PD-1;anti-PD1 therapy;anti-tumor immune response;cell type;clinical efficacy;clinically relevant;combinatorial;cytokine;exhaust;experience;immune checkpoint blockade;improved;lymphoid structures;melanoma;neoplastic cell;novel therapeutics;preclinical study;preservation;prevent;progenitor;programs;response;self-renewal;stem cell niche;stem cells;tertiary lymphoid organ;transcriptomics;tumor;tumor eradication Role of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacy Project NarrativeDespite robust CD8 T cell reinvigoration by PD-1 blockade in the majority of melanoma patients only aminority gain clinical responses. The goal of this proposal is to understand why robust reinvigoration ofexhausted CD8 T cells by PD-1 does not necessarily translate to clinical efficacy. We test whether loss ofprogenitor exhausted CD8 T cells after PD-1 blockade is associated with clinical failure and whether a tumor-related niche is important in maintaining the pool of progenitor exhausted CD8 T cells. NCI 10682523 8/17/23 0:00 PA-20-185 5R01CA273018-02 5 R01 CA 273018 2 "SINGH, ANJU" 9/1/22 0:00 8/31/27 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 12287707 "HUANG, ALEXANDER " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 550500 NCI 338769 211731 Project SummaryAnti-PD-1 therapy reinvigorates exhausted CD8 T cells which can lead to complete tumor eradication as earlyas 3 weeks. Yet despite robust T cell reinvigoration in >78% of patients less than 40% are cured. The goal ofthis proposal is to understand why robust reinvigoration of exhausted CD8 T cells by PD-1 therapy does notnecessarily translate to clinical efficacy.Exhausted CD8 T cells (TEX) are a major cell type responding to PD-1 blockade. We and others have shownthat PD-1 therapy (PD-1) reinvigorates exhausted CD8 T cells as defined by enhanced proliferation andcytokine production. TEX are heterogeneous with progenitor and terminally differentiated TEX that have differentroles in anti-tumor immune responses. Progenitor TEX (ProgEX) replenish terminally differentiated TEX (TermEX)which in turn provide anti-tumor activity. Thus similar to stem cells ProgEX represent a reservoir for CD8 T cellresponses against the tumor. Importantly it is the ProgEX rather than TermEX that respond to PD-1 andalmost exclusively contribute to the early burst of CD8 T cell reinvigoration. Reinvigoration of TEX results inaccelerated differentiation of ProgEX to TermEX resulting in a numerically greater pool of TermEX and improvedtumor control. However at the same time the accelerated differentiation induced by PD-1 places increasedstress on ProgEX homeostasis. This raises the possibility that a ProgEX niche is key for providing the cells andsignals necessary to prevent the depletion of ProgEX and may prove crucial for the efficacy of PD-1 blockade.Our central hypothesis is that depletion of ProgEX after PD-1 impairs clinical efficacy and that a tumor-associated niche is important in maintaining the pool of ProgEX. In Aim 1 we will test the hypothesis thatPD-1 results in enhanced differentiation of ProgEX and that that depletion of ProgEX is associated with clinicalprogression. We will use combinatorial tetramers and single cell RNA+TCR sequencing to understand howPD-1 alters the pool of melanoma-specific ProgEX and how the size of ProgEX pool in turn impacts the clinicalefficacy of PD-1. In Aim 2 we test the hypothesis that tertiary lymphoid structures serve as a tumor-associated niche for ProgEX and that increased number or size of ProgEX niches after PD-1 is associated withthe preservation of ProgEX and clinical efficacy. We will use multiparameter immunofluorescence and spatialtranscriptomics to define the cellular composition of the ProgEX niche the transcriptional circuits utilized byProgEX in the niche and the importance of the ProgEX niche in preserving the pool of ProgEX. 550500 +No NIH Category available Address;Affect;Animal Model;Antibodies;CTLA4 gene;Cancer Patient;Credentialing;DNA Repair;Foundations;Genetic;Genetic Determinism;Genomics;Genotype;Goals;Immune;Immunogenomics;Immunologics;Immunooncology;Immunotherapy;Individual;Malignant Neoplasms;Modeling;Molecular;Mutation;Patients;Phenotype;Pre-Clinical Model;Research;Resistance;Sampling;Somatic Mutation;Therapeutic;Treatment Efficacy;Tumor Immunity;Work;anti-CTLA4;anti-PD-1;cancer immunotherapy;design;driver mutation;immune checkpoint blockade;improved outcome;pre-clinical;programmed cell death ligand 1;programmed cell death protein 1;programs;response;side effect;tumor Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and Mechanisms Underlying Immunotherapy Efficacy and Resistance PROJECT NARRATIVEThis proposal focuses on elucidating the genetic determinants and mechanisms underlying immune checkpointblockade therapy efficacy and resistance. We propose to use a combination of systematic large-scalegenomics preclinical animal modeling integrated immunogenomics profiling and mechanism-directedimmunologic analyses to establish a robust understanding of sensitivity and resistance to immune checkpointblockade. Our studies will build the foundation for the precise and individual application on immunotherapy forcancer patients. NCI 10682519 8/30/23 0:00 PAR-17-494 5R35CA232097-07 5 R35 CA 232097 7 "SOMMERS, CONNIE L" 5/1/20 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 9306964 "CHAN, TIMOTHY AN-THY" Not Applicable 11 OTHER BASIC SCIENCES 135781701 M5QFLTCTSQN6 135781701 M5QFLTCTSQN6 US 41.502657 -81.622127 10000858 CLEVELAND CLINIC LERNER COM-CWRU CLEVELAND OH SCHOOLS OF MEDICINE 441950001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 992049 NCI 633570 358479 PROJECT SUMMARY/ABSTRACTTitle: Towards Precision Immuno-Oncology: Unraveling the Genomic Determinants and MechanismsUnderlying Immunotherapy Efficacy and Resistance Immunotherapy has shown considerable promise for improving outcomes for cancer patients.Treatment of patients with antibodies against CTLA4 PD-1 or PD-L1 can result in dramatic responses anddurable tumor control in some patients. However most patients do not benefit and ICB treatment can causesevere side effects. Therefore it is of paramount importance in the field to understand the mechanismsunderlying sensitivity and resistance to ICB and other immunotherapies. The long-term goal of our researchprogram is to unravel the molecular mechanisms underlying sensitivity and resistance to immunotherapiessuch as ICB and to work towards a better understanding of how to use immunotherapy in a precise andindividualized manner. We propose to investigate how tumor and patient genetics/genomics affect tumorimmune phenotypes and influence the response and resistance to immunotherapies. Over the next 7 yearsour efforts will be focused on addressing three important questions with clear mechanistic and translationalrelevance. First we will undertake a comprehensive analysis of how the diversity of mutational landscapesand densities and DNA damage repair (DDR) deficiencies affect immunotherapy response in cancers treatedwith ICB (anti-PD1 or anti-CTLA4). This is aimed at developing and credentialing a precise model for ICBsensitivity and resistance to allow the design of rationale therapeutic combinations and personalization of ICBtreatment. Second we will use pre-clinical models and patient samples to evaluate how driver mutations incritical DDR mutations influence tumor immunity ICB response and acquired resistance. Third we willcharacterize how the patient germline genotype (HLA) together with somatic mutation profiles of tumorsinfluence response to ICB. 992049 +No NIH Category available Acceleration;Behavior Therapy;Caring;Clinical;Clinical Trials;Collaborations;Communication;Communities;Development;Education;Equity;Ethics;Evaluation;Feedback;Goals;Grant;Healthcare;Healthcare Systems;Hospitals;Infrastructure;Institutional Policy;Lead;Leadership;Maintenance;Methods;Monitor;Newsletter;Oncology;Pilot Projects;Policies;Procedures;Process;Publications;Research;Research Methodology;Research Personnel;Resources;Risk Behaviors;Universities;Work;cancer care;cancer risk;clinical infrastructure;clinical practice;evidence base;experience;informatics infrastructure;insight;interdisciplinary collaboration;operation;organizational structure;pragmatic trial;preference;program dissemination;programs;research study;synergism;telehealth;timeline;tool;treatment services;web site;working group Administrative Core n/a NCI 10682517 7/21/23 0:00 RFA-CA-21-029 5P50CA271353-02 5 P50 CA 271353 2 8/1/22 0:00 7/31/27 0:00 ZCA1-SRB-2 9885 9482269 "GARCIA, SOFIA F." Not Applicable 5 Unavailable 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL Domestic Higher Education 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 250064 156237 93827 Abstract Administrative CoreThe Administrative Core of the Scalable TELeheaLth cancer cARe (STELLAR) Center on Telehealth Researchwill provide the overall organizational and administrative oversight and management of Center activities. Thiswill include developing and applying a cohesive operational framework as well as overseeing the fiscalmanagement evaluation communication and dissemination activities of the Center (including the Researchand Methods Core Rapid Cycle Pilot Studies Clinical Practice Network and Pragmatic Trial). TheAdministrative Core will facilitate STELLAR communications within and beyond the Center (e.g. via a websitee-newsletter and annual retreats). It will create and employ policies and procedures for the organizationalstructure leadership ethical conduct and clinical trials oversight of all Center activities. The AdministrativeCore will develop and implement methods and processes for monitoring the fiscal scientific and disseminationprogress timelines and milestones of all Center components and activities. It will establish and convene anExternal Advisory Board Internal Advisory Board Community Advisory Board and Policy Advisory Group ofkey stakeholders who will help guide the Centers work by identifying strategies that optimize telehealthdelivery maximize the external validity of research findings and support dissemination of project findings andresources. The Administrative Core will be comprised of five components created to direct work integral toCenter goals the: Steering Committee; Operations Team Evaluation Center Equity Working Group andDissemination and Education Committee. The latter will lead efforts to promote opportunities for trainees andearly-stage investigators to participate across Center components and activities. The Administrative Coresaims are to (1): provide management coordination and evaluation of STELLAR components and activitieswithin a cohesive organizational infrastructure; (2) facilitate and oversee communication and engagementacross the Center in order to enhance the research capacity of the proposed studies and sustainability ofclinical tools and programs; and (3) accelerate dissemination of project processes tools and findings (locallyand nationally) in order to advance a robust evidence base for fully integrated telehealth-basedcomprehensive cancer care. Efforts will emphasize synergistic collaborations of transdisciplinary teams towardSTELLARs overarching goal to optimize comprehensive and accessible cancer care by leveraging telehealthdelivery and emphasizing cancer risk behavior treatment services. +No NIH Category available Acceleration;Address;Adopted;Bioconductor;Bioinformatics;Biometry;Cancer Center Support Grant;Clinical;Collaborations;Combined Modality Therapy;Communities;Comprehension;Computer software;Data;Data Coordinating Center;Data Science;Data Set;Databases;Development;Drug Kinetics;Drug resistance;Ecosystem;Ensure;Fostering;Funding;Goals;Hand;Immunooncology;Immunotherapy;Informatics;Information Technology;Infrastructure;Malignant Neoplasms;Methods;Multiomic Data;National Human Genome Research Institute;Patients;Pharmacodynamics;Police;Policies;Principal Investigator;Productivity;PubMed;Records;Reproducibility;Research;Research Personnel;Research Project Grants;Resistance;Resource Sharing;Resources;Services;Text;Therapeutic;Translating;United States National Institutes of Health;Visualization;biobank;biomedical informatics;cancer therapy;cloud based;community engagement;cost;data acquisition;data ecosystem;data harmonization;data integration;data management;data repository;data sharing;data sharing networks;data standards;drug sensitivity;experience;genomic data;improved;interoperability;multidisciplinary;open source;operation;outreach;pharmacokinetics and pharmacodynamics;pre-clinical;predictive marker;quality assurance;real time monitoring;resistance mechanism;response;shared repository;support network;therapy resistant;tool;translational oncology;tumor microenvironment;virtual Coordinating and Data Management Center for Acquired Resistance to Therapy Network Project NarrativeWhile advances in cancer therapeutics have resulted in remarkable clinical responses in some patients acquiredresistance remains one of the biggest challenges towards expanding the clinical benefits to more patients.Tackling acquired therapy resistance will require collaborative efforts to elucidate resistance mechanismscharacterize the tumor microenvironment discover new targets identify predictive biomarkers evaluatecombination therapies and develop real-time monitoring approaches. The goal of our proposed Coordinatingand Data Management Center (CDMC) application is to coordinate the activities across the Acquired Resistanceto Therapy Network (ARTNet) and to manage integrate and disseminate the data and resources generatedthrough the network. Leveraging cutting-edge multi-disciplinary team approaches we will support the ARTNetto inform new strategies that can be better translated to overcome significant challenges in acquired resistanceto cancer therapies. NCI 10682495 8/21/23 0:00 RFA-CA-21-053 5U24CA274159-02 5 U24 CA 274159 2 "SAID, RABIH" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-E(M1) 6773960 "HUTSON, ALAN DAVID" "GOODRICH, DAVID W.; LIU, SONG ; MORGAN, MARTIN T" 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Other Research-Related 2023 1024775 NCI 593580 431195 Project SummaryThe goal of our proposed Coordinating and Data Management Center (CDMC) application is to coordinate theactivities across the Acquired Resistance to Therapy Network (ARTNet) and to manage integrate anddisseminate the data and resources generated through the network. Leveraging cutting-edge multi-disciplinaryteam approaches we will support the ARTNet to inform new strategies that can be better translated to overcomesignificant challenges in acquired resistance to cancer therapies. Our strategy is to enhance the productivity ofARTNet investigators by fostering a collaborative and supportive research community accelerate the progressof ARTNet research by reducing barriers to accessing analytical expertise ensure the reproducibility of ARTNetdata by deploying best practices for data acquisition and harmonization and unleash the full potential of ARTNetactivities by developing enhanced tools to enable resource sharing to the broader scientific community.First we will provide a centralized administrative infrastructure to coordinate ARTNet activities building uponour well-functioning infrastructure that currently coordinates network studies under the umbrella of the NCICancer Moonshot initiatives. Second we will actively promote the ARTNet and engage in trans-consortiuminteractions where we will leverage our demonstrable experience in Cross-Moonshot outreach andBioconductors decades-long record in community engagement. Third we will provide multidisciplinary analyticalexpertise to support ARTNet collaborative research leveraging five of Roswell Park CCSGs shared resources:Biostatistics Bioinformatics Biomedical Informatics Pharmacokinetics/Pharmacodynamics and Data Bank andBioRepository. Our analytical support will be provided at no cost to ARTNet investigators in need of analyticalexpertise based on collaboration transparency and sharing. Fourth we will develop improved data integrationsoftware and workflows to enhance ARTNets research capacity capitalizing on our extensive track-record indeveloping NIH-supported Moonshot Bioconductor and AnVIL ecosystems.The main deliverables from the proposed aims will be administrative and outreach support to coordinatenetwork activities facilitate network collaboration and engage in interaction with the broader community (Aim1); polices and infrastructures to ensure that all resources generated by the ARTNet will be findable in acentralized virtual resource sharing repository and that all resources will be shared with the broader scientificcommunity (Aim 2); workflows to ensure that all data generated by the ARTNet will be harmonized usingstandards interoperable with the broader cancer data ecosystem analysis tools to integrate ARTNet data andfacilitate cross-study analysis within and beyond the ARTNet and multidisciplinary analytical supports toaccelerate ARTNet research progress.(Aim 3). 1024775 +No NIH Category available Address;Androgens;Apoptosis;Attenuated;Caspase;Cell Nucleus;Cell Proliferation;Cell Survival;Cells;Chaperonin 60;Data;Data Analyses;Development;Disease;Generations;Genetic;Genetic Engineering;Gleason Grade for Prostate Cancer;Human;Hypoxia;Immune response;Inhibition of Apoptosis;Knock-out;Knockout Mice;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Mitochondria;Mitochondrial Proteins;Organoids;Patients;Primary Neoplasm;Production;Prognosis;Prostatic Neoplasms;Prostatic Tissue;Proteins;Reactive Oxygen Species;Regulation;Reporter;Research;Resistance;Resistance development;Role;Signal Transduction;Stress;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Uses;Treatment Efficacy;Tumor Burden;activating transcription factor;alternative treatment;androgen sensitive;cancer cell;cancer subtypes;castration resistant prostate cancer;chromatin immunoprecipitation;clinically relevant;docetaxel;enzalutamide;immunogenic cell death;in silico;in vivo;inhibitor;men;neoplastic cell;neuroendocrine phenotype;novel;novel therapeutics;overexpression;patient derived xenograft model;promoter;prostate cancer cell;prostate cancer progression;prostate carcinogenesis;proteostasis;response;standard of care;targeted treatment;therapy outcome;therapy resistant;transcription factor;tumor;tumor growth;tumor progression;tumorigenesis Hsp60 Regulation of Prostate Cancer Progression This proposal will characterize the role of mitochondrial unfolded protein response inprostate cancer progression leading to aggressive disease. The proposed research willdefine the underlying mechanism of mitochondrial regulation of therapeutic resistance andits translational relevance in prostate cancer. The successful completion this study willprovide alternative treatment options for men with this lethal prostate cancer. NCI 10682487 8/28/23 0:00 PA-20-185 5R01CA246437-03 5 R01 CA 246437 3 "SALNIKOW, KONSTANTIN" 9/1/21 0:00 8/31/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 7767901 "CHANDRA, DHYAN " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 377062 NCI 224175 152887 Mitochondrial protein homeostasis (proteostasis) has been implicated in cancer and isregulated by mitochondrial unfolded protein response (UPRmt). However it is unknown whetherUPRmt promotes tumorigenesis and whether it could be targeted for therapeutic benefit in prostatecancer (PCa). This proposal will define how heat shock protein 60 (HSP60) a key component ofUPRmt promotes aggressive and resistant PCa. Using genetically-engineered triple knockout (TKO:deletion of Pten Trp53 and Rb1) tumors we observed that HSP60 is upregulated in aggressivetumors and castration-resistant prostate cancer (CRPC) compared to WT prostatic tissues. TCGAdata analysis and our preliminary data using human PCa-specific TMAs demonstrated that HSP60is upregulated in prostate tumors with higher Gleason Scores. HSP60-silencing induced caspaseactivation and inhibited cellular proliferation whereas HSP60 overexpression promoted cancer cellsurvival and proliferation. We provide the first evidence that genetic deletion of HSP60 in TKOmouse and inhibition of HSP60 oligomerization by introducing HSP60D3G KI during prostatetumorigenesis reduced tumor burden in vivo. We observed that activating transcription factor 5(ATF5) specific for HSP60 expression and UPRmt activation was upregulated with higher GleasonScores and ATF5 was translocated to nucleus during stress. Using in silico analysis we haveidentified a novel UPRmt inhibitor (referred to as DCEM1) which induced robust apoptosis in PCacells and blocked tumor growth in vivo. Based on these findings we hypothesized that HSP60-dependent mitochondrial unfolded protein response promotes cancer cell adaptation duringtumor progression and therapeutic resistance in PCa. Identification of UPRmt inhibitor providesalternative treatment option for patients with PCa. We propose the following Specific Aims to testthis hypothesis. Aim 1. Define the role of transcription factor ATF5 in activating mitochondrial unfolded proteinresponse. Aim 2: Evaluate whether HSP60 oligomerization maintains functional mitochondria andinhibits apoptosis to develop aggressive PCa. Aim 3. Explore the clinical relevance of HSP60inhibition using patient-derived xenografts (PDXs) and primary tumor cells. Impact: The findings will provide fundamental understanding on how UPRmt is activated andhow persistent mitochondrial stress is attenuated by UPRmt leading to development of aggressiveand lethal PCa. Identification of unique UPRmt inhibitor represents a new therapeutic vulnerability inPCa that does not rely on androgen modulation. Therefore UPRmt inhibition by DCEM1 will havegreater therapeutic benefits for patients with androgen-dependent and androgen-independentCRPC. 377062 +No NIH Category available Address;American Cancer Society;Attitude;Cancer Patient;Client satisfaction;Clinical;Clinical Nursing;Clinical Trials;Cluster randomized trial;Communication;Communities;Community Clinical Oncology Program;Community Healthcare;Community Networks;Comprehensive Cancer Center;Consent;Continuity of Patient Care;Control Groups;Counseling;Diagnosis;Disclosure;Distress;Educational process of instructing;Effectiveness;Emotions;Empathy;Evaluation;Family;Foundations;Friends;Funding;General Population;Goals;Guilt;Health;Health Personnel;Hour;Intervention;Lung;Malignant neoplasm of lung;Measures;Medical;Medical History;Nurse Practitioners;Nurses;Oncology;Outcome;Participant;Patient Care;Patient Outcomes Assessments;Patient advocacy;Patient-Focused Outcomes;Patients;Perception;Personal Satisfaction;Physician Assistants;Physicians;Pilot Projects;Provider;Psychosocial Assessment and Care;Pulmonology;Regrets;Reporting;Research;Self Efficacy;Services;Shame;Site;Smoke;Smoker;Smoking;Smoking Behavior;Smoking History;Social isolation;Symptoms;Thoracic Oncology;Thoracic Surgical Procedures;Tobacco Use Cessation;Training;Training Activity;Waiting Lists;Well in self;advocacy organizations;arm;cancer care;cancer diagnosis;care delivery site;care outcomes;care providers;care systems;clinical encounter;clinically relevant;effective intervention;empowerment;experience;former smoker;group intervention;health assessment;help-seeking behavior;improved;multi-site trial;patient-clinician communication;pilot test;pilot trial;primary care provider;primary outcome;psychological distress;psychological outcomes;public health relevance;relapse prevention;response;routine provider;satisfaction;secondary outcome;skills;skills training;social stigma;stem;treatment as usual;uptake Empathic Communication Skills Training to Reduce Lung Cancer Stigma PROJECT NARRATIVEPUBLIC HEALTH RELEVANCE: Research indicates that perceived stigma within medical encounters isprevalent and problematic for lung cancer patients well-being and quality of cancer care. Promoting empathiccommunication appears to be a potentially effective intervention target to help reduce patients perceptions ofstigma within clinical encounters; however no formal trainings exist that focus on teaching empathiccommunication to oncology care providers (OCPs). Building upon favorable findings from a prior R21(R21CA202793) and the importance of developing interventions to address lung cancer stigma our goal is toconduct a national trial of empathic communication skills (ECS) training to facilitate improvements in themedical and psychosocial care of patients through de-stigmatizing interactions with OCPs for patientsdiagnosed with lung cancer. NCI 10682462 9/7/23 0:00 PAR-18-559 5R01CA255522-03 5 R01 CA 255522 3 "VANDERPOOL, ROBIN CLINE" 9/9/21 0:00 8/31/26 0:00 Interdisciplinary Clinical Care in Specialty Care Settings Study Section[ICSC] 10546823 "BANERJEE, SMITA " "OSTROFF, JAMIE S" 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 714650 NCI 403757 310893 PROJECT SUMMARYNearly all (95%) patients diagnosed with lung cancer report perceiving stigma defined as a perception andinternalization of negative appraisal and devaluation by self and others attributable to a lung cancer diagnosis.Prior research indicates that 48% of patients with lung cancer experience stigma during clinical encounterswith their oncology care providers (OCPs) which may be potentially triggered and/or exacerbated by OCPsroutine assessment of smoking history. Perceived stigma has negative effects on patients psychological well-being as well as their medical outcomes. Promoting empathic communication appears to be a potentiallyeffective intervention target to help reduce patients perceptions of stigma within clinical encounters; howeverno formal trainings exist that focus on teaching empathic communication to OCPs. To address this key needwe developed an Empathic Communication Skills (ECS) training focusing on the communication challengesinherent in OCPs discussions of smoking behavior and history with lung cancer patients. Building uponfavorable findings from a prior R21 (R21CA202793) our goal is to conduct a national trial of ECS training tofacilitate improvements in the medical and psychosocial care of lung cancer patients through de-stigmatizinginteractions with OCPs. We will conduct a cluster randomized trial at 16 lung cancer care delivery sitescomparing ECS training (intervention group) with a Waitlist Control Group (WLC) among 160 OCPs (thoraciconcology physicians and advance practice providers) and 960 lung cancer patients (6 patients per clinician).The ECS training will be offered remotely and include all the didactic and experiential training materials thatwere developed for the pilot trial. To increase the real-world generalizability of our trial we will leverage twonational networks of community oncology practices the Care Continuum Centers of Excellence coordinated byour lung cancer patient advocacy partner the Go2 Foundation for Lung Cancer and the Extension forCommunity Healthcare Outcomes (ECHO) sites for lung cancer care supported by an American Cancer SocietyECHO Hub. The aims of this study are (1) to evaluate the impact of the ECS training on OCP primary outcomes(communication and empathic skill uptake) and secondary outcomes (training appraisal relevance noveltyclarity; self-efficacy attitude towards communication with patients); (2) to evaluate the impact of the ECStraining vs. WLC on patients reported primary outcomes (lung cancer stigma) and secondary outcomes(perceived clinician empathy satisfaction with communication psychological distress social isolation andpatients experience of clinical encounter). Additionally acceptance of referral to tobacco cessation (for currentsmokers) and relapse prevention (for former smokers) will be explored; and (3) to examine potentialmoderators of OCP and patient outcomes. Our central hypothesis is that the ECS training will demonstratesignificant improvements in clinicians uptake of empathic skills and self-efficacy and will be superior to WLCwith regards to patient reported measures of stigma clinician empathy satisfaction and overall experience. 714650 +No NIH Category available Acceleration;Antineoplastic Agents;Biochemical;Biological Assay;Biomedical Technology;Cancer Biology;Cell Death;Cell Proliferation;Cell division;Cells;Cellular Stress;Chronic Myeloid Leukemia;Complex;Confusion;Core Protein;Detection;Development;Fluorouracil;Glioblastoma;Goals;Heart Diseases;Histologic;Hybrids;Image;Imaging technology;In Situ;Individual;Label;Life;Literature;Lung;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Measures;Methods;Modeling;Molecular;Molecular Target;Nuclear;Nuclear RNA;Pathology;Pathway interactions;Performance;Process;Proliferating;RNA;RNA Decay;RNA Probes;RNA marker;RNA metabolism;Research;Ribonucleases;S-Phase Fraction;Sampling;Shapes;Solid Neoplasm;Specificity;Stroke;Techniques;Technology;Testing;Time;Tissue Sample;Tissues;Visualization;Work;anticancer research;assay development;biomedical imaging;cancer therapy;cell fixing;exosome;improved;in situ imaging;innovation;innovative technologies;melanoma;molecular imaging;neoplastic cell;novel;novel anticancer drug;proliferation potential;sample archive;tissue fixing;treatment response;tumor In situ assay imaging nuclear RNA exosome activity for cancer studies Narrative StatementThe goal of the proposed research is to introduce a new enabling technology for biomedicalimaging. This will produce a new and useful histological assay with broad application in thedevelopment of more efficient therapies and for molecular research in cancer as well as strokeheart disease and other pathologies. NCI 10682455 9/7/23 0:00 RFA-CA-20-017 5R21CA255979-03 5 R21 CA 255979 3 "LI, JERRY" 9/10/21 0:00 8/31/24 0:00 ZCA1-TCRB-J(M1) 7511453 "DIDENKO, VLADIMIR V" Not Applicable 9 NEUROSURGERY 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 170520 NCI 106575 63945 In situ assay imaging nuclear RNA exosome activity for cancer studiesAbstract The goal of this project is the initial development and demonstration of a new molecular technology whichoffers highly novel measurement and targeting capabilities potentially transformative for cancer research. Thisinnovative approach will enable a new type assessment of molecular mechanisms of RNA turnover essentialfor cancer biology. The project will introduce the first in situ technology capable of labeling the RNA degradingactivity of nuclear RNA exosome. RNA exosome (not to be confused with the unrelated vesicular exosomes) isthe major enzymatic complex controlling RNA metabolism in cells. It is essential for life. Its fundamentalfunction is to keep cells in the proliferating state. An overactive exosome complex leads to higher rates ofcellular proliferation and is implicated in cancer development and progression. It is also a key molecular targetof anticancer therapies. Nuclear RNA exosome activity is critical in assessments of tumor cell stress and celldeath propensity and in evaluating cancer response to therapies. In spite of the high utility of an assay labeling RNA exosome activity in situ in fixed cells and tissuesections presently there is no such imaging technology. The process is currently studied by using bulkbiochemical approaches which have limited value in heterogeneous tissue samples. In this project we will overcome this limitation and will develop the first assay for labeling activity of nuclearRNA exosome in the fixed tissue section format. The project will demonstrate the core functional capabilities ofthe new molecular imaging technology with wide applicability in cancer studies.Specific Aims of the proposal are:1. To develop the first approach for specific labeling of nuclear RNA exosome activity in the fixed tissue sectionformat. The approach will permit visualization of nuclear exosome activity by using the innovative cappedhybrid RNA probe.2. To test and validate the core functional capabilities of the newly developed in situ labeling technique intissue sections from models with activated and normal nuclear RNA exosome activity including glioblastoma.To optimize the new methods specificity sensitivity and assure the robust reliability of detection. 170520 +No NIH Category available Address;Adverse event;Allergic Disease;Antigen Targeting;Antigens;Autoantigens;Autoimmune;Autoimmune Diseases;Autoimmune Responses;Autoimmunity;Biological Markers;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cell Compartmentation;Cells;Characteristics;Clinical;Clone Cells;Collaborations;Cytometry;Data Analyses;Development;Disease;Frequencies;Goals;Heterogeneity;Human;Hypersensitivity;Immune;Immune checkpoint inhibitor;Immune response;Immunophenotyping;Individual;Joints;Knowledge;Longitudinal cohort;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;National Cancer Institute;Oncologist;Oncology;Patient Care;Patients;Phenotype;Play;Positioning Attribute;Property;Regulatory T-Lymphocyte;Role;Sampling;Self Tolerance;Solid Neoplasm;Source;T cell regulation;T cell response;T-Lymphocyte;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Antigens;Work;antigen-specific T cells;autoreactive T cell;biomarker identification;cancer type;checkpoint inhibition;checkpoint therapy;cohort;high dimensionality;immune-related adverse events;improved;individual response;inhibitor therapy;innovation;insight;novel strategies;peripheral blood;pharmacodynamic biomarker;predict clinical outcome;predicting response;predictive marker;programmed cell death protein 1;response;side effect;single-cell RNA sequencing;success;transcriptome sequencing;treatment response;tumor Defining the features of T cell response to tumor and self-antigens as predictors of response to checkpoint therapy PROJECT NARRATIVEImmune checkpoint inhibitors are drugs that have revolutionized the treatment of lung and bladder cancer aswell as other cancer types. Despite their success at improving patient survival they do not work in all patientsand often have serious side effects. The goal of this project is to identify biomarkers that predict immunecheckpoint inhibitor efficacy and/or side effects. NCI 10682446 8/18/23 0:00 RFA-CA-18-019 5R01CA231226-05 5 R01 CA 231226 5 "SONG, MIN-KYUNG H" 9/1/19 0:00 8/31/25 0:00 ZCA1-SRB-K(M2)R 7703043 "BUCKNER, JANE HOYT" "LINSLEY, PETER S" 7 Unavailable 76647908 PK9FMGRDRVD5 76647908 PK9FMGRDRVD5 US 47.609997 -122.329217 8961401 BENAROYA RESEARCH INST AT VIRGINIA MASON SEATTLE WA Research Institutes 981012795 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 845601 NCI 541506 304095 PROJECT SUMMARY/ABSTRACTImmune checkpoint inhibitor therapies have revolutionized the field of solid tumor oncology - in particular theyhave played a substantial role in improving the survival of patients with advanced lung or bladder cancer.However despite clinical successes immune checkpoint inhibitors are not effective in all cases and may beassociated with serious immune-related adverse events. This application is in response to the National CancerInstitutes Provocative Question #8: What are the predictive biomarkers for the onset of immune-related adverseevents (irAE) associated with checkpoint inhibition and are they related to markers for efficacy? The goal of theproposed studies is to identify T cell biomarkers that predict autoimmune-related irAE associated with ICItherapy. The central hypothesis for the proposed studies is that the frequency and phenotype of T cellsspecific for self-antigens predicts autoimmune irAE which in turn predicts therapeutic efficacy in somepatients. The following four Specific Aims will address this hypothesis. Aim 1 studies will determine how immunecheckpoint inhibitor therapy alters the frequency and phenotype(s) of tumor- and autoantigen-specific T cellsusing an innovative approach to isolate antigen-specific T cells and a longitudinal cohort of subjects before andafter immune checkpoint inhibitor therapy. Aim 2 studies will use an innovative single cell RNA-sequencingapproach to determine if expanded T cell clones arise with immune checkpoint inhibitor therapy and whetherthese T cells have phenotypic or functional properties predictive of anti-tumor and autoimmune responses. Aim3 studies will determine whether immune checkpoint inhibitor therapy alters the CD4 and CD8 T cell landscapein cancer making it similar to that seen in individuals with natural autoimmunity. Aim 4 studies will test thehypothesis that immune checkpoint inhibitor therapy releases quiescent autoreactive T cells from regulationleading to increased frequency and activation distinct from the global T cell response. Together these studieswill systematically elucidate the relationship between tumor- and auto- immunity following immune checkpointinhibitor therapy and will provide insight into the potential of T cell biomarkers to predict clinical outcome. 845601 +No NIH Category available Ablation;Affect;Antibodies;Behavior;Binding;Biochemical;CRISPR screen;Cancer cell line;Carcinoma;Cell Communication;Cell Line;Cells;Cessation of life;Communication;Data;Dermal;Development;Exhibits;Fibroblasts;Fibronectins;Genes;Genetic;Heterogeneity;Histologic;Human;Immune;Institution;Integrins;Intrinsic factor;Invaded;Knock-out;Knowledge;Ligands;Link;Malignant - descriptor;Malignant Neoplasms;Mediating;Mentorship;Minority;Modeling;Molecular;Morbidity - disease rate;Multiplexed Ion Beam Imaging;Neoplasms;Neoplastic Keratinocyte;Oncogenic;Organoids;Pathway interactions;Patients;Physicians;Pre-Clinical Model;Process;Prognosis;Recurrence;Research;Risk;Role;Scientist;Signal Transduction;Site;Skin;Skin Cancer;Stromal Cells;Stromal Invasion;Therapeutic;Tumor Cell Invasion;Tumor Promotion;United States;Universities;Unresectable;Up-Regulation;Work;Xenograft procedure;cancer cell;cancer genetics;cancer type;cell type;cohort;connective tissue growth factor;genetic manipulation;genetic signature;in vivo;keratinocyte;mouse model;mutant;neoplastic cell;novel;novel therapeutic intervention;prevent;receptor;single-cell RNA sequencing;skin squamous cell carcinoma;transcriptomics;treatment strategy;tumor;tumor growth;tumor heterogeneity;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Cancer Cell-Extrinsic and Intrinsic Regulators of Tumorigenesis PROJECT NARRATIVE Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer overall in the United Statesof which a substantial number of cases are unresectable and lack treatment options. Therapeutic strategies arelimited in part due to poor understanding of how intratumoral heterogeneity (ITH) arises and triggers invasivebehavior in cSCC but recent work suggests that factors from the tumor microenvironment (TME) and cancercell-intrinsic factors both contribute to ITH. This work aims to identify specific crosstalk pathways between thetumor and TME that lead to invasion and tumor progression to aid in developing therapeutic strategies to disablethese processes. NCI 10682445 8/29/23 0:00 PA-20-203 5K08CA263187-03 5 K08 CA 263187 3 "BIAN, YANSONG" 9/2/21 0:00 8/31/26 0:00 Career Development Study Section (J)[NCI-J] 15204667 "JI, ANDREW " Not Applicable 13 DERMATOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 217004 NCI 200930 16074 PROJECT SUMMARY/ABSTRACT Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer overall in the U.S. andcauses substantial morbidity with a significant risk of metastatic spread and death. Treatment options are limitedin unresectable cases which are estimated at up to 40000 per year. Advances in treatment have been hinderedby incomplete knowledge of intratumoral heterogeneity (ITH) in cSCC particularly regarding how different tumorsubpopulations behave within a growing tumor. ITH can be driven by cell-intrinsic abnormalities within cancercells but increasing evidence suggests that cancer cells communicate with diverse cell types such as immuneor stromal cells in the tumor microenvironment (TME) to coordinate malignant behavior such as invasion. Thusa deeper understanding of how ITH arises in cSCC from both TME and cell-intrinsic contributions has thepotential to yield new treatment strategies. Recent discovery of a novel subpopulation of cSCC tumor cells was facilitated through single-cell profiling ofpatient cSCC tumors. This tumor-specific keratinocyte (TSK) subpopulation was found to express a genesignature that was absent in normal skin suggestive of invasive capacity and associated with worse prognosisacross several epithelial cancers. Spatial profiling demonstrated that TSKs resided at the tumor leading edgeadjacent to cancer-associated fibroblasts (CAFs) suggesting that crosstalk among these cell types in the TMEmay control TSK cell state or function. Global ligand-receptor analyses integrating single-cell and spatial datanominated specific CAF-derived ligands matched with receptors expressed by TSKs including several integrins.Integrin signaling genes mediating TME signals were required for tumor growth in CRISPR screens in vivoincluding ITGB1 FERMT1 CD151 and ARPC2. Thus these data support a model in which signals derived fromTME cells proximal to TSKs promote tumorigenesis and potential invasion through ITGB1-mediated signaling. Through two specific aims this work will determine if blocking cSCC-specific CAF-derived factors anddisabling cancer subpopulation-intrinsic factors can impede TSK formation and subsequent tumor invasion andprogression in preclinical models. Aim I will employ a human organoid model of cSCC to assess the contributionof CAF-derived ligands toward emergence of TSKs and invasion through genetic ablation and therapeuticblockade. Aim II will determine how TSK subpopulation-specific factors cooperate to facilitate invasion inorganoids and tumorigenesis in xenograft mouse models through genetic manipulation of cancer cells to preventfactor interaction. This work will be performed under the mentorship of Dr. Paul Khavari a physician-scientistand expert in skin cancer genetics at Stanford University a world-class research institution. These studies couldaid the development of novel therapeutic strategies to treat unresectable cSCC and lead to a deeper molecularunderstanding of pathways enabling tumor invasion heterogeneity and progression. 217004 +No NIH Category available ADAMTS;Address;Amino Acids;Antibodies;Antigen-Presenting Cells;Autologous Stem Cell Transplantation;Avian Leukosis Virus;Binding;Bone Marrow;Bone Marrow Stem Cell Transplantation;CRISPR/Cas technology;Carcinoma;Cell Density;Cell secretion;Cells;Coupled;Cytometry;Dendritic Cells;Distal;Eligibility Determination;Engraftment;Equilibrium;Extracellular Matrix;FDA approved;FLT3 ligand;Generations;Goals;Hematologic Neoplasms;Hematopoietic Neoplasms;Human;IL17 gene;IL6 gene;Immune;Immunity;Immunologics;Immunomodulators;Immunotherapy;In Vitro;Inferior;Infiltration;Interleukin-10;Investigation;Knowledge;Lentivirus Vector;Ligands;MEKs;Macrophage;Maintenance;Mediating;Modeling;Multiple Myeloma;Mutate;Myelogenous;Myeloid Cells;N-terminal;Oral;Parents;Pathway interactions;Patients;Physiological;Process;Protein Isoforms;Proteoglycan;Proteolysis;Regulatory Pathway;Relapse;Reporting;Resolution;Revlimid;Role;Safety;Signal Transduction;Site;TLR2 gene;Testing;Thalidomide;Therapeutic;Transcript;Transplantation;Vertebral column;adverse outcome;analog;cell growth;cytokine;design;experimental study;extracellular;immunoregulation;in vivo;inhibitor;lenalidomide;macromolecule;molecular targeted therapies;neutralizing antibody;novel;paracrine;polarized cell;prevent;relapse patients;relapse prevention;response;standard of care;success;therapeutic target;transplantation therapy;treatment strategy;tumor;versican Tumor matrix remodeling in anti-myeloma immunity and immunotherapy PROJECT NARRATIVEMultiple myeloma (MM) is the second most common hematological malignancy. Despite the incorporation ofnovel agents in the autologous stem cell transplant (ASCT) backbone for MM treatment MM remains incurable.In this application we propose to target a novel immune regulatory pathway the versican (VCAN) pathway inorder to optimize post-ASCT therapy for myeloma and thus to prevent or delay relapses. NCI 10682439 7/20/23 0:00 PA-19-056 5R01CA252937-04 5 R01 CA 252937 4 "HOWCROFT, THOMAS K" 7/1/20 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 9506934 "ASIMAKOPOULOS, FOTIOS " Not Applicable 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 506049 NCI 325659 180390 PROJECT SUMMARY/ ABSTRACTMultiple myeloma (MM) ranks as the second most common blood cancer and it remains incurable. Autologousstem cell transplantation (ASCT) remains a mainstay of therapy for eligible patients. Despite the routine use ofnovel agents as post-ASCT maintenance to delay or prevent relapse most patients will succumb aftertransplant. There is considerable body of evidence to suggest that immunoregulatory mechanisms establishedin post-ASCT bone marrow (BM) microenvironment favor relapse and constitute attractive therapeutic targets.Post-ASCT relapses depend on tolerogenic IL10-producing myeloid cells (dendritic cells (DC) and macrophagescollectively referred to as tol-DC) and IL17 proposed to act on MM cells in a cell-autonomous manner. Howeverthe upstream signals or microenvironmental triggers that elicit these processes are unclear.Tol-DC polarization and Th17 differentiation are promoted through Toll-like receptor (TLR)-2 signaling. Wepreviously reported that MM-accessory cells secrete the TLR2-ligand matrix proteoglycan versican (VCAN).VCAN promotes tol-DC polarization in carcinomas and therefore it constitutes a prime suspect for triggeringrelapse-promoting TLR2-dependent processes in MM.In the MM microenvironment specifically post-ASCT VCAN undergoes ADAMTS-mediated extracellularproteolysis to release an N-terminal fragment versikine. Versikine acts as a matrikine (an extracellular matrix-derived fragment that regulates cell activity often in a manner distinct from that of its parent macromolecule).Versikine is a weak IL6/IL10 trigger therefore it is unlikely to be a potent tol-DC/Th17 inducer. Instead versikinestimulates IRF8-dependent transcripts and promotes the IRF8-dependent Batf3-DC subset in vitro and in vivo.We hypothesize that the versikine-IRF8-Batf3-DC axis may engage the potent (and perhaps dominant)tolerogenic VCAN-TLR2 pathway in a dynamic crosstalk.We have delineated 2 specific Aims to investigate the mechanisms by which VCAN and versikine regulate anti-MM immunity post-ASCT: In Aim 1 we shall dissect VCAN-TLR2 signaling in anti-MM immunity and designnovel post-ASCT treatment strategies based on targeting tolerogenic VCAN-TLR2 signaling. In Aim 2 we shallstudy in-depth the role of the matrikine versikine in anti-MM immunity.Success of our Aims will optimize MM treatment (maintenance) strategies to prolong post-ASCT survival. Theexperiments proposed here are facilitated by our recent generation of the first Ras-driven MM model VQ. RASpathway is the most commonly mutated pathway in human MM. In contrast to current state-of-art MM modelsVQ is readily transducible by lentiviral vectors and engrafts in C57BL/6J recipients (facilitating mechanistic invivo studies). Several of the studies proposed here have been impossible or impractical using existing MMmodels. 506049 +No NIH Category available Acceleration;Acute Lymphocytic Leukemia;Acute T Cell Leukemia;Adopted;Adult;Advisory Committees;Animals;B-Cell Acute Lymphoblastic Leukemia;Biopsy;Bone Marrow;Bone Marrow Aspiration;Cancer Patient;Cells;Characteristics;Child;Childhood;Childhood Acute Lymphocytic Leukemia;Clinic;Clinical;Clinical Trials;Data;Diagnosis;Disease;Drug Combinations;Drug Kinetics;Drug Monitoring;Drug resistance;Engraftment;Ensure;Evaluation;Experimental Models;Exposure to;Failure;Foundations;Funding;Future;Gene Expression Profiling;Government;Health Benefit;Heterogeneity;Human;Immune;Industry Collaboration;Infant;Infiltration;Lesion;Leukemia Lymphocytic Acute L2;Leukemic Cell;Liver;Luciferases;MLL-rearranged leukemia;Malignant Childhood Neoplasm;Manuscripts;Measures;Methodology;Methods;Modeling;Molecular;Monitor;Mus;Mutation;New Agents;Organ;Outcome;Outcomes Research;PTPRC gene;Patients;Performance;Ph+ ALL;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Philadelphia Chromosome;Play;Preclinical Testing;Preparation;Publications;Quality Control;Quality of life;Relapse;Reproducibility;Research;Research Personnel;Resources;Role;SNP genotyping;Schedule;Spleen;Statutes and Laws;Systemic disease;T-Lymphocyte;Tail;Testing;Time;Toxic effect;Transplantation;United States National Institutes of Health;Variant;Veins;animal imaging;bioluminescence imaging;clinical development;cost estimate;data submission;design;drug response prediction;drug testing;early phase clinical trial;exome sequencing;experience;experimental study;flexibility;follow-up;high risk;improved;improved outcome;in vivo;in vivo evaluation;lentivirally transduced;leukemia;novel;novel therapeutics;patient derived xenograft model;peripheral blood;pre-clinical;programs;public-private partnership;response;skills;standard of care;transcriptome sequencing;treatment response NCI Pediatric In Vivo Testing Program - Leukemia Project NarrativeThis application seeks renewal of funding for a Research Program for acute lymphoblastic leukemia(ALL) in vivo testing as part of the NCI Pediatric In Vivo Testing Program (Ped-In Vivo-TP). Bycompleting the major objectives outlined in this proposal the long term health benefit aims to improvethe treatment options and quality of life for children with aggressive forms of ALL who would otherwisesuccumb to their disease. NCI 10682420 7/4/23 0:00 RFA-CA-20-034 5U01CA199000-08 5 U01 CA 199000 8 "SMITH, MALCOLM M" 8/1/15 0:00 6/30/26 0:00 ZCA1-GRB-I(M1) 10156377 "LOCK, RICHARD B" Not Applicable n/a Unavailable 751020900 QHAHG1WUM3J1 751020900 QHAHG1WUM3J1 AS -33.86785 151.20732 5905701 UNIVERSITY OF NEW SOUTH WALES SYDNEY Unavailable 2052 AUSTRALIA N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 454977 NCI 538419 43074 Project Summary/AbstractThis application seeks renewal of funding for a Research Program for acute lymphoblastic leukemia(ALL) in vivo testing as part of the NCI Pediatric In Vivo Testing Program (Ped-In Vivo-TP). Recent USGovernment legislation combined with the relative rarity and higher cure rates of childhood cancercompared with adults emphasize the importance of new agent preclinical testing programs aimed atmaximizing the likelihood that only the most active drugs will be advanced into early phase clinical trials.The broad aim of this application is to improve the treatment options for children with aggressive and/ordrug resistant ALL by prioritizing new drugs for clinical trials in the disease using state-of-the-artpreclinical experimental models. This aim will be accomplished using a large panel of 90 pediatric ALLpatient-derived xenografts (PDXs) that have undergone a high level of cell and molecularcharacterization and authentication. The PDXs to be used in this study were all established as models of orthotopic disease in immune-deficient (NOD/SCID or NSG) mice from direct patient explants without prior ex vivo culture. The PDXsdevelop as systemic disease in NSG mice and infiltrate the same major organs in mice as the primarydisease in human patients. Engraftment and responses to treatment are monitored by measuring theproportion of human leukemia cells in the peripheral blood of mice on a weekly basis which provides areliable representation of overall leukemia burden in the animals. Where luciferase-expressing PDXsare available this testing will be augmented by bioluminescence imaging of animals. The broad methodology will involve inoculation of PDX cells into NSG mice a lag time to allow thedisease to establish followed by drug treatment and monitoring to assess drug responses. Methods ofresponse evaluation have been developed using stringent criteria modeled after the clinical setting inorder to minimize the likelihood of over-predicting drug responses in mice leading to failure of drugs inthe clinic. The proposed drug testing will adopt multiple formats including conventional drug testing (6-10 mice/group) single-mouse trial testing (1 PDX x 1 mouse x 1 drug) and testing of new agents incombination with standard-of-care drugs. In this fashion this Research Program aims to test 8-10 newagents per year. By completing the major objectives outlined in this proposal the long term health benefit aims toimprove the treatment options and quality of life for children with aggressive forms of ALL who wouldotherwise succumb to their disease. 454977 +No NIH Category available Automobile Driving;Bathing;Cancer Center;Cancer Patient;Clinic;Clinical;Clinical Trials;Devices;Dose;Equipment;Hospitals;Hour;Hybrids;Immobilization;Individual;Infrastructure;Joints;Methods;Modeling;Organ;Outcome;Patients;Photons;Physicians;Procedures;Protons;Radiation therapy;Radiotherapy Research;Recording of previous events;Risk;Speed;Structure;System;Technology;Testing;Toxic effect;Travel;Treatment Cost;Uncertainty;Work;cancer radiation therapy;clinical application;deep learning;improved;innovation;novel;prospective;simulation;success;synergism;treatment planning;treatment site Novel Optimization Methods and Treatment Planning System for Clinically-Deliverable Truly-Hybrid Proton-Photon Radiotherapy Project Narrative This project will develop truly-2D proton-photon joint optimization methods for clinically-deliverable truly-hybrid RT with unprecedented superior plan quality to proton-only and photon-only RT and first-of-its-kind TPSto bridge truly-hybrid RT from research to clinic. This hybrid TPS can facilitate prospective clinical trials of abroad spectrum of treatment sites for many patients. If succeed truly-hybrid RT via this first-of-its-kind TPS willlikely warrant improved clinical outcomes with reduced OAR toxicities and potentially become a new paradigmfor cancer RT in general with compelling benefits in both treatment cost and clinical outcomes. NCI 10682384 9/1/23 0:00 PA-20-185 5R37CA250921-04 5 R37 CA 250921 4 "OBCEMEA, CEFERINO H" 4/1/21 0:00 8/31/26 0:00 Radiation Therapeutics and Biology Study Section[RTB] 15658128 "GAO, HAO " Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 16060860 YXJGGNC5J269 16060860 YXJGGNC5J269 US 39.026584 -94.636347 1484303 UNIVERSITY OF KANSAS MEDICAL CENTER KANSAS CITY KS SCHOOLS OF MEDICINE 661608500 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 347471 NCI 224175 123296 Project Summary Radiotherapy (RT) aims to deliver tumoricidal dose to clinical target volume (CTV) while sparing organs atrisk (OAR) for which proton and photon beams are naturally complementary to each other: protons aregenerally better for OAR sparing while photons are more robust to delivery uncertainties for CTV coverage.The hybrid proton-photon RT has a long history. However as it generates proton and photon plans separatelywithout fully utilizing joint proton-photon optimization during the planning stage current hybrid RT is pseudo-hybrid and very limited in plan quality treatment sites and broad applicability. The key to leapfrog frompseudo-hybrid to truly-hybrid RT is new joint proton-photon optimization method that synergizescomplementary proton and photon beams. The hypothesis is that truly-hybrid RT via appropriate joint proton-photon optimization will be more favorable than proton or photon-only RT in terms of CTV coveragerobustness and OAR sparing optimality. Broad applicability of truly-hybrid RT to patients: (A) Clinical applicability: unlike pseudo-hybrid RT that islimited in plan quality and treatment sites truly-hybrid RT may become a new paradigm for general cancer RTowing to its superior plan quality and thus potentially clinical outcomes to proton-only or photon-only RT.(B) Clinical workflow: our truly-hybrid plans can be individually and safely delivered on existing proton andphoton machines and this effort envisions patients being treated in an integrated cancer center like ours withboth proton and photon equipment under the direction of a single physician using shared immobilizationdevices simulation procedure and structure set and integrated treatment planning and delivery system.(C) Patient coverage: truly-hybrid RT can be made broadly available to many cancer patients through existinginfrastructures in US since (1) most hospitals with proton centers also have photon centers; (2) 76% of cancerpatients live in the states with operational proton centers while 85% are within 100-mile (2-hour-driving)distances to these proton centers; (3) cancer patients are more willing to travel for advanced treatment options. Proposed effort: Inspired by unprecedented plan quality and broad applicability of truly-hybrid RT via ourjoint proton-photon optimization method the next step is to test the hypothesis prospectively via clinical trials.However a missing prerequisite to advance truly-hybrid RT from research to clinic is a treatment planningsystem (TPS) that can generate clinically-deliverable hybrid plans. To meet this urgent need this effort willdevelop novel optimization methods and TPS for clinically-deliverable truly-hybrid RT which is a radical steptowards prospective clinical trials for testing the hypothesis. Aim 1: Optimization methods and TPS for clinically-deliverable truly-hybrid RT. Aim 2: Optimization methods for accurate and efficient MCO truly-hybrid planning. Aim 3: Deep learning based optimization methods for efficient truly-hybrid planning. 347471 +Cancer; Prevention; Prostate Cancer; Urologic Diseases African American population;Asian population;Biological Assay;Biological Markers;Clinical;Detection;Early Detection Research Network;Early Diagnosis;Family member;Gleason Grade for Prostate Cancer;Hispanic Populations;Laboratories;Malignant Neoplasms;Malignant neoplasm of prostate;Minority;Monoclonal Antibodies;Mutate;Oncogenic;Pathologic;Resources;Specificity;Specimen;Testing;Validation;cohort;gene product;improved;overexpression;validation studies;verification and validation Early Detection Research Network (EDRN) Biomarker Reference Laboratory n/a NCI 10682368 ACN17005001-1-0-1 Y01 15244058 "CREENAN, CDFM-A, MICHAEL " Not Applicable n/a Unavailable NATIONAL CANCER INSTITUTE Other Domestic Non-Profits UNITED STATES N Interagency Agreements 2022 498374 NCI The CPDR Biomarker Reference Laboratory will share unique resources such as a minority enriched cohort for verification and validation of panel/s of Early Detection Research Network developed biomarkers that are fitted to improve early detection among African Americans Hispanics and Asians; continue to develop monoclonal antibodies and clinical grade assays to detect oncogenic rearrangements of ETS family members and other frequently mutated or overexpressed gene products in prostate cancer (SPOP CHAD1 AR etc.); support pre-validation and validation studies of promising EDRN developed biomarkers; support longitudinal testing of validated biomarkers to improve the panels specificity in detection of aggressive prostate cancers; and to support centralized pathological examination of specimens for EDRN related pre-validation and validation studies to better determine which biomarkers could be used to predict significant progression from Gleason score 6 cancers to 7+ cancers. 498374 +No NIH Category available ATAC-seq;Adult;Animal Model;Animals;Automobile Driving;Binding;Biological Assay;Biological Models;Cancer Patient;Cell Differentiation process;Cells;Chemoresistance;Child;Childhood;Chromatin;Complement;Coupling;DNA Binding;Data;Development;Developmental Gene;Diagnosis;Disease;Drug Targeting;Embryo;Embryonal Rhabdomyosarcoma;Embryonic Development;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Generations;Genes;Genetic;Genome engineering;Genomics;Growth;Human;Individual;Invaded;Knock-out;Knowledge;Lead;Life;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mass Spectrum Analysis;Mesoderm Cell;Mission;Modeling;Molecular;Morbidity - disease rate;Mus;Muscle;Muscle Development;Muscle satellite cell;Myoblasts;Myogenic Regulatory Factors;Neoplasm Metastasis;Normal Cell;Patients;Pediatric Neoplasm;Pediatric Oncology;Persons;Phenotype;Physicians;Play;Proliferating;Proteins;Public Health;Research;Rhabdomyosarcoma;Role;Scientific Advances and Accomplishments;Scientist;Soft Tissue Neoplasms;Survival Rate;System;Techniques;Testing;Tissue Differentiation;Tissues;Toxic effect;Treatment-related toxicity;Tumor stage;Undifferentiated;Work;Xenograft procedure;Zebrafish;cancer cell;childhood cancer survivor;chromosome fusion;cofactor;design;epigenomics;experience;experimental study;gain of function;genome-wide;human model;insight;knock-down;knockout gene;malignant phenotype;migration;mortality;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;overexpression;pharmacologic;pre-clinical;precursor cell;progenitor;programs;sarcoma;side effect;small molecule inhibitor;stem;stem cells;targeted treatment;therapeutic development;tool;transcription factor;transcriptomics;treatment strategy;tumor;tumor growth;tumor progression Reprogramming myogenic regulatory factors in RMS to promote differentiation and halt growth NarrativeThe proposed research is relevant to public health because understanding themechanism of Embryonal Rhabdomyosarcoma progression is expected to deepen ourunderstanding of how developmental transcription factors are reactivated in disease andto provide evidence that targeting these developmental genes (which are no longerrequired in most differentiated cells) may be a novel means to inhibit RMS without theassociated toxicities of most therapies. Such toxicities can be particularly devastating tochildren and thus novel therapies developed through the generation of unique animalmodels such as human xenograft into mice and zebrafish models are clearly needed toidentify new means to treat the disease. Thus the proposed research is relevant to theNCI mission that pertains to advancing scientific knowledge and helping all peopleto live longer healthier lives. NCI 10682281 5/16/23 0:00 PA-20-185 1R01CA275187-01A1 1 R01 CA 275187 1 A1 "YASSIN, RIHAB R" 5/16/23 0:00 4/30/28 0:00 Special Emphasis Panel[ZRG1-BTC-W(02)M] 1889696 "FORD, HEIDE L." "ARTINGER, KRISTIN " 6 PHARMACOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 5/16/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 672698 NCI 478602 194096 SummaryRhabdomyosarcoma (RMS) accounts for 3-4% of all pediatric cancers with less than a 30% overall 5-year survivalrate for children diagnosed with metastatic RMS. Sarcoma patients also experience higher rates of morbidity andmortality than other cancer patients and this is particularly evident in children. As a result of their therapies 42%of childhood cancer survivors experience severe disabling or life threatening conditions including secondarytumors. Thus there is clearly a need to develop new more targeted treatment strategies for pediatric tumorssuch as RMS; treatments that inhibit tumor progression yet confer limited side effects. In many cancersembryonic programs including the acquisition of stem/progenitor states are instituted to contribute to tumorprogression. Such reinstatement or retention of developmental programs may be a key driving factor inEmbryonal Rhabdomyosarcoma (ERMS which are generally fusion negative and also referred to as FN-RMS).In RMS high expression of myogenic-lineage transcription factors (TF) MYOD1 and MYOG is observed.However despite high expression of these TFs RMS cells fail to differentiate. Instead these TFs drive the RMSmalignant phenotype since knockout of these MRFs results in lethality to the RMS cell. Thus a key unansweredquestion in the field is why and how the myogenic regulatory factors (MRFs) depart from their canonical roles asdrivers of muscle differentiation to instead maintain RMS cells in an undifferentiated state. In this proposal weare examining whether SIX1 a critical TF that regulates muscle development is responsible for globally alteringthe function of MRFs. Our data show that elevated SIX1 expression promotes FN-RMS progression and growthby promoting an RMS progenitor-like state. Intriguingly SIX1 knockdown induces a muscle differentiationsignature concomitant with re-localization of key MRFs genome-wide. These data suggest that in FN-RMS SIX1overexpression alters MRF function promoting an RMS progenitor-like phenotype and enhancing tumor growthand progression. Thus in this proposal we will test the following hypothesis: SIX1 and its obligate cofactorsEYA2/3 cooperatively drive the progression of FN-RMS by altering the genomic landscape causing MRFsto favor growth over differentiation. Since SIX1 expression in differentiated tissues is low targeting it maytherefore be a means to inhibit FN-RMS with limited side effects to untransformed cells where SIX1 isdispensable. Specific aims are as follows: 1) To determine the molecular mechanism by which SIX1 serves asa master regulator of the muscle progenitor vs differentiated state in development and in RMS. 2) To identify thecritical SIX1 cofactors (with a focus on EYA proteins) that when targeted can induce differentiation and inhibitRMS growth. This work will take advantage of normal developmental regulatory mechanisms to inhibit the tumorand thus may have limited toxicity due to the paucity of SIX/EYA expression in adult tissue. Our ability to combinezebrafish and human models will maximize the benefits of each model system to rapidly and inexpensivelyidentify means to inhibit RMS growth and progression. Understanding the mechanisms by which RMS cells aretrapped in an early developmental state may therefore lead to novel means to target the disease. 672698 +No NIH Category available Ablation;Adjuvant;Adjuvant Therapy;Anti-CD47;Architecture;Attenuated;Automobile Driving;B-Lymphocytes;Beds;Biological Models;CD4 Positive T Lymphocytes;CD47 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Cell Adhesion;Cells;Clinical;Clinical Trials;Clone Cells;Common Terminology Criteria for Adverse Events;Cytotoxic Chemotherapy;Data;Dependence;Disease-Free Survival;Dose;Enteral Feeding;Excision;Frequencies;HPV oropharyngeal cancer;Head and Neck Squamous Cell Carcinoma;Heterogeneity;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Immune;Immunocompetent;Immunologic Surveillance;Immunotherapy;In complete remission;Incidence;Infiltration;Lymphatic;Malignant Neoplasms;Measures;Metastatic/Recurrent;Morbidity - disease rate;Neck Dissection;Neoadjuvant Therapy;Nivolumab;Nodal;Operative Surgical Procedures;Outcome;PD-1 inhibitors;Pathologic;Patients;Phase;Phase I Clinical Trials;Pre-Clinical Model;Primary Neoplasm;Quality of life;Radiation;Radiation therapy;Radioimmunotherapy;Randomized;Research;Resectable;Risk;Safety;Sentinel Lymph Node;Structure of germinal center of lymph node;T cell clonality;T cell infiltration;T-Lymphocyte;Therapeutic;Throat Cancer;Toxic effect;Treatment Protocols;Tumor Antigens;Tumor Expansion;Tumor Immunity;Tumor Volume;United States;Up-Regulation;anti-PD-1;anti-PD1 therapy;anti-cancer;antigen-specific T cells;arm;cancer immunotherapy;cancer infiltrating T cells;chemokine;chemoradiation;chemotherapy;cytotoxic CD8 T cells;design;draining lymph node;head and neck cancer patient;immune activation;immune checkpoint blockade;immune function;improved;inhibitor;irradiation;lymph nodes;novel;pembrolizumab;phase I trial;phase II trial;pre-clinical;preservation;programmed cell death protein 1;response;standard of care;trial comparing;tumor;tumor ablation Neoadjuvant immunoradiotherapy for HPV mediated oropharynx cancer NarrativeCancer immunotherapies have led to major treatment breakthroughs for a number of different cancers but themajority of head and neck cancer patients do not respond to immunotherapies and clinical responses are oftennot durable. We have demonstrated that targeting tumors with stereotactic radiation in combination withimmunotherapy while sparing draining lymphatics enhances anticancer immunity resulting in significantlyimproved response profiles. The research outlined in this proposal will leverage targeted tumor radiation and acombination of anti-CD47 and anti-PD-1 therapy to improve the response to PD-1 inhibitor immunotherapy inhuman papilloma virus related cancers of the throat. NCI 10682257 9/18/23 0:00 PAR-21-033 1R01CA281286-01 1 R01 CA 281286 1 "VIKRAM, BHADRASAIN" 9/18/23 0:00 7/31/28 0:00 Special Emphasis Panel[ZRG1-TIR-W(01)Q] 1900169 "CALIFANO, JOSEPH A" Not Applicable 50 SURGERY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 9/18/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 644774 NCI 470900 173874 Project SummaryHPV mediated oropharynx cancer (HPVOPC) is projected to increase in incidence in the United States over thenext 20 years. Attempts to de-escalate nonsurgical treatment for HPVOPC have not been successful and currenttreatment regimens incur significant long-term morbidity. Recently PD-1 inhibitors received approval as first linetherapy for recurrent/metastatic head and neck squamous cell carcinoma (r/mHNSCC) achieving ~15-20%overall response rates. However PD-1 inhibition has demonstrated no benefit in patients with previouslyuntreated locally advanced HPVOPC/HNSCC and emerging neoadjuvant window of opportunity trialsexamining PD-1 inhibition have documented only modest response. Targeting stereotactic body radiation(SBRT) to the tumor while sparing the tumor draining lymphatics may increase the response to PD-1 inhibitionas part of a novel rational therapeutic strategy. In support of this hypothesis we have shown that ablating tumor-draining lymphatics blocks the response to PD-1 inhibition and that elective nodal irradiation attenuates antitumorimmunity and T cell infiltration in multiple experimental HNSCC model systems. In addition we found that earlybut not delayed lymphatic ablation blocks the response to combined SBRT and PD-1 inhibition indicating thatan immunologically competent draining lymph node bed is critical to mount effective antitumor immunity afterPD-1 inhibition. We explored this premise in our recent Phase 1 clinical trial in resectable HNSCC patients whoreceived nivolumab in combination with SBRT to gross tumor volume (GTV) followed by definitive surgicalresection (NCT03247712). Astonishingly the pathologic complete response rate in HPV+ patients was 90% andno patient required adjuvant radiation or chemoradiation. In addition the combination of a CD47 inhibitor(evorpacept) with PD-1 inhibition shows enhanced response compared to PD-1 inhibition alone in both preclinicalmodels and in r/mHNSCC. Our overall hypothesis is that preserving the immune-lymphatic axis duringneoadjuvant immunoradiotherapy (NIRT) for HPVOPC will promote anti-tumor immunity potentiate checkpointblockade therapy and reinstate effective cancer immunosurveillance. Therefore we propose a phase IIb singlearm clinical trial of neoadjuvant 8Gy x 3 SBRT to GTV followed by combination evorpacept and pembrolizumabin patients with previously untreated locally advanced resectable HPVOPC followed by risk adapted adjuvanttherapy. We specifically hypothesize that combination neoadjuvant SBRT and evorpacept + pembrolizumab will1) provide >80% complete/major pathologic response in patients with resectable HPVOPC 2) is safe and willresult in functional and quality of life metrics that are similar or better to those for patients treated with standardtherapy and 3) enhance cytotoxic CD8 T cell antitumor immunity by driving the priming and expansion of tumor-reactive T cells along the tumor-immune-lymphatic axis. A high pathologic response rate and favorabletoxicity profile in the proposed trial will support a subsequent paradigm-shifting randomized phase IItrial comparing nonsurgical treatment with SBRT to GTV followed by immunotherapy versus standardof care radiation with concurrent cytotoxic chemotherapy. 644774 +No NIH Category available 3-Dimensional;Acceleration;Acrylamides;Address;Affect;Affinity;Baptist Church;Binding;Biochemical;Biological;Biological Assay;Cancer cell line;Cell Culture Techniques;Cell Line;Cell membrane;Cells;Chemicals;Chronic;Clinical;Clinical Trials;Complex;Comprehensive Cancer Center;Computer Analysis;Computer Models;Crystallography;Cysteine;Data;Development;Drug Design;Environment;Exhibits;FDA approved;Fluorescence;Foundations;Frequencies;Future;Gene Frequency;Genetic;Goals;Guanine Nucleotides;Human;Hydrogen Peroxide;In Situ;In Vitro;KRAS oncogenesis;KRAS2 gene;KRASG12D;Kinetics;Knowledge;Ligands;Ligation;Location;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medicine;Methods;Modeling;Modification;Molecular Conformation;Mutate;Mutation;Non-Small-Cell Lung Carcinoma;Nucleotides;Oncogenic;Operative Surgical Procedures;Organoids;Output;Oxidants;Oxidation-Reduction;Pathologic;Patient Care;Patients;Pharmaceutical Preparations;Physiological;Positioning Attribute;Predisposition;Production;Property;Protein Isoforms;Proteins;Publications;RAS genes;Reaction;Recombinant Proteins;Sampling;Series;Signal Transduction;Site;Smoking;Specimen;Spectrum Analysis;Sulfinic Acids;System;Technology;Testing;Therapeutic;Time;Tissues;Treatment Efficacy;Tumor Tissue;Work;adduct;bench to bedside;cell growth;clinical development;clinical efficacy;cold temperature;covalent bond;dosage;drug discovery;experimental study;forest;improved;inhibitor;lung cancer cell;molecular dynamics;mutant;next generation sequencing;novel strategies;oxidation;preclinical efficacy;prevent;ras Proteins;resistance mechanism;response;scaffold;spatiotemporal;targeted treatment;therapy development;therapy resistant;thioether;treatment response;tumor;tumorigenesis KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition NARRATIVEDespite RAS proteins being frequently mutated in human cancers (~25%) efforts to develop targetedtherapies against RAS proteins have been largely unsuccessful until recently (06/21) when FDA approved thefirst drug to shut down the activity of a cysteine-containing oncogenic mutant of RAS that is prevalent inpatients with advanced non-small cell lung cancer. This is the first in a rapidly expanding set of relatedinhibitors under development which take advantage of the reactivity of cysteine (C12 in the case of KRASG12C) to permanently attach drugs to target proteins. We propose studies to investigate the underlyingmechanism of RAS inactivation by these inhibitors and how oxidation modulated by the tumor environmentmay impact the response to treatment by taking a comprehensive bench-to-bedside approach based on novelapproaches and high-end technologies. NCI 10682167 2/1/23 0:00 PA-20-185 1R01CA281295-01 1 R01 CA 281295 1 "FU, YALI" 3/1/23 0:00 2/29/28 0:00 Macromolecular Structure and Function A Study Section[MSFA] 1898880 "CAMPBELL, SHARON L" "FURDUI, CRISTINA MARIA; POOLE, LESLIE B" 4 BIOCHEMISTRY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 395 Non-SBIR/STTR 2023 582947 NCI 484758 98189 ABSTRACTInhibition of oncogenic KRAS is a highly pursued goal in drug discovery efforts as RAS mutations are found in~25% of human cancers. One key oncogenic KRAS mutation (KRASG12C) contains a reactive cysteine at ahotspot location is the fourth most prevalent mutation in KRAS-driven tumors and is found at particularly highfrequency (40% of RAS mutations 13% overall) in non-small cell lung cancer (NSCLC). Excitement hasaccelerated rapidly around the discovery and application of covalent Cys12-specific inhibitors of KRASG12C inrecent years as these compounds have shown efficacy in advanced clinical trials with Sotorasib (AMG510LUMAKRAS) recently receiving FDA approval for treatment of locally advanced or metastatic NSCLC.However the kinetic mechanisms underlying the activity of this class of inhibitors remain poorly understoodimpeding rational drug design efforts. To address this gap in knowledge we developed a new fluorescence-based approach to kinetically characterize the reactions of the proteins with these acrylamide-based inhibitors.Intriguingly we find that the two clinical compounds AMG510 (Amgen) and MRTX849/Adagrasib (MiratiTherapeutics) possess distinctly different kinetic properties which we propose to investigate in further detailhere. Recognizing the oxidative environment promoted by oncogenic KRAS signaling and tumorigenesis wealso evaluated the redox sensitivity and oxidative status in cells and found that Cys12 of KRASG12C is prone tooxidation. Moreover oxidation at this site prevents inhibitor attachment suggesting that redox modification ofKRASG12C may constitute a mechanism of resistance to AMG510 and other covalent inhibitors. Otherunanswered questions remain in the field including the propensity of the protein-drug adducts to undergochemical reversibility of the Michael addition reactions through which they bind and how this could be affectedby altered acrylamide warheads. Aim 1 proposes structural and kinetic studies combined with computationalmodeling and molecular dynamics simulations to elucidate the differential mechanisms of KRASG12C inhibitorengagement inactivation and reversal. As development of treatment resistance remains a significant hurdle fortargeted inhibition strategies Aims 2 and 3 propose to investigate the linkage between the redox sensitivity ofKRASG12C and inhibitor efficacy by measuring functional signaling-relevant outputs for recombinant proteins andbiological samples (lung cancer cell lines and patient-derived organoids). For Aim 2 lung cancer cells undervariably oxidizing conditions with and without inhibitor present will be assessed for KRASG12C modifications anddownstream signaling outputs; use of HyPer-DAAO genetic constructs with targeting to the plasma membranewill allow spatiotemporal and dosage control over hydrogen peroxide production within cells near KRASG12C. InAim 3 the relationship between tumor redox properties and inhibitor efficacy will be investigated using freshNSCLC tumor specimens carrying KRASG12C mutations. Cumulatively the results will provide improved under-standing of the drugs and will serve as a platform for characterizing and developing future direct KRAS inhibitors. 582947 +No NIH Category available Address;Age;Attention;Biological;Black American;Black Populations;Black race;California;Cancer Etiology;Cause of Death;Cessation of life;Characteristics;Clinical Practice Guideline;Collaborations;Colon;Colonoscopy;Colorectal Cancer;Communities;Data;Data Element;Death Rate;Detection;Diagnosis;Diagnostic;Disadvantaged;Disease Outcome;Disparity;Early Diagnosis;Education;Ethnic Origin;Ethnic Population;Evaluation;Foundations;Goals;Guidelines;Health;Improve Access;Incidence;Indigenous;Information Systems;Intervention;Interview;Intestines;Location;Longitudinal trends;Malignant Neoplasms;Medicare/Medicaid;Methods;Modeling;Native Americans;Operative Surgical Procedures;Outcome;Patients;Pattern;Persons;Phase;Population;Positioning Attribute;Preparation;Prevention;Process;Productivity;Race;Reporting;Research;SEER Program;Screening Result;Standardization;Survival Rate;Testing;Treatment outcome;United States;United States Preventative Services Task Force;Variant;Woman;Work;adenoma;attributable mortality;cancer health disparity;cohort;colorectal cancer risk;colorectal cancer screening;disparity elimination;ethnic minority;ethnic minority population;experience;follow-up;health equity;human very old age (85+);implementation evaluation;implementation strategy;innovation;member;men;models and simulation;mortality;mortality disparity;multidisciplinary;older men;older women;public health priorities;racial disparity;racial minority;racial minority population;racial population;screening;screening program;sex;social;social disparities;social factors;social group;sociodemographics;success;therapy design Addressing Disparities in Outcomes of Screening for Colorectal Cancer in Community-Based Settings PROJECT NARRATIVEColorectal cancer is the second leading cause of cancer death in the United States and disparities in mortalityby race and ethnicity persist. This application seeks to elucidate why colorectal cancer disparities may persisteven when similar rates of screening have been achieved by comprehensively evaluating the entire screeningcontinuum from the tests used and screening quality to follow-up care and guideline-concordant treatment in adynamic cohort of about 3.8 million people per year over the 2003-2019 17-year period. We will perform mixed-methods studies among people 45-85 years old in Kaiser Permanente in both Northern and Southern Californiaand model the extent to which differences along the screening process cumulatively contribute to disparities. NCI 10682099 5/4/23 0:00 PA-20-185 1R01CA278052-01A1 1 R01 CA 278052 1 A1 "MARCUS, PAMELA M" 5/4/23 0:00 4/30/28 0:00 Cancer and Hematologic Disorders Study Section[CHD] 8656295 "DOUBENI, CHYKE ABADAMA" "CORLEY, DOUGLAS ALLEN" 3 FAMILY MEDICINE 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 5/4/23 0:00 4/30/24 0:00 393 Non-SBIR/STTR 2023 700356 NCI 621262 79094 PROJECT SUMMARY/ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer deaths inthe United States and although the overall CRC mortality rate has been decreasing disparities have persistedparticularly for Black and Native American people. CRC screening is highly effective and there is a welcomenational attention on improving access to screening for groups that are socially disadvantaged. However thebenefits of screening depend on receiving both high-quality testing and timely follow-up care when abnormal.Thus disparities may persist even when rates of participation in screening are similar across populations.Recently the US Preventive Services Task Force highlighted a gap in the understanding of CRC disparities andthe relative lack of interventions that have been shown to eliminate disparities by race and ethnicity. The goalof this application is to inform feasible and effective strategies for advancing health equity by elucidating theextent to which differences in care along the entire screening process cumulatively contribute to disparities. Wewill comprehensively evaluate the entire screening continuum from the tests used and screening quality toreceipt of follow-up care and guideline-concordant treatment in a cohort of about 3.8 million people per yearover a nearly 2-decade period in Kaiser Permanente Northern California (KPNC) and Kaiser PermanenteSouthern California (KPSC). We will use a mixed methods approach informed by health equity frameworks toexamine: 1) the receipt and quality of screening for CRC including follow-up when abnormal; 2) post-screeningtreatment and disease outcomes including interval CRCs 5-year survival and age-standardized incidence andmortality overall and by location; 3) the reasons for variations in quality and timely follow-up using qualitativeinterviews; and 4) the relative contributions of differences along the screening continuum to disparities inmortality by using microsimulation modeling. We will conduct our studies in a dynamic cohort of 45-85-year-oldmen and women in KPNC/KPSC during the 2003-2019 period. The members of KPNC and KPSC mirror thecharacteristics in terms of social factors of people in the regions served across California. The completecapture of all screening steps and diverse well-defined populations enable studies of strategies across thescreening continuum among social groups. Our analyses will compare the racial and ethnic groups andstratifications by race for each outcome over a nearly 2-decade period. We will interview patient-clinician dyadsto elucidate reasons for variations in quality follow-up and outcome. We will also use the MISCAN-Colonmicrosimulation model to examine the extent to which disparities in mortality are attributable to differences foundacross each step in the screening continuum. The proposed research has a high potential to inform theprioritization of strategies for advancing health equity across disadvantaged racial and ethnic minority groupsand thus advance a national public health priority. The 1 decades of high-impact collaboration in our teamand the setting and rigor of our application support the feasibility and high potential for impact in the field. 700356 +No NIH Category available Adoption;Bilateral;California;Clinic;Clinical;Clinical Data;Clinical Investigator;Computer software;Data;Data Set;Diagnosis;Diagnostic;Dose;Environment;Evaluation;Feedback;Generations;Healthcare;Human;Hybrids;Image;Injections;Investigation;Label;Lesion;Liver;Mathematics;Modeling;Noise;Organ;Patients;Performance;Physicians;Positron-Emission Tomography;Procedures;Production;Provider;Research;Research Personnel;Scanning;Services;Site;Structure;System;Techniques;Testing;Time;Training;Translating;Translations;University Hospitals;Validation;Vendor;Visual;X-Ray Computed Tomography;artificial intelligence algorithm;clinical decision-making;clinical imaging;clinical practice;deep learning;deep learning model;diagnostic accuracy;experience;imaging modality;improved;industry partner;learning network;learning strategy;real world application;reconstruction;virtual;virtual model Multi-Center Academic-Industrial Partnership for Personalized Al-Enabled High Count PET Project Narrative Through this multi-center AIP project we will develop a robust deep learning-based software solution andintegrate into the clinical PACS system to convert any clinical PET image into a high-quality counterpart withmuch lower image noise levels that can only be obtained with >90min long scan or extremely long field-of-viewscanners. The translation into PACS servers with one-button convenient workflow will lead to fast clinicaladoption and substantially benefit clinical practice to improve diagnostic accuracy and increase decisionconfidence. NCI 10682066 5/5/23 0:00 PAR-20-155 1R01CA275188-01A1 1 R01 CA 275188 1 A1 "AVULA, LEELA RANI" 5/5/23 0:00 4/30/28 0:00 Special Emphasis Panel[ZRG1-ISB-S(57)R] 10611481 "LIU, CHI " "BADAWI, RAMSEY D.; EL FAKHRI, GEORGES ; LIN, MINGDE " 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 5/5/23 0:00 4/30/24 0:00 394 Non-SBIR/STTR 2023 669658 NCI 574473 95185 Abstract High image noise degrades the diagnostic efficacy and quantitative accuracy of PET as noise could easilyresults in overestimation of SUV and cause false positive lesion detections in diagnosis. High image noise alsodecreases the confidence of clinical decision making leading to additional unnecessary follow-ups through otherimaging modalities and invasive procedure. Deep learning-based noise reduction has shown promises for PETimaging. However existing approaches only focus on converting low-count image (e.g. acquired through low-dose injection or shorter scan time) to standard-count image in typical clinical scans. However for both low-count and the vast majority of routinely acquired clinical PET images with normal dose and scan time there isno approach to convert such clinical images to high-count images to further reduce the image noise mainly dueto the challenge of obtaining high-count PET images as training labels. Another challenge in the real-worldapplication is to match the training data with the testing data in terms of noise level noise structurereconstruction parameters scanner model etc. Such matching is particularly challenging in a multi-center multi-scanner setting. In this Academic-Industrial Partnership R01 project we formed an ideal partnership betweenVisage Imaging a leading PACS company and three leading academic centers (Yale MGH UC Davis) todevelop evaluate deploy and translate robust deep learning methods to generate virtual-high-count PETimages in a highly personalized manner by taking into account the noise level of each organ in each patient aswell as associated non-imaging patient information. The academic sites have access to a large number of high-count data that are acquired either through long dynamic scans (at least 90 minutes) or by the ultra-sensitivelong axial field-of-view (FOV) Explorer scanner. The developed product would be deep learning networks thatcan convert any clinical PET images data from all major vendors (Siemens GE United Imaging Healthcare(UIH)) into virtual-high-count ultra-low noise images. Since Yale MGH and UC Davis are all serviced by VisageImaging the developed deep learning technique can be seamlessly translated into Visage PACSresearch/clinical servers for validation and evaluation beta testing and user feedback and ultimate translationand regulatory filings. In Aim 1 we will develop deep learning models for virtual-high-count PET generation. InAim 2 we will evaluate and deploy the models into Visage research PACS server and evaluate virtual-high-countPET in clinical environments. In Aim 3 we will integrate the developed virtual-high-count PET deep learningmodels into the clinical production PACS server and generate regulatory documents and supporting data forFDA 510(k). 669658 +Biotechnology; Cancer; Clinical Research; Health Disparities; Minority Health Applications Grants;Archives;Award;Biopsy Specimen;Cancer Center;Cancer Model;Cancer Patient;Characteristics;Clinical;Clinical Trials;Colorectal Cancer;Communities;Consent Forms;Development;Diagnostic;Disease;Funding;Generations;Genetic Fingerprintings;Goals;Grant;Growth;Human;Institution;Investigation;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Metastatic/Recurrent;Modeling;Molecular;Moon;Neoplasm Metastasis;Operative Surgical Procedures;Pathologic;Patients;Positioning Attribute;Pre-Clinical Model;Precision therapeutics;Primary Neoplasm;Procedures;Public Health;Recording of previous events;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Specimen;Study models;Testing;Texas;Translational Research;Universities;University of Texas M D Anderson Cancer Center;anticancer research;biomarker-driven;cancer subtypes;cancer therapy;clinically relevant;drug sensitivity;exome sequencing;fighting;human tissue;improved;malignant breast neoplasm;molecular subtypes;next generation sequencing;novel therapeutics;patient derived xenograft model;pre-clinical;programs;quality assurance;repository;standard of care;transcriptome sequencing;tumor PDX Core n/a NCI 10681978 9/21/22 0:00 RFA-CA-17-003 3U54CA224065-04S2 3 U54 CA 224065 4 S2 "WITHERSPOON, KIM" 9/30/17 0:00 6/30/23 0:00 ZCA1-RTRB-E 9858 1972016 "FANG, BINGLIANG " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 96544 59595 36949 Abstract The goal of the PDX Core is to provide high-quality clinically relevant and molecularly annotated PDX models for the research projects described in the University of Texas PDX Development and Trial Center (UTPDTC) grant application by leveraging PDX resources at our institutions and developing new PDX models using rigorous quality standards so that the models can be used to guide clinical trial development. Because of U54 funding limitations and to keep things as simple as possible this U54 PDX Core will only function at the MD Anderson Cancer Center which has more than enough surgical specimens coming in to fulfill the needs of this grant. The existing UTSW PDX lung cancer models (~40) developed through the NCI SPORE in Lung Cancer (P50CA70907) will be used by UTSW in Project 1 and new and existing UTMDACC PDX models created by the PDX Core at MDACC will be supplied to the various projects including for the UTSW component of Project 1. The PDX models developed and/or characterized under this UTPDTC grant will be available to other cancer researchers through the NCI Patient-Derived Models Repository and PDX Development and Trial Centers Research Network (PDXNet). We are in a unique position to provide high-quality PDX models for studies described in this grant application and for the cancer research community. Our research team has established 506 PDX models from human lung breast colorectal and pancreatic cancers and completed whole exome sequencing and RNA sequencing for 176 and 94 of these models respectively. We are currently participating in the NCI's collaborative initiative on PDX models through two separate NCI supplemental awards. We will use the rigorous quality standards developed by the NCI to generate and characterize PDX models and provide high- quality PDX models for preclinical investigations. Furthermore we will enhance the diversity of PDX models for answering clinical and/or translational questions by leveraging the world-class translational expertise and access to human tissues unique to our institutions for generating new PDX models. For example more than 20000 surgical procedures and 50000 diagnostic and/or treatment procedures are performed annually at UTMDACC. Our patient consent forms have already been reviewed by NCI staff and are appropriate for sharing PDXs with the cancer research community through NCI's Patient-Derived Models Repository and PDXNet. To achieve our goal of supporting the UTPDTC projects and PDXNet activities we will provide high-quality clinically and molecularly annotated PDXs after rigorous quality testing of established PDX models and enhance the diversity of PDX models by generating and characterizing new models. The proposed study has significant public health implications because providing the highest quality PDX models for the preclinical investigations described in this application and to the cancer research community will ultimately improve and accelerate the development of new effective biomarker-driven cancer therapies helping cancer patients fight their disease. +Biotechnology; Cancer; Clinical Research; Genetics; Health Disparities; Lung; Lung Cancer; Minority Health; Precision Medicine; Women's Health Academic Medical Centers;Antineoplastic Agents;Area;Biologic Characteristic;Biological Markers;CDKN2A gene;Cancer Patient;Clinical;Clinical Trials;Coenzyme A Ligases;Collaborations;Complex;Coupled;DNA Sequence Alteration;Data;Development;Drug Combinations;Drug Targeting;Failure;Family member;Gene Amplification;Genomics;Goals;Growth Factor Receptors;Human;Investigational Drugs;Joints;KRAS oncogenesis;KRAS2 Gene Mutation;KRAS2 gene;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Medical;Medical center;MicroRNAs;Mitogen-Activated Protein Kinase Kinases;Modeling;Molecular;Molecular Abnormality;Moon;Mutation;Non-Small-Cell Lung Carcinoma;Normal Cell;Nuclear Export;Oncogenes;Outcome;Patient-Focused Outcomes;Patients;Positioning Attribute;Precision medicine trial;Precision therapeutics;Predisposition;Primary Neoplasm;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Public Health;Quality of life;RAS genes;Radiation therapy;Reporting;Research;Research Project Grants;Resistance;STK11 gene;Signal Transduction;Solid Neoplasm;Subgroup;System;TP53 gene;Testing;Texas;Therapeutic;Therapeutic Agents;Therapeutic Effect;Therapy Evaluation;Translating;Universities;anticancer activity;base;cancer biomarkers;cancer cell;cancer therapy;cancer type;chemotherapy;clinically relevant;docetaxel;druggable target;early phase clinical trial;fatty acid oxidation;improved;ineffective therapies;inhibitor;innovation;kinase inhibitor;lung tumorigenesis;molecular marker;molecular subtypes;mutant;next generation sequencing;novel therapeutic intervention;overexpression;patient derived xenograft model;pre-clinical;precision medicine;predictive marker;programs;receptor;response;screening;small molecule;small molecule libraries;success;targeted treatment;therapeutic development;therapeutically effective;transcription factor;treatment responders;treatment response;tumor Research Project 1: PDX-based trials of precision medicine for treatment of KRAS mutant lung cancers n/a NCI 10681976 9/21/22 0:00 RFA-CA-17-003 3U54CA224065-04S2 3 U54 CA 224065 4 S2 "WITHERSPOON, KIM" 9/30/17 0:00 6/30/23 0:00 ZCA1-RTRB-E 9856 1972016 "FANG, BINGLIANG " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 97231 60019 37212 Abstract The objective of this project is to develop effective precision medicine for treatment of KRAS-mutant non-small cell lung cancer (NSCLC) by determining responses of molecularly characterized patient-derived xenograft (PDX) models with or without KRAS mutations to targeted therapeutic agents. The priority will be given to the agents in the NCI Investigational New Drugs (NCI-IND agents) portfolio to increase the success of early-phase clinical trials in patients with KRAS-mutant NSCLCs. The central hypothesis of the proposed study is that a large set of well-characterized KRAS-mutant NSCLC PDXs that recapitulate multiple characteristics of the biological context of human KRAS-mutant cancers will provide a preclinical platform for identifying effective therapeutic strategies for KRAS-mutant NSCLC and molecular biomarkers capable of identifying treatment responders. Activating mutations of the KRAS gene are known to be among the major genomic alterations associated with lung adenocarcinoma. Thus far treatment of KRAS-mutant NSCLC remains an unmet medical need. Moreover development of active anticancer drugs is challenged by high failure rates caused by a lack of preclinical tumor models highly predictive of therapeutic effects in humans and of biomarkers that identify responders in clinical trials. We will overcome this challenge by determining the therapeutic activities of targeted drugs and identifying potential predictive biomarkers capable of identifying responders to those agents in clinically and molecularly annotated PDX models derived from NSCLC. Our research team has extensive expertise in establishing NSCLC PDXs molecularly characterizing PDXs and primary tumors developing novel therapeutic strategies for NSCLC and translating effective preclinical therapeutic strategies for clinical trials. We have generated 190 NSCLC PDXs and completed genomic characterization of 82 PDXs (22% with oncogenic KRAS mutations) and their respective primary tumors. Together our team is positioned to make a major contribution to the overall objectives of the NCI's PDXNet to generate data on PDX models to support early clinical trials of precision therapies. To that end we propose three specific aims: 1) determine molecular subtypes of NSCLC PDXs with KRAS mutations; 2) determine responses of NSCLC PDX models with or without KRAS mutations to treatment with investigational new drugs approved for patient use with priority given to the NCI-IND agents; and 3) characterize molecular biomarkers and the mechanistic relationship between molecular subtypes and treatment responses. The proposed studies are highly relevant to the following Research Areas of NCI's PDX Development and Trial Centers: 1) mechanism-based drug combinations in treatment of genetically defined tumor subgroups that explore the correlation of genetic abnormalities with tumor response; and 2) mechanisms that contribute to the sensitivity or resistance of PDX models to therapeutic agents. The success of the proposed studies will lead to effective precision therapy for KRAS-mutant lung cancers for which current therapies are ineffective. +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Colo-Rectal Cancer; Digestive Diseases; Genetics; Health Disparities; Minority Health; Pancreatic Cancer; Precision Medicine; Rare Diseases; Women's Health Aftercare;Biochemical;Biological Assay;Biological Markers;Biological Models;Biopsy Specimen;CDK4 gene;Cancer Center;Cancer Therapy Evaluation Program;Cell Line;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical effectiveness;Colorectal;Colorectal Cancer;Complex;Coupled;Cytotoxic Chemotherapy;Data;Development;Drug Combinations;Enrollment;Event;Exhibits;Expression Profiling;Extinction (Psychology);Failure;Feedback;Financial compensation;Future;Gene Expression;Generations;Genes;Genetic Transcription;Goals;Heterogeneity;Human;KRAS2 Gene Mutation;KRAS2 gene;Lead;Link;MEKs;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Methods;Modeling;Molecular;Mutation;Organoids;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Play;Pre-Clinical Model;Preclinical Testing;Primary Cell Cultures;Probability;Ras/Raf;Regimen;Research Personnel;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;System;Testing;Texas;Therapeutic;Tissues;Translating;Tumor Tissue;United States Food and Drug Administration;Universities;anticancer activity;base;biological heterogeneity;cancer initiation;cancer therapy;clinical efficacy;clinical predictors;clinical translation;clinically relevant;cohort;combinatorial;design;drug sensitivity;drug testing;effectiveness evaluation;improved;in vivo;inhibitor;innovation;molecular subtypes;mutant;novel;novel drug combination;patient derived xenograft model;patient stratification;predictive marker;protein expression;resistance mechanism;response;response biomarker;success;targeted treatment;tissue culture;transcriptome sequencing;treatment strategy;tumor;tumor microenvironment;tumor xenograft Project 2: Building Combinatorial Therapies against KRAS-mutant Colorectal and Pancreatic Cancer n/a NCI 10681975 9/21/22 0:00 RFA-CA-17-003 3U54CA224065-04S2 3 U54 CA 224065 4 S2 "WITHERSPOON, KIM" 9/30/17 0:00 6/30/23 0:00 ZCA1-RTRB-E 9855 8210070 "KOPETZ, SCOTT " Not Applicable 9 Unavailable 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX Domestic Higher Education 770304009 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 96541 59593 36948 Abstract Activating mutations of the KRAS gene are found in ~90% of pancreatic (PDAC) and ~50% of colorectal (CRC) cancers. However therapeutic strategies designed to counter or extinguish KRAS signaling remain unsuccessful. Redundant signaling pathways and a complex solid tumor microenvironment are key barriers to current KRAS targeting efforts. Most conventional drug testing targeting KRAS has commonly used conventional cell line systems that lack clinical relevance and biological heterogeneity and thereby failed in patients. More recently patient-derived models including primary cell cultures organoids or spheroids have been deployed in large screens designed to identify effective combination regimens. Since patient-derived models more clinically representative lead single agents or combinations are exhibiting a higher likelihood of translational success. Our approach long-term goal is to establish and test agents using patient-derived xenografts (PDX) coupled with an ex-vivo tumor tissue culture assay that more effectively tests drug sensitivity. Using this ex-vivo method we tested 36 drug combinations against a panel of 10 PDAC PDX tumors to identify drug combinations that demonstrate synergistic effects. These combinations include MEK inhibitors along with multi-kinase inhibitor suntinib or CDK4/6 inhibitors. Synergistic anticancer activity using MEK-CDK4/6 combinations also occurs in our CRC PDX models that have translated to an ongoing clinical trial. Our preliminary studies and ongoing clinical trial provide a strong rationale to further test these combinations in large cohorts of PDXs. In the proposed study we aim to: 1) determine the effectiveness of the MEK inhibitor-based combinations through in vivo PDX trials; 2) establish and characterize PDXs from patients enrolled in a clinical trial that combines MEK and CDK4/6 inhibitors; and 3) identify biomarkers of responding tumors and explore the mechanisms of resistance. The identification of lead combinations in studies using clinically relevant patient-derived model systems predicts a higher chance of success in future clinical studies. In addition all proposed test agents are approved for use against cancer or are being evaluated in the clinical trials. Thus there is a high probability that these efforts will be quickly translated to the clinic and rapidly benefit PDAC and CRC patients. +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome; Networking and Information Technology R&D (NITRD) Address;Antineoplastic Agents;Benchmarking;Bioinformatics;Biological Models;Biomedical Research;Cancer Biology;Cancer Patient;Clinical Trials;Clinical Trials Design;Cloud Computing;Collaborations;Communities;Computer software;Consensus;Coordination and Collaboration;Credentialing;Data;Data Analyses;Data Commons;Data Coordinating Center;Data Discovery;Data Set;Data Storage and Retrieval;Databases;Development;Drug resistance;Engineering;Environment;Experimental Designs;Genomics;Goals;Individual;Laboratories;Leadership;Malignant Neoplasms;Methods;Modeling;Molecular;National Cancer Institute;Ontology;Patients;Performance;Pharmaceutical Preparations;Phenotype;Pilot Projects;Precision therapeutics;Public Health;Recording of previous events;Reproducibility;Research;Research Personnel;Resource Sharing;Resources;Risk;Secure;Specimen;Standardization;System;Technology;The Jackson Laboratory;Training Activity;United States National Institutes of Health;Work;Xenograft procedure;anticancer research;cancer genomics;cancer therapy;clinical practice;cloud based;cohesion;computer infrastructure;cost;data mining;data resource;data sharing;data standards;design;drug efficacy;experience;genomics cloud;improved;innovation;large datasets;large scale data;leadership development;meetings;outreach;patient derived xenograft model;pre-clinical;precision oncology;repository;response;symposium;synergism;tool Data Coordination Center for PDX Net RELEVANCE TO PUBLIC HEALTHTo realize the full promise of patient-derived xenografts (PDXs) to advance precision therapies for cancerstandardized PDX procedures and coordinated sharing of PDX specimens is needed to validate results acrossresearch groups and determine which results may be robust for cancer patients. To address this need we willbuild and administer a PDX Data Commons and Coordination Center that will unify the activities of NIH-supported PDX Development and Trial Centers and the National Cancer Institutes Patient-Derived ModelsRepository. Our Data Commons and Coordination Center will use innovative administrative cloud computingand bioinformatic approaches to enable PDX method standardization model sharing data sharing andmassive-scale data analysis. NCI 10681868 9/22/22 0:00 RFA-CA-17-004 3U24CA224067-04S1 3 U24 CA 224067 4 S1 "HENDERSON, LORI A" 9/25/17 0:00 8/31/23 0:00 ZCA1-RTRB-E(A1) 8556573 "CHUANG, JEFFREY HSU-MIN" "DAVIS-DUSENBERY, BRANDI NICOLE" 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 9/1/21 0:00 8/31/23 0:00 353 Other Research-Related 2022 794406 NCI 482074 312332 PROJECT SUMMARYPatient-derived xenografts (PDXs) are a powerful model system for assessing drug efficacy of anti-canceragents and understanding molecular mechanisms of drug resistance. However results from individualresearch groups have been difficult to validate due to the lack of standardized PDX procedures lack of scalefor adequately powered PDX studies and the inability to efficiently share PDX specimens. A key contributor tothis challenge is the lack of well-managed resources for community sharing and large-scale analysis ofintegrated standardized datasets from PDX models. The JAX-Seven Bridges PDX Data Commons andCoordination Center (PDCCC) seeks to address this challenge and unite the efforts of the component data-generating (PDX Development and Trial Centers/PDTCs) and PDX model sharing (NCIs Patient-DerivedModel Repository/PDMR) parts of the PDX Development and Trials Centers Research Network (PDXNet) intoa cohesive trans-Network whole. Using innovative cloud computing and bioinformatic approaches ourPDCCC will provide administrative and computational infrastructure for PDXNet to enable PDX methodstandardization model sharing data sharing and massive-scale data analysis. We will build a data storagesharing and analysis platform that harmonizes PDXNet data with other large datasets and analysis workflowsavailable in the NCI Cancer Genomics Cloud. Simultaneously we will administer planning meetings trainingactivities and research pilots to build synergies within the PDXNet enhancing the ability of the PDXNet todevelop clinical trials from PDX studies. Our Specific Aims are to 1) establish a leadership andadministration unit to manage and coordinate activities within PDXNet including annual meetingsregular conference calls training activities trans-Network pilot projects and outreach; 2) develop a cloud-integrated PDXnet Data Commons that integrates PDXNet data with the existing cloud-based data analysisplatform - the Seven Bridges Cancer Genomics Cloud (SB-CGC); and 3) build analysis workflows and datasharing practices to optimize PDXNet research and enable PDXNet data to facilitate clinical trial design. Toaccomplish these Aims we have assembled a team with unique expertise in PDXs cancer treatment genomicanalysis data coordination and project management from The Jackson Laboratory and Seven Bridges. Ourcombined institutional strengths include a history of leadership in (and commitment) to PDX data resourceanalytic and consensus standards development and application; practical expertise in PDX model sharing andcollaborative community efforts; a broad array of statistical bioinformatic and software-related PDX resources;leadership expertise in large-scale cloud-based biomedical data projects notably the SB-CGC; and deepexperience in high-performance database engineering and development. Our goal is to build an innovativesystematically organized PDCCC that will advance the efforts of PDXNet to improve the validityand expanduseof the PDX system as a preclinical platform for precision oncology. 794406 +Cancer; Clinical Research; Emerging Infectious Diseases; Hematology; Hodgkin's Disease; Infectious Diseases; Lymphatic Research; Lymphoma; Rare Diseases; Tuberculosis AIDS-Related Lymphoma;Address;Algorithms;Autopsy;Biological Assay;Biopsy;Cause of Death;Cessation of life;Characteristics;Chemotherapy-Oncologic Procedure;Chromosomes;Classification;Clinical;Clinical Trials;Consent;Control Groups;Country;Coupled;DNA;Deterioration;Diagnosis;Diagnostic;Diagnostic Procedure;Disease;Enrollment;Ensure;Epstein-Barr Virus-Related Lymphoma;Evaluation;Excision biopsy;Fine needle aspiration biopsy;General Population;HIV;HIV Infections;Histologic;Hodgkin Disease;Hospitals;Human Herpesvirus 4;Immunoglobulins;Inferior;Infrastructure;Knowledge;Laboratories;Lead;Lymphoma;Malignant Neoplasms;Measures;Modernization;Molecular;Mutation;Newly Diagnosed;Observational Study;Odds Ratio;Operative Surgical Procedures;Organ;Outcome;Participant;Pathologic;Patient Triage;Patients;Pattern;Performance;Performance Status;Persons;Plasma;Population Study;Predictive Value;Prognosis;Progression-Free Survivals;Reporting;Resources;Risk Factors;Role;Sensitivity and Specificity;Somatic Mutation;South Africa;South African;Specificity;Specimen;Symptoms;Techniques;Testing;Time;Tuberculosis;Tumor Markers;Validation;antiretroviral therapy;base;cancer care;chemotherapy;co-infection;cohort;cost;diagnostic algorithm;diagnostic strategy;experience;follow-up;high risk;improved;infection rate;lymph nodes;minimally invasive;molecular diagnostics;molecular marker;mortality;novel diagnostics;programs;prospective;response;standard of care;treatment response;tuberculosis diagnostics;tuberculosis treatment;tumor;tumor progression Hodgkin Lymphoma in PLWH in South Africa: TB EBV and Tumor Molecular Markers PROJECT NARRATIVEWe propose to investigate factors that may contribute to poor outcomes in Hodgkin lymphomain people living with HIV in South Africa where the difference in outcomes is striking. Presentevidence suggests that at least part of the difference in outcomes reflects long delays inHodgkin lymphoma diagnosis in PLWH. As such we will develop and test a new diagnosticalgorithm based on plasma tumor molecular markers that may expedite the diagnosis ofHodgkin lymphoma in PLWH. NCI 10681861 9/1/22 0:00 RFA-CA-19-032 3R01CA250069-03S1 3 R01 CA 250069 3 S1 "LIDDELL HUPPI, REBECCA" 4/1/20 0:00 3/31/25 0:00 ZCA1-SRB-1(J2) 1942371 "AMBINDER, RICHARD FREDERICK" "XIAN, RENA " 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 310 Non-SBIR/STTR 2022 104391 OD 63750 40641 PROJECT SUMMARY Hodgkin lymphoma (HL) outcomes in PLWH in South Africa (S.A.) are inferior to those in HIV(-) patientsalthough outcomes compare favorably in clinical trials. Advanced stage disease and consistent EBV-associationare well recognized in PLWH. In S.A. at the time of diagnosis some PLWH are in such poor clinical conditionthat they are not treated. Diagnostic delays contribute to late presentations as HL diagnoses require surgicalbiopsies for a definitive pathologic evaluation. Resources and infrastructure in S.A. are limited in this regard. To better understand disparate outcomes in PLWH in standard-of-care settings we propose a prospectiveobservational study of HIV(+) and HIV(-) HL in S.A. (Aim 1). Performance status (PS) organ function clinicalstage tumor histological subtype EBV association and mutational landscape will all be assessed as willchemotherapy regimen response to treatment and cause of death as determined by a minimally invasiveautopsy in consenting participants. Since tuberculosis (TB) is the leading cause of death in PLWH in S.A. thesymptoms of which mimic HL HL patients are often empirically treated and repeatedly tested for TB beforeexcisional biopsies are pursued. A high co-infection rate coupled with immunosuppressive chemotherapy maylead to TB progression in PLWH during therapy and may contribute to ultimate mortality. Therefore Aim 1 willalso have a major focus on the contributions of TB. The results of this study will lead to a better understandingof the roles that PS organ function and TB have in HL prognosis in PLWH as well as aspects of the EBVassociation and the mutational features. The near uniform association of EBV in HIV(+) HL may aid in the recognition of HL in PLWH via a non-invasiveplasma EBV test that can identify patients needing urgent excisional biopsy. To explore this possibility wepropose to develop a diagnostic algorithm (Aim 2A) in a discovery cohort of PLWH with HL and withoutmalignancy. EBV DNA will be assessed along with additional plasma markers to increase specificity. The optimalcombination of markers will be used to develop an algorithm that will be tested in a validation cohort of high riskPLWH (Aim 2B). Baseline PS and organ function will be obtained and a rigorous yearlong follow-up will ensureaccurate classification of persons with lymphoma. In those who are diagnosed with HL or other lymphoma PSand organ function will be re-assessed. Participants who experience a marked decline in these measures to thepoint that they do not receive standard chemotherapy will be considered potential lives saved if the diagnosticalgorithm could be applied clinically. We note that much of the infrastructure needed to implement the moleculartechniques is available in S.A. and that our South African collaborators have a track record of introducingsophisticated molecular diagnostics for TB to the entire country.1 104391 +No NIH Category available Adjuvant Chemotherapy;Agreement;Algorithms;Alleles;Amino Acid Substitution;Amino Acids;Antigen Presentation;Antigens;Binding;Biological Markers;Biopsy;Cancer Etiology;Cancer Patient;Cessation of life;Charge;Clinical;Clinical Data;Combination Drug Therapy;Data;Development;Disease;Disease Progression;Disease-Free Survival;Dissociation;Early identification;Electrostatics;Epidermal Growth Factor Receptor;Ethnic Population;Evaluation;Event;Gene Expression;HLA Antigens;Immune;Immune response;Immunofluorescence Immunologic;Immunologic Markers;Immunologics;In complete remission;Inflammatory;Lead;Ligands;Malignant neoplasm of lung;Methods;Minority;Mismatch Repair Deficiency;Modeling;Mutation;Neoadjuvant Therapy;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Outcome;Pathologic;Patient Selection;Patients;Peptides;Peripheral Blood Mononuclear Cell;Population;Positioning Attribute;Predictive Value;Prevalence;Role;Sampling;Slide;Specimen;Testing;The Cancer Genome Atlas;Therapeutic;Tumor-Infiltrating Lymphocytes;United States;Up-Regulation;anti-tumor immune response;antigen binding;bak protein;biomarker evaluation;biomarker identification;chemotherapy;clinical care;clinically relevant;combinatorial;exome sequencing;genetic signature;immune checkpoint;improved;inhibitor;neoantigens;outcome prediction;patient population;predict clinical outcome;predictive marker;programmed cell death ligand 1;programmed cell death protein 1;racial population;response;single-cell RNA sequencing;spatial relationship;standard of care;transcriptomics;treatment strategy;tumor;tumor microenvironment HLA B44 motif neoepitopes in NSCLC: Evaluating their effects on the TME and adding them to established markers in a model to predict durable benefit from PD- 1 inhibition with and without chemotherapy PROJECT NARRATIVEAmong the 40% of patients with an HLA-B44 supertype allele greater clinical activity of programmed cell death1 (PD-1) inhibitors is seen when mutations lead to peptides in which a neutral or positively charged amino acidis substituted with a negatively charged amino acid presumably based on favorable binding to the positivelycharged HLA-B44 binding pocket. We propose comprehensive studies to characterize the effects of thesespecific mutational events on the tumor microenvironment. We will also evaluate whether these specificmutational events can assist in directing patients to appropriate therapeutic approaches in both early andadvanced stage non-small cell lung cancer. NCI 10681851 7/26/23 0:00 PA-20-185 1R01CA276917-01A1 1 R01 CA 276917 1 A1 "BHARTI, SANITA" 8/1/23 0:00 7/31/28 0:00 Molecular Cancer Diagnosis and Classification Study Section[MCDC] 2055300 "GARON, EDWARD B" Not Applicable 36 INTERNAL MEDICINE/MEDICINE 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 620831 NCI 395434 225397 PROJECT SUMMARYLung cancer is the leading cause of cancer related deaths in the United States and the World. We recentlydemonstrated that programmed cell death 1 (PD-1) inhibitors which lead to durable responses in a minority ofnon-small cell lung cancer (NSCLC) patients have greater efficacy in patients with charged HLA-B bindingpockets whose tumors harbor mutation(s) leading to what we have designated as motif neoepitopes. Motifneoepitopes have an amino acid substitution in the second position of a nonamer generating a change in chargefrom the wild type peptide with the resultant amino acid having a charge opposite from the HLA-B binding pocket.To date the immunological changes induced by motif neoepitopes have not been explored. We propose acomprehensive evaluation of the underlying mechanism focusing on patients with HLA-B44 supertype allelesbecause of the prevalence (approximately 40% of the population) and distribution of HLA-B44 across racial andethnic groups. We will evaluate HLA-B44 samples in the cancer genome atlas (TCGA) to explore differences inthe tumor microenvironment (TME) among patients with or without motif neoepitopes by examining geneexpression and cellular composition by slide review and algorithms based on gene expression profiles. We willevaluate surgical specimens from treatment nave patients with or without HLA-B44 motif neoepitopes andevaluate spatial signatures of the TME by multiplex immunofluorescence (MIF). We will assess multiple sectionsfrom each specimen to identify biomarkers most significantly associated with motif neoepitopes. We will furtherexamine immune contextures of the TME associated with motif neoepitopes by single cell RNA-seq analysis.To elucidate the predictive value of motif neoepitopes in early and advanced stage NSCLC patients and toassess relevant clinical questions we will perform analyses of patients in three separate clinical scenarios. Aswhole exome sequencing (WES) and transcriptomic data is now routinely obtained in our NSCLC patients aspart of patients clinical care we will analyze the presence and expression of genes harboring motif neoepitopes.We will evaluate baseline tumor biopsies from 75 early stage patients with an HLA-B44 allele who receiveneoadjuvant chemotherapy plus PD-1 inhibition correlating motif neoepitopes with pathologic completeresponse. Among 75 advanced stage patients with an HLA-B44 allele who are receiving single agent PD-1inhibition and 75 additional patients being treated with chemotherapy plus PD-1 inhibition we will correlate motifneoepitopes with progression of disease within 6 months of initiation of therapy.Together these studies will provide a better understanding of the TME and other immunologic changesassociated with the presence of motif neoepitopes. In addition results could enable us to identify patients inwhom evaluation of this marker of neoantigen presentation could be utilized to select patients with clinicallyrelevant benefit in three separate clinical scenarios utilizing PD-1 inhibitor-based therapy. As a corollary resultscould also identify populations of patients in whom other treatment strategies should be considered. 620831 +Biotechnology; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Genetics; Health Disparities; Minority Health; Precision Medicine Affect;Apoptosis Regulation Gene;Apoptotic;BCL-2 Protein;BCL2 gene;BCL2L11 gene;BRAF gene;Biological Markers;Cell Line;Clinical;Clinical Trials;Combined Modality Therapy;Cutaneous Melanoma;Data;Effectiveness;Genotype;Growth;Heterogeneity;High Prevalence;Human;In Vitro;MAP Kinase Gene;MAPK Signaling Pathway Pathway;MDM2 gene;MEK inhibition;MEKs;Malignant Neoplasms;Maximum Tolerated Dose;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Mutation;Outcome;Pathway interactions;Patient Selection;Patients;Phase;Phase I Clinical Trials;Pre-Clinical Model;Protein Family;Protein-Serine-Threonine Kinases;Proteins;Randomized;Ras/Raf;Regimen;Research Project Grants;Resistance;Resistance development;Safety;Skin Cancer;Solid;Solid Neoplasm;Somatic Mutation;TP53 gene;Testing;Therapeutic;Translating;Tumor Suppressor Genes;base;chemotherapy;combinatorial;disease heterogeneity;efficacy evaluation;experimental study;improved;in vivo;inhibitor;inhibitor therapy;kinase inhibitor;melanoma;member;mimetics;mutant;mutational status;new therapeutic target;novel;patient derived xenograft model;personalized medicine;personalized strategies;phase II trial;preclinical study;prevent;pro-apoptotic protein;research clinical testing;resistance mechanism;response;targeted agent;targeted treatment;therapy resistant;tumor Research Project 2 - Targeting Melanoma Tumor Survival and Apoptotic Machinery n/a NCI 10681845 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "WITHERSPOON, KIM" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E 9853 9439732 "DAVIES, MICHAEL " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 129712 129712 0 Project Summary Project 2Melanoma the most aggressive form of skin cancer is characterized by a very high rate of somatic mutations.Approximately 50% of cutaneous melanomas have a mutation that affects the V600 residue in Braf. Theactivity of the mutant form of the protein (BRAFV600) is markedly increased and results in constitutive activationof the RAS-RAF-MAPK signaling pathway. This information has rapidly translated into clinical benefit as fivetargeted therapy regimens have been approved for the treatment of metastatic melanoma patients with aBrafV600 mutation. While these agents have very high clinical response rates unfortunately the majority ofpatients develop resistance within 2 years. Further these targeted therapies cannot be used in patients whodo not have a BrafV600 mutation. Thus there remain unmet clinical needs to identify strategies to preventresistance to approved targeted therapies in metastatic melanoma patients with an activating BrafV600 mutationand new targeted therapy approaches for patients without a BrafV600 mutation (BRAF Wild-Type). While manystudies are ongoing to evaluate the therapeutic potential of other kinase inhibitors there is growing evidence tosupport the rationale for the testing of agents that target the apoptotic machinery. In contrast to many othercancers cutaneous melanomas have a low rate (~20%) of mutations in Tp53. Additional studies have shownanti-apoptotic members of the BCL2 family of proteins can promote resistance to targeted therapies againstthe RAS-RAF-MAPK pathway and that pro-apoptotic proteins (i.e. BIM) are critical to their effectiveness.Based on promising results in a limited number of preclinical models clinical trials targeting the apoptoticmachinery in combination with RAS-RAF-MAPK pathway inhibitors are ongoing in metastatic melanomapatients. However currently there are no biomarkers to optimize patient selection for these strategies norunderstanding of resistance mechanisms to them. The central hypothesis of this proposal is that specificmolecular features will predict sensitivity and resistance to combinatorial strategies utilizing pro-apoptotic agents and MAPK pathway targeted therapies. In order to test this hypothesis we will evaluatepro-apoptotic agents in combination with MAPK pathway inhibitors in molecularly characterized melanomaPDX models which accurately replicate the molecular features and heterogeneity of this disease. In AIM 1 wewill evaluate the efficacy and molecular effects of navitoclax a BH3 mimetic that inhibits BCL2 alone and incombination with dabrafenib (BRAFi) and trametinib (MEKi) in melanoma PDX with a BrafV600 mutation. Theseexperiments mirror an ongoing randomized phase II of these agents in metastatic melanoma patients and theresults of that trial will be used to clinically validate markers associated with resistance in the PDX. In AIM 2we will evaluate the efficacy of the MDM2 inhibitor AMG232 alone and in combination with trametinib. Testingwill be performed in BRAF WT melanomas with wild-type Tp53 including a subset with MDM2 amplification.These studies will help to refine and prioritize strategies using these agents in metastatic melanoma patients. +Biotechnology; Cancer; Clinical Research; Genetics; Health Disparities; Minority Health; Precision Medicine 3-Dimensional;BRAF gene;Biological;Biological Markers;Biology;Cancer Therapy Evaluation Program;Cell Line;Clinical;Clinical Trials;Collaborations;Collagen;Data;Development;Disease;Drug Combinations;Drug usage;FGFR1 gene;Gene Amplification;Genes;Genetic;Genomics;Growth;Growth Factor;HGF gene;Immune;Immunotherapy;In Vitro;Investigational Drugs;KDR gene;Knowledge;Ligands;MAP Kinase Gene;MEK inhibition;MEKs;Malignant Neoplasms;Melanoma Cell;Methods;Mitogen-Activated Protein Kinase Inhibitor;Modeling;Mus;Mutation;NF1 gene;Neoplasm Metastasis;Oncogenes;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Phosphotransferases;Preclinical Testing;Prediction of Response to Therapy;Process;Property;Protein Array;Protein Isoforms;Protein Overexpression;Proteins;Proto-Oncogene Protein c-kit;RNA;Receptor Protein-Tyrosine Kinases;Relapse;Research;Research Project Grants;Resistance;Signal Transduction;Somatic Mutation;Subgroup;Therapeutic;Time;Toxic effect;Transplantation;autocrine;base;biomarker selection;cancer cell;cancer therapy;clinical subtypes;in vivo;inhibitor;melanoma;member;mutant;new combination therapies;novel;novel therapeutic intervention;novel therapeutics;overexpression;patient derived xenograft model;personalized approach;preclinical study;protein expression;response;targeted cancer therapy;targeted sequencing;tumor Research Project 1 - Targeting the MAPK and PI3K pathways in melanoma PDX n/a NCI 10681844 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "WITHERSPOON, KIM" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E 9852 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 144672 79359 65313 Project Summary Project 1Melanoma cells adapt well when transplanted to immune-deficient mice and the group has established >450PDX which allow us to identify in-depth those subgroups of tumors that are most suitable for selected drugs.The PDX have been extensively characterized for their growth properties in vitro and in vivo includingmetastasis formation somatic mutations in 108 genes through targeted sequencing and expression of 305proteins related to signal transduction. The models are superbly suited to investigate two major pathways thatare consistently activated in melanoma and in most other cancers: MAPK and PI3K pathways. Our overallworking hypothesis is that we can predict therapy responses based on the genetic genomic and biologicsignatures of tumors. We expect that we can define short of a complete personalized approach subgroups ofmelanomas that will respond to new therapies and new combinations of therapies in a predictable way. Usingdrugs that are available through NCI-CTEP we will define in the first aim those melanomas that are mostsensitive to inhibitors of MET in combination with MAPK inhibitors. We will also investigate multi-kinaseinhibitors as single agents and in combination with MAPK inhibitors. Our working hypothesis is that insubgroups of melanomas MET as well as other receptor tyrosine kinases (PDGFR VEGFR c-KIT FGFR1)and non-receptor kinases (SRC) are important targets. We expect to develop biomarkers that will pinpointthose melanomas that are most (or least) susceptible to kinase inhibition. In the second aim we will definemelanomas that are most sensitive to combined inhibition of the MAPK and PI3K pathways. Our workinghypothesis is that a subgroup of BRAF-mutant melanomas exists which is highly susceptible to thecombination of BRAF/MEK with PI3K inhibitors. Based on our preliminary studies we will use loss of PTEN asone biomarker for selection but expect further refinements especially for tumors resistant to BRAF andBRAF/MEK inhibitors. Since IGFR-1 signals predominantly through the PI3K pathway and is in selectedmelanomas a key player in acquired resistance we will include the appropriate CTEP inhibitor(s). At the sametime we will determine whether isoform specific PI3K inhibitors are more appropriate in combination withMAPK inhibitors. We expect to define biomarkers for the selection of both treatment-nave and BRAF/MEKinhibitor-resistant tumors. Our studies should provide a strong rationale for initiating clinical trials. +Cancer; Clinical Research; Health Disparities; Minority Health Fostering;Foundations;Funding;Goals;Measures;Monitor;Peer Review;Pilot Projects;Process;Progress Reports;Publications;Research;Research Personnel;Resources;Technology;Underrepresented Minority;Woman;expectation;high standard;melanoma;programs;success Pilot Projects and Trans-Network Activities Core n/a NCI 10681843 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "WITHERSPOON, KIM" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E 9851 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 124749 84174 40575 Project Summary Pilot Project CoreThe overall goals of the Pilot Core are to advance high-quality research foster new ideas for the PDTC and thePDXNet to strengthen the foundation of ongoing studies in the Projects and to interact with investigators insideand outside of PDTC.Specific Aim 1: To attract select and fund the most outstanding proposals with significant potential to benefitthe PDTC and the PDXNet.Specific Aim 2: To support and integrate the selected pilot projects into the PDTC program with establishedprocesses to review and monitor progress.Women and underrepresented minorities will be strongly encouraged to participate. The Pilot has a transparentpeer-reviewed selection process that incorporates defined criteria for funding decisions.We will require that Pilot Project awardees be active in PDTC functions use the PDTC other Core resourcesand provide formal written progress reports. Within the context of the Core we have established highstandards and expectations of the investigators and have established a formal process to review and monitorprogress of funded pilot projects. The program measures success by resulting publications resulting fundingstimulating new aims in existing PDTC projects and strengthening the resources technologies andapproaches within the PDTC and PDXNet.! +Cancer; Health Disparities; Minority Health Address;Bioinformatics;Characteristics;Combined Modality Therapy;Consultations;Data;Data Analyses;Data Security;Development;Ensure;Environment;Experimental Designs;Generations;Individual;Lead;Manuscripts;Messenger RNA;MicroRNAs;Molecular;Mutation;Pharmacotherapy;Preclinical Testing;Preparation;Process;Protocols documentation;Quality Control;Reporting;Research;Research Design;Research Personnel;Research Proposals;Sample Size;Statistical Data Interpretation;Time;Writing;data management;experimental study;melanoma;member;preclinical study;programs;protein expression;transcriptome sequencing;treatment response Bioinformatics Core n/a NCI 10681842 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "WITHERSPOON, KIM" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E 9850 10441510 "KOSSENKOV, ANDREW V" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 26120 14328 11792 Project Summary Bioinformatics CoreThe Bioinformatics Core will conduct bioinformatics and statistical analyses of data generated by Projectsand Cores to address research hypotheses defined in the project-specific proposals as well as performintegrative analyses in order to combine data from all experiments. The Core will provide central storage datamanagement and information security for generated raw and processed high-throughput data within thePTDC. The Core will assist with preparation and writing of final reports abstracts manuscripts and futureresearch proposals. During the span of the Research Program Bioinformatics Core will ensure a timelyprogress tracking of PDX trials and sharing of generated results between members of PTDC. +Biotechnology; Cancer; Clinical Research; Genetics; Health Disparities; Infectious Diseases; Minority Health Biological;Biological Assay;Biological Models;Cell Line;Cells;Cellular biology;Clinical;Collaborations;Collagen;Communicable Diseases;DNA;Data;Data Storage and Retrieval;Databases;Disease;Ensure;Freezing;Future;Genetic;Genetic Fingerprintings;Human;Immunodeficient Mouse;In Vitro;Laboratories;Lesion;Medical Genetics;Melanoma Cell;Methodology;Modeling;Molecular;Molecular Abnormality;Monitor;Mus;Neoplasm Metastasis;Patients;Pilot Projects;Proteins;Quality Control;RNA;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Scientist;Seeds;Services;Skin;Testing;Training;Validation;cell bank;experimental study;in vitro Model;in vivo Model;investigator training;melanoma;member;neoplastic cell;novel therapeutics;pathogen;patient derived xenograft model;preclinical study;programs;protein expression;screening;success;three-dimensional modeling;tool;tumor;tumor growth PDX Core n/a NCI 10681841 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "WITHERSPOON, KIM" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E 9849 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 94085 51610 42475 Project Summary PDX Core The PDX Core provides major resources to the program investigators including melanoma PDX melanoma cell lines and 3D models to explore new therapies. The melanoma PDX encompasses >450 different tumors representing all clinical and genetic groups of the disease. The primary focus of the PDX core is to establish new PDX and coordinate their characterization at the DNA RNA and protein levels. It then maintains the master cell bank monitors for mouse pathogens and collaborates with other investigators within the program within the overall PDTC and outside scientists. The Core is also to central facilitator for exchanging PDX within the PDXNet for a coordinated effort on collaborations. The Core coordinates data storage and distribution to other investigators within the Program. The PDX Core is available to train investigators of the Program in all biological assays and models. Overall this Core will provide efficient and high-quality service to all laboratories within this PDTC. 1 +Cancer; Health Disparities; Minority Health Cancer Center;Communication;Development;Ensure;Environment;Fostering;Government;Leadership;Occupational activity of managing finances;Pennsylvania;Pilot Projects;Policies;Process;Regulation;Research;Research Personnel;Services;Structure;The Wistar Institute;Translational Research;Universities;design;meetings;melanoma;patient derived xenograft model;programs Administrative Core n/a NCI 10681840 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "WITHERSPOON, KIM" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E 9848 2795105 "HERLYN, MEENHARD F" Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 70392 38613 31779 Project Summary Administrative CoreSummaryThe Administrative Core is designed to provide scientific leadership effective communication and anadministrative support structure to ensure the coordination of all PDTC activities. The essential servicesprovided by the Core include: administrative support for all of the investigators in each project and core;scientific oversight and progress review for each project; coordination of selection processes for Pilot Studiesand integration of these investigators and their projects into full PDTC program as they evolve; fiscal andfinancial management and oversight for all components of the PDTC; and organization and communication ofall PDTC meetings and activities. The Administrative Core is also responsible for all interactions with the NCIstaff including scientific and administrative.The overall objectives of the Administrative Core are to:1. Establish and maintain an administrative structure to provide support for and management of all PDTCactivities.2. Foster an environment to maximize collaborative and translational research among PDTC investigators between Wistar MD Anderson and Penn and between other PDTC/PDXNet and NCI initiatives.3. Ensure compliance with all institutional governmental and NCI regulations and policies.. +No NIH Category available Apoptosis;Apoptotic;Area;BRAF gene;Bioinformatics;Biologic Characteristic;Biological Markers;Biological Response Modifier Therapy;CTLA4 gene;Cancer Therapy Evaluation Program;Cell Line;Characteristics;Clinical;Clinical Trials;Collection;Cutaneous Melanoma;DNA;DNA Damage;Development;Disease;Drug resistance;Enrollment;Ensure;FDA approved;Fine needle aspiration biopsy;Foundations;Future;Genes;Genetic;Genetic Heterogeneity;Heterogeneity;Histologic;Human;Immune checkpoint inhibitor;Immunotherapeutic agent;Institution;Investigation;Laboratories;Lesion;MAP Kinase Gene;MEKs;Malignant Neoplasms;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Mutation;Neoplasm Metastasis;Oncogenic;PD-1 inhibitors;Pathway interactions;Patient Selection;Patient-Focused Outcomes;Patients;Pharmacotherapy;Phenotype;Pilot Projects;Pre-Clinical Model;Property;Proteins;Proto-Oncogene Proteins c-akt;RNA;Receptor Protein-Tyrosine Kinases;Regimen;Relapse;Resistance;Resources;Selection for Treatments;Signal Transduction;Solid;Specimen;Subgroup;Testing;Therapeutic;Time;Translating;Tumor stage;cancer cell;combinatorial;disease heterogeneity;established cell line;improved;in vivo;inhibitor;inhibitor therapy;kinase inhibitor;melanoma;multidisciplinary;mutant;novel drug combination;novel marker;novel therapeutic intervention;patient derived xenograft model;patient subsets;personalized medicine;personalized therapeutic;potential biomarker;prevent;programmed cell death ligand 1;programs;research clinical testing;resistance mechanism;response;success;targeted treatment;tool;tumor;tumor progression Rational approaches to melanoma therapy n/a NCI 10681839 9/21/22 0:00 RFA-CA-17-003 3U54CA224070-04S3 3 U54 CA 224070 4 S3 "HENDERSON, LORI A" 9/30/17 0:00 8/31/23 0:00 ZCA1-RTRB-E(A1) 2795105 "HERLYN, MEENHARD F" "DAVIES, MICHAEL " 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 9/1/21 0:00 8/31/23 0:00 353 Research Centers 2022 589729 NCI 397796 191933 Project Summary OverallThe outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to animproved understanding of the molecular drivers of this disease. In particular multiple targeted therapy regimenshave been approved for patients with a BRAFV600E/K mutation which are present in ~50% of cutaneous melanomas.These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation thus providing proof-of-concept of the therapeutic potential for personalized therapeutic strategies. However most of the patients willprogress within 2 years of starting those therapies. Further currently there are no targeted therapies that have beenshown to be effective in patients with a wild-type BRAF. Thus there are unmet clinical needs to develop treatmentsthat prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation and that areeffective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategiesover the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinicalhistological and genetic heterogeneity of this disease. Our collection of >450 PDX models represents one of thelargest collections for any human malignancy and our initial testing demonstrates that the collection accuratelyrecapituluates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection alsoincludes a subset of PDX established from patients with acquired resistance to targeted therapies that have beenmaintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated arobust resource to develop refine and prioritize new personalized combinatorial therapies for patients. Thus wepropose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continuedexpansion of our robutst melanoma PDX collection to identify new therapeutic approaches that fill important clinicalgaps in this disease. Project 1 will characterize kinase inhibitors targeting receptor tyrosine kinases (RTKs) and thePI3K-AKT pathway in combination with approved targeted therapies in PDX models in treatment-nave and drug-resistant BRAFV600E/K-mutant melanomas. Project 2 will characterize targeting the apoptotic machinery of cancercells as a combinatorial approach with MAPK pathway inhibitors in PDX with and without BRAFV600E/K mutationsincluding in subsets with aberrancies in anti-apoptotic genes. Both Projects will utilize baseline characteristics of thePDX models to identify potential biomarkers of sensitivity and resistance to guide personalized patient selection forfuture clinical testing. In addition tumors will be analyzed for treatment-induced effects that correlate with sensitivityto identified resistance mechanisms and potential new combinatorial strategies. Finally markers identified in thepreclinical models will be compared to parallel biomarker studies of metastatic melanoma patients enrolled inclinical trials utilizing the same agents. These studies will be supported by the PDX Bioinformatics andAdministrative Cores to ensure their success along with a Pilot Project program to open new areas of investigation.Together these studies will have high potential to translate into new personalized clinical trials for patients. 589729 +No NIH Category available Advanced Development;Alleles;Biological Assay;Cancer Etiology;Cell Line;Cells;Cessation of life;Chromatin;Clinical Trials;Cre driver;Data;Diagnosis;Disease;Disease Progression;Epitopes;Erinaceidae;Family;Fibroblasts;GLI gene;Genetic;Genetic Models;Genetic Transcription;Glioma;Growth;Health;Human;Immune;In Vitro;Incidence;Individual;Knock-in;Laboratories;Ligands;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Migration Assay;Mus;Neoplasm Metastasis;Organoids;Pancreas;Pathway interactions;Primary Neoplasm;Proteins;RNA;Regulation;Role;Signal Transduction;Signaling Protein;Speed;Survival Rate;T cell infiltration;T-Lymphocyte;Testing;Transcriptional Regulation;Transplantation;Tumor-Derived;United States;Work;cancer therapy;cell motility;effective therapy;genetic approach;improved;in vivo;inhibitor;mouse model;novel;pancreatic cancer model;pancreatic neoplasm;paracrine;patient prognosis;pharmacologic;smoothened signaling pathway;transcription factor;transplant model;tumor;tumor growth;tumor microenvironment;tumor progression Investigating GLI transcription factors as regulators of the pancreatic cancer microenvironment PROJECT NARRATIVEPancreatic cancer is a deadly malignancy with poor prognosis for patients at all stages of diagnosis. In thisproposal we will investigate novel roles for GLI transcription factors the effectors of the Hedgehog signalingpathway as key regulators of the pancreatic cancer microenvironment. Specifically we will: 1) employ novelgenetic approaches to assess the contribution of GLI transcription factors to pancreatic cancer progression 2)elucidate GLI-dependent fibroblast-immune crosstalk and 3) define GLI transcriptional targets in pancreaticfibroblasts to positively impact the treatment of pancreatic cancer. NCI 10681714 4/27/23 0:00 PA-20-185 1R01CA275182-01A1 1 R01 CA 275182 1 A1 "MERCER, NATALIA" 5/1/23 0:00 4/30/28 0:00 Special Emphasis Panel[ZRG1-BTC-W(80)S] 9342948 "ALLEN, BENJAMIN " "PASCA DI MAGLIANO, MARINA " 6 ANATOMY/CELL BIOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 396 Non-SBIR/STTR 2023 591242 NCI 383317 207925 PROJECT SUMMARY/ABSTRACTPancreatic cancer is a deadly human malignancy with a five-year survival rate of 11%. Further the incidence ofpancreatic cancer is rising and is projected to be the second-leading cause of cancer-related death in the UnitedStates by 2030. The increasing occurrence of this disease combined with the lack of effective treatmentscreates an urgent need to better understand the factors that contribute to the progression of pancreatic cancerand to develop improved therapies that will tangibly benefit human health. One pathway that has been implicatedin pancreatic cancer for nearly twenty years is the Hedgehog (HH) signaling pathway. Initial work demonstratedthat HH ligand expression increases during pancreatic cancer progression while more recent studies have foundthat tumor-derived HH ligands signal in a paracrine fashion to activate HH signaling in pancreatic fibroblasts. Aswith many efforts to treat pancreatic cancer clinical trials with HH pathway inhibitors have proven ineffective oractually sped disease progression. However work from our laboratories has identified three novel findingsregarding the role of HH signaling in pancreatic cancer progression: First we have found that the levels of HHsignaling can determine whether HH signaling promotes or inhibits pancreatic tumor growth; Second we haverecently discovered that HH pathway inhibition can alter the fibroblast composition in the pancreatic cancermicroenvironment; Third our data indicate that HH pathway inhibition dramatically alters immune compositionthrough altered fibroblast-immune crosstalk. Together these data suggest that an improved understanding ofthe role of HH signaling in the pancreatic cancer microenvironment including HH-dependent fibroblast-immunecrosstalk will provide an opportunity to advance the development of more effective pancreatic cancer treatmentoptions. In this proposal we will investigate the role of glioma-associated proteins (GLIs) a family of threeproteins (GLI1-3) that are the transcriptional effectors of the HH signaling pathway in pancreatic cancerprogression. Specifically we will use novel pancreatic fibroblast cell lines lacking Gli1 Gli2 or Gli3 individuallyand in combination to investigate the consequences on pancreatic tumor growth in co-transplantation assays.We will also investigate Gli deletion in vivo using two different Cre driver alleles (PdgfraCreER and Gli1CreER)in a novel FlpO-driven mouse model of pancreatic cancer progression. Further we will investigate GLI-dependent effects on fibroblast-immune crosstalk through assessment of macrophage and T cell migrationpolarization and function. Finally we will define GLI transcriptional targets in pancreatic fibroblasts both in vitroand in vivo in the normal pancreas and in the context of pancreatic cancer using a novel set of epitope-taggedknock-in alleles. This work will advance our understanding of the role of HH/GLI signaling in pancreatic cancer. 591242 +Cancer; Health Disparities; Minority Health Administration Core n/a NCI 10681692 9/8/22 0:00 PA-20-272 3U54CA210962-05S1 3 U54 CA 210962 5 S1 "AGUILA, HECTOR NELSON" 9/21/17 0:00 8/31/23 0:00 9814 7354246 "FORD, MARVELLA ELIZABETH" Not Applicable 6 Unavailable 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC Domestic Higher Education 294074636 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 583601 400000 183601 ADMINISTRATIVE COREThe South Carolina Cancer Disparities Research Center (SC CADRE) is a partnership between the SouthCarolina State University (SCSU an institution serving underserved health disparity populations andunderrepresented students (ISUPS)) and the Medical University of South Carolina Hollings Cancer Center(MUSC-HCC a National Cancer Institute-designated cancer center). The overarching goals of the SCCADRE are to increase SCSU's capacity to conduct transdisciplinary cancer research and to furtherstrengthen and extend a longitudinal research education pipeline that will catalyze a new diverse generation ofbiomedical researchers focused on cancer disparities. To ensure the success of the SC CADRE's goals andstrategies outlined throughout this application the Administrative Core is charged with the following aims:Aim 1. Provide inter-institutional as well as external scientific and community-based leadership in the guidanceand oversight of the activities of SC CADRE.Aim 2. Support the SC CADRE's efforts in cancer research research education community outreach and theCenter's planning and evaluation efforts by providing the essential day-to-day administrative and financialsupport coordination and logistical services needed to make this inter-institutional partnership functioneffectively.Aim 3. Facilitate the inter-institutional as well as external communications required to ensure the promotion ofSC CADRE activities +Biotechnology; Breast Cancer; Cancer; Genetics; Women's Health Aftercare;Behavior Therapy;Binding;Biological Assay;Breast Cancer therapy;CD44 gene;Carboplatin;Cell physiology;Cell surface;Cells;Chemoresistance;Clinical Trials;Collection;Coupled;DNA sequencing;Data;Epithelial;Erinaceidae;FDA approved;Fatty acid glycerol esters;Gene Expression;Genes;Heterogeneity;Human;Impairment;Individual;Laboratories;Lead;Light;Mammospheres;Mediating;Mesenchymal;Microfluidics;Modeling;Molecular;Natural regeneration;Pathway interactions;Pattern;Physiological;Population;Process;Proteins;Proteome;Radio;Regulator Genes;Regulatory Pathway;Reporter;Reporter Genes;Research Project Grants;Resistance;STAT3 gene;Signal Pathway;Signal Transduction;Site;Systemic Therapy;Testing;Transplantation;Tumor-Derived;Visualization;Work;activity marker;aldehyde dehydrogenase 1;base;cancer stem cell;cell type;chemoradiation;chemotherapy;comparative;exome;in vivo;mRNA Expression;mammary;metabolome;neoplastic cell;notch protein;novel;patient derived xenograft model;precision medicine;predicting response;prevent;protein expression;response;single-cell RNA sequencing;targeted agent;targeted treatment;therapeutic target;transcription factor;transcriptome sequencing;treatment effect;treatment response;triple-negative invasive breast carcinoma;tumor Research Project 2: Targetin Tumor-Initiating Cell (TIC) Heterogeneity To Overcome Chemotherapy Resistance n/a NCI 10681678 8/26/22 0:00 RFA-CA-17-003 3U54CA224076-04S3 3 U54 CA 224076 4 S3 "WITHERSPOON, KIM" 9/25/17 0:00 6/30/23 0:00 ZCA1-RTRB-E 9813 1972445 "LEWIS, MICHAEL T." Not Applicable 1 Unavailable 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT Domestic Higher Education 841129049 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 223982 223982 0 PROJECT SUMMARY We and others have shown that a subset of tumor cells capable of regenerating new tumors termed variously as tumor-initiating cells (TIC) or cancer stem cells (CSC) are comparatively resistant to current systemic chemo- and radio-therapies relative to the bulk of the tumor. As such the guiding premise for our work over the past decade is that therapeutic targeting of processes required for survival or function of TIC will allow elimination of such cells at both the primary and metastatic sites thereby enhancing response to current systemic therapies. However it has become clear from several laboratories using current cell surface markers enzymatic activity markers and lentiviral signaling reporters for Wnt Hedgehog and STAT3-mediated signaling that TIC are heterogeneous not only across tumors but also show different behaviors treatment responses and reporter gene expression at the primary and metastatic sites within a given tumor model. Thus it is critical to understand the diversity of TIC types both within and across tumors as well as to understand how such cells differ in function between the primary and metastatic site in order to target them effectively particularly in triple-negative breast cancer (TNBC) for which there are no approved targeted therapies. We hypothesize that there exist molecularly distinct classes of TIC in TNBC. As a consequence differential responses to individual chemotherapies depend in part on the class(es) of TIC present in a given tumor. If true we further assert that identifying and targeting class-specific TIC functions may help overcome chemotherapy resistance. In order to identify candidate regulatory genes or pathways functioning in a spectrum of PDX-derived TIC isolated from primary and metastatic sites we propose to determine first whether TIC derived from either the primary or metastatic site show identical or different patterns of activation of signaling networks implicated in TIC function using lentiviral fluorescent reporters specific for signaling pathways and transcription factors implicated in TIC function. We will then identify candidate molecular mechanisms required for TIC activity at the population and single cell levels using RNAseq. In order to determine whether in vivo targeting of TIC-related genes/pathways can augment response to carboplatin and lead to elimination of different classes of TIC at both the primary and metastatic sites we will evaluate the ability of FDA-approved agents targeting TIC to augment treatment response alone or in combination with carboplatin at the primary and metastatic sites and assay the effect of treatment on TIC function in vivo. Results may be used to guide planning and execution of human clinical trials and inform precision medicine efforts. +No NIH Category available Age;Award;Cancer Etiology;Cardiology;Cellular biology;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Complex;Creativeness;Development;Discipline;Disease;Drug Targeting;Environment;Evolution;Genome;Genomic Instability;Genomics;Immune Evasion;Individual;Knowledge;Language;Lesion;Malignant Neoplasms;Metabolism;Mission;Mutation;Neoplasm Metastasis;Nephrology;Neurology;Pathology;Patients;Pharmacogenomics;Pharmacology;Process;Proliferating;Proteomics;Public Health;Radiogenomics;Radiology Specialty;Regulatory Element;Research;Research Project Grants;Signal Transduction;Somatic Mutation;Structure;Technology;Time;Tumor Promotion;United States National Institutes of Health;Untranslated RNA;angiogenesis;cancer gene expression;cancer genome;cancer type;data integration;driver mutation;drug discovery;epigenomics;genetic disorder diagnosis;genomic data;high reward;high risk;innovation;innovative technologies;insight;precision medicine;premalignant;programs;response;technological innovation;transcriptomics;tumor;unsupervised learning;weapons;whole genome Defining the universal genomic language of hallmarks in tumor development PROJECT NARRATIVEThe proposed research is relevant to public health because it represents a broad and innovative paradigm shiftin diagnosing the genetic causes of cancer from individual driver mutations in 2% of the genome towardprograms of combinations of mutations in the entire genome. The powerful technology developed herein willbe universally applicable to the genomes of all cancer types as well as other age-associated diseases driven bysimilar genomic mechanisms. It has the long-term potential to turn genomes into powerful weapons againstseveral genome-driven diseases thereby advancing NIHs mission to reduce illness and enhance the survivalof millions of patients. NCI 10681670 8/23/23 0:00 RFA-RM-22-019 1DP2CA290196-01 1 DP2 CA 290196 1 "LI, JERRY" 9/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-RCCS-L(70)] 14918049 "DIETLEIN, FELIX " Not Applicable 7 Unavailable 76593722 Z1L9F1MM1RY3 76593722 Z1L9F1MM1RY3 US 42.337481 -71.104964 1504801 BOSTON CHILDREN'S HOSPITAL BOSTON MA Independent Hospitals 21155724 UNITED STATES N 9/1/23 0:00 8/31/26 0:00 310 Non-SBIR/STTR 2023 1593000 OD 900000 693000 PROJECT SUMMARYGenomic changes are a universal and near inevitable cause of tumor development. The field has focused mostlyon tumors that rely on singular driver mutations to proliferate and these insights have inspired driver-directedtherapies that provide effective clinical options for ~20% of patients. However most genomes are more complexharboring hundreds of somatic mutations without a single druggable driver. Comprehensive discovery of tumor-promoting mechanisms in these complex genomes would broadly impact genome-inspired drug discoveries formillions of patients. This New Innovator Award project represents a creative paradigm shift beyond individualdrivers by discovering genomic programs of multiple coordinated mutations that interact and activateessential hallmarks in tumor development (e.g. uncontrolled proliferation deregulated metabolism genomeinstability angiogenesis immune evasion and metastasis). This innovative cutting-edge technology willuniquely combine the discovery potential of unsupervised machine learning the information value of leadingstatistical approaches and data from genomics epigenomics radiology pathology pharmacologytranscriptomics proteomics CRISPR and cell biology. Genomic programs will elucidate essential mechanismsin tumor development beyond singular driver mutations which include: 1) Activation of genomic regulatoryelements to unleash cancer gene expression. 2) Tumor-specific epigenomic structures to control tumor signaling.3) Mechanisms in tumor evolution to select precancer lesions. 4) Interactions that enable tumors to adapt andsurvive in metastatic environments. Identifying the shared underlying cause of these mechanisms will overcomethe biases of field-specific approaches and define interactions of coordinated processes in tumor development.The proposed research is conceptually innovative as it pivots precision medicine toward identifying genome-inspired drug targets beyond drivers. It also introduces numerous technological innovations to identify complexstructures in radiogenomics pharmacogenomics noncoding genomes organotropism tumor evolutionepigenomics regulatomes and interactomes. It comes at a pivotal time since many whole cancer genomesbecame available only recently emphasizing their potential to produce an unusually high impact in a short periodof time. Moreover this proposal fundamentally differs from traditional research grants in its ambitious scopebroad applicability integration of data and technologies from diverse disciplines and a creative leap in researchtrajectory. In sum this high-risk high-reward project will create an innovative technology universally applicableto the genomes of all cancer types. It will generate fundamental knowledge to advance driver-directedmonotherapies toward hallmark-directed combination therapies with the ultimate potential to produce moredurable responses in millions of patients. Its impact extends beyond cancer including age-associated diseasesin neurology cardiology and nephrology that are driven by similar genomic principles. 1593000 +Biotechnology; Cancer; Cancer Genomics; Clinical Research; Genetics; Human Genome Antineoplastic Agents;Biodiversity;Bioinformatics;Breast;Cancer Center;Clinical;Clinical Research;Clinical Trials;Collaborations;Combined Modality Therapy;Complex;Data;Development;Disease;Drug usage;Early Therapeutic-Clinical Trials Network;Engraftment;Ensure;Evaluation;Fostering;Foundations;Funding;Genome;Genomics;Germ-Line Mutation;Goals;Grant;Histology;Human;Image;Infrastructure;Institutes;Institution;Leadership;Malignant Neoplasms;Malignant neoplasm of pancreas;Methods;Modeling;Molecular;Molecular Target;Mus;Neoplasm Metastasis;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Physicians;Pre-Clinical Model;Preclinical Testing;Protein Isoforms;Protocols documentation;Recording of previous events;Records;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Sampling;Solid;Somatic Mutation;Standardization;Technology;Testing;Translational Research;Treatment Protocols;Tumor Tissue;Universities;Validation;Variant;Washington;Work;anticancer research;cancer subtypes;cancer therapy;cancer type;capsule;clinical predictors;combinatorial;data analysis pipeline;drug testing;early phase clinical trial;emerging pathogen;exome sequencing;experience;human pathogen;improved;improved outcome;inhibitor;innovation;malignant breast neoplasm;medical schools;member;pancreatic PDX models;patient derived xenograft model;personalized medicine;programs;proteogenomics;rational design;relational database;research clinical testing;response;targeted agent;transcriptome sequencing;translational impact;treatment response;tumor Washington University PDX Development and Trial Center Cancer is a complex disease. A single cancer type may be result from alterations in various distinct molecularpathways. It is likely that combination therapies will be needed to significantly improve the outcomes of patientswith advanced malignancies. It is unrealistic to test all possible combinations in human clinical trials. PDXmodels provide means to test various combinations. Apart from selecting the ideal therapies for clinical testingthese models will also provide material for molecular testing to identify mechanisms underlying responses totherapy. NCI 10681606 9/14/22 0:00 RFA-CA-17-003 3U54CA224083-04S2 3 U54 CA 224083 4 S2 "HENDERSON, LORI A" 9/30/17 0:00 6/30/23 0:00 ZCA1-RTRB-E(A1) 8579775 "GOVINDAN, RAMASWAMY " "DING, LI ; LI, SHUNQIANG " 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/22 0:00 6/30/23 0:00 353 Research Centers 2022 521719 NCI 331250 190469 With the discovery of a number of new molecular targets and exponential increase in the number of anti-canceragents it has become imperative to optimize preclinical models in order to design rational clinical trials.Recognizing the unique advantage of the patient-derived xenografts (PDXs) models in drug testing andpersonalized medicine physicians and researchers at Washington University School of Medicine (WUSM) andthe Siteman Cancer Center have been actively generating and utilizing PDX models for cancer research andthe evaluation of molecularly targeted agents. Building on our strength and existing infrastructure we proposeto establish the Washington University PDX Development and Trial Center (WU-PDTC) as part of PDXNetprogram to promote preclinical testing in a collaborative nation-wide effort.The PDX core within WU-PDTC will develop and characterize at least 1000 new pathogen-free PDX modelsacross major tumor types. The PDX models will be genomically and phenotypically characterized using thelatest omics technologies and expertly analyzed using the most current data analysis pipelines that have beendeployed for other large scale NCI programs. The Bioinformatics Core will integrate these analyzes with clinicalannotation from the originating patient to include patient treatment history and tumor response (Aim 1). Our tworesearch projects will conduct PDX clinical trials using single agent and combinational agents using drugsunder NCI-IND (Aim 2). Project 1 will test pan- or beta isoform specific class I PI3K inhibitors in over 100breast PDX models while Project 2 will study combinatorial approaches that overcome tumor intrinsic andextrinsic mechanisms to ERK inhibition in over 100 already available pancreatic PDX models. Proteogenomicand clinical response data will be collected in these models as part of a broader effort of characterizing PDXmodels and conducting clinical correlation and treatment response analyses by the Bioinformatics Core (Aim3). All relevant information including proteogenomic features of PDX models and treatment/response historywill be tracked in a dedicated relational database that will be accessible to PDXNet and PDMR-FNLCR. Thegoal is to identify candidates for human clinical trials for the ET-CTN. In Aim 4 the WU-PDTC will leverageexisting expertise and programs from the NCI-designated Comprehensive Siteman Cancer Center Institute ofClinical and Translational Research (ITCS) McDonnell Genome Institute Mallinkrodt Imaging ResearchCenter and Early Therapeutic Clinical Trials Network (ET-CTN) to support the goals of developing and utilizingPDX models to test and improve cancer treatment in collaboration with other components of the PDXNet.Finally WU-PDTC through coordination by the Administration Core will support pilot research projectsutilizing the PDX resources and fostering collaboration across PDTCs PNMR-FNLCR and other NCIprograms. The goal is to increase the spectrum of agents tested in PDX clinical trials and to improve thereliability validation utility and standardization of PDX models through innovative Cross-PDXNet research.Our demonstrated capability in generating and utilizing PDX models extensive existing infrastructure andstrong institutional commitment set a solid foundation for a successful PDTC that will help achieve goals set byNCI in advancing the use of PDX models in preclinical testing. 521719 +No NIH Category available Acinar Cell;Address;Alpha Cell;Area;Autoimmune;Biological;Biological Assay;Biology;Cell Communication;Cell Therapy;Cell secretion;Cells;Clinical;Collaborations;Communication;Communities;Data;Dedications;Development;Diabetes Mellitus;Digestion;Discipline;Disease;Disparate;Ductal Epithelial Cell;Duodenum;Endocrine;Endocrinologist;Environment;Enzymes;Exocrine pancreas;Fellowship;Female;Food;Fostering;Functional disorder;Gastroenterologist;Gene Expression Regulation;Generations;Genetic;Genomics;Glucagon;Glucose;Goals;Health;Health system;Homeostasis;Hormones;Human;Image;Immune system;Impairment;In Vitro;Insulin;Interdisciplinary Study;International;Islet Cell;Islets of Langerhans;Italy;Life;Link;Maintenance;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Medical;Mentors;Mentorship;Metabolic;Modeling;Molecular;Mus;Natural regeneration;Oral;Organ;Organoids;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Diseases;Pancreatitis;Physiological;Positioning Attribute;Postdoctoral Fellow;Prevention;Process;Research;Research Personnel;Resolution;Risk Factors;Role;Scientist;Somatostatin;Structure of beta Cell of islet;Students;Surgeon;Time;Training;Underrepresented Minority;Underrepresented Populations;Work;Workplace;career;career development;cell behavior;cell type;chronic pancreatitis;comorbidity;computerized tools;design;diversity and inclusion;empowerment;epidemiology study;exosome;extracellular vesicles;human disease;insight;interdisciplinary approach;islet;lectures;meetings;microbiome;minority investigator;novel;novel strategies;pancreas development;pancreatic cancer model;pancreatic cancer patients;pancreatic juice;peer;pharmacologic;posters;programs;recruit;response;symposium;tool;translational approach 2023 Pancreatic Diseases Gordon Research Conference and Gordon Research Seminar PROJECT NARRATIVEThis Gordon Research Conference (GRC) aims to link the understanding of the biology of the exocrine andendocrine pancreas to applications for human diseases and for the first time will be paired with a trainee-ledGordon Research Seminar (GRS) which will enhance mentorship and career development in these areas. ThisGRC is unique in that it is the only conference that convenes experts from all aspects of pancreas biology aswell as clinicians working on translational approaches for various pancreatic diseases including diabetespancreatitis and pancreatic cancer. By providing a forum for the presentation and discussion of cutting edgeunpublished concepts and approaches the goal of this GRC is to stimulate discussion and collaboration acrossfields and disciplines foster career development female and underrepresented minority researchers as well asto empower young scientists to showcase their work to peers and leaders in the field. NCI 10681581 4/28/23 0:00 PA-21-151 1R13CA281305-01 1 R13 CA 281305 1 "BERA, TAPAN K" 4/28/23 0:00 6/30/23 0:00 ZCA1-PCRB-9(J1) 7337359 "EL-BARDEESY, NABEEL " Not Applicable 2 Unavailable 75712877 XL5ANMKWN557 75712877 XL5ANMKWN557 US 41.480003 -71.569648 2988701 GORDON RESEARCH CONFERENCES East Greenwich RI Domestic For-Profits 28183465 UNITED STATES N 4/28/23 0:00 6/30/23 0:00 396 Other Research-Related 2023 6000 NCI 6000 0 "PROJECT SUMMARYGordon Research Conferences (GRCs) are a group of prestigious non-profit international scientific conferencesthat have been held since 1931. This R13 proposal relates to the GRC on Pancreatic Diseases: ""PancreaticDiseases: Understanding cell behavior and communication and the associated trainee-led Gordon ResearchSeminar (GRS) held April 29 - May 5 2023 in Lucca Italy. Recent years have brought rapid advances in ourunderstanding of the molecular mechanisms underlying pancreatic development regeneration and malignanttransformation as well as our ability to model these processes in mice and human cells. These studies haverevealed lineage relationships between the different pancreatic cell types and plasticity in response toenvironmental influences. Moreover epidemiological studies show a clear association between pancreaticdiseases in particular between diabetes and pancreatic cancer. Yet the mechanisms involved in the co-occurrence of pancreatic diseases are poorly understood. This GRC aims to link the understanding of the biologyof the exocrine and endocrine pancreas to applications for human diseases. This conference is unique in that itconvenes experts from all aspects of pancreas biology as well as clinicians working on translational approachesfor diabetes pancreatic cancer and pancreatitis. By providing a forum for the presentation and discussion ofcutting edge unpublished concepts and approaches the goal of this GRC is to stimulate discussion acrossdisciplines. This exchange will foster interdisciplinary approaches and promote exchange of ideas to lead to newcollaborations as well as empower young scientists to showcase their work to peers and leaders in the field.The upcoming fifth Pancreatic Diseases GRC will focus on understanding cell behavior and communication inpancreatic diseases with the goal of gaining insights into how the systemic and local environment impactendocrine and exocrine cells in health and disease. The program that has been assembled is first-ratebenefitting from the contribution of international world-class scientists engaged in research relevant to differentaspects of pancreatic diseases. The ultimate goal of the conference is the identification of novel concepts inpancreatic diseases that might be exploitable for pharmacological and cell-based therapeutic approaches. Asfor all GRCs the guiding principle of this conference is the presentation of new unpublished results and the freeunhampered discussion that follows. Participation of young scientists is especially emphasized withopportunities of short talks and poster presentations. To further enhance career development opportunities aGordon Research Seminar (GRS) has been integrated into this meeting. Taking place immediately prior to theGRC proper the GRS features posters and talks exclusively by trainees as well as mentorship sessions designedto provide trainees with established mentors willing to help guide their careers. Together this makes for a rareplatform to promote young researchers integrate trainees into the interdisciplinary pancreatic disease researchcommunity and impact their career trajectory at a critical time in their training." 6000 +No NIH Category available Actomyosin;Address;Affect;Biochemical;Biogenesis;Biological;Biology;Cancer Patient;Cell membrane;Cell secretion;Cell surface;Cells;Cellular Membrane;Circulation;Classification;Clinical;Cues;Deposition;Diagnostic;Disease;Distal;Endosomes;Extracellular Matrix Degradation;Family;GTPase-Activating Proteins;Goals;Hodgkin Disease;Immune response;Individual;Instruction;Investigation;Knowledge;Laboratories;Learning;Ligase;Lipids;Malignant Neoplasms;Mediator;Membrane;MicroRNAs;Modeling;Molecular;Nature;Nodule;Nucleic Acids;Paracrine Communication;Parents;Pathologic;Pathway interactions;Patients;Physiological;Pilot Projects;Population;Positioning Attribute;Pre-Clinical Model;Process;Property;Proteins;Proteomics;Recycling;Regulation;Research;Resistance;Role;Secretory Vesicles;Signal Pathway;Signal Transduction;Site;Solid;Spleen;Testing;Therapeutic;Therapeutic Intervention;Tumor Expansion;Tumor Promotion;Tumor-Derived;Vesicle;angiogenesis;cell type;exosome;experience;extracellular;extracellular vesicles;frontier;insight;intercellular communication;interest;laboratory experience;lymph nodes;microvesicles;neoplastic cell;novel;novel strategies;novel therapeutic intervention;paracrine;pre-clinical;prognostic;recruit;rho;trafficking;tumor;tumor microenvironment;tumor progression;vesicular release New approaches to study tumor microvesicles PROJECT NARRATIVE Microvesicles are small membrane enclosed sacs shed by tumor cells and a growingbody of evidence implicates these vesicles as a novel form of intercellular communication in thetumor microenvironment. However we only have a rudimentary understanding about thecellular cues that drive their biogenesis and how they are shed from their parent cells. Byinvestigating the composition of TMVs and mechanisms involved in their release we expect togain new insights into TMVs that in turn will inform new strategies for therapeutic intervention. NCI 10681484 8/23/23 0:00 PAR-20-052 5R03CA273469-02 5 R03 CA 273469 2 "GEORGE, CHRISTINA DAWN" 9/1/22 0:00 8/31/24 0:00 ZCA1-PCRB-9(M1)S 6381341 "D'SOUZA-SCHOREY, CRISLYN " Not Applicable 2 BIOLOGY 824910376 FPU6XGFXMBE9 824910376 FPU6XGFXMBE9 US 41.693901 -86.239284 6169301 UNIVERSITY OF NOTRE DAME NOTRE DAME IN SCHOOLS OF ARTS AND SCIENCES 465565708 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 78250 NCI 50000 28250 ABSTRACT Tumor-derived microvesicles (TMVs) a vesicle subtype in the family of extracellularvesicles (EVs) contain bioactive protein and nucleic acid cargoes and have emerged asimportant mediators of intercellular communication in the tumor microenvironment (TME). Byvirtue of their roles in the TME EVs have been thought to support the spread of metastaticdisease by promoting tumor expansion and tumor invasive activity dampening immuneresponses and facilitating angiogenesis. Thus identifying and targeting molecules andsignaling pathways that control EV biogenesis and/or function has the potential to lead to noveland complementary therapeutic strategies. Moreover the discovery that EVs are found incirculation has heightened interest in these vesicles as promising diagnostic and prognosticplatforms. Although we have learned a great deal about EV function over the past decade thereis need to learn much more about how the various EV subtypes are formed and how theyengage and affect recipient cells in the TME. In particular there is a critical need to define thecellular pathways and signaling mechanisms that underlie TMV biogenesis to better understandtheir paracrine properties and function. Relative to tumor exosomes the other prominent EVsubtype shed by tumor cells we know significantly less about TMVs. Our understanding of themolecular principles that control TMV formation and cargo incorporation remains limited in largepart due to limitations in isolating and precisely defining the molecular makeup of individual EVpopulations. To begin to explore the molecular mechanisms of TMV formation and release wehave adapted a biochemical screen for TMV proteomic studies aimed at identifying TMV-specific cargo and testing novel regulation of TMV biogenesis. The findings that result from thispilot study will form the basis of delineating and testing a mechanistic framework underlyingTMV biogenesis and function in preclinical models of tumor progression. Given our experienceand expertise our laboratory is well position to carry out these investigations. 78250 +No NIH Category available Adjuvant Chemotherapy;Advanced Malignant Neoplasm;Biodistribution;Biological Products;Biopsy;Bulky Disease;Cancer Patient;Cancer cell line;Cancerous;Chemistry;Clinical;Clinical Research;Collaborations;Cyclic GMP;Data;Detection;Development;Diagnostic Neoplasm Staging;Disease;Dose;Drug Kinetics;Dyes;Early Diagnosis;Endoscopy;Evaluation;Excision;Eye;Feasibility Studies;Female;Fluorescence;Fluorescent Dyes;Formulation;Freeze Drying;Human;Image;In Vitro;Intra-abdominal;Investigational Drugs;Lesion;Letters;Light;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Meta-Analysis;Methods;Modeling;Molecular Target;Mus;Near-infrared optical imaging;Neoadjuvant Therapy;Neoplasm Metastasis;Normal tissue morphology;Operative Surgical Procedures;Outcome;Palpation;Patient-Focused Outcomes;Patients;Peritoneal;Pharmaceutical Preparations;Phase;Platinum;Prior Chemotherapy;Procedures;Rattus;Recurrence;Recurrent disease;Recurrent tumor;Resected;Residual Neoplasm;Second Look Surgery;Sensitivity and Specificity;Serous;Small Business Innovation Research Grant;Solid;Stains;Surgeon;Surgical Oncology;Techniques;Technology;Time;Tissues;Toxic effect;Toxicology;Translating;Tumor Debulking;Validation;Vial device;Visual;Visualization;Woman;cancer surgery;chemotherapeutic agent;chemotherapy;experience;first-in-human;human study;image guided;imaging modality;improved;improved outcome;in vivo Model;intraperitoneal;manufacture;medical schools;mouse model;novel;personalized medicine;pre-clinical;prognostic indicator;real-time images;scale up;standard of care;subcutaneous;surgery outcome;targeted treatment;tool;tumor Instantaneous Tumor Spray for Real-Time Surgical Guidance There is no reliable way for surgeons to see all cancerous tissue including small lesions in real-time whileoperating. We are developing a sprayable fast-acting sensitive and tumor specific fluorescent agent whichmakes ovarian cancer tumors glow under near infrared light during surgery. Our technology can potentiallymake the ovarian cancer debulking procedure more precise and safer enabling the surgeon to see morecancerous tissue improving surgical outcomes and reducing the odds of recurrence. NCI 10681383 7/31/23 0:00 PA-21-259 5R44CA275434-02 5 R44 CA 275434 2 "ZHAO, MING" 9/1/22 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-Z(10)B] 1961873 "GRAY, BRIAN DAVID" Not Applicable 6 Unavailable 928315084 Y2FNW7N1V267 928315084 Y2FNW7N1V267 US 39.974774 -75.593742 3327601 "MOLECULAR TARGETING TECHNOLOGIES, INC." WEST CHESTER PA Domestic For-Profits 193804471 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 SBIR/STTR 2023 999432 NCI 830627 109572 Early stage ovarian cancer is typically asymptomatic. Undiagnosed until the disease has reached anadvanced stage the disease presents extensive intra-abdominal peritoneal metastases.Standard of care treatment includes either a surgical cytoreduction to remove tumor bulk then platinum-basedchemotherapy or primary neoadjuvant chemotherapy followed by interval cytoreduction after tumor shrinkage.Despite successful initial treatments 8090% of women with advanced cancer experience tumor recurrence.Surgical outcomes can vary considerably since some cancerous lesions are not visible to naked-eyesurveillance or palpation the only tools available to the surgeon in real-time. There is significant evidence thatan extended disease-free period or even a cure are causally related to how much cancerous tissue is excised.A sensitive specific easy to visualize dye which precisely highlights small (< 5mm) and otherwise hiddenlesions would better differentiate healthy from cancerous tissue enable better informed surgical decisions andlead to better outcomes for ovarian cancer patients.In this collaboration between Molecular Targeting Technologies Inc. and Weill Cornell Medical School we aredeveloping a novel tumor-specific agent for intraoperative near-infrared fluorescence imaging to guide ovariancancer surgeries in real-time. In preliminary feasibility studies we have identified an optimized pH-sensitivenear-infrared fluorogenic dye (CypH-11) which is non-fluorescent in normal tissues but fluoresces immediatelywhen sprayed onto cancer tissue whose microenvironment is slightly acidic. We hypothesize that the cancerselective staining by CypH-11 will make the surgical debulking procedure precise and effective by locatingnormally unseen small and occult lesions achieving a better surgical outcome. This approach could herald aparadigm shift in surgical oncology.In direct to Phase II SBIR studies we will scale-up synthesis and manufacture of CypH-11 and the finalformulated vial in compliance with cGMP; perform preclinical optimization and validation of the CypH-11formulation in a subcutaneous murine model and validate its sensitivity and specificity in an orthotopic modelthat simulates the clinical setting; and obtain pharmacokinetic biodistribution and toxicity data to support anexploratory IND filing. The application will be submitted to the FDA anticipating a Phase 0 first-in-human study. 999432 +No NIH Category available 3-Dimensional;8 year old;Address;Affect;Agreement;Anterior;Biological Markers;Birth;Blindness;Brain Neoplasms;Categories;Central Nervous System;Child;Childhood;Childhood Brain Neoplasm;Clinical;Clinical Trials;Complete Blindness;Data;Devices;Disease Progression;Enrollment;Excision;Friends;Future;Glioma;Goals;Growth;Heterogeneity;Human;Image;Imaging Device;Incidence;Magnetic Resonance Imaging;Manufacturer;Measurement;Measures;Methods;Modeling;Monitor;Neurofibromatoses;Neurofibromatosis 1;Operative Surgical Procedures;Optic Chiasm;Optic Nerve;Optic Nerve Glioma;Optics;Outcome;Pathway interactions;Pattern;Pediatric Neoplasm;Phase III Clinical Trials;Physicians;Prediction of Response to Therapy;Protocols documentation;Recommendation;Resolution;Severity of illness;Shapes;Standardization;Structure;Syndrome;Time;Treatment Failure;Tumor Volume;Vision;Visual;Visual Acuity;Visual Pathways;Visualization;automated segmentation;brain magnetic resonance imaging;cancer predisposition;clinical care;clinical predictors;clinically relevant;cohort;data harmonization;experience;functional outcomes;graphical user interface;image processing;imaging modality;imaging software;improved;machine learning algorithm;machine learning method;novel;precision medicine;quantitative imaging;response;standard of care;success;treatment response;tumor;two-dimensional;user-friendly Quantitative MRI for Pediatric Optic Pathway Glioma Treatment Response PROJECT NARRATIVE In children with brain tumors impacting their vision physicians have difficulty determining when thetreatment is working. We will improve upon the very basic and often inaccurate human measurements of tumorsize by developing quantitative imaging tools to make accurate and automated measures of tumor volume andshape. From these measures we will create methods that will enable clinical trials and physicians to makeinformed decisions about the treatments success and whether the child will recover their vision. NCI 10681375 7/26/23 0:00 PAR-18-248 5UH3CA236536-04 5 UH3 CA 236536 4 "TATA, DARAYASH B" 6/17/20 0:00 7/31/25 0:00 ZCA1-SRB-X(J1)S 10524940 "AVERY, ROBERT ANDREW" "LINGURARU, MARIUS GEORGE " 3 Unavailable 73757627 G7MQPLSUX1L4 73757627 G7MQPLSUX1L4 US 39.946632 -75.196604 1499101 CHILDREN'S HOSP OF PHILADELPHIA PHILADELPHIA PA Independent Hospitals 191462305 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 711517 NCI 588594 122923 ABSTRACT Low-grade glioma is the most common brain tumor in children and often involves one or more structures ofthe anterior visual pathway (i.e. optic nerves chiasm and tracts). Nearly 20% of children withneurofibromatosis type 1 (NF1) will develop a low-grade glioma of the anterior visual pathway which are calledoptic pathway gliomas (OPGs). NF1-OPGs are not amenable to surgical resection and can cause permanentvision loss ranging from a mild decline in visual acuity to complete blindness. Children with NF1-OPGs typicallyexperience vision loss between 1 and 8 years of age and are monitored with brain magnetic resonanceimaging (MRI) to assess disease progression. However traditional two-dimensional (2D) measures of tumorsize are not appropriate to assess change over time and how NF1-OPGs are responding to treatment. Our proposal addresses the lack of robust and standardized quantitative imaging (QI) tools and methodsneeded for NF1-OPG clinical trials. We will develop and validate a novel three-dimensional (3D) MRI-based QIapplication for automated and comprehensive quantification of these unique pediatric tumors. We will usemachine learning algorithms to accommodate MRI sequences from different manufacturers and protocols. Wehypothesize that the novel QI application will accurately assess treatment response in clinical trials. In thisproject we will validate our QI software and machine learning methods to make accurate and automatedmeasures of tumor volume and shape using data from a phase 3 clinical trial of NF1-OPGs. From thesemeasures we will create methods to assess response to therapy that will enable physicians to make informedand objective treatment decisions. Our specific aims are: 1) Develop a comprehensive QI application to perform accurate automatedquantification of NF1-OPGs; 2) Determine and predict treatment response using our 3D QI measures of tumorvolume; and 3) Validate our 3D QI measures using visual acuity outcomes. Upon study completion our QI application could transform clinical care for NF1-OPG by identifying theearliest time to determine a favorable versus unfavorable treatment response. The QI application's ability toaccurately measure treatment response along with harmonizing data across MRI manufacturers andprotocols will standardize imaging assessments essential to NF1-OPG clinical trials. 711517 +No NIH Category available ATAC-seq;Ablation;Algorithms;Androgen Antagonists;Androgen Receptor;Androgens;Area;Award;Binding;Binding Sites;Biological Assay;Cancer Patient;Chromatin;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Computer Models;Data;Data Set;Development;Enhancers;Environment;Epigenetic Process;Event;Funding;Genomics;Goals;Growth;Hormones;Invaded;Laboratories;Learning;Malignant neoplasm of prostate;Molecular and Cellular Biology;Morbidity - disease rate;Nucleosomes;Patients;Pattern;Positioning Attribute;Prostate Cancer therapy;Proteomics;Research;Resistance;Resistance development;Role;Series;Specialist;System;Systems Analysis;Techniques;Therapeutic;Tissues;Transcriptional Regulation;Translations;Work;advanced prostate cancer;anticancer research;base editing;cancer cell;design;epigenome;epigenome editing;epigenomics;experimental study;genetic regulatory protein;genome-wide;hormone therapy;innovation;member;novel;programs;prostate cancer cell;prostate cancer progression;receptor binding;refractory cancer;targeted treatment;tool;transcription factor;transcriptome sequencing Systems analysis of the prostate cancer epigenome Project NarrativeWhile early-stage prostate cancer is commonly treated with anti-hormone therapies advanced cases developresistance to these treatments and become more lethal. Our studies focus on novel epigenetic mechanisms thatare exploited by hormone-resistant prostate cancer cells to gain growth and invasion advantages. Bysystematically analyzing the prostate cancer epigenome at an unprecedented level of detail we will learn whathormone-resistant prostate cancer cells need to survive and inform the design of new potential treatments tobenefit advanced prostate cancer patients. NCI 10681367 7/12/23 0:00 PAR-19-291 5R50CA251843-04 5 R50 CA 251843 4 "JOHNSON, ERIC MICHAEL" 8/14/20 0:00 7/31/25 0:00 ZCA1-SRB-1(M1)S 11712834 "CHEN, ZHONG " Not Applicable 4 PATHOLOGY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 198304 NCI 123170 75134 Project Summary/AbstractAlthough androgen ablation is initially effective for advanced prostate cancer treatment resistance ultimatelydevelops through various mechanisms causing patient morbidity. Systems analysis of the prostate cancerepigenome is a genome-scale approach to understanding the under-studied epigenetic events that characterizeprostate cancer progression to the resistant state. This proposed work is an integral part of the NCI-fundedresearch program U54 CA217297 which focuses on studying epigenetic mechanisms exploited by hormone-resistant cancer cells to acquire growth and invasion advantages. Dr. Qianben Wangs laboratory has recentlyperformed an integrative analysis of strand specific paired-end ChIP-exo (ChIP-ePENS) and MNase-seq dataand discovered an epigenetic mechanism by which genomic and transcriptional regulation are controlled byprecise changes to nucleosome positioning within transcription factor (TF) binding sites. This represents thelatest in a series of findings that have come out of the work of the research specialist Dr. Zhong Chen as theonly key senior member of the Wang laboratory. Dr. Chen facilitated this breakthrough by developing the ChIP-ePENS assay and working with colleagues to develop a new algorithm to perform integrative analysis of ChIP-ePENS and MNase-seq data. The intersection of these innovative techniques led to the identification of uniquefootprint boundary patterns (FBPs) of TF binding that determine how nucleosomes are positioned in and aroundandrogen receptor (AR)-bound enhancers. Additional evidence that AR bound by anti-androgen activatesenhancers with unique FBPs suggested that this epigenetic mechanism is hijacked by hormone-resistant cancercells for AR redeployment under a therapeutic condition. The U54 project will determine the role of nucleosomerepositioning as well as its regulatory proteins in supporting AR redeployment for hormone-resistant prostatecancer. Dr. Chen will be responsible for: (1) generating the high-throughput ChIP-ePENS MNase-seq ATAC-seq and RNA-seq datasets from prostate cancer cells and patient tissues; (2) analyzing sequencing data andparticipating in the development of computational models to assess nucleosome positioning and spacing; and(3) performing molecular and cellular biology experiments including developing novel CRISPR-dCas9-basedediting tools to study nucleosome positioning and prostate cancer progression and using proteomics to identifytranscription factors and chromatin remodelers regulating nucleosome positioning. He will design and utilize afunctional omics-oriented CRISPR/dCas9-based system for therapeutic prostate cancer epigenome editingopening up new areas of research in the Wang lab while facilitating the translation of the U54 epigeneticdiscoveries into therapeutic tools and clinical benefits. The Research Specialist award would provide a stableand ideal research environment in which to pursue his goals in genomic and epigenomic cancer research andto open up a range of opportunities to develop targeted therapies for hormone-resistant cancers. 198304 +No NIH Category available Acute Myelocytic Leukemia;Applications Grants;BCL2 gene;Clinical Research;Development;Disease;Epigenetic Process;Genetic;Goals;Heterogeneity;Human;Intervention;Metabolic;Newly Diagnosed;Oxidative Phosphorylation;Patients;Pharmaceutical Preparations;Property;Regimen;Relapse;Therapeutic;Translations;Work;design;improved;improved outcome;inhibitor;interest;leukemia;leukemic stem cell;standard of care;stem cell biology;stem cell population;therapeutic development;therapeutic target Therapeutic Targeting of Human AML Stem Cells Project NarrativeAcute myelogenous leukemia (AML) is a lethal disease with limited therapeutic options. Thisgrant proposal seeks to develop improved drug regimens to provide better treatment options forpatients with AML.! NCI 10681358 8/8/23 0:00 PAR-19-349 5R35CA242376-04 5 R35 CA 242376 4 "KLAUZINSKA, MALGORZATA" 9/8/20 0:00 8/31/27 0:00 ZCA1-GRB-S(M1) 3051020 "JORDAN, CRAIG T." Not Applicable 6 PEDIATRICS 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 895854 NCI 586951 325757 SummaryThis proposal is focused on the development of improved therapies for acute myeloid leukemia (AML).The central premise of our all our work is that AML is driven by a biologically distinct leukemia stem cell(LSC) population. While the conceptual importance of targeting leukemic disease at its root is clearstudies in recent years have demonstrated that the inherent intra-patient heterogeneity of LSCpopulations makes complete eradication a very challenging objective for most patients. Our studieshave therefore attempted to identify common foundational properties of primary human LSCs that canemployed in the development of therapeutic strategies in the hope that intrinsic heterogeneity can beovercome. Of particular interest we have described distinct metabolic properties in LSCs that providenew opportunities for intervention. Specifically inhibition of BCL2 acts to inhibit oxidativephosphorylation in LSCs resulting in selective eradication of the LSC population. Recent translationof this observation to clinical studies has demonstrated strong efficacy for newly diagnosed AMLpatients and appears to be on the verge of altering the current standard of care. Despite these excitingadvances though relapse remains common and further elucidation of LSC properties is essential. Tothis end we have recently begun to describe the mechanisms that drive relapse of AML patientsfollowing treatment with a BCL2 inhibitor. These studies have identified entirely unexpected and newaspects of LSC biology that have important ramifications for our basic understanding of AML as wellas the design of improved therapeutic regimens. Specifically we have demonstrated that at least twodistinct LSC populations can co-exist in the same patient. The genetic epigenetic and metabolicproperties of co-resident LSC subpopulations can vary giving rise to differing levels of drugresponsiveness. The focus of our studies going forward will be to understand and exploit these findingstowards the goal of improved outcomes for AML patients. 895854 +No NIH Category available Address;Adherence;Age;American Joint Committee on Cancer;Award;Biological;Biology;Breast;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer Treatment;Breast Cancer survivor;Caring;Cellular Phone;Cessation of life;Characteristics;Clinic;Cost Savings;Data;Data Collection;Data Set;Databases;Development;Diagnosis;Dimensions;Disease;Disparity;Ethnic Origin;Female Breast Carcinoma;Focus Groups;Future;Genomics;Geographic Locations;Guidelines;Health system;Healthcare;Healthcare Systems;High Risk Woman;Individual;Inferior;Institution;Interdisciplinary Study;Intervention;Interview;Life;Malignant Neoplasms;Measures;Modeling;Modification;National Comprehensive Cancer Network;Odds Ratio;Oncologist;Online Systems;Outcome;Patient Care;Patient Outcomes Assessments;Patients;Positioning Attribute;Primary Care;Prognosis;Provider;Quality of Care;Race;Recurrence;Recurrent Malignant Neoplasm;Research;Research Personnel;Resources;Risk;Risk Factors;Secure;Socioeconomic Status;Staging;Sterile coverings;System;Tablets;Testing;Time;Tobacco use;United States;United States Department of Veterans Affairs;Validation;Veterans Health Administration;Woman;breast cancer diagnosis;cancer care;cancer recurrence;clinical decision-making;cohort;cost;design;glycemic control;health disparity;improved;improved outcome;indexing;instrument;malignant breast neoplasm;modifiable risk;mortality;neoplasm registry;novel strategies;patient home care;precision medicine;predictive modeling;prognostication;programs;prospective;psychosocial;response;risk prediction model;simulation;tool;treatment and outcome;treatment disparity Using Modifiable Risk Factors to Predict Inferior Care and Survival after Breast Cancer Diagnosis: A Novel Approach to Addressing Health Disparities PROJECT NARRATIVEWe believe the Breast cancer Risk of Inferior Survival and Care (BRISC) prediction model will be an importantcontributor to shared clinical decision-making for breast cancer patients. In the future we hope to develop asmartphone- and tablet-enabled app and web-based calculator that will respectively facilitate clinic-baseddata collection and calculation of the BRISC index as part of routine oncologic care. The BRISC model willallow us to proactively identify some of our most vulnerable patients soon after diagnosis thereby enablinginterventions that can facilitate their receipt of guideline-concordant care and mitigate their risk of avoidablerecurrence and cancer-specific mortality. NCI 10681334 8/10/23 0:00 PAR-18-337 5K08CA241390-05 5 K08 CA 241390 5 "RODRIGUEZ, LARITZA MARIA" 8/6/21 0:00 8/31/24 0:00 Career Development Study Section (J)[NCI-J] 14810441 "FAYANJU, OLUWADAMILOLA M." Not Applicable 3 SURGERY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 194446 NCI 180043 14403 RESEARCH SUMMARY / ABSTRACTDespite overall declines in breast cancer mortality in the United States significant disparities in breast cancertreatment and outcomes persist. Access-related biological psychosocial and provider-specific factorspreviously demonstrated to be associated with disparities after breast cancer diagnosis are on the wholestatic systemic or individual features that are difficult or impossible to change. As an alternative approach toaddressing disparities in breast cancer we propose creating a risk prediction model for Breast cancer Risk ofInferior Survival and Care (BRISC) that incorporates dynamic modifiable risk factors to identify women atgreatest risk for compromised care and worse survival after diagnosis with breast cancer. After developmentand validation we will use the BRISC model to conduct statistical simulations and costing activities to estimatethe improvement in value (i.e. outcomes achieved per health-care dollar spent) achieved via implementation ofhigh-impact risk-modifying interventions to facilitate receipt of guideline-concordant breast cancer treatment.Finally we will develop a parsimonious clinic-based data collection tool to be completed by patients andproviders for the purpose of operationalizing the BRISC model as a component of routine oncologic care. 194446 +No NIH Category available Aminolevulinic Acid;Antibodies;Antibody Therapy;Biological;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Neoplasms;Clinical;Clinical Research;Clinical Trials;Consumption;Contrast Media;Craniotomy;Disease;Dose;Drug Delivery Systems;Epidermal Growth Factor Receptor;Excision;Failure;Fc Receptor;Fluorescence;Geography;Glioblastoma;Glioma;Heterogeneity;Histologic;Human;Image;Image-Guided Surgery;Infusion procedures;Investments;Label;Lead;Light;Magnetic Resonance Imaging;Malignant Neoplasms;Measures;Methods;Modality;Molecular;Molecular Biology;Normal tissue morphology;Operative Surgical Procedures;Patient Schedules;Patient Selection;Patients;Penetration;Pharmaceutical Preparations;Proteins;Radiology Specialty;Safety;Sensitivity and Specificity;Specificity;Surgeon;Surgical complication;Systemic Therapy;Techniques;Technology;Therapeutic;Therapeutic antibodies;Time;Tissues;Tumor Tissue;Visualization;biomarker identification;cancer imaging;contrast enhanced;cost;density;drug distribution;first-in-human;fluorescence imaging;fluorophore;improved;in vivo;molecular marker;optical imaging;overexpression;panitumumab;patient prognosis;predictive marker;prevent;radiological imaging;surgery outcome;targeted treatment;tumor Optical Imaging to Improve Surgery & Targeted Therapy in Brain Tumors PROJECT NARRATIVEThe overall survival and prognosis of patients depends on performing more accurate surgical resections andincreasing penetration of therapeutic drugs into the blood-brain barrier. We propose to use an antibody-basedimaging strategy to improve extent of tumor resection in a first in human clinical trial using fluorescently labeledantibodies. Furthermore we propose to qualitatively and quantitatively measure antibody delivery into braintumors in order to develop predictive markers for associated with increased the efficiency of antibody delivery inthis devastating disease. NCI 10681315 9/4/23 0:00 PAR-18-560 5R01CA239257-05 5 R01 CA 239257 5 "TATA, DARAYASH B" 9/2/19 0:00 8/31/24 0:00 Imaging Guided Interventions and Surgery Study Section[IGIS] 8921030 "LI, GORDON " "ROSENTHAL, EBEN L" 16 NEUROSURGERY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 508841 NCI 325138 183703 PROJECT ABSTRACTThe overall survival and prognosis of patients suffering from brain tumors remain dismal; most patients die fromtheir disease. Hope for these patients depends on performing more accurate surgical resections and increasingpenetration of therapeutic drugs into the blood-brain barrier. We propose to use an antibody-based imagingstrategy to improve extent of tumor resection and to develop new methods to quantify and increase the efficiencyof antibody delivery in this devastating disease.We propose to use an antibody (panitumumab) targeting the epidermal growth factor receptor (EGFR) labeledwith a near-infrared fluorophore (IRDye800) to conduct a first-in-human trial in brain tumor patients scheduled toundergo surgical resection. For our clinical study we will first evaluate the sensitivity and specificity ofpanitumumab-IRDye800 to detect brain tumors at different doses of the study drug and assess its safety. Thenwe propose to quantitate antibody delivery into tumor and peritumoral tissue and correlate with pre-surgicalimaging to predict increased antibody delivery. Furthermore we will determine if manipulation of the blood-brainbarrier can improve delivery of antibody into the tumor leveraging the use of fluorescently labeled antibodies totrack antibody delivery into the tumor. Through this application we hope to improve tumor visualization duringsurgery and to develop techniques to predict antibody delivery to brain tumors. This would be the first time thata fluorescently-labeled antibody is used for real-time intraoperative imaging and quantification of antibodydelivery to human brain tumors. 508841 +No NIH Category available Ablation;Animal Model;Biomimetics;Blood coagulation;Blood specimen;CD8-Positive T-Lymphocytes;Cancer Cell Growth;Cancer Etiology;Cessation of life;Chemoresistance;Clinical;Coagulation Process;Collagen;Data;Deposition;Desmoplastic;Disease;Drug Delivery Systems;Drug resistance;Economics;Evaluation;Extracellular Matrix;Extracellular Matrix Proteins;FDA approved;Feedback;Fibrin;Fibrinogen;Fibroblasts;Fibrosis;Goals;Growth;Healthcare;Healthcare Systems;Hyaluronan;Immune;Invaded;Knowledge;Lead;Libraries;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Molecular;Molecular Target;Outcome;Outcomes Research;PAR-1 Receptor;Pancreatic Ductal Adenocarcinoma;Patients;Peptide Hydrolases;Pharmaceutical Preparations;Reagent;Reporting;Research;Resistance;Role;Signal Pathway;Signal Transduction;Survival Rate;Syndrome;System;T-Lymphocyte;Testing;Therapeutic;Thrombin;Tissue Model;Translating;Translational Research;Treatment outcome;Tumor-associated macrophages;clinically relevant;drug efficacy;efficacy validation;improved;in vivo;inhibitor;novel strategies;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pharmacologic;programs;recruit;standard of care;therapeutically effective;therapy resistant;translational potential;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;vascular inflammation;venous thromboembolism Reprogramming PDAC Stroma by Targeting Coagulation in the Tumor Microenvironment PROJECT NARRATIVEPancreatic cancer is the third leading cause of cancer deaths in the U.S. with approximately 60430 newcases anticipated in 2021 resulting in a projected $3.2 billion burden to the healthcare system. The diseaseposes significant healthcare economic and societal challenges. The proposed research will test a promisingnew idea of targeting the blood clotting system to improve drug delivery and efficacy for treating pancreaticcancer. NCI 10681313 9/11/23 0:00 RFA-CA-21-041 5U01CA274304-02 5 U01 CA 274304 2 "NOTHWEHR, STEVEN F" 9/1/22 0:00 8/31/27 0:00 ZCA1-SRB-K(M1) 8525980 "HAN, BUMSOO " "FISHEL, MELISSA L; FLICK, MATTHEW J" 4 ENGINEERING (ALL TYPES) 72051394 YRXVL4JYCEF5 72051394 YRXVL4JYCEF5 US 40.41872 -86.910361 1481402 PURDUE UNIVERSITY WEST LAFAYETTE IN BIOMED ENGR/COL ENGR/ENGR STA 47906 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 928040 NCI 791046 136994 PROJECT SUMMARYThe overarching goal of this research program is to identify therapeutic strategies to convert the stroma ofpancreatic ductal adenocarcinoma (PDAC) to a chemo- and immune-sensitive tumor microenvironment (TME).PDAC is characterized by a desmoplastic stroma that facilitates tumor growth/invasion chemoresistance ofpancreatic cancer cells (PCC) and immunosuppressive TME. Highly packed cancer-associated fibroblasts(CAFs) and dense extracellular matrix (ECM) are hallmarks of the PDAC stroma and constitute physical drugdelivery barriers. Several stromal components have been targeted to enhance drug delivery but recent studieshave suggested anti-tumor roles for the stroma as complete ablation of stromal components leads to moreaggressive tumors. New strategies are highly desired to reprogram stroma without compromising its anti-tumorroles. The central hypothesis is that the coagulation system in the PDAC TME can be targeted to reprogramPDAC stroma to overcome chemoresistance drug delivery barriers and immunosuppressive TME. Cancer-associated coagulation has been reported as a key functional signaling pathway in PDAC. Notably severalcoagulation molecular targets including thrombin protease-activated receptor 1 (PAR1) and fibrinogen/fibrinhave been implicated in important roles contributing to tumor progression and therapeutic resistance.Specifically it is hypothesized that the thrombin-PAR1 signaling axis can be targeted to suppress PCCgrowth/invasion and CAF growth/fibrosis. In addition thrombin-mediated fibrin deposition can be targeted tosuppress the drug delivery barrier and immunosuppressive TAM activities which suppresses anti-tumor T cellactivities. This hypothesis will be tested mechanistically and evaluated for translational potential by pursuingthe following two integrated aims: Aim 1) Mechanistic Research: Determine the contribution of the coagulationtargets in the PDAC TME. Specifically the team will determine the role of thrombin-PAR1 signaling axis toCAF-mediated fibrosis thrombin-mediated fibrin deposition on drug resistance and PAR1/fibrin on theimmunosuppressive TME. Aim 2) Translational Research: Evaluate the pharmacological inhibition of thecoagulation targets. Especially the team will expand the mechanistic understanding from Aim 1 using patient-derived PDAC models with FDA-approved inhibitors of thrombin and PAR1 and fibrinogen depleting agents.The effects of pharmacological inhibition will feedback to Aim 1 to delineate the efficacy of inhibitingcoagulation targets. The outcome of this research will establish a new mechanistic understanding of the role ofcoagulation activities in the PDAC TME. It will determine whether blockade of the coagulation is a promisingstrategy to reprogram the PDAC stroma and ultimately suppress PCC/CAF growth and improve drug deliveryand efficacy. 928040 +No NIH Category available Achievement;African American population;Area;Biological Markers;Biopsy;Blood;Blood specimen;Body Fluids;Cancer Patient;Cells;Cerebrospinal Fluid;Cessation of life;Clinical;Collaborations;DNA;Data;Decision Making;Detection;Development;Disease;European;Evaluation;Excision;Feasibility Studies;Future;Genes;Genetic;Genomics;Goals;Grant;Health;Historically Black Colleges and Universities;Human;Joints;Legal patent;Lipids;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Measures;Messenger RNA;Modality;Molecular;Monitor;Neoplasm Metastasis;Newly Diagnosed;Normal Cell;Operative Surgical Procedures;Outcome;Outcomes Research;Patients;Physicians;Preparation;Process;Prostate;Prostate-Specific Antigen;Prostatectomy;Prostatic;Proteins;RNA;Radiation Monitoring;Radiation therapy;Radical Prostatectomy;Recurrence;Research;Research Infrastructure;Rest;Risk;Risk Assessment;Saliva;Sampling;Site;Testing;Time Study;Tissues;Toxic effect;Universities;Urine;Urologic Oncology;Urology;Vesicle;Virginia;Work;anticancer research;cancer genomics;clinical decision-making;cohort;detection method;exosome;extracellular vesicles;follow-up;improved;liquid biopsy;medical schools;men;microvesicles;neoplastic cell;non-invasive monitor;novel;particle;prognostic;prostate biopsy;proton therapy;recruit;response;response biomarker;serum PSA;specific biomarkers;tool;trafficking;treatment response;tumor;tumor microenvironment;unnecessary treatment Exosomal RNA: A Novel Signature Guide for Prostate Cancer Proton Therapy Project Narrative and relevance to human health and diseaseCurrent clinical tool in prostate cancer serum Prostate Specific Antigen (PSA) can only suggest abnormalitiesin prostatic glands but cannot clearly ascertain cancer. Exosomes are tiny vesicles shed by cells into body fluidsthat can be used to evaluate disease condition including cancer. By determining if analysis of these exosomescan let physicians monitor response to proton therapy we will further the goal of providing tailored proton therapytreatment to prostate cancer patients. NCI 10681297 9/8/23 0:00 PAR-18-911 5P20CA264075-03 5 P20 CA 264075 3 9/22/21 0:00 8/31/25 0:00 ZCA1-SRB-2 9719 9035623 "HEYLIGER, SIMONE OLIVIA" Not Applicable 3 Unavailable 3135068 KSJKE3KVNBB4 3135068 KSJKE3KVNBB4 US 37.025661 -76.347732 3163501 HAMPTON UNIVERSITY HAMPTON VA Domestic Higher Education 236680108 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 87553 58369 29184 Project Summary / AbstractProton therapy (PT) is a form of radiation therapy used to treat prostate cancer patients that can be analternative to surgery. While PT is thought to risk less toxicity than conventional radiation therapy much aboutPT is still not understood. To help serve their local area of tidewater Virginia which has one of the highestrates of prostate cancer in the world especially in African-Americans Hampton University (HU) a HistoricallyBlack University has opened the Hampton University Proton Therapy Institute. To help build the researchcapacity at HU leveraging their clinical expertise in proton therapy the Icahn School of Medicine at MountSinai (ISMMS) and HU propose this joint project aimed at developing a noninvasive biomarker for response toPT. The team at ISMMS will bring their expertise in genomics and exosome profiling a noninvasive way tomeasure particles that are thought to shed from the tumor to this project and in the process help build theresearch capacity at HU. The research goal of this project is to determine changes in the exosomal RNA(exoRNA) profile of exosomes taken from prostate cancer patients before and after radiotherapy with PT. Allaims of the study use patient samples collected at the HUPTI by the HU team. In aim 1 we will ask if anexosomal signature of radical prostatectomy shows similar changes before and after PT. In aim 2 todetermine if there are specific changes in the mRNA profile in response to PT we will globally profile RNAisolated from exosomes before and after PT. In aim 3 to continue to build this project in preparation for afuture collaborative R01 submission we will recruit additional patients from HUPTI to this study and obtainblood specimens before during and after PT. At the end of the study time period our scientific achievementwill have been to determine what changes in the RNA profile of exosomes can be observed in response to PT.This will be important preliminary data demonstrating the utility of exosomes for noninvasive monitoring of PT.More importantly through this collaborative partnership between ISMMS and HU we will have enhanced theresearch infrastructure of HU in a way that will allow HU to pursue further research both jointly with ISMMS andindependently building on their clinical expertise in proton therapy. +No NIH Category available Acceleration;Advisory Committees;Applications Grants;Area;Biomedical Research;Biometry;Clinical;Clinical Research;Collaborations;Communication;Complex;Coupled;Data Science;Development;Distance Learning;Education;Educational Curriculum;Electronic Mail;Epidemiology;Faculty;Feasibility Studies;Fostering;Funding;Genetic;Genomics;Goals;Grant;Health Disparities Research;Human Resources;Hybrids;Impact evaluation;Institution;Intervention;Mentorship;Minority;Minority Groups;Monitor;Online Systems;Persons;Play;Population;Productivity;Progress Reports;Publications;Research;Research Methodology;Research Personnel;Research Project Grants;Research Support;Research Training;Role;Schedule;Series;Site;Students;System;Teacher Professional Development;Training;Training and Education;Underrepresented Minority;United States National Institutes of Health;Universities;Update;Videoconferencing;anticancer research;cancer genetics;cancer genomics;cancer health disparity;community engaged research;design;equity diversity and inclusion;faculty community;genome sciences;health disparity;innovation;insight;lectures;medical schools;meetings;member;minority investigator;novel;people of color;programs;response;skills;success;symposium;translational cancer research;translational genomics;virtual;web site Administrative Core Project Narrative: Training and Education ProgramDiverse investigators play an integral role in identifying novel research questions perspectives and solutionsto complex biomedical challenges. Yet diversifying the biomedical research workforce remains a majorchallenge in the USdespite the fact thatunderrepresented minorities make up the most rapidly growingsegment of the US population Thus in a unique partnership between the Icahn School of Medicine at MountSinai and Hampton University we propose to provide hybrid training and education to increase the researchcapacity engagement and success of the HU scientific workforce with particular emphasis on genetics andgenomics and cancer disparities research. NCI 10681294 9/8/23 0:00 PAR-18-911 5P20CA264075-03 5 P20 CA 264075 3 9/22/21 0:00 8/31/25 0:00 ZCA1-SRB-2 9717 9035623 "HEYLIGER, SIMONE OLIVIA" Not Applicable 3 Unavailable 3135068 KSJKE3KVNBB4 3135068 KSJKE3KVNBB4 US 37.025661 -76.347732 3163501 HAMPTON UNIVERSITY HAMPTON VA Domestic Higher Education 236680108 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Research Centers 2023 60808 40538 20270 PROJECT SUMMARY: TRAINING AND EDUCATION PROGRAM While minority faculty in the clinical and translational sector may provide an innovative perspective fromwhich we identify problems disproportionately plaguing populations of color they often lack the researchcapacity needed to both rigorously evaluate the causal predictors of these problems and identify mechanisticmodes of intervention for the elimination of health disparities. Moreover minority investigators encounter majorbarriers to successful competition for federal research funding which include but are not limited to: inadequateresearch training a lack of opportunities for professional development insufficient mentorship and inadequatesupport for research focused on minority populations (Shavers 2005). Thus in response to PAR-18-911 our goal is to partner with Hampton University (HU) faculty in orderto provide hybrid training and education to increase HU research capacity in the area of cancer genomics andhealth disparities while also providing a rigorous curriculum in introductory and advanced biostatistics anddata science clinical genome science epidemiology community-engaged research health disparitiesresearch and clinical research methods. The curriculum will be administered through online asynchronous andsynchronous lectures coupled with intensive on-site training sessions in Years 2 through 4 of the proposedfour-year partnership. Our objectives are to: 1) successfully implement the online cancer genomics researchtraining and education program; 2) design and successfully implement the on-site research training educationprogram; and 3) conduct a rigorous evaluation of the impact of the proposed training and education programon building research capacity and increasing research engagement and productivity. Additionally HU will beproviding extensive insight and guidance to help foster a culture of inclusion diversity and equity amongmembers of the ISMMS research workforce through a series of in-person and virtual lectures. In summary we are confident that our proposed comprehensive online and on-site training andeducation program will increase the competitive success of federal grant submissions by HU faculty for cancerhealth disparities genomics research projects while also providing them with an optimal skill-set that they candisseminate to the larger HU community of faculty and students. +No NIH Category available Address;African American population;Area;Behavioral;Biological;Biometry;Clinical Investigator;Collaborations;Complement;Consultations;Coupled;Data;Data Collection;Detection;Disparity;Educational Activities;Educational Materials;Educational process of instructing;Ensure;Environment;Environmental Risk Factor;Epidemiology;Etiology;Exposure to;Extramural Activities;Faculty;Feasibility Studies;Funding;Genetic;Genetic Variation;Genomics;Goals;Health;Health Disparities Research;Institution;Interdisciplinary Study;Joints;Lead;Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Mentors;Methodology;Methods;Minority;Outcome;Pilot Projects;Population;Productivity;Records;Registries;Research;Research Institute;Research Personnel;Research Project Grants;Resources;Scientist;Series;Site;Students;Time;Training;Training Activity;Training and Education;Translational Research;Travel;Universities;Vulnerable Populations;anticancer research;cancer epidemiology;cancer genetics;cancer genomics;cancer health disparity;cancer type;didactic education;education research;epidemiology study;experience;faculty research;genetic epidemiology;genomic epidemiology;hands on research;health disparity;improved;innovation;malignant breast neoplasm;medical schools;model building;novel;programs;proton therapy;social factors;statistics;success;survivorship;treatment and outcome;treatment response;undergraduate education 2/2: Feasibility study to build a collaboration in genetics and genomic cancer research Project NarrativeThis is a partnership between Hampton University (HU) and the Tisch Cancer Institute (TCI) atMount Sinai School of Medicine that seeks to establish robust collaborations through on-siteand online training and education to increase HU research capacity in the area of genetics andgenomics and health disparities using the examples of prostate and breast cancer. The finalgoal is to create a competitive and sustainable joint Center for Genetics and Genomics CancerResearch encompassing the genetics and genomics aspects of health disparities to explainpopulation differences in breast and prostate cancer occurrence and outcome. NCI 10681293 9/8/23 0:00 PAR-18-911 5P20CA264075-03 5 P20 CA 264075 3 "RODRIGUEZ, LARITZA MARIA" 9/22/21 0:00 8/31/25 0:00 ZCA1-SRB-2(M2) 9035623 "HEYLIGER, SIMONE OLIVIA" "AZAD, NEELAM " 3 PHARMACOLOGY 3135068 KSJKE3KVNBB4 3135068 KSJKE3KVNBB4 US 37.025661 -76.347732 3163501 HAMPTON UNIVERSITY HAMPTON VA SCHOOLS OF PHARMACY 236680108 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 397 Research Centers 2023 199848 NCI 133232 66616 Project SummaryThis is a partnership between Hampton University (HU) and the Tisch Cancer Institute (TCI) atMount Sinai School of Medicine that seeks to establish robust collaborations on-site and onlinetraining and education to increase HU facultys research capacity in the area of genetics andgenomics and health disparities while increasing TCI research in health disparities using theexamples of prostate and breast cancer. The final goal is to create a competitive and sustainablejoint Center for Genetics and Genomics Cancer Research encompassing the genetics andgenomics aspects of health disparities to explain population differences in breast and prostatecancer occurrence and outcome. The proposal is grounded in a longstanding and productiveundergraduate educational collaboration between faculty at these two institutions but is distinctin its focus methods and goals. Hence the proposed program will utilize the best practiceslearned from previous collaborative endeavors to inform and create an innovative platform whichwill enhance research capacity at both institutions while addressing key institutional challenges.Our goals will be accomplished through a series of well-coordinated training/educational activitiesand two pilot research projects that were strategically chosen to meet our overarching goals of 1)improving health outcomes in vulnerable populations 2) addressing gaps in cancer disparitiesresearch 3) augmenting genomic statistics epidemiology expertise and 4) enhancinginvestigator productivity and extramural funding competitiveness. Training and education will aimto increase HU facultys research capacity in the area of genetics and genomics and healthdisparities using the examples of prostate and breast cancer. It will provide TCI ISMMS withaccess and collaboration to scientific projects in breast and prostate cancer disparity etiologytreatment and outcome as well as to a mechanism to increase the diversity of the genetics andgenomics faculty which has traditionally lacked diversity. To ensure the success of the trainingand education program we have assembled an excellent team of faculty with outstandingmentoring and teaching track records along with extensive expertise in developing andimplementing new initiatives aimed at diversifying the clinical investigator workforce andeliminating health disparities. HU faculty will also be exposed to the most novel and cutting edgemethods in cancer genomics through the completion of the pilot research project. 199848 +No NIH Category available ATM gene;Address;BARD1 gene;BRCA1 gene;BRCA2 gene;Base Sequence;Benign;Breast;Breast Cancer Detection;Breast Cancer Risk Factor;C-terminal;CHEK2 gene;Catalogs;Classification;ClinVar;Clinical;Clinical Management;Clinical Trials;Consensus;Data;Databases;Development;Diagnosis;Disease;Endoscopic Ultrasonography;Family;Family member;Genes;Germ-Line Mutation;Guidelines;Hereditary Malignant Neoplasm;Individual;Inherited;Intervention;Knowledge;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Mammography;Mediating;Medical;Methods;Modeling;Mutation;Odds Ratio;Oncogenes;Operative Surgical Procedures;Ovarian;PALB2 gene;Pancreas;Pathogenicity;Platinum Compounds;Poly(ADP-ribose) Polymerase Inhibitor;Prevention;Preventive;Process;Qualifying;RAD51C gene;RNA Decay;RNA Splicing;Risk;Risk Assessment;Risk Management;Salpingo-Oophorectomy;Site;Specific qualifier value;Susceptibility Gene;Testing;Therapeutic;Variant;Vertebral column;Woman;Work;brca gene;cancer predisposition;clinical practice;clinically relevant;family genetics;genetic testing;high risk;in silico;individualized medicine;loss of function;malignant breast neoplasm;prophylactic;research clinical testing;screening;segregation;targeted treatment;ultrasound;variant of unknown significance;web site BRCA1/2 and Hereditary Breast Ovarian and Pancreatic (HBOP) Cancer Variant Curation Expert Panels PROJECT NARRATIVEThe catalogs of variants in the BRCA1 BRCA2 and Hereditary Breast Ovarian and Pancreatic (HBOP) cancergenes that will be established as pathogenic or benign are expected to greatly impact clinical management ofindividuals diagnosed with variants in these cancer genes. NCI 10681272 7/26/23 0:00 PAR-20-101 5U24CA258058-02 5 U24 CA 258058 2 "ROTUNNO, MELISSA" 8/10/22 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-GGG-B(50)R] 1899922 "COUCH, FERGUS JOSEPH" "SPURDLE, AMANDA BARBARA" 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Other Research-Related 2023 251798 NCI 214534 37264 PROJECT SUMMARYWomen with germline variants in breast ovarian and pancreatic cancer predisposition genes are at significantlyelevated risk of developing these cancers in their lifetime. Clinical hereditary cancer genetic testing forpathogenic variants in these genes has become an important part of clinical practice. Much of the benefits ofgenetic testing are associated with the BRCA1 and BRCA2 genes because of the risk management surgicalprevention and targeted treatment benefits associated with knowledge of the presence of a cancer predisposingpathogenic variants. However identification of pathogenic variants in other predisposition genes including ATMBARD1 BRIP1 CHEK2 PALB2 RAD51C and RAD51D is also clincially meaningful because carriers mayqualify for enhanced screening for breast ovarian and pancreatic cancer. However this process is oftencomplicated by an inability to establish the clinical relevance of variants in these genes. This lack of informationabout these variants means that individuals carrying germline variants often cannot benefit from enhanced riskassessment and management or make informed decisions about surgical prevention or tailored treatmentoptions. To address this issue we have developed a ClinGen BRCA1/2 Variant Curation Expert Panel (VCEP)and a Hereditary Breast Ovarian and Pancreatic (HBOP) VCEP. We will develop ACMG-like rules-basedmethods for variant classification in each of the genes described above and apply these rules to classification ofobserved variants in these genes. Thus the Aim of this application is to curate and classify the clinicalrelevance of germline variants in BRCA1 and BRCA2 through a BRCA1/2 VCEP and variants in ATMBARD1 BRIP1 CHEK2 PALB2 RAD51C and RAD51D through the HBOP VCEP. The results from theproposed curation efforts will be entered into the ClinGen Variant Curation Interface and made available to thepublic through the ClinVar and BRCA Exchange websites. 251798 +No NIH Category available Address;Affect;Automobile Driving;BNIP3L gene;CHD1 gene;Cancer Patient;Cells;Communities;Computer Models;Data;Data Set;Development;Disease;Disease Progression;Drug Combinations;Drug Synergism;Drug Targeting;Engineering;Engraftment;Evaluation;Gene Expression;Gene Expression Regulation;Genes;Genetic Engineering;Genetic Transcription;Genetically Engineered Mouse;Genitourinary system;Gleason Grade for Prostate Cancer;Goals;Growth;Human;Human Pathology;Immunocompetent;In Vitro;Kidney;Kidney Transplantation;Lasers;Localized Disease;MAP3K7 gene;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Mesenchyme;Methods;Modeling;Molecular;Morphology;Mus;Neoplasm Metastasis;Network-based;PTEN gene;Pathologic;Pathology;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Phenotype;Primary Neoplasm;Process;Prognostic Marker;Prostate;Prostate Cancer therapy;Protocols documentation;Publishing;RB1 gene;Research;Resources;Site;Structure;System;Systems Analysis;TP53 gene;Testing;Tetanus Helper Peptide;Therapeutic;Therapeutic Uses;Tissue Differentiation;Tissue Recombination;Tissues;Tumor Subtype;Tumor Suppressor Proteins;Tumor stage;Xenograft procedure;cancer cell;capsule;cell type;clinically actionable;cost effective;curative treatments;drug efficacy;drug testing;fetal;gain of function;genetic manipulation;genomic aberrations;human disease;in silico;in vivo;in vivo Model;innovation;interest;knockout gene;models and simulation;molecular marker;molecular subtypes;molecular targeted therapies;mouse model;neoplastic;network models;novel;novel therapeutic intervention;novel therapeutics;patient subsets;pharmacologic;pre-clinical;prevent;prostate cancer model;prostate cancer progression;stem cell model;stem cells;success;synergism;targeted treatment;therapeutic target;transcriptome sequencing;treatment strategy;tumor;tumor growth Systems analysis of aggressive prostate cancer pathology NarrativePrimary prostate cancer tissue morphology is highly predictive of disease aggressiveness. Leveraging novelcomputational and in vivo experimental approaches we will model characterize and pharmacologically targetmulti-genic molecular subtypes that promote aggressive primary prostate cancer pathology. NCI 10681271 8/28/23 0:00 PAR-16-131 5U01CA231978-05 5 U01 CA 231978 5 "DUECK, HANNAH RUTH" 9/1/19 0:00 8/31/24 0:00 ZCA1-SRB-C(J1) 10562004 "COSTELLO, JAMES CHRISTOPHER" "CRAMER, SCOTT D" 6 PHARMACOLOGY 41096314 MW8JHK6ZYEX8 41096314 MW8JHK6ZYEX8 US 39.745098 -104.837605 1199905 UNIVERSITY OF COLORADO DENVER Aurora CO SCHOOLS OF MEDICINE 800452571 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 598524 NCI 387283 211241 Project SummaryTissue pathology is a manifestation of the genomic aberrations that define cancer (i.e. stage grade type). Inprostate cancer the best prognostic marker is Gleason score the composite tumor grading system thatsummarizes primary tumor morphology. Subsets of patients with localized disease inevitably developmetastases a point where it is often too late for curative treatment. Thus we propose to model andtherapeutically target molecular subtypes that drive aggressive primary prostate cancer. We start from largeomic datasets and use tissue pathology and gene expression as the readout of disease development. Toevaluate the direct effect of molecular drivers of aggressive primary disease we use a novel prostate stem celltissue recombination mouse model that recapitulates prostate development and tissue pathology. To modelspecific molecular subtypes we will genetically engineer mouse prostate stem cells to introduce geneknockouts or Tet-regulated genes. These engineered cells will then be combined with fetal urogenitalmesenchyme and engrafted under the mouse kidney capsule to produce prostate structures. We will evaluatetissue pathology and isolate regions of interest with aggressive tissue morphology (e.g. cribriform patterning)for RNA sequencing. Using this approach to model three mutually exclusive molecular subtypes we candirectly compare and contrasts gene expression and pathways changes to identify common and subtype-specific effects. Using these data along with omic data from patients we will use two network-basedcomputational models to identify novel therapeutic treatments and capture the systems-level gene regulationand functional relationships. The therapeutic predictions will be screened in vitro using engineered mouse andhuman cells with promising treatments being promoted for testing in the tissue recombination mouse model.Overall through this project we will study drivers of aggressive primary prostate cancer characterizemechanisms of disease development and identify pre-clinical pharmacological treatment strategies.Computational models and the prostate stem cells will be valuable resources for the CSBC and larger researchcommunities. 598524 +No NIH Category available Address;Advanced Malignant Neoplasm;Age of Onset;Cancer Biology;Cells;Clinical;Clinical Data;Clinical Sciences;Collaborations;Common Data Element;Communication;Community Outreach;Comprehensive Cancer Center;Controlled Vocabulary;DNA;DNA Sequence;DNA Sequence Alteration;Data;Data Collection;Databases;Development;Diagnostic Procedure;Disparity;Dissemination and Implementation;Documentation;Education;Ensure;Equity;FAIR principles;Faculty;Fostering;Future;Gene Expression;Genes;Genomics;Goals;Incidence;Ions;Knowledge;Malignant Neoplasms;Medicine;Office of Administrative Management;Ohio;Participant;Policies;Population;Positioning Attribute;Postdoctoral Fellow;Prevention strategy;Process;Public Relations;Research;Research Personnel;Research Support;Resources;Route;STEM research;Scholars Program;Scientist;Site Visit;Technology;The Cancer Genome Atlas;Training;Translational Research;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Universities;Work;cancer cell;cancer genome;cancer genomics;cancer health disparity;cancer therapy;clinical center;collected works;college;community based participatory research;community engagement;data standards;data submission;epidemiologic data;ethnic minority;experience;genome sequencing;genomic data;genomic profiles;health disparity;health equity promotion;improved;innovation;insight;meetings;member;mortality;neoplastic cell;next generation sequencing;novel;outreach;patient engagement;preference;programs;racial minority;rare cancer;success;support network;web site;working group Participant Engagement and Cancer Genome Sequencing (PE-CGS): Coordinating Center Project NarrativeCancer genomics helps advance cancer treatments by identifying how DNA and genes differ in cancer cells.Greater participant engagement in genomics studies is needed to address gaps in knowledge among rarecancers highly lethal cancers cancers with an early age of onset cancers with high disparities inincidence/mortality and cancers among under-represented minorities. The Participant Engagement and CancerGenome Sequencing (PE-CGS) Network will promote participant engagement in genomics studies. As theCoordinating Center of this Network we will help with coordination and community outreach identify best-practices in participant engagement and genomics and address health disparities in cancer genomics. NCI 10681269 9/7/23 0:00 RFA-CA-19-046 5U24CA252977-04 5 U24 CA 252977 4 "FILIPSKI, KELLY" 8/12/20 0:00 7/31/25 0:00 ZCA1-TCRB-O(M1) 9046115 "BRIDGES, JOHN F." Not Applicable 3 MISCELLANEOUS 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 353 Other Research-Related 2023 491400 NCI 399968 223983 AbstractCancer genomics aims to improve our understanding and treatment of all cancers by identifying differences inDNA sequence and gene expression between tumor cells and normal host cells. Cancer genomics hascontributed to many advances in treating several cancers but the field is limited by a lack of genomics data. TheParticipant Engagement and Cancer Genome Sequencing (PE-CGS) Network will promote and supportresearch on direct participant engagement approaches to address these gaps especially among rare cancershighly lethal cancers cancers with an early age of onset cancers with high disparities in incidence/mortality andcancers among under-represented minorities. Our team wishes to contribute to the important work of the (PE-CGS) Network by serving as itscoordinating center. We have the necessary faculty resources and experience to address the needs andgoals of the Network by supporting network coordination promoting effective and equitable outreach andpromotion and establishing and disseminating network best practices. In addition to meeting all the requirementsof the RFA we bring innovation by establishing Participant Engagement Community (PEC) by applying theprinciples of community-based participatory research and by promoting a diverse pool of future scientistsespecially those from underrepresented groups through a Summer Scholar Program and by two post-doctoralpositions that will be supported by our comprehensive cancer center. Our proposal for the coordinating center is focused around four specific aims. First we will effectivelymanage administrative and scientific coordination of the PE-CGS network. This will include providingadministration/coordination governing all advisory organizing meetings/site visits fostering collaborationdissemination and implementation and coordinating communication. Second we will foster effective andculturally appropriate outreach and promotion activities. We will establish a common branded public relationscommunication resources facilitating interactions and managing outreach. Third we will develop anddisseminate network best practices and data collection/processing standards. We provide support for participantengagement and cancer genome sequencing activities establish data standards ensure data are accessible tothe public data are appropriately shared and support efforts to make the Network sustainable. Finally we wantto address health disparities and promote equity throughout the Network and ensure there is a diverse pool offuture scientists including those from underrepresented groups to support future efforts in participantengagement and cancer genomics. We envision that the network will need to evolve to address emerging issuesin participant engagement and believe that being based in a university setting will provide us the capacity toanticipate and address these issues as they emerge. We are strongly supported by the OSU College of Medicinethe OSU Comprehensive Cancer Center and the OSU Center for Clinical and Translational Science. 491400 +No NIH Category available Automobile Driving;Basic Science;Cancer Patient;Center for Translational Science Activities;Clinical;Clinical Oncology Supplement (K12);Clinical Research;Clinical Skills;Clinical Trials;Communication;Competence;Comprehensive Cancer Center;Development;Discipline;Ensure;Environment;Ethics;Evaluation;Faculty;FarGo;Funding;Goals;Grant;Infrastructure;Language;Malignant Neoplasms;Mentored Clinical Scientist Development Program;Mentors;Mentorship;National Center for Advancing Translational Sciences;Oncology;Patients;Physicians;Program Development;Research;Research Design;Research Personnel;Research Project Grants;Research Training;Scholars Program;Science;Scientist;Time;Training;Translational Research;Vision;Writing;cancer clinical trial;career;career development;clinical investigation;didactic education;drug development;drug discovery;evidence base;improved outcome;innovation;interest;medical schools;multidisciplinary;patient oriented;patient oriented research;programs;research and development;skills;success;translational scientist UC Davis Paul Calabresi K12 Clinical Oncology Research Career Development Program NARRATIVEThe UC Davis Paul Calabresi K12 Clinical Oncology Research Career Development Program (CDP) aims tonurture junior faculty to become team-driven researchers who are able to conduct patient-oriented cancerresearch that is enhanced by basic/translational (laboratory) science. This caliber of research - which forexample identifies biomarkers or optimizes how drugs work - is at the forefront of cancer clinical research andhas the highest potential to improve outcomes for patients with cancer. Through this program exceptionalclinical and basic/translational scientists will hone their skills to become leaders in translational multi-disciplinary research. NCI 10681247 8/3/23 0:00 PAR-19-242 5K12CA138464-13 5 K12 CA 138464 13 "DAMICO, MARK W" 8/1/11 0:00 7/31/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 6094231 "LARA, PRIMO N." Not Applicable 4 INTERNAL MEDICINE/MEDICINE 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 734729 NCI 750000 60000 "PROJECT SUMMARYThe overarching goal of the UC Davis Paul Calabresi K12 Clinical Oncology Research Career DevelopmentProgram (CDP) is to nurture clinician or basic/translational junior faculty to become independent patient-oriented cancer researchers who are highly trained in translational team-driven research. Using 1) corecompetencies 2) advanced oncology coursework 3) career development 4) mentored research and 5) cross-discipline exposure the CDP provides two new scholars per year (six at any one time) a three-year careerdevelopment program aimed at honing ideas and skills that go far beyond their initial disciplinary boundaries.Scholars will overcome language and cultural barriers that typically exist between clinical andbasic/translational researchers take advantage of the collaborative research environment at UC Davisparticipate in multidisciplinary and translational forums and gather essential skills in research design clinicaltrial development team science grant writing ethical conduct of research communication and careerdevelopment. The vision is to enhance translational research by training physician-scientists to incorporate andutilize basic/correlative science in their pursuit of clinical trials (""Clinical Track"") and conversely driving basicscientists towards patient-driven drug development and clinical research (""Basic/Translational Track""). Tomaintain the emphasis on patient-driven clinical research CDP scholars under the mentorship of both aclinical mentor and basic/translational mentor will be required to develop and initiate/conduct their owninvestigator-initiated clinical trial during the training period. The program will leverage the outstanding researchtraining and evaluation expertise and infrastructure of the NCI-designated UC Davis Comprehensive CancerCenter NCATS-funded Clinical and Translational Research Center (CTSC) and School of Medicine CareerDevelopment Program. It will be overseen and enhanced by a highly organized internal Oversight Committeeand external Advisory Board. Overall the CDP seeks to accomplish the following specific aims: 1) Offer acompetency-based didactic curriculum to promote team science encourage translational research and honeessential skills for clinical trial development and career/research success; 2) Oversee individualized patient-oriented research projects customized to the interests and needs of each scholar; and 3) Provide oversight ofscholar training to ensure the progressive development of fully competent interdisciplinary researchers whocan successfully conduct cancer clinical trials. These specific aims will build a critical mass of trained scientistsat the forefront of innovative impactful evidence-based research who can oversee projects encompassing theentire continuum of research from basic science (target identification and drug discovery) through translationalscience (drug development and correlative science) to clinical investigation. By doing so we offer the potentialof enhancing the success of clinician scientists and improving outcomes for cancer patients." 734729 +No NIH Category available Area;Award;Bioethics;Bioinformatics;Biomedical Research;Cancer Biology;Cancer Center;Cancer Research Project;Career Choice;Climacteric;Communication;Communities;Computing Methodologies;Data;Databases;Dedications;Development;Education;Educational workshop;Ensure;Environment;Ethics;Etiology;Evaluation;Evolution;Faculty;Feedback;Fellowship;Fellowship Program;Foundations;Funding;Future;Genome;Genomic medicine;Genomics;Glioblastoma;Glioma;Goals;Grant;Growth;Home;Housing;Human;Immunotherapy;Individual;Institution;Internships;Laboratories;Leadership;Learning;Love;Malignant Bone Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of ovary;Medical;Mentors;Mission;Molecular;Molecular Biology;NCI-Designated Cancer Center;Occupations;Participant;Personal Growth;Plants;Privatization;Procedures;Process;Public Health;Publications;Recruitment Activity;Research;Research Personnel;Research Project Grants;Resources;Science;Scientific Inquiry;Scientist;Societies;Solid;Student Selections;Student recruitment;Students;Talents;The Jackson Laboratory;Training;Transportation;Travel;Underrepresented Populations;Underrepresented Students;United States National Institutes of Health;Variant;advanced analytics;analytical method;analytical tool;anticancer research;biomedical scientist;cancer genomics;cancer immunotherapy;career;career networking;cohort;collaborative environment;college;computerized tools;computing resources;cost;design;disadvantaged student;economic disparity;education research;ethical legal and social implication;experience;faculty mentor;formal learning;human disease;informal learning;innovation;instrumentation;interest;leukemia;life-long learning;malignant breast neoplasm;meetings;member;novel;outreach;peer;personalized cancer therapy;programs;recruit;role model;scientific literacy;summer research;summer student;symposium;undergraduate education;undergraduate research;undergraduate student Summer Undergraduate Research Fellowship in the Molecular Biology and Genomics of Human Cancer PROJECT NARRATIVE / RELEVANCE TO PUBLIC HEALTHThe proposed summer undergraduate research fellowship in the molecular biology and genomics of humancancer will offer students the opportunity to contribute to real research progress in understanding the originbackground and treatment of gliomas glioblastomas leukemia breast bone and ovarian cancers in the highlycollaborative environment of The Jackson Laboratory for Genomic Medicine (JAX-GM). The 10-week experiencewill actively recruit students underrepresented in science and help plant the seeds for future diversity in thescientific medical and education workforces. Program alumni will be science ambassadors with a solidgrounding in ethics an appreciation for the challenges and promises of human disease research and a zeal toshare their love of science for the benefit of society. NCI 10681245 6/19/23 0:00 PAR-18-478 5R25CA233420-04 5 R25 CA 233420 4 "RADAEV, SERGEY" 7/1/19 0:00 6/30/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 8556573 "CHUANG, JEFFREY HSU-MIN" Not Applicable 2 Unavailable 42140483 XR6LMXNKDJJ1 42140483 XR6LMXNKDJJ1 US 44.365361 -68.196303 7096501 JACKSON LABORATORY BAR HARBOR ME Research Institutes 46091523 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 Other Research-Related 2023 123585 NCI 127974 3298 PROJECT SUMMARY / ABSTRACTThe long-term goal of the proposed program is to establish a summer undergraduate research fellowship in themolecular biology and genomics of human cancer at The Jackson Laboratory for Genomic Medicine (JAX-GM)in Farmington CT that will support the need for enhanced education in cancer research and genomics for thefuture biomedical workforce. This proposed program will function as a defined cohort within the existing JAXSummer Student Program (SSP). The Jackson Laboratory is a NCI-designated Cancer Center and JAX-GMprovides a collaborative highly innovative research environment of scientists with diverse cancer expertise thatwill support the following aims of this program: (1) Provide an authentic and mentored research experience.JAX-GM will recruit ten students to join a cutting-edge collaborative research team using molecular andcomputational methods to investigate the etiology and evolution of human breast ovarian bone and braincancers leukemia cancer immunotherapy and genome structural variation and instability. (2) Promotediversity in science. The participants will be chosen through a competitive nationwide application process andmembers of underrepresented groups will be actively recruited through targeted national outreach. Each internwill receive a full fellowship including subsistence round-trip transportation research supplies and funds tooffset the cost of housing. These funds will enable economically disadvantaged students to forgo summer jobsand participate in this life-changing educational experience. (3) Encourage careers in science and lifelongscientific literacy. Each participant will join a sponsoring scientist's team and will design and conduct anindependent hypothesis-driven project using advanced analytic methods and tools and the outstanding scientificresources available at JAX-GM. The cancer research fellowship program will require students to attendworkshops on the ethical legal and social issues facing scientists today and complete pre-fellowship onlineprequels on cancer genomics. (4) Incorporate evaluation to strengthen the program. JAX GenomicEducation staff will collect formative and summative evaluation data that will directly inform program leadershipto guide future administration of the program. The JAX institutional commitment ensures student access tointellectual and research resources including on-campus courses and conferences state-of-the-artinstrumentation and computational resources dedicated program direction by JAX Genomic Education staffhousing in a college setting and a professionally staffed residential program. The SSPsupported byinstitutional funds private foundations and federal grantshas well-established administrative procedures forrecruitment and selection mentor training guidance program design management and evaluation. JAX-GMoffers a stimulating environment in which motivated talented students from diverse backgrounds can learn thefundamentals of scientific inquiry contribute to real research progress and make great strides in intellectual andpersonal growth that will guide them in career choices and lifelong learning. 123585 +No NIH Category available 3-Dimensional;Address;Adipocytes;Affect;BRCA1 Mutation;BRCA1 gene;Basal Cell;Binding;Breast;Breast Cancer Model;Breast Epithelial Cells;C-terminal;Cancer Patient;Cancerous breast;Catalytic Domain;Cell Maintenance;Cell Proliferation;Cells;Coculture Techniques;Cues;Development;Disease Outcome;Drug Targeting;Duct (organ) structure;Engineering;Epithelial Cells;Epithelium;Extracellular Matrix;Fibroblasts;Genomics;Goals;Growth;Hemopexin;Homeostasis;Human;Hyperplasia;Imaging Device;In Vitro;Inflammation;Knowledge;Ligands;Link;MMP3 gene;Maintenance;Malignant Neoplasms;Mammary Gland Parenchyma;Mammary gland;Matrix Metalloproteinases;Mediating;Mediator;Modeling;Molecular;Multimodal Imaging;Mutation;Neoplasm Metastasis;Patients;Peptide Hydrolases;Play;Population;Predisposition;Primary Cancer Prevention;Proliferating;Recurrence;Regulation;Research;Role;Source;Stromal Cells;System;Tissues;Transplantation;Tumor Promotion;Visit;WNT Signaling Pathway;Woman;Work;adult stem cell;breast tumorigenesis;cancer clinical trial;cancer initiation;cell behavior;cell type;clinically relevant;cohort;experimental study;extracellular;gain of function;high risk;improved;in vivo;inhibitor;innovation;lentivirally transduced;loss of function;malignant breast neoplasm;mammary;mammary epithelium;mouse model;mutation carrier;novel therapeutic intervention;overexpression;premalignant;promoter;prophylactic mastectomy;single-cell RNA sequencing;small molecule inhibitor;stem cell expansion;stem cell function;stem cell homeostasis;stem cell proliferation;stem cells;therapeutic target;transcriptomics;tumor;tumor growth;tumor initiation;tumor microenvironment;tumor progression;tumorigenic Microenvironmental regulation of breast tumorigenesis PROJECT NARRATIVE Breast cancer arises from breast epithelial cells that gather pro-tumorigenic mutations leading touncontrolled cell proliferation and tumor initiation. Knowledge of how tumor initiation can be regulated by thecellular microenvironment will enable us to specifically interfere with the function of tumor-initiating cells to stoptumor growth and potentially recurrence of breast cancer. Here we will focus on matrix metalloproteinases(MMPs) and study how these extracellular proteases are involved in the regulation of normal homeostasis andBRCA1-related breast cancer initiation by orchestrating the Wnt signaling pathway. This may lead to thedevelopment of novel therapeutic approaches for primary cancer prevention and to treat patients suffering frombreast cancer. NCI 10681204 2/28/23 0:00 PA-18-484 5R01CA234496-05 5 R01 CA 234496 5 "HILDESHEIM, JEFFREY" 2/1/19 0:00 1/31/24 0:00 Tumor Microenvironment Study Section[TME] 11043433 "KESSENBROCK, KAI " Not Applicable 47 BIOCHEMISTRY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 2/1/23 0:00 1/31/24 0:00 396 Non-SBIR/STTR 2023 496350 NCI 337845 158505 PROJECT SUMMARYThe tissue microenvironment dictates adult stem cell behavior during normal homeostasis and cancer. Themicroenvironment of the breast contains numerous distinct cell types including basal and luminal mammaryepithelial cells that form a ductal network surrounded by stromal cell types such as adipocytes and fibroblasts.One of the key regulators of the tumor microenvironment are the matrix metalloproteinases (MMPs) which aresecreted proteolytic enzymes that affect multiple aspects of cancer including extracellular matrix remodelinginflammation and metastasis. MMPs have been implicated in breast cancer for many years and they havebeen considered as therapeutic targets to treat cancer patients. However previous clinical cancer trials usingsynthetic small molecule inhibitors to interfere with MMP catalytic activity yielded disappointing results. Ourprevious research has shown that MMPs such as MMP3 may work in a non-proteolytic manner through theirhemopexin domain. This may explain why compound inhibitors targeting the catalytic function of MMPs failedto improve disease outcome. Here we will focus on the role of stromal fibroblast-derived MMP3 and its interaction with the non-canonical Wnt signaling pathway during BRCA1-related breast cancer initiation. In our previous work we haveestablished that MMP3 can modulate the non-canonical Wnt signaling pathway by binding and inactivatingWnt5b via the hemopexin domain and that this plays an important role in stem cell maintenance during normalhomeostasis of the mammary epithelium. We will now determine whether this interaction of MMP3 with Wnt5baffects breast cancer initiation. In particular we will employ lentiviral transduction transplantation of mammaryepithelial cells mouse models of breast cancer in combination with cutting single cell genomics and multi-modal imaging tools to address whether (1) fibroblast-derived MMP3 promotes pro-tumorigenic changes inbreast epithelial cells in vitro and in vivo in a potentially non-proteolytic manner (2) Wnt5b is the criticalsubstrate mediating the tumor-promoting effects associated with MMP3 (3) Wnt5b specifically regulatesmammary stem cell proliferation and exerts tumor suppressing effects within the breast epithelium. Takentogether these studies will unravel new molecular mechanisms through which the microenvironment promotestumor initiation and yield a better understanding of the non-canonical Wnt signaling pathway in regulatingnormal epithelial homeostasis and breast cancer initiation. Ultimately our work may implicate theMMP3/Wnt5b axis as a potential therapeutic target for primary cancer prevention in BRCA1 mutation carriers. 496350 +No NIH Category available Address;Adult;Animal Model;Applications Grants;Blood - brain barrier anatomy;Brain;Cancer Control;Caring;Cell Compartmentation;Cells;Cerebellar Neoplasms;Cerebellum;Chemoresistance;Chemotherapy and/or radiation;Childhood;Clinical Trials;Cognitive deficits;Cytoplasmic Granules;Data;Development;Disease;Down-Regulation;Epigenetic Process;Evaluation;Exhibits;Future;Genetically Engineered Mouse;Genomics;Human;In Vitro;Intervention;Knowledge;Laboratories;Libraries;Malignant - descriptor;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of brain;Medical;Membrane Glycoproteins;MicroRNAs;Mission;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mus;Mutation;Neurocognitive;Neurons;PIK3CG gene;PTEN gene;Pathogenesis;Pathway interactions;Patients;Pediatric Neoplasm;Pharmacogenomics;Phenotype;Phosphatidylinositide 3-Kinase Inhibitor;Protein Isoforms;Proto-Oncogene Proteins c-akt;Public Health;Regulation;Reporting;Research;Resistance;Role;SHH gene;Sampling;Signal Pathway;Signal Transduction;Sonic Hedgehog Pathway;Subgroup;Survivors;System;Testing;Therapeutic;Therapeutic Intervention;Toxic effect;Transgenic Mice;Transgenic Organisms;Tumor Suppressor Proteins;United States National Institutes of Health;Validation;Work;Xenograft procedure;cancer stem cell;cancer therapy;chemoradiation;chemotherapy;clinically relevant;design;disability;genetic analysis;genomic signature;in vivo;inhibitor;innovation;kinase inhibitor;medulloblastoma;mouse genetics;mouse model;nerve stem cell;novel;patient derived xenograft model;precursor cell;recombinase;resistance mechanism;response;smoothened signaling pathway;stem cell biology;stem-like cell;targeted agent;targeted treatment;transcriptomics;tumor;tumor growth;tumor initiation;tumorigenesis Role of PTEN and PI-3 Kinase in Medulloblastomagenesis Project NarrativeThe proposed research is relevant to public health because the discovery of signaling pathways that controlmedulloblastoma tumor growth survival and progression will ultimately be expected to increase ourunderstanding of the pathogenesis of malignant diseases involving cancer stem cells. Thus the proposedresearch is relevant to the part of the NIHs mission that pertains to fundamental knowledge that will help toreduce the burden of human disability as relates to the treatment of adult and childhood cancer. NCI 10681197 5/15/23 0:00 PA-16-160 6R01CA172513-06 6 R01 CA 172513 6 "XU, WANPING" 7/3/17 0:00 2/29/24 0:00 Tumor Cell Biology Study Section[TCB] 1882337 "DURDEN, DONALD " Not Applicable 5 PEDIATRICS 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 3/1/23 0:00 2/29/24 0:00 396 Non-SBIR/STTR 2023 309307 NCI 199553 109754 Medulloblastoma (MB) is a cancer arising within the cerebellum and is the most common malignant braintumor in children. Current care which relies on radiotherapy and chemotherapy only cures 60% of patientsand has serious long-term neurocognitive sequelae in survivors hence the unmet medical need to developmore efficacious less toxic therapies for this disease. Malignant brain tumors including the sonic hedgehog(SHH) subgroup of MB are driven by tumor propagating cells (cancer stem cells; CSCs) expressing the cellsurface glycoprotein CD15. A knowledge gap exist in that the molecular mechanisms controlling CSC and nonCSC phenotypes are poorly delineated. The central hypothesis for this proposal is that the PI3K/PTENsignaling axis exerts control over the CSC phenotype in SHH MB and hence represents a target for therapeuticexploitation with PI3K inhibitors. Importantly work from our laboratory has demonstrated that PTENexpression is suppressed in the CSC compartment of the Smo transgenic (SHH pathway) mouse model of MB.The clinical relevance of the PTEN deficient Smo transgene mouse model is highlighted by our finding thatPTEN expression is lost in human MB and the observation that PTEN loss correlates with poor survival in MBpatients. Our grant proposal guided by our preliminary data proposes 3 specific aims: 1) Determine if geneticalterations in PTEN or specific isoforms of PI3K are necessary and/or sufficient for SHH driven CSC phenotypeand tumorigenesis 2) Utilize high throughput kinome library screens and genomic profiling of mouse andhuman MB CSCs and non CSCs to identify a molecular signature and synthetic lethality effects which willpredict sensitivity or resistance to a PI-3K inhibitor. 3) Elucidate the epigenetic mechanism by which PTEN isregulated in the CSC compartment in human SHH PDX models and the SmoTg GEMM model; Focused onPTEN specific miRNA regulatory networks. We will use the Math1creER recombinase to generate theconditional deletion of PTEN p110 and/or p110 in normal cerebellar granule neuronal precursor cells(GNPs) or in the CSC compartment and determine the effects on the development of MB and CSC phenotype.In Aim 2 we will expand upon our recent report demonstrating the activity of the PI3K inhibitor BKM120against CSCs to include synthetic lethality screens with other targeted agents and conventionalchemotherapeutics. An innovative component of our application is the recent discovery of a novel miRNAnetwork which epigenetically regulates PTEN in the CSC compartment which is associated with the CSCphenotype. This observation will be explored in our GEMMs MB PDX models and in human MB tumorsamples to determine the role of these miRNAs in the regulation of PTEN PI3K and the CSC phenotypesincluding tumor initiating activity. The proposed work is significant in that it will: 1) establish a role for PTENp110 and p110 in CSC biology in MB 2) identify novel synthetic lethalities in combination with PI3K inhibitionin MB CSCs and 3) elucidate a role for miRNA networks in the control of PTEN and CSC phenotypes. 309307 +No NIH Category available Address;Adherens Junction;Adhesions;Angiogenesis Inhibitors;Antibodies;Apoptosis;Binding Proteins;Blood;Blood Vessels;CD8-Positive T-Lymphocytes;CDH5 gene;Cancer Control;Cancer Patient;Cell Adhesion;Cell Adhesion Molecules;Cell membrane;Cells;Cellular biology;Complex;Cytotoxic T-Lymphocytes;Data;Defect;Disease;Embryonic Development;Endothelial Cells;Endothelium;Genes;Genetic;Goals;High Endothelial Venule;Human;Hypoxia;Immune;Immune response;Immune system;Immunity;Investigation;KDR gene;Knock-out;Knockout Mice;Link;Macrophage;Malignant Neoplasms;Membrane Proteins;Modality;Molecular;Monoclonal Antibodies;Mus;Outcome;Output;Pathologic;Pathway interactions;Perfusion;Permeability;Phase;Phosphorylation;Play;Property;Proteins;Proteomics;Regulation;Reporting;Role;Small Interfering RNA;Solid Neoplasm;Structure;T cell infiltration;T-Lymphocyte;Testing;Therapeutic;Tight Junctions;Tissues;Tumor Angiogenesis;Tumor Immunity;angiogenesis;anti-PD-1;anti-PD1 antibodies;cancer therapy;cell motility;comparison control;cytotoxic CD8 T cells;effective therapy;efficacy evaluation;immune checkpoint blockade;improved;knock-down;member;migration;novel;novel therapeutics;overexpression;programmed cell death protein 1;recruit;rho GTP-Binding Proteins;single-cell RNA sequencing;translational potential;treatment strategy;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Myct1 control of the angioimmune interface PROJECT NARRATIVENew vessel formation is critical for proper embryonic development and pathological progression of manydiseases. We identified Myct1 (Myc target 1) as a novel and crucial endothelial gene required for tumorangiogenesis and tumor growth. Unexpectedly Myct1 deficiency in endothelial cells leads to enhanced anti-tumor immunity suggesting that Myct1 can modulate endothelial cell remodeling of the tumor immunity. Theoverall goal of the proposed studies is to investigate the mechanisms by which Myct1 regulates angiogenesisand tumor immunity and develop novel therapeutic modalities against Myct1 for treating cancer or relatedpatho-angiogenic diseases. NCI 10681090 6/8/23 0:00 PA-20-185 1R01CA271714-01A1 1 R01 CA 271714 1 A1 "WOODHOUSE, ELIZABETH" 6/9/23 0:00 5/31/28 0:00 Special Emphasis Panel[ZRG1-BTC-W(80)S] 1882749 "CHOI, KYUNGHEE " "PARK, CHANGWON " 1 PATHOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 6/9/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 559360 NCI 430397 128963 ABSTRACTEndothelial cells (ECs) form an essential part of the vasculature and are strategically located between blood andtissues functioning as a fundamental barrier between the tissue and the immune system. As such ECs can beviewed as an essential and active component regulating immune responses. We propose that EC's angiogenicvs. immune-modulatory function can be linked through the same genetic mechanism. We recently reported thatMyct1 (MYC target 1) encoding a plasma membrane protein is a novel regulator of angiogenesis. Myct1expression is mainly restricted to ECs and tumor ECs. Global and EC-specific (Cdh5-Cre; Myct1f/f) Myct1 KOmice display decreased tumor angiogenesis and reduced tumor growth. Unexpectedly defective tumorangiogenesis leads to an anti-tumor immune microenvironment. Particularly tumors from Myct1 KO mice containmore CD8+ cytotoxic T lymphocytes (CTLs) than tumors from littermate control mice. While Myct1 deficient ECsdisplay defects in EC motility they support more robust CD8+ T cell trans-endothelial migration (TEM).Importantly analysis of human cancers has also identified MYCT1 as a modulator of cancer patients' angiogenicand immune outcomes. Inhibition of Myct1 through knockout siRNA treatment or blocking monoclonalantibodies in combination with anti-PD1 antibody significantly improved complete tumor regression suggestingthat the better control of cancer depends on reduced angiogenesis and enhanced recruitment of CD8+ CTLs.We identified that Myct1 could control the outcome of angiogenesis vs. CTL recruitment to tumors through Rhoavs. Rac1 Rho GTPase pathways. Moreover we identified ZO1 also known as tight junction protein 1 toassociate with MYCT1. Deeper mechanistic investigations on the Myct1-Rho GTPases and MYCT1-ZO1interaction will help better understand how ECs control angiogenesis vs. immunity. As Myct1 function isconserved between mice and humans findings from the proposed studies have high translational potential andcan be applied to human anti-cancer therapies. The overall goal is to uncover novel molecular mechanisms andfunctions of MYCT1 in ECs and anti-tumor immunity. Particularly we will test the hypothesis that Myct1 canmodulate EC angiogenesis vs. immune regulatory outcome. Aim 1 determines how Myct1-Rho GTPaseregulates tumor angiogenesis vs. tumor immunity. Aim 2 investigates the functional significance of MYCT1-ZOin EC permeability and vessel integrity. Aim 3 is to further assess the efficacy of anti-MYCT1 antibodies fortargeting MYCT1 in tumor angiogenesis and growth. By completing the proposed studies we will gain a deepermechanistic understanding of how Myct1 regulates angiogenesis and the consequence of immune output playedby ECs. The outcome will significantly impact the basic EC biology and therapeutic modality for cancer treatment. 559360 +No NIH Category available Adjuvant;Advanced Malignant Neoplasm;Animal Model;Antigen-Presenting Cells;Antigens;Antitumor Response;Biodistribution;Bone Marrow;COVID-19;Cancer Vaccines;Cells;Chemical Structure;Chemistry;Circulation;Deposition;Disseminated Malignant Neoplasm;Dose;Drug Kinetics;Engineering;Esters;Formulation;Freeze Drying;Generations;Homing;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Adjuvants;Immunotherapeutic agent;Immunotherapy;Infiltration;Kinetics;Ligands;Mediating;Messenger RNA;Methodology;Methods;Modeling;Mus;Patients;Peripheral;Polymers;Population;Procedures;Production;Property;RNA vaccine;Reporter;Role;STING agonists;Safety;Solid Neoplasm;Spleen;Standardization;Structure-Activity Relationship;Surface;T-Cell Activation;Testing;Time;Tissues;Training;Transfection;Treatment Efficacy;Tumor Antigens;Tumor Tissue;Vaccines;anti-tumor immune response;biomaterial compatibility;cancer immunotherapy;combinatorial;design;efficacy validation;experience;gene therapy;immune activation;improved;in vivo;innovation;intravenous injection;lymph nodes;mRNA delivery;manufacturing scale-up;melanoma;monocyte;mouse model;nanomedicine;nanoparticle;nanoparticle delivery;neoantigens;plasmid DNA;polycation;programs;rational design;response;secondary lymphoid organ;success;targeted delivery;therapeutic target;trafficking;tumor;tumor growth;tumor microenvironment;vaccine platform Kinetic Assembly of Polymer-mRNA Nanoparticles Targets Circulating Monocytes to Enhance Cancer Immunotherapy PROJECT NARRATIVEThis proposed study aims to develop kinetically assembled biodegradable poly(beta-amino ester)/mRNAnanoparticles (KaNPs) specifically engineered to target circulating monocytes for the purpose of enhance tumor-specific immune response. If successful this study will deliver a more potent mRNA-based immunotherapies fortreatment of solid tumors and metastatic cancers. NCI 10681055 5/23/23 0:00 PA-20-185 1R01CA281143-01 1 R01 CA 281143 1 "SOMMERS, CONNIE L" 5/23/23 0:00 4/30/28 0:00 Gene and Drug Delivery Systems Study Section[GDD] 7664957 "MAO, HAI-QUAN " "GREEN, JORDAN " 7 OPHTHALMOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 5/23/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 560955 NCI 342568 218387 PROJECT SUMMARYCancer vaccines have significantly advanced cancer immunotherapy; and recent successes of mRNAvaccines have raised prospect of generating potent anti-tumor response by specifically delivering mRNAsencoding tumor-associated antigens to antigen presenting cells (APCs). However APC activation elicited bynanoparticles containing antigen mRNAs is rather limited. Circulating monocytes offer a promising cell target asan abundant APC precursor that can be deposited to spleen lymph nodes and tumor tissue followingpolarization and activation. The overall objective of this study is to engineerkinetically assembled poly(beta-amino ester) (PBAE)/mRNA nanoparticles (KaNPs) that can specifically deliver mRNAs encoding tumor antigensand immunoadjuvants into circulating monocytes in vivo and demonstrate the safety and efficacy of this newmRNA cancer vaccine platform. This study is built on the preliminary results showing biodegradablePBAE/mRNA KaNPs with an optimized size of 400 nm mediated preferential transfection of circulatingmonocytes following intravenous (i.v.) injection leading to more effective transfection and deposition ofcirculating monocytes and a higher level of tumor-killing activity compared to the standard small sizePBAE/mRNA nanoparticles. In this proposed study we plan to pursue four specific aims: (1) optimize thecomposition size and surface functionality of PBAE/mRNA KaNPs to improve targeted mRNA delivery efficiencyinto circulating monocytes in vivo (2) characterize pharmacokinetic profile of PBAE/mRNA KaNPs and definefunctions of transfected circulating monocytes in vivo (3) assess the immunotherapeutic efficacy of PBAE/mRNAKaNPs in suppressing tumor growth in combination with TLR9 and STING agonists in mouse tumor models and(4) develop an GMP-compliant shelf-stable lyophilized PBAE/mRNA KaNP formulation and validate the efficacyin a mouse model. If successful this study will uncover structure-function relationships in a previouslyinaccessible size range (2001000 nm) for gene therapy carriers demonstrate circulating monocytes as a potentmRNA therapeutic target and the role of KaNP-transfected circulating monocytes in potentiating antitumorimmune responses and inspire rational design of new mRNA-based immunotherapies for treatment of solidtumors and metastatic cancers. 560955 +No NIH Category available Address;Aftercare;Animals;Area;Bone Marrow;CDKN2A gene;Cell Communication;Cell Separation;Cells;Chemotherapy and/or radiation;Clinical;Data Set;Development;Dexamethasone;Epidermal Growth Factor Receptor;Event;Evolution;Experimental Models;Flow Cytometry;Genetically Engineered Mouse;Genomics;Glioblastoma;Glioma;Heterogeneity;Human;Immune;Immunology;Immunosuppression;Immunotherapy;Infiltration;Inflammatory;Institution;International;Ionizing radiation;Knowledge;Lesion;Macrophage;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Maps;Mediating;Microglia;Modality;Molecular;Mouse Strains;Mus;Mutation;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Nature;Output;PTEN gene;Pathology;Pathway interactions;Patient Care;Patients;Population;Population Dynamics;Property;Radiation;Reaction;Research;Resistance;Sampling;Signal Transduction;Spatial Distribution;T-Lymphocyte;Technology;The Cancer Genome Atlas;Therapeutic;Time;Tumor Suppressor Genes;Tumor-infiltrating immune cells;cancer cell;checkpoint inhibition;checkpoint therapy;clinically relevant;clinically significant;design;effective therapy;epidermal growth factor receptor VIII;human data;immune cell infiltrate;immune checkpoint blockade;immune resistance;insight;longitudinal analysis;member;mouse model;multiple omics;multiplexed imaging;mutant;neoplastic;neoplastic cell;new therapeutic target;novel therapeutic intervention;overexpression;pre-clinical;protein biomarkers;recruit;single cell analysis;single-cell RNA sequencing;standard of care;success;targeted treatment;temozolomide;therapeutic development;transcriptome sequencing;transcriptomics;tumor;tumor immunology;tumor-immune system interactions;tumorigenic Understanding the cellular and functional changes in the immune tumor microenvironment of glioblastoma during progression and treatments. Project NarrativeGlioblastoma (GBM) is a lethal brain cancer with no effective treatment available due to its high heterogeneityand ineffective immune cell composition which still remains uncharacterized especially during radiation andchemotherapy treatment. We will use advanced technologies in single cell analysis to determine thecomposition activation and localization of the immune cells of GBM in patient samples and in mouse modelsthat recapitulate features of human GBM before during and after treating the animals with the same standardof care that patients receive. This research will uncover new information on how tumor cells and immune cellsreact to radiation and chemotherapy and interact with each other which we will leverage to design newtreatment modalities. NCI 10681034 4/17/23 0:00 PAR-20-131 1R01CA271601-01A1 1 R01 CA 271601 1 A1 "KAI, MIHOKO" 4/17/23 0:00 3/31/28 0:00 Special Emphasis Panel[ZRG1-CTH-B(55)R] 8805407 "CHAREST, ALAIN " "BOUSSIOTIS, VASSILIKI A; VERHAAK, ROEL GW" 7 Unavailable 71723621 C1CPANL3EWK4 71723621 C1CPANL3EWK4 US 42.33982 -71.10568 758101 BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA Independent Hospitals 22155400 UNITED STATES N 4/17/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 672634 NCI 437072 235562 Project SummaryGlioblastoma (GBM) is an incurable primary malignant brain cancer characterized by a high degree ofinterpatient and intratumoral genomic and cellular heterogeneity a brief median survival (~15 months) andabsence of an effective treatment. Even the successes of checkpoint blockade immunotherapies observed inmany cancers have not translated to GBM. The GBM tumor immune microenvironment (TIME) is highlyimmunosuppressive and is dominated by resident and infiltrating myeloid cells (30-40% of the tumor mass)compared to rare T cells (<5%). Although recent single-cell RNA-sequencing (scRNAseq) studies haveprovided broad characterization of the cellular makeup and evolution of GBM tumor cells dissecting thediversity function and regional localization of the immune composition of GBM remains incomplete. There isalso a widespread lack of knowledge on the evolution of intratumoral immune cells during GBM progressionand throughout treatment with standard of care (SOC) therapies (ionizing radiation/temozolomide/dexamethasone IR/TMZ/DEX). Major challenges to achieving scientific and clinical impact inGBM remain including an in-depth understanding of the interactions between cancer cells and the immunemicroenvironment in the context of SOC and immunotherapy treatments. Such knowledge is difficult to obtainusing freshly excised patient samples. The main hypothesis of the proposal is that critical and clinically relevantchanges in GBM neoplastic and immune cells brought about by treatment modalities can be revealed usinggenetically accurate mouse models to parse and redirect analyses of human patient datasets. A mechanisticunderstanding of the effects of therapies on immune and tumorigenic cell population dynamics in pre-clinicalmouse models in combination with analysis of human patient datasets will yield transformative advancementsin the field. We will leverage archival patient samples mouse models of GBM and GLASS consortium datasetsto uncover SOC-related cellular and molecular evolutionary changes using scRNA seq and spatialtranscriptomics. We will also unveil factors determining sensitivity and resistance to checkpoint blockadetherapy. By integrating detailed mouse and human data we will identify areas of unrecognized therapeuticvulnerabilities and pave the way for the development of new treatment approaches. 672634 +No NIH Category available Acoustics;Adjuvant Chemotherapy;Adverse effects;Anisotropy;Benign;Biological Markers;Biopsy;Breast;Cancer Detection;Cessation of life;Clinical;Collagen;Collagen Fiber;Complex;Custom;Data;Data Collection;Death Rate;Dependence;Development;Diagnosis;Diagnostic Neoplasm Staging;Diagnostic Sensitivity;Digital Breast Tomosynthesis;Digital Mammography;Disease Progression;Early Diagnosis;Feasibility Studies;Functional disorder;Goals;Imaging technology;In complete remission;Investigation;Learning;Lesion;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Manuals;Mass in breast;Measurement;Monitor;Neoadjuvant Therapy;Neoplasm Metastasis;Outcome;Pathologic;Patients;Pattern;Performance;Prognosis;Public Health;Radiation;Radiation Dose Unit;Reporting;Sensitivity and Specificity;Specificity;Stress;Technology;Tissues;Woman;Women's Health;Work;breast cancer diagnosis;cancer biomarkers;cancer diagnosis;cancer therapy;cancer type;clinically relevant;contrast enhanced;cost;elastography;histological studies;improved;in silico;in vivo;interest;malignant breast neoplasm;radiological imaging;response;restraint;screening;success;treatment response;trend;ultrasound;viscoelasticity VisR Ultrasound for Noninvasively Interrogating Stromal Collagen Organization in Women as a Breast Cancer Biomarker RELEVANCE TO PUBLIC HEALTHBreast cancer is the worlds most prevalent cancer with 2.3 million women diagnosed and 685000 deathsglobally in 2021. While breast cancer maintains a chokehold on womens health the death rate has declinedby about 1% per year over the last decade due in large part to earlier detection. The goal of this work is todevelop a new noninvasive ultrasound-based imaging technology that expands understanding of breastcancer pathophysiology and improves breast cancer diagnosis and treatment monitoring. NCI 10680931 4/11/23 0:00 PA-20-185 1R01CA281150-01 1 R01 CA 281150 1 "PEREZ, J MANUEL" 4/15/23 0:00 3/31/27 0:00 Special Emphasis Panel[ZRG1-ISB-J(03)M] 8225946 "GALLIPPI, CATERINA M" Not Applicable 4 BIOMEDICAL ENGINEERING 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 4/15/23 0:00 3/31/24 0:00 394 Non-SBIR/STTR 2023 593548 NCI 400763 192785 PROJECT SUMMARYBreast cancer is now the most prevalent cancer with 2.3 million women diagnosed and 685000 deathsglobally. Although the death rate has declined by about 1% per year over the last decade due in large part toearlier detection through screening the current screening standard digital mammography lacks sensitivity andis challenged in radiographically dense breasts. Sensitivity in dense breasts is improved by magneticresonance imaging (MRI) but required contrast enhancement and substantial additional cost are drawbacks. Anon-contrast low-cost alternative ultrasound strain elastography (SE) has been shown to achieve highsensitivity and specificity for breast cancer diagnosis. However while SE diagnoses suspicious breast massedby interrogating tissue stiffness the underlying cause of stiffening is not discerned. Among the many possiblecauses stromal collagen organization is newly a focus of intense interest due to its recently proven associationwith breast cancer stage prognosis treatment response and other clinical features. Therefore delineatingstromal collagen organization in vivo would not only improve breast cancer diagnosis and treatmentmanagement but also help to elucidate the complex and poorly understood pathophysiology of breast cancerdevelopment progression and aggressiveness. One approach to noninvasively evaluating stromal collagenorganization in the breast is ultrasound shear wave elastography (SWE) but shear wave propagation isinhibited in 63% of malignant breast masses leading to low-quality measurements. The lack of a robustultrasound approach to interrogating stromal collagen organization represents a major gap in exploiting arapidly emerging and highly promising biomarker for breast cancer. To fill this gap our group has developedViscoelastic Response (VisR) ultrasound an on-axis approach to interrogating collagen fiber organization viastiffness anisotropy in breast masses and surrounding stroma without observing shear wave propagation. Ourpreliminary in vivo data acquired in 30 women with BIRADS-4 or -5 masses demonstrate that VisR-derivedratio of mass-to-surrounding tissue stiffness anisotropy (RMSA) differentiated biopsy-confirmed malignant(n=9) from benign (n=21) breast masses with a sensitivity of 95% and a specificity of 89%. Further in our pilotfeasibility study of four women monitored serially while undergoing neoadjuvant chemotherapy (NAC) VisRRMSA trended from malignant to benign indication with response to treatment. The success of ourinvestigations motivates further advancement of VisR RMSA measurement technology its extension torevealing the relationship between VisR RMSA outcomes and stromal collagen organization and broaderapplication to cancer detection and treatment monitoring. We hypothesize: Advanced VisR RMSA correlates tostromal collagen fiber organization which is relevant to differentiating malignant from benign breast massesand predicting pathologic complete response (pCR) to NAC in women in vivo. 593548 +Cancer; Immunotherapy; Pediatric; Pediatric Cancer; Rare Diseases Biometry;Budgets;Childhood;Communication;Contracts;Data;Ensure;Environment;Evaluation;Ewings sarcoma;Expenditure;Genomics;Goals;Immunologic Monitoring;Immunotherapy;Malignant Neoplasms;Minnesota;Monitor;New York;Office of Administrative Management;Ohio;Pediatric Hospitals;Progress Reports;Research;Resistance;Resource Sharing;Time;Travel;Universities;medical schools;meetings;member;outreach;programs;success;synergism;tumor-immune system interactions Core A:Administrative Core n/a NCI 10680851 9/20/22 15:55 PA-20-272 3U54CA232561-01A1S6 3 U54 CA 232561 1 A1S6 "BOURCIER, KATARZYNA" 9/9/22 0:00 8/31/24 0:00 9605 1884239 "CRIPE, TIMOTHY P" Not Applicable 3 Unavailable 147212963 EYMJXLN2MFB4 147212963 EYMJXLN2MFB4 US 39.95251 -82.979302 1495302 RESEARCH INST NATIONWIDE CHILDREN'S HOSP COLUMBUS OH Research Institutes 432052664 UNITED STATES N 8/1/19 0:00 7/31/20 0:00 Research Centers 2022 245000 218000 27000 Abstract - Administrative CoreThe Peds-ONC Immunotherapy Center Administrative Core will handle all of the administrative activitiesrequired to coordinate the Center activities within Nationwide Children's Hospital The Ohio State UniversityNew York Medical College the University of Minnesota (Project 1 subcontract) Internal and External ScientificAdvisory Boards the NCI and other members of the PI-DDN. The Core will manage budgets of ProjectLeaders and Core Directors monitor expenditures and provide progress reports. The Core will coordinate allmeetings and travel of Peds-ONC Immunotherapy Center members relative to PI-DDN activities. The Core willalso handle biostatistical analyses as well as tabular and graphical presentation of all data generated in theprojects to ensure uniformity. Finally the Core team will also coordinate the contracts and annual meeting ofthe external scientific advisory board. Thus the Administrative Core budget includes travel for membershonoraria for external scientific advisory board members and time and effort for a biostatistical team. +Biotechnology; Cancer; Genetics Affect;Affinity;Antibodies;Binding;Biological Assay;Cell Line;Cell model;Cells;Cellular Assay;ChIP-seq;Characteristics;Chemicals;Childhood Alveolar Rhabdomyosarcoma;Chimeric Proteins;Chromatin;Chromosomal translocation;Collaborations;Communities;Coupled;DNA;Development;Disease;Engineering;Epitopes;FOXO1A gene;Fusion Oncogene Proteins;Gene Expression;Genetic Transcription;Goals;Label;Laboratories;Length;Ligands;Luciferases;Mass Spectrum Analysis;Oncogenic;PAX3 gene;Patient-Focused Outcomes;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phenotype;Protac;Proteins;Reporter;Research;Role;Structure;Structure-Activity Relationship;Therapeutic;Toxic effect;Transcript;Validation;analog;biophysical properties;design;drug candidate;experience;genetic approach;improved;mouse model;multidisciplinary;new technology;novel;novel strategies;programs;screening;small molecule;therapeutic target;transcription factor;transcriptome sequencing;tumor Chemical probe discovery for PAX3-FOXO1 n/a NCI 10680802 9/8/22 0:00 PA-20-272 3U54CA231630-01A1S3 3 U54 CA 231630 1 A1S3 "WITKIN, KEREN L" 8/1/22 0:00 7/31/23 0:00 9580 1930899 "LINARDIC, CORINNE MARY" Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/17/19 0:00 8/31/24 0:00 Research Centers 2022 195920 165420 30500 ABSTRACT Project 3: Chemical probe discovery for PAX3-FOXO1The majority of pediatric alveolar rhabdomyosarcoma (ARMS) cases are characterized by a chromosomaltranslocation encoding the PAX3-FOXO1 fusion oncoprotein a transcription factor correlated with poor patientoutcomes. The overarching goal of this FusOnc2 Center is to advance the therapeutic tractability of the PAX3-FOXO1 fusion protein in ARMS by comprehensively identifying the druggable co-regulators modulators andintrinsic activities of PAX3-FOXO1. Transcription factor fusion proteins such as PAX3-FOXO1 have beenvalidated through genetic approaches as key therapeutic targets since they may represent tumor-specificAchilles heels. Unfortunately to date there are no small molecules that can modulate the function of PAX3-FOXO1. Hence novel approaches are needed to develop chemical probes or drugs that can target this fusiononcoprotein. Similar to other fusion transcription factors PAX3-FOXO1 is intrinsically disordered and lacks thetraditional small-molecule binding pockets observed in historically tractable targets complicating structure-drivendesign or small-molecule screening efforts to identify drug candidates. This Projects objective is to developchemical probes for PAX3-FOXO1 using a novel emerging strategy developed within the Koehler Laboratoryagainst other transcription factors and recalcitrant targets. The strategy involves the use of high-throughput andunbiased binding assays involving small-molecule microarrays (SMMs) screened with purified full-lengthtranscription factor or transcription factor residing in cell lysates. We will exploit this novel technology to developchemical probes against PAX3-FOXO1 as the first step in drugging this protein through the following four SpecificAims: 1) Execute binding assays for PAX3-FOXO1 using SMMs containing >55000 small molecules; 2) Performphenotypic and biophysical characterization of putative PAX3-FOXO1 binders; 3) Synthetically optimizechemical probes and evaluate target engagement in cells; 4) Conduct mechanistic studies of chemical probesin cellular and murine models in collaboration with the Validation Core. This Project will establish gross structure-activity relationships for 1-3 compounds and use principles of medicinal chemistry to develop new analogs withimproved potency in cellular assays and physicochemical characteristics and will synthesize proteolysis targetingchimeras (PROTACs) in an effort to explore targeted degradation of the PAX3-FOXO1 fusion protein. While theaims of this multi-disciplinary proposal are ambitious the Project will be enabled by the cumulative experienceof the team as well as the extensive capabilities of our FusOnC2 Center and its Projects and Cores. Ourapproach will lead to high-quality probes of PAX3-FOXO1 function that may clarify the role of the fusion as adirect therapeutic target for ARMS. Through these efforts we also expect to define general strategies for targetingother recalcitrant oncogenic fusion proteins with small molecules. +Cancer; Genetics Achievement;Alveolar Rhabdomyosarcoma;Amino Acids;Animal Model;Binding;Binding Proteins;Biotin;CHD4 gene;CRISPR/Cas technology;Catalogs;Cell model;Characteristics;Chemicals;Chimeric Proteins;Chromatin;Co-Immunoprecipitations;DNA Binding;Dependence;Drug Targeting;Emerging Technologies;FOXO1A gene;Face;Fusion Oncogene Proteins;Future;Genes;Goals;Immunodeficient Mouse;In Vitro;Label;Libraries;Ligands;Malignant Childhood Neoplasm;Maps;Mediating;Molecular;Mutagenesis;Neighborhoods;Oncogenic;Oncoproteins;PAX3 gene;Patients;Pharmaceutical Preparations;Pharmacology;Portraits;Post-Translational Protein Processing;Proteins;Resolution;Signal Transduction;Techniques;Technology;Therapeutic;Validation;Work;combinatorial;drug development;genetic approach;genetic manipulation;in vivo;insight;knockout gene;lead candidate;loss of function;member;mutant;mutation screening;neoplastic cell;patient derived xenograft model;protein function;protein protein interaction;screening;therapeutic development;therapeutic target;tool;tumorigenesis Defining and targeting the PAX3-FOXO1 interactome n/a NCI 10680800 9/8/22 0:00 PA-20-272 3U54CA231630-01A1S3 3 U54 CA 231630 1 A1S3 "WITKIN, KEREN L" 8/1/22 0:00 7/31/23 0:00 9578 1930899 "LINARDIC, CORINNE MARY" Not Applicable 4 Unavailable 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC Domestic Higher Education 277054673 UNITED STATES N 9/17/19 0:00 8/31/24 0:00 Research Centers 2022 173498 127749 45749 ABSTRACT Project 2: Defining and targeting the PAX3-FOXO1 interactome Alveolar rhabdomyosarcoma (ARMS) is a deadly childhood malignancy driven by the PAX3-FOXO1 fusion oncoprotein. While genetic approaches have rigorously validated this oncoprotein as a therapeutic target the lack of compounds inhibiting PAX3-FOXO1 function has earned it the moniker of being undruggable. Althoughundruggable proteins can be pharmacologically targeted doing so requires a thorough understanding of how the protein functions. It is well established that PAX3-FOXO1 exerts its transforming activities both through functional domains and physical interactions with other cellular proteins that either serve as modulators or co-regulators. Indeed members of this team previously found that CHD4 co-regulates PAX3-FOXO1 function by indirectly associating with the oncoprotein via co-localization in chromatin neighborhoods. The overarching goalof this FusOnc2 Center is to advance the therapeutic tractability of the PAX3-FOXO1 fusion protein in ARMS by comprehensively identifying the druggable co-regulators modulators and intrinsic activities of PAX3-FOXO1. This Projects objective is to systematically identify therapeutically exploitable components of the oncogenicPAX3-FOXO1 interactome the catalog of proteins that interact with PAX3-FOXO1 that are also essential for its oncogenic activity. To identify the PAX3-FOXO1 domains and interacting proteins that mediate oncogenesis this Project proposes a stepwise comprehensive approach through the following Specific Aims: 1) Define the differential interactome of functional PAX3-FOXO1 using BirA proximity labeling; 2) Map PAX3-FOXO1 functional domains at amino acid resolution using saturation mutagenesis; 3) Define functional and combinatorialdependencies within the PAX3-FOXO1 interactome; 4) Credential interactome dependencies in cellular and animal models of PAX3-FOXO1 ARMS. The protein interactome defined in Aim 1 will be used to generate single-and dual-targeting CRISPR/Cas9 loss-of-function libraries in Aim 3. Work in Aim 2 will reveal the key functionaldomains and amino acid residues necessary for the oncogenic activity of the fusion oncoprotein an achievement exploited throughout the Center to inform regions involved in PAX3-FOXO1 stability in Project 1 and prioritization of chemical probes in Project 3 and to refine the interacting proteins mediating PAX3-FOXO1 transformation inAim 3 of this Project. Top candidates emerging from Aim 3 will then be nominated for in-depth analysis in Aim 4 using established cellular and animal models to define validated targets for near- and long-term development of drugs targeting either key interacting proteins themselves or their interactions with PAX3-FOXO1. +Cancer; Clinical Research Administrative Core n/a NCI 10680743 8/9/22 12:07 PA-20-272 3U10CA180821-09S2 3 U10 CA 180821 9 S2 "MOONEY, MARGARET M" 3/1/22 0:00 2/28/25 0:00 ZCA1(O1) 9573 1879065 "BERTAGNOLLI, MONICA M" "GEORGE, SUZANNE ; HAHN, OLWEN " 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 1400000 1304337 95663 No abstract available +Cancer; Clinical Research Administrative Core n/a NCI 10680712 8/9/22 10:54 PA-20-272 3U10CA180821-09S1 3 U10 CA 180821 9 S1 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 ZCA1(O1) 8216 1879065 "BERTAGNOLLI, MONICA M" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 2408803 1953797 455006 No abstract available +Cancer; Health Disparities; Minority Health; Social Determinants of Health; Women's Health Cancer Center;Collaborations;Communication;Development;Electronic Mail;Faculty;Florida;Funding;Health Sciences;Hispanic Populations;Individual;Infrastructure;Institution;Leadership;Logistics;Monitor;Play;Preparation;Principal Investigator;Productivity;Progress Reports;Publications;Puerto Rico;Reduce health disparities;Reporting;Research Institute;Research Personnel;Research Project Grants;Resource Sharing;Role;Science;Scientific Evaluation;Services;Structure;Supervision;Teleconferences;Underserved Population;Universities;Vision;Visit;Work;anticancer research;biobank;cancer therapy;career development;education research;expectation;experience;health disparity;improved;innovation;meetings;member;outreach;precision medicine;programs;recruit Administrative Core n/a NCI 10680687 9/2/22 0:00 PA-20-272 3U54CA163071-10S1 3 U54 CA 163071 10 S1 "SAN MIGUEL-MAJORS, SANDRA L" 9/1/22 0:00 8/31/23 0:00 9562 7890165 "MATTA, JAIME L" Not Applicable 98 Unavailable 105742043 LMF5HEYNM148 105742043 LMF5HEYNM148 US 18.01462 -66.614749 1565401 PONCE SCHOOL OF MEDICINE PONCE PR Domestic Higher Education 7327004 UNITED STATES N 9/1/21 0:00 8/31/22 0:00 Research Centers 2022 627180 399987 227193 PROJECT SUMMARY/ABSTRACT The Administrative Core (AC) exists to promote the vision of the Ponce Health Sciences University-Moffitt Cancer Center (PHSU-MCC) Partnership which is to reduce health disparities in a variety of differentways ultimately resulting in improved cancer treatments and precision medicine approaches best suited for thePuerto Rico and Florida Hispanic populations. The AC plays a significant role serving as the functional infrastructure of the Partnership promotinginnovative cancer research outreach and biobanking toward an underserved population and researcheducation of under-represented individuals. Specifically it provides oversight organization and ongoingevaluation for the scientific and administrative aspects of the Partnership. Such oversight includes but is notlimited to day-to-day administrative and financial oversight coordination of activities and logistical support.Administrative and coordinating activities occur at both institutions with continuous communications being oneof the principal responsibilities of the AC. In the renewal the AC will retain a composition/configuration similarto that in the current Partnership. This structure is highly effective in providing scientific and administrativeoversight while promoting collaboration among the multiple components. For the competitive renewal theSpecific Aims of the AC are to: 1) Provide the functional infrastructure of the Partnership in terms of innovationdirection leadership and fiscal/administrative support for the individual scientific projects and cores 2)Facilitate communications at all levels 3) Set expectations provide support and monitor the productivity of thePartnerships projects and cores. +No NIH Category available 2019-nCoV;African American;Age;Autoimmunity;B lymphoid malignancy;B-Cell Lymphomas;B-Lymphocytes;Blood;Bone Marrow;COVID-19;COVID-19 morbidity;COVID-19 mortality;COVID-19 pandemic;COVID-19 patient;COVID-19 risk;COVID-19 vaccination;COVID-19 vaccine;Cancer Patient;Clinical Data;Data;Development;Disease;Disease Progression;Health;Hematologic Neoplasms;Immune;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologic Memory;Immunologics;Immunology;Immunosuppression;Immunotherapy;Impairment;Individual;Inflammation;Inflammatory Response;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Morbidity - disease rate;Multiple Myeloma;Natural Immunity;Non-Small-Cell Lung Carcinoma;Outcome;Paresis;Pathology;Patient Care;Patients;Plasma Cell Neoplasm;Plasma Cells;Population;Recording of previous events;Regulation;Research Personnel;Risk;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;Serology;T cell response;Vaccines;Viral;Viral Cancer;Virus;Virus Diseases;adaptive immunity;antiviral immunity;cohort;comorbidity;coronavirus disease;experience;global health;high risk;hypogammaglobulinemia;immune checkpoint;immune checkpoint blockade;immune-related adverse events;immunopathology;immunoregulation;insight;mortality;multidisciplinary;pathogen;post SARS-CoV-2 infection;research clinical testing;response;severe COVID-19;standard care;standard of care;targeted treatment;tumor;tumor immunology Immune Regulation of COVID-19 Infection in Cancer and Autoimmunity Narrative:Requirement in the Overall component only. NCI 10680633 9/19/22 0:00 RFA-CA-20-038 4U54CA260563-02 4 U54 CA 260563 2 9/30/20 0:00 11/30/24 0:00 ZCA1-GRB-I 9545 2102018 "DHODAPKAR, MADHAV V" Not Applicable 5 Unavailable 66469933 S352L5PJLMP8 66469933 S352L5PJLMP8 US 33.791247 -84.3249 2384501 EMORY UNIVERSITY ATLANTA GA Domestic Higher Education 303221007 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 Research Centers 2022 359168 229500 129668 Project 3:Title: Regulation of SARS CoV-2 immunity in cancer patientsProject leaders: Madhav Dhodapkar and Rafi AhmedProject Summary:Patients with cancer are at increased risk of morbidity and mortality relating to SARS CoV-2 infection.However the immunologic underpinnings of wide variance in COVID-19 disease course in cancerpatients are unknown. In addition to underlying cancer associated immune paresis therapies used totreat cancer can further increase the risk of COVID related pathology. In this proposal we haveassembled a multidisciplinary team to tackle these questions. These studies build directly on our priorexpertise and experience in studying immunity in viral infections and cancer. We will focus inparticular on patients with B/plasma cell tumors treated with B/plasma cell depleting therapies andthose with lung cancer treated with immune checkpoint blockade. Studies in aim 1 will evaluate theimpact of therapy-related immune paresis on protective immunity to SARS CoV-2 and viral clearancein patients with B/plasma cell malignancies. Studies in aim 2 will evaluate anti-viral immunity andimmunopathology in patients with lung cancer receiving immune checkpoint blockade. Studies in aim3 will evaluate immunologic responses to SARS CoV-2 vaccines in patients with B/plasma cell tumorsand lung cancer once they are approved and administered as a part of standard care. These studieswill not only provide basic insights into protective immunity to SARS CoV-2 but also provide essentialinformation for optimal care of these patients in the face of concurrent SARS CoV-2 infection. +No NIH Category available 2019-nCoV;ACE2;Address;Affect;Affinity;Age;Animal Model;Antibodies;Antibody Response;B cell repertoire;B-Lymphocytes;Biological Assay;Biology;Blocking Antibodies;Blood;Blood Cells;Blood Circulation;COVID-19;COVID-19 diagnosis;COVID-19 outbreak;Cells;Clinical;Clinical Trials;Communicable Diseases;Coronavirus Infections;Development;Disease;Evaluation;Event;Female;Frequencies;Future;Generations;Hour;Household;Human;Humoral Immunities;Immune;Immune response;Immunity;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunologic Memory;Immunologics;Immunology;Impairment;In Vitro;Individual;Infection;Inflammatory Response;Innate Immune Response;Knowledge;Learning;Long-Term Effects;Lymphopenia;Measures;Mediating;Memory;Modeling;Molecular;Molecular Biology;Mucosal Immunity;Mucous Membrane;Nature;Onset of illness;Oral;Oral cavity;Oropharyngeal;Patients;Peripheral;Peripheral Blood Lymphocyte;Peripheral Blood Mononuclear Cell;Post-Translational Protein Processing;Production;Proteins;Proteomics;Public Health;RNA;Role;SARS coronavirus;SARS-CoV-2 exposure;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 positive;Saliva;Sampling;Secretory Immunoglobulin A;Serology test;Severity of illness;Shapes;Site;Symptoms;T-Lymphocyte;Testing;Time;Vaccines;Validation;Variant;Viral;Viral Load result;Viral Proteins;Viremia;Virus;adaptive immune response;antigen-specific T cells;cell killing;chemokine;comparative;cross reactivity;cytokine;experience;high risk population;indexing;long term memory;male;multidisciplinary;nasopharyngeal swab;neutralizing antibody;novel;peripheral blood;prevent;prospective;receptor;response;serological marker;transcriptome sequencing;vaccine immunogenicity;virology Early Drivers of Humoral Immunity to SARS-CoV-2 Infections The study examines events associated with initial exposure to COVID-19 by following close householdcontacts of individuals with documented COVID-19 over a period of 28 days. From this study we will begin tolearn why most individuals are asymptomatic or develop mild symptoms following infection and whether somepre-existing immunity is important. We will also learn whether they develop partial immunity to the SARS-CoV2virus what are markers of this immunity and how long this persists. We will develop novel tests using the mostinformative markers to screen the mouth upper airways and blood in high risk populations which will predictwho will get seriously sick and who will be minimally impacted by the virus. NCI 10680626 9/20/22 0:00 RFA-CA-20-039 4U01CA260539-02 4 U01 CA 260539 2 "KUO, LILLIAN S" 9/18/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 1877985 "KING, CHRISTOPHER L" Not Applicable 11 PATHOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2022 679626 NCI 422128 257498 C6 The duration and nature of humoral immunity to SARS-CoV-2 (CoV2) infection is poorly understood. Moststudies have focused on the immune response in patients with clinical illness but little is known about antibodyresponse to CoV2 regarding the earliest immunological events immediately after exposure and prior to onset ofillness or in asymptomatic individuals and how this impacts long-term immunological memory. This proposaladdresses these gaps in our knowledge by prospectively following household contacts with clinical cases ofCoV2 to determine innate and adaptive immune events associated with this early viral exposure over a 28 dayperiod. Detailed evaluation of samples from these patients including RNAseq of peripheral blood cells andproteomic analysis of oral secretions the site of initial CoV2 replication. We will determine whether potentiallycross-reactive T cells and secretory IgA may contribute to this early protective immune response and if presentdo they enhance the subsequent humoral immune responses by providing greater T cell help to B cells. Thesestudies will also provide a detailed knowledge of innate immune responses to CoV2 and how this shapes thenature and duration humoral immunity. Our central hypothesis is that peripheral blood lymphocytes andoropharyngeal secretions collected from individuals at the time of viral exposure and prior to onset ofsymptoms will show innate and adaptive immune responses that correlate with viral clearance andpredict whether or not effective humoral immunity and long-term immunological memory develops.This hypothesis will be addressed by exploring the following aims; i) evaluating the early immune humoral andcellular immune responses to CoV2 in close contacts of individuals diagnosed with COVID-19; ii) to assessearly innate immune responses in close contacts of individuals diagnosed with COVID-19 and assess theirrelationship with humoral immune responses and viremia; and iii) to examine early drivers of humoral immunityon the durability of immunological memory and responses to vaccines. This comprehensive evaluation of therelationships between early infection with innate and adaptive immune on long-term memory and immunity willprovide a rigorous basis for the development of highly informative and scalable serological tests. Our approachis therefore highly responsive to RFA-CA-20-039 through the development and validation of novel assays thatsimultaneously measure innate and adaptive immune responses to CoV2 from early infection; this approachwill help define immune parameters and serological markers associated with asymptomatic vs. symptomaticinfection and disease severity. 679626 +No NIH Category available 2019-nCoV;Antibodies;Automobile Driving;Bar Codes;Biological Assay;Biology;COVID-19;COVID-19 monitoring;COVID-19 pandemic;COVID-19 patient;COVID-19 risk;COVID-19 severity;COVID-19 vaccine;Cancer Patient;Cardiovascular system;Cells;Cessation of life;Clinical;Complex;Data;Disease;Enzyme-Linked Immunosorbent Assay;Flow Cytometry;General Population;Hematologic Neoplasms;Hematological Disease;Hematology;Hematopathology;Hematopoietic Neoplasms;Immune;Immune response;Immunoassay;Immunoglobulin G;Immunoglobulin M;Immunosuppression;Institutional Review Boards;Laboratories;Lymphopenia;Malignant Neoplasms;Measurement;Measures;Mediating;Medicine;Memorial Sloan-Kettering Cancer Center;Microfluidics;Molecular;Monitor;Motivation;Multiple Myeloma;Multiple Organ Failure;Myelosuppression;Pathology;Patient Monitoring;Patients;Peripheral Blood Mononuclear Cell;Plasma;Plasma Proteins;Population;Production;Prospective cohort;Proteins;Public Health;Research Personnel;Retrospective cohort;Risk;Role;SARS-CoV-2 antibody;SARS-CoV-2 infection;Sampling;Serology;Serology test;Severities;Specimen;Stains;Technology;Testing;Time;Tissue Banks;Vaccination;Vaccines;Validation;Vulnerable Populations;angiogenesis;blood treatment;cell type;chemokine;clinical translation;cohort;combat;coronavirus disease;cytokine;density;design;effective therapy;high risk;high throughput screening;immune activation;immune function;improved;individualized medicine;lung injury;microchip;novel;peripheral blood;personalized strategies;protein biomarkers;response;success;synergism;thrombotic;transcriptome sequencing;vaccine efficacy;vaccine evaluation;vaccine response Immuno-Serological Assays for Monitoring COVID19 in Patients with Hematologic Malignancies PROJECT NARRATIVEThis project aims to develop two novel immuno-serological assays for highly informative measurement of plasmaprotein markers and single-cell cytokine signatures in order to identify molecular correlates with COVID-19 riskseverity vaccine response in patients with hematologic malignancies. They can be applied to monitoring ofCOVID-19 patients without a malignancy or other cancers and potentially guide the design of effective treatments.This project is of vital importance and urgency to public health during the COVID-19 pandemic. NCI 10680624 9/16/22 0:00 RFA-CA-20-039 4U01CA260507-02 4 U01 CA 260507 2 "KOHAAR, INDU" 9/30/20 0:00 11/30/24 0:00 ZCA1-RTRB-C(A1) 9372328 "FAN, RONG " "HALENE, STEPHANIE " 3 ENGINEERING (ALL TYPES) 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT BIOMED ENGR/COL ENGR/ENGR STA 65208327 UNITED STATES N 9/1/22 0:00 11/30/24 0:00 394 Non-SBIR/STTR 2022 711873 NCI 424999 286874 C6 SUMMARYPatients with hematologic malignancies appear to have a higher risk of SARS-CoV-2 infection. Diseasecourses are variable in severity influenced by immunosuppression due to the malignancy and its treatmentdetermining the degree of immune-mediated hyperinflammation implicated in lung damage multi-organ failureand death. This highlights the need for comprehensive clinical tests to monitor COVID19 patients specificallywith hematologic malignancies. We propose to develop and validate two novel immuno-serological assays thatwill be deployed to conduct longitudinal measurement of plasma markers and peripheral blood immune cellsfrom COVID patients with different hematologic malignancies. First we will develop an automated 32-plexedplasma protein assay to quantify SARS-COV-2 IgG/IgM antibodies cytokines/chemokines angiogenesismarkers endotheliopathy markers and pro-thrombotic markers all combined in a high-density antibodybarcode array microchip. Second we will develop a microchip assay for single-cell immune functionmeasurement to quantify cell types and 30+ immune effector proteins in peripheral blood immune frompatients. Single-cell transcriptome sequencing will be performed on select samples to cross-validate the resultsand reveal the mechanisms of action in COVID-induced immune activation. Third these new assays will bedeployed to measure a cohort of COVID19 patients with or without hematological malignancies and healthydonors in order to identify potential molecular correlates with immune-mediated pathology and COVID diseaseseverity uniquely in hematological cancer patients. As the COVID19 vaccines become available we will applythese assays to monitoring vaccine-induced humoral cellular and immunological response in hematologicalcancer patients and compare to non-cancer populations to understand differences and ways to improve thesuccess of vaccination in patients with hematologic malignancies a vulnerable group of patients who may notfollow the same mechanisms as general populations in COVID19. 711873 +Cancer; Clinical Research; Health Disparities; Health Services; Minority Health; Prevention Address;African American;Biometry;Cancer Center;Cancer Control;Church;Clinical;Clinical Medicine;Clinical Research;Collaborations;Communities;Community Health Aides;Detection;Early Diagnosis;Effectiveness;Evaluation Research;Evidence based intervention;Faculty;Family;Fostering;Foundations;Funding;Goals;Grant;Health Personnel;Health Services Research;Intervention;Journals;Lead;Los Angeles;Malignant Neoplasms;Minority;Patients;Peer Review;Pilot Projects;Prevention;Procedures;Publications;Research;Research Personnel;Screening for cancer;Seeds;Students;Training;Wellness Center;Work;anticancer research;base;cancer health disparity;cancer prevention;cancer survival;community based participatory research;community engagement;design;disadvantaged population;education research;experience;faculty community;feasibility testing;improved;innovation;interest;member;outreach;outreach program;programs;recruit;socioeconomic disadvantage;symposium Outreach Core n/a NCI 10680621 9/7/22 0:00 PAR-15-103 3U54CA143931-10S3 3 U54 CA 143931 10 S3 "AGUILA, HECTOR NELSON" 9/29/09 0:00 8/31/23 0:00 ZCA1-PCRB-C 9537 12172270 "LUCAS-WRIGHT, ANNA " Not Applicable 43 Unavailable 785877408 PFBDNBDS57H3 785877408 PFBDNBDS57H3 US 33.923952 -118.245687 489501 CHARLES R. DREW UNIVERSITY OF MED & SCI LOS ANGELES CA Domestic Higher Education 900593051 UNITED STATES N 9/1/19 0:00 8/31/20 0:00 Research Centers 2022 25025 17439 7586 OUTREACH CORE ABSTRACT The overarching goal of the Outreach Core is to improve the prevention detection treatment and survival from cancer by integrating community engagement practices with cancer research strategies. During the past five years the Cancer Outreach Core has been an integral part of the CDU-UCLA Cancer Center Partnership. We have strengthened relationships with predominantly African American community members and organizations; identified cancer-related priorities in this community; organized four large community cancer conferences; supported three seed grants that were conducted in South Los Angeles each with an academic and a community investigator; developed publications in peer-reviewed journals each with community authors; and obtained new grant support including funding for the first Patient Navigation Program and Wellness Center for South Los Angeles. In short we have successfully engaged the community in South Los Angeles in research to reduce cancer disparities. We have also contributed to the training of minority junior faculty community faculty and students which is an important goal of the CDU-UCLA Cancer Center Partnership. Based on our experience in the current funding cycle and the advice of the Program Steering Committee we will maintain the strong features of the Cancer Outreach Core and add new components that build on the work we have accomplished to date and the expertise of our diverse team of community and academic faculty from UCLA and CDU. The partnership will benefit CDU by building a strong foundation for community- partnered cancer disparities research; and will benefit UCLA by broadening outreach opportunities to South Los Angeles. +Cancer; Dietary Supplements; Digestive Diseases; Nutrition; Pancreatic Cancer; Prevention; Rare Diseases Affect;Anorexia;Antineoplastic Agents;Blood Circulation;Cachexia;Caloric Restriction;Cancer Biology;Cancer Model;Cancer Patient;Cell Death;Cell Signaling Process;Cells;Communication;Consumption;Dependence;Desire for food;Desmoplastic;Development;Development Plans;Diet;Diet and Nutrition;Diet therapy;Dietary Factors;Dietary Fats;Dietary Intervention;Dietary Practices;Digestion;Drug Combinations;Drug Targeting;Educational process of instructing;Environment;Epidemiology;Exocrine pancreatic insufficiency;Extracellular Matrix;Fatty acid glycerol esters;Food;Foundations;Genes;Goals;Growth;Impairment;Intercellular Fluid;Learning;Lipid Peroxidation;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Mentors;Metabolic;Metabolic Pathway;Metabolism;Molecular;Mus;Nutrient;Pancreatic Ductal Adenocarcinoma;Pancreatic enzyme;Patient Care;Patients;Peripheral;Polyunsaturated Fatty Acids;Positioning Attribute;Quality of life;Recommendation;Reducing diet;Research;Research Personnel;Research Proposals;Science;Scientist;Shapes;Stromal Cells;Survival Rate;Technology;Testing;Therapeutic;Tissues;Training;Translations;Work;base;cancer cell;cancer therapy;career development;chemotherapy;dietary;enzyme replacement therapy;fatty acid metabolism;food restriction;improved;in vivo;inhibitor;lipid metabolism;lipidomics;metabolomics;mouse model;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;response;skills;stable isotope;standard of care;synergism;transcriptome sequencing;treatment response;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;wasting Understanding the effects of dietary interventions on pancreatic ductal adenocarcinoma therapy cancer Project NarrativePancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is associated with dysregulatedtumor and whole-body metabolism that impacts therapy and quality of life. An opportunity for better exploitingmetabolic vulnerabilities in PDAC for cancer treatment is to systematically examine how dietary interventionsimpact PDAC progression therapy responses and survival. This proposed research will elucidate themetabolic mechanisms underlying potential synergies between dietary factors and standard-of-care oremerging PDAC therapies in an effort to provide scientific evidence that can benefit patients with guidance onhow to best incorporate diet and nutrition into PDAC treatment. NCI 10680617 9/14/22 0:00 PA-20-188 4R00CA255928-02 4 R00 CA 255928 2 "XI, DAN" 4/1/22 0:00 8/31/25 0:00 Transition to Independence Study Section (I)[NCI-I] 11626616 "LIEN, EVAN CHEN" Not Applicable 3 Unavailable 129273160 QLRCUJ8JTN53 129273160 QLRCUJ8JTN53 US 42.969389 -85.666402 4239601 VAN ANDEL RESEARCH INSTITUTE GRAND RAPIDS MI Research Institutes 495032518 UNITED STATES N 9/2/22 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2022 248982 NCI 131043 117939 Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment optionsthat has a five-year survival rate of <10%. PDAC progression is associated with dysregulated tumor and whole-body metabolism that impacts therapy and quality of life which has motivated research on how to best exploitmetabolic dependencies in PDAC for better cancer treatment. Nutrient utilization by cancer cells is regulated inpart by the availability of metabolites in the environment and the PDAC tumor microenvironment in particular ishighly desmoplastic consisting of stromal cells extracellular matrix and nutrient-poor interstitial fluid. Thesemicroenvironmental factors can impact therapy response suggesting that the efficacies of metabolism-targeteddrugs can be improved by manipulating components of the PDAC tumor microenvironment. One determinant ofmetabolite levels in the tumor microenvironment is diet and how diet affects cancer progression and treatmentis an important question for many patients. Since dietary recommendations to patients must be made in thecontext of therapies being received the value of any dietary intervention likely lies in its ability to enhance tumorresponses to cancer therapies. Understanding the molecular mechanisms that drive synergistic interactionsbetween diet and cancer therapies is critical for the translation of dietary recommendations into patient care. The main objective of this proposal is to identify dietary interventions that synergize with cancer therapiesto impair PDAC progression. Mouse PDAC models will be used to examine how different diets enhance theefficacies of standard-of-care FOLFIRINOX chemotherapy (Aim 1) lipid metabolism inhibitors in developmentfor cancer treatment (Aim 2) and inducers of ferroptosis a non-apoptotic form of cell death being explored forPDAC treatment (Aim 3). Mass spectrometry-based metabolomics and lipidomics stable isotope nutrient tracingand RNA sequencing will be used to determine how diet-mediated changes to nutrient levels in the tumormicroenvironment alter the metabolism of PDAC tumors to shape their responses to these therapies. Elucidatingthe metabolic mechanisms that underlie synergistic diet-drug combinations will provide scientific evidence thatcan benefit patients with guidance on how to best incorporate diet and nutrition into cancer therapy. The proposed training plan will help me transition into an independent academic position. A team ofoutstanding scientists will mentor me to help me achieve this goal: Dr. Tyler Jacks a leader in mouse cancermodels; Dr. Omer Yilmaz a leader in dietary effects on cancer progression; Dr. Caroline Lewis a leader in massspectrometry-based metabolomics and lipidomics technologies; and Dr. Brian Wolpin a leader in PDACepidemiology. My training plan also outlines activities that will help me cultivate mentors improve my scientificskillset improve science communication skills develop teaching and mentoring skills build my network andlearn lab management skills. Together the research proposal and career development plan will provide me withthe expertise needed to become a successful independent investigator and educator in the cancer biology field. 248982 +No NIH Category available Academic Medical Centers;Address;Adjuvant;Adjuvant Study;Advanced Malignant Neoplasm;Aftercare;Albert Einstein Cancer Center;American College of Radiology Imaging Network;Anal carcinoma;Area;Biological Markers;Black race;Breast Cancer Detection;Cancer Center;Cancer Control;Cancer Patient;Clinical;Clinical Research;Collection;Committee Members;Communities;Community Clinical Oncology Program;County;Coupled;Diagnosis;Doctor of Philosophy;Eastern Cooperative Oncology Group;Ethnic Origin;Evaluation;Faculty;Foundations;Funding;Goals;Health system;Hematopoietic Neoplasms;Hispanic;Home;Infrastructure;Institution;Language;Leadership;Malignant Neoplasms;Measurement;Medical center;Medicine;Mentored Clinical Scientist Development Program;Mentors;Methodology;Methods;Minority;Minority Groups;Minority Participation;Mission;Morbidity - disease rate;NCI-Designated Cancer Center;Neuropathy;New York;Nivolumab;Outcome;Outcomes Research;Patient Care;Patients;Pilot Projects;Prevention;Protocols documentation;Recording of previous events;Research;Research Personnel;Resources;Role;Science;Site;System;Therapeutic;Therapeutic Trials;Training;Training Programs;Training Support;Training and Education;Translational Research;Underrepresented Minority;United States;Urban Community;anticancer research;base;biomarker validation;black women;cancer care;cancer clinical trial;cancer health disparity;cancer imaging;cancer prevention;cancer therapy;care delivery;career;college;experience;federal poverty level;financial toxicity;health care delivery;health related quality of life;innovation;institutional capacity;malignant breast neoplasm;member;minority engagement;minority patient;minority subjects;mortality;novel;oncology program;patient engagement;population based;postgraduate education;precision medicine;programs;prospective;screening;success;taxane;team-based care;treatment trial;trial design;trial planning;underserved community;underserved minority MINORITY-BASED COMMUNITY ONCOLOGY PROGRAM The goal of the Montefiore-Einstein Minority/Underserved National Community OncologyResearch Program (MU NCORP) is to advance the prevention diagnosis treatment andmanagement of early and advanced cancer. Our goals are to: 1) accrue at least 80 subjects totrials sponsored by the NCORP research bases (including at least 40 to therapeutic trials) 2)provide scientific and administrative leadership to the ECOG-ACRIN NRG and Allianceresearch bases; 3) expand our capacity for cancer care delivery research (CCDR) to include atleast 3 active CCDR protocols; 4) train and mentor young investigators in all areas of NCORPresearch; and 5) contribute expertise in novel methodology to address cancer health disparitiesincluding patient engagement trial design and outcomes measurement. NCI 10680599 7/27/23 0:00 RFA-CA-18-017 5UG1CA189859-10 5 UG1 CA 189859 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-SRB-H(M1) 8683247 "HALMOS, BALAZS " "GARTRELL, BENJAMIN ADAM; RAPKIN, BRUCE D" 15 Unavailable 41581026 FP1VD1HU5HV7 41581026 FP1VD1HU5HV7 US 40.88083 -73.879943 5451101 "MONTEFIORE MEDICAL CENTER (BRONX, NY)" NEW YORK NY Independent Hospitals 104672490 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 929392 NCI 677884 315234 The overall goals of the Montefiore-Einstein minority-based NCORP community site are to advance thediagnosis prevention and management of early and advanced cancer by participating in NCORPtrials as a minority/underserved community site and contributing scientifically and administratively to theNCORP research bases. This will be accomplished by leveraging the strengths of the Montefiore HealthSystem (MHS) including Montefiore Medical Center (MMC) which brings strengths in integrated patientcare and innovative health care delivery systems in an academic medical center serving a largelyminority population and the Albert Einstein College of Medicine and Cancer Center (Einstein) whichbrings strength in training and education and in baslc translational and clinical research through its NCI-designated cancer center. The MMC-Einstein program also brings critical leadership to the NCORPResearch Bases including ECOG-ACRIN Alliance and NRG including leadership roles at the level of thegroup chair's office scientific committee chair (or co-chair) and protocol chair (or co-chair). Our plansbuild upon our long-standing involvement in all aspects of cancer research as a main member ofECOG for 45 years and an NCI-designated cancer center for 48 years and a strong history of minorityaccrual to cancer treatment trials (about 65%of all patients). MMC serves the Bronx an urban community of1.47 million residents of whom 89% are minorities and 29% live below the federal poverty level. In theprior funding period we had a strong track record scientific contributions to the NCORP research bases andmet our accrual targets with exceptionally strong minority participation. In the next funding period we willcontinue our strong leadership in cancer therapeutics (EA2165) expand the spectrum of our activities toinclude new programs in cancer imaging and screening (TMIST) cancer control/prevention (EAZ171) andcancer care delivery research (CCDR). The MMC-Einstein NCORP program is led by faculty withexperience in cancer therapeutics and biomarker research (J. Sparano MD) precision medicine andimmunoncology (B. Halmos MD) and CCDR and cancer prevention/control (B. Rapkin PhD) and issupported by a cadre of other investigators with a broad range of expertise some of whom benefited from NCI-funded K12 training program in clinical cancer research. 929392 +No NIH Category available 3-Dimensional;3D ultrasound;Abdomen;Address;Anatomy;Biological Markers;Blood Vessels;Cancer Patient;Cessation of life;Clinical;Clinical Trials;Clinical assessments;Collaborations;Colorectal;Combined Modality Therapy;Compensation;Computer software;Contrast Media;Data;Development;Disease;Early treatment;Evaluation;Foundations;Functional Imaging;Future;Goals;Grant;Healthcare;Image;Imaging Techniques;Industry;Inflammatory Response;Interobserver Variability;Lesion;Liver;Liver neoplasms;Malignant Neoplasms;Measurement;Metastatic Neoplasm to the Liver;Methods;Modality;Monitor;Morbidity - disease rate;Motion;Multi-Institutional Clinical Trial;Organ;Outcome;Patient Care;Patient Monitoring;Patients;Perfusion;Phase;Prediction of Response to Therapy;Radiation;Radiology Specialty;Reporting;Reproducibility;Research Project Grants;Resources;Sampling Errors;Scanning;Site;Spectrum Analysis;Survival Rate;System;Techniques;Technology;Therapeutic;Three-Dimensional Imaging;Tissue imaging;Tissues;Transducers;Tumor Volume;Ultrasonography;Validation;Vendor;Work;anatomic imaging;cancer imaging;cancer therapy;cancer type;chemotherapy;clinical application;clinical care;clinical research site;colorectal cancer metastasis;contrast enhanced;cost;data acquisition;design;effective therapy;experience;imaging approach;improved;improved outcome;industry partner;innovation;liver visualization;metastatic colorectal;novel;novel marker;patient response;portability;quantitative ultrasound;response;side effect;success;tool;treatment response;tumor;tumor heterogeneity;ultrasound Three-Dimensional Multi-Parametric Ultrasound for Monitoring Therapy of Liver Metastasis NARRATIVEThe development of safe non-invasive and inexpensive approaches to predict early which patients willrespond to therapy including combined therapy strategies is of crucial importance for advancing themanagement of cancer patients. Our research project in collaboration with our industry partner Philips is thefirst multi-site clinical trial to assess the feasibility repeatability and reproducibility of a novel combinedvolumetric perfusion and tissue characterization approach in patients with liver metastases from colorectalcancer and whether these tumor characterizations can predict early response to therapy. This trial will lay thefoundation for future clinical trials for better guiding of cancer therapy in patients with liver metastases fromcolorectal as well as other cancer types. NCI 10680583 9/7/23 0:00 PAR-18-530 5R01CA195443-06 5 R01 CA 195443 6 "TANDON, PUSHPA" 4/1/16 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 14889818 "EL KAFFAS, AHMED " Not Applicable 16 RADIATION-DIAGNOSTIC/ONCOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 652072 NCI 474727 177345 PROJECT SUMMARY/ABSTRACTThe ability to non-invasively predict or monitor early patient response to cancer therapy will have significantimplications for patient care with the potential to spare non-responding patients the high morbidity and costassociated with failed treatments. Due to its wide accessibility lack of radiation relatively low cost andexcellent visualization of the liver ultrasound is a demonstrated and potentially ideal modality to repeatedlyimage and monitor patient responses over the course of therapy. In the first phase of this work wedemonstrated that current 2D dynamic contrast-enhanced ultrasound (DCE-US) is fundamentally limited inquantification due to tumor heterogeneities resulting in consecutive sampling errors with substantial over- orunderestimation of treatment response in patients. We then showed that these limitations could be overcomeby a novel 3D DCE-US imaging approach using innovative matrix array transducer technology to providemotion-compensated accurate quantitative and volumetric assessment of tissue perfusion of liver metastases.In this competitive renewal proposal framed as an industry-academic partnership with Philips who iscommitted to our proposal our aim to clinically advance 3D multi-parametric tissue and perfusioncharacterization with ultrasound (3D MPUS) to predict or monitor early response in patients with metastaticcolorectal cancers to the liver (mCRC). For this we have proposed a set of specific aims where we will: i) workwith Philips to enhance 3D DCE-US data acquisition to overcome previously reported limitations enablesimultaneous acquisition of raw RF/Bmode data for tissue characterization and develop an analysis softwaresuite for MPUS quantification ii) carry-out a multi-site clinical feasibility acquisition repeatability andquantification reproducibility assessment of 3D MPUS in 300 patients and iii) determine whether 3D MPUSquantification can predict or monitor early therapy response. For this baseline and early changes of tumorperfusion and tissue parameters (obtained before and at 2-3 weeks after initiation of therapy) will be correlatedto treatment response. Treatment response as defined on abdominal radiological scans acquired at 2 monthsfollowing treatment initiation will be determined using standard RECIST 1.1 reporting. Our proposal builds onthe recent FDA approval of ultrasound contrast agents for liver tumor imaging increased clinical availability ofcommercial 3D US abdominal probes and our initial clinical validation of 3D DCE-US and extensiveexperiences in QUS. 652072 +No NIH Category available Grant;Malignant Neoplasms;Training Integrative Cancer Scholars Training Grant Program NarrativeThe Integrative Cancer Scholars (ICS) training program is an innovative comprehensive plan to prepare thenext generation of cancer researchers by emphasizing critical thinking skills adapting novel technologies andrequiring a co-mentoring plan with clinical and basic science faculty mentors. The development of innovativeand impactful therapies must integrate information from clinical experience and fundamental discoveries ofbasic science to understand and act on the abnormal transformations of key molecules or pathways in cancer.ICS trainees are expected to produce original creative and significant cancer research and have advancedcommunication skills for dissemination of their discoveries. NCI 10680574 8/24/23 0:00 PA-18-403 5T32CA009213-44 5 T32 CA 9213 44 "DAMICO, MARK W" 9/1/83 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9207584 "CAREW, JENNIFER S" "CURIEL-LEWANDROWSKI, CLARA ; ROGERS, GREGORY CHARLES" 7 ANATOMY/CELL BIOLOGY 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 263644 NCI 289890 15597 AbstractOur goal is to recruit train and develop the next generation of leaders in cancer research. To achieve thisobjective we will implement the Integrative Cancer Scholars (ICS) program as described in this competitiverenewal of our long-standing Cancer Biology Training Program. ICS is an innovative predoctoral andpostdoctoral fellows training program that embraces a paired-mentor team approach to maximize the impactand significance of cancer research. Specifically Scholars choose one basic science mentor and one clinicalscience mentor from among nationally competitive basic and physician scientists. From the mentor pair theScholar selects a `lead' mentor from among the faculty with well-funded collaborative research programs with abroad range of cancer research specialties: Genomic and Epigenetic Instability Tumor MicroenvironmentCancer Prevention and Control Developmental Therapeutics Cancer Imaging Tumor Viruses andImmunology Tumor Progression and Metastasis and Cancer Pain. ICS is a unique program with distincttraining events designed to integrate current molecular and clinical cancer concepts. Each Scholar is expectedto conduct original cutting-edge research under the guidance of the mentor-pair and to participate in clinicalcases with their chosen physician mentor. Progress of each trainee is ensured through compulsory committeemeetings and annual evaluations by the mentor-pair. Scholars also participate in career development andnational networking opportunities including hosting thought leaders in our Cancer Biology Seminar Seriesacquiring new targeted skills in educational workshops and community engagement with oncologists andbiotechnology experts. Additionally Scholars are provided support to travel and present their work at a nationalmeeting. ICS is associated with the Cancer Biology Graduate Interdisciplinary Program which providesinstruction in cancer causation epidemiology prevention and grant writing through specific coursework and asymposium featuring presentations of pre- and postdoctoral research. The postdoctoral training plan ensuresthat each trainee navigates a path of comprehensive training leading to a mature scholarship and ability toconduct independent cutting-edge research. The program is designed to expose each trainee to the range ofcurrent thought in the cancer field to teach state-of-the-art laboratory techniques to emphasize critical thinkingskills to introduce real-world aspects of clinical work and to refine their career-development skills particularlyin networking communication and grant/manuscript preparation. Pre- and postdoctoral researchers fromlaboratories of the participating mentors are eligible for ICS support and Scholars are selected through acompetitive process. Support from the UA state-of-the-art research core facilities and opportunities forunderrepresented-minority researchers (UA is top of all Research I institutions for URMs in graduate school)round out a rich environment for training the future leaders of cancer research. 263644 +No NIH Category available Address;Aftercare;Agreement;Animals;Binding;Biopsy;Blood Volume;Brain;Brain Neoplasms;Cell Density;Cell Proliferation;Cells;Clinic;Clinical;Community Hospitals;Contrast Media;Data;Detection;Dose;Europe;Evolution;Excision;Exhibits;Functional Imaging;Functional disorder;Glioma;Goals;Healthcare;Heterogeneity;Human;Hypoxia;Image;Imaging Techniques;Immunohistochemistry;Injections;Lesion by Morphology;Magnetic Resonance Imaging;Malignant Neoplasms;Maps;Metabolic;Methodology;Methods;Mission;Molecular Target;Morphology;Multimodal Imaging;Operative Surgical Procedures;Patients;Perfusion;Phenotype;Physiological;Pimonidazole;Population;Positron-Emission Tomography;Pre-Clinical Model;Prediction of Response to Therapy;Predisposition;Prodrugs;Protocols documentation;Public Health;Radiation therapy;Recurrent tumor;Regional Perfusion;Reporting;Research;Scanning;Site;Techniques;Technology;Therapeutic;Translating;United States National Institutes of Health;azomycin;blood-brain barrier disruption;brain magnetic resonance imaging;brain tumor imaging;cancer imaging;clinical imaging;commercialization;contrast enhanced;cost;fluorescence imaging;hemodynamics;imaging approach;innovation;neuro-oncology;outcome prediction;patient derived xenograft model;personalized medicine;predicting response;prognostic of survival;radiotracer;response;targeted treatment;therapeutic target;therapy resistant;treatment effect;treatment planning;tumor;tumor growth;tumor hypoxia One-shot morphologic hemodynamic and metabolic MR imaging of brain tumors Project NarrativeThe proposed research is relevant to public health because it aims to validate and apply a practical integratedimaging approach for tumor imaging that will reduce patient costs and discomfort while enabling a morecomprehensive assessment of tumors. This project is relevant to NIHs mission as it focuses on a significanttechnological and clinically meaningful refinement in brain tumor imaging methodology that could enablepersonalized therapy based on lesion morphology regional perfusion and metabolic heterogeneity. NCI 10680562 7/21/23 0:00 PA-20-185 5R01CA264934-03 5 R01 CA 264934 3 "KIM, BOKLYE" 7/5/21 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(03)M] 8544630 "KODIBAGKAR, VIKRAM D." "QUARLES, CHRISTOPHER CHAD" 4 Unavailable 943360412 NTLHJXM55KZ6 943360412 NTLHJXM55KZ6 US 33.423954 -111.940687 488301 ARIZONA STATE UNIVERSITY-TEMPE CAMPUS TEMPE AZ Domestic Higher Education 852876011 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 577735 NCI 480694 97041 PROJECT SUMMARY/ABSTRACT:The goal of this project is to validate a clinically feasible one-shot contrast-enhanced multiparametric MRIapproach for mapping the morphologic hemodynamic and metabolic features of brain tumors using a singlecontrast agent. Contrast-enhanced (CE) MRI is the clinical imaging standard for guiding nearly all aspects ofbrain tumor management including surgical biopsy/resection radiation treatment planning and post-treatmentsurveillance for response assessment. Dynamic susceptibility contrast (DSC) MRI is a complementarytechnique that leverages the dynamic passage of the contrast agents utilized for CE-MRI in order to providemaps of tumor perfusion. An unmet clinical need in the assessment of tumor pathophysiology is the ability toroutinely detect hypoxia and its evolution. Brain tumors exhibit considerable hypoxia which leads to therapyresistance triggers more aggressive and invasive phenotypes is considered a potential therapeutic target andis prognostic of overall survival. The most widely used method for interrogating hypoxia in the clinic relies onPET radiotracers which in the context of brain tumors necessitates multiple scans and injections in additionto routine CE-MRI and DSC-MRI. This limitation increases costs dose and patient discomfort while reducingefficiency and the likelihood of widespread use particularly in non-academic community hospitals wherepatients are unlikely to undergo multi-modality imaging. Consequently an MRI-based hypoxia imagingapproach could significantly enhance the metabolic characterization and therapeutic management of braintumor patients. We have developed a GdDOTA monoamide conjugate of 2-nitroimidazole (a well-establishedhypoxia binding moiety) termed GdDO3NI that enables detection of regional hypoxia. We hypothesize thatCE-MRI DSC-MRI and hypoxia data can be acquired in brain tumors in a single imaging session following asingle-injection of GdDO3NI and can help predict outcome of hypoxia targeted therapy. We anticipate thatoptimal acquisition and analysis protocols for dynamic GdDO3NI MRI will provide hypoxia maps that regionallycolocalize with pimonidazole IHC and FMISO PET and will provide congruous estimates of hypoxic tumorfraction between the various techniques. Towards this end we propose to 1) validate GdDO3NI based CE-MRIand DSC-MRI in orthotopic human-derived glioma preclinical models 2) establish optimal GdDO3NI basedhypoxia mapping protocols and validate using immunohistochemistry (IHC) and clinically comparable PETmarkers and 3) demonstrate the potential of GdDO3NI to predict response to a hypoxia activated prodrugevofosfamide. Our innovative one-shot multi-parametric strategy represents a transformational shift in braintumor imaging that could enable personalized therapy based on lesion morphology regional perfusion andmetabolic heterogeneity. The proposed one-shot strategy could also be translated to cancers outside the brainincreasing the range of patients impacted by this research and feasibility of translating GdDO3NI to the clinic. 577735 +No NIH Category available ALK gene;Accounting;Address;Autoantibodies;Biological Assay;Biological Markers;Biology;Blood;Child;Childhood;Childhood Lymphoma;Chromosome abnormality;Clinical;Clinical Trials;Combination Drug Therapy;Detection;Development;Disease;Disease Progression;Early identification;Future;Genetic;Goals;Human;Immune response;Inflammatory Pseudotumor;Ki-1 Large-Cell Lymphoma;Lesion;Lymphoma;Malignant Neoplasms;Malignant neoplasm of lung;Mature T-Lymphocyte;Mediating;Methods;Modeling;Molecular;Monitor;Mutation;NPM1 gene;Neuroblastoma;Newly Diagnosed;Non-Hodgkin's Lymphoma;Patients;Pediatric Oncology Group;Plasma;Play;Population;Prognosis;Prognostic Marker;Prophase;Protein Tyrosine Kinase;Randomized;Receptor Protein-Tyrosine Kinases;Recurrence;Relapse;Research;Research Personnel;Residual Neoplasm;Resources;Risk;Role;Sampling;Subgroup;T-Cell Lymphoma;Therapeutic Agents;Time;Toxic effect;Transcript;anaplastic lymphoma kinase;chemotherapy;circulating biomarkers;cohort;constitutive expression;crizotinib;digital;experience;high risk;melanocyte;minimally invasive;multidisciplinary;novel;novel therapeutics;participant enrollment;peripheral blood;personalized diagnostics;phase 2 study;prognostic;prognostic significance;prognostic value;prognostication;relapse risk;response;specific biomarkers;t(2;5)(p23;q35);targeted treatment;treatment response;tumorigenesis Circulating biomarkers of ALK+ anaplastic large cell lymphoma Project Narrative:NPM-ALK+ anaplastic large cell lymphomas are aggressive forms of pediatric mature T cell lymphoma andover 30% of patients experiences disease progression or relapse without robust prognostic biomarkers. Ourstudies will lead to development of simple blood-based robust and sensitive quantitatve assays that will helpfacilitate decisions about discontinuation of treatment and identify patients with risk of relapse. NCI 10680558 7/31/23 0:00 PA-20-185 5R01CA255350-04 5 R01 CA 255350 4 "AGRAWAL, LOKESH" 10/1/22 0:00 7/31/25 0:00 Cancer Biomarkers Study Section[CBSS] 7518345 "LIM, MEGAN S." Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 297632 NCI 183781 113851 Project SummaryAnaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the ALK gene located on 5q35.Structural alterations including translocations copy number gains and activating mutations targeting ALKoccur in many types of human cancer including lung cancer non- Hodgkin lymphomas Spitzoidmelanocytic lesions neuroblastoma and inflammatory myofibroblastic tumor. In over 80% of pediatricanaplastic large cell lymphoma (ALCL) the most common form of mature T cell lymphoma in this populationthe chromosomal aberration t(2;5)(p23;q35) results in the expression of the constitutively active tyrosinekinase NPM-ALK. NPM-ALK positive lymphoma has served as a model for understanding ALK-mediatedoncogenesis and development of targeted therapies thus NPM-ALK related studies carry profoundimplications for the cancer field in general. Unfortunately even with current intensive combinedchemotherapy approximately 30% of patients experiences disease progression or recurrence within twoyears of treatment. However clinical or genetic factors that cause ALCL relapse are not known.Furthermore prognostic biomarkers that can be easily obtained using non-invasive methods have not beenclearly defined in patients receiving targeted therapies in ALCL. Our central hypothesis is that sensitive andspecific quantitative assessment of circulating NPM-ALK transcript using digital droplet (dd)PCR inconjunction with plasma levels of ALK auto- antibody will serve as unique disease-specific biomarkers thatwill provide an opportunity for assessment of response to therapy and lead to prognostic biomarkers thatmay identify patients with high risk for relapse. Using plasma samples from uniformly treated patientsenrolled in a Children's Oncology Group (COG) Phase II study of Brentuximab Vedotin and Crizotinib withnewly diagnosed ALCL we address our hypothesis through the following specific aims: 1) Determine theutility of ddPCR for minimal disease detection and disease monitoring in ALK+ ALCL 2) Determine theprognostic utility of anti-ALK immune response in ALK+ ALCL 3) Investigate the prognostic significance of amultivariate model combining ddPCR and immune response to ALK in patients with ALK+ ALCL. Thedevelopment of sensitive and precise assessment of minimal disseminated disease and/or minimal residualdisease will play an important role in management of patients with ALK+ ALCL and facilitate decisions aboutdiscontinuation of treatment and identifying patients at risk of relapse/progression. 297632 +No NIH Category available Address;Adolescent and Young Adult;Affect;Biological Markers;Biology;Biopsy Specimen;Blood;Cause of Death;Cell Differentiation process;Cells;Chemoresistance;Clinical Trials;Collaborations;Complex;Data;Diagnosis;Differentiation Antigens;Differentiation and Growth;Disease;Equilibrium;Excision;Foundations;Gene Expression;Genetic;Genetically Engineered Mouse;Harvest;Human;Immune;Investigation;Laboratories;Laboratory Finding;Ligands;Localized Disease;MAP Kinase Gene;MAPK8 gene;Malignant - descriptor;Malignant Childhood Neoplasm;Measures;Medical;Metastatic Osteosarcoma;Modeling;Monoclonal Antibodies;Mus;Neoplasm Metastasis;Newly Diagnosed;Nuclear Translocation;Operative Surgical Procedures;Pathway interactions;Patients;Phosphotransferases;Pre-Clinical Model;Primary Neoplasm;Process;Prognosis;Prognostic Marker;Proliferating;Recurrence;Relapse;Reporting;Resected;Role;Serum;Signal Pathway;Signal Transduction;Survival Rate;Testing;WNT Signaling Pathway;Xenograft Model;antagonist;beta catenin;bone;burden of illness;chemotherapy;clinically relevant;effective therapy;established cell line;glycogen synthase kinase 3 beta;improved;inhibitor;mouse model;neoplastic cell;neutralizing antibody;novel;novel therapeutic intervention;osteoblast differentiation;osteosarcoma;patient derived xenograft model;peripheral blood;pharmacologic;pre-clinical;predicting response;predictive marker;prevent;primary bone cancer;receptor;relapse risk;responders and non-responders;small molecule inhibitor;targeted treatment;treatment response;tumor;tumor growth Targeting DKK-1 To Prevent Osteosarcoma Metastasis Project NarrativeAn effective treatment for metastatic osteosarcoma is a critical unmet medical need. Ourpreclinical data demonstrate that a neutralizing antibody against the canonical Wnt signalingantagonist DKK-1 slows primary tumor growth induces nuclear translocation of -cateninupregulates markers of differentiation and abolishes metastasis in a mouse model ofosteosarcoma based on patient-derived xenografts. We propose testing a small moleculeinhibitor of DKK-1 in a similar model to determine effects on both canonical and noncanonicalWnt signaling on the growth and differentiation of osteosarcoma patient-derived xenograftsand on osteosarcoma metastasis as well as validating DKK-1 serum levels as a biomarker ofdisease burden and response to therapy in patients newly diagnosed with osteosarcoma. NCI 10680557 8/23/23 0:00 PA-20-185 5R01CA262802-03 5 R01 CA 262802 3 "KONDAPAKA, SUDHIR B" 7/9/21 0:00 6/30/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 1927437 "LOEB, DAVID M." Not Applicable 14 Unavailable 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY Domestic Higher Education 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 661767 NCI 410283 251484 AbstractOsteosarcoma is the most common primary bone tumor of adolescents and young adults.Aggressive surgery and intensive chemotherapy provide long term survival to up to 75% ofpatients diagnosed with localized disease but this approach only cures 20% of patients whopresent with metastasis. Numerous attempts at treatment intensification have failed to improvethis dismal prognosis so there is an urgent need for new treatment approaches based on adeeper understanding of osteosarcoma biology. The Wnt signaling pathway has been a focus ofinvestigation in osteosarcoma because of its role in normal bone biology. Canonical -catenin-dependent Wnt signaling drives normal osteoblast differentiation. It has been reported that thesecreted inhibitor of canonical Wnt (cWnt) signaling Dickkopf-1 (DKK-1) is found at high levels inthe blood of newly diagnosed osteosarcoma patients and is preferentially expressed byosteosarcoma cells at the invasive edge of growing tumors. Inhibition of DKK-1 increasesnoncanonical Wnt (ncWnt) signaling in murine osteosarcoma cells. Our laboratory demonstratedthat human DKK-1 can be detected in the blood of immune deficient mice bearing osteosarcomapatient-derived xenografts and that a neutralizing antibody against DKK-1 increased cWntsignaling in the primary tumor inducing markers of differentiation and abolishing metastasis.Taken together these findings suggest the hypothesis that DKK-1 regulates the balance betweencWnt and ncWnt signaling in OS affecting expression of genes important for tumor celldifferentiation and metastasis. We will test this hypothesis and generate preclinical data to guidethe implementation of treatments targeting DKK-1 in osteosarcoma patients through three specificaims. SA1: To define the mechanism by which DKK-1 regulates the balance between cWnt andncWnt signaling in osteosarcoma. SA2: To optimize the timing and implementation of DKK-1inhibition in preclinical models of osteosarcoma. SA3: To validate serum DKK-1 level as abiomarker of disease burden and response to therapy in osteosarcoma patients. Successfulcompletion of this study will better define the role of Wnt signaling in OS biology provide robustpreclinical data to inform a clinical trial of DKK-1 targeted therapy to prevent OS metastasis anddevelop a novel noninvasive biomarker of relapse risk and response to treatment. 661767 +No NIH Category available Advisory Committees;Agonist;Antigen Targeting;Antigen-Presenting Cells;Applications Grants;Automobile Driving;Beds;Blood Circulation;CD8-Positive T-Lymphocytes;Cancer Vaccines;Cells;Chemotherapy and/or radiation;Clinical;Collaborations;Combined Modality Therapy;Coupled;Coupling;Data;Dendritic Cells;Deposition;Development;Development Plans;Dose;Educational workshop;Encapsulated;Engineering;Ensure;Faculty;Future;Goals;Hepatotoxicity;Histopathology;Hydrophobicity;Immune;Immune checkpoint inhibitor;Immunity;Immunosuppression;In Vitro;Inflammatory;Institution;Interdisciplinary Study;Interferon Type I;Interferon-beta;Investigation;Kinetics;Laboratories;Link;Lipid A;Lipids;Longitudinal Studies;Macrophage;Macrophage Activation;Malignant Neoplasms;Memory;Methods;PD-1 inhibitors;Paper;Pathway interactions;Periodicity;Perivascular Neoplasm;Production;Public Health;Publishing;Qualifying;Recurrence;Regimen;Reporting;Research;Research Personnel;Safety;Schedule;Shapes;Stimulator of Interferon Genes;T-Lymphocyte;TLR4 gene;Testing;Toxic effect;Training;Treatment Protocols;Tumor Antigens;Vaccination;Vaccines;Vision;anti-PD-1;anti-tumor immune response;anticancer research;cancer vaccination;career;career development;cell motility;cytokine;design;efficacy evaluation;engineering design;exhaust;hydrophilicity;immune activation;immunoengineering;immunosuppressed;in vivo;innovation;interest;lymph nodes;malignant breast neoplasm;medical schools;melanoma;mouse model;nanomaterials;nanoparticle;neoplastic cell;novel;particle;pre-clinical;programs;recruit;response;success;surface coating;tool;tumor;tumor microenvironment;vaccination strategy Tumor-directed immunostimulatory nanoparticles for novel 'prime-pull'cancer vaccination PROJECT NARRATIVEDespite their transformative public health promise traditional cancer vaccines have had poor clinicalresponses since vaccine-specific systemic T cells often cannot traffic to immunosuppressed tumors. Ourcentral hypothesis is that precise coupling of a standard lymph node-directed vaccine prime with a noveltumor-directed immunostimulatory nanoparticle that reverses local immunosuppression to pull or recruitsystemic vaccine-specific T cells is the key missing link in effective cancer vaccination. Successfulimplementation of this proposed prime-pull cancer vaccination strategy has the potential for far-reachingpublic health impact in treatment particularly of otherwise lethal cancers. NCI 10680496 8/18/23 0:00 PAR-18-467 5K22CA262355-03 5 K22 CA 262355 3 "JAKOWLEW, SONIA B" 9/1/21 0:00 8/31/24 0:00 ZCA1-RTRB-R(M2) 12521423 "ATUKORALE, PRABHANI " Not Applicable 2 NONE 153926712 VGJHK59NMPK9 153926712 VGJHK59NMPK9 US 42.386914 -72.521131 850904 UNIVERSITY OF MASSACHUSETTS AMHERST HADLEY MA BIOMED ENGR/COL ENGR/ENGR STA 10359450 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 194090 NCI 179713 14377 PROJECT SUMMARYDespite their transformative promise traditional cancer vaccines have had poor clinical responses sincevaccine-specific systemic T cells often cannot traffic to immunosuppressed cold tumors. Traditional vaccinesgenerate only a lymph node-derived augmentation or prime of systemic CD8+ T cells that are trained tocomprehensively seek and eliminate specific target tumor cells. Traditional strategies however have beenshort-sighted in that they have failed to develop methods to recruit these T cells to the cold tumormicroenvironment (TME) that advances by building a formidable local immunosuppressive barrier drivenlargely by dysfunctional innate immune cells. Our strategy seeks to reprogram dysfunctional tumor-residentinnate antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages by driving a local anti-tumor immune response with a proinflammatory cytokine gradient that reshapes the TME from non-inflamedand cold to inflamed and hot to recruit or pull systemic T cells in from a prime. In our recent CancerResearch paper (Atukorale et al. 2019) and additional preliminary data we report on the development of apull strategy based on a novel immunostimulatory nanoparticle (immuno-NP) that is significant due to keyengineering design features. Immuno-NPs co-encapsulate two synergistic immune agonists on the sameparticle cdGMP an agonist of the STING pathway and MPLA an agonist of the TLR4 pathway to promote arobust production of proinflammatory Type I interferon in target APCs. Immuno-NPs can be safely deliveredin the systemic blood circulation to achieve widespread and preferential deposition in the tumor perivascularregions that are rich in their target APCs. Immuno-NPs drive a powerful local self-amplifying anti-tumorimmune response that harnesses otherwise exhausted immunosuppressed local CD8+ T cells as the keyeffectors of tumor clearance which suggests highly effective cold-to-hot TME reprogramming. Our centralhypothesis is that precise coupling of a standard lymph node-directed CD8+ T cell vaccine prime with atumor-directed immuno-NP pull for a novel prime-pull approach can provide the key missing link for effectivecancer vaccination. Specific Aim 1 will identify optimal function of an immuno-NP pull in terms of immuno-NPdesign and co-treatment with anti-PD1. Specific Aim 2 will develop a precise prime-pull coupling schedule.Specific Aim 3 will evaluate safety and toxicity for effective dose/scheduling prime-pull regimens. Dr.Atukorale's career goals are to establish a nanomaterials-based cancer immuno-engineering laboratory as anindependent investigator. She will develop immuno-nanomaterials tools that drive quantify and interrogateimmunity specifically in the context of lethal cancers. Dr. Atukorale's strong career development plan includessignificant new research collaborations a senior advisory committee research presentations faculty-levelworkshops and plans for subsequent grant proposals. Her future sponsoring institution will be based in bothSchools of Medicine and Engineering in direct line with her highly interdisciplinary research interests. 194090 +No NIH Category available 3-Dimensional;Adipocytes;Adipose tissue;Affect;Benign;Biological Models;Cell Count;Cells;ChIP-seq;Coculture Techniques;DNA Methylation;Development;Diagnosis;Disease;Endometrial;Endometrial Carcinoma;Endometrial Neoplasms;Endometrial adenocarcinoma;Endometrium;Environment;Epigenetic Process;Epithelial Cells;Estrogens;FOXO1A gene;Fostering;Gene Expression;Genes;Genomics;Goals;Growth;Histones;Hormones;Human;In Vitro;Incidence;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Menstrual cycle;Metformin;Microfluidics;Modernization;Molecular;Obesity;Organ;Organoids;Pathway interactions;Patients;Phenotype;Premenopause;Process;Progesterone;Progesterone Receptors;Proto-Oncogene Proteins c-akt;Public Health;Research;Resistance;Risk;Risk Factors;Role;Sample Size;Signal Transduction;Stromal Cells;System;Technology;Testing;Time;Tissues;Woman;Work;bisulfite sequencing;carcinogenesis;deep sequencing;endometrial cancer prevention;endometrial organoid;epigenome;genome-wide analysis;high risk;high risk population;in vitro Model;inhibitor;innovative technologies;insight;microfluidic technology;obese person;permissiveness;prevent;protective effect;receptor;release factor;response;single-cell RNA sequencing;theories;transcriptome;tumor;tumorigenesis;tumorigenic;whole genome Understanding Progesterone Receptor action in Obesity for Endometrial Cancer Prevention Prevention of endometrial cancer in obese women is the ultimate goal of this proposal and this is only achievable if we understand the mechanisms associated with obesity driven endometrial cancer. We will investigate how fat cells influence the epigenome of the endometrial epithelial cells that alter the protective mechanisms of progesterone receptor thereby increase the risk of developing endometrial cancer. NCI 10680493 7/17/23 0:00 PA-18-484 5R01CA243249-05 5 R01 CA 243249 5 "MERCER, NATALIA" 7/1/19 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-EMNR-V(02)M] 7096766 "KIM, JI-YONG JULIE" Not Applicable 5 OBSTETRICS & GYNECOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 627496 NCI 449678 177818 The incidence of endometrial cancer is on the rise each year reaching over 60000 new cases in the US in 2018. Obesity remains a significant public health problem and is a major risk factor for developing endometrial cancer. Although excess estrogen from adipose tissues is thought to predispose a woman from developing endometrial cancer the protective role of progesterone in obesity is unknown. Studies demonstrate that the excess estrogen theory in obese women does not always hold true particularly in the premenopausal state. We hypothesize that adipose tissue release factors that activate the AKT pathway in endometrial epithelial cells to blunt progesterone receptor (PR) action thereby increasing the risk of endometrial neoplasia. In this study we will decipher the actions of PR in the human endometrium in the presence or absence of adipocytes using 3D spheroid cultures in microfluidic systems. These innovative technologies allow us to study for the first time the effect of adipocytes on the signaling and genomic activities that affect progesterone sensitivity. We will determine how adipocytes affect progesterone driven differentiation and survival of the endometrial organoids and how changes in epigenetics including DNA methylation and histone marks affect the ER and PR cistrome. Unbiased sequencing will be done using technologies that allow for deep sequencing of small cell numbers. This research will generate insight into the early changes that may lead to tumorigenesis which will be useful to determine how to effectively prevent endometrial cancer in the obese women who are at high risk. 627496 +No NIH Category available Academic support;Achievement;Address;African American;African American population;Applied Skills;Area;Behavioral;Behavioral Research;Behavioral Sciences;Biomedical Research;Cancer Center;Cancer health equity;Child Rearing;Cognitive;Color;Communities;Development;Disparity;Education;Educational Activities;Educational Curriculum;Educational Models;Educational process of instructing;Ensure;Equity;Evaluation;Future;Goals;Graduation Rates;Health;Health Disparities Research;Health Status;High School Faculty;High School Student;Home;Immigrant;Knowledge;Latinx;Leadership;Malignant Neoplasms;Mentors;Mentorship;Methods;Minnesota;Native Americans;Outcome;Parenting Education;Parents;Process;Recording of previous events;Research;Research Methodology;Research Personnel;Schools;Science;Scientist;Self Efficacy;Student Persistence;Students;Teacher Professional Development;Time;Twin Cities;Underrepresented Populations;Underrepresented Students;United States;Universities;Youth;anticancer research;cancer health disparity;career;career development;cohort;community engagement;design;education research;evidence base;experience;hands on research;high school;innovation;laboratory experience;patient population;programs;school district;service learning;skill acquisition;skills;social;success;summer program;systemic barrier;teacher;teacher community;theories;undergraduate student;urban school Minnesota Cancer Research And Teaching Excellence: M-CREATE University of Minnesota Cancer Research And Teaching Excellence: M-CREATE is a theoretically guidedevidence driven program designed to support the academic persistence of high school and undergraduatestudents underrepresented in science and promote their developmental progress towards future careers incancer research. M-CREATE will combine best practices with innovative approaches from educationmentorship service learning and parent education within an equity-oriented frame to engage educate andsupport students to achieve the knowledge skills science identity and self-efficacy required to supportacademic persistence and long-term success within the biomedical and behavioral sciences. Diversifying thecancer research workforce is critical to addressing the pressing needs of increasingly diverse patientpopulations in Minnesota and across the U.S. NCI 10680492 9/7/23 0:00 PAR-17-059 5R25CA250987-04 5 R25 CA 250987 4 "LOPEZ, BELEM G" 9/2/20 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 7608807 "ALLEN, MICHELE L" "PENNELL, CHRISTOPHER A" 5 FAMILY MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 431856 NCI 399968 31888 The innovative University of Minnesota Cancer Research And Teaching Excellence: M-CREATE programleverages ten years of high school and undergraduate health equity cancer research-focused mentorship andeducation activities to implement a theoretically guided evidence driven program designed to grow thenumbers of cancer-focused scientists from groups underrepresented in science and promote their academicdevelopmental progress towards future careers in cancer research. M-CREATE will combine the experiencesof our unique team including Masonic Cancer Center and Program in Health Disparities Research leadershipwith best practices from education mentorship service learning and parent education within a theoretical andequity-oriented frame to engage educate and support students to achieve the knowledge skills scienceidentity and self-efficacy required to support academic persistence and long-term success within thebiomedical and behavioral sciences. The long-term goal of this proposal is to address the pressing needs ofour increasingly diverse patient population in Minnesota and the United States (U.S.) by enhancing thediversity of the cancer-focused research workforce. We will support the academic persistence of first 240 earlyhigh school students attending two urban school districts comprised of approximately seventy percent NativeAmerican students and students of color through a multicomponent staged program combining hands onresearch mentorship academic and professional development science-oriented identity development parentsupport and community-engaged service learning. Four cohorts of 60 students will participate in an initialengagement year comprised of supportive and exciting hands-on experiences. Ten students per cohort willcontinue in an intensive experience including two nine-week summer mentored research experiences and acommunity-engaged service learning experience. Next 60 early-stage undergraduate studentsunderrepresented in science will participate in a nine-week summer program combining academic andprofessional development and hands on research mentorship. Finally we will deepen the science-focusedskills of high school teachers from collaborating districts serving students underrepresented in science througha hands-on research lab experience paired with evidence-based support to develop curricula responsive to theneeds of diverse learners. Diversifying the cancer research workforce is critical to addressing the pressingneeds of increasingly diverse patient populations in Minnesota and across the U.S. M-CREATE aligns stronglywith NCI strategic priorities to strengthen the cancer research workforce and mitigate cancer disparities. 431856 +No NIH Category available Advisory Committees;Attention;Awareness;Basic Science;Biomedical Research;Cancer Burden;Cancer Center;Catchment Area;Clinical;Clinical Research;Communication;Community Outreach;Decision Making;Development;Device or Instrument Development;Drug Targeting;Ecosystem;Education;Ethics;Evaluation;Exposure to;Faculty;Foundations;Funding;Future;Goals;Home;Immunology;Individual;Institution;Knowledge;Laboratories;Leadership;Learning;Life;Malignant Neoplasms;Measures;Medical Students;Mentors;Nanotechnology;National Institute of General Medical Sciences;New Hampshire;Norris Cotton Cancer Center;Oncology;Participant;Pharmaceutical Preparations;Physicians;Population Sciences;Postdoctoral Fellow;Professional Competence;Qualifying;Research;Research Personnel;Rural;Scientist;Secure;Source;Structure;Student Selections;Students;Time;Training;Underrepresented Minority;Underrepresented Populations;Universities;Work;anticancer research;career;cohort;college;design;education research;experience;graduate student;innovation;interest;member;minority undergraduate;multimodality;next generation;oncology program;outreach;programs;recruit;resilience;skills;success;tool;undergraduate student;underrepresented minority student Program for Oncology Workforce Education and Research Experience at Dartmouth NarrativePOWERED is designed as a significant experience in cancer research for students from groupsthat are underrepresented in professional cancer research. The students will be recruited fromthe 10-college network NH-INBRE and will participate in a program with 2 summers of full timeresearch at Norris Cotton Cancer Center and 4 semesters of part time research at their homeinstitution. The goal is to establish these students on a path to becoming professional cancerresearchers. NCI 10680490 9/7/23 0:00 PAR-17-059 5R25CA250956-04 5 R25 CA 250956 4 "LOPEZ, BELEM G" 9/1/20 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1912096 "FIERING, STEVEN " Not Applicable 2 INTERNAL MEDICINE/MEDICINE 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 170048 NCI 164044 6004 Abstract POWEREDThe proposed Program for Oncology Workforce Education and Research at Dartmouth (POWERED) willidentify recruit and train underrepresented minority undergraduates for independent careers in cancerresearch with specific attention to related scientific and life/career skills. Qualified students will be from groupsunderrepresented in biomedical research. They will receive a holistic multi-modal two-year intensive trainingexperience spanning the summer following sophomore year through their senior year. We propose building onthe foundation we have developed with three years of an NCI-funded P30 CURE supplement that introducedundergrads from underrepresented minorities to oncology research at Dartmouth. POWERED is a two-yearprogram including two 8-week summers (16 weeks total) of full-time mentored research at Dartmouth's NorrisCotton Cancer Center (NCCC) boosted by 4 semesters (16 weeks each) of part-time coordinated scientificresearch at their home institutions. Considerable effort will be made to customize each participant's programaccording to their scientific interests in cancer. Each student will have a mentor at their home laboratory and atNCCC. Together with the PI they will form Individual Mentoring Team(s) to track the progress of each student.Faculty from colleges and universities throughout New Hampshire that make up New Hampshire INBRE (NH-INBRE Idea Network of Biomedical Research Excellence) will recruit and nominate promisingunderrepresented minority students to apply and subsequently arranged for mentoring the selected studentsas research trainees at the home institution. A specific emphasis in the senior year is securing post-graduationwork or training in cancer research or a related biomedical field. A set of Educational Tools to achieve theSpecific Aims will be developed and evaluated using formative and summative measures to allow for dynamicchange as appropriate to meet the Specific Aims and dissemination to other educators. 170048 +No NIH Category available AKT1 gene;Acceleration;Alleles;Apoptosis;Brain;Brain region;Cell Proliferation;Cells;Cerebellum;ChIP-seq;Characteristics;DNA Sequence;DNA Sequence Alteration;Data;Development;Enhancers;Epigenetic Process;Equilibrium;Future;G Protein-Coupled Receptor Signaling;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Heritability;Heterozygote;Histone H3;Histones;Human;Loss of Heterozygosity;LoxP-flanked allele;Lysine;MLL2 gene;Malignant - descriptor;Mathematics;Mediating;Methylation;Methyltransferase;Modeling;Molecular;Motor;Mus;Mutate;Mutation;NCOR2 gene;Neuronal Differentiation;Neurons;Nucleic Acid Regulatory Sequences;Oncogenic;Oncoproteins;Oxidation-Reduction;PTCH gene;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Pattern;Pediatric Neoplasm;Phenotype;Phosphotransferases;Post-Translational Protein Processing;Primary Brain Neoplasms;Process;Regulator Genes;Reporting;Repression;Role;SHH gene;Signal Pathway;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Transcription Coactivator;Transcriptional Regulation;Tretinoin;Tumor Promotion;Tumor Suppressor Genes;Tumor Suppressor Proteins;cancer type;clinically relevant;design;epigenetic regulation;epigenomics;gene interaction;genome-wide;granule cell;histone demethylase;histone methylation;histone methyltransferase;in vivo;insight;medulloblastoma;motor control;mouse model;neoplastic cell;nestin protein;programs;promoter;rational design;side effect;spatiotemporal;stem cells;tumor;tumorigenesis Heterozygous KMT2D Loss and Medulloblastoma PROJECT NARRATIVEThe proposed studies are designed to define the in vivo pathogenic role of heterozygous loss of the epigeneticmodifier KMT2D in medulloblastoma genesis using mouse models and to provide epigenetic and mechanisticinsights into how heterozygous KMT2D loss promotes medulloblastoma. Because KMT2D is one of the mostfrequently mutated genes in human medulloblastoma and a majority of KMT2D mutations are heterozygousour epigenetic and mechanistic findings from the proposed studies will be fundamental to a betterunderstanding of the molecular basis of human medulloblastoma and be beneficial for development of astrategy for therapeutic intervention of human medulloblastoma. NCI 10680489 7/10/23 0:00 PA-20-185 5R01CA262324-02 5 R01 CA 262324 2 "OKANO, PAUL" 8/9/22 0:00 7/31/27 0:00 Cancer Genetics Study Section[CG] 10386574 "LEE, MIN GYU " Not Applicable 9 MICROBIOLOGY/IMMUN/VIROLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 431585 NCI 266411 165174 PROJECT SUMMARYMedulloblastoma (MB) is the most common malignant primary brain tumor in children. MB is frequently inducedby the alterations of cellular signaling pathways such as sonic hedgehog and wingless pathways which havebeen extensively characterized. Nevertheless current treatment of MB causes severe life-long side effects andfails to cure many patients. Thus there is an unmet need for a new mechanistic understanding that would behelpful for designing a mechanism-based approach for MB treatment. Epigenetic aberrations which are heritableaberrations in gene expression or cellular phenotypes without accompanying changes in DNA sequences are amajor factor for tumorigenesis. Epigenetic modifiers often harbor DNA alterations such as mutations anddeletions in human MB. However the roles of epigenetic modifiers in MB development remain largely unknown.Histone lysine methylation a type of histone posttranslational modification is a hallmark of epigenetic andtranscriptional regulation of gene expression and is reversibly modified by histone methyltransferases anddemethylases. Of histone lysine methylation methylations at histone H3 lysine 4 (H3K4) are key gene-activatingepigenomic marks. For example monomethyl H3K4 is a mark for enhancers which activate genes by interactingwith gene promoters. In addition trimethyl H3K4 occupies as much as 75 % of all human gene-regulatory regionsand broad trimethyl H3K4 is a gene-activating signature that denotes tumor suppressor and cell identity genes.We have previously reported that the H3K4 methyltransferase KMT2D (also called MLL4 ALR and MLL2; atranscriptional coactivator) is required for retinoic acid-induced neuronal differentiation of human neuron-lineageNT2/D1 stem cells. Notably our other study showed that homozygous loss of Kmt2d in the mouse braindeveloped spontaneous MB in the cerebellum a brain region that controls motor coordination and balance.Strikingly our additional results showed that heterozygous loss (single-allelic) of Kmt2d highly promoted MB.Based on these compelling findings our long-term goal is to define the oncogenic role of heterozygous loss ofKmt2d in MB pathogenesis. Our central hypothesis is that heterozygous loss of Kmt2d causes epigenomicalterations to downregulate tumor suppressor genes and thereby promotes MB. Here we propose to study to 1)characterize the MB-promoting effect of heterozygous Kmt2d loss using genetically engineered mouse models;2) define the molecular mechanism by which heterozygous Kmt2d loss promotes MB; and 3) determine howheterozygous Kmt2d loss causes epigenomic alterations. Because KMT2D is one of the most frequently mutatedgenes in MB and a majority of KMT2D mutations in MB are heterozygous and truncations our proposed studiesare significant and clinically relevant. In addition our studies using genetically engineered mouse models willdefine an in vivo MB-promoting role for heterozygous Kmt2d loss. Furthermore our results will uncover thepreviously unappreciated epigenetic mechanism underlying MB pathogenesis and provide valuable informationfor the rational design of a therapeutic approach for MB treatment. 431585 +No NIH Category available Achievement;Advanced Malignant Neoplasm;Antisense Oligonucleotides;Area;Award;Biological;Cancer Intervention;Cancer Patient;Clinical;Communities;Data;Development;Diagnosis;Diagnostic;Disseminated Malignant Neoplasm;ERG gene;Gene Fusion;Goals;Human;Individual;Malignant Neoplasms;Malignant neoplasm of prostate;Mission;Modeling;Molecular;Molecular Target;PSA level;Pathogenesis;Patients;Peptides;Prognosis;Prostate;Reporting;Research;Research Personnel;Resources;Role;Sampling;Screening for Prostate Cancer;Serum;TMPRSS2 gene;Therapeutic Intervention;Untranslated RNA;Urine;Validation;Work;bioinformatics resource;biomarker identification;cancer type;clinical sequencing;disease diagnosis;efficacious treatment;experience;inhibitor;knowledgebase;novel marker;peptidomimetics;precision medicine;precision oncology;prognostic;programs;research clinical testing;single cell sequencing;targeted treatment;therapeutic development;therapeutic target;transcriptome;transcriptomics;translational cancer research;tumor progression Exploring Precision Oncology: From Gene Fusions to lncRNAs Project NarrativeThe field of precision oncology continues to evolve with the overarching goal of providing cancer patients withenhanced diagnostic/prognostic capabilities and efficacious treatments. Through the research proposed herewe will use our expertise in translational cancer research to advance this mission by contributing newbioinformatics resources to the research community identifying biomarkers of disease for diagnosis or prognosisof different cancer types nominating these markers for development of therapeutic targeting agents andperforming studies to understand their biological roles in cancer progression. NCI 10680474 8/3/23 0:00 PAR-17-494 5R35CA231996-06 5 R35 CA 231996 6 "MCKEE, TAWNYA C" 9/1/18 0:00 8/31/25 0:00 ZCA1-RPRB-M(M1) 1866290 "CHINNAIYAN, ARUL M" Not Applicable 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 910078 NCI 588000 322078 Project Summary / AbstractThe potential of precision medicine to benefit the lives of cancer patients continues to emerge. The mission ofthe Chinnaiyan lab is to advance the field of precision oncology and we aim to achieve this through the discoveryand development of molecular targets that will aid in diagnosis prognosis or therapeutic intervention of cancers.Over the past several years we have made a number of significant advancements in these areas. One of theselandmark studies found that TMPRSS2-ETS gene fusions exist in the majority of prostate cancers. This discoveryled to our development of a non-invasive clinical test (Mi-Prostate Score MiPS) that combines analysis of urinelevels of TMPRSS2-ERG and the long non-coding RNA (lncRNA) PCA3 with serum levels of PSA to detectprostate cancers. Due to its subsequently established roles in prostate cancer pathogenesis we also reportedon the development of peptidomimetic inhibitors (ERG inhibitory peptides EIPs) of the ERG gene fusion product.A monumental achievement in the field of precision oncology has also been establishment of our comprehensivesequencing program for advanced cancer patients called Mi-Oncoseq. Mi-Oncoseq has become a model forintegrative clinical sequencing and generated several pivotal findings including our recent report on theintegrative sequencing analysis of metastatic cancers. Data from our sequencing program were also included inour report of the lncRNA landscape of the human transcriptome. Studies of individual lncRNAs have additionallyemerged in our lab such as validation of SChLAP1 as a marker for aggressive prostate cancer.This brief description of selected achievements highlights our commitment to advancing precision oncology andour vast foundational experience in this arena. Through the NCI Outstanding Investigator Award we propose tocontinue these lines of research to further explore the diagnostic potential of precision oncology therapeutictargeting of identified markers and roles of nominated targets in cancer development. The future researchprogram centered on diagnostic potential will include such initiatives as creation of new bioinformatic resources(e.g. Mi-PANDA a compendia of transcriptomic data) high throughput single cell sequencing analysis ofpatient samples and creation of cancer-specific lncRNA panels for use with non-invasive clinical isolates.Therapeutic targeting will be explored through the use of antisense oligos to lncRNAs and studies on the efficacyof peptidomimetics for gene fusions and undruggable targets. These avenues of research will provide impetusfor studying the roles of selected noteworthy targets in cancer development. In particular we have alreadydiscovered two lncRNAs ARlnc1 and THOR1 which appear to be involved in cancer progression. Overall thisambitious research program will advance the field of precision oncology by providing new community resourcesidentifying novel biomarkers exploring the therapeutic targeting of nominated molecular players and adding tothe knowledge-base of cancer development mechanisms particularly those of lncRNAs. Importantly this awardand the proposed work would assist our lab in its mission to remain a leader in the field of precision oncology. 910078 +No NIH Category available Acidity;Acidosis;Atomic Force Microscopy;Basic Science;Binding;Binding Proteins;Biochemical;Biological Assay;Biosensor;Brain;Cell Survival;Cell membrane;Cells;Cellular Stress;Cellular biology;Creatine Kinase;Cryoelectron Microscopy;Crystallography;Data;Development;Disease;Disseminated Malignant Neoplasm;Electron Spin Resonance Spectroscopy;Electrons;Enzymes;Foundations;Goals;Golgi Apparatus;Human;Hypoxia;Impairment;In Vitro;Knowledge;Lipids;Liposomes;MAPK3 gene;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Measures;Mediating;Membrane;Membrane Potentials;Methodology;Methods;Mission;Modeling;Molecular;Molecular Chaperones;Molecular Conformation;Neoplasm Metastasis;Organelles;Pathologic;Pathway interactions;Phosphoserine;Physiological;Process;Production;Prognosis;Protein Conformation;Protein Isoforms;Protein Kinase;Protein Secretion;Protein translocation;Proteins;Proteolysis;Protomer;Public Health;Regulation;Research;Resolution;Role;Route;Site;Solvents;Speed;Stimulus;Structure;Testing;Translational Research;Validation;cancer cell;colon cancer cell line;dimer;endosome membrane;extracellular;flexibility;fluorescence imaging;innovation;membrane model;metastatic colorectal;model organism;mutant;novel;novel therapeutic intervention;protein structure;recruit;research study;restraint;sphingosine kinase;therapeutic target;tumor progression Novel molecular mechanism for extracellular release of proteins implicated in metastatic cancer Project NarrativeThe proposed research is of high significance because it explores at the molecular level how brain-type creatinekinase and sphingosine kinase isoforms are regulated and released from cells to drive cancer progression andmetastasis. It is relevant to public health because it will drive new therapeutic strategies for the diseasesassociated with their perturbed cellular distributions. Thus the proposed research is relevant to the part of theNCIs mission that pertains to advancing the knowledge foundation for greater understanding of the molecularbasis of enzyme regulation in molecular pathways associated with cancer development and progression. NCI 10680461 7/3/23 0:00 PAR-21-038 5R37CA265877-02 5 R37 CA 265877 2 "AMIN, ANOWARUL" 8/15/22 0:00 6/30/27 0:00 Biochemistry and Biophysics of Membranes Study Section[BBM] 12214679 "DASTVAN, REZA " Not Applicable 1 BIOCHEMISTRY 50220722 JNBLLTBTLLD8 50220722 JNBLLTBTLLD8 US 38.633829 -90.213138 7915401 SAINT LOUIS UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631032006 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 428511 NCI 327710 100801 Project Summary/AbstractSome critical proteins with functions both inside and outside of cells circumvent conventional secretion via theER and Golgi and are released through Unconventional Protein Secretion (UPS) pathways. These routes areevolved either to spatially and temporally control the function and the triggered release of these UPS cargoes bycertain stimuli or to activate upon impairment of the conventional pathway. Hence UPS pathways are oftentriggered by cellular stress e.g. in hypoxic metastatic tumors and cells under low energy conditions. Some UPScargos are assisted by chaperones but many others are released independently. Their release involves self-sustained direct crossing of a membrane either the cell membrane (Type I UPS) or organelles (Type III UPS).The fundamental question here is how UPS secreted proteins enter organelles and how their essentialtranslocation across membranes is regulated. Defining the molecular regulatory mechanisms is of highsignificance to drive new therapeutic strategies (e.g. UPS modulators) for diseases associated with theirperturbed cellular distributions. We propose a novel hypothesis that explains the regulated and directed releaseof these key proteins in tumor progression. Hypoxia instigates a transient or enduring cellular acidification. Inthis model the interplay between the local acidity and membrane curvature determines the conformational statesand membrane-binding mode of these cargoes. In the context of a Type III UPS this promotes self-sustainedprotein translocation across endosomal membranes and ultimate secretion. To test this hypothesis we willdetermine the extracellular release mechanism of two important UPS cargo proteins the brain-type creatinekinase and sphingosine kinase isoforms 1 and 2. Extracellular release of these proteins in various cancerscontributes substantially to the survival of metastatic cells. This mechanism is mediated by extracellularproduction of their biologically active products. The subjects of this proposal as potential amphitropic proteinsare able to reversibly interact with a membrane. Thus defining the conformational rearrangements triggering therelease of these proteins entails identifying the conformational states that are populated under low energy statusof the hypoxic metastatic cells. Testing the involvement of reversible structural refolding and incorporation intothe membrane is challenging due to their dynamic states and the difficulties of gaining high-resolution structuralinformation of membrane-bound protein states particularly the effects of membrane curvature on the proteinstructure. Thus we have combined approaches encompassing a range of complementary and cutting-edgemethods as well as cell biology studies. Using a similar methodology to study the release mechanism of otherkey therapeutic targets will test commonalities and differences in their extracellular release mechanism.Ultimately our research has the potential to define an unconventional protein secretion pathway employed bycancer cells and other pathological conditions. In addition as a long-term goal we will bridge our basic researchstudies that elucidate mechanism with translational research by testing our key conclusions in model organisms. 428511 +No NIH Category available 3-Dimensional;ATP-G-actin;Abdominal Cavity;Actins;Adipocytes;Affect;Animals;Ascites;Autophagocytosis;Autophagosome;Biological Assay;Biosensor;Cell Survival;Cells;Cellular Metabolic Process;Chemoresistance;Cytosol;Data;Development;Diagnosis;Disease;Disease Progression;Drug resistance;Energy Metabolism;Energy-Generating Resources;Ensure;Environment;Epithelial ovarian cancer;Fatty Acids;Fatty acid glycerol esters;Free Energy;Genetic;Genus Hippocampus;Glycolysis;Growth;Heterogeneity;Human;Hypoxia;In Vitro;Individual;Inflammatory;Intermediate Filaments;Lipids;Lipolysis;Liquid substance;Lysosomes;Malignant Female Reproductive System Neoplasm;Measures;Mediating;Metabolic;Metabolic stress;Metabolism;Microspheres;Mitochondria;Modeling;Molecular;Mus;Nature;Neoplasm Metastasis;Nonesterified Fatty Acids;Nutrient;Omentum;Organoids;Ovary;Oxidative Phosphorylation;Pathway interactions;Peritoneal;Peritoneum;Phenotype;Polymers;Primary Neoplasm;Production;Proteins;Reactive Oxygen Species;Research;Resistance;Role;Small Interfering RNA;Source;Stress;Stromal Cells;Structure;Testing;Therapeutic;Tumor Promotion;Vimentin;biophysical analysis;cancer cell;cancer therapy;cell motility;cell type;chemotherapy;fatty acid oxidation;high resolution imaging;in vivo Model;inhibition of autophagy;inhibitor;lipid metabolism;lipid transport;metabolomics;migration;neoplastic cell;new therapeutic target;novel;nutrient deprivation;paracrine;pharmacologic;polarized cell;polymerization;programs;recruit;scaffold;single-cell RNA sequencing;three dimensional cell culture;tumor;tumor growth;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumor progression Lipid Metabolism Switch Triggers Invasive and Chemoresistant Epithelial Ovarian Cancer Phenotype PROJECT NARRATIVEDysregulated lipid metabolism is a hallmark of epithelial ovarian cancer which is associated with widespreadand rapid metastasis throughout the lipid rich abdominal cavity. A key fact is that epithelial ovarian cancer cellscan metabolically reprogram themselves to use other energy sources such as lipids and fat cells in theabdominal cavity to sustain their incredibly fast growth metabolic changes that also help them survive afterchemotherapy. We hypothesize that EOC cells store energy in intracellular lipid droplets and under metabolicstress use this stored energy to fuel growth and invasive cell migration; this hypothesis will be explored using anovel 3D culture model to track metabolic changes in chemoresistant EOC cells as well as to study their lipiddroplet metabolism and autophagy. NCI 10680460 7/24/23 0:00 PA-20-185 5R01CA266415-02 5 R01 CA 266415 2 "AULT, GRACE S" 8/9/22 0:00 7/31/27 0:00 Tumor Cell Biology Study Section[TCB] 9822976 "DAWSON, MICHELLE R" Not Applicable 1 BIOCHEMISTRY 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF MEDICINE 29034202 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 375748 NCI 42057 20091 PROJECT SUMMARYEpithelial ovarian cancer (EOC) is the most lethal gynecological cancer; frequently diagnosed after it has spreadfrom the ovary to the omentum fat pad. A major challenge to understanding and targeting EOC is theheterogeneous nature of the disease which makes it difficult to develop treatments that effectively target anddestroy all cancer cells. This heterogeneity results in complicated molecular landscapes with subpopulations ofhighly invasive and chemoresistant tumor cells. It is critical to understand how this heterogeneity in cancer cellsdevelops and contributes to EOC disease progression. Polyploidal giant cancer cells represent a smallsubpopulation of drug-resistant and dormant cancer cells that survive treatment and later awaken to form newtumor cells through amitotic budding. Single cell biophysical analysis of tumor organoid cultures will be used todetermine how polyploidal giant cancer cells and other invasive cells contribute to EOC disease progression.In the EOC tumor microenvironment cancer cells frequently encounter metabolic stress from nutrientdeprivation hypoxia and toxic therapeutics which can trigger metabolic reprogramming to promote cell survival.Cells can undergo a metabolic shift from glycolysis to oxidative phosphorylation to meet energy demands ofsurvival and invasiveness; this shift in metabolism has been correlated with highly energetic mitochondria lipiddroplet disappearance (lipolysis) and autophagy. This is especially important in PGCCs which have increasednutrient demands in part to their larger size and more invasive phenotype. Additionally EOC metastases formfrom multicellular aggregates that are shed from the primary tumor into the adipocyte-rich abdominal cavity.Previous studies have demonstrated that peritoneal adipocytes can transfer free fatty acids to EOC cells toprovide cellular energy for metastatic tumor growth. Fatty acids provide a rich energy source for ATP-dependentactin polymerization and actin-based protrusions are critical for cell migration and during metastasis.We hypothesize that invasive EOC cells store energy from exogenous lipid sources (including adipocytes andlipid-rich ascites fluid) in cytosolic lipid droplets and under metabolic stress use these lipid droplets to generatemitochondrial ATP that is required for invasive cell migration through autophagy. To prove this hypothesis wewill use a novel 3D culture model and animal studies to track metabolic changes in individual chemoresistantEOC cells as well as study heterogeneity in lipid droplet metabolism. The proposed research will investigate therole of metabolic and treatment stress in activating lipid metabolism (Aim 1) and autophagy (Aim 2) anddetermine how metabolic alterations in subpopulations of highly invasive cells (including PGCCs) contribute tothe development of aggressive tumors (Aim 3). The proposed studies will reveal novel mechanisms contributingto cellular heterogeneity and dysregulated metabolism along with new therapeutic targets to investigate in EOC. 62148 +No NIH Category available 3-Dimensional;ATP-G-actin;Abdominal Cavity;Actins;Adipocytes;Affect;Animals;Ascites;Autophagocytosis;Autophagosome;Biological Assay;Biosensor;Cell Survival;Cells;Cellular Metabolic Process;Chemoresistance;Cytosol;Data;Development;Diagnosis;Disease;Disease Progression;Drug resistance;Energy Metabolism;Energy-Generating Resources;Ensure;Environment;Epithelial ovarian cancer;Fatty Acids;Fatty acid glycerol esters;Free Energy;Genetic;Genus Hippocampus;Glycolysis;Growth;Heterogeneity;Human;Hypoxia;In Vitro;Individual;Inflammatory;Intermediate Filaments;Lipids;Lipolysis;Liquid substance;Lysosomes;Malignant Female Reproductive System Neoplasm;Measures;Mediating;Metabolic;Metabolic stress;Metabolism;Microspheres;Mitochondria;Modeling;Molecular;Mus;Nature;Neoplasm Metastasis;Nonesterified Fatty Acids;Nutrient;Omentum;Organoids;Ovary;Oxidative Phosphorylation;Pathway interactions;Peritoneal;Peritoneum;Phenotype;Polymers;Primary Neoplasm;Production;Proteins;Reactive Oxygen Species;Research;Resistance;Role;Small Interfering RNA;Source;Stress;Stromal Cells;Structure;Testing;Therapeutic;Tumor Promotion;Vimentin;biophysical analysis;cancer cell;cancer therapy;cell motility;cell type;chemotherapy;fatty acid oxidation;high resolution imaging;in vivo Model;inhibition of autophagy;inhibitor;lipid metabolism;lipid transport;metabolomics;migration;neoplastic cell;new therapeutic target;novel;nutrient deprivation;paracrine;pharmacologic;polarized cell;polymerization;programs;recruit;scaffold;single-cell RNA sequencing;three dimensional cell culture;tumor;tumor growth;tumor heterogeneity;tumor metabolism;tumor microenvironment;tumor progression Lipid Metabolism Switch Triggers Invasive and Chemoresistant Epithelial Ovarian Cancer Phenotype PROJECT NARRATIVEDysregulated lipid metabolism is a hallmark of epithelial ovarian cancer which is associated with widespreadand rapid metastasis throughout the lipid rich abdominal cavity. A key fact is that epithelial ovarian cancer cellscan metabolically reprogram themselves to use other energy sources such as lipids and fat cells in theabdominal cavity to sustain their incredibly fast growth metabolic changes that also help them survive afterchemotherapy. We hypothesize that EOC cells store energy in intracellular lipid droplets and under metabolicstress use this stored energy to fuel growth and invasive cell migration; this hypothesis will be explored using anovel 3D culture model to track metabolic changes in chemoresistant EOC cells as well as to study their lipiddroplet metabolism and autophagy. NCI 10680460 7/24/23 0:00 PA-20-185 5R01CA266415-02 5 R01 CA 266415 2 "AULT, GRACE S" 8/9/22 0:00 7/31/27 0:00 Tumor Cell Biology Study Section[TCB] 9822976 "DAWSON, MICHELLE R" Not Applicable 1 BIOCHEMISTRY 1785542 E3FDXZ6TBHW3 1785542 E3FDXZ6TBHW3 US 41.826136 -71.404513 1003201 BROWN UNIVERSITY PROVIDENCE RI SCHOOLS OF MEDICINE 29034202 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 375748 NIGMS 212219 101381 PROJECT SUMMARYEpithelial ovarian cancer (EOC) is the most lethal gynecological cancer; frequently diagnosed after it has spreadfrom the ovary to the omentum fat pad. A major challenge to understanding and targeting EOC is theheterogeneous nature of the disease which makes it difficult to develop treatments that effectively target anddestroy all cancer cells. This heterogeneity results in complicated molecular landscapes with subpopulations ofhighly invasive and chemoresistant tumor cells. It is critical to understand how this heterogeneity in cancer cellsdevelops and contributes to EOC disease progression. Polyploidal giant cancer cells represent a smallsubpopulation of drug-resistant and dormant cancer cells that survive treatment and later awaken to form newtumor cells through amitotic budding. Single cell biophysical analysis of tumor organoid cultures will be used todetermine how polyploidal giant cancer cells and other invasive cells contribute to EOC disease progression.In the EOC tumor microenvironment cancer cells frequently encounter metabolic stress from nutrientdeprivation hypoxia and toxic therapeutics which can trigger metabolic reprogramming to promote cell survival.Cells can undergo a metabolic shift from glycolysis to oxidative phosphorylation to meet energy demands ofsurvival and invasiveness; this shift in metabolism has been correlated with highly energetic mitochondria lipiddroplet disappearance (lipolysis) and autophagy. This is especially important in PGCCs which have increasednutrient demands in part to their larger size and more invasive phenotype. Additionally EOC metastases formfrom multicellular aggregates that are shed from the primary tumor into the adipocyte-rich abdominal cavity.Previous studies have demonstrated that peritoneal adipocytes can transfer free fatty acids to EOC cells toprovide cellular energy for metastatic tumor growth. Fatty acids provide a rich energy source for ATP-dependentactin polymerization and actin-based protrusions are critical for cell migration and during metastasis.We hypothesize that invasive EOC cells store energy from exogenous lipid sources (including adipocytes andlipid-rich ascites fluid) in cytosolic lipid droplets and under metabolic stress use these lipid droplets to generatemitochondrial ATP that is required for invasive cell migration through autophagy. To prove this hypothesis wewill use a novel 3D culture model and animal studies to track metabolic changes in individual chemoresistantEOC cells as well as study heterogeneity in lipid droplet metabolism. The proposed research will investigate therole of metabolic and treatment stress in activating lipid metabolism (Aim 1) and autophagy (Aim 2) anddetermine how metabolic alterations in subpopulations of highly invasive cells (including PGCCs) contribute tothe development of aggressive tumors (Aim 3). The proposed studies will reveal novel mechanisms contributingto cellular heterogeneity and dysregulated metabolism along with new therapeutic targets to investigate in EOC. 313600 +No NIH Category available Address;Area;Biogenesis;Biology;Blood;Cell membrane;Cell secretion;Cells;Clinical;Complex;Diameter;Disease;Endosomes;Engineering;Genetic;Genomic DNA;Lipid Bilayers;Lipids;Malignant Neoplasms;Malignant neoplasm of pancreas;Messenger RNA;Methodology;MicroRNAs;Mus;Oncogenes;Organ;Pathogenesis;Pathology;Physiology;Production;Prognosis;Proteins;Research;Role;Source;Therapeutic Intervention;Tissues;Tropism;Tumor Immunity;United States;Untranslated RNA;cancer cell;design;engineered exosomes;exosome;extracellular;extracellular vesicles;in vivo;in vivo evaluation;intercellular communication;mouse model;nanosized;neoplastic cell;novel;novel diagnostics;novel therapeutics;programs;trafficking;translational applications;translational potential;treatment response;tumor microenvironment;tumor progression;tumor-immune system interactions Biology and Function of Exosomes in Cancer NarrativeExosomes are nano-sized extracellular vesicles that are naturally present in the blood and all organs and theyare secreted by all cells. The origin and function/s of exosomes in normal physiology and cancer progressionremains largely unknown and challenged by the need for precise methodologies for their purification andcharacterization and the need for new genetic mouse models for in vivo evaluation. This program is designedto understand the functional contribution of exosomes in normal physiology and in pancreatic cancer with afocus on developing new diagnostic and therapy options. NCI 10680453 9/11/23 0:00 PAR-21-333 5R35CA263815-02 5 R35 CA 263815 2 "WOODHOUSE, ELIZABETH" 9/1/22 0:00 8/31/29 0:00 ZCA1-GRB-I(M1) 1858925 "KALLURI, RAGHU " Not Applicable 9 BIOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 952559 NCI 588000 364559 AbstractTrillions of exosomes a subset of extracellular vesicles are naturally present in the blood and tissue and allcells secrete them into the extracellular milieu. Exosomes are on average around 100 nm in diameter and arespeculated to have an endosomal origin with a membrane lipid bilayer of similar orientation as the plasmamembrane of the cells they originate from and with capacity to enter other cells to deliver their constituents. Thecargo exosomes include proteins lipids mRNA non-coding RNAs (ncRNAs) microRNAs (miRNAs) andgenomic DNA; and their production and content can vary depending on the cellular source. Exosomes mayrepresent a novel mean of intercellular communication but their biogenesis trafficking organ tropism andimpact on normal physiology and pathology in the in vivo setting is largely unknown. Similarly the function ofexosomes in pancreatic cancer remains understudied. Our research program is currently designed to addresskey unanswered scientific questions related to the basic biology of exosomes their functional role inpathogenesis and therapeutic intervention of pancreatic cancer a disease with dismal prognosis and on the risein the United States. Employing newly engineered mice we propose to address the role of exosomes in thecomplex interplay between cancer cells and the cells of the tumor microenvironment. Additionally employingour established platform for clinical grade exosomes production we will investigate the potential of engineeredexosomes to target driver oncogenes and modulate the pancreatic cancer immune microenvironment/tumorimmunity to facilitate therapeutic response. The proposed focus areas are rooted in the expertise we havedeveloped within our research program over the last decade and our track record provides the rationale andguidance for a higher chance of feasibility of the proposed studies with potential for translational application. 952559 +No NIH Category available Acceleration;Affect;Ampicillin;Antibiotic Therapy;Antibiotics;Blood Vessels;Cancer Patient;Cell Adhesion Molecules;Cellular immunotherapy;Ciprofloxacin;Clinic;Clinical;Congenic Mice;Data;Defect;Development;Distal;Dorsal;Effectiveness;Endothelial Cells;Endothelium;Extravasation;Flow Cytometry;Fluorescence Microscopy;Foundations;Frequencies;Future;Gastrointestinal tract structure;Goals;Homeostasis;Human;Image;Immune;Immune checkpoint inhibitor;Immune system;Immunosuppression;Immunotherapy;Incidence;Infection;Intercellular adhesion molecule 1;Investigational Therapies;Knowledge;Leukocyte Trafficking;Leukocytes;MEL Gene;Malignant Neoplasms;Metronidazole;Modeling;Molecular;Morbidity - disease rate;Mus;Neomycin;Nude Mice;Patients;Publishing;Solid Neoplasm;Supplementation;T cell infiltration;T cell therapy;T-Lymphocyte;TNF gene;Therapeutic;Time;Treatment Efficacy;Trimethoprim-Sulfamethoxazole;Tumor Immunity;Tumor Suppression;Vancomycin;Work;chimeric antigen receptor T cells;combat;commensal bacteria;dysbiosis;effector T cell;fecal transplantation;fighting;gut microbiome;gut microbiota;immunogenic;improved;intravital microscopy;melanoma;microbiome;optoacoustic tomography;pathogenic bacteria;rRNA Genes;response;success;therapy development;trafficking;transcriptome sequencing;tumor;tumor microenvironment;tumor progression;unpublished works Improvement of cellular immunotherapy during dysbiosis- Resubmission NarrativeAntibiotics severely alter the gut microbiome producing a state of microbial imbalance called dysbiosis. Howdysbiosis affects cancer progression is largely unknown. This project will expand our understanding of thecrosstalk between the gut microbiome the tumor microenvironment and cellular immunotherapy duringantibiotic-induced dysbiosis. NCI 10680445 8/30/23 0:00 PA-19-056 5R01CA245083-03 5 R01 CA 245083 3 "CARDONE, MARCO" 9/15/21 0:00 8/31/26 0:00 Cancer Immunopathology and Immunotherapy Study Section[CII] 10476569 "DINGS, RUUD P.M." Not Applicable 2 RADIATION-DIAGNOSTIC/ONCOLOGY 122452563 VDFYLZPJEAV6 122452563 VDFYLZPJEAV6 US 34.749005 -92.320097 1471106 UNIV OF ARKANSAS FOR MED SCIS LITTLE ROCK AR SCHOOLS OF MEDICINE 722057101 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 859 Non-SBIR/STTR 2023 343184 NCI 225779 117405 Summary/AbstractThe use of antibiotics has significantly increased in recent years. Antibiotics (ABX) severely alter thegut microbiome destroying potentially pathogenic bacteria as well as beneficial onesproducing astate of microbial imbalance called dysbiosis. Notably a diminished gut microbiome has severe defects onthe immune system yet how these defects may affect cellular immunotherapy is largely unknown. To better understand how dysbiosis influences cellular immunotherapy we focused on melanoma asan exemplary immunogenic solid tumor. The incidence of melanoma has increased drastically over thepast decades with its morbidity rate continuing to outpace that of most other cancers. Early stages ofmelanoma are often successfully controlled and treated; yet patients with advanced stages of melanoma aretreated with cellular immunotherapy and only 50% respond. We hypothesize that ABX-induced dysbiosisdictates at least in part the reduction in treatment efficacy. Our overall goal is to define the systemic effects of antibiotic-induced dysbiosis on the distaltumor microenvironment and develop therapies to promote antitumor immunity. The majorobjective of this application is to overcome dysbiosis-induced ICAM-1 suppression and thereby enhancethe effectiveness of cellular immunotherapy. Attaining this objective will be the next step in increasing theefficacy and response rate of immunotherapies. We formulated a robust and unbiased approach usingvarious melanoma models to accomplish the following Aims:Aim 1. Identify ABX primarily responsible for stromal immune suppression resulting in tumor progression.Aim 2. Increase ICAM-1 on tumor-associated endothelial cells during dysbiosis.Aim 3. Increase cellular immunotherapy efficacy in melanoma during dysbiosis. Completing these aims will expand our understanding on how antibiotics-induced perturbation of thegut microbiome impacts the distal tumor microenvironment. This work has the potential to establish newparadigms aimed at enhancing the efficacy and response rate of immunotherapies by modulating thetumor vasculature as all types of immunotherapy ultimately dependent on efficient trafficking of effectorleukocytes into the tumor. 343184 +No NIH Category available Cancer Biology;Training Programs Training Program in Cancer Biology Project NarrativeThe overall goal of this Training Program is to develop highly trained research scientists that have a broadunderstanding of the development progression and treatment of cancer and are ready to pursue independentcareers in cancer research and therapeutics. The next generation of cancer researchers will rely on amechanistic understanding of cancer as the foundation for translational approaches to treat cancer giving thisTraining Program significant relevance to public health. NCI 10680403 8/18/23 0:00 PA-18-403 5T32CA236736-05 5 T32 CA 236736 5 "LIM, SUSAN E" 9/19/19 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 7800553 "LANGUINO, LUCIA R." "APLIN, ANDREW ERIC" 2 PHARMACOLOGY 53284659 R8JEVL4ULGB7 53284659 R8JEVL4ULGB7 US 39.948207 -75.157825 4050801 THOMAS JEFFERSON UNIVERSITY PHILADELPHIA PA SCHOOLS OF MEDICINE 191074418 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 142401 NCI 239404 16970 Project Abstract/SummaryThis application requests support for a Training Program in Cancer Biology at the Sidney Kimmel Cancer Centerat Thomas Jefferson University. This Program provides broad multidisciplinary pre-doctoral and postdoctoraltraining in understanding the development progression and treatment of cancer. The Program will providetrainees with a rigorous basic mechanistic understanding of cancer and participation in laying the groundworkfor translational approaches to treat cancer. In addition trainees will interact with clinical researchers to gaininsight into the use of cancer therapeutics and the mechanism through which basic research findings are broughtinto the clinic. Mentors in this Training Program include established faculty members that have cancer-focusedresearch programs and significant experience in mentoring as well as a core group of cancer-focused juniorfaculty. A significant number of mentors are involved in translational research and clinical trials activities that arefocused on cancer. This unique combination of participating faculty will provide training through direct mentoringinteractions specialized educational activities and course work.The Training Program in Cancer Biology includes 37 members of the Sidney Kimmel Cancer Center from 12basic and clinical departments. The Training Program is administered by the co-Principal Investigators andseveral Administrative Committees. The leadership team is focused on delivering training excellence to anethnically and scientifically diverse cadre of trainees. The Program will be evaluated through both internal andexternal review mechanisms to ensure that the trainees are receiving the best possible training experience.Overall this Program will provide outstanding career development for trainees to pursue careers dependentupon understanding the mechanistic basis of cancer and its application to cancer therapeutics; it will provide acritical team-based educational experience in the multi-disciplinary nature of translational research and stimulatethe trainees to actively consider clinical trials design and clinical research activities. 142401 +No NIH Category available Behavioral;Cancer Control;Research Training;cancer prevention;psychosocial Behavioral and Psychosocial Research Training in Cancer Prevention and Control PROJECT NARRATIVEThis Training Program is designed to prepare the next generation of researchers who will fill workforce needsin cancer behavioral and psychosocial research. Cancer remains a leading cause of death and a major sourceof disability in the United States and throughout the world. The goal of the Training Program is to ensure that atalented and well-trained group of PhD and MD researchers is available in the years ahead to meet researchneeds to understand behavioral and psychosocial determinants and sequelae of cancer reduce cancer riskincrease early disease detection and improve the lives of community members who have developed cancer. NCI 10680402 8/24/23 0:00 PA-18-403 5T32CA193193-09 5 T32 CA 193193 9 "DAMICO, MARK W" 9/23/15 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1865141 "CELLA, DAVID " "HITSMAN, BRIAN L; YANEZ, BETINA " 5 PUBLIC HEALTH & PREV MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 447057 NCI 450516 33545 PROJECT SUMMARY/ABSTRACT This application the first competing renewal for our T32 program requests funds to continue to providemulti-disciplinary post-doctoral research training focused on behavioral and psychosocial aspects of cancerprevention and control at the Northwestern University (NU) Feinberg School of Medicine (FSM) and Robert H.Lurie Comprehensive Cancer Center (RHLCCC). The goal of this program is to provide outstanding training forits postdoctoral fellows so that they become successful independent leaders in cancer research. The programwill accomplish this goal by providing each trainee with a mentored research experience in cancer preventionor control. The programs 24 participating faculty are funded PIs of grants totaling $53 million in direct costsannually an average of $2.2 million per PI. The group includes 19 PhDs and 5 MDs from 7 departments atNorthwestern. All mentors are leading experts in the areas of cancer risk behaviors and screeningmeasurement and intervention science patient reported outcomes or community engagement. By teachingtrainees to apply cutting edge measurement and intervention science strategies to the behavioral andpsychosocial aspects of cancer prevention and control we will train a next generation of researchers to reducecancer risk address disparities and improve the lives of community members affected by cancer in a moreefficient and more cost-effective fashion. Research experiences will be complemented by a weekly seminarprofessional development activities and the opportunity to enroll in either the MPH MSCI MSEB or HSORmasters programs. The Program creates an individual development plan (IDP) for each trainee and providesregular oversight by a primary mentor and co-mentor to meet training goals. Trainees also have access to a vast array of educational resources made available by the University forall postdoctoral trainees including biweekly sessions dedicated to career development survival skills andlearning to succeed and flourish. The program enrolls three new postdoctoral fellows in each of years 1-4 withbalanced representation of fellows in cancer prevention and cancer control. We expect to continue to have alarge pool of potential trainees of whom a majority have a research background (PhD in a behavioral or socialscience exercise science or nutrition) and a minority have a clinical background (MD intending to pursue aphysician/scientist career). External and Internal Advisory Committees will continue to oversee all aspects ofthe Program. Ongoing evaluation and feedback from the Advisory Committees will ensure that changes areimplemented as needed and that training goals are consistently met. The program meets a pressing need totrain a next generation of career investigators who can develop optimize and evaluate behavioral andpsychosocial assessments and interventions to prevent and control cancer and improve quality of life. 447057 +No NIH Category available ABCG2 gene;Address;Affinity;Allergic;Androgens;Binding;Binding Sites;Cancer Patient;Cell Line;Clinical;Clinical Trials;Colchicine;DU145;Data;Daughter;Development;Disease;Dose;Dose Limiting;Drug Kinetics;Drug resistance;Drug usage;FDA approved;FOLH1 gene;Fracture;Frequencies;Funding;Future;Generations;Goals;Grant;Hematopoietic;Hybrids;Immunotherapy;In Vitro;Lead;Length;Malignant Neoplasms;Malignant neoplasm of prostate;Metastatic Neoplasm to the Bone;Metastatic Prostate Cancer;Modeling;Neoplasm Metastasis;Neutropenia;Oral;Pain;Patients;Peripheral Nervous System Diseases;Pharmaceutical Preparations;Phase II Clinical Trials;Productivity;Property;Prostate Cancer therapy;Prostatic Neoplasms;Quality of life;Resistance;Resolution;Roentgen Rays;Site;Solubility;Structure;Therapeutic;Therapeutic Index;Toxic effect;Tubulin;X-Ray Crystallography;Xenograft Model;acquired drug resistance;analog;aqueous;bisphosphonate;bone;cancer therapy;cancer type;chemotherapeutic agent;chemotherapy;clinical candidate;clinical effect;clinical efficacy;design;docetaxel;drug candidate;efficacious treatment;efficacy study;improved;in vivo;in vivo Model;inhibitor;mortality;nerve damage;neurotoxicity;next generation;novel therapeutics;overexpression;patient derived xenograft model;phase II trial;phase III trial;prostate cancer cell line;prostate cancer metastasis;prostate cancer model;pyrrolidin-3-yl-methanesulfonic acid;resistance mechanism;scaffold;side effect;spinal cord compression;success;surfactant;targeted agent;targeted treatment;taxane;triple-negative invasive breast carcinoma;tumor Targeting the colchicine binding site in tubulin for cancer therapy Despite revolutionary advancement in immunotherapy and targeted therapy the overallsurvival of metastatic prostate cancer patients remains limited. Tubulin inhibitors are first linechemotherapeutic agents for prostate cancer but prolonged use of existing anti-tubulin drugsoften results in drug resistance and neurotoxicities. We proposed in this grant to continue ourproductive efforts to develop a new generations of tubulin inhibitors that can overcome clinicallyimportant drug resistance problems in prostate cancer; completion of the proposed studies willprovide the next generation of tubulin inhibitors as more efficacious therapy to treat metastaticprostate cancer and other types of cancers. NCI 10680394 9/8/23 0:00 PA-20-185 5R01CA148706-13 5 R01 CA 148706 13 "FU, YALI" 1/1/11 0:00 6/30/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 8363577 "LI, WEI " "MILLER, DUANE D" 9 PHARMACOLOGY 941884009 X1M1PN3KG3E7 941884009 X1M1PN3KG3E7 US 35.138829 -90.033163 578302 UNIVERSITY OF TENNESSEE HEALTH SCI CTR MEMPHIS TN SCHOOLS OF PHARMACY 381034903 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 389817 NCI 265707 124110 Despite recent advances in both targeted therapy and immunotherapy the overall survival (OS) formetastatic prostate cancer (PCa) remains low. This renewal application is to continue our productive efforts todevelop a new tubulin inhibitor that can overcome drug resistance associated with FDA approved tubulininhibitors and will therefore increase OS in PCa and other types of cancers where anti-tubulin drugs are used. The support from the previous periods of funding has resulted in a new drug candidate Veru-111 which isunder Phase 2 clinical trials for metastatic PCa. While Veru-111 is on a promising path to gain future FDAapproval there are significant room for improvement. The goals of this renewal are: (1) to develop the nextgeneration of Veru-111 to proactively address its anticipated drug resistance; and (2) to develop targeted Veru-111 drug conjugates to increase drug accumulation in prostate tumors and to target PCa bone metastasis. Aim 1. Develop a new generation of Veru-111 that can overcome both taxane resistance and theanticipated Veru-111 resistance. Preliminary data: We have discovered a hybrid scaffold based on Veru-111and Azixa represented by SHIP-216 that can overcome resistances to both taxanes and Veru-111. Approaches:Guided by high-resolution X-ray crystal structures we will optimize the SHIP-216 scaffold to further improve itspotency and drug-like properties. New analogs will be evaluated against a panel of PCa cell lines including bothtaxane- and Veru-111-resistant cell lines to select the best five analogs for in vivo efficacy studies in Aim 3. Aim 2. Conjugate Veru-111 with PSMA targeting moieties to increase drug accumulation in PCatumors and conjugate Veru-111 with bisphosphonates for more efficacious targeting of bone metastasis.Preliminary data: we have demonstrated Veru-111 itself can significantly reduce bone metastasis in a PDX model.We have also developed linkers for conjugating Veru-111 with PSMA targeting moieties or bisphosphonates.Approaches: we will optimize the length and composition of the linkers to PSMA targeting moieties and usedifferent bisphosphonates in conjugation to generate focused sets of Veru-111 drug conjugates. Theseconjugates will be first evaluated in vitro for stability and activation to select the best four conjugates (two inPMSA and two in bisphosphonates conjugates) for further in vivo efficacy studies in Aim 3. Aim 3. We will determine the maximum tolerable dose (MTD) pharmacokinetics (PK) and in vivoefficacy of the selected nine compounds from Aims 1-2 in both PCa cell line models and a PDX model toselect the overall best compound to support subsequent clinical trials in the Veru-111 portfolio.Preliminary data: we have already shown that SHIP-216 as a new Veru-111 analog is highly efficacious againstmultiple xenograft models including the 22Rv1 PCa and the Veru-111 resistant DU-145/VxR PCa models.Approaches: We will evaluate all selected new compounds for their designed ability to treat prostate tumorsusing both cell line and PDX models in vivo. 389817 +No NIH Category available Acids;Affinity;Amino Acids;Antibodies;Bacteria;Binding;Cell Line;Cell physiology;Cells;Childhood;Comparative Study;Enzymes;Fab Immunoglobulins;Histidine;Histone H4;Human;Immunofluorescence Immunologic;Individual;Malignant Neoplasms;Malignant neoplasm of pancreas;Mammals;Methods;Molecular;Monoclonal Antibodies;Mus;NME1 gene;Neuroblastoma;Normal Cell;Peptides;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Post-Translational Protein Processing;Potassium Channel;Primary carcinoma of the liver cells;Protein Isoforms;Proteins;Protocols documentation;Reagent;Recording of previous events;Role;Series;Serine;Signal Transduction;Site;Site-Directed Mutagenesis;Stains;Structure;Surface;System;Threonine;Tumor Cell Line;Tumor Suppressor Proteins;Tumor Tissue;Tyrosine;Western Blotting;detection of nutrient;experimental study;human disease;improved;inorganic phosphate;novel therapeutic intervention;phosphohistidine;receptor;targeted cancer therapy;therapeutic target;tool;tumor Histidine phosphorylation as a new target for cancer therapy Project NarrativeThe studies proposed in this application seek to elucidate at the molecular level how the reversibleattachment of phosphate to the amino acid histidine in proteins regulates their activity. By analogy withaddition of phosphate to serine threonine and tyrosine the phosphorylation of histidine is likely to play animportant role in normal cell function and in human disease and in particular cancer and could serve as anew cancer therapeutic target. NCI 10680390 7/25/23 0:00 PAR-18-880 5R35CA242443-05 5 R35 CA 242443 5 "XU, WANPING" 9/18/19 0:00 8/31/26 0:00 ZCA1-RPRB-N(M1) 1866203 "HUNTER, TONY R." Not Applicable 50 Unavailable 78731668 NNJ6BMBTFGN5 78731668 NNJ6BMBTFGN5 US 32.8863 -117.243929 7210001 SALK INSTITUTE FOR BIOLOGICAL STUDIES La Jolla CA Research Institutes 920371002 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 1131312 NCI 588000 543312 Project Summary/AbstractPhosphorylation of histidine (His) in proteins has a 60-year history initially identified as a P-enzymeintermediate but subsequently as a regulatory mechanism in bacteria essential for signal transduction bysurface receptors that sense nutrients. Such signaling systems are lacking in mammals but phosphohistidine(pHis) is not only a key P-enzyme intermediate in mammalian enzymes (e.g. NME1/2 ACLY) but also occursas a reversible end-state protein modification e.g. pHis18 in histone H4. His phosphorylation is labile to acidand heat making it challenging to study and to circumvent this our group developed a series of monoclonalantibodies (mAbs) that recognize the 1-pHis or 3-pHis isoforms in a sequence-independent manner. ThesemAbs were used to detect pHis in cells by immunoblotting and immunofluorescence (IF) staining and foraffinity enrichment of pHis proteins for MS analysis revealing ~700 potential pHis proteins and implying theexistence of large hidden phosphoproteome not detectable by conventional methods. In a collaborative studythese mAbs were used to demonstrate site and isoform specific His phosphorylation of the KCa3.1 K+ channeland deduce how pHis triggers channel opening. In a second collaborative study the mAbs were used todemonstrate increased levels of pHis proteins in mouse and human hepatocellular carcinoma (HCC) andshow that the increase was due to reduced expression of the LHPP pHis phosphatase in the tumorssuggesting that LHPP acts as a tumor suppressor and that elevated His phosphorylation plays a driver role inthis cancer. On this basis studies are planned to investigate whether increased His phosphorylation plays abroader role in human cancer. Initially our structures of mAb-derived Fab fragments bound to pHis peptideswill be exploited to develop better tools for studying His phosphorylation in cancer - mAbs with higher affinityand scFvs for intracellular expression to localize and perturb pHis proteins sequence specific pHis antibodiesfor studying individual proteins and improved MS-based pHis site identification. In parallel in-depth studieswith existing 1/3-pHis mAbs as well as new pHis reagents as they come online will be conducted on threeselected tumor types - HCC pediatric neuroblastoma and pancreatic cancer where there is evidence thataberrant His phosphorylation may play a role. Immunoblotting and IF and IHC staining will be performed ontumor tissues/cell lines and normal controls combined with use of optimized pHis peptide enrichment and siteidentification protocols to define changes in His phosphorylation unique to tumor tissues. Where warranted thefunction of individual pHis sites in cancer will be studied by site-directed mutagenesis in tumor cell lines. Ineach case further experiments will be guided by the identity and function of pHis proteins found in a particularcancer. Overall it is anticipated that comparative studies on HCC neuroblastoma and PDAC will shed light onwhether His phosphorylation plays a general role in cancers whether there are common mechanisms andwhether targeting His phosphorylation could be a viable new therapeutic approach. 1131312 +No NIH Category available Automobile Driving;Bacteria;Biochemical Process;Bioinformatics;Biological Assay;Biological Models;Cancer Etiology;Cause of Death;Cell Proliferation;Cells;Cessation of life;Clinical;Colorectal;Colorectal Cancer;Colorectal Neoplasms;Coupled;Early Diagnosis;Early treatment;Ecology;Epithelial Cells;Epithelium;Exhibits;Experimental Models;Functional disorder;Galaxy;Generations;Genes;Growth;Human;Hypoxia;Immune response;Intestines;Investigation;Knowledge;Laboratories;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Microbe;Microbiology;Modality;Modeling;Molecular;Morphology;Multiomic Data;Organism;Organoids;Pathway interactions;Patients;Physiological;Physiological Processes;Pre-Clinical Model;Prognosis;Proliferating;Proteins;Resistance;Resources;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;Study models;Survival Rate;System;Technology;Testing;Therapeutic;Treatment Protocols;Tumor stage;Vascularization;Woman;Work;bacterial community;colon cancer patients;colorectal cancer treatment;conventional therapy;effective therapy;experience;fecal microbiota;gut microbiota;improved;improved outcome;infancy;men;metabolomics;metatranscriptomics;microbial;microbiome;microbiota;multiple omics;neoplastic cell;pre-clinical;proteogenomics;response;small molecule;survival outcome;therapy resistant;tool;tumor;tumor microbiota;tumorigenesis Microbiome-derived regulators of therapy-resistant colorectal tumors PROJECT NARRATIVEColorectal cancer (CRC) remains the third most lethal cancer due in large part to lack of effective treatment oflate-stage tumors. Bacteria found the human intestinal tract offer a promising means to treat these tumors butwe lack understanding of the mechanisms by which these organisms regulate this cancer. We will apply state-of-the-art technologies and a preclinical experimental model of CRC to identify the molecules and bacteria thatcould be used for treatment ultimately decreasing the suffering and death caused by this cancer. NCI 10680364 8/1/23 0:00 PAR-19-194 5R21CA267707-02 5 R21 CA 267707 2 "RASOOLY, AVRAHAM" 8/9/22 0:00 7/31/24 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 6363230 "GRIFFIN, TIMOTHY J." "JAGTAP, PRATIK D; SUBRAMANIAN, SUBBAYA " 5 BIOCHEMISTRY 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 178483 NCI 115150 63333 PROJECT SUMMARYColorectal cancer (CRC) is the third most deadly cancer for both men and women in the U.S. Despite effectivetreatments for early-stage CRC late-stage solid tumors exhibiting hypoxic and/or poor vascularization are moredifficult to treat. To improve the prognosis for these tumors new treatment regimes for CRC are urgently needed.Intestinal tract bacterial communities (microbiota) present a possible solution. Evidence from our team as wellas others indicates small molecule metabolites produced via metabolic processes of the microbiota canpromote and in some cases inhibit CRC tumorigenesis. These findings have suggested the possibility ofBacterial-derived Metabolite Therapy (BdMT) as a transformative treatment of resistant CRC tumors. Howeverour understanding of these tumor-microbe interactions is only in its infancy and more work is needed to makeBdMT a reality. In particular we lack knowledge on the identity of microbe-derived metabolites that regulateCRC tumors and also the underlying molecular mechanisms by which these molecules regulate the tumor cells.In order to fill in these gaps we use a powerful preclinical experimental model system (tumoroids) for assayingphysiological effects of microbe-derived metabolites on tumor cells coupled with cutting-edge multi-omicanalysis tools to investigate molecular mechanisms of tumor response and identify their small molecularregulators. Our hypothesis is that CRC tumoroids treated with metabolite fractions obtained from fecal samplesof CRC patients and analyzed via multi-omics will reveal microbiome-derived small molecule tumor regulatorswhich can be further leveraged for therapeutic applications. We will test this hypothesis via these Specific Aims:Aim 1. Establish a CRC tumoroid model and test tumor cell response to fecal metabolite fractions.Leveraging the expertise of PI Subramanian we will establish patient-derived CRC tumoroids and treat thesewith metabolite fractions isolated from fecal samples of CRC patients and healthy controls. Tumor cellproliferation will be assayed for each fraction tested; Aim 2. Identify and validate molecular regulators andmechanisms of CRC tumoroid response using multi-omics. For metabolite fractions eliciting proliferativetumor cell response in Aim 1 advanced multi-omic analysis will be performed on the tumor cells to investigateresponse mechanisms. Metatranscriptomic analysis of fecal samples will identify microbiota functional pathwaysactive in tumor-bearing patients. Tumor response mechanisms and active microbial metabolic pathways will beused to predict potential small molecule regulators active in the fecal fractions. Mass spectrometry-basedmetabolomics will identify potential small molecule tumor regulators. Enabled by the diverse expertise of ourteam in cancer microbiology tumor-microbe interactions and multi-omic analysis we will identify potential newtumor-regulating metabolites for further investigation a critical step towards making BdMT a reality for improvingoutcomes of CRC. 178483 +No NIH Category available Animals;Antibodies;BRCA1 Mutation;BRCA1 gene;Bioinformatics;Biological Assay;Brain;Breast cancer metastasis;Cancer Biology;Cause of Death;Cell Differentiation process;Cells;Cessation of life;Chromatin;Clonal Evolution;Complex;Computer Analysis;Custom;DNA;DNA Repair;DNA copy number;DNA sequencing;Data;Development;Disease;Disseminated Malignant Neoplasm;Duct (organ) structure;Educational process of instructing;Epigenetic Process;Epithelial Cells;Evolution;Faculty;Gene Expression;Gene Expression Profile;Genetic;Genetic Transcription;Genomic Instability;Genomics;Genotype;Goals;Harvest;Heterogeneity;Human Resources;Impairment;Injections;Investigation;Laboratories;Laboratory Animals;Learning;Liver;Localized Malignant Neoplasm;Lung;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mentors;Metastatic breast cancer;Methodology;Milk;Mission;Modeling;Mouse Strains;Multiomic Data;Mus;Mutant Strains Mice;Mutate;Mutation;Mutation Analysis;Myoepithelial cell;Neoplasm Metastasis;Organ;Patients;Pattern;Phenotype;Pilot Projects;Population;Positioning Attribute;Postdoctoral Fellow;Primary Neoplasm;Property;RNA;Resistance;Resolution;Students;Surveys;Systems Biology;TP53 gene;Techniques;Technology;Testing;Training;Trees;Variant;Woman;Work;XCL1 gene;advanced breast cancer;bioinformatics tool;cancer cell;cancer genomics;cell type;data integration;design;epigenomics;exome;exome sequencing;experimental study;genomic tools;improved;innovation;insight;malignant breast neoplasm;mammary epithelium;metastatic process;molecular marker;molecular oncology;molecular pathology;mouse model;multiple omics;mutant;neoplastic cell;personalized medicine;prevent;progenitor;stem cells;symposium;transcriptomics;tumor;tumor heterogeneity;undergraduate student Intratumor heterogeneity in BRCA1-mutated breast cancer metastasis NarrativeThe vast majority of breast cancer related deaths are caused by the metastatic spread of cancer from thebreast to other organs in the body. This project would help to understand which types of cells from the tumorare capable of colonizing the major organs in the body. In the long term this information should point to waysof preventing metastasis and more effective ways to treat patients who already have metastatic breast cancer. NCI 10680318 5/9/23 0:00 PA-21-052 1F31CA281331-01 1 F31 CA 281331 1 "DIBELLO, ANTHONY THOMAS" 5/9/23 0:00 5/8/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 77824295 "LEV, TATYANA " Not Applicable 47 PHYSIOLOGY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 5/9/23 0:00 5/8/24 0:00 398 "Training, Individual" 2023 42381 NCI 42381 0 AbstractMetastasis continues to cause the vast majority of breast cancer related deaths because the metastaticprocess is poorly understood and therapies for effectively inhibiting it do not exist. Women with BRCA1mutations develop the most aggressive and highly metastatic basal-like breast cancer at a high rate. Despiteresembling basal epithelial cells recent studies have identified the luminal progenitor as the cell type whichundergoes malignant transformation in basal-like breast cancer. Preliminary sequencing data included in thisproposal from same-cell gene expression and chromatin accessibility epigenetics assay in a mouse model ofbasal-like breast cancer reveal the presence of several differentiation states of luminal progenitor cells withinthe tumor. Additionally several tumor cell states appear to have unique DNA copy-number mutationalsignatures. These observations prompt the questions of whether a particular differentiation state is involved inmetastasis and if mutations drive the differentiation and metastasis trajectory.To investigate the metastatic potentials of the cellular differentiation states and mutational cell subpopulationsin the tumors the proposed study will consist of the following methodological steps: 1) harvestingspontaneously generated Brca1&p53-mutant mouse tumors 2) injection of tumor cells into mice to generatemetastasis replicates 3) isolation of metastatic cells using mouse strain-specific antibodies 4) splitting ofmetastatic cells and original mammary tumor cells for parallel single cell profiling with a) gene expression andchromatin accessibility assay and b) custom-built high-resolution mutation panel 5) data integration toincorporate the contribution of mutations epigenetic chromatin states and gene expression 6) computationalcomparison of metastatic cells to original tumor cells. This study is expected to reveal the molecular markerswhich define metastatic cells in Brca1&p53-mutant tumors to inspire metastasis inhibiting therapy.This study will be carried out by a student with substantial training in molecular pathology and systems biologywho wishes to further her cancer genomics and bioinformatics training. Laboratory animal personnel will assistwith animal work the bioinformatics director will guide the computational analysis and statistical tests and thefaculty advisor/sponsor will oversee experiments and interpretations of results. The student will work closelywith the sponsor and the bioinformatics collaborator to learn the proper use of cutting edge genomics andbioinformatics tools to advance the breast cancer metastasis field. Additionally the student will be givenprofessional development opportunities such as attending conferences mentoring undergraduates andteaching a summer course to prepare her for a post-doctoral position in a cancer-related field. 42381 +No NIH Category available Affinity Chromatography;Antisense RNA;Binding;Binding Proteins;Binding Sites;Cancerous;Cell Cycle;Cell Nucleus;Cells;Chromatin;Complex;DNA Binding;DNA-Binding Proteins;Data;Enzymes;Future;Gene Expression;Gene Expression Regulation;Gene Silencing;Gene Targeting;Genes;Genetic;Genome;Guide RNA;HDAC1 gene;HDAC3 gene;Health;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone Deacetylation;Human;Immunoprecipitation;Knock-out;Link;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Mediating;Methods;Mission;Molecular;Multiprotein Complexes;Mutate;Nuclear;Pathology;Patients;Pharmaceutical Preparations;Protein Isoforms;Proteins;RNA;RNA Binding;RNA-Binding Proteins;Repression;Research;Research Project Grants;Role;Site;Specificity;Suppressor-Effector T-Lymphocytes;Testing;Therapeutic;Time;Toxic effect;Tumor Suppressor Genes;United States National Institutes of Health;Untranslated RNA;Work;X Chromosome;cancer therapy;cancer type;chromatin modification;crosslink;effective therapy;experimental study;gene repression;genetic manipulation;genetic regulatory protein;genomic locus;improved;in vivo;inhibitor;link protein;mRNA Precursor;novel;pharmacologic;protein complex;public database;recruit;side effect;therapeutic target;transcription factor;tumor Characterizing the RNA-mediated recruitment of histone deacetylases to chromatin PROJECT NARRATIVEThe proposed research project is aimed at elucidating the role of RNA and RNA-binding proteins (RBPs) inregulating histone deacetylase (HDAC) recruitment to gene targets. This molecular understanding has thepotential to identify highly precise therapeutic targets for inhibition of HDACs in cancers where HDACs areoverrepresented. Thus the proposed work is relevant to the NIH mission of health as it could lead to improvedcancer treatments with fewer side effects. NCI 10680276 5/8/23 0:00 PA-21-050 1F30CA278005-01A1 1 F30 CA 278005 1 A1 "DAMICO, MARK W" 6/1/23 0:00 5/31/28 0:00 Special Emphasis Panel[ZRG1-F08-M(20)L] 78496259 "GUO, JAMES KANG" Not Applicable 28 NONE 9584210 U2JMKHNS5TG4 9584210 U2JMKHNS5TG4 US 34.134332 -118.12652 1073501 CALIFORNIA INSTITUTE OF TECHNOLOGY PASADENA CA SCHOOLS OF ARTS AND SCIENCES 911250001 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARYGlobal histone deacetylation is linked to many types of cancer and is controlled by histone deacetylases(HDACs). Although HDAC inhibitors are widely used in cancer treatment their activity does not target specificHDAC isoforms nor specific genes and therefore results in significant side effects for patients. Thus there is apressing need to target HDAC activity in a highly precise gene-specific manner to develop safer and moreeffective treatments. The overall objective of this proposal is to understand how HDACs are recruited to specificgenome regions. Because HDACs do not possess intrinsic DNA binding activity they are thought to be recruitedto chromatin through interactions with DNA binding proteins though this mechanism has not been fully explored.Recently our lab and others identified that the SHARP RNA-binding protein directly interacts with the Xist longnoncoding RNA (lncRNA) to specifically recruit HDAC3 to the future inactive X chromosome (Xi). In this way theXist-SHARP/SMRT/HDAC3 repressive complex deacetylates histones and silences gene expression on the Xi.Our lab has also demonstrated that SHARP localizes to many nuclear sites (beyond the Xi) in an RNA-dependentmanner raising the question of which additional RNAs recruit it (along with HDAC3) and to what specific genomiclocations. Notably nearly all human HDACs associate within multi-protein complexes containing SHARP andother RNA-binding proteins suggesting that this mechanism of RNA-guidance may extend beyond SHARP andXist.I hypothesize that HDAC complexes are recruited by RNAs to achieve specificity to their various regulatorytargets throughout the nucleus. First I will determine which SHARP-RNA interactions are functionally importantby genetically perturbing the SHARP binding sites of candidate RNAs. I will then measure effects on geneexpression and if HDAC3 activity is required for these effects (Aim 1). Second I will comprehensively identifyRNA-binding proteins associated with other cancer-associated HDACs and define their in vivo RNA binding sites.I will then determine which protein-bound candidate RNAs from this screen are regulated in an HDAC-dependentmanner (Aim 2). The proposed research has the potential to transform our understanding of RNAs and RNA-binding proteins as central regulators in organizing chromatin modifications by HDACs in both normal andcancerous cell states. 52694 +Bioengineering; Biomedical Imaging; Cancer; Radiation Oncology Address;Algorithms;Anesthesia procedures;Animals;Clinic;Clinical;Clinical Research;Clinical Treatment;Collimator;Communities;Computational Technique;Computer software;Cost Analysis;Development;Development Plans;Dose;Engineering;Ensure;Freedom;Functional Imaging;Generations;Hour;Human;Hypoglycemia;Image;Immune response;Impairment;Intensity-Modulated Radiotherapy;Interruption;Intuition;Investigation;Joints;Learning;Lung;Malignant Neoplasms;Manuals;Mechanics;Medical;Medical center;Modality;Modernization;Normal tissue morphology;Organ;Physiological;Positron-Emission Tomography;Price;Process;Radiation;Radiation Dose Unit;Radiation therapy;Radiobiology;Radiotherapy Research;Rattus;Research;Resources;Risk;Sales;Sample Size;Shapes;Side;Software Design;Speed;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Translating;Translations;Validation;anatomic imaging;base;cone-beam computed tomography;cost;design;design and construction;evidence base;experience;frontier;image guided;imaging modality;imaging platform;improved;industry partner;innovation;natural hypothermia;next generation;novel;pre-clinical;pre-clinical research;preclinical study;product development;programs;prototype;reconstruction;research study;response;systems research;treatment planning;treatment response;tumor Next generation small animal radiation research platform NARRATIVETechnology in current small animal radiation research (SARR) has significantly lagged behind that in humanradiotherapy (RT) impairing SARR study relevance to human RT impeding explorations in RT research andhindering rapid conduction of SARR studies. This project will develop a next-generation SARR platform withnovel imaging planning delivery and computation techniques to fill this critical void between SARR andhuman RT. The developed system will become an essential component in preclinical research for theexploration of novel radiotherapeutic strategies with high relevance to human RT. NCI 10680056 9/13/22 0:00 PA-21-268 7R37CA214639-06 7 R37 CA 214639 6 "OBCEMEA, CEFERINO H" 9/1/22 0:00 8/31/23 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)] 10291013 "JIA, XUN " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 395 Non-SBIR/STTR 2022 158789 NCI 97250 61539 PROJECT SUMMARYSmall Animal Radiation Research (SARR) is of paramount importance for the advancement of humanradiotherapy (RT) by serving as a critical counterpart to perform comprehensive preclinical studies on a largenumber of subjects under controlled experimental conditions at low costs. SARR relies on dedicated platformsto administer radiation dose to animals in a similar way as in the clinic. Current-generation SARR irradiatorsdeveloped in the past decade have failed to keep pace with technology advancements in human RT. In starkcontrast to modern RT treatments where novel anatomical and functional imaging inverse treatment planningand intensity modulated delivery techniques are routinely employed to precisely form an extremely conformaldose distribution to the tumor the therapeutic form in current SARR systems resembles an obsolete form ofhuman RT. This technology disparity has substantially impaired SARR study relevance to human RT impededexplorations in RT research and hindered rapid conduction of SARR studies. Towards addressing thisproblem in response to PAR-15-075 this project will develop and translate a next-generation SARR platformthrough an academic-industrial partnership joining medical physicists and radiobiologists at UT SouthwesternMedical Center (UTSW) with engineering experts at Faxitron Bioptics LLC (Faxitron). The developed systemwill be substantially superior to the current state-of-the-art SARR platform due to its novel imaging methods(dual energy cone beam CT and PET) intensity modulated radiotherapy and high computation and treatmentdelivery efficiency. These novel features are expected to improve SARR research relevance to human RT bydelivering treatments of clinical quality to support exploration in modern RT by offering technical freedom torealize novel imaging and therapy approaches and to increase research efficiency by enhancingcomputational speed and workflow. We will perform studies with the following specific aims (SAs): SA1: Refinehardware design and construct the hardware system including mechanical imaging and therapy subsystems.SA2: Refine software design and develop an imaging and treatment planning system accompanied with thehardware platform. SA3: Perform comprehensive system tests develop a translation plan and demonstrateachieved advantages of the system via an animal study on image-guided intensity-modulated lung stereotacticbody radiotherapy using rats. The innovation of this project includes novel technological capabilities enabled bythe next-generation SARR platform as well as coherent translation activities to deliver new capabilities to end-users. Project feasibility is ensured by extensive preliminary studies and the research team integrating medicalphysicists and radiobiologists (UTSW) with strong clinical and research expertise and engineers (Faxitron) withextensive commercial product development experience. By filling the critical void between SARR and humanRT the developed system will become an essential component in preclinical research for the exploration ofnovel radiotherapeutic strategies with high relevance to human RT. 158789 +No NIH Category available 3-Dimensional;3D Print;Address;African American;African-American Graduate Student;Anatomy;Anterior;Award;Beds;Biomedical Engineering;Biomedical Research;Biopsy;Black race;Cancer Patient;Clinical;Clinical Management;Clinical Research;Code;Collaborations;Complex;Coupling;Detection;Development;Development Plans;Disease;Distant;Education;Electronics;Elements;Eligibility Determination;Engineering;Extracapsular;Fellowship;Frequencies;Funding;Geometry;Goals;Grant;Head;Health;Image;Incidence;Infrastructure;Joints;Knowledge;Learning;Liver;Localized Malignant Neoplasm;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Measures;Metabolic;Methods;Modernization;National Research Service Awards;Neck;Neoplasm Metastasis;Newly Diagnosed;Noise;Not Hispanic or Latino;Nursing Research;Organ;Patients;Performance;Periprostatic;Phase I Clinical Trials;Prostate;Prostatic;Pyruvate;RF coil;Research;Research Design;Research Project Grants;Research Training;Residual state;Risk;Scanning;Science;Signal Transduction;Site;Software Design;Staging;Statistical Study;Students;Techniques;Testing;Time;Training;Underrepresented Minority;Underrepresented Populations;advanced disease;advanced prostate cancer;bone;cancer imaging;career;career development;clinical care;computer design;design;design and construction;detector;experience;graduate student;healthy volunteer;improved;industry partner;interest;lymph nodes;member;men;minority scientist;molecular imaging;mortality;novel;performance tests;pre-doctoral;professor;programs;prototype;radiologist;reconstruction;research study;safety testing;simulation;skills;software development;technology development;transmission process;treatment response;ultrasound;volunteer New Hardware and Software Developments for Improving Prostate Metabolic MR Imaging PROJECT NARRATIVEThe goal of this F31 NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research project isto develop new MR molecular imaging hardware and techniques to better detect aggressive cancersmetastasizing beyond the prostate gland and local spread to the prostatic bed & adjacent lymph nodes. This isof particular relevance for identifying and treating patients presenting with advanced stage disease which istwo-fold higher in African-American men. NCI 10680043 8/10/23 0:00 PA-21-052 1F31CA275389-01A1 1 F31 CA 275389 1 A1 "DIBELLO, ANTHONY THOMAS" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F15-B(20)L] 14207097 "GEBREZGIABHIER, DANIEL TEWELDE" Not Applicable 11 RADIATION-DIAGNOSTIC/ONCOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 40213 NCI 40213 0 Project Summary/AbstractThe proposed F31 NRSA Predoctoral Fellowship to Promote Diversity in Health-Related Research project aimsto develop new MR detector hardware and acquisition & analysis methods to enable a major improvement in theclinical management of prostate cancer. This is of relevance to all prostate cancer patients but also especiallyfor under-represented minorities. African-American men have the world's highest incidence of prostate cancerand a more than two-fold higher mortality rate compared with whites. Also African-American men have twicethe risk of non-Hispanic whites for presenting with advanced-stage prostate cancer. This means that it isimportant to identify and stage aggressive advanced prostate cancer accurately in this under-representedpopulation. Prior studies by our group have been focused on improved MR molecular imaging of primary organ-confined prostate-cancer and detecting response to therapy in bone and liver (distant) metastases. The PI anAfrican-American graduate student has designed the proposed research training in this diversity fellowshipproject to focus on developing novel 13C/1H RF detector hardware and methods for increased HP [1-13C]pyruvate& 1H mpMRI sensitivity and coverage to detect aggressive cancers within the prostate and local spread to theprostatic bed & adjacent lymph-nodes. This is important for newly diagnosed patients and of particular relevancefor African-American patients who more often present with advanced stage disease that has extra-capsularspread beyond the prostate and to nearby lymph nodes.As shown in his attached biosketch and through his outstanding initial research the candidate is a highlymotivated successful trainee who meets the eligibility criteria as an African-American graduate student and willbenefit greatly from this fellowship in terms of his research education and efforts to promote diversity inbiomedical research. This project was designed by the PI applicant (with sponsor input & guidance) to fit hiscareer goal of becoming a professor leading advanced MRI technology development to improve the clinical careof prostate cancer patients specifically and patients with other deadly diseases in general. This award will alsoenable the PI candidate to promote diversity within the joint Bioengineering program at UC Berkeley and UCSFand ultimately science nationally to expand the number and input of under-represented minority scientistsespecially in the field of Bioengineering. He has been highly active in promoting diversity currently as a UC BioEgraduate student and a member of Black Graduate Engineering and Science Students (BGESS). The diversityfellowship career development plan is designed to expand the scientific knowledge and independent researchcapabilities of the candidate. The goals are to: 1) Improve knowledge and research skills in MR hardware andacquisition methods; 2) Learn research study design and conduct; 3) Statistical and clinical study considerations;and 4) the conduct of first-rate research designed to ultimately improve prostate cancer imaging of newlydiagnosed patients presenting with advanced disease. 40213 +No NIH Category available Acute;Antibodies;Antitumor Response;Automobile Driving;B-Lymphocytes;Biological;CD8-Positive T-Lymphocytes;CDK4 gene;CDKN2A gene;Cells;Chemotactic Factors;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Dendritic Cells;Diagnosis;Drug resistance;Excision;Flow Cytometry;Goals;Human;Immune;Immune response;Immunity;Immunocompetent;Immunotherapy;Impairment;Infiltration;Laboratory Finding;Leucocytic infiltrate;Location;MEK inhibition;MEKs;Malignant Neoplasms;Measures;Mediating;Modeling;Mus;NF1 gene;NF1 mutation;Natural Immunity;Nerve;Neurofibrosarcoma;Oncogenic;Operative Surgical Procedures;Patients;Pharmaceutical Preparations;Plasma Cells;RAS driven tumor;Radiation therapy;Role;T-Lymphocyte;Testing;Time;Treatment Efficacy;Tumor Immunity;Tumor-infiltrating immune cells;Up-Regulation;Wild Type Mouse;adaptive immunity;anti-tumor immune response;chemokine;cytokine;effective therapy;experimental study;human disease;immune cell infiltrate;immune checkpoint blockade;improved;interest;kinase inhibitor;mouse model;novel;programmed cell death ligand 1;response;sarcoma;standard of care;targeted treatment;tertiary lymphoid organ;transcriptome;transcriptome sequencing;treatment strategy;tumor Intratumoral plasma cells in MPNST response to CDK4/6 targeted therapy and sensitization to immune checkpoint blockade Project NarrativeMPNSTs lack effective therapies highlighting a critical need to develop novel treatment strategies. I hypothesizethat MEK-CDK4/6 inhibition causes MPNST regression and increased response to immune checkpoint blockadetherapy through a plasma cell-dependent modulation of tumor infiltrating immune cells. These studies will definefor the first time in any tumor type the biological significance of intratumoral plasma cells in therapy-inducedantitumor immunity. NCI 10680009 5/16/23 0:00 PA-21-052 1F31CA281312-01 1 F31 CA 281312 1 "GHOSH, SANGEETA AHUJA" 6/1/23 0:00 5/31/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 79414353 "LINGO, JOSHUA J" Not Applicable 1 NEUROSCIENCES 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA SCHOOLS OF MEDICINE 522421320 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 "Training, Individual" 2023 34491 NCI 34491 0 Project Summary / AbstractMalignant peripheral nerve sheath tumors (MPSNTs) are deadly essentially incurable sarcomas that lackeffective therapies. Hallmark alterations driving MPNSTs are NF1 mutation leading to Ras-MEK activationand loss of CDKN2A leading to hyperactivation of CDK4/6. Our lab found that dual inhibition of MEK andCDK4/6 (simplified as CDK4/6 targeted therapy since both drugs downregulate CDK4/6) acts synergisticallyto dramatically shrink de novo MPNSTs in immune competent mice. Tumor regression coincides with anincrease in intratumoral plasma cells (IPCs) which was not observed in vehicle control and drug-resistanttumors. IPCs prognose better overall survival increased formation of tertiary lymphoid structures (TLS)containing activated CD8+ T cells and improved response to immune checkpoint blockade (ICB) therapies inmany human cancers including other sarcomas. I found that CDK4/6 targeted therapy sensitizes de novoMPNSTs to ICB using Programmed Death Ligand 1 (PD-L1) antibodies with the combination achievingapparent cure in 10% of mice. These findings support my central hypothesis that CDK4/6 targeted therapycauses tumor regression and enhanced response to ICB therapy through a plasma-cell dependent modulationof tumor infiltrating immune cells. This will be tested through two complementary aims:Aim 1: Define IPC associations with immune composition changes in MPNSTs caused by CDK4/6 targeted therapy with or without anti-PDL1 therapy.Aim 2: Determine the mechanism and significance of IPCs in the MPNST immune response to CDK4/6 targeted and/or anti-PDL1 therapy.Proposed studies employ an established model of de novo MPNSTs generated by CRISPR editing ofNf1+Cdkn2a in immune competent mice closely mimicking the human disease. Changes in the immunecomposition of MPNSTs following therapy will be determined through histopathological flow cytometriccytokine/chemokine arrays and transcriptome analyses and results correlated with the antitumor efficacy of thetherapies. Through these aims I will elucidate therapy-induced changes in IPCs and other tumor infiltratingimmune cells and determine if plasma cell loss reduces the antitumor efficacy of CDK4/6 targeted and/or ICBtherapy. Such experiments will for the first time in any tumor type establish the significance of therapy-induced IPCs in the antitumor immune response. The role of IPCs in potentiating kinase inhibitor and ICBtherapies is of growing interest but so far remains untested; it will be defined here in the setting of MPNSTs.Findings may guide new treatments for MPNSTs including immunotherapy involving ICB agents and havebroad applicability to other cancers. 34491 +Cancer; Cervical Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS; Infectious Diseases; Rare Diseases; Sexually Transmitted Infections; Women's Health AIDS Malignancy Consortium;AIDS clinical trial group;AIDS related cancer;African;Area;Cervical Intraepithelial Neoplasia;Clinical Research;Clinical Trials;Collaborations;Communication;Country;Data;Detection;Electronic Mail;Evaluation;Flowers;Funding;Genotype;Goals;Grant;HIV;HPV-High Risk;Hospitals;Human Subject Research;Individual;Infrastructure;Institution;Kaposi Sarcoma;Leadership;Lymphoma;Malawi;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Names;Performance;Postdoctoral Fellow;Progress Reports;Records;Reporting;Research;Research Activity;Research Personnel;Research Support;Research Training;Resource Sharing;Resources;Sampling;Schedule;Site;South Africa;Testing;Trust;Universities;Work;cancer care;low and middle-income countries;meetings;member;operation;programs;success;web site Administrative Core PROJECT NARRATIVE: ADMINISTRATIVE COREThis application responds to RFA-CA-20-001 and will establish a HIV-Associated Malignancy Research Centerin the U.S. and Low- and Middle-Income Countries (LMIC) named the UNC-Malawi-South Africa CancerConsortium (UMSACC). This is a collaborative research center between sites in the USA Malawi and SouthAfrica. The Administrative Core will oversee operation coordination management evaluation of projects andcores and collaborations of the consortium. NCI 10679965 9/27/22 16:58 PA-20-272 3U54CA254564-03S1 3 U54 CA 254564 3 S1 "DOMINGUEZ, GERALDINA" 8/13/20 0:00 7/31/25 0:00 ZCA1 9517 6931559 "DAMANIA, BLOSSOM A" Not Applicable 4 Unavailable 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC Domestic Higher Education 275995023 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 Research Centers 2022 125000 99206 25794 ABSTRACT: ADMINISTRATIVE COREThis application responds to RFA-CA-20-001 and will establish a HIV-Associated Malignancy Research Centerin the U.S. and Low- and Middle-Income Countries (LMIC) named the UNC-Malawi-South Africa CancerConsortium (UMSACC). This is a collaborative research center between sites in the USA Malawi and SouthAfrica and builds upon strong prior collaborations. The Administrative Core is led by a team of leaders whoalso serve as multiple PIs for the overall U54 application. These include Dr. Blossom Damania (USA) Dr. SamPhiri (Malawi) Dr. Paul Ruff (South Africa) Dr. Carla Chibwesha (USA and South Africa) Dr. Yuri Fedoriw(USA) and Dr. Dirk Dittmer (USA). The Administrative Core is supported by strong administrative units at allUMSACC participating institutions in the USA Malawi and South Africa.The Administrative Core will coordinate and manage the individual components including projects and coresof the consortium. The Administrative Core will assist with operational and budgetary aspects includingsubmission of progress reports communication among consortium partners local stakeholders and the NCI.The Administrative Core will initiate and conduct activities that enhance collaborations among partners in theUSA Malawi and South Africa as well as partners and consortia in other sub-Saharan African countries.These activities will focus on research and training related to HIV-associated malignancies at UNC Chapel HillUSA; Lighthouse Trust Malawi; UNC Project-Malawi; Kamuzu Central Hospital Malawi; University ofWitwatersrand South Africa; and Stellenbosch University South Africa. The Administrative Core will alsoassemble an External Advisory Board and a Scientific Advisory Board and coordinate UMSACC participationin annual NCI consortia Meetings. Thus in summary the Administrative Core will oversee operationcoordination management evaluation of projects and cores and collaborations of the consortium. +No NIH Category available Address;Affect;Age;Behavior;Biological Markers;Cessation of life;Characteristics;Cigarette;Cigarette Smoker;Data;Data Analyses;Data Set;Dependence;Development;Disease;Economic Burden;Electronic cigarette;Environmental Risk Factor;Exposure to;Goals;Grant;Harm Reduction;Health;Health Care Costs;Human;Intervention;Knowledge;Lead;Longitudinal Studies;Measurable;Methods;Mission;Modeling;Modified Risk Tobacco Product;Morbidity - disease rate;Nicotine;Outcome;Perception;Population Assessment of Tobacco and Health;Public Health;Race;Recording of previous events;Regulation;Relapse;Research;Research Priority;Risk;Smoke;Smokeless Tobacco;Smoker;Smoking;Smoking History;Tobacco;Tobacco use;United States National Institutes of Health;cigarette smoking;design;economic cost;health economics;health warning;heated tobacco products;innovation;interest;mortality;nicotine replacement;polytobacco use;sex;smoking cessation;snus;sociodemographics;tobacco products;tobacco user Personal Factors Product Characteristics and Changes in Biomarkers of Exposure Among Cigarette Smokers Who Switch to Noncombustible Tobacco Products The proposed research is relevant to public health because it will identify characteristics of smokers that areswitching to noncombustible products which product characteristics facilitate switching and whether switchingresults in meaningful improvements to health. These data will provide information about tobacco users who aretransitioning away from the most harmful tobacco product and thus may aid development of targetedinterventions and inform product regulations that will impact public health. This project is consistent with NIHsmission by generating data about behavior product characteristics and health effects associated with tobaccoproduct transitions with a long-term goal to promote strategies that reduce the health and economic burdensassociated with cigarette smoking. NCI 10679940 9/7/22 0:00 PA-21-268 7R21CA268198-02 7 R21 CA 268198 2 "RODITIS, MARIA LEIA" 9/20/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-PSE-G(55)] 14622345 "FELICIONE, NICHOLAS JOHN" Not Applicable 26 PUBLIC HEALTH & PREV MEDICINE 38633251 LMCJKRFW5R81 38633251 LMCJKRFW5R81 US 43.003074 -78.785924 5992614 STATE UNIVERSITY OF NEW YORK AT BUFFALO AMHERST NY SCH ALLIED HEALTH PROFESSIONS 142282567 UNITED STATES N 9/1/22 0:00 8/31/24 0:00 77 Non-SBIR/STTR 2022 258774 OD 185332 73442 Cigarettes are the leading preventable cause of morbidity and mortality in the US and though quitting is theoptimal method to reduce smoking-related harms most smokers are unable to quit. Smokers who are unableto quit but wish to reduce potential harms of smoking may consider switching to noncombustible tobaccoproducts such as smokeless tobacco or electronic cigarettes. However unintended consequences such asdual use may mitigate the potential of these noncombustible products to reduce smoking -related harms. Thelong-term goal is to reduce the health and economic burden caused by cigarette smoking. The overall objectivein this application is to characterize product transitions among cigarette smokers to evaluate the factorsassociated with transitioning to noncombustibles and assess the potential of noncombustibles as a harmreduction strategy. The transition model outlines four trajectories that a smoker may follow continuedsmoking (least optimal outcome) complete cessation (most optimal outcome) exclusive noncomb ustible use(possible harm reduction) or dual/poly tobacco use (unlikely to be harm reduction). These trajectories will beevaluated through a secondary data analysis using the Population Assessment of Tobacco and Health Study a longitudinal nationally representative dataset on tobacco use behaviors and health. This project fills a gap bydefining who is switching to noncombustible products which products and features may lead them tosuccessfully switch and how their health and exposure to biomarkers changes as a result of switchingproducts. Aim 1 is to identify personal characteristics associated with switching from cigarettes tononcombustibles focusing on sociodemographic characteristics smoking history harm perceptions andexposure to messaging. Aim 2 is to characterize product characteristics associated with switching fromcigarettes to noncombustibles focusing both on cigarette characteristics and noncombustible characteristics(e.g. flavor nicotine content) that facilitate switching. Aim 3 is to examine health outcomes and exposurebiomarkers in smokers that have switched to noncombustible products to determine if these transitions resultin meaningful improvements to health. This project is responsive to FDA Center for Tobacco Products researchpriorities relating to behavior and health effects such as the impact of product characteristics on tobacco usebehaviors and human health. This project is innovative because it includes comprehensive assessment offactors associated with switching to noncombustibles using a large nationally representative dataset. Thisproject is impactful because it will evaluate the utility of noncombustibles as a harm reduction strategy.Successful completion of this project will generate data on potential targets for intervention and productregulation that can benefit public health by reducing the immense societal health and economic costsassociated with cigarette smoking. 258774 +No NIH Category available Adenosine;Behavior;Biology;Brain;CRISPR/Cas technology;Cancer Biology;Cancer Etiology;Cancer Patient;Cell Line;Cells;Cephalic;Cessation of life;Characteristics;Chromosomal Instability;Chromosome Arm;Chromosome Segregation;Chronic;Coupled;Cytosol;DNA;Data Set;Databases;Development;Disease;Drug resistance;Environment;Evolution;Failure;Future;GENIE;Generations;Genetic;Genetic Engineering;Goals;Human;Image;Immune Evasion;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In Situ;In Vitro;Injections;Interferon Type I;Investigation;KRASG12D;Label;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Mentors;Metastatic malignant neoplasm to brain;Methods;Mitosis;Modeling;Molecular;Mus;Mutate;Mutation;NF-kappa B;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Output;Pathway interactions;Phosphotransferases;Physicians;Primary Neoplasm;Process;Production;Proteins;Recycling;Research;Resistance;Risk;Role;Rupture;STK11 gene;Scientist;Signal Transduction;Stimulator of Interferon Genes;Surface;System;TP53 gene;Tail;Testing;The Cancer Genome Atlas;Tissues;Tumor Escape;Tumor Promotion;Tumor Subtype;Universities;Up-Regulation;Validation;Veins;Work;blood-brain barrier permeabilization;cancer cell;cancer type;career;chromosome loss;combinatorial;ds-DNA;ecto-nucleotidase;experimental study;genome sequencing;genomic data;immune checkpoint blockade;immunoregulation;in vivo;melanoma;micronucleus;mouse model;multimodality;mutant;neoplastic cell;refractory cancer;response;spatiotemporal;therapeutic development;transcriptomics;tumor;tumor behavior;tumor microenvironment;tumor progression;tumor-immune system interactions Chromosomal instability as a driver of non-small cell lung cancer immune evasion and brain metastasis PROJECT NARRATIVEBrain metastasis (BM) frequently arises from non-small cell lung cancer (NSCLC) and represents the mostcommon cause of cancer related death in the US yet our understanding of BM biology is rudimentary. Ourgroup has identified excessive chromosomal instability (CIN) as a hallmark of BM and as a putativecharacteristic of NSCLCs harboring mutation in STK11 (encoding LKB1) a subtype of lung cancer associatedwith increased risk of brain metastasis (BM) and immunotherapy resistance and thus a relevant archetypicaldisease that may broadly inform the role of CIN in BM biology. This proposal seeks to identify tumor-cellintrinsic and extrinsic adaptations to CIN that enables immune evasion and BM in LKB1-deficient NSCLCs;because CIN is pervasive in cancer and particularly high in brain-metastatic lesions across different cancertypes this work will have implications for our broader understanding of BM biology and pave the way for futuretherapeutic development of CINhigh tumors. NCI 10679841 5/3/23 0:00 PA-21-049 1F30CA281104-01 1 F30 CA 281104 1 "BIAN, YANSONG" 7/1/23 0:00 6/30/28 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16529522 "CAPRIO, LINDSAY ANNE" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARY/ABSTRACTBrain metastasis (BM) frequently arises from non-small cell lung cancer (NSCLC) and represents the mostcommon cause of cancer related death in the US yet our understanding of BM biology is rudimentary. Our grouphas recently identified excessive chromosomal instability (CIN) as a hallmark of BM19. In in vitro studies inaddition to validation in multiple independent NSCLC patient datasets (TCGA GENIE CCLE and CPTAC)detailed in this proposal we have identified CIN as a hallmark of NSCLCs harboring mutations in STK11(encoding LKB1). LKB1-deficient NSCLCs are an aggressive tumor subtype associated with increased risk ofBM and immunotherapy resistance and thus serves as a relevant archetypical disease that may broadly informthe role of CIN in BM biology and cancer immune evasion. CIN arises from failures in correct chromosomesegregation during mitosis leading to perpetual gains and losses of chromosome arms and the creation ofrupture-prone micronuclei. Upon rupture these micronuclei expose DNA to the cytosol activating cGAS-STINGsignaling. This would seemingly present a conundrum for CINhigh cancers as prototypical outputs of cGAS-STING activation promote anti-tumor type I interferon (IFN) responses. However it has been recently shownthat chronic cGAS-STING signaling characteristic of CINhigh tumors promotes metastatic non-canonical NF-kBoutput in addition to immune-evasive adenosine generation in the tumor microenvironment the latteraccomplished through adaptive increases in cGAMP export and upregulation of surface ectonucleotidasesENPP1 and NT5E. In addition to its ability to promote immunosuppression adenosine also permeabilizes theblood brain barrier and thus may potentially mechanistically link BM to CIN. This proposal seeks to understandhow cancer cell adaptations to CIN enable BM and immune evasion namely through investigation of tonicactivation of cGAS-STING signaling. In Aim 1 I propose to delineate the respective contributions of CIN andLKB1 loss per se to metastatic behavior and immunotherapy resistance in vivo. In Aim 2 I will perform spatio-temporal resolved in vivo studies to delineate CIN-intrinsic (i.e. STING signaling) and -extrinsic (e.g. adenosinegeneration) interactions that enable immune evasion and BM. Through generation of genetic perturbations inLKB1-deficient and WT models I will investigate whether chronic cGAMP-triggered STING recycling is ahallmark of CINhigh LKB1-deficient NSCLC that favors immune-evasive tumor behavior and establishment of BM.Together these aims offer unparalleled study of interactions critical for the establishment of the brain metastaticniche and will pave the way for therapeutic development of malignant treatment-resistant CINhigh tumors. Withthe guidance from exceptional mentors and collaborators and access to the unparalleled scientific researchenvironment at Columbia University Irving Medical Center this project will prepare me for a successful careeras a physician-scientist in the field of cancer biology. 47694 +No NIH Category available Address;Affect;Alanine;Apoptosis;Biochemical;Cancer Biology;Cancer Etiology;Cell Culture Techniques;Cell Death;Cell Death Induction;Cells;Cessation of life;Chemoresistance;Clinic;Clinical Research;Collaborations;Combination Drug Therapy;Culture Techniques;Cysteine;Cysteine Metabolism Pathway;Cystine;Cytolysis;Dependence;Diagnosis;Diffuse;Disease;Drops;Equilibrium;Event;Exhibits;Extracellular Matrix;Future;Genetic;Glutathione;Goals;Growth;Human Cell Line;Immune;Immunotherapy;In Vitro;Individual;Iron;Link;Lipid Peroxides;Literature;Malignant Neoplasms;Malignant neoplasm of pancreas;Membrane;Metabolic;Metabolism;Michigan;Modeling;Mouse Cell Line;Mus;Nature;Osmolar Concentration;Osmosis;Osmotic Pressure;Oxidation-Reduction;Oxidative Stress;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Proline;Publications;Regulation;Research;Resistance;Resources;Role;Scheme;Signal Transduction;Stress;Survival Rate;System;Taurine;Testing;Therapeutic;United States;Universities;cancer cell;cell type;combat;density;experience;extracellular;in vivo;insight;interest;metabolomics;monolayer;mortality;novel therapeutic intervention;pancreatic cancer cells;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;pharmacologic;pressure;programs;response;scale up;therapeutic target;therapy resistant;three dimensional cell culture;treatment strategy;tumor Defining cell intrinsic and extrinsic regulators of ferroptosis in pancreatic cancer Project NarrativeInducing selective cell death in tumors lies at the core of ongoing research in pancreatic cancer. This proposalseeks to trigger pancreatic cancer cells for ferroptosis a form of cell death independent from apoptosis and inculture pancreatic cancer cells exhibit a native sensitivity to ferroptosis while they exhibit mechanisms ofintrinsic and adaptive resistance in vivo. This proposal will identify the factors that permit potent ferroptotic celldeath in vitro so as to deploy these in pancreatic tumors. NCI 10679812 5/2/23 0:00 PA-21-051 1F31CA281241-01 1 F31 CA 281241 1 "SCHMIDT, MICHAEL K" 5/2/23 0:00 5/1/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 78672585 "GIZA, HEATHER MARIE" Not Applicable 6 PHYSIOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 5/2/23 0:00 5/1/24 0:00 398 "Training, Individual" 2023 40819 NCI 40819 0 Project Summary Pancreatic cancer most commonly diagnosed as pancreatic ductal adenocarcinoma (PDAC) isamongst the top three leading causes of cancer death in the United States. These tumors are notoriouslyresistant to apoptosis and richly populated by stromal and immune cells that create a therapy-resistantmicroenvironment. Immunotherapy shows no benefit to patient survival and despite advances in combinationalchemotherapy the 5-year survival rate sits around 11%. Therefore investigating alternative forms of cell deathrepresents a unique strategy for targeting PDAC. Ferroptosis is a recently described form of cell death distinctfrom apoptosis. It is dependent on an accumulation of lipid peroxides generated by free labile iron resulting inosmotic cell lysis. Targeting ferroptosis can potently induce cell death in cultured PDAC cells. Yet in PDACtumors in mice triggering ferroptosis has a modest response with distinct cases of intrinsic and acquiredresistance currently limiting its therapeutic utility. It is therefore urgent that we address the gap between the invitro and in vivo responses for future clinical studies. In pursuit of this I am taking a reductionist approach todistill the mechanisms that regulate ferroptosis by osmotic and reductive-oxidative (redox) forces.Mechanistically it is known that ferroptosis requires osmotic pressure to induce cell lysis but this fact is notwell studied within the current growing literature on ferroptosis in cancer. We hypothesize that cell death viaferroptosis requires an imbalance of redox metabolism and sufficient osmotic pressure to which PDAC cellsare particularly vulnerable. AIM I studies the biochemical dependencies between osmolarity and redoxmetabolism. AIM II distinguishes changes in the external osmotic pressure from the cellular biochemicaladaptations scaling up from monolayer to 3D culture techniques. Together these aims investigate whetherferroptotic cell death can be simplified to a balance of redox and osmotic pressure. The overall goals of thisstudy are to outline the boundary of these parameters and explore their application for targeting ferroptosis inPDAC. 40819 +No NIH Category available Ablation;Acute Myelocytic Leukemia;Address;Affect;Allogenic;American;Antibodies;Antibody Therapy;Antigen Targeting;Antigens;Automobile Driving;B lymphoid malignancy;Bispecific Antibodies;Blood;Bone Marrow;Bone Marrow Purging;Cell Therapy;Cell secretion;Cells;Cessation of life;Data;Development;Disease;Drug resistance;Elements;Engineering;Face;Future;Genetic Transcription;Goals;Hematologic Neoplasms;Hematology;Hematopoietic Neoplasms;Heterogeneity;Home;Homing;IL3RA gene;Immune system;Immunotherapy;In Vitro;Malignant Neoplasms;Marrow;Measurable;Myeloid Cells;Myelosuppression;Neoadjuvant Therapy;Normal Cell;Patients;Pharmacy facility;Physicians;Population;Positioning Attribute;Relapse;Reporter;Research;Residual Neoplasm;Residual state;Resistance;Risk;Scientist;Stem cell transplant;Surface;Surface Antigens;Survival Rate;Synthetic immunology;System;T cell therapy;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic Index;Toxic effect;Training;Work;Xenograft Model;acute myeloid leukemia cell;antibody engineering;antibody immunotherapy;cellular engineering;chemotherapy;chimeric antigen receptor T cells;cytokine release syndrome;design;engineered T cells;experience;experimental study;feasibility testing;in vivo;in vivo Model;innovation;leukemic stem cell;mouse model;neoplastic cell;next generation;novel strategies;novel therapeutic intervention;patient derived xenograft model;relapse prediction;small molecule;stem cell niche;success;systemic toxicity;targeted treatment;therapeutic protein;therapeutic target;therapeutically effective;tumor;tumor heterogeneity Multi-functional cellular therapies to overcome tumor heterogeneity and limit toxicity in acute myeloid leukemia PROJECT NARRATIVEAcute myeloid leukemia (AML) is among the deadliest blood cancers affecting 20000 Americans peryear with a 5-year survival rate of only 30%. While engineering cells of the immune system to targetcancer is one of the most promising approaches in treatment today this approach has been difficultto apply in AML due both to lack of specific targets on tumor cells as well as the fact that many tumorcells may not express a single targeted antigen. Here I aim to perform initial development of a newtype of engineered cell that can specifically eliminate the relapse-driving residual tumor cells afterinitial chemotherapy with the long term goal of achieving more AML cures with lower toxicity thancurrent approaches. NCI 10679763 3/10/23 0:00 PA-21-048 1F32CA271812-01A1 1 F32 CA 271812 1 A1 "JAKOWLEW, SONIA B" 9/10/23 0:00 9/9/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 10738081 "KASAP, CORYNN " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/10/23 0:00 8/9/24 0:00 398 "Training, Individual" 2023 82928 NCI 82928 0 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) is a devastating disease with only 30% 5-year overall survival. As a bloodcancer AML appears poised to benefit from the revolution in engineered cellular therapies and bispecificantibodies. These agents are making an enormous impact in B-cell malignancies. However extending thissuccess to AML faces two significant hurdles: 1) lack of highly disease-specific targets where engagingcurrent AML therapeutic targets leads to severe cytokine release syndrome and severe myeloablationprecluding an effective therapeutic index; and 2) significant intratumoral heterogeneity where targeting a singlesurface antigen is likely to lead to antigen-negative relapse. In practice these two challenges leave fewtherapeutic targets sufficient to achieve cures in most patients. Here my long-term goal is to develop a newtherapeutic approach to overcome these hurdles. This proposal will be led by myself under the sponsorship ofDr. Arun Wiita an expert in hematologic malignancies and drug resistance with collaborative support from Dr.Kole Roybal expert in advanced cellular engineering; and Dr. Jim Wells expert in antibody engineering.Specifically I hypothesize that employing SNIPR the newly-described next-generation humanized platformbased on the SynNotch cellular engineering technology (Zhu et al. Cell 2022) will enable development of amulti-functional T-cell therapy that can eliminate residual AML after induction chemotherapy clearing relapse-driving leukemic stem cells and increasing cure rates while avoiding toxicities of systemic therapeutics. Mymajor design pillars include 1) develop engineered T-cells that home specifically to the leukemic stem cellniche; and 2) locally but not systemically have SNIPR T-cells secrete multiple protein therapeutics to ablateheterogenous leukemic stem cells and AML blasts in and near this niche. In Specific Aim 1 I test the feasibilityand initial in vitro and in vivo potency of SNIPR engineered T-cells designed to simultaneously secretefunctional bispecific antibodies against 3 AML targets. In Specific Aim 2 I use PDX models to test whetherSNIPR T-cells can selectively home to the bone marrow niche with CD70 as the optimal leukemic stem celltrigger. Successful completion of these Aims will set the stage for subsequent work outside the scope of thisproposal to validate using additional in vitro and in vivo models the ability of CD70-sensing multi-bispecific-secreting T-cells to eliminate AML more completely than other therapies while minimizing toxicities.Furthermore this approach will ultimately enable delivery of other therapeutic payloads to the leukemic stemcell niche ideally targeting this disease-driving cellular population with unprecedented precision. Success heremay also outline a new therapeutic strategy for use across cancers to eliminate heterogeneous tumor in themicroenvironment while sparing normal cells. Completion of the work in this proposal in conjunction with theassociated training plan will provide critical expertise and experience to support my goal of becoming anindependent physician-scientist focused on translational immunotherapy research. 82928 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; HIV/AIDS Cancer Trials Support Unit;Contractor;Contracts;Procedures;Recommendation;Reporting;Services;Standardization;Summary Reports;System;Work;base;meetings;programs;symposium TASK ORDER 1A: PROJECT KICK-OFF MEETING AND TASK ORDER 2A: CTSU CORE SUPPORT SERVICES & THE CTSU ENTERPRISE OF SYSTEMS; CANCER TRIALS SUPPORT UNIT (CT n/a NCI 10679729 75N91022D00009-0-759102200001-1 N01 8/1/22 0:00 7/31/23 0:00 78788334 "HERING, MARTHA " Not Applicable 8 Unavailable 49508120 NVUWAFWQ57S5 49508120 NVUWAFWQ57S5 US 39.094626 -77.181453 9611701 "WESTAT, INC." ROCKVILLE MD Domestic For-Profits 208503129 UNITED STATES N R and D Contracts 2022 12099432 NCI The contractor will attend a Kick-off Programmatic Meeting by conference call with the Contracting Officers Representative (COR) Contracting Officer (CO) and other Program and Office of Acquisition Staff where the Contractor shall provide a presentation and participate in discussion of best practices and other standardized procedures that will be used under all Task Orders for the Base Statement of Work as well as discussion of potential expansion or improvement of the CTSU program.The contractor will also submit a Meeting Summary Report that includes the Contractors recommendations for best practices potential expansion and improvement of the CTSU Program. The report shall also include a summary of the Programmatic Meeting. 12099432 +No NIH Category available Address;Bar Codes;Biochemical;Biological;Camptothecin;Cancer cell line;Cell Survival;Cells;Chemicals;Chemoresistance;Chronic;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Colon Carcinoma;Combined Modality Therapy;DNA;DNA Damage;DNA Repair;DNA biosynthesis;Data;Dissection;Drug Synergism;Drug Targeting;Event;Excision;Exhibits;Generations;Genes;Genetic;Genomic Instability;HCT116 Cells;Human;Hybrids;Intelligence;Knowledge;Libraries;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Molecular;Molecular Profiling;Monitor;Mutate;Oncogenes;Outcome;Pharmaceutical Preparations;Pharmacotherapy;Phosphorylation;Phosphotransferases;Play;Poison;Poly(ADP-ribose) Polymerase Inhibitor;Predisposition;Process;Proteins;RNA;RNA Processing;Regulation;Replication-Associated Process;Resistance;Resolution;Role;Signal Induction;Signal Transduction;Source;Structure;Synthetic Peptide Libraries;System;Techniques;Therapeutic;Topoisomerase;Work;cancer cell;cancer therapy;cancer type;cell type;chemotherapeutic agent;chemotherapy;clinically relevant;ds-DNA;experimental study;genotoxicity;inhibitor;insight;novel;nuclease;overexpression;phosphoproteomics;refractory cancer;replication stress;response;ribonuclease H1;scale up;sensor;stressor;synergism;therapy outcome Uncovering ATR signaling networks underlying chemotherapeutic synergies PROJECT NARRATIVECancer cells rely on the DNA damage sensor kinase ATR to tolerate chemotherapy-induced replication stress.The use of ATR inhibitors in combination with chemical stressors of the DNA replication process has revealedstrong therapeutic synergies but the mechanisms behind these synergies are unclear due to the complexity ofthe ATR signaling response. By mapping and barcoding cancer- and drug-specific ATR signaling responsesusing unbiased mass spectrometry techniques this work will compare molecular signatures and respectivecellular outcomes to identify potential mechanisms of clinically relevant chemotherapeutic synergies. NCI 10679717 5/3/23 0:00 PA-21-051 1F31CA281247-01 1 F31 CA 281247 1 "ODEH, HANA M" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16120494 "COMSTOCK, WILLIAM " Not Applicable 19 MISCELLANEOUS 872612445 G56PUALJ3KT5 872612445 CCV3WG2JG248; D4H1NV4APKP3; ELS2M3C6V2S5; EQA8NBEN9WD5; FFAZGE9NH3M8; G56PUALJ3KT5; K6JRCJJXFET1; M8FBSLHASMT3; P4LRVQT1H4K5; PJUVN8AT5416; RT1JPM9UMGM5; ZBMGUAZYFGC4; ZMP8BDLJTUW9 US 42.438 -76.4625 1514802 CORNELL UNIVERSITY ITHACA NY ORGANIZED RESEARCH UNITS 148502820 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 44174 NCI 44174 0 PROJECT SUMMARY/ABSTRACTThe DNA damage sensor kinase ATR is essential for human cell viability and plays a crucial role in cell toleranceto DNA replication stress13. Cancer cells often feature elevated levels of replication stress due to oncogeneaction and are therefore susceptible to inhibitors of ATR making ATR a prime target in anti-cancer therapies47.While ATR inhibitors have been shown to be particularly effective in combination with replication stress-inducingagents the molecular mechanisms behind these drug synergies remain poorly understood primarily due to thesheer complexity of the ATR signaling network5811. To uncover the signaling events that underlie thesetherapeutic synergies I will utilize mass spectrometry to perform both unbiased and targeted phosphoproteomicscreens in cancer cells lines treated with different chemotherapeutic agents shown to synergize with ATRinhibitors. Pilot unbiased screens I conducted in HCT116 cancer cells have begun to identify and quantify ATRsignaling in response to chemotherapies CPT and Olaparib allowing each response to be barcoded for directcomparison. Comparing pilot barcodes revealed dramatic differences in ATR signaling induced by each drugalso raising questions regarding whether such ATR signaling varies further between cancers resistant to thesechemotherapies812. Moreover when investigating CPT-induced ATR signaling we uncovered a set of non-canonical signaling events that are independent of DNA resection a process required for the activation ofcanonical ATR signaling113. These non-canonical signaling substrates include proteins involved in the dissolutionof R-loops: DNA:RNA hybrids that increase in abundance upon CPT treatment and contribute to genomeinstability1416. Faced with these data I hypothesize that ATR signaling varies between drug treatmentsand cancer cell types and that non-canonical ATR signaling contributes to CPT resistance via regulationof DNA:RNA hybrid processing. I aim to expand signaling barcodes for CPT and Olaparib-induced ATRresponses several fold via scaled up phosphoproteomic screens curating a synthetic peptide library from eventsuncovered. This library will enable high-throughput targeted barcoding of ATR signaling responses acrosscancers differentially resistant to CPT Olaparib and ATR inhibitor combination therapy allowing for correlationof chemotherapy resistance with cancer-specific ATR signaling. I also aim to investigate the role of novelresection-independent ATR signaling events in cancer resistance to CPT by using genetic biochemical and cellbiological techniques. Overall results will delineate drug- and cancer-specific ATR responses and establish thecontribution of a new mode of ATR signaling to chemotherapy outcomes. Generated knowledge will serve as aframework for systems-wide dissection of the mechanisms underlying ATR inhibitor chemotherapeutic synergiesand resistances potentially revealing drug targets and opportunities for more selective combination therapies. 44174 +No NIH Category available ATR gene;Acceleration;Alleles;Apical;Automobile Driving;Award;Cancer Biology;Cancer Etiology;Cell Cycle;Cell Cycle Arrest;Cells;Cessation of life;Chromosome Segregation;Clinic;Clinical;Communication;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;Data;Defect;Development;Disease;Disease Progression;Drug resistance;Educational process of instructing;Engineering;Ensure;Exhibits;Failure;Fluorescence Resonance Energy Transfer;Funding;Genome Stability;Genomic Instability;Goals;Institution;Interphase;Label;Laboratories;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Mentors;Mitosis;Mitotic;Mitotic Chromosome;Molecular;Mutation;Neoplasm Metastasis;PLK1 gene;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Phosphotransferases;Polynucleotide 5'-Hydroxyl-Kinase;Population;Positioning Attribute;Predisposition;Proteins;Regulation;Research;Research Personnel;Role;Running;Science;Signal Transduction;Survival Rate;Testing;Therapeutic;Tissues;Training;Treatment Protocols;Unresectable;Work;Writing;analog;cancer cell;cancer genome;cancer therapy;career;career development;chemotherapy;chromosome missegregation;effective therapy;experimental study;gemcitabine;genome integrity;in vitro activity;inhibitor;insight;live cell imaging;loss of function;loss of function mutation;member;mortality;mouse model;novel;novel marker;novel therapeutics;pancreatic ductal adenocarcinoma cell;patient prognosis;pharmacologic;prevent;repaired;research faculty;response;sensor;skill acquisition;targeted treatment;therapeutic target;therapy resistant;tumor Defining the Mitotic Role of Chk2 for the Treatment of Pancreatic Cancer PROJECT NARRATIVEGenome instability is a hallmark of many cancers that both initiates and accelerates disease development. Mypreliminary data demonstrate that Chk2 an important DNA damage response kinase protects against genomeinstability through a novel and mitosis-specific pathway that ensures proper chromosome segregation. Workproposed here will provide molecular insight into this mitotic Chk2-driven pathway including its regulationmolecular substrates and potential utility as a pharmacological target in pancreatic cancer. NCI 10679609 3/6/23 0:00 PA-21-051 1F31CA275096-01A1 1 F31 CA 275096 1 A1 "ODEH, HANA M" 4/1/23 0:00 3/31/25 0:00 Special Emphasis Panel[ZRG1-F05-Q(20)L] 16489172 "BLACK, ELIZABETH MAUREEN" Not Applicable 3 BIOCHEMISTRY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 398 "Training, Individual" 2023 35293 NCI 35293 0 PROJECT SUMMARYGenome instability (GIN) is a hallmark of cancer and a leading cause of therapeutic resistance. This is especiallytrue for pancreatic ductal adenocarcinoma (PDAC) where an estimated 95% of PDAC cells exhibit GIN. GIN ischaracterized by both a failure to accurately repair DNA in interphase and high rates of chromosome mis-segregation in mitosis. It is not fully understood how these pathways work in concert throughout the cell cycle todefend against GIN. Our previous work has demonstrated a link between the DNA damage response (DDR)protein ATR and the mitotic machinery in promoting faithful chromosome segregation. This observation hasprompted me to hypothesize that other components of the DDR promote faithful chromosomesegregation and genome stability.My preliminary work has elucidated a novel mitotic function for Chk2 an important DDR kinase that is activatedfollowing DNA double-stranded breaks. I have shown that Chk2 is active in a DNA damage-independent mannerin mitosis. Moreover I have demonstrated that Chk2 promotes proper activity of the major mitotic kinase PLK1.In this application I propose to investigate the mechanism by which Chk2 promotes faithful chromosomesegregation (Aim 1) determine how Chk2 activity is regulated in mitosis (Aim 2) and use PLK1 inhibition tospecifically target Chk2-deficient cancer cells (Aim 3). My proposed studies will define the mitotic and DNAdamage-independent role for Chk2. This will further our understanding of how the DDR pathway and mitoticmachinery work in concert to promote faithful chromosome segregation and genome stability. Lastlyexperiments from this proposal may develop a targeted therapeutic strategy to specifically kill Chk2-deficientcancers. This is critically important as Chk2 loss-of-function mutations make up a significant portion of familialPDAC cases and Chk2 mutations render cells insensitive to current front-line treatments.My career goal is to obtain a research faculty position at a leading institution where I will dissect the noncanonicaland understudied mechanisms by which DDR proteins promote genome stability. My scientific development willbe bolstered by successful completion of this project including gaining expertise in cancer biology and mousemodels. I will use these acquired skills to investigate whether PLK1 inhibitors can be used to specifically targetChk2-deficient cancer cells. Importantly funding for this application will also enhance my training in sciencecommunication writing teaching mentoring and career development all of which will be essential forsuccessfully running my own laboratory. This project is supported by an outstanding network of sponsors andcollaborators that will ensure this project is successfully completed. Receipt of this award will allow me to expandmy research plan and establish myself as a primary investigator in the field of cancer biology and genomestability. 35293 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Machine Learning and Artificial Intelligence Academic Medical Centers;Address;American College of Surgeons;American College of Surgeons Oncology Group;Artificial Intelligence;Cancer and Leukemia Group B;Clinical Research;Clinical Trials;Collaborations;Community Clinical Oncology Program;Decision Making;Development;Effectiveness;Ensure;Environment;Funding;Goals;Infrastructure;Leadership;Machine Learning;Malignant Neoplasms;North Central Cancer Treatment Group;Oncology;Operative Surgical Procedures;Policies;Positioning Attribute;Principal Investigator;Procedures;Process;Productivity;Readiness;Research;Research Personnel;Research Priority;Structure;System;Time;Translational Research;cancer clinical trial;conflict resolution;design;health care delivery;innovation;meetings;member;operation;organizational structure;programs;response;rural setting;symptom management;urban setting Administrative Core The Project Narrative has been addressed in the Overall Component per the RFA NCI 10679108 9/20/22 14:47 PA-20-272 3U10CA180821-09S4 3 U10 CA 180821 9 S4 "MOONEY, MARGARET M" 4/17/14 0:00 2/28/25 0:00 ZCA1 9462 1879065 "BERTAGNOLLI, MONICA M" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 Other Research-Related 2022 207570 199570 8000 The Project Summary/Abstract has been addressed in the Overall Component per the RFA +No NIH Category available Ablation;Acute;American;Animal Model;Animals;Autophagocytosis;Biochemical;Bioenergetics;Biological;Biological Assay;Biophysics;CRISPR/Cas technology;Calcium;Cancer Patient;Cancer cell line;Cause of Death;Cell Culture Techniques;Cell Line;Cell Survival;Cells;Cellular Metabolic Process;Cessation of life;Citric Acid Cycle;Cytoplasm;Dependence;Development;Diagnosis;Disease;Early Diagnosis;Early identification;Electrophysiology (science);Endoplasmic Reticulum;Fibroblasts;Future;Gel;Genetic;Genetic Models;Growth;Homeostasis;Human;ITPR1 gene;Immune response;In Vitro;Interruption;Invaded;Ion Channel;Life;Luciferases;Maintenance;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mediating;Membrane;Metabolic;Metabolism;Methods;Mitochondria;Modeling;Molecular;Morphology;Mus;NOD/SCID mouse;Neoplasm Metastasis;Normal Cell;Organelles;Oxidoreductase;Oxygen Consumption;Pancreatic Adenocarcinoma;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patient-Focused Outcomes;Patients;Permeability;Pharmaceutical Preparations;Play;Process;Prognosis;Proliferating;Property;Proteins;Regulation;Renal carcinoma;Reporter Genes;Role;Signal Transduction;Site;Survival Rate;System;Tail;Technology;Therapeutic;Veins;Work;advanced disease;anti-cancer;anti-cancer therapeutic;biophysical techniques;calcium uniporter;cancer cell;cancer therapy;cell motility;cell type;designer receptors exclusively activated by designer drugs;epithelial to mesenchymal transition;falls;genetic predictors;genetically modified cells;improved;in vivo;innovation;live cell imaging;malignant breast neoplasm;migration;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;pancreatic cancer patients;pancreatic cell line;pharmacologic;response;targeted treatment;therapeutic target;three-dimensional modeling;tumor;tumor progression;tumorigenesis;tumorigenic;uptake Endoplasmic Reticulum-to-Mitochondria Calcium Transfer in Pancreatic Cancer Development Metastasis and Treatment Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with about 50000 new cases and 45000deaths every year. Whereas new therapeutics have increased the overall survival rate of cancer patients ingeneral these improvements are rarely seen in PDAC emphasizing the need for new therapeutic targets.Because endoplasmic reticulum-to-mitochondria transfer of calcium is required for cancer cell survival wepropose to use animal and cell-culture models to identify the role of this process in the development andmetastasis in pancreatic cancer anticipating that this may lead to treatments that significantly improve patientoutcomes for this highly lethal disease. NCI 10679078 9/7/23 0:00 PA-20-185 5R01CA250173-03 5 R01 CA 250173 3 "WILLIS, KRISTINE AMALEE" 8/15/21 0:00 7/31/26 0:00 Tumor Progression and Metastasis Study Section[TPM] 6321082 "FOSKETT, JAMES KEVIN" Not Applicable 3 PHYSIOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 516066 NCI 317579 198487 Pancreatic adenocarcinoma (PDAC) is a particularly lethal form of cancer that kills over 40000 Americansevery year. PDAC is most often diagnosed when disease is advanced with metastases that lead to death.Patient outcomes are further negatively-impacted by a typical poor response to currently-available treatments.It is thus critical to develop a stronger understanding of the processes which lead to PDAC development andmetastasis as well as to determine novel more-efficacious targets for therapies. Low-level constitutiveendoplasmic reticulum (ER)-to-mitochondria transfer of calcium is required for optimal bioenergetics andcancer-cell survival. We hypothesize that this pathway contributes to pancreatic cancer developmentmetastasis and tumor maintenance and may therefore present a viable anticancer target. The ER-localizedIP3R calcium-release ion channel and the mitochondrial calcium-uniporter ion channel MCU mediate calciumtransfer between the two organelles at membrane-contact sites. However it has been impossible to target thispathway in vivo because of the lack of selective cell-permeable pharmacological agents against these ionchannels. We therefore propose to examine the role of ER-to-mitochondria calcium transfer in PDACdevelopment metastasis and tumor maintenance through the use of novel animal and cell-culture models. Wewill genetically delete MCU during early development in a murine genetic-model of PDAC the KPCY mouse toobserve the role of this protein in tumor development. In addition we will use tumor cells as well as genetically-modified cells using Cre/lox and CRISPR/Cas9 systems as well as patient-derived cell lines and theestablished human PDAC cell line Panc-1. We will assay proliferation cellular bioenergetics oxygenconsumption rates and mitochondrial calcium homeostasis using biochemical cell biological and biophysicalapproaches including electrophysiology live-cell imaging and fluorimetry to define the role of ER-to-mitochondria calcium transfer in these processes. To determine the role of MCU in metastasis we will quantifymetastasis in the KPCY model using the sensitive YFP-reporter gene and we will use an in vivo tail-veinmetastasis model with genetically-modified Panc-1 cells expressing luciferase in NOD/SCID mice as well as invitro transwell-invasion and gel-degradation assays and biochemical and morphological assessment ofmetastasis-associated markers of epithelial-to-mesenchymal transition. To observe the role of ER-to-mitochondria calcium transfer in tumor maintenance and thus its therapeutic potential for more advanceddisease we will use an inducible CRISPR/Cas9 cell-culture model of murine PDAC in vitro and an in vivoinducible orthotopic model to observe the effects of acute MCU ablation in already-growing tumors and cells asa method to simulate profound pharmacological inhibition. These studies will elucidate the role of ER-to-mitochondria calcium transfer in PDAC development metastasis and maintenance and they may informfuture development of novel therapeutic targets in PDAC potentially saving lives. 516066 +No NIH Category available Address;Adrenal Cortex Hormones;Adverse event;Algorithms;Animal Testing;Animals;Antigens;Antitumor Response;B lymphoid malignancy;Biological Markers;Biology;Biometry;Brain Neoplasms;Brain Stem Glioma;Brain Stem Neoplasms;CAR T cell therapy;CD47 gene;Cancer Etiology;Cells;Cessation of life;Characteristics;Child;Childhood;Childhood Brain Neoplasm;Childhood Malignant Brain Tumor;Clinical;Clinical Management;Clinical Research;Coin;Collaborations;Credentialing;Data;Diffuse intrinsic pontine glioma;Disease;Dose;Dose Limiting;Edema;Eligibility Determination;Engineering;Enrollment;Ensure;Event;Exhibits;Ganglioside GD2;Glean;Hematologic Neoplasms;Histones;Human;Hydrocephalus;Image;Immunotherapy;Inflammation;Institution;Intracranial Hypertension;Intracranial Pressure;Machine Learning;Macrophage;Magnetic Resonance Imaging;Malignant Childhood Neoplasm;Malignant Neoplasms;Measures;Mediating;Monitor;Mus;Mutate;Myelogenous;Myeloid Cell Activation;Myeloid Cells;Neuroblastoma;Outcome;Patient-Focused Outcomes;Patients;Pediatric Neoplasm;Phase;Phase I Clinical Trials;Pre-Clinical Model;Progression-Free Survivals;Radiation therapy;Recommendation;Regimen;Reporting;Research Personnel;Risk;Safety;Signal Transduction;Solid Neoplasm;Spinal;Spinal Cord;Standardization;Supportive care;Survival Rate;Swelling;T-Lymphocyte;Testing;Texture;Therapeutic;Toxic effect;Translating;Translations;Treatment Efficacy;Vertebral column;Xenograft Model;aged;antitumor effect;bench to bedside;bench-to-bedside translation;biomarker identification;cancer immunotherapy;cell free DNA;childhood cancer mortality;chimeric antigen receptor;chimeric antigen receptor T cells;clinical efficacy;cohort;cytokine;design;diffuse midline glioma;experience;improved;improved outcome;insight;intravenous administration;machine learning algorithm;mouse model;mutant;neuro-oncology;neurosurgery;neurotoxicity;novel;novel strategies;overexpression;participant enrollment;participant safety;phase I trial;pre-clinical;preclinical study;prevent;radiological imaging;radiomics;resistance mechanism;response;safety assessment;single cell analysis;tool;trial design;tumor;tumor DNA;tumor immunology;young adult Developing Safe and Effective GD2-CAR T Cell Therapy for Diffuse Midline Gliomas PROJECT NARRATIVE:CAR based immunotherapies are now credentialed as potent tools against hematologic malignancies and earlysignals suggest that these therapeutics may prove beneficial against brain tumors. Building upon impressiveresults in preclinical models this project will undertake a Phase I trial of GD2-CAR T cells in H3K27M diffusemidline gliomas universally lethal tumors of childhood and young adults. The project seeks to ensure the safetyof this therapy for patients with brainstem gliomas where the risk of toxicity due to tumor edema is high will usenovel approaches to measure clinical efficacy and seek to define biomarkers or response and will undertakestudies focused on interrogating the biology of myeloid cell activation following CNS directed CAR T celltherapies that has been observed both in preclinical and clinical studies. NCI 10679077 7/31/23 0:00 PAR-18-560 5R01CA263500-03 5 R01 CA 263500 3 "UNDALE, ANITA H" 8/6/21 0:00 7/31/26 0:00 Clinical Oncology Study Section[CONC] 14354500 "MACKALL, CRYSTAL " "MONJE-DEISSEROTH, MICHELLE " 16 PEDIATRICS 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 658390 NCI 430771 227619 PROJECT SUMMARYBrain tumors are the leading cause of cancer related death in children; among these diffuse intrinsic pontineglioma (DIPG) and other histone-3 K27M (H3K27M) mutated diffuse midline gliomas (DMGs) are the mostaggressive and are universally fatal with current standard therapies. Despite several decades of investigationaltrials testing dozens of therapeutic approaches median overall survival for DIPG is 11 months. Chimeric antigenreceptor (CAR)-expressing T-cells have mediated impressive clinical activity in B-cell malignancies and recentpreclinical and early clinical results suggest benefit in CNS malignancies. We discovered homogenous highoverexpression of the GD2 ganglioside on H3K27M DMGs and demonstrated impressive antitumor effects inxenograft models of H3K27M-mutant DIPG following treatment with GD2-CAR T cells (GD2-CART Mount NatMed 2018). Significant clinical experience with GD2 targeting CAR T cells available mostly from studies inneuroblastoma demonstrate safety and some early signals of antitumor activity. Safe and effective translationof these findings to children with DMGs would transform the landscape for this universally lethal pediatric braintumor. This bench-to-bedside-to-bench project will conduct three aims in parallel leveraging a recently launchedsingle institution Phase I trial of GD2.BB.z.iCasp9-CAR T cells administered intravenously following alymphodepleting preparative regimen in children and young adults with H3K27M DMGs. The first aim focuseson safety integrating insights gleaned in our preclinical models into trial design to diminish the risk of tumorinflammation associated neurotoxicity (TIAN) to establish best practices and to develop improved grading andtreatment algorithms for this novel toxicity. The second aim focuses on efficacy assessing clinical activity ofGD2-CART in DMG and identifying biomarkers and clinical features associated with response. We furtheraddress the limitations of standard radiographic imaging in these infiltrative tumors using a novel machinelearning aided MRI radiomics approach to quantify textural changes within the tumor and assess whether suchchanges correlate with clinical outcome and we assess whether GD2-CART induced changes in CSF cell freeDNA can provide a rapid quantitative assessment of antitumor response. Our third aim is a discovery aimfocused on improving understanding of the biology associated with myeloid cell activation following GD2-CARTtherapy for DMGs which we observe in preclinical models and we observed in the first patient treated. Here weundertake comprehensive single cell profiling of CSF myeloid cells emerging post-GD2-CART in patientsenrolled on the study and in preclinical models and bedside-to-bench translation using murine models to testthe hypotheses that GD2-CART induced CNS myeloid cell expansion/activation limit the efficacy of GD2-CARTare modulated by corticosteroid therapy and that this obstacle can be overcome by engineering CD47overexpression in the GD2-CART. 658390 +No NIH Category available Acute;Address;Affinity;Area;Biopsy;Cancer Patient;Cessation of life;Chest;Chest imaging;Chronic;Clinical;Collagen;Collagen Type I;Cyclic GMP;DNA Damage;Diagnosis;Disease;Disease Progression;Dose;Early Diagnosis;Early treatment;Etiology;Exclusion;Exposure to;Fibrosis;Formulation;Free Radicals;General Hospitals;High Resolution Computed Tomography;Hospitalization;Image;Infection;Inflammation;Inflammatory Response;Injury;Investigational New Drug Application;Ionizing radiation;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Massachusetts;Medical;Morbidity - disease rate;Non-Small-Cell Lung Carcinoma;Patient imaging;Patients;Phase;Positron-Emission Tomography;Production;Pulmonary Edema;Pulmonary Fibrosis;Pulmonary Inflammation;Pulmonary function tests;Radiation;Radiation Injuries;Radiation therapy;Recording of previous events;Recurrence;Scanning;Schedule;Severities;Signal Transduction;Source;Specificity;Sterility;Structure of parenchyma of lung;Symptoms;Testing;Time;Tissues;cGMP production;cancer radiation therapy;experience;follow-up;idiopathic pulmonary fibrosis;imaging approach;imaging study;manufacturing process;molecular imaging;mortality;radiation-induced lung injury;side effect;standard of care;surveillance imaging;targeted imaging;tissue injury;tool;uptake PET imaging of radiation induced lung injury Project NarrativeRadiation therapy is the standard of care for inoperable non-small cell lung cancer and confers a significantsurvival benefit. Unfortunately an important side effect of radiation therapy is Radiation Induced Lung Injury(RILI). This project employs a collagen-targeted PET probe to accurately quantify the severity and distribution ofRILI and repeatedly assess disease activity and progression in cancer patients. NCI 10679068 5/31/23 0:00 PA-19-273 5R44CA250771-03 5 R44 CA 250771 3 "EVANS, GREGORY" 5/4/20 0:00 5/31/24 0:00 Special Emphasis Panel[ZRG1-SBIB-T(10)B] 11329405 "HUMBLET, VALERIE " Not Applicable 5 Unavailable 967097218 GJLBDQT8K757 967097218 GJLBDQT8K757 US 42.392805 -71.168546 10028861 "COLLAGEN MEDICAL, LLC" BELMONT MA Domestic For-Profits 24783006 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 SBIR/STTR 2023 805334 NCI 609035 143614 Project SummaryWith 2.1 million new cases in 2018 and 1.8 million deaths lung cancer is the most common cancer in the world.Radiation therapy is the standard of care for inoperable non-small cell lung cancer and confers a significantsurvival benefit. Unfortunately an important side effect of radiation therapy for cancer is Radiation Induced LungInjury (RILI) - the direct tissue injury due to DNA damage and free radical injury as well as the subsequentinflammatory response caused by exposure of the lungs to ionizing radiation. 50-76% of patients undergoingradiation therapy for lung cancer each year develop some form of radiation injury as seen on surveillanceimaging. Not only is RILI a significant source of morbidity and mortality but the lungs sensitivity to radiationlimits the amount of radiation which can be given to treat cancer. RILI can be divided into two phases: 1) Acutepneumonitis (1-6 months post-radiation) causing lung inflammation and edema which may require hospitalizationand rarely is fatal. 2) Chronic fibrosis phase (months to years post radiation) during which smolderinginflammation causes fibrotic tissue to replace normal lung tissue and results in significant morbidity. CurrentlyRILI diagnosis is based on clinical history symptoms lung function tests and chest imaging. RILI is typically adiagnosis of exclusion after recurrent malignancy and infection have been ruled out and rarely may require aninvasive lung tissue biopsy to exclude alternative etiologies. At best we can use the current tools to diagnosethe presence of RILI but we are unable to: 1) accurately quantify the severity and distribution of RILI 2)repeatedly assess disease activity and progression. This proposal aims to addresses these unmet needs throughnon-invasive molecular imaging of type 1 collagen which is prevalent in active fibrotic disease such as RILI.We hypothesize that a newly developed positron emission tomography probe 68Ga-CBP8 targeted to type Icollagen will enable earlier detection and accurate quantification of RILI. We further hypothesize that the use ofthis new targeted imaging approach will allow to better predict disease progression and thus ultimately help toidentify which patients may benefit from early treatment. The affinity and specificity of 68Ga-CPB8 for type 1collagen are well established and we have clinical experience with this agent in the imaging of idiopathicpulmonary fibrosis. Here for the first time we propose to use the agent to image radiation-induced lung injury.The proposal is divided into two phases. First we aim to establish that 68Ga-CPB8 specifically accumulates inregions of RILI and can be imaged with PET. Subjects that underwent radiation therapy for lung cancer and areknown to have RILI will be imaged in this proof-of-concept aim and results will be compared to high-resolutioncomputed tomography (HRTC) images. We will conduct this study under a current IND held at MassachusettsGeneral Hospital. In Phase 2 Collagen Medical will obtain its own IND to conduct a larger study where patientswill be scanned prior to radiation therapy than followed up early when conventional HRTC imaging is notaccurate. We also aim to demonstrate that PET imaging can predict disease progression after exposure toradiation in the chest area. 805334 +No NIH Category available Address;Adjuvant;Antibody Therapy;Arthritis;CD8-Positive T-Lymphocytes;Cancer Patient;Chronic;Clinical Management;Clinical Oncology;Clinical Research;Colitis;Colon;Combination immunotherapy;Data;Development;Distant;Engineering;Foundations;Future;Generations;Genetic;Genetic Engineering;Genetic Variation;Heat-Shock Proteins 70;Human;IL8RB gene;Immune;Immune checkpoint inhibitor;Immune response;Immunooncology;Immunotherapeutic agent;Immunotherapy;Incidence;Individual;Inflammasome;Inflammatory;Innate Immune System;Institutional Review Boards;Investigation;Knock-out;Lamina Propria;Link;Lung;Mediating;Modality;Modeling;Mus;Mutation;Neutrophil Infiltration;Nivolumab;Organ;Outcome;PD-1 blockade;Pathogenesis;Pathology;Pathway interactions;Patients;Plasma;Prediction of Response to Therapy;Prevalence;Protocols documentation;Pulmonary Inflammation;Quality of life;Recurrence;Regimen;Reproducibility;Role;Signal Transduction;Specimen;Steroid Resistance;Steroids;Structure of parenchyma of lung;TLR4 gene;Therapeutic;Tissue Harvesting;Tissues;Toxic effect;Transgenic Model;Transgenic Organisms;Tumor Tissue;Work;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;antibody immunotherapy;biomarker development;cancer type;candidate marker;chemokine;design;immune-related adverse events;immunomodulatory therapies;improved;inhibitor;inhibitor therapy;insight;ipilimumab;melanoma;neutrophil;novel;novel therapeutic intervention;pharmacologic;predictive marker;programmed cell death ligand 1;response;side effect;small molecule inhibitor;success;treatment strategy;tumor;tumor DNA;tumor ablation Role of the tumor NLRP3 inflammasome in the generation of anti-PD-1 antibody immunotherapy-associated toxicities This proposed project promises to contribute significantly to the growing field of immuno-oncology by providinginsights into a novel mechanism contributing to the development of immune-related adverse events (irAEs). Indoing so this work will lay the foundation for the development of a novel therapeutic strategy to suppress theside-effects associated with checkpoint inhibitor immunotherapies while also establishing previously unknowncandidate biomarkers for predicting the development of these irAEs in cancer patients. NCI 10679040 7/20/23 0:00 PAR-19-325 5R01CA251136-03 5 R01 CA 251136 3 "PERLOFF, MARJORIE" 7/20/21 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-OTC-M(08)F] 11800128 "HANKS, BRENT ALLEN" Not Applicable 4 INTERNAL MEDICINE/MEDICINE 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 297705 NCI 184910 112795 The recent success and expanded use of the checkpoint inhibitor immunotherapies in clinical oncologyhas resulted in an increased incidence of a variety of immune-related adverse events (irAEs) some ofwhich can have a lasting impact on the lives of our patients. The continued development of adjuvantimmunotherapy protocols and more potent immunotherapy combinations such as theipilimumab/nivolumab regimen is expected to increase the incidence and societal impact of these irAEs.Despite their growing prevalence the underlying pathogenesis of individual irAEs is poorly understoodand our therapeutic management of these conditions remains crude. Using a genetically engineered model of melanoma we have found that anti-PD-1 antibody (ab)immunotherapy routinely leads to neutrophilic infiltration of the lung parenchyma and colon laminapropria closely resembling the pathology noted in human checkpoint inhibitor-associated pneumonitisand colitis respectively. This work further revealed that anti-PD-1 ab treatment of non-tumor-bearingmice eliminates the development of these irAEs suggesting the presence of a tumor-intrinsic pro-inflammatory mechanism. As part of this work we have recently identified a tumor-intrinsic PD-L1:NLRP3:HSP70 signaling axis that drives the accumulation of neutrophils in distant organs includingthe lungs and colon in response to PD-1 blockade. Additional studies have shown that genetic knock-out of tumor HSP70 expression and the pharmacological inhibition of the NLRP3 inflammasomesuppresses the accumulation of neutrophils in these distant tissues. Based on these findings we nowhypothesize that the tumor NLRP3 inflammasome promotes the development of checkpoint inhibitor-associated colitis and pneumonitis and that NLRP3 represents a promising pharmacological target forsuppressing the development of these irAEs. To address this hypothesis we have generated atransgenic melanoma tissue-specific NLRP3-/- model to examine the role of tumor-intrinsic NLRP3 inthe development of checkpoint inhibitor-induced colitis and pneumonitis. Additional studies will addressa potential role for this tumor NLRP3 pathway in Th17 differentiation in these distant organ tissues andwhether a small molecule inhibitor of NLRP3 would be a superior option over steroids for themanagement of colitis and pneumonitis in an autochthonous melanoma model undergoing anti-PD-1ab immunotherapy. We will further utilize tumor tissue and DNA collected from patients undergoingcheckpoint inhibitor immunotherapy on an active IRB-approved clinical study to determine if geneticvariations of NLRP3 may contribute to the development of these irAEs. Overall this work will provideunique mechanistic insight into the development of irAEs and identify rational therapeutic strategiesand predictive biomarkers for improving the management of patients undergoing immunotherapy. 297705 +No NIH Category available Address;Adolescent and Young Adult;Advocate;Asian Americans;Cancer Burden;Cancer Center;Cancer Control;Caring;Chinese;Clinical Oncology;Clinical Trials;Communication;Communities;Community Clinical Oncology Program;Decision Aid;Disease;Disparity;Elderly;Enrollment;Ethnic Population;Filipino;Goals;Grant;Guam;Guideline Adherence;Hawaii;Health Personnel;Healthcare;Hospitals;Image;Individual;Infrastructure;Institution;Intervention;Japanese;Koreans;Leadership;Lesbian Gay Bisexual Transgender;Lesbian Gay Bisexual Transgender Queer;Malignant Neoplasms;Minority;Modality;Native Hawaiian;Oncologist;Pacific Islander;Patient-Focused Outcomes;Patients;Persons;Physicians' Offices;Population;Populations at Risk;Prevention;Provider;Race;Reduce health disparities;Research;Research Design;Research Infrastructure;Research Personnel;Risk;Rural;Sexual and Gender Minorities;Site;Symptoms;Training;Underrepresented Populations;Underserved Population;Universities;University Hospitals;Work;base;cancer care;cancer clinical trial;cancer prevention;cancer therapy;care delivery;cultural competence;data management;ethnic minority;experience;financial toxicity;health care delivery;health care disparity;improved;low socioeconomic status;multi-ethnic;personalized medicine;racial minority;racial minority population;research study;screening;survivorship;underserved minority;working group The Hawaii Minority/Underserved NCORP The Hawaii Minority/Underserved NCORP aims to: 1) conduct cancer clinical trials andcancer care delivery research 2) continue contributing to NCORP research bases andNCI priorities and 3) enhance participation of Hawaiis diverse multiethnic and at riskpopulation in NCI sponsored trials in order to reduce health care disparities and the burdenof cancer for the people of Hawaii and elsewhere.! NCI 10679036 7/31/23 0:00 RFA-CA-18-017 5UG1CA189804-10 5 UG1 CA 189804 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-SRB-H(M1) 10728916 "BERENBERG, JEFFREY LEE" "ACOBA, JARED " 1 NONE 965088057 NSCKLFSSABF2 965088057 NSCKLFSSABF2 US 21.299198 -157.820371 820005 UNIVERSITY OF HAWAII AT MANOA HONOLULU HI ORGANIZED RESEARCH UNITS 968222234 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1352932 NCI 980881 372462 The overall goal of the Hawaii Minority/Underserved NCORP is to provide access andfacilitate enrollment of Hawaiis diverse multiethnic population to NCI sponsored trials.Thus we will enhance accrual of underrepresented populations including NativeHawaiians other Pacific Islanders Asian-Americans (Chinese Japanese Filipino andKorean) adolescents and young adults (AYA) the elderly and sexual and genderminorities (LGBTQ). Our NCORP is the primary provider of NCI clinical trials and cancercare delivery research (CCDR) in the State of Hawaii where nearly 75% of the populationis comprised of multiple minority racial/ethnic groups. The Hawaii M/U NCORP supportsan integrated network of affiliates and sub-affiliates with the extensive menu of cancerstudies research infrastructure and data management. Our NCORP has successfullyextended CCDR studies from the originally designated sites to other hospital affiliate siteswith plans to further extend them to physician office sites. We solicit community input fromNative Hawaiian and LGBTQ advocates to review the suitability of trials as well as toaddress their healthcare needs. Non medical oncology community investigators and staffhave leadership responsibility in imaging prevention and CCDR studies. Our NCORPleaders have extensive experience in cancer clinical trials health care delivery anddisparities. They have served on multiple NCI committees. Participation in NCIspersonalized medicine cancer control prevention treatment and CCDR research willfurther reduce cancer health care disparities and the cancer burden for the people ofHawaii and beyond. 1352932 +No NIH Category available Address;Aftercare;Aging;Alabama;Appalachian Region;Area;Behavior;Behavior Therapy;Behavioral;Breast Cancer survivor;Cancer Burden;Cancer Center;Cancer Prognosis;Cancer Survivor;Cancer Survivorship;Cardiovascular Diseases;Caring;Centers for Disease Control and Prevention (U.S.);Collaborations;Cost Analysis;Country;Darkness;Data;Diabetes Mellitus;Diagnosis;Diet;Dietary Intervention;Dissemination and Implementation;Early Diagnosis;Early treatment;Eating;Economics;Future;General Population;Goals;Guidelines;Health;Health Sciences;Health behavior;Health behavior change;Home;Individual;Intervention;Learning;Life;Life Style;Life Style Modification;Malignant Neoplasms;Mediating;Minority;Mississippi;Modeling;Obesity;Osteoporosis;Outcome;Persons;Physical activity;Population;Prevalence;Price;Process;Public Health;Randomized Controlled Trials;Regional Cancer;Research;Research Project Grants;Resource Sharing;Risk;Rural;Sampling;Science;Scientist;Screening for cancer;Second Primary Cancers;Second Primary Neoplasms;Survival Rate;Survivors;Technology;Tennessee;Testing;Time;Transportation;Travel;Unhealthy Diet;Universities;Visiting Nurse;Waiting Lists;Weight;Work;arm;behavior change;cancer care;cancer diagnosis;cancer risk;cancer therapy;cancer type;comorbidity;comparative efficacy;cost;effective intervention;efficacious intervention;efficacy testing;empowerment;exercise adherence;exercise intervention;functional decline;good diet;health disparity;high risk;implementation research;improved;neoplasm registry;physical inactivity;population based;programs;recruit;treatment arm;trend;unhealthy lifestyle Adapting MultiPLe behavior Interventions that eFfectively Improve (AMPLIFI) Cancer Survivor Health PROJECT NARRATIVECancer survivors are at much greater risk for second malignancies cardiovascular disease osteoporosisdiabetes and functional decline. Many of these conditions result or are exacerbated by unhealthy lifestylebehaviors (e.g. poor diet resulting in obesity and physical inactivity). In order to improve the health of survivorsthere is a need to develop and test multi-behavior interventions that are scalable effective and able to reachthe growing population and broad array of cancer survivors especially those who historically have beenunderserved i.e. older rural and minority survivors. NCI 10679027 9/8/23 0:00 PAR-16-457 5P01CA229997-06 5 P01 CA 229997 6 "AGURS-COLLINS, TANYA" 9/1/18 0:00 8/31/24 0:00 ZCA1-SRB-2(M1) 10316531 "DEMARK-WAHNEFRIED, WENDY " Not Applicable 7 NUTRITION 63690705 YND4PLMC9AN7 63690705 YND4PLMC9AN7 US 33.50591 -86.799772 1288803 UNIVERSITY OF ALABAMA AT BIRMINGHAM BIRMINGHAM AL SCH ALLIED HEALTH PROFESSIONS 352940001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Non-SBIR/STTR 2023 1506689 NCI 1049963 456726 Adapting MultiPLe behavior Interventions that eFfectively Improve (AMPLIFI) Cancer Survivor Health By 2020 the number of cancer survivors in the US will exceed 20 million due to trends toward agingand improved cancer screening and treatment. Cancer survivorship is a victory but it comes at a price. Oncean individual is diagnosed with cancer they are at much higher risk for second malignancies cardiovasculardisease diabetes osteoporosis and functional decline (resulting in a loss of independence). Currently thecosts for these downstream effects are estimated to be at least $135 billion annually. Unhealthy lifestyle behaviors (e.g. a poor diet resulting in obesity and physical inactivity) associate withpoorer outcomes after a cancer diagnosis. These behaviors also tend to cluster i.e. people who practice oneunhealthy behavior tend to practice another. It is hypothesized that cancer survivors may be able to improvetheir overall health and reduce comorbidity through lifestyle modification particularly since estimates indicatethat only 15-47% of cancer survivors adhere to national guidelines for weight status diet and physical activity.While effective interventions in each of these domains exists there has been little effort to disseminate theseinterventions broad scale and to survivors most in need (older rural minorities). Moreover there is a relativedearth of research in determining optimal means of combining interventions which is critical since manysurvivors practice more than one or multiple suboptimal behaviors. The overarching aims AMPLIFI are to learn how to: 1) improve health behaviors in cancer survivors whopractice multiple suboptimal health behaviors; and 2) adapt efficacious interventions to optimize their reach bythe use of technology among cancer survivors while also collecting data to inform the future dissemination andimplementation (D&I) potential of these interventions. AMPLIFI involves 3 highly interrelated research projectssupported by 4 highly integrated cores. It will enlist the efforts of 852 survivors of a broad array of cancers thathave favorable 5-year cancer-free survival rates (oversampling those who are older rural and minority) andgather the input of 48 key stakeholders to accomplish the following Specific Aims: 1) Understand how to adaptefficacious interventions for widespread dissemination through the use of technology while maintaining theintegrity of key components which drive behavior change; 2) Optimize acceptability and use of interventions(largely developed and tested in homogeneous samples of breast cancer survivors) to older rural minoritysurvivors of many cancer types; 3) Test the efficacy of the adapted interventions delivered alone in sequenceor combined; 4) Contribute to the science of D&I research by developing a new adaptation model; and 5)Determine factors that improve the D&I potential of distance-delivered health behavior change interventions bydetermining how they mediate behavior change and in whom they work best. Our ultimate goal is to improvethe health of the highly vulnerable and ever increasing population of cancer survivors. 1506689 +No NIH Category available Acceleration;Address;Advocate;Aftercare;Agreement;Alaska;California;Cancer Center;Cancer Control;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Collection;Communities;Community Clinical Oncology Program;Credentialing;Disparity;Ensure;Environment;Fostering;Funding;Generations;Goals;Idaho;Image;Improve Access;Individual;Infrastructure;Institutional Review Boards;Knowledge;Legal;Malignant Neoplasms;Medical center;Mentors;Minority Groups;Minority Participation;Montana;National Cancer Institute;Oregon;Organizational Efficiency;Patient-Focused Outcomes;Patients;Population Heterogeneity;Prevention;Procedures;Process;Quality Control;Research;Research Personnel;Resources;Science;Site;Structure;Underrepresented Populations;Underserved Population;United States;Washington;Work;anticancer research;base;cancer care;cancer health disparity;cancer prevention;cancer therapy;care delivery;clinical practice;clinically significant;community setting;data submission;demographics;evidence base;experience;feasibility trial;health disparity;improved;knowledge translation;next generation;organizational structure;programs;quality assurance;research study;sample collection;screening;treatment center;trial design;trial enrollment;tumor The Pacific Cancer Research Consortium (PCRC) an NCORP Community Site PROJECT NARRATIVE (RELEVANCE)The NCORP Community Site outlined in this continuation application comes from our experiencebuilding a multicenter infrastructure in the Western United States that excels in patient accrual andfosters new and close collaboration between investigators. We believe that our structure will acceleratethe translation of knowledge gained from trials in cancer treatment cancer control and preventioncancer care delivery research screening and imaging into clinical practice and thereby enhance thescience the treatments and the delivery of care to patients with cancer in community settings. NCI 10678961 7/28/23 0:00 RFA-CA-18-016 5UG1CA189953-10 5 UG1 CA 189953 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 9987726 "DRESCHER, CHARLES " "ALLURI, NITYA ; CONLIN, ALISON K" 9 Unavailable 79264420 GZ5WW5GZY2A5 79264420 GZ5WW5GZY2A5 US 47.608392 -122.322135 10001759 "SWEDISH MEDICAL CENTER, FIRST HILL" SEATTLE WA Independent Hospitals 981224307 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 2544202 NCI 1987402 711665 PROJECT SUMMARY/ABSTRACTIn 2013 the Pacific Cancer Research Consortium (PCRC) was created to bring clinical trials andcancer care delivery research to community cancer treatment centers in the Western United States asan NCI Community Oncology Research Program (NCORP) Community Site. Under a multiple PI/PDstructure the 3 primary component sitesSwedish Cancer Institute in Seattle Providence PortlandMedical Center in Portland and Mountain States Tumor Institute in Boisehave facilitated the conductof NCORP-sponsored trials at more than 40 affiliate sites in Alaska Washington Oregon IdahoMontana and California. Over the past 5 years the PCRC built on its collective experience in clinicalresearch its shared organizational structure and its diverse community demographics to achieve theresearch and accrual goals of the initial round of funding. As an established NCORP Community Sitefor the next round of funding the PCRC will continue to bring cancer clinical research studies toindividuals in their own communities by (1) developing clinically important trials and achieving robustaccruals that focus on underrepresented populations (2) participating in cancer treatment cancercontrol and prevention cancer care delivery research screening and imaging trials proposed by theNCORP Research Bases (3) optimizing and streamlining procedures to ensure timely and accuratedata submission and specimen collection (4) enhancing the participation of minorities and underservedpopulations by involving patient advocates and (5) mentoring the next generation of community-basedcancer clinical trialists. 2544202 +No NIH Category available Adolescent;Agreement;Ancillary Study;Bacterial Drug Resistance;Biometry;Body Composition;Clinical Oncology;Clinical Research;Collaborations;Collection;Common Data Element;Communication;Communities;Complications of Diabetes Mellitus;Cost effectiveness research;Data;Data Collection;Data Reporting;Development;Diabetes Mellitus;Diet;Dietary Intervention;Educational Materials;Electronic Mail;Emergency department visit;Ensure;Epidemiology;Evaluation;Exercise;Faculty;Failure;Goals;Health Sciences;Hospitalization;Interest Group;Interruption;Intervention;Lead;Leadership;Life;Malignant Neoplasms;Malnutrition;Maternal-Fetal Medicine Units Network;Medical;Non-Insulin-Dependent Diabetes Mellitus;Oncology;Outcome;Outcome Study;Patient Outcomes Assessments;Patients;Physical activity;Pilot Projects;Policies;Procedures;Protocols documentation;Public Health Schools;Publications;Qualifying;Recommendation;Recording of previous events;Reporting;Research;Research Design;Research Personnel;Research Support;Resources;Role;School Nursing;Site;System;Training;Treatment Protocols;Treatment outcome;Treatment-Related Cancer;Universities;Washington;Work;Youth;cancer therapy;cohort;comparative effectiveness study;data management;data resource;data sharing;design;diabetes control;diabetes prevention program;dissemination science;exercise intervention;exercise prescription;experience;flexibility;implementation science;improved;innovation;insulin secretion;lean body mass;medical schools;meetings;multidisciplinary;novel;nutrition;performance site;personalized approach;research study;skills;success;web site;working group ENICTO Consortium Coordinating Center PROJECT NARRATIVEThe ENICTO Consortium will conduct studies to evaluate the role of exercise and nutrition interventions inimproving cancer treatment outcomes. The ENICTO Coordinating Center will enhance and support thisresearch by: leading the development collection and analyses of common data across studies; facilitatingcommunication within the Consortium and between the Consortium with external audiences; and providingadministrative support for the Consortium. NCI 10678940 7/18/23 0:00 RFA-CA-21-032 5U24CA271246-02 5 U24 CA 271246 2 "MCKOY, TOMMIE W" 8/8/22 0:00 6/30/27 0:00 ZCA1-RPRB-L(J2)R 7894701 "EVANS, SCOTT " "ROBIEN, KIMBERLY Z" 98 BIOSTATISTICS & OTHER MATH SCI 43990498 ECR5E2LU5BL6 43990498 ECR5E2LU5BL6 US 38.898075 -77.043933 2863301 GEORGE WASHINGTON UNIVERSITY WASHINGTON DC SCHOOLS OF PUBLIC HEALTH 200520042 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Other Research-Related 2023 981227 NCI 759583 221644 PROJECT SUMMARY ABSTRACTThe goal of the Exercise and Nutrition Interventions to Improve Cancer Treatment-related Outcomes (ENICTO)Consortium is to support and enhance exercise and/or medical nutrition intervention research designed toevaluate interventions that may improve cancer treatment-related outcomes among patients being treated withcurative of life-extending intent. The aims of the ENICTO Coordinating Center are to facilitate the work of theENICTO consortium by: 1) supporting the scientific goals of the ENICTO consortium through collectionharmonization and analysis of common data across Consortium sites 2) facilitating communication within theConsortium and between the Consortium with external audiences and 3) coordinating administrative functionsof the ENICTO consortium. Under the direction of the ENICTO Steering Committee the ENICTO CoordinatingCenter will work with Consortium investigators to identify common data elements and procedures acrossConsortium sites harmonize cohort variables and identify opportunities for novel data collection to enrich theENICTO data resources. The Coordinating Center will organize training sessions for Consortium site staff toensure the quality consistency and completeness of the data across sites develop and implement a datamanagement platform for data collection and reporting from the Consortium sites and train and supportConsortium sites on platform use. The Coordinating Center will lead analyses for cross-consortium pilotprojects examining common research questions and make the harmonized ENICTO data available to qualifiedresearchers based on Consortium policies and data sharing agreements. The Coordinating Center will planand coordinate the ENICTO Consortium Annual Meeting and meetings of the Steering Committee establishemail listservs develop and maintain a website for the ENICTO Consortium plan and facilitate communicationamong the scientific working groups support the distribution of research materials such as study protocols andeducation materials and disseminate research findings to the scientific and cancer communities.Administrative functions of the Coordinating Center will include development and implementation of ENICTOoperating policies and procedures pertaining to data sharing publications and presentation externalcollaborations and ancillary studies under the guidance of the ENICTO Steering Committee and an evaluationsystem to track U01 site performance and project progress. The Coordinating Center will prepare meetingagendas compile meeting materials record meeting minutes and action items and provide generaladministrative support and oversight. 981227 +No NIH Category available 3-Dimensional;Academia;Address;Admission activity;Advocate;Behavioral;Biomedical Research;Cancer Biology;Career Choice;Charge;Clinical;Committee Members;Communication;Community Outreach;Comprehensive Cancer Center;Core Facility;Development;Education;Educational Curriculum;Educational workshop;Elevator;Ensure;Environment;Evaluation;Faculty;Family;Fostering;Funding;Goals;Habits;Health Professional;Hematology;Immersion;Individual;Industry;Institution;Journals;Laboratories;Learning Module;Link;Malignant Neoplasms;Medical;Medical Students;Medicine;Mentors;Mentorship;Minority Groups;Oncology;Oral;Outcome;Patients;Persons;Positioning Attribute;Postdoctoral Fellow;Reporting;Reproducibility;Research;Research Personnel;Research Technics;Scientist;Series;Social Interaction;Solid;Structure;Students;Training;Underrepresented Minority;Underserved Population;Universities;Vocational Guidance;War;Writing;anticancer research;cancer education;cancer therapy;career;cohort;college;curriculum development;doctoral student;experience;graduate school;innovation;lectures;medical schools;meetings;member;novel;posters;programs;recruit;responsible research conduct;satisfaction;skill acquisition;skills;student participation;summer program;symposium;undergraduate research;undergraduate research experience;undergraduate student;university student;workforce needs Cancer-focused Summer Undergraduate Research (CanSUR) Program NARRATIVETo help ensure that the nations biomedical clinical and behavioral cancer research workforce remains strongwe propose the development of a Cancer-focused Summer Undergraduate Research (CanSUR) Program. Theobjectives of the program are to recruit 32 highly motivated undergraduate students from diverse backgroundseach year and (1) provide them with a cancer research experience including project development executioninterpretation and reporting of research results; (2) educate them about available cancer research careeropportunities; and (3) provide scientific enrichment and professional skills development curricula to help preparethem for the next step in a cancer research-focused career. NCI 10678931 8/21/23 0:00 PAR-15-152 5R25CA225461-06 5 R25 CA 225461 6 "RADAEV, SERGEY" 9/1/18 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 9492815 "JACKSON, MARK W." "NARLA, GOUTHAM " 11 PATHOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 211324 NCI 195869 15669 PROJECT SUMMARYCancer has been a major focus of biomedical research since the war on cancer began with the NationalCancer Act of 1971. Despite this focus nearly 8 million people die of cancer each year worldwide. To helpensure that the nations biomedical clinical and behavioral cancer research workforce remains strong wepropose the development of a Cancer-focused Summer Undergraduate Research (CanSUR) Program torecruit highly motivated undergraduate students from diverse backgrounds and foster their excitement for acareer in cancer research. The CanSUR program will support 32 undergraduate scholars each year recruitedfrom regional and national colleges/universities for a 10-week period to participate in a cancer researchexperience with members of the Case Comprehensive Cancer Center (Case CCC). Key objectives of theCanSUR Program are to: (1) provide each scholar with a summer cancer research experience in a Case CCCmembers lab; (2) foster an understanding of biomedical cancer research career opportunities and (3)providing scientific enrichment and professional skills curriculum to help prepare them for the next step in acancer research focused career. Four major components have been developed to meet these objectivesincluding an Intensive Week 1 Cancer Immersion Workshop a series of interactive cancer research lectureson the fundamentals of cancer biology current cancer therapies cancer research techniques cancer careerpaths and innovative 3-dimensional cancer education modules (called the HoloLens). We propose a novel 2-tier mentorship structure that includes both the primary mentor (lab leader) and a junior mentor which will bethe person in charge of the day-to-day training of the CanSUR scholar within the research environment.Beyond their individual research experience we have developed a series of Scientific Enrichment componentswhich address important issues in cancer research such as developing professional habits effectivecommunication strategies and an appreciation of how cancer impacts individuals and their families (using talksby patient advocates). Numerous cancer-focused career paths will be introduced and guidance about how toprepare for the next step of a specific career path will be provided by graduate and medical school admissionsdirectors professionals who have achieved their cancer-related career goals and current trainees. Given theimportance of our objectives we have been pledged significant institutional support and have 82 faculty andinstitutional leaders who focus on cancer education prepared to recruit and train outstanding undergraduates inthis summer program. As such we are well-positioned to convert highly-motivated undergraduates into thenations next cancer research workforce. 211324 +No NIH Category available Cancer Control;cancer prevention;post-doctoral training Postdoctoral Training in Cancer Prevention and Control PROJECT NARRATIVEThere is strong evidence that lifestyle and behavior are associated with cancer risk and that cancer preventionand control activities can impact population levels of cancer incidence and mortality. With the increasinglycomplex public health problem researchers need to be versed in transdisciplinary and team science.Widespread implementation of interventions known to be effective and efforts to reduce cancer healthdisparities are critical areas are our under-addressed in cancer prevention and control. Our unique programaims to train the next generation of cancer prevention and control leaders by post-doctoral training in cancerdisparities implementation science and transdisciplinary collaboration. NCI 10678913 8/24/23 0:00 PA-18-403 5T32CA190194-10 5 T32 CA 190194 10 "LIM, SUSAN E" 9/24/14 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 8023991 "JAMES, AIMEE S" "COLDITZ, GRAHAM A." 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 370463 NCI 408844 28068 ABSTRACT / PROJECT SUMMARYThere is strong evidence linking lifestyle and behavioral risk factors with incidence and survival after a range ofcancers. Evidence-based interventions using implementation science approaches can substantially reducedisparities and the population burden of cancer. The number of individuals affected by cancer continues togrow as the U.S. population ages and disparities in cancer incidence and mortality remain by race/ethnicitysocioeconomic level and geography. As the NCI Blue Ribbon Research Panel noted this is acritical time to use implementation science methods and insure that we train investigators in cancer preventionand control research who can reach multiple groups within a population. Increasingly our health promotiongoals cannot be achieved by working within a single discipline. Thus our ongoing T32 PostdoctoralTraining Program in Cancer Prevention and Control aims to bridge this gap. During our first cycle of fundingwe have demonstrated success in recruiting retaining and training successful researchers and note that halfour trainees come from under-represented minority backgrounds. Trainees also represented multiple homedisciplines. Trainees from our first funding cycle have gone on to obtain faculty positions and grant fundingincluding a K99-R00. We will continue to leverage institutional resources and ongoing NIH-funded research tosustain our training program and enhance the training experience. Our training program includes structuredelements such as individual development plans mentored research experiences and customizable didactictraining opportunities to complement training in implementation science and cancer health disparities. Ourinnovative training also includes a transdisciplinary journal club career development programming andtraining in communicating with media and lay audiences. Our process of evaluation and adaptation of thetraining experience based on internal and external advisors and the ever-changing field of cancer preventionand control have resulted in us adding required training in cancer health disparities and implementationscience. Washington University School of Medicine and Siteman Cancer Center offer a rich environment fortrainees and our transdisciplinary training in cancer prevention and control offers a unique resource to theuniversity environment. This T32 mechanism allows us to train PhD and MD scientists to conducttransdisciplinary research and lead the next generation of cancer prevention and control researchers. 370463 +No NIH Category available ATAC-seq;Acute Myelocytic Leukemia;Back;CBFA2T1 gene;CBFbeta-MYH11 fusion protein;Cell model;Cells;ChIP-seq;Clinical Trials Design;Communities;Core-Binding Factor;DNA;DNA sequencing;DNMT3B gene;DNMT3a;DNMT3a mutation;Data Analyses;Data Set;Databases;Development;Disease;Epigenetic Process;Event;Funding;Genetically Engineered Mouse;Genomics;Goals;Growth;HDAC1 gene;Hematopoietic;Hematopoietic Neoplasms;Hematopoietic stem cells;Histones;Human;Methods;Molecular;Mutation;PML-RARalpha protein;Pathogenesis;Patients;Pharmaceutical Preparations;Precision therapeutics;Preleukemia;Process;Protein Isoforms;Proteins;Proteomics;RUNX1 gene;Sampling;Series;Work;acute myeloid leukemia cell;bisulfite sequencing;blastomere structure;embryo cell;engineered stem cells;epigenomics;fitness;genetic approach;genomic locus;induced pluripotent stem cell;inhibitor;insight;leukemia initiating cell;mouse model;mutant;novel;overexpression;phosphoproteomics;programs;proteogenomics;single cell technology;targeted treatment;therapy design;transcriptome sequencing;whole genome Molecular Pathogenesis of Acute Myeloid Leukemia Project NarrativeAcute Myeloid Leukemia (AML) is a devastating hematopoietic malignancy that is fatal for most of the patientswho develop this disease. In this proposal we will develop and analyze comprehensive genomic epigenomicand proteomic databases using samples from AML patients and genetically defined mouse models withcommon AML initiating events. The long-term goal of this project is to use these datasets to develop effectivemechanistically-driven therapies directed against the initiating mutations of this disease. NCI 10678908 8/1/23 0:00 PAR-21-333 5R35CA197561-09 5 R35 CA 197561 9 "KLAUZINSKA, MALGORZATA" 8/13/15 0:00 6/30/29 0:00 ZCA1-GRB-I(M1) 1893888 "LEY, TIMOTHY J." Not Applicable 1 INTERNAL MEDICINE/MEDICINE 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 914339 NCI 587999 326340 "Project SummaryThe long-term goal of this project is to develop effective precision therapies directed against theinitiating mutations of Acute Myeloid Leukemia (AML). During the current funding period we performed aseries of genomic and epigenomic studies that have clarified the mechanisms that AML initiating mutations useto ""reprogram"" hematopoietic stem progenitor cells (HSPCs) increasing their fitness for transformation. In thenext funding period we will use primary human AML samples induced pluripotent stem cells (iPSCs)and genetically engineered mouse models to further evaluate the molecular mechanisms involved inpreleukemic reprogramming and progression to AML. Four well characterized events (that initiate morethan half of AML cases) will be studied in detail. We will continue our work with DNMT3A mutations and PML-RARA and add the study of Core Binding Factor AML fusions (RUNX1-RUNX1T1 and CBFB-MYH11). The""toolkit"" for these studies will involve the analysis of preleukemic and fully transformed hematopoietic cells fromthese models using bulk DNA and RNA sequencing whole genome bisulfite sequencing ATAC-seq ChIP-seq and/or CUT&RUN to detect the genomic locations of activating and repressive histone marks (and thefusions themselves) and single cell technologies for RNA DNA and ATAC-seq. We will also be performingcomprehensive proteomic studies to complete ""proteogenomic"" datasets for these initiating eventsincluding 1) the identification of the hematopoietic proteins that interact with the initiating proteinslisted above and 2) the development of quantitative deep-scale proteomic and phosphoproteomicdatasets broadly representative of all AML subtypes. The integrative analysis of these datasets (and theiravailability to the AML community) should provide important new insights about AML pathogenesis andsuggest mechanistically targeted therapies. In this proposal we provide one representative example of thisprocess: using novel methods to identify proteins that interact with DNMT3A we discovered several mutationsthat disrupt the normal interaction of DNMT3A with an inactive isoform of DNMT3B (DNMT3B3); thesemutations destabilize DNMT3A and decrease its activity. Remarkably we found that we can restore the activityof many mutant DNMT3A proteins by retrovirally overexpressing DNMT3L a protein that normally interactswith DNMT3A and 3B in embryonic cells to increase their activity. ""Addback"" of DNMT3L into hematopoieticcells with the Dnmt3aR878H mutation remethylates DNA and decreases the growth of AML cells initiated by thismutation. Since DNMT3L is epigenetically silenced in nearly all AMLs a program to identify drugs and geneticstrategies to reactivate DNMT3L in AML cells will be developed. We have already found that Romidepsin anHDAC1 inhibitor potently induces DNMT3L expression and a clinical trial designed to evaluate the activity ofthis drug in DNMT3A mutant AMLs is planned. Additional approaches for developing mechanistically driventherapies designed to thwart initiating mutations will be developed during the next funding period." 914339 +No NIH Category available ALCAM gene;Address;Aftercare;Apoptotic;Automobile Driving;Bar Codes;Biological Assay;Biopsy;CD44 gene;Cancer Etiology;Cancer Patient;Cell Fraction;Cell Line;Cell Separation;Cells;Clinical;Coculture Techniques;Critical Pathways;Cryoultramicrotomy;Custom;Cytotoxic Chemotherapy;DNA Repair;Data;Disease Progression;Down-Regulation;Drug Efflux;Drug resistance;Elements;Endowment;Equilibrium;Excision;Exhibits;Exposure to;Fibroblasts;Gene Expression;Gene Expression Profile;Gene Expression Profiling;Generations;Genetic;Genetic Transcription;Genomics;Goals;Growth;Heterogeneity;Human;Immune signaling;In Vitro;Ionizing radiation;Lentivirus Vector;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Modeling;Molecular;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Play;Population;Population Growth;Prognostic Marker;Proliferating;Property;Protocols documentation;RNA;Regulation;Regulator Genes;Research;Resistance;Resolution;Role;Sampling;Selection for Treatments;Serial Passage;Signal Pathway;Signal Transduction;Sorting;Specificity;Stimulus;Stromal Cells;Surface;Therapeutic;Time;Time Series Analysis;Tissue-Specific Gene Expression;Transfection;Translating;Tumor Tissue;United States;Up-Regulation;Validation;Variant;Woman;cancer cell;cancer drug resistance;cancer stem cell;cancer therapy;computerized tools;drug sensitivity;experience;high dimensionality;improved;in vivo;informatics tool;insight;lung cancer cell;matrigel;men;mortality;multimodality;multiple omics;neoplastic cell;new therapeutic target;next generation sequencing;novel;pressure;progenitor;receptor;response;self-renewal;single-cell RNA sequencing;stem cells;targeted biomarker;targeted treatment;therapy resistant;transcriptome sequencing;transcriptomics;tumor;tumor growth;tumor heterogeneity;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis Defining and targeting the lung cancer progenitor cell niche using a high-resolution multi-omics approach Project NarrativeTargeted therapies have revolutionized the treatment of non-small cell lung cancer (NSCLC) but responses remain transient with the majority of patients experiencing drug resistance and tumor progression. Lung tumor initiating cells (TICs) are a subpopulation of tumor cells believed to sustain tumor growth promote treatment resistance and drive metastasis. This proposal leverages multi-scale bulk spatial and single-cell next generation sequencing data in combination with custom informatics tools to identify transcriptomic profiles and surface markers specific to TICs and characterize the tumor microenvironment that sustains this pervasive cellular phenotype with the goal of identifying novel therapeutic targets for treating NSCLC. NCI 10678892 8/22/23 0:00 PA-21-049 5F30CA265288-03 5 F30 CA 265288 3 "DAMICO, MARK W" 9/7/21 0:00 9/6/25 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 15121634 "CHARYTONOWICZ, DANIEL " Not Applicable 13 GENETICS 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 9/7/23 0:00 9/6/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 Project SummaryDespite advances in treatment options 5-year overall survival (OS) for non-small cell lung cancer (NSCLC) patients remains around 20% [1]. Subpopulations of tumor initiating cells (TICs) representing <1.5% of the overall tumor population exhibit the capacity for self-renewal drug-resistance and are believed to drive disease progression [2]. Although surface markers including CD133 CD44 CD166 and EPCAM have been proposed to isolate lung TICs results are inconsistent. Micro-heterogeneity within the tumor microenvironment (TME) is believed to regulate balance between progenitor-like and differentiated tumor cell phenotypes and consequently supports heterogeneous drug responses. This proposed research attempts to definitively characterize expression profiles of TICs and study the relationship between the tumor micro-environment and TIC dynamics in the context of drug response with the goal of identifying critical pathways that mediate transitions to a progenitor-like state. Aim 1 - Lineage tracing studies suggest that TICs exhibit clonal dominance in culture whereby a small fraction of tumor cells tend to drive outgrowth of the overall population. Having already established a protocol using cell line models I will transfect patient-derived NSCLC cells with RNA-expressed barcodes and analyze growing populations using serial passaging assays under normal and drug-treated conditions. Using transcriptional analysis of time-series single-cell RNA Sequencing (scRNA-Seq) data in combination with custom computational tools I aim to identify gene expression profiles and surface markers unique to progenitor-like subclones that drive population growth under treatment selection pressure. Aim 2 - TICs are dependent on niche signalling from a heterogeneous tumor microenvironment (TME) to support the progenitor phenotype. We hypothesize that micro-heterogeneity within the TME regulates the ratio of progenitor-to-differentiated tumor cells and influences drug sensitivity. I will first develop an in-vitro spheroid culture platform combining clonally barcoded patient-derived tumor and stromal cells exposed to cytotoxic therapy processing them with the 10X Genomics Spatial Transcriptomics platform. This data will enable assessment of essential TME crosstalk signalling and its impact on spatial cancer projenitor-like transcriptional signatures defined from Aim 1. We will confirm these insights by integrating scRNA-Seq and Spatial Transcriptomics data from naive and post-treatment patient-derived lung samples used for Aim 1 to characterize patient-specific TIC niches. Through the robust profiling of the TIC transcriptional profile and its associated microenvironment using multimodal sequencing approaches we hope to potentially identify new targets or prognostic biomarkers to aid in the treatment of NSCLC. 52694 +No NIH Category available Acetates;Address;American;Androgen Antagonists;Androgen Receptor;Androgens;Animal Model;Anthelmintics;Antiandrogen Therapy;Antibodies;Binding Sites;Biodistribution;Biological Assay;Biological Availability;Blood;Bypass;Calorimetry;Cancer Patient;Cell Culture Techniques;Cell Survival;Cell model;Cells;Characteristics;Chronic;Clinic;Clinical;Clinical Trials;Co-Immunoprecipitations;Complex;Data;Deposition;Development;Diagnosis;Disease;Disease Resistance;Drug Kinetics;Drug resistance;Drug usage;Enzymes;Flow Cytometry;Future;Goals;Half-Life;Heat-Shock Proteins 70;Immunocompetent;Immunofluorescence Immunologic;In Vitro;Label;Ligation;Longevity;Luciferases;Lysine;MYC Family Protein;Malignant Neoplasms;Malignant neoplasm of prostate;Molecular Chaperones;Molecular Target;Oncogenic;Oral;Organoids;Outcome;Parasitic infection;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Post-Translational Protein Processing;Precipitation;Primary Neoplasm;Property;Prostatic Neoplasms;Proteins;Quality of life;Reagent;Receptor Signaling;Regulation;Reporter;Research Personnel;Resistance;Sprague-Dawley Rats;Stains;Surface Plasmon Resonance;System;Technology;Testing;Testosterone;Therapeutic;Time;Titrations;Toxic effect;Translating;Translations;Tumor-Derived;Ubiquitin;Ubiquitin-mediated Proteolysis Pathway;Ubiquitination;United States Food and Drug Administration;Variant;abiraterone;analog;cancer cell;cancer therapy;castration resistant prostate cancer;clinically relevant;effective therapy;enzalutamide;improved;in vivo;liquid chromatography mass spectrometry;male;men;mouse model;multicatalytic endopeptidase complex;next generation;novel;patient derived xenograft model;prostate cancer cell;protein aggregation;protein degradation;proteostasis;receptor;resistance mechanism;small molecule;success;therapy resistant;tumor;tumor progression;ubiquitin-protein ligase Modulating HSP70/STUB1 machinery in therapy-resistant prostate cancer PROJECT NARRATIVEImbalanced protein homeostasis (proteostasis) disrupts protein clearance and increases abnormaldeposition of protein aggregates which facilitates cancer cell survival and progression. HSP70 protectsoncogenic protein degradation from STUB1 in anti-androgen resistant prostate cancer. This proposal willdevelop novel HSP70/STUB1 modulators to overcome the therapeutic resistance. NCI 10678891 9/11/23 0:00 PA-20-185 5R01CA251253-03 5 R01 CA 251253 3 "KONDAPAKA, SUDHIR B" 9/1/21 0:00 8/31/26 0:00 Developmental Therapeutics Study Section[DT] 12621986 "LIU, CHENGFEI " Not Applicable 4 UROLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 355216 NCI 226252 128964 PROJECT ABSTRACTProstate cancer will claim lives of over 30000 American men in 2020 alone. The disease evolves from primarytumors to castrate-resistant prostate cancer (CRPC) which only takes around 2-3 years. CRPC is still drivenby androgens such as testosterone which is why anti-androgen drugs are widely used to treat the disease.These drugs include enzalutamide (XTANDI) abiraterone acetate (ZYTIGA) and apalutamide(ERLEADA). Although these drugs are highly effective initially patients often quickly develop resistantdisease to these drugs. Therefore there is an urgent need to find strategies that control the emergence of anti-androgen resistant prostate cancer. Researchers have shown that drug resistant CRPC often occurs due toexpression of a variant form of receptor called androgen receptor variant-7 (AR-V7). This receptor can beactivated independent of androgen. Data from my group shows that protein degrading enzyme (STUB1) and itschaperone protein (HSP70) are altered in resistant CRPC cells. This HSP70/STUB1 complex is a criticalregulator of protein stability/half-life. We found that HSP70/STUB1 is responsible for AR/AR-V7 proteinshomeostasis (proteostasis) and remaining active for long periods. We have shown that modulating theHSP70/STUB1 complex with a Food and Drug Administration (FDA) approved drug used for parasite infectionnamely niclosamide reduces the levels of AR-V7 and importantly resensitizes resistant prostate cancer toanti-androgen therapy. However niclosamide has a poor characteristic that is hard to reach satisfiedconcentration in blood as a cancer therapeutic. To address this we modified niclosamide to yield a range ofpotent HSP70/STUB1 modulators (HSMs) and one of the small molecule compounds known as HSM-7 whichhas a better bio-distribution profile and superior effects on killing drug resistant prostate tumors. Theoverarching goal of this application is to develop HSMs and build a strong rationale for translating the drug tothe clinic to treat patients with lethal CRPC disease. In this project we will study HSM-7 on its regulation ofHSP70/STUB1/AR-V7 ternary complex which will be critical to strategize to overcome anti-androgen resistance.We will discover the multiplicity targets regulated by HSMs through HSP70/STUB1 machinery and dissect howubiquitination alteration by HSMs treatment controls oncogenic protein turnover. Additionally we will evaluatethe drug properties of HSM-7 and test its efficacy in novel patient tumor derived animal and cell models ofCRPC for future clinical trial initiation. The outcomes of the proposed studies will provide a strong rationale fortranslating HSM-7 into the clinical setting and in addressing the major unmet need of overcoming nextgeneration anti-androgen resistance in CRPC patients. We believe that HSM-7 will ultimately increase theoverall survival and improve the quality of life men diagnosed with CRPC. 355216 +No NIH Category available Adverse effects;Aerodigestive Tract;Aftercare;Ambulatory Monitoring;Barium swallow;Biomechanics;Bolus Infusion;Breathing;Cancer Survivor;Clinical Trials;Complex;Controlled Clinical Trials;Custom;Deglutition;Deglutition Disorders;Eating;Environment;Epidemic;Fibrosis;Food;Frequencies;Goals;Head and Neck Cancer;Hour;Human Papillomavirus;Impairment;Individual;Ingestion;Intervention;Invaded;Larynx;Learning;Limb structure;Liquid substance;Measures;Mission;Monitor;Movement;National Cancer Institute;Operative Surgical Procedures;Oropharyngeal;Outcome;Participant;Patients;Pattern;Penetration;Pharyngeal structure;Phase;Physiological;Physiology;Positioning Attribute;Posture;Radiation;Randomized;Recovery;Research Institute;Respiration;Safety;Severities;Sexually Transmitted Diseases;Signal Transduction;Survival Rate;Survivors;Testing;Therapeutic;Time;Tissues;Tongue;Toxic effect;Traction;Training;Treatment-related toxicity;United States;Wakefulness;Work;arm;aspirate;cancer therapy;chemotherapy;clinical translation;curative treatments;drinking;expiration;functional gain;health training;improved;innovation;novel;novel therapeutics;primary endpoint;recruit;remote therapy;respiratory;response;secondary endpoint;sensor;smartphone application;telehealth;traditional therapy;visual feedback;vocal cord;wearable sensor technology Training Swallowing Initiation during Expiration: Impact on Safety and Efficiency Following Treatment for Oropharyngeal Head and Neck Cancer PROJECT NARRATIVEOropharyngeal head and neck cancers have escalated to epidemic levels in the United States and survivorsare suffering from life-long devastating swallowing disorders with limited therapeutic options. This clinical trialinvestigates a novel swallowing treatment that trains initiation of swallowing during the expiratory phase ofrespiration to improve swallowing safety and efficiency. Consistent with the National Cancer Institute's researchmission this study may discover a new therapy option that could be combined with traditional therapies toimprove swallowing recovery for survivors of oropharyngeal head and neck cancer. NCI 10678843 9/7/23 0:00 PAR-18-560 5R01CA262502-03 5 R01 CA 262502 3 "UNDALE, ANITA H" 8/12/21 0:00 7/31/26 0:00 "Motor Function, Speech and Rehabilitation Study Section[MFSR]" 2409380 "MARTIN-HARRIS, BONNIE J" Not Applicable 5 OTHER HEALTH PROFESSIONS 160079455 EXZVPWZBLUE8 160079455 EXZVPWZBLUE8 US 42.050479 -87.680046 6144601 NORTHWESTERN UNIVERSITY Chicago IL SCHOOLS OF ARTS AND SCIENCES 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 582677 NCI 368920 213757 PROJECT SUMMARY ABSTRACTOropharyngeal head and neck cancers (OP HNC) have increased to epidemic levels in the United States.12Despite good response to cancer treatment3 survivors are suffering life-long toxicities that result in swallowingproblems (dysphagia).45 Treatment options for dysphagia after OP HNC are extremely limited focus onswallowing movements alone and do not consider the importance of respiratory-swallow phase patterning.6-11Prior evidence has demonstrated thatofimpairmentswhen aberrant respiratory-swallow phase patterning is present ( initiation swallowing during nspiration ) in patients with OP HNC there is a higher occurrence of swallowingincreased residue and airway invasion. 1213iFurther it has been well established that the expiratorylimb of the respiratory cycle provides a biomechanically advantageous set point in which to initiate safe andefficient swallowing.14-17 Thus we developed and tested an innovative approach to train individuals withdysphagia after OP HNC to initiate swallowing during expiration.18 In this preliminary trial we found that traininginitiation of swallowing during expiration resulted in marked improvements in airway protection and keyphysiologic components of swallowing function.18 These compelling findings led us to the current randomizedPhase II sham-controlled clinical trial to test if this respiratory-swallow phase training approach will improveairway protection and swallowing efficiency in OP HNC survivors in the subacute phase (3-6 mo.) of recovery.Our primary goal (Aim 1) is to determine if respiratory-swallow phase training results in increased frequency (%)of swallows initiated during expiration and improved swallowing safety. Our secondary goal (Aim 2) is to examinethe impact of respiratory-swallow phase training on the frequency of swallows initiated during expiration inwakeful naturalistic swallowing environments including eating and drinking. We will recruit 88 OP HNC survivorswith dysphagia impaired respiratory-swallow phase patterning and airway compromise. They will berandomized 1:1 into Experimental (n=44) or Sham (n=44) group arms. We will deliver therapy remotely using atelehealth platform and an innovative wearable sensor that provides real-time visual feedback of respiratory-swallow movements. Primary endpoints for Aim 1: frequency (%) of swallows initiated during expiration andPenetration-Aspiration Scale19 scores. Secondary endpoints: Normalized Residue Ratio Scale20 and ModifiedBarium Swallow Impairment Profile2122 scores. Endpoints will be measured from synchronized videofluoroscopicand respiratory-swallow sensor recordings at baseline within 1-week post-treatment and 1-month and 3-monthspost-treatment. The primary endpoint for Aim 2 is frequency (%) of swallows initiated during expiration in wakefulnatural contexts measured at baseline during training within 1-week post-treatment and 2- 4- 6- 8- 10- and12-weeks post-treatment. Consistent with the NCI's mission this proposed study investigates a new therapyoption that could be combined with traditional therapies to improve swallowing recovery for survivors of OP HNC. 582677 +No NIH Category available Adopted;Affect;Aftercare;Aging;Alveolar Macrophages;Automobile Driving;BMP7 gene;Bone Marrow;Breast;CSPG4 gene;Cancer Model;Cancer Patient;Carcinoma;Cell Survival;Clinical Trials;Cues;Data;Epigenetic Process;Evolution;Genes;Genetic Transcription;Goals;Hematopoietic stem cells;Homeostasis;Hypoxia;Impairment;Inflammatory;Link;Lung;Macrophage;Malignant Neoplasms;Mediating;Mesenchymal;Mesenchymal Stem Cells;Metastatic Neoplasm to the Bone;Metastatic Neoplasm to the Lung;Methods;Monitor;Mus;Neoplasm Metastasis;Organ;Primary Lesion;Primary Neoplasm;Proteins;Publishing;Residual Cancers;Signal Induction;Signal Transduction;Site;Systemic disease;TGFB2 gene;Testing;Therapeutic;Tissues;Transforming Growth Factor Beta 2;Tretinoin;Up-Regulation;WNT5A gene;Work;age effect;aged;cancer cell;cancer therapy;imprint;malignant breast neoplasm;nestin protein;novel;pluripotency;programs;rational design;relapse prevention;response;stem cell function;stem cell niche;therapy development;tumor hypoxia Functional Determinants of Metastatic Dormancy NARRATIVE. In this proposal we will determine 1) how hypoxia primes DCCs for dormancy 2) howNG2+/Nestin+ MSCs orchestrate dormancy niches and how aging affects these mechanisms and 3) howtissue resident lung alveolar macrophages (AMs) dictate DCC fate and how aging impacts the function of theseniches. NCI 10678829 7/10/23 0:00 PA-20-185 5R01CA109182-21 5 R01 CA 109182 21 "GRIL, BRUNILDE M" 1/12/22 0:00 6/30/26 0:00 Tumor Microenvironment Study Section[TME] 7852195 "AGUIRRE-GHISO, JULIO A." Not Applicable 14 NONE 81266487 H6N1ZF5HJ2G3 81266487 H6N1ZF5HJ2G3 US 40.85103 -73.844379 10053556 ALBERT EINSTEIN COLLEGE OF MEDICINE BRONX NY UNIVERSITY-WIDE 104611900 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 623104 NCI 405839 217265 SUMMARY. The majority of cancer patients die of metastases originating from disseminated cancer cells(DCCs) years and decades after treatment. This has been linked to the ability of DCCs to survive in a dormantstate and evade therapies. Our long-term goal is to understand dormancy of DCCs as a systemic diseasemechanism to target them and prevent relapse. Our overarching hypothesis is that complementary mechanismbetween gene programs in primary lesions and target organs niche signals converge to instruct DCCs intarget organs to enter dormancy via quiescence pluripotency and survival programs. We further hypothesizethat such signals can be manipulated to suppress metastasis. Using epithelial cancer models we havediscovered that early dissemination spawns mesenchymal-like (M-Like) dormant breast cancer (BC) DCCs.We also discovered that hypoxia in advanced primary tumors can prime DCC precursors to activatequiescence programs and enter dormancy in target organs. Importantly M-like early DCC precursors alsodisplay a strong hypoxia response. Both early and late DCCs were found to respond to retinoic acid WNT5ABMP7 and TGF2 signals derived from stromal target organ niches. These activate transcriptional programsintegrated by ZFP281 (a novel early DCC dormancy regulator) and NR2F1 to induce dormancy. Our new aimsbuild on these findings and explore three significant new discoveries: 1) Hypoxia signals in early and lateprimary lesions turn on quiescence programs that epigenetically imprint DCC precursors to enter dormancywhen they arrive to target organs 2) early or late DCCs that arrive to the bone marrow (BM) enter dormancy inresponse to TGF2 and BMP7 produced by Nestin+/NG2+ mesenchymal stem cells (N+MSCs) which controlhematopoietic stem cells (HSCs) dormancy; loss of N+MSCs or TGF2 expression in these MSCs led to bonemetastasis and 3) in lungs early and late DCCs reside in pro-dormancy niches orchestrated by alveolarmacrophages (AMs) which when depleted awaken dormant DCCs. We propose to study how signals fromprimary lesion hypoxia along with BM and lung homeostatic niches are integrated to keep DCCs dormant. Thespecific aims are: AIM 1. Determine how hypoxia primes DCCs for dormancy. AIM 2. Determine howNG2+/Nestin+ MSCs orchestrate dormancy niches and how aging affects these mechanisms. AIM 3.Determine how tissue resident lung alveolar macrophages (AMs) dictate DCC fate and how aging impacts thefunction of these niches. Our proposal will integrate how primary lesions (early or late) may pre-program DCCsfor dormancy in defined target organ niches which further reinforce dormancy via specific cues which may beaffected by aging. This approach will aid the design of rational methods to predict dormancy onset monitorresidual cancer and develop therapies to induce and maintain dormancy or eradicate minimal residual cancer. 623104 +No NIH Category available Address;Affinity;Agonist;Biochemical;Biological Assay;Biophysics;Breast Cancer cell line;Cell Proliferation;Cells;Cessation of life;Chimera organism;Data;Dimerization;Endocytosis;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Epiregulin;ErbB4 gene;Feedback;Future;G-Protein-Coupled Receptors;Goals;Image;Kinetics;Ligands;MAP Kinase Modules;Malignant Neoplasms;Mass Spectrum Analysis;Measures;Methods;Microscopy;Motivation;Mutation;Nature;Nerve Growth Factors;Neuregulins;Oncogenic;Outcome;PC12 Cells;Pathway interactions;Phosphorylation Site;Play;Proliferating;Property;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Resistance;Role;Signal Induction;Signal Pathway;Signal Transduction;Specific qualifier value;Specificity;T-Cell Receptor;Testing;Therapeutic;Transducers;Tyrosine Kinase Receptor Inhibition;Work;cancer cell;design;dimer;epigen;insight;molecular imaging;network models;pharmacologic;receptor;response;single molecule;targeted treatment;therapeutic target;trafficking Understanding how receptor tyrosine kinase activation dynamics specify proliferative cellular responses Project NarrativeReceptor tyrosine kinases (RTKs) have been targeted therapeutically in cancer with agents designed to blockall activity and shut down aberrant signaling. The work proposed in this application will investigate whether it ispossible to alter the dynamics of receptor signaling and correct (rather than simply inhibit) aberrant signalingby oncogenic receptors causing them to promote death or quiescence of cancer cells. NCI 10678825 5/26/23 0:00 PA-19-056 5R01CA248166-04 5 R01 CA 248166 4 "XU, WANPING" 9/15/20 0:00 5/31/25 0:00 Molecular and Integrative Signal Transduction Study Section[MIST] 2091948 "LEMMON, MARK A" "LIDKE, DIANE " 3 PHARMACOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 518201 NCI 388074 130127 Project SummaryWe propose to combine biophysical imaging and biochemical approaches to address two key unansweredquestions in the field of signaling by receptor tyrosine kinases (RTKs) a principal class of therapeutic targetsin cancer where resistance to current therapies necessitates new pharmacological approaches: a. What defines the distinct set of responses and cell fate downstream of a particular RTK? b. How can different ligands for a given RTK promote distinct cellular responses?It is well known that epidermal growth factor (EGF) and nerve growth factor (NGF) promote proliferative anddifferentiative responses respectively in PC12 cells through EGFR and TrkA apparently using the same set ofsignaling pathways. Early studies showed that Erk activation kinetics plays a key role in determining thedifferent cell fates induced by these ligands with transient Erk activation being associated with proliferationand sustained Erk activation with differentiation. Rather than being defined solely by different feedback wiringin the intracellular MAP kinase cascade we and others have found that the RTK activation kinetics play adirect role in defining the dynamic properties of the signaling network. Several recent studies further argue thatthe strength of ligand-induced RTK dimers (and/or their lifetime) dictates signaling specificity offering thepossibility of dynamically-determined biased agonism in RTK signaling. To gain insight into the mechanistic basis for biased agonism in RTK signaling we propose to elucidatehow activating the same RTK intracellular region in different ways can result in dramatically different cellularresponses (proliferation vs differentiation). Our previous structural biophysical and biochemical data suggestthe hypothesis that signaling outcome is determined by RTK dimer stability and dynamics. Using intact andchimeric receptors we will test this hypothesis by asking how altering RTK dimerization kinetics influencesreceptor endocytosis post-endocytic trafficking and dynamics of the downstream signaling network. Wecombine single-molecule imaging and microscopy studies of RTK trafficking with mass spectrometry andbiochemical studies of downstream signaling networks to yield an integrated picture of this. Our primarymotivation is to investigate how modifying RTK signaling dynamics (rather than simply inhibiting RTKs) mightbe used in future therapeutic approaches in cancer. Our Specific Aims address the following questions:1 How can the same RTK intracellular region elicit orthogonal cellular responses depending on how it isactivated?2 What are the lifetimes of ErbB4/HER4 dimers induced by different neuregulin (NRG) ligands and what is the basis for their sustained signaling?Our overall goal is to understand how dimerization dynamics can define signaling specificity possibly througha kinetic proofreading similar to that seen in the T-cell receptor. 518201 +No NIH Category available Address;Adoptive Transfer;Antigen-Presenting Cells;Binding;Bone Diseases;Bone Resorption;Bone Resorption Stimulation;Cell Lineage;Cells;Cytoskeletal Modeling;Development;Disease;Disease Progression;Disease remission;Dose;Environment;Goals;Grant;Hand;Hematopoietic;Homologous Gene;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune response;Immunologic Surveillance;Immunosuppression;In Vitro;Integral Membrane Protein;Knock-out;Lesion;Link;Lytic;Malignant Neoplasms;Mediating;Metalloproteases;Mixed Lymphocyte Culture Test;Modeling;Multiple Myeloma;Mus;Osteoclasts;Pathologic;Pathway interactions;Patients;Phenotype;Play;Population;Proteins;Receptor Signaling;Regulation;Research;Role;Signal Pathway;Signal Transduction;Structure;T-Lymphocyte;Testing;Time;Work;antigen-specific T cells;bone;checkpoint receptors;collagenase 3;healing;immune cell infiltrate;immune checkpoint;in vivo;in vivo Model;knock-down;mouse model;novel;osteoclast activating factor;profiles in patients;programmed cell death protein 1;receptor;skeletal;treatment strategy Binding of MMP13 to Immune Checkpoint Receptor PD-1H links Bone Disease with Immune Suppression in Multiple Myeloma Multiple Myeloma (MM) is an incurable cancer characterized by the development of devastating lytic bonedisease and accompanied by compromised immunosurveillance. We found that matrix metallopeptidase-13(MMP-13) secreted by MM cells induces bone resorption resulting in lytic bone lesions and discovered thatMMP-13 binds to the novel immune checkpoint protein programmed death-1 homologue (PD-1H) which isexpressed on osteoclasts antigen presenting cells and T cells. This grant for the first time investigates the roleof MMP-13/PD-1H interaction and their functions in linking bone disease and immunosuppression in MMhence will form the basis for novel treatment strategies and help better understand the role of MM bonedisease in the suppressed myeloma immune environment. NCI 10678676 7/17/23 0:00 PA-20-185 5R01CA252756-03 5 R01 CA 252756 3 "HOWCROFT, THOMAS K" 8/20/21 0:00 7/31/26 0:00 Tumor Microenvironment Study Section[TME] 8658676 "LENTZSCH, SUZANNE " "FU, JING ; MAPARA, MARKUS Y." 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 468878 NCI 303447 165431 Multiple Myeloma (MM) bone disease remains one of the most dreaded complications of this still incurablecancer. Osteoclast-activating factors produced by MM cells induce osteoclasts cause excessive boneresorption and lytic bone lesions in ~80% of patients with poor healing even after achieving disease remission.In an effort to screen for potential myeloma-derived factors that activate osteoclasts we identified matrixmetalloproteinase 13 (MMP-13) to be highly secreted by primary MM cells and elevated in patients with bonedisease. MMP-13 dose-dependently induces extensive bone resorption in vitro and in vivo. In MM bone diseasemouse models MMP-13 knockdown in MM cells significantly inhibits the development of lytic bone lesionsconfirming that MMP-13 is critical for the development of multiple myeloma bone disease. It is of particularimportance that MMP-13-dependent osteoclast activation occurs independently of its enzymatic activity therebyestablishing a new paradigm in the regulation of bone resorption. In overview we have shown that MMP-13plays a pivotal role in MM-induced bone destruction.We now have compelling evidence that immune checkpoint protein programmed death-1 homolog (PD-1H) atransmembrane protein broadly expressed on various hematopoietic cell lineages serves as apreviously unrecognized signaling receptor for MMP-13. We found that Pd-1h knockout in osteoclast blocksMMP-13-induced osteoclast activation and bone resorption suggesting that MMP-13 binding to PD-1H plays acritical role in MM induced bone disease. Furthermore we show that MMP-13 has a PD-1H mediated inhibitoryeffect on T cell expansion. Mmp-13-/- antigen presenting cells have increased stimulatory capacity onalloreactive T cells in vitro. In an in vivo model of alloreactivity donor T cells expand significantly more in Mmp-13-/- recipients confirming that host MMP-13 expression mitigates the expansion of T cells.It is the central hypothesis of this grant that PD-1H is the key receptor for MMP-13 signaling and mediatesits effects on osteoclasts antigen presenting cells and T cells resulting in bone resorption andimmunosuppression in MM. We propose the following 4 Aims: 1) Define the role of PD-1H as the MMP-13receptor in osteoclasts; 2) Characterize the role of the MMP-13/PD-1H axis in skeletal remodeling and MM bonedisease; 3) Investigate the role of the MMP-13/PD-1H axis as an immune checkpoint in MM; and 4) Confirm therole of MMP-13/PD-1H axis in MM bone disease and immunosuppression in MM patients. Together our findingshighlight a previously unrecognized and new pathway of osteoclasts activation involving MMP-13/PD-1H axisthat links the bone disease with immunosuppression in MM. We propose that our work will form the basis for noveltreatment strategies in MM bone disease associated with suppressed immune response. Furthermore thisresearch will help to better understand the interaction between MM bone disease and the myeloma immuneenvironment. 468878 +No NIH Category available Address;Allogenic;Animals;Biological;Biometry;Biostatistics Core;Clinical Research;Clinical Trials;Clinical Trials Design;Consult;Data Analyses;Experimental Designs;Formulation;Goals;Hematological Disease;Immunobiology;Manuscripts;Methodology;Methods;Outcome Assessment;Phase;Population;Preparation;Principal Investigator;Procedures;Program Research Project Grants;Protocols documentation;Randomized;Reporting;Research;Research Personnel;Research Project Grants;Role;Safety;Sample Size;Statistical Data Interpretation;Translating;Writing;clinical trial analysis;data exploration;design;experience;experimental study;feasibility trial;hematopoietic cell transplantation;laboratory experiment;member;pre-clinical;preclinical study;primary endpoint;programs;protocol development;secondary endpoint Core B: Biostatistics Core NarrativeThe Biostatistics Core is essential to the design ongoing review and final analysis of preclinicalexperiments and clinical trials to translate biological questions into experimentally testablehypotheses yielding interpretable results and to insure that planned clinical trials are feasibleinvoke appropriate design and stopping rules to insure safety and are appropriately analyzedand interpreted. NCI 10678665 8/1/23 0:00 PAR-18-290 5P01CA023766-43 5 P01 CA 23766 43 9/30/97 0:00 6/30/24 0:00 ZCA1-RTRB-R 9376 11148360 "DEVLIN, SEAN " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 197953 110219 87734 Abstract:The Biostatistics Core will provide biostatistical expertise in the design conduct and analysis ofthe clinical trials animal studies and related research projects generated under this proposal.The goals of the Core are to provide biostatistical support to the six projects at all stages of theresearch. Prior to the initiation of studies Core staff will consult with investigators to reviewstudy objectives and assist in selecting efficient designs and sample sizes that will provideadequate power to address study objectives. For clinical studies a Core member will conduct aprotocol review with investigators and assist in protocol development sample sizedetermination plans for interim analyses and if applicable randomization. Core staff willperform statistical analyses and data exploration for P01 investigators using appropriatestatistical methodologies; prepare reports of results; assist investigators with the preparation ofpresentations and writing of statistical components of manuscripts; and consult on the design ofsubsequent research. The biostatistical team also has widespread experience in applied andmethodologic statistical research which will allow for the most appropriate methodologies to beutilized as well as to modify or develop new methods if needed. +No NIH Category available Acute Graft Versus Host Disease;Acute Myelocytic Leukemia;Address;Allogenic;Allografting;Anti-Bacterial Agents;Antibiotics;B lymphoid malignancy;Bacteria;Bacterial Infections;CD19 Antigens;CD19 gene;CD34 gene;CTF1 gene;Cefepime;Cell Therapy;Cells;Clinical Trials;Cytomegalovirus;Cytotoxic T-Lymphocytes;Development;Dysmyelopoietic Syndromes;EBV specific T-cells;Engraftment;Event;Fever;Future;Goals;Grant;Hematologic Neoplasms;Human Herpesvirus 4;Immune;Immunobiology;In Vitro;Infection;Maintenance;Malignant - descriptor;Multi-Drug Resistance;Natural Killer Cells;Neutropenia;Non-Neoplastic Hematologic and Lymphocytic Disorder;Outcome;Patients;Performance;Peripheral Blood Stem Cell;Pharmaceutical Preparations;Phase;Piperacillin-Tazobactam;Prevention strategy;Procedures;Program Research Project Grants;Prophylactic treatment;Randomized;Recovery;Recurrence;Recurrent disease;Regimen;Relapse;Risk;Risk Reduction;Role;Safety;Series;T-Cell Depletion;T-Lymphocyte;Testing;Time;Treatment Failure;United States;Virus Diseases;chimeric antigen receptor T cells;chronic graft versus host disease;conditioning;fecal transplantation;graft vs host disease;gut microbiome;gut microbiota;hematopoietic cell transplantation;high risk;immune reconstitution;improved;infection risk;insight;microbiome;microbiota;novel;novel strategies;open label;phase 2 study;phase I trial;phase II trial;preservation;prevent;randomized trial;relapse prevention;remediation;success Project 6: Clinical Trials Focusing on Microbiota and Novel Cell Therapies Project Narrative:Project 6 encompasses 4 clinical trials. Two trials focus on new cellular therapies. CT1 compares a novel graftmanipulation strategy (alpha/beta T cell depletion) to our established CD34 selection in patients withhematologic malignancies undergoing allogeneic HCT to enhance immune recovery. CT2 is a phase I trial of athird party derived chimeric antigen receptor T cells made from EBV Cytotoxic T Lymphocytes (EBV CD19CAR T cells). Two other trials focus on the impact of the gastrointestinal microbiota on allogeneic HCToutcomes. The completion of these trials will result in a safer and more effective HCT. NCI 10678663 8/1/23 0:00 PAR-18-290 5P01CA023766-43 5 P01 CA 23766 43 9/30/97 0:00 6/30/24 0:00 ZCA1-RTRB-R 9374 6714656 "GIRALT, SERGIO A" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Non-SBIR/STTR 2023 393942 219344 174598 Project Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an established curative strategy for a variety ofmalignant and non malignant hematologic disorders. Although significant advances have been made; 30-50%of patients will still die from either relapse infections or complications of graft versus host disease. The primaryobjective of Project 6 is to conduct a series of clinical trials (CTs) testing novel approaches that address majorchallenges to the success of alloHCT. The CTs included in this project address one of two specific aims. SA1will test and develop novel cellular approaches to prevent relapse or enhance immune reconstitution postalloHCT. This aim will be addressed by two CTs. CT1 is A randomized phase 2 study of donor allograftCD34+ selection versus TCR-+ cell depletion GVHD prophylaxis for patients undergoing allogeneichematopoietic cell transplantation for high risk hematologic malignancies in which we will compare immunereconstitution between a novel graft manipulation strategy that depletes only alpha/beta T cells and our wellestablished CD34 selection procedure. The goal of this study is to demonstrate that the novel graftmanipulation strategy will result in a more robust immune reconstitution with reduction in the risk of infectionsand improved HCT outcomes. CT2 is a Phase I Trial Using In Vitro Expanded Allogeneic Epstein-Barr VirusSpecific Cytotoxic T-Lymphocytes (EBV-CTLs) Genetically Targeted to the CD19 Antigen in B-cellMalignancies. SA2 will ascertain the impact of gastrointestinal (GI) microbiota on HCT outcomes. This aim willbe addressed through the performance of two CTs. CT3 addresses microbiome preservation through rationaleantibiotic use (Open-label phase II randomized trial of empiric treatment of fever and neutropenia (F&N) withpiperacillin-tazobactam vs. cefepime in recipients of unmodified allogeneic HCT). CT4 will test the ability of 3rdparty fecal microbiota transplants to restore microbiota diversity (Phase II Trial of 3rd Party Fecal MicrobiotaTransplantation (FMT) in Recipients of Allogeneic HCT). More than 9000 allo-HCTs will be performed in the United States this year. The two SAs with the sixproposed clinical trials in this project address the most common causes of treatment failure. The three trialsexploring the impact of the GI microbiome on HCT outcomes will either devise new strategies to prevent orremediate loss of GI microbiome diversity while at the same time increasing our understanding of themechanisms by which bacteria or their products can cause or prevent harm after an allo-HCT. The threeclinical trials proposed will test novel cellular strategies to address relapse and immune reconstitution. Thesestrategies will allow us to develop less toxic and more effective allo-HCT regimens in the future. +No NIH Category available Acute Myelocytic Leukemia;Adoption;Allogenic;Biochemistry;Biological Assay;Biological Markers;Blood;Bone Transplantation;Cessation of life;Clinical;Clinical Trials;Collaborations;DNA;Data;Data Set;Detection;Development;Diagnosis;Diagnostic Procedure;Disease remission;Evaluation;Event;Face;Flow Cytometry;Frequencies;Funding;Genes;Goals;Guidelines;Hematopoietic Neoplasms;In complete remission;Informatics;Institution;Interview;Laboratories;Leadership;Leukemic Cell;Malignant Neoplasms;Marrow;Measurable;Methods;Microscope;Molecular;Monitor;Morphology;Mutation;Mutation Detection;Newly Diagnosed;Patients;Performance;Phase;Polymerase Chain Reaction;Polymerase Gene;Protocols documentation;Relapse;Reproducibility;Residual Neoplasm;Residual state;Sensitivity and Specificity;Small Business Innovation Research Grant;Standardization;Stem cell transplant;Technology;Testing;Transplantation;Transplantation Conditioning;United States;Variant;acute myeloid leukemia cell;aggressive therapy;chemotherapy;clinical decision-making;clinical remission;cohort;detection limit;detection method;drug development;evidence base;exome;gene panel;genetic variant;genome sequencing;genomic locus;hematopoietic cell transplantation;high risk;improved;leukemia;mortality;next generation sequencing;novel therapeutics;patient subsets;post-transplant;prognostic value;programs;prospective;relapse prediction;relapse risk;research study;standard of care;tool;tumor;whole genome Development of a Universal Assay for Minimal Residual Disease in Acute Myeloid Leukemia using Duplex Sequencing PROJECT NARRATIVEDespite the fact that most patients with acute myeloid leukemia receiving intensive chemotherapy are able toachieve a remission many have residual disease below the level of morphological detection (measurableresidual disease MRD) which eventually leads to relapse. Current methods of MRD detection are limited insensitivity are not applicable to all AML patients and are challenging to perform and interpret. In this Phase 2bproject we propose utilizing our Duplex Sequencing AML-29 MRD assay to generate a comprehensive clinicalutility data set through a collaboration with the world-class US National Marrow Donor Program (NMDP). Thecurrently accruing MEASURE (Molecular Evaluation of AML patients after Stem cell transplant to UnderstandRelapse Events) protocol offers a historical opportunity to generate definitive evidence of the clinical utility ofour commercial DuplexSeq AML MRD testing product before and after bone transplant in a 500 patient cohort. NCI 10678621 8/15/23 0:00 RFA-CA-22-025 2R44CA233381-05A1 2 R44 CA 233381 5 A1 "ZANE, LINDA KARINE" 7/16/18 0:00 7/31/26 0:00 ZCA1-TCRB-J(J2) 10380432 "HIGGINS, JACOB EMERSON" Not Applicable 7 Unavailable 80451837 HPY9BJWV8X31 80451837 HPY9BJWV8X31 US 47.644796 -122.228737 10043592 "TWINSTRAND BIOSCIENCES, INC." SEATTLE WA Domestic For-Profits 981211044 UNITED STATES N 8/15/23 0:00 7/31/24 0:00 394 SBIR/STTR 2023 1139103 NCI 774900 309960 Problem: With a 5-year survival of ~30% AML is the 6th deadliest cancer and >20000 new patients arediagnosed each year in the United States. Although most patients achieve Complete Remission (CR) withaggressive therapy most will eventually relapse. The criteria for CR however is based on historical diagnosticmethods and patients in CR may carry up to 1010 residual leukemia blasts. Significant effort has gone intodeveloping tools to detect Minimal amounts of Residual Disease (MRD) including multi-parametric flowcytometry (MFC) and polymerase chain reaction (PCR). MRD is the strongest predictor of relapse and severalAML trials have demonstrated that survival was significantly better when MRDpos patients were subjected tointensified therapy. Yet lack of sensitivity is a clear problem with MFC and PCR. For example relapses occurin ~40% of patients who are MRDneg by MFC after chemotherapy. Next Generation Sequencing (NGS) holds thepromise to identify MRD by detecting mutations associated with residual AML cells. Yet the sensitivity ofconventional NGS is limited by a relatively high error rate which makes it difficult to differentiate sequencingerrors from true low-frequency mutations. Solution: Duplex Sequencing (DS) is an ultra-sensitive NGStechnology which uses specialized biochemistry and informatics to improve the accuracy of standard DNAsequencers by more than ten-thousand-fold. In our prior Phase I SBIR study we developed a broadly-applicableDS-based AML MRD assay that overcomes the above limitations. The DS assay targets many MRD-relevantgenes simultaneously with sensitivity and specificity rivaling or exceeding single-gene PCR assays. In Phase IIwe demonstrated excellent reproducibility across labs applied the optimized assay to retrospectively bankedcohorts and showed superior clinical performance vs. MFC. However based on many customer interviews themost substantial barrier to widespread commercial adoption we face is the lack of large-scale prospective clinicaltrial data. Specific Aims: In the present Phase 2b application we propose generating this comprehensive clinicalutility data set through collaboration with the world-class US National Marrow Donor Program (NMDP) and othertop AML MRD key opinion leaders. The primary goals of our proposed study include: Aim 1: Prospectivelyvalidate the prognostic value of pre-transplantation DS AML MRD testing for predicting post-transplant relapseand survival; Aim 2: Prospectively generate data supporting the ability of post-transplantation DS AML MRDtesting to assess relapse risk for patients treated with different transplant conditioning intensities; and Aim 3:Demonstrate the potential of using tumor-informed DS AML MRD testing for patients without a driver gene varianttargeted by our fixed gene panel. Impact: This combined approach may bring NGS MRD testing up to 100%patient applicability. Blood MRD comparison may present an equally sensitive but less invasive alternative tomarrow. Our anticipated data will also support the use of the technology in assigning high-risk patients tointensified therapies and as an early marker of anti-leukemic efficacy for novel drug development efforts. 1139103 +No NIH Category available ATAC-seq;Address;Affect;BRCA2 gene;Binding;Biochemical;Biological;Biological Assay;Biological Models;Breast Cancer Treatment;California;Cancer Patient;Cell Line;Cell Survival;Cessation of life;Chromatin;Clinical;Clinical Trials;Collagen;Collagen Type I;DNA Damage;Data;Deposition;Extracellular Matrix;Extracellular Matrix Degradation;Failure;Fibronectins;Fibrosis;Gene set enrichment analysis;Genes;Genetic Transcription;Genomics;Glean;Goals;Grant;Hormonal;Hour;Impairment;In Vitro;Incidence;Knowledge;Laminin;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metalloproteases;Modeling;Molecular;Mutation;Pathogenicity;Pathologic;Pathway interactions;Patients;Phosphotransferases;Plasmin;Plasminogen Activator Inhibitor 1;Poly(ADP-ribose) Polymerase Inhibitor;Poly(ADP-ribose) Polymerases;Polymerase;Promoter Regions;Prostate;Proteins;RNA analysis;Recurrence;Resistance;Resistance development;Risk;Role;SERPINE1 gene;San Francisco;Signal Pathway;Signal Transduction;Solid Neoplasm;Stains;System;Tissues;Transcriptional Activation;Trichrome stain;United States;United States Food and Drug Administration;Universities;Up-Regulation;Urokinase;advanced breast cancer;advanced prostate cancer;cancer cell;carcinogenesis;castration resistant prostate cancer;clinical prognosis;clinically relevant;in vitro activity;in vivo;in vivo Model;inhibitor;inhibitor therapy;men;mutant;new therapeutic target;novel;overexpression;patient derived xenograft model;prevent;prostate cancer model;response;small molecule;therapy resistant;transcription factor USF;transcriptome sequencing;treatment response;tumor Elucidating mechanisms of therapy response in BRCA2 mutant prostate cancers PROJECT NARRATIVEPoly (ADP-ribose) polymerase inhibitors (PARPis) were recently approved to treat advanced BRCA2 mutantprostate cancers yet little is known about the molecular response of these tumors to this therapy. This proposalemploys novel model systems of BRCA2 mutant prostate cancer to explore the molecular alterations that occurin response to PARPi therapy with specific focus on extracellular matrix (ECM) pathways identified in preliminaryresults. The proposed studies will interrogate the impact of PARPi on ECM modulation and examine thecontribution of the ECM gene SERPINE1 with the long-term goal of utilizing the knowledge gleaned to developnovel targeted therapies. NCI 10678578 6/13/23 0:00 PA-21-049 1F30CA281268-01 1 F30 CA 281268 1 "PURI, ANU" 8/1/23 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 15914864 "HOFSTAD, MIA E" Not Applicable 30 INTERNAL MEDICINE/MEDICINE 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 38431 NCI 38431 0 ABSTRACTProstate cancer is the most common non-skin malignancy in men and is projected to cause 34500 deaths in2022 in the United States alone. Sequencing studies of advanced lethal castrate resistant prostate cancer(CRPC) have identified a high incidence (~13%) of pathogenic BRCA2 mutations. These findings have enabledclinical trials and subsequent Food and Drug Administration (FDA) approval of the poly (ADP-ribose) polymerase(PARP) inhibitors (PARPis) olaparib and rucaparib in advanced CRPC patients harboring a pathogenic BRCA2mutations. Despite initial responses therapy resistance to PARPis is common. However the molecularadaptations that occur in BRCA2 mutant CRPC in response to PARPi are poorly understood due to a lack ofbiologically and clinically relevant models. Our proposed studies leveraging two new patient-derived modelsystems of pathogenic BRCA2 mutant CRPC will elucidate the biological mechanisms implicated in PARPitherapy response and help address a critical clinical unmet need to prevent or overcome resistance to PARPis.In this proposal we will use two new models of pathogenic BRCA2 mutations in CRPC including the 40511cell line and matched PARPi-sensitive and resistant LTL-610 PDXs. Gene Set Enrichment Analysis (GSEA) andOver-Representation Analysis (ORA) of RNA-sequencing data utilizing these novel models point to significantupregulation in genes involved in Extracellular Matrix (ECM) modulation in response to both short and long termPARPi therapy. In particular the ECM associated gene SERPINE1 which encodes for the protein PlasminogenActivator Inhibitor 1 (PAI-1) is the most significantly implicated gene after 72 hours of olaparib treatment viaGSEA leading edge analysis. Since PAI-1 canonically prevents ECM degradation we then used MassonsTrichrome staining to evaluate the PARPi resistant LTL-610 PDX and found dramatically increased Type ICollagen deposition compared to its PARPi sensitive parental line. Since stromal alterations are known to affectcancer cell survival we hypothesize that the induction of ECM genes like SERPINE1 by PARPis in BRCA2mutant CRPC results in enhanced tumor stroma and enables therapy resistance. Two specific aims areproposed in this grant to study this hypothesis: in Aim 1 we will elucidate the role of SERPINE1 signaling inECM deposition in BRCA2 mutant CRPC in vitro ex vivo and in vivo. In Aim 2 we will investigate the mechanismof transcriptional activation of SERPINE1 in BRCA2 mutant CRPC in response to PARPi. The results from thesestudies will enable systematic approaches to modulate ECM alterations in response to PARPi in BRCA2 mutantCRPCs. 38431 +No NIH Category available Acetic Acids;Affect;Africa;Biological Specimen Banks;Buffers;Cell Line;Cellular Phone;Cervical;Cervical Cancer Screening;Cessation of life;Clinical;Collection;Communicable Diseases;Computer software;Country;Cytology;Cytolysis;DNA;DNA amplification;Detection;Development;Diagnosis;Disease;Doctor of Philosophy;Educational process of instructing;Ensure;Environment;Equipment;Fluorescence;Freeze Drying;Genomic DNA;Goals;HIV-1;HPV-High Risk;Heating;Hela Cells;Human Papillomavirus;Human Resources;Human papilloma virus infection;Human papillomavirus 16;Human papillomavirus 18;Image;Image Analysis;Improve Access;Infrastructure;Life;Malignant neoplasm of cervix uteri;Membrane;Mentorship;Microfluidic Microchips;Microscope;Monitor;Morbidity - disease rate;Mozambique;Nucleic Acid Amplification Tests;Nucleic Acids;Optics;Pap smear;Paper;Pathology;Patients;Performance;Pilot Projects;Plastics;Polymerase;Preventive measure;Process;Reaction;Reagent;Recommendation;Reporting;Resource-limited setting;Resources;Risk;Sampling;Site;Specificity;Specimen;System;Technology;Testing;Time;Training;Translating;Translational Research;Translations;Tube;Update;Visual;Woman;Work;World Health Organization;burden of illness;cervical cancer prevention;cost;design;detection limit;detection platform;efficacy testing;experience;fluorescence imaging;imager;imaging platform;imaging system;improved;instrument;isothermal amplification;low and middle-income countries;medically underserved;mortality;multidisciplinary;new technology;novel;point of care;recombinase;screening;screening program;success;synthetic construct;two-dimensional;underserved area;underserved community;usability Low-cost integrated nucleic acid amplification testing platform for cervical cancer screening in low- and middle-income countries PROJECT NARRATIVECervical cancer is a life-threatening pathology highly associated with human papilloma virus (HPV) infectionthat disproportionally affects low- and middle- income countries. A major barrier in implementing and sustainingscreening programs for cervical cancer in low-resource countries is the lack of an affordable and effectivescreening test that can provide HPV results at the point-of-care. This proposal will develop and evaluate anovel DNA-based approach that combines isothermal recombinase polymerase amplification with fluorescentquantification in an accurate and low-cost test which could improve access to cervical cancer screening andsignificantly decrease mortality due to the disease. NCI 10678488 5/19/23 0:00 PA-21-049 1F30CA281115-01 1 F30 CA 281115 1 "DAMICO, MARK W" 6/1/23 0:00 8/31/26 0:00 Special Emphasis Panel[ZRG1-F05-Q(20)L] 78009839 "MAKER, YAJUR NAMAN" Not Applicable 9 BIOMEDICAL ENGINEERING 50299031 K51LECU1G8N3 50299031 K51LECU1G8N3 US 29.717236 -95.402761 9291001 RICE UNIVERSITY HOUSTON TX BIOMED ENGR/COL ENGR/ENGR STA 770051827 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 PROJECT SUMMARY/ABSTRACTAn estimated 90% of cervical cancer related deaths take place in low- and middle-income countries (LMICs)where the burden of disease is highest and there is limited access to effective screening and diagnosis [1]. InJuly 2021 the World Health Organization updated their recommended approach for cervical cancer screeningto focus on human papillomavirus (HPV) DNA testing. However it remains difficult for many women to accessHPV DNA testing due to the necessary costs high level of infrastructure and requirement for trainedpersonnel. Compared to expensive commercial platforms a variety of promising point-of-care (POC) strategieshave proposed isothermal amplification of DNA as an affordable avenue for testing [2][6]; however there areimportant gaps to fully incorporate integrated sample-to-answer platforms that eliminate the risk of workspacecontamination and subsequent false positive results. The objective of this project is to develop a low-cost(<$3/test $500/instrument) fully integrated quantitative HPV DNA test platform that is simple to use foreffective HPV screening at the POC. The Richards-Kortum lab has shown that isothermal amplification withRecombinase Polymerase Amplification can be performed in paper membranes [7]. More recently the Posnergroup demonstrated the capability to detect discrete fluorescent amplification nucleation sites using a papermembrane to quantify HIV-1 DNA using a mobile phone-based imager [8]. This proposal builds upon recentadvances to design a two-dimensional paper microfluidic device and low-cost imaging platform for detection ofhigh risk HPV types HPV16 and HPV18 the primary causes of cervical cancer. This proposal will accomplishthese goals by pursuing the following three specific aims: 1) Designing a test to accept and process cervicalcytology specimens with pre-loaded lyophilized reagents for amplification of HPV 16/HPV 18 DNA 2)Developing a low-cost instrument including a heater and fluorimeter to monitor multiplexed real-timeisothermal nucleic acid amplification reactions and 3) Conducting a proof-of-principle study to assess usabilityand efficacy of the test and instrument designed using banked clinical samples in Houston and within a lowresource setting in Mozambique Africa. Sensitivity specificity and limit of detection analysis will be used todetermine comparability to gold standard technologies. Completing these aims will improve cervical cancerscreening and reduce morbidity and mortality in underserved areas of the world. This project benefits greatlyfrom co-mentorship from Dr. Rebecca Richards-Kortum and her colleague Kathleen Schmeler who both haveextensive experience in evaluating new technologies for cervical cancer prevention and translating them tolow-resource settings. The training plan and environment have been specifically tailored focusing on multi-disciplinary hands-on coursework lab work and teaching and translational research aims with deploymentwithin an LMIC to ensure project success and scalability. 52694 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Genetics; Health Services; Orphan Drug; Pediatric; Pediatric Cancer; Prevention; Radiation Oncology; Rare Diseases; Rehabilitation Address;Adolescent;Aging;Biological;Cancer Survivorship;Child;Childhood;Childhood Cancer Survivor Study;Cohort Studies;Communities;DNA sequencing;Data;Data Analyses;Data Collection;Diagnosis;Disease susceptibility;Ecosystem;Ensure;Functional disorder;Funding;Future;Genetic Predisposition to Disease;Genotype;Goals;Grant;Guidelines;Health;Health Services Research;Healthcare Systems;Home;Immunotherapy;International;Intervention;Intervention Trial;Investigation;Knowledge;Late Effects;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Modeling;Morbidity - disease rate;Neurocognitive;Outcome;Participant;Patients;Performance;Phenotype;Physiological;Population;Provider;Publications;Publishing;Quality of life;Radiation;Research;Research Personnel;Resources;Risk;SNP array;Source;Survival Rate;Survivors;Time;Visualization;age related;base;biobank;care costs;career;childhood cancer survivor;clinical care;cloud based;cohort;data access;data tools;follow-up;genetic analysis;health related quality of life;high risk population;improved;innovation;mortality;multidisciplinary;novel therapeutics;proton beam;randomized trial;recruit;sample collection;screening guidelines;shared database;sharing platform;survivorship CHILDHOOD CANCER SURVIVOR STUDY: Somatic and Germline Sequencing RELEVANCESurvival rates for many childhood and adolescent cancers have improved at a remarkable pace over the pastfive decades. The CCSS cohort has been the source of some of the most significant publications to dateaddressing the long-term mortality morbidity and quality of life of survivors of childhood cancer. Understandingthe risk for late effects of childhood cancer and its therapy provides the basis for health screeningrecommendations and interventions that can mitigate long-term health problems in this high-risk population. NCI 10678480 9/9/22 0:00 PA-20-272 3U24CA055727-28S1 3 U24 CA 55727 28 S1 "HENDERSON, LORI A" 7/20/93 0:00 11/30/26 0:00 8819228 "ARMSTRONG, GREGORY " Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 8/6/22 0:00 11/30/22 0:00 395 Other Research-Related 2022 3847289 NCI 3458196 389093 ABSTRACTThe Childhood Cancer Survivor Study (CCSS) is a multi-institutional multi-disciplinary collaborative researchresource established to systematically evaluate long-term outcomes among children diagnosed with cancer whosurvived five or more years from diagnosis. With the successful recruitment and longitudinal follow-up of thecohort that includes survivors diagnosed and treated over three decades (1970-1999) the CCSS is the worldslargest established open resource for survivorship research with 38036 eligible survivors available forinvestigation of late mortality and 25665 participants who have contributed health-related and quality of lifeoutcomes. The resource includes comprehensive annotation of treatment exposures ongoing longitudinalfollow-up and an established biorepository from which genotype (SNP array) and DNA sequencing of 8380survivors are available to investigators for identification of genetic susceptibility for disease- and treatment-related late effects. Extensive use by the research community has resulted in: 381 published or in pressmanuscripts now cited over 26500 times; 347 presented abstracts; 59 investigator-initiated grants fundedtotaling $67 million in funding; utilization by a diverse group of 1225 investigators including 91 early careertrainees; conduct of 11 randomized trials; increased knowledge to inform exposure-based clinical careguidelines; and a highly successful model for multiple national and international collaborative initiatives ofpediatric cancer survivorship research. During the next five years activities will ensure the functioning of CCSSas a strong and productive resource by maintaining enhancing and promoting its use. We will expand thecollection of data to evaluate physiologic and neurocognitive function with aging characterize accelerated agingand investigate underlying pathophysiology of aging of survivors as they enter into their fourth fifth and sixthdecades of life. To develop a population resource for intervention trials targeting age-related outcomes in-homefunctional performance assessment and specimen collection will be performed in a sub-cohort of 1000 survivors.Further we will enhance the CCSS resource by facilitating the conduct of health services research throughcollection of data to evaluate patient provider and health care system factors and their associations with accessquality and cost of care. To maximize the research communitys access and use of the CCSS resource we willleverage a cloud-based data sharing platform and develop a data analysis ecosystem with tools for data accessvisualization and analysis of genetic treatment and phenotypic/outcome data. In the future assessment of lateoutcomes of novel therapies (immunotherapy targeted/biologic proton beam radiation) will be essential.Therefore with NCI oversight CCSS will formulate a comprehensive plan for future expansion. These initiativeswill enhance and promote CCSS to further achieve the overarching goal of the CCSS resource to increase theconduct of innovative and high impact research related to pediatric cancer survivorship. 3847289 +No NIH Category available Accounting;Acute Myelocytic Leukemia;Adopted;Automobile Driving;Biological Assay;Blood;CD86 gene;CRISPR screen;CRISPR/Cas technology;Cell Cycle;Cell Differentiation process;Cell model;Cells;Cellular Assay;Cessation of life;ChIP-seq;Characteristics;Chromatin;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Combinatorics;Combined Modality Therapy;Data;Differentiated Gene;Differentiation Therapy;Disease;Disease remission;Epigenetic Process;Experimental Models;Genes;Genomics;Hematopoietic Neoplasms;Human;Human Cell Line;ITGAM gene;Individual;KDM1A gene;Libraries;MLL-rearranged leukemia;Malignant Neoplasms;Menin;Methodology;Methods;Modeling;Molecular;Mus;Myelogenous;Oncogenes;Pathway interactions;Patients;Pharmacologic Substance;Phenotype;Prognosis;Progranulocytes;Proliferating;Proteins;Regulation;Relapse;Reporting;Repression;Rest;Role;Sampling;Surface;Testing;Therapeutic;Transcription Coactivator;Transcription Repressor;Treatment Efficacy;Xenograft Model;acute myeloid leukemia cell;chemotherapy;cofactor;cohort;combinatorial;cytotoxicity;derepression;differential expression;epigenomics;experimental study;gene repression;histological stains;histone demethylase;improved;in vivo;inhibitor;interest;leukemia;mouse model;novel;pharmacologic;preclinical efficacy;prevent;progenitor;programs;self-renewal;small molecule;small molecule inhibitor;standard of care;stem;stemness;synergism;targeted treatment;therapeutic evaluation;transcription factor;transcriptome sequencing;transcriptomics;transplant model;treatment strategy Differentiation-focused CRISPR Screen identifies LSD1 and Menin as combination therapy targets that induce terminal differentiation in AML Project Narrative Differentiation therapy is curative in one subtype of Acute Myeloid Leukemia (AML) and underexplored in therest. We conducted gain-of-differentiation screens in AML models and identified that combined inhibition of LSD1and MEN1 synergizes to induce terminal potentially curative differentiation in many AMLs. Validating thetherapeutic efficacy of these pre-clinical differentiation therapy targets and determining the mechanisms ofinhibitor-induced differentiation will change the principles of AML treatment strategies. NCI 10678478 8/11/23 0:00 PA-21-052 1F31CA281117-01 1 F31 CA 281117 1 "DIBELLO, ANTHONY THOMAS" 9/1/23 0:00 8/31/25 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16287270 "CARRERA RODRIGUEZ, MARIA FERNANDA" Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 Project Summary Acute myeloid leukemia (AML) is a lethal blood cancer characterized by a differentiation block that preventsmyeloid progenitor maturation resulting in uncontrolled proliferation. Chemotherapy the current standard of careis often ineffective and can result in cytotoxicity and relapse. New treatment options are desperately needed totreat AMLs poor prognosis. Differentiation therapy is a novel method that aims to reactivate latent maturationprograms and induce cell cycle exit. This therapeutic strategy is curative in the promyelocytic (APL) AML subtypebut underexplored in other AMLs. Epigenetic factors help sustain the characteristic AML differentiation block.The demethylase LSD1 has emerged as a promising target for differentiation therapy. Pharmacologic inhibitionof LSD1 (LSD1i) induces cellular differentiation in many AML subtypes. However the extent of differentiationvaries between AML models with a modest effect in aggressive AML models. Therefore LSD1i will not induceterminal differentiation as a monoagent treatment. We hypothesized that targeting additional epigeneticregulators simultaneously with LSD1i may induce complete terminal differentiation and lead to diseaseremission. To identify potentiators of LSD1i we conducted CRISPR gain-of-differentiation screens with achromatin-focused sgRNA library in multiple AML cell models with or without LSD1i co-treatment. These screensunveiled a synergistic induction of differentiation when KO of MEN1 is combined with LSD1i. I confirmed thatcombinatorial small molecule inhibition of LSD1 and MEN1 induces differentiation and reduces proliferation mostcommonly in MLL-rearranged AMLs and to a lesser extent in selected MLL-wild type AMLs. This proposal hastwo aims: First I will test the therapeutic potential of targeting MEN1 in combination with LSD1 inhibitors inprimary patient samples ex vivo and in patient-derived AML transplant models. Patient samples will be treatedwith a MEN1 inhibitor in combination with LSD1 inhibitors and effects on differentiation and proliferation will bequantified. Secondly I will determine the epigenomic mechanisms by which MEN1 and LSD1 inhibition synergizeto induce terminal differentiation and then test whether these mechanisms are conserved in primary patientsamples. 47694 +No NIH Category available 3-Dimensional;Abdomen;Acute;Address;Adult;Affect;Angiography;Animal Model;Applications Grants;Area;Arteries;Authorization documentation;Award;Biodistribution;Blood;Brain;Brain Diseases;Cancer Detection;Cancer Survivor;Central Nervous System;Chronic Kidney Failure;Clinical;Clinical Data;Clinical Trials;Compensation;Contrast Media;Cyclic GMP;Deposition;Devices;Diagnostic Neoplasm Staging;Disease;Dissociation;Dose;Drug Kinetics;Electrocardiogram;End stage renal failure;Enhancing Lesion;Enrollment;Equilibrium;European;Excretory function;Family suidae;Future;Gadolinium;General Hospitals;Goals;Grant;Hepatobiliary;High-Risk Cancer;Image;Injections;Injury to Kidney;Ions;Kidney;Kidney Diseases;Kidney Failure;Lesion;Life;Macaca fascicularis;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of brain;Manganese;Marketing;Massachusetts;Medical;Medicine;Metals;Modeling;Monkeys;Mus;Myocardial Infarction;Nephrogenic Systemic Fibrosis;New Agents;Papio;Patient Monitoring;Patient imaging;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology Study;Phase;Physicians;Population;Rattus;Renal function;Resolution;Risk;Rodent;Safety;Signal Transduction;Site;Suspending Agents;Technology;Time;Toxic effect;Toxicology;United States National Institutes of Health;Venous blood sampling;Vial device;Woman;adverse event monitoring;authority;bone;chemotherapy;clinical development;comorbidity;contrast enhanced;contrast enhanced computed tomography;contrast imaging;first-in-human;follow-up;glomerular filtration;high risk;imaging study;improved;invention;manufacture;nephrotoxicity;patient population;phase 1 study;safety assessment;safety testing;screening;tumor;uptake Manganese Based MRI Contrast Agent Project NarrativeGadolinium based contrast agents (GBCAs) are used with MRI to detect and stage cancers and other diseasesand to guide treatment. However there are safety concerns about the potentially toxic gadolinium metal ion. Wehave invented a gadolinium-free contrast agent to replace GBCAs. The goal of this proposal is to test the safetyand imaging efficacy of this new agent RVP-001 in patients with brain cancer or other brain disorders. NCI 10678476 6/6/23 0:00 RFA-CA-22-025 9R44CA261240-04A1 9 R44 CA 261240 4 A1 "EVANS, GREGORY" 6/5/23 0:00 5/31/25 0:00 ZCA1-TCRB-J(J2) 14731324 "HOFFMAN, VERA " Not Applicable 5 Unavailable 80345910 LAS2A8MTAR45 80345910 LAS2A8MTAR45 US 42.384566 -71.117011 10042814 REVEAL PHARMA CAMBRIDGE MA Domestic For-Profits 21402239 UNITED STATES N 6/5/23 0:00 5/31/24 0:00 395 SBIR/STTR 2023 2025000 NCI 1358945 533578 Gadolinium (Gd)-based MRI contrast agents (GBCAs) are used in clinical magnetic resonance imaging (MRI)for cancer detection and staging particularly of primary and metastatic brain cancers. However there areconcerns about the potential long-term toxicity of GBCAs. GBCAs cause nephrogenic systemic fibrosis (NSF)a devastating disorder that affects patients with kidney disease. FDA imposed a black box warning againstGBCA use in this population. This has a significant medical impact: 16% of US adults suffer from moderate orsevere chronic kidney disease (CKD) and this patient population is disproportionately afflicted with comorbiditieslike cancer (where many chemotherapies are nephrotoxic). There is no alternative imaging for these patients.Contrast enhanced CT can cause acute and irreversible kidney injury and is also contraindicated. All GBCAscause accumulation of Gd in the brain and bone even in patients with normal kidney function. Gd is highly toxicin its free form and little is known about the toxicological implications of deposited Gd: concern is rising amongphysicians patients and regulatory agencies. In 2017 the FDA announced a new class warning for all GBCAs.The European Medicines Agency suspended the marketing authorizations for the 4 GBCAs that are associatedwith the highest risk of Gd deposition and arguably may have removed all GBCAs had there been a safe Gd-free alternative. Accumulation of Gd is particularly worrisome for cancer survivors and those at high risk forcancer e.g. BRCA positive women. They require regular GBCA-enhanced MRIs for surveillance or screeningand may have dozens of MRIs through life. Avoiding GBCAs forces physicians to make key patient managementdecisions with limited imaging information while continued use may put these vulnerable patients at risk. Reveal Pharmaceuticals is developing the gadolinium-free MRI contrast agent RVP-001 invented atMassachusetts General Hospital. RVP-001 provides equivalent image contrast to commercial GBCAs in differentanimal models. Manganese (Mn) injected as RVP-001 is more efficiently eliminated than Gd from an equal doseof Gd-DOTA which is considered the best in class GBCA for safety with respect to stability. Nonclinical studiesestablished a very high safety margin for RVP-001. A Phase 1 study to assess safety tolerability andpharmacokinetics in healthy subjects demonstrated that RVP-001 is safe and well tolerated up to doses higherthan the anticipated clinical dose. This grant will support first in human MR imaging studies. We will perform adose range finding study in patients with GBCA-enhancing central nervous system lesions e.g. brain cancersto assess imaging efficacy pharmacodynamics and safety. We will assess the degree of RVP-001 lesionenhancement compared to unenhanced MRI and compared to the patients GBCA enhanced MRI. The goal ofthe study is to establish an effective dose for further clinical development and approval. This grant application is predicated on the Fast Track NIH grant award R44 DK113906-03 and is aresubmission of the grant application 9 R44 CA261240-04 2025000 +No NIH Category available Adjuvant Chemotherapy;Antioxidants;Binding;Blocking Antibodies;Breast Cancer Cell;Breast Cancer Patient;Breast-Conserving Surgery;Cell Death;Cell Survival;Cells;DNA Damage;Data;Effectiveness;Extinction;Failure;Fellowship;Gene Expression Profile;Genes;Genetic Transcription;Goals;Growth;Homeostasis;In complete remission;Literature;Mediating;Metabolic;Metabolic Pathway;Molecular;Nature;Neoadjuvant Therapy;Neuropilin-2;Nitric Oxide;Nitric Oxide Synthase;Nuclear;Organoids;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pathologic;Pathway interactions;Patients;Phenotype;Physicians;Population;Prognosis;Property;Radiation;Radiation Tolerance;Radiation therapy;Reactive Inhibition;Reactive Oxygen Species;Recurrence;Regulation;Research;Residual Neoplasm;Resistance;Role;Scientist;Signal Induction;Signal Transduction;Surgical Management;Survival Rate;Technology;Testing;Therapeutic;Training;Variant;Vascular Endothelial Growth Factors;Vascular Endothelium;bench to bedside;cancer stem cell;cancer subtypes;carcinogenesis;clinically significant;effectiveness evaluation;improved;in vivo Model;insight;irradiation;knock-down;malignant breast neoplasm;molecular subtypes;neoplastic cell;novel;novel therapeutic intervention;patient derived xenograft model;pre-clinical;radiation resistance;radioresistant;receptor;relapse patients;relapse prevention;resistance mechanism;response;self-renewal;single-cell RNA sequencing;stem cells;targeted treatment;therapeutic target;therapy outcome;therapy resistant;traditional therapy;treatment response;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor heterogeneity VEGF/Neuropilin-2 Signaling and Radioresistance in Triple-Negative Breast Cancer PROJECT NARRATIVEThis proposal will investigate a novel mechanism that contributes to radioresistance. Specifically I will focus onthe role of Vascular Endothelia Growith Factor (VEGF) binding to Neuropilin-2 (NRP2) in limiting oxidative stressduring radiation treatment. Furthermore I will collect preclinical data regarding the use of a function blockingantibody against VEGF/NRP2 (aNRP2-10) during radiation treatment to examine its efficacy as a noveltherapeutic approach for TNBC patients. NCI 10678449 6/8/23 0:00 PA-21-049 1F30CA275327-01A1 1 F30 CA 275327 1 A1 "PURI, ANU" 6/28/23 0:00 3/27/27 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16080629 "KUMAR, AYUSH " Not Applicable 2 ANATOMY/CELL BIOLOGY 603847393 MQE2JHHJW9Q8 603847393 MQE2JHHJW9Q8 US 42.2802 -71.758245 850903 UNIV OF MASSACHUSETTS MED SCH WORCESTER WORCESTER MA SCHOOLS OF MEDICINE 16550002 UNITED STATES N 6/28/23 0:00 6/27/24 0:00 398 "Training, Individual" 2023 34855 NCI 34855 0 PROJECT SUMMARYTriple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer with standard therapy involvingneoadjuvant chemotherapy surgical management and radiation therapy. However the high recurrence rate andlow pathological complete response of TNBC suggest that radioresistance is a critical factor in the diminishedtherapeutic efficiency of the current treatment strategy. There is limited literature exploring the specific pathwaysresponsible for radiation resistance in TNBC but most data support the role of limiting reactive oxygen species(ROS) accumulation. Our lab has studied the role of Vascular Endothelia Growth Factor (VEGF) binding toNeuropilin-2 (NRP2) and initiating several cancer stem cell properties. Preliminary data indicate that radiationenriches for NRP2 expressing cells and using a function blocking antibody specific to VEGF/NRP2 withirradiation decreases cell viability compared to either treatment alone in a TNBC organoid. The centralhypothesis of this proposal is that VEGF/NRP2 induces radioresistance by altering redox homeostasis andcan be targeted for better therapeutic outcomes in TNBC. This proposal will seek to investigate a possiblerole of NRP2 regulating NOS2 transcription and its contribution to mitigating ROS accumulation. I will also usesingle-cell RNA sequencing technology to identify the subpopulations of TNBC that are radioresistant andwhether they utilize the NRP2/NOS2 signaling axis. Another aspect of this proposal is to observe theeffectiveness of a function blocking antibody of NRP2 with radiation using an in vivo model. I plan to identify ifthis approach reduces the radioresistant clones in TNBC. The completion of this proposal will heighten theunderstanding of radioresistance in TNBC and identify a novel molecular pathway responsible for this phenotype. 34855 +No NIH Category available 3-Dimensional;Address;Adult;Anxiety;Authorization documentation;Biopsy;Client;Clinical;Consultations;Contracts;Country;Data;Development;Devices;Diagnosis;Diagnostic;Diagnostic Errors;Documentation;Engineering;Equipment;Equipment and Supplies;Evaluation;Failure;Feedback;Funding;General Practitioners;Health Sciences;Hearing;Hematoxylin and Eosin Staining Method;Histology;Hospitals;Hour;Human;Image;Imaging Device;Immunohistochemistry;Instruction;Laboratories;Malignant Neoplasms;Manufacturer;Marketing;Molecular Analysis;Morphologic artifacts;Noise;Output;Pathologic;Pathologist;Pathology;Patient Care;Patients;Phase;Preparation;Privatization;Procedures;Prostatic Neoplasms;Qualifying;Readiness;Recording of previous events;Records;Remote Consultation;Research;Research Contracts;Research Design;Resolution;Risk;Risk Management;Savings;Scanning;Signal Transduction;Slice;Slide;Small Business Innovation Research Grant;Specimen;System;Technology;Testing;Thick;Tissue imaging;Tissues;Translating;United States National Institutes of Health;Validation;Wait Time;Waxes;Work;Workload;authority;breast cancer diagnosis;cancer diagnosis;cancer subtypes;clinical development;clinical diagnostics;cost;design;digital imaging;digital pathology;digital platform;experience;falls;health economics;imaging platform;improved;interest;machine vision;malignant breast neoplasm;manufacture;medical schools;multiphoton microscopy;novel;preservation;pressure;prospective;response;stem;submicron;tissue processing;verification and validation;whole slide imaging Commercial Readiness for Direct-to-Digital Pathology Project NarrativeApplikate Technologies has developed a new direct-to-digital platform for processing and imaging tissuebiopsies that will reduce errors lower costs and enable same-day diagnosis for patients waiting to hear if theyhave cancer. This proposal will provide funds to develop risk and quality management systems and to collectthe clinical and non-clinical validation data all of which is necessary for regulatory approval by the FDA. NCI 10678409 9/19/23 0:00 RFA-CA-22-025 2R44CA189522-04A1 2 R44 CA 189522 4 A1 "ZHAO, MING" 9/19/23 0:00 12/31/23 0:00 ZCA1-TCRB-J(J2) 12052274 "LEVENE, MICHAEL JOHN" "TORRES, RICHARD " 4 Unavailable 79159115 ZB4HQTBNJ6D4 79159115 ZB4HQTBNJ6D4 US 41.220386 -73.330183 10035356 "APPLIKATE TECHNOLOGIES, INC." WESTON CT Domestic For-Profits 68832616 UNITED STATES N 9/19/23 0:00 12/31/23 0:00 394 SBIR/STTR 2023 224924 Project SummaryApplikate Technologies has developed Clearing Histology with Multiphoton Microscopy (CHiMP) a noveltissue processing and imaging platform that provides direct-to-digital images from intact pathology tissuespecimens such as biopsies without the need for wax embedding slicing or scanning of slides. Theapplication of this technology to cancer diagnosis will reduce errors lower costs ameliorate technician staffingissues and provide same-day diagnosis for patients waiting to hear if they have cancer.The aim of this Phase IIb SBIR proposal is to support the development of risk management and qualitysystems management required for the manufacture of clinical devices as well as the clinical and non-clinicalvalidation testing required for an application for premarket approval by the FDA.CHiMP has many advantages for general histology including: H&E-like images familiar to pathologists but withsuperior image quality sub-micron effective thickness and without artifacts common to slide preparation; non-destructive imaging that preserves intact tissue for ancillary molecular analysis and immunohistochemistry;rapid turnaround with images ready within a few hours of receiving tissue; greatly reduced labor costs; true 3Dprospective; and digitized images for remote consultation and machine vision. The market for pathologyequipment and consumables is $2B and for digital pathology scanners it is $1B. CHiMP is poised to not onlyenter these markets as a unique and strong competitor but to actually expand upon them by lowering thebarrier to entry for digital pathology through seamless integration into the laboratory workflow and raising thevalue of equipment and supplies while still lowering overall costs to hospitals through significant labor savings.The specific aims of this proposal are to: 1) Perform risk analysis; 2)Develop and implement a QualityManagement System; 3) Collect data for an FDA premarket submission and facility registration.Successful completion of these aims will enable CHiMP to enter the clinical diagnostic market where it canhave maximum impact on patient care and health economics. +No NIH Category available Affect;Age;Apoptosis;Apoptotic;Biological Assay;Biological Markers;CRISPR/Cas technology;Cancer Patient;Cancer cell line;Cell Cycle;Cell Death;Cell Death Induction;Cell Line;Cell Survival;Cells;Cessation of life;Chromosomal Duplication;Chromosomes;Clonality;Clustered Regularly Interspaced Short Palindromic Repeats;Coculture Techniques;Complex;Cytotoxic agent;DNA;DNA Damage;DNA Double Strand Break;DNA Repair;DNA Sequence Alteration;DNA Sequence Rearrangement;Dana-Farber Cancer Institute;Data;Development;Double Minutes;Effectiveness;Elements;Encyclopedias;Enzymes;Evaluation;Event;Excision;Future;Gene Rearrangement;Gene Targeting;Genes;Genome;Genomics;Guide RNA;Hour;Human;Immunotherapy;Institution;Investigation;Journals;Knock-out;Malignant Neoplasms;Measures;Mediating;Medical;Mentors;Methods;Modality;Mutate;Mutation;Natural Killer Cells;Normal Cell;Nucleic Acids;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Peer Review;Predisposition;Proteins;Publications;Radiation therapy;Research;Resistance;Scientist;Series;Site;Stains;System;Therapeutic;Tissues;Toxic effect;Training;United States;Variant;cancer cell;cancer genome;cancer genomics;cancer therapy;cancer type;career;cell killing;cell type;chemotherapy;chromosome loss;chromosome missegregation;chromothripsis;computational pipelines;cytotoxic;cytotoxicity;data repository;design;experience;experimental study;genome database;genome editing;genomic locus;improved;new therapeutic target;next generation;novel;novel therapeutics;pan-genome;professor;repaired;research faculty;screening;small molecule;symposium;targeted nucleases;targeted treatment;tool;tumor;whole genome Targeting the cancer neo-genome for destruction with CRISPR-Cas enzymes Project NarrativeDespite the presence of thousands of mutations in the cancer genome including over one hundred structuralvariants per genome we lack a targeted therapy to treat many cancers. This proposal is designed to takeadvantage of the multiple structural variants in the cancer genome and use them as unique genomic sites forCRISPR nuclease targeting and cleavage which in turn could lead to cancer cell cytotoxicity. This proposal willdesign validate and characterize a multi-cut CRISPR approach to cause cytotoxicity in targeted cancer cellswhile leaving normal cells intact and is the first step in developing this approach to becoming a broad-spectrum cancer therapeutic in the future. NCI 10678361 5/11/23 0:00 PA-21-048 1F32CA281185-01 1 F32 CA 281185 1 "ELJANNE, MARIAM" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 78216312 "LEIBOWITZ, MITCHELL L" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 69080 NCI 69080 0 Project Summary/Abstract Advances in understanding the cancer genome have led to the development of novel therapeutics thattarget distinct alterations in protein products of cancer DNA. The resulting targeted therapies together withprotein-targeting immunotherapies have led to significant advances in cancer patient survival. However not allpatients benefit from these new therapies and instead many cancers continue to be treated with DNA double-strand break (DSB)-generating radio- and chemo- therapies. Nucleic acid targeting approaches such as the CRISPR-Cas9 system now enable investigation of a newmodality for experimental cancer therapeutics: targeting DNA directly rather than its protein products. Thisproposal is aimed at the initial investigation and evaluation of this modality. Hypothesis: Targeted induction of DNA DSBs at multiple rearrangement junctions specific to the cancergenome can lead to cancer-cell specific cytotoxicity and spare damage to healthy tissue. Specific Aim 1. Characterize the landscape of cancer-specific Cas9-targetable genomic sites acrosscancers and cancer cell lines. In this aim a computational pipeline will be developed to characterize the spectrumof Cas9-targetable genome alterations across the Cancer Cell Line Encyclopedia and Pan-Cancer Analysis ofWhole Genomes databases of over 300 cancer cell lines and 2500 cancer genomes. Sequence features thatmay affect target effectiveness in cancer therapy will be characterized including target clonality target copynumber and the distribution of targetable genomic alterations across cancer types. This pipeline will become apublicly available tool to generate lists of Cas9-targetable rearrangement breakpoints for use in future studies. Aim 2. Develop methods to induce cytotoxicity in cancer cells using Cas9 targeted to cancer-specificDNA rearrangement breakpoints. In a series of proof-of-principle experiments this aim will assess whether Cas9can induce targeted cell death through targeting DNA breaks to either single highly amplified sites or severalunique sites in the cancer neo-genome and whether this generates toxicity in healthy tissue. Aim 3. Identify protein factors responsible for resistance or sensitivity to Cas9-mediated DNA damage:This aim will comprise a CRISPR knockout screen to discover proteins that affect cell sensitivity to multiple Cas9-induced DNA breaks. This proposal will provide training in cancer genomics and targeted therapeutics under the guidance ofProfessor Matthew Meyerson at Dana-Farber Cancer Institute who is experienced in both fields. In addition toexperimental and computational research the applicant will present results at conferences train future scientistsand interact with colleagues and mentors in the cancer genomics genome editing and cancer therapeuticsfields. The planned research is intended to culminate in publication in peer-reviewed journals. Ultimately thistraining should prepare the applicant for a career as research faculty at a United States research institution. 69080 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Patient Safety; Precision Medicine Administrative Supplement;Area;Award;Back;Belief;Biological Markers;California;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Data;Development;Drug Delivery Systems;Drug Kinetics;Early Therapeutic-Clinical Trials Network;Faculty;Florida;Funding;Geography;Goals;Grant;Infrastructure;Institution;Investigation;Investigational Therapies;Kansas;Laboratories;Lead;Leadership;Letters;Malignant Neoplasms;Mentors;Mentorship;Methods;Minority Groups;Mission;Molecular;Oklahoma;Parents;Patient Recruitments;Patient Selection;Patients;Pharmacodynamics;Pharmacopoeias;Phase;Philosophy;Population;Protocols documentation;Recommendation;Reporting;Research;Research Design;Research Personnel;Rural Population;Science;Selection for Treatments;Serum;Services;Site;Special Population;Therapeutic;Therapeutic Agents;Toxic effect;Training;Translating;Translational Research;Translations;Underserved Population;Universities;Variant;Washington;Work;Yale Cancer Center;career;clinical investigation;cohesion;cost;design;drug development;early phase clinical trial;early phase trial;follow-up;imaging biomarker;improved outcome;member;minority patient;next generation;novel;novel anticancer drug;novel therapeutics;patient biomarkers;racial and ethnic;rare cancer;recruit;resistance mechanism;response;student mentoring;targeted cancer therapy;tissue biomarkers;translational medicine;treatment optimization;tumor Supplement to UM1 grant for NCI's Early Therapeutics Clinical Trials Network (ETCTN) This application is being submitted to request the addition of an Affiliated Organization (AO) to an ETCTN UM1Lead Academic Organization (Yale University). Addition of the AO the University of Kansas Cancer Center willprovide continuity for a productive site still conducting active ETCTN trials but which was not included in a fundedETCTN UM1 Type 2 award. Their inclusion enhances the ability of our consortium to perform comprehensiveconduct of early clinical trials conduct more selective and sophisticated clinical and translational investigationalstrategies and will increase accrual of underserved populations to trials conducted under our ETCTN UM1. NCI 10678278 9/7/22 0:00 PA-20-272 3UM1CA186689-06S5 3 UM1 CA 186689 6 S5 "IVY, S PERCY" 9/1/22 0:00 2/28/23 0:00 2790620 "LORUSSO, PATRICIA M." Not Applicable 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/22 0:00 2/28/23 0:00 395 Non-SBIR/STTR 2022 500000 NCI 492500 7500 ABSTRACT: This application is being submitted to request the addition of University of Kansas Cancer Center(KUCC) as an Affiliated Organization (AO) to our NCI Experimental Therapeutics-Clinical Trials Network(ETCTN) UM1 Lead Academic Organization. KUCC previously a Create Access to Targeted Cancer Therapyfor Underserved Populations (CATCH-UP) site will enhance access of trials in the Early Therapeutics ClinicalTrials Network for underserved populations (USP) in Kansas and enhance USP to our ETCTN consortium. Thepurpose of the ETCTN is to develop new therapeutic options while also defining better approaches for thedevelopment of novel anticancer agents that capitalize on the ability to characterize tumors molecularly. As aresult a unique network such as the ETCTN consisting of multiple scientifically-driven sites and investigatorswith a vast array of expertise is needed. In 2020 we were awarded a UM1 grant (2UM1CA186689-06). In July2022 the NCI Cancer Therapy Evaluation Program (CTEP) recommended that we submit this administrativesupplement to offset some of the costs of absorbing KUCC as an additional AO to provide continuity for CATCH-UP sites participating on ETCTN active trials (those with patients on treatment and in follow-up) as well asrecruit additional patients from USP to increase access of novel therapeutic agents to these respectivepopulations. Our original partnerships included Vanderbilt-Ingram University of California San Diego Universityof Oklahoma Stephenson Cancer Center and the Yale Cancer Center (VICtOrY). We subsequently addedColumbia University Washington University in St. Louis and the University of Florida. We now plan to addKUCC to our consortium to form VICtOrY-CWFK. Our team aims to 1) leverage novel scientific discoveries fortranslation into early phase trials using the CTEP pharmacopeia in rare cancers common cancers anduncommon variants of common cancers; 2) incorporate serum tissue and imaging biomarkers to betterunderstand the effects of novel agents either alone or in combination; 3) train early career investigators to beknowledgeable and proficient in conducting early phase clinical trials by providing clinical research leadershipopportunities and mentoring; and 4) include as a component of our early phase clinical trial recruitment no lessthan 30% USP populations including 20% consisting of traditional ethnic/racial minority patients with recruitmentof at least 50% USP recruited at KUCC. The members of our team along with the proposed additional sitehave a unique set of complementary expertise and a similar philosophy regarding collaborative research andmentorship of the next generation of cancer investigators. Together VICtOrY-CWFK is committed to utilizingour areas of expertise integrating the science at our institutions and maximizing our collaborative relationshipsto conduct cutting-edge early phase trials within the ETCTN with the ultimate mission of improving outcomesfor cancer patients. 500000 +No NIH Category available Advanced Malignant Neoplasm;Algorithms;Anxiety;Aptitude;Archives;Area;Artificial Intelligence;Award;Benign;Big Data;Biometry;Cessation of life;Characteristics;Classification;Clinical;Clinical Informatics;Clinical Management;Clinical/Radiologic;Data;Decision Making;Diagnosis;Diagnostic;Diagnostic Errors;Diagnostic Procedure;Disease;Early Diagnosis;Engineering;Environment;Epidemic;Evaluation;Exhibits;Fellowship;Future;Goals;Growth;Health Care Costs;Healthcare Systems;Histologic;Histology;Histopathology;Image;Image Analysis;Incidence;Indolent;Institution;Intervention;Joints;Laboratories;Language;Learning;Lung;Lung Adenocarcinoma;Lung nodule;Machine Learning;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Measures;Medical;Medical History;Medical Imaging;Mentors;Metastatic Neoplasm to the Lung;Methods;Modality;Modeling;Modernization;Morbidity - disease rate;Nodule;Oncology;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Pattern;Performance;Phenotype;Physicians;Positioning Attribute;Predictive Value;Probability;Prospective cohort;Public Health;Radiation;Radiologic Finding;Radiology Specialty;Recording of previous events;Records;Research;Resources;Retrospective cohort;Risk;Risk Reduction;Scientist;Smoking;Smoking History;Standardization;Subgroup;Techniques;Time;Training;Universities;Vision;Work;X-Ray Computed Tomography;anxiety reduction;artificial intelligence method;biomedical informatics;cancer imaging;cancer subtypes;career;chest computed tomography;clinical phenotype;clinical predictive model;clinically actionable;cohort;cost efficient;deep learning;design;electronic health data;health record;high dimensionality;high risk;improved;innovation;learning strategy;lens;low dose computed tomography;lung cancer screening;mortality;multimodal data;multimodality;noninvasive diagnosis;novel;novel strategies;personalized approach;precision oncology;predictive modeling;prospective;radiomics;risk stratification;screening;segregation;serial imaging;standard of care;success;symposium;tumor Risk stratifying indeterminate pulmonary nodules with jointly learned features from longitudinal radiologic and clinical big data PROJECT NARRATIVEThe epidemic of screen- or incidentally detected indeterminate pulmonary nodules (IPNs) presents asubstantial public health problem and is associated health care costs of $28 billion annually as well asincreased burden on patients in the form of anxiety morbidity from diagnostic procedures excessive radiationand death from missed lung cancer. Clinical predictive models represent an opportunity to reduce this publichealth burden by noninvasively estimating the probability of malignancy and segregating IPNs into clinicallyactionable risk groups thereby reducing the risk of mismanaging IPNs. By leveraging machine learning/deeplearning techniques to analyze data that are multi-modal and longitudinal this project works towards a futurewhere predictive models are used at scale to improve patient outcomes by aiding earlier diagnosis ofmalignancy and reducing the diagnostic burden of benign IPNs. NCI 10678264 6/2/23 0:00 PA-21-049 1F30CA275020-01A1 1 F30 CA 275020 1 A1 "PURI, ANU" 7/1/23 0:00 6/30/26 0:00 Special Emphasis Panel[ZRG1-F18-L(20)L] 16496166 "LI, THOMAS ZHIHE" Not Applicable 5 ENGINEERING (ALL TYPES) 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN BIOMED ENGR/COL ENGR/ENGR STA 372032408 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 32846 NCI 32846 0 PROJECT SUMMARYIndeterminate pulmonary nodules (IPNs) are highly prevalent radiologic findings that represent a substantialburden to patients and the national health care system because of the diagnostic challenge they present.There is a dire need to accurately stratify IPNs into low and high malignancy risk subgroups which areassociated with clinical management pathways that are standardized and well validated. Clinical predictionmodels have the potential to do so in a scalable cost-efficient automated and noninvasive manner butadvances in predictive accuracy must be made before they can make a substantial impact in medical practice.An unexplored direction in this area is integrating repeated measures of computed tomography (CT) studiesand clinically-collected information within the same prediction model. This joint learning strategy has advantageof potentially modeling how dynamic radiologic changes like nodule growth rate vary with the trajectory ofclinical variables such as smoking patterns and laboratory abnormalities. This perspective motivates thehypothesis that integrating information from longitudinal imaging and longitudinal clinical records willimprove personalized IPN risk stratification and lung cancer subclassification From a clinicians lensthis finding would not be surprising given the many time-varying modalities that are involved in diagnosis anddecision making. This project leverages artificial intelligence (AI) and radiomic methods to analyze threeretrospective cohorts with the possible addition of a large prospective cohort. The proposed work in Aim 1 willextend upon existing deep learning techniques to train a joint learning model on longitudinal images andclinical records to estimate the malignancy probability across time in patients with IPNs in a combined cohortexceeding 2000 subjects. This novel strategy will be evaluated against single-modality models and conventionmodels that are used in practice. The evaluation will compare the models performance in stratifying IPNs intothe low and high risk subgroups as a measure of clinical utility. Aim 2 asks if longitudinal change in radiomicfeatures can distinguish between indolent and aggressive lung adenocarcinoma other lung cancer subtypesand pulmonary metastases. The proposed study will be the first to comprehensively characterize longitudinalradiomics across lung cancer subtypes and has the potential to identify novel longitudinal radiomic featuresthat will aid early IPN evaluation and noninvasive lung cancer subclassification in patients with repeatedimaging. In summary the proposed research asks if clever integration of longitudinal information acrossdifferent modalities can be leveraged to advance IPN risk stratification and lung cancer subclassification. Thisfellowship will be conducted at Vanderbilt University in a highly collaborative training environment with mentorsin medical imaging AI pulmonary oncology biomedical informatics radiology and biostatistics. The proposedresearch and training plans are synergistically designed to ultimately prepare the candidate for a physicianscientist career at the intersection of engineering innovation and precision oncology. 32846 +No NIH Category available 20 year old;Address;Adolescent;Adolescent and Young Adult;Adult;Aftercare;Age;Alkylating Agents;Anthracycline;Award;Canada;Cancer Survivor;Cancer Survivorship;Cardiac;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chest;Child;Childhood Cancer Survivor Study;Childhood Cancer Treatment;Combination Drug Therapy;Data;Data Analyses;Dedications;Development;Development Plans;Diabetes Mellitus;Diagnosis;Dyslipidemias;Event;Exercise;Foundations;Funding;General Population;Goals;Health Promotion;Heart Valve Diseases;Heart failure;Hodgkin Disease;Hypertension;Incidence;Individual;Intention;Intervention;Knowledge;Late Effects;Life;Malignant Childhood Neoplasm;Malignant Neoplasms;Metabolic;Methods;Monoclonal Antibodies;Morbidity - disease rate;Myocardial Infarction;Myocardial Ischemia;National Cancer Institute;Neck;Nurses;Obesity;Oncology Nurse;Patient Self-Report;Physical Fitness;Physical activity;Play;Population;Prospective cohort study;Quality of life;Radiation;Reporting;Research;Research Personnel;Resources;Risk Factors;Role;Scientist;Siblings;Site;Stroke;Structure;Survivors;Testing;Time;Topoisomerase Inhibitors;Training;Tyrosine Kinase Inhibitor;United States;Work;age group;cancer complication;cancer therapy;cancer type;cardiovascular risk factor;career;career development;chemoradiation;chemotherapy;clinical care;cohort;experience;improved;mortality;mortality risk;negative affect;research and development;risk stratification;secondary analysis;skills;survivorship;young adult Incidence and Time on Onset of Cardiovascular Risk Factors and Cardiovascular Disease in Adult Survivors of Adolescent and Young Adult Cancer and Association with Exercise PROJECT NARRATIVECardiovascular complications negatively affect the quality and quantity of life in cancer survivors. This projectwill explore the role that known cardiotoxic treatments have on cardiovascular complications and the roleexercise may play in mitigating these late effects within a specific age group (those diagnosed between the agesof 15 and 20 years old) of cancer survivors. This award will support my development towards becoming anindependent nurse scientist dedicated to understanding the effects of cardiotoxic treatments on adolescent andyoung adult cancer survivors. NCI 10678157 4/19/23 0:00 PA-21-051 1F31CA275332-01A1 1 F31 CA 275332 1 A1 "BOULANGER-ESPEUT, CORINNE A" 5/15/23 0:00 5/14/25 0:00 Special Emphasis Panel[ZRG1-F18-L(20)L] 77796861 "HOOVER, BECKY LEIGH" Not Applicable 4 NONE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC ORGANIZED RESEARCH UNITS 275995023 UNITED STATES N 5/15/23 0:00 5/14/24 0:00 398 "Training, Individual" 2023 40570 NCI 40570 0 ABSTRACTMany cancer survivors are at risk for cardiovascular complications after treatment. These complications caninclude cardiovascular risk factors (CVRF) such as diabetes hypertension dyslipidemia and obesity andcardiovascular disease (CVD) such as heart failure valvular heart disease ischemic heart disease/myocardialinfarction and stroke. Those diagnosed between 15 and 20 years old are considered adolescent and youngadult survivors (AYA) and frequently treated with cardiotoxic treatments which may increase their risk for CVRFand CVD. Yet little research has focused on understanding CVRF and CVD incidence in this population. Anunderstanding of the incidence and time to onset of CVRF and CVD in this population is needed to informsurveillance and health promotion interventions. Health promotion interventions such as exercise may protectagainst the development of CVRF and CVD because exercise has been shown to mitigate CVRF and CVD inother populations. Yet an understanding of the relationships between CVRF CVD and exercise is unclear amongthis population. Utilizing data from the Childhood Cancer Survivor Study (CCSS) we will assess the incidenceand time to onset of CVRF and CVD as well as relationships between CVRF CVD and exercise for thosediagnosed with cancer in the 15-to-20-year-old age group. We will identify if interventions such as exercise areneeded for this population and if the need is increased for those who receive cardiotoxic treatments. Guided bythe Cancer Survivor Research Framework the study will address the following specific aims in 15-20 year oldAYA cancer survivors: 1) Compare the incidence and time to onset of CVRF between survivors who wereexposed and not exposed to cardiotoxic treatment and according to the type of cardiotoxic cancer treatments(chemotherapy radiation or chemo + radiation) received 2) Compare the incidence and time to onset of CVDbetween survivors who were exposed and not exposed to cardiotoxic treatments and according to the type ofcardiotoxic cancer treatments received and 3) Examine longitudinal associations between self-report exercise(weekly metabolic equivalence tasks) and the incidence of CVRF and CVD in survivors across three time points(1999 2007 and 2014). The accompanying career development plan will provide training in a) the unique needsand experiences of adult survivors of AYA cancers b) the role exercise plays in mitigating CVRF and CVD forcancer survivors and c) longitudinal and secondary data analyses methods. Together the career developmentand research plan will support the development of an independent nurse scientist in cancer survivorshipcardiotoxicity and exercise. This proposal will generate important knowledge related to cardiovascularcomplications for cancer survivors by creating risk stratification for receipt of cardiotoxic treatments. Additionallythis research will increase understanding of the effects that exercise has on CVRF and CVD laying thefoundation for future research focused on developing and testing interventions to mitigate CVRF and CVD amongcancer survivors diagnosed between 15-and-20-years of age. 40570 +No NIH Category available Adjuvant;Adjuvant Therapy;Aftercare;Alcohols;Benchmarking;Biological Assay;Biological Markers;Biopsy;CD8-Positive T-Lymphocytes;Cells;Cervical;Cisplatin;Clinical;Clinical Trials;Clinical assessments;Code;Cytometry;DNA;DNA analysis;Data;Decision Making;Detection;Disease;Dose;Effector Cell;Ensure;Environment;Equation;Excision;Extranodal;Future;Gene Expression;Gene Frequency;Goals;HPV-High Risk;HPV-negative head and neck cancer;Homing;Hour;Human Papillomavirus;Image;Immune;Immune Response Genes;Immunophenotyping;Incidence;Individual;Infiltration;Inflammatory;Kinetics;Laceration;Length;Leukocytes;Liquid substance;Lymph;Lymphatic System;Malignant Neoplasms;Measures;Metastatic Neoplasm to Lymph Nodes;Micrometastasis;Molecular;Morbidity - disease rate;Mutation;Neck Dissection;Nodal;Operative Surgical Procedures;Oropharyngeal Squamous Cell Carcinoma;Pathologic;Pathology;Patient risk;Patient-Focused Outcomes;Patients;Pattern;Plasma;Population;Postoperative Period;Primary Neoplasm;Proxy;Quality of life;Radiation Dose Unit;Recurrence;Recurrent disease;Regimen;Residual Neoplasm;Risk;Risk Assessment;Risk Marker;Saliva;Sampling;Signal Transduction;Site;Surgical Pathology;Survival Rate;Tobacco;Treatment outcome;Treatment-related toxicity;Tumor stage;Urine;Variant;anti-tumor immune response;cancer cell;cancer surgery;candidate selection;cell free DNA;chemoradiation;clinical diagnostics;comorbidity;digital;exome sequencing;genetic variant;high risk;human papilloma virus oropharyngeal squamous cell carcinoma;improved;leukocyte activation;liquid biopsy;lymph nodes;malignant oropharynx neoplasm;minimally invasive;mutant;neoplastic cell;next generation sequencing;novel;patient stratification;prognostic;prospective;relapse prediction;risk stratification;salivary assay;side effect;success;tool;trafficking;treatment response;tumor;tumor DNA;tumor microenvironment;tumor-immune system interactions;wound bed A Novel Postoperative Prognostic Liquid Biopsy: Tumor-Associated cfDNA and Leukocyte Analysis in Oropharyngeal Cancer Surgical Drain Fluid PROJECT NARRATIVE Subjective clinical assessments of patient risk in HPV-associated oropharyngeal squamous cellcarcinoma (OPC) could be improved with our novel objective liquid biopsy assay of the inflammatory fluid thatcollects in Jackson Pratt surgical drains. We believe we can use this proximal liquid analyte to sensitivelydetect tumor-shed cell-free HPV (cf-HPV) and comprehensively characterize tumor homing effector immunecells. We predict the integration of surgical drain fluid cf-HPV analysis with leukocyte immunophenotyping willpredict patient pathological risk and patterns of recurrence and could eventually be used to prospectivelyselect candidates for treatment de-intensification clinical trials. NCI 10678080 4/24/23 0:00 PA-21-049 1F30CA281071-01 1 F30 CA 281071 1 "BIAN, YANSONG" 5/1/23 0:00 4/30/26 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 16030557 "EARLAND, NOAH JACKSON" Not Applicable 1 RADIATION-DIAGNOSTIC/ONCOLOGY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 398 "Training, Individual" 2023 33646 NCI 33646 0 PROJECT SUMMARY/ABSTRACTThe incidence of oropharyngeal squamous cell carcinoma (OPC) driven by high-risk (HR) HPV strainscontinues to rise. As HPV (+) disease is prognostic for good post-treatment outcomes and arises in relativelyyoung patients with fewer co-morbidities clinicians now recognize it as a distinct clinical entity from tobacco-associated HPV (-) disease. But despite improved survival following surgery and adjuvant chemoradiation(CRT) many HPV (+) OPC patients suffer prolonged morbidity from severe treatment-associated toxicities.This has led to many treatment de-intensification clinical trials which seek to reduce toxic side effects whilemaintaining historic survival rates. Ideally high-risk patients would remain on standard regimens while low tointermediate-risk patients would receive de-escalated therapy. However there is a great clinical need for anobjective biomarker of risk to aid the subjective clinical assessments: pre-treatment imaging and postoperativepathology. Liquid biopsies can offer such objectivity; they quantify cell-free DNA (cfDNA) shed by cancer cellscalled circulating tumor DNA (ctDNA) in biofluids like saliva or plasma. Further in HPV (+) OPC cell-free HPVDNA (cf-HPV) parallels ctDNA as a measure of minimal residual disease (MRD). But plasma and saliva assayslack sensitivity to detect this cf-HPV MRD after surgery. To this clinical challenge we offer our novel liquidbiopsy assay of Jackson Pratt (JP) surgical drain fluid (SDF). We believe SDF will be enriched with cf-HPVcompared to plasma because it's more proximal to the primary tumor resection site and to the lymph nodeswhere locoregional micrometastases are seeded. Additionally because the JP drains also capture lymph fluidfrom the lacerated cervical lymphatic system we also believe the SDF contains informative effector leukocytesthat were in transit to the tumor microenvironments (TMEs) of metastatic nodes and the primary tumor. Tobegin to elucidate the prognostic potential of SDF we have collected paired SDF plasma tumor biopsy andmetastatic lymph node samples. First using PCR and next-generation sequencing approaches we will quantifythe cf-HPV burden in paired plasma and SDF samples. Then we will compare cf-HPV in each sample typeindividually to histopathological markers of risk (extranodal extension and tumor stage) and recurrences. Wewill then track tumor-informed variants on ctDNA isolated from plasma and SDF to show that ctDNA levelsalign with cf-HPV and further validate that cf-HPV is a good proxy for MRD. Lastly we will use digital cytometrytools and mass cytometry to immunophenotype the immune cells within the SDF to determine if they reflectimmune response gene expression levels in paired metastatic nodes and tumors. If confirmed our study hasthe potential to demonstrate that tri-biomarker analysis (immune cell cf-HPV and ctDNA) in a novel liquidanalyte (SDF) can provide precision risk-stratification to aid subjective clinical diagnostics. 33646 +Cancer; Clinical Research; Lung; Urologic Diseases Address;Binding;Bioinformatics;Biological Process;Bladder Neoplasm;C-terminal;Cell Nucleus;Cells;Cessation of life;ChIP-seq;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collagen;Collagen Receptors;Communication;Conceptions;DNA Binding;Data;Disease;Disease Management;Distal;Ectopic Expression;Extracellular Matrix;Family;Fibroblasts;Funding;Genes;Goals;Image;Investigation;Kininogenase;Knock-out;Knowledge;Ligands;Luciferases;Lung;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mediating;Metastatic Neoplasm to the Lung;Modality;Mutate;N-terminal;Nature;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Pattern;Peptide Hydrolases;Pharmacology;Phenotype;Phosphorylation;Phosphorylation Site;Pilot Projects;Play;Primary Neoplasm;Process;Progression-Free Survivals;Property;Protein Fragment;Proteins;Receptor Activation;Receptor Signaling;Regulation;Role;Signal Transduction;Site;Smooth Muscle Myocytes;Specific qualifier value;Survival Rate;Testing;Therapeutic Intervention;Tumor Volume;Tyrosine Phosphorylation;Tyrosine Phosphorylation Site;bladder Carcinoma;bladder transitional cell carcinoma;cancer cell;cancer type;clinical translation;design;gamma secretase;in vivo;innovation;lead candidate;metastatic process;migration;neoplastic cell;notch protein;novel;novel strategies;overexpression;precision medicine;receptor;respiratory smooth muscle;scaffold;src Homology Region 2 Domain;success;therapeutic target;tumor;tumor microenvironment Distinct Tumor and Metastatic Collagen Microenvironments: Divergent Targeting Approaches PROJECT NARRATIVEMetastatic bladder cancer is a devastating disease with a 5-year survival rate of only 5.4%. While the initialsteps of the metastatic cascade are rather well defined identification of targets to block this processcontinues to be a major clinical challenge. Discovering the regulatory mechanisms by which the metastaticmicroenvironment support tumor cell colonization and survival will enable design of new strategies not onlytargeting the primary tumors but also eradicating metastatic foci a potential new breakthrough. NCI 10678008 8/17/22 0:00 PA-19-056 3R01CA175397-08S1 3 R01 CA 175397 8 S1 "SNYDERWINE, ELIZABETH G" 9/30/13 0:00 12/21/22 0:00 Tumor Microenvironment Study Section[TME] 8781273 "CHAN, KEITH SYSON " Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 5/1/22 0:00 12/21/22 0:00 353 Non-SBIR/STTR 2022 1 NCI 1 0 PROJECT SUMMARYMetastatic progression of the primary tumor accounts for the majority of cancer deaths. While the initial steps ofthe metastatic cascade are rather well defined identification of targets to block this process remains a majorclinical challenge. Previous studies have elegantly investigated the mechanistic contribution of tumor cell intrinsicproperties that promote metastasis in bladder urothelial carcinomas. However the functional significance of thetumor microenvironment and its contribution to this complicated process is not well characterized and thereforewarrants investigation. The long-term goal of this renewal application is to continue explore how collagensamajor extracellular matrix component of the microenvironmentact as a ligand to mediate crosstalk with theirreceptor on tumor cells to facilitate the metastatic cascade. We will investigate the downstream regulatorymechanisms of collagen receptor signaling in both the primary tumor and metastatic sites and to exploit theseregulatory processes as a revolutionizing approach to target metastases. Such innovative approaches to perturbcollagen-cancer crosstalknot only at the primary tumor but also at the metastatic nichewill move the fieldforward by providing a new conception in metastatic disease management and likely extend beyond bladdercarcinomas to other cancer types. 1 +No NIH Category available Actins;Aggressive behavior;Automobile Driving;Cell surface;Cells;Coculture Techniques;Colorectal Cancer;Common Carcinoma;Communication;Development;Disease;Disease Progression;Distal;Distant;Experimental Designs;Fibroblasts;Future;Genes;Goals;Growth;Head and neck structure;Immune;Immune checkpoint inhibitor;Immune system;Immunocompetent;Immunotherapy;Indolent;Inflammatory;Ligands;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of thyroid;Modeling;Molecular Target;Monitor;Morphology;Mus;Myofibroblast;Organoids;Papillary thyroid carcinoma;Patients;Phenotype;Population;Proliferating;Publishing;Resolution;Role;Shapes;Signal Transduction;Signaling Protein;Smooth Muscle;Space Perception;Specimen;Stromal Cells;System;Techniques;Testing;Therapeutic;Thyroid Gland;Thyroid carcinoma;Time;Training;Translational Research;Transplantation;Tumor Cell Invasion;Tumor Promotion;WNT Signaling Pathway;WNT2 gene;Work;Xenograft procedure;anaplastic thyroid cancer;anticancer research;autocrine;biobank;cancer cell;cancer heterogeneity;cancer subtypes;cancer type;career;cohort;differential expression;digital;effective therapy;efficacious treatment;exome sequencing;experimental study;fibroblast activation protein alpha;genetic signature;improved;in vivo;inhibitor;insight;malignant breast neoplasm;mouse model;nano-string;neoplastic cell;new therapeutic target;novel;novel therapeutic intervention;overexpression;pancreatic cancer model;paracrine;pharmacologic;receptor;response;single-cell RNA sequencing;spatial relationship;stem;therapeutic target;thyroid neoplasm;transcriptome sequencing;treatment response;tumor;tumor growth;tumor microenvironment;tumor progression Cancer-associated fibroblasts promote thyroid cancer malignancy through Wnt signaling PROJECT NARRATIVECancer-associated fibroblasts (CAFs) are a heterogeneous stromal cell population that influence disease courseand treatment responses in aggressive cancers. Anaplastic thyroid carcinoma has a substantial stromalcomponent yet the composition of the stroma and its role in promoting malignancy remain unclear. In thisproposal I will elucidate the subtypes of CAFs in thyroid carcinoma and investigate the tumor-promoting effectsof CAF-driven Wnt signaling providing a novel therapeutic target for a disease with an urgent need for newtreatment options. NCI 10677942 5/22/23 0:00 PA-21-049 1F30CA281125-01 1 F30 CA 281125 1 "PURI, ANU" 6/1/23 0:00 5/31/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 14400234 "LOBERG, MATTHEW A" Not Applicable 5 PATHOLOGY 965717143 GTNBNWXJ12D5 965717143 DWH7MSXKA2A8; GTNBNWXJ12D5 US 36.143381 -86.803365 8721001 VANDERBILT UNIVERSITY Nashville TN SCHOOLS OF MEDICINE 372032408 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 "Training, Individual" 2023 32884 NCI 32884 0 PROJECT SUMMARYMany aggressive cancers have a robust tumor microenvironment composed of heterogenous stromal andimmune cells. Although the advent of immune checkpoint inhibitors has shifted therapeutic targets of cancerresearch to include tumor-cell extrinsic targets the therapeutic potential of targeting the tumor stroma remainsunderexploited. Recently cancer-associated fibroblasts (CAFs) have been implicated as drivers of diseaseprogression. From preliminary attempts to harness the therapeutic potential of targeting CAFs it has becomeclear that targeting CAFs as a bulk population of cells will not be sufficient. As such there have been efforts inbreast and pancreatic cancer to define the heterogeneity of CAFs. These efforts have yielded diverse subtypescommonly described by two overarching groups: myofibroblast CAFs (myCAFs) and inflammatory CAFs (iCAFs).In pancreatic cancer myCAFs are observed to be tumor-adjacent and iCAFs are more distant from tumor cells.While defining subtypes of CAFs is a necessary first step the development of novel therapeutic approaches willlikely require the identification of specific functions of CAF subtypes. To this end Wnt2 has been identified asupregulated in CAFs from pancreatic breast and colorectal cancer yet the role of CAF-driven Wnt signaling ontumor progression remains largely unknown. Anaplastic thyroid carcinoma (ATC) is a lethal disease (~3-5 monthmedian survival) with an abundant tumor stroma and no efficacious treatment options. The composition of thetumor stroma in ATC has been largely unexplored. My preliminary work identifies a prominent fibroblastpopulation in ATC that expresses WNT2. As ATC is known to have upregulated Wnt signaling relative to otherthyroid neoplasms this provides a unique opportunity to study the dynamics of CAF-driven Wnt signaling. Thegoal of this proposal is to define the CAF subtypes present in thyroid carcinoma and determine the functionalrole of CAF-derived Wnt2 on tumor growth. I hypothesize that distinct CAF populations promote tumor growthand invasion in thyroid carcinoma through Wnt signaling and have unique spatial relationships. To test myhypothesis I will perform experiments in ATC models and papillary thyroid carcinoma (PTC) models. PTC is apredominantly indolent thyroid carcinoma that can transform to ATC in vivo making it ideal for examining theability of CAFs to promote disease progression. In aim 1 I will elucidate subtypes of CAFs present in ATC andPTC and probe Wnt ligand-receptor interactions. Further I will determine spatial resolution of myCAF and iCAFfibroblast populations in thyroid carcinoma. In aim 2 I will utilize >40 primary patient thyroid carcinoma CAFcultures that our lab has collected to demonstrate the role of CAF-derived Wnt2 signaling both paracrine on PTCand ATC tumor cells and autocrine to shape the phenotype of CAFs. In completing these studies I will for thefirst time define the heterogeneity of CAFs in thyroid carcinoma and characterize a potential novel therapeutictarget applicable to CAFs in multiple cancer types. 32884 +No NIH Category available Acetylation;Acute;Advisory Committees;Animals;Award;Bioinformatics;Biological Assay;Biology;Bromodomain;CRISPR interference;Cancer Patient;Carboplatin;Carcinoma;Cell Line;Cell Lineage;Cell Proliferation;Cell physiology;Cells;ChIP-seq;Chromosomal Instability;Cisplatin;Clinical;Clinical Trials;DNA;DNA Methylation;DNA Methyltransferase Inhibitor;DNA Repair;Data;Deacetylation;Decision Making;Defect;Dependence;Development;Development Plans;Diagnostic;Disease;Dose;Drug Targeting;Enhancers;Epigenetic Process;Equipment;Face;Genes;Genetic;Genetic Transcription;Genomics;Goals;Grant;Growth;Histone Acetylation;Histone Deacetylase;In Vitro;Inflammatory;Lead;Location;Malignant Neoplasms;Malignant neoplasm of ovary;Manuscripts;Maps;Mediating;Mentors;Mentorship;Methylation;Modeling;Modification;Mutation;Normal Cell;Nucleic Acid Regulatory Sequences;Oncogene Activation;Oncogenes;Oncogenic;Organoids;Outcome;Ovarian Serous Adenocarcinoma;Pathogenesis;Patient-Focused Outcomes;Patients;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Platinum;Play;Pre-Clinical Model;Regulation;Research Design;Research Personnel;Research Training;Rheumatoid Arthritis;Role;Route;Safety;Serous;Site;Solid Neoplasm;Specificity;Structure;Survival Rate;System;TP53 gene;Testing;Therapeutic;Tissues;Tumor Cell Line;Tumor Tissue;Tumor stage;Work;Writing;Xenograft Model;Xeroderma Pigmentosum;anti-cancer;cancer diagnosis;cancer subtypes;cancer therapy;cancer type;career development;chemotherapy;clinical care;clinical decision-making;drug resistance development;efficacy evaluation;efficacy testing;epigenetic drug;improved;improved outcome;in vitro Model;in vivo;inhibitor;meetings;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;prognostic;prognostic indicator;recruit;response;responsible research conduct;standard of care;synergism;targeted agent;targeted treatment;therapeutically effective;transcription factor TFIIH;transcriptome sequencing;treatment response;treatment strategy;triptolide;tumor;tumor growth;tumorigenesis Characterization of the role of super-enhancers in ovarian cancer treatment response PROJECT NARRATIVEThe identification of super-enhancers in ovarian cancer that contribute to growth and therapeutic response willbe instrumental in diagnostic prognostic and therapeutic decision making. Not only will this work identifyovarian cancer-specific super-enhancers but it will also determine how they are modified in response tostandard-of-care chemotherapies as well as identify new drugs to target them directly. By better understandingthe location and functional role of these master transcriptional hubs in ovarian cancer we can more specificallytreat each ovarian cancer patient to achieve the best possible outcome. NCI 10677883 8/11/23 0:00 PA-18-398 5R00CA234391-05 5 R00 CA 234391 5 "FINGERMAN, IAN M" 8/1/19 0:00 8/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 10947813 "LANG, JESSICA DIANE" Not Applicable 2 PATHOLOGY 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI SCHOOLS OF MEDICINE 537151218 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Non-SBIR/STTR 2023 246961 NCI 160959 86002 Project Summary: Despite advances in our understanding of the underlying genomic landscape of high-grade serous ovarian carcinoma (HGSC) few new targeted treatments have entered clinical care withsignificant survival benefit. Super-enhancers (SEs) are epigenetic features previously understudied in HGSCthat are targetable with a variety of drugs. In cancer SEs regulate expression of oncogenes such as MYC butthe specific set of oncogenes regulated by SEs depends on the cancer type and these have not beenpreviously defined in HGSC. Preliminary data suggests that SEs underlie the oncogenic functions of ovariancancer as SE-targeting drugs such as triptolide and bromodomain inhibitors are effective in ovarian cancermodels in vitro and a rare ovarian cancer subtype in vivo. The work proposed here will lead to newunderstandings of how SEs influence HGSC growth and therapy response and how HGSC might be bettertreated with new therapeutic strategies targeting SEs ultimately improving outcomes for patients with HGSC.Hypothesis: Based both on the proven role of SEs in the pathogenesis of other cancers through uniqueregulation of oncogenes and also on data showing sensitivity of HGSC to SE-targeting drugs this proposaltests the hypothesis that SE dysregulation plays a central role in HGSC tumorigenesis and treatmentresponse. Specific Aims: Aim 1: Map HGSC SEs contributing to oncogenic phenotypes. Aim 2: Determinedynamic SE modification following standard-of-care treatment. Aim 3: Evaluate the efficacy of SE-targetingdrugs in HGSC. Study Design: To identify HGSC-specific SEs six serous HGSC cell lines and twenty tumorswill be examined by RNA-Seq and ChIP-Seq for H3K27 acetylation. SEs will be identified both bioinformaticallyand through functional characterization for roles in cell proliferation and response to chemotherapy using theCRISPR interference system. In the independent phase of this award the dynamics of SEs will be assessed inresponse to platinum treatment and SE-targeting drugs will be tested as single agents and for synergy incombination with platinum-based chemotherapies in HGSC cell lines patient-derived xenograft organoidmodels and animal xenograft models of HGSC. Career Development: Towards the goal of becoming anindependent investigator studying novel therapies for ovarian cancer treatment this proposal has alsoassembled a career development plan. This includes K99 phase mentorship by leaders in genomics (Dr.Jeffrey Trent mentor) and ovarian cancer (Dr. Lorna Rodriguez co-mentor) and an advisory team thatincludes experts in bioinformatics super-enhancers and ovarian cancer. As an institute TGen provides all thescientific support facilities and equipment necessary to complete this project. TGen has a structured plan forresponsible conduct of research training and other professional development. Additional coursework inbioinformatics analysis of ChIP-Seq and RNA-Seq data is built into the plan as well as attendance at relevantnational meetings and participation and/or lead the writing of a number of manuscripts and grants. 246961 +No NIH Category available Address;Alopecia;Blood;Body Image;Breast Cancer therapy;Caring;Charge;Clinic;Clinical Research;Color;Common Terminology Criteria for Adverse Events;Development;Devices;Dry Ice;Engineering;Fees;Gel;Goals;Growth;Hair;Hair follicle structure;Head;Health Personnel;Hour;Ice;Individual;Infusion procedures;Insurance Coverage;Intervention;Liquid substance;Literature;Malignant Neoplasms;Marketing;Measures;Mental Depression;Meta-Analysis;Minoxidil;Monitor;Occupations;Oncologist;Patient-Focused Outcomes;Patients;Performance;Personal Satisfaction;Persons;Phase;Plant Leaves;Provider;Quality of life;Reporting;Research Design;Risk;Risk Reduction;Scalp structure;Shapes;Small Business Innovation Research Grant;Source;Spheniscidae;System;Technology;Temperature;Testing;Texture;Time;Training;Well in self;cancer therapy;chemotherapeutic agent;chemotherapy;commercialization;comparative efficacy;cost;design;efficacy evaluation;efficacy testing;experience;flexibility;improved;meetings;patient oriented;poor health outcome;portability;prevent;prospective;sensor;side effect;societal costs;success;taxane;usability;vasoconstriction Portable Patient-Administered Scalp Cooling Cap to Reduce Provider Burden Improve Patient Access and Improve Patient Outcomes for Chemotherapy-Induced Alopecia PROJECT NARRATIVEPatients facing the prospect of chemotherapy consistently report that hair loss is one of their biggest concernsand patients who experience hair loss due to chemotherapy suffer from poor body image decreasedpsychological well-being and higher rates of depression. Cooling the scalp before during and afterchemotherapy greatly reduces the risk of hair loss from chemotherapy but the available devices have severallimitations that prevent about 80% of chemotherapy infusion centers from offering them to patients. This studyis designed to test the efficacy of using a portable patient-administered scalp cooling device which is expectedto eliminate the burden for infusion centers reduce costs and expand access to essentially any patient anywherein the US resulting in improved patient well-being and quality of life. NCI 10677863 9/6/23 0:00 PA-21-260 5R44CA254560-03 5 R44 CA 254560 3 "WEBER, PATRICIA A" 2/1/21 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-RPHB-Z(10)B] 16292413 "DILLIGAN, KATE " "RUGO, HOPE S" 50 Unavailable 116482614 VX8DS9KMYGT4 116482614 VX8DS9KMYGT4 US 32.718773 -117.12866 10057677 COOLER HEADS CARE INC SAN DIEGO CA Domestic For-Profits 921021714 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 SBIR/STTR 2023 1036917 NCI 692201 276880 PROJECT SUMMARYApproximately two-thirds of patients undergoing cancer treatment experience hair lossfrom chemotherapy-induced alopecia (CIA). Patients say CIA is one of the most concerning side effects ofchemotherapy and it is a significant contributor to poor body image decreased psychological well-being andhigher rates of depression. Scalp cooling which causes vasoconstriction that protects sensitive hair follicleswhile harsh chemotherapeutic agents are at the highest concentrations in the blood is the most effective way toprevent CIA. A recent meta-analysis found scalp cooling reduced the risk of significant CIA by 43% and flexiblecaps that conform to the shape of the head provide even better protection (e.g. 66% reduction in patientsreceiving taxanes). Oncologists and patients are enthusiastic about this technology but infusion centers havebeen slow to make it available for several reasons: 1) the center must lease and maintain the device; 2) staffmust administer the device before during and after chemotherapy; 3) only two patients can use the device at atime; 4) use extends occupation of the infusion chair by up to 3.5 hours; and 5) inconsistent insurance coveragepresents challenges for charging. As a result < 20% of infusion centers offer FDA-cleared scalp cooling systems.Patients can rent gel cap systems but they must source dry ice and a person to administer the treatment costing$5000 or more over a course of therapy. To overcome these challenges Cooler Heads designed a compacthighly-portable device patients can rent and use for a flat fee of $2000 for the duration of chemotherapy. Thedevice includes an electric chiller connected to a comfortable multi-leaf cap that conforms to the patients head.Sensors monitor fluid temperature and modulate coolant flow without intervention by the patient or clinic staff.The device also includes an onboard battery and car charger that allow patients to continue post-infusion coolingafter leaving the infusion center freeing up the chair for other patients. The device is fully patient administeredand the infusion center would only need to provide an electrical outlet and ice (standard for chemotherapy). In aPhase I SBIR (1R43CA254560-01A1) Cooler Heads developed training materials and conducted usabilitytesting to demonstrate patients could use the device as intended without support from healthcare providers. Inthis follow-on Phase II Cooler Heads proposes to conduct a prospective clinical study to establish the efficacyof the patient-administered device for reducing the risk of significant CIA. Aim. Establish the efficacy of scalpcooling with a patient-administered device. Milestone: Demonstrate patient-administered device has efficacycomparable to or better than provider-administered scalp cooling as reported in literature. Success Criterion: 50% of patients have hair loss of 50% at 3 weeks after final treatment. ImpactIf shown to provide benefitcomparable to provider-administered scalp cooling devices this patient-administered device has the potential totransform how scalp cooling is delivered meeting NCIs Cancer Moonshot priority for reducing major side effectsof cancer therapy by reducing the barriers that prevent most patients from accessing this effective technology. 1036917 +No NIH Category available Apoptosis;Basic Science;Bypass;Cell Aging;Cell Cycle;Cell Cycle Arrest;Cell Cycle Progression;Cell Death;Cell Line;Cell Maintenance;Cell Proliferation;Cell physiology;Cells;ChIP-seq;Childhood;Chromatin;Chromosomal translocation;Chromosome 11;Chromosome 22;DNA;DNA Damage;DNA Methylation;DNA Repair;DNA biosynthesis;DNA-protein crosslink;Data;Deubiquitination;Development;Disease Progression;E2F transcription factors;EWSR1 gene;Epigenetic Process;Ewings sarcoma;FLI1 gene;Family;Fiber;Gene Expression;Gene Fusion;Generations;Genes;Genetic Transcription;Genome;Genome Stability;Genomic Instability;Growth;HELLS gene;Histones;In Vitro;Lysine;Malignant Bone Neoplasm;Malignant Neoplasms;Maps;Mediating;Mesenchymal Stem Cells;Molecular;Normal Cell;Oncogenes;Oncogenic;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phenocopy;Proteins;Regulation;Role;S phase;Site;Testing;Therapeutic;Treatment Efficacy;Ubiquitin;Ubiquitination;Xenograft Model;biological adaptation to stress;bone;cancer cell;cell growth;chemotherapy;chromatin remodeling;comparative;epigenetic regulation;genome wide methylation;genome-wide analysis;improved;in vivo;inhibitor;insight;knock-down;methylation pattern;mutant;new therapeutic target;novel;overexpression;repaired;replication stress;response;sarcoma;senescence;small molecule;standard of care;stem cells;t(11;22)(q24;q12);targeted treatment;transcription factor;transcriptome sequencing;treatment strategy;tumor;tumor growth;tumorigenesis;ubiquitin isopeptidase;ubiquitin-protein ligase;ubiquitin-specific protease Mechanisms underlying USP1-mediated bypass of EWS-FLI1 oncogene-induced replication stress in Ewing sarcoma PROJECT NARRATIVEEWS-FLI1 oncogenic transcription factor regulates the expression of USP1 in Ewing sarcoma an aggressivepediatric bone cancer. USP1 deubiquitinase regulates HELLS and is required for stem cell maintenance genomestability and promotes cell proliferation bypassing oncogene-induced replication stress. NCI 10677857 7/26/23 0:00 PA-20-185 5R01CA263504-02 5 R01 CA 263504 2 "LUO, RUIBAI" 8/5/22 0:00 7/31/27 0:00 Cancer Etiology Study Section[CE] 11328261 "GHOSAL, GARGI " Not Applicable 2 GENETICS 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 859 Non-SBIR/STTR 2023 344109 NIGMS 208468 111532 PROJECT SUMMARY Replication stress leading to genome instability is an early driver of tumorigenesis and has beenassociated with overexpression of oncogenes. In normal cells activation of the DNA damage response (DDR)pathway serves as a barrier to tumorigenesis leading to cell cycle arrest inducing cellular senescence or celldeath in response to high burden of genome instability. However in cancer cells upon oncogene-inducedreplication stress the protective barrier of DDR cell death and senescence is bypassed leading to uncontrolledcell proliferation. Therefore deciphering the mechanisms that bypass oncogene-induced replication stress andsenescence will help understand the basic science underlying disease progression and will identify new targetsfor therapy. Ewing sarcoma (EWS) is driven by a chromosomal translocation and in-frame gene fusion betweenEWSR1 and ETS family of transcription factors. In majority of the EWS cases the chromosomal translocationresults in the generation of EWS-FLI1 oncogene. EWS-FLI1 functions as an aberrant transcription factor thatdrives the development and progression of EWS. Expression of EWS-FLI1 oncogene leads to oncogene-inducedreplication stress and genome instability. However the molecular mechanism underlying bypass of EWS-FLI1oncogene-induced replication stress response pathways is largely unknown. Our preliminary data shows thatUSP1 deubiquitinase is overexpressed in EWS cell lines and tumors. USP1 regulates DDR and is required forgenome stability and stem cell maintenance. We find that USP1 expression is regulated by EWS-FLI1 in EWS.Importantly inhibition of USP1 activity using small molecule USP1 inhibitors resulted in growth arrest of EWScell lines indicating that USP1 expression and activity is important for EWS cell proliferation and progression.Notably USP1 depletion led to a decrease in the levels of HELLS chromatin remodeling protein. The function ofUSP1 or HELLS in EWS pathogenesis has not been investigated. In this study we will examine the regulationof HELLS by USP1 deubiquitinase (Aim 1) determine the mechanism by which USP1 promotes EWS cellproliferation (Aim 2) and determine the effect of USP1 knockdown on EWS tumor formation in vivo and theefficacy of USP1 inhibition in combination with chemotherapeutic drugs at suppressing EWS cell proliferation(Aim 3). Successful completion of this study will unravel novel mechanistic insights into USP1 mediated bypassof EWS-FLI1 oncogene-induced replication stress and help evaluate USP1 targeted treatment strategies forEWS. 320000 +No NIH Category available Apoptosis;Basic Science;Bypass;Cell Aging;Cell Cycle;Cell Cycle Arrest;Cell Cycle Progression;Cell Death;Cell Line;Cell Maintenance;Cell Proliferation;Cell physiology;Cells;ChIP-seq;Childhood;Chromatin;Chromosomal translocation;Chromosome 11;Chromosome 22;DNA;DNA Damage;DNA Methylation;DNA Repair;DNA biosynthesis;DNA-protein crosslink;Data;Deubiquitination;Development;Disease Progression;E2F transcription factors;EWSR1 gene;Epigenetic Process;Ewings sarcoma;FLI1 gene;Family;Fiber;Gene Expression;Gene Fusion;Generations;Genes;Genetic Transcription;Genome;Genome Stability;Genomic Instability;Growth;HELLS gene;Histones;In Vitro;Lysine;Malignant Bone Neoplasm;Malignant Neoplasms;Maps;Mediating;Mesenchymal Stem Cells;Molecular;Normal Cell;Oncogenes;Oncogenic;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Phenocopy;Proteins;Regulation;Role;S phase;Site;Testing;Therapeutic;Treatment Efficacy;Ubiquitin;Ubiquitination;Xenograft Model;biological adaptation to stress;bone;cancer cell;cell growth;chemotherapy;chromatin remodeling;comparative;epigenetic regulation;genome wide methylation;genome-wide analysis;improved;in vivo;inhibitor;insight;knock-down;methylation pattern;mutant;new therapeutic target;novel;overexpression;repaired;replication stress;response;sarcoma;senescence;small molecule;standard of care;stem cells;t(11;22)(q24;q12);targeted treatment;transcription factor;transcriptome sequencing;treatment strategy;tumor;tumor growth;tumorigenesis;ubiquitin isopeptidase;ubiquitin-protein ligase;ubiquitin-specific protease Mechanisms underlying USP1-mediated bypass of EWS-FLI1 oncogene-induced replication stress in Ewing sarcoma PROJECT NARRATIVEEWS-FLI1 oncogenic transcription factor regulates the expression of USP1 in Ewing sarcoma an aggressivepediatric bone cancer. USP1 deubiquitinase regulates HELLS and is required for stem cell maintenance genomestability and promotes cell proliferation bypassing oncogene-induced replication stress. NCI 10677857 7/26/23 0:00 PA-20-185 5R01CA263504-02 5 R01 CA 263504 2 "LUO, RUIBAI" 8/5/22 0:00 7/31/27 0:00 Cancer Etiology Study Section[CE] 11328261 "GHOSAL, GARGI " Not Applicable 2 GENETICS 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 859 Non-SBIR/STTR 2023 344109 NCI 15707 8402 PROJECT SUMMARY Replication stress leading to genome instability is an early driver of tumorigenesis and has beenassociated with overexpression of oncogenes. In normal cells activation of the DNA damage response (DDR)pathway serves as a barrier to tumorigenesis leading to cell cycle arrest inducing cellular senescence or celldeath in response to high burden of genome instability. However in cancer cells upon oncogene-inducedreplication stress the protective barrier of DDR cell death and senescence is bypassed leading to uncontrolledcell proliferation. Therefore deciphering the mechanisms that bypass oncogene-induced replication stress andsenescence will help understand the basic science underlying disease progression and will identify new targetsfor therapy. Ewing sarcoma (EWS) is driven by a chromosomal translocation and in-frame gene fusion betweenEWSR1 and ETS family of transcription factors. In majority of the EWS cases the chromosomal translocationresults in the generation of EWS-FLI1 oncogene. EWS-FLI1 functions as an aberrant transcription factor thatdrives the development and progression of EWS. Expression of EWS-FLI1 oncogene leads to oncogene-inducedreplication stress and genome instability. However the molecular mechanism underlying bypass of EWS-FLI1oncogene-induced replication stress response pathways is largely unknown. Our preliminary data shows thatUSP1 deubiquitinase is overexpressed in EWS cell lines and tumors. USP1 regulates DDR and is required forgenome stability and stem cell maintenance. We find that USP1 expression is regulated by EWS-FLI1 in EWS.Importantly inhibition of USP1 activity using small molecule USP1 inhibitors resulted in growth arrest of EWScell lines indicating that USP1 expression and activity is important for EWS cell proliferation and progression.Notably USP1 depletion led to a decrease in the levels of HELLS chromatin remodeling protein. The function ofUSP1 or HELLS in EWS pathogenesis has not been investigated. In this study we will examine the regulationof HELLS by USP1 deubiquitinase (Aim 1) determine the mechanism by which USP1 promotes EWS cellproliferation (Aim 2) and determine the effect of USP1 knockdown on EWS tumor formation in vivo and theefficacy of USP1 inhibition in combination with chemotherapeutic drugs at suppressing EWS cell proliferation(Aim 3). Successful completion of this study will unravel novel mechanistic insights into USP1 mediated bypassof EWS-FLI1 oncogene-induced replication stress and help evaluate USP1 targeted treatment strategies forEWS. 24109 +No NIH Category available Age;Aneuploidy;Barrett Esophagus;Biological Assay;Biological Markers;Biopsy;Biopsy Specimen;Cancer Etiology;Cessation of life;Clinical;Colon;Colon Carcinoma;Colonic Adenoma;Colonoscopy;Colorectal Cancer;Cytology;DNA;DNA Markers;DNA Methylation;Data;Detection;Devices;Dysplasia;Early Detection Research Network;Early Diagnosis;Esophageal Adenocarcinoma;Esophagus;Funding;Genetic Markers;Goals;High grade dysplasia;Incidence;Individual;Lesion;Life;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Methylation;Molecular;Mucous Membrane;Natural History;Patients;Performance;Persons;Phase;Prevention;Progressive Disease;Prospective cohort;Recurrence;Retrospective cohort study;Risk;Risk Marker;Sampling;Screening for cancer;Sensitivity and Specificity;Stable Disease;Surveillance Program;Testing;Vision;adenoma;base;biomarker development;biomarker identification;biomarker validation;cancer therapy;candidate identification;candidate marker;clinically relevant;cohort;colon cancer risk;colon cancer screening;colorectal cancer risk;colorectal cancer screening;cost effective;early detection biomarkers;follow-up;genomic locus;high risk;laboratory development;methylation biomarker;molecular marker;mortality;novel;phase IV trial;predictive marker;progression risk;prospective;risk prediction;risk stratification;risk variant;screening;screening program Biomarker Development Laboratory n/a NCI 10677827 7/7/23 0:00 RFA-CA-21-035 5U2CCA271902-02 5 U2C CA 271902 2 8/5/22 0:00 7/31/27 0:00 ZCA1-PCRB-D 9338 1865649 "GRADY, WILLIAM MALLORY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 327576 200260 127316 PROJECT SUMMARY The goal of this BDL proposal is the discovery and validation of biomarkers for reducing mortality fromgastrointestinal cancers. We focus on colorectal cancer (CRC) the second leading cause of cancer deaths inthe U.S. and on esophageal adenocarcinoma (EAC) which is increasing rapidly and has an 83% mortality rate.For CRC we propose to develop biomarkers to accurately identify individuals at high risk for CRC who benefitfrom aggressive screening programs. We will conduct EDRN phase 1 and 2 studies to discover and validate aclass of methylated DNA based molecular markers found in the normal colon mucosa which our prior studieshave implicated as identifying individuals at increased CRC risk. For EACs we propose to identify biomarkersthat will accurately detect high grade dysplasia (HGD) and early EAC in esophageal cytology samples whichcan be obtained with a non-endoscopic device and can be used in a cost-effective BE surveillance program.Thirdly we will conduct EDRN Phase 1 and 2 studies to discover and validate biomarkers that predict the risk ofBE progressing to HGD or early EAC. Our overall vision is to develop accurate biomarker-based tests ofesophageal samples that ultimately can be used to predict the risk for HGD and EAC and to detect early HGDand EAC to achieve cost-effective effective BE surveillance using non-endoscopic esophageal cytology samples.We base these Phase 1 and 2 studies on our identification of novel methylated DNA biomarkers that highlydiscriminate many early EAC and HGD from BE as well on our identification of candidate methylated DNAmarkers and genetic markers that associate with BE progression to HGD or EAC. We will develop an optimalpanel of methylated DNA markers for detecting HGD and early EAC. For the risk marker studies we will developa panel of methylated DNA markers and genetic markers for predicting the risk of BE progressing to HGD orEAC. The specific aims of this proposal accordingly are:Aim 1. To assess in EDRN phase 1/2 studies the sensitivity and specificity of a set of candidate biomarkerswhose detection in the normal colon mucosa identifies individuals at increased risk of developing advancedadenoma or CRC.Aim 2. To assess in EDRN phase 1/2 studies the sensitivity and specificity of a set of candidate DNA methylationbiomarkers aneuploidy markers and copy number alteration (CNA) markers for identifying Barretts esophagusthat is at risk for progressing to HGD or EACAim 3. To develop in EDRN phase 1/2 studies a set of candidate biomarkers for detecting early EAC and HGDas well as high-risk low grade dysplasia (LGD) in esophageal cytology samples. +No NIH Category available Administrative Coordination;Administrator;Biological Assay;Biological Markers;CLIA certified;Cancer Intervention and Surveillance Modeling Network;Clinical;Collaborations;Communication;Data;Data Analyses;Data Commons;Data Coordinating Center;Development;Early Detection Research Network;Early Diagnosis;Education;Environment;Funding;Funding Agency;Future;Industrialization;Institution;Letters;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Mission;Process;Productivity;Rana;Research;Research Personnel;Running;Scientist;Screening for cancer;Structure;System;Teleconferences;United States National Institutes of Health;Validation;Work;biomarker discovery;biomarker validation;clinical biomarkers;clinical development;colon cancer screening;data dissemination;data sharing;data submission;industry partner;innovation;interest;meetings;member;operation;organizational structure;programs;protocol development;risk prediction;success;validation studies Administrative Core-Biomarkers for optimizing risk prediction and early detection of cancers of the colon and esophagus n/a NCI 10677826 7/7/23 0:00 RFA-CA-21-035 5U2CCA271902-02 5 U2C CA 271902 2 8/5/22 0:00 7/31/27 0:00 ZCA1-PCRB-D 9337 1865649 "GRADY, WILLIAM MALLORY" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Other Research-Related 2023 417366 237140 180226 PROJECT SUMMARY The Administrative Core (AC) of our Biomarker Characterization Center (BCC) will facilitate and optimizethe integration of biomarker discovery and initial validation studies by the Biomarker Discovery Lab (BDL) andthe development and validation studies to create clinical-grade CLIA compliant biomarker assays by theBiomarker Reference Lab (BRL). The Administrative Core will be managed by the Center Administrator and runby the PIs of the BDL and BRL. It will support and enhance cross BCC and cross EDRN communication datadissemination and data review and analysis which will promote the BCCs core mission to discovery and validateclinical grade biomarker assays for GI cancer risk prediction and early detection The Administrative Core willprovide administrative support for collaborations and communications between the EDRN BCCs ClinicalValidation Centers (CVCs) Data Management Center (DMCC); collaborating industrial partners (e.g. CernosticsQiagen etc.) and academic partners and collaborating NCI programs (e.g. CISNET NIST etc.). Through thefunctions of the Administrative Core the BCC with other EDRN BCCs CVC and DMCC industrial partners andacademic partners will collaborate not only on the BCCs studies but also on resulting derivative studies andother EDRN BCC and CVC projects that arise from the BCCs highly innovative productive and significantprogram of biomarker discovery and validation for GI cancer risk prediction and early detection and the programsof other BCCs. The Administrative Core has the following aims:Aim 1: To provide the organizational structure for supporting the key objectives of the BCC which are the BDLsand BRLs scientific and educational missions and the successful collaboration among the BDL and BRL PI andscientists EDRN partners academic partners and industrial partners.Aim 2: To provide efficiency in management of large-scale collaborative research efforts involving multipleinstitutions and multiple PDs/PIs including local and national meetings management.Aim 3: To coordinate with EDRN DMCC for protocol development biospecimen sharing biospecimen blindingdata analysis data sharing data deposition populating Biomarker Data Commons and any other relevantfunctions deemed necessary for BCC operations as well as for the larger Network. +No NIH Category available Affect;Age;Age Years;Barrett Esophagus;Biological Assay;Biological Markers;CLIA certified;Cancer Etiology;Cancer Prevention Trial;Cessation of life;Chronic;Clinical;Collaborations;Colon;Colonoscopy;Colorectal Cancer;Cytology;Development;Devices;Dysplasia;Early Detection Research Network;Early Diagnosis;Economics;Effectiveness;Eligibility Determination;Endoscopy;Esophageal Adenocarcinoma;Esophageal Precancerous Condition;Esophagus;Familial Adenomatous Polyposis Syndrome;Family history of;Gastroesophageal reflux disease;Goals;Healthcare;Healthcare Systems;Hereditary Neoplastic Syndromes;Hereditary Nonpolyposis Colorectal Neoplasms;High grade dysplasia;Histologic;Incidence;Individual;Lesion;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Methods;Modeling;Morbidity - disease rate;Patients;Persons;Phase;Population;Prevention;Prevention program;Program Efficiency;Progress Reports;Recommendation;Recording of previous events;Resources;Risk;Risk Factors;Risk Marker;Sampling;Screening for cancer;Serrated Adenoma;Stress;Surveillance Program;Survival Rate;System;Testing;Treatment Cost;Tubular Adenoma;United States National Institutes of Health;adenoma;clinic ready;colon cancer patients;colon cancer screening;colorectal cancer prevention;colorectal cancer risk;colorectal cancer screening;colorectal cancer treatment;cost;cost effective;detection assay;early detection biomarkers;effectiveness evaluation;esophageal cancer prevention;financial toxicity;high risk;high risk population;improved;mortality;premalignant;prevent;preventable death;progression risk;risk prediction;risk stratification;screening;screening program;social;standard of care;success;trend;virtual Biomarkers for optimizing risk prediction and early detection of cancers of the colon and esophagus PROJECT NARRATIVEColorectal cancer (CRC) and (EAC) account for the majority of gastrointestinal cancer deaths but can beprevented with screening. For the screening tests to be most effective they need to be optimized for individualsat low-risk and high-risk for CRC and EAC; however the current methods for CRC and EAC risk prediction havelow accuracy. We propose to create an integrated and highly collaborative Biomarker Characterization Centerto discover validate and develop into clinic-ready assays tests for accurate CRC and EAC risk prediction. Wefurther propose to discover and validate tests based on simple brushing samples of the esophagus that candetect a nascent cancer condition called high grade dysplasia (HGD) and early EAC in people with Barrettsesophagus (BE) a high risk precancerous condition for EAC which will decrease deaths from EAC and theburden of BE surveillance. NCI 10677825 7/7/23 0:00 RFA-CA-21-035 5U2CCA271902-02 5 U2C CA 271902 2 "YOUNG, MATTHEW R" 8/5/22 0:00 7/31/27 0:00 ZCA1-PCRB-D(M1) 1865649 "GRADY, WILLIAM MALLORY" "YEUNG, CECILIA C" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Other Research-Related 2023 1009158 NCI 606640 402518 Project Summary Gastrointestinal (GI) cancers are a major cause of mortality and morbidity in the U.S. and their treatmentuses a substantial proportion of healthcare resources. Of the GI cancers colorectal cancer (CRC) andesophageal cancer (EAC) account for a majority of the cancer related deaths and both are preventable byscreening and surveillance. The current screening tests are suboptimal and have variable success. A major goal of CRC screening tests is to identify advanced tubular and serrated adenomas which arehigh-risk for becoming CRC as well as early stage CRC. The risk for CRC is variable with some people beingat high risk because of family histories of CRC hereditary cancer syndromes or a personal history of adenomas.High risk people are placed on aggressive colonoscopy based surveillance programs and low-risk people areplaced on minimal surveillance programs. Unfortunately our current system for identifying high and low CRCrisk is suboptimal resulting in under and over surveillance and preventable interval CRCs. Better risk markersfor CRC to are needed to prevent interval CRCs and improve the overall effectiveness of CRC screening. Analogous to CRC EAC arises from a precancerous condition of the esophagus called Barrettsesophagus (BE) which is a specialized intestinal metaplasia of the esophagus and the highest risk factor forEAC. It is present in 5% of the US population. BE progresses to EAC through successive histologic steps oflow grade dysplasia (LGD) high grade dysplasia (HGD) and then EAC. Screening and surveillance for BE isrecommended using serial upper endoscopy which is controversial in its effectiveness for preventing deathsfrom EAC. This is in part because as with CRC BE patients have variable risk of EAC and are placed on high-risk and low-risk screening programs. However the current system for assigning risk is not accurate and thecurrent screening test is expensive. More cost effective and accurate EAC and HGD screening/surveillanceassays and accurate BE risk biomarkers are needed. We propose to develop an EDRN BCC that is integrated into the EDRN consortium and throughcollaborations within and outside the EDRN will develop effective GI cancer screening biomarkers. We proposeto identify validate and develop accurate CLIA compliant risk biomarkers for CRC and for EAC in order toprevent EAC and CRC missed under current screening protocols. Moreover the accurate risk stratification ofpatients for CRC and EAC will reduce the financial impact of current CRC and EAC prevention programs. Wealso propose to identify and validate accurate CLIA compliant early detection markers for HGD and early stageEAC that can be used in an inexpensive non-endoscopic surveillance test. 1009158 +No NIH Category available Amino Acid Transporter;Antineoplastic Agents;Biochemical Pathway;CRISPR screen;Cell Death;Cell Death Induction;Cell Line;Cell Survival;Cells;Cysteine;Cystine;Data;Dependence;Development;Disulfides;Equilibrium;Exhibits;Genetic;Glucose;Glucose Transporter;Goals;Homeostasis;Human;Immune system;Impairment;Link;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;Metabolism;Mutation;NADP;Nature;Normal Cell;Nutrient;Outcome;Oxidation-Reduction;Pathway interactions;Pentosephosphate Pathway;Pharmaceutical Preparations;Pre-Clinical Model;Radiation therapy;Research;Role;Solid Neoplasm;Starvation;Testing;Therapeutic;Translations;Xenograft procedure;antiporter;cancer cell;cancer therapy;clinical care;inhibitor;innovation;insight;leukemia;lung cancer cell;mutant;novel;novel therapeutic intervention;novel therapeutics;nutrient metabolism;overexpression;patient derived xenograft model;pre-clinical;programs;small molecule;standard of care;success;targeted agent;therapeutic target;tumor;uptake Targeting SLC7A11-induced nutrient dependency in cancer: mechanisms and preclinical translation Project Narrative There is a critical need to understand the mechanisms of action of anti-neoplastic agents that targetnutrient dependency in cancer cells. The objectives of this application are to determine the roles and mechanismsof cystine transporter SLC7A11 in regulating nutrient dependency and to therapeutically target nutrientdependency in cancers with aberrant expression of SLC7A11. Our proposed studies will have significant impacton both our understanding of the fundamental mechanisms of nutrient dependency and our ability totherapeutically target nutrient dependency in cancer treatment. NCI 10677816 6/7/23 0:00 PA-19-056 5R01CA244144-04 5 R01 CA 244144 4 "WILLIS, KRISTINE AMALEE" 7/1/20 0:00 6/30/25 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 9939858 "GAN, BOYI " Not Applicable 9 RADIATION-DIAGNOSTIC/ONCOLOGY 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 417377 NCI 257640 159737 Project Summary Specific genetic alterations in cancer cells may reprogram their metabolic networks and render them highlydependent on particular nutrients for survival. A mechanistic understanding of nutrient dependency in cancercells has important implications for cancer treatment because drugs that impair nutrient metabolism may beeffective for killing cancer cells that depend on specific nutrients for survival while sparing normal cells. Whiletargeting nutrient dependency has been successful in leukemia to date there has been limited success intargeting nutrient dependency in solid tumors. Therefore there is a significant need to understand themechanisms of action of anti-neoplastic agents that target nutrient dependency in cancer cells. SLC7A11 is anamino acid transporter that enables cystine uptake and its subsequent conversion to cysteine which is criticalfor maintaining redox balance and cell survival. SLC7A11 is frequently overexpressed in human cancersincluding KEAP1-mutant lung cancers. This application aims to determine the roles and mechanisms ofSLC7A11 in regulating nutrient dependency and to therapeutically target nutrient dependency in cancers withaberrant expression of SLC7A11. Our specific aims are: Specific Aim 1: To determine the metabolic mechanismsunderlying SLC7A11-induced glucose dependency in cancer cells. Specific Aim 2: To determine the therapeuticpotential of inhibiting GLUTs or the PPP in treating tumors with aberrant SLC7A11 expression. The rationale forthe proposed research is that studying the roles of SLC7A11 in regulating glucose dependency will not onlyadvance our mechanistic understanding of nutrient dependency in cancer cells but also provide importantinsights into the development of novel therapeutic strategies to target metabolic vulnerabilities in SLC7A11-overexpressing tumors. Our proposed studies will have significant impact on both our understanding of thefundamental mechanisms of nutrient dependency and our ability to therapeutically target nutrient dependency incancer treatment. 417377 +No NIH Category available Acute Megakaryocytic Leukemias;Acute Myelocytic Leukemia;Adult;Animal Model;Biology;CRISPR screen;Chemoprevention;Childhood;Childhood Leukemia;Chromosome 21;Development;Disease;Disparate;Down Syndrome;Event;GATA1 gene;Genes;Genetic;Hematological Disease;Hematopoiesis;Hematopoietic;Laboratories;Malignant - descriptor;Malignant Neoplasms;Megakaryocytes;Mutation;Myelofibrosis;Myeloproliferative disease;Pathogenesis;Pathway interactions;Patients;Preleukemia;Prevention strategy;Role;Sampling;Tumor Suppressor Genes;Work;insight;leukemia;new therapeutic target;novel strategies;novel therapeutics;prevent;tumor Identifying the mechanisms of leukemia progression PROJECT NARRATIVEMy laboratory is at the forefront of studies in leukemia in children with Down syndrome and in the role ofmegakaryocytes in myelofibrosis. In this project we will leverage our expertise to compare the mechanisms ofleukemia progression in pediatric and adult pre-leukemia disorders. Our work will shed new light on the biologyof leukemia progression and may reveal novel strategies to treat or prevent transformation of these clonaldisorders. NCI 10677759 9/5/23 0:00 PAR-20-278 5R35CA253096-03 5 R35 CA 253096 3 "KLAUZINSKA, MALGORZATA" 9/22/21 0:00 8/31/28 0:00 ZCA1-GRB-S(M1) 1928314 "CRISPINO, JOHN D" Not Applicable 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 1055460 NCI 588000 467460 PROJECT SUMMARYSince 2002 when my laboratory discovered GATA1 mutations in all cases acute megakaryocytic leukemia inchildren with Down syndrome I have been at the forefront of defining the specific genetic events that promoteleukemia. I have extensively studied the role of GATA1 in normal and malignant hematopoiesis and gained manyinsights into the contributions of several chromosome 21 genes including DYRK1A ERG and CHAF1B inleukemia. My laboratory is also well established in the field of the myeloproliferative neoplasms (MPNs)especially in the role of megakaryocytes in the pathogenesis of myelofibrosis and the development of newtherapies for this disease. In this R35 application I propose to focus my laboratory over the next 7 years (andbeyond) on understanding the mechanisms of leukemia progression from clonal hematopoietic disorders.Specifically we will identify and compare the ways that pediatric and adult disorders progress to acute myeloidleukemia. We will leverage large scale CRISPR/Cas9 screening animal models and primary patient samples todeeply characterize the mechanisms of transformation and focus on answering three questions: 1) What are thesimilar and disparate events that promote malignant progression of pediatric versus adult blood disorders? 2)How does dysregulation of pathways downstream of identified tumor suppressor genes promote malignantprogression? 3) Which investigational or approved therapies can prevent progression or treat the tumors? Theanswers to these questions will increase our basic understanding of cancer reveal new therapeutic targets andpossibly shed light on chemoprevention strategies. 1055460 +No NIH Category available 3-Dimensional;Adaptor Signaling Protein;Adult;Amaze;Biochemistry;Biological Assay;Biology;Biotinylation;Bone Diseases;Cancer Model;Cell Fate Control;Cell Nucleus;Cell Proliferation;Cell Survival;Cell membrane;Cell surface;Cells;Cellular biology;Chemicals;Clathrin;Colorectal Cancer;Complex;Consensus;Data;Development;Docking;Down-Regulation;Drug Targeting;Embryonic Development;Endocytosis;Evaluation;Event;Excision;Family;Feedback;Flow Cytometry;Future;Genes;Genetic Transcription;Goals;Homeostasis;Human;Hyperactivity;Informatics;Ligands;Ligation;Literature;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Measures;Mediating;Microscopy;Molecular;Nature;Neoplasm Metastasis;Normal Cell;Pathway interactions;Patient-Focused Outcomes;Pharmacology;Phosphorylation;Phosphotransferases;Physiological;Postdoctoral Fellow;Proliferating;Protein Family;Protein Isoforms;Protein Kinase;Proteins;Proteomics;Publications;Regulation;Reporter;Reporting;Repression;Research;Research Personnel;Research Project Grants;Role;Signal Transduction;Structure;Testing;Therapeutic;Therapeutic Intervention;Time;Tissues;Training;Transcription Coactivator;Tumor Suppressor Proteins;Validation;WNT Signaling Pathway;Western Blotting;Work;attenuation;beta catenin;cancer therapy;career;casein kinase I;developmental disease;drug discovery;experience;experimental study;extracellular;functional genomics;gain of function;genetic manipulation;human disease;improved;in silico;inhibitor;kinase inhibitor;live cell imaging;loss of function;malignant breast neoplasm;member;migration;nervous system disorder;new therapeutic target;novel;phosphoproteomics;programs;protein protein interaction;protein structure;receptor;response;small molecule inhibitor;structural biology;therapeutic target;therapeutically effective Mechanism of Action of the TBX3 Gene in Breast Cancer PROJECT NARRATIVEVarious mechanisms drive hyperactivity of the WNT signaling pathway in cancer. Defining and understandingthese mechanisms will facilitate cancer treatment and improve patient outcome. This training proposal aims toclarify the roles of the WTX tumor suppressor and the druggable CSNK1g kinase isoforms in WNT signalingregulation. NCI 10677744 8/16/23 0:00 RFA-CA-19-002 5K00CA245724-05 5 K00 CA 245724 5 "DAMICO, MARK W" 9/1/21 0:00 8/31/25 0:00 ZCA1-RTRB-R(A1) 14310548 "AGAJANIAN, MEGAN " Not Applicable 16 ANATOMY/CELL BIOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 100527 NCI 93414 7113 PROJECT SUMMARYWNT signaling is crucial for embryonic development and adult tissue homeostasis with aberrant signalingresulting in developmental disorders and disease including cancer. Although much is known a deepermechanistic understanding of this signaling cascade will improve our understanding of cancer formationprogression and metastasis allowing for the development of more effective therapeutics. WNT/b-cateninsignaling is driven by the stabilization of the transcriptional co-activator b-catenin. In the absence of WNT liganda cytosolic destruction complex phosphorylates ubiquitylates and degrades b-catenin. In the presence of WNTligand the WNT receptors Frizzled and LRP6 and intracellular proteins form an alternative complex called theWNT signalosome. This results in b-catenin accumulation and activation of b-catenin target genes. Recent datademonstrate that upon WNT ligand engagement the signalosome is endocytosed. Although conflicting dataexist within the literature a consensus is beginning to emerge that clathrin-dependent endocytosis of thesignalosome results in signalosome degradation. This training proposal and my thesis project is devoted toelucidating the molecular events and dynamics of signalosome formation stabilization and endocytosis in normalcells and in cancer with an emphasis on kinases. In the first half of my graduate training I utilized a gain-of-function screen of the kinome to identify AAK1 as a negative regulator of WNT signaling. I demonstrated thatAAK1 activates a transcription independent negative feedback loop to promote LRP6 internalization resulting inWNT signaling downregulation. In the course of these studies we demonstrated that AAK1 promotes thephosphorylation of a clathrin adapter protein AP2M1 8-10 hrs post-WNT3A and that AAK1 and AP2M1 interactwith the tumor suppressor WTX. My lab previously discovered the WTX tumor suppressor as a component ofthe signalosome and b-catenin destruction complex. Therefore I will define comprehensive WNT3A and WTX-dependent changes to the phosphoproteome by quantitative mass spectrometry and test whether WTX regulatessignalosome endocytosis via AAK1. Additionally CSNK1g is known to regulate phosphorylation of LRP6 anessential step for signalosome formation. CSNK1g has 3 isoforms CSNK1g1/2/3 all identified as understudiedkinases. My preliminary data suggest each isoform functions differently to activate WNT signaling and promoteLRP6 internalization. A main focus for the remainder of my graduate work will be to functionally characterize therole of each CSNK1g isoform in regulating WNT signaling define comprehensive protein-protein interactionnetworks and evaluate isoform specific changes to the WNT-driven phosphoproteome. Because this work isdescriptive in nature I expect it to be submitted for publication in 14 months. To summarize the precise role ofendocytosis in WNT signaling remains unclear with numerous questions surrounding the mechanism(s) andcomponents of endocytosis and its effects on signaling. This work and my future postdoctoral work will provideme training in and experience in the mechanisms of WNT signaling and feedback attenuation. 100527 +No NIH Category available 3-Dimensional;3D ultrasound;Ablation;Acoustics;Adoption;Advanced Development;Algorithms;Anatomy;Animal Model;Animals;Breathing;Cattle;Cirrhosis;Clinical;Collaborations;Compensation;Diffusion;Diffusion Magnetic Resonance Imaging;Elements;Equipment;Etiology;Family suidae;Feedback;Fluoroscopy;Freedom;Goals;Hand;Human;Image;Institution;Intervention;Interventional Ultrasonography;Intestines;Iowa;Lesion;Liver;Location;Lung;Magnetic Resonance Imaging;Methods;Modality;Modeling;Monitor;Motion;Navigation System;Needles;Operative Surgical Procedures;Organ;Pathology;Patient-Focused Outcomes;Patients;Performance;Perfusion;Positioning Attribute;Procedures;Recurrence;Research;Roentgen Rays;Safety;Scientist;Site;Sum;System;Techniques;Technology;Temperature;Thermometry;Time;Tissue Model;Tissues;Translating;Ultrasonography;United States National Institutes of Health;Universities;Validation;Wisconsin;Work;X-Ray Computed Tomography;clinical practice;comparative;contrast enhanced;curative treatments;deep learning;experimental study;flexibility;image guided;image guided intervention;image guided radiation therapy;image registration;improved;in vivo imaging system;industry partner;innovation;liver ablation;liver tumor ablation;microwave ablation;microwave electromagnetic radiation;minimally invasive;multidisciplinary;novel;operation;pre-clinical;real-time images;respiratory;skills;soft tissue;success;technology validation;temporal measurement;treatment response;tumor;ultrasound;user-friendly;virtual Simultaneous MRI/US for real-time liver ablation guidance and confirmation Project Narrative:Current approaches to guiding percutaneous liver ablation have significant limitations yielding poor tumorcontrol rates. This multi-disciplinary multi-institutional Academic Industrial Partnership will develop andvalidate a simultaneous US and MR solution in combination with advanced MR methods for real-timeguidance treatment monitoring and margin assessment during liver ablations with the ultimate goal ofimproving patient outcomes. NCI 10677721 8/1/23 0:00 PAR-20-155 5R01CA266879-02 5 R01 CA 266879 2 "PEREZ, J MANUEL" 8/15/22 0:00 7/31/27 0:00 Special Emphasis Panel[ZRG1-SBIB-Q(57)R] 14803357 "HOLMES, JAMES H" "WELLS, SHANE A; YEO, DESMOND TECK BENG " 1 NONE 62761671 Z1H9VJS8NG16 62761671 Z1H9VJS8NG16 US 41.664405 -91.542152 3972901 UNIVERSITY OF IOWA IOWA CITY IA UNIVERSITY-WIDE 522421320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 766670 NCI 721525 45145 Project Summary:Percutaneous liver tumor ablation procedures are performed with ultrasound (US) computed tomography (CT)and CT-fluoroscopy guidance. Each image guidance modality has strengths and weakness. US providessuperior tissue contrast and real-time guidance; however suboptimal or absent acoustic windows motion(respiratory bulk) and poor applicator conspicuity compromise precise tumor targeting and a widening skillgap limit widespread adoption. The larger field-of-view (FOV) provided by CT is critical for evaluating proximityof non-target anatomy; however poor tissue contrast limited access along the X-Y-Z axis motion and non-real-time guidance limit accurate tumor targeting. Magnetic resonance imaging (MRI) provides superior softtissue contrast but presents challenges with the comparatively long acquisition times for real-time guidanceand limited access within the scanner bore. Image fusion technologies attempt to harness the strengths ofeach modality. Unfortunately current image fusion technologies are unable to sufficiently account for liverdeformation bulk respiratory and patient motion which compromise targeting. Further they do not addresschallenges associated with US. An Academic Industrial Partnership is proposed to develop and validate asolution comprised of two primary elements. The first is a combined platform with a novel MRI compatiblehands-free US and fast 3D deformable image registration for optimized simultaneous US and virtual MR imageguidance in the ablation setting. The second element will be development of advanced MRI methods for real-time treatment monitoring through MR Thermometry in combination with near-real-time assessment of ablationzone margins using advanced diffusion and perfusion MRI. This solution will improve primary efficacy andreduce local recurrence after ablation of liver tumors. This proposal will focus on microwave ablation howeverthe solution is applicable for a wide variety of thermal therapies. 766670 +No NIH Category available Adjuvant;Bathing;Blood specimen;Cell Line;Chemotherapy-Oncologic Procedure;Clinical;Cytotoxic Chemotherapy;Cytotoxic agent;DNA;DNA Damage;DNA Mismatch Repair Protein MLH1;DNA Repair Disorder;Data;Defect;Deposition;Disease;Disease Progression;Disseminated Malignant Neoplasm;Eligibility Determination;Excision;Exhibits;Genomic Instability;Greater sac of peritoneum;Heat shock proteins;Human;Hyperthermia;Immune System Diseases;Immune checkpoint inhibitor;Immunotherapy;In Vitro;Inflammation;Inflammatory Response;MLH1 gene;MSH2 gene;Malignant Neoplasms;Measurement;Measures;Microsatellite Instability;Microscopic;Mismatch Repair;Mitomycin C;Monoclonal Antibodies;Multi-Institutional Clinical Trial;Mutation;Neoplasm Metastasis;Operative Surgical Procedures;Organoids;Outcome;Pathway interactions;Patients;Peritoneal;Phase;Physiological;Process;Prognosis;Progression-Free Survivals;Proteins;Randomized Controlled Trials;Regimen;Relapse;Research;Resected;Safety;Site;Specimen;Stress;Testing;Therapeutic heat application;Tissue Sample;Tissues;Toxic effect;Tumor Debulking;anti-PD-1;cancer cell;cancer surgery;cancer survival;checkpoint therapy;chemotherapy;clinical predictors;colon cancer patients;cytokine;drug sensitivity;experience;improved;inhibitor therapy;intraperitoneal therapy;member;metastatic colorectal;neoantigens;operation;pembrolizumab;programmed cell death protein 1;response;tumor Alterations in DNA Damage following Major Surgery and Hyperthermic Intraperitoneal Chemotherapy PROJECT NARRATIVEOur proposal examines whether the major inflammation heat and chemotherapy of cytoreductive surgery (CRS)and heated intraperitoneal chemotherapy (HIPEC) increases the genomic instability of patients with metastaticcolorectal cancer (mCRC). Our ultimate objective is to identify changes in tumor mutation burden neoantigensor microsatellite instability as a result of CRS/HIPEC so that patients with mCRC are eligible to receiveefficacious and safe immune therapies. NCI 10677711 8/21/23 0:00 PAR-20-052 5R03CA267326-02 5 R03 CA 267326 2 "THURIN, MAGDALENA" 8/5/22 0:00 7/31/24 0:00 ZCA1-PCRB-E(M1)S 7907525 "KIM, JOSEPH " Not Applicable 6 SURGERY 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 76331 NCI 50000 26331 ABSTRACT/SUMMARYNearly 10% of patients with metastatic colorectal cancer (mCRC) have progression of disease involving thespread of metastatic cancer to the peritoneal cavity. These patients generally have the worst outcomes for allpatients with mCRC. A recent phase III multicenter clinical trial has shown that single-agent immune checkpointinhibitor (ICI) has greater efficacy and better safety profile than standard cytotoxic chemotherapy regimens forpatients with mCRC. Importantly indications to receive ICI therapy are dependent on the measurement of hightumor mutation burden (TMB) neoantigen burden and microsatellite instability (MSI) status. These direct andindirect measures of genomic instability predict clinical response to ICIs however only 5% of patients arecurrently eligible to receive these therapies.Patients with mCRC with peritoneal spread of disease may undergo major cytoreductive surgery (CRS) duringwhich all gross sites of disease are resected. CRS is combined with heated intraperitoneal chemotherapy(HIPEC) with mitomycin C at 43C to eradicate microscopic disease. We hypothesize that major surgicalinflammation from CRS and the heat and chemotherapy of HIPEC altogether increase genomic instability.Surgical inflammation is known to activate heat shock proteins (Hsps) which may destabilize its regulatory controlover mismatch repair (MMR) proteins leading to deficient DNA repair. This condition combined with the DNAdamaging effects of mitomycin c and heat may lead to high TMB increased neoantigens and altered MSI inoccult microscopic mCRC cells. Our overarching hypothesis is that patients undergoing CRS/HIPEC will beeligible to receive and will benefit from ICI therapy.We propose to obtain blood samples and surgical tissues before and after CRS/HIPEC from patients with mCRC.These specimens will be assessed for changes in TMB and neoantigens (Aim 1) and MMR/MSI (Aim 2). Fromthe surgical tissues we will also create paired patient-derived organoids (PDOs) from which we will investigateHsps MMR proteins and MSI. Our prior studies using PDOs from CRS/HIPEC patients support their use toassess sensitivities to ICI therapies before and after CRS/HIPEC. We propose the following specific aims:Specific Aim 1. To measure alterations in TMB and neoantigens as a result of the heat and DNA damagingeffects of mitomycin C in mCRC patients undergoing CRS/HIPEC.Specific Aim 2. To determine whether surgical inflammation combined with heat and DNA damaging effects ofmitomycin C from CRS/HIPEC disrupt Hsp-stabilization of MMR proteins to increase MSI. 76331 +No NIH Category available Acceleration;Actins;Amino Acids;Animal Model;Biological Models;Bypass;Cancer Etiology;Cell Proliferation;Cell Survival;Cells;Cessation of life;Consumption;Cytoskeleton;Data;Development;Disease;EGFR inhibition;Ecosystem;Enzymes;Epidermal Growth Factor Receptor;Evaluation;Extracellular Protein;Funding;Gene Expression;Glutamine;Growth;Human;In Vitro;Ligands;Liquid substance;Malignant Neoplasms;Metabolic;Metabolic stress;Metabolism;Microtubules;Modality;Molecular;Norleucine;Normal tissue morphology;Nutrient;Oncogenes;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Phosphorylation;Phosphotransferases;Play;Process;Production;Proliferating;Proteins;Reaction;Regulation;Research;Role;Route;Signal Transduction;Small Interfering RNA;Source;Specimen;Starvation;Strategic Planning;Stress;Testing;Tumor Suppressor Proteins;United States;Work;analog;atypical protein kinase C;cancer cell;cancer therapy;cell growth;deprivation;experimental study;glutamine analog;in vivo;knock-down;mimetics;mimicry;neoplastic cell;new therapeutic target;novel;novel therapeutics;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;response;stress tolerance;tumor;tumor growth;tumor microenvironment;uptake Regulation of Nutrient Stress-Induced Macropinocytosis in Pancreatic Ductal Adenocarcinoma PROJECT NARRATIVEPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer-related deathin the United States and has been recognized as a recalcitrant cancer that requires accelerated research via theimplementation of a long-term strategic plan. Glutamine is the most depleted amino acid in PDAC tumors and tobypass nutrient deficiency the tumor cells augment their metabolism through macropinocytosis a mechanismof fluid uptake that serves as an amino acid supply route. We have identified new regulators of macropinocytosisthat represent novel drug targets for this disease and we propose to study how these enzymes function in PDACtumor growth and therapy. NCI 10677661 8/10/23 0:00 PA-20-185 5R01CA207189-08 5 R01 CA 207189 8 "SALNIKOW, KONSTANTIN" 7/1/16 0:00 8/31/26 0:00 Tumor Cell Biology Study Section[TCB] 10376567 "COMMISSO, COSIMO " Not Applicable 50 Unavailable 20520466 PHMKYKKJLQS1 20520466 PHMKYKKJLQS1 US 32.9036 -117.24298 1180101 SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE LA JOLLA CA Research Institutes 920371005 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 456813 NCI 234263 222550 PROJECT SUMMARYRecent years have witnessed a growing appreciation of the role that metabolic reprogramming plays in conferringgrowth and survival advantages to tumor cells. Of particular relevance to this proposal is the now widely acceptednotion that pancreatic ductal adenocarcinoma (PDAC) cells depend on macropinocytosis as an amino acidsupply route. By stimulating the uptake of extracellular protein and targeting it for lysosomal degradation themacropinocytosis pathway provides cancer cells with a source of protein-derived amino acids allowing tumorsto circumvent amino acid depletion and survive nutrient stress. Glutamine is a vital nutrient to tumors as itsupports the metabolic reactions necessary to sustain tumor cell growth; however hearty consumption by thetumor often leads to a glutamine-depleted tumor ecosystem. Our previously funded research demonstrated thatglutamine depletion in PDAC tumors has the capacity to modulate macropinocytosis dialing the process up ordown as required. We attributed this inducible form of macropinocytic uptake to the activation of EGFR-Paksignaling. Interestingly we have found that macropinocytosis is also induced by a glutamine structural analogthat broadly suppresses glutamine metabolism; however uptake in this setting does not employ EGFR signaling.Since the inhibition of glutamine metabolism is being actively pursued as a therapy for cancer we set out todecipher how glutamine mimicry might elicit macropinocytosis as an adaptive response. We performed a high-throughput siRNA screen and identified the atypical protein kinase C (aPKC) subfamily of kinases PKC andPKC as the most potent regulators of uptake. This proposal is based on our preliminary data demonstratingthat knockdown of either PKC or PKC not only suppresses macropinocytosis caused by glutamine analogsbut also abrogates uptake caused by glutamine starvation suggesting that the aPKCs are general modulatorsof nutrient stress-induced macropinocytosis. Based on these data our central hypothesis is that aPKC signalingis integral to nutrient stress-driven macropinocytosis and that the aPKCs support metabolic stress tolerance inPDAC tumors. We will 1) examine the molecular mechanisms underlying the role of aPKCs in nutrient stress-driven macropinocytosis and 2) determine the functional consequences of suppressing aPKC-dependentmacropinocytosis in PDAC. This project constitutes the first evaluation of the role that the aPKCs play in themodulation of macropinocytosis and the first to interrogate aPKC function from the perspective of glutaminesupply. Moreover because our work will establish aPKC-dependent macropinocytosis as a critical metabolicadaptation in response to glutamine mimetics our findings could have tremendous impact on the developmentof novel therapeutic modalities for PDAC. 456813 +No NIH Category available Adhesions;Architecture;Behavior;Bilateral;Bone Marrow;Cell physiology;Cell-Cell Adhesion;Cells;Chemotaxis;Complex;Cytokine Signaling;Disease;Engineering;Exclusion;Goals;Hematopoietic Neoplasms;Home;Immune;Immunocompetent;Immunological Models;Immunologics;Immunotherapeutic agent;In Vitro;Infiltration;Libraries;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Modeling;Mus;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Performance;Predisposition;Proliferating;Regulation;Signal Transduction;Solid;Solid Neoplasm;Spleen;Suppressor-Effector T-Lymphocytes;T cell infiltration;T-Lymphocyte;Testing;Therapeutic;Tissue Model;Tissues;Tumor Antigens;Tumor Suppressor Proteins;cell motility;chimeric antigen receptor T cells;combinatorial;design;effective therapy;engineered T cells;exhaustion;experimental study;immune cell infiltrate;improved;in silico;in vivo;lymph nodes;mesothelin;migration;mouse model;multi-scale modeling;neoplastic cell;novel therapeutics;pancreatic ductal adenocarcinoma model;programs;receptor;residence;response;single cell analysis;success;trafficking;tumor;tumor xenograft Synthetic circuits that drive infiltration of therapeutic T cells into immunologically cold tumors Project narrativeThe goal of this project is to engineer therapeutic immune cells that migrate to and accumulate in tumors suchthat they can more effectively kill tumor cells. The resulting next-generation therapeutic immune cells couldlead to much more effective therapies against a broad range of challenging solid tumors. NCI 10677659 8/2/23 0:00 RFA-CA-20-054 5U01CA265697-03 5 U01 CA 265697 3 "SOMMERS, CONNIE L" 9/10/21 0:00 8/31/26 0:00 ZCA1-TCRB-Q(A1) 1928388 "LIM, WENDELL A" "EL-SAMAD, HANA " 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 572845 NIBIB 109274 66177 Project summary/abstractEngineering trafficking circuits that drive therapeutic T cell infiltration into immune-excluded tumorsEngineered chimeric antigen receptor (CAR) T cells have yet to achieve efficacy against solid cancers.Particularly challenging are immune-excluded cold tumors which fail to accumulate large numbers of infiltratingT cells. In such cases even if therapeutic T cells recognize and kill tumor cells in vitro they will fail in vivo if theycannot infiltrate the tumor. We propose to engineer synthetic circuits that regulate T cell trafficking as ageneral strategy to drive therapeutic T cell infiltration into immunologically cold tumors.Immune cells naturally rely on complex trafficking behaviors. They patrol the body to surveil for diseases. Oncediseased tissue is identified they establish local residence and focally expand. Cell trafficking programs largelyrely on regulation of three core cellular functions: 1) chemotaxis (modulating cell ingress and egress) 2) cell-celladhesion (reducing cell egress) and 3) local proliferative signaling (cytokine signaling). While these mechanismsare naturally exploited by T cells the evolved pathways are susceptible to suppression by numerous tumoralmechanisms. We hypothesize that synthetic regulatory circuits that directly wire tumor antigen signals to controltherapeutic T cell chemotaxis adhesion and local proliferative signaling will improve targeted infiltration ofimmune excluded tumors. We propose to develop synthetic trafficking circuit designs through cycles of in silicomodeling and in vitro experiments. We will test if synthetic trafficking circuits can improve CAR T cell efficacy invivo using an immunocompetent murine model of immune-excluded pancreatic cancer. The resulting celltrafficking circuits should be applicable to a broad range of solid cancers as well as other diseases.AIM 1. Design and characterize synthetic T cell trafficking circuits that coordinately regulate chemotaxisadhesion and local proliferation in response to tumor antigen recognition1.A. Use multi-scale computational modeling to explore design space of possible T cell trafficking circuits. Usemodel to identify circuit architectures and parameters that robustly increase tumor-selective infiltration1.B. Construct a toolbox of modular trafficking circuits using synNotch receptors to control chemotaxis adhesionand proliferation in response to tumor antigen recognition; Construct combinatorial library of circuits.1.C. Test synthetic trafficking circuits in vitro using multicompartment tissue models that measure T cell traffickingand migration. Evaluate circuits in vivo by measuring T cell trafficking in bilateral tumor xenograft mouse models.AIM 2. Use engineered trafficking circuits to improve anti-tumor efficacy in an immune excludedimmunocompetent murine model of pancreatic ductal adenocarcinoma.Leverage synthetic trafficking circuits to improve murine -Mesothelin CAR-T cell infiltration and clearance ofKPC pancreatic ductal adenocarcinoma syngeneic mouse model. Use single cell analysis to assess impact ontumoral suppressor cells stroma host immune cell infiltration and CAR T cell exhaustion. 175000 +No NIH Category available Adhesions;Architecture;Behavior;Bilateral;Bone Marrow;Cell physiology;Cell-Cell Adhesion;Cells;Chemotaxis;Complex;Cytokine Signaling;Disease;Engineering;Exclusion;Goals;Hematopoietic Neoplasms;Home;Immune;Immunocompetent;Immunological Models;Immunologics;Immunotherapeutic agent;In Vitro;Infiltration;Libraries;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Modeling;Mus;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Performance;Predisposition;Proliferating;Regulation;Signal Transduction;Solid;Solid Neoplasm;Spleen;Suppressor-Effector T-Lymphocytes;T cell infiltration;T-Lymphocyte;Testing;Therapeutic;Tissue Model;Tissues;Tumor Antigens;Tumor Suppressor Proteins;cell motility;chimeric antigen receptor T cells;combinatorial;design;effective therapy;engineered T cells;exhaustion;experimental study;immune cell infiltrate;improved;in silico;in vivo;lymph nodes;mesothelin;migration;mouse model;multi-scale modeling;neoplastic cell;novel therapeutics;pancreatic ductal adenocarcinoma model;programs;receptor;residence;response;single cell analysis;success;trafficking;tumor;tumor xenograft Synthetic circuits that drive infiltration of therapeutic T cells into immunologically cold tumors Project narrativeThe goal of this project is to engineer therapeutic immune cells that migrate to and accumulate in tumors suchthat they can more effectively kill tumor cells. The resulting next-generation therapeutic immune cells couldlead to much more effective therapies against a broad range of challenging solid tumors. NCI 10677659 8/2/23 0:00 RFA-CA-20-054 5U01CA265697-03 5 U01 CA 265697 3 "SOMMERS, CONNIE L" 9/10/21 0:00 8/31/26 0:00 ZCA1-TCRB-Q(A1) 1928388 "LIM, WENDELL A" "EL-SAMAD, HANA " 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 572845 NCI 248426 150447 Project summary/abstractEngineering trafficking circuits that drive therapeutic T cell infiltration into immune-excluded tumorsEngineered chimeric antigen receptor (CAR) T cells have yet to achieve efficacy against solid cancers.Particularly challenging are immune-excluded cold tumors which fail to accumulate large numbers of infiltratingT cells. In such cases even if therapeutic T cells recognize and kill tumor cells in vitro they will fail in vivo if theycannot infiltrate the tumor. We propose to engineer synthetic circuits that regulate T cell trafficking as ageneral strategy to drive therapeutic T cell infiltration into immunologically cold tumors.Immune cells naturally rely on complex trafficking behaviors. They patrol the body to surveil for diseases. Oncediseased tissue is identified they establish local residence and focally expand. Cell trafficking programs largelyrely on regulation of three core cellular functions: 1) chemotaxis (modulating cell ingress and egress) 2) cell-celladhesion (reducing cell egress) and 3) local proliferative signaling (cytokine signaling). While these mechanismsare naturally exploited by T cells the evolved pathways are susceptible to suppression by numerous tumoralmechanisms. We hypothesize that synthetic regulatory circuits that directly wire tumor antigen signals to controltherapeutic T cell chemotaxis adhesion and local proliferative signaling will improve targeted infiltration ofimmune excluded tumors. We propose to develop synthetic trafficking circuit designs through cycles of in silicomodeling and in vitro experiments. We will test if synthetic trafficking circuits can improve CAR T cell efficacy invivo using an immunocompetent murine model of immune-excluded pancreatic cancer. The resulting celltrafficking circuits should be applicable to a broad range of solid cancers as well as other diseases.AIM 1. Design and characterize synthetic T cell trafficking circuits that coordinately regulate chemotaxisadhesion and local proliferation in response to tumor antigen recognition1.A. Use multi-scale computational modeling to explore design space of possible T cell trafficking circuits. Usemodel to identify circuit architectures and parameters that robustly increase tumor-selective infiltration1.B. Construct a toolbox of modular trafficking circuits using synNotch receptors to control chemotaxis adhesionand proliferation in response to tumor antigen recognition; Construct combinatorial library of circuits.1.C. Test synthetic trafficking circuits in vitro using multicompartment tissue models that measure T cell traffickingand migration. Evaluate circuits in vivo by measuring T cell trafficking in bilateral tumor xenograft mouse models.AIM 2. Use engineered trafficking circuits to improve anti-tumor efficacy in an immune excludedimmunocompetent murine model of pancreatic ductal adenocarcinoma.Leverage synthetic trafficking circuits to improve murine -Mesothelin CAR-T cell infiltration and clearance ofKPC pancreatic ductal adenocarcinoma syngeneic mouse model. Use single cell analysis to assess impact ontumoral suppressor cells stroma host immune cell infiltration and CAR T cell exhaustion. 397845 +No NIH Category available Address;Adoptive Transfer;Allogenic;Animal Model;Antigen Presentation;Antigen-Presenting Cells;Antigens;Antitumor Response;Autoantigens;Automobile Driving;CD8-Positive T-Lymphocytes;CXCL9 gene;Cell Separation;Cell physiology;Cross Presentation;Cross-Priming;Defect;Dendritic Cells;Development;Exhibits;FLT3 ligand;Failure;Flow Cytometry;Immune response;Immunologic Monitoring;Immunotherapy;Inbred BALB C Mice;Interferon Type II;Interleukin-12;Interleukin-2;Intrinsic factor;Knock-out;Luciferases;Lymphoma;Measures;Mediating;Methods;Modeling;Monitor;Mus;Mutation;Outcome;Outcome Study;PD-1 blockade;Patients;Phenotype;Radiation therapy;Resistance;Role;Sorting;T cell response;T cell therapy;T-Cell Activation;T-Lymphocyte;Techniques;Tissues;Transfection;Tumor Antigens;Vaccination;anti-PD-1;antigen-specific T cells;antitumor effect;cancer infiltrating T cells;cancer therapy;chemokine;cytotoxicity;design;effective therapy;immune checkpoint blockade;improved;in situ vaccination;in situ vaccine;in vivo;malignant breast neoplasm;mouse model;neoantigens;neoplastic cell;new therapeutic target;novel;patient subsets;pre-clinical;predicting response;programs;receptor;recruit;response;success;targeted treatment;therapy design;tool;transcriptome sequencing;transcriptomics;tumor;tumor growth Defining a cross-primed anti-tumor T cell signature to guide immunotherapy development PROJECT NARRATIVECross-priming of CD8+ T cells by conventional Type 1 dendritic cells (cDC1) is necessary for effective antitumortherapy yet there is no established method for measuring T cell cross- or direct-priming in vivo. This projectseeks to define a signature of cross-primed T cells using RNA-seq of tumor-specific T cells isolated fromH2Kd-/- tumor-bearing mice that can only cross-prime T cells or allogeneic mice that can only directly prime Tcells via direct tumoral antigen presentation. This will produce cross- and direct-primed T cell signatures that canbe used to guide design of immunotherapies by targeting novel checkpoints or costimulatory receptors tomonitor responses to immunotherapy and to predict responses to checkpoint blockade and similar therapies. NCI 10677596 9/11/23 0:00 PA-21-051 5F31CA275326-02 5 F31 CA 275326 2 "PURI, ANU" 7/11/22 0:00 7/10/25 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 78417653 "LUBITZ, GABRIELLE " Not Applicable 13 RADIATION-DIAGNOSTIC/ONCOLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 7/11/23 0:00 7/10/24 0:00 398 "Training, Individual" 2023 46094 NCI 46094 0 PROJECT SUMMARY/ABSTRACTImmunotherapies such as checkpoint blockade have revolutionized cancer therapy but responses are seen onlyin a subset of patients. Though tumor-intrinsic factors such as tumor mutational burden (TMB) or IFN inflamedsignature partially predict sensitivity to checkpoint blockade these correlations are limitedmost patients withinflamed tumors or high TMB still fail to respond. A critical step for efficacy of T cell-mediated immunotherapiesincluding checkpoint blockade is dendritic cell cross-presentation of tumor antigen (Ag) to CD8+ T cells. Cross-presentation in vivo requires Batf3-expressing type 1 dendritic cells (cDC1) though these DC have additionalfunctions including secretion of T cell-recruiting chemokines driving tumor-reactive T cell (TRT) responses.Because patients with cDC1-enriched tumors have improved responses to anti-PD1 we developed an in situvaccination (ISV) combining FLT3L radiotherapy (XRT) and TLR agonism to enhance cDC1 cross-priming ofTRT and observed that ISV potentiated anti-tumor effects of PD1 blockade and induced systemic tumorregressions in treated patients. Additionally we have shown that adoptive transfer of tumor-specific T cells intosyngeneic RAG-/- mice clears tumors while transfer into allogeneic RAG-/- mice fails to control tumor growthhighlighting that APC cross-priming of CD8+ T cells is required for efficacy of antitumor T cells. Despite the criticalrole of cDC1 cross-priming of CD8+ T cells for effective therapy there is no established method for measuring Tcell cross- or direct-priming in vivo. Consequently there is a critical need for methods to directly measure CD8+T cell cross-priming for identifying novel therapeutic targets to enhance cross-priming and to understandmechanisms of therapy resistance. We hypothesize that cross- and direct-primed T cells and ISV-primed vsuntreated T cells will harbor distinct signatures mirroring their differential antitumor efficacy. In Aim 1 we willdevelop mouse models of cross- and direct-priming using H2Kd knockout H2Kb-transfected GFP/OVA-expressing lymphoma and breast cancers and transfer of Ag-specific T cells into syngeneic and allogeneicRAG-/- mice. We will sort tumor-reactive T cells and perform bulk RNA-seq and spectral flow cytometry to identifya cross-primed CD8+ T cell signature. In Aim 2 we will use bulk RNA-seq and spectral flow cytometry tocharacterize the T cell response to ISV and checkpoint blockade across tumors (lymphoma breast cancer)model antigens (GFP OVA luciferase) and endogenous tumor antigens. The outcome of this study will beelucidation of a cross-primed CD8+ T cell phenotype and a novel immune monitoring technique that allowstargeted design of novel immunotherapies by targeting novel checkpoints or costimulators to increase cross-priming of tumor-reactive T cells. 46094 +No NIH Category available Address;Affect;Binding;Binding Proteins;Binding Sites;Bioinformatics;Biological Assay;Biotinylation;C2H2 Zinc Finger;Canada;Cell Line;Cells;ChIP-seq;Clustered Regularly Interspaced Short Palindromic Repeats;CpG Islands;DNA-Binding Proteins;Data;Disease;Down-Regulation;Family;Family member;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genomics;Health;Human;Human Cell Line;In Situ;Individual;Knock-out;Label;Learning;Ligation;MCF7 cell;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Mediating;Mediator;Mentors;Messenger RNA;Methods;Molecular Biology;Molecular Biology Techniques;Mutate;Mutation;N-terminal;Nuclear Proteins;Oncogenic;Pattern;Peptides;Physicians;Proliferating;Promoter Regions;Proteins;Proteomics;Proto-Oncogene Proteins c-myc;Publishing;Quantitative Reverse Transcriptase PCR;Regulation;Research;Site;Small Interfering RNA;Techniques;Testing;Training;Transactivation;Transcription Coactivator;Transcription Initiation Site;Transcriptional Regulation;Universities;ZFY protein;candidate identification;candidate validation;cdc Genes;cell type;experimental study;human disease;insight;knock-down;mutant;promoter;protein protein interaction;transcription factor;transcriptome;transcriptome sequencing;tumorigenesis How does the ubiquitously expressed ZFX mediate cell type-specific transcriptional regulation ZFX is a transcriptional activator with large effects on the human transcriptome in multiple celllines. Despite preliminary data from the Farnham Lab that demonstrates almost completeoverlap of ZFX binding to thousands of promoter regions in several cell lines the sets of genesactivated by ZFX are surprisingly unique to each cell line. To determine how ZFX regulates celltype-specific gene expression while binding to the same set of promoters this proposal willidentify ZFX protein binding partners and other transcription factors bound to promoters of ZFXregulated genes in multiple cell lines. NCI 10677572 8/1/23 0:00 PA-21-048 5F32CA264890-02 5 F32 CA 264890 2 "ELJANNE, MARIAM" 8/1/22 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-F08-M(20)L] 15277631 "HSU, EMILY " Not Applicable 37 BIOCHEMISTRY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 69080 NCI 69080 0 My research in the Farnham lab is centered on the ZFX family of C2H2 zinc finger transcription factors (TFs)including the highly related ZFX ZFY and ZNF711. Previously our lab established CRISPR-mediated knockouts of ZFX and ZNF711 in HEK293T cells and demonstrated defective proliferation and altered expression ofthousands of genes. Additional preliminary data from the Farnham lab has determined that ZFX and ZNF711function as transcriptional activators which preferentially bind +240 bp downstream of transcription start sites(TSSs) at the majority of CpG island promoters in HEK293T cells. Further ZFX ChIP-seq experiments inseveral human cell lines revealed that the majority of ZFX binding occurs at the same promoters in all testedcell lines. Interestingly RNA-seq experiments in these cell lines after ZFX siRNA knockdown revealed cell-typespecific sets of ZFX-bound downregulated genes. However the transcriptional mechanisms by which ZFXregulates cell type-specific gene expression remain unclear. Therefore in my proposal I will determine howZFX can regulate a distinct set of target genes in each cell type when it binds to mostly the same set ofpromoters in the different cell types. I hypothesize that ZFX interacts with different protein partners ineach cell type to provide cell type-specific regulation from common promoter binding sites. In Aim#1 Ipropose to identify proteins that interact with ZFX in multiple cell lines using IP-MS and a sensitive proximitylabeling technique TurboID-MS. Candidate ZFX binding partners will be individually validated with co-IP and insitu proximity ligation assay (PLA) experiments. To determine if candidates are key mediators of ZFX-regulatedtranscription RNA-seq experiments after siRNA knockdown of corresponding mRNAs will be performed. I alsoaim to construct ZFX mutants focusing first on the highly conserved peptide regions in the N-terminaltransactivation domain and perform co-IP experiments to map sites of protein interaction followed bytransactivation assays to determine the effects of these mutations on transcription. In Aim#2 I will performmotif analysis in promoters of genes which are bound and regulated by ZFX in a cell type-specific manner toidentify TFs that bind cooperatively with ZFX in the different cell lines. Binding of candidate TFs will bevalidated using ChIP-seq. Cell lines with CRISPR-mediated mutations of candidate transcription factor bindingsites will be made and qRT-PCR experiments will be performed to determine if candidate TF binding affectsZFX-mediated transcription of cell type-specific genes. My thorough mechanistic characterization in multiplecell lines of this interesting TF with a unique genomic binding pattern will make significant contributions to thefield of transcription. 69080 +No NIH Category available Adult;Affect;Algorithms;Atlases;Automobile Driving;Biological;Cancer Model;Cancer Patient;Clinical;Communities;Comparative Study;Complement;Data;Databases;Development;Early Diagnosis;Effectiveness;Epigenetic Process;Evolution;Frequencies;Genes;Genetic;Genome;Genomics;Goals;Graph;Human;Immune system;In Vitro;Incidence;Individual;Joints;Link;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Mammalian Genetics;Maps;Methods;Modeling;Neoplasm Metastasis;Oncogenes;Oncology;Pan Genus;Pathway interactions;Patients;Pattern;Platinum;Predisposition;Process;Proliferating;Reporting;Research;Research Personnel;Resistance;Resources;Risk;Role;Sampling;Scientist;Surveys;Time;Training;Translating;Variant;Work;Zoo Animals;anticancer research;biomedical scientist;cancer gene expression;cancer initiation;cancer risk;cancer therapy;cohort;comorbidity;comparative;comparative genomics;deep learning algorithm;experience;genetic resource;genetic signature;genome resource;genomic data;high throughput analysis;human data;human model;improved;improved outcome;insight;large scale data;machine learning method;machine learning model;machine learning prediction;mammalian genome;new therapeutic target;novel;open source library;pre-clinical;precision medicine;rare cancer;recruit;reference genome;skills;success;tool;tumor;tumor microenvironment;tumor progression;user-friendly Leveraging Mammalian Cancers Platinum-Quality Genome Assemblies and Large-Scale Data to Identify Mechanisms of Rare Human Cancers PROJECT NARRATIVEThe emerging field of comparative oncology may provide a novel solution to rare human cancer studies asgenomic resources reference genomes and non-human model cancer sequencing data are proliferating rapidly.We propose to for the first time develop and apply new machine learning methods to jointly analyze andintegrate information from hundreds of mammalian genomes to identify pan-mammalian mechanisms of cancerresistance and susceptibility and apply those insights in human cancers. To disseminate this date to the widercommunity and catalyze further research we will develop a tumor compendium portal and toolkit that will allowother researchers to leverage pan-mammalian comparative genomics. NCI 10677546 7/28/23 0:00 PAR-21-038 5R01CA265907-02 5 R01 CA 265907 2 "LI, JERRY" 8/5/22 0:00 7/31/27 0:00 Biodata Management and Analysis Study Section[BDMA] 12230025 "GRAIM, KILEY " Not Applicable 3 ENGINEERING (ALL TYPES) 969663814 NNFQH1JAPEP3 969663814 NNFQH1JAPEP3 US 29.643443 -82.349637 513806 UNIVERSITY OF FLORIDA GAINESVILLE FL BIOMED ENGR/COL ENGR/ENGR STA 326115500 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 290921 NCI 201758 89163 PROJECT SUMMARYStudying cancer across a diverse array of species provides a unique opportunity to interrogate factorsunderpinning cancer initiation and progression and facilitating the modeling of new therapeutic targets in thesetting of spontaneous tumors complicated by comorbidities and metastases. While there is extensive reportingof the frequency and diversity of tumors in animals from zoos it has not been systematically linked to the plethoraof genomic resources available. To facilitate the transition of comparative oncology studies from human plus oneor two other species to pan-mammalian analyses we propose building a pan-mammalian tumor compendiumand portal to easily disseminate our resource. We will develop and apply machine learning tools to detectpatterns of cancer emergence and cancer resistance in human and non-human mammalian tumors. Ourapproach provides opportunities to leverage the largely understudied mammalian tumor data jointly with humandata to identify reciprocal links between evolution and cancer resistance. This will allow us to make new humancancer discoveries through integrative analysis of high-throughput biological data in the context of mammalianspecies. We offer a powerful approach combining high-quality reference genomes and genomic data fromhundreds of mammalian species with machine learning that has the promise to unearth the evolutionary geneticunderpinnings that are cornerstones of cancer initiation and progression. We will develop and apply models toidentify mammalian tumors that effectively mimic rare human cancers work with collaborators to acquire tumorsamples from strongest identified mammalian models then sequence and analyze these samples to validatetheir effectiveness as models of human cancers. 290921 +No NIH Category available Address;Adjuvant Chemotherapy;Aftercare;Cancer Biology;Cancer Patient;Cancer Relapse;Carboplatin;Cell Survival;Cell physiology;Cells;Chemoresistance;Chemotherapy-Oncologic Procedure;Clinical;Clinical Data;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Cytotoxic Chemotherapy;Cytotoxic agent;Data;Development;Diagnosis;Disease;Disease Resistance;Disease remission;Drug resistance;Early identification;Ensure;Environment;Event;Experimental Designs;Family;Family member;Genes;Goals;Human;Imaging technology;Immunocompetent;Investigation;Knock-out;Knowledge;Macrophage;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Morbidity - disease rate;NF-kappa B;NF-kappaB-inducing kinase;Natural regeneration;Neoadjuvant Therapy;Paclitaxel;Pathway interactions;Patients;Play;Population;Proliferating;Property;Publishing;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Recurrent tumor;Relapse;Reporter;Reproducibility;Research;Resected;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Solid Neoplasm;Stimulus;Stromal Cells;Tissues;United States;Work;Xenograft procedure;aldehyde dehydrogenases;cancer cell;cancer drug resistance;cancer recurrence;cancer survival;cell type;chemotherapy;cytokine;design;improved;inhibitor;interest;mortality;mouse model;neoplastic cell;notch protein;novel;ovarian neoplasm;response;self-renewal;standard of care;stemness;targeted treatment;therapeutically effective;transcription factor;transcriptome sequencing;tumor;tumor initiation;tumor microenvironment;tumor progression Alternative NF-kB activation in post-chemotherapy setting to elucidate novel mechanisms of ovarian cancer relapse NarrativeOvarian cancer is usually diagnosed at a late stage when survival is only about 10% rendering this disease thedeadliest gynecological malignancy. Disease recurrence is the major cause of mortality and despite a greaterunderstanding of ovarian cancer biology there have been no significant improvements in mortality rates in thelast five decades. Investigation of tumor cells that are resistant to chemotherapy and have the capacity toregenerate tumors is crucial for achieving cures for ovarian cancer patients. NCI 10677542 7/31/23 0:00 PA-20-185 5R01CA260281-02 5 R01 CA 260281 2 "BERA, TAPAN K" 9/1/22 0:00 8/31/27 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 12551897 "HOUSE, CARRIE DANIELLE" Not Applicable 51 BIOLOGY 73371346 H59JKGFZKHL7 73371346 H59JKGFZKHL7 US 32.762178 -117.069156 513614 SAN DIEGO STATE UNIVERSITY SAN DIEGO CA SCHOOLS OF ARTS AND SCIENCES 921821901 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 387223 NCI 257837 129386 Scientific AbstractOvarian cancer is the most lethal gynecological malignancy in the United States and although patients initiallyrespond to cytotoxic chemotherapy most relapse with chemoresistant disease within 24 months. There areseveral critical gaps in our knowledge of the mechanisms that support disease recurrence but research over thelast decade support the notion tumor-initiating cells (TICs) a subpopulation of drug resistant tumor cells areresponsible for facilitating relapse and combination therapies targeting these elusive cells may lead to longerremission or even cures. Although numerous genes and signaling pathways have been implicated in maintainingTICs there are several critical gaps in our understanding of the processes these cells use to survive cytotoxicchemotherapy and successfully re-establish tumors. For example it is unclear whether pathways active in TICsare constitutive or if they can be induced by factors in the tumor microenvironment (TME). Our previous studiesrevealed an important role for alternative NF-kB signaling in maintaining ovarian TICs and resistance to cytotoxicchemotherapy. NF-kB is a family of transcription factors that respond to signals in the TME to promoteproliferation chemoresistance and survival of cancer cells. Emerging evidence suggest alterations of the TMEfollowing cytotoxic chemotherapy can result in the release of signaling factors that can activate NF-kB in cancercells. Our recent data show that TWEAK a multifunctional cytokine secreted from macrophages and stromalcells is elevated in the TME following chemotherapy and can induce activation of alternative NF-kB andexpression of stemness genes in a variety of ovarian cancer cells. Clinical data from patients undergoingneoadjuvant chemotherapy show that genes encoding TWEAK and alternative NF-kB family members aresignificantly elevated in tumors resected following cytotoxic chemotherapy relative to pre-treatment levels. Thesedata lead us to our central hypothesis that chemotherapy provides an environment that favors TIC developmentthrough activation of alternative NF-kB. To investigate this hypothesis we will 1) determine whetherchemotherapy-induced TWEAK signaling in the ovarian TME activates alternative NF-kB in ovarian cancer cells2) establish the function of the alternative NF-kB kinase NIK in ovarian cancer chemoresistance and relapseand 3) investigate the role of NF-kB-mediated activation of Notch in supporting ovarian TICs followingchemotherapy. Unlike most published studies we are focusing on the pathways and activities in these cells afterchemotherapy to generate new paradigms for evaluating relapse mechanisms. Given the strong initial responseto chemotherapy it is of great interest to identify an early post-treatment event that could be targeted incombination with cytotoxic drugs to inhibit pathways that maintain TICs. Clarifying novel mechanism(s) by whichthis under-examined pathway supports chemoresistance will guide the design of better therapies to prolongremission or potentially achieve cures for ovarian cancer patients. 387223 +No NIH Category available Antibiotics;Antibodies;Antitumor Response;Bacteria;Bioinformatics;Biological;Blocking Antibodies;Breeding;CD8-Positive T-Lymphocytes;Cancer Model;Cancer Patient;Cell Communication;Cell physiology;Cells;Cellular Assay;Chemistry;Clinic;Coculture Techniques;Collaborations;Colon;Combined Modality Therapy;Data;Dendritic Cells;Disease;Drug Industry;Environment;Epithelium;Exclusion;Flow Cytometry;Germ-Free;Gnotobiotic;Goals;Human Microbiome;Immune;Immune response;Immune system;Immunotherapy;In Vitro;Individual;Industry;Intestines;Ion-Exchange Chromatography Procedure;Knockout Mice;Label;Learning;Legal patent;Macrophage;Malignant Neoplasms;Mediating;Microbe;Microfluidics;Motivation;Mus;Organoids;PD-1 blockade;Pathway interactions;Patients;Play;Qualifying;Research;Role;Running;Signal Pathway;Signaling Molecule;Site;Sterility;Structure;Surface;T-Lymphocyte;T-bet protein;Testing;Therapeutic;Therapeutic Uses;Training;Translations;Tumor Immunity;Work;anti-CTLA4;anti-PD-1;anti-PD-L1;anti-PD-L1 therapy;anti-cancer;anti-tumor immune response;cancer cell;cancer therapy;checkpoint therapy;clinical translation;commensal microbes;draining lymph node;experience;gastrointestinal epithelium;gut bacteria;gut microbes;gut microbiota;immune checkpoint;immune checkpoint blockade;in vivo;medical schools;mesenteric lymph node;microbiota;novel therapeutics;pharmacologic;pre-clinical;professional atmosphere;programmed cell death ligand 1;programmed cell death protein 1;response;skills;stem;therapeutically effective;transcriptome sequencing;tumor Identifying gut bacterial molecules and mechanisms that promote an anti-tumor response to immunotherapy Project NarrativeOf the 800000 cancer patients who qualify for checkpoint blockade therapy each year nearly 700000 fail torespond. The purpose of this project is to identify molecules from gut bacteria that promote an anti-tumorresponse to checkpoint blockade therapy and discover their mechanisms of action. The results will lead tomore effective cancer therapeutics that will increase the number of cancer patients who respond toimmunotherapy. NCI 10677530 7/7/23 0:00 PAR-18-467 5K22CA258960-02 5 K22 CA 258960 2 "JAKOWLEW, SONIA B" 8/5/22 0:00 7/31/25 0:00 ZCA1-RTRB-R(J1) 10281423 "GAZZANIGA, FRANCESCA SMYLIE" Not Applicable 7 MICROBIOLOGY/IMMUN/VIROLOGY 47006379 JDLVAVGYJQ21 47006379 JDLVAVGYJQ21 US 42.335672 -71.104237 3212902 HARVARD MEDICAL SCHOOL BOSTON MA SCHOOLS OF MEDICINE 21201616 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 187056 NCI 173200 13856 Project Summary The immune system is capable of mounting a robust anti-cancer response. However cancer cells candisrupt this immune response hijacking immune checkpoint mechanisms which act as brakes on theendogenous anti-cancer response. Antibodies that block immune checkpoints (e.g. a-PD-L1 a-PD-1 and a-CTLA4) have revolutionized cancer treatments yet only a fraction of patients respond. Understanding theunderlying mechanisms that promote a durable anti-tumor response to checkpoint blockade therapy is crucialto develop effective therapeutics that can treat a wider range of cancer patients. The gut microbiota is a keyvariable in the anti-tumor response to immunotherapy even for tumors outside of the intestine. The goal of thisproject is to identify gut bacterial molecules that promote an anti-tumor response to PD-1 blockade and theirmechanisms of action. I hypothesize that certain gut bacterial surface components prime immune cells andthese bacterial-immune interactions within the gut are essential for the anti-tumor immune response to PD-1blockade at extra-intestinal sites. I propose to test this hypothesis by determining the key immune componentsof the microbe-dependent immune response in the tumor (Aim 1) the key bacterial molecules which promotethe anti-tumor response (Aim 2) and the mechanisms by which microbes and immune cells interact within thegut (Aim 3). These studies are significant because by identifying active anti-tumor gut bacterial molecules andmechanisms more effective therapeutics can be developed that will broaden the range of patients whorespond to checkpoint therapy. My long-term goal is to run a research group that investigates the interactions between gut bacteria andthe immune system. My motivation is to identify new bacterial molecules and their mechanisms of action thatcan be harnessed in the clinic as therapeutics for cancer and other diseases. I trained in Dennis Kaspers labgaining expertise in gnotobiotic mouse work microbiota analysis and culture click chemistry and bacterialmolecule separation leading to the preliminary data for Aims 1-3. To learn about the immune response to PD-1blockade and co-signaling molecules I collaborated with Arlene Sharpes lab and obtained preliminary data forAims 1-3. This collaboration has led to two patent applications and discussions with industry for drugtranslation. To understand how bacteria directly interact with gut cells I developed a mouse microfluidic gutchip in a collaboration with Donald Ingbers lab at the Wyss institute at Harvard that I plan to use in Aims 2 and3. By taking advantage of the excellent work environment at Harvard Medical School I have acquired aunique skill set stemming from experience with both the academic research environment and with industrydiscussions for clinical translation. This training enables me to run my own research group that will investigategut bacterial/immune interactions that can be employed to create novel therapeutics. 187056 +No NIH Category available Abdominal Cavity;Address;Adult;Adverse effects;Advocate;Affect;Agreement;Area;Authorization documentation;Baptist Church;Carcinomatosis;Cessation of life;Clinical;Clinical Research;Clinical Trials;Colon;Colorectal Cancer;Consultations;Coupling;Cues;Data;Data Set;Detection;Development Plans;Diagnosis;Diagnostic;Disease;Distant;Dose;Dose Limiting;Electrocardiogram;Eligibility Determination;Endoscopy;Enrollment;Evaluation;Excision;Feedback;Fluorescence;Funding;Goals;Grant;Greater sac of peritoneum;Gynecologic Oncologist;Health;Healthcare Systems;Heterogeneity;Hour;Hyperthermia;Image;Image-Guided Surgery;Imaging Device;Information Dissemination;Intervention;Label;Laboratories;Left;Lesion;Liver;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of appendix;Malignant neoplasm of ovary;Marketing;Medicine;Modality;Neoplasm Metastasis;Ohio;Oncogenic;Operative Surgical Procedures;Optics;Ovary;Palliative Care;Palpable;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Pennsylvania;Peritoneal;Peritoneum;Pharmaceutical Preparations;Phase;Phase III Clinical Trials;Phenotype;Physical Examination;Positron-Emission Tomography;Preoperative Care;Preparation;Primary Neoplasm;Privatization;Radiation therapy;Randomized;Rectum;Reporting;Research Design;Residual Neoplasm;Residual state;Robotics;Safety;Sensitivity and Specificity;Site;Small Business Innovation Research Grant;Solid Neoplasm;Sorting;Staging;Stomach;Surgeon;Surgical Oncologist;Surgical margins;Tactile;Time;Toxic effect;Translating;Tumor Debulking;United States National Institutes of Health;Universities;Uterine Cancer;Visual;Work;arm;authority;cancer biomarkers;cancer therapy;chemotherapy;clinical development;clinical research site;commercial launch;commercialization;cost;design;fluorescence imaging;forest;haptics;imaging agent;imaging modality;improved;intraperitoneal therapy;intravenous administration;malignant stomach neoplasm;meetings;minimally invasive;novel therapeutics;open label;participant enrollment;patient prognosis;peritoneal cancer;phase 2 study;phase 3 study;phase II trial;programs;rectal;standard of care;study population;tool;tumor;ultrasound Image-guided Surgical Detection of Metastatic Disease to the Peritoneum Narrative: Peritoneal metastasis results from dissemination of metastatic lesions originating from local or distantprimary tumors (e.g. ovaries colon rectum appendix liver or stomach). The presence of peritoneal metastasisportends poor patient prognoses affecting tens of thousands of patients each year in the U.S. Front line standardof care treatment relies heavily on cytoreductive surgery to enable chemotherapy (e.g. HIPEC) or radiationtherapy treatments where patient outcomes are predicated on the completeness of lesion resection; the goal forthe proposed project is to execute a Phase 3 clinical study for the detection of peritoneal metastasis usingpegsitacianine (ONM-100) an intravenously administered fluorescent imaging agent designed to aid surgeonsin the intraoperative resection of peritoneal lesions and meet this significant unmet need. NCI 10677506 9/19/23 0:00 RFA-CA-22-025 2R44CA217528-04A1 2 R44 CA 217528 4 A1 "POND, MONIQUE ADRIANNE" 9/21/17 0:00 8/31/25 0:00 ZCA1-TCRB-J(J2) 8681525 "KRISHNAN, KARTIK " Not Applicable 24 Unavailable 80314716 FSRUUQKHD749 80314716 FSRUUQKHD749 US 32.751346 -97.340906 10042613 "ONCONANO MEDICINE, INC." Southlake TX Domestic For-Profits 760927631 UNITED STATES N 9/19/23 0:00 8/31/24 0:00 394 SBIR/STTR 2023 1999999 NCI 667557 267022 Summary (application predicated on NIH NCI Phase II 5R44CA217528-03): Surgical resection is a commonfront-line treatment for cancer that relies heavily on the surgeons ability to identify disease preoperatively andintraoperatively. While typical standard of care (SOC) preoperative diagnostics such as PET CT ultrasoundand MRI afford the surgeon critically important tools they suffer from limitations associated with sensitivity andspecificity that are critical to the intraoperative setting. Thus the surgeon must rely on subjective visual andpalpable cues during surgery which are subjective and often result in residual disease and positive surgicalmargins. Minimally invasive endoscopy and robotic surgeries further challenge the optics and haptics availableto surgeons. Disease left behind leads to poorer patient outcomes (second surgeries inaccurate sorting/stagingfor chemo and radiation therapy) and ultimately an increased burden on the healthcare system all of whichpoint to a significant unmet need. Approximately 70000 peritoneal metastasis (PM) diagnoses have been madein 2020 alone. Patient prognosis from front line SOC cytoreductive surgery in conjunction with chemotherapy(such as hyperthermic intraperitoneal chemotherapy) or radiotherapy is dependent on completeness of removalof lesions that are small in size and heterogeneous in their oncogenic phenotype - especially challenging for thepre- and intraoperative detection modalities noted above. To address this unmet need OncoNano Medicine hasdeveloped pegsitacianine (ONM-100) a single-dose IV administered imaging agent that utilizes pH as auniversal biomarker for cancer to assist the surgeon during resection of solid tumors regardless of theironcogenic phenotype. Safety and efficacy have been established in highly successful Phase 1 and Phase 2 trialsfor tumor detection both primary and residual and results are similarly encouraging for a nearly completedPhase 2 trial for PM that will form the indication for commercial launch. Realization of the value of pegsitacianinelies in a tumor-agnostic label claim that would encompass metastatic disease in the peritoneum regardless ofprimary tumor origin providing an incredibly powerful and singular solution with significant potential that doesnot exist commercially. The noted heterogeneity in PM is expected to provide a pathway to substantiate FDAapproval of a tumor-agnostic label. Investors and potential commercial partners (camera suppliers) who workwith OncoNano in our clinical trials recognize the importance value and challenges of detecting peritonealmetastases and are actively engaged in pegsitacianine progress. However their commitment to trigger privatefinancing required for commercialization is predicated on demonstration of a de-risking clinical study. Critical tobridging this valley of death is the use non-dilutive funding from this grant as well as matching funds that havealready been procured. The focus of this SBIR Phase IIB proposal is to conduct a pivotal Phase 3 study togenerate a definitive data set to advance discussions with potential strategics and investors and obtain regulatoryapproval for pegsitacianine for metastatic disease in the peritoneum regardless of primary site of tumor origin. 999999 +No NIH Category available Acceleration;BRAF gene;Benchmarking;Cancer Etiology;Cell Death;Cell Line;Cell Proliferation;Conflict (Psychology);Data;Development;Disease;Epidermal Growth Factor Receptor;FRAP1 gene;Genes;Genetic;Genetic Epistasis;Genotype;Growth;Human;Individual;KRAS oncogenesis;KRAS2 gene;Laboratories;Lung Adenocarcinoma;MAP Kinase Gene;Maintenance;Malignant Neoplasms;Modeling;Mus;Mutate;Mutation;Oncogenes;Oncogenic;PIK3CG gene;Pathway interactions;Patients;Pattern;Protein Biosynthesis;Proto-Oncogene Proteins c-akt;Role;STK11 gene;Signal Transduction;Testing;Therapeutic Intervention;Therapeutically Targetable;Tumor Burden;Tumor Cell Line;Tumor Promotion;Tumor Suppressor Proteins;Tumor-Derived;Work;antagonist;cancer cell;cancer genome;cancer therapy;cancer type;driver mutation;fitness;genome sequencing;histone methyltransferase;improved;insight;mouse model;neoplastic cell;new therapeutic target;outcome disparities;prevent;synergism;tumor;tumor growth;tumorigenesis;tumorigenic Paradoxical Effects of SETD2 Inactivation in EGFR- and KRAS-driven Lung Adenocarcinoma PROJECT NARRATIVECo-occurring and mutually exclusive patterns of cancer-promoting mutations reveal context-dependent effectsof driver alterations in tumorigenesis. This project seeks to investigate the paradoxical effects of the frequentlyinactivated gene SETD2 in KRAS- and EGFR-driven lung adenocarcinoma. Understanding the mechanism ofSETD2's relationship with each oncogene will identify targetable therapeutic vulnerabilities in human cancer. NCI 10677503 4/28/23 0:00 PA-21-051 1F31CA281076-01 1 F31 CA 281076 1 "SCHMIDT, MICHAEL K" 5/1/23 0:00 4/30/26 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 16287050 "DOERIG, KATHERINE " Not Applicable 3 BIOSTATISTICS & OTHER MATH SCI 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 398 "Training, Individual" 2023 47694 NCI 47694 0 PROJECT SUMMARY Mutual exclusivity and co-occurrence of cancer causing mutations are due to pairwise geneticrelationships that include oncogenic redundancy and synthetic lethality. These interactions suggest that thecancer-promoting effects of one mutation are dependent on the presence of another a contingency that can beexploited in the development of new cancer therapies. Certain mutations have contrasting effects promotingcancer in one mutational context but limiting it in another. SETD2 inactivation in lung adenocarcinoma occursin 9% of tumors overall and frequently co-occurs with oncogenic KRAS but is mutually exclusive withoncogenic EGFR the most frequent driver genes of this disease. Our lab was the first to identify SETD2 as apotent tumor suppressor in a KRAS-driven mouse model. However paradoxically Setd2 inactivation preventstumor growth in the context of oncogenic EGFR suggesting an antagonism between these alterations. Theopposing effects of Setd2 inactivation are surprising given that KRAS is directly downstream of EGFR andactivates the MAPK pathway a driver of many cancer types. Given that KRAS and EGFR share this majortumorigenic pathway I hypothesize that Setd2 inactivation is specifically synergistic with activation of theMAPK pathway but incompatible with a separate pathway that is also downstream of EGFR. An important clue in deciphering this incompatibility is the epistatic relationship between SETD2 andLKB1 another frequently inactivated gene. Although both genes are powerful tumor suppressors in KRAS-driven models co-mutation conferred no additional growth advantage indicating that these genes act in thesame pathway. Additionally Lkb1 inactivation has the same paradoxical antagonism in EGFR-driven tumors.Inactivation of Lkb1 results in constitutively activated mTORC1 signaling which is a common feature of manycancers. My preliminary data demonstrate that Setd2 inactivation also promotes mTORC1 activity in KRAS-driven tumors. Likewise oncogenic EGFR directs mTORC1 signaling via the PI3K-AKT axis and is reliant onthis pathway for tumor maintenance while oncogenic KRAS is not. Given the stimulation of mTORC1 signalingby Setd2 and its synthetic lethality with oncogenic EGFR which also activates mTOR I hypothesize that theheightened mTORC1 activity present in Setd2-inactivated tumors is incompatible with oncogenic EGFR. Totest these hypotheses I first aim to determine whether Setd2 inactivation is synergistic with oncogenic MAPKsignaling using a BRAF-driven mouse model. Second I will determine whether excess mTORC1 signaling isresponsible for EGFR-SETD2 antagonism by modulating this pathway in each driver context using tumor celllines. This study will begin to characterize the synthetic lethal relationship between two frequently mutatedgenes in lung adenocarcinoma. Understanding these interactions will enable development of new therapiesthat target genotype specific vulnerabilities. 47694 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Comparative Effectiveness Research; Health Disparities; Orphan Drug; Patient Safety; Precision Medicine; Rare Diseases; Rural Health; Social Determinants of Health Address;Administrative Supplement;Antineoplastic Agents;Award;Basic Science;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Therapy Evaluation Program;Clinical;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Clinical Treatment;Clinical Trials;Clinical Trials Design;Clinical Trials Network;Collaborations;Component of the National Cancer Institute;Comprehensive Cancer Center;Conduct Clinical Trials;Development;Disease;Engineering;Evaluation;Funding;Funding Opportunities;Geographic Locations;Goals;Grant;Health;Image;Immunology;Infrastructure;Investigational Therapies;Laboratories;Lead;Leadership;Malignant Neoplasms;Mission;Monitor;Multi-Institutional Clinical Trial;National Cancer Institute;National Clinical Trials Network;New England;Participant;Patients;Peer Review;Phase;Positioning Attribute;Process;Protocols documentation;Rare Diseases;Request for Applications;Research;Research Personnel;Schools;Science;Services;Signal Transduction;Site;Testing;Therapeutic;Translational Research;Underserved Population;base;cancer imaging;cancer therapy;data management;drug development;early phase clinical trial;early phase trial;improved;improved outcome;innovation;interest;medical schools;meetings;member;multidisciplinary;patient population;phase III trial;programs;ranpirnase;rare cancer;response;rural underserved;targeted cancer therapy;treatment trial Administrative supplement for Early Drug Development Opportunity Program (EDDOP) NARRATIVE:Our geographic location provides access to clinical trials to a rural underserved population. Ouroverarching mission is to participate and be a leader in the ETCTNs collaborative clinicalresearch program of early phase clinical trials designed to provide a sufficiently unequivocalsignal of clinical benefit to justify definitive large multi-institutional phase 3 trials to demonstrateimproved outcomes and change standards of practice. NCI 10677500 9/9/22 0:00 PA-20-272 3P30CA023108-43S2 3 P30 CA 23108 43 S2 "BELIN, PRECILLA L" 9/1/22 0:00 11/30/24 0:00 1899930 "LEACH, STEVEN D" Not Applicable 2 INTERNAL MEDICINE/MEDICINE 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 397 Research Centers 2022 75000 NCI 65455 9545 ABSTRACTThis proposal addresses Dartmouth Cancer Centers (DCC) ability to conduct and participate incancer early phase clinical trials through the Experimental Therapeutics Clinical Trials Network(ETCTN) of the National Cancer Institute (NCI). It serves as a comprehensive response to theNCIs P30 Cancer Center Support Grant Administrative Supplement to NCI-designated CancerCenters previously participating in Create Access to Targeted Cancer Therapy for UnderservedPopulations (CATCH-UP) to promote continued collaboration with CTEPs ETCTN underfunding opportunity PA-20-272. DCCs objectives as an NCI-designated comprehensive cancercenter are aligned with ETCTNs goals to conduct early phase clinical treatment trials across abroad range of cancers and diverse patient populations with an emphasis on rare diseases.DCC was approved through peer review for the NCI Cancer Centers Early Phase ClinicalResearch component of NCI Center Grants. Dartmouth is a Lead Academic Participating Sitein the NCI National Clinical Trials Network. We currently are not affiliated with any ETCTN UM1grantees that are funded to conduct studies of NCI-IND agents with a phase 1 and morerecently also with phase 2 emphasis. Our proposal utilizes a pre-existing and functioningcadre of established inter- and multidisciplinary investigators at DCC The Geisel School ofMedicine at Dartmouth (Geisel) Dartmouth Health (DH) and the Thayer School of Engineeringat Dartmouth which share common clinical basic science and clinical translational researchinterests in cancer treatment and imaging. We have core laboratories and an infrastructure thatsupports the conduct of a wide spectrum of correlative science studies typically associated withearly phase trials and basic research in cancer biology immunology and imaging. As anacademic NCI-designated comprehensive cancer center we are well-positioned to providescientific leadership in developing and conducting innovative early phase studies of anti-canceragents held under CTEPs IND as well as substantial numbers of patients eligible for accrual toclinical trials conducted across the entire ETCTN. 75000 +No NIH Category available Allografting;American;Androgens;Automobile Driving;Biomass;Brain;Bypass;Cancer Etiology;Caring;Castration;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemicals;Chemoresistance;Citric Acid Cycle;Combined Modality Therapy;Cystine;DU145;Data;Development;Diagnosis;Disease;Distant;Drug Synergism;Drug resistance;Enzymes;Epigallocatechin Gallate;Essential Amino Acids;Event;Exhibits;Formulation;Generations;Glutamate Dehydrogenase;Glutamate Metabolism Pathway;Glutamates;Glutaminase;Glutamine;Goals;Growth;Homeostasis;In Vitro;Kidney;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Neoplasm Metastasis;Nutrient;Oxidation-Reduction;PC3 cell line;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Physiological;Probability;Process;Production;Prognosis;Proliferating;Protein Isoforms;Reporting;Research;Resistance;Role;Signal Transduction Pathway;Site;Survival Rate;Techniques;Testing;Therapeutic;Therapeutic Agents;Tissues;Tracer;Treatment Efficacy;Treatment outcome;Validation;Work;acquired drug resistance;advanced prostate cancer;alpha ketoglutarate;androgen deprivation therapy;androgen sensitive;antiporter;bone;cancer cell;cancer diagnosis;cancer drug resistance;cancer subtypes;cancer type;carbon skeleton;castration resistant prostate cancer;chemotherapy;combinatorial;common treatment;comparative efficacy;curative treatments;docetaxel;druggable target;effective therapy;efficacy outcomes;experimental study;improved;improved outcome;in vivo;in vivo Model;inhibitor;insight;lymph nodes;men;metabolomics;meter;mortality;novel;novel therapeutic intervention;prevent;prostate cancer cell line;prostate cancer progression;resistance mechanism;stable isotope;standard of care;synergism;therapeutically effective;treatment strategy;tumor growth Targeting Metabolic Vulnerabilities with Synergistic Therapeutic Agents for Treatment of Metastatic Castration-Resistant Prostate Cancer. Project Narrative: Patients with metastatic castration-resistant prostate cancer (mCRPC) have poor prognosis(median overall survival = 3 years) due to the lack of effective or curative treatment options. Recent evidencehas implicated metabolic reprogramming especially related to glutamine and glutamate metabolism as a majordriver of mCRPC progression and drug resistance but there are currently no treatments that capitalize on thismetabolic vulnerability. The proposed research will validate druggable targets related to glutamine and glutamatemetabolism in mCRPC both in vitro and in vivo for improved treatment efficacy and patient outcomes. NCI 10677412 8/2/23 0:00 PA-21-052 1F31CA275318-01A1 1 F31 CA 275318 1 A1 "DIBELLO, ANTHONY THOMAS" 8/21/23 0:00 8/20/26 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16289130 "HACKMAN, GABRELLE LAVENDER " Not Applicable 37 NUTRITION 170230239 V6AFQPN18437 170230239 V6AFQPN18437 US 30.291188 -97.737568 578403 UNIVERSITY OF TEXAS AT AUSTIN AUSTIN TX SCHOOLS OF ARTS AND SCIENCES 787121139 UNITED STATES N 8/21/23 0:00 8/20/24 0:00 398 "Training, Individual" 2023 38259 NCI 38259 0 PROJECT SUMMARYBroad Impact: Prostate cancer (PCa) is the most commonly diagnosed cancer in American men and in 2022alone will result in the death of over 34000 men. PCa mortality is typically caused by disease that hasadvanced to the metastatic castration-resistant stage (mCRPC) and has spread to distant sites such as thebone brain liver and lymph nodes. Currently there are no effective or curative therapeutic strategies formCRPC which is in part due to high rates of acquired drug resistance to androgen deprivation therapy (ADT)and the standard-of-care chemotherapy drug for mCRPC docetaxel (DTX). Consequently there is a criticalneed for novel and effective therapeutic options for mCRPC. Recent findings have indicated glutamine andrelated glutamate metabolism as significant drivers of the metabolic reprogramming of mCRPC that contributesto drug resistance mechanisms. Indeed a metabolic switch has been identified in PCa following ADT thatallows the cells to rely on the androgen-independent isoform of glutaminase (GLS1 the enzyme that convertsglutamine to glutamate) rather than the isoform that is inhibited by ADT affording drug resistance. Efforts tochemically inhibit GLS1 to overcome this issue have failed since there is a steady influx of glutamate via thexCT transporter when there are physiologically-relevant levels of cystine. However our preliminary data showsthat concurrently inhibiting GLS1 as well as glutamate dehydrogenase (GDH the enzyme that convertsglutamate to the TCA cycle intermediate alpha-ketoglutarate) may be sufficient to overcome this resistancemechanism across PCa subtypes including mCRPC. The overall goal of this project is to identify novelcombinatorial treatments for mCRPC that synergize with DTX to target metabolic vulnerabilities and overcomedrug resistance for improved treatment outcomes. Central hypothesis: Concurrent inhibition of GLS1 and GDHin combination with DTX can circumvent drug resistance mechanisms and increase therapeutic efficacycompared to SOC in mCRPC. Aim 1: Determine the metabolic role of GLS1 inhibition with CB-839 plus DTXfor the synergistic inhibition of PCa tumor growth in vivo. Aim 2: Elucidate the impact of concurrent GLS1 andGDH inhibition plus DTX on PCa growth proliferation metabolism aggressiveness and invasivenesscompared to SOC in vitro. Aim 3: Evaluate whether combination treatment with a GLS1 inhibitor and a GDHinhibitor plus DTX can synergistically inhibit PCa growth more effectively than SOC in vivo. Experimentaltechniques including metabolomics metabolic flux analysis using stable isotope tracers in vitro and in vivomodeling of mCRPC and validation of drug treatment efficacy will be undertaken to achieve the researchgoals. These findings will be used to inform novel treatment strategies to accompany docetaxel to preventcancer growth proliferation and aggressiveness in mCRPC for more effective treatments and improvedoutcomes for patients with mCRPC. 38259 +No NIH Category available Ablation;Affect;Aneuploidy;Automobile Driving;Binding;Biological Assay;Cell division;Cells;Chromosome Segregation;Chromosomes;Complex;Consumption;Data;Defect;Disease;Dynein ATPase;Energy consumption;Failure;Generations;Genome;Human;Image Analysis;In Vitro;Lasers;Lead;Length;Link;Malignant Neoplasms;Mechanics;Metaphase;Microtubules;Minus End of the Microtubule;Mitosis;Mitotic;Molecular;Motor;Play;Property;Proteins;Regulation;Role;Structure;System;Testing;University of Pittsburgh Cancer Institute;Walking;Work;cancer cell;cancer type;cell motility;crosslink;daughter cell;knock-down;malignant mouth neoplasm;microscopic imaging;mutant;novel therapeutic intervention;novel therapeutics;overexpression;prevent;quantitative imaging;recruit;response;segregation Defining the mechanisms by which NuMA drives spindle mechanical robustness Project NarrativeWhen a cell divides it must segregate the genome equally into two daughter cells and segregationerrors can lead to cancer. The spindle is the machine that segregates our chromosomes and theprotein NuMA is essential for building a spindle with two focused poles and thereby for segregatingchromosomes accurately into two groups. NuMA is misregulated in cancer and here I propose touncover how NuMA generates force to build the spindle which in the long term may lead to newtherapeutic avenues. NCI 10677401 4/19/23 0:00 PA-21-051 1F31CA275394-01A1 1 F31 CA 275394 1 A1 "ODEH, HANA M" 12/1/23 0:00 11/30/25 0:00 Special Emphasis Panel[ZRG1-F05-Q(20)L] 16107502 "CHO, NATHAN " Not Applicable 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 12/1/23 0:00 11/30/24 0:00 398 "Training, Individual" 2023 43612 NCI 43612 0 Project Summary/Abstract Errors in chromosome segregation lead to aneuploidy a hallmark of cancer where daughter cellshave extra or missing chromosome copies. Spindle pole defects such as multipolarity are one causeof aneuploidy indicating that pole integrity is critical to segregation fidelity. Thus understanding howthe spindles mechanical robustness emerges to build and maintain proper poles is crucial tounderstanding how the spindle accurately functions and how it fails in disease such as cancer. The protein NuMA and the motor dynein drive pole focusing by clustering microtubule minus-ends.Given this role in pole focusing altering NuMA expression or function could lead to cancer byincreasing multipolarity and aneuploidy. Indeed NuMA is overexpressed in certain cancer types andNuMA overexpression correlates with increased multipolarity and aneuploidy. However the molecularmechanisms by which NuMA gives rise to spindle mechanics and pole integrity and its role in cancerare far from clear. Based on recent work and preliminary data I hypothesize that NuMA plays twoseparate roles in spindle mechanics and that NuMA disruptions in cancer cells affect both roles: apassive (non-energy consuming) role crosslinking microtubules and a role regulating the motility ofthe active motor dynein. Either or both roles could be disrupted and targeted in a cancer context. Here I propose to test this hypothesis by combining molecular and mechanical perturbationsmicroscopy and quantitative image analysis in human metaphase cells. In Aim 1 I will test whetherand how NuMA plays a dynein-independent passive role in spindle mechanics. To do so I will usePDMS-based cell confinement to mechanically challenge normal and cancer spindles where NuMAcan and cannot interact with dynein and will compare how poles structurally fail under force. In Aim 2I will determine how NuMA regulates dynein function to drive spindle mechanics. Using a functionalNuMA/dynein transport assay I will test whether and how NuMA regulates dynein force generation inthe spindle. Specifically I will compare the ability of different NuMA mutants to change dynein forcegeneration focusing on a mutant that lacks the coiled-coil suspected necessary for dynein activationand a mutant preventing NuMA from oligomerizing and clustering dyneins together. Finally I will usethese same NuMA mutants and cell confinement to test if NuMA regulating dynein is essential forpole mechanical integrity in cancer spindles. Together these aims will determine how the essential protein NuMA drives spindle mechanicsand how NuMAs active and passive roles contribute to its disrupted function in cancer cells. As suchthis work will allow us to identify mechanisms for spindle pole failures and may provide newtherapeutic strategies to control multipolarity and aneuploidy in cancer. 43612 +Bioengineering; Biotechnology; Cancer; Cancer Genomics; Clinical Research; Data Science; Genetics; Human Genome; Networking and Information Technology R&D (NITRD); Precision Medicine Alleles;Bar Codes;Biotechnology;Cells;Chromosomal Rearrangement;Chromosome abnormality;Clinical;Clonal Evolution;Clonality;Collaborations;Computational algorithm;Computer software;Cues;Custom;DNA;DNA Sequence Alteration;DNA sequencing;Data;Development;Evolution;Genes;Genetic Heterogeneity;Genomic DNA;Genomic Instability;Genomics;Goals;Hodgkin Disease;Malignant Neoplasms;Maps;Measurement;Methods;Modeling;Nature;Organ;Pattern;Protocols documentation;RNA;Research Personnel;Resolution;Sampling;Scientist;Slide;Spatial Distribution;Specimen;Technology;Time;Tissues;Transposase;Work;cancer genome;computational platform;computerized tools;genome sequencing;genomic platform;neoplastic cell;new technology;novel;precision oncology;reconstruction;single cell sequencing;single-cell RNA sequencing;spatiotemporal;transcriptomics;treatment response;tumor;tumor heterogeneity;tumor progression;user-friendly;whole genome IMAT-ITCR Collaboration: An integrated experimental and computational platform for analyzing the spatial organization of tumor clones Project NarrativeCells are the unit building blocks of tissues and organs thus to understand how tumorsprogress and develop in tissues and organs it is important to understand where different typesof healthy and tumor cells reside in the tissue. Here we are developing new technologies thatallows clinical scientists to simultaneously look at who cells are via the genes they express andwhere they reside across many different tumor types. NCI 10677381 9/9/22 0:00 PA-20-272 3R33CA246455-03S1 3 R33 CA 246455 3 S1 "LI, JERRY" 3/2/20 0:00 2/28/23 0:00 12232352 "CHEN, FEI " "ASHENBERG, ORR ; RODIG, SCOTT J" 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 3/1/22 0:00 2/28/23 0:00 396 Non-SBIR/STTR 2022 77571 NCI 49725 27846 Cancer genomes evolve by acquiring a diverse repertoire of DNA mutations copy numberaberrations (CNAs) and large chromosomal rearrangements giving rise to genetically diverseclonal lineages. Decoupling and quantifying genetic heterogeneity and spatial cues within atumor is critical for understanding the basis for tumor progression and response to therapies.The goals of PI Chens IMAT project are to develop Slide-seq into a high-resolution spatialgenomics platform for cancer precision medicine. This project seeks to develop robustprotocols pipelines and computational algorithms to democratize spatial transcriptomic profilingfor clinical specimens and demonstrate them across tumor types working directly in the clinicalsetting. The goals of PI Raphaels ITCR project are to develop a comprehensive user-friendlyand modular software suite for tumor heterogeneity and clonal evolution studies across spacetime and genomic scale using data from both bulk and single-cell sequencing technologies.Here we seek to merge we will develop an integrated experimental and computationalplatform to analyze the spatial organization of clones in tumor samples. This platform willcombine the Slide-RNA-SeqV2 and Slide-DNA-seq technologies under development in PIChens IMAT project with customized computational algorithms that extend methods developedin PI Raphaels ITCR project. 77571 +No NIH Category available Area;Blood Vessels;CCL2 gene;Cancer Etiology;Cells;Cessation of life;Coculture Techniques;Communication;Data;Development;Disease;Disease Progression;Environment;Exclusion;Fibrinogen;Fibroblasts;Gene Expression;Goals;HIF1A gene;Human;Hypoxia;Hypoxia Inducible Factor;Immune;Immune System Diseases;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Infiltration;Inflammatory;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Modeling;Mus;Myelogenous;Outcome;Oxygen;Pancreas;Pancreatic Ductal Adenocarcinoma;Patients;Phenotype;Play;Population;Regulation;Resistance;Role;Signal Transduction;Stress;Stromal Cells;Survival Rate;T-Lymphocyte;Testing;United States;cell type;chemokine;cytokine;density;effective therapy;experience;immunosuppressive macrophages;insight;migration;monocyte;neoplastic cell;neutralizing antibody;normoxia;pancreatic cancer cells;pancreatic neoplasm;pancreatic tumorigenesis;recruit;response;therapy resistant;transcription factor;tumor;tumor hypoxia;tumor progression;tumor-immune system interactions Hypoxic regulation of macrophage migration and function via fibroblast reprogramming in pancreatic cancer PROJECT NARRATIVEPancreatic cancer is a highly lethal disease and is characterized by extensive hypoxic fibroinflammatory stromawhich contributes to the ineffectiveness of immunotherapies. Interactions between tumor cells and surroundingstromal cells substantially influence immune suppression and tumor progression and the goal of this proposalis to elucidate how hypoxia regulates the recruitment and function of macrophages in pancreatic cancer. Mystudies will expand our understanding of how hypoxia drives an immunosuppressive tumor microenvironmentand provide insight into the development of effective immunotherapeutic strategies against pancreatic cancer. NCI 10677376 7/27/23 0:00 PA-21-052 1F31CA281194-01 1 F31 CA 281194 1 "DIBELLO, ANTHONY THOMAS" 8/1/23 0:00 7/31/27 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 78233762 "HANNIFIN, SEAN MATTHEW" Not Applicable 6 PHARMACOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 40814 NCI 40814 0 PROJECT SUMMARYPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the UnitedStates despite representing only 2% of all cancer cases. PDAC is characterized by an extensivefibroinflammatory stroma and a hypoxic microenvironment which contributes to disease progression andtherapeutic resistance. Macrophages and cancer-associated fibroblasts (CAFs) are the predominant cell typeswithin the PDAC stroma. Macrophages are a major immunosuppressive population in PDAC. These cells arehighly plastic and as a result their environment plays an important role in regulating their function. Macrophagesadapt to hypoxia a condition of low oxygen availability primarily through the stabilization of oxygen-liabletranscription factors called hypoxia-inducible factors (HIFs). Although PDAC is extremely hypoxic and both thetumor cells and stromal cells experience hypoxia the effects of hypoxia and HIFs on macrophages and theircommunication with other stromal cells in PDAC remain largely unknown. Our group has recently found thathypoxia promotes the acquisition of inflammatory cancer-associated fibroblasts (inflammatory CAFs) a recentlydefined PDAC fibroblast subtype that produces high levels of inflammatory cytokines and chemokines. Byinjecting a hypoxia probe into mice bearing PDAC we have observed that inflammatory CAFs and macrophagespredominantly reside in hypoxic tumor regions compared with normoxic regions whereas T cells are largelyexcluded from hypoxic tumor areas. Based on these preliminary data I hypothesize that inflammatory fibroblastsinduced by hypoxia promote macrophage infiltration into hypoxic tumor regions and facilitate animmunosuppressive macrophage phenotype. This hypothesis will be investigated with the following two Aims:(1) to determine the role of hypoxia-induced fibroblast-secreted factors in regulating macrophage migration andfunction in PDAC and (2) to define the role of macrophage HIFs in regulating macrophage migration and functionin PDAC. To complete Aim 1 I will culture macrophages with conditioned media derived from mono- and co-cultures of pancreatic tumor cells and fibroblasts under either hypoxia or normoxia and then assess theexpression of immunosuppressive macrophage markers as well as their migration. To complete Aim 2 I willculture HIF1-deficient and HIF2-deficient macrophages under hypoxia with fresh media or conditioned mediafrom co-cultures of pancreatic tumor cells and fibroblasts under hypoxia. Then I will assess the expression ofimmunosuppressive markers in these macrophages and evaluate their migration. Finally I will define the role ofmacrophage HIFs in mediating pancreatic tumorigenesis using orthotopic tumors from mice lacking myeloidexpression of HIF1 or HIF2. My proposal will provide new insights into how hypoxia promotes animmunosuppressive PDAC microenvironment by modulating the macrophage-fibroblast crosstalk and ultimatelyinform strategies to overcome resistance to immunotherapy. 40814 +No NIH Category available Adenomatous Polyps;Animals;Antibodies;Antigen Presentation;Antineoplastic Agents;ApcMin/+ mice;Apoptosis;Autologous;Binding;Biological Assay;Biological Markers;Biopsy;CD4 Positive T Lymphocytes;CD8B1 gene;Cell Culture Techniques;Cell Proliferation;Cell Survival;Cell surface;Cells;Cellular Structures;Clinic;Clinical;Clinical Research;Clinical Trials;Coculture Techniques;Colectomy;Colon;Colonic Neoplasms;Colonic Polyps;Colorectal Cancer;Complex;Coupled;Critiques;Data;Diet;Dose;Drug Combinations;Duodenal Neoplasms;Duodenum;Duodenum Cancer;EGFR gene;Ectoderm;Effectiveness;Embryo;Epidermal Growth Factor Receptor;Epigenetic Process;Epithelium;Erlotinib;Eye;Familial Adenomatous Polyposis Syndrome;Female;Fostering;Future;Gene Expression;Genes;Genetic;Granzyme;Histocompatibility Antigens Class II;Histones;Human;Image;Immune;Immune Evasion;Immune Targeting;Immune response;Immune system;Immunologic Surveillance;Interferons;Intervention;Knockout Mice;Lesion;Major Histocompatibility Complex;Malignant Neoplasms;Modeling;Modification;Mus;Non-Steroidal Anti-Inflammatory Agents;Normal Cell;Operative Surgical Procedures;Oral;Oral Administration;Organoids;Patients;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Phase;Polycomb;Polyps;Pre-Clinical Model;Proteins;Rattus;Reader;Receptor Inhibition;Recommendation;Regulation;Research;Resistance;Risk;Risk Reduction;Safety;Signal Transduction;Sulindac;T-Lymphocyte;Testing;Therapeutic Equivalency;Time;Tissues;Titrations;Toxic effect;Translating;Tumor Escape;Up-Regulation;Western Blotting;Woman;adaptive immune response;adenoma;anti-cancer;cancer cell;cell killing;chemokine;clinical care;clinical translation;cytokine;drug candidate;efficacy study;epigenetic drug;histone methylation;human subject;inhibitor;innovation;insight;male;member;men;mutant;neoplastic;next generation;novel;novel strategies;overexpression;perforin;pharmacologic;polyposis;pre-clinical;premalignant;recruit;response;response biomarker;standard of care;stem;transcriptomics;tumor Immunoepigenetic targeting of MHC regulators in FAP Project NarrativeThe major histocompatibility complex (MHC) is critical for effective immune responses but isderegulated in common malignancies such as duodenal and colorectal cancer. Using cell cultureanimal and patient organoid approaches this project repurposes standard-of-care clinical agentsand a novel epigenetic drug candidate in the context of an evolving new paradigm for immune-based cancer interception in the gut. Increasing MHC expression according to the centralhypothesis will enhance immune surveillance and foster clearing of precancerous lesions atdoses likely to be well-tolerated when translated to at-risk human subjects. NCI 10677375 3/27/23 0:00 PA-20-185 1R01CA257559-01A1 1 R01 CA 257559 1 A1 "MALONE, WINFRED F" 4/1/23 0:00 3/31/28 0:00 Cancer Prevention Study Section[CPSS] 1901902 "DASHWOOD, RODERICK H" "VILAR SANCHEZ, EDUARDO " 10 GENETICS 835607441 HFT7XTHB6563 835607441 HFT7XTHB6563 US 30.551654 -96.242881 8266910 TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR COLLEGE STATION TX OVERALL MEDICAL 778454375 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 393 Non-SBIR/STTR 2023 605411 NCI 437561 167850 Major histocompatibility complex class I and class II (MHC-I/II) members are critical for antigen presentation andadaptive immune responses but are downregulated in sporadic and genetic cases of duodenal and colorectalcancer (CRC) such as Familial Adenomatous Polyposis (FAP). There is an urgent need for novel approachesto reverse MHC-I/II silencing and overcome tumor immune evasion starting at the adenoma stage. Based onthe prior Critique standard-of-care sulindac and erlotinib (SUL ERL) and a new histone methyl `reader' inhibitorMAK683 that shows clinical promise will be repurposed for immune-based interception of FAP. From the rigorof prior research and extensive preliminary data the revised CENTRAL HYPOTHESIS is that low-dose ERL+SULcombinations along with MAK683 upregulate MHC-I/II components to enhance immune surveillance via CD8and CD4 T cell recruitment into preneoplastic and later stages of FAP. Low-dose non-cytotoxic test agents andtheir combinations augment MHC complexes at the cell surface to re-engage the host immune system foranticancer efficacy and will be translatable to FAP patients via oral administration with a good safety margin.Aim 1 MECHANISMS Aim 1A Perform dose-response and time-course studies with ERL SUL MAK683 andselected combinations for MHC-I/II upregulation in human and murine CRC duodenal cancer and adenomacells compared with normal cells. Aim 1B Corroborate for ERL SUL and MAK683 the increased cell surfaceoccupancy of MHC-I/II complexes coupled to enhanced cancer cell killing in CD8+ and CD4+ T cell co-cultures.Aim 1C Overexpress silence and pharmacologically inhibit mechanistic targets (e.g. EED NLRC5 CIITA) toidentify key roles in MHC-I/II regulation and immune evasion in adenoma and later stages relevant to FAP.Aim 2 PRECLINICAL Aim 2A In the polyposis in rat colon (Pirc) model perform biomarker analyses withMAK683 via i.g. drug administration and corroborate histone methylation changes and immune target modulationin colon and duodenal polyps for up to 14 days. Aim 2B Test the antitumor efficacy and safety of MAK683 aloneand combined with ERL or SUL in the Pirc model. Mechanistic targets will be validated via RT-qPCR immunoblotand multiplex CyTOF as predictors of antitumor efficacy. Aim 2C Test selected drug combinations in ApcMin/+ApcMin/+Nlrc5/ and ApcMin/+Ciita/ mice for insights into Nlrc5- and Ciita-dependent/independent mechanisms.Aim 3 TRANSLATIONAL Aim 3A In colon and duodenal biopsies from FAP patients corroborate the predictedinterrelationships between MHC-I/II members (B2M CD74) coactivators (NLRC5 CIITA) mechanistic targets(EED) and epigenetic readouts (histone H3K27me3) in epithelial and immune cell components via CyTOF.Aim 3B In FAP patient organoids define MAK683 ERL and SUL doses that increase MHC-I/II-dependent geneexpression and examine autologous effector functions and the capacity to kill tumor organoids in T cell co-cultures. Aim 3C In organoids from Aim 3B test the hypothesis that MAK683 ERL and SUL increase MHC-I/II-bound peptides using MS-based peptidomic approaches to aid in precision immunoepigenetic clinical strategies. 605411 +Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Patient Safety; Precision Medicine; Rural Health Administrative Supplement;Baptist Church;Biological;Biological Assay;Biological Markers;Biopsy Specimen;Cancer Center;Cancer Patient;Cancer Therapy Evaluation Program;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Collection;Colorado;Comprehensive Cancer Center;Discipline;Disease;Educational Activities;Eligibility Determination;Enrollment;Environment;Evaluation;Evolution;Fostering;General Population;Goals;Good Clinical Practice;Grant;Image;Infrastructure;Institutes;Institution;Intervention;Investigational Therapies;Laboratories;Laboratory Study;Lead;Leadership;Letters;Location;Malignant Neoplasms;Maryland;Medical;Memorial Sloan-Kettering Cancer Center;Mentors;Methodology;Minority Groups;Molecular;Monitor;NCI-Designated Cancer Center;National Clinical Trials Network;New Agents;Participant;Pathologist;Pathway interactions;Patients;Phase;Phase I Clinical Trials;Population Heterogeneity;Protocols documentation;Quality of Care;Research;Research Personnel;Resource Sharing;Resources;Rural;Rural Population;Safety;Site;Statistical Data Interpretation;Team Process;Toxic effect;Training;Translating;Translational Research;Underserved Population;Universities;University of Virginia Cancer Center;Wisconsin;biomarker development;biomarker validation;cancer clinical trial;career;clinical care;clinical development;clinical investigation;cohesion;data sharing;design;diversity and inclusion;drug development;early phase clinical trial;early phase trial;experience;forest;innovation;interest;meetings;member;molecular subtypes;next generation;novel;novel anticancer drug;novel therapeutics;patient population;radiologist;rare cancer;response;sound;stem;success;trial design;underserved minority The Johns Hopkins Translational Science Team and Consortium for ETCTN Studies Our Consortium will continue its long- standing contribution to the drug development efforts of the NCI byleveraging its collective experience commitment to collaboration and legacy of training young investigators toimpact the clinical care of cancer patients. We promote inclusiveness of the many medical disciplines that arerequired to conduct innovative informative and insightful early phase clinical trials. We anticipate enhancedinteractions with the National Clinical Trials Network to bring forward successes from the efforts of the ETCTN. NCI 10677365 9/7/22 0:00 PA-20-272 3UM1CA186691-06S3 3 UM1 CA 186691 6 S3 "IVY, S PERCY" 9/1/22 0:00 2/28/23 0:00 1877600 "CARDUCCI, MICHAEL A" "RUDEK, MICHELLE A" 7 INTERNAL MEDICINE/MEDICINE 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/22 0:00 2/28/23 0:00 395 Non-SBIR/STTR 2022 400000 NCI 374796 25204 With the evolution of the Experimental Therapeutics Clinical Trials Network (ETCTN) the Johns HopkinsTranslational Science Team (JHTST) expanded in 2019 by bringing 8 Affiliate Organizations (AO) under ourLead Academic Organization (LAO) with the goal to enhance and accelerate our collective contribution to thedrug development efforts of the NCI. We have organized a comprehensive and cohesive infrastructure that canconduct high-quality clinical trials evaluating novel anticancer agents in combinations in molecularly selectedpatient populations or rare tumor sites. Our infrastructure stems from the need to be clinically efficientregulatory compliant and scientifically rigorous in our approach as we collaborate as network members withinthe ETCTN. With the submission of this administrative supplement our infrastructure will now consist of nineexperienced NCI-designated Cancer Centers: Johns Hopkins Sidney Kimmel Comprehensive Cancer CenterEmory Winship Cancer Institute Georgetown Lombardi Comprehensive Cancer Center Memorial SloanKettering Cancer Center University of Virginia Cancer Center University of Wisconsin Carbone CancerCenter University of Colorado Comprehensive Cancer Center The University of Maryland GreenebaumCancer Center and Wake Forest Baptist Comprehensive Cancer Center (the newest and focus of thissupplement). This collection of Centers brings together many unique discovery strengths diverse patientvolumes and locations both urban and rural. We will focus on 5 Specific Aims: Aim 1- To lead and maintain aclinical trial consortium that will support cancer clinical trials from Phase 1 initiation through proof-of-activityand foster seamless Phase 2 clinical development of NCI CTEP IND agents; Aim 2- To actively participate andengage disease-focused clinical investigators in the ETCTN by promoting accrual to a range of ETCTN studiesled by other LAO/AO members; Aim 3- To incorporate and implement innovative correlative and biologicallaboratory studies in the context of or as eligibility for participation in early phase clinical studies that enhanceour understanding of determinants of toxicity and response that will be used for further definitive practice-changing clinical trial evaluation; Aim 4- To train the next generation of investigators in drug development; andAim 5- To promote diversity and inclusion of underserved/minority participants on ETCTN trials. With 9 Centerswithin our Consortium we anticipate little problem in meeting the grant metrics of 100 accruals per yearsubmitting up to 8 LOI concepts/year to have at least 2 new studies approved each year functioning as anetwork by having Disease-Focused Clinical Investigators champion ETCTN studies at each Site acrossdisease sites and to provide opportunities to engage and train early career investigators in drug development.We anticipate that our contributions within the ETCTN will impact the clinical care of cancer patients. 400000 +No NIH Category available Address;Allografting;Amino Acids;Antibodies;Antigen Presentation;Antigens;Arsenic;B-Lymphocytes;Basic Science;Biological Models;Bispecific Antibodies;Bispecific Monoclonal Antibodies;Cancer Patient;Carcinogens;Cell surface;Cells;Clinical;Clinical Trials;Code;Credentialing;Cultured Tumor Cells;DNA Binding Domain;DNA Vaccines;Data;Development;Drug Targeting;Engraftment;Environment;Environmental Carcinogens;Exhibits;Experimental Models;Family;Frequencies;Genes;Genetic;Genetic Engineering;Hereditary Disease;Human;Human Cell Line;Human Genome;Immune response;Immune system;Immunocompetent;Immunologic Deficiency Syndromes;Immunotherapeutic agent;Immunotherapy;Infiltration;Inherited;Li-Fraumeni Syndrome;Major Histocompatibility Complex;Malignant Neoplasms;Mediating;Missense Mutation;Modeling;Monoclonal Antibodies;Mouse Cell Line;Mouse Strains;Mus;Mutate;Mutation;Natural Immunity;Oncogene Activation;Oncogenic;Patients;Penetrance;Performance;Phosphoric Monoester Hydrolases;Physiologic pulse;Plasma Cells;Predisposition;Prognosis;Property;Proteins;Research;Role;Serum;Somatic Mutation;Supporting Cell;System;T cell response;T-Cell Receptor;T-Lymphocyte;TP53 gene;Targeted Research;Testing;Therapeutic;Tissues;Traction;Translational Research;Tumor Antigens;Tumor Cell Line;Tumor Suppression;Tumor Suppressor Genes;Tumor Tissue;United States Food and Drug Administration;Vaccines;Work;Xenograft Model;Xenograft procedure;anticancer research;antigen-specific T cells;autosome;cancer care;cancer initiation;cancer therapy;cancer type;cellular targeting;drug development;immune checkpoint blockade;improved;inhibiting antibody;mouse model;mutant;neoantigens;neoplasm immunotherapy;neoplastic cell;novel;novel strategies;patient derived xenograft model;precision medicine;precision oncology;prevent;programs;research and development;response;small molecule;stressor;targeted agent;therapeutic development;transcription factor;tumor;tumor progression;tumorigenesis;vector Optimizing Syngeneic Mouse Models to Target Mutant p53 Project NarrativeDespite decades of basic research and therapeutic development p53 mutant proteins remain undruggable dueto the lack of enzymatic activity and intracellular localization. There is a critical gap between existing mousemodels and the translational research targeting mutant p53 in the era of immunotherapy. We will use theoptimized syngeneic mouse models to develop precision cancer therapeutics against the top hotspot p53mutants in immunocompetent systems. NCI 10677353 4/17/23 0:00 PAR-20-131 1R01CA278089-01A1 1 R01 CA 278089 1 A1 "VENKATACHALAM, SUNDARESAN" 4/17/23 0:00 3/31/28 0:00 Special Emphasis Panel[ZRG1-CTH-B(55)R] 8146758 "LI, YONG " Not Applicable 9 INTERNAL MEDICINE/MEDICINE 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX SCHOOLS OF MEDICINE 770303411 UNITED STATES N 4/17/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 596803 NCI 373002 223801 Optimizing Syngeneic Mouse Models to Target Mutant p53Project AbstractThe tumor suppressor gene p53 is the guardian of the human genome. p53 is a transcription factor thattransactivates a battery of target genes in cells upon diverse stressors including environmental carcinogensand oncogene activation. Inherited mutations in the p53 coding sequence occur in ~80% of all families with Li-Fraumeni syndrome (LFS) a rare autosomal dominant hereditary disorder characterized by a high-penetrancepredisposition to multiple types of cancers. Somatic mutation of the p53 coding sequence occurs in about halfof all cancers. Most alterations in the p53 coding sequence either germline in LFS patients or somatic incancer tissues are missense mutations in the DNA-binding domain that result in an oncogenic protein. Due toits high mutation frequency and critical role in cancer initiation and progression mutant p53 is a high-priority target for the development of anticancer therapies. Several small molecules have been developedto convert mutant p53 to a form that exhibits some wild-type properties (i.e. p53 reactivation). Suchcompounds are in clinical trials yet none of them have been approved by the FDA. There are several majortypes of mouse models for cancer research each with weaknesses and strengths: syngeneic human cell line-derived xenograft patient-derived xenograft genetically engineered and carcinogen-induced. Most therapeuticprograms against mutant p53 use human cell line-derived xenograft which is immunodeficient. Syngeneicmouse models also known as allograft tumor systems consist of tumor tissues derived from the same geneticbackground as a given mouse strain. Syngeneic mouse models with a functional immune system are superiorto human cell line-derived xenografts for immunotherapeutic development. Syngeneic mouse models areinstrumental in developing novel antitumor immunotherapies yet there are no corresponding models to mostp53 hotspot mutations found in human cancers. In this project we will study the potential vulnerability oftop somatic human p53 hotspot mutants using optimized syngeneic mouse models. Specifically we willknock the top ten human p53 hotspot mutations into representative syngeneic mouse tumor cell lines. We willtest monoclonal antibodies and vaccines targeting the p53 mutants in mice with a functional immune system.This work will define new uses of syngeneic mouse cell lines and test approaches to validate and credentialthe optimized p53 experimental model systems. Our findings will have broad and far-reaching translationalsignificance by addressing the unmet clinical need for precision medicine against mutant p53. 596803 +No NIH Category available American;Antibody Formation;Antigens;B-Lymphocyte Subsets;B-Lymphocytes;BRCA1 Mutation;BRCA1 gene;Biological Assay;Biological Markers;Biological Models;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Prevention;Breast Cancer Risk Factor;Breast Cancer Treatment;Breast Epithelial Cells;Cell Communication;Cell Separation;Cell physiology;Cell surface;Cells;Coculture Techniques;Color;Counseling;DNA Repair Gene;Development;Early treatment;Epigenetic Process;Epithelial Cells;Epithelium;Event;Exhibits;Extracellular Matrix;Family;Fibroblasts;Flow Cytometry;Foundations;Future;Genetic;Germ-Line Mutation;Gland;Goals;Histopathology;Immune;Immune system;Immunization;Incidence;Infection;Inflammation;Knock-out;Knockout Mice;Laboratory Finding;Life;Life Style;Link;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Mature B-Lymphocyte;Medical History;Molecular;Mus;Mutation;Organoids;Outcome;Ovum;Pathway interactions;Patients;Physicians;Play;Population;Pregnancy;Prevention;Prevention therapy;Research;Risk;Risk Assessment;Risk Factors;Role;Scientist;Signal Transduction;Solid Neoplasm;System;Testing;Tissues;Training;Transplantation;Tumor Expansion;Urinary tract infection;Woman;Work;biomarker development;cancer risk;cancer stem cell;career;clinically relevant;demographics;differential expression;disorder prevention;early detection biomarkers;experience;experimental study;gene environment interaction;improved;in vivo evaluation;life history;loss of function;loss of function mutation;malignant breast neoplasm;mammary;mammary epithelium;mutation carrier;novel;response;single-cell RNA sequencing;targeted treatment;transcriptome;tumor;tumor growth;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Investigating the relationship between the systemic response to infection and tumor initiation and progression in Brca1 breast cancer Project NarrativeRisk factors for breast cancer the second most lethal cancer in American women require identification andfurther study. This project will investigate a link between the whole-body response to urinary tract infection andthe development of breast cancer. This proposal represents an opportunity for improved disease preventionand targeted therapy. NCI 10677263 5/10/23 0:00 PA-21-049 1F30CA281082-01 1 F30 CA 281082 1 "PURI, ANU" 6/1/23 0:00 5/31/27 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16051856 "LEWIS, STEVEN MACAULEY" Not Applicable 1 PHARMACOLOGY 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY SCHOOLS OF MEDICINE 117943362 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 398 "Training, Individual" 2023 39997 NCI 39997 0 AbstractBreast cancer (BC) is one of the most common solid tumors in women world-wide. Loss-of-function mutations inthe DNA repair gene BRCA1 is among the most clinically relevant factors that increases BC incidence. Despitesuch a strong link with BC not every woman with a BRCA1 mutation will develop BC. Therefore identificationof cooperating risk factors such as life history events that initiate tumor development will enable developmentof biomarkers for early detection prevention and potentially targeted treatments. The dos Santos lab has foundthat whole body changes resulting from urinary tract infection (UTI) remodel the transcriptome of mammaryepithelial cells (MECs) and the tissue microenvironment. Therefore we hypothesize that UTI is a life historyevent that promotes BC incidence. Specifically I hypothesize that UTI induces alterations to MECs and modifiesmammary stromal and immune cells in such a way that tumors in Brca1 knockout mice will develop faster. I haveevaluated changes to mammary tissue with single cell RNA-sequencing and will further investigate these findingsthrough the proposed aims using multi-color flow cytometry histopathology transplantation experiments andorganoid studies. Overall the significance of this proposed research is to: i) better understand mechanisms oftumor initiation and early progression in Brca1-BC ii) identify immune-suppressive cellular changes in mammarytissue resulting from UTI and iii) provide justification for UTI as a novel BC risk factor in patients with BRCA1mutations. The outcome of these approaches will provide a deeper mechanistic understanding of how a specificlife history event modulates the responsiveness of MECs to cancer promoting signals. Additionally this proposalwill provide a novel appreciation of the role of Brca1 and the effects of systemic signals produced after infectionin modifying mammary stromal and immune cell function. 39997 +No NIH Category available 16S ribosomal RNA sequencing;Adoptive Cell Transfers;Agonist;Androgens;Antibiotic Therapy;Antibodies;Antibody Therapy;Antigens;BAY 54-9085;Bacteroides;Bacteroides thetaiotaomicron;C57BL/6 Mouse;CD8-Positive T-Lymphocytes;CTLA4 gene;Cancer Model;Carbon Tetrachloride;Cells;Combined Modality Therapy;Development;Disease;Growth;Hepatic;Hepatocarcinogenesis;Hepatocyte;Histology;Homeostasis;Human;Immune;Immune Tolerance;Immune response;Immunity;Immunization;Immunology;Immunotherapeutic agent;Immunotherapy;Inflammatory;Knowledge;Ligands;Liver;Liver Fibrosis;Macrophage;Malignant Neoplasms;Marketing;Mediating;Microbe;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Nucleic Acids;Oncogenic;PTPNS1 gene;Pathogenesis;Patients;Phagocytosis;Phenotype;Play;Population;Primary carcinoma of the liver cells;Progression-Free Survivals;Regulatory T-Lymphocyte;Resistance;Role;SHPS-1 protein;SV40 T Antigens;Shapes;Testing;Therapeutic;Therapeutic Effect;Therapeutic antibodies;Transgenic Mice;Treatment Efficacy;Tumor Antigens;Tumor Biology;Tumor Immunity;Tumor-associated macrophages;Unresectable;Up-Regulation;anti-PD-1;anti-PD-L1 antibodies;anti-PD1 antibodies;cancer immunotherapy;cancer initiation;checkpoint therapy;clinically relevant;design;exhaust;fecal transplantation;gut microbiota;human disease;immune activation;improved;in vivo;invention;knock-down;loss of function;melanoma;member;microbial;monocyte;novel;novel therapeutic intervention;overexpression;phase 3 study;programmed cell death ligand 1;programmed cell death protein 1;programs;single-cell RNA sequencing;transcription factor;treatment response;tumor;tumor growth;tumor initiation;tumor microbiota;tumor progression;tumorigenesis Targeting KLF2 in macrophages to improve immune checkpoint therapy for hepatocellular cancer PROJECT NARRATIVEAnti-programmed death-1 antibody (PD-1 Ab) as a single agent for treating human hepatocellular cancer (HCC)was withdrawn from the US market on July 26 2021 because a multi-center phase III study did not demonstrateits efficacy in improving patient survival over controls. We invented a novel microbe-based strategy thatsignificantly improves the therapeutic efficacy of PD1 Ab for HCC. We now propose to dissect the underlyingcellular and molecular mechanisms to identify unrecognized regulators for designing new immune checkpointtherapy strategies against HCC. NCI 10677187 5/1/23 0:00 PA-20-185 1R01CA274959-01A1 1 R01 CA 274959 1 A1 "CARDONE, MARCO" 5/1/23 0:00 4/30/28 0:00 Special Emphasis Panel[ZRG1-TIO-D(01)Q] 10533160 "LI, GUANGFU " "STAVELEY-O'CARROLL, KEVIN FINNBAR" 3 SURGERY 153890272 SZPJL5ZRCLF4 153890272 SZPJL5ZRCLF4 US 38.948231 -92.327335 578002 UNIVERSITY OF MISSOURI-COLUMBIA COLUMBIA MO SCHOOLS OF MEDICINE 652110001 UNITED STATES N 5/1/23 0:00 4/30/24 0:00 395 Non-SBIR/STTR 2023 567522 NCI 374424 193098 ABSTRACTAnti-programmed death-1 antibody (PD-1 Ab) as a single agent for treating human hepatocellular cancer (HCC)was withdrawn from the US market on July 26 2021 because a multi-center phase III study did not demonstrateits efficacy in improving patient survival over controls. Thus there is an urgent need to identify and target criticalcellular and molecular regulators to design new immune checkpoint therapy (ICT) strategies against HCC. Aunique orthotopic and clinically relevant murine HCC model was established that mimics HCC initiation andprogression in humans and reflects the tumor biology immunology and histology typical of human disease. Inthis model SV40 T antigen (TAg) is expressed solely in tumors as a trackable tumor-specific antigen (TSA)enabling TSA immunity study during tumor initiation progression and response to treatments. Using this modelseveral immune-based therapeutic strategies for HCC were developed and a novel microbe-based strategy wasrecently established that significantly improves the therapeutic efficacy of PD-1 Ab for HCC. SpecificallyBacteroides thetaiotaomicron (B.th) one member of genus Bacteroides with CpG-rich nucleic acid whichfunctions as TLR9 agonist was identified as a microbial regulator to significantly boost PD-1 Ab therapeuticefficacy for HCC. This exciting finding led to studies of the underlying cellular and molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) revealed that HCC growth upregulated Kruppel like factor-2 (KLF2) in tumor-associated macrophages (TAMs) and B.th addition activated effector CD8+ T cells and improved PD-1therapeutic effect against HCC which was associated with reduced KLF2 expression in TAMs. Moreoveradoptive cell transfer (ACT) of macrophages (Ms) with KLF2 knockdown (KD) enabled TSA immunization tosignificantly suppress HCC growth. Conversely KLF2 overexpression (OE) in Ms compromised B.th/PD-1-induced therapeutic suppression of HCC. These compelling results highlight KLF2 as a key regulator mediatingmicrobes impact on hepatocarcinogenesis and B.th/PD-1 immunotherapy by modulating Ms. Further studiesindicate that KLF2 controls M expression of TLR9 and signal-regulatory protein (SIRP) to regulate Mtumor phagocytosis and immune regulatory function. These findings generate the following hypothesis: B.th withCpG-rich nucleic acid reinvigorates PD-1 Ab ICT in HCC by phenotypically and functionally programming Mvia KLF2-controlled expression of TLR9 and SIRP. In Aim 1 KLF2-directed Ms as the cellular basis mediatingHCC pathogenesis and immune tolerance will be studied toward the development of a new therapeutic approachby integrating KLF2-KO Ms withPD-1 Ab. In Aim 2 the molecular mechanism and regulators by whichB.th/PD-1 suppress KLF2 to reprogram M by controlling TLR9 and SIRP expression will be studied. Theknowledge generated from this study will not only identify unrecognized endogenous regulators with a role inprogramming M in HCC but also make a case that these factors are effective targets to trigger Ms and leadto improved ICT for HCC. 567522 +Cancer; Clinical Research; Clinical Trials and Supportive Activities Address;Adverse event;Appointment;Asian;California;Cancer Center;Catchment Area;Clinical;Clinical Investigator;Clinical Nursing Research;Clinical Pharmacists;Clinical Research;Clinical Research Associate;Clinical Trials Network;Competence;Comprehensive Cancer Center;Cost Sharing;Data;Data Reporting;Development;Disease;Early Therapeutic-Clinical Trials Network;Enrollment;Environment;Equipment and supply inventories;Family;Goals;Human Resources;Investigational Drugs;Investigational Therapies;Latino;Lead;Leadership;Malignant Neoplasms;Network Infrastructure;Outcome;Patients;Peer Review;Performance;Pharmaceutical Preparations;Phase;Process;Reporting;Research Personnel;Resources;Site;Training;Underserved Population;United States National Institutes of Health;Universities;Work;adverse outcome;base;cancer care;cancer clinical trial;early phase clinical trial;experience;meetings;member;minority patient;novel strategies;patient population;programs;racial and ethnic;success;targeted cancer therapy;underserved area CATCH-UP: NCI ETCTN Pittsburgh Cancer Consortium (PCC) NARRATIVEThe overarching goal of the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) is to enhance andfacilitate the efficient and comprehensive conduct of early-phase clinical trials of NCI Investigation New Drug(IND) agents.The University of California Irvine (UCI) Chao Family Comprehensive Cancer Center (CFCCC) will be integratedinto the Pittsburgh Cancer Consortium (PCC) Lead Academic Organization which currently includes the UPMCHillman Cancer Center (HCC) and the Montefiore Einstein Cancer Center (MECC).The long-term goal is to guide the development and conduct of early-phase clinical trials that may have thepotential to change the standard of cancer care in the U.S. and worldwide. NCI 10677058 9/12/22 0:00 PA-20-272 3UM1CA186690-06S1 3 UM1 CA 186690 6 S1 "IVY, S PERCY" 3/25/14 0:00 2/28/23 0:00 8952707 "BEUMER, JAN HENDRIK" "LUKE, JASON JOHN; VILLARUZ, LIZA COSCA" 12 INTERNAL MEDICINE/MEDICINE 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 5/7/20 0:00 2/28/23 0:00 395 Non-SBIR/STTR 2022 400000 NCI 346493 53507 ABSTRACTThis application is being submitted to request the addition of an Affiliated Organization(s) to the EarlyTherapeutics Clinical Trial Network (ETCTN) UM1 Lead Academic Organization.The Chao Family Comprehensive Cancer Center (CFCCC) of the University of California Irvine (UCI) hasdemonstrated to be a well performing site in the Create Access to Targeted Cancer Therapy for UnderservedPopulations (CATCH-UP) program enrolling a total of 34 patients with nearly half (48%) coming from diversepatient populations (e.g. Latino Asian and underserved areas). With the success of CFCCCs participation inCATCH-UP CFCCC will be integrated into the Pittsburgh Cancer Consortium (PCC) providing access for theirpatients to all ETCTN trials.The PCC will integrate CFCCC by providing regulatory support data coordination and reporting of adverseevents and outcomes on the studies led by UCI investigators. In addition the PCC will support CFCCC throughdevelopment of concepts and leadership in ETCTN trials. Conversely CFCCC will use their experience andsuccess in the CATCH-UP program to deploy best practices in underserved patient accrual in the PCC. 400000 +No NIH Category available Abdomen;Acceleration;Address;Age;Aging;Atlases;Biological;Biological Aging;Biological Markers;Biometry;Blood;Blood Pressure;Body Weight;Body Weight decreased;Body mass index;Cancer Control;Cancer Patient;Cancer Prevention Intervention;Cancer Prognosis;Cancer Survivor;Cardiometabolic Disease;Cardiovascular Diseases;Categories;Cells;Cessation of life;Characteristics;Chronic;Classification;Clinical;Clinical Management;Colorectal;DNA Methylation;Data;Diabetes Mellitus;Diagnosis;Disease;Epidemiology;Epigenetic Process;Esophagus;Etiology;Fatty acid glycerol esters;Female;Framingham Heart Study;Gallbladder;Goals;Health;Health and Retirement Study;High Density Lipoprotein Cholesterol;Homeostasis;Human;Huntsman Cancer Institute at the University of Utah;Incidence;Individual;Intervention;Jackson Heart Study;Link;Liver;Longevity;Malignant Neoplasms;Measures;Mediating;Mediation;Metabolic;Metabolic dysfunction;Metabolic syndrome;Metabolism;Modification;Multiple Myeloma;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Obesity associated cancer;Ovary;Overweight;Pancreas;Participant;Patients;Persons;Phase;Phenotype;Physical Function;Play;Postdoctoral Fellow;Premature aging syndrome;Prevalence;Prevention;Process;Public Health;Quality of life;Race;Renal carcinoma;Research;Research Personnel;Risk;Role;Stomach;Testing;The Cancer Genome Atlas;Thinness;Thyroid Gland;Time;Training;Triglycerides;United States;Utah;Uterus;Women's Health;bariatric surgery;cancer diagnosis;cancer genomics;cancer risk;cancer survival;cancer type;career;cell injury;cohort;diabetes risk;disorder prevention;disorder risk;epidemiology study;fasting glucose;follow-up;high risk;improved;improved outcome;male;malignant breast neoplasm;medical schools;meningioma;mortality;obesity risk;population based;pre-doctoral;prevent;prospective;resilience;response;risk stratification;sex;subcutaneous;waist circumference Metabolic health phenotype accelerated aging and obesity-related cancer risk and mortality NARRATIVEObesity-related cancers type 2 diabetes mellitus and cardiovascular diseases and their co-occurrence arethe biggest killers in the United States dramatically impacting quality of life and longevity. The proposed studywill evaluate how the health of your metabolism regardless of body weight impacts aging in your cells risk ofcancer and cancer survival. Findings could support changes in clinical management of obesity-related cancersto focus on diabetes and accelerated aging prevention and help to better identify those at risk for diseaseprevention. NCI 10677020 7/24/23 0:00 RFA-CA-20-048 5K00CA264400-03 5 K00 CA 264400 3 "DAMICO, MARK W" 9/21/21 0:00 7/31/26 0:00 ZCA1-SRB-H(M1) 16076938 "KARRA, PRASOONA " Not Applicable 2 OTHER BASIC SCIENCES 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 98771 NCI 91455 7316 PROJECT SUMMARYObesity-related cancers type 2 diabetes mellitus and cardiovascular disease are characterized by a chronicbreakdown in metabolic functioning that impacts quality of life physical functioning and longevity. Thoughobesity plays a pivotal role in the etiology of at least 13 cancer types the traditional metric for measuringobesity body mass index (BMI) is imperfect and may fail to identify a third of individuals at risk of thesecancers owing to metabolic dysfunction. While accumulated cellular damage and abrogated resiliencemechanisms are part of the natural aging process damage accumulation and dysregulation of homeostasismechanisms potentially driven by metabolic dysfunction may lead to accelerated biological aging that hasrecently been linked to cancer risk and survival. A better understanding of the relationship between metabolichealth regardless of BMI with accelerated aging and cancer is needed to inform who to target for preventionefforts. The long-term goal of this application is to understand how metabolic dysfunction influences biologicalaging and risk of cancer at all levels of adiposity to inform interventions that prevent or delay these deadlydiseases. The central hypothesis is that metabolic dysfunction independent of obesity is associated withaccelerated biological aging and obesity-related cancers. Aim 1 (F99 phase) will leverage data from the UtahObesity Study to measure the association between metabolic dysfunction (metabolic syndrome and diabetes)across BMI categories (i.e. metabolic health phenotype) and risk of developing obesity-related cancer(esophageal gastric colorectal liver gallbladder pancreas uterus ovary thyroid meningioma kidney andbreast cancers and multiple myeloma). In the Womens Health Initiative (WHI) diabetes status at cancerdiagnosis will be measured in relation to cancer-specific and overall survival. This research will be extended inAim 2 (K00 phase) where metabolic health phenotype will be studied in relation to accelerated biological agingand obesity-related cancer risk. In Aim 2a data from the prospective WHI Jackson Heart Study Health andRetirement Study Framingham Heart Study and others will be used to measure the extent to whichaccelerated biological age explains the association of metabolic health phenotype with obesity-related cancerrisk. In Aim 2b using data from The Cancer Genomic Atlas (TCGA) cohort accelerated biological aging will beevaluated in relation to survival after obesity-related cancer diagnosis. The pre-doctoral to post-doctoralcandidate will expand upon her didactic and experiential training in biostatistics epidemiology aging andepigenetics research both at the University of Utah Huntsman Cancer Institute and Yale School of Medicine.Practical training will be obtained in human metabolism biostatistics epidemiology aging and epigeneticsresearch. The proposed project will help to better identify those at risk of obesity-related cancers and supportchanges in clinical cancer management to support diabetes and accelerated aging prevention. 98771 +No NIH Category available Abstinence;Adult;American;Belief;Biochemical;Contracts;Costs and Benefits;Counseling;Data;Economics;Education;Effectiveness;Eligibility Determination;Evidence based practice;Exclusion;Exposure to;Group Homes;Health Care Costs;Home;Hour;Human;Hybrids;Intervention;Low Income Population;Low income;Measures;Medicaid;Participant;Policies;Population;Poverty;Practical trial;Prevalence;Provider;Psychological Stress;Randomized;Readiness;Recommendation;Reporting;Research;Services;Smoke-free home;Smoker;Smoking;Smoking treatment;Societies;Subgroup;Telephone;Testing;Tobacco;Treatment Cost;Uninsured;cigarette smoke;comparison intervention;cost effectiveness;design;economic cost;environmental tobacco smoke;evidence base;follow-up;home smoking ban;hybrid type 2 design;long term abstinence;non-smoker;policy implication;programs;quitline;randomized trial;recruit;service providers;smoking prevalence;smoking-related cancer;treatment services Expanding population-level interventions to help more low-income smokers quit NarrativeLow-income Americans are much more likely to smoke cigarettes than other population sub-groups and sufferserious and costly health consequences because of it. Telephone quitlines that are designed to help low-income smokers only provide services to those who are ready to quit in the next 30 days but 70-80% of low-income smokers are NOT ready to quit in the next 30 days. This study will test a new strategy that helps low-income smokers get ready to quit by combining a proven Smoke Free Homes program with Quitline services. NCI 10677019 6/26/23 0:00 PAR-18-559 5R01CA235773-05 5 R01 CA 235773 5 "MAYER, MARGARET ELIZABETH" 7/23/19 0:00 6/30/24 0:00 Interventions to Prevent and Treat Addictions Study Section[IPTA] 1911852 "KREUTER, MATTHEW W." "MCQUEEN, AMY " 1 SOCIAL SCIENCES 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF SOCIAL WELFARE/WORK 631304862 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 552705 NCI 386113 166592 AbstractThere is an urgent need to engage more low-income smokers in activities that lead to quitting. The currentstandard of practice for population-level tobacco treatment is phone-based cessation counseling delivered bystate tobacco quitlines. But quitline services are restricted to smokers who are ready to quit in the next 30days a criterion met by only 20-30% of low-income smokers. Thus current population level tobacco treatmenthas nothing to offer 70-80% of low-income U.S. smokers. Based on extensive preliminary research by ourstudy team we assert that offering a pre-cessation intervention Smoke Free Homes to low-incomesmokers who are not yet ready to quit will: (1) engage more smokers in using proven interventions; (2)increase their readiness to quit and quit attempts; (3) reduce the number of cigarettes they smoke per day; and(4) increase cessation. These benefits will accrue in addition to reducing exposure to harmful secondhandsmoke for non-smokers in the home. In a Hybrid Type 2 randomized trial 1980 low-income smokers from ninestates with high smoking prevalence will be recruited from 2-1-1 helplines to receive either current standardpractice (Quitline) or expanded services (Quitline + Smoke Free Homes) both delivered by Optum the largestU.S. quitline service provider. In the latter condition smokers will be offered cessation counseling first just likecurrent standard practice but those who decline will then be offered Smoke Free Homes. At 3-month follow-up those in the latter condition who accepted quitline services but did not quit will be offered Smoke FreeHomes and those that accepted Smoke Free Homes but did not quit will be offered quitline services. Theeffectiveness portion of the Hybrid Type 2 design (Aim 1) will use intent-to-treat analyses to compare groupdifferences at 3- and 6-month follow-up in 7- and 30-day point prevalence abstinence with biochemicalverification as well as 24-hour quit attempts and cigarettes smoked per day. The implementation portion of theHybrid Type 2 design (Aims 2-3) will measure smokers acceptance and use of the interventions as well ascost-effectiveness and cost-benefits of adding Smoke Free Homes to quitline services. With rates of smokingand smoking-related cancers much higher in low-income populations and treatment costs exceeding tens ofbillions of dollars annually in Medicaid alone this large-scale practical trial will provide strong evidence withhigh external validity to answer an important policy question : Will changing the standard practice forpopulation-level treatment of smoking result in increased cessation in low-income populations? 552705 +No NIH Category available Acquaintances;Address;Affect;Appointment;Attention;Brain Neoplasms;Cancer Center;Caregiver Burden;Caregiver support;Caregiver well-being;Caregivers;Caring;Catalogs;Clinic Visits;Consultations;Data;Diagnosis;Disease;Disease Progression;Distress;Dose;Effectiveness of Interventions;Electronics;Enrollment;Face;Family;Family Caregiver;Feedback;Feeling;Foundations;Friends;Funding;Future;Goals;Health;Healthcare Systems;Home;Hospital Costs;Hospitalization;Impaired cognition;Intervention;Interview;Knowledge;Literature;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Methods;Modeling;National Cancer Institute;Online Systems;Outcome;Outpatients;Participant;Patient Care;Patient Participation;Patients;Personal Satisfaction;Personality;Persons;Play;Population;Population Intervention;Problem Solving;Psychosocial Assessment and Care;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Reporting;Research;Resources;Role;Services;Social Network;Social Work;Social support;Source;Technology;Telephone;Testing;Training;Underrepresented Populations;Underserved Population;Visit;Visualization;Waiting Lists;Work;acceptability and feasibility;behavior change;caregiver education;caregiving;coping;design;efficacy evaluation;efficacy testing;experience;follow-up;health care service utilization;high risk;implementation intervention;improved;informal caregiving;informal support;intervention effect;intervention participants;mortality;navigator intervention;outreach;patient navigator;patient population;programs;prospective;psychosocial;public health priorities;recruit;service utilization;social organization;support network;therapy design;treatment planning;web app;web-based tool A Stepped-care Psychosocial Intervention for Brain Tumor Family Caregivers PROJECT NARRATIVEThe impact of cancer extends beyond the patient to the millions of informal family caregivers and the networksof people who they rely on for support. In this proposal we test an intervention designed to help familycaregivers of patients with primary malignant brain tumors identify and leverage existing sources of supportand connect with formal support resources as needed. We hypothesize our intervention will improve familycaregiver and patient well-being and health care utilization as well as provide a foundation of knowledge aboutcaregiving in this population. NCI 10677018 6/8/23 0:00 PAR-18-246 5R01CA236034-05 5 R01 CA 236034 5 "MOLLICA, MICHELLE A" 7/1/19 0:00 6/30/24 0:00 Special Emphasis Panel[ZRG1-RPHB-R(56)R] 6488699 "BYRNE, MARGARET M" "REBLIN, MAIJA " 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 380441 NCI 236701 143740 PROJECT SUMMARY/ABSTRACTPrimary malignant brain tumor is associated with a high risk of family caregiver burden which can negativelyimpact caregiver and patient well-being. Caregivers play an important role in caring for patients at home but ifcaregivers become too overwhelmed to care for the patient patient health care utilization can increase. Thereis strong evidence that high quality social support is a vital component to caregiver well-being but barriersexist to caregivers receiving informal and formal support and few interventions for this population. Ourobjective is to address the caregiver social support gap by implementing a stepped-care intervention tosupport informal family caregivers (FCGs). We use a blended approach of technology and personal contact toleverage informal social support and connect caregivers to formal support services with the web-basedelectronic Social Network Assessment Program (eSNAP) and a Caregiver Navigator. We hypothesize that byintervening with the caregiver to address informal and formal support needs we will improve caregiver andpatient well-being and reduce patient health care utilization. Our Specific Aims are to: 1) Determine theefficacy of eSNAP + Caregiver Navigator support intervention on FCG well-being; 2) Determine the efficacy ofeSNAP + Caregiver Navigator on patient well-being and health care utilization; and 3) Identify key interventioncomponents using mixed methods to inform future intervention implementation. To achieve these aims wewill conduct a prospective longitudinal randomized controlled trial of the 8-week eSNAP + Caregiver Navigatorintervention. The intervention is targeted to family caregivers of patients with a primary diagnosis of malignantbrain cancer but both caregivers and patients will participate in the study. Participants will be recruited at thepatient's first treatment planning appointment and randomly assigned to either the intervention condition or to awaitlist control condition. Caregivers in the intervention condition will receive access to eSNAP a web-basedapp to help caregivers catalogue and visualize informal social network resources. eSNAP also provides a basicresource list. eSNAP will alert a trained Caregiver Navigator to contact participants who demonstrate a lack ofsupport. The Caregiver Navigator will problem-solve with caregivers and make arrangements/referrals inongoing phone consultations. The Caregiver Navigator's goal is to help caregivers identify and utilize informaland formal sources of support to place caregivers on a successful trajectory of support. Questionnaires will becollected from all participants at enrollment and 8 weeks coinciding with patient clinic visits. Caregivers willalso complete questionnaires at 4 weeks and a short debriefing interview at 8 weeks. Waitlist participants maythen receive the intervention and will be asked to complete questionnaires mirroring intervention participants.Follow-up data will be collected at 6 months and 1 year. The proposed intervention supports caregivers toimprove well-being and optimize health care utilization in the dyad while also providing important foundationalwork in understudied FCGs and patients with primary malignant brain tumor. 380441 +No NIH Category available Acute Myelocytic Leukemia;Adverse event;Allogenic;Apical;Apoptosis;Attenuated;Automobile Driving;BCL1 Oncogene;Bone Marrow;Cells;Clinic;Clinical Trials;Correlative Study;Data;Disease Resistance;Dose;Down-Regulation;Drug Kinetics;Dynamin;Endothelial Cells;Endothelium;Energy-Generating Resources;Funding;Future;Growth;Hematopoietic;Hematopoietic stem cells;Homeostasis;Human;Investigation;Investigational New Drug Application;Leukemic Cell;Maximum Tolerated Dose;Membrane Potentials;Metabolic;Metabolism;MicroRNAs;Mitochondria;Molecular;Molecular Mechanisms of Action;Mus;Output;Oxidative Phosphorylation;Patients;Pharmacodynamics;Phase;Phase I Clinical Trials;Population;Principal Investigator;Production;Proteins;Rattus;Reactive Oxygen Species;Recommendation;Refractory;Refractory Disease;Relapse;Resistance;Schedule;Signal Transduction;Small RNA;Source;Stem cell transplant;Testing;Therapeutic;Toxicology;Translating;Transplantation;curative treatments;deprivation;design;exhaustion;experimental study;first-in-human;inhibitor;invention;leukemia;leukemia treatment;leukemic stem cell;mitochondrial membrane;mitochondrial metabolism;nonhuman primate;novel;novel therapeutic intervention;pharmacodynamic model;pharmacokinetics and pharmacodynamics;pharmacologic;phase I trial;prevent;protein biomarkers;safety assessment;self renewing cell;stem cell homeostasis;therapeutically effective Targeting MicroRNAs to Eradicate Leukemia Stem Cells Project Narrative:Acute myeloid leukemia (AML) patients have a poor five-year survival (<30%) likely due to the persistence of avery resistant leukemic cell population called leukemia stem cells (LSCs). We identified a small RNA moleculecalled miR-126 as a potential target in LSCs and have invented and produced a miR-126 inhibitor called miRistento eliminate the otherwise treatment-resistant AML LSCs. We are planning to test this new compound byconducting mechanistic pharmacokinetic pharmacodynamic and toxicology studies followed by a phase 1clinical trial in AML patients with resistant disease. NCI 10677007 7/24/23 0:00 PAR-21-033 5R01CA205247-07 5 R01 CA 205247 7 "HENDERSON, LORI A" 8/1/17 0:00 7/31/27 0:00 Developmental Therapeutics Study Section[DT] 7266595 "KUO, YA-HUEI " "MARCUCCI, GUIDO ; NGUYEN, LE XUAN TRUONG " 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 495641 NCI 281614 214027 PROJECT SUMMARYLeukemia stem cells (LSCs) are at the apex of the acute myeloid leukemia (AML) cellular hierarchy. Thequiescent fraction of LSCs provides a reservoir of self-renewing cells that sustain leukemia growth prevent clonalexhaustion and are treatment resistant; thus eliminating LSCs is the `holy grail' of any anti-leukemia treatment.In previous studies we showed that miR-126 is necessary to maintain a quiescent subfraction of LSCs thatprevent clonal exhaustion. We demonstrated how SPRED1/miR-126 autoregulatory loop in LSCs and in BMendothelial cells (ECs) converge to increase miR-126 levels in LSCs protect them and support leukemia growth.We showed that high miR-126 levels are due to both LSC autonomous mechanisms resulting in enhancedendogenous production and non-autonomous mechanisms through exogenous miR-126 supply from ECs.To deplete miR-126 in LSCs and ECs we designed a novel oligodeoxynucleotide anti-miR-126 inhibitor calledmiRisten. Our data show that pharmacological miR-126 deprivation by miRisten significantly decreases LSCendogenous production of miR-126 and decreases the exogenous supply of endothelial miR-126. The net resultis a significant decrease of miR-126 that damages the homeostasis and activity of LSCs as demonstrated inserial transplant experiments. In addition we now have evidence that miR-126 enhances mitochondrialmetabolism (i.e. oxidative phosphorylation) and mitochondrial dynamics (i.e. mitochondrial fusion) in LSCsthrough SPRED1/ERK/p-BCL-2/NRF2 signaling. Accordingly depletion of miR-126 by miRisten treatmentsignificantly downregulates BCL-2 and disrupts mitochondrial metabolism leading to increased levels of reactiveoxygen species and apoptosis of LSCs. In addition miRisten disrupts LSC mitochondrial function by upregulatingthe dynamin related protein 1 (DRP1) inducing mitochondrial fission decreasing mitochondrial membranepotential and inducing expression of mitophagy marker proteins. Since mitochondria-centered metabolism isthe main metabolic energetic source for LSCs we propose to dissect how miRisten exploits the mitochondrialmetabolic vulnerability as a novel mechanism of action to eliminate LSCs. Furthermore after conductingInvestigational New Drug application (IND)-enabling pharmacokinetic pharmacodynamic and toxicology studieswe will rapidly translate miRisten from bench to beside with a first-in-human phase 1 clinical trial of miRisten inpatients with relapsed/refractory (r/r) AML. The central hypothesis of this proposal is that miRisten targets miR-126-depended metabolic vulnerability of LSCs and will provide a novel therapeutic approach for LSC eliminationin AML. We propose the following Specific Aims (SAs): SA#1: Determine the mechanisms of miRisten-inducedmitochondrial metabolic vulnerability in LSCs. SA#2: Conduct pharmacokinetic pharmacodynamic efficacyand toxicology studies of miRisten to inform dose and schedule selection for human studies. SA#3: Conducta first-in-human phase 1 trial of miRisten in patients with r/r AML. This project will translate novel discoveries onmiR-126 into the clinic by conducting preclincal studies that culminate in a first-in-human trial of miRisten. 495641 +No NIH Category available Acceleration;Address;Anxiety;Behavior Therapy;Breast Cancer Prevention;CDK4 gene;Cancer Survivor;Cancer Survivorship;Clinical;Clinical Trials;Cognitive Therapy;Computers;Data;Deterioration;Development;Diagnosis;Dimensions;Ecological momentary assessment;Effectiveness;Environment;Exclusion;Fatigue;Female;Future;General Population;Goals;Individual;Information Systems;Intervention;Interview;Life;Literature;Malignant Neoplasms;Measurement;Mental Depression;Metastatic breast cancer;Methods;Monitor;Nature;Neoplasm Metastasis;Newly Diagnosed;Oral;Outcome;Pain interference;Participant;Patient Outcomes Assessments;Pattern;Persons;Pharmacologic Substance;Physical Function;Population;Protocols documentation;Quality of Life Assessment;Quality of life;Recurrence;Reporting;Research;Resources;Sampling;Severities;Supportive care;Symptoms;Testing;Time;Well in self;breast cancer diagnosis;cancer therapy;chemotherapy;clinically significant;comorbidity;design;efficacy testing;evidence base;experience;functional decline;improved;inhibitor;innovation;interest;malignant breast neoplasm;mindfulness intervention;physical symptom;preference;programs;psychological symptom;symptom management;symptomatic improvement Ecological Momentary Assessment of Quality of Life in Metastatic Breast Cancer PROJECT NARRATIVEMetastatic breast cancer is treatable but incurable; for this reason quality of life is a critical outcome. The pro-posed study will use an ecological momentary assessment (EMA) measurement-burst protocol to assess qualityof life among females with metastatic breast cancer. These unique data will increase our understanding of qualityof life in this population and accelerate the development of behavioral interventions specifically designed formetastatic breast cancer ultimately enabling us to intervene in ways that improve quality of life and reducesuffering. NCI 10677003 8/21/23 0:00 PAR-20-052 5R03CA273489-02 5 R03 CA 273489 2 "JENSEN, ROXANNE ELAINE" 8/4/22 0:00 7/31/24 0:00 ZCA1-RTRB-B(M1)S 14149143 "CONLEY, CLAIRE C" Not Applicable 98 NONE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC UNIVERSITY-WIDE 200570001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 78000 NCI 50000 28000 PROJECT SUMMARYDespite advances in breast cancer prevention and treatment thousands of people are either newly-diagnosedwith or progress to metastatic breast cancer (MBC). MBC can lead to significant decrements in quality of life(QoL) a multidimensional construct including physical and emotional well-being. Given the incurable nature ofMBC QoL is a critical outcome. Furthermore data from our group and others demonstrate that individuals livingwith MBC have unmet needs related to QoL and desire MBC-specific QoL resources and interventions. Howeverlittle is known about changes in QoL over time in those with MBC. The longitudinal QoL data that do exist pri-marily come from pharmaceutical clinical trials and have two key limitations. First clinical trials may includeselected higher-functioning individuals with no significant comorbidities; thus findings may not generalize to thebroader MBC population. Second clinical trials typically assess QoL at time points that align with treatmentcycles. There is little data on changes in QoL between cycles of treatment. The proposed research addressesthis gap in the literature by collecting longitudinal QoL data from people living with MBC. In-depth data on QoLconcerns and intervention preferences of individuals with MBC will allow us to adapt and apply existing behav-ioral interventions to this group who are often excluded from cancer survivorship studies. Our long-term goal isto support the experience of those living with MBC through behavioral interventions. However additional dataon QoL are needed in order to identify the optimal content and timing of such interventions. Thus the overallobjective of this application is to collect in-depth longitudinal observational data on QoL in MBC. To achieve thisobjective we will pursue two specific aims using mixed methods. In Aim 1 we will use an innovative ecologicalmomentary assessment (EMA) measurement-burst protocol to collect QoL data in a sample of females withMBC (N=120). EMA involves repeated sampling of subjects current experiences in real time in subjects naturalenvironments. The measurement-burst design incorporates short periods (i.e. days) of intensive assessmentsthat are repeated longitudinally over longer intervals (i.e. weeks). In the proposed study participants will com-plete EMA bursts (3 prompts/day) once per week for four consecutive weeks. EMA bursts will assess overallQoL and symptom severity (anxiety depression fatigue pain interference and physical function). In Aim 2 wewill conduct in-depth individual qualitative interviews with a convenience sample of Aim 1 participants (N=10) toassess participants experiences with the EMA protocol and their preferences for a future intervention. We willalso explore the potential impact of self-monitoring on participants lived experiences with MBC. The proposedstudy will provide pilot data for a future trial to adapt an existing behavioral intervention targeting QoL amongcancer survivors for metastatic breast cancer and test the efficacy of the adapted intervention. This program ofresearch has the potential to increase our understanding of QoL in this population ultimately enabling us toidentify targeted intervention strategies to improve QoL and reduce suffering. 78000 +No NIH Category available 3-Dimensional;3D Print;Accounting;Address;Algorithms;Anatomy;Area;Biopsy;Bronchoscopes;Bronchoscopy;Cancer Etiology;Cessation of life;Clinical;Clinical Skills;Complication;Computational algorithm;Computer Simulation;Computer Vision Systems;Coupled;Data;Data Set;Devices;Diagnosis;Diagnostic;Diameter;Disease;Distal;Drops;Early Diagnosis;Electromagnetics;Ensure;Environment;Equipment;Family suidae;Freedom;Frequencies;Future;Health Benefit;Hour;Human;Individual;Lesion;Localized Disease;Localized Lesion;Location;Lung;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Medical;Medicine;Mentors;Minor;Modeling;Morbidity - disease rate;Motion;Needles;Neoplasm Metastasis;Neural Network Simulation;Nodule;North Carolina;Operative Surgical Procedures;Patient observation;Patients;Physicians;Positioning Attribute;Preparation;Procedures;Psyche structure;Public Health;Puncture procedure;Radial;Reproducibility;Research;Robot;Robotics;Scientist;Secondary to;Site;Survival Rate;System;Techniques;Technology;Time;Tissues;Trachea;Training;United States;Universities;Woman;Work;X-Ray Computed Tomography;cancer diagnosis;career;chest computed tomography;computer science;data-driven model;deep neural network;experience;experimental study;follow-up;improved;in vivo;laboratory experiment;large datasets;lung cancer screening;lung lesion;machine learning model;men;millimeter;minimally invasive;mortality;real time model;screening guidelines;simulation;skills;software development;success;tool;ultrasound;virtual;virtual human Real-Time Bronchoscope Localization Using Machine Learning To Improve Lung Cancer Diagnosis Project NarrativeLung cancer continues to be the leading cause of cancer-related deaths in both men and women in the UnitedStates accounting for over 140000 deaths per year (nearly one quarter of all cancer deaths). Bronchoscopyis currently the safest least invasive and least expensive diagnostic option but yields conclusive results only50-60% of the time forcing many patients to consider more invasive procedures or leading to delayed diagnoses.We propose to develop computer algorithms that address localization limitations with existing bronchoscopes toimprove diagnostic yield and achieve earlier lung cancer diagnosis in more patients. NCI 10676966 8/25/23 0:00 PA-21-049 5F30CA265234-03 5 F30 CA 265234 3 "DAMICO, MARK W" 9/1/21 0:00 5/31/26 0:00 Special Emphasis Panel[ZRG1-F15-P(20)L] 15179831 "FRIED, INBAR " Not Applicable 4 INTERNAL MEDICINE/MEDICINE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 45856 NCI 45856 0 Project Summary/AbstractLung cancer 5-year survival rates drop from 61% for early stage diagnosis to just 6% for late stage diagnosis.Currently fewer than 1 in 5 cases are diagnosed at an early stage. The increasing frequency of chest CT scansand changes in lung cancer screening guidelines are expected to increase the number of incidentally discoveredlung lesions representing an opportunity for earlier lung cancer diagnosis. Bronchoscopy is currently the safestleast invasive and least expensive diagnostic option but its poor diagnostic yield greatly limits its proceduralbenet. Even when advanced techniques like radial endobronchial ultrasound and electromagnetic navigationare used the diagnostic yield is just 50-60%. This is primarily due to challenges with intraoperative localizationof the bronchoscope prior to needle deployment. Additionally access to these techniques is limited because theyrequire expensive equipment and unique expertise. Efforts relying on the bronchoscope's built-in camera requireno additional equipment or specialization but have struggled with generalizability across individuals in part dueto limited data availability and assumptions about airway features. The objective of this proposal is to improve the success rate of traditional bronchoscopes by addressing limita-tions in intraoperative localization using a data-driven model that is robust to differences in human anatomy. Thiswork has potential for signicant public health benet by (1) increasing early lung cancer detection (2) reducingmorbidity and mortality by reducing the number of invasive procedures and (3) making minimally invasive bron-choscopy more accessible in areas without expert bronchoscopists. The proposed work will be accomplished viatwo Specic Aims. In Aim 1 a dataset will be generated of virtual and real bronchoscopy videos with video-framematched six degrees-of-freedom poses (position and orientation in three-dimensions) of the bronchoscope's dis-tal tip. This data will be made publicly available as the rst large dataset of its kind to promote future research andreproducibility. In Aim 2 a real-time bronchoscope localization model will be developed using advances in ma-chine learning including deep neural networks that have shown success in camera localization for non-medicalapplications. These models will regress the pose of the bronchoscope's distal tip using current and past videoframes of the bronchoscope's built-in camera. The clinical utility of the system will be evaluated in simulation 3Dprinted lung phantoms and ex-vivo porcine lung experiments. The research tightly coupled clinical experienceand associated training plan will provide a unique interdisciplinary skill-set in computer science medical roboticsand procedural medicine. The outstanding research and clinical environment for this training at the University ofNorth Carolina at Chapel Hill ensures exceptional preparation for a career conducting cutting-edge research asa physician-scientist in medical robotics. 45856 +No NIH Category available Address;Age;Albumins;Apoptosis;Automobile Driving;Cancer Etiology;Carcinoma;Cell Death;Cell Death Induction;Cells;Cessation of life;Complex;Cytoprotection;DNA Damage;Disease;Disease Progression;Early Diagnosis;Etiology;Fatty Liver;Female;Fibrosis;Functional disorder;Genes;Genetic Transcription;Genomic Instability;Goals;HAF deficiency;Hepatitis;Hepatocyte;Heterozygote;Human;Hypoxia;Hypoxia Pathway;In Vitro;Incidence;Infiltration;Inflammatory;Inflammatory Response;Link;Liver;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of liver;Measures;Mediating;Mediator;Medical;Metabolic;Molecular;Monitor;Mus;Neoplastic liver;Nuclear;Obesity;Obesity Epidemic;Outcome;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Physiological;Play;Prevalence;Primary Malignant Neoplasm of Liver;Primary carcinoma of the liver cells;Prognostic Marker;Proteins;Role;Sampling;Severities;Signal Transduction;Small Interfering RNA;Stress;TNF gene;TNFRSF5 gene;Testing;Time;Tissues;Transfection;Transforming Growth Factor beta;Tumor Necrosis Factor-Beta;Tumor Suppressor Proteins;Viral hepatitis;cytokine;diagnostic strategy;dietary;effective therapy;fatty liver disease;in vivo;insight;knock-down;liver inflammation;liver injury;male;metabolic-associated fatty liver disease;mortality;mouse model;neoplastic;new therapeutic target;nonalcoholic steatohepatitis;novel;novel diagnostics;novel therapeutic intervention;overexpression;p65;potential biomarker;predictive marker;prevent;response;screening;therapeutic target;therapy resistant;treatment response;treatment strategy;ubiquitin-protein ligase A Role for the Novel HAF-NFkappaB Axis in Driving Obesity-Associated Liver Cancer The obesity epidemic has led to the increased incidence of fatty liver disease that can lead to hepatocellularcarcinoma (HCC) which is the 4th leading cause of cancer deaths in the US. There are no effective treatmentsfor this disease and the molecular pathways that lead to HCC in the context of obesity are not well understood.The studies proposed here will investigate a novel molecular pathway mediated by HAF which protects cellsagainst the stresses associated with fatty liver disease that can lead to HCC and thus reveal new treatmentstrategies. NCI 10676965 8/21/23 0:00 PA-20-185 5R01CA262262-02 5 R01 CA 262262 2 "MAAS, STEFAN" 9/1/22 0:00 8/31/27 0:00 Tumor Cell Biology Study Section[TCB] 10775792 "KOH, MEI YEE " Not Applicable 1 PHARMACOLOGY 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF PHARMACY 841129049 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 421432 NCI 287379 134053 Hepatocellular carcinoma (HCC) the predominant primary cancer of the liver is 4th leading cause of cancerdeaths and the fastest growing malignancy in the US. Advanced-stage HCC remains largely incurable due to adismal response rate (<20%) and therapeutic resistance. The current obesity epidemic has been associated withthe rising prevalence of metabolic (dysfunction) associated fatty liver disease (MAFLD) and its inflammatorycomponent non-alcoholic steatohepatitis (NASH) which can lead to HCC. MAFLD-HCC incidence is increasingdramatically underscoring an unmet medical need for new diagnostic and treatment strategies. Here wedescribe a novel tumor suppressor role of the Hypoxia-Associated Factor HAF in MAFLD-HCC. Both globalhaploinsufficiency and hepatocyte-specific deletion of HAF in mice result in HCC with hallmarks of NASHincluding severe steatosis with hepatocyte degeneration (hepatocyte ballooning) fibrosis and increasedinflammatory cell infiltration. HAF loss in both mouse models or by siRNA transfection in HCC cells is associatedwith decreased activation of the p65/p50 NF-B transcriptional subunits and in decreased levels of theirupstream regulators TAK1 and NEMO. Endogenous HAF forms a complex with NEMO and TAK1 suggestingthat HAF modulates the NF-B pathway by directly modulating the stability of these proteins potentially throughHAFs E3 ubiquitin ligase activity. HAF knockdown was associated with increased spontaneous apoptosiswhereas HAF overexpression protected cells against TNF-induced cell death suggesting that HAF may play atumor suppressor role by protecting cells against death associated with liver inflammation (hepatitis) that canlead to HCC. Indeed HAF levels are suppressed by conditions prevalent during hepatitis such as hypoxia andelevated TNF or TGF- whereas HAF are increased by DNA damage suggesting that HAF may contribute toNF-B activation in response to genomic instability in pre-neoplastic hepatocytes. Significantly HAF was highlyexpressed in most cases of human hepatitis but was undetectable in 94% of human HCCs examined (65 cases).Thus our hypothesis is that HAF plays a novel tumor suppressor role in HCC by facilitating NF-B activationthat promotes the survival of hepatocytes during hepatitis. Suppression of HAF by hypoxia or inflammatorycytokines during hepatitis results in increased cellular turnover that drives progression to NASH and HCC. Ouroverall goal is to identify new predictive/prognostic biomarkers or therapeutic targets for HCC particularly thoserelevant to MAFLD-HCC. In Aim 1 we will test the hypothesis that HAF activates the NF-B pathway bymodulating the stability of TAK1 and NEMO and thus identify the molecular mechanisms regulating the HAF-NF-B axis. In Aim 2 we will test the hypothesis that HAF protects cells from excessive cell death during hepatitisthus preventing progression to NASH and HCC. In Aim 3 we will test the hypothesis that HAF deregulation isassociated with progression to HCC by investigating HAF expression in > 500 patient samples to determine theassociation of HAF and its downstream targets to HCC initiation and progression or to treatment response. 421432 +No NIH Category available AIDS-Related Lymphoma;Acquired Immunodeficiency Syndrome;Address;African Burkitt's lymphoma;Automobile Driving;B lymphoid malignancy;B-Lymphocytes;Binding;CRISPR screen;Cells;Central Nervous System Lymphoma;Cessation of life;ChIP-seq;Chromatin Loop;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;DNA;Data;Dependence;Development;Disease;Elderly;Enhancers;Epigenetic Process;Epstein-Barr Virus Nuclear Antigens;Epstein-Barr Virus latency;Genes;Genomics;Goals;Growth;HIV;HIV Infections;Highly Active Antiretroviral Therapy;Hodgkin Disease;Human;Human Herpesvirus 4;IRF4 gene;Immunocompromised Host;Individual;LMP1;Large-Cell Immunoblastic Lymphoma;Licensing;Lymphomagenesis;Lymphoproliferative Disorders;MYC gene;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Mediating;Membrane Proteins;Modeling;NF-kappa B;Nuclear;Nuclear Antigens;Nuclear Translocation;Oncogenes;Oncogenic;Oncogenic Viruses;Oncoproteins;Population;Proteomics;Rest;Risk;Role;Site;Therapeutic;Transcription Factor AP-1;Viral;Viral Oncogene;Viral Proteins;Virus;Virus Activation;antagonist;c-myc Genes;cancer cell;cell growth;cell transformation;chaperonin;cofactor;gammaherpesvirus;genome-wide;infected B cell;insight;large cell Diffuse non-Hodgkin's lymphoma;lymphoblastoid cell line;mortality;novel;novel therapeutic intervention;nuclear reprogramming;post-transplant;programs;promoter;restraint;therapeutic target;transcription factor;transcriptome sequencing;transforming virus Epstein-Barr virus LMP1 mediated oncogenicity NarrativeEpstein-Barr virus (EBV) is a leading cause of disease in HIV-infected individuals in theU.S. These studies seek to identify how key viral proteins reprogram infected B cells tolock on a particularly important oncogene. A detailed understanding of this criticalaspect of the EBV/host cell relationship may guide novel therapeutic approaches. NCI 10676959 8/9/23 0:00 PA-16-426 5R01CA228700-05 5 R01 CA 228700 5 "DASCHNER, PHILLIP J" 9/19/19 0:00 8/31/24 0:00 AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC] 9613146 "GEWURZ, BENJAMIN ELISON" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 409463 NCI 228750 180713 Abstract Gamma-herpesvirus-driven lymphoproliferative disorders cause significant mortality in HIV+populations. Despite highly active antiretroviral therapy HIV+ individuals remain at elevated riskfor Epstein-Barr virus (EBV)-associated B-cell cancers. EBV is identified in >40% ofimmunoblastic diffuse large B-cell lymphomas and nearly 100% of Hodgkin lymphoma andprimary central nervous system lymphomas in HIV+ individuals. EBV transforms human B-cellsinto lymphoblastoid cell lines (LCL) a major model of EBV-driven immunoblastic lymphomas ofimmunosuppressed hosts. Yet key EBV-induced host dependency factors remain to beelucidated. We therefore used systematic approaches to gain insights into key EBV oncoproteintargets. We used: 1) Genome-wide CRISPR screens to identify host dependency factorsdownstream of EBV oncoproteins; 2) Multiplexed mass spectrometry to create a proteomic mapof EBV-mediated B-cell transformation; and 3) ChIP-seq to identify EBV oncoprotein hostgenomic targets which found the first viral super-enhancers (SE) comprised of 5 LMP1-activated NF-kB and 4 EBV nuclear antigen subunits. These converged on the transcriptionfactors BATF IRF4 and IRF2 as key LMP1-targeted host dependency factors. Our preliminarystudies indicate that BATF/IRF4 and IRF2 complexes have key dependency factor roles in EBVoncoprotein-driven MYC expression necessary for LCL growth and survival. We propose todefine how the interplay between viral oncoprotein superenhancers BATF/IRF4 and IRF2complexes drive MYC expression in lymphoblastoid B-cells. Our Specific Aims are to (1)Identify how EBV oncoproteins activate dependency factor BATF/IRF4 complexes to induceMYC; (2) Identify key BATF/IRF4 roles in EBV oncoprotein-induced MYC induction inlymphoblastoid B-cells; and (3) Identify how the viral SE-driven dependency factor IRF2 isnecessary to support lymphoblastoid cell MYC expression. These studies specifically addressPA-16-426 by advancing understanding of development progression and treatment ofmalignancies observed in individuals with underlying HIV infection. The proposed studies areexpected to contribute to understanding of how EBV oncoproteins and key genetically-defineddownstream host dependency factors reprogram lymphoblastoid cell MYC expression. EBVoncoproteins may not be druggable but SE and IRF4 are increasingly therapeutic targets. Sinceviral oncoprotein-induced MYC expression is critical for EBV-transformed B-cell growth thelongterm goal of these studies is to support rational approaches to restrain viral oncogenesubversion of MYC. 409463 +No NIH Category available Academy;Address;Adoption;Area;Automobile Driving;Award;BRAF gene;BRCA1 gene;BRCA2 gene;Clinic;Clinical;Clinical Data;Collection;Communication;Complex;Data;Disease;Disparity;Documentation;Early Diagnosis;Engineering;Epidermal Growth Factor Receptor;Evidence based practice;Exhibits;Family;Family health status;Feasibility Studies;Genetic;Genetic Heterogeneity;Genetic Services;Genomic medicine;Genomics;Goals;Health;Heritability;Heterogeneity;Individual;Investigation;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Medicine;Methods;Modeling;Molecular;Molecular Profiling;Multiple Myeloma;Mutation;Oncogenes;Outcome;Patients;Phase;Phenotype;Population;Positioning Attribute;Postdoctoral Fellow;Preparation;Preventive care;Primary Care;Prognosis;Publications;Recommendation;Recording of previous events;Reporting;Research;Research Personnel;Research Project Grants;Research Technics;Risk;Risk Assessment;Screening for cancer;Signal Transduction;Solid;Somatic Mutation;Subgroup;Training;Translating;Variant;Work;bridge program;cancer care;cancer genetics;cancer genomics;cancer prevention;cancer risk;cancer therapy;career;clinical implementation;clinical practice;combat;evidence based guidelines;experience;gene discovery;genetic information;genetic pedigree;genetic testing;genome sciences;genome wide association study;high risk;high risk population;implementation science;implementation study;improved;individualized medicine;melanoma;model organism;novel;personalized care;post-doctoral training;pre-doctoral;primary care provider;primary care setting;rare variant;risk variant;screening;screening guidelines;segregation;skills;translational genomics;treatment response;tumor;tumor heterogeneity;user centered design Genetics of Common Cancers: Discovery to Implementation My career goal is to become an independent researcher leading a program that bridges genetic discovery andimplementation to personalize common-cancer prevention and treatment. The F99 phase of this award will buildon my expertise in genetic discovery by expanding my skill set to tumor genomics and will prepare me for mypostdoctoral research direction through the investigation of family-health history in primary care. The K00 phaseof this award will build my expertise in implementation science for genomic medicine by investigating thefeasibility of implementing proven risk communication approaches in primary care settings. NCI 10676955 8/30/23 0:00 RFA-CA-18-001 5K00CA234943-06 5 K00 CA 234943 6 "DAMICO, MARK W" 9/10/18 0:00 8/31/24 0:00 ZCA1-TCRB-T(O1) 14152274 "GRIFFIN, ROSALIE " Not Applicable 1 Unavailable 6471700 Y2K4F9RPRRG7 6471700 Y2K4F9RPRRG7 US 44.02432 -92.46011 4976101 MAYO CLINIC ROCHESTER ROCHESTER MN Other Domestic Non-Profits 559050001 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Other Research-Related 2023 102254 NCI 94680 7574 My ultimate goal is to become an independent cancer researcher with a program that bridges genetic discoveryand implementation science for common and complex cancers. My predoctoral training in genomic discoveryand my postdoctoral direction in implementation science will build solid research pillars to support myindependent research program bridging translational genomic science. My F99 training will provide expertise ingenomic discovery by tackling critical barriers that exist for common and complex cancers including: germlinegenetic and tumor heterogeneity and mapping functional variants for genomewide association studies (GWAS)loci. Cancers are phenotypically complex with multiple germline risk variants and tumors that exhibit differentmolecular profiles. These heterogeneities complicate studies attempting to identify factors influencing riskprognosis and response to therapies or other clinical outcomes. GWASs have identified many significantcommon low-risk loci but the functional variants driving GWAS signals are largely unmapped. Further the vastmajority of heritability is unexplained and rare variants are largely undiscovered. In my recent first-authorpublication I propose a novel method to address germline genetic heterogeneity in high-risk pedigree studies. Iapplied this method to myeloma to discover the first segregating risk variants for the disease (Waller et al PLoSGenetics 2018). I have subsequently expanded the approach to identify overlapping evidence from multiplepedigrees uncovering additional regions likely to harbor rare-risk variants (Waller et al in preparation). I havealso investigated strategies to utilize family-based data to map functional variants at GWAS loci (Waller et al inpreparation). During the F99 phase I will complete my graduate work in discovery with novel methods to improvemolecular characterization of myeloma tumors another strategy to combat heterogeneity. My F99 training willalso prepare me for my postdoctoral direction in implementation science by tackling barriers to the use of family-health history (FHx) in primary care. Genetic discoveries are rapidly advancing but personalizing clinicalscreenings and implementing complex patient-specific risk assessments is challenging in todays overwhelmedprimary care settings. FHx is still the most valuable piece of information a clinician and patient have to identifypotential health risks and personalize care. However FHx remains largely underutilized in routine cancerprevention due to low collection and low adoption of evidence-based guidelines. In my F99 I will investigate theimpact of FHx documentation workflows on compliance with cancer screening guidelines. For my postdoctoralwork (K00 phase) I will identify research and training experiences to build expertise in implementation sciencefor genomic medicine. Specifically one research project I could pursue is a feasibility study of implementingproven risk communication approaches in the primary care setting. My background in genomic discovery forcommon cancers will allow me to bring an understanding of genomics to my implementation sciencework and will uniquely position me to bring more complex findings to the clinic when the field is ready. 102254 +No NIH Category available 3-Dimensional;Acetylation;Actins;Acute;Affect;American;Benign;Binding;Biological Models;Biology;CDKN2A gene;Cancer cell line;Cell Cycle;Cell Cycle Progression;Cell model;Cells;Chemoresistance;Combination Drug Therapy;Combined Modality Therapy;Cyclins;Cytotoxic Chemotherapy;Data;Data Set;Development;Disease;Dominant Genes;Down-Regulation;Enhancers;Enzymes;Epigenetic Process;Excision;Flavins;Gene Mutation;Genes;Genetic;Genetic Transcription;Genetically Engineered Mouse;Genome;Goals;Growth;Histones;Human;In Vitro;Invaded;Ionizing radiation;KRAS2 gene;Knockout Mice;Lesion;Libraries;Link;Liver;Lung;Lysine;MADH4 gene;Malignant neoplasm of pancreas;Maps;Mitosis;Mixed Function Oxygenases;Modeling;Mus;Neoplasm Metastasis;Nuclear;Nucleic Acid Regulatory Sequences;Operative Surgical Procedures;Organoids;Outcome;Pancreas;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Play;Pre-Clinical Model;Primary Neoplasm;Prognosis;Proliferating;Regimen;Research;Resected;Resistance;Role;Serum Response Factor;Signal Transduction;Slice;Stromal Cells;Systemic Therapy;TP53 gene;Testing;Therapeutic;Time;Tissues;Toxic effect;Transcriptional Regulation;advanced disease;cancer cell;cancer survival;cancer therapy;cell motility;chemotherapeutic agent;chemotherapy;cofactor;disorder control;experimental study;gain of function;gemcitabine;human disease;human tissue;improved;in vivo;in vivo Model;loss of function;mouse genetics;mouse model;myocardin;neoplastic cell;new therapeutic target;novel;novel drug combination;novel therapeutic intervention;optimal treatments;overexpression;pancreas development;pancreatic cancer cells;pancreatic cancer model;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pre-clinical;programs;recombinase;response;targeted treatment;therapeutically effective;therapy resistant;transcription factor;transcriptome sequencing;tumor;tumor growth Targeting the MICAL2 signaling axis in pancreatic cancer PROJECT NARRATIVEIn this project we will explore the therapeutic potential of inhibiting the flavin monooxygenase MICAL2 inpancreatic cancer pre-clinical in vivo and ex vivo models. We will investigate the cell intrinsic and extrinsic effectsof MICAL2 inhibition using mouse genetics and human tissue-based model systems. We will determine ifMICAL2 promotes pancreatic cancer survival growth and resistance to therapy using orthogonal experimentalapproaches and explore potential off target effect of MICAL2 silencing. NCI 10676946 6/6/23 0:00 PAR-20-292 5R21CA273973-02 5 R21 CA 273973 2 "CHEN, WEIWEI" 8/4/22 0:00 6/30/24 0:00 ZCA1-TCRB-V(M1)S 1886399 "LOWY, ANDREW M" Not Applicable 50 SURGERY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 217163 NCI 137445 79718 PROJECT SUMMARY/ABSTRACTThere is a critical need for novel therapeutic approaches for pancreatic ductal adenocarcinoma (PDAC) as thecurrent chemotherapeutic regimens fail to control the disease for a majority of patients. To identify novelregulators of PDAC we compared the epigenetic landscape of surgically resected tumors to normal pancreasusing histone-3 lysine-27 acetylation (H3K27ac). This analysis revealed super-enhancer regions which are hot-spots for transcription factor binding. Super-enhancer profiling of PDAC tissue revealed a distinctive landscapecompared to that of normal pancreas. Amongst the most highly acetylated enhancers mapped to the MICAL2gene. The MICAL2 enzyme is a flavin monooxygenase that regulates nuclear actin dynamics resulting indownstream modulation of transcription by myocardin-related transcription factor-A and serum response factor.As an enzyme whose class has been successfully inhibited in human disease we believe MICAL2 representsan exciting and potentially tractable target for pancreatic cancer therapy.We examined human and murine pancreatic cancer cell lines and organoids as well as several independentdatasets and confirmed that MICAL2 is overexpressed in PDAC and that its overexpression confers a poorprognosis. In addition we have generated robust preliminary data demonstrating that loss of MICAL2 results indownregulation of key cell cycle regulators which slows proliferation and causes stalling in G1 and G2/M phases.Furthermore silencing of MICAL2 inhibits colony formation and cell migration in vitro which are key phenotypesof advanced disease. Importantly these phenotypes are conserved in vivo where the loss of MICAL2 in eithermouse or human PDAC cells markedly inhibits tumor growth as well as metastatic spread to both liver and lung.Finally MICAL2 appears to promote chemoresistance to gemcitabine a common PDAC chemotherapeutic.The evidence we have gathered strongly suggests that targeting the MICAL2 program in PDAC will betherapeutically effective. To validate our hypothesis our goals are to determine how inhibition of MICAL2 impactsPDAC response to cytotoxic therapies and to define the cell extrinsic effects of MICAL2 inhibition in PDACmodels. To accomplish this we will use orthogonal approaches to define the potential benefits and outcomes ofMICAL2 targeting. We will leverage our extensive pre-clinical modeling expertise to assess cell intrinsic andextrinsic effects of MICAL2 inhibition. We will define MICAL2 dependent programs that promote chemoresistanceand assess novel drug combinations to overcome these programs. Importantly we will thoroughly investigatethe potential toxicity of our therapeutic approach. The findings from these studies will enhance our understandingof MICAL2 biology and thereby serve to inform the development and testing of MICAL2-directed therapies inpancreatic cancer. 217163 +No NIH Category available Advanced Development;Affinity;Antibodies;Antibody Binding Sites;Antigens;Binding;Binding Proteins;Biochemical;Biological;Biological Process;Biology;Biophysics;Biopsy;Cell Count;Cell Line;Cell model;Cells;Cellular biology;Characteristics;Chimeric Proteins;Chromatin;Communities;Complementarity Determining Regions;Complex;DNA;DNA Repair;DNA Sequence;DNA mapping;DNA-Binding Proteins;Development;Disease;Embryo;Escherichia coli;Family;Future;Gene Expression;Generations;Genes;Genetic Transcription;Goals;Heterogeneity;Histones;Human;Immune response;Immunoglobulin G;Individual;Joints;Location;Manuscripts;Methods;Methyltransferase;Micrococcal Nuclease;Molecular;Molecular Conformation;Mus;Noise;Normal Cell;Nucleic Acid Regulatory Sequences;Nucleosome Core Particle;Pathology;Pathway interactions;Patients;Play;Population;Post-Translational Protein Processing;Process;Production;Proteins;Proteomics;Protocols documentation;RNA Splicing;Recombinant DNA;Recombinant Proteins;Reporting;Research;Resolution;Role;Sampling;Shapes;Signal Transduction;Solubility;Specificity;Structure;Suspensions;Techniques;Technology;Testing;Time;Tissue Sample;Tissues;analytical method;antigen binding;blastocyst;cell type;chromatin immunoprecipitation;chromatin protein;cohort;embryonic stem cell;genome-wide;genomic locus;genomic profiles;histone modification;improved;insight;interest;nanobodies;novel;pluripotency;preimplantation;protein profiling;recruit;skills;technology development;thermostability;transcription factor Using nanobodies to increase the sensitivity and resolution of chromatin profiling through uliCUT&RUN PROJECT NARRATIVEWe recently had two technological breakthroughs in both developing a robust technological pipeline to producelarge versatile repertoire of antigen-specific camelid VHH single-chain antibodies/nanobodies and optimizing achromatin-bound protein localization technique for single cells which previously had not been possible. Thesebreakthroughs enable us to conceive of combining nanobody application to chromatin protein localizationstudies. Development of this advanced technology will enable higher resolution maps of DNA binding proteinlocalization on chromatin and permit better application to rare and low cell populations. NCI 10676926 8/10/23 0:00 RFA-CA-20-017 5R21CA261737-03 5 R21 CA 261737 3 "LI, JERRY" 9/6/21 0:00 8/31/24 0:00 ZCA1-TCRB-J(M1) 11572135 "HAINER, SARAH JANE" "SHI, YI " 12 BIOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF ARTS AND SCIENCES 152133320 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 186813 NCI 114538 72275 PROJECT SUMMARY/ABSTRACT DNA-binding proteins play crucial roles in all DNA templated processes such as transcription splicingreplication and DNA repair. DNA binding proteins include transcription factors that bind preferentially to certainDNA sequences and histone proteins that form the core of nucleosomes. Importantly genomic location offactors or histone proteins cannot be predicted in cell types by DNA sequence alone. Therefore protein profilingtechnologies are used to identify cell specific characteristics of functional binding. The importance of DNA-binding proteins has motivated the continued development of experimental andanalytical methods to better identify and characterize these interactions. Genome-wide profiling by ChIP-seq isa widely-used technique that has assisted in the characterization of countless chromatin binding proteins.However this technique is limited in its ability to characterize factor occupancy in samples with small cellnumbers and by the availability of specific and robust antibodies. These limitations have necessitated thedevelopment of complementary methods and extensions of ChIP-seq to provide a more complete of biologicalprocesses in the cell. Very recently we optimized CUT&RUN a new localization method to profile factoroccupancy in extremely low cell populations down to single cells and individual mouse blastocyst embryos(termed uliCUT&RUN). This technical advancement has opened the opportunity to profile factor occupancy inrare cell populations such as patient biopsies. Furthermore it permits for testing cell heterogeneity that occursin cell populations. However practical limitations of this technology still include antibody development andefficiency. Camelid single-chain VHH antibodies or Nanobodies (Nbs) are a compelling new class of antibodiescharacterized by exceptionally high solubility and thermostability. We have recently developed a robust pipelinefor the discovery and characterization of high-quality antigen-specific Nb repertoires. This pipeline has beenextensively tested and optimized for a dozen of antigens with different structures and immune responses. Withthis approach a large cohort of high-quality conformational Nb binders can be identified. Here we propose to couple our expertise on Nb development and uliCUT&RUN to develop nanobodyspecific CUT&RUN for low cell populations and apply this technology to single cells and rare cell populations.The development and application of Nb-based uliCUT&RUN will be of wide use to the community and we arewell poised to develop this technology given our optimization of CUT&RUN is the first time single cell transcriptionfactor profiling has been accomplished and our expertise in the new field of Nb development. Further resultsfrom applying this technology to samples will continue to further our understanding of normal cell biology butalso provide crucial information that will benefit efforts to determine the causes and consequences of abnormalcellular states that are associated with disease. 186813 +No NIH Category available Applications Grants;Area;Arizona;Artificial Intelligence;Basic Science;Biological Assay;Cancer Center;Cancer Center Support Grant;Cell Separation;Cellular biology;Certification;Clinical;Clinical Trials;Collaborations;Collection;Color;Communities;Computer software;Consultations;Cryopreservation;Custom;Data Analyses;Development;Dissociation;Doctor of Philosophy;Education;Energy Metabolism;Equipment;Evaluation;Experimental Designs;Extramural Activities;Flow Cytometry;Flow Cytometry Shared Resource;Funding;Future;Genus Hippocampus;Goals;Grant;Head and Neck Cancer;Human;Image;Imagery;Immune;Immune response;Immunologic Monitoring;Immunology procedure;International;Knowledge;Laboratories;Lasers;Machine Learning;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Microscopy;Monitor;Mus;NCI Center for Cancer Research;Names;Peer Review;Pharmacologic Substance;Phenotype;Population;Primary Neoplasm;Publications;Quality Control;Reagent;Research Personnel;Resource Sharing;Resources;Sampling;Services;Site;Speed;Stains;System;Techniques;Technology;Time;Tissues;Training;Translational Research;Universities;Vision;biobank;cancer cell;cost effective;design;experience;high resolution imaging;high standard;innovation;innovative technologies;insight;instrument;instrumentation;medical specialties;member;multiple omics;new technology;novel;particle;primary endpoint;programs;quality assurance;response;secondary endpoint;synergism;translational cancer research Flow Cytometry and Immune Monitoring Shared Resource (FCIMSR) n/a NCI 10676924 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9266 8352439 "CENTUORI, SARA M." Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 194429 126664 67765 FLOW CYTOMETRY & IMMUNE MONITORING: ABSTRACTThe Flow Cytometry & Immune Monitoring Shared Resource (FCIMSR) has served investigators of theUniversity of Arizona Cancer Center (UACC) for more than 30 years. With the establishment of new cutting-edge comprehensive immune monitoring services for basic and translational research FCIMSR has beenrenamed from the previous Flow Cytometry Shared Resource to highlight the full breadth of services nowavailable. The goal of FCIMSR is to offer UACC Members efficient and reliable flow cytometric andcomprehensive immune monitoring services with a high standard of quality control and in a cost-effectivemanner. Led by Sara Centuori PhD and supported by three full-time staff FCIMSR provides the knowledgeand expertise necessary to design experiments develop new assays perform flow cytometric functions andinterpret data. FCIMSR is supported by chargebacks and UACC funding with the intent to prioritize cancer-related services to UACC Members. In CY20 FCIMSR was utilized by 83 unique users 55% of which wereUACC Members (86% with peer-reviewed extramural funding). The volume of FCIMSR usage has steadilyincreased since 2016 supporting 60 publications by UACC Members and 256 funded grant proposals. Inresponse to UACC Member needs FCIMSR expanded its breadth of services to include human immunemonitoring in 2020. FCIMSR now houses a Cytek Aurora flow cytometer an instrument capable of detecting40 markers in one sample allowing for state-of-the-art multiparametric flow cytometry profiling and immuneprofiling capabilities. The Specific Aims of FCIMSR are focused on three pillars: Service Education andCollaboration. The short-term goals of FCIMSR are to increase knowledge of advanced flow cytometric andimmune monitoring assays provide and expand services offered in these areas and encourage collaborationsbetween FCIMSR and other UACC Shared Resources to meet UACC Member needs more efficiently andeconomically. The long-term goal and vision for this facility is to evolve as a well-established comprehensiveflow cytometric and immune monitoring facility offering the latest and most innovative technologies to UACCMembers in areas of both fundamental and translational cancer research. +No NIH Category available Advisory Committees;Analytical Chemistry;Applications Grants;Arizona;Basic Science;Biochemistry;Biological;Biological Assay;Biological Availability;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Carcinogen exposure;Carcinogens;Chemistry;Chemoprevention;Clinical Research;Clinical Trials;Collaborations;Computer software;Consultations;Data;Data Analyses;Development;Disease Progression;Doctor of Philosophy;Drug Kinetics;Drug or chemical Tissue Distribution;Education;Elements;Ensure;Environmental Risk Factor;Funding;Goals;Grant;Hour;Knowledge;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Medicine;Metabolic;Methodology;Methods;Nutrient;Nutritional Science;Pharmacodynamics;Preclinical Drug Development;Preparation;Preventive;Productivity;Protocols documentation;Publications;Research;Research Assistant;Research Design;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Sampling;Services;Specimen;Surveys;Therapeutic;Therapeutic Intervention;Tissues;Training;Translational Research;Universities;Work;bioactive food component;cancer initiation;cancer prevention;cancer risk;cancer therapy;carcinogenesis;cost effective;design;experience;innovation;instrument;instrumentation;lifestyle factors;lipidomics;member;metabolomics;method development;novel;novel therapeutic intervention;population based;preclinical evaluation;preventive intervention;professor;programs;recruit;repository;research clinical testing;small molecule;timeline Analytical Chemistry Shared Resource (ACSR) n/a NCI 10676912 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9258 1878826 "CHOW, H-H. SHERRY" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 132286 86180 46106 ANALYTICAL CHEMISTRY SHARED RESOURCE: ABSTRACTThe Analytical Chemistry Shared Resource (ACSR) enhances the capabilities and productivity of University ofArizona Cancer Center (UACC) investigators by providing a state-of-the-art centralized resource forbioanalytical chemistry assays to support basic translational and clinical research. ACSR providescomprehensive services from study design consultation and method development to sample storagepreparation assay and data analysis. Established in 2001 ACSR offers a wide variety of bioanalytical assaysalong with the capabilities to develop and validate new methods. Using cutting-edge instrumentation ACSRproduces highly sensitive quantitative measurements of cancer therapeutics preventive agents bioactive foodcomponents nutrients carcinogens inorganic elements and endogenous metabolites in various biologicalspecimens as well as qualitative studies in untargeted metabolomics and lipidomics profiling. ACSR alsosupports pharmacokinetic (PK) study design data analysis and data interpretation. Co-Directed by Hsiao-Hui(Sherry) Chow PhD and Justin Snider PhD ACSR is supported by two staff members with deep expertise inquantitative analysis of exogenous and endogenous small molecules and untargeted metabolomics analysis.ACSR utilizes various mechanisms to assess programmatic needs and relies heavily on input from theScientific Advisory Committee and member surveys to prioritize development of services and capabilities. Anexpanding repository of bioanalytical assay protocols many of which can be readily applied to new projectssupport a broad spectrum of research projects in a cost-effective manner to meet user timelines. ACSR iscapable of performing untargeted metabolomics/lipidomics analyses with the recruitment of Snider in 2020 andrecently acquired access to state-of-the art instrumentation for such analyses. Services provided by ACSR areessential for assessing the systemic bioavailability and tissue distribution of novel cancer therapeutics andpreventive interventions; measuring the extent of systemic and target tissue carcinogen exposure; measuringendogenous metabolites in biofluids and tissues as surrogate cancer-risk and/or end-point biomarkers inpopulation-based clinical and translational research; and assessing metabolic changes to define themechanisms underlying carcinogenesis and develop new treatment strategies. During CY20 ACSR hassupported 33 investigators (70% UACC Members). Of the 8243 hours of instrument usage in CY20 86% werefor UACC Members. This work supported projects from 23 funded grants and three investigator-initiated clinicaltrials (IITs) on cancer therapeutics and preventive interventions. ACSR provided bioanalytical chemistry and/orintegrated PK support for nine novel agents in preclinical drug development. Since 2016 ACSR services havesupported 37 publications from Member research and the submission of 61 grant applications. +No NIH Category available Arizona;Authorization documentation;Cancer Center;Cancer Center Support Grant;Clinical Research;Data;Disease;Ensure;Feasibility Studies;Feedback;Goals;Malignant Neoplasms;Mission;Monitor;NCI Center for Cancer Research;National Cancer Institute;Oncologist;Outcome Study;Peer Review;Population;Process;Protocols documentation;Recommendation;Research;Review Committee;Risk;Safety;Scientist;Specialist;Structure;System;Universities;anticancer research;authority;cancer prevention;data integrity;expedited review;human subject;multidisciplinary;research study;sound;therapeutic development Protocol Review and Monitoring System (PRMS) n/a NCI 10676906 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9256 2002666 "GELMANN, EDWARD P" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 79372 51708 27664 PROTOCOL REVIEW AND MONITORING SYSTEM: ABSTRACTThe University of Arizona Cancer Center (UACC) Protocol Review and Monitoring System (PRMS) overseesand provides independent peer review of the scientific merit priority and progress of all cancer studiesinvolving human subjects conducted at the University of Arizona (UA). The Scientific Review Committee (SRC)is the principal functional component of PRMS and has final and independent authority with regard todetermining which studies will be activated and when studies will be closed. It is a multidisciplinary committeethat includes oncologists cancer prevention specialists basic and population scientists therapeuticdevelopment specialists biostatisticians and others that reflects the breadth of UACC research. The PRMS isa two-step process. First the Clinical Research Teams (CRTs) assess the value fit and prioritization withinthe existing portfolio of studies as well as an assessment of each studys feasibility regarding both conductand accrual. In the second step the Scientific Review Committee (SRC) provides peer review and feedbackultimately determining based on scientific merit whether the study should proceed. The SRC has the primarygoal of ensuring that all cancer-relevant research studies involving human subjects at UA are: 1) scientificallysound; 2) statistically valid; 3) appropriately prioritized and without redundancy. The SRC also reviews thedata and safety monitoring plans to assure that they are consistent with the risk level of the study. In 2020 theCRTs vetted 213 studies and forwarded 113 (4 were from Dec 2019) (51%) of these studies for SRC review.Of the studies reviewed by the SRC 52 of studies received an expedited review due to having alreadyundergone an external scientific peer review. These predominantly were NCTN trials. The other 60 trialsunderwent full committee review. Of all trials subject to full review 109 were approved and 4 weredisapproved. The SRC also conducted scientific and accrual progress reviews for all actively accruing UACCstudies. In 2020 85 trials were determined to be underperforming and given low accrual notices. Of these 68received warnings and were subject to near-term monitoring causing 20 to be administratively closed by theSRC and 44 to be closed by PI. The UACC PRMS mission is to ensure the highest quality of clinical researchat the UACC. +No NIH Category available Asia;Asian ancestry;Bioinformatics;Biological Assay;Biological Process;Breast Cancer Risk Factor;CRISPR interference;CRISPR-mediated transcriptional activation;Cancer Biology;Cancer Patient;Cancer-Predisposing Gene;Carcinoma;Cell physiology;Cessation of life;Chemoprevention;Code;Collaborations;Colon;Colorectal;Colorectal Cancer;Complex;Data;Data Pooling;Data Set;Disease;Distant;East Asian;Epidemiology;Etiology;European;European ancestry;Gene Expression;Genes;Genetic;Genetic Predisposition to Disease;Genetic Transcription;Genotype;Genotype-Tissue Expression Project;Heritability;Heterogeneity;In Vitro;Individual;Malignant Neoplasms;Malignant neoplasm of prostate;Modeling;Newly Diagnosed;Pathway interactions;Patient Care;Phenotype;Play;Regulation;Research Design;Role;Scanning;Small RNA;Susceptibility Gene;Testing;Time;Tissues;Translations;United States;Untranslated RNA;Variant;cancer genetics;cancer prevention;cancer therapy;causal variant;colon cancer cell line;colon cancer patients;colorectal cancer risk;cost efficient;density;design;disorder prevention;disorder risk;experimental study;genetic variant;genome wide association study;genomic locus;improved;in vitro Assay;innovation;interest;model building;novel;novel strategies;predictive modeling;risk variant;trait;transcriptome;transcriptome sequencing;tumor Transcriptome-wide association study to identify susceptibility genes for colorectal cancer NARRATIVEUsing an innovative approach and cost-efficient research design this proposed study will integratetranscriptome genetic regulation GWAS data and in vitro assays to discover candidate susceptibility genes forcolorectal cancer. Results from this study will significantly improve the understanding of colorectal cancerbiology and genetics. These novel genes could serve as targets for cancer treatments and chemoprevention. NCI 10676904 8/14/23 0:00 PA-16-160 5R37CA227130-06 5 R37 CA 227130 6 "MECHANIC, LEAH E" 9/4/18 0:00 8/31/24 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 10250493 "GUO, XINGYI " Not Applicable 7 Unavailable 79917897 GYLUH9UXHDX5 79917897 GYLUH9UXHDX5 US 36.143784 -86.800995 10040927 VANDERBILT UNIVERSITY MEDICAL CENTER NASHVILLE TN Independent Hospitals 372320011 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 393 Non-SBIR/STTR 2023 602189 NCI 351521 250668 PROJECT SUMMARYGenetic factors play an important role in the etiology of colorectal cancer (CRC). To date approximately 50genetic loci have been identified for CRC through genome-wide association studies (GWAS). However theseloci explain only a small fraction of heritability. Moreover target genes and underlying mechanisms for most ofthese risk loci remain unclear. The large majority are noncoding variants many of which have been shown toregulate gene expression. Recent studies suggest that ~80% of disease heritability can be explained byregulatory variants. However these variants are each associated with only a small alteration in disease risk;thus they are difficult to identify using GWAS. Recently a novel approach the transcriptome-wide associationstudy (TWAS) was developed to systematically investigate the transcriptome's association with disease risk.In TWAS models are built to predict gene expression with cis-SNPs using a reference transcriptome and thenapplied to GWAS data to evaluate their associations with disease risk. Here we propose to use this innovativeapproach to scan the whole transcriptome to discover novel CRC susceptibility genes and uncover likelycausal genes in loci revealed in previous GWAS. In Aim 1 we will conduct a TWAS in European descendants.We will build expression prediction models for coding genes and non-coding RNAs in hundreds of colorectaltissues other multiple tissues and cross tissues using transcriptome and high-density genotyping data fromindividuals of European ancestry in the Genotype-Tissue Expression (GTEx) project. The models will be usedto predict gene expression levels using GWAS data from approximately 27911 CRC cases and 23059controls included in the ColoRectal Transdisciplinary Study (CORECT) and the Genetics and Epidemiology ofColorectal Cancer (GECCO) consortia and then to evaluate their associations with CRC risk. In Aim 2 we willconduct a TWAS in East-Asian descendants. We will generate transcriptome data and high-density genotypingdata from 400 CRC patients of Asian ancestry from the Asia Colorectal Cancer Consortium (ACCC). We willuse these data to build expression prediction models for coding genes and non-coding RNAs and perform aTWAS in approximately 18999 CRC cases and 31269 controls from the ACCC. In Aim 3 we will experi-mentally evaluate biological function of the top 30 genes identified in Aims 1 and 2. Based on the associationdirection between their expression levels and CRC risk we will either suppress expression using CRISPRi orpromote it using CRISPRa in multiple normal colon epithelial and CRC cell lines. We will then perform in vitroassays and analyze bioinformatics evidence to examine the biological functions of these selected genes and toassess their potential roles in regulating known cancer-related pathways. Our proposed study is extremelycost-efficient as both the transcriptome dataset (GTEx) for European descendants and the GWAS data arealready available to us. This proposed study will provide strong evidence for pinpointing CRC susceptibilitygenes thereby facilitating the translation of our findings to cancer prevention and patient care. 602189 +No NIH Category available Age;Arizona;COVID-19;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Clinical Trials;Clinical Trials Data Monitoring Committees;Clinical Trials Network;Communication;Communities;Community Outreach;Conduct Clinical Trials;Data;Data Management Resources;Development;Enrollment;Ensure;Faculty;Female;Future;Good Clinical Practice;Hispanic;Individual;Industry;Information Management;Infrastructure;Institution;Intervention;Intervention Studies;Intervention Trial;Leadership;Life Cycle Stages;Longevity;Malignant Neoplasms;Minority;Minority Participation;Monitor;National Clinical Trials Network;Nursing Research;Participant;Peer Review;Performance;Policies;Progress Reports;Protocols documentation;Reporting;Research;Research Personnel;Risk;Safety;Serious Adverse Event;Services;Strategic Planning;Suspensions;System;Technology;Training;Training and Education;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Universities;Woman;Work;cancer clinical trial;community engagement;data integrity;data management;ethnic minority;frontier;human old age (65+);improved;investigator-initiated trial;member;patient safety;process improvement;quality assurance;racial minority;real time monitoring;recruit;risk minimization;treatment trial Clinical Protocol and Data Management (CPDM) n/a NCI 10676902 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9254 3124555 "HSU, CHARLES C" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 380260 247726 132534 CLINICAL PROTOCOL AND DATA MANAGEMENT (CPDM): ABSTRACTPart I: Clinical Protocol and Data Management (CPDM). Clinical research at the University of ArizonaCancer Center (UACC) is supported by the UACC Clinical Trials Office (CTO) which functions as the UACCClinical and Protocol Data Management (CPDM) resource. The CTO staffing includes 79 FTEs to supportUACC investigators conducting both interventional and non-interventional cancer clinical trials. The CTOsupports Institutional National Clinical Trials Network Externally Peer-Reviewed and Industry-sponsoredclinical trials and provides comprehensive services for the entire trial lifecycle including regulatory supportdata management clinical research coordination research nursing training and education and technologyservices. The CTO uses a centralized clinical trials management system OnCore to manage protocol conductand to provide reports and performance metrics to the Cancer Center leadership. These metrics facilitateoversight and strategic planning and support ongoing process improvement and training needs. In the currentproject period the CTO oversaw the activation of 327 interventional trials and 23 non-interventional trials. Inthe same period the CTO supported the accrual of 6116 participants to interventional trials 1259 tointerventional treatment trials and an additional 4857 to non-interventional trials. This included the activationof 71 new trials and the recruitment of 3535 participants during the 2020 COVID-19 period (2835 tointerventional accruals of which 342 were to interventional treatment trials and 700 to non-interventional trials).Part II: Data and Safety Monitoring (DSM). All interventional trials are required to include a DSM plan. ForUACC-led interventional investigator-initiated trials (IITs) UACCs DSM Board (DSMB) approves and executesthe DSM plan by performing risk-based monitoring to ensure the highest levels of patient safety under an NCI-approved DMSB charter. In 2020 DSMB conducted 91 reviews that encompassed 48 serious adverse eventsacross 15 trials. There were no findings that prompted an audit or trial suspension.Part III: Inclusion of Women and Minorities in Clinical Research. UACC actively promotes therecruitment of women and minorities. In the current review period 3153 women and 2780 members ofunderrepresented minorities participated in clinical trials. In 2020 among the 2835 individuals enrolled oninterventional studies 54% were female 35% identified as an ethnic minority (Hispanic) and 11% identified asa racial minority. As a major new initiative UACC is launching its Arizona Clinical Trials Network (ACTN) toimprove clinical trial access to underrepresented populations across the Catchment Area and the entire state.Part IV: Inclusion of Individuals Across the Lifespan in Clinical Research. UACC complies with NIH policyon the inclusion of individuals across the lifespan in research. In the review period 46 participants under theage of 20 and 651 over the age of 65 were enrolled on interventional treatment trials. +No NIH Category available Address;African;African American;African American population;American;Area;Behavior;Binding;Biological;Breast;Breast Cancer Cell;Breast Epithelial Cells;Breast cancer metastasis;Carcinoma;Cartilage;Cell surface;Cells;Chemoresistance;Clinical;Complex;Data;Detection;Development;Diagnostic;Disparity;Doxycycline;Epithelium;Event;Extracellular Matrix;Foundations;Frequencies;Funding;Generations;Genetic Transcription;Goals;Growth;HMGA2 gene;Histologic;Histopathology;Human;In Vitro;Inbred BALB C Mice;Invaded;Investigation;Knock-out;Knockout Mice;Laboratories;Ligands;Link;Malignant Epithelial Cell;Mammary Gland Parenchyma;Mammary Neoplasms;Mediating;Mesenchymal;Metaplastic carcinoma of the breast;Modeling;Molecular;Morphology;Mouse Mammary Tumor Virus;Mus;Mutate;Mutation;Neoplasm Metastasis;Nuclear;Oncogenic;Organoids;Pathologic;Pathway interactions;Patients;Phenotype;Productivity;Prognosis;Proteins;Race;Reagent;Reporting;Research Personnel;Risk;Role;Signal Transduction;TP53 gene;Testing;Tissue Sample;Tissues;Translating;Tumor Suppressor Proteins;Up-Regulation;WISP3 gene;WNT Signaling Pathway;Woman;Women's Health;Work;beta catenin;cancer subtypes;cancer type;cell motility;clinical application;clinical prognostic;cohort;diagnostic biomarker;epithelial to mesenchymal transition;extracellular;follow-up;health disparity;human disease;in vivo;innovation;insight;knowledge integration;malignant breast neoplasm;mammary epithelium;mouse model;neoplastic;novel diagnostics;potential biomarker;specific biomarkers;stem-like cell;therapeutic target;translational impact;translational study;triple-negative invasive breast carcinoma;tumor Role of CCN6 (WISP3) in the progression and metastasis of breast cancer Metaplastic breast carcinomas (mBrCAs) are an aggressive subset of triple negative breast cancer (TNBC)more frequent in African Americans with high metastatic potential. We will investigate how reduced orabsent CCN6 expression in the breast leads to the development and progression of mBrCAs. Our functionalmechanistic and translational studies are expected to provide the foundation for treatment and prognosticclinical application and address an important aspect of womens health and a significant cause of healthdisparities. NCI 10676901 6/19/23 0:00 PA-18-484 5R01CA125577-15 5 R01 CA 125577 15 "WOODHOUSE, ELIZABETH" 9/1/08 0:00 6/30/24 0:00 Tumor Progression and Metastasis Study Section[TPM] 7753298 "KLEER, CELINA G" Not Applicable 6 PATHOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 370500 NCI 237500 133000 Metaplastic breast carcinomas (mBrCAs) are a subset of triple negative breast cancer (TNBC) that occurswith higher frequency in African and African-American (AA) women have histological evidence ofepithelial-to-mesenchymal transition (EMT) and poor prognosis compared with other TNBC. mBrCAsconsisting of spindle cells are the most frequent and the most lethal subtype. In humans TP53 is mutatedwith similar frequency in mBrCAs and in non-metaplastic TNBC (60-80% of cases). At present the definingmolecular alterations of mBrCAs are far from understood and the 5-year overall survival for patients withmBrCA is 54% compared to 73% for TNBC. Our lab has discovered that CCN6 protein is reduced in 68%of human mBrCAs compared to 33% of other breast cancer types (p<0.02). A major breakthrough in ourlab during the previous cycle has been the generation of a mammary epithelial cell-specific Ccn6 knockoutmouse model that demonstrates a tumor suppressor function for Ccn6 in mBrCAs. All mammary tumors inMMTV-Cre;Ccn6fl/fl mice resemble human spindle mBrCAs morphologically and at the transcriptional leveland they share increased nuclear localization of beta-catenin in 78% of tumors and increased expressionof the canonical Wnt target genes HMGA2 and IMP2 (IGF2BP2). Since the initial submission we havediscovered that extracellular CCN6 antagonizes the effect of Wnt ligands on beta-catenin activation in vivoand in vitro but the mechanisms cooperating events and functional consequences need furtherinvestigation. Our CENTRAL HYPOTHESIS is that loss of CCN6 expression is required to drive spindlemBrCAs at least in part by enhancing Wnt/beta-catenin mediated activation of pro-invasive and pro-metastatic targets such as HMGA2 and IMP2 and that detection of CCN6 beta-catenin HMGA2 andIMP2 proteins may serve as specific biomarkers of mBrCA in clinical tissue samples with diagnostic andtreatment utility. We propose three independent and complementary specific aims: AIM 1. To investigatethe consequences of inducible mammary epithelial cell-specific Ccn6 knockout as a driver of the uniquespindle mBrCA phenotype and to investigate the cooperation with p53. AIM 2. To elucidate the molecularmechanism(s) by which CCN6 suppresses progression of spindle mBrCAs in vivo and in vitro. AIM 3. Toevaluate the translational impact of CCN6 beta-catenin HMGA2 and IMP2 in breast tissue samples ofAfrican AA and Whites. We have developed a unique mouse model and have characterized cohorts ofhuman breast cancer tissues (n>4000 including 200 from Ghanaian and 275 cases of mBrCAs of allraces) with clinical information and >15 years of follow-up. We have generated critical preliminary datawhich provide a strong scientific premise. The reagents and expertise are in place in the PI and co-Investigator's laboratories. Our innovative studies are expected to provide insights into new diagnosticmarkers and therapeutic targets for this aggressive subtype of TNBC which are currently nonexistent. 370500 +No NIH Category available Address;Advanced Malignant Neoplasm;Advisory Committees;Alaska Native;American Indians;Area;Arizona;Awareness;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer health equity;Caring;Catchment Area;Centers for Disease Control and Prevention (U.S.);Clinical Services;Clinical Trials;Collaborations;Communities;Community Health Education;Community Outreach;Country;County;Disparity;Disparity population;Doctor of Philosophy;Education and Outreach;Elderly;Environmental Exposure;Fostering;Foundations;Funding;Future;Genitourinary system;Goals;Grant;Health Sciences;Health Services;Health Services Accessibility;Hispanic;Hispanic Populations;Institution;Knowledge;Lead;Leadership;Link;Logic;Lung;Malignant Neoplasms;Measurable;Medical;Mexico;Minority;Modeling;Monitor;NCI Center for Cancer Research;Persons;Policies;Population;Population Heterogeneity;Recording of previous events;Research;Rural;Screening for cancer;Skin Cancer;Strategic Planning;Underrepresented Minority;Universities;Voice;Walking;Work;bilingualism;cancer health disparity;cancer prevention;cancer risk;clinical care;community center;community engagement;community partnership;experience;frontier;gastrointestinal;health assessment;innovation;meetings;melanoma;member;outreach;patient population;policy recommendation;population health;programs;recruit;retiree;synergism;tool;tribal Nation;virtual Community Outreach and Engagement (COE) n/a NCI 10676886 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9247 8003903 "HATCHER, JENNIFER " Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 209162 136262 72900 COMMUNITY OUTREACH AND ENGAGEMENT: ABSTRACTThe University of Arizona Cancer Centers (UACC) rural and urban Catchment Area reaches the US-Mexicoborder and spans five Southern Arizona counties (Cochise Pima Pinal Santa Cruz and Yuma) comprisingmore than 1.8M residents of which 39% are Hispanic and 2.5% American Indian/Alaskan Native (AI/AN)populations with high cancer burden and disparities. The goal of the Office of Community Outreach andEngagement (COE) is to serve as a critical bridge linking the UACCs diverse Catchment population to thescientific community to enhance participation in research clinical trials and clinical care and decrease cancerburden. Formalized at UACC for 3 years under the leadership of Jennifer Hatcher RN MPH PhD COE isdriven by a team of multicultural bilingual members representative of Arizonas diverse population. The team isadvised by a diverse set of external stakeholders and community members who comprise the CommunityAdvisory Board (CAB) and internal stakeholders who comprise an Internal Advisory Committee (IAC). TheSpecific Aims of COE are to: (1) Characterize and monitor cancer burden and cancer-related needs within theUACC Catchment Area; (2) Facilitate impactful research and clinical trials focusing on UACC priority cancers inalignment with the Strategic Plan; (3) Lead community outreach that synergizes institutional and communityefforts to reduce Catchment cancer health disparities; and (4) Promote policy recommendations focusing onreduction of cancer disparities and cancer burden in Arizona and beyond. COE facilitates UACC efforts toeffectively address the specific cancer burden of the Catchment population including priority cancers (lungbreast gastrointestinal [GI] genitourinary [GU] and melanoma); low cancer screening rates among Hispanicsand AI/ANs; and challenges to treatment access including in rural and frontier areas. Disparities areaddressed through a combination of Catchment-wide partnerships; targeted community-based education andoutreach guided by an active CAB; and support for impactful cutting-edge innovative research. Efforts areevaluated using a comprehensive logic model that demonstrates the impact and interconnectedness of COEactivities across the institution and community. COE efforts have included completion of a granularcharacterization of the Catchment Area to support the selection of high priority cancers and establishment of aformal partnership with the Arizona Department of Health Services. Impact of efforts includes increasedknowledge regarding Catchment-relevant cancers grant submissions focused on Catchment-relevant cancersand populations Catchment-relevant programming and outreach and connections for Catchment residents toresearch and clinical services. Future directions include partnering with UACCs AD of Population HealthSciences to conduct a population health assessment further characterizing the cancer burden/priorities of theCatchment Area and building a culturally responsive tool kit to enhance recruitment of underrepresentedminorities in clinical trials. +No NIH Category available Basic Science;Big Data;Bioinformatics;Biology;Biometry;Clinical Sciences;Collaborations;Communities;Complex;Computational Biology;Computer software;Computing Methodologies;Data;Data Science;Data Storage and Retrieval;Development;Dryness;Education;Elements;Ensure;Evolution;Faculty;Fostering;Generations;Genomics;Image;Image Analysis;Institution;Investigation;Laboratories;Laboratory Scientists;Learning;Light;Liquid substance;Malignant Neoplasms;Malignant neoplasm of prostate;Medicine;Methodology;Methods;Mission;Modernization;Molecular Analysis;Pathology;Persons;Population;Positioning Attribute;Process;Production;Radiation Oncology;Recording of previous events;Reproducibility;Research;Research Design;Research Personnel;Research Project Grants;Resources;Role;Scientist;Standardization;Systems Biology;Technology;Training;Training Activity;Work;algorithmic methodologies;analytical method;cloud based;coping;data integration;data sharing;educational atmosphere;empowerment;experience;file format;genome sciences;genomic data;hands-on learning;in situ imaging;innovation;interest;medical schools;meetings;member;metabolomics;multimodal data;multimodality;novel;programs;radiomics;tool;transcriptomics Cross Training Core n/a NCI 10676882 8/18/23 0:00 RFA-CA-21-040 5U54CA273956-02 5 U54 CA 273956 2 8/4/22 0:00 7/31/27 0:00 ZCA1-SRB-X 9246 9292110 "MARCHIONNI, LUIGI " Not Applicable 7 Unavailable 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD Domestic Higher Education 212011508 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 191755 191755 0 The Cross-Training Core (CTC) for the U54 ROBIN OligoMET Center will consist of experienced facultymembers of the Division of Computational and Systems Biology (CSP) in the Department of Pathology andLaboratory Medicine of Weill Cornell Medical College (WCM). The team at WCM will work in close collaborationwith teams at the other Institutions and a history of collaboration already exists between the CTC team membersand the investigators leading the Research Projects and the other Research Cores which will further ensure thesuccessful progression of the Center. The CTC activities will be centered around the following purposes: Aim 1)To provide a unified analytical framework across the U54 ROBIN OligoMET Center to foster cross-project dataintegration and comparison. Imaging omics and radiomics data are found in a variety of forms (e.g. differentplatforms file formats etc.) and training people on how to manage each of these instances is challenging andinefficient. We will have unified analytical framework within the U54 ROBIN OligoMET Center where data isaggregated and standardized greatly decreases the training complexity and increases reproducibility whichresults in a more fluid training process. Aim 2) To provide educational support and training across the U54 ROBINOligoMET Center. Advances in genomics transcriptomics metabolomics and radiomics technologies have ledto exponential rises in both production and availability of multimodal data. In light of these rapid evolutionsdisseminating the latest bioinformatics methods within the U54 Center and the broader biomedical community is a challenge of paramount importance. The CTC will address such challenge by creating an open educationalplatform that will provide a rich interactive learning environment leveraging a cloud-based framework tocollaboratively create and share tutorials and learning experiences. To this end the CTC will build upon a 10-year experience in the computational genomics and data science domains and training biologists and cliniciansin computational methods. Aim 3) To develop novel analytical approaches for the comprehensivecharacterization of oligometastatic prostate cancer (PCa) via integrated analyses of multimodal big data. Omicsand radiomics technologies multiparametric in situ imaging and spatially-resolved molecular and imageanalyses are rapidly evolving fields. Therefore continually evolving technologies software algorithms andanalytical methods are efforts of essence. PCa investigations across the U54 ROBIN OligoMET Centerencompass a multitude of these domains hence it is of paramount importance that a versatile and innovativeportfolio of approaches is developed to fully support the ongoing and future research. The U54 ROBIN OligoMETCenter will therefore provide an ideal platform for such cross-disciplinary training and the CTC will support suchcrucial endeavor through developing and disseminating ad-hoc training modules across the whole U54 ROBINOligoMET Center and the other ROBIN Centers. +No NIH Category available Address;Adopted;Aftercare;American Indians;Area;Arizona;Award;Behavioral;Biological Markers;Biomedical Engineering;Breast;Breast Cancer survivor;Broccoli - dietary;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Control Research Program;Cancer Detection;Cancer health equity;Carcinogens;Caregivers;Catchment Area;Cellular Phone;Centers for Disease Control and Prevention (U.S.);Clinical;Clinical Research;Clinical Trials Network;Collaborations;Country;DNA Methylation;Detection;Development;Direct Costs;Dissemination and Implementation;Dose;Drug Metabolic Detoxication;Environment;Funding;Future;Goals;Grant;Guidelines;Health;Health Promotion;Hispanic Populations;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Imaging technology;Institution;Intervention;Latina;Lead;Legal patent;Malignant Neoplasms;Microscope;Mission;National Cancer Institute;National Cancer Program;Not Hispanic or Latino;Occupational Malignant Neoplasm;Organizational Policy;Participant;Peer Review;Policies;Population;Preventive;Publications;Recording of previous events;Renal carcinoma;Reporting;Research;Resource Sharing;Risk Factors;Scientist;Screening for cancer;Series;Site;Source;Statutes and Laws;Structure;Survivors;System;Tobacco Use Cessation;Tobacco-Associated Carcinogen;United States National Institutes of Health;Universities;Vaccination;World Health Organization;X-Ray Computed Tomography;anticancer research;base;cancer care;cancer clinical trial;cancer health disparity;cancer imaging;cancer prevention;cancer risk;dissemination science;early phase clinical trial;evidence base;exercise physiologist;fire fighter;imaging system;implementation science;improved;improved outcome;innovation;inter-institutional;interdisciplinary collaboration;investigator-initiated trial;melanoma;member;methylation pattern;neoplasm registry;non-invasive imaging;novel;novel strategies;novel therapeutic intervention;preadolescence;preventive intervention;programs;psychosocial;recruit;skin cancer prevention;symptom management;wasting;working group Cancer Prevention and Control Program (CPCP) n/a NCI 10676872 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9243 10162095 "BEA, JENNIFER WRIGHT" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 74793 48725 26068 CANCER PREVENTION & CONTROL PROGRAM: ABSTRACTThe Cancer Prevention & Control Program (CPCP) at the University of Arizona Cancer Center (UACC)conducts highly interactive transdisciplinary cancer prevention and control research to reduce the cancerburden. CPCP maintains a strong emphasis on catchment-relevant cancer research that informs and impactsthe UACC Catchment Area. The Specific Aims are to: (1) advance understanding and early detection of cancerthrough identification of risk factors and development of detection biomarker and imaging technologies(Discovery); (2) evaluate novel cancer preventive agents and strategies to reduce the cancer burden(Intervention); and (3) implement evidence-based behavioral psychosocial and system-level strategies topromote health and improve outcomes (Dissemination and Implementation). CPCP Members have madesignificant progress on cancer prevention and control research in the following areas: (1) demonstratedexposure of firefighters to carcinogens that alter their DNA methylation patterns leading to changes in policy;(2) identified differences in drivers of renal cancer in Hispanics versus non-Hispanic Whites; (3) developed anew highly sensitive breast-CT imaging system and smartphone confocal microscope; (4) showed that abroccoli seed extract upregulated detoxification of tobacco carcinogens; (5) completed HPV vaccine dosingstudies that informed on WHO policy for worldwide vaccination guideline; (6) developed a highly effectivesymptom management program for support of Latina breast cancer survivors and caregivers; and (7)increased cancer screening rates in American Indians from 9% to 19%. CPCP has a peer-reviewed cancerfocused funding base of $8.9M (direct costs) of which $6M (67%) is from the National Cancer Institute (NCI)$2.1M (24%) from other National Institutes of Health sources and $0.8M (9%) from other peer-reviewedsources. Of note CPCPs NCI funding is 50% higher than that reported during the prior reporting period.During the reporting period CPCP Members were awarded $47M in 33 peer-reviewed cancer-relevant multi-PIgrants. These MPIs included 12 R01s two P01s one U54 and partnerships with 66 institutions across thecountry of which three were NCI-designated cancer centers. Funding includes a new P01 in skin cancerprevention; a new UG1 grant to lead early-phase clinical trials of cancer preventive agents one of only fiveNCI-funded programs; new Centers for Disease Control and Prevention cancer funding as the Arizona site forthe national Cancer Prevention Clinical Trials Network; and P42 funding to address mine waste exposures andcancer promotion. During the current project period CPCP Members authored 525 cancer-relevantpublications of which 122 (23%) were intraprogrammatic 76 (14%) were interprogrammatic 311 (59%) wereinter-institutional. In addition CPCP members filed 59 patents of which 12 (20%) were issued. During theproject period CPCP accrued 8941 participants to clinical studies 6496 of which were accrued toinvestigator-initiated trials representing a 2-fold increase compared to the prior period. +No NIH Category available Academic Medical Centers;Adjuvant Therapy;Automobile Driving;Bar Codes;Biological Models;Biology;Bromodomain;CDKN2C gene;Cell Count;Cell Line;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;DNA Sequence Alteration;Data;Development Plans;Diagnosis;Diagnostic;Disease;Enhancers;Epidermal Growth Factor Receptor;Epigenetic Process;Event;Exposure to;FGFRL1 gene;Gene Expression;Gene Expression Regulation;General Hospitals;Genes;Genetic;Genomics;Goals;Heterogeneity;Laboratories;Libraries;MAP Kinase Gene;Malignant Neoplasms;Massachusetts;Melanoma Cell;Mentors;Molecular;Mutation;Oncologist;Pathologist;Pathology;Pathway interactions;Patients;Play;Population;Positioning Attribute;Principal Investigator;Process;Recurrent disease;Regulator Genes;Reporting;Research;Research Proposals;Resistance;Role;Sampling;Secondary to;System;Systems Biology;Techniques;Technology;Testing;Time;Training;Treatment Failure;Tumor Escape;Variant;Work;accurate diagnostics;biological systems;cancer therapy;career;experience;genome-wide;human disease;inhibitor;insight;interest;melanoma;non-genetic;novel;novel therapeutic intervention;novel therapeutics;personalized medicine;pharmacologic;precision medicine;prevent;programs;resistance gene;single-cell RNA sequencing;success;targeted treatment;tenure track;therapeutic target;therapy resistant;tumor Mechanisms of non-genetic variation in melanoma Project NarrativeFor many patients with melanoma treatment with targeted therapies initially shows great promise onlyfor the disease to return often without any new mutations that explain why the treatment stoppedworking. This proposal aims to define non-genetic mechanisms that explain how cancers likemelanoma become resistant to therapy. By understanding these mechanisms we can unlock newtherapeutic strategies to overcome treatment failure. NCI 10676871 8/8/23 0:00 PA-19-117 5K08CA237856-05 5 K08 CA 237856 5 "LIM, SUSAN E" 9/1/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 14749029 "GARG, SALIL " Not Applicable 3 PATHOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 195134 NCI 180680 14454 Project Summary/AbstractThis proposal details a five year training plan for the development of a research program focused onnon-genetic mechanisms of therapy resistance in melanoma. Therapies that target the MAPK pathwayin melanoma have remarkable success in shrinking patients initial tumors but disease recurs oftenwithout new mutations that explain therapy failure. This appears to be due to a small population of rarecells present in the initial tumor that display high levels of resistance genes such as epidermal growthfactor receptor (EGFR) and are not killed by initial MAPK targeted therapy. The mechanisms that driveformation of these rare pre-resistant cells are unknown though preliminary studies implicate generegulation by enhancers. The goals of this research proposal are to characterize the key geneticpathways that define pre-resistant cells in patient tumors identify enhancers that drive expression ofresistance genes and cellular variation and to identify pharmacologic targets for preventing therapyresistance. Since EGFR plays an important role in many cancers and non-genetic variation appears toundergird treatment failure in many different malignancies the implications of this work for humandisease may be far-reaching. The work will be mentored by Phillip A. Sharp at the MassachusettsInstitute of Technology a leader in understanding gene regulation in cancer and whose laboratory hasproduced numerous distinguished alumni.I am a practicing molecular pathologist at the Massachusetts General Hospital interested in howvariation arises naturally within biological systems. In diagnostic pathology we are attempting toachieve ever greater personalized medicine in cancer treatment using sequencing. To achieve thebest precision medicine possible we must understand the mechanisms by which tumors evade therapythat go beyond genetic changes such as mutations. This will allow us to build better more accuratediagnostics and give our oncologist colleagues the best actionable information. My career objectiveduring the proposal period is to obtain a tenure-track position at an academic medical center continuingwork as a Principal Investigator. Specifically during the proposal period I will gain experience withmelanoma model systems enhancer biology genomics and systems biology approaches. My longterm objective is to define how variation and heterogeneity arise within biological systems and how wecan diagnose and manipulate these processes in human disease. 195134 +No NIH Category available ATAC-seq;Acceleration;Advanced Malignant Neoplasm;Award;Biological Markers;Biology;Breast Cancer Genetics;Cancer Prognosis;Cells;Characteristics;Chromosome Mapping;Clinical;Clinical Data;Clinical Research;Communities;Computer software;Data;Data Commons;Data Science;Ethnic Origin;Etiology;Event;Genes;Genetic;Genetic Medicine;Genetic Research;Genome;Goals;Hematopoiesis;Heritability;Immunotherapy;Joints;Length;Leukocytes;Malignant Neoplasms;Malignant neoplasm of lung;Mediation;Medicine;Mendelian randomization;Methods;Pathway interactions;Performance;Phenotype;Population;Population Study;Prevention strategy;RNA;Reduce health disparities;Research Personnel;Risk;Silicon;Statistical Methods;United States National Institutes of Health;Variant;anticancer research;biobank;cancer epidemiology;cancer genetics;cancer health disparity;cancer prevention;cancer subtypes;causal variant;cloud based;data resource;empowerment;epidemiologic data;exome sequencing;genetic analysis;genetic epidemiology;genetic variant;genome sequencing;genomic data;improved;machine learning method;mitochondrial dysfunction;multi-ethnic;multiple omics;non-genetic;phenome;phenotypic data;population based;precision cancer prevention;precision medicine;profiles in patients;rare variant;response;statistical and machine learning;telomere;tool;treatment strategy;tumor;whole genome Statistical Methods for Analysis of Massive Genetic and Genomic Data in Cancer Research NarrativeThis project aims to develop and apply advanced and scalable and interpretable statistical and machinelearning methods and tools to empower the integrative analysis of large-scale biobanks germline and somaticwhole genome/exome sequencing (WGS/WES) cancer studies and experimental single cell based cell-specificomic data. These methods and tools will accelerate the progress in advancing from cancer gene mapping tomechanisms to cancer precision prevention and medicine. We will develop open access high-performancecluster and cloud based software of these methods and data resources and make them available to the cancerresearch community. NCI 10676866 7/31/23 0:00 PAR-21-333 5R35CA197449-09 5 R35 CA 197449 9 "CHEN, HUANN-SHENG" 8/5/15 0:00 7/31/29 0:00 ZCA1-GRB-I(M1) 7043086 "LIN, XIHONG " Not Applicable 7 BIOSTATISTICS & OTHER MATH SCI 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 908788 NCI 582642 326645 Project SummaryWith massive data from genome exposome and phenome rapidly available in population and clinical studiesdata science has emerged to be critically important and provides unprecedented opportunities for newdiscoveries in cancer. This competing renewal application of an NCI Outstanding Investigator Award (R35)aims at developing and applying scalable interpretable and transferable statistical and machine learning (ML)methods for integrative analysis of massive germline whole genome sequencing (WGS) and somatic wholeexome sequencing (WES) data epidemiological and clinical data in large-scale multi-ethnic biobankspopulation and clinical studies of cancer with experimental cell specific multi-omic functional data such assingle cell RNA/ATAC-seq data. Our ultimate goal is to use advanced data science methods and differenttypes of population clinical and experimental data to accelerate progress in advancing from cancer genemapping to mechanisms to cancer prevention and medicine discover new effective trans-ethnic precisioncancer prevention and treatment strategies and reduce health disparities in cancer genetic research. Thisapplication aims to meet the pressing quantitative needs for the analysis of massive data in cancer research.Specifically (A) for genetic cancer epidemiology we will develop scalable interpretable and transferablestatistical and ML methods for (1) rare variant analysis by integrating population-based WGS and experimentalsingle cell functional data; (2) advancing from associated variants with unknown causality and biology to causalvariants genes and pathways using causal mediation analysis and Mendelian Randomization by integratinggenetic cell-specific omic biomarkers and phenotype data; (3) estimating transferable trans-ethnic polygeneticrisk scores (PRSs) and heritability using common and rare variants by integrating WGS data with experimentalin-silicon cell-specific functional annotations and non-genetic data for actionable prevention strategies; (3)federated and transferable trans-ethnic single phenotype and phenome-wide genetic analysis in large WGSstudies and biobanks. (B) For cancer genetic medicine we will develop scalable and interpretable statisticaland machine learning methods for (1) joint analysis of germline WGS and tumor somatic WES data to identifygenetic variants that predispose to cancer subtypes; (2) integrative analysis of tumor somatic WES data andclinicopathological characteristics to identify patient profiles for improved efficacy of immunotherapies; (3)analysis of the effects of clonal hematopoiesis mitochondrial dysfunctions leukocyte telomere length calledfrom germline WGS data on tumor somatic events cancer prognosis and responses to immunotherapies. Wewill apply the proposed methods in lung cancer and breast cancer genetic epidemiological and clinical studiesand biobanks. We will develop open access cluster and cloud-based software of these methods and dataresources and make them available at NIH Data Commons to the cancer research community. 908788 +No NIH Category available Agonist;American Indians;Androgen Receptor;Area;Arizona;Award;Biological;Biological Markers;Biological Process;Bone Pain;Breast;Breast Cancer Patient;Businesses;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Catchment Area;Cell Proliferation;Cells;Cementation;Centrosome;Chelating Agents;Clinic;Clinical Oncology;Coculture Techniques;Collaborations;Colon Carcinoma;Combined Modality Therapy;Complex;Country;DNA Repair;Defect;Development;Direct Costs;Disease;Educational workshop;Epidermal Growth Factor Receptor;Estrogen Receptors;Ethnic Origin;Ethnic Population;Etiology;European;Faculty;Focus Groups;Fostering;Fumarate Hydratase;Funding;Future;Gene Expression;Genetic;Genomic Instability;Glycogen (Starch) Synthase;Goals;Grant;Helicobacter pylori;Hepatobiliary;High School Student;Hispanic;Immune;Immune Evasion;Immune system;Institution;Integrin alpha6beta1;International;Invaded;Iron Chelation;Knowledge;Lead;Leadership;Legal patent;Link;Malignant Neoplasms;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mentors;Mentorship;Molecular;Mutation;NCI-Designated Cancer Center;National Cancer Institute;Neoplasm Metastasis;Normal Cell;Organoids;Pathway interactions;Peer Review;Peptides;Phosphotransferases;Play;Population Heterogeneity;Process;Prostate;Publications;RNA;Renal carcinoma;Research;Research Personnel;Research Project Grants;Rest;Role;Science;Source;Testing;Training;Translating;Translational Research;United States National Institutes of Health;Universities;base;cancer cell;cancer diagnosis;cancer health disparity;cancer initiation;cannabinoid receptor;castration resistant prostate cancer;cell growth;clinical translation;college;design;gastrointestinal;gene environment interaction;innovation;inter-institutional;malignant breast neoplasm;malignant stomach neoplasm;mechanical drive;meetings;member;molecular subtypes;new therapeutic target;next generation;novel therapeutics;oncology program;physical property;programs;protein TDP-43;racial population;recruit;social;specific biomarkers;stress granule;survivorship;therapeutic biomarker;therapeutically effective;trafficking;translational oncology;tumor;tumor microenvironment;tumor progression;working group Cancer Biology Program (CBP) n/a NCI 10676864 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9241 1925352 "ELLIS, NATHAN A." Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 80818 52650 28168 CANCER BIOLOGY PROGRAM: ABSTRACTThe overarching scientific goal of the Cancer Biology Program (CBP) at the University of Arizona CancerCenter (UACC) is to understand the basic biological processes that underlie cancer etiology and progression.Our goal is to use the knowledge we generate on these processes to identify new therapeutic targets andbiomarkers and to establish interprogrammatic collaborations to bring them to the clinic. The Specific Aims ofCBP are to: (1) elucidate the basic mechanisms that control tumor-relevant cell growth and proliferation; (2)identify etiologic mechanisms in cancer initiation and progression; and (3) determine how the tumormicroenvironment influences progression invasion and metastasis. CBP is comprised of 52 Members in 16departments and five colleges. CBP Members have made a significant impact on basic cancer mechanisms asevidenced by being the first to: (1) identify a quiescence switch in dormant cells; (2) find a link betweenfumarate hydratase and ferroptosis in kidney cancer; (3) demonstrate centrosome loss as a major driver ofprostate cancer initiation; (4) decipher the underlying functional defects in cancer-specific Pol mutations; (5)identify a role for TDP-43 in DNA repair and stress granules; (6) identify a link between the androgen receptor(AR) and integrin 61 in metastatic castration-resistant prostate cancer; (7) find a role for estrogen receptor insuppressing mechanical-driven invasion in breast cancer; and (8) decipher how Helicobacter pylori evades theimmune system to initiate gastric cancer. Through interprogrammatic collaborations and hand-offs to theClinical & Translational Oncology Program CBP Members are translating their findings by designing newdrugs to target the androgen receptor and glycogen synthetase kinase in prostate and colon cancerrespectively; testing new Fe+ chelating agents in kidney cancer; designing peptides to target EGFR andintegrin 61 in breast and prostate cancer respectively; evaluating miR130b as a new biomarker for gastriccancer; using organoid/immune cell co-cultures to design personalized combination therapies for pancreaticcancer; and testing cannabinoid receptor agonists to overcome bone pain in breast cancer patients. UACCprovided support to CBP through funding of pilot awards and coordination of programmatic meetingsseminars retreats and workshops that foster intra- and interprogrammatic collaborations and transdisciplinarytranslational research. These meetings supported strategic recruitment of 17 new faculty since 2016. CBP hasa peer-review funding base of $9.8M (direct costs) of which $2M (20%) is from the National Cancer Institute$7.2M (73%) from other National Institutes of Health sources and $0.6M (6%) from other peer-reviewedsources. This represents a 49% increase in peer-reviewed funding over the previous project period. Duringthe current project period Members authored 386 cancer-relevant publications of which 46 (12%) wereintraprogrammatic 78 (20%) were interprogrammatic and 187 (48%) were inter-institutional. In addition CBPMembers filed 29 patents of which two were issued and mentored over 50 trainees. +No NIH Category available Academia;American Society of Clinical Oncology;Appointment;Arizona;Award;Back;Cancer Center;Cancer Center Support Grant;Cancer Patient;Catchment Area;Clinical Research;Databases;Development;Diverse Workforce;Doctor of Philosophy;Educational Activities;Educational workshop;Extramural Activities;Faculty;Fellowship;Funding;Funding Mechanisms;Government;Grant;Health Professional;Individual;Industry;Institution;K-Series Research Career Programs;Learning;Learning Module;Malignant Neoplasms;Medical Students;Mentors;Mission;NCI Center for Cancer Research;Online Systems;Outcome;Population Scientist Supplement (R25);Postbaccalaureate;Postdoctoral Fellow;Publishing;Reporting;Research;Research Personnel;Research Training;Science;Series;Site;Training;Training Programs;Training Support;Training and Education;Translational Research;Travel;Underrepresented Minority;United States National Institutes of Health;Universities;Vision;anticancer research;cancer education;career;career development;clinical training;effectiveness measure;ethnic diversity;graduate student;high school;high school program;meetings;member;mid-career faculty;minority trainee;next generation;operation;prevent;programs;racial diversity;recruit;science teacher;skills;summer internship;symposium;tool;undergraduate student;underrepresented minority student Cancer Research Training & Education Coordination (CRTEC) n/a NCI 10676860 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9239 1888513 "BRIEHL, MARGARET M" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 134400 87557 46843 CANCER RESEARCH TRAINING & EDUCATION COORDINATION: ABSTRACTTraining the next generation of cancer researchers and health professionals has been a central mission of theUniversity of Arizona Cancer Center (UACC) since its founding in 1976. UACCs Office of Cancer ResearchTraining & Education Coordination (CRTEC) is led by the Associate Director of CRTEC Margaret Briehl PhDand Assistant Director of Clinical Training and Education Aaron Scott MD. They are assisted by three full-timestaff members including an Operations Manager a Science Educator and a Grant Writer. A CRTEC Councilcomprised of 12 leaders of training and education programs provides oversight of CRTEC efforts. CRTECsvision is to promote the development of the next generation of cancer researchers across a pipeline of learnersby engaging individuals from elementary to high-school (K-12) through junior to mid-career level faculty andhealth professionals. This vision is realized through promotion of high-impact training that supports teamscience approaches to prevent and cure cancer. Developing a diverse workforce of cancer researchers andhealth professionals to serve UACCs unique Catchment Area is a high priority for CRTEC. During the currentreporting period UACC Members have led eight T32s three R25s and one U54 training grant that providecancer-focused research opportunities. The Centers two newest training programs are funded through R25awards with a focus on building the research skills of underrepresented minority (URM) trainees at theundergraduate post-baccalaureate and graduate-level. During the current funding period 178 mentors (165UACC Members) have mentored 1198 trainees through UACC-led and other institutional training programs.Collectively these programs engage trainees from high school through postdoctoral fellowships. Thirty-sevenpercent of UACC trainees are URM. UACC trainees who have entered the workforce are contributing to thecancer field through careers in academia industry government publishing and working as healthprofessionals caring for cancer patients. CRTECs concerted efforts are accomplished through three SpecificAims: (1) coordinate and develop cancer-focused training and education activities across the continuum oftrainees (2) facilitate and expand cancer-focused professional development activities and (3) track andevaluate the impact of UACCs cancer research training and education activities. CRTEC efforts over the next5 years are expected to lead to a substantially more integrated learning pipeline particularly among URMsthat promotes transdisciplinary translational research and professional careers in the cancer field. +No NIH Category available Arizona;Award;Cancer Center;Cancer Center Support Grant;Clinical Research;Collaborations;Collection;Communication;Community Outreach;Development;Educational Activities;Ensure;Evaluation;Extramural Activities;Funding;Goals;Grant;Human Resources;Information Technology;Institution;Knowledge;Leadership;Mission;NCI Center for Cancer Research;National Cancer Institute;Operations Research;Play;Policies;Preparation;Reporting;Research;Research Infrastructure;Research Support;Resource Sharing;Role;Science;Scientific Advances and Accomplishments;Services;Strategic Planning;Training and Education;Universities;Vision;anticancer research;cancer research center director;college;community engagement;cost effective;meetings;member;operation;process improvement;programs;skills;symposium Administrative Core n/a NCI 10676856 7/28/23 0:00 PAR-20-043 5P30CA023074-42 5 P30 CA 23074 42 7/1/97 0:00 7/31/27 0:00 ZCA1-RTRB-Y 9237 79285779 "BANKHEAD, TERI L" Not Applicable 7 Unavailable 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ Domestic Higher Education 857210158 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 457409 297987 159422 ADMINISTRATIVE CORE: ABSTRACTThe University of Arizona Cancer Center (UACC) Administration oversees all administrative functions thatsupport the Centers research infrastructure Members and Research Programs. UACC Administration plays avital role in supporting the Centers mission vision and strategic priorities in alignment with the CentersStrategic Plan by providing comprehensive support services that enable effective communication andcoordination among the Senior Leadership Members staff and institutional stakeholders. Through theseefforts Administration drives collaboration and maximizes the quality of science conducted by the Centersthree Research Programs while also advancing scientific impact through Community Outreach andEngagement Cancer Research Training & Education Coordination and Shared Resources. Under thedirection of the Associate Director of Administration 22 FTEs are organized within six administrative units:Human Resources Research Services Finance Communications Facilities Management and Development.These units are responsible for ensuring the efficiency and efficacy of UACCs research infrastructureincluding oversight of all Cancer Center Support Grant activities and reporting; facilitation of strategic planningefforts; organization of programmatic and Center-led research meetings retreats and symposia; managementof research support services (i.e. Shared Resources seed funding space grant support services);administrative support of UACC training and educational activities; and coordination with clinical researchleadership. UACC Administration provides the expertise knowledge and skills to assure quality andconsistency of operations while also conducting rigorous evaluations of progress toward the goals andobjectives as outlined in UACCs 20202025 Strategic Plan. UACC Administration continually refines andimproves processes and policies to ensure centralized cost-effective services. UACC Administration currentlysupports 151 Members spanning 11 colleges and 36 departments across the University of Arizona with afunding portfolio of more than $34M. During the project period UACC Administration facilitated the award of$2.7M in 15 NCI supplements and more than 75 seed funding awards garnering nearly $11M in extramuralfunding. +No NIH Category available Address;Aftercare;Biological;Biopsy;Blood;Cancer Biology;Cancer Patient;Cancerous;Cells;Clinical;Clinical Data;Code;Collaborations;Competence;Complex;Computational Biology;DNA;DNA Methylation;DNA Sequence Alteration;Data;Data Analyses;Data Set;Dedications;Diagnosis;Disease;Epigenetic Process;Event;Evolution;Future;Genes;Genetic;Genome;Genome Data Analysis Center;Genome Data Analysis Network;Genomic Data Commons;Genomics;Goals;Heterogeneity;Individual;International;Journals;Knowledge;Machine Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Messenger RNA;Methods;Methylation;Microsatellite Repeats;Molecular Abnormality;Mutation;Mutation Analysis;Normal Cell;Nucleotides;Oncogenes;Outcome;Paper;Pathway interactions;Patients;Pattern;Play;Point Mutation;Process;Production;Prognosis;Publishing;Quality Control;RNA;Regulatory Element;Repetitive Sequence;Research;Resistance;Role;Sample Size;Sampling;Techniques;The Cancer Genome Atlas;Therapeutic;Tissues;Untranslated RNA;Variant;Work;cancer genome;cancer genomics;cancer subtypes;cancer type;cell free DNA;cohort;driver mutation;epigenome;flexibility;genome analysis;genome sequencing;improved;innovation;insertion/deletion mutation;interest;neoantigens;next generation;novel;personalized medicine;precision medicine;predictive modeling;promoter;rare cancer;resistance mechanism;single-cell RNA sequencing;subclonal heterogeneity;targeted treatment;therapeutic target;therapeutically effective;tool;translational oncology;translational scientist;tumor;whole genome;working group Comprehensive analysis of point mutations in cancer PROJECT NARRATIVECancer is a disease of the genome and arises due an accumulation of mutations that drive normal cells tobecome cancerous. As a Genome Data Analysis Center (GDAC) with expertise in discovering and characterizingpoint mutations in the cancer genome we aim to integrate our state-of-the-art rigorous tools and pipelines forrobust point mutation characterization and driver discovery into the Genome Data Analysis Network (GDAN)alongside other GDACs with expertise in complementary fields. Understanding the significance of the point-mutation drivers in the context of analyses from other GDACs in the GDAN will provide the cancer field with adeep comprehensive understanding of many cancer types that can inform future clinical therapeutics andadvance precision medicine at the single-patient level. NCI 10676830 8/22/23 0:00 RFA-CA-20-053 5U24CA264024-03 5 U24 CA 264024 3 "YANG, LIMING" 9/20/21 0:00 8/31/26 0:00 ZCA1-RTRB-B(M1) 9774810 "GETZ, GAD A" "RHEINBAY, ESTHER " 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 394 Other Research-Related 2023 392189 NCI 279559 115030 PROJECT SUMMARYPrecision medicine in cancer a disease of the genome relies on a deep and comprehensive understanding ofthe genetic mutations and abnormalities that accumulate in normal cells and drive transformation to cancer. TheGetz and Rheinbay Labs have expertise in the discovery and characterization of point mutations through rigorouscancer genome analysis. In this proposal we aim to create a Genome Data Analysis Center (GDAC) focusedon employing our existing tools to robustly and comprehensively characterize point mutations (single-nucleotidevariations and small indels) across the entire cancer genome to address scientific questions related to biologicalunderpinnings of cancer that arise in each project we are assigned. We also have the flexibility to adapt our toolsas deemed necessary by the unique needs of each project. Specifically we plan to integrate and characterizemutations mutational signatures and other data types to comprehensively discover cancer drivers in coding andnon-coding regions of the genome including the often ignored more difficult-to-analyze regions of the genome.We will do this by incorporating methods to determine DNA methylation signatures as well as by interrogatingthe epigenome in both coding and non-coding regions of the genome. We further plan to advance our ability todetermine trajectories of tumor evolution and heterogeneity by adapting our PhylogicNDT suite of tools toanalyze the evolution subclonal heterogeneity and timing and order of mutational events from multiple samples(e.g. samples acquired longitudinally or spatially) from the same patient or even from cell-free DNA (cfDNA)from non-invasive blood biopsy. In the interest of advancing the GDCs goal of improving personalized medicinewe teamed with expert clinicians and translational scientists Dr. Keith Flaherty and Dr. Kirsten Kbler that willinterpret our findings associate them with clinical data and direct them towards clinical impact. They will alsoenhance our tools for identifying the tissue- and cell-of-origin of cancers to not only better understand theunderlying mechanisms of transformation in a particular cancer type or subtype but also provide more effectivetherapeutic targets. Moreover our final Aim is to perform patient-specific analysis to improve and enableprecision medicine especially in patients whose tumors do not have any identified actionable driver events.Here we will employ machine learning techniques to build predictive models of therapeutic vulnerabilities.Overall we offer primary competencies in DNA point mutation characterization analysis of cfDNA anddetermination of mutational signatures to the GDAN. We also bring added value with secondary competenciesin methylation analysis (in the context of mutational signatures) mRNA analysis single-cell RNA sequencingand pathway/integrative data analysis. Bringing our extensive expertise to the various newly assembled AnalysisWorking Groups and collaborating with other GDACs within the GDAN can help to answer outstanding questionsin cancer with the ultimate goal of improving diagnosis prognosis and treatment for every cancer patient. 392189 +No NIH Category available Active Learning;Address;Affect;Antineoplastic Protocols;Arkansas;Basic Science;Behavioral Research;Biomedical Research;Cancer Biology;Cancer Research Project;Career Choice;Caring;Cause of Death;Cellular biology;Clinic;Clinical;Clinical Research;Clinical Trials;Communities;Coupled;Course Content;Diagnosis;Educational Activities;Educational Grants;Entrepreneurship;Evaluation;Faculty;Future;Goals;Health Policy;Health Services Accessibility;Heart;Hour;Imagination;Improve Access;Individual;Knowledge;Laboratories;Learning;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Medical;Medical Students;Medicine;Mentors;Molecular Biology;Molecular and Cellular Biology;Obesity;Outcome;Palliative Care;Participant;Patients;Persons;Physicians;Population;Poverty;Prevention;Public Health;Quality of life;Reporting;Research;Research Personnel;Research Project Grants;Science;Screening for cancer;Secure;Specialist;Students;Support Groups;Surveys;Testing;Time;Training;Underrepresented Minority;Universities;Vision;Visit;anticancer research;cancer rehabilitation;cancer therapy;career;clinical care;clinical practice;cohort;community engaged research;community setting;design;education planning;education research;experience;health care availability;improved;innovation;insight;interest;member;outcome disparities;palliation;programs;recruit;simulation;social media;student participation Partnership in Cancer Research (PCAR) Cancer is the second leading cause of death in the US. The Partnership in Cancer Research programprovides hands-on experiences in cancer research coupled with knowledge of cancer biology and clinical careto ignite the imagination of future physicians to solve difficult problems and improve cancer outcomes. NCI 10676820 8/21/23 0:00 PAR-18-478 5R25CA250979-04 5 R25 CA 250979 4 "ZAHIR, NASTARAN" 9/1/20 0:00 8/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1942869 "KELLY, THOMAS JOSEPH" Not Applicable 2 PATHOLOGY 122452563 VDFYLZPJEAV6 122452563 VDFYLZPJEAV6 US 34.749005 -92.320097 1471106 UNIV OF ARKANSAS FOR MED SCIS LITTLE ROCK AR SCHOOLS OF MEDICINE 722057101 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 77532 NCI 152297 3704 Partnership in Cancer Research (PCAR) seeks to provide first and second-year medical students aninnovative hands-on cancer research experience in a laboratory clinical or community setting. The PCARexperience will serve a class of 12 participants for 10 weeks during the summer. The research experience willbe enriched by team-based learning on the molecular and cell biology of cancer alongside clinical simulationsand experiences of cancer screening treatment and palliation. The overarching goal of the cancer researchexperiences is to spark the participants interest in future careers as cancer clinical specialists andresearchers. The program will enhance the training of a workforce to meet the nations biomedical behavioraland clinical research needs. Individual cancer research projects are where the students spend most of their time. The research will beput into context with weekly active learning sessions on the biology of cancer. Clinical experiences will exposeparticipants to current issues in the treatment and ongoing care of people with cancer; this aspect will also giveparticipants insight into how basic and community-engaged science affect clinical practice and how clinicalproblems can be turned into research questions. The entrepreneurship program features teams of 3participants independently proposing marketable cancer research solutions through weekly sessions withentrepreneur mentors. The aims are to: 1) Provide individual medical students an outstanding hands-on experience in cancer research.Students will perform research with one of about 50 different faculty members performing cancer research inbasic science clinical research or community engaged research. Throughout the course teams ofparticipants will integrate their research experiences and ideas in the online and in-person mentored CureCancer Entrepreneurship program . 2) Provide context for participants research with team-based learning and clinical exposures.Weekly team-based learning sessions will engage students in learning detailed information on molecular andcellular biology of cancer as well as principles of community based medicine. Clinical exposure includeshands-on medical simulations of cancer related topics social media interaction with a moderated patientsupport group and a visit to the palliative care clinic that will take up no more than 2 hours per week. 3) Determine program outcomes through rigorous evaluation. Pre and post testing will be used todetermine students gain in cancer research knowledge. Surveys will be used to evaluate all aspects of thecourse content faculty and activities. Long term tracking of participants and similar sized cohort of medicalstudents who did not participate in PCAR will be used to investigate efficacy in influencing career choice incancer research. 77532 +No NIH Category available Abdomen;Address;Authorization documentation;Biomedical Engineering;Biopsy;Businesses;Carbon Dioxide;Chest;Cidex;Classification;Client satisfaction;Clinical;Collaborations;Color;Computers;Contract Services;Country;Data;Devices;Electricity;Engineering;Ensure;Equipment;Excision;Fiber Optics;Foundations;Gases;Good Manufacturing Process;Health Expenditures;Home;Hospitals;Human Resources;Image;Immersion;Income;Industrialization;Infection;Instruction;Interdisciplinary Study;Intra-abdominal;Laparoscopes;Laparoscopic Surgical Procedures;Lawyers;Length of Stay;Lifting;Light;Link;Maintenance;Malignant Neoplasms;Malignant neoplasm of abdomen;Maryland;Measures;Mechanics;Medical;Mentors;Monitor;Oncologist;Operating Rooms;Operative Surgical Procedures;Pain;Pathologic;Pathway interactions;Patients;Performance;Pharmaceutical Preparations;Poverty;Power Sources;Procedures;Process;Production;Protocols documentation;Qualifying;Quality Control;Radiation;Recovery;Regulation;Research Institute;Resource-limited setting;Resources;Rural Hospitals;Safety;Semiconductors;Shipping;Source;Surgeon;Surgical incisions;System;Technology;Testing;Time;Tissues;Training;Uganda;Universities;Work;Wound Infection;abdominal wall;authority;cancer care;cancer diagnosis;cancer therapy;cardiovascular collapse;chemotherapy;commercialization;cost;design;detector;experience;first-in-human;global health;health care delivery;human study;improved;instrument;interdisciplinary approach;laptop;light emission;loss of function;low and middle-income countries;manufacture;manufacturing process;manufacturing technology;metal oxide;operation;optical fiber;patient safety;porcine model;predicting response;pressure;prevent;primary outcome;product development;prototype;quality assurance;repaired;safety and feasibility;secondary outcome;social stigma;standard of care;success;tumor;willingness KeyScope: The Key to Sustainable Cancer Diagnosis and Treatment in Uganda Project NarrativeLaparoscopic surgery is the standard of care in high-income countries for many cancer procedures but islargely inaccessible in low- and middle-income countries. We describe a multi-disciplinary collaborationbetween biomedical engineers surgeons oncologists global healthcare delivery teams and businessdevelopers to move a low-cost and durable laparoscopic system to the next stage. Construction of thelaparoscopic system will be demonstrated in Uganda its clinical performance will be tested in a clinical First-in-Human study and regulatory approval will be achieved to bring this system to commercialization in Uganda. NCI 10676811 5/17/23 0:00 RFA-CA-21-030 5U01CA269190-02 5 U01 CA 269190 2 "WANG, YISONG" 8/4/22 0:00 5/31/27 0:00 ZCA1-TCRB-Q(J2) 8509755 "FITZGERALD, TAMARA N" Not Applicable 4 SURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 525794 NCI 392428 133366 AbstractLaparoscopic surgery is the standard of care in high-income countries for many cancer operations in the chestand abdomen. Laparoscopic surgery avoids large incisions by using a tiny camera and fine instrumentsmanipulated through keyhole incisions but it is generally unavailable in low- and middle-income countries(LMICs) due to high cost of installment lack of qualified maintenance personnel unreliable electricityand shortage of consumable items. Patients in LMICs would benefit from laparoscopic surgery asadvantages include: decreased pain improved recovery time fewer wound infections and shorter hospitalstays. Laparoscopic surgery would reduce recovery time enabling patients to return to home and work morequickly thereby mitigating impoverishing health expenditure.KeyScope and KeyLoop (collectively called KeySuite) are laparoscopic prototypes that we havedesigned for the resources needs and challenges of LMICs. KeyScope is a laparoscope that can bemade for $150 (cost of goods) plugs into a laptop computer to display images during surgery exists as asingle unit without complicated assembly and is sterilizable by immersion in Cidex. It links to a tele-mentoringapplication so that experienced surgeons can mentor surgeons in capacity-building partnerships. KeyLoop is alaparoscopic retractor that lifts the abdominal wall during surgery obviating the need for a constant powersupply and medical-grade carbon dioxide. This would enable laparoscopic surgery to be performed in ruralhospitals where most patients live in LMICs and increase access in tertiary centers where laparoscopicequipment is rare and expensive. We describe a multi-disciplinary collaboration between surgeonsengineers oncologists attorneys global health experts and business executives to take this technologyto the next stage.We will perform a clinical First-in-Human study at the Uganda Cancer Institute. Ugandan surgeons will use theKeySuite devices to perform biopsies of intra-abdominal tumors. Primary outcome will be the ability to performbiopsies laparoscopically without conversion to open surgery. Secondary outcomes include: 1) devicefeasibility and safety data and 2) patient satisfaction.We will demonstrate that KeySuite devices can be constructed in Uganda through the Duke-MUK ShippingContainer Makerspace. We will create a bill of materials manufacturing process instructions training videosand measures of quality control. Once we have achieved exceptional construction quality we will transfer thiswork to the Uganda Industrial Research Institute (UIRI) which will move the KeySuite to a product forcommercialization. Using the WHO Good Manufacturing Practices (GMP) we will establish quality assuranceprotocols for sustainable local manufacturing and regulatory approval of the KeyScope and KeyLoop throughthe Uganda National Drug Authority and CE mark. 525794 +No NIH Category available Biochemistry;Biocompatible Materials;Bioinformatics;Biological;Biological Assay;Biology;Blood;Cancer Biology;Cell model;Cells;Ceramides;Chemicals;Chemistry;Culture Media;Data;Data Analyses;Databases;Development;Educational workshop;Ensure;Enzymes;Evaluation Methodology;Experimental Designs;Family;Functional disorder;Future;Goals;High Pressure Liquid Chromatography;Home;Human Resources;Image;In Situ;In Vitro;Individual;Institution;International;Length;Lipid Chemistry;Lipids;Liquid substance;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Measures;Mentors;Metabolic;Metabolism;Methodology;Methods;Molecular;Molecular Analysis;Monitor;Neoplasm Metastasis;Pathway interactions;Pharmaceutical Preparations;Physiologic pulse;Plasma;Postdoctoral Fellow;Procedures;Program Research Project Grants;Proteins;Proteomics;Protocols documentation;Radioactive;Regulation;Research Personnel;Resource Sharing;Resources;Role;Serum;Services;Signal Transduction;Site;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Sphingolipids;Students;Technology;Therapeutic;Tissues;Training;Update;Variant;Work;advanced analytics;analog;analytical method;analytical tool;biochemical tools;cancer therapy;computerized data processing;design;enzyme activity;experimental study;in vivo;inhibitor;lipid mediator;lipid metabolism;lipidomics;metabolomics;programs;response;success;tandem mass spectrometry;tool;transcriptome sequencing;translational model;tumor metabolism;tumor progression;web site Core B: Lipodomics Core PROJECT NARRATIVEThis Core serves as an analytical platform to simplify the study of a large family of lipids(sphingolipids) and their metabolizing enzymes. These are key analysis for all theexperimental projects in this PPG. Using targeted mass spectrometry the core providesunique well stablished and consolidated methods to measure the more than 300 individualdifferent species of sphingolipids home-developed methods to monitor the enzymaticactivities and the protein levels of the enzymes involved in the metabolism of these lipids.To facilitate the study of the role of sphingolipids in cancer this core provides intellectualsupport on the experimental design and post data processing and data interpretation tothe investigators. This close interaction between the core and the PPG investigators allowefficient adaptability from the Core to the needs of each project and their interconnection. NCI 10676805 8/8/23 0:00 PAR-18-290 5P01CA097132-20 5 P01 CA 97132 20 8/1/03 0:00 8/31/24 0:00 ZCA1-RPRB-F 9228 1873587 "HALEY, JOHN DOUGLAS" Not Applicable 1 Unavailable 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY Domestic Higher Education 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 193044 121031 72013 AbstractThe purpose of the Lipidomics Shared Resource Core (LSR Core) in the PPG is to provideintellectual and physical resources (particularly state-of-the-art mass spectrometry analysis ofsphingolipids and flux analysis) to enhance our understanding of the role of bioactive lipids incancer biology with the goal to discover future drugs. The diversity of bioactive lipids and theirinterconnected metabolism generates a network of pathways regulating intra- and inter-cellularsignaling and function. Dysfunctions in these pathways contribute to the pathobiology of cancerprogression and metastasis the study of which is the main goal for the four experimental projectsin this PPG. The vast diversity in sphingolipids with non-redundant but often opposite functionshas resulted in a necessity for the development of new protocols and analytical methods for theiridentification and quantification. Appreciation for the depth of complexity involved in sphingolipidmetabolism and signaling has recently expanded since (i) same species of sphingolipids couldact differently depending on the subcellular compartment and (ii) variations in the acyl chain lengthor saturation status could lead to specific biological responses. These two new considerationsexponentially increase the complexity on sphingolipid studies and they have not been able to beinterrogated until now. The LSR Core was created based on unique expertise of the key personnelin lipid chemistry analysis and metabolism and it has evolved into a key Core for the programproject grant (PPG) entitled Sphingolipids in Cancer Biology and Therapeutics. Furthermore thisCore has developed into an institutional national and international resource in the emergingfields of lipidomics and lipid chemical biology. Core services include: 1) qualitative andquantitative analysis of lipid components from different biological materials (cells tissue andbiological fluids) primarily employing high performance liquid chromatography-tandem massspectrometry (HPLC-MS/MS) technologythe Core currently provides quantitative analysis ofmore than 300 distinct lipid molecular species at a basic metabolomic level; 2) development ofbiochemical tools to study lipid metabolism (e.g. Sphingoproteomics Sphingolipid Flux Analysisutilizing a Pulse-Chase of non-natural C17-sphingolipids functionalized and fluorescentceramides site-specific radioactive sphingolipids); and 3) assisting PPG investigators inexperimental design selection of appropriate methods and interpretation of analytical results.The LSR Core has been instrumental to the success of the PPG investigators over the past 16years by providing them with unique capabilities and critical results that will continue to ensurethe successful progress of this PPG. +No NIH Category available Accountability;Address;Administrator;Advisory Committees;Binding;Bioinformatics Shared Resource;Biometry;Budgets;Cancer Biology;Cancer Center;Collaborations;Communication;Ensure;Equipment;Experimental Designs;Fostering;Friction;Glues;Goals;Human Resources;Individual;Joints;Laboratories;Lead;Leadership;Manuscripts;Mathematics;Medicine;Participant;Phase;Postdoctoral Fellow;Preventive Medicine;Progress Reports;Publications;Recommendation;Reporting;Research;Research Personnel;Resolution;Resource Sharing;Sample Size;Source;Sphingolipids;Statistical Data Interpretation;Students;Supervision;Therapeutic;Time;United States National Institutes of Health;Universities;Writing;cancer therapy;field study;meetings;mid-career faculty;programs;research and development;statistics Administrative Core n/a NCI 10676804 8/8/23 0:00 PAR-18-290 5P01CA097132-20 5 P01 CA 97132 20 8/1/03 0:00 8/31/24 0:00 ZCA1-RPRB-F 9227 1869058 "HANNUN, YUSUF AWNI" Not Applicable 1 Unavailable 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY Domestic Higher Education 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 85629 53686 31943 PROJECT SUMMARYThe project and core leaders have 23-30 years of coordinated and collaborative research in the field of study(sphingolipids in cancer biology and therapy). Moreover the group continues to coordinate jointly the strategicdevelopment of the research questions as well as address specific research issues. Indeed a highly coordinatedgroup has emerged comprised of approximately 30 investigators students and postdoctoral fellows from the 4primary laboratories and 2 Shared Resources. The group shares contiguous or adjacent laboratory space atStony Brook University Cancer Center with many common equipment in a set up that allows fostering of theindividual identities of each lab while encouraging collaboration and sharing. The entire group meets weeklyand program leadership meets monthly. Consequently this group has acquired a highly advanced team spiritwith focus on studying sphingolipids in cancer biology and therapeutics. The group has a high level of jointpublications (in all permutations that also involve the core leaders).Core A the Administrative Shared Resource will continue to provide seamless integration at the operationallevel for the component projects and research shared resources of this Program. Thus the core will assist inthe overall administration and financial accountability of the Program Project the overall leadership thepromotion of the goals of the program and arranging the required meetings for the various program-relatedgroups and committees including the internal and external advisory committees. We have now 14+ years ofproof of the efficacy of this Core as no issues have emerged regarding budgeting meetings conflicts in coreuse or other possible sources of friction or discontent. +No NIH Category available Acute Erythroblastic Leukemia;Acute Megakaryocytic Leukemias;Acute Myelocytic Leukemia;Address;Aftercare;Anthracycline;Apoptosis;Cancer Biology;Cancer cell line;Cell Death Induction;Cell Line;Cell Proliferation;Cell Survival;Cell physiology;Cells;Ceramides;Chronic Myeloid Leukemia;Consumption;Cytarabine;Data;Diglycerides;Disease;Dose;Encyclopedias;Enzymes;Erythroblasts;Erythroid;GATA1 gene;Gene Expression;Genetic Transcription;Goals;Growth;Hematopoietic Neoplasms;Impairment;K-562;K562 Cells;Knowledge;Leukemic Cell;Link;Lipids;Maintenance;Malignant - descriptor;Malignant Neoplasms;Mediating;Megakaryoblast;Megakaryocytes;Messenger RNA;Metabolic;Molecular;Patients;Population;Probability;Production;Proliferating;Proteins;Publishing;Regulation;Residual Neoplasm;Resistance;Role;Sampling;Sphingolipids;Sphingosine;Testing;Therapeutic;Therapeutic Intervention;Work;acute myeloid leukemia cell;cancer cell;cancer therapy;chemotherapy;chronic myeloid leukemia cell;cytotoxic;effective therapy;efficacy evaluation;erythroleukemic cell;improved;inhibitor;leukemia;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;pharmacologic;promoter;protein activation;protein kinase D;sphingomyelin synthase;treatment response;tumor Project 4: Role and Function of Sphingomyelin Synthase 1 in Leukemia PROJECT NARRATIVE Acute Myeloid Leukemia (AML) is a blood cancer which presents a mere 26% 5-yearoverall survival after treatment with chemotherapy and a dismal probability of long termsurvival. This is mostly due to the presence of residual tumor cells after chemotherapythat have become resistant to the treatment. Unfortunately the therapeutic regiment forAML has mostly remained the same over the last three decades thus finding alternativeeffective treatments for this disease is an urgent unmet need. Since AML is aheterogeneous disease different therapeutic strategies may be needed to treat specificAML subclasses. Our results have pointed us to investigate the role and function ofparticular lipids (sphingolipids and glycerolipids) in the regulation of growth and survivalof a specific class of AML cells. Moreover the results have also shown promise insensitization of AML cells to current antileukemic chemotherapy; this would allow us touse lower doses of chemodrugs for the initial treatment of AML leaving the option ofescalating the dose in case of insurgence of resistance once the treatment is completed.These are all aspects that we will test with our proposed experimentation. NCI 10676803 8/8/23 0:00 PAR-18-290 5P01CA097132-20 5 P01 CA 97132 20 8/1/03 0:00 8/31/24 0:00 ZCA1-RPRB-F 9226 8354785 "LUBERTO, CHIARA " Not Applicable 1 Unavailable 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY Domestic Higher Education 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 197964 126306 71658 ABSTRACT The long-term goal of this project is to elucidate the role regulation and therapeutic potential ofsphingomyelin synthase (SMS) in cancer. The current proposal focuses on the function of SMS1 in growth ofGATA1 positive leukemic cells (in particular erythroblasts and megakaryoblasts) and on SMS1 as a potentialnovel therapeutic target in acute myeloid leukemias (AML) that are enriched in such malignant immaturepopulations (particularly M6 and M7 AML). SMS represents a class of lipid-metabolizing enzymes that consumes ceramide and producesdiacylglycerol (DAG) two critical bioactive lipids with opposing functions in the control of key cellular processesoften dysregulated during transformation including proliferation apoptosis and differentiation. Thus SMS maybe linked to cancer but knowledge on SMS regulation and downstream functions is limited. We previously showed that elevated expression of SMS1 is critical for proliferation of erythroleukemicK562 cells. Published and preliminary results also show that the elevated expression of SMS1 is aconsequence of enhanced transcription occurring through a novel alternative promoter positively regulated bythe transcription factor GATA1. Guided by gene expression data from the Cancer Cell Line Encyclopedia wediscovered that the highest SMS1 expression (mRNA and protein) in blood cancer cells is found in GATA1positive AML blasts (erythroblasts and megakaryoblasts). Importantly pharmacological and molecularinhibition of SMS1 in these leukemic cells revealed a critical role for SMS1 in proliferation and survival of thesecells that is not observed in GATA1-negative AML blasts. Thus based on these observations we hypothesize that SMS1 is an important novel regulator ofproliferation and maintenance of GATA1 positive AMLs and a potential novel target for improving thedismal therapeutic response of these leukemias. To address our hypothesis we will: 1. Determine the roleand function of SMS1 in GATA1 positive AML cells and 2. Establish SMS1 as a novel target fortherapeutic intervention against GATA1 positive AMLs.Our proposal aims at establishing SMS1 as a novel critical regulator of GATA1+ AML cells and might provide amolecularly informed and much needed novel therapeutic option for treatment of AML with erythroid ormegakaryocytic enrichment. +No NIH Category available Affect;Applications Grants;Area;Automobile Driving;Award;Bioinformatics;Biological Assay;Biology;Biopsy;Breast;CCND1 gene;CDK4 gene;Cancer Etiology;Categories;Cessation of life;Characteristics;Classification;Clinical;Clinical Trials;DNA Sequence Alteration;Data;Data Set;Development;Diagnosis;Disease;Distant Metastasis;ERBB2 gene;Exhibits;FGF19 gene;Fibroblast Growth Factor Receptors;Fluorescent in Situ Hybridization;Frequencies;Genes;Genome;Genomic approach;Genomics;Goals;Health;In Situ;Institution;Intelligence;Knowledge;Learning;Length;Life;Ligands;Malignant Neoplasms;Mammary Neoplasms;Mentorship;Metastatic breast cancer;Metastatic/Recurrent;Methods;Molecular;Multiomic Data;Neoplasm Metastasis;Oncologist;Participant;Pathway interactions;Patients;Phase Ib Clinical Trial;Plasma;Proteomics;Public Health;Receptor Inhibition;Recurrence;Research;Resistance;Role;Safety;Sampling;Signal Pathway;Specimen;System;Testing;The Cancer Genome Atlas;Therapeutic;Time;Tissue Sample;Training;Tumor Tissue;Tumor stage;United States;Universities;Woman;biomarker development;breast cancer genomics;cancer subtypes;career;career development;cohort;design;effective therapy;genetic variant;genome sequencing;genome-wide;high risk;hormone receptor-positive;hormone therapy;improved;improved outcome;inhibitor;insight;instructor;machine learning algorithm;machine learning method;malignant breast neoplasm;novel;novel strategies;novel therapeutic intervention;overexpression;patient subsets;personalized approach;personalized therapeutic;precision oncology;resistance mechanism;response;targeted treatment;transcriptome sequencing;translational scientist;treatment response;tumor;tumor-immune system interactions;whole genome Integrative subtyping to improve therapeutic options for metastatic hormone receptor-positive breast cancer Project NarrativeMetastatic breast cancer of which hormone receptor-positive breast cancer is the most common is estimatedto affect approximately 150000 women in the United States; most of these women will die of breast cancermaking it the second leading cause of cancer death among women. This proposal will examine distinctmolecular categories of hormone receptor-positive metastatic breast cancer to understand whether differenttreatments may affect these groups differently. The knowledge gained will lay the groundwork for apersonalized approach to therapy for metastatic breast cancer to improve health and lengthen life. NCI 10676801 8/21/23 0:00 PA-19-116 5K08CA252457-04 5 K08 CA 252457 4 "RADAEV, SERGEY" 9/3/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 14821177 "CASWELL-JIN, JENNIFER " Not Applicable 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 225518 NCI 208813 16705 Project Summary/AbstractThis is an application for a K08 Award to Dr Jennifer Caswell-Jin an Instructor and breast oncologist atStanford University establishing a career in translational breast cancer genomic research. The Award willsupport her career development by providing training in clinical trials biomarker development andbioinformatic analysis of multi-omic data under the expert mentorship of Dr Christina Curtis computational andcancer systems biologist and Dr George Sledge breast cancer clinical trialist and translational researcher.The proposed research focuses on the major public health problem of metastatic breast cancer estimated toaffect over 150000 women and to cause over 40000 deaths each year in the United States. Hormonereceptor-positive (HR+) breast cancer is the most common subtype. Eight integrative subtypes of HR+ breastcancer have been identified based on the integration of genome-wide copy number and expression informationin early-stage breast tumors. Four integrative subtypes together comprising one-quarter of all HR+ early-stagebreast cancers exhibit a very high risk of distant metastasis; each of these subtypes is characterized by adistinct area of the genome that exhibits concomitant copy number gain and overexpression. The studies inthis proposal will examine for the first time how integrative subtypes behave after metastasis with the drivinghypothesis that they may derive benefit from personalized therapeutic approaches. Aim 1 is to investigate thebiology and impact of integrative subtypes in metastatic HR+ breast cancer. We will develop novel approachesto assess integrative subtypes and will learn whether they change across metastasis whether they areassociated with timing of metastasis and whether they have differential lengths of response to standardtherapies. Aim 2 is to evaluate the effects of a novel combination of targeted therapy in two integrativesubtypes of metastatic breast cancer. We will perform a clinical trial that tests a targeted therapeutic approachin tumors classifying as one of two of the four high-risk integrative subtypes. Because these two subtypes aredefined by focal areas of genomic alteration involving either the fibroblast growth factor receptor ligand (FGF3;integrative subtype 2) or the fibroblast growth factor receptor (FGFR1; integrative subtype 6) we hypothesizethat these tumors may benefit from FGFR inhibition. Participants in this trial will receive standard endocrinetherapy in combination with CDK4/6 inhibition as well as an investigational agent that inhibits the fibroblastgrowth factor receptor pathway. We will also perform tumor biopsies before and during treatment to evaluatefor changes that occur with this combination targeted therapy approach. Successful completion of theproposed studies will lay the groundwork for continued efforts to develop a precision oncology approach formetastatic HR+ breast cancer with next steps to be proposed in an R01 grant application before the end of theK08 Award. 225518 +No NIH Category available Age Months;Apoptosis;Atlases;Autophagocytosis;Cancer Biology;Cancer Etiology;Cells;Ceramidase;Ceramides;Cessation of life;Chemotherapy-Oncologic Procedure;Clinical;Clinical Management;Coupled;DNA Damage;Databases;Development;Diethylnitrosamine;Disease;Down-Regulation;Epigenetic Process;Family;Genes;Genetic Transcription;Genomic Instability;Goals;Hepatocarcinogenesis;Hepatocyte;Human;Hydrolysis;Incidence;Lipids;Liver;Liver neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of liver;Mammals;Mediating;Mediator;Modality;Modeling;Molecular;Mus;Mutate;Mutation;Organoids;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Play;Predisposition;Primary carcinoma of the liver cells;Radiation therapy;Radio;Refractory;Repression;Resistance;Role;Saccharomyces cerevisiae;Signal Transduction;Sphingolipids;Sphingosine;Stress;Susceptibility Gene;TP53 gene;Testing;The Cancer Genome Atlas;Therapeutic;Time;Tissues;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;Xenograft Model;Yeasts;age related;cancer therapy;chemotherapy;improved;insight;member;mouse alkaline ceramidase;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;premalignant;response;targeted treatment;tumor;tumor xenograft Project 2: Role of ACER2 in Liver Cancer NarrativeLiver cancer is a leading cause of cancer deaths worldwide. Liver cancer remains refractory to many treatmentoptions; hence new therapeutic modalities are urgently needed. The specific goal of this application is toinvestigate how the alkaline ceramidase 2 gene (ACER2) a newly identified tumor suppressor gene suppressesliver cancer development and progression and whether increasing its expression can boost liver cancerchemotherapy. NCI 10676797 8/8/23 0:00 PAR-18-290 5P01CA097132-20 5 P01 CA 97132 20 8/1/03 0:00 8/31/24 0:00 ZCA1-RPRB-F 9224 6875190 "MAO, CUNGUI " Not Applicable 1 Unavailable 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY Domestic Higher Education 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 198738 126478 72260 AbstractHepatocellular carcinoma (HCC) a major type of liver cancer is a leading cause of cancer deaths worldwide.HCC remains refractory to most treatment options; hence new therapeutic modalities are urgently needed. Ourlong-term goal is to develop novel HCC therapeutics based on a deep understanding of its pathogenesis. Thespecific goal of this application is to define a novel tumor suppressive role for the alkaline ceramidase 2(ACER2) pathway in HCC development and progression. ACER2 is a member in the alkaline ceramidase familythat we identified initially from the yeast Saccharomyces cerevisiae and then from mammals. ACER2 catalyzesthe hydrolysis of ceramides to generate sphingosine (SPH) a bioactive lipid implicated in programmed cell death(PCD) and autophagy. We identify ACER2 as a novel transcriptional target of p53 and demonstrate that theACER2/SPH pathway is a novel signaling axis that operates downstream of p53 to mediate PCD in response toDNA damage. According to the TCGA database ACER2 is mutated or deleted suppressed in several cancers.A previous study finds that ACER2 is epigenetically repressed in HCC and our preliminary results reveal thatACER2 is downregulated in liver tumors compared to patient-matched adjacent non-tumor liver tissues.Remarkably we find that mice deficient in the alkaline ceramidase 2 (Acer2) gene are more susceptible to age-related development of various spontaneous tumor types including liver tumors suggesting that ACER2 is anovel tumor suppressor. According to these exciting findings we hypothesize that ACER2 is a novel tumorsuppressor whose suppression promotes HCC development progression and resistance to DNA-damagingchemotherapeutics. As a further corollary we hypothesize that rectifying the ACER2/SPH pathway will inhibitHCC and overcome the resistance of HCC to chemotherapeutics. These hypotheses will be tested in threeinterrelated specific aims: Aim 1 Establish that ACER2 plays a key tumor suppressive role in HCC using a livercarcinogenesis mouse model and liver organoid model Aim 2 Define the cellular and molecular mechanisms bywhich the repression of the ACER2/SPH pathway promotes liver tumorigenesis and Aim 3 Establish the role ofthe ACER2 pathway in improving the radio/chemotherapy of HCC. Successful completion of these aims will 1)validate the tumor suppressive role of the newly-identified tumor suppressor ACER2; 2) offer novel insights intothe mechanisms by which the newly identified p53/ACER2/SPH signaling axis mediates the DNA damageresponse and tumor suppression; and 3) provide a proof of concept to develop the ACER2/SPH pathway into anovel therapeutic target for HCC. Given the poor clinical outcome of patients with HCC these studies may havewidespread impact on the clinical management of these patients. +No NIH Category available Behavior;Biology;Breast Cancer Cell;Breast Cancer Model;Breast cancer metastasis;Cancer Biology;Cells;Ceramides;Cessation of life;Clustered Regularly Interspaced Short Palindromic Repeats;Coupled;Coupling;Data;Development;Enzymes;Family;Fatty acid glycerol esters;Future;Genetically Engineered Mouse;Goals;Growth;IL6 gene;Inflammation;Inflammation Mediators;Inflammatory;Injections;Interleukin-1;Invaded;Knock-out;Knockout Mice;Lipids;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator;Metabolism;Molecular;Mus;Neoplasm Metastasis;Pathway interactions;Phenotype;Play;Production;Publishing;RANTES;Regulation;Role;Signal Pathway;Solid;Sphingolipids;Structure;TNF gene;Tail;Tumor Cell Invasion;Veins;Woman;acid sphingomyelinase;cancer cell;cancer therapy;ceramide 1-phosphate;ceramide kinase;chemokine;cohort;cytokine;in vivo;inhibitor;malignant breast neoplasm;mammary;migration;neoplastic cell;new therapeutic target;novel;novel therapeutics;p38 Mitogen Activated Protein Kinase;polyoma middle tumor antigen;response;therapeutic development;transcription factor;tumor Project 1: The Acid Sphingomyelinase/Ceramide Kinase Pathway in Breast Cancer NarrativeThe studies proposed in this project aim at defining how an enzyme of lipid (fat)metabolism (ceramide kinase) regulates some key functions of cancer cells that result inthe production of factors that regulate the ability of the tumor cells to migrate and invade.These factors also regulate how the host cells respond to the tumor cells. Thesepathways are turning out to have key functions in the regulation of cancer invasion andmetastasis. Understanding these novel pathways and mechanisms not only enhancesour understanding of cancer behavior but also promises to lead us to the identificationof novel targets for developing new inhibitors of cancer metastasis. NCI 10676796 8/8/23 0:00 PAR-18-290 5P01CA097132-20 5 P01 CA 97132 20 8/1/03 0:00 8/31/24 0:00 ZCA1-RPRB-F 9223 1869058 "HANNUN, YUSUF AWNI" Not Applicable 1 Unavailable 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY Domestic Higher Education 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Non-SBIR/STTR 2023 207756 131990 75766 PROJECT SUMMARY Bioactive sphingolipids constitute a family of related molecules with profound effects on keycancer attributes. This proposal focuses specifically on heretofore unappreciated roles for an acidsphingomyelinase (ASM)/ceramide kinase (CERK)-mediated pathway of sphingolipid metabolismin regulating the formation of tumor cytokines and chemokines with roles in tumor inflammationand invasion. Our recent published studies demonstrate that ASM-generated ceramide is coupledto the action of CERK resulting in the formation of ceramide 1-phosphate (C1P) with a key rolein mediating the specific production of chemokines (e.g. CCL5) and cytokines (e.g. IL6) inresponse to TNF and IL1. Additional studies also disclose a key role for ASM and CERK inregulating tumor cell invasion and metastasis. These results coupled with the increasedappreciation of roles of TNF IL1 CCL5 and IL6 in cancer inflammation and metastasis have ledus to the hypothesis that this novel ASM/CERK/C1P pathway defines a previously unappreciatedmechanism regulating invasiveness and metastasis of breast cancer with potentially importantroles in cancer metastasis. We will evaluate this hypothesis by pursuing the following specificaims: 1.To define the roles and mechanisms by which the ASM/CERK/C1P pathway regulatesthe production of inflammatory mediators. 2. To establish the role of CERK in cancer growth andmetastasis. 3. To advance CERK as a novel therapeutic target for breast cancer by solving itsstructure. Taken together these studies are key in not only defining novel pathways andmechanisms of sphingolipid-mediated cancer biology at a molecular and cellular level but alsofor charting novel therapeutic potentials. The studies proposed in this project aim at defining how an enzyme of lipid (fat) metabolismregulates some key functions of cancer cells that result in the production of factors that regulatethe ability of the tumor cells to migrate and invade which are critical for cancer metastasis.Understanding these novel pathways and mechanisms not only enhances our understanding ofcancer behavior but also promises to lead us to the identification of novel targets for developingnew inhibitors of cancer metastasis. +No NIH Category available Acute;Address;Animals;Antitumor Response;Apoptosis;Area;Attenuated;Basic Science;Behavior;Biochemical;Biology;Breast;Breast cancer metastasis;Cancer Biology;Cell Death;Cell Survival;Cells;Ceramidase;Ceramides;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complex;DNA Damage;Development;Discipline;Enzymes;Erythroid;Fatty acid glycerol esters;Fingerprint;GATA1 gene;Goals;Golgi Apparatus;Growth;Head;Individual;Inflammation;Invaded;Knock-out;Legal patent;Link;Lipid Chemistry;Lipids;Malignant Neoplasms;Malignant neoplasm of liver;Manuscripts;Mediating;Mediator;Megakaryocytes;Metabolic;Metabolic Pathway;Metabolism;Methodology;Neoplasm Metastasis;Pathology;Pathway interactions;Primary carcinoma of the liver cells;Principal Investigator;Production;Productivity;Proliferating;Publications;Publishing;Reaction;Regulation;Research;Research Personnel;Resource Sharing;Role;SPHK1 enzyme;Sphingolipids;Sphingosine;TP53 gene;Technology;Testing;Therapeutic;Translational Research;Tumor Promotion;Tumor Suppressor Proteins;acid sphingomyelinase;advanced analytics;anticancer research;biobank;cancer cell;cancer therapy;carcinogenesis;ceramide kinase;deprivation;frontier;improved;in vivo Model;inhibitor;innovation;insight;interest;leukemia;leukemia/lymphoma;lipidomics;migration;mutant;neoplastic cell;novel;novel therapeutic intervention;physical property;preclinical study;programs;response;senescence;sphingomyelin synthase;sphingosine kinase;therapeutic target;therapeutically effective;treatment response;tumor;tumor initiation Sphingolipids in Cancer Biology and Therapy The studies proposed in this program project aim at defining how specific pathwaysof lipid (fat) metabolism and specific enzymes in these pathways regulate key functionsof cancer cells. These include the production of factors that regulate the ability of thetumor cells to migrate and invade; pathways that regulate responses to DNA damagemechanisms of cancer cell viability and death pathways of cancer differentiation andsenescence. These pathways are turning out to have key functions in the regulation ofcancer growth invasion differentiation and metastasis. Understanding these novelpathways and mechanisms not only enhances our understanding of cancer behavior butalso promises to lead us to the identification of novel targets for developing newinhibitors of cancer by focusing on specific enzymes (ceramide kinase alkalineceramidase sphingosine kinase and sphingomyelin synthase). The study of sphingolipids is very difficult and highly specialized yet very promisingfor cancer research. Our program brings together several investigators withcomplementary and overlapping interests and expertise. We have also developed twounique shared resources; an Animal cancer pathology core and a lipidomics core. NCI 10676784 8/8/23 0:00 PAR-18-290 5P01CA097132-20 5 P01 CA 97132 20 "KONDAPAKA, SUDHIR B" 8/1/03 0:00 8/31/24 0:00 ZCA1-RPRB-F(M1) 1869058 "HANNUN, YUSUF AWNI" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 804878247 M746VC6XMNH9 804878247 M746VC6XMNH9 US 40.914561 -73.125169 5992612 STATE UNIVERSITY NEW YORK STONY BROOK STONY BROOK NY SCHOOLS OF MEDICINE 117943362 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 395 Non-SBIR/STTR 2023 1299443 NCI 823319 476124 The overall organizing hypothesis of this Program posits that bioactive sphingolipids functionas important regulators of several key tumor cell attributes including tumor initiationdifferentiation growth apoptosis senescence inflammation invasion and metastasis. As acorollary enzymes of sphingolipid metabolism are emerging as specific and novel targets inmodulating these important cancer attributes. Unfortunately the study of bioactive lipids is rifewith complications both conceptual and technical and thus the study of lipids necessitates thecollaborative interactions of various disciplines and specialized cores. Thus we have evolved 4distinct projects that collaborate to investigate the overall hypothesis. These projects addresshighly interrelated metabolic pathways that converge on the Golgi apparatus. Each project hasidentified a key node in these pathways that constitutes a specific vulnerability in the target cancerunder study. Thus Project 1 will test and advance the hypothesis that the novel acidsphingomyelinase/ceramide kinase pathway defines a previously unappreciated mechanismregulating invasiveness and metastasis of breast cancer. Project 2 will test the hypothesis thatalkaline ceramidase 2 is a novel tumor suppressor whose suppression promotes developmentand progression of hepatocellular carcinoma. Project 3 will test the hypothesis that sphingosinekinase 1 (SK1) is a therapeutic target for p53 null and mutant cancers and that Ser/Glydeprivation can be harnessed therapeutically to degrade SK1 and lead to cancer cell death.Project 4 will test the hypothesis that sphingomyelin synthase 1 is an indispensable novelregulator of proliferation of GATA1-positive AMLs (including the poorly studied acute erythroidM6 and megakaryocytic M7 leukemias) and a potential novel target for improving the dismaltherapeutic response of these leukemias. These 4 projects will be supported by two uniqueresearch cores: The Lipidomics Shared Resource which will provide advanced analytical lipidchemistry and flux analysis and by a Sphingolipid Animal Cancer Pathobiology SharedResource that focuses on mutants/knock outs in enzymes of sphingolipid metabolism and modelsof in vivo carcinogenesis. It has recently introduced biobanking and CRISPR-mediated nock outs.This Program group has been highly integrated and productive (having published in the past 5years 76 manuscripts 50 of which were in collaboration) and has advanced significantly ourunderstanding of sphingolipids (one of the last frontiers of basic research) in caner biology andtherapeutics. We are now poised to advance pre-clinical studies and translational research basedon our understanding of these novel pathways. These studies continue to identify novel targetsand strategies for cancer therapeutics. 1299443 +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Acute leukemia;Adult;Advisory Committees;Age;Allogenic;Antigen Targeting;Antigens;Autologous;Award;Bone Marrow;Bone Marrow Cells;Bone Marrow Purging;CAR T cell therapy;CD 200;CD19 gene;CD3 Antigens;CRISPR/Cas technology;Cell Therapy;Cell model;Cells;Cellular immunotherapy;Chemotherapy and/or radiation;Clinical;Complication;Data;Detection;Diagnosis;Disease;Engineering;Engraftment;Exhibits;Funding;Gene Modified;Generations;Genes;Genomics;Goals;Granzyme;Hematopoietic;Hematopoietic stem cells;Heterogeneity;Immune;Immune Evasion;Immune System Diseases;Immune response;Immuno-Chemotherapy;Immunologic Stimulation;Immunosuppression;Immunotherapy;In complete remission;Interleukin-12;Laboratories;Legal patent;Leucine Zippers;Leukemic Cell;Malignant Neoplasms;Mediating;Memorial Sloan-Kettering Cancer Center;Mentorship;Molecular;Myelogenous;Myeloid-derived suppressor cells;Names;Patients;Physicians;Process;Progenitor Cell Engraftment;Proteins;Recurrent disease;Regimen;Regulatory T-Lymphocyte;Relapse;Research;Resistance;Risk;Running;Safety;Scientist;Signal Transduction;Site;Sorting;Specificity;System;T-Cell Activation;T-Cell Depletion;T-Cell Immunologic Specificity;T-Lymphocyte;Technology;Toxic effect;Transforming Growth Factor beta;Transgenes;Translations;Transplantation;Transplantation Chimera;Tumor Antigens;United States National Institutes of Health;Viral;Viral Vector;Xenograft procedure;acute myeloid leukemia cell;antigen binding;chemotherapy;chimeric antigen receptor;chimeric antigen receptor T cells;comorbidity;conditioning;cytokine;design and construction;efficacious treatment;engineered T cells;exhaustion;gene therapy;graft vs host disease;hematopoietic cell transplantation;humanized mouse;immune checkpoint;improved;interleukin-12 receptor;knowledge base;leukemia;novel;novel therapeutics;patient derived xenograft model;perforin;prevent;programmed cell death ligand 1;receptor;recruit;skills;success;synthetic biology;tenure track Multi-antigen-specific CAR T cells to treat acute myeloid leukemia NARRATIVEAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults and most patients will diefrom their disease. Chimeric antigen receptor (CAR) T cell therapy is a novel form of cellular immunotherapy thathas demonstrated great success in acute lymphoblastic leukemia but translation of CAR T cell therapy to AMLis complicated by (1) heterogeneous target antigen expression in AML (2) expression of some target antigenson normal bone marrow cells in addition to AML and (3) active immune-suppressive strategies employed byAML. The goals of this project are to generate multi-antigen-specific CAR T cells to eliminate AML by mitigatingescape of antigen-negative leukemia to identify sets of AML target antigens that are either non-myelosuppressive when targeted or that are myeloablative and can facilitate donor hematopoietic cellengraftment and to further engineer CAR T cells to overcome AML-induced immune suppression. NCI 10676774 8/25/23 0:00 PA-19-117 5K08CA252157-04 5 K08 CA 252157 4 "BIAN, YANSONG" 9/1/20 0:00 8/31/25 0:00 Career Development Study Section (J)[NCI-J] 7755274 "JAMES, SCOTT E" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 Other Research-Related 2023 263034 NCI 243550 19484 PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy is a novel form of cellular immunotherapy in which theantigen specificity of T cells is redirected using synthetic receptors. CD19-CAR T cells have achieved completeresponses in up to 90% of patients with acute lymphoblastic leukemia. However many malignancies do notpossess a single highly expressed tumor-associated antigen (TAA) such as CD19. Furthermore CD19-negativerelapses have been frequently encountered following CD19-CAR T cell therapy suggesting that multi-antigen-targeting approaches will be needed to reduce relapse. Acute myeloid leukemia (AML) is the most commonacute leukemia in adults and the majority of patients will die from their disease. We and others are evaluatingCAR T cells to treat AML. However AML exhibits heterogeneous expression of TAAs and many of these TAAsare expressed on hematopoietic progenitor cells (HPCs) increasing the risk of antigen-negative AML immuneescape and bone marrow toxicity following AML-targeting CAR T cell therapy respectively. Additionally AMLemploys many active immune-suppressive strategies that may inhibit CAR T cells. To overcome these challenges I have recently developed a novel viral co-transduction and sortingsystem to allow generation and purification of T cells with multiple transgenes such as multiple CARs immune-stimulating molecules safety switches and secreted cytokines. Preliminary data suggest that multi-functionalCAR T cells can be engineered to overcome antigen-negative leukemia escape and immune suppressionmechanisms. I hypothesize that this novel sorting system can be used to engineer T cells to overcome AMLTAA heterogeneity and immune suppressive strategies. Aim 1 will investigate CAR T cells simultaneouslytargeting a set of AML TAAs and predicted to avoid toxicity to HPCs. CAR T cells engineered to overcome AML-induced immune suppression will also be evaluated. In Aim 2 the goal is to target a set of TAAs expressed byboth AML and HPCs as part of a pre-transplant CAR T cell immunotherapy strategy. During the award period the candidate will conduct research at Memorial Sloan Kettering Cancer Centerunder the mentorship of Dr. Marcel van den Brink and an Advisory Committee. He will obtain the critical skills heneeds to become a tenure-track physician-scientist running his own academic laboratory developing syntheticbiology approaches to improve cellular therapies and successfully competing for independent NIH funding. Hewill cultivate a detailed and comprehensive skill set for syngeneic xenograft and humanized mouse models ofcellular immunotherapy build upon an existing knowledge base of molecular construct design and cellular genemodification by mastering multiplexed CRISPR/Cas9 gene disruptions and site-specific gene integration anddevelop proficiency in genomic analysis to better define T cell activation and exhaustion states and to identifynovel targets for gene therapy. 263034 +No NIH Category available Adopted;Affect;Alveolar;Binding;Biological Assay;Cancer Etiology;Cell Line;Cells;Cessation of life;ChIP-seq;Chromatin;Data;Development;Differentiation and Growth;Disease;Disparate;Epigenetic Process;Evolution;Gastrointestinal tract structure;Genes;Genetic;Genetic Transcription;Growth;HNF4A gene;Heterogeneity;Human;K-ras mouse model;KRAS2 gene;Knowledge;Ligation;Lung;Lung Adenocarcinoma;MAP Kinase Gene;MEKs;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Modeling;Molecular;Mus;Mutation;Nuclear Receptors;Oncogenic;Organoids;Pathway interactions;Phosphorylation;Proliferating;Research;Role;Signal Pathway;Signal Transduction;Specific qualifier value;Stomach;Testing;Therapeutic;Visualization;Work;Xenograft Model;Xenograft procedure;experimental study;gastrointestinal;genetic approach;innovation;insight;interest;knock-down;liver development;mortality;mouse model;mutant;neoplastic cell;pharmacologic;programs;protein complex;subcutaneous;targeted treatment;transcription factor;transcriptome sequencing;treatment response;tumor;tumor growth;tumor progression;tumorigenesis Investigating molecular regulators of a mixed-lineage state in lung adenocarcinoma PROJECT NARRATIVELung adenocarcinoma (LUAD) is the most common cause of cancer mortality worldwide and is difficult to targettherapeutically due to substantial heterogeneity and lineage plasticity that arises during progression andtherapeutic response. However the mechanisms controlling differentiation state and plasticity in LUAD are notwell understood and there is an urgent unmet need to identity drivers of LUAD plasticity both during progressionand therapeutic response. This proposal will investigate the mechanisms by which key lineage specifyingtranscription factors and oncogenic signaling pathways concomitantly influence LUAD growth and differentiationstate and the results that derive from this study may help to inform development of lineage-targeted therapiesfor LUAD. NCI 10676765 8/1/23 0:00 PA-21-051 5F31CA275328-02 5 F31 CA 275328 2 "SCHMIDT, MICHAEL K" 8/1/22 0:00 7/31/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 78128340 "FORT, GABRIELA M" Not Applicable 1 INTERNAL MEDICINE/MEDICINE 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 37806 NCI 37806 0 PROJECT ABSTRACT:Lung adenocarcinoma (LUAD) is the largest subtype of lung cancer and is the most common cause of cancerrelated death. LUAD progression is driven by a combination of genetic alterations and epigenetic changes thatconfer increased plasticity and heterogeneity but underlying mechanisms dictating cell fate and plasticity inLUAD remain poorly understood. Interestingly the lineage defining transcription factors NKX2-1 and FoxA1/2coordinately maintain a pulmonary identity in LUAD. In the absence of NKX2-1 FoxA1/2 can activate gastrictranscription factors including HNF4 to substantially alter the differentiation state of LUAD. Recent worksuggests that NKX2-1-positive (NKX2-1+) LUAD evolves from an alveolar-like state and adopts various disparatecell fates that drive progression including mixed lineage states characterized by acquisition of gastrointestinal(GI) and pulmonary-like states in the same cell. This proposal will investigate how these gastric states aremaintained and how they may promote LUAD tumorigenesis. HNF4 levels increase over the course of LUADprogression and HNF4 and NKX2-1 are co-expressed in a subset of human and mouse NKX2-1+ LUADtumors. This supports a putative model by which HNF4 drives LUAD progression and promotes a mixed-lineagestate by competing with NKX2-1 for FoxA1/2 binding. Additionally given previous findings that MAPK signalingis important for LUAD progression and alveolar fate and that NKX2-1 is known to be phosphorylated andinactivated by ERK MEK/ERK signaling may promote mixed-lineage states by destabilizing NKX2-1/FoxA1/2interactions and favoring HNF4/FoxA1/2 binding. I hypothesize that HNF4 promotes LUAD tumorigenesisand proliferation and that MAPK signaling modulates the mixed-lineage state by altering the activity andinteractions of key lineage specifiers. To test this hypothesis I will modulate MAPK signaling usingcomplementary pharmacological and genetic approaches and assess expression of key mixed lineage genesas well as visualizing protein complexes upon MAPK manipulation using a Proximity Ligation Assay. AdditionallyI will perform ChIP-seq to determine how modulating MEK/ERK alters NKX2-1 and FoxA1/2 chromatin bindingat gastric and pulmonary targets. I will also expand on preliminary data from our group demonstrating that HNF4drives tumorigenesis and proliferation in murine organoids as well as a KRAS-driven LUAD mouse model. I willgenetically modulate HNF4A in human LUAD cell lines expressing both NKX2-1 and HNF4A performproliferation assays and create cell line xenograft models to measure tumor growth. I will perform integrativeRNA-seq and ChIP-seq analysis to understand key factors underlying HNF4-mediated growth and progressionin NKX2-1+ LUAD. Completion of these aims will unveil key insights into the mechanisms by which LUADheterogeneity drives tumor growth and progression knowledge which will be critical for development of effectivelineage-targeted therapies for this disease. This proposal will also explore the innovative notion that oncogenicsignaling pathways and key transcription factors coordinately regulate cellular fate in cancer. 37806 +No NIH Category available Area;Bioinformatics;Biometry;Cancer Patient;ChIP-seq;Computer software;Data;Data Analyses;Data Science;Data Science Core;Databases;Development;Ensure;Experimental Designs;FAIR principles;Faculty;Genomics;Goals;Guidelines;Immunotherapy;In Vitro;Informatics;Knowledge Discovery;Lead;Location;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Mass Spectrum Analysis;Metabolic;Metabolism;Metadata;Methods;Mission;Molecular;Molecular Analysis;Outcome;Pathologic;Pathology;Pre-Clinical Model;Preparation;Procedures;Program Research Project Grants;Proteomics;Quality Control;Randomized;Reporting;Reproducibility;Research;Research Personnel;Research Project Grants;Research Support;Sampling;Services;Specimen;Statistical Data Interpretation;Therapeutic;Translations;Visualization;Visualization software;Work;bioinformatics tool;data exchange;data integration;data quality;data repository;data sharing;data visualization;design;digital;experience;experimental study;high dimensionality;improved;in vitro Model;in vivo Model;innovation;member;metabolomics;method development;multidisciplinary;novel therapeutic intervention;programs;research and development;response;skills;synergism;therapeutic target;tool;transcriptome sequencing;transcriptomics;translational research program;virtual Data Science Core CORE 4 PROJECT NARRATIVE DATA SCIENCE COREThe Data Science Core (Core #4) is an integral part of the research mission of this P01 to identify metabolicvulnerabilities in lung cancer. The goal of the Core #4 is to provide comprehensive multidisciplinary expertiseto support the data science needs of program investigators with a focus on reproducible research. The Core#4 consists of faculty and staff with a diverse skill set and expertise in providing data science support in theareas of biostatistics statistical genomics bioinformatics and informatics. NCI 10676758 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9214 8895208 "FRIDLEY, BROOKE L" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 154984 94101 60883 CORE 4 PROJECT SUMMARY DATA SCIENCE COREThe mission of the Data Science Core (Core #4) is to serve as the focal point from which Program Projectinvestigators can draw statistical bioinformatic and informatics expertise for the completion of their lungresearch projects. Core #4 members have extensive experience in applied cancer biostatistics andbioinformatics and will be involved in all projects to help investigators with the data science needs of theirprojects. As studies proceed Core #4 members will contribute to the refinement of standard operatingprocedures in response to realities of fieldwork integrate data conduct data quality-control studies and producenecessary reports. As projects yield results the Core #4 will conduct analyses and assist investigators with thepreparation of presentations and manuscripts. To achieve the overarching goal to develop a comprehensiveresearch program focused on the translation of new treatments for lung cancer the Core #4 has the followingspecific aims. Aim 1: To provide statistical expertise from project initiation through completion. The Core #4 willsupport all statistical analyses required for the completion of the projects including but not limited to:experimental design (randomization); power calculation; statistical association analysis of molecular data(metabolomics transcriptomic); and analysis of data from in vitro and in vivo models. Aim 2: To providebioinformatics analysis and support for the research projects. Using state of the art bioinformatics tools the Core#4 will analyze various types of high-dimensional molecular data such as data generated via sequencing ormass spectrometry resulting from the various projects. Aim 3: To provide database and data integration servicesfor projects and cores. As part of Aim 3 the Core #4 will develop the Lung Cancer Data Repository (LCDR) tostorage all data and metadata related to the experiments into a single virtual location for cross-project integration.In summary the Core #4 will provide value and scientific impact to the proposed projects through quantitativeexpertise aligned with the goal of determining metabolic vulnerabilities in lung cancer that would lead to newtreatment strategies for lung cancer patients. +No NIH Category available Address;Archives;Biological;Biological Assay;Cancer Biology;Cancer Center;Cancer Patient;Cell Communication;Cell Line;Collaborations;Complex;Computer software;Conceptions;Core Grant;Cysteine Metabolism Pathway;Data;Data Analyses;Data Science;Data Science Core;Data Scientist;Data Set;Dedications;Development;Enzyme Inhibition;Enzymes;Equipment;Experimental Designs;Faculty;Family member;Gas Chromatography;Genetically Engineered Mouse;Genomics;Glycolysis;Goals;Grant;Guidelines;Human;Immune system;Individual;Intervention;Knowledge;Location;Lung Neoplasms;Malignant neoplasm of lung;Maps;Mass Chromatography;Mass Fragmentography;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular;Monitor;Myeloid-derived suppressor cells;Pathology;Pathway interactions;Phenotype;Play;Post Translational Modification Analysis;Pramlintide;Pre-Clinical Model;Preparation;Program Research Project Grants;Protein Analysis;Proteins;Proteomics;Publications;Publishing;Quality Control;Research;Research Personnel;Research Support;Role;Sampling;Services;Stable Isotope Labeling;Sulfhydryl Compounds;TP53 gene;Techniques;Testing;Tumor Biology;Tumor Escape;Tumor-infiltrating immune cells;Work;Xenograft procedure;activity-based protein profiling;assay development;data acquisition;data integration;data repository;design;experience;experimental study;improved outcome;interest;lipid metabolism;liquid chromatography mass spectrometry;member;metabolomics;method development;molecular scale;multiple datasets;novel;potential biomarker;preservation;public repository;quality assurance;response;sample collection;small cell lung carcinoma;success;synergism;tool;tumor;tumor immunology;tumor metabolism Metabolomics Core CORE 3 PROJECT NARRATIVE METABOLISM COREThe Metabolism Core (Core #3) provides services to support the projects and is a central and key componentof this program project grant (PPG). The goal of Core #3 is to provide experience and expertise to supportexperimental design sample preparation data acquisition quality control collaboration with Core #4 foranalysis and assistance with biological interpretation of results to support the research proposed by the PPGproject investigators. The faculty and staff involved in Core #3 apply complementary metabolomics andproteomics approaches to address complex hypotheses in preclinical models (e.g. cell lines xenografts andgenetically engineered mouse models) as well as human tumors and actively collaborate to maximize theavailability and utility of the results. NCI 10676752 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9213 8611981 "KOOMEN, JOHN M" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 189026 114770 74256 CORE 3 PROJECT SUMMARY METABOLISM COREThe Metabolism Core (Core #3) supports the metabolomics and proteomics experiments designed by programproject grant (PPG) investigators as integral parts of their proposed research. These large-scale moleculardata analysis strategies are used by all four projects in this PPG which provides synergistic linkage pointsfacilitated by Core #3 across projects for cross identification of metabolites and proteins that play importantroles in lung cancer biology and immunology. Core #3 members have extensive experience in cancermetabolism metabolomics proteomics liquid chromatography-mass spectrometry gas chromatography-massspectrometry collaboration with investigators collaboration with data scientists (including members of Core#4) and customer service. These efforts will contribute to projects from inception to completion (i.e. fromhypothesis to publication). Core #3 will support optimization of experimental design for mass spectrometry-based omics (Aim 1) which includes implementation of previously published strategies and development ofnovel methods for sample preparation separations including gas and liquid chromatography and massspectrometry to support the experiments required by PPG investigators. Datasets will be acquired withuntargeted metabolomics discovery proteomics analysis of post-translational modifications and targetedassay development for metabolites and proteins utilizing state-of-the-art separations and mass spectrometryequipment at Moffitt Cancer Center (Aim 2). Core #3 members will contribute to quality assurance/qualitycontrol for data acquired for each project and collaborate with PPG investigators and other PPG Cores toproduce high quality datasets and develop data analysis strategies to maximize availability and usage of omicsdata across PPG Projects (Aim 3). In summary Core #3 will make a significant contribution to the proposedresearch by elucidating molecular mechanisms underlying lung tumor biology and tumor-immune cellinteractions which may ultimately reveal potential biomarkers and novel treatment targets to be furtherinvestigated in functional studies proposed by the PPG Projects. +No NIH Category available Acceleration;Adenocarcinoma;Adenocarcinoma Cell;Alleles;Animal Experiments;Animals;Antibodies;Artificial Intelligence;Biological Markers;Brassicaceae;Breeding;Cancer Center;Cancer Model;Cells;Chimera organism;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Complex;Consultations;Core Facility;Critical Pathways;DNA cassette;Data;Data Set;Derivation procedure;Development;Diagnosis;Diagnostic;Environment;Enzymes;Evaluation;Experimental Designs;Fertilization in Vitro;Gene Expression;Gene Targeting;Generations;Genes;Genetically Engineered Mouse;Genotype;Histology;Histopathology;Human;Image;Image Analysis;Immunofluorescence Immunologic;Immunohistochemistry;Individual;Injections;Investigation;Knowledge;Libraries;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Manuscripts;Measurement;Metabolic;Microscopic;Modeling;Molecular;Mus;Organoids;Outcome;Pathologic;Pathologist;Pathology;Patients;Pre-Clinical Model;Process;Production;Research;Research Personnel;Resolution;Resource Sharing;Resources;Services;Slide;Specimen;Speed;Squamous cell carcinoma;Structure;Tissue Microarray;Training;Transgenic Organisms;Tumor Burden;Validation;Writing;algorithm development;animal tissue;blastocyst;cancer imaging;cohort;data dictionary;deep learning;digital;digital pathology;embryo cryopreservation;embryonic stem cell;fluorescence imaging;high resolution imaging;histological specimens;homologous recombination;human tissue;immune cell infiltrate;in vivo;inducible gene expression;innovation;interest;learning strategy;lung tumorigenesis;machine learning algorithm;method development;model development;mouse model;novel;pre-clinical;predictive modeling;programs;quantitative imaging;repository;service learning;small cell lung carcinoma;sperm cryopreservation;success;tissue resource;tumor;tumor growth;tumor metabolism;zygote Pre-Clinical Core CORE 2 PROJECT NARRATIVEPRECLINICAL MODELS AND PATHOLOGY COREThe Preclinical Models and Pathology Core (Core #2) is a central component of the Program in Lung CancerMetabolism. Core #2 will provide three extraordinary services and expertise that are not provided as CancerCenter standard shared resources: 1) generation of speedy mouse models with alterations in metabolic genes2) digital pathology driven by artificial intelligence to rapidly and quantitatively assess the cancer outcome inthese mouse models and 3) integrated research-focused pathology services and resources to validate theconclusions from mouse models using well-annotated human specimens and organoid models. NCI 10676748 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9212 1896485 "CRESS, WILLIAM DOUGLAS" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 336200 204129 132071 CORE 2 PROJECT SUMMARYPRECLINICAL MODELS AND PATHOLOGY COREThe Preclinical Core (Core #2) leverages the knowledge and expertise from several Moffitt investigators andcore facilities and will pursue three aims that systematically support the Program Projects at three criticalstages; 1) model development 2) measurement and analysis of outcome and 3) validation in human cohortsand organoid models. In the Aim 1 Core #2 is tasked with mouse model generation and characterization. TheCore will use the embryonic stem cell-genetically engineered mouse model (ESC-GEMM) approach to enablethe rapid generation of lung cancer mouse models. To this end ESCs will be established from existing lungcancer GEMMs that also harbor regulatory alleles for efficient targeting of ESCs and control of geneexpression. ESCs will be targeted with inducible expression cassettes followed by injection into blastocysts togenerate chimeric animals. ESC-derived lung cells in such chimeras carry the alleles necessary to induce lungtumorigenesis and chimeras will be used as experimental animals without further breeding. This approachallows for the very rapid generation of lung cancer models having modulated expression or activity of metabolicenzymes of interest. In Aim 2 Core #2 will streamline the quantification of tumor burden in these mousemodels by providing digital pathological (DP) analysis of murine lung cancer models. As input histology slidesare imaged at multiple magnifications using automated slide scanners. The resulting high-resolution imagesare processed and analyzed using innovative machine learning algorithms we have developed. The platformallows for the identification characterization and quantification of lung tumors and individual cells within wholelung sections. Deep learning methods will be applied to provide a comprehensive characterization of lungtumors including tumor grading and the assessment of immune cell infiltration. Histology samples anddatasets created by the program projects will be used to create training libraries for new algorithmdevelopment. The DP platform allows for highly accurate and rapid image analysis accelerating thecharacterization of lung tumor models. In Aim 3 Core #2 will provide resources and expertise to validateoutcomes from the mouse studies of the first two Aims. The Core will provide large well-annotated humancohorts represented by tissue microarrays and a centralized workflow for the generation of organoid models.The Core will assist with project planning and method development diagnostic consultation biomarker scoringresult interpretation and manuscript writing. Additional pathology resources will include microscopic evaluationof animal and human tissues for adequacy and diagnosis antibody selection guidance optimization forimmunohistochemistry (IHC) and multiplexed immunofluorescence imaging. +No NIH Category available Achievement;Administrator;Area;Biological;Budgets;Cancer Center;Collaborations;Communication;Communities;Conceptions;Data;Data Analyses;Data Science;Data Science Core;Databases;Development;Disease;Doctor of Philosophy;Ensure;Experimental Designs;Fostering;Goals;Institution;Institutional Policy;Laboratories;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolism;Methods;Modeling;Molecular;National Cancer Institute;Phenotype;Postdoctoral Fellow;Preparation;Procedures;Program Research Project Grants;Progress Reports;Publications;Records;Regulation;Reproducibility;Resource Sharing;Resources;Role;Sampling;Scientist;Services;Training;United States National Institutes of Health;Work;animal imaging;cancer subtypes;comparative;data repository;data sharing;data submission;experience;experimental analysis;experimental study;meetings;member;mouse model;operation;programs;public database;quality assurance;success;synergism;timeline;tumor metabolism Administrative Core CORE 1 PROJECT NARRATIVE ADMINISTRATIVE COREThe Administrative Core serves as the central node for all Projects and Cores of the Program Project Grant(PPG) with the overarching goal of providing resources and facilitating interactions between the laboratoriesinvolved. The Administrative Core has 3 goals: 1.) to provide administrative services including organization ofmeetings and annual retreats 2.) to ensure robust integration of project and core activities with the highest levelof scientific rigor and reproducibility of data and 3.) to support internal and external resource and datasharing. These goals will be accomplished through the efforts of the leadership of the Core Leaders and twoPhD level support staff the Program Management Director and the Administrative Director. NCI 10676745 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9211 1900074 "FLORES, ELSA R" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 101646 61716 39930 CORE 1 PROJECT SUMMARY ADMINISTRATIVE COREThe Administrative Core serves as the central node for all Projects and Cores of the Program Project Grant(PPG) with the overarching goal of providing resources and facilitating interactions between the laboratoriesinvolved. To accomplish this goal two PhD level scientists have been appointed to distinct and complementaryroles within the Administrative Core. The PPG Administrative Director will specialize in providing administrativeorganizational and communication support in order to facilitate the completion of program project goals (Aim 1).To accomplish this aim the PPG Administrative Director will organize regular meetings of the program projectgroup plan an annual retreat including the Internal and External Advisory Boards and oversee the fiscaloperations of all projects and cores to ensure compliance with the proposed budgets and timelines. The PPGProject Management Director will be responsible for ensuring robust integration of project and core activities withthe highest level of scientific rigor and reproducibility of data (Aim 2). This aim will include the developmentof a database of standard operating procedures (SOPs) for both experimental design and data analysis in orderto optimize the reproducibility of experiments across disease platforms and program project laboratories.Additionally the PPG Project Management Director will implement clear experimental pipelines to facilitate thetransition of samples and data across multiple program project and/or institutional cores. Finally the membersof the Administrative Core will work together with Core #4 (Data Science Core) to support the internal andexternal sharing of program project generated resources (Aim 3). For the internal sharing of data Core #1 andCore #4 will maintain the Lung Cancer Data Repository (LCDR) which will allow comparative analyses acrossprojects species and lung cancer subtypes. As the point of contact for both internal and external sharing ofresources the Administrative Core is essential for fostering synergy among the program project members andfor ensuring the long-term success of the PPG team. +No NIH Category available Animal Model;Antigen Presentation;Bioinformatics;Cells;Cellular immunotherapy;Clinical;Clinical Research;Combination immunotherapy;Combined Modality Therapy;Cross Presentation;Data;Dendritic Cells;Development;Disease;Distant;Dose;Environment;Failure;Fractionation;Genetic Engineering;Goals;Growth and Development function;Head and Neck Squamous Cell Carcinoma;Immune;Immune response;Immunity;Immunocompetent;Immunology;Immunotherapy;Infiltration;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Modeling;Mus;Neoplasm Metastasis;Organ Preservation;Outcome;Patient-Focused Outcomes;Patients;Phenotype;Play;Population;Pre-Clinical Model;Predisposition;Radiation;Radiation Dose Unit;Radiation Interaction;Radiation therapy;Regulation;Research Design;Resectable;Residual state;Role;Sampling;Site;T cell response;T-Lymphocyte;Testing;Time;Tumor Antigens;Tumor Immunity;Vaccines;anti-tumor immune response;antigen-specific T cells;cancer cell;checkpoint therapy;draining lymph node;functional restoration;genetic analysis;immune cell infiltrate;immunogenic;implantation;improved;improved outcome;in situ vaccine;novel;pre-clinical;prevent;radiation effect;radiation response;response;success;therapy outcome;tumor;tumor growth High dose radiation therapy to direct immune responses to pancreatic cancer PROJECT NARRATIVEThis proposal aims to investigate the contribution of pre-existing responses to local treatment success and themechanisms limiting T cell priming by radiation therapy in preclinical models and in patients. We use highquality preclinical models of radiation therapy and immunotherapy to understand the mechanisms of successand failure in T cell control of residual local and distant disease. This is combined with analysis of clinicalsamples to understand the interactions of immune cells and radiation therapy in tumor control. NCI 10676741 5/31/23 0:00 PA-18-484 5R01CA182311-10 5 R01 CA 182311 10 "VIKRAM, BHADRASAIN" 6/15/14 0:00 5/31/24 0:00 Radiation Therapeutics and Biology Study Section[RTB] 10127825 "GOUGH, MICHAEL JAMES" Not Applicable 3 Unavailable 99142093 C11KXJTP6ED1 99142093 C11KXJTP6ED1 US 45.527846 -122.613886 2574706 PROVIDENCE PORTLAND MEDICAL CENTER PORTLAND OR Independent Hospitals 972132933 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 384038 NCI 232750 151288 PROJECT SUMMARYThe critical preliminary data for this proposal is that in preclinical models pre-existing tumor-resident T cellsare both necessary and sufficient for tumor control by radiation therapy and immunotherapy. We demonstratethat in poorly immunogenic tumors cross-presenting dendritic cells in the tumor-draining lymph node may beplaying no significant role in tumor control. In these models radiation and immunotherapy are an effectivemeans of local control but fail to engender new systemic immunity. The aim of this proposal is to understandhow radiation interacts with tumor resident T cells for local control and how to restore cross-presentation oftumor-associated antigens to generate new systemic anti-tumor immune responses. We hypothesize that theendogenous vaccine effect of radiation therapy is limited in poorly immunogenic tumors and current successrelies on amplifying pre-existing anti-tumor immunity. The specific aims of this study are to 1: Test thehypothesis that in the presence of pre-existing immunity tumor control by radiation therapy andimmunotherapy occurs independent of cross-presentation and new immune responses; 2: Test the hypothesisthat deficient DC cross-presentation limits the ability of radiation therapy to initiate new systemic anti-tumorimmune responses; 3: Test the hypothesis that regulation of antigen presentation and cross-presenting DCcan be assessed in patient tumors using genetic analysis. Our study design incorporates CT-guided radiationtherapy and results are validated in multiple tumor models including those from genetically engineeredspontaneous models using a range of RT doses and fractionations. Our analyses of clinical samples use highquality bioinformatic approaches that allow us to evaluate the infiltrating immune cells and antigen presentationin patient tumors. These are applied to a unique clinical study that allows us to validate our preclinicalobservations in patients. 384038 +No NIH Category available Alanine;Amino Acids;Binding;Biological Assay;CRISPR screen;Cancer Model;Cancer Patient;Cancer cell line;Carbon;Cell Death;Cell Survival;Chemoresistance;Cholesterol;Cisplatin;Classification;Clinic;Clinical;Collaborations;Combined Modality Therapy;Cysteine;Data Set;Development;Disease;Disease Resistance;Drug Screening;Enzymes;Epidermal Growth Factor Receptor;Etoposide;Fatty Acids;Genetic;Genetic Engineering;Genetic study;Genetically Engineered Mouse;Genomics;Glucose;Glutamates;Glutamine;Glycolysis;Growth;Hexoses;Human;Immunologic Surveillance;Immunosuppression;Impairment;Knock-out;Lactate Transporter;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Metabolic;Metabolism;Mus;Neoplasm Circulating Cells;Non-Small-Cell Lung Carcinoma;Oleates;Oncogenic;Oxidative Phosphorylation;Patients;Phosphotransferases;Primary Neoplasm;Proteome;Proteomics;Proto-Oncogene Proteins c-myc;Resistance;Retinoblastoma Protein;Role;Structure of parenchyma of lung;Survival Rate;TP53 gene;Testing;Therapeutic;Tumor Tissue;Tumor-infiltrating immune cells;Up-Regulation;Xenobiotics;Xenograft procedure;cancer genomics;cancer therapy;checkpoint therapy;chemotherapy;data integration;druggable target;effective therapy;efficacy study;embryonic stem cell;enzyme activity;experimental study;genetic approach;in vivo;inhibitor;inorganic phosphate;lipid metabolism;lipidomics;loss of function mutation;metabolome;metabolomics;mouse model;mutant;neoplastic cell;new therapeutic target;novel therapeutics;overexpression;patient derived xenograft model;pharmacologic;prevent;purine metabolism;relapse patients;response;retinoblastoma tumor suppressor;safety study;safety testing;small cell lung carcinoma;standard of care;synergism;targeted treatment;transcription factor;transcriptome sequencing;treatment strategy;tumor;tumor metabolism;tumor xenograft;validation studies Project 3 PROJECT 3 NARRATIVEROLES AND MECHANISMS OF ACTION OF METABOLIC VULNERABILITIES OF SCLCTo identify new therapeutic targets for small cell lung cancer (SCLC) a recalcitrant disease that lacks targetedtherapies we performed state-of-the-art mass spectrometry-based screens for SCLC-specific changes in theATP binding proteome expressed proteome and the metabolome. We identified metabolic hubs that areselectively up-regulated in both treatment nave and chemoresistant SCLC and showed that combinedpharmacological inhibition or genetic loss of MCT lactate transporters and the PFKFB3 glycolytic enzymeprovokes SCLC metabolic collapse growth arrest and cell death. Using new and established mouse models ofSCLC patient-derived SCLC tumors and circulating tumor cells from SCLC patients Project #3 will assess theroles of MCT transporters and PFKFB3 in controlling the metabolism development and maintenance of SCLCwill test if co-targeting MCT and PFKFB3 delays or eliminates emergence of resistant disease alone or whencombined with standard-of-care chemotherapy and will identify additional metabolic vulnerabilities of SCLC. NCI 10676736 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9209 1877243 "CLEVELAND, JOHN L." Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 338052 205253 132799 PROJECT 3 SUMMARYROLES AND MECHANISMS OF ACTION OF METABOLIC VULNERABILITIES OF SCLCSmall cell lung cancer (SCLC) lacks targeted therapies and with only 7% overall survival on standard-of-carecisplatin/etoposide chemotherapy and only 10% survival on immune checkpoint therapy NCI has classifiedSCLC as a recalcitrant malignancy. Thus there is an urgent need to identify new and effective targeted therapiesfor SCLC. In non-small cell lung cancer (NSCLC) genomic studies led to effective targeted therapies directed atdrivers such as mutant EGFR. Unfortunately drivers of SCLC are undruggable where there are loss-of-functionmutations in the tumor suppressors retinoblastoma protein (RB1) p53 (TP53) and p73 as well as amplificationand/or overexpression of MYC oncogenic transcription factors. To identify vulnerabilities for SCLC we performedunbiased mass spectrometry-based screens for SCLC-specific changes in the ATP-binding proteome viaactivity-based proteome profiling (ABPP) and in the metabolome (metabolomics and lipidomics) using a largebank of SCLC and NSCLC cell lines patient-derived xenografts (PDX) and primary tumor tissue. Further weperformed screens with compounds that inhibit different aspects of metabolism. Integrating these data revealedSCLC has highly elevated levels of glycolysis 1-carbon and purine and lipid metabolism and that combinedtreatment with inhibitors of two metabolic regulators MCT lactate transporters (MCTi) and the glycolytic enzymePFKFB3 (PFKFB3i) triggers SCLC cell line metabolic collapse growth arrest and cell death. Genetic studiesvalidated these findings and confirmed the paradoxical observation that PFKFB3 inhibition provokes a collapsein oxidative phosphorylation (OxPhos). Given these findings we will assess the roles of MCTs and PFKFB3 inthe metabolism development and maintenance of SCLC using established (from Project 1) and new (from Core2) genetically engineered SCLC mouse models (GEMM) SCLC PDX and circulating SCLC xenografts (CDX)(Aim 1). These SCLC models will also be used to test the safety and efficacy of the MCTi/PFKB3i combinationas a therapeutic strategy for SCLC and we will also assess effects of targeting MCTs and/or PFKB3 on therepertoire and activity of intratumoral immune cells using SCLC GEMM (with Project 4). Further we will useABPP in vivo tracing (with Project 2) metabolic flux and metabolomics studies (with Core 3) to identify and thentarget adaptive metabolic changes provoked by the loss or inhibition of MCTs and/or PFKFB3. These studieswill define the mechanism by which PFKFB3 inhibition impairs OxPhos and how combined MCTi/PFKFB3itreatment provokes SCLC metabolic collapse (Aim 2). Importantly our metabolomic studies of paired sensitiveand cisplatin/etoposide-resistant SCLC PDX supports the hypothesis that MCTi/PFKB3i therapy represents anopportunity to treat and prevent emergence of chemoresistant disease which we will test using these SCLCPDX models and SCLC GEMM (Aim 3). Finally guided by our ABPP metabolomic and lipidomic analyses wewill use targeted CRISPR screens to identify new metabolic vulnerabilities in SCLC which we will validate andcharacterize using our SCLC models and ABPP metabolic flux and metabolomics experiments (Aim 4). +No NIH Category available Alveolar;Cancer cell line;Catalysis;Cell Culture Techniques;Cell Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Compensation;Consumption;Culture Media;Cyst;Cystathionine;Cysteine;Cysteine Metabolism Pathway;Cystine;Cytoprotection;Dependence;Diet;Dipeptides;Energy Transfer;Environment;Enzyme Induction;Enzymes;Epithelial Cells;Exhibits;Genotype;Glutamates;Glutathione;Glycine;Goals;Immune;Impairment;KRASG12D;Liquid substance;LoxP-flanked allele;Lung;Lung Neoplasms;Malignant neoplasm of lung;Mediating;Metabolic;Metabolism;Mus;Non-Small-Cell Lung Carcinoma;Oxidation-Reduction;Play;Population;Primary carcinoma of the liver cells;Proliferating;Proteins;Resistance;Role;Serine;Serum;Source;Starvation;Sulfur;Testing;Therapeutic Intervention;Tissues;Treatment Efficacy;Work;cancer cell;deprivation;extracellular;in vivo;interstitial;lung cancer cell;metabolome;neoplastic cell;resistance mechanism;response;therapeutic target;transcription factor;tumor;tumor microenvironment;uptake Project 2 PROJECT 2 NARRATIVEINVESTIGATING CYSTEINE ESSENTIALITY IN LUNG CANCERCysteine plays a crucial role in cellular survival and proliferation by generating multiple functional biomoleculesbut the factors influencing the cellular response to cysteine starvation are incompletely understood. We havefound that lung cancer cells are dependent on exogenous cystine due to a lack of transsulfuration capacity butexhibit a heterogeneous response to cystine limitation. This work will evaluate the influence of metaboliccircuits cellular genotype and microenvironmental factors on cellular responses to cystine limitation. NCI 10676733 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9208 10865291 "DENICOLA, GINA MARIE" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 338913 205776 133137 PROJECT 2 SUMMARYINVESTIGATING CYSTEINE ESSENTIALITY IN LUNG CANCERCancer cells accumulate significant intracellular cysteine due to increased cystine uptake and loss ofhomeostatic control. Cysteine-derived molecules are crucial for cancer cell survival and proliferation as aconsequence of their sulfur moiety which facilitates diverse functions including enzyme catalysis energytransfer and redox metabolism. Consistently we have found that many lung cancer cell lines are highly sensitiveto cystine starvation and lack the capacity for de novo cysteine synthesis suggesting they are dependent onexogenous cystine as a source of cysteine. Importantly the recently developed cyst(e)inase enzyme depletesextracellular cystine and cysteine efficiently suggesting it may have therapeutic efficacy against lung cancer.However intracellular metabolic circuits can modify the cellular response to starvation independent oftranssulfuration capacity. Thus understanding the compensatory mechanisms to cysteine starvation is crucialfor efficient therapeutic targeting of cysteine in lung cancer. Importantly our results suggest the glutathionesynthesis machinery an important target of the NRF2 transcription factor has a glutathione-independent role toprotect cells against cysteine starvation-induced ferroptosis. In addition the tumor microenvironment hassignificant levels of alternative sources of cysteine including glutathione cystathionine and protein that arelacking in cell culture and may promote survival in the absence of cystine. The central hypothesis of this proposalis that tissue of origin metabolic responses to cystine starvation and alteration in sulfur sources within the tumormicroenvironment influence cystine essentiality in lung cancer thereby leading to targetable metabolicvulnerabilities. We will test this hypothesis in the following specific aims:In Aim 1 we will evaluate the influence of tissue and cell of origin on cysteine metabolism and essentiality.In Aim 2 we will decipher metabolic circuits that dictate responsiveness to cysteine limitation.In Aim 3 we will evaluate cysteine metabolism in the tumor microenvironment.The ultimate goal and the overall impact of this project is to characterize key determinants of cysteinemetabolism and dependence in lung cancer in order to define opportunities for therapeutic intervention. +No NIH Category available Apoptosis;Binding;Biogenesis;Cell Maintenance;ChIP-seq;Collaborations;Compensation;Cysteine Metabolism Pathway;Data;Disease;Down-Regulation;Family;Family member;Functional disorder;Gene Expression Profile;Gene Family;Genomics;Glutathione Metabolism Pathway;Glycolysis;Goals;Homeostasis;Human;Immune;KRASG12D;Knockout Mice;Knowledge;Length;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Metabolic Pathway;Metabolism;Methionine Metabolism Pathway;Mus;Mutate;Mutation;Nature;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Pathway interactions;Phenocopy;Phenotype;Pramlintide;Pre-Clinical Model;Protein Isoforms;Publishing;Role;Squamous Cell Lung Carcinoma;TP53 gene;Techniques;Testing;Tissues;Transactivation;Transcriptional Regulation;Tumor Burden;Tumor Suppression;Untranslated RNA;Work;anticancer research;cancer cell;cancer subtypes;cancer therapy;conditional knockout;efficacy evaluation;gain of function;glucose metabolism;in vivo;interest;metabolomics;mouse model;mutant;neoplastic cell;new therapeutic target;novel;novel strategies;pre-clinical;programs;purine metabolism;pyrimidine metabolism;skin organogenesis;small cell lung carcinoma;stem cells;targeted treatment;therapeutic target;tool;tumor;tumor metabolism;tumor-immune system interactions Project 1 PROJECT 1 NARRATIVEIDENTIFYING METABOLIC VULNERABILITIES REGULATED BY THE P53 FAMILY IN LUNG CANCERp53 is commonly mutated in human lung cancer including lung adenocarcinoma lung squamous cell carcinomaand small cell lung cancer (SCLC) and is part of a family of genes including p63 and p73 that interactextensively in human cancer. Project #1 will identify metabolic pathways utilizing novel mouse models of lungcancer with p53 gain of function and p63/p73 mutations found in human lung cancer and cutting-edgemetabolomics and genomics techniques to unveil novel therapeutic targets for lung tumors with p53 mutationsor alterations in p63 and p73. Project #1 will also identify metabolic pathways regulated by p73 altered in 10%of human SCLC a recalcitrant disease that lacks targeted therapies. NCI 10676731 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K 9207 1900074 "FLORES, ELSA R" Not Applicable 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 Non-SBIR/STTR 2023 232431 141124 91307 PROJECT 1 SUMMARYIDENTIFYING METABOLIC VULNERABILITIES REGULATED BY THE P53 FAMILY IN LUNG CANCERp53 is commonly mutated in all subtypes of human lung cancer. p53 is part of a family of genes that includesp63 and p73. The functions of p63 and p73 are beginning to be understood in contexts in which p53 functionhas been well established including tumor suppression and metabolism. The complexity of p63 and p73 functionis due in part to the existence of multiple isoforms that previously could not be studied independently in vivo. Fulllength TA isoforms of p63 and p73 contain a transactivation domain structurally and functionally resemblingp53 whereas the N isoforms of p63 and p73 while also possessing transactivation activity antagonize theactivities of p53 and the TA isoforms of p63 and p73. Interestingly mutant p53 present in a wide variety ofhuman cancers has been shown to interact with TAp63 and TAp73 to inactivate their tumor-suppressivefunction. This interaction has also been shown to be partly responsible for gain of function activity of p53 mutants.Moreover Np63 and Np73 which are amplified in many cancers including non-small cell lung cancer bindand inhibit the activity of p53 TAp63 and TAp73. Lung cancer subtypes also share Np63 driven transcriptionalsignatures (Abbas et al. Cancer Research 2017). We have shown previously that p53 deficient and mutanttumors can be metabolically reprogrammed to decrease tumor glycolysis and result in tumor regression throughdownregulation of Np63 or Np73 (Venkatanarayan et al. Nature 2015; Napoli et al. Cancer Cell 2016).Although our knowledge on the functions of the p53 family in cancer has expanded their roles in tumormetabolism are not understood and the metabolic pathways regulated by the p53 family members in lung cancerhave not been examined. Our overarching goal is to understand the metabolic pathways regulated by the p53family in lung cancer to develop strategies to target p53 mutant cancers. We have made great strides towardthis goal by generating p63/p73 isoform-specific conditional knockout mice to allow for temporal and contextdependent deletions of each isoform. These tools have allowed us to gain a greater mechanistic understandingof the interplay of the p53 family in cancer. We have recently demonstrated that conditional deletion of Np63 inthe KrasG12D mouse model of lung adenocarcinoma results in dramatically decreased lung tumor burden.Additionally we have found that KrasG12D/+;TAp73td/td mice develop increased and more aggressive lungadenocarcinomas that phenocopy mouse models with Kras and p53 mutations similar to the ones found inhuman lung cancer. Lastly we have developed a novel mouse model of small cell lung cancer (SCLC) lackingTAp73 which is mutated in 10% of cases. The phenotypes of these mice are associated with changes in keymetabolic pathways including glycolysis and cysteine metabolism. Our primary objective in this application isto define and understand metabolic pathways regulated by the p53 family in lung cancer. Based on our publishedwork and preliminary data we hypothesize that Np63 can be downregulated to metabolically reprogram tumorcells and the microenvironment to compensate for p53 dysfunction. +No NIH Category available Biology;Brassicaceae;Cancer Center;Cancer Etiology;Cancer Patient;Cell Line;Cells;Cessation of life;Collaborations;Country;Cysteine;Cysteine Metabolism Pathway;Data;Data Science Core;Development;Disease;Doctor of Philosophy;Drug resistance;Ensure;Family;Florida;Genes;Genotype;Goals;Immune;Immunosuppression;Immunotherapy;Knowledge;Maintenance;Malignant neoplasm of lung;Manuscripts;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;Molecular Profiling;Mutate;Myeloid-derived suppressor cells;Newly Diagnosed;Operative Surgical Procedures;Organoids;PERK kinase;Pathogenesis;Pathology;Patients;Pre-Clinical Model;Prognosis;Program Research Project Grants;Proliferating;Radiation;Regulation;Research;Resource Sharing;Sampling;Signal Transduction;Survival Rate;TP53 gene;Therapeutic;Tissue Microarray;Tyrosine Kinase Inhibitor;chemotherapy;data repository;endoplasmic reticulum stress;experimental study;genetic signature;in vivo;innovation;machine learning algorithm;metabolomics;mouse model;neoplastic cell;novel;patient subsets;pre-clinical;programs;small cell lung carcinoma;synergism;targeted treatment;therapeutic target;therapeutically effective;transcription factor;tumor;tumor microenvironment Identifying Metabolic Vulnerabilities in Lung Cancer OVERALL PROJECT NARRATIVEIDENTIFYING METABOLIC VULNERABILITIES IN LUNG CANCERLung cancer is the leading cause of cancer deaths worldwide and common therapy for both NSCLC and SCLCincludes surgery radiation chemotherapy and immunotherapy. Many of the driver genes mutated in lung cancerare transcription factors and are difficult to target therapeutically and have been dubbed undruggable. Ourgoal in this application is to develop a deep molecular understanding of the metabolic pathways regulated bykey drivers in lung cancer using sophisticated and novel mouse models of lung cancer patient derived samplesand organoids and state-of-the-art approaches in the analysis of metabolites to identify metabolic vulnerabilitiesin lung cancer as potential therapeutic targets. NCI 10676730 8/2/23 0:00 PAR-20-077 5P01CA250984-03 5 P01 CA 250984 3 "WILLIS, KRISTINE AMALEE" 6/25/21 0:00 5/31/26 0:00 ZCA1-SRB-K(J1)P 1900074 "FLORES, ELSA R" "HAURA, ERIC B." 15 Unavailable 139301956 DVHKP4N619V9 139301956 DVHKP4N619V9 US 28.062583 -82.419596 3736101 H. LEE MOFFITT CANCER CTR & RES INST TAMPA FL Research Institutes 336129497 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 2019244 NCI 1226014 793230 OVERALL PROJECT SUMMARYIDENTIFYING METABOLIC VULNERABILITIES IN LUNG CANCERLung Cancer is the most common cause of cancer deaths world-wide. Tyrosine kinase inhibitors andimmunotherapy have been shown to be effective in a subset of patients; however the overall survival rate forthis disease remains low especially for metastatic disease. Moreover small cell lung cancer (SCLC) patientshave a poor prognosis and there especially exists a gap in knowledge in understanding SCLC and identifyingeffective therapeutic strategies. Our goal in this proposal is to understand the underlying biology of key driversin lung cancer by identifying metabolic vulnerabilities that can ultimately be used as single agents or combinedwith immunotherapy to target lung cancer therapeutically. We will achieve this goal by engaging experts thathave developed preclinical models with common molecular signatures in non-small cell (NSCLC) and small celllung cancer (SCLC) and cutting-edge metabolomics. We have an active and collaborative group that meets twicemonthly with projects and manuscripts that are co-authored by the leaders of each project and core. Additionallyour Program Project Grant (PPG) team is located at Moffitt Cancer Center which is an ideal place to study thepathogenesis of lung cancer. Florida is number 2 in the country in terms of newly diagnosed lung cancer patients.Moffitt treats 10% of these cases. The PPG consists of four projects and four cores. These projects and corescollaborate and synergize to meet four objectives: i. To identify metabolic vulnerabilities in lung cancers throughintegrative analysis of in vivo and ex vivo models with common molecular signatures including p53NRF2/KEAP1 and MYC (Project #1 led by Dr. Flores Project #2 led by Dr. DeNicola Project #3 led by Drs.Cleveland and Haura and Project #4 led by Dr. Rodriguez with support from the Administrative Core #1 ledby Drs. Flores and Haura Preclinical Models and Pathology Core #2 led by Drs. Cress and Karreth MetabolismCore #3 led by Dr. Koomen and Data Science Core #4 led by Dr. Fridley) ii. To identify metabolicvulnerabilities that synergize with immunotherapy through examining the tumor microenvironment and gaining adeep molecular understanding of myeloid derived suppressor cells (MDSCs). (Project #4 in collaboration withProjects #1 and #2 and Core #2) iii. To build mouse models as a platform to understand the metabolic pathwaysutilized by lung cancers with different genetic signatures and to assess therapeutic strategies for lung cancer.(Core #2 supporting Projects #1-4) and iv. To share resources and data locally and globally to obtain anintegrated molecular understanding of metabolic vulnerabilities in lung cancer. (Core #4 leading efforts from AllProjects and Cores). 2019244 +No NIH Category available 3-Dimensional;Alleles;Animals;Antitumor Response;Autologous;B-Lymphocytes;Basic Science;Behavior;Biological;Biological Markers;Biological Models;Biology;CD34 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;Cell Communication;Cell Lineage;Cells;Clinical;Clinical Data;Data Set;Dermal;Development;Diagnosis;Differentiation Antigens;Disease;Disease Outcome;Disease Progression;Epigenetic Process;Etiology;Exhibits;Experimental Models;Failure;Fetal Liver;Future;Gene Expression Profile;Genes;Genetic Transcription;Genetically Engineered Mouse;Genome;Goals;Growth;HLA-A gene;Hematopoietic stem cells;Host Defense Mechanism;Human;Immune;Immune response;Immune signaling;Immune system;Immunohistochemistry;Immunological Models;Implant;In Vitro;Innate Immune Response;Interferons;Invaded;Macrophage;Malignant - descriptor;Malignant Neoplasms;Melanoma Cell;Modeling;Molecular;Mus;Mutation;Natural Killer Cells;Neoplasm Metastasis;Organ;Pathway interactions;Patients;Phase;Phenotype;Prevention strategy;Prognosis;Proteins;Radial;Reproducibility;Research;Role;STING agonists;Signal Pathway;Signal Transduction;Skin;Stimulator of Interferon Genes;System;Techniques;Testing;Thick;Thymic Tissue;Time;Tissue Sample;Ultraviolet B Radiation;Validation;Work;advanced system;antagonist;anti-CD20;anti-tumor immune response;clinical practice;cohort;draining lymph node;genetic signature;human data;human model;human tissue;humanized mouse;immune cell infiltrate;immunoregulation;in vivo;in vivo Model;innovation;irradiation;malignant state;melanocyte;melanoma;mouse model;neoplastic cell;novel;pathogen;potential biomarker;predictive marker;prevent;prognostic;prognostic assays;prognostication;reconstitution;survival prediction;transcriptome;tumor;tumor growth;tumor progression;tumor-immune system interactions;ultraviolet Dissecting Phenotype Switching in Early Stage Melanomas Project NarrativeThe majority of melanomas diagnosed and treated in the US are in early stages and a significant percentageexhibit a high potential for metastasis. Research on early disease has been limited due to lack of appropriatemodel systems and relevant human tissues. In this proposal by overcoming prior limitations throughinnovation we will study the determinants of the tumor and the host during non-aggressive to aggressiveprogression in early disease. NCI 10676721 7/27/23 0:00 PA-20-185 5R01CA259295-02 5 R01 CA 259295 2 "KAI, MIHOKO" 8/4/22 0:00 7/31/27 0:00 Tumor Microenvironment Study Section[TME] 7340875 "CELEBI, JULIDE T." "HERLYN, MEENHARD F" 12 DERMATOLOGY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 612946 NCI 481674 131272 Project SummaryMelanoma continues to be a devastating cancer. Early stage melanomas represent the majority of melanomasthat are diagnosed and managed in the US. It is becoming clearer that metastatic dissemination and seedingoccurs very early during tumor progression while the tumor is still localized to the skin without signs of otherorgan involvement. To effectively battle with this disease we must understand the molecular underpinnings ofbiologically early tumors in particular host defense mechanisms against the tumor cells. Basic research inearly melanomas has not made significant progress over the past decades mostly due to lack of murinesystems that model early disease. Genetically engineered murine models of melanoma represent manyshortcomings and at best they mimic late aggressive tumors (murine genome) within the mice immunesystem. In this proposal we will mimic early malignant states in novel in vivo humanized murine models thatwe have developed in which highly immune deficient mice are reconstituted with human CD34+ hematopoieticstem cells and challenged with HLA-A allele-matched human melanoma cells. By ultraviolet (UVB/A)irradiation we will induce additional mutations as in human skin and study the progression of tumors as theygrow in time and space. Our preliminary studies indicate that a transcriptional switch occurs within thetumor cells it accompanies unique host immune responses and this crosstalk dictates the fate of thetumor towards progression or elimination. Stimulator of interferon STING signaling gets activated oncemelanoma cells acquire an aggressive phenotype suggesting a role during tumor progression. Here wepropose to establish paradigm-shifts in the concept of non-aggressive melanomas transitioning into anaggressive phenotype that will directly impact clinical practice. We will investigate: 1) changes within the tumor(mutations pathways) that co-occur within the immune microenvironment (cell lineages signals) during earlydisease progression using humanized mouse models (Aim1) 2) pro- or anti-tumor responses in the presenceor absence of STING activation in early disease leveraging the humanized mouse and 3D skin models (Aim 1)3) reversal of phenotypes and testing causality by modulating immune cell subpopulations (Aim 2) and 4)development and validation of a prognostic assay applied to early melanomas that predicts survival (Aim 3).Successful completion of this project promises to bring new model systems to the melanoma (and cancer) fieldthat enable studying human tumor and human immune system interactions. If offers a major leap in early stagemelanoma research and deepens our understanding by revealing new tumor cell intrinsic or extrinsicmechanisms of disease progression. 612946 +Cancer Biology;Chemical Structure;Chemicals;Collection;Databases;Diversity Library;Ensure;Environment;Equipment and supply inventories;Film;Individual;Informatics;Knowledge;Libraries;Monitor;Mothers;Sampling;Solid;Structure;Test Result;Tube;Update;Vendor;Vial device;Work;base;design;indexing;interest;screening;small molecule;stereochemistry CBC LIBRARY SCREENING POP 9/29/2020 - 9/28/2021 n/a NCI 10676712 261201500010I-P00004-759102000001-1 N01 9/29/20 0:00 9/28/23 0:00 77858333 "JOBLING, MICHAEL " Not Applicable Unavailable 930243360 LA7FUVX1EZQ7 930243360 LA7FUVX1EZQ7 US 37.66323 -122.385783 -410278 SOUTH SAN FRANCISCO CA Other Domestic Non-Profits 940801934 UNITED STATES N R and D Contracts 2022 276534 NCI Chemical Biology Consortium Screening Library Center (CBCSLC) 276534 +No NIH Category available Address;Aging;Antibodies;Binding;Biological Assay;Biological Models;Biology;Biophysics;Breast Cancer Cell;Cell physiology;Cells;Chemicals;Chromosomal Rearrangement;Clinical;Complex;Cytosine;Cytosine deaminase;DNA;DNA Repair Enzymes;DNA Transposable Elements;Data;Deamination;Defect;Development;Diagnosis;Disease;Disease Progression;Disease Resistance;Drug resistance;Enzymes;Estrogen receptor positive;Family;Foundations;Genomics;Goals;Inherited;Knowledge;Lead;Leadership;Lesion;Malignant Neoplasms;Mammary Neoplasms;Metastatic breast cancer;Mission;Molecular;Monoclonal Antibodies;Mutagenesis;Mutation;Neoplasm Metastasis;Nucleic Acids;Oncoproteins;Outcome;PIK3CA gene;Patients;Persons;Primary Lesion;Primary Neoplasm;Process;Proteins;Publishing;Reagent;Recurrence;Recurrent disease;Regulation;Reporter;Reporting;Research;Research Project Grants;Residual state;Resistance;Scientific Advances and Accomplishments;Services;Single-Stranded DNA;Site;Source;System;Techniques;Testing;The Cancer Genome Atlas;Therapeutic;Time;Uracil;Virus Replication;Water;Woman;Work;antibody diagnostic;anticancer research;base;biophysical techniques;brca gene;cancer recurrence;clinical care;clinical translation;computational chemistry;computerized tools;diagnostic assay;ds-DNA;experience;homologous recombination;improved;inhibitor;innovation;interdisciplinary approach;malignant breast neoplasm;member;molecular recognition;mouse model;multidisciplinary;new technology;novel;novel diagnostics;overexpression;preference;prevent;programs;repaired;small molecule;structural biology;technology development;therapy outcome;therapy resistant;tumor;tumor heterogeneity;tumor progression APOBEC MUTAGENESIS IN BREAST CANCER OVERALL APOBEC MUTAGENESIS IN BREAST CANCERNARRATIVE Mutations continue to accumulate in breast cancer cells even after the cancer is first diagnosed andtreated leading to treatment-resistant disease and metastasis. APOBEC contributes to this mutagenesis inmany cancers and thus provides an opportunity to therapeutically slow or prevent cancer recurrence andprogression after initial treatment. Our Program takes a multidisciplinary approach to better understand themechanism of APOBEC mutagenesis in breast cancer with the goal of diagnosing and improving treatmentsfor patients whose tumors are fueled by this process. NCI 10676574 9/19/22 0:00 PAR-18-290 3P01CA234228-04S1 3 P01 CA 234228 4 S1 "READ-CONNOLE, ELIZABETH LEE" 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L(M1) 8004071 "HARRIS, REUBEN S" "YEE, DOUGLAS " 20 BIOCHEMISTRY 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 396 Non-SBIR/STTR 2022 95930 NCI 82180 13750 OVERALL APOBEC MUTAGENESIS IN BREAST CANCERABSTRACT APOBEC signature mutations make up 20% of base-substitution mutations in primary tumors whichincreases to over 50% in metastases. Additional enrichment is often observed in estrogen receptor (ER)-positive disease. APOBEC-catalyzed C-to-U lesions in single-stranded (ss)DNA lead to signature C-to-T andC-to-G mutations within 5-TCA and 5-TCT trinucleotide motifs. In addition APOBEC-derived C-to-U lesionscan be (mis)processed by cellular DNA repair enzymes resulting in single- and double-stranded DNA breaksand more complex chromosomal rearrangements. APOBEC expression levels and mutagenesis correspondwith poor clinical outcomes such as shorter disease-free and overall survival in women with operable ER-positive breast cancer. Elevated APOBEC levels also predict poor overall survival for patients diagnosed withrecurrent ER-positive metastases. These and other published data demonstrate that APOBEC mutagenesis isongoing in breast tumor cells and underpin our overarching Program hypothesis that inhibiting APOBEC willprevent a large proportion of additional mutations from happening in residual ER-positive disease and willthereby improve the durability of current treatments and result in better overall therapeutic outcomes. Threemultidisciplinary Projects will work together in an integrated and comprehensive manner to test this idea.Project 1 will develop reporter systems for quantifying APOBEC activity in living cells and determine themolecular mechanisms responsible for APOBEC regulation and for genomic uracil processing in breast cancercells. Project 2 will use chemical biology approaches to investigate the mechanism of APOBEC-catalyzedssDNA deamination and will develop nucleic acid and small molecule probes to inhibit APOBEC activity.Project 3 will leverage structural and biophysical approaches to investigate global mechanisms for APOBECbinding to ssDNA as well as the local structural features important for target sequence preferences andinhibition of APOBEC enzymes in breast cancer. These Projects will be supported by service Cores foradministration murine models computational chemistry and biophysics and enzymes and antibodies. OurProgram is poised to have both immediate and long-term impact for ER-positive breast cancer: immediateimpact by producing novel technologies and a comprehensive understanding of the mechanism of APOBECmutagenesis and long-term impact on clinical translation through the development of technologies fordiagnosing APOBEC-positive disease and the creation of novel chemical matter to inhibit this mutationalprocess for therapeutic benefit. 95930 +No NIH Category available Adoptive Transfer;Antigen-Presenting Cells;Antigens;Attenuated;Autopsy;Brain;Brunhilde Virus;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;Cancer Patient;Cell physiology;Cells;Cervical lymph node group;Chemotaxis;Clinical;Clinical Trials;Cross Presentation;Cytoplasm;Dendritic Cells;Dendritic cell activation;Disease;Double-Stranded RNA;Engineering;Focal Infection;Glioblastoma;Glioma;Human;Human poliovirus;ITGAM gene;ITGAX gene;Immune;Immunity;Immunologic Stimulation;Immunologic Surveillance;Immunology;Immunotherapy;In Vitro;Infection;Infiltration;Inflammatory;Injections;Interferon Type I;Interferons;Internal Ribosome Entry Site;Investigation;Lymphatic System;Lymphoid Tissue;Macaca;Macrophage;Malignant Neoplasms;Mediating;Modeling;Mononuclear;Mus;Myelogenous;Myeloid Cells;Natural Killer Cells;Necrosis;Nodal;Non-Malignant;Normal Cell;Oral;Outcome;Pan Genus;Pathogenicity;Patients;Pattern;Pattern recognition receptor;Peripheral;Phagocytes;Proteins;RNA Viruses;Reaction;Receptor Signaling;Recombinants;Recurrence;Reporting;Repression;Research;Resistance;Resolution;Rhinovirus;Role;Schedule;Signal Transduction;Site;Slice;Spleen;Stimulus;T cell response;T-Lymphocyte;TAP1 gene;Testing;Tropism;Tumor Antigens;Tumor Immunity;Tumor-associated macrophages;Vaccines;Viral;Virulence;Virus;Widespread Disease;antitumor effect;cancer immunotherapy;cell motility;cytotoxic;gastrointestinal;glymphatic system;immune checkpoint blockade;imprint;in vivo;insight;lymph nodes;lymphoid structures;melanoma;migration;pathogen;patient subsets;radiological imaging;recruit;response;safety study;sensor;spatiotemporal;trafficking;translational study;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions Resolving Spatiotemporal Dynamics of Recombinant Poliovirus Immunotherapy Durable antitumor immunity requires presentation of tumor antigens by professional antigen presenting cells(APCs) for priming of antitumor T cell responses but APC function is repressed in the immunosuppressive tumormicroenvironment. This project will decipher the mechanisms of the unique immune stimulation provided byrecombinant poliovirus resulting from non-lethal infection and pro-inflammatory activation of APCs. Thesignificance of this research is the potential to achieve significant clinical benefits for cancer patients byreinstating tumor immune surveillance. NCI 10676548 7/28/23 0:00 PA-20-185 1R01CA281320-01A1 1 R01 CA 281320 1 A1 "HU, ZHANG-ZHI" 7/28/23 0:00 6/30/28 0:00 Cellular Immunotherapy of Cancer Study Section[CIC] 6404984 "GROMEIER, MATTHIAS " Not Applicable 4 NEUROSURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/28/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 377656 NCI 234569 143087 Priming of antitumor immunity relies on a specialized subset of conventional Dendritic Cells (cDC1s) CD103+DCs that have unique capabilities of trafficking tumor antigens to lymph nodes for cross-presentation. The criticalrole of cDC1s in cancer immune surveillance make them highly coveted targets for immunotherapy; howevertheir scarcity the difficulty of specifically engaging DCs and the suppressive tumor microenvironment (TME)pose severe obstacles. We are investigating immunotherapy with attenuated recombinant poliovirus (PV)PVSRIPO because of the naturally evolved tropism of PV for DCs. In humans or chimpanzees oral PV infectionleads to remarkably effective targeting of CD11c+DCs in peripheral (gastrointestinal) and lymphoid tissues.PVSRIPO engineered with an IRES from human rhinovirus type 2 lacks cytopathogenicity in normal cells eg.DCs. Rather DC infection yields sustained type-I interferon (IFN) responses elicited by specific viral dsRNApatterns that engage the PV pattern recognition receptor (PRR) MDA5. Mechanistic investigations of PVSRIPOtreatment in ex vivo human tumor slices revealed that: (i) the main outcome is sustained type-I IFN release frommyeloid cell subsets in the non-malignant TME; (ii) PVSRIPOs unique innate imprint provides optimal DCactivation stimuli for CD4+T cell TH1-polarization and CD8+T cell priming; (iii) PVSRIPOs PRR-contextualizedIFN response induces polyfunctional GzmB+ IFNg+ T-bet+ antitumor CD8+T cells that control tumor growth afteradoptive transfer. We reported very promising Ph1 clinical trial results with PVSRIPO in challengingindications: recurrent glioblastoma and recurrent nonresectable melanoma. Our premise is that PVSRIPOtherapy recruits cDC1s leads to local infection of these cells induces migration to lymph nodes/spleenand stimulates tumor antigen cross-presentation via the intrinsic innate inflammatory signature it elicits.We propose mechanistic and translational studies to gain insight into targeting of DCs by PVSRIPO the waysublethal infection of distinct myeloid subsets activates tumor antigen cross-presentation and rational means ofenhancing DC engagement by intranodal virus administration. We propose the following Specific Aims: (1)Unravel mechanisms of cDC1 recruitment activation and lymph node migration upon PVSRIPO infection of theTME. (2) Determine the mononuclear phagocyte compartment(s) that mediate PVSRIPO antitumor effects; testthe roles of T cell-intrinsic IFN signaling and chemotaxis. (3) Reinforce cDC1 engagement by perinodal deliveryor upon infection of the PVSRIPO-reactive glioma myeloid infiltrate.Significance: these studies explore a unique opportunity for effectively engaging CD103+DCs in tumor antigencross-presentation and CD8+T cell priming based on the natural tropism for DCs and unique innate inflammatoryimprint of PVSRIPO. The long-term objective of this research is to provide means for re-instating effective cancerimmune surveillance in patients by overcoming tumor-associated deficits in DC function and CD8+T cell priming. 377656 +Behavioral and Social Science; Cancer; Climate-Related Exposures and Conditions; Clinical Research; Clinical Trials and Supportive Activities; Dissemination and Implementation Research; Health Disparities; Minority Health; Networking and Information Technology R&D (NITRD); Prevention; Social Determinants of Health Adopted;Adult;African American;African American population;Algorithms;American;Area;Asbestos;Attention;Attitude;Benzene;Carcinogens;Cessation of life;Communities;Control Groups;Databases;Development;Diagnosis;Diffusion of Innovation;E-learning;Education;Educational Curriculum;Effectiveness;Employee;Enrollment;Evaluation;Exposure to;Focus Groups;Funding;Goals;Health;Health Care Costs;Hispanic Americans;Human Resources;Industry;International;Intervention;Learning;Literature;Malignant Neoplasms;Mediating;Names;National Cancer Institute;National Institute of Environmental Health Sciences;Occupational;Occupations;Phase;Policies;Prevention Research;Principal Investigator;Process;Production;Protocols documentation;Publishing;Quality of life;Randomized Controlled Trials;Readiness;Recreation;Reporting;Research;Research Personnel;Resources;Risk;Safety;Schools;Skin Cancer;Small Business Innovation Research Grant;Staging;Students;Surgeon;System;Technology;Testing;The Sun;Training;Treatment Cost;United States;Update;Vendor;Vinyl Chloride;Work;Workplace;base;educational atmosphere;effectiveness testing;evidence base;high risk;implementation strategy;improved;innovation;keratinocyte;melanoma;primary outcome;programs;prototype;randomized trial;safety education;safety practice;school district;skin cancer prevention;solar ultraviolet radiation;sun protection;sun safety;theories;usability;vector SSW Works: A Virtual Learning Environment for Occupational Skin Cancer Prevention Americans who work outdoors are exposed to an extreme amount of solar ultraviolet radiation over a lifetimethat substantially increases their risk for developing skin cancer. In Phase I the feasibility of a virtual learningenvironment (VLE) for distributing our effective Sun Safe Workplaces (SSW) intervention to Americanemployers will be established with input from senior managers and Hispanic and African American outdoorworkers and development and evaluation of a prototype of the SSW Works VLE. In Phase II the full SSWWorks will be produced and tested for effectiveness at improving outdoor workers' sun protection in arandomized trial enrolling employers nationwide. NCI 10676503 8/26/22 0:00 PA-20-262 4R44CA257778-02 4 R44 CA 257778 2 "WEBER, PATRICIA A" 8/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-RPHB-Z(10)B] 7678026 "BULLER, MARY K" Not Applicable 7 Unavailable 117936042 NWQ2AMLQTLN6 117936042 NWQ2AMLQTLN6 US 39.74171 -105.155318 4368501 "KLEIN BUENDEL, INC." GOLDEN CO Domestic For-Profits 804013313 UNITED STATES N 9/1/22 0:00 8/31/23 0:00 393 SBIR/STTR 2022 979566 NCI 560114 355368 Americans who work outdoors are exposed to an extreme amount of solar ultraviolet radiation (UV) over alifetime that substantially increases their risk for developing skin cancer. Annually skin cancer is diagnosed inover 3.5 million U.S. adults melanoma kills nearly 7000 Americans and treatment costs at least $8 billion.The U.S. Surgeon General has identified occupational sun safety as a national priority. Our team has spent thepast two decades developing a successful comprehensive approach to occupational sun protection in 5 trialsfunded largely by the National Cancer Institute. Sun Safe Workplaces (SSW) combines policy and education toincrease workplace actions on sun safety and employee sun protection practices. In this SBIR Fast-Trackapplication we will develop a virtual learning environment (VLE) SSW Works to distribute the SSW programto American workplaces. It will be comprised of a database content management (interactive toolbox) andmedia platform (trackable training) that tailors the SSW program to management's readiness to innovate onsun safety based Diffusion of Innovations Theory. SSW Works will better integrate SSW into safety training byimproving appropriateness for Hispanic and African American workers and conforming with the latest learningmanagement systems technology (LMS). Strong scientific premise comes from the published literature and our5 previous studies that demonstrated SSW is feasible and effective in public works public safety and outdoorrecreation workplaces. The Phase I specific aims will establish the feasibility of SSW Works by 1) creating andvalidating an algorithm to tailor resources and implementation strategies to employers' stages in the diffusionof innovations process; 2) identifying unique attitudes barriers and practices related to sun safety amongHispanic and African American employees in focus group discussion and adjusting the SSW content; and 3)creating a prototype of the SSW Works VLE including inputs staging algorithm and tailored report employeetraining compatible with a popular LMS and storyboards of brief videos for managers and employees andtesting it for feasibility and usability with managers and Hispanic and African American outdoor workers andconfirming that the training can operate within a popular LMS. In Phase II SSW Works will be fullyprogrammed and tested for effectiveness by achieving the specific aims of: 1) producing the full SSW Works inEnglish and Spanish for distribution of the evidence-based SSW and 2) conducting a randomized controlledtrial with 20 workplaces evaluating impact of SSW distributed over the SSW Works on employees' sun safetypractices (primary outcome). The primary hypothesis is: compared to employers in the minimal informationcontrol group employers assigned to receive SSW Works will have employees that practice more sunprotection at posttest. The SBIR Fast-Track research is significant and innovative. SSW Works will have highimpact and commercial potential because outdoor workforce is large and at very high risk for skin cancerimproving sun safety will reduce health care costs and save lives and there are few commercial competitors. 979566 +No NIH Category available Actinic keratosis;Antigen Presentation;Antigen Presentation Pathway;Area;Binding Proteins;Cancer Model;Cancer Vaccines;Carcinogen exposure;Cell Fraction;Cell physiology;Clinical;Cytoprotection;Data;Development;Genetic;Human;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunocompromised Host;Immunologist;Immunotherapy;Incidence;Individual;Irradiated tumor;Laboratories;Lesion;Light;MHC Class I Genes;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mentorship;Missense Mutation;Modeling;Mus;Mutate;Nude Mice;Pathway interactions;Patients;Peptides;Process;Recurrence;Research;Resistance;Role;Shapes;Skin;Skin Cancer;Solid;Systemic Therapy;T cell response;T-Cell Activation;T-Cell Receptor;T-Lymphocyte;Tacrolimus;Testing;Tissues;Transplant Recipients;Transplantation;Vaccination;Vaccines;Work;cancer cell;cancer immunotherapy;checkpoint inhibition;efficacy testing;high risk;immune cell infiltrate;immunogenic;immunogenicity;immunosuppressed;innovation;neoantigen vaccine;neoantigens;neoplastic cell;novel strategies;organ transplant recipient;preservation;response;skin squamous cell carcinoma;targeted treatment;transplant model;tumor;vaccine efficacy;vaccine evaluation Immunoediting in Cutaneous Squamous Cell Carcinoma PROJECT NARRATIVEHigh incidence and poor treatment options for cutaneous squamous cell carcinoma in immunosuppressed solidorgan transplant recipients have led to an important unmet clinical need. The proposed research will comparethe mutated peptides in cutaneous squamous cell carcinoma from immunosuppressed and immunocompetentindividuals to test an innovative approach to cancer immunotherapy. NCI 10676479 6/7/23 0:00 PA-21-050 1F30CA281056-01 1 F30 CA 281056 1 "BIAN, YANSONG" 7/1/23 0:00 8/31/27 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 15961248 "BORDEN, ELIZABETH " Not Applicable 7 OTHER BASIC SCIENCES 806345617 ED44Y3W6P7B9 806345617 ED44Y3W6P7B9 US 32.232844 -110.959467 490201 UNIVERSITY OF ARIZONA TUCSON AZ SCHOOLS OF MEDICINE 857210158 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 42097 NCI 42097 0 PROJECT SUMMARY:Immunosuppressed transplant recipients have a 65-253 fold higher risk of developing cutaneous squamouscell carcinoma (cSCC) and are contraindicated for treatment with immune checkpoint inhibitors presenting animportant unmet clinical need. The ability of T cells to constrain cSCC is demonstrated by the response of 32-46% of immunocompetent patients to immune checkpoint inhibitors. However cSCC has the potential to evadean active T cell response as demonstrated by the formation of cSCC in immunocompetent patients andresistance to immune checkpoint inhibition in some patients. Prior work suggests that evasion of an active Tcell response occurs through the process of immunoediting in which T cells destroy tumors that presentmutated tumor proteins that bind the T cell receptor (neoantigens) and thus select for less immunogenictumors. This proposal will compare the neoantigen profile and immune escape mechanisms in tumors andtumor-adjacent skin from immunosuppressed and immunocompetent individuals as a novel approach toevaluate the role of T cells in immunoediting. Evaluating the neoantigen profile in carcinogen-exposed tumor-adjacent skin will additionally provide evidence for immunoediting before the formation of a clinically apparentlesion. Furthermore since cSCC in immunosuppressed patients develops in the context of diminished T cellfunction this proposal tests the innovative concept that these patients will have a neoantigen profile that ismore amenable to treatment with a personalized neoantigen vaccine. The Hastings laboratory has created anMHC class I neoantigen prioritization model with high accuracy in predicting neoantigens that elicit a T cellresponse which will be applied to evaluate the neoantigen profiles of cSCC from immunosuppressed andimmunocompetent individuals. The Hastings laboratory has also generated and characterized a solar-simulated light induced transplantable cSCC tumor that will be used to test vaccine efficacy in the proposedstudies. Preliminary data demonstrate that the cSCC transplantable model is constrained by T cells andvaccination with irradiated tumor cells protects from tumor challenge. This proposal will test the centralhypothesis that cSCC and carcinogen-exposed tumor-adjacent skin from immunosuppressed individuals willhave a more immunogenic neoantigen profile and less frequent immune escape mechanisms compared tocSCC from immunocompetent individuals. Aim 1 of this proposal will compare the neoantigen profile andimmune escape mechanisms between immunosuppressed and immunocompetent patients. Aim 2 willcompare the neoantigen profile and immune escape mechanisms of cSCC from mice with and without afunctional T cell repertoire and demonstrate the efficacy of cancer vaccines in immunosuppressed mice. Theimpact of the project is to provide evidence for neoantigen vaccines as an important treatment option forimmunosuppressed patients and systematically characterize the immune escape mechanisms in cSCC todetermine additional targets of therapy for cSCC in immunocompetent patients. 42097 +No NIH Category available Acceleration;Address;Age;Alleles;Attenuated;Basal cell carcinoma;Basement membrane;Binding;Biological Markers;Biological Process;COL7A1;Cause of Death;Cell Line;Cell Nucleus;Childhood;Chromatin;Cicatrix;Clinical;Code;Collagen Type VII;Complex;Cutaneous;DNA;DNA Binding;DNA Damage;DNA Repair;DNA Repair Enzymes;DNA Repair Pathway;DNA biosynthesis;Defect;Development;Diagnosis;Disease;Epidermolysis Bullosa;Epidermolysis Bullosa Dystrophica;Epithelial Cells;Exposure to;Extracellular Matrix;Extracellular Space;Fellowship;Fibrosis;Foundations;Genes;Genetic Diseases;Genetic Skin Diseases;Genetic Transcription;Genome;Genome Stability;Genomic Instability;Goals;HMGB1 gene;Human;In Vitro;Incidence;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Knowledge;Life;Location;Longevity;Maintenance;Malignant Epithelial Cell;Malignant Neoplasms;Melanoma Cell;Membrane Proteins;Mentorship;Minnesota;Molecular;Mus;Mutagens;Mutation;Nature;Nuclear;Nuclear Protein;Oncologist;Oxidation-Reduction;Pathogenesis;Pathway interactions;Patients;Pattern;Pediatric Hematologist;Pediatric Oncologist;Physicians;Play;Positioning Attribute;Post-Translational Protein Processing;Prevention;Production;Productivity;Proteins;Research;Role;Scientist;Serum;Severity of illness;Signal Pathway;Signal Transduction;Site;Skin;Squamous cell carcinoma;Stimulator of Interferon Genes;TLR4 gene;TP53 gene;Testing;Time;Training;Tumor Suppressor Proteins;Universities;attenuation;cancer initiation;carcinogenesis;career;career development;cell injury;cell transformation;chemical carcinogenesis;chronic wound;cytokine;disease-causing mutation;early onset;effective therapy;healing;improved;in vivo;in vivo Model;inflammatory milieu;inhibitor;keratinocyte;mouse model;mutant;new therapeutic target;patient population;pediatric patients;prevent;primary endpoint;protein function;protein protein interaction;public health relevance;rare genetic disorder;receptor for advanced glycation endproducts;recruit;response;skin squamous cell carcinoma;small molecule inhibitor;tumor;tumor progression;tumorigenesis;wound;wound healing HMGB1 in EB-Associated Squamous Cell Carcinoma Public Health RelevanceSquamous cell carcinoma arising in chronic wounds is the leading cause of death in patients with recessivedystrophic epidermolysis bullosa. This project aims to elucidate the mechanisms underlying cancer initiation inthese patients by interrogation of HMGB1 a protein involved in both inflammation and genome maintenance.The results from this study will provide a foundation for new drug targets in this fragile patient population and willshed new light on carcinogenesis in the broader context of inflammatory disease. NCI 10676346 5/5/23 0:00 PA-21-052 1F31CA281039-01 1 F31 CA 281039 1 "GHOSH, SANGEETA AHUJA" 8/1/23 0:00 7/31/27 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 12021203 "BUI, KACEY LINNEA GUENTHER" Not Applicable 5 PEDIATRICS 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Individual" 2023 41609 NCI 41609 0 Project Summary/AbstractRecessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease characterized by chronic woundsand shortened lifespan due to a high incidence of early-onset squamous cell carcinoma (SCC). The highlyaggressive nature of SCC in RDEB patients warrants further mechanistic study. High mobility group box 1(HMGB1) is a serum biomarker of disease severity in RDEB but its role in tumorigenesis in patients with RDEBhas not been thoroughly investigated. HMGB1 is a chromatin-associated protein that functions in the nucleus asa regulator of DNA replication and repair. In response to inflammatory signals HMGB1 is secreted from thenucleus and functions as a damage associated molecular pattern that stimulates the innate immune response.The central hypothesis of this proposal is that depletion of nuclear HMGB1 in keratinocytes drives carcinogenesisin RDEB by promoting inflammation and accelerating genome instability. This hypothesis will be tested throughtwo specific aims investigating the effects of sequestering HMGB1 in the nucleus. The first aim explores theimpact of altered HMGB1 localization on inflammatory response and genomic instability in RDEB keratinocytes.The second aim evaluates the usefulness of small molecule inhibitors of HMGB1 secretion in preventing tumorformation using an in vivo mouse model of RDEB. Successful completion of these aims will provide newinformation on the biological function of HMGB1 in patients with RDEB SCC. The results of this study have thepotential to reveal new drug targets for a fragile patient population in desperate need of safe and effectivetreatment options.This proposal will be completed at the University of Minnesota under the co-mentorship of Dr. Jakub Tolar aphysician-scientist and pediatric oncologist specializing in RDEB and Dr. Anja-Katrin Bielinsky an expert ingenome maintenance and DNA repair defects in the initiation of cancer. The complementary expertise of the co-sponsors uniquely positions the candidate to complete the aims described in this proposal and achieve her goalof becoming an academic pediatric hematologist-oncologist leading a research lab focused on examiningmechanisms underlying rare genetic diseases and cancer. The career development and fellowship training plansoutlined in this application build the foundation for a long and productive career investigating better treatmentsfor pediatric patients with complex and difficult-to-treat genetic conditions. 41609 +No NIH Category available Malignant Neoplasms;Therapeutic;Training Programs Investigational Cancer Therapeutics Training Program PROJECT NARRATIVEAccelerating the future development of new cancer treatments requires educating the next generation ofleaders in this field in the complex interactions between tumors their surroundings and the immune systemand preparing them to efficiently conduct research in todays regulatory and administrative environment. TheT32 Investigational Cancer Therapeutics Training Program (ICTTP) at Memorial Sloan Kettering CancerCenter addresses this need by providing fellows in medical oncology who are committed to careers intranslational cancer research with comprehensive mentored research and didactic training for two years. TheICTTP program is designed to optimally train physician scientists to translate discoveries regarding the biologyof cancer into new approved molecular/cytotoxic immunotherapeutic and cell-based treatments throughstate-of-the-art experimental trials.! NCI 10676318 9/6/23 0:00 PA-18-403 5T32CA009207-45 5 T32 CA 9207 45 "LIM, SUSAN E" 9/30/77 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 11033212 "DRILON, ALEXANDER " "BAJORIN, DEAN F.; IYER, GOPA " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 759367 NCI 704784 54583 PROJECT SUMMARY/ABSTRACTThe goal of the T32 Investigational Cancer Therapeutics Training Program (ICTTP) at Memorial Sloan-Kettering Cancer Center (MSKCC) is to provide highly select physician trainees in hematology and medicaloncology with the research training necessary for successful careers in the translation of cancer biologydiscoveries into novel molecular immune or cell-based therapeutics and those experimental treatments intoclinical trials that have the potential to change standards of care. The T32 ICTTP program accomplishes thisgoal by combining a comprehensive mentored training program an extensive didactic curriculum in clinical andtranslational research methodologies and experiential programs supporting development of the critical careerskills (e.g. collaboration research management grant writing) necessary for academic success. Each year weselect 4 highly committed postdoctoral trainees from the pool of outstanding physicians at MSKCC who havecompleted at least 3-4 years of both internal medicine and oncology/hematology clinical training. T32 traineesare then supported for 2 consecutive years so that 80% of their time and effort is dedicated to researchtraining. Based on individual research interests and career goals ICCTP trainees develop either a laboratory-based or a prospective clinical research program with guidance from their mentors who are establishedindependently funded investigators. These programs involve extensive collaborative scientific interactionsincluding additional clinical scientist mentorship for laboratory-based trainees and laboratory scientistmentorship for clinical research trainees. The T32 ICTTP supplements mentored research training with acurriculum of symposia workshops in-person didactic programs and online courses that prepares trainees toconduct successful independently supported research at the faculty level. We continue to enhance theprogram by revising and adding new educational programs in clinical research methodology research ethicsnational and international clinical trial requirements and conduct as well as hands-on writing workshops forgrants and protocols. Participating faculty mentors are continually reviewed and selected based on strictcriteria for research productivity independent funding and quality of mentoring. T32 ICTTP mentors haveresearch programs on cancer genetics genomics epigenetics signal transduction and metabolism; tumorimmunology and immunotherapy; drug and cellular therapeutic development; and tumor evolution usingsystems and computational approaches. Projects conducted by T32 ICTTP trainees in the proposed fundingperiod continue similar themes in cancer therapeutics research. All T32 ICTTP graduates from the last fundingcycle are continuing in oncology research and all who are working in academia have secured independentresearch funding. This success continues the ICTTPs 40-year track record of training leaders in cancertherapeutic development and translational research. 759367 +No NIH Category available Adhesions;Adjuvant Chemotherapy;Affect;Binding;Blood;Blood Vessels;Blood capillaries;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;CRISPR/Cas technology;Cell Adhesion;Cell Communication;Cell surface;Cells;Circulation;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Complex;Consensus;Data;Disease;Distant;Distant Metastasis;Drops;Education;Elements;Endothelial Cells;Endothelium;Exposure to;Extravasation;Fellowship;Future;Gene Expression;Gene Expression Profile;Genetic Complementation Test;Genetic Transcription;Hematogenous;ICAM1 gene;In Vitro;Injections;Invaded;Knock-out;Leukocytes;Ligands;Link;Liquid substance;Localized Disease;Lung;Lymphatic;Mediating;Metastatic breast cancer;Microfluidics;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Oncology;Operative Surgical Procedures;Organ;Outcome;Pathway interactions;Patients;Phenotype;Physicians;Proteins;Research;Research Proposals;Role;Scientist;Series;Signal Transduction;Students;Survival Rate;System;Tail;Testing;Therapeutic;Therapeutic Intervention;Tissues;Training;Tumor Angiogenesis;Tumor Promotion;Tumor-Derived;Vascular Endothelial Cell;Vascular Endothelium;Vascular System;Veins;Visualization;Work;aggressive breast cancer;breast cancer diagnosis;cancer cell;cancer subtypes;cancer type;candidate identification;clinically actionable;education planning;effective therapy;expectation;improved;in vivo;insight;knock-down;malignant breast neoplasm;migration;molecular subtypes;mortality;neoplastic cell;new therapeutic target;notch protein;novel;paracrine;programs;shear stress;skills;transcriptome sequencing;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;vascular bed The Study of Jag1-Notch in the Extravasation of Triple Negative Breast Cancer Cells in Metastasis. Project NarrativeTriple negative breast cancer (TNBC) makes up to 20% of breast cancer diagnoses with a 5-year survival aslow as 11% for late-stage metastatic disease. This research proposal aims to study JAG1-mediated signaling asa potential target for TNBC metastatic spread by specifically focusing on tumor-endothelial interactions duringtumor cell extravasation from circulation into secondary organs. Integrated into this proposal is a clinicaleducational plan and a bi-directional student-patient partnership. NCI 10676314 9/7/23 0:00 PA-21-049 5F30CA257269-03 5 F30 CA 257269 3 "DAMICO, MARK W" 9/16/21 0:00 3/15/25 0:00 Special Emphasis Panel[ZRG1-F09B-M(20)L] 15178310 "GORDON, BENJAMIN " Not Applicable 7 PHYSIOLOGY 98987217 W8XEAJDKMXH3 98987217 W8XEAJDKMXH3 US 41.871509 -87.667721 577703 UNIVERSITY OF ILLINOIS AT CHICAGO Chicago IL SCHOOLS OF MEDICINE 606124305 UNITED STATES N 9/16/23 0:00 9/15/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 Project SummaryTriple negative breast cancer (TNBC) makes up to 15-20% of breast cancer diagnoses. While surgery andadjuvant chemotherapy are effective treatment options for early-stage disease there are very few therapeuticoptions for advanced metastatic TNBC and the 11% relative five-year survival rate highlights an urgent need todiscover actionable targets. In the hematogenous metastatic cascade a few aggressive tumor cells are capableof crossing the endothelial barrier at least twice: when entering systemic circulation (intravasation) and thenagain when exiting circulation to colonize distant organs (extravasation). High expression of JAGGED-1 (JAG1)a Notch ligand is strongly associated with TNBC metastasis and consequent mortality. Our preliminary work instatic culture suggests that JAG1 enhances TNBC binding to the endothelium and transendothelial migration(TEM) thereby promoting dissemination of tumor cells through vascular beds. We propose to study two distinctmechanisms for JAG1 in the metastatic cascade. In Aim 1 we will investigate how tumor JAG1 signals in transto the endothelium to prime the vascular barrier for invasion. We will examine extravasation of our recentlygenerated TNBC CRISPR JAG1 knockout clones and control cells using a microfluidics system that faithfullymodels capillary fluid shear forces and permits visualization of multiple critical steps of extravasation in vitro. Wewill also test the role of JAG1 in vivo by examining the rate of lung capillary extravasation and pulmonary seedingfollowing tail vein injection of JAG1 knockout and control TNBC cells. In Aim 2 we will define the tumor cell-intrinsic transcriptional program regulated by JAG1. Our preliminary RNA sequencing data suggest that novelJAG1 targets promote cell surface interactions distinct from Notch targets. We will determine the metastaticimportance of key JAG1 targets by restoring expression and testing for TEM phenotypes. In the training plan ofthe fellowship I highlight an integrated scientific clinical and educational blueprint to enhance my personalresearch and doctoring skills as an aspiring physician-scientist in oncology. 52694 +No NIH Category available AKT Signaling Pathway;Address;Binding;Biochemical;Biological Assay;Biophysics;C-terminal;Cell membrane;Cells;Chemicals;Complex;Core Protein;Dedications;Development;Disease;Enzymes;Event;Excision;FDA approved;FRAP1 gene;Family;Glucocorticoids;Grant;Hand;Kinetics;Knowledge;Ligase;Malignant Neoplasms;Measurement;Mediating;Methods;Mind;Modification;Molecular;Mutate;N-terminal;Oncogenic;PIK3CG gene;PTEN gene;Pathway interactions;Pharmaceutical Preparations;Phosphatidylinositol 45-Diphosphate;Phosphatidylinositols;Phospholipids;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Phosphotransferases;Portraits;Post-Translational Protein Processing;Protein Kinase;Protein Kinase C;Protein Subunits;Proteins;Reaction;Recombinants;Regulation;Research;Research Personnel;Serum;Signal Pathway;Signal Transduction;Signaling Protein;Site;Structure;Substrate Specificity;Training;Tumor Suppressor Genes;Ubiquitin;Ubiquitination;Work;cancer cell;cancer therapy;combat;insight;interest;member;next generation;novel;novel therapeutic intervention;phosphatidylinositol 345-triphosphate;polypeptide;programs;protein function;protein protein interaction;protein structure;recruit;therapeutic development;therapeutic target;tripolyphosphate;tumor;ubiquitin isopeptidase;ubiquitin ligase;ubiquitin-protein ligase Chemical Approaches to Cell Signaling Enzymes Narrative:These studies will investigate how key cancer cell signaling pathway genes areregulated by chemical modifications. New chemical methods will be developed andapplied to elucidate the functions of these modifications and our findings can lead to newstrategies for the treatment of cancer. NCI 10676298 7/17/23 0:00 PA-20-185 5R01CA074305-29 5 R01 CA 74305 29 "FU, YALI" 4/1/97 0:00 7/31/27 0:00 Macromolecular Structure and Function A Study Section[MSFA] 1928078 "COLE, PHILIP A" Not Applicable 7 Unavailable 30811269 QN6MS4VN7BD1 30811269 QN6MS4VN7BD1 US 42.336107 -71.107481 1080401 BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA Independent Hospitals 21156110 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 382613 NCI 213750 168863 AbstractThis is a competing renewal application of our longstanding R01 Grant CA74305 thatconcerns the development and application of chemical approaches to enhance theunderstanding of cell signaling pathways and the attachment removal and function ofprotein post-translational modifications (PTMs). In the next cycle we plan to investigatehow ubiquitination regulates two key cancer-related signaling enzymes PTEN and Akthow several cancer-connected E3 ubiquitin (Ub) ligases target and catalyze Ub transferto their protein substrates and how mTORC2 phosphorylates its major substrate Akt.PTEN is one of the most commonly mutated tumor suppressor genes and catalyzes theconversion of phospholipid phosphatidylinositol-345-triphosphate (PIP3) to PIP2 and inthis way antagonizes the action of the PI3-kinase/Akt oncogenic signaling pathway. Aktis a protein Ser/Thr kinase that is activated by PIP3 and drives tumor formation. Akt is anintensively studied cancer therapeutic target. E3 Ub ligases are a large family (>600members) of enzymes that target Akt PTEN and thousands of cellular substrates forLys ubiquitination. Our research program will continue to develop and employ proteinsemisynthetic methods including ubiquitin hydrazide installation to generate mimics ofmono-ubiquitinated proteins and covalent E3-Ub-substrate ternary complexes. Our threespecific aims are: 1. Elucidate the basis of PTEN and Akt regulation by Lysubiquitination; 2. Delineate the catalytic mechanisms and protein substrate recognition ofkey E3 ubiquitin ligases; 3. Determine the molecular basis of mTORC2 mediated-phosphorylation of Akt. With site-specifically modified signaling proteins in hand we willintegrate kinetic assays structural analysis binding measurements and cell-basedstudies to clarify key regulatory and signaling features. Upon completion of this researcheffort we will broaden the knowledge of how Lys ubiquitination targets critical cancer-related proteins and influences their functions. We will also deepen our understandingof how the multisubunit mTORC2 complex is able to activate Akt. Moreover thesestudies should pave the way for new therapeutic strategies to combat pathwaydysregulation in cancer. This research program will also enable the training of the nextgeneration of biochemical investigators with an interest in cancer. 382613 +No NIH Category available Algorithms;Area;Artificial Intelligence;Biological Assay;Biological Markers;Biological Specimen Banks;Biometry;Blood;Blood specimen;Breast;Breast Cancer Detection;Breast Cancer Early Detection;Breast Cancer Risk Factor;Breast Magnetic Resonance Imaging;CLIA certified;Cancer Biology;Cancer Etiology;Cessation of life;Clinical;Collaborations;Colorectal;Colorectal Cancer;Computers;Data;Development;Diagnostic;Early Detection Research Network;Epidemiology;Estrogen receptor positive;Funding;Future;Goals;High Risk Woman;Image;Lead;Leadership;Magnetic Resonance Imaging;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mammographic screening;Mammography;Mass Spectrum Analysis;Methodology;Oncology;Ovary;Paper;Patients;Performance;Phase;Positioning Attribute;Prospective cohort;Public Health;Research Design;Research Personnel;Resources;Sampling;Scientist;Series;Techniques;Testing;Tissue Sample;Tumor Tissue;Universities;Validation;Washington;Woman;Women's Health;Work;artificial intelligence algorithm;biomarker development;biomarker panel;blood-based biomarker;breast imaging;cancer biomarkers;cancer type;candidate marker;clinical application;clinical development;cohort;design;design verification;early detection biomarkers;good laboratory practice;high risk;improved;industry partner;magnetic resonance imaging biomarker;malignant breast neoplasm;multidisciplinary;multimodality;novel;novel strategies;patient screening;phase 2 study;phase 3 study;phase 3 testing;phase 4 study;pre-clinical;predictive modeling;prospective;protein biomarkers;screening;tool;validation studies Fred Hutchinson Breast Cancer Clinical Validation Center PROJECT NARRATIVEDespite improvements in screening and treatment breast cancer remains the 2nd most common cause ofcancer related death among U.S. women. With current EDRN funding we conducted successful Phase 2 and 3validation studies of breast cancer biomarkers for clearly defined clinical applications. Herein we proposePhase 2 3 and 4 validation studies development of clinical grade assays and integration of imaging data withthe goal of implementing a novel strategy to improve the early detection of breast cancer. NCI 10676289 6/26/23 0:00 RFA-CA-21-033 5U01CA152637-13 5 U01 CA 152637 13 "ABRAMS, NATALIE" 8/16/10 0:00 7/31/27 0:00 ZCA1-PCRB-D(M1) 6603731 "LI, CHRISTOPHER I" "PARTRIDGE, SAVANNAH CORRINA" 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 1060017 NCI 763906 330393 ABSTRACTThere remain clear clinical and public health needs to improve the early detection of breast cancer. Whilemammography is an effective tool there are issues with respect to optimizing its use and performance anddespite widespread screening breast cancer remains the 2nd most common cause of cancer related deathamong U.S. women. Through the current EDRN Clinical Validation Center (CVC) led by Dr. Li we havevalidated 15 candidate biomarkers through a series of Phase 2 and Phase 3 validation studies that involvedsuccessive series of three independent sets of preclinical samples. Outside of EDRN funding Dr. Partridgehas led the development of novel strategies to improve breast cancer detection based on quantitative markersderived from screening MRIs in high-risk women and application of artificial intelligence (AI) approaches incollaboration with Microsoft. Our overarching goal is to conduct Phase 2 and 3 validation studies of blood-based biomarkers and imaging strategies that will be integrated and jointly assessed in a Phase 4 validationstudy. Supporting this goal we propose the following 4 projects: Project 1: Phase 3 validation of early detectionbiomarkers for ER+ breast cancer; Project 2: Phase 2 and 3 validation of protein biomarkers for the earlydetection of breast cancer discovered using a mass spectrometry-based platform; Project 3: Phase 3 validationof quantitative markers and AI algorithms applied to MRI screening exams for the early detection of breastcancer in women at high risk; and Project 4: Phase 4 validation of blood-based biomarkers and imagingalgorithms for the early detection of breast cancer. Additionally we will provide biospecimens and expertise tosupport high quality PRoBE compliant EDRN discovery and validation studies across several cancer types.With the combined expertise of our multidisciplinary team of investigators and our engagement with keycommercial partners this CVC will both lead well-justified rigorously designed validation studies and provideabundant resources to EDRN. Given the strength of our biomarker candidates the sets of biospecimens thatwill be used the study designs employed and the clearly delineated clinical applications proposed weanticipate that this work will yield near-term clinical impact. 1060017 +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Advanced Malignant Neoplasm;Apoptosis;Award;Binding;Biological;Biological Assay;Biology;Breast;CRISPR screen;Cancer Model;Cause of Death;Cell Cycle;Cell Cycle Regulation;Cell Death Induction;Cell surface;Cells;Cessation of life;Cities;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Code;Collaborations;Colon;Colon Carcinoma;Combined Modality Therapy;Complex;Computer Models;Cutaneous T-cell lymphoma;Data;Docking;Drug Targeting;Energy Transfer;Essential Genes;FDA approved;Fellowship;Genes;Goals;Impairment;In Vitro;Integrin alphaV;Integrin beta Chains;Integrins;Invaded;Knock-out;Laboratories;Liquid substance;MAPK10 gene;Machine Learning;Malignant Neoplasms;Malignant neoplasm of pancreas;Mass Spectrum Analysis;Measurable;Methods;Mitogen-Activated Protein Kinases;Modeling;Monitor;Mutate;Mutation;Oncogenic;Pancreas;Patients;Pharmaceutical Preparations;Phase;Phosphotransferases;Play;Postdoctoral Fellow;Proteomics;Research;Research Project Grants;Role;Scanning;Scientist;Signal Pathway;Signal Transduction;Solid;Solid Neoplasm;Structure;System;Techniques;Technology;Therapeutic;Time;Training;Translational Research;United States;Validation;Western Blotting;Work;beta catenin;biomarker discovery;cancer cell;cancer survival;cell killing;comparison control;density;design;effective therapy;high throughput screening;improved;in silico;inhibitor;lead candidate;malignant breast neoplasm;mathematical model;migration;nemo-like kinase;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;pre-doctoral;predictive modeling;prevent;skills;small molecule;statistics;triple-negative invasive breast carcinoma;tumor Targeting a Novel Pocket on ITGAV Project NarrativeThe proposed research aims to fill an unmet clinical need in treating aggressive cancers such as colonpancreatic and breast. We found that Integrin Alpha V (ITGAV) is necessary for the survival of these cancersand that a novel pocket on its structure can be targeted with a drug. Additionally we will investigate the complexsignaling controlled by ITGAV to propose combinational therapies and create new therapeutic strategies to treatthese cancers. NCI 10676274 8/21/23 0:00 RFA-CA-21-059 5F99CA274649-02 5 F99 CA 274649 2 "ELJANNE, MARIAM" 8/3/22 0:00 9/22/23 0:00 ZCA1-PCRB-H(M1) 16553342 "MATTSON, NICOLE " Not Applicable 31 Unavailable 27176833 NPH1VN32EWN5 27176833 NPH1VN32EWN5 US 34.127716 -117.972442 3058203 BECKMAN RESEARCH INSTITUTE/CITY OF HOPE DUARTE CA Research Institutes 910103012 UNITED STATES N 8/1/23 0:00 9/22/23 0:00 398 Other Research-Related 2023 6799 NCI 6799 0 Project Summary. Cancer deaths remain at an all-time high in the United States leaving an urgent clinical needto develop novel therapeutic strategies to help patients. The lack of effective treatments is in part due tounderlying complexities in cancer that current scientific approaches are just beginning to uncover. Technologicaladvances are rapidly changing the landscape of scientific discovery; for example the combination ofmathematical modeling in tandem with laboratory based validation leading to better combinational therapies totreat cancer. For this reason I propose training in both with the F99/K00 Predoctoral to Postdoctoral FellowTransition Award. For the F99 phase the dissertation research I will focus on laboratory based research skillsto identify and propose a novel therapeutic to treat cancers. In a high level CRISPR screen targeting about 580genes on the cell surface we found that Integrin Alpha V (ITGAV) is essential for the survival of solid tumors(colon pancreatic and breast cancer). To validate ITGAV as the most essential integrin we designed a secondlayer screen targeting all 26 integrins and found that ITGAV and Integrin Beta 5 (ITGB5) are the only essentialintegrins in solid tumors. Interestingly integrins must for an obligate heterodimer between an alpha and a betasubunit of which ITGAV and ITGB5 are one of the known 24. As the more essential pair ITGAV was probed witha high-density CRISPR tiling scan and we found a small pocket to be essential for ITGAV function and it wasamendable to small molecule binding. A structure based analysis found a loop structure of the beta pair of ITGAVinteracts with the discovered pocket leading to our hypothesis that the pocket is essential for the heterodimerstability between ITGAV and its beta pair. Indeed from a high-throughput screen of 500 small molecules wefound one compound that appears to bind in our pocket and disrupt the heterodimer between ITGAV and ITGB5.Further validation of this potential will be the remaining work to be done for the dissertation research and uponcompletion will fill an unmet clinical need since no there no FDA approved drugs targeting integrins approvedfor cancer indications. To further advance the potential to treat cancer I plan to use mathematical modelingapproaches to identify novel therapeutic strategies by understanding the complexities of cancer signaling duringthe K00 phase the proposed postdoctoral work. To study complex cancer signaling in collaboration with Dr.Pirrotte we generated kinase activity scores in cells where ITGAV was knocked out. With this data we can modelthe effects of signaling as it relates to measurable changes in the cancer cells. Specifically we will study cellcycle control which is inhibited with ITGAV loss. Additionally we can model known inhibitors to commonsignaling cascades as novel combinational therapeutic strategies. To confirm our model I will use laboratorybased skill developed during the F99 phase. Overall with the training with the F99/K00 award I will gain skills tobe able to build mathematical models to study cancer and validate those models with laboratory based skills.This will allow me to become and independent research and leading scientist in translational research. 6799 +No NIH Category available Address;Adult;African American population;American College of Radiology Imaging Network;Ancillary Study;Area;Award;Cancer Center;Cancer Control;Cancer Control Research;Cancer Patient;Caring;Catchment Area;Childhood;Clinical;Clinical Research;Clinical Treatment;Clinical Trials;Collaborations;Collection;Colorectal Cancer;Communities;Community Clinical Oncology Program;Community Practice;Detection;Development;Disparity;Eastern Cooperative Oncology Group;Educational Status;Enrollment;Ethnic Population;Feedback;Funding;Geography;Goals;Gynecologic;Health Personnel;Human Resources;Image;Incidence;Individual;Lead;Low income;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measures;Medical Oncologist;Minority;Minority Enrollment;Minority Groups;Minority-Based Community Clinical Oncology Program;Mission;Oncologist;Oncology;Outcome;Participant;Patients;Pediatric Oncology Group;Personal Satisfaction;Phase;Population;Prevention;Prevention Research;Primary Health Care;Prognosis;Protocols documentation;Public Health;Quality of life;Radiation Oncologist;Recording of previous events;Research;Research Personnel;Resources;Rural;Rural Community;Rural Population;Science;Site;Socioeconomic Factors;Specialist;Surgeon;Underserved Population;Universities;Urban Population;Virginia;anticancer research;base;biobank;cancer care;cancer clinical trial;cancer health disparity;cancer prevention;cancer therapy;care delivery;clinical trial enrollment;clinically significant;demographics;ethnic disparity;ethnic minority;experience;forest;health care disparity;improved;insight;interest;malignant breast neoplasm;malignant stomach neoplasm;medically underserved;member;mortality;outreach;programs;protocol development;racial disparity;racial minority;racial population;research study;rural African American;rural patients;screening;socioeconomic disparity;treatment research;treatment trial;underserved community;underserved minority VCU Massey Cancer Center Minority/Underserved NCI Community Oncology Research Program PROJECT NARRATIVEThe proposed research is relevant to public health as it will bring cancer clinical trials and cancer caredelivery research to minority and underserved individuals in their own communities. The inclusion of theseindividuals in the research will both broaden the applicability of the science and help to reduce health caredisparities experienced by minority and underserved cancer patients. NCI 10676243 7/26/23 0:00 RFA-CA-18-017 5UG1CA189869-10 5 UG1 CA 189869 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-SRB-H(M1) 14583618 "MATIN, KHALID " "BEAR, HARRY D; SHEPPARD, VANESSA B" 4 INTERNAL MEDICINE/MEDICINE 105300446 MLQFL4JSSAA9 105300446 MLQFL4JSSAA9 US 37.549807 -77.452775 353201 VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND VA SCHOOLS OF MEDICINE 232980568 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1075978 NCI 787251 434956 PROJECT SUMMARYVirginia Commonwealth University (VCU) Massey Cancer Center (MCC) will serve as the primary componentsite for an NCORP Minority/Underserved Community Site (MU-NCORP) UG1 award in partnership with 6collaborating community affiliate sites in the Commonwealth of Virginia. Over 30% of patients seen in the MCCMU-NCORP are from minority populations primarily African Americans. This proposal emphasizes the uniqueurban and rural population available to the MCC MU-NCORP the history of extensive participation by primaryhealth care providers and specialists in particular surgeons pediatric/AYA oncologists gynecologic surgeonsradiation oncologists neuro-oncologists and medical oncologists in clinical research and VCU initiatives incancer outreach conducted at rural sites across Virginia. This community-based NCORP focused onparticipation in clinical research of minority populations was initially funded as a Minority-Based CommunityClinical Oncology Program in 1990 and has been continuously funded including since 2014 as a MU-NCORP.The MCC MU-NCORP has affiliations with 5 Research Bases (Alliance for Clinical Trials in OncologyChildrens Oncology Group ECOG-ACRIN Cancer Research Group NRG Oncology and the Wake ForestNCORP Research Base). Our application describes the working relationships with the Research Bases andthe focus of the MCC MU-NCORP to accrue significant numbers of minority participants in cancer control andprevention treatment/imaging and cancer care delivery clinical research studies. Working relationships of theprimary sites investigators research staff and support personnel with the affiliate sites are also described.Accordingly the specific aims of this proposal are (1) to increase the overall enrollment of racial/ethnic andrural populations in our catchment areas to NCI-approved studies with a greater focus on cancer controlresearch cancer prevention research and cancer care delivery research (CCDR) in addition to cancertreatment research; (2) to collaborate with the NCORP Research Bases by (i) providing insight into relevancefor community practices during concept development (ii) identifying care disparities our catchment areas thatshould be studied and (iii) providing input on feasibility during concept and protocol development; (3) toexceed the required annual minimum participation in CCDR protocols; (4) to participate in biospecimencollection for biobanks that serve as scientific resources for NCORP Research Bases; and (5) to participate inNCORP initiatives such as DCP-001 to document screening efforts for clinical trial enrollment and to addresscancer health disparities.The proposed research is relevant to the mission of the NCI as MCC and the community affiliates will bringcancer clinical trials and research to low-income minority and medically underserved individuals whootherwise would not have access to such studies. Targeting the minority/underserved populations in theircommunities is a critical step toward alleviating the cancer care disparities prevalent in these populations. 1075978 +No NIH Category available A549;Algorithms;Antineoplastic Agents;Biological;Biological Markers;CLIA certified;Cancer Etiology;Cancer cell line;Cell Line;Cells;Cessation of life;Chest;Clinical Oncology;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Computational Biology;DNA Sequence Alteration;Data;Development;Diagnosis;Disease;Drug resistance;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;FDA approved;Fellowship;Gene Expression;Genetic Transcription;Genomics;Hematology;Histologic;Hospitals;Immune checkpoint inhibitor;Immunocompetent;In Vitro;Internal Medicine;Laboratories;Lung Adenocarcinoma;Machine Learning;Malignant neoplasm of lung;Measures;Medical;Medical Oncology;Medical center;Methods;Modality;Mutate;New York;Oncogenic;Oncologist;Oncoproteins;Pathway Analysis;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Physicians;Presbyterian Church;Protein-Serine-Threonine Kinases;Proteins;Quality of life;Research Project Grants;Residencies;Resistance;Scientist;Serine;Statistical Methods;Surgeon;Systems Biology;Technology;Training;Transcription Regulatory Protein;Translational Research;Tumor Markers;Tumor Suppressor Proteins;Tyrosine Kinase Inhibitor;United States;Universities;Update;Work;cancer gene expression;cancer subtypes;career;clinical training;clinically actionable;cohort;college;computer studies;driver mutation;drug sensitivity;genomic biomarker;high throughput analysis;immunohistochemical markers;improved;in silico;in vivo;knock-down;machine learning classifier;machine learning prediction;mortality;mouse model;mutant;next generation sequencing;novel;patient derived xenograft model;pharmacologic;pre-doctoral;precision oncology;prognostic value;programs;reconstruction;response;single-cell RNA sequencing;standard of care;success;synergism;targeted treatment;transcription regulatory network;transcriptomics;treatment strategy;tumor Identifying and Targeting Master Regulators of Drug Resistance in Lung Adenocarcinoma through Network Analysis of Tumor Transcriptomic Data Project NarrativeAlthough lung cancer is the leading cause of cancer-related mortality each year in the United States optimalbiomarkers for tumor sensitivity to targeted therapy and immune checkpoint inhibitors are lacking. Throughcomputational systems biology analyses of lung cancer gene expression data we propose to identify andpharmacologically target Master Regulator proteins which coordinate resistance to these treatment modalities.The activity of these Master Regulators which can be inferred in silico for the development of predictive machinelearning biomarkers of drug sensitivity in lung cancer will be abrogated in vitro and in vivo using FDA-approvedand investigational compounds to destabilize drug-resistant phenotypes thereby improving the quantity andquality of life for patients diagnosed with this deadly disease. NCI 10676216 9/1/23 0:00 PA-21-049 5F30CA257765-03 5 F30 CA 257765 3 "BIAN, YANSONG" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F09C-Z(20)L] 15099892 "GRIFFIN, AARON TIMOTHY" Not Applicable 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 52694 NCI 52694 0 Project Summary/AbstractLung cancer the leading cause of cancer-related mortality in the United States is responsible for more than100000 deaths each year. The treatment of metastatic lung adenocarcinoma (LUAD) the most commonhistological subtype of lung cancer has improved substantially in recent decades through the advent of targetedtherapy for tumors with oncogenic driver mutations and immune checkpoint inhibitors for those without. Howeverup to 50% of metastatic LUAD tumors will not respond to standard-of-care antineoplastic therapy. Previousprecision oncology efforts to discover genomic or immunohistochemical biomarkers of LUAD tumor drugsensitivity have achieved limited success. To remedy these shortcomings we propose to leverage a translationalsystems biology approach to identify and target the biological determinants of drug resistance in LUAD throughnetwork analysis of tumor transcriptomic data. Due to advances in computational biology and next-generationsequencing technologies the dynamic expression of genes within each patients LUAD tumor may be accuratelymeasured providing a novel window for the identification of the key transcriptional regulatory proteins whichinitiate and maintain drug-resistant tumor phenotypes (i.e. Master Regulators). The systematic identification ofMaster Regulator proteins can be achieved with Non-parametric analytical Rank-based Enrichment Analysis(NaRnEA) a newly developed statistical method capable of leveraging context-specific transcriptional regulatorynetworks to extract highly mechanistic information from LUAD tumor transcriptomic data for in silico precisiononcology thus overcoming the limitations of previous genomic and immunohistochemical approaches. NaRnEA-inferred activity of Master Regulator proteins which coordinate resistance to targeted therapy will be leveragedfor the development of a transcriptomic machine learning biomarker of drug-sensitivity. Additionally one-of-a-kind perturbational gene expression profiles for >400 FDA-approved and investigational compounds in the LUADcell line NCIH1793 will be interrogated to identify drugs capable of targeting these Master Regulators of drug-resistance using the OncoTreat algorithm a novel systems biology precision oncology method which hasreceived NYS CLIA certification and is currently in use for multiple clinical trials at the Columbia University IrvingMedical Center. This translational research project will coincide with simultaneous scientific and clinical trainingas the applicant studies computational biology and works closely with thoracic oncologists at CUIMCrespectively. Following the completion of this research project the applicant will complete clinical training at theNew York Presbyterian Hospital through the Columbia University Vagelos College of Physicians and Surgeons.This combined scientific and medical predoctoral fellowship will prepare the applicant for an Internal Medicineresidency and a Hematology/Oncology clinical fellowship culminating in a career as an independent physician-scientist in the field of precision medical oncology. 52694 +No NIH Category available programs Next-Gen Oncopathology Program The Next-Gen Oncopathology (NGO) Program will provide trainees in pathology an opportunityto conduct cancer research and train in cutting-edge methodologies relevant for cancerunderstanding and precision diagnosis. Our goal is to prepare young pathologists to lead anddrive innovations in laboratory cancer diagnosis into the future. NCI 10676213 8/17/23 0:00 PA-20-142 5T32CA260293-02 5 T32 CA 260293 2 "LIM, SUSAN E" 9/1/22 0:00 8/31/27 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1883862 "CESARMAN, ETHEL " "GREENBLATT, MATTHEW BLAKE" 12 PATHOLOGY 60217502 YNT8TCJH8FQ8 60217502 YNT8TCJH8FQ8 US 40.7607 -73.9603 1514803 WEILL MEDICAL COLL OF CORNELL UNIV NEW YORK NY SCHOOLS OF MEDICINE 100654805 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 361841 NCI 336804 25037 The Next-Gen Oncopathology (NGO) program has the overall mission of training young diagnosticians to meetadvances in our understanding of the mechanisms of cancer pathogenesis and new oncological interventionalapproaches thereby leading the field of pathology into the future. Specialized pathologists have been involvedin cancer diagnostics by examining tissues and other specimens since at least the 19th century and training inpathology has been incrementally structured and subspecialized. Pathology training programs traditionally teachresidents to examine tissue under the microscope and analyze laboratory data for diagnosis with pathologyresearch being largely descriptive. This approach is no longer sufficient and it is essential that we preparepathologists to understand and apply advanced technologies to perform more precise and personalizeddiagnostics in addition to utilizing innovative and improved ways to conduct research and diagnose cancer. TheWeill Cornell Department of Pathology and Laboratory Medicine has trained numerous outstanding pathologistsin many subspecialty areas but it is only with the use of an innovative approach incorporating a view towardsthe future that we will be able to produce leaders that will advance the field of cancer pathology. The NGOprogram takes a holistic and multidisciplinary approach where all aspects of a cancer patient are consideredranging from the tumors themselves to in vitro and in vivo cancer models to changes in the patients blood andmicrobial infections. Thus trainees in both Anatomic and Clinical Pathology (i.e. Laboratory Medicine) will beincluded which will be individuals with MD or MD/PhD degrees doing a Pathology Residency or Fellowship ortrainees with PhD degrees doing a clinical fellowship in Laboratory Medicine who are committed to an academiccareer that includes cancer research. Our trainees will gain expertise and depth by spending two years in aresearch laboratory working in one or more of the following major themes: 1) molecular diagnosis and cellulartherapies 2) cancer pathobiology 3) advanced imaging and 4) tumor microenvironment. The foundationalprinciples of the NGO program will be to ensure that all the pathology projects relate to the study of cancerpatient samples as well as the comparative pathology of cancer models. Overarching methodologies that willsupport all of the projects are: i) biostatistics and data science ii) machine learning and artificial intelligence andiii) genomics epigenomics proteomics and metabolomics. Faculty in the program have expertise in the majorthemes and specific methodologies which will allow for the teaching of foundational skills as well as a highlycustomized educational plan. This will be accomplished by the establishment of a mandatory NGO Course aswell as additional course requirements on data science and career development which will allow traineesflexibility to design a personalized curriculum with their mentoring committee. We will also leverage the MeyerCancer Center and the Weill Cornell Clinical and Translational Science Center (CTSC) resources to educate thenext generation of pathologists working on cancer. 361841 +No NIH Category available tumor immunology Tumor Immunology NarrativeThe purpose of this training program is to prepare post-doctoral researchers for careers in immunologic researchso that they can have a significant impact on the prevention diagnosis and treatment of cancer. Successfulcompletion of this will foster the development of the trainee's scientific research skills in preparation for animmunologic research career that will have a positive impact on the health needs of our nation's cancer patients. NCI 10676207 8/24/23 0:00 PA-18-403 5T32CA090223-20 5 T32 CA 90223 20 "LIM, SUSAN E" 7/25/02 0:00 8/31/24 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1871184 "CARSON, WILLIAM E." Not Applicable 3 SURGERY 832127323 DLWBSLWAJWR1 832127323 DLWBSLWAJWR1 US 39.999598 -83.033131 6218701 OHIO STATE UNIVERSITY COLUMBUS OH SCHOOLS OF MEDICINE 432101016 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Institutional" 2023 323426 NCI 318280 23359 Project SummaryThe purpose of this training program is to prepare postdoctoral researchers for careers in immunologic researchthat will enable them to have a significant impact on the prevention diagnosis and treatment of cancer. Overthe past decade the field of immunology has witnessed an unprecedented level of discovery on every front.These exciting advances have led to an improved understanding of how cancers evade the immune system andhow innate and specific immunity can be manipulated to generate an anti-tumor immune response. In order totranslate this new knowledge into effective treatments for cancer it will be necessary to train a new generationof immunologists who are well versed in the most recent concepts in immunology. Trainees will engage in anintensive program of immunologic research under the guidance of an accomplished mentor with expertise in aspecific area of immunology. This will permit the young investigator to develop a focused immunologic researchquestion and relate it to important clinical and scientific problems. In order that they have thorough exposure tothe principles underlying the conduct of immunologic research trainees will participate in a carefully designedprogram of courses conferences and meetings sponsored by the Ohio State University Comprehensive CancerCenter (OSUCCC) and the Immunology Program. Trainees will also benefit from significant exposure to relateddisciplines such as bioinformatics biostatistics human cancer genetics translational medicine andexperimental therapeutics as well as training in grant writing and the responsible conduct of research. Traineeswill be introduce to state of the art methodologies and scientific techniques. This program will encourage theparticipation of both physician-scientists and trainees with a basic science background in order to enhance theexchange of ideas stimulate intellectual curiosity and broaden the perspectives of the participants. There hasbeen and will continue to be a concerted effort to recruit persons from under-represented groups into thisprogram. Successful completion of this inter-disciplinary training program will foster the development of thetrainee's scientific research skills in preparation for an immunologic research career that will have a positiveimpact on the health needs of our nation's cancer patients. Indeed all 25 former trainees have continued withacademic pursuits and have maintained the expected career trajectory. Seventeen of these former trainees arestill involved in tumor immunology research (of which 10 have garnered staff positions at academic institutions)and four others remain in medical training. Since the last renewal three trainees from under-represented groupswere recruited to this training program. 323426 +No NIH Category available Address;Autophagocytosis;Breast Cancer Patient;CDK2 gene;CDK4 gene;CRISPR screen;Cancer cell line;Canis familiaris;Cell Cycle;Cell Cycle Progression;Cell Cycle Proteins;Cell Line;Cell Proliferation;Cell Survival;Cells;Chemoresistance;Clinic;Clinical Trials;Complex;Cyclin D1;Cyclin-Dependent Kinase Inhibitor;Cyclins;Down-Regulation;Drug resistance;FDA approved;G1 Phase;Genetic;Genetic Transcription;Genotoxic Stress;Head and Neck Squamous Cell Carcinoma;Holoenzymes;Human;Immunodeficient Mouse;Investigation;Knock-out;Link;Maintenance;Malignant Neoplasms;Mediating;Mitogens;Mus;Mutation;Nature;Non-Small-Cell Lung Carcinoma;Normal Cell;Oncogenic;Organoids;Patients;Pharmaceutical Preparations;Pharmacy (field);Phenotype;Phosphorylation;Protein Phosphatase 2A Regulatory Subunit PR53;Protein phosphatase;Proteins;Proteolysis;Publishing;Rattus;Replication Initiation;Research Personnel;Resistance;Role;Seminal;Signal Transduction;Testing;Therapeutic;Toxic effect;Translations;Tumor Suppression;Tumor Suppressor Proteins;Ubiquitin;Up-Regulation;Xenograft procedure;anti-cancer;antitumor agent;antitumor effect;biological systems;cancer cell;cancer type;cell type;follow-up;genome-wide;in vivo Model;in vivo evaluation;inhibitor;mRNA Stability;melanoma;mouse model;multicatalytic endopeptidase complex;neoplastic cell;novel;novel therapeutics;nutrient deprivation;overexpression;patient population;pharmacologic;preclinical study;protein complex;protein degradation;resistance mechanism;response;retinoblastoma tumor suppressor;sensor;small molecule;targeted cancer therapy;therapeutic target;tumor;tumorigenesis;ubiquitin-protein ligase;uncontrolled cell growth Overcoming drug resistance using small molecule activators of protein phosphatase 2A NARRATIVEA hallmark of tumors is uncontrolled cell growth resulting from aberrant activity of protein complexes such ascyclin D-CDK4 and cyclin D-CDK6 that control cell replication. A class of FDA-approved drugs that inhibit theactivity of cyclin D-CDK4/6 have promising activity against a variety of tumor types but resistance to theseagents inevitably emerges. In a mechanism-driven approach the proposed studies will test the ability of noveldrugs called Small Molecule Activators of PP2A (SMAPs) to overcome tumor resistance to CDK4/6 inhibitors. NCI 10676204 7/13/23 0:00 PAR-20-292 5R21CA273979-02 5 R21 CA 273979 2 "COVELL, DAVID G" 8/3/22 0:00 7/31/24 0:00 ZCA1-TCRB-V(M1)S 1966553 "BLACK, JENNIFER D." Not Applicable 2 INTERNAL MEDICINE/MEDICINE 168559177 G15AG3BLLMH4 168559177 G15AG3BLLMH4 US 41.265996 -96.010026 578104 UNIVERSITY OF NEBRASKA MEDICAL CENTER OMAHA NE SCHOOLS OF MEDICINE 681987835 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 176961 NCI 140194 36767 Uncontrolled cell proliferation resulting from aberrant activity of cell cycle proteins is a hallmark of cancer.Overexpression of the mitogen sensor cyclin D1 is among the most frequent abnormalities in tumors enhancingthe activity of cyclin dependent kinases 4 and 6 (CDK4/6) to drive G1S phase progression and promote cellsurvival and chemoresistance. Increased expression of D-type cyclins is required not only for tumorigenesis butalso for tumor maintenance and progression. Thus aberrant cyclin D-CDK4/6 activity represents an actionabletarget for cancer therapy and D-type cyclin function is among the top therapeutic targets for cancer management.Inhibitors of CDK4/6 activity have shown promise in the clinic and palbociclib abemaciclib and ribociclib areFDA-approved for use in patients. Several hundred clinical trials are currently ongoing to evaluate the antitumoreffects of these agents in a broad spectrum of cancer types. However the therapeutic promise of CDK4/6inhibitors is dampened by inevitable emergence of resistance. Recent seminal studies have identified a novelmechanism of resistance to these agents mediated by deficiency of autophagy and beclin 1 regulator 1(AMBRA1) an E3 ligase adaptor and master regulator of cyclin D1 D2 and D3 protein stability. Loss or mutationof AMBRA1 is seen in a significant subset of human cancers in association with poor patient survival. AMBRA1deficiency promotes the accumulation of D-type cyclins a hyperproliferative phenotype and tumorigenesis whilereducing the sensitivity of tumor cells to all three FDA-approved CDK4/6 inhibitors. Evidence that upregulationof D-type cyclins and the formation of non-canonical cyclin D-CDK2 and p27-cyclin D-CDK4 complexesunderpins resistance to these agents forms the basis of this proposal. Strategies are proposed to explore themechanism-driven application of Small Molecule Activators of PP2A (SMAPs) for overcoming resistance toCDK4/6 inhibitors in the context of AMBRA1 deficiency. SMAPs are a novel class of antitumor agents thatselectively activate a subset of PP2A holoenzymes for potent tumor suppression in a variety of cancer types.This project builds on our discovery that SMAPs potently downregulate cyclins D1 D2 and D3 in all cell typestested. Importantly SMAPs act as AMBRA1-independent D-type cyclin degraders promoting rapid proteolysisof these molecules via a proteasome-dependent mechanism that remains functional following loss of AMBRA1.Based on these findings we hypothesize that combining CDK4/6 inhibitor treatment with a SMAP D-type cyclindegrader will enhance antitumor activity and reverse resistance to CDK4/6 inhibitors driven by AMBRA1deficiency. Proof-of-concept studies will be performed in two Specific Aims: (1) Explore the effects of combiningCDK4/6 inhibitors and SMAPS in the context of AMBRA1-deficiency and (2) Evaluate the effects of SMAP-CDK4/6 inhibitor combinations in tumor models in vivo. Importantly in addition to addressing consequences ofAMBRA1-deficiency our proof-of-concept findings are anticipated to be broadly applicable to tumors harboringincreased levels of D-type cyclins and aberrant CDK activity resulting from other tumor-associated alterations. 176961 +No NIH Category available Address;Adoption;Adult;Cancer Etiology;Caring;Cessation of life;Clinic;Colonoscopy;Colorectal Cancer;Communities;Community Healthcare;Data;Disparity;Educational workshop;Effectiveness;Endoscopy;Evidence based intervention;Exclusion;Feasibility Studies;Geographic Locations;Goals;Health;Health Status;Health system;Hispanic;Home;Infrastructure;Institution;Intervention;Interview;Learning;Location;Logistics;Maintenance;Malignant Neoplasms;Measures;Medicaid;Methods;Modality;Modeling;Native Americans;Oregon;Patients;Persons;Phase;Pilot Projects;Policies;Population;Provider;Quasi-experiment;Research;Research Methodology;Risk Factors;Rural;Rural Community;Rural Population;Sample Size;Testing;Trainers Training;Training;Training Programs;Translations;Underserved Population;United States;Use Effectiveness;Vendor;acceptability and feasibility;aged;cancer health disparity;care coordination;care outcomes;colon cancer patients;colorectal cancer screening;community-level factor;design;effectiveness evaluation;effectiveness/implementation study;effectiveness/implementation trial;experience;feasibility testing;follow-up;frontier;frontier counties;health care availability;health care disparity;health plan;implementation evaluation;implementation facilitation;implementation intervention;implementation study;implementation trial;improved;learning strategy;mortality;multi-component intervention;multidisciplinary;organizational readiness;outreach;patient engagement;patient navigation;patient outreach;patient registry;pilot test;practice-based research network;pragmatic study;pragmatic trial;prevent;primary care clinic;program dissemination;programs;recruit;rural area;rural counties;rural environment;rural health clinic;rural setting;scale up;screening;screening disparities;success;tool;urban area;webinar Screening More patients for CRC through Adapting and Refining Targeted Evidence-based Interventions in Rural settings (SMARTER CRC) PROJECT NARRATIVEDisparities in colorectal cancer (CRC) screening follow-up and referral to care exist in ruralcommunities and for sub-populations within (e.g. Medicaid enrollees Hispanic patients). In SMARTERCRC our multidisciplinary team will adapt pilot then test the implementation and scale-up of targeteddirect-mail and patient navigation programs two effective multicomponent interventions inpartnership with rural clinics health plans (payers) and commercial vendors. Our approach leveragesan established rural practice-based research network; addresses patient clinic and community levelfactors; and will ultimately reduce CRC disparities in rural Medicaid patients and support Biden'sCancer Moonshot objectives. NCI 10676161 9/8/23 0:00 RFA-CA-19-018 5UH3CA244298-05 5 UH3 CA 244298 5 "GRIMES, GENEVIEVE M" 9/23/19 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-AARR-N(52)R] 10844684 "DAVIS, MELINDA MARIE" "CORONADO, GLORIA D" 1 NONE 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR OVERALL MEDICAL 972393098 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 353 Non-SBIR/STTR 2023 1064330 NCI 887022 177308 PROJECT SUMMARY/ABSTRACT:This two-phase project is designed to achieve the Cancer Moonshot objectives by reducing the burdenof CRC on the US population. Specifically we aim to improve CRC screening rates follow-upcolonoscopy and referral to care in rural Medicaid patients by implementing a direct mail fecal testingprogram with targeted outreach and patient navigation for follow-up colonoscopy. We leveragepartnerships with the Oregon Rural Practice-based Research Network (ORPRN) Kaiser NorthwestCenter for Health Research and Medicaid Health Plans and deliver training and implementationsupport to participating rural primary care clinics using practice facilitation. In total we anticipateworking with 30 organizations to facilitate implementation with 130 primary care clinics(reaching 17000+ rural Medicaid patients).In Phase I (Year 01) we will conduct a milestone driven pilot to build the necessary infrastructure for alarge-scale implementation-effectiveness trial including adapting the clinic-health plan-vendorsupported direct mail program for rural Medicaid patients that have not established care and/or neverbeen screened; conducting a pilot study testing the feasibility and acceptability of patient navigation tosupport follow-up colonoscopy following an abnormal fecal test; engaging Medicaid Health Plans andrecruiting 30 primary care clinics located in rural and frontier counties in Oregon; and developing thetraining and support materials needed to implement a large-scale trial in these settings.In Phase II (Years 02-05) we will conduct an implementation-effectiveness study using a quasi-experimental stepped wedge design in 30 rural primary care clinics using program training and practicefacilitation to support implementation. As in the pilot the intervention combines: (1) a clinic-health plan-vendor supported direct-mail fecal testing program with targeted outreach for patients who have neverbeen screened or who have yet to establish care and (2) patient navigation for those who are referredfor colonoscopy as either the primary screening or for follow-up from an abnormal fecal test. We willevaluate effectiveness implementation and maintenance of the intervention through quantitative andqualitative measures. Results from the implementation study will inform scale-up of the programthrough partnerships with 20 regional and national organizations that serve rural/frontier primary careclinics using webinars train-the-trainer workshops and collaborative learning activities using the ECHO(Extension for Community Healthcare Outcomes) model. 1064330 +No NIH Category available Address;Anxiety;Area;Behavior Therapy;Behavioral;Behavioral Symptoms;Cancer Patient;Cancer Survivorship;Chronic Disease;Clinical;Coping Skills;Diagnostic;Disease;Distress;Dose;Dyspnea;Educational process of instructing;Effectiveness;Elements;Emotions;Environmental Risk Factor;Evidence based intervention;Exclusion;Fatigue;Feedback;Focus Groups;Fright;Future;Goals;Guilt;Health;Health Benefit;Hour;Immunocompromised Host;Intervention;Interview;Length;Link;Malignant Neoplasms;Malignant neoplasm of lung;Manuals;Mental Depression;National Cancer Institute;National Comprehensive Cancer Network;Outcome;Outcome Measure;Pain;Participant;Patient Education;Patients;Persons;Phase;Population;Production;Prognosis;Protocols documentation;Provider;Psychological Impact;Psychotherapy;Public Health;Quality of life;Randomized;Reporting;Research;Research Priority;Science;Shame;Symptoms;Target Populations;Thermometers;Thoracic Oncology;Time;Uncertainty;Visit;Work;anticancer research;behavior change;cancer therapy;cancer type;coping;cost;distress tolerance;efficacy trial;emotion regulation;emotional symptom;evidence base;experience;implementation science;improved;innovation;mindfulness;novel;patient population;physical symptom;pilot test;post intervention;primary outcome;prognostic indicator;psychological distress;psychological symptom;psychosocial;satisfaction;secondary outcome;skills;skills training;survivorship;symptom management;trial comparing;understudied cancer Dialectical Behavioral Therapy Skills Training for Metastatic Lung Cancer Patients Project NarrativePatients with metastatic lung cancer endorse high rates of psychological distress (i.e. depression anxiety)which is associated with worse clinical outcomes and poorer overall survival in cancer patients. The proposedresearch addresses the unmet psychological and physical symptom needs of patients with metastatic lungcancer by novelly adapting and pilot testing dialectical behavioral therapy skills training to reduce psychologicaldistress through improved physical symptom management emotion regulation and tolerance of uncertainty.This intervention has the potential to produce significant public health benefit by impacting psychologicaldistress a variable that is consistently linked to worse quality of life and health outcomes in patients withchronic illness. NCI 10676154 8/22/23 0:00 PA-21-048 5F32CA265058-03 5 F32 CA 265058 3 "ODEH, HANA M" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F16-L(21)L] 77899923 "HYLAND, KELLY ALEXANDRA" Not Applicable 4 PSYCHIATRY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 69500 NCI 69500 0 Metastatic lung cancer patients experience significantly greater psychological distress (i.e. depressionanxiety) compared to other cancers. Psychological distress is as a prognostic indicator for worse clinicaloutcomes and poorer overall survival in cancer patients. Due to their historically poor prognosis patients withmetastatic lung cancer are often excluded from psychosocial intervention protocols. Existing interventions donot address factors that contribute to elevated psychological distress in these patients including managinghigh physical symptom burden (fatigue dyspnea pain) regulating challenging emotions (shame guilt fear)and tolerating uncertainty about the future. Dialectical behavioral therapy (DBT) is a transdiagnostic evidence-based psychotherapy that teaches participants a core set of behavioral skills (distress tolerance emotionregulation mindfulness interpersonal effectiveness) to cope more effectively with emotional and physicalsymptoms. DBT skills training has been adapted for a variety of clinical populations and has demonstratedefficacy in reducing psychological distress. To date DBT skills training has not been evaluated in patients withmetastatic lung cancer who stand to benefit immensely. We anticipate DBT skills training will need to beadapted to increase acceptability and relevance in patients with metastatic lung cancer including 1) delivery2) dose and 3) materials. The proposed study seeks to adapt and pilot test DBT skills training for patients withmetastatic lung cancer using the ADAPT-ITT framework. Participants will be metastatic lung cancer patientswho score >3 on the NCCN distress thermometer. Phase I aims to use focus groups and interviews with keystakeholders (metastatic lung cancer patients (N=20) thoracic oncology providers (N=6) clinicians withexpertise in survivorship and behavioral symptom management (N=6)) to determine if and how DBT skillstraining must be modified for implementation with metastatic lung cancer patients. Adapted material will bereviewed by topical experts in DBT and implementation science. It is hypothesized that these activities willproduce a manualized adapted DBT skills training protocol for metastatic lung cancer patients (DBT-MLC).Phase II aims to pilot test DBT-MLC to assess feasibility acceptability and examine pre-to-post interventionoutcomes. It is hypothesized that participants will report improvement on primary (psychological distress i.e.depression and anxiety) and secondary outcome measures (fatigue dyspnea pain emotion regulationtolerance of uncertainty DBT coping skill use). This project meets the National Cancer Institute's priorityresearch area of cancer survivorship and involves innovative adaptation of an evidence-based intervention foran underserved cancer population. Positive findings would rapidly inform the next step of research conductinga phase 2b randomized efficacy trial comparing DBT-MLC to a control condition. This work has the potential toreduce psychological distress and enhance clinical outcomes in metastatic lung cancer patients. Promisingresults may encourage future adaptation for other disease types and stages of survivorship. 69500 +No NIH Category available Acceleration;Address;Adolescent and Young Adult;Advocate;Aftercare;California;Cancer Control;Caring;Cities;Clinical Trials;Collection;Communities;Community Clinical Oncology Program;Community Participation;Data;Development;Discipline;Disparity;Early Diagnosis;Educational Activities;Elderly;Enrollment;Environment;Ethnic Origin;Foundations;Funding Opportunities;Goals;Health Personnel;Hematologist;Image;Incidence;Maintenance;Malignant Neoplasms;Medical;Michigan;Mission;Morbidity - disease rate;Names;National Cancer Institute;Nevada;Oncologist;Participant;Patients;Physicians;Population;Prevention;Protocols documentation;Quality of life;Race;Radiation Oncologist;Research;Research Activity;Research Design;Research Personnel;Resources;Safety;Sexual and Gender Minorities;Site;Technology;Time;Underrepresented Populations;Underserved Population;Work;anticancer research;base;biobank;cancer care;cancer health disparity;cancer prevention;cancer therapy;care delivery;clinical trial enrollment;clinical trial participant;clinically significant;community based research;ethnic minority;gender minority;health related quality of life;high standard;insight;interest;medical specialist;member;mortality;participant enrollment;programs;protocol development;racial minority;rehabilitation management;research study;rural dwellers;screening;welfare NCI Community Oncology Research Program (NCORP) Community Sites (UG1 Clinical Trial Required) This state-wide program (that also has 3 out-of-state affiliates) provides access to cancerresearch in prevention screening post-treatment surveillance treatment imaging biospecimencollection health-related quality of life studies cancer control cancer care delivery researchand cancer disparities to all interested professionals from varied medical and academicdisciplines for state-wide participation thereby providing access for participation in NCIclinical trials to Nevada residents. NCI 10676138 7/31/23 0:00 RFA-CA-18-016 5UG1CA189829-10 5 UG1 CA 189829 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 1969167 "ELLERTON, JOHN A" "IKEDA, ALAN " 4 Unavailable 173852054 VYNWU2X8FMY7 173852054 VYNWU2X8FMY7 US 36.177468 -115.176531 1657801 SOUTHERN NEVADA CANCER RESEARCH FDN LAS VEGAS NV Other Domestic Non-Profits 891064825 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1820248 NCI 1491037 329211 The Nevada Cancer Research Foundation (NCRF) was established in 1983 to conduct cancer research.The NCRF main office is located in Las Vegas with satellite offices in Reno and Carson City Nevada andArroyo Grande California and Port Huron Michigan. Over 80% of the oncologists hematologists andradiation oncologists in Nevada are investigator members of the NCRF and participate in NCI clinicaltrials and projects. NCRFs primary mission is to provide quality and state-of-the-art cancer treatment inNevada through participation in active cancer research studies for the residents of Nevada throughthe participation of the local physicians and health care providers. NCRF also has as part of itsmission the provision of high quality timely data to the NCI Community Oncology ResearchProgram (NCORP) Research Bases in a research environment that sets the highest standards forthe safety and welfare of the clinical trials participants. NCRF will continue to enrollpatients/participants on NCI clinical trials and plans to exceed the required annual 80 newunique patient/participant accruals evenly distributed between cancer control prevention andscreening/post-treatment surveillance trials and treatment and imaging trials respectively thatis required for participation in NCORP. NCRF also plans to participate in at least three cancercare delivery protocols annually and to continue to participate in bio-specimen collection forbiobanks that serve as scientific resources for the NCORP Research Bases. NCRF plans toactively work with the NCI to develop an integrated community-based research network inorder to reduce the cancer incidence morbidity and mortality in Nevada by accelerating thetransfer of newly developed cancer prevention early detection treatment patient managementrehabilitation quality of life and continuing care technology. NCRF will involve NCRF staffand physicians in the scientific and educational activities of the Research Bases and willparticipate in studies to enhance participation of racial/ethnic and other underservedpopulations underrepresented in research. To accomplish these goals the NCRF opens theprogram for state-wide participation thereby providing access for participation to the residentsof Nevada. 1820248 +No NIH Category available Academic Medical Centers;Acceleration;Address;African American;Aftercare;Amish;Area;Cancer Center;Cancer Control;Cancer Hospital;Catchment Area;Clinical;Clinical Research;Clinical Skills;Clinical Trials;Collaborations;Communities;Community Health;Community Networks;Community Outreach;County;Data;Disparity;Education;Enrollment;Evaluation;Feedback;Geography;Goals;Health care facility;Healthcare;Hispanic Populations;Hospitals;Image;Infrastructure;Institution;Latino Population;Lead;Location;Malignant Neoplasms;Medical Oncology;Medically Underserved Area;Mentors;Michigan;Minority Groups;Mission;National Cancer Institute;Outcome;Outcome Study;Palliative Care;Participant;Patient Representative;Patients;Pediatric Oncology;Performance;Population;Population Heterogeneity;Prevention;Procedures;Process;Protocols documentation;Qualifying;Radiation Oncology;Research;Research Design;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Rural;Rural Minority;Rural Population;Saints;Sister;Site;Structure;Subgroup;Training;Underserved Population;Urban Population;Vision;Wisconsin;anticancer research;base;cancer care;cancer health disparity;care delivery;clinical imaging;community setting;compliance behavior;disparity reduction;empowerment;ethnic minority;ethnic minority population;expectation;experience;health professional shortage areas;improved;member;minority communities;multidisciplinary;outcome disparities;patient population;patient retention;programs;protocol development;racial minority;recruit;rural area;screening;success;underserved community;urban minority Cancer Research of Wisconsin and Northern Michigan (CROWN) Consortium Project NarrativeCurrently cancer clinical research is predominantly performed at academic medical centers partially due tothe operational challenges and limitations of resources at community sites. A core premise of the NCORPnetwork is expanding the reach and execution of cancer control prevention and cancer care delivery researchdeeper into community settings which will diversify trial participants and accelerate promising treatmentsthrough clinical trials and into broader use. The CROWN Consortium supports the NCORP mission byleveraging a network of community sites throughout Wisconsin and northern Michigan with a shared missiontraining procedures and clinical resources and will be able to provide the necessary clinical support to offerimproved enrollment numbers and diversity enhancing study outcomes and reducing disparities. NCI 10676130 8/3/23 0:00 RFA-CA-18-016 5UG1CA239769-05 5 UG1 CA 239769 5 "HECKMAN-STODDARD, BRANDY" 8/23/19 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 11630851 "JASLOWSKI, ANTHONY J" Not Applicable 8 Unavailable 74776592 SSMYSXM9Z9T1 74776592 SSMYSXM9Z9T1 US 44.501495 -88.012749 4444601 ST. VINCENT HOSPITAL GREEN BAY WI Independent Hospitals 543013526 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 2128916 NCI 2160341 170268 The Cancer Research of Wisconsin and Northern Michigan (CROWN) Consortium is a collaboration betweenthree of the largest cancer centers in Wisconsin: St. Vincent Hospital of the Hospital Sisters of the Third Orderof St. Francis (St. Vincent Hospital through the Saint Vincent Hospital Cancer Centers (SVHCC)) WheatonFranciscan Healthcare - Southeast Wisconsin Inc. Columbia St. Marys Inc. and Ministry Health Care Inc.(Ascension Wisconsin (AW)) and Aspirus Inc. (Aspirus). With SVHCC as the project/performance primarysite the three main institutions and their cooperating affiliates provide access to National Cancer Institute(NCI)-sponsored clinical trials to community members throughout Wisconsin and northern Michigan. Theconsortium covers an extensive catchment area that includes both rural and urban counties as well as minorityand underserved communities. The CROWN Consortium looks to broaden recruitment capabilities regularlyshare best practices through established consortium committees reach a more diversified patient portfolio andimplement cancer care delivery research (CCDR) at multiple affiliate locations. In addition the consortium willactively participate and engage in NCORP Research Base trials beyond accrual by serving on committeescontributing to protocol development and developing young investigators to be engaged with clinical research.The CROWN Consortium brings together an experienced research infrastructure with a multidisciplinary teamof qualified investigators across many areas of clinical research including medical and radiation oncologypalliative care and pediatric oncology. The consortium provides a vast portfolio of cancer control preventionand care delivery biospecimen screening/post-treatment surveillance trials as well as treatment and imagingclinical studies to the community setting. As a result the CROWN Consortium will address gaps in clinicalresearch in rural urban minority and underserved populations. The CROWN Consortium will address this bythe following specific aims: 1) Broaden CROWN Consortium participation in NCI-sponsored clinical trials byexpanding recruitment clinical capabilities and sharing of resources; 2) Expand recruitment and retention ofurban rural racial and ethnic minorities and other underrepresented patient populations; 3) Execute high-quality Cancer Care Delivery Research (CCDR) throughout the CROWN Consortium; and 4) Increaseinvestigator engagement in NCORP initiatives by contributing to best practices and research findings.The CROWN Consortium represents a proven high-performing addition to the NCORP network. Theconsortium will expand NCORPs access to populations in Wisconsin and northern Michigan. The consortiumwill further NCORP Research Bases programs by providing a more representative population for studies andby providing feedback on study design feasibility for community sites and for appropriateness for diverseparticipants. CROWN Consortiums emphasis on understudied subgroups further underscores the value ofCROWN Consortium to the NCORP network. 2128916 +No NIH Category available Address;Adolescent Risk Behavior;Adoption;Adult;Advertising;Affect;American;American Medical Association;Area;Authorization documentation;Behavioral Risk Factor Surveillance System;Cessation of life;Chronic Obstructive Pulmonary Disease;Code;Communities;County;Data Set;Databases;Decision Making;Dimensions;Disease;Drug usage;Electronic cigarette;Ethnic Origin;Foundations;Future;Gender;Government;Health;Health Policy;Health behavior;Healthy People 2020;Individual;Institute of Medicine (U.S.);Knowledge;Laws;Legal;Licensure;Malignant neoplasm of lung;Measures;National Health Interview Survey;Outcome;Persons;Policies;Population;Public Health;Public Policy;Quasi-experiment;Race;Reproducibility;Research;Rights;Rural Community;Rural Population;Smoke;Smoking;Smoking Behavior;Subgroup;Surveys;System;Tobacco;Tobacco use;Urban Community;Urban Population;Youth;authority;catalyst;cigarette smoking;diverse data;electronic cigarette use;evidence base;experience;indoor air;innovation;non-smoker;preempt;prevent;preventable death;restraint;smoke-free policy;substance abuse epidemiology;tobacco control;trend Assessing the Impact of State Preemption Laws Project NarrativeTobacco use continue to pose significant public health concerns in the U.S. State states laws (preemptionlaws) prevent local communities from implementing policies to address these health behaviors. The proposedstudy will assess the effects of preemptive laws on tobacco and e-cigarette use. NCI 10676115 9/1/23 0:00 PA-19-056 5R01CA249052-03 5 R01 CA 249052 3 "MAYER, MARGARET ELIZABETH" 8/1/21 0:00 7/31/26 0:00 Social Sciences and Population Studies B Study Section[SSPB] 14743508 "AZAGBA, SUNDAY " Not Applicable 15 NONE 3403953 NPM2J7MSCF61 3403953 NPM2J7MSCF61 US 40.870717 -77.83415 1524202 "PENNSYLVANIA STATE UNIVERSITY, THE" UNIVERSITY PARK PA SCHOOLS OF NURSING 168027000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 1 NCI 1 0 Project Summary/AbstractTobacco use remains the leading cause of preventable death contributing to 480000 deaths in the U.S.annually. Smoking alone causes 90% of all lung cancer-related deaths and 80% of all chronic obstructivepulmonary disease-related deaths. Another 16 million people in the U.S. live with a disease caused bysmoking. Despite unknown long-term health effects the increasing popularity of e-cigarettes (10.8 millionadults are current users) is a growing concern especially given that this is the most popular form of tobaccoamong youth. In recent years there has been an increase in the number and variety of laws that preempt localpublic policies. Preemption occurs when a higher level of government restricts or withdraws the authority of alower level of government to act on a particular issue thereby prohibiting lower levels of government fromenacting more stringent laws. Preemptive laws are common on a variety of health issues including tobacco.For example about 32 states had at least one form of preemption of local tobacco control ordinances as ofSeptember 30 2018. The laws vary by states in many aspects including whether e-cigarettes are included.Numerous stakeholders have concerns about the potential negative impacts of these laws. For instance theAmerican Medical Association the Institute of Medicine and Healthy People 2020 have recognizedpreemption law(s) as a barrier to public health. However to date there is no existing rigorous empiricalevidence on how or if these preemption laws affect local policy innovation and key health outcomes. Theproposed study will address these critical knowledge gaps by using a rigorous quasi-experimental design toassess the impact of state preemption laws on tobacco and e-cigarette use. Specifically we propose anoriginal systematic legal analysis to characterize and code state tobacco preemption laws as well as theirdimensions (Aim 1) assess the impact of state preemption laws on county smoke-free indoor policy (Aim 2)cigarette smoking (Aim 3) and e-cigarette use (Aim 4). Aims 3 and 4 will also assess the heterogeneousimpact of state preemption laws among (a) subgroups (defined based on gender and race/ethnicity) andwhether the effects of these laws vary between (b) rural and urban communities. Our interdisciplinary team hasextensive experience in substance abuse epidemiology quantitative analysis policy and legal research. Theproposed research will address a severely understudied area with high public health significance: statepreemption laws functioning as a significant barrier to public health. This is an area of critical importance asthe number and variety of preemption laws are increasing in the U.S. The results of this highly innovative studywill provide timely empirical evidence and have a sustained impact in informing future decision making onpreemptive policies and laws. 1 +Cancer American;Funding;Location;Malignant Neoplasms;Methodology;National Cancer Institute;Process;Registries;Research Personnel;System;Time;minimal risk;neoplasm registry;surveillance data;virtual VIRTUAL POOLED REGISTRY (VPR) PROJECT n/a NCI 10676063 75N91021D00018-P00003-759102100002-1 N02 9/19/21 0:00 6/30/23 0:00 78362694 "KPHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2022 337156 NCI Coordinated by the North American Association of Cancer Registries (NAACCR) with funding from the National Cancer Institute the Virtual Pooled Registry Cancer Linkage System provides a single location to facilitate timely access to and use of high quality cancer surveillance data for minimal risk linkage studies. Use of an automated standard linkage methodology and streamlined application process will significantly reduce the level of effort researchers and registries must dedicate to the linkage and approval process. 337156 +Cancer; Social Determinants of Health Communication;Country;Education;Information Systems;Knowledge;Malignant Neoplasms;Politics;Public Health;Regional Cancer;Resource Sharing;Resource-limited setting;Resources;System;Training;improved;interest;member;neoplasm registry;surveillance data;surveillance network;tool ENHANCING GLOBAL CANCER REGISTRY-CENTERED SURVEILLANCE (GLOBAL CR-CS) PROJECT n/a NCI 10676062 75N91021D00018-P00003-759102100003-1 N02 9/26/21 0:00 6/30/23 0:00 78423607 "KOHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2022 104000 NCI The purpose of this Global Cancer Registry-Centered Surveillance Task Order is to:1.Build and enhance relationships with cancer surveillance organizations worldwide improve the availability of good global cancer registry-centered surveillance data strengthen regional cancer surveillance networks and improve resource sharing among high quality cancer surveillance systems tailored to limited resource environments.2.Facilitate communications and knowledge transfer through NAACCR members NAACCR staff and consultants in the use of technical resources which build on existing PBCR expertise and assets to provide direct and tangible benefits for limited resource countries. Priority shall be given to countries with strong interest and political commitment but unrealized action towards their potential for developing public health data systems with a focus on cancer surveillance.3.Coordinate engagement and provide relevant education materials and training tools as a platform for building capacity and enhancing cancer registry-centered surveillance in resource-limited countries. 104000 +Cancer American;Area;Cancer Surveillance Research;Cancer Surveillance Research Program;Collaborations;Contracts;Institutes;Malignant Neoplasms;Methods;National Cancer Institute;Registries;Services;Time;data registry;improved;neoplasm registry;operation;surveillance data TASK ORDER 75N91021F00001 FOR SUPPORT SERVICES FOR DEVELOPING AND PROMOTING METHODS AND STANDARDS FOR CANCER REGISTRY OPERATIONS AND SURVEILLANCE DATA n/a NCI 10676059 75N91021D00018-P00003-759102100001-1 N02 7/1/21 0:00 6/30/23 0:00 78314328 "KOHLER, BETSY " Not Applicable 13 Unavailable 831496661 XMD5M9LLKJV6 831496661 XMD5M9LLKJV6 US 39.769797 -89.690386 4155401 NORTH AMERICAN ASSN/CENTRAL CANCER REG SPRINGFIELD IL Other Domestic Non-Profits 627047412 UNITED STATES N R and D Contracts 2022 1150000 NCI The objective of this contract is to provide support to the North American Association of Central Cancer Registries (NAACCR) in order to make the National Cancer Institutes (NCI) cancer Surveillance Research Program (SRP) more responsive to the needs of the division institute and nation and more integrated with other partners within the national cancer surveillance enterprise.This contract focuses on three specific areas:1.Strengthening the national capacity for collecting analyzing and using comparable cancer registry data for cancer surveillance and research.2.Developing and improving methods for assessing the quality and comparability of cancer registry data. This includes but is not limited to timeliness completeness and accuracy.3.Improving the efficiency and quality of registry operations through promoting established standards disseminating technical information and facilitating collaboration among Federal state provincial and local registry professionals. 1150000 +Cancer; Women's Health Admin-Core-002 n/a NCI 10676034 2/9/22 0:00 PAR-20-043 2P30CA012197-47 2 P30 CA 12197 47 "BELIN, PRECILLA L" 2/1/97 0:00 1/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 9149 2090144 "BLACKSTOCK, ARTHUR W" Not Applicable 5 Unavailable 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC Domestic Higher Education 271570001 UNITED STATES N 2/9/22 0:00 1/31/23 0:00 Research Centers 2022 45872 29595 16277 The Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) Administrative Core is a principalorganizational component supporting the coordination and management of the Senior Leadership and theactivities of the Research Programs Shared Resources Office of Cancer Health Equity and Training andEducation. The Administrative Core has additional responsibilities for fiscal oversight of all WFBCCC functionsand ensuring cohesiveness and alignment with WFBCCCs strategic goals and priorities. Specific AdministrativeCore functions include Cancer Center Support Grant (CCSG) management; all Center-related financial andhuman resources support including the nine WFBCCC Shared Resources and the Office of Clinical Protocoland Data Management; coordination with the WFBCCC philanthropic development team as well as the Office ofCancer Health Equity; all internal and external communications; WFBCCC-driven cancer education and traininginitiatives and outcomes tracking; and informatics support required to manage the CCSG and produce metricsthat are meaningful in evaluating the overall Centers progress. Reporting to the WFBCCC Director BorisPasche MD PhD the Administrative Core is led by the Associate Director of Administration M. Jennifer KimMBA in collaboration with a 16-member team of highly qualified and experienced individuals who oversee allCenter-related activities and foster an environment of collaboration and interaction among the WFBCCCmembership. The Administrative Core has accomplished a number of notable achievements in the currentproject period including: organizing and developing WFBCCCs 2021-2026 Strategic Plan; facilitating thereorganization of three of the WFBCCC research programs; coordinating the recruitment and start-up packagesfor 47 new cancer-focused faculty; onboarding a new Shared Resource; organizing and supporting theimplementation of a Community Advisory Board and several new internal advisory entities; supporting theproposal development of 12 funded CCSG supplements; designing and deploying a new data system to supportthe collection of membership training and education outcomes data; and instituting new and revised policiesregarding membership and cancer relevance for grants and publications. The Administrative Core and SeniorLeadership are closely linked through frequent formal and informal meetings and the Core coordinates theefforts of external and internal planning and evaluation committees including: External Advisory BoardCommunity Advisory Board Internal Advisory Board Executive Committee and its Space ManagementSubcommittee Scientific Leadership Council Shared Resources Oversight Committee Community Outreachand Engagement Steering Committee and the Cancer Research Training and Education Coordination AdvisoryCommittee. The Administrative Core has been instrumental to the continued success of this 45-year-old cancercenter and is well positioned to support the strategic efforts planned for the next project period which will includethe research integration efforts with Atrium Health. +No NIH Category available Academia;Adult;Aging;Alzheimer's Disease;Amino Acids;Antineoplastic Agents;Applications Grants;Area;Asia;Basic Science;Biological Markers;Biological Models;Biology;Biotechnology;COVID-19 pandemic;Cancer Biology;Cancer Prevention Trial;Cell physiology;Cells;Childhood;Childhood Neurological Disorder;Clinic;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Communities;DL-alpha-Difluoromethylornithine;Degenerative Disorder;Development;Diabetes Mellitus;Discipline;Disease;Disorder of neurometabolic regulation;Drosophila genus;Drug Targeting;Environment;Epigenetic Process;Europe;FDA approved;Female;Fostering;Funding;Future;Genes;Genetic Transcription;Goals;Grant;Home;Human;Immunobiology;Immunologic Surveillance;Infection;Infusion procedures;Ion Channel;Life;Link;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Mammals;Metabolic;Metabolic Diseases;Metabolism;Names;Natural Products;Neoplasm Metastasis;Neuroblastoma;Neurodevelopmental Disorder;Organism;Outcome;Parasites;Parasitic infection;Participant;Pathway interactions;Pediatric Oncology Group;Pharmaceutical Chemistry;Pharmacologic Substance;Phase I/II Clinical Trial;Physicians;Plants;Play;Polyamines;Postdoctoral Fellow;Prevention;Productivity;Prokaryotic Cells;Proteins;Randomized;Regulation;Request for Applications;Research;Research Personnel;Resort;Role;Running;Scientist;Series;Structural Biologist;Students;Syndrome;Training;Translational Research;Translations;Travel;United States National Institutes of Health;Vertebrates;Virulent;Work;Writing;bench to bedside;cancer chemoprevention;cancer clinical trial;cancer prevention;cancer therapy;career;career development;cost;data exchange;drug discovery;eIF-5A;experience;forging;gain of function mutation;graduate student;human disease;inhibitor;male;meetings;member;microbiome;multidisciplinary;next generation;pathogen;phase II trial;polycation;posters;programs;stemness;success;symposium;translational impact;tumor metabolism;tumorigenesis 2023 Polyamines Gordon Research Conference and Gordon Research Seminar Project NarrativeThe 2023 Polyamines Gordon Research Conference (GRC) and the associated Gordon Research Seminar(GRS) provide excellent forums for the presentation of polyamine research by both established and younginvestigators. The goal of the 2023 Polyamines GRC the 24th such meeting since 1975 (the 2021 meeting waspostponed due to the COVID pandemic) is to provide a venue for the polyamine research community todiscuss the most impactful findings relating to the role and regulation of polyamines in human cancer biologyand other diseases and to build upon recent clinical successes which target the polyamine pathway for theprevention and treatment of human cancers infections and other disorders. A conference format is proposedwhich maximizes exposure for both early career scientists and new investigators in the field provides for thedelivery of unpublished provocative research findings encourages extensive discussions and fostersproductive collaborations to propel the field forward including the advancement of clinical trials. NCI 10675969 3/16/23 0:00 PA-21-151 1R13CA260996-01A1 1 R13 CA 260996 1 A1 "LUO, RUIBAI" 3/25/23 0:00 7/30/23 0:00 ZCA1-PCRB-9(J1) 6278580 "BACHMANN, ANDRE S" Not Applicable 2 Unavailable 75712877 XL5ANMKWN557 75712877 XL5ANMKWN557 US 41.480003 -71.569648 2988701 GORDON RESEARCH CONFERENCES East Greenwich RI Domestic For-Profits 28183465 UNITED STATES N 3/25/23 0:00 7/30/23 0:00 396 Other Research-Related 2023 15000 NICHD 5000 0 Project SummaryThe Polyamines Gordon Research Conference (GRC) has run continuously since 1975 and provides amultidisciplinary forum that brings together leading polyamine researchers as well as young and establishedinvestigators new to the field. The 2023 Polyamines GRC will be held at Waterville Valley Resort in NH fromJune 25-30 2023. This GRC will have a broad focus on the role of polyamines in human diseases with amajor focus on cancer including breakthroughs in cancer metabolism and immune surveillance advancedclinical trials for cancer prevention & treatment metastasis and cancer stemness protein translation andmedicinal chemistry-based cancer drug discovery. Other human diseases include several recently discoveredinborn metabolic neurodevelopmental disorders linked to polyamine genes diabetes degenerative disordersand pathogens. The meeting is unique in that it attracts a diverse array of top investigators assessing thecontrol and roles of polyamines across a broad spectrum of model systems (prokaryotes parasitesDrosophila plants vertebrates and mammals). Polyamines are small amino acid-derived polycations found inall forms of life and play essential roles in many cellular processes including transcription translationreplication metabolism epigenetic control and ion channel functions. The 2023 Polyamines GRC willemphasize targeting polyamine pathways in cancer and other diseases. The Program has a strong mix ofbasic translational and clinical researchers. This GRC is attended by biologists chemists physician-scientists and clinicians and includes investigators from academia biotech and pharmaceutical sectors. Thediversity of scientific disciplines is unique among GRCs is highly stimulating and will emphasize new findingsrelating to upstream and downstream pathways and new diseases only recently linked to alterations inpolyamine biology. We will bring the latest studies new investigators to the field and early career investigatorsto this forum. Of the 28 named speakers 22 are new since the last GRC and have never spoken and/or areearly career scientists. We will also choose 5 speakers from the Gordon Research Seminar (GRS) and theposters which will add more new speakers. The specific aims seek to obtain funds to support 42 GRC & 15GRS registrations and travel costs for 15 GRC/GRS participants. The long-term objective is to enhanceunderstanding of the interplay between polyamine metabolism and human diseases and to enhance thetraining of young scientists from diverse backgrounds to become contributing members of the polyaminescientific community. Presentations by invited speakers will be 25-30 minutes with a 10-minute discussion.The GRC will be held in conjunction with the 8th Polyamines providing graduate students and fellows with astudent-run venue that fosters exchange of data and ideas. The GRS makes the GRC a richer experience bypromoting young scientists during the main conference. Interactions between GRS & GRC conferees facilitatesharing of ideas and create new partnerships that will drive the field forward. 5000 +No NIH Category available Academia;Adult;Aging;Alzheimer's Disease;Amino Acids;Antineoplastic Agents;Applications Grants;Area;Asia;Basic Science;Biological Markers;Biological Models;Biology;Biotechnology;COVID-19 pandemic;Cancer Biology;Cancer Prevention Trial;Cell physiology;Cells;Childhood;Childhood Neurological Disorder;Clinic;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Communities;DL-alpha-Difluoromethylornithine;Degenerative Disorder;Development;Diabetes Mellitus;Discipline;Disease;Disorder of neurometabolic regulation;Drosophila genus;Drug Targeting;Environment;Epigenetic Process;Europe;FDA approved;Female;Fostering;Funding;Future;Genes;Genetic Transcription;Goals;Grant;Home;Human;Immunobiology;Immunologic Surveillance;Infection;Infusion procedures;Ion Channel;Life;Link;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Mammals;Metabolic;Metabolic Diseases;Metabolism;Names;Natural Products;Neoplasm Metastasis;Neuroblastoma;Neurodevelopmental Disorder;Organism;Outcome;Parasites;Parasitic infection;Participant;Pathway interactions;Pediatric Oncology Group;Pharmaceutical Chemistry;Pharmacologic Substance;Phase I/II Clinical Trial;Physicians;Plants;Play;Polyamines;Postdoctoral Fellow;Prevention;Productivity;Prokaryotic Cells;Proteins;Randomized;Regulation;Request for Applications;Research;Research Personnel;Resort;Role;Running;Scientist;Series;Structural Biologist;Students;Syndrome;Training;Translational Research;Translations;Travel;United States National Institutes of Health;Vertebrates;Virulent;Work;Writing;bench to bedside;cancer chemoprevention;cancer clinical trial;cancer prevention;cancer therapy;career;career development;cost;data exchange;drug discovery;eIF-5A;experience;forging;gain of function mutation;graduate student;human disease;inhibitor;male;meetings;member;microbiome;multidisciplinary;next generation;pathogen;phase II trial;polycation;posters;programs;stemness;success;symposium;translational impact;tumor metabolism;tumorigenesis 2023 Polyamines Gordon Research Conference and Gordon Research Seminar Project NarrativeThe 2023 Polyamines Gordon Research Conference (GRC) and the associated Gordon Research Seminar(GRS) provide excellent forums for the presentation of polyamine research by both established and younginvestigators. The goal of the 2023 Polyamines GRC the 24th such meeting since 1975 (the 2021 meeting waspostponed due to the COVID pandemic) is to provide a venue for the polyamine research community todiscuss the most impactful findings relating to the role and regulation of polyamines in human cancer biologyand other diseases and to build upon recent clinical successes which target the polyamine pathway for theprevention and treatment of human cancers infections and other disorders. A conference format is proposedwhich maximizes exposure for both early career scientists and new investigators in the field provides for thedelivery of unpublished provocative research findings encourages extensive discussions and fostersproductive collaborations to propel the field forward including the advancement of clinical trials. NCI 10675969 3/16/23 0:00 PA-21-151 1R13CA260996-01A1 1 R13 CA 260996 1 A1 "LUO, RUIBAI" 3/25/23 0:00 7/30/23 0:00 ZCA1-PCRB-9(J1) 6278580 "BACHMANN, ANDRE S" Not Applicable 2 Unavailable 75712877 XL5ANMKWN557 75712877 XL5ANMKWN557 US 41.480003 -71.569648 2988701 GORDON RESEARCH CONFERENCES East Greenwich RI Domestic For-Profits 28183465 UNITED STATES N 3/25/23 0:00 7/30/23 0:00 396 Other Research-Related 2023 15000 NCI 10000 0 Project SummaryThe Polyamines Gordon Research Conference (GRC) has run continuously since 1975 and provides amultidisciplinary forum that brings together leading polyamine researchers as well as young and establishedinvestigators new to the field. The 2023 Polyamines GRC will be held at Waterville Valley Resort in NH fromJune 25-30 2023. This GRC will have a broad focus on the role of polyamines in human diseases with amajor focus on cancer including breakthroughs in cancer metabolism and immune surveillance advancedclinical trials for cancer prevention & treatment metastasis and cancer stemness protein translation andmedicinal chemistry-based cancer drug discovery. Other human diseases include several recently discoveredinborn metabolic neurodevelopmental disorders linked to polyamine genes diabetes degenerative disordersand pathogens. The meeting is unique in that it attracts a diverse array of top investigators assessing thecontrol and roles of polyamines across a broad spectrum of model systems (prokaryotes parasitesDrosophila plants vertebrates and mammals). Polyamines are small amino acid-derived polycations found inall forms of life and play essential roles in many cellular processes including transcription translationreplication metabolism epigenetic control and ion channel functions. The 2023 Polyamines GRC willemphasize targeting polyamine pathways in cancer and other diseases. The Program has a strong mix ofbasic translational and clinical researchers. This GRC is attended by biologists chemists physician-scientists and clinicians and includes investigators from academia biotech and pharmaceutical sectors. Thediversity of scientific disciplines is unique among GRCs is highly stimulating and will emphasize new findingsrelating to upstream and downstream pathways and new diseases only recently linked to alterations inpolyamine biology. We will bring the latest studies new investigators to the field and early career investigatorsto this forum. Of the 28 named speakers 22 are new since the last GRC and have never spoken and/or areearly career scientists. We will also choose 5 speakers from the Gordon Research Seminar (GRS) and theposters which will add more new speakers. The specific aims seek to obtain funds to support 42 GRC & 15GRS registrations and travel costs for 15 GRC/GRS participants. The long-term objective is to enhanceunderstanding of the interplay between polyamine metabolism and human diseases and to enhance thetraining of young scientists from diverse backgrounds to become contributing members of the polyaminescientific community. Presentations by invited speakers will be 25-30 minutes with a 10-minute discussion.The GRC will be held in conjunction with the 8th Polyamines providing graduate students and fellows with astudent-run venue that fosters exchange of data and ideas. The GRS makes the GRC a richer experience bypromoting young scientists during the main conference. Interactions between GRS & GRC conferees facilitatesharing of ideas and create new partnerships that will drive the field forward. 10000 +No NIH Category available Address;Androgen Receptor;Antigen Targeting;BRCA2 Mutation;BRCA2 gene;Biometry;CAR T cell therapy;CRISPR screen;CRISPR-mediated transcriptional activation;Cancer Biology;Cancer Etiology;Cancer Patient;Caring;Castrate sensitive prostate cancer;Castration;Cells;Cellular biology;Cessation of life;Clinical;Clinical Oncology;Clinical Trials;Clinical Trials Design;Combined Modality Therapy;DNA Double Strand Break;DNA Repair;DNA Sequence Alteration;Data;Development;Discipline;Disease;Epidemiology;Exhibits;FOLH1 gene;Foundations;Gene Mutation;Genes;Genomic Instability;Goals;Heterozygote;Immunology;Immunotherapy;Indolent;Induced Mutation;Knock-out;Lesion;Link;Malignant neoplasm of prostate;Molecular;Mutation;Organoids;PARP inhibition;Pathology;Patients;Poly(ADP-ribose) Polymerase Inhibitor;Pre-Clinical Model;Process;Prognosis;Prostate Cancer therapy;Radiation therapy;Radiochemistry;Reporting;Research Personnel;Resistance;Role;Signal Pathway;Targeted Radiotherapy;Testing;Therapeutic;Time;Transcriptional Regulation;Treatment Failure;Up-Regulation;Work;androgen deprivation therapy;castration resistant prostate cancer;chimeric antigen receptor T cells;cohort;effective therapy;efficacy study;gain of function;gene repair;immunogenic;in vivo;insight;loss of function;men;mortality;novel;pharmacologic;pre-clinical;programs;prospective;prostate cancer cell;prostate cancer cell line;prostate cancer progression;rational design;receptor function;response;synergism;targeted treatment;therapeutic development;therapy resistant;treatment strategy;tumor Functional Characterization and Development of Therapeutic Paradigms for DNA Damage Repair (DDR)-deficient Lethal Prostate Cancer NarrativeMetastatic castration-resistant prostate cancer remains an incurable disease. Alterations in the genes thatregulate the bodys processes for repairing damaged DNA particularly BRCA2 have been linked to treatmentfailure and poor prognosis for men with prostate cancer. In this project we aim to comprehensively investigatethe role of such alterations in the development of lethal untreatable prostate cancer with the goal of identifyingand developing novel combination treatments such as targeted immunotherapy and radiotherapy. NCI 10675929 2/9/23 0:00 PA-20-185 1R01CA274967-01A1 1 R01 CA 274967 1 A1 "PRASANNA, PAT G" 4/1/23 0:00 3/31/28 0:00 Developmental Therapeutics Study Section[DT] 10445869 "CHAKRABORTY, GOUTAM " "PILLARSETTY, NAGAVARAKISHORE ; PONOMAREV, VLADIMIR " 13 UROLOGY 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY SCHOOLS OF MEDICINE 100296574 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 395 Non-SBIR/STTR 2023 729450 NCI 519558 209892 AbstractA leading contributor to the significant mortality burden of prostate cancer the second cause of cancer deathamong U.S. men is the short-lived efficacy of androgen deprivation therapy (ADT) the mainstay of care foradvanced and symptomatic disease. Increasingly alterations in DNA damage repair (DDR) genespredominantly BRCA2 have been linked to ADT resistance and poor prognosis. We previously showed thatdeleterious alteration of BRCA2 is sufficient to induce ADT resistance in castration-sensitive prostate cancer(PC) cells. Our current proposal will investigate the molecular mechanism underlying BRCA2 loss/mutation-induced ADT resistance and progression to lethal prostate cancer.Using a panel of 107 DDR-associated genes from the PROREPAIR B cohort we made the novel observationthat ~82% of patients with mCRPC harbor alterations of one or more DDR genes. Herein we aim tocomprehensively investigate the role of DDR alterations (other than BRCA2) in the development of mCRPCand resistance to therapy. To do so we will use CRISPR screening to prospectively investigate how the gainor loss-of-function alterations of DDR genes induce castration resistance.We have observed high expression levels of prostate-specific membrane antigen (PSMA) in response to theloss of BRCA2 and other DDR genes (e.g. ATM). Our second aim will investigate the impact of PSMA-targeted radiotherapy with [177Lu]-PSMA-617 and PARP inhibitor combination in BRCA2/DDR-deficient PC.Prostate cancer is predominantly resistant to immunotherapy. Since BRCA2-deficient cells also exhibit higherPSMA expression and are possibly immunogenic due to increased genomic instability we will explore theeffect of PSMA-targeted CAR T cells on BRCA2-deficient prostate cancer. Finally as two PARP inhibitors(olaparib and rucaparib) have been approved to treat patients with DDR-deficient prostate cancer we willinvestigate whether PARP inhibitors synergize with CAR T-cell therapy.For the first time the proposed project will demonstrate the crucial importance of BRCA2/DDR alterations inprostate cancer biology and possibly lay the foundation for consideration of DDR alteration as the master driverof the transformation from indolent localized prostate cancer to lethal mCRPC. We believe this work will leadto clinical trials that will establish new and effective treatments for this deadly disease. 729450 +Bioengineering; Cancer; Data Science; Machine Learning and Artificial Intelligence; Networking and Information Technology R&D (NITRD) Administrative Supplement;Advanced Malignant Neoplasm;Algorithmic Software;Algorithms;Architecture;Artificial Intelligence;Cell model;Cells;Classification;Code;Collaborations;Communities;Computer Assisted;Computing Methodologies;Consumption;Data;Data Analyses;Data Analytics;Data Set;Development;Educational Curriculum;Enhancers;Environment;Equilibrium;Fractionation;Funding;Goals;Head;Hematoxylin;Hybrids;Image;Image Analysis;Image Enhancement;Individual;Informatics;Knowledge;Libraries;Location;Machine Learning;Manuals;Maps;Masks;Methodology;Methods;Modeling;Morphologic artifacts;Neoplasm Circulating Cells;Network-based;Occupations;Optics;Parents;Pattern;Positioning Attribute;Process;Protocols documentation;Research;Research Personnel;Residual state;Resolution;Resources;Running;Security;Services;Signal Transduction;Software Design;Speed;Stains;Structure;System;Technology;TensorFlow;Testing;Time;Tissue imaging;Training;Tumor Tissue;Update;Variant;Vertebral column;Visualization;Work;adaptation algorithm;anticancer research;application programming interface;base;cell type;cellular imaging;computer infrastructure;computerized data processing;deep learning;deep learning algorithm;experience;experimental study;fluid flow;fluorescence microscope;generative adversarial network;handheld mobile device;improved;informatics tool;innovation;learning strategy;loss of function;microchip;microscopic imaging;novel;operation;preservation;restoration;simulation;tool;user-friendly;web services IMAT-ITCR Collaboration: Develop deep learning-based methods to identify subtypes of circulating tumor cells from optical microscope images IMAT-ITCR Collaboration: Develop deep learning-based methods to identify subtypes of circulating tumorcells from optical microscope imagesProject narrativeThis Supplement application in support of collaboration between IMAT and ITCR-funded projects aims to develop deeplearning-based methods to identify subtypes of circulating tumor cells (CTCs) from optical microscope images. Thedevelopment of deep learning methods will provide automatic characterization and classification of CTCs captured on HUstructured microchips. This proposed collaborative project will leverage the technologies developed by both projects whichwill bring together and enhance the capabilities of complementary technology platforms and methodologies to advancecancer research. NCI 10675886 9/8/22 0:00 PA-20-272 3R21CA240185-01A1S1 3 R21 CA 240185 1 A1S1 "AMIN, ANOWARUL" 9/1/22 0:00 7/31/23 0:00 12637191 "LI, WEI " Not Applicable 19 ENGINEERING (ALL TYPES) 41367053 EGLKRQ5JBCZ7 41367053 EGLKRQ5JBCZ7 US 33.584696 -101.872767 8285901 TEXAS TECH UNIVERSITY LUBBOCK TX BIOMED ENGR/COL ENGR/ENGR STA 794091035 UNITED STATES N 9/1/22 0:00 7/31/23 0:00 396 Non-SBIR/STTR 2022 71919 NCI 50000 21919 IMAT-ITCR Collaboration: Develop deep learning-based methods to identify subtypes of circulating tumorcells from optical microscope imagesProject Summary/AbstractThe goal of the parent IMAT project (R21CA240185) is to develop a new platform for fractionation and profiling of CTCsubpopulations and elucidate the metastatic potential of CTCs. Currently this work requires researchers to record hundredsof individual microscope images of the cells captured on the microchip integrate all images with flow fluid simulationsand analyze three features of the capture cells (including angular position normalized velocity and shear) for identificationof CTC subtypes. This process is very labor-intensive and time-consuming as most of the steps rely on manual operations.The goal of the ITCR project (1U01CA249245) is to develop an informatics platform iSEE-Cell (image-based Spatialpattern ExplorEr for Cells) which features a suite of informatics tools for tissue image analysis visualization explorationand spatial modeling at the single-cell level. This proposed Administrative Supplement application in support ofcollaboration between IMAT and ITCR-funded projects aims to develop deep learning-based methods to identify subtypesof CTCs from optical microscope images. The rationale underlying this proposal is that the development of deep learningmethods will provide automatic characterization and classification of CTC captured on HU structured microchips. Thisproposed collaborative project will leverage the technologies developed by both projects which will bring together andenhance the capabilities of complementary technology platforms and methodologies to advance cancer research. Innovationof the proposed methods include the following: 1) Identification of multiple subtypes of CTCs using their locationinformation on an HU microchip without destructive immunostaining analysis; 2) Novel Restore-GAN model to improvequality of microscope image obtained in CTC capture experiments and enhance predication accuracy for CTC subtypes; 3)The proposed informatics tools will provide computer-assisted automated tools to empower CTC research with artificialintelligence. Specific aims include: Aim 1: Using the microscope images and analysis/prediction results (from the IMATproject) as data input to test whether algorithms to classify different types of cell from tumor tissue images (iSEE-Celldeveloped in the ICTR project) can be applied for microscope images; Aim 2: Apply novel computational methods (Restore-GAN developed in the ICTR project) to improve image quality of the images obtained from the IMAT project and testwhether they can improve prediction accuracy for CTC subtypes; Aim 3: Develop a user-friendly interface to incorporatethe iSEE-Cell platform for analyzing optical/fluorescent microscope images remotely. The ability to automaticallyextract/analyze information from captured cells in the microscope images is urgently needed and will dramatically enhancethe throughput and work efficiency of the IMAT project. 71919 +Behavioral and Social Science; Cancer; Cardiovascular; Chronic Pain; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Health Services; Neurosciences; Pain Research; Prevention; Rural Health; Social Determinants of Health; Women's Health Address;Age;Aging;Area;Behavioral Sciences;Biological;Biometry;Blood;Cancer Control;Cardiology;Cardiovascular system;Caregivers;Caring;Chemotherapy and/or radiation;Clinical Research;Collaborations;Collection;Communities;Community Clinical Oncology Program;Comprehensive Cancer Center;Country;Data;Development;Dissemination and Implementation;Early treatment;Enrollment;Faculty;Family;Funding;Future;Goals;Health Sciences;Health Services Research;Image;Individual;Infrastructure;Interdisciplinary Study;Intervention;Investigation;Late Effects;Liquid substance;Malignant Neoplasms;Mentors;NCI Center for Cancer Research;NCI-Designated Cancer Center;Neurocognitive;Neurosciences;Oncology;Outcome;Participant;Patients;Personal Satisfaction;Postdoctoral Fellow;Prevention;Primary Health Care;Process;Protocols documentation;Public Health;Research;Research Activity;Research Design;Research Personnel;Resources;Salivary;Sampling;Science;Site;Specimen;Students;Supportive care;Symptoms;Time;Toxic effect;Training;Treatment Efficacy;Treatment outcome;Underserved Population;Urine;Woman;base;biobank;cancer care;cancer complication;cancer health disparity;cancer site;cancer therapy;care delivery;care systems;clinical investigation;early-career faculty;ethnic minority;ethnic minority population;evidence base;forest;health disparity;improved;innovation;knowledge translation;medical schools;multidisciplinary;next generation;novel;patient oriented;patient population;protocol development;racial and ethnic;racial minority;recruit;research study;rural dwellers;survivorship;underserved community;underserved minority Wake Forest NCORP Research Base The Wake Forest NCORP Research Base develops and implements multi-site Cancer Control and Cancer CareDelivery (CCDR) clinical research studies in partnership with NCORP Community and Minority/UnderservedCommunity Sites to improve patient well-being and the quality of cancer care. NCI 10675883 9/12/22 0:00 RFA-CA-18-015 3UG1CA189824-09S1 3 UG1 CA 189824 9 S1 "MCCASKILL-STEVENS, WORTA J" 8/1/14 0:00 7/31/25 0:00 ZCA1-GRB-S(M1) 1880766 "LESSER, GLENN J" "WEAVER, KATHRYN ELIZABETH" 5 INTERNAL MEDICINE/MEDICINE 937727907 SN7KD2UK7GC5 937727907 SN7KD2UK7GC5 US 36.059402 -80.321981 9021205 WAKE FOREST UNIVERSITY HEALTH SCIENCES WINSTON-SALEM NC SCHOOLS OF MEDICINE 271570001 UNITED STATES N 8/1/22 0:00 7/31/23 0:00 399 Other Research-Related 2022 1574957 NINDS 1064364 510593 This study is part of the NIHs Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to understand the basis of pain and enhance clinical pain management. 1574957 +No NIH Category available Address;Adult;Advocate;Aftercare;Businesses;Cancer Control;Cancer Patient;Caring;Catchment Area;Childhood;Chromosome Mapping;Clinical;Clinical Trials;Collection;Communities;Community Clinical Oncology Program;Continuity of Patient Care;County;Dedications;Development;Disparity;Employee;Enrollment;Ensure;Family;Future;Goals;Grant;Growth;Health;Health care facility;Health system;Healthcare Systems;Hospitals;Image;Individual;Institutional Practice;Joints;Knowledge;Malignant Neoplasms;Mentors;Methods;Minority;Minority Groups;Mission;Molecular Target;Oncologist;Outcome;Palliative Care;Participant;Patient-Focused Outcomes;Patients;Pediatric Research;Phase;Physicians;Positioning Attribute;Prevention;Prevention trial;Protocol Compliance;Quality of life;Research;Research Personnel;Resources;Services;Societies;South Carolina;Strategic Planning;Study Subject;Technology;Time;Underrepresented Populations;Underserved Population;anticancer research;base;cancer care;cancer health disparity;cancer prevention;care delivery;clinical imaging;clinical practice;community based participatory research;community engagement;community organizations;community setting;cost;data management;data submission;eligible participant;evidence base;human subject;imaging study;improved;individualized medicine;marginalization;medical specialist;meetings;outreach;participant enrollment;patient engagement;patient outreach;programs;recruit;research study;screening;screening program;success;symptom management;treatment trial NCORP of the Carolinas (Greenville Health System NCORP) PROJECT NARRATIVEA robust clinical trials program is relevant to achieving advances in addressing unmet needs of cancer patientsin the realm of treatment cancer control prevention and care delivery. NCORP of the Carolinas is positionedto provide a sustained powerful influence on cancer care through research in the community setting. NCI 10675775 8/22/23 0:00 RFA-CA-18-016 6UG1CA189972-10 6 UG1 CA 189972 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 15654630 "CHUNG, KI YOUNG" Not Applicable 4 Unavailable 77990745 DML4HJNAFE44 77990745 DML4HJNAFE44 US 34.821513 -82.413605 457301 PRISMA HEALTH - UPSTATE GREENVILLE SC Other Domestic Non-Profits 296012842 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1372191 NCI 877360 494831 PROJECT SUMMARY/ABSTRACTNCORP of the Carolinas is positioned to provide a sustained powerful influence on cancer care throughresearch in the community setting. The investigators commit to shift current research and clinical practiceparadigms based on the outcomes of NCTN research. The goals of NCORP of the Carolinas are as follows: toengage community oncologists and other medical specialists in NCTN cancer control prevention and caredelivery research as well as quality-of-life studies embedded within treatment and imaging studies; to offer theadult and pediatric communities cancer control prevention treatment and care delivery trial opportunities; toengage recruit and enroll participants from the community inclusive of minorities underrepresented andunderserved populations; to ensure all eligible participants are offered the opportunity for biospecimencollections; to inform the community of advances made through research; to assure accurate and timely datasubmission and protocol compliance; to participate with the respective research bases in concept developmentand identification of study opportunities for disparities in the community; to enhance and improve involvementof patient advocates by including advocates in research concepts and recruitment strategies; and to mentornew investigators partners and research staff.The expansion of GHS (Upstate) and Palmetto Health System (Midlands) into the SC Health Company and thejoint facilities and resources more than adequately support future growth and accruals through NCORP of theCarolinas cancer initiatives. More than 300 clinical trials are active at any given time at the GHS CancerInstitute and include Phase I Phase II Phase III treatment trials prevention trials symptom managementtrials and quality of life trials all of which provide patients with the latest technology throughout their cancercare continuum. Research offerings across the spectrum from prevention to palliative care ensure patientsreceive the best care possible. New research initiatives include state-of-the-art genetic mapping for moleculartargets that enable patients to stay in the catchment area for cutting-edge treatment tailored specifically tothem. Data management is important to both the clinical and business management of cancer services.NCORP of the Carolinas is poised to succeed in all aspects of the NCORP mission and contributemeaningfully to the NCORP goals by engaging patients and conducting the anticipated range of clinical trialsand human subject studies. 1372191 +No NIH Category available Adopted;Amaze;Anogenital venereal warts;Binding;Binding Sites;Biology;Cancer Etiology;Capsid Proteins;Cell Nucleus;Cell physiology;Cells;Cellular biology;Cytoplasm;Funding;Future;Genetic;Grant;HIV;HPV analysis;Human;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Infection;Integral Membrane Protein;Journals;L2 viral capsid protein;Malignant Neoplasms;Maps;Membrane;Minority Groups;National Cancer Institute;Oncogenic Viruses;Papilloma;Papillomavirus;Pathway interactions;Penetration;Peptides;Persons;Phenotype;Proteins;Public Health;Publishing;Role;Seminal;Sorting;System;Testing;Time;Vaccination;Vaccines;Virion;Virus;Virus Diseases;anticancer research;design;experimental study;genetic analysis;genetic approach;innovation;insight;mutant;novel;novel strategies;pathogen;prevent;protein aminoacid sequence;receptor;retrograde transport;trafficking;tumor;unvaccinated;vaccine acceptance;virology;virome Mechanisms of human papillomavirus entry NarrativeThe human papillomaviruses (HPV) are responsible for approximately 5% of all cancers worldwide andmost people including minority populations in the U.S. will remain unvaccinated against HPV for theforeseeable future. We have identified and characterized cellular proteins required for HPV infection andhere we will focus on the role of these proteins in trafficking of HPV to the nucleus during infection. Thesestudies will provide proof-of-principle of new approaches to inhibit infection by these important human tumorviruses and the cancers they cause and provide new insights into fundamental cellular processes. NCI 10675774 7/19/23 0:00 PAR-19-349 5R35CA242462-04 5 R35 CA 242462 4 "READ-CONNOLE, ELIZABETH LEE" 8/17/20 0:00 7/31/27 0:00 ZCA1-GRB-S(M1) 1871265 "DIMAIO, DANIEL C." Not Applicable 3 GENETICS 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 984892 NCI 587995 396897 This is a revised application for an R35 grant from the National Cancer Institute entitled Mechanisms ofhuman papillomavirus entry. HPV is responsible for 5% of human cancer millions of cases of genital wartsand countless cases of other types of papillomas (most caused by non-vaccine HPV types). Despite theexistence of effective vaccines HPV infection and the cancers it causes will remain a major public healthproblem for decades because vaccine uptake is poor and vaccination does not clear established infections.There are no specific treatments for HPV or HPV-associated cancers. The DiMaio lab has received more than35 years of continuous funding from the NCI during which time it has made seminal contributions to tumorvirology. We recently discovered that HPV traffics via the retrograde transport pathway during infectionshowed that retromer is required for sorting of the incoming virus particle into this pathway and that HPV is anovel type of retromer cargo and discovered a cell-penetrating peptide (CPP) that drives the HPV L2 capsidprotein into the cytoplasm to engage retromer. This is the first example where either retromer or a CPP hasbeen shown to play a role in virus entry. These results have been paradigm-shifting in the field and have beenpublished since 2013 in Cell PLoS Pathogens mBio PNAS and Journal of Cell Biology and they havefundamentally changed our understanding of HPV entry and the role of retromer and CPPs in biology. Herewe will discover how HPV accomplishes these amazing feats. We will determine the requirements for L2membrane protrusion and establish how sequences flanking the core CPP modulate its activity. We will testwhether the abundance of CPP sequences in the extant papillomavirus virome reflects their membrane-penetrating activity determine whether L2 truly adopts a transmembrane existence and map L2 segmentsexposed in the cytoplasm. We have designed an innovative new functional genetics approach and used it toisolate artificial small transmembrane proteins that inhibit HPV entry and we will use these artificial proteins toidentify new HPV entry factors and dissect their role in HPV entry. We will exploit our understanding of HPVentry to design inhibitory peptides that harness the membrane-penetrating activity of CPPs to deliver theretromer binding site into the cytoplasm to compete for binding with incoming HPV validating an entirely newapproach to prevent virus infections. We will develop the first genetic system to select HPV mutants withinformative phenotypes attempt to identify the HPV entry receptor and extend these studies to additionaltumor viruses and HIV. These experiments will elucidate important aspects of the mechanisms of HPV entryvalidate new approaches to prevent and treat HPV infection and revolutionize genetic analysis of HPV.Critically our studies will provide new insights into fundamental cell biology. If this proposal is funded we willcontinue to make novel and important contributions to virology and cancer research for many years. 984892 +No NIH Category available ARID1A gene;Adopted;Affect;Alleles;Animals;Automobile Driving;B cell differentiation;B lymphoid malignancy;B-Cell Development;B-Cell Lymphomas;B-Lymphocytes;Binding Sites;Biology;Bladder;Burkitt Lymphoma;Catalytic Domain;Cell Communication;Cell Line;Cells;Characteristics;Chromatin;Chromatin Remodeling Factor;Complex;Darkness;Dependence;Disease;Disease Progression;Enhancers;Epigenetic Process;Etiology;Failure;Family;Frequencies;Future;Gene Activation;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Genomic approach;Genomics;Histologic;Human;Immunologics;Knockout Mice;Lead;Light;Lymphoma;Lymphomagenesis;Malignant - descriptor;Malignant Neoplasms;Maps;Modeling;Molecular;Molecular Analysis;Mutation;Nucleosomes;Organoids;Outcome;Patient-Focused Outcomes;Patients;Pattern;Phenotype;Play;Process;Progression-Free Survivals;Public Health;RELA gene;Reaction;Recurrence;Refractory;Regulatory Element;Role;SMARCA4 gene;SPI1 gene;Signal Transduction;Somatic Mutation;Stomach;Structure of germinal center of lymph node;T-Lymphocyte;TNFRSF5 gene;Therapeutic;Toxic effect;Transcriptional Activation;Tumor Suppressor Genes;Tumor Suppressor Proteins;Uterus;Work;chemotherapy;chromatin remodeling;cohort;conditional knockout;driver mutation;epigenetic regulation;immunological synapse;immunological synapse formation;improved outcome;insight;large cell Diffuse non-Hodgkin's lymphoma;loss of function;mortality;overexpression;patient derived xenograft model;precision medicine;prevent;programs;promoter;protein expression;response;rituximab;standard care;targeted treatment;tositumomab;transcription factor;transcriptome sequencing;tumor;tumor-immune system interactions BAF complex deregulation in lymphoma PROJECT NARRATIVEBurkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are highly aggressive and geneticallycomplex B-cell lymphomas. Standard treatment with high-intensity chemotherapy leads to treatment-related mortality in approximately 10% of patients and fails to cure approximately 36-40% of patients.Investigating the genetic epigenetic and immunological etiology of BL may inform future rationaltherapeutic strategies and is likely to improve the outcome of these patients and have a substantialimpact on public health. NCI 10675768 7/31/23 0:00 PA-20-185 5R01CA266279-02 5 R01 CA 266279 2 "JHAPPAN, CHAMELLI" 8/2/22 0:00 7/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 12257403 "GREEN, MICHAEL RICHARD" "MASON, CHRISTOPHER EDWARD" 9 INTERNAL MEDICINE/MEDICINE 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX HOSPITALS 770304009 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 672389 NCI 546351 126038 PROJECT SUMMARYBurkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are highly aggressive B-cell malignanciesthat are commonly treated with chemotherapy plus an anti-CD20 antibody Rituximab. High-intensitychemotherapy is required in BL patients which is associated with severe toxicity and treatment-related mortalityin 10% of patients. Of the patients able to endure therapy 36% will suffer disease progression and have a dismaloutcome with only a 1% 3-year progression-free-survival in patients that are primary-refractory. A similar fractionof DLBCL patients progress during/following first-line therapy and have a median overall survival of 6.3 months.Recent genomic studies have identified co-occurring genetic alterations that are highly-recurrent in BL andDLBCL tumors. However detailed functional analyses have not been performed for the majority of these drivermutations and hence there are currently no available targeted therapeutic strategies in either disease.Mutations of the SMARCA4 and ARID1A genes are together found in approximately 40% of BL tumors and 12%of DLBCL tumors. These genes encode two components of a multi-subunit complex the BAF (aka SWI/SNF)complex which functions to activate gene expression by unpacking closed and silent states to become openand active genes. Mutations of SMARCA4 perturb its activity by affecting the catalytic domain and mutations ofARID1A lead to loss of protein expression together representing two alternative mechanisms for loss of functionin the BAF complex. Although the function of the BAF complex has been recently described in othermalignancies its function during B-cell development and therefore the consequence of its inactivation in B-celllymphoma remains to be explored.We have developed animal and cell line models of SMARCA4 and ARID1A inactivation and found that theyregulate distinct processes in B-cell development. We will leverage these models and cutting-edge genomicsapproaches to understand both the molecular and immunological consequences of BAF complex deregulationin B-cell lymphoma. By contrasting and comparing the roles of two key components of the BAF complexSMARCA4 and ARID1A we hope to gain detailed insight into the role of discrete BAF complexes and theirredundant and non-redundant roles. This work will uncover the biology of BL and DLBCL tumors carrying BAFcomplex mutations which can lead to advances in precision medicine targeting and therapies for this diseaseas well as for other cancers. 672389 +No NIH Category available Abdominal Cavity;Affect;Appendiceal Neoplasms;Behavior;Benign;Biological;Biological Models;Biology;CDK4 gene;CDX2 gene;Carcinomatosis;Cell Proliferation;Cells;Cessation of life;Clinical;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cystic Neoplasm;Cytotoxic Chemotherapy;Data;Data Set;Development;Disease;Disease Progression;Doxycycline;FDA approved;Flow Cytometry;GTP-Binding Proteins;Gastrointestinal Neoplasms;Gastrointestinal tract structure;Gene Expression;Genome;Histology;Human;Immunohistochemistry;Individual;Intestinal Cancer;Intestinal Obstruction;Intestines;KRAS2 gene;KRASG12D;Laboratories;MAP Kinase Gene;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of appendix;Malignant neoplasm of gastrointestinal tract;Messenger RNA;Modeling;Mucinous;Mucinous Neoplasm;Mucins;Mus;Mutation;Nature;Neoplasm Metastasis;Oncogenes;Operative Surgical Procedures;Organoids;Pancreas;Pancreatic Ductal Adenocarcinoma;Papillary;Pathogenicity;Patients;Peritoneal;Phenocopy;Pre-Clinical Model;Precision therapeutics;Predisposition;Proliferating;Protein-Protein Interaction Map;Pseudomyxoma Peritonei;Quality of life;RNA-Binding Proteins;Recurrence;Refractory;Reporting;Research Personnel;Signal Transduction;Signaling Protein;Slice;Stable Disease;Surface;Syndrome;System;Testing;Tetanus Helper Peptide;Therapeutic;Toxic effect;Tumor Debulking;Tumor Promotion;Work;cancer cachexia;chemotherapy;clinical phenotype;colorectal cancer treatment;gain of function;inducible gene expression;inhibitor;knock-down;loss of function;multidisciplinary;mutant;neoplastic cell;new therapeutic target;novel;novel strategies;novel therapeutic intervention;novel therapeutics;pancreatic neoplasm;pharmacologic;protein activation;proteogenomics;rare cancer;standard of care;targeted treatment;tool;transcriptome sequencing;treatment strategy;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions CDK4/6 inhibition: a novel therapeutic strategy for GNAS-mutant gastrointestinal malignancies PROJECT NARRATIVEMucinous neoplasms of the appendix are characterized by pathogenic alterations in the GNAS and KRASoncogenes. Our preliminary data suggests that these tumors may be exquisitely sensitive to inhibition of cyclindependent kinase (CDK) 4/6 activity and that this vulnerability is related to alterations in GNAS and the resultantactivation of protein kinase A signaling. In this proposal we will explore the hypothesis that GNAS mutant tumorsare sensitive to CDK4/6 inhibition by treating them alone and in combination with other approved therapies andby exploring the mechanisms by which mutant GNAS promotes tumor growth. NCI 10675743 6/19/23 0:00 PAR-20-292 5R21CA273974-02 5 R21 CA 273974 2 "CHEN, WEIWEI" 8/2/22 0:00 6/30/24 0:00 ZCA1-TCRB-V(M1)S 1886399 "LOWY, ANDREW M" Not Applicable 50 SURGERY 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 217163 NCI 137445 79718 ABSTRACTMucinous neoplasms of the appendix (MNA) are rare tumors that may progress from benign to malignant diseaseand ultimately assume an aggressive biological behavior. The metastatic tumor cells often secrete largequantities of mucin resulting in the clinical syndrome known as pseudomyxoma peritonei (PMP) the vast majorityof which originates from the appendix. Once peritoneal metastasis has occurred disease progression isfrequently fatal often with massive accumulation of tumor masses and mucin that can fill the abdominal cavityresulting in death from intestinal obstruction and cancer cachexia. While the primary treatment of PMP is surgicalpatients with higher-grade mucinous cancers and those with inoperable disease typically receive cytotoxictherapies approved for colorectal cancer (CRC) which generally have limited efficacy. New approaches areclearly needed to elucidate the underlying biology of PMP and to develop new and more effective targetedtreatment strategies. Discoveries by the Lowy lab revealed the mutational landscape of PMP (Genome Med.2014) which is characterized by pathogenic alterations in the KRAS and GNAS oncogenes. The latter has beenthe focus of the Gutkind lab for many years who pioneered the study of G proteins in cancer (Nature Rev.Cancer 2010 2013). Recently our collaborative work has suggested that MNA may be exquisitely sensitive toinhibition of cyclin dependent kinase (CDK) 4/6. Our preliminary data includes treatment of a patient withmucinous carcinomatosis-low grade of appendiceal origin whose disease progressed on standard of carechemotherapy but who has had stable disease for greater than 6 years on single agent Palbociclib the firstFDA-approved CDK4/6 inhibitor. Recently we have developed further evidence that this sensitivity to CDK4/6inhibition may in fact be related to the activation of PKA signaling downstream of GNAS and therefore wehypothesize that GNAS mutant tumors of the appendix and colon and possibly those of other histologys (ie-pancreas) may be sensitive to this targeted therapy as well. In this proposal we will test this hypothesis explorehow CDK4/6 inhibition may modulate the tumor microenvironment to control GNAS mutant tumor progressionand explore the underlying mechanisms underpinning this sensitivity. 217163 +No NIH Category available Address;Antibody-drug conjugates;Assessment tool;Biological Assay;Blood;Blood specimen;CD19 gene;Cancer Center;Cancer Patient;Clinical;Clinical Trials;DNA Sequence Alteration;Data;Detection;Development;Diagnosis;Disease;Doctor of Medicine;Doctor of Philosophy;Drops;Early Diagnosis;Early treatment;Europe;Evaluation;FDA approved;Failure;Foundations;Functional Imaging;Future;Genomic approach;Genomics;Genotype;Goals;Hematologic Neoplasms;Image;Immuno-Chemotherapy;Individual;Institution;International;Lymphoma;Measures;Metabolic;Methods;Modeling;Molecular;Monitor;Newly Diagnosed;North America;Outcome;Patients;Prediction of Response to Therapy;Prognostic Factor;Public Health;Randomized;Recurrence;Refractory;Relapse;Residual Neoplasm;Retrospective cohort;Risk;Risk Assessment;Risk Factors;Risk Reduction;Specimen;Surrogate Endpoint;Testing;Training;Treatment Failure;Treatment outcome;Tumor Volume;Validation;Work;burden of illness;cancer risk;cancer type;chimeric antigen receptor T cells;cohort;conventional therapy;detection method;genetic profiling;high risk;improved;indexing;innovation;large cell Diffuse non-Hodgkin's lymphoma;lenalidomide;novel;novel marker;novel strategies;novel therapeutics;outcome prediction;personalized medicine;personalized predictions;prospective;radiological imaging;response;risk prediction;risk prediction model;risk stratification;surrogacy;survival prediction;targeted agent;tool;treatment effect;treatment response;trial design;tumor;tumor DNA A Genomic Framework for Molecular Risk Prediction & Individualized Lymphoma Therapy PROJECT NARRATIVEPIs: Ash Alizadeh M.D./Ph.D. & Maximilian Diehn M.D./Ph.D.In this study we will develop a novel approach for predicting how patients with Diffuse large B-cell lymphoma will respond to treatment. Our approach is personalized and includes clinicalvariables molecular risk factors and early treatment responses measured using blood samplesand imaging. This work is relevant to public health because new strategies for predictingtreatment response before and early during treatment have the potential to improve clinicallyoutcomes of cancer patients. NCI 10675738 7/31/23 0:00 PA-18-484 5R01CA233975-05 5 R01 CA 233975 5 "AGRAWAL, LOKESH" 8/1/19 0:00 7/31/24 0:00 Clinical Oncology Study Section[CONC] 9743829 "ALIZADEH, ASH ARASH" "DIEHN, MAXIMILIAN " 16 INTERNAL MEDICINE/MEDICINE 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 548151 NCI 351891 196260 PROJECT SUMMARY/ABSTRACTPIs: Ash Alizadeh M.D./Ph.D. & Maximilian Diehn M.D./Ph.D.For patients with Diffuse large B-cell lymphoma (DLBCL) the most common lymphoma subtypecurative outcomes are common. Unfortunately despite many large clinical trials survival has notsignificantly improved over the last 15 years and nearly a third of patients continue to succumb tothis disease. For these patients effective strategies to predict early treatment failures have beenelusive.Our long-term goal is to study the ability of baseline and dynamic risk factors including geneticmutations and circulating tumor DNA (ctDNA) to accurately predict treatment outcomes in DLBCLpatients. Our central hypothesis is that novel biomarkers of cancer risk such as detection ofctDNA and detailed genetic profiling can be used for early detection of residual disease to identifydynamic changes that anticipate treatment failure and to provide early surrogate endpoints forfuture clinical trials. We will test our hypothesis via three specific aims: (1) To build an accurateand dynamic predictor of survival for patients newly diagnosed with DLBCL (2) To test the validityand utility of this predictor in a large multi-institutional cohort of patients from around the globeand (3) To assess the ability of this dynamic risk assessment tool to serve as an early surrogateendpoint in prospective clinical trials. We will apply our novel approach in both the frontline andrelapse/refractory setting and to a variety of treatment types including immunochemotherapy anantibody-drug conjugate and Chimeric Antigen Receptor (CAR) T cells.If successful our project will lead to novel ways to select better therapies for patients at highestrisk of failure. Our innovative approach in which we will employ novel blood-based methods fortumor genotyping and disease monitoring that were developed by our group will lay thefoundation for studies aimed at reducing risk of treatment failure in DLBCL patients.Demonstrating that this approach can serve as a robust early surrogate endpoint for patients withaggressive lymphomas would be transformative for future trial design and for rapid evaluation ofnovel personalized treatment approaches in patients at highest risk for recurrence. Our work willserve as proof-of-principle for an approach that could also be applied to other cancer types. 548151 +No NIH Category available Ablation;Accounting;Address;Adherence;Adjuvant;Adjuvant Therapy;African;Aftercare;Area;Biopsy;Cervical;Cervical Cancer Screening;Cervical Intraepithelial Neoplasia;Cessation of life;Combined Modality Therapy;Community Health Education;Community Outreach;Disease;Disparity;Dose;Enrollment;Excision;Fluorouracil;Focus Groups;Frequencies;Generations;Generic Drugs;Genital;Genitalia;Genotype;Goals;HIV;HIV-1;Health;Health Personnel;High Risk Woman;Histology;Human Papilloma Virus Vaccination;Human Papillomavirus;Immune;Immune response;Incidence;Inflammation;Inflammatory;Infrastructure;Interleukin-1 alpha;Interleukin-10;Interleukin-12;Interview;Investments;Irrigation;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Measures;Mediating;Modality;Nurses;Operative Surgical Procedures;Outcome;Participant;Patients;Perception;Placebos;Population;Prevention strategy;RNA;Randomized;Recurrence;Reporting;Research;Resource-limited setting;Resources;Risk;Risk Reduction;Rural;Safety;Self Administration;Series;Sexually Transmitted Diseases;South Africa;South African;Specimen;TNF gene;Testing;Treatment outcome;Woman;acceptability and feasibility;access disparities;cancer prevention;cancer therapy;cervical cancer prevention;cervicovaginal;cost;cytokine;efficacy evaluation;efficacy study;efficacy testing;experience;feasibility trial;high risk population;immune activation;improved;lifetime risk;loop electrosurgical excision procedure;low and middle-income countries;male;mortality;novel;premalignant;prevent;primary outcome;secondary outcome;standard care;treatment strategy;trial enrollment;tumor-immune system interactions Acceptability and feasibility of combination treatment for cervical precancer among South Africa women living with HIV NARRATIVEWomen living with HIV are at increased risk of precancerous cervical intraepithelial neoplasia (CIN2/3) andstandard treatment modalities for CIN2/3 are less effective in HIV-infected women. We propose to evaluate theacceptability feasibility (safety tolerability adherence retention) and preliminary efficacy of a combinationtreatment strategy (i.e. surgery followed by topical therapy with 5% 5-fluorouracil [5FU]) in order to improvecervical cancer prevention and long-term treatment outcomes in this high-risk population. If successful ourproposed combination strategy would have broad relevance for women living with HIV in both resource-rich andresource-poor regions worldwide including rural and remote areas of the U.S. NCI 10675732 6/16/23 0:00 PAR-18-559 5R01CA250850-04 5 R01 CA 250850 4 "SAHASRABUDDHE, VIKRANT V" 6/1/20 0:00 5/31/25 0:00 HIV Comorbidities and Clinical Studies Study Section[HCCS] 10974946 "CHIBWESHA, CARLA J" "RAHANGDALE, LISA " 4 OBSTETRICS & GYNECOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 638580 NCI 606330 32250 ABSTRACTCancer incidence mortality and disparities between rich and poor are projected to rise at staggering rates. It isestimated for example that cancer will kill one million Africans each year by 2030 with cervical canceraccounting for the most cancer deaths in African women. Global efforts to eliminate cervical cancer are currentlyfocused on expanding access to HPV vaccination and cervical cancer screening. However these efforts lackequal investment in treatment of precancerous cervical intraepithelial neoplasia grade 2/3 (CIN2/3) particularlyamong HIV-infected women. This gap leaves a generation of HIV-infected women at high risk ofpersistent/recurrent CIN2/3 and progression to cervical cancer because standard treatment for CIN2/3 (excisionor ablation) is far less effective in this population. The need for novel treatment approaches for CIN2/3 in HIV-infected women is therefore substantial. The central hypothesis of our proposal is that topical 5-fluorouracil(5FU) a widely available low-cost generic drug can be repurposed as a patient-controlled adjuvant treatmentfor CIN2/3 after surgical excision to reduce the risk of persistent/recurrent CIN2/3 and progression to cervicalcancer among HIV-infected women. Our overarching goal is to build on U.S. efficacy studies and test theacceptability and feasibility of combination treatment for CIN2/3 (i.e. surgical excision followed by self-applied adjuvant 5FU) in a low-resource setting. First we will explore South African perspectives on currentcervical cancer prevention strategies and identify barriers to and facilitators of combination treatment in the localcontext. We will accomplish this through a series of focus groups and in-depth interviews with diversestakeholders (HIV-infected women male partners healthcare personnel). Second and informed by ourformative research we will conduct a feasibility trial of the combination treatment strategy to determine safetytolerability adherence and retention. We will randomize 180 HIV-infected women with CIN2/3 who will undergoloop excision (LEEP) followed by self-apply 5FU versus placebo (8 doses once every 2 weeks). Women will befollowed for 24 weeks. Third to better understand the immune response to combination treatment in HIV-infectedwomen we will assess changes in genital HIV-1 shedding and local immune activation associated with surgicalexcision followed by 5FU/placebo. Our study will be conducted in South Africa where more than 4 million womenare living with HIV and womens lifetime risk of cervical cancer is among the highest in the world. If successfulour findings will have broad relevance for HIV-infected women in both resource-rich and resource-poor regionsworldwide including rural and remote areas of the U.S. 638580 +No NIH Category available Address;Adolescent and Young Adult;Adolescent and young adult cancer patients;Catchment Area;Certification;Child;Childhood;Clinical Research Associate;Clinical Trials;Communities;Continuing Education;Data;Development;Diagnosis;Education;Educational Materials;Enrollment;Family;Goals;Health Disparities Research;Health Services Accessibility;Home;Institution;Joints;Malignant Neoplasms;Mentors;Mentorship;Mexico;Patient Education;Patients;Provider;Research;Research Personnel;Research Project Grants;Site;Societies;South Texas;System;Texas;Time;Training;Translating;Travel;barrier to care;base;cancer care;cancer clinical trial;cancer survival;care delivery;clinical development;digital media;experience;health care delivery;health care disparity;improved;innovation;meetings;posters;programs;recruit;research study;treatment center Texas Pediatric NCORP MU PROJECT NARRATIVEBy providing access to cancer clinical trials closer to home the Texas Pediatric NCORP MU aim atimproving cancer survival for children adolescents and young adults living in the vast catchment areacomprised of Central South and West Texas and encompassing the entire Texas-Mexico border region. NCI 10675716 7/19/23 0:00 RFA-CA-18-017 5UG1CA189855-10 5 UG1 CA 189855 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-SRB-H(M1) 7770446 "LANGEVIN, ANNE-MARIE R." Not Applicable 20 PEDIATRICS 800772162 C3KXNLTAAY98 800772162 C3KXNLTAAY98 US 29.513091 -98.577742 578418 UNIVERSITY OF TEXAS HLTH SCIENCE CENTER SAN ANTONIO TX SCHOOLS OF MEDICINE 782293901 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 960445 NCI 869807 95874 PROJECT SUMMARYThe overarching goals of the Texas Pediatric (TP) NCORP MU formerly the South Texas Pediatric (STP)NCORP MU are to: 1) Decrease healthcare disparities faced by children adolescents and young adults(AYAs) diagnosed with cancer and living in the TP NCORP MU catchment area by increasing enrollmenton clinical trials; 2) Expand the TP NCORP MUs involvement in the Cancer Care Delivery Research(CCDR) arena; and 3) Maintain and retain a cadre of trained Clinical Research Associates (CRAs) tosupport participation of children and AYAs with cancer in the NCTN and NCORP clinical trials in theircommunity.To achieve our goals activities targeting providers patients/families and systems will be utilized.Recruitment strategies using innovative digital media platforms along with increase access to treatmentcenters along the Texas-Mexico border and increased availability of Spanish-translatedresearch/education documents will be implemented. Development of new CCDR concepts andinvestigator-initiated health-disparities research projects focusing on the hurdles experienced by thechildren and AYAs treated in our catchment area will be undertaken. Mentoring and education programsfor our investigators and CRAs will be developed. 960445 +No NIH Category available Acculturation;Address;Adolescence;Affect;American;American Heart Association;Asian Indian;Asian population;Behavior;Behavioral;Belief;Blood Pressure;Body Weight decreased;Cardiometabolic Disease;Child;Child Health;Communication;Communities;Conflict (Psychology);Control Groups;Counseling;Daughter;Disparity;East Asian;Education;Effectiveness;Environment;Environmental Risk Factor;Exercise;Family;Fathers;Feeling;Female Adolescents;Foundations;Gender;Generations;Glycosylated hemoglobin A;Growth;Happiness;Health;Heterogeneity;High Prevalence;Hispanic Populations;Hypertension;Immigrant;Immigrant community;Immigration;India;Individual;Intervention;Language;Life Cycle Stages;Linguistics;Lipids;Maintenance;Mediating;Mediator;Methods;Mothers;Motivation;Neighborhoods;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Pakistan;Physical activity;Pilot Projects;Population;Positioning Attribute;Process;Public Health;Randomized;Randomized Controlled Trials;Research Design;Resources;Risk;Risk Factors;Role;Running;Same-sex;Self Efficacy;Shapes;Social isolation;Social support;South Asian;Spouses;Strenuous Exercise;System;Thinness;Time;United States;Waiting Lists;Walking;Weight;Woman;Work;aspirate;cardiometabolic risk;community based participatory research;community organizations;effective intervention;effectiveness testing;efficacy evaluation;efficacy testing;empowerment;exercise intervention;expectation;experience;girls;health disparity;high risk;implementation evaluation;improved;intervention effect;motivational enhancement therapy;peer;physical inactivity;physical model;process evaluation;psychosocial;role model;secondary outcome;sedentary;social culture;theories;vigorous intensity;waist circumference A Multilevel Physical Activity Intervention for South Asian Women and Girls Project NarrativeSouth Asian immigrant women and girls are at increased risk for insufficient physical activity and are not beingreached by current approaches to physical activity promotion. This randomized control trial study will test theeffectiveness and implementation of a multicomponent physical activity intervention directed at theenvironment family interpersonal and individual levels to promote physical activity among South Asianimmigrant mothers and daughters. NCI 10675709 8/24/23 0:00 PA-18-284 5R01CA242520-05 5 R01 CA 242520 5 "DEAN, DAVID WORTH" 8/1/19 0:00 7/31/24 0:00 Community-Level Health Promotion Study Section[CLHP] 8355312 "KANDULA, NAMRATHA R" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 560557 NCI 470396 90161 Project SummaryAsian Indian and Pakistani (South Asian) immigrants have a high prevalence of physical inactivity andcardiometabolic risk factors. South Asian (SA) women and girls are particularly at high risk due to a confluenceof immigration culture and gender which shape the health risk of SA women and girls across the life course.Our community-based participatory research found that SA women (85% of whom were 1st generationimmigrants) experienced: a) social isolation and low social support which reduced physical activity (PA)motivation and self-efficacy; b) desire to maintain traditional values and norms which conflicted with local PAenvironments (e.g. mixed-gender exercise classes); and c) linguistic and environmental barriers. When SAgirls (majority 2nd generation) entered adolescence they described: a) acculturation-related family conflictbecause exercise was perceived as an American behavior; b) gender constraints; c) lack of role models; andd) their community's shared illness belief that if you are thin you don't need to exercise. Importantly thecommunity also identified individual interpersonal and familial processes that empowered SA women and girlsto become more active including holistic benefits of PA aspirations for children's health and feelingconnected and happy when exercising with other women and family. Building on a pilot study demonstratingfeasibility and preliminary efficacy the proposed study aims to testing the efficacy and implementation of theSouth Asians Active Together (SAATH) intervention. The 16-week intervention targets individualinterpersonal and family levels through four main components: 1) group exercise classes for mother-daughterdyads; 2) dyadic mother-daughter PA counseling using motivational interviewing; 3) peer discussion groupsand 3) family walking groups. The intervention also targets the environment level by working with park districtsa public health department and community organizations to make changes to the local environment that takeinto account sociocultural (e.g. gender family focus) and environmental (e.g. same sex classes) expectationsof SA. Aim 1 of the study is to determine the efficacy of the SAATH intervention to increase moderate-vigorousPA in SA mother-daughter dyads using a randomized wait-list control study design. Secondary outcomes are:walking and sedentary time in dyads and cardiometabolic risk factors in mothers. Aim 2 will evaluate theimpact of the intervention on individual (self-efficacy autonomy support social support motivation) and dyadic(acculturation conflict communication connectedness) factors hypothesized to mediate the intervention effecton PA. Aim 3 is to evaluate implementation and sustainability of SAATH including the environment andsystems changes made by cross-sector partners to promote and sustain PA in SA women and girls. Given thegrowth of the SA population and their increased risk for cardiometabolic disease identifying interventions thatincrease PA among Asian Indian and Pakistani immigrant women is of significant public health import. 560557 +No NIH Category available Accounting;Address;Adipose tissue;Affect;Age;American Society of Clinical Oncology;Archives;Area;Behavior Therapy;Behavioral;Biological;Biological Process;Body Composition;Body Size;Body Weight;Body mass index;Body measure procedure;Cancer Patient;Cancer Survivorship;Classification;Clear cell renal cell carcinoma;Clinical;Colorectal Cancer;Data;Development;Disease;Fatty acid glycerol esters;Future;Gene Chips;Gene Expression;Genes;Genetic Transcription;Guidelines;Immune;Immune system;Immunologics;Immunotherapy;Incidence;Inflammatory;Intervention;Link;Longterm Follow-up;Malignant Neoplasms;Measurement;Mediating;Memorial Sloan-Kettering Cancer Center;Messenger RNA;Metabolic;Metabolic Diseases;Modeling;Molecular;Molecular Epidemiology;Muscle;Nephrectomy;Nonmetastatic;Nutritional;Obesity;Obesity Epidemic;Outcome;Pathway interactions;Patient Selection;Patients;Pharmacological Treatment;Population;Positioning Attribute;Prognosis;Prognostic Factor;Recommendation;Renal carcinoma;Research;Research Personnel;Risk;Risk Factors;Scanning;Skeletal Muscle;Smoking;Specimen;Time;Tissues;Tumor Markers;Tumor Subtype;Up-Regulation;Visceral;Weight;X-Ray Computed Tomography;cancer epidemiology;clinically relevant;comorbidity;density;design;disease heterogeneity;energy balance;epidemiology study;high body mass index;immune cell infiltrate;improved;individual patient;insight;molecular scale;molecular subtypes;mortality;mortality risk;novel;novel strategies;patient population;patient subsets;pharmacologic;predict clinical outcome;premature;prognostic model;progression risk;resistance exercise;response;risk prediction;risk prediction model;sex;subcutaneous;tertiary prevention;therapy design;transcriptomics;treatment response;treatment trial;tumor;urologic Body composition and the obesity paradox in clear cell renal cell carcinoma PROJECT NARRATIVEObesity usually measured by body mass index (BMI) increases the risk of developing kidney cancer but howit influences prognosis is not clear. Our study will improve the measurement of BMI by calculating exactly howmuch muscle and fat a kidney cancer patient has and determining for the first time how those tissues relate totumor aggressiveness and to survival. Findings from our project will help patients and their doctors betterunderstand how body size can affect survival and also help researchers design new weight-related interventionsto improve prognosis. NCI 10675702 9/1/23 0:00 PA-18-484 5R01CA233885-05 5 R01 CA 233885 5 "GALLICCHIO, LISA M" 8/1/19 0:00 7/31/24 0:00 "Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]" 8250870 "FURBERG-BARNES, ANNA HELENA " Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 587431 NCI 393748 193683 ABSTRACTClear cell renal cell carcinoma (ccRCC) is the most lethal urologic malignancy and its incidence is increasing.The proposed molecular epidemiology study moves beyond body mass index (BMI) to identify ccRCC patientsat risk of poor prognosis while considering molecular tumor subtype based on gene expression and is in directresponse to an ASCO position statement that calls for more obesity-related research to ultimately informweight recommendations and refine prognostic factors for cancer patients. The inverse association betweenBMI and mortality that is consistently observed among ccRCC patients presents a significant clinical challengefor patients clinicians and researchers because it is not clear how to interpret it. Mechanisms underlying theobesity paradox remain largely unexplored. In the proposed study we will derive new body compositionvariables from existing pre-surgical computed tomography (CT) scans and transcriptomically-characterize thearchived tumor specimens from 1200 non-metastatic ccRCC patients who were treated by nephrectomy atMemorial Sloan Kettering Cancer Center between 1995-2017 and followed for clinical outcomes. Based onstrong preliminary data we hypothesize that the obesity paradox is influenced by disease heterogeneity andspecific body composition features including low skeletal muscle and visceral adipose tissue radiodensity. InAim 1 we will examine how body composition variables (i.e. area and density of skeletal muscle and adiposetissues) are associated with BMI and with validated ccRCC molecular tumor subtypes that are stronglyassociated with prognosis. In Aim 2 we will identify which aspects of body composition are independentlyassociated with survival after accounting for molecular tumor subtype. By exploring how tumor RNA expressionof immunologic inflammatory angiogenic and other cancer-related genes differ by body composition andsurvival in Aim 3 we will not only further our understanding of the link between body size and biologicalprocesses but may also identify novel targets for tertiary prevention studies. The proposed research has thepotential to make a lasting impact on the fields of cancer epidemiology and survivorship by clarifying theclinical interpretation of the obesity paradox identifying novel prognostic factors derived from readily availableCT scans and informing the development of future behavioral or pharmacological interventions designed toimprove clinical outcomes for the growing population of ccRCC patients. 587431 +No NIH Category available Address;Amino Acids;Amplifiers;Area;Atlas of Cancer Mortality in the United States;Biopsy;Carbohydrates;Cells;Cellular Metabolic Process;Chemicals;Cholesterol;Cholesterol Esters;Cisplatin;Detection;Development;Diameter;Digital Signal Processing;Drug resistance;Electronics;Fatty Acids;Fingerprint;Frequencies;Glucose;Goals;Image;Imaging Device;Lateral;Lighting;Lipids;Lipoproteins;Location;Malignant Neoplasms;Malignant neoplasm of brain;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Maps;Mass Spectrum Analysis;Measurement;Measures;Mediating;Metabolic;Metabolism;Microscope;Microscopy;Molecular;NMR Spectroscopy;Noise;Nucleic Acids;Organism;Pathogenesis;Pattern;Performance;Photons;Physiologic pulse;Play;Predisposition;Proteins;Pump;Raman Spectrum Analysis;Refractive Indices;Renal carcinoma;Research;Resistance;Resolution;Role;Sampling;Scanning;Scheme;Semiconductors;Serum;Signal Transduction;Spectroscopy Fourier Transform Infrared;Speed;Subcellular structure;System;Technology;Testing;Tissue Extracts;Tissues;Universities;absorption;cancer cell;detection limit;drug resistance development;glucose uptake;high resolution imaging;imaging platform;imaging system;improved;indexing;infrared spectroscopy;innovation;leukemia;lipid biosynthesis;malignant breast neoplasm;malignant mouth neoplasm;metabolic imaging;metal oxide;microscopic imaging;nanoparticle;neoplastic cell;oxidation;programs;refractory cancer;submicron;success;tool;tumor metabolism;uptake;vibration Mapping Cancer Metabolism by Mid-infrared Photothermal Microscopy Program Narrative Although altered cell metabolism is emerging as a hallmark of cancer there is an unmet need for new toolsfor quantitation of metabolites. We address this unmet need via development of a digital signal processing wide-field mid-infrared photothermal imaging microscope. Our technology will enable quantitative vibrational imagingof metabolites in live tumor cells and intact biopsies at sub-micron spatial resolution. NCI 10675665 8/14/23 0:00 RFA-CA-20-018 5R33CA261726-03 5 R33 CA 261726 3 "AMIN, ANOWARUL" 9/20/21 0:00 8/31/24 0:00 ZCA1-TCRB-J(M1) 7835719 "CHENG, JI-XIN " Not Applicable 7 ENGINEERING (ALL TYPES) 49435266 THL6A6JLE1S7 49435266 THL6A6JLE1S7 US 42.349594 -71.099726 10001093 BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) BOSTON MA BIOMED ENGR/COL ENGR/ENGR STA 22151390 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 390792 NCI 243252 147540 Program Summary While altered cell metabolism is emerging as a hallmark of cancer there is an unmet need for new tools forquantitation of metabolites. NMR spectroscopy mass spectrometry FTIR and Raman spectroscopy are widelyused for molecular detection in tissue extracts or intact tissues. Yet these tools do not indicate the spatiallocations of the analytes inside the cell. We address this unmet need via development of a lock-in free wide-field mid-infrared photothermal (MIP) microscope. Our technology will enable quantitative vibrational imaging ofmetabolites in live tumor cells and intact biopsies. In MIP microscopy recently developed in the PI lab (Sci Adv2016) a visible beam probes the thermal effect (e.g. change of refractive index and thermal expansion) inducedby a pulsed infrared beam. The MIP signal is then extracted through a lock-in amplifier. To match the IR/visibleillumination area the PI lab further developed a wide-field MIP microscope in which a complementary metaloxidesemiconductor (CMOS) camera and synchronization electronics are harnessed for whole-field lock-indetection (Sci Adv 2019). Despite these initial successes the sensitivity of MIP microscopy is limited by thedetection schemes. First the golden standard lock-in detection misses all the harmonic frequencies in the MIPsignal. Second the well-depth of a typical CMOS camera seriously limits the probe power to 0.01 mW at sample.Thus many averages are needed to reach a reasonable signal to noise ratio. We overcome these difficultiesthrough two innovations. The first one is to digitize the probe photons received by a fast photodiode. Then inthe frequency domain a match filter is used to extract all MIP signals at fundamental and harmonic frequencies.The second one is to perform patterned probe illumination and collect photons with a photodiode which has asaturation threshold of tens of mW. Then a MIP image is recovered by matrix inversion. In this single-pixelcamera approach the probe power can be increased by 1000 times which indicates that the speed can beimproved 30 times to reach the same signal to noise ratio of wide field MIP at the shot noise limit. The goal ofthis R33 proposal is to develop a digital signal processing single pixel camera MIP microscope and validate itspotential for high-content cancer metabolic imaging. In particular we aim to validate a metabolic switch fromglucose-mediated lipogenesis to fatty acids uptake/oxidation in ovarian cancers that become resistant to cisplatin.By accomplishing the proposed studies we will generate a high-speed hyperspectral mid-infrared photothermalchemical imaging platform that is able to map the live cell metabolism at sub-micron spatial resolution. Metabolicimaging of live drug-resistant cancer cells by this platform opens new opportunities of unveiling hidden signaturesthat can potentially lead to adaptive therapies that inhibit the development of drug resistance in cancers. 390792 +No NIH Category available Articulation;Biological;Brain Neoplasms;Cancer Model;Cancer Patient;Cells;Classification;Clinical Research;Computer Analysis;Dependence;Development;Dissection;Genes;Genomics;Glioblastoma;Goals;Human;Individual;Investigation;Laboratories;Malignant Glioma;Malignant Neoplasms;Modeling;Molecular;Motion;Oncogenes;Oncogenic;Outcome;Pathogenesis;Pathway interactions;Patients;Phenotype;Proteins;Proteomics;Research;Resistance;Route;Solid Neoplasm;Stratification;Subgroup;Testing;Therapeutic;Tissues;Treatment Failure;Universities;Validation;Work;cancer genome;cancer heterogeneity;computerized tools;design;drug sensitivity;high throughput technology;in vitro Model;in vivo;innovation;neoplastic cell;new technology;new therapeutic target;novel;operation;personalized therapeutic;programs;targeted treatment;therapeutic target;tool;transcriptomics;tumor Oncogenic mechanisms molecular stratification and therapeutic targets of brain tumors Project narrativeThe genomic and phenotypic complexity of malignant glioma has been implicated as the root causes of mosttreatment failure. Long-term goal of our research program is to develop strategies to model predict and targettherapeutic sensitivity and resistance of glioblastoma. This research plan is articulated around the developmentof a novel and integrated computational-experimental framework for the dissection of biologically homogeneoussubgroups of glioblastoma the study of cancer heterogeneity at the single cell level that will inform on theirreplaceable tumor cell-specific core pathways and the therapeutic exploitation of synthetically lethal drivermodules. NCI 10675651 9/5/23 0:00 PAR-20-278 5R35CA253183-04 5 R35 CA 253183 4 "DUECK, HANNAH RUTH" 9/24/21 0:00 8/31/28 0:00 ZCA1-GRB-S(M1) 6189067 "IAVARONE, ANTONIO " Not Applicable 27 NEUROSURGERY 52780918 F8THLJQSAF93 52780918 F8THLJQSAF93 US 25.713468 -80.277246 5221250 UNIVERSITY OF MIAMI SCHOOL OF MEDICINE CORAL GABLES FL SCHOOLS OF MEDICINE 331462926 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 396 Non-SBIR/STTR 2023 824785 NCI 588000 314580 AbstractThe work to be pursued in this application will continue and expand the program pioneered by Dr. Iavarone tocombine innovative computational tools and state-of-the-art experimental cancer models in vitro and in vivo toidentify homogeneous subgroups of cancer patients in order to dissect the pathogenesis of cancer and designtailored and fully validated personalized therapeutic approaches. The application is focused on glioblastomamultiforme one of the most lethal forms of human cancer. The investigation of glioblastoma has represented along-standing effort of Dr. Iavarones laboratory which in recent work has produced novel targeted therapeuticopportunities currently being tested in clinical studies. The proposal will also benefit from the organizationalcontexts recently set in motion by the large network operations coordinated by the PI. The research plan isarticulated around the development of a novel and integrated computational-experimental framework for: i) theidentification of homogeneous groups of tumors sharing activation of the same biological pathways; ii) the studyof cancer heterogeneity at the single cell level to accurately inform tumor classifications; iii) the therapeuticprediction emerging from the identification of driver modules and synthetic lethal relationships of malignantglioma. We will develop and apply novel technologies for high-throughput transcriptomic and proteomic analysisof individual cells within malignant glioma tissues. These approaches which we have pioneered in our laboratoryat Columbia University during the last few years will serve as the basis for the multifaceted computationalanalysis that will extract genes and proteins responsible for the phenotypic state of individual cells. Experimentalvalidations will be selectively applied to the novel and most exciting molecular pathways and will be performedby our laboratory that has an array of experimental tools and sequence-annotated patient-derived models topursue each individual question. As for the selection of oncogene-dependent and independent vulnerabilitiesidentified by our previous work the ability of our studies to identify novel driver phenotypes and master regulatorsof individual tumor cells will be geared towards routing the new mechanisms into pathway-based syntheticlethality that will inform specific drug sensitivities. The successful outcome of this proposal is an integratedcomputational-experimental pipeline that will be able to mechanistically identify the determinants of tumorgenomes and phenotypes of solid tumors. This information will be of invaluable significance to decipher evolvingtumor dependencies and provide the most accurate therapeutic predictions. 824785 +No NIH Category available ATAC-seq;Bioinformatics;Cancer Center;Cancer Center Support Grant;Cancer Center at Cold Spring Harbor Laboratory;Capital;Cell Culture Techniques;Cell Nucleus;Cell Separation;Cells;Cellular biology;Communities;Complex;Copy Number Polymorphism;Custom;Data;Data Analyses;Data Set;Dissociation;Doctor of Philosophy;Educational workshop;Equipment;Evolution;Experimental Designs;Faculty;Gene Expression;Gene Expression Profiling;Generations;Genomics;Genotype;Head;Heterogeneity;Hour;Human Resources;Immune response;Immunologic Receptors;Informatics;Investigation;Laboratories;Learning;Libraries;Lipids;Logistics;Malignant Neoplasms;Manuscripts;Mission;Mutation;Population;Preparation;Process;Proteins;Protocols documentation;Publications;Quality Control;Reagent;Research;Research Personnel;Resolution;Resource Sharing;Resources;Sampling;Services;Side;Techniques;Technology;Tissues;Training and Education;Work;cell type;community center;computational pipelines;computerized data processing;design;digital;genomic data;member;novel;programs;proteogenomics;protocol development;single cell analysis;single cell sequencing;tool;transcriptome;transcriptome sequencing;transcriptomic profiling;transcriptomics;tumor heterogeneity;tumor microenvironment;tumor progression Single-Cell Biology Shared Resource SINGLE-CELL BIOLOGY SHARED RESOURCE PROJECT NARRATIVENot required per PAR-20-043 NCI 10675645 8/9/23 0:00 PAR-20-043 5P30CA045508-36 5 P30 CA 45508 36 8/1/97 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 9100 10724595 "GILLIS, JESSE " Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 209612 109173 100439 SINGLE-CELL BIOLOGY SHARED RESOURCE PROJECT SUMMARY/ABSTRACTThe Single-Cell Biology Shared Resource was founded in 2017 with the mission of pioneering and deployingcutting-edge single-cell genomics technologies to members of the CSHL Cancer Center and surroundingresearch community. The Shared Resource is led by Faculty Head Jesse Gilis Ph.D. and Director JonathanPreall Ph.D. The Single-Cell Biology Shared Resource is designed to be a comprehensive collaborative SharedResource facility that supports every stage of a single-cell genomics project including experimental designprotocol development sample preparation library construction sequencing logistics primary data processingand in-depth embedded analysis. Shared Resource personnel frequently work side-by-side with researcherscustomizing the workflow to meet the unique needs of the project. Examples of the most common single-cellworkflows supported by the Shared Resource include: 3-digital transcriptome profiling immune receptorprofiling ATAC-sequencing copy-number variation proteogenomics and single-nucleus RNAseq. In addition tostandard established protocols the Shared Resource assists users in designing and executing custom single-cell workflows with downstream tailored data analysis. The Single-Cell Biology Shared Resource houses andoperates capital equipment for handling most stages of common single-cell workflows. A critical component ofthis Shared Resources mission is to provide education and training on the analysis of single-cell genomics data.Semi-annual workshops and regular computational office hours give researchers the opportunity to learncommon computational pipelines and become familiar with emerging techniques in data analysis. Since itsestablishment the Shared Resource has been used by 12 CSHL Cancer Center laboratories (32% of members)resulting in 5 co-authored publications. In summary the Single-Cell Biology Shared Resource providescomprehensive bench-to-publication support of both off-the-shelf and customized genomics workflowsdramatically streamlining the process of collecting these challenging and high-impact datasets. +No NIH Category available Acceleration;Address;Adjuvant Chemotherapy;Adopted;Affect;Algorithms;Benchmarking;Biological Markers;Biopsy;CDK4 gene;Cancer Patient;Cells;Cisplatin;Clinical;Clinical Trials;Clinics and Hospitals;Collection;Cryopreservation;DNA;DNA Sequence Alteration;Development;Doxorubicin;Fox Chase Cancer Center;Funding;Genes;Goals;Hour;Immunotherapy;In complete remission;Institution;Intention;Knowledge;Libraries;Life;Malignant neoplasm of urinary bladder;Medical Oncologist;Methodology;Methods;Methotrexate;Muscle;Mutate;Mutation;Nature;Neoadjuvant Therapy;Neoplasm Metastasis;Nivolumab;Nucleic Acids;Operative Surgical Procedures;Organ;Outcome;Pathologic;Patients;Point Mutation;Predictive Value;Preparation;Procedures;Process;Protocols documentation;Public Health;Publishing;Radiation;Radiation Oncologist;Radical Cystectomy;Recurrence;Research;Residual Cancers;Residual Neoplasm;Residual state;Sampling;Shipping;Specimen;Staging;Temperature;Testing;Time;Triage;Tumor Tissue;Urinary Diversion;Urine;Urologist;Urostomy;Validation;Vinblastine;cancer clinical trial;cancer therapy;chemoradiation;chemotherapy;clinically relevant;cohort;deep sequencing;experimental study;improved;inhibitor;interest;mortality;muscle invasive bladder cancer;next generation sequencing;performance tests;preservation;prospective;responders and non-responders;response;skills;success;tool;tumor;urinary Optimization of urinary DNA deep sequencing tests to enhance clinical staging of bladder cancer patients PROJECT NARRATIVE (RELEVANCE TO PUBLIC HEALTH) Radical cystectomy is a morbid expensive and complicated procedure which requires urinary diversionusually with a urostomy. Because the response rates to pre-surgical chemotherapy and other therapies is highmany patients achieve complete response and therefore may be cured without radical cystectomy. Our intentionis to further develop UTeRD a urine biopsy test for the purpose of distinguishing responders and nonrespondersso that responders can be accurately detected and be triaged into radical cystectomy avoidance algorithms. NCI 10675644 8/3/23 0:00 PAR-18-947 5U01CA260369-03 5 U01 CA 260369 3 "AGRAWAL, LOKESH" 8/1/21 0:00 7/31/26 0:00 ZCA1-SRB-T(J1) 14327752 "ABBOSH, PHILIP " Not Applicable 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 413702 NCI 235832 177870 PROJECT SUMMARY/ABSTRACT Muscle-invasive bladder cancer (MIBC) is optimally treated with neoadjuvant chemotherapy followed byradical cystectomy (RC) whereby ~35% of patients will have a pathologic complete response (pCR). Given themorbid complicated and expensive nature of RC and the well-established pCR rate there is a groundswell ofinterest in RC avoidance for patients achieving pCR. However identifying pCR clinically (as opposed topathologically) is an inaccurate process. In published studies patients who avoid RC after being deemed clinicalcomplete responders have a 25-60% likelihood of recurrence metastasis or bladder cancer mortality. Bettertools to assess residual disease status are needed. To address this need we developed a urine biopsy test which we call UTeRD (Urine Test for ResidualDisease). In UTeRD DNA is isolated from urine and subjected to next generation sequencing to detect pointmutations in a targeted panel of genes. Using UTeRD most mutations in tumor tissue are detectable asmutations in urine. Further presence or absence of residual MU after completion of chemotherapy stronglyassociates with residual disease or pCR at the time of RC respectively. Therefore UTeRD could be used afterneoadjuvant therapy to better identify patients for RC avoidance. Although UTeRD performs well in distinguishing patients with pCR from residual disease the negativepredictive value (NPV) of UTeRD is only 76% some urine samples were nondiagnostic and a urinary DNApreservation protocol needs to be developed in order for the test to be widely adopted. Pre-analytical factorsand methodology improvements which we believe will increase the NPV and decrease nondiagnostic rates willbe studied in Aim 1. In Aim 2 we will determine if urine preservatives can be used to facilitate shipping to acentralized lab without loss of fidelity of the test. Lastly in Aim 3 we will determine if the absence of mutationsfrom a urine biopsy is associated with pCR regardless of the pre-surgical therapy. To answer this questionsamples obtained on 5 prospective MIBC clinical trials from multiple institutions will be studied using theoptimized protocols identified through this research. The research team is comprised of a urologist medical oncologists a radiation oncologist a statisticiana computational biologist who are experts in their fields. The skills and contributions of the team arecomplimentary and will culminate in the development of a unique and robust biomarker that addresses asignificant clinical need using a one-of-a-kind sample cohort. UTeRD may enhance the ability of a bladder cancerclinician to answer highly relevant clinical question namely Does this patient have residual disease after pre-surgical therapy and therefore will he/she benefit from RC? 413702 +No NIH Category available 3-Dimensional;American Type Culture Collection;Anatomy;Basic Science;Biological Models;Biological Process;Cancer Center;Cancer Center Support Grant;Cancer Model;Cell Line;Cells;Chemicals;Communities;Consultations;Contracts;Cost Savings;Dedications;Development;Diagnostic;Doctor of Philosophy;Drug Modelings;Education;Ensure;Equipment;Faculty;Fostering;Funding;Generations;Head;Health;Human;Image;Institution;Laboratories;Licensing;Link;Malignant Neoplasms;Methods;Modeling;Molecular;Mus;Organoids;Patients;Population Heterogeneity;Primary Neoplasm;Printing;Protocols documentation;Publications;Reagent;Research;Research Personnel;Resource Sharing;Resources;Standardization;Technology;Tissue Banks;Tissue Sample;Training;Translational Research;Tumor Biology;Work;biobank;cancer health disparity;cancer type;cost;drug development;experience;experimental study;human tissue;instrumentation;member;neoplastic;operation;programs;protocol development;three dimensional cell culture;tumor;tumor progression;two-dimensional Organoid Shared Resource ORGANOID SHARED RESOURCE PROJECT NARRATIVENot required per PAR-20-043 NCI 10675640 8/9/23 0:00 PAR-20-043 5P30CA045508-36 5 P30 CA 45508 36 8/1/97 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 9098 11852640 "DOS SANTOS, CAMILA " Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 142489 74213 68276 ORGANOID SHARED RESOURCE ABSTRACTThe Organoid Shared Resource was established to provide Cancer Center members with access to thereagents equipment and expertise needed to culture and perform experiments with three-dimensional organoidmodels. The organoid technology was introduced to the Cold Spring Harbor Laboratory Cancer Center in 2012by David Tuveson with the rationale that these three dimensional cultures recapitulate numerous aspects ofprimary tumor biology more faithfully than standard two-dimensional cell lines. There are now 18 Cancer Centermember labs (47% of members) using human and murine organoids in their research and organoids have beenused in 40 Cancer Center publications or preprints. To support the growing use of organoids the new SharedResource was launched in 2020 with dedicated lab space and staff. The Organoid Shared Resource is beingproposed in this application as a new Cancer Center Shared Resource led by Faculty Head Camila dos SantosPh.D. and manager Dennis Plenker Ph.D. The Shared Resource offers members centralized access toprotocols for generating and working with organoid cultures training in methods and standardized culturereagents as well as equipment for performing high-throughput chemical screens on either two dimensional celllines or organoid cultures. Cancer Center members will benefit from access to a biorepository of human organoidmodels that have been validated and well characterized. The Shared Resource will be able to offer CancerCenter members substantial cost-savings due to bulk purchasing of culture reagents and the development ofprotocols to produce media additives in-house. The use of organoids has already fostered several collaborativeCancer Center projects in line with Cancer Center strategic priorities including investigating cancer healthdisparities in diverse populations integrating quantitative and wet-bench biologists and expanding translationalresearch. +No NIH Category available Acceleration;Accounting;Aneuploidy;Animal Model;Apoptosis;Cancer Center;Cancer Center Support Grant;Cell Cycle Progression;Cell Separation;Cells;Cellular biology;Collaborations;Complement;Computer software;Consultations;Continuing Education;Data;Data Analyses;Doctor of Medicine;Ensure;Equipment;Experimental Designs;Faculty;Flow Cytometry;Flow Cytometry Shared Resource;Fluorescent Antibody Technique;Fluorochrome;Funding;Generations;Grant;Head;Immune;Individual;Laboratories;Lasers;Malignant Neoplasms;Modality;Newsletter;Phenotype;Ploidies;Population;Population Analysis;Preparation;Printing;Publications;Recovery;Research;Research Personnel;Research Support;Resource Sharing;Role;Running;Sampling;Services;Sorting;Techniques;Training;Tube;anticancer research;cancer cell;cell analyzer;cell type;computerized data processing;data acquisition;design;flexibility;innovation;instrument;instrumentation;interest;investigator training;member;operation;programs;protocol development;response;service utilization;single cell analysis;single cell sequencing;stem cells;user-friendly Flow Cytometry Shared Resource FLOW CYTOMETRY SHARED RESOURCE PROJECT NARRATIVENot required per PAR-20-043 NCI 10675633 8/9/23 0:00 PAR-20-043 5P30CA045508-36 5 P30 CA 45508 36 8/1/97 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 9094 2417038 "FEARON, DOUGLAS T" Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 217476 113269 104207 FLOW CYTOMETRY SHARED RESOURCE PROJECT SUMMARY/ABSTRACTFlow Cytometry is essential for cancer research and is widely used to identify purify and analyze specific cellpopulations. The Flow Cytometry Shared Resource has provided high-quality service and access to criticalinstrumentation to members of the Cold Spring Harbor Laboratory (CSHL) Cancer Center for over thirty years.The Shared Resource is led by Faculty Head Douglas Fearon M.D. and Senior Manager Pamela Moody. Overthe last funding period this Shared Resource was heavily used to characterize cellular phenotypes using cellcycle progression DNA content apoptosis levels and resolving multiple cell types through the use of fluorescentantibodies. The Shared Resource offers four state-of-the-art instruments with up to five different lasers for cellsorting and analysis. Expert staff is also available for training in the use of equipment consultation onexperimental design and assistance with operation of instruments. Access to Flow Cytometry has alloweddevelopment of protocols for single-cell sequencing the generation and analysis of innovative animal modelsand isolation and characterization of the stem cells and immune cells involved in cancer. The Flow CytometryShared Resource is well used by Cancer Center members; in the last funding period 31 members (82% of themembership) used this Shared Resource accounting for 93% of its use. In the last five years the Flow CytometryShared Resource supported 61 Cancer Center publications or preprints. Without the Flow Cytometry SharedResource it would be extremely difficult for individual investigators to have access to this sophisticatedinstrumentation and these types of services which are critical to their research programs. In summary theShared Resource provides CSHL Cancer Center members with a complete complement of state-of-the-artinstrumentation and advanced technical support to help accelerate cancer research and discovery. +No NIH Category available Address;Affinity;Alpaca;Animals;Antibodies;Antibody Affinity;Antibody Formation;Area;B-Lymphocytes;Binding;Biological Assay;Biological Markers;Biotechnology;Bispecific Antibodies;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Center at Cold Spring Harbor Laboratory;Cell Line;Cell Separation;Cell Surface Proteins;Cells;Cloning;Collaborations;Consultations;Development;Diagnostic;Disease;Doctor of Philosophy;Engineering;Epitope Mapping;Epitopes;Experimental Designs;Faculty;Funding;Generations;Genomics;Goals;Head;Hybridomas;Immune;Immunization;Immunize;Individual;Investigational Therapies;Laminin;Libraries;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Methods;Molecular Cloning;Nature;Phage Display;Plasmids;Play;Post-Translational Protein Processing;Procedures;Process;Production;Property;Proteoglycan;Protocols documentation;Publications;Reagent;Receptor Signaling;Research;Research Personnel;Resource Sharing;Resources;Rodent;Role;Sampling;Science;Scientist;Services;Spleen;Surface;Techniques;Technology;Testing;Therapeutic;Therapeutic antibodies;Tissues;Translating;Validation;Work;Yeasts;antibody engineering;anticancer research;cell immortalization;cost effectiveness;design;differential expression;experimental study;humanized antibody;improved;innovation;malignant breast neoplasm;member;nanobodies;novel;pre-clinical;programs;protein expression;response;single cell analysis;tool;tumor;tumor microenvironment;tumorigenesis;vector Antibody & Phage Display Shared Resource ANTIBODY & PHAGE DISPLAY SHARED RESOURCE PROJECT NARRATIVENot required per PAR-20-043 NCI 10675632 8/9/23 0:00 PAR-20-043 5P30CA045508-36 5 P30 CA 45508 36 8/1/97 0:00 7/31/26 0:00 Cancer Centers Study Section (A)[NCI-A] 9093 1859429 "KRAINER, ADRIAN R" Not Applicable 3 Unavailable 65968786 GV31TMFLPY88 65968786 GV31TMFLPY88 US 40.86755 -73.473456 4577101 COLD SPRING HARBOR LABORATORY COLD SPRING HARBOR NY Research Institutes 117242209 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 235597 122707 112890 ANTIBODY & PHAGE DISPLAY SHARED RESOURCE - PROJECT SUMMARY/ABSTRACTThe Antibody & Phage Display Shared Resource offers a variety of cutting-edge technologies to developantibodies for use as key research reagents. The Shared Resource is led by Faculty Head Adrian Krainer Ph.Dand Director Johannes Yeh Ph.D. The Shared Resource collaborates with Cancer Center members to addressfundamental and compelling questions in cancer biology in research areas including: (1) The understanding ofthe tumor microenvironment; (2) The discovery of surface biomarkers and their differential expression duringtumorigenesis; and (3) Receptor signaling in cancer. Shared Resource staff work closely with scientists to selectthe best approach for their experimental needs and specialized screens are developed in close coodination withindividual scientists. The Shared Resource also tests and implements new techniques reagents and assayimprovements related to the different stages of antibody production. Technologies currently available in theShared Resource include hybridoma development by fusion of rodent spleen cells with immortalized cell linesgeneration of nanobodies from immunized alpacas and direct cloning of the VH-VL domains from B cells fromimmunized rodents or alpacas into expression plasmids. Yeast or phage display techniques are used to optimizethe binding affinities of antibodies identified after the first round of immunization and selection. A library ofhybridomas generated in the Shared Resource is maintained and staff will produce and purify antibodies fromthese lines on request. In the last funding period this Shared Resouce was used by twelve Cancer Centermembers (32%) and has contributed towards seven publications by members. Novel antibodies have generatedreagents that have been used for genomics (e.g. ChIP) cell separation (e.g. FACS) and single-cell analysis.Finally recently developed antibodies are currently being investigated for potential diagnostic or therapeuticapplications by members and are thus playing an essential role in cancer programs at CSHL. +No NIH Category available Adolescent and Young Adult;Advocate;Aftercare;American College of Radiology Imaging Network;Applications Grants;Area;Cancer Center;Cancer Control;Catchment Area;Caucasians;Clinical Investigator;Clinical Research;Clinical Trials;Collection;Communication;Communities;Community Clinical Oncology Program;County;Data;Development;Eastern Cooperative Oncology Group;Education;Elderly;Enrollment;Ensure;Funding;Grant;Health;IT collaborator;Image;Individual;Infrastructure;Institution;Institutional Review Boards;Leadership;Malignant Neoplasms;Minority Participation;Mission;Missouri;Ozarks;Participant;Patient-Focused Outcomes;Patients;Pediatric Oncology Group;Population;Prevention;Process;Protocols documentation;Provider;Recording of previous events;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Rural Community;Rural Population;Secure;Sexual and Gender Minorities;Site;Southwest Oncology Group;Tissue Procurements;Underserved Population;United States;Woman;anticancer research;base;cancer care;cancer health disparity;cancer prevention;cancer therapy;care delivery;community engagement;disparity reduction;experience;forest;high standard;imaging study;improved;interest;member;outreach;participant safety;programs;research study;rural patients;rural setting;screening Ozark Health Ventures LLC dba Cancer Research for the Ozarks (CRO) NarrativeCancer Research for the Ozarks though this NCORP grant will continue to be the primaryaccess to NCI sponsored research for the poor rural patients across 42 counties in its five statecatchment area. This access is critical to providing these patients with cutting edge qualitycancer treatment prevention and care delivery research in their local communities. NCI 10675608 7/24/23 0:00 RFA-CA-18-016 5UG1CA189822-10 5 UG1 CA 189822 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 11898658 "CARLSON, JAY W" Not Applicable 7 Unavailable 808197565 DZNEK4C3J4H5 808197565 DZNEK4C3J4H5 US 37.178172 -93.274157 10017624 "OZARK HEALTH VENTURES, LLC" SPRINGFIELD MO Domestic For-Profits 658046520 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1304619 NCI 1304619 0 1 Ozark Health Ventures LLC d/b/a Cancer Research for the Ozarks (CRO) is submitting 2 this grant application as it desires to continue to be involved with the cooperative efforts 3 of the NCI Community Oncology Research Program (NCORP) to focus on the broader 4 needs of cancer prevention and treatment cancer care delivery imaging studies and 5 cancer disparities. 6 Cancer Research for the Ozarks has a long and mutually beneficial history with the NCI 7 for over 31 years of offering clinical trial access to rural communities within the central 8 United States. Since its inception CRO has grown from southwest Missouri to 9 increasing its network to 15 component sites that incorporate 42 counties in five states10 with a predominately rural population of more than 4300000. CRO would be the11 primary access for NCI-sponsored and NTCN network trials for the vast majority of these12 patients. The population in CROs catchment area is generally Caucasian and slightly13 older and poorer than national averages. CRO has been a significant contributor to14 enrollments in protocols involving cancer prevention and treatment cancer care delivery15 imaging studies and cancer disparities. CRO has also had numerous registrations to16 cancer care delivery and tissue procurement protocols. CRO routinely meets the NCI17 criteria for enrollments and for the number of CCDR protocols it has open. CRO has a18 plan for further expansion of components and investigators to secure even higher19 enrollments. CRO participates with the following research bases: Alliance: member since20 June 2012; NRG: member since their merger in 2014 and the preceding legacy groups;21 SWOG: member since its inception in 1987; Wake Forest: member since their inception22 in 2014 and participated in protocols with the preceding Cancer Center; ECOG-ACRIN:23 member since 2014 and the preceding legacy groups. In addition CRO has been24 involved in the Childrens Oncology Group at Mercy St. Louis since June 2011. The25 major collective strengths of the CRO application would be the tremendous support and26 commitment of the two primary components the broad network of component sites the27 quality integrity and experience of CROs leadership and the program and the many28 investigators and collaborators that it supports.29 1304619 +No NIH Category available Adult;Brain;Colorectal;Complement;DNA Insertion Elements;Data;Data Collection;Elements;Epithelium;Genome;Goals;Human;Human Genome;L1 Elements;Length;Lung;Malignant Neoplasms;Mediating;Methods;Methylation;Mission;Mobile Genetic Elements;Mutagenesis;Mutagens;Mutate;National Cancer Institute;Normal tissue morphology;Oncogenes;Pancreas;Regulation;Reporting;Repression;Resources;Retrotransposon;Role;Sampling;Somatic Cell;Source;Suggestion;The Cancer Genome Atlas;Tissues;Tumor Suppressor Genes;Tumor Tissue;Work;human disease;human tissue;novel;offspring;tumor;tumorigenesis Mobile element mutagenesis as a driver of human cancers Project Narrative. The central goal of our project is to better understand the role of mobile genetic elements in humancancers. Because new mobile element insertions (MEIs) can initiate human cancers our work is relevant to themission of the National Cancer Institute. NCI 10675557 7/26/23 0:00 PA-20-185 5R01CA261934-02 5 R01 CA 261934 2 "WEINREICH, MICHAEL DALE" 8/2/22 0:00 7/31/27 0:00 Cancer Genetics Study Section[CG] 6486214 "DEVINE, SCOTT E" Not Applicable 7 INTERNAL MEDICINE/MEDICINE 188435911 Z9CRZKD42ZT1 188435911 Z9CRZKD42ZT1 US 39.292248 -76.625629 820104 UNIVERSITY OF MARYLAND BALTIMORE BALTIMORE MD SCHOOLS OF MEDICINE 212011508 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 346350 NCI 224175 122175 Project Summary. Human LINE-1 (L1) elements are autonomous retrotransposons that continue to produce newoffspring L1 insertions in human genomes. Until recently L1 elements were thought to be mobilized primarilyin the germline and then silenced in somatic cells throughout adulthood. However several recent reports haveshown that L1 elements are active in at least some adult somatic tissues including the brain and epithelialsomatic tumors. These observations have led to the suggestion that L1 might play a role in initiating humancancers by mutating specific tumor suppressor genes and oncogenes in somatic cells. In the three aims of thisproposal we will further explore this hypothesis with an emphasis on studying the expression regulation andmobilization of the full-length L1 source elements that generate new L1 insertions. In Specific Aim 1 we willgenerate a comprehensive resource of full-length human-specific L1 (FL-L1Hs) source elements that will beused throughout this proposal (Aims 1-3) to study the role of L1 mobilization in human tissues and tumors. InSpecific Aim 2 we will examine the expression and regulation of FL-L1Hs elements that can evade somaticrepression and will study the mechanism(s) whereby these elements manage to do this. Finally in SpecificAim 3 we will examine the mobilization capacities of FL-L1Hs elements. Combined with the data generated inAims 1 and 2 these data will allow us to better understand the expression regulation and mobilization of theFL-L1Hs elements that mutagenize the human genome. The successful completion of the three Aims of thisstudy will transform our understanding of how mobile elements impact human diseases including cancers. 346350 +No NIH Category available Address;Adolescent;Adoption;Behavioral Sciences;Biology;Cancer Center;Cancer Control;Cancer Patient;Cancer Research Infrastructure;Catchment Area;Child;Child Health;Child health care;Clinic;Clinical;Clinical Trials;Collaborations;Communication Tools;Communities;Community Clinical Oncology Program;Community Health Education;Consent;Continuity of Patient Care;Cultural Backgrounds;Databases;Dedications;Disease;Doctor of Medicine;Educational Materials;Electronic Health Record;Electronics;Eligibility Determination;Enrollment;Ensure;Environment;Ethnic Origin;Family;Florida;Fostering;Functional disorder;Funding;Geography;Goals;Health;Health Policy;Health system;Healthcare;Healthcare Systems;Heart;Hematological Disease;Informatics;Infrastructure;Institution;International;Investments;Leadership;Learning;Malignant Childhood Neoplasm;Malignant Neoplasms;Mentors;Methodology;Minority Enrollment;Mission;Monitor;Monitoring Clinical Trials;Multicultural Education;Patients;Pediatric Hospitals;Pediatric Oncology;Pediatric Oncology Group;Pediatrics;Physicians;Population;Prevention;Principal Investigator;Procedures;Productivity;Provider;Quality of Care;Rare Diseases;Recording of previous events;Records;Registries;Research;Research Infrastructure;Resources;Site;Structure;System;Therapeutic;Therapeutic Trials;Time;Training;base;cancer care;cancer prevention;cancer therapy;cancer type;care delivery;clinical trial enrollment;community engagement;community organizations;community setting;data quality;data submission;design;ethnic minority;experience;improved;innovation;integrated care;minority patient;oncology program;pediatrician;programs;racial minority;recruit;school health;socioeconomics;success;survivorship;symptom management;tool;treatment research;treatment trial;trial enrollment Nemours NCI Community Oncology Research Program (NCORP) PROJECT NARRATIVEThe Nemours NCORP will provide the leadership and clinical trial infrastructure to support five geographicallydistinct community-based pediatric oncology programs in enrollment of children on cancer care preventioncare delivery therapeutic and biology trials. Childhood cancer is an ultra-rare disease and the NemoursNCORP is among the leaders in clinical trial enrollment. Progress in childhood cancer will only be possiblewith expertly led administered and monitored clinical trial participation. NCI 10675545 7/26/23 0:00 RFA-CA-18-016 5UG1CA189958-10 5 UG1 CA 189958 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 9748558 "CAYWOOD, EMI H" Not Applicable At-Large Unavailable 38004941 ETGMYV7CKAJ7 38004941 ETGMYV7CKAJ7 US 39.778191 -75.557506 1804102 ALFRED I. DU PONT HOSP FOR CHILDREN WILMINGTON DE Independent Hospitals 198033607 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 607598 NCI 570556 202006 PROJECT SUMMARY Nemours is internationally recognized multi-site pediatric healthcare system that is built upon acentralized efficient and collaborative research infrastructure committed to improving the health of all children.In 2014 with over 25 years' experience in clinical trials research the four Nemours Center for Cancer andBlood Disorders (NCCBD) sites received funding as a NCI Community Oncology Research Program dedicatedto children with cancer through participation in the Children's Oncology Group (COG) Research Base trials.The Nemours Alfred I duPont Hospital for Children (NCCBD-Wilmington DE) Nemours Children's Clinics(NCCBD-Jacksonville Florida) Nemours Children's Hospital (NCCBD-Orlando FL) and Sacred HeartPensacola FL all had outstanding records of clinical trial participation and collaboration under the NemoursNCORP operational structure. In the current application the Nemours NCORP will add a fifth site BrowardHeath (Ft. Lauderdale Florida) to improve the enrollment of minority and underserved patients. The mission of the Nemours NCORP is to ensure that each child and young adolescent within ourcommunity-based catchment area has the opportunity to participate in national cancer control cancerprevention and cancer treatment trials as appropriate. The Nemours NCORP will continue to sustain systemssupportive of cancer control cancer prevention care delivery and treatment research as well as to maintainrobust quality management and improvement practices. Through Nemours' already well-established network ofhealthcare institutions community-based physician practices and strong community ties we will continue toextend access to research trials to children from all ethnicities and cultural backgrounds. Inclusive of all sitesthe Nemours NCORP is consistently among the highest enrolling contributors to the Children's OncologyGroup Research Base studies providing the opportunity to learn from all children with ultra-rare diseases. TheNemours NCORP will continue and grow a childhood cancer research infrastructure that achieves the followingaims: 1) To ensure continued robust accrual to NCI-funded clinical trials through the meaningful use ofelectronic resources and best practices across the continuum of care 2) To expand and maintain aninfrastructure supportive of productive and efficient participation in NCI-funded Cancer CarePrevention (CCP) and Care Delivery (CD) Research (CCDR) and 3) To foster community engagementthrough dissemination discussion and adoption of results from clinical trials and through physicianfamily and community education. 607598 +No NIH Category available Ablation;Acceleration;Affect;Antineoplastic Agents;BRCA1 Mutation;BRCA1 gene;BRCA2 Mutation;BRCA2 gene;Base Excision Repairs;Biological Assay;Biological Models;Breast Cancer cell line;Breast Cancer therapy;Cancer cell line;Cell Line;Cells;Chromosomal Rearrangement;Chromosome Breakage;Chromosomes;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;DNA;DNA biosynthesis;DNA replication fork;DNA sequencing;Data;Defect;Dependence;Development;Diploid Cells;Double Strand Break Repair;Dropout;Drug Targeting;Engineering;Epigenetic Process;Essential Genes;Evaluation;Evolution;Frequencies;Genes;Genetic;Genetic study;Genomic DNA;Genomic Instability;Genomics;Germ-Line Mutation;Goals;Guide RNA;Hereditary Breast and Ovarian Cancer Syndrome;Homologous Gene;Human;Human Genome;In Vitro;Informatics;Inherited;Knock-out;Knowledge;Laboratories;Lethal Genes;Libraries;Maintenance Therapy;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Metaphase;Mining;Mus;Mutate;Mutation;Okazaki fragments;PARP inhibition;Pathway Analysis;Poly(ADP-ribose) Polymerase Inhibitor;Process;Progression-Free Survivals;RTH-1 Nuclease;Research;Resistance;Screening Result;Small Interfering RNA;Specificity;Suppressor Genes;Testing;Therapeutic Agents;Validation;Yeasts;brca gene;cancer cell;cancer genome;cancer genomics;cancer therapy;cancer type;candidate selection;candidate validation;endonuclease;genome integrity;genome-wide;homologous recombination;improved;in silico;in vivo;inhibitor;knock-down;malignant breast neoplasm;mutant;nuclease;pharmacologic;predictive signature;rational design;recombinational repair;replication stress;resistance mechanism;response;small molecule;synthetic lethal interaction;targeted cancer therapy;therapeutic development;therapeutic target;therapy design;transcriptomics;tumor xenograft;validation studies;yeast genetics;yeast genome FEN1 Endonuclease as a Synthetic Lethal Target for Cancer Therapy PROJECT NARRATIVEThe instability of the cancer genome a driver of malignant evolution can be targeted for the rational design oftherapy exemplified by the application of PARP inhibitors as maintenance therapy for cancers with BRCA1 orBRCA2 defects that inactivate homologous recombination repair (HRR) of genomic DNA. From yeast geneticstudies of synthetic lethal interactions among genome instability suppressor genes we identified and verifiedthat HRR-deficiency also sensitizes cancer cells to the loss of the FEN1 endonuclease. This study willinvestigate the FEN1 endonuclease as a rational drug target for HRR-deficient cancers and establish aplatform for further identification of synthetic lethal interactions to target cancer genome instability. NCI 10675534 7/7/23 0:00 PA-20-185 5R01CA255341-03 5 R01 CA 255341 3 "WEINREICH, MICHAEL DALE" 8/15/21 0:00 7/31/26 0:00 Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2] 8005932 "KOLODNER, RICHARD D" "PUTNAM, CHRISTOPHER DAVID; WANG, JEAN Y.J." 50 OTHER BASIC SCIENCES 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 626700 NCI 401400 225300 PROJECT SUMMARYGross chromosomal rearrangements (GCRs) a type of genome instability are often seen in inherited andsporadic cancers and are an important driver of malignant progression. For example hereditary breast andovarian cancers resulting from BRCA1 and BRCA2 germline mutations suffer from homologous recombinationrepair (HRR) defects that increase GCRs in model systems. Our previous studies have established acomprehensive network of genome instability suppressor (GIS) genes in yeast and demonstrated in silico thathuman homologs of these yeast GIS genes are genetically and/or epigenetically altered across many cancertypes. From yeast genetic studies we have also identified and rank-ordered synthetic lethal (SL) partners ofnon-essential GIS genes. The feasibility of targeting SL genetic interactions for rational cancer therapy hasbeen supported by the application of PARP inhibitors for maintenance therapy of breast and ovarian cancerswith BRCA1 or BRCA2 defects. To exploit additional SL interactions for cancer therapy this proposal aims toleverage the wealth of knowledge on GIS genes and their SL partners developed in yeast to guide thedevelopment of therapeutics that target human GIS gene defects that cause GCRs in cancer. Specifically theproposed studies will focus on the human Flap Endonuclease 1 (FEN1) the homolog of yeast RAD27 whichhas the highest number of SL-interactions with GIS genes of a variety of functions. FEN1 processes Okazakifragments during lagging strand DNA synthesis and acts in long-patch base excision repair but is itself non-essential. To develop this nuclease as a target for treating cancers with defects in BRCA1 BRCA2 and otherFEN1-SL partner GIS genes we propose to carry out the following lines of research: AIM 1) To expandongoing CRISPR-dropout screens and validation studies in cell lines and mice to (a) identify human genes inwhich defects cause sensitivity to our proprietary FEN1-inhibitors of highly potency and specificity and (b)define FEN1 SL-partner genes as well as cancer omics signatures that can be targeted with FEN1 inhibitors toinduce SL; AIM 2) To combine informatics and cell-based validation approaches for a deep-dive into canceromics and gene essentiality data to identify the spectrum and signatures of cancers amenable to therapeutictargeting with FEN1 inhibitors; AIM 3) To apply an array of genetics-based approaches to investigatemechanisms for acquired resistance to FEN1 inhibitors and to compare resistance to FEN1 versus PARPinhibitors; and AIM 4) To determine the effects of FEN1 inhibition on DNA replication fork stability andchromosome integrity in BRCA1 and BRCA2 mutant cells to test the hypothesis that FEN1 inhibitors induceirreparable damage to replication forks in HRR-deficient cancer cells to cause lethality. These mechanisticstudies will be extended to other validated FEN1-SL partner genes. These projects will greatly accelerate thedevelopment of FEN1 inhibitors to target cancer genome instability and will establish an experimental platformfor evaluation and development of other potential therapeutic targets to be identified by the proposed research. 626700 +No NIH Category available Aneuploidy;Award;Biology;Biotechnology;Cancer Model;Characteristics;Chromosome abnormality;Classification;Clinical;Collaborations;Computational Molecular Biology;DNA Damage;Data;Data Reporting;Data Science;Decision Making;Development;Development Plans;Early identification;Event;Evolution;Genetic;Goals;Grant;Human;Investigation;Knowledge;Learning;Machine Learning;Malignant Neoplasms;Medical;Mentors;Methodology;Methods;Mission;Modeling;Molecular Evolution;Mutation;Oncogenic;Outcome;Pathway interactions;Pattern;Performance;Phase;Phenotype;Postdoctoral Fellow;Public Health;Research;Research Personnel;Route;Solid;Techniques;Therapeutic;Time;Training;United States National Institutes of Health;United States National Library of Medicine;anticancer research;cancer type;career;career development;clinical decision-making;clinical predictors;comparative genomics;computer studies;computerized tools;deep learning;driver mutation;genomic data;improved;innovation;insight;learning strategy;mathematical model;member;neural network;novel;novel strategies;predict clinical outcome;predicting response;recurrent neural network;response;treatment response;tumor;tumor progression;tumorigenesis Modeling cancer evolution for prediction with neural networks: methods and applications PROJECT NARRATIVEThe proposed research is relevant to public health because it entails new strategies to study cancerevolution that will uncover distinct therapeutic vulnerabilities and determinants of clinical outcome. Theestablishment of the proposed methodologies will offer temporal models for data representation andneural network frameworks for cancer research that will contribute to enhancement of clinicalprediction tasks. Thus the proposed research is relevant to the part of the NLMs mission that pertains toenhancing human intellectual capacities through dynamic modeling and machine learning strategies toimprove medical decision-making. NCI 10675533 7/31/23 0:00 PA-19-130 5R00CA252025-04 5 R00 CA 252025 4 "MILLER, DAVID J" 8/1/20 0:00 7/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 12453732 "AUSLANDER, NOAM " Not Applicable 3 Unavailable 75524595 DW1XZMGNFBL4 75524595 DW1XZMGNFBL4 US 39.951288 -75.195771 9340401 WISTAR INSTITUTE PHILADELPHIA PA Research Institutes 191044265 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Non-SBIR/STTR 2023 249000 NCI 136043 112957 PROJECT SUMMARY/ABSTRACT The study of tumor evolution can uncover events and interactions that drive tumor developmentthrough alternative routes reveal differences in therapeutic vulnerabilities and improve clinical decisionmaking. Yet studying tumor evolution is challenging hindered by the difficulty to interpret noisy genomicdata and the lack of temporal ordering of major genetic events. There is therefore a critical need for thedevelopment of computational approaches that can facilitate efficient investigation of cancer data underan evolutionary temporal perspective. The long-term goal of this project is to develop computational toolscombining advanced machine learning with molecular evolution techniques and provide novel strategiesto investigate tumor evolution. The overall objective is to establish a deep-learning framework to studytumor development that will be used to distinguish early and late genetic events that are associated withtumor characteristics survival and therapeutic vulnerabilities. The rationale of the proposed research isthat the study of tumor evolution through integration of machine learning with molecular evolutiontechniques could enhance the performance of otherwise difficult clinical classification tasks. The specificaims of this project are to (1) Characterize the interplay between driver mutations and aneuploidy in tumorevolution and identify determinants of clinical outcome and therapeutic vulnerabilities (2) Introducecomputational approaches to represent snapshot genomic data through temporal and functional orderingof genetic events (3) Develop a recurrent neural network approach to learn different dynamics in tumorevolution from ordered genomic data and predict phenotypic features and clinical outcome. Theproposed research is innovative because it will combine recent advances in machine learning withevolutionary techniques into a single framework establishing novel computational tools that will facilitatea comprehensive investigation of cancer development. The proposed framework is significant because itwill enable application of temporal modeling with machine learning to cancer data for prediction of clinicalfeatures. To achieve the proposed goals the candidate Dr. Noam Auslander requires additional trainingand mentoring in evolutionary research comparative genomics and mathematical modeling. During theK99 phase Dr. Auslander will conduct this research as a postdoctoral fellow at the National Center forBiotechnology Information. She will be mentored by Dr. Eugene Koonin a recognized expert in the fieldsof molecular evolution and computational biology and additional mentoring from senior members fromthe Koonin lab. Together with her previous training in machine learning and cancer data science thisapplication for the NIH Pathway to Independence Award (K99/R00) describes a career development planthat will allow Dr. Auslander to achieve her career goals and become an independent investigator andleader in computational research of cancer evolution. 249000 +No NIH Category available 3-Dimensional;Address;Adoption;Benign;Biopsy;Cancer Detection;Classification;Core Biopsy;Data;Detection;Diagnosis;Diffusion;Discrimination;Disease;Epithelium;Fingerprint;Gland;Goals;Image;Indolent;Lead;Lesion;Life;Magnetic Resonance;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Maps;Measurement;Methods;Mission;Morbidity - disease rate;Pathologic;Pathology;Pathway interactions;Patients;Performance;Positioning Attribute;Process;Property;Prostate;Protocols documentation;Public Health;Radical Prostatectomy;Reproducibility;Research;Resolution;Sampling;Scanning;Screening for Prostate Cancer;Selection for Treatments;Sepsis;Signal Transduction;Standardization;Structure;T2 weighted imaging;Technology;Testing;Time;Tissues;United States National Institutes of Health;Validation;Work;aggressive therapy;clinically significant;experience;human disease;imaging approach;imaging detection;imaging modality;improved;innovation;millimeter;quantitative imaging;reconstruction;standard of care;ultrasound 3D High Resolution Magnetic Resonance Fingerprinting for Prostate Cancer Project NarrativeThe proposed research is relevant to public health because it focuses on advancing the detectionand characterization of prostate cancer by developing reproducible and repeatable quantitativeMR imaging methods. Once proposed technologies have been developed they have potentialsto provide an objective identification and classification of prostate cancer thus reducingunnecessary biopsies and facilitating appropriate treatment selection. Thus the proposedresearch is relevant to the part of the NIHs mission that pertains to improving the diagnosis ofhuman diseases. NCI 10675529 6/26/23 0:00 PA-20-185 5R37CA263583-03 5 R37 CA 263583 3 "ZHANG, HUIMING" 8/1/21 0:00 7/31/26 0:00 Emerging Imaging Technologies and Applications Study Section[EITA] 14136210 "JIANG, YUN " Not Applicable 6 RADIATION-DIAGNOSTIC/ONCOLOGY 73133571 GNJ7BBP73WE9 73133571 GNJ7BBP73WE9 US 42.275494 -83.743038 1506502 UNIVERSITY OF MICHIGAN AT ANN ARBOR ANN ARBOR MI SCHOOLS OF MEDICINE 481091276 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 632972 NCI 405751 227221 Project Summary AbstractThe goal is to identify and characterize prostate cancer objectively and accurately using a rapidquantitative Magnetic Resonance Imaging (MRI) approach. The standard-of-care in patientsbeing evaluated for suspicion of prostate cancer is systematic sampling of the entire gland with12 biopsy cores without an identified focus suspicious for cancer on imaging. Current qualitativeMR images while mostly successful in highlighting prostate cancer may look different fromscanner to scanner or even when repeated on the same scanner. This variability adds complexityto an already subjective interpretive process of detecting cancer and discriminating betweenclinically significant and indolent disease. Thus more robust and standardized MRI methods todetect and characterize clinically significant prostate cancer are needed.This project plans to address this issue with following specific aims:(1) A rapid high-resolution 3D MRF acquisition will be developed and optimized for prostatecancer assessment by innovating reduced field-of-view imaging 3D Cartesian sampling andadvanced reconstruction in MRF. The proposal MRF acquisition will enable accurate T1 and T2mapping over the prostate gland with an isotropic submillimeter resolution (0.8 mm3) in anacquisition time of less than 5 minutes.(2) Contrast-weighted images synthesized using MRF-based T1 and T2 maps will replaceconventional qualitative images for detecting prostate cancer.(3) MRF-based T1 and T2 with apparent diffusion coefficient will be validated to separate cancerfrom non-cancer and differentiate cancers with different grades.(4) Microstructural signatures of prostate cancer derived from MRF will provide information aboutsubvoxel components (epithelium stroma lumen and their volume fractions) to reveal occultcancers and enable the discrimination of different grades of cancer.This project will advance prostate imaging by providing reproducible and repeatable non-invasivequantitative imaging metrics. These innovations will replace conventional contrast-weightedimaging with a single rapid high-resolution standard MRF protocol provide an objectiveidentification of prostate cancer and grading and improve the classification of prostate cancerusing microstructural signatures thus reducing unnecessary biopsies and facilitating appropriatetreatment selection. 632972 +No NIH Category available Address;Advocate;American Cancer Society;American College of Radiology Imaging Network;Award;Awareness;Cancer Center;Cancer Control;Cancer Hospital;Cancer Patient;Cancer Research Project;Catchment Area;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Support Unit;Clinics and Hospitals;Collaborations;Communication;Communities;Community Clinical Oncology Program;Community Hospitals;Community Participation;Community Physician;Comprehensive Cancer Center of Wake Forest University;Discipline of obstetrics;Eastern Cooperative Oncology Group;Enrollment;Ensure;Environment;Evaluation;Funding;Funding Opportunities;Future;Goals;Grant;Growth;Gynecologic Oncology;Gynecology;Health;Health Care Reform;Health Planning Councils;Health Professional;Hematology;Hospital Administrators;Hospitals;Image;Improve Access;Individual;Intervention;Knowledge;Malignant Neoplasms;Marketing;Medical Oncology;Methods;Minnesota;Minority Groups;Modeling;Names;National Cancer Institute;Nurse Practitioners;Oncologist;Oncology;Outcome;Palliative Care;Pamphlets;Participant;Patient advocacy;Patient-Focused Outcomes;Patients;Personal Satisfaction;Persons;Physician Assistants;Population Heterogeneity;Positioning Attribute;Prevention;Primary Care;Procedures;Process;Protocols documentation;Quality of life;Radiation Oncology;Radiology Specialty;Recording of previous events;Research;Research Institute;Research Personnel;Research Proposals;Resources;Rural;Services;Site;Southwest Oncology Group;Surgical Oncology;Testing;Thoracic Surgical Procedures;Time;Underrepresented Populations;Underserved Population;Universities;Wisconsin;advocacy organizations;base;cancer care;cancer clinical trial;cancer health disparity;cancer prevention;cancer therapy;care delivery;community setting;design;disparity reduction;health assessment;health care availability;health plan;improved;member;neuro-oncology;organizational structure;outcome disparities;outreach program;participant enrollment;patient population;precision medicine;programs;screening;social media;socioeconomics;success;symptom management;web site Metro-Minnesota Community Oncology Research Consortium (MMCORC) Project NarrativeClinical trials are a vital part of the research process. Access to oncology clinical trials remains essential toaddress the many unmet needs in cancer prevention control screening and treatment. The bulk of cancercare takes place in community settings so allowing patients from community hospitals to participate innational clinical research allows access to a larger more diverse patient population to promote increasedpatient outcomes and reduce disparities. With this funding opportunity the Metro-Minnesota CommunityOncology Research Consortium (MMCORC) will continue to provide people in our community access to thenewest therapies available for cancer treatment symptom management and cancer prevention along with theopportunity to participate in trials that examine how the cancer care delivery process influences clinicaloutcomes and patient well-being. NCI 10675507 7/19/23 0:00 RFA-CA-18-016 5UG1CA189863-11 5 UG1 CA 189863 11 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 12049320 "ANDERSON, DANIEL M" "JI, YAN ; KING, DAVID " 3 Unavailable 29191355 H65GNDPBTRY7 29191355 H65GNDPBTRY7 US 44.85364 -93.225576 3566002 HEALTHPARTNERS INSTITUTE Bloomington MN Research Institutes 554401524 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 3913879 NCI 2492917 1420962 Project SummaryThe Metro-Minnesota Community Oncology Research Consortium (MMCORC) formerly known as the Metro-Minnesota Community Clinical Oncology Program (MMCCOP) has a long history of success as demonstratedby the ongoing commitment of is original members and the consortium's growth from 1979 to 2018. TodayMMCORC is an established community program that began through its National Cancer Institute (NCI)-fundedCommunity Hospital Cancer Program Award. This program improved cancer care delivery in the communityand was the cornerstone for the Community Clinical Oncology Program (CCOP) initiative. It received the initialNCI CCOP grant in 1983 and has been awarded subsequent CCOP grants in 3- to 5-year increments until the5-year NCI Community Oncology Research Program (NCORP) grant in 2014. In 2010 hospitals clinics andoncologists in the MN Community Group Outreach Program joined MMCCOP resulting in a metro-widecommunity cancer research program in Minneapolis-St. Paul. In 2014 MMCCOP received funding under thenew NCORP grant program. In 2016 MMCCOP was renamed MMCORC to represent the disbanding of theNCI CCOP grant program and show the broad scope of oncology research services available to thecommunity consistent with a consortium model. MMCORC represents 25 hospital and clinics with a commonapproach and established mechanisms for identifying enrolling and following participants on NCI- sponsoredtreatment cancer prevention and control symptom management and care delivery research protocols. Thestate health market remains extremely competitive and is constantly changing due to mergers and healthcarereform initiatives. Despite this environment MMCORC hospitals and staff continue to collaborate and supportthe added time and expense of offering clinical research trials to patients in the communities we serve.The consortium incorporates a substantial segment of the oncology community and has provided a basis forcommunication partnership and collaboration among practicing oncologists their hospital administrators andother health professionals for 35 years. Combined the consortium members see on average more than17170 new analytic cancer patients per year. In the consortium 165 MD investigators represent medicaloncology hematology and radiation and surgical oncology including thoracic surgery gynecologic oncologyradiology neuro-oncology obstetrics and gynecology palliative care and primary care with 57 mid-levelclinicians (nurse practitioners and physician assistants) considered associate investigators.MMCORC intends to continue to offer the community the most recent advances in cancer preventiontreatment symptom management and care delivery through continued affiliations with NCORP researchbases such as Alliance ECOG-ACRIN NRG Oncology SWOG via CTSU URCC and CCCWFU. Byimplementing proactive strategies to improve access and encourage participation from underrepresented andunderserved groups MMCORC is well positioned to achieve the goals of the NCORP set forth by the NCI. 3913879 +No NIH Category available ATAC-seq;Adolescent;Adult;Affect;African American;Age;Algorithms;American;Anthracycline;Area;Biochemical;Biological;Biological Assay;Blastoma;Body mass index;CRISPR/Cas technology;Cancer Patient;Candidate Disease Gene;Cardiac Myocytes;Cardiomyopathies;Cardiotoxicity;Chest;Child;Chromatin;Clinical;Clinical Data;Common Terminology Criteria for Adverse Events;Complication;Correlation Studies;Coupled;Cryopreservation;Data;Detection;Dose;Doxorubicin;Drug Prescriptions;Drug usage;Enhancers;Etiology;European;Exposure to;Gene Expression;Genes;Genetic;Genetic study;Genome;Genomics;Genotype;Heart Transplantation;Heart failure;Hematologic Neoplasms;High Prevalence;Human;In Vitro;Individual;Knowledge;Linkage Disequilibrium;Lymphoma;Malignant Childhood Neoplasm;Maps;Mediating;Metabolism;Methodology;Modality;Oncologist;Online Systems;Participant;Pathway interactions;Patients;Performance;Pharmaceutical Preparations;Phenotype;Physiological;Predisposition;Process;Quantitative Trait Loci;RARG gene;RNA Splicing;Radiation therapy;Regulatory Element;Research;Risk;Risk Factors;Risk Reduction;Role;Route;Saint Jude Children's Research Hospital;Sampling;Single Nucleotide Polymorphism;Solid;Survivors;Time;Translating;Validation;Variant;Work;alternative treatment;cancer diagnosis;cardioprotection;chemotherapy;childhood cancer survivor;clinical application;clinical risk;cohort;differential expression;epigenome;experience;genetic variant;genome editing;genome sequencing;genome wide association study;genomic predictors;genomic tools;human model;induced pluripotent stem cell derived cardiomyocytes;innovation;interest;leukemia;member;novel;pediatric patients;prevent;promoter;racial disparity;response;risk prediction;risk prediction model;sarcoma;sex;tool;transcriptome;transcriptome sequencing;user-friendly;whole genome Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children Project NarrativeWe have identified 2.5-fold higher prevalence of doxorubicin-induced cardiotoxicity (DIC) in African American(AA) than European American survivors yet the biological basis of this racial disparity in DIC is poorly understood.We will use human induced pluripotent stem cell-derived cardiomyocytes derived from AA survivors to discovernovel genetic variants for DIC and validate the mechanisms by which these genetic variants influence thispotentially fatal drug complication. This knowledge will provide clinicians with a validated genomic tool to predictif a patient will experience DIC and a route to discover genotype-specific cardioprotective drugs. NCI 10675503 7/28/23 0:00 RFA-CA-20-027 5R01CA261898-03 5 R01 CA 261898 3 "SHELBURNE, NONNIEKAYE F" 8/5/21 0:00 7/31/26 0:00 ZCA1-SRB-T(M1) 10489626 "BURRIDGE, PAUL W." "SAPKOTA, YADAV " 5 PHARMACOLOGY 5436803 KG76WYENL5K1 5436803 KG76WYENL5K1 US 42.050479 -87.680046 6144650 NORTHWESTERN UNIVERSITY AT CHICAGO CHICAGO IL SCHOOLS OF MEDICINE 606114579 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 678833 NCI 558320 120513 Project SummaryDoxorubicin is a member of the anthracycline group of chemotherapy drugs prescribed to approximately 60% ofpediatric cancer patients suffering with sarcomas blastomas leukemia and lymphoma. Although doxorubicin ishighly effective in these patients ~16% of pediatric patients suffer doxorubicin-induced cardiotoxicity (DIC) whichcan lead to heart failure requiring heart transplant. Our recent work has shown that DIC is 2.5x moreprevalent in African American (AA) survivors of childhood cancer. Despite more than 50 years of researchin this field there is still at present little potential for either predicting or preventing DIC. There is an obviousneed for novel and innovative approaches to overcome this hurdle. Candidate gene and genome-wideassociation studies predominantly in Europeans have identified >100 single nucleotide polymorphisms (SNPs)that are statistically correlated with DIC yet experimental validation has not been feasible due to the difficulty inisolating and culturing human cardiomyocytes in vitro. In our recent work we showed that patient-specific humaninduced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are efficient predictors of a patientslikelihood of developing DIC confirming for the first time that there is a genomic basis to DIC. Here wehypothesize that hiPSC-CMs can be utilized in three different modalities to study genetic variants associatedwith DIC in AA survivors: firstly to discover novel predictive SNPs; secondly to validate SNPs; and thirdly toexamine the modulated pathways and determine genotype-specific cardioprotective methodologies. In Aim 1we will generate hiPSC from 100 AA adult survivors of childhood cancer with diverse biological covariates whowere exposed to doxorubicin assess their response to doxorubicin in vitro to validate our previous findings andverify the power of this tool. In Aim 2 we will use these 100 patient-specific lines to identify drug responsedifferential expression splicing and chromatin accessibility quantitative trait loci (deQTL dsQTL and dcaQTL)assessing biological covariates such as doxorubicin dose age at cancer diagnosis attained age sex BMIradiotherapy (other than involving chest) and cancer diagnosis both individually and combined. We will thenvalidate these variants with genome editing and mechanistically examine pathways causative to DICsusceptibility concentrating on genes with known roles in cardiomyopathy cardioprotection and doxorubicinmetabolism. We will then use the discoveries above to discover/repurpose genome-informed cardioprotectivedrugs to prevent DIC in a genotype-specific manner. In Aim 3 we will build a risk prediction model for DIC amongAA survivors incorporating clinical risk factors and functionally assessed genetic variants above evaluate itsprediction performance validate it in independent AA survivors and implement it in a web-based and user-friendly tool for broader clinical and research use. In summary this work will deliver us the genetic rationale forwhy AA survivors experience DIC and provide 1 fully human validated SNP data for clinical application througha user-friendly tool and 2 novel cardioprotective pathways that can be targeted to protect against DIC. 678833 +No NIH Category available 4T1;Adenovirus Vector;Adjuvant Chemotherapy;Adoptive Cell Transfers;Aftercare;Algorithms;Breast Cancer Model;Breast Cancer Patient;CSF1 gene;CSF1R gene;Cancer Center;Clinical;Clinical Research;Communicable Diseases;DNA Vaccines;Data;Disease;Embryo;Enrollment;Epitopes;Evaluation;Generations;HIV vaccine;Histocompatibility Antigens Class II;Human;Immune response;Immunotherapy;Inflammatory;Lymphoid;Macrophage;Malignant Neoplasms;Modeling;Modernization;Mus;Myelogenous;Myeloid Cells;Neoadjuvant Therapy;Outcome;Patients;Peptide Vaccines;Phase I Clinical Trials;Phenotype;Population;Pre-Clinical Model;Property;Publications;Randomized;Recombinants;Reporting;Series;Source;T cell response;Testing;Tissues;Tumor Immunity;Tumor Promotion;Tumor-associated macrophages;Vaccinated;Vaccination;Vaccine Therapy;Vaccines;Validation;anti-PD-L1;antigen-specific T cells;arm;cancer clinical trial;cancer immunotherapy;design;enzyme linked immunospot assay;high dimensionality;immune checkpoint blockade;improved;innovation;innovative technologies;malignant breast neoplasm;manufacture;monocyte;mouse model;neoantigen vaccination;neoantigen vaccine;neoantigens;next generation sequencing;peripheral blood;phase I trial;plasmid DNA;preclinical study;prediction algorithm;recombinant adenovirus;recruit;response;restraint;single-cell RNA sequencing;trial comparing;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;vaccine platform;vaccine strategy;vaccine trial;vector vaccine Targeting Neoantigens in Triple Negative Breast Cancer PROJECT NARRATIVEWe propose both clinical and preclinical studies on neoantigen DNA vaccines +/- anti-PD-L1. We will conduct arandomized phase 1 clinical trial of neoantigen DNA vaccines +/- anti-PD-L1 (durvalumab) in patients withpersistent triple negative breast cancer following neoadjuvant chemotherapy. Preclinical studies in breastcancer mouse models will focus on recombinant adenovirus-plasmid DNA neoantigen vaccine prime-booststrategies or targeting of macrophages in the tumor microenvironment. Combined these studies will allowfunctional validation of our epitope prediction algorithms and inform the design of second generationneoantigen vaccine strategies. NCI 10675496 7/18/23 0:00 PAR-18-560 5R01CA240983-05 5 R01 CA 240983 5 "SONG, MIN-KYUNG H" 8/1/19 0:00 7/31/24 0:00 Clinical Oncology Study Section[CONC] 1938279 "GILLANDERS, WILLIAM E." "SCHREIBER, ROBERT DAVID" 1 SURGERY 68552207 L6NFUM28LQM5 68552207 L6NFUM28LQM5 US 38.664368 -90.323797 9083901 WASHINGTON UNIVERSITY SAINT LOUIS MO SCHOOLS OF MEDICINE 631304862 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 625110 NCI 396895 228215 "PROJECT SUMMARY/ABSTRACTNeoantigens have been identified by us and others as important targets of immunotherapy in the context ofcheckpoint blockade therapy adoptive cell therapy and vaccine therapy. We have recently initiated two phase1 clinical trials of first generation neoantigen vaccines in breast cancer based on the neoantigen DNA vaccineand synthetic long peptide vaccine platforms. In preclinical models we have optimized sequencing and epitopeprediction algorithms for the identification and prioritization of neoantigens and we have leveraged innovativetechnologies (CyTOF single cell RNA sequencing) to comprehensively interrogate the immune response toneoantigen vaccination and other cancer immunotherapies. We propose to build on these observations byperforming a randomized phase 1 trial of neoantigen DNA vaccine alone vs. neoantigen DNA vaccine plusanti-PD-L1 in patients with persistent triple negative breast cancer (TNBC) following neoadjuvantchemotherapy. The overall hypothesis is that enhancing neoantigen-specific T cell responses can improveclinical outcomes in TNBC. This hypothesis will be tested by completing the following aims:Specific Aim 1. Test the hypothesis that neoantigen vaccines +/- anti-PD-L1 can induce and/or enhanceneoantigen-specific T cell responses. We have recently initiated a randomized phase 1 clinical trial ofneoantigen DNA vaccines +/- anti-PD-L1 in TNBC patients with persistent disease following neoadjuvantchemotherapy. Next-generation sequencing and epitope prediction algorithms will be used to prioritizeneoantigens. Neoantigen DNA vaccines will be designed and manufactured in the GMP facility at SCC.Specific Aim 2: Test the hypothesis that targeting tumor-associated macrophages (TAM) can enhanceneoantigen-specific T cell responses in TNBC. Both embryonically-derived tissue-resident TAM andinflammatory monocyte-derived TAM restrain antitumor immunity in TNBC. We propose to combineCSF1/CSF1R blockade with CCR2 inhibition to simultaneously target both sources of TAM in the context ofneoantigen vaccination in two mouse breast cancer models. The tumor microenvironment will be characterizedby CyTOF and single cell RNA sequencing.Specific Aim 3: Test the hypothesis that a neoantigen simian Ad vector vaccine ""prime"" followed by aneoantigen DNA vaccine ""boost"" can enhance the response to breast cancer neoantigens. We proposea ""prime/boost"" strategy consisting of a simian recombinant Ad vaccine ""prime"" followed by a plasmid DNAvaccine ""boost."" This ""prime/boost"" neoantigen vaccine strategy represents a state-of-the-art vaccine strategyto more effectively induce antitumor immunity and leverages expertise at WUSM within the fields ofneoantigen DNA vaccines and recombinant Ad vector vaccines. Photocleavable tetramer analysis CyTOFand single cell RNA sequencing will be performed on neoantigen-specific T cells in the peripheral blood andthe tumor microenvironment to rigorously evaluate the neoantigen-specific T cell response to vaccination." 625110 +No NIH Category available Address;Antineoplastic Agents;Appearance;Autophagocytosis;BIRC5 gene;BRAF gene;Binding;Cancer Etiology;Cancer Model;Carbon;Cell Line;Cells;Cessation of life;Clinical;Colorectal;Colorectal Cancer;Combined Modality Therapy;Cytostatics;DNA Binding Domain;Dependence;Drug resistance;Exhibits;Family;Fostering;Foundations;Gene Expression;Genes;Genetic;Genetic Transcription;Glycolysis;Goals;Growth;KRAS2 gene;Lung;MAP Kinase Gene;MAP2K1 gene;MEKs;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Maps;Mediating;Metabolism;Mitochondria;Mitogen-Activated Protein Kinases;Modeling;Mutation;Nutrient;Oncogenes;Oncogenic;Oncoproteins;Overlapping Genes;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patients;Process;Publishing;Relapse;Reporting;Research;Research Personnel;Resistance;Role;Signal Transduction;Testing;Therapeutic;Transcription Coactivator;Transcriptional Regulation;Tumor Suppressor Proteins;addiction;cancer cell;cancer therapy;career development;clinical application;clinical candidate;cytotoxic;drug development;drug discovery;genetic signature;inhibitor;mutant;overexpression;pancreatic ductal adenocarcinoma cell;pharmacologic;research clinical testing;resistance mechanism;targeted treatment;therapeutic target;transcription factor;treatment strategy;tumor;tumor metabolism Mechanisms of YAP1-driven resistance to KRAS-G12C inhibition Project NarrativeKRAS mutations are found in the top three causes of cancer deaths: lung colorectal and pancreatic cancer.Following FDA approval of the first anti-KRAS therapy identifying and targeting mechanisms responsible for theonset of resistance will be essential to enhance the long-term efficacy of these inhibitors. Accordingly my studiesaddress the mechanisms by which the YAP1 oncoprotein drives resistance to anti-KRAS therapies to developcombination treatment strategies to block resistance to KRAS-targeted therapies. NCI 10675482 9/8/23 0:00 PA-21-051 5F31CA275260-02 5 F31 CA 275260 2 "ODEH, HANA M" 8/1/22 0:00 9/29/24 0:00 Special Emphasis Panel[ZRG1-F09B-Z(20)L] 16052067 "EDWARDS, ALEXANDER COLE" Not Applicable 4 PHYSIOLOGY 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF MEDICINE 275995023 UNITED STATES N 9/30/23 0:00 9/29/24 0:00 398 "Training, Individual" 2023 38784 NCI 38784 0 Mutationally activated KRAS comprises the major oncogenic driver in the top three causes of cancer deaths inthe US: lung (LAC) colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC). In 2021 a milestone inanti-KRAS drug discovery was achieved with the first clinically effective direct inhibitor of KRAS approved forthe treatment of KRASG12C mutant lung cancer. However as with essentially all targeted anti-cancer therapiesboth de novo resistance and treatment-associated acquired resistance have recently been reported. Asanticipated mutations that reactivate RAS and RAS effector signaling through the RAF-MEK-ERK mitogen-activated protein kinase signaling network (e.g. activating mutations in BRAF MEK1) were identified in LAC andCRC patients treated with KRASG12C selective inhibitors (G12Ci) and combinations that concurrently target theseresistance mechanisms are now under clinical evaluation. However no genetic mechanisms were identified inup to 50% of patients who relapsed on G12Ci treatment. To address possible ERK MAPK-independentresistance mechanisms my studies have identified and validated the downstream target of the Hippo tumorsuppressor pathway the YAP1 transcriptional coactivator and oncoprotein as a driver of resistance to G12Ci-mediated growth suppression. Consistent with previous studies that established the ability of YAP1 activation toovercome addiction to mutant KRAS my preliminary analyses demonstrated that ectopic overexpression of wild-type or activated YAP1 drives resistance to G12Ci treatment in KRASG12C mutant LAC CRC and PDAC celllines. This finding establishes the rationale and foundation for my research goal: to determine the mechanisticbasis for YAP1-mediated resistance to G12Ci treatment. I hypothesize that identification of YAP1-drivenresistance mechanisms will establish combinations of pharmacologic inhibitors that can enhance thelong-term anti-tumor efficacy of G12Ci and other KRAS-targeted therapies. I have developed three aims toaddress the mechanisms by which YAP1 drives resistance. First I will determine the role of the TEADtranscription factors in YAP1-driven KRAS-independence. These studies may validate the clinical application ofTEAD inhibitors for the treatment of KRAS-mutant PDAC and other cancers. Second I will identify YAP1-regulated genes that sustain KRAS-independent growth in support of a model where YAP1 overcomes KRAS-addiction by restoring expression of key KRAS-regulated genes. Finally I will identify KRAS-regulated metabolicprocesses that are both sustained by YAP1 activation and important for PDAC growth. Taken together mystudies may validate an important driver of resistance to all KRAS-targeted therapies and define therapeuticapproaches to overcome YAP1-driven drug resistance. These studies will require my application of a diversespectrum of experimental approaches advance my understanding of key steps in anti-cancer drug developmentand foster my career development as an independent cancer researcher. 38784 +No NIH Category available Advanced Malignant Neoplasm;Affect;Aftercare;Architecture;Autopsy;Bioinformatics;Biological Assay;Biological Process;Biopsy;Biopsy Specimen;Bone Tissue;Brain;Cancer Patient;Cessation of life;Chemoresistance;Cisplatin;Clinic;Clinical;Clonal Evolution;Clonality;Collection;Complement;Comprehensive Cancer Center;Consent;DNA Sequence Alteration;DNA analysis;Detection;Development;Development Plans;Diagnosis;Disease Resistance;Disease remission;Doctor of Philosophy;Educational workshop;Etoposide;Evaluation;Extensive Stage;Feedback;Genetic;Genetic Fingerprintings;Genomics;Goals;Heterogeneity;In complete remission;Institutional Review Boards;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Medical Oncology;Mentors;Metastatic Neoplasm to the Liver;Methods;Monitor;Mutation;Neoplasm Metastasis;Ohio;Organ;Pathway interactions;Patients;Pattern;Physicians;Plasma;Platinum;Productivity;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Recurrent tumor;Refractory;Refractory Disease;Research;Resistance;Resistance development;Sampling;Scientist;Smoker;Solid;Solid Neoplasm;Specimen;Structure;Therapeutic;Therapeutic Intervention;Time;Tissues;Training;Tumor Tissue;Universities;Variant;cancer recurrence;cancer therapy;career;career development;chemotherapy;cohort;exome sequencing;genetic analysis;genomic data;genomic profiles;improved;individual patient;innovation;interdisciplinary approach;liquid biopsy;lymph nodes;meetings;molecular diagnostics;new therapeutic target;next generation sequencing;novel;novel therapeutics;physician-scientist training program;programs;prospective;response;small cell lung carcinoma;soft tissue;symposium;targeted treatment;therapy development;therapy resistant;treatment response;tumor;tumor DNA;tumor heterogeneity Genomic characterization of tumor heterogeneity in recurrent small cell lung cancer through research autopsy PROJECT NARRATIVEFor the last several decades extensive stage small cell lung cancer (SCLC) has remained an incurable anddeadly cancer. Recurrent SCLC or cancer that develops after an initial period of remission is highly resistant tomultiple different therapies. An understanding of how recurrent SCLC develops resistance through novelsequencing approaches and an innovative Research Autopsy Program will help identify targets for therapeuticintervention to improve survival. NCI 10675465 9/6/23 0:00 PA-18-373 5K08CA241309-06 5 K08 CA 241309 6 "BIAN, YANSONG" 8/1/19 0:00 7/31/24 0:00 Career Development Study Section (J)[NCI-J] 15635861 "CHEN, HUI-ZI " Not Applicable 4 INTERNAL MEDICINE/MEDICINE 937639060 E8VWJXMMUQ67 937639060 E8VWJXMMUQ67 US 43.04575 -88.020374 46001 MEDICAL COLLEGE OF WISCONSIN MILWAUKEE WI SCHOOLS OF MEDICINE 532263548 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 248735 NCI 230310 18425 PROJECT SUMMARYHui-Zi Chen MD PhD is a Medical Oncology fellow in her final year of the Physician Scientist Training Program(80% research 20% clinic) at The Ohio State University Comprehensive Cancer Center. Dr. Chen's career goalis to become an independent and productive physician scientist whose research will focus on identifyingmechanisms of therapeutic resistance in advanced solid tumor malignancies through combining rapid researchautopsy and genomics. As a vehicle for career development and further training towards independence Dr.Chen's K08 proposal focuses on the application of genomics for rapid research autopsy of patients with recurrentsmall cell lung cancer (SCLC). To assist her research she assembled a mentoring committee consisting ofSameek Roychowdhury MD PhD (primary mentor expertise in genomics and molecular diagnostics); DavidCarbone MD PhD (co-mentor expertise in lung cancer and therapeutics); and Lang Li PhD (co-mentorexpertise in bioinformatics). She has further devised a career development plan with clear objectives of (1)gaining proficiency in leadership and project management (2) developing expertise in the analysis andinterpretation of genomic data and (3) obtaining continuous evaluation and feedback. These objectives will beachieved through regular and structured meetings with mentors formal didactics and attendance of workshopsand regional/national conferences. Recurrent SCLC is a relentless and aggressive cancer affecting patientsglobally that responds to few if any therapies despite an initial response rate of 60-70% to platinum-basedchemotherapy. The study of recurrent SCLC has been limited by scarce tumor samples at time of recurrencedue to the rapid clinical demise of patients. To solve this unmet need Dr. Chen has launched a new researchautopsy study for advanced cancer patients at OSU one of just ten programs nationally. The main objective ofDr. Chen's K08 proposal is to characterize genomic alterations underlying chemoresistance in SCLC. Througha multi-disciplinary approach combining research autopsy genomics and bioinformatics she will completewhole exome sequencing (WES) of multiple metastatic tumor samples and plasma circulating tumor DNA of fortySCLC patients with chemorefractory disease. Thus far Dr. Chen has demonstrated the feasibility of her projectas she has already supervised the autopsy exome sequencing and bioinformatics analysis of five patients withrecurrent SCLC. These autopsies enable the assessment of clonality in metastatic tumors and havedemonstrated that SCLC is genetically heterogeneous with early clonal diversification. Finally Dr. Chen showedhigh level of concordance between mutations in ctDNA and multiple metastatic tumors showcasing the utility ofctDNA in SCLC patients. Dr. Chen hopes to expand on these findings by analyzing a large cohort (n=40) ofSCLC patients. It is her long-term goal as an independent physician scientist to identify key genomic alterationsmediating chemoresistance devise `liquid biopsy' assays to detect their emergence in SCLC patients anddevelop therapies targeting these alterations. 248735 +No NIH Category available Accounting;Acetyl Coenzyme A;Acetylcysteine;Acute;Affect;Albumins;Animals;Antioxidants;Apoptosis;Appearance;Blood Urea Nitrogen;Branched-Chain Amino Acids;Catabolism;Cell Line;Cell Proliferation;Cell physiology;Cells;Citric Acid Cycle;Clear Cell;Clear cell renal cell carcinoma;Complex;Creatinine;Cytoplasm;Data;Dietary intake;Disease;Enzymes;Epithelial Cells;Essential Amino Acids;Etiology;Experimental Models;Fatty Acids;Genes;Genetic;Genetically Engineered Mouse;Glycogen;Histologic;Histology;Human;Impairment;Implant;In Vitro;Incidence;Isoleucine;Isotopes;Keto Acids;Kidney;Leucine;Link;Lipid Peroxidation;Lipids;Malignant Epithelial Cell;Malignant Neoplasms;Measurement;Measures;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mitochondria;Molecular Analysis;Monitor;Multienzyme Complexes;Mus;NIH-III Mouse;North America;Nude Mice;Obesity;Oxidative Phosphorylation;Oxidoreductase;Oxygen Consumption;Pathway interactions;Patients;Phosphotransferases;Predisposition;Production;Prognosis;Proliferating;Reaction;Reactive Oxygen Species;Renal carcinoma;Renal function;Resected;Respiration;Risk Factors;Role;Serum;Survival Rate;Tamoxifen;Testing;Tissues;Tumor Promotion;Tumor Volume;Valine;Work;Xenograft procedure;amino acid metabolism;branched-chain-amino-acid transaminase;cancer type;cell growth;combat;fatty acid oxidation;gain of function;in vivo;knock-down;loss of function;mouse model;new therapeutic target;novel;novel therapeutics;peroxidation;pharmacologic;protein complex;renal epithelium;small hairpin RNA;succinyl-coenzyme A;treatment strategy;tumor;tumor growth;tumorigenesis Investigating the Role of Reduced Branched-Chain Amino Acid Catabolism in Clear Cell Renal Cell Carcinoma PROJECT NARRATIVEClear cell renal cell carcinoma (ccRCC) has a poor prognosis especially once it becomes metastatic and is inurgent need of novel treatment strategies. Branched-chain amino acid (BCAA) catabolism is reduced in ccRCCand decreased expression of BCAA enzymes correlates with poorer overall patient survival. We propose herethat reduced BCAA catabolism promotes ccRCC cell growth and tumorigenesis and will test this hypothesiswith a range of in vitro experiments and mouse models to understand in depth how modulation of BCAAmetabolism regulates ccRCC tumorigenesis. NCI 10675456 6/30/23 0:00 PA-21-049 5F30CA271654-02 5 F30 CA 271654 2 "DAMICO, MARK W" 7/1/22 0:00 6/30/25 0:00 Special Emphasis Panel[ZRG1-F09A-R(20)L] 78225056 "COFFEY, NATHAN JACKSON" Not Applicable 3 DENTISTRY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF DENTISTRY/ORAL HYGN 191046205 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 398 "Training, Individual" 2023 35133 NCI 35133 0 PROJECT SUMMARY North America has the highest incidence of renal cancer in the world with the most common subtypebeing clear cell renal cell carcinoma (ccRCC). Alarmingly the incidence of ccRCC is on the rise in the U.S. andglobally. The overall five-year survival rate for ccRCC is only 10-12% once it becomes metastaticdemonstrating the need for new therapies. Metabolic dysfunction is common in ccRCC based on histologic andmolecular analysis. New therapies to treat ccRCC could target its dysregulated metabolic pathways. Theetiology of ccRCC is complex but a major risk factor is obesity. High levels of branched-chain amino acids(BCAAs) are present in the serum of patients with ccRCC and obesity suggesting a potential mechanistic link.BCAAs (leucine isoleucine and valine) are essential amino acids whose concentrations are regulated bydietary intake and catabolism. BCAA metabolism promotes tumor growth in many different types of cancer butthe role of BCAAs in ccRCC is unknown. BCAA catabolism occurs primarily via the first two enzymes BCAAtransaminase (BCAT) and branched chain ketoacid dehydrogenase (BCKDH) respectively. BCKDH is anenzyme complex that catalyzes the rate-limiting reaction. The products of BCAA catabolism are then oxidizedwithin the mitochondria to produce succinyl-CoA and acetyl-CoA which can be used by the TCA cycle foranaplerosis and mitochondrial respiration. My preliminary data demonstrate that BCAA catabolic enzyme BCAT2 and BCKDH subunits arefrequently reduced in human ccRCC tumors compared to normal adjacent kidney tissue (NAT). This decreasedexpression occurs as early as stage 1 and is associated with reduced overall survival. Additionally BCAAs andtheir catabolic metabolites are decreased in ccRCC. These results suggest that BCAA catabolism is reducedearly in ccRCC and contributes to ccRCC aggressiveness. ccRCC may reduce BCAA metabolism to decreasemitochondrial respiration and ROS because ccRCC is susceptible to ROS due to the large amount ofintracellular lipids that can undergo peroxidation. ccRCC decreases mitochondrial respiration and ROS bydownregulating genes involved in fatty acid oxidation and oxidative phosphorylation. I hypothesize thatreduced BCAA metabolism promotes ccRCC cell growth and tumorigenesis and does so bydecreasing mitochondrial respiration and the production of ROS. Aim 1 will determine how reducedBCAA catabolism promotes ccRCC cell growth in vitro. I will use genetic and pharmacologic approaches toassess how gain or loss of BCAA metabolism affects proliferation of ccRCC and immortalized renal epithelialcell lines. Aim 2 will identify how reduced BCAA catabolism contributes to ccRCC tumorigenesis in vivo. I willuse novel genetic mouse models to determine the role of BCAA catabolic flux on renal epithelial cell functionand ccRCC tumorigenesis. Together these approaches will identify the mechanisms by which BCAAcatabolism regulates ccRCC tumorigenesis and identify novel therapeutic targets to combat this disease. 35133 +No NIH Category available Acculturation;Address;Adopted;Aftercare;American;Asian;Asian Americans;Attention;Biological Markers;Breast Cancer survivor;California;Cancer Survivor;Chinese;Chinese American;Chinese population;Color;Communities;Diagnosis;Emotional;Emotions;Equipment;Ethnic Population;Evidence based program;Fright;Goals;Health;Health Benefit;Health Disparities Research;Health Professional;Health Promotion;Human Resources;Hydrocortisone;Immigrant;Incidence;Informal Social Control;Intervention;Language;Loneliness;Mainstreaming;Malignant Neoplasms;Medical Records;Mental Health;Mental Health Services;Methods;Minority;Morbidity - disease rate;New York;Not Hispanic or Latino;Outcome;Participant;Patient Self-Report;Patients;Population;Posttraumatic growth;Qualitative Methods;Quality of life;Randomized;Randomized Controlled Trials;Recovery;Recovery Support;Reduce health disparities;Research;Resource-limited setting;Salivary;Stress;Stressful Event;Subgroup;Testing;Texas;Thinking;Underserved Population;United States;Writing;alpha-amylase;breast cancer diagnosis;brief intervention;cancer care;cancer health disparity;cancer therapy;cognitive process;community organizations;cultural competence;cultural values;design;effective intervention;experience;expressive writing;follow-up;healing;health disparity;improved;innovation;internalized stigma;malignant breast neoplasm;medical appointment;minority communities;people of color;perceived stress;physical conditioning;primary outcome;psychologic;psychosocial;public health relevance;recruit;secondary outcome;social stigma;stress management;stress reduction;theories;traumatic event;underserved community Writing to Heal: A Culturally Based Brief Expressive Writing Intervention for Chinese Immigrant Breast Cancer Survivors Project Narrative/Public Health Relevance StatementPsychosocial interventions have been shown to be effective for the mainstream population of breast cancersurvivors but few psychosocial interventions have been successfully designed for ethnic groups of color. Thisproposed study is a randomized controlled trial to assess the impact of a culturally based brief writingintervention among Chinese immigrant breast cancer survivors an underserved and understudied population.The study will help to reduce or eliminate the unnecessary emotional and physical health disparities in cancercare among Asian American breast cancer survivors and potentially other ethnic groups of color as well. NCI 10675433 6/30/23 0:00 PAR-18-559 5R01CA248213-03 5 R01 CA 248213 3 "CHOU, WEN-YING" 7/1/21 0:00 6/30/26 0:00 "Social Psychology, Personality and Interpersonal Processes Study Section[SPIP]" 8714872 "LU, QIAN " Not Applicable 9 MISCELLANEOUS 800772139 S3GMKS8ELA16 800772139 S3GMKS8ELA16 US 29.706319 -95.397195 578407 UNIVERSITY OF TX MD ANDERSON CAN CTR HOUSTON TX OVERALL MEDICAL 770304009 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 393 Non-SBIR/STTR 2023 590040 NCI 379709 210331 Project Summary/AbstractThe unavailability of culturally competent mental health care for Chinese immigrant breast cancer survivorsand their unmet psychological needs characterize the health disparity experienced by Chinese immigrantbreast cancer survivors. Breast cancer is the cancer with the highest incidence rate among the Chinesepopulation and Chinese immigrant breast cancer survivors have lower quality of life compared to their non-Hispanic white counterpart. However interventions to improve quality of life are lacking among thisimmigrant population. Expressive writing intervention uses writing prompts to promote health by facilitatingemotional and cognitive processes. Guided by Western and Eastern theories and preliminary studiesshowing the benefits of expressive writing among Chinese immigrants this study proposes to test the healtheffects of an innovative and brief writing intervention among Chinese immigrant breast cancer survivorsusing a randomized controlled trial and mixed methods design. Chinese immigrant breast cancer survivors(N=240) will be randomly assigned either to a control condition to write about neutral topics or to one of twointervention conditions self-regulation and self-cultivation which both aim to promote adaptive cognitiveprocesses but differ in how they achieve this goal. The self-regulation intervention incorporates a traditionalWestern expressive writing paradigm whereas the self-cultivation intervention incorporates Asian culturalvalues. Participants in all three conditions will be asked to write in Chinese during three weekly 30-minutesessions. The primary outcome will be QOL and the secondary outcomes will be perceived stress stressbiomarkers and medical appointments for cancer-related morbidities. Self-reported health outcomes (QOLand perceived stress) will be assessed at baseline and 6- and 12-month follow-ups. Stress biomarkers(salivary cortisol and alpha-amylase) will be assessed at baseline and 6-week follow-up and perceivedstress will also be self-reported at the 6-week follow-up. Medical appointments up to the 12-month follow-upwill be self-recorded and verified by medical record. We hypothesize that the two intervention conditions willimprove quality of life reduce perceived stress and medical appointments for cancer-related morbidities andnormalize stress biomarkers. Few studies have tested evidence-based programs in communities of colorand even fewer have tested culturally based interventions that adopted the cultural values of theunderserved communities. We expect that the proposed study guided by theory practices and methodsand tailored for an underserved population will inspire new directions in research to address thesescientific and practical needs in health disparities research. 590040 +No NIH Category available Address;Adolescent;Affect;Attitude;Awareness;Behavioral;Behavioral Research;Behavioral Sciences;Belief;Black Populations;Black race;Cancer Prevention Intervention;Catchment Area;Clinic;Communication;Communities;Complement;Complex;Data;Development Plans;Disparity;Dose;Education;Eligibility Determination;Enrollment;Environment;Equity;Ethnic Population;Family;Focus Groups;Funding;Funding Opportunities;Goals;Health Services Research;High Prevalence;Hispanic Populations;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Individual;Intervention;Intervention Trial;Interview;Knowledge;Link;Literature;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Maps;Medical;Methods;Motivation;New Jersey;Parents;Patients;Process;Provider;Randomized;Randomized Controlled Trials;Recommendation;Research;Research Infrastructure;Research Personnel;Resources;Risk;Self Efficacy;Shapes;Source;Southern Africa;Surveys;System;Testing;Text Messaging;Training;Transition Career Development Award (K22);Trust;United States;Vaccinated;Vaccination;Vaccines;Woman;Work;aged;arm;behavior change;black women;cancer health disparity;cancer type;career;career development;community engaged research;design;effective intervention;experience;follow-up;health equity;high risk;implementation barriers;implementation intervention;improved;informant;insight;intervention mapping;multi-site trial;perceived discrimination;pilot test;post intervention;prevent;programs;prototype;racial discrimination;racial disparity;racial population;randomized trial;recruit;safety net;screening;skills;social;sociocultural determinant;systematic review;tailored messaging;tailored text messaging;text messaging intervention;timeline;underserved community;vaccine acceptance;vaccine hesitancy;vaccine safety Addressing HPV vaccination disparities through tailored messaging for hesitant families PROJECT NARRATIVEHPV vaccination among adolescents is suboptimal and parental delays and refusals are common. Addressingthe unique vaccine hesitancy concerns and information needs of underserved families is critical to increasevaccination. This study will engage multiple stakeholders to develop and pilot a tailored intervention to addressHPV vaccine hesitancy among Black families to increase vaccine confidence vaccination and ultimately helpreduce HPV-related cancer disparities. NCI 10675432 9/7/23 0:00 PAR-18-466 5K22CA258675-02 5 K22 CA 258675 2 "JAKOWLEW, SONIA B" 8/2/22 0:00 7/31/25 0:00 ZCA1-RTRB-R(O2) 11879034 "KOHLER, RACQUEL ELIZABETH" Not Applicable 10 PUBLIC HEALTH & PREV MEDICINE 90299830 YVVTQD8CJC79 90299830 YVVTQD8CJC79 US 40.520984 -74.473247 10034168 RUTGERS BIOMEDICAL AND HEALTH SCIENCES Newark NJ SCHOOLS OF PUBLIC HEALTH 71073001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 219899 NCI 203610 16289 PROJECT SUMMARYHuman papillomavirus (HPV) causes over 34800 cancers in the United States each year that disproportionatelyaffect Black women. The HPV vaccine is highly effective but less than half of adolescents aged 13-15 yearshave received recommended doses with Blacks having the greatest disparity in completion. HPV vaccinehesitancy is associated with under-vaccination and refusal. An estimated 23% of parents with adolescents arehesitant about the HPV vaccine but parents concerns vary due to a myriad of individual interpersonal andsociocultural factors. Effective strategies to overcome parents concerns are needed especially among Blackfamilies who have higher prevalence of general vaccine hesitancy and medical mistrust due to racial inequities.The purpose of this NCI Transition Career Development Award (K22) is to support me through specific trainingand research experiences as I become an independent investigator specializing in multilevel cancer preventioninterventions to reduce cervical cancer disparities. Building on my strong health services research and behavioralscience background in HPV screening I will develop expertise in HPV vaccination communication community-engaged intervention planning and intervention trials. The objectives of this rigorous mixed methods proposalare to: (1) use a stakeholder-engaged approach to develop and refine an interactive tailored text messagingintervention to address Black parents HPV vaccine hesitancy determinants and vaccination barriers; and (2)conduct a two-arm pilot RCT to determine feasibility acceptability appropriateness and preliminary efficacy ofthe tailored messages compared to untailored messages. Following a providers initial recommendation theintervention will allow parents of young adolescents to process HPV vaccination information on their preferredtimeline answer lingering questions and concerns provide links to additional information from trusted sourcesand support connections to local resources to help overcome barriers. By accomplishing these aims I willaddress current gaps in strategies to increase vaccine confidence and motivation among high-risk Black families.Rutgers Cancer Institute with its well-funded behavioral research program robust research infrastructure anddeep community connections is an exceptional environment to conduct high-impact community-engaged cancerdisparities research. As a logical next step in my career development this K22 will give me the skills required todesign implement and evaluate multilevel interventions to achieve HPV health equity. Findings and preliminaryefficacy estimates will inform an R01 application of a multi-site trial to test a multiple component interventionaddressing the complex context-specific determinants of HPV vaccine hesitancy to motivate vaccination andchange behaviors. Ultimately this K22 proposal will facilitate my long-term goal to build an independent researchprogram investigating community-driven solutions to reduce HPV disparities and advance the elimination ofcervical cancer. 219899 +No NIH Category available Acetates;Androgen Antagonists;Androgen Receptor;Antiandrogen Therapy;Antibodies;Automobile Driving;Binding Sites;Biochemical;Biological Assay;Bone marrow biopsy;Calorimetry;Cancer Etiology;Cancer Patient;Cell Culture Techniques;Cell Survival;Cells;Cessation of life;Chronic;Co-Immunoprecipitations;Complex;Data;Deposition;Diagnosis;Disease;Drug Sensitization;Drug resistance;Evolution;Flow Cytometry;Genes;Gleason Grade for Prostate Cancer;Glucocorticoid Receptor;Goals;Human;Immunofluorescence Immunologic;Impairment;In Vitro;Label;Length;Ligation;Longevity;Lysine;Malignant neoplasm of prostate;Mass Spectrum Analysis;Mediating;Molecular Chaperones;Neoadjuvant Therapy;Oncogenic;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Play;Population;Precipitation;Primary Neoplasm;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Radiation;Radical Prostatectomy;Recurrent Malignant Neoplasm;Reporting;Resistance;Resistance development;Role;Specimen;Stains;System;Technology;Testing;Therapeutic;Time;Tissue Microarray;Titrations;Treatment outcome;Ubiquitin;Ubiquitin-mediated Proteolysis Pathway;Ubiquitination;United States;Variant;abiraterone;advanced prostate cancer;androgen deprivation therapy;cancer cell;cancer drug resistance;cancer recurrence;castration resistant prostate cancer;clinically relevant;effective therapy;effectiveness testing;efficacy testing;enzalutamide;improved;in vivo;inhibitor;insight;men;multicatalytic endopeptidase complex;next generation;novel;novel strategies;patient derived xenograft model;programs;prostate cancer cell;prostate cancer progression;protein aggregation;proteostasis;receptor expression;resistance mechanism;small molecule;small molecule inhibitor;success;targeted treatment;therapy resistant;tumor;tumor growth;tumor progression;tumorigenesis;ubiquitin-protein ligase Dissecting the Role of Proteostasis in Anti-Androgen Resistant Prostate Cancer PROJECT NARRATIVEImbalanced protein homeostasis (proteostasis) disrupts protein clearance and increases abnormaldeposition of protein aggregates which facilitates cancer cell survival and progression. Ubiquitin mediatedproteolysis pathway and proteasome activity are suppressed in next generation anti-androgen resistantprostate cancer cells which results in stabilized androgen receptor variant protein in these resistant cellsthrough Hsp70/Stub1 machinery. This proposal will provide new insights into the role of chaperone-ubiquitin-proteasome alteration in advanced prostate cancer and devise the strategies to overcome thetherapeutic resistance. NCI 10675431 9/14/23 0:00 PA-20-185 5R37CA249108-03 5 R37 CA 249108 3 "KAI, MIHOKO" 7/1/21 0:00 6/30/26 0:00 Molecular Oncogenesis Study Section[MONC] 12621986 "LIU, CHENGFEI " Not Applicable 4 UROLOGY 47120084 TX2DAGQPENZ5 47120084 TX2DAGQPENZ5 US 38.543366 -121.72946 577503 UNIVERSITY OF CALIFORNIA AT DAVIS DAVIS CA SCHOOLS OF MEDICINE 956186153 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 351955 NCI 224175 127780 PROJECT ABSTRACTIn the United States prostate cancer (PCa) is predicted to be the second leading cause of cancer relateddeath in men in the United States in 2020. After initial diagnosis of PCa radical prostatectomy radiation andandrogen deprivation therapy (ADT) are used to treat the primary tumors. When cancer recurs castrate-resistant prostate cancer (CRPC) is treated by anti-androgen drugs such as enzalutamide (XTANDI)abiraterone acetate (ZYTIGA) or apalutamide (ERLEADA). Although these drugs are highly effective initiallypatients quickly develop resistance through mechanisms that are not completely understood. Therefore thereis an urgent need to identify resistant mechanisms to improve the treatment outcome of CRPC. Proteinhomeostasis (proteostasis) deficiency and oncogenic activation plays important roles during tumorigenesis;however proteostasis modulation involved in anti-androgen resistant PCa is still rudimentarily understood. Wehave reported that ubiquitin mediated proteolysis pathway and proteasome activity are suppressed inenzalutamide and abiraterone resistant PCa cells. As a result androgen receptor (AR) and its variant form AR-V7 protein are stabilized and accumulated in these resistant cells through chaperone-ubiquitin-proteasome-system alteration. The chaperone (Hsp70)/E3 ubiquitin ligase (Stub1) machinery regulates full length AR andAR variant proteostasis. Hsp70 inhibition by small molecules promotes Hsp70 AR-V7 and Stub1 proximitywhich significantly disrupts AR/AR-V7 gene programs and suppresses prostate tumor growth. This proposalinitiates a new paradigm to explore the underlying mechanisms driving next generation anti-androgenresistance in CRPC. The ultimate goal of this program is to dissect the roles of chaperone-ubiquitin-proteasome-system in anti-androgen resistance and develop new pharmaceutical approaches to provide co-targeting neoadjuvant with anti-AR agents to personalized CRPC patients treatment. We will provide a novelmechanism of next generation anti-androgen resistance via proteostasis impairment and uncover thatHsp70/Stub1 machinery in anti-androgen resistant CRPC may trigger accumulation of oncogenic proteins suchas AR variants and glucocorticoid receptor (GR) due to inability of protein clearance. We will functionallyinterrogate the Hsp70/Stub1/AR-V7 ternary complex through biochemical assays and uncover themechanisms of inhibition of Hsp70 activity in inducing AR-V7 degradation through the proximity of Stub1. Wewill unveil the underlying mechanisms of AR and AR-V7 ubiquitination through the ubiquitination binding sitesidentification and large-scale ubiquitin remnants sequencing. Importantly we will provide the rationale tocorrect proteostasis imbalance through modulation of Hsp70/Stub1 as a potential therapeutic strategy toovercome resistance to AR-targeted therapies in CRPC patients and develop conditional reprogramed cellcultures (CRCs) and patient derived xenograft (PDX) models to dissect the mechanisms in vivo. This proposalwill fill the gap in overcoming next generation anti-androgen resistance in CRPC patients and point the way tofuture research by improving current AR-targeted therapies. 351955 +No NIH Category available ATM Gene Mutation;ATM deficient;Ablation;Acceleration;Affect;Alzheimer's Disease;Animal Genetics;Animal Model;Animals;Autophagocytosis;Biology;CD8-Positive T-Lymphocytes;Cell Death;Cells;Clinical;Clinical Oncology;Clinical Research;Clinical Trials;Combination Drug Therapy;Data;Development;Disease;Disease Progression;Distant Metastasis;Drug resistance;Energy Metabolism;FPS-FES Oncogene;Frequencies;Functional disorder;Future;Genetic;Genetically Engineered Mouse;Goals;Growth;HIF1A gene;HMGB1 gene;Heterozygote;Human;Hypoxia;Immune;Immune checkpoint inhibitor;Immuno-Chemotherapy;Immunophenotyping;Immunotherapy;In Vitro;Infection;Inflammation;Inflammatory Response;Intervention;KRAS2 gene;Knock-out;Knockout Mice;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolic Pathway;Metabolism;Modeling;Molecular;Mus;Myeloid-derived suppressor cells;Natural History;Neoplasm Metastasis;Neoplasms;Nuclear;Nuclear Receptors;Oncogenes;Oncogenic;Paclitaxel;Pancreas;Pancreatic Ductal Adenocarcinoma;Pancreatic Intraepithelial Neoplasia;Pathway interactions;Patients;Pattern recognition receptor;Phenotype;Play;Production;Proliferating;Receptor Inhibition;Regulatory T-Lymphocyte;Research;Resistance;Role;Signal Transduction;Sterility;T cell response;T-Lymphocyte;TLR4 gene;Testing;Tissues;Work;Xenograft Model;Xenograft procedure;anti-PD-L1;anti-tumor immune response;anticancer activity;ataxia telangiectasia mutated protein;attenuation;cancer cell;cancer invasiveness;cancer therapy;chemotherapy;clinically relevant;conditional knockout;gemcitabine;immune cell infiltrate;improved;in vivo;inhibitor;insight;migration;mouse model;neoplastic cell;neutralizing antibody;novel;novel therapeutic intervention;novel therapeutics;overexpression;pancreatic ductal adenocarcinoma cell;pancreatic neoplasm;pancreatic tumorigenesis;pharmacologic;prevent;receptor for advanced glycation endproducts;subcutaneous;therapeutic target;transcription factor;treatment response;tumor;tumor initiation;tumor microenvironment;tumor-immune system interactions The Pancreatic Cancer Microenvironment Project Narrative Significant scientific progress has been made in the last decade towards understanding the biology andnatural history of pancreatic ductal adenocarcinoma (PDAC); major clinical advances however have notoccurred. We postulate that RAGE is a novel oncogene and therapeutic target in the tumor microenvironment ofPDAC. Our proposal will provide new insights into our understanding of the pathophysiology of PDAC and maylead to new therapeutic strategies to treat this lethal disease. NCI 10675422 3/27/23 0:00 PA-16-160 5R01CA211070-05 5 R01 CA 211070 5 "HILDESHEIM, JEFFREY" 6/8/17 0:00 3/31/24 0:00 Tumor Microenvironment Study Section[TME] 10393266 "KANG, RUI " Not Applicable 30 SURGERY 800771545 YZJ6DKPM4W63 800771545 YZJ6DKPM4W63 US 32.811963 -96.837534 578404 UT SOUTHWESTERN MEDICAL CENTER DALLAS TX SCHOOLS OF MEDICINE 753909105 UNITED STATES N 4/1/23 0:00 3/31/24 0:00 396 Non-SBIR/STTR 2023 366246 NCI 224175 142071 Abstract The tumor microenvironment (TME) is recognized as a key factor in multiple stages of disease progressionparticularly local resistance immune-escape and distant metastasis thereby substantially impacting the futuredevelopment of frontline interventions in clinical oncology. The receptor for advanced glycation end products(RAGE) is a pattern recognition receptor predominantly involved in the recognition of endogenous moleculesreleased in the context of sterile inflammation and infection. We recently demonstrated that RAGE plays a uniqueoncogenetic role in pancreatic ductal adenocarcinoma (PDAC). We demonstrated that: 1) RAGE was highlyexpressed in mouse and human PDAC; 2) Global ablation of RAGE in mice prevented pancreatic cancer growthin a genetically-modified spontaneous mouse model (Pdx1-Cre;K-RasG12D/+;RAGE-/-) and a xenograft mousemodel; 3) RAGE was essential for oncogenic K-Ras-mediated hypoxic signaling in PDAC development; and 4)The mechanism by which this occurs in part involves inflammatory response-associated metabolic changes celldeath-promoting limitations in autophagy and a reduction in the accumulation of myeloid-derived suppressorcells and regulatory T cells. These exciting findings raise several important questions regarding RAGE's novelrole in PDAC. We hypothesize that RAGE expression in multiple components of the TME is critical for PDACdevelopment and therapy resistance. We will pursue the following aims. Aim 1: identify RAGE as a criticalreceptor of nuclear danger signal in the TME; Aim 2: define the cell-specific role of RAGE in the TME; and Aim3: investigate antitumor efficacy of the combination of the RAGE inhibitor with chemoimmunotherapy in differenttumor models in mice. The completion of these exciting studies will provide new insights into our understandingof the TME and guide future development of RAGE-based novel therapeutic strategies for PDAC patients. 366246 +No NIH Category available Aconitate Hydratase;Acute Lymphocytic Leukemia;Adolescent and Young Adult;Adult;Adult Acute Lymphocytic Leukemia;Aftercare;Alanine Transaminase;Amino Acid Substitution;Amino Acids;Apoptosis;Asparagine;Aspartate Transaminase;Bilirubin;Bioenergetics;Biological;Biological Markers;Body mass index;Caucasians;Cells;Cessation of life;Characteristics;Child;Childhood;Clinical;Cluster Analysis;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Computer Models;Cytoprotection;DNA;Data;Enzymes;Ethnic Origin;Ethnic Population;Etiology;Exhibits;Frequencies;Future;Genetic;Genetic Polymorphism;Genetic Variation;Genotype;Glutamine;Hepatocyte;Hepatotoxicity;High Prevalence;Hispanic;Hispanic Populations;Hydrogen Peroxide;Impairment;Incidence;Inferior;Link;Lipids;Liver;Los Angeles;Malignant Childhood Neoplasm;Measurement;Measures;Mediating;Metabolic;Metabolic Diseases;Mitochondria;Modeling;Mutation;Not Hispanic or Latino;Obesity;Outcome;Oxidation-Reduction;Oxidative Stress;Oxygen;Patient risk;Patients;Pediatric Hospitals;Permeability;Pharmaceutical Preparations;Pharmacogenomics;Phase III Clinical Trials;Population;Prevalence;Proteins;Reactive Oxygen Species;Recommendation;Regimen;Reporting;Research;Risk;SOD2 gene;Sampling;Severities;Superoxide Dismutase;Superoxides;Survival Rate;Therapeutic Effect;Toxic effect;Training;Treatment-related toxicity;Underrepresented Populations;age group;antioxidant enzyme;asparaginase;biological adaptation to stress;cancer type;chemotherapy;classification trees;clinical phenotype;cohort;computerized tools;drug induced liver injury;experience;genetic variant;high body mass index;high risk;improved;insight;machine learning method;mitochondrial dysfunction;novel therapeutics;oxidation;pediatric patients;predictive modeling;predictive tools;regression trees;risk variant;therapeutically effective;therapy development;treatment risk;trend;young adult Mitochondrial Dysfunction underlies treatment related hepatotoxicity in Hispanics with acute lymphoblastic leukemia NARRATIVE:The incidence of acute lymphoblastic leukemia (ALL) and toxicities related to its treatment are higher in Hispanicpatients than in other ethnicities. The overall survival rate of adult patients with ALL is less than 50% which ispartly mediated by treatment-related toxicities that limit the use of effective therapeutic regimens such asasparaginase. This proposed research aims to reduce asparaginase-mediated toxicity and improve the clinicaloutcomes of Hispanic patients with ALL a population underrepresented in pharmacogenomic and functionalstudies. NCI 10675403 9/15/23 0:00 PAR-21-323 1R21CA274416-01A1 1 R21 CA 274416 1 A1 "WALLACE, TIFFANY A" 9/14/23 0:00 8/31/25 0:00 Basic Mechanisms of Cancer Health Disparities Study Section[BMCD] 11957198 "ALACHKAR, HOUDA " Not Applicable 37 PHARMACOLOGY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF PHARMACY 900894304 UNITED STATES N 9/14/23 0:00 8/31/25 0:00 393 Non-SBIR/STTR 2023 442404 NCI 270286 172118 PROJECT TITLE: Mitochondrial dysfunction underlies treatment related hepatotoxicity in Hispanics withacute lymphoblastic leukemiaABSTRACT:Acute Lymphoblastic leukemia is the most common type of cancer in children with higher prevalence inHispanics. While overall survival for children with acute lymphoblastic leukemia (ALL) has reached approximately90% the outcome for adult patients with ALL remains poor (<45%). Hispanic children and adolescent and youngadult (AYA) both also suffer inferior outcomes. The intensive use of asparaginase in pediatric regimens hasenhanced the cure rate of children but the higher rate of asparaginase-related toxicity in adults has limited itswidespread use in this age group. Hepatotoxicity is a particularly important drug-induced contraindication ascurrent recommendations of withholding asparaginase treatment when grade 3 or 4 hepatotoxicity developswhich occurs in approximately 30% of ALL patients may compromise its therapeutic effect. Hispanic patientsdeveloped hepatotoxicity at an increased rate compared with other ethnicities. Obese and/or older children areparticularly at risk for hepatotoxicity. Unfortunately pharmacogenomic studies of asparaginase in ALL are limitedand mostly focus on Caucasian pediatric patients. In a predominantly non-Hispanic population we previouslyreported that genetic variant rs4880 in SOD2 which encodes a key mitochondrial enzyme protective againstreactive oxygen species (ROS) is associated with asparaginase-induced hepatotoxicity in adult ALL patients.The high-risk CC genotype is more common in Hispanic individuals who also exhibit a greater prevalence ofALL and asparaginase-induced hepatotoxicity than other ethnicities. In a largely Hispanics cohort of 143 pediatricpatients with ALL who have received asparaginase based regimen we found higher elevation of liver enzymespost treatment with asparaginase in Hispanics than non-Hispanics. The rs4880 CC genotype was significantlyalso more frequent in Hispanics and was associated with elevated liver enzymes post asparaginase treatmentand higher body mass index which was also higher is Hispanic patients. Altogether these data suggest anoxidative stress etiology involved in a wide range of metabolic disorders leading to liver toxicities associated withasparaginase in patients with ALL. Here we propose to explore the link between the mitochondrial enzymes andmitochondrial dysfunction and asparaginase induced hepatotoxicity in Hispanics. We hypothesize thatmitochondrial dysfunction and oxidative stress contribute to asparaginase-induced hepatotoxicity inHispanics. Our aims are: Aim 1) Identify genetic and metabolic alterations in the mitochondria that contributeto asparaginase-induced hepatotoxicity in Hispanics. Aim 2) Develop a computational model to predictasparaginase-induced hepatotoxicity in Hispanic patients with ALL.Our study will provide functional evidence of the association between the mitochondrial dysfunction andasparaginase related hepatotoxicity in Hispanics and provide clinically useful tool for predicting asparaginase-induced hepatotoxicity in Hispanic patients with ALL. More broadly our findings will reveal mechanistic insightsneeded to develop therapies with reduced toxicity and improved efficacy in patients with ALL. 442404 +Cancer; Cervical Cancer; Clinical Research; Clinical Trials and Supportive Activities; Health Disparities; Health Services; Infectious Diseases; Minority Health; Prevention; Sexually Transmitted Infections; Women's Health Accounting;Administrative Supplement;Adult;African American;Asian;Asian Americans;Asian population;Black race;Cervical Cancer Screening;Chinese;Chinese American;Chinese population;Clinic;Communities;Community Health Education;Data;Emerging Technologies;English Language;Ethnic group;Evidence based program;Face;Future;Goals;Health Personnel;Human Papillomavirus;Immigrant;Insurance;Language;Light;Limited English Proficiency;National Health Interview Survey;Not Hispanic or Latino;Pap smear;Population;Randomized;Reporting;Research;Resource-limited setting;Sampling;Screening for cancer;Subgroup;Testing;Time;Woman;base;community setting;design;empowered;evidence base;evidence based guidelines;follow-up;medically underserved;programs;racial and ethnic;screening Evidence-Based Approach to Empower Asian American Women in Cervical Cancer Screening PROJECT NARRATIVEFew programs have been designed to increase cervical cancer screening among Chinese American women withlimited English proficiency (LEP). The proposed supplement project will be valuable for informing evidence-basedguidelines to increase cervical cancer screening coverage among underserved Chinese American women withLEP who face significant barriers to screening and are unable to access clinic-based screening. NCI 10675168 9/21/22 0:00 PA-20-272 3R01CA248655-03S1 3 R01 CA 248655 3 S1 "CHOLLETTE, VERONICA" 4/1/20 0:00 3/31/25 0:00 1866225 "FANG, CAROLYN Y." "MA, GRACE X." 2 Unavailable 64367329 FF1XVJMDYVR1 64367329 FF1XVJMDYVR1 US 40.067891 -75.091086 1190002 RESEARCH INST OF FOX CHASE CAN CTR PHILADELPHIA PA Research Institutes 191112434 UNITED STATES N 4/1/22 0:00 3/31/23 0:00 393 Non-SBIR/STTR 2022 425750 OD 337750 88000 PROJECT SUMMARYAsian Americans are the fastest growing population across all US racial/ethnic groups and individuals ofChinese origin represent the largest US Asian subgroup accounting for up to 24% of the total US Asianpopulation. Among adult Chinese Americans approximately 43% report limited English language proficiency(LEP); this rate is even higher among foreign-born Chinese Americans among which 56% have LEP. Thesedata are meaningful in light of studies demonstrating a strong negative association between LEP andparticipation in cancer screening. Indeed LEP may be contributing to the disparity observed in cervical cancerscreening rates which are lower among Chinese American women (65.8%) compared with non-Hispanic Whitewomen (82.8%). Estimates from the National Health Interview Survey (NHIS) also note similar disparities inscreening with Chinese women reporting lower Pap test use (68.7%) compared to Black/African Americanwomen (84.3%) and AI/AN women (81.2%) and in comparison with other Asian subgroups such as Filipinas(82.7%). Importantly among recent immigrants proportions of Pap test use were lowest for Chinese women.Multiple factors contribute to non-screening among Chinese American women with LEP including lack ofinsurance or regular healthcare provider lack of time language difficulties and embarrassment. Emergingtechnologies supporting self-sampling for human papillomavirus (HPV) testing may offer a valuableevidence-based strategy for empowering underscreened and medically underserved Chinese American womenwith LEP to be able to participate in cervical cancer screening. Although prior studies have demonstrated thatHPV self-sampling can be feasibly offered in low-resource community settings not one study has focused onChinese American women despite the fact that this population has among the lowest cervical cancer screeningrates. Therefore the goal of this administrative supplement is to examine HPV self-sampling in a communitysample of 150 Chinese American women with LEP. In this randomized study 75 women will receive ourpreviously tested community education program on cervical cancer screening plus navigation along with HPVself-sampling kits; and 75 women will receive our previously tested community education program plusnavigation to clinic-based screening. The aim of the proposed supplement is to: (1) Compare rates of providinga self-collected sample vs. obtaining clinic-based cervical cancer screening among 150 Chinese Americanwomen with LEP. Participation in self-sampling or clinic-based screening will be assessed at 6-month follow-up. Itis hypothesized that the proportion of Chinese American women in the HPV self-sampling program who providea self-collected sample will be higher than the proportion of women in the clinic-based program who obtain clinic-based screening. The research proposed in this supplement will be the first randomized study to evaluate HPVself-sampling among underserved Chinese American women with LEP. Our findings will inform future evidence-based programs to enhance screening in this understudied population. 425750 +Biotechnology; Brain Cancer; Brain Disorders; Cancer; Cancer Genomics; Genetics; Human Genome; Immunization; Immunotherapy; Infectious Diseases; Neurosciences; Orphan Drug; Rare Diseases; Vaccine Related Aftercare;Agonist;Antibodies;Antigen-Presenting Cells;Antigens;Autologous;Bilateral;Biological Assay;Biometry;Brain;Brain Neoplasms;Breast Melanoma;CD14 gene;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Patient;Capsid;Cell Density;Cell physiology;Cells;Chemosensitization;Childhood;Clinical;Communicable Diseases;Complement;Cytolysis;Data;Dendritic Cells;Fatty acid glycerol esters;Flow Cytometry;Gene set enrichment analysis;Glioblastoma;Glioma;Goals;Helper-Inducer T-Lymphocyte;Human;I-antigen;Immune;Immune response;Immune system;Immunity;Immunization;Immunize;Immunobiology;Immunologic Surveillance;Immunotherapy;Infiltration;Inflammation;Inflammatory;Injections;Ligation;Malignant Neoplasms;Measures;Mediating;Memory;Mentors;Modeling;Molecular Target;Monitor;Mus;Myeloid Cell Activation;Myeloid Cells;Natural Immunity;Natural Killer Cells;Oncolytic poliovirus;PTPRC gene;Pathway interactions;Patients;Pattern recognition receptor;Phase;Phenotype;Play;Poliomyelitis;Poliovirus Vaccines;Poly I-C;Principal Component Analysis;Public Health;Qi;RNA analysis;Recurrence;Research;Role;Route;SILV gene;STING agonists;Seeds;Slice;T-Lymphocyte;TNFRSF5 gene;Testing;Tetanus;Tetanus Toxoid;Tetanus Vaccine;Therapeutic;Tumor Antigens;Tumor Immunity;Tumor-associated macrophages;Vaccinated;Vaccination;Vaccines;Virotherapy;Work;adaptive immunity;antitumor effect;base;cancer cell;cancer immunotherapy;cancer therapy;cancer type;cell type;clinical translation;clinically actionable;cytokine;design;differential expression;draining lymph node;granulocyte;immunogenic;macrophage;melanoma;neoplasm immunotherapy;neoplastic cell;novel;novel therapeutics;pathogen;programs;response;single cell analysis;subcutaneous;success;targeted cancer therapy;transcriptome;transcriptome sequencing;tumor;tumor growth;tumor microenvironment Reviving cancer immune surveillance with CD4 T cell help Project NarrativeCD4+ T cell help is required for optimal effector CD8+ T cell function; however therapies that enlist CD4+ T cellsfor cancer immunotherapy are lacking. I discovered that intratumor activation of childhood vaccine CD4+ T cellrecall responses inflame the tumor microenvironment and mediate antitumor efficacy. This work will defineinflammatory reprogramming CD8+ T cell potentiating and `helper' functions induced by CD4+ T cell recall withintumors to leverage CD4+ T cells for cancer immunotherapy. NCI 10675117 9/19/22 0:00 PA-20-188 4R00CA263021-02 4 R00 CA 263021 2 "LIU, YIN" 7/8/21 0:00 6/30/25 0:00 Transition to Independence Study Section (I)[NCI-I] 10983362 "BROWN, MICHAEL CLAVON" Not Applicable 4 NEUROSURGERY 44387793 TP7EK8DZV6N5 44387793 TP7EK8DZV6N5 US 36.007766 -78.926475 2221101 DUKE UNIVERSITY DURHAM NC SCHOOLS OF MEDICINE 277054673 UNITED STATES N 7/1/22 0:00 6/30/23 0:00 398 Non-SBIR/STTR 2022 248602 NCI 154411 94191 AbstractThe immune system is capable of eliminating advanced malignant tumors yet cancer immunotherapy successhas been limited to a subset of cancer types. Conventional CD4 or `helper' T cells play an integral role inorchestrating immune responses and can potentiate the function of antitumor immunity: both via activation andpotentiation of antigen presenting cell function and antitumor CD8 T cells. My postdoctoral work demonstratedthat reactivating childhood vaccine-specific CD4 T cells after intratumor injection of recall antigen (e.g. poliocapsid or tetanus toxoid) mediates antitumor efficacy and causes both innate and adaptive inflammation withintumors. The antitumor efficacy of intratumor recall responses were partially dependent upon CD8 T cells andcoincided with infiltration of activated granulocytic macrophages with phenotypes distinct from tumor associatedmacrophages after direct innate stimulation with Poly IC. Thus inducing CD4 T cell recall represents a noveltherapeutic opportunity with a distinct mode of inflammatory and antitumor potential. We hypothesize thatintratumor childhood vaccine-specific CD4+ T cell recall responses instigate distinct and durable inflammatoryreprograming of myeloid cells to potentiate antitumor CD8+ T cell function and mediate antitumor efficacy. Totest this hypothesis we will define reprogramming of innate immunity after triggering intratumor recall responsesand determine its role in mediating antitumor efficacy (Aim 1) and test if polio vaccine-specific CD4+ T cell recallresponses `help' antitumor CD8+ T cells (Aim 2). These analyses will inform clinically actionable routes to developrecall antigen-based therapies that enlist CD4 T cell help within tumors (the goal of the independent R00 phase).The clinical translation of these findings will be informed by identifying therapeutic strategies such as combinedinnate pattern recognition receptor agonist therapy that may synergize with recall antigens in mediating systemicantitumor efficacy; as well as identifying more targeted molecular routes to recapitulate CD4 T cell help in tumorstherapeutically (Aim 3). The K99 phase of this work will be mentored by several distinguished experts in tumorimmunobiology and cancer immunotherapy: including Drs. Darell Bigner (primary Mentor cancer immunotherapyof brain tumors) Simon Gregory (computational expert) Qi Jing-Li (T cell biologist using transcriptome analysesto gauge T cell function) Amy Heimberger (tumor associated myeloid cell expert who has previously appliedtranscriptome analyses to define activation/suppressive features of tumor associated myeloid cells) and JamesHerndon II (biostatistical support). This proposal will enable clinical translation of recall antigens to cancerpatients and will seed a research program that leverages the potent immune-stimulating effects of CD4+ T cellhelp to develop novel cancer therapies. 248602 +No NIH Category available Acetaminophen;Address;Adverse effects;Affect;Aminophenols;Analgesic and Antipyretic;Anatomy;Antibiotics;Birth;Cancer Etiology;Chemicals;Child;Classification;Code;Collaborations;Communicable Diseases;Conceptions;Confidence Intervals;Cryptorchidism;Data;Data Sources;Databases;Diagnosis;Diagnostic;Diethylstilbestrol;Disease;Dose;Europe;Exposure to;Fetal Development;Fetus;Functional disorder;Headache;Health;Hepatoblastoma;Hepatotoxicity;ICD-9;Injury;Intake;Link;Low Birth Weight Infant;Malignant Childhood Neoplasm;Malignant Neoplasms;Maternal Health;Maternal and Child Health;Medical Records;National Health Insurance;Neuroepithelial Perineurial and Schwann Cell Neoplasm;Neurological outcome;Outcome;Parents;Pharmaceutical Preparations;Pharmacoepidemiology;Pharmacologic Substance;Pharmacy facility;Physicians;Polypharmacy;Population Study;Pregnancy;Pregnant Women;Premature Birth;Property;Prospective Studies;Publishing;Recommendation;Records;Registries;Reporting;Research;Research Design;Research Personnel;Resources;Risk;Risk Factors;Role;Safety;Selection Bias;Source;Taiwan;Testing;Therapeutic;Time;Tylenol;United States Food and Drug Administration;Vaginal Adenocarcinoma;Voice;Woman;anogenital distance;anticancer research;autism spectrum disorder;cancer risk;carcinogenicity;cohort;data registry;design;developmental toxicity;early childhood;epidemiology study;insurance claims;interest;maternal risk;medulloblastoma;neoplasm registry;offspring;population based;prenatal exposure;prospective Maternal acetaminophen use and childhood cancer Project NarrativeAcetaminophen (APAP or paracetamol) is a commonly used medication by pregnant women howeverconcerns have been raised over possible adverse effects of APAP on fetal development. We propose to utilizedata sources available from Taiwan from a large population-based pregnancy cohort to investigate whetherprenatal exposures to APAP affect childhood cancer risk. Our project is among the first on this topic andaddresses needs voiced by regulatory agencies for more thorough research to better understand the safety ofAPAP in pregnancy and to inform regulatory recommendations. NCI 10675108 8/10/23 0:00 PAR-20-052 5R03CA273608-02 5 R03 CA 273608 2 "MAHABIR, SOMDAT" 8/1/22 0:00 7/31/24 0:00 ZCA1-RTRB-B(M1)S 9958106 "HECK, JULIA " Not Applicable 13 NONE 614168995 G47WN1XZNWX9 614168995 G47WN1XZNWX9 US 33.21077 -97.147769 6108501 UNIVERSITY OF NORTH TEXAS DENTON TX SCHOOLS OF ARTS AND SCIENCES 762035017 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 57988 NCI 53212 4776 Project summaryApproximately 65% of US pregnant women take acetaminophen (in the US branded as Tylenol;in Europe paracetamol). Despite increasing concerns for its safety in pregnancy with reportedliver and developmental toxicity and risks for adverse child outcomes including hyperkineticdisorders and autism it remains widely used and continues to be endorsed by US physiciangroups and the US FDA. It is well-established that pregnancy intake of medications can havecarcinogenic impacts on offspring as shown by diethylstilbestrol (DES) and vaginaladenocarcinoma. Yet potential carcinogenic impacts from acetaminophen are understudied.This study will be conducted via linkage of national health insurance claims databases inTaiwan including the Taiwan Maternal and Child Health Database (which includes thePharmaceutical Register and the Birth Registry among other sources) and the Cancer Registry.Data on demographic gestational and other factors will be available from other nationalregisters. The Aims of this study are to investigate the role of acetaminophen in cancer riskaddressing needs voiced by regulatory agencies for more thorough research to betterunderstand the safety of acetaminophen in pregnancy and to inform regulatoryrecommendations. 57988 +No NIH Category available ATR gene;Acute;Adenosine Diphosphate Ribose;Alkylating Agents;Alkylating Antineoplastic Agents;Ancillary Study;Apoptosis;Award;Base Excision Repairs;Biological Assay;Biological Markers;CHEK1 gene;Cancer Hospital;Cancer Therapy Evaluation Program;Cell Line;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collaborations;Colorectal Cancer;Critical Pathways;DNA Damage;DNA Repair;DNA Repair Pathway;DNA replication fork;Data;Development;Disease;Disease Progression;Dreams;Enrollment;Epigenetic Process;Faculty;Futile Cycling;Future;Gamma-H2AX;Genomics;Glioma;Goals;Grant;Granzyme;Health;Heterogeneity;Hypermethylation;Immune;Immune Targeting;Immune response;Immune system;Immunofluorescence Immunologic;Immunologic Markers;Immunologic Stimulation;Immunology;Immunotherapy;In Vitro;Individual;Innovative Therapy;Instruction;Lesion;Life;MGMT gene;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Measures;Medical Oncologist;Mentors;Mentorship;Methods;Mismatch Repair;Mutation;National Cancer Institute;Oncology;Pathogenesis;Pathway interactions;Patient Agents;Patient-Focused Outcomes;Patients;Pattern;Phase Ib/II Clinical Trial;Phosphorylation;Physicians;Play;Poly(ADP-ribose) Polymerase Inhibitor;Polymerase;Polyps;Predisposition;Prevalence;Prognostic Marker;Property;Public Health;Research Personnel;Resistance;Role;Sampling;Scientist;Site;Specimen;T-Lymphocyte;Techniques;Testing;Therapeutic;Thymine;Tissue Microarray;Training;Translating;Work;Xenograft procedure;anticancer research;biomarker driven;biomarker identification;cancer type;clinical trial implementation;colon cancer cell line;colorectal cancer progression;colorectal cancer treatment;design;early phase clinical trial;experience;experimental study;immune cell infiltrate;immunogenicity;immunoregulation;immunostimulatory therapy;improved;in vivo;inhibitor;innovation;investigator-initiated trial;multidisciplinary;neoantigens;new therapeutic target;next generation;novel;novel marker;novel therapeutic intervention;novel therapeutics;pre-clinical;predictive marker;promoter;repaired;replication stress;response;skills;targeted treatment;temozolomide;therapeutic target;tool;tumor;tumor heterogeneity;tumor immunology;tumor microenvironment;tumor-immune system interactions;virtual Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer PROJECT NARRATIVEColorectal cancer (CRC) remains a significant public health problem and there is an urgent need for newtreatments with the development novel biomarker driven therapies and immunotherapies as the most importanttherapeutic priorities in CRC. The clinical trials in this award have the potential to rapidly translate into newtherapeutic strategies that will enhance health and prolong life for numerous patients with advanced CRC.Furthermore the DNA damage and immune biomarker translational work has the potential to developinnovative future strategies in CRC research and develop novel DNA damage and immunostimulatorytherapies to significantly improve clinical outcomes for patients with CRC. NCI 10675088 7/12/23 0:00 PA-20-202 5K08CA255465-03 5 K08 CA 255465 3 "RADAEV, SERGEY" 8/5/21 0:00 7/31/26 0:00 Career Development Study Section (J)[NCI-J] 15305547 "CECCHINI, MICHAEL " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 260958 NCI 241628 19330 ABSTRACTDNA repair plays an important role in the pathogenesis of virtually all cancer types and the identification ofaberrant DNA repair pathways has identified predictive and prognostic biomarkers to targeted therapies. Forexample epigenetic hypermethylation of the promoter of O6-methylguanine DNA methyltransferase (MGMT)predicts for better patient survival and increased sensitivity to temozolomide (TMZ) in multiple cancersincluding colorectal cancer (CRC). TMZ is a monofunctional alkylator and the DNA damage caused by TMZ isprincipally repaired by MGMT which is silenced by promoter hypermethylation. The base excision repair (BER)pathway also serves as a critical pathway to repair TMZ DNA damage. Preclinically the simultaneous inhibitionof BER with polyp ADP ribose polymerase (PARP) inhibitors further sensitizes MGMT deficient tumors to TMZ.However our preliminary findings reveal an alternative and parallel mechanism: TMZ damage causes acutereplication stress and fork collapse leading to Ataxia Telangiectasia and Rad3 related (ATR) dependentphosphorylation of Checkpoint Kinase 1 (Chk1). We have leveraged these findings and additional in vivoexperiments to advance novel TMZ combinations into the clinic with two investigator-initiated clinical trials forMGMT silenced CRC: 1) TMZ + olaparib (PARP inhibitor) and TMZ + AZD 6738 (ATR inhibitor). Enrollment willproceed at Yale Smilow Cancer Hospital with future opportunities expand to collaborating sites through ourCRC Stand up to Cancer (SU2C) Dream Team. Furthermore we aim to develop new biomarker assaysincluding a biomarker assessing MGMT heterogeneity to identify tumors most sensitive to TMZ combinationsand perform genomic profiling. Leveraging DNA damage additionally represents a potential tool to stimulate animmune response and through ancillary studies and using specimens obtained from our trials we will study theeffects TMZ combinations on the immune microenvironment to lend support to the addition of immunotherapyin the future. I am a medical oncologist focusing on the treatment of advanced gastrointestinal (GI) cancerswith an emphasis on innovative therapies for CRC. This award will facilitate my development as a physician-scientist equipped to design and conduct investigator-initiated early phase clinical trials based on innovativepreclinical evidence regarding DNA repair and immunotherapies. My training will include didactic courseworkfor tumor immunology practical experience of clinical trial implementation and formal instruction in biomarkertechniques. To achieve these goals I have assembled a multidisciplinary mentorship team led by my primarymentor Dr. Patricia LoRusso who has a proven track record of successfully mentoring junior faculty andextensive expertise in investigator-initiated clinical trials. At the conclusion of this award I will have gainedvaluable skills into the underpinnings of clinical research generically and specifically for clinical trial designand biomarker identification for DNA repair and immunology. This award will help establish me as anindependent investigator conducting early phase clinical trials for CRC and other GI cancers. 260958 +No NIH Category available Abbreviations;Affect;Area;Area Under Curve;Blood;Blood - brain barrier anatomy;Blood capillaries;Brain;Carmustine;Cell Membrane Permeability;Cerebrospinal Fluid;Cessation of life;Chemotherapy-Oncologic Procedure;Clinic;Clinical;Combined Modality Therapy;Contralateral;DNA Sequence Alteration;Data;Dextrans;Dose;Dose Limiting;Doxorubicin;Drug Combinations;Drug Delivery Systems;Drug Formulations;Drug Kinetics;Drug usage;Excision;Genetic;Genetic Engineering;Genetically Engineered Mouse;Genotype;Gliadel;Glioblastoma;Glycolates;Histopathology;Hydrophobicity;Immunohistochemistry;Implant;In Vitro;Individual;Intravenous;Isopropanol;Kinetics;Left;Location;Malignant Neoplasms;Malignant neoplasm of brain;Maximum Tolerated Dose;Modeling;Molecular Target;Morphology;Mus;Mutation;Nature;Nude Mice;Operative Surgical Procedures;Outcome;Paclitaxel;Pathologic;Patients;Penetration;Pharmaceutical Preparations;Polyesters;Polymers;Predisposition;Primary Brain Neoplasms;Property;Radiation;Radiation therapy;Recurrence;Recurrent tumor;Residual Cancers;Resistance;Role;SDZ RAD;Solubility;Surface;Surgically-Created Resection Cavity;TNF-related apoptosis-inducing ligand;Therapeutic;Thinness;Tight Junctions;Time;Toxic effect;Translating;Tumor Cell Invasion;Tumor Tissue;Xenograft procedure;anticancer research;biodegradable polymer;bioluminescence imaging;blood-brain barrier crossing;brain tissue;cancer cell;cancer invasiveness;cancer therapy;chemotherapeutic agent;chemotherapy;controlled release;cytotoxic;drug release kinetics;fabrication;flexibility;improved;in vivo;indexing;interstitial;mTOR Inhibitor;mortality;mouse model;nanofiber;neural implant;novel;poly(lactic acid);polycaprolactone;precision oncology;rate of change;scaffold;standard of care;success;targeted cancer therapy;temozolomide;tumor;tumor growth Tunable Temporal Drug Release for Optimized Synergistic Combination Therapy of Glioblastoma NARRATIVEGlioblastoma is a devastating brain cancer that needs new treatment options because even with chemotherapyradiation and surgical resection tumor recurrence almost always leads to death. Here we propose synergisticcombination therapy that relies on optimized elution of chemotherapeutics from a nanofibrous controlled-releasescaffold placed in the brain at time of surgery to remove the tumor. NCI 10675073 7/19/23 0:00 PA-20-185 5R01CA257009-03 5 R01 CA 257009 3 "AVULA, LEELA RANI" 8/1/21 0:00 7/31/26 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 8299299 "AINSLIE, KRISTY M" Not Applicable 4 NONE 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PHARMACY 275995023 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 342991 NCI 230893 112098 ABSTRACTGlioblastomas (GBM) invasive nature is part of the reason this primary brain tumor results in near 100%mortality. Even with surgical resection radiation and chemotherapy the median survival remains of only 12-15months. Tumor invasion make complete surgical resection difficult leading to local recurrence within 2centimeters of the original tumor in 90-95% of patients. Most systemically delivered chemotherapy agents areineffective against GBM because they cannot reach the brain at therapeutic concentrations due to the blood-brain barrier. The blood-brain barrier is a highly selective and semi-permeable membrane that separates thecirculating blood from the brain tissues as a protective mechanism. The capillaries that line the blood brain barrierhave especially restrictive tight-junctions that significantly reduce permeation of systemically administeredchemotherapeutics to brain tissues. A promising strategy to avoid the blood-brain barrier and reduce dose-limiting toxicities observed with systemic delivery is to administer drugs directly to the brain by implanting themwithin the cavity left after GBM resection. One way to achieve this it to load drug into a biodegradable polymerwhich allows for controlled temporal release of drug as the polymer degrades. Gliadel a biodegradablepolymeric wafer that delivers carmustine into the resection cavity is a clinical example of this type of therapyand increased patient survival by 10-18 weeks. However the use of more efficacious drugs facilitated by recentadvancement in cancer genotyping could greatly improve the success of interstitial therapy. This could lead topersonalized chemotherapeutic selection where one or more drugs can be co-administered based on a patientstumor-specific genetic mutations. In addition our preliminary data suggests that the release rate of drugs fromthe polymer can greatly affect outcomes. Drug release rate can be controlled via polymer degradation rate aswell as formulation of the drug within the polymer. We hypothesize that more potent chemotherapies loaded intobiodegradable polymers tailored for optimal drug release rate would generate a platform that could be translatedto the clinics to improved GBM therapy. 342991 +No NIH Category available Aftercare;Behavioral Sciences;Businesses;Cancer Burden;Cancer Center;Cancer Control;Cancer Patient;Caring;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collection;Communities;Community Clinical Oncology Program;Community Networks;Cultural Diversity;Data;Development;Diagnosis;Doctor of Philosophy;Enrollment;Ensure;Equity;Ethnic Origin;Ethnic Population;Geography;Health;Health Personnel;Health Professional;Health Sciences;Healthcare;Image;Individual;Institution;International;Intervention;Investments;Joints;Knowledge;Leadership;Malignant Neoplasms;Medical;Medical Oncology;Mentors;Minority;Minority Recruitment;Mission;Oncology;Outcome;Participant;Patient Outcomes Assessments;Patients;Positioning Attribute;Prevention;Protocols documentation;Provider;Psychiatry;Public Health;Race;Radiation Oncology;Research;Research Infrastructure;Research Methodology;Research Personnel;Research Priority;Resources;Services;Shapes;Site;South Carolina;Survivors;Training;Universities;Vision;Work;anticancer research;base;cancer care;cancer health disparity;cancer prevention;cancer type;care delivery;care providers;clinical infrastructure;community setting;dissemination science;ethnic diversity;ethnic minority;evidence base;experience;geographic population;health related quality of life;imaging study;implementation science;improved;medically underserved population;minority health;neoplasm registry;operation;patient population;population based;population health;preference;programs;racial diversity;racial minority;racial population;recruit;research study;retention rate;screening;service utilization;treatment research;underserved community;underserved minority Medical University of South Carolina NCORP Minority/Underserved Community Site PROJECT NARRATIVEContinuation of the Medical University of South Carolina NCORP Minority/UnderservedCommunity Site will provide greater emphasis and availability for residents and healthcareproviders of South Carolina to participate in cancer prevention and control screening posttreatment surveillance cancer care delivery treatment and imaging research studies. NCI 10675064 7/20/23 0:00 RFA-CA-18-017 5UG1CA189848-10 5 UG1 CA 189848 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-SRB-H(M1) 10829102 "MARSHALL, DAVID T." "FORD, MARVELLA ELIZABETH; LOCKHART, ALBERT CRAIG" 6 INTERNAL MEDICINE/MEDICINE 183710748 NHV3GTWSALA7 183710748 NHV3GTWSALA7 US 32.786754 -79.947265 7575301 MEDICAL UNIVERSITY OF SOUTH CAROLINA CHARLESTON SC SCHOOLS OF MEDICINE 294074636 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 993808 NCI 686326 339731 PROJECT SUMMARYThe Medical University of South Carolina/Hollings Cancer Center (MUSC/HCC) was establishedas a Minority Underserved site in 2014 to expand and enhance the NCORP trial portfolio byaccruing racially/ethnically diverse patients and those from other medically underserved groupsinto NCORP studies share expertise and experience on minority recruitment and retention andcultural diversity within the NCORP community and contribute to the development andimplementation of cancer care and cancer delivery research. During the current project periodthe MUSC NCORP-MU which is comprised of two MUSC/HCC sub-affiliates and five communityoncology primary affiliates has made significant contributions to the NCORP program throughthe effective and efficient accrual of diverse patient populations and leadership that has shapedthe scientific agenda for clinical trials cancer health disparities and cancer care deliveryresearch. These accomplishments were made possible through a highly invested andtransdisciplinary investigative team consisting of Chanita Hughes-Halbert PhD (Psychiatry &Behavioral Sciences) Marvella E. Ford PhD (Public Health Sciences) Carolyn D. Britten MD(Medical Oncology) and David T. Marshall MD (Radiation Oncology) that has worked hand-in-hand with the clinical research operational leaders at the MUSC/HCC to establish and manage arobust clinical research operation to add value to NCORP. This leadership team has also workedcollaboratively with other committed clinical and cancer control researchers oncology careproviders cancer patients and survivors in our catchment areas to advance all types of cancerresearch through the NCORP research bases. The MUSC NCORP-MU aims to improve equityand access to clinical research among racial/ethnic minorities and other medically underservedgroups in order to improve cancer outcomes enhance the quality of cancer care delivery andreduce cancer health disparities within South Carolina and communities across the US. 993808 +No NIH Category available Malignant Neoplasms;Population Sciences;Training Programs Training Program for Quantitative Population Sciences in Cancer PROJECT NARRATIVE/RELEVANCEWe will continue our goal of improving the resources available for future cancer research by providinginnovative interdisciplinary training for postdoctoral fellows. This program is designed to provide early careerresearchers with opportunities to integrate specialized research knowledge and methodologies within the fieldsof bioinformatics biostatistics and epidemiology. Trainees will be positioned to expedite the translation ofcancer science into clinical and public health practice as leaders on multidisciplinary research teams. NCI 10675063 8/10/23 0:00 PA-18-403 5T32CA134286-14 5 T32 CA 134286 14 "LIM, SUSAN E" 8/7/09 0:00 7/31/25 0:00 ZCA1-RTRB-R(J2) 1870861 "KARAGAS, MARGARET RITA" "TOSTESON, TOR D; WHITFIELD, MICHAEL L" 2 FAMILY MEDICINE 41027822 EB8ASJBCFER9 41027822 EB8ASJBCFER9 US 43.711386 -72.270611 2021601 DARTMOUTH COLLEGE HANOVER NH SCHOOLS OF MEDICINE 37551421 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 259488 NCI 401556 29844 PROJECT SUMMARY/ABSTRACTModern biomedical research relies on new approaches to advance our understanding of complex andmultifaceted illnesses of growing public health significance such as cancer. Emerging technologies enablepopulation scientists to generate data on a scale never before imaginable (i.e. through whole genome arrayscans). Thus there is a critical need to not only train the next generation of scientists in the classic disciplinesinvolved in studies of human malignancies but to cross-train them in complementary disciplines to allow themto bring their scientific discoveries to light. Therefore we propose to continue a highly successful postdoctoralprogram that combines specialized research knowledge and methodologies in the fields of bioinformaticsbiostatistics and epidemiology. This novel program entitled Training Program for Quantitative PopulationSciences in Cancer is structured to complement the existing resources for cancer research and education atthe Geisel School of Medicine and the Norris Cotton Cancer Center (NCCC) an NCI designatedComprehensive Cancer Center affiliated with the Geisel School of Medicine at Dartmouth and DartmouthHitchcock Medical Center (DHMC). Our training efforts will continue to be led by investigators withcomplementary expertise in the fields of bioinformatics biostatistics and epidemiology primarily within theDepartments of Biomedical Data Science Epidemiology and Molecular and Systems Biology. We willcapitalize on Dartmouths talented cadre faculty in these disciplines who can offer expert mentorship and aversatile portfolio of research and center grants that can supply access to a wealth of population science databiologic samples and core research facilities. To accomplish our objectives we propose to cross-train eightpostdoctoral trainees in epidemiology bioinformatics or biostatistics for a period of 2 to 3 years. Trainees willbe paired with a primary and secondary mentor from two of the focus disciplines and complete cross-disciplinary coursework with an optional MS degree in Quantitative Biomedical Sciences. In years two andthree of the program trainees will concentrate on the conduct of mentored research activities prepare a mockNIH grant application and participate in the preparation of professional manuscripts presentations atsymposia and scientific conferences and an optional research externship. Program leaders in consultationwith an Advisory Committee will select trainees monitor their progress and provide recommendations toensure that the necessary didactic and research experiences are provided to produce highly knowledgeableinvestigators for the future of interdisciplinary cancer research in the population sciences. The ultimate goal ofthe training program is to accelerate cancer research by enhancing the existing pool of cancer researcherswith the skills to meet the present and future challenges in translational cancer research in the populationsciences. 259488 +No NIH Category available Adherence;Adopted;Age;Anxiety;Biological;Black Populations;Breast;Breast Cancer Patient;Breast Cancer Risk Factor;Breast Cancer Treatment;California;Cancer Burden;Cancer Patient;Cessation of life;Clinic;Clinical;Collaborations;Communication;Computerized Medical Record;Computers;Data;Data Collection;Databases;Detection;Development;Diagnosis;Diagnostic Neoplasm Staging;Disease;Disparity;Distant Metastasis;Early Diagnosis;Epidemiologist;Ethnic Origin;Evaluation;Fatigue;Funding;Future;Guidelines;Health system;Healthcare;Hispanic;Hispanic Populations;Hospitals;Hour;Human;Immunotherapy;Informatics;Institution;Insurance Coverage;Intervention;Lead;Learning;Malignant Neoplasms;Malignant neoplasm of prostate;Manuals;Medical center;Mental Depression;Methodology;Methods;Mission;Modeling;Morbidity - disease rate;Natural Language Processing;Nausea;Neoplasm Metastasis;Not Hispanic or Latino;Oncologist;Operative Surgical Procedures;Outcome;Paper;Pathology;Pathology Report;Patient-Focused Outcomes;Patients;Pattern;Performance;Population;Population Heterogeneity;Primary Neoplasm;Process;Prognosis;Psyche structure;Quality of life;Race;Radiation;Radiology Specialty;Recording of previous events;Recurrence;Recurrent Malignant Neoplasm;Registries;Reporting;Research Personnel;Role;Running;Scientist;Site;Software Tools;Stage at Diagnosis;Structure;Team Nursing;Technology;Testing;Text;Time;Tumor Subtype;Tumor stage;University Hospitals;Validation;Visit;Woman;anticancer research;artificial intelligence algorithm;biological systems;breast cancer survival;cancer classification;cancer prevention;cancer recurrence;cancer site;cancer survival;cancer therapy;chemotherapy;clinical center;clinical encounter;comorbidity;cost;data curation;data integration;experience;flexibility;follow-up;hormone therapy;informatics tool;low income country;malignant breast neoplasm;molecular subtypes;multidisciplinary;multimodal data;neoplasm registry;open source;outcome prediction;patient population;physical conditioning;population based;radiologist;relational database;socioeconomic disparity;surveillance data;survival disparity;tool;treatment and outcome;treatment planning;trend Flexible NLP toolkit for automatic curation of outcomes for breast cancer patients Project NarrativeWhile evidence of long-term clinical outcomes and quality-of-life data for cancer patients is trivialfor treatment planning manual extraction of data is an extremely challenging task for humancurators and needs hours of manual chart-review. We propose to develop an open-source NLPtoolkit for curating treatment administered (chemotherapy immunotherapy radiation surgery)and clinical outcome (progression recurrence) data longitudinally by parsing varying types ofclinical narratives for performing population-wide cancer research. In this study we willcollaborate with two state-wide cancer registries (Georgia and California) for evaluating our NLPdevelopments for cancer data curation and obtain a robust performance evaluation acrossheterogeneous populations. NCI 10675009 8/2/23 0:00 PAR-20-170 5U01CA269264-02 5 U01 CA 269264 2 "HOWLADER, NADIA" 8/1/22 0:00 7/31/27 0:00 ZCA1-SRB-1(J1) 14792841 "BANERJEE, IMON " "KEEGAN, THERESA H M; RUBIN, DANIEL L" 1 Unavailable 153665211 ULMJJBL7ZXX3 153665211 ULMJJBL7ZXX3 US 33.589113 -111.79394 4976104 MAYO CLINIC ARIZONA SCOTTSDALE AZ Other Domestic Non-Profits 852595499 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 540872 NCI 416532 124340 Project summary/AbstractBreast cancer has the largest number of new cases in world (11.7%). Although the prognosis ofbreast cancer patients is generally favorable due to early detection and comprehensive treatment20%30% of patients will still develop distant metastases and cases with progressive stage onlyhave a median two-year survival time. Breast cancer is widely recognized as a heterogeneousdisease in the sense of both primary tumor metastatic capacity and time to metastatic spread ofdisease. High-quality population-based cancer surveillance data are needed to: (1) describecancer burden patterns and outcomes in order to (2) inform cancer prevention detection andcontrol activities; and (3) evaluate interventions on the basis of past and future trends so thatoptimal approaches to alleviate burden and suffering from cancer can be adopted. However thelaborious manual curation process makes the population wise surveillance data collectionchallenging. It has been shown in studies that a large percentage of total registry cost is devotedto labor for data curation even in the low-income countries. In this project our mission is to builda flexible NLP toolset that can be executed locally at the institution level and will curate the clinicaland patient-centered outcomes of breast cancer patients by parsing longitudinally acquired clinicnotes radiology and pathology reports. In order to test the generalizability of the tools and toinitiate their deployment for data collection we will partner with both Georgia SEER and Californiastate cancer registry and will curate the outcome data of past 10-years breast cancer patientsfrom two institutions across US representing diverse patient populations - Emory Universityhospital (Georgia) and Stanford Medical Center (California). We will leverage the previouslydeveloped tools and technologies and extend them to automatically curate the clinical and patient-centered outcome data recurrence date and site of recurrence treatment administered mentaland physical outcomes from clinic notes and convert these into structured and query-ableformat. The NLP tools will be dockerized and run locally at the hospital registry level for automatedoutcome curation. Finally the NLP extracted outcomes will be shared with State Cancer registryfor evaluation. From a methodological perspective the framework and the open-source softwaretools developed can be employed for cancer research beyond the scope of our project for curatingoutcomes regardless of the problem domain. 540872 +No NIH Category available Academia;Affect;Animal Model;Antineoplastic Agents;Apoptosis;Automobile Driving;Binding;Biochemical;Biological Assay;Biotechnology;Cancer Patient;Cancer cell line;Cell Culture System;Cell Proliferation;Cells;Chemicals;Clinic;Clinical Trials;Covalent Interaction;Cysteine;DNA Binding;DNA Binding Domain;Development;Diagnosis;Dose;Drug Kinetics;Exposure to;Future;Gene Expression;Genes;Goals;Growth;Human;Hypersensitivity;In Vitro;Lead;Length;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant neoplasm of pancreas;Missense Mutation;Modeling;Molecular Conformation;Mus;Mutate;Mutation;Oxidation-Reduction;Oxidative Stress;Perception;Pharmaceutical Preparations;Predisposition;Prevention;Program Development;Property;Proteins;Reporting;Series;Site;Solid Neoplasm;Sulfhydryl Compounds;System;TP53 gene;Testing;Therapeutic;Translations;Tumor Suppression;Tumor Suppressor Proteins;United States;Xenograft Model;cancer cell;cancer therapy;chemical synthesis;drug development;drug-like compound;experience;gain of function;improved;in vivo;mutant;neoplastic cell;novel therapeutic intervention;patient population;personalized cancer therapy;personalized strategies;preclinical evaluation;reconstitution;research clinical testing;side effect;small molecule;success;targeted treatment;therapeutic protein;therapeutic target;tissue culture;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor progression Developing corrector small molecules for reactivation of mutant p53 in cancer Project NarrativeThe gene encoding the tumor suppressor protein p53 is the most frequently mutatedgene in cancer. Therapeutics that restore p53 activity in cancer could havetransformative impact on treatment of cancer patients. This proposal explores strategiesto restore p53 activity in cancer. NCI 10675004 8/1/23 0:00 PAR-20-292 5R21CA267495-02 5 R21 CA 267495 2 "VENKATACHALAM, SUNDARESAN" 8/1/22 0:00 7/31/24 0:00 ZCA1-PCRB-9(M1)S 6981288 "KAISER, PETER " "RYCHNOVSKY, SCOTT D." 47 BIOCHEMISTRY 46705849 MJC5FCYQTPE6 46705849 MJC5FCYQTPE6 US 33.64852 -117.82136 577504 UNIVERSITY OF CALIFORNIA-IRVINE IRVINE CA SCHOOLS OF MEDICINE 926970001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 169239 NCI 114538 54701 PROJECT SUMMARYThe tumor suppressor protein p53 is the most frequently mutated protein in human cancers. About 600000new cancer patients in the United States are diagnosed each year with tumors expressing mutated p53. Mostof the mutations associated with p53 are missense mutations that affect one of six hotspot sites in the DNAbinding domain. These cancers express full length p53 that has lost tumor suppressor activity but acquiredgain-of-function oncomorphic properties that provide selective advantage to cancer cells.Therapeutic approaches targeting p53 are challenging and require reactivation of mutated p53. Developingsuch reactivation or corrector drugs is further complicated by very limited experience in pharma biotech andacademia in this domain. These challenges in exploring novel therapeutic approaches by developing p53corrector drugs have led to very slow and limited success in clinical trials with proposed p53 reactivatorcompounds. However one can argue that genuine p53 corrector drugs have not yet been tested in the clinicbecause in vivo the available compounds (i.e. APR-246 and other thiol reactive molecules) are most likely notacting on mutant p53 but rather exploit redox-sensitivity of cells expressing p53 mutants. Development ofgenuine p53 mutant corrector drugs that bind p53 and restore a wild-type like conformation/activity in p53cancer mutants thus remains a crucial goal with potentially very high impact.We have developed a small molecule series that binds the L1/S3 pocket of mutant p53 and thereby restoresDNA binding activity of mutant p53 in a reconstituted purified in vitro system. These results are reflected ininduction of p53 target gene expression when cells harboring p53 hotspot mutants are exposed to thesecompounds. Furthermore cell proliferation is halted and apoptosis is induced in a p53 mutant dependentmanner. Importantly growth of solid tumors carrying p53 mutants is blocked by this compound series in animalmodels. Tumors lacking p53 or expressing wild-type p53 are not affected by such treatment. Thesecompounds provide strong support for feasibility to develop drug-like molecules that can restore tumorsuppressor activity in p53 hotspot mutants. However these compounds act in the low micromolar range in cellculture systems and activity needs to be improved to generate lead compounds for drug development. Wepropose two parallel approaches to achieve this goal.This proposal will generate promising lead compounds for mutant p53 corrector drug development. 169239 +No NIH Category available Area;Biochemical;Biological;Cells;Cellular biology;Communication;Complex;Development;FRAP1 gene;Family;Funding;Genetic;Genetic Models;Goals;Grant;Growth;Growth Factor;Guanosine Triphosphate Phosphohydrolases;Human;Investigation;Link;Malignant Neoplasms;Metabolic;Metabolic Pathway;Methodology;Molecular;Monomeric GTP-Binding Proteins;Normal Cell;Nutrient;Oncogenes;Oncogenic;PIK3CG gene;Pathway interactions;Proliferating;Publishing;Regulation;Research;Resources;Role;Signal Pathway;Signal Transduction;Therapeutic;Tuberous Sclerosis;Tumor Suppressor Proteins;Work;analytical tool;anticancer research;cancer cell;cell growth;in vivo;innovation;mTOR Inhibitor;member;mouse model;novel;novel therapeutic intervention;protein complex;therapeutic target;tumor;tumor metabolism;tumor microenvironment;uncontrolled cell growth Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer PROJECT NARRATIVEResearch under this grant is aimed at defining how the major lines of communication function in normal cellsand become dysfunctional in cancer cells to promote uncontrolled cell growth with a focus on one of themost commonly activated pathways in human cancers (the mTOR pathway). Development of noveltherapeutic strategies to destroy cancer cells displaying activation of this pathway is a major aim of thesestudies. NCI 10674995 6/12/23 0:00 PAR-21-333 5R35CA197459-09 5 R35 CA 197459 9 "MAAS, STEFAN" 8/1/22 0:00 7/31/29 0:00 ZCA1-GRB-I(M1) 8471894 "MANNING, BRENDAN D." Not Applicable 7 GENETICS 149617367 UNVDZNFA8R29 149617367 UNVDZNFA8R29 US 42.335306 -71.102775 3212904 HARVARD SCHOOL OF PUBLIC HEALTH BOSTON MA SCHOOLS OF PUBLIC HEALTH 21156028 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 932003 NCI 602462 338056 ABSTRACTThe major growth factor signaling pathways in normal cells (e.g. PI3K and RAS) are also the ones that aremost frequently genetically activated in cancer cells leading to cell autonomous growth and proliferation.mTOR complex 1 (mTORC1) is a shared downstream effector of these pathways and a central driver of cellgrowth and is aberrantly activated in the majority of human cancers. This activation occurs through a networkof upstream oncogenes and tumor suppressors that converge on a small G protein switch directly upstream ofmTORC1. This switch involves the tuberous sclerosis complex (TSC) tumor suppressors which form a proteincomplex (the TSC complex) that regulates a member of the Ras family of GTPases called Rheb an essentialdirect activator of mTORC1. Our previous studies have found that the TSC complex and Rheb serve as thekey molecular link between the PI3K pathway and mTORC1 signaling and that this regulation promoteschanges in key metabolic pathways underlying cell growth in both normal and cancer cells. Supported by thelast 6 years of funding from this R35 we have greatly advanced and expanded this area of research openingup several previously unforeseen new avenues of investigation through both published and ongoing work.Taking advantage of the long-term stable funding afforded by this mechanism we have also developedinnovative new genetic mouse models and methodologies that set us up for new breakthrough discoveriesover the next cycle of this grant especially related to PI3K-mTOR signaling within the poorly understoodnutrient and metabolic niche of the tumor microenvironment which is a major focus of this renewal. Fourmajor areas of research will include defining A) the biochemical and pathophysiological mechanismsunderlying the regulation and function of the TSC complex B) the capacity of mTORC1 to properly integrateoncogenic and nutrient signals within the tumor microenvironment C) the metabolic consequences of PI3K-mTOR activation and inhibition in tumors of different origins stages and niches and D) targetable metabolicvulnerabilities accompanying its aberrant regulation in tumors. While key mechanistic questions regarding thisubiquitous signaling network will continue to be answered through rigorous biochemical and cell biologicalstudies much of our efforts will combine novel genetic models with state-of-the-art analytical tools to definethe salient in vivo features of the PI3K-mTOR network as they apply to tumor metabolism growth andprogression. The overarching goals of our research are to define the precise roles of this signaling network incancer and how best to therapeutically target the high percentage of tumors with uncontrolled mTORC1signaling beyond the single-agent use of mTOR inhibitors. I am confident that if given the resources we willcontinue to gain a deeper understanding of cancer cell biology the tumor microenvironment and therapeuticvulnerabilities while also making leaps into new currently unpredictable domains of cancer research. 932003 +No NIH Category available Acceleration;Acute;Address;Affect;Animal Model;Animals;Binding Proteins;Bioinformatics;Biology;CRISPR-mediated transcriptional activation;CRISPR/Cas technology;Cell Line;Cell model;Cells;Chemicals;Chromatin;Collaborations;Development;Disease;Disease Progression;Dissociation;Dominant-Negative Mutation;Down-Regulation;Doxycycline;Effectiveness;Event;Gene Expression;Genes;Genetic Models;Genetic Transcription;Goals;Human;Inflammatory;KRAS2 gene;Knock-out;Lung Adenocarcinoma;MALAT1 gene;Malignant Neoplasms;Mediating;Mediator;Modeling;Molecular;Molecular Biology;Mus;Neoplasm Metastasis;Patients;Predisposition;Prognosis;RNA Splicing;Regulation;Role;Series;Signal Transduction;System;TP53 gene;Technology;Testing;Therapeutic;Time;Tumor Promotion;Untranslated RNA;Up-Regulation;Work;cohort;conditional knockout;cytokine;design;differential expression;experimental study;feasibility testing;gain of function;innovation;mouse model;novel;novel therapeutic intervention;overexpression;patient prognosis;pleiotropism;posttranscriptional;programs;therapeutic target;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis;tumorigenic Deregulation of long noncoding RNAs in cancer Project NarrativeLong noncoding RNAs (lncRNAs) are a poorly understood class of genes that are subject to frequentderegulation in lung adenocarcinoma suggesting a potential wealth of unexplored therapeutic targets. Wehave developed innovative approaches to model the aberrant expression of lncRNA in cell and animal modelsof lung adenocarcinoma providing a unique opportunity to study the contributions of lncRNAs to thedevelopment and treatment of this aggressive disease. NCI 10674961 6/29/23 0:00 PA-20-185 5R01CA262286-02 5 R01 CA 262286 2 "JOHNSON, RONALD L" 8/1/22 0:00 7/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 10405163 "DIMITROVA, NADYA M" Not Applicable 3 BIOCHEMISTRY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF ARTS AND SCIENCES 65208327 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 495683 NCI 303857 191826 Project Summary/AbstractAberrantly high expression of the long noncoding RNA (lncRNA) Malat1 is strongly associated with lungadenocarcinoma (LUAD) progression and poor patient prognosis and has been pursued as a potentialtherapeutic target. However these correlative observations do not reveal whether the aberrant expression ofMalat1 is a driver of tumorigenesis and what are the mechanisms by which Malat1 overexpression promotesdisease progression. In preliminary studies we developed an innovative CRISPR activation (CRISPRa)system that successfully models Malat1 overexpression in patient-derived cell lines and autochthonous murinemodels of LUAD. Strikingly we uncovered that tumor-specific overexpression of Malat1 at the time of tumorinitiation is sufficient to accelerate the progression of murine LUAD to aggressive and metastatic diseasedemonstrating that Malat1 overexpression is a driver of cancer development. We further determined thatMalat1 overexpression leads to pleiotropic effects on the tumor microenvironment through the alteredexpression of cytokines and stromal factors. Based on these promising findings our central hypothesis is thatprogressive accumulation of Malat1 in LUAD drives the development of aggressive disease through theactivation of a metastasis-promoting gene expression program and the establishment of a pro-metastatic tumormicroenvironment. In Aim 1 we describe our use of advanced temporally controlled mouse models to clarifythe stage of tumorigenesis when overexpression of Malat1 promotes tumor progression the requirement forsustained Malat1 overexpression and the window of opportunity when downregulation of Malat1 may have atherapeutic impact. Aim 2 seeks to investigate the non-cell autonomous effects of Malat1 overexpression in theestablishment of a pro-metastatic niche. We propose to perform detailed characterization of Malat1-dependentchanges in the tumor stroma at different stages of tumorigenesis as well as use genetic models to explore thecontributions of candidate secreted factors such as inflammatory cytokines. Finally Aim 3 outlines our plans toelucidate the molecular mechanism by which overexpressed Malat1 alters the expression of tumormicroenvironment effectors. We propose to utilize state-of-the-art molecular biology approaches and work withlong-term collaborators who are experts in bioinformatics and chemical biology to determine whether Malat1overexpression affects target genes at the transcriptional or post-transcriptional level through dominantnegative or gain-of-function mechanisms and through direct or indirect activities. In summary this proposaloutlines a highly innovative experimental and conceptual framework for dissecting the poorly understood roleof overexpressed Malat1 as a driver in LUAD. Beyond Malat1 the broad significance of this work lies in itspotential to elucidate how aberrantly expressed lncRNAs modulate cancer development and to uncoverwhether targeting aberrantly expressed lncRNAs might hold a therapeutic promise. 495683 +No NIH Category available Address;Affect;Aneuploidy;Animals;Back;Bioinformatics;Biological;Breast Cancer Model;Cancer Diagnostics;Cancer Model;Cause of Death;Cessation of life;Characteristics;Classification;Clinical;Clinical Management;Clinical Trials Design;Communities;Complex;Data;Data Set;Derivation procedure;Development;Diagnostic;Disease;Disease Management;Disease Progression;Disease model;Epigenetic Process;Event;Evolution;Foundations;Future;Gene Expression Profiling;Gene Mutation;Genes;Genetic;Goals;Heterogeneity;Human;Individual;Interdisciplinary Study;Investigation;Learning;Lesion;Life;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammary Gland Parenchyma;Maps;Mathematics;Modeling;Molecular;Molecular Profiling;Mutation;Operative Surgical Procedures;Outcome;Pathologic;Pathway interactions;Patients;Pattern;Phenotype;Prevalence;Process;Progressive Disease;Recurrence;Research;Research Design;Resources;Sampling;Series;Specimen;Structure;Subgroup;System;Systemic Therapy;Therapeutic;Therapeutic Intervention;Time;Tissue Sample;Tissues;Trees;Tumor Biology;Tumor Tissue;Validation;Visualization;Work;anticancer research;breast cancer progression;cancer diagnosis;carcinogenesis;computational suite;computerized tools;design;disease natural history;experimental study;genomic data;high dimensionality;improved;innovation;insight;malignant breast neoplasm;molecular marker;molecular subtypes;multidimensional data;novel;novel strategies;pressure;prognostic;targeted treatment;theories;tool;tumor;tumor progression Disease Progression Modeling of Bladder Cancer PROJECT NARRATIVEHuman cancer is one of the leading causes of death worldwide a reflection of the fact that the molecular basisof the disease is yet poorly understood. We propose to apply an advanced computational strategy to build acancer progression model using genomic data obtained from excised tumor tissue samples (static data). Thedelineation of the dynamic processes involved and the identification of pivotal molecular events that drivestepwise cancer progression will provide new insights into tumor biology and guide the development ofimproved cancer diagnostics prognostics and targeted therapeutics. The over-arching goal of the project is todevelop an annotated bladder cancer roadmap that can be used by ourselves and the research community toprovide insights into the mechanisms and factors that drive bladder cancer to malignancy. NCI 10674950 8/16/23 0:00 PA-20-185 5R01CA266113-02 5 R01 CA 266113 2 "MILLER, DAVID J" 8/1/22 0:00 7/31/27 0:00 Modeling and Analysis of Biological Systems Study Section[MABS] 8339086 "GOODISON, STEVE " "SUN, YIJUN " 5 Unavailable 153223151 GKPBCFV1QMM3 153223151 GKPBCFV1QMM3 US 30.264703 -81.444793 4976105 MAYO CLINIC JACKSONVILLE JACKSONVILLE FL Other Domestic Non-Profits 322241865 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 485702 NCI 375784 109918 PROJECT SUMMARY/ABSTRACTCarcinogenesis may be viewed as a multistep evolutionary process characterized by accumulation ofgenetic and epigenetic alterations driven by selective pressures imposed by the microenvironment. Thedelineation of tumor evolution would provide invaluable insights into tumor biology and lay a foundation forthe development of improved diagnostics prognostics and targeted therapeutics.Time-series data are ideal for deriving models of dynamic progression but this is impossible to collect inhuman cancer because of the need for timely surgical intervention and systemic therapy which alter thenatural history of the disease and exert selection pressures that affect tumor evolution. To overcome thehuman serial sampling issue we have devised a computational strategy to understand cancer evolution byderiving pseudo time-series data from static samples (excised tissue specimens). The design is based onthe rationale that each sample can provide a snapshot of the disease process and if the number of samplesis sufficiently large we can recover a visualization of disease progression. We demonstrated the utility of thedeveloped pipeline - referred to as CancerMapp - by applying it to the analysis of gene expression data fromover 9000 breast tissue samples. Breast cancer progression modeling identified 2 major trajectories tomalignancy an early split to basal tumors and a continuum through luminal tumors. The computationalapproach and the breast cancer model concept have since been validated in independent studies and ourfindings have provided the impetus for a number of investigations at our institute and by colleagues in thefield.Built logically on our previous work we now propose a large-scale interdisciplinary research plan to derive aprogression model for bladder cancer (BLCA). BLCA is among the five most common malignanciesworldwide. In the US alone new cases for 2018 are estimated at 72500 with estimated deaths at over15000 figures that are anticipated to increase in the near future. Classification of BLCA into multiplemolecular subtypes has recently been proposed and has the potential to impact clinical management.Nonetheless significant biologic subgroup heterogeneity remains and more work is needed before a unifiedclassification system can gain wide acceptance. More importantly there is as yet no understanding of theinter-relationships between subtypes. Insights into how subtypes are related and how cancer evolutioninfluences the observed changes in molecular pathologic phenotype is the next level of analysis requiredand is the focus of this proposal.The proposed work will inform a range of research directions that were previously unattainable. Thederivation of a BLCA roadmap and the identification of pivotal molecular events that drive stepwise cancerprogression will provide new insights into tumor biology and guide the development of improved cancerdiagnostics prognostics and targeted therapeutics. Annotated progression maps can also guide the designof clinical trials and animal studies to focus on pivotal points of cancer development which may yield thebest return with limited resources. 485702 +No NIH Category available 2 arm randomized control trial;Address;Adherence;Adult;American Cancer Society;Cancer Intervention;Caring;Clinical;Collaborations;Colonoscopy;Colorectal Cancer;Cost Analysis;Counseling;Coupled;Data;Decision Making;Detection;Disparity;Education;Ethnic Origin;Ethnic Population;Evidence based practice;Federally Qualified Health Center;Funding;Guidelines;Health;Health Care Research;Health Personnel;Health Sciences;Healthcare Systems;Instruction;Intervention;Knowledge;Learning;Literature;Louisiana;Low Income Population;Low income;Medicaid;Methods;Minority Groups;Motivation;National Cancer Institute;Patient Preferences;Patients;Preparation;Printing;Provider;Race;Research;Resources;Rural;Rural Community;Rural Health;Rural Health Centers;Rural Population;Schedule;Screening for cancer;Services;Site;Socioeconomic Status;Standardization;Technology;Telephone;Testing;Text;Text Messaging;Universities;adenoma;arm;colon cancer patients;colorectal cancer screening;design;effectiveness study;effectiveness testing;ethnic diversity;evidence base;follow-up;gender disparity;health disparity;health inequalities;health literacy;implementation barriers;improved;literacy;literate;novel;outreach;patient oriented;patient population;personalized approach;point of care;primary care patient;primary care provider;primary outcome;racial disparity;racial diversity;racial minority;rural area;rural dwellers;rural health clinic;rural patients;screening;screening disparities;screening guidelines;sex;shared decision making;treatment as usual;usual care arm Patient-Centered Reminders to Inform Motivate and Engage Colorectal Cancer Screening Adherence in Rural Communities: The PRIME-CRC Trial Project NarrativeDespite significant gains in colorectal cancer (CRC) screening promotion disparities persistamong low-income individuals those with fewer years of education racial/ethnic minorities andrural populations. Residents of rural areas suffer significant health inequities and encounterbarriers to CRC screening which are often overlooked in healthcare research. This project seeksto address these disparities with a health literacy shared decision making strategy coupled withtailored stepped care automated telephone outreach (recorded by the patients primary careprovider) that promotes long-term adherence to CRC screening in resource-limited rural healthcenters via colonoscopy or annual fecal immunochemical test (FIT). NCI 10674940 5/5/23 0:00 PA-18-722 5R01CA240496-04 5 R01 CA 240496 4 "SARMA, ELIZABETH ANNE" 6/1/20 0:00 5/31/25 0:00 Dissemination and Implementation Research in Health Study Section[DIRH] 3105512 "ARNOLD, CONNIE L." Not Applicable 4 INTERNAL MEDICINE/MEDICINE 95439774 FA4VKPTJRLY8 95439774 FA4VKPTJRLY8 US 32.481648 -93.760821 577905 LOUISIANA STATE UNIV HSC SHREVEPORT SHREVEPORT LA SCHOOLS OF MEDICINE 711034228 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 394483 NCI 315330 79153 Project Summary/Abstract: We will expand an existing patient-centered health literacy strategy to promotelonger-term adherence to colorectal cancer (CRC) screening in resource-limited rural health clinics viacolonoscopy or annual fecal immunochemical test (FIT). Guided by recently completed trials we will leverageconsumer technologies that are now available in rural areas and implement a multifaceted approach -designed for scale in resource-limited federally qualified health centers (FQHCs). While significant gains havebeen made to improve CRC screening compliance with those guidelines is sub-optimal and disparities remain.In particular adults who receive care at rural FQHCs that have limited resources struggle to initiate andmaintain annual CRC screening via the most common method FIT. Over the past decade our team hasstudied the effectiveness of specific interventions to enhance initial and repeat CRC screening completionamong lower income lower health literate racial/ethnically diverse adults in rural FQHC settings. The majorityof patients will complete the initial test (67% - 69%) yet fewer (32% - 40%) complete an annual test in years 2and 3. This indicates a stepped care approach is needed to promote long-term CRC screening. Our ruralhealth literacy interventions have until now been limited to the FIT due to restrictions of state Medicaidcoverage and clinical bandwidth of colonoscopy services available to rural FQHCs. Changes to Medicaid havenow expanded the availability of colonoscopy. We now propose a novel intervention guided by evidencelearned from our previous studies and recent literature - the Patient-centered Reminders to Inform Motivateand Engage-CRC Screening (PRIME-CRC).In our proposed 2-arm randomized control trial (N=1200) bothPRIME-CRC and enhanced usual care arms will receive our health literacy evidence-based practices fordelivering CRC patient information and counseling to aid patient decision making for selecting FIT orcolonoscopy and simplified test instructions. PRIME-CRC will additionally have a stepped care approach forreminding patients on proper CRC screening preparation for scheduled colonoscopy or completion of annualFIT. Patients in the PRIME-CRC arm will have frequent follow-up with tailored contact via automated call orSMS text (based on patient preference) from their healthcare provider (audio recorded or personalized text).The primary outcome will be completion of either colonoscopy or annual FIT over 3 years. Our specific aimsare to: Test the effectiveness of the PRIME-CRC intervention to improve CRC screening completion rates inrural FQHCs compared to enhanced usual care. Investigate whether the intervention can reduce CRCscreening disparities by patient health literacy race or sex. Determine the fidelity or reliability of PRIME-CRCcomponents and explore patient provider and healthcare system barriers to implementation. Evaluate thecost associated with the intervention from a FQHC perspective. This study extends our teams longstandingcollaboration on health literacy health disparities rural health and cancer screening. 394483 +No NIH Category available Genetic;Malignant Neoplasms;Molecular;Training Programs;cellular targeting Molecular Genetic and Cellular Targets of Cancer Training Program Narrative:The goal of this training program at the University of Minnesota Masonic Cancer Center is to train a diversegroup of highly qualified individuals to become future scientific leaders working in basic and translationallaboratory research and/or science-related careers to address fundamental problems in cancer biology. Astrong scientific work force and the new knowledge they gain will translate to better cancer outcomes. NCI 10674938 8/11/23 0:00 PA-18-403 5T32CA009138-49 5 T32 CA 9138 49 "LIM, SUSAN E" 7/1/80 0:00 7/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1868359 "LANGE, CAROL A" Not Applicable 5 INTERNAL MEDICINE/MEDICINE 555917996 KABJZBBJ4B54 555917996 KABJZBBJ4B54 US 44.975143 -93.227003 1450402 UNIVERSITY OF MINNESOTA MINNEAPOLIS MN SCHOOLS OF MEDICINE 554552070 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 480502 NCI 591948 39090 Abstract:The Molecular Genetic and Cellular Targets of Cancer Training Program (TCTP; formerly the Cancer BiologyTraining Grant) at the University of Minnesota Masonic Cancer Center (MCC) combines rigorous training inlaboratory-based cancer research with interdisciplinary and translational perspectives that prepares TCTPtrainees for independent research careers focused on discovery of the mechanisms of cancer development andprogression. Our trainees who do not choose an academic path are highly competitive for leadership positionsin a variety of science-related careers. Now in its 44th year of NCI support the TCTP supports 4 predoctoral and5 postdoctoral trainees. The 36 preceptors provide research training in three interrelated areas of moleculargenetic and cellular cancer research that represent particular strengths at the MCC: molecular targets & cancercell signaling cancer genetics/epigenetics & DNA damage/repair and cellular targets & cancerimmunology/immunotherapy. The Program consists of intensive one-on-one research mentoring didactictraining in cancer biology and basic and translational cancer research and regular meetings where traineesdevelop critical presentation skills obtain feedback and establish new research collaborations. Trainees alsoparticipate in networking opportunities with prominent external cancer research scientists and take part in careerdevelopment activities. Historically participation of the TCTP Director and Steering Committee members in keyleadership positions associated with biomedical research and technology graduate education careerdevelopment mentoring and trainee recruitment at the University of Minnesota have enhanced the TCTPapplicant pool and improved the career outcomes of trainees. These efforts have also enhanced our success atrecruiting individuals from under-represented groups. New initiatives during the next funding period include arecurring financial commitment from the Medical School and the MCC to support a postdoctoral fellow (salaryand benefits) expanding our training capability to 6 postdoctoral trainees. In addition we will implement shorttraining modules focused on essential skill sets requested by our postdoctoral trainees including cancerbioinformatics/omics emerging technologies and hot topics in cancer research as well as new workshopsfocused on navigating career transitions. Finally we have recently partnered with the University of WisconsinTraining in Cancer Biology Training Grant for program-specific retreats. These regional gatherings designed toenhance trainee networking and regional exposure will include scientific content as well as career developmentand mentoring activities designed to meet the specific needs of pre- vs. postdoctoral trainees. Theseimprovements will ensure a robust future of the highest quality training in the molecular genetic and cellularmechanisms of cancer at the University of Minnesota. The TCTP is central to the MCCs mission of educatingand training the next generation of scientists and leaders pursuing solutions to the problem of cancer. 480502 +No NIH Category available Agreement;Biochemistry;Biological Assay;Biological Markers;Canada;Cervical;Clinical;Custom;DNA analysis;Development;Ensure;Genetic;Genome;Genomics;Health;Irrigation;Laboratories;Machine Learning;Methylation;Patients;Performance;Phase;Probability;Proteins;Proteomics;Qualifying;Recovery;Research Personnel;Sampling;Scheme;Screening for Ovarian Cancer;Signal Transduction;Specific qualifier value;Swab;Testing;Training;Universities;Uterus;Validation;Work;cohort;experience;genome wide methylation;protein biomarkers;research clinical testing;success Biomarker Reference Laboratory (BRL) n/a NCI 10674914 8/30/23 0:00 RFA-CA-21-035 5U2CCA271871-02 5 U2C CA 271871 2 9/1/22 0:00 8/31/27 0:00 ZCA1-PCRB-D 8959 11598306 "KULASINGAM, VATHANY " Not Applicable 8 Unavailable 73130411 FLJ7DQKLL226 73130411 FLJ7DQKLL226 US 42.363198 -71.068772 4907701 MASSACHUSETTS GENERAL HOSPITAL BOSTON MA Independent Hospitals 21142621 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 Other Research-Related 2023 183554 122422 61132 Project Summary/Abstract Biomarker Reference LaboratoryThe proposed BCC will develop sensitive genomic and proteomic tests for the early detection of ovarian cancerin uterine lavage samples. The genomic component will assess genome-wide methylation and the proteomiccomponent will assay proteins using the proximity extension assays (PEAs) which provide relative quantitationbetween samples. The test will be optimized on samples from a training cohort. The methylation signal will beaggregated and optimized across the genome using machine learning approaches by the biomarkerdevelopmental lab (BDL). Optimization of the proteomic component will identify a custom panel of up to 21proteins for absolute quantitation. The Biomarker Reference Laboratory (BRL) will work with Fulgent Geneticsto ensure that optimized methylation signal and the custom panel of protein assays comply with CLIA/CAPstandards and achieve analytical performance metrics specified by the BRL. The PI of BRL has extensiveexperience in ensuring assays in her clinical biochemistry lab serving the University Health Network thelargest in Canada achieve clinical grade before analysis of patient samples are implemented in the labsworkstream. The BRL will apply similar standards agreed upon by all investigators in the BCC to themethylation aggregated signal the custom panel and the classifier formed by combining the methylationsignal with the protein abundances in the custom panel. This test using the classifier combining the genomicand proteomic signals qualified with these standards will give the highest probability of success for a test forthe early detection of ovarian cancer when applied to uterine lavage samples from an independent validationcohort and to cervical swabs as a readily accessible biospecimen with high patient acceptability. +No NIH Category available Accreditation;Authorization documentation;Benchmarking;Biometry;Caliber;Cancer Center;Cancer Center Support Grant;Cancer Control;Clinical;Clinical Data;Clinical Protocols;Clinical Research;Clinical Trials;Complementary Medicine;Conduct Clinical Trials;Conflict of Interest;Consultations;Data;Disease;Doctor of Philosophy;Early Therapeutic-Clinical Trials Network;Ensure;Goals;Industry;Institution;Institutional Review Boards;Malignant Neoplasms;Medical Oncology;Modality;Monitor;Names;Nursing Faculty;Pathologist;Patients;Pediatric Oncology;Peer Review;Pharmacists;Protocols documentation;Radiation Oncology;Recommendation;Research Design;Research Personnel;Resources;Review Committee;Role;Safety;Surgical Oncology;System;Work;authority;biobehavior;cancer clinical trial;cancer epidemiology;cancer prevention;cancer research center director;data management;data quality;investigator-initiated trial;member;oncology trial;tumor progression Protocol Review and Monitoring System n/a NCI 10674913 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8958 1928120 "APPLEMAN, LEONARD J." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 85170 53566 31604 Abstract: Protocol Review and Monitoring System (PRMS)Chaired by Leonard Appleman MD PhD Hillman Cancer Centers (HCC) Protocol Review Committees(PRC) (Protocol Review and Monitoring System (PRC/PRMS) goal is to promote the highest scientific caliberclinical trials and ensure adequate internal oversight of the scientific aspects of cancer clinical trials with afocus on scientific merit priorities and progress following these specific aims: 1) provide clinical protocolscientific review before IRB submission 2) monitor open clinical trials for ongoing scientific merit andprogress and 3) close trials that fail to meet benchmarks for continued scientific merit and timely accrual.The priority order of clinical trials for are as follows: external peer-reviewed investigator-initiated trialsinstitutional (investigator-initiated) clinical trials investigator-initiated industry-supported trials national (ET-CTN and NCTN) trials and industry-sponsored trials. PRC/PRMS works in concert with Clinical Protocol andData Management (CPDM) and the Data and Safety Monitoring Committee (DSMC) to ensure safe andefficient conduct of clinical trials at HCC. The PRC/PRMS role is distinct from the DSMC responsibility ofensuring protocol safety and data quality. The PRC/PRMS also works in conjunction with three other parts ofthe clinical trials enterprise: the IRB the UPMC HCC Biostatistics Facility and the UPMC HCCDisease/Modality Center (DMC) teams. The PRC/PRMS has three committees (A B and C). Committees Aand B alternately review all oncology trials such that one of the Committees meets every 2 weeks to ensurerapid review of studies and facilitate prompt progression of cancer protocols from the PRC/PRMS to theresponsible IRB. Committee C reviews biobehavioral cancer epidemiology cancer prevention and controland complementary medicine protocols on an ad hoc basis as required. The PRC/PRMS members areappointed by the HCC Director Robert Ferris MD PhD in consultation with Antoinette Wozniak MD HCCAssociate Director for Clinical Research. The PRC/PRMS committee consists of representative keyacademic and clinical faculty from medical oncology radiation oncology surgical oncology pediatriconcology and also includes biostatisticians pharmacists CPDM staff clinical fellows and basic cancerresearchers. Pathologists who are members of our DMC teams may be assigned ad hoc as required. ThePRC/PRMS evaluates each protocol for study design scientific quality and availability of patient andfinancial resources required to complete the proposed trial. PRC/PRMS approval of cancer clinical trials isrequired prior to study submission to the Pitt IRB NCI CIRB or other accredited IRBs. Once a trial isopened the PRC/PRMS reviews its ongoing scientific merit and progress every 6 months. PRC/PRMS hasthe authority to request explanations for slow accrual and plans to increase accrual from the study PI allowslow accruing trials to remain open with monitoring or close studies for lack of scientific merit or progress orsafety reasons (upon DSMC recommendations). +No NIH Category available Achievement;Advisory Committees;Appointment;Area;Award;Basic Science;Cancer Center;Cancer Center Support Grant;Catchment Area;Chad;Clinical Cancer Center;Clinical Research;Clinical Sciences;Communities;Community Healthcare;Community Outreach;Decision Making;Doctor of Philosophy;Effectiveness;Ensure;Equipment;Evaluation;Evaluation Research;Event;Extramural Activities;Feedback;Funding;Future;Goals;Growth and Development function;Health Professional;Individual;Institution;Leadership;Mission;Monitor;Operations Research;Policies;Population;Population Sciences;Process;Research;Research Activity;Research Personnel;Research Priority;Research Support;Resource Sharing;Resources;Science;Site Visit;Strategic Planning;Strategic vision;Structure;Surveys;System;Training and Education;Translational Research;Vision;Work;anticancer research;cancer education;cancer research center director;community engagement;health equity;improved;meetings;member;operation;organizational structure;outreach;programs;recruit;symposium;training opportunity Leadership Planning and Evaluation n/a NCI 10674896 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8950 1900219 "FERRIS, ROBERT L" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 1007573 633694 373879 Abstract: Leadership Planning and EvaluationUPMC Hillman Cancer Centers (HCC) planning and evaluation activities are well-developed and provideinvaluable guidance to the HCC Senior Leadership Team (SLT): Director (Robert L. Ferris MD PhD) HCCDeputy Director (Edward Chu MD) Deputy Director for Research Administration (Chad A. Ellis PhD) and theAssociate Directors for Basic Research (Shivendra Singh PhD) Clinical Research (Antoinette Wozniak MD)Population Sciences (Jian-Min Yuan MD PhD) Training and Education (Christopher Bakkenist PhD)Catchment Area Research (Margaret Rosenzweig PhD CRNP-C AOCN FAAN) and Health Equity andCommunity Outreach & Engagement (Linda Robertson RN MSN DrPH). Individually accomplished withstrong scientific and leadership achievements they work collectively as the SLT HCCs primary decision-making body for setting the Centers overall strategic direction. The SLT provides direction in issues relevant toHCC operations management and policy and oversees all research activities. This leadership team also setsbudgetary and fiscal priorities and reviews HCC membership.In addition to the SLT several key internal and external governance structures provide the primary means bywhich the HCC conducts ongoing planning and evaluation: the Research Executive Advisory Committee(REAC) Shared Resources Oversight Committee (SROC) Clinical Research Oversight Committee (CROC)Committee for Health Equity and Community Outreach & Engagement (CHECOE) Committee for Excellencein Cancer Education and Training (CECET) Facilities and Common Equipment Committee (FACE) and theInternal and External Advisory Boards. The REAC includes the SLT Program and Shared Resourcesleadership and key senior HCC members and is an effective mechanism for information exchange amongHCC stakeholders and serves as the primary forum for strategic planning. The External Advisory Board (EAB)comprising recognized leaders in basic clinical translational and population sciences and cancer centeradministration meets at least annually to review all aspects of HCC operations and new initiatives. Since hisappointment Dr. Ferris augmented EAB membership to better align with HCC scientific priorities and goals.Additional planning input is provided by retreats other Center advisory committees surveys and ad hocexternal reviews.With careful planning and critical input from the different advisory groups HCC leadership initiated animportant strategic visioning and planning process reorganized the research program structure and creatednew committees to continuously improve oversight and governance. These coordinated teams provide criticaladvice and guidance ensuring that the HCC effectively sets priorities and pursues objectives that promote itsmission. +No NIH Category available Address;Adopted;Advisory Committees;Aging;Appointment;Area;Attention;Award;Basic Science;Behavior;Bioinformatics;Cancer Center;Cancer Center Support Grant;Catchment Area;Categories;Clinical;Clinical Investigator;Clinical Sciences;Clinical Trials;Collaborations;Communities;Core Facility;Development;Education;Ensure;Evaluation;Extramural Activities;Faculty;Faculty Recruitment;Funding;Goals;Grant;Guidelines;Incubated;Institution;Investments;Leadership;Malignant Neoplasms;NCI Center for Cancer Research;Obesity;Pilot Projects;Population;Population Sciences;Preparation;Process;Research;Research Personnel;Research Priority;Research Project Grants;Resource Sharing;Science;Scientist;Secure;Strategic Planning;Strategic vision;Translating;Translational Research;Translations;Vision;Work;anticancer research;cancer genomics;cancer research center director;care delivery;clinical care;equipment acquisition;fundamental research;high risk;improved;innovation;member;metabolomics;microbiome;microbiome research;new technology;novel strategies;population survey;programs;recruit;success;translational immunology;translational scientist;virology Developmental Funds n/a NCI 10674891 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8948 1900219 "FERRIS, ROBERT L" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 776186 488167 288019 Abstract: Developmental FundsCancer Center Support Grant (CCSG) Developmental Funds provide discretionary support to help HillmanCancer Center (HCC) achieve the goals established during strategic planning and evaluation activities. Duringthe current period HCC used these funds to make key faculty recruitments launch innovative ideas adopttechnical advances within our Shared Resources and support Staff Investigators. The HCC Senior LeadershipTeam (SLT) determines the priorities for the allocation of Developmental Funds and supplemental institutionalsupport with input from the Research Executive Advisory Committee (REAC) and the External Advisory Board(EAB) to ensure alignment with CCSG guidelines and the HCC strategic plan. CCSG Developmental Fundssupported 10 faculty recruits; 21 pilot projects that allowed members to pursue innovative high-risk ideas orwork in high priority research areas; added new technologies and capabilities for re-configuration of HCCShared Resources; and supported 3 Staff Investigators who significantly contributed to research clinical andeducational efforts at HCC.Developmental Funds leveraged institutional support and generated a significant return on investment with$948K CCSG funds allocated to 10 new faculty recruits over this grant period generating a total of $19.5M inexternal awards and clinical trials; a 20.5-fold return on investment (ROI). The $19.5M includes $7.5M millionin NCI funding an ROI of 7.9-fold on the invested CCSG funds. Given the successful use of DevelopmentalFunds in the current project period we request $534736 per year to be used in the following categories: 1)Recruit faculty in areas of strategic need to strengthen basic clinical translational and population sciencesresearch; 2) Support pilot projects that allow HCC scientists to pursue innovative high-risk ideas or work inhigh priority research areas including team science projects; 3) Develop new Shared Resources orcapabilities such as the Microbiome Facility and Population Survey Facility; and 4) Support CCSG ResearchClinical and Early-Stage Clinical Staff Investigators to drive collaboration science and clinical activity acrossthe HCC. +No NIH Category available Adenocarcinoma;Adult;Affect;Angiogenesis Inhibition;Angiogenesis Inhibitors;Animals;Antibodies;Attenuated;Atypical adenomatous hyperplasia;Awareness;Binding;Biology;Blood Coagulation Disorders;Blood Vessels;Blood coagulation;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Cancer Patient;Carbon Dioxide;Categories;Cells;Clinic;Clinical Research;Collaborations;Colorectal;Data;Deterioration;Development;Disease;Dose;Drug Kinetics;Drug or chemical Tissue Distribution;Drug usage;Endothelial Cells;Endothelial Growth Factors Receptor;Ensure;Genes;Genetic;Growth;Health;Human;Hypertension;Hypothyroidism;Immune;Immune checkpoint inhibitor;Immunity;Immunosuppression;Immunotherapy;Intestines;KDR gene;Kidney;Knock-out;Knockout Mice;Life;Lung;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Molecular;Molecular Target;Molecular Weight;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mus;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Nutrient;Oncogenes;Oxygen;Pathologic;Pathway interactions;Patients;Perforation;Perfusion;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Physiologic Neovascularization;Physiological;Physiological Processes;Play;Process;Proteins;Proteinuria;Receptor Protein-Tyrosine Kinases;Regulatory T-Lymphocyte;Reporting;Resistance;Role;Safety;Signal Transduction;Signaling Molecule;Speed;Starvation;T cell infiltration;Testing;Testis;Therapeutic;Time;Tissues;Treatment Efficacy;Tumor Angiogenesis;Tumor Immunity;Tumor Tissue;Tyrosine Kinase Inhibitor;Vascular Endothelial Growth Factors;Vascular blood supply;Vascularization;angiogenesis;bevacizumab;blood vessel development;cancer cell;cancer therapy;chemotherapeutic agent;chemotherapy;cytotoxic;density;experimental study;gene function;immune function;improved;male fertility;neutralizing monoclonal antibodies;novel;pharmacodynamic biomarker;preclinical study;prion-like;receptor;response;restraint;selective expression;side effect;thrombotic;tumor;tumor growth;tumor microenvironment;tumor progression;tumor-immune system interactions;tumorigenic;vascular bed;wasting;wound healing Targeting of Doppel-axis to Control Lung Tumor Angiogenesis and Immunity Project narrativeAngiogenesis performs many essential bodily functions such as wound healing blood clotting and maintaining thehealth of blood vessels as well as it also drives blood vessel formation and immune functions in tumors; howevercurrent drugs cannot distinguish between angiogenesis in tumors and angiogenesis in heathy tissues because oftargeting key angiogenic molecules that are important for both heathy and disease conditions. We discovered thata protein called doppel is present only in tumor tissues but not in healthy tissues and that doppel collaborates withtumors creating new blood vessels for them. In this project we propose to establish doppel as a new player intumor causing them to branch their own vascular networks create immunosuppressive microenvironment andgrow and develop a drug that will specifically block doppel activity in tumors while eliminating the serious sideeffects of existing anti-angiogenic drugs. NCI 10674889 7/26/23 0:00 PA-20-185 5R01CA262788-02 5 R01 CA 262788 2 "SALOMON, RACHELLE" 8/1/22 0:00 7/31/27 0:00 Developmental Therapeutics Study Section[DT] 16171554 "AL-HILAL, TASLIM A" Not Applicable 16 BIOSTATISTICS & OTHER MATH SCI 132051285 C1DEGMMKC7W7 132051285 C1DEGMMKC7W7 US 31.770518 -106.504149 578405 UNIVERSITY OF TEXAS EL PASO EL PASO TX SCHOOLS OF ARTS AND SCIENCES 799680001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 342190 NCI 224175 118015 Project summaryTumors just like normal tissues require blood vessels to receive nutrients and oxygen and to eliminate wastes andcarbon dioxide. To ensure this blood supply tumors create their own vascular beds from established blood vesselsby a process called angiogenesis. This process plays a major role in tumor growth survival and invasiveness.Currently various monoclonal antibodies (mAb) and small-molecular-weight drugs are used to restrainangiogenesis and starve tumors of nutrients. Bevacizumab and ramucirumab for example are two mAbs that inhibitangiogenesis-bevacizumab by binding with vascular endothelial growth factors (VEGF) and ramucirumab byblocking VEGF receptors (VEGFR). When used alone or in combination with chemotherapy anti-angiogenic drugsslow down metastasis stop disease deterioration and extend the overall survival time of cancer patients. Howeverangiogenesis not only drives the growth of blood vessels in tumors it also performs many important physiologicalfunctions in the body. The good (physiological) angiogenesis regulates the thrombotic process maintains vasculartone and speeds up wound healing. Unfortunately current anti-angiogenic drugs indiscriminately inhibit both goodand bad (tumor-directed) angiogenesis thus resulting in blood-coagulation disorders hypertensionhypothyroidism proteinuria and bowel perforation. In principle it should be possible to reduce or eliminate manyof the side effects of current anti-angiogenic drugs by blocking signaling molecules that are expressed only in tumorendothelial cells (TECs) but not in normal endothelial cells (NECs). Recently we discovered that a prion-like proteincalled doppel is expressed only in TECs but not in NECs. In preliminary study we showed that (i) doppel isexpressed in both human and animal cancers; (ii) increased doppel expression in TECs (Dplhi-TECs) is associatedwith increased blood vessel density in tumors; (iii) doppel erasure from TECs and from mice (i.e. doppel knockout)reduces the number of vessels in tumors; (iv) anti-doppel mAb slows tumor growth in mice; and (v) doppel-knockoutmice shows higher ratio of intratumoral CD8 versus regulatory T cells. Thus we posit that Dplhi-TECs promoteneoangiogenesis and create an immunosuppressive TME and targeting of Dplhi-TECs using novel monoclonalantibodies increase the efficacy of chemo- and immune-therapies. We will test this assumption under three majorsets of experiments: (i) elucidate the molecular mechanisms by which doppel activates neoangiogenesis and tumorprogression in a spontaneous model of non-small cell lung carcinoma (NSCLC); (ii) assess the pharmacokineticspharmacodynamic and antitumor efficacy of anti-Doppel mAbs in KrasLSL-G12D;p53Frt/FRT mice in combination withchemotherapeutics; and (iii) assess how Dplhi-TECs control lung tumor immune microenvironment. This project hasboth basic and translational applicability because we will understand the biology of Dplhi-TECs in tumormicroenvironment as well use construct new mAbs to block this novel molecular target that has no known roles inphysiological angiogenesis. 342190 +No NIH Category available Antineoplastic Agents;Bioinformatics;Biological Assay;Cancer Center;Cancer Center Support Grant;Clinical;Clinical Data;Clinical Investigator;Clinical Protocols;Clinical Trials;Collaborations;Complement;Credentialing;Development;Developmental Therapeutics Program;Direct Costs;Doctor of Philosophy;Funding;Goals;Human;Industry;Interdisciplinary Study;Investigation;Laboratories;Leadership;Malignant Neoplasms;Mission;NCI Center for Cancer Research;National Cancer Institute;Peer Review;Phase;Publications;Publishing;Regimen;Research;Research Personnel;Research Support;Resistance;Resource Sharing;Schools;Science;Scientist;Therapeutic;Translating;Translational Research;Translations;Treatment Protocols;Universities;anticancer research;cancer pharmacology;cancer therapy;clinical development;data management;design;drug development;drug discovery;improved;innovation;inter-institutional;interest;member;novel;novel anticancer drug;novel therapeutics;pre-clinical;preclinical development;programs;recruit;translational scientist Cancer Therapeutics Program n/a NCI 10674880 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8944 1888578 "BRUFSKY, ADAM M" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 57679 36276 21403 Abstract: Cancer Therapeutics (CT)The overarching goal of the Cancer Therapeutics (CT) Program is to develop innovative approaches todiscover design develop and validate novel anticancer agents and combination regimens for the treatment ofhuman cancers. To achieve this mission the Program focuses on three main themes: (1) discover and developin a pre-clinical setting novel targets and assays to complement the innovative approaches to drug discoverynovel agents and combination regimens; (2) investigate the mechanisms of action of new and existinganticancer agents; and (3) conduct early-phase (I/II) clinical trials with a focus on translation of UPMC HillmanCancer Center (HCC) science and discoveries of novel agents as well as in partnership with the NationalCancer Institute (NCI) NCI cancer centers other academic centers cooperative groups and industry. Thestrategy for successfully carrying out this mission requires the involvement of the entire continuum of basicpreclinical and clinical/translational research. Under the leadership of Adam Brufsky MD PhD EdwardChu MD and Peter Wipf PhD CT has 58 members representing 16 academic departments and 5 schoolswithin the University of Pittsburgh. CT members conduct cancer-focused research supported by $14.9M in totalannual direct costs funding of which $2.8M is NCI funding $2.0M is other peer-reviewed and $10.1M is non-peer reviewed. From 2015-August 2019 CT members published 1116 cancer-related publicationsrepresenting 26% intra-programmatic 41% inter-programmatic and 64% inter-institutional collaborations. HCCsupport including Clinical Protocol and Data Management and all Shared Resources greatly facilitate andenhance CTP research. +No NIH Category available Address;Affect;Androgen Receptor;Androgens;Bacterial Artificial Chromosomes;Biological;Biological Availability;Biology;Bladder;Bladder Neoplasm;Chemicals;Chromatin;Clinical;Data;Development;Disease;Down-Regulation;Environmental Risk Factor;Epigenetic Process;Exhibits;Female;Four Core Genotypes;Future;Gene Expression;Gene Expression Regulation;Gene Family;Gene Targeting;Genes;Genitourinary system;Glucuronosyltransferase;Gonadal Hormones;Gonadal Steroid Hormones;Gonadal structure;Histones;Hormonal;Human;Incidence;Infection;Investigation;Knockout Mice;Lead;Libido;Link;Lysine;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Measures;Mediating;Modeling;Mus;Mutation;Oncogenes;Outcome;Ovary;Pathway interactions;Patients;Physiological;Regulation;Regulatory Element;Reporting;Repression;Risk Factors;Role;Screening for cancer;Sex Bias;Sex Chromosomes;Sex Differences;Shapes;Smoking;System;Technology;Testing;Testis;Transgenic Mice;Tumor Biology;Tumor Suppressor Genes;Tumor Suppressor Proteins;UGT1A1 gene;Uridine;Urothelium;Woman;X Chromosome;XX male;XY females;biological sex;cancer type;carcinogenesis;conditional knockout;design;epigenome;gain of function;histone methylation;improved;in vivo;male;men;mortality;multiple omics;mutant;novel;occupational hazard;prevent;sex;sex disparity;sexual dimorphism;success;transcription factor;transcriptome;tumor;tumorigenesis Sexual Dimorphism in Bladder Cancer Bladder cancer one of the most common genitourinary malignancies is a highly sex-biased disease thatdisproportionately affects males. In this proposal we aim to shed new light on the overlooked and largelyundefined epigenetic basis of observed sex differences as they remain largely undefined. Our expected findingswill catalyze the identification of sex-biased genes and regulatory elements for the design of sex-specific bladdercancer screening and treatment. NCI 10674879 7/14/23 0:00 PAR-19-183 5R01CA267108-02 5 R01 CA 267108 2 "JOHNSON, RONALD L" 8/2/22 0:00 7/31/27 0:00 Cancer Genetics Study Section[CG] 2563587 "LI, XUE SEAN" Not Applicable 30 Unavailable 75307785 NCSMA19DF7E6 75307785 NCSMA19DF7E6 US 34.076544 -118.380004 1225501 CEDARS-SINAI MEDICAL CENTER LOS ANGELES CA Independent Hospitals 900481804 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 592550 NCI 378023 214527 Bladder cancer (BCa) exhibits a striking sex bias: men are 3-5 times more likely than women to develop and diefrom BCa. Even when known risk factors such as smoking infection occupational hazards cultural andenvironmental factors are corrected for this phenomenon persists. Despite this long-standing clinical observationmen and women still receive relatively similar treatments due to a lack of mechanistic understanding to deriveuseful treatments based on biological sex. In this proposal we seek to elucidate the mechanistic basis of sexualdimorphism in tumor biology. It is well established that gonadal hormone effects (GHE) defined by gonad-derived hormonal factors that drive sex disparities in BCa are primarily mediated by male dominant androgensand androgen receptor (AR). Recently we reported an unexpected sex chromosome effect (SCE) thatindependently contributes to the sexual dimorphism of BCa; we found that SCE is predominantly mediated bylysine (K) demethylase 6a (KDM6A) which functions as a female-biased tumor suppressor gene in the bladder.KDM6A demethylase is a versatile epigenetic regulator that controls histone methylations in both enzymaticactivity development and independent mechanisms. We will refer the sex-specific epigenome to as the sexepigenome. We hypothesize that the sex epigenome programed by KDM6A directly and AR indirectly controlssexual dimorphism in gene expression and BCa. We designed three specific aims to test this hypothesis: 1) todetermine whether KDM6A shapes directly the sex epigenome and regulates the local bioavailability of sexhormones in the bladder; 2) to determine whether AR opposes the KDM6A-dependent sex epigenome in thebladder; and 3) to determine whether the sex epigenome differentially regulates genes during bladdercarcinogenesis. Success of the proposal will catalyze the identification of sex-biased genes and regulatoryelements for the design of sex-specific BCa screening and treatment. Results from our proposed studies willalso advance the mechanistic understanding behind greater BCa incidence in males and lead future efforts toprevent and treat BCa according to a patient's biological sex. Because male dominance in cancer incidence andmortality is observed across most non-reproductive cancer types an improved understanding of sexualdimorphism in BCa will also have widespread implications on these cancers. 592550 +No NIH Category available Acceleration;Address;Automobile Driving;Biotechnology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Therapy Evaluation Program;Cancer Vaccines;Catchment Area;Clinic;Clinical;Clinical Investigator;Clinical Trials;Collaborations;Colon Carcinoma;Combination immunotherapy;Complement;Development;Disease;Doctor of Philosophy;Ensure;Epigenetic Process;Funding;Genetic Transcription;Geography;Goals;Grant;Head and Neck Cancer;Human;Immune;Immune system;Immunologist;Immunooncology;Immunophenotyping;Immunoprevention;Immunotherapeutic agent;Immunotherapy;Intervention;Laboratory Finding;Laboratory Research;Leadership;Malignant Neoplasms;Malignant neoplasm of lung;Mission;Molecular;Obesity;Operative Surgical Procedures;Outcome;Pathologist;Patients;Peer Review;Pre-Clinical Model;Prevention;Publications;Publishing;Radiation;Recording of previous events;Research;Research Personnel;Research Support;Sampling;Schools;Science;Sun Exposure;Testing;Therapeutic;Tobacco use;Training and Education;Translating;Translational Research;Translations;Tumor Escape;Tumor Immunity;Universities;Validation;Work;bench to bedside;cancer care;cancer immunotherapy;cancer prevention;cancer therapy;chemotherapy;clinical practice;clinical translation;design;fighting;immune checkpoint;immunoregulation;immunotherapy clinical trials;immunotherapy trials;improved;industry partner;innovation;inter-institutional;malignant breast neoplasm;melanoma;member;new therapeutic target;next generation;novel;novel marker;precision medicine;predictive marker;prevent;programs;prophylactic;recruit;response biomarker;targeted biomarker;targeted treatment;therapy resistant;translational scientist;tumor;tumor immunology;tumor microenvironment;tumor-immune system interactions Cancer Immunology and Immunotherapy Program n/a NCI 10674874 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8942 1927655 "EMENS, LEISHA A" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 57065 35890 21175 Abstract: Cancer Immunology and Immunotherapy (CII)The overarching mission of the Cancer Immunology and Immunotherapy (CII) Program is to discover validateand implement new molecular and cellular immune agents and novel combination immunotherapies for theimmune-based treatment and prevention of human cancers. CII members work to realize the program missionthrough three specific aims: (a) define the basic regulatory mechanisms that promote anti-tumor immunity orfacilitate tumor immune evasion; (b) dissect the epigenetic transcriptional and cellular geography of the tumorimmune microenvironment to discover new immunotherapeutic targets and predictive biomarkers; and (c)develop and translate novel laboratory research findings into more effective immunotherapies for cancertreatment and prevention. Three themes holistically integrate research conducted under the these aims andinclude (1) immunoregulatory mechanisms in cancer (2) modulators of the tumor immune microenvironmentand (3) cancer immunotherapies. CII prioritizes translating immuno-oncology science developed at HillmanCancer Center (HCC) in early proof-of-concept trials and works with the Cancer Therapeutics Program (CT) tocollaborate with the NCI-CTEP CITN other NCI cancer centers cooperative groups and biotech/industrypartners for clinical validation and late-stage testing.Under the leadership of Leisha Emens MD PhD Dario Vignali PhD and Hassane Zarour MD CII has 43members representing 10 academic departments and 1 school within the University of Pittsburgh. CII membersconduct cancer-focused research supported by $17.0M in total annual direct funding of which $4.9M is NCIfunding (including R01 R21 P30 and T32 grants) $4.0M is other peer-reviewed and $8.1M is non-peer-reviewed. From 2015-August 2019 CII members published 848 cancer-related publications representing 14%intra-programmatic 46% inter-programmatic and 65% inter-institutional collaborations. HCC support greatlyfacilitates and enhances CII research through the extensive use of HCC SR. CII research in immunecheckpoints for head and neck lung and breast cancer as well as melanoma directly addresses the burden ofcancer in the HCC catchment area related to tobacco use obesity and sun exposure and have positivelychanged clinical practice across the U.S. and the world. CII investigators have also developed a prophylacticcolon cancer vaccine that addresses unmet cancer control needs in the HCC catchment area. Together theseefforts will ensure the translation of novel research findings in cancer immunology and immunotherapy to thebedside with the goal of improving clinical outcomes. +No NIH Category available Activities of Daily Living;Address;Adherence;Adolescent;Age;Behavior;Behavioral;Behavioral Mechanisms;Behavioral Sciences;Biological;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Survivor;Cancer Survivorship;Caregivers;Catchment Area;Clinic;Clinical Research;Clinical Trials;Collaborations;Development;Diet;Disease;Doctor of Philosophy;Etiology;Funding;Goals;Grant;High Prevalence;Intervention;Intervention Trial;Investments;Leadership;Length;Link;Maintenance;Malignant Neoplasms;Obesity;Oncology;Pathway interactions;Patients;Peer Review;Pennsylvania;Persons;Phase;Physical activity;Population;Productivity;Publications;Publishing;Quality of life;Randomized;Research;Research Activity;Research Personnel;Research Support;Risk;Risk Behaviors;Risk Reduction;Schools;Strategic Planning;Survivors;Symptoms;Testing;Tobacco Use Cessation;Tobacco use;Translational Research;Treatment-Related Cancer;Underserved Population;United States;Universities;Vulnerable Populations;Work;biobehavior;cancer prevention;cancer risk;cancer therapy;common symptom;experience;improved;improved outcome;innovation;inter-institutional;member;personalized management;pre-clinical research;prevent;programs;psychosocial;randomized clinical trials;reduce symptoms;reduce tobacco use;research study;sedentary lifestyle;socioeconomic disadvantage;survivorship;symptom management;treatment adherence;tumor Biobehavioral Cancer Control Program n/a NCI 10674867 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8940 1865777 "BENDER, CATHERINE M." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 40109 25226 14883 Abstract: Biobehavioral Cancer Control (BCC)Recognizing the importance of research focused on the person in whom cancer develops and is treated aswell as on the tumor itself Hillman Cancer Center (HCC) has included a program focused on behavioral issuesin oncology since its inception in 1985. The overarching goal of the Biobehavioral Cancer Control (BCC)Program is to reduce the burden of cancer across all phases of the cancer control continuum from cancer riskthrough cancer survivorship via research centered on behavioral factors and the patient/person experience.Grounded in the behavioral sciences program investigators conduct preclinical translational and clinicalresearch studies (including randomized interventional trials) that are largely encompassed by two centralthemes: (1) Cancer risk reduction focuses on behavioral factors known to contribute to cancer riskparticularly tobacco use and the biobehavioral mechanisms underlying the initiation maintenance andcessation of tobacco use; and (2) Cancer survivorship focuses on characterization of disease and treatment-related symptoms in cancer survivors the biobehavioral mechanisms underlying those symptoms andpersonalized management strategies to prevent or reduce cancer and cancer therapy-related symptoms andimprove outcomes. BCC is a highly transdisciplinary program with a strong track record of researchproductivity as evidenced by publications and grant support. Under the leadership of Catherine Bender PhDRN and Dana Bovbjerg PhD BCC has 45 members representing 15 departments and 6 schools within theUniversity of Pittsburgh. BCC members conduct cancer-focused research supported by $5.4M in total annualdirect funding of which $3.3M is NCI funding $2.0M is other peer-reviewed and $0.1M is non-peer-reviewed. Areturn of $3.2M was obtained on investment of $251K of CCSG developmental funds. From 2015-2019 BCCmembers published 493 cancer-related publications representing 17% intra-programmatic 16% inter-programmatic and 58% inter-institutional collaborations. Consistent with HCCs overall strategic plan and thecancer challenges of our catchment area the specific aims of BCC are to: (a) investigate behavioral factorsknown to contribute to cancer risk reduction with a particular focus on biobehavioral mechanisms underlyinginitiation maintenance and cessation of tobacco use (Theme 1); (b) develop and test innovative biobehavioralinterventions to reduce cancer risk behaviors with a particular emphasis on tobacco use and cancer preventionbehaviors (Theme 1); (c) characterize disease and treatment-related symptoms in cancer survivors includingthe biobehavioral mechanisms underlying those symptoms (Theme 2); and (d) develop and test personalizedmanagement strategies to prevent or reduce cancer and cancer therapy-related symptoms and improveadherence to therapy quality of life and functional ability of cancer survivors (Theme 2). These aims will beaddressed with key HCC support for BCC research activities at both strategic and logistical levels. +No NIH Category available Activities of Daily Living;Award;Behavioral;Biological;Body Weight decreased;Breast;Breast Cancer Early Detection;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Etiology;Cancer Patient;Cancer Prevention Intervention;Cancer Survivorship;Cancer Vaccines;Catchment Area;Cessation of life;Clinical;Clinical Data;Clinical Research;Clinical Trials;Collaborations;Colorectal Cancer;Development;Doctor of Philosophy;Early Diagnosis;Environmental Exposure;Epidemiologic Methods;Etiology;Funding;Future;Genetic;Goals;Grant;Head and neck structure;Imaging Techniques;Imaging technology;Immune response;Incidence;International;Large Intestine Carcinoma;Leadership;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Methodology;Mission;Modernization;Mucin 1 protein;NCI-Designated Cancer Center;Natural Compound;Nature;Outcome;Ovarian;Pancreatic carcinoma;Paper;Peripheral;Population;Population Research;Population Sciences;Prevention Research;Prevention program;Prevention strategy;Primary Cancer Prevention;Primary carcinoma of the liver cells;Publications;Publishing;Quality of life;Research;Research Activity;Research Design;Research Personnel;Research Project Grants;Resources;Risk;Risk Factors;Sampling;Schools;Science;Scientific Advances and Accomplishments;Scientist;Screening for cancer;Source;Strategic Planning;Sulforaphane;Symptoms;Technology;Training and Education;Translating;Translational Research;Universities;Vaccines;Validation;Weight maintenance regimen;Woman;anti-cancer;anticancer research;biobank;biomarker validation;cancer biomarkers;cancer diagnosis;cancer epidemiology;cancer genomics;cancer initiation;cancer prevention;cancer type;cohort;detection method;dietary;education research;efficacy evaluation;epidemiology study;experience;gene environment interaction;improved;innovation;inter-institutional;malignant breast neoplasm;melanoma;member;metabolomics;microbiome;mortality;next generation;novel;novel marker;novel strategies;population based;pre-clinical;prevention effectiveness;programs;radiological imaging;randomized clinical trials;response biomarker;screening;smoking cessation;synergism;ultrasound;working group Cancer Epidemiology and Prevention Program n/a NCI 10674857 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8937 6365905 "HERMAN, JAMES G." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 40109 25226 14883 Abstract: Cancer Epidemiology and Prevention (CEP)The overarching goal of the Cancer Epidemiology and Prevention (CEP) Program is to reduce cancer burdenand mortality in our catchment area and beyond through three interactive themes on the continuum fromcancer initiations to cancer prevention and early detection. Theme 1 is Discovery of Risk and CausativeFactors for Cancer Development and Progression with a specific aim to discover and characterize novelmodifiable and unmodifiable risk and causal factors for cancer development. Theme 2 is Cancer Preventionwith a specific aim to discover and evaluate novel anti-cancer natural compounds and vaccines for reduction ofcancer incidence. Theme 3 is Cancer Screening and Early Detection with a specific aim to develop andvalidate novel biomarkers and modern imaging technologies for early diagnosis of cancer for improvement ofcancer outcomes and reduction of cancer death. These themes reflect major working groups and initiativesthat coalesce program members with other cancer center investigators through inter-programmaticcollaborations to achieve these specific aims.Under the leadership of James Herman MD (co-leader) and Jian-Min Yuan MD PhD (co-leader) the CEPhas 26 members representing 11 departments in 2 schools of the University of Pittsburgh. These Programmembers have been awarded $5.4M (annual total direct) research grant funding of which $3.6M is from theNCI and $1.8M from other sources. All CEP members are engaged in cancer-relevant research focusing onthe discovery of novel risk/causative factors for the development of cancer the efficacy of primary cancerprevention strategies and effectiveness of cancer screening and early detection methods. CEP memberscollaborate with and compliment the efforts of the BCC program which focuses on implementation of riskbehavioral change programs such as smoking cessation and weight control and reduction. Between 2015 andAugust 2019 CEP members published 639 cancer-relevant papers that resulted from 10% intra-programmatic27% inter-programmatic and 81% inter-institutional collaborations and included high-impact publications inScience Nature JAMA Lancet JNCI and JCO. The program members bring their scientific vigor andpopulation-based research expertise to UPMC Hillman Cancer Center (HCC) and provide unique educationand training experience to the next generation of scientists to conduct cutting-edge translational research oncancer etiology and prevention. With the outstanding support of HCC this highly effective CEP hassuccessfully created synergy among the Program members with members of HCC other programs as well asother cancer centers which have resulted in many team science projects that advance the programs researchagenda. Guided by the HCC strategic plan the CEP members will develop and build large initiatives andimplement research projects that have significant impact on cancer burden in the HCC catchment area. +No NIH Category available Acceleration;Area;Award;Biology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Catchment Area;Cellular biology;Chemicals;Clinic;Clinical Investigator;Clinical Research;Collaborations;Data Science;Development;Diagnosis;Diagnostic;Disease model;Doctor of Philosophy;Drug resistance;Equipment;Event;Faculty;Financial Support;Fostering;Funding;Goals;Hematology;Hormones;In Vitro;Incidence;Internal Medicine;International;Joints;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of ovary;Malignant neoplasm of prostate;Mentors;Mission;Modeling;Molecular;Neoplasm Metastasis;Oncology;Peer Review;Pharmacology;Pilot Projects;Prevention;Preventive;Publications;Publishing;Research;Research Activity;Research Personnel;Resource Sharing;Schools;Seminal;Series;Signal Transduction;Strategic vision;Talents;Therapeutic;Translational Research;Universities;Work;cancer initiation;improved;in silico;in vivo;inter-institutional;malignant breast neoplasm;meetings;member;mortality;next generation;novel;professor;programs;recruit;response;scientific organization;symposium;treatment strategy;tumor initiation;tumor progression Cancer Biology Program n/a NCI 10674852 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8935 9076039 "BUCKANOVICH, RONALD J" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 39496 24840 14656 Abstract: Cancer Biology (CB)The Cancer Biology (CB) Program brings together basic cancer biology and data science investigators to studyand modelat the in vitro in vivo and in silico levelsthe biology of malignant transformation and tumorprogression. The main objective of CB is to foster basic discoveries of molecular and cellular mechanisms ofcancer that are then used in other Hillman Cancer Center (HCC) programs to advance translational and clinicalresearch. The program is led by Ronald Buckanovich MD PhD and Steffi Oesterreich PhD. Buckanovichis Professor of Internal Medicine in the Division of Hematology-Oncology and Oesterreich is Professor andVice-Chair in the Department of Pharmacology and Chemical Biology. These two leaders have highlycomplementary expertise that they use to synergistically drive the thematic goals of the program.CB has three primary themes: (a) hormone response and signaling (b) drug resistance and metastases and(c) data science. CB has world-class investigators focused on these cancer-relevant thematic areas. All threeareas are characterized by extensive collaborations within and across various other programs and aresignificantly facilitated by the expertise and equipment available through HCC shared resources. The aims ofCB are to: (1) discover and elucidate cellular and molecular mechanisms of cancer initiation progression andmetastases (2) transfer program discoveries to other HCC programs for application in the clinic in the form ofnovel preventive diagnostic or therapeutic approaches (3) educate and mentor the next generation of cancerbiologists (4) accelerate research in areas of special importance in our catchment area particularly throughthe work directed at the high incidence and mortality of breast and prostate cancers and finally (5) facilitatecollaborations within and outside CB via seminars regular meetings focused symposia and a yearly retreat.CB has 43 members representing 17 academic departments and 5 schools within the University of Pittsburgh.CB members cancer-focused research is supported by $12.2M in total annual direct funding of which $5.3M isNCI funding $5.0M is other peer-reviewed and $1.9M is non-peer-reviewed. From 2015- August 2019 CBmembers published 834 cancer-related publications representing 14% intra-programmatic 40% inter-programmatic and 65% inter-institutional collaborations.HCC provides value to CB through the support of a significant number of shared resources facilitating jointresearch activities weekly HCC seminar series scientific retreats and via financial support for novelcollaborative efforts. HCC support and strategic vision planning allows recruitment of talented CB investigators.CB adds value to HCC through expertise in basic biology data science and modeling of disease. CBmembers also contribute to the HCC mission through mentoring of trainees inter and intra-programmaticcollaborations and through the organization of scientific symposia and interdisciplinary retreats. +No NIH Category available Address;Automobile Driving;Biological Assay;Biological Models;Cancer Burden;Carcinogen exposure;Carcinogens;Cell Compartmentation;Cells;Chemical Agents;Chemical Exposure;Chemicals;Clonal Expansion;DNA Sequence Alteration;DNA sequencing;Development;Dorsal;Early Diagnosis;Epithelium;Exposure to;Foundations;Genetic;Genetic Anticipation;Homeostasis;Individual;Injury;Intestines;Knowledge;Lung;Malignant Neoplasms;Mus;Mutate;Mutation;Normal tissue morphology;Pattern;Population;Predisposition;Skin;System;Time;Tissues;carcinogenicity;human tissue;in vivo;regeneration model;regenerative;sequencing platform;single cell analysis;single cell sequencing;stem cell population;stem cells;tissue repair;tumor;tumorigenesis Single cell analysis of the evolving mutational landscape in carcinogen exposed skin NarrativeHere we dissect the evolving mutation co-occurrence patterns in stem cell compartments usingsingle cell sequencing of carcinogen-exposed normal skin a basis to predict the carcinogenicityof different chemical agents without the necessity of long term in vivo tumor assays. NCI 10674848 8/2/23 0:00 PAR-19-291 5R50CA251479-04 5 R50 CA 251479 4 "SHARMAN, ANU" 8/11/20 0:00 7/31/24 0:00 ZCA1-SRB-1(M1)S 12674613 "KANDYBA, EVE " Not Applicable 11 INTERNAL MEDICINE/MEDICINE 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 101243 NCI 62689 38554 AbstractThe development of early detection approaches is fundamental to reduce the growing cancerburden. Cellular accumulation of genetic mutations is believed to be the foundation of tumordevelopment however there is a fundamental lack of knowledge regarding the earliest stages oftumorigenesis and whether certain cell populations may be more predisposed to acquire initialdriving mutations. Stem cells are long-lived cells which reside in tissues and serve as aregenerative pool that actively maintain normal homeostasis and can repair tissue after injury.Accumulating evidence indicates that stem cells may also serve as the cells of origin fortumorigenesis in certain tissues and generate clonal expansions of mutated cells which could bemore susceptible to further genetic insults over time. As it is not feasible to address the evolvingmutational burden of stem cells in tissues of human individuals this study will exploit mouse dorsalskin a highly informative regenerative model system with well characterized and distinct stem cellpopulations. The dynamic mutation co-occurrence profiles of specific skin mouse stem cellpopulations will be determined following exposure to known carcinogens utilizing a customizablesingle cell DNA-sequencing platform. This approach will identify whether certain mutationalprofiles are selectively enriched and tolerated in specific stem cell populations over long periodsof time in functionally normal tissue following carcinogen exposure. The approach used by thisstudy could easily be adapted to screen many different chemical exposures and has the potentialto detect the earliest signs of cancer in similar epithelial tissue systems with shared stem cellpopulations such as the lung and intestine which are often exposed to long term environmentaland chemical insult - before tumors are evident and determine distinct carcinogen-exposuresignatures in cells. 101243 +No NIH Category available Actins;Address;Adenocarcinoma;Adenocarcinoma Cell;Animal Model;Automobile Driving;Bioinformatics;Biological Markers;Blood Cells;CRISPR/Cas technology;Cancer Etiology;Cancer Patient;Cancer cell line;Cell Line;Cell Separation;Cell model;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Decision Making;Development;Disease;Disease Outcome;Disease Progression;EGF gene;Epidermal Growth Factor Receptor;Extracellular Matrix;Extracellular Matrix Degradation;Family;GTP Binding;Gene Expression;Gene Expression Profile;Genes;Goals;Growth Factor;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate;Histologic;Human;Human Cell Line;Individual;Invaded;KRAS oncogenesis;KRAS2 gene;KRASG12D;LoxP-flanked allele;Lung;Lung Adenocarcinoma;Malignant - descriptor;Malignant Pleural Effusion;Malignant neoplasm of lung;Mediating;Mediator;Modeling;Monomeric GTP-Binding Proteins;Mouse Cell Line;Mus;Mutation;Nature;Neoplasm Circulating Cells;Neoplasm Metastasis;Newly Diagnosed;Non-Small-Cell Lung Carcinoma;Oncogenic;Outcome;Pathway interactions;Patients;Peptide Hydrolases;Phenotype;Play;Population;Primary Neoplasm;Production;Prognosis;Protein Isoforms;Receptor Protein-Tyrosine Kinases;Role;Sampling;Signal Transduction;Site;Specimen;Structure;TACSTD1 gene;TIAM1 gene;TP53 gene;Tumor Cell Line;Up-Regulation;cancer cell;cancer invasiveness;cell motility;experimental study;genetic signature;in vivo;lung cancer cell;lung metastatic;member;mouse model;mutant;mutational status;neoplastic cell;novel;patient prognosis;peripheral blood;permissiveness;rac1 GTP-Binding Protein;rho;screening;transcriptome;translational potential;tumor;tumor heterogeneity;tumor progression;tumorigenesis Rac guanine nucleotide exchange factors in lung cancer NARRATIVEOur studies identified specific Guanine nucleotide Exchange Factors (GEFs) for the small G-protein Rac1 expressed in human lung adenocarcinoma cells that were required for their motility and invasive activities. The goal is to elucidate the involvement of these Rac-GEFs in disease progression. We will generate animal models to determine their roles in metastasis and examine at a mechanistic level their relationship with oncogenic KRAS and EGFR. NCI 10674846 7/28/23 0:00 PA-20-185 5R01CA265999-02 5 R01 CA 265999 2 "WATSON, JOANNA M" 8/1/22 0:00 7/31/27 0:00 Tumor Progression and Metastasis Study Section[TPM] 1878620 "KAZANIETZ, MARCELO G." Not Applicable 3 PHARMACOLOGY 42250712 GM1XX56LEP58 42250712 GM1XX56LEP58 US 39.953462 -75.193983 6463801 UNIVERSITY OF PENNSYLVANIA PHILADELPHIA PA SCHOOLS OF MEDICINE 191046205 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 461082 NCI 283743 177339 ABSTRACTKRAS and EGFR mutations are the most prevalent genetic alterations detected in human lung adenocarcinomas and play essential roles in malignant transformation and disease progression. The small GTPase Rac1 a member of the Rho family is a key signaling effector of KRAS and EGFR oncogenic pathways. Rac1 has been widely implicated in the formation of actin-rich protrusive structures required for cancer cell motility and invasion as well as in the activation of oncogenic and metastatic gene expression networks. Activation of Rac1 (i.e. GTP loading) is mediated by Rac-GEFs a large family of Guanine nucleotide Exchange Factors largely associated with tumorigenesis and invasiveness. Strikingly there is limited information on the contribution of Rac-GEFs to lung cancer progression. Moreover their relationship to specific lung cancer oncogenic mutations remains unknown. We carried out a systematic and unbiased screening for Rac-GEFs responsible for driving pro-motile phenotypes in KRAS mutant NSCLC cell lines. This analysis unambiguously identified three Rac-GEFs (ARHGEF39 FARP1 and TIAM2) as mediators of ruffle formation and motility in NSCLC cells. To our surprise well-studied GEFs such as TIAM1 TRIO VAV isoforms and P-REX isoforms were either poorly expressed or dispensable in our model. We therefore hypothesize that these Rac-GEFs are major players in lung cancer progression. In Aim 1 we will generate KRAS mutant cell lines deficient in RacGEFs using a CRISPR/Cas9 approach and determine their contribution to invasion ECM protease production and metastasis in mouse models. In addition the requirement of selected Rac-GEFs to the development of autochthonously-arising metastatic lung cancer will be determined using a lentiviral CRISPR-based gene editing approach in Kras G12D/WT; p53 flox/flox mice (KP mice). In Aim 2 the goal is to identify and characterize Rac-GEFs as EGFR effectors in NSCLC. To unequivocally elucidate their permissive roles in mutant EGFR lung cancer progression phenotypes in vivo lentiviral CRISPR-based Rac-GEF gene editing in an EGFR L858R-driven p53 deficient lung adenocarcinoma mouse model will be performed. Mechanistically we aim to disentangle the basis of Rac-GEF activation by pursuing a comprehensive signaling analysis of proximal EGFR adaptors and effectors. In Aim 3 we will first elucidate Rac-GEF-dependent gene transcriptomes and network signatures driven by mutant KRAS and mutant EGFR. Finally we will determine Rac-GEF expression in single tumor cells isolated from malignant pleural effusions (a site of lung metastatic dissemination) as well as in single and clustered circulating tumor cells (CTCs) from peripheral blood of mutant KRAS and mutant EGFR lung adenocarcinoma patients. The identification of novel Rac-GEFs provides unprecedented information to predict metastatic disease outcome in lung cancer patients and increase the likelihood of identifying metastasis biomarkers ultimately aiding in refining patient prognosis and decision-making in a clinical setting. 461082 +No NIH Category available AIDS related cancer;Acquired Immunodeficiency Syndrome;Antiviral Agents;Area;Biological Models;Burkitt Lymphoma;Cancer Center;Cancer Center Support Grant;Caring;Catchment Area;Chronic;Collaborations;Doctor of Philosophy;Environment;Epidemiology;Funding;General Population;Generations;Goals;HIV;Hepatitis B Virus;Hepatitis C virus;Hodgkin Disease;Human;Human Herpesvirus 4;Human Herpesvirus 8;Human Papillomavirus;Human T-lymphotropic virus 1;Immunization Programs;Incidence;International;Intervention;Kaposi Sarcoma;Knowledge;Leadership;Malignant Neoplasms;Medical;Mentors;Merkel Cells;Mission;Morbidity - disease rate;Nasopharynx Carcinoma;Non-Hodgkin's Lymphoma;Pathway interactions;Patient Care;Patients;Peer Review;Pharmaceutical Preparations;Pilot Projects;Polyomavirus;Population;Prevention;Primary carcinoma of the liver cells;Productivity;Publications;Publishing;Recruitment Activity;Research;Research Personnel;Research Project Grants;Research Support;Resources;Schools;Scientist;Therapeutic;Universities;Vaccines;Viral;Viral Cancer;Virus;Virus Diseases;anti-cancer;anti-hepatitis C;anticancer research;antiretroviral therapy;cancer prevention;cost;inter-institutional;malignant stomach neoplasm;meetings;member;mortality;new therapeutic target;novel marker;prevent;programs;success;symposium;targeted treatment;vaccine access;virology;virus related cancer Cancer Virology Program n/a NCI 10674843 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8934 8531594 "GUO, HAITAO " Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 39496 24840 14656 Abstract: Cancer Virology (CV) Viruses are the cause of approximately 15% of human cancers. While significant advancements have been made in the last few decades there is no vaccine or specific targeted therapy for numerous cancer viruses and their associated malignancies. The mission of the Cancer Virology (CV) Program which is closely aligned with that of Hillman Cancer Center (HCC) is to prevent and cure viral and nonviral cancer by acquiring new knowledge of viral infection. CV members will achieve this goal by identifying new cancer pathways targeted by cancer viruses (Aim 1); identifying novel therapeutic targets/agents for viral cancer and developing new anticancer virus-based therapeutics (Aim 2); identifying novel biomarkers for viral cancers (Aim 3); and discovering new cancer-causing viruses (Aim 4). To facilitate the execution of these specific aims CV has developed tangible goals which are to establish a productive highly collaborative group of investigators devoted to these aims provide unique intellectual resources to HCC in the area of cancer virology and build an exceptional research program with multiple generations of scientists studying cancer viruses. As an integral program of HCC CV takes advantage of the exceptional academic environment and rich resources of HCC. CV achieves these goals by providing fertile ground for fundamental cancer research using cancer viruses and viral cancers as model systems active recruitment of investigators in cancer virology support for internal and external interactions and collaborations for program symposiums for internal and external seminars and retreats and for pilot project research in cancer virology stimulation of research in the catchment area and for mentoring of junior investigators and trainees. Under the leadership of Shou-Jiang (SJ) Gao PhD CV has 27 members representing 9 departments and 3 schools within the University of Pittsburgh. CV members conduct cancer-focused research supported by $8.1M in total annual direct funding of which $2.9M is NCI funding $5.0M is other peer-reviewed and $0.2M is non-peer-reviewed. From 2015-August 2019 CV members published 428 cancer-related publications representing 9% intra-programmatic 19% inter- programmatic and 65% inter-institutional collaborations. CV is internationally recognized as a leading hub for the discovery and characterization of new human cancer viruses. The high research productivity of the program members in the current funding cycle reflects the success of CV in meeting these goals which will be realized and augmented in the next funding cycle. +No NIH Category available Algorithmic Analysis;American;Antibodies;Apoptosis;Bioinformatics;Biological;Biological Specimen Banks;Bromodeoxyuridine;Budgets;Cancer Center;Cancer Center Support Grant;Cell Proliferation;Certification;Clinical;Clinical Data;Clinical Laboratory Information Systems;Clinical Research;Collection;Community Hospitals;Computerized Medical Record;Cytoplasm;Data;Databases;Development;Diagnostic;Equipment;Ethics;Evaluation;Frozen Sections;Funding;Glass;Goals;Head and neck structure;Health Sciences;Histology;Hospitals;Hour;Human;Image;Image Analysis;Image Enhancement;Immunohistochemistry;Immunologic Monitoring;Individual;Information Retrieval;Institution;Institutional Review Boards;Investigation;Laboratories;Lung;Malignant Neoplasms;Malignant neoplasm of ovary;Medical;Modeling;Monitor;Nuclear;Paraffin Tissue;Pathologist;Pathology;Patients;Pattern;Pediatric Hospitals;Play;Presbyterian Church;Price;Process;Proteomics;Protocols documentation;Registries;Research;Research Personnel;Resource Sharing;Resources;Retrieval;Role;Sampling;Science;Services;Site;Skin Cancer;Slide;Specimen;Stains;Supervision;System;Systems Analysis;TdT-Mediated dUTP Nick End Labeling Assay;Techniques;Text;The Cancer Genome Atlas;Tissue Banks;Tissue Microarray;Tissue Preservation;Tissue Sample;Tissues;Translational Research;Triage;Trichrome stain method;Universities;Woman;Work;automated image analysis;biobank;college;cost;data centers;data management;design;experience;imaging facilities;innovation;interest;liquid crystal polymer;manufacture;melanoma;member;morphometry;novel;pre-clinical research;programs;quantitative imaging;research facility;research study;sample collection;service utilization;tumor;whole slide imaging Tissue and Research Pathology Services n/a NCI 10674830 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8930 6682480 "DHIR, RAJIV " Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 125666 79035 46631 Abstract: Tissue and Research Pathology Services (TARPS)One of the essential components of any translational research investigation is the availability of high qualityappropriately selected human biospecimen samples. The Hillman Cancer Center (HCC) recognized the valueof a good systematic scientifically and ethically correct biospecimen repository more than 18 years ago andimplemented a system-wide initiative for tissue and biological specimen accrual with the establishment of theTissue and Research Pathology Service (TARPS) Shared Resource under the umbrella of the University ofPittsburgh (Pitt) resource also known as the Pitt Biospecimen Core (formerly the Health Sciences TissueBank). TARPS has been housed and extensively supported by HCC and the Department of Pathology. Thishas led to the development of a well-organized biospecimen resource providing high-quality well-bankedspecimens with extensive database support providing the clinical annotation so essential to good research.TARPS is a CAP-certified biorepository and serves as the central hub acquiring and triaging biospecimenmaterials and de-identified patient information. It is currently housed within the Department of Pathologydiagnostic evaluation facilities thus providing immediate access to specimens and patient information ofinterest. The resource has Pathologist administrative oversight and medical supervision at the three flagshiphospitals (Presbyterian Shadyside Magee) and the largest community hospital (Passavant) with plans inprogress to add Childrens Hospital of Pittsburgh later in 2019.At HCC TARPS has played an instrumental role in supporting multi-investigator and multi-institutional effortsincluding: The Cancer Genome Atlas Project (TCGA); the caHUB project as a funded site for the BiospecimenPre-analytical Variables (BPV) task order; the NCIs Clinical Proteomic Tumor Analysis Consortium (CPTAC)SPOREs in lung head and neck melanoma and skin and ovarian cancers and many other collaborative teamscience projects. In FY2019 65 out of 121 users were HCC members representing 6 CCSG researchprograms (CB CEP CII CT CV and GS). Usage was stable from 79% to 91% between 2015 and 2019. +No NIH Category available Address;Aftercare;Algorithms;Animal Cancer Model;Antigens;Antineoplastic Agents;Apoptosis;Back;Biological Markers;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Model;Cell Communication;Cell physiology;Cells;Clinical;Clinical Oncology;Clinical Research;Clinical Trials;Clinical assessments;Communication;Contrast Media;Detection;Development;Diagnosis;Disease;Drug Monitoring;Early treatment;Evaluation;Event;FDA approved;Funding;Genomics;Goals;Head and Neck Squamous Cell Carcinoma;Human;Image;Imaging Techniques;Imaging technology;Immune;Immune response;Immunity;Immunotherapy;Journals;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Medical Imaging;Methodology;Methods;Modality;Monitor;Names;Nature;Neoplasm Metastasis;Nuclear;Optics;PET/CT scan;Peer Review;Pharmacotherapy;Positron-Emission Tomography;Production;Prognosis;Proliferating;Protocols documentation;Publications;Radiogenomics;Radiology Specialty;Radionuclide therapy;Receptor Cell;Research Personnel;Resource Sharing;Rodent Model;Scanning;Services;Solid Neoplasm;Staging;Testing;Tracer;Treatment Efficacy;Tumor Markers;Tumor Volume;Validation;Visualization;bioluminescence imaging;cancer cell;cancer imaging;cancer research center director;cancer therapy;clinical imaging;co-clinical trial;early detection biomarkers;fluorodeoxyglucose;fluorodeoxyglucose positron emission tomography;glucose metabolism;high dimensionality;human model;imaging biomarker;imaging facilities;immune- related response criteria;in vivo;in vivo imaging;in vivo imaging system;melanoma;member;molecular imaging;molecular marker;multimodality;non-invasive imaging;novel;novel therapeutics;pre-clinical;pre-clinical assessment;preclinical imaging;programs;quantitative imaging;radiomics;radiotracer;receptor;recruit;repository;response;targeted agent;theranostics;treatment response;tumor;tumor diagnosis;tumor growth;tumor microenvironment;tumorigenesis In Vivo Imaging Facility n/a NCI 10674826 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8928 10489866 "COLEN, RIVKA R" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 252303 158681 93622 Abstract: In Vivo Imaging Facility (IVIF) Advances in cancer management require the development of new therapies and state-of-the-art imaging technologies are needed to assess response to those therapies. The Hillman Cancer Center (HCC) In Vivo Imaging Facility (IVIF) provides novel quantitative imaging techniques that trace biomarkers of molecular events and immunotherapy response associated with effective cancer therapy. Validation of advanced imaging techniques that are specific for relevant cellular processes are required to detect and measure the efficacy of novel anticancer therapies and measure early tumoricidal response. As part of this facility PET tracers targeting various tumor markers and immune cells in the tumor microenvironment as well as complementary optical and MR methodologies are being developed to sensitively and specifically quantify drug-cancer cell interactions. The IVIF provides a critical shared resource for testing PET tracers in in vivo rodent models of cancer and validating promising agents in humans through quantitative imaging trials. The overall goal of the IVIF is to provide pre-clinical and clinical imaging services to HCC investigators to assist in visualizing mechanisms of biomarker action provide approaches for early disease detection and monitor therapeutic efficacy. The IVIF supports all 7 programs at HCC and has contributed to high impact publications in Immunity Cancer Cell Theranostics and Nature Communications among other journals. IVIF had 76 users of which 66 were HCC investigators. Of the 66 HCC users 42 had peer-reviewed funding. The Specific Aims of the IVIF: (1) Assess biomarker expression throughout cancer treatment using a single modality or a combination of modalities both clinically and pre-clinically; (2) provide non-invasive imaging services for monitoring therapeutic efficacy in humans and animal models of cancer; (3) provide standard imaging assessment services to evaluate all types of treatment response using the FDA-approved and other standard imaging assessment criteria; (4) provide and incorporate novel imaging analytics such as radiomics and radiogenomics for clinical and preclinical tumor characterizations; and (5) develop novel imaging algorithms advanced imaging analytics radiotracers and contrast agents for clinical and pre-clinical oncological imaging to monitor and evaluate treatment response and agents for targeted radionuclide therapy. Key Services Include: (1) PET radiotracer development and production for human PET-CT and PET-MRI; (2) pre-clinical PET-CT and clinical or preclinical assessment of biomarker expression during cancer treatment; and (3) developing methods for monitoring drug treatments and other types of therapy with PET-CT CT and/or MRI through the use of molecular imaging standard imaging assessments tumor volumetrics radiomics and radiogenomics. +No NIH Category available American;Bioinformatics;Biological Assay;Biological Response Modifier Therapy;Biological Specimen Banks;Blood;Body Fluids;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Patient;Cell Therapy;Cells;Cellular Assay;Certification;Characteristics;Clinic;Clinical;Clinical Laboratory Improvement Amendments;Clinical Protocols;Clinical Trials;Computers;Conduct Clinical Trials;Core Facility;Correlative Study;Development;Enrollment;Foundations;Funding;Future;Goals;Good Manufacturing Process;Grant;Human Resources;Image Analysis;Immune;Immunologic Monitoring;Immunooncology;Immunotherapy;Laboratories;Legal patent;Malignant Neoplasms;Mission;Molecular Profiling;Monitor;NCI Center for Cancer Research;Pathologist;Pathology;Patient Monitoring;Patient Participation;Phenotype;Preparation;Procedures;Process;Production;Protocols documentation;Research;Research Design;Research Personnel;Research Project Grants;Sampling;Services;Societies;Specimen;System;Technology;Testing;Therapeutic;Therapeutic Clinical Trial;Tissue Procurements;Tissue Stains;Training;Translational Research;Translations;Tumor Tissue;Viral;anticancer research;cancer diagnosis;cancer immunotherapy;cancer prevention;cancer therapy;cell preparation;cellular development;college;digital;equipment acquisition;exosome;gene therapy;imaging facilities;imaging system;in vivo imaging;insight;liquid crystal polymer;manufacture;member;nano-string;novel;participant enrollment;pre-clinical;preclinical development;preclinical study;programs;quality assurance;response;scale up;single cell analysis;tissue preparation;tissue processing;transcriptome sequencing;treatment response;tumor-immune system interactions Immunologic Monitoring and Cellular Products Laboratory n/a NCI 10674820 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8926 14822487 "HSU, YEN-MICHAEL S." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 517408 325414 191994 Abstract: Immunologic Monitoring and Cellular Products Laboratory (IMCPL) The goals of the Immunologic Monitoring and Cellular Products Laboratory (IMCPL) are to support the development of cellular viral or gene therapies for cancer and monitor immunological responses to these therapies in patents enrolled in clinical trials at the Hillman Cancer Center (HCC). IMCPL is a unique facility offering a comprehensive set of state-of-the-art technologies and assays to the HCC investigators conducting clinical trials with various biotherapies and monitoring immune responses to these therapies. IMCPL also supports pre-clinical developmental projects for future translation to clinical trials. IMCPL is led by Dr. Theresa Whiteside (CII) who oversees a staff of 20 FTE in the facility located within the HCC Research Pavilion. Services are provided by trained personnel in a CLIA/CAP certified laboratory with independent quality assurance (QA) oversight. IMCPL primarily supports the clinical and translational CII and CT research programs. In FY2019 the IMCPL serviced 62 independent clinical trials for 35 HCC members (87% of the usage)/research protocols all relevant to the HCC mission of providing novel immunotherapy-driven clinical trials to cancer patients. During the next project period IMCPL will add 9 new clean rooms thus expanding therapeutic cell production capabilities and plans to increase the repertoire of cellular products for therapy in the future. It is also upgrading its monitoring capabilities to analyses of single-cell and exosome molecular profiles. +No NIH Category available Address;Archives;Biological;Biological Assay;Biometry;Budgets;Calibration;Cancer Center;Cancer Center Support Grant;Cell Separation;Cells;Cellular biology;Collaborations;Color;Complex;Continuing Education;Custom;Cytometry;Data;Data Analyses;Data Display;Data Set;Dedications;Detection;Disease;Education;Equipment;Event;Experimental Designs;Flow Cytometry;Fluorescence-Activated Cell Sorting;Fluorochrome;Funding;Genomics;Growth;Health Science Library;Heterogeneity;Hour;Immune;Immunity;Immunology;Information Services;Investments;Journals;Knowledge;Laboratories;Lasers;Maintenance;Malignant Neoplasms;Methods;Mission;Modernization;Molecular Analysis;Molecular Biology;Monitor;NCI Center for Cancer Research;Nature;Performance;Population;Publications;Qualifying;Reagent;Research;Research Personnel;Residual Neoplasm;Resource Sharing;Role;Services;Speed;Statistical Methods;System;Techniques;Training;Universities;analytical tool;assay development;cancer cell;complex data;computerized tools;design;experience;experimental study;improved;innovation;instrument;instrumentation;member;operation;recruit;tool;transcriptomics;tumor;user-friendly Cytometry Facility n/a NCI 10674815 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8924 8461537 "BRUNO, TULLIA CARMELA" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 237457 149344 88113 Abstract: Cytometry Facility (CF)The Hillman Cancer Center (HCC) Cytometry Facility (CF) has been in continuous operation since 1991 andhas consistently provided HCC members with state-of-the-art cytometry instrumentation and expertise. Ourmission is to provide superior training access to cutting edge instrumentation expertise in assaydevelopment and data analysis and opportunities for cross-collaboration with other sharedresources at HCC. CF has been located in the HCC Research Pavilion since September 2002. Thelaboratory consists of a 1000 ft2 laboratory dedicated to preparative and analytical flow cytometry. CFprovides services to over 100 users within HCC. The current instrumentation includes a Beckman CoulterMoFlo Astrios high-speed cell sorter equipped with a Class II Biocontainment hood two Becton Dickinson15/18-color SORP Fortessa analyzers with custom high-power lasers and a Becton Dickinson Accuri C6 4-color analyzer. Recent additions of a Sony MA900 cell sorter also equipped with a Class II Biocontainmenthood and a Cytek Aurora a spectral cytometer have addressed the increasing demand for more access tostate-of-the-art instrumentation. Education initiatives have expanded considerably including a tiered systemof user expertise advanced education seminars on spectral cytometry and user-operated cell sorting on theSony MA900. The Specific Aims focus on providing access and training on existing equipment integratingnew equipment and providing expert research staff and continuing education to users on new experimentalmethods. +No NIH Category available Adopted;Advisory Committees;Antineoplastic Agents;Award;Biological Assay;Budgets;Cancer Center;Cancer Center Support Grant;Capital;Cells;Clinical;Clinical Pharmacology;Clinical Trials;Clinical Trials Network;Communities;DNA Damage;DNA Markers;Data;Data Analyses;Development;Drug Kinetics;Early Therapeutic-Clinical Trials Network;Ensure;Equipment;Exclusion;Exposure to;Funding;High Pressure Liquid Chromatography;Human Resources;Hybrids;Injections;Investments;Ions;Joints;Label;Lead;Liquid substance;Malignant Neoplasms;Measures;Medicine;Methodology;Methods;NCI Center for Cancer Research;Nitrogen;Outcome;Peer Review Grants;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology;Phase I Clinical Trials;Phase II Clinical Trials;Philosophy;Population;Power Sources;Procedures;Process;Publications;Quality Control;Reader;Reagent;Research;Research Design;Research Personnel;Resource Sharing;Role;Sampling;Science;Scientist;Scintillation Counter;Services;Site;Specialist;Therapeutic Studies;Training;Translational Research;Validation;Water;absorption;drug development;early phase clinical trial;experience;instrumentation;meetings;member;mid-career faculty;novel;novel anticancer drug;pharmacodynamic biomarker;pharmacokinetics and pharmacodynamics;pharmacologic;pre-clinical;professor;programs;sample collection;skills;small molecule Cancer Pharmacokinetics and Pharmacodynamics Facility n/a NCI 10674803 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8918 8952707 "BEUMER, JAN HENDRIK" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 223977 140866 83111 Abstract: Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF)The Hillman Cancer Center (HCC) Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) is animportant shared resource that supports science conducted by the HCC research programs and has a majorimpact on cancer drug development on a national level by providing state-of-the-art and comprehensivequantitative and qualitative bioanalytical support for preclinical and clinical cancer therapeutic studies. Theactivities of CPPF have earned national recognition for its exceptional service in developing and deliveringPK and PD analyses of investigational agents.CPPF: (1) provides extensive pharmacology expertise to investigators by assisting in PK and PD study designand sample collection; (2) develops and provides quality-assured/quality-controlled quantitative and qualitativeassay capabilities for rapid and efficient PK and PD bioanalyses; and (3) integrates PK/PD data throughsophisticated data analyses.CPPF is located in two contiguous lab spaces with a shared office pod in the HCC Research Pavilion. Majorequipment includes 3 Waters QuattroMicro LC-MS/MS 2 SCIEX4000 LC-MS/MS (1 hybrid linear ion-trap) 2HPLC-UV/FL/DAD 1 HPLC-UV/RAD 1 atomic absorption spectrometer a LICOR Odyssey infra-red scannera Tecan Infinite Microplate Reader and a Nexcelom Cellometer K2 Cell counter. Ancillary equipment includes-20 C and -80 C freezers a nitrogen generator and an uninterrupted power supply as well as access toshared instrumentations including a liquid scintillation counter.CPPF is directed by Drs. Jan Beumer Professor of Pharmaceutical Sciences and Medicine and JohnSchmitz Associate Professor of Medicine and is overseen by an HCC Advisory Committee made up ofHCC members. Dr. Beumer leads and Dr. Schmitz actively participates in the weekly Merrill EgorinTranslational Research meeting where HCC early drug development projects are discussed by an inter-disciplinary group of basic translational and clinical scientists thereby ensuring appropriate considerationof CPPFs role in these projects.During this funding period CPPF analyzed samples for a total of 36 unique investigators and providedsupport for all 7 HCC research programs. During this funding period CPPF developed 37 new assays anaverage of 22 assays were used per year and more than 30000 samples were analyzed (excludingcalibrators quality controls or assay validation samples). CPPF supported 30 peer-reviewed grants and 70publications 30 of which were focused on clinical trials and 19 of which focused on development of novelassay methodologies. +No NIH Category available ATAC-seq;Agreement;Attention;Award;Big Data;Bioinformatics;Biometry;Budgets;Cancer Center;Cancer Center Support Grant;Cells;ChIP-seq;Collaborations;Custom;DNA methylation profiling;Data;Data Analyses;Data Coordinating Center;Data Science;Data Sources;Development;Educational process of instructing;Ensure;Faculty;Foundations;Funding;Genomics;Health;Health Science Library;High Performance Computing;Hour;Immunogenetics;Individual;Infrastructure;Institution;Internet;Laboratories;Malignant Neoplasms;Malignant neoplasm of lung;Metadata;Metagenomics;Metastatic breast cancer;Molecular Biology;Pathology;Play;Policies;Postdoctoral Fellow;Process;Reproducibility;Research;Research Personnel;Resource Sharing;Role;Services;Shotguns;Skin Cancer;Specialized Program of Research Excellence;Specimen;Students;Supercomputing;System;The Cancer Genome Atlas;Tissues;Universities;Work;anticancer research;biomedical informatics;cancer genome;cancer genomics;computer infrastructure;cost;cost effective;data integration;data mining;data privacy;data sharing;exome;genome resource;genome sequencing;genomic data;informatics tool;machine learning algorithm;malignant breast neoplasm;member;microbiome;microbiome analysis;precision medicine;predictive marker;recruit;repository;single-cell RNA sequencing;tool;transcriptome sequencing;transcriptomics;variant detection;whole genome Cancer Bioinformatics Services n/a NCI 10674796 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8916 15181523 "BAO, RIYUE " Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 512508 322332 190176 Abstract: Cancer Bioinformatics Services (CBS)The complexity of cancer genome studiesfrom whole exome whole genome methylation and RNAsequencing to emerging applications such as single cell and immunogenetic sequencingposes significantchallenges in data analysis and computing. The aim of the Cancer Bioinformatics Services (CBS) is to assistHillman Cancer Center (HCC) investigators with bioinformatics data analysis provide high performancecomputing and storage and create high-value data sources such as the regulatory compliant local repositoryof TCGA data known as Pittsburgh Genome Resource Repository. CBS with scientific support from theDepartment of Biomedical Informatics (DBMI) is co-directed by Drs. Chandran and Bao and includes two full-time masters level analysts and partial effort for several additional analysts. CBS supports all genomicsstudies from individual investigator projects to collaborative and consortia projects with expertise in genomicanalysis metadata annotation data integration HPC computing genomics data privacy and data sharingpolicies. CBS is a highly collaborative effort involving CBS staff DBMI faculty the Pittsburgh SupercomputingCenter (an NSF infrastructure) the University of Pittsburghs Center for Research Computing the Institute ofPrecision Medicine and the Health Science Library Systems Molecular Biology Service. In addition CBSworks closely with other HCC shared resources including the Biostatistics Facility Cancer Genomics Facilityand Tissue and Research Pathology Services. +No NIH Category available Cancer Patient;Caring;Clinical Research;Clinical Trials;Communities;Early Diagnosis;Education;Feedback;Health Personnel;Health Professional;Illinois;Improve Access;Knowledge;Malignant Neoplasms;Missouri;Patient Care;Patients;Pilot Projects;Productivity;Research;Research Personnel;Resource-limited setting;Resources;Rural;Rural Population;Services;Tissues;Training;Underserved Population;Urban Population;Vision;Vulnerable Populations;anticancer research;base;biobank;biomarker driven;cancer care;cancer clinical trial;cancer education;cancer prevention;cancer therapy;care delivery;community setting;high standard;improved;multidisciplinary;prevent;recruit;screening;survivorship;treatment planning;treatment trial;vector Heartland Cancer Research NCORP The Heartland Cancer Research NCORP (Heartland NCORP) will be the premier community cancer research organizationof the states of Illinois and Missouri by providing state of the art cancer clinical trials cancer care delivery researchinterdisciplinary cancer treatment planning and coordinated biomarker driven research throughout our service region.Cancer patients in specific will benefit as a direct result of these clinical trials and the consequential knowledge onpreventing and treating malignancy in community settings will improve patient care. NCI 10674791 7/27/23 0:00 RFA-CA-18-016 5UG1CA189830-10 5 UG1 CA 189830 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 15453802 "FALLER, BRYAN " Not Applicable 15 Unavailable 46584991 XNLXJGLVACC9 46584991 XNLXJGLVACC9 US 39.865817 -88.960798 2062001 DECATUR MEMORIAL HOSPITAL DECATUR IL Independent Hospitals 625264163 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 3480144 NCI 3078420 581365 The specific aims of the Heartland Cancer Research NCORP are to:To be the primary vector for delivering implementing and executing NCI approved cancer treatment clinical trials;cancer prevention screening and control clinical trials; and Cancer Care Delivery Research clinical trials to a largeMidwestern rural and urban population;Enhance Midwestern cancer care by providing convenient access for patients to a region-wide high standard ofmultidisciplinary integrated cancer care delivery;Participate in pilot studies for NCORP research bases and provide feedback on proposed trials.Participate in NCI-sponsored tissue acquisition and biobanking studies including those related to the Cancer Moonshotinitiative.Reach out to underserved and vulnerable populations across Illinois and Missouri to improve access to cancer clinicaltrials state of the art care and cancer prevention and early detection strategies;Coordinate with local and state agencies to leverage resources to improve state wide cancer education regarding cancerprevention early detection treatment and clinical trials;Improve cancer prevention treatment screening and survivorship education for healthcare professionals throughoutIllinois and Missouri. Educate healthcare providers across rural and urban Illinois and Missouri regarding cancer clinicaltrials and incorporation of new findings into daily patient care.Continue to recruit train and support new investigators and clinical research staff who share the vision and embracethe objectives of the Heartland NCORP.Explore and share best practices for improving the productivity of Heartland NCORP within an environment of limitedresources. 3480144 +No NIH Category available Acceleration;Address;African American;African American population;Age;Alcohol consumption;Bioenergetics;Birth;Blood specimen;Cessation of life;Child Development;Child Health;Cohort Studies;County;Daughter;Development;Diagnostic;Disparity;Endocrine Disruptors;Endocrine disruption;Environmental Exposure;Environmental Risk Factor;Fathers;Foundations;Generations;Income;Life;Life Cycle Stages;Link;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of prostate;Measures;Metabolic;Metabolic Pathway;Mitochondria;Mothers;Occupations;Onset of illness;Outcome;Pathway interactions;Pregnancy;Prevention;Prevention strategy;Race;Research;Resolution;Risk;Sampling;Serum;Son;Testing;Time;cancer diagnosis;cancer health disparity;carcinogenesis;chemical association;cigarette smoking;design;early onset;environmental chemical;follow-up;health disparity;high risk;innovation;male;malignant breast neoplasm;men;metabolome;metabolomics;mortality;prenatal;programs;prospective;prostate cancer risk;protective pathway;racial disparity;repository;screening;sex;study population;young adult;young man Discriminatory Mechanisms in Early-Onset and Lethal Prostate Cancer This research will have sustained impact by showing in a race-specific manner whether mitochondrialmetabolic pathways vary with lethal and early-onset prostate cancer risk decades before cancer onsetwhether these changes associate with concurrent environmental exposures and whether multi-generationalassociations occur between metabolic or environmental exposures and early-onset prostate cancer. Theresults will help define men who will benefit from intense screening and accelerate prevention with directcritical relevance to populations of African Americans who have unacceptably high risk of early onset and lethalprostate cancer. NCI 10674785 9/5/23 0:00 PAR-18-654 5R01CA264519-03 5 R01 CA 264519 3 "SUEN, CHEN S" 8/13/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-J(55)R] 3090907 "COHN, BARBARA A" "JONES, DEAN PAUL" 12 Unavailable 128663390 NJH3YBU1VHB7 128663390 NJH3YBU1VHB7 US 37.803785 -122.275259 1618201 PUBLIC HEALTH INSTITUTE OAKLAND CA Research Institutes 946074046 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 246025 NCI 422536 54070 Reprogramming of conventional mitochondrial function is a key component of carcinogenesis and prostatecancer aggressiveness. We hypothesize that key discriminatory mechanisms in early-onset and lethalprostate cancer occur through environmental exposures in early development and in young adult life whichreprogram mitochondrial function causing or enabling early-onset and fatal prostate cancer.Rationale and Innovation. While mechanisms cannot be proven by retrospective analyses our access torepository samples collected in young men (median age 34) years before prostate cancer onset and alsoperi-conceptual paternal and maternal pregnancy repository samples for men who later developed early-onset prostate cancer enable us to apply powerful analytical capabilities to link predictive metabolic signaturesof outcome with concurrent prospective measures of exposures. This creates an unprecedentedopportunity to test the central hypothesis that endocrine-disrupting exposures in early developmentand young adulthood are associated with metabolic signatures of mitochondrial reprogramming andsubsequent early-onset (< age 60) and lethal prostate cancer. If correct findings will provide a foundationfor prevention strategies to augment protective pathways and block risk pathways.Design. The study population is a 60 y two-generation follow-up of the Child Health and Development Studies(CHDS) cohort a unique representative sample of Alameda County CA in the 1960s with a sizeable AfricanAmerican population. This design allows us to address disparities in risk. Aim 1 is a Metabolome-WideAssociation Study (MWAS) to test the hypothesis that mitochondria-associated metabolic signatures in pre-diagnostic serum of young adult men predict subsequent lethal prostate cancer in African American and non-African Americans in the CHDS fathers generation. Aim 2 is an Exposome-Wide Association Study (ExWAS)to test the hypothesis that pre-diagnostic serum of young adult men contain endocrine-disrupting chemicalsassociated with lethal prostate cancer in African Americans and non-African Americans in the CHDS fathersgeneration. Aim 3 uses paternal peri-conceptual serum and maternal pregnancy serum to test for metabolicsignatures and environmental exposures that predict early-onset prostate cancer in CHDS sons generation.This research will have sustained impact by showing in a race-specific manner whether mitochondrialmetabolic pathways vary with early-onset and lethal prostate cancer risk decades before cancer onsetwhether these changes associate with concurrent environmental exposures and whether multi-generationalassociations occur between metabolic or environmental exposures and early-onset prostate cancer. The studyhas the potential to distinguish the time in the life-course when prevention is most effective. Results will helpdefine men who will benefit from intense screening and accelerate prevention with critical relevance toAfrican Americans who have unacceptably high risk of early-onset and lethal prostate cancer. 246025 +No NIH Category available Academy;Accountability;Appointment;Award;Biology;Biomedical Research;Cancer Center;Cancer Center Support Grant;Cancer Research Project;Career Mobility;Catchment Area;Clinical;Communities;Disadvantaged;Education;Educational Activities;Educational workshop;Effectiveness;Enrollment;Ensure;Equity;Faculty;Foundations;Funding;Future;Goals;Government;Grant;Growth;Health Personnel;High School Student;Industry;Informatics;Internships;Investments;Journals;Leadership;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Nurse Practitioners;Physician Assistants;Population;Positioning Attribute;Postdoctoral Fellow;Publishing;Research Personnel;Science;Strategic Planning;Students;Study Section;Training;Training Programs;Training and Education;Translational Research;Travel;Underrepresented Minority;Underrepresented Populations;Underrepresented Students;Universities;Wages;Work;Writing;anticancer research;cancer care;cancer education;cancer therapy;career;career development;college;computer science;design;disadvantaged student;doctoral student;education research;experience;faculty mentor;graduate student;high school;improved;innovation;literacy;next generation;programs;racism;recruit;success;summer internship;training opportunity;undergraduate student;underrepresented minority student Cancer Research Career Enhancement and Related Activities n/a NCI 10674783 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8913 8581860 "BAKKENIST, CHRISTOPHER J." Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 84917 53407 31510 Abstract: Career Enhancement and Related ActivitiesA major strategic initiative for UPMC Hillman Cancer Center (HCC) is to develop a well-trained diversebiomedical workforce through research education training and career-development activities that promote theunderstanding of the biology and treatment of cancer. To this end the HCC Committee for Excellence inCancer Education and Training (CECET) meets 4 times a year to review the breadth depth accessibility andeffectiveness of available education and training opportunities and to develop new programs as needed.CECET overseas an HCC investment of ~$1.4M/year in education and training. Our work is organized throughthree main specific aims designed to provide career enhancement opportunities across the biomedical trainingpipeline. The first aim is to educate and inspire high school and undergraduate students about careers incancer research with a focus on serving underrepresented populations. The Hillman Academy has provided an8-week summer internship introducing careers in cancer research to 433 high school students including 175(40%) underrepresented minority and disadvantaged (URM/DA) in our catchment area (CA). The Academy issupported by the Doris Duke Charitable Foundation CURE and the Jack Kent Foundation and the award of anew R25CA236620 allows an immediate 70% increase in the number of URM/DA students. This newR25CA236620 also provides support to improve the science literacy of our surrounding community bydeveloping 1-day workshops that include hands-on activities tours of facilities and career seminars on cancerresearch. Our second aim is to encourage medical and doctoral students as well as clinical and postdoctoralfellows to pursue careers in cancer research. We have used HCC philanthropy to recruit the first class ofHillman Medical Student and Postdoctoral Fellows for Innovative Cancer Research. We have increased thenumber of NCI T32 training grants from 4 to 6 to support the cancer research focus of all CCSG programs. Ourcommitment to graduate student researcher (GSR) education is evidenced by our support of more GSRs thanany other Pitt SOM Institute or Department. At the request of the newly formed HCC postdoctoral associationwe have established a new grant writing class that tailors K99 R00 applications to the NCI. This initiative buildson previous F30 F31 F99 K00 and K00 R01 successes. We will extend our Hillman Fellows for InnovativeCancer Research program into a new Bridge to Faculty positions that will guarantee faculty positions whenkey metrics are attained. Our third aim is to enhance the professional growth of faculty through an extensivemulti-faceted faculty mentorship program that eliminates barriers to innovative cancer research andstrengthens R01 applications to the NCI. We will also increase efforts across our network to ensure equalaccess of our health care providers to exceptional cancer education and training programs such asAccountability for Cancer Care through Undoing Racism and Equity and AP-POWER (R25CA148050). +No NIH Category available American Association of Cancer Research;Basic Science;Behavior;Behavioral;Behavioral Research;Biological;California;Cancer Burden;Cancer Science;Cancer Survivorship;Cessation of life;Clinical Research;Collaborations;Communities;Data;Development;Discipline;Disparity;Environmental Exposure;Environmental Risk Factor;Ethnic Population;Fostering;Future;Genetic;Genetic Predisposition to Disease;Goals;Growth;Health Disparities Research;Health Professional;Hormonal;Incidence;Life Style;Location;Mainstreaming;Malignant Neoplasms;Molecular;Pathogenesis;Pathway interactions;Physicians;Policies;Population;Population Sciences;Public Health;Quality of Care;Research;Research Personnel;Research Technics;San Francisco;Science;Scientist;Senior Scientist;Series;Students;Therapeutic;Tumor Biology;United States;Work;cancer health disparity;career;comorbidity;disparity elimination;disparity reduction;ethnic disparity;ethnic minority;falls;genetic variant;medically underserved;racial disparity;racial minority;racial population;screening policy;skills;socioeconomics;statistics;symposium;treatment response AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved PROJECT NARRATIVECancer incidence and death statistics show that certain racial and ethnic groups in the UnitedStates suffer disproportionately from cancer and its associated effects. These disparities may beexplained by socioeconomic and cultural factors biological basis differences in hormonal statusand genetic variants or differences in inherited susceptibilities and molecular pathways forpathogenesis. Over the next 5 years this conference will continue to bring together basicscientists physicians behavioral researchers population researchers and other healthprofessionals to foster discussions and collaborations between early-career and seniorscientists moving the field forward and continue to make progress in reducing and eliminatingcancer health disparities. NCI 10674779 7/31/23 0:00 PA-18-648 5R13CA239609-05 5 R13 CA 239609 5 "LIU, JIEXIN" 8/1/19 0:00 7/31/24 0:00 ZCA1-PCRB-G(J1) 8011666 "FOTI, MARGARET " Not Applicable 2 Unavailable 139203590 K4LZTWHBSGN6 139203590 K4LZTWHBSGN6 US 39.949341 -75.150986 210901 AMERICAN ASSOCIATION FOR CANCER RESEARCH PHILADELPHIA PA Other Domestic Non-Profits 191064404 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Other Research-Related 2023 99500 NCI 99500 0 PROJECT SUMMARYThe proposed conference series titled The Science of Cancer Health Disparities inRacial/Ethnic Minorities and the Medically Underserved will be held annually in the fall(2019-2023). The 2019 conference will be held September 20-23 2019 in San FranciscoCalifornia. The locations of the 2020-2023 conferences remain to be selected but will bechosen based upon the future needs and growth of the conference series. This proposedconference series will be the 12th-16th in an AACR series focused specifically on the science ofcancer health disparities. The first conference on The Science of Cancer Health Disparities inRacial/Ethnic Minorities and the Medically Underserved was held in 2007 then annually from2009-2018. While most conferences on cancer health disparities focus on policy and publichealth issues the goal of this conference is to incorporate perspectives from basic scientistsand clinicians in conjunction with policy and public health. Transdisciplinary interactionsbetween a variety of disciplines including basic science clinical research population sciencebehavioral research and cancer survivorship are needed to move the field forward and makeprogress in reducing and eliminating disparities as they relate to cancer.Racial and ethnic disparities in cancer rates are well documented. While data suggest thatdiffering levels of access to quality care contribute to cancer disparities other factors also play arole including tumor biology genetics hormonal status lifestyle and behavior screeningpolicies comorbidities environmental exposure and risk quality of and response to therapyand post-therapeutic surveillance. The goal of this conference and the conference series is tobring together scientists and other professionals working in a variety of disciplines to discuss thelatest findings in the field and to stimulate the development of new research in cancer healthdisparities. 99500 +No NIH Category available Award;Budgets;Cancer Center;Cancer Center Support Grant;Catchment Area;Chad;Clinical;Collaborations;Communication;Communities;Comprehensive Cancer Center;Contracts;County;Data;Development;Doctor of Philosophy;Education;Education and Outreach;Ensure;Equipment;Evaluation;Faculty;Faculty Recruitment;Fostering;Funding;Funding Opportunities;Grant;Healthcare;Human Resources;Informatics;Information Technology;Infrastructure;Institution;Leadership;Malignant Neoplasms;Marketing;Mission;Monitor;NCI Center for Cancer Research;National Cancer Institute;Newsletter;Office of Administrative Management;Output;Pennsylvania;Play;Population Research;Process;Productivity;Publications;Recommendation;Reporting;Research;Resource Sharing;Role;Schools;Science;Services;State Government;Strategic Planning;Surveys;Translational Research;Travel;United States National Institutes of Health;Universities;University resources;Wages;anticancer research;cancer research center director;computer network;cost;data resource;meetings;member;microbiome;multidisciplinary;outreach;population survey;programs;recruit;web site Cancer Center Administration n/a NCI 10674777 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8912 1900219 "FERRIS, ROBERT L" Not Applicable 12 Unavailable 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA Domestic Higher Education 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 212796 133835 78961 Abstract: Cancer Center AdministrationThe UPMC Hillman Cancer Center (HCC) Administrative Core (Admin Core) provides infrastructure to facilitateand stimulate the cancer research education and outreach activities of 280 HCC faculty members in 7research programs with particular focus on research that is transdisciplinary and translational. It also supportsthe HCC Director Senior Leaders Program Leaders Shared Resources Directors and internal and externaladvisors through effective strategic planning and evaluation operational management and centralized dataresources.The Admin Core supports the matrix Cancer Center by overseeing one of the largest research units ($115Moverall budget in FY2020) at the University of Pittsburgh (Pitt). It provides grant and fiscal management andother administrative services for 128 HCC faculty in center-controlled space and 10 state-of-the-art SharedResources many residing in 530795 ft2 of HCC-controlled space that is also managed by administrative staff.The Admin Core is responsible for: performing human resource functions and administering partial salarysupport for >1200 FTEs; managing the Cancer Centers finances personnel grants and contractspurchasing and philanthropy; providing administrative and financial oversight to HCCs shared resources;overseeing space utilization and common equipment; facilitating faculty recruitment efforts; managing CancerCenter membership; facilitating pilot award programs; and coordinating planning and evaluation activities thatinclude faculty surveys leadership and programmatic meetings seminars annual retreat and internal andExternal Advisory Board meetings. The Admin Core also supports communication to HCC faculty membersand the larger Pitt community through newsletters publications and a website; and educates residents of our29-county western Pennsylvania catchment area and lawmakers regarding HCC activities and other cancer-related issues through outreach efforts. The Admin Core monitors and reports member accomplishmentsfunding and other cancer-related activities to the Senior Leadership Team as a part of an annual membershipevaluation and for reporting HCC progress to the National Cancer Institute.Admin Core accomplishments during 2015-2019 included: significantly contributing to HCC research programrestructuring; developing new Microbiome and Population Survey shared resources and a formal pilot grantprogram; recruiting and onboarding over 40 new faculty members; and facilitating submission of several largeteam science multi-component grants. For CCSG year 32 the Center requests $146605 to support partialsalary for 10 FTEs plus costs for supplies travel and other operational expenses. The Admin Core represents3.5% of the total CCSG budget request and 2.2% of the overall HCC Administration annual operating budget($6.6M). +No NIH Category available Address;Adult;Aging;Appointment;Area;Articulation;Basic Science;Bioinformatics;Caliber;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Cancer Survivor;Catchment Area;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Communication;Communities;Community Networks;Community Outreach;Consent;County;Cyclic GMP;Databases;Decision Making;Dedications;Development;Diagnosis;Disadvantaged;Disease;Disparity;Doctor of Philosophy;Education;Education and Outreach;Educational Status;Enrollment;Ensure;Environmental Risk Factor;Equipment;Evaluation;Faculty;Faculty Recruitment;Funding;Future;Genome Stability;Genomic medicine;Goals;Health;Healthcare Systems;High-Throughput Nucleotide Sequencing;Immune;Immunologic Monitoring;Infrastructure;Institution;Intervention;Investments;Laboratories;Leadership;Learning;Malignant Neoplasms;Mission;Modality;National Cancer Institute;Patient Care;Pennsylvania;Personal Satisfaction;Philanthropic Fund;Population;Population Sciences;Process;Protocols documentation;Publications;Publishing;Recommendation;Research;Research Personnel;Resource Sharing;Risk;Science;Scientific Advances and Accomplishments;Services;Site;Source;Strategic Planning;Therapeutic;Time;Training;Training and Education;Translational Research;Transplantation;Underrepresented Minority;United States National Institutes of Health;Universities;University resources;Update;Vision;anticancer research;biobehavior;cancer education;cancer epidemiology;cancer genomics;cancer health disparity;cancer immunotherapy;cancer prevention;community engagement;cost effective;early-career faculty;experience;faculty support;health equity;high school;improved;member;operation;organizational structure;pediatric patients;peer;population survey;precision medicine;prevent;programs;recruit;rural dwellers;tumor;tumor immunology;urban minority;virology Cancer Center Support Grant Project Narrative: OverallThe mission of the UPMC Hillman Cancer Center (HCC) is to reduce the burden of cancer in westernPennsylvania and the nation through research patient care education and outreach. Since its founding in1985 HCC has been at the forefront in discovery and advancement of scientific findings that have led to newstrategies for preventing detecting diagnosing and treating cancer and for addressing the health-relatedneeds and well-being of cancer patients and survivors. NCI 10674776 7/21/23 0:00 PAR-17-095 5P30CA047904-35 5 P30 CA 47904 35 "PTAK, KRZYSZTOF" 9/10/97 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 1900219 "FERRIS, ROBERT L" Not Applicable 12 OTOLARYNGOLOGY 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 397 Research Centers 2023 5995559 NCI 3770792 2224767 Abstract: OverallThe UPMC Hillman Cancer Center (HCC) at University of Pittsburgh is a matrix cancer center currently led byRobert L. Ferris MD PhD who has served as Director of HCC since 2017. With funding from the NationalCancer Institute and other peer- and non-peer-reviewed sources HCC conducts impactful basicclinical/translational and population science research that is changing the way we detect diagnose and treatcancer. Through our research and community outreach efforts we address the needs and disparities of cancerpatients and those who are at risk of developing cancer in our 29-county western Pennsylvania catchmentarea and through our strong efforts in educating and training new cancer researchers and clinicians we areensuring that those needs will continue to be met in the years to come.HCC integrates the expertise and resources of the University of Pittsburgh a top-5 institution in NIH fundingand UPMC one of our nations largest health care systems to provide our 280 members with state-of-the-artfacilities and equipment and numerous opportunities for interaction and collaboration. Organized into 7research programs focused on Cancer Biology Genome Stability Cancer Virology Cancer Immunology andImmunotherapy Cancer Therapeutics Cancer Epidemiology and Prevention and Biobehavioral CancerControl our members published over 4000 articles and enrolled more than 12700 adult and pediatric patientsonto interventional clinical trials from 2014-2018. These efforts were enabled by our 10 shared resources andextensive infrastructure for supporting clinical research at central academic and community network sites.HCC is guided by an experienced Senior Leadership Team of Deputy and Associate Directors who join Dr.Ferris in overseeing our science and operations. With input from the leaders of our research programs andother key HCC members this team sets the vision and develops the strategic plan for our future developmentwhich includes a new HCC-wide Administrative Core for supporting team science. Over the next 5 years HCCaims to: 1) expand upon our existing scientific strengths; 2) augment our shared resources; 3) develop andimplement strategies for reducing cancer-related health problems in our catchment area population; 4)increase transdisciplinary research in topics that include tumor genomics and precision medicine translationalcancer immunotherapy and environmental factors that impact cancers in our catchment area and cancer andaging; 5) increase focus on education and learning at all levels of training; 6) implement precision medicine; 7)seek institutional and philanthropic funding to support faculty recruitment and retention and the facilities andshared resources needed to advance our research initiatives; and 8) continue to engage in the dynamicplanning and decision-making process that was instituted by our new Director. 5995559 +No NIH Category available Address;Animal Model;Apoptosis;Asparagine;Biological Models;Bypass;Catalytic Domain;Cell Cycle Arrest;Cell Proliferation;Cell Surface Proteins;Cell Survival;Cells;Chemicals;Clinic;Clinical Trials;Combined Modality Therapy;Complex;Coupled;Couples;Data;Diagnosis;Disease;Drug Kinetics;Endoplasmic Reticulum;Epidermal Growth Factor Receptor;FGFR1 gene;Fluorescence;Gene Amplification;Glycoproteins;Goals;Immune;Immune checkpoint inhibitor;In Vitro;Individual;KRAS2 gene;Lead;Link;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane Glycoproteins;Modality;Molecular;Morbidity - disease rate;Morphology;Mutation;Non-Small-Cell Lung Carcinoma;Normal tissue morphology;Oncogenic;Pathway interactions;Patient-Focused Outcomes;Pharmaceutical Chemistry;Polysaccharides;Post-Translational Protein Processing;Prevention;Process;Property;Protein Complex Subunit;Protein Overexpression;Proteins;Radiation Tolerance;Radiation therapy;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Research;Resistance;Series;Signal Pathway;Signal Transduction;Site;Specificity;Subgroup;Systemic Therapy;Testing;Therapeutic;Therapeutic Effect;Toxic effect;Translating;Translations;Treatment Efficacy;Tyrosine Kinase Inhibitor;United States;Work;analog;cancer subtypes;cancer survival;cancer therapy;cell killing;clinical translation;combinatorial;design;drug development;drug discovery;drug sensitivity;efficacy testing;epithelial to mesenchymal transition;experimental study;gene product;glycosylation;high throughput screening;immune checkpoint;improved;in vivo;in vivo evaluation;inhibitor;lung cancer cell;mortality;mutant;neoplastic cell;novel;novel strategies;novel therapeutics;overexpression;pharmacologic;programs;receptor;senescence;small molecule;small molecule inhibitor;therapeutic development;therapy resistant;treatment strategy;tumor;tumor growth;tumor xenograft OST Inhibition in NSCLC A major challenge for treatment of non-small cell lung cancer (NSCLC) is the presence or emergence oftherapeutic resistance to receptor tyrosine kinase (RTK) inhibitors. We have identified a new approach fortargeting cell surface glycoprotein receptors (such as RTKs) through inhibition of the oligosaccharyltransferase(OST). To advance this therapeutic strategy the proposed research will characterize and test OST inhibitors ingenetically defined subgroups of NSCLC to identify mechanisms of drug sensitivity as well as novel inhibitorswith the potential for clinical translation. NCI 10674770 5/31/23 0:00 PA-19-056 5R01CA240418-04 5 R01 CA 240418 4 "CHEN, WEIWEI" 6/1/20 0:00 5/31/25 0:00 Drug Discovery and Molecular Pharmacology Study Section[DMP] 10642789 "CONTESSA, JOSEPH N." Not Applicable 3 RADIATION-DIAGNOSTIC/ONCOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 395 Non-SBIR/STTR 2023 478219 NCI 285504 192715 Non-small cell lung cancers (NSCLC) are aggressive tumors that are a major cause of morbidity and mortalityin the United States. In the past decade the introduction of systemic therapies such as receptor tyrosinekinase targeted inhibitors and immune checkpoint inhibitors have significantly improved patient outcomes.However therapeutic resistance to these therapies frequently develops and is characterized by parallelsignaling through other co-expressed receptor glycoproteins. We have therefore investigated the feasibility ofdisrupting asparagine (N) linked glycosylation a co- and post-translational protein modification as a strategyto block both primary and bypass glycoprotein survival signaling in NSCLC. Although this pathway is targetrich and involves at least 34 gene products pharmacologic inhibitors that regulate this process have notpreviously been available. We have identified a first in class small molecule inhibitor of theoligosaccharyltransferase (OST) the multi-subunit enzymatic complex that transfers glycans to elongatingproteins in the endoplasmic reticulum. This inhibitor reduces OST fidelity by targeting the catalytic subunit andresults in a site-specific and partial inhibition of glycosylation. In NSCLC with activation of RTK dependentoncogenic signaling OST inhibition blocks tumor cell proliferation and couples favorably with TKIs to enhanceapoptosis and xenograft tumor growth. We now propose to characterize and advance novel small moleculeinhibitors of the OST with respect to catalytic subunit inhibition and effects on EGFR driven NSCLC. Becauseglycoprotein bypass signaling is also operative in NSCLC subtypes with FGFR1 amplification or KRASmutation we will define the signaling mechanisms and determine the sensitivity of these tumors to OSTinhibition. This project will also investigate the effects of OST inhibition on NSCLC radiosensitivity and identifyhow glycoprotein dependent cellular programs mediate intrinsic and immune mediated therapeutic resistance.Together this work will advance OST inhibition as a novel treatment strategy for NSCLC with the potential ofdelivering an OST inhibitor that can be translated to the clinic. 478219 +No NIH Category available Research Training;Training Programs;Urologic Oncology T32 Urologic Oncology Research Training Program PROJECT NARRATIVEThe T32 Urologic Oncology Research Training Program at Memorial Sloan Kettering Cancer Center(MSK) trains qualified urologists for academic careers as clinician-scientists focused on eliminatingsuffering and death from genitourinary cancers which comprise 21% of all non-skin cancers and cause10% of all cancer deaths in the United States. NCI 10674756 8/10/23 0:00 PA-18-403 5T32CA082088-24 5 T32 CA 82088 24 "LIM, SUSAN E" 9/1/99 0:00 7/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 7835134 "CARVER, BRETT STEWART" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 371627 NCI 345640 25987 PROJECT SUMMARY/ABSTRACTSince its inception in 1999 the primary objective of the T32 Urologic Oncology Research TrainingProgram at Memorial Sloan Kettering Cancer Center (MSK) has been to train select urologists forproductive careers in translational research in urologic oncology. Dedicated research training in urologiconcology is essential to the mission of the National Cancer Institute (NCI) to reduce morbidity andmortality from genitourinary cancers which cause about 10% of all cancer-related deaths in the UnitedStates and which are expected to rise steadily in incidence as the population ages. For the proposedfunding period we seek to continue our interactive multidisciplinary research training strategy thatintegrates the following: (1) a multidisciplinary faculty of basic clinical and translational researchersspanning the disciplines of surgery medicine cancer biology and therapeutics molecular pathology andgenetics immunotherapy molecular radiology biostatistics and epidemiology and laboratory medicine(2) an intensive mentored research practicum tailored to the T32 trainees research interests and goals(3) a core curriculum of required didactic and discussion-based courses to enhance the quality of thehands-on research training (4) structured career development workshops in grant writing and careerdevelopment awards and (5) elective activities that will allow T32 trainees to further immerse themselvesin the world of cancer research and to network with peers and established leaders. Each year 2 highlycommitted postdoctoral trainees from the Urologic Oncology Fellowship Program at MSK are selected forthe T32 Urologic Oncology Research Training Program. They must have an MD must have completedresidency training in urology and must be board-eligible urologists. These 2 trainees are supported bythis T32 training grant during 2 years dedicated to urologic oncology research training with appointmentto the 2nd year contingent on suitable progress. At the completion of their training graduates of theT32Urologic Oncology Research Training Program are expected to be attractive candidates for junior facultyappointments at research-focused academic organizations. In the past 10 years 90% of T32 traineegraduates have matriculated to faculty positions at academic institutions and are engaged in laboratoryand/or clinical research aimed at understanding and overcoming genitourinary cancers. 371627 +No NIH Category available Active Biological Transport;Affect;Animal Model;Antineoplastic Agents;Area;Biochemical;Biological Models;Blood - brain barrier anatomy;Brain;Brain Neoplasms;Cardiovascular system;Carrier Proteins;Central Nervous System;Cerebral cortex;Characteristics;Clinical;Clinical Pharmacology;Clinical Trials;Collaborations;Computer Models;Data;Data Set;Decision Making;Development;Diffusion;Dose;Drug Delivery Systems;Drug Kinetics;Drug Modelings;Enzymes;Formulation;Glioblastoma;Goals;Health Personnel;Heterogeneity;Human;In Vitro;Individual;Infiltration;Kinetics;Knowledge;Malignant neoplasm of brain;Mediating;Metabolism;Methods;Modeling;Necrosis;Oncology;Outcome;Patients;Penetration;Permeability;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Pharmacotherapy;Physiological;Plasma;Predictive Factor;Process;Property;Proteins;Proteomics;Regimen;SDZ RAD;Specimen;Structure;System;Translational Research;Validation;biological systems;blood perfusion;blood-brain barrier disruption;blood-brain barrier function;blood-brain barrier permeabilization;blood-brain tumor barrier;brain parenchyma;clinical development;comparative;contrast enhanced;design;drug development;effective therapy;improved;in vitro Assay;in vitro Model;in vivo;innovation;inter-individual variation;inter-institutional;model development;neurosurgery;novel;novel therapeutics;pharmacokinetic model;physiologically based pharmacokinetics;pre-clinical;predictive modeling;programs;restraint;small molecule;tool;translational research program;tumor;uptake Physiologically Based Pharmacokinetic Modeling of Drug Penetration into the Human Brain and Brain Tumors PROJECT NARRATIVEThe difficulty in early reliable prediction of drug penetration into the human brain and brain tumors makes thedevelopment of new drugs and use of existing drugs for treating brain cancer a challenging and usuallyunsuccessful task. This project will develop a physiologically based pharmacokinetic model platform that willimprove our ability to more readily and reliably predict the levels of anticancer drugs in the human brain andbrain tumors. This mechanism-based computational model platform promises to become a valuable tool to assistdrug developers and health care providers in the development of more effective therapies and optimal use ofcurrent therapies to treat brain cancer. NCI 10674753 8/25/23 0:00 PA-20-185 5R01CA255124-03 5 R01 CA 255124 3 "FORRY, SUZANNE L" 8/1/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-MDCN-M(91)S] 8761880 "LI, JING " "SANAI, NADER " 13 INTERNAL MEDICINE/MEDICINE 1962224 M6K6NTJ2MNE5 1962224 M6K6NTJ2MNE5 US 42.357466 -83.065294 9110501 WAYNE STATE UNIVERSITY DETROIT MI SCHOOLS OF MEDICINE 482024000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 369429 NCI 258059 111370 ABSTRACTDrug delivery to the brain is restrained by the blood-brain barrier (BBB) a physical and biochemical barrierseparating the brain from the circulatory system. Small molecule drugs move across the BBB mainly viatranscellular passive diffusion and transporter-mediated active transport. The BBB in brain tumors is disruptedto varying extent leading to large intra- and inter-individual variability in drug tumor exposure. Mechanisticunderstanding and prediction of heterogeneous drug penetration across the intact BBB and disrupted blood-brain tumor barrier (BBTB) is of paramount importance to rational drug development and treatment for braincancer. Given the fact that the rate and extent of drug penetration across the BBB is determined by bothbiological system characteristics and drug properties prediction of human BBB/BBTB permeability frompreclinical in vitro or animal models is complicated by biological system differences. Hence the development ofinnovative approaches is imperative. The in vitro-in vivo extrapolation-physiologically based pharmacokinetic(IVIVE-PBPK) model offers a unique platform that allows simultaneous incorporation of drug- and system-specific parameters into a PK model and enables a priori prediction of individual in vivo kinetic processes basedon mechanistic scaling of in vitro data (e.g. in vitro enzyme and transporter kinetics). The overall goal of thisproject is to develop a mechanism-based PBPK model platform for predicting heterogeneous drug penetrationinto the human brain and brain tumors. We will employ an integrated translational research approach to achievethis goal which leverages in vitro pharmacology studies PK modeling and clinical trials. Three drugs (AZD1775ceritinib and ribociclib) will be used for initial model development and verification and additional 3 drugs(everolimus abemaciclib and LY3214996) will be used for further model validation. These drugs have been oris being evaluated in glioblastoma patients in our clinical trial program. Observed clinical plasma and brain tumorPK data are available for model development and validation. As the first step towards resolving the gap of ourknowledge on BBB transporter abundances which is essential to establishing IVIVE scaling factors for predictingtransporter-mediated active clearance at the human BBB and BBTB Aim 1 is to determine transporter proteinabundances in isolated microvessels of non-cancerous cortex as well as contrast-enhancing and non-enhancingglioblastoma specimens. Aim 2 is to determine drug-specific parameters for metabolism passive transcellularpermeability and interaction with efflux and uptake drug transporters. Aim 3 is to develop and validate a novel7-compartment permeability-limited brain (7Brain) PBPK model which accounts for brain and tumor regionalphysiological differences in blood perfusion pH BBB/BBTB integrity and transporter expression. The 7BrainPBPK model is the first-of-its kind mechanism-based model platform for the prediction of heterogeneous drugpenetration across the human BBB and BBTB. It promises to be a valuable tool to assist the development anddesign of improved drugs and dosing regimens for more effective treatment of brain cancer. 369429 +No NIH Category available Address;Advanced Malignant Neoplasm;Affect;Area;Biological;Cancer Center;Cancer Control;Caring;Clinical Research;Clinical Trials;Communities;Community Clinical Oncology Program;Community Health;Complex;Comprehensive Cancer Center;Development;Disparity;Funding;Funding Agency;Genomics;Goals;Health system;Hospitals;Human Subject Research;Immune system;Immunologics;Individual;Infrastructure;Intervention;Knowledge;Lead;Malignant Neoplasms;Massachusetts;Michigan;Mission;Molecular Target;National Cancer Institute;National Clinical Trials Network;Oncology;Patient-Focused Outcomes;Patients;Pennsylvania;Performance;Process;Productivity;Protocols documentation;Research;Research Personnel;Resources;Saints;Site;Tissues;Vision;anticancer research;biobank;cancer care;cancer health disparity;cancer prevention;cancer therapy;care delivery;community based research;disparity reduction;evidence base;experience;improved;innovation;next generation;programs;research study;screening;symptom science Michigan Cancer Research Consortium NCORP PROJECT NARRATIVEThe overall goal of NCORP is to bring cancer clinical research studies to individuals intheir own communities thereby generating a broadly applicable evidence base thatcontributes to improved patient outcomes and a reduction in cancer disparities. NCI 10674747 7/27/23 0:00 RFA-CA-18-016 5UG1CA189971-10 5 UG1 CA 189971 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 15619189 "AL BAGHDADI, TAREQ " Not Applicable 6 Unavailable 807606249 U7LTK2STCS59 807606249 U7LTK2STCS59 US 42.233132 -83.623767 10011140 SAINT JOSEPH MERCY HEALTH SYSTEM ANN ARBOR MI Other Domestic Non-Profits 481060995 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 3096276 NCI 2248658 847618 PROJECT SUMMARYThe ongoing mission of the Michigan Cancer Research Consortium (MCRC) NCORP is toimprove the oncologic health of the communities it serves by assuring access to state-of-the-art clinical trials. MCRC will achieve this goal through participation in cancer control andprevention screening cancer care delivery treatment and other relevant human subjectsresearch to contributing to knowledge development in the field of oncology care. The MCRCwill utilize its proven resources to serve the objectives of the National Cancer Institute'sNCORP program. First funded in 1994 as a single hospital CCOP the MCRC is nowcomprised of 15 hospitals and 85 oncology investigators from 47 practices in three states. Bystrategically leveraging our partnerships with the NCI Comprehensive Cancer Centers andother funding sources MCRC will contribute to the development of the next generation ofstudies particularly in the area of Cancer Care Delivery Research with a focus on reducingcancer disparities. Our specific aims are:Serve Our Patients - Meet our patients needs as one of the strongest performing NCORPprograms within the NCI network providing access to protocols.Advance Cancer Care Delivery Research (CCDR) Utilize our unique communityinfrastructure and support from our strategic partnerships and NCTN counterparts toconduct CCDR protocols that address major issues in the delivery of cancer care .Decrease Cancer Disparities - Assure our consortium of community sites stay at theforefront of understanding how disparities affect outcomes of the patients we serve whileimplementing and studying the impact of targeted interventions to reduce disparities.Expand Biorepository Banking - Expand our successful biorepository banking to allMCRC hospitals so we can provide high quality fully-annotated tissues to researchers.Aligned with NCI goals focus on innovative trials exploring the biologic basis ofcancer treatment and symptom science - Explore the interface between genomicsimmune system and host milieu through innovative trials. 3096276 +No NIH Category available Acute Lymphocytic Leukemia;Acute Myelocytic Leukemia;Adolescent and Young Adult;Adult Acute Myeloblastic Leukemia;Alternative Therapies;Apoptosis;Automobile Driving;Biological Models;Bromodomain;Bromodomains and extra-terminal domain inhibitor;CRISPR interference;Cell Line;Chemotherapy-Oncologic Procedure;Child;Childhood Acute Myeloid Leukemia;Childhood Leukemia;Clinical;Combined Modality Therapy;DNMT3a;Data;Dependence;Development;Diagnosis;Drug Combinations;Drug Synergism;Drug resistance;Elderly;Engraftment;Epigenetic Process;Gene Expression Profile;Genes;Genetic;Genetic Heterogeneity;Genetic Transcription;Genomics;Goals;Growth;Human;Immunocompetent;Insertional Mutagenesis;KRAS2 gene;Knowledge;Laboratories;Leukemic Cell;MEK inhibition;MEKs;MLL gene;Malignant Neoplasms;Methodology;Modeling;Molecular;Mus;Mutation;NF1 mutation;Outcome;Pathway interactions;Patients;Play;Proliferating;Proteins;Ras Signaling Pathway;Refractory;Relapse;Resistance;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Somatic Mutation;System;TP53 gene;Testing;Therapeutic;Translating;Transplantation;Treatment-related toxicity;Work;acute myeloid leukemia cell;candidate validation;cohort;congenic;drug testing;experimental study;genome-wide analysis;hyperactive Ras;improved;in vivo;inhibitor;knock-down;leukemia;leukemia relapse;leukemic transformation;mouse model;mutant;next generation;overexpression;patient derived xenograft model;pediatric patients;permissiveness;programs;resistance mechanism;response;retransplantation;synergism;transcription factor;transcriptome sequencing;validation studies Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML. PROJECT NARRATIVEAcute myeloid leukemia (AML) in children adolescents and young adults (AYA) is characterized by highlyprevalent transcription factor fusions and RAS pathway mutations with the first of these genetic alterationshypothesized to promote a transcriptional signature that is permissive for AML development and the latterplaying a central role in driving leukemic growth. Our data revealed that targeting these pathwayssimultaneously results in potent synergistic effects that converge upon key survival programs. This K08application proposes to extend these studies to pediatric AML patient-derived xenografts and to define themolecular basis of drug synergy and resistance with the goal of translating this new knowledge into bettertreatments for pediatric AML. NCI 10674738 7/13/23 0:00 PA-20-203 5K08CA256489-03 5 K08 CA 256489 3 "BOULANGER-ESPEUT, CORINNE A" 8/1/21 0:00 7/31/26 0:00 Career Development Study Section (J)[NCI-J] 12367854 "HUANG, BENJAMIN " Not Applicable 11 PEDIATRICS 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF MEDICINE 941432510 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 247985 NCI 229616 18369 PROJECT SUMMARYAcute myeloid leukemia (AML) comprises 20% of childhood leukemia cases. In contrast to acute lymphoblasticleukemia (ALL) cure rates for AML remain poor with the majority of patients dying from refractory leukemia ortreatment related toxicities. In contrast to AML in older adults genome-wide studies of AML in childrenadolescents and young adults (AYA) revealed a lower mutational burden and highly prevalent transcriptionfactor fusions and RAS pathway mutations. Additionally while transcription factor fusions are hypothesized topromote a transcriptional signature that is permissive for AML development experimental data suggest thatsignaling mutations play a central role in driving leukemic growth in vivo. Thus simultaneously targeting theabnormal transcriptional program and aberrant signaling pathways in AML is a rational therapeutic approachthat is particularly relevant in children and AYA patients.The overall goals of this proposal are to investigate the efficacy of promising drug combinations thatsimultaneously target key pathways in pediatric AML and to elucidate molecular mechanisms underlying drugsynergy and resistance to these targeted approaches through the following specific aims: (1) to identify andvalidate mechanisms of drug synergy and resistance to BET + MEK inhibition; and (2) to investigate the invivo efficacy of this combination in patient derived xenograft (PDX) models of pediatric AML. 247985 +No NIH Category available Biometry;Genomics;Malignant Neoplasms;Research Biostatistics for Research in Genomics and Cancer NarrativeThis training grant clearly has major relevance in public health as it is designed to train the nextwave of biostatistical researchers in cancer genomics which is one of the largest and growingareas of biomedical research in which the demand for well trained biostatistical researchers ismuch greater than the supply. NCI 10674737 8/14/23 0:00 PA-20-142 5T32CA106209-18 5 T32 CA 106209 18 "LIM, SUSAN E" 5/1/04 0:00 7/31/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1901879 "IBRAHIM, JOSEPH G" Not Applicable 4 BIOSTATISTICS & OTHER MATH SCI 608195277 D3LHU66KBLD5 608195277 D3LHU66KBLD5 US 35.9316 -79.057377 578206 UNIV OF NORTH CAROLINA CHAPEL HILL CHAPEL HILL NC SCHOOLS OF PUBLIC HEALTH 275995023 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 229665 NCI 254970 12998 Project SummaryThis 5 year program is designed to continue to train predoctoral (PhD) students in statisticalgenomics with the major emphasis in cancer genomics. The goal is to train biostatisticians inthe biology etiology and genetics of cancer as well as to train them to conduct state-of-the-artbiostatistical methodologic research relevant to the genomics of cancer as well as in relatedareas of genomics. The goal is to also produce biostatisticians who can collaborate with otherscientific researchers and oncologists on research issues related to genomics and cancer. Thetypical predoctoral trainee will be a college graduate or master's level graduate with an excellentacademic record appropriate for this training area. Funding is requested for the support of 5predoctoral trainees. The Department of Biostatistics at UNC is one of the largest in the worldand has highly qualified personnel and the available facilities to provide the mostcomprehensive predoctoral and postdoctoral training in this research area. Several membersfrom the Department of Genetics and the Bioinformatics and Computational Biology (BCB)program will be deeply involved in all phases of this training program and will play an integralrole in this training program. 229665 +No NIH Category available Advanced Malignant Neoplasm;Alaska;Cancer Control;Cancer Research Project;Caring;Catchment Area;Clinical Research;Clinical Trials;Collaborations;Collection;Colorado;Communities;Community Clinical Oncology Program;Community Hospitals;Dedications;Disease;Enrollment;Funding;Future;Goals;Grant;Group Meetings;Health Personnel;Health Professional;Healthcare Systems;Home;Hospitals;Image;Innovative Therapy;Institution;Knowledge;Malignant Neoplasms;Measures;Mentors;Minority Participation;Montana;Native Americans;Newsletter;Oncology;Outcome;Patients;Pediatric Hospitals;Pediatric Oncology;Physicians;Physicians' Offices;Population;Private Practice;Protocols documentation;Provider;Research;Research Personnel;Research Priority;Research Project Grants;Resources;Site;System;Training;Travel;Underrepresented Populations;Utah;Washington;Work;Wyoming;anticancer research;base;cancer care;cancer clinical trial;cancer health disparity;cancer prevention;care delivery;community setting;health care service;innovation;member;multidisciplinary;operation;outreach;patient oriented;precision medicine;programs;recruit;social media;symposium;treatment trial Western States Cancer Research NCORP Project NarrativeThe Colorado Cancer Research Program is a cancer clinical trial research organization whoseeks to provide access to NCI sponsored clinical trials for our consortium members located inthe mountain states of Colorado Wyoming Montana Utah Washington and Alaska. Bypartnering with Healthcare systems and community hospitals we will provide access toinnovative therapies and cancer related research projects for patients in their homecommunities all the while pursuing and supporting NCI strategic research priorities. We workwith Healthcare systems Hospitals Providers and Patients to disseminate knowledge aboutclinical trial options clinical trial participation and clinical trial outcomes. NCI 10674732 8/21/23 0:00 RFA-CA-18-016 5UG1CA189805-10 5 UG1 CA 189805 10 "HECKMAN-STODDARD, BRANDY" 8/1/14 0:00 7/31/25 0:00 ZCA1-RTRB-E(M1) 8761485 "DIBELLA MD, NICHOLAS " Not Applicable 1 Unavailable 148748325 D13WXXL3LNC7 148748325 D13WXXL3LNC7 US 39.685337 -104.936838 2599301 WESTERN STATES CANCER RESEARCH NCORP DENVER CO Other Domestic Non-Profits 802468001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 1005015 NCI 637010 368005 Project SummaryBy serving as a dedicated NCORP the Colorado Cancer Research Program (CCRP) seeks to advance cancerresearch for patients local communities healthcare providers and hospitals in the Western mountain stateregion. The goal is to provide and maintain access to NCI research and trials focused on cancer control (CC)cancer prevention (CP) cancer disparities cancer care delivery (CCDR) as well as provide access to NCTNtreatment and imaging trials. In the next funding cycle CCRP has developed strategic partnerships withregionally focused mid-sized Healthcare systems whose organizations have a common ethos of patient-centered high value care and a shared commitment to implementing NCI trials in the community setting. Theconsortium is diverse in its membership not only from a regional perspective but also in regards to the make-up of its providers of healthcare services ranging from Healthcare Systems to Independent Hospitals toprivate practice physician offices. This diversity of recruitment sites will allow for broader participation inNCORP projects so as to achieve CCRPs main goal of providing patients and communities within itscatchment area the opportunity to participate in and potentially benefit from the innovative and scientificallyrigorous research projects of the NCI. 1005015 +No NIH Category available Address;Adopted;Affect;Amino Acids;Antibodies;Architecture;Binding;Biochemical;Biological Assay;Biological Products;Biophysics;Caenorhabditis elegans;Cells;Cellular Assay;Cessation of life;Childhood;Clinical;Complex;Complex Analysis;Crystallography;Cysteine;Development;Disease;Drosophila genus;Embryonic Development;Epitope Mapping;Epitopes;Family;Fibronectins;Foundations;Genetic;Genetic study;Glycine;Goals;Homologous Gene;Immunoglobulin Fragments;In Vitro;Invertebrates;Knowledge;LTK gene;Length;Ligand Binding;Ligands;Link;Logic;Malignant Childhood Neoplasm;Malignant Neoplasms;Maps;Mass Spectrum Analysis;Mediating;Membrane;Molecular;Monoclonal Antibodies;Mutation;Neuroblastoma;Normal tissue morphology;Oncogenic;Outcome;Pathogenicity;Pathway interactions;Peptides;Peripheral Nervous System;Phage Display;Phosphotransferases;Play;Proteins;Receptor Activation;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Regulation;Regulatory Element;Reporting;Research;Sensory;Signal Induction;Signal Pathway;Signal Transduction;Structure;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Translating;Vertebrates;anaplastic lymphoma kinase;biophysical properties;design;dimer;disorder risk;extracellular;high risk;inhibitor;insight;member;mutant;neural;neuron development;new therapeutic target;novel therapeutics;overexpression;polyglycine;pre-clinical;rational design;receptor;receptor expression;receptor function;response;targeted treatment;tool;transmission process;tumor;virtual Identifying opportunities for extracellular inhibition of ALK signaling Project NarrativeALK receptor expression and mutation are oncogenic drivers in multiple cancers particularly inpediatric neuroblastoma. The ALK receptors form a unique family of receptor tyrosine kinases whosemechanisms of regulation are poorly understood. This proposal aims to elucidate the molecularunderpinnings that dictate and direct ALK receptor signal transduction to uncover novel therapeuticopportunities. NCI 10674722 5/18/23 0:00 PA-19-056 5R01CA248532-04 5 R01 CA 248532 4 "AMIN, ANOWARUL" 9/1/20 0:00 5/31/25 0:00 Macromolecular Structure and Function C Study Section[MSFC] 10308038 "KLEIN, DARYL EWALD" Not Applicable 3 PHARMACOLOGY 43207562 FL6GV84CKN57 43207562 FL6GV84CKN57 US 41.310925 -72.926428 9420201 YALE UNIVERSITY NEW HAVEN CT SCHOOLS OF MEDICINE 65208327 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 396 Non-SBIR/STTR 2023 375493 NCI 224175 151318 Project SummaryThis proposal aims to resolve the molecular basis for activation of an atypical receptor tyrosine kinase (RTK)family ALK. The ALK family consists of two receptors ALK and LTK. ALKs are involved in neuronaldevelopment and like other RTKs are critically important in numerous cancers. In particular ALK is theoncogenic driver in neuroblastoma an aggressive and often lethal childhood cancer. Significantly ALKreceptors are distinct from the 19 other RTK families (56 receptors in total). Perhaps most prominent they donot share the standard RTK architecture. Typically RTKs are composed of multiple repeats of common domains(e.g. Ig fibronectin cysteine-rich) in their extracellular region. On the contrary ALKs extracellular sensoryregion is highly enriched in glycines (termed the glycine rich domain GRD). Only recently the ALK GRD hasbeen shown to be a receiver for Augmentor (AUG) signals. Augmentors are small peptides with ~50 highlyconserved amino acids that are sufficient for stimulating ALKs kinase activity. Given ALKs remarkable moleculardesign we expect ALK to have an equally distinguishable mechanism of receptor control potentially broadeningthe paradigm for RTK regulation. Despite the importance of this receptor family in cancer surprisingly little isknown about how the receptor functions: 1) there are no reported structures for the GRD AUG or their complexand 2) it remains unknown how engagement of ligand translates into receptor kinase activity. The researchproposed here focuses on understanding the molecular mechanism of ALK and LTK activation by AUG. Withthis foundation we hope to reveal how oncogenic dysregulation usurps the control mechanisms in place duringnormal development. Our goals over the next 10 years are: 1) To develop a complete mechanistic understandingof how ALK receptors perceive Augmentors and transmit their signals 2) To understand how receptor mutationsand matrix changes alter ALK signal transduction in cancer and 3) to determine if ALKs unique structural andregulatory elements present novel targets for therapeutic interventions. We will study ligand-receptor complexesbiochemically and with structural techniques in order to understand in detail how AUG peptide binding leads toactivation of ALKs in the signaling complex. In pursuing studies of ALKs activation we will investigate howpreclinical monoclonal antibodies and discovered Fabs modulate and inhibit ALK function. In sum our studieswill provide necessary fundamental insight into signaling by this unique family of receptors that does not fit intothe canonical RTK schema. Understanding the mechanism of receptor activation in this family will be crucial fordesigning and deploying effective inhibitors that will need to differ from those targeting other well-studied RTKs.In addition our findings will reveal the signaling differences induced by common cancer mutations that will steerclinical strategies to approach ALK dependent diseases. 375493 +No NIH Category available Antigen Presentation;Biological;Biological Assay;Breast Cancer Cell;CD8-Positive T-Lymphocytes;CRISPR/Cas technology;Cells;Chronic;Cytoplasm;DNA Damage;DNA Methylation;Detection;Double-Stranded RNA;Elements;Epigenetic Process;Exhibits;Family;Gene Deletion;Gene Expression;Genetically Engineered Mouse;Genomic Instability;Homeostasis;Human;Immune;Immune Evasion;Immune response;Immune signaling;Immune system;Immunocompetent;Immunologics;Immunomodulators;Immunotherapeutic agent;Immunotherapy;Infiltration;Inflammation;Innate Immune Response;Interferon Type I;Interferons;Invaded;Link;Luciferases;MHC Class I Genes;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Metastatic breast cancer;Mitochondria;Modification;Molecular;Mus;Normal Cell;Oxidative Stress;Pathway interactions;Production;RNA;RNA Editing;RNA Helicase;RNA Processing;Regulation;Reporting;Role;STAT1 gene;Signal Transduction;Somatic Cell;Source;System;Therapeutic;Transcriptional Silencer Elements;Tumor Immunity;Viral;Virus Diseases;anti-PD1 antibodies;anti-cancer;aspartylglutamate;cancer cell;cancer immunotherapy;cancer therapy;cellular targeting;conditional knockout;crosslinking and immunoprecipitation sequencing;experimental study;glutamylalanine;helicase;human disease;immune activation;immune checkpoint blockade;immunogenic;immunogenicity;inhibitor;innate immune sensing;knock-down;malignant breast neoplasm;mouse model;new therapeutic target;novel;overexpression;pathogen;promoter;response;sensor;small molecule inhibitor;therapeutic target;transcriptomics;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions;tumorigenesis Targeting cellular double-stranded RNA homeostasis in breast cancer Project NarrativeMost breast cancer exhibits an immunologically inactive tumor microenvironment which is considered as asignificant challenge for effective immunotherapies. Here we will study how DDX3X controls the level ofcellular double-stranded RNAs and targeting DDX3X to restore tumor immunogenicity and enhance antitumoractivity in breast cancer. NCI 10674720 6/13/23 0:00 PA-20-185 5R01CA262418-03 5 R01 CA 262418 3 "KUO, LILLIAN S" 7/1/21 0:00 6/30/26 0:00 Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1] 12268422 "HAN, CECIL " Not Applicable 98 INTERNAL MEDICINE/MEDICINE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200570001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 366299 NCI 234807 131492 Summary/AbstractThe immunologically inactive (cold) tumor is a major challenge for effective immunotherapies in many cancersincluding breast cancer. Increasing evidence has demonstrated that human cells express various types ofendogenous double-stranded RNAs (dsRNAs) regardless of pathogen invasion and aberrant accumulation ofcellular dsRNAs could trigger a detrimental innate immune response in cells. In cancer these endogenousimmunogenic dsRNAs are suggested as a source of immune induction to increase tumor response toimmunotherapy. However to exploit the cellular dsRNAs in immunotherapy for cancer we need to understandthe molecular mechanism for cellular dsRNA homeostasis in normal and malignant cells and find the specificways to modulate immunogenic dsRNAs. We found that inhibition of DEAD-box RNA helicase 3X (DDX3X)resulted in the cytoplasmic accumulation of endogenous dsRNAs in the breast cancer cells. Loss of DDX3Xincreased the type I interferon production STAT1 activation IFN-stimulated genes (ISGs) expression and theMHC class I expression with the enhanced antigen presentation on the breast cancer cells. DDX3X inhibitionalso suppressed the tumor growth and increased the tumor infiltration of active CD8+ T cells and DC in thesyngeneic breast cancer mouse model. We hypothesize that inhibiting DDX3X leads to aberrant accumulationof endogenous dsRNAs which triggers type I IFN responses and induces an innate immune response in thetumor. The proposed studies will be focused on understanding the molecular mechanism by which DDX3Xregulates cellular dsRNA homeostasis providing a link between cellular dsRNAs and immune signals in breastcancer cells and establishing novel immunotherapeutic strategies for breast cancer. In Aim 1 we willdetermine the molecular mechanism by which DDX3X regulates cellular dsRNAs; In Aim 2 we will studyDDX3X-dsRNAs-Type I IFN axis in cancer cells and human tumor; In Aim 3 we will explore the effect ofinhibiting DDX3X to increase anti-tumor immunity and sensitize tumors to immunotherapy. Our study will reveala novel regulatory mechanism of endogenous dsRNAs in cancer and may lead to novel therapeutics targetingDDX3X for new combinatory immunotherapy. 366299 +No NIH Category available 9p24;African American;African American population;Aneuploidy;Biological Process;Caucasians;Cell Nucleus;Chromosomes;Clustered Regularly Interspaced Short Palindromic Repeats;Colorectal Cancer;Copy Number Polymorphism;Cytosol;DNA;DNA Double Strand Break;DNA Repair;Data;Defect;Disease;Disparity;Double Strand Break Repair;Ethnic Origin;Ethnic Population;Functional disorder;Genes;Impairment;Incidence;Inflammation;Inflammatory;Interleukin-6;Loss of Heterozygosity;MLH1 gene;MSH2 gene;MSH3 gene;MSH6 gene;Malignant Neoplasms;Microsatellite Repeats;Mutation;PMS2 gene;Patient-Focused Outcomes;Patients;Phenotype;Process;Proteins;Race;Rectal Cancer;Reporting;Role;Signal Transduction;Testing;Tetranucleotide Repeat;United States;colon cancer patients;cytokine;homologous recombination;loss of function;mismatch repair protein 1;mortality;novel;patient retention;prevent;public database;racial population;repaired;survival outcome Inactivation of MSH3 in Colorectal Cancer and Race Project Narrative African Americans have the highest incidence and mortality rates from colorectal cancer over any othermajor racial or ethnic group in the United States but it is not fully clear what drives the aggressiveness ofdisease in these patients. We discovered that pro-inflammatory cytokines like IL6 are persistently releasedduring inflammation and directly impede specific repair processes centered around the DNA mismatch repairprotein MSH3 such that subsequent mutations within DNA accumulate and associates with poor patientoutcome. We aim to understand the contribution of MSH3 dysfunction to the poor survival outcome of AfricanAmerican colorectal cancer patients. NCI 10674712 8/1/23 0:00 PAR-18-654 5R01CA258519-04 5 R01 CA 258519 4 "SHARMAN, ANU" 8/1/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-OBT-B(55)R] 1877321 "CARETHERS, JOHN M" "ASHKTORAB, HASSAN " 50 INTERNAL MEDICINE/MEDICINE 804355790 UYTTZT6G9DT1 804355790 UYTTZT6G9DT1 US 32.876991 -117.24087 577507 "UNIVERSITY OF CALIFORNIA, SAN DIEGO" LA JOLLA CA SCHOOLS OF MEDICINE 920930621 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 561716 NCI 408188 153528 Abstract The occurrence of CRC in the United States shows a large disparity among recognized races andethnicities with African Americans demonstrating the highest incidence and mortality from this disease. Wehave observed a novel loss of function phenotype for the DNA mismatch repair protein MSH3 that is inducedby pro-inflammatory interleukin-6 (IL6) to shuttle MSH3 from the nucleus (where it normally repairs DNAmicrosatellites and double strand breaks) to the cytosol where it no longer can repair DNA with coincidentaccumulation of tetranucleotide microsatellite frameshifts (termed EMAST elevated microsatellite alterations atselected tetranucleotide repeats). These inflammation-associated microsatellite alterations are observed in50% of all sporadic CRCs and is associated with advance-staged disease and poor patient survival. Thisinflammation-induced somatic MSH3 defect is observed in twice as many African American than Caucasianrectal cancers and is associated with poor patient outcome. In this proposal we hypothesize that MSH3disruption contributes to the consequence of advanced stage and poor survival in African American CRCpatients. Our preliminary data demonstrates clear evidence that MSH3 participates in HomologousRecombination repair of DNA double strand breaks as well as prevents aneuploidy. We have identified 6unique somatic deleterious MSH3 mutations among African American CRCs that have not been reported inpublic databases. And we have characterized that chromosome 9p24.2 loss of heterozygosity (LOH) isassociated with EMAST and dramatically modifies survival of patients whose primary CRC demonstratesEMAST and 9p24.2 LOH. In this proposal we will examine the central role of MSH3 dysfunction in itscontribution to the survival outcome of African American CRC patients. Our aim is to assess the role of MSH3-disrupted double strand break mis-repair among African American CRCs determine the functionality of 6unique MSH3 mutations observed in African American CRCs and ascertain the contribution of MSH3-deficiency with chromosome 9p24.2 LOH in the aggressiveness of African American CRCs. Overall thisproposal examines the role and contribution of defective MSH3 protein that likely contributes to the poorphenotype associated with African American CRC patients. 561716 +No NIH Category available Address;Adolescent and Young Adult;Area;Awareness;Black Populations;Breast;Cancer Burden;Cancer Center;Cancer Control;Cancer Patient;Cancer Survivor;Capital;Caring;Catchment Area;Cause of Death;Clinical Research;Clinical Trials;Clinical Trials Cooperative Group;Collaborations;Colorectal Cancer;Communities;Community Outreach;Comprehensive Cancer Center;County;Coupled;Disparity;District of Columbia;Education;Faculty;Faith-based organization;Goals;Health;Health Disparities Research;Healthcare;Hispanic Populations;Hospitals;Latino;Latino Population;Leadership;Light;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of prostate;Mammographic screening;Maryland;Minority;Minority Groups;Neighborhoods;Nonprofit Organizations;Obesity;Oncologist;Outcome;Outpatients;Participant;Patient-Focused Outcomes;Patients;Population;Prevention;Prevention trial;Primary Care Physician;Quality of Care;Recording of previous events;Research;Research Personnel;Resources;Risk Factors;Schedule;Smoking;Subgroup;Underserved Population;Uninsured;University Hospitals;Virginia;Visit;Washington;Woman;aging population;arm;base;cancer care;cancer clinical trial;cancer health disparity;cancer prevention;cancer risk;care delivery;care outcomes;community center;community engagement;community organizations;community partnership;design;disparity elimination;ethnic diversity;experience;health assessment;health disparity;imaging study;improved;interest;malignant breast neoplasm;medical specialist;medically underserved;minority health;minority health disparity;mortality;outreach;physical inactivity;programs;racial diversity;recruit;screening National Capital Area (NCA) Minority/Underserved NCORP Project NarrativeThe National Capital Area (NCA) Minority/Underserved NCORP based at Georgetown LombardiComprehensive Cancer Center (LCCC) and comprises MedStar Georgetown University Hospital (MGUH) andMedStar Washington Hospital Center (MWHC) will conduct cancer clinical research towards efforts to reducecancer-related disparities and health care outcomes. The NCA NCORP will address the needs of our catchmentarea via cancer prevention control screening as well as treatment and imaging studies. NCI 10674709 7/19/23 0:00 RFA-CA-18-017 5UG1CA239758-05 5 UG1 CA 239758 5 "HECKMAN-STODDARD, BRANDY" 8/7/19 0:00 7/31/25 0:00 ZCA1-SRB-H(M1) 1859826 "ADAMS-CAMPBELL, LUCILE LAUREN" "NOEL, MARCUS S" 98 INTERNAL MEDICINE/MEDICINE 49515844 TF2CMKY1HMX9 49515844 TF2CMKY1HMX9 US 38.905206 -77.07547 2869001 GEORGETOWN UNIVERSITY WASHINGTON DC SCHOOLS OF MEDICINE 200570001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 399 Other Research-Related 2023 878218 NCI 564771 313447 AbstractThe National Capital Area (NCA) Minority/Underserved NCORP will be based at Georgetown LombardiComprehensive Cancer Center (LCCC) comprising Medstar Georgetown University Hospital (MGUH) andMedStar Washington Hospital Center (MWHC) as the primary affiliate with a catchment area comprising 48.3%non-Latino Blacks (NLB) and 10.6% Hispanics/Latinos (H/L) that includes Washington D.C. and adjacentcounties in Maryland and Virginia. MWHC serves predominantly i.e. > 85% minority and underservedpopulations; and treats more than 2000 predominantly minority cancer patients and 48000 outpatientsannually. The cancer burden and disparities are greatest among NLB population in the catchment area asevident by some of the highest mortality rates in the nation for breast prostate and colorectal cancers. Amongthe H/L population cancer is the leading cause of death with H/L patients typically presenting at a later stagecompared to Non-Latino White (NLW) patients. High rates of preventable cancer risk factors such as obesityphysical inactivity and smoking coupled with much lower screening rates for certain cancers such as colorectaland cervical cancers in minorities contribute to the cancer disparities seen in the catchment area. The NCANCORP proposes to address one of the most significant factors associated with these cancer disparities - limitedaccess to optimal and cutting edge prevention cancer control and cancer care delivery by increasing awarenessand providing access to cancer clinical trials among NLB and H/L in the catchment area. LCCCs Office ofMinority Health and Health Disparities Research (OMH) represents the community outreach arm that is led byDr. Adams-Campbell that has established viable academic-community partnerships that enable the NCANCORP to conduct clinical research in areas of prevention control screening health disparities and cancercare delivery among the minority populations of interest. In light of an aging population and the increasing numberof cancer survivors this NCORP has the expertise and leadership as evident by demonstrable research in theseareas that address cancer control and patient centered cancer care delivery. Furthermore the ability to addresscancer prevention and control among adolescents and young adults (AYA) is also a key strength of our team.The NCA NCORP will address the needs of our catchment area via cancer prevention control screening as wellas treatment and imaging studies. The specific aims of the proposed National Capital Area NCORP are to: (1)Design and participate in clinical trials in cancer clinical research that improves the quality of care and the healthoutcomes of the US population in our catchment area; (2) Increase the participation of the greater DC areascommunity oncologists and medical specialists and their patients in NCORP-led clinical research; and (3)Expand health disparities research focused on clinical research participation via community outreachengagement and education. 878218 +No NIH Category available Acceleration;Address;Adherence;Affect;Age;Area;Attitude;Award;Cancer Control;Cancer Model;Clinical;Collaborations;Colonoscopy;Colorectal Adenocarcinoma;Colorectal Adenoma;Colorectal Cancer;Cost Savings;DNA;DNA Repair;Deimplementation;Development;Effectiveness;Feces;Focus Groups;Foundations;Gender;Genes;Genotype;Goals;Guidelines;Health;Health Personnel;Hereditary Breast and Ovarian Cancer Syndrome;Hereditary Nonpolyposis Colorectal Neoplasms;Hybrids;Incidence;Individual;Inherited;Interdisciplinary Study;MLH1 gene;MSH2 gene;MSH6 gene;Malignant Neoplasms;Methodology;Mismatch Repair;Modality;Modeling;Outcome;PMS2 gene;Pathogenicity;Patient risk;Patients;Polyps;Precision Medicine Initiative;Provider;Quality of life;Recommendation;Regimen;Research;Resources;Risk;Risk Estimate;Risk Factors;Surveys;Syndrome;Testing;autosome;cancer care;cancer prevention;cohort;colorectal cancer risk;colorectal cancer screening;comorbidity;cost effectiveness;gene repair;genetic variant;genomic data;high risk;improved;improved outcome;insight;lifetime risk;models and simulation;mortality;mutation carrier;novel;overtreatment;prevent;risk stratification;screening;surveillance strategy Optimal Colorectal Cancer Surveillance Strategy for Lynch Syndrome by Genotype Lynch syndrome is caused by defective DNA repair related to one of four genes each associated with varyingrisks of colorectal cancer. In this proposal we will determine optimal risk-tailored surveillance strategies bygenotype to minimize unnecessary screening tests and reduce overtreatment. These results will allow forbroader insights into cancer prevention and control based on genomic data for the advancement of precisionmedicine initiatives. NCI 10674701 7/27/23 0:00 PA-20-185 5R01CA257333-03 5 R01 CA 257333 3 "YOUNG, MATTHEW R" 8/1/21 0:00 7/31/26 0:00 Special Emphasis Panel[ZRG1-HDM-Z(02)] 7040249 "HUR, CHIN " "KASTRINOS, FAY " 13 INTERNAL MEDICINE/MEDICINE 621889815 QHF5ZZ114M72 621889815 QHF5ZZ114M72 US 40.8415 -73.9414 1833205 COLUMBIA UNIVERSITY HEALTH SCIENCES NEW YORK NY SCHOOLS OF MEDICINE 100323725 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 394 Non-SBIR/STTR 2023 364833 NCI 232744 132089 The overall goal of the proposed research is to optimize colorectal cancer (CRC) screening strategies forindividuals at the highest risk for CRC development attributable to Lynch Syndrome (LS). Germline alterationsin one of four DNA mismatch repair (MMR) genes causes LS an autosomal dominant condition associated withmultiple malignancies and the most common inherited CRC syndrome. LS affects nearly 1/300 individuals and~1 million individuals in the US similar to BRCA-related hereditary breast and ovarian cancer syndrome.Current CRC surveillance recommendations for LS involve colonoscopy every 1-2 years starting at age 25 years;in their lifetime individuals with LS will have completed ~50 colonoscopies (vs. 3 for average-risk screening).This intensive strategy is based on inflated lifetime CRC risk estimates and do not account for variable risk basedon genotype. As a result the current one-size-fits-all approach to CRC surveillance in LS individualswith the less aggressive genotypes subjects them to over-testing and overtreatment with a negativeimpact on quality of life and significant resource utilization. The overarching hypothesis of our proposal isthat CRC surveillance in LS should be tailored to the risk of CRC incidence and mortality associated with eachgenotype to improve individual health outcomes resource utilization and acceptability to providers and patientsalike. The hypothesis will be tested with three aims:Aim 1: Determine the optimal gene-specific colonoscopy regimen in LS and estimate the improvedresource utilization (colonoscopy demand) with a personalized LS surveillance approach. Usingsimulation modeling we will refine the LS-CRC model to project the long-term outcomes for numerous strategiesfor each of the four MMR genes (MLH1 MSH2 MSH6 and PMS2) with varying (a) surveillance intervals. Thiswill allow us to estimate the number of colonoscopies with current and various regimens evaluated.Aim 2: Evaluate the impact of incorporating non-invasive CRC screening modalities such as stoolstudies (fecal immunohistochemical testing (FIT) and FIT-fecal DNA) to colonoscopy surveillance for LScarriers. We will use our model to evaluate a novel hybrid approach to CRC surveillance that will incorporatenon-invasive approaches to colonoscopy to minimize overutilization of colonoscopy potentially improvingoutcomes by increasing adherence and saving costs.Aim 3: Assess barriers facilitators and attitudes towards current and new personalized gene-specificCRC surveillance strategies. We will assess attitudes towards colonoscopy with or without non-invasive CRCscreening tests among healthcare providers and patients.Impact: By award period end we will have produced personalized risk-tailored CRC surveillance regimens withLS that optimize effectiveness and cost-effectiveness. Results of this proposal will provide evidence to supportthe de-implementation of colonoscopy overuse in LS. 364833 +No NIH Category available AIDS related cancer;Address;Affect;Animal Model;Animals;Artificial skin;Automobile Driving;Biogenesis;CD19 gene;Cancer Etiology;Cell Reprogramming;Cell fusion;Cells;Coculture Techniques;Colon Carcinoma;Data;Development;Endothelial Cells;Endothelium;Engineering;Event;Exclusion;Experimental Animal Model;Extravasation;Foundations;G-Protein-Coupled Receptors;Gene Expression;Goals;HIV;HIV Seropositivity;Human;Human Herpesvirus 8;Immune;Immunity;In Vitro;Individual;Inflammation;Injections;Kaposi Sarcoma;Keratin;Knockout Mice;Knowledge;Lymphocyte;Lytic;Maintenance;Malignant Neoplasms;Mediating;Modeling;Molecular;Mus;Natural Killer Cells;Neoplasm Metastasis;Oncogenic;Organ;Parabiosis;Pathogenesis;Pathogenicity;Phenotype;Process;Proteins;Rag1 Mouse;Reporter;Role;Series;Serum;Skin;Solid;System;Therapeutic;Vascularization;Viral;Viral Genes;Viral Oncogene;Viral Proteins;Virion;Virus;Work;cadherin 5;cancer initiation;cell type;cofactor;design;exosome;extracellular vesicles;gain of function;humoral immunity deficiency;implantation;in vitro Model;innovation;insight;keratinocyte;malignant breast neoplasm;metaplastic cell transformation;microphysiology system;neoplastic cell;novel;paracrine;promoter;transdifferentiation;tumor;tumorigenesis;uptake (PQ6) vGPCR-Mediated Paracrine Transformation for Kaposi Sarcoma PROJECT NARRATIVEKaposis sarcoma (KS) is one of the most common AIDS-associated malignancies. This cancer is known to becaused by Kaposis sarcoma herpes virus (KSHV). Despite years of the progress on our knowledge of how thevirus causes this cancer an outstanding paradox still remains unresolved. The viral gene vGPCR has beenknown to be necessary and sufficient for KS tumor development. However vGPCR is produced in the lytic stagecells that destined to die to produce more virus particles. In this study we aim to tackle the provocative questionhow can vGPCR a lytic viral gene expressed in cells destined to die can cause cancer? To address thisdecades-long conundrum we have development novel animal models and an engineered artificial skin platform.Our study will identify a totally new way of cancer initiation advance our understanding of KS tumor developmentand help to design novel anti-KS therapeutics. NCI 10674700 7/21/23 0:00 RFA-CA-19-032 5R01CA250065-04 5 R01 CA 250065 4 "READ-CONNOLE, ELIZABETH LEE" 8/1/20 0:00 7/31/25 0:00 ZCA1-SRB-1(J2) 7929213 "HONG, YOUNG-KWON " Not Applicable 37 SURGERY 72933393 G88KLJR3KYT5 72933393 G88KLJR3KYT5 US 34.017282 -118.281254 7636101 UNIVERSITY OF SOUTHERN CALIFORNIA Los Angeles CA SCHOOLS OF MEDICINE 900894304 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 577551 NCI 350031 227520 PROJECT SUMMARYThis project is proposed to respond to Provocative Question 6 in RFA-CA-19-032.Objective: Paracrine transformation is a theoretical concept that was proposed years ago to explain theunconventional non-autonomous oncogenesis observed during development of Kaposis sarcoma (KS) one ofthe most common AIDS-associated malignancies. This proposal is designed to prove its existence to dissect itsmechanism identify the players therein and to define its roles in KS tumorigenesis using our novel animalmodels and an engineered microphysiological platform.Rationale: Kaposis sarcoma herpes virus (KSHV) causes an endothelial cell tumor KS in the skin and internalorgans. A paradox in KS oncogenesis is that while most KS tumor cells are latently infected with minimal viralgene expression only lytic-stage cells express vGPCR the only known viral oncogene that is necessary andsufficient for KS development.Provocative Question: How vGPCR a lytic viral gene expressed in cells destined to die can cause cancer?Challenges: This question remained unanswered due to the lack of proper animal models engineered in vitroor ex vivo systems to study pathogenesis persistence and tumor development that recapitulate this HIV/AIDS-associated malignancies.Innovation & Strategy: We have developed a series of novel animal models and Vascularized Skin Chipplatform. Using these technical advancements we will prove the existence of paracrine transformation identifyits cellular (immune cells HIV) and molecular (vGPCR-loaded exosome) players and characterize itsmechanism as the main oncogenic driver for KS tumorigenesis.Impact: Our study will address the decades-long conundrum on KS tumor development by defining theexistence and mechanism of paracrine transformation. This provocative concept of paracrine transformationwill not only force us to move our focus beyond the lytic-infected cells as the oncogenic drivers but alsoexpand the way we understand the initiation progression and metastasis of cancer. In addition this study willopen a new door to novel anti-KS therapeutics and provide a solid justification to investigate the presence ofequivalent non-autonomous transformation in other non-viral oncogenesis such as breast and colon cancers. 577551 +No NIH Category available Absence of pain sensation;Acute Lymphocytic Leukemia;Affect;Age Years;Animal Model;Apoptotic;B-Lymphocytes;Binding;Cell Death;Cell Line;Cell Separation;Cell Survival;Central Nervous System;Cessation of life;Chemoresistance;Chemotherapy-Oncologic Procedure;Child;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Collection;Data;Diagnosis;Dimensions;Disease;Drug Interactions;Drug Kinetics;Drug resistance;Enrollment;Ensure;Fentanyl;Flow Cytometry;Frequencies;Genes;Glioblastoma;Goals;Hematopoietic Neoplasms;Image;Immunophenotyping;In Vitro;K-562;Knock-out;Leukemic Cell;Life;Link;Literature;Malignant Neoplasms;Malignant neoplasm of esophagus;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mediating;Medical;Metabolic;Molecular;Molecular Target;Morphine;Neoplasm Metastasis;Newly Diagnosed;Opioid;Opioid Analgesics;Outcome;Oxycodone;Pathway interactions;Patients;Pharmaceutical Preparations;Philadelphia Chromosome Positive Chronic Myelogenous Leukemia;Physiological;Plasma;Population;Proliferating;Public Health;Recurrent disease;Relapse;Research Proposals;Resistance;Risk;Role;Sampling;Signal Pathway;Signal Transduction;Study models;Supportive care;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Treatment Efficacy;Treatment Failure;Tyrosine Kinase Inhibitor;United States National Institutes of Health;acute leukemia cell;biobank;cancer cell;cancer diagnosis;cancer therapy;cancer type;cell killing;cell type;chemotherapy;chronic myeloid leukemia cell;clinically relevant;cytotoxic;early experience;experience;genetic approach;genotoxicity;high throughput screening;insight;interpatient variability;leukemia;leukemia treatment;malignant breast neoplasm;malignant stomach neoplasm;mu opioid receptors;opioid exposure;opioid use;peripheral blood;personalized medicine;pharmacologic;precision medicine;prescription opioid;prospective;response;standard of care;synergism;treatment response;treatment risk;tumor growth Opioid-induced changes to chemotherapeutic activity in blood cancer PROJECT NARRATIVEIt is desirable to avoid detrimental drug interactions to ensure each patient achieves the best possibleresponse to their chemotherapy. The goal of this research proposal is to determine the impact of opioid-chemotherapy interactions on chemotherapeutic efficacy in blood cancer. NCI 10674695 7/28/23 0:00 PAR-18-467 5K22CA258671-02 5 K22 CA 258671 2 "JAKOWLEW, SONIA B" 8/1/22 0:00 7/31/25 0:00 ZCA1-RTRB-R(O2) 14228461 "CONSTANCE, JONATHAN ERIC" Not Applicable 1 PEDIATRICS 9095365 LL8GLEVH6MG3 9095365 LL8GLEVH6MG3 US 40.764542 -111.850317 514002 UNIVERSITY OF UTAH SALT LAKE CITY UT SCHOOLS OF MEDICINE 841129049 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 201457 NCI 186534 14923 PROJECT SUMMARY/ABSTRACTRoutinely prescribed analgesic opioids are potent activators of the mu-opioid receptor (OR; OPRM1 gene)expressed in many cancer types and can impact cancer cell survival and the efficacy of lifesavingchemotherapy. For patients with cancer opioid use often coincides with chemotherapy making opioid-chemotherapy interactions inevitable. For some cancers including lung prostate gastric breast andesophageal cancers opioid use and increased OR expression are linked to increased tumor growthmetastases and shorter patient survival. In contrast in vitro and animal model studies for glioblastoma certainbreast cancers and T- and B-cell acute leukemias opioids stimulate cancer cell death and in some casesenhance cytotoxic chemotherapeutic response. The seemingly paradoxical effects likely have a concentration-dependent dimension as physiologic opioid exposures have tended to induce pro-proliferative effects whilesupraphysiologic opioid exposures are typically associated with cancer cell death. While OR activation canenhance the killing effect of genotoxic chemotherapy in acute lymphoblastic leukemia our preliminary datademonstrate opioids antagonize the apoptotic response of Philadelphia chromosome-positive (Ph+) chronicmyeloid leukemia cells (K562) to molecularly-targeted tyrosine kinase inhibitor (TKI) chemotherapy. Asleukemias are treated with both genotoxic and molecularly targeted chemotherapy assessing the potential forclinically used opioids to antagonize or synergize in leukemic cell killing is an urgent medical need. Wepropose to test the central hypothesis that chemotherapeutic response will change in the presence ofclinically relevant concentrations of opioids in three Aims. Specific Aim 1: Quantify standard-of-careopioid exposures and determinants of exposure in patients with leukemia. Hypothesis 1: Interpatient variabilityin opioid exposure will exceed 50% due to inherent metabolic differences disease status and treatment-related pharmacokinetic alterations. Specific Aim 2: In leukemic cell lines changes in response tochemotherapy based on leukemic subtype and OR function will be determined. Hypothesis 2: Clinically-experienced concentrations of opioids will change chemotherapeutic response in different leukemic subtypescorresponding with OR function by >25%. Specific Aim 3: In patients with leukemia the frequency of opioid-chemotherapy DDIs based on clinical and molecular factors will be determined. Hypothesis 3: Clinical andmolecular features associated with opioid-chemotherapy DDI conferring chemotherapy resistance are presentin >20% of patients prescribed opioids. Understanding the impact of OR activity on chemotherapeuticresponse across similar but biologically distinct leukemia cell types will provide new insights into mechanismsunderlying drug resistance relapse or non-response and drive precision medicine in opioid prescribing. Thisproposal will provide key preliminary data to support an NIH R01 aimed at predicting altered chemotherapeuticresponse due to supportive care medication exposure among patients undergoing treatment for leukemia. 201457 +Biotechnology; Cancer; Cancer Genomics; Genetics; Human Genome Biocompatible Materials;Clinical;Custom;DNA Methylation;DNA Sequence Alteration;Data;Deposition;Ensure;Fingerprint;Freezing;Genome;Genomics;Informatics;Institutes;Malignant Neoplasms;Methods;Methylation;Molecular;Performance;Procedures;Proteomics;Public Domains;Qualifying;Quality Control;Research;Resolution;Resources;Sampling;Services;Site;Specimen;Time;Validation;advanced analytics;analytical tool;data integration;data quality;deep sequencing;exome;exome sequencing;experience;genome sequencing;improved;targeted sequencing;whole genome NCI'S GENOMIC CHARACTERIZATION CENTER IDIQ n/a NCI 10674663 75N91019D00029-P00001-759102100001-1 N02 9/10/21 0:00 9/9/26 0:00 78357946 "GABRIEL, STACY " Not Applicable 7 Unavailable 623544785 H5G9NWEFHXN4 623544785 H5G9NWEFHXN4 US 42.363082 -71.087893 10021177 "BROAD INSTITUTE, INC." CAMBRIDGE MA Research Institutes 21421027 UNITED STATES N R and D Contracts 2022 666887 NCI The Broad Institute will continue to build on our 30 year track record as a Genome Center and apply a suite of well-validated platforms and advanced analytic tools to comprehensively characterize genomic alterations of cancer specimens. For this Task Order we will characterize up to 3650 samples (with optional quantities of up to 2650 additional samples). We will apply whole exome whole genome methylation arrays and deep custom sequencing to identify somatic alterations from both fresh frozen and FFPE specimens and have documented extensive experience with these types of analytes. Specific activities will include: (1) receiving qualifying and fingerprinting 3650 samples (with optionalquantities of up to 2650 additional samples). (2) performing sample prep and sequencing at a scale (3) performing QC of resulting sequence data to ensure correct sample identity and suitable data quality for downstream analysis; (4) depositing data into the public domain in a timely and accessible format to allow broad access and usage of the sequence data. 666887 +No NIH Category available Amendment;Authorization documentation;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Cancer Therapy Evaluation Program;Cell Therapy;Clinic;Clinical;Clinical Cancer Center;Clinical Protocols;Clinical Research Protocols;Clinical Trials;Complement;Comprehensive Cancer Center;Concept Review;Conduct Clinical Trials;Data;Descriptor;Development;Diagnostic Trial;Eligibility Determination;Funding;Funding Mechanisms;Goals;Health system;Hospitals;Industry;Institution;Institutional Review Boards;Intervention;Lead;Malignant Neoplasms;Medical center;Medicine;Methodist Church;Monitor;Observational Study;Pediatric Hospitals;Peer Review;Policies;Prevention;Process;Protocols documentation;Research;Research Personnel;Review Committee;Safety;Site;Supportive care;System;Texas;Time;United States National Institutes of Health;authority;cancer prevention;cancer research center director;college;epidemiology study;expedited review;gene therapy;group intervention;member;programs;working group Protocol Review and Monitoring System n/a NCI 10674570 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8897 1972554 "BERG, STACEY L" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 46561 29099 17462 PROTOCOL REVIEW AND MONITORING SYSTEM (PRMS) PROJECT SUMMARYThe Dan L. Duncan Comprehensive Cancer Center (DLDCCC) at Baylor College of Medicine (BCM) hasestablished the Protocol Review and Monitoring Committee (PRMC) to provide systematic internal oversight ofthe scientific and research aspects of all interventional cancer clinical protocols conducted in DLDCCCinstitutional facilities. By BCM and DLDCCC policy the PRMC has authority to approve and close all DLDCCCclinical research protocols. Chaired by Stacey Berg MD the PRMC is organized into an Executive Committeeand 3 Working Groups with a total of 49 members. The PRMC assigns each protocol a scientific merit score of19 according to standard NIH review descriptors. In addition a DLDCCC priority score of High Medium or Lowis assigned to aid protocol prioritization. Studies that have been approved by the NCI Cancer Therapy EvaluationProgram or Cancer Prevention and Control Protocol Review Committee or that are supported by an NIH fundingmechanism that required full peer review as part of the funding process undergo an expedited administrativereview. In addition for multi-site institutional trials the protocol may be eligible for expedited PRMC review ifBCM is not the lead site and the approved PRMS of the lead site has performed full scientific review of theprotocol.The PRMC also monitors progress and accrual of active studies. At the time of each open protocol's annual IRBreview or more often if deemed necessary the Executive Committee conducts a full review to ensure thatadequate scientific progress is being made. In addition the Executive Committee reviews the accrual to all openprotocols in each Program on a quarterly basis. Protocols whose accrual continues to lag are subject to closureby the PRMC as are protocols whose scientific goals may have been superseded by developments in the field.PRMC review complements but does not duplicate IRB or Data Safety Monitoring Committee review.From 2016 to 2018 the PRMC reviewed an average of 64 new submissions per year including 10 DLDCCCinvestigator-initiated institutional 27 National Group 2 other externally peer reviewed and 17 industry-sponsored protocols. In addition an average of 226 progress reviews and 27 amendment reviews per year werealso performed. +No NIH Category available Advisory Committees;Area;Authorization documentation;Basic Science;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Therapy;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communication;Communities;Community Outreach;Complement;Decision Making;Department chair;Development;Disease;Education;Education and Outreach;Ensure;Evaluation;Faculty;Feedback;Funding;Goals;Group Meetings;Immunooncology;Investigational Therapies;Investments;Leadership;Malignant Neoplasms;Medicine;Mission;Monitor;NCI-Designated Cancer Center;Obesity;Phase;Population;Population Sciences;Process;Program Evaluation;Program Reviews;Reporting;Research;Research Personnel;Resource Sharing;Source;Strategic Planning;Structure;Time;Translational Research;Vision;Work;authority;clinical care;college;community engagement;meetings;member;precision medicine;programs;recruit;working group Leadership Planning and Evaluation n/a NCI 10674567 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8894 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 345232 215756 129476 PROJECT SUMMARY LEADERSHIP PLANNING AND EVALUATIONThe Dan L Duncan Cancer Center (DLDCCC) has a committee structure that provides a robust frameworkfor evaluating activities in its research clinical education and outreach missions as well as reviewingprograms disease working groups and shared resources. The Director Kent Osborne has broad authorityacross strategic planning and evaluation and engages senior leaders and external advisors to provide input andrefine his vision. The senior leadership including Dr Osborne a Deputy Director and 11 AssociateDirectors comprise the Executive Committee (EC) which is the key decision-making entity along with theProgram Leaders Committee which includes the EC as well as program leaders. A number of othercommittees support specific areas such as Clinical Research Shared Resources Education and Communityoutreach and report metrics to the EC as part of the evaluation process for all DLDCCC components. TheDirector and the leadership team develop strategies to enhance the DLDCCCs basic translationalclinical and population science research efforts monitor education and community outreach andengagement efforts and identify opportunities for collaborations and new research directions. Dr Osborne andthe senior leadership obtain additional advice from an Internal Advisory Committee that includes DepartmentChairs and Center Directors at Baylor College of Medicine and an engaged External Advisory Committeewhich meets annually and has provided valuable input in the last funding period. The DLDCCC has recentlycompleted an extensive strategic planning process with input from all members which has resulted in new 5-yearstrategic plan in 2016. This plan focuses on promoting high impact collaborative basic translational clinical andpopulation science research that serves our catchment area. +No NIH Category available Address;Animal Cancer Model;Area;Award;Budgets;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Model;Catchment Area;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Comprehensive Cancer Center;Core Facility;Development;Disease;Effectiveness;Emerging Technologies;Evolution;Fostering;Funding;Goals;Grant;Immune checkpoint inhibitor;Immunotherapy;Institution;Investments;Malignant Neoplasms;Medicine;Monitor;NCI Center for Cancer Research;Nursing Faculty;Patients;Phase;Pilot Projects;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Strategic Planning;Surveys;T-Lymphocyte;Technology;Time;Toxic effect;clinical investigation;college;in vivo;innovation;investigator-initiated trial;member;microbiome signature;patient derived xenograft model;programs;response;success;working group Developmental Funds n/a NCI 10674566 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8893 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 419048 261888 157160 DEVELOPMENTAL FUNDSPROJECT SUMMARY:In the last 5-year cycle the Dan L Duncan Comprehensive Cancer Center (DLDCCC) leveraged CCSGDevelopment Funds ($300K) with more than $1.1M in Director's Discretionary Funds to fund 28 Pilot Projectsfrom 2015 to 2019. The Executive Committee (EC) targeted the RFAs for these awards to meet DLDCCCstrategic plan goals including promoting high priority areas of research fostering inter-programmaticcollaborations and addressing the cancer burden of our Catchment Area. The 28 projects garnered a 9.5 foldreturn on investment based on new grant support arising from the scientific pilot projects. The EC also usedinstitutional funds to develop a new PDX shared resource. In addition with the discontinuation of the Early PhaseClinical Research mechanism during this past funding period the Center requested that those funds ($100k) berepurposed to provide protected time for young clinical investigators to develop their research programs. Earlymetrics from this strategy are promising with the first recipient Brandon Smaglo opening two investigator-initiated trials that have accrued 30 patients. The current recipient Daniel Wang from the Mechanisms in CancerEvolution Program is developing studies to validate a microbiome signature in recipients of checkpoint inhibitorsand genetically modified T cells. He also created the Immunotherapy Toxicity Working Group.In the next 5 years the DLDCCC is requesting an increase in the Developmental Funds budget to $450K/year.Developmental Funds in this renewal are being requested for two purposes: 1) $250k/year to enhance aneffective and successful Pilot Project program and 2) $200K/year to expand support of junior clinicalinvestigators which has been identified both nationally and in the DLDCCC strategic plan as an importantpriority for NCI cancer centers. +No NIH Category available Acute;Address;Adolescent;Africa South of the Sahara;African;Basic Science;Biological;Budgets;Cancer Center;Cancer Center Support Grant;Cancer Survivorship;Caregivers;Catchment Area;Cell Therapy;Child;Childhood;Childhood Solid Neoplasm;Cities;Clinical;Clinical Research;Clinical Trials;Collaborations;Confusion;Country;County;Coupled;Developmental Therapeutics Program;Diagnostic;Disease;Early Diagnosis;Education;Enrollment;Funding;Genetic;Genomics;Goals;Hematology;Histiocytosis;Inequity;Infrastructure;International;Investigation;Journals;Laboratories;Lymphoma;Malignant Childhood Neoplasm;Malignant Neoplasms;Manuscripts;Medicine;Mexico;Mission;Molecular;Nature;Nurses;Oncology;Operative Surgical Procedures;Pathology;Pediatric Hematology;Pediatric Hospitals;Pediatric Neoplasm;Pediatric Oncology;Pediatrics;Peer Review;Physicians;Population Heterogeneity;Population Sciences;Population Study;Positioning Attribute;Productivity;Program Description;Proteomics;Psychology;Radiology Specialty;Research;Research Personnel;Research Support;Resource Sharing;Risk;Scientific Advances and Accomplishments;Site;Texas;Therapeutic;Therapeutic Studies;Time;Toxic effect;Training;Training Programs;Translational Research;Treatment outcome;United States;United States National Institutes of Health;Work;anticancer research;cancer cell;cancer diagnosis;cancer genetics;cancer genomics;cancer prevention;clinical trial enrollment;college;demographics;early phase clinical trial;ethnic diversity;gene therapy;genomic tools;improved;improved outcome;innovation;inter-institutional;leukemia;member;neuro-oncology;neurosurgery;prognostic;programs;racial diversity;side effect Pediatric Cancer Program n/a NCI 10674565 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8892 7354296 "BLANEY, SUSAN M." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 32567 20353 12214 PEDIATRIC CANCER PROGRAM (PCP) PROJECT SUMMARYThe overall goal of the Pediatric Cancer Program (PCP) is to improve the outcome for children andadolescents with pediatric malignancies by facilitating early detection increasing cure rates and decreasingacute and long-term side effects. The PCP includes 24 Research and 21 Clinical Members from numerousBCM Departments including Pediatrics Surgery Neurosurgery Medicine Radiology Pathology andPsychology. Dr. Susan Blaney Director of Texas Childrens Cancer and Hematology Centers was appointedas Leader of the PCP in 2018. Dr. Sharon Plon continues to Co-Lead the PCP. During the last budget yearPCP had a total direct funding of $17.4 million that included $4.1 million in NCI funding $2.4 million from otherNIH institutes $4.4 million direct in other peer-reviewed funding and $6.5 million direct from other non-peerreviewed funding. Productivity of the Program is exemplified by the 750 cancer-related manuscripts in peer-reviewed journals over the last 5 years of which 52% represented intra-programmatic 22% inter-programmatic and 74% inter-institutional collaborations. There are substantial collaborations between the PCPand other DLDCCC Programs highlighted by the multiple projects developed over the last funding period withthe Cancer Prevention and Population Sciences (CPPS) and Cancer Cell and Gene Therapy (CCGT)Programs. The PCP performs basic translational and clinical research aimed at improving diagnosticprognostic and therapeutic approaches for childhood cancer as well as enhancing cancer prevention for at-risk children. The PCPs Specific Aims include: Specific Aim 1: To increase our biological understanding ofpediatric malignancies through comprehensive molecular genomic and proteomic analyses. Specific Aim 2:To improve diagnostic prognostic and therapeutic approaches with decreased toxicity for pediatric cancersincluding the conduct of innovative early-phase clinical trials in our clinical programs. Specific Aim 3: Tocontinue to perform crosscutting research relevant to pediatric cancer diagnoses in our catchment area as wellas nationally and internationally. The PCP is organized around 6 Research Themes that are transdisciplinaryand involve both laboratory and clinical researchers: 1. Biologic and Therapeutic Studies of Pediatric SolidTumors; 2. Pediatric Neuro-Oncology; 3. Leukemia Lymphoma and Histiocytosis; 4. Pediatric Cancer Geneticsand Genomics; 5. Pediatric Cancer Developmental Therapeutics; and 6. Pediatric Cancer Survivorship. Inaddition our work extends beyond our catchment area to the Rio Grande Valley on the border of Mexico andmost recently to sub-Saharan Africa where the vast majority of children with cancer die. To address thisinequity we are developing a capacity building initiative Global HOPE (Hematology-Oncology PediatricExcellence) that is focused on building pediatric hematology-oncology Centers of Excellence in 6 Africancountries. +No NIH Category available Address;Adult;Affect;Area;Behavior Therapy;Behavioral;Behavioral Sciences;Biological Sciences;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Etiology;Cancer Patient;Cancer Survivor;Catchment Area;Child;Childhood;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Community Outreach;Computer Models;Data;Data Sources;Discipline;Disease;Early Diagnosis;Environmental Exposure;Epidemiology;Etiology;Family;Funding;Genetic;Genetic study;Goals;Health Services Research;Home;Incidence;Individual;Infectious Agent;International;Intervention;Intervention Studies;Journals;Leadership;Malignant - descriptor;Malignant Neoplasms;Measures;Medicine;Methods;Mission;Modeling;Morbidity - disease rate;Obesity;Observational Study;Operative Surgical Procedures;Outcome;Outcomes Research;Paper;Patient risk;Patient-Focused Outcomes;Patients;Peer Review;Persons;Population Sciences;Population Study;Prevention Research;Primary Prevention;Publications;Publishing;Rehabilitation therapy;Research;Research Contracts;Research Personnel;Research Priority;Research Project Grants;Resolution;Resources;Risk;Risk Assessment;Risk Factors;Risk Reduction;Science;Scientific Inquiry;Scientist;Second Primary Cancers;Secondary Prevention;Statistical Methods;Strategic Planning;Texas;Tobacco;Training;Translational Research;Underserved Population;Variant;Virus;Work;biomedical informatics;cancer health disparity;cancer prevention;cancer risk;college;community engagement;data modeling;gene environment interaction;high risk;high risk population;improved;individualized prevention;innovation;inter-institutional;interest;member;metropolitan;mortality;multidisciplinary;next generation;novel;pre-clinical;predictive tools;preventive intervention;prognostic;programs;recruit;risk prediction model;screening;secondary outcome;symptom management;working group;young adult Cancer Prevention and Population Sciences n/a NCI 10674564 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8891 7852459 "BADR, HODA J" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 32229 20142 12087 CANCER PREVENTION AND POPULATION SCIENCES (CPPS) PROGRAMPROJECT SUMMARYThe mission of the Cancer Prevention and Population Sciences (CPPS) Program is to conduct exceptionaltranslational research in cancer prevention and control. CPPS achieves this goal by promoting and facilitatinginnovative multi-disciplinary scientific interactions focused on reducing cancer incidence morbidity andmortality and improving cancer outcomes. CPPS membership is comprised of nationally and internationallyrecognized scientists with expertise that spans the cancer continuum. The setting of CPPS' research prioritiesincludes promoting scientific inquiry directed at addressing the cancer prevention and control needs of the peopleand communities of the Houston Texas Metropolitan Statistical Area (MSA) our catchment area (CA). Thisincludes special emphasis to facilitate the conduct of research that addresses the cancer health disparitiesspecific to our CA. Following extensive strategic planning and exceptional targeted recruitments we havefocused and expanded our research efforts to reflect our expertise and the urgent needs of our CA into 3 SpecificAims as foundational to CPPS research.Aim 1 (Cancer Etiology and Primary Prevention) encompasses our scientific breadth and depth in the geneticand environmental causes of childhood and adult cancers and aims to advance risk assessment and guideprimary prevention efforts. Aim 2 (Secondary Prevention and Cancer Outcomes Research) combines ouroutstanding secondary prevention and outcomes research to advance early detection predictive prognosticbehavioral and surgical measures of cancer outcomes. Included are innovative behavioral interventions toreduce the negative consequences of cancer in our CA via individual family and community engagement. CPPSis also the programmatic home for national experts in quantitative methods and risk modeling (Aim 3). Their workintegrates biomedical data and computational models to enable precision-based cancer prevention and improvecancer outcomes.CPPS has 35 Research and 14 Clinical members representing multiple scientific disciplines. Many of ourmembers have research interests spanning 2 or even all 3 Specific Aims. CPPS members have been successfulin obtaining independent funding to support their research: 100% of our Research members have peer-reviewedcancer-related research grants or contracts resulting in a research portfolio (annual direct) totaling $17.5million of which $16.2 million is peer reviewed $4.0 million is from NCI and $9.6 million from other peerreviewed funding with $7.1 of that from CPRIT. During the current funding period CPPS Program memberspublished 1208 papers of which 26% were intra-programmatic 21% were inter-programmatic and 40% wereinter-institutional. About 37% of the publications are in journals with an impact factor above 5 and 13% areabove 10. Our leaders are nationally and internationally recognized and our members strive to train the nextgeneration of cancer prevention researchers. +No NIH Category available Address;Adoptive Immunotherapy;Adult;Basic Science;Cancer Center;Cancer Center Support Grant;Cell Therapy;Cells;Cellular Immunity;Cellular biology;Characteristics;Childhood;Clinical;Clinical Research;Clinical Trials;Collaborations;Cytotoxic T-Lymphocytes;Development;Doctor of Philosophy;Ensure;Funding;Goals;Good Manufacturing Process;Graft-Versus-Tumor Induction;Grant;Head and neck structure;Hematologic Neoplasms;Hematopoietic Stem Cell Transplantation;Hodgkin Disease;Hospitals;Human Genetics;Immune;Immune system;Immunology;Immunotherapy;Industrialization;Industry;Institution;Journals;Laboratories;Laboratory Study;Licensure;Liver diseases;Malignant Childhood Neoplasm;Malignant Neoplasms;Malignant neoplasm of nasopharynx;Manuscripts;Medicine;Methodist Church;Mission;Molecular;Molecular Biology;Molecular Genetics;Neck Disorder;Neuroblastoma;Neurosciences;Operative Surgical Procedures;Pancreatic Diseases;Pathology;Pediatric Hospitals;Pediatrics;Peer Review;Phase;Production;Protocols documentation;Publications;Publishing;Reagent;Recording of previous events;Reporting;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Running;Scientist;Series;Stem cell transplant;Systems Analysis;T-Cell Lymphoma;T-Lymphocyte;Testing;Texas;Translational Research;Translations;Transplantation;Tumor Antigens;Virus;Work;antiviral immunity;bench to bedside;cancer cell;cancer immunotherapy;cancer stem cell;cancer therapy;cell type;clinical implementation;clinical translation;college;first-in-human;gene therapy;hematopoietic cell transplantation;improved outcome;malignant breast neoplasm;manufacturing facility;member;neurosurgery;novel therapeutic intervention;post-transplant;predicting response;programs;reconstitution;stem cell biology;stem cell growth;stem cells;success;translational scientist;tumor;vector;virus related cancer Cancer Cell and Gene Therapy n/a NCI 10674563 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8890 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 32567 20353 12214 CANCER CELL AND GENE THERAPY (CCGT) PROGRAM PROJECT SUMMARYThe goals of the Cancer Cell and Gene Therapy (CCGT) Program are to incorporate advances in cellular andgene therapy into the treatment of cancer. The CCGT Program is a sub-component of the Center for Cell andGene Therapy and has 21 Research members and 9 Clinical members from multiple departments at BCMincluding Medicine Pediatrics Surgery Pathology and Immunology Molecular and Cell Biology Neuroscienceand Molecular and Human Genetics. The Program received a total of $3.1 million in direct support from the NCIlast year and overall received $14.6 million in direct peer-reviewed funding and $23.1 million in total directfunding. In the last 5 years members of the Program published 412 cancer-related manuscripts in peer-reviewedjournals of which 42% represented intra-programmatic collaborations and 31% inter-programmatic while 37%included external collaborators and 34% were published in journals with an Impact Factor >10. Our researchfocuses on three themes: normal and malignant stem cells adoptive immunotherapy of cancer and improvingoutcomes of stem cell transplantation for cancer. CCGT has basic translational and clinical researchcomponents. Our basic investigators work on understanding the mechanisms by which normal and malignantstem cell growth is controlled and on the molecular and cellular interactions involved in the development oftumor vasculature and stroma. These researchers are also identifying new targets for immunotherapy andoptimizing presentation of weak tumor antigens to the immune system. Our translational investigators are movingcell- and gene-based therapies from the bench to the bedside in a series of small-scale iterative laboratory-clinical-laboratory protocols and are also developing pivotal trials. We have a long history of successful andtimely implementation of clinical translational projects in gene and cellular therapy and we have the resourcesto supply and test all the clinical reagents required through our clinical research infrastructure and the Cellprocessing and Vector Production Shared Resource. Major accomplishments in the last 5 years include first-in-man trials of 10 new cell types/constructs and transfer of several strategies to industry for late-phase testing. Wehave shown activity of virus specific cytotoxic T lymphocytes in virus-associated cancers (resulting in licensureof the approach to three companies for late-phase trials) and in ongoing studies are showing anti-tumor activityof genetically modified T cells in subjects with T cell lymphoma Hodgkin lymphoma neuroblastoma andnasopharyngeal cancer. Our clinical researchers run the adult and (in collaboration with the Pediatric CancerProgram) pediatric hematopoietic stem cell transplant programs and are extending the applicability oftransplantation for malignancy by using pre-transplant immunotherapy to enable transplant and post-transplantimmunotherapy to augment graft-versus-tumor activity and reconstitute anti-viral immunity.. +No NIH Category available Acceleration;Acute Myelocytic Leukemia;Address;Agonist;Androgen Receptor;Area;Basic Science;Biology;Cancer Center;Cancer Center Support Grant;Cancer Model;Cancer Prevention Intervention;Chromatin;Clinic;Clinical;Clinical Trials Design;Clinical assessments;Collaborations;Cytoskeleton;Defect;Dependence;Development;Direct Costs;Disclosure;Disease;Dysmyelopoietic Syndromes;Epigenetic Process;Estrogen Receptors;Evaluation;Funding;Genetic;Genetic Transcription;Glucocorticoid Receptor;Goals;Grant;Human;Human Genetics;International;Link;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Mediating;Medicine;Metastatic Prostate Cancer;MicroRNAs;Molecular Genetics;Molecular Target;Molecular and Cellular Biology;Mutation;Names;Nuclear Receptors;Oncogenic;Pathogenesis;Peer Review;Pharmaceutical Preparations;Pharmacology;Preclinical Testing;Prognostic Marker;Publications;RUNX1 gene;Regulation;Research;Research Personnel;Resistance;Role;Scientific Advances and Accomplishments;Sertraline;Signal Transduction;Tamoxifen;Therapeutic;Therapeutic Intervention;Training;Transcriptional Regulation;Translational Research;Translations;United States National Institutes of Health;Validation;apoAI regulatory protein-1;cancer cell;cancer clinical trial;carcinogenesis;college;epigenetic regulation;experience;hormone therapy;insight;inter-institutional;investigator-initiated trial;malignant breast neoplasm;member;men;new therapeutic target;novel;novel therapeutics;patient derived xenograft model;pre-clinical;preventive intervention;programs;prostate cancer metastasis;racial disparity;small molecule;targeted treatment;treatment response;tumorigenesis Nuclear Receptor Transcription and Chromatin Biology Program n/a NCI 10674560 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8887 1883878 "FUQUA, SUZANNE AW" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 32567 20353 12214 NUCLEAR RECEPTOR TRANSCRIPTION AND CHROMATIN BIOLOGY (NRTBC) PROGRAMPROJECT SUMMARYThe overall objective of the NRTCB program is to conduct impactful basic research and to promote rapidtranslation of discoveries linked to NR-dependent and epigenetic mechanisms of transcriptional regulation ofcarcinogenesis to the clinic to accelerate development of new preventative and therapeutic interventions. Theprogram has 2 main themes: (1) Identification of NRs that contribute to cancer pathogenesis and progressiondisclosure of their mechanisms of action and evaluation of their potential as novel therapeutic targets and (2)Biology and function of chromatin regulators that mediate epigenetic regulation of transcription in cancer. Theprogram has 20 actively funded Research Members 2 Clinical 2 Adjunct and one Shared Member withextensive research experience related to the 2 themes and drawn from several departments including MedicineMolecular and Cellular Biology Molecular and Human Genetics and Pharmacology. The program is led by Dr.Suzanne Fuqua a translational research expert in estrogen receptor action in breast cancer together with 2 Co-Leaders Dr. Cheryl Walker an internationally recognized expert on environmental genetic and epigenetic factorinteractions in cancer and Dr. Nicholas Mitsiades a clinical researcher with extensive experience in oncologyclinical trial design and execution in the area of NRs and prostate cancer. Members of the Program have $15.9million (direct costs) in cancer-related research funding of which $9.9 million is peer-reviewed and $6 million isnon peer-reviewed. Peer-reviewed funding includes nearly $6.4 million in NIH support of which $5.3 million isfrom the NCI. NRTCB Program members have a strong record of programmatic interactions as evidenced by 16externally funded programmatic grants. Members continue to make outstanding research progress as evidencedby over 321 cancer-related publications over the past 5 years of which 25% and 70% involve intra- and inter-programmatic collaborations and 52% are inter-institutional. Major scientific accomplishments include noveldiscoveries of (1) a role of androgen receptors in breast cancer resistance to endocrine therapies (2) a role forthe NR CAR in liver cancer (3) a novel miRNA-regulated signaling axis required for suppression of COUP-TFIIdriven prostate cancer metastasis (4) glucocorticoid receptors as novel therapeutic targets for RUNX1-ETOpositive acute myeloid leukemia (5) a role for epigenetic regulators in control of cytoskeletal dynamics (6) a rolefor Warburg-associated glycolytic reprogramming in epigenetic activation of SRC-3 driven oncogenictranscriptional programs and (7) a role for prostate cancer associated mutations in SPOP in regulation ofandrogen receptor turnover. Translational advances include: (1) Preclinical validation of the NR4A activatordihydroergotamine as a novel therapeutic drug for AML (2) Four new investigator-initiated trials including:tamoxifen for treatment of bladder cancer; meclizine an inverse agonist for CAR for treatment of liver cancer;Sertraline for treatment of myelodysplastic syndrome; and racial disparities in hormonal therapy response in menwith metastatic prostate cancer and (3) Commercial development of new first-in-class therapies targeting SRC-3 with Coactigon Inc. +No NIH Category available Advisory Committees;Applications Grants;Area;Basic Science;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Science;Clinical;Clinical Research;Clinical Sciences;Collaborations;Community Health Education;Community Outreach;Comprehensive Cancer Center;Computer software;Data;Education;Experimental Designs;Faculty;Funding;Future;High Performance Computing;Human Resources;Information Technology;Infrastructure;Journals;Leadership;Licensing;Malignant Neoplasms;Medicine;Methods;Mission;Monitor;Names;Patient Care;Peer Review;Peer Review Grants;Play;Positioning Attribute;Prevention;Publications;Research;Research Support;Resource Sharing;Resources;Role;Science;Services;Source;Strategic Planning;Students;Technology;Training and Education;Translational Research;bioinformatics infrastructure;biomedical informatics;cancer therapy;cluster computing;college;computer infrastructure;data analysis pipeline;data management;design;high throughput technology;improved;informatics shared resource;innovation;member;multiple omics;recruit;response;virtual Quantitative Science Shared Resource n/a NCI 10674558 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8885 2408334 "HILSENBECK, SUSAN G." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 233324 145818 87506 PROJECT SUMMARY: Quantitative Science Shared Resource (QSSR)Quantitative science shared resources have been from the beginning of cancer centers a centerpiece of thesupport that underpins and adds value to a cancer center. The same holds true today although needs andsolutions have evolved. At present as a matrix Shared Resource (SR) within the Dan L Duncan Cancer Centerand the Advanced Technology Cores of Baylor College of Medicine the Quantitative Science Shared Resource(QSSR) continues to play a critical role. The Resource originally titled Biostatistics and Informatics SharedResource (BISR) was initially established as part of the first CCSG application in 2006. In response to changingneeds we have renamed the SR and restructured services and collaborative support to focus on biostatisticsbioinformatics and computational infrastructure in the form of our High Performance Compute (HPC) cluster.Specific Aims of the Shared Resource include:Aim 1. To provide state-of-the-art design conduct analysis and interpretation to clinical translational and basic science cancer-related research through biostatistical bioinformatic and multi-omic methods;Aim 2. To provide access to high quality professionally managed high performance computing;Aim 3. To coordinate with other high-throughput oriented Shared Resources on their analytic and data management needs;Aim 4. To assist the DLDCCC with education and training scientific review data monitoring and strategicplanning.The QSSR is a critical resource to the Cancer Center. During the last 4 years we contributed to virtually everyaspect of Cancer Center endeavor ranging from basic through clinical research coordination of data flows withother shared resources scientific review and education. Despite having transitioned to management as a BCM-wide matrix SR we continue to have a very high level of cancer focus. We are well represented at the leadershiplevel of the Cancer Center where QSSR leaders serve on a number of committees including the ExecutiveCommittee. We are well-positioned to advise the DLDCCC on quantitative aspects of strategic initiatives and torespond to new or changing priorities. During the last funding period we continued to grow strategically addingfaculty staff and restructuring services according to the plans put forward in our initial and subsequentapplications and on advice of oversight and advisory committees and Cancer Center leadership. Future plansinclude additional faculty and staff recruitment promoting enhanced access to High Performance Computingand assisting high-throughput technology-oriented shared-resources with improved data management andanalysis pipelines. +No NIH Category available Acceleration;Acute;Address;Affinity;Antibodies;Antineoplastic Agents;Big Data;Binding Proteins;Biological Assay;Biology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cell physiology;Chemicals;Clinical;Complex;Custom;DNA Damage;DNA-Protein Interaction;Data;Data Analyses;Decision Making;Dependence;Development;Enzymes;Event;Expression Profiling;Follow-Up Studies;Gene Proteins;Genomics;Goals;Knowledge;Laboratories;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Medicine;Methods;Molecular;Mus;Oncogenic;Phase;Post-Translational Protein Processing;Protein Array;Protein Biochemistry;Protein Dynamics;Proteins;Proteome;Proteomics;Proteomics Shared Resource;Research;Research Design;Research Personnel;Resistance;Resource Sharing;Role;Sampling;Services;Signal Pathway;Signaling Protein;Technology;Therapeutic Intervention;Work;anticancer research;cancer proteomics;clinical development;college;data communication;diagnostic assay;drug action;experimental analysis;informatics tool;instrumentation;new technology;new therapeutic target;novel;patient derived xenograft model;pre-clinical;predicting response;protein expression;protein function;protein profiling;repaired;resistance mechanism;small molecule therapeutics;technology platform;therapeutic biomarker;therapeutic target;tool;transcriptomics;translational study;tumor progression;tumor xenograft Proteomics Shared Resource n/a NCI 10674557 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8884 10494128 "MALOVANNAYA, ANNA " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 258833 161760 97073 PROJECT SUMMARY: Proteomics Shared Resource (PSR)Proteins are the ultimate executors of biology with nearly all cellular processes being dependent on themolecular work performed by protein products of genes. Furthermore there is a tremendous regulatory potentialthat can be acutely utilized through fine-tuning of protein function through reversible chemical post-translationalmodifications and interactions with other protein partners. Because of these functionalities a majority of cancerdrugs act directly on protein targets or create a dependency on a protein function (e.g. DNA damage agentsthat overwhelm protein enzymes involved in repair). It is now an increasing realization in the cancer researchfield that without knowledge of the dynamics of protein networks (i.e. proteome dynamics) genomic andtranscriptomic data are often insufficient for determination of targetable or actionable events and mechanismsof resistance to treatment. The goal of proteomics in cancer research is to define perturbations of complex anddynamic protein signaling networks that are associated with development and progression of cancer and to usethis information for identification of novel therapeutic targets and biomarkers that can predict response orresistance to specific therapies. We have established a comprehensive Shared Resource for protein biology witha strong background in cancer biology and protein biochemistry. Since there is no single technology platform toanalyze all aspects of the cellular proteome multiple enrichment purification and measurement approacheshave been developed to address diverse research questions studied by DLDCCC investigators. Specifically ourShared Resource provides targeted antibody-based protein profiling with custom RPPA platform and a suite ofmass spectrometry-based assays for expression profiling and determination of protein interactions. Furthermorerecognizing the challenges of big data we strive for excellence in data analysis and communication. Ourservices are therefore provided as beginning-to-end packages to assist investigators with up-front study designand feasibility assessment execution of experimental analysis by various technology platforms specializedanalysis and interpretation of data troubleshooting and decision-making in follow-up studies. +No NIH Category available Antibodies;Award;Biology;Cancer Center;Cancer Center Support Grant;Cell Communication;Cell Cycle Progression;Cell Separation;Cell Survival;Cells;Cellular Metabolic Process;Chromatin;Consultations;Core Facility;Cytometry;DNA;Data Analyses;Development;Ensure;Equipment;Evolution;Flow Cytometry;Funding;Future;Generations;Genetic Transcription;Goals;Grant;Growth;Hour;Image;Immune;In Situ;Individual;Inflammation;Laboratories;Letters;Life;Magnetism;Malignant Childhood Neoplasm;Malignant Neoplasms;Medicine;Metals;Mutation;Neoplasm Metastasis;Nuclear Receptors;Oncogenes;Peer Review;Phenotype;Preparation;Protocols documentation;Publications;Reagent;Research;Research Design;Research Institute;Research Personnel;Resource Sharing;Resources;Sampling;Services;Signal Pathway;Signal Transduction;Sorting;Suspensions;Technology;Texas;Tissue Sample;Tissues;Training;Transcriptional Regulation;Translating;Tumor Suppression;Tumor Suppressor Proteins;Work;angiogenesis;anticancer research;cancer cell;cancer prevention;cancer stem cell;cancer therapy;cell type;college;cost effective;data management;experience;imaging platform;imaging system;instrument;instrumentation;malignant breast neoplasm;meetings;member;neoplastic cell;new technology;new therapeutic target;novel;novel therapeutics;particle;prevent;programs;recruit;repaired;submicron;success;tissue culture;tool;transforming virus;tumor;tumor eradication;tumor microenvironment High-Parameter Cytometry Shared Resource n/a NCI 10674556 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8883 9394043 "BEETON, CHRISTINE " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 141320 88319 53001 PROJECT SUMMARY: High-Parameter Cytometry Shared Resource (HPCSR)Cytometry is an essential and broadly applicable technology for cancer research to assist with elucidatingmechanisms of tumor suppressor and oncogenes cell-cycle progression transforming viruses and to evaluatecancer therapies. It is integral to studies of cancer stem cells angiogenesis inflammation transcriptionalregulation in tumor cells and mechanisms of DNA break and repair. The goal of the High-Parameter CytometryShared Resource (HPCSR) is to provide a wide range of Cancer Center investigators with access to cost-effective state-of-the-art instrumentation expertise and training for their cell sorting and analysis needs. Thistechnology continues to develop at a rapid pace especially with the advent of novel tools and reagentsincreased computational capacity and more cost-effective equipment. To keep pace with changing technologiesincreased utilization and growth of users over the past 4 years the HPCSR has expanded its space with newlab renovations acquired substantial upgrades of existing equipment and acquired new major equipmentutilizing mass imaging high-parameter and large and small particle cytometry. The main facility is housed incentrally located space and is available to trained users 24 hours a day 7 days a week by key-card access.Current major instrumentation includes a mass cytometer and imaging system high-parameter fluorescentcytometer an imaging cytometer 4 florescence-activated cell sorters 7 flow analyzers and magnetic and largeparticle cell sorters. The Resource is directed by Dr. Christine Beeton and Mr. Joel Sederstrom whom both haveover 20 years of experience in flow cytometry and is staffed by 5 full-time experienced flow cytometrists whoperform operator-assisted cytometry and assist users with data analysis. To ensure optimal use of servicesHPCSR provides consultations group and individually tailored training and protocols for sample preparationflow analysis and cell sorting. This is a heavily used Shared Resource that provided service for 119 CancerCenter investigators during the last year a substantial increase from 87 users in the first year of the CCSGaward. It serves all Programs of the DLDCCC with the Programs in Cell Signaling and Metabolism (CSM)Nuclear Receptor Transcription and Chromatin Biology (NRTCB) Breast Cancer (BCP) Mechanisms in CancerEvolution (MCEP) and Pediatric Cancer (PCP) being the biggest users of this Shared Resource. This usetranslates into an average of 50 publications annually. Future plans include development of new technologiesand instrumentation for mass high-parameter imaging large and small particle and spectral cytometry that arepushing the boundaries of conventional cytometry beyond 50 parameters. Further expansion of space andresearch staff are required for these new technologies and anticipated continued growth of HPCSR. +No NIH Category available Acceleration;Adoption;Awareness;Bioinformatics;Biological Assay;Biological Process;Cancer Center;Cancer Center Support Grant;Cells;Chromatin;Complex;Comprehensive Cancer Center;Computational Biology;Consultations;Cost efficiency;Custom;DNA;DNA Methylation;Data;Data Analyses;Data Storage and Retrieval;Detection;Development;Disease;Disease Progression;Education;Educational workshop;Emerging Technologies;Ensure;Epigenetic Process;Experimental Designs;Funding;Gene Expression;Gene Expression Profiling;Gene Mutation;Gene Rearrangement;Genes;Genome;Genomics;Genomics Shared Resource;Germ-Line Mutation;Goals;Grant;Heterogeneity;Individual;Investments;Libraries;Malignant Neoplasms;Medicine;Mission;Modification;Molecular Biology;Molecular Conformation;Mutation;NCI Center for Cancer Research;Pathway interactions;Positioning Attribute;Predisposition;Preparation;Production;Protein Isoforms;Protocols documentation;Quality Control;RNA;Research;Research Personnel;Research Project Grants;Research Support;Resolution;Resource Sharing;Sampling;Services;Single Nucleotide Polymorphism;Somatic Mutation;Specialist;Speed;Technology;Tissues;Training;Training and Education;Transcript;Vendor;Work;anticancer research;cancer cell;college;community center;computerized data processing;cost;cost effective;data management;design;differential expression;epigenome;epigenomic profiling;epigenomics;exome;experience;flexibility;genome sequencing;histone modification;innovation;insight;instrument;instrumentation;interest;member;new technology;next generation sequencing;operation;programs;single cell sequencing;single cell technology;single-cell RNA sequencing;success;targeted sequencing;transcriptome;transcriptome sequencing;transcriptomics;treatment response;tumor progression;whole genome Genomic Transcriptomic Epigenomic and Single Cell Shared Resource n/a NCI 10674554 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8881 1940905 "CHEN, RUI " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 204689 127922 76767 PROJECT SUMMARY: Genomic Transcriptomic Epigenomic and Single Cell (GTESC) SharedResourceThe Genomic Transcriptomic Epigenomic and Single Cell (GTESC) Shared Resource (SR) of the Dan L.Duncan Comprehensive Cancer Center (DLDCCC) meets the academic needs of Cancer Center investigatorsby providing cutting-edge technologies and supports research flexibility by assisting with development ofinnovative new applications. This is a dynamic facility (formerly Genomic and RNA Profiling [GARP] SR) with amission of keeping pace with emerging technologies and instrumentation and the changing needs of theCancer Center. Over the last 4 years $2 million has been invested to purchase new high-end instruments.DLDCCC investigators have made significant advancements in cancer research by utilizing GTESC state-of-the-art next generation (NextGen) sequencing and single cell technologies for their genomic transcriptomicand epigenetic studies. As a rapidly evolving field the barriers and costs of NextGen sequencing and singlecell approaches can be high and the costs of constantly changing instrumentation needs for these technologiesare far more than most individual investigators can support. Therefore a SR facility such as GTESC will closethe technology gap and enable individual and collaborative DLDCCC research groups to successfully utilizecurrent and emerging NGS technologies in their research with cost efficiency accuracy and convenience thatwould otherwise not be possible. +No NIH Category available Adenovirus Vector;Basic Science;Biological Testing;Cancer Center;Cancer Center Support Grant;Cell Therapy;Cells;Chemistry;Clinical;Clinical Research;Clinical Trials;Contracts;Data;Development;Disease;Documentation;Environment;Environmental Monitoring;Equipment;Flow Cytometry;Genes;Good Manufacturing Process;Infrastructure;Investigational New Drug Application;Laboratories;Maintenance;Medicine;National Heart Lung and Blood Institute;Phase I/II Clinical Trial;Preparation;Procedures;Production;Protocols documentation;Quality Control;Quality Indicator;Regulation;Research Personnel;Resource Sharing;Resources;Retroviral Vector;Somatic Cell;Specific qualifier value;Standard Preparations;System;Testing;Therapeutic;Training;Translations;United States Food and Drug Administration;Validation;Viral Vector;Work;cancer therapy;cell bank;college;cost comparison;early phase clinical trial;experience;follow-up;gene therapy;good laboratory practice;manufacture;neoplastic;pre-clinical;preclinical study;programs;quality assurance;research study;stability testing;tissue repair;vector Cell Processing and Vector Production n/a NCI 10674550 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8879 10011571 "LAPTEVA, NATALIA " Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 93121 58197 34924 PROJECT SUMMARY: Cell Processing and Vector Production (CPVP) Shared Resource The Cell Processing and Vector Production (CPVP) Shared Resource provides manufacturing of therapeutic grade cellular therapy products and viral vector for use in early phase clinical trials. These must be prepared according to current Good Manufacturing Practices (GMP) as mandated by the Food and Drug Administration. This Shared Resource provides the infrastructure and environment to prepare test and release these products for use. It consists of a state-of-the-art facility with 22 manufacturing clean rooms and support facilities (quality control and flow cytometry laboratories material management facilities etc.) and highly experienced manufacturing and quality control and assurance staff. This DLDCCC Resource will work with investigators to develop clinical scale manufacturing procedures and release test specifications testing procedures quality assurance oversight and regulatory assistance to assist in IND submissions. The resource has therefore facilitated the transition of cellular and gene therapy products from the basic science laboratories in the DLDCCC into early-phase clinical trials. The CPVP currently supports more than 50 clinical trials (21 actively accruing 18 in follow-up and 11 in stages of translation to investigational new drug applications [INDs]) held by DLDCCC investigators and does so at a much-reduced cost compared to commercial manufacturing and testing entities. +No NIH Category available Acquired Immunodeficiency Syndrome;Animal Model;Animals;Basic Science;Biological Assay;Blood;Cancer Center;Cancer Center Support Grant;Cancer Model;Clinical;Clinical Data;Collaborations;Collection;Comprehensive Cancer Center;Consent;Consultations;DNA;Data;Databases;Development;Enrollment;Ensure;Epidemiology;Etiology;Formalin;Frozen Sections;Funding;Future;Genomics;Histology;Histopathology;Hospitals;Human;Human Resources;Image Analysis;Immunohistochemistry;Informed Consent;Investigation;Maintenance;Malignant Neoplasms;Medicine;Metagenomics;National Cancer Institute;Normal tissue morphology;Paraffin Embedding;Pathologic;Pathologist;Pathology;Peripheral Blood Mononuclear Cell;Play;Population Research;Population Sciences;Prevention;Proteomics;Questionnaires;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Risk Factors;Role;Scanning;Science;Secure;Services;Slide;Specimen;Stains;Structure;Technology;Tissue Embedding;Tissue Microarray;Tissues;Training;Translational Research;Urine;Venous blood sampling;anticancer research;biobank;cancer specimen resource;cancer therapy;cell preparation;clinical care;college;epidemiologic data;experience;follow-up;histological stains;human tissue;in vivo;laser capture microdissection;metabolomics;microbiome;mouse model;multidisciplinary;multiplexed imaging;operation;optimal treatments;patient derived xenograft model;programs;tissue processing;transcriptomics;translational scientist;tumor Integrated Biobanking Shared Resource n/a NCI 10674547 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8878 1922205 "ITTMANN, MICHAEL M" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 298016 186248 111768 PROJECT SUMMARY: Integrated Biobanking Shared Resource (IBSR)The purpose of the Integrated Biobanking Shared Resource is to provide access to biospecimens bycoordinated general and targeted biospecimen acquisition along with relevant expertise and technicalresources to enhance basic translational and clinical cancer biospecimen-based research activities at the DanL. Duncan Comprehensive Cancer Center. Access to such resources is critical for biospecimen-based cancerinvestigations. This Shared Resource (SR) is a merger of the prior Human Tissue Acquisition and Pathology(HTAP) and the Population Sciences Biorepository (PSB) SRs into a single Integrated Biobanking SR (IBSR).This is a natural outgrowth of the close working relationship of the HTAP and PSB SRs over many years.Merger of HTAP and PSB SRs will allow us to further integrate our operations within a common managementstructure. The Shared Resource personnel have extensive experience in pathology epidemiologybiospecimen acquisition and processing bank maintenance and distribution. In addition personnel are trainedin the various technical services offered including peripheral blood mononuclear cell preparation DNAextraction routine histology services frozen sections tissue microarray construction immunohistochemistrytissue microarray scanning and multiplex image analysis. We also provide pathology consultation by expertpathologists for both human tissue specimens and mouse models and risk factor questionnaire developmentand collection. +No NIH Category available Antibodies;Area;Award;Biological Assay;Cancer Center;Cancer Center Support Grant;Cell Culture Techniques;Cell Cycle;Cells;Certification;Communities;Consultations;Core Facility;Custom;Data Analyses;Data Analytics;Digestive System Disorders;Dimensions;Educational process of instructing;Educational workshop;Experimental Designs;Image;Image Analysis;Individual;Institution;Investments;Libraries;Medicine;Microscope;Microscopy;Miniaturization;Modeling;Phenotype;Proteins;Protocols documentation;Quality Control;Research;Research Institute;Research Personnel;Robotics;Sampling;Services;Spottings;Techniques;Technology;Texas;Training;Training and Education;United States National Institutes of Health;Validation;Vendor;analysis pipeline;anticancer research;assay development;cancer prevention;college;data acquisition;design;graduate student;imaging facilities;imaging informatics;informatics shared resource;instrument;instrumentation;light microscopy;member;new technology;screening;superresolution microscopy;symposium;three dimensional cell culture;tissue culture;tool;ultra high resolution Advanced Microscopy and Image Informatics n/a NCI 10674544 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8877 1947202 "MANCINI, MICHAEL A." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 100965 63099 37866 PROJECT SUMMARY: Advanced Microscopy and Image Informatics (AMII) Shared ResourceThe Advanced Microscopy and Image Informatics (AMII) Shared Resource provides high quality microscopy andanalytics services to DLDCCC members through availability of state-of-the-art imaging instrumentation customimage analysis one-on-one training by expert staff plus consultation for experimental setup data acquisitionand analysis. AMII is also invested in education and training through graduate level teaching symposia andseminar organization and via one-on-one training for most of the services. AMII also offers fully-assistedservices including most notably STORM super-resolution microscopy and assay development for highthroughput imaging-based phenotypic or mechanistic screening. AMII is also part of a Multi-Institutional CancerPrevention and Research Institute of Texas (CPRIT) Core Facility Support Award (CFSA) for an imaging facilitythat provides Cancer Center members additional access to unique instruments and an image informatics groupfor higher level assistance with custom image analysis. +No NIH Category available 3-Dimensional;Adoptive Cell Transfers;Animal Model;Area;Bioinformatics;Biological;Biology;CRISPR/Cas technology;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Model;Catchment Area;Cell Line;Cells;Charge;Chick;Chickens;Clinic;Clinical;Collaborations;Collection;Communities;Comprehensive Cancer Center;Credentialing;DNA;DNA sequencing;Data;Development;Disease;Embryo;Embryo Transfer;Emerging Technologies;Ensure;Equipment;Evaluation;Faculty;Fertilization in Vitro;Freezing;Funding;Generations;Genes;Genetic Engineering;Genetically Engineered Mouse;Genome;Hepatic;Human;Immune system;Immunocompromised Host;International;Invaded;Investigational Therapies;Knock-in;Knock-out;Lung;Maintenance;Malignant Neoplasms;Medicine;Methods;Microinjections;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;Organoids;Patients;Pre-Clinical Model;Process;Proteomics;Protocols documentation;Reproducibility;Research Personnel;Resource Sharing;Resources;Science;Service delivery model;Services;Site;System;Techniques;Technology;Therapeutic Studies;Tissues;Transformed Cell Line;Transgenes;Transgenic Organisms;Translating;Treatment Efficacy;Validation;Work;Xenograft Model;angiogenesis;animal resource;anticancer research;cell immortalization;chicken egg;chimeric antigen receptor T cells;chorioallantoic membrane;college;computer infrastructure;conditional knockout;cost;cost effective;embryo cryopreservation;embryonic stem cell;exome;experimental study;gene replacement;genome editing;in vivo;in vivo Model;interest;metabolomics;mouse model;multiple omics;nuclease;patient derived xenograft model;preservation;rat genome;reconstitution;repository;response;sperm cryopreservation;tissue resource;transcriptome sequencing;tumor;tumor xenograft;whole genome Advanced in Vivo Cancer Models n/a NCI 10674541 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8876 1972445 "LEWIS, MICHAEL T." Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 232806 145494 87312 PROJECT SUMMARY: Advanced In Vivo Cancer Models (AICM) Shared ResourceThe Advanced In Vivo Cancer Models (AICM) Shared Resource of the Dan L Duncan Comprehensive CancerCenter (DLDCCC) is constructed to meet the needs of Cancer Center investigators wishing to useexperimentally demanding state-of-the-art in vivo cancer models that require specialized techniques and ahigh degree of experimental ingenuity. These models include genetically engineered mice (knockoutknockin and transgenics) and patient-derived tumor xenografts (PDX) grown either in immunocompromisedmice or in alternative platforms such as the chicken egg chorioallantoic membrane (CAM). Both mouse andhuman-derived models require substantial validation work to credential that they are reflective of the biologyof the disease or process under study. Since patient-derived tissues used to generate the models haveconsiderable associated clinical and omic information computational infrastructure is also required toabstract store organize retrieve and display such information so that investigators can make rational choicesas to which model(s) to use and to help interpret their results. The AICM Shared Resource will coordinatethese activities for the Cancer Center to enhance in vivo model access use and utility in a cost-effectivemanner. +No NIH Category available Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Patient;Clinical;Clinical Sciences;Comprehensive Cancer Center;Education;Education and Outreach;Educational Curriculum;Effectiveness;Evaluation;Faculty;Funding;Goals;Health Professional;High School Student;Institution;Leadership;Malignant Neoplasms;Medicine;Middle School Student;Modeling;Participant;Patient Care;Physicians;Play;Postdoctoral Fellow;Productivity;Research;Research Personnel;Scientist;Series;Students;Training;Training Activity;Underrepresented Students;anticancer research;cancer education;career;career development;college;design;evidence base;experience;graduate student;interest;lectures;member;next generation;programs;science technology engineering mathematics and medicine;summer research;synergism;undergraduate student Cancer Research Career Enhancement and Related Activities n/a NCI 10674538 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8875 1883878 "FUQUA, SUZANNE AW" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 86825 54262 32563 PROJECT SUMMARY/NARRATIVE CANCER RESEARCH CAREER ENHANCEMENT (CRCE)One of the main goals of the Dan L Duncan Comprehensive Cancer Center (DLDCCC) at Baylor College ofMedicine (BCM) is to educate and train the next generation of cancer researchers and physician-scientists andto support the career development of trainees at all levels specializing in cancer research and patient care. TheCRCE Core at the DLDCCC plays a key role in integrating and developing programmatic activities to leverageexisting career enhancement activities across BCM. The CRCE Core provides coordination to ongoing careerenhancement activities as well as initiating new directions to enrich and synergize trainees postdoctoral fellowsand faculty at BCM. The Core Specific Aims are: (1) To provide cancer research career enhancement activitiesacross the continuum of trainees; and (2) To coordinate cancer education and training activities across theDLDCCC. These activities will be evaluated both formatively and summatively to gauge (1) the quality andeffectiveness with which career enhancement components are delivered and implemented and (2) the overallvalue of the experiences provided to students fellows and faculty members. Existing evaluation strategiesconducted by each contributing program will be leveraged to document impact on DLDCCC participants. Thegoal of the CRCE Core is to provide career enhancement activities that prepares all trainees and faculty forproductive careers as biomedical cancer researchers or cancer healthcare professionals. The CRCE Core isactively engaged with middle and high school students through BCMs Center for Educational Outreach todevelop evidence-based models that support high quality science technology engineering mathematics andmedicine educational. For undergraduate involvement the CRCE has taken initiatives with helping coordinatesummer research programs for students interested in cancer-focused research through the SMART programR25 PREP program (focused on underrepresented students) and a recently funded P20 collaborative researchand education program. The CRCE is active in graduate student enhancement through the involvement ofleadership members in the curriculum design and career development activities. Finally the CRCE has beenenhancing the education and career development for senior-level trainees including post-doctoral fellows bothbasic science and clinical and junior faculty through organization of cancer-related (clinical and basic science)lecture series and facilitating career-enhancing activities in conjunction with the BCM Career DevelopmentCenter and other programs at BCM and surrounding institutions. +No NIH Category available Address;Basic Science;Budgets;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Research;Clinical Sciences;Communication;Community Outreach;Complex;Databases;Education;Ensure;Environment;Evaluation;Financial Support;Goals;Grant;Health;Infrastructure;Institution;Leadership;Malignant Neoplasms;Medicine;Mission;Monitor;Patient Care;Play;Population;Population Sciences;Process;Productivity;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Role;Standardization;Strategic Planning;Translational Research;Work;college;cost effective;health disparity;improved;member;mortality;outreach;programs;tool Cancer Center Administrative Core n/a NCI 10674536 6/28/23 0:00 PAR-17-095 5P30CA125123-17 5 P30 CA 125123 17 7/1/07 0:00 6/30/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8874 2413379 "HESLOP, HELEN E" Not Applicable 9 Unavailable 51113330 FXKMA43NTV21 51113330 FXKMA43NTV21 US 29.70926 -95.400851 481201 BAYLOR COLLEGE OF MEDICINE HOUSTON TX Domestic Higher Education 770303411 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 Research Centers 2023 212902 133054 79848 Project Summary - Cancer Center AdministrationThe DLDCCCs overarching role is to coordinate cancer-relevant research education patient care andcommunity outreach activities and to address the cancer-related health issues of the residents in ourCatchment Area (CA). Cancer Center Administration is organized and staffed to provide operational andfinancial support to Senior Leadership the general membership and manage the mission critical activities ofthe DLDCCC in a complex matrix organizational environment. The Administrative Core plays a major role infacilitating the creation and implementation of the DLDCCC Strategic Plan managing evaluation and planningand the activities of our external and internal committees monitoring progress and ensuring that researchershave the resources needed to enable optimal research both within the Center and across the BCM and partnerinstitution matrix. Administration continues to improve on previously created or introduced tools databasesand standardized processes and works closely with their departmental and central administrative colleagues inthe College to achieve our goals. +No NIH Category available Address;Adrenal Cortex Hormones;Affect;Allogenic;Autoimmune Diseases;B-Lymphocytes;Biological;Biology;Biopsy;Blood;Blood specimen;Body Fluids;Cells;Clinical;Collaborations;Complication;Data;Dendritic Cells;Development;Disease;Early Intervention;Endothelial Cells;Enrollment;Etiology;Evaluable Disease;Evaluation;Event;Evolution;Eye;Feces;Fibroblasts;Fred Hutchinson Cancer Research Center;Functional disorder;Helper-Inducer T-Lymphocyte;Hematologic Neoplasms;Hematological Disease;Homologous Transplantation;Human;Image;Imaging Techniques;Immune;Immune system;Immunosuppression;Immunosuppressive Agents;Institution;Knowledge;Laboratories;Lichen Planus;Life;Liquid substance;Liver;Longitudinal observational study;Macrophage;Measurement;Measures;Medicine;Morbidity - disease rate;Mus;National Cancer Institute;Onset of illness;Optical Coherence Tomography;Oral;Oral cavity;Organ;Organ Transplantation;Participant;Patients;Phenotype;Population;Population Control;Prophylactic treatment;Proteins;Quality of life;Regimen;Regulatory T-Lymphocyte;Research Personnel;Rest;Risk;Saliva;Sampling;Scientist;Signs and Symptoms;Site;Sjogren's Syndrome;Skin;Solid;Survivors;Symptoms;Syndrome;System;Systemic Lupus Erythematosus;Systemic Scleroderma;T-Lymphocyte;Testing;Therapeutic;Tissues;Transplantation;United States National Institutes of Health;Universities;Washington;bioimaging;chemokine;chronic graft versus host disease;clinical center;clinical development;cohort;conditioning;cytokine;fecal microbiome;functional status;graft vs host disease;hematopoietic cell transplantation;impaired functional status;individual patient;isoimmunity;longitudinal prospective study;microbiome;monocyte;mortality;multidisciplinary;new therapeutic target;organ growth;pharmacologic;post-transplant;response;success;transplant survivor Biologic correlatives of chronic GVHD onset PROJECT NARRATIVEChronic graft-versus-host disease (GVHD) is the major cause of morbidity and non-relapse mortality insurvivors of allogeneic transplantation. Our understanding of the early events determinants of which organsare affected and the biologic changes associated with clinically evident cGVHD is poorly developed. Theproposed study will bring together clinical and laboratory investigators to address these knowledge gaps. NCI 10674533 7/14/23 0:00 PAR-18-646 5U01CA236229-06 5 U01 CA 236229 6 "HENDERSON, LORI A" 7/2/19 0:00 6/30/24 0:00 ZCA1-RTRB-4(O1) 1901140 "LEE, STEPHANIE J" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 839470 NCI 628971 178625 PROJECT SUMMARYAllogeneic hematopoietic cell transplantation (HCT) can cure many hematologic cancers and other life-threatening hematologic diseases but 20-50% of survivors develop chronic graft-versus-host disease(cGVHD) the leading cause of morbidity and mortality in transplant survivors. In cGVHD the donor's immunecells attack the patient setting up a cascade of events resulting in a pleomorphic multi-organ syndromereminiscent of autoimmune diseases such as systemic sclerosis systemic lupus erythematosus Sjogren'ssyndrome and lichen planus. Chronic GVHD is associated with poor quality of life impaired functional statusand need for prolonged treatment with potent immunosuppressive agents. There are many competinghypotheses about the etiology of human cGVHD with data supporting involvement of T and B cellsmacrophages dendritic cells fibroblasts and endothelial cells. Cytokines chemokines and other proteins havebeen implicated. To our knowledge the microbiome has not been investigated in cGVHD patients. This projectwill address key gaps in our understanding of human cGVHD development: what are the early events thatoccur in the skin eyes mouth and blood before cGVHD clinical onset? Do early changes in local tissuesmirror changes in the rest of the body and do they reflect the pathophysiology of cGVHD? Can we detectsubclinical cGVHD using new testing strategies potentially allowing the opportunity for targeted pre-emptivetreatment? To address these questions we will enroll 100 evaluable patients (80 at Fred Hutchinson 20 at theNational Cancer Institute) in a prospective longitudinal study involving intensive bimonthly assessments.Entitled the CATCH study (Close Assessment and Testing for Chronic GVHD) this unique cohort will allowus to watch cGVHD as it develops in humans. No other situation in medicine except solid organtransplantation provides a similar window into the evolution of an alloimmune response and findings could berelevant to many other auto- and alloimmune phenomenon. Participants will be studied before transplant thenat bimonthly intervals through the first post-transplant year starting at month 3. Assessments include physicalexams symptom measurement and sampling of blood conjunctival washings saliva and feces. Participantswill undergo skin and oral biopsies at 2-3 timepoints and also have optical coherence tomography and otherspecialized imaging of the skin eyes and mouth every other month. Biologic analyses of cytokineschemokines microbiome and cellular subsets will be performed on informative samples to test priorobservations in the murine and human systems and to generate new hypotheses. Completion of this projectwill advance our understanding of the biologic underpinnings of human cGVHD and guide therapeuticapproaches based on a comprehensive understanding of systemic and tissue-specific pathophysiology inorder to decrease the morbidity and mortality of this common transplant complication. 627094 +No NIH Category available Address;Adrenal Cortex Hormones;Affect;Allogenic;Autoimmune Diseases;B-Lymphocytes;Biological;Biology;Biopsy;Blood;Blood specimen;Body Fluids;Cells;Clinical;Collaborations;Complication;Data;Dendritic Cells;Development;Disease;Early Intervention;Endothelial Cells;Enrollment;Etiology;Evaluable Disease;Evaluation;Event;Evolution;Eye;Feces;Fibroblasts;Fred Hutchinson Cancer Research Center;Functional disorder;Helper-Inducer T-Lymphocyte;Hematologic Neoplasms;Hematological Disease;Homologous Transplantation;Human;Image;Imaging Techniques;Immune;Immune system;Immunosuppression;Immunosuppressive Agents;Institution;Knowledge;Laboratories;Lichen Planus;Life;Liquid substance;Liver;Longitudinal observational study;Macrophage;Measurement;Measures;Medicine;Morbidity - disease rate;Mus;National Cancer Institute;Onset of illness;Optical Coherence Tomography;Oral;Oral cavity;Organ;Organ Transplantation;Participant;Patients;Phenotype;Population;Population Control;Prophylactic treatment;Proteins;Quality of life;Regimen;Regulatory T-Lymphocyte;Research Personnel;Rest;Risk;Saliva;Sampling;Scientist;Signs and Symptoms;Site;Sjogren's Syndrome;Skin;Solid;Survivors;Symptoms;Syndrome;System;Systemic Lupus Erythematosus;Systemic Scleroderma;T-Lymphocyte;Testing;Therapeutic;Tissues;Transplantation;United States National Institutes of Health;Universities;Washington;bioimaging;chemokine;chronic graft versus host disease;clinical center;clinical development;cohort;conditioning;cytokine;fecal microbiome;functional status;graft vs host disease;hematopoietic cell transplantation;impaired functional status;individual patient;isoimmunity;longitudinal prospective study;microbiome;monocyte;mortality;multidisciplinary;new therapeutic target;organ growth;pharmacologic;post-transplant;response;success;transplant survivor Biologic correlatives of chronic GVHD onset PROJECT NARRATIVEChronic graft-versus-host disease (GVHD) is the major cause of morbidity and non-relapse mortality insurvivors of allogeneic transplantation. Our understanding of the early events determinants of which organsare affected and the biologic changes associated with clinically evident cGVHD is poorly developed. Theproposed study will bring together clinical and laboratory investigators to address these knowledge gaps. NCI 10674533 7/14/23 0:00 PAR-18-646 5U01CA236229-06 5 U01 CA 236229 6 "HENDERSON, LORI A" 7/2/19 0:00 6/30/24 0:00 ZCA1-RTRB-4(O1) 1901140 "LEE, STEPHANIE J" Not Applicable 7 Unavailable 806433145 TJFZLPP6NYL6 806433145 TJFZLPP6NYL6 US 10068583 FRED HUTCHINSON CANCER CENTER Seattle WA Other Domestic Non-Profits 98109 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 395 Non-SBIR/STTR 2023 839470 NIDCR 213012 60494 PROJECT SUMMARYAllogeneic hematopoietic cell transplantation (HCT) can cure many hematologic cancers and other life-threatening hematologic diseases but 20-50% of survivors develop chronic graft-versus-host disease(cGVHD) the leading cause of morbidity and mortality in transplant survivors. In cGVHD the donor's immunecells attack the patient setting up a cascade of events resulting in a pleomorphic multi-organ syndromereminiscent of autoimmune diseases such as systemic sclerosis systemic lupus erythematosus Sjogren'ssyndrome and lichen planus. Chronic GVHD is associated with poor quality of life impaired functional statusand need for prolonged treatment with potent immunosuppressive agents. There are many competinghypotheses about the etiology of human cGVHD with data supporting involvement of T and B cellsmacrophages dendritic cells fibroblasts and endothelial cells. Cytokines chemokines and other proteins havebeen implicated. To our knowledge the microbiome has not been investigated in cGVHD patients. This projectwill address key gaps in our understanding of human cGVHD development: what are the early events thatoccur in the skin eyes mouth and blood before cGVHD clinical onset? Do early changes in local tissuesmirror changes in the rest of the body and do they reflect the pathophysiology of cGVHD? Can we detectsubclinical cGVHD using new testing strategies potentially allowing the opportunity for targeted pre-emptivetreatment? To address these questions we will enroll 100 evaluable patients (80 at Fred Hutchinson 20 at theNational Cancer Institute) in a prospective longitudinal study involving intensive bimonthly assessments.Entitled the CATCH study (Close Assessment and Testing for Chronic GVHD) this unique cohort will allowus to watch cGVHD as it develops in humans. No other situation in medicine except solid organtransplantation provides a similar window into the evolution of an alloimmune response and findings could berelevant to many other auto- and alloimmune phenomenon. Participants will be studied before transplant thenat bimonthly intervals through the first post-transplant year starting at month 3. Assessments include physicalexams symptom measurement and sampling of blood conjunctival washings saliva and feces. Participantswill undergo skin and oral biopsies at 2-3 timepoints and also have optical coherence tomography and otherspecialized imaging of the skin eyes and mouth every other month. Biologic analyses of cytokineschemokines microbiome and cellular subsets will be performed on informative samples to test priorobservations in the murine and human systems and to generate new hypotheses. Completion of this projectwill advance our understanding of the biologic underpinnings of human cGVHD and guide therapeuticapproaches based on a comprehensive understanding of systemic and tissue-specific pathophysiology inorder to decrease the morbidity and mortality of this common transplant complication. 212376 +No NIH Category available AIDS-Related Lymphoma;AIDS-Related Non-Hodgkin's Lymphoma;Acquired Immunodeficiency Syndrome;Automobile Driving;B-Cell Activation;B-Cell Lymphomas;B-Cell Neoplasm;B-Lymphocytes;BCL1 Oncogene;BLR1 gene;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCL13 gene;Cell Communication;Cell Proliferation;Cell Survival;Cell physiology;Cells;Chronic;Circulation;Cytometry;Cytotoxic T-Lymphocytes;DNA;Development;Diagnosis;Disease;Disease Progression;Environment;Event;Functional disorder;Generations;Genetic Transcription;Growth;Gut associated lymphoid tissue;HIV;HIV Infections;HIV Seronegativity;Helper-Inducer T-Lymphocyte;Human Herpesvirus 4;IL6 gene;Image;Immune;Immunoglobulin Class Switching;Immunoglobulin G;Immunoglobulin Genes;Immunoglobulin Somatic Hypermutation;Immunoglobulin Switch Recombination;Impairment;Individual;Inflammation;Inflammatory;Interferon Type II;Interleukin-10;Lymphocytic choriomeningitis virus;Lymphoid;Lymphoid Tissue;Lymphoma;Lymphoma cell;Lymphomagenesis;Maintenance;Malignant Neoplasms;Measures;Memory;Modeling;Molecular;Mutation;Non-Hodgkin's Lymphoma;Oncogenes;Oncogenic;Pathogenesis;Persons;Plasma Cells;Play;Population;Production;Risk;Role;Site;Structure of germinal center of lymph node;T-Lymphocyte;TNF gene;TNFRSF5 gene;TNFSF5 gene;Testing;Tissues;Tumor Subtype;Virion;Virus Diseases;activation-induced cytidine deaminase;cytokine;exhaust;exhaustion;immune activation;immunoregulation;infected B cell;interleukin-21;lymph nodes;microbial;mouse model;neoplastic cell;novel;peripheral blood;programmed cell death ligand 1;programmed cell death protein 1;receptor;tumor;tumor growth;tumor microenvironment The Role of Follicular CD8+ T Cells in Pathogenesis of AIDS-NHL. PROJECT NARRATIVEChronic B cell activation contributes to the genesis of AIDS-related non-Hodgkin's lymphoma (ARL) andCD8+ T cell dysfunction may contribute to the growth ARLs many of which are EBV-positive. The studiesoutlined in this proposal aim to determine whether CD8+CXCR5+ T cells termed follicular CD8 (fCD8+) Tcells which are elevated in HIV infection contribute to the tumor niche and induce oncogenic molecularchanges in B cells and/or support the growth of ARL cells thereby promoting lymphomagenesis and tumorgrowth. NCI 10674532 8/1/23 0:00 RFA-CA-17-030 5R01CA228157-05 5 R01 CA 228157 5 "READ-CONNOLE, ELIZABETH LEE" 8/9/19 0:00 7/31/24 0:00 ZCA1-RPRB-L(J2) 10212968 "EPELDEGUI, MARTA " Not Applicable 36 OBSTETRICS & GYNECOLOGY 92530369 RN64EPNH8JC6 92530369 RN64EPNH8JC6 US 34.070199 -118.45102 577505 UNIVERSITY OF CALIFORNIA LOS ANGELES LOS ANGELES CA SCHOOLS OF MEDICINE 900952000 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 307711 NCI 212412 95299 PROJECT SUMMARYHIV infection is associated with a greatly increased risk for the development of non-Hodgkin lymphoma (NHL).Nearly all AIDS-related lymphomas (ARL) are of B cell origin. Two major mechanisms are believed tocontribute to the genesis of ARL: 1) loss of immunoregulation of EBV+ B cells resulting from impaired T cellfunction late in the course of HIV disease and 2) chronic B cell activation leading to DNA-modifying events thatcontribute to oncogene mutations/translocations. Therefore both chronic B cell activation and impaired CD8 Tcell function are important contributors to lymphomagenesis. Recently two different groups described asubpopulation of CD8+ T cells that expresses CXCR5 (the receptor for CXCL13) in the LCMV model a mousemodel of chronic viral infection. In these studies this novel population of CD8+CXCR5+ T cells also calledfollicular CD8 (fCD8+) T cells were shown to express PD1 and were seen to be LCMV-specific and located insecondary lymphoid tissues. Additionally fCD8+ T cells were recently shown to be present in tumors and topromote B cell activation. Moreover large numbers of fCD8+ T cells have been observed in a lymphomamouse model. Inflammation and immune activation may be responsible for driving the accumulation of fCD8+T cells in the B cell follicles since there is an accumulation of inflammatory cells and CXCL13 in lymph nodesof HIV+ individuals. Since inflammation and microbial translocation precede ARL development and play animportant role in lymphomagenesis it is reasonable to think that inflammation and microbial translocation maybe important in the accumulation of fCD8+ T cells in HIV infection. fCD8+ T cells may also play a role in thedevelopment and maintenance of the tumor niche. Together this had led us to hypothesize that fCD8+ T cellswhich are known to be elevated in HIV infection result from inflammation/microbial translocation are part ofthe tumor niche and induce B cell activation contributing to lymphomagenesis and tumor growth as well as Bcell dysfunction. In this study we will test this hypothesis by determining if: 1) fCD8+ T cells from HIV-negativeand HIV+ individuals induce B cell activation and/or Breg cells both present prior to ARL diagnosis (aim 1) 2)immune activation-associated inflammation and/or microbial translocation contribute to the generation of fCD8+T cells and if fCD8+ T cells are present in gut associated lymphoid tissue in HIV+ individuals the site wheremicrobial translocation/inflammation take place (aim 2) and 3) fCD8+ T cells function as part of the tumormicro-environment in ARLs and defining how they may be contributing to tumor development (aim 3). 307711 +No NIH Category available Adult;Adverse event;Advisory Committees;Affect;Age;Body Image;Cancer Patient;Cancer Survivor;Cancer Survivorship;Caring;Cessation of life;Childhood;Childhood Cancer Survivor Study;Chronic;Clinical;Clinical Data;Cognitive;Cohort Studies;Combined Modality Therapy;Common Terminology Criteria for Adverse Events;Communities;Complex;Comprehension;Data;Development;Diagnosis;Dimensions;Distress;Early Intervention;Enrollment;Evaluation;Event;Exhibits;Exposure to;Fatigue;Foundations;Frequencies;Goals;Guidelines;Health;Health Personnel;Health Status;Impairment;Individual;International;Intervention;Interview;Investigation;Late Effects;Long-Term Survivors;Longevity;Malignant Childhood Neoplasm;Malignant Neoplasms;Measurement;Medical;Methodology;Methods;Monitor;Morbidity - disease rate;National Cancer Institute;Neurocognitive;Neuropsychology;North America;Oncology;Outcome;Outcomes Research;Pain;Palliative Care;Participant;Patient Outcomes Assessments;Patient-Focused Outcomes;Patients;Pediatric Oncology Group;Performance;Prevalence;Process;Property;Psychometrics;Quality of life;Race;Research;Research Personnel;Resources;Risk;Saint Jude Children's Research Hospital;Second Primary Neoplasms;Severities;Signal Transduction;Structure;Subgroup;Surveys;Survivors;Symptoms;Testing;Time;Toxic effect;Translational Research;Validation;aged;cancer therapy;care providers;childhood cancer survivor;clinical decision-making;cohort;comprehension test;design;experience;high risk;improved;innovation;insight;long-term sequelae;patient oriented;premature;psychosocial;recruit;reproductive;screening;sex;support tools;survivorship;symptomatic improvement;therapy design;tool Patient-Reported Outcomes Version of CTCAE involving Childhood Cancer Survivors PROJECT NARRATIVE We propose to adapt an existing symptomatic adverse event tool the Patient-Reported OutcomesCommon Terminology Criteria for Adverse Events (PRO-CTCAE) to be content appropriate and clinicallymeaningful for adult survivors of childhood cancer using two well-established childhood cancer survivor cohorts.Psychometric methodologies will be used to validate this tool by incorporating objective clinical anchors collectedfrom medical evaluations. Our symptomatic AE tool has the potential to augment the Children Oncology GroupSurvivorship Care Guidelines by implementing risk-based symptom screening to track and anticipate adversehealth events. NCI 10674530 9/1/23 0:00 PAR-18-352 5R01CA238368-05 5 R01 CA 238368 5 "SMITH, ASHLEY" 8/15/19 0:00 7/31/24 0:00 Special Emphasis Panel[ZRG1-BBBP-B(55)R] 8886807 "HUANG, I-CHAN " "BAKER, JUSTIN N" 9 Unavailable 67717892 JL4JHE9SDRR3 67717892 JL4JHE9SDRR3 US 35.155607 -90.045279 7893501 ST. JUDE CHILDREN'S RESEARCH HOSPITAL MEMPHIS TN Independent Hospitals 381053678 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 720093 NCI 401166 318927 PROJECT SUMMARY/ABSTRACT Childhood cancer survivors are vulnerable to treatment-related late effects including physical andpsychosocial morbidities subsequent malignancies and premature death. Symptom assessment provides aunique insight into survivorship care since symptoms not only signal the potential occurrence of chronic healthconditions but also impact quality of life and survival. The National Cancer Institute (NCI) has developed aPatient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) toassess symptomatic adverse events (AEs) for adult-onset cancer patients who are receiving therapies. Howeverno evidence supports that the PRO-CTCAE can be used post-therapy for adult survivors of childhood cancerwho may experience different symptomatic AEs compared to adult patients undergoing cancer therapies. Our long-term goal for cancer survivorship care is to identify symptomatic AEs for early indication ofadverse health events and design interventions targeting these symptoms for improving health and quality oflife outcomes. This proposed study plans to adapt the PRO-CTCAE for use in adult survivors of childhood cancer(PRO-CTCAE-SCC) through three Specific Aims based on unique resources of the Childhood Cancer SurvivorStudy (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE): 1) conduct a symptom selection process for thePRO-CTCAE-SCC by identifying symptomatic AEs in adult survivors of childhood cancer and create items notincluded in the current PRO-CTCAE; 2) validate the PRO-CTCAE-SCC using psychometric methods andobjective clinical parameters; and 3) develop tailored versions of the PRO-CTCAE-SCC for survivors of differentdiagnoses exposed to different cancer therapies and establish meaningful cut-points and minimally importantdifferences in symptom burden scores for clinical decision-making. We plan to recruit 135 SJLIFE survivors and 45 healthcare providers who are currently caring forchildhood cancer survivors to evaluate content validity. We will recruit 1200 CCSS survivors to test thepsychometric properties of the PRO-CTCAE-SCC and recruit 600 SJLIFE survivors to evaluate clinical known-groups validity and responsiveness to change. The CCSS and SJLIFE are the two largest well-establishedchildhood cancer survivor cohorts in North America. In addition 1200 age/sex/race matched adults from acommunity panel will be used to compare the prevalence of symptoms between cancer survivors and non-cancerindividuals leading to a selection of appropriate symptomatic AEs for validation. We will collect chronic healthcondition and physical and neurocognitive performance data from the SJLIFE participants followingcomprehensive medical evaluations to validate the PRO-CTCAE-SCC. Our team includes researchers withexpertise in patient-reported outcomes symptom measurement neuropsychology survivorship care palliativecare and translational science. We have invited six international experts in oncological patient-centeredoutcomes research and five adult survivors of childhood cancer to serve on the Advisory Committee. 720093 +No NIH Category available Address;Appointment;Area;Black race;Breast Cancer Patient;Breast Cancer Treatment;Cancer Patient;Caring;Categories;Chemotherapy and/or radiation;Chronic Disease;Clinic;Depression screen;Dietary Intervention;Disease;Disparity;Drug Prescriptions;Economics;Emergency Situation;Financial Hardship;Food;Foundations;Fruit;Health;Hispanic;Home;Hospitals;Household;Immigrant;Immigrant community;Individual;Intake;Interruption;Intervention;Kentucky;Life;Love;Malignant Neoplasms;Mediating;Medical;Memorial Sloan-Kettering Cancer Center;Mental Depression;Minority;New York City;Not Hispanic or Latino;Nutritional;Oncology;Patients;Persons;Policies;Prevalence;Process;Proteins;Quality of life;Randomized Controlled Trials;Reporting;Risk;Saints;Seminal;Services;Supportive care;Surveys;Time;Treatment Protocols;United States Department of Agriculture;Vegetables;Vulnerable Populations;Weight;Well in self;Work;World Health Organization;active method;arm;cancer health disparity;cancer therapy;cohort;depressive symptoms;dietary;ethnic minority;evidence base;food insecurity;food resource;food security;health disparity;improved;incremental cost;intervention cost;medically underserved population;metropolitan;minority communities;outcome disparities;patient population;preference;programs;social;socioeconomics;symptomatic improvement;treatment adherence;treatment arm;voucher FOOD (Food to Overcome Outcomes Disparities) Project NarrativeThis is the first study to address the impact of food insecurity among the growing underserved and immigrantand minority breast cancer patient population in active treatment for cure. The FOOD study builds upon theteam's unique approaches to addressing and studying food insecurity and cancer treatment completionincluding implementing food pantries co-located within oncology clinics and studying the impact of a pilot foodvoucher program and a home grocery delivery program. FOOD has the potential to significantly improve thegrowing issues of food insecurity and barriers to emergency food resources that hamper breast cancertreatment completion among medically underserved populations in New York City and across the nation inlarge metropolitan areas. NCI 10674529 5/23/23 0:00 PA-16-160 5R01CA230446-06 5 R01 CA 230446 6 "AGURS-COLLINS, TANYA" 6/1/18 0:00 5/31/24 0:00 Health Disparities and Equity Promotion Study Section[HDEP] 1988063 "GANY, FRANCESCA M" Not Applicable 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 6/1/23 0:00 5/31/24 0:00 394 Non-SBIR/STTR 2023 428511 NCI 242097 186414 Project SummaryThe World Health Organization defines food security as having access to sufficient safe nutritious food tomaintain a healthy and active life. Food security includes both physical and economic access to food thatmeets people's dietary needs and preferences. The 18-item 12-month time-referenced U.S. Household FoodSecurity Survey Module (USDA) categorizes individuals as having high food security marginal food securitylow food security or very low food security. Food insecurity is growing in the U.S. with an overall prevalence of12.7% (low and very low food security). The prevalence of food insecurity among immigrant and minoritycommunities exceeds the national average. Food insecurity is associated with non-adherence to treatment.Food-insecure patients are more likely to postpone care and often cannot afford prescribed medication(s).Food-insecure patients have significantly higher levels of nutritional risk depression financial strain and lowerquality of life. Nutrition interventions result in enhanced quality of life. Cancer patients are particularlyvulnerable to both food insecurity and its impact due to the intensity of treatment protocols and the diseaseprocess itself. A study among a cohort of underserved cancer patients in New York City showed that 56% werefood insecure with 38% of the cohort with very low food security. Treatment adherence is an importantdeterminant of survival among cancer patients. However among ethnic minority cancer patients unmetsocioeconomic and supportive care needs are associated with patient-reported missed radiation and/orchemotherapy appointments. Food insecurity potentially acts as a mediating factor as functional social andemotional well-being decrease significantly with increasing food insecurity. Prior to our work there had beenonly one study examining food insecurity in cancer patients. There is to date no evidence base oninterventions to address food insecurity and their potential to ameliorate cancer and other chronic diseasetreatment completion disparities. Food to Overcome Outcomes Disparities (FOOD) addresses this gap as thefirst large study of its kind to examine food interventions in vulnerable populations and their impact on breastcancer treatment completion. Results have the potential to guide program and policy change. FOOD will utilizea three arm randomized controlled trial to assess the impact of a hospital-based medically tailored food pantry(Pantry) versus a food voucher program (Voucher) versus a home grocery delivery program (Delivery) oncancer treatment completion. FOOD is a partnership between the Memorial Sloan Kettering Cancer Center(MSK) Immigrant Health and Cancer Disparities (IHCD) Service the Food Bank for New York City the NewYork City Council the New York City Health and Hospitals God's Love We Deliver and Saint BarnabasHospital. This study builds upon the foundation laid by a seminal pilot feasibility randomized controlled trialwhich examined a scalable clinic-based food pantry a food voucher program and home grocery delivery. 428511 +No NIH Category available Address;Adopted;Age;Alaska Native;American Indians;Area;Australia;Award;Biopsy;Centers for Disease Control and Prevention (U.S.);Cervical;Cervical Cancer Screening;Cervix Uteri;Clinical;Colposcopy;Communities;Country;Coupled;Cross-Sectional Studies;Data;Development;Diagnosis;Discipline of obstetrics;Disease;Disparity;Dysplasia;Early treatment;Educational Curriculum;Epidemiology;Exhibits;Female;Focus Groups;Foundations;Gender;Goals;Gynecology;HPV-High Risk;Health;Health Personnel;Heterogeneity;High Prevalence;Human Papilloma Virus Vaccination;Human Papilloma Virus Vaccine;Human Papillomavirus;Human papillomavirus 16;Human papillomavirus 18;Immunization Programs;Incidence;Intervention;K-Series Research Career Programs;Learning;Lesion;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Mentors;Mentorship;Minority;Mission;National Cancer Institute;National Health and Nutrition Examination Survey;Not Hispanic or Latino;Oregon;Pacific Northwest;Pap smear;Patients;Play;Population;Prevalence;Prevention;Primary Prevention;Procedures;Public Health;Publishing;Recommendation;Reproducibility;Research;Resources;Risk Factors;Role;Science;Scientist;Smoking;Socioeconomic Status;Study models;Teacher Professional Development;Time;Time trend;Training;Tribes;Universities;Urban Population;Vaccinated;Vaccination;Vision;Visual;Woman;Wood material;Youth;burden of illness;cancer health disparity;career;cervical cancer prevention;clinical care;clinical research site;data registry;disparity elimination;experience;follow-up;health disparity;high risk;male;member;mortality;prevent;professor;reservation-based;screening;surveillance strategy;tool;trend;tribal organization;vaccine acceptance;vaccine efficacy Utilization of cervical cancer prevention tools and role of high-risk HPV type in the persistent cervical cancer disparities experienced by American Indian/Alaska Native women PROJECT NARRATIVEThis project seeks to address the cervical cancer health disparities experienced by American Indian/AlaskaNative women by comprehensively assessing the utilization and applicability of available cervical cancerprevention tools such as HPV vaccination pap smear compliance and high-risk HPV types that play canimpact all levels of clinical care. NCI 10674523 7/26/23 0:00 PAR-18-337 5K08CA245200-03 5 K08 CA 245200 3 "RODRIGUEZ, LARITZA MARIA" 8/1/21 0:00 7/31/26 0:00 Career Development Study Section (J)[NCI-J] 14455073 "BRUEGL, AMANDA S" Not Applicable 1 OBSTETRICS & GYNECOLOGY 96997515 NPSNT86JKN51 96997515 NPSNT86JKN51 US 45.49882 -122.685647 6297007 OREGON HEALTH & SCIENCE UNIVERSITY PORTLAND OR SCHOOLS OF MEDICINE 972393098 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 251528 NCI 232896 18632 PROJECT SUMMARY Dr. Bruegl is an Assistant Professor in the Department of Obstetrics and Gynecology at Oregon Health andScience University and a national Robert Wood Johnson Foundation Harold Amos Minority FacultyDevelopment Fellow. Her long-term career goal is to eliminate the disparities in cervical cancer incidence andmortality in the American Indian/Alaska Native (AI/AN) population; a goal that aligns with the mission andvision of the National Cancer Institute. AI/AN women are 1.5 times more likely to be diagnosed with cervical cancer and 2X as likely to die of thedisease compared to Non-Hispanic White women. Multiple risk factors contribute to the development ofcervical cancer including not accessing pap smear screening smoking socioeconomic status and acquisitionof high-risk subtypes of the human papillomavirus (hrHPV). This proposal seeks to look deeper in to thesepersistent health disparities by critically evaluating the utilization and applicability of cervical cancer preventiontools such as HPV vaccination pap smear screening and distribution of high-risk HPV (hrHPV) types in theAI/AN population. HPV vaccination is a primary prevention tool to prevent cervical cancer and its precursorlesions with U.S. recommendations to vaccination youth ages 11-12. There are 14 types of high-risk HPV(hrHPV) associated with cancer and types 16 and 18 contribute to ~70% of cancer cases. One of the proposedstudy goals is to fully evaluate the HPV vaccination rates and trends and pap smear rates among OregonAI/AN. This data will to identify communities with high and low vaccination rates and focus groups ofhealthcare providers and community members will occur to identify barriers and facilitators of HPV vaccination. There are few studies evaluating the prevalence of hrHPV subtypes in AI/AN women and data suggest thatthe distribution of the 14 types differ from the general U.S. population which can lead to real clinicalconsequences. First vaccination may provide inadequate coverage for prevalent subtypes. Secondcolposcopy an office-based procedure to more fully evaluate the cervix is less sensitive at detecting dysplasiadue to non hrHPV 16 and 18 subtypes. A greater prevalence of other hrHPV subtypes in the AI/AN populationcan lead to missed early-stage disease. A cross-sectional study will be performed to determine the prevalenceand distribution of hrHPV among AI/AN women. As part of the NCI mentored clinical scientist research career development award training award Dr. Brueglwill participate in a robust educational curriculum to successfully meet her goal of becoming an independentclinician scientist. She has identified created a robust mentorship team and identified specific learningobjectives to help her meet this goal. 251528 +No NIH Category available Acquired Immunodeficiency Syndrome;Affect;African;Alternative Splicing;Binding;Binding Proteins;Biogenesis;CRISPR/Cas technology;Cell physiology;Cells;Communities;Country;Data Set;Etiology;Funding;Genetic Transcription;Genome;Goals;HIV Seropositivity;Herpesviridae Infections;Highly Active Antiretroviral Therapy;Human;Human Herpesvirus 8;Immunity;Immunoprecipitation;Individual;Intervention;Kaposi Sarcoma;Knock-out;Life Cycle Stages;Malignant Neoplasms;Maps;Mediating;Messenger RNA;Methyltransferase;MicroRNAs;Modeling;Modification;Morbidity - disease rate;Multicentric Angiofollicular Lymphoid Hyperplasia;Nuclear Export;Nucleotides;Pathogenesis;Patients;Phase;Point Mutation;Poly(A)+ RNA;Population;Prevention;Prognostic Marker;Protein Overexpression;Proteins;RNA;RNA Degradation;RNA Splicing;RNA Viruses;RNA immunoprecipitation sequencing;Reader;Reagent;Regulation;Resolution;Role;Site-Directed Mutagenesis;Societies;Stains;System;Testing;Time;Transcript;Translations;Viral;Virus Diseases;Virus Latency;Virus Replication;Work;base;carcinogenesis;cell type;clinically relevant;crosslink;epitranscriptome;expectation;gain of function;innovation;insight;knock-down;loss of function;lytic replication;mRNA Translation;metaplastic cell transformation;mortality;neoplastic cell;new technology;novel;novel therapeutics;overexpression;primary effusion lymphoma;programs;reverse genetics;therapeutic target;transcriptome;tumor;tumorigenesis Regulation of KSHV replication by N6-methyladenosine (m6A) Project NarrativeKaposi's sarcoma-associated herpesvirus (KSHV) causes several human cancers including Kaposi'ssarcoma primary effusion lymphoma and multicentric Castleman's disease. These malignancies inflictmorbidity and mortality to the society in US and worldwide. This project will investigate the mechanismsregulating the replication of KSHV by RNA modifications and identify potential therapeutic targets fordeveloping novel prevention and treatment approaches. NCI 10674521 8/2/23 0:00 PA-19-056 5R01CA124332-15 5 R01 CA 124332 15 "READ-CONNOLE, ELIZABETH LEE" 4/1/07 0:00 7/31/26 0:00 HIV Coinfections and HIV Associated Cancers Study Section[HCAC] 11026736 "GAO, SHOU-JIANG " Not Applicable 12 GENETICS 4514360 MKAGLD59JRL1 4514360 MKAGLD59JRL1 US 40.440909 -79.959125 2059802 UNIVERSITY OF PITTSBURGH AT PITTSBURGH PITTSBURGH PA SCHOOLS OF MEDICINE 152133320 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 339863 NCI 213750 126113 N6-methyladenosine (m6A) is the most abundant internal modification on poly(A) RNA. Dynamic regulation ofthe m6A epitranscriptome is involved in diverse cellular functions. m6A mediates these functions by affectingmRNA translation alternative splicing nuclear export and degradation and miRNA biogenesis and bindingthrough three groups of proteins: methyltransferases or writers demethylases or erasers and m6A-bindingproteins or readers. m6A is present in the genomes of RNA viruses and regulates the replication of theseviruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS) andprimary effusion lymphoma (PEL) commonly found in AIDS patients. Understanding the mechanism regulatingKSHV latent and lytic replication can not only provide insights into the pathogenesis of KSHV-induced cancersbut also serve as the basis for developing novel therapy. In the current funding period we have madesignificant progresses toward this goal. For this renewal we have discovered that m6A is abundant on KSHVtranscripts and that m6A reader protein YTHDF2 acts as an antiviral factor during viral lytic replication. Wedemonstrate m6A dynamics during KSHV latent and lytic replications and in different cell types that supportdistinct viral replication programs. Despite these works the roles of m6A in KSHV infection have just started tobe revealed. The Objective of this application is to systematically map the dynamics of m6A modifications at asingle base resolution and bindings of m6A reader proteins in KSHV epitranscriptome and determine theirfunctions in different phases of KSHV life cycle and KSHV-induced tumorigenesis. The Central Hypothesis isthat KSHV m6A modifications are dynamically regulated and these modifications mediate different phases ofKSHV life cycle and hence KSHV-induced tumorigenesis. We will test this hypothesis by mapping m6A marksin KSHV transcriptome at a single base resolution and determine the roles of m6A writer and eraser proteins indifferent phases of KSHV life cycle and KSHV-induced tumorigenesis (Aim 1); determining the functions ofm6A reader proteins in different phases of KSHV life cycle by gain- and loss-of-function approaches and byexamining their bindings to KSHV transcripts (Aim 2); and examining the functions of KSHV m6A marks in thecontext of viral infection using Crispr-Cas9-guided m6A writer and eraser and by site-specific mutagenesis(Aim 3). It is our expectations that this project will provide comprehensive mapping and functional delineationof m6A marks and m6A writer eraser and reader proteins in different phases of KSHV life cycle and KSHV-induced tumorigenesis. This work is highly significant as it will for the first time systematically reveal thefunctions of these RNA modifications in KSHV infection thus providing insights into the mechanism regulatingKSHV life cycle and KSHV-induced pathogenesis. This study will also identify potential prognostic markers andtherapeutic targets. The proposed work is highly innovative as it will use new technologies to map m6A marksand bindings of m6A reader proteins as well as directly manipulate m6A marks on key viral transcripts byCrispr-Cas9-guided m6A writer and eraser KSHV reverse genetics and innovative tumor models.Furthermore the generated datasets information and reagents will be valuable to the scientific community. 339863 +No NIH Category available Acute;Address;Adoption;Awareness;Breast;Breast Cancer survivor;Cancer Survivor;Cancer Survivorship;Caring;Case Based Learning;Chronic;Clinic;Colorectal;Colorectal Cancer;Community Healthcare;Community of Practice;Development;Diagnosis;Documentation;Dose;Educational Curriculum;Electronic Health Record;Evaluation;Evidence based practice;Focus Groups;Guidelines;Infrastructure;Intervention;Kansas;Knowledge;Lead;Left;Longevity;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Managed Care;Measures;Modeling;Observational Study;Oncology;Participant;Persons;Phase;Primary Care;Primary Health Care;Process;Promoting Action on Research Implementation in Health Services framework;Provider;Psychological reinforcement;Quality of Care;Randomized;Reporting;Research Personnel;Resources;Risk;Rural;Specialist;Structure;Survivors;System;Testing;Time;Training;Update;Work;acceptability and feasibility;acute care;cancer care;cancer risk;cancer therapy;care outcomes;care providers;case-based;effectiveness evaluation;effectiveness testing;end of life;evidence base;evidence based guidelines;falls;follow-up;implementation barriers;implementation facilitators;implementation science;improved;innovation;interest;malignant breast neoplasm;model development;novel;peer;prevent;primary care clinic;primary care practice;primary care provider;programs;prostate cancer survivors;recruit;survivorship KanSurvive: Testing a model for improving cancer survivorship care in rural practice Project NarrativeThis will be an observation study to evaluate the reasons practices providing care to rural cancer survivors(time of diagnosis through the life-span) do/do not implement evidence-based practice (EBP) cancer survivorship care and subsequently to test KanSurvive Project ECHO an implementation and practice transformationintervention to increase EBP guidelines in rural cancer survivors. NCI 10674520 7/14/23 0:00 RFA-CA-18-026 5R01CA240103-05 5 R01 CA 240103 5 "WEAVER, SALLIE JAYNE" 8/23/19 0:00 7/31/24 0:00 ZCA1-SRB-2(M1)R 10792076 "KLEMP, JENNIFER ROSE" "GREINER, K ALLEN" 3 INTERNAL MEDICINE/MEDICINE 16060860 YXJGGNC5J269 16060860 YXJGGNC5J269 US 39.026584 -94.636347 1484303 UNIVERSITY OF KANSAS MEDICAL CENTER KANSAS CITY KS SCHOOLS OF MEDICINE 661608500 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 393 Non-SBIR/STTR 2023 461845 NCI 301859 159986 ABSTRACTCancer survivors in the acute and extended phases of care would benefit from improvements in the quality andcoordination of primary and cancer care they receive. Cancer researchers have left the management of ruralcancer survivors largely unstudied. While evidence-based practice guidelines exist implementation in ruralprimary care practices has fallen short. Studies have yet to fully identify the barriers preventing successfulimplementation of guidelines in these settings. Opportunities exist to improve the understanding of both thereasons why cancer survivorship care is sub optimal in rural primary care as well as to test mechanisms forhelping practices implement systems that assure all cancer survivors can be identified and are receivingguideline concordant care. This study sets out to evaluate current practices in managing rural cancer survivorsand test a KanSurvive Project ECHO intervention to transform practices for delivery of evidence-basedsurvivorship care. The primary aims are to 1) describe gaps in care infrastructure needs and processes ofcare for acute and chronic cancer survivorship in rural primary care clinics focusing on rural breast colorectallung and prostate cancer survivors while finalizing the KanSurvive Project ECHO intervention; 2) evaluate theeffectiveness of practice facilitation integrated with telementoring program for enhancing adoption of evidence-based practice guidelines for breast colorectal lung and prostate survivors; and 3) describe key facilitatorsand barriers to implementation of KanSurvive Project ECHO and evidence of related EHR documentationchange in these practices. This novel project will provide a model for use of implementation science and thedevelopment of a community of practices working together to improve rural cancer survivorship care fromdiagnosis to the end-of-life. 461845 +No NIH Category available Accountability;Adult;African American;African American population;Age;Award;Budgets;Cancer Center Support Grant;Cancer Patient;Caring;Catchment Area;Child;Childhood;Clinical;Clinical Data;Clinical Nursing Research;Clinical Protocols;Clinical Research;Clinical Trials;Clinical Trials Data Monitoring Committees;Communication;Data;Dedications;Development;Disease;Event;Family;Geographic Locations;Geography;Guidelines;Hispanic;Hispanic Populations;Individual;Intervention;Lead;Longevity;Malignant Childhood Neoplasm;Malignant Neoplasms;Minority;Minority Groups;Minority Women;Mission;Monitor;Monitoring Clinical Trials;Oncologist;Oncology;Participant;Patients;Pediatric Hematology;Pediatric Oncology Group;Phase;Population;Protocols documentation;Reporting;Research;Research Personnel;Safety;Structure;Therapeutic;Therapeutic Clinical Trial;Therapeutic Intervention;Therapeutic Trials;Training;Training and Education;Woman;age group;aged;cancer care;cancer clinical trial;cancer therapy;clinical trial enrollment;data management;evidence base;high risk;human old age (65+);improved;innovation;malignant breast neoplasm;medical schools;member;minority patient;multidisciplinary;participant enrollment;patient population;recruit;repository;safety study;sound;timeline Clinical Protocol and Data Management n/a NCI 10674517 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8872 10505007 "GALSKY, MATTHEW " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 280419 165439 114980 PROJECT SUMMARY/ABSTRACTPart I: Clinical Protocol and Data ManagementThe primary mission of the Clinical Protocol and Data Management team also referred to as the Cancer ClinicalTrials Office (CCTO) is to assist Tisch Cancer Institute investigators in the development conduct and reportingof innovative clinical research in an efficient regulatory-compliant and scientifically sound manner. The CCTOcomprises the following functions: study coordination data management regulatory management pre-awardbudgeting training and education.Part II: Data and Safety MonitoringAll cancer clinical trials are monitored according to the guidelines set forth in the TCI Data and Safety MonitoringPlan (DSMP) which was previously reviewed and approved by the NCI. A formal Data and Safety MonitoringCommittee (DSMC) was established in 2008 to ensure that investigator-initiated clinical trials in the TCI arecompliant with the data and safety monitoring plans approved by the PRMC. The DSMC is accountable to andreports to the Associate Director for Clinical Research.Part III: Inclusion of Women and Minorities and Part IV: Inclusion Across the LifespanTCI successfully recruits significant proportions of minority patients onto clinical trials. The TCI is highlycommitted to adhering to CCSG principles in providing state-of-the-art evidence-based family-and-child-oriented multi-disciplinary cancer treatment for women minorities and patients of all ages. +No NIH Category available Address;Affect;African;Alcohols;Biological;Black race;Breast Cancer Detection;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cities;Collaborations;Colon Carcinoma;Colonoscopy;Colorectal;Colorectal Cancer;Communities;Community Actions;Community Outreach;Development;Diagnosis;Disease;Disparity;Diverse Workforce;Drops;Early Diagnosis;Evaluation;Excess Mortality;Face;Future;Geography;Health;Hepatitis;Hepatitis C;Hispanic;Improve Access;Incidence;Institution;Language;Lead;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Malignant neoplasm of prostate;Mammography;Methods;Minority;Minority Groups;Monitor;Morbidity - disease rate;Multiple Myeloma;Needle-Exchange Programs;Neighborhoods;New York City;Poverty;Prostate;Public Housing;Recovery;Research;Research Institute;Risk Factors;Services;Side;Site;Sterile coverings;Testing;Thyroid Gland;Uterine Cancer;Voice;Work;cancer care;cancer health disparity;cancer risk;care coordination;cohort;college;colon cancer patients;community engaged research;community engagement;disparity reduction;experience;health care delivery;improved;leukemia;lung cancer screening;male;malignant breast neoplasm;medical schools;melanoma;mortality;outreach;patient navigation;programs;screening;training opportunity;treatment disparity;underserved area;working class Community Outreach and Engagement n/a NCI 10674514 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8869 3150322 "BICKELL, NINA A." Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 119377 70429 48948 PROJECT SUMMARY/ABSTRACTThe Tisch Cancer Institute (TCI) is geographically situated at the crossroads of some of New YorkCitys (NYC) wealthiest and poorest neighborhoods. Our immediate catchment area includes CentralHarlem (CH) East Harlem (EH) the Upper East Side (UES) and the rescue and recovery workersof the World Trade Center (WTC). We choose these neighboring communities as they represent theepitome of cancer disparities and the challenges our nation faces in redressing them. Mount Sinaisrelationship with its Harlem and Upper East Side neighbors is a long-standing one as seen by itscommunity action boards emphasis on URM training opportunities and diverse workforce. TCI alsoconducts research on diseases relevant to the catchment area as well community-engagingresearch that focuses on varying strategies to increase screening among minority populations andresidents of public housing improving treatment and reducing disparities. +No NIH Category available Acceleration;Address;Area;Award;Basic Science;Biochemical;Biological Markers;Biological Models;Biology;Cancer Center Support Grant;Cancer Control;Catchment Area;Cells;Chromatin;Clinical;Clinical Paths;Clinical Trials;Collaborations;Communities;Development;Diagnosis;Direct Costs;Disease;Drosophila genus;Epigenetic Process;Focus Groups;Fostering;Funding;Gene Expression Regulation;Genetic;Genetic Transcription;Goals;Grant;Growth;Hospitals;Incidence;Indolent;International;Knowledge;Lead;Liquid substance;Maintenance;Malignant Neoplasms;Malignant neoplasm of liver;Modeling;Modification;NCI-Designated Cancer Center;Neoplasm Metastasis;Organoids;Output;Paper;Pathway interactions;Patient-Focused Outcomes;Peer Review;Phase;Population;Positioning Attribute;Primary Cancer Prevention;Primary Neoplasm;Principal Investigator;Publications;Publishing;Recurrence;Recurrent Malignant Neoplasm;Research;Research Personnel;Residual Neoplasm;Resistance;Science;Signal Transduction;Solid Neoplasm;Strategic Planning;Therapeutic Intervention;Training and Education;Translating;Universities;Vision;Work;cancer cell;cancer initiation;cancer prevention;cancer recurrence;cancer type;clinical investigation;clinical translation;improved;industry partner;meetings;member;mortality;mouse model;neoplastic cell;new therapeutic target;novel marker;novel therapeutic intervention;personalized medicine;premalignant;programs;success;targeted treatment;therapeutic biomarker;therapeutic target;training opportunity;translational impact;translational potential;tumor immunology;tumor initiation;tumor microenvironment;tumor progression;working group Cancer Mechanisms n/a NCI 10674513 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8868 7852195 "AGUIRRE-GHISO, JULIO A." Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 25074 14793 10281 PROJECT SUMMARY/ABSTRACTThe Cancer Mechanisms (CM) Program of The Tisch Cancer Institute (TCI) is comprised of 49 members whoshare a common goal to catalyze basic research pertinent to cancer-relevant mechanistic discovery with theultimate goal of generating new knowledge that will lead to improving the diagnosis treatment and preventionof primary cancer and systemic cancer recurrence in our unique catchment area across three key themes: 1.CELL AND NICHE BIOLOGY 2. CELL SIGNALING NETWORKS and 3. CHROMATIN AND GENEREGULATION (see Figure 1 in the Research Strategy).Principal investigators in CM represent 15 Departments and 10 Institutes. As of February 2019 CM programmembers were awarded over $17 million in direct cost funding with NCI support of $4.7 million and peer-reviewed cancer-related support of $13.7 million. In 2018 the program published 82 papers of which 22% wereintra- and 17% were inter-programmatic.Our premise is that basic research focused on genetic epigenetic biochemical micro-environmental anddevelopmental pathways that drive primary cancer initiation and maintenance minimal residual diseasedormancy and overt metastasis will reveal novel biomarkers and therapeutic targets to address each of thesestages across both liquid and solid tumors. We aim to elucidate critical mechanisms across the three CMthemes and foster intra- and inter-program collaborations in order to accelerate the transfer of discoveries intotranslational and clinical efforts. We will achieve this goal using orchestrated intra-programmatic efforts withinCM themes (e.g. working groups monthly meetings) and inter-programmatic collaborations with otherprograms such as Cancer Clinical Investigation (CCI) Cancer Prevention and Control (CPC) and CancerImmunology (CI) or with disease focus groups such as Liver Cancer. In particular our new strategic planallows CM investigators upon identifying targets biomarkers or molecules for therapeutic intervention to workclosely with the newly created CCI program which facilitates an accelerated translational or clinical path.Finally our strategic plan will facilitate new collaborative research training and education opportunities withinour program and in our community (via efforts with CPC) high-impact publications MPI/P01 submissionsclinical trials and translational output through partnership with CCI and other team efforts that encompassCM's exceptional science. +No NIH Category available Animal Model;Award;Biological Models;CRISPR screen;Cancer Center Support Grant;Cancer Patient;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Dendritic Cells;Development;Direct Costs;Doctor of Philosophy;Elements;Equilibrium;Functional disorder;Funding;Genomics;Goals;Human;Immune;Immune System Diseases;Immune Targeting;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Markers;Immunology;Immunotherapeutic agent;Immunotherapy;Innate Immune System;Intrinsic factor;Leadership;Lesion;Macrophage;Malignant Neoplasms;Mediating;Modeling;Molecular;Myeloid-derived suppressor cells;Natural Killer Cells;Paper;Pathway interactions;Patients;Peer Review;Population;Pre-Clinical Model;Publishing;Refractory;Research Personnel;Resistance;Risk;Role;Sampling;Stromal Cells;T cell therapy;T-Lymphocyte;Technology;Testing;Translating;Work;anti-CTLA4;anti-PD-1;anti-PD-L1;cancer care;cancer cell;cancer therapy;chimeric antigen receptor T cells;clinical application;clinical investigation;design;human disease;improved;in silico;innate immune function;innovation;medical schools;member;novel;pre-clinical;programs;recruit;response;response biomarker;single cell sequencing;treatment response;tumor;tumor growth;tumor immunology;tumor microenvironment;tumor progression Cancer Immunology n/a NCI 10674510 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8866 1864115 "BHARDWAJ, NINA " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 26344 15542 10802 PROJECT SUMMARY/ABSTRACT CANCER IMMUNOLOGY (CI) PROGRAMThe Cancer Immunology (CI) Program of The Tisch Cancer Institute (TCI) is comprised of 30 members whoshare a common goal to investigate the premise that immune-mediated dysregulation adversely impacts theTME. They represent 15 Departments and 7 Institutes. As of February 2019 CI program members wereawarded $8.8 million in direct cost funding with NCI support of $2.5 million and peer-reviewed cancer relatedsupport of $5 million. In 2018 the program published 72 papers of which 30% were intra- and 18% were inter-programmatic.The major scientific themes of the CI program are to investigate: 1. Immune dysregulation in the TumorMicroenvironment (TME); 2. Develop models to reverse immune dysfunction and restore immune balance; and3. Validate correlates of response in cancer patients receiving immunotherapy. Cancer progression ischaracterized by gradual dysregulation of the immune system at multiple levels that directly contributes tounchecked tumor growth. While the role of T cell dysfunction is well acknowledged evidence is accumulatingthat the innate immune system is analogously hijacked to enable tumor growth. In this regard CI Programmembers are focused on identifying new mechanisms whereby the tumor microenvironment (TME) impacts thefunction of innate immune cells including macrophages dendritic cells and NK cells in addition to tumor-reactiveT cells.Accordingly the CI program has three main scientific goals. The first is to identify genomic molecular andcellular pathways underlying immune dysfunction in the TME. CI members use preclinical model systemsCRISPR screens and human tumor lesions to identify novel mechanisms/targets underlying immunedysregulation and prioritize targets of immunotherapy resistance/response ultimately tested in novel clinicaltrials. Second CI members strive to develop scientifically based strategies that will improve and/or expandcurrent immunotherapeutic platforms and identify immune biomarkers of risk and response to treatment. Theoverarching goal is to progress discoveries that are made into innovative clinical trials to test and validateproposed correlates of resistance and response. A third goal is to develop novel clinically applicable immunetargets to effectively control or eradicate cancers. CI members work in partnership and inter-programmaticallyto validate correlates of resistance to immunotherapy. +No NIH Category available Alleles;Attenuated;BRAF gene;Biochemical;CDX2 gene;Cancer Etiology;Cell physiology;Cells;Clinical;Common Neoplasm;Complex;Data;Development;Drug Targeting;Endogenous Retroviruses;Enzymes;Epidermal Growth Factor Receptor;Epigenetic Process;Extracellular Matrix;Family;Gene Silencing;Genes;Genetically Engineered Mouse;Goals;Heterochromatin;Histones;Human;In Vitro;Invaded;KRAS oncogenesis;KRAS2 gene;KRASG12D;Link;Lung;Lung Adenocarcinoma;Lysine;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methylation;Methyltransferase;Modeling;Modification;Molecular;Monoubiquitination;Mus;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenic;Pathway interactions;Patients;Phenotype;Play;Process;Prognosis;Proteins;Proteomics;Refractory;Regulation;Repression;Role;SETDB1 gene;Signal Transduction;System;Therapeutic;Transcriptional Activation;Tumor Suppressor Genes;Ubiquitination;Up-Regulation;Xenograft Model;biomarker development;biomarker driven;cell motility;cohort;driver mutation;gain of function;gene repression;genetic signature;histone modification;human disease;in vivo;innovation;insight;loss of function;lung cancer cell;migration;molecular targeted therapies;mortality;mouse model;mutant;neoplastic cell;novel;novel therapeutics;restraint;subcutaneous;targeted treatment;therapeutically effective;transcription factor;transcriptional reprogramming;tumor;tumor growth;tumor progression Dissecting the Mechanism of SETDB1 and its K867 Monoubiquitination in Lung Cancer Progression NARRATIVENon-small cell lung cancer is one of the most common neoplasms worldwide and associates with poor survivaland high mutation rate. Despite the significant advances in the development of molecularly targeted therapy inlast decade tumors with the most prevalent KRAS mutations remain refractory to targeted therapy. Based oncompelling preliminary data we will dissect the functional roles of SETDB1 a major H3K9 methyltransferase inregulating malignant progression of KRAS mutant non-small cell lung cancer determine the importance of itsmonoubiquitination and catalytic activity and elucidate the underlying mechanisms. This innovative project willnot only decipher epigenetic mechanisms contribute to oncogenic KRAS-induced transcription reprogrammingin lung cancer progression but also highlight novel therapeutic opportunities for targeting. NCI 10674509 7/20/23 0:00 PA-20-185 5R01CA273231-02 5 R01 CA 273231 2 "AULT, GRACE S" 8/5/22 0:00 7/31/27 0:00 Cancer Molecular Pathobiology Study Section[CAMP] 9760657 "FANG, JIA " Not Applicable 26 Unavailable 824771034 YDWAYVVQHNK5 824771034 YDWAYVVQHNK5 US 42.873378 -78.869243 3934901 ROSWELL PARK CANCER INSTITUTE CORP BUFFALO NY Independent Hospitals 142630001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 396 Non-SBIR/STTR 2023 394014 NCI 227187 166827 Project SummaryDissecting the Mechanism of SETDB1 and its K867 Monoubiquitination in Lung Cancer Progression Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwideand associated with high mutation burdens. During the last decade biomarker-driven targeted therapies haveachieved clear clinical benefits in patients with several oncogenic driver mutations such as EGFR BRAF andALK. However the treatments for tumors with the most prevalent KRAS mutations remain challenging despiteof recent breakthrough in targeting KRAS-G12C mutation. In KRAS mutant NSCLC the constitutively activateddownstream signaling ultimately leads to transcription reprogramming to sustain tumor growth and progression.This process is orchestrated by a cohort of crucial transcription factors whose temporal and spatial expressionis associated with distinct epigenetic changes. Thus dissecting epigenetic mechanisms in this process couldopen new avenues for targeting strategies. SETDB1 is a principal methyltransferase catalyzing histone H3K9methylation a major repressive epigenetic modification. The focal amplification and upregulation of SETDB1have been observed in a wide range of cancers including NSCLC suggesting it has pro-oncogenic function.However the mechanisms of action of SETDB1 in NSCLC remain elusive. In preliminary study we uncoveredthat SETDB1 upregulation in lung adenocarcinoma (ADC) correlates with poorer prognosis and significantlyco-occurs with KRAS gene alternations. In NSCLC cells harboring oncogenic RAS SETDB1 loss attenuatesmigration and invasion invadopodia formation and ECM degradation. These phenotypic changes correlatewith reactivation of transcription factors FOXA2 and CDX2 which function as key regulatory nodes to impedemetastatic progression of KRAS mutant lung ADC. More importantly Setdb1 loss in tumor cells derived frommetastatic KrasG12D;p53fl/fl lung ADC abolished their spontaneous ability to metastasize from the subcutaneoustumor to the lungs. These findings argue for a novel concept that SETDB1-mediated epigenetic mechanismsare critical for oncogenic KRAS-induced transcription reprogramming during lung ADC progression. Moreoverwe have demonstrated that SETDB1 is monoubiquitinated at lysine-867 by the UBE2E family of E2 enzymesindependent of E3s and this monoubiquitination is essential for SETDB1-mediated H3K9 methylation and ERVsilencing. Accordingly one objective of this proposal is to delineate SETDB1's pro-metastatic activity in KRASmutant lung ADC using various genetically engineered mouse models and xenograft models. Another objectiveis to dissect the mechanisms of lysine-867 monoubiquitination in SETDB1's pro-metastatic activity in vivo andin vitro. Our central hypothesis is that SETDB1 plays important roles in KRAS mutant lung ADC progressionthrough epigenetic mechanisms that require its monoubiquitination dependent enzymatic activity. This projectis significant because it will characterize SETDB1 as an actionable drug target in KRAS mutant lung cancerand identify novel molecular interfaces for targeting. Our long-term goal is to develop better and more effectivetherapeutic strategies by delineating epigenetic mechanisms in lung cancer. 394014 +No NIH Category available Applications Grants;Area;Basic Science;Bioinformatics;Biological Assay;Blood;Body Fluids;Bone Marrow;Bone Tissue;Cancer Center Support Grant;Cancer Etiology;Cancer Patient;Cells;Clinical;Clinical Research;Collaborations;Core Facility;DNA;Data;Data Analyses;Data Management Resources;Data Set;Dedications;Development;Disease;Doctor of Philosophy;Ensure;Flow Cytometry;Foundations;Funding;Goals;Human;Immune;Immunogenomics;Immunologic Factors;Immunologic Monitoring;Immunologist;Immunology;Industry;Institution;Laboratories;Language;Link;Malignant Neoplasms;Maps;Methods;Mission;Molecular;Pathway interactions;Patients;Phenotype;Preparation;Procedures;Proteins;Proteomics;Protocols documentation;Publications;RNA;Reagent;Reproducibility;Research;Research Personnel;Resource Sharing;Sampling;Services;Technology;Therapeutic;Tissue Sample;Tissue imaging;Tissues;United States National Institutes of Health;analytical tool;complex data;cost effectiveness;data quality;enzyme linked immunospot assay;high dimensionality;high throughput technology;immunotherapy trials;innovation;insight;instrument;machine learning pipeline;medical schools;member;microbiome;novel marker;programs;response;technology platform;tissue mapping;transcriptomics;translational study Human Immune Monitoring Center n/a NCI 10674506 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8864 9612909 "GNJATIC, SACHA " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 120386 71024 49362 PROJECT SUMMARY/ABSTRACTThe Tisch Cancer Institute (TCI) Human Immune Monitoring Core Shared Resource Facility (HIMCSRF)provides TCI members access to a comprehensive suite of immune monitoring assays allowing for thequantification of circulating proteins and immune cell characterization along with spatial organization intissues to support basic science clinical and translational studies. This is achieved by balancing innovationwith robust protocols and operating procedures to ensure data quality and reproducibility with dedicatedplatforms for biospecimen processing and sample management soluble factor profiling phenotypic andfunctional immune cell characterization immunogenomics single cell transcriptomics and multiplexedtissue imaging. The HIMCSRF is comprised of over twenty full time experts who specialize in characterizingimmune profiles and responses across a diverse range of disease settings. The HIMC currently supports over45 federal and foundation funded projects across a diverse range of clinical areas including cancer and alsoserves as a central analysis hub for several multi-institutional consortia including the NIH Human ImmunologyProject Consortium (HIPC). The HIMCSRF is also an NCI-designated Cancer Immune Monitoring and AnalysisCenter (CIMAC) as part of a U24 consortium funded through the Cancer Moonshot program and also activelysupports 13 industry-sponsored research collaborations. Since its inception in 2011 the HIMCSRF contributedto the TCIs mission by providing state-of-the-art technologies project development consistencyinterpretations and cost-effectiveness to all TCI programs. +No NIH Category available Address;Biometry;Biostatistics Shared Resource;Cancer Center Support Grant;Clinical Investigator;Clinical Research;Consultations;Core Facility;Data;Databases;Development;Doctor of Philosophy;Education;Ensure;Environment;Faculty;Language;Lead;Malignant Neoplasms;Manuscripts;Methodology;Nature;Play;Population Sciences;Preparation;Research;Research Design;Research Personnel;Science;Statistical Data Interpretation;Statistical Methods;Structure;analytical method;anticancer research;cancer type;design;innovation;laboratory experience;medical schools;multidisciplinary;novel;programs;research study;statistical service Biostatistics n/a NCI 10674505 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8863 8567717 "MAZUMDAR, MADHU " Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 281140 165864 115276 PROJECT SUMMARY/ABSTRACTThe Tisch Cancer Institute (TCI) Biostatistics Shared Resource Facility (BSRF) provides statistical services suchas study design for basic population science and clinical studies; statistical analysis (including development oftables and graphics for presentation); interpretation of the findings in language understandable by theinvestigators; and assistance with manuscript preparation and revision. These activities are performedinteractively with the primary investigators with a thorough understanding of science required to provideappropriate statistical input. The BSRF is also very involved in education programs developed for trainees andjunior faculty in cancer research. +No NIH Category available Biological;Calcium;Cancer Center Support Grant;Cell Communication;Cell Count;Cell Lineage;Cells;Characteristics;Collaborations;Computer software;Computers;Consultations;Cultured Cells;Dedications;Development;Doctor of Philosophy;Education;Educational workshop;Electron Microscopy;Engineering;Equipment;Fluorescence;Fluorescence Resonance Energy Transfer;Funding;Grant;Hour;Image;Image Analysis;Imaging Device;Immune;Immunofluorescence Immunologic;International;Invaded;Laboratories;Lead;Light;Malignant Neoplasms;Maps;Methodology;Microscope;Microscopy;Mission;Modality;Neoplasm Metastasis;Organ;Organoids;Paper;Primary Neoplasm;Productivity;Proteins;Protocols documentation;Publications;Publishing;Quantitative Microscopy;Recording of previous events;Research;Research Personnel;Resolution;Resource Sharing;Resources;Role;Science;Scientist;Series;Services;Signal Transduction;Site;Specialist;Speed;System;Techniques;Time;Tissues;Training;Transmission Electron Microscopy;Tumor Cell Migration;Vendor;Work;anticancer research;cell behavior;cell growth;computerized data processing;cost;design;experience;experimental study;gigabyte;graduate school;imaging approach;imaging study;improved;in vivo;in vivo imaging;instrument;instrumentation;intravital imaging;light microscopy;light transmission;live cell imaging;medical schools;medical specialties;member;multi-photon;neoplastic cell;new technology;operation;particle;programs;protein expression;skills;superresolution imaging;superresolution microscopy;training opportunity;tumor diagnostic;ultra high resolution Microscopy n/a NCI 10674503 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8862 1878834 "BENSON, DEANNA L" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 117791 69493 48298 PROJECT SUMMARY/ABSTRACTThe Tisch Cancer Institute (TCI) Microscopy Shared Resource Facility (MSRF) provides TCI members accessto equipment training expert consultation and collaborative opportunities across a full-range of light andelectron microscopy applications including: confocal multiphoton super-resolution in vivo imaging light sheetwidefield and transmission electron microscopy (EM). Three high-end workstations equipped with state-of-the-art software accompanied by a local server and high-speed connectivity permit a wide range of image analysisand quantification strategies. Five full time scientists staff the MSRF during regular hours and provide real-timeassistance to both novice and experienced users. All of the MSRF scientists can be tapped for implementingadvanced approaches. Each holds a PhD or was otherwise trained intensively in a field having particularrelevance to their imaging specialty such as super-resolution microscopy or computer engineering. In particularthe EM specialist is a leader in the field and has published over ninety papers covering everything from correlativelight-EM (CLEM) to traditional EM techniques and the scientific advisor is also a TCI member who is expert inintravital imaging approaches and works collaboratively with novice TCI users needing to apply this strategy tocancer-related questions. The MSRF also sponsors monthly seminars featuring scientists using microscopy orvendors developing relevant new technology and its scientists co-direct an annual hands-on microscopy coursefor graduate school trainees and host workshops throughout the year. The capabilities of the microscopesystems together with the skills and training of the team are crucial for supporting TCI studies that includemultichannel immunofluorescence for tumor diagnostics localization of cell signaling and growth regulatorymolecules tumor cell migration and invasion and cell biological mechanisms of metastasis and dormancy. +No NIH Category available CRISPR/Cas technology;Cancer Center Support Grant;Cancer Model;Cells;Clone Cells;Core Facility;Cryopreservation;DNA;Dedications;Derivation procedure;Doctor of Philosophy;Education;Embryo;Embryology;Gene Targeting;Generations;Genes;Germ Cells;Individual;Injections;Institution;Knock-out;Laboratories;Lead;Maintenance;Malignant Neoplasms;Methods;Modernization;Mus;Price;Production;Recording of previous events;Research Personnel;Resource Sharing;Resources;Rodent;Role;System;Techniques;Transgenic Mice;Transgenic Organisms;anticancer research;embryo cryopreservation;embryonic stem cell;genome editing;in vivo;male;medical schools;member;mouse genetics;mouse model;mutant;mutant mouse model;novel;programs;sperm cell;sperm cryopreservation;zygote Mouse Genetics n/a NCI 10674500 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8861 1926896 "KELLEY, KEVIN A" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 124213 73282 50931 PROJECT SUMMARY/ABSTRACTThe Tisch Cancer Institute (TCI) Mouse Genetics Shared Resource Facility (MGSRF) provides TCI memberswith access to state-of-the-art facilities for the production of transgenic and knockout cancer models in mice aswell as related rodent embryology techniques. The MGSRF produces transgenic mice by injection of DNAfragments into pronuclear stage single-cell mouse embryos and assists laboratories with the production oftargeted mutant lines of mice through the use of mouse embryonic stem (ES) cells or CRISPR/Cas9 gene editing.In addition to the creation of novel mouse lines the MGSRF assists TCI laboratories with the maintenance ofexisting lines through the cryopreservation of sperm and with the import of novel lines from other institutions byrecovering mice from cryopreserved embryos or sperm live embryos or through the use of IVF rederivation ofindividual males that are shipped to ISMMS. This Shared Resource Facility has a long-standing history ofcreating mice for TCI laboratories and the MGSRFs role in the cancer programs will continue to strengthen andenhance the ability of TCI members to conduct cutting-edge cancer research using novel mutant mouse models. +No NIH Category available Adverse event;Affinity;Androgens;Animal Model;Animals;Antibodies;Antibody-drug conjugates;Antigen Targeting;Antigens;Antineoplastic Agents;Binding;Biochemical;Biological Markers;Cancer Etiology;Canis familiaris;Carcinoma;Cell Death;Cessation of life;Chemicals;Chemoresistance;Clinical;Clinical Trials;Collection;Combination Drug Therapy;Combined Modality Therapy;Companions;Complex;Cytotoxic agent;Data;Diagnosis;Disease;Dose;Drug Delivery Systems;Drug Synergism;Drug resistance;Drug toxicity;Effectiveness;Exhibits;FOLH1 gene;Future;Generations;Genetic;Goals;Hematologic Neoplasms;Hormones;Human;Immune response;Immunocompetent;Immunologic Stimulation;Immunologics;Implant;Ligands;Light;Local Therapy;Localized Disease;Location;Malignant Neoplasms;Malignant neoplasm of prostate;Membrane;Methodology;Methods;Microtubules;Modification;Molecular Weight;Movement;Normal Cell;Normal tissue morphology;Operative Surgical Procedures;PUVA Photochemotherapy;Pathology;Pathway interactions;Patients;Peptides;Pharmaceutical Preparations;Photosensitizing Agents;Physiology;Prodrugs;Prostate Cancer therapy;Prostate carcinoma;Radiation therapy;Radical Prostatectomy;Reactive Oxygen Species;Recurrence;Refractory;Relapse;Reporting;Resistance;Risk;Site;Solid Neoplasm;Structure of base of prostate;Systemic Therapy;Technology;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Toxic effect;Toxicology;Trastuzumab;United States;Weight;cancer biomarkers;cancer cell;cancer heterogeneity;cancer therapy;cell killing;chemotherapy;clinical application;clinical efficacy;clinical translation;combat;cost efficient;design;disorder risk;drug clearance;drug development;drug efficacy;efficacy evaluation;efficacy study;efficacy trial;high risk;human model;humanized antibody;improved;irradiation;men;minimally invasive;mouse model;multimodality;novel;novel therapeutic intervention;novel therapeutics;overexpression;phthalocyanine;prevent;prostate cancer model;refractory cancer;response;screening;serum PSA;side effect;small molecule;systemic toxicity;targeted delivery;targeted imaging;targeted treatment;theranostics;translational therapeutics;treatment strategy;tumor;virtual Highly selective targeted theranostics for prostate cancers NarrativeThe proposed methods will develop a PSMA-targeted therapeutic agent that combines chemotherapy andphotodynamic therapy for the treatment of prostate cancer optimize it in small animal models of prostate cancerand then obtain toxicity and efficacy data in a large animal model dogs. Dogs spontaneously develop prostatecancer that closely replicates the disease pathology and progression in humans. The agent is fluorescent as wellas a therapeutic allowing for a theranostic approach in small animals that will decrease the time for moleculeoptimization; future clinical translation of the technology will have the potential to impact prostate cancer therapy. NCI 10674499 8/4/23 0:00 PA-20-185 5R01CA255925-03 5 R01 CA 255925 3 "AGYIN, JOSEPH KOFI" 8/11/21 0:00 7/31/25 0:00 Imaging Probes and Contrast Agents Study Section[IPCA] 8479886 "BASILION, JAMES PETER" "HOLT, DAVID ; WANG, XINNING " 11 RADIATION-DIAGNOSTIC/ONCOLOGY 77758407 HJMKEF7EJW69 77758407 HJMKEF7EJW69 US 41.502739 -81.607334 218601 CASE WESTERN RESERVE UNIVERSITY CLEVELAND OH SCHOOLS OF MEDICINE 441061712 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 395 Non-SBIR/STTR 2023 641402 NCI 466379 175023 Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancerdeath in men in the United States. Although surgery and radiation therapy in patients with low risk disease appearappropriate and effective those with high-risk localized disease almost always become hormone refractory andthen rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostatecancer particularly an approach that considers the use of a multimodal approach and that includes both localand systemic therapies. Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and under certainclinical conditions have changed the natural course of some of these diseases. While effective due to theirintrinsic mode of action they may also cause significant off-target adverse events that could preclude their fullclinical efficacy possibly resulting in early discontinuation of medication and a consequent increased risk oftumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeuticdrugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (alsoknown as Antibody Drug Conjugates ADCs). The durable clinical responses reported with brentuximab vedotin(SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership withImmunoGen) which have recently obtained regulatory approval have profoundly changed the outlook for ADCcancer therapy. These approaches although showing strong potential are extremely expensive and lesscomplex and more cost-efficient methodologies are needed. Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA a biomarkerfor prostate cancer) to target a potent microtubule inhibiting agent MMAE and a photodynamic therapy (PDT)agent IR700 selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approachand simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs withdifferent therapeutic mechanisms to cancer cells improved antitumor activity with less toxicity is expected. Thereduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses) site specificprodrug activation and rapid clearance of the drug molecule preventing off target delivery. This molecule willbe developed using two animal models of prostate cancer heterotopic human prostate cancer in mice andspontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulateimmune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs. Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used indrug development trials. Since efficacy trials in mice are not predictive of human results efficacy studies in dogswill substantially encourage clinical translation of the developed agent. 641402 +No NIH Category available Accreditation;Address;American Society of Clinical Oncology;Area;Award;Cancer Biology;Cancer Burden;Cancer Center Support Grant;Cancer Control;Career Mobility;Caring;Clinical;Clinical Investigator;Clinical Oncology;Clinical and Translational Science Awards;Communities;Dedications;Disease;Disparity;Education;Ethnic Origin;Evaluation;Faculty;Fellowship;Fostering;Funding;Future;Goals;Grant;Health;Health Professional;Home;Individual;Investments;Knowledge;Lead;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of liver;Medical Students;Medicine;Mentors;Methodology;Mission;National Center for Advancing Translational Sciences;Outcome;Physicians;Population;Postbaccalaureate;Race;Recommendation;Research;Research Personnel;Research Training;Resources;Scholars Program;Science;Scientist;Social Work;Students;Training;Training Programs;Translating;Translational Research;Underrepresented Minority;anticancer research;cancer prevention;career;career development;clinical encounter;clinically relevant;design;doctoral student;experience;graduate school;hackathon;high school;improved;innovation;interdisciplinary collaboration;medical schools;multidisciplinary;next generation;novel;post-doctoral training;pre-doctoral;programs;skills;student training;translational cancer research;translational immunology;translational scientist;undergraduate student Cancer Research Career Enhancement and Related Activities n/a NCI 10674495 8/3/23 0:00 PAR-17-095 5P30CA196521-09 5 P30 CA 196521 9 8/1/15 0:00 7/31/25 0:00 Cancer Centers Study Section (A)[NCI-A] 8857 1901145 "GABRILOVE, JANICE L" Not Applicable 13 Unavailable 78861598 C8H9CNG1VBD9 78861598 C8H9CNG1VBD9 US 40.790284 -73.946781 3839801 ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NY Domestic Higher Education 100296574 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 37744 22268 15476 PROJECT SUMMARY/ABSTRACTThe overarching goal of the Tisch Cancer Institutes Cancer Research Career Enhancement and RelatedActivities is to effectively nurture inspire and advance the career development of cancer-focused clinical andtranslational investigators. In particular we aspire to prepare a diverse biomedical and healthcare professionalworkforce armed with the methodological skills analytical acumen & scientific knowledge to successfullyaddress unmet needs of our catchment population. Our career development strategy is in keeping with themission of TCI to advance translational cancer research to improve the lives of the community we serve. TCIsactivities promote multidisciplinary team science and foster future research leaders that are aligned with TCIscientific programs and capitalize upon the rich educational offerings of the Graduate School of BiomedicalSciences (GSBS) and the Icahn School of Medicine at Mount Sinai (ISMMS) and the resources of our NCATS-funded Clinical and Translational Science Award (CTSA). +Aging; Cancer; Clinical Research; Clinical Trials and Supportive Activities; Estrogen; Uterine Cancer; Women's Health Atypical Endometrial Hyperplasias;Atypical hyperplasia;Complex;Contractor;Diagnosis;Endometrial;Endometrial Carcinoma;Endometrial Hyperplasia;Endometrial Intraepithelial Neoplasia;Exemestane;Intraepithelial Neoplasia;Measures;Operative Surgical Procedures;Pilot Projects;Postmenopause;S-Phase Fraction;Tissues;Woman;cancer cell PILOT STUDY OF DAILY EXEMESTANE IN WOMEN WITH COMPLEX ATYPICAL HYPERPLASIA OF THE ENDOMETRIUM/ENDOMETRIAL INTRAEPITHELIAL NEOPLASIA OR GRADE 1 ENDOMETRIAL CANCER n/a NCI 10674471 261201200033I-P00008-26100011-1 N02 9/15/17 0:00 3/31/23 0:00 15213133 "BAILEY, HOWARD " Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N R and D Contracts 2022 296637 NCI The contractor will conduct a pre-surgical pilot study to evaluate the effect of daily exemestane on proliferation of endometrial tissue in post-menopausal women diagnosed with complex atypical hyperplasia/endometrial intraepithelial neoplasia or Grade 1 endometrial cancer. 296637 +Cancer; Clinical Research; Data Science; Pediatric; Pediatric Cancer; Rare Diseases Adolescent and Young Adult;Age;Cancer Burden;Cancer Etiology;Cancer Patient;Cause of Death;Childhood;Clinical Research;Collaborations;Communities;Congresses;Continuity of Patient Care;Contracts;Data;Data Analyses;Data Collection;Data Commons;Databases;Diagnosis;Ecosystem;Ensure;Federal Government;Foundations;Funding;Goals;Grant;Health;Institutes;Institution;Lead;Malignant Childhood Neoplasm;Malignant Neoplasms;Methods;Modeling;National Cancer Institute;Newly Diagnosed;Participant;Recommendation;Registries;Research;Research Personnel;Research Support;Research Training;Resources;SEER Program;Services;Treatment outcome;United States;Visualization;anticancer research;cancer care;clinical care;data ecosystem;data ingestion;data science infrastructure;data sharing;diverse data;improved;infancy;interoperability;prevent;programs;repository;sharing platform;tool ENABLING NCI CLINICAL & RESEARCH DATA SHARING n/a NCI 10674469 75N91019D00024-P00003-759102100013-1 N01 8/31/21 0:00 8/30/23 0:00 78341052 "DMITROVSKY, ETHAN " Not Applicable 6 Unavailable 159990456 HV8BH9BPG8Y9 159990456 HV8BH9BPG8Y9 US 39.4944 -77.45352 10008928 "LEIDOS BIOMEDICAL RESEARCH, INC." FREDERICK MD Domestic For-Profits 217029242 UNITED STATES N R and D Contracts 2022 15219907 NCI The National Cancer Institute (NCI) is the Federal governments principal agency supporting cancer research. The Institute conducts research in its own facilities directs research executed under contracts and provides grant support for research and training in non-Federal institutions in the United States and abroad. One of the overarching goals of the NCI is to enhance and enable data sharing for NCI programs. CBIIT seeks to achieve this in many ways including creating a foundational platform for sharing data (Cancer Research Data Commons - CRDC) and creating new models for community-wide research using the collaborative efforts of childhood cancer community as a model.Childhood cancers are rare but are the leading cause of death past infancy. They make up approximately 1% of all newly diagnosed cancers and causes of most childhood cancers are not known. Adolescent and young adult (defined by NCI as between ages 15 and 39) cancers constitute 5% of all cancers according to the NCI Surveillance Epidemiology and End Results (SEER) program. In December 2019 Congress approved funding for the Childhood Cancer Data Initiative (CCDI). CCDI is aimed at improving treatment and outcomes for childhood cancer patients by accelerating data collection analysis and sharing. Currently data for pediatric cancer are often fragmented and stored in many separate databases and it can be difficult for researchers and clinicians to get access. It is necessary to build a pediatric data ecosystem to maximize access use and interoperability of childhood cancer data and improve our ability to prevent diagnose and treat childhood cancer patients. 15219907 +No NIH Category available Address;Adipose tissue;Adverse effects;Adverse event;Affect;Age;BCG Live;Bacillus Calmette-Guerin Therapy;Biological Markers;Body Composition;Body mass index;Cancer Patient;Cancer Prognosis;Cancer Survivor;Chronic;Clinical;Clinical Data;Data;Diagnosis;Diet;Disease;Disease Outcome;Environment;Failure;Fatty acid glycerol esters;Genetic;Immune;Immune response;Immunity;Immunologic Markers;Immunosuppression;Immunotherapy;Infiltration;Inflammation;Inflammatory;Intravesical Administration;Investigation;Life Style;Link;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Managed Care;Measures;Mediating;Modeling;Muscle;Newly Diagnosed;Obesity;Outcome;Patients;Performance;Phenotype;Physical activity;Prognosis;Prognostic Factor;Prognostic Marker;Prospective Studies;Prospective cohort;Prospective cohort study;Recurrence;Recurrent Malignant Neoplasm;Recurrent disease;Research;Risk;Role;Scanning;Sex Differences;Shapes;Skeletal Muscle;Smoking;System;Testing;Time;Treatment Failure;Treatment outcome;Visceral;X-Ray Computed Tomography;age related;age-related muscle loss;cancer diagnosis;cancer epidemiology;cancer recurrence;clinical care;disease prognosis;effective therapy;experience;follow-up;high risk;improved;individualized medicine;intravesical;lifestyle factors;mortality;muscle form;muscle invasive bladder cancer;non-muscle invasive bladder cancer;older patient;participant enrollment;patient stratification;prevent;prognostic;progression risk;risk stratification;sarcopenia;sarcopenic obesity;sex;skeletal muscle wasting;subcutaneous;success;survivorship;treatment planning;treatment response;tumor;tumor progression Impact of Body Composition and Related Inflammatory and Immune States on Prognosis of Non-Muscle Invasive Bladder Cancer Project NarrativeBladder cancer is one of the top ten most common cancers in the U.S. with 75% diagnosed with non-muscleinvasive disease (NMIBC) and up to 70% of which experience recurrence making it one of the most expensivecancers to treat per patient. Body composition which is the amount of fat and muscle tissue affects theinflammatory and immune environments and thus can possibly influence treatment response and diseaseprognosis in NMIBC patients. In a prospective study of 1472 NMIBC patients we will conduct acomprehensive study of body composition inflammation and immunity to evaluate their impact on treatmentand prognosis outcomes over eight years of follow-up. NCI 10674401 6/14/23 0:00 PAR-22-162 1U01CA280991-01 1 U01 CA 280991 1 "FILIPSKI, KELLY" 6/14/23 0:00 5/31/28 0:00 ZCA1-TCRB-9(J2) 8801406 "KWAN, MARILYN L" "TANG, LI " 12 Unavailable 150829349 P1RTMASB37B5 150829349 P1RTMASB37B5 US 37.805769 -122.265214 3497005 KAISER FOUNDATION RESEARCH INSTITUTE Oakland CA Research Institutes 946123610 UNITED STATES N 6/14/23 0:00 5/31/24 0:00 393 Non-SBIR/STTR 2023 881405 NCI 738025 143380 AbstractBladder cancer is one of the top ten most common cancers in the U.S. and one of the most expensive to treat.Most cases (75%) are non-muscle-invasive bladder cancer (NMIBC) with high rates of recurrence (70%) andprogression (25%). While prognostic factors remain largely unknown the success of Bacillus Calmette-Guerin(BCG) an intravesical immunotherapy as the most effective therapy for NMIBC for over four decadeshighlights the potential of the inflammatory and immune environments in determining treatment response andprognosis. Given the median age of bladder cancer diagnosis is 73 years patients are commonly faced withage-related loss of muscle mass (sarcopenia) increase of fat accumulation (obesity) or both (sarcopenicobesity) which are all characterized by chronic inflammation and altered immune responses. These bodycomposition phenotypes are associated with tumor progression and increased mortality. Thus we hypothesizethat body composition at diagnosis may shape the host inflammatory and immune milieu and impact bladdercancer prognosis. This hypothesis will be tested in the Bladder Cancer Epidemiology Wellness and LifestyleStudy (Be-Well; R01 CA172855 MPI: Kwan/Tang/Kushi) of newly diagnosed NMIBC patients from 2015-2019at Kaiser Permanente one of the largest prospective cohort studies of NMIBC with 1472 patients enrolledwith rich patient clinical and biospecimen data to examine genetic and lifestyle factors in prognosis andsurvival. We propose to conduct a full investigation of body composition inflammation and immunityin bladder cancer outcomes in Be-Well to determine how adiposity muscle and inflammatory andimmune biomarkers at diagnosis can identify NMIBC patients at high risk for treatment failure and/ordisease recurrence and progression. Our aims are: 1) to determine the association of computedtomography (CT)-derived body composition phenotypes (sarcopenia adiposity myosteatosis) with NMIBCrecurrence (first and multiple) and progression; 2) to determine the association of body composition with BCGimmunotherapy outcomes including adverse events and treatment failure; 3) to examine the association ofcirculating inflammatory and immune biomarkers with body composition and BCG outcomes and NMIBCprognosis; 4) explore if the addition of body composition measures and inflammatory and immune biomarkersimproves the performance of current risk stratification models for NMIBC patients. Given the common clinicaluse of CT body composition measures could be readily incorporated into the current clinicopathological factor-based risk stratification system to improve the clinical care of NMIBC. 881405 +Bioengineering; Biomedical Imaging; Cancer; Clinical Research; Digestive Diseases; Health Disparities; Liver Cancer; Liver Disease; Minority Health; Patient Safety; Radiation Oncology; Rare Diseases Adoption;Algorithms;Anatomy;Breathing;Caliber;Cancer Etiology;Cessation of life;Clinical;Clinical Trials;Contrast Media;Data;Development;Dictionary;Dose;Effectiveness;Elements;Ensure;Goals;Hepatic;Image;Implant;Incidence;Inferior;Injections;Intravenous;Iodine;Liver;Liver Dysfunction;Liver diseases;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of liver;Methods;Morphologic artifacts;Motion;Nature;Normal tissue morphology;Patients;Positioning Attribute;Procedures;Radiation;Radiation therapy;Scanning;System;Systems Development;Techniques;Testing;Toxic effect;Training;Tumor Volume;Uncertainty;Unresectable;Validation;X-Ray Computed Tomography;base;clinically significant;clinically translatable;cone-beam computed tomography;contrast enhanced;cost;experience;image guided;image reconstruction;imaging approach;imaging capabilities;imaging study;imaging system;improved;innovation;mortality;novel;patient population;patient safety;reconstruction;respiratory;safety and feasibility;safety testing;simulation;spectrograph;standard care;success;treatment planning;tumor Precise image guidance for liver cancer stereotactic body radiotherapy using element-resolved motion-compensated cone beam CT Project NarrativeStereotactic body radiotherapy (SBRT) has been established as an effective safe and feasible first-line optionin the local control of unresectable hepatic malignancies. A large margin of ~1cm has to be used in currentliver SBRT to accommodate tumor positioning uncertainty under cone-beam CT (CBCT) image guidance. Thisstudy will develop a novel element resolved motion compensated CBCT system to image low-dose iodinecontrast agent. Successful completion of this study will lead to a safe clinically feasible and accurate imageguidance approach that substantially reduces the tumor positioning uncertainty therefore reducing margin sizeand normal tissue toxicity.!! NCI 10674275 9/13/22 0:00 PA-21-268 7R01CA227289-06 7 R01 CA 227289 6 "AVULA, LEELA RANI" 3/15/18 0:00 2/29/24 0:00 Biomedical Imaging Technology B Study Section[BMIT-B] 10291013 "JIA, XUN " Not Applicable 7 RADIATION-DIAGNOSTIC/ONCOLOGY 1910777 FTMTDMBR29C7 1910777 FTMTDMBR29C7 US 39.325256 -76.605131 4134401 JOHNS HOPKINS UNIVERSITY BALTIMORE MD SCHOOLS OF MEDICINE 212182680 UNITED STATES N 9/1/22 0:00 2/29/24 0:00 394 Non-SBIR/STTR 2022 347188 NCI 232721 114467 Project Summary Liver cancers both primary and metastatic are increasing in incidence and are associated with significantmortality. Stereotactic Body Radiotherapy (SBRT) has been established as an effective safe and feasible first-line option in the local control of unresectable hepatic malignancies. Nonetheless a large margin (typically~1cm) has to be used in current liver SBRT to accommodate tumor positioning uncertainty under cone-beamCT (CBCT) image guidance. Because of respiratory motion and vanishing tumor contrast the tumor targetcannot be visualized in CBCT. Inferior tumor positioning approach based on anatomical or implantedsurrogates are clinical standard leading to substantial tumor position uncertainty and a typical margin size of~1cm. Consequently high dose to a large volume of normal tissue is delivered causing a toxicity concernespecially in patients with liver dysfunction caused by cancer and/or treatments is more substantial. In additionnormal tissue toxicity limits further dose escalation to improve clinical benefits. This issue is expected tobecome more severe when extending SBRT to a wider patient population e.g. those with a large tumor size.Several emerging imaging approaches have showed potential to improve image guidance accuracy but alsoencountered challenges. To date there is no approach that can provide accurate reliable and clinicallytranslatable image guidance for liver SBRT. Recently our group has made a breakthrough towardsreconstructing elemental composition image using a standard CBCT platform. Employing a kVp-switchingtechnique a novel image reconstruction method with spatial and spectral image regularization as well as asparse-dictionary based element decomposition method we achieved ~3% accuracy in elemental compositionas tested in phantom studies. We have also accumulated extensive experience in reconstructing high-qualityCBCT images under respiratory motion. Armed with these successes the overall goal of this study is todevelop a novel element-resolved and motion-compensated (ERMC-) CBCT to image iodine contrast agentusing only 20% contrast injection in a standard treatment planning CT scan for precise (uncertainty <2mm)image guidance in liver SBRT. We will pursue three specific aims (SAs): SA1. Develop the overall ERMC-CBCT system. SA2. Optimize scan parameters via phantom studies. SA3. Perform studies in 10 patient casesto test safety feasibility and tumor positioning accuracy of ERMC-CBCT based image guidance. Theinnovation of this project is a novel ERMC-CBCT system and its application for a clinically significant problemof tumor localization in liver SBRT. Besides the significance of substantially improved localization accuracy andtherefore clinical potential of normal tissue sparing and dose escalation our project also holds the significanceof utilizing CBCT to its maximal potential for many other advanced image guidance tasks and quantitativeapplications. The ERMC-CBCT system is developed on a conventional CBCT platform the most widelyavailable image-guidance platform in radiotherapy ensuring its translatability. 347188 +Cancer; Cancer Genomics; Digestive Diseases; Esophageal Cancer; Genetics; Human Genome; Prevention; Rare Diseases 3-Dimensional;Advanced Development;Area;Barrett Esophagus;Biological;Biological Assay;Biology;Chest;Chromatin;Collaborations;Coupled;Custom;DNA Sequence Alteration;Data;Data Set;Detection;Development;Disease;Embryo;Enhancers;Esophageal Adenocarcinoma;Esophagogastric Junction;Esophagus;Etiology;Expression Profiling;FOXF1 gene;FOXP1 gene;Future;GATA4 gene;Genes;Genetic;Genetic Research;Genetic Risk;Genetic Transcription;Genetic Variation;Genome Scan;Genotype-Tissue Expression Project;Goals;HNF4A gene;Heritability;Human;Inherited;International;Intervention;Laboratories;Lasso;Light;Link;MADH4 gene;Malignant Neoplasms;Maps;Methods;Molecular;Molecular Target;Mutation;Network-based;Pathway interactions;Positioning Attribute;Predisposition;Prevention strategy;Preventive;Primitive foregut structure;Public Health;Recurrence;Regulatory Element;Research;Resources;Risk;Role;Sample Size;Signal Transduction;Source;Statistical Methods;Susceptibility Gene;Testing;The Cancer Genome Atlas;Therapeutic;Therapeutic Intervention;Tissue Sample;Tissues;Validation;Variant;Weight;Work;base;cancer genome;cost effective;disorder risk;genetic architecture;genetic association;genome sequencing;genome wide association study;genome-wide;interest;mortality;multidisciplinary;novel;preventive intervention;promoter;public health relevance;rare cancer;risk variant;sex;therapeutic target;transcription factor;transcription regulatory network;transcriptome;transcriptome sequencing;tumor;validation studies Leveraging tissue-specific regulatory maps and network-assisted analysis to identify novel genetic risk loci for esophageal adenocarcinoma PROJECT NARRATIVE (PUBLIC HEALTH RELEVANCE)Esophageal adenocarcinoma (EAC) is a highly lethal cancer that represents a significant public health burdenin the U.S. In this proposal we capitalize on the availability of large-scale existing datasets derived frominternational collaborations and publicly-sponsored research initiatives and perform new analyses to expandour understanding of how inherited genetics influences susceptibility to EAC and its precursor Barrettsesophagus (BE). Findings from this study will help elucidate key molecular pathways underlying this cancerand ultimately help advance the development of better strategies for prevention and treatment. NCI 10674212 9/13/22 0:00 PA-21-268 7R03CA262845-02 7 R03 CA 262845 2 "DIVI, RAO L" 3/3/22 0:00 2/29/24 0:00 ZCA1-PCRB-9(J1) 8826333 "BUAS, MATTHEW FRANK" "YAN, LI " 12 Unavailable 64931884 KUKXRCZ6NZC2 64931884 KUKXRCZ6NZC2 US 40.764045 -73.956024 5079202 SLOAN-KETTERING INST CAN RESEARCH NEW YORK NY Research Institutes 100656007 UNITED STATES N 9/14/22 0:00 2/28/23 0:00 393 Non-SBIR/STTR 2022 61619 NCI 34813 26806 PROJECT SUMMARY / ABSTRACTEsophageal adenocarcinoma (EAC) is a rare yet lethal cancer with median survival <1 year. Genome-wideassociation studies (GWAS) have estimated a substantial heritable component of risk (25-35%) for EAC and itsprecursor Barretts esophagus (BE). Nearly 20 novel genetic risk loci have been discovered but mostheritability remains unexplained. Missing heritability hinders the power of GWAS to illuminate molecularpathways underlying disease risk and identify novel targets for intervention. In this proposal we seek toovercome inherent limits on sample sizes for BE/EAC and identify novel susceptibility loci by integratingadvanced network-based methods and tissue-specific regulome resources into a biologically-motivateddiscovery framework. Several lines of evidence implicate transcriptional regulatory networks in BE/EAC biologyand motivate use of network-based approaches to probe undiscovered genetic underpinnings of this cancer.These findings include reactivation of key embryonic transcriptional regulators in BE/EAC tissues; somaticgenomic alterations in transcription factor (TF) genes in EAC tumors; and genome-wide-significant GWASsignals in close proximity to genes encoding esophageal/foregut TFs. Building on these observations and theprevailing view that disease-linked genetic variation functionally converges on a limited set of core biologicalpathways we hypothesize that genetic signals embedded in developmental transcriptional networks representan important source of missing heritability for BE/EAC. Using customized disease-relevant reference networksoverlaid with GWAS-derived node weights we will screen for gene-level and enhancer/promoter-level geneticassociations missed by prior genome-wide scans. Our multi-disciplinary MPI team draws on a strong trackrecord in BE/EAC genetics leveraging access to the largest available GWAS datasets and extensive omicsdata from GTEx RoadMap/ENCODE and promoter-capture HiC. In Aim 1 we will identify co-expressed genesenriched in risk-associated genetic variation using transcriptional regulatory networks derived from RNA-seqprofiles. Co-expression networks assembled via mutual information and graphical lasso methods applied totranscriptomes of 330 gastro-esophageal junction tissues will be populated with weights from gene-levelGWAS tests and analyzed using Hierarchical Hotnet (HHN). In Aim 2 we will identify linked promoters andenhancers with concentrated GWAS signal using regulatory maps from 3D chromatin interaction profiles.Enhancer-target reference networks built using promoter-capture-HiC data in normal esophagus will be loadedwith weights from custom SNP-set-based tests and evaluated via HHN. Our proposed research will helpelucidate the genetic architecture of EAC and its only known precursor (BE). Candidate risk genes andenhancers/promoters will be advanced to functional validation studies currently underway for known locithrough an ongoing collaboration with the goal of defining new preventive/therapeutic targets for BE/EAC. 61619 +No NIH Category available Aftercare;Antibodies;Archives;Biological Assay;Biological Markers;Blood;Blood Volume;Blood specimen;Cancer Detection;Cancer Patient;Clinical;Cohort Studies;Colorectal;Communities;Custom;DNA;Data;Detection;Development;Diagnosis;Diagnostic;Early Diagnosis;Genotype;HPV oropharyngeal cancer;Head and Neck Cancer;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papillomavirus 16;Incidence;Individual;Joints;Kinetics;Logistic Regressions;Lung;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of nasopharynx;Methods;Monitor;Monitoring for Recurrence;Morbidity - disease rate;National Cancer Institute;National Institute of Dental and Craniofacial Research;Nested Case-Control Study;Ovarian;Patients;Plasma;Prospective cohort;Prospective cohort study;Prostate;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Recurrence;Recurrent Malignant Neoplasm;Research;Risk;Sampling;Screening for cancer;Specificity;Testing;Time;Tumor Burden;United States;Virus;Woman;Work;biological specimen archives;cancer cell;cancer diagnosis;cancer recurrence;cohort;comparison control;detection assay;diagnostic biomarker;digital;early detection biomarkers;experience;high risk;innovation;interest;liquid biopsy;malignant oropharynx neoplasm;men;middle age;novel;response;screening;seroconversion;seropositive;tool;tumor;validation studies;viral DNA;viral detection;virtual Circulating HPV DNA as a Prediagnostic Marker of Oropharyngeal Cancer PROJECT NARRATIVEHuman papillomavirus-driven oropharyngeal cancer (HPV-OPC) a type of head and neck cancer is rapidly increasing inincidence and has surpassed cervical cancer as the most common HPV-associated malignancy in the United States;however unlike cervical cancer there are no methods for early detection of HPV-OPC. The proposed research will studyif circulating tumor HPV DNA is detectable in the blood before patients are diagnosed with HPV-OPC using a customliquid biopsy developed by our team. This research may lead to new methods for early detection of HPV-OPC. NCI 10674048 8/16/23 0:00 PA-20-195 5R21CA267152-02 5 R21 CA 267152 2 "WANG, WENDY" 7/29/22 0:00 6/30/24 0:00 "Cancer, Heart, and Sleep Epidemiology A Study Section[CHSA]" 14510566 "KUHS, KRYSTLE A." "FADEN, DANIEL " 6 PUBLIC HEALTH & PREV MEDICINE 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF PUBLIC HEALTH 405260001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 394 Non-SBIR/STTR 2023 147289 NCI 124730 22559 PROJECT SUMMARYThe incidence of HPV-driven oropharyngeal cancer (HPV-OPC) a type of head and neck cancer is rapidly increasing inthe United States (US). HPV-OPC recently surpassed cervical cancer as the most common HPV-associated malignancy.Unlike cervical cancer there are no methods of early detection for HPV-OPC. HPV16 E6 antibody positivity has beenidentified as a promising early biomarker of HPV-OPC. Previous work from our group showed that HPV16 E6 antibodiesare present in up to 90% of HPV-OPC patients and appear more than 10 years prior to diagnosis. However given thelong lag time between HPV16 E6 seroconversion and cancer diagnosis HPV16 E6 seropositive individuals may need to befollowed for a decade or more before the cancer is clinically diagnosable. Thus early detection biomarkers that indicatethe presence or absence of tumor are needed before considering HPV16 E6 antibody testing for clinical use. Circulatingtumor (ct)HPV DNA detection is a promising marker for detection of HPV-OPC. Work from our group has demonstratedthat ctHPVDNA is 98.4% sensitive and 98.6% specific for HPV-OPC at the time of diagnosis. Prior studies of ctHPVDNAhave focused on the utility of ctHPVDNA for diagnosing HPV-OPC and monitoring for recurrence post-treatment. Todate the potential of ctHPVDNA for early detection of HPV-OPC has not been explored. A major barrier to evaluatingctHPVDNA in a pre-diagnostic setting is that assays developed to date require a high volume of blood (>1ml) which hasprecluded nested studies in prospective cohorts given that blood samples collected prior to HPV-OPC diagnosis arelimited and precious. Leveraging our experience in ctDNA we have re-optimized our droplet digital PCR (ddPCR) basedassay for detecting ctHPVDNA in small volumes of archived specimen. The objective of this study is to conduct the firstlarge study to evaluate the kinetics of ctHPVDNA prior to diagnosis and to compare this biomarker to HPV16 E6seropositivity. A nested case-control study will be conducted within the Prostate Lung Colorectal and Ovarian (PLCO)Cancer Screening Trial a prospective cohort study of 154935 middle aged men and women from across the US. Pre-diagnostic blood samples from 81 OPC cases and 162 matched controls (1:2 ratio) will be tested for ctHPVDNA. All serialsamples from ctHPVDNA positive cases will also be tested to evaluate kinetics of the marker leading up to diagnosis. Wehypothesize that ctHPVDNA will be detectable prior to cancer diagnosis and that ctHPVDNA will be more sensitive thanHPV16 E6 seropositivity. This proposal is innovative given the use of a novel ctHPVDNA assay specifically optimized forsmall volumes of archived specimen which will allow us to conduct the first study to evaluate ctHPVDNA in a pre-diagnostic setting. This research may lead to better methods for early detection of HPV-OPC and directly responds to thejoint Notice of Special Interest issued by the National Cancer Institute (NCI) and National Institute for Dental andCraniofacial Research (NIDCR): Advancing Head and Neck Cancer Early Detection Research (AHEAD); NOT-CA-20-031. 147289 +No NIH Category available 3-Dimensional;AML1-ETO fusion protein;Acute Myelocytic Leukemia;Address;Age;Apoptosis;Binding;Biological Assay;Bone Marrow;Cell Communication;Cell Surface Proteins;Cell Transplantation;Cell surface;Clinical;Colony-Forming Units Assay;Colony-forming units;Complete Blood Count;Data;Databases;Development;Diagnosis;Dipeptidyl Peptidases;Disease;Engraftment;Exhibits;Extracellular Fluid;Feedback;Gene Expression;Goals;Growth;Hematologic Neoplasms;Human;In Vitro;Investigation;Knock-out;MLL-AF9;Malignant Neoplasms;Mediating;Medicine;Membrane Proteins;Methods;Molecular;Mus;Myelosuppression;NF-kappa B;Non-Insulin-Dependent Diabetes Mellitus;Patients;Peripheral;Persons;Play;Proteins;Regulation;Research;Role;Serum;Signal Transduction;Stromal Cells;Survival Rate;Testing;Treatment Protocols;Tumor Burden;United States;Xenograft Model;Xenograft procedure;acute myeloid leukemia cell;cancer stem cell;cancer therapy;cell growth;chemotherapy;comorbidity;cytokine;high resolution imaging;imaging study;improved;improved outcome;in silico;in vivo;inhibitor;knock-down;leukemia;leukemia treatment;leukemic stem cell;migration;mortality;mouse model;novel;novel strategies;p65;prevent;progenitor;restoration;restraint;self-renewal;small hairpin RNA;src-Family Kinases;standard care;therapy development;trafficking;transcriptome sequencing Membrane protein target for leukemia therapy Project NarrativeAcute myeloid leukemia (AML) is an aggressive hematologic malignancy with no major progress in therapy inthe past 20 years. The lack of specific targets and an understanding of the molecular and cellular mechanismsof AML stem cells (AML-SC) restrict the development of treatments to improve the outcome. The proposedstudies aim to identify the utility of DPP4 inhibitors (a useful type two diabetes medicine) in human AMLtreatment and to understand the role of DPP4 in the regulation of AML development. NCI 10674030 7/7/23 0:00 PA-19-056 5R37CA241603-04 5 R37 CA 241603 4 "KLAUZINSKA, MALGORZATA" 9/1/20 0:00 6/30/25 0:00 Molecular Oncogenesis Study Section[MONC] 12527983 "KANG, XUNLEI " Not Applicable 3 INTERNAL MEDICINE/MEDICINE 153890272 SZPJL5ZRCLF4 153890272 SZPJL5ZRCLF4 US 38.948231 -92.327335 578002 UNIVERSITY OF MISSOURI-COLUMBIA COLUMBIA MO SCHOOLS OF MEDICINE 652110001 UNITED STATES N 7/1/23 0:00 6/30/24 0:00 396 Non-SBIR/STTR 2023 454038 NCI 289196 164842 PROJECT SUMMARY/ABSTRACTAcute myeloid leukemia (AML) accounts for more than 40% of leukemia mortality in the United States. Eachyear around ten thousand people die from the disease most within a few years of diagnosis. Despite advancesin our understanding of the disease few improvements in the therapy of AML have been made. Specifictargets and novel strategies to eliminate AML stem cells are required for AML treatment. In preliminary studiesthe PIs lab has observed the following: 1) The expression of DPP4 negatively correlates with AML patientoverall survival in 3 different databases. 2) DPP4 inhibitors can prevent AML development in vivo. 3) DPP4inhibitors can prevent both human and mouse AML cells growth in vitro. 4) DPP4 knock out (KO) AML cellstransplanted mice exhibit delay and reversal of AML development in two retroviral-induced AML mousemodels. 5) DPP4 KO AML stem cells and progenitors (AML-SCP) are restrained in the bone marrow withincreased apoptosis and reduced self-renewal ability. 6) DPP4 knockdown prevents the growth of human AMLcells. 7) The activation of Src IkB and p65 is reduced in DPP4 KO AML cells. Based on these preliminarydata the central hypothesis is: DPP4 regulated trafficking activation and apoptosis of AML-SCPs arecritical for human AML development which will be addressed in three specific aims. Aim 1: Determinethe role of DPP4 in human AML development. The localization apoptosis and self-renewal of DPP4deficient human AML-SCP will be investigated by colony forming unit assay and human AML cells xenograftedmouse model. Using the xenograft model the effect of DPP4 inhibitors treatment alone or in combination withstandard chemotherapy to prevent AML development will be evaluated. Aim 2: Examine regulation of AML-SCP engraftment to the BM by DPP4. This will include identification of the critical cytokines regulated byDPP4 for AML-SCP trafficking. To test this the PI will use migration and engraftment assays. In addition thePI will investigate localization and niche cells interaction of DPP4 KO AML-SCPs in the BM microenvironmentby imaging studies. Aim3: Investigate the role of DPP4 in AML-SCP survival. We will explore the criticaldomain of DPP4 if DPP4-Src interaction is essential for AML-SCP survival how DPP4 regulates the activityand protein level of Src in AML-SCP and determine if dual therapy with DPP4 and Src inhibitors has greaterbenefits against human AML-SCP survival. Collectively the proposed research will broadly impact the field byidentification of a novel treatment for AML via the strategy of confinement of AML-SCP to bone marrow andimproving the understanding of the role of microenvironment in the development of AML-SCPs. 454038 +No NIH Category available Academic Training;Advisory Committees;Antibodies;Antibody Binding Sites;Antibody Therapy;Antibody-drug conjugates;Antineoplastic Agents;Architecture;Automobile Driving;Cancer Detection;Career Mobility;Cell Communication;Cells;Cetuximab;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;Computing Methodologies;Cytotoxic T-Lymphocytes;Data;Dendritic Cells;Development;Diagnosis;Disease;Dose;Drug Delivery Systems;Drug Interactions;Drug resistance;Encapsulated;Environment;Epidermal Growth Factor Receptor;Extracellular Matrix;Extracellular Matrix Proteins;Fibroblasts;Fluorescence;Goals;Human;Image;Immune;Immune checkpoint inhibitor;Immunologics;Immunosuppression;Intravenous;Machine Learning;Malignant Neoplasms;Malignant neoplasm of pancreas;Maps;Measures;Mediating;Mentors;Mentorship;Methods;Molecular;Monoclonal Antibodies;Mus;Operative Surgical Procedures;Pancreatic Ductal Adenocarcinoma;Pathway interactions;Patient-Focused Outcomes;Patients;Penetration;Pharmaceutical Preparations;Phase;Phenotype;Physicians;Play;Postdoctoral Fellow;Predisposition;Primary Neoplasm;Program Development;Research;Research Personnel;Research Project Grants;Resistance;Resolution;Role;Scientist;Shapes;Solid Neoplasm;Structure;T-Lymphocyte;Techniques;Technology;Testing;Therapeutic antibodies;Thick;Tissues;Training;Transgenic Mice;Tumor-associated macrophages;anti-PD-L1 antibodies;cancer cell;cancer surgery;cancer therapy;cancer type;career;career development;cell type;cellular imaging;chemotherapy;clinical efficacy;clinical imaging;computerized tools;deep learning;drug action;fibrogenesis;first-in-human;graduate student;imaging modality;imaging platform;immune cell infiltrate;immunoregulation;improved;insight;invention;mouse model;multiple omics;multiplexed imaging;novel;novel anticancer drug;novel therapeutic intervention;overexpression;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;panitumumab;patient derived xenograft model;periostin;preclinical efficacy;programs;resistance mechanism;response;spatial integration;transcriptomics;tumor;tumor microenvironment;tumor-immune system interactions;uptake Integrating Spatial Omics and Drug Imaging to Dissect the Role of Pancreatic Tumor Microenvironment in Drug Resistance PROJECT NARRATIVEMany anti-cancer drugs are ineffective in solid tumors but the underlying mechanism is not fully understood.This proposal aims to identify the factors in the tumor microenvironment that drive drug resistance in pancreaticcancer by integrating single-cell drug imaging and spatial multi-omics. This project will result in computationaltools to chart the spatial landscape of the cell-cell and drug-cell interactions within the tumor microenvironmentrevolutionize our understanding of the drug resistance mechanisms in pancreatic cancer and facilitate thedevelopment of new treatment strategies to improve patient outcomes with this devastating disease. NCI 10674023 8/1/23 0:00 PA-20-188 5K99CA267171-02 5 K99 CA 267171 2 "JAKOWLEW, SONIA B" 8/1/22 0:00 7/31/24 0:00 Transition to Independence Study Section (I)[NCI-I] 15124098 "LU, GUOLAN " Not Applicable 16 OTOLARYNGOLOGY 9214214 HJD6G4D6TJY5 9214214 HJD6G4D6TJY5 US 37.426852 -122.17047 8046501 STANFORD UNIVERSITY STANFORD CA SCHOOLS OF MEDICINE 943052004 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 Other Research-Related 2023 147262 NCI 136354 10908 PROJECT SUMMARY This proposal describes a career development program to prepare Dr. Lu for an independent research careerthat focuses on developing computational and experimental methods to improve cancer detection diagnosisand treatment. This program will provide Dr. Lu with new expertise in single-cell spatial omics integrating withher background in machine learning-based image computation (gained as a graduate student) and clinical single-cell drug imaging (gained as a postdoctoral researcher) to advance our understanding of the mechanism thatdrives drug resistance of pancreatic cancer. Dr. Lu will be mentored by Dr. Garry Nolan who invented theCODEX technology for highly multiplexed single-cell imaging and co-mentored by Dr. Eben Rosenthal aphysician-scientist who pioneered the first-in-human clinical studies for fluorescence-guided cancer surgery andDr. Robert West who developed the Smart-3SEQ technology for spatial transcriptomics. The K99 phase of Dr.Lus training will consist of (i) structured mentorship by the primary mentor and co-mentors (ii) close interactionswith advisory committee and collaborators (iii) technical and academic training (iv) a provocative researchproject and (v) a program of career transition. Elucidating the role of the tumor microenvironment (TME) in drug resistance is critical to developing effectivecancer therapies but quantifying the drug delivery and action together with host environment factors withinclinical tumors remains technically challenging. Antibody-based therapeutics such as antibody-drug conjugates(ADCs) and immune checkpoint inhibitors (ICIs) are especially susceptible to blockade by TME barriers. Theoverall objective of this project is to identify the TME factors driving drug resistance in pancreatic ductaladenocarcinoma (PDAC) by integrating single-cell geospatial mapping of therapeutic antibodies with the deepspatial profiling of the TME. The central hypothesis is that periostin and tumor-associated macrophages (TAMs)play a key role in inhibiting drug delivery and response in PDAC. The central hypothesis will be tested by pursuingthree aims: (Aim 1) establish a computational spatial omics platform by integrating CODEX and Smart-3SEQ tochart the baseline architecture of PDAC TME in an unbiased way; (Aim 2) combine single-cell drug imaging withspatial omics to determine the impact of stromal barriers to antibody delivery into PDAC and evaluate whetherinhibiting periostin improves the delivery of anti-EGFR antibodies and ADCs in patient-derived xenograft mousemodels; and (Aim 3) examine the role of chemotherapy in altering the phenotype and function of TAMs in humanand mouse PDAC; identify chemo-induced alterations in TAM-ICI interactions in PDAC patients infused with afluorescent anti-PD-L1 antibody; and validate whether inhibiting TAM-ICI interactions improves response to ICIplus chemotherapy in a transgenic mice model of PDAC. This project will provide novel computational tools toquantify cell-cell and cell-drug interactions in clinical tumors offer new mechanistic insights on drug resistancein pancreatic cancer and lead to new treatment strategies to improve patient survival. 147262 +No NIH Category available Achievement;Applications Grants;Area;Attitude;Award;Clinical;Development;Educational Curriculum;Environment;Extramural Activities;Faculty;Fostering;Funding;Future;Goals;Grant;Head and Neck Cancer;Head and neck structure;Institution;Knowledge;Leadership;Malignant Neoplasms;Marketing;Mentors;Methods;Minority Groups;Oncology;Physicians;Process;Progress Reports;Research;Research Personnel;Resources;Scientist;Secure;Solid;Structure;Time;Training;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;Wisconsin;anticancer research;bench to bedside;career;career development;experience;innovation;member;next generation;prevent;programs;recruit;skills;translational cancer research;translational research program;translational scientist Career Enhancement Program n/a NCI 10674010 8/9/23 0:00 PAR-20-305 5P50CA278595-07 5 P50 CA 278595 7 8/2/16 0:00 7/31/27 0:00 ZCA1-RPRB-7 8807 6405234 "CONNOR, NADINE P" Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 97618 62821 34809 PROJECT SUMMARYAn increase in the number of investigators who possess the research knowledge and training from the bench tothe bedside is essential to our overarching goal of advancing translational research in head and neck cancer(HNC). This Career Enhancement Program (CEP) provides an outstanding structure and mechanism to cultivatethe development of solid research careers for junior and mid-level faculty who strive to focus their careers ontranslational HNC research. The specific aim of the CEP is to provide scientists with essential training andcareer enhancement support to encourage the development of successful independently fundedtranslational research programs in the area of HNC. Our goal is to produce HNC scientists includingphysician-scientists who will meet the great need for innovation in methods to prevent and treat thesedevastating malignancies. The CEP will support up to three awardees at any given time with one award for theCEP or DRP reserved for a member of an underrepresented minority group. Awardees will receive $50000 peryear for up to two years to support their research career enhancement activities in the area of HNC. The programhas strong leadership a wealth of expertise and resources the option to embark on individualized clinical andscientific curricula a strong pool of exceptional mentors and well-defined processes for recruitment andassessment. The program will continue to foster the development of knowledge skills professional attitudesand experience required for successful academic careers in HNC translational research. The past/current CEPaward recipients have been highly successful in securing competitive extramural (NIH/DOD n=10 grants) andintramural (n=7) grants. +No NIH Category available 3-Dimensional;Affinity;Aneuploidy;Binding;Biological Assay;Breast;Breast Cancer Cell;Cancer Etiology;Cell division;Cells;Chromosomal Instability;Chromosome Segregation;Chromosomes;Color;Compensation;Congenital Abnormality;Crowding;Cues;Development;Drug resistance;Ensure;Event;Fiber;Grasshoppers;Heart;Image;Individual;Inherited;Kinetochores;Laboratories;MCF10A cells;MDA MB 231;Malignant Neoplasms;Mammalian Cell;Mammals;Measures;Microtubule Stabilization;Microtubules;Mitosis;Mitotic;Modeling;Molecular;Monitor;Needles;Normal Cell;Oncogenic;Patients;Phosphotransferases;Polymerase;Positioning Attribute;Proteins;Resolution;Role;Signal Transduction;Sister;Spermatocytes;Structure;Testing;Therapeutic;Time;Tumor stage;Up-Regulation;Work;cancer cell;cancer therapy;daughter cell;experimental study;improved;insight;live cell imaging;mutant;new therapeutic target;novel;novel therapeutics;overexpression;prevent;protein expression;real-time images;response;segregation;sensor;therapy development;tool;tumor Error Correction in Mammalian Mitosis: Defining Physical Cues and Integration Mechanisms Project NarrativeDuring cell division each daughter cell must inherit exactly one copy of each chromosome as errors can leadto cancer and birth defects. The kinetochore is the structure responsible for connecting chromosomes to thecell's chromosome segregation machine and here we probe how it ensures that it is correctly attached to thismachine and how it may fail to do so in cancer. This work will provide insight into the mechanisms promotingaccurate chromosome segregation and as such may help better target dividing cells for cancer therapy. NCI 10674003 8/25/23 0:00 PA-21-051 5F31CA265136-03 5 F31 CA 265136 3 "ODEH, HANA M" 9/1/21 0:00 8/31/24 0:00 Special Emphasis Panel[ZRG1-F05-U(20)L] 12227222 "CHONG, MEGAN KAIULANI" Not Applicable 11 PHARMACOLOGY 94878337 KMH5K9V7S518 94878337 KMH5K9V7S518 US 37.767442 -122.413937 577508 "UNIVERSITY OF CALIFORNIA, SAN FRANCISCO" SAN FRANCISCO CA SCHOOLS OF PHARMACY 941432510 UNITED STATES N 9/1/23 0:00 8/31/24 0:00 398 "Training, Individual" 2023 43079 NCI 43079 0 Project Summary/AbstractErrors in chromosome segregation give rise to aneuploidy a hallmark of cancer. Breakdown of mitotic fidelitycorrelates with both tumor stage and patient drug resistance. Identifying mechanisms that prevent errors inchromosome segregation and determining how they go wrong in cancer are essential to developing therapiesto either decrease or increase segregation error rates in cancer. The kinetochore attaches chromosomes to spindle microtubules. It segregates chromosomes andmonitors their microtubule attachments stabilizing correct attachments and destabilizing incorrect ones. Wenow know nearly all mammalian kinetochore proteins and many have dysregulated expression in cancer. Howdoes the kinetochore detect and correct attachment errors and fail to do so in cancer? The idea that tensionfrom bi-orientation signals correct attachments is decades-old originating in Nicklas' pioneering experiments ingrasshopper spermatocytes. Yet how the kinetochore monitors tension and robustly integrates informationacross its many bound microtubules to regulate attachment stability is not known. In large part this is due tochallenges in applying tension on kinetochores inside cells in quantitatively tuning kinetochore compositionand in imaging short-lived error correction events in real-time. Our laboratory has recently overcome thesechallenges uniquely positioning us to answer these questions. Notably two candidate kinetochore proteinshave been proposed for sensing tension the kinase AurKB and microtubule polymerase chTOG and theexpression of both is dysregulated in cancer as is that of the main microtubule binder Hec1. Here we test defining hypotheses on how normal and cancer cells detect and correct mitotic errorscombining high resolution 3D live-cell imaging state-of-the-art physical perturbations and molecular tools innormal and breast cancer cells. In Aim 1 we test the hypothesis that AurKB and chTOG sense tension. Weuse microneedles to directly apply force to kinetochore-microtubules measure how attachment stabilityresponds and assess how these proteins' dysregulated expression alters this response in cancer. In Aim 2 wetest models for whether microtubules respond independently or cooperatively to attachment cues such astension and test the hypothesis that Hec1 overexpression in cancer cells leads to hyper-stable attachmentsthat may be more challenging to properly correct. We do so by quantitatively tuning kinetochore microtubulebinding capacity using mixed Hec1 mutants and measuring microtubule attachment lifetime using photomarks. In defining critical mechanisms for correcting mitotic errors and how they are modified in cancer weexpect to identify adapted mechanisms of error correction in cancer cells. For example some cancer cells maybe deficient in error correction leading to aneuploidy or have improved error correction to compensate forextra chromosomes. Mechanisms uniquely or preferentially employed in cancer would offer a new therapeuticwindow. 43079 +No NIH Category available Address;Inequity;Malignant Neoplasms;Rural Addressing Rural cancer Inequities through Scientific Excellence (ARISE) PROJECT NARRATIVEAmong current T32 training programs for cancer prevention control and survivorship few focus on healthequity among rural populations and none focus on cancer in the rural Appalachian population. AddressingRural cancer Inequities through Scientific Excellence (ARISE) is a postdoctoral training program at theUniversity of Kentucky that will be a collaboration among the Center for Health Equity Transformation (CHET)the NCI-designated Markey Cancer Center (MCC) Center for Clinical and Translational Science (CCTS) UKCenter for Appalachian Research in Environmental Sciences (UK-CARES) six colleges and 10 departments toprovide interdisciplinary training in behavioral cancer research focused on rural disparities. The trainingprogram will have three tracks environment risk behavior and health care delivery and will provide didacticresearch experience and mentoring. NCI 10673994 9/7/23 0:00 PA-20-142 5T32CA261786-03 5 T32 CA 261786 3 "DAMICO, MARK W" 8/1/21 0:00 7/31/26 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1871398 "DIGNAN, MARK B" "SCHOENBERG, NANCY E." 6 INTERNAL MEDICINE/MEDICINE 939017877 H1HYA8Z1NTM5 939017877 H1HYA8Z1NTM5 US 38.040959 -84.505885 2793601 UNIVERSITY OF KENTUCKY LEXINGTON KY SCHOOLS OF MEDICINE 405260001 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 252506 NCI 308764 22461 ABSTRACTThe Addressing Rural cancer Inequities through Scientific Excellence (ARISE) program aims to providetransdisciplinary and translational postdoctoral research training in rural cancer prevention control andsurvivorship. To achieve health equity and reduce the highest cancer morbidity and mortality rates in thenation University of Kentuckys (UK) behavioral cancer training efforts must develop a new generation ofcollaborative and rigorous scientists. Led by two well-established cancer and health equity researchers withextensive track records of training ARISE will meet this critical need by providing multifaceted trainingopportunities to well-qualified postdoctoral scholars in applied behavioral science including intervention anddissemination and implementation science. Training will emphasize translating knowledge of risk factors intoevidence-based behavioral interventions across the cancer spectrum (prevention to survivorship) forvulnerable rural residents. ARISE postdoctoral trainees will select one of three thematic behavioral cancertracks: environment risk behavior and health care delivery. We will recruit two trainees each year for a two-year fellowship. The training program based in the Center for Health Equity Transformation will operate inclose collaboration with UKs National Cancer Institute-designated Markey Cancer Center; Center for Clinicaland Translational Science; Center for Appalachian Research in Environmental Sciences; Office of PostdoctoralAffairs; Office of the Vice President for Research and departments across UKs 16 colleges. The 25preceptors co-mentors and methodology mentors include well-funded investigators in transdisciplinaryresearch with established collaborative relationships representing diverse yet complementary areas ofexpertise including behavioral science; environmental carcinogenesis; clinical and translational research; andintervention and implementation science. Additional mentoring includes geospatial analysis mHealth andcluster randomized designs. Each trainee will have a mentoring committee with one primary mentor in her/hisspecified track and two secondary mentors with one from another track and a methodology mentor. Traineeswill participate in a rigorous structured program that includes formal coursework training in the responsibleconduct of research and workshops and seminars. Trainees will gain career development experiences andbuild a professorial network through scientific writing; presentations; grant preparation and review; andleadership opportunities. Special programming designed to improve expertise in rural cancer disparitiesincludes research shadowing experience a personalized rural cancer patient experience and attendance atrural health disparities conferences. We will track trainee progress and mentor support through detailedannual evaluation. ARISE will build a next generation of cancer behavioral researchers aiming to achieve ruralhealth equity. 252506 +No NIH Category available Oncology;Physicians;Research Training;Scientist;gastrointestinal Research Training for Physician-Scientists in Gastrointestinal Oncology NarrativeA renewal of this T32 program designed to continue training aspiring physician-scientists in GI cancer research.Trainees are drawn from Medical Oncology Radiation Oncology Surgery and Gastroenterology and will enroll ineither a Basic/Translational Science track or a Population Science track led by mentors accomplished in bothscientific research and training. Our goal is to graduate physician-scientists armed with the capacity and credentialsto lead their own innovative research programs and develop into leaders in investigative GI oncology. NCI 10673988 8/7/23 0:00 PA-18-403 5T32CA193111-09 5 T32 CA 193111 9 "LIM, SUSAN E" 7/1/15 0:00 7/31/25 0:00 Institutional Training and Education Study Section (F)[NCI-F] 1894156 "BAR-SAGI, DAFNA " "SIMEONE, DIANE M" 12 SURGERY 121911077 M5SZJ6VHUHN8 121911077 M5SZJ6VHUHN8 US 40.669895 -73.974354 5998304 NEW YORK UNIVERSITY SCHOOL OF MEDICINE NEW YORK NY SCHOOLS OF MEDICINE 10016 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 398 "Training, Institutional" 2023 245581 NCI 319852 23924 SummaryThis is the first application for renewal of T32 CA193111 to continue funding the training of next generation ofphysician-scientists in gastrointestinal oncology. We believe that physician-scientists armed with rigorousresearch training are necessary to discover and translate new advances in GI oncology as well as to investigatecritical issues facing delivery of cancer care to patients. Our trainees are drawn from NYUs renowned clinicalfellowship programs in Medical Oncology or Gastroenterology or top-notch residency programs in RadiationOncology or Surgery. Trainees take a 2-3 year hiatus from clinical activities to engage in intensive full-timetraining in GI cancer research. Our program is composed of (i) a Basic/Translational Science track aimed atindividuals who wish to direct their own basic science laboratory in GI oncology or individuals who want to leadtranslational research programs that comfortably interface between the pre-clinical laboratory and clinicalinvestigation and (ii) a Population Sciences tract for trainees who seek careers in the diverse fields of populationsciences including cancer epidemiology comparative effectiveness disparities health services or outcomesresearch. The program for our Basic/Translational Science track consists of two years of individualized mentoredresearch in faculty laboratories enhanced by a strong parallel didactic program in cancer biology. The PopulationSciences track is centered on a rigorous Masters-level curriculum that teaches clinical trial design epidemiologycomparative-effectiveness and outcomes research methodologies along with a mentored research projectbased in population sciences. The two tracks are united through a weekly 2-hour core curriculum coveringessential topics in GI cancer and critical lessons for cancer physicians embarking on independent investigativecareers. We plan to continue to have a steady-state of 4 trainees at any given time. Our first group of graduateshave been very successful in acquiring the research skills and credentials to eventually lead their own researchgroups. We are proud that our first graduates have obtained academic positions in oncology and submitted highlyscored K grants. Our trainees are nurtured by a cadre of mentors with substantial accomplishments in cancerresearch and stellar training records. The aim of our training program is to continue to graduate physician-scientists armed with the intellectual capacity and tools to lead their own research programs and become leadersand role models in investigative GI oncology. 245581 +No NIH Category available Address;Architecture;Biological Markers;Biomedical Engineering;Blood;Cancer Model;Carcinoma;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Cetuximab;Chemotherapy and/or radiation;Clinical;Clinical Research;Complex;Data;Data Set;Detection;Disease;Dose;Eastern Cooperative Oncology Group;Environment;Epidermal Growth Factor Receptor;Fibroblasts;Future;Gene Expression;Gene Expression Profile;Genomics;Goals;HPV oropharyngeal cancer;Head and Neck Cancer;Human Papillomavirus;Immune;Individual;Infrastructure;Larynx;Lymphatic;Measures;Modeling;Molecular;Neoplasm Circulating Cells;Nivolumab;Operative Surgical Procedures;Oral cavity;Organoids;PIK3CG gene;Patient Care;Patient-Focused Outcomes;Patients;Phenotype;Pilot Projects;Population;Postoperative Period;Prediction of Response to Therapy;Primary Neoplasm;Progression-Free Survivals;Proteins;Proteomics;Quality of life;Radiation;Radiation Tolerance;Radiation therapy;Regimen;Reporting;Research;Risk;Sampling;Stains;Stratification;Stromal Cells;Survival Rate;T-cell inflamed;Testing;Therapeutic;Time;Tissue Microarray;Tissue Sample;Tissue-Specific Gene Expression;Tissues;Treatment Efficacy;Treatment outcome;Tumor Tissue;Universities;Wisconsin;Work;advanced disease;angiogenesis;anti-PD-1;biomarker identification;cancer biomarkers;chemoradiation;clinical decision-making;cohort;data modeling;effective therapy;efficacy testing;experience;experimental study;feasibility testing;head and neck cancer patient;improved;in vivo;individual patient;molecular marker;multiple omics;novel;novel marker;oral HPV-positive head and neck cancers;patient stratification;phase 2 study;predictive marker;predictive modeling;predictive tools;primary endpoint;protein expression;reconstitution;response;response biomarker;secondary endpoint;single-cell RNA sequencing;standard of care;success;systemic toxicity;targeted treatment;timeline;tool;transcriptomics;treatment group;treatment response;treatment strategy;treatment stratification;tumor;tumor growth;tumor microenvironment Project 2: Predicting Treatment Responses Using Single Cell RNA Sequencing and Bioengineered Patient-derived Organotypic Models of HNC PROJECT NARRATIVE PROJECT 2Successful completion of this research would provide a new tool to stratify HNC patients who are more likely torespond to specific treatments. Single cell CITE-seq of HNC tumors combined with patient-specificbioengineered models could identify biomarkers and provide a platform to test many treatments and therebypredict the most effective treatment strategies for individual patients. Our clinical pilot study which will investigatethe feasibility of using bioengineered models to direct patient treatment contributes to our goal of improvingclinical decision making and helping provide the most effective treatment for each HNC patient which would havea major impact on patient treatment outcomes and quality of life. NCI 10673977 8/9/23 0:00 PAR-20-305 5P50CA278595-07 5 P50 CA 278595 7 8/2/16 0:00 7/31/27 0:00 ZCA1-RPRB-7 6225 1923039 "BEEBE, DAVID J" Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 368063 236740 131336 PROJECT SUMMARY - PROJECT 2Our current inability to accurately predict treatment outcomes for head and neck cancer (HNC) patientsrepresents a major challenge for clinicians and undoubtedly contributes to both the poor overall and progressionfree survival rates in advanced disease. Currently no predictive biomarkers are used clinically for definitivetherapies thus there is a compelling need to develop new biomarkers and tools to improve clinical decisionmaking. Functional biomarkers that can provide multiple orthogonal endpoints are well suited to reporting on acomplex and dynamic environment such as the tumor microenvironment (TME). For this reason we intend toinvestigate HNC biomarkers both directly in tumor samples and in a bioengineered patient-specific model tocreate a novel suite of endpoints. We will use state of the art single cell RNA sequencing (scCITE-seq) proteinexpression signatures from tumor tissue microarrays (TMAs) and analysis of circulating tumor cells (CTCs). Wewill utilize this multi-omic patient-specific data set to identify and validate signatures of treatment efficacy andstratify patient outcomes. We will then test the feasibility of using patient specific bioengineered models to informpatient care in a clinical pilot study. The bioengineered model of the HNC TME is made entirely of cells derivedfrom the same patient tumor sample from the same patient cohort used for CITEseq TMA and CTC analysis.These microscale patient-specific (built from the individual patients own cells) bioengineered models recapitulatethe TME architecture containing a HNC epithelial spheroid surrounded by a matrix containing fibroblasts andimmune cells and flanked by blood and lymphatic microvessels. Our specific aims are: 1) Evaluate the ability ofHNC patient-specific bioengineered models to predict treatment efficacy where we will build patient-specificbioengineered models for 22 HNC patients (representing HPV-positive and HPV-negative disease and patientstreated with primary surgery with (chemo)radiation or primary chemoradiation) and treat them with the sametreatment the patient receives. Metrics of treatment success in the models will be correlated with actual patientoutcomes including progression free survival. 2) Identify HNC biomarkers using scCITE-seq and TMA wherewe will perform scCITE-seq and will correlate gene expression and cell populations with patient outcomes toinvestigate existing putative biomarkers and identify additional novel biomarkers. Biomarkers will be furtherinvestigated in a TMA and in CTCs. 3) Use of bioengineered models to inform dose de-escalation in a clinicalpilot study where tissue will be acquired from surgery from 24 HPV+ HNC patients and used for patient-specificbioengineered model creation. Models will be treated to determine the radiosensitivity of a patients tumor andto stratify intermediate risk patients between 50 or 60 Gy treatment groups. Primary endpoints will focus onfeasibility of model integration with secondary endpoints including local control. The successful completion ofthese aims will provide powerful new tools for the stratification of HNC patients and improved clinical decisionmaking to help inform the most effective treatment selections for individual HNC patients in the future. +No NIH Category available Administrative Coordination;Administrator;Budgets;Cancer Center;Clinical Research;Collaborations;Communication;Communities;Complex;Ensure;Evaluation;Goals;Grant;Head and Neck Cancer;Head and neck structure;Human;Infrastructure;Leadership;Minority;Mission;Monitor;Performance;Principal Investigator;Program Development;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Services;Structure;Supervision;Translation Process;Translational Research;Translations;Universities;Wisconsin;data communication;data exchange;data quality;data sharing networks;experience;meetings;programs;translational progress Administrative Core n/a NCI 10673966 8/9/23 0:00 PAR-20-305 5P50CA278595-07 5 P50 CA 278595 7 8/2/16 0:00 7/31/27 0:00 ZCA1-RPRB-7 8796 1901895 "HARARI, PAUL M" Not Applicable 2 Unavailable 161202122 LCLSJAGTNZQ7 161202122 LCLSJAGTNZQ7 US 43.068519 -89.400858 578503 UNIVERSITY OF WISCONSIN-MADISON MADISON WI Domestic Higher Education 537151218 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 197243 126888 70368 PROJECT SUMMARY ADMIN COREThe Administrative Core will provide the operational structure necessary for the planning implementation andmanagement of all SPORE activities by providing the leadership and organizational supervision required forthe efficient progressive and successful conduct consistent with the program goals and SPORE mission.The Administrative Core will centrally provide a wide variety of administrative coordination oversight andresearch support services to all leaders co-leaders investigators and core directors and offer these services ina centralized manner to promote efficiency and ensure that all SPORE research and activities are focusedconnected complex scientific objectives are met and existing cancer center resources are utilized and notduplicated.The Administrative Core will also provide the oversight monitoring and auditing required to ensure projects aremeeting translational endpoints and reach a human application within five years consistent with the SPOREmission.Specific Aims: 1. Research - Scientific Management: Provide the operational structure necessary for managing and supporting the scientific research activities of SPORE projects cores and development programs.2. Monitoring and Oversight: Provide strategic oversight monitoring and evaluation of projects cores and development programs to ensure scientific connection collaboration and translational progression.3. Clinical Research Application: Provide the oversight regulatory support coordination and management for the translation of SPORE research and oversee efforts to assure minority accrual.4. Regulatory Compliance: Ensure compliance with all administrative and programmatic mandates of the grant and assure data quality and compliance with regulatory requirements for clinical research.5. Collaborations and Sharing: Facilitate translational research collaboration and oversee research resource sharing.6. Fiscal Management: Management of SPORE budget subcontracts record keeping and all other fiscalactivities of the grant +No NIH Category available Advisory Committees;Appointment;Award;Biology;Cancer Center;Collaborations;Dana-Farber Cancer Institute;Department chair;Diagnosis;Discipline;Doctor of Philosophy;Electronic Mail;Environment;Epidemiologist;Exposure to;Faculty;Fellowship Program;Female;Funding;Goals;Individual;Institution;Instruction;Leadership;Letters;Lung;Malignant neoplasm of lung;Medical Oncologist;Mentors;Minority;Minority Recruitment;Monitor;Nature;Postdoctoral Fellow;Prevention;Program Description;Radiation Oncologist;Request for Applications;Research;Research Personnel;Research Support;Surgeon;Training;Translational Research;career;diversity and inclusion;faculty mentor;member;multidisciplinary;next generation;programs;radiologist;success;translational cancer research;translational progress;translational research program;translational scientist;tumor Career Enhancement Program n/a NCI 10673960 7/20/23 0:00 PAR-20-305 5P50CA265826-02 5 P50 CA 265826 2 8/1/22 0:00 7/31/27 0:00 ZCA1-RPRB-N 8794 8944904 "COSTA, DANIEL BOTELHO" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 126804 79605 47199 PROJECT SUMMARYThe Career Enhancement Program (CEP) will support early career lung cancer researchers who have researchconcepts focused on the biology prevention diagnosis and treatment of lung cancer. The purpose of the CEPis to help develop the careers of young investigators committed to lung cancer and our goal is that these fundswill support the awardees efforts to become independent researchers. Career enhancement of young facultymembers is vital to the success and continued progress of translational research programs and our SPOREteam and wider Lung Cancer Program have a broad roster of available willing and accomplished mentors tomeet the challenges of training translational researchers.The CEP is focused on young investigators at a junior faculty level typically within 3 years of faculty appointment.Individuals in a post-doctoral fellowship program may apply if their Department Chair will guarantee a facultyappointment should the applicant receive a CEP award. Applicants need to have a nominating letter from afaculty mentor which must detail the mentoring plan and a mentoring committee with lung cancer expertiserepresented. Because of the need to identify and develop lung cancer researchers from underrepresentedbackgrounds we have prioritized recruitment of minorities to our CEP awards and have a plan to do this asdetailed in the description of the program. The annual Request for Applications will be announced by e-mailposted throughout the DF/HCC institutions via message boards and circulated widely through the help of ourfaculty our Governance Committee and our Diversity and Inclusion Advisory Committee. The announcementwill describe the purpose of the award provide instructions for applicants and detail the review criteria. Therequirements for mentors review criteria and steps to monitor progress are described in this section. +No NIH Category available Address;Advisory Committees;Award;Basic Science;Boston;Cancer Center;Collaborations;Credentialing;Dana-Farber Cancer Institute;Development;Doctor of Philosophy;Eligibility Determination;Ensure;Faculty;Funding;Funding Mechanisms;Future;Goals;Growth;Institution;Knowledge;Leadership;Lung;Malignant neoplasm of lung;Mentors;Minority Groups;Mission;Monitor;Peer Review;Phase;Process;Program Research Project Grants;Request for Applications;Research;Research Personnel;Research Project Grants;Research Proposals;Secure;Standardization;Talents;Underrepresented Minority;Woman;diversity and inclusion;high risk;innovation;interest;medical specialties;member;novel;posters;programs;research and development;response;success Developmental Research Program n/a NCI 10673956 7/20/23 0:00 PAR-20-305 5P50CA265826-02 5 P50 CA 265826 2 8/1/22 0:00 7/31/27 0:00 ZCA1-RPRB-N 8792 7791249 "HEIST, REBECCA SUK" Not Applicable 7 Unavailable 76580745 DPMGH9MG1X67 76580745 DPMGH9MG1X67 US 42.337593 -71.108279 1464901 DANA-FARBER CANCER INST BOSTON MA Independent Hospitals 22155450 UNITED STATES N 8/1/23 0:00 7/31/24 0:00 Research Centers 2023 126004 75970 50034 PROJECT SUMMARYThe DF/HCC Lung SPORE Developmental Research Program (DRP) is essential to the growth and futuresuccess of our SPORE program because it is a mechanism to advance high quality innovative lung cancerresearch proposals from the pilot stage to full-fledged expanded projects including future SPORE projects. Wewill leverage the DRP to create opportunities for research development of a diverse range of both junior facultyand senior investigators with an interest in lung cancer and to stimulate new research ideas and newcollaborations. Both basic science and translational projects will be considered and we have a robust plan toencourage and promote proposal submission by researchers from underrepresented minority groups diversespecialties and from women.The DRP will initiate a broad call for proposals that will be circulated widely through the help of our faculty ourGovernance Committee and our Diversity and Inclusion Advisory Committee to ensure the most promising early-phase research projects receive meritorious funding. Investigators at all DF/HCC member institutions will beeligible to submit applications in addition to some partner institutions throughout Boston. Applications willundergo a formal standardized review process with a large scientifically-diverse committee of reviewers toassess scientific merit potential impact the applicants credentials and likelihood of success and progressionto independent funding. Awards are intended to be two years in duration but each project will be reviewed atthe one-year mark to ensure that reasonable progress is being made prior to the second year of funding.Recipients of DRP funding will participate consistently in the SPORE program with posters and/or presentationsat the Annual Lung Cancer Retreat and regular mentoring by the DRP leadership. We have secured significantinstitutional funding to supplement Federal funds allowing multiple DRP awardees per year and allowing eachawardee to be supported for up to two years. The DF/HCC has a large and talented investigator group to providea wealth of applications from which to choose and we anticipate a robust response to each request forapplications that is announced. \ No newline at end of file